PMID- 22484346 TI - A novel double cryoballoon strategy in persistent atrial fibrillation: a pilot study. AB - AIMS: Cryoballoon technology is a promising technique in paroxysmal atrial fibrillation (AF) ablation. However, success rates in patients with persistent AF have not been convincing. There is a trend toward performing more extensive procedures that are referred to as 'pulmonary vein isolation plus.' To combine pulmonary vein isolation (PVI) and antral substrate modification, we used both the 23-mm and 28-mm cryoballoon in a single approach in patients with persistent AF. METHODS AND RESULTS: 33 consecutive patients (26 men, age 60 +/- 10 years, LA size 44 +/- 5 mm) with persistent AF were prospectively included. All patients underwent the "double balloon strategy:" at least two applications at each pulmonary vein (PV) using the smaller 23-mm balloon to isolate the PV at the ostial level plus at least one additional freeze by the 28-mm balloon at the wide PV antral level. 7-day Holter monitors were performed during follow-up at 1, 3, 6, 9, 12, 18 and 24 months post-ablation. 131 of 133 PVs were targeted and isolated (98.4 %). A mean of 14 +/- 2 cryoballoon applications per patient or 3.5 +/- 1.5 applications per vein were performed. After a single procedure and mean follow-up of 15 +/- 3 months, 69.7 % of patients remained in sinus rhythm (3 month blanking period). There were no major complications. CONCLUSIONS: In persistent AF, the "double balloon strategy;" combining the small and large cryoballoon allowed ostial PV isolation followed by antral cryoablation is feasible, safe and associated with a favorable outcome. PMID- 22484347 TI - Looking for a sequence based allostery definition: a statistical journey at different resolution scales. AB - The aim of this work was to detect allosteric hotspots signatures characterizing protein regions acting as the 'key drivers' of global allosteric conformational change. We computationally estimated the relative strength of intra-molecular interaction in allosteric proteins between two putative allostery-susceptible sites using a co-evolution model based upon the optimization of the cross correlation in terms of free-energy-transfer hydrophobicity scale (Tanford scale) distribution along the chain. Cross-Recurrence Quantification Analysis (Cross RQA) applied on the sequences of allostery susceptible sites showed evidence of strong interaction amongst allosteric susceptible sites. This could be due to transient weak molecular bonds between allostery susceptible patches enabling regions far-apart to come together. Further, using a large protein dataset, by comparing allosteric protein set with a randomly generated sequence population as well as a generic protein set, we reconfirmed our earlier findings that hydrophobicity patterning (as formalized by Recurrence Quantification Analysis (RQA) descriptors) may serve as determinant of allostery and its relevance in the transmission of allosteric conformational change. We applied RQA to free-energy transfer hydrophobicity-transformed amino acid sequences of the allostery dataset to extract allostery specific global sequence features. These free-energy transfer hydrophobicity-based RQA markers proved to be representative of allosteric signatures and not related to the differences between randomly generated and real proteins. These free-energy-transfer hydrophobicity-based RQA markers when evaluated by pattern recognition tools could distinguish allosteric proteins with 92% accuracy. PMID- 22484348 TI - BALB/c mice, but not C57BL/6 mice immunized with a DeltaclpB mutant of Francisella tularensis subspecies tularensis are protected against respiratory challenge with wild-type bacteria: association of protection with post vaccination and post-challenge immune responses. AB - Francisella tularensis subspecies tularensis is highly virulent for humans especially when it is inhaled. Therefore, it has the potential to be used as a biothreat agent. Vaccines against F. tularensis will need to be approved in accordance with the FDA Animal Rule. This will require identification of robust correlates of protection in experimental animals and the demonstration that similar immune responses are generated in vaccinated humans. Towards this goal, we have developed an experimental live vaccine strain by deleting the gene, clpB, encoding a heat shock protein from virulent subsp. tularensis strain, SCHU S4. SCHU S4DeltaclpB administered intradermally protects BALB/c, but not C57BL/6 mice from subsequent respiratory challenge with wildtype SCHU S4. A comparison of post vaccination and post-challenge immune responses in these two mouse strains shows an association between several antibody and cytokine responses and protection. In particular, elevated IFNgamma levels in the skin 2 days after vaccination, sero conversion to hypothetical membrane protein FTT_1778c, and to 30S ribosomal protein S1 (FTT_0183c) of F. tularensis after 30 days of vaccination, and elevated levels of pulmonary IL-17 on day 7 after respiratory challenge with SCHU S4 were all associated with protection. PMID- 22484349 TI - Comparison of serologic responses to vaccination with one dose or two doses of 7 valent pneumococcal conjugate vaccine in HIV-infected adult patients. AB - BACKGROUND: Vaccination with 7-valent pneumococcal conjugate vaccine (PCV) has been shown to decrease the incidence of recurrent invasive pneumococcal disease among HIV-infected adults in Africa. Longitudinal follow-up studies of serologic responses to different doses of 7-valent PCV are rarely performed in HIV-infected adult patients receiving combination antiretroviral therapy (cART). METHODS: From October 2008 to June 2010, 115 CD4-matched pairs of HIV-infected patients aged >= 20 years who had no prior pneumococcal vaccination received one or two doses of 7 valent PCV. Anticapsular antibodies against 4 serotypes (6B, 14, 19F, and 23F) were examined at the 12th, 24th, 36th, and 48th week following vaccination. Significant antibody responses were defined as >= 2-fold increase in the IgG level plus a post-vaccination antibody level >= 1000 ng/ml. RESULTS: The most common reported adverse effects were injection site soreness (19.3%) and pain (4.8%). Significant antibody response rate was highest for serotype 14, followed by 23F, 19F, and 6B in all of the four time points examined. At week 48, patients who received two doses of 7-valent PCV had a significantly higher response rate to serotype 6B (P=0.03) and 23F (P=0.01) than those who received one dose; moreover, the former group also had a higher response rate to at least one (P=0.03) and two serotypes (P=0.02) in intention-to-treat analysis than the latter group. CONCLUSIONS: HIV-infected adult patients on cART who received two doses of 7-valent PCV achieved better serological responses to at least one serotype than those who received one dose during the 48 weeks of follow-up. PMID- 22484350 TI - Association between obesity and vulnerability and serologic response to influenza vaccination in older adults. AB - BACKGROUND: Serologic response to influenza vaccination declines with age. Few other host factors are known to be associated with serologic response. Our objective was to determine whether obesity and vulnerability independently predicted serologic response to influenza vaccination. METHODS: Adults >= 50 years were recruited during the 2008-2009 influenza season. Subjects provided pre and post-vaccination sera for measuring antibody titers to 2008-2009 vaccine components. Body mass index (BMI) was calculated as weight (kg)/height (m(2)). Data were collected on vulnerability using the vulnerable elders survey (VES13). Logistic regression evaluated the associations between obesity and vulnerability and the serologic response to vaccination (both seroprotection and seroconversion), adjusting for gender, age, comorbidities, pre-vaccination titer, and site. RESULTS: Mean (+/- standard deviation) age of 415 study subjects was 65 +/- 10 years; 40% were obese. Mean BMI was 29 +/- 5.6 kg/m(2); mean VES13 was 1.6 +/- 1.8. The proportions of subjects who seroconverted and had seroprotective titers were 40% and 49%, respectively, for A/Brisbane/59 (H1N1); 73% and 80% for A/Brisbane/10 (H3N2); and 34% and 94% for B/Florida. Modified VES-13 (score 0-10, with 10 being most vulnerable) was not associated with seroprotection against H1N1 or H3N2, and VES-13 was directly associated with seroconversion to H1N1 but not H3N2 or B. Obesity (BMI >= 30 kg/m(2) vs. BMI 18.5-30 kg/m(2)) was not associated with seroprotection for H1N1 or H3N2; obesity was directly associated with seroconversion to H3N2 but not H1N1 or B. Age was inversely associated with seroprotection and seroconversion against H1N1 and with seroconversion to influenza B. CONCLUSION: Based on this sample of older healthy subjects, there were no consistent relationships between VES 13 or obesity and either seroprotection or seroconversion to three influenza vaccine antigens. PMID- 22484351 TI - Improvac does not modify the expression and activities of the major drug metabolizing enzymes cytochrome P450 3A and 2C in pigs. AB - In the present study, we investigated hepatic mRNA expression and activities of CYP3A and 2C in entire, surgically castrated and pigs vaccinated with Improvac. Additionally, we examined the mRNA expression of the two nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR), known to regulate CYP3A and 2C mRNA expression, respectively. Activities of CYP3A and 2C were estimated as a rate of 7-benzyloxy-4-trifluoromethylcoumarin and 7 benzyloxyquinoline metabolism (CYP3A) and tolbutamide metabolism (CYP2C). We found no effect of Improvac treatment or surgical castration on either CYP3A or 2C activities. Similarly, the mRNA expressions of CYP3A29, 2C33 and PXR were not changed. CAR mRNA expression differed only between entire and surgically castrated male pigs (p=0.005), being greater in surgically castrated pigs. Our results indicated that neither CYP3A nor 2C are affected by Improvac. PMID- 22484352 TI - Quality of life in youth with type 1 diabetes. PMID- 22484353 TI - Follow-up care after an emergency department visit for asthma and subsequent healthcare utilization in a universal-access healthcare system. AB - OBJECTIVES: To describe the follow-up care within 28 days of an emergency department (ED) visit for asthma and to determine the association of follow-up visits within 28 days with ED re-visits and hospital admissions in the subsequent year. STUDY DESIGN: Population-based retrospective cohort study of children with asthma aged 2-17 years treated in an ED in Ontario, Canada between April 14, 2006 and February 28, 2009. Multiple linked health administrative datasets and Cox proportional hazard multivariable survival models were used to test the association of characteristics of 28-day follow-up visits with 1-year outcomes. RESULTS: The final cohort consisted of 29391 children, of whom 32.8% had follow up, 6496 (22.1%) had an ED re-visit, and 801 (2.7%) had a hospital admission. Having a follow-up visit was not associated with ED re-visit or hospitalizations (hazard ratio 0.98; 95% CI 0.93, 1.03 and hazard ratio 1.06; 95% CI 0.92, 1.23, respectively). Younger children and those with indices of more severe acute or chronic asthma were more likely to have ED re-visits and hospitalizations. Other follow-up care characteristics (number of visits, type of physician providing care) were not associated with outcomes. CONCLUSIONS: Despite a universal healthcare setting, most children did not access follow-up care after an ED visit for asthma, and those that did had no associated benefit in terms of reduced ED re-visits and hospitalizations in the subsequent year. PMID- 22484355 TI - Feasibility of evaluating treatment of early hypotension in extremely low birth weight infants. PMID- 22484354 TI - Calcineurin inhibitor treatment of intravenous immunoglobulin-resistant Kawasaki disease. AB - OBJECTIVE: To describe the clinical course and outcome of 10 patients with Kawasaki disease (KD) treated with a calcineurin inhibitor after failing to respond to multiple therapies. STUDY DESIGN: Demographic and clinical data were prospectively collected using standardized case report forms. T-cell phenotypes were determined by flow cytometry, and KD risk alleles in ITPKC (rs28493229), CASP3 (rs72689236), and FCGR2A (rs1801274) were genotyped. RESULTS: Intravenous followed by oral therapy with cyclosporine (CSA) or oral tacrolimus was well tolerated and resulted in defervescence and resolution of inflammation in all 10 patients. There were no serious adverse events, and a standardized treatment protocol was developed based on our experiences with this patient population. Analysis of T-cell phenotype by flow cytometry in 2 subjects showed a decrease in circulating activated CD8(+) and CD4(+) T effector memory cells after treatment with CSA. However, suppression of regulatory T-cells was not seen, suggesting targeting of specific, proinflammatory T-cell compartments by CSA. CONCLUSION: Treatment of refractory KD with a calcineurin inhibitor appears to be a safe and effective approach that achieves rapid control of inflammation associated with clinical improvement. PMID- 22484356 TI - Predictors of gluten avoidance and implementation of a gluten-free diet in children and adolescents without confirmed celiac disease. AB - OBJECTIVES: To determine independent predictors of gluten avoidance and of a physician's decision to initiate a gluten-free diet (GFD) in children and adolescents without confirmed celiac disease. STUDY DESIGN: We performed a structured medical record review of 579 patients aged 1-19 years presenting for evaluation of celiac disease between January 2000 and December 2010 at a large Boston teaching hospital. We collected data including demographic information, medical history, serology, small intestinal biopsy, history of gluten avoidance, and the postworkup recommendation of implementation of a GFD. Predictors of gluten-related issues were identified by multivariate logistic regression. RESULTS: Among 579 children without a previous diagnosis of celiac disease (mean age, 8.7 years), 43 (7.4%) had ever avoided gluten. Independent predictors of gluten avoidance were irritability or poor temper (OR, 3.2), diarrhea (OR, 2.5), weight issues (OR, 0.4), pervasive developmental disorder (OR, 5.3), and family history of celiac disease (OR, 2.2). Among 143 children without confirmed celiac disease who underwent diagnostic evaluation, several predictive factors were associated with a physician- recommended/parent-initiated GFD: irritability (OR, 6.4), diarrhea (OR, 3.4), pervasive developmental disorder (OR, 7.9), and positive serology before the referral (OR, 4.3). CONCLUSION: Gluten avoidance among children and adolescents without a previous diagnosis of celiac disease is relatively common. The identified predictors suggest that gluten avoidance is associated with nonspecific behavioral and gastrointestinal complaints and perhaps with the perceived dietary responses in another family member thought to have celiac disease. PMID- 22484357 TI - High dose bisphenol A impairs hippocampal neurogenesis in female mice across generations. AB - Bisphenol A (BPA) is used as a monomer during the manufacture of polycarbonate plastics and epoxy resins. However, BPA adversely affects reproductive organ growth and development, and it has been proposed that the detrimental effects of BPA could extend to future generations. The present study was conducted to evaluate the transgenerational effects of BPA on hippocampal neurogenesis and neurocognitive function. Pregnant female C57BL/6 mice (F0) were exposed to BPA (0.1-10 mg/kg) from gestation day 6 to 17, and female offspring (F2) from F1 generation mice were prepared. It was found that exposure of F0 mice to BPA at 10 mg/kg decreased the number of newly generated cells in the hippocampi of F2 female mice. Passive avoidance testing revealed that high-doses BPA (1 mg/kg and 10 mg/kg) decreased cross-over latency time in F2 mice, suggesting a BPA-mediated neurocognitive deficit in terms of memory retention. Furthermore, it was found that levels of phospho-ERK, brain-derived neurotrophic factor (BDNF), and phospho CREB in hippocampi were significantly lower in F2 mice. Interestingly, the effects of BPA on hippocampal neurogenesis were found to be correlated with altered DNA methylation. In particular, high-dose BPA exposure increased DNA methylation of the CREB regulated transcription coactivator 1 (Crtc1) generated in F2 mice. These findings suggest that BPA exposure of pregnant mothers could adversely affect hippocampal neurogenesis and cognitive function in future generations by modulating the ERK and BDNF-CREB signaling cascades. PMID- 22484359 TI - Repetitive exposure to a 7 Tesla static magnetic field of mice in utero does not cause alterations in basal emotional and cognitive behavior in adulthood. AB - In the past three decades, magnetic resonance imaging (MRI) has been increasingly used in obstetrics to aid diagnostics of maternal and fetal conditions and has generally been considered a safe imaging method. However, the development of higher-performance systems employing, for example, stronger fields to improve the technique's diagnostic potential, necessitates on-going safety evaluation. Rodent studies provide an excellent opportunity to investigate not only acute but also long-term effects of magnetic field exposure in a systematic manner, and a behavioral analysis might help to uncover subtler effects which might result from magnetic field exposure of the vulnerable developing brain. We conducted a comprehensive investigation of emotional and cognitive behavior in adult mice which had been repeatedly exposed to a 7 Tesla static magnetic field in utero. Using well-validated tests, we did not observe any adverse behavioral alterations regarding emotional behavior as well as spatial and emotional learning. PMID- 22484358 TI - Non-monophyly and deep genetic differentiation across low-elevation barriers in a Neotropical montane bird (Basileuterus tristriatus; Aves: Parulidae). AB - Most widespread birds of Neotropical cloud forests exhibit phenotypic variation that is partitioned geographically suggesting allopatric divergence, but little is known about the extent to which such phenotypic differentiation is consistent with genetic variation. We studied geographic patterns of genetic differentiation in the Three-striped Warbler (Basileuterus tristriatus), a polytypic and widespread understory bird of the foothills and mid-elevation zone of the tropical Andes and adjacent mountains of Central and South America. We sequenced mitochondrial DNA for 196 samples covering the entire range of B. tristriatus, as well as 22 samples of its putative closest relatives: the Three-banded (B. trifasciatus) and Santa Marta (B. basilicus) warblers. We found deep genetic structure across the range of B. tristriatus, which consisted of ten major clades including B. trifasciatus, a species that was nested within B. tristriatus. In contrast, B. basilicus was not closely related to B. tristriatus but part of a clade of Myiothlypis warblers. Geographic boundaries among clades were clearly related to lowland gaps separating subspecies groups. The subspecies melanotis of the mountains of Central America was sister to a large clade including B. t. tacarcunae, and the rest of South American clades, including B. trifasciatus. Five clades are found in the northern Andes, where no signs of gene flow were found across barriers such as the Tachira Depression or the Magdalena valley. Our study highlights the importance of valleys in promoting and maintaining divergence in a lower montane forest bird. The substantial genetic and phenotypic differentiation, and the paraphyly uncovered in B. tristriatus, may call for revising its species boundaries. PMID- 22484360 TI - Transgenerational toxicity of Zearalenone in pigs. AB - Zearalenone (ZEN) is a mycotoxin that can be a contaminant of food and feed commodities. ZEN acts as a xenoestrogen and is considered an endocrine disruptor. Since estrogens influence oogenesis during fetal growth, the effect of ZEN on oocytes was investigated in the F1-generation. Pregnant and lactating pigs were exposed to feed naturally contaminated with ZEN (200, 500 and 1000MUg/kg feed). Ovaries of F1-animals were examined for follicle development, expression of estrogen converting enzymes and estrogen receptors, and oocyte quality. In F1 newborns, ZEN did not affect follicle dynamics, but follicle integrity decreased with increasing ZEN concentrations. Expression of estrogen receptor beta mRNA increased following ZEN exposure, whereas expression of genes coding for estrogen converting enzymes remained unchanged. In F1-prepubertal gilts, follicular atresia and oocyte maturation with subsequent embryo development remained unchanged. In conclusion, ZEN reduced the quantity of healthy follicles, which may lead to premature oocyte depletion in adulthood. PMID- 22484362 TI - Ebselen reduces hyperglycemia temporarily-induced by diazinon: a compound with insulin-mimetic properties. AB - The present study investigated the effect of ebselen (EB) against hyperglycemia induced by the organophosphate (OPI) diazinon (DI) in rats. The insulin-mimetic properties of EB were investigated in vitro with the aim of better understanding the hypoglycemic effect of this compound. The protective effect of EB against pancreatic and hepatic damage caused by DI in rats was also appraised. In the in vivo experiments, rats were pre-treated with a single injection of EB (50mg/kg, intraperitoneal, i.p.). Afterward, animals were treated with a single injection of DI (200 mg/kg, i.p.). The parameters indicative of pancreatic and hepatic damage such as, serum amylase, lipase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) activities as well as serum glucose levels, hepatic glycogen content and glucose-6-phosphatase (G6Pase) activity were determined. EB pre-treatment was effective in reducing serum amylase, lipase, AST, ALT, ALP, and LDH activities, protecting against pancreatic and hepatic damage. EB reduced hyperglycemia and increased hepatic glycogen content in animals exposed to DI. In the in vitro assays, EB (150 MUM) or insulin (IN 10 MUM, positive control) was incubated with either skeletal muscle or hepatic tissue with the aim of measuring glucose uptake, glycogen synthesis and glycogen breakdown. EB increased the glucose uptake in skeletal muscle, stimulated hepatic glycogen synthesis and inhibited glycogen breakdown in a similar way to IN. In conclusion, EB, possibly through its insulin-mimetic action, protected against pancreatic and hepatic damage caused by DI in rats. PMID- 22484361 TI - Methoxychlor inhibits growth and induces atresia through the aryl hydrocarbon receptor pathway in mouse ovarian antral follicles. AB - Methoxychlor (MXC) is an organochlorine pesticide used against pests that attack crops, vegetables, and livestock. MXC inhibits growth and induces atresia (death) of mouse ovarian antral follicles in vitro. Since several studies indicate that many chemicals act through the aryl hydrocarbon receptor (AHR) pathway, the current study tested the hypothesis that MXC binds to the AHR to inhibit growth and induce atresia of antral follicles. The data indicate that MXC binds to AHR. Further, a relatively high dose of MXC (100MUg/ml) inhibits growth and induces atresia in both wild-type (WT) and AHR null (AHRKO) follicles, whereas a lower dose of MXC (10MUg/ml) inhibits growth and induces atresia in WT, but not in AHRKO follicles. These data indicate that AHR deletion partially protects antral follicles from MXC induced slow growth and atresia. Collectively, these data show that MXC may act through the AHR pathway to inhibit follicle growth and induce atresia in antral follicles of the ovary. PMID- 22484363 TI - Temperature-dependent viral replication and antiviral apoptotic response in viral haemorrhagic septicaemia virus (VHSV)-infected olive flounder (Paralichthys olivaceus). AB - The olive flounder (Paralichthys olivaceus) shows a high rate of mortality to viral haemorrhagic septicaemia virus (VHSV) in the winter and spring but has zero mortality over 20 degrees C. In this experiment, we studied the effect of rearing temperature on viral replication, viral transcription and antiviral apoptotic immune response in VHSV-infected olive flounder by real-time polymerase chain reaction. Olive flounder were given intra-peritoneal injections of VHSV (10(7.8) TCID(50)/ml) and were reared at 15 degrees C or 20 degrees C. Five fish were randomly sampled for head kidney at 3, 6 and 12 h post-infection (hpi) and 1, 2, 4 and 7 days post-infection (dpi). Total RNA extracted from the tissue was reverse transcribed and used as template for real-time PCR. In the 15 degrees C group, the number of viral gRNA copies peaked after 2 dpi and remained high through 7 dpi, while in the 20 degrees C group, the copy number was at the highest at 1 dpi but drastically declined at later stages. Viral mRNA levels in the 15 degrees C group gradually increased starting at 3 hpi to reach their maximum value at 12 hpi and remained high until 2 dpi, whereas the other group showed much lower copy numbers that were undetectably low at 4 and 7 dpi. Type II IFN expression increased as the viral copies increased and the 20 degrees C group showed quicker and stronger expression than the 15 degrees C group. The MHC class I and CD8 expression was high in both the groups at early stage of infection (3-6 hpi) but at later stages (2-7 dpi) in 15 degrees C group expression reduced below control levels, while they expressed higher to control in 20 degrees C group. The expression of granzyme in 15 degrees C fish showed a single peak at 2 dpi, but was consistently expressing in 20 degrees C fish. Individuals expressed very high levels of perforin expressed very high levels of caspase 3. In 15 degrees C fish, TNFalpha, FasL and p53 expressed significantly higher than 20 degrees C only at initial stages of infection (3-6 hpi). Caspase 3 expression found to be low in 15 degrees C fish whereas it was significantly elevated in 20 degrees C group. Interestingly individual fish with high caspase 3 expression contained very low viral RNA. Thus, from our experiment, we can conclude that an effective apoptotic immune response in VHSV-infected olive flounder plays a crucial role in the survival of the host at higher temperatures. PMID- 22484364 TI - Selective deactivation of serum IgG: a general strategy for the enhancement of monoclonal antibody receptor interactions. AB - Serum IgG is a potent inhibitor of monoclonal antibody (mAb) binding to the cell surface Fcgamma receptors (FcgammaRs), which mediate cytotoxic and phagocytic effector functions. Here, we show that this competition can be eliminated, selectively, by the introduction to serum of (i) an enzyme that displaces Fc from FcgammaRs and (ii) a modification present in the therapeutic mAb that renders it resistant to that enzyme. Specifically, we show that (i) EndoS (endoglycosidase S) cleaves only complex-type glycans of the type found on IgG but (ii) is inactive against an engineered IgG Fc with oligomannose-type glycans. EndoS thus reduces FcgammaR binding of serum IgG, but not that of engineered mAb. Introduction of both the engineered mAb and endoglycosidase in serum leads to a dramatic increase in FcgammaR binding compared to the introduction of mAb in serum alone. Antibody receptor refocusing is a general technique for boosting the effector signal of therapeutic antibodies. PMID- 22484365 TI - The body adiposity index (hip circumference / height(1.5)) is not a more accurate measure of adiposity than is BMI, waist circumference, or hip circumference. AB - Based on cross-sectional analyses, it was suggested that hip circumference divided by height(1.5) -18 (the body adiposity index (BAI)), could directly estimate percent body fat without the need for further correction for sex or age. We compared the prediction of percent body fat, as assessed by dual-energy X-ray absorptiometry (PBF(DXA)), by BAI, BMI, and circumference (waist and hip) measurements among 1,151 adults who had a total body scan by DXA and circumference measurements from 1993 through 2005. After accounting for sex, we found that PBF(DXA) was related similarly to BAI, BMI, waist circumference, and hip circumference. In general, BAI underestimated PBF(DXA) among men (2.5%) and overestimated PBF(DXA) among women (4%), but the magnitudes of these biases varied with the level of body fatness. The addition of covariates and quadratic terms for the body size measures in regression models substantially improved the prediction of PBF(DXA), but none of the models based on BAI could more accurately predict PBF(DXA) than could those based on BMI or circumferences. We conclude that the use of BAI as an indicator of adiposity is likely to produce biased estimates of percent body fat, with the errors varying by sex and level of body fatness. Although regression models that account for the nonlinear association, as well as the influence of sex, age, and race, can yield more accurate estimates of PBF(DXA), estimates based on BAI are not more accurate than those based on BMI, waist circumference, or hip circumference. PMID- 22484366 TI - Longitudinal association between marital disruption and child BMI and obesity. AB - This research examines whether family disruptions (i.e., divorces and separation) contribute to children's weight problems. The sample consists of 7,299 observations for 2,333 children, aged 5-14, over the 1986-2006 period, from a US representative sample from the Child and Young Adult Survey accompanying the National Longitudinal Survey of Youth (NLSY). The study uses individual-fixed effects models in a longitudinal framework to compare children's BMI and weight problems before and after a disruption. Furthermore, besides doing a before-after comparison for children, the study also estimates the effects at various periods relative to the disruption in order to examine whether children are affected before the disruption and whether any effects change as time passes from the disruption, as some effects may be temporary or slow to develop. Despite having a larger sample than the previous studies, the results provide no evidence that, on average, children's BMI and BMI percentile scores (measured with continuous outcomes) are affected before the disruption, after the disruption, and as time passes from the disruption, relative to a baseline period a few years before the disruption. However, children experiencing a family disruption do have an increased risk of obesity (having a BMI percentile score of 95 or higher) in the two years leading up to the disruption as well as after the disruption, and as time passes from the disruption. PMID- 22484368 TI - Pricing of drugs with heterogeneous health insurance coverage. AB - In this paper, we examine the role of insurance coverage in explaining the generic competition paradox in a two-stage game involving a single producer of brand-name drugs and n quantity-competing producers of generic drugs. Independently of brand loyalty, which some studies rely upon to explain the paradox, we show that heterogeneity in insurance coverage may result in higher prices of brand-name drugs following generic entry. With market segmentation based on insurance coverage present in both the pre- and post-entry stages, the paradox can arise when the two types of drugs are highly substitutable and the market is quite profitable but does not have to arise when the two types of drugs are highly differentiated. However, with market segmentation occurring only after generic entry, the paradox can arise when the two types of drugs are weakly substitutable, provided, however, that the industry is not very profitable. In both cases, that is, when market segmentation is present in the pre-entry stage and when it is not, the paradox becomes more likely to arise as the market expands and/or insurance companies decrease deductibles applied on the purchase of generic drugs. PMID- 22484367 TI - Inflammatory and prothrombotic states in obese children of European descent. AB - Adipose tissue may release mediators that induce a chronic inflammatory state and alterations in coagulation, which contribute to insulin resistance, atherosclerosis, and thrombosis. We investigated whether inflammatory and/or prothrombotic states exist in obese children and assessed their interrelationship. Sixty-one subjects were recruited, aged between 6 and 16 years, to participate in a cross-sectional study at Children's University Hospital of Geneva. Selected pro/anti-inflammatory cytokines/chemokines and hemostasis parameters were measured in obese children and lean controls. Cardiovascular risk factors in the family were indexed. Fasting glucose level, insulin, prothrombin time (PT), fibrinogen, activated partial thromboplastin time (aPTT), D-dimer, endogenous thrombin potential (ETP), C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-gamma-inducible-protein (IP-10), monocyte chemoattractant protein 1 (MCP-1), and interleukin-1 receptor antagonist (IL-1Ra) were measured. We estimated insulin resistance by homeostatic model assessment (HOMA). Anti- (IL-1Ra) and proinflammatory cytokines (MCP-1, IL 6) were significantly increased in obese children in comparison to the control group, even before puberty. Hemostasis was also altered in obese children with a significantly increased fibrinogen level, increased D-dimer, a shortened PT, as well as an increased ETP. No correlation was found between cytokine levels and hemostasis parameters, except for IL-6 and fibrinogen. Obese children present with inflammatory and prothrombotic states as early as 6 years of age and these states are similar in prepubertal and pubertal obese children. The cytokines IL 1Ra and MCP-1 were most significantly increased in obese children. Further investigation is necessary to determine if these cytokines, together with ETP, can reliably predict the development of diabetes and atherosclerosis. PMID- 22484369 TI - Arthroscopic extraarticular reconstruction of the medial patellofemoral ligament with gracilis tendon autograft - surgical technique. AB - The standard approach to reconstruct the medial patellofemoral ligament (MPFL) is by mini-open incision at its patellar insertion and femoral origin. At the medial patella rim, the MPFL insertion may be visualized in most cases by dissection during surgery. On the femur, it is more difficult to localize the MPFL remnants by a mini-open incision due to soft tissue covering the anatomical origin. Therefore, the femoral MPFL origin is usually identified by intraoperative lateral fluoroscopy. However, the insertion and origin of the MPFL at the patella and femur might be directly visualized using an arthroscopic extraarticular approach from the knee joint through a window of the synovial layer. This is especially helpful on the femoral side but also at the patella to find the individual anatomical MPFL footprints. Arthroscopic extraarticular reconstruction may then be performed using one additional medial mid-parapatellar portal. The major advantages of this technique are an individualized anatomical procedure, which is minimal invasive and cosmetically appealing. The aim of this study was to describe the arthroscopic extraarticular approach to the MPFL insertion at the patella and origin at the femur through synovial windows and to explain the procedure of arthroscopic MPFL reconstruction with a gracilis tendon autograft. Level of evidence Expert opinion, surgical technique, Level V. PMID- 22484370 TI - Local anaesthetics use does not suppress muscle activity following an ankle injection. AB - PURPOSE: To determine if peroneus longus (PL), peroneus brevis (PB), medial gastrocnemius (MG) and tibialis anterior (TA) muscle activation patterns during inversion perturbation and running tasks are suppressed following lidocaine injection to the anterior talofibular (ATF) and calcaneofibular (CF) ligament regions. METHODS: Fourteen recreationally active male subjects (age, 24.8 +/- 2.9 years; height, 177.0 +/- 6.0 cm; mass, 77.7 +/- 6.7 kg) participated. Testing was performed under five injection conditions to the ATF and CF regions: 1 ml saline, 1 ml lidocaine, 3 ml saline, 3 ml lidocaine or no injection. Following injection condition, traditional ankle taping was applied. Electromyography patterns of the PL, PB, MG and TA were collected while subjects performed continuous lateral jumps on a custom-built device which elicited an ankle inversion perturbation and treadmill running (3.35 m s(-1), 0.5 % incline). RESULTS: No significant differences were demonstrated in muscle activation patterns of the PL (n.s.), PB (n.s.), MG (n.s.) or TA (n.s.) for any variable across injected conditions during both tasks. Statistical power was 0.214-0.526 for the PL, 0.087-0.638 for the PB, 0.115-0.560 for the MG and 0.118-0.410 for the TA. CONCLUSIONS: Injection of lidocaine up to 3 ml to the ATF and CF regions did not suppress muscle activity of the PL, PB, MG or TA during the inversion perturbation or running tasks. Injection up to 3 ml of 1 % lidocaine to the ATF and CF regions may be used without sacrificing the muscle activation patterns about the ankle. This finding is clinically relevant since the use of the injection does not put the patient at any higher risk of reinjury to the site. PMID- 22484371 TI - Horizontal suture placement influences meniscal repair fixation strength. AB - PURPOSE: This in vitro biomechanical study investigated the influence of horizontal suture placement distance from the medial meniscal lesion repair site on fixation characteristics during submaximal cyclic and load to failure test conditions. METHODS: Eighteen cadaveric (20-45 years of age) medial menisci with intact joint capsules were harvested within 24-48 h after death and divided into two groups of 9 specimens each for biomechanical testing. A 2.0-cm-long antero posterior vertical longitudinal lesion was created with a #15 scalpel 2.0-3.0 mm from the outer edge of each meniscus. Menisci were repaired using #2-0 suture material with two horizontal suture loops placed either 1.0 mm (Group 1) or 3.0 mm (Group 2) from the lesion site. Following repair, the lesion was extended completely through the meniscal horns so that no tissue secured the repair, only the two horizontal suture loops representing a "worst-case" testing scenario. Following repair, specimens were placed in a servo hydraulic device using a pair of 1.2-mm-diameter steel wire loops and underwent submaximal cyclic loading between 5 and 50 N (1 Hz) for 500 cycles prior to load to failure testing (5 mm/min crosshead speed, 20 Hz data collection). An alpha level of P < 0.05 was selected to indicate statistical significance. RESULTS: Five of nine (55.6 %) Group 1 specimens did not complete submaximal cyclic testing. All Group 2 specimens completed submaximal cyclic testing (Fisher's exact test P = 0.029). Statistically significant mean group differences were not observed for displacement during submaximal cyclic loading (Group 1 = 5.0 +/- 1.5 mm and Group 2 = 5.7 +/- 1.6 mm) or for construct stiffness during load to failure testing (Group 1 = 50.1 +/- 6.3 N/mm and Group 2 = 52.6 +/- 11.9 N/mm). Group 2 displayed greater mean load at failure (112.1 +/- 40.8 N vs. 72.7 +/- 11.2 N, P = 0.02) and mean displacement at failure (11.1 +/- 2.2 mm vs. 7.6 +/- 1.4 mm, P = 0.03) than Group 1. CONCLUSIONS: Horizontal sutures placed slightly farther away from the meniscus lesion displayed superior repair fixation than sutures placed closer to the lesion. The superior biomechanical meniscal repair fixation provided by capturing greater tissue volume may enable safe earlier participation in functional exercise activities. Studies are needed to verify these findings in vivo. PMID- 22484373 TI - Application of co-expressed genes to articular cartilage: new hope for the treatment of osteoarthritis (review). AB - Osteoarthritis (OA), with a high prevalence and economic impact, is a progressive diarthrodial joint disease that substantially reduces quality of life and is mainly characterized by degradation of the extracellular matrix (ECM) and the loss of a chondrogenic phenotype in articular cartilage. Strategic targeting of therapeutic genes to OA cartilage may offer potent alternatives for restoring the structure of the damaged cartilage. alpha2-macroglobulin (alpha2M), a member of the alpha2M family of proteins, prevents the degradation of the ECM by inhibiting the activity of a disintegrin-metalloproteinases with thrombospondin motifs (ADAMTSs) and matrix metalloproteinases (MMPs). Sox9, a key chondrogenic transcription factor, plays a crucial role in the development and maintenance of the chondrogenic phenotype. Therefore, modulation of the OA cartilage by genetically modifying the levels of alpha2M and Sox9 expression may be advantageous in ameliorating the course of OA. To acquire long-lasting expression of the alpha2M and Sox9 genes, gene transfer systems are required. The chitosan vector system is expected to be useful for direct gene therapy for joint disease. Thus, we conclude that co-expression of the alpha2M and Sox9 genes, combined with chitosan-mediated gene delivery, will offer potential as a novel means by which to treat OA via intra-articular injection. PMID- 22484374 TI - Phospholipase A2 activating protein is required for 1alpha,25-dihydroxyvitamin D3 dependent rapid activation of protein kinase C via Pdia3. AB - 1alpha,25-Dihydroxyvitamin D(3) (1,25D3) regulates musculoskeletal cells via two different mechanisms: vitamin D receptor (VDR)-dependent gene transcription and rapid membrane-signaling via VDR as well as protein disulfide isomerase, family A, member 3 (Pdia3). In chondrocytes from the costochondral cartilage growth zone (GC), ligand binding to Pdia3 causes a rapid increase in phospholipase A(2) (PLA(2)) activity leading to release of arachidonic acid and formation of lysophospholipid (LPL). LPL activates phospholipase C (PLC), and resulting inositol trisphosphate (IP(3)) and diacylglycerol contribute to PKCalpha activation and downstream activation of ERK1/2. PLA(2) activating protein (PLAA) is increased in the growth zone of rat growth plates suggesting that it mediates the 1,25D3-dependent pathway. This study examined the role of PLAA in mediating 1,25D3-dependent PKC activation using GC cells and MC3T3-E1 wild-type and PLAA silenced osteoblasts as models. PLAA, Pdia3, and caveolin-1 (Cav-1) were detected in plasma membranes and caveolae of GC and MC3T3-E1 cells. Pdia3 immunoprecipitated samples were positive for PLAA only after 1,25D3 treatment. Cav-1 was detected when immunoprecipitated with anti-Pdia3 and anti-PLAA in both vehicle and 1,25D3 treated cells. These observations were confirmed by immunohistochemistry. 1,25D3 failed to activate PLA(2) and PKC or cause PGE(2) release in PLAA-silenced cells. PLAA-antibody successfully blocked the PLAA protein and consequently suppressed PKC activity in GC and MC3T3-E1 cells. Crosslinking studies confirmed the localization of PLAA on the extracellular face on the plasma membrane in untreated MC3T3-E1 cells. Taken together, our results suggest that PLAA is an important mediator of 1alpha,25(OH)(2)D(3) rapid membrane mediated signaling. 1alpha,25(OH)(2)D(3) likely causes conformational changes bringing Pdia3 into proximity with PLAA, and aiding in transducing the signal from caveolae to the plasma membrane. PMID- 22484375 TI - Melanoma coordinates general and cell-specific mechanisms to promote methotrexate resistance. AB - Melanoma, the most aggressive form of skin cancer, is notoriously resistant to all current modalities of cancer therapy, including to the drug methotrexate. Melanosomal sequestration and cellular exportation of methotrexate have been proposed to be important melanoma-specific mechanisms that contribute to the resistance of melanoma to methotrexate. In addition, other mechanisms of resistance that are present in most epithelial cancer cells are also operative in melanoma. This report elucidates how melanoma orchestrates these mechanisms to become extremely resistant to methotrexate, where both E2F1 and checkpoint kinase 1 (Chk1), two molecules with dual roles in survival/apoptosis, play prominent roles. The results indicated that MTX induced the depletion of dihydrofolate in melanoma cells, which stimulated the transcriptional activity of E2F1. The elevate expression of dihydrofolate reductase and thymidylate synthase, two E2F1 target genes involved in folate metabolism and required for G(1) progression, favored dTTP accumulation, which promoted DNA single strand breaks and the subsequent activation of Chk1. Under these conditions, melanoma cells are protected from apoptosis by arresting their cell cycle in S phase. Excess of dTTP could also inhibit E2F1-mediated apoptosis in melanoma cells. PMID- 22484376 TI - Antimicrobial lipopeptaibol trichogin GA IV: role of the three Aib residues on conformation and bioactivity. AB - The lipopeptaibol trichogin GA IV is a natural, non-ribosomally synthesized, antimicrobial peptide remarkably resistant to the action of hydrolytic enzymes. This feature may be connected to the multiple presence in its sequence of the non coded residue alpha-aminoisobutyric acid (Aib), which is known to be responsible for the adoption of particularly stable helical structures already at the level of short peptides. To investigate the role of Aib residues on the 3D-structure and bioactivity of trichogin GA IV, we synthesized and fully characterized four analogs where one or two Aib residues are replaced by L-Leu. Our extensive conformational studies (including an X-ray diffraction analysis) and biological assays performed on these analogs showed that the Aib to L-Leu replacements do not affect the resistance to proteolysis, but modulate the bioactivity of trichogin GA IV in a 3D-structure related manner. PMID- 22484377 TI - An in situ study investigating dentine tubule occlusion of dentifrices following acid challenge. AB - OBJECTIVES: To investigate the dentine occlusion and acid resistance of dentifrices developed to treat dentine hypersensitivity. METHODS: This was a single centre, single blind, randomised, split mouth, four treatments, two period crossover, in situ study in healthy subjects. Subjects wore buccal intra-oral appliances each fitted with four dentine samples over four consecutive days with one study product applied per appliance; 8% strontium acetate in silica base, 1040 ppm sodium fluoride (Sensodyne((r)) Rapid Relief), 8% arginine, calcium carbonate, 1450 ppm sodium monofluorophosphate (Colgate Sensitive Pro Relief((r))), 1450 ppm sodium fluoride (control paste) and water. On days 3 and 4, two agitated grapefruit juice challenges (ex vivo) occurred for 1 min. At the end of each treatment day 1 dentine sample was removed from each appliance for scanning electron microscopy (SEM). The extent of tubule occlusion was measured using an examiner-based visual scoring index (three trained examiners). RESULTS: In total, 28 subjects ((12 males and 16 females with a mean age of 34.7 years (SD 8.41 years)) completed the study. On day 2, both test dentifrices demonstrated significantly better dentine tubule occlusion than water (p < 0.0001) and control paste (8% strontium p = 0.0003 and 8% arginine p = 0.0019). After 3 and 4 days of twice daily brushing with acid challenges on days 3 and 4 the strontium-based dentifrice demonstrated significantly better dentine occlusion than all other treatments (p < 0.0001). CONCLUSIONS: Strontium acetate and arginine-based dentifrice result in statistically significant dentine tubular occlusion compared to controls, but the arginine-based dentifrice is more susceptible to acid challenge. CLINICAL SIGNIFICANCE: Erosive beverages are an important aetiology in DH by exposing dentine tubules. Their consumption has increased significantly over the past decade in the UK. This 4-day in situ study investigated the properties of commercially available dentifrices designed to occlude dentine tubules and their resistance to an agitated acid challenge. PMID- 22484378 TI - Does central sleep apnea occur in children with syndromic craniosynostosis? AB - AIM: To evaluate the prevalence and cause of central sleep apnea (CSA) and central sleep apnea syndrome (CAS) in patients with syndromic craniosynostosis. MATERIALS AND METHODS: This prospective study included ambulant sleep study data to assess, central apneas and obstructive apneas. Data on hindbrain herniation were obtained using cerebral magnetic resonance imaging. RESULTS: One-hundred and thirty-eight syndromic craniosynostosis patients with a median (range) age of 7.8 (1.0-18.0) were included. Central apneas decreased significantly with increasing age (R=-0.25, p=0.003). An increased central apnea index according to the AASM was present in 5 of 138 patients (3.6%; median central apnea index 2.38 (1.12 3.04)). The prevalence of OSAS was 34%, but the median central apnea index in OSAS patients was not pathologically increased. Patients with hindbrain herniation did not have more central apneas compared to patients without hindbrain herniation (F=1.38, p=0.24). CONCLUSION: There is no CSA syndrome in children with syndromic craniosynostosis despite white matter abnormalities, OSAS and hindbrain herniation. PMID- 22484379 TI - Tonic and phasic drive to medullary respiratory neurons during periodic breathing. AB - It is unknown how central neural activity produces the repetitive termination and restart of periodic breathing (PB). We hypothesized that inspiratory and expiratory neural activities would be greatest during the waxing phase and least during the waning phase. We analyzed diaphragmatic and medullary respiratory neural activities during PB in intact unanesthetized adult cats. Diaphragmatic activity was increased and phasic during the waxing phase and was decreased and tonic during the waning phase. Activity of expiratory (n=21) and inspiratory (n=40) neurons was generally increased and phasic during the waxing phase and was decreased and more tonic during the waning phase. During apneas associated with PB, diaphragmatic activity was silent and most, but not all, inspiratory cells were inactive whereas most expiratory cells decreased activity but remained tonically active. We suggest that reduced strength of reciprocal inhibition, secondary to reduced respiratory drive, allows for simultaneous tonic activity of inspiratory and expiratory neurons of the central pattern generator, ultimately resulting in central apnea. PMID- 22484380 TI - Silver compounds used in dentistry for caries management: a review. AB - OBJECTIVE: Silver compounds have been used for their medical properties for centuries and in dentistry for more than a century. The aim of this review is to examine the evidence supporting the therapeutic use of silver in dentistry and the outcomes from the clinical trials, as well as mode of action and biocompatibility. DATA SOURCES: Literature was searched using the PubMed database between the year 1966 and 2011, with principle key terms such as "Silver Nitrate", "Silver Fluoride", "Silver Diammine Fluoride", "Silver compounds" and "Dental caries". Hand searching was performed for relevant papers cited in the indices back to the year 1905. RESULTS: In vitro, in vivo and clinical evidence have demonstrated that silver compounds are viable agents for preventing and arresting caries both in the primary and permanent dentition; however they are associated with adverse tooth discolouration and some reports that pulp irritation may occur. Further research has investigated its effectiveness as a dentine desensitiser, root canal disinfectant and even in silver impregnated restorative materials. The mode of action of silver compounds on carious tooth tissues is thought to include inhibition of the demineralization process, as well as an anti-bacterial effect by interference of bacterial cell membranes, cytoplasmic enzymes and inhibition of bacterial DNA replication. CONCLUSION: Silver compounds have been shown to be an effective anti-caries agent; however, there is an incomplete understanding of how silver compounds prevent caries. Further research is required to help identify its most efficacious use and limitations. PMID- 22484381 TI - Preoperative risk stratification for thoracic surgery using the American College of Surgeons National Surgical Quality Improvement Program data set: functional status predicts morbidity and mortality. AB - BACKGROUND: Preoperative risk stratification for noncardiac thoracic surgery focuses on predicting postoperative lung capacity and cardiac risk. We hypothesized that preoperative functional status may be a predictor of morbidity and mortality after thoracic surgery. METHODS: The National Surgical Quality Improvement Program Participant Use Files from 2005 to 2009 were accessed, and current procedural terminology codes for procedures involving the lung and pleura were used to identify thoracic surgery patients. Patients were grouped by independent or dependent preoperative functional status. Risks of infectious and noninfectious complications were evaluated. Chi-square, Fisher exact, and multivariate analyses with stepwise logistic regression were used. This study was approved by the Institutional Review Board. RESULTS: Of 6,373 patients, 812 had a preoperative dependent functional status. Dependent patients had significantly higher rates of infection, other adverse events, and mortality. They were 9.3 times more likely (odds ratio [OR] 9.3) to have prolonged ventilation (P < 0.001) and 3.1 times more likely to be reintubated (P < 0.001). Postoperative pneumonia occurred in 10% (OR 2.7, P < 0.001). Postoperative mortality was 7.7 times higher (P < 0.001). Preoperative functional status, wound classification 3, and emergency procedures were independent predictors of both morbidity and mortality. Performing a thoracotomy was an independent risk factor for postoperative morbidity but not mortality (P < 0.001, OR 2 versus P = 0.415, OR 1.1). CONCLUSIONS: Thoracic surgery patients, classified as functionally dependent preoperatively are at high risk for major morbidity and mortality. Although a limited observational study, results show that functional status is an essential component of preoperative assessment for thoracic surgery patients. PMID- 22484382 TI - Optimizing chimerism level through bone marrow transplantation and irradiation to induce long-term tolerance to composite tissue allotransplantation. AB - BACKGROUND: Mixed chimerism with long-term composite tissue allotransplant (CTA) acceptance can be achieved through allogeneic bone marrow transplantation (BMT). The present study investigated the optimal chimerism level by giving different irradiation dosages to recipients to induce tolerance to CTA. METHODS: Chimera were prepared using Brown-Norway and Lewis rats with strong major histocompatibility complex incompatibility. The Lewis rats received 5 mg antilymphocyte globulin (day -1 and 10) and 16 mg/kg cyclosporine (day 0-10) and were separated into groups 1, 2, 3, 4, and 5 according to the day -1 irradiation dosage: 0, 200, 400, 600, and 950 cGy, respectively. The Lewis rats were then reconstituted with 100 * 10(6) T-cell-depleted Brown-Norway bone marrow cells (day 0) and received vascularized Brown-Norway-CTA on day 28. Chimerism was assessed monthly by flow cytometry starting on day 28 after BMT. Graft-versus host disease (GVHD) was assessed clinically and histologically. RESULTS: Chimerism, 4 weeks after BMT, averaged 0.2%, 9.2%, 30.7%, 58%, and 99.3% in groups 1 to 5, respectively. GVHD occurred as follows: groups 1 and 2, none; group 3, 1 case of GVHD; group 4, 7 cases of GVHD (of which 3 died); and group 5, 10 cases of GVHD (of which 6 died). The percentage of long-term CTA acceptance was 0%, 0%, 90%, 70%, and 40% in groups 1 to 5, respectively. The percentage of regulatory T cells was significantly lower in high-chimerism (>= 20%, n = 15) than in low-chimerism (<20%, n = 5) rats that accepted CTA long-term . CONCLUSIONS: The chimerism level correlated positively with GVHD occurrence and long-term CTA acceptance but correlated negatively with regulatory T-cell levels. Optimal chimerism for CTA acceptance through pre-CTA BMT and irradiation occurs at 20-50% at day 28 after BMT in the rat model. PMID- 22484383 TI - Transcriptome analysis of HeLa cells response to Brucella melitensis infection: a molecular approach to understand the role of the mucosal epithelium in the onset of the Brucella pathogenesis. AB - Brucella spp. infect hosts primarily by adhering and penetrating mucosal surfaces, however the initial molecular phenomena of this host:pathogen interaction remain poorly understood. We hypothesized that characterizing the epithelial-like human HeLa cell line molecular response to wild type Brucella melitensis infection would help to understand the role of the mucosal epithelium at the onset of the Brucella pathogenesis. RNA samples from B. melitensis infected HeLa cells were taken at 4 and 12 h of infection and hybridized in a cDNA microarray. The analysis using a dynamic Bayesian network modeling approach (DBN) identified several pathways, biological processes, cellular components and molecular functions altered due to infection at 4 h p.i., but almost none at 12 h p.i. The in silico modeling results were experimentally tested by knocking down the expression of MAPK1 by siRNA technology. MAPK1-siRNA transfected cell cultures decreased the internalization and impaired the intracellular replication of the pathogen in HeLa cells after 4 h p.i. DBN analysis provides important insights into the role of the epithelial cells response to Brucella infection and guide research to novel mechanisms identification. PMID- 22484384 TI - Plasminogen activator inhibitor type I may contribute to transient, non-specific changes in immunity in the subacute phase of murine tuberculosis. AB - Tuberculosis, caused by Mycobacterium (M.) tuberculosis, is a devastating infectious disease causing many deaths worldwide. Non-specific host defense mechanisms such as the coagulation and fibrinolytic system may give insight in possible new therapeutic targets. Plasminogen activator inhibitor type-1 (PAI-1), an important regulator of inflammation and fibrinolysis, might be of interest as tuberculosis patients have elevated plasma levels of PAI-1. In this study we set out to investigate the role of PAI-1 during tuberculosis in vivo. Wildtype (WT) and PAI-1 deficient (PAI-1-/-) mice were intranasally infected with M. tuberculosis H37rv and sacrificed after 2, 5 and 29 weeks. Five weeks post infection, bacterial loads in lungs of PAI-1-/- mice were significantly higher compared to WT mice, while no differences were seen 2 and 29 weeks post infection. At two weeks post-infection increased influx of macrophages and lymphocytes was observed. PAI-1 deficiency was associated with a reduced cytokine response in the lungs; however, upon stimulation with tuberculin purified protein derivative (PPD), PAI-1-/- splenocytes released increased levels of IFN-gamma compared to WT. No clear differences were found between PAI-1-/- and WT mice at 29 weeks after infection. In conclusion, these data suggest that PAI-1 contributes to transient, non-specific changes in immunity during the early phase of murine tuberculosis. PMID- 22484385 TI - Porphyromonas gingivalis stimulates IL-18 secretion in human monocytic THP-1 cells. AB - Porphyromonas gingivalis is a major pathogen implicated in chronic periodontitis. We examined whether P. gingivalis affected the secretion of the pro-inflammatory cytokine interleukin-18 (IL-18) in macrophage-like THP-1 cells and in monocytic THP-1 cells in suspension. Live P. gingivalis-induced significant IL-18 secretion. Heat-inactivation of P. gingivalis greatly reduced the IL-18 stimulation; the IL-18 levels were similar to that observed with P. gingivalis LPS alone. Live P. gingivalis caused a cytotoxic effect that was reduced greatly by heat-inactivation. Our observations indicate that P. gingivalis specifically stimulates the production and release of the active form of IL-18, which may contribute to the progression of periodontitis. PMID- 22484386 TI - Mood stabilizers commonly restore staurosporine-induced increase of p53 expression and following decrease of Bcl-2 expression in SH-SY5Y cells. AB - Adult neurogenesis in dentate gyrus (DG) is involved in the action mechanism of mood stabilizers. However, it is poorly understood how mood stabilizers affect adult neurogenesis in DG. Neurogenesis consists of proliferation, survival (anti apoptosis) and differentiation of neural precursor cells in adult DG. Using in vitro culture of adult rat DG-derived neural precursor cells (ADP), we have already shown that four mood stabilizers, such as lithium (Li), valproate (VPA), carbamazepine (CBZ) and lamotrigine (LTG), commonly decrease staurosporine (STS) induced apoptosis of ADP. These suggest that the common anti-apoptotic effect of mood stabilizers could be involved in mood-stabilizing effects. Past studies have shown that Li and VPA increase the expression of Bcl-2, an anti-apoptotic gene. In addition, it has been shown that Li decreases the expression of p53, which plays a prominent role in apoptosis and regulates the expression of Bcl-2. Therefore, p53 and Bcl-2 can be considered to mediate the common anti-apoptotic effects of Li, VPA, CBZ and LTG. To elucidate the molecular mechanism underlying the common anti-apoptotic effects of mood stabilizers, we investigated the effects of Li, VPA, CBZ and LTG on STS-induced expression changes of p53, Bcl-2 and other p53-related molecules using SH-SY5Y cells as a model of neural precursor-like cells. STS increased the expression of p53 and decreased that of Bcl-2. These effects of STS on p53 and Bcl-2 are restored by all of Li, VPA, CBZ and LTG. In addition, p53 overexpression decreased the expression of Bcl-2. Taken together, these results suggest that p53 and Bcl-2 may be involved in a part of mood-stabilizing effects. PMID- 22484387 TI - Leg fat might be more protective than arm fat in relation to lipid profile. AB - PURPOSE: The objective of this study was to determine the independent relationships of trunk fat, leg fat and arm fat to cardiovascular (CVD) risk factors, after controlling for relevant confounders such as fat mass index, cardiorespiratory fitness and objectively measured physical activity. METHODS: This is a cross-sectional study involving 683 university students, aged 18-30 years. Total and regional body fat distribution was measured using dual-energy X ray absorptiometry. The associations of trunk, leg and arm fat with CVD risk factors (triglycerides-TG-, high-density lipoprotein cholesterol-HDL-c-, TG/HDL-c ratio, HOMA(IR), mean arterial pressure, C-reactive protein) were examined using regression linear models, controlling for age, sex, fat mass index [total body fat(kg)/height(m(2))], maximal oxygen consumption and physical activity by accelerometer. RESULTS: After controlling for fat mass index, and other confounders, higher levels of trunk fat were found to be associated with a poorer lipid profile, while higher levels of leg fat were found to be associated with a better lipid profile. We did not find any association between arm fat and lipid profile after controlling for total fatness and other confounders. Neither trunk, leg or arm fat was found to be related to insulin resistance, blood pressure or inflammation markers. CONCLUSIONS: Our data suggest that the region where fat is accumulated might have a differential effect on lipid profile: trunk fat has an adverse effect, leg fat has a protective effect, and arm fat has no effect. The differences observed between upper- and lower-body peripheral fat depots should be further explored. PMID- 22484388 TI - Treatment of scapular winging with modified Eden-Lange procedure in patient with pre-existing glenohumeral instability. PMID- 22484389 TI - Fifty most cited articles in orthopedic shoulder surgery. AB - BACKGROUND: The number of times an article has been cited has been used as a marker of its influence in a medical specialty. The purpose of this study was to determine the 50 most cited articles in shoulder surgery and their characteristics. METHODS: Science Citation Index Expanded was searched for citations of articles published in any of the 61 journals in the category "Orthopedics." Each of the journals was searched to determine the 50 most often cited articles specific to shoulder surgery. The following characteristics were determined for each article: authors, year of publication, source journal, geographic origin, article type, and level of evidence for clinical articles. Citation density (total number of citations/years since publication) was also determined. RESULTS: The number of citations ranged from 1211 to 192. The 50 most often cited articles were published in 8 journals. The majority of the articles (42) were clinical, with the remaining representing some type of basic science research. The most common level of evidence was IV (23). The mean number of citations for methodologic articles (437 citations per article) was greater than that for non-methodologic articles (301 citations per article) (P = .034). CONCLUSIONS: Articles that introduced instruments for outcome evaluation or that introduced classification systems (methodologic) were highly cited regardless of the date of publication. The top 50 list presented provides residency and fellowship directors with a group of "classic" articles in the subspecialty of orthopedic shoulder surgery that can be included in reading curriculums for their trainees. PMID- 22484390 TI - The upper band of the subscapularis tendon in the rat has altered mechanical and histologic properties. AB - BACKGROUND: The subscapularis is an important mover and stabilizer of the glenohumeral joint. Since the advent of shoulder arthroscopy, partial tears are found in 43% of rotator cuff patients. While partial tears to the upper band occur more commonly, little is known about the structure and mechanical behavior of the individual bands. Therefore, the objective of this study was to measure tensile mechanical properties, corresponding collagen fiber alignment, and histology in the upper and lower bands of the rat subscapularis tendon. MATERIALS AND METHODS: Thirty adult Sprague-Dawley rats were euthanized and subscapularis tendons dissected out for mechanical organization (n = 24) and histologic assessment (n = 6). Collagen organization was measured with a custom device during mechanical testing. RESULTS: Linear-region modulus at the insertion site was significantly lower in the upper band compared to the lower band, while no differences were found at the midsubstance location. The upper band was found to be significantly less aligned and demonstrated a more rounded cell shape than the lower band at the insertion site. DISCUSSION: This study demonstrated that the 2 bands of the subscapularis tendon have differential mechanical, organizational, and histological properties, which suggests a functional deficit exists to the upper band of the subscapularis and may be contributing to the prevalence of partial subscapularis tears. CONCLUSIONS: Clinicians should be aware that the upper band of the subscapularis tendon may be at higher risk of developing tears, based on decreased mechanical properties and a more disorganized collagen fiber distribution. PMID- 22484391 TI - Characterization of the relationship between microbial degradation processes at a hydrocarbon contaminated site using isotopic methods. AB - Decisions to employ monitored natural attenuation (MNA) as a remediation strategy at contaminated field sites require a comprehensive characterization of the site specific biodegradation processes. In the present study, compound-specific carbon and hydrogen isotope analysis (CSIA) was used to investigate intrinsic biodegradation of benzene and ethylbenzene in an aquifer with high levels of aromatic and aliphatic hydrocarbon contamination. Hydrochemical data and isotope fractionation analysis of sulfate and methane was used complementarily to elucidate microbial degradation processes over the course of a three year period, consisting of six sampling campaigns, in the industrial area of Weibetaandt Golzau (Saxony-Anhalt, Germany). Enrichment of (13)C and (2)H isotopes in the residual benzene and ethylbenzene pool downgradient from the pollution sources provided evidence of biodegradation of BTEX compounds at this site, targeting both compounds as the key contaminants of concern. The enrichment of heavy sulfur isotopes accompanied by decreasing sulfate concentrations and the accumulation of isotopically light methane suggested that sulfate-reducing and methanogenic processes are the major contributors to overall biodegradation in this aquifer. Along the contaminant plume, the oxidation of methane with delta(13)C(CH4) values of up to +17.50/00 was detected. This demonstrates that methane formed in the contaminant source can be transported along groundwater flow paths and be oxidized in areas with higher redox potentials, thereby competing directly with the pollutants for electron acceptors. Hydrochemical and isotope data was summarized in a conceptual model to assess whether MNA can be used as viable remediation strategy in Weibetaandt-Golzau. The presented results demonstrate the benefits of combining different isotopic methods and hydrochemical approaches to evaluate the fate of organic pollutants in contaminated aquifers. PMID- 22484392 TI - Clustering of risk factors for chronic diseases among adolescents from Southern Brazil. AB - OBJECTIVE: To investigate the clustering of risk behaviors for chronic non communicable diseases and their associated factors among adolescents from Southern Brazil. METHODS: In 2008, a survey was conducted with 3990 adolescents aged 14-15 years (mean: 14.3; SD: 0.6) from the 1993 Pelotas Birth Cohort Study. Clustering was determined by comparing observed (O) and expected (E) prevalence of all possible combinations of the four risk factors investigated (smoking, alcohol intake, low fruit intake, and physical inactivity). We carried out Poisson regression to evaluate the effect of individual characteristics on the presence of at least three risk behaviors. RESULTS: All risk factors tended to cluster together (O/E prevalence=3.0), especially smoking and alcohol intake (odds ratio to present on behavior in the presence of other >5.0). Approximately 15% of adolescents displayed three or more risk behaviors. Females (adjusted OR=1.55), people 15 years and older (OR=1.47), with black skin color (OR=1.23), and of low socioeconomic level (OR=1.29) were more likely to display three or more risk factors. CONCLUSION: These findings suggest that lifestyle-related risk factors tend to cluster among adolescents. Identifying subgroups at greater risk of simultaneously engaging in multiple risk behaviors may aid in the planning of preventive strategies. PMID- 22484393 TI - Micro and nanotechnological tools for study of RNA. AB - Micro and nanotechnologies have originally contributed to engineering, especially in electronics. These technologies enable fabrication and assembly of materials at micrometer and nanometer scales and the manipulation of nano-objects. The power of these technologies has now been exploited in analyzes of biologically relevant molecules. In this review, the use of micro and nanotechnological tools in RNA research is described. PMID- 22484394 TI - Molecular dynamics, crystallography and mutagenesis studies on the substrate gating mechanism of prolyl oligopeptidase. AB - Altered prolyl oligopeptidase (PREP) activity is found in many common neurological and other genetic disorders, and in some cases PREP inhibition may be a promising treatment. The active site of PREP resides in an internal cavity; in addition to the direct interaction between active site and substrate or inhibitor, the pathway to reach the active site (the gating mechanism) must be understood for more rational inhibitor design and understanding PREP function. The gating mechanism of PREP has been investigated through molecular dynamics (MD) simulation combined with crystallographic and mutagenesis studies. The MD results indicate the inter-domain loop structure, comprised of 3 loops at residues, 189-209 (loop A), 577-608 (loop B), and 636-646 (loop C) (porcine PREP numbering), are important components of the gating mechanism. The results from enzyme kinetics of PREP variants also support this hypothesis: When loop A is (1) locked to loop B through a disulphide bridge, all enzyme activity is halted, (2) nicked, enzyme activity is increased, and (3) removed, enzyme activity is only reduced. Limited proteolysis study also supports the hypothesis of a loop A driven gating mechanism. The MD results show a stable network of H-bonds that hold the two protein domains together. Crystallographic study indicates that a set of known PREP inhibitors inhabit a common binding conformation, and this H bond network is not significantly altered. Thus the domain separation, seen to occur in lower taxa, is not involved in the gating mechanism for mammalian PREP. In two of the MD simulations we observed a conformational change that involved the breaking of the H-bond network holding loops A and B together. We also found that this network was more stable when the active site was occupied, thus decreasing the likelihood of this transition. PMID- 22484395 TI - Sense of community and informal social control among lower income households: the role of homeownership and collective efficacy in reducing subjective neighborhood crime and disorder. AB - We examine the link between homeownership, collective efficacy, and subjective neighborhood crime and disorder. Although prior research suggests that homeownership provides social benefits, the housing downturn and foreclosure crisis, coupled with mounting evidence that people self-select into housing, raise questions about the role of homeownership. We adjust for respondents' decision to own or rent using a nationwide sample of lower-income households. We account for demographic and neighborhood characteristics as well as ratings of individual efficacy. We present a structural equation model that identifies how sense of community and informal social control jointly contribute to collective efficacy. The latent collective efficacy construct mediates the impact of homeownership on resident's perceptions of neighborhood disorder. Such perceptions matter because they have been linked to resident's physical and mental health. Our findings demonstrate that when coupled with sustainable mortgages, homeownership exerts a robust yet indirect effect in reducing subjective neighborhood crime and disorder. Our model also links collective efficacy to neighborhood racial homogeneity, a finding which presents challenges for the study of diversity and community. We discuss sense of community research as well as sustainable mortgages and implications of the foreclosure crisis for the future of homeownership opportunities among lower income households and neighborhoods. PMID- 22484396 TI - Therapeutic monitoring of benzodiazepines in the management of pain: current limitations of point of care immunoassays suggest testing by mass spectrometry to assure accuracy and improve patient safety. AB - BACKGROUND: Concomitant use of opioids and benzodiazepines can result in significant untoward effects. Point of care (POC) urine testing devices are commonly used tools to monitor patient use of medications. These useful devices are relatively inexpensive and yield immediate results that can be acted upon at the time of the appointment, although numerous limitations have been identified for specific medications or medication classes. We established the diagnostic accuracy of a commonly used POC testing method for benzodiazepines. METHODS: One thousand patients, from a single interventional pain practice receiving opioid therapy provided urine specimens as part of the usual practice of monitoring consistency with prescribed medications. These de-identified urine specimens were tested using LC-MS/MS and the results were compared using the standard calculations for sensitivity, specificity, and predicted value. Five specimens were excluded from the study because the prescribed flurazepam could not be confirmed by LC-MS/MS (the LC-MS/MS instrumentation was not set to identify flurazepam), resulting in 995 specimens. RESULTS: Point of care assays yielded false negative results for patients prescribed benzodiazepines nearly 20% of the time (98 out of 498 patients). The point of care cup often failed to produce positive results for persons who were shown by LC-MS/MS to be taking lorazepam or clonazepam. Although only 26 out of 498 patients (5%) were prescribed >=2 benzodiazepines, 73 out of 498 patients (15%) were found to be positive for that drug class. CONCLUSIONS: POC immunoassay for benzodiazepines could fail to provide accurate information regarding patient specific medication use. The false positive and false negative rates of the immunoassay were particularly high for clonazepam and lorazepam. Further testing of patient specimens using more accurate methods such as LC-MS/MS is necessary to provide definitive data that can assist in clinical decision making, and potentially protect these patients from untoward effects, morbidity and mortality. PMID- 22484397 TI - Breast augmentation with extra-projected and high-cohesive Dual-Gel Prosthesis 510: a prospective study of 75 consecutive cases for a new method (the Zenith system). AB - BACKGROUND: Extra-projected Natrelle 510 belongs to a new generation of silicone breast implants. A single-surgeon prospective study set out to investigate the device's features, outcomes, and complications, and devise a proper measurement method based on the zenith system. METHODS: From December 2004 to June 2010, 75 subjects (150 implants) were enrolled in four cohorts: primary augmentation (66.7%), primary mastopexy augmentation (17.3%), secondary implant exchange (9.3%), and secondary implant exchange+pexy (6.7%). The system used to select the implant correlated the point of maximal projection (vertex-zenith) and nipple position. The surgical approach included (1) narrow pocket, preferably dual plane; (2) device vertex 1-2.5 cm beneath nipple (zenith range=12 degrees -23 degrees ) related to a nipple-inframammary fold distance of 7-7.5 cm at maximal stretch and a nipple-sternum/lower-pole line distance of 4-5 cm; (3) inframammary fold lowered minimally; (4) vertex at +/-1 cm from the midbreast meridian crossing the nipple; and (5) maximizing the biomechanical effects between soft tissue dynamics, firmer gel pressure, and pectoralis major counterpressure to expand the lower skin (dynamic tension). RESULTS: Mean follow-up was 26.5 months (range=6-72); in 20 subjects; follow-up was over 3 years (average=50 months) with a 90.8% patient satisfaction rate. This rate was lower in patients with preoperative ptosis. There was inframammary preservation with 60% of the implants and modification in 40% (0.80+/-0.45 cm). The overall complication rate per implant was 16.6% and included wound healing/scarring (7%), malrotation (2.6%, only 1% after primary augmentation), rippling (2%), capsular contracture (1.3%), and bottoming-out (0.6%). The revision rate was 6%, of which 3.3% were pocket revisions. Greater skills are required through the learning curve, patient education, case selection, planning using the nipple-vertex relationship (the zenith system), and improved surgical manipulation. Indications and contraindications were analyzed. Cosmetic results were compliant with different breast shapes, and excellent for the breast with poor projection, in thin subjects, and those with low BMI. Ptotic breast should require a larger amount of pexy, 510 did not lift the breast enough. CONCLUSION: Based on vertex-nipple distance, dynamic tension, and skin extensibility, this new approach gives guidelines and methods to perform breast augmentation with extra-projected implants. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22484398 TI - Taxol-oligoarginine conjugates overcome drug resistance in-vitro in human ovarian carcinoma. AB - OBJECTIVE: Multidrug resistance is the major cause of failure of many chemotherapeutic agents. While resistance can arise from several factors, it is often dominated by drug efflux mediated by P-glycoprotein (P-gp), a membrane bound polysubstrate export pump expressed at high levels in resistant cells. While co-administration of pump inhibitors and a drug could suppress efflux, this two-drug strategy has not yet advanced to therapy. We recently demonstrated that the reversible attachment of a guanidinium-rich molecular transporter, polyarginine, to a drug provides a conjugate that overcomes efflux-based resistance in cells and animals. This study is to determine whether this strategy for overcoming resistance is effective against human disease. METHODS: Tumor samples from ovarian cancer patients, both malignant ascites cells and dissociated solid tumor cells, were exposed to Taxol-oligoarginine conjugates designed to release free drug only after cell entry. Cell viability was determined via propidium-iodide uptake by flow cytometry. To analyze bystander effect, toxicity of the drug conjugates was also tested on peripheral blood leucocytes. RESULTS: Human ovarian carcinoma specimens resistant to Taxol in vitro demonstrated increased sensitivity to killing by all Taxol-transporter conjugates tested. These studies also show that the drug conjugates were not significantly more toxic to normal human peripheral blood leukocytes than Taxol. CONCLUSIONS: These studies with human tumor indicate that oligoarginine conjugates of known drugs can be used to overcome the efflux-based resistance to the drug, providing a strategy that could improve the treatment outcomes of patients with efflux-based drug-resistance. PMID- 22484399 TI - Preoperative identification of a suspicious adnexal mass: a systematic review and meta-analysis. AB - OBJECTIVE: To systematically review the existing literature in order to determine the optimal strategy for preoperative identification of the adnexal mass suspicious for ovarian cancer. METHODS: A review of all systematic reviews and guidelines published between 1999 and 2009 was conducted as a first step. After the identification of a 2004 AHRQ systematic review on the topic, searches of MEDLINE for studies published since 2004 was also conducted to update and supplement the evidentiary base. A bivariate, random-effects meta-regression model was used to produce summary estimates of sensitivity and specificity and to plot summary ROC curves with 95% confidence regions. RESULTS: Four meta-analyses and 53 primary studies were included in this review. The diagnostic performance of each technology was compared and contrasted based on the summary data on sensitivity and specificity obtained from the meta-analysis. Results suggest that 3D ultrasonography has both a higher sensitivity and specificity when compared to 2D ultrasound. Established morphological scoring systems also performed with respectable sensitivity and specificity, each with equivalent diagnostic competence. Explicit scoring systems did not perform as well as other diagnostic testing methods. Assessment of an adnexal mass by colour Doppler technology was neither as sensitive nor as specific as simple ultrasonography. Of the three imaging modalities considered, MRI appeared to perform the best, although results were not statistically different from CT. PET did not perform as well as either MRI or CT. The measurement of the CA-125 tumour marker appears to be less reliable than do other available assessment methods. CONCLUSION: The best available evidence was collected and included in this rigorous systematic review and meta-analysis. The abundant evidentiary base provided the context and direction for the diagnosis of early-staged ovarian cancer. PMID- 22484400 TI - Completed versus aborted radical hysterectomy for node-positive stage IB cervical cancer in the modern era of chemoradiation therapy. AB - OBJECTIVE: Debate continues about optimal management of patients with node positive stage I cervical cancer. Our objective was to determine if patient outcomes are affected by radical hysterectomy in the modern era of adjuvant chemoradiation. METHODS: Cervical cancer patients diagnosed from 2000 to 2008 were identified. Demographics, therapy, clinicopathologic data, progression free survival (PFS), overall survival (OS), total radiation exposure, and grade 3-4 complications were analyzed by student t, Mann-Whitney, Fisher's exact, Kaplan Meier, and log rank tests. RESULTS: This single-institution review evaluated forty-one of 334 (13.4%) patients scheduled to undergo radical hysterectomy that had gross nodal disease diagnosed intraoperatively. 15 underwent aborted radical hysterectomy following lymphadenectomy; the remaining 26 underwent radical hysterectomy and lymphadenectomy. Eleven patients undergoing radical hysterectomy underwent whole pelvic radiation therapy (WPRT) while 8 (30.7%) patients underwent WPRT and postoperative vaginal brachytherapy (BT) for local treatment secondary to close margins. All patients undergoing aborted radical hysterectomy underwent WPRT and BT. With mean follow-up of 42.3 months, there were no significant differences in urinary, gastrointestinal, or hematologic complications between groups. When comparing those undergoing radical hysterectomy to aborted radical hysterectomy, there were no significant differences in local recurrence (11.5% vs 26.7%, p=0.39) or distant recurrence (19.2% vs. 33.3%, p=0.45), PFS (74.9 months vs 46.8 months, p=0.106), or OS (91.8 months vs 69.4 months, p=0.886). CONCLUSIONS: Treatment of patients with early stage cervical cancer and nodal metastasis may be tailored intraoperatively. Completion of radical hysterectomy and lymphadenectomy decreases radiation exposure without apparently compromising safety or outcome in the era of adjuvant chemoradiation. PMID- 22484401 TI - High-mobility group protein B1 (HMGB1) is a novel biomarker for human ovarian cancer. AB - BACKGROUND: High mobility group box l (HMGB1), a nuclear and extracellular protein, is implicated in some physiologic and pathologic conditions. In this study, we investigated the expression and function of HMGB1 in ovarian cancer. METHODS: cDNA microarray analysis was performed to compare gene expression profiles of the highly invasive and the low invasive subclones derived from the SKOV3 human ovarian cancer cell line. Immunohistochemistry (IHC) staining was performed to investigate HMGB1 expression in a total of 100 ovarian tissue specimens. In functional assays, effects of HMGB1 knockdown on the biological behavior of ovarian cancer cells were investigated. RESULTS: HMGB1 was overexpressed in the highly invasive subclone compared with the low invasive subclone. High HMGB1 expression was associated with poor clinicopathologic features. Knockdown of HMGB1 expression significantly suppressed ovarian cancer cell proliferation accompanied by decreased cyclin D1 and PCNA expression, and inhibited cell migration and invasion accompanied by decreased MMP2 and MMP9 activities. CONCLUSION: HMGB1 is a newly identified gene overexpressed in ovarian cancer and associated with poor clinicopathologic features. HMGB1 may serve as a new biomarker and a therapeutic target for ovarian cancer in the future. PMID- 22484402 TI - Somatic hypermutation and outcomes of platinum based chemotherapy in patients with high grade serous ovarian cancer. AB - OBJECTIVE: The standard treatment for high grade ovarian serous cancer (HG-OSC) is aggressive cytoreductive surgery followed by platinum based chemotherapy. However, approximately 30% of patients exhibit platinum resistance, and those patients show aggressive clinical courses. Currently, it is difficult to predict which HG-OSC patients will respond to platinum-based chemotherapy. METHODS: We analyzed whole exome sequences for 174 HG-SOC patients using data obtained from The Cancer Genome Atlas (TCGA) data portal regarding platinum response. Patients were categorized as having either hypermutation or hypomutation according to the number of mutations in their sample. RESULTS: HG-SOC showed multiple somatic mutations in individual patients with an average mutated gene number of 61.9. The mean mutation number per patient significantly differed between the platinum sensitive and resistant groups (P<0.001). Patients who were platinum sensitive were more likely to have somatic hypermutation in their cancer cells and multivariate logistic regression analysis revealed that somatic hypermutation was an independent factor for risk estimation of platinum sensitivity (odds ratio [OR]=3.616; P=0.002). In multivariate Cox hazard analysis, we identified that somatic hypermutation, as well as platinum response and surgical outcome, were independent prognostic factors in HG-OSC (overall survival, P=0.012; progression free survival, P=0.036). CONCLUSIONS: Somatic hypermutation was significantly associated with platinum sensitivity and was an independent prognostic factor in HG-OSC patients treated with platinum based chemotherapy. PMID- 22484403 TI - Structure of selenium incorporated in pyrite and mackinawite as determined by XAFS analyses. AB - Selenium has a toxic potential leading to diseases by ingestion and a radiotoxic potential as (79)Se radionuclide if discharged from a high-level nuclear waste repository in deep geological formations into the biosphere. Selenium is often associated with sulfides, such as pyrite, the most important near-surface iron sulfide and constituent of host rocks and bentonite backfills considered for radioactive waste disposal. This study was aimed at investigating the incorporation of Se(2-) and Se(4+) into pyrite and mackinawite to determine the relevance of iron sulfides to Se retention and the type of structural bonding. The syntheses of pyrite and mackinawite occurred via direct precipitation in batches and also produced coatings on natural pyrite in mixed-flow reactor experiments (MFR) under anoxic conditions at Se concentrations in the solutions of up to 10(-3) mol/L. Mineralogical analyses by SEM and XRD reveal the formation of pyrite and mackinawite phases. The average Se(2-) uptake in pyrite in batch experiments amounts to 98.6%. In MFR syntheses, it reaches 99.5%, both suggesting a high potential for retention. XAFS results indicate a substitution of sulfur by selenide during instantaneous precipitation in highly supersaturated solutions only. In selenide-doted mackinawite S(2-) was substituted by Se(2-), resulting in a mackinawite-type compound. S(-) is substituted by Se(-) in selenide-doted pyrite, yielding a FeSSe compound as a slightly distorted pyrite structure. Under slighter supersaturated conditions, XAFS results indicate an incorporation of Se(2-) and Se(4+) predominantly as Se(0). This study shows that a substitution of S by Se in iron sulfides is probable only for highly supersaturated solutions under acidic and anoxic conditions. Under closer equilibrium conditions, Se(0) is expected to be the most stable species. PMID- 22484404 TI - Is the rapid adaptation paradigm too rapid? Implications for face and object processing. AB - Rapid adaptation is an adaptation procedure in which adaptors and test stimuli are presented in rapid succession. The current study tested the validity of this method for early ERP components by investigating the specificity of the adaptation effect on the face-sensitive N170 ERP component across multiple test stimuli. Experiments 1 and 2 showed identical response patterns for house and upright face test stimuli using the same adaptor stimuli. The results were also identical to those reported in a previous study using inverted face test stimuli (Nemrodov and Itier, 2011). In Experiment 3 all possible adaptor-test combinations between upright face, house, chair and car stimuli were used and no interaction between adaptor and test category, expected in the case of test specific adaptation, was found. These results demonstrate that the rapid adaptation paradigm does not produce category-specific adaptation effects around 170-200 ms following test stimulus onset, a necessary condition for the interpretation of adaptation results. These results suggest the rapid categorical adaptation paradigm does not work. PMID- 22484405 TI - Individuated finger control in focal hand dystonia: an fMRI study. AB - OBJECTIVES: To better understand deficient selective motor control in focal hand dystonia by determining changes in striatal activation and connectivity in patients performing individuated finger control. METHODS: Functional imaging with a 3-Tesla magnetic resonance scanner was performed on 18 patients and 17 controls during non-symptom producing tasks requiring right-handed individuated or coupled finger control. A global linear model and psychophysiologic interaction model compared individuated to coupled tasks for patients and controls separately, and the results were submitted to a group analysis. The sensorimotor (posterior) and associative (anterior) parts of the putamen were considered as seed regions for the connectivity analysis. RESULTS: Compared to controls, patients had significant differences in activations and connectivity during individuated compared to coupled tasks: (i) decreased activations in the bilateral postcentral gyri, right associative posterior parietal areas, right cerebellum and left posterior putamen, while activations in the left anterior putamen were not different; (ii) increased connectivity of the left posterior putamen with the left cerebellum and left sensorimotor cortex; and (iii) increased connectivity of the left anterior putamen with bilateral supplementary motor areas, the left premotor cortex, and left cerebellum. INTERPRETATION: Decreased activations in the sensorimotor putamen and cerebellum controlling the affected hand might underlie low levels of surround inhibition during individuated tasks. For identical motor performance in both groups, increased connectivity of sensorimotor and associative striato-cortical circuits in FHD suggests that both affected and unaffected territories of the striatum participate in compensatory processes. PMID- 22484406 TI - Quantitative assessment of a framework for creating anatomical brain networks via global tractography. AB - Interregional connections of the brain measured with diffusion tractography can be used to infer valuable information regarding both brain structure and function. However, different tractography algorithms can generate networks that exhibit different characteristics, resulting in poor reproducibility across studies. Therefore, it is important to benchmark different tractography algorithms to quantitatively assess their performance. Here we systematically evaluated a newly introduced tracking algorithm, global tractography, to derive anatomical brain networks in a fiber phantom, 2 post-mortem macaque brains, and 20 living humans, and compared the results with an established local tracking algorithm. Our results demonstrated that global tractography accurately characterized the phantom network in terms of graph-theoretic measures, and significantly outperformed the local tracking approach. Results in brain tissues (post-mortem macaques and in vivo humans), however, showed that although the performance of global tractography demonstrated a trend of improvement, the results were not vastly different than that of local tractography, possibly resulting from the increased fiber complexity of real tissues. When using macaque tracer-derived connections as the ground truth, we found that both global and local algorithms generated non-random patterns of false negative and false positive connections that were probably related to specific fiber systems and largely independent of the tractography algorithm or tissue type (post-mortem vs. in vivo) used in the current study. Moreover, a close examination of the transcallosal motor connections, reconstructed via either global or local tractography, demonstrated that the lateral transcallosal fibers in humans and macaques did not exhibit the denser homotopic connections found in primate tracer studies, indicating the need for more robust brain mapping techniques based on diffusion MRI data. PMID- 22484407 TI - Optimizing parameter choice for FSL-Brain Extraction Tool (BET) on 3D T1 images in multiple sclerosis. AB - BACKGROUND: Brain atrophy studies often use FSL-BET (Brain Extraction Tool) as the first step of image processing. Default BET does not always give satisfactory results on 3DT1 MR images, which negatively impacts atrophy measurements. Finding the right alternative BET settings can be a difficult and time-consuming task, which can introduce unwanted variability. AIM: To systematically analyze the performance of BET in images of MS patients by varying its parameters and options combinations, and quantitatively comparing its results to a manual gold standard. METHODS: Images from 159 MS patients were selected from different MAGNIMS consortium centers, and 16 different 3DT1 acquisition protocols at 1.5 T or 3T. Before running BET, one of three pre-processing pipelines was applied: (1) no pre processing, (2) removal of neck slices, or (3) additional N3 inhomogeneity correction. Then BET was applied, systematically varying the fractional intensity threshold (the "f" parameter) and with either one of the main BET options ("B" - bias field correction and neck cleanup, "R" - robust brain center estimation, or "S" - eye and optic nerve cleanup) or none. For comparison, intracranial cavity masks were manually created for all image volumes. FSL-FAST (FMRIB's Automated Segmentation Tool) tissue-type segmentation was run on all BET output images and on the image volumes masked with the manual intracranial cavity masks (thus creating the gold-standard tissue masks). The resulting brain tissue masks were quantitatively compared to the gold standard using Dice overlap coefficient (DOC). Normalized brain volumes (NBV) were calculated with SIENAX. NBV values obtained using for SIENAX other BET settings than default were compared to gold standard NBV with the paired t-test. RESULTS: The parameter/preprocessing/options combinations resulted in 20,988 BET runs. The median DOC for default BET (f=0.5, g=0) was 0.913 (range 0.321-0.977) across all 159 native scans. For all acquisition protocols, brain extraction was substantially improved for lower values of "f" than the default value. Using native images, optimum BET performance was observed for f=0.2 with option "B", giving median DOC=0.979 (range 0.867-0.994). Using neck removal before BET, optimum BET performance was observed for f=0.1 with option "B", giving median DOC 0.983 (range 0.844-0.996). Using the above BET-options for SIENAX instead of default, the NBV values obtained from images after neck removal with f=0.1 and option "B" did not differ statistically from NBV values obtained with gold-standard. CONCLUSION: Although default BET performs reasonably well on most 3DT1 images of MS patients, the performance can be improved substantially. The removal of the neck slices, either externally or within BET, has a marked positive effect on the brain extraction quality. BET option "B" with f=0.1 after removal of the neck slices seems to work best for all acquisition protocols. PMID- 22484408 TI - Dynamic connectivity regression: determining state-related changes in brain connectivity. AB - Most statistical analyses of fMRI data assume that the nature, timing and duration of the psychological processes being studied are known. However, often it is hard to specify this information a priori. In this work we introduce a data driven technique for partitioning the experimental time course into distinct temporal intervals with different multivariate functional connectivity patterns between a set of regions of interest (ROIs). The technique, called Dynamic Connectivity Regression (DCR), detects temporal change points in functional connectivity and estimates a graph, or set of relationships between ROIs, for data in the temporal partition that falls between pairs of change points. Hence, DCR allows for estimation of both the time of change in connectivity and the connectivity graph for each partition, without requiring prior knowledge of the nature of the experimental design. Permutation and bootstrapping methods are used to perform inference on the change points. The method is applied to various simulated data sets as well as to an fMRI data set from a study (N=26) of a state anxiety induction using a socially evaluative threat challenge. The results illustrate the method's ability to observe how the networks between different brain regions changed with subjects' emotional state. PMID- 22484409 TI - Teaching an adult brain new tricks: a critical review of evidence for training dependent structural plasticity in humans. AB - A growing number of structural neuroimaging studies have reported significant changes in gray matter density or volume and white matter microstructure in the adult human brain following training. Such reports appear consistent with animal studies of training-dependent structural plasticity showing changes in, for example, dendritic spines. However, given the microscopic nature of these changes in animals and the relatively low spatial resolution of MRI, it is unclear that such changes can be reliably detected in humans. Here, we critically evaluate the robustness of the current evidence in humans, focusing on the specificity, replicability, and the relationship of the reported changes with behavior. We find that limitations of experimental design, statistical methods, and methodological artifacts may underlie many of the reported effects, seriously undermining the evidence for training-dependent structural changes in adult humans. The most robust evidence, showing specificity of structural changes to training, task and brain region, shows changes in anterior hippocampal volume with exercise in elderly participants. We conclude that more compelling evidence and converging data from animal studies is required to substantiate structural changes in the adult human brain with training, especially in the neocortex. PMID- 22484410 TI - NODDI: practical in vivo neurite orientation dispersion and density imaging of the human brain. AB - This paper introduces neurite orientation dispersion and density imaging (NODDI), a practical diffusion MRI technique for estimating the microstructural complexity of dendrites and axons in vivo on clinical MRI scanners. Such indices of neurites relate more directly to and provide more specific markers of brain tissue microstructure than standard indices from diffusion tensor imaging, such as fractional anisotropy (FA). Mapping these indices over the whole brain on clinical scanners presents new opportunities for understanding brain development and disorders. The proposed technique enables such mapping by combining a three compartment tissue model with a two-shell high-angular-resolution diffusion imaging (HARDI) protocol optimized for clinical feasibility. An index of orientation dispersion is defined to characterize angular variation of neurites. We evaluate the method both in simulation and on a live human brain using a clinical 3T scanner. Results demonstrate that NODDI provides sensible neurite density and orientation dispersion estimates, thereby disentangling two key contributing factors to FA and enabling the analysis of each factor individually. We additionally show that while orientation dispersion can be estimated with just a single HARDI shell, neurite density requires at least two shells and can be estimated more accurately with the optimized two-shell protocol than with alternative two-shell protocols. The optimized protocol takes about 30 min to acquire, making it feasible for inclusion in a typical clinical setting. We further show that sampling fewer orientations in each shell can reduce the acquisition time to just 10 min with minimal impact on the accuracy of the estimates. This demonstrates the feasibility of NODDI even for the most time sensitive clinical applications, such as neonatal and dementia imaging. PMID- 22484411 TI - A generalized form of context-dependent psychophysiological interactions (gPPI): a comparison to standard approaches. AB - Functional MRI (fMRI) allows one to study task-related regional responses and task-dependent connectivity analysis using psychophysiological interaction (PPI) methods. The latter affords the additional opportunity to understand how brain regions interact in a task-dependent manner. The current implementation of PPI in Statistical Parametric Mapping (SPM8) is configured primarily to assess connectivity differences between two task conditions, when in practice fMRI tasks frequently employ more than two conditions. Here we evaluate how a generalized form of context-dependent PPI (gPPI; http://www.nitrc.org/projects/gppi), which is configured to automatically accommodate more than two task conditions in the same PPI model by spanning the entire experimental space, compares to the standard implementation in SPM8. These comparisons are made using both simulations and an empirical dataset. In the simulated dataset, we compare the interaction beta estimates to their expected values and model fit using the Akaike information criterion (AIC). We found that interaction beta estimates in gPPI were robust to different simulated data models, were not different from the expected beta value, and had better model fits than when using standard PPI (sPPI) methods. In the empirical dataset, we compare the model fit of the gPPI approach to sPPI. We found that the gPPI approach improved model fit compared to sPPI. There were several regions that became non-significant with gPPI. These regions all showed significantly better model fits with gPPI. Also, there were several regions where task-dependent connectivity was only detected using gPPI methods, also with improved model fit. Regions that were detected with all methods had more similar model fits. These results suggest that gPPI may have greater sensitivity and specificity than standard implementation in SPM. This notion is tempered slightly as there is no gold standard; however, data simulations with a known outcome support our conclusions about gPPI. In sum, the generalized form of context-dependent PPI approach has increased flexibility of statistical modeling, and potentially improves model fit, specificity to true negative findings, and sensitivity to true positive findings. PMID- 22484412 TI - Mutation analysis of the ATP7B gene in a new group of Wilson's disease patients: contribution to diagnosis. AB - Wilson's disease (WD), an autosomal recessive disorder of copper transport with a broad range of genotypic and phenotypic characteristics, results from mutations in the ATP7B gene. Herein we report the results of mutation analysis of the ATP7B gene in a group of 118 Wilson disease families (236 chromosomes) prevalently of Italian origin. Using DNA sequencing we identified 83 disease-causing mutations. Eleven were novel, while twenty one already described mutations were identified in new populations in this study. In particular, mutation analysis of 13 families of Romanian origin showed a high prevalence of the p.H1069Q mutation (50%). Detection of new mutations in the ATP7B gene in new populations increases our capability of molecular analysis that is essential for early diagnosis and treatment of WD. PMID- 22484413 TI - The effect of trimetazidine on cardiac function in diabetic patients with idiopathic dilated cardiomyopathy. AB - AIMS: Trimetazidine is an anti-ischemic metabolic agent which improves myocardial glucose utilization. Whether it may improve cardiac function and physical tolerance in diabetic patients with idiopathic dilated cardiomyopathy is still not confirmed. In this study we have investigated the effectiveness of trimetazidine in these patients. MAIN METHODS: Volunteers with diabetes and idiopathic dilated cardiomyopathy were recruited for participation in this study. Patients were randomized into two groups. One group received trimetazidine (20mg, t.i.d.) for 6 months (n=40), while another group received a placebo during the same period (n=40). All patients received an echocardiographic examination, 6 minute walk test and an inflammation biochemical analysis (C reactive protein) at baseline and after 6 months of treatment. KEY FINDINGS: No significant adverse events or changes in clinical or biochemical parameters were detected through the study. After 6 months, TMZ-treated patients had a significant improvement in systolic function as compared with control patients associated with an increased ratio of E/A. C reactive protein concentrations remained stable throughout the study in trimetazidine group at baseline and at the 6 month on follow up. In comparison, it increased significantly in the control group at the 6-month follow up. The NT-pro BNP levels did not change in the control group, whereas they significantly decreased in the trimetazidine group. The physical activity tolerance level improved in the trimetazidine group compared to the control group. SIGNIFICANCE: Trimetazidine treatment was associated with a significant improvement of cardiac function and physical tolerance. Results also suggested that the inflammatory response was decreased in trimetazidine group as compared with control patients. PMID- 22484414 TI - Urinary bisphenol A concentrations and implantation failure among women undergoing in vitro fertilization. AB - BACKGROUND: Bisphenol A (BPA) is a synthetic chemical widely used in the production of polycarbonate plastic and epoxy resins found in numerous consumer products. In experimental animals, BPA increases embryo implantation failure and reduces litter size. OBJECTIVE: We evaluated the association of urinary BPA concentrations with implantation failure among women undergoing in vitro fertilization (IVF). METHODS: We used online solid phase extraction-high performance liquid chromatography-isotope dilution tandem mass spectrometry to measure urinary BPA concentrations in 137 women in a prospective cohort study among women undergoing IVF at the Massachusetts General Hospital Fertility Center in Boston, Massachusetts. We used logistic regression to evaluate the association of cycle-specific urinary BPA concentrations with implantation failure, accounting for correlation among multiple IVF cycles in the same woman using generalized estimating equations. Implantation failure was defined as a negative serum beta-human chorionic gonadotropin test (beta-hCG < 6 IU/L) 17 days after egg retrieval. RESULTS: Among 137 women undergoing 180 IVF cycles, urinary BPA concentrations had a geometric mean (SD) of 1.53 (2.22) ug/L. Overall, 42% (n = 75) of the IVF cycles resulted in implantation failure. In adjusted models, there was an increased odds of implantation failure with higher quartiles of urinary BPA concentrations {odds ratio (OR) 1.02 [95% confidence interval (CI): 0.35, 2.95}, 1.60 (95% CI: 0.70, 3.78), and 2.11 (95% CI: 0.84, 5.31) for quartiles 2, 3, and 4, respectively, compared with the lowest quartile (p-trend = 0.06). CONCLUSION: There was a positive linear dose-response association between BPA urinary concentrations and implantation failure. PMID- 22484415 TI - Posterior cruciate ligament tears: functional and postoperative rehabilitation. AB - PURPOSE: Historically, the results of posterior cruciate ligament (PCL) reconstructions are not as favourable as anterior cruciate ligament (ACL) reconstructions, and it is well recognized that nonoperative treatment and postoperative rehabilitation for PCL injuries must be altered compared to those for ACL injuries. The purpose of this article was to review current peer-reviewed PCL rehabilitation programmes and to recommend a nonoperative and postoperative programme based on basic science and published outcomes studies. METHODS: To discover the current practices being used to rehabilitate PCL injuries, we conducted a search of PubMed with the terms "posterior cruciate ligament" and "rehabilitation" from 1983 to 2011. All articles within the reference lists of these articles were also examined to determine their rehabilitation programmes. RESULTS: A review of peer-reviewed PCL rehabilitation protocols revealed that the treatment of PCL injuries depends on the timing and degree of the injury. Rehabilitation should focus on progressive weight bearing, preventing posterior tibial subluxation and strengthening of the quadriceps muscles. General principles of proper PCL rehabilitation, whether nonoperative or postoperative, should include early immobilization (when necessary), prone passive range of motion to prevent placing undue stress on grafts or healing tissue, and progression of rehabilitation based on biomechanical, clinical, and basic science research. CONCLUSIONS: An optimal set of guidelines for the nonoperative or postoperative management of PCL injuries has not yet been defined or agreed upon. Based on the current review study, suggested guidelines are proposed. LEVEL OF EVIDENCE: IV. PMID- 22484416 TI - Reoperative characteristics after microfracture of knee cartilage lesions in 454 patients. AB - PURPOSE: There is only limited information on those patients who fail following microfracture treatment at the knee joint. Evaluation was made of factors associated with treatment failure and clinical outcome assessment among this collective. METHODS: The study included a total of 560 patients who had previously undergone microfracture for the treatment of symptomatic knee joint cartilage lesions. For the remainder of this study, inclusion criteria were patients that underwent reoperation at the initially operated knee joint (index knee) due to symptoms related to the primary site of microfracture intervention (failure patients) with a minimum postoperative follow-up of 2 years. The remaining cohort of patients served as internal control (non-failure patients). Chart reviews were performed to identify patient and defect characteristics. Patients were evaluated for postoperative Lysholm knee scores, Tegner activity scale, as well as preoperative and postoperative numeric analogue scales (NAS) for function and pain (10 = highest possible function, no pain). RESULTS: A total of 454/560 (81.1 %) subjects were completely evaluated. Overall, 123/454 patients (26.9 %) (age at operation 43.9 +/- 14.1 years, 56 female, BMI 25.8 +/- 3.6, 30 smokers, 61.1 +/- 68.3 month symptom duration, postoperative follow-up 5.0 +/- 2.1) met the inclusion criteria. The postoperative Lysholm score was 63.0 +/- 24.6 and the Tegner score was 4.0; NAS function improved from 2.8 +/- 1.8 to 4.8 +/- 2.2 (P < 0.001), and NAS pain improved from 3.2 +/- 2.1 to 5.0 +/- 2.4 (P < 0.001). Exclusively, the overall defect size/knee joint was smaller (P = 0.006), postoperative follow-up was longer (P = 0.002), and existense of previous surgery (77.2 vs. 51.6 %, P < 0.001) was more frequent in failure subjects when comparing to non-failure patients (n = 331). The overall clinical outcome among failure subjects was significantly worse when comparing to non-failure subjects. Regression analysis identified that lower preoperative NAS values, being a smoker, and patello-femoral lesions were associated with a higher probability of reoperation. CONCLUSION: Within the collective presented here, microfracturing was associated with a high frequency of reoperation. Clinical outcome is worse when compared with that of patients without reoperation. Specific parameters can be identified that increase the eventuality of failure following microfracture treatment. LEVEL OF EVIDENCE: IV. PMID- 22484417 TI - The controversy of patellar resurfacing in total knee arthroplasty: Ibisne in medio tutissimus? AB - Early arthroplasty designs were associated with a high level of anterior knee pain as they failed to cater for the patello-femoral joint. Patellar resurfacing was heralded as the saviour safeguarding patient satisfaction and success but opinion on its necessity has since deeply divided the scientific community and has become synonymous to topics of religion or politics. Opponents of resurfacing contend that the native patella provides better patellar tracking, improved clinical function, and avoids implant-related complications, whilst proponents argue that patients have less pain, are overall more satisfied, and avert the need for secondary resurfacing. The question remains whether complications associated with patellar resurfacing including those arising from future component revision outweigh the somewhat increased incidence of anterior knee pain recorded in unresurfaced patients. The current scientific literature, which is often affected by methodological limitations and observer bias, remains confusing as it provides evidence in support of both sides of the argument, whilst blinded satisfaction studies comparing resurfaced and non-resurfaced knees generally reveal equivalent results. Even national arthroplasty register data show wide variations in the proportion of patellar resurfacing between countries that cannot be explained by cultural differences alone. Advocates who always resurface or never resurface indiscriminately expose the patella to a random choice. Selective resurfacing offers a compromise by providing a decision algorithm based on a propensity for improved clinical success, whilst avoiding potential complications associated with unnecessary resurfacing. Evidence regarding the validity of selection criteria, however, is missing, and the decision when to resurface is often based on intuitive reasoning. Our lack of understanding why, irrespective of pre-operative symptoms and patellar resurfacing, some patients may suffer pain following TKA and others may not have so far stifled our efforts to make the strategy of selective resurfacing succeed. We should hence devote our efforts in defining predictive criteria and indicators that will enable us to reliably identify those individuals who might benefit from a resurfacing procedure. Level of evidence V. PMID- 22484418 TI - The accuracy of the extramedullary and intramedullary femoral alignment system in total knee arthroplasty for varus osteoarthritic knee. AB - PURPOSE: The intramedullary (IM) femoral alignment system does not alway guarantee accuracy of the component position in the total knee arthroplasty (TKA). In some cases, the extramedullary (EM) femoral alignment system in total knee arthroplasty (TKA) is a useful alternative surgical option to adjust femoral component alignment. In the EM technique, accuracy of the femoral head center location is mandatory. The purpose of this prospective randomized study was to compare the alignment after TKA using two different femoral alignment systems. METHODS: From January 2009 to December 2009, 91 patients (106 knees) with osteoarthritis underwent TKA. The IM femoral alignment system was used in 50 TKAs, and the EM system was used in 56 TKAs. We measured the coronal, sagittal alignment of the femoral component, and overall alignment from full-length standing. Anteroposterior radiographs were taken 1 year after surgery. RESULTS: The overall limb alignment was 0.2 degrees +/- 1.9 degrees varus in the EM group and 1.1 degrees +/- 1.9 degrees valgus in the IM group (p = 0.001). The coronal alignment of the femoral component was 90.0 degrees +/- 1.1 degrees in the EM group and 90.3 degrees +/- 1.2 degrees in the IM group, not statistically different (n.s.). The sagittal alignment of the femoral component was 2.3 degrees +/- 1.7 degrees in the EM group and 2.5 degrees +/- 1.0 degrees in the IM group (n.s.). Clinically acceptable overall limb alignment was achieved in 91.1 % of EM group and 84.0 % of IM group (n.s.). CONCLUSION: The present study suggests that by applying our EM technique that uses a newly designed mechanical axis marker system, the alignment of the femoral component and overall limb alignment is reliable and at least as accurate as the standard IM technique. LEVEL OF EVIDENCE: I. PMID- 22484419 TI - Revision total knee arthroplasty with varus-valgus constrained prosthesis versus posterior stabilized prosthesis. AB - PURPOSE: The aims of this retrospective study were to provide the basis for the choice of prosthesis in revision total knee arthroplasty (TKA) and to evaluate the outcome with varus-valgus constrained prosthesis compared with posterior stabilized (PS) prosthesis. METHODS: One hundred and five patients (121 knees) received revision TKA; of which thirty-seven patients (42 knees) received PS prosthesis and sixty-eight patients (79 knees) received varus-valgus constrained prosthesis. The mean follow-up duration was 64.8 +/- 31.5 months and 63.2 +/- 28.1 months in the PS and varus-valgus constrained groups, respectively. The criterion of prosthesis choice was a subjective laxity assessed by the surgeon intraoperatively. A multivariate analysis was performed to evaluate the preoperative factors in the choice of the prosthesis. RESULTS: The grade of femoral bone defect was the only factor that affected the choice of prosthesis. Clinical results improved significantly in both groups after surgery. There were no significant differences in clinical results between the two groups. Complication rates were 9.5 % in the PS group and 10.1 % in the varus-valgus constrained group, and the Kaplan-Meier survivorship analysis revealed 8-year component survival rates of 83.1 and 93.0 % in the PS and varus-valgus constrained groups, respectively. CONCLUSIONS: Femoral bone defect is an important factor to be considered in the choice of prosthesis for revision TKA. The varus-valgus constrained prosthesis showed an outcome similar to that of the PS prosthesis. For clinical relevance, varus-valgus constrained prosthesis is recommended in revision TKA when the PS prosthesis seems unsuitable for the management of instability. LEVEL OF EVIDENCE: III. PMID- 22484420 TI - Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies. AB - Spliceosome mutations represent a new generation of acquired genetic alterations that affect both myeloid and lymphoid malignancies. A substantial proportion of patients with myelodysplastic syndromes (MDSs) or chronic lymphocytic leukemia (CLL) harbor such mutations, which are often missense in type. Genotype-phenotype associations have been demonstrated for one of these mutations, SF3B1, with ring sideroblasts in MDS and 11q22 deletions in CLL. Spliceosome mutations might result in defective spliceosome assembly, deregulated global mRNA splicing, nuclear-cytoplasm export and altered expression of multiple genes. Such mutations are infrequent in other lymphomas, which instead display a separate group of novel mutations involving genes whose products are believed to affect histone acetylation and methylation and chromatin structure (for example, EZH2 and MLL2). On the other hand, some mutations (for example, NOTCH1) occur in both CLL and other immature and mature lymphoid malignancies. In the current review, we discuss potential mechanisms of cell transformation associated with spliceosome mutations, touch upon the increasing evidence regarding the clonal involvement of hematopoietic stem cells in some cases of otherwise mature lymphoid disorders and summarize recent information on recently described mutations in lymphomas. PMID- 22484421 TI - Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia. AB - Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has achieved an 80% cure rate as a result of a risk-adapted therapy largely based on minimal residual disease (MRD) monitoring. However, relapse is still the most frequent adverse event, occurring mainly in the patients with intermediate MRD levels (intermediate risk, IR), emphasizing the need for new prognostic markers. We analyzed the prognostic impact of cytokine receptor-like factor 2 (CRLF2) over expression and P2RY8-CRLF2 fusion in 464 BCP-ALL patients (not affected by Down syndrome and BCR-ABL negative) enrolled in the AIEOP-BFM ALL2000 study in Italy. In 22/464 (4.7%) samples, RQ-PCR showed CRLF2 over-expression (>=20 times higher than the overall median). P2RY8-CRLF2 fusion was detected in 22/365 (6%) cases, with 10/22 cases also showing CRLF2 over-expression. P2RY8-CRLF2 fusion was the most relevant prognostic factor independent of CRLF2 over-expression with a threefold increase in risk of relapse. Significantly, the cumulative incidence of relapse of the P2RY8-CRLF2 + patients in the IR group was high (61.1% +/- 12.9 vs 17.6% +/- 2.6, P<0.0001), similar to high-risk patients in AIEOP-BFM ALL2000 study. These results were confirmed in a cohort of patients treated in Germany. In conclusion, P2RY8-CRLF2 identifies a subset of BCP-ALL patients currently stratified as IR that could be considered for treatment intensification. PMID- 22484422 TI - Clinical utility and implications of asparaginase antibodies in acute lymphoblastic leukemia. AB - Hypersensitivity to asparaginase is common, but the differential diagnosis can be challenging and the diagnostic utility of antibody tests is unclear. We studied allergic reactions and serum antibodies to E. coli asparaginase (Elspar) in 410 children treated on St. Jude Total XV protocol for acute lymphoblastic leukemia. Of 169 patients (41.2%) with clinical allergy, 147 (87.0%) were positive for anti Elspar antibody. Of 241 patients without allergy, 89 (36.9%) had detectable antibody. Allergies (P=0.0002) and antibodies (P=6.6 * 10(-6)) were higher among patients treated on the low-risk arm than among those treated on the standard/high-risk arm. Among those positive for antibody, the antibody titers were higher in those who developed allergy than in those who did not (P<1 * 10( 15)). Antibody measures at week 7 of continuation therapy had a sensitivity of 87 88% and a specificity of 68-69% for predicting or confirming clinical reactions. The level of antibodies was inversely associated with serum asparaginase activity (P=7.0 * 10(-6)). High antibody levels were associated with a lower risk of osteonecrosis (odds ratio=0.83; 95% confidence interval, 0.78-0.89; P=0.007). Antibodies were related to clinical allergy and to low systemic exposure to asparaginase, leading to lower risk of some adverse effects of therapy. PMID- 22484423 TI - p53 modulates homologous recombination at I-SceI-induced double-strand breaks through cell-cycle regulation. AB - Inhibition of homologous recombination (HR) is believed to be a transactivation independent function of p53 that protects from genetic instability. Misrepair by HR can lead to genetic alterations such as translocations, duplications, insertions and loss of heterozygosity, which all bear the risk of driving oncogenic transformation. Regulation of HR by wild-type p53 (wtp53) should prevent these genomic rearrangements. Mutation of p53 is a frequent event during carcinogenesis. In particular, dominant-negative mutants inhibiting wtp53 expressed from the unperturbed allel can drive oncogenic transformation by disrupting the p53-dependent anticancer barrier. Here, we asked whether the hot spot mutants R175H and R273H relax HR control in p53-proficient cells. Utilizing an I-SceI-based reporter assay, we observed a moderate (1.5 * ) stimulation of HR upon expression of the mutant proteins in p53-proficient CV-1, but not in p53 deficient H1299 cells. Importantly, the stimulatory effect was exactly paralleled by an increase in the number of HR competent S- and G2-phase cells, which can well explain the enhanced recombination frequencies. Furthermore, the impact on HR exerted by the transactivation domain double-mutant L22Q/W23S and mutant R273P, both of which were reported to regulate HR independently of G1-arrest execution, is also exactly mirrored by cell-cycle behavior. These results are in contrast to previous concepts stating that the transactivation-independent impact of p53 on HR is a general phenomenon valid for replication-associated and also for directly induced double-strand break. Our data strongly suggest that the latter is largely mediated by cell-cycle regulation, a classical transactivation dependent function of p53. PMID- 22484424 TI - eIF4F suppression in breast cancer affects maintenance and progression. AB - Levels of eukaryotic initiation factor 4E (eIF4E) are frequently elevated in human cancers and in some instances have been associated with poor prognosis and outcome. Here we utilize transgenic and allograft breast cancer models to demonstrate that increased mammalian target of rapamycin (mTOR) signalling can be a significant contributor to breast cancer progression in vivo. Suppressing mTOR activity, as well as levels and activity of the downstream translation regulators, eIF4E and eIF4A, delayed breast cancer progression, onset of associated pulmonary metastasis in vivo and breast cancer cell invasion and migration in vitro. Translation of vascular endothelial growth factor (VEGF), matrix metallopeptidase 9 (MMP9) and cyclin D1 mRNAs, which encode products associated with the metastatic phenotype, is inhibited upon eIF4E suppression. Our results indicate that the mTOR/eIF4F axis is an important contributor to tumor maintenance and progression programs in breast cancer. Targeting this pathway may be of therapeutic benefit. PMID- 22484425 TI - MYCN and ALKF1174L are sufficient to drive neuroblastoma development from neural crest progenitor cells. AB - Neuroblastoma is an embryonal tumor with a heterogeneous clinical course. The tumor is presumed to be derived from the neural crest, but the cells of origin remain to be determined. To date, few recurrent genetic changes contributing to neuroblastoma formation, such as amplification of the MYCN oncogene and activating mutations of the ALK oncogene, have been identified. The possibility to model neuroblastoma in mice allows investigation of the cell of origin hypothesis in further detail. Here we present the evidence that murine neural crest progenitor cells can give rise to neuroblastoma upon transformation with MYCN or ALK(F1174L). For this purpose we used JoMa1, a multipotent neural crest progenitor cell line, which is kept in a viable and undifferentiated state by a tamoxifen-activated c-Myc transgene (c-MycER(T)). Expression of MYCN or ALK(F1174L), one of the oncogenic ALK variants identified in primary neuroblastomas, enabled these cells to grow independently of c-MycER(T) activity in vitro and caused formation of neuroblastoma-like tumors in vivo in contrast to parental JoMa1 cells and JoMa1 cells-expressing TrkA or GFP. Tumorigenicity was enhanced upon serial transplantation of tumor-derived cells, and tumor cells remained susceptible to the MYC-inhibitor, NBT-272, indicating that cell growth depended on functional MYCN. Our findings support neural crest progenitor cells as the precursor cells of neuroblastoma, and indicate that neuroblastomas arise as their malignant progeny. PMID- 22484426 TI - Rapid generation of human B-cell lymphomas via combined expression of Myc and Bcl2 and their use as a preclinical model for biological therapies. AB - Although numerous mouse models of B-cell malignancy have been developed via the enforced expression of defined oncogenic lesions, the feasibility of generating lineage-defined human B-cell malignancies using mice reconstituted with modified human hematopoietic stem cells (HSCs) remains unclear. In fact, whether human cells can be transformed as readily as murine cells by simple oncogene combinations is a subject of considerable debate. Here, we describe the development of humanized mouse model of MYC/BCL2-driven 'double-hit' lymphoma. By engrafting human HSCs transduced with the oncogene combination into immunodeficient mice, we generate a fatal B malignancy with complete penetrance. This humanized-MYC/BCL2-model (hMB) accurately recapitulates the histopathological and clinical aspects of steroid-, chemotherapy- and rituximab resistant human 'double-hit' lymphomas that involve the MYC and BCL2 loci. Notably, this model can serve as a platform for the evaluation of antibody-based therapeutics. As a proof of principle, we used this model to show that the anti CD52 antibody alemtuzumab effectively eliminates lymphoma cells from the spleen, liver and peripheral blood, but not from the brain. The hMB humanized mouse model underscores the synergy of MYC and BCL2 in 'double-hit' lymphomas in human patients. Additionally, our findings highlight the utility of humanized mouse models in interrogating therapeutic approaches, particularly human-specific monoclonal antibodies. PMID- 22484427 TI - Activation of p53 following ionizing radiation, but not other stressors, is dependent on the proline-rich domain (PRD). AB - The tumor suppressor protein, p53 is one of the most important cellular defences against malignant transformation. In response to cellular stressors p53 can induce apoptosis, cell cycle arrest or senescence as well as aid in DNA repair. Which p53 function is required for tumor suppression is unclear. The proline-rich domain (PRD) of p53 (residues 58-101) has been reported to be essential for the induction of apoptosis. To determine the importance of the PRD in tumor suppression in vivo we previously generated a mouse containing a 33-amino-acid deletion (residues 55-88) in p53 (mDeltapro). We showed that mDeltapro mice are protected from T-cell tumors but not late-onset B-cell tumors. Here, we characterize the functionality of the PRD and show that it is important for mediating the p53 response to DNA damage induced by gamma-radiation, but not the p53-mediated responses to Ha-Ras expression or oxidative stress. We conclude that the PRD is important for receiving incoming activating signals. Failure of PRD mutants to respond to the activating signaling produced by DNA damage leads to impaired downstream signaling, accumulation of mutations, which potentially leads to late-onset tumors. PMID- 22484428 TI - WWOX-mediated apoptosis in A549 cells mainly involves the mitochondrial pathway. AB - The human WWOX gene, known as WW domain-containing oxidoreductase, is located on 16q23.3-24.1, a chromosome region that spans the common fragile site, FRA16D. Abnormal transcripts or even loss of expression are frequently found in a number of cancer cell types, including breast, ovarian, prostate and lung cancer cells. It has therefore been proposed that the WWOX gene encodes a candidate tumor suppressor, possibly a pro-apoptotic protein. However, the mechanism behind this is not entirely clear. In the present study, we examined the pro-apoptotic action of WWOX using transient expression in A549 cells. We observed that the ectopic expression of WWOX caused apoptosis in A549 cells. We further observed procaspase 3 and procaspase-9 activation and the release of cytochrome C from the mitochondria in A549 cells transfected with pcDNA3.0-WWOX. These data indicate that WWOX induces apoptosis in A549 cells via the mitochondrial pathway. PMID- 22484430 TI - CXCL12: role in neuroinflammation. AB - CXCL12, also known as SDF-1 (stromal cell derived factor-1) is a small protein that belongs to the chemokine family, whose members have a crucial role in directing cell migration. CXCL12 has an essential role in neural and vascular development, hematopoiesis and in immunity. It acts through two receptors, CXCR4 and CXCR7. While the former is a classic G protein-coupled transmembrane chemokine receptor, the latter primarily function as a scavenger of CXCL12. CXCL12 has been considered as a standard pro-inflammatory molecule for a long time, as it attracts leukocytes to inflammatory sites and contributes to their activation. However, recent findings indicate that this chemokine has the opposite role in neuroinflammation. In this review, basic data about molecular and functional properties of CXCL12 are presented, while its role in CNS autoimmunity is addressed in details. PMID- 22484429 TI - Somatic problems and self-injurious behaviour 18 years after teenage-onset anorexia nervosa. AB - The aim of this study was to study long-term outcome of physical health and self injurious behaviour (SIB) in anorexia nervosa (AN). Fifty-one adolescent-onset AN cases, originally recruited after community screening, and 51 matched controls (COMP) were interviewed regarding somatic problems and SIB and physically examined 18 years after AN onset, at mean age 32 years. Six individuals had an eating disorder (ED). No one had died. The AN group weighed less than the COMP group. The frequency of somatic problems did not differ between groups. Dental enamel lesions and shorter than expected stature occurred only in the AN group. Dysdiadochokinesis was overrepresented in the AN group and age of AN onset was lower among those with the neurological deficit. Severe SIB occurred only in the AN group, predominantly during adolescence. To conclude, somatic problems were common in both groups. Most individuals in the AN group had recovered from their ED, but weight revealed a persistent restricted eating behaviour. PMID- 22484431 TI - [Smoking paradox: smoking or not smoking]. PMID- 22484433 TI - Drowning associated pneumonia. PMID- 22484435 TI - King LTS-D use by EMT-intermediates in a rural prehospital setting without intubation availability. PMID- 22484436 TI - The Los Angeles public access defibrillator (PAD) program: ten years after. AB - BACKGROUND: Public access automated external defibrillator (PAD) programs have been shown to be successful in several municipalities. This study sought to determine the usage of and survival rate from a large, urban PAD program in the first 10 years since its implementation. METHODS: This was a prospective, longitudinal, observational study from January 2002-2012 conducted in Los Angeles, California, a city with a population of 3.8 million. An incremental rollout resulted in a current total of 1300 automated external defibrillators (AEDs) in place in city-owned buildings and other public places, including all 3 area airports, golf-courses, and public pools. All instances where an AED was applied were included in the study. RESULTS: There were 59 incidents of cardiac arrest with a public access AED applied, of which 42 (71%) occurred at an airport. 51 (86%) of the patients were male, with a median age of 64 years (interquartile range, 56.5 to 70 years). A shockable rhythm was detected and shocks were applied in 39 (66%) patients, with 30 (77%) of these patients achieving a return of spontaneous circulation (ROSC). Of those patients who received shock(s) by public access AED, 27 (69%) survived to hospital discharge. The youngest survivors were a 25 year old male and a 34 year old female. CONCLUSION: While the majority of PAD cases occurred at an airport, there were also survivors from other public locations. AEDs deployed as part of a large PAD program resulted in a very high survival rate for patients with cardiac arrest. PMID- 22484437 TI - Clinical significance of combined assessment of the maximum standardized uptake value of F-18 FDG PET with nodal size in the diagnosis of cervical lymph node metastasis of oral squamous cell carcinoma. AB - RATIONALE AND OBJECTIVES: This study aimed to elucidate the diagnostic accuracy of F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) for nodal involvement in oral squamous cell carcinoma (OSCC), and to reveal clinically useful factors to distinguish between true-positive (TP) and false-positive (FP) nodes. MATERIALS AND METHODS: Thirty-eight patients with primary OSCC who underwent neck dissection were assessed. The diagnostic accuracy of F-18 FDG PET/CT was evaluated, and then compared with that of CT/ultrasonography (US). Furthermore, the association of the maximum standardized uptake value (SUVmax) and nodal size with the histopathologic findings was examined. RESULTS: Sensitivity and specificity using F-18 FDG PET/CT were 77.1% and 97.3%, and those using CT/US were 72.9% and 98.9%, respectively. The SUVmax of TP nodes was significantly higher than that of FP nodes. Nodes with SUVmax >4.5 were pathologically confirmed as metastasis. Nodes with SUVmax <=4.5 were further discriminated between TP and FP nodes by using the long axis diameters or the ratios of long to short axis diameter as clinical parameters. Positive correlation between the SUVmax and the short-axis diameter was found in TP nodes. The AUC obtained from the ROC curves of the SUVmax alone (AUC, 0.804) was improved by combination with the long-axis diameter (AUC, 0.867) or the short axis diameter (AUC, 0.846), although no significant difference was found. CONCLUSIONS: These results indicated that F-18 FDG PET/CT was potentially useful in diagnosing preoperative nodal state. Furthermore, combined assessment of SUVmax with nodal size could be significant in the identification of metastatic lymph nodes in OSCC patients. PMID- 22484438 TI - X-rays can harm you and others. PMID- 22484439 TI - Cloning, expression, and characterization of a cellobiose dehydrogenase from Thielavia terrestris induced under cellulose growth conditions. AB - The enzyme cellobiose dehydrogenase (CDH) is of considerable interest, not only for its biotechnological applications, but also its potential biological role in lignocellulosic biomass breakdown. The enzyme catalyzes the oxidation of cellobiose and other cellodextrins, utilizing a variety of one- and two-electron acceptors, although the electron acceptor employed in nature is still unknown. In this study we show that a CDH is present in the secretome of the thermophilic ascomycete Thielavia terrestris when grown with cellulose, along with a mixture of cellulases and hemicellulases capable of breaking down lignocellulosic biomass. We report the cloning of this T. terrestris CDH gene (cbdA), its recombinant expression in Aspergillus oryzae, and purification and characterization of the T. terrestris CDH protein (TtCDH). The TtCDH shows spectral properties and enzyme activity similar to other characterized CDH enzymes. Substrate specificity was determined for a number of carbohydrate electron donors in the presence of the two-electron acceptor 2,6-dichlorophenol indophenol. The TtCDH also shows dramatic synergy with Thermoascus aurantiacus glycoside hydrolase family 61A protein in the presence of a beta-glucosidase for the cleavage of cellulose. PMID- 22484440 TI - Autophagic adapter protein NBR1 is localized in Lewy bodies and glial cytoplasmic inclusions and is involved in aggregate formation in alpha-synucleinopathy. AB - Macroautophagy is a dynamic process whereby cytoplasmic components are initially sequestered within autophagosomes. Recent studies have shown that the autophagosome membrane can selectively recognize ubiquitinated proteins and organelles through interaction with adapter proteins such as p62 and NBR1. Both proteins are structurally similar at the amino acid level, and bind with ubiquitin and ubiquitinated proteins. Although p62 is incorporated into a wide spectrum of pathological inclusions in various neurodegenerative diseases, abnormalities of NBR1 have not been reported in these diseases. Our immunohistochemical examination revealed that the vast majority of Lewy bodies (LBs) in Parkinson's disease and dementia with LBs (DLB) as well as of glial cytoplasmic inclusions in multiple system atrophy (MSA) were positive for NBR1. Neuronal and glial inclusions in tauopathies and TAR DNA-binding protein of 43 kDa proteinopathies were rarely immunolabeled, or were unstained. Using cultured cells bearing LB-like inclusions, formation of alpha-synuclein aggregates was repressed in cells with NBR1 knockdown. Immunoblot analysis showed that the level of NBR1 was significantly increased by 2.5-fold in MSA, but not in DLB. These findings suggest that NBR1 is involved in the formation of cytoplasmic inclusions in alpha-synucleinopathy. PMID- 22484441 TI - Gap junction pathology in multiple sclerosis lesions and normal-appearing white matter. AB - Oligodendrocyte gap junctions (GJs) are vital for central nervous system myelination, but their involvement in multiple sclerosis (MS) pathology remains unknown. The aim of this study was to examine alterations of oligodendrocyte and related astrocyte GJs in MS lesions and normal-appearing white matter (NAWM). Post-mortem brain samples from 9 MS and 11 age-matched non-MS control patients were studied. Tissue sections that included both chronic active and inactive lesions were characterized neuropathologically with Luxol Fast Blue staining and immunostaining for myelin oligodendrocyte glycoprotein (MOG) and the microglial marker Iba1. We analyzed the expression of Cx32 and Cx47 in oligodendrocytes and of Cx43, the major astrocytic partner in oligodendrocyte-astrocyte (O/A) GJs by quantitative immunoblot and real-time PCR. Formation of GJ plaques was quantified by immunohistochemistry. Compared to control brains, both Cx32 and Cx47 GJ plaques and protein levels were reduced in and around MS lesions, while Cx43 was increased as part of astrogliosis. In the NAWM, Cx32 was significantly reduced along myelinated fibers whereas Cx47 showed increased expression mainly in oligodendrocyte precursor cells (OPCs). However, OPCs showed only limited connectivity to astrocytes. Cx43 showed modestly increased levels in MS NAWM compared to controls, while GJ plaque counts were unchanged. Our findings indicate that oligodendrocyte GJs are affected not only in chronic MS lesions but also in NAWM, where disruption of Cx32 GJs in myelinated fibers may impair myelin structure and function. Moreover, limited O/A GJ connectivity of recruited OPCs in the setting of persistent inflammation and astrogliosis may prevent differentiation and remyelination. PMID- 22484442 TI - Effects of alcohol on the solubility and structure of native and disulfide modified bovine serum albumin. AB - Differential precipitation of human plasma by ethanol is one of the most important processes for purifying therapeutic proteins, including human serum albumin. Better understanding of the effects of ethanol on the structure and stability of proteins is critical for effective and safe application of ethanol induced protein precipitation. Here, we examined the effects of ethanol on the structure and solubility of bovine serum albumin (BSA) and SH-modified BSA. Ethanol caused BSA denaturation in a bimodal fashion, i.e., reduction of alpha helix at low concentration and subsequent induction of the alpha-helical structure at higher concentration. In contrast, the solubility of BSA decreased monotonically. The secondary structure of SH-modified BSA was different from that of native BSA. Ethanol resulted in enhanced secondary structures of SH-modified BSA and decreased solubility monotonically. These results suggest the favorable interaction of ethanol with hydrophobic residues, leading to protein denaturation, but the unfavorable interaction with charged residues, leading to a reduction of protein solubility. PMID- 22484443 TI - Concentration dependence of chaperone-like activities of alpha-crystallin, alphaB crystallin and proline. AB - Chaperone-like activities of alpha-crystallin, alphaB-crystallin and proline were studied using a test system based on aggregation of UV-irradiated glycogen phosphorylase b (Phb) from rabbit skeletal muscle. The biphasic character of the dependence of the initial rate of aggregation (v(agg)) of UV-irradiated Phb on the concentration of alpha-crystallin or alphaB-crystallin is indicative of the existence of two types of chaperone-protein substrate complexes differing significantly in affinity between the components of the complex. The dependence of v(agg) on the proline concentration is sigmoid (Hill coefficient is equal to 1.6) suggesting that the positive cooperative interactions between the proline molecules bound on the surface of the protein particles occur. When studying the combined suppressive action of alpha-crystallin and proline on aggregation of UV irradiated Phb, a slight antagonism between proline used at a fixed concentration (0.15M) and alpha-crystallin was observed. At higher concentration of proline (0.5M) each chaperone acts independent of one another. PMID- 22484444 TI - Formation of chitin-based nanomaterials using a chitin-binding peptide selected by phage-display. AB - Targeting polymers with peptides is an efficient strategy to functionalize biomaterials. Phage display technology is one of the most powerful techniques for selecting specific peptides for a wide variety of targets. A method to select a chitin-binding peptide from a 12-mer random peptide library was successfully performed against chitin immobilized in wells of microtiter plates. The synthetic chitin binding peptide (ChiBP) could bind to chitin beads and disrupt their structure. This selected peptide was successfully used to immobilize alkaline phosphatase on chitin. In addition, the peptide could induce colloidal chitin in water to form a chitin coat on the surface of plastic tubes. Scanning electron microscopy (SEM) revealed that the peptide could induce colloidal chitin and chitohexaose to form networks when the temperature was raised to 42 degrees C. PMID- 22484445 TI - Antibacterial cotton fabrics treated with core-shell nanoparticles. AB - Multifinishing treatment of cotton fabrics was carried out using core-shell nanoparticles that consists of silver nanoparticles (Ag(0)) as core and chitosan O-methoxy polyethylene glycol (CTS-O-MPEG) as shell. The synthesized (Ag(0)-CTS-O MPEG) core-shell nanoparticle was applied to cotton fabrics using the conventional pad-dry-cure method. The finished fabrics were examined for their morphological features and surface characteristics by making use of scanning electron microscope (SEM-EDX), which reveals the well dispersion of (Ag(0)-CTS-O MPEG) core-shell nanoparticles on cotton fabrics. Factors affecting the treatment such as core shell nanoparticles, citric acid (CA) concentration as well as curing temperature were studied. The treated fabrics, at optimum condition of 1% core shell nanoparticles, 5% citric acid, drying at 80 degrees C, curing at 160 degrees C for 2 min, showed excellent antibacterial activity against Gram negative Escherichia coli (E. coli) and Gram-positive bacteria Staphylococcus aureus (S. aureus), even after 20 washing cycles in addition to an enhancement in crease recovery angles (CRA) along with a slight improvement in tensile strength (TS). PMID- 22484446 TI - Gastroprotective activities of a polysaccharide from the fruiting bodies of Pleurotus ostreatus in rats. AB - In this study, a water-soluble polysaccharide (POPw) was successfully purified and identified from the fruiting bodies of Pleurotus ostreatus, with a molecular weight of 2.3*10(4)Da. POPw contained 97.1% total sugar, 0.3% uronic acid and 0.2% protein. Gas chromatography (GC) analysis suggested that POPw was composed of Glc (52.3%), Gal (25.8%), Man (10.0%), Rha (6.1%), and Ara (5.2%). Animal experiments showed that oral administration with POPw significantly inhibited acetic acid-induced gastric lesions in rats, accompanied with a significant increase in mucus synthesis and the prostaglandin production. In addition, POPw could significantly increase the level of glutathione (GSH) and the activity of superoxide dismutase (SOD), as well as decreasing the content of thiobarbituric acid-reactive substances (TBARS) in acetic acid-treated rats with gastric ulcer. These results suggested that the gastroprotective effects of POPw on mice ulcer models can be attributed to its ameliorating effect on oxidative damage and reinforcing effect of gastric mucosal resistance. PMID- 22484447 TI - Protective effects of astragalosides on dexamethasone and Abeta25-35 induced learning and memory impairments due to decrease amyloid precursor protein expression in 12-month male rats. AB - Alzheimer's disease (AD) is a chronic neurodegenerative disorder of the elderly characterized by learning and memory impairment. Stress level glucocorticoids (GCs) and beta-amyloid (Abeta) peptide deposition are found to be correlated with dementia progression in patients with AD. The astragalosides (AST) was extracted from traditional Chinese herb Astragalus membranaceous. In this study, 12 months male rats were treated with Abeta(25-35) (10 MUg/rat, hippocampal CA1 injection) and dexamethasone (DEX, 1.5mg/kg, ig) and AST (8, 16 and 32 mg/kg, ig) or ginsenoside Rg1 (Rg1, 5 mg/kg, ig) for 14 days. We investigated the protective effect of AST against DEX+Abeta(25-35) injury in rats and its mechanisms of action. Our results indicate that DEX+Abeta(25-35) can induce learning and memory impairments and increase APP and Abeta(1-40) expression. AST (16, 32 mg/kg) or Rg1 (5mg/kg) treatment significantly improve learning and memory, down-regulate the mRNA levels of APP and beta-secretase, decrease expression of APP and Abeta(1 40) in hippocampus. The results indicated that DEX might increase hippocampal vulnerability to Abeta(25-35) and highlight the potential neuronal protection of AST. PMID- 22484449 TI - Apoptosis, necrosis and autophagy are influenced by metabolic energy sources in cultured rat spermatocytes. AB - Apoptosis, necrosis and autophagy are mechanistically related processes that control tissue homeostasis and cell survival. In the testis, germ cell death is important for controlling sperm output, but it is unknown whether or not germ cells can switch from apoptosis to necrosis, as has been reported in other tissues. Furthermore, autophagy has not been reported in spermatogenesis. Spermatocytes (meiotic cells) and spermatids (haploid cells) use lactate rather than glucose as their primary substrate for producing ATP. The metabolism of glucose, but not lactate, reduces ATP levels and increases intracellular [H(+)] and [Ca(2+)], both of which are associated with apoptosis and/or necrosis in somatic cells. In this work, we evaluated whether different energy sources, such as lactate or glucose, can influence spermatocyte death type and/or survival in primary cultures. Spermatocytes cultured for 12 h without an energy source died by necrosis, while spermatocytes cultured with 5 mM glucose showed a significant increase in apoptosis, as evidenced by caspase activity, TUNEL assay and phosphatidylserine exposure. Apoptosis was not observed in spermatocytes cultured with 5 mM lactate or deoxyglucose. Autophagy markers, such as LC3-II and autophagosomes, were detected after 12 h of culture, regardless the culture conditions. These results suggest that the availability of glucose and/or lactate affect the type of death or the survival of primary spermatocytes, where glucose can induce apoptosis, while lactate is a protective factor. PMID- 22484448 TI - Axonal transport and neurodegenerative disease: can we see the elephant? AB - Although it is well established that axonal transport defects are part of the initiation or progression of some neurodegenerative diseases, the precise role of these defects in disease development is poorly understood. Thus, in this article, rather than enumerate the already well-reviewed evidence that there are transport deficits in disease, I will focus on a discussion of two crucial and unanswered questions about the possible role of axonal transport defects in HD and AD. (1) Are alterations in axonal transport caused by changes in the normal function of proteins mutated or altered in HD and AD and/or do such alterations in transport occur as a result of the formation of toxic aggregates of peptides or proteins? (2) Do alterations in axonal transport contribute to the causes of HD and AD or are they early, or late, secondary consequences of other cellular defects caused by disease-induction? PMID- 22484450 TI - BmEts upregulates promoter activity of lebocin in Bombyx mori. AB - The Ets family protein BmEts is assumed to be implicated in determination of diapause in the embryogenesis of Bombyx mori. In this study, we found that expression of BmEts was increased in the fat body and other tissues of the 5th instar larvae in response to Escherichia coli injection. Cotransfection experiments using a silkworm cell line revealed that overexpression of BmEts significantly elevated the activity of lebocin promoter but not of cecropin B1, cecropin D, attacin, and moricin promoters. Activation of the lebocin promoter by BmEts was dependent on at least two kappaB elements and the most proximal GGAA/T motif located on the 5'-upstream region. BmEts further synergistically enhanced E. coli or BmRelish1-d2 (active form)-stimulated lebocin promoter activation. Two kappaB elements were also found to be involved in promoter activation by BmRelish1-d2 and in synergistic promoter activation by BmEts and BmRelish1-d2 in the silkworm cells. Specific binding of recombinant BmEts to the proximal kappaB element and the most proximal GGAA/T motif and interaction between BmEts and BmRelish1 were also observed. To our knowledge, this is the first report of an Ets family protein directly regulating immune-related genes in invertebrates. PMID- 22484451 TI - Garlic provides protection to mice heart against isoproterenol-induced oxidative damage: role of nitric oxide. AB - Garlic has been widely recognized as a cardioprotective agent. However, the molecular mechanism of its cardioprotective effects is not well established. Here we hypothesized that aqueous garlic homogenate may mediate cardioprotection via nitric oxide (NO). Mice were fed with saline and aqueous garlic homogenate (250 and 500 mgkg(-1)day(-1) orally) for 30 days. In another set of experiment, mice were pre-treated with saline, aqueous garlic homogenate (AGH) (250 mgkg(-1)day( 1) for 30 days), and AGH (30 days) along with L-NAME (20 mgkg(-1)day(-1) i.p. for last 7 days) before inducing acute myocardial infarction by isoproterenol (s.c. injection of isoproterenol 150 mgkg(-1)day(-1) for 2 days) and sacrificed after 48 h. Dose dependent increase in serum NO level was observed after garlic 250 and 500 mgkg(-1) dose feeding. While no change in serum SGPT and SGOT level, a significant decrease in serum LDH level was observed after garlic feeding. Garlic induced NO formation was further confirmed in human aortic endothelial cells (HAEC). Administration of isoproterenol caused a significant decrease in endogenous antioxidants i.e., myocardial catalase, GSH and GPx activity, and mitochondrial enzyme activities like citrate synthase and beta hydroxyacyl CoA dehydrogenase. All those deleterious cardiac changes induced by isoproterenol were significantly attenuated by garlic homogenate. However this beneficial effect of garlic was blunted when garlic was administered with L-NAME, a nonspecific inhibitor of nitric oxide synthase (NOS). Further, a significant increase in myocardial TBARS and decrease in total antioxidant activity was observed in L-NAME treated group compared to isoproterenol treated group. Administration of L-NAME in mice from control group lowered serum and cardiac NO levels without any change of oxidative stress parameters. In conclusion, our study provides novel evidence that garlic homogenate is protective in myocardial infarction via NO-signaling pathway in mice. PMID- 22484452 TI - Species-specific real-time PCR cell number quantification of the bloom-forming cyanobacterium Planktothrix agardhii. AB - A species-specific method to detect and quantify Planktothrix agardhii was developed by combining the SYBR Green I real-time polymerase chain reaction technique with a simplified DNA extraction procedure for standard curve preparation. Newly designed PCR primers were used to amplify a specific fragment within the rpoC1 gene. Since this gene exists in single copy in the genome, it allows the direct achievement of cell concentrations. The cell concentration determined by real-time PCR showed a linear correlation with the cell concentration determined from direct microscopic counts. The detection limit for cell quantification of the method was 8 cells MUL(-1), corresponding to 32 cells per reaction. Furthermore, the real-time qPCR method described in this study allowed a successful quantification of P. agardhii from environmental water samples, showing that this protocol is an accurate and economic tool for a rapid absolute quantification of the potentially toxic cyanobacterium P. agardhii. PMID- 22484453 TI - A novel and simple method for culturing pericytes from mouse brain. AB - Pericytes play critical roles in the development, maturation and remodeling of blood vessels, and in the central nervous system (CNS), evidence suggests that pericytes also regulate blood flow and form an integral part of the blood-brain barrier. The study of this important cell type has been hampered by the lack of any pericyte-specific marker and by the difficulty of culturing pericytes in adequate numbers to high purity. Here we present a novel yet simple approach to isolate and culture large numbers of pericytes from the mouse CNS that nevertheless leads to very pure pericyte cultures. In our method, vascular cells obtained from adult mice brains are cultured initially under conditions optimized for endothelial cells, but after two passages switched to a medium optimized for pericyte growth. After growing the cells for 1-2 additional passages we obtained a largely homogeneous population of cells that expressed the pericyte markers NG2, PDGFbeta-receptor, and CD146, but were negative for markers of endothelial cells (CD31), microglia (Mac-1) and astrocytes (GFAP). Under these conditions, pericytes could be grown to high passage number, and were maintained highly pure and largely undifferentiated, as determined by antigen expression profile and low levels of alpha-SMA expression, a marker of pericyte differentiation. Furthermore, switching the cells from pericyte medium into DMEM containing 10% FBS promoted alpha-SMA expression, demonstrating that high passage pericytes could still differentiate. Thus, we provide an alternative approach to the culture of CNS pericytes that is easy to establish and provides large numbers of highly pure pericytes for extended periods of time. This system should provide others working in the pericyte field with a useful additional tool to study the behavior of this fascinating cell type. PMID- 22484454 TI - Clinicopathological features of human brainstem gliomas. AB - We describe the clinicopathological features of 25 brainstem gliomas (BSGs). Twenty BSGs located in the pons and were all in children. Four BSGs located in the medulla oblongata were in 2 children and 2 adults. One (in a child) was located in the midbrain. Radiological findings on MR images were low-intensity on T1 weighted images and high-intensity on T2 weighted images. Mean survival when pontine glioma was treated by radiotherapy and/or use of temozolomide was 14 months, although 4 patients (3 cervicomedullary types and one focal type arising from midbrain) are alive. Follow up was from 5 months to 6 years. Histopathological features of 10 cases of the diffuse type were: 4 grade II astrocytomas, 4 grade III astrocytomas, and 2 glioblastomas. MIB-1 index was from 0.8 to 38 %. P53 was positive for 80 % of 15 tumors and there were no negative results. MGMT was positive in 60 % of 15 tumors and negative in 12.4 %. IDH1 was negative in 61.6 %. There was no positive result for IDH1 in this study. Thus, our histopathological results were indicative of high p53 immunoreactivity and no IDH1 immunoreactivity related to secondary malignant change. PMID- 22484455 TI - FLASH assembly of TALENs for high-throughput genome editing. AB - Engineered transcription activator-like effector nucleases (TALENs) have shown promise as facile and broadly applicable genome editing tools. However, no publicly available high-throughput method for constructing TALENs has been published, and large-scale assessments of the success rate and targeting range of the technology remain lacking. Here we describe the fast ligation-based automatable solid-phase high-throughput (FLASH) system, a rapid and cost effective method for large-scale assembly of TALENs. We tested 48 FLASH-assembled TALEN pairs in a human cell-based EGFP reporter system and found that all 48 possessed efficient gene-modification activities. We also used FLASH to assemble TALENs for 96 endogenous human genes implicated in cancer and/or epigenetic regulation and found that 84 pairs were able to efficiently introduce targeted alterations. Our results establish the robustness of TALEN technology and demonstrate that FLASH facilitates high-throughput genome editing at a scale not currently possible with other genome modification technologies. PMID- 22484456 TI - Locomotor activity assay in zebrafish larvae: influence of age, strain and ethanol. AB - Several characteristics warrant the zebrafish a refining animal model for toxicity testing in rodents, thereby contributing to the 3R principles (Replacement, Reduction, and Refinement) in animal testing, e.g. its small size, ease of obtaining a high number of progeny, external fertilization, transparency and rapid development of the embryo, and a basic understanding of its gene function and physiology. In this context we explored the motor activity pattern of zebrafish larvae, using a 96-well microtiter plate and a video-tracking system. Effects of induced light and darkness on locomotion of zebrafish larvae of different wild-type strains and ages (AB and TL, 5, 6 and 7 dpf; n=25/group) were studied. Locomotion was also measured in zebrafish larvae after exposure to different concentrations of ethanol (0; 0.5; 1; 2 and 4%) (AB and TL strain, 6 dpf; n=19/group). Zebrafish larvae showed a relatively high swimming activity in darkness when compared to the activity in light. Small differences were found between wild-type strains and/or age. Ethanol exposure resulted in hyperactivity (0.5-2%) and in hypo-activity (4%). In addition, the limitations and/or relevance of the parameters distance moved, duration of movements and velocity are exemplified and discussed. Together, the results support the suggestion that zebrafish may act as an animal refining alternative for toxicity testing in rodents provided internal and external environmental stimuli are controlled. As such, light, age and strain differences must be taken into account. PMID- 22484457 TI - Cryoglobulinemia (review). AB - Cryoglobulins are immunoglobulins that precipitate at low temperatures and redissolve upon rewarming. Cryoglobulinemia refers to the presence of circulating cryoglobulins in serum, and generally leads to a systemic inflammatory syndrome characterized by fatigue, arthralgia, purpura, neuropathy and glomerulonephritis. The disease mainly involves small to medium-sized blood vessels and causes vasculitis due to cryoglobulin-containing immune complexes. Cryoglobulinemia is classified into three types (I, II and III) on the basis of immunoglobulin composition. Predisposing conditions include lymphoproliferative disease, collagen disease and hepatitis C virus (HCV) infection. The diagnosis of cryoglobulinemic syndrome is predominantly based on the laboratory demonstration of serum cryoglobulins. Treatment is often directed towards the underlying disease state. For patients with chronic HCV infection, anti-viral therapy is indicated. Intense immunosuppressive or immunomodulatory therapy, including steroids, plasmapheresis and cytotoxic agents, is reserved for organ-threatening or recalcitrant disease. In this review, we discuss the clinical characteristics of the three types of cryoglobulinemia. PMID- 22484458 TI - An ORS-ICP-MS method for monitoring trace levels of cobalt and chromium in whole blood samples from hip arthroplasty patients with metal-on-metal prostheses. AB - OBJECTIVE: To develop a rapid and reliable method, using an octopole reaction system (ORS) ICP-MS, capable of monitoring trace levels of Co and Cr in whole blood samples from hip arthroplasty patients with metal-on-metal prostheses. DESIGN AND METHOD: Whole blood is diluted 10-fold with an alkaline diluent and analyzed using an Agilent 7500 CE ORS-ICP-MS. RESULTS: Limit of quantification of 0.03 MUg/L Co and 0.20 MUg/L Cr in patient samples. <6% covariance obtained for quality control materials analyzed over 10 runs. CONCLUSION: This method is capable of monitoring trace levels of Co and Cr in diluted whole blood samples with a vial to vial run time of approximately 2 min. Results are comparable to those obtained using high resolution (HR) ICP-MS with sample digestion. PMID- 22484459 TI - Role of mitochondria in nonalcoholic fatty liver disease--from origin to propagation. AB - OBJECTIVES: Mitochondria play a major role in cell energy-generating processes and integrate several signalling pathways to control cellular life and death. DESIGN AND METHODS: Several liver diseases are characterized by mitochondrial alterations which are directly or indirectly dependent on the activation of intracellular stress cascades or receptor-mediated pathways. This article examines the role of mitochondrial dysfunction in critical initiating or propagating events in fatty liver infiltration and nonalcoholic fatty liver disease (NAFLD). Genetic variants and the role of drug-induced toxicity have been considered. RESULTS: Key alterations of mitochondrial physiology associated with hepatocyte fatty changes are described. The value of novel non-invasive diagnostic methods to detect mitochondrial metabolic alterations is also discussed. CONCLUSIONS: Mitochondrial metabolic remodeling is a predominant factor in the appearance and perpetuation of hepatocyte fat accumulation. Non invasive techniques to identify mitochondrial dysfunction and proper mitochondria protection are two necessary clinical steps for an efficient management of NAFLD. PMID- 22484460 TI - Palmitate enhances the differentiation of mouse embryonic stem cells towards white adipocyte lineages. AB - The number of adipocyte progenitors is determined early in foetal and neonatal development in a process which may be altered by gender and excess nutrient intake, and which in turn determines fat mass in adulthood and the risk of developing obesity. Here we investigate the hypothesis that excess nutrients, in this case the long chain fatty acid palmitate, can program differentiating stem cells towards white fat lineages. The experiments were performed on mouse embryonic stem cells in chemically defined media (CDM) supplemented with bone morphogenetic protein 4 (BMP4) and all trans-retinoic acid (RA). Subsequent treatment for 21 days with palmitate not only promoted the expression of adipocyte markers and monolocular lipid deposition as observed by RT/QPCR and immunocytochemistry, but also stimulated a considerable enrichment in adipocytes as measured by flow cytometry and a lipolytic response to catecholamines. Palmitate increased protein levels of adiponectin that is preferentially expressed in subcutaneous fat, while inhibiting IGFBP2 and IGFBP3 that are associated with visceral fat. In keeping with this finding, palmitate also increased expression of the subcutaneous markers Shox2 and Twist1 and oestrogenising enzymes. Collectively, these results suggest that palmitate induces differentiation towards subcutaneous fat and that this could occur through its oestrogenising effects on the preadipocyte, suggesting a role for palmitate in programming fat development towards a metabolically favourable profile. PMID- 22484461 TI - PKR plays a positive role in osteoblast differentiation by regulating GSK-3beta activity through a beta-catenin-independent pathway. AB - Double-stranded RNA-dependent protein kinase (PKR) is involved in various cellular functions. We previously reported that PKR regulates osteoblast differentiation, but the specific mechanisms by which this occurs remain unclear. In this study, we investigated the role of PKR in Glycogen synthase kinase 3beta (GSK-3beta) regulation of osteoblast differentiation. Lithium chloride (LiCl), a GSK-3beta inhibitor, increased GSK-3beta phosphorylation in MC3T3-E1 and MG-63 cells. LiCl also inhibited Runx2 and expression of its regulated genes, causing inhibition of Alkaline phosphatase activity and mineralization. LiCl injection to the calvaria in mice suppressed bone formation. Further, GSK-3beta phosphorylation was increased in osteoblasts, by Akt-independent mechanisms, in which PKR was constitutively inactivated. A PKR inhibitor, 2-aminopurine, also induced GSK-3beta phosphorylation in MC3T3-E1 and MG-63 cells. Further, Runx2 and its regulated genes were inhibited in PKR-inactivated osteoblasts, and differentiation was suppressed through a beta-catenin-independent pathway. PKR positively regulates the differentiation of osteoblasts by mediating GSK-3beta activity through a beta-catenin-independent pathway. PMID- 22484462 TI - Exposure to secondhand smoke outside of a bar and a restaurant and tobacco exposure biomarkers in nonsmokers. AB - BACKGROUND: With an increase in indoor smoking bans, many smokers smoke outside establishments and near their entrances, which has become a public health concern. OBJECTIVES: We characterized the exposure of nonsmokers to secondhand smoke (SHS) outside a restaurant and bar in Athens, Georgia, where indoor smoking is banned, using salivary cotinine and urinary 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanol (NNAL). METHODS: In a crossover study, we assigned 28 participants to outdoor patios of a restaurant and a bar and an open-air site with no smokers on three weekend days; participants visited each site once and stayed for 3 hr. We collected saliva and urine samples immediately before and after the visits (postexposure) and on the following morning and analyzed samples for cotinine and total NNAL, respectively. Regression models were fitted and changes in biomarkers were contrasted between locations. RESULTS: Postexposure and preexposure geometric mean salivary cotinine concentrations differed by 0.115 ng/mL [95% confidence interval (CI): 0.105, 0.126)] and by 0.030 ng/mL (95% CI: 0.028, 0.031) for bar and restaurant visits, respectively. There were no significant post- and preexposure differences in cotinine levels after control site visits, and changes after bar and restaurant site visits were significantly different from changes after control site visits (p < 0.001). Results comparing next-day and preexposure salivary cotinine levels were similar. Next-day creatinine-corrected urinary NNAL concentrations also were higher than preexposure levels following bar and restaurant visits [1.858 pg/mg creatinine higher (95% CI: 0.897, 3.758) and 0.615 pg/mg creatinine higher (95% CI: 0.210, 1.761), respectively], and were significantly different from changes after the control visits (p = 0.005). CONCLUSION: Salivary cotinine and urinary NNAL increased significantly in nonsmokers after outdoor SHS exposure. Our findings indicate that such exposures may increase risks of health effects associated with tobacco carcinogens. PMID- 22484463 TI - An inverted blood-brain barrier model that permits interactions between glia and inflammatory stimuli. AB - The blood-brain barrier (BBB) is increasingly being recognized as a site of special scientific importance. Numerous models of the BBB have been constructed over the past years with increasingly mechanistic studies of fundamental questions of cell biology and neuroimmunology. However, there has been a limiting factor of not being able to perform real-time studies of BBB function utilizing 3D models. Equally, real-time models have been limited mainly to 2D models comprised solely of endothelial cells (ECs). To measure changes in the electrical resistance across a BBB model, when adding inflammatory or stem cells which will interact with co-cultured glial cells has, to date, been beyond the capabilities of models. We have cultured an inverted BBB model with ECs on electrodes which are on the lower surface of xCELLigence Cell Invasion Migration plates. Glial cells were cultured in the basal well with foot processes extending through the filters to make contact with the ECs. SIV-infected macrophages decreased electrical resistance of the EC monolayer when added to the "parenchymal" face of the model. We present a novel inverted blood-brain barrier model that allow real time analyses of endothelial cell adhesion during modeled neuroinflammation. PMID- 22484464 TI - Theranostic applications of nanoparticles in cancer. AB - Nanoparticles are the moieties that have undergone the most investigation in recent years for biomedical applications. They are applied in the field of oncology in the same way as in other branches of biomedical nanotechnology. Regarding cancer, nanoparticles, and especially magnetic nanoparticles, are studied for diagnosis, drug delivery, gene delivery, bioseparation, hyperthermia, phototherapy, chemotherapy, imaging mechanisms, among other uses. Different techniques are used to prepare multifunctional nanoparticles and modify nanoparticle surfaces required for different applications. This review focuses on the basic theranostic approach, the different materials used in theranostics, theranostic applications and future directions based on recent developments in these areas. PMID- 22484465 TI - Voltage-gated sodium channel activity promotes prostate cancer metastasis in vivo. AB - Epigenetic upregulation of voltage-gated sodium channels (VGSCs) has been reported in a number of carcinoma cell lines and tissues. Furthermore, a large body of experimental evidence suggested that functional VGSC expression enhances various in vitro cell behaviours, such as directional motility, that would be involved in the metastatic cascade. However, it is not known if VGSC activity promotes metastasis in vivo. Here, using the Copenhagen rat model of prostate cancer and blocking VGSC activity in primary tumours with tetrodotoxin, we show (1) that the number of lung metastasis is reduced by >40% and (2) that lifespan is significantly improved. PMID- 22484466 TI - Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones. AB - Development of resistance to endocrine therapy is a clinical issue in estrogen receptor (ER)-positive breast cancer. Here we show that persistent activation of AKT/mTOR signaling is crucial to the acquisition of letrozole resistance in cell clones generated from MCF-7/AROM-1 aromatase-expressing breast cancer cells after prolonged letrozole exposure. ERalpha plays a marginal role in this context. As a proof of concept, the association between PI3K/AKT/mTOR signaling and insensitivity to endocrine therapies was confirmed in breast cancer patients who developed early letrozole resistance in neoadjuvant setting. In addition our results suggest that, regardless of the mechanism mediating the activation of AKT/mTOR pathway, either RAD001 or NVP-BEZ235 treatment may represent a promising strategy to overcome acquired resistance to letrozole in breast cancers dependent on AKT/mTOR signaling. PMID- 22484468 TI - Oxidative stress, DNA damage and repair in carcinogenesis: have we established a connection? AB - The production of a plethora of reactive oxygen and nitrogen species in the cell and tissues as the result of endogenous or exogenous mechanisms and interaction of our cells with the environment define the so called 'oxidative load'. The final balance between the oxidatively-induced stress and the various cellular defense mechanisms draw the picture on the landscape of oxidative injury and biological consequences. In this Special Issue, I have compiled a synthesis of concise reviews by leading experts in their fields. The articles focus on the current status and advances in the various pathways leading to the production of high oxidative stress, DNA damage and its processing in human cells and tissues. Significant mechanistic insights are offered as well as connections with biological and clinical significance. PMID- 22484467 TI - HPV DNA, E6*I-mRNA expression and p16INK4A immunohistochemistry in head and neck cancer - how valid is p16INK4A as surrogate marker? AB - It has been proposed that p16(INK4A) qualifies as a surrogate marker for viral oncogene activity in head and neck cancer (HNSCC). By analyzing 78 HNSCC we sought to validate the accuracy of p16(INK4A) as a reliable marker of active HPV infections in HNSCC. To this end we determined HPV DNA (HPVD) and E6*I mRNA (HPVR) expression status and correlated these results with p16(INK4A) staining. In tonsillar SCC 12/20 were HPVD+ and 12/12 of these showed active HPV infections whereas in non-tonsillar SCC 10/58 were HPVD+ and 5/10 showed active HPV infections. Thus, we prove about 8% of non-tonsillar SCC to be also correlated with HPV-associated carcinogenesis. Strikingly, 3/14 (21.4%) of tonsillar and non tonsillar HPVD+/HPVR+ cases did not show p16(INK4A) overexpression and these cases would have been missed when applying initial p16(INK4A) staining only. However, in 13 cases negative for HPV, DNA p16(INK4A) was overexpressed. In conclusion, our data confirm tonsillar SCC to be predominantly but not only associated with active HPV infections. Furthermore, our data show that p16(INK4A) overexpression is not evident in a subgroup of HNSCC with active HPV infection. Definitive HPV data should therefore be utilized in diagnostics and treatment modalities of HPV positive and HPV negative HNSCC patients, resulting in a paradigm shift regarding these obviously different tumor entities. PMID- 22484469 TI - Potential use of nucleic acid-based agents in the sensitization of nasopharyngeal carcinoma to radiotherapy. AB - Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer. The 2-year survival rate of patients with stage III or IV disease is only about 50%. Due to its high radiosensitivity, radiotherapy is the standard treatment for early-stage of NPC. However, the radioresistance observed in some patients can cause distant metastases and local recurrence after radiotherapy. Special emphasis has been given to the discovery of effective radiosensitizers. Oncogenic proteins encoded by EBV genomes may serve as part of targeted radiosensitization, such as NF kB mediated expression of latent membrane protein-1. We here review the major nucleic acid-based options currently used in cancer therapeutic approaches and the selected candidate genes that can be targeted for NPC radiosensitization. PMID- 22484470 TI - Genistein inhibits the stemness properties of prostate cancer cells through targeting Hedgehog-Gli1 pathway. AB - Cancer stem cells (CSCs) are involved in tumorigenesis and progression of prostate cancer (PCa). Conventional anticancer therapeutics failed to eradicate CSCs, which may eventually lead to the disease relapse and metastasis. Therefore, targeting prostate CSCs may be an ideal strategy to cure PCa. Genistein is a major isoflavone constituent of soybeans and soy products, which has been shown to exhibit potent anticancer effect on many cancers. We have previously reported that genistein can inhibit PCa cell invasion by reversing epithelial to mesenchymal transition, suggesting that genistein may be effective against metastatic PCa. In addition, we have recently demonstrated that PCa tumorsphere cells (TCs) possess CSC properties. Here, we found that tumorsphere formation and colony formation of Pca cells were noticeably suppressed in the presence of genistein. Pretreatment of PCa TCs with genistein also suppressed tumorigenicity in vivo. Additionally, genistein treatment inhibited tumor growth of PCa TCs. Further studies showed that genistein treatment not only led to the down regulation of PCa CSC markers CD44 in vitro and in vivo, but also inhibited Hedgehog-Gli1 pathway, which may contribute to the anti-CSC effect of genistein in PCa TCs. Therefore, our findings demonstrated that genistein may be a dietary phytochemical with potential to target prostate CSCs. PMID- 22484471 TI - Iodine-129, iodine-127 and caesium-137 in the environment: soils from Germany and Chile. AB - Soil profiles from Bavaria in southern Germany and from Chile were analysed for (129)I by accelerator mass spectrometry (AMS), for (127)I by inductively coupled plasma mass spectrometry (ICP-MS), and for (137)Cs by gamma-spectrometry. The mean deposition density of (137)Cs in soils from Bavaria was (41*1.5(+/-1)) kBq m(-2) (geometric mean and geometric standard deviation), originating mostly from the Chernobyl fall-out. The deposition density of (129)I in these soils was (109*1.5(+/-1)) mBq m(-2). The dominant sources of (129)I in Bavaria are, however, the reprocessing plants La Hague and Sellafield and not the Chernobyl fall-out. The (129)I/(127)I isotopic ratios of the Bavarian soils were between 10(-7) and 10(-10), i.e. 10(2)-10(5) times higher than the ratios observed for the samples from Chile. The (129)I integral deposition densities in Chile, Easter Island and Antarctica were between 0.3 mBq m(-2) and 2 mBq m(-2). In these soils, the observed (129)I/(127)I ratios were about 10(-12). The soils from Chile allow the determination of the (129)I fall-out from the atmospheric nuclear weapons explosions undisturbed from contaminations due to releases from reprocessing plants. An upper limit of the integral (129)I deposition density of the atmospheric nuclear weapons explosions on the Southern Hemisphere (27 degrees S) is about 1 mBq m(-2). Finally, the dependence of the migration behaviour of (137)Cs, (127)I and of (129)I on the soil properties is discussed. It turns out that there is a distinctly different behaviour of (127)I, (129)I, and (137)Cs in the soils exhibiting different sorption mechanisms for old and recent iodine as well as for (137)Cs. PMID- 22484472 TI - Vertical distribution and inventories of (239+240)Pu and mercury in Sagua la Grande estuary, Cuba. AB - The vertical activity distribution and inventories of (239+240)Pu profile and Hg were determined in Sagua la Grande estuary, Cuba. The shape of the (239+240)Pu profile in the core column resembled very closely the history of atmospheric nuclear weapons' testing, and the maximum deposition in 1963 was recorded in the sediment core history. The (239+240)Pu activity concentrations in the surface layer sediments varied from 0.163 to 0.611 mBq g(-1). The inventory of (239+240)Pu was 42 +/- 5.6 Bq m(-2), a value close to that expected from direct global fallout. Using the (239+240)Pu as a chronomarker the mass sedimentation rate in the area for the last 60 years was calculated, reaching values of 0.173 g cm(-2) y(-1). The mercury profile reflects the history of anthropogenic pollution in the estuary and perfectly describes the operation of the mercury-cell chlor alkali plant, for production of NaOH, which began operations in 1980. The inventory of Hg was 2.42 +/- 0.19 MUg cm(-2). These results contribute to the scarce regional database for pollutants and anthropogenic radionuclides in the Caribbean marine environment, particularly in relation to (239+240)Pu. PMID- 22484473 TI - Effects of caffeine on renal and pulmonary function in preterm newborn lambs. AB - INTRODUCTION: Caffeine administration is associated with a reduction in bronchopulmonary dysplasia, assisted ventilation, patent ductus arteriosus (DA) and cerebral palsy in preterm infants, but the mechanisms are unknown. Our aim was to determine the effects of acute caffeine administration on renal and pulmonary function in preterm lambs. METHODS: Lambs were delivered by caesarean section at ~126 days of gestation and ventilated with a tidal volume of 5 ml/kg, 60 breaths/min and 5 cmH(2)O positive end-expiratory pressure. After 30 minutes, lambs received 40 mg/kg caffeine i.v (n=7) or saline (controls; n=6) over 30 minutes and were ventilated for 2 hours. RESULTS: Arterial caffeine concentrations reached 35.9 +/- 7.8 mg/l. Urine output was significantly higher after caffeine treatment than in controls (5.86 +/- 1.95 vs 0.76 +/- 0.94 ml/kg, area under curve p=0.041). Mean heart rate was significantly higher after caffeine treatment than in controls (211 +/- 8 vs 169 +/- 15 beats per minute, p<0.05) and remained higher for the experimental period. DISCUSSION: Caffeine did not affect pulmonary artery or DA blood flows or other renal, respiratory or cardiovascular parameters examined. Neonatal caffeine administration increased heart rate and urine output but had little effect on pulmonary function in ventilated preterm lambs. PMID- 22484474 TI - Differences in amplitude among electrode locations on amplitude-integrated electroencephalograms in preterm infants. AB - INTRODUCTION: To assess differences in amplitude among electrode locations on amplitude-integrated electroencephalograms (aEEGs) in preterm infants and change therein between preterm age and term-equivalent age (TEA), we investigated aEEGs in preterm infants at both 30-32 wk post-conceptional age (PCA) and TEA. METHODS: The median values of upper- and lower-margin amplitudes were quantitatively calculated every 5 min (Med-UMA5 and Med-LMA5, respectively), and peak, median, and bottom values were extracted at each location for the trans-frontal, trans central, trans-occipital, fronto-central, and centro-occipital electrodes. RESULTS: In 38 clinically stable preterm infants studied, most measurement items showed significant differences among the electrode locations at both preterm age and TEA. At 30-32 wk PCA, the bottom of Med-LMA5 was significantly higher for the trans-frontal electrodes than for the trans-central electrodes. In contrast, all measurements for Med-LMA5 were significantly lower for the trans-frontal electrodes than for the trans-central electrodes. DISCUSSION: Amplitudes on aEEGs were significantly different among the electrode locations in preterm infants, and locational differences in amplitude changed between preterm age and TEA. It is necessary to understand the differences in amplitudes among the electrode locations on aEEGs in infants to appropriately evaluate them. PMID- 22484475 TI - The role of metaplasticity mechanisms in regulating memory destabilization and reconsolidation. AB - Memory allows organisms to predict future events based on prior experiences. This requires encoded information to persist once important predictors are extracted, while also being modifiable in response to changes within the environment. Memory reconsolidation may allow stored information to be modified in response to related experience. However, there are many boundary conditions beyond which reconsolidation may not occur. One interpretation of these findings is that the event triggering memory retrieval must contain new information about a familiar stimulus in order to induce reconsolidation. Presently, the mechanisms that affect the likelihood of reconsolidation occurring under these conditions are not well understood. Here we speculate on a number of systems that may play a role in protecting memory from being destabilized during retrieval. We conclude that few memories may enter a state in which they cannot be modified. Rather, metaplasticity mechanisms may serve to alter the specific reactivation cues necessary to destabilize a memory. This might imply that destabilization mechanisms can differ depending on learning conditions. PMID- 22484476 TI - N-methyl-D-aspartate receptor 2B subunit (GRIN2B) gene variation is associated with alerting, but not with orienting and conflicting in the Attention Network Test. AB - Appropriate attention levels are pivotal for cognitive processes, and individual differences in attentional functioning are related to variations in the interplay of neurotransmitters. The attention network theory reflects attention as a non homogenous set of separate neural networks: alerting, orienting and conflicting. In the present study, the role of variations in GRIN2B, which encodes the NR2B subunit of N-methyl-d-aspartate (NMDA) receptors, was explored with regard to the regulation of arousal and attention by comparing the efficiency of the three attentional networks as measured with the Attention Network Test (ANT). Two synonymous SNPs in GRIN2B, rs1806201 (T888T) and rs1806191 (H1178H) were genotyped in 324 young Caucasian adults. Results revealed a highly specific modulatory influence of SNP rs1806201 on alerting processes with subjects homozygous for the frequent C allele displaying higher alerting network scores as compared to the other two genotype groups (CT and TT). This effect is due to the fact that in the no cue condition faster reaction times were evident in participants carrying at least one of the rare T alleles, possibly as a result of more effective glutamatergic neurotransmission. The results might be further explained by a dissociation between tonic and phasic alertness modulated by the GRIN2B genotype and by a ceiling effect, meaning that subjects cannot be phasicly alert in excess to a certain level. Altogether, the results show that variations in GRIN2B have to be taken into consideration when examining attentional processes. PMID- 22484477 TI - Role of altered rpoB alleles in Bacillus subtilis sporulation and spore resistance to heat, hydrogen peroxide, formaldehyde, and glutaraldehyde. AB - Mutations in the RNA polymerase beta-subunit gene rpoB causing resistance to rifampicin (Rif(R)) in Bacillus subtilis were previously shown to lead to alterations in the expression of a number of global phenotypes known to be under transcriptional control. To better understand the influence of rpoB mutations on sporulation and spore resistance to heat and chemicals, cells and spores of the wild-type and twelve distinct congenic Rif(R) mutant strains of B. subtilis were tested. Different levels of glucose catabolite repression during sporulation and spore resistance to heat and chemicals were observed in the Rif(R) mutants, indicating the important role played by the RNA polymerase beta-subunit, not only in the catalytic aspect of transcription, but also in the initiation of sporulation and in the spore resistance properties of B. subtilis. PMID- 22484478 TI - Effect of AT1R knockdown on ishikawa cell proliferation induced by estrogen. AB - OBJECTIVE: This study aimed to study the effects of angiotensin receptor (AT1R) on proliferation, cell cycle progression, and apoptosis of estrogen-induced ishikawa cell by the transfection of AT1R-siRNA. METHODS: Immunofluorescence method was used to detect AT1R in ishikawa cell. Western blot was used to detect the expression of AT1R protein in ishikawa cell before and after the transfection of AT1R-siRNA. MTT method was used to test the cell proliferation of estrogen induced ishikawa cell before and after the transfection. Western blot was used to detect the expression of extracellular regulated protein kinase1/2(ERK1/2). RESULTS: The result of immunofluorescence shows that AT1R was expressed in ishikawa cell. The expression of AT1R protein was inhibited obviously by 72 h after the transfection of AT1R-siRNA. The results of MTT show that estrogen could induce the cell proliferation of ishikawa cell. The expression of ERK1/2 was down regulated after the transfection of AT1R-siRNA. CONCLUSION: AT1R can promote the cell proliferation of estrogen-induced ishikawa cell. The possible mechanism may be down-regulating the expression of ERK1/2 protein. PMID- 22484479 TI - Gestational diabetes in a tertiary care hospital: implications of applying the IADPSG criteria. AB - BACKGROUND: The American Diabetes Association has endorsed the International Association of Diabetes and Pregnancy Groups (IADPSG) recommendation that every pregnant woman should undergo the 75 g oral glucose tolerance test (OGTT) to screen for gestational diabetes mellitus (GDM). PURPOSE: To find the cost and workload implications of switching from the current two-step screening of GDM to the one-step IADPSG approach. METHODS: The cost (US $) and laboratory workload units (WLU) were calculated for three possible strategies: (1) 50 g glucose screen, if positive, followed by the 100 g OGTT; (2) universal 75 g OGTT; and (3) screening with the initial fasting plasma glucose of the OGTT. RESULTS: For the 1,101 pregnant women screened in 1 year, the cost of the three strategies was $ 31,985, $ 55,250 and $ 35,875, respectively; the laboratory burden was 28,975 WLU, 18,662 WLU and 12,215 WLU, respectively. CONCLUSIONS: Switching to the one step, strategy 2 (IADPSG) would increase the cost by 42 % but decrease the laboratory workload by 36 % compared to the two-step, strategy 1. However, an initial screen by the fasting plasma glucose of the OGTT is the ideal strategy, both in terms of cost and laboratory workload. PMID- 22484480 TI - Apoptin induces apoptosis by changing the equilibrium between the stability of TAp73 and DeltaNp73 isoforms through ubiquitin ligase PIR2. AB - Apoptin, a protein derived from the chicken anaemia virus, induces cell death in various cancer cells but shows little or no cytotoxicity in normal cells. The mechanism of apoptin-induced cell death is currently unknown but it appears to induce apoptosis independent of p53 status. Here we show that p73, a p53 family member, is important in apoptin-induced apoptosis. In p53 deficient and/or mutated cells, apoptin induced the expression of TAp73 leading to the induction of apoptosis. Knockdown of p73 using siRNA resulted in a significant reduction in apoptin-induced cytotoxicity. The p53 and p73 pro-apoptotic target PUMA plays an important role in apoptin-induced cell death as knockdown of PUMA significantly reduced cell sensitivity to apoptin. Importantly, apoptin expression resulted in a marked increase in TAp73 protein stability. Investigation into the mechanisms of TAp73 stability showed that apoptin induced the expression of the ring finger domain ubiquitin ligase PIR2 which is involved in the degradation of the anti apoptotic ?Np73 isoform. Collectively, our results suggest a novel mechanism of apoptin-induced apoptosis through increased TAp73 stability and induction of PIR2 resulting in the degradation of ?Np73 and activation of pro-apoptotic targets such as PUMA causing cancer cell death. PMID- 22484481 TI - Juglanthraquinone C, a novel natural compound derived from Juglans mandshurica Maxim, induces S phase arrest and apoptosis in HepG2 cells. AB - Juglanthraquinone C (1,5-dihydroxy-9,10-anthraquinone-3-carboxylic acid, JC), a naturally occurring anthraquinone isolated from the stem bark of Juglans mandshurica, shows strong cytotoxicity in various human cancer cells in vitro. Here, we first performed a structure-activity relationship study of six anthraquinone compounds (JC, rhein, emodin, aloe-emodin, physcion and chrysophanol) to exploit the relationship between their structural features and activity. The results showed that JC exhibited the strongest cytotoxicity of all compounds evaluated. Next, we used JC to treat several human cancer cell lines and found that JC showed an inhibitory effect on cell viability in dose-dependent (2.5-10 MUg/ml JC) and time-dependent (24-48 h) manners. Importantly, the inhibitory effect of JC on HepG2 (human hepatocellular carcinoma) cells was more significant as shown by an IC(50) value of 9 +/- 1.4 MUg/ml, and 36 +/- 1.2 MUg/ml in L02 (human normal liver) cells. Further study suggested that JC-induced inhibition HepG2 cell proliferation was associated with S phase arrest, decreased protein expression of proliferation marker Ki67, cyclin A and cyclin-dependent kinase (CDK) 2, and increased expression of cyclin E and CDK inhibitory protein Cip1/p21. In addition, JC significantly triggered apoptosis in HepG2 cells, which was characterized by increased chromatin condensation and DNA fragmentation, activation of caspase-9 and -3, and induction of a higher Bax/Bcl2 ratio. Collectively, our study demonstrated that JC can efficiently inhibit proliferation and induce apoptosis in HepG2 cells. PMID- 22484483 TI - MicroRNAs miR-144/144* and miR-16 in peripheral blood are potential biomarkers for naturalistic stress in healthy Japanese medical students. AB - Non-coding microRNAs (miRNAs) are suggested to serve fundamental roles in cellular stress responses and in coping with sudden environmental changes in experimental animals. We examined whether naturalistic stressor-responsive miRNAs were detectable in whole blood. Blood and saliva were collected between 16:00 and 17:00 from 10 healthy medical students (5 males and 5 females; aged 22.4+/-0.8 years, mean+/-SD) 7 weeks before, one day before, immediately after, and one week after a nationally administered examination for academic promotion. Samples obtained one week after the examination were used as baseline controls. State anxiety and salivary cortisol levels reached maximum levels the day before the examination. Eleven candidate miRNAs (miR-144, -144*, -16, -15a, -19a, -19b, 26b, -30b, -106b, -126, and -142-3p) were extracted using a human miRNA microarray, and quantitative real-time reverse transcription PCR confirmed significant elevation of miR-144/144* and miR-16 levels immediately after finishing the examination. miR-16 levels in individual students were positively correlated with those of serum tumor necrosis factor (TNF)-alpha measured immediately after the examination. Percentage changes in miR-144* and miR-16 levels from immediately after to one week after the examination were significantly correlated with percentage changes in circulating interferon-gamma and/or TNF-alpha levels over the same time points. Our results suggest that miR 144/144* and miR-16 may constitute a part of an integrated response to naturalistic stressors in healthy young adults. PMID- 22484484 TI - Correlation between acceleration magnitude and ocular vestibular-evoked myogenic potential. AB - This study combined bone-conducted vibration (BCV) stimulation with triaxial accelerometry to correlate the acceleration magnitudes of BCV stimuli with ocular vestibular-evoked myogenic potential (oVEMP) test results. Fourteen healthy volunteers underwent oVEMP test using BCV stimuli with simultaneous monitoring the triaxial acceleration. All (100%) subjects exhibited clear oVEMPs in response to BCV stimuli from a vibrator. The lowest acceleration magnitudes for eliciting oVEMPs along the x-, y- and z-axes were 0.05+/-0.01 g, 0.16+/-0.08 g, and 0.04+/ 0.01 g, respectively, exhibiting significantly higher acceleration magnitude along the y-axis than those along the x- and z-axes. In addition, significantly positive correlations were noted between the acceleration magnitude along each axis and the oVEMP amplitude. In conclusion, measuring the acceleration magnitude throughout oVEMP testing revealed a significant correlation between linear acceleration and oVEMP responses. Restated, increasing acceleration magnitude may have more synchronization of firing of vestibular afferents, resulting in more synchronized evoked potentials and greater oVEMP amplitude. PMID- 22484482 TI - Functional alterations in GABAergic fast-spiking interneurons in chronically injured epileptogenic neocortex. AB - Progress toward developing effective prophylaxis and treatment of posttraumatic epilepsy depends on a detailed understanding of the basic underlying mechanisms. One important factor contributing to epileptogenesis is decreased efficacy of GABAergic inhibition. Here we tested the hypothesis that the output of neocortical fast-spiking (FS) interneurons onto postsynaptic targets would be decreased in the undercut (UC) model of chronic posttraumatic epileptogenesis. Using dual whole-cell recordings in layer IV barrel cortex, we found a marked increase in the failure rate and a very large reduction in the amplitude of unitary inhibitory postsynaptic currents (uIPSCs) from FS cells to excitatory regular spiking (RS) neurons and neighboring FS cells. Assessment of the paired pulse ratio and presumed quantal release showed that there was a significant, but relatively modest, decrease in synaptic release probability and a non-significant reduction in quantal size. A reduced density of boutons on axons of biocytin filled UC FS cells, together with a higher coefficient of variation of uIPSC amplitude in RS cells, suggested that the number of functional synapses presynaptically formed by FS cells may be reduced. Given the marked reduction in synaptic strength, other defects in the presynaptic vesicle release machinery likely occur, as well. PMID- 22484485 TI - Increased chromosome mobility facilitates homology search during recombination. AB - Homologous recombination, an essential process for preserving genomic integrity, uses intact homologous sequences to repair broken chromosomes. To explore the mechanism of homologous pairing in vivo, we tagged two homologous loci in diploid yeast Saccharomyces cerevisiae cells and investigated their dynamic organization in the absence and presence of DNA damage. When neither locus is damaged, homologous loci occupy largely separate regions, exploring only 2.7% of the nuclear volume. Following the induction of a double-strand break, homologous loci co-localize ten times more often. The mobility of the cut chromosome markedly increases, allowing it to explore a nuclear volume that is more than ten times larger. Interestingly, the mobility of uncut chromosomes also increases, allowing them to explore a four times larger volume. We propose a model for homology search in which increased chromosome mobility facilitates homologous pairing. Finally, we find that the increase in DNA dynamics is dependent on early steps of homologous recombination. PMID- 22484486 TI - Increased mobility of double-strand breaks requires Mec1, Rad9 and the homologous recombination machinery. AB - Chromatin mobility is thought to facilitate homology search during homologous recombination and to shift damage either towards or away from specialized repair compartments. However, unconstrained mobility of double-strand breaks could also promote deleterious chromosomal translocations. Here we use live time-lapse fluorescence microscopy to track the mobility of damaged DNA in budding yeast. We found that a Rad52-YFP focus formed at an irreparable double-strand break moves in a larger subnuclear volume than the undamaged locus. In contrast, Rad52-YFP bound at damage arising from a protein-DNA adduct shows no increase in movement. Mutant analysis shows that enhanced double-strand-break mobility requires Rad51, the ATPase activity of Rad54, the ATR homologue Mec1 and the DNA-damage-response mediator Rad9. Consistent with a role for movement in the homology-search step of homologous recombination, we show that recombination intermediates take longer to form in cells lacking Rad9. PMID- 22484487 TI - Distinct and separable activities of the endocytic clathrin-coat components Fcho1/2 and AP-2 in developmental patterning. AB - Clathrin-mediated endocytosis occurs at multiple independent import sites on the plasma membrane, but how these positions are selected and how different cargo is simultaneously recognized is obscure. FCHO1 and FCHO2 are early-arriving proteins at surface clathrin assemblies and are speculated to act as compulsory coat nucleators, preceding the core clathrin adaptor AP-2. Here, we show that the MU homology domain of FCHO1/2 represents an endocytic interaction hub. Translational silencing of fcho1 in zebrafish embryos causes strong dorsoventral patterning defects analogous to Bmp signal failure. The Fcho1 MU-homology domain interacts with the Bmp receptor Alk8, uncovering an endocytic component that positively modulates Bmp signal transmission. Still, the fcho1 morphant phenotype is distinct from severe embryonic defects apparent when AP-2 is depleted. Our data thus challenge the primacy of FCHO1/2 in coat initiation. PMID- 22484488 TI - Prostaglandin F2alpha facilitates collagen synthesis in cardiac fibroblasts via an F-prostanoid receptor/protein kinase C/Rho kinase pathway independent of transforming growth factor beta1. AB - Accumulation of collagen I and III in the myocardium is a prominent feature of interstitial fibrosis. Prostaglandin F(2alpha) (PGF(2alpha)) facilitates fibrosis by increasing collagen synthesis. However, the underlying mechanisms mediating the effect of PGF(2alpha) on collagen expression in cardiac fibroblasts are not yet fully elucidated. We measured the mRNA and protein levels of collagen I and III by quantitative real-time PCR and ELISA, respectively. Activation of signaling pathways was determined by western blot analysis. In primary rat cardiac fibroblasts, treatment with PGF(2alpha) stimulated both the mRNA and protein levels of collagen I and III, and pretreatment with the F-prostanoid (FP) receptor antagonist AL-8810, protein kinase C inhibitor LY-333531, and Rho kinase inhibitor Y-27632 significantly inhibited PGF(2alpha)-induced collagen I and III expression. FP receptor, protein kinase C, and Rho kinase were activated with PGF(2alpha) treatment. PGF(2alpha) may be an important regulator in the synthesis of collagen I and III via an FP receptor/protein kinase C/Rho kinase cascade in cardiac fibroblasts, which might be a new therapeutic target for myocardial fibrosis. PMID- 22484489 TI - The family of mammalian small heat shock proteins (HSPBs): implications in protein deposit diseases and motor neuropathies. AB - A number of neurological and muscular disorders are characterized by the accumulation of aggregate-prone proteins and are referred to as protein deposit or protein conformation diseases. Besides some sporadic forms, most of them are genetically inherited in an autosomal dominant manner, although recessive forms also exist. Although genetically very heterogeneous, some of these diseases are the result of mutations in some members of the mammalian small heat shock protein family (sHSP/HSPB), which are key players of the protein quality control system and participate, together with other molecular chaperones and co-chaperones, in the maintenance of protein homeostasis. Thus, on one hand upregulation of specific members of the HSPB family can exert protective effects in protein deposit diseases, such as the polyglutamine diseases. On the other hand, mutations in the HSPBs lead to neurological and muscular disorders, which may be due to a loss-of-function in protein quality control and/or to a gain-of-toxic function, resulting from the aggregation-proneness of the mutants. In this review we summarize the current knowledge about some of the best characterized functions of the HSPBs (e.g. role in cytoskeleton stabilization, chaperone function, anti aggregation and anti-apoptotic activities), also highlighting differences in the properties of the various HSPBs and how these may counteract protein aggregation diseases. We also describe the mutations in the various HSPBs associated with neurological and muscular disorders and we discuss how gain-of-toxic function mechanisms (e.g. due to the mutated HSPB protein instability and aggregation) and/or loss-of-function mechanisms can contribute to HSPB-associated pathologies. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology. PMID- 22484490 TI - Thyroid hormone receptors, cell growth and differentiation. AB - BACKGROUND: Tissue homeostasis depends on the balance between cell proliferation and differentiation. Thyroid hormones (THs), through binding to their nuclear receptors, can regulate the expression of many genes involved in cell cycle control and cellular differentiation. This can occur by direct transcriptional regulation or by modulation of the activity of different signaling pathways. SCOPE OF REVIEW: In this review we will summarize the role of the different receptor isoforms in growth and maturation of selected tissues and organs. We will focus on mammalian tissues, and therefore we will not address the fundamental role of the THs during amphibian metamorphosis. MAJOR CONCLUSIONS: The actions of THs are highly pleiotropic, affecting many tissues at different developmental stages. As a consequence, their effects on proliferation and differentiation are highly heterogeneous depending on the cell type, the cellular context, and the developmental or transformation status. Both during development and in the adult, stem cells are essential for proper organ formation, maintenance and regeneration. Recent evidence suggests that some of the actions of the thyroid hormone receptors could be secondary to regulation of stem/progenitor cell function. Here we will also include the latest knowledge on the role of these receptors in proliferation and differentiation of embryonic and adult stem cells. GENERAL SIGNIFICANCE: The thyroid hormone receptors are potent regulators of proliferation and differentiation of many cell types. This can explain the important role of the thyroid hormones and their receptors in key processes such as growth, development, tissue homeostasis or cancer. This article is part of a Special Issue entitled Thyroid hormone signalling. PMID- 22484491 TI - Yeast 14-3-3 proteins participate in the regulation of cell cation homeostasis via interaction with Nha1 alkali-metal-cation/proton antiporter. AB - BACKGROUND: In yeast, 14-3-3 proteins bind to hundreds of phosphorylated proteins and play a role in the regulation of many processes including tolerance to NaCl. However, the mechanism of 14-3-3 involvement in the cell answer to salt or osmotic stresses is weakly understood. METHODS: We studied the role of the Saccharomyces cerevisiae 14-3-3 homologs Bmh1 and Bmh2 in the regulation of alkali-metal-cation homeostasis using the genetic-interaction approach. Obtained results were confirmed with the Bimolecular-Fluorescence-Complementation method. RESULTS: Deletion of BMH1, encoding the major 14-3-3 isoform, resulted in an increased sensitivity to Na+, Li+ and K+ and to cationic drugs but did not affect membrane potential. This bmh1Delta phenotype was complemented by overexpression of BMH2. Testing the genetic interaction between BMH genes and genes encoding plasma-membrane cation transporters revealed, that 14-3-3 proteins neither interact with the potassium uptake systems, nor with the potassium-specific channel nor with the Na+(K+)-ATPases. Instead, a genetic interaction was identified between BMH1 and NHA1 which encodes an Na+(K+)/H+ antiporter. In addition, a physical interaction between 14-3-3 proteins and the Nha1 antiporter was shown. This interaction does not depend on the phosphorylation of the Nha1 antiporter by Hog1 kinase. Our results uncovered a previously unknown interaction partner of yeast 14-3-3 proteins and provided evidence for the previously hypothesized involvement of Bmh proteins in yeast salt tolerance. GENERAL SIGNIFICANCE: Our results showed for the first time that the yeast 14-3-3 proteins and an alkali-metal-cation efflux system interact and that this interaction enhances the cell survival upon salt stress. PMID- 22484492 TI - Implantation of a newly developed direct optic nerve electrode device for artificial vision in rabbits. AB - The purpose of this study was to investigate the surgical procedures involved in the implantation of a newly developed direct optic nerve electrode device for inducing artificial vision. The electrode device comprised seven wire stimulation electrodes and a return electrode (diameter 50 MUm), one manipulation rod (diameter 100 MUm), and a cylindrical silicone board (diameter 2.0 mm). The stimulation electrodes and the manipulation rod protruded through the board to allow implantation of the electrode tips into the optic disc of the rabbit eye. The surgical procedures required to insert the device into the vitreous cavity and implant the device into the optic disc were evaluated. When the electrodes were stimulated, electrically evoked potentials (EEPs) were recorded at the visual cortex. The electrode device was inserted into the vitreous cavity with no damage using a trocar through a scleral incision. The device was easily manipulated using vitreoretinal forceps in the vitreous cavity, and the electrode tips were implanted into the optic disc in a single insertion after vitrectomy. When electrical stimulation was applied, EEPs were recorded from all electrode pairs. The newly developed electrode device was inserted into the eye and implanted into the optic nerve disc smoothly and safely, suggesting that these surgical procedures are useful for our artificial vision system. PMID- 22484493 TI - Higher prevalence of obesity in gastric cardia adenocarcinoma compared to gastric non-cardia adenocarcinoma. AB - BACKGROUND AND AIMS: Obesity is one of the main risk factors for gastric cardia adenocarcinoma (GCA) in the West. Also, recent studies have suggested that GCA is distinct from distal stomach tumor, with differing risk factors, tumor characteristics, and biological behavior. The objective of our research was to evaluate the relationship between obesity and GCA compared to non-cardia adenocarcinoma. MATERIALS AND METHODS: A total of 298 patients who were diagnosed with gastric adenocarcinoma and underwent surgery at Seoul National University Bundang Hospital were evaluated. Ninety-one cases were GCA, and 207 cases were non-cardiac adenocarcinoma. Obesity was estimated by body mass index (BMI, kg/m(2)). The degree of obesity was determined by using BMI <18.5, 18.5-23.9, 24 27.9, and >= 28 (kg/m(2)) as the cut-off points for underweight, normal weight, overweight, and obese, respectively. Association with obesity was estimated by odds ratio (OR) and 95% confidence interval (CI). RESULTS: Obesity was more prevalent in patients with GCA at the time of diagnosis for gastric cancer. Among obese persons with a BMI of 28 kg/m(2) or higher, the OR was 3.937 (95% CI, 1.492 10.389; p = 0.006) for GCA compared to non-cardia adenocarcinoma. For overweight individuals, the OR was 2.194 (95% CI, 1.118-4.305; p = 0.022). Multivariate analysis of age, Helicobacter pylori infection, smoking, stage, and BMI with logistic regression was performed. BMI was an independent risk factor for GCA (OR, 1.123; 95% CI, 1.037-1.217; p = 0.004). CONCLUSION: Obesity was more prevalent in patients with GCA compared to that in patients with gastric non cardia adenocarcinoma. Also, BMI was an independent risk factor for GCA. PMID- 22484495 TI - Tissue inhibitor of metalloproteinases in oral squamous cell carcinomas - a therapeutic target? AB - Matrix metalloproteinases (MMPs) are proteases responsible for remodeling the extracellular matrix (ECM) and enabling spreading and metastasis of tumor cells, a common phenomenon in oral squamous cell carcinomas (OSCC). They are strongly blocked by several inhibitors, among which we must highlight, for their specificity and potency, the endogenous tissue inhibitors of metalloproteinases (TIMP-1, -2, -3 and -4). The goal of this paper is to describe the expression of TIMPs in OSCC, determining their relation with clinical, histological and prognostic factors, delving into OSCC regulation mechanisms and discussing the use of exogenous TIMPs to treat this type of tumors. Expression of TIMPs in OSCC is higher in tumors than in normal tissue, which correlates with an increase of metastatic risk and regional lymph node affectation. Although some metalloproteinases inhibitors (MMIs) have shown promising results in the treatment of these tumors, their use in OSCC has not been widely tested; and although some indirect MMIs, like COX-2 inhibitors, flavonoids and endostatin seem to have beneficial effects on the invasive capacity of OSCC through regulation of MMPs and TIMP levels, routine clinical use has not been accepted yet. PMID- 22484494 TI - Time to rethink antiviral treatment for hepatitis C in patients with coexisting mental health/substance abuse issues. AB - BACKGROUND: A new era has dawned in the treatment of chronic hepatitis C (HCV) virus with the use of direct-acting antiviral medications augmenting combination therapy. Unfortunately, the significant impact of improvements may not be realized if antiviral treatment is not expanded to include a larger proportion of patients, many of whom have coexisting mental health and/or substance abuse issues and have been historically deferred from treatment. METHODS: We reviewed the extent literature on HCV treatment for individuals with co-occurring mental health and/or substance abuse issues. RESULTS: A number of empirically-based arguments exist in favor of treating HCV-infected individuals with mental health and/or substance abuse issues within the context of multidisciplinary team approaches. Integrated, collaborative, or hybrid models of care are just a few examples of multidisciplinary approaches that can combine the care of HCV treating providers with mental health and/or addictions providers to safely and effectively treat these patients. Collectively, these arguments and the empirical evidence that supports them, provides a strong rationale for why expanding antiviral therapy to these patients is critical and timely. CONCLUSIONS: A decade of evidence suggests that HCV-infected individuals with mental health and/or substance abuse issues can safely and effectively undergo antiviral treatment when delivered through multidisciplinary care settings. Multidisciplinary approaches that combine HCV treating providers with mental health, addictions, and other support systems can facilitate preparation and successful treatment of these patients on antiviral therapy. PMID- 22484496 TI - Mitofusin 1 inhibits an apoptosis-associated amino-terminal conformational change in Bax, but not its mitochondrial translocation, in a GTPase-dependent manner. AB - Mitochondrial fusion and fission are dynamically regulated during apoptotic cell death, and mitofusin (Mfn) and related proteins have been shown to be involved in apoptosis-associated changes in mitochondrial morphology and function. Here, we investigated the involvement of Mfn proteins in the conformational activation and mitochondrial translocation of Bax, a key molecule responsible for apoptosis associated mitochondrial changes. When ectopically expressed, Mfn1 inhibited the amino-terminal activation, but not the mitochondrial translocation, of Bax during staurosporine-induced apoptosis; overexpression of Mfn2 had no effect. Overexpression of Mfn1 mutants carrying point mutations in the GTPase domain (Mfn1-K88T and Mfn1-T109A) did not inhibit the amino-terminal activation of Bax. Furthermore, staurosporine-induced amino-terminal activation of Bax was significantly delayed in Mfn1-shRNA transfected (Mfn1-depleted) HeLa cells compared to cells transfected with control shRNA. These results collectively suggest a role for Mfn1 in regulating the activation of Bax on the outer mitochondrial membrane in a GTPase-dependent manner. PMID- 22484497 TI - Interference of Frizzled 1 (FZD1) reverses multidrug resistance in breast cancer cells through the Wnt/beta-catenin pathway. AB - Multidrug resistance (MDR) represents a major obstacle in the successful treatment of breast cancer. The MDR1 gene is a direct target of the Wnt/beta catenin signaling pathway, which controls tumor development. Overexpression of P glycoprotein, encoded by the MDR1 gene, is one of the most common causes of MDR. We found that the Frizzled 1 (FZD1) protein, which is an essential component of the Wnt/beta-catenin pathway, is overexpressed in the multidrug resistant breast cancer cell subline MCF-7/ADM, coincident with MDR1/P-gp. FZD1 silencing induced down-regulation of MDR1/P-gp, restored sensitivity to four chemotherapy drugs, and significantly decreased cytoplasmic and nuclear beta-catenin levels. FZD1 appears to mediate multidrug resistance by regulating the Wnt/beta-catenin pathway. PMID- 22484498 TI - Synthesis, characterization, and anticancer activity of ruthenium-pyrazole complexes. AB - A series of new water soluble Ru(III) pyrazole complexes mer-[RuCl(3)(DMSO S)(pyz)(2)] 1, mer-[RuCl(3)(DMSO-S)(DMSO-O)(pyz)] 2, mer-[RuCl(3)(bpy)(dmpyz)] 3, and mer-[RuCl(3)(DMSO-S)(dmpyz)(2)] 4 (pyz=pyrazole; dmpyz=3,5-dimethylpyrazole, bpy=2,2'-bipyridine) have been synthesized and characterized by use of a combination of spectroscopy (IR and UV-visible), X-ray diffraction, and cyclic voltammetry. The molecular X-ray structure of all reported compounds (1-4) revealed distorted octahedral coordination around ruthenium. The cytotoxicity assay on human breast cancer cells (MCF7) demonstrated that compounds 1 and 4 affect cell viability, whereas compounds 2 and 3 do not show appreciable activity. The IC(50) values for 1 and 4 lie within the range of 71-32MUM in MCF7 cells. PMID- 22484499 TI - Copper(II) complex formation processes of alloferon I with point mutation H1K; combined spectroscopic and potentiometric studies. AB - Mononuclear and polynuclear complexes of the alloferon I with point mutation (H1K) Lys-Gly-Val-Ser-Gly-His(6)-Gly-Gln-His(9)-Gly-Val-His(12)-Gly (AlloK) and its acetylated derivative Ac-Lys-Gly-Val-Ser-Gly-His(6)-Gly-Gln-His(9)-Gly-Val His(12)-Gly (Ac-AlloK) have been studied by potentiometric, UV-visible, CD, EPR spectroscopic and mass spectrometry (MS) methods. The high water solubility of the resulting metal complexes allowed us to obtain a complete complex speciation at different metal-to-ligand ratios ranging from 1:1 to 4:1 for AlloK while to 3:1 for Ac-AlloK. At physiological pH 7.4 and the metal-to-ligand 1:1molar ratio the AlloK peptide forms the CuL complex with the 4N {NH(2), N(-), 2N(Im)} binding mode. In the Cu(II)-AlloK 4:1 system in wide pH 6.5-10 range the Cu(4)H(-7)L complex dominates with the 3N {NH(2),2N(-)} 3*{N(Im),2N(-)} coordination mode. Imidazole nitrogen donor atoms are the primary and exclusive metal binding sites of Ac-AlloK. For Ac-AlloK and 1:1 metal-to-ligand molar ratio the CuHL complex with the 3N {3N(Im)} binding sites in pH 4.5-7.5 range is present in solution. The amine nitrogen donor and all of the histidine residues can be considered to be independent metal-binding sites in the species formed in the systems studied. As a consequence, tri- (for the Ac-AlloK) and tetra-nuclear (for the AlloK peptide) complexes for the metal-to-ligand 3:1 and 4:1molar ratios, respectively, are present in the solution. PMID- 22484500 TI - Coordination chemistry and solution structure of Fe(II)-peplomycin. Two possible coordination geometries. AB - The solution structure of Fe(II)-peplomycin was determined from NMR data collected for this molecule. As found previously for Fe(II)- and Co(II)-bound bleomycin; the coordination sphere of the metal is composed of the primary and secondary amines in beta-aminoalanine, the pyrimidine and imidazole rings in the pyrimidinylpropionamide, and beta-hydroxyhistidine moieties, respectively, the amine nitrogen in beta-hydroxyhistidine, and either the carbamoyl group in mannose or a solvent molecule. The two most discussed coordination geometries for the aforementioned ligands in metallo-bleomycins have been tested against the NMR data generated for Fe(II)-peplomycin. The interpretation of the experimental evidence obtained through molecular dynamics indicates that both geometries are equally likely in solution for this compound in the absence of DNA, but arguments are offered to explain why one of these geometries is preferred in the presence of DNA. PMID- 22484501 TI - Copper(II) interaction with peptide fragments of histidine-proline-rich glycoprotein: Speciation, stability and binding details. AB - GHHPH is the peptide repeat present in histidine-proline rich glycoprotein (HPRG), a plasma glycoprotein involved in angiogenesis process. The copper(II) ions interaction with mono (Ac-GHHPHG-NH(2)) and its bis-repeat (Ac-GHHPHGHHPHG NH(2)) was investigated by means of potentiometric and spectroscopic techniques. To single out the copper(II) coordination environments of different species formed with Ac-GHHPHG-NH(2), three single point mutated peptides were also synthesized and their ability to coordinate Cu(2+) investigated. Ac-GHHPHG-NH(2) binds Cu(2+) by the imidazole side chain and the amide nitrogen deprotonation that takes place towards the N-terminus. The bis-repeat is able to bind Cu(2+) more efficiently than Ac-GHHPHG-NH(2). This difference is not only due to the number of His residues in the sequence but also to the different binding sites. In fact, the comparison of the potentiometric and spectroscopic data of the copper(II) complexes with a bis-repeatPeg construct Ac-(GHHPHG)-Peg-(GHHPHG) NH(2) and those of the metal complexes with Ac-HGHH-NH(2), indicates that the central HGHH amino acid sequence is the main copper(II) binding site. PMID- 22484502 TI - Theoretical investigation of astacin proteolysis. AB - Astacin, acting as the prototype of astacin family and of the metzincin superfamily, is a mononuclear zinc enzyme that catalyzes the hydrolysis of polypeptides and proteins. In the present article, the reaction mechanism of astacin has been investigated using density functional theory (DFT) method. Using a model of the active site constructed on the basis of the X-ray crystal structure of astacin, the potential energy surface for catalytic reaction has been mapped and the transition states and intermediates along the reaction pathway are characterized. The calculations give general support to the previously proposed mechanism by experiments, which mainly involve nucleophilic attack on carbonyl group of substrate and C-N bond cleavage, and reveal more detailed mechanistic features. The Glu93 functions as a crucial general base to activate the zinc-bound water and the resulting zinc-bound hydroxide acts as the real nucleophile. It is demonstrated that there exists a "reactant region", where the interconversion between zinc-bound water and zinc-bound hydroxide occurs rapidly. The rate-limiting step is predicted to be the nucleophilic attack, which leads to an anionic gem-diolate tetrahedral intermediate. During the catalysis, zinc ion provides main catalytic power by stabilizing the developing charge of tetrahedral intermediate, while the Tyr149 residue also partially contributes to the catalysis by stabilizing the anionic intermediate. In addition, it is shown that the Cys64 plays roles in assisting in binding and orientating the substrate via electrostatic interaction. PMID- 22484503 TI - Exploring the applicability of future air quality predictions based on synoptic system forecasts. AB - For a given emissions inventory, the general levels of air pollutants and the spatial distribution of their concentrations are determined by the physiochemical state of the atmosphere. Apart from the trivial seasonal and daily cycles, most of the variability is associated with the atmospheric synoptic scale. A simple methodology for assessing future levels of air pollutants' concentrations based on synoptic forecasts is presented. At short time scales the methodology is comparable and slightly better than persistence and seasonal forecasts at categorical classification of pollution levels. It's utility is shown for air quality studies at the long time scale of a changing climate scenario, where seasonality and persistence cannot be used. It is demonstrated that the air quality variability due to changes in the pollution emissions can be expected to be much larger than that associated with the effects of climatic changes. PMID- 22484504 TI - Evaluation of the performance and limitations of empirical partition-relations and process based multisurface models to predict trace element solubility in soils. AB - Here we evaluate the performance and limitations of two frequently used model types to predict trace element solubility in soils: regression based "partition relations" and thermodynamically based "multisurface models", for a large set of elements. For this purpose partition-relations were derived for As, Ba, Cd, Co, Cr, Cu, Mo, Ni, Pb, Sb, Se, V, Zn. The multi-surface model included aqueous speciation, mineral equilibria, sorption to organic matter, Fe/Al-(hydr)oxides and clay. Both approaches were evaluated by their application to independent data for a wide variety of conditions. We conclude that Freundlich-based partition relations are robust predictors for most cations and can be used for independent soils, but within the environmental conditions of the data used for their derivation. The multisurface model is shown to be able to successfully predict solution concentrations over a wide range of conditions. Predicted trends for oxy anions agree well for both approaches but with larger (random) deviations than for cations. PMID- 22484505 TI - Testosterone replacement therapy promotes angiogenesis after acute myocardial infarction by enhancing expression of cytokines HIF-1a, SDF-1a and VEGF. AB - In order to investigate the effects of testosterone-replacement therapy on peripheral blood stem cells and angiogenesis after acute myocardial infarction, a castrated rat acute myocardial infarction model was established by ligation of the left anterior descending coronary followed by treatment with testosterone. CD34(+) cells in myocardium and in peripheral blood after 1 and 3 days were measured by immunohistochemistry and flow cytometry, respectively. In the early phase of acute myocardial infarction, the expression levels of hypoxia-inducible factor 1a (HIF-1a), stromal cell-derived factor 1a (SDF-1a) and vascular endothelium growth factor (VEGF) in ischemic myocardium were determined by real time RT-PCR and immunohistochemistry, respectively. Infarct size, cardiomyocyte apoptosis, capillary density and cardiac function were assessed after 28 days. These results showed that the number of CD34(+) cells in the peripheral blood and in myocardium was significantly decreased in castrated rats, and the early expression levels of HIF-1a, SDF-1a and VEGF in the myocardium were also decreased. Furthermore, reduced capillary density, worsened cardiac function, increased infarct size and cardiomyocyte apoptosis at 28 days post-infarction were found in castrated rats. But these adverse effects could be reversed by testosterone-replacement therapy. These findings suggested that testosterone can increase the mobilization and homing of CD34(+) cells into the ischemic myocardium and further promote neoangiogenesis after myocardial infarction. The pro-angiogenesis effect of testosterone-replacement therapy is associated with the enhanced expression of HIF-1a, SDF-1a and VEGF in myocardium after myocardial infarction. PMID- 22484506 TI - KS370G, a synthetic caffeamide derivative, improves left ventricular hypertrophy and function in pressure-overload mice heart. AB - Cardiac hypertrophy is an important compensatory mechanism in response to a pressure overload, but a sustained excessive cardiac workload may deteriorate to maladaptive hypertrophy and to increased risk of heart failure. In this study, we evaluated the effects of KS370G on left ventricular hypertrophy and function. Abdominal aortic banding was performed by constricting the abdominal aorta. Hypertrophied heart was studied at 8 weeks after the operation. After the operation, KS370G 1mg/kg (K1 group) was administered by oral gavage once a day. Left ventricular function was measured by a 1.2F pressure-volume catheter (Scisense, Canada). The levels of protein for alpha-SMA (smooth muscle actin), p AKT (protein kinase B), p-GSK3beta (glycogen synthase kinase 3beta) and p-ERKs (extracellular signal-regulated kinases) in myocardium were analyzed by Western blot. Plasma levels of angiotensin II, atrial natriuretic peptide and lactate dehydrogenase were analyzed by commercial kits. H.E. staining and M.T. staining methods were also used to observe diameter of cardiomyocytes and collagen accumulation. Chronic oral treatment with 1mg/kg KS370G inhibited cardiac hypertrophy and improved cardiac function induced by pressure overload. KS370G also decreased the plasma levels of atrial natriuretic peptide and lactate dehydrogenase. Besides, pressure overload-induced increase of alpha-SMA and phosphorylation of ERK, AKT and GSK3beta were significantly reduced by chronic oral treatment with KS370G. We also found that chronic oral treatment with KS370G reduced cardiac collagen accumulation. KS370G improved left ventricular function and inhibited cardiac hypertrophy through the decrease of the phosphorylation of ERK, AKT and GSK3beta in pressure-overload mice heart. PMID- 22484507 TI - Religion, ethnicity, and attitudes toward psychotherapy. AB - Many presume that White culture supports psychotherapy utilization. However, cultural analyses suggest that many aspects of White culture are antithetical to the values and practices underlying psychotherapy, which appear more congruent with Ashkenazic Jewish attitudes and values. The current research empirically tested this possibility by comparing older Jewish White people, non-Jewish Whites, and Black participants on attitudes relevant to psychotherapy. Results indicated that Jews had greater confidence in a therapist's ability to help, were more tolerant of stigma, and more open to sharing their feelings and concerns than participants in the other groups. Furthermore, initial differences between Whites and African Americans were lessened when Jewish identity was included in the analysis. Results suggest that Jewish culture is relatively accepting of psychotherapy, and that previous reports of different rates of mental health seeking attitudes and utilization by Whites and Blacks may be due, in part, to the inclusion of Jewish individuals in these samples. PMID- 22484508 TI - KOMA: ELISA-microarray calibration and data analysis based on kinetic signal amplification. AB - Antibody microarrays with enzyme-linked immunosorbent technology are used for quantitative, simultaneous and high-throughput analysis of multiple proteins in a single probe. Kinetic detection can significantly improve precision and quantification range of microarray measurements. Here we present the open source software Kinetic Operating Microarray Analyzer (KOMA) that enables calibration and high-throughput analysis of quantitative microarray data collected using a time-resolved kinetic detection protocol of the enzymatic signal. This tool can also be helpful for analyzing data from any other analytical assays employing enzymatic signal amplification, in which a broader range of quantification is reached by the time-resolved recording of readouts. KOMA is open for download at http://www.uni heidelberg.de/fakultaeten/biowissenschaften/ipmb/biologie/woelfl/Research.html together with a set of test raw data and requires R version 2.12 and Java RE version 6.0. PMID- 22484509 TI - A novel flow cytometric approach to distinguish circulating endothelial cells from endothelial microparticles: relevance for the evaluation of endothelial dysfunction. AB - Circulating endothelial cells (CEC) and endothelial microparticles (EMP) are emerging as markers of endothelial repair and activation/apoptosis. Although significant changes in the number of CEC and EMP in pathological conditions have been reported, their reliable identification and quantification still remain a technical challenge. Here, we present a novel methodology for the identification and quantitation of CEC and EMP based on multicolor flow cytometry. Using a lyse/no wash protocol, we observed that in 50 MUl of peripheral blood, the large majority of events expressing an endothelial phenotype (CD45-/CD146+/CD34+) are due to non-nucleated particles (DRAQ5-) carrying mitochondrial activity (MitoTracker+) and, therefore, classified as EMP. We enumerated circulating EMP by single platform absolute count in a lyse/no wash four-color flow-cytometric procedure, which allowed the distinction, within the whole endothelial compartment, of EMP derived from endothelial progenitors (CD45 /CD146+/CD34+/CD117+) and from mature endothelial cells (CD45-/CD146+/CD34+/CD117 ). A significant increase in both subsets was observed in patients with diabetes mellitus. Thus, this simple and highly reproducible method may be useful for monitoring endothelial dysfunction in clinical settings. PMID- 22484510 TI - An illusion of hormesis in the Ames test: statistical significance is not equivalent to biological significance. AB - A recent report (Calabrese et al., Mutat. Res. 726 (2011) 91-97) concluded that an analysis of Ames test mutagenicity data provides evidence of hormesis in mutagenicity dose-response relationships. An examination of the data used in this study and the conclusions regarding hormesis reveal a number of concerns regarding the analyses and possible misinterpretations of the Salmonella data. The claim of hormesis is based on test data from the National Toxicology Program using Salmonella strain TA100. Approximately half of the chemicals regarded as hormetic, and the majority of the specific dose-responses identified as hormetic, were actually nonmutagenic. We conclude that the data provide no evidence of hormetic effects. The Ames test is an excellent measure of bacterial mutagenicity, but the numbers of revertant (mutant) colonies on the plate are the result of a complex interaction between mutagenicity and toxicity, which renders the test inappropriate for demonstrating hormesis in bacterial mutagenicity experiments. PMID- 22484511 TI - Taurine stimulates proliferation and promotes neurogenesis of mouse adult cultured neural stem/progenitor cells. AB - This study reports an effect of taurine (1-10 mM) increasing markedly (120%) the number of neural precursor cells (NPCs) from adult mouse subventricular zone, cultured as neurospheres. This effect is one of the highest reported for adult neural precursor cells. Taurine-containing cultures showed 73-120% more cells than controls, after 24 and 96 h in culture, respectively. Taurine effect is due to enhanced proliferation as assessed by BrdU incorporation assays. In taurine cultures BrdU incorporation was markedly higher than controls from 1.5 to 48 h, with the maximal difference found at 1.5 h. This effect of taurine reproduced at every passage with the same window time. Taurine effects are not mimicked by glycine, alanine or GABA. Clonal efficiency values of 3.6% for taurine cultures and 1.3% for control cultures suggest a taurine influence on both, progenitor and stem cells. Upon differentiation, the proportion of neurons in control and taurine cultures was 3.1% (+/-0.5) and 10.2% (+/-0.8), respectively. These results are relevant for taurine implication in brain development as well as in adult neurogenesis. Possible mechanisms underlying taurine effects on cell proliferation are discussed. PMID- 22484512 TI - Di-(2-ethylhexyl)-phthalate migration from irradiated poly(vinyl chloride) blood bags for graft-vs-host disease prevention. AB - Irradiation with 20-25 kGy is a process commonly used for sterilizing poly(vinyl chloride) (PVC) medical devices. Moreover, whole blood and blood components undergo additional irradiation with 25-50 Gy to inhibit the proliferative capacity of lymphocytes and reduce the risk of transfusion-associated graft-vs host disease (GVHD). Di-(2-ethylhexyl)-phthalate (DEHP) plasticized PVC is extensively used for the production of flexible medical devices including blood bags, but since DEHP is not covalently bound to PVC, it tends to migrate and leach out of the medical device, with harmful consequences for the patients. In this study, the effects of different doses of gamma irradiation on DEHP migration from PVC blood bags was investigated using differential scanning calorimetry (DSC) analysis. Our findings indicate that irradiation with 25-100 Gy reduces the ability of DEHP to migrate from the blood bags, and in the case of a primary container a correlation between the doses of gamma ray irradiation was also observed. In particular, a decrease in DEHP leachability was obtained by increasing the dose of gamma ray irradiation. PMID- 22484513 TI - Comparison of hepatocarcinogen-induced gene expression profiles in conventional primary rat hepatocytes with in vivo rat liver. AB - At present, substantial efforts are focused on the development of in vitro assays coupled with "omics" technologies for the identification of carcinogenic substances as an alternative to the classical 2-year rodent carcinogenicity bioassay. A prerequisite for the eventual regulatory acceptance of such assays, however, is the in vivo relevance of the observed in vitro findings. In the current study, hepatocarcinogen-induced gene expression profiles generated after the exposure of conventional cultures of primary rat hepatocytes to three non genotoxic carcinogens (methapyrilene hydrochloride, piperonyl butoxide, and Wy 14643), three genotoxic carcinogens (aflatoxin B1, 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone, and 2-nitrofluorene), and two non-carcinogens (nifedipine and clonidine) are compared with previously obtained in vivo data after oral administration for up to 14 days of the same hepatocarcinogens to rats. In addition to the comparison of deregulated genes and functions per compound between in vivo and in vitro models, the major discriminating cellular pathways found in vivo in livers of exposed rats were examined for deregulation in vitro. Further, in vivo-derived gene signatures for the identification of genotoxic versus non-genotoxic carcinogens are used to classify in vitro-tested hepatocarcinogens and non-carcinogens. In the primary hepatocyte cultures, two out of the three tested genotoxic carcinogens mimicked the in vivo-relevant DNA damage response and were correctly assessed. Exposure to the non-genotoxic hepatocarcinogens, however, triggered a relatively weak response in the in vitro system, with no clear similarities to in vivo. This study contributes to the further optimization of toxicogenomics predictive tools when applied in in vitro settings. PMID- 22484514 TI - Transoral CO2 laser surgery for supraglottic cancer. AB - There are several therapeutic options for laryngeal cancer, including those that provide a functional preservation without worsening the oncological results, such as transoral laser microsurgery (TLM). The aim of this study was to analyze both oncological and functional results of TLM in supraglottic cancer. We studied 49 consecutive patients with a primary supraglottic carcinoma who underwent a TLM between the years 1999 and 2009. Nineteen patients were classified as stage I-II and 30 as stage III-IV disease. Forty-five patients underwent also neck dissection. Thirteen patients received postoperative radiotherapy. The minimum follow-up was 24 months. Three- and five-year disease-specific survival rate was 93.2 and 82.2 %, respectively. Of the patients, 36.7 % had some complication after surgery, aspiration being the most frequent (16.32 %). Of the 43 patients who were alive, 39 (91 %) without evidence of disease 3 years after diagnosis had a functional larynx. Our results suggest that TLM is a safe and effective treatment for supraglottic cancer, with a low morbidity rate and excellent functional results. PMID- 22484515 TI - Toward a comprehensive approach to pharmacoinvasive therapy for patients with ST segment elevation acute myocardial infarction. AB - What exactly is "pharmacoinvasive therapy" for treatment of patients with ST segment elevation myocardial infarction (STEMI)? When this term was introduced in 2003, it addressed the need for clinical trials besides those comparing fibrinolysis with primary percutaneous coronary intervention (PCI). Primary PCI is recognized as the best strategy for treatment of patients for whom it is applicable. However, use of fibrinolytic drugs initially is necessary in many patients for logistic reasons. Studies of pharmacoinvasive therapy addressed the question of what should be done after initial fibrinolysis. Confusion of the terms pharmacoinvasive therapy, facilitated PCI, rescue PCI, and delayed invasive approaches has obscured the principles that have emerged from such studies. In our view, a uniform conceptualization of pharmacoinvasive therapy emerges on the basis of three key considerations--transfer time, initial pharmacologic therapy, and time to PCI. We propose the following definition: Pharmacoinvasive therapy is the treatment of choice for patients with STEMI who require greater than a 60 min transfer time to a PCI center. It entails immediate use of full doses of fibrinolytic agents followed by prompt transfer to a PCI center and a plan to implement PCI within 2-12 h of the time of onset of initial therapy. PMID- 22484517 TI - Marital, reproductive, and educational behaviors covary with life expectancy. AB - Theories of "life history evolution" suggest that individuals might adjust the timing of marriage and reproduction, as well as their propensity to terminate a marriage or pregnancy and invest in skill development, in response to indicators of the locally prevailing level of life expectancy. In particular, such theories generate the hypothesis that foreshortened time horizons lead to hastened reproduction and marriage whereas lengthier time horizons increase the likelihood of reproductive and marital termination and lead to greater investment in education. Here, I show that the scheduling and occurrence of marital and reproductive behavior (including both initiation and termination), as well as levels of educational attainment and investment, covary with life expectancy, even after controlling for the effects of affluence. In analyses of variation in marital, reproductive, and educational behaviors at two jurisdictional levels in Canada, life expectancy was positively correlated with patterns of age-specific fertility, age at first marriage, divorce, abortion, conferral of high school and higher education degrees (with the exception of the trades) and mean number of years of schooling. The large and highly consistent relationships observed between life expectancy and the behaviors under investigation suggest that these associations may be mediated by individual "perceptions" of life expectancy, though more research is needed before conclusions can be firmly reached. PMID- 22484516 TI - Sensation seeking predicts brain responses in the old-new task: converging multimodal neuroimaging evidence. AB - Novel images and message content enhance visual attention and memory for high sensation seekers, but the neural mechanisms associated with this effect are unclear. To investigate the individual differences in brain responses to new and old (studied) visual stimuli, we utilized event-related potentials (ERP) and functional Magnetic Resonance Imaging (fMRI) measures to examine brain reactivity among high and low sensation seekers during a classic old-new memory recognition task. Twenty low and 20 high sensation seekers completed separate, but parallel, ERP and fMRI sessions. For each session, participants initially studied drawings of common images, and then performed an old-new recognition task during scanning. High sensation seekers showed greater ERP responses to new objects at the frontal N2 ERP component, compared to low sensation seekers. The ERP Novelty-N2 responses were correlated with fMRI responses in the orbitofrontal gyrus. Sensation seeking status also modulated the FN400 ERP component indexing familiarity and conceptual learning, along with fMRI responses in the caudate nucleus, which correlated with FN400 activity. No group differences were found in the late ERP positive components indexing classic old-new amplitude effects. Our combined ERP and fMRI results suggest that sensation-seeking personality affects the early brain responses to visual processing, but not the later stage of memory recognition. PMID- 22484518 TI - Responses of two invasive plants under various microclimate conditions in the Seoul metropolitan region. AB - The possible consequences of global warming on plant communities and ecosystems have wide-ranging ramifications. We examined how environmental change affects plant growth as a function of the variations in the microclimate along an urban suburban climate gradient for two allergy-inducing, invasive plants, Humulus japonicus and Ambrosia artemisiifolia var. elatior. The environmental factors and plant growth responses were measured at two urban sites (Gangbuk and Seongbuk) and two suburban sites (Goyang and Incheon) around Seoul, South Korea. The mean temperatures and CO(2) concentrations differed significantly between the urban (14.8 degrees C and 439 ppm CO(2)) and suburban (13.0 degrees C and 427 ppm CO(2)) sites. The soil moisture and nitrogen contents of the suburban sites were higher than those at the urban sites, especially for the Goyang site. The two invasive plants showed significantly higher biomasses and nitrogen contents at the two urban sites. We conducted experiments in a greenhouse to confirm the responses of the plants to increased temperatures, and we found consistently higher growth rates under conditions of higher temperatures. Because we controlled the other factors, the better performance of the two invasive plants appears to be primarily attributable to their responses to temperature. Our study demonstrates that even small temperature changes in the environment can confer significant competitive advantages to invasive species. As habitats become urbanized and warmer, these invasive plants should be able to displace native species, which will adversely affect people living in these areas. PMID- 22484519 TI - The influence of contrast on coherent motion processing in dyslexia. AB - The aim of the experiments was to investigate how manipulating the contrast of the signal and noise dots in a random dot kinematogram (RDK), influenced on motion coherence thresholds in adults with dyslexia. In the first of two experiments, coherent motion thresholds were measured when the contrasts of the signal and noise dots in an RDK were manipulated. A significantly greater processing benefit was found for the group with dyslexia than a control group when the signal dots were of higher contrast than the noise dots. However, a significant processing disadvantage was found for the group with dyslexia relative to the control group when the signal dots were of lower contrast than the noise dots. These findings were interpreted as supporting evidence for the noise exclusion hypothesis of dyslexia. In Experiment 2, the effect on coherent motion thresholds of presenting a cue that alerted observers to which stimuli, high or low contrast contained the signals dots was investigated. When the cue directed attention to low contrast signal dots presented in high contrast noise, coherent motion thresholds were only enhanced for the group with dyslexia. This manipulation produced equivalent coherent motion thresholds in the reader groups. In other conditions, the group with dyslexia had significantly higher coherent motion thresholds than the control group. It was concluded that adults with dyslexia who show evidence of a coherent motion deficit (37% of the dyslexia group in each experiment), have a specific difficulty in noise exclusion. This appears to occur as consequence of a sensory processing deficit in the magnocellular or dorsal stream. PMID- 22484521 TI - Dynamics of signaling, cytoskeleton and cell cycle regulation proteins in glioblastoma cells after sub-lethal photodynamic treatment: antibody microarray study. AB - BACKGROUND: Photodynamic therapy (PDT) that induces oxidative stress and cell death is used for tumor destruction in oncology. To characterize early molecular events in photosensitized glioblastoma cells, we studied expression of 224 proteins after sublethal PDT that doesn't kill but wounds cells. METHODS: Cultured glioblastoma D54Mg cells were photosensitized with 5-aminolevulinic acid so that cell survival was 95-100%. At following 0.5-5.5h protein expression and phosphorylation was assayed using proteomic antibody microarrays. RESULTS: Within the first post-treatment hour we observed phosphorylation of protein kinase Raf, adhesion-related kinases FAK and Pyk2, and microtubule-associated protein tau. Protein kinase Cgamma and microtubule-associated protein MAP-1B were overexpressed. Dystrophin, calponin, and vinculin, components of the actin cytoskeleton scaffold, microtubule-associated proteins MAP2 and CNP, cytokeratins 4 and 7 were down-regulated that indicated changes in adhesion and cell shape. Down-regulation of cyclins A, D1 and D3, c-Myc, checkpoint proteins chk1/2 and up regulation of Smad4 could arrest the cell cycle. Overexpression of Bcl-xL and down-regulation of caspase 9 demonstrated anti-apoptotic response. At 2h post treatment protein expression changed lesser but at 5.5h levels of PKCgamma and beta-synuclein and phosphorylation of Raf, FAK, Pyk2, and tau increased again. CONCLUSIONS: Sub-lethal PDT induces complex response of glioblastoma cells including changes in activity and expression of proteins involved in adhesion mediated signaling, signal transduction, cytoskeleton remodeling, cell cycle regulation and anti-apoptotic processes. GENERAL SIGNIFICANCE: Multiple reactions of various cellular subsystems including adhesion, cytoskeleton, signal transduction, cell cycle, and apoptosis are integrated into the general cell response to a sublethal impact. PMID- 22484520 TI - Age differences in default and reward networks during processing of personally relevant information. AB - We recently found activity in default mode and reward-related regions during self relevant tasks in young adults. Here we examine the effect of aging on engagement of the default network (DN) and reward network (RN) during these tasks. Previous studies have shown reduced engagement of the DN and reward areas in older adults, but the influence of age on these circuits during self-relevant tasks has not been examined. The tasks involved judging personality traits about one's self or a well known other person. There were no age differences in reaction time on the tasks but older adults had more positive Self and Other judgments, whereas younger adults had more negative judgments. Both groups had increased DN and RN activity during the self-relevant tasks, relative to non-self tasks, but this increase was reduced in older compared to young adults. Functional connectivity of both networks during the tasks was weaker in the older relative to younger adults. Intrinsic functional connectivity, measured at rest, also was weaker in the older adults in the DN, but not in the RN. These results suggest that, in younger adults, the processing of personally relevant information involves robust activation of and functional connectivity within these two networks, in line with current models that emphasize strong links between the self and reward. The finding that older adults had more positive judgments, but weaker engagement and less consistent functional connectivity in these networks, suggests potential brain mechanisms for the "positivity bias" with aging. PMID- 22484522 TI - Proteomic analysis of Holm oak (Quercus ilex subsp. ballota [Desf.] Samp.) pollen. AB - This paper presents an analysis of Holm oak pollen proteome, together with an evaluation of the potentiality that a proteomic approach may have in the provenance variability assessment. Proteins were extracted from pollen of four Holm oak provenances, and they were analyzed by gel-based (1- and 2-DE in combination with MALDI-TOF/TOF) and gel-free (nLC-LTQ Orbitrap MS) approaches. A comparison of 1- and 2-DE protein profiles of the four provenances revealed significant differences, both qualitative and quantitative, in abundance (18 bands and 16 spots, respectively). Multivariate statistical analysis carried out on bands and spots clearly showed distinct associations between provenances, which highlight their geographical origins. A total of 100 spots selected from the 402 spots observed on 2-DE gels were identified by MALDI-TOF/TOF. Moreover, a complementary gel-free shotgun approach was performed by nLC-LTQ Orbitrap MS. The identified proteins were classified according to biological processes, and most proteins in both approaches were related to metabolism and defense/stress processes. The nLC-LTQ Orbitrap MS analysis allowed us the identification of proteins belonging to the cell wall and division, transport and translation categories. Besides providing the first reference map of Holm oak pollen, our results confirm previous studies based on morphological observations and acorn proteomic analysis. Moreover, our data support the valuable use of proteomic techniques as phylogenetic tool in plant studies. PMID- 22484523 TI - Intake of alcohol-free red wine modulates antioxidant enzyme activities in a human intervention study. AB - Wine intake affects the antioxidant enzyme activities that contribute to the overall antioxidant properties of wine. The purpose of this study is to evaluate whether alcohol-free wine has any effect on antioxidant enzymes. The study was a randomized cross-over human intervention. A low phenolic diet (LPD) was designed to prevent interference from polyphenols in other food sources. In the first period, the volunteers ate only this low phenolic diet; in the second, they ate this diet and also drank 300 mL of alcohol-free wine. The enzymes under study were: superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. The activities of glutathione reductase, superoxide dismutase and catalase decreased during the LPD period and increased in the LPD+dealcoholized wine period. On the third day of intervention, significant changes were observed in glutathione reductase and superoxide dismutase activity for both intervention periods under study. Catalase activity changed significantly on the seventh day of intervention. Antioxidant enzymes modulated their activity more easily than the endogenous antioxidants, which did not undergo any changes. Our results show for the first time that the increase in the activity of the antioxidant enzymes is not due to the alcohol content in wine but to the polyphenolic composition. Therefore, alcohol-free wine could be an excellent source of antioxidants to protect people suffering from oxidative stress (cancer, diabetes, alzheimer, etc.) who should not consume alcohol. PMID- 22484524 TI - [The widening challenge of extended spectrum beta-lactamases]. AB - Since 1980, the prescription of new semi-synthetic molecules of third generation cephalosporins changed the course of modern medicine. However, the acquired resistance against these antibiotics was rapidly developed with the production of extended spectrum beta-lactamases (ESBL) (TEM and SHV types) disseminated mainly by nosocomial Klebsiella pneumoniae clones. Since around 2000, we are facing a watershed in ESBL epidemiology because of the widespread of the CTX-M enzymes among Escherichia coli isolates in community as well as in hospitals. The dissemination of these new ESBL in community within a commensal bacterium is a threat for the public health. The risk is to be in front of an uncontrollable resistance existing everywhere. It is the purpose of this review to focus, in particular, on the changing epidemiology and the spread of ESBL(s) and to provide updated data on definition, classification and laboratory detection of ESBL(s) that will help to control this resistance. PMID- 22484525 TI - [Automated hematology analysers and spurious counts Part 2. Leukocyte count and differential]. AB - Using hematology analysers, white blood cell (WBC) counts and differentials (either three or five parameters) may be ascertained after Red Blood Cell (RBC) lysis and analysis using either impedance and/or optical (laser) technology. Cells or particles not destroyed by lytic agents are enumerated as WBC: abnormal particles may be observed on WBC differential scattergrams, if performed, appearing as a variable number of dots, which location may help to ascertain the nature of the abnormality. Spuriously low WBC counts are rare, mainly related to agglutination in the presence of ethylenediamine tetra-acetic acid. Cryoglobulins, lipids, insufficiently lysed RBC, erythroblasts and platelet aggregates are common situations increasing WBC counts. So far, many current high performance analysers clearly identify and enumerate erythroblasts now. In normal patients and in reactive disorders automated differential provides true and accurate results. However, failure to enumerate accurately basophilic granulocytes and monocytes is not uncommon. Using myeloperoxidase cytochemistry to ascertain differential may lead to slide review if the enzyme expression is low or absent. Low number of abnormal cells (blasts, lymphoma cells, dysplastic granulocytes) may be missed, more frequently if leukopenia is present. In many but not all instances flagging and/or an abnormal WBC differential scattergram will alert the operator. Although these flags are sensitive enough to allow the identification of several spurious counts, only the most sophisticated analysers have optimal flagging, whereas more simple ones, especially those without a WBC differential scattergram, do not demonstrate the same sensitivity for the detection of abnormal results. PMID- 22484526 TI - [Automated hematology analysers and spurious counts Part 3. Haemoglobin, red blood cells, cell count and indices, reticulocytes]. AB - Several situations lead to abnormal haemoglobin measurement or to abnormal red blood cells (RBC) counts, including hyperlipemias, agglutinins and cryoglobulins, haemolysis, or elevated white blood cells (WBC) counts. Mean (red) cell volume may be also subject to spurious determination, because of agglutinins (mainly cold), high blood glucose level, natremia, anticoagulants in excess and at times technological considerations. Abnormality related to one measured parameter eventually leads to abnormal calculated RBC indices: mean cell haemoglobin content is certainly the most important RBC parameter to consider, maybe as important as flags generated by the haematology analysers (HA) themselves. In many circumstances, several of the measured parameters from cell blood counts (CBC) may be altered, and the discovery of a spurious change on one parameter frequently means that the validity of other parameters should be considered. Sensitive flags allow now the identification of several spurious counts, but only the most sophisticated HA have optimal flagging, and simpler ones, especially those without any WBC differential scattergram, do not share the same capacity to detect abnormal results. Reticulocytes are integrated into the CBC in many HA, and several situations may lead to abnormal counts, including abnormal gating, interference with intraerythrocytic particles, erythroblastosis or high WBC counts. PMID- 22484527 TI - [Antibacterial activity of rare Streptomyces species against clinical resistant bacteria]. AB - In the search for new antibiotics from Steptomyces, investigating extremes habitats enhances the probability of isolating novel producers. In this context, the antibacterial activity of four Streptomyces strains isolated from Ezzmoul saltpans was studied. Two of them showed antibacterial activity against antibiotic's resistant bacteria (Bacillus cereus: beta-lactamines and sulfamides resistant, Streptococcus faecalis: penicillin, tetracycline and cotrimoxazole resistant, and Staphylococcus aureus Mu 50: vancomycine resistant). The most active Streptomyces strain produces one type of polar bioactive molecules that resists to temperature variation and light exposition. Its activity appears in the first culture day and reaches its maximal value in the fourth day. The second strain presents themoresistant activity that reaches its maximal value in the first culture day. It produces two types of bioactive molecules, one is polar and the second is non polar (according to thin layer chromatography technique results). PMID- 22484528 TI - Allele and haplotype frequencies at human leukocyte antigen class I and II genes in Venezuela's population. AB - Population studies represent an integral part and link in understanding the complex chain of host-pathogen interactions, disease pathogenesis, and MHC gene polymorphisms. Genes of Mongoloid, Caucasoid, and Negroid populations have created a distinctive HLA genetic profile in the Venezuelan population. Our objective was to determine the predominant HLA class I and II alleles and haplotype frequencies in the hybrid population of Venezuela. The study population consisted of 486 healthy unrelated native Venezuelans and 180 families. We examined the frequency of HLA A-B-C, HLA-DQ and HLA-DR genes by polymerase chain reaction and subsequent hybridization with sequence-specific oligonucleotide probes. Phenotypic, allelic and haplotype frequencies were estimated by direct counting and using the maximum-likelihood method. The predominant HLA class I alleles were A*02, A*24, A*68, B*35, B*44, B*51, B*07, B*15 and Cw*07. Regarding HLA class II, the most frequent alleles were DQB1*03 and DRB1*04, DRB1*15, DRB1*13, DRB1*07. The prevailing haplotype was HLA-A*02B*35 DQB1*03 DRB1*04. Some of these alleles and haplotype frequencies were predominantly present in Amerindians (A*02, A*24, B*35, Cw*07, DRB1*04, A*24 B*35). Previous reports have shown high incidence of A*02, B*44, B*51, DRB1*15, DRB1*13, DRB1*07 alleles in several European populations and A*68, B*07, B*15 alleles in African Americans, which could have contributed to the ethnic admixture of the Venezuelan population. We conclude that our results provide strong evidence that Venezuela's population represents an admixture of the primitive Mongoloid Aborigines, Caucasoid Europeans and Western African Negroid migrants. PMID- 22484529 TI - [Lipid, lipoproteins and atherogenesis profiles in sickle cell disease among Central African patients]. AB - Lipid and lipopproteins disorders are well established in sera from sickle cell disease (SCD) patients out of Central Africa. The present case-control study was conducted to compare serum levels of total cholesterol (TC), HDL-C, triglycerides (TG), LDL-C and TC/HDL-C ratio (atherogenic index) from SCD homozygotes (SS) in steady state, SCD heterozygotes (AS) and controls (AA) in Brazzaville, Congo. Significant reductions of TC and LDL-C vs. increase in TG were reported in SS. However, significant decrease in HDL-C and increase in atherogenic index were observed in AS. We recommend prevention of oxidative stress, dyslipidemia and atherosclerosis in SCD using hygiene-diet measures. Only longitudinal studies in large populations will provide pathophysiological basis of lipid and lipoproteins disorders in SCD. PMID- 22484530 TI - [Genetic variability of type 3 echoviruses]. AB - The aim of the present work was to assess the genetic and antigenic variability in the VP1 region of type 3 echviruses (E-3), an enterovirus serotype associated to meningitis, neuro-muscular diseases and type 1 diabetes in human. Forty-six VP1 sequences of E-3, among which 9 were isolated in tunisian infants, were included. Phylogenetic analyses and nucleotidic divergence rates were studied in the complete VP1 region and in a 290-nucleotides fragment in the 5' part of the P1. Aminoacid sequences were deduced in the aim to identify genotype-specific antigenetic determinants. E-3 sequences divided into two genogroups, I and II; the genetic variability within the E-3 serotype reached 29.1%. Genogroup I included sequences with a relatively high genetic diversity among each other, some of them grouped in one genotype with at most 15.1% divergence rate. The sequences included in Genogroup II have a maximum of 13.8% divergence corresponding probably to only one genotype. The two genogroups have a concomitant circulation and a wide geographical and temporal distribution. Aminoacid substitutions that may be specific to genogroups, genotypes and special variant were noted. This work provides a first tentative of classification of E-3 into genogroups and genotypes and reports new E-3 sequences from North Africa. It contributes to a better understanding of the molecular epidemiology of human enteroviruses, and of Echoviruses type 3 in particular, a serotype that remains insufficiently studied in the international literature. PMID- 22484531 TI - [Risk of hyperthyroidism in a Tunisian population of smokers]. AB - OBJECTIVES: This study aimed to examine the effect of cigarette smoking on thyroid function especially TSH and FT4 levels and to determine the correlation between these parameters and the biological tobacco markers: plasma thiocyanate and cotininuria. METHODS: The initial study was conducted on 300 voluntary subjects, 162 current smokers, 27 former smokers and 111 nonsmokers aged respectively 35.4+/-16.1, 31.6+/-1.8 and 38.0+/-14.6 years. TSH and FT4 levels were determined using electrochemiluminescence, cotinine by homogenous enzymes immunoassay and thiocyanate by selective electrode. RESULTS: Before and after adjustment for potentials confounder factors, we found a significant decrease of TSH and a significant increase of FT4 levels according to smoking status. In current and former smokers, we found significant decrease in TSH and increase in FT4 levels compared to nonsmokers. Moreover, we noted a significant decrease of TSH levels in subjects smoking more than 40 cigarettes/day compared to those smoking less than 20 cigarettes/day. Additionally, TSH levels were significantly reduced in subjects smoking more than 5 years compared to those who smoked < 5 years. In smokers, cotininuria and plasma thiocyanates presented a negative correlation with TSH and a positive correlation with FT4 levels. CONCLUSION: cigarette smoking is associated to perturbations in FT4 and TSH levels, these perturbations were strongly correlated with smoking status parameters. The associations with smoking cessation suggest that smoking may have reversible effects on thyroid function. Therefore, it is recommended to stop or reduce smoking and to introduce testing of thyroid estimation as a routine test, especially in subjects at risk. PMID- 22484532 TI - [Recurring peritonitis due to Streptococcus from the upper respiratory tract in a saxophone player under peritoneal dialysis]. AB - This is a nephrectomized patient of 77 years, musician (saxophonist), in peritoneal dialysis, with diabetes, hypertension, and coronary disease. He presented a few months apart two successive episodes of peritonitis due to Streptococcus mitis/oralis and Streptococcus parasanguis. Before each episode he played the saxophone he played twice and each time he has peritonitis. Colonoscopy objectifying a sigmoid polyp. The assumption of self-contamination of the patient was supported by the fact that S. mitis/oralis and S. parasanguis are oral streptococci, and the intraperitoneal pressure (IPP) from 8 to 32 cm of water when the patient plays the saxophone. In this measurement of IPP we have also seen how the saliva is spread on all sides when playing the saxophone. Our patient is now cured and did not include the saxophone. PMID- 22484533 TI - A comparison of corrected serum calcium levels to ionized calcium levels in haemodialysis patients. AB - Aberrations in calcium homeostasis are common observed in patients with chronic renal failure. Measure of total calcium does not reflect the real variation of the calcium status. The proper method to evaluate this issue in hemodialysis patients has not been completely defined. This study aimed to compare the corrected serum calcium levels to ionized calcium levels in hemodialysis patients. Thirty one patients on chronic haemodialysis admitted at the hemodialysis department were retrospectively reviewed. Calcium status was evaluated by measure of ionized levels and as a function of serum calcium levels corrected for albumin aberrations. Based on the measurement of ionized calcium and total calcium corrected, patients were classified into three categories: hypocalcemic, normocalcemic and hypercalcemic. Our result showed that the corrected serum calcium values failed to accurately classify calcium status in 41% of cases. The sensitivity and specificity of the corrected serum calcium formula to evaluate hypocalcemia were 53% and 85%, respectively. Corrected serum values underestimated the prevalence of hypocalcemia and overestimated the prevalence of normocalcemia. In total, the results obtained allow to conclude the lack of interest in the use of correction formulas. Calcium homeostasis should be evaluated by ionized calcium levels rather than as a function of serum calcium and albumin. PMID- 22484534 TI - An unusual three-way translocation t(21;8;1)(q22;q22;q32) in a case of acute myeloid leukemia (M2). AB - Variant forms of the classic translocation t(8;21) are uncommon and account approximately 3% of all t(8;21)(q22;q22) in acute myeloid leukemia (AML) patients. These forms involve chromosomes 8, 21, and other chromosomes. Here we report a Tunisian patient with a complex rearrangement t(21;8;1)(q22;q22;q32) revealed by conventional chromosomal study at diagnosis. Fluorescence in situ hybridization study revealed the presence of the AML1-ETO chimeric gene on the derivative chromosome 8. To the best of our knowledge, this is the second case of t(21;8;1) of AML-M2 reported in the literature with the involvement of the same breakpoint at 1q32. This illustrates that this complex translocation is rarely encountered in AML and reinforces the fact that this region may harbour a critical gene candidate that may play an important role in the pathogenesis of AML. More cases are needed to elucidate its clinical features and prognosis. PMID- 22484535 TI - [Extra medullary hematopoiesis associated to congenital dyserythropoietic anemia II in adult]. AB - The congenital dyserythropoietic anemias comprise a group of rare hereditary disorders of erythropoiesis characterized by anemia with ineffective erythropoiesis and morphological abnormalities of erythroblasts in the bone marrow. Congenital dyserythropoietic anemia type II or HEMPAS is the more frequent type. It is rare in adults. Extra medullary hematopoiesis is also a rare entity; it is a physiological response to chronic anemia observed in certain hemopathies like congenital dyserythropoietic anemia type II. We report the observation of a patient for who diagnosis of extra medullary hematopoiesis associated to congenital dyserythropoietic type II was made in adulthood. PMID- 22484536 TI - [Munchhausen syndrome by proxy revealed by falsely toxic methotrexate levels]. AB - Methotrexate is an antifolate drug used intravenously at high-dose in acute lymphocytic leukemia (ALL). Therapeutic drug monitoring is required to identify patients at risk of developing toxicity and to control folinic acid rescue. We report a case of Munchausen syndrome by proxy revealed by high and persistent falsely toxic methotrexate plasmatic levels. A 12 year-old child was treated with chemotherapy including methotrexate every 70 days for an ALL. The last methotrexate plasmatic level was 0.15 MUmol/L at the 72th hour of the infusion. Then, he was treated by oral rout low-dose methotrexate. Ten days after methotrexate infusion, the patient consulted for asthenia, vomiting and presented a mucositis. Methotrexate plasmatic level was 2323 MUmol/L. Renal function was normal. All drugs' intake was stopped. Folinic acid rescue was instituted. Even though there was no clinical sign of toxicity, therapeutic drug monitoring showed persistent high methotrexate plasmatic levels. Investigations eliminated measurement errors and pharmacokinetic problems. A deliberate methotrexate addition in each child blood sample brought by the mother was highly suspected. We confirmed this hypothesis by measuring methotrexate plasmatic levels in three samples: one brought by the mother, the second brought by the child's doctor and the last collected in our laboratory. Methotrexate plasmatic levels were respectively over 10,000 MUmol/L (first sample) and lower than 0.02 MUmol/L (the two others). The diagnosis of Munchausen's syndrome by proxy revealed by falsely toxic methotrexate plasmatic levels was made and the mother was addressed to the psychiatric department. PMID- 22484537 TI - [Lupus anticoagulant-hypoprothrombinemia syndrome revealing systemic lupus in an 11-year old girl in a context of clinical and biological emergency]. AB - We report a case of lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) in an 11 year old girl initially hospitalized for bleeding. The patient presented with petechia, persisting bleeding after tooth extraction performed two days before, nephritic syndrome (renal failure, proteinuria and macroscopic hematuria), severe anemia, thrombocytopenia, lymphopenia. The association of these abnormalities suggested LAHPS secondary to severe systemic lupus. Immediate treatment with fresh frozen plasma and intravenous immunoglobulins (400 mg/kg/5d) was started and followed by steroid (500 mg/d) and cyclophosphamide (800 mg/m(2)) pulse therapy leading to rapid improvement of bleeding, renal involvement and prothrombin levels within 13 days. Lupus diagnosis was confirmed by immunological investigations and renal biopsy. Two early relapses occurred despite adequate treatment. After a follow-up of two years, no further disease activity is noted while the patient is treated only by mycophenolate mofetil (1 200 mg/m(2)/d). LAHPS did not relapse during this follow-up. PMID- 22484538 TI - [Update on Mycobacterium bovis infections in France: 4 cases reports]. AB - Mycobacterium bovis (M. bovis) is a cause of zoonosis. It is rare in developed countries since cattle control. We report four cases of M. bovis infection in people aged more 60 years. They were probably infected during infancy, consuming unpasteurized milk. It is the main transmission mode in developing countries where veterinary controls aren't made. M. bovis infections clinical aspects are varied and treatment is complicated by natural pyrazinamide resistance. Recent diagnostic methods using molecular biology are quick and specific and facilitate identification. PMID- 22484539 TI - [A rare cause of hyperamylasemia]. PMID- 22484540 TI - [Are D-dimer levels still indicative of thromboembolic disease?]. PMID- 22484541 TI - Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells. AB - Peroxiredoxins (Prxs) are potential therapeutic targets for major diseases such as cancers. However, isotype-specific inhibitors remain to be developed. We report that adenanthin, a diterpenoid isolated from the leaves of Rabdosia adenantha, induces differentiation of acute promyelocytic leukemia (APL) cells. We show that adenanthin directly targets the conserved resolving cysteines of Prx I and Prx II and inhibits their peroxidase activities. Consequently, cellular H(2)O(2) is elevated, leading to the activation of extracellular signal-regulated kinases and increased transcription of CCAAT/enhancer-binding protein beta, which contributes to adenanthin-induced differentiation. Adenanthin induces APL-like cell differentiation, represses tumor growth in vivo and prolongs the survival of mouse APL models that are sensitive and resistant to retinoic acid. Thus, adenanthin can serve as what is to our knowledge the first lead natural compound for the development of Prx I- and Prx II-targeted therapeutic agents, which may represent a promising approach to inducing differentiation of APL cells. PMID- 22484542 TI - A Scalable, Flexible Workflow for MethylCap-Seq Data Analysis. AB - Advances in whole genome profiling have revolutionized the cancer research field, but at the same time have raised new bioinformatics challenges. For next generation sequencing (NGS), these include data storage, computational costs, sequence processing and alignment, delineating appropriate statistical measures, and data visualization. The NGS application MethylCap-seq involves the in vitro capture of methylated DNA and subsequent analysis of enriched fragments by massively parallel sequencing. Here, we present a scalable, flexible workflow for MethylCap-seq Quality Control, secondary data analysis, tertiary analysis of multiple experimental groups, and data visualization. This workflow and its suite of features will assist biologists in conducting methylation profiling projects and facilitate meaningful biological interpretation. PMID- 22484543 TI - Brain-derived neurotrophic factor facilitates memory consolidation and reconsolidation of a weak training stimulus in the day-old chick. AB - Recent research has pointed to a role for brain-derived neurotrophic factor (BDNF) in long-term potentiation and memory. The present series of experiments examined the effects of the application of exogenous BDNF on memory consolidation and reconsolidation of a weak training stimulus with the day-old chick, using the passive avoidance learning paradigm. Chicks injected intracranially with 12.5 MUg/mL recombinant BDNF immediately after a single-trial training event displayed enhanced retention relative to saline up to 24h post-training. Furthermore, this dose was also shown to enhance retention when administered following initial weak training. Thus, exogenous BDNF was shown to enhance both consolidation and reconsolidation of memory when administered acutely to the day-old chick. PMID- 22484544 TI - Decreased GABABR expression and increased neuronal cell death in developing rat brain after PTZ-induced seizure. AB - The objective of this study was to evaluate the PTZ-induced seizures effects on GABAB receptor (R) expression and to observe its neurodegenerative effect in hippocampal part of developing rat brain. In the present study, high dose of pentylenetetrazol (PTZ 40 mg/kg) was injected in developing rats of age 5 weeks having average weight of 60-65 g for 4 days. Further, baclofen (B 3 mg/kg i.p) agonist and phaclofen (P 30 MUg/rat) antagonist of GABABR were injected along with PTZ. Western blot analysis was used to elucidate expression of GABABR protein upon PTZ, baclofen and phaclofen exposure in the developing rat brain. Furthermore, PTZ-induced apoptotic neurodegeneration was also observed through the release of caspase-3 antibody and propidium iodide (PI) staining using confocal microscopy. Seizure was confirmed using electroencephalography (EEG) data obtained from the Laxtha EEG-monitoring device in the EEG recording room and EEG was monitored 5-15 min after PTZ injection. The results of the present study showed that PTZ-induced seizure significantly decreased GABABR expression and induced neuronal apoptosis in cortical and hippocampal part of brain. While, baclofen reverse the effect of PTZ by increasing the expression of GABABR as compared to the PTZ- , PTZ plus B- and PTZ plus P-treated groups. Our findings indicated that PTZ-induced seizure showed not only decrease in GABABR expression but also cause neuronal apoptosis in the developing rat brain. PMID- 22484545 TI - Multiple myeloma-associated iliopsoas muscular amyloidoma first presenting with bilateral femoral nerve entrapment. AB - We report a 38-year-old man of multiple myeloma with bilateral femoral nerve entrapment caused by bilateral huge protruding masses in the inguinal areas. The masses were identified as iliopsoas muscular amyloidoma after the operation. He was diagnosed with multiple myeloma 1 year ago before he was admitted to our hospital. He complained of muscle weakness in the bilateral thigh and protruding lumps in the bilateral inguinal areas with tenderness for 6 month. The pelvic MRI revealed round masses in the iliopsoas muscles of bilateral inguinal areas. To implement the nerve decompression, the resection of the bilateral masses was done. The pathological result showed Congo red-positive substance with green birefringence to polarized light in a dense fibrous background. Before the operation, six cycles of chemotherapy with VAD (vincristine, adriamycin, dexamethasone) and two cycles of chemotherapy with PAD (bortezomib, adriamycin, dexamethasone) regimen were performed. One month after the operations, one cycle of chemotherapy with PADT (bortezomib, adriamycin, dexamethasone, thalidomide) regimen was used and the patient reached complete remission. The function of the bilateral femoral nerves restored to normal 7 months after the operation with a Karnofsky score of 100. Twenty-two months follow-up showed that there was no evidence of the recurrence of the iliopsoas muscular amyloidoma and no progression of multiple myeloma. PMID- 22484546 TI - Microtissue size and hypoxia in HTS with 3D cultures. AB - The three microenvironmental factors that characterize 3D cultures include: first, chemical and/or biochemical composition, second, spatial and temporal dimensions, and third, force and/or substrate physical properties. Although these factors have been studied individually, their interdependence and synergistic interactions have not been well appreciated. We make this case by illustrating how microtissue size (spatial) and hypoxia (chemical) can be used in the formation of physiologically more relevant constructs (or not) for cell-based high-throughput screening (HTS) in drug discovery. We further show how transcriptomic and/or proteomic results from heterogeneously sized microtissues and scaffold architectures that deliberately control hypoxia can misrepresent and represent in vivo conditions, respectively. We offer guidance, depending on HTS objectives, for rational 3D culture platform choice for better emulation of in vivo conditions. PMID- 22484547 TI - Strategic alliances and market risk. AB - Strategic alliances in product development and marketing are crucial to the biotechnology industry. Many alliances, however, are terminated before the drug reaches the market. In this article we make the case that strategic alliances can fail because of how they are negotiated. Alliance contracts are often inflexible and do not allow for changes in market conditions. We propose a model for contract valuation that can assist biotech and/or pharma deal makers in negotiating alliances that have a higher chance of survival in uncertain market conditions. The model makes use of variable royalties and milestone payments. Because licensing is key to the biotech and/or pharma business model this article will be of interest not only to professionals in licensing, but to all professionals active in the industry. PMID- 22484548 TI - Immigrant students' emotional and cognitive engagement at school: a multilevel analysis of students in 41 countries. AB - Central to student learning and academic success, the school engagement of immigrant children also reflects their adaptation to a primary institution in their new country. Analysis of questionnaire responses of 276,165 fifteen-year olds (50 % female) and their 10,789 school principals in 41 countries showed that school engagement has distinct, weakly-linked cognitive and emotional components. Native students had weaker attitudes toward school (cognitive engagement) but greater sense of belonging at school (emotional engagement) than immigrant students or students who spoke a foreign language at home. Students with better teacher-student relationships, teacher support or a classroom disciplinary climate often had a greater sense of belonging at school and had better attitudes toward school than other students. While immigrant students often have solid attitudes toward school, teachers can help them feel a greater sense of belonging at school. PMID- 22484549 TI - Costs and cost-effectiveness of hematopoietic cell transplantation. AB - Interest is growing in economic and comparative effectiveness analyses, with increasing emphasis on optimizing healthcare resources and costs. Limited information is available on the economic aspects of hematopoietic cell transplantation (HCT). We review contemporary literature on the costs and cost effectiveness of HCT in the United States and worldwide. Published studies confirm the high costs associated with HCT, although the reported costs are highly variable, related to the differing methodologies used across studies. We examine the challenges in reviewing costs and cost-effectiveness across studies specific to HCT and highlight factors identified as associated with higher costs of HCT. We also discuss opportunities for future research in this area. PMID- 22484550 TI - Dendritic cell subsets in neoplastic tissue and peripheral blood of laryngeal cancer patients: relation with grade and stage of the disease. AB - Despite improvements in immunotherapy, little is known about dendritic cell (DC) subpopulations naturally occurring in the laryngeal cancer tissue (LCT) and peripheral blood (PB) of untreated laryngeal cancer (LC) patients. The purpose of the present study was to evaluate mature, immature myeloid and plasmacytoid DCs in the LCT and PB of patients with various stages and grades of squamous cell carcinoma of the larynx (n=66) and PB of healthy donors (n=20), and to explore the correlation of the percentages of the DCs to clinical parameters. The percentage of DCs in LCT and PB was determined using monoclonal antibodies and flow cytometry. It has been revealed that DCs accumulate in LCT in comparison with their content in PB. The myeloid to lymphoid/plasmacytoid DC ratio was higher in LCT compared to PB. It was found that in cases of poorly-differentiated LC, there were higher percentages of lymphoid/plasmacytoid DCs in LCT in comparison to their content in the PB. Moreover, in the blood of patients with T4 cancers we found significantly lower percentages of myeloid DCs in comparison to individuals with T1 neoplasms. The percentage of myeloid DCs infiltrating cancer tissue positively correlated with the T stage. In patients with no metastases in the lymph nodes, PB contained less mature DCs but higher amount of myeloid DCs compared to LCT. Alteration of the DC proportion in LC patients may result in the development of immunotolerance. PMID- 22484551 TI - Lipread-induced phonetic recalibration in dyslexia. AB - Auditory phoneme categories are less well-defined in developmental dyslexic readers than in fluent readers. Here, we examined whether poor recalibration of phonetic boundaries might be associated with this deficit. 22 adult dyslexic readers were compared with 22 fluent readers on a phoneme identification task and a task that measured phonetic recalibration by lipread speech (Bertelson, Vroomen, & De Gelder, 2003). In line with previous reports, we found that dyslexics were less categorical in the labeling of the speech sounds. The size of their phonetic recalibration effect, though, was comparable to that of normal readers. This result indicates that phonetic recalibration is unaffected in dyslexic readers, and that it is unlikely to lie at the foundation of their auditory phoneme categorization impairments. For normal readers however, it appeared that a well-calibrated system is related to auditory precision as the steepness of the auditory identification curve positively correlated with recalibration. PMID- 22484552 TI - Evaluation of 2-deoxy-2-[18F]fluoro-D-glucose- and 3'-deoxy-3' [18F]fluorothymidine-positron emission tomography as biomarkers of therapy response in platinum-resistant ovarian cancer. AB - PURPOSE: We evaluated whether 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) positron emission tomography (PET) could be used as imaging biomarkers of platinum resensitization in ovarian cancer. PROCEDURES: Paired platinum-sensitive and platinum-resistant ovarian cancer cells from the same patient, PEO1 and PEO4, grown as tumor xenografts in nude mice, were assessed by PET. RESULTS: The AKT inhibitor, API-2, resensitized platinum-resistant PEO4 tumors to cisplatin, leading to a markedly lower Ki67 labeling index (p <= 0.006, n = 6 per group). [(18)F]FDG-PET and [(18)F]FLT-PET imaging variables were lower after combination treatment compared with vehicle treatment (p <= 0.006, n = 6 per group). No changes were seen with either drug alone. PRAS40 phosphorylation status was a sensitive biochemical marker of pathway inhibition, whereas reductions thymidine kinase 1 expression defined the [(18)F]FLT response. CONCLUSIONS: Therapeutic inhibition of AKT activation in acquired platinum-resistant disease can be imaged noninvasively by [(18)F]FDG-PET and [(18)F]FLT-PET warranting further assessment. PMID- 22484553 TI - Letter regarding "management of ear lobule keloids using 980-nm diode laser". PMID- 22484554 TI - Maturity-dependent fractionation of neutrophil progenitors: a new method to examine in vivo expression profiles of differentiation-regulating genes. AB - To investigate differentiation-dependent gene expression during granulopoiesis, we established a new method to isolate six sequential differentiation stages of neutrophil progenitors from bone marrow. Neutrophil progenitors were divided into three populations by density centrifugation, followed by depletion of other lineages, and further separated by fluorescence-activated cell sorting based on the expressions of CD34, CD11b, and CD16: CD34(+) fraction from a low-density population (F1), CD11b(-)/CD16(-) (F2), CD11b(+)/CD16(-) (F3), and CD11b(+)/CD16(low) (F4) fractions with intermediate density, and CD11b(+)/CD16(int) (F5) and CD11b(+)/CD16(high) (F6) fractions from a high density population. To examine whether this fractionation was applicable to the study of in vivo gene expression profiles during granulopoiesis, we analyzed messenger RNA levels of AML-1 and CCAAT/enhancer binding protein (EBP)-epsilon and two target genes of C/EBP-epsilon, granulocyte-macrophage colony-stimulating factor receptor common beta subunit and lactoferrin, in the six fractions and peripheral blood-derived neutrophils (F7). Expression of AML-1 and C/EBP-epsilon peaked at F1 and F4, respectively, followed by a gradual decrease. Although granulocyte-macrophage colony-stimulating factor receptor common beta subunit messenger RNA levels remained low from F1 through F6 and elevated at F7, lactoferrin messenger RNA showed a drastic increase at F3 and dropped at F5. The difference in the expression profiles of the two C/EBP-epsilon target genes suggests the involvement of regulators other than C/EBP-epsilon in the induction of the two genes. The new fractionation method is able to provide new information on maturation-dependent gene expression during granulopoiesis. PMID- 22484555 TI - Converted lumbar BMD values derived from sagittal reformations of contrast enhanced MDCT predict incidental osteoporotic vertebral fractures. AB - We obtained baseline and follow-up bone mineral density (BMD) values of the lumbar spine from sagittal reformations of routine abdominal contrast-enhanced multidetector computed tomography (MDCT) using a reference phantom and assessed their performance in differentiating patients with no, existing, and incidental osteoporotic fractures of the spine. A MDCT-to-QCT (quantitative computed tomography) conversion equation for lumbar BMD measurements was developed by using 15 postmenopausal women (63 +/- 12 years), who underwent standard lumbar QCT (L1-L3) and afterward routine abdominal contrast-enhanced MDCT. Sagittal reformations were used for corresponding lumbar BMD measurements. The MDCT-to-QCT conversion equation was applied to baseline and follow-up routine abdominal contrast-enhanced MDCT scans of 149 postmenopausal women (63 +/- 10 years). Their vertebral fracture status (no, existing, or incidental osteoporotic fracture) was assessed in the sagittal reformations. A correlation coefficient of r = 0.914 (p < 0.001) was calculated for the BMD values of MDCT and standard QCT with the conversion equation BMD(QCT) = 0.695 * BMD(MDCT) - 7.9 mg/mL. Mean follow-up time of the 149 patients was 20 +/- 12 months. Fifteen patients (10.1 %) had an existing osteoporotic vertebral fracture at baseline. Incidental osteoporotic vertebral fractures were diagnosed in 13 patients (8.7 %). Patients with existing and incidental fractures showed significantly (p < 0.05) lower converted BMD values (averaged over L1-L3) than patients without fracture at baseline and at follow-up. In this longitudinal study, BMD values of the lumbar spine derived from sagittal reformations of routine abdominal contrast-enhanced MDCT predicted incidental osteoporotic vertebral fractures. PMID- 22484556 TI - Genetic and environmental multidimensionality of well- and ill-being in middle aged twin men. AB - The goals of the study were to determine the extent to which the underlying structure of different types of well-being was multidimensional and whether well- and ill-being were influenced by similar or different genetic and environmental factors. Participants were 1226 male twins ages 51-60, from the Vietnam Era Twin Study of Aging. Measures included: psychological well-being, Multidimensional Personality Questionnaire Well-Being scale (MPQWB), life satisfaction, self esteem, and depressive symptoms. A two-orthogonal-factor common pathway model fit the data well. Psychological well-being and self-esteem loaded most strongly on Factor 1, which was highly heritable (h(2) = .79). Life satisfaction loaded most strongly on Factor 2, which was only moderately heritable (h(2) = .32). Only MPQWB had measure-specific genetic influences. Depressive symptoms loaded on both factors, and only depressive symptoms had measure-specific common environmental influences. All measures had specific unique environmental influences. Results indicate that well-being is genetically and environmentally multidimensional and that ill-being has partial overlap with both latent factors. PMID- 22484557 TI - Intercapillary bridging cells: immunocytochemical characteristics of cells that connect blood vessels in the retina. AB - Intervascular bridges are fibrous strands that connect neighboring capillaries. These strands present associated cells, intervascular bridging cells (IBCs), whose nature and functional significance remains controversial. The aim of this study was to characterize the immunophenotype of IBCs, and contribute to understand their mechanical and intercellular communication properties in the retina. Quantification and retinal distribution of IBCs were also determined. For this purpose, C57BL/6N and nestin-GFP transgenic mice, as well as human retinas, were used. Whole-mount retinas were studied by means of immunohistochemistry and cytochemistry, and isolation of retinal vasculature was achieved by trypsin/pepsin digest technique. PAS reaction and the immunolabeling with anti collagen IV and laminin antibodies revealed that IBCs were completely surrounded by a basement membrane, connecting two or more neighboring capillaries. IBCs were scarce and their number decreased with age. They were preferentially localized in the deep vascular plexus. In a murine model of experimental glaucoma, methylcellulose injected eyes showed retinal neovascularization and increased number of IBCs in the deep vascular plexus. IBCs were marked with anti-NG2, anti PDGFR-beta and anti-CD34 antibodies, and with tomato lectin, and were negative for PECAM-1. IBCs expressed nestin and filamentous actin, but desmin and alpha smooth muscle actin were not detected. Moreover, these cells expressed the gap junction protein connexin 43. These results showed that IBCs had a pericytic nature since they expressed NG2 and the receptor for PDGF-B, and they were negative for PECAM-1. However, they were marked with CD34 and the tomato lectin, suggesting that they constitute a special subtype of pericytes, sharing characteristics with endothelial cells. IBCs presumably present mechanical functions due to the presence of filamentous actin. Connexin 43 was found in IBCs, suggesting that these cells allow intercellular communication between adjacent capillaries. This may represent an advantage for vasomotor tone integration and coordination in blood vessels without innervation, such as those of the retina. PMID- 22484558 TI - Enzymatic digestion improves the purity of harvested cerebral microvessels. AB - The harvest of intact cerebral microvessel yields could permit the in vitro characterization of mechanisms that underlie numerous vascular-linked central nervous system (CNS) phenomena. Here, we test (1) the effect of mild enzyme digestion on microvessel purity and yield; and then (2) the effect of variable centrifugation and filtration methods on microvessel yields. The brains of female Sprague-Dawley rats (4 weeks-old; n=38) were removed rapidly and homogenized. In Experiments 1 and 2, brain homogenates were incubated in DMEM or a solution of papain (2.5 U/ml), DNAse I (250 U/ml) and dispase II (1 U/ml) in DMEM for 15 min at 37 degrees C before microvessels were purified using differential (20% Ficoll) and then discontinuous (15/20% Dextran) centrifugation (@3500 * g) and collected with glass bead column filtration. Enzymatic digestion decreased microvessel yields (27 vs. 12 k/g tissue; p=0.053) but increased microvessel purity by decreasing adherent cells (p=0.002), which included NF-L(+) neurons (p<0.05) and GFAP+ astrocytes (p<0.001) and astrocyte endfeet (p<0.01). After one week in culture, >85% of harvested cells morphologically resembled microvessels and expressed the vascular proteins lectin and/or RECA-1. Finally, microvessels yields decreased when discontinuous centrifugation was omitted or nylon mesh filtration was employed. In summary, we found that digesting brain homogenates enzymatically could improve the purity of harvested microvessels that could be cultured for at least a week. PMID- 22484559 TI - A novel method to study the local mitochondrial fusion in myelinated axons in vivo. AB - Mitochondrial remodeling (replication, fission/fusion) is a dynamically regulated process with diverse functions in neurons. A myelinated axon is an extension from the cell soma of a fully differentiated neuron. Mitochondria, once synthesized in the cell body, enter the axon displaying robust trafficking and accumulation at nodes of Ranvier to match metabolic needs. This long-distance deployment of mitochondria to axons raises the issue of whether myelinated axons can function independently of the cell body to execute mitochondrial remodeling to match local demands. Mitochondrial fusion has been suggested to occur in axons in simple neuronal cultures in vitro. However, whether such events occur in vivo in an intact nervous system remains unanswered. Here we describe a novel technique which allows monitoring of mitochondrial fusion in intact sciatic nerve of frog (Xenopus laevis). Mitochondrial population was labeled by injecting two different MitoTracker dyes (Red and Green), spatially apart along sciatic nerves surgically and then allow to "meet"in vivo. At 24h post-surgery, the sciatic nerves were taken out for mitochondrial imaging at the half-way point. During the post injection periods, the anterograde-directed Green mitochondria meet with the retrograde-directed Red mitochondria. If fusion occurs, the merged of Green and Red fluorophores in the same mitochondrion will produce a Yellow color in merged images. The labeled mitochondria were observed with a Nikon A1 confocal microscope. Our new mitochondrial imaging method opens an avenue to separately assess the role of local axonal mitochondrial fusion, independent of the cell body of nerve fibers. PMID- 22484560 TI - Metastatic disease: a drug discovery perspective. AB - Disseminated tumor cells are present in many patients at diagnosis. At a time when the disseminated disease becomes prominent, patients have already been treated with many cycles of therapy to which their metastases were also exposed. These metastases have genetically evolved from primary tumors. Furthermore, their interaction with the tissue microenvironment plays an important role in all phases of disease development. These facts have only partially been taken into consideration when profiling anti-cancer compounds foreseen to treat patients with disseminated metastatic disease. In this perspective, we discuss the unique features of metastatic disease and review the model systems available for drug profiling. Based on an analysis of how compounds are profiled today in pre clinical models of metastatic disease and what would be desirable and possible with the present know-how, we recommend a refined profiling process to validate drugs with potential to treat patients with overt metastatic disease. PMID- 22484561 TI - Molecular networks that regulate cancer metastasis. AB - Tumor metastases are responsible for approximately 90% of all cancer-related deaths. Although many patients can be cured, in the US and UK, cancer still causes 730,000 deaths every year, and it is second only to cardiovascular disease as a cause of death. The functional roles of many critical players involved in metastasis have been delineated in great detail in recent years, due to the draft of the human genome and to many associated discoveries. Here, we address several genetic events and critical factors that define the metastatic phenotype acquired during tumorigenesis. This involves molecular networks that promote local cancer cell invasion, single-cell invasion, formation of the metastatic microenvironment of primary tumors, intravasation, lymphogenic metastasis, extravasation, and metastatic outgrowth. Altogether, these functional networks of molecules contribute to the development of a selective environment that promotes the seeding and malignant progression of tumorigenic cells in distant organs. We include here candidate target proteins and signaling pathways that are now under clinical investigation. Although many of these trials are still ongoing, they provide the basis for the development of new aspects in the treatment of metastatic cancers, which involves inhibition of these proteins and their molecular networks. PMID- 22484562 TI - Facial expressions of mice in aggressive and fearful contexts. AB - Some animals display a variety of context dependent facial expressions. Previous studies have shown that rodents display a facial grimace while in pain. To determine if the facial expressions of mice extend beyond pain, facial expressions were analyzed in the presence of non-social, social and predator stimuli. In a vibrissae contact test, the whiskers of mice were stroked by the bristles of a brush. In a social proximity test, two mice were placed together in a small chamber where contact was virtually unavoidable. In a resident-intruder test of aggression, an unknown mouse was placed into the homecage of another mouse. In a cat odor exposure test and in a live rat exposure test, mice were presented with the respective stimuli. Results from this study indicated that mice showed two patterns of expression, either a full display of changes in the measured facial components, characterized by tightened eyes, flattened ears, nose swells and cheek swells; or a more limited display of these facial changes. The full display of changes occurred in the vibrissae contact test, the social proximity test, and in resident mice in the resident-intruder test. The more limited display of facial changes occurred in the cat odor exposure test, the rat exposure test and in intruder mice in the resident-intruder test. The differential display of facial changes across conditions indicated that mice showed tightened eyes and flattened ears in situations that provided the immediate potential for contact, suggesting that such changes are involved in protection of sensitive and/or vulnerable body parts. Furthermore, the display of facial expressions by mice indicates that these expressions are widely distributed across evolution. PMID- 22484563 TI - Taste neophobia and palatability: the pleasure of drinking. AB - Taste neophobia is manifested behaviorally as lower intake of a novel, potentially dangerous tastant relative to the same tastant when it is perceived as safe and familiar. To further characterize this phenomenon, microstructural analysis of lick patterns was used to track the transition from novel to familiar for three tastants: saccharin, quinine and Polycose. The results revealed that in addition to an increase in the amount consumed (for saccharin and quinine but not Polycose), cluster size (an index of palatability) became larger as familiarity with the benign tastants increased. The current finding suggests that the pleasure of drinking increases as the novel, potentially dangerous tastant becomes accepted as safe. PMID- 22484564 TI - Macronutrient-induced differences in food intake relate with hepatic oxidative metabolism and hypothalamic regulatory neuropeptides in rainbow trout (Oncorhynchus mykiss). AB - This study examines how dietary macronutrient-induced changes in voluntary food intake (FI) relate to changes in markers of hepatic oxidative metabolism and in the expression of FI regulatory neuropeptides in a teleost model, the rainbow trout. Rainbow trout were fed for 6weeks with one of four iso-energetic diets (2*2 factorial design), containing either a high (HP, ~500 g.kg(-1) DM) or a low (LP, ~250 g.kg(-1) DM) protein level (PL) with, at each PL, fat (diets HP-F and LP-F) being substituted by an iso-energetic amount of gelatinized corn starch (diets HP-St and LP-St) as non-protein energy source (ES). Irrespective of the dietary PL, FI (g.kg(-0.8).d(-1)) and digestible energy intake (DEI, kJ.kg( 0.8).d(-1)) were significantly (P<0.05) reduced by the iso-energetic replacement of fat by starch as non-protein ES. Interestingly, trout fed these St-diets had higher gene expression of markers of hepatic oxidative phosphorylation (OxPhos), i.e., ubiquinol-cytochrome c reductase subunit 2 (UCR2) and cytochrome oxidase subunit 4 (COX4) and of aerobic oxidative capacity (CS, citrate synthase), which paralleled glucokinase (GK) transcription. This positive relation suggests that glucose phosphorylation and markers of mitochondrial OxPhos are linked at the hepatic level and possibly triggered the observed reduction in FI. Moreover, trout displaying the reduced FI had higher cocaine amphetamine regulator transcript (CART) mRNA in hypothalamus, whereas neuropeptide Y (NPY) mRNA did not follow the macronutrient-induced changes in FI. Further studies are needed to unravel the mechanisms by which diet-induced changes in hepatic metabolism inform central feeding centers involved in the regulation of FI in fish. PMID- 22484565 TI - Attenuated reproduction of Strombus gigas by an Apicomplexa: Emeriidae-like parasite in the digestive gland. AB - An intense and generalized sporozoan infection was detected in every population of the queen conch, Strombus gigas through the Caribbean. In this contribution we establish the relationship between occurrences of an Apicomplexa: Emeriidae-like organism and reproductive activity at San Andres archipelago, Colombia. Occurrence of the parasites was estimated counting the feeding stage Merozoites and cysts Sporozoites at 40* magnification. Nonmetric multidimensional scaling analysis (NMDS) was made to correlate the parasites stages abundance with frequency of the reproductive stages. Gametogenesis and spawning were always low coinciding with high numbers of Merozoites, a positive correlation was established between parasite abundance with reabsorption and undifferentiated stages, and negative correlation was observed between parasite abundance with maturity and spawning stages. The nonmetric multidimensional scaling (NMDS) shows that gametogenesis, maturity and spawning increase as the number of parasites decrease, factor that could be threatening reproduction of S. gigas through the Caribbean. PMID- 22484566 TI - Comparison of fresh-frozen cadaver and high-fidelity virtual reality simulator as methods of laparoscopic training. AB - BACKGROUND: The aim of this study was to compare fresh-frozen cadavers (FFC) with a high-fidelity virtual reality simulator (VRS) as training tools in minimal access surgery for complex and relatively simple procedures. METHODS: A prospective comparative face validity study between FFC and VRS (LAP Mentor(TM)) was performed. Surgeons were recruited to perform tasks on both FFC and VRS appropriately paired to their experience level. Group A (senior) performed a laparoscopic sigmoid colectomy, Group B (intermediate) performed a laparoscopic incisional hernia repair, and Group C (junior) performed basic laparoscopic tasks (BLT) (camera manipulation, hand-eye coordination, tissue dissection and hand transferring skills). Each subject completed a 5-point Likert-type questionnaire rating the training modalities in nine domains. Data were analysed using nonparametric tests. RESULTS: Forty-five surgeons were recruited to participate (15 per skill group). Median scores for subjects in Group A were significantly higher for evaluation of FFC in all nine domains compared to VRS (p < 0.01). Group B scored FFC significantly better (p < 0.05) in all domains except task replication (p = 0.06). Group C scored FFC significantly better (p < 0.01) in eight domains but not on performance feedback (p = 0.09). When compared across groups, juniors accepted VRS as a training model more than did intermediate and senior groups on most domains (p < 0.01) except team work. CONCLUSIONS: Fresh frozen cadaver is perceived as a significantly overall better model for laparoscopic training than the high-fidelity VRS by all training grades, irrespective of the complexity of the operative procedure performed. VRS is still useful when training junior trainees in BLT. PMID- 22484567 TI - Evaluation of lymph nodes in patients with colon cancer undergoing colon resection: a population-based study. AB - BACKGROUND: Though lymph node status may predict long-term outcome of patients with non-metastatic colon cancer, discordant findings exist among various expressions of lymph node status. The present study was designed to assess the prognostic value among these lymph node evaluations. METHODS: The analysis was based on surgical patients with newly diagnosed colon adenocarcinoma registered in the Taiwan Cancer Database from 2003 to 2005. Exclusion criteria included those patients who had stage IV disease, those whose survival period was <1 month, or those whose lymph node information was unavailable. Studied variables included total number of lymph nodes (LNT), number of positive lymph nodes (LNP), number of negative lymph nodes (LNN), ratio of positive lymph nodes (LNR), and log odds of positive lymph nodes (LODDS). RESULTS: Of 16,790 newly diagnosed colon cancer patients, there were 9,644 (65.4 +/- 13.5 years; male 54.9 %) patients with non-metastatic disease who met the criteria. Correlation analyses for patients with stage III disease showed that LNR and LODDS were highly correlated, as were LNT and LNN. By the Cox proportional hazard model, LNT was prognostic of long-term survival in patients with stage II disease, while LNR and LNP were the most powerful prognosticators for patients with stage III disease (p < 0.001). Both the receiver operating characteristics curve analysis and area under the curve indicated that LNR had the best discriminating capability to predict 5-year survival (0.704, 0.700, and 0.709 for overall, disease-free, and disease-specific survival, respectively), followed by LODDS. CONCLUSIONS: For patients undergoing resection for colon cancer, LNR, LODDS, and LNP are better prognostic factors for those with stage III disease than LNT is for patients with stage III disease. PMID- 22484568 TI - Timing of two-stage liver resection during chemotherapy for otherwise unresectable colorectal metastases. AB - BACKGROUND: Tumor downsizing by effective chemotherapy while increasing remnant liver volume by two-stage hepatectomy can expand eligibility for resection of otherwise unresectable liver metastases. However, optimal timing of two-stage hepatectomy with respect to chemotherapy is undetermined. METHODS: We retrospectively analyzed the effect of timing of two-stage hepatectomy and chemotherapy using data from 95 patients whose colorectal liver metastases initially were considered unresectable. RESULTS: In 21 of 22 (95 %) patients whose first liver resection preceded chemotherapy (Hx-CTx group) and in 39 of 73 (53 %) patients whose chemotherapy preceded surgery (CTx-Hx group), macroscopic complete resection ultimately was achieved (P < 0.01). Overall and disease-free survivals were comparable between groups. However, overall survival of patients not achieving complete resection in the CTx-Hx group was significantly poorer than that for patients achieving complete resection (P < 0.01). When the 21 patients with complete resection in the Hx-CTx group were compared to the 39 patients with complete resection in the CTx-Hx group, no difference in overall or disease-free survival was observed (P = 0.12 and P = 0.24, respectively), although poor response to chemotherapy was more frequent in the Hx-CTx group. CONCLUSIONS: Optimal timing of hepatectomy and chemotherapy is difficult to specify, but performing the initial resection in a two-stage hepatectomy before chemotherapy may increase likelihood of macroscopic complete resection, even in patients with a poor response to chemotherapy or with limited courses of chemotherapy. PMID- 22484569 TI - Open abdomen treatment with dynamic sutures and topical negative pressure resulting in a high primary fascia closure rate. AB - BACKGROUND: Open abdomen (OA) treatment with negative-pressure therapy is a novel treatment option for a variety of abdominal conditions. We here present a cohort of 160 consecutive OA patients treated with negative pressure and a modified adaptation technique for dynamic retention sutures. METHODS: From May 2005 to October 2010, a total of 160 patients--58 women (36 %); median age 66 years (21 88 years); median Mannheim peritonitis index 25 (5-43) underwent emergent laparotomy for diverse abdominal conditions (abdominal sepsis 78 %, ischemia 16 %, other 6 %). RESULTS: Hospital mortality was 21 % (13 % died during OA treatment); delayed primary fascia closure was 76 % in the intent-to-treat population and 87 % in surviving patients. Six patients required reoperation for abdominal abscess and five patients for anastomotic leakage; enteric fistulas were observed in five (3 %) patients. In a multivariate analysis, factors correlating significantly with high fascia closure rate were limited surgery at the emergency operation and a Bjork index of 1 or 2; factors correlating significantly with low fascia closure rate were male sex and generalized peritonitis. CONCLUSIONS: With the aid of initially placed dynamic retention sutures, OA treatment with negative pressure results in high rates of delayed primary fascia closure. OA therapy with the technical modifications described is thus considered a suitable treatment option in various abdominal emergencies. PMID- 22484570 TI - Effects of preoperative oral carbohydrate supplementation on postoperative metabolic stress response of patients undergoing elective abdominal surgery. AB - BACKGROUND: The goal of the present study was to evaluate the effects of preoperative oral carbohydrate supplementation (OCH) on the postoperative metabolic stress response of patients undergoing elective abdominal surgery. METHODS: The study was designed as a controlled, prospective, cohort study including 38 patients treated with OCH (800 mL the day before surgery and 400 mL within 3 h before the induction of anesthesia) and 38 controls matched for surgical procedure. Fasting glucose, insulin, insulin resistance (HOMA-IR index), cortisol, and interleukin 6 (IL-6) were assessed before and after surgery (postoperative day (POD) 1, 2, and 3). RESULTS: The administration of OCH resulted in lower fasting glucose, HOMA-IR index, cortisol, and IL-6 on both POD 1 and POD 2. At multivariable regression analyses, the reduction of these parameters was independent of sex, age, body mass index, and major abdominal surgery. Particularly, models including OCH treatment explained 70, 63, and 66 % of the variance of the increase in IL-6 levels at POD 1, POD 2, and POD 3, respectively. The effect of OCH on changes in glucose, insulin resistance, and cortisol on POD 1 and POD 2 disappeared after the inclusion of IL-6 in the models. CONCLUSIONS: Treatment with OCH was associated with attenuation of the postoperative metabolic stress response. We hypothesize that modulation of the inflammatory response is one of the mechanisms involved. PMID- 22484571 TI - Localized microstimulation of primate pregenual cingulate cortex induces negative decision-making. AB - The pregenual anterior cingulate cortex (pACC) has been implicated in human anxiety disorders and depression, but the circuit-level mechanisms underlying these disorders are unclear. In healthy individuals, the pACC is involved in cost benefit evaluation. We developed a macaque version of an approach-avoidance decision task used to evaluate anxiety and depression in humans and, with multi electrode recording and cortical microstimulation, we probed pACC function as monkeys performed this task. We found that the macaque pACC has an opponent process-like organization of neurons representing motivationally positive and negative subjective value. Spatial distribution of these two neuronal populations overlapped in the pACC, except in one subzone, where neurons with negative coding were more numerous. Notably, microstimulation in this subzone, but not elsewhere in the pACC, increased negative decision-making, and this negative biasing was blocked by anti-anxiety drug treatment. This cortical zone could be critical for regulating negative emotional valence and anxiety in decision-making. PMID- 22484572 TI - microRNA-9 regulates axon extension and branching by targeting Map1b in mouse cortical neurons. AB - The capacity of neurons to develop a long axon and multiple dendrites defines neuron connectivity in the CNS. The highly conserved microRNA-9 (miR-9) is expressed in both neuronal precursors and some post-mitotic neurons, and we detected miR-9 expression in the axons of primary cortical neurons. We found that miR-9 controlled axonal extension and branching by regulating the levels of Map1b, an important protein for microtubule stability. Following microfluidic separation of the axon and the soma, we found that miR-9 repressed Map1b translation and was a functional target for the BDNF-dependent control of axon extension and branching. We propose that miR-9 links regulatory signaling processes with dynamic translation mechanisms, controlling Map1b protein levels and axon development. PMID- 22484573 TI - Expression dynamics of microRNA biogenesis during preimplantation mouse development. AB - The role of microRNAs (miRNAs) in early development, and particularly in the post transcriptional regulation of maternal mRNAs remains controversial. Hence, we have assessed how miRNA processing is regulated during preimplantation mouse development, from the fully-grown oocyte to the blastocyst, quantifying the expression of genes whose proteins are involved in miRNAs biogenesis and function. The expression of the Drosha, Dgcr8, Exportin 5, Dicer, Ago1, Ago2, Ago3, Ago4 and Ago5 genes was downregulated from the zygotic cleavage stage, except for the increase of Ago1, Ago3 and Ago4 expression in the 2-cell embryo, and of Ago2 in 4- and 8-cell embryos. These findings suggest that the capacity to process miRNAs, by the considered canonical pathway, diminishes after fertilization, primarily reducing miRNA activity in the later stages of preimplantation development. However, by analyzing the different precursor and mature forms of specific miRNAs that are abundantly expressed in the blastocyst, such as miR-292-3p and miR-292-5p, we identified miRNA-duplexes and/or miRNAs bound to target mRNAs that may serve as potential stockpiles of miRNAs. In response to the demand, such stockpile could directly provide functional and mature miRNAs. PMID- 22484574 TI - Incidence and risk factors for radiographic lumbar spondylosis and lower back pain in Japanese men and women: the ROAD study. AB - OBJECTIVE: To determine the incidence of radiographic lumbar spondylosis (LS)and lower back pain, and their risk factors in Japan using a large-scale population from the nationwide cohort Research on Osteoarthritis/osteoporosis Against Disability (ROAD) Study. METHODS: Participants in the ROAD study who had been recruited between 2005 and 2007 were followed up with lumbar spine radiography for 3 years. A total of 2,282 paired radiographs (75% of the original sample) were scored using Kellgren and Lawrence (KL) grades, and the incidence and progression rate of radiographic LS was analyzed. The incidence of lower back pain was also examined. In addition, associations between risk factors and incident and progressive radiographic LS as well as incident lower back pain were tested. RESULTS: Given a 3.3-year follow-up, the incidence of KL>=2 radiographic LS was 50.0% and 34.4% (15.3% and 10.5% per year), while that of KL>=3 LS was 15.3% and 23.7% (4.6% and 7.2% per year) in men and women, respectively. The progression rate of LS was 20.5% and 27.4% (6.2% and 8.3% per year) in men and in women, respectively. In addition, the incidence of lower back pain was 28.3% and 31.2% (8.6% and 9.5% per year) in men and women. Lower back pain was not significantly associated with incident radiographic LS, while a more severe KL grade at baseline was associated with incident lower back pain. CONCLUSION: The present longitudinal study revealed a high incidence of radiographic LS in Japan. PMID- 22484575 TI - Acute inflammation with induction of anaphylatoxin C5a and terminal complement complex C5b-9 associated with multiple intra-articular injections of hylan G-F 20: a case report. AB - OBJECTIVE: The purpose of this case report was to investigate local immune mechanisms present during an acute inflammatory flare initiated by viscosupplementation with hylan G-F 20 in a patient with osteoarthritis (OA) and past meniscectomy. EXPERIMENTAL DESIGN: A patient with a history of bilateral OA and partial left knee meniscectomy, who had received three injections of hylan G F 20, was diagnosed with an acute flare reaction in the left knee. Her chart was evaluated for clinical, radiological, and laboratory findings and for clinical follow-up. Histopathological synovial examination and real-time polymerase chain reaction (RT-PCR) for genes with major roles in local inflammation and enzyme linked immunosorbent assays (ELISAs) for markers of complement activation and cytokines were performed. To study the impact of the inflammatory and immune features we compared the case patient with groups of three representative OA and three rheumatoid arthritis (RA) patients. RESULTS: The patient exhibited evidence of highly increased acute phase reactant C-reactive protein (CRP) in the blood. The pathological examination of the synovial membrane identified abundant fibrinous exudate with numerous particles of hyaluronan surrounded by a dense infiltrate of neutrophils and eosinophils. The synovium had moderate hypertrophy and sclerosis as well as an inflammatory infiltrate predominantly composed of T lymphocytes and macrophages with scattered perivascular eosinophils and neutrophils. Immunoperoxidase staining identified numerous deposits of C5b-9 in the fibrinous exudates and the synovial membrane of the patient. Similar findings were observed in the RA patients, whereas deposits were rare in OA synovial samples. In addition, both anaphylatoxin C5a and the terminal complement complex C5b-9 were present at high levels, comparable to those in RA patients. The levels of mRNA for interleukin-1 beta (IL-1beta), IL-6, and the neutrophil marker myeloperoxidase (MPO) were markedly increased compared to those in the RA and OA patients. CONCLUSIONS: This present study is indicative of a pseudo-septic acute inflammatory reaction in response to local accumulation of hylan G-F 20 with the activation of complement and local invasion of pro-inflammatory cells. PMID- 22484576 TI - Feasibility and toxicity of docetaxel before or after fluorouracil, epirubicin and cyclophosphamide as adjuvant chemotherapy for early breast cancer. AB - BACKGROUND: The tolerance and safety associated with the administration order of the anthracycline and taxane drugs have not been evaluated. PATIENTS AND METHODS: Breast cancer patients with node-positive or high-risk patients with node negative were eligible. The feasibility and toxicity were evaluated in the following regimens--arm A, 3 courses of fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2) and cyclophosphamide 500 mg/m(2) (FEC) followed by 3 courses of docetaxel 100 mg/m(2) (DOC); arm B, 3 courses of DOC followed by 3 courses of FEC. RESULTS: Forty-two patients were registered. The relative dose intensity was 94.2 % for FEC and 97.8 % for DOC in arm A, and 98.9 % for DOC and 95.2 % for FEC in arm B. In arm A, grade 3 or higher hematological toxicity was observed in nine patients, and febrile neutropenia developed in three patients with FEC. In arm B, grade 3 or higher hematological toxicity was observed in seven patients, but febrile neutropenia was not noted in any patient. CONCLUSION: The regimens in both arms A and B were safe regarding adjuvant chemotherapy for early breast cancer. However, DOC followed by FEC might be more tolerable. Further studies will maximize the results obtained with DOC followed by FEC. PMID- 22484577 TI - Tumor ablation with nanosecond pulsed electric fields. PMID- 22484578 TI - Association of polymorphisms in non-classic MHC genes with susceptibility to autoimmune hepatitis. AB - BACKGROUND: Autoimmune hepatitis is a chronic, generally progressive inflammatory disorder of the liver, of which the cause is unclear. It was demonstrated that genetic factors are involved in its pathogenesis. Previous studies showed that human leukocyte antigen in the major histocompatibility complex (MHC) is associated with susceptibility to autoimmune hepatitis. Current genome scanning studies suggest that genes outside the MHC also play a critical role in autoimmune disorders. This article focuses on our current understanding of the polymorphisms of these genes and their roles in the pathogenesis of autoimmune hepatitis. DATA SOURCES: Studies were identified by searching MEDLINE and PubMed for articles using the keywords autoimmune hepatitis, polymorphism, CTLA-4, Fas, TNF-alpha, TGF-beta1, TBX21 and VDR up to May 2011. Additional papers were identified by a manual search of the references from key articles. RESULTS: According to the case-control studies on genetic polymorphisms, at least six genes (CTLA-4, Fas, TNF-alpha, TGF-beta1, TBX21 and VDR) are involved in autoimmune hepatitis besides HLA. So far, there has been no agreement about gene susceptibility and the actual clinical significance of these genes is still controversial. CONCLUSION: Studies on gene polymorphisms outside the MHC and knowledge of genetic predispositions for autoimmune hepatitis may not only elucidate pathogenic mechanisms, but also provide new targets for therapy in the future. PMID- 22484579 TI - Cerebral protective effect of nicorandil premedication on patients undergoing liver transplantation. AB - BACKGROUND: Neurological injury is a common complication in the early period after liver transplantation, posing an enormous obstacle to treatment efficiency and patient survival. Nicorandil is a mitochondrial ATP-sensitive potassium channel (mitoKATP) opener. It has been reported to be effective in reducing brain injury in recent studies. However, it is still unclear whether nicorandil has cerebral protective effect in patients undergoing liver transplantation. METHODS: Fifty patients scheduled for liver transplantation were randomly divided into a nicorandil group (group N) (n=25), in which patients received 10 mg nicorandil through a nasogastric tube 30 minutes before induction of anesthesia, and a control group (group C) (n=25) who received 10 mL normal saline. The Mini-Mental State Examination (MMSE) was performed before anesthesia (day 0), and on days 3 and 7 after surgery. Blood samples were obtained before induction of anesthesia (T1), and at 12 (T2) and 36 hours (T3) after surgery for determination of serum neuron-specific enolase (NSE) and S100beta protein (S100beta) concentrations. RESULTS: During surgery, 5 patients in each group were eliminated due to severe reperfusion or renal insufficiency. Therefore, 20 patients remained in each group. The MMSE scores after operation were significantly lower than those before operation in group C. However, there was no difference at days 3 and 7 compared with day 0 in group N. Serum NSE concentrations after surgery were significantly higher than baseline (at T1) in both groups, except at T3 in group N. Serum S100beta concentration after surgery was significantly higher than baseline (at T1) in both groups. The MMSE scores at days 3 and 7 in group N were significantly higher than those in group C. The concentrations of serum NSE and S100beta at T2 and T3 in group N were significantly lower than those in group C. CONCLUSIONS: Oral nicorandil, as a premedication before liver transplantation, improves postoperative MMSE scores. It also attenuates the increase of NSE and S100beta in blood, indicating its cerebral protective effect. PMID- 22484580 TI - Steroid elimination within 24 hours after orthotopic liver transplantation: effectiveness and tolerability. AB - BACKGROUND: Steroids have been the mainstay of immunosuppressive regimen in liver transplantation. However, the use of steroids is associated with various post transplant complications. This study evaluated the efficacy and safety of reduced immunosuppressive regimen with steroids (steroid elimination within 24 hours post transplant) in a cohort of Chinese liver transplant recipients. METHODS: Seventy six patients in line with the selection criteria were enrolled in this prospective study. All patients received anti-IL-2 receptor antibody induction and tacrolimus-based maintenance therapy. The recipients were divided into two groups according to the duration of steroid use: 40 transplant in a 3-month withdrawal group and the remaining 36 in a 24-hour elimination group. Recipient survival, post-operative infections, biopsy-proven acute rejection and steroid resistant acute rejection, non-healing wound, recurrence of hepatitis B virus (HBV) and hepatocellular carcinoma (HCC), de novo diabetes, hyperlipidemia and hypertension were assessed in the two groups. RESULTS: There was no significant difference in patient survival, incidence of acute rejection episodes and hyperlipidemia, and recurrence of HBV and HCC between the two groups. However, the incidence rates of post-transplant infection, non-healing wound, de novo diabetes and hypertension were significantly lower in the 24-hour elimination group than in the 3-month withdrawal group (all P values <0.05). CONCLUSION: Under anti-IL-2 receptor antibody induction and tacrolimus-based maintainance, steroid elimination within 24 hours post-transplant is associated with reduced steroid-related complications without increasing the risk of rejection. PMID- 22484581 TI - Feasibility of orthotopic fetal liver transplantation: an experimental study. AB - BACKGROUND: The use of livers from nonviable fetuses is particularly attractive for its potential to solve the current limitations of organ availability for the pediatric recipient. Therefore, it is essential to study the feasibility of orthotopic fetal liver transplantation. METHOD: We measured the hepatic and extra hepatic anatomical structures of fetal and neonatal lambs and established an orthotopic liver transplantation model of the fetal lamb. RESULTS: Mean weight of the liver of fetal lambs at 142 to 145 days gestation was 34.75 g and the mean diameter of the portal vein was 3.03 mm, the supra-hepatic vena cava was 5.88 mm, and the infra-hepatic vena cava was 4.00 mm, which matched the corresponding sizes in neonatal lambs aged up to 2 weeks. Using standard surgical procedures we completed the vascular inosculation of fetal liver. However, all the newborn lamb recipients survived less than 24 hours. CONCLUSIONS: Orthotopic transplantation of the fetal liver is anatomically and technically feasible. However, perioperative issues need to be resolved prior to clinical application. PMID- 22484582 TI - Immunological tolerance of human hepatocyte xenograft induced by adenovirus vector-mediated CTLA4Ig gene transfer. AB - BACKGROUND: Systemic administration of CTLA4Ig has been applied in inducing immunological tolerance of hepatocyte implants, but has potential for systemic immune inhibition. This study was designed to induce hepatocyte immunological tolerance by locally expressing CTLA4Ig in an attempt to improve the effectiveness of cell transplantation. METHODS: A normal human liver cell line (L02) was transfected with adenovirus vector containing the CTLA4Ig gene (Ad CTLA4Ig-EGFP) in vitro, and the expression of CTLA4Ig by transfected cells was assessed by fluorescent imaging and immunocytochemical staining. Transfected cells then were injected into the spleen of Sprague-Dawley rats, the survival of cells was determined by immunohistochemistry, and the immune status was examined through CD4+ and CD69+ T cell-counts and ELISA detection of IL-2 in peripheral blood. RESULTS: L02 cells expressed CTLA4Ig in the cytoplasm for >4 weeks. Surviving L02 cells were observed in the experimental group at 3 and 4 weeks post transplantation, while none was detected in the control group. Furthermore, the percentages of CD4+ and CD4+CD69+ T cells in the CTLA4-transfected group were 24.5% and 45.1%, markedly lower than those in the control group at 4 weeks post transplantation (P<0.01). Furthermore, the IL-2 level was also lower in the CTLA4 transfected group than in the control group. CONCLUSION: Adenovirus-mediated CTLA4Ig gene transfer into human hepatocytes has the potential to become an effective method of inducing immunological tolerance in hepatocyte transplantation. PMID- 22484583 TI - Percutaneous transhepatic portal catheterization guided by ultrasound technology for islet transplantation in rhesus monkey. AB - BACKGROUND: Pig islet xenotransplantation has the potential to overcome the shortage of donated human islets for islet cell transplantation in type 1 diabetes. Testing in non-human primate models is necessary before clinical application in humans. Intraportal islet transplantation in monkeys is usually performed by surgical infusion during laparotomy or laparoscopy. In this paper, we describe a new method of percutaneous transhepatic portal catheterization (PTPC) as an alternative to current methods of islet transplantation in rhesus monkeys. METHODS: We performed ultrasound-guided PTPC in five adult rhesus monkeys weighing 7-8 kg, with portal vein catheterization confirmed by digital subtraction angiography. We monitored for complications in the thoracic and abdominal cavity. To evaluate the safety of ultrasound-guided PTPC, we recorded the changes in portal pressure throughout the microbead transplantation procedure. RESULTS: Ultrasound-guided PTPC and infusion of 16 000 microbeads/kg body weight into the portal vein was successful in all five monkeys. Differences in the hepatobiliary anatomy of rhesus monkeys compared to humans led to a higher initial complication rate. The first monkey died of abdominal hemorrhage 10 hours post-transplantation. The second suffered from a mild pneumothorax but recovered fully after taking only conservative measures. After gaining experience with the first two monkeys, we decreased both the hepatic puncture time and the number of puncture attempts required, with the remaining three monkeys experiencing no complications. Portal pressures initially increased proportional to the number of transplanted microbeads but returned to pre-infusion levels at 30 minutes post transplantation. The changes in portal pressures occurring during the procedure were not significantly different. CONCLUSIONS: Ultrasound-guided PTPC is an effective, convenient, and minimally invasive method suitable for use in non human primate models of islet cell transplantation provided that care is taken with hepatic puncture. Its advantages must be weighed against the risks of procedure-related complications. PMID- 22484584 TI - The impact of family history of hepatocellular carcinoma on its patients' survival. AB - BACKGROUND: Family history of hepatocellular carcinoma (HCC) has been identified as a risk factor for the development of the disease. The aim of this study is to evaluate the impact of such a history on HCC patients' survival. METHODS: Data of all HCC patients (n=4532) managed at our center from 1989 to 2008 were prospectively collected. The patients were quizzed on their various characteristics including family HCC history. RESULTS: Totally 475 (10.48%) patients had a family history of HCC. They presented the disease at a significantly earlier age (median 53 vs 59 years, P<0.0001) and at an earlier stage (the United Network for Organ Sharing staging system). They had significantly better liver function in terms of Child-Pugh classification and serum albumin and bilirubin levels. Significantly more of them presented the disease without symptoms (44.0% vs 29.4%, P<0.0001). They also had significantly better overall survival under these specifications: patients in the whole study cohort, patients who had minor hepatectomy, patients with stage I disease, patients with stage II disease, and patients with stage III disease. CONCLUSIONS: Contrary to what is generally believed, we found in this study cohort that patients with a family history of HCC had better overall survival than those without such a history. We believe this was in part due to earlier diagnosis of the disease and better liver function in this group of patients. However, the effects of genetic factors on the risk of HCC cannot be overlooked and are yet to be identified. PMID- 22484585 TI - Management of hypersplenism in non-cirrhotic portal hypertension: a surgical series. AB - BACKGROUND: Hypersplenism is commonly seen in patients with non-cirrhotic portal hypertension (NCPH). While a splenectomy alone can effectively relieve the hypersplenism, it does not address the underlying portal hypertension. The present study was undertaken to analyze the impact of shunt and non-shunt operations on the resolution of hypersplenism in patients with NCPH. The relationship of symptomatic hypersplenism, severe hypersplenism and number of peripheral cell line defects to the severity of portal hypertension and outcome was also assessed. METHODS: A retrospective analysis of NCPH patients with hypersplenism managed surgically between 1999 and 2009 at our center was done. Of 252 patients with NCPH, 64 (45 with extrahepatic portal vein obstruction and 19 with non-cirrhotic portal fibrosis) had hypersplenism and constituted the study group. Statistical analysis was done using GraphPad InStat. Categorical and continuous variables were compared using the chi-square test, ANOVA, and Student's t test. The Mann-Whitney U test and Kruskal-Wallis test were used to compare non-parametric variables. RESULTS: The mean age of patients in the study group was 21.81+/-6.1 years. Hypersplenism was symptomatic in 70.3% with an incidence of spontaneous bleeding at 26.5%, recurrent anemia at 34.4%, and recurrent infection at 29.7%. The mean duration of surgery was 4.16+/-1.9 hours, intraoperative blood loss was 457+/-126 (50-2000) mL, and postoperative hospital stay 5.5+/-1.9 days. Following surgery, normalization of hypersplenism occurred in all patients. On long-term follow-up, none of the patients developed hepatic encephalopathy and 4 had a variceal re-bleeding (2 after a splenectomy alone, 1 each after an esophago-gastric devascularization and proximal splenorenal shunt). Patients with severe hypersplenism and those with defects in all three peripheral blood cell lineages were older, had a longer duration of symptoms, and a higher incidence of variceal bleeding and postoperative morbidity. In addition, patients with triple cell line defects had elevated portal pressure (P=0.001), portal biliopathy (P=0.02), portal gastropathy (P=0.005) and intraoperative blood loss (P=0.001). CONCLUSIONS: Hypersplenism is effectively relieved by both shunt and non-shunt operations. A proximal splenorenal shunt not only relieves hypersplenism but also effectively addresses the potential complications of underlying portal hypertension and can be safely performed with good long-term outcome. Patients with hypersplenism who have defects in all three blood cell lineages have significantly elevated portal pressures and are at increased risk of complications of variceal bleeding, portal biliopathy and gastropathy. PMID- 22484586 TI - Correlation of the occurrence of YMDD mutations with HBV genotypes, HBV-DNA levels, and HBeAg status in Chinese patients with chronic hepatitis B during lamivudine treatment. AB - BACKGROUND: Continuous lamivudine therapy is associated with high rates of YMDD mutations, which are the main causes of drug resistance. The current study explores the association of the emergence of YMDD mutations with pretherapy HBV genotype, HBV-DNA levels, HBeAg status, and serum alanine aminotransferase (ALT) levels in Chinese patients receiving lamivudine therapy for chronic hepatitis B. METHODS: A total of 319 chronic hepatitis B patients who received lamivudine therapy for more than a year were enrolled in this study. YMDD mutations, HBV genotype, HBV-DNA levels, HBeAg status, and ALT levels were determined prior to their lamivudine treatment and every three months for a year of this therapy. RESULTS: Among the 319 patients, 137 (42.95%) were infected with genotype B and 182 (57.05%) with genotype C. Up to 94 patients (29.47%) developed YMDD mutations within one year of lamivudine therapy. Furthermore, 50 patients with HBV genotype B and 44 patients with genotype C developed YMDD mutations (36.50% vs 24.18%, P<0.05). Logistic regression analysis showed that pretherapy HBV genotype, HBV DNA levels, and HBeAg status are independent factors for the emergence of YMDD mutations (HBV genotype: OR=2.159, 95% CI 1.291-3.609, P=0.003; HBV-DNA: OR=1.653, 95% CI 1.231-2.218, P=0.001; HBeAg: OR=2.021, 95% CI 1.201-3.399, P=0.008). CONCLUSIONS: HBV genotype, HBV-DNA levels, and HBeAg status at baseline are the independent factors associated with the emergence of YMDD mutations among Chinese patients receiving lamivudine therapy for chronic hepatitis B. These findings are helpful to the development of therapeutic strategies for these patients. PMID- 22484587 TI - Prognostic significance and clinical relevance of Sprouty 2 protein expression in human hepatocellular carcinoma. AB - BACKGROUND: In vitro experiments and mice models have confirmed the importance of Sprouty 2 (Spry2) in inhibiting tumorigenesis and the progression of human cancer. However, the prognostic value of Spry2 in cancer patients remains unknown. This study is aimed to investigate the clinical relevance and prognostic significance of Spry2 expression in patients with hepatocellular carcinoma (HCC). METHODS: With samples from 240 randomly-selected HCC patients who underwent surgery, immunohistochemistry was used to investigate Spry2 expression on tissue microarrays. The correlation of Spry2 expression with survival was estimated by the Kaplan-Meier method and univariate/multivariate Cox proportional hazard regression analysis. Spry2, ERK and phospho-ERK expression in HCC cell lines was detected by Western blotting. RESULTS: Among the patients, 86.3% (207 of 240) exhibited down-regulation of Spry2 expression. Patients negative for Spry2 showed poorer survival (P=0.002) and increased recurrence (P=0.003). Multivariate analysis further established Spry2 as an independent predictor of postoperative recurrence in HCC patients (HR=1.47; 95% CI, 1.02-2.08; P=0.037). Down-regulation of Spry2 was associated with highly malignant phenotypes like vascular invasion and advanced tumor stages, and was positively correlated with the metastatic potential of HCC cell lines. CONCLUSION: In the era of molecular targeted therapy, the expression of Spry2 in HCC may have relevant clinical significance and turn out to be a key factor in prognostic assessment and in treatment planning. PMID- 22484588 TI - Efficacy and factors influencing treatment with peginterferon alpha-2a and ribavirin in elderly patients with chronic hepatitis C. AB - BACKGROUND: In China, hepatitis C virus (HCV) infection is characterized by an increasing prevalence during aging. This study was undertaken to evaluate the efficacy of treatment with peginterferon alpha-2a and ribavirin in elderly chronic hepatitis C (CHC) patients and study the factors related to the sustained virologic response (SVR). METHODS: The medical records of 417 patients treated with peginterferon and ribavirin were retrospectively analyzed. These patients were divided into two groups according to age: patients aged >= 65 years (n=140) and patients aged <65 years (n=277). The rate of ribavirin reduction or discontinuation and virologic response rates of the two groups were compared. The factors influencing SVR were studied by multivariate analysis. RESULTS: Ribavirin reduction or discontinuation was more frequent in patients aged >= 65 years than patients aged <65 years (37.1%, 52/140 vs 20.2%, 56/277; X2=13.883, P<0.001). For genotype 1, patients aged >= 65 years had a higher relapse rate (50.0%, 42/84 vs 29.2%, 52/178; X2=10.718, P=0.001) and a lower SVR rate (40.0%, 42/105 vs 60.0%, 126/210; X2=11.250, P=0.001) than patients aged <65 years. There were no significant differences in virologic response rates between the two groups for patients with genotype 2. For genotype 1, in patients aged >= 65 years, the SVR rate of females was lower than that of males (28.6%, 12/42 vs 47.6%, 30/63; X2=8.150, P=0.004); in the high viral load group, patients aged >= 65 years had a lower SVR rate than patients aged <65 years (30.0%, 18/60 vs 54.8%, 69/126; X2=10.010, P=0.002). In multivariate logistic regression analysis, the independent factors associated with SVR in patients aged >= 65 years were sex (P=0.020), genotype (P=0.005), ribavirin reduction or discontinuation (P=0.009) and presence of rapid virologic response (RVR) (P=0.001). CONCLUSIONS: The rate of ribavirin reduction or discontinuation and relapse rate of patients aged >= 65 years with genotype 1 are high, and the SVR rate is low. Age has no impact on virologic responses rates for genotype 2. Among patients >= 65 years old, genotype 2 patients and genotype 1 patients with a low baseline viral load or achieving RVR or male may benefit from combination therapy. PMID- 22484589 TI - Inhibition of 12-lipoxygenase reduces proliferation and induces apoptosis of hepatocellular carcinoma cells in vitro and in vivo. AB - BACKGROUND: 12-lipoxygenase (12-LOX) has been reported to be an important gene in cancer cell proliferation and survival, and tumor metastasis. However, its role in hepatocellular carcinoma (HCC) cells remains unknown. METHODS: Expression of 12-LOX was assessed in a diethyl-nitrosamine-induced rat HCC model, and in SMMC 7721, HepG2 and L-02 cells using immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR). GST-pi and Ki-67 were determined in vivo by immunohistochemical staining. Apoptosis was evaluated by TUNEL assay. Cell viability and apoptosis were determined by MTT assay and flow cytometry, respectively. Apoptosis-related proteins in SMMC-7721 and HepG2 cells were detected by Western blotting. RESULTS: Immunohistochemical staining and RT PCR showed that 12-LOX was over-expressed in rat HCC and two HCC cell lines, while the expression was inhibited by baicalein, a specific inhibitor of 12-LOX. Baicalein inhibited cell proliferation and induced apoptosis in rat HCC and both cell lines in a dose- and time-dependent manner. Our in vivo study demonstrated that baicalein also reduced neoplastic nodules. Mechanistically, baicalein reduced Bcl-2 protein expression coupled with a slight increase of the expression of Bax and activation of caspase-3. Furthermore, baicalein inhibited the activation of ERK-1/2 (phosphorylated). Interestingly, the effects of baicalein were reversed by 12(S)-HETE, a metabolite of 12-LOX. CONCLUSIONS: Inhibition of 12-LOX leads to reduced numbers of HCC cells, partially caused by increased apoptosis. 12-LOX may be a potential molecular target for HCC prevention and treatment. PMID- 22484590 TI - Rapamycin combined with allogenic immature dendritic cells selectively expands CD4+CD25+Foxp3+ regulatory T cells in rats. AB - BACKGROUND: Dendritic cells (DCs) can initiate the expansion of regulatory T cells (Tregs), which play an indispensable role in inducing transplantation tolerance. Some studies have investigated the effect of the immunosuppressant rapamycin (Rapa) on Tregs in vitro. However, the in vivo effect of Rapa combined with immature DCs (iDCs) on Tregs is unknown. This study was undertaken to determine whether allogenic iDCs combined with a short course of Rapa have the ability to selectively expand the CD4+CD25+Foxp3+ Tregs in a rat model. METHODS: Brown Norway rats were injected intravenously with 2X10(6) Lewis iDCs followed by 1 mg/kg per day Rapa intraperitoneally for 7 consecutive days. On day 8, the levels of CD4+CD25+Foxp3+ Treg cells in peripheral blood and spleen cells were analyzed by flow cytometry. IL-2, IL-4, TGF-beta1, and IFN-gamma levels in serum were assessed by ELISA. The experimental animals were divided into four groups: control, Rapa-treated, iDC-treated, and combination-treated. RESULTS: CD4+CD25+Foxp3+ Tregs comprised 7%-8% of CD4+ T cells in control rats. Rapa combined with iDCs enhanced this percentage in the peripheral blood and spleen. However, the levels of Tregs did not significantly change after treatment with Rapa or iDCs alone. The levels of CD4+CD25-Foxp3+ T cells and CD4+CD25+Foxp3- T cells in CD4+ T cells did not significantly change in the combined group. The TGF beta1 level in serum from the combined group increased significantly compared with the other groups. CONCLUSIONS: A significantly higher percentage of CD4+ CD25+ Foxp3+ Tregs was found in rats treated with allogenic iDCs and a short course of Rapa, along with an increase in the TGF-beta1 level in serum. This improved protocol may be a promising therapeutic strategy to increase Tregs, which are beneficial to the induction of peritransplant tolerance. PMID- 22484591 TI - Clinical outcome in patients with hilar malignant strictures type II Bismuth Corlette treated by minimally invasive unilateral versus bilateral endoscopic biliary drainage. AB - BACKGROUND: Stenting of malignant hilar strictures remains a standard endoscopic treatment in patients with unresectable tumors. The aim of this two-center prospective study was to compare unilateral versus bilateral drainage in hilar malignant stenosis Bismuth-Corlette type II. METHODS: During a 3-year period, a total of 49 patients with hilar tumors (Bismuth-Corlette type II) were referred for endoscopic treatment, following the criteria of unresectability. Ultrasound, computed tomography scan and magnetic resonance cholangiopancreatography (MRCP) were previously performed in all patients in order to facilitate endoscopic retrograde cholangiopancreatography (ERCP). The stricture was first passed by the hydrophilic guide-wire and then contrast medium was injected. Mechanical bile duct dilation was performed, followed by plastic stent placement only in the liver lobe which was previously opacified. The procedures were performed under conscious sedation. The patients were followed up for the next 12 months with a stent exchange every 3 months. Primary outcome was assessed by patient survival in the first 12 months after the procedure. RESULTS: All 49 patients were treated with ERCP while 39 (79.59%) had successful stent placement. Among these, 32 had hilar cholangiocarcinoma (82%) and 7 (18%) had gallbladder cancer. Two groups of patients had Bismuth II strictures: A, 21 patients (54%) with unilateral contrast injection and drainage, and B, 18 (46%) with bilateral contrast injection and drainage. A total of 57 plastic stents were used (10 Fr, 89%; 11.5 Fr, 11%). Group B showed a lower bilirubin level 7 days after the procedure (P=0.008). Early complications were cholangitis (3 patients, 2 in group A and 1 in group B) and acute pancreatitis (2 patients, 1 each in A and B) with no statistical difference between the groups. Late complications were stent migration (5 patients, 1 in A and 4 in B) and stent clogging (6 patients, 2 in A and 4 in B) showing a significant difference between the groups (P<0.01). The first stent replacement after 3 months was successful in 87% of patients (four died due to disease progression and one due to cardiopulmonary insufficiency) showing no statistical difference between the groups. At 6 months follow-up, 72% patients survived, with no statistical difference between the groups. A final follow-up (12 months) showed the survival rate of 18% (4 patients from group A and 3 from group B) (P>0.05). CONCLUSIONS: A minimally invasive approach, based on the criterion that every bile duct being opacified needs to be drained, is associated with a lower incidence of early complications. Considering that the clinical outcome measured by bilirubin level was lower in patients with bilateral drainage 7 days after the procedure, we assumed that drainage of 50% or more of the liver volume leads to sufficient drainage effectiveness. PMID- 22484592 TI - Pancreaticopleural fistula: etiology, treatment and long-term follow-up. AB - BACKGROUND: Pancreaticopleural fistula (PPF) are uncommon. Complex multidisciplinary treatment is required due to nutritional compromise and sepsis. This is the first description of long-term follow-up of patients with PPF. METHODS: Eleven patients with PPF treated at a specialist unit were identified. Causation, investigation, treatment and outcomes were recorded. RESULTS: Pancreatitis was the etiology of the PPF in 9 patients, and in the remaining 2 the PPF developed following distal pancreatectomy. Cross-sectional imaging demonstrated the site of duct disruption in 10 cases, with endoscopic retrograde cholangiopancreatography identifying the final case. Suppression of pancreatic exocrine secretion and percutaneous drainage formed the mainstay of treatment.Five cases resolved following pancreatic duct stent insertion and three patients required surgical treatment for established empyema. There were no complications. In all cases that resolved there has been no recurrence of PPF over a median follow-up of 50 months (range 15-62). CONCLUSIONS: PPF is an uncommon event complicating pancreatitis or pancreatectomy; pancreatic duct disruption is the common link. A step-up approach consisting of minimally invasive techniques treats the majority with surgery needed for refractory sepsis. PMID- 22484593 TI - Double inferior vena cava does not complicate para-aortic nodal dissection for the treatment of pancreatic carcinoma. AB - Duplication of the inferior vena cava (IVC) involves large veins on both sides of the aorta that join anteriorly at the level of the renal arteries to become the suprarenal IVC. We report CT scan and intraoperative images of a patient with duplication of the IVC who underwent pancreaticoduodenectomy with para-aortic lymphadenectomy for carcinoma of the pancreatic head: nodal dissection along the left caval vein was not carried out. The anatomical background of the lymphatic flow to the para-aortic lymph nodes and the theoretic basis for lymph node dissection of the para-aortic area in cases of double IVC are highlighted. Lymphadenectomy along the left caval vein is not necessary in patients with double IVC who undergo pancreaticoduodenectomy with extended lymphadenectomy for carcinoma of the pancreatic head in the absence of preoperative appearance of para-aortic disease. PMID- 22484594 TI - A case of hemoglobin Hiroshima (beta146 histidine to aspartic acid) with compensatory erythremia and undetectable HbA1c. AB - Hemoglobin (Hb) Hiroshima is an Hb variant that travels rapidly on electrophoresis and shows a fourfold increase in oxygen affinity and a decreased Bohr effect. We encountered a 40-year-old male patient with erythremia and an undetectable HbA(1c) level. The presence of an abnormal hemoglobin molecule was suggested by the results of high-performance liquid chromatography analysis. Subsequent gene analysis by direct sequencing confirmed Hb Hiroshima (beta146 histidine -> aspartic acid). Caution should be exercised when diagnosing erythremia. PMID- 22484595 TI - Identification of a novel duplication CFTRdup2 and functional impact of large rearrangements identified in the CFTR gene. AB - In European populations, large rearrangements contribute to approximately 2% of CF mutations. Here, we reported a novel duplication, the CFTRdup2, identified in a patient heterozygous for Phe508del and suffering from a mild CF. Using a combination of functional tests, we studied the impact of duplication/deletion on CFTR expression. We showed that the copy number variations of exon 2, in addition to abolishing the rate of the mature CFTR protein, affect the CFTR mRNA levels. These data illustrate the importance to perform functional analysis to better understand the molecular basis responsible for cystic fibrosis. Determining the impact of deletions or duplications is relevant for a more comprehensive diagnosis and prognosis of patients. PMID- 22484596 TI - Bayesian inference of the fully specified subdistribution model for survival data with competing risks. AB - Competing risks data are routinely encountered in various medical applications due to the fact that patients may die from different causes. Recently, several models have been proposed for fitting such survival data. In this paper, we develop a fully specified subdistribution model for survival data in the presence of competing risks via a subdistribution model for the primary cause of death and conditional distributions for other causes of death. Various properties of this fully specified subdistribution model have been examined. An efficient Gibbs sampling algorithm via latent variables is developed to carry out posterior computations. Deviance information criterion (DIC) and logarithm of the pseudomarginal likelihood (LPML) are used for model comparison. An extensive simulation study is carried out to examine the performance of DIC and LPML in comparing the cause-specific hazards model, the mixture model, and the fully specified subdistribution model. The proposed methodology is applied to analyze a real dataset from a prostate cancer study in detail. PMID- 22484597 TI - Efficacy and safety of atovaquone-proguanil in treating imported malaria in Japan: the second report from the research group. AB - Malaria remains an important health risk among travelers to tropical/subtropical regions. However, in Japan, only 2 antimalarials are licensed for clinical use - oral quinine and mefloquine. The Research Group on Chemotherapy of Tropical Diseases introduced atovaquone-proguanil in 1999, and reported on its excellent antimalarial efficacy and safety for treating non-immune patients with uncomplicated Plasmodium falciparum malaria (20 adult and 3 pediatric cases) in 2006. In the present study, additional cases of malaria were analyzed to confirm the efficacy and safety of this antimalarial drug. Fourteen adult and 2 pediatric cases of P. falciparum malaria and 13 adult cases and 1 pediatric case of P. vivax/ovale malaria were successfully treated with atovaquone-proguanil, including 3 P. falciparum cases in which the antecedent treatment failed. Two patients with P. vivax malaria were treated twice due to primaquine treatment failure as opposed to atovaquone-proguanil treatment failure. Except for 1 patient with P. falciparum malaria who developed a moderate liver function disturbance, no significant adverse effects were observed. Despite the intrinsic limitations of this study, which was not a formal clinical trial, the data showed that atovaquone-proguanil was an effective and well-tolerated therapeutic option; licensure of this drug in Japan could greatly contribute to individually appropriate treatment options. PMID- 22484598 TI - The Nme gene family in fish. AB - The Nme gene family, also known as Nm23 or NDPK, is a very ancient gene family that can be found in all kingdoms of life. In the late eighties, a gene of the Nme family, NME1, was identified as the first metastatic suppressor gene, resulting in a major interest for this family. Due to the complexity of the family, the need for a unified and evolutionary-supported gene nomenclature was recently stressed by the scientific community. Based on a complete evolutionary history study of the gene family in metazoans and vertebrates, a unified nomenclature was recently proposed and accepted by gene nomenclature consortia. In addition to its well-documented role in tumor metastasis, members of the Nme family are also involved in a wide variety of cellular and physiological processes. Available data in non-mammalian species remain, however, scarce with the noticeable exception of Drosophila in which a major role in development was reported. In fish, very few studies have specifically investigated the role of nme genes. Several transcriptomic and proteomic studies have, however, revealed the expression of nme genes in various fish organs and tissues, in mature oocytes, and during embryonic development. Altogether, interest for the Nme gene family in fish is growing and new functions/roles in fish biology are expected to be discovered in the forthcoming years. Here, we briefly review the current knowledge of the Nme family in fish. PMID- 22484599 TI - Effects of dietary yeast Saccaromyces cerevisiae on the antioxidant system in the liver of juvenile sea bass Dicentrarchus labrax. AB - The main goal of this work was to determine the effect of dietary live yeast Saccharomyces cerevisiae on the oxidative status of sea bass Dicentrarchus labrax juveniles. Fishes were fed on three diets: the GM group were fed a diet containing lyophilized yeast grown on grape must, the CS group were fed a diet containing lyophilized yeast grown on cornstarch, and the control group were fed a diet without yeast. The activity of the main antioxidative enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase, glutathione S transferase (GST), and glutathione (GSH) content, as well as lipid peroxidation, was measured in the liver of sea bass juveniles 90 days after hatching. Supplementation of the diet with S. cerevisiae significantly reduced the SOD and CAT activity, increased the GST activity, decreased the GSH content, and had no effect on lipid peroxidation. The results support the already reported radical scavenging properties of yeast and usefulness of its employment as antiperoxidative agent in fish. PMID- 22484600 TI - Familial dorsalization of the skin of the proximal palm and the instep of the sole of the foot. PMID- 22484601 TI - DEHP: genotoxicity and potential carcinogenic mechanisms-a review. AB - Di(ethylhexyl) phthalate (DEHP) is a manufactured chemical commonly added to plastics: it is a ubiquitous environmental contaminant to which humans are exposed through multiple routes. DEHP is a rodent carcinogen with an extensive data base on genotoxicity and related effects spanning several decades. Although DEHP has been reported to be negative in most non-mammalian in vitro mutation assays, most studies were performed under conditions of concurrent cytotoxicity, precipitation, or irrelevant metabolic activation. However, a number of in vitro rodent tissue assays have reported DEHP to be positive for effects on chromosomes, spindle, and mitosis. A robust database shows that DEHP increases transformation and inhibits apoptosis in Syrian hamster embryo cells. In a transgenic mouse assay, in vivo DEHP exposure increased the mutation frequency only in the liver, which is the target organ for cancer. In vitro exposure of human cells or tissues to DEHP induced DNA damage; altered mitotic rate, apoptosis, and cell proliferation; increased proliferation, tumor mobility, and invasiveness of tumor cell lines; and activated a number of nuclear receptors. DEHP has been shown to be an agonist for CAR2, a novel constitutive androstane receptor occurring only in humans. Environmental exposures of humans to DEHP have been associated with DNA damage. After taking into account study context and relevant issues affecting interpretation, in vitro studies reported that a similar DEHP concentration range induced both mutagenic and non-mutagenic effects in human tissues and, using a much more limited rodent database, transformation of embryonic rodent tissues. The human and rodent data suggest that DEHP induces cancer through multiple molecular signals, including DNA damage. The analyses presented here may provide guidance for similar data sets used in structure activity relationships, computational-toxicology extrapolations, and attempts to extrapolate in vitro results to predict in vivo effects for hazard characterization. PMID- 22484602 TI - Comparative study of the contents of analogues of aristolochic acid in two kinds of Aristolochiae Fructus by high-performance liquid chromatography. AB - Aristolochiae Fructus ("Madouling") is derived from the fruits of Aristolochia contorta and A. debilis (Aristolochiaceae). These two species contain potentially nephrotoxic constituents, but are officially used in China. Distinction of constituents and toxicity between these two species remains unclear. A high performance liquid chromatography method was developed and validated for the simultaneous determination of seven analogues of aristolochic acid (aristolochic acids I, II, IIIa, IVa and VIIa), as well as aristololactams I and II in Aristolochiae Fructus. Chromatographic separation was achieved on a Zorbax SB C(18) column with a gradient mobile phase comprising acetonitrile and 1 % acetic acid-30 mM triethylamine (20:1, v/v) buffer. Analytes were detected with a diode array detector at 250 and 260 nm. The contents of seven constituents in samples (11 batches of A. contorta fruits, 15 batches of A. debilis fruits and 33 commercial samples of Madouling) were determined. The content of aristolochic acid IVa was higher than that of aristolochic acid VIIa in A. contorta fruits, whereas the opposite was true in A. debilis fruits. This feature can be used to distinguish the two species from each other and identify the resource plant of Madouling. Through a morphological method and a newly found principle based on the ratio AA-IVa/AA-VIIa, we found that the 33 commercial samples collected from 12 provinces in China were all derived from the fruits of A. contorta. PMID- 22484603 TI - Rose oil (from Rosa * damascena Mill.) vapor attenuates depression-induced oxidative toxicity in rat brain. AB - Oxidative stress is a critical route of damage in various physiological stress induced disorders, including depression. Rose oil may be a useful treatment for depression because it contains flavonoids which include free radical antioxidant compounds such as rutin and quercetin. We investigated the effects of absolute rose oil (from Rosa * damascena Mill.) and experimental depression on lipid peroxidation and antioxidant levels in the cerebral cortex of rats. Thirty-two male rats were randomly divided into four groups. The first group was used as control, while depression was induced in the second group using chronic mild stress (CMS). Oral (1.5 ml/kg) and vapor (0.15 ml/kg) rose oil were given for 28 days to CMS depression-induced rats, constituting the third and fourth groups, respectively. The sucrose preference test was used weekly to identify depression like phenotypes during the experiment. At the end of the experiment, cerebral cortex samples were taken from all groups. The lipid peroxidation levels in the cerebral cortex in the CMS group were higher than in control whereas their levels were decreased by rose oil vapor exposure. The vitamin A, vitamin E, vitamin C and beta-carotene concentrations in the cerebral cortex were lower in the CMS group than in the control group whereas their concentrations were higher in the rose oil vapor plus CMS group. The CMS-induced antioxidant vitamin changes were not modulated by oral treatment. Glutathione peroxidase activity and reduced glutathione did not change statistically in the four groups following CMS or either treatment. In conclusion, experimental depression is associated with elevated oxidative stress while treatment with rose oil vapor induced protective effects on oxidative stress in depression. PMID- 22484605 TI - Development and efficacy of an attenuated Vibrio harveyi vaccine candidate with cross protectivity against Vibrio alginolyticus. AB - Vibrio harveyi is a Gram-negative bacterial pathogen that can infect a wide range of marine animals. In previous studies, we have reported a virulent V. harveyi strain, T4D. In the present study, an attenuated mutant of T4D, T4DM, was obtained by selection of rifampicin resistance. Compared to the wild type, T4DM was different in whole-cell protein profile and much slower in growth rate when cultured in stress conditions caused by iron depletion. Virulence analysis showed that compared to T4D, T4DM exhibited a dramatically increased median lethal dose, impaired tissue dissemination capacity, defective hemolytic activity, and significantly reduced resistance against the killing effect of host serum. To examine the potential of T4DM as a live attenuated vaccine, Japanese flounder (Paralichthys olivaceus) were vaccinated with T4DM via intraperitoneal injection or immersion. The results showed that at one and two months post-vaccination, fish administered with T4DM via both approaches, in particular that of immersion, were effectively protected against not only V. harveyi but also Vibrio alginolyticus, another important fish pathogen. Microbiological analysis showed that following immersion vaccination, T4DM was recovered from the internal organs of the vaccinated fish in a time-dependent manner within the first 6 days post vaccination. Serum antibodies against V. harveyi and V. alginolyticus were detected in T4DM-vaccinated fish, and, compared to serum from control fish, serum from T4DM-vaccinated fish was significantly enhanced in bactericidal activity. These results indicate that T4DM is an attenuated strain with residual infectivity and that T4DM can induce effective cross-species protection against both V. harveyi and V. alginolyticus when used as a live immersion vaccine. PMID- 22484604 TI - Chelidonium majus leaves methanol extract and its chelidonine alkaloid ingredient reduce cadmium-induced nephrotoxicity in rats. AB - The kidney is one of the critical target organs for chronic cadmium toxicity. Cadmium is a cumulative nephrotoxicant, and preferentially accumulates and persists in the kidneys. The natriuretic and antidiuretic effects of methyl alcohol extracts of Chelidonium majus L. (C. majus) leaves were evaluated in kidney of cadmium-intoxicated rats. Ninety-six male Sprague-Dawley Albino rats were divided into two major groups (toxicity and biochemical, 60 and 36 rats, respectively). There was a decrease in kidney weight and serum electrolytes, but an increase in urinary volume, excretion of electrolytes, serum urea and creatinine, after 9 weeks of cadmium chloride intoxication. Treatment of C. majus methyl alcohol extract for 10 weeks starting 1 week before cadmium administration shifted the above parameters towards the normal values. These results were supported by molecular and histological investigations. Treatment with C. majus methyl alcohol extract has natriuretic and antidiuretic effects against cadmium induced nephrotoxicity in rats. PMID- 22484606 TI - Molecular characterization, immune responses and DNA protection activity of rock bream (Oplegnathus fasciatus), peroxiredoxin 6 (Prx6). AB - In this study, we describe the molecular characterization, immune responses of rock bream, Oplegnathus fasciatus peroxiredoxin 6 cDNA (RbPrx6) and DNA protection activity of its recombinant protein. The full-length cDNA sequence of RbPrx6 was identified after pyrosequencing of rock bream cDNA library. RbPrx6 consists of 663 bp open reading frame (ORF) that codes for a putative protein of 221 amino acids with predicted molecular mass of 27 kDa. It showed characteristic peroxiredoxin super-family domain similar to vertebrate Prx counterparts. In the pair-wise comparison, RbPrx6 showed the highest amino acid identity (92.8%) to Scophthalmus maximus Prx6. Real-time RT-PCR analysis revealed that constitutive expression of RbPrx6 transcripts in eleven tissues selected from un-challenged fish showing the highest level in liver. Synthetic polyinosinic:polycytidylic acid (poly I:C) and iridovirus containing supernatant, up-regulated the RbPrx6 mRNA in liver. Purified recombinant RbPrx6 protein was able to protect supercoiled plasmid DNA from damages that is induced by metal-catalyzed generation of reactive oxygen species. Our results suggest that RbPrx6 may play an important role in regulating oxidative stress by scavenging of ROS, involving immune reactions and minimizing the DNA damage in rock bream. PMID- 22484607 TI - Identification and characterization of a putative lipopolysaccharide-induced TNF alpha factor (LITAF) gene from Amphioxus (Branchiostoma belcheri): an insight into the innate immunity of Amphioxus and the evolution of LITAF. AB - Innate immunity defenses against infectious agent in all multicultural organisms. TNF-alpha is an important cytokine that can be stimulated by Lipopolysaccharide (LPS) to regulate the innate immunity. The lipopolysaccharide-induced TNF-alpha factor (LITAF) functions as a transcription factor for regulating the expression of TNF-alpha as well as various inflammatory cytokines in response to LPS stimulation. The physiological significance of LITAF gene in the innate immunity of various animals has recently been reported. However, no LITAF gene has yet been identified in amphioxus, which is the best available stand-in for the proximate invertebrate ancestor of the vertebrates. In this study, we identified and characterized an amphioxus LITAF gene (designated as AmphiLITAF). First, we identified the AmphiLITAF from the amphioxus and found that AmphiLITAF gene with ~1.6 kb in length has a 827bp cDNA transcription product which encodes a putative protein with 127 amino acids containing conserved LITAF-domain, and the deduced amino acid of AmphiLITAF shared 37-60% similarity with the LITAFs from other species; second, we uncovered the spatial distribution of the LITAF in different tissues, the expression level of AmphiLITAF mRNA was the highest in hepatic cecum and intestine, moderate in muscles, gills and gonad, and the lowest in notochord. Our findings provide an insight into the innate immune response in the amphioxus and the evolution of the LITAF family. PMID- 22484608 TI - Inonotus obliquus containing diet enhances the innate immune mechanism and disease resistance in olive flounder Paralichythys olivaceus against Uronema marinum. AB - The present study describes the effect of diet supplementation with Chaga mushroom, Inonotus obliquus extract at 0%, 0.01%, 0.1%, and 1.0% levels on the innate humoral (lysozyme, antiprotease, and complement), cellular responses (production of reactive oxygen and nitrogen species and myeloperoxidase), and disease resistance in olive flounder, Paralichythys olivaceus against Uronema marinum. The lysozyme activity and complement activity significantly increased in each diet on weeks 2 and 4 against pathogen. The serum antiprotease activity and reactive nitrogen intermediates production significantly increased in fish fed with 0.1% and 1.0% diets from weeks 1-4. However, reactive oxygen species production and myeloperoxidase activity significantly increased in 1.0% and 2.0% diets on weeks 2 and 4. In fish fed with 0.1% and 1.0% diets and challenged with U. marinum the cumulative mortality was 50% and 40% while in 0% and 0.01% diets the mortality was 85% and 55%. The results clearly indicate that supplementation diet with I. obliquus at 0.1% and 1.0% level positively enhance the immune system and confer disease resistance which may be potentially used as an immunoprophylactic in finfish culture. PMID- 22484609 TI - Natural micro-scale heterogeneity induced solute and nanoparticle retardation in fractured crystalline rock. AB - We studied tracer (Tritiated Water (HTO); Tritium replaces one of the stable hydrogen atoms in the H(2)O molecule) and nanoparticle (quantum dots (QD)) transport by means of column migration experiments and comparison to 3D CFD modeling. Concerning the modeling approach, a natural single fracture was scanned using micro computed tomography (MUCT) serving as direct input for the model generation. The 3D simulation does not incorporate any chemical processes besides the molecular diffusion coefficient solely reflecting the impact of fracture heterogeneity on mass (solute and nanoparticles) transport. Complex fluid velocity distributions (flow channeling and flowpath heterogeneity) evolve as direct function of fracture geometry. Both experimental and simulated solute and colloidal breakthrough curves show heavy tailing (non-Fickian transport behavior), respectively. Regarding the type of quantum dots and geochemical conditions prevailing (Grimsel ground water chemistry, QD and diorite surface charge, respectively and porosity of the Aspo diorite drill core) experimental breakthrough of the quantum dots always arrives faster than the solute tracer in line with the modeling results. Besides retardation processes like sorption, filtration, straining or matrix diffusion, the results show that natural 3D fracture heterogeneity represents an important additional retardation mechanism for solutes and colloidal phases. This is clearly verified by the numerical simulations, where the 3D real natural fracture geometry and the resulting complex flow velocity distribution is the only possible process causing solute/nanoparticle retardation. Differences between the experimental results and the simulations are discussed with respect to uncertainties in the MUCT measurements and experimental and simulation boundary conditions, respectively. PMID- 22484610 TI - High-risk human papillomavirus E6/E7 mRNA and L1 DNA as markers of residual/recurrent cervical intraepithelial neoplasia. AB - The aim of this study was to assess the use of human papillomavirus (HPV) E6/E7 mRNA testing in the follow-up of women treated for cervical intraepithelial neoplasia (CIN) by conization and to compare the prognostic value of HPV E6/E7 mRNA to HPV L1 DNA and cytology. One hundred and forty-three women underwent cytological/histological testing, HPV DNA genotyping by Linear Array, and HPV E6/E7 mRNA testing by APTIMA HPV assay during follow-up after surgical treatment for histologically verified CIN. High-grade residual/recurrent disease (CIN2+/HSIL+) was identified in 7 (4.9%) women, and low-grade disease (CIN1/LSIL) in 25 (17.5%). At the inclusion visit 33 (23%) women were HPV DNA-positive; 13 (9.0%) were HPV E6/E7 mRNA-positive. HPV E6/E7 mRNA did not identify three women with high-grade disease. Presence of high-risk HPV DNA at the inclusion visit predicted 100% (95% CI 64.6-100) of high-grade residual/recurrent disease, with a specificity of 80.9% (95% CI 73.5-86.6); cytology had a sensitivity of 85.7%, and a specificity of 87.5%. HPV E6/E7 mRNA testing was a poor predictor of treatment failure, with a sensitivity of 57.1% (95% CI 25.0-84.2), but high specificity (93.4%; 95% CI 87.9-96.5). Detection of high-risk HPV DNA after treatment by conization identified 100% of women with residual/recurrent high-grade disease, whereas HPV E6/E7 mRNA testing was a poor predictor of treatment failure. This study suggests that a negative HPV mRNA result cannot exclude the risk of malignant progression, and that HPV E6/E7 mRNA testing by APTIMA HPV assay is not useful in the follow-up of women treated for CIN. PMID- 22484612 TI - A highly sensitive single-tube nested PCR assay for the detection of Pineapple mealybug wilt associated virus-2 (PMWaV-2). AB - An assay was developed for the detection of Pineapple mealybug wilt associated virus-2 (PMWaV-2), an important factor in the etiology of mealybug wilt of pineapple. The assay combines reverse transcription of RNA isolated from pineapple with a specific and very sensitive, single, closed-tube nested polymerase chain reaction (PCR) to amplify a segment of the coat protein gene of the PMWaV-2. The outer primers were designed to anneal at higher temperatures than the nested primers to prevent primer competition in consecutive amplification reactions. To reduce potential competition further, the outer primers were used at one-thousandth the concentration of the nested primers. The specificity and sensitivity of this assay are much greater than PCR using only a single primer-pair. A TaqMan((r)) probe was also designed for use in quantitative PCR to detect and quantify the PCR amplification products directly in a single tube assay. The advantages of the single-tube assays using both conventional and quantitative PCR are reduced handling time and prevention of cross contamination compared to regular nested PCR in which the reactions are carried out in two separate tubes. PMID- 22484613 TI - A multiplex reverse transcription PCR assay for simultaneous detection of five tobacco viruses in tobacco plants. AB - Tobacco viruses including Tobacco mosaic virus (TMV), Cucumber mosaic virus (CMV), Tobacco etch virus (TEV), Potato virus Y (PVY) and Tobacco vein banding mosaic virus (TVBMV) are major viruses infecting tobacco and can cause serious crop losses. A multiplex reverse transcription polymerase chain reaction assay was developed to detect simultaneously and differentiate all five viruses. The system used specific primer sets for each virus producing five distinct fragments 237, 273, 347, 456 and 547 bp, representing TMV, CMV subgroup I, TEV, PVY(O) and TVBMV, respectively. These primers were used for detection of the different viruses by single PCR and multiplex PCR and the results were confirmed by DNA sequencing analysis. The protocol was used to detect viruses from different parts of China. The simultaneous and sensitive detection of different viruses using the multiplex PCR is more efficient and economical than other conventional methods for tobacco virus detection. This multiplex PCR provides a rapid and reliable method for the detection and identification of major tobacco viruses, and will be useful for epidemiological studies. PMID- 22484614 TI - The prevalence of Torque teno sus virus (TTSuV) is common and increases with the age of growing pigs in the United States. AB - Infection with the Torque teno sus virus (TTSuV) is believed to be common yet limited information is available on the epidemiology of TTSuV. The objectives of this study were to develop novel and improve existing diagnostic methods for TTSuV infection and to investigate the prevalence of TTSuV species 1 (TTSuV1) and 2 (TTSuV2) in the USA. Three hundred and four blood or fetal thoracic fluid samples were collected from pigs on 40 US farms in 12 States. Samples were collected from fetuses and in pre-suckle neonates (n=73), suckling pigs (1-20 days of age; n=27), nursery pigs (21-55 days of age; n=60), finisher pigs (8-25 weeks of age; n=90) and adults (>25 weeks of age; n=54). Samples were tested by a new quantitative differential real-time PCR for TTSuV1 and TTSuV2 DNA and by ELISA for detection of anti-TTSuV2-antibodies. The prevalence of TTSuV1 DNA ranged from 8.2% (fetuses and neonates) to 81% (finisher pigs) and the prevalence of TTSuV2 DNA ranged from 3.7% (suckling pigs) to 67% (finisher pigs). Evidence of fetal TTSuV infection was minimal. Mixed infection of TTSuV1 and TTSuV2 was seen in 6.7% of the nursery pigs, 52.2% of the finisher pigs, and 22.2% of the mature pigs. The prevalence of TTSuV1 was higher than that of TTSuV2. Anti-TTSuV2 antibodies were not detected in the fetuses and neonates and the seroprevalence of TTSuV2 was between 3.8% and 100% in growing pigs. The results of this study indicate that vertical transmission may not be a main route of TTSuV transmission in pigs in the USA. PMID- 22484611 TI - Intestinal redox biology and oxidative stress. AB - The intestinal epithelium sits at the interface between an organism and its luminal environment, and as such is prone to oxidative damage induced by luminal oxidants. Mucosal integrity is maintained by the luminal redox status of the glutathione/glutathione disulfide (GSH/GSSG) and cysteine/cystine (Cys/CySS) couples which also support luminal nutrient absorption, mucus fluidity, and a diverse microbiota. The epithelial layer is uniquely organized for rapid self renewal that is achieved by the well-regulated processes of crypt stem cell proliferation and crypt-to-villus cell differentiation. The GSH/GSSG and Cys/CySS redox couples, known to modulate intestinal cell transition through proliferation, differentiation or apoptosis, could govern the regenerative potential of the mucosa. These two couples, together with that of the thioredoxin/thioredoxin disulfide (Trx/TrxSS) couple are the major intracellular redox systems, and it is proposed that they each function as distinctive redox control nodes or circuitry in the control of metabolic processes and networks of enzymatic reactions. Specificity of redox signaling is accomplished in part by subcellular compartmentation of the individual redox systems within the mitochondria, nucleus, endoplasmic reticulum, and cytosol wherein each defined redox environment is suited to the specific metabolic function within that compartment. Mucosal oxidative stress would result from the disruption of these unique redox control nodes, and the subsequent alteration in redox signaling can contribute to the development of degenerative pathologies of the intestine, such as inflammation and cancer. PMID- 22484615 TI - Development and validation of a novel reporter assay for human papillomavirus type 16 late gene expression. AB - To facilitate the investigations of HPV-16 late gene expression HPV-16 reporter plasmids were generated using previously described sub-genomic HPV-16 plasmids, named pBEL and pBELM, that, similar to the full viral genome, produce primarily HPV-16 early mRNAs and very little, if any, late mRNAs in cervical cancer cells. The HPV-16 late L1 gene was replaced by the chloramphenicol acetyltransferase (CAT) reporter gene, or green fluorescent protein (GFP), preceded by the poliovirus internal ribosome entry site (IRES). Results show that the reporter genes mimic the expression of L1 from these plasmids. For example, overexpression of adenovirus E4orf4 protein (E4orf4), polypyrimidine tract binding protein (PTB), arginine/serine-rich SRp30c protein (SRp30c) or alternative splicing factor/splicing factor 2 (ASF/SF2) induced an increased expression of CAT or GFP. Stable cell lines with reporter plasmids pBELCAT and pBELMCAT were also generated. An induction of CAT was observed in HPV-16 reporter cell lines in the presence of the small molecule phorbol 12-myristate 13-acetate (TPA). Further experiments identified the TPA-inducible, hnRNP A2/B1 protein as a regulator of HPV-16 late gene expression. In conclusion, the HPV-16 reporter plasmids and reporter cell lines described herein can be used to identify small molecules and cellular factors that regulate HPV-16 gene expression. PMID- 22484616 TI - Use of reverse transcription-real time polymerase chain reaction (real time RT PCR) assays with Universal Probe Library (UPL) probes for the detection and genotyping of infectious pancreatic necrosis virus strains isolated in Chile. AB - Reverse transcription-real time polymerase chain reaction (real time RT-PCR) assay with Universal Probe Library (UPL) probes has been developed for the detection and genotyping of Chilean infectious pancreatic necrosis virus (IPNV) isolates from infected cell culture. Partial nucleotide sequences (1175 bp) of the VP2 coding region from a selection of 7 Chilean IPNV isolates showed that they clustered into two main groups strongly correlated with Genogroups 1 and 5 proposed by Blake et al. (2001), corresponding to types West Buxton (WB) and Spajarup (Sp), respectively. Based on the VP2 gene sequences of those 7 Chilean isolates and different reference IPNV strains, 2 sets of candidate primer/UPL probes (# 8 and # 117) were designed and evaluated with a total of 32 field isolates isolated from Atlantic salmon (Salmo salar), rainbow trout (Oncorhynchus mykiss) and Pacific salmon (Oncorhynchus kisutch) farms from 2006 to 2010 in Chile. The UPL probes clearly differentiated the same two major Genogroups that those recognized by sequencing analysis. Among the Chilean isolates examined, 18 yielded amplification with UPL probe # 8, and 14 with probe # 117, respectively corresponding to types Sp and WB, as demonstrated by typing by sequencing. Based on the findings reported below, it has been demonstrated that the combined real time RT-PCR protocol with UPLs approach was efficient in discriminating distinct Genogroups of IPNV cultured in fish cell lines and, therefore, recommended its use for detection and typing of IPN viruses. The study also confirmed the existence of two IPNV type strains in Chilean salmonid aquaculture. PMID- 22484617 TI - Splenectomy protects the kidneys against ischemic reperfusion injury in the rat. AB - BACKGROUND: Ischemic reperfusion (I/R) injury of the kidney is closely associated with delayed graft function, increased acute rejection, and late allograft dysfunction. Splenectomy reduced hepatic I/R injury by inhibiting leukocyte infiltration in the liver, release of TNF-alpha, cell apoptosis, and expression of caspase-3. Thus, we investigated the effects of splenectomy on renal I/R injury in the rat. METHODS: Male Wistar rats were assigned to four groups: sham operation (sham group), sham operation+splenectomy (sham+SPLN group), right nephrectomy followed by clamping the left renal pedicle for 30min (I/R 30 group), and I/R 30+splenectomy (I/R 30+SPLN group). Renal function was determined by measuring the concentration of blood urea nitrogen (BUN) and serum creatinine (S Cr). The serum level of tumor necrosis factor-alpha (TNF-alpha) was measured as the marker for inflammation. Left kidneys were obtained 24h after reperfusion. TUNEL assay was assessed for cell apoptosis. Spleens were obtained immediately (0 h group) and 3h after reperfusion (3-h group). The removed spleens were histologically evaluated. RESULTS: The BUN and S-Cr levels were significantly lower in the I/R 30+SPLN group than in the I/R 30 group (p<0.05 for both). Apoptotic cells were significantly lower in the I/R 30+SPLN group than in the I/R 30 group. The serum level of TNF-alpha, which was increased after I/R, was significantly lower in the I/R 30+SPLN group than in the I/R 30 group (p<0.05). Spleen weights were significantly lower in the 3-h group than in the 0-h group (p<0.05). CONCLUSION: These results suggest that splenectomy reduces renal I/R injury, and this effect may occur by an anti-inflammatory pathway and inhibition of cell apoptosis. PMID- 22484618 TI - Differentiation and enrichment of cardiomyocytes from human pluripotent stem cells. AB - Human cardiomyocytes derived from pluripotent stem cells hold great promise for cardiac cell therapy, disease modeling, drug discovery, and the study of developmental biology. Reaching these potentials fully requires the development of methods that enable efficient and robust generation of cardiomyocytes with expected characteristics. This review summarizes and discusses up-to-date methods that have been used to derive and enrich human cardiomyocytes from pluripotent stem cells, provides a brief overview of in vitro and in vivo characterization of these cardiomyocytes, and considers future advancement needed to further harness the power of these cells. PMID- 22484619 TI - Neuronal nitric oxide synthase is up-regulated by angiotensin II and attenuates NADPH oxidase activity and facilitates relaxation in murine left ventricular myocytes. AB - Angiotensin II (Ang II) is critical in myocardial pathogenesis, mostly via stimulating NADPH oxidase. Neuronal nitric oxide synthase (nNOS) has recently been shown to play important roles in modulating myocardial oxidative stress and contractility. Here, we examine whether nNOS is regulated by Ang II and affects NADPH oxidase production of intracellular reactive oxygen species (ROS(i)) and contractile function in left ventricular (LV) myocytes. Our results showed that Ang II induced biphasic effects on ROS(i) and LV myocyte relaxation (TR(50)) without affecting the amplitude of sarcomere shortening and L-type Ca(2+) current density: TR(50) was prolonged at 30 min but was shortened after 3h (or after Ang II treatment in vivo). Correspondingly, ROS(i) was increased, followed by a reduction to control level. Quantitative RT-PCR and immunoblotting experiments showed that Ang II (3h) increased the mRNA and protein expression of nNOS and increased NO production (nitrite assay) in LV myocyte homogenates, suggesting that nNOS activity may be enhanced and involved in mediating the effects of Ang II. Indeed, n(omega)-nitro-l-arginine methyl ester (l-NAME) or a selective nNOS inhibitor, S-methyl-l-thiocitrulline (SMTC) increased NADPH oxidase production of superoxide/ROS(i) and abolished faster myocyte relaxation induced by Ang II. The positive lusitropic effect of Ang II was not mediated by PKA-, CaMKII-dependent signaling or peroxynitrite. Conversely, inhibition of cGMP/PKG pathway abolished the Ang II-induced faster relaxation by reducing phospholamban (PLN) Ser(16) phosphorylation. Taken together, these results clearly demonstrate that myocardial nNOS is up-regulated by Ang II and functions as an early adaptive mechanism to attenuate NADPH oxidase activity and facilitate myocardial relaxation. PMID- 22484620 TI - Adenosine-mediated inhibition of 5'-AMP-activated protein kinase and p38 mitogen activated protein kinase during reperfusion enhances recovery of left ventricular mechanical function. AB - Attenuation of excessive rates of myocardial glycolysis limits proton production and Ca(2+) overload during reperfusion and improves recovery of post-ischemic left ventricular (LV) function. In order to elucidate mechanisms underlying glycolytic inhibition by adenosine (ADO), this study tested the hypothesis that the beneficial effects of ADO are due to Ser/Thr protein phosphatase (PP) mediated inhibition of 5'-AMP-activated protein kinase (AMPK) and phosphofructokinase-2 (PFK-2). In isolated perfused working rat hearts subjected to global ischemia (GI) and reperfusion, ADO (500MUmol/l), added 5min prior to the onset of GI and present throughout reperfusion, inhibits glycolysis and proton production during reperfusion and improves post-ischemic LV work. These metabolic effects of ADO are also evident during aerobic perfusion. Assays of glycolytic intermediates show that ADO-induced glycolytic inhibition occurs at the step catalyzed by PFK-1, an effect mediated by reduced activation of PFK-2 by AMPK. The PP1 and PP2A inhibitors, cantharidin (5MUmol/l) or okadaic acid (0.1MUmol/l), added 10min prior to ADO prevent ADO-induced inhibition of glycolysis and AMPK, as well as ADO-induced cardioprotection. ADO also inhibits p38 MAPK phosphorylation during reperfusion in a cantharidin-sensitive manner, and pharmacological inhibition of p38 MAPK (by SB202190, 10MUmol/l) during reperfusion also reduces glycolysis and is cardioprotective. These results indicate that attenuation of glycolysis during reperfusion and cardioprotection can be achieved by inhibition of the stress kinases, AMPK and p38 MAPK. PMID- 22484621 TI - Cholesterol and the biosynthesis of glycosphingolipids are required for sperm activation in Caenorhabditis elegans. AB - Ejaculated mammalian sperm must acquire fertilization capacity after residing into the female reproductive tract, a process collectively known as capacitation. Cholesterol efflux was required for sperm maturation. Different from flagellated sperm, C. elegans sperm are crawling cells. C. elegans sperm are highly enriched with cholesterol though this animal species lacks biosynthetic pathway for cholesterol and its survival requires an exogenous cholesterol supply. The low abundance of cholesterol in C. elegans lipid extract is thought insufficient to form lipid microdomains ubiquitously in this organism. We present evidence that cholesterol is enriched in the plasma membrane of C. elegans spermatids and that cholesterol- and glycosphingolipids (GSLs)-enriched membrane microdomains (lipid microdomains) mediate sperm activation. Disruption of sperm lipid microdomains by acute manipulation of cholesterol in vitro blocks the sperm activation. Restriction of cholesterol uptake also results in the abnormal sperm activation in both males and hermaphrodites. Manipulation of the integrity of lipid microdomains by targeting the biosynthesis of GSLs inhibits sperm activation and the inhibition can be rescued by the addition of exogenous GSLs. The cleavage of glycosylphosphatidylinositol (GPI)-anchored proteins, which are exclusively found in lipid microdomains, also affects sperm activation. We conclude that localized signaling mediated by lipid microdomains is critical for worm sperm activation. Lipid microdomains composed of cholesterol and GSLs have been observed in flagellated sperm of several animal species, thus cholesterol, before its efflux from the plasma membrane, might be needed to assemble into a platform for some more important upstream signal sorting during spermatogenesis than was previously thought. PMID- 22484622 TI - Effects of CYP7B1-related steroids on androgen receptor activation in different cell lines. AB - The widely expressed steroid hydroxylase CYP7B1 is involved in metabolism of a number of steroids reported to influence estrogen and androgen signaling. Several studies by us and other investigators have linked this enzyme to effects on estrogen receptor activation. In a previous report we examined the effect of CYP7B1-mediated hormone metabolism for estrogen-mediated response in kidney derived HEK293 cells. In the current study we used an androgen response element (ARE) reporter system to examine androgen-dependent response of some CYP7B1 substrates and CYP7B1-formed metabolites in several cell lines derived from different tissues. The results indicate significantly lower androgen receptor activation by CYP7B1-formed steroid metabolites than by the corresponding steroid substrates, suggesting that CYP7B1-mediated catalysis may decrease some androgenic responses. Thus, CYP7B1-dependent metabolism may be of importance not only for estrogenic signaling but also for androgenic. This finding, that CYP7B1 activity may be a regulator of androgenic signaling by converting AR ligands into less active metabolites, is also supported by real-time RT-PCR experiment where a CYP7B1 substrate, but not the corresponding product, was able to stimulate known androgen-sensitive genes. Furthermore, our data indicate that the effects of some steroids on hormone response element reporter systems are cell line-specific. For instance, despite transfection of the same reporter systems, 5-androstene 3beta,17beta-diol strongly activates an androgen-dependent response element in prostate cancer cells whereas it elicits only ER-dependent responses in kidney HEK293 cells. Potential roles of cell-specific metabolism or comodulator expression for the observed differences are discussed. PMID- 22484623 TI - Development of a method for oral administration of hydrophobic substances to Caenorhabditis elegans: pro-longevity effects of oral supplementation with lipid soluble antioxidants. AB - Methods for quantitative oral administration of various substances to Caenorhabditis elegans are needed. Previously, we succeeded in oral administration of hydrophilic substances using liposomes. However, an adequate system for delivery of hydrophobic chemicals was not available. In this study, we developed a method for oral administration of lipid-soluble substances to C. elegans. gamma-cyclodextrin (gammaCD), which delivers hydrophobic chemicals, was used to make micro-particles of inclusion compounds that can be ingested by bacteriophagous nematodes, which do not distinguish these micro-particles from their food bacteria. Successful oral delivery of the hydrophobic fluorescent reagent 3,3'-dioctadecyloxacarbocyanine perchlorate into the intestines of C. elegans was observed. Oral administration of the hydrophobic antioxidants tocotrienol, astaxanthin, or gamma-tocopherol, prolonged the nematode lifespan; tocotrienol rendered them resistant to infection with the opportunistic pathogen Legionella pneumophila. In contrast, older conventional delivery methods that involve incorporation of chemicals into the nematode growth medium or pouring chemicals onto the plate produced weaker fluorescence and no longevity effects. Our method efficiently and quantitatively delivers hydrophobic solutes to nematodes, and a minimum effective dose was estimated. In combination with our liposome method, this gammaCD method expands the usefulness of C. elegans for the discovery of functional food factors and for screening drug candidates. PMID- 22484624 TI - Tissue-specific and age-dependent expression of protein arginine methyltransferases (PRMTs) in male rat tissues. AB - Protein arginine methyltransferases (PRMTs) generate asymmetric and symmetric dimethyl-arginines by catalyzing the transfer of methyl groups from S: -adenosyl L-methionine to arginines in target proteins. Previously, we observed that the expression and activity of PRMTs were significantly down-regulated in replicatively senescent fibroblasts compared to young fibroblasts. In this study, we determined the level of three PRMT family members (PRMT1, PRMT4, and PRMT5) and the arginine methylation status in eight tissues from 6- and 24-month-old rats. We observed tissue-specific down-regulation of individual PRMT members in testis, thymus, kidney, lung, and heart from 24-month-old as compared to 6-month old rats. Specifically, we observed reduced levels of PRMT1 in thymus and lung, reduced levels of PRMT4 in testis, thymus, and hearts, and reduced levels of PRMT5 in all five tissues. PRMT enzyme activity on histones generally correlated with PRMT expression. Furthermore, we observed a reduction in asymmetric and symmetric dimethylation on proteins in aged thymus and lung, and a reduction in symmetric dimethylation in aged testes relative to the testes harvested from young rats. These results suggest that individual PRMT proteins have tissue specific functions and are regulated in a tissue-specific and age-dependent manner. PMID- 22484625 TI - ADME of biologics-what have we learned from small molecules? AB - Thorough characterization and in-depth understanding of absorption, distribution, metabolism, and elimination (ADME) properties of a drug candidate have been well recognized as an important element in small molecule (SM) drug discovery and development. This has been the area of focus for drug metabolism and pharmacokinetics (DMPK) scientists, whose role has been evolving over the past few decades from primarily being involved in the development space after a preclinical candidate was selected to extending their involvement into the discovery stage prior to candidate selection. This paradigm shift has ensured the entry into development of the best candidates with optimal ADME properties, and thus has greatly impacted SM drug development through significant reduction of the failure rate for pharmacokinetics related reasons. In contrast, the sciences of ADME and DMPK have not been fully integrated into the discovery and development processes for large molecule (LM) drugs. In this mini-review, we reflect on the journey of DMPK support of SM drug discovery and development and highlight the key enablers that have allowed DMPK scientists to make such impacts, with the aim to provide a perspective on relevant lessons learned from SM drugs that are applicable to DMPK support strategies for LMs. PMID- 22484626 TI - Bayesian method to predict individual SNP genotypes from gene expression data. AB - RNA profiling can be used to capture the expression patterns of many genes that are associated with expression quantitative trait loci (eQTLs). Employing published putative cis eQTLs, we developed a Bayesian approach to predict SNP genotypes that is based only on RNA expression data. We show that predicted genotypes can accurately and uniquely identify individuals in large populations. When inferring genotypes from an expression data set using eQTLs of the same tissue type (but from an independent cohort), we were able to resolve 99% of the identities of individuals in the cohort at P(adjusted) <= 1 * 10(-5). When eQTLs derived from one tissue were used to predict genotypes using expression data from a different tissue, the identities of 90% of the study subjects could be resolved at P(adjusted) <= 1 * 10(-5). We discuss the implications of deriving genotypic information from RNA data deposited in the public domain. PMID- 22484628 TI - Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. AB - Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers (6/110) and FAT4 genomic deletions in 4% (3/83) of gastric tumors. Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) also occurred in 47% of the gastric cancers. We detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. In functional assays, we observed both FAT4 and ARID1A to exert tumor-suppressor activity. Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers. PMID- 22484630 TI - Liposomal cytarabine in central nervous system disease of haematological malignancies: more effective but more toxic? PMID- 22484629 TI - Dietary inorganic nitrate alleviates doxorubicin cardiotoxicity: mechanisms and implications. AB - Doxorubicin (DOX) is one of the most powerful and widely prescribed chemotherapeutic agents to treat divergent human cancers. However, the clinical use of DOX is restricted due to its severe cardiotoxic side-effects. There has been ongoing search for cardioprotectants against DOX toxicity. Inorganic nitrate has emerged as a bioactive compound that can be reduced into nitrite and nitric oxide in vivo and in turn plays a therapeutic role in diseases associated with nitric oxide insufficiency or dysregulation. In this review, we describe a novel concept of using dietary supplementation of inorganic nitrate to reduce DOX induced cardiac cellular damage and dysfunction, based on our recent promising studies in a mouse model of DOX cardiotoxicity. Our data show that chronic oral ingestion of sodium nitrate, at a dose equivalent to ~400% of the Acceptable Daily Intake of the World Health Organization, alleviated DOX-induced left ventricular dysfunction and mitochondrial respiratory chain damage. Such cardioprotective effects were associated with reduction of cardiomyocyte necrosis/apoptosis, tissue lipid peroxidation, and mitochondrial H(2)O(2) generation following DOX treatment. Furthermore, proteomic studies revealed enhanced cardiac expression of mitochondrial antioxidant enzyme - peroxiredoxin 5 in the nitrate-treated animals. These studies suggest that inorganic nitrate could be an inexpensive therapeutic agent for long-term oral administration in preventing DOX-induced cardiac toxicity and myopathy during the prolonged pathological process. Future clinical trials in the cancer patients undergoing DOX chemotherapy are warranted to translate these experimental findings into an effective new therapy in preventing the DOX-induced cardiomyopathy. PMID- 22484627 TI - A genome-wide association meta-analysis identifies new childhood obesity loci. AB - Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (>=95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 * 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 * 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 * 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI(1). PMID- 22484632 TI - Lynch syndrome diagnostics: decision-making process for germ-line testing. AB - Cancer risks and medical management of Lynch syndrome (LS) differ from other hereditary or familial clustering of colorectal cancer. Differential diagnosis has improved as a result of the growing clinical and molecular knowledge about LS. Appropriate application of these advances in several scenarios constitutes a decision-making process to further decide germ-line testing with accuracy and efficiency. However, an only molecular-screening algorithm, with a limited number of steps and choices, may be difficult to devise. How, when, where and at what expense to use the different diagnostic tools remain dynamic and changeable under different circumstances. From a clinical point of view, it is advisable to discuss conflicting aspects to guide LS diagnosis. PMID- 22484633 TI - Consensus on treatment of endometrium carcinoma with brachytherapy. AB - Radiotherapy (RT) is commonly used as adjuvant treatment following hysterectomy and double oophorectomy in endometrial carcinoma. Prophylactic vaginal brachytherapy (BT) is the most common treatment in BT units. The PORTEC and GOG 99 studies have attempted to clarify the indications of BT and postoperative external RT, changing treatment standards. However, prophylactic BT regimens are very varied and there is currently no consensus on how to treat patients in terms of dose per fraction and number of fractions. Moreover, unoperated cases of endometrium are uncommon and there is limited experience in their treatment with BT. The 9th Consensus Meeting of the SEOR and SEFM Brachytherapy Group, held in Malaga on 11 March 2011, was therefore dedicated to "Brachytherapy in Endometrial Carcinoma". This article presents the consensus on treatment of endometrial carcinoma in operated (prophylactic vaginal BT) and unoperated (endouterine BT) patients. PMID- 22484631 TI - Epithelial to mesenchymal transition in the pathogenesis of uterine malignant mixed Mullerian tumours: the role of ubiquitin proteasome system and therapeutic opportunities. AB - Malignant mixed Mullerian tumours (malignant mixed mesodermal tumours, MMMT) of the uterus are metaplastic carcinomas with a sarcomatous component and thus they are also called carcinosarcomas. It has now been accepted that the sarcomatous component is derived from epithelial elements that have undergone metaplasia. The process that produces this metaplasia is epithelial to mesenchymal transition (EMT), which has recently been described as a neoplasia-associated programme shared with embryonic development and enabling neoplastic cells to move and metastasise. The ubiquitin proteasome system (UPS) regulates the turnover and functions of hundreds of cellular proteins. It plays important roles in EMT by being involved in the regulation of several pathways participating in the execution of this metastasis-associated programme. In this review the specifi c role of UPS in EMT of MMMT is discussed and therapeutic opportunities from UPS manipulations are proposed. PMID- 22484634 TI - Lack of T-cell responses following autologous tumour lysate pulsed dendritic cell vaccination, in patients with relapsed osteosarcoma. AB - BACKGROUND: Immunotherapy using autologous dendritic cell (DC) vaccination has not been systematically evaluated in osteosarcoma. We therefore conducted a phase I trial to assess feasibility, safety and tumour-specific immune responses in patients with relapsed disease. PATIENTS AND METHODS: Of 13 recruited patients with relapsed osteosarcoma, 12 received 3 weekly vaccines of autologous DCs matured with autologous tumour lysate and keyhole limpet haemocyanin (KLH), to a maximum of 6 vaccinations. An additional 3 paediatric patients afflicted with other tumour types and with relapsed disease received vaccines generated with identical methodology. Immune responses were assessed using an ELISpot assay for the detection of interferon gamma, whilst interleukin-2 and granzyme B were additionally assessed in cases where interferon-gamma responses were induced. RESULTS: In total 61 vaccines, of homogeneous maturation phenotype and viability, were administered with no significant toxicity. Only in 2 out of 12 treated osteosarcoma cases was there an induction of specific T-cell immune response to the tumour, whilst a strong but non-specific immune response was induced in 1 further osteosarcoma patient. Immune response against KLH was induced in only 3 out of 12 osteosarcoma patients. In contrast, three additional non-osteosarcoma patients showed significant T-cell responses to vaccine. CONCLUSION: We have shown the strategy of DC vaccination in relapsed osteosarcoma is safe and feasible. However, significant anti-tumour responses were induced in only 2 out of 12 vaccinated patients with no evidence of clinical benefit. Comparison of results with identically treated control patients suggests that osteosarcoma patients might be relatively insensitive to DC-based vaccine treatments. PMID- 22484635 TI - Efficacy and safety of liposomal cytarabine in children with primary CNS tumours with leptomeningeal involvement. AB - PURPOSE: To assess the efficacy and safety of liposomal cytarabine in the treatment of de novo and relapsed leptomeningeal involvement in children with primary CNS tumours. METHODS: Data from clinical charts were entered into a database for consecutive unselected patients (n=20) from nine Spanish centres. Diagnosis of leptomeningeal involvement was confirmed by cytology, MRI and/or CT scan. The dose of liposomal cytarabine used varied from 20 to 50 mg, by age. RESULTS: There were 8 females and 12 males, mean age 7.3 years (range 8 months to 18 years). The tumours were: 10 medulloblastomas, 4 ependymomas, 3 primitive neuroectodermal tumours and 3 other tumours. Fourteen had undergone previous chemotherapy and 12 radiotherapy. Nine received concurrent chemotherapy and 2 concurrent radiotherapy. Median follow-up was 244.5 days (range 12- 869). Patients received a median of 5 doses (range 1-9) of liposomal cytarabine. A neurological response (complete or partial) was seen in 11/19 (58%) and a cytological response in 7/10 (64%). Median time to neurological progression exceeded 180 days (range 12-869). Adverse effects were reported in 11/20 patients, but none was grade IV. DISCUSSION: Liposomal cytarabine was well tolerated and efficacious in this patient group, but prospective randomised trials are needed. PMID- 22484636 TI - Increased expression of PRL-1 protein correlates with shortened patient survival in human hepatocellular carcinoma. AB - BACKGROUND: The purposes of the current study were to investigate whether overexpression of the PRL-1 is clinically relevant to hepatocellular carcinoma (HCC) and whether expression patterns of PRL-1 in HCC have diagnostic and prognostic value. METHODS: Immunohistochemistry analysis was performed for PRL-1 in 60 HCC samples. The data were correlated with clinicopathological features. The univariate and multivariate survival analyses were also performed to determine their prognostic significance. RESULTS: PRL-1 protein was overexpressed (83%) in HCC as compared with the adjacent normal tissue. PRL-1 expression was not influenced by chronic alcohol exposure or cirrhosis. High expression of PRL-1 was correlated with smoking (p=0.012), cirrhosis (p=0.047) and histological grade (p=0.055). The Kaplan-Meier survival curves showed that high PRL-1 expression related to a poor survival with statistical significance (I vs. III, p=0.010; II vs. III, p=0.001). Univariate analysis showed that PRL-1 expression was associated with tumour size, stage and PRL-1 score. Multivariate analysis revealed that the PRL-1 protein expression level was an independent factor for overall survival (HR, 5.367; 95% CI, 2.270-12.692; p=0.001). This is the first demonstration that the expression level of PRL-1 is correlated with tumour progression and prognosis in HCC. CONCLUSIONS: Along with other results, the PRL 1 protein is a candidate biomarker and a potential target for novel therapies against human HCC progression. PMID- 22484637 TI - Prognostic factors for overall survival in paediatric patients with Ewing sarcoma of bone treated according to multidisciplinary protocol. AB - BACKGROUND: The purpose of this study is to assess the outcome of patients with Ewing sarcoma (EWS) of the bone and to identify prognostic factors. MATERIALS AND METHODS: Seventy-seven patients younger than 18 years old, diagnosed with EWS of the bone between 1979 and 2009, were analysed retrospectively. Four different protocols of chemotherapy were used successively. Local treatment consisted of surgery (N=32), radiotherapy (N=20) and a combination of both (N=19). RESULTS: The median age at diagnosis was 10 years old (range, 2-17) and the median follow up for survivors 8.6 years (range, 1-18.8). Thirty-two relapses occurred (21 distant, 5 local and 6 both). The 2- and 5-year overall survival rates were 70% and 51%, respectively. Multivariate analysis showed four significant independent predictors for death: age >=14 years old (HR: 5.06; p=0.019), lack of complete response (HR: 8.04; p<0.001), tumour volume >=150 ml (HR: 2.21; p=0.045) and distant recurrences (HR: 1.45; p=0.001). CONCLUSIONS: Outcome of EWS of bone is influenced by many clinical and treatment-correlated variables. Criteria to stratify patients should include all the variables that have shown prognostic significance. The development of novel therapies should target these high-risk groups. PMID- 22484638 TI - Curcumin abrogates bile-induced NF-kappaB activity and DNA damage in vitro and suppresses NF-kappaB activity whilst promoting apoptosis in vivo, suggesting chemopreventative potential in Barrett's oesophagus. AB - INTRODUCTION: Curcumin has been suggested to possess anti-neoplastic properties. As oesophageal adenocarcinoma (OA) and Barrett's oesophagus (BO) represent a neoplastic series, we postulated that curcumin supplementation may slow neoplastic progression at this site. Our aim was to investigate the effects of curcumin in vitro and in vivo on markers of oesophageal cancer progression. METHODS: We investigated the in vitro ability of curcumin to prevent bile acid induced DNA damage using micronucleus assay and nuclear factor-kappaB (NF-kappaB) activity in the oesophageal cell lines (OE33) using real-time PCR of the extracted RNA. We also analysed NF-kappaB p65 activation in curcumin-pre-treated OE33 cells exposed to deoxycholic acid (DCA) using ELISA. In another pilot study, BO patients took a daily 500 mg curcumin tablet for 7 days prior to their endoscopy. In biopsies collected from these patients (n=33, 16 curcumin, 17 control), we examined NF-kappaB-driven gene expression (interleukin (IL)-8, inhibitor- kappaB (I-kappaB)) using real-time PCR of the extracted RNA from the biopsy sample. The apoptotic frequency was assessed by counting the number of apoptotic bodies in the epithelial cells from the Barrett's tissue with and without curcumin. RESULTS: In vitro, curcumin (50 MUM) significantly abrogated DNA damage and NF-kappaB activity induced by bile. Pretreating OE33 cells with curcumin (50 MUM) completely abolished the ability of DCA (300 MUM) to activate NF-kappaB. In vivo, IL-8 expression was non-significantly suppressed in the curcumin-supplemented patients compared to the squamous control tissue, whilst also showing a doubling in the apoptotic frequency compared to non-supplemented control patients. CONCLUSIONS: Curcumin abrogated bile-driven effects in vitro. The in vivo data also suggests that curcumin supplementation had beneficial effects (increased apoptosis, potentially reduced NF-kappaB activity) in the Barrett's tissues themselves, despite poor delivery of the curcumin to the oesophagus. PMID- 22484639 TI - Correlation between surgical modality and clinicopathologic characteristics for ureteral transitional cell carcinoma. AB - PURPOSE: To investigate the relationship between surgical modality and clinicopathologic features for ureteral transitional cell carcinoma. METHODS: The correlation between surgical modality and clinicopathology characteristics of 146 patients with ureteral carcinoma having undergone surgery was evaluated using univariate analysis by a general linear model. RESULTS: 43.8%, 51.4% and 4.8% of patients experienced nephroureterectomy, renal conservation management and palliative operations, respectively, with a mean survival time of 97.3, 101.3 and 51.0 months (p=0.069) accordingly. Univariate analysis by general linear model indicated that the size of lesions, pathologic stage and tumour grade had a statistically significant impact on surgical modality (p=0.000, p=0.001 and p=0.017, respectively). CONCLUSION: Tumour stage and grade, as well as tumour size, correlate with surgical modality. PMID- 22484640 TI - Prophylactic cranial irradiation: the state of the art and areas of uncertainty. PMID- 22484641 TI - Spatiotemporal patterns and essential role of TNF receptor-associated factor 5 expression after rat spinal cord Injury. AB - TRAF5 (TNF receptor-associated factor 5), which has a tumor necrosis factor receptor-associated factor (TRAF) domain in its carboxyl terminus, was identified CD40-associated factor. It was a signal transducer for NF-kappaB signal pathway and other pathway. To elucidate the expression and roles of TRAF5 in nervous system lesion and repair, we performed an acute spinal cord injury (SCI) model in adult rats and studied the dynamic changes of TRAF5 expression in spinal cord. Western blot and immunohistochemistry analysis revealed that TRAF5 was present in normal spinal cord. It gradually increased, reached a peak at 5 days after SCI, and then declined during the following days. Immunofluorescence double-labeling revealed that TRAF5 was co-expressed with NeuN and GFAP, respectively. Interesting, after injury, TRAF5 expression was increased predominantly in astrocytes, which highly expressed PCNA, a marker for proliferating cells. In conclusion, this is the first description of TRAF5 expression in spinal cord. Our data suggested that TRAF5 might play important roles in CNS pathophysiology after SCI. PMID- 22484642 TI - Severe intraglomerular detachment of podocytes in a Gitelman syndrome patient. AB - We report the case of a 38-year-old woman diagnosed with Gitelman syndrome. A kidney biopsy showed abundant floating cells in the Bowman's space of the mildly cystic glomeruli, moderate tubulointerstitial changes and apparent intimal thickening of small arteries. These floating cells were immunohistologically identified as podocytes, by the expression of podocalyxin, vimentin, Wilms' tumor 1, synaptopodin and nephrin with positivities of 100%, 88.4%, 80.4%, 74.7% and 22.6%, respectively. In these phenotypes, nephrin expression was notably decreased in both detached and capillary-attached podocytes in comparison with normal control podocytes. Immunostaining of both detached and capillary-attached podocytes for Bax, Bcl-2, desmin, fibroblast-specific protein-1, alpha-smooth muscle actin and Ki-67 was negative, as were TUNEL assays. These results suggest that apoptosis and epithelial-mesenchymal transition were not the main cause of podocyte detachment in this patient. In addition, levels of urinary podocalyxin were not elevated, suggesting the detached podocytes were not excreted in the urine. To the best of our knowledge, this is the first report of severe intraglomerular non-apoptotic detachment of podocytes in Gitelman syndrome. This podocyte detachment may be associated with nephron obstruction and reduced nephrin expression. PMID- 22484644 TI - Increased toxicity when fibrates and statins are administered in combination--a metabolomics approach with rats. AB - Combination therapies with fibrates and statins are used to treat cardiovascular diseases, because of their synergistic effect on lowering plasma lipids. However, fatal side-effects like rhabdomyolysis followed by acute renal necrosis sometimes occur. To elucidate biochemical changes resulting from the interaction of fibrates and statins, doses of 100 mg/kg fenofibrate, 50mg/kg clofibrate, 70 mg/kg atorvastatin and 200 mg/kg pravastatin as well as combinations thereof were administered to Crl:Wi(Han) rats for 4 weeks. Plasma metabolome profile was measured on study days 7, 14 and 28. Upon study termination, clinical pathology parameters were measured. In a separate experiment plasmakinetic data were measured in male rats after 1 week of drug administration in monotherapy as well as in combinations. Lowering of blood lipid levels as well as toxicological effects, like liver cell degradation (statins) and anemia (fibrates) and distinct blood metabolite level alterations were observed in monotherapy. When fibrates and statins were co-administered metabolite profile interactions were generally underadditive or at the utmost additive according to the linear mixed effect model. However, more metabolite levels were significantly altered during combination therapy. New effects on the antioxidant status and the cardiovascular system were found which may be related to a development of rhabdomyolysis. Accumulation of drugs during the combination therapy was not observed. PMID- 22484643 TI - Sar1 translocation onto the ER-membrane for vesicle budding has different pathways for promotion and suppression of ER-to-Golgi transport mediated through H89-sensitive kinase and ER-resident G protein. AB - ER-to-Golgi protein transport involves transport vesicles of which formation is initiated by assembly of Sar1. The assembly of Sar1 is suppressed by protein kinase inhibitor H89, suggesting that ER-to-Golgi transport is regulated progressively by H89 sensitive kinase. ER-resident G(i2) protein suppresses vesicle formation with inhibition of Sar1 assembly. This study examined whether these promotion and suppression of vesicle transport share the same signal pathway, by examining the effects of G(i/o) protein activator mastoparan 7 (Mp-7) and H89 on Sar1 and Sec23 recruitment onto microsomes. In a cell-free system for Sar1 translocation assay, GTPgammaS addition induced the translocation of Sar1 onto microsomes. Mp-7 and H89 decreased the Sar1 translocation. Double treatment of Mp-7 and H89 strongly decreased Sar1 translocation. In single and double treatments, however, G(i/o) protein inactivator pertussis toxin (IAP) partially restored the suppressive effect of Mp-7, but had not any effect on H89-induced effect. Then, the assembly of Sec23 onto the microsome was also increased by the addition of GTPgammaS. Sec23 translocation was decreased by Mp-7 and/or H89 treatment and recovered by IAP pretreatment except for H89 single treatment, similarly to Sar1 translocation in each treatment. Inhibitory effects of H89 and Mp-7on ER-to-Golgi vesicle transport by H89 or Mp-7 were also confirmed in a cell culture system by BFA-dispersion and BFA-reconstruction experiments. These findings indicate that promotion and suppression of ER-to-Golgi vesicle transport are modulated through separate signal pathways. PMID- 22484645 TI - Inflammatory response modulation of airway epithelial cells exposed to formaldehyde. AB - The two main difficulties when assessing the role and action mechanism of environmental pollutant exposure on the respiratory tract using in vitro methodology are firstly to create exposure conditions that closely mimic the human situation, and secondly to choose an experimental model that accurately represents lung compartment complexity, with different types of cell interaction. The aim of this study was to resolve these two challenges. The first of our difficulties was to find the closest experimental conditions to mimic respiratory environmental pollutant exposure. We compared the effects of formaldehyde (FA) on two cellular models, alveolar and bronchial cell lines, respectively A549 and BEAS-2B. The cells were exposed for 30 min to an environmental dose of gaseous FA (50 MUg/m3) at the air-liquid interface. In order to mimic macrophage-epithelial cell cooperation, sensitizations (with TNFalpha or with conditioned medium from macrophages--CM) prior to gas exposure were applied. After toxicity evaluation, local inflammation was assessed by IL-8 and MCP-1 production 24h after exposure. In our experimental conditions FA had no effects on alveolar and bronchial epithelial cells without any sensitization. FA exposure after TNFalpha sensitization alone induced a moderate increase of IL-8 by A549 cells. After sensitization with CM, FA exposure induced a strong increase of IL-8 production by A549 cells in comparison to air, whereas a decrease of MCP-1 production was observed on BEAS-2B cells. It appears that the response of alveolar and bronchial epithelial cells to FA was moderate and that complex sensitization refines the inflammatory response to environmental stresses. When sensitized with CM, these cell lines responded differently to FA exposure. Finally by interacting with the respiratory epithelium, FA could exacerbate the inflammation of airways that occurs in severe asthma, and even synergize the effects of other air pollutants such as allergens. Evaluation of nasal cell inflammatory response could shed further light on the effects of FA on respiratory epithelium. PMID- 22484646 TI - Postmortem device reuse. PMID- 22484647 TI - Point/Mandatory ECG screening of young competitve athletes. PMID- 22484648 TI - Counterpoint/Mandatory ECG screening of young competitive athletes. PMID- 22484649 TI - Traumatic right ventricular aneurysm and ventricular tachycardia. PMID- 22484650 TI - Characteristics of ectopic triggers associated with paroxysmal and persistent atrial fibrillation: evidence for a changing role. AB - BACKGROUND: Atrial premature contractions (APCs) are well described to precede the initiation of paroxysmal atrial fibrillation (pAF). However, whether APC characteristics alter with progression of the arrhythmia is unknown. OBJECTIVE: To determine the APC characteristics in terms of burden and relative coupling interval with progression of the AF disease process. METHODS: Fifty consecutive patients with pAF, 50 consecutive patients with persistent AF (perAF), and 25 age matched controls underwent clinical review, transthoracic echocardiography, and ambulatory electrocardiogram monitoring. After excluding 29 patients who had AF for the entire recording (n = 24) or unreliable recordings (n = 5), we analyzed data from 49 patients with pAF, 24 patients with perAF, and 23 healthy controls. All normal morphology R-R intervals with a >25% decrease in R-R coupling compared with the previous R-R interval (coupling interval index) were deemed APCs (n = 95,873). RESULTS: The median APC burden was higher in patients with pAF (2 [1-22] APCs/h; P = .004) and perAF (3 [1-6] APCs/h; P = .04) than in controls (1 [0-1] APCs/h) but was not different (P = .66) between the AF subgroups. Patients with pAF had a distinct increase in ectopy burden after 7 PM and elevation throughout the night (P = .002) in comparison with a blunted and complementary temporal response in the perAF cohort (P = .01). Patients with pAF demonstrated a greater proportion of shortly coupled APCs (29% [13-45]; P = .04) compared with persistent arrhythmia (17% [5-29]). CONCLUSIONS: "Real-life" atrial trigger statistics of APC burden, timing, and diurnal rhythms track the transition from a trigger-based, autonomically sensitive paroxysmal arrhythmia to a more substrate based persistent disease. PMID- 22484652 TI - Class I recall of defibrillator leads: a comparison of the Sprint Fidelis and Riata families. AB - BACKGROUND: In recent years, 2 popular implantable cardioverter-defibrillator (ICD) leads have undergone a class I recall by the Food and Drug Administration (FDA): the Sprint Fidelis and the Riata leads. OBJECTIVE: To examine the failure rates of these 2 leads with respect to their date of FDA recall. METHODS: All patients implanted with a Sprint Fidelis, Riata, or Sprint Quattro lead at our institution were included. Kaplan-Meier failure-free survival curves were constructed with and without censoring at the dates of announcement of the FDA recall for each lead. RESULTS: A total of 2270 patients (623 Sprint Fidelis, 627 Riata, and 1020 Sprint Quattro) were included. The failure-free survival of the Sprint Quattro lead was significantly better than that of the Riata lead (P <.0001), which in turn was better than that of the Sprint Fidelis lead (P = .0214). After censoring events at the time of the FDA recall for each lead, the failure-free survival of the Sprint Quattro lead continued to be superior to that of the Riata (P <.0001) and Sprint Fidelis (P = .0124) leads but the difference between the Riata and Sprint Fidelis leads was eliminated (P = .123). CONCLUSIONS: In this study, a comparative analysis of the failure-free survival of 2 recalled leads demonstrates discrepancies in the timing of the recall despite comparable failure-free survival patterns leading to the recall. The causes of these discrepancies are unclear and raise questions regarding the consistency of postmarketing surveillance and manufacturers' reporting of malfunctions of medical devices. PMID- 22484653 TI - Performance evaluation of a photo-Fenton process applied to pollutant removal from textile effluents in a batch system. AB - In this work, the performance of a photo-Fenton process-based textile effluent treatment was investigated using both solar and artificial light sources. A full 3(3) factorial experimental design was applied for the optimisation with respect to three parameters: initial pH, amounts of Fe(2+) (0.01-0.09 g L(-1)) and H(2)O(2) (1-7 g L(-1)). The photo-Fenton process response was evaluated on the basis of chemical oxygen demand (COD) removal and decolourisation. The optimum conditions of the photo-Fenton process were attained at concentration values of 0.05 g Fe(2+) L(-1) and 6.0 g H(2)O(2) L(-1) and pH 3, for both solar and artificial light sources. The effects of initial pH, and Fe(2+) and H(2)O(2) concentrations were evaluated. From the monitoring of TOC, COD, turbidity and decolourisation over time, the progress of the mineralisation of dyes was analysed, forming nitrate, ammonia nitrogen and nitrite. Low amounts of residual peroxide and iron, which were below the limit allowed by Brazilian environmental legislation, were attained after 360 min of irradiation time for both artificial and solar sources. An operational cost of US$ 6.85 per m(3) of treated effluent was estimated using solar irradiation. PMID- 22484654 TI - Solid waste bin level detection using gray level co-occurrence matrix feature extraction approach. AB - This paper presents solid waste bin level detection and classification using gray level co-occurrence matrix (GLCM) feature extraction methods. GLCM parameters, such as displacement, d, quantization, G, and the number of textural features, are investigated to determine the best parameter values of the bin images. The parameter values and number of texture features are used to form the GLCM database. The most appropriate features collected from the GLCM are then used as inputs to the multi-layer perceptron (MLP) and the K-nearest neighbor (KNN) classifiers for bin image classification and grading. The classification and grading performance for DB1, DB2 and DB3 features were selected with both MLP and KNN classifiers. The results demonstrated that the KNN classifier, at KNN = 3, d = 1 and maximum G values, performs better than using the MLP classifier with the same database. Based on the results, this method has the potential to be used in solid waste bin level classification and grading to provide a robust solution for solid waste bin level detection, monitoring and management. PMID- 22484655 TI - A compatibility-based procedure designed to generate potential sanitation system alternatives. AB - Regarding multi-criteria decision analysis (MCDA), the problem of generating alternatives has not received the attention it deserves. Most research is currently devoted to the problem of alternative selection, where it is assumed that a set of appropriate alternatives is already given. This paper addresses the generation of potential alternatives in the domain of sanitation systems planning and decision-making. A compatibility assessment procedure is proposed to determine the set of technically feasible or potential sanitation system alternatives. This is based on a clear definition of such an alternative containing sub-processes that include a user interface, storage, conveyance treatment and reuse/disposal. A newly developed compatibility matrix is applied to identify incompatibilities between the options of the sub-processes. A potential sanitation system alternative is therefore defined by the absence of two-by-two incompatibility between all its options. The compatibility assessment acts as a first filter on the set of sanitation system alternatives to eliminate those that are inoperable before the feasibility assessment. The objective of both steps is to obtain a set of alternatives that are of reasonable and manageable size from which the final solution may be selected. PMID- 22484656 TI - Basic characteristics of leachate produced by various washing processes for MSWI ashes in Taiwan. AB - Approximately 19.2% of Taiwan's municipal solid waste (MSW) that passes through incineration disposal is converted into ashes (including bottom ash and fly ash). Although bottom ash can pass nearly all of the standards of the toxicity characteristic leaching procedure (TCLP), its high chloride content makes its reuse limited; it generally cannot be used as a fine aggregate material in concrete applications. This research examined washing four types of bottom ash (BA) and fly ash (FA) with water to reduce their chloride content. The optimal water intensity for washing pretreated bottom ash was found to be 7-8L of water per kg of bottom ash, and the optimal water intensity for washing untreated fly ash was found to be 20-25 L of water per kg of fly ash. Based on regression analyses of the chloride concentrations of the leachates and their electrical conductivity (EC) values, each MSW incineration plant has its own ash characteristics as well as a specific regression line in bottom or fly ash leachate. Clearly, it is possible to monitor the EC values of the leachates online by estimation from regression equations to determine the chloride concentrations in the leachates. PMID- 22484657 TI - Beneficiation of coal pond ash by physical separation techniques. AB - In this study, investigations to develop a beneficiation process for separating coal pond ash into various products were undertaken. To this end, coal pond ash samples with different particle size ranges were tested in terms of their washability characteristics in a float-and-sink analysis. It was found that coal pond ash was heterogeneous in nature consisting of particles that varied in terms of their size and composition. However, it can be made more homogenous using a gravity separation method. Therefore, the possibility of separating coal pond ash was tested on standard equipment typically used for gravity concentration. To increase the separation efficiency, coal ash was separated according to the size of the particles and each size fraction was tested using equipment appropriate for the corresponding sizes. A hindered-settling column and a shaking table were tested for their ability to treat the 1.19 * 0.074 mm size fraction, and a Falcon concentrator was evaluated for its ability to treat the -0.074 mm size fraction. The results showed that various marketable products, such as lightweight aggregate, sand and high-carbon fuel, can be recovered from coal pond ash using simple physical separation techniques. PMID- 22484658 TI - Effects of NH4+ on Ce(IV) electro-regeneration in simulated and real spent TFT LCD Cr-etching solutions. AB - This investigation studies the electro-regeneration of Ce(IV) from Ce(III) in 4 M HNO(3) in the presence/absence of NH(4)(+) and real spent thin-film transistor liquid-crystal display (TFT-LCD) Cr-etching solutions. On Pt, at 2 A and 70 degrees C for 100 min, the Ce(IV) yield and apparent rate constant of Ce(III) oxidation in 4 M HNO(3) without NH(4)(+) were 100% and 5.54 * 10(-4) s(-1), respectively (and the activation energy was 13.1 kJ mol(-1)). Cyclic voltammetric and electrolytic measurements consistently support the noticeable inhibition by NH(4)(+) of Ce(III) oxidation and lowering of the Ce(IV) yield, respectively. The apparent diffusion coefficients for 0.2 and 0.02 M Ce(III) oxidation in 4 M HNO(3) that contained 0-0.6 M NH(4)(+) were (0.38-0.25) * 10(-5) and (1.6-0.9) * 10(-5) cm(2) s(-1), respectively. Because of combined effects of NH(4)(+) and anion impurities, the 100 min Ce(IV) yield of a real spent TFT-LCD Cr-etching solution (with [NH(4)(+)]/[Ce(III)] = 0.74 M/0.39 M) was 82%, lower than that of 4 M HNO(3) without NH(4)(+), but higher than those of 4 M HNO(3) that contained anion impurities with/without 0.4 M NH(4)(+). PMID- 22484659 TI - The green roof dilemma - discussion of Francis and Lorimer (2011). AB - Urban ecosystems are the most complex mosaics of vegetative land cover that can be found. In a recent paper, Francis and Lorimer (2011) evaluated the reconciliation potential of living roofs and walls. For these authors, these two techniques for habitat improvement have strong potential for urban reconciliation ecology. However they have some ecological and societal limitations such as the physical extreme environmental characteristics, the monetary investment and the cultural perceptions of urban nature. We are interested in their results and support their conclusions. However, for a considerable time, green roofs have been designed to provide urban greenery for buildings and the green roof market has only focused on extensive roof at a restricted scale within cities. Thus, we have strong doubts about the relevance of their use as possible integrated elements of the network. Furthermore, without dynamic progress in research and the implementation of well-thought-out policies, what will be the real capital gain from green roofs with respect to land-use complementation in cities? If we agree with Francis and Lorimer (2011) considering that urban reconciliation ecology between nature and citizens is a current major challenge, then "adaptive collaborative management" is a fundamental requirement. PMID- 22484660 TI - GSTT1 and GSTM1 gene polymorphisms as major risk factors for asthma in a North Indian population. AB - BACKGROUND: According to the National Family Health Survey, asthma is one of the leading diseases in India. In order to understand the complexity of asthma, the susceptibility genes need to be targeted for their association. Glutathione S transferases play a major role in the detoxification of metabolites of oxidative stress resulting in inflammation and asthma. In the present study, the hypothesis that GSTT1 and GSTM1 gene polymorphisms are associated with asthma was examined. METHODS: This is the first study to investigate the role of GSTT1 and GSTM1 gene polymorphisms in asthma pathogenesis in a North Indian population. A total of 824 subjects were recruited, of which 410 were asthma patients, including 323 patients suffering from allergic rhinitis. The other 414 recruits were healthy controls from regions of North India. Multiplex PCR was used for genotyping the GSTT1 and GSTM1 gene polymorphisms. RESULTS: The GSTT1 null allele was more prevalent in asthma patients (40 %) than in the control subjects (13.3 %), which yielded a nearly fourfold risk towards asthma with odds ratio (OR) (95 % CI) = 4.35 (3.04-6.24), chi(2) = 75.34, and p = 0.000. The GSTM1 polymorphism also revealed a greater prevalence of the GSTM1 null allele in asthma patients (46.6 %) than in controls (39.4 %). Statistical analysis yielded a marginal risk toward asthma with OR (95 % CI) = 1.34 (1.01-1.79), chi(2) = 4.37, and p = 0.036. CONCLUSIONS: Polymorphisms as a result of deletions in the GSTT1 and GSTM1 genes confer an increased risk towards asthma thereby suggesting the protective role of these functional genes in the development of the disease. PMID- 22484661 TI - Sensitivity studies of pediatric material properties on juvenile lumbar spine responses using finite element analysis. AB - The objective of the study was to determine the sensitivity of material properties of the juvenile spine to its external and internal responses using a finite element model under compression, and flexion-extension bending moments. The methodology included exercising the 8-year-old juvenile lumbar spine using parametric procedures. The model included the vertebral centrum, growth plates, laminae, pedicles, transverse processes and spinous processes; disc annulus and nucleus; and various ligaments. The sensitivity analysis was conducted by varying the modulus of elasticity for various components. The first simulation was done using mean material properties. Additional simulations were done for each component corresponding to low and high material property variations. External displacement/rotation and internal stress-strain responses were determined under compression and flexion-extension bending. Results indicated that, under compression, disc properties were more sensitive than bone properties, implying an elevated role of the disc under this mode. Under flexion-extension moments, ligament properties were more dominant than the other components, suggesting that various ligaments of the juvenile spine play a key role in modulating bending behaviors. Changes in the growth plate stress associated with ligament properties explained the importance of the growth plate in the pediatric spine with potential implications in progressive deformities. PMID- 22484662 TI - A cable theory based biophysical model of resistance change in crab peripheral nerve and human cerebral cortex during neuronal depolarisation: implications for electrical impedance tomography of fast neural activity in the brain. AB - Electrical impedance tomography (EIT) is a medical imaging method with the potential to image resistance changes which occur during neuronal depolarisation in the brain with a resolution of milliseconds and millimetres. Most biomedical EIT is conducted with applied current over 10 kHz, as this reduces electrode impedance and so instrumentation artefact. However, impedance changes during neuronal depolarization are negligible at such frequencies. In order to estimate optimal recording frequency and specify instrumentation requirements, we have modelled their amplitude and frequency dependence during evoked activity using cable theory. Published values were used for the electrical properties and geometry of cell processes. The model was adjusted for the filtering effect of membrane capacitance and proportion of active neurons. At DC, resistance decreases by 2.8 % in crab nerve during the compound action potential and 0.6 % (range 0.06-1.7 %) locally in cerebral cortex during evoked physiological activity. Both predictions correlate well with independent experimental data. This encourages the view that true tomographic imaging of fast neural activity in the brain is possible, at least with epicortical electrodes in the first instance. It is essential to undertake this at low frequencies below about 100 Hz as above 1 kHz the signal becomes vanishingly small. PMID- 22484663 TI - Viral genome RNA degradation by sequence-selective, nucleic-acid hydrolyzing antibody inhibits the replication of influenza H9N2 virus without significant cytotoxicity to host cells. AB - Influenza A virus infection is a great threat to avian species and humans. Targeting viral proteins by antibody has a limited success due to the antigen drift and shift. Here we present a novel antibody-based antiviral strategy of targeting viral genomic RNA (vRNA) for degradation rather than neutralizing viral proteins. Based on the template of a sequence-nonspecific nucleic acid hydrolyzing, single domain antibody of the light chain variable domain, 3D8 VL, we generated a synthetic library on the yeast surface by randomizing putative nucleic acid interacting residues. To target nucleocapsid protein (NP)-encoding viral genomic RNA (NP-vRNA) of H9N2 influenza virus, the library was screened against a 18-nucleotide single stranded nucleic acid substrate, dubbed asNP(18), the sequence of which is unique to the NP-vRNA. We isolated a 3D8 VL variant, NP25, that had ~15-fold higher affinity (~54nM) and ~3-fold greater selective hydrolyzing activity for the target substrate than for off targets. In contrast to 3D8 VL WT, asNP(18)-selective NP25 constitutively expressed in the cytosol of human lung carcinoma A549 cells does not exhibit any significant cytotoxicity and selectively degrades a reporter mRNA carrying the target asNP(18) sequence in the stable cell lines. NP25 more potently inhibits the replication of H9N2 influenza virus than 3D8 VL WT in the stable cell lines. NP25 more selectively reduces the amount of the targeted NP-vRNA than 3D8 VL WT from the early stage of virus infection in the stable cell lines, without noticeable harmful effects on the endogenous mRNA, suggesting that NP25 indeed more specifically recognizes to hydrolyze the target NP-vRNA of H9N2 virus than off-targets. Our results provide a new strategy of targeting viral genomic RNA for degradation by antibody for the prevention of influenza virus infection in humans and animals. PMID- 22484665 TI - Costs and cost-effectiveness of allogeneic stem cell transplantation in children are predictable. AB - The overall costs of pediatric stem cell transplantation (SCT), including donor search and costs during the first year post-SCT, were calculated in a cohort of 141 consecutive children undergoing SCT in a single institution. Costs were correlated with patient and transplantation characteristics and with a risk score for transplantation-related mortality. Cost-effectiveness was calculated based on the overall cost per surviving patient. Life-years gained were extrapolated from overall survival, and the costs per expected life-year gained were calculated. The overall median cost was ?136,382 (175,815$), with a wide range, of ?26,897 (34,679$) to ?601,348 (775,343$). Increased costs were significantly associated with age, use of donors other than matched siblings, and advanced disease. There was a strong correlation of costs with a simple transplantation-related mortality risk score; median total costs were ?89,550 (115,463$) for a score of 0, ?127,349 (164,179$) for a score of 1, ?156,578 (201,861$) for a score of 2, and ?274,915 (354,499$) for a score of 3 (P < .001). Cost-effectiveness decreased with increasing transplantation-related mortality risk score; costs per survivor increased from ?93,209 (120,200$) for a score of 0 to a maximum of ?1,216,348 (1,568,579$) for a score of 3. Costs associated with pediatric SCT vary substantially; however, the combination of variables such as age, disease, and donor type is predictive of costs and cost-effectiveness. Costs per life-year gained are within the broadly accepted range in life-threatening hemato-oncologic diseases, even in the most cost-intensive patient cohort. PMID- 22484664 TI - Nitrite therapy is neuroprotective and safe in cardiac arrest survivors. AB - Cardiac arrest results in significant mortality after initial resuscitation due in most cases to ischemia-reperfusion induced brain injury and to a lesser degree myocardial dysfunction. Nitrite has previously been shown to protect against reperfusion injury in animal models of focal cerebral and heart ischemia. Nitrite therapy after murine cardiac arrest improved 22 h survival through improvements in myocardial contractility. These improvements accompanied transient mitochondrial inhibition which reduced oxidative injury to the heart. Based on preliminary evidence that nitrite may also protect against ischemic brain injury, we sought to test this hypothesis in a rat model of asphyxia cardiac arrest with prolonged survival (7d). Cardiac arrest resulted in hippocampal CA1 delayed neuronal death well characterized in this and other cardiac arrest models. Nitrite therapy did not alter post-arrest hemodynamics but did result in significant (75%) increases in CA1 neuron survival. This was associated with increases in hippocampal nitrite and S-nitrosothiol levels but not cGMP shortly after therapy. Mitochondrial function 1h after resuscitation trended towards improvement with nitrite therapy. Based on promising preclinical data, the first ever phase I trial of nitrite infusions in human cardiac arrest survivors has been undertaken. We present preliminary data showing low dose nitrite infusion did not result in hypotension or cause methemoglobinemia. Nitrite thus appears safe and effective for clinical translation as a promising therapy against cardiac arrest mediated heart and brain injury. PMID- 22484667 TI - Construction and characterization of a PDCD5 recombinant lentivirus vector and its expression in tumor cells. AB - The function and mechanism of the programmed cell death 5 (PDCD5) gene is not completely understood, so it is necessary to build a stable and efficient PDCD5 recombinant lentiviral expression vector. The coding region of the PDCD5 gene was PCR amplified from pCMV-SPORT6. Next, the PDCD5 fragment and the pGC-FU vector were digested with the restriction enzyme AgeI and ligated by in-Fusion technology to build the pGC-FU-PDCD5 plasmid. Competent E. coli DH5alpha cells were transformed and positive clones were identified by PCR. The PCR products were digested and sequenced. After sequencing, positive clones were selected to grow and propagate. The pGC-FU-PDCD5 plasmid DNA was purified and mixed with the pHelper1.0 and pHelper2.0 packaging plasmids. They were co-transfected into 293T cells. The viral titer was measured by real-time PCR. The expression of GFP and PDCD5 was detected by both Western blotting and fluorescence microscopy. Additionally, the A498, ACHN, HCT116 and LoVo tumor cell lines were transfected with the virus supernatant, and PDCD5 expression was detected in these cells. The constructed pGC-FU-PDCD5 plasmid contained the correct PDCD5 gene sequence. Strong green fluorescence in both the cytoplasm and cell membrane was observed following transfection with purified pGC-FU-PDCD5 into 293T cells. The transfection rate was greater than 95%, and the expression of the PDCD5-GFP fusion protein was confirmed by Western blotting. The titer of the recombinant PDCD5 lentiviral condensed supernatant was measured to be 2 x 10(9) Tu/ml. The transfection efficiencies of A498, ACHN and HCT116 cells were greater than 90%. However, transfection efficiency of LoVo cells was lower but still greater than 70%. The PDCD5-GFP fusion protein was stable in these transfected tumor cells, as detected by Western blotting. In conclusion, a PDCD5 recombinant lentiviral vector was successfully constructed, and high expression of the plasmid was observed in tumor cells. PMID- 22484668 TI - Vectors and agrobacterium hosts for Arabidopsis transformation. AB - INTRODUCTIONArabidopsis can be stably transformed using Agrobacterium tumefaciens mediated transfer of T-DNA. A. tumefaciens is a soil-dwelling bacterium that transforms normal plant cells into tumor-forming cells by inserting a piece of bacterial DNA (the transfer, or "T," DNA) into the plant cell genome. The T-DNA, which is flanked by left- and right-border (LB and RB) sequences, resides on a tumor-inducing (Ti) plasmid. The Ti plasmid also carries many of the transfer functions for mobilizing the T-DNA. This article provides a brief discussion of the principles of T-DNA transformation, including consideration of T-DNA vectors and their hosts. PMID- 22484666 TI - Multicenter experience using total lymphoid irradiation and antithymocyte globulin as conditioning for allografting in hematological malignancies. AB - A non myeloablative conditioning with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) was shown to protect against graft-versus-host disease (GVHD). To evaluate the effects of TLI-ATG in a multicenter study, 45 heavily pretreated patients, median age 51, with lymphoid (n = 38) and myeloid (n = 7) malignancies were enrolled at 9 centers. Twenty-eight patients (62%) received at least 3 lines of treatment before allografting, and 13 (29%) had refractory/relapsed disease at the time of transplantation. Peripheral blood hematopoietic cells were from HLA identical sibling (n = 30), HLA-matched (n = 9), or 1 antigen HLA-mismatched (n = 6) unrelated donors. A cumulative TLI dose of 8 Gy was administered from day -11 through -1 with ATG at the dose of 1.5 mg/kg/day (from day -11 through -7). GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. Donor engraftment was reached in 95% of patients. Grade II to IV acute GVHD (aGVHD) developed in 6 patients (13.3%), and in 2 of these patients, it developed beyond day 100. Incidence of chronic GVHD (cGVHD) was 35.8%. One-year nonrelapse mortality was 9.1%. After a median follow-up of 28 months (range, 3-57 months) from transplantation, median overall survival was not reached, whereas median event-free survival was 20 months. This multicenter experience confirms that TLI-ATG protects against GVHD and maintains graft-vs tumor effects. PMID- 22484669 TI - 6-azauracil sensitivity assay for yeast. AB - INTRODUCTIONTreatment of yeast with 6-Azauracil (6AU) leads to a reduction of intracellular GTP levels. The reduction in GTP levels is not itself lethal, but can block yeast growth when combined with mutations that affect transcriptional elongation. 6AU sensitivity thus can be used as a crude assay to test for mutations that affect transcriptional elongation. The assay described here requires growing saturated cultures of yeast, counting, and spotting serial dilutions of yeast on both CSM and CSM + 6AU plates. PMID- 22484670 TI - Freeze-thaw lysis for extraction of proteins from Mammalian cells. AB - INTRODUCTIONThis protocol describes the extraction of proteins from mammalian cells grown in 6- or 10-cm tissue-culture dishes. It is useful for making very concentrated extracts for Western blotting, and is particularly helpful when low abundance proteins such as Myc are being studied. PMID- 22484671 TI - Detection of ubiquitylated proteins in yeast. AB - INTRODUCTIONThis assay is performed to detect ubiquitylated proteins in yeast. Yeast that have been transformed with a vector expressing polyhistidine-tagged ubiquitin (Ub) under the control of a copper-inducible promoter are grown, induced with copper, and harvested. Total ubiquitylated proteins are then recovered by nickel-affinity chromatography, and specific proteins are detected by Western blotting. PMID- 22484672 TI - Constructing and Expressing GFP Fusion Proteins. AB - INTRODUCTIONGFP (green fluorescent protein) fusion proteins have been used to address a wide range of questions in individual cells, as well as in tissues of a particular organism. GFP fusion proteins can be transiently or stably expressed. Although transient expression is quick and can provide informative results, in many cases it is beneficial and/or essential to develop stable cell lines expressing the fusion protein of interest. In addition to providing more native levels of expression, individual clones can be generated from single cells, the integration site of the plasmid mapped, and the copy number determined. Because every cell in the population is expressing the fusion protein, cell cycle analyses and biochemical fractionation are significantly easier to accomplish. The following protocol can be used for the development of stable cell lines expressing GFP fusion proteins. Although optimal transfection procedures (e.g., calcium phosphate, electroporation, or FuGENE 6 [Roche Applied Science]) vary depending on cell type, this general transfection procedure has been successful for stable transfection of HeLa, A-431, U2OS, BHK, and HT1080 cells. PMID- 22484673 TI - Plating cells for microinjection. AB - INTRODUCTIONThis protocol describes a method for plating cells for microinjection onto etched coverslips. The coverslips for microinjection must be marked so that microinjected cells can be identified at time points after injection. A procedure for etching coverslips is given below; alternatively, pre-etched coverslips can be purchased at slightly higher cost. PMID- 22484674 TI - Preparation (pulling) of needles for gene delivery by microinjection. AB - INTRODUCTIONThis protocol contains methods for pulling microinjection needles using two different models of pipette pullers. The advantage of pulling needles in the laboratory is that a variety of different needle types can be pulled, depending on the samples and cells being injected. An added advantage is cost; once a pipette puller has been purchased, boxes of glass capillaries are inexpensive compared to premade microinjection needles. The advantages to buying preformed and sterilized needles include increased uniformity of needles from one to another, ease of use, high quality, and not having to invest in a pipette puller. The pipette puller models described in this article are the Flaming/Brown Pipette Puller Model P-97 (Sutter) and the PUL-1 Micropipette Puller (World Precision Instruments). The PUL-1 instrument is the less expensive of the two, but it requires more user input, and it cannot be used to pull Femtotip-like microinjection pipettes. PMID- 22484675 TI - DNA preparation and needle loading for gene delivery by microinjection. AB - INTRODUCTIONFor microinjection into cells, high-quality plasmid DNA is purified using standard procedures. The resulting preparation is then delivered into the microinjection needle by either a back-filling or a forward-filling approach. PMID- 22484676 TI - Gene delivery by direct injection (microinjection) using a pulsed-flow system. AB - INTRODUCTIONThis protocol describes a method for pulsed-flow microinjection using the Eppendorf FemtoJet injector and Eppendorf InjectMan; this is the most common type of pulsed-flow microinjection system currently being used. The advantage of this type of system over a controlled-flow system is that much more control is available over the injection parameters, reducing variability in injections. In addition, the system allows a diagonal insertion of the needle into the cell, causing a direct piercing of the cell. This is fast and may do less damage to the cell than a traditional system, in which the cell is briefly distorted before it is pierced. PMID- 22484677 TI - Gene delivery by direct injection (microinjection) using a controlled-flow system. AB - INTRODUCTIONThis protocol describes a method for constant-flow microinjection using the Pneumatic PicoPump (World Precision Instruments). This type of system is very simple and can be assembled on a relatively low budget. In this method, a constant flow of sample is delivered from the tip of the pipette, and the amount of sample injected into the cell is determined by how long the pipette remains in the cell. A typical system is composed of a pressure regulator that can be adjusted for two pressures (back pressure and injection pressure), a capillary holder, and a coarse and fine micromanipulator. PMID- 22484678 TI - Silver Staining, Digestion, and Extraction of Peptides from an Acrylamide Gel for MS Analysis. AB - INTRODUCTIONIndividual components of protein complexes separated by sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) are visualized by silver (or Coomassie) staining. For subsequent analysis by mass spectrometry (MS), it is important to use silver staining protocols with no glutaraldehyde, as this reagent chemically modifies the protein and inhibits subsequent steps. The individual stained protein bands are excised from the gel, the proteins are enzymatically digested into peptides, and the peptides are extracted. The peptides from each protein can be subsequently analyzed by high-pressure liquid chromatography (HPLC) fractionation and electrospray ionization (ESI) MS. This generates a mass fingerprint of the peptides that comprise the unknown protein. Further structural data for peptides can be obtained by fragmenting the ionized peptides to generate a tandem mass spectrum. Alternatively, a mass fingerprint of the peptides is obtained by matrix-assisted laser desorption/ionization in combination with a time-of-flight instrument (MALDI/TOF). PMID- 22484679 TI - Direct Enzymatic Digestion of Protein Complexes for MS Analysis. AB - INTRODUCTIONThe individual components of a purified protein complex can be determined by MS. Components can be separated by SDS-PAGE and subsequently digested, or the entire protein complex can be digested by chemical agents or by proteases. The mixture of peptides that results from digestion without prior separation is more complex than that obtained from the digestion of a single protein, and can best be resolved subsequently using HPLC in combination with a biphasic column. Protein complexes can be digested directly using several different protocols. Common methods include a double digest with endoproteinase Lys-C and trypsin, or a triple digest with elastase, subtilisin, and trypsin. Endoproteinase Lys-C cleaves carboxy-terminal to lysine residues, while trypsin cleaves carboxy-terminal to lysine and arginine residues. The triple digest uses the relatively nonspecific proteases elastase and subtilisin to create a large number of overlapping peptides for the analysis of post-translational modifications. The double and triple digest protocols begin with the reduction and alkylation of cysteine residues to disrupt disulfide bonds and, therefore, higher-order protein structure. PMID- 22484680 TI - HPLC separation of digested proteins and preparation for matrix-assisted laser desorption/ionization analysis. AB - INTRODUCTIONTwo types of columns are commonly used for the separation of peptides by HPLC. A single-phase column contains the reverse-phase resin C18, which interacts with the hydrophobic moieties of the peptides. Peptides resulting from digestion of simple mixtures of proteins are loaded onto the single-phase column and eluted into the mass analyzer using an increasing gradient of an organic solvent. Peptides resulting from the digestion of more complex mixtures of proteins are resolved using a biphasic column. This column integrates both a strong cation exchange SCX resin, which interacts with peptides as a result of their positive charge, and a reverse-phase C18 resin, packed in tandem. Peptides initially interact with the SCX resin and are eluted into the C18 resin by ammonium acetate that competes for the peptide-binding sites. Peptides are then eluted from the C18 resin into the mass analyzer. This process is repeated using increasing concentrations of ammonium acetate to differentially elute peptides in a stepwise fashion. The biphasic column also uses an additional C18 reverse-phase resin linked through an Inline MicroFilter Assembly (Upchurch) to desalt the peptides prior to loading onto the SCX. The desalting and biphasic columns are combined to give an integrated desalting/biphasic column. PMID- 22484681 TI - Transformation of agrobacterium using electroporation. AB - INTRODUCTIONThis protocol describes a method for transforming Agrobacterium with plasmid DNA using electroporation in a manner similar to that commonly used for Escherichia coli. Although the transformation efficiency for Agrobacterium is lower than that for E. coli, it is possible to obtain adequate numbers of Agrobacterium transformants with this technique. PMID- 22484682 TI - Transformation of agrobacterium using the freeze-thaw method. AB - INTRODUCTIONThis protocol describes a method for transforming Agrobacterium with plasmid DNA using a freeze-thaw technique. Although the transformation efficiency for Agrobacterium is lower than that for Escherichia coli, it is possible to obtain adequate numbers of transformants with this technique. PMID- 22484683 TI - PCR analysis of agrobacterium. AB - INTRODUCTIONBecause transformation of Arabidopsis is a relatively long-winded process, it is a good idea to verify the presence of the T-DNA plasmid in the Agrobacterium strain before proceeding with transformation experiments. This protocol describes a method to determine the presence of plasmid DNA in an Agrobacterium culture. Compared to selection of transformed Agrobacterium, which can be ambiguous and normally takes several days for resistant colonies to appear, the approach described here is both rapid and accurate. PMID- 22484684 TI - In planta transformation of Arabidopsis. AB - INTRODUCTIONA breakthrough in Arabidopsis research was the invention of the vacuum-infiltration procedure, a simple and reliable method of obtaining transformants at high efficiency while avoiding the use of tissue culture. The plant transformation procedures described here involve floral dip, vacuum infiltration, and spraying. They yield transformants at frequencies ranging up to several percent, with the most common frequency being 0.1%-1%. PMID- 22484685 TI - Kanamycin selection of transformed Arabidopsis. AB - INTRODUCTIONThe most commonly used markers for selection of transgenic Arabidopsis are resistance to the antibiotic kanamycin and to the herbicide glufosinate ammonium. Resistance to kanamycin is conferred by a bacterial gene encoding the enzyme neomycin phosphotransferase (NPT). In this protocol, kanamycin-resistant seedlings are selected on solid medium. PMID- 22484686 TI - Glufosinate ammonium selection of transformed Arabidopsis. AB - INTRODUCTIONOne of the most commonly used markers for the selection of transgenic Arabidopsis is resistance to glufosinate ammonium, an herbicide that is sold under a variety of trade names including Basta and Finale. Resistance to glufosinate ammonium is conferred by the bacterial bialophos resistance gene (BAR) encoding the enzyme phosphinotricin acetyl transferase (PAT). This protocol describes the use of glufosinate ammonium to select transformed Arabidopsis plants. The major advantage of glufosinate ammonium selection is that it can be performed on plants growing in soil and does not require the use of sterile techniques. PMID- 22484687 TI - Root transformation of Arabidopsis. AB - INTRODUCTIONArabidopsis can be stably transformed using Agrobacterium tumefaciens mediated transfer of T-DNA. We describe the generation of transgenic plants via root transformation in tissue culture, which can be useful for transforming sterile mutants. PMID- 22484688 TI - Overview of affinity purification in combination with mass spectrometry. PMID- 22484689 TI - Inhibition of cathepsin K reduces cartilage degeneration in the anterior cruciate ligament transection rabbit and murine models of osteoarthritis. AB - OBJECTIVE: To investigate the disease modifying effects of cathepsin K (CatK) inhibitor L-006235 compared to alendronate (ALN) in two preclinical models of osteoarthritis (OA). METHODS: Skeletally mature rabbits underwent sham or anterior cruciate ligament transection (ACLT)-surgery and were treated with L 006235 (L-235, 10 mg/kg or 50 mg/kg, p.o., daily) or ALN (0.6 mg/kg, s.c., weekly) for 8-weeks. ACLT joint instability was also induced in CatK(-/-) versus wild type (wt) mice and treated for 16-weeks. Changes in cartilage degeneration, subchondral bone volume and osteophyte area were determined by histology and MU CT. Collagen type I helical peptide (HP-I), a bone resorption marker and collagen type II C-telopeptide (CTX-II), a cartilage degradation marker were measured. RESULTS: L-235 (50 mg/kg) and ALN treatment resulted in significant chondroprotective effects, reducing CTX-II by 60% and the histological Mankin score for cartilage damage by 46% in the ACLT-rabbits. Both doses of L-235 were more potent than ALN in protecting against focal subchondral bone loss, and reducing HP-I by 70% compared to vehicle. L-235 (50 mg/kg) and ALN significantly reduced osteophyte formation in histomorphometric analysis by 55%. The Mankin score in ACLT-CatK(-/-) mice was ~2.5-fold lower than the ACLT-wt mice and was not different from sham-CatK(-/-). Osteophyte development was not different among the groups. CONCLUSION: Inhibition of CatK provides significant benefits in ACLT model of OA, including: 1) protection of subchondral bone integrity, 2) protection against cartilage degradation and 3) reduced osteophytosis. Preclinical evidence supports the role of CatK as a potential therapeutic target for the treatment of OA. PMID- 22484690 TI - Neuropeptide Y Y1 receptor antagonism increases bone mass in mice. AB - The neuropeptide Y system has emerged as one of the major neural signalling pathways regulating bone homeostasis. Absence of Y1 receptor signalling from bone forming osteoblasts is responsible for an enhancement on bone mass in mice, suggesting that pharmacological blockade of Y1 receptors may offer a novel anabolic treatment option for improving bone mass. Here we show that oral administration of the selective Y1 receptor antagonist BIBO3304 for 8 weeks dose dependently increases bone mass in mice. Histomorphometric analysis revealed a significant 1.5-fold increase in cancellous bone volume in the femora of mice treated with BIBO3304. Furthermore, bone microarchitecture was improved, with greater trabecular number and trabecular thickness. This increase in bone mass was associated with a significant increase in bone anabolic activity of osteoblasts and, interestingly, was evident despite a coincident increase in bone resorption, as evidenced by an increase in the number of the osteolytic osteoclasts. Changes were also evident in cortical bone, with a significant increase in periosteal mineral apposition rate. Importantly, no adverse extra skeletal side effects were observed through Y1 receptor antagonism over the 8 week treatment period, with no effects of even the higher BIBO3304 dose on body weight, adiposity, energy metabolism or circulating corticosterone levels. Taken together, this work describes the first NPY-based anabolic treatment for improving bone mass, and highlights the therapeutic potential of blocking Y1 receptor signalling for the prevention of, or recovery from, degenerative skeletal diseases. PMID- 22484692 TI - Photoacoustic mammography: initial clinical results. AB - PURPOSE: Photoacoustic tomography can image the hemoglobin distribution and oxygenation state inside tissue with high spatial resolution. The purpose of this study is to investigate its clinical usefulness for diagnosis of breast cancer and evaluation of therapeutic response in relation to other diagnostic modalities. MATERIALS AND METHODS: Using a prototype machine for photoacoustic mammography (PAM), 27 breast tumor lesions, including 21 invasive breast cancer (IBC), five ductal carcinoma in situ (DCIS), and one phyllodes tumor, were measured. Nine out of twenty-one IBC patients had received primary systemic therapy (PST). RESULTS: Eight out of twelve IBC without PST were visible. Notably, detection was possible in all five cases with DCIS, whereas it was not in one case with phyllodes tumor. Seven out of nine IBC with PST were assigned as visible in spite of decreased size of tumor after PST. The mean value of hemoglobin saturation in the visible lesions was 78.6 %, and hemoglobin concentration was 207 MUM. The tumor images of PAM were comparable to those of magnetic resonance imaging (MRI). CONCLUSIONS: It is suggested that PAM can image tumor vascularity and oxygenation, which may be useful for diagnosis and characterization of breast cancer. PMID- 22484693 TI - Contributions of aging to the fatigue crack growth resistance of human dentin. AB - An evaluation of the fatigue crack resistance of human dentin was conducted to identify the degree of degradation that arises with aging and the dependency on tubule orientation. Fatigue crack growth was achieved in specimens of coronal dentin through application of Mode I cyclic loading and over clinically relevant lengths (0 <= a <= 2 mm). The study considered two directions of cyclic crack growth in which the crack was either in-plane (0 degrees ) or perpendicular (90 degrees ) to the dentin tubules. Results showed that regardless of tubule orientation, aging of dentin is accompanied by a significant reduction in the resistance to the initiation of fatigue crack growth, as well as a significant increase in the rate of incremental extension. Perpendicular to the tubules, the fatigue crack exponent increased significantly (from m=14.2 +/- 1.5 to 24.1 +/- 5.0), suggesting an increase in brittleness of the tissue with age. For cracks extending in-plane with the tubules, the fatigue crack growth exponent does not change significantly with patient age (from m=25.4 +/- 3.03 to 22.9 +/- 5.3), but there is a significant increase in the incremental crack growth rate. Regardless of age, coronal dentin exhibits the lowest resistance to fatigue crack growth perpendicular to the tubules. While there are changes in the cyclic crack growth rate and mechanisms of cyclic extension with aging, this tissue maintains its anisotropy. PMID- 22484694 TI - In vitro feasibility study of the use of a magnetic electrospun chitosan nanofiber composite for hyperthermia treatment of tumor cells. AB - Hyperthermia has been reported to be an effective cancer treatment modality, as tumor cells are more temperature-sensitive than their normal counterparts. Since the ambient temperature can be increased by placing magnetic nanoparticles in an alternating magnetic field it has become of interest to incorporate these magnetic nanoparticles into biodegradable nanofibers for possible endoscopic hyperthermia treatment of malignant tumors. In this preliminary investigation we have explored various characteristics of biodegradable electrospun chitosan nanofibers containing magnetic nanoparticles prepared by different methods. These methods included: (1) E-CHS-Fe(3)O(4), with electrospun chitosan nanofibers directly immersed in a magnetic nanoparticle solution; (2) E-CHS-Fe(2+), with the electrospun chitosan nanofibers initially immersed in Fe(+2)/Fe(+3) solution, followed by chemical co-precipitation of the magnetic nanoparticles. The morphology and crystalline phase of the magnetic electrospun nanofiber matrices were determined by scanning electron microscopy, transmission electron microscopy, selected area electron diffraction, and X-ray diffraction spectroscopy. The magnetic characteristics were measured using a superconducting quantum interference device. The heating properties of these magnetic electrospun nanofiber matrices in an alternating magnetic field were investigated at a frequency of 750 kHz and magnetic intensity of 6.4 kW. In vitro cell incubation experiments indicated that these magnetic electrospun nanofiber matrices are non cytotoxic and can effectively reduce tumor cell proliferation upon application of a magnetic field. PMID- 22484695 TI - Silk cocoon (Bombyx mori): multi-layer structure and mechanical properties. AB - Bombyx mori cocoon is a natural composite made of silk fibre with a distinctive multi-layer structure that provides mechanical protection for its biological functions. Here we investigate the components, structure and mechanical properties of cocoon layers, and quantify the contributions of the multi-layer structure to the mechanical properties of cocoon. A better understanding of the multi-layer mechanism of a natural composite could help the further design of biomimetic multiscale artificial materials. PMID- 22484696 TI - Revision joint replacement, wear particles, and macrophage polarization. AB - Currently, younger, more active patients are being offered total joint replacement (TJR) for end-stage arthritic disorders. Despite improved durability of TJRs, particle-associated wear of the bearing surfaces continues to be associated with particulate debris, which can activate monocyte/macrophages. Activated macrophages then produce pro-inflammatory factors and cytokines that induce an inflammatory reaction that activates osteoclasts leading to bone breakdown and aseptic loosening. We hypothesized that activated macrophages in tissues harvested from revised joint replacements predominantly express an M1 pro inflammatory phenotype due to wear-particle-associated cell activation, rather than an M2 anti-inflammatory phenotype. We further questioned whether it is possible to convert uncommitted monocyte/macrophages to an M2 phenotype by the addition of interleukin-4 (IL-4), or whether it is necessary to first pass through an M1 intermediate stage. Retrieved periprosthetic tissues demonstrated increased M1/M2 macrophage ratios compared to non-operated osteoarthritic synovial tissues, using immunohistochemical staining and Western blotting. Uncommitted monocyte/macrophages with/without polymethyl-methacrylate particles were transformed to an M2 phenotype by IL-4 more efficiently when the cells were first passed through an M1 phenotype by exposure to endotoxin. Wear particles induce a pro-inflammatory microenvironment that facilitates osteolysis; these events may potentially be modulated favorably by exposure to IL-4. PMID- 22484697 TI - Multiple release of polyplexes of plasmids VEGF and bFGF from electrospun fibrous scaffolds towards regeneration of mature blood vessels. AB - Key challenges associated with the outcomes of vascular grafting (for example, to fully vascularize engineered tissues and promptly regenerate blood vessel substitutes) remain unsolved. The local availability of angiogenic growth factors is highly desirable for tissue regeneration, and plasmid loading in scaffolds represents a powerful alternative for local production of tissue-inductive factors. No attempt has been made so far to clarify the efficacy of electrospun fibers with the loading of multiple plasmids to promote tissue regeneration. In the present study, core-sheath electrospun fibers with the encapsulation of polyplexes of basic fibroblast growth factor-encoding plasmid (pbFGF) and vascular endothelial growth factor-encoding plasmid (pVEGF) were evaluated to promote the generation of mature blood vessels. In vitro release indicated a sustained release of pDNA for ~4 weeks with as low as ~10% initial burst release, and the release patterns from the single and twofold plasmid-loaded systems coincided. In vitro investigations on human umbilical vein endothelial cells showed that the sustained release of pDNA from fibrous mats promoted cell attachment and viability, cell transfection and protein expression, and extracellular secretion of collagen IV and laminin. The acceleration of angiogenesis was assessed in vivo after subcutaneous implantation of fibrous scaffolds, and the explants were evaluated after 1, 2 and 4 weeks' treatment by histological and immunohistochemical staining. Compared with pDNA polyplex infiltrated fibrous mats, the pDNA polyplex encapsulated fibers alleviated the inflammation reaction and enhanced the generation of microvessels. Although there was no significant difference in the total number of microvessels, the density of mature vessels was significantly enhanced by the combined treatment with both pbFGF and pVEGF compared with those incorporating individual pDNA. The integration of the core-sheath structure, DNA condensation and multiple delivery strategies provided a potential platform for scaffold fabrication to regenerate functional tissues. PMID- 22484698 TI - Why are religious individuals more obsessional? The role of mental control beliefs and guilt in Muslims and Christians. AB - BACKGROUND AND OBJECTIVES: The cognitive-behavioural perspective on obsessions recognizes that certain cultural experiences such as adherence to religious beliefs about the importance of maintaining strict mental control might increase the propensity for obsessional symptoms via the adoption of faulty appraisals and beliefs about the unacceptability and control of unwanted intrusive thoughts. Few studies have directly investigated this proposition, especially in a non-Western Muslim sample. METHOD: In the present study high religious, low religious and religious school Canadian Christian and Turkish Muslim students were compared on measures of OCD symptoms, obsessive beliefs, guilt, religiosity, and negative affect. RESULTS: Analysis revealed that religiosity had a specific relationship with obsessional but not anxious or depressive symptoms in both samples, although the highly religious Muslim students reported more compulsive symptoms than highly religious Christians. In both samples the relationship between religiosity and obsessionality was mediated by importance/control of thoughts and responsibility/threat beliefs as well as generalized guilt. LIMITATIONS: The sample composition was limited to non-clinical undergraduates and only two major religions were considered without recognition of denominational differences. CONCLUSIONS: These findings indicate that the tendency for highly religious Christians and Muslims to experience greater obsessionality is related to their heightened sense of personal guilt and beliefs that they are responsible for controlling unwanted, threatening intrusive thoughts. PMID- 22484699 TI - Genes and processed paralogs co-exist in plant mitochondria. AB - RNA-mediated gene duplication has been proposed to create processed paralogs in the plant mitochondrial genome. A processed paralog may retain signatures left by the maturation process of its RNA precursor, such as intron removal and no need of RNA editing. Whereas it is well documented that an RNA intermediary is involved in the transfer of mitochondrial genes to the nucleus, no direct evidence exists for insertion of processed paralogs in the mitochondria (i.e., processed and un-processed genes have never been found simultaneously in the mitochondrial genome). In this study, we sequenced a region of the mitochondrial gene nad1, and identified a number of taxa were two different copies of the region co-occur in the mitochondria. The two nad1 paralogs differed in their (a) presence or absence of a group II intron, and (b) number of edited sites. Thus, this work provides the first evidence of co-existence of processed paralogs and their precursors within the plant mitochondrial genome. In addition, mapping the presence/absence of the paralogs provides indirect evidence of RNA-mediated gene duplication as an essential process shaping the mitochondrial genome in plants. PMID- 22484700 TI - Comparison of tear osmolarity and ocular comfort between daily disposable contact lenses: hilafilcon B hydrogel versus narafilcon A silicone hydrogel. AB - The aim of this study was to evaluate tear osmolarity and ocular comfort with two different types of hydrogel daily disposable lenses. The right eyes of 15 first time contact lens users were included in this prospective study. All eyes wore hilafilcon B silicone hydrogel contact lenses for 8 h (group 1). After 1 week without contact lenses, all eyes wore narafilcon A silicone hydrogel contact lenses for 8 h (group 2). Tear osmolarity measurement was performed before and after 4 and 8 h of each contact lens wear. Ocular comfort was assessed after 4 and 8 h of each contact lens wear. In group 1, the mean baseline, 4- and 8-h tear osmolarity values were 293 +/- 10.57, 303.00 +/- 10.5 mOsm/L (p = 0.023), and 295.0 +/- 1.4 mOsm/L (p > 0.05), respectively. In group 2, the mean baseline, 4- and 8-h tear osmolarity values were 294 +/- 13.65, 300.9 +/- 11.3 mOsm/L (p = 0.007), and 298.80 +/- 7.2 mOsm/L (p > 0.05), respectively. In group 1, the mean comfort score was 7.20 +/- 0.45 and 8.60 +/- 0.45 at 4 and 8 h, respectively (p = 0.038). In group 2, the mean comfort score significantly decreased from 9.80 +/- 0.45 to 7.80 +/- 0.84 at 4 h (p = 0.039). Both hydrogel and silicone hydrogel daily disposable contact lenses elevated tear osmolarity during 8 h of contact lens wear. The increase in tear osmolarity with both contact lenses was below the cut-off value for dry eye and was not associated with ocular comfort. PMID- 22484701 TI - Effects of pterygium surgery on front and back corneal surfaces and anterior segment parameters. AB - The purpose of this study was to evaluate the effects of pterygium surgery on front and back corneal surfaces and anterior segment parameters. This prospective study included 96 eyes with primary pterygium that underwent surgery. Preoperatively and at 1, 3, and 6 months postoperatively, Pentacam was used to evaluate front and back corneal surfaces, anterior chamber depth (ACD), anterior chamber angle (ACA) and anterior chamber volume (ACV). Mean simulated keratometry at the front corneal surface increased from 42.73 +/- 2.21 D preoperatively to 44.45 +/- 2.05 D at 1 month (P < 0.001); it then decreased to 44.32 +/- 2.07 D at 3 months (P < 0.001) and 44.19 +/- 2.10 D at 6 months (P = 0.01). There was no statistically significant change in mean simulated keratometry at the back corneal surface. Radius of the front corneal best-fit sphere (BFS) decreased from 7.99 +/- 0.29 mm preoperatively to 7.77 +/- 0.25 mm at 1 month postoperatively (P < 0.001), without further change up to 6 months. Radius of the back corneal BFS increased from 6.42 +/- 0.24 mm preoperatively to 6.50 +/- 0.24 mm at 1 month (P < 0.001), without further change. Postoperative changes in mean simulated keratometry and radii of BFS had statistically significant positive correlations with pterygium extension onto the cornea and grade of pterygium morphology but, not with the surgical technique. There were no significant changes in ACD, ACA, and ACV values after pterygium surgery. Furthermore, the spherical equivalent of manifest refraction changed from +0.75 +/- 1.06 D preoperatively to -0.72 +/- 1.33 D at 1 month postoperatively (P = 0.001), with no further significant change. In conclusion, after pterygium surgery there were significant changes in front mean keratometry and front and back corneal radii of BFS. These were correlated with preoperative pterygium size and morphology grade. No significant changes in anterior segment parameters were noted postoperatively. PMID- 22484702 TI - Management of postoperative lymphoceles after lymphadenectomy: percutaneous catheter drainage with and without povidone-iodine sclerotherapy. AB - PURPOSE: To report our single-center experience in managing symptomatic lymphoceles after lymphadenectomy for genitourinary and gynecologic malignancy and to compare clinical outcomes of percutaneous catheter drainage (PCD) alone versus PCD with transcatheter povidone-iodine sclerotherapy (TPIS). METHODS: The medical records of patients who presented for percutaneous drainage of pelvic lymphoceles from February 1999 to September 2007 were retrospectively reviewed. Catheters with prolonged outputs >50 cc/day were treated with TPIS. Technical success was defined as the ability to achieve complete resolution of the lymphocele. Clinical success was defined as resolution of the patient's symptoms that prompted the intervention. RESULTS: Sixty-four patients with 70 pelvic lymphoceles were treated. Forty-six patients (71.9 %) had PCD, and 18 patients (28.1 %) had multisession TPIS. The mean initial cavity size was 294.9 cc for those treated with TPIS and 228.2 cc for those treated with PCD alone (range 15 1,600) (p = 0.59). Mean duration of catheter drainage was 19 days (29 days with TPIS, 16 days with PCD, p = 0.001). Mean clinical follow-up was 22.6 months. Technical success was 74.3 % with PCD and 100 % with TPIS. Clinical success was 97 % with PCD and 100 % with TPIS. Postprocedural complications included pericatheter fluid leakage (n = 4), catheter dislodgement (n = 3), catheter occlusion (n = 9), and secondary infection of the collection (n = 4). CONCLUSION: PCD of symptomatic lymphoceles is an effective postoperative management technique. Initial cavity size is not an accurate predictor of the need for TPIS. When indicated, TPIS is safe and effective with catheter outputs >50 cc/day. PMID- 22484703 TI - Single-center experience and 1-year follow-up results of "sandwich technique" in the management of common iliac artery aneurysms during EVAR. AB - PURPOSE: Abdominal aortic aneurysm (AAA) accompanied by common iliac artery (CIA) aneurysms requires a more demanding procedure owing to the difficulties in obtaining an adequate distal landing zone for the stent-graft limb(s), a potential site of endoleak. The "sandwich technique" is a procedure to increase EVAR feasibility in the setting of adverse or challenging CIA anatomy. Its main advantages include no restrictions in terms of CIA diameter or length or internal iliac artery (IIA) diameter, no need to wait for a specific stent-graft. Our purpose is to describe our single-center experience and one year follow-up results of this new procedure. MATERIALS AND METHODS: From April 2009 to June 2010, the sandwich technique was performed in our institution in 7 patients treated for AAA and unilateral CIA aneurysms (n. 5) or bilateral CIA aneurysms (n. 2). Inclusion criteria were the presence of unilateral or bilateral CIA aneurysm (independently from its diameter), IIA artery measuring up to 9 mm in its maximum diameter, not dilatation of IIA and EIA. RESULTS: The mean follow-up length was 15 months (range: 14-20 months). All stent-implanted iliac branches remained patent on 1 year follow-up and IIA flow was preserved. None of the patients had symptoms of pelvic ischemia. CT scan follow-up showed aneurysm shrinkage in five patients, without any sign of endoleaks in all cases. CONCLUSIONS: In selected cases, the "sandwich technique" showed good outcomes confirming to be a safe and easy to perform way to overcome anatomical constraints and expanding the limits of EVAR. PMID- 22484704 TI - Ruptured aortic aneurysm from late type II endoleak treated by transarterial embolization. AB - Endoleak is the most common complication after endovascular aneurysm repair. The most common type of endoleak, a type II endoleak, typically follows a benign course and is only treated when associated with increasing aneurysm size. In this case report, we describe a ruptured abdominal aortic aneurysm due to a late, type II endoleak occurring 10 years after endovascular aneurysm repair that was successfully treated by transarterial embolization. PMID- 22484705 TI - Synthesis and characterization of a novel polydepsipeptide contained tri-block copolymer (mPEG-PLLA-PMMD) as self-assembly micelle delivery system for paclitaxel. AB - A series of biodegradable polydepsipeptides based new triblock copolymers, poly (ethylene glycol)-poly(L-lactide)-poly(3(S)-methyl-morpholine-2,5-dione) (mPEG PLLA-PMMD) have been synthesized and characterized as self-assembly micelle delivery system for paclitaxel (PTX). Compared to the mPEG(2000)-PLLA(2000) diblock copolymers, the triblock copolymers present more benefits such as lower CMC value, positive-shifted zeta potential, better drug loading efficiency and stability. Among the triblock polymers, mPEG(2000)-PLLA(2000)-PMMD(1400) micelles present low cytotoxicity and promote the anti-cancer activity of PTX on A-549 and HCT-116cells. In addition, mPEG(2000)-PLLA(2000)-PMMD(1400) micelles prolongs the circulation time of PTX in rat after i.v. injection (5 mg/kg) than that of mPEG(2000)-PLLA(2000) micelles and Taxol. The half life (t(1/2beta)), mean residence time (MRT), AUC(0-infinity) and clearance (CL) for PTX-loaded mPEG(2000)-PLLA(2000)-PMMD(1400) micelles are determined to be 1.941 h, 2.683 h, 5.220 MUg/m Lh (1.8-fold to mPEG(2000)-PLLA(2000) group), 0.967 L/h kg(-1), respectively. In conclusion, mPEG(2000)-PLLA(2000)-PMMD(1400) copolymer could be developed as one of the promising vectors to anti-cancer agents for chemotherapeutics. PMID- 22484706 TI - Fluid bed porosity mathematical model for an inverse fluidized bed bioreactor with particles growing biofilm. AB - A new mathematic model to estimate bed porosity as a function of Reynolds and Archimedes numbers was developed based in experimental data. Experiments were performed using an inverse fluidized bed bioreactor filled with polypropylene particles, Lactobacillus acidophillus as the immobilized strain and fluidized with a Man-Rogosa-Sharpe culture medium under controlled temperature and pH conditions. Bed porosity was measured at different flow rates, starting from 0.95 to 9.5 LPM. The new model has several advantages when compared with previously reported. Among them, advantages such as standard deviation values <= 1% between experimental and calculated bed porosity, its applicability in traditional and inverse fluidization, wall effects do not take account, it gives excellent agreement with spherical particles with or without biofilm, and inertial drag coefficient allow extend the new model a non-spherical particles. PMID- 22484707 TI - Natural pretreatment and passive remediation of highly polluted acid mine drainage. AB - Acid mine drainage (AMD) from the Iberian Pyrite Belt has high acidity and metal concentrations. Earlier pilot experiments, based on limestone sand dispersed in wood shavings (dispersed alkaline substrate; DAS) have been shown to be an efficient treatment option. However, complete metal removal was not achieved, principally due to the high ferrous iron concentration in the inflow AMD. In order to oxidize and remove iron, a natural Fe-oxidizing lagoon (NFOL) was added prior to treatment with limestone-DAS. The NFOL comprises several pre-existing Fe stromatolite terraces and cascades, and a lagoon with a volume of 100 m(3) built near the mine shaft. Downstream of the NFOL, the limestone-DAS treatment consists of two reactive tanks of 3 m(3) each filled with limestone-DAS reactive substrate, connected in series with two decantation ponds of 6 m(3) each and several oxidation cascades. The AMD emerging from the mine shaft displayed a pH near 3, a net acidity of 1800 mg/L as CaCO(3) equivalents, and mean concentrations of 440 mg/L Zn; 275 mg/L Fe (99% Fe(II)); 3600 mg/L SO(4); 250 mg/L Ca; 100 mg/L Al; 15 mg/L Mn; 5 mg/L Cu; and 0.1-1 mg/L As, Pb, Cr, Cd, Co, and Ni. The oxidation induced in the NFOL enhanced ferric iron concentration, showing an average of 65% oxidation and 38% retention during the monitoring period. The whole system removed a mean of 1350 mg/L net acidity as CaCO(3) equivalents (71% of inflow); corresponding to 100% of Fe, Al, Cu, Pb and As, and 6% of Zn. PMID- 22484708 TI - Effects of dehydration on cardiovascular development in the embryonic American alligator (Alligator mississipiensis). AB - Effects of dehydration on reptilian embryonic cardiovascular function are unknown. Here, we present the first morphological and physiological data quantifying the cumulative effects of four acute dehydration events on the embryonic American alligator, Alligator mississipiensis. We hypothesized that dehydration would alter embryonic morphology, reduce blood volume and augment the response to angiotensin II (Ang II), a key osmotic and blood volume regulatory response element in adult vertebrates. Drying events at 30%, 40%, 50%, and 60% of embryonic incubation reduced total egg water content by 14.43 +/- 0.37 g, a 3.4 fold increase relative to controls. However, embyronic blood volume was greater in the dehydration group at 70% of embryonic incubation compared to controls (0.39 +/- 0.044 mLg(-1) and 0.22 +/- 0.03 mLg(-1), respectively), however, both groups were similar at 90% of incubation (0.18 +/- 0.02 mLg(-1) in the controls and 0.23 +/- 0.03 mLg(-1) in the dehydrated group). Dehydration altered the morphological phenotype and resulted in an overall reduction in embryonic mass at both incubation time points measured. Dehydration also altered the physiological phenotype, resulting in embryonic alligators that were relatively bradycardic at 90% of incubation. Arterial Ang II injections resulted in a dose dependent hypertension, which increased in intensity over the span of incubation studied. While progressive incubation altered the Ang II response, dehydration had no impact on the cardiovascular responses to the peptide. Quantification of Ang II type-1 receptor protein using western blot analysis illustrated that dehydration condition and incubation time point did not alter protein quantity. Collectively, our results show that dehydration during embryonic development of the American alligator alters embryonic morphology and baseline heart rate without altering arterial pressure and response to Ang II. PMID- 22484709 TI - Renal involvement in primary Sjogren syndrome of childhood: case report and literature review. AB - Renal tubular acidosis (RTA) is common in adults with primary Sjogren syndrome (pSS) but to date this condition has only been identified in 12 pediatric cases of pSS. Here we present the case of a 13-year-old, otherwise asymptomatic girl in whom the search for the etiology of incidentally found nephrocalcinosis led to diagnosis of distal RTA and nephrogenic diabetes insipidus secondary to SS associated tubulointerstitial nephritis. Immunosupressive treatment and alkali/electrolyte supplementation resulted in stable renal function over the 6 year follow-up. A review of the literature focuses on two aspects of pSS: (1) the difficulties in diagnosing pSS in childhood and (2) clinical-pathological features, treatment and outcome of renal tubulointerstitial disease in childhood pSS. SS should be considered in older children, particularly females with otherwise unexplained RTA. A careful search for other renal dysfunctions is necessary, and renal biopsy may be of value in assessing the extent of renal damage and the need for immunomodulatory therapy. PMID- 22484710 TI - Heart rate variability analysis of single-channel electrocardiogram can help to differentiate high-risk patients with obstructive sleep apnea syndrome - a study on diagnostic accuracy. AB - OBJECTIVE: To evaluate the usefulness of heart rate variability analysis (HRV) analysis from the long duration electrocardiogram (ECG) recordings as a screening test for the diagnosis of moderate-to-severe obstructive sleep apnea syndrome (OSAS). METHODS: Recordings from 87 patients who were admitted to sleep laboratory for polysomnographic study (PSG) were evaluated. Finally 30 cases with apnea-hypopnea index (AHI)>=15/hour included in patient's group (male/female: 22/8; mean age: 49+/-10 years) and 21 cases with AHI<5 were included in control group (male/female: 10/11; mean age: 48+/-11 years). From the ECG recordings taken as a part of PSG, time -domain and frequency -domain HRV parameters were evaluated and their accuracy in the diagnosis of OSAS was investigated using ROC analysis. RESULTS: Statistically significant differences were found in HRV variables in time- domain parameters such as SDNN, SDNN index; frequency-domain parameters VLF, LF, nuLF, nuHF, LF/HF and geometric parameter HRV triangular index values in between groups. Cut- off value of 16 for the HRV triangular index was found to be 50% sensitive and 85.7% specific with a positive likelihood ratio (LR) of 3.50% and negative LR of 0.58% When the total power was higher than 9.611, then the analysis sensitivity was 53.3%, specificity was 95.6%, positive LR was 11.2% and negative LR was 0.49% When the SDNN was higher than 83 then its sensitivity was 80%, specificity was 76.2%, positive LR was 3.36% and negative LR was 0.26% For the cut off value of 62 calculated for SDNN index, sensitivity was 73.3%, specificity was 85.7%, positive LR was 5.13% and negative LR was 0.31%, for the cut off value of 9.12 was calculated for VLF, sensitivity was 90.4% specificity was 50% positive LR was 1.81% and negative LR was 0.19%. CONCLUSION: Heart rate variability analysis done over routine single channel ECG data gathered through routine Holter applications may be helpful in distinguishing moderate-to-severe OSAS patients from mild OSAS patients and non-OSAS control subjects. PMID- 22484711 TI - [Assessment of left ventricular functions with tissue Doppler, strain and strain rate echocardiography in children with juvenile idiopathic arthritis: An observational study]. AB - OBJECTIVE: In juvenile idiopathic arthritis (JIA) cardiac involvement is usually silent without typical symptoms. The purpose of this study was to assess left ventricular functions with tissue Doppler echocardiography (TDE), strain and strain rate in children with JIA. METHODS: Our study was designed as a cross sectional observational study. Thirty pediatric patients with JIA and 30 age- and sex-matched healthy controls were studied. In addition to standard echocardiographic methods, tissue Doppler, strain and strain rate imaging's were performed to assess left ventricular functions in all participants. The means of variables that did not distributed normally were compared with Mann-Whitney U test. RESULTS: In patients with JIA, E' values of mid and apical regions of left ventricular lateral wall were significantly lower than those of the controls (15.76+/-3.24 vs 17.91+/-3.29 cm/s, 11.10+/-2.96 vs12.64+/- 2.42 cm/s, p<0.05). In longitudinal strain reflecting left ventricular regional systolic functions, apical-lateral, basal and mid-septum peak S values, lateral peak S values in circumferential strain (-17.30+/-6.22 vs -21.97+/-4.32, -18.23+/-4.62 vs -21.53+/ 2.69, -20.35+/-3.75 vs -22.75+/-3.50, -9.68+/-7.12 vs -13.70+/-6.81 cm/s, p<0.05, r:0.42, 0.41, 0.42), in longitudinal strain reflecting diastolic functions, apical-lateral, mid-lateral, apical-septum, mid-septum peak E values (2.22+/-1.00 vs 3.17+/-0.87, 1.62+/-0.84 vs 2.15+/-0.72, 2.51+/-0.76 vs 3.31+/-0.87, 1.99+/ 0.64 vs 2.47+/-0.57 cm/s, p<0.05, r:-0.39,-0.55,-0.43) and in circumferential strain lateral and posterior peak E values (1.32+/-0.83 vs 1.88+/-0.94, 1.31+/ 0.71 vs 1.85+/-0.91 cm/s, p<0.05, r:-0.33, -0.22) were significantly lower than those of the controls. CONCLUSION: Although marked myocardial involvement was not detected with tissue Doppler imaging in JIA patients with subclinical cardiac disease, regional impairments in left ventricular strain and strain rates were found. PMID- 22484712 TI - Risk factors for postoperative arrhythmia in patients with physiologic univentricular hearts undergoing Fontan procedure. AB - OBJECTIVE: Advanced age, dilated right atrium, increased preoperative pulmonary artery pressure, increased right atrial pressure, technique of operation, and poor ventricular function were reported to be risk factors for postoperative arrhythmia. Aim of this study is to determine the risk factor for postoperative arrhythmia after Fontan operation with regard to ventricle dominancy and hemodynamic parameters. METHODS: In this retrospective study, the data of the patients including age, weight, dominant ventricle, type of cardiac anomaly, previous operations, duration of cardiopulmonary bypass (CPB), duration of aortic clamping, cardiac rhythm, pulmonary artery pressure, the Nakata Index, systemic atrioventricular (AV) valve insufficiency were obtained from the hospital records, the echocardiographic files, and cardiac catheterization records. Patients were assigned to dominant left ventricle or dominant right ventricle groups. Statistical analysis was performed using the Mann-Whitney U test. RESULTS: Arrhythmia was observed in 21 (52.5%) patients in the postoperative period. No postoperative arrhythmia was observed in patients with a right atrial pressure of <5 mmHg, whereas postoperative arrhythmias were observed in patients with a right atrial pressure of >=5 mmHg (p<0.05). When the effects of preoperative and postoperative pulmonary artery pressures on postoperative arrhythmia were evaluated, postoperative arrhythmia was determined in only 2 (12.5%) of 8 patients with a preoperative mean pulmonary artery pressure of <=9 mmHg, whereas postoperative arrhythmia was observed in 19 (59.3%) of 32 patients with a preoperative pulmonary artery pressure of >=10 mmHg. A preoperative mean pulmonary artery pressure of >10 mmHg increased the risk of postoperative arrhythmia (p<0.02). Postoperative arrhythmia was determined in 8 (53%) of 15 patients with a dominant right ventricle, and in 13 (52%) of 25 patients with a dominant left ventricle (p>0.05). CONCLUSION: While a preoperative mean pulmonary artery pressure of >10 mmHg and a preoperative right atrial pressure of >5 mmHg were the risk factors for postoperative arrhythmia in patients undergoing Fontan procedure, the right or left ventricular dominance was not a risk factor. PMID- 22484713 TI - The quality of life after cardiac surgery in octogenarians and evaluation of its early and mid-term results. AB - OBJECTIVE: The aim of this study is to evaluate our early and mid- term results and the qualities of life of the patients aged eighty years or older who underwent heart surgery. METHODS: Eighty- eight patients aged 80 years and older who underwent open-heart surgery at Goztepe Safak Hospital between May 2004 and December 2010 have been included to the study. This study was designed as two stage: in the first stage, determinants of survival were analyzed retrospectively. In the second stage, the quality of life of survived patients was evaluated by using Short- Form 36 (SF-36), Turkish version in the cross sectional study. The statistical analysis was performed using Fischer's exact, Pearson Chi-square test, Student t-test, Mann-Whitney U test and logistic regression analysis. RESULTS: In the logistic regression analysis; the left ventricular ejection fraction as <50% (OR: 11.02, 95% CI: 2.6-46.6, p<0.05), application of redo surgery (OR: 8.3, 95% CI: 1.04-66.6, p<0.05), coronary bypass and mitral surgery procedures in the same session (OR: 9.2, 95% CI: 1.6-53.7, p<0.05), left main coronary lesion as >50% (OR: 4.3, 95% CI: 1.1-17.7, p<0.05), preoperative creatinine as >1.8 mg/dl (OR: 14.1, 95% CI: 2.6-76.1, p<0.01), New York Heart Association class III-IV (OR: 4.9, 95% CI: 1.2-20.1, p<0.05), chronic obstructive pulmonary disease (OR: 10.3, 95% CI: 2.5-41.7, p<0.01) were found to be risk factors of hospital mortality. Physical functions, social functions and all sub-scales other than the role limitation depending on the emotional situation were evaluated as general population mean or above. CONCLUSION: We think that with a successful heart surgery in patients aged 80 years and older under appropriate conditions, their life qualities and mean life expectations can return to normal and they can lead a symptomless life. PMID- 22484714 TI - First virtual interactive symposium with synchronous distance education techniques. PMID- 22484715 TI - The bisphosphonate incadronate inhibits intraperitoneal dissemination in an in vivo pancreatic cancer model. AB - Pancreatic cancer is characterized by intraperitoneal dissemination and often by large volumes of ascites. Aminobisphosphonates exhibit potent antitumor effects and are currently being tested against human solid tumors. Several aminobisphosphonates inhibit cancer cell migration by preventing the activation of Rho through inhibition of the mevalonate pathway. We evaluated the ability of an aminobisphosphonate, incadronate, to inhibit the growth of disseminated pancreatic cancer in vivo. We established an in vivo pancreatic cancer model with i.p. carcinomatosis in nude mice. Incadronate administration started from the day of tumor inoculation, and reduced tumor burden and ascites accumulation. Further, we evaluated the effect of incadronate on the inhibition of pancreatic cancer cell proliferation, migration and invasion in vitro. Incadronate induced growth inhibition and apoptotic death of pancreatic cancer cells. It also inhibited migration presumably by preventing the activation of Rho by lysophosphatidic acid. Thus, the in vivo antitumor effect may result from the inhibition of cancer cell proliferation and migration. The potent effects of incadronate in reducing tumor burden and ascites suggest that it will be of value in regimens for the treatment of pancreatic cancer. PMID- 22484716 TI - A comparison of the clinical and induced sputum characteristics of early- and late-onset asthma. AB - BACKGROUND: There are few studies describing the phenotype of late-onset asthma (LOA). We sought to investigate the clinical and induced sputum characteristics of patients with LOA. METHODS: Nineteen patients with LOA diagnosed after the age of 40 years and 19 patients with early-onset asthma (EOA) diagnosed before the age of 20 years were recruited. Subjects performed lung function, reversibility, asthma control questionnaire (ACQ), exhaled nitric oxide (NO), and sputum induction. RESULTS: The FEV(1) % predicted was lower in EOA compared to LOA (87.6 % vs. 103 %, respectively, p = 0.02), while ACQ scores were significantly higher in EOA (1.46 vs. 0.89, respectively, p = 0.03). NO was not different between the groups, but the percentage neutrophil counts were lower in the EOA group compared to the LOA group (36.6 vs. 57.3, respectively, p = 0.02). Asthma duration, but not age, was negatively associated with lung function (r = -0.4, p = 0.01). Neutrophil counts in healthy age-matched controls (n = 10) were similar to EOA and lower than LOA. CONCLUSION: Raised sputum neutrophils in LOA are not an indicator of severe disease and could be a characteristic feature of this asthma phenotype. Duration of asthma influences lung function. PMID- 22484717 TI - Thiol-ene-based biological/synthetic hybrid biomatrix for 3-D living cell culture. AB - Although various cell encapsulation materials are available commercially for a wide range of potential therapeutic cells, their combined clinical impact remains inconsistent. Synthetic materials such as poly(ethylene glycol) (PEG) hydrogels are mechanically robust and have been extensively explored but lack natural biofunctionality. Naturally derived materials including collagen, fibrin and alginate-chitosan are often labile and mechanically weak. In this paper we report the development of a hybrid biomatrix based on the thiol-ene reaction of PEG diacrylate (PEGdA) and cysteine/PEG-modified gelatin (gel-PEG-Cys). We hypothesized that covalent crosslinking decreases gelatin dissolution thus increasing gelatin resident time within the matrix and the duration of its biofunctionality; at the same time the relative ratio of PEGdA to gel-PEG-Cys in the matrix formulation directly affects hydrogel bulk and local microenvironment properties. Bulk viscoelastic properties were highly dependent on PEGdA concentration and total water content, while gel-PEG-Cys concentration was more critical to swelling profiles. Microviscoelastic properties were related to polymer concentration. The covalently crosslinked gel-PEG-Cys with PEGdA decreased gelatin dissolution out of the matrix and collagenase-mediated degradation. Fibroblasts and keratinocyte increased adhesion density and formed intercellular connections on stiffer hydrogel surfaces, while cells exhibited more cytoplasmic spreading and proliferation when entrapped within softer hydrogels. Hence, this material system contains multiparametric factors that can easily be controlled to modulate the chemical, physical and biological properties of the biomatrix for soft tissue scaffolding and cell presentation to reconstruct lost tissue architecture and physical functionality. PMID- 22484718 TI - Development and implementation of an integrated mobile situational awareness iPhone application VigiVUTM at an academic medical center. AB - PURPOSE: We describe the decision drivers, development and implementation of an integrated mobile situational awareness application for the perioperative environment. This digital operating room tool for anesthesiologists facilitates direct supervision of in-room staff without requiring being tied to a stationary computer workstation. METHODS: The iOS platform was used to create the VigiVUTM mobile application at Vanderbilt University Medical Center. The first working version was completed in 3 weeks with a scalable application for department-wide distribution requiring less than 1,000 development hours. RESULTS: The VigiVUTM application provides situational awareness via access to real time operating room video, patient vital signs, anesthetic interventions, OR management visualization tools, patient data protection, bidirectional voice and text communication, and integrated electronic medical record access. The application allows anesthesiologists to know the status of their patients in up to four locations simultaneously. The application provides the ability to visually follow the flow of patients through the operative suite and prioritize which patients need attention. The application provides a consistent user environment on several compatible iOS devices. A group of 40 beta testers has consistently used and maintained their copy of the application, suggesting user acceptance. CONCLUSIONS: We have demonstrated that it is possible to develop and implement an integrated mobile situational awareness application at a large academic medical center. Future research may determine whether perioperative deployment and utilization of VigiVUTM at our institution enhances patient safety and/or operating room efficiency. PMID- 22484719 TI - Computer-aided simple triage (CAST) for coronary CT angiography (CCTA). AB - PURPOSE: Following a recent introduction of computer-aided simple triage (CAST) as a new subclass of computer-aided detection/diagnosis (CAD), we present a CAST software system for a fully automatic initial interpretation of coronary CT angiography (CCTA). We show how the system design and diagnostic performance make it CAST-compliant and suitable for chest pain patient triage in emergency room (ER). METHODS: The processing performed by the system consists of three major steps: segmentation of coronary artery tree, labeling of major coronary arteries, and detection of significant stenotic lesions (causing > 50% stenosis). In addition, the system performs an automatic image quality assessment to discards low-quality studies. For multiphase studies, the system automatically chooses the best phase for each coronary artery. Clinical evaluation results were collected in 14 independent trials that included more than 2000 CCTA studies. Automatic diagnosis results were compared with human interpretation of the CCTA and to cath lab results. RESULTS: The presented system performs a fully automatic initial interpretation of CCTA without any human interaction and detects studies with significant coronary artery disease. The system demonstrated higher than 90% per patient sensitivity and 40-70% per patient specificity. For the chest pain, ER population, the specificity was 60-70%, yielding higher than 98% NPV. CONCLUSIONS: The diagnostic performance of the presented CCTA CAD system meets the CAST requirements, thus enabling efficient, 24/7 utilization of CCTA for chest pain patient triage in ER. This is the first fully operational, clinically validated, CAST-compliant CAD system for a fully automatic analysis of CCTA and detection of significant stenosis. PMID- 22484720 TI - Accelerating effect of hydroxylamine and hydrazine on nitrogen removal rate in moving bed biofilm reactor. AB - In biological nitrogen removal, application of the autotrophic anammox process is gaining ground worldwide. Although this field has been widely researched in last years, some aspects as the accelerating effect of putative intermediates (mainly N2H4 and NH2OH) need more specific investigation. In the current study, experiments in a moving bed biofilm reactor (MBBR) and batch tests were performed to evaluate the optimum concentrations of anammox process intermediates that accelerate the autotrophic nitrogen removal and mitigate a decrease in the anammox bacteria activity using anammox (anaerobic ammonium oxidation) biomass enriched on ring-shaped biofilm carriers. Anammox biomass was previously grown on blank biofilm carriers for 450 days at moderate temperature 26.0 (+/-0.5) degrees C by using sludge reject water as seeding material. FISH analysis revealed that anammox microorganisms were located in clusters in the biofilm. With addition of 1.27 and 1.31 mg N L-1 of each NH2OH and N2H4, respectively, into the MBBR total nitrogen (TN) removal efficiency was rapidly restored after inhibitions by NO2-. Various combinations of N2H4, NH2OH, NH4+, and NO2- were used as batch substrates. The highest total nitrogen (TN) removal rate with the optimum N2H4 concentration (4.38 mg N L-1) present in these batches was 5.43 mg N g-1 TSS h-1, whereas equimolar concentrations of N2H4 and NH2OH added together showed lower TN removal rates. Intermediates could be applied in practice to contribute to the recovery of inhibition-damaged wastewater treatment facilities using anammox technology. PMID- 22484721 TI - A randomized, double-blind, placebo-controlled study assessing the safety and tolerability of regadenoson in subjects with asthma or chronic obstructive pulmonary disease. AB - BACKGROUND: Adenosine receptor stress agents for myocardial perfusion imaging (MPI) may cause A(2B) and/or A(3) receptor-mediated bronchoconstriction, of particular concern to physicians testing patients with asthma or chronic obstructive pulmonary disease (COPD). METHODS: A Phase 4, randomized, double blind study (NCT00862641) assessed the safety of the selective A(2A) receptor agonist, regadenoson, compared with placebo in subjects with asthma or COPD who represented likely candidates for MPI. RESULTS: Overall, 356 and 176 subjects with asthma and 316 and 151 subjects with COPD received regadenoson and placebo, respectively. The percentage of subjects experiencing a >15% decrease in FEV(1) from baseline to any assessment up to 24 hours post-baseline was not statistically significantly different between the regadenoson and the placebo groups in the asthma or COPD stratum. Dyspnea, the most frequent respiratory adverse event, occurred with higher incidence (P < .0001) in the regadenoson group than the placebo group in the asthma (10.7% vs 1.1%) and COPD (18.0% vs 2.6%) strata. No subjects experienced severe bronchoconstriction, although the occurrence of such reactions with adenosine receptor agonists cannot be ruled out, such that caution is advised. CONCLUSIONS: This information may be helpful to physicians selecting a pharmacologic stress agent for MPI in patients with asthma or COPD. PMID- 22484722 TI - A comprehensive safety analysis confirms rhabdomyolysis as an uncommon adverse reaction in patients treated with trabectedin. AB - PURPOSE: This analysis determined the incidence of serious rhabdomyolysis events reported during trabectedin treatment since the first phase I clinical trial in April 1996 up to September 2010. METHODS: Search was done in the Yondelis((r)) Pharmacovigilance and Clinical Trials databases using a list of terms according to the Medical Dictionary for Regulatory Activities (MedDRA, v. 13.1), followed by a medical review of all cases retrieved. Total estimated sample was 10,841 patients: 2,789 from clinical trials; 3,926 from compassionate use programs; and 4,126 treated in the marketplace. Two groups were identified: (1) rhabdomyolysis and (2) clinically relevant creatine phosphokinase (CPK) increases without acute renal failure (ARF). Descriptive analysis included demographic, clinical/laboratory data, and contributing/confounding factors. Potential predictive factors were evaluated by multivariate stepwise logistic regression analysis. Possible changes of pharmacokinetics (PK) in patients with rhabdomyolysis were explored using a population PK model. RESULTS: The global incidence of rhabdomyolysis was 0.7%, and most cases occurred in Cycle 2 of treatment. The incidence of fatal cases was 0.3%. None of the variables evaluated to detect potential risk factors of rhabdomyolysis were predictive. Additionally, CPK increases (without ARF) were detected in 0.4% of patients as an incidental finding with good prognosis. CONCLUSIONS: Rhabdomyolysis is an uncommon event during trabectedin treatment. Multivariate analyses did not show any potential factor that could be predictive or represent a significantly higher risk of developing rhabdomyolysis. Nevertheless, close patient monitoring and adherence to drug administration guidelines may help to limit the incidence of this event. PMID- 22484723 TI - Chronic migraine classification: one more attempt of optimization and criteria revision. PMID- 22484724 TI - Initial report of quantification of retinal blood flow velocity in normal human subjects using the Retinal Functional Imager (RFI). AB - The Retinal Functional Imager (RFI) is a novel method for assessing retinal blood flow (RBF) velocity. The purpose of this study was to evaluate RBF velocities in normal human retinas using the RFI. RBF velocity measurements were performed in normal subjects using the RFI (Optical Imaging Ltd., Rehovot, Israel) at the Retina Center of The New York Eye and Ear Infirmary, New York, USA. Using proprietary software processing, the characteristics of the RBF were visualized and measured. The study population comprised fifty-four eyes of 27 normal subjects (20 male and 34 female). The average arterial blood flow velocity was 4.6 +/- 0.6 mm/s in males and 4.8 +/- 0.7 mm/s in females (the difference was not statistically significant, p value = 0.27). The average venous blood flow velocity was 3.8 +/- 0.5 mm/s in males and 3.6 +/- 0.4 mm/s in females (the difference again was not statistically significant, p value = 0.11). The average arterial blood flow velocity was 4.8 +/- 0.5 mm/s in the right eye and 4.6 +/- 0.7 mm/s in the left eye. The average venous blood flow velocity was 3.7 +/- 0.4 mm/s in the right eye and 3.6 +/- 0.3 mm/s in the left eye. Venous and arterial blood flow velocities were found to be faster in the right eye than in the left eye in our sample, but the differences were not statistically significant (p value = 0.53 and 0.33, respectively). This is the first report of quantification of the RBF using the RFI. The RFI appears to be an effective tool in quantitative evaluations of RBF velocities. The values from the study constitute a normative database which can be used to evaluate and compare eyes with known or suspected pathology. PMID- 22484725 TI - The mystery of angiographically silent macular oedema due to taxanes. AB - Taxanes are widely used anticancer agents, produced from the plants of the genus Taxus (yews). One of the rare side-effects caused by taxanes is a bilateral cystoid macular oedema (CMO). The particularity of this type of CMO is that it is angiographically silent showing no leakage or pooling on fluorescein angiography (FA). To date, the mechanism of this oedema has not been clearly understood and existing theories do not explain this phenomenon very well. Our aim was to report a case of paclitaxel-induced CMO and put forward a putative explanation for this occurrence. A 64-year-old woman presented with a 7-month history of progressively decreasing bilateral visual acuity with an apparently normal fundus. At entry her best-corrected visual acuity (BCVA) was 0.4 for far and near OD and 0.5 for far and near OS. Optical coherence tomography (OCT) revealed a CMO with a central thickness of 561 MUm OD and 488 MUm OS; there were no signs of intraocular inflammation. FA showed no capillary leakage and quasi absent late hyperfluorescence OU. Indocyanine green angiography was within normal limits. Classical CMO treatment was ineffective and only discontinuation of paclitaxel resulted in recovery of a normal macular structure after 4 weeks with an increase of BCVA to 0.9 OD and 1.0 OS. In order to understand the properties of taxane drug-induced cystoid macular oedema (TDICMO) we compared the spectral OCT findings of our case to an inflammation-induced CMO of equal thickness and to a case of multifocal choroiditis. The plane of separation of TDICMO was above the external limiting membrane in both cases. In contrast to inflammation-induced CMO where the four external bands were well identified, there was attenuation of these bands in TDICMO but no disruption of the layers as seen in multifocal choroiditis, indicating that the fluid in TDICMO had a high viscosity producing a shadow underneath. TDICMO most probably originates from retinal pigment epithelium dysfunction by their effect on microtubule functions and not from vascular leakage. The content of the CMO seems to be made up of viscous fluid. As the origin of the CMO is not inflammatory, classical CMO treatments have no effect and only discontinuation of the taxane drug allows reversal of the CMO. PMID- 22484726 TI - Intravitreal infliximab for refractory pseudophakic cystoid macular edema: results of the Pan-American Collaborative Retina Study Group. AB - Inflammation is the major etiologic factor in the development of pseudophakic cystoid macular edema (CME). Several soluble mediators of inflammation such as tumor necrosis factor alpha (TNF-alpha) have been implicated in the pathogenesis of ocular inflammation. The purpose of this study is to report the short-term visual and anatomic outcomes following intravitreal injections of infliximab in eyes with refractory CME secondary to cataract surgery. An interventional, retrospective study of 7 eyes with refractory CME that were injected with 1 mg of infliximab. The main outcome measures were best-corrected visual acuity (BCVA) and central macular thickness (CMT) at 6-month follow-up. At the 6 month follow up, BCVA improved from 1.14 +/- 0.59 logMAR at baseline to 0.51 +/- 0.35 logMAR (p = 0.0156). CMT also improved from 584 +/- 159 MUm at baseline to 327 +/- 127 MUm at 6 months (p = 0.0111). No systemic adverse events were reported in these patients. There was a single episode of uveitis that responded to topical steroids. Inhibition of TNF-alpha may be beneficial in the treatment of refractory pseudophakic CME. PMID- 22484727 TI - Hypercalciuria, hyperoxaluria, and hypocitraturia screening from random urine samples in patients with calcium lithiasis. AB - Calcium lithiasis is the most frequently diagnosed renal lithiasis and is associated with a high percentage of patients with metabolic disorders, such as hypercalciuria, hypocitraturia, and hyperoxaluria. The present study included 50 patients with recurrent calcium lithiasis. We conducted a random urine test during nocturnal fasting and a 24-h urine test, and examined calcium, oxalate, and citrate. A study of the linear correlation between the metabolites was performed, and the receiver operator characteristic (ROC) curves were analyzed in the random urine samples to determine the cutoff values for hypercalciuria (excretion greater than 200 mg), hyperoxaluria (excretion greater than 40 mg), and hypocitraturia (excretion less than 320 mg) in the 24-h urine. Linear relationships were observed between the calcium levels in the random and 24-h urine samples (R = 0.717, p = 0.0001), the oxalate levels in the random and 24-h urine samples (R = 0.838, p = 0.0001), and the citrate levels in the random and 24-h urine samples (R = 0.799, p = 0.0001). After obtaining the ROC curves, we observed that more than 10.15 mg/dl of random calcium and more than 16.45 mg/l of random oxalate were indicative of hypercalciuria and hyperoxaluria, respectively, in the 24-h urine. In addition, we found that the presence of less than 183 mg/l of random citrate was indicative of the presence of hypocitraturia in the 24-h urine. Using the proposed values, screening for hypercalciuria, hyperoxaluria, and hypocitraturia can be performed with a random urine sample during fasting with an overall sensitivity greater than 86%. PMID- 22484728 TI - Law, bioethics and practice in France: forging a new legislative pact. AB - In France, bioethics norms have emerged in close interaction with medical practices. The first bioethics laws were adopted in 1994, with provisions for updates in 2004 and most recently, in 2011. As in other countries, bioethics laws indirectly refer to certain fundamental values. The purpose of this paper is threefold. First, I shall briefly describe the construction of the French bioethics laws and the values they are meant to protect. Secondly, I will show that the practice of clinical ethics, as reported in a few studies on ART, living organ donation and PGD, challenge the role attributed to doctors as "gatekeepers" of those fundamental values. Thirdly, I will suggest that the quality of medical practices would improve if the law focused on strengthening the tacit pact between doctors and patients, rather than putting doctors in charge of enforcing societal values. Doctors, for their part, would limit their role to what they can do best: provide sufficient patient support and safe care. Against those who argue that we should dispense with bioethics laws altogether, I hold that the laws are useful in order to limit the development of abusive practices. However, a new legislative approach should be adopted which would a positive presumption in favor of patients' requests. PMID- 22484729 TI - Antioxidant activities of five polysaccharides from Inonotus obliquus. AB - Five polysaccharides (IOP1b, IOP2a, IOP2c, IOP3a and IOP4) were isolated and purified from Inonotus obliquus by DEAE-Sepharose fast flow and SepharoseCL-6B column chromatography. Their chemical and physical characteristics were determined and antioxidant activities were investigated on the basis of hydroxyl radical assay, superoxide radical assay and ferric-reducing antioxidant power assay. The results showed that five polysaccharides exhibited antioxidant activities, and the higher content of uronic acid and proteinous substances, the stronger antioxidant activities of polysaccharides. Besides, molecular weights of polysaccharides also influence their antioxidant activities. IOP3a and IOP4 showed higher antioxidant properties than IOP1b, IOP2a and IOP2c. PMID- 22484730 TI - Impact of metal oxide nanoparticles on oral release properties of pH-sensitive hydrogel nanocomposites. AB - In this article, modified kappa-carrageenan hydrogel nanocomposites were synthesized to increase the release ability of carrageenan hydrogels under gastrointestinal conditions. The effect of MgO nanoparticle loading in a model drug (methylene blue) release is investigated. Characterization of hydrogels were carried out using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Field Emission Scanning Electron Microscope (FESEM) and Differential Scanning Calorimetry (DSC). Genipin was used to increase the delivery performance in gastrointestinal tract delivery by decreasing release in simulated stomach conditions and increasing release in simulated intestine conditions. It is shown that the amount of methylene blue released from genipin cross-linked nanocomposites can be 67.5% higher in intestine medium and 56% lower in the stomach compared to kappa-carrageenan hydrogel. It was found that by changing the nanoparticle loading and genipin concentration in the composite, the amount of drug released can be monitored. Therefore, applying nanoparticles appears to be a potential strategy to develop controlled drug delivery especially in gastrointestinal tract studies. PMID- 22484731 TI - Variability in hormone and growth factor receptor expression in primary versus recurrent, metastatic, and post-neoadjuvant breast carcinoma. AB - The introduction of selective molecular targeted therapy, specifically tamoxifen and trastuzumab, has significantly altered the clinical behavior of breast carcinoma. Several questions remain, however, regarding potential phenotypic drifts in estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor (Her-2/neu) expression between the primary and metastatic site. Whether patients should be tested for ER, PR, and Her-2/neu expression in the nodal or distant metastatic site, local recurrence and following neoadjuvant therapy, and whether this has an effect on prognosis remains elusive. A review of 45 studies addressing ER, PR, and Her-2/neu expression in lymph node metastasis, distant metastasis, local recurrence, and post-neoadjuvant therapy revealed the following average phenotypic drift in ER, PR, and Her-2/neu expression, respectively: 13.1 % (median = 10.0 %), 13.8 % (median = 16.0 %), and 7.7 % (median = 5.0 %) for lymph node metastasis; 21.8 % (median = 19.5 %), 30.8 % (median = 33.5 %), and 7.6 % (median = 6.1 %) for distant metastasis; 19.8 % (median = 13.4 %), 27.1 % (median = 28.6 %), and 6.6 % (median = 1.6 %) for local recurrence; and 12.9 % (median = 8.0 %), 32.0 % (median = 20.0 %), and 8.9 % (median = 0 %) post-neoadjuvant therapy. The above findings support the notion of re-evaluating ER, PR, and Her-2/neu expression in distant metastasis, lymph node metastasis and to a lesser extent local recurrence. The effects of neoadjuvant therapy on receptor expression are more pronounced for PR, which may have a prognostic role in therapy efficacy. PMID- 22484732 TI - Vorinostat enhances protein stability of p27 and p21 through negative regulation of Skp2 and Cks1 in human breast cancer cells. AB - Vorinostat is a histone deacetylase inhibitor that blocks cancer cell proliferation through the regulation of cyclin-dependent kinase inhibitors. We, herein, examined the involvement of S-phase kinase-associated protein 2 (Skp2) and cyclin-dependent kinase subunit 1 (Cks1), the components of the SCFSkp2-Cks1 (Skp1/Cul1/F-box protein) ubiquitin ligase complex, in the regulation of p27 and p21 during vorinostat-induced growth arrest of MDA-MB-231 and MCF-7 human breast cancer cells. Vorinostat significantly reduced BrdU incorporation in MDA-MB-231 and MCF-7 cells, which was associated with increased p27 and p21 protein levels without concomitant induction of p27 mRNA. Vorinostat-induced accumulation of p27 and p21 proteins was inversely correlated with the mRNA and protein levels of Skp2 and Cks1. Cycloheximide chase analysis revealed that vorinostat increased the half-life of p27 and p21 proteins. The accumulation of p27 and p21 proteins was attenuated by forced expression of Skp2 and Cks1, which conferred resistance to the vorinostat-induced S-phase reduction. These results suggest that vorinostat-induced growth arrest may be in part due to the enhanced protein stability of p27 and p21 through the downregulation of Skp2 and Cks1. PMID- 22484733 TI - NLRC4-driven production of IL-1beta discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. AB - Intestinal phagocytes transport oral antigens and promote immune tolerance, but their role in innate immune responses remains unclear. Here we found that intestinal phagocytes were anergic to ligands for Toll-like receptors (TLRs) or commensals but constitutively expressed the precursor to interleukin 1beta (pro IL-1beta). After infection with pathogenic Salmonella or Pseudomonas, intestinal phagocytes produced mature IL-1beta through the NLRC4 inflammasome but did not produce tumor necrosis factor (TNF) or IL-6. BALB/c mice deficient in NLRC4 or the IL-1 receptor were highly susceptible to orogastric but not intraperitoneal infection with Salmonella. That enhanced lethality was preceded by impaired expression of endothelial adhesion molecules, lower neutrophil recruitment and poor intestinal pathogen clearance. Thus, NLRC4-dependent production of IL-1beta by intestinal phagocytes represents a specific response that discriminates pathogenic bacteria from commensal bacteria and contributes to host defense in the intestine. PMID- 22484736 TI - Falling between two stools: operational inconsistencies between ICDS and NRHM in the management of severe malnutrition. AB - There has been a welcome interest in the issue of malnutrition by policy makers as well as technical experts in the recent years. The current public health systems for management of malnutrition, the ICDS and NRHM, have attempted to evolve approaches to the management of severe malnutrition. This paper makes a fresh analysis of data from well-accepted existing sources, indicating that 36 44% of all children with Severe Acute Malnutrition (SAM) are likely to be missed by current criteria of screening and referral; simultaneously, a large proportion of children selected for referral to Nutritional rehabilitation centres are likely not to have SAM. The paper also highlights other areas of inconsistencies between the ICDS and the NRHM in the continuum of care required for the prevention and proper management of severe malnutrition. Thus, the paper identifies areas that need further exploration to achieve a seamless and effective program for tackling severe malnutrition. PMID- 22484734 TI - Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells. AB - The maintenance of immune homeostasis requires regulatory T cells (Treg cells). Here we found that Treg cell-specific ablation of Ubc13, a Lys63 (K63)-specific ubiquitin-conjugating enzyme, caused aberrant T cell activation and autoimmunity. Although Ubc13 deficiency did not affect the survival of Treg cells or expression of the transcription factor Foxp3, it impaired the in vivo suppressive function of Treg cells and rendered them sensitive to the acquisition of T helper type 1 (TH1) cell- and interleukin 17 (IL-17)-producing helper T (TH17) cell-like effector phenotypes. This function of Ubc13 involved its downstream target, the kinase IKK. The Ubc13-IKK signaling axis controlled the expression of specific Treg cell effector molecules, including IL-10 and SOCS1. Collectively, our findings suggest that the Ubc13-IKK signaling axis regulates the molecular program that maintains Treg cell function and prevents Treg cells from acquiring inflammatory phenotypes. PMID- 22484737 TI - Intrapartum perinatal mortality. PMID- 22484738 TI - Maternal risk factors affecting perinatal mortality. PMID- 22484739 TI - T-cells and cardiac complications in infectious mononucleosis. PMID- 22484740 TI - Inequity in childhood immunization in India: a systematic review. AB - BACKGROUND: Despite a reduction in disease burden of vaccine preventable diseases through childhood immunization, considerable progress needs to be made in terms of ensuring efficiency and equity of vaccination coverage. OBJECTIVE: To conduct a systematic review to identify and explore factors associated with inequities in routine vaccination of children in India. METHODS: Publications reporting vaccination inequity were retrieved through a systematic search of Medline and websites of the WHO, UNICEF and demographic health surveys in India. No restrictions were applied in terms of study designs. The primary outcome measure was complete vaccination or immunization defined as per the standard WHO definition. RESULTS: There were three nationwide data sets viz. the three National Family Health Surveys (NFHS), a research study conducted by the Indian Council of Medical Research (ICMR) and a UNICEF coverage evaluation survey. In addition, several publications representing different population groups or geographic regions were available. A small number of publications were reanalyses of data from the NFHS series. There is considerable inequity in vaccination coverage in different states. Within states, traditionally poor performing states have greater inequities, although there are significant inequities even within better performing states. There are significant inequities in childhood vaccination based on various factors related to individual (gender, birth order), family (area of residence, wealth, parental education), demography (religion, caste), and the society (access to health-care, community literacy level) characteristics. Girls fare uniformly worse than boys and higher birth order infants have lower vaccination coverage. Urban infants have higher coverage than rural infants and those living in urban slums. There is an almost direct relationship between household wealth and vaccination rates. The vaccination rates are lower among infants with mothers having no or low literacy, and families with insufficient empowerment of women. Paternal literacy has an inconsistent positive relationship with infant vaccination. There is a relationship between religion and caste and childhood vaccination. Access to health services and other infrastructure, is associated with better vaccination coverage of infants. The precise impact of specific risk factors operating singly or in combination cannot be calculated from this systematic review. CONCLUSION: This systematic review identifies and explores factors associated with inequity in childhood immunization in India; and provides information for urgent action to redress the imbalances. PMID- 22484741 TI - Glycogen storage disease 1a with piebaldism. AB - A 3 and half years old male child born by consanguineous marriage presented with white forelock and symmetric hypopigmented areas present since birth, similar to his mother and elder sister. Hepatomegaly was noticed at one year of age. Liver biopsy revealed enlarged pale hepatocytes distended with glycogen. Skin biopsy revealed absence of melanin pigment in white depigmented skin. G727T gene splice mutation was diagnosed in exon 5 of 17q21 chromosome. PMID- 22484742 TI - Anaphylaxis due to Red fire ant bite. AB - Ant allergy is a rare problem and most published reports are from outside India. We report a toddler who suffered from severe anaphylaxis reaction due to bite of Red fire ant (Solenopsis geminata). PMID- 22484743 TI - Neurodevelopmental outcome of neonates with vertically transmitted Chikungunya fever with encephalopathy. AB - Neurodevelopmental follow-up of neonates with vertically transmitted Chikungunya fever has been infrequently reported. We herein report neurodevelopment follow up of two such babies at 3 year of age. PMID- 22484744 TI - Pemphigus foliaceus. AB - Pemphigus foliaceus is an autoimmune blistering disease, which affects the skin but rarely affects the mucosae. There are two variants of pemphigus foliaceus : endemic and sporadic. Erythroderma due to pemphigus foliaceus is unusual and its occurrence in a child is very rare. We describe a case of erythrodermic pemphigus foliaceus in a 12- year- old boy. PMID- 22484745 TI - Hemothorax following snakebite. AB - We report a 12 year old girl with snakebite, who developed hemothorax 5 days after admission. One liter of blood was aspirated. The bite was presumed to be that of saw scaled viper (Echis carinatus) that resulted in DIC and direct endothelial injury leading to bleed. Selective bleed into the pleural cavity is a rarity. PMID- 22484746 TI - Lane-Hamilton syndrome: association or coincidence. AB - The combination of idiopathic pulmonary hemosiderosis (IPH) and celiac disease (CD) is rare. The clinical importance of this association is that a significant improvement can be obtained with gluten free diet not only in intestinal but also in pulmonary symptoms. A four and half-years old girl was admitted with complaints of cough, difficulty in breathing and paleness. She had intermittent episodes of abdominal pain and diarrhea. She had dyspnea and tachycardia, and oxygen saturation 88%. The patient was diagnosed with CD and concomitant IPH. With gluten-free diet and corticosteroid treatment, both intestinal and pulmonary symptoms were controlled. PMID- 22484747 TI - Hirschsprungs disease with congenital hypothyroidism. AB - We report a female newborn baby who presented with vomiting and abdominal distension on day 21 of life. Examination revealed facial puffiness, open posterior fontanelles, dry skin, cold peripheries and prominent abdominal veins with visible peristalsis. Barium enema revealed dilated proximal colon, empty rectum, funnel like transition zone between proximal dilated and distal constricted bowel. Serum TSH level was >;150 uIU/mL. Biopsy revealed aganglionic segment suggesting Hirschsprungs disease, an unusual association with congenital hypothyroidism. PMID- 22484748 TI - Poisoning due to accidental ingestion of Dieffenbachia plant (Dumb cane). PMID- 22484749 TI - Does choice of treatment protocol have impact on outcome in T-cell lymphoblastic leukemia? PMID- 22484750 TI - Childhood deaths in India- the invisible disasters. PMID- 22484752 TI - Sleep rituals. PMID- 22484751 TI - The other side of L-asparaginase. PMID- 22484753 TI - Rickettsial diseases in central India. PMID- 22484756 TI - Perspective on challenges in scaling up of special care newborn units. PMID- 22484757 TI - Cutaneous manifestations of Chikungunya fever: significance. PMID- 22484758 TI - A boy with claw fingers. PMID- 22484759 TI - Phylodynamics of HIV-1 subtype F1 in Angola, Brazil and Romania. AB - The HIV-1 subtype F1 is exceptionally prevalent in Angola, Brazil and Romania. The epidemiological context in which the spread of HIV occurred was highly variable from one country to another, mainly due to the existence of a long-term civil war in Angola and the contamination of a large number of children in Romania. Here we apply phylogenetic and Bayesian coalescent-based methods to reconstruct the phylodynamic patterns of HIV-1 subtype F1 in such different epidemiological settings. The phylogenetic analyses of HIV-1 subtype F1 pol sequences sampled worldwide confirmed that most sequences from Angola, Brazil and Romania segregated in country-specific monophyletic groups, while most subtype F1 sequences from Romanian children branched as a monophyletic sub-cluster (Romania CH) nested within sequences from adults. The inferred time of the most recent common ancestor of the different subtype F1 clades were as follow: Angola=1983 (1978-1989), Brazil=1977 (1972-1981), Romania adults=1980 (1973-1987), and Romania-CH=1985 (1978-1989). All subtype F1 clades showed a demographic history best explained by a model of logistic population growth. Although the expansion phase of subtype F1 epidemic in Angola (mid 1980s to early 2000s) overlaps with the civil war period (1975-2002), the mean estimated growth rate of the Angolan F1 clade (0.49 year(-1)) was not exceptionally high, but quite similar to that estimated for the Brazilian (0.69 year(-1)) and Romanian adult (0.36 year(-1)) subtype F1 clades. The Romania-CH subtype F1 lineage, by contrast, displayed a short and explosive dissemination phase, with a median growth rate (2.47 year( 1)) much higher than that estimated for adult populations. This result supports the idea that the AIDS epidemic that affected the Romanian children was mainly caused by the spread of the HIV through highly efficient parenteral transmission networks, unlike adult populations where HIV is predominantly transmitted through sexual route. PMID- 22484760 TI - CCL3L gene copy number and survival in an HIV-1 infected Zimbabwean population. AB - The C-C motif chemokine ligand 3-like (CCL3L) protein is a potent chemoattractant which by binding to C-C chemokine receptor type 5 (CCR5) inhibits human immunodeficiency virus (HIV) entry. Copy number variation (CNV) of the CCL3L has been shown to be associated with HIV susceptibility and progression to AIDS, but these results have been inconsistent. We examined a Zimbabwean study population for an association of CCL3L CNV with HIV status, progression (CD4 T-cells and viral load), and survival. Another aim was to investigate the possible effects of CCL3L CNV on CCL3 protein concentration. A treatment-naive cohort, which included 153 HIV infected and 159 HIV uninfected individuals, was followed for up to 4.3 years. The CNV of the CCL3L was determined by duplex real-time polymerase chain reaction. We found no association between four CCL3L CNV strata and HIV status (P=0.7), CD4 T-cell count (P=0.9), viral load (P=0.9), or CCL3 protein levels (P=1.0). Survival among the HIV infected individuals did not differ according to CCL3L copy number. In this cohort, CCL3L CNV did not affect HIV status, pathogenesis, or survival. PMID- 22484761 TI - Molecular investigations of chikungunya virus during outbreaks in Orissa, Eastern India in 2010. AB - Chikungunya virus (CHIKV), an arthritogenic alphavirus, is transmitted to humans by mosquitoes of genus Aedes, mainly Aedes aegypti and Aedes albopictus. The resurgence of CHIKV in different parts of India is a point of major public health concern. In 2010, chikungunya outbreaks with high epidemic magnitude were recorded in coastal areas of Orissa, Eastern India, affecting more than 15,000 people coupled with severe arthralgia and prolonged morbidites. Detailed entomological, serological and molecular investigation of this unprecendented outbreak was carried out by collecting and studying 1359 mosquito samples belonging to A. albopictus, A. aegypti, A. vittatus, A. edwardsii and Culex species and 220 patients serum from the affected areas. In this study, CHIKV specific IgM capture-ELISA and reverse-transcription PCR (RT-PCR) were done to detect recent infection of CHIKV in serum samples and adult mosquitoes collected from the affected areas. The high maximum likelihood estimate (MLE) (15.2) in A. albopictus mosquitoes indicated that it was the principal vector involved in transmission of CHIKV in Orissa. Phylogenetic analysis revealed that the CHIKV strains involved in the outbreak belonged to the Indian Ocean Lineage (IOL) group within the East, Central and South African (ECSA) genotype. Genetic characterization of envelope glycoprotein (E1 and E2) genes revealed that all the CHIKV isolates from Orissa had the E1-A226V mutation that enhances viral dissemination and transmissibility by A. albopictus mosquitoes along with E2 L210Q and E2-I211T mutations, which play an epistatic role with E1-A226V mutation in adaptation of CHIKV to A. albopictus by increasing its midgut infectivity, thereby favoring its vectorial capacity. Our results showed the involvement of A. albopictus vector in the recent outbreaks in Orissa and circulation of IOL strains of ECSA genotype of CHIKV with E1-A226V, E2-L210Q and E2-I211T mutations in vectors and patients serum. PMID- 22484762 TI - Porcine reproductive and respiratory syndrome virus diversity of Eastern Canada swine herds in a large sequence dataset reveals two hypervariable regions under positive selection. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is known to be genetically highly variable, but knowledge of sequence diversity from Eastern Canada and its degree of genetic plasticity in or near the principal neutralizing epitope (PNE) in association with evolutionary selective pressure is limited. The purposes of our study were to investigate the extent of strain diversity, the existing glycotypes and the amino acid sites under selective evolutionary pressure in its encoded protein, GP5, for a dataset of 1301 sequences (1998 2009). This was addressed by partitioning and clustering into subgenotypes a large number of open reading frame 5 sequences from the province of Quebec and analyzing the content of these subgenotypes. The overall pairwise diversity was 12% and was comparable to what has been reported around the world. The mean diversity for sequences within subgenotypes was around 7%. No marked variations in subgenotype emergence could be observed through time. Thirty-eight GP5 glycotype patterns were observed which included a newly identified site at position N57 which was already present in 1998. These patterns possessed one to six N-glycosylation sites in total and could be located in eight different positions. No obvious grouping of glycotypes could be established in relation to subgenotypes. Positions N44 and N51 were confirmed to be fixed N-glycosylation positions, whereas other positions where found to be shifting and located in or near hypervariable regions (HVRs) 1 and 2. Both HVRs were under selective evolutionary pressure in half of all subgenotypes including vaccine-like groups. Conversely, the PNE flanked by both HVRs was well conserved among most subgenotypes demonstrating potential molecular constraint in a probable viral binding region. The analysis of this dataset increased knowledge of evolutionary change inferred from genetic data, more specifically regarding the implications of both HVRs in PRRSV diversity. PMID- 22484763 TI - CCL3L1 copy number and susceptibility to malaria. AB - Copy number variation can contribute to the variation observed in susceptibility to complex diseases. Here we present the first study to investigate copy number variation of the chemokine gene CCL3L1 with susceptibility to malaria. We present a family-based genetic analysis of a Tanzanian population (n=922), using parasite load, mean number of clinical infections of malaria and haemoglobin levels as phenotypes. Copy number of CCL3L1 was measured using the paralogue ratio test (PRT) and the dataset exhibited copy numbers ranging between 1 and 10 copies per diploid genome (pdg). Association between copy number and phenotypes was assessed. Furthermore, we were able to identify copy number haplotypes in some families, using microsatellites within the copy variable region, for transmission disequilibrium testing. We identified a high level of copy number haplotype diversity and find some evidence for an association of low CCL3L1 copy number with protection from anaemia. PMID- 22484764 TI - Host cell/Orientia tsutsugamushi interactions: evolution and expression of syndecan-4 in Asian rodents (Rodentia, Muridae). AB - Scrub typhus is an acute febrile zoonotic disease and worldwide more than a billion people may be at risk for infection. Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular bacterium. Rodents are reported to be the primary reservoir hosts of the disease and according to the most recent surveys, all species within the Rattus sensu lato complex of the tribe Rattini are carriers of scrub typhus. There is no evidence that any of mouse (Mus) species serves as the primary reservoir of the bacterium even when occurring in sympatry with wild infected rats. This contrast in the host/syndecan 4 interactions between Rattini and Asian Murini may be due to intrinsic (i.e., genetic) differences. Herein we compare the sequence and expression levels of syndecan-4 (the putative cell receptor of O. tsutsugamushi) between Rattini species that are known to be natural reservoirs for the typhus agents, and Murini species that are not. Although it was not possible to conclusively link the structural variations detected in syndecan-4 with carrier status in either Rattini and Murini, our findings indicate the absence of a strong Orientia mediated selective regime acting on gene structure. In contrast, variable spleen specific syndecan-4 expression levels show a strong correlation between under expression of syndecan-4 in Murini and seropositive Rattini, compared to seronegative Rattini rodents. We postulate that two divergent responses may be at work in Murini and Rattini, both linked with differential expression of syndecan 4: (i) reduced syndecan-4 transcription in Murini decreases the likelihood that the host cells will become infected by the Orientia bacterium, while (ii) reduced syndecan-4 expression in seropositive Rattini limits the pathogenicity of Orientia and consequently improves the longevity of the rat hosts. These patterns may underpin the poor carrier status of wild mice on the one hand, and the effective role of wild rats as reservoir hosts on the other. PMID- 22484765 TI - Evaluation of interspinous process distraction device (X-STOP) in a representative patient cohort. AB - OBJECTIVE: To test the hypothesis that the level of clinical efficacy reported in the investigational device exemption (IDE) study of the X-STOP device that led to its approval by the U.S. Food and Drug Administration could also be achieved in patients who are representative of the population approved for treatment, irrespective of whether they met all the stringent requirements of the IDE study. METHODS: A retrospective analysis was conducted of a consecutive series of 31 patients who received the X-STOP interspinous process distraction device as treatment for neurogenic intermittent claudication. Outcome was assessed at an average of 2 years after surgery by use of the Zurich Claudication Questionnaire (ZCQ), which used the definition of clinical success used in the IDE study. RESULTS: On the basis of the ZCQ, clinically significant improvement occurred in 38% of the evaluable patients (21 patients), compared with 48.4% in the IDE study; at the sites other than those of the device's inventors, the improvement level was 37%. Four patients needed additional surgery, which was a rate comparable with that reported in the IDE study. CONCLUSIONS: The success level in the controlled IDE study that established the safety and efficacy of the X-STOP device was achieved in a representative patient cohort that did not necessarily meet all the strict requirements of the IDE plan. Nevertheless, the overall results were not good, suggesting that the ZCQ definition of success might not have captured the true outcome of surgical treatment with the X-STOP device. PMID- 22484766 TI - Brainstem cavernous malformations: 1390 surgical cases from the literature. AB - OBJECTIVE: Although surgical resection of brainstem cavernous malformations (CM) has been reviewed, numerous large surgical series have been recently reported. METHODS: Eighteen new surgical series with 710 patients were found via a PubMed search, in addition to our previous meta-analysis. Complete excision, complications, and long-term outcome results were compiled across these series. They were then compared and subsequently combined with those of our previous report. RESULTS: We combined results of 68 surgical series with 1390 patients, incorporating results from our previous meta-analysis. Across 61 series, 1178 of 1291 (91%) CMs were completely excised. Of 105 partially resected CMs with ample follow-up, 65 rebled (62%). Across 46 series providing information on early neurologic morbidity, the overall rate was 45%. Specifically, 12% of patients required tracheostomy and/or gastrostomy procedures. Overall long-term condition was improved in 62% of patients across 51 series. Across 60 series, overall long term condition was improved or the same in 84% of patients, with worsening in the remaining 16%. The overall surgical and/or cavernoma related mortality rate for all 1390 patients was 1.5%. Notably, these results did not differ significantly between our initial review and the combined data from the subsequent 18 surgical series recently reported in the literature. CONCLUSION: Surgical resection of brainstem CM continues to present a considerable challenge with resultant morbidity akin to another CM hemorrhage. We therefore prefer to offer surgery only to patients with at least one previous hemorrhage with CM pial representation. Appropriate patient counseling about expected early morbidity and the potential for long-term worsening is crucial. PMID- 22484767 TI - Characteristics of brain arteriovenous malformations in patients presenting with nonhemorrhagic neurologic deficits. AB - OBJECTIVE: To identify the specific angioarchitectural characteristics of arteriovenous malformations (AVMs) that are associated with a clinical presentation of nonhemorrhagic neurologic deficits. METHODS: Between 1999 and 2008, 302 consecutive patients with AVMs were referred to our institution. Twenty four patients (7.9%) presented with neurologic deficits without hemorrhage before treatment. We tested for statistical associations between angioarchitectural characteristics and neurological deficits at presentation. RESULTS: When we compared the 24 (7.9%) patients with nonhemorrhagic neurological deficits with the 278 patients who did not experience neurologic deficits initially (total of 302 patients), female sex (P = 0.002), deep AVM location (P = 0.015), AVM size greater than 3 cm (P = 0.001), more than three arterial feeders present (P = 0.004), only perforating feeding artery (P = 0.007), the presence of more than three draining veins (P = 0.016), the presence of varices in the venous drainage (P = 0.013), and a Spetzler-Martin grade of III to V (P = 0.004) were statistically associated with neurological deficits. Patient age, eloquent location, deep venous drainage, venous drainage restriction, and coexisting aneurysms were not statistically associated with neurological deficits without hemorrhage. CONCLUSION: The characteristics of AVM associated with nonhemorrhagic neurological deficits include female sex, deep AVM location, more than three arterial feeders, only perforating feeding artery, more than three draining veins, the presence of varices in the venous drainage, and a Spetzler-Martin grade of III to V. PMID- 22484768 TI - Intramedullary spinal cord metastases: a 20-year institutional experience with a comprehensive literature review. AB - OBJECTIVES: To review previous reports as well as our institutional experience to address the issues regarding patient management and also to assess the predisposing factors that might influence outcome and survival. METHODS: We undertook a 20-year (1989-2009) retrospective study of a series of eight patients diagnosed with intramedullary spinal cord metastases (ISCMs) in our institute. We further reviewed 293 cases of ISCMs reported in the English literature since 1960. Characteristics regarding the site of the primary cancer, location of ISCM, the presence of other metastases, presenting neurological symptoms/signs, duration of symptoms, and the time interval from diagnosis of the primary tumor to ISCM were pooled. We analyzed the different treatment approaches, the functional outcome, and the factors influencing survival. RESULTS: Lung and breast cancers appear to be the most frequent source of ISCM with cervical, thoracic, and lumbar spine being equally affected. Motor weakness predominates as the commonest symptom at presentation, followed by pain and sensory disturbance. At diagnosis, most patients with ISCM have a known primary cancer often associated with cerebral and other systemic metastases. Overall survival of ISCM is poor (median: 4 months from the time of diagnosis). Survival in surgical patients is 6 months, compared with 5 months in those conservatively managed. Clinical improvement was observed in more than one-half of those treated surgically, whereas neurological status was maintained in most patients treated conservatively. CONCLUSION: ISCM is an unusual site for metastasis. Regardless of the treatment, its prognosis is generally poor as its presence often signifies end-stage cancer. However, with early diagnosis and appropriate treatment, selected patients may benefit from improved neurological outcome and quality of life. PMID- 22484769 TI - Intravascular ultrasound in the evaluation and management of cerebral venous disease. AB - BACKGROUND: Intravascular ultrasound (IVUS) is an important diagnostic tool in many interventions, particularly coronary and carotid artery angioplasty and stenting. In contrast, its application in the management of diseases of the cerebral venous system remains an unexplored territory. We report three patients in whom IVUS was used during angiography for the evaluation of venous flow obstruction secondary to venous sinus thrombosis, venous sinus stenosis, and a transverse sinus mass lesion, respectively. In addition, we review current literature to summarize previous experience, focusing on the advantages and limitations of IVUS technology in interventional cardiology, carotid artery disease, and venous disease. CASE DESCRIPTIONS: In all three cases, IVUS was used without any complications and provided critical information that guided further management of these distinct diseases. IVUS helped diagnose the presence of intraluminal thrombus, severe stenosis, and a mass lesion in the transverse sinuses and also helped assess the response to angioplasty of the stenotic regions. CONCLUSIONS: IVUS is a promising tool that has potential to improve diagnostic accuracy and to guide the management of several diseases of the cerebral venous system. The cases we describe suggest that IVUS can be successfully used when performing endovascular interventions in patients with obstruction of venous outflow secondary to venous sinus stenosis, thrombosis, or mass lesions. PMID- 22484770 TI - Cochlea radiation dose correlates with hearing loss after stereotactic radiosurgery of vestibular schwannoma. AB - OBJECTIVE: For multisession radiosurgery, no published data relate the volume and dose of cochlear irradiation to quantified risk of hearing loss. We conducted a retrospective, dosimetric study to evaluate the relationship between hearing loss after stereotactic radiosurgery (SRS) and the dose-volume of irradiated cochlea. METHODS: Cochlear dose data were retrospectively collected on consecutive patients who underwent SRS (18 Gy in 3 sessions) for vestibular schwannoma between 1999 and 2005 at Stanford University Hospital. Inclusion criteria included Gardner-Robertson (GR) grade I or II hearing prior to radiosurgical treatment, complete audiograms, and magnetic resonance imaging (MRI) follow-up. A cochlea dose-volume histogram was generated for each of the 94 patients who qualified for this study. RESULTS: GR grade I-II hearing posttreatment was maintained in 74% of patients (70/94). Median time to last follow-up audiogram was 2.4 years (range 0.4-8.9) and to last MRI was 3.6 years (range 0.5-9.4). Each higher level of cochlear irradiation was associated with increased risk of hearing loss. Larger cochlear volume was associated with lower risk of hearing loss. Controlling for differences in cochlear volume among subjects, each additional mm(3) of cochlea receiving 10 to 16 Gy (single session equivalent doses of 6.6-10.1 Gy3) significantly increased the odds of hearing loss by approximately 5%. CONCLUSIONS: Larger cochlear volume is associated with lower risk of hearing loss following trisession SRS for vestibular schwannoma. Controlling for this phenomenon, higher radiation dose and larger irradiated cochlear volume are significantly associated with higher risk of hearing loss. This study confirms and quantifies the risk of hearing loss following trisession SRS for vestibular schwannoma. PMID- 22484771 TI - Minimally invasive intradural spinal dural arteriovenous fistula ligation. AB - BACKGROUND: Dural arteriovenous fistulas (DAVFs) have traditionally been approached through a bilateral laminectomy procedure with intradural exploration and ligation of the fistulae. A minimally invasive approach for DAVF ligation may be associated with fewer complications and a shorter recovery than the traditional laminectomy procedure. Our objective was to determine the feasibility, safety, and efficacy of intradural DAVF ligation via the use of a minimally invasive microsurgical technique. METHODS: Seven patients with thoracolumbar DAVFs were microsurgically treated with a minimally invasive technique. The procedure entailed localization with the use of fluoroscopy followed by a midline 2.2-cm skin opening. Exposure was facilitated by the use of a tubular retractor. Intradural access was obtained after hemilaminectomy, and the fistula was identified and ligated. Dural closure was facilitated by the use of self-closing nitinol clips. The incidence of postoperative complications, blood loss, and length of hospital stay were reviewed. RESULTS: Each patient tolerated the procedure well. There were no intraoperative or postoperative complications. Specifically, there were no new neurological deficits and no cerebrospinal fluid leaks. Each patient was ambulatory within 18 hours with only mild incisional back pain. Mean length of stay was 1.6 days. One-year follow-up demonstrated obliteration of the fistula with improvement or stabilization of neurological deficits in all cases. CONCLUSIONS: The minimally invasive approach for intradural ligation of DAVFs appears to be a reasonable alternative to bilateral full laminectomies. Although no direct comparison with the more extensive bilateral laminectomy approach has been performed, our initial experience suggests that this novel approach may reduce blood loss and length of hospital stay. PMID- 22484772 TI - Improvement happens: doctors talk about the medical home. An interview with Charles Mayer, MD, MPH and Eric Seaver, MD. Interview by Robert J. Reid and Eric B. Larson. PMID- 22484773 TI - Bradykinin in the treatment of arterial hypertension: friend or foe? PMID- 22484774 TI - Leukocyte labile iron pool in patients with systolic heart failure. AB - INTRODUCTION: Data regarding sources of oxidative stress in the failing myocardium are sparse. Leukocytes actively participate in the oxidative damage observed in human heart failure (HF). The intracellular labile iron pool (LIP) represents a source of toxic reactive oxygen species. METHODS: We studied patients with chronic systolic HF who had a left ventricular ejection fraction (LVEF) 45%. We examined the LIP status in different populations of leukocytes in HF patients and we investigated its association with clinical and laboratory parameters, including conventional inflammatory markers. RESULTS: Sixty patients were finally included in the analysis (mean age: 67 +/- 11 years, 54 men, 42 with ischemic cardiomyopathy). The multivariate logistic regression analysis showed that only LIP in granulocytes (OR: 0.73; 95% CI: 0.55-0.98; p=0.039) and right ventricular systolic pressure (RVSP) (OR: 0.95; 95% CI: 0.92-0.99; p=0.027) were independently associated with severe LV systolic dysfunction (LVEF30%). The correlation analysis revealed that LVEF was inversely associated with LIP in granulocytes (Spearman's rho: -0.39, p=0.002), LIP in monocytes (Spearman's rho: 0.35, p=0.007), and RVSP (Spearman's rho: -0.43, p=0.003). No significant correlation between LVEF and inflammatory indexes was noted. CONCLUSIONS: LIP in granulocytes is independently associated with the severity of LV dysfunction in patients with systolic HF. Intracellular redox active iron may represent a source of leukocyte reactive oxygen species in this setting. PMID- 22484775 TI - The effect of propranolol on aortic structure and function in normotensive rats. AB - INTRODUCTION: Beta-blocking agents are widely used for the treatment of many cardiovascular diseases. The effect of these agents, however, on the aortic wall structure and function has not been well defined. The present study was undertaken to investigate the effect of therapy with propranolol on wall structure and aortic function in rats. METHODS: 20 healthy Wistar rats (350-400 g) were assigned to a control group (n=8), with rats receiving only water and food, and an experimental group (n=12), in which 100 mg/kg/day propranolol was administered in the drinking water. Three months after initiation of treatment, aortic pressures and aortic pulse wave velocity (PWV) were measured using high fidelity Millar catheters. Extensive histopathologic studies were performed in the wall of the descending thoracic aorta. RESULTS: Systolic, mean, diastolic, and pulse pressure were significantly lower in the propranolol-treated rats compared to controls (p<0.05). For any given systolic, mean, and pulse pressure, PWV was greater in the propranolol-treated animals (p<0.05). The heart rate was lower and the response to isoproterenol infusion was less in the propranolol treated animals. Smooth muscle content was decreased and collagen content was increased in the aortic wall of the propranolol-treated animals compared to controls. CONCLUSIONS: Long-term propranolol administration elicits an increase in PWV adjusted for aortic pressure. This may be related to accumulation of collagen in the aortic wall at the expense of smooth muscle cells. The aortic stiffening may explain some of the reported data, suggesting that the effect of beta-blockade therapy in patients with arterial hypertension may be inferior to other pharmacologic agents. PMID- 22484776 TI - Radiofrequency ablation procedures in Greece: initial experience and results from the national registry 2008-2010. AB - INTRODUCTION: In 2008 the radiofrequency ablation procedures (RFA) registry of the Hellenic Cardiological Society (HCS) was created. This is a dynamic, web based application, which acts as the interface for storing and retrieving patients' demographic data and ablation procedures. Access to the site is permitted only to registered users. The purpose of this study is to report the results of RFA procedures performed in Greece over the 2008-2010 period. METHODS: There are 27 centers in 24 hospitals that are licensed to perform RFA in Greece. During the period 2008-2010, 3541 RFA procedures were performed in 3344 patients in 23 centers. Four centers did not contribute data at all for various reasons. It is interesting that nearly 50% of the total number of procedures were performed at 3 high volume centers (>100 cases/year). RESULTS: The most common procedure was slow pathway ablation for atrioventricular reentrant tachycardia, the second was ablation of accessory pathway related tachycardias, and the third was ablation of atrial fibrillation. Success rates were high (92.1%), the complication rate was 3% (serious complications <1%) and total relapse rate was 8.7% at six months' follow up. CONCLUSIONS: The electronic RFA registry in Greece confirmed that all RFA procedures are performed in Greece with high success and low complication rates, comparable to the European and US standards. The experience and results from the first three-year period using the registry are very interesting and encouraging, thus indicating the need for development of similar databases at the national level. PMID- 22484777 TI - Inadequate heart rate control is associated with worse quality of life in patients with coronary artery disease and chronic obstructive pulmonary disease. The RYTHMOS study. AB - INTRODUCTION: Significant evidence shows that elevated heart rate (HR) is an independent risk factor in patients with coronary artery disease (CAD) and influences their prognosis. In addition, patients with chronic obstructive pulmonary disease (COPD) have more frequent episodes of angina and their compliance with heart rate agents, such as beta blockers, is poor. The purpose of the multicenter observational RYTHMOS study was to evaluate the role of heart rate management in the prognosis and quality of life in patients with CAD and COPD. METHODS: Baseline data from 280 patients, enrolled in 22 hospitals representing all types of hospital and all geographical areas of the country, were analyzed. All patients had either a prior myocardial infarction or angiographically documented CAD, and COPD verified either after spirometry or from a clinical evaluation by pulmonologists. RESULTS: The mean age of the enrolled patients was 71.8 +/- 9.3 years, 76% were males, mean body mass index was 28.6 +/- 7.9 kg/m2, 76.3% had hypertension, 31% had diabetes mellitus, and 53.5% of them suffered from heart failure. About 31% of the patients had an angina episode the week before the enrollment and the Canadian Cardiovascular Society (CSS) classification was class I, II, III and IV in 55%, 30%, 14% and 1%, respectively. The mean resting HR was 72.5 bpm; 51% of the patients had resting HR>70 bpm and 22% of them had HR80 bpm. Only 52.8% of the study patients were receiving beta-blockade (BB) therapy; they were more likely to have resting HR70 bpm (57.4% vs. 42.7%, p<0.001). 16.4% of the patients were receiving ivabradine and they had a higher initial HR compared to the others (78.5 vs. 71.3, p<0.001). Multivariate analysis showed that diabetes mellitus was independently associated with HR>70 bpm. Patients with resting HR>70 bpm had significantly more frequent angina episodes (p<0.001), were less satisfied with treatment (p<0.001), and had a lower quality of life (p<0.001). CONCLUSION: The baseline data of this study showed that patients with CAD and COPD present inadequate HR control and frequent angina episodes. Apart from the special characteristics of these patients related to COPD management, underuse of BB therapy largely contributes to the inadequate control of HR. Patients with HR>70 bpm had significantly worse quality of life. PMID- 22484778 TI - "First, do no harm": chemotherapy or healthy heart? PMID- 22484779 TI - Novel oral anticoagulants in atrial fibrillation: will the benefit outweigh the cost? PMID- 22484780 TI - Myocarditis in systemic diseases and the role of cardiovascular magnetic resonance. PMID- 22484781 TI - Three-dimensional coronary tomographic reconstructions using in vivo intracoronary optical frequency domain imaging in the setting of acute myocardial infarction: the clinical perspective. PMID- 22484782 TI - Severe superior vena cava obstruction: a late complication of pacemaker implantation. PMID- 22484783 TI - Cryptogenic stroke after percutaneous closure of an atrial septal defect. AB - We present the case of a patient who underwent a percutaneous secundum atrial septal defect (ASD II) closure with an undersized septal occluder device. One week and one month later she experienced two transient ischemic attacks. Three dimensional transesophageal echocardiography (TEE) revealed a residual patent foramen ovale (PFO) with a positive Valsalva bubble test. She underwent a second procedure under the 3D TEE guidance and the PFO was successfully closed percutaneously using a PFO occluder device that was attached to the ASD device. Accurate ASD and PFO morphology assessment and appropriate device selection are the key factors in the success of percutaneous closure. 3D TEE is an innovative diagnostic technique, providing a complete description of the cardiac defect and improving spatial orientation. Real-time 3D TEE is the appropriate guidance for successful and accurate positioning of the device. PMID- 22484784 TI - The role of biventricular assistance in primary graft failure after heart transplantation. AB - A 37-year-old man suffered from systolic heart failure as a result of idiopathic dilated cardiomyopathy since 1995 and was followed up in our cardiology department. In June 2006, the patient arrived at our outpatient clinic with an acute renal impairment and all manifestations of acute heart failure. He was already registered on the waiting list for heart transplantation (Eurotransplant) as a highly urgent request. The patient underwent heart transplantation but the reperfused allograft was totally akinetic and we decided to place a biventricular assist device immediately. The patient fully recovered after seven days of biventricular circulatory support and was discharged on the 38th day after the transplantation. Three years later, he is in good general condition without any manifestation of rejection. We conclude that biventricular assist device implantation is a good indication after post-cardiotomy failure and it should be started as early as possible before shock and possible irreversible organ damage. PMID- 22484785 TI - The use of the multi-electrode duty-cycled radiofrequency ablation catheter PVAC for the ablation of a left atrial tachycardia. AB - The multi-electrode ablation catheter PVAC is used to simplify pulmonary vein isolation in patients undergoing ablation of atrial fibrillation. The use of the PVAC in cases of atrial tachycardia has not been reported before. In the present report, we present the use of the PVAC for the ablation of a left atrial tachycardia following pulmonary vein isolation. This case may suggest that the PVAC could ablate some atrial tachycardias without any adjunctive ablation catheter, given its ability to map, pace and apply energy over a relatively broad area. PMID- 22484786 TI - Primary angioplasty programme in Greece. PMID- 22484787 TI - Cardiovascular medicine in 2025: assessments and priorities. PMID- 22484788 TI - Distributed lag associations between respiratory illnesses and mortality with suspended particle concentration in Tula, a highly polluted industrial region in Central Mexico. AB - PURPOSE: We aimed to evaluate the association between changes in airborne particulate matter concentration (PM) with changes in cases of mortality, acute respiratory infections (ARI) and asthma over 2004-2008 in an industrialized and polluted region in central Mexico. METHODS: A generalized linear model with a Poisson distribution and a negative binomial analysis was used to evaluate the influence of PM and temperature on all-cause mortality (All-cause-M), cause specific mortality (Cause-specific-M), ARI and asthma, using cubic spline functions and distributed lags of PM. Estimated changes in relative risk were calculated for an exposure corresponding to each increase of 10 MUg/m(3) in PM level. RESULTS: Associations between PM and mortality and morbidity were statistically most consistent for total suspended particulate (TSP) than for particulate matter <10 MUM aerodynamic diameter (PM10). The greatest effects in mortality were observed with a 3-week lag, and effects were greater for Cause specific-M. We also found a displacement effect up to 4-week lag for Cause specific-M and TSP. The greatest effects in morbidity were observed at 0-week lag, yet they were statistically marginal and were greater for asthma. We found a displacement effect at 4-5-6-week lag for asthma and TSP. All associations of mortality and morbidity, expressed as change in relative risk, were greater with PM10; however, all of them were statistically marginal. CONCLUSIONS: Increased respiratory morbidity and mortality is associated with weekly changes of PM air pollution in the region. A reduction in air pollutants from industrial sources would benefit life quality and health of the exposed population. PMID- 22484789 TI - Investigation of the influence of reflection on the attenuation of cancellous bone. AB - The model proposed in this paper is based on the fact that the reflection might have a significant contribution to the attenuation of the acoustic waves propagating through the cancellous bone. The numerical implementation of the mentioned effect is realized by the development of a new representative volume element that includes an infinitesimally thin 'transient' layer on the contact surface of the bone and the marrow. This layer serves to model the amplitude transformation of the incident wave by the transition through media with different acoustic impedances and to take into account the energy loss due to the reflection. The proposed representative volume element together with the multiscale finite element is used to simulate the wave propagation and to evaluate the attenuation coefficient for samples with different effective densities in the dependence of the applied excitation frequency. The obtained numerical values show a very good agreement with the experimental results. Moreover, the model enables the determination of the upper and the lower bound for the attenuation coefficient. PMID- 22484790 TI - Identification and expression of C2H2 transcription factor genes in Carica papaya under abiotic and biotic stresses. AB - C2H2 proteins belong to a group of transcription factors (TFs) existing as a superfamily that plays important roles in defense responses and various other physiological processes in plants. The present study aimed to screen for and identify C2H2 proteins associated with defense responses to abiotic and biotic stresses in Carica papaya L. Data were collected for 47,483 papaya-expressed sequence tags (ESTs). The full-length cDNA nucleotide sequences of 87 C2H2 proteins were predicated by BioEdit. All 91 C2H2 proteins were aligned, and a phylogenetic tree was constructed using DNAman. The expression levels of 42 C2H2 were analyzed under conditions of salt stress by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Methyl jasmonate treatment rapidly upregulated ZF(23.4) and ZF(30,912.1) by 18.6- and 21.7-fold, respectively. ZF(1.3), ZF(138.44), ZF(94.49), ZF(29.160), and ZF(20.206) were found to be downregulated after low temperature treatment at very significant levels (p < 0.01). ZF(23.4), ZF(161.1), and ZF(30,912.1) were upregulated while ZF1.3, ZF(158.1), ZF(249.5), ZF(138.44), ZF(94.49), ZF(29.160), and ZF(20.206) were significantly downregulated by Spermine treatment. ZF(23.4) was upregulated while ZF(1.3), ZF(249.5), ZF(94.94), ZF(29.160), ZF(138.44), and ZF(20.206) were significantly repressed after SA treatment. ZF(23.4) and ZF(30,912.1) were significantly upregulated after sap inoculation with papaya ringspot virus pathogen. ZF(30,912.1) was subcellularly localized in the nucleus by a transgenic fusion of pBS-ZF(30,912.1)-GFP into the protoplast of papaya. The results of the present study showed that ZF(30,912.1) could be an important TF that mediates responses to abiotic and biotic stresses in papaya. PMID- 22484792 TI - Leisure activities in Prader-Wili syndrome: implications for health, cognition and adaptive functioning. AB - Although hyperphagia and compulsivity in Prader-Willi syndrome (PWS) are well described, recreation and adaptive skills are relatively unexplored. Parents of 123 participants with PWS (4-48 years) completed measures of their child's adaptive, recreation, and problem behaviors. Offspring received cognitive testing. Watching TV was the most frequent recreational activity, and was associated with compulsivity and skin picking. BMIs were negatively correlated with physical play, and highest in those who watched TV and played computer games. Computer games and physical activities were associated with higher IQ and adaptive scores. People with PWS and other disabilities need to watch less TV and be more engaged in physical activities, games, and leisure pursuits that are fun, and may bring cognitive or adaptive advantages. PMID- 22484793 TI - Network characteristics, perceived social support, and psychological adjustment in mothers of children with autism spectrum disorder. AB - This study examined the characteristics of the support networks of 106 mothers of children with ASD and their relationship to perceived social support, depressed mood, and subjective well-being. Using structural equation modeling, two competing sets of hypotheses were assessed: (1) that network characteristics would impact psychological adjustment directly, and (2) that network effects on adjustment would be indirect, mediated by perceived social support. Results primarily lent support to the latter hypotheses, with measures of network structure (network size) and function (proportion of network members providing emotional support) predicting increased levels of perceived social support which, in turn, predicted decreased depressed mood and increased well-being. Results also indicated that increased interpersonal strain in the maternal network was directly and indirectly associated with increased maternal depression, while being indirectly linked to reduced well-being. Study limitations and implications are discussed. PMID- 22484794 TI - Predicting developmental status from 12 to 24 months in infants at risk for Autism Spectrum Disorder: a preliminary report. AB - The study examined whether performance profiles on individual items of the Toddler Module of the Autism Diagnostic Observation Schedule at 12 months are associated with developmental status at 24 months in infants at high and low risk for developing Autism Spectrum Disorder (ASD). A nonparametric decision-tree learning algorithm identified sets of 12-month predictors of developmental status at 24 months. Results suggest that identification of infants who are likely to exhibit symptoms of ASD at 24 months is complicated by variable patterns of symptom emergence. Fine-grained analyses linking specific profiles of strengths and deficits with specific patterns of symptom emergence will be necessary for further refinement of screening and diagnostic instruments for ASD in infancy. PMID- 22484795 TI - The Tolz Temporal Topography Study: mapping the visual field across the life span. Part I: the topography of light detection and temporal-information processing. AB - Temporal performance parameters vary across the visual field. Their topographical distributions relative to each other and relative to basic visual performance measures and their relative change over the life span are unknown. Our goal was to characterize the topography and age-related change of temporal performance. We acquired visual field maps in 95 healthy participants (age: 10-90 years): perimetric thresholds, double-pulse resolution (DPR), reaction times (RTs), and letter contrast thresholds. DPR and perimetric thresholds increased with eccentricity and age; the periphery showed a more pronounced age-related increase than the center. RT increased only slightly and uniformly with eccentricity. It remained almost constant up to the age of 60, a marked change occurring only above 80. Overall, age was a poor predictor of functionality. Performance decline could be explained only in part by the aging of the retina and optic media. In Part II, we therefore examine higher visual and cognitive functions. PMID- 22484796 TI - Size-brightness correspondence: crosstalk and congruity among dimensions of connotative meaning. AB - Following Karwoski, Odbert, and Osgood (Journal of General Psychology 26:199-222, 1942), in the present article, cross-sensory correspondences are proposed to reflect the alignment of, and extensive bidirectional cross-activation among, dimensions of connotative meaning. The size-brightness correspondence predicted on this basis (in which smaller is aligned with brighter) was confirmed in two ways. First, when participants explored three wooden balls of different size by touch alone and indicated how bright they thought each of them was, the smaller ball was judged to be brighter than the bigger ball. Second, when these two balls served as response keys in a speeded brightness-classification task, participants were quicker and more likely to be correct when confirming that a stimulus was bright (dark) when this required them to press the smaller (bigger) key, than when it required them to press the bigger (smaller) key. This congruity effect originated from interactions embedded in the later stages of information processing concerned with stimulus classification and response selection. These results, together with the observation that the cross-sensory features associated with smallness are the same as those associated with higher pitch sounds (i.e., both attributes are more active, brighter, faster, lighter in weight, quieter, sharper, and weaker than their opposites), support the suggestion that there exists a core set of cross-sensory correspondences that emerges whichever stimulus feature is used to probe it. PMID- 22484797 TI - Comparison of the gut microbe profiles and numbers between patients with liver cirrhosis and healthy individuals. AB - Human liver was closely associated with gut through various biological mechanisms, such as bacterium-gut interactions. Alterations of gut microbiota seemed to play an important role in induction and promotion of liver damage progression. The aim of this study was to characterize the gut microbiota in liver cirrhosis patients and assess whether there are alterations in the diversity and similarity of intestinal flora in cirrhotic patients when compared with healthy individuals. PCR-denaturing gradient gel electrophoresis (DGGE) with universal primers targeting V3 region of the 16S rRNA gene was employed to characterize the overall intestinal microbiota composition, and some excised gel bands were cloned for sequencing. Real-time PCR was further utilized to quantitatively analyze the subpopulation of microbiota using group-specific primers targeting the Enterobacteriaceae, Enterococcus and Bifidobacterium genus. The DGGE profiles of two groups demonstrated significant differences between cirrhotic and healthy groups (P < 0.05). While real-time PCR revealed significant increase of Enterobacteriaceae and Enterococcus (P < 0.05) in the cirrhotic group compared with the healthy group. The ratio of Bifidobacterium genus and Enterobacteriaceae decreased in the cirrhotic patients group, but no statistical significance. This study revealed strong relationship between alterations of gut microbiota and liver cirrhosis. PMID- 22484798 TI - Comparison of bioconcentration and biomagnification factors for poorly water soluble chemicals using common carp (Cyprinus carpio L.). AB - Existing regulatory criteria for bioaccumulation assessment of chemicals are mainly based on a bioconcentration factors (BCF) not a biomagnification factors (BMF). We performed dietary exposure tests for nine poorly water-soluble chemicals and developed a linear regression between the 5 % lipid normalized BCF (BCF(L)) and the lipid-corrected BMF (BMF(L)). The BMF(L) of substances with BCF(L) = 5,000 was 0.31 (95 % CI 0.11-0.87), whereas the BCF(L) of substances with BMF(L) = 1 was 13,000 (95 % CI 5,600-30,000). Five substances can be considered very bioaccumulative (vB) according to the BCF end point (BCF > 5,000), but only two substances were recognized to biomagnify according to the BMF end point (BMF >= 1). Although our results are highly suggestive of a relationship between BCF and BMF, additional BMF and trophic magnification factor data for chemicals are required to support this relationship, and new techniques (e.g., fugacity approach) may help in resolving the apparent contradiction in hazard categorization. PMID- 22484799 TI - Breast cancer incidence in postmenopausal women with osteoporosis or low bone mass using arzoxifene. AB - The Generations trial, a multicenter, placebo-controlled, double-blind trial, compared arzoxifene 20 mg/day and placebo in 9,354 postmenopausal women with osteoporosis (N=5,252) or low bone mass (N=4,102). Primary outcomes were vertebral fracture in the osteoporotic population and invasive breast cancer in all study participants. Here, we report the detailed breast cancer findings from the trial. Breast cancers were detected by annual mammograms and clinical examination. After 48 months follow-up, breast cancer incidence was compared between treatment groups by estrogen receptor (ER) and progesterone receptor (PR) status and baseline risk factors. Baseline breast cancer risk factors, including age, estimated Gail risk, and bone mineral density, were well balanced between treatment groups. A total of 75 breast cancers occurred 53 in the placebo group and 22 in the arzoxifene group (HR 0.41, 95% CI 0.25-0.68, P<0.001). There were 62 invasive breast cancers, 39 identified as invasive ER-positive (placebo 30, arzoxifene 9; HR 0.30, 95% CI 0.14-0.63, P=0.001) and 30 identified as invasive PR-positive (placebo 23, arzoxifene 7; HR 0.30, 95% CI 0.13-0.71, P=0.003). Breast cancer risk reduction with arzoxifene was similar between Gail risk groups (P interaction=0.31) and between low bone mass and osteoporosis groups (P interaction=0.35). Although generally well tolerated, there was a significant increase in venous thromboembolism, vasomotor symptoms, muscle cramps, and some gynecological events with arzoxifene. These findings demonstrate that in this study arzoxifene reduced the risk of ER-positive breast cancer in this population of postmenopausal women with low bone mass or osteoporosis, an effect similar to that seen with other SERMs. PMID- 22484800 TI - Quality of life over time in women diagnosed with ductal carcinoma in situ, early stage invasive breast cancer, and age-matched controls. AB - Little is known about quality-of-life (QOL) differences over time between incident ductal carcinoma in situ (DCIS) and early-stage invasive breast cancer (EIBC) cases as compared with same-aged women without breast cancer (controls). We prospectively recruited and interviewed 1,096 women [16.8% DCIS, 33.3% EIBC (25.7% Stage I; and 7.6% Stage IIA), 49.9% controls; mean age 58; 23.7% non white] at mean 6.7 weeks (T1), and 6.2 (T2), 12.3 (T3), and 24.4 months (T4) after surgery (patients) or screening mammogram (controls). We tested two hypotheses: (1) DCIS patients would report lower levels of QOL compared with controls but would report similar QOL compared with EIBC patients at baseline; and (2) DCIS patients' QOL would improve during 2-year follow-up and approach levels similar to that of controls faster than EIBC patients. We tested hypothesis 1 using separate general linear regression models for each of the eight subscales on the RAND 36-item Health Survey, controlling for variables associated with at least one subscale at T1. Both DCIS and EIBC patients reported lower QOL at T1 than controls on all subscales (each P<0.05). We tested hypothesis 2 using generalized estimating equations to examine change in each QOL subscale over time across the three diagnostic groups adjusting for covariates. By T3, physical functioning, role limitations due to physical problems, energy/fatigue, and general health each differed significantly by diagnostic group at P<0.05, because of larger differences between EIBC patients and controls; but DCIS patients no longer differed significantly from controls on any of the QOL subscales. At T4, EIBC patients still reported worse physical functioning (P=0.0001) and general health (P=0.0017) than controls, possibly because of lingering treatment effects. DCIS patients' QOL was similar to that of controls two years after diagnosis, but some aspects of EIBC patients' QOL remained lower. PMID- 22484801 TI - Bacterial cell surface structures in Yersinia enterocolitica. AB - Yersinia enterocolitica is a widespread member of the family of Enterobacteriaceae that contains both non-virulent and virulent isolates. Pathogenic Y. enterocolitica strains, especially belonging to serotypes O:3, O:5,27, O:8 and O:9 are etiologic agents of yersiniosis in animals and humans. Y. enterocolitica cell surface structures that play a significant role in virulence have been subject to many investigations. These include outer membrane (OM) glycolipids such as lipopolysaccharide (LPS) and enterobacterial common antigen (ECA) and several cell surface adhesion proteins present only in virulent Y. enterocolitica, i.e., Inv, YadA and Ail. While the yadA gene is located on the Yersinia virulence plasmid the Ail, Inv, LPS and ECA are chromosomally encoded. These structures ensure the correct architecture of the OM, provide adhesive properties as well as resistance to antimicrobial peptides and to host innate immune response mechanisms. PMID- 22484802 TI - Prostate cancer and immunoproteome: awakening and reprogramming the guardian angels. AB - Prostate cancer is a life-threatening molecular disorder that is undruggable to date because of stumbling blocks in the standardization of therapy. An emerging framework of research is addressing how pathways that are derailed during tumorigenesis are linked to immunological responses, which are instrumental in immunosurveillance of cancer. However, interestingly, cancer cells circumvent such immunosurveillance through development of poorly immunogenic tumor cell variants (immunoselection) and through subversion of the immunological nanomachinery (immunosubversion). Detailed mechanistic insights of molecular specificities that regulate natural killer (NK) cell function suggest that it might be promising to design NK cell-based immunotherapeutic interventions against prostate cancer. Here, we elucidate evidence for NK cell targeting of prostate cancer proteome and address critical questions that, in our view, need thoughtfulness for the development of successful NK cell-based therapies. This review also disproves our contemporary understanding of the versatile regulators of DNA damage repair (ATM, ATR) that trigger cell surface expression of NKG2D ligands and consequent elimination of the tumor cells by NK cells and other lymphocytes that express NK cell receptors. Substantial fraction of information has been generated that guarantees productive future for this technology as more optimized constructs, better trial designs, and improved platforms are being brought from benchtop to bedside. PMID- 22484803 TI - Lactobacillus rhamnosus exopolysaccharide ameliorates arthritis induced by the systemic injection of collagen and lipopolysaccharide in DBA/1 mice. AB - Oral administration of some probiotic bacteria (e.g. Lactobacillus rhamnosus) attenuates various types of experimental arthritis, including collagen-induced arthritis (CIA) and inhibits arthritogenic autoantibodies. Much less is known about the possible anti-arthritogenic properties of exopolysaccharide (EPS), the major component of lactic bacteria biofilm. In this study, we asked the question whether systemic administration of EPS derived from L. rhamnosus KL37 depresses the production of anti-collagen IgG and affects the development of CIA in DBA/1 mice. Arthritis was induced employing two models of active CIA, in which mice were immunized with type II collagen (CII) either in the presence of lipopolysaccharide (LPS; mild arthritis with moderate CII-specific IgG production) or with Complete Freund's Adjuvant and LPS (severe arthritis with massive CII-specific IgG production). Passive CIA was induced by intravenous injection of CII-specific monoclonal antibodies and LPS. Disease progression, the incidence and severity of arthritis, were determined. Serum concentration of CII specific IgG was measured by enzyme-linked immunosorbent assay. Systemic administration of EPS markedly reduced CII-specific antibody production. Moreover, EPS significantly ameliorated arthritis in the active models of CIA, especially, when LPS alone was used as an adjuvant. In contrast, when arthritogenic antibodies were injected to mice in high amounts, the effect of EPS on the development of passive CIA was negligible and transient. These results show that EPS can suppress active CIA by the inhibition of arthritogenic antibodies production. Therefore, we suggest that EPS or EPS-producing probiotics may be promising agents for the supporting therapy of patients with rheumatoid arthritis. PMID- 22484804 TI - The role and regulation of mTOR in T-lymphocyte function. AB - The conversion of naive T cells into effector T cells is initiated by stimulation through the T-cell receptor (TCR). Upon activation, T cells undergo significant morphological and functional changes, putting new metabolic demands on the cell. Past research has identified the mammalian target of rapamycin (mTOR) as a critical regulator of cell metabolism, and the development of new genetic models has begun to reveal an important role for this pathway in the homeostasis and function of T lymphocytes. In this review, we focus on the most recent findings that demonstrate the ability of mTOR to regulate T-cell activation, CD8(+) memory cell formation and function, and helper T lineage differentiation. Furthermore, we highlight the importance of tight control of mTOR signaling by tuberous sclerosis complex 1 for T-cell homeostasis, and the regulation of mTOR signaling by diacylglycerol kinases and the RasGRP1-Ras-Erk1/2 pathway in the context of TCR signaling. PMID- 22484806 TI - Pharmacology and therapeutic potential of interferons. AB - Interferon (IFN) is widely recognised to be an integral part of the innate immune response to viral infection. Since its initial discovery in 1957 by Isaacs and Lindenmann, various IFN sub-types have been identified and there are now three distinct classes recognised-Type I (IFN-alpha and IFN-beta), Type II (IFN-gamma) and Type III (IFN-lambda), distinguished by their differing receptors. As well as displaying profound antiviral activity in vivo, IFN has anti-proliferative, cytotoxic and anti-tumoural roles. In an attempt to harness their immunomodulatory potential, investigators and clinicians have investigated the use of IFNs for the treatment of human diseases with considerable success. For example, IFN-alpha preparations are now a critical component in the treatment of chronic Hepatitis C infection and IFN-beta therapy is now the first line treatment for relapsing remitting multiple sclerosis. However, IFN therapy is also associated with significant morbidity and in some patients is poorly tolerated. In this review, we explore the scientific basis for IFN therapy and outline its therapeutic scope. We describe the commonly encountered side effects and attempt to explain the less well recognised pulmonary complications including emerging evidence of life threatening and irreversible pulmonary vascular pathology. Finally, we look to the future of interferon drug treatment, examining the potential for emerging therapies. PMID- 22484805 TI - Estrogen and the cardiovascular system. AB - Estrogen is a potent steroid with pleiotropic effects, which have yet to be fully elucidated. Estrogen has both nuclear and non-nuclear effects. The rapid response to estrogen, which involves a membrane associated estrogen receptor(ER) and is protective, involves signaling through PI3K, Akt, and ERK 1/2. The nuclear response is much slower, as the ER-estrogen complex moves to the nucleus, where it functions as a transcription factor, both activating and repressing gene expression. Several different ERs regulate the specificity of response to estrogen, and appear to have specific effects in cardiac remodeling and the response to injury. However, much remains to be understood about the selectivity of these receptors and their specific effects on gene expression. Basic studies have demonstrated that estrogen treatment prevents apoptosis and necrosis of cardiac and endothelial cells. Estrogen also attenuates pathologic cardiac hypertrophy. Estrogen may have great benefit in aging as an anti-inflammatory agent. However, clinical investigations of estrogen have had mixed results, and not shown the clear-cut benefit of more basic investigations. This can be explained in part by differences in study design: in basic studies estrogen treatment was used immediately or shortly after ovariectomy, while in some key clinical trials, estrogen was given years after menopause. Further basic research into the underlying molecular mechanisms of estrogen's actions is essential to provide a better comprehension of the many properties of this powerful hormone. PMID- 22484807 TI - Circadian rhythms, symptoms, physical functioning, and body mass index in breast cancer survivors. AB - INTRODUCTION: Research has been limited in circadian activity rhythms and their relationship with health status in early-stage breast cancer survivors. Maintaining strong circadian parameters may reduce symptoms and improve physical functioning and disease-free survival. METHODS: This is a descriptive, correlational, secondary analysis of data from a randomized controlled trial collected 1 year after the first chemotherapy treatment; n = 156 cases with 7 days of wrist actigraph data of six circadian activity rhythm parameters; measures of function, fatigue, sleep, and anxiety/depression; and demographic/medical data including body mass index (BMI). RESULTS: In the total sample and three BMI categories, acrophase was the only circadian parameter that reached means established in healthy adults. In the total sample, phase-delayed acrophase was associated with higher depression (r = 0.180, p = 0.025) and lower morning energy (r = -0.194, p = 0.016) and trended for higher fatigue (r = 0.153, p = 0.057). Lower morning energy was also associated with a lower circadian quotient (r = 0.158, p = 0.05). As BMI increased, weaker circadian parameters were recorded consistently. When compared with women in normal BMI categories, obese women's amplitude and 24-h autocorrelation coefficient were significantly weaker (p = 0.011-0.015). In obese women, phase-delayed acrophase was correlated with higher fatigue and anxiety and with lower morning energy and physical functioning. DISCUSSION/CONCLUSIONS: Amplitude and 24-h autocorrelation parameters were significantly weaker, and phase-delayed acrophase was linked to several more intense symptoms and lower physical functioning in obese women. IMPLICATIONS FOR CANCER SURVIVORS: Clinicians need to target high-risk women with phase-delayed rhythms, higher symptoms, and lower physical functioning for intervention. PMID- 22484809 TI - Unbiased identification of target antigens of CD8+ T cells with combinatorial libraries coding for short peptides. AB - Cytotoxic CD8(+) T cells recognize the antigenic peptides presented by class I major histocompatibility complex (MHC) molecules. These T cells have key roles in infectious diseases, autoimmunity and tumor immunology, but there is currently no unbiased method for the reliable identification of their target antigens. This is because of the low affinities of antigen-specific T cell receptors (TCR) to their target MHC-peptide complexes, the polyspecificity of these TCRs and the requirement that these TCRs recognize protein antigens that have been processed by antigen-presenting cells (APCs). Here we describe a technology for the unbiased identification of the antigenic peptides presented by MHC class I molecules. The technology uses plasmid-encoded combinatorial peptide libraries and a single-cell detection system. We validated this approach using a well characterized influenza-virus-specific TCR, MHC and peptide combination. Single APCs carrying antigenic peptides can be detected among several million APCs that carry irrelevant peptides. The identified peptide sequences showed a converging pattern of mimotopes that revealed the parent influenza antigen. This technique should be generally applicable to the identification of disease-relevant T cell antigens. PMID- 22484808 TI - NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components. AB - Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. Drusen accumulation is the major pathological hallmark common to both dry and wet AMD. Although activation of the immune system has been implicated in disease progression, the pathways involved are unclear. Here we show that drusen isolated from donor AMD eyes activates the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, causing secretion of interleukin-1b (IL-1b) and IL-18. Drusen component C1Q also activates the NLRP3 inflammasome. Moreover, the oxidative-stress-related protein-modification carboxyethylpyrrole (CEP), a biomarker of AMD, primes the inflammasome. We found cleaved caspase-1 and NLRP3 in activated macrophages in the retinas of mice immunized with CEP-adducted mouse serum albumin, modeling a dry-AMD-like pathology. We show that laser-induced choroidal neovascularization (CNV), a mouse model of wet AMD, is exacerbated in Nlrp3(-/-) but not Il1r1(-/-) mice, directly implicating IL-18 in the regulation of CNV development. These findings indicate a protective role for NLRP3 and IL-18 in the progression of AMD. PMID- 22484811 TI - Treating myeloma cast nephropathy without treating myeloma. AB - Cast nephropathy is the result of coprecipitation of immunoglobulin free light chains (FLCs) with Tamm-Horsfall glycoprotein (THP). It is a hallmark of multiple myeloma that has significant consequences. Treatment strategies in the past focused on reduction of serum FLC by control of the myeloma. In this issue, Ying et al. report on their successful synthesis of a cyclized competitor peptide that blocks the binding of FLC to THP. In animal studies, this cyclized peptide was capable of reducing cast formation and kidney injury, representing a novel treatment strategy for cast nephropathy that does not depend on the responsiveness of the myeloma to chemotherapy. PMID- 22484810 TI - RNA-mediated gene silencing in Candida albicans: inhibition of hyphae formation by use of RNAi technology. AB - The introduction of RNA silencing machinery in fungi has led to the promising application of RNAi methodology to knock down essential vital factor or virulence factor genes in the microorganisms. Efg1p is required for development of a true hyphal growth form which is known to be essential for interactions with human host cells and for the yeast's pathogenesis. In this paper, we describe the development of a system for presenting and studying the RNAi function on the EFG1 gene in C. albicans. The 19-nucleotide siRNA was designed on the basis of the cDNA sequence of the EFG1 gene in C. albicans and transfection was performed by use of a modified-PEG/LiAc method. To investigate EFG1 gene silencing in siRNA treated cells, the yeasts were grown in human serum; to induce germ tubes a solid medium was used with the serum. Quantitative changes in expression of the EFG1 gene were analyzed by measuring the cognate EFG1 mRNA level by use of a quantitative real-time RT-PCR assay. Compared with the positive control, true hyphae formation was significantly reduced by siRNA at concentrations of 1 MUM, 500 nM, and 100 nM (P < 0.05). In addition, siRNA at a concentration of 1 MUM was revealed to inhibit expression of the EFG1 gene effectively (P < 0.05). On the basis of the potential of post-transcriptional gene silencing to control the expression of specific genes, these techniques may be regarded as promising means of drug discovery, with applications in biomedicine and functional genomics analysis. PMID- 22484812 TI - Comparing human pancreatic cell secretomes by in vitro aptamer selection identifies cyclophilin B as a candidate pancreatic cancer biomarker. AB - Most cases of pancreatic cancer are not diagnosed until they are no longer curable with surgery. Therefore, it is critical to develop a sensitive, preferably noninvasive, method for detecting the disease at an earlier stage. In order to identify biomarkers for pancreatic cancer, we devised an in vitro positive/negative selection strategy to identify RNA ligands (aptamers) that could detect structural differences between the secretomes of pancreatic cancer and non-cancerous cells. Using this molecular recognition approach, we identified an aptamer (M9-5) that differentially bound conditioned media from cancerous and non-cancerous human pancreatic cell lines. This aptamer further discriminated between the sera of pancreatic cancer patients and healthy volunteers with high sensitivity and specificity. We utilized biochemical purification methods and mass-spectrometric analysis to identify the M9-5 target as cyclophilin B (CypB). This molecular recognition-based strategy simultaneously identified CypB as a serum biomarker and generated a new reagent to recognize it in body fluids. Moreover, this approach should be generalizable to other diseases and complementary to traditional approaches that focus on differences in expression level between samples. Finally, we suggest that the aptamer we identified has the potential to serve as a tool for the early detection of pancreatic cancer. PMID- 22484813 TI - Cooperation between Rb and Arf in suppressing mouse retinoblastoma. AB - Retinoblastoma is a pediatric cancer that has served as a paradigm for tumor suppressor gene function. Retinoblastoma is initiated by RB gene mutations, but the subsequent cooperating mutational events leading to tumorigenesis are poorly characterized. We investigated what these additional genomic alterations might be using human retinoblastoma samples and mouse models. Array-based comparative genomic hybridization studies revealed deletions in the CDKN2A locus that include ARF and P16INK4A, both of which encode tumor suppressor proteins, in both human and mouse retinoblastoma. Through mouse genetic analyses, we found that Arf was the critical tumor suppressor gene in the deleted region. In mice, inactivation of one allele of Arf cooperated with Rb and p107 loss to rapidly accelerate retinoblastoma, with frequent loss of heterozygosity (LOH) at the Arf locus. Arf has been reported to exhibit p53-independent tumor suppressor roles in other systems; however, our results showed no additive effect of p53 and Arf coinactivation in promoting retinoblastoma. Moreover, p53 inactivation completely eliminated any selection for Arf LOH. Thus, our data reveal important insights into the p53 pathway in retinoblastoma and show that Arf is a key collaborator with Rb in retinoblastoma suppression. PMID- 22484814 TI - Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice. AB - Current interventions for arresting autoimmune diabetes have yet to strike the balance between sufficient efficacy, minimal side effects, and lack of generalized immunosuppression. Introduction of antigen via the gut represents an appealing method for induction of antigen-specific tolerance. Here, we developed a strategy for tolerance restoration using mucosal delivery in mice of biologically contained Lactococcus lactis genetically modified to secrete the whole proinsulin autoantigen along with the immunomodulatory cytokine IL-10. We show that combination therapy with low-dose systemic anti-CD3 stably reverted diabetes in NOD mice and increased frequencies of local Tregs, which not only accumulated in the pancreatic islets, but also suppressed immune response in an autoantigen-specific way. Cured mice remained responsive to disease-unrelated antigens, which argues against excessive immunosuppression. Application of this therapeutic tool achieved gut mucosal delivery of a diabetes-relevant autoantigen and a biologically active immunomodulatory cytokine, IL-10, and, when combined with a low dose of systemic anti-CD3, was well tolerated and induced autoantigen specific long-term tolerance, allowing reversal of established autoimmune diabetes. Therefore, we believe this method could be an effective treatment strategy for type 1 diabetes in humans. PMID- 22484815 TI - Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model. AB - A common renal complication of multiple myeloma is "myeloma kidney," a condition also known as cast nephropathy. The renal lesions (casts) are directly related to the production of monoclonal immunoglobulin free light chains (FLCs), which coprecipitate with Tamm-Horsfall glycoprotein (THP) in the lumen of the distal nephron, obstructing tubular fluid flow. Here, we report that analysis of the binding interaction between FLCs and THP demonstrates that the secondary structure and key amino acid residues on the complementarity-determining region 3 (CDR3) of FLCs are critically important determinants of the molecular interaction with THP. The findings permitted development of a cyclized competitor peptide that demonstrated strong inhibitory capability in the binding of FLCs to THP in vitro. When used in a rodent model of cast nephropathy, this cyclized peptide construct served as an effective inhibitor of intraluminal cast formation and prevented the functional manifestations of acute kidney injury in vivo. These experiments provide proof of concept that intraluminal cast formation is integrally involved in the pathogenesis of acute kidney injury from cast nephropathy. Further, the data support a clinically relevant approach to the management of renal failure in the setting of multiple myeloma. PMID- 22484816 TI - Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. AB - Cancer development, progression, and metastasis are highly dependent on angiogenesis. The use of antiangiogenic drugs has been proposed as a novel strategy to interfere with tumor growth, but cancer cells respond by developing strategies to escape these treatments. In particular, animal models show that antiangiogenic drugs currently used in clinical settings reduce tumor tissue oxygenation and trigger molecular events that foster cancer resistance to therapy. Here, we show that semaphorin 3A (Sema3A) expression overcomes the proinvasive and prometastatic resistance observed upon angiogenesis reduction by the small-molecule tyrosine inhibitor sunitinib in both pancreatic neuroendocrine tumors (PNETs) in RIP-Tag2 mice and cervical carcinomas in HPV16/E2 mice. By improving cancer tissue oxygenation and extending the normalization window, Sema3A counteracted sunitinib-induced activation of HIF-1alpha, Met tyrosine kinase receptor, epithelial-mesenchymal transition (EMT), and other hypoxia dependent signaling pathways. Sema3A also reduced tumor hypoxia and halted cancer dissemination induced by DC101, a specific inhibitor of the VEGF pathway. As a result, reexpressing Sema3A in cancer cells converts metastatic PNETs and cervical carcinomas into benign lesions. We therefore suggest that this strategy could be developed to safely harnesses the therapeutic potential of the antiangiogenic treatment. PMID- 22484817 TI - Liver LXRalpha expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice. AB - Liver X receptors (LXRalpha and LXRbeta) are important regulators of cholesterol and lipid metabolism, and their activation has been shown to inhibit cardiovascular disease and reduce atherosclerosis in animal models. Small molecule agonists of LXR activity are therefore of great therapeutic interest. However, the finding that such agonists also promote hepatic lipogenesis has led to the idea that hepatic LXR activity is undesirable from a therapeutic perspective. To investigate whether this might be true, we performed gene targeting to selectively delete LXRalpha in hepatocytes. Liver-specific deletion of LXRalpha in mice substantially decreased reverse cholesterol transport, cholesterol catabolism, and cholesterol excretion, revealing the essential importance of hepatic LXRalpha for whole body cholesterol homeostasis. Additionally, in a pro-atherogenic background, liver-specific deletion of LXRalpha increased atherosclerosis, uncovering an important function for hepatic LXR activity in limiting cardiovascular disease. Nevertheless, synthetic LXR agonists still elicited anti-atherogenic activity in the absence of hepatic LXRalpha, indicating that the ability of agonists to reduce cardiovascular disease did not require an increase in cholesterol excretion. Furthermore, when non-atherogenic mice were treated with synthetic LXR agonists, liver-specific deletion of LXRalpha eliminated the detrimental effect of increased plasma triglycerides, while the beneficial effect of increased plasma HDL was unaltered. In sum, these observations suggest that therapeutic strategies that bypass the liver or limit the activation of hepatic LXRs should still be beneficial for the treatment of cardiovascular disease. PMID- 22484818 TI - Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis. AB - Cooperativity between oncogenic mutations is recognized as a fundamental feature of malignant transformation, and it may be mediated by synergistic regulation of the expression of pro- and antitumorigenic target genes. However, the mechanisms by which oncogenes and tumor suppressors coregulate downstream targets and pathways remain largely unknown. Here, we used ChIP coupled to massively parallel sequencing (ChIP-seq) and gene expression profiling in mouse prostates to identify direct targets of the tumor suppressor Nkx3.1. Further analysis indicated that a substantial fraction of Nkx3.1 target genes are also direct targets of the oncoprotein Myc. We also showed that Nkx3.1 and Myc bound to and crossregulated shared target genes in mouse and human prostate epithelial cells and that Nkx3.1 could oppose the transcriptional activity of Myc. Furthermore, loss of Nkx3.1 cooperated with concurrent overexpression of Myc to promote prostate cancer in transgenic mice. In human prostate cancer patients, dysregulation of shared NKX3.1/MYC target genes was associated with disease relapse. Our results indicate that NKX3.1 and MYC coregulate prostate tumorigenesis by converging on, and crossregulating, a common set of target genes. We propose that coregulation of target gene expression by oncogenic/tumor suppressor transcription factors may represent a general mechanism underlying the cooperativity of oncogenic mutations during tumorigenesis. PMID- 22484819 TI - Impact of mechanical ventilation and fluid load on pulmonary glycosaminoglycans. AB - The combined effect of mechanical ventilation and fluid load on pulmonary glycasaminoglycans (GAGs) was studied in anaesthetized rats ((BW 290+/-21.8 (SE)g) mechanically ventilated for 4h: (a) at low (~7.5mlkg(-1)) or high (~23mlkg(-1)) tidal volume (V(T)) and zero alveolar pressure; (b) at low or high V(T) at 5cmH(2)O positive end-expiratory pressure (PEEP); (c) with or without 7mlkg(-1)h(-1) intravenous infusion of Phosphate Buffer Solution (PBS). Compared to spontaneous breathing, GAGs extractability decreased by 52.1+/-1.5% and 42.2+/ 7.3% in not-infused lungs mechanically ventilated at low V(T) or at high V(T) and PEEP, respectively. In contrast, in infused lungs, GAGs extractability increased by 56.1+/-4.0% in spontaneous ventilation and PEEP and up to 81.1% in all mechanically ventilated lungs, except at low V(T) without PEEP. In the absence of an inflammatory process, these results suggest that PEEP was protective at low but not at high V(T) when alveolar structures experience exceedingly high stresses. When combined to mechanical ventilation, fluid load might exacerbate edema development and lung injury. PMID- 22484820 TI - Practical considerations for in vivo MRI with higher dimensional spatial encoding. AB - OBJECT: This work seeks to examine practical aspects of in vivo imaging when spatial encoding is performed with three or more encoding channels for a 2D image. MATERIALS AND METHODS: The recently developed 4-Dimensional Radial In/Out (4D-RIO) trajectory is compared in simulations to an alternative higher-order encoding scheme referred to as O-space imaging. Direct comparison of local k space representations leads to the proposal of a modification to the O-space imaging trajectory based on a scheme of prephasing to improve the reconstructed image quality. Data were collected using a 4D-RIO acquisition in vivo in the human brain and several image reconstructions were compared, exploiting the property that the dense encoding matrix, after a 1D or 2D Fourier transform, can be approximated by a sparse matrix by discarding entries below a chosen magnitude. RESULTS: The proposed prephasing scheme for the O-space trajectory shows a marked improvement in quality in the simulated image reconstruction. In experiments, 4D-RIO data acquired in vivo in the human brain can be reconstructed to a reasonable quality using only 5 % of the encoding matrix--massively reducing computer memory requirements for a practical reconstruction. CONCLUSION: Trajectory design and reconstruction techniques such as these may prove especially useful when extending generalized higher-order encoding methods to 3D images. PMID- 22484821 TI - Dynamics of plant-pollinator-robber systems. AB - Plant-pollinator-robber systems are considered, where the plants and pollinators are mutualists, the plants and nectar robbers are in a parasitic relation, and the pollinators and nectar robbers consume a common limiting resource without interfering competition. My aim is to show a mechanism by which pollination mutualism could persist when there exist nectar robbers. Through the dynamics of a plant-pollinator-robber model, it is shown that (i) when the plants alone (i.e., without pollination-mutualism) cannot provide sufficient resources for the robbers' survival but pollination-mutualism can persist in the plant-pollinator system, the pollination-mutualism may lead to invasion of the robbers, while the pollinators will not be driven into extinction by the robbers' invasion. (ii) When the plants alone cannot support the robbers' survival but persistence of pollination-mutualism in the plant-pollinator system is density-dependent, the pollinators and robbers could coexist if the robbers' efficiency in translating the plant-robber interactions into fitness is intermediate and the initial densities of the three species are in an appropriate region. (iii) When the plants alone can support the robbers' survival, the pollinators will not be driven into extinction by the robbers if their efficiency in translating the plant-pollinator interactions into fitness is relatively larger than that of the robbers. The analysis leads to an explanation for the persistence of pollination mutualism in the presence of nectar robbers in real situations. PMID- 22484822 TI - Pharmacologic cardiac resynchronization of a 1-year-old boy with severe left ventricular dysfunction. AB - Postero-septal accessory pathways (AP) are a rare cause of intraventricular dyssynchrony and severe LV dysfunction in children. Beside the common treatment with radiofrequency ablation of septal substrates we present the case of a successful pharmacologic resynchronization in a 13/12 years old male toddler with Wolff-Parkinson-White syndrome (WPW) and severe LV dysfunction (left ventricular biplane EF of 31 %) due to intraventricular dyssynchrony with septal to posterior wall motion delay (SPWMD) of 350 ms. Interventricular mechanical delay (IVMD) was 65 ms. Using propafenone, pharmacologic cardiac resynchronization could be achieved. Pharmacologic resynchronization should be considered as safe and effective alternative to catheter ablation in very young children. PMID- 22484823 TI - Diagnostic challenge in desmin cardiomyopathy with transformation of clinical phenotypes. AB - Desmin cardiomyopathy is a rare cause of congestive heart failure. Its clinical manifestation in adulthood often is associated with conduction disorders and a neuromuscular phenotype. Only a few cases have been reported, with early manifestation in childhood mostly due to severe cardiomyopathy dilation and conduction abnormalities. However, the disease can result in the variety of clinical phenotypes, including hypertrophic, restrictive, and arrhythmogenic cardiomyopathy. This report describes the first case of desmin cardiomyopathy with early manifestation in adolescence and transformation of several clinical phenotypes over time, representing sufficient difficulties for the correct clinical diagnosis and treatment of the disease at an early stage. PMID- 22484825 TI - Validity of an automatic measure protocol in distal femur for allograft selection from a three-dimensional virtual bone bank system. AB - Osteoarticular allograft is one possible treatment in wide surgical resections with large defects. Performing best osteoarticular allograft selection is of great relevance for optimal exploitation of the bone databank, good surgery outcome and patient's recovery. Current approaches are, however, very time consuming hindering these points in practice. We present a validation study of a software able to perform automatic bone measurements used to automatically assess the distal femur sizes across a databank. 170 distal femur surfaces were reconstructed from CT data and measured manually using a size measure protocol taking into account the transepicondyler distance (A), anterior-posterior distance in medial condyle (B) and anterior-posterior distance in lateral condyle (C). Intra- and inter-observer studies were conducted and regarded as ground truth measurements. Manual and automatic measures were compared. For the automatic measurements, the correlation coefficients between observer one and automatic method, were of 0.99 for A measure and 0.96 for B and C measures. The average time needed to perform the measurements was of 16 h for both manual measurements, and of 3 min for the automatic method. Results demonstrate the high reliability and, most importantly, high repeatability of the proposed approach, and considerable speed-up on the planning. PMID- 22484826 TI - Spontaneous organization of the cortical structure through endogenous neural firing and gap junction transmission. AB - We explore the effects of gap junctions, direct neural transmission between adjacent cells, on activity-dependent network formation. It is found that endogenous neural activities and weak firing correlations via gap junctions can regulate elaborately both the topographic structure in vertical connections and the radial structure in horizontal connections. Provided that pre-establishment of the lateral connection structure is required for the postnatal cortical map organization and genetic factors cannot perform such detailed regulation of synaptic connections, neural interactions via gap junctions could play an indispensable role in the brain development. PMID- 22484828 TI - Heat shock response in photosynthetic organisms: membrane and lipid connections. AB - The ability of photosynthetic organisms to adapt to increases in environmental temperatures is becoming more important with climate change. Heat stress is known to induce heat-shock proteins (HSPs) many of which act as chaperones. Traditionally, it has been thought that protein denaturation acts as a trigger for HSP induction. However, increasing evidence has shown that many stress events cause HSP induction without commensurate protein denaturation. This has led to the membrane sensor hypothesis where the membrane's physical and structural properties play an initiating role in the heat shock response. In this review, we discuss heat-induced modulation of the membrane's physical state and changes to these properties which can be brought about by interaction with HSPs. Heat stress also leads to changes in lipid-based signaling cascades and alterations in calcium transport and availability. Such observations emphasize the importance of membranes and their lipids in the heat shock response and provide a new perspective for guiding further studies into the mechanisms that mediate cellular and organismal responses to heat stress. PMID- 22484827 TI - Combined effects of a neutrophil elastase inhibitor (sivelestat sodium) and a free radical scavenger (edaravone) on lipopolysaccharide-induced acute lung injury in rats. AB - OBJECTIVE AND DESIGN: The present study aimed to investigate the combined effects of a neutrophil elastase inhibitor, sivelestat sodium, with a free radical scavenger, edaravone, on lipolysaccharide (LPS)-induced acute lung injury (ALI). MATERIALS AND METHODS: Adult male Sprague-Dawley rats were anesthetized and instilled intratracheally with 2 mg/kg LPS. Sivelestat sodium (10 mg/kg, i.p.) and/or edaravone (8 mg/kg, i.p.) were administered 1 h after LPS instillation. The severity of pulmonary injuries was evaluated 12 h after inducing acute lung injury. RESULTS: In lung tissues, either sivelestat or edaravone treatment alone showed significant protective effects against neutrophil infiltration and tissue injury, as demonstrated by myeloperoxidase activity and histopathological analysis. Sivelestat or edaravone treatment also attenuated the LPS-induced production of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor alpha (TNF-alpha) in rat lungs. However, the LPS-induced elevation of malondialdehyde levels in rat lungs was reduced only by edaravone, but not by sivelestat. In addition, combined treatment with both sivelestat and edaravone demonstrated additive protective effects on LPS-induced lung injury, compared with single treatments. CONCLUSIONS: Combination of sivelestat and edaravone shows promise as a new treatment option for ALI/acute respiratory distress syndrome patients. PMID- 22484829 TI - Ex vivo gene delivery to hepatocytes: techniques, challenges, and underlying mechanisms. AB - Gene delivery to primary hepatocytes is an important tool for a number of applications including the study of liver cell biology and pathology, drug screening, and gene therapy. Robust transfection of primary hepatocytes, however, is significantly more difficult to achieve than in cell lines or readily dividing primary cells. In this report, we investigated in vitro gene delivery to both primary rat hepatocytes and Huh7.5.1 cells (a hepatoma cell line) using a number of viral and non-viral methods, including Lipofectamine 2000, FuGene HD, Nucleofection, Magnetofection, and lentiviruses. Our results showed that Lipofectamine 2000 is the most efficient reagent for green fluorescent protein (GFP) gene delivery to primary rat hepatocytes (33.3 +/- 1.8% transfection efficiency) with minimal adverse effect on several hepatic functions, such as urea and albumin secretion. The lentiviral vectors used in this study exhibited undetectable gene delivery to primary rat hepatocytes but significant delivery to Huh7.5.1 cells (>80% transfection efficiency). In addition, we demonstrated lentiviral-based and spatially defined delivery of the GFP gene to Huh7.5.1 cells for use in biological microelectromechanical systems. PMID- 22484830 TI - Quantitative analysis of molecular absorption into PDMS microfluidic channels. AB - Microfluidic devices fabricated using poly(dimethylsiloxane) (PDMS) polymer are routinely used for in vitro cell culture for a wide range of cellular assays. These assays typically involve the incubation of cultured cells with a drug molecule or a fluorescent marker while monitoring a cellular response. The accuracy of these assays depends on achieving a consistent and reproducible concentration of solute molecules in solution. However, hydrophobic therapeutic and fluorescent molecules tend to diffuse into the PDMS walls of the microfluidic devices, which reduce their concentration in solution and consequently affect the accuracy and reliability of these assays. In this paper, we quantitatively investigate the relationship between the partition coefficient (log P) of a series of markers routinely used in in vitro cellular assays including [3H] dexamethasone, [3H]-diazepam, [14C]-mannitol, [3H]-phenytoin, and rhodamine 6G and their absorption into PDMS microfluidic channels. Our results show that the absorption of a given solute into PDMS depends on the hydrophilic/hydrophobic balance defined by its log P value. Specifically, results demonstrate that molecules with log P less than 2.47 exhibit minimal absorption (<10%) into PDMS channels whereas molecules with log P larger than 2.62 exhibit extensive absorption (>90%) into PDMS channels. Further investigations showed that TiO(2) and glass coatings of PDMS channels reduced the absorption of hydrophobic molecules (log P > 2.62) by 2- and 4.5-folds, respectively. PMID- 22484831 TI - Unusual case of cutaneous and synovial Paecilomyces lilacinus infection of hand successfully treated with voriconazole and review of published literature. AB - Paecilomyces lilacinus infection is rare and is found worldwide. The majority of infections occur in immunocompromised people. Among immunocompetent patients, cutaneous infections are the second most common site of infection but are difficult to treat because of antifungal resistance. We report a case of hand cutaneous involvement with synovitis in an immunocompetent patient that improved after treatment with oral voriconazole. To the best of our knowledge, there are only five published cases of cutaneous P.lilacinus infection, all in immunocompromised patient, treated with oral voriconazole. We review all previously reported cases. PMID- 22484832 TI - Ultrafast transient generation of spin-density-wave order in the normal state of BaFe2As2 driven by coherent lattice vibrations. AB - The interplay among charge, spin and lattice degrees of freedom in solids gives rise to intriguing macroscopic quantum phenomena such as colossal magnetoresistance, multiferroicity and high-temperature superconductivity. Strong coupling or competition between various orders in these systems presents the key to manipulate their functional properties by means of external perturbations such as electric and magnetic fields or pressure. Ultrashort and intense optical pulses have emerged as an interesting tool to investigate elementary dynamics and control material properties by melting an existing order. Here, we employ few cycle multi-terahertz pulses to resonantly probe the evolution of the spin density-wave (SDW) gap of the pnictide compound BaFe(2)As(2) following excitation with a femtosecond optical pulse. When starting in the low-temperature ground state, optical excitation results in a melting of the SDW order, followed by ultrafast recovery. In contrast, the SDW gap is induced when we excite the normal state above the transition temperature. Very surprisingly, the transient ordering quasi-adiabatically follows a coherent lattice oscillation at a frequency as high as 5.5 THz. Our results attest to a pronounced spin-phonon coupling in pnictides that supports rapid development of a macroscopic order on small vibrational displacement even without breaking the symmetry of the crystal. PMID- 22484833 TI - Use of quantitative microbiological analyses to trace origin of contamination of parenteral nutrition solutions. AB - In the summer of 2010, parenteral nutrition (PN) admixtures were administered to neonates in the Pediatric Department of the University Medical Center Mainz that provoked severe clinical sequelae. Contamination of a dummy infusion with Enterobacter cloacae and Escherichia hermannii was detected on the day of the incident, and the same isolates were subsequently grown from all PN admixtures as well as from the parent amino acid solution from which the admixtures had been prepared. Quantitative microbiological analyses paired with the determination of endotoxin concentrations enabled the conclusion to be reached that the amino acid solution had represented the primary source of contamination, which must have occurred in the distant past and may have derived from passage of the bacteria through a crack in the glass container. The findings have large implications, and the approaches employed should become of value when similar incidents occur again in the future. PMID- 22484834 TI - Stress-related serotonergic systems: implications for symptomatology of anxiety and affective disorders. AB - Previous studies have suggested that serotonergic neurons in the midbrain raphe complex have a functional topographic organization. Recent studies suggest that stimulation of a bed nucleus of the stria terminalis-dorsal raphe nucleus pathway by stress- and anxiety-related stimuli modulates a subpopulation of serotonergic neurons in the dorsal part of the dorsal raphe nucleus (DRD) and caudal part of the dorsal raphe nucleus (DRC) that participates in facilitation of anxiety-like responses. In contrast, recent studies suggest that activation of a spinoparabrachial pathway by peripheral thermal or immune stimuli excites subpopulations of serotonergic neurons in the ventrolateral part of the dorsal raphe nucleus/ventrolateral periaqueducal gray (DRVL/VLPAG) region and interfascicular part of the dorsal raphe nucleus (DRI). Studies support a role for serotonergic neurons in the DRVL/VLPAG in inhibition of panic-like responses, and serotonergic neurons in the DRI in antidepressant-like effects. Thus, data suggest that while some subpopulations of serotonergic neurons in the dorsal raphe nucleus play a role in facilitation of anxiety-like responses, others play a role in inhibition of anxiety- or panic-like responses, while others play a role in antidepressant-like effects. Understanding the anatomical and functional properties of these distinct serotonergic systems may lead to novel therapeutic strategies for the prevention and/or treatment of affective and anxiety disorders. In this review, we describe the anatomical and functional properties of subpopulations of serotonergic neurons in the dorsal raphe nucleus, with a focus on those implicated in symptoms of anxiety and affective disorders, the DRD/DRC, DRVL/VLPAG, and DRI. PMID- 22484835 TI - Brain pathways involved in the modulatory effects of noradrenaline in lateral septal area on cardiovascular responses. AB - We have previously reported that stimulation of alpha-1 adrenoceptors by noradrenaline (NA) injected into the lateral septal area (LSA) of anaesthetized rats causes pressor and bradycardic responses that are mediated by acute vasopressin release into the circulation through activation of the paraventricular nucleus (PVN). Although the PVN is the final structure of this pathway, the LSA has no direct connections with the PVN, suggesting that other structures may connect these areas. To address this issue, the present study employed c-Fos immunohistochemistry to investigate changes caused by NA microinjection into the LSA in neuronal activation in brain structures related to systemic vasopressin release. NA microinjected in the LSA caused pressor and bradycardic responses, which were blocked by intraseptal administration of alpha 1 adrenoceptor antagonist (WB4101, 10 nmol/200 nL) or systemic V-1 receptor antagonist (dTyr(CH2)5(Me)AVP, 50 MUg/kg). NA also increased c-Fos immunoreactivity in the prelimbic cortex (PL), infralimbic cortex (IL), dorsomedial periaqueductal gray (dmPAG), bed nucleus of the stria terminalis (BNST), PVN, and medial amygdala (MeA). No differences in the diagonal band of Broca, cingulate cortex, and dorsolateral periaqueductal gray (dlPAG) were found. Systemic administration of the vasopressin receptor antagonist dTyr AVP (CH2)5(Me) did not change the increase in c-Fos expression induced by intra septal NA. This latter effect, however, was prevented by local injection of the alpha-1 adrenoceptor antagonist WB4101. These results suggest that areas such as the PL, IL, dmPAG, BNST, MeA, and PVN could be part of a circuit responsible for vasopressin release after activation of alpha-1 adrenoceptors in the LSA. PMID- 22484836 TI - Synthesis of molecularly imprinted polymer as a sorbent for solid phase extraction of citalopram from human serum and urine. AB - This paper describes a new method for the determination of citalopram in biological fluids using molecularly imprinted solid-phase extraction as the sample cleanup technique combined with high performance liquid chromatography. The molecularly imprinted polymers were prepared using methacrylic acid as functional monomer, ethylene glycol dimethacrylate as crosslinker, chloroform as porogen and citalopram hydrobromide as the template molecule. The novel imprinted polymer was used as a solid-phase extraction sorbent for the extraction of citalopram from human serum and urine. Effective parameters on citalopram retention were studied. The optimal conditions for molecularly imprinted solid phase extraction consisted of conditioning with 1 mL methanol and 1 mL of deionized water at neutral pH, loading of citalopram sample (50 MUg L(-1)) at pH 9.0, washing using 1 mL acetone and elution with 3 * 1 mL of 10 % (v/v) acetic acid in methanol. The MIP selectivity was evaluated by checking several substances with similar molecular structures to that of citalopram. Results from the HPLC analyses showed that the calibration curve of citalopram using MIP from human serum and urine is linear in the ranges of 1-100 and 2-120 MUg L(-1) with good precisions (2.5 and 1.5 % for 10.0 MUg L(-1)), and recoveries (between 82-86 and 83-85 %), respectively. PMID- 22484837 TI - Fluorescent (rhodamine), folate decorated and doxorubicin charged, PEGylated nanoparticles synthesis. AB - PEGylated silica nanoparticles, giving very stable aqueous sols, were successfully functionalised with rhodamine, one of the more stable fluorophore; they were also decorated with the targeting agent folic acid (FA) and charged with the well known drug doxorubicin. Rhodamine functionalization required a modification of the synthesis route of the nanoparticles (NP). Functionalization with FA required activation with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride. Folate decorated NP were easily charged with doxorubicin. The experimental results proved the successfulness of the functionalization. The bond to the NP does not reduce the therapeutic efficacy of the drug. The calculated encapsulation efficiency (32 %) was only a little lower than the value (47 %) reported for the very popular PEGylated PLGA NP. PMID- 22484838 TI - Prevalence of Chlamydia trachomatis endocervical infection in systemic lupus erythematosus patients and evaluation of the risk for HPV-induced lesions. AB - Chlamydia trachomatis (CT) is the most common bacterial cause of sexually transmitted disease. It has been associated with arthritis and it is a risk factor for human papillomavirus (HPV)-induced lesions. There are few studies on the frequency of CT infection among systemic lupus erythematosus (SLE) patients. The aim of this study was to determine the prevalence of endocervical CT infection among SLE patients and evaluate whether or not CT infection is a risk factor for HPV-induced lesions. A cross-sectional study included a group of patients who fulfilled the American College Rheumatology criteria for a definite diagnosis of SLE and a control group of non-SLE female individuals from Bahia, Brazil. Polymerase chain reaction was used on endocervical swab specimens to test for CT; a gynecological examination including a cervical cytology and biopsy was done for the identification of HPV lesions. A total of 105 SLE patients were studied, and the control group was composed of 104 age-matched apparently normal women. The prevalence of CT endocervical infection was 3.0 % [confidence interval (CI) 95 % = 0.6-8.0 %] in the SLE group and 5.0 % (95 % CI = 2.0-11.0 %) in the control group; the prevalence ratio was 0.60 (95 % CI = 0.1-2.5). The prevalence of vulvar condyloma was higher among SLE patients (11.0 vs. 1.0 %, p < 0.001), as were the prevalences of low-grade lesion (12.0 vs. 1.0 %, p < 0.001) and cervical intraepithelial neoplasia 1 (9.0 vs. 1.0 %, p = 0.02). There was no association between the presence of HPV lesions and CT infections. However, the small number of patients with CT prevents a definite conclusion from being drawn. The prevalence of endocervical CT infection in women with SLE is low and similar to that of the normal population. This suggests that this infection has no role in the pathogenesis of SLE or the development of HPV-induced lesions. PMID- 22484839 TI - Relationship of the sexual functions with the clinical parameters, radiological scores and the quality of life in male patients with ankylosing spondylitis. AB - The aim of this study was to explore the impact of ankylosing spondylitis (AS) and the disease-related variables on the patients' sexual function according to the International Index of Erectile Function (IIEF) scoring system. A total of 70 sexually active male AS patients and 60 healthy controls were enrolled in this study. Their demographic data were evaluated, and the pain was assessed according to the visual analogue scale (VAS). Laboratory tests were conducted in order to measure the C-reactive protein (CRP) and erythrocyte sedimentation rates (ESR) of the patients. The disease activity was evaluated using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Functional statement was evaluated with the help of the Bath Ankylosing Spondylitis Functional Index (BASFI) and with the scores obtained from the spinal measurements with the Bath Ankylosing Spondylitis Metrology Index (BASMI). The Bath Ankylosing Spondylitis Radiology Index (BASRI) was used to evaluate the radiological damage. The disease-related quality of life was measured with the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL). The anxiety and depression level of the patients was revealed through the Hospital Anxiety and Depression Scale (HADS). In comparison with the healthy control group, patients with AS had significantly lower scores in each of the 5 domains of the IIEF (p < 0.0001). The BASDAI, BASFI, BASMI, BASRI, ASQoL, HADS scores and CRP levels were negatively correlated with IIEF (p < 0.05). Orgasmic function and sexual desire scores were significantly lower in patients with peripheral arthritis (p < 0.05). No significant correlation was observed with the disease duration, smoking status, pain (VAS), and ESR levels when the total scores and the scores from the domains of IIEF were compared. The multivariate regression analyses indicated that BASFI and BASMI were independently associated with the sexual function. The sexual function is impaired in male patients with AS. This impairment in the sexual function is especially correlated with the BASFI and BASMI among the clinical and laboratory parameters. PMID- 22484841 TI - Determination of dopamine in pharmaceutical formulation using enhanced luminescence from europium complex. AB - Biologically important compound dopamine plays an important role in the central and peripheral nervous systems. Insufficient dopamine level due to the loss of dopamine producing cells may lead to disease called Schizophrenia and Parkinson's disease. Hence, a simple and fast detection of dopamine is necessary to study in the fields of neurophysiology and clinical medicine. An enhanced fluorimetric determination of dopamine in the presence of ascorbic acid is achieved using photoluminescence of europium complex, Eu(III)-dipicolinic acid. In order to obtain better responses, several operational parameters have been investigated. Under the optimum conditions, the method showed good stability and reproducibility. The application of this method for the determination of dopamine neurotransmitters was satisfactory. Linear response was found down to 3.0 * 10( 7)M with limit of detection 1.0 * 10(-8)M. The relative standard deviation was found to be 3.33% from 20 independent measurements for 1.0 * 10(-5)M of dopamine. PMID- 22484842 TI - Different effects of light irradiation on the photosynthetic electron transport chain during apple tree leaf dehydration. AB - Effects of light irradiation on the photosynthetic electron transport chain between P680 and P700 in apple tree leaves was probed with chlorophyll a fluorescence transient and 820 nm transmission measurements during dehydration under different light intensities. The results showed that light accelerated the leaf water-loss rate during dehydration. Leaf dehydration lowered the maximum quantum yield of PSII and the far-red light induced maximal transmission change at 820 nm, but increased the relative variable fluorescence intensity at J-step, especially under increasing irradiation conditions. During leaf dehydration, irradiation lowered the relative variable fluorescence intensity at I-step. At the beginning of leaf dehydration, moderate light accelerated the leaf water-loss rate and then lowered the maximal light-trapping efficiency of P680. Upon further dehydration under moderate light or dehydration under high light, light accelerated the water-loss rate and also directly decreased the maximal light trapping efficiency of P680. The more significant decrease in the exchange capacity of plastoquinones at the Q(B) site was mainly attributed to the faster water-loss rate under moderate light than in the dark. Under high light, irradiation also directly lowered the capacity. The reoxidation of PQH2 in the dehydrated leaves was enhanced by the light irradiation. The rapidly decreased contents of P700 + plastocyanin were mainly attributed to the faster water-loss rate under light conditions in contrast with that in the dark. The different effects of light irradiations on the photosynthetic electron transport chain might be involved in the acclimation of apple tree leaves to dehydration. PMID- 22484840 TI - Inflammation-hemostasis relationship in infected malnourished mice: modulatory effect of Lactobacillus casei CRL 431. AB - OBJECTIVE AND DESIGN: The coagulation system is considered part of the defense machinery, but its excessive activation can lead to additional damage. We studied the effects of oral administration of Lactobacillus casei CRL 431--a probiotic bacterium--on the activation of coagulation and the relationship with inflammatory parameters during a respiratory infection in malnourished mice. MATERIALS AND METHODS: Malnourished Swiss albino mice were nourished with a balanced commercial diet (BCD) for 7 days or BCD with L. casei for the last 2 days (BCD + Lc). BCD, BCD + Lc, malnourished (MNC) and well-nourished controls (WNC) were infected with Streptococcus pneumoniae. Blood and bronchoalveolar lavage samples were obtained at different times post-infection. RESULTS AND CONCLUSIONS: Malnutrition altered most of the evaluated parameters before and after infection. The repletion diet with supplemental L. casei was the most effective in limiting coagulation activation and normalizing coagulation inhibition mechanisms. These findings will help develop further strategies to reduce the damaging effects of clotting and enhance its beneficial contribution to immune reactions. PMID- 22484843 TI - Reduced models for unidirectional block conduction and their geometrical setting. AB - This article revisits a reduced model of cardiac electro-physiology which was proposed to understand the genesis of unidirectional block pathology and of ectopic foci. We underline some specificities of the model from the viewpoint of dynamical systems and bifurcation theory. We point out that essentially the same properties are shared by a simpler system more accessible to analysis. With this simpler system, it becomes possible to give a new presentation of the phenomenon in a phase plane with time moving slow manifolds. This presentation can be of interest both for cardiac electro-physiologists and for mathematicians. PMID- 22484844 TI - Reconsidering outcomes that matter to patients. PMID- 22484845 TI - Immunomodulators for multiple sclerosis may ameliorate spinal bone loss. AB - BACKGROUND: The effect of immunomodulator therapy (IMT) for multiple sclerosis (MS) on bone turnover is unknown. AIM: The aim of this study was to assess bone turnover in MS patients on IMT. METHODS: MS patients (n = 29) on maintenance IMT had repeat measurement of bone mineral density (BMD) after a 4.0 +/- 0.4 years; bone turnover markers (BTM) were measured at the time of repeat BMD. RESULTS: BMD was unchanged at the spine but declined at the hip. BTMs, both resorption and formation, were reduced compared to normative range that may indicate an anti resorptive action of IMT. Significant negative correlations were noted between BTMs and changes in BMD at spine but not hip. CONCLUSION: These observations suggest that IMT may have a beneficial effect on spinal bone by an antiresorptive action. A prospective study of the effect of IMT on BMD and bone turnover is warranted. PMID- 22484846 TI - Derivation of iPSCs in stirred suspension bioreactors. AB - Induced pluripotent stem cells (iPSCs) are typically derived in adherent culture. Here we report fast and efficient derivation of mouse iPSCs in stirred suspension bioreactors, with and without the use of c-Myc. Suspension-reprogrammed cells expressed pluripotency markers, showed multilineage differentiation in vitro and in vivo, and contributed to the germline in chimeric mice. Suspension reprogramming has the potential to accelerate and standardize iPSC research. PMID- 22484847 TI - Accurate identification of human Alu and non-Alu RNA editing sites. AB - We developed a computational framework to robustly identify RNA editing sites using transcriptome and genome deep-sequencing data from the same individual. As compared with previous methods, our approach identified a large number of Alu and non-Alu RNA editing sites with high specificity. We also found that editing of non-Alu sites appears to be dependent on nearby edited Alu sites, possibly through the locally formed double-stranded RNA structure. PMID- 22484848 TI - Genome-scale promoter engineering by coselection MAGE. AB - Multiplex automated genome engineering (MAGE) uses short oligonucleotides to scarlessly modify genomes; however, insertions >10 bases are still inefficient but can be improved substantially by selection of highly modified chromosomes. Here we describe 'coselection' MAGE (CoS-MAGE) to optimize biosynthesis of aromatic amino acid derivatives by combinatorially inserting multiple T7 promoters simultaneously into 12 genomic operons. Promoter libraries can be quickly generated to study gain-of-function epistatic interactions in gene networks. PMID- 22484849 TI - FLEXIQinase, a mass spectrometry-based assay, to unveil multikinase mechanisms. AB - We introduce a mass spectrometry-based method that provides residue-resolved quantitative information about protein phosphorylation. In this assay we combined our full-length expressed stable isotope-labeled protein for quantification strategy (FLEXIQuant) with a traditional kinase assay to determine the mechanisms of multikinase substrate phosphorylation such as priming-dependent kinase activities. The assay monitors the decrease in signal intensity of the substrate peptides and the concomitant increase in the (n * 80 Da)-shifted phosphorylated peptide. We analyzed the c-Jun N-terminal kinase (JNK)-dependent glycogen synthase kinase 3beta (GSK3beta) activity on doublecortin (DCX) revealing mechanistic details about the role of phosphorylation cross-talk in GSK3beta activity and permitting an advanced model for GSK3beta-mediated signaling. PMID- 22484850 TI - Segregation of molecules at cell division reveals native protein localization. AB - We introduce a nonintrusive method exploiting single-cell variability after cell division to validate protein localization. We found that Clp proteases, widely reported to form biologically relevant foci, were uniformly distributed in Escherichia coli cells, and that many commonly used fluorescent proteins caused severe mislocalization when fused to homo-oligomers. Retagging five other reportedly foci-forming proteins with the most monomeric fluorescent protein tested suggests that the foci were caused by the fluorescent tags. PMID- 22484851 TI - Small molecules enable highly efficient neuronal conversion of human fibroblasts. AB - Forced expression of proneural transcription factors has been shown to direct neuronal conversion of fibroblasts. Because neurons are postmitotic, conversion efficiencies are an important parameter for this process. We present a minimalist approach combining two-factor neuronal programming with small molecule-based inhibition of glycogen synthase kinase-3beta and SMAD signaling, which converts postnatal human fibroblasts into functional neuron-like cells with yields up to >200% and neuronal purities up to >80%. PMID- 22484852 TI - Tumor suppressor miR-22 suppresses lung cancer cell progression through post transcriptional regulation of ErbB3. AB - BACKGROUND: Development of efficient therapies of lung cancer and deep understanding of their anti-tumor mechanism are very important. The aim of the present study is to investigate the therapeutic effect of microRNA-22 (miR-22) on lung cancer using in vitro and in vivo methods. METHODS: Expression level of miR 22 in lung cancer specimens and relative normal tissues was detected by microRNA specific quantitative real-time PCR (Q-PCR). Invasion assay, cell counting kit-8 assay, and Annexin V/7-AAD analysis were performed to test the invasion and proliferation of lung cancer cell after transfection. The effect of miR-22 on lung cancer in vivo was validated by murine xenograft model. RESULTS: Q-PCR detection of miR-22 in clinical samples showed that the relative expression level of miR-22 in lung cancer tissues and lung cancer cell lines was lower than that in normal tissues. Transfection of miR-22 expression plasmids could significantly inhibit the increased cell numbers and invasion of A549 and H1299 lung cancer cell lines. Furthermore, miR-22 was demonstrated to inhibit the expression of ErbB3 through post-transcriptional regulation via binding to ErbB3 3'-UTR. Co transfection of ErbB3 expression plasmid could promote the proliferation and invasion of A549 and H1299. In vivo experiments using nude mice demonstrated that over-expression of miR-22 could significantly decrease the volume and weight of tumors. CONCLUSIONS: miR-22 exhibited excellent anti-lung cancer activity in vitro and in vivo, and post-transcriptional regulation of ErbB3 might be a potential mechanism. PMID- 22484853 TI - The link between genetic polymorphism of glutathione-S-transferases, GSTM1, and GSTT1 and diffuse large B-cell lymphoma in Egypt. AB - BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. A number of studies have examined the role of genetic polymorphisms in the risk of DLBCL, and several variants have been identified as potential susceptibility genes, of those glutathione-S-transferases T1 and M1 (GSTT1 and GSTM1). AIM OF THE WORK: The aim of the current study was to investigate the influence of inherited genetic polymorphisms of GSTM1 and GSTT1 genes on the susceptibility to DLBCL in Egypt. METHODS: Genotyping of the candidate genes was performed for 71 Egyptian DLBCL patients and 100 age- and gender-matched healthy controls by multiplex polymerase chain reaction technique. RESULTS: The frequencies of GSTT1 null, GSTM1 null, and dual null genotypes among DLBCL patients were 47.9, 52.1, and 23.9 % respectively. CONCLUSION: GSTT1 null genotype conferred almost fourfold increased risk of DLBCL (OR = 3.9, 95 % CI = 1.97-7.75), and the risk increased when confined to male patients (OR = 4.4, 95 % CI = 1.57-12.63), while GSTM1 null genotype was not associated with DLBCL risk. Further studies on the functional consequences of GSTT1 and GSTM1 genetic polymorphisms would pave the way to declare their role in the pathogenesis of DLBCL or as possible predictors for response to therapy. PMID- 22484854 TI - Delayed formation of FancD2 foci in glioma stem cells treated with ionizing radiation. AB - BACKGROUND: Glioblastoma multiforme (WHO grade IV) is a highly lethal brain tumor. Its malignancy is in part due to cell populations refractory to radiotherapy and chemotherapy, which in some patients display stem properties (glioma stem cells-GSC). We and others have recently shown that a major mechanism of resistance of GSC to therapies resides in their slow proliferation that in turn is linked to constitutive activation of the DNA damage response. FancD2, a central player of the Fanconi anemia pathway, is induced when replication forks stall at DNA damage sites. METHODS: We have analyzed the kinetics of FancD2 induction in two glioma cell lines with pronounced (Borru) and poor (DR177) stem phenotypes, by fluorescence analysis of nuclear foci. RESULTS: FancD2 activation was significantly delayed in Borru, consistent with the slow replication fork progression in these cells. On the contrary, no significant difference between Borru and DR177 was observed for pH2AX nuclear foci formation that hallmarks a number of DNA structure variations including double-strand breaks. CONCLUSION: GSC display reduced FancD2 activation following radiation damage, most probably due to their elongated cell cycle. PMID- 22484855 TI - Sudden death and myocardial lesions after damage to catecholamine neurons of the nucleus tractus solitarii in rat. AB - Lesions that remove neurons expressing neurokinin-1 (NK1) receptors from the nucleus tractus solitarii (NTS) without removing catecholaminergic neurons lead to loss of baroreflexes, labile arterial pressure, myocardial lesions, and sudden death. Because destruction of NTS catecholaminergic neurons expressing tyrosine hydroxylase (TH) may also cause lability of arterial pressure and loss of baroreflexes, we sought to test the hypothesis that cardiac lesions associated with lability are not dependent on damage to neurons with NK1 receptors but would also occur when TH neurons in NTS are targeted. To rid the NTS of TH neurons we microinjected anti-dopamine beta-hydroxylase conjugated to saporin (anti-DBH-SAP, 42 ng/200 nl) into the NTS. After injection of the toxin unilaterally, immunofluorescent staining confirmed that anti-DBH-SAP decreased the number of neurons and fibers that contain TH and DBH in the injected side of the NTS while sparing neuronal elements expressing NK1 receptors. Bilateral injections in eight rats led to significant lability of arterial pressure. For example, on day 8 standard deviation of mean arterial pressure was 16.8 +/- 2.5 mmHg when compared with a standard deviation of 7.83 +/- 0.33 mmHg in six rats in which phosphate buffered saline (PBS) had been injected bilaterally. Two rats died suddenly at 5 and 8 days after anti-DBH-SAP injection. Seven-treated animals demonstrated microscopic myocardial necrosis as reported in animals with lesions of NTS neurons expressing NK1 receptors. Thus, cardiac and cardiovascular effects of lesions directed toward catecholamine neurons of the NTS are similar to those following damage directed toward NK1 receptor-containing neurons. PMID- 22484856 TI - Ionizable side chains at catalytic active sites of enzymes. AB - Catalytic active sites of enzymes of known structure can be well defined by a modern program of computational geometry. The CASTp program was used to define and measure the volume of the catalytic active sites of 573 enzymes in the Catalytic Site Atlas database. The active sites are identified as catalytic because the amino acids they contain are known to participate in the chemical reaction catalyzed by the enzyme. Acid and base side chains are reliable markers of catalytic active sites. The catalytic active sites have 4 acid and 5 base side chains, in an average volume of 1,072 A(3). The number density of acid side chains is 8.3 M (in chemical units); the number density of basic side chains is 10.6 M. The catalytic active site of these enzymes is an unusual electrostatic and steric environment in which side chains and reactants are crowded together in a mixture more like an ionic liquid than an ideal infinitely dilute solution. The electrostatics and crowding of reactants and side chains seems likely to be important for catalytic function. In three types of analogous ion channels, simulation of crowded charges accounts for the main properties of selectivity measured in a wide range of solutions and concentrations. It seems wise to use mathematics designed to study interacting complex fluids when making models of the catalytic active sites of enzymes. PMID- 22484857 TI - On the simple random-walk models of ion-channel gate dynamics reflecting long term memory. AB - Several approaches to ion-channel gating modelling have been proposed. Although many models describe the dwell-time distributions correctly, they are incapable of predicting and explaining the long-term correlations between the lengths of adjacent openings and closings of a channel. In this paper we propose two simple random-walk models of the gating dynamics of voltage and Ca(2+)-activated potassium channels which qualitatively reproduce the dwell-time distributions, and describe the experimentally observed long-term memory quite well. Biological interpretation of both models is presented. In particular, the origin of the correlations is associated with fluctuations of channel mass density. The long term memory effect, as measured by Hurst R/S analysis of experimental single channel patch-clamp recordings, is close to the behaviour predicted by our models. The flexibility of the models enables their use as templates for other types of ion channel. PMID- 22484858 TI - Importance of observation interval in two-dimensional video analysis of individual diatom cells. AB - The effect of the observation interval on two-dimensional trajectory analysis of motility of individual diatom cells of Navicula sp. was studied by comparing thinned-out observation data. The trajectory of cell movement was visualized accurately even after thinning the data interval. However, the analysis of velocity fluctuations of individual cells was found to be significantly affected by the data interval. Reproducibility of the results was guaranteed by analyzing many independent cells. In addition, comparison between automatic and manual determination of cell positions proved that automatic determination was a reliable process. Our data indicated that two-dimensional trajectory analysis using a computer can be a powerful technique to study diatom locomotion. PMID- 22484859 TI - Predictive markers in early research and companion diagnostic developments in oncology. AB - Predictive biomarkers are discovered and used in oncology research to formulate hypotheses aimed at the identification of patients benefiting from specific therapeutic intervention(s). They pave the way to the development of companion diagnostic tests which are tools readily implemented in the clinic and serve to qualify a patient for treatment with a particular targeted drug or the continued use of a particular drug, thus maximizing the benefit to risk ratio of the medical intervention to the patient. Predictive biomarkers are defined by biological characteristics of the patient's or tumor status that can be measured objectively and correlated with clinical outcome: these can be molecular, cellular or biochemical features. Predictive markers need extensive analytical validation - specific for the tool utilized for their assessment - as well as rigorous clinical qualification in the context of the drug treatment for which they define clinical utility. The process of companion diagnostic development is a highly interdisciplinary and complex one, driven by key crucial milestones and accompanying the same and typical process of a whole drug discovery and development continuum, from marker discovery and validation, assay development, clinical qualification until test approval and commercialization. PMID- 22484860 TI - Molecular cloning and characterization of the light-regulation and circadian rhythm of the VDE gene promoter from Zingiber officinale. AB - Ginger (Zingiber officinale Rosc.) is prone to photoinhibition under intense sunlight. Excessive light can be dissipated by the xanthophyll cycle, where violaxanthin de-epoxidase (VDE) plays a critical role in protecting the photosynthesis apparatus from the damage of excessive light. We isolated ~2.0 kb of ginger VDE (GVDE) gene promoter, which contained the circadian box, I-box, G box and GT-1 motif. Histochemical staining of Arabidopsis indicated the GVDE promoter was active in almost all organs, especially green tissues. beta glucuronidase (GUS) activity driven by GVDE promoter was repressed rather than activated by high light. GUS activity was altered by hormones, growth regulators and abiotic stresses, which increased with 2,4-dichlorophenoxyacetic acid and decreased with abscisic acid, salicylic acid, zeatin, salt (sodium chloride) and polyethylene glycol. Interestingly, GUS activities with gibberellin or indole-3 acetic acid increased in the short-term (24 h) and decreased in the long-term (48 and 72 h). Analysis of 5' flank deletion found two crucial functional regions residing in -679 to -833 and -63 to -210. Northern blotting analysis found transcription to be regulated by the endogenous circadian clock. Finally, we found a region necessary for regulating the circadian rhythm and another for the basic promoter activity. Key message A novel promoter, named GVDE promoter, was first isolated and analyzed in this study. We have determined one region crucial for promoter activity and another responsible for keeping circadian rhythms. PMID- 22484861 TI - A comparative transcriptomic analysis of the extremely boron tolerant plant Puccinellia distans with the moderately boron tolerant Gypsophila arrostil. AB - The Turkish ecotype of Puccinellia distans displays exceptional boron (B) tolerance, >1,250 mg B L-1, compared to <50 mg B L-1 for Gypsophila arrostil. In the present study, we compare the molecular basis for the difference in B tolerance between the two species by constructing high B-responsive suppression subtractive hybridization libraries to identify the upregulated genes. A total of 219 and 113 unique non-redundant expressed sequence tags (ESTs) were identified and functionally classified in P. distans and G. arrostil, respectively. In addition, 63 ESTs were down-regulated in P. distans in response to high B. The majority of the high B upregulated genes belong to four categories: metabolism, protein synthesis, cellular organization, and stress/defense. We hypothesize that the superior B tolerance exhibited by P. distans may be due to its ability to restrict the accumulation of B in plant tissues through the upregulated expression of efflux transporters comparable to the Bot1 transporter of barley. In addition, our results are consistent with the view that other molecular mechanisms involved in stress/defense, such as detoxification, anti-oxidative, and signaling pathways, are needed to tolerate B-toxicity stress. KEY MESSAGE: The molecular basis of boron tolerance of two plant species (Puccinellia distans and Gypsophila arrostil) that differ greatly in their boron tolerance was studied in this manuscript. PMID- 22484862 TI - Detachment strength of human osteoblasts cultured on hydroxyapatite with various surface roughness. Contribution of integrin subunits. AB - Hydroxyapatite (HA) has been widely used as a bone substitute in dental, maxillofacial and orthopaedic surgery and as osteoconductive bone substitute or precoating of pedicle screws and cages in spine surgery. The aim of the present study was to investigate the osteoblastic adhesion strength on HA substrata with different surface topography and biochemistry (pre-adsorption of fibronectin) after blocking of specific integrin subunits with monoclonal antibodies. Stoichiometric HA was prepared by precipitation followed by ageing and characterized by SEM, EDX, powder XRD, Raman spectroscopy, TGA, and specific surface area analysis. Human bone marrow derived osteoblasts were cultured on HA disc-shaped substrata which were sintered and polished resulting in two surface roughness grades. For attachment evaluation, cells were incubated with monoclonal antibodies and seeded for 2 h on the substrata. Cell detachment strength was determined using a rotating disc device. Cell detachment strength was surface roughness, fibronectin preadsorption and intergin subunit sensitive. PMID- 22484863 TI - Ultrasound monitoring of the setting of calcium-based bone cements. AB - In this study, the setting of calcium-sulphate (CS) and -phosphate (CP) based bone cements (BCs) was monitored by ultrasound. The objective was to link acoustic and material properties of ceramic-based BCs from the early stages of the cement curing process. The powder phase of the CS-cement consisted of CS hemihydrate; the CP-cement was a mixture of alpha-tricalcium phosphate, CS dihydrate and hydroxyapatite. For the CS-cement, the acoustic impedance z (c)(t), the speed of sound c (c)(t) and the density rho(c)(t) were measured at the interval of liquid-to-powder ratios LPRs from 0.20 to 3.00 ml/g. For the CP cement, the acoustic characteristics obtained were the z (c)(t) and the reflection coefficient R (p,c)(t), and the LPRs ranged from 0.30 to 0.40 ml/g. The resulting acoustic properties indicated that CP- and CS-cements exhibited distinctly different curing behaviour; while CS-cement expanded, CP-cement shrank with time. PMID- 22484864 TI - Evaluation of craniofacial morphology in patients with obstructive sleep apnea using lateral cephalometry and dynamic MRI. AB - CONTEXT: Obstructive sleep apnea (OSA) is a potentially life-threatening disorder, characterized by repeated collapse of the upper airway during sleep with cessation of breathing. The altered mouth breathing produces morphological changes in craniofacial region. AIM: This study was designed to compare and validate the craniofacial morphological characteristics in patients with OSA using lateral cephalometry and to investigate the dentofacial characteristics of patients with OSA with respect to the obstructive sites determined by dynamic magnetic resonance imaging (MRI) to more accurately clarify the pathophysiological features. MATERIALS AND METHODS: 10 patients with OSA were divided into two groups of five each according to their obstructive site determined by dynamic MRI. (1) Obstruction at the retropalatal and retroglossal region (Rp + Rg group) and (2) obstruction at the retropalatal region (Rp group). Lateral cephalogram both in upright and supine position was taken for all the subjects. In addition, dynamic MRI was performed to identify the sites of obstruction of the upper airway. STATISTICAL ANALYSIS USED: Independent t-test was performed to evaluate the significant difference in the upright cephalometric variables between the study and control group and between the two groups. The changes in skeletal and soft tissue parameters with change in posture was assessed within the study and control group by paired t test. P value of <= 0.05 was considered as statistically significant. RESULTS: The study indicated that the first group of patients with both retropalatal and retroglossal obstruction showed signs of skeletal discrepancy that predisposed to obstruction at the retroglossal level and the soft tissue components like the soft palate and tongue that contributed to retropalatal obstruction. However, the second group of patients with only retropalatal obstruction had primarily soft tissue components associated with increased BMI that contributed to retropalatal obstruction. CONCLUSION: Evaluation of craniofacial morphology in OSA patients is bound to help the concerned specialist in recognizing the morphological changes induced by altered sleep pattern so as to provide the appropriate treatment. PMID- 22484865 TI - Evaluation of resorbable membrane in treatment of human gingival isolated buccal recession. AB - BACKGROUND: Gingival recession in its localized or generalized form is an undesirable condition which results in root exposure. Several different techniques have been described in order to cover the exposed root surface, and increase the dimensions of the keratinized tissue in gingival recession defects. The aim of the present study is to evaluate the result using a bio resorbable membrane for the treatment of human isolated buccal gingival recession. MATERIALS AND METHODS: Ten patients, i.e. 6 males and 4 females, mean age 34.5 years, with Miller's classification class I or II facial mucogingival defects were selected. A full thickness flap up to the mucogingival junction, followed by a split thickness flap was reflected. This was done so as to cover the membrane at the defect site, at the same time cover the denuded root surface. All parameters were recorded by a single investigator for each surgical site before surgery (baseline), after 3 weeks, 3 months, 6 months and 9 months. RESULTS: The selected sites clinically presented with initial mean recession of 4.4 mm, mean area of recession of 10.5 mm and initial mean keratinized tissue width 4.2 mm. The results of this study had showed a mean coverage of the recession defects by 3.45 mm and a significant gain in keratinized tissue width of 0.8 mm post operatively at nine months. There was also a significant reduction in area of recession. The difference between the base line reading and post operative readings was both clinically and statistically significant. The mean percentage of root coverage was 79.75%. CONCLUSION: Resorbable membrane is a versatile treatment modality for coverage of isolated buccal gingival recession. Although membrane exposure occurred in four patients, it did not interfere with post operative healing. PMID- 22484866 TI - Eruption times and patterns of permanent teeth in school children of India. AB - AIM: To study the eruption pattern of permanent teeth excluding third molars in school children of Mysore, South India. OBJECTIVES: To compare the eruption times determined with previous studies. To determine range of variation of the eruption time of each tooth and evaluate if any preponderance exists in the eruption timings of maxillary and mandibular teeth and between boys and girls. MATERIALS AND METHODS: This was a descriptive cross sectional study. A random sample of 5007 school children in the age group of 5-14 years was selected. The mean age of eruption of individual permanent teeth was recorded and results were analyzed using Probit analysis. RESULTS: The study population included 2371 boys constituting 47.26% and 2636 girls constituting 52.65% of the total sample. In the age group of 5 years, one of the permanent teeth was found to be erupted. In the age group of 14 years, all the permanent teeth except third molar had erupted. Girls showed early tooth eruption compared to boys. Mandibular teeth erupted earlier than maxillary teeth in both the sexes. Right and left sided teeth erupted at the same time in both the arches. CONCLUSION: The mean ages of eruption obtained from the present study are strikingly comparable with those of other investigators in different populations across the world. Since the current study involves a large sample of children, the data reported in this study could be used as standards when assessing permanent tooth eruption in Indian children. PMID- 22484867 TI - Efficacy of various spray disinfectants on irreversible hydrocolloid impression materials: an in vitro study. AB - BACKGROUND: Most of the materials (casts, impressions, etc.) that are sent to the dental laboratories show the presence of numerous pathogenic microorganisms. All the spray disinfectants are not equally effective against these microorganisms. AIMS AND OBJECTIVES: The aim was to compare the effectiveness of different spray disinfectants on irreversible hydrocolloid impressions and to find out the most effective dilution, contact time, and effect against each microorganism studied. MATERIALS AND METHODS: The effects of four spray disinfectants, 5.25% sodium hypochlorite, 0.525% sodium hypochlorite, 1:213 (1 part in 213 parts of water) povidone iodine, and 2% glutaraldehyde along with control (distilled water) on irreversible hydrocolloid impressions contaminated with Staphylococcus aureus, Bacillus subtilis and Streptococcus viridans were studied. RESULTS: Sodium hypochlorite, 5.25%, showed 1-min exposure time which was able to effect a 4 log 10 reduction in bacterial counts against S. aureus and S. viridans followed by 0.525% sodium hypochlorite and 2% glutaraldehyde for 10 min. None were able to effect a 4 log10 reduction against B. subtilis. CONCLUSION: Sodium hypochlorite with a concentration of 5.25% was the most effective disinfectant and required the shortest contact time (1 min). Not all ADA-approved concentrations of surface disinfectants work equally well on irreversible hydrocolloid impression materials. PMID- 22484869 TI - Radiographic versus electronic root canal working length determination. AB - PURPOSE: The aim of this ex vivo study was to compare the accuracy of radiographic and electronic root canal length determination methods, compared with actual root canal length obtained with stereomicroscope. MATERIALS AND METHODS: Thirty extracted single-rooted permanent teeth were used for this study. After access preparation, actual length (AL) of the root canal were determined for each tooth by inserting a #15 file until the tip of the file was visible at the apical foramen under a stereomicroscope. The radiographic working length determination was determined with a digital radiographic system and for the electronic measurement all teeth were embedded in an alginate model to test apex locator in-vitro. Data was analyzed using the descriptive statistic and intraclass correlation coefficient. RESULTS: No significant difference was found between the radiographic and electronic root canal working length determination (P>0.05). The percentage of electronic measurements within +/- 0.5 mm to the apical constriction was 93.34% and 90% for radiographic methods within +/- 0.5 mm of all cases compared with AL. CONCLUSIONS: The present ex vivo study showed that electronic root canal working length determination is not superior to radiographic methods. Both methods provided a good performance in determining the root canal working length. PMID- 22484868 TI - In vitro study on tooth enamel lesions related to whitening dentifrice. AB - BACKGROUND: The tooth whitening substances for extrinsic use that are available in Brazil contain hydrogen peroxide or carbamide peroxide. Several studies have attributed the appearance of lesions in the enamel morphology, including hypersensitivity, to these substances. Such lesions justify fluoride therapy and application of infrared lasers, among other procedures. However, there is no consensus among researchers regarding the relevance of the severity of lesions detected on the tooth surface. OBJECTIVES: The present study was carried out with an aim of evaluating in vitro the effects of the hydrogen peroxide, carbamide peroxide and sodium bicarbonate contained in dentifrice formulations, on human tooth enamel. MATERIALS AND METHODS: After darkening process in laboratory, human premolars were brushed using dentifrice containing the two whitening substances (Rembrandt - carbamide peroxide and Mentadent - hydrogen peroxide) and the abrasive product (Colgate - sodium bicarbonate). The degree of specimen staining before and after this procedure was determined using spectrophotometry. Scanning electron microscopy (SEM) was used to obtain images, which were analyzed to show the nature of the lesions that appeared on the enamel surface. RESULTS: The effectiveness of the whitening caused by hydrogen peroxide and carbamide peroxide and the abrasion caused by bicarbonate were confirmed, given that the treated test pieces returned to their original coloration. Based on SEM, evaluation of the enamel surfaces subjected to the test products showed that different types of morphologic lesions of varying severity appeared. CONCLUSIONS: Whitening dentifrice containing hydrogen peroxide and carbamide peroxide produced lesions on the enamel surface such that the greatest sequelae were associated with exposure to hydrogen peroxide. PMID- 22484870 TI - Variability in the proportion of components of iodoform-based Guedes-Pinto paste mixed by dental students and pediatric dentists. AB - OBJECTIVE: Guedes-Pinto paste (GPP) is an iodoform paste used in most dental schools in Brazil. The paste is a composite of medicines (Rifocort , camphorated paramonochlorophenol [PMCC], and iodoform) used for endodontic treatment of primary teeth. The aim of this study was to evaluate the proportion variability of GPP components when mixed by undergraduate dentistry students and pediatric dentists. MATERIALS AND METHODS: The study was divided into 4 groups: G1 (15 undergraduate students), G2 (15 specialists in Pediatric Dentistry), G3 (15 professors with clinical activity), and G4 (7 professors-researchers). All volunteers prepared GPP according to the original specifications: the same visual proportion for each component. The components were weighed using an analytical balance and the percentage was calculated. RESULT: After normality (Kolmogorov Smirnov) and homogeneity tests (Levene test), the data were submitted to analysis of variance and intraclass correlation coefficient tests (P<0.05). The percentage means of each respective group were as follows: Rifocort 20.2%, 20.8%, 26.7%, 27.3%; camphorated PMCC 9.2%, 8.1%, 6.7%, 5.1%; and the iodoform 70.6%, 71.1%, 64.7%, 67.6%. There were no significant differences between groups for the component percentages. There was a high intraclass correlation coefficient (G1 0.945; G2 0.951; G3 0.921; and G4 0.870). CONCLUSION: The proportion of GPP was similar in all the groups, allowing us to conclude that ideal GPP proportion, based on the entire group mean, was 23.8% of Rifocort(r) ; 7.0% of camphorated PMCC; and 69.2% of iodoform. PMID- 22484871 TI - Osteotome sinus floor elevation without bone grafting and simultaneous implant placement in the atrophic maxilla: a pilot study. AB - AIMS: This study evaluated the clinical and radiographic outcome of implants placed in the posterior maxilla with the osteotome sinus floor elevation (OSFE) technique without graft material. MATERIALS AND METHODS: Twenty-seven 4.1-mm diameter dental implants (Straumann AG, Basel, Switzerland) were placed to 17 sinuses with residual bone height of <= 10 mm and >= 5 mm to rehabilitate 23 molar and 4 premolar sites. Implants were simultaneously placed with the OSFE procedure without graft material. RESULTS: All implants were successfully integrated after 8-12 weeks healing time. At the 2-year follow-up, all the implants presented the survival criteria proposed by Buser et al. and Cochran et al. CONCLUSION: The OSFE technique without grafting material may be predictable because the success rate was 100% in this study. Implants gained endo-sinus bone despite the lack of graft material. More patients and longer follow-up are needed to validate the results of this pilot study. PMID- 22484872 TI - Influence of different light sources on the conversion of composite resins. AB - AIMS: The purpose of this paper was to evaluate the influence of different light curing units on the conversion of four composite resins with different compositions (Durafill VS - Heraeus-Kulzer, Tetric Ceram - Ivoclar/Vivadent, Filtek Supreme XT - 3M ESPE e Aelite LS Packable - Bisco), using differential scanning calorimetry. MATERIALS AND METHODS: A stainless steel matrix was used to prepare 48 cylindrical composite test samples (n=6), measuring 3 mm in diameter and 1 mm in thickness. The samples were photoactivated using a halogen lamp (Optilux 500 - Demetron/Kerr) and three different generations of light-emitting diodes (LEDs) (LEC-470 I - MMOptics, Radii Plus - SDI and Ultra-Lume LED 5 - Ultradent). After removal of the matrix, each sample was weighed and hermetically sealed in an aluminum pan and analyzed. The amount of heat liberated by thermopolymerisation of residual monomers after photoactivation was measured in Joules/gram (J/g). The data were submitted to Analysis of Variance (ANOVA) test (P <= 0.002) and the Tukey test (P < 0.05). RESULTS: The Ultra-Lume LED 5 was superior on degree of conversion for all resins. The Radii Plus was equal to the Ultra-Lume LED 5, except for the resin Tetric Ceram , were the Optilux 500 was superior. The LEC-470 I was inferior for the conversion of all resins. CONCLUSION: The study proves the importance of the compatibility of the different photoinitiators in resin composites with the different light sources. PMID- 22484873 TI - Non-doctor consultations and self-medication practices in patients seen at a tertiary dental center in Ibadan. AB - AIM: The aim of this study was to determine the prevalence of self-medication practices among dental out patients presenting at a tertiary health care center in Ibadan, and to determine factors that are associated with these practices. MATERIALS AND METHODS: All patients presenting over a 4-month period, who consented to participate in the study, had a semi-structured questionnaire, highlighting age, sex, income and educational qualification, history of past practice of self-medication, substances used and reasons for resorting to self medication administered to them. Data obtained were analyzed with the SPSS 12.0.1 software. Frequency tables were generated and statistical relationship between the variables was analyzed using the Chi-square test. Statistical significance was set at P>0.05. RESULTS: There were 108 (38.03%) males and 176 (61.97%) females. A total of 139 (48.9%) of the respondents claimed that they have been involved in self-medication. 54.7% of the people involved in self-medication were female, while 41.7% were male. There was a statistically significant difference in self-medication between males and females (P=0.001). 71.2% of the respondents had post-secondary education and only 28.8% had secondary education or less. CONCLUSION: Self-medication practices were quite high in this study, and these practices were also prevalent among the educated people. Drug control enforcement needs to be intensified and dental public health education needs to be given greater priority in the overall public health campaigns. PMID- 22484875 TI - Role of colors in prosthodontics: application of color science in restorative dentistry. AB - Shade selection procedure depends on various factors including translucency, contour and surface texture. Tooth shade selection using a conventional means involves a high degree of subjectivity. Traditional shade guides are available that use several methods for quantifying shade. Technology-based systems provide with an advantage of natural looking restorations. They include RGB devices, colorimeters, spectrophotometers. The impact of the color science can be seen on various restorative materials ranging from ceramics to maxillofacial prosthetic materials. PMID- 22484874 TI - Repair of amalgam restorations with composite resin and bonded amalgam: a microleakage study. AB - BACKGROUND: Total replacement is the most common technique for defective amalgam restorations, and it represents a major part of restorative dental treatment. Repair is an alternative option for amalgam restorations with localized defects. AIMS: This study compared microleakage of amalgam restorations repaired by bonded amalgam or composite resin. MATERIALS AND METHODS: Thirty extracted human pre molars were prepared and restored with class I amalgam. A simulated defect was prepared that included the cavosurface margin on restorations, and the pre-molars were assigned to two treatment groups (n=15): In group 1, premolars were treated by composite resin (34% Tooth Conditioner Gel + Adper Single Bond 2 + Z100) and in group 2, premolars were repaired by bonded amalgam (34% Tooth Conditioner Gel + Prime and Bond 2.1 + Permite C). The teeth were immersed in a 50% silver nitrate solution, thermocycled, sectioned longitudinally and then observed by three examiners using a stereomicroscope. Microleakage was evaluated using a 0-4 scale for dye penetration, and data was analyzed by Kruskal Wallis and Dunn tests. RESULTS: Neither of the two methods eliminated microleakage completely. Composite resin was significantly the most effective for repair/tooth interface sealing (score 0 = 80.0%; P=0.0317). For the repair/restoration interface, composite resin was also statistically more effective as a sealant (score 0=66%; P=0.0005) when compared to the bonded amalgam technique (score 0=13%; P=0.0005). CONCLUSIONS: The use of adhesive systems significantly affected the ability to seal the repair/ tooth interface. However, at the level of the repair/restoration interface, the bonded amalgam technique may increase microleakage. PMID- 22484876 TI - Colposcopy: a new ray in the diagnosis of oral lesions. AB - Oral squamous cell carcinoma is the most common cancer of the oral cavity. The survival rates for oral cancer patients will significantly be improved provided lesions are detected and treated at the infancy stage. Early diagnosis is therefore of paramount importance. Histopathological examination is considered as the gold standard in diagnosing oral lesions. Therefore, the selection for a biopsy site is highly significant. In this article, we present a current review of the colposcope and oral application of the colposcopy technique and its use as an adjunct in the early diagnosis of premalignant and malignant lesions of the oral mucosa. We stress upon the fact that colposcopy (direct oral microscopy) of oral mucosal lesions helps in selecting more representative sites for biopsy than routine clinical examination alone. Because of its precision, versatility, ease of use, and being a non-invasive technique, colposcopy might prove to be a useful step toward continuing to learn and improve the care for our patients. PMID- 22484877 TI - Ergonomic applications to dental practice. AB - The term "work-related musculoskeletal disorders (WMSDs)," refers to musculoskeletal disorders to which the work environment contributes significantly, or to musculoskeletal disorders that are made worse or longer lasting by work conditions or workplace risk factors. In recent years, there has been an increase in reporting WMSDs for dental persons. Risk factors of WMSDs with specific reference to dentistry include - stress, poor flexibility, improper positioning, infrequent breaks, repetitive movements, weak postural muscles, prolonged awkward postures and improper adjustment of equipment. Ergonomics is the science of designing jobs, equipment and workplaces to fit workers. Proper ergonomic design is necessary to prevent repetitive strain injuries, which can develop over time and can lead to long-term disability. In this article, 20 strategies to prevent WMSDs in the dental operatory are discussed. PMID- 22484878 TI - Perlecan (basement membrane heparan sulfate proteoglycan) and its role in oral malignancies: an overview. AB - Perlecan means pearl-like structures. Perlecan is a large proteoglycan (400-500 kDa) present in virtually all vascularized tissues with a distribution that is primarily confined to basement membranes including those of oral mucosa. It is a basement membrane-type heparan sulfate proteoglycan. Perlecan is synthesized by basal cells and fibroblasts adjacent to the basal lamina . Perlecan is also synthesized by vascular endothelial and smooth muscle cells present in the extracellular matrix. It has been demonstrated in recent years that perlecan is distributed in the stromal space of various pathophysiological conditions. The complex pleiotropy of perlecan suggests that this gene product is involved in several developmental processes, at both early and late stages of embryogenesis, as well as in cancer and diabetes. In the oral cavity, perlecan expression is reported to basal cells in normal mucosa and its expression increases in precancer and cancerous conditions. It is also expressed in various odontogenic tumors such as ameloblastoma, keratocyst odontogenic tumor, and also salivary gland tumors such as adenoid cystic carcinoma, mucoepidermoid carcinoma, etc. PMID- 22484879 TI - Oral lichenoid lesions: clinico-pathological mimicry and its diagnostic implications. AB - Oral cavity is commonly affected by number of lichenoid lesions, whose clinical and histopathologic features overlap due to the presence of inflammatory cells in connective tissue. Segregation of these lichenoid lesions is mandatory as each may embody a distinct disease entity in terms of cause, diagnosis and prognosis. The literature discussed in the article is an attempt to segregate individual lichenoid lesions by defining clinical and histopathologic variations among each other, which avoids the diagnostic problem. PMID- 22484880 TI - Primary tuberculosis of the oral cavity. AB - There is a well-known phrase that states, "The more things change, the more they stay the same." This expression continues to apply to tuberculosis (TB), a widespread infectious disease traced back to the earliest of centuries. TB has claimed its victims throughout much of known human history. Mycobacterium tuberculosis may have killed more persons than any other microbial pathogen and is one of the major causes of ill health and death worldwide. Although the overall incidence of TB has decreased, recently, the incidence of this disease appears to be increasing. Oral lesions of TB though uncommon are seen in both the primary and secondary stages of the disease. In secondary TB, the oral manifestations may be accompanied by lesions in the lungs, lymph nodes, or in any other part of the body and can be detected by a systemic examination. Most of the cases are secondary to pulmonary disease and the primary form is uncommon. Here, we present a case of primary oral TB, affecting the gingiva and hard palate in a 40-year-old Indian female patient. PMID- 22484881 TI - Accidental ingestion of a barbed wire broach and its endoscopic retrieval: prevention better than cure. AB - Ingestion of instruments is a potential complication that can occur during dental procedures. We report a case of accidental ingestion of an endodontic barbed wire broach during root canal treatment and its subsequent retrieval by endoscopic methods. Although prevention is the best approach, proper management of such an event is also crucial. The objective of this report is to draw attention to the potentially serious complications that can occur if preventive techniques are not practised, and to discuss the accepted guidelines for management of such an event. PMID- 22484882 TI - Darier disease with oral and esophageal involvement: a case report. AB - A 58-year-old man presented with itchy papular eruptions all over the body since 15 years. Intraoral examination revealed raised papular lesions on the labial mucosa, hard palate, and tongue. The histopathology of the oral and skin lesions was confirmative of Darier disease (DD). This patient also showed esophageal involvement, which was confirmed histopathologically. Such a presentation of DD, with oral and esophageal involvement, is rare. PMID- 22484883 TI - Multiple glass pieces in paranasal sinuses. AB - Here, a case has been reported of a road traffic accident with multiple glass pieces arranged in an unusual pattern in the left maxillary sinus, ethmoid sinus, nasopharynx and medial side of the orbit, as seen in the radiographs. Combined surgical approach through the existing wound and endoscopic surgery was successfully used to remove nearly all the glass pieces. PMID- 22484884 TI - Report of rare palatal expression of Nevus of Ota with amendment of Tanino's classification. AB - Nevus of Ota, a benign melanocytic pigmentary disorder with rare malignant transformation potential, affects 0.014-0.034% of the Asian and Black population and has a strong predilection for females. It occurs in the area innervated by the first and second division of the trigeminal nerve. Oral manifestation is rarely noted with only 14 cases reported till date. This report documents a case of Nevus of Ota with the infrequently noted oral involvement, in an Indian lady. Since oral manifestation is not acknowledged in Tanino's classification, the authors propose a modification to the same. PMID- 22484885 TI - Pleomorphic adenoma of the soft palate: myoepithelial cell predominant. AB - The pleomorphic adenoma is the most common salivary gland tumor. A remarkable morphological diversity can exist from one tumor to the next. We present here a case of pleomorphic adenoma of minor salivary glands of the soft palate which had predominantly myoepithelial cells with minimal stroma, ductal cells, or tubular elements. PMID- 22484886 TI - Restoration of blinking reflex and facial symmetry in a Bell's palsy patient. AB - Patients afflicted with Bell's palsy are faced with both functional and esthetic impairment. Prominent among these are the inability to close the eyelids and abnormal facial appearance, with concomitant difficulty in eating, drinking and speaking. Rehabilitation of such patients can be achieved by a multispecialty approach, with the prosthodontist functioning as an integral part of the treatment team. This article describes a simple and effective approach to restore the blinking reflex of the upper eyelid with custom gold implant and facial esthetics with cheek support prosthesis. PMID- 22484887 TI - Exostosis: a donor site for autograft. AB - This article reports the utilization of exostosis as a source of autogenous bone for the treatment of osseous defects. A patient presented with an exostosis on the mandibular lingual region on the right side of the jaw. Exostosis was surgically removed using a chisel and mallet. The autograft thus obtained was used to treat a shallow osseous crater between 46 and 47. New bone formation was noticed at the grafted site 6 months after grafting. Bone formed in the grafted areas showed comparable clinical features to those of native bone. PMID- 22484889 TI - Is the concept of ethics misplaced in the migration of Indian trained dentists to Australia? The need for better international co-operation in dentistry. AB - The purpose of this article is to discuss the ethics involved in the migration of Indian trained dentists to Australia. It develops from interviews of senior oral health leaders in both the countries to provide evidence that ethics in migration is diluted in practice and to suggest that migratory procedures in both the countries should be reconsidered. There is also an urgent need for more organized bilateral communication and negotiation between the concerned organizations of both the countries (dental councils, immigration departments and research centers) in order to prevent the somewhat irreversible and intensive brain drain of top quality dentists from India to Australia. We would suggest as a starting point better monitoring of the migrants' academic and social background, the nature of the educational investment in India and the nature of the stay in Australia. This new information base could possibly lay the groundwork for more restrictive policies to be introduced both in Australia and India. PMID- 22484888 TI - A modified technique for retention of orbital prosthesis. AB - An orbital defect (congenital or acquired) causes severe facial asymmetry and disfigurement, which results in psychological and social disturbances to the patient. It becomes a challenging task for a maxillofacial prosthodontist to fabricate a prosthesis that replicates the healthy side of the face. Success of the prosthesis depends primarily on satisfactory retention of the same. This clinical report illustrates rehabilitation of a patient with an orbital defect by fabricating a hollow orbital prosthesis, utilizing anatomical undercuts for retention using an acrylic resin template relined by a resilient denture liner. PMID- 22484890 TI - Oral lesions associated with hydroxyurea treatment. AB - Hydroxyurea (HU) is an antimetabolic agent commonly used in myeloproliferative disorders and hematological diseases as well as in severe psoriasis. Despite of usually be well tolerated, sometimes it can induce immunosuppression and mucocutaneous adverse effects associated with discomfort or pain. Nevertheless, oral mucosal adverse reactions are extremely uncommon and present as ulcers, tongue depapilation and dyschromia. Complete remission of adverse effects is usually observed after withdrawal of the medication. The aim of this paper is to report two patients with oral lesions related to HU treatment. T0 he patients were adequately managed by changing hydroxyurea with imatinib mesilate. Oral lesions are rare complications of long-term hydroxyurea treatment and may be an indication of stopping therapy and substitution with imatinib mesilate. PMID- 22484891 TI - Intermuscular lipoma of the submandibular space. AB - Deep lipomas, especially in the head and neck region, are uncommon. This report describes the case of a patient with a large intermuscular lipoma of the submandibular space, which had been present for 10 years and was diagnosed by computed tomography. The clinical, imaging, and histopathological features, as well as the management of the tumor, are described. PMID- 22484892 TI - A conservative approach to pediatric mandibular fracture management: outcome and advantages. AB - Pediatric mandibular fractures are rare and their treatment remains controversial. Management is extremely complicated in mixed dentition as it is inherently dynamic and unstable. Treatment options include soft diet, intermaxillary fixation with eyelet wires, arch bars, circummandibular wiring, or stents. Alternative options include open reduction and internal fixation through either an intraoral or extraoral approach. This case report describes and evaluates the conservative technique of acrylic splint in the treatment of pediatric mandible fracture in a 12-year-old female child. The patient with isolated mandibular fracture was treated with acrylic splint and interdental wiring followed by evaluation of clinical and radiographic healing as well as the somatosensory status. Patient demonstrated clinical union to her pre-injury occlusion by three to four weeks. Panoramic finding supported the finding of clinical examination throughout the study. High osteogenic potential of the pediatric mandible allowed conservative management to be successful in this case. PMID- 22484893 TI - Comparison of fracture resistance of teeth restored with ceramic inlay and resin composite: an in vitro study. AB - AIM: The aim of this study was to evaluate the in vitro fracture resistance of teeth restored with bonded ceramic inlay and direct composite resin restoration in comparison to the normal tooth. MATERIALS AND METHODS: This study evaluated the fracture strength of the teeth restored with bonded ceramic inlay and direct composite resin restoration in comparison to the normal teeth. Thirty intact human maxillary first premolars were assigned to three groups: Group 1 - comprising sound/unprepared teeth (control). Group 2 - comprising of Class-II direct composite resin restored teeth and Group 3 - comprising Class-II ceramic inlay restored teeth. Cavities were prepared with occlusal width of 1/3 intercuspal distance and 2 mm deep pulpally. Group 2 teeth were restored with hybrid composite resin (Z350 3M ESPE, USA) and group 3 teeth were restored with Vitadur Alpha alumina (Ivoclare Vivadent, Liechtenstein, Europe). Ceramic inlay was bonded with adhesive cement (rely X resin cement of 3MESPE, USA). The specimens were subjected to a compressive load until they fractured. Data were analyzed statistically by unpaired Student's t test. RESULTS: The fracture resistant strength, expressed as kilonewton (KN), was group 1 - 1.51 KN, group 2 1.25 KN, and group 3 - 1.58 KN. Statistically, group III had highest fracture resistance followed by group I, while group II had the lowest average fracture resistance. CONCLUSION: The fracture resistant strength of teeth restored with ceramic inlay was comparable to that of the normal intact teeth or slightly higher, while teeth restored with direct composite resin restoration showed less fracture resistant strength than that of the normal teeth. PMID- 22484894 TI - Oxidation heat treatment affecting metal-ceramic bonding. AB - AIM OF THE STUDY: There is dearth of literature regarding the effects of oxidation heat treatment (OHT) as surface pretreatments on bond strength of base metal alloys and porcelain. MATERIALS AND METHODS: Forty-five bar specimens of each two commercially available base metal alloys Mealloy and Wirorn-99 (were fabricated. Dimensions of each specimen were 15.0 * 2.0 * 0.5 mm (according to the ISO 6872-1984). According to the surface pretreatments the samples of the two groups were categorized into three subgroups: With OHT only, with sandblasting only (with Al2O3 of 110 MUm) and with OHT and sandblasting. Application of commercially available Duceram porcelain in thickness of 2.00 mm was applied over the surface of metal with the pretreatments. Samples were then placed under SEM for EDX examination to evaluate ionic changes that occurred at the metal-ceramic interface. Flexural bond strength of each sample was calculated under Universal Testing Machine. RESULTS: The one-way ANOVA indicated no significant influence of either metal type (P=0.811) or any surface pretreatment (P=0.757) on the metal ceramic bond strength. CONCLUSION: OHT resulted in the increase in amount of oxides at the metal-ceramic interface. However, neither metal type nor surface pretreatments affected bond strength. PMID- 22484895 TI - Alveolar bone mass in pre- and postmenopausal women with serum calcium as a marker: a comparative study. AB - CONTEXT: In most women bone mass reaches its peak in the third decade of life and declines thereafter with the onset of menopause and might lead to osteoporosis. Osteoporosis may result in reduced jaw bone mass and alterations of the mandibular structure. Qualitative and quantitative indices have been used for panoramic radiographs to assess the alveolar bone quality. AIMS: The purpose of this study was to compare the alveolar bone quality of premenopausal and postmenopausal women using the panoramic mandibular index (PMI). This study also aimed to estimate the levels of serum calcium in premenopausal and postmenopausal women. SETTINGS AND DESIGN: Single centre case control study. MATERIALS AND METHODS: A total of 30 patients were divided into three groups of ten each - the healthy group, control group, and study group. Alveolar bone mass was evaluated by the PMI. Serum calcium was also assessed for all the patients. STATISTICAL ANALYSIS USED: The results obtained were subjected to statistical analysis by one way analysis of variance using Statistical Software SPSS version 17, Tukey test for comparision, Pearson's correlation coefficient was employed. RESULTS: Premenopausal women had the highest values for alveolar cortical bone mass as recorded by the PMI, followed by postmenopausal women with a healthy periodontium. The lowest values were recorded in the group of postmenopausal women with chronic generalized periodontitis. Similar results were found for serum calcium values. CONCLUSION: Postmenopausal women exhibit a reduced alveolar bone mass and lowered levels of serum total calcium with the increasing age. These changes may be useful indicators for low skeletal bone mineral density or osteoporosis. PMID- 22484896 TI - Proliferative and morphologic characterization of buccal mucosal fibroblasts in areca nut chewers: a cell culture study. AB - OBJECTIVE: To isolate, culture and characterize fibroblasts from the buccal mucosa of areca nut chewers with and without oral submucous fibrosis (OSF). MATERIALS AND METHODS: Primary fibroblast cultures were established by the collagenase disaggregation technique and the phenotypic and growth characteristics were studied. RESULTS: Cells cultured from OSF showed a statistically significant increase in both the post-mitotic fibroblast subpopulation and the population doubling time when compared with controls. CONCLUSION: There was a significant increase in the pro-fibrotic, post-mitotic subpopulation of fibroblasts in areca nut chewers with OSF. PMID- 22484897 TI - Rigidity, retention, and resistance of titanium versus double taper light root canal posts: an in vitro evaluation. AB - AIM: to evaluate and compare the physical properties of titanium posts and double taper (DT) light posts. MATERIALS AND METHODS: Sixty posts (30 titanium post and 30 DT light post) were selected and divided into three groups. In Group I: Ten posts of each type were subjected to a three-point bending test. In Group II: 20 posts extracted maxillary central incisors were restored with ten posts of each type and subjected to tensile loading. In Group III: 20 posts extracted maxillary central incisors were restored with ten posts of each type and subjected to compressive loading at an angle of 135 degrees . RESULTS: The results showed that DT light posts were significantly less rigid (P <0.001), more retentive and significantly less resistant to fracture (P <0.001) as compared to titanium posts. CONCLUSION: It is suggested that although the DT light post system does not completely fulfill the requirements claimed by manufacturer but it would meet the requirements to combat the physiological forces operating in the oral cavity. PMID- 22484898 TI - A comparative study to evaluate the discrepancy in condylar guidance values between two commercially available arcon and non-arcon articulators: a clinical study. AB - AIM: The purpose of this study was comparative evaluation of sagittal condylar values of arcon and non-arcon articulators with cephalometric readings and to determine the amount of discrepancy in sagittal condylar guidance values between arcon and non-arcon articulators using same protrusive record. MATERIALS AND METHODS: Twenty subjects in the age group of 19-35 years, free from temporomandibular joint dysfunction, and occlusal disharmony, with healthy dentition participated in the study. Hanau H2 (non-arcon type) and Hanau Wide-Vue (arcon type) articulators were programmed for sagittal condylar guidance values using the same protrusive record made in polysiloxane bite registration material with edge to edge degree of protrusion. The resultant values for both the articulators on either side were compared with values obtained from tracing of digital lateral cephalogram using Kodak Dental imaging Window software 6.6.3.0-C program. The tabulated data were subjected to statistical analysis, ANOVA (Fishers 'F' test) for group comparison, Tukey's HSD test for inter-comparison, student's unpaired 't' test for intra-group comparison, and level of significance (P) was calculated using the same. RESULTS: The mean sagittal condylar guidance values of the three different groups were found to be very highly significant (P=0.001) and highly significant (P=0.002) on the right and left sides respectively. There was a very highly significant difference (P=0.001) and highly significant difference (P=0.003) between the arcon and non-arcon group on the right and left side respectively. No significant difference was found between the arcon and cephalometric group (P=0.284 right, P=0.853 left) and a statistically significant difference was found between the non-arcon and cephalometric group (P=0.049 right, P=0.015 left). On intragroup comparison there was no statistically significant difference in sagittal condylar values on the right and left sides. CONCLUSION: The mean difference in the sagittal condylar guidance values obtained from non-arcon and arcon articulators shows a low level of reproducibility, and no significant difference found in mean sagittal condylar values obtained from arcon articulator and cephalometric tracings indicates replication of sagittal condylar guidance value from image of articular eminence. PMID- 22484899 TI - A SEM evaluation of dentinal adaptation of root canal obturation with GuttaFlow and conventional obturating material. AB - OBJECTIVE: The aim of this in-vitro study was to compare dentinal adaptation of conventional obturating material and GuttaFlow in young permanent teeth of child patients. MATERIALS AND METHODS: Ten young permanent anterior teeth with closed foramen were selected for the study. Root canal preparations were carried out using a step back technique. The canal was alternately irrigated with 5.25% sodium hypochlorite solution and 17% EDTA and normal saline. After root canal preparation specimens were randomly divided into two groups (n=5). GROUP "A": Obturated with zinc-oxide eugenol sealer and gutta-percha cone using cold lateral obturation technique. GROUP "B": Obturated with GuttaFlow as per the manufacturer's instruction. The teeth were split into two halves. Five randomly chosen longitudinal split teeth samples each from Group "A" and Group "B" was observed under scanning electron microscope to access the interface between obturating material and dentin at the level of 2 mm from the apex. RESULTS: On statistical analysis the dentinal adaptation (MUm) of Group A was observed with a mean of 0.52 and standard deviation 0.15, while the value of mean and standard deviation were noted 0.12 and 0.02 for Group B. The "t" value on comparison of Group A and Group B is 5.79 with "P " value of <0.001, which is highly significant. CONCLUSION: From result of the study it can be concluded Group B samples showed significantly superior seal when compared with Group A. Complete seal was not observed in any of Group A samples. PMID- 22484900 TI - Dimensional accuracy and detail reproduction of two hydrophilic vinyl polysiloxane impression materials tested under different conditions. AB - BACKGROUND AND OBJECTIVES: A limitation of vinyl polysiloxane (VPS) impression materials is hydrophobicity, and manufacturers have added surfactants and labeled these new products as "hydrophilic." The purpose of this investigation was to evaluate and compare the dimensional accuracy and surface detail reproduction of two hydrophilic VPS impression materials under dry, moist, and wet conditions. MATERIALS AND METHODS: Ten impressions were made under dry, moist, and wet conditions respectively, with monophase, and regular body VPS impression material using a stainless steel metal die similar to that described in American Dental Association (ADA) specification 19, with lines scribed on it. Dimensional accuracy was measured by comparing the average length of the middle horizontal line in each impression to the same line on the metal die, by using a measuring microscope. The surface detail was evaluated. A one-way analysis of variance and Student t-test were used to compare mean dimensional changes (alpha = 0.05). RESULTS: Conditions (dry, moist, and wet) did not cause significant adverse effects on the dimensional accuracy of either material. The mean dimensional changes were 0.00084% (+0.00041%) for monophase and 0.00119% (+0.00033%) for regular body. Monophase material was satisfactory in detail reproduction 100% of the time in dry conditions, 90% in moist, and only 20% in wet conditions. The regular body showed 100% satisfactory impressions in dry, 80% in moist, and 10% in wet conditions. With the additional smooth surface evaluation, only under dry conditions impressions with clinically acceptable surface quality were produced. CONCLUSIONS: Dimensional changes for both materials were well within ADA standards of minimal shrinkage value of 0.5%. PMID- 22484901 TI - A correlative study of dental age and skeletal maturation. AB - INTRODUCTION: Skeletal age had been assessed by comparison between maturation of hand-wrist with stages of cervical vertebrae or canine calcification stages in past and this had been closely related to craniofacial growth. The importance of pubertal growth spurt in various types of orthodontic therapies is already established. AIMS AND OBJECTIVES: Hence, this study was aimed to evaluate the relationship of skeletal maturity by hand-wrist with cervical vertebral maturation indicators and canine calcification stages. MATERIALS AND METHODS: The study consisted of randomly selected 90 children from Lucknow population with 45 males (age range 10-13 years) and 45 females (age range 9-12 years). Lateral Cephalogram, hand-wrist x-ray, and periapical x-rays of maxillary and mandibular right canines were taken. STATISTICAL ANALYSIS: Mean, standard deviation was calculated of different groups. Correlation was made among cervical vertebral maturation, hand wrist maturation, and canine calcification stages at various age groups. RESULTS: There was strong correlation between skeletal maturation indicator and cervical vertebral maturation indicator for both male (0.849) and female (0.932), whereas correlation between skeletal maturation indicator and canine calcification was good for both male and female (0.635, 0.891). CONCLUSION: It was concluded that cervical vertebral maturation indicator and canine calcification stages can also be used for assessing skeletal maturity. PMID- 22484902 TI - Salvation of a severely resorbed mandibular ridge with a neutral zone technique. AB - The objective of any prosthodontic service is to restore the patient to normal function, contour, esthetics, speech, and health. An optimum denture stability is difficult to achieve in conventional complete dentures. This problem is more magnified in mandibular dentures. The design of prostheses to replace lost teeth and resorbed ridges is largely determined by the position and amount of morphological change in the denture-bearing area of the jaws. A neutral zone may be defined as the space where, during function, the forces of the lips and cheeks pressing inward neutralize the forces of the tongue pressing outward. The neutral zone concept implies acquired muscle control, especially by tongue, lips, and cheeks toward the denture stability. Advocates of the neutral zone concept agree that a lack of favorable leverage is observed when teeth are positioned directly over the ridge. By employing the neutral zone concept, the dislodging muscle energy can easily become a retentive and stabilizing force. PMID- 22484903 TI - Preconcentration of trace lead and iron on activated carbon functionalized by o Anisic acid derivatives prior to their determination in environmental samples. AB - Two solid-phase adsorbents (phase I and phase II) were synthesized successfully that o-Anisic acid derivatives were evenly functionalized on the surface of activated carbon. It was certified that the two adsorbents were applied to preconcentrate and separate trace levels of Pb(II) and Fe(III) from natural liquid samples with satisfactory results. It can be found that the adsorption capacity of the ions adsorbed on phase I and phase II was 48.3 and 85.7 mg g(-1) for Pb(II), 39.5 and 72.5 mg g(-1) for Fe(III), respectively. The detection limit (3sigma) of the method separated on phase I and phase II was 0.12 and 0.09 ng mL( 1) for Pb(II), 0.23 and 0.17 ng mL(-1) for Fe(III), respectively. The relative standard deviation (R.S.D.) of the method was lower than 3.0%. The adsorption and desorption property of two kinds of adsorbents was comparatively studied, respectively. The adsorption selectivity of heavy metal ions at certain pH, the adsorption kinetics, the condition of complete elution, the effect of coexisting ions, the adsorption capacity and adsorption isotherm modes were examined. Based on the experimental datum determined by inductively coupled plasma optical emission spectrometry (ICP-OES), it was certified that the adsorption on the surface of adsorbents was in strict accordance with the monolayer adsorption principle. The structural features of series of multidentate ligand modified on adsorption matrix had been obtained. These conclusions can provide reference for synthesizing an efficient adsorbent which is specific to remove a particular kind of contaminant. PMID- 22484904 TI - Synthesis, spectroscopic characteristic of novel fluorescent dyes of pyrazoline compounds. AB - Four novel fluorescence dyes of the pyrazoline were synthesized and fully characterized by means of (1)H, (13)C NMR, and HRMS. The optical, electrochemical properties were also investigated. Solvent effect on the fluorescence characteristics of the four compounds indicates that the emission wavelength was red-shifted with the increase of solvent polarity. As we expected, the results indicated that these compounds exhibited high quantum yields. Quantum chemical calculations were used to obtain optimized ground-state geometry, spatial distributions of the HOMO, LUMO levels of the compounds. PMID- 22484905 TI - Spectral and in vitro antimicrobial properties of 2-oxo-4-phenyl-6-styryl-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid transition metal complexes. AB - 2-oxo-4-phenyl-6-styryl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid (ADP) was complexed with acetates of Mn(II), Ni(II), Cu(II) and Zn(II). The structures of the ligand and its metal complexes were characterized by microanalysis, IR, NMR, UV-vis spectroscopy, magnetic susceptibility and TGA-DTA analyses. Octahedral and square planar geometries were suggested for the complexes in which the central metal ion coordinated with O donors of ligand and acetate ions. Each ligand binds the metal using carboxylate oxygens. The ligand and complexes were evaluated for their antimicrobial activities against different species of pathogenic bacteria and fungi. The present novel pyrimidine containing complexes could constitute a new group of antibacterial and antifungal agents. PMID- 22484906 TI - Synthesis, spectroscopic characterization, DNA interaction and antibacterial study of metal complexes of tetraazamacrocyclic Schiff base. AB - The template condensation reaction between benzil and 3,4-diaminotoulene resulted mononuclear 12-membered tetraimine macrocyclic complexes of the type, [MLCl(2)] [M=Co(II), Ni(II), Cu(II) and Zn(II)]. The synthesized complexes have been characterized on the basis of the results of elemental analysis, molar conductance, magnetic susceptibility measurements and spectroscopic studies viz. FT-IR, (1)H and (13)C NMR, FAB mass, UV-vis and EPR. An octahedral geometry has been envisaged for all these complexes, while a distorted octahedral geometry has been noticed for Cu(II) complex. Low conductivity data of all these complexes suggest their non-ionic nature. The interactive studies of these complexes with calf thymus DNA showed that the complexes are avid binders of calf thymus DNA. The in vitro antibacterial studies of these complexes screened against pathogenic bacteria proved them as growth inhibiting agents. PMID- 22484907 TI - Visual assessment of magnetic resonance imaging perfusion lesions in a large patient group. AB - PURPOSE: Few magnetic resonance imaging (MRI) studies of stroke have evaluated the value of visual assessment of perfusion/diffusion mismatch, which is crucial for routine application. In this study an attempt was made to visually assess perfusion lesions resembling the acute clinical situation and identify parameters with the highest interobserver reliability when used to define a perfusion/diffusion mismatch and the highest accuracy for prediction of infarct growth. METHODS: Magnetic resonance imaging was performed within 6 h of symptom onset and again 1-11 days thereafter in 86 consecutive stroke patients who received intravenous thrombolytic therapy. The MRI protocol included diffusion weighted imaging apparent diffusion coefficient (DWI/ADC), fluid-attenuated inversion recovery (FLAIR) and perfusion imaging (PI). Maps for different perfusion parameters, e.g. cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT) and time to peak (TTP) were calculated. Areas of perfusion deficits of all perfusion parameters were visually compared to corresponding ADCs and final infarct size by two independent observers. RESULTS: The final infarct size was overestimated by TTP (in 81/83 patients by raters 1 and 2, respectively), MTT (82/83) and CBF (65/74) lesions. The ADC lesions were rated smaller than the final infarct size in 43/38 cases by raters 1 and 2 and the CBV decrease was rated to underestimate final infarct size in 40/31 cases. The only significantly increased OR of 3.883 (95 % CI 1.466-10.819, p = 0.004, rater 1)/5.142 (95 % CI 1.828-15.142, p = 0.001, rater 2) for predicting infarct growth was observed for the presence of a CBV > ADC mismatch, which also showed the highest kappa value of 0.407. CONCLUSIONS: All mismatch patterns were prone to high interrater variability when assessed under conditions resembling the clinical setting. Of all tested mismatch patterns the CBV > ADC mismatch was the strongest predictor of lesion growth while visual assessment of TTP and CBF generally resulted in an overestimation of infarct sizes and the presence of a TTP > ADC or CBF > ADC mismatch was not significantly predictive for lesion growth. Visual inspection of these most commonly used mismatch patterns has a low value for the prediction of infarct growth and thus the estimation of the penumbra in ischemic stroke patients. PMID- 22484908 TI - Inhibition of ARNT severely compromises endothelial cell viability and function in response to moderate hypoxia. AB - Hypoxia inducible factor (HIF) is a master heterodimeric transcriptional regulator of oxygen (O(2)) homeostasis critical to proper angiogenic responses. Due to the distinctive coexpression of HIF-1alpha and HIF-2alpha subunits in endothelial cells, our goal was to examine the genetic elimination of HIF transcriptional activity in response to physiological hypoxic conditions by using a genetic model in which the required HIF-beta subunit (ARNT, Aryl hydrocarbon Receptor Nuclear Translocator) to HIF transcriptional responses was depleted. Endothelial cells (ECs) and aortic explants were isolated from Arnt ( loxP/loxP ) mice and infected with Adenovirus-Cre/GFP or control-GFP. We observed that moderate levels of 2.5 % O(2) promoted vessel sprouting, growth, and branching in control aortic ring assays while growth from Adenovirus-Cre infected explants was compromised. Primary Adenovirus-Cre infected EC cultures featured adverse migration and tube formation phenotypes. Primary pulmonary or cardiac ARNT deleted ECs also failed to proliferate and survive in response to 8 or 2.5 % O(2) and hydrogen peroxide treatment. Our data demonstrates that ARNT promotes EC migration and vessel outgrowth and is indispensible for the proliferation and preservation of ECs in response to the physiological environmental cue of hypoxia. Thus, these results demonstrate that ARNT plays a critical intrinsic role in ECs and support an important collaboration between HIF-1 and HIF-2 transcriptional activity in these cells. PMID- 22484909 TI - Overactivation of Ras signaling pathway in CD133+ MPNST cells. AB - Cancer stem cells (CSCs) are believed to be the regenerative pool of cells responsible for repopulating tumors. Gaining knowledge about the signaling characteristics of CSCs is important for understanding the biology of tumors and developing novel anti-cancer therapies. We have identified a subpopulation of cells positive for CD133 (a CSC marker) from human primary malignant peripheral nerve sheath tumor (MPNST) cells which were absent in non-malignant Schwann cells. CD133 was also found to be expressed in human tissue samples and mouse MPNST cells. CD133+ cells were capable of forming spheres in non-adherent/serum free conditions. The activation levels of Ras and its downstream effectors such as ERK, JNK, PI3K, p38K, and RalA were significantly increased in this population. Moreover, the CD133+ cells showed enhanced invasiveness which was linked to the increased expression of beta-Catenin and Snail, two important proteins involved in the epithelial to mesenchymal transition, and Paxilin, a focal adhesion protein. Among other important characteristics of the CD133+ population, endoplasmic reticulum stress marker IRE1alpha was decreased, implying the potential sensitivity of CD133+ to the accumulation of unfolded proteins. Apoptotic indicators seemed to be unchanged in CD133+ cells when compared to the wild (unsorted) cells. Finally, in order to test the possibility of targeting CD133+ MPNST cells with Ras pathway pharmacological inhibitors, we exposed these cells to an ERK inhibitor. The wild population was more sensitive to inhibition of proliferation by this inhibitor as compared with the CD133+ cells supporting previous studies observing enhanced chemoresistance of these cells. PMID- 22484910 TI - Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression. AB - The leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family is comprised of three integral membrane proteins: LRIG1, LRIG2, and LRIG3. LRIG1 is a negative regulator of growth factor signaling. The expression and subcellular localization of LRIG proteins have prognostic implications in primary brain tumors, such as oligodendrogliomas and astrocytomas. The expression of LRIG proteins has not previously been studied in meningiomas. In this study, the expression of LRIG1, LRIG2, and LRIG3 was analyzed in 409 meningiomas by immunohistochemistry, and potential associations between LRIG protein expression and tumor grade, gender, progesterone receptor status, and estrogen receptor (ER) status were investigated. The LRIG proteins were most often expressed in the cytoplasm, though LRIG1 also showed prominent nuclear expression. Cytoplasmic expression of LRIG1 and LRIG2 correlated with histological subtypes of meningiomas (p = 0.038 and 0.013, respectively). Nuclear and cytoplasmic expression of LRIG1 was correlated with ER status (p = 0.003 and 0.004, respectively), as was cytoplasmic expression of LRIG2 (p = 0.006). This study is the first to examine the expression of LRIG proteins in meningiomas, and it shows a correlation between ER status and the expression of LRIG1 and LRIG2, which suggests a possible role for LRIG proteins in meningioma pathogenesis. PMID- 22484911 TI - Treatment of type 2 diabetes in the elderly. AB - As the number of older adults increases in the United States and worldwide, management of patients with multiple coexisting chronic diseases has become a critical component in health care. Management of diabetes is particularly challenging in this population due to significant risks of microvascular and macrovascular diseases on the one hand, and complications of the treatment strategies (e.g., hypoglycemia) with intensive control on the other hand. To provide a balanced approach to diabetes in the elderly, a comprehensive and holistic strategy, with consideration of overall health, functional status, psychosocial environment, financial resources and, finally but most importantly, quality of life is needed. Understanding the unique challenges faced by older adults with diabetes and issues pertaining to antidiabetes medications with aging is an important first step in the direction of better and tailored care of this burgeoning population. PMID- 22484912 TI - Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. AB - The blood vessels of cancerous tumours are leaky and poorly organized. This can increase the interstitial fluid pressure inside tumours and reduce blood supply to them, which impairs drug delivery. Anti-angiogenic therapies--which 'normalize' the abnormal blood vessels in tumours by making them less leaky--have been shown to improve the delivery and effectiveness of chemotherapeutics with low molecular weights, but it remains unclear whether normalizing tumour vessels can improve the delivery of nanomedicines. Here, we show that repairing the abnormal vessels in mammary tumours, by blocking vascular endothelial growth factor receptor-2, improves the delivery of smaller nanoparticles (diameter, 12 nm) while hindering the delivery of larger nanoparticles (diameter, 125 nm). Using a mathematical model, we show that reducing the sizes of pores in the walls of vessels through normalization decreases the interstitial fluid pressure in tumours, thus allowing small nanoparticles to enter them more rapidly. However, increased steric and hydrodynamic hindrances, also associated with smaller pores, make it more difficult for large nanoparticles to enter tumours. Our results further suggest that smaller (~12 nm) nanomedicines are ideal for cancer therapy due to their superior tumour penetration. PMID- 22484913 TI - Remote Joule heating by a carbon nanotube. AB - Minimizing Joule heating remains an important goal in the design of electronic devices. The prevailing model of Joule heating relies on a simple semiclassical picture in which electrons collide with the atoms of a conductor, generating heat locally and only in regions of non-zero current density, and this model has been supported by most experiments. Recently, however, it has been predicted that electric currents in graphene and carbon nanotubes can couple to the vibrational modes of a neighbouring material, heating it remotely. Here, we use in situ electron thermal microscopy to detect the remote Joule heating of a silicon nitride substrate by a single multiwalled carbon nanotube. At least 84% of the electrical power supplied to the nanotube is dissipated directly into the substrate, rather than in the nanotube itself. Although it has different physical origins, this phenomenon is reminiscent of induction heating or microwave dielectric heating. Such an ability to dissipate waste energy remotely could lead to improved thermal management in electronic devices. PMID- 22484914 TI - A retained catheter fragment in radial artery caused by accidental catheter transection during arterial catheter removal. PMID- 22484915 TI - Inhibiting galectin-1 reduces murine lung metastasis with increased CD4(+) and CD8 (+) T cells and reduced cancer cell adherence. AB - Galectin-1 is a beta-galactoside-binding protein overexpressed by cancer cells. The primary roles of galectin-1 in cancer progression and metastasis are attributed to suppression of T cell immune responses, promotion of tumor angiogenesis and increased tumor cell adhesion and invasion. Using pulmonary metastasis models of murine breast (4T1) and colon (CT26) cancer, we demonstrate that targeting galectin-1 with thiodigalactoside (TDG) or shRNA galectin-1 knockdown (G1KD) results in a significant reduction in lung metastasis. Increased numbers of CD4(+) helper T cells and CD8(+) cytotoxic T lymphocytes were found in the peripheral blood of both TDG-treated and G1KD cell challenged mice. The levels of TUNEL(+) apoptotic cancer cells and the presence of CD3(+) T cells were also increased in lung metastases. Furthermore, galectin-1 was found to bind to the adhesion molecules, CD44 and CD326, which are also known as markers of breast and colon cancer stem cells, and TDG likely blocks galectin-1 binding to these molecules. The TDG-mediated inhibition of galectin-1 binding reduced 4T1 cell adhesion to the basement membrane protein laminin, Matrigel and EAhy926 endothelial cell surfaces. These findings establish possible mechanisms for the anti-metastatic effect of galectin-1 inhibition and suggest that targeting galectin-1 may represent a promising and effective anti-metastatic therapy. PMID- 22484916 TI - In vivo imaging of colorectal cancer growth and metastasis by targeting MACC1 with shRNA in xenografted mice. AB - We previously identified the gene metastasis-associated in colon cancer-1 (MACC1) and demonstrated its important role for metastasis prediction in colorectal cancer. MACC1 induces cell motility and proliferation in vitro as well as metastasis in several mouse models. Here we report non-invasive real time imaging of inhibition of colorectal tumor progression and metastasis in xenografted mice by MACC1 shRNA. First, we demonstrated reduction of tumors and liver metastases by endpoint imaging of mice transplanted with MACC1 endogenously high expressing colorectal cancer cells and treated with shRNAs acting on MACC1 or Met. Next, we generated a novel bicistronic IRES vector simultaneously expressing the reporter gene firefly luciferase and MACC1 to ensure a direct correlation of bioluminescence signal with MACC1 expression. We transfected MACC1 endogenously low expressing colorectal cancer cells with this luciferase-IRES-MACC1 construct, transplanted them intrasplenically, and monitored MACC1 induced tumor growth and metastasis by in vivo imaging over time. Transfection of an IRES construct harboring the firefly luciferase reporter gene together with MACC1 lacking the SH3-domain reduced tumor growth and metastasis. Finally, we counteracted the luciferase-IRES-MACC1 induced effects by shRNA targeting MACC1 and monitored reduced tumor growth and metastasis by in vivo imaging over weeks. In summary, the new bicistronic luciferase-IRES-MACC1 construct is suitable for in vivo imaging of tumor progression and metastasis, and moreover, for imaging of therapy response such as treatment with MACC1 shRNA. Thereby, we provide proof-of-concept for employment of this MACC1-based in vivo model for evaluating therapeutic intervention strategies aiming at inhibition of tumor growth and metastasis. PMID- 22484917 TI - Targeting monocyte chemotactic protein-1 synthesis with bindarit induces tumor regression in prostate and breast cancer animal models. AB - Prostate and breast cancer are major causes of death worldwide, mainly due to patient relapse upon disease recurrence through formation of metastases. Chemokines are small proteins with crucial roles in the immune system, and their regulation is finely tuned in early inflammatory responses. They are key molecules during inflammatory processes, and many studies are focusing on their regulatory functions in tumor growth and angiogenesis during metastatic cell seeding and spreading. Bindarit is an anti-inflammatory indazolic derivative that can inhibit the synthesis of MCP-1/CCL2, with a potential inhibitory function in tumor progression and metastasis formation. We show here that in vitro, bindarit can modulate cancer-cell proliferation and migration, mainly through negative regulation of TGF-beta and AKT signaling, and it can impair the NF-kappaB signaling pathway through enhancing the expression of the NF-kappaB inhibitor IkB alpha. In vivo administration of bindarit results in impaired metastatic disease in prostate cancer xenograft mice (PC-3M-Luc2 cells injected intra-cardially) and impairment of local tumorigenesis in syngeneic Balb/c mice injected under the mammary gland with murine breast cancer cells (4T1-Luc cells). In addition, bindarit treatment significantly decreases the infiltration of tumor-associated macrophages and myeloid-derived suppressor cells in 4T1-Luc primary tumors. Overall, our data indicate that bindarit is a good candidate for new therapies against prostate and breast tumorigenesis, with an action through impairment of inflammatory cell responses during formation of the tumor-stroma niche microenvironment. PMID- 22484919 TI - Retroperitoneal schwannomas in the anterior pararenal space: dynamic enhanced multi-slice CT and MR findings. AB - BACKGROUND: To evaluate the imaging features of schwannomas in the anterior pararenal space (APS), especially focusing on dynamic enhanced multi-slice CT (MSCT) and MR findings. PATIENTS AND METHODS: Eight patients with pathologically proved retroperitoneal schwannomas in the APS underwent dynamic enhanced multi slice CT (MSCT), while three of these patients also had a contrast-enhanced MR examination. The imaging findings were retrospectively reviewed. RESULTS: All eight cases exhibited forward displacement of the pancreas, and three cases showed lateral displacement and compression of the inferior vena cava. The tumors had round or oval shape with a maximal axial diameter of 4.0-12.3 cm (average, 6.7 cm). All eight tumors were solitary and well circumscribed. Of the eight retroperitoneal schwannomas in the APS, six exhibited a capsule with thickness of 1.0-2.0 mm, one showed punctate calcification, two displayed cystic degeneration, and three revealed a "target sign" on CT and MR. The tumors were hypo-dense on unenhanced CT images, hyper-intense on T2W images, and homogeneously hypo-intense on T1W images. All eight tumors exhibited gradual enhancement on dynamic enhanced CT or MR images. One case showed delayed enhancement. Heterogeneous enhancement was the dominant pattern occurring in seven out of eight tumors. CONCLUSION: The imaging findings of schwannoma in the APS correspond with its pathological composition. Schwannoma should be included in the differential diagnosis of tumors in the APS. PMID- 22484918 TI - Changes in micro RNA expression in a wild tuber-bearing Solanum species induced by 5-Azacytidine treatment. AB - Phenotypic plasticity is often postulated as a principal characteristic of tuber bearing wild Solanum species. The hypotheses to explore this observation have been developed based on the presence of genetic variation. In this context, evolutionary changes and adaptation are impossible without genetic variation. However, epigenetic effects, which include DNA methylation and microRNAs expression control, could be another source of phenotypic variation in ecologically relevant traits. To achieve a detailed mechanistic understanding of these processes, it is necessary to separate epigenetic from DNA sequence-based effects and to evaluate their relative importance on phenotypic variability. We explored the potential relevance of epigenetic effects in individuals with the same genotype. For this purpose, a clone of the wild potato Solanum ruiz-lealii, a non-model species in which natural methylation variability has been demonstrated, was selected and its DNA methylation was manipulated applying 5 Azacytidine (AzaC), a demethylating agent. The AzaC treatment induced early flowering and changes in leaf morphology. Using quantitative real-time PCR, we identified four miRNAs up-regulated in the AzaC-treated plants. One of them, miRNA172, could play a role on the early flowering phenotype. In this work, we showed that the treatment with AzaC could provide meaningful results allowing to study both the phenotypic plasticity in tuber-bearing Solanum species and the inter-relation between DNA methylation and miRNA accumulations in a wide range of species. PMID- 22484920 TI - States of low pulmonary blood flow can be detected non-invasively at the bedside measuring alveolar dead space. AB - We tested whether the ratio of alveolar dead space to alveolar tidal volume (VD(alv)/VT(alv)) can detect states of low pulmonary blood flow (PBF) in a non invasive way. Fifteen patients undergoing cardiovascular surgeries with cardiopulmonary bypass (CPB) were studied. CPB is a technique that excludes the lungs from the general circulation. The weaning of CPB is a model that manipulates PBF in vivo because each time blood flow through the CPB decreases, expected PBF (ePBF) increases. Patients were liberated from CPB in steps of 20 % every 2' starting from 100 % CPB (very low ePBF) to 0 % CPB (100 % ePBF). During constant ventilation, volumetric capnograms were recorded and Bohr's dead space ratio (VD(Bohr)/VT), VD(alv)/VT(alv) and the ratio of airway dead space to tidal volume (VD(aw)/VT) were calculated. Before CPB, VD(Bohr)/VT was 0.36 +/- 0.05, VD(aw)/VT 0.21 +/- 0.04 and VD(alv)/VT(alv) 0.18 +/- 0.06 (mean +/- SD). During weaning from CPB, VD(aw)/VT remained unchanged while VD(Bohr)/VT and VD(alv)/VT(alv) decreased with increasing ePBF. At CPB of 80, 60, 40 and 20 % VD(Bohr)/VT was 0.64 +/- 0.06, 0.55 +/- 0.06, 0.47 +/- 0.05 and 0.40 +/- 0.04, respectively; p < 0.001 and VD(alv)/VT(alv) 0.53 +/- 0.07, 0.40 +/- 0.07, 0.29 +/ 0.06 and 0.25 +/- 0.04, respectively; p < 0.001). After CPB, VD(Bohr)/VT and VD(alv)/VT(alv) reached values similar to baseline (0.37 +/- 0.04 and 0.19 +/- 0.06, respectively). At constant ventilation the alveolar component of VD(Bohr)/VT increased in proportion to the deficit in lung perfusion. PMID- 22484921 TI - [B symptoms, lymphadenopathy and signs of systemic disease in a 21-year-old female]. AB - Sarcoidosis is a multi-systemic disease. A 21-year-old female patient was admitted to our department with lymphadenopathy, B symptoms, erythema nodosum and joint pain. Sarcoidosis showed a very atypical course, lacking any pulmonary symptoms or typical laboratory values. The diagnosis was finally confirmed histologically and thus various differential diagnoses such as microbiological and malignant diseases could be excluded. Oral steroid medication led to remission. PMID- 22484922 TI - Anti-aging effects of hesperidin on Saccharomyces cerevisiae via inhibition of reactive oxygen species and UTH1 gene expression. AB - This study used a replicative lifespan assay of K6001 yeast to screen anti-aging food factors in commercial flavonoids. Hesperidin derived from the Citrus genus extended the lifespan of yeast at doses of 5 and 10 uM as compared with the control group (p<0.01, p<0.01). Reactive oxygen species (ROS), real-time PCR (RT PCR), and lifespan assays of uth1 and skn7 mutants with the K6001 background were used to study the anti-aging mechanisms in yeast. The results indicate that hesperidin significantly inhibits the ROS of yeast, and UTH1 gene expression, and that SKN7 gene are involved in hesperidin-mediated lifespan extension. Further, increases in the Sir2 homolog, SIRT1 activity, and SOD gene expression were confirmed at doses of 5 (p<0.01) and 10 uM (p<0.05). This suggests that Sir2, UTH1 genes, and ROS inhibition after administration of hesperidin have important roles in the anti-aging effects of yeast. However, the aglycon hesperetin did not exhibit anti-aging effects in yeast. PMID- 22484923 TI - Construction of a metagenomic library for the marine sponge Halichondria okadai. AB - Symbionts of the marine sponge Halichondria okadai are promising as a source of natural products. Metagenomic technology is a powerful tool for accessing the genetic and biochemical potential of bacteria. Hence, we established a method of recovering bacterial-enriched metagenomic DNA by stepwise centrifugation. The metagenomic DNA was analyzed by ultrafast 454-pyrosequencing technology, and the results suggested that more than three types of bacterial DNA, Alphaproteobacteria, Actinobacteria, and Cyanobacteria, had been recovered, and that eukaryotic genes comprised only 0.02% of the metagenomic DNA. These results indicate that stepwise centrifugation and real-time quantitative PCR were effective for separating sponge cells and symbiotic bacteria, and that we constructed a bacteria-enriched metagenomic library from a marine sponge, H. okadai, selectively for the first time. PMID- 22484924 TI - CUE domain-containing protein Vps901 is required for vacuolar protein transport in Schizosaccharomyces pombe. AB - The functions of two Schizosaccharomyces pombe Vps9-like genes, SPBC4F6.10/vps901(+) and SPBC29A10.11c/vps902(+), were characterized. Genomic sequence analysis predicted that Vps901p contains a VPS9 domain, whereas cDNA analyses revealed that Vps901p contains a CUE domain (coupling of ubiquitin to ER degradation) in its C-terminal region. Deletion of vps901(+) resulted in mis sorting and secretion of S. pombe vacuolar carboxypeptidase Cpy1p, whereas deletion of vps902(+) had no effect, suggesting that only Vps901p functions in vacuolar protein transport in S. pombe. Deletion of vps901(+) further produced pleiotropic phenotypes, including vacuolar homotypic fusion and endocytosis defects. Heterologous expression of the budding yeast VPS9 gene corrected the CPY mis-sorting defect in vps901Delta cells. These findings suggest that the VPS9 domain of Vps901p is required for vacuolar protein trafficking in S. pombe. PMID- 22484925 TI - A polyphenol extract of Hibiscus sabdariffa L. ameliorates acetaminophen-induced hepatic steatosis by attenuating the mitochondrial dysfunction in vivo and in vitro. AB - Oxidative stress is the major contributor to acetaminophen (AAP)-caused liver damage. It promotes mitochondrial oxidative stress and collapses the mitochondrial membrane potential to cause cell death. We have previously shown that a polyphenol extract of Hibiscus sabdariffa L. (HPE) potentiated the antioxidative effect. We further examined in this study the possible mechanism of HPE against AAP-caused liver damage. BABL/c mice were orally fed with HPE (100, 200 or 300 mg/kg) for two weeks prior to an i.p. injection of 1000 mg/kg of AAP. The mice were decapitated 6 h after the AAP injection to collect the blood and liver for further determination. The results show that pretreating with HPE increased the level of glutathione (GSH), decreased the level of lipid peroxidation, and increased catalase activity in the liver. A histopathological evaluation shows that HPE could decrease AAP-induced liver sterosis accompanied by a decreased expression of AIF, Bax, Bid, and p-JNK in the liver. An in vitro assay revealed that HPE could reduce AAP-induced death of BABL/c normal liver cells (BNLs), reverse the lost mitochondrial potency and improve the antioxidative status, similarly to the results of the in vivo assay. We show in this study that HPE possessed the ability to protect the liver from AAP-caused injury. The protective mechanism might be regulated by decreasing oxidative stress and attenuating the mitochondrial dysfunction. PMID- 22484926 TI - SHRSP/Izm and WKY/NCrlCrlj rats having a missense mutation in Abcg5 deposited plant sterols in the body, but did not change their biliary secretion and lymphatic absorption-comparison with Jcl:Wistar and WKY/Izm rats. AB - We had previously found plant sterols deposited in the bodies of stroke-prone spontaneously hypertensive rats (SHRSP)/Sea and Wistar Kyoto (WKY)/NCrlCrlj rats that had a missense mutation in the Abcg5 cDNA sequence that coded for ATP binding cassette transporter (ABC) G5. We used SHRSP/Izm, WKY/NCrlCrlj, and WKY/Izm rats in the present study to determine the mechanisms for plant sterol deposition in the body. Jcl:Wistar rats were used as a control strain. A diet containing 0.5% plant sterols fed to the rats resulted in plant sterol deposition in the body of SHRSP/Izm, but not in WKY/Izm or Jcl:Wistar rats. Only a single non-synonymous nucleotide change, G1747T, resulting in a conservative cysteine substitution for glycine at amino acid 583 (Gly583Cys) in Abcg5 cDNA was identified in the SHRSP/Izm and WKY/NCrlCrlj rats. However, this mutation was not found in the WKY/Izm or Jcl:Wistar rats. No significant difference in the biliary secretion or lymphatic absorption of plant sterols was apparent between the rat strains with or without the missense mutation in Abcg5 cDNA. Our observations suggest that plant sterol deposition in rat strains with the missense mutation in Abcg5 cDNA can occur, despite there being no significant change in the biliary secretion or lymphatic absorption of plant sterols. PMID- 22484927 TI - Detection of Aeromonas salmonicida by reverse transcription-multiplex polymerase chain reaction. AB - Aeromonas salmonicida is one of the major fish pathogens causing economically devastating losses in aquaculture. A. salmonicida subsp. salmonicida is a typical A. salmonicida causing furunculosis, while the other subspecies are atypical strains causing ulcer diseases. PCR-based methods of detecting A. salmonicida suffer from the drawback that they do not distinguish living (pathogenic) from dead cells. In this study, a method of detecting A. salmonicida was developed based on reverse transcription-multiplex PCR (RT-MPCR) using two sets of primers, SV1/SV2 and SF1/SF2, specific to the vapA gene and the fstB gene of A. salmonicida respectively. This method was found to detect A. salmonicida specifically with detection limits of 10 CFU in pure culture and 30 CFU in the presence of tissue debris. It was also found distinguish not only between viable and nonviable cells but also between typical and atypical strains of A. salmonicida. Using RT-MPCR, two DNA fragments, of 542 and 1,258 bp, were amplified from RNA of typical A. salmonicida, whereas only one DNA fragment, of 542 bp, was amplified from the RNA of the atypical ones. The proposed assay was also used successfully to detect A. salmonicida in artificially infected rainbow trout (Oncorhyncus mykiss). PMID- 22484928 TI - A comparison of the production of ethanol between simultaneous saccharification and fermentation and separate hydrolysis and fermentation using unpretreated cassava pulp and enzyme cocktail. AB - The processes of separate hydrolysis and fermentation (SHF) and simultaneous saccharification and fermentation (SSF) were employed using Saccharomyces cerevisiae for the production of ethanol from cassava pulp without any pretreatment. A combination of amylase, cellulase, cellobiase, and glucoamylase produced the highest levels of ethanol production in both the SHF and the SSF method. A temperature of 37 degrees C, a pH of 5.0, and an inoculum size of 6% were the optimum conditions for SSF. For the batch process at a pulp concentration of 20%, ethanol production levels from SHF and SSF were the highest, at 23.51 and 34.67 g L(-1) respectively, but in the fed-batch process, the levels of ethanol production from SHF and SSF rose to 29.39 and 43.25 g L(-1) respectively, which were 25% and 24.7% higher than those of the batch process. Thus SSF using the fed-batch provided a more efficient method for the utilization of cassava pulp. PMID- 22484929 TI - Cytotoxic steroids from the trunk of Berberis koreana. AB - A new steroid, itesmol 3-O-palmitate (1), along with two known steroids were isolated from the trunk of Berberis koreana. The structure of 1 was determined on the basis of spectroscopic analyses involving 2D NMR and chemical reactions. Compound 1 exhibited potential antiproliferative activity against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines (respective IC(50) values of 7.41, 9.20, 4.53, and 12.91 uM). PMID- 22484930 TI - Urinary volatile compounds as biomarkers for lung cancer. AB - Lung cancer is a leading cause of deaths in cancer. Hence, developing early-stage diagnostic tests that are non-invasive, highly sensitive, and specific is crucial. In this study, we investigated to determine whether biomarkers derived from urinary volatile organic compounds (VOCs) can be used to discriminate between lung cancer patients and normal control patients. The VOCs were extracted from the headspace by solid-phase microextraction and were analyzed by gas chromatography time-of-flight mass spectrometry. Nine putative volatile biomarkers were identified as elevated in the lung cancer group. Receiver operating characteristic curve analysis was also performed, and the markers were found to be highly sensitive and specific. Next we used principal component analysis (PCA) modeling to make comparisons compare within the lung cancer group, and found that 2-pentanone may have utility in differentiating between adenocarcinoma and squamous cell carcinomas. PMID- 22484931 TI - Effect of the uncharged imidazolium moiety in adenine on endothelium-independent relaxation in the contracted thoracic aorta of Sprague-Dawley rats. AB - Adenine had a concentration-dependent relaxation action on the phenylephrine contracted aorta ring, with an EC(50) value of 0.40+/-0.12 mM. This effect was also observed in the endothelium-denuded aorta. Among the adenine analogues, N methyladenine and benzimidazole still evoked an apparent relaxation effect, while 1-, 3- or 7-methyladenine and imidazole were no longer vasodilators. These findings demonstrate that the imino group from the uncharged imidazolium moiety in adenine played a key role in the relaxation of the contracted aorta. PMID- 22484932 TI - Detection and characterization of a thermophilic biotin biosynthetic enzyme, 7 keto-8-aminopelargonic acid synthase, from various thermophiles. AB - By detailed BLAST searches of the genome database of various thermophiles, five ORFs with similarity to the bioF gene, which encodes 7-keto-8-aminopelargonic acid synthase (BioF) involved in biotin biosynthesis, of Escherichia coli were found: AqbioF, CltbioF, GkbioF, SytbioF, and TsebioF, from Aquifex aeolicus VF5, Clostridium thermocellum ATCC27405, Geobacillus kaustophilus JCM12893, Symbiobacterium thermophilum IAM14863, and Thermosynechococcus elongatus BP-1 respectively. The five purified recombinant bioF gene products, which were overexpressed in E. coli, had the enzyme activity of BioF. The optimum temperature range and thermostability of five BioFs, AqBioF, CltBioF, GkBioF, SytBioF, and TseBioF, were higher than those of E. coli BioF. In particular, AqBioF was found to show the highest thermostability of the alpha-oxoamine synthase family enzymes reported to date. Substrate specificity experiments revealed that SytBioF was also able to catalyze the reaction of 2-amino-3 ketobutyrate CoA ligase, a member of the alpha-oxoamine synthase family, and that it used acetyl-CoA and glycine as substrates, like the TTHA1582 protein of Thermus thermophilus. The other purified BioFs, AqBioF and GkBioF, did not show any activity with acyl-CoAs and amino acids other than pimeloyl-CoA and L-alanine as substrates. PMID- 22484933 TI - Flexible plastic bioreactors for photobiological hydrogen production by hydrogenase-deficient cyanobacteria. AB - Uptake hydrogenase mutant cells of the cyanobacterium Nostoc sp. PCC 7422 photobiologically produced H(2) catalyzed by nitrogenase for several days in H(2) barrier transparent plastic bags, and accumulated H(2) in the presence of O(2) evolved by photosynthesis. Their H(2) production activity was higher in the sealed flexible bags than in stoppered serum bottles of fixed gas volume. PMID- 22484934 TI - Amino acid sequence of Egyptian goose egg-white lysozyme and effects of amino acid substitution on the enzymatic activity. AB - The amino acid sequence of Egyptian goose lysozyme (EGL) from egg-white and its enzymatic properties were analyzed. The established sequence had the highest similarity to wood duck lysozyme (WDL) with five amino acid substitutions, and had eighteen substitutions difference from hen egg-white lysozyme (HEL). Tyr34 and Gly37 were found at subsites E and F of the active site when compared with HEL. The experimental time-course characteristics of EGL against the N acetylglucosamine pentamer substrate, (GlcNAc)(5), revealed higher production of (GlcNAc)(4) and lower production of (GlcNAc)(2) when compared with HEL. The saccharide-binding ability of subsites A-C in EGL was also found to be weaker than in HEL. An analysis of the enzymatic reactions of five mutants in respect of positions 34, 37 and 71 in HEL indicated the time-course characteristics of EGL to be caused by the combination of three substitutions (F34Y, N37G and G71R) between HEL and EGL. A computer simulation of the EGL-catalyzed reaction suggested that the time-course characteristics of EGL resulted from the difference in the binding free energy for subsites A, B, E and F and the rate constant of transglycosylation between EGL and HEL. PMID- 22484935 TI - Differential expression of virulence and stress fitness genes during interaction between Listeria monocytogenes and Bifidobacterium longum. AB - Bifidobacterium is well known to have an inhibitory effect on the survival, growth, and proliferation of various foodborne pathogens, but the mechanism of the molecular action of B. longum in blocking the invasion of Listeria monocytogenes is not yet well defined. In the present study, following RNA extraction and cDNA synthesis, differential expression of virulence and stress fitness genes in L. monocytogenes and B. longum was determined by real-time PCR. The results indicate that L. monocytogenes virulence factors, including actA, hly, inlA, and plcA, showed significantly downregulated expression during co incubation of B. longum and L. monocytogenes in phosphate-buffered saline. The relative mRNA levels of oppA and serpin, two stress fitness genes in B. longum, were significantly higher than for the control group. These results indicate that downregulation of L. monocytogenes virulence factors during co-incubation with B. longum might be responsible for the inhibitory effects. PMID- 22484936 TI - Radical scavenging activity of spring mountain herbs in the Shikoku mountain area and identification of antiradical constituents by simple HPLC detection and LC-MS methods. AB - The functionality of spring mountain herbs, which were collected in the Kajigamori mountain area of Shikoku area in Japan, was investigated in the course of our studies for utilizing local plant resources. The radical scavenging activity of the extracts from seventeen herbs was measured. Among these herbs, two extracts from Polystichym ovato-paleaceum (Japanese name: Tsuyanashiinode) and Sambucus racemosa subsp. sieboldiana (Japanese name: Niwatoko) showed potent DPPH radical scavenging activity. The material evidence for the potent activity of the extracts was studied by a combination of our developed method for detecting antiradical compounds, LC-MS/MS, and enzymatic hydrolysis. PMID- 22484937 TI - Cloning, monoclonal antibody production, and bodily distribution pattern of a bovine lipocalin. AB - A bovine lipocalin, previously identified as a putative odorant-binding protein in bovine colostrum (bcOBP), was cloned and expressed, and its monoclonal antibody was established. bcOBP was constantly secreted into milk on day of parturition until at least 10 d postpartum at a concentration of 181+/-39 ug/L. Besides milk, bcOBP occurred in the nasal mucus, saliva, amniotic fluid, vaginal discharge, and blood plasma. Despite its low concentration, the distribution pattern and the finding that bcOBP harbored a characteristic sequence motif, CxxxC, which is conserved among insect and mammal pheromone binding proteins, suggest that bcOBP functions as a pheromone carrier. The presence of bcOBP in the plasma at varied concentrations depending on the lactation period does not exclude the possibility that bcOBP is secreted into milk from the blood. Cross reactivity of the monoclonal antibody indicated presence of proteins homologous to bcOBP in the colostrum of farm animals of Cetartiodactyla. PMID- 22484938 TI - Practical removal of radioactivity from sediment mud in a swimming pool in Fukushima, Japan by immobilized photosynthetic bacteria. AB - About 90% of the radioactive Cs in the sediment mud of a school's swimming pool in Fukushima, Japan was removed by treatment for 3 d using the alginate immobilized photosynthetic bacterium Rhodobcater sphaeroides SSI. Even though batch treatment was carried out 3 times repeatedly, the activity of immobilized cells in removing Cs was maintained at levels of about 84% (second batch) and 78% (third batch). Cs was strongly attached to the sediment mud because, even with HNO(3) treatment at pH of 2.00-1.60 for 24 h, it was not eluted into the water. Furthermore, more than 75% of the Cs could be removed without solubilization with HNO(3). This suggests that the Cs attached to the sediment mud was transformed into immobilized cells via the Cs(+) ion by the negative charge of the immobilized cell surface and/or the potassium transport system of the photosynthetic bacterium. PMID- 22484939 TI - Purification and characterization of highly branched alpha-glucan-producing enzymes from Paenibacillus sp. PP710. AB - Highly branched alpha-glucan molecules exhibit low digestibility for alpha amylase and glucoamylase, and abundant in alpha-(1->3)-, alpha-(1->6)-glucosidic linkages and alpha-(1->6)-linked branch points where another glucosyl chain is initiated through an alpha-(1->3)-linkage. From a culture supernatant of Paenibacillus sp. PP710, we purified alpha-glucosidase (AGL) and alpha-amylase (AMY), which were involved in the production of highly branched alpha-glucan from maltodextrin. AGL catalyzed the transglucosylation reaction of a glucosyl residue to a nonreducing-end glucosyl residue by alpha-1,6-, alpha-1,4-, and alpha-1,3 linkages. AMY catalyzed the hydrolysis of the alpha-1,4-linkage and the intermolecular or intramolecular transfer of maltooligosaccharide like cyclodextrin glucanotransferase (CGTase). It also catalyzed the transfer of an alpha-1,4-glucosyl chain to a C3- or C4-hydroxyl group in the alpha-1,4- or alpha 1,6-linked nonreducing-end residue or the alpha-1,6-linked residue located in the other chains. Hence AMY was regarded as a novel enzyme. We think that the mechanism of formation of highly branched alpha-glucan from maltodextrin is as follows: alpha-1,6- and alpha-1,3-linked residues are generated by the transglucosylation of AGL at the nonreducing ends of glucosyl chains. Then AMY catalyzes the transfer of alpha-1,4-chains to C3- or C4-hydroxyl groups in the alpha-1,4- or alpha-1,6-linked residues generated by AGL. Thus the concerted reactions of both AGL and AMY are necessary to produce the highly branched alpha glucan from maltodextrin. PMID- 22484940 TI - Effects of chitosan intake on fecal excretion of bisphenol A and di(2 ethyl)phthalate in rats. AB - We evaluated the effects of chitosan intake on fecal excretion of bisphenol A (BPA) and di(2-ethyl)phthalate (DEHP) in rats. The rats were fed a chitosan diet (CHI group) or a control diet (control group) for 10 d and orally administrated BPA or DEHP (100, 500 mg/kg body weight, respectively) on day 4. Feces were collected and the rates of fecal excretion of BPA and DEHP were calculated. Fecal excretion rates of BPA and DEHP were significantly higher in the CHI group than in the control group. A significant negative correlation was observed between the fecal excretion rates of BPA and DEHP and apparent fat digestibility. Furthermore, the CHI group showed not only increased but also accelerated BPA excretion into the feces. In conclusion, we found that that chitosan intake significantly increased the fecal excretion of BPA, DEHP, and fat, suggesting that it might be useful for reducing adverse effects caused by lipophilic xenobiotics. PMID- 22484941 TI - Chemopreventive effects of Rubus coreanus Miquel on prostate cancer. AB - The growing incidence of prostate cancer and the traditional use of Rubus coreanus Miquel (RCM) for prostate health led us to compare RCM extracts and to test their efficacy in inhibiting the growth of prostate cancer cells differing in androgen dependency. Ethanol extracts of unripe RCM (EUR) were more effective in reducing cell viability than water extracts or ripe RCM. EUR-induced growth inhibition, as indicated by significant reductions in numbers of proliferating cells and decreases in the protein levels of proliferating cell nuclear antigen (PCNA), cyclin D1 and CDK4, was greater in the androgen-dependent LNCaP cells than in the androgen-independent DU145 cells. EUR also induced mitochondrial mediated apoptosis in prostate cancer cells by reducing Bcl-2 and Bcl-(X)L levels, but increased Bax levels. Nevertheless, the LNCaP cells were more sensitive to EUR-induced apoptosis and displayed sub-G1 and late apoptotic cell populations, whereas the DU145 cells did not. Our findings suggest that EUR suppresses the growth of prostate cancer cells by anti-proliferative and/or pro apoptotic effects, and that these effects are stronger in androgen-dependent cells. PMID- 22484943 TI - Attempts to express the A1-GMCSF immunotoxin in the baculovirus expression vector system. AB - Immunotoxins are fusion proteins consisting of two elements, a targeting and a toxin moiety, and are designed for specific elimination of tumor cells. Previously we expressed a recombinant fusion protein consisting of the toxic fragment of Shiga toxin (A1) and GMCSF (A1-GMCSF) in Escherichia coli, and evaluated its cytotoxic properties in acute myeloid leukemia and colon carcinoma cell lines. In view of the specific cytotoxic effects of this immunotoxin, further detailed in-vitro and preclinical studies were undertaken. Large amounts of the recombinant protein of high purity and free of unwanted side products, such as lipopolysaccharides (LPS), were required. Since GMCSF is of mammalian origin and it requires proper disulfide bond formation, we intended to use the baculovirus expression vector system (BEVS) for the expression of the recombinant fusion protein. However, despite previous reports on the expression of several other immunotoxins by this system, the A1 derived fusion proteins revealed an inhibitory effect on baculoviral particle formation and even caused cell death in insect cells. This observation was further pursued and confirmed by the use of other baculoviral specific promoters. The salient features of this finding are described below. PMID- 22484942 TI - A new meroterpenoid, chrodrimanin C, from YO-2 of Talaromyces sp. AB - The new meroterpenoid, chrodrimanin C (3), together with chrodrimanins A (2) and B (1) were isolated from okara (the insoluble residue of whole soybean) that had been fermented with strain YO-2 of Talaromyces sp. Their structures were elucidated by spectroscopic methods. The partial structures of 1 essential for exhibiting insecticidal activity were investigated by using a silkworm assay. The absolute configuration of 1 was also determined. PMID- 22484944 TI - Serum cholesterol reduction by feeding a high-cholesterol diet containing a lower molecular-weight polyphenol fraction from peanut skin. AB - Feeding a high-cholesterol diet with a water-soluble peanut skin polyphenol fraction to rats reduced their plasma cholesterol level, with an increase in fecal cholesterol excretion. The hypocholesterolemic effect was greater with the lower-molecular-weight rather than higher-molecular-weight polyphenol fraction. This effect was possibly due to some oligomeric polyphenols which reduced the solubility of dietary cholesterol in intestinal bile acid-emulsified micelles. PMID- 22484945 TI - Anti-obesity properties of a Sasa quelpaertensis extract in high-fat diet-induced obese mice. AB - This study explores the anti-obesity properties of a Sasa quelpaertensis leaf extract (SQE) in high-fat diet (HFD)-induced obese C57BL/6 mice and mature 3T3-L1 adipocytes. SQE administration with HFD for 70 d significantly decreased the body weight gain, adipose tissue weight, and serum total cholesterol and triglyceride levels in comparison with the HFD group. SQE administration also reduced the serum levels of glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and lactate dehydrogenase, and the accumulation of lipid droplets in the liver, suggesting a protective effect against HFD-induced hepatic steatosis. SQE administration restored the HFD-induced decreases with phosphorylation of AMP activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in epididymal adipose tissue. SQE also induced AMPK phosphorylation in mature 3T3-L1 adipocytes. These results suggest that SQE exerted an anti-obesity effect on HFD induced obese mice by activating AMPK in adipose tissue and reducing lipid droplet accumulation in the liver. PMID- 22484946 TI - Oxidative degradation of 4-hydroxyacetophenone in Arthrobacter sp. TGJ4. AB - The 4-hydroxyacetophenone assimilating bacterium Arthrobacter sp. TGJ4 was isolated from a soil sample. The resting cell reaction suggested that the strain cleaved 4-hydroxyacetophenone and its 3-methoxy derivative to the corresponding carboxylic acids and formaldehyde. Some properties of the enzyme catalyzing the cleavage reaction were examined. PMID- 22484947 TI - Inhibition of aggregation of amyloid beta42 by arginine-containing small compounds. AB - Aggregations of proteins are in many cases associated with neurodegenerative diseases such as Alzheimer's (AD). Small compounds capable of inhibiting protein aggregation are expected to be useful for not only in the treatment of disease but also in probing the structures of aggregated proteins. In previous studies using phage display, we found that arginine-rich short peptides consisting of four or seven amino acids bound to soluble 42-residue amyloid beta (Abeta42) and inhibited globulomer (37/48 kDa oligomer) formation. In the present study, we searched for arginine-containing small molecules using the SciFinder searching service and tested their inhibitory activities against Abeta42 aggregation, by sodium dodecyl sulfate (SDS)-PAGE and thioflavine T binding assay. Commercially available Arg-Arg-7-amino-4-trifluoromethylcoumarin was found to exhibit remarkable inhibitory activities to the formation of the globulomer and the fibril of Abeta42. This chimera-type tri-peptide is expected to serve as the seed molecule of a potent inhibitor of the Abeta aggregation process. PMID- 22484948 TI - Screening and identification of disaccharides with insulin mimetic activity against L6 cells. AB - Insulin mimetics are considered as prospective anti-diabetic agents, and the disaccharide, neohesperidose, has been found to show insulin mimetic activity against L6 cells. We screened several other disaccharides for their insulin mimetic activity and identified three new insulin mimetic disaccharides. PMID- 22484949 TI - Inhibition of melanogenesis by Xanthium strumarium L. AB - Xanthium strumarium L. (Asteraceae) is traditionally used in Korea to treat skin diseases. In this study, we investigated the effects of a X. strumarium stem extract on melanin synthesis. It inhibited melanin synthesis in a concentration dependent manner, but it did not directly inhibit tyrosinase, the rate-limiting melanogenic enzyme, and instead downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase expression. MITF, the master regulator of pigmentation, is a target of the Wnt signaling pathway, which includes glycogen synthase kinase 3beta (GSK3beta) and beta-catenin. Hence, the influence of X. strumarium stem extract on GSK3beta and beta-catenin was further investigated. X. strumarium induced GSK3beta phosphorylation (inactivation), but the level of beta-catenin did not change. Moreover, a specific GSK3beta inhibitor restored X. strumarium-induced melanin reduction. Hence, we suggest that X. strumarium inhibits melanin synthesis through downregulation of tyrosinase via GSK3beta phosphorylation. PMID- 22484950 TI - Comparison of the efficacy of alpha-lactalbumin from equine, bovine, and human milk in the growth of intestinal IEC-6 cells. AB - Native alpha-lactalbumins (alpha-LA) from equine, bovine, and human milk were not cytotoxic. However, after treatment with trifluoroethanol (TFE), all three alpha LAs exhibited cytotoxicity. Toxic potencies were distinctly different among them. Equine alpha-LA was the most robust, bovine alpha-LA was moderate, and human alpha-LA was weak. There were no significant structural changes as between the native and the TFE-treated alpha-LAs. PMID- 22484951 TI - Synthesis of a spacer-linked derivative of heptopyranosyl(alpha1-3)heptopyranose expressed in lipooligosaccharide and lipopolysaccharide. AB - Glycosylation of penta-O-acetyl heptopyranosyl trichloroacetimidate with the 3-OH acceptor, methyl 2-O-benzyl-4,6-O-benzylidene-7,8-dideoxy-alpha-D-manno-oct-7 enopyranoside, gave the desired alpha1-3-linked disaccharide in a 94% yield. The oct-enopyranoside moiety of the disaccharide was converted to the heptoside by oxidative cleavage with osmium tetroxide/NaIO(4) and subsequent reduction with NaBH(4). The resulting alpha1-3-linked heptose disaccharide was converted to a tricholoroacetaimidate derivative containing a benzoyl group at C-2. This donor was glycosylated with 2-(carbobenzoxyamino)-1-ethanol to give an alpha spacer linked disaccharide derivative in a 90% yield. Zemplen deacylation of the derivative and subsequent hydrogenolysis gave a 2-aminoethyl glycoside of heptopyranosyl(alpha1-3)heptopyranose. PMID- 22484952 TI - Sinensetin attenuates LPS-induced inflammation by regulating the protein level of IkappaB-alpha. AB - Sinensetin is one of the polymethoxyflavones (PMFs) having five methoxy groups on the basic benzo-gamma-pyrone skeleton with a carbonyl group at the C(4) position. We investigated in this study the anti-inflammatory activity of sinensetin in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Sinensetin showed anti inflammatory activity by regulating the protein level of inhibitor kappaB-alpha (IkappaB-alpha). PMID- 22484953 TI - Role of tryptophan residues in a class V chitinase from Nicotiana tabacum. AB - Tryptophan residues located in the substrate-binding cleft of a class V chitinase from Nicotiana tabacum (NtChiV) were mutated to alanine and phenylalanine (W190F, W326F, W190F/W326F, W190A, W326A, and W190A/W326A), and the mutant enzymes were characterized to define the role of the tryptophans. The mutations of Trp326 lowered thermal stability by 5-7 degrees C, while the mutations of Trp190 lowered stability only by 2-4 degrees C. The Trp326 mutations strongly impaired enzymatic activity, while the effects of the Trp190 mutations were moderate. The experimental data were rationalized based on the crystal structure of NtChiV in a complex with (GlcNAc)(4), in which Trp190 is exposed to the solvent and involved in face-to-face stacking interaction with the +2 sugar, while Trp326 is buried inside but interacts with the -2 sugar through hydrophobicity. HPLC analysis of anomers of the enzymatic products suggested that Trp190 specifically recognizes the beta-anomer of the +2 sugar. The strong effects of the Trp326 mutations on activity and stability suggest multiple roles of the residue in stabilizing the protein structure, in sugar residue binding at subsite -2, and probably in maintaining catalytic efficiency by providing a hydrophobic environment for proton donor Glu115. PMID- 22484954 TI - Cold-induced accumulation of omega-3 polyunsaturated fatty acid in a liverwort, Marchantia polymorpha L. AB - The liverwort Marchantia polymorpha L. synthesizes various long-chain polyunsaturated fatty acids including arachidonic acid and eicosapentaenoic acid, neither of which is produced by higher plants. Here we report the effects of temperature on long-chain polyunsaturated fatty acid accumulation in the liverwort. The accumulation of omega-3 polyunsaturated fatty acids increased significantly as the growth temperature decreased. Specifically, the relative content of eicosapentaenoic acid to total fatty acids at 5 degrees C was approximately 3-fold higher than at 25 degrees C. On the other hand, the accumulation of omega-6 polyunsaturated fatty acids decreased at low temperatures. An analysis of gene expression indicated that the mRNA of the MpFAD3 gene for ER omega-3 desaturase increased significantly at 5 degrees C. These results indicate that in the liverwort the n-3 pathway was enhanced at low temperature, mainly via expression of the cold-induced omega-3 desaturase gene, leading to increased accumulation of eicosapentaenoic acid. PMID- 22484955 TI - Termitomycesphins G and H, additional cerebrosides from the edible Chinese mushroom Termitomyces albuminosus. AB - Two new cerebrosides, termitomycesphins G and H, were isolated from the edible Chinese mushroom, Termitomyces albuminosus (Berk.) Herm., and exhibited neuritogenic activity against PC12 cells. Their structures and absolute stereochemistry were elucidated by spectroscopic methods and by a comparison of the specific rotation of the hydrogenated products from termitomycesphins H and C. These cerebrosides possessed a unique modification by a hydroxyl group at the middle of the long-chain base, like earlier congeners termitomycesphins A-F. Termitomycesphin G with a 16-carbon-chain fatty acid showed higher neuritogenic activity than that of termitomycesphin H with an 18-carbon-chain fatty acid. This effect was observed within the termitomycesphins, suggesting that the chain length of the fatty acyl moiety played a key role in the neuritogenic activity. PMID- 22484956 TI - Reduction of overall Helicobacter pylori colonization levels in the stomach of Mongolian gerbil by Lactobacillus johnsonii La1 (LC1) and its in vitro activities against H. pylori motility and adherence. AB - The effects of Lactobacillus johnsonii La1 (LC1) on Helicobacter pylori colonization in the stomach were investigated. H. pylori colonization and gastritis in LC1-inoculated Mongolian gerbils were significantly less intense than those in the control animals. LC1 culture supernatant (>10-kDa fraction) inhibited H. pylori motility and induced bacterial aggregation in human gastric epithelial cells, suggesting the potential of clinical use of LC1 product. PMID- 22484957 TI - Quality evaluation of rice crackers based on physicochemical measurements. AB - The processing suitability as a material for rice crackers was characterized in the present study, based on physicochemical measurements and sensory testing of high-quality premium rice, low-amylose rice, Japonica-Indica hybrid rice, and red rice as the rice cultivar samples. Puffed rice crackers were prepared and the relationship between the physicochemical properties of the rice grains and the quality of the resulting products was investigated. It was possible to estimate the physical properties of a rice cracker by using multiple-regression analysis based on the chemical components, pasting properties and physical properties of the constituent rice. A formula for estimating the amylose content of the constituent rice was developed from the results of physicochemical measurements of the rice crackers. We assayed the quality of commercial rice crackers and examined the deterioration during the storage by measuring the physicochemical properties. The hardness and fat acidity of crackers increased markedly during storage for 20 d at 35 degrees C. The novel method of a one-bite test with a Tensipresser was useful to assay the quality of a rice cracker and made it possible to evaluate the quality deterioration of the rice cracker during storage. PMID- 22484958 TI - Purification, characterization, and cDNA cloning of a novel lectin from the green alga, Codium barbatum. AB - A novel lectin (CBA) was isolated from the green alga, Codium barbatum, by conventional chromatographic methods. The hemagglutination-inhibition profile with sugars and glycoproteins indicated that CBA had preferential affinity for complex type N-glycans but not for monosaccharides, unlike the other known Codium lectins specific for N-acetylgalactosamine. CBA consisted of an SS-linked homodimer of a 9257-Da polypeptide containing seven cysteine residues, all of which were involved in disulfide linkages. The cDNA of the CBA subunit coded a polypeptide (105 amino acids) including the signal peptide of 17 residues. The calculated molecular mass from the deduced sequence was 9705 Da, implying that the four C-terminal amino acids of the CBA proprotein subunit were post translationally truncated to afford the mature subunit (84 amino acids). No significantly similar sequences were found during an in silico search, indicating CBA to be a novel protein. CBA is the first Codium lectin whose primary structure has been elucidated. PMID- 22484959 TI - Enzymatic characteristics of cellobiose phosphorylase from Ruminococcus albus NE1 and kinetic mechanism of unusual substrate inhibition in reverse phosphorolysis. AB - Cellobiose phosphorylase (CBP) catalyzes the reversible phosphorolysis of cellobiose to produce alpha-D-glucopyranosyl phosphate (Glc1P) and D-glucose. It is an essential enzyme for the metabolism of cello-oligosaccharides in a ruminal bacterium, Ruminococcus albus. In this study, recombinant R. albus CBP (RaCBP) produced in Escherichia coli was characterized. It showed highest activity at pH 6.2 at 50 degrees C, and was stable in a pH range of 5.5-8.8 and at below 40 degrees C. It phosphorolyzed only cellobiose efficiently, and the reaction proceeded through a random-ordered bi bi mechanism, by which inorganic phosphate and cellobiose bind in random order and D-glucose is released before Glc1P. In the synthetic reaction, RaCBP showed highest activity to D-glucose, followed by 6 deoxy-D-glucose. D-Mannose, 2-deoxy-D-glucose, D-glucosamine, D-xylose, 1,5 anhydro-D-glucitol, and gentiobiose also served as acceptors, although the activities for them were much lower than for D-glucose. D-Glucose acted as a competitive-uncompetitive inhibitor of the reverse synthetic reaction, which bound not only the Glc1P site (competitive) but also the ternary enzyme-Glc1P-D glucose complex (uncompetitive). PMID- 22484960 TI - Characterization of D-lactate dehydrogenase producing D-3-phenyllactic acid from Pediococcus pentosaceus. AB - D-Lactate dehydrogenase (D-LDH) from Pediococcus pentosaceus ATCC 25745 was found to produce D-3-phenyllactic acid from phenylpyruvate. The optimum pH and temperature for enzyme activity were pH 5.5 and 45 degrees C. The Michaelis Menten constant (K(m)), turnover number (k(cat)), and catalytic efficiency (k(cat)/K(m)) values for the substrate phenylpyruvate were estimated to be 1.73 mmol/L, 173 s(-1), and 100 (mmol/L)(-1) s(-1) respectively. PMID- 22484961 TI - Screening of an alpha-amylase inhibitor peptide by photolinker-peptide array. AB - Peptide arrays in which peptides were immobilized on cellulose membranes through photolinkers were synthesized. The peptides were subsequently detached from the arrays by ultraviolet (UV) photolysis for 3 h, and were used to search for functional peptides that inhibit the activity of alpha-amylase derived from human pancreatic juice. Amino acid replacement with high-molecular-size amino acids, Arg (R), Phe (F), Trp (W), or Tyr (Y), for the first and seventh residues of amylase inhibitor peptide, GHWYYRCW, as previous reported, led to enhancement of the inhibitory effect of the peptide on alpha-amylase. In particular, one of the resulting peptides, RHWYYRYW, showed a stronger inhibitory effect than acarbose (which is used as a hypoglycemic agent) or inhibitor peptide GHWYYRCW. PMID- 22484962 TI - Properties of Jack bean alpha-mannosidase in the presence of hyaluronan. AB - An enzymatic reaction within a mesh-like structure constructed using hyaluronan was investigated in order to understand the influence of specific reaction environments in a living body on the reaction. This mesh-like structure, which mimicked extracellular matrix conditions, was found to accelerate glycohydrolysis by Jack bean alpha-mannosidase. PMID- 22484963 TI - The Objective Borderline method (OBM): a probability-based model for setting up an objective pass/fail cut-off score in medical programme assessments. AB - The decision to pass or fail a medical student is a 'high stakes' one. The aim of this study is to introduce and demonstrate the feasibility and practicality of a new objective standard-setting method for determining the pass/fail cut-off score from borderline grades. Three methods for setting up pass/fail cut-off scores were compared: the Regression Method, the Borderline Group Method, and the new Objective Borderline Method (OBM). Using Year 5 students' OSCE results from one medical school we established the pass/fail cut-off scores by the abovementioned three methods. The comparison indicated that the pass/fail cut-off scores generated by the OBM were similar to those generated by the more established methods (0.840 <= r <= 0.998; p < .0001). Based on theoretical and empirical analysis, we suggest that the OBM has advantages over existing methods in that it combines objectivity, realism, robust empirical basis and, no less importantly, is simple to use. PMID- 22484964 TI - Exploring the impact of mental workload on rater-based assessments. AB - When appraising the performance of others, assessors must acquire relevant information and process it in a meaningful way in order to translate it effectively into ratings, comments, or judgments about how well the performance meets appropriate standards. Rater-based assessment strategies in health professional education, including scale and faculty development strategies aimed at improving them have generally been implemented with limited consideration of human cognitive and perceptual limitations. However, the extent to which the task assigned to raters aligns with their cognitive and perceptual capacities will determine the extent to which reliance on human judgment threatens assessment quality. It is well recognized in medical decision making that, as the amount of information to be processed increases, judges may engage mental shortcuts through the application of schemas, heuristics, or the adoption of solutions that satisfy rather than optimize the judge's needs. Further, these shortcuts may fundamentally limit/bias the information perceived or processed. Thinking of the challenges inherent in rater-based assessments in an analogous way may yield novel insights regarding the limits of rater-based assessment and may point to greater understanding of ways in which raters can be supported to facilitate sound judgment. This paper presents an initial exploration of various cognitive and perceptual limitations associated with rater-based assessment tasks. We hope to highlight how the inherent cognitive architecture of raters might beneficially be taken into account when designing rater-based assessment protocols. PMID- 22484965 TI - Academic and professional career outcomes of medical school graduates who failed USMLE Step 1 on the first attempt. AB - This study sought to determine the academic and professional outcomes of medical school graduates who failed the United States Licensing Examination Step 1 on the first attempt. This retrospective cohort study was based on pooled data from 2,003 graduates of six Midwestern medical schools in the classes of 1997-2002. Demographic, academic, and career characteristics of graduates who failed Step 1 on the first attempt were compared to graduates who initially passed. Fifty medical school graduates (2.5 %) initially failed Step 1. Compared to graduates who initially passed Step 1, a higher proportion of graduates who initially failed Step 1 became primary care physicians (26/49 [53 %] vs. 766/1,870 [40.9 %]), were more likely at graduation to report intent to practice in underserved areas (28/50 [56 %] vs. 419/1,939 [ 21.6 %]), and more likely to take 5 or more years to graduate (11/50 [22.0 %] vs. 79/1,953 [4.0 %]). The relative risk of first attempt Step 1 failure for medical school graduates was 13.4 for African Americans, 7.4 for Latinos, 3.6 for matriculants >22 years of age, 3.2 for women, and 2.3 for first generation college graduates. The relative risk of not being specialty board certified for those graduates who initially failed Step 1 was 2.2. Our observations regarding characteristics of graduates in our study cohort who initially failed Step 1 can inform efforts by medical schools to identify and assist students who are at particular risk of failing Step 1. PMID- 22484966 TI - Abnormal gangliosides are localized in lipid rafts in Sanfilippo (MPS3a) mouse brain. AB - Allogenic stem cell transplantation can reduce lysosomal storage of heparan sulfate-derived oligosaccharides by up to 27 % in Sanfilippo MPS3a brain, but does not reduce the abnormal storage of sialolactosylceramide (G(M3)) or improve neurological symptoms, suggesting that ganglioside storage is in a non-lysosomal compartment. To investigate this further we isolated the Triton X100-insoluble at 4 degrees C, lipid raft (LR) fraction from a sucrose-density gradient from cerebral hemispheres of a 7 month old mouse model of Sanfilippo MPS3a and age matched control mouse brain. HPLC/MS/MS analysis revealed the expected enrichment of normal complex gangliosides, ceramides, galatosylceramides and sphingomyelin enrichment in this LR fraction. The abnormal HS-derived oligosaccharide storage material was in the Triton X100-soluble at 4 degrees C fractions (8-12),whereas both GM3 and sialo[GalNAc]lactosylceramide (GM2) were found exclusively in the LR fraction (fractions 3 and 4) and were >90 % C18:0 fatty acid, suggesting a neuronal origin. Further analysis also revealed a >threefold increase in the late endosome marker bis (monoacylglycerol) phosphate (>70 % as C22:6/22:6-BMP) in non LR fractions 8-12 whereas different forms of the proposed BMP precursor, phosphatidylglycerol (PG) were in both LR and non-LR fractions and were less elevated in MPS3a brain. Thus heparan sulfate-derived oligosaccharide storage is associated with abnormal lipid accumulation in both lysosomal (BMP) and non lysosomal (GM3 and GM2) compartments. PMID- 22484968 TI - Gangliosides, NGF, brain aging and disease: a mini-review with personal reflections. AB - In this mini-review I summarize our research efforts in ascertaining the possible neuro-reparative properties of the GM1 ganglioside and its cooperative effects with NGF in stroke-lesion models. We also review aspects of our NGF investigations which have recently led to the discovery that NGF is released in an activity-dependent manner in the form of its precursor molecule, proNGF. These studies support the notion that in the CNS NGF metabolism conversion and degradation occur in the extracellular milieu. We have also validated this pathway in vivo demonstrating that the pharmacological inhibition of the pro-to mature NGF conversion results in the brain accumulation of proNGF and loss and atrophy of cortical cholinergic synapses. Furthermore, we have gathered neurochemical evidence for a compromise of this newly discovered NGF metabolic pathway in Alzheimer's disease, explaining the vulnerability of NGF-dependent forebrain cholinergic neurons in this disease despite normal NGF synthesis and abundance of NGF precursor. PMID- 22484969 TI - Special Issue honoring Bob Ledeen. PMID- 22484967 TI - Chronic hyperhomocysteinemia increases inflammatory markers in hippocampus and serum of rats. AB - This study investigated the effects of chronic homocysteine administration on some parameters of inflammation, such as cytokines (TNF-alpha, IL-1beta and IL 6), chemokine CCL(2) (MCP-1), nitrite and prostaglandin E(2) levels, as well as on immunocontent of NF-kappaB/p65 subunit in hippocampus and/or serum of rats. Since acetylcholinesterase has been associated with inflammation, we also evaluated the effect of homocysteine on this enzyme activity in hippocampus of rats. Wistar rats received daily subcutaneous injections of homocysteine (0.3-0.6 MUmol/g body weight) or saline (control) from the 6th to the 28th days-of-age. One or 12 h after the last injection, rats were euthanized and hippocampus and serum were used. Results showed that chronic hyperhomocysteinemia significantly increased pro-inflammatory cytokines (TNF-alpha, IL-1beta and IL-6), chemokine CCL(2) (MCP-1) and prostaglandin E(2) in hippocampus and serum of rats at 1 and 12 h after the last injection of homocysteine. Nitrite levels increased in hippocampus, but decreased in serum at 1 h after chronic hyperhomocysteinemia. Acetylcholinesterase activity and immunocontent of citoplasmic and nuclear NF kappaB/p65 subunit were increased in hippocampus of rats subjected to hyperhomocysteinemia at 1 h, but did not alter at 12 h after the last injection of homocysteine. According to our results, chronic hyperhomocysteinemia increases inflammatory parameters, suggesting that this process might be associated, at least in part, with the cerebrovascular and vascular dysfunctions characteristic of some homocystinuric patients. PMID- 22484971 TI - [Detection of Burkholderia cepacia complex strains in the University Hospital Olomouc]. AB - BACKGROUND: The aim was to assess the epidemiology of Burkholderia cepacia complex strains isolated at the Department of Microbiology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, determine the most frequent strains and confirm or rule out potential clonal spread of the strains. MATERIAL AND METHODS: Over a period of eight months, all strains classified as Burkholderia cepacia complex were collected. Susceptibility to selected antimicrobial agents was determined and adequate molecular genetic methods were used to assess their genetic relationship. RESULTS: A total of 52 isolates were tested, with the most frequent (88.5 %) being genomovar II (Burkholderia multivorans). More than 46 % of them were genetically related; 58.3 % of them were detected in intensive care units. All isolates were highly resistant to antimicrobial agents. In four cases, deaths associated with Burkholderia multivorans infection were reported. CONCLUSION: It may be assumed that genetically related strains of Burkholderia multivorans spread from the hospital setting. As yet, the source of infection has not been determined and further investigations are needed. PMID- 22484970 TI - Duret hemorrhage: demonstration of ruptured paramedian pontine branches of the basilar artery on minimally invasive, whole body postmortem CT angiography. AB - A 25 year old male died suddenly and unexpectedly. Postmortem CT scanning revealed marked raised intracranial pressure with brainstem compression due to subarachnoid, subdural and parenchymal hemorrhage. A hyperdense mass at the termination of the right internal carotid artery was thought to represent an aneurysm. Postmortem, whole body CT angiography failed to fill the aneurysm but did demonstrate multiple central pontine linear enhancing structures in continuity with the mid basilar artery and small foci of contrast leak into the adjacent mid pontine parenchyma. Autopsy confirmed subarachnoid hemorrhage, a thrombosed and ruptured proximal right middle cerebral artery aneurysm and Duret hemorrhages in the mid pons. This finding supports the theory that Duret hemorrhages occur as a result of perforating pontine branch of the basilar arterial rupture but does not exclude the contribution of venous congestion. PMID- 22484972 TI - [Animal sources of Clostridium difficile]. AB - The bacterium Clostridium difficile is pathogenic for both humans and animals. This feared nosocomial infectious agent is increasingly more important in the community as well. Like in humans, the gastrointestinal tract is infected in animals. The bacterium may be transmitted from animals to humans via the food chain (e.g. pork meat) or by direct contact. Identical human and animal isolates of C. difficile have been reported in several studies. The article presents results from a small local study aimed at detecting C. difficile and its toxins in the District of Olomouc, Czech Republic, by 3 different methods. PMID- 22484973 TI - [Viral gastroenteritis]. AB - The causative agents of viral gastroenteritis belong to generally little known pathogens. But according to some studies, these viruses make up a considerable proportion of agents causing diarrhea in children and adults. In this review, the authors focused on both relatively known pathogens such as adenoviruses, rotaviruses or caliciviruses and not so well known or newly recognized viral gastroenteritis pathogens like toroviruses, astroviruses, bocaviruses or parechoviruses. The first part of this review is concerned with basic information about each etiological agent. The second one deals with their detection and identification. The last part is about therapy and prophylaxis of viral pathogens. PMID- 22484974 TI - [Invasive pulmonary aspergillosis and esophageal candidiasis in a patient with decompensated liver cirrhosis due to chronic hepatitis C and alcohol]. AB - We present a rare case of combined fungal infection in a critically ill 47 year old patient with chronic hepatitis C at the stage of liver cirrhosis. The patient was admitted for signs of decompensated cirrhosis caused by hepatitis C and increased alcohol consumption. After 2 week hospital stay, his condition was complicated by a pulmonary infiltrate and rapid deterioration followed. Despite intensive care, the patient died. Autopsy findings showed invasive pulmonary aspergillosis. The aim of this case report is to point to a broad differential diagnosis of jaundice and pulmonary infiltrates, thus stressing the value of interdisciplinary cooperation and the need to consider the possibility of invasive fungal infections when caring for liver cirrhosis patients. In addition, several risk factors contributing to the development of fungal diseases in these patients are discussed in the article. PMID- 22484975 TI - Anesthetic management of a child with Ullrich myopathy. PMID- 22484976 TI - Phosphorylation of signal transducer and activator of transcription 3 (STAT3) correlates with Her-2 status, carbonic anhydrase 9 expression and prognosis in esophageal cancer. AB - The signal-transcriptional factor signal transducer and activator of transcription (STAT3) is overexpressed in various tumor entities and promotes tumor progression and metastasis. The tyrosine-kinase receptor Her-2 was shown to activate STAT3-expression and is overexpressed in a subtype of esophageal cancer (EC). STAT3 also regulates carbonic anhydrase IX (CAIX) expression in vivo, promoting IL-6-dependent tumor invasion.Tumor-tissue from 324 patients with EC and 45 patients with precursor lesions were analyzed for the expressions of tyrosine-705 phosphorylated STAT3 (pSTAT3). Data on Her-2-status and CAIX expression were available from previous studies. pSTAT3 was overexpressed in 40 % of adenocarcinomas (AC) and 50 % of squamous cell carcinomas of the esophagus and was associated with worse overall (OS) (p = 0.001) and disease free survival (DFS) (p = 0.001). In Barrett's mucosa without/low-grade dysplasia, pSTAT3 was expressed in 14 % compared to 27 % in patients with high-grade dysplasia (p = 0.018). A significant association between Her-2 and pSTAT3 was found in ACs (p = 0.013), showing that patients with tumors expressing both proteins have significantly worse OS (p = 0.0039) and DFS (p = 0.029). One hundred-fifty (46.3 %) cancer cases were considered as positive for CAIX expression, and a strong correlation between pSTAT3 and CAIX expression was seen (p < 0.001). pSTAT3 plays an important role in the development of AC. Expression of pSTAT3 correlates with Her-2 status and CAIX expression and is associated with tumor progression and worse outcome, offering expectantly therapeutical implications. PMID- 22484977 TI - VEGFR-1 expression levels predict occurrence of disseminated tumor cells in the bone marrow of patients with esophageal carcinoma. AB - Blocking angiogenesis by inhibiting VEGF represents an established therapeutic strategy in many cancers. The role of placental growth factor (PlGF) and of its receptor VEGFR-1 in tumor biology remain more elusive. Currently, humanized monoclonal antibodies against PlGF are studied in early phase clinical trials because PlGF inhibition blocked murine tumor growth and angiogenesis. In contrast to mice exclusively expressing one PlGF isoform (PlGF-2), humans can produce four PlGF isoforms (PlGF1-4). Surprisingly nothing is yet known about expression of all four PlGF isoforms in human cancer, because until now mostly total PlGF levels or PlGF-1/2 were analyzed without discriminating further. In this study we determined mRNA expression levels of PlGF1-4 and of VEGFR-1 by QRT-PCR in human esophageal tumor tissue and investigated whether gene expression levels correlate with clinical data. PlGF-1 and -2 were expressed in virtually all analyzable tumors, whereas PlGF-3 and -4 were present in tumors of 59 and 74 % of patients, respectively. MRNA Expression levels of all four splice variants correlated with each other. In contrast, PlGF-1 and -2 mRNA expression was lower in esophageal control tissue and PlGF-3 and -4 mRNA were undetectable. VEGFR-1 was expressed by more than 80 % of patients. Interestingly, VEGFR-1 expression levels significantly correlate with presence of disseminated tumor cells (DTCs) in bone marrow. Patients with DTCs exhibit lower VEGFR-1 mRNA expression than patients without DTCs. Pending validation in other types of cancer, expression levels of VEGFR-1 might be useful as surrogate marker for DTCs. PMID- 22484978 TI - Functional limitations predict the risk of rehospitalization among patients with chronic heart failure. AB - BACKGROUND: Although functional limitations (FLs) can predict clinical deterioration in chronic heart failure (CHF), few studies have focused on the associated clinical significance. The aim of the present study was to examine the association between FL and changes in the related time course with subsequent hospital readmission in CHF patients. METHODS AND RESULTS: FLs were analyzed using the Performance Measure for Activities of Daily Living-8 (PMADL-8; higher scores indicate worse FLs) for 215 CHF patients at 1 and 3 months after discharge in a multicenter cohort study. The mean follow-up was 20 months. In a multivariate Cox regression analysis including covariates, only the PMADL-8 score remained significantly related to rehospitalization of CHF (hazard ratio, 2.49; 95% confidence interval: 1.27-4.90; P<0.01). Event-free survival differed significantly among the 4 PMADL-8 time-course groups (P<0.01). The persistent low FL group had lower event rates than the other 3 time-course groups (P<0.01). CONCLUSIONS: FLs as measured by the PMADL-8 and the time course of the PMADL-8 score predict readmission in CHF patients after discharge. Accordingly, FL assessment is recommended as part of the clinical management because it not only identifies decline in physical function but also guides prognosis in CHF patients. PMID- 22484979 TI - Predictor of early mortality for severe heart failure patients with left ventricular assist device implantation: significance of INTERMACS level and renal function. AB - BACKGROUND: The preoperative risk factors for left ventricular assist device (LVAD) implantation and their impact on the clinical outcome was analyzed to evaluate the optimal timing of LVAD implantation for severe heart failure patients. METHODS AND RESULTS: From January 2006 to August 2011, 82 patients underwent 84 LVAD implantations at the Osaka University Hospital. These patients were categorized into 2 groups: Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level 1 (n=41) and INTERMACS level 2/3 (n=43). The preoperative characteristics, early mortality, and cumulative survival between the 2 groups was compared. Ten (24.4%) patients died within 90 days in the INTERMACS level 1 group (multiple organ failure: 6, cerebrovascular event: 3, sepsis: 1), whereas 1 (2.3%) patient died because of a cerebrovascular event in the INTERMACS level 2/3 group (P=0.003). The cumulative survival rate was 82.9% at 30 days, 75.6% at 90 days, and 63.7% after 1 year in the INTERMACS level 1 group, and 100%, 97.7%, and 85.3% in the level 2/3 group (P=0.015). Using multivariate analysis for the INTERMACS level 1 group data, the preoperative serum creatinine level was the independent predictor of 90-day mortality. CONCLUSIONS: LVAD implantation in a stable condition contributes to better clinical outcome for severe heart failure patients. If critical cardiogenic shock occurs, LVAD implantation must be considered immediately before other organs' functions, especially renal function, deteriorate. PMID- 22484980 TI - Percutaneous coronary intervention with bare metal stent vs. drug-eluting stent in hemodialysis patients. AB - BACKGROUND: Percutaneous coronary intervention (PCI) with drug-eluting stent (DES) is widely performed in patients with coronary artery disease, but the high restenosis rate remains a major clinical problem after implantation of DES in patients on hemodialysis (HD). Until now, there are limited reports regarding the long-term clinical outcome after implantation of DES in this patient population. METHODS AND RESULTS: We compared bare metal stent (BMS) and DES for long-term clinical outcomes, such as target lesion revascularization (TLR), in HD patients undergoing PCI. BMS and DES were implanted in 204 and 301 patients, respectively. Baseline and lesion characteristics were comparable between the 2 groups. By Kaplan-Meier analysis, event rates of major adverse cardiac events for 6 years were significantly lower in the DES group than in the BMS group (42.5% vs. 58.0%, P=0.036). Although there were no significant differences in TLR rates between patients treated with DES and those with BMS at 1 year after PCI (17.8% vs. 21.3%, P=0.32), patients treated with DES had significantly lower rates of TLR compared with those treated with BMS beyond the 1-year follow-up after PCI (16.4% vs. 30.9%, P=0.019). CONCLUSIONS: In patients on HD, implantation of DES might be more effective for preventing TLR in the medium to long follow-up period than BMS, although restenosis after PCI with DES is common in the short term. PMID- 22484982 TI - Primary pulmonary Ewing's sarcoma: report of a case. AB - The Ewing's sarcoma family of tumors has been reported to originate in a variety of sites, most commonly in the extremities. We herein describe a rare case of primary pulmonary Ewing's sarcoma in a patient with a family history of sarcoma. The patient was a 42-year-old male, who presented with hemoptysis. Chest radiographs revealed a pulmonary mass in the right lower lobe. Clinical and radiological examinations (computed tomography and positron emission tomography) revealed that the lesion was a primary lesion. The lesion was resected by right lower lobectomy. The tumor was located in the pulmonary parenchyma, and there was no evidence of an extrapulmonary involvement by the tumor. Histologically, the tumor was composed of uniform cells with round nuclei and scant cytoplasm which were arranged in cohesive lobules with rare pseudorosette formation. Immunohistochemically, the tumor cells were positive for CD99, and negative for epithelial markers, neuroendocrine markers, myogenic markers and lymphoma markers. This diagnosis was further supported by the cytogenic and reverse transcriptase-polymerase chain reaction findings of EWS/FLI-1 fusion transcripts. This demonstrated the presence of a very rare primary pulmonary Ewing's sarcoma. The patient was treated with chemotherapy after the operation because Ewing's sarcoma is an aggressive neoplasm. The patient has had no recurrent disease for 6 months after the operation. PMID- 22484983 TI - Collision metastasis of breast and thyroid carcinoma to a single cervical lymph node: report of a case. AB - We herein report a rare case of collision lymph node metastases of breast and thyroid carcinomas. A 49-year-old female had undergone an extensively radical mastectomy of the right breast for inflammatory breast cancer at our hospital. Eleven months later, she presented with enlarged lymph nodes in her right lateral neck and multiple nodules in bilateral thyroid lobes. The patient underwent total thyroidectomy and radical dissection of the bilateral cervical lymph nodes. A histological examination showed multiple foci of papillary thyroid carcinoma (PTC) in the bilateral lobes. Surprisingly, concurrent metastases of breast carcinoma and PTC were shown in one of the lymph nodes from the right jugular region. This rare case of collision metastasis and the related literature are discussed. PMID- 22484984 TI - Primary epithelioid hemangioendothelioma of the retroperitoneum: report of a case. AB - We herein report the case of a 48-year-old Japanese female with retroperitoneal epithelioid hemangioendothelioma (EHE), a rare malignant vascular tumor of intermediate grade. She was referred to our hospital because a retroperitoneal tumor was found during a medical checkup, in which strong accumulation of (18)F fluorodeoxyglucose (FDG) was observed by (18)F-FDG-positron emission tomography (PET). A histological examination of the resected tumor revealed that it consisted of large epithelioid cells with vesicular nuclei, and clear cells with vacuolated cytoplasm and intracytoplasmic lumina. These cells expressed CD31 and vimentin, and the final pathological diagnosis was EHE. Postoperative surveillance with FDG-PET revealed distant metastasis in Virchow's lymph node 7 months after the operation. After dissection of the metastatic lymph node, the patient has been free from recurrence for 13 months. Close follow-up with FDG-PET seemed to be useful for surveillance of the recurrence of this tumor with unpredictable behavior, making an early treatment for the recurrent lesions possible. PMID- 22484986 TI - Mycotic aneurysm of the tibioperoneal trunk which precipitated acute compartment syndrome: report of a case. AB - Mycotic aneurysms located in the tibioperoneal trunk are extremely rare, with only a few cases reported in the literature. Because of their infrequency and clinical presentations mimicking other etiologies, clinicians generally do not arrive at the diagnosis until the diameter becomes large enough to detect pulsation. We herein report a case of a 52-year-old male with an aneurysm of the tibioperoneal trunk resulting from infective endocarditis. His early clinical presentation was acute compartment syndrome of unknown cause, and a fasciotomy was performed by orthopedists who did not recognize the underlying aneurysm. Later, enhanced computed tomography revealed that an irregularly shaped aneurysm existed in his right tibioperoneal trunk. After the sepsis was controlled with the use of systemic antibiotics, resection of the aneurysm was performed in advance of cardiac surgery. No clinical symptoms due to ischemia were observed without any revascularization. Postoperative computed tomography demonstrated fine enhancement of the peroneal and post-tibial arteries via collaterals. PMID- 22484985 TI - Pneumonectomy for non-small cell lung cancer. AB - PURPOSE: To assess the mortality, complications and major morbidity of pneumonectomy for non-small cell lung cancer (NSCLC) and to establish the importance of various prognostic factors. METHODS: We reviewed retrospectively the hospital records of 71 consecutive patients who underwent pneumonectomy for NSCLC between 1992 and 2007 to evaluate the significance of risk factors for an adverse outcome. Patients were divided into two period groups according to the period when they were treated: early (1992-1999; n = 47) and late (2000-2007; n = 24). RESULTS: Both the 30-day and the in-hospital mortality rates were 4.2 % (3/71). Complications developed in 31.3 % (22/71) and overall 5-year survival was 23.1 %. Pathological stage III or more, T3 or more, and N2 or more were risk factors of an adverse outcome. Survival was not significantly influenced by histological type, the side of surgery, or curability. The 5-year survival rates for the early and late periods were 19.6 and 32.9 %, respectively. There were more patients with clinical N2 or 3 disease in the early period than in the late period (66.0 vs. 33.3 %). CONCLUSIONS: Pneumonectomy is associated with acceptable overall morbidity and mortality; however, patients with pathological stage III or more, T3 or more, and N2 or more disease require special consideration. Pneumonectomy should be performed only in selected patients. PMID- 22484987 TI - Management of acute portomesenteric venous thrombosis induced by protein S deficiency: report of a case. AB - Hereditary protein S deficiency is a risk factor which may predispose patients to venous thrombosis. Deep venous thrombosis of the lower extremities can result in painful congestion, while the presence of mesenteric venous thrombosis (MVT) can cause abdominal emergencies. We herein report a protein S-deficient patient presenting with acute portomesenteric venous thrombosis. Early management using anticoagulant therapy was initially successful. However, the subsequent bowel stricture resulting from the ischemic insult was further managed with a surgical bypass. The patient was kept on long-term thrombophylaxis. The treatment strategy for MVT with bowel ischemia has evolved from aggressive portomesenteric thrombectomy with resection of the involved bowel, to conservative anticoagulation to recanalize thrombotic mesenteric veins with bowel preservation. Surgical intervention is reserved for transmural necrosis or bowel perforation. The perioperative thrombophylaxis of inherited thrombophilic patients is also important for preventing further thromboembolic events. PMID- 22484988 TI - Double anal canal cancers associated with a long history of perianal Paget's disease: report of a case. AB - Extramammary Paget's disease (EPD) is rare. We report a case of double anal canal cancers in a patient with a long history of perianal Paget's disease. The patient, a 68-year-old Japanese woman, refused surgery initially and was treated with electron beam therapy, which achieved remission. However, 6 years later, Paget's disease was found to be progressing again and double anal canal tumors were also detected in the proctos and external skin area. We performed abdominoperineal resection (Miles' operation) and lymph node dissection for the Paget's disease with double anal canal tumors. Immunohistochemical staining revealed cytokeratin (CK)-20 expression in the adenocarcinomas and Paget's disease lesion, but not CK-7 or gross cystic disease fluid protein-15 expression. The lesion was joined to the carcinoma by a stalk. The immunohistochemistry results suggested secondary EPD, although it was originally considered to be Paget's carcinoma (primary EPD) based on the clinical history. PMID- 22484989 TI - Preface: Human immunology at SIgN. PMID- 22484991 TI - A critical overview of the imaging arm of the ASAS criteria for diagnosing axial spondyloarthritis: what the radiologist should know. AB - The Assessment in SpondyloArthritis international Society (ASAS) defined new criteria in 2009 for the classification of axial spondyloarthritis (SpA) in patients with >= 3 months of back pain who were aged <45 years at the onset of back pain. This represents a culmination of a number of efforts in the last 30 years starting with the 1984 modified New York criteria for ankylosing spondylitis, followed by the 1990 Amor criteria and the 1991 European Spondyloarthropathy Study Group criteria for SpA. The importance of new ASAS criteria for radiologists is that magnetic resonance imaging (MRI) takes center stage and is one of the major criteria for the diagnosis of axial SpA when active (or acute) inflammation is present on MRI that is highly suggestive of sacroiliitis associated with SpA. According to the new criteria, sacroiliitis on imaging plus >= 1 SpA features (such as inflammatory back pain, arthritis, heel enthesitis, uveitis, dactylitis, psoriasis, Crohn's disease/colitis, good response to non-steroidal anti-inflammatory drugs, family history for SpA, HLA B27 positivity, or elevated C-reactive protein) is sufficient to make the diagnosis of axial SpA. A number of rules and pitfalls, however, are present in the diagnosis of active sacroiliitis on MRI. These points are highlighted in this review, and a potential shortcoming of the imaging arm of the ASAS criteria is addressed. PMID- 22484990 TI - Regulation of the immune response by soybean isoflavones. AB - Soybeans are rich in immuno-modulatory isoflavones such as genistein, daidzein, and glycitein. These isoflavones are well-known antioxidants, chemopreventive and anti-inflammatory agents. Several epidemiological studies suggest that consumption of traditional soy food containing isoflavones is associated with reduced prevalence of chronic health disorders. Isoflavones are considered to be phytoestrogens because of their ability to bind to estrogen receptors. The literature is extensive on the chemistry, bio-availability, and bio-activity of isoflavones. However, their effects on immune response are yet to be fully understood, but are beginning to be appreciated. We review the role of isoflavones in regulation of the immune response and their potential clinical applications in immune-dysfunction. Special emphasis will be made regarding in vivo studies including humans and animal model systems. PMID- 22484994 TI - Cytological features of well-differentiated tumors of uncertain malignant potential: Indeterminate cytology and WDT-UMP. AB - The purpose of this study was to clarify the cytopathological features of well differentiated tumors of uncertain malignant potential (WDT-UMP), a possible borderline lesion of thyroid follicular cell tumor. We analysed the cytopathological findings of fine needle aspiration (FNA) smears from 6 cases histologically diagnosed as WDT-UMP. WDT-UMP, benign and malignant lesions were compared retrospectively and morphologically. No (0%) nuclear pseudoinclusions were found in adenomatous goiter (AG), follicular adenoma (FTA) and WDT-UMP. Nuclear pseudoinclusions were increased in number in papillary thyroid carcinoma (PTC) with indeterminate cytology (0.8%) and PTC with malignant cytology (1.2%). The incidence of nuclear grooves increased gradually from AG/FTA (0%), WDT-UMP (4.5%), PTC with indeterminate cytology (6.2%) and PTC with malignant cytology (6.5%). The nuclear area of WDT-UMP, an average of 40.0 um(2), was between that for benign AG/FTA and PTC with malignant cytology. The maximum/minimum axis of WDT-UMP (0.934) lied between that of AG/FTA and PTC. The degree of the nuclear circularity of WDT-UMP was less than that for PTC. WDT-UMP belong to indeterminate category between PTC and follicular adenoma morphologically, and this is one of the major reasons why some of PTC can be found in the indeterminate category. Questionable PTC-N including questionable nucler inclusions (artifact vacuole) may be seen in WDT-UMP, but absolute or definite nuclear inclusions with sharp border are not found in our 6 cases. Therefore this group of thyroid tumors (EnFVPTC and WDT-UMP) may be found in indeterminate category more often, because of intermediate nuclear morphology and incomplete nuclear vacuoles. PMID- 22484993 TI - The cost of generalized anxiety disorder in primary care settings: results of the ANCORA study. AB - To assess the cost of illness of generalized anxiety disorder (GAD) in a primary healthcare setting in Spain. A cross-sectional, retrospective study was conducted. The sample comprised patients diagnosed with GAD according to ICD-10 criteria and a control group. Healthcare/non-healthcare resource utilization was recorded retrospectively for the 12 months prior to the study visit. Costs were estimated from a societal perspective. Two models have been produced to study the variables that influence the cost of the illness both, without and with controls. The study enrolled 456 patients [76.8 % women, 49.2 (17.0) years] with GAD and 74 controls without GAD [42.5 % women, 47.9 (16.7) years]. 67.8 % of subjects were on combination therapy (antidepressant + anxiolytic); 6 % were using 2 or more drugs to treat anxiety; and 23.4 % were on monotherapy. Total annual average costs were higher in the GAD group (?7,739 vs. ?2,609), with mean costs attributable to GAD of ?5,139 (healthcare costs: ?1,329, indirect costs: 75 % of total cost, approximately). Age and health status measured by Hamilton Anxiety Rating Scale and clinical global impression were related to costs. The improvements in quality of life measured by EQ-5D index are associated to lower cost. GAD treated in Spanish primary healthcare settings generated considerable healthcare costs and, particularly, loss-of-productivity costs. PMID- 22484992 TI - A randomized controlled trial to evaluate a structural intervention to promote the female condom in New York state. AB - We conducted a structural intervention to promote the female condom (FC), comparing 44 agencies randomized to a Minimal Intervention (MI) [developing action plans for promotion and free access] or an Enhanced Intervention (EI) [with the addition of counselor training]. Intervention effects were evaluated via surveys with agency directors, counselors and clients at baseline and 12 months. Agency-level outcomes of the FC did not differ between the two interventions at follow-up. Counselors in the EI showed significantly greater gains in FC knowledge and positive attitudes, although there was no difference in the proportion of clients counseled on the FC, which significantly increased in both conditions. There was a greater increase in intention to use the FC among clients in EI agencies. Intervention effects were stronger in medical agencies. Findings suggest that making subsidized FCs available and assisting agencies to formulate action plans led to increased FC promotion. Limitations and implications for future research and intervention efforts are discussed. PMID- 22484995 TI - Neuropeptide W stimulates adrenocorticotrophic hormone release via corticotrophin releasing factor but not via arginine vasopressin. AB - Neuropeptide W (NPW) was isolated as an endogenous ligand for NPBWR1, an orphan G protein-coupled receptor localized in the rat brain, including the paraventricular nucleus. It has been reported that central administration of NPW stimulates corticosterone secretion in rats. We hypothesized that NPW activates the hypothalamic-pituitary-adrenal (HPA) axis via corticotrophin-releasing factor (CRF) and/or arginine vasopressin (AVP). NPW at 1 pM to 10 nM did not affect basal or ACTH-induced corticosterone release from dispersed rat adrenocortical cells, or basal and CRF-induced ACTH release from dispersed rat anterior pituitary cells. In conscious and unrestrained male rats, intravenous administration of 2.5 and 25 nmol NPW did not affect plasma ACTH levels. However, intracerebroventricular (icv) administration of 2.5 and 5.0 nmol NPW increased plasma ACTH levels in a dose-dependent manner at 15 min after stimulation (5.0 vs. 2.5 nmol NPW vs. vehicle: 1802 +/- 349 vs. 1170 +/- 204 vs. 151 +/- 28 pg/mL, respectively, mean +/- SEM). Pretreatment with astressin, a CRF receptor antagonist, inhibited the increase in plasma ACTH levels induced by icv administration of 2.5 nmol NPW at 15 min (453 +/- 176 vs. 1532 +/- 343 pg/mL, p<0.05) and at 30 min (564 +/- 147 vs. 1214 +/- 139 pg/mL, p<0.05) versus pretreatment with vehicle alone. However, pretreatment with [1-(beta-mercapto beta, beta-cyclopentamethylenepropionic acid), 2-(Omicron-methyl)tyrosine]-arg vasopressin, a V1a/V1b receptor antagonist, did not affect icv NPW-induced ACTH release at any time (p>0.05). In conclusion, we suggest that central NPW activates the HPA axis by activating hypothalamic CRF but not AVP. PMID- 22484996 TI - Arousal and gambling mode preference: a review of the literature. AB - The purpose of this paper is to review the literature examining subjective and physiological arousal associated with an individual's preferred modes of gambling. Arousal is hypothesised to play a central role in the onset and maintenance of problem gambling. Most studies have failed to differentiate relevant patterns of arousal elicited by stimuli associated with preferred versus non-preferred modes of gambling on the assumption that similar processes motivate all gamblers. At the conceptual level, sub-typing theories of problem gambling propose differences in the motivation to gamble, and the associated role arousal plays in maintaining behaviours. A review of the existing literature reveals preliminary findings that indicate that gamblers respond differentially to preferred compared to non-preferred gambling stimuli, and that gamblers may display greater reactivity in arousal to gambling cues compared to non-gamblers. Understanding differences in such patterns of arousal can be used to inform clinical interventions by effectively targeting the nature and role of arousal associated with preferred modes of gambling, and determining the extent to which non-preferred modes act as secondary reinforces triggering by gambling urges. PMID- 22484998 TI - Zoonoses and poverty - a long road to the alleviation of suffering. AB - Populations living in poverty in the developing world suffer a heavy burden caused by infectious diseases, most of them zoonoses. The poorer populations also tend to be marginalised from the health sector and so are many of the diseases that affect them. The poor in every society, and particularly in developing countries, bear a disproportionately high share of the disease burden. There is a broad range of viral, bacterial, mycotic, chlamydial, rickettsial and parasitic diseases of global and regional importance given their major impact on the health and socio-economic development of many populations. Endemic infectious diseases, including zoonoses, together with emerging and re-emerging diseases, are mostly shouldered by poor and vulnerable populations. Livestock are important in supporting the livelihoods of poor farmers, consumers and traders throughout the developing world. The animals of poor people are particularly vulnerable to disease because of costs, absence or unsuitability of the animal health sector, etc. The impact of endemic animal diseases are mainly felt at the farm level, while a broader economic impact can occur with these diseases through the restriction of trade in livestock and their products. Addressing comprehensive and sustainable solutions to public health problems created by endemic infections cannot be achieved solely by the public health sector alone. Partnerships with other sectors, particularly agriculture, environment, education, local administration, will be necessary to contain and effectively control zoonotic and foodborne diseases that affect mainly the poor. International organisations could support developing countries by coordinating national intersectoral activities, promoting appropriate technology and public health education, community participation and encouraging decision-makers to commit themselves. This is the only perspective for improved quality of life of poor and marginalised populations. PMID- 22484999 TI - Transport temperatures observed during the commercial transportation of animals. AB - Current temperature standards and those proposed by the European Food Safety Authority (EFSA) were compared with the actual practices of commercial transport in the European Union. Temperature and humidity records recorded for a year on 21 vehicles over 905 journeys were analysed. Differences in temperature and humidity recorded by sensors at four different positions in the vehicles exceeded 10 degrees C between the highest and lowest temperatures in nearly 7% of cases. The number and position of temperature sensors are important to ensure the correct representation of temperature conditions in the different parts of a vehicle. For all journeys and all animal categories, a relatively high percentage of beyond threshold temperatures can be observed in relation to the temperature limits of 30 degrees C and 5 degrees C. Most recorded temperature values lie within the accepted tolerance of +/-5 degrees C stipulated in European Community Regulation (EC) 1/2005. The temperature thresholds proposed by EFSA would result in a higher percentage of non-compliant conditions which are more pronounced at the lower threshold, compared to the thresholds laid down in Regulation (EC) 1/2005. With respect to the different animal categories, the non-compliant temperature occurrences were more frequent in pigs and sheep, in particular with regard to the thresholds proposed by EFSA. PMID- 22484997 TI - Alternative molecular tests for virological diagnosis. AB - Several nucleic acid amplification techniques (NAATs), particularly PCR and real time PCR, are currently used in the routine clinical laboratories. Such approaches have allowed rapid diagnosis with a high degree of sensitivity and specificity. However, conventional PCR methods have several intrinsic disadvantages such as the requirement for temperature cycling apparatus, and sophisticated and costly analytical equipments. Therefore, amplification at a constant temperature is an attractive alternative method to avoid these requirements. A new generation of isothermal amplification techniques are gaining a wide popularity as diagnostic tools due to their simple operation, rapid reaction and easy detection. The main isothermal methods reviewed here include loop-mediated isothermal amplification, nucleic acid sequence-based amplification, and helicase-dependent amplification. In this review, design criteria, potential of amplification, and application of these alternative molecular tests will be discussed and compared to conventional NAATs. PMID- 22485000 TI - Factors influencing diagnostic sample submission by food animal veterinarians in Mississippi. AB - A focus group was organised to gather information and opinions from food animal veterinarians in Mississippi regarding sample submission to diagnostic laboratories. The research found that a range of factors influence the veterinarian's decision regarding whether samples will be submitted to a diagnostic laboratory, with the cost of diagnostics as the key influence. The veterinarians believed that the relationship they had with diagnostic laboratories was important in the protection of public health, but they thought that their role in disease surveillance was under-utilised. More attention needs to be directed towards strengthening veterinary surveillance at ground level to ensure that emergent diseases are detected effectively by a partnership approach between veterinary practitioners in the field and diagnosticians in diagnostic laboratories. This partnership is a vital component of the 'One Health' concept for the protection of both animal and human health. This study demonstrates that qualitative social science methodologies, such as focus groups, can usefully be applied to topics of relevance to veterinary public health. PMID- 22485001 TI - A serological investigation of bluetongue virus in cattle of south-east Iran. AB - The aim of this study was to describe the seroprevalence rate of bluetongue virus (BTV) in cattle herds in south-east Iran. A total of 188 serum samples were collected from 20 cattle herds (10 animals in each herd) that were randomly selected between 2009 and 2010. A total of 12 samples were eliminated because of inadequacy. Antibodies to BTV in sera were detected using a commercial competitive enzyme-linked immunosorbent assay (c-ELISA). The seroprevalence rate in cattle was 2.13%. All sampled animals were female and age did not affect the prevalence of infection. PMID- 22485002 TI - Occurrence of Culicoides species Diptera: Ceratopogonidae) in the Khomas region of Namibia during the winter months. AB - Although African horse sickness (AHS) is considered to be endemic in Namibia, limited data on its Culicoides midge vector (Diptera: Ceratopogonidae) are available. The principal study objective was to determine the presence, species composition and the richness and diversity of Culicoides adults during the colder and drier months in the Khomas region of central Namibia. Five sites were selected, ranging from relatively high to low altitudes with high to low annual rainfall. Onderstepoort suction UV-light traps were used for Culicoides species collection and were run during the winter from 6 July to 21 September 2009. A relatively high diversity of 25 species from 9 091 Culicoides individuals were collected in 34 collections. The abundance of the proven vector of AHS virus, Culicoides imicola, varied from 94% near Windhoek at a high altitude and relatively higher annual rainfall, to 12% at the site situated farthest south west, with the lowest altitude and annual rainfall. This relatively high Culicoides midge abundance, coupled with the presence of a cycling host (zebra) in the area, imply that AHS virus may overwinter in the Khomas region of Namibia. PMID- 22485003 TI - Immunogenicity of two adjuvant formulations of an inactivated African horse sickness vaccine in guinea-pigs and target animals. AB - Monovalent, inactivated and adjuvanted vaccines against African horse sickness, prepared with serotypes 5 and 9, were tested on guinea-pigs to select the formulation that offered the greatest immunity. The final formulation of the vaccines took into account the immune response in the guinea-pig and the inflammatory properties of two types of adjuvant previously tested on target animals. A pilot study was subsequently conducted on horses using a vaccine prepared with serotype 9. The vaccine stimulated neutralising antibodies from the first administration and, after the booster dose, 28 days later; high antibody levels were recorded for at least 10 months. The guinea-pig appears to be a useful laboratory model for the evaluation of the antigenic properties of African horse sickness vaccines. PMID- 22485004 TI - Pasteurella multocida in backyard chickens in Upper Egypt: incidence with polymerase chain reaction analysis for capsule type, virulence in chicken embryos and antimicrobial resistance. AB - The prevalence of Pasteurella multocida strains among 275 backyard chickens from different regions of Upper Egypt was studied. A total of 21 isolates of P. multocida were recovered in 21 out of 275 chickens tested (7.6%) and were confirmed using phenotypic characterisation. Somatic serotyping of the 21 isolates resulted in 12 isolates being classed as serotype A:1 (57.14%), 4 as serotype A:3 (19.05%) and 5 could not be typed (23.8%). Capsular typing, using multiplex polymerase chain reaction (PCR), demonstrated that 18 strains were capsular type A (85.7%), and 3 were type D (14.3%). The present findings suggest that a multiplex capsular PCR could be valuable for the rapid identification of P. multocida in cases of fowl cholera infection. A total of 5 isolates of P. multocida were selected to study their pathogenicity in embryonated chicken eggs instead of conducting a study in mature chickens. The results showed a variation in pathogenicity between the strains tested, namely: serotype A:1 strains caused 80% mortality, in contrast to 20% mortality by type D strains. Pathological findings included severe congestion of the entire embryo, haemorrhaging of the skin, feather follicles and toe, and ecchymotic haemorrhages on the liver of the inoculated embryos. The observations in this study indicate that P. multocida serogroup A could be highly pathogenic for mature chickens and therefore might be a cause of considerable economic losses in commercial production. A total of 10 isolates were subjected to antimicrobial susceptibility to determine the minimal inhibitory concentration of 7 antimicrobials. All isolates were susceptible to ciprofloxacin, florfenicol, streptomycin and sulphamethoxazol with trimethoprim and with varying degrees of sensitivity to the other agents. PMID- 22485005 TI - Response of Nigerian farmers to a questionnaire on chloramphenicol application in commercial layers. AB - The authors assessed the occurrence of chloramphenicol (CAP) residues in commercial eggs. Of the 105 farmers surveyed for the use of CAP, 35 (33.3%) and 70 (66.7%) responded regarding their awareness or complete lack of awareness of the legislation that stipulates the use of CAP in food animals, including poultry, respectively. Only 28 (26.7%) of respondent farmers were aware that CAP was one of the drugs that is not recommended for use in food animals. Amongst the farms surveyed in the preliminary phase of this study, 24 were randomly sampled for further investigation, of which 21 (20.0%) admitted the use of CAP in forms of human and veterinary preparations, while 15 (62.5%) admitted the use of human CAP preparation only. The presence of antimicrobial residues was confirmed using specific thin-layer chromatography (STLC) in 8 out of 144 pooled egg samples (10 eggs per sample). The only positive CAP sample was identified on a farm that adopted the use of a human CAP preparation. PMID- 22485006 TI - Prevalence of tick infestation (Rhipicephalus sanguineus and Hyalomma anatolicum anatolicum) in dogs in Punjab, Pakistan. AB - This study was conducted to identify ticks that infest dogs in the Rawalpindi region of Punjab, Pakistan. A total of 525 dogs were examined between June and September 2010. Of these, 60 (11.42%) were infested with ticks. The morphological features of the ticks were identified by using a stereomicroscope to confirm their identity using morphological keys. Two species were observed, namely: Rhipicephalus sanguineus and Hyalomma anatolicum anatolicum. The prevalence rate of these species was 98.33% and 1.66%, respectively. Of the 508 specimens collected, 265 male, 224 female ticks and 19 nymphs were identified. No larvae were collected from the infested dogs during the study period. There was no significant difference observed during the study months. PMID- 22485007 TI - Histopathology of protozoal infection in animals: a retrospective study at the University of Philippines College of Veterinary Medicine (1972-2010). AB - The authors describe the first parasitological survey of protozoal infections on tissue slide sections of field cases processed at the histopathology laboratory of the College of Veterinary Medicine (CVM) at the University of the Philippines Los Banos (UPLB). Over 80% of the field cases were from Region 4 (CALABARZON) and the rest were equally distributed from other areas of the Philippines, namely: Region 2 (Cagayan Valley), Metropolitan Manila (National Capital Region), Region III (Central Luzon) and Region VI (Western Visayas). Histopathological analyses of tissue sections from 51 archived cases (1972-2010) of parasitic aetiology were performed. Microscopic examination of a total of 286 histopathological slides revealed the presence of several protozoa, including sarcosporidiosis, hepatic coccidiosis, intestinal coccidiosis, balantidiosis and leucocyto-zoonosis. In addition, the finding of Balantidium and Sarcocystis may have zoonotic implications and can therefore be used as markers of public health importance. PMID- 22485008 TI - In memoriam: Cristiana Patta, DVM, 1958-2012. Virologist and specialist in African swine fever and exotic animal diseases. AB - The veterinary world is shocked and deeply saddened by the untimely death of Cristiana Patta, manager at Sardinia's Istituto Zooprofilattico Sperimentale. Cristiana was a nationally and internationally acclaimed virologist, distinguished throughout her intense but all-too-brief life by her talent and professionalism. After studying microbiology and virology at the University of Sassari, specialising in microbiological and virological techniques, she began her career as a researcher in the viral animal diseases sector at the Istituto di Sassari. Her work included the main aspects of exotic animal diseases, from diagnosis to control, as well as the planning and management of eradication programmes for the principal infectious diseases (swine fever, brucellosis, tuberculosis and bluetongue) under European Union surveillance. Her knowledge of swine fever - and particularly African swine fever - led her to become a national and international expert in the control of this disease. In this role, she became a member of the roster of experts of the Ministry of Health and the European Commission. She contributed to numerous European research projects and was an invited speaker at many scientific assemblies sponsored by international organisations such as the OIE, FAO and EU. Cristiana also provided an authoritative contribution to training activities promoted by the Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise 'G. Caporale' in Teramo in its capacity as OIE collaboration centre for veterinary training, epidemiology, food safety and animal welfare, offering her expertise in exotic livestock diseases. The Italian veterinary service and national and European reference centres all benefitted from her experience and knowledge, through training events organised by the Ministry of Health and the regional authorities. Her technical expertise was matched by her managerial skills, in particular in the clinical management of veterinary public health facilities. The gap left by Cristiana cannot be filled: she will be missed not only for her professional services to the veterinary community but, above all, for her humanity, warmth and great empathy. She will leave an indelible trace in the hearts of all those who had the good fortune to know her. PMID- 22485009 TI - In memoriam: Adriano Mantovani, DVM, 1926-2012. One of the world's most prominent contributors to veterinary public health and a committed advocate of the importance of One Medicine. AB - Adriano Mantovani was born in 1926 in Altedo, Malalbergo (Bologna). After graduating in veterinary medicine from Bologna University in 1948, he gained his Masters in public health from the University of Minnesota in 1952 and qualified to lecture in microbiology and immunology in 1957 and in parasitology in 1963. He held numerous positions over the years: Assistant, Aide and Vice-Director of the Istituto Zooprofilattico Sperimentale di Teramo(1949-1962), Researcher at the Faculty of Medicine in Rome (1962-1965), Professor of Infectious Diseases, Prophylaxis and Veterinary Police Work at the Faculty of Veterinary Medicine in Bologna, Director of the Institute of the same name (1965-1982) and Research Manager and Director of the Parasitology Laboratory at the Italian National Institute of Health and the WHO/FAO Collaboration Centre for Veterinary Public Health in Rome (1983-1991). He was active in numerous national and international organisations, including as a member of the National Health Council (1974-1982), Secretary of the World Federation of Parasitologists (1971-1987) and from 1972 President, Vice President or presenter in various WHO, FAO and OIE working groups. He worked in numerous countries in Africa, Asia, Europe, Latin America and North America as an expert, presenter and lecturer. From 1978, the year in which the Mediterranean Zoonoses Control Plan was established, he was one of the major collaborators of the WHO Mediterranean Zoonoses Control Centre in Athens (MZCC). In 1989, he was the first Italian to be awarded the OIE's international award for contributions to veterinary public health and in 2001 was publicly recognised by the MZCC for his many years of activities carried out to support the zoonoses control plan and promote well-being in the Mediterranean. He had been a member of the Italian National Guard's Commission for Predicting and Preventing Great Risks since 1994. In 2002, he was presented with the Italian Parasitology Society's Battista Grassi medal. He covered leading roles in the executive boards of various Italian and international scientific associations, including the Italian Small Animal Veterinary Association, the World Association for the Advancement of Veterinary Parasitology, the Italian Society of Tropical Medicine, the Italian Society of Parasitology, the World Association for the History of Veterinary Medicine and the World Small Animal Veterinary Association. Professor Mantovani's principal areas of activity were in veterinary public health, above all the epidemiology and control of zoonoses and animal diseases, veterinary urban hygiene, health education and veterinary actions in emergency situations. His interests were not limited to transmissible diseases but included all problems connected with the relationship between humans, animals and the environment in both urban and rural areas, especially disadvantaged areas. He was particularly involved in the development and organisation of public veterinary services, the social and economic aspects of health and animal production and prevention and control activities. He was a committed advocate of the overriding importance of One Medicine and inter- and intra-professional cooperation. He authored over 250 publications. PMID- 22485010 TI - Design of the novel protraction mechanism of insulin degludec, an ultra-long acting basal insulin. AB - PURPOSE: Basal insulins with improved kinetic properties can potentially be produced using acylation by fatty acids that enable soluble, high-molecular weight complexes to form post-injection. A series of insulins, acylated at B29 with fatty acids via glutamic acid spacers, were examined to deduce the structural requirements. METHODS: Self-association, molecular masses and hexameric conformations of the insulins were studied using size exclusion chromatography monitored by UV or multi-angle light scattering and dynamic light scattering, and circular dichroism spectroscopy (CDS) in environments (changing phenol and zinc concentration) simulating a pharmaceutical formulation and changes following subcutaneous injection. RESULTS: With depletion of phenol, insulin degludec and another fatty diacid-insulin analogue formed high molecular mass filament-like complexes, which disintegrated with depletion of zinc. CDS showed these analogues adopting stable T(3)R(3) conformation in presence of phenol and zinc, changing to T(6) with depletion of phenol. These findings suggest insulin degludec is dihexameric in pharmaceutical formulation becoming multihexameric after injection. The analogues showed weak dimeric association, indicating rapid release of monomers following hexamer disassembly. CONCLUSIONS: Insulins can be engineered that remain soluble but become highly self-associated after injection, slowly releasing monomers; this is critically dependent on the acylation moiety. One such analogue, insulin degludec, has therapeutic potential. PMID- 22485011 TI - Coronary artery calcification by computed tomography in epidemiologic research and cardiovascular disease prevention. AB - Both American and European guidelines recommend coronary artery calcification (CAC) as a tool for screening asymptomatic individuals at intermediate risk for coronary heart disease (CHD). These recommendations are based on epidemiologic studies mostly in the United States. We review (1) the use of CAC in primary prevention of CHD in the United States, (2) epidemiologic studies of CAC in asymptomatic adults outside of the United States, and (3) international epidemiologic studies of CAC. This review will not consider clinical studies of CAC among patients or symptomatic individuals. US studies have shown that CAC is a strong independent predictor of CHD in both sexes among middle-aged and old age groups, various ethnic groups, and individuals with and without diabetes and that CAC plays an important role in reclassifying individuals from intermediate to high risk. Studies in Europe support these conclusions. The Electron-Beam Tomography, Risk Factor Assessment Among Japanese and US Men in the Post-World War-II birth cohort (ERA JUMP) Study is the first international study to compare subclinical atherosclerosis, including CAC among Japanese, Japanese Americans, Koreans, and whites. It showed that as compared with whites, Japanese had lower levels of atherosclerosis, whereas Japanese Americans had similar or higher levels. CAC is being increasingly used as a screening tool for asymptomatic individuals in Europe and the United States. CAC is a powerful research tool, because it enables us to describe differences in atherosclerotic burden across populations. Such research could identify factors responsible for differences among populations, which may improve CHD prevention. PMID- 22485012 TI - Evaluation of a fotonovela to increase depression knowledge and reduce stigma among Hispanic adults. AB - Fotonovelas-small booklets that portray a dramatic story using photographs and captions-represent a powerful health education tool for low-literacy and ethnic minority audiences. This study evaluated the effectiveness of a depression fotonovela in increasing depression knowledge, decreasing stigma, increasing self efficacy to recognize depression, and increasing intentions to seek treatment, relative to a text pamphlet. Hispanic adults attending a community adult school (N = 157, 47.5 % female, mean age = 35.8 years, 84 % immigrants, 63 % with less than high school education) were randomly assigned to read the fotonovela or a low-literacy text pamphlet about depression. They completed surveys before reading the material, immediately after reading the material, and 1 month later. The fotonovela and text pamphlet both produced significant improvements in depression knowledge and self-efficacy to identify depression, but the fotonovela produced significantly larger reductions in antidepressant stigma and mental health care stigma. The fotonovela also was more likely to be passed on to family or friends after the study, potentially increasing its reach throughout the community. Results indicate that fotonovelas can be useful for improving health literacy among underserved populations, which could reduce health disparities. PMID- 22485013 TI - Hidden treasures in unspliced EST data. AB - Several classes of exclusively--or at least predominantly--unspliced non-coding RNAs have been described in the last years, including totally and partially intronic transcripts and long intergenic RNAs. Functionally, they appear to be involved in regulating gene expression, at least in part by associating with the chromatin. Intron-less transcripts have received little attention, even though recent findings indicate that intron-less protein-coding genes have several features that set them apart from the more abundant and much better understood spliced mRNAs. Even less is known about unspliced non-coding transcripts. Thus we systematically analyze the distribution of unspliced ESTs in the human genome. These form a large source of transcriptomic data that is almost always excluded from detailed studies. Most unspliced ESTs appear in clusters overlapping, or located in the close vicinity of, annotated RefSeq genes. Partially intronic unspliced ESTs show complex patterns of overlap with the intron/exon structure of the RefSeq gene. Distinctive patterns of CAGE tags indicate that a large class of unspliced EST clusters is forming long extensions of 3'UTRs, at least several hundreds of which probably appear also as independent 3'UTR-associated RNAs. PMID- 22485014 TI - Long-term follow-up after coronary stenting with the sirolimus-eluting stent in clinical practice: results from the prospective multi-center German Cypher Stent Registry. AB - AIMS: To obtain long-term follow-up data of the sirolimus-eluting coronary stent (SES) and to determine factors associated with clinical events and target vessel revascularization (TVR). METHODS AND RESULTS: Between 2002 and 2005, 5,946 patients were treated with at least one SES. A follow-up after a median of 4.1 years was obtained in 5,247 patients (88.2 %). During the follow-up, death occurred in 9.2 % of patients, nonfatal myocardial infarction in 5.9 %, nonfatal stroke in 2.2 % and MACCE (death/myocardial infarction/stroke) in 16.3 %. Any TVR was performed in 20.3 %. Independent predictors of MACCE were: older age (p < 0.0001), renal insufficiency (p < 0.0001), prior myocardial infarction (p < 0.0001), diabetes mellitus (p < 0.0001), cardiogenic shock (p = 0.0002), three vessel disease (p = 0.0012), reduced left ventricular function (p = 0.0048), target vessel = bypass graft (p = 0.0122), indication for treatment = ACS (p = 0.0181) and PCI before implantation (p = 0.0308). Independent predictors of TVR were target vessel = coronary bypass (<0.0001), two- or three-vessel disease (p < 0.0001), ostial lesions (p < 0.0001), total length of SES implanted (p = 0.0012) and older age being a protective factor (p = 0.0187). CONCLUSIONS: Long-term follow-up of the SES in clinical practice showed clinical event rates that were comparable to randomized trials with a MACCE rate of 16.3 % and TVR rate of 20.3 %. PMID- 22485016 TI - Microalbuminuria independently correlates to cardiovascular comorbidity burden in patients with hypertension. AB - BACKGROUND: Microalbuminuria (MAU) is a marker for endothelial dysfunction and a predictor of cardiovascular events. Cardiovascular risk and mortality are mainly influenced by associated morbidities and risk factors. METHODS AND RESULTS: The present analysis aimed to investigate the relationship between the number of cardiovascular comorbidities and both the prevalence of MAU and the extent of albuminuria (measured as urinary albumin excretion, UAE) in 21,867 high-risk hypertensive patients included in the I-SEARCH study. A total of 6,945 patients (32 %) suffered from at least one comorbidity, out of which 5,437 patients (25 %) had one cardiovascular comorbidity, 1,163 (5 %) patients had two, and 345 (2 %) had >=3. The prevalence of MAU increased from 54 % in patients without cardiovascular comorbidity to 74 % in the presence of >=3 comorbidities (p < 0.01). In a multivariate analysis, the presence of >=3 cardiovascular comorbidities nearly doubled the risk for MAU (HR 1.79, CI 1.07-2.68, p = 0.025). Compared to other comorbidities, patients with left ventricular hypertrophy had the highest prevalence of MAU (68 %, p < 0.01). The extent of UAE was related to the number of concomitant disease and increased significantly in patients with >=3 comorbidities compared to patients with no comorbidity (UAE of 80 mg/L: 12-22 %, p < 0.01; UAE of 150 mg/L: 8-19 %, p < 0.01). CONCLUSIONS: In hypertensive patients at high cardiovascular risk, both the prevalence of MAU and the extent of albuminuria increase with the number of comorbidities. PMID- 22485015 TI - Cardiogoniometry as a diagnostic tool in patients with acute coronary syndromes: results of the CGM@ACS trial. AB - BACKGROUND: Cardiogoniometry (CGM) is a novel electrocardiac method utilising computer-assisted three-dimensional information on cardiac potentials. OBJECTIVE: To investigate the potential of CGM in discriminating non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and relevant coronary stenosis upon hospital admission by prospectively comparing its sensitivity, specificity and accuracy against those of a single troponin test and a 12-lead ECG performed on admission DESIGN: A multicenter prospective observational trial. SETTING: Eight interventional cardiac centres in Germany. PATIENTS: A cohort of 216 patients (mean age 67 years, 34.7 % female) who presented with acute chest pain or dyspnoea without ST-segment elevation and were scheduled for coronary angiography within 72 h of admission. INTERVENTION: Pre-angiography screening by CGM, troponin test, 12-lead ECG MAIN OUTCOME MEASURES: ECG, troponin and CGM on admission compared with final diagnosis of NSTE-ACS or relevant diameter stenosis >=70 % verified by an independent review board and an angiographic core laboratory. RESULTS: NSTE-ACS was finally confirmed in 162 cases, whereas the remaining 54 cases without proof of NSTE-ACS served as controls. Diagnostic sensitivity for NSTE-ACS was 28, 50 and 69 % and specificity 78, 96 and 54 % for first ECG, serial troponin and first CGM, respectively. Accuracy was 40, 62 and 65 %. The sensitivity of the tests to detect relevant coronary stenosis (n = 126) was 32, 53 and 74 %, respectively. The sensitivity of CGM to detect NSTE-ACS (65 %) or relevant stenosis (71 %) was high even in patients with normal troponin and ECG. CONCLUSIONS: CGM can detect NSTE-ACS at first medical contact. CGM in conjunction with traditional markers, 12-lead ECG and troponin may effectively aid early decision making in patients presenting with acute chest pain. PMID- 22485018 TI - Bronchial carcinoid tumors metastatic to the sella turcica and review of the literature. AB - We review here the literature on neuroendocrine neoplasms metastatic to the pituitary and present an example of the disease. Metastasis of bronchial carcinoid tumors to the sellar region are rare. Herein, we describe the case of a 63-year-old woman who presented with constant cough and headaches. She had previously been operated for carcinoid tumor of the lung. During the preoperative investigation, a CT scan of the head revealed a sellar mass. Six months after a left lower lobectomy, the sellar lesion was removed by transsphenoidal surgery. The two tumors were evaluated by histology, immunohistochemistry and electron microscopy. Both showed identical morphologic features, those of carcinoid tumor. Immunohistochemistry revealed immunoreactivity for the endocrine markers, synaptophysin and chromogranin, as well as CD-56, serotonin, bombesin and vascular endothelial growth factor. The sellar neoplasm showed nuclear immunopositivity for thyroid transcription factor-1, supporting the diagnosis of a metastatic bronchial carcinoid tumor. In conclusion, this is the first report of a serotonin- and bombesin-immunopositive atypical bronchial carcinoid tumor metastatic to the sella. PMID- 22485017 TI - Herniation of cerebellar tonsils in acromegaly: prevalence, pathogenesis and clinical impact. AB - Herniation of cerebellar tonsils (CTH) might occur in acromegaly patients and improve after acromegaly treatment. Our study investigated CTH prevalence in acromegaly, its relationship with clinical, laboratory and neuroimaging findings and its possible pathogenesis and clinical impact. 150 acromegaly patients (median-age 56 years, age-range 21-88, 83 females) underwent brain magnetic resonance imaging (MRI). Clinical data, laboratory and pituitary adenoma imaging findings were recorded. CTH, posterior cranial fossa area, tentorial angle, clivus, supraocciput and Twining's line length were measured in acromegaly patients and controls, who included MRI of 115 consecutive subjects with headache or transient neurological deficits (control group-1) and 24 symptomatic classic Chiari 1 malformation patients (control group-2). Acromegaly patients were interviewed for symptoms known to be related with CTH. 22/150 acromegaly patients (15 %) and 8/115 control group-1 subjects presented with CTH (p = 0.04). In acromegaly patients, CTH correlated positively with younger age and inversely with GH-receptor antagonist treatment. Control group-2 had a shorter clivus than CTH acromegaly patients (40.4 +/- 3.2 mm vs 42.5 +/- 3.3 mm, p < 0.05), while posterior fossa measures did not differ among acromegaly subgroups (with and without CTH) and control group-1. Headache and vision problems were more frequent in CTH acromegaly patients (p < 0.05); two acromegaly patients presented with imaging and neurological signs of syringomyelia. Despite no signs of posterior fossa underdevelopment or cranial constriction, CTH is more frequent in acromegaly patients and seems to contribute to some disabling neurological symptoms. PMID- 22485019 TI - Histopathological changes in parotid and submandibular glands of patients treated with preoperative chemoradiation therapy for oral cancer. AB - We retrospectively evaluated the relationship between computed tomography (CT)- and histopathological findings of parotid and submandibular glands in six patients treated for advanced oral cancer. Eligibility criteria were a pathologic diagnosis of oral squamous cell carcinoma, preoperative chemoradiation therapy (CRT) with a total dose of 30 Gy and oral S-1 (80 mg/m2/day), the availability of morphological assessments by CT and of functional assessments with the Saxon test before- and 2 weeks after CRT, and the availability of histopathological slides of irradiated parotid and submandibular glands. In the histopathological interpretation, gland structures were divided into acinar-, duct-, and adipose cells and other tissues. The Mann-Whitney test and the Spearman rank correlation test were used to determine histopathological changes. After 30-Gy irradiation, saliva production and parotid and submandibular volumes were significantly decreased (P < 0.05 each). Histopathological analysis demonstrated that 30-Gy irradiation resulted in a loss of acinar cells although acinar cells in the submandibular gland were relatively retained; the median acinar rate in the parotid and submandibular glands was 1.1% and 19.0%, respectively. The CT values after CRT were inversely correlated with adipose ratios (r = -0.98, P < 0.01) and there was a strong correlation between CT values before and after CRT (r = 0.97, P < 0.01). Our results suggested that acinar cell loss is a main contributor to changes in the volume and function of irradiated human parotid and submandibular glands. The CT value may reflect the adipose ratio rather than salivary function. PMID- 22485020 TI - Assessment of daily needle applicator displacement during high-dose-rate interstitial brachytherapy for prostate cancer using daily CT examinations. AB - To improve treatment conformity for prostate cancer, we investigated daily applicator displacement during high-dose-rate interstitial brachytherapy (HDR ISBT). Thirty patients treated with HDR-ISBT as monotherapy were examined. All patients received a treatment dosage of 49 Gy per 7 fractions over 4 days. For dose administration, we examined 376 flexible applicators (1128 points) using our unique ambulatory implant technique. Using CT images with a 3-mm slice thickness, we calculated the relative coordinates of the titanium markers and the tips of the applicators. We calculated the distance between the center of gravity of the markers and the tips of the catheters, and compared the distances measured on the day of implantation and the second, third, and fourth treatment days. The mean displacement distance for all applicators was 4.3 +/- 3.4 mm, 4.6 +/- 4.1 mm, and 5.8 +/- 4.5 mm at 21, 45, and 69 hours after initial planning CT. We used a 15-mm margin for needle displacement and only 2 points of 2 patients (16 mm and 18 mm at 69 hours, 2/1128 = 0.2%) exceeded this range. Almost patients (87%) showed the largest displacement within the first 21 hours. The relative doses that covered 100% of CTV (D100(CTV)) values compared with the initial treatment plan were reduced to 0.96 +/- 0.08, 0.96 +/- 0.08 and 0.94 +/- 0.1 at 21, 45 and 69 hours. However, the relative D90(CTV) values kept acceptable levels (1.01 +/- 0.02, 1.01 +/- 0.03 and 1.01 +/- 0.03). Cranial margin of 15 mm seems to be effective to keep D90(CTV) level if we do not do corrective action. PMID- 22485021 TI - Do phonological constraints on the spoken word affect visual lexical decision? AB - Reading a word may involve the spoken language in two ways: in the conversion of letters to phonemes according to the conventions of the language's writing system and the assimilation of phonemes according to the language's constraints on speaking. If so, then words that require assimilation when uttered would require a change in the phonemes produced by grapheme-phoneme conversion when read. In two experiments, each involving 40 fluent readers, we compared visual lexical decision on Korean orthographic forms that would require such a change (C stimuli) or not (NC stimuli). We found that NC words were accepted faster than C words, and C nonwords were rejected faster than NC nonwords. The results suggest that phoneme-to-phoneme transformations involved in uttering a word may also be involved in visually identifying the word. PMID- 22485022 TI - Effects of local and global context on processing sentences with subject and object relative clauses. AB - An eye tracking study investigated the effects of local and global discourse context on the processing of subject and object relative clauses, whereby the contexts favored either a subject relative clause interpretation or an object relative clause interpretation. The fixation data replicated previous studies showing that object relative clause sentences were more difficult to process than subject relative sentences. Crucially, however, the reading difficulty asymmetry between subject and object relative clause sentences disappeared when the sentences were presented with a local or a global discourse context that favored the objects in the object relative clauses. These findings demonstrate that the evidence for a syntax-based account of sentence processing is found when sentences are presented in isolation. However, if sentences are placed more naturally, in context, discourse factors outweigh the initial structural assignment. PMID- 22485023 TI - Adjective semantics, world knowledge and visual context: comprehension of size terms by 2- to 7-year-old Dutch-speaking children. AB - The interpretation of size terms involves constructing contextually-relevant reference points by combining visual cues with knowledge of typical object sizes. This study aims to establish at what age children learn to integrate these two sources of information in the interpretation process and tests comprehension of the Dutch adjectives groot 'big' and klein 'small' by 2- to 7-year-old children. The results demonstrate that there is a gradual increase in the ability to inhibit visual cues and to use world knowledge for interpreting size terms. 2- and 3-year-old children only used the extremes of the perceptual range as reference points. From age four onwards children, like adults, used a cut-off point in the mid-zone of a series. From age five on, children were able to integrate world knowledge and perceptual context. Although 7-year-olds could make subtle distinctions between sizes of various object classes, their performance on incongruent items was not yet adult-like. PMID- 22485025 TI - Environmental risk and protective factors of adolescents' and youths' mental health: differences between parents' appraisal and self-reports. AB - PURPOSE: We investigated the effect of parents' mental health, life events, and home life (among other factors) on adolescents'/youths' mental health, whether such an effect varies when several variables are assessed jointly, and also whether the informant source of the mental health problem modifies the estimations. METHODS: We studied a representative sample of 454 Spanish adolescents/youths studied longitudinally (2 assessments, 3 years apart). We considered factors associated with adolescents'/youths' mental health (conduct, emotional, and hyperactivity scores [SDQ]): risk factors (parents' mental health and life events) and mediators (social and financial support). Structural equation modeling was applied. We constructed two models: (a) with parents' SDQ responses and (b) with self-reported SDQ responses (in a subsample of N = 260). RESULTS: Model fit was adequate for parents' appraisal. Parents' mental health (p < 0.05) and undesirable life events (p < 0.05) were the most important risk factors. The same model showed poorer fit when self-reported measures were used. Home life exerted a stronger protective effect on adolescents'/youths' mental health when reported by adolescents/youths. The negative effect of parents' mental health was significantly protected by home life in emotional [-0.14 (0.07)] and hyperactivity scores [-0.2 (0.08)]. CONCLUSIONS: Even in the presence of other factors, parents' mental health has an important effect on adolescents'/youths' mental health. Good levels of home life are protective, especially when adolescents'/youths' mental health is self-reported. PMID- 22485024 TI - Characteristics associated with low resilience in patients with depression and/or anxiety disorders. AB - PURPOSE: Despite a growing body of research on resilience and its clinical significance in depression and anxiety disorders, relatively little is known about contributing factors for resilience in patients with these illnesses. We aimed to find characteristics of patients having low resilience for elucidating its clinical implications in depression and/or anxiety disorders, primarily focused on potentially modifiable variables. METHODS: A total of 121 outpatients diagnosed with depression and/or anxiety disorders completed questionnaires measuring socio-demographic, clinical, and positive psychological factors. We divided patients into the three groups based on their Connor-Davidson resilience scale scores and investigated predictors of the low- and medium- versus high resilience groups using multinomial logistic regression analysis. RESULTS: In the final regression model, low spirituality was revealed as a leading predictor of lower-resilience groups. Additionally, low purpose in life and less frequent exercise were associated with the low- and medium-resilience groups, respectively. Severe trait anxiety characterized the low- and medium-resilience groups, although it was not included in the final model. CONCLUSIONS: Spirituality, purpose in life, and trait anxiety contribute to different levels of resilience in patients with depression and/or anxiety disorders. Our results would deepen the understanding of resilience and provide potential targets of resilience-focused intervention in these patients. PMID- 22485026 TI - Health-related quality of life and emotional problems in juvenile idiopathic arthritis. AB - PURPOSE: Children with juvenile idiopathic arthritis (JIA) are at an increased risk of developing emotional problems. This study evaluated the associations between levels of depressive and anxiety symptoms and health-related quality of life (HRQOL) in these children. METHODS: Sixty-seven children with JIA, together with one parent, participated. Anxiety symptoms were identified using the Screen for Child Anxiety Related Emotional Disorders Questionnaire (SCARED), while depressive symptoms were identified using the Mood and Feeling Questionnaire (MFQ). The Pediatric Quality of Life Inventory (PedsQL) was used for HRQOL assessments. Using hierarchical multiple-regression analysis, demographics, clinical factors, and pain were control variables, while anxiety (the SCARED score) and depressive symptoms (the MFQ score) were HRQOL (the PedsQL score) predictors. RESULTS: The regression model emerged with specified variables explaining 63 % of the variance in the PedsQL score (F = 11.92, p < 0.01) among children. Among parents, the same set of variables accounted for 49 % the variance (F = 6.99, p < 0.01). The MFQ score, but not the SCARED, added most to the variance. CONCLUSIONS: Depressive symptoms, but not anxiety, accounted for substantial variability in levels of HRQOL when considered with demographics, clinical factors, and pain. Thus, screening for depression needs to be considered as a part of multimodal assessment and treatment approaches in JIA. PMID- 22485027 TI - [How to repair a mitral valve prolapse;an assessment of operative techniques dependent on late results]. AB - BACKGROUND: In this study, we assessed the repair techniques employed for mitral valve prolapse. PATIENTS AND METHODS: Between 1992 and 2011, we repaired 173 consecutive patients with mitral valve prolapse. The mean age of the patients was 60.1 years and 68.6% were male. For anterior leaflet (AL) prolapse, 27 patients with fibroelastic deficiency (FED) were treated with chordal replacement (CR). In 21 patients with Barlow type, 2 were repaired with CR and the remaining 19 were repaired with resection. In 130 patients with a prolapse of the posterior leaflet (PL), we selected quadrangular resection( QR:44), sliding plasty( SP:12), folding plasty and CR. More recently, triangular resection (TrR:22) was selected for <=18 mm height leaflets, and an hourglass resection( HgR:21) for high leaflets.Hourglass represents the shape of the resection. RESULTS: In 1 patient of the AL CR group, the expanded polytetrafluoroethylene (ePTFE) was broken. Other patients in this group showed no mitral regurgitation (MR) and no re operation during 16 years. Two patients receiving CR for AL Barlow received re repair, whilst the other 19 patients in this group displayed good results over the following 19 years. In the QR and SP groups, 1 patient was rerepaired,whilst 3 patients displayed complicated mitral stenosis. In the TrR and HgR groups, no MR,no re-operation and no late deaths occurred during the following 4.5 years. CONCLUSIONS: CR for AL FED, resection for AL Barlow and TrR or HgR for PL were durable techniques for the treatment of mitral valve prolapse. PMID- 22485028 TI - [Toward a paradigm for universal procedures of valve repair]. AB - We developed novel methods to simplify valve repair techniques.Adequate exposure is crucial for mitral valve surgery. The right side of the pericardium is sutured to the chest wall, and both cava are mobilized and hitched up to the left. Then a longitudinal incision of the right side of the left atrium allows excellent exposure of the mitral valve.We have developed a new device for replace neochordae. This double-armed, double-hooked device is inserted through the loop formed by the neochordae, which is anchored on the papillary muscle and pass through the prolapsing segment. The device pulls up both leaflets and maintains the neochordae at the same length as that of the opposing normal chordae during tying slippery neochordae.A simple method to repair large prolapsing posterior leaflet was developed. The middle of the prolapsed portion is cut, and both sides are laid each other. The water test is made to confirm accurate closure,and 2 layers are sutured.A novel method for adjustable tricuspid annuloplasty was developed. A flexible annuroplasty band,through which an expanded polytetrafluoroethylene (ePTFE) thread was passed, was secured to the tricuspid annulus. The thread was snared from outside of the ejecting heart under observation by echocardiogram. PMID- 22485029 TI - [Long-term outcome of repair of prolapsing anterior mitral leaflet with artificial chordae replacement]. AB - OBJECTIVE: We have performed a simple and uniform technique for reconstruction of artificial chordae in patients with anterior mitral prolapse since 1994. In this study, we investigated the long-term clinical and echocardiographic results of chordae replacement with Gore-Tex sutures for anterior mitral leaflet prolapse. METHODS: A pair of Gore-Tex sutures is passed through a small autologous pericardium and tied on one side of the pericardium. Double-armed mattress stitches on the side without a knot are passed through the head of the papillary muscle and another small pericardium and then tied down. Using this simple technique, 2 pairs of artificial chordae are made. The length of the artificial chordae is determined during the leak test. Chordal replacement with this technique was performed in 30 patients (mean age, 59.3 years) with anterior mitral leaflet prolapse. Echocardiography was performed annually in these patients. Follow-up ranged from 0.2~16.2( 8.0+/-5.1) years. RESULTS: There were no hospital deaths. Twenty-one patients had no mitral regurgitation( MR) and the others had trivial or mild MR. There were 2 reoperations and 4 cases with recurrent moderate MR in this series. Kaplan-Meier survival and freedom from reoperation at 15 years were 84% and 93%,respectively. Overall, freedom from recurrent moderate or severe MR at 15 years was 81%. CONCLUSIONS: Our simple chordae replacement technique with Gore-Tex sutures for anterior mitral prolapse, results in good long-term durability. To avoid recurrence of regurgitation, intraoperative complete repair is essential. PMID- 22485030 TI - [Leaflet resection for the degenerative mitral valve regurgitation; early/long term assessment]. AB - Leaflet resection for posterior leaflet prolapse has been a standard repair procedure with good longterm durability. The aim of this study was to review our experience of mitral valve repair, in which resection of the anterior and/or posterior leaflets was performed. Between October 1991 and December 2010, 172 patients with degenerative mitral valve regurgitation underwent mitral valve reconstruction,including 98 patients with the posterior leaflet prolapse, 47 patients with the anterior leaflet prolapse, 17 patients with both leaflets and 10 patients with the commissure prolapse. Most patients in this study were supposed to be caused by fibroelastic deficiency and we have not experienced systolic anterior motion after repair. The mean follow-up period was 8.7 +/- 5.5 years. The freedom from reoperation rates at 15 years in 88.7 +/- 5.3% of the anterior leaflet procedure, 96.6 +/- 2.5% of the posterior leaflet, and 100% of both leaflets. The results of resection of a diseased prolapsed mitral leaflet have been promising so far. However, reoperation was required in 7 patients (4.1%) and reoperation rate was higher in patients with anterior prolapse and longer follow-up will evaluate precisely be benefit. PMID- 22485031 TI - [Surgical treatment for non-ischemic mitral regurgitation]. AB - Non-ischemic mitral regurgitation( MR) is classified in degenerative MR, infective endocarditis( IE) and rheumatic MR. For degenerative MR, although 100% achievement of successful mitral valve plasty (MVP), it still important to evaluate mitral morphology preoperatively and to select suitable procedure.MR due to IE, the most important thing is to exclude vegetation completely. Then MVP is considered depends on its area of defect. Rheumatic MR is still difficult to accomplish MVP. Mitral valve replacement(MVR) is a main strategy for rheumatic MR. PMID- 22485032 TI - [Mitral valve repair with artificial chordal creation]. AB - To achieve optimal long-term result of mitral valve repair, artificial chordae creation has got to be an important technique. Artificial chordae creation can preserve leaflet motion of the posterior mitral leaflet and soft coaptation area. Loop technique is suitable technique for creation of multiple artificial chordae, especially in minimally invasive minithoracotomy setting. Loop-in-loop technique is a new technique to realize easy adjusting of the length of the neochordae using slippery Gore-Tex suture. Loop-in-loop technique helps surgeons to afford variety of mitral valve repair techniques and manage complex mitral valve pathologies. PMID- 22485033 TI - [Mitral valve repair for active infectious endocarditis]. AB - Between December 2005 and November 2011, 11 patients with mitral valve regurgitation (MVR) resulting from native valve endocarditis underwent mitral valve plasty (MVP). These patients were aged 44.4 +/- 11.3 years. The mean follow up period of the patients was 3.1 +/- 0.63 years. Five patients were men. Emergency or urgent surgery was required in 5 patients. Three patients were categorized as New York Heart Association( NYHA) functional class IV. Infection of the mitral valve, occurred in the anterior leaflet in 3 patients, the posterior leaflet in 5 patients, and the anterior-posterior leaflet in 3 patients. Nine patients had a resection suture technique. One patient had chordae replacement with expanded polytetrafluoroethylene (ePTFE), and 1 patient had replacement using the pericardium. All patients received ring annuloplasty with a partial flexible ring. After surgery, all patients were categorized as NYHA functional class I. There were no valve associated complications, no hospital deaths, no late deaths, and no reoperations. We conclude that MVP is an effective treatment for active infective endocarditis( AIE) with mitral regurgitation. PMID- 22485034 TI - [A surgical technique of tricuspid valve repair for infective endocarditis using an autologous pericardium]. AB - We report a surgically treated case of tricuspid valve endocarditis. A 33-year old man was diagnosed with ventricular septal defect (VSD) and active infective endocarditis associated with severe tricuspid regurgitation. Ultrasonic echocardiography (UCG) showed vegetations attached to the tricuspid valve. His blood culture was positive for Streptococcus oralis. Although intravenous antibiotics therapy was effective, chest computed tomography( CT) revealed multiple septic pulmonary enboli in right lung and UCG showed severe tricuspid valve regurgitation. So we performed tricuspid valve repair by reconstructing septal leaflet using an autologous pericardium, expanded polytetrafluoroethylene( ePTFE) artificial chordae and annuloplasty ring. The postoperative course was uneventful, without tricuspid regurgitation or stenosis. He has been free from any complication for over 8 months. This surgical technique of tricuspid valve repair with an autologous pericardium and ePTFE artificial chordae for infective endocarditis might be useful choice of procedure for patients with leaflet destruction, in particular for young patients because of less recurrence of infection, less chance of anticoagulant therapy and expected long uneventful course. PMID- 22485035 TI - [The formula of the aortic valve repair for bicuspid aortic valve]. AB - BACKGROUND: The treatment of aortic regurgitation( AR) with bicuspid aortic valve( BAV) repair is still uncommon as the reproducibility of the repair is low and the 5-year durability is poor. In this study, we examined a method of cusp suspension after triangular resection. In addition, the relationship between the length of the cusp margin and diameter of the sino-tubular( ST) junction was evaluated. PATIENTS AND METHODS: We repaired 8 regurgitant BAVs between 1997 and 2011. The mean patient age was 35+/-14 years and 87.5% were male. All lesions were raphe type:7 were anterior-posterior type and 1 was left-right type. The basic technique was triangular resection of the pseudo-commissure.When the annulus or ST junction was dilated, annuloplasty or ST junction plication was added. Cusp suspension was performed in 7 patients. In 2 patients, the half length of the cusp margin (d) was related to the diameter of the ST junction( D) as described by d=D/2+1. RESULTS: Two cases were on a 2nd pump run because of residual AR. The valve was replaced in 1 case, while the cause of AR was found to be symmetric prolapse in the analysis. The coaptation depth was 6.2 mm. Another case was re-repaired because AR was caused by an untied suspension suture.Seven cases( 87.5%) were repaired successfully. No in-hospital deaths or complications occurred. The mean follow-up period was 5.42 years (range 1~15). No patients required re-operation and no recurrent AR greater than moderate occurred. The mean coaptation depth of the 7 successful patients was 11+/-3 mm. CONCLUSION: When repairing a regurgitant BAV, triangular resection alone is sometimes ineffective due to the occurrence of symmetric prolapse. For reproducible repair, it is useful to add cusp suspension.Lastly, the rate of suspension is related to the diameter of the ST junction. PMID- 22485036 TI - [Our technical modification of aortic valve sparing operation focused on standardization and reproducibility]. AB - BACKGROUND: The aortic valve-sparing operation has been accepted as an ideal procedure for the treatment of aortic root aneurysm, especially in young patients. However, this operation is thought to be technically difficult due to lack of conceptual understanding of the procedure for many surgeons. In order to overcome the surgical problem, we have developed a simple valve-sparing aortic root replacement focused on standardization and reproducibility. METHODS: Seven consecutive patients underwent the aortic valve-sparing operation in our institution.Our surgical strategy to restore valvular competency is based on the concept of inserting a dilated aortic annulus into small sized graft. Regardless of annular diameter, the Valvalva graft of 26 mm was used in all patients. Proximal end of the graft is secured on the outside of the left ventricular outflow tract with 12 mattress sutures. The 3 commissures are suspended upward inside the graft as possible. The remnants of aortic sinuses are sutured to the graft in U-shaped manner using continuous suture line. If necessary, aortic cusp repair was performed. Coronary arteries are reconstructed by Piehler's method. RESULTS: There was no operative death. Valve-sparing procedure was completed without conversion to valve replacement and no significant postoperative aortic insufficiency was noted. CONCLUSIONS: The excellent outcome was demonstrated with our simple modification. Although we recommend this technique of the aortic valve sparing procedure which is reproducible and technically less demanding, close observation would be mandatory concerning with valvular durability in this particular circumstance. PMID- 22485037 TI - [UT modification of the "David-V" procedure]. AB - Valve-sparing aortic root reimplantation with creation of pseudosinuses, so called "David-V" procedure,is a promising surgical choice to treat annuloaortic ectasia (AAE). We have developed a simple modification of this procedure, which facilitates exposure and also enables good adjustment of the native aortic root anatomy and the graft. In this article we describe our original technique and its mid-term results. PMID- 22485038 TI - [Ideal suture methods for skin, subcutaneous tissues and sternum]. AB - Non-absorbable sternal closure methods such as stainless steel wiring have been widely used, but biocompatibility and osteoconductivity of absorbable materials have advantages in acceleration of wound healing. Combined use of stainless steel wires with absorbable materials may contribute to minimizing sternal complications.Fascial tension reduction sutures, where the tension is placed on the layer of deep fascia and superficial fascia, are recommended for skin/subcutaneous closure. This means that the use of dermal sutures is minimized;indeed, dermal sutures can be avoided altogether if the wound edges can be joined naturally under very small tension. We prefer 0, 2-0 polydioxanone sutures (PDS II) for deep/superficial fascia sutures, 4-0 or 5-0 PDS II for dermal sutures (if they are necessary), and 6-0 or 7-0 polypropylene or nylon sutures (Proline or Ethilon) for superficial sutures. The consequence of such suturing is that the wound edges are elevated smoothly with minimal tension on the dermis that appears to prevent the development of large scars. PMID- 22485039 TI - [Congenital broncho-esophageal fistula in an elderly patient with lung abscess]. AB - A 60-year-old man who had been treated for pneumonia by another hospital was suspected to have a broncho-esophageal fistula, and was referred to our hospital for surgical treatment. Chest computed tomography( CT) demonstrated a lung abscess. Upper gastrointestinal endoscopic examination demonstrated an esophageal diverticulum. He underwent the resection of the fistula and left lower lobectomy of lung under left thoracotomy. Operative findings showed no severe adhesion around fistula, suggesting its congenital origin, which was also pathologically supported later. He suffered from postoperative empyema by anaerobe infection, which was successfully controlled by open drainage. PMID- 22485040 TI - [Lung metastasis of basaloid-squamous cell carcinoma of the esophagus; report of a case]. AB - A 69-year-old woman had undergone a subtotal esophagectomy for basaloid-squamous cell carcinoma of the esophagus 2 years before (pT3, ly1, v2, pN0, pStage II). Right lung metastasis was detected by follow up chest computed tomography( CT). A partial resection of the right lung was performed. Histopathological diagnosis was basaloid-squamous cell carcinoma. She is doing well 17 months after surgery for metastasis.To our knowledge, no case of radical surgery for the lung metastasis of basaloid-squamous cell carcinoma has not been reported in the Japanese literature to date. PMID- 22485041 TI - [Pleural solitary fibrous tumor from diaphragm, being suspected of liver invasion; report of a case]. AB - We report a case of solitary fibrous tumor (SFT) from diaphragmatic pleura. A 71 year-old female was admitted to our hospital because of an abnormal shadow on chest X-ray. A preoperative imaging study revealed a mass on her right diaphragm. At thoracoscopic exploration, the tumor was found to originate from diaphragm and was suspected of liver invasion. The conversion to open thoracotomy was introduced to perform appropriate surgical procedure. Pathological examination revealed proliferation of spindle cells and collagen fibers. Immuno-histochemical findings showed positive immunostaining for cell differentiation (CD) 34 and vimentin. The tumor was diagnosed as SFT with malignant potential. PMID- 22485042 TI - [Abdominal lymph node metastases detected five years after surgery for the lung cancer; report of a case]. AB - A 73-year-old woman who had underwent right lower lobectomy for adenocarcinoma of the lung( S10,pT1aN0M0, stage I A) 5 years before, visited our hospital with back pain. Whole body computed tomography (CT) revealed the enlargement of the abodominal lymph nodes surrounding the celiac artery,which was positive for fluorodeoxyglucose-positron emission tomography( FDG-PET). Open biopsy of the lymph node was performed and histopathological diagnosis was metastases of adenocarcinoma.Additional immunohistological examination showed positive findings for cytokeratin( CK) 7 and thyroid transcription factor( TTF)-1, but negative for CK20, suggesting the lesion to be metastases of lung cancer. Abdominal lymph node should be kept in mind in patients with lower lobe lung cancer. PMID- 22485043 TI - The effect of morphological complexity on verbal working memory: results from Arabic speaking children. AB - To examine the role of morphology in verbal working memory. Forty nine children, all native speakers of Arabic from the same region and of the same dialect, performed a Listening Word Span Task, whereby they had to recall Arabic uninflected words (i.e., base words), inflected words with regular (possessive) morphology, or inflected words with irregular (broken plural) morphology. Each of these words was at the end of a sentence (henceforth, target word). The participant's task was to listen to a series of sentences and then recall the target words. Recall of inflected words was significantly poorer than uninflected words, and recall of words with regular morphology was significantly poorer than recall of words with irregular morphology. These findings, albeit preliminary, suggest a role of morphology in verbal working memory. They also suggest that, at least in Arabic, regular morphological forms are decomposed into their component elements and hence impose an extra load on the central executive and episodic buffer components of working memory. Furthermore, in concert with findings from other studies, they suggest that the effect of morphology on working memory is probably language-specific. The clinical implications of the present findings are addressed. PMID- 22485044 TI - Interference and facilitation in spoken word production: effects of morphologically and semantically related context stimuli on picture naming. AB - We report two picture-word interference experiments investigating conceptual and lexical activation, and response selection, in speaking. We varied stimulus onset asynchrony to investigate potential fine-grained activation and competition effects. Morphologically related existing and pseudoword adjectives, as well as associatively related adjectives, served as context stimuli in Experiment 1. In Experiment 2, we focused on semantic interference by using morphologically related and unrelated subordinates of the target concept as context stimuli. Morphologically complex pseudowords were also included as context stimuli. Pseudowords should not interfere, given that they have no lexical or conceptual representation. We consistently obtained facilitation with all morphologically related context stimuli, irrespective of their lexical status. We argue that effects originate at the word-form level, and discuss how our results may help decide among the many explanations of semantic interference in picture naming. PMID- 22485046 TI - New vaccines needed for pathogens infecting animals and humans: One Health. AB - The field of "One Health" encourages researchers to collaborate across a wide range of disciplines to improve health at the animal-human-ecosystems interface. One Health recognizes the potential of emerging infectious diseases to impact public health and global food security, and the need for a multidisciplinary approach to counteract the effect of these diseases. Vaccinologists are also beginning to engage in research related to One Health, recognizing that preventing transmission of emerging infectious diseases at the animal-human interface is critically important for protecting the world population from epizootics and pandemics. In this synopsis of recent work in the One Health field, we describe some emerging One Health pathogens, discuss the importance of One Health to food safety and biodefense, propose strategies for improving One Health including the development of new vaccines and new vaccine design approaches, and close with a brief discussion of the opportunities and risks related to One Health vaccine research. PMID- 22485045 TI - PLAG1 alteration in carcinoma ex pleomorphic adenoma: immunohistochemical and fluorescence in situ hybridization studies of 22 cases. AB - Carcinoma ex pleomorphic adenoma (CA-ex-PA) may arise with nearly any histologic subtype of carcinoma of the salivary gland. In the absence of recognizable residual pleomorphic adenoma (PA) or a prior history of PA, distinction of CA-ex PA from morphologically similar de novo carcinomas may be difficult. Oncogenic rearrangement of PLAG1 (pleomorphic adenoma gene 1) has been established in PA; however, it has not yet been proven that PLAG1 alteration persists in carcinomas developed from preceding PA. We evaluated 22 histologically diverse CA-ex-PA by immunohistochemistry for PLAG1, and/or by FISH targeting PLAG1. Of these, 17 cases were immunoreactive (1+ to 3+) and 5 were immunonegative/rare positive for PLAG1. For comparison, 39 various salivary gland neoplasms were immunostained for PLAG1, of which all scored negative/rare positive. Twelve of 19 CA-ex-PA analyzed by PLAG1 FISH (63 %) were positive for gene rearrangement, 2 showed only a trisomy/polysomy profile, and 5 had a normal pattern. One FISH-positive tumor showed amplification of PLAG1. One of 3 cases analyzed for HMGA2 FISH was positive for gene rearrangement. In our series, the majority of CA-ex-PA harbored altered PLAG1 or HMGA2 genes detectable by FISH. While PLAG1 immunostain was specific for CA-ex-PA against other carcinomas, its application as a standalone discriminatory test was limited by variable expression. We conclude that most CA ex-PA, regardless of morphologic subtype, carry altered PLAG1 or HMGA2 genes, and that FISH for PLAG1, along with immunohistochemistry for PLAG1, may help discriminate CA-ex-PA from its de novo carcinoma counterpart. PMID- 22485047 TI - Influenza vaccination coverage and uptake predictors among Spanish adults suffering COPD. AB - The aim of this study is to compare influenza vaccination coverage among Spaniards aged 40 y or over who suffer from chronic obstructive pulmonary disease (COPD) with those without this illness to identify the factors that influence vaccination uptake among patients with COPD. Data was extracted from the European Health Survey performed in Spain in 2009/10, and analyzed data on 15,355 Spaniards (>= 40 y of age), of whom 1,309 (8.2% 95%CI 7.7-8.7) had COPD was used. We considered the answer (yes/no) to the question about whether or not the interviewed person had been vaccinated against influenza in the previous flu season. We used the answer to this question as the dependent variable. For independent variables, we analyzed social demographic characteristics, health related variables, and the utilization of health care services. Vaccination coverage among patients with COPD is 49.4% (95% CI: 46.3-52.5%) and 21.3% (95% CI: 20.7-21.9) among people without (p < 0.001). The probability of being vaccinated is three times greater for COPD patients (crude OR = 3.0, 95% CI: 2.6 3.5). Among COPD patients the uptake of vaccination increased with age. Other factors associated with an increase in vaccination coverage were: being male, perceiving one's health as fair or poor, not smoking, and having seen a doctor during the previous month. The rate of flu vaccination among adult Spaniards with COPD is lower than desired. Urgent strategies for increasing vaccination coverage are necessary for COPD sufferers aged under 65 of age and those with unhealthy lifestyles. PMID- 22485048 TI - The investigational meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate vaccine (ACWY-TT) and the seasonal influenza virus vaccine are immunogenic and well-tolerated when co-administered in adults. AB - Co-administration of meningococcal serogroups A, C, W-135 and Y conjugate vaccine (ACWY-TT) with seasonal influenza vaccine was investigated in a subset of adults enrolled in a larger study evaluating lot-to-lot consistency of ACWY-TT and non inferiority to licensed tetravalent meningococcal polysaccharide vaccine (MenPS). Subjects in this sub-study were randomized (3:1:1) to receive ACWY-TT alone (ACWY TT group) or with seasonal influenza vaccine (Coad), or licensed MenPS alone. Serum bactericidal antibodies (rSBA) and serum haemagglutination-inhibition (HI) antibody titers were measured pre- and 1 mo post-vaccination. Non-inferiority of the Coad group compared with ACWY-TT group was demonstrated in terms of rSBA geometric mean antibody titers (GMTs) to serogroups A, W-135 and Y. For serogroup C the pre-defined non-inferiority limit was marginally exceeded. Post-vaccination rSBA GMTs were significantly higher (exploratory analysis) in the Coad group compared with the MenPS group for serogroups A, W-135, and Y and were similar to the MenPS group for serogroup C. Overall, > 97% of subjects achieved rSBA titers >= 1:128 for all serogroups. The Coad group met all criteria defined by the Committee on Human Medicinal Products (CHMP) for seroprotection, seroconversion and seroconversion factor for HI antibodies for all three influenza strains. Grade 3 solicited local/general symptoms were reported by <= 1.9% of subjects in any group. These data support the co-administration of ACWY-TT with seasonal influenza vaccine when protection is needed against both diseases. This study is registered at clinicaltrials.gov NCT00453986. PMID- 22485049 TI - Antibody persistence and immune memory 15 months after priming with an investigational tetravalent meningococcal tetanus toxoid conjugate vaccine (MenACWY-TT) in toddlers and young children. AB - The present extension study, conducted in children originally vaccinated at 12-14 mo or 3-5 y of age, assessed antibody persistence and immune memory induced by an investigational tetravalent meningococcal serogroups A, C, W-135 and Y tetanus toxoid conjugate vaccine (MenACWY-TT). In the original study, participants were randomized to receive one dose of MenACWY-TT or licensed age-appropriate meningococcal control vaccines. Fifteen months post-vaccination, all participants underwent serum sampling to evaluate antibody persistence and participants previously vaccinated as toddlers received a polysaccharide challenge to assess immune memory development. Exploratory comparisons showed that (1) All children and >= 92.3% of the toddlers maintained serum bactericidal (rSBA) titers >= 1:8 at 15 mo post MenACWY-TT vaccination; statistically significantly higher rSBA geometric mean titers (GMTs) were observed compared with control vaccines. (2) At one month after polysaccharide challenge, all toddlers primed with MenACWY-TT or with the monovalent serogroup C conjugate vaccine had rSBA titers >= 1:8 and >= 1:128 for serogroup C and similar rSBA-GMTs; rSBA-GMTs for serogroups A, W-135 and Y were statistically significantly higher in toddlers primed with MenACWY-TT compared with the control vaccine. Thus, a single dose of MenACWY-TT induced persisting antibodies in toddlers and children and immune memory in toddlers. This study has been registered at www.clinicaltrials.gov NCT00126984. PMID- 22485050 TI - The immunogenicity and safety of an investigational meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate vaccine (ACWY-TT) compared with a licensed meningococcal tetravalent polysaccharide vaccine: a randomized, controlled non inferiority study. AB - Immunogenicity and safety of ACWY-TT compared with licensed ACWY polysaccharide vaccine (MenPS) in healthy adults, and lot-to-lot consistency of three ACWY-TT lots were evaluated in a phase 3, open, controlled study. Adults aged 18-55 y were randomized to receive ACWY-TT (one of three lots) or MenPS. Serum bactericidal antibodies (rSBA) were measured pre- and 1 mo post-vaccination. Adverse events (AEs) were assessed 4 d (solicited symptoms) and 31 d (unsolicited symptoms) post-vaccination. Serious AEs were reported up to 6 mo after vaccination. The number of vaccinated subjects was 1247 (ACWY-TT, n = 935; MenPS, n = 312). ACWY-TT lot-to-lot consistency and non-inferiority of ACWY-TT as compared with MenPS groups were demonstrated according to pre-specified criteria. The percentages of subjects with a vaccine response (VR = rSBA titer >= 1:32 in initially seronegative; >= 4-fold increase in initially seropositive) to ACWY-TT vs. MenPS were 80.1%/69.8% (serogroup A), 91.5%/ 92.0% (C), 90.2%/85.5% (W-135), 87.0%/78.8% (Y). Exploratory analyses showed that for serogroups A, W-135 and Y, VR rates and GMTs were significantly higher for ACWY-TT compared with MenPS. For each serogroup, >= 98.0% of subjects had rSBA titers >= 1:128. Grade 3 solicited AEs were reported in <= 1.6% of subjects in any group. The immunogenicity of ACWY TT vaccine was non-inferior to MenPS for all four serogroups in adults, with significantly higher VR rates to serogroups A, W-135 and Y and an acceptable safety profile. Consistency of 3 ACWY-TT production lots was demonstrated. These data suggest that, if licensed, ACWY-TT conjugate vaccine may be used for protection against invasive meningococcal disease in healthy adults. This study is registered at clinicaltrials.gov NCT00453986. PMID- 22485051 TI - Diffusive transfer between two intensely interacting cells with limited surface kinetics. AB - The diffusive transfer, or paracrine delivery, of chemical factors during the interaction of an emitting cell and a receiving cell is a ubiquitous cellular process that facilitates information exchange between the cells an/or to bystander cells. In the cellular immune response this exchange governs the magnitude and breadth of killing of cellular targets, inflammation or tolerance. Paracrine delivery is examined here by solving the the steady-state diffusion equation for the concentration field surrounding two intensely interacting, equi sized cells on which surface kinetics limits the rates of factor emission and absorption. These chemical factors may be cytokines, such as Interlukins and Interferons, but the results are presented in a generic form so as to be applicable to any chemical factor and/or cell-type interaction. In addition to providing overall transfer rates and transfer efficiencies, the results also indicate that when the receiving cell is naive, with few factor receptors on its surface, there may be a significant accumulation of factor in the synaptic region between the cells with a consequent release of factor to the medium where it can signal bystander cells. This factor accumulation may play a critical role in activating a naive receiving cell. As the receiving cell activates and becomes more absorbent, the factor accumulation diminishes, as does potential bystander signaling. PMID- 22485052 TI - Efficacy of a Reading Intervention for Middle School Students Identified with Learning Disabilities. AB - This experimental study reports findings on the effects from a year-long reading intervention providing daily, 50-minute sessions to middle-school students with identified learning disabilities (n = 65) compared with similar students who did not receive the reading intervention (n = 55). All students continued to receive their special education services as provided by the school. Results indicated statistically significant findings favoring the treatment group for sight word reading fluency following intervention. Small effects were found for phonemic decoding fluency and passage comprehension. No other statistically significant differences were noted between groups. The findings suggest that while gains on word reading fluency resulted from the additional reading treatment, accelerating the reading performance of students identified with learning disabilities may be unlikely to result from a one-year, daily intervention provided to students in groups of 10-15. PMID- 22485053 TI - Focused ion beam induced deflections of freestanding thin films. AB - Prominent deflections are shown to occur in freestanding silicon nitride thin membranes when exposed to a 50 keV gallium focused ion beam for ion doses between 10(14) and 10(17) ions/cm(2). Atomic force microscope topographs were used to quantify elevations on the irradiated side and corresponding depressions of comparable magnitude on the back side, thus indicating that what at first appeared to be protrusions are actually the result of membrane deflections. The shape in high-stress silicon nitride is remarkably flattopped and differs from that in low-stress silicon nitride. Ion beam induced biaxial compressive stress generation, which is a known deformation mechanism for other amorphous materials at higher ion energies, is hypothesized to be the origin of the deflection. A continuum mechanical model based on this assumption convincingly reproduces the profiles for both low-stress and high-stress membranes and provides a family of unusual shapes that can be created by deflection of freestanding thin films under beam irradiation. PMID- 22485054 TI - Are Divorce Studies Trustworthy? The Effects of Survey Nonresponse and Response Errors. AB - Researchers rely on relationship data to measure the multifaceted nature of families. This article speaks to relationship data quality by examining the ramifications of different types of error on divorce estimates, models predicting divorce behavior, and models employing divorce as a predictor. Comparing matched survey and divorce certificate information from the 1995 Life Events and Satisfaction Study (N = 1,811) showed that nonresponse error is responsible for the majority of the error in divorce data. Misreporting the divorce event was rare, and more than two thirds of respondents provided a divorce date within 6 months of the actual date. Nevertheless, divorce date error attenuated effects of time since divorce on outcomes. Gender, child custody, marital history, and education were associated with divorce error. PMID- 22485055 TI - Nonparametric estimation of multivariate scale mixtures of uniform densities. AB - Suppose that U = (U(1), ... , U(d)) has a Uniform ([0, 1](d)) distribution, that Y = (Y(1), ... , Y(d)) has the distribution G on [Formula: see text], and let X = (X(1), ... , X(d)) = (U(1)Y(1), ... , U(d)Y(d)). The resulting class of distributions of X (as G varies over all distributions on [Formula: see text]) is called the Scale Mixture of Uniforms class of distributions, and the corresponding class of densities on [Formula: see text] is denoted by [Formula: see text]. We study maximum likelihood estimation in the family [Formula: see text]. We prove existence of the MLE, establish Fenchel characterizations, and prove strong consistency of the almost surely unique maximum likelihood estimator (MLE) in [Formula: see text]. We also provide an asymptotic minimax lower bound for estimating the functional f ? f(x) under reasonable differentiability assumptions on f ? [Formula: see text] in a neighborhood of x. We conclude the paper with discussion, conjectures and open problems pertaining to global and local rates of convergence of the MLE. PMID- 22485056 TI - Diffusion, cohort change, and social patterns of smoking(). AB - In noting that common explanations of smoking cannot account for both its current inverse relationship with SES and the shift over time toward greater concentration among low SES groups, this paper presents an explanation based on diffusion and status distinctions. The explanation predicts that, as cigarette diffusion proceeds and fashions change, the social determinants of smoking will shift across cohorts, such that initially positive relationships between pre adult components of socioeconomic status and smoking in early cohorts become negative in later cohorts. Tests using historical, cohort-linked aggregate data on cigarette diffusion, and individual-level data from the General Social Surveys covering the years from 1978 to 1994 and cohorts from 1889 to 1976 largely support the predictions. In comparing older to newer cohorts, the results show correspondence between the stage of cigarette diffusion and the direction and strength of the relationships of education, parental status, urban residence, and gender with cigarette smoking. PMID- 22485057 TI - Fabrication of plastic microlens array for array microscopy by three-dimensional diamond micromilling. AB - Two lens arrays of 20 lenses (4*5) are fabricated in polystyrene (Rexolite 1422) using a 3-D, three-axis micromilling process. The lenses of one array are concave (R(curv) = -2 mm) and the lenses of the other array are convex (R(curv) = 2 mm). A method for correcting a 3-D micromilling program for a single lens is described and evaluated. The lens separation is 4 mm and O(diam) = 2.6 mm for all lenses. Based on a measurement of key optical parameters (radius error, wavefront error, and surface roughness), micromilled lenses are shown to be of high optical quality compared with the form error and surface roughness obtained with plastic injection molded lenses. PMID- 22485059 TI - Author disambiguation using multi-aspect similarity indicators. AB - Key to accurate bibliometric analyses is the ability to correctly link individuals to their corpus of work, with an optimal balance between precision and recall. We have developed an algorithm that does this disambiguation task with a very high recall and precision. The method addresses the issues of discarded records due to null data fields and their resultant effect on recall, precision and F-measure results. We have implemented a dynamic approach to similarity calculations based on all available data fields. We have also included differences in author contribution and age difference between publications, both of which have meaningful effects on overall similarity measurements, resulting in significantly higher recall and precision of returned records. The results are presented from a test dataset of heterogeneous catalysis publications. Results demonstrate significantly high average F-measure scores and substantial improvements on previous and stand-alone techniques. PMID- 22485058 TI - Impact of Stress Reduction Interventions on Hostility and Ambulatory Systolic Blood Pressure in African American Adolescents. AB - This study examined the impact of breathing awareness meditation (BAM), life skills (LS) training, and health education (HE) interventions on self-reported hostility and 24-hour ambulatory blood pressure (ABP) in 121 African American (AA) ninth graders at increased risk for development of essential hypertension. They were randomly assigned to BAM, LS, or HE and engaged in intervention sessions during health class for 3 months. Before, after, and 3 months following intervention cessation, self-reported hostility and 24-hour ABP were measured. Results indicated that between pre- and postintervention, BAM participants displayed significant reductions in self-reported hostility and 24-hour systolic ABP. Reductions in hostility were significantly related to reductions in 24-hour systolic ABP. Between postintervention and follow-up, participants receiving LS showed a significant reduction in hostility but not in 24-hour ABP. Significant changes were not found for the HE group in 24-hour ABP or self-reported hostility, but these change scores were significantly correlated. The implications of the findings are discussed with regard to behavioral stress reduction programs for the physical and emotional health of AAs. PMID- 22485060 TI - ? AB - We introduce an object-based method to automatically classify topography from SRTM data. The new method relies on the concept of decomposing land-surface complexity into more homogeneous domains. An elevation layer is automatically segmented and classified at three scale levels that represent domains of complexity by using self-adaptive, data-driven techniques. For each domain, scales in the data are detected with the help of local variance and segmentation is performed at these appropriate scales. Objects resulting from segmentation are partitioned into sub-domains based on thresholds given by the mean values of elevation and standard deviation of elevation respectively. Results resemble reasonably patterns of existing global and regional classifications, displaying a level of detail close to manually drawn maps. Statistical evaluation indicates that most of classes satisfy the regionalization requirements of maximizing internal homogeneity while minimizing external homogeneity. Most objects have boundaries matching natural discontinuities at regional level. The method is simple and fully automated. The input data consist of only one layer, which does not need any pre-processing. Both segmentation and classification rely on only two parameters: elevation and standard deviation of elevation. The methodology is implemented as a customized process for the eCognition(r) software, available as online download. The results are embedded in a web application with functionalities of visualization and download. PMID- 22485061 TI - Self-competence Among Early and Middle Adolescents Affected by Maternal HIV/AIDS. AB - Adolescent children of mothers with HIV face a host of stressors that place them at increased risk for poor outcomes. Using covariance structure analysis, this study examines adolescent risk outcomes and their relationships to maternal health, as well as the potentially protective factors of family environment and self-competence. The final model indicated that poor maternal health was negatively related to a protective family environment, which in turn was negatively related to adolescent risk outcomes. A protective family environment was also positively related to adolescent self-competence, which was negatively related to adolescent risk outcomes. Implications of the study are discussed, including how these findings can influence interventions aimed at reducing the risk for poor outcomes among adolescent youth with HIV-infected mothers. PMID- 22485063 TI - RETRACTED ARTICLE: Choices Which Change Life Statisfaction: Revising SWB Theory to Account for Change. PMID- 22485062 TI - Language and Literacy Development of Children with Williams Syndrome. AB - Children with Williams syndrome, a rare neurodevelopmental disorder caused by deletion of ~25 genes on chromosome 7q11.23, evidence large individual differences in both broad language and reading abilities. Nevertheless, as a group, children with this syndrome show a consistent pattern characterized by relative strengths in concrete vocabulary and phonological processing (language skills strongly related to single-word reading) and relative weaknesses in relational concepts, receptive grammar, verbal working memory, comprehension monitoring, and discourse (language skills strongly related to reading comprehension). Children with Williams syndrome who have been taught reading using a systematic phonics approach both decode and comprehend significantly better than children who have been taught using a whole-word approach. Consideration of these patterns in the context of what is known about the reading development of children in the general population provides a strong foundation for facilitating the reading development of children with Williams syndrome. PMID- 22485064 TI - ? AB - Entanglement between degrees of freedom, namely between the spin, path and (total) energy degrees of freedom, for single neutrons is exploited. We implemented a triply entangled Greenberger-Horne-Zeilinger(GHZ)-like state and coherently manipulated relative phases of two-level quantum subsystems. An inequality derived by Mermin was applied to analyze the generated GHZ-like state: we determined the four expectation values and finally obtained [Formula: see text]. This demonstrates the violation of a Mermin-like inequality for triply entangled GHZ-like state in a single-particle system, which, in turn, exhibits a clear inconsistency between noncontextual assumptions and quantum mechanics and confirms quantum contextuality. PMID- 22485065 TI - ? AB - The structural, electronic and vibrational properties of InN under pressures up to 20 GPa have been investigated using the pseudo-potential plane wave method (PP PW). The generalized-gradient approximation (GGA) in the frame of density functional theory (DFT) approach has been adopted. It is found that the transition from wurtzite (B4) to rocksalt (B1) phase occurs at a pressure of approximately 12.7 GPa. In addition, a change from a direct to an indirect band gap is observed. The mechanism of these changes is discussed. The phonon frequencies and densities of states (DOS) are derived using the linear response approach and density functional perturbation theory (DFPT). The properties of phonons are described by the harmonic approximation method. Our results show that phonons play an important role in the mechanism of phase transition and in the instability of B4 (wurtzite) just before the pressure of transition. At zero pressure our data agree well with recently reported experimental results. PMID- 22485066 TI - A synthesis of fluency interventions for secondary struggling readers. AB - Previous research studies examining the effects of fluency interventions on the fluency and comprehension outcomes for secondary struggling readers are synthesized. An extensive search of the professional literature between 1980 and 2005 yielded a total of 19 intervention studies that provided fluency interventions to secondary struggling readers and measured comprehension and/or fluency outcomes. Findings revealed fluency outcomes were consistently improved following interventions that included listening passage previewing such as listening to an audiotape or adult model of good reading before attempting to read a passage. In addition, there is preliminary evidence that there may be no differential effects between repeated reading interventions and the same amount of non-repetitive reading with older struggling readers for increasing reading speed, word recognition, and comprehension. PMID- 22485067 TI - Mycobacterium aromativorans JS19b1(T) Degrades Phenanthrene through C-1,2, C-3,4 and C-9,10 Dioxygenation Pathways. AB - Mycobacterium aromativorans strain JS19b1(T) can utilize phenanthrene as a sole source of carbon and energy. Strain JS19b1(T) degrades phenanthrene through highly branched metabolic pathways, including dioxygenation on C-1,2, C-3,4 and C 9,10 positions and ring opening by both ortho- and meta-cleavage. The presence of novel metabolic pathways was confirmed by replacement cultivation using synthetic metabolite standards. The metabolites were isolated and identified by gas chromatography-mass spectrometry. Both ortho and meta-cleavage products of 1,2- and 3,4-dihydroxyphenanthrene were detected. Two ortho-cleavage products, 1-[(E) 2-carboxyvinyl]-2-naphthoic acid and 2-[(E)-2-carboxyvinyl]-1-napthoic acid were further metabolized to naphthalene-1,2-dicarboxylic acid and then to 1,2 dihydroxynaphthalene, which can also be produced from the meta-cleavage products hydroxynaphthoic acids. These results suggest that part of the branched pathways is merged into 1,2-dihydroxynaphthalene. The concentrations of the products from C-9,10 dioxygenation were higher than those from other pathways. C-9,10 dioxygenation of phenanthrene produced phthalic acid through decarboxylation and mono-/di-oxygenation. The diverse phenanthrene metabolic pathways in JS19b1(T) give a new insight of the bacterial degradation of polycyclic aromatic hydrocarbons. PMID- 22485068 TI - Depression Among Adults With Diabetes: Prevalence, Impact, and Treatment Options. PMID- 22485069 TI - The Association of Birth Complications and Externalizing Behavior in Early Adolescents: Direct and Mediating Effects. AB - Prior studies have shown that birth complications interact with psychosocial risk factors in predisposing to increased externalizing behavior in childhood and criminal behavior in adulthood. However, little is known about the direct relationship between birth complications and externalizing behavior. Furthermore, the mechanism by which the birth complications predispose to externalizing behavior is not well explored. This study aims to assess whether birth complications predispose to early adolescent externalizing behavior and to test whether Intelligence Quotient (IQ) mediates relationships between predictor and outcome variables. We used data from a prospective, longitudinal birth cohort of 1,795 3-year-old boys and girls from Mauritius to test hypotheses. Birth complications were assessed from hospital record data, malnutrition from a pediatric exam at age 3 years, psychosocial adversity from parental interviews at age 3 years, and externalizing behavior problems from parental ratings at age 11 years. We found that babies with birth complications are more likely to develop externalizing behavior problems at age 11. Low IQ was associated with birth complications and was found to mediate the link between early predictors and later externalizing behavior. These prospective, longitudinal findings have potential clinical implications for the identification of early adolescent externalizing behavior and for public health attempts to prevent the occurrence of child externalizing behavior problems. PMID- 22485070 TI - Substance Use and Sexual Orientation Among East and Southeast Asian Adolescents in Canada. AB - The purpose of this study was to examine the relationship between substance use and sexual orientation among Asian adolescents in Canada. We analyzed an East and Southeast Asian subsample of a province-wide, school-based survey (weighted N = 51,349). Compared to heterosexual adolescents of the same gender, gay, lesbian, bisexual, and mostly heterosexual adolescents were more likely to use alcohol, marijuana, or other illicit drugs. Particularly, sexual minority girls were at increased risk for substance use. The findings suggest the need for substance use prevention interventions that are sensitive to gender, sexual orientation, and culture. PMID- 22485071 TI - Measuring physical activity in preschoolers: Reliability and validity of The System for Observing Fitness Instruction Time for Preschoolers (SOFIT-P). AB - The purpose of this study is describe the initial feasibility, reliability, and validity of an instrument to measure physical activity in preschoolers using direct observation. The System for Observing Fitness Instruction Time for Preschoolers was developed and tested among 3- to 6-year-old children over fall 2008 for feasibility and reliability (Phase I, n=67) and in fall 2009 for concurrent validity (Phase II, n=27). Phase I showed that preschoolers spent >75% of their active time at preschool in light physical activity. The mean inter observer agreements scores were >=.75 for physical activity level and type. Correlation coefficients, measuring construct validity between the lesson context and physical activity types with and with the activity levels, were moderately strong. Phase II showed moderately strong correlations ranging from .50 to .54 between the System for Observing Fitness Instruction Time for Preschoolers and Actigraph accelerometers for physical activity levels. The System for Observing Fitness Instruction Time for Preschoolers shows promising initial results as a new method for measuring physical activity among preschoolers. PMID- 22485072 TI - Strongly Phosphorescent Iridium(III)-Porphyrins - New Oxygen Indicators with Tuneable Photophysical Properties and Functionalities. AB - Synthesis and characterization of four iridium(III)-octaethylporphyrins and a pi extended iridium(III)-benzoporphyrin are presented. Strong room-temperature phosphorescence was observed for all of the complexes with quantum yields of up to 30 %. Axial ligands were introduced to tune the photophysical properties and the solubility. Complexes bearing lipophilic ligands such as pyridine or N-(n butyl)imidazole were incorporated into polystyrene to obtain optical oxygen sensors. Covalent coupling of the dye is possible by introduction of ligands with binding domains (1-imidazoleacetic acid). This enabled preparation of a water soluble oxygen probe (by staining bovine serum albumin) and a trace oxygen sensor (by coupling to amino-modified silica gel). PMID- 22485075 TI - Letter from the editor. PMID- 22485076 TI - Advances in the treatment of hepatitis C virus infection. AB - Therapy for chronic hepatitis C virus (HCV) infection with pegylated interferon alpha and ribavirin leads to suboptimal rates of viral eradication in patients with genotype 1 HCV, the most common viral strain in the United States and many other countries. Recent advances in the study of viral kinetics, host factors that predict response to antiviral therapy, and viral protein structure have established the foundation of a new era in the treatment of HCV infection. The HCV NS3/4A protease inhibitors boceprevir and telaprevir, the first 2 agents in a new and promising generation of direct-acting antiviral agents to have completed phase III studies, were approved by the US Food and Drug Administration in May 2011. The addition of these HCV protease inhibitors to standard therapy has been demonstrated to dramatically improve sustained virologic response rates, both in treatment-naive patients and in prior relapsers and nonresponders. These novel agents represent only the beginning of a revolution in HCV therapy, which will include additional protease inhibitors as well as other classes of drugs currently under investigation, such as polymerase inhibitors, NS5A inhibitors, and host factor inhibitors such as cyclophilin antagonists. The future of HCV therapy holds promise for significantly higher sustained virologic response rates with shorter treatment durations, as well as the intriguing potential to achieve virologic cure with interferon-free combination therapy regimens. PMID- 22485074 TI - Alcohol Use after Combat-Acquired Traumatic Brain Injury: What We Know and Don't Know. AB - Military personnel engage in unhealthy alcohol use at rates higher than their same age, civilian peers, resulting in negative consequences for the individual and jeopardized force readiness for the armed services. Among those returning from combat deployment, unhealthy drinking may be exacerbated by acute stress reactions and injury, including traumatic brain injury (TBI). Combat-acquired TBI is common among personnel in the current conflicts. Although research suggests that impairments due to TBI leads to an increased risk for unhealthy drinking and consequences among civilians, there has been little research to examine whether TBI influences drinking behaviors among military personnel. This article examines TBI and drinking in both civilian and military populations and discusses implications for clinical care and policy. PMID- 22485077 TI - Mimicry and deception in inflammatory bowel disease and intestinal behcet disease. AB - Behcet disease (BD) is a rare, chronic, multisystemic, inflammatory disease characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. Intestinal BD occurs in 10-15% of BD patients and shares many clinical characteristics with inflammatory bowel disease (IBD), making differentiation of the 2 diseases very difficult and occasionally impossible. The diagnosis of intestinal BD is based on clinical findings-as there is no pathognomonic laboratory test-and should be considered in patients who present with abdominal pain, diarrhea, weight loss, and rectal bleeding and who are susceptible to intestinal BD. Treatment for intestinal BD is similar to that for IBD, but overall prognosis is worse for intestinal BD. Although intestinal BD is extremely rare in the United States, physicians will increasingly encounter these challenging patients in the future due to increased immigration rates of Asian and Mediterranean populations. PMID- 22485078 TI - New technologies for examination of the esophagus: are they really better than white-light endoscopy? PMID- 22485079 TI - Mucosal healing with infliximab: results from the active ulcerative colitis trials. PMID- 22485080 TI - Vaccinating patients with chronic liver disease. PMID- 22485081 TI - Risks and potential cost savings of not sending diminutive polyps for histologic examination. PMID- 22485082 TI - Measurement of infliximab and anti-infliximab antibody levels can help distinguish maintenance versus loss of response. PMID- 22485083 TI - Optimizing infliximab therapy for inflammatory bowel disease- the tools are getting sharper. PMID- 22485084 TI - Mucormycosis of the intestine: a rare complication in Crohn's disease. PMID- 22485085 TI - Gastrointestinal mucormycosis: an evolving disease. PMID- 22485087 TI - Selection of Efficient Features for Discrimination of Hand Movements from MEG Using a BCI Competition IV Data Set. AB - The aim of a brain-computer interface (BCI) system is to establish a new communication system that translates human intentions, reflected by measures of brain signals such as magnetoencephalogram (MEG), into a control signal for an output device. In this paper, an algorithm is proposed for discriminating MEG signals, which were recorded during hand movements in four directions. These signals were presented as data set 3 of BCI competition IV. The proposed algorithm has four main stages: pre-processing, primary feature extraction, the selection of efficient features, and classification. The classification stage was a combination of linear SVM and linear discriminant analysis classifiers. The proposed method was validated in the BCI competition IV, where it obtained the best result among BCI competitors: a classification accuracy of 59.5 and 34.3% for subject 1 and subject 2 on the test data respectively. PMID- 22485086 TI - Inhibiting Glutathione Metabolism in Lung Lining Fluid as a Strategy to Augment Antioxidant Defense. AB - Glutathione is abundant in the lining fluid that bathes the gas exchange surface of the lung. On the one hand glutathione in this extracellular pool functions in antioxidant defense to protect cells and proteins in the alveolar space from oxidant injury; on the other hand, it functions as a source of cysteine to maintain cellular glutathione and protein synthesis. These seemingly opposing functions are regulated through metabolism by gamma-glutamyl transferase (GGT, EC 2.3.2.2). Even under normal physiologic conditions, lung lining fluid (LLF) contains a concentrated pool of GGT activity exceeding that of whole lung by about 7-fold and indicating increased turnover of glutathione at the epithelial surface of the lung. With oxidant stress LLF GGT activity is amplified even further as glutathione turnover is accelerated to meet the increased demands of cells for cysteine. Mouse models of GGT deficiency confirmed this biological role of LLF GGT activity and revealed the robust expansiveness and antioxidant capacity of the LLF glutathione pool in the absence of metabolism. Acivicin, an irreversible inhibitor of GGT, can be utilized to augment LLF fluid glutathione content in normal mice and novel GGT inhibitors have now been defined that provide advantages over acivicin. Inhibiting LLF GGT activity is a novel strategy to selectively augment the extracellular LLF glutathione pool. The enhanced antioxidant capacity can maintain lung epithelial cell integrity and barrier function under oxidant stress. PMID- 22485088 TI - Neuronal calcium sensor proteins - recognizing a face in a crowd. PMID- 22485089 TI - Species-Specific Flight Styles of Flies are Reflected in the Response Dynamics of a Homolog Motion-Sensitive Neuron. AB - Hoverflies and blowflies have distinctly different flight styles. Yet, both species have been shown to structure their flight behavior in a way that facilitates extraction of 3D information from the image flow on the retina (optic flow). Neuronal candidates to analyze the optic flow are the tangential cells in the third optical ganglion - the lobula complex. These neurons are directionally selective and integrate the optic flow over large parts of the visual field. Homolog tangential cells in hoverflies and blowflies have a similar morphology. Because blowflies and hoverflies have similar neuronal layout but distinctly different flight behaviors, they are an ideal substrate to pinpoint potential neuronal adaptations to the different flight styles. In this article we describe the relationship between locomotion behavior and motion vision on three different levels: (1) We compare the different flight styles based on the categorization of flight behavior into prototypical movements. (2) We measure the species-specific dynamics of the optic flow under naturalistic flight conditions. We found the translational optic flow of both species to be very different. (3) We describe possible adaptations of a homolog motion-sensitive neuron. We stimulate this cell in blowflies (Calliphora) and hoverflies (Eristalis) with naturalistic optic flow generated by both species during free flight. The characterized hoverfly tangential cell responds faster to transient changes in the optic flow than its blowfly homolog. It is discussed whether and how the different dynamical response properties aid optic flow analysis. PMID- 22485090 TI - The effects of supplementation with omega-3 polyunsaturated Fatty acids on cardiac rhythm: anti-arrhythmic, pro-arrhythmic, both or neither? It depends.... AB - Supplementation of omega-3 fatty acids (Omega-3) has been associated with a decreased cardiovascular risk, thereby concentrating attention on a potentially preventive effect regarding tachyarrhythmias and sudden cardiac death. However, recent randomized controlled trials challenge the efficacy of the additional application of Omega-3 and its anti-arrhythmic effect under certain clinical conditions. The present paper reflects the results of earlier and recent clinical studies with respect to the individual background conditions that may determine the clinical outcome of Omega-3 supplementation and thereby explain apparently conflicting clinical results. It is concluded that the efficacy of Omega-3 supplementation to prevent cardiac arrhythmias strongly depends on the underlying clinical and pharmacological conditions, a hypothesis that also is supported by data from experimental animal studies and by molecular interactions of Omega-3 at the cellular level. PMID- 22485091 TI - Vascular aging and hemodynamic stability in the intraoperative period. AB - The proportion of elderly people in the population is steadily increasing, and the inevitable consequence is that this subpopulation is more frequently represented in common medical procedures and surgeries. Understanding the circulatory changes that accompany the aging process is therefore becoming increasingly timely and relevant. In this short review, we discuss aspects of vascular control in aging that are particularly relevant in the maintenance of intraoperative hemodynamic stability. We subsequently review the effects of certain notable anesthetic agents with respect to the aging vasculature. PMID- 22485092 TI - Dietary Omega-3 Polyunsaturated Fatty Acids Suppress NHE-1 Upregulation in a Rabbit Model of Volume- and Pressure-Overload. AB - BACKGROUND: Increased consumption of omega-3 polyunsaturated fatty acids (omega3 PUFAs) from fish oil (FO) may have cardioprotective effects during ischemia/reperfusion, hypertrophy, and heart failure (HF). The cardiac Na(+)/H(+) exchanger (NHE-1) is a key mediator for these detrimental cardiac conditions. Consequently, chronic NHE-1 inhibition appears to be a promising pharmacological tool for prevention and treatment. Acute application of the FO omega3-PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) inhibit the NHE-1 in isolated cardiomyocytes. We studied the effects of a diet enriched with omega3 PUFAs on the NHE-1 activity in healthy rabbits and in a rabbit model of HF induced by volume- and pressure-overload. METHODS: Rabbits were allocated to four groups. The first two groups consisted of healthy rabbits, which were fed either a diet containing 1.25% (w/w) FO (omega3-PUFAs), or 1.25% high-oleic sunflower oil (omega9-MUFAs) as control. The second two groups were also allocated to either a diet containing omega3-PUFAs or omega9-MUFAs, but underwent volume- and pressure-overload to induce HF. Ventricular myocytes were isolated by enzymatic dissociation and used for intracellular pH (pH(i)) and patch-clamp measurements. NHE-1 activity was measured in HEPES-buffered conditions as recovery rate from acidosis due to ammonium prepulses. RESULTS: In healthy rabbits, NHE-1 activity in omega9-MUFAs and omega3-PUFAs myocytes was not significantly different. Volume and pressure-overload in rabbits increased the NHE-1 activity in omega9-MUFAs myocytes, but not in omega3-PUFAs myocytes, resulting in a significantly lower NHE-1 activity in myocytes of omega3-PUFA fed HF rabbits. The susceptibility to induced delayed afterdepolarizations (DADs), a cellular mechanism of arrhythmias, was lower in myocytes of HF animals fed omega3-PUFAs compared to myocytes of HF animals fed omega9-MUFAs. In our rabbit HF model, the degree of hypertrophy was similar in the omega3-PUFAs group compared to the omega9-MUFAs group. CONCLUSION: Dietary omega3-PUFAs from FO suppress upregulation of the NHE-1 activity and lower the incidence of DADs in our rabbit model of volume- and pressure-overload. PMID- 22485093 TI - Commensal Flora, is it an Unwelcomed Companion as a Triggering Factor of Autoimmune Pancreatitis? AB - The etiopathogenesis of many autoimmune disorders has not been identified. The aim of this paper is to focus on the involvement of bacterial exposure, as an environmental factor, in the pathogenesis of autoimmune pancreatitis (AIP), which is broadly categorized as autoimmune disorders involving pancreatic lesions. Avirulent and/or commensal bacteria, which may have an important role(s) as initiating/progressing factors in the pathogenesis of autoimmune disorder AIP, will be emphasized. PMID- 22485094 TI - Rodent animal models for surrogate analysis of cell therapy in acute liver failure. AB - Without therapeutic intervention acute liver failure (ALF) is the consequence of a progredient destruction of the liver parenchyma due to metabolic exhaustion of the hepatocytes. Perivenous hepatocytes are responsible for the detoxification of noxious compounds via the cytochrome P450 enzyme system. Liver transplantation is the only remaining therapeutic option in the end-stage of the disease. Assuming that metabolic capacity could be provided by healthy hepatocytes and thus substitute for the genuine parenchymal cells hepatocyte transplantation since quite some time is considered to be an alternative to whole liver transplantation. While this hypothesis achieved proof-of-concept in animal trials clinical breakthrough is still awaiting success, the reasons of which are ongoing matter of debate. In recent times mesenchymal stem cells (MSC) came into focus as a transplantable cell source to treat ALF. Interestingly, as demonstrated in various rodent animal models their mode of action is rather based on trophic support of hepatocytes remaining in the damaged host parenchyma rather than substitution of tissue loss. Mechanistically, either direct or indirect paracrine effects from the transplanted cells acting pro-proliferative, anti-apoptotic, and anti-inflammatory seem to trigger the regenerative response of the residual healthy hepatocytes in the otherwise lethally injured liver parenchyma. Thus, allogeneic MSC may be the best choice for the treatment of ALF taking advantage of their short-term benefit to sustain the critical phase of the acute insult avoiding long-term immunosuppression. PMID- 22485095 TI - Mechanisms of cell death in acute liver failure. AB - Acute liver failure (ALF) can be the consequence of various etiologies, that might vary between different geographic regions. Most frequent are intoxications with acetaminophen, viral hepatitis, or liver damage of unknown origin. ALF occurs when the extent of hepatocyte death exceeds the regenerative capacity of the liver. The mode of liver cell death that is predominantly induced in ALF, i.e., apoptosis or necrosis, is still controversial and presumably determined by the etiology, duration, and magnitude of liver injury. Severe liver damage involves oxidative stress and depletion of ATP resulting in necrosis. In contrast, maintenance of ATP stores is required for the execution of apoptosis. Recent data suggest that necrosis resulting from severe liver damage is associated with poor outcome of ALF patients. Discrimination between apoptosis and necrosis might be therefore useful for the identification of ALF patients requiring liver transplantation. Identification of the molecular cell death mechanisms remains an important issue not only for early prediction of ALF outcome, but also for therapeutic interventions. In view of the pleiotropic functions of critical mediators of cell death and tissue regeneration, a particular challenge will be to reduce hepatocellular death without inhibiting the regenerative capacity of the liver. Here, we review the molecular mechanisms of hepatocyte injury and the pathways leading to apoptosis and necrosis, which might represent potential diagnostic and therapeutic targets in ALF. PMID- 22485096 TI - A Peephole into the Brain: Neuropathological Features of Alzheimer's Disease Revealed by in vivo Two-Photon Imaging. AB - Alzheimer's disease (AD) is a protein conformational disorder characterized by two major neuropathological features: extracellular accumulations of amyloid-beta peptides in the form of plaques and intracellular tangles, consisting of hyperphosphorylated tau proteins. Several morphological and functional changes are associated with these lesions in the diseased brain, such as dendritic and synaptic alterations, as well as microglial and astroglial recruitment and their activation. The availability of transgenic mouse models that mimic key aspects of the disease in conjunction with recent advances in two-photon imaging facilitate the study of fundamental aspects of AD pathogenesis and allow for longitudinally monitoring the efficacy of therapeutic interventions. Here, we review the ambitious efforts to understand the relationship between the main neuropathological hallmarks of AD and their associated structural and functional abnormalities by means of in vivo two-photon imaging. PMID- 22485097 TI - Treatment of early onset schizophrenia: recent trends, challenges and future considerations. AB - Early onset schizophrenia (onset before adulthood) is a rare, severe, and chronic form of schizophrenia. The clinical presentation of schizophrenia at this unusually early age of onset has been associated with premorbid developmental abnormalities, poor response to neuroleptic treatment, greater admission rates, and poor prognosis. This is a brief, condensed review of current treatment strategies for the early onset population highlighting the need for novel treatment strategies for these generally treatment-refractory cases. Based on the current literature, second-generation antipsychotics remain the mainstay of treatment, although current medications provide suboptimal response at best. Based on the adult literature, combining antipsychotic treatment with psychotherapeutic intervention may be a more comprehensive treatment strategy. Indeed, early detection, identification of relevant biomarkers, coupled with advancing knowledge of the neurochemical and neuroanatomic pathways may help design informed and novel treatment strategies. PMID- 22485098 TI - Psychoanalysis and the brain - why did freud abandon neuroscience? AB - Sigmund Freud, the founder of psychoanalysis, was initially a neuroscientist but abandoned neuroscience completely after he made a last attempt to link both in his writing, "Project of a Scientific Psychology," in 1895. The reasons for his subsequent disregard of the brain remain unclear though. I here argue that one central reason may be that the approach to the brain during his time was simply not appealing to Freud. More specifically, Freud was interested in revealing the psychological predispositions of psychodynamic processes. However, he was not so much focused on the actual psychological functions themselves which though were the prime focus of the neuroscience at his time and also in current Cognitive Neuroscience. Instead, he probably would have been more interested in the brain's resting state and its constitution of a spatiotemporal structure. I here assume that the resting state activity constitutes a statistically based virtual structure extending and linking the different discrete points in time and space within the brain. That in turn may serve as template, schemata, or grid for all subsequent neural processing during stimulus-induced activity. As such the resting state' spatiotemporal structure may serve as the neural predisposition of what Freud described as "psychological structure." Hence, Freud and also current neuropsychoanalysis may want to focus more on neural predispositions, the necessary non-sufficient conditions, rather than the neural correlates, i.e., sufficient, conditions of psychodynamic processes. PMID- 22485099 TI - Cognitive and electrophysiological correlates of the bilingual stroop effect. AB - The color word Stroop effect in bilinguals is commonly half the magnitude when the written and naming languages are different (between) than when they are the same (within). This between-within language Stroop difference (BWLS) is likened to a response set effect, with greater response conflict for response relevant than irrelevant words. The nature of the BWLS was examined using a bilingual Stroop task. In a given block (Experiment 1), color congruent and incongruent words appeared in the naming language or not (single), or randomly in both languages (mixed). The BWLS effect was present for both balanced and unbalanced bilinguals, but only partially supported a response set explanation. As expected, color incongruent trials during single language blocks, lead to slower response times within than between languages. However, color congruent trials during mixed language blocks led to slower times between than within languages, indicating that response-irrelevant stimuli interfered with processing. In Experiment 2, to investigate the neural timing of the BWLS effect, event related potentials were recorded while balanced bilinguals named silently within and between languages. Replicating monolingual findings, an N450 effect was observed with larger negative amplitude for color incongruent than congruent trials (350-550 ms post stimulus onset). This effect was equivalent within and between languages, indicating that color words from both languages created response conflict, contrary to a strict response set effect. A sustained negativity (SN) followed with larger amplitude for color incongruent than congruent trials, resolving earlier for between than within language Stroop. This effect shared timing (550 700 ms), but not morphology or scalp distribution with the commonly reported sustained potential. Finally, larger negative amplitude (200-350 ms) was observed between than within languages independent of color congruence. This negativity, likened to a no-go N2, may reflect processes of inhibitory control that facilitate the resolution of conflict at the SN, while the N450 reflects parallel processing of distracter words, independent of response set (or language). In sum, the BWLS reflects brain activity over time with contributions from language and color conflict at different points. PMID- 22485100 TI - Word-Initial Letters Influence Fixation Durations during Fluent Reading. AB - The present study examined how word-initial letters influence lexical access during reading. Eye movements were monitored as participants read sentences containing target words. Three factors were independently manipulated. First, target words had either high or low constraining word-initial letter sequences (e.g., dwarf or clown, respectively). Second, targets were either high or low in frequency of occurrence (e.g., train or stain, respectively). Third, targets were embedded in either biasing or neutral contexts (i.e., targets were high or low in their predictability). This 2 (constraint) * 2 (frequency) * 2 (context) design allowed us to examine the conditions under which a word's initial letter sequence could facilitate processing. Analyses of fixation duration data revealed significant main effects of constraint, frequency, and context. Moreover, in measures taken to reflect "early" lexical processing (i.e., first and single fixation duration), there was a significant interaction between constraint and context. The overall pattern of findings suggests lexical access is facilitated by highly constraining word-initial letters. Results are discussed in comparison to recent studies of lexical features involved in word recognition during reading. PMID- 22485101 TI - Sound-induced activity in voice-sensitive cortex predicts voice memory ability. AB - The "temporal voice areas" (TVAs; Belin et al., 2000) of the human brain show greater neuronal activity in response to human voices than to other categories of non-vocal sounds. However, a direct link between TVA activity and voice perception behavior has not yet been established. Here we show that a functional magnetic resonance imaging measure of activity in the TVAs predicts individual performance at a separately administered voice memory test. This relation holds when general sound memory ability is taken into account. These findings provide the first evidence that the TVAs are specifically involved in voice cognition. PMID- 22485102 TI - Attention and conscious perception in the hypothesis testing brain. AB - Conscious perception and attention are difficult to study, partly because their relation to each other is not fully understood. Rather than conceiving and studying them in isolation from each other it may be useful to locate them in an independently motivated, general framework, from which a principled account of how they relate can then emerge. Accordingly, these mental phenomena are here reviewed through the prism of the increasingly influential predictive coding framework. On this framework, conscious perception can be seen as the upshot of prediction error minimization and attention as the optimization of precision expectations during such perceptual inference. This approach maps on well to a range of standard characteristics of conscious perception and attention, and can be used to interpret a range of empirical findings on their relation to each other. PMID- 22485103 TI - Gesture's Neural Language. AB - When people talk to each other, they often make arm and hand movements that accompany what they say. These manual movements, called "co-speech gestures," can convey meaning by way of their interaction with the oral message. Another class of manual gestures, called "emblematic gestures" or "emblems," also conveys meaning, but in contrast to co-speech gestures, they can do so directly and independent of speech. There is currently significant interest in the behavioral and biological relationships between action and language. Since co-speech gestures are actions that rely on spoken language, and emblems convey meaning to the effect that they can sometimes substitute for speech, these actions may be important, and potentially informative, examples of language-motor interactions. Researchers have recently been examining how the brain processes these actions. The current results of this work do not yet give a clear understanding of gesture processing at the neural level. For the most part, however, it seems that two complimentary sets of brain areas respond when people see gestures, reflecting their role in disambiguating meaning. These include areas thought to be important for understanding actions and areas ordinarily related to processing language. The shared and distinct responses across these two sets of areas during communication are just beginning to emerge. In this review, we talk about the ways that the brain responds when people see gestures, how these responses relate to brain activity when people process language, and how these might relate in normal, everyday communication. PMID- 22485104 TI - Experimental animal models for studies on the mechanisms of blast-induced neurotrauma. AB - A blast injury is a complex type of physical trauma resulting from the detonation of explosive compounds and has become an important issue due to the use of improvised explosive devices (IED) in current military conflicts. Blast-induced neurotrauma (BINT) is a major concern in contemporary military medicine and includes a variety of injuries that range from mild to lethal. Extreme forces and their complex propagation characterize BINT. Modern body protection and the development of armored military vehicles can be assumed to have changed the outcome of BINT. Primary blast injuries are caused by overpressure waves whereas secondary, tertiary, and quaternary blast injuries can have more varied origins such as the impact of fragments, abnormal movements, or heat. The characteristics of the blast wave can be assumed to be significantly different in open field detonations compared to explosions in a confined space, such an armored vehicle. Important parameters include peak pressure, duration, and shape of the pulse. Reflections from walls and armor can make the prediction of effects in individual cases very complex. Epidemiological data do not contain information of the comparative importance of the different blast mechanisms. It is therefore important to generate data in carefully designed animal models. Such models can be selective reproductions of a primary blast, penetrating injuries from fragments, acceleration movements, or combinations of such mechanisms. It is of crucial importance that the physical parameters of the employed models are well characterized so that the experiments can be reproduced in different laboratory settings. Ideally, pressure recordings should be calibrated by using the same equipment in several laboratories. With carefully designed models and thoroughly evaluated animal data it should be possible to achieve a translation of data between animal and clinical data. Imaging and computer simulation represent a possible link between experiments and studies of human cases. However, in order for mathematical simulations to be completely useful, the predictions will most likely have to be validated by detailed data from animal experiments. Some aspects of BINT can conceivably be studied in vitro. However, factors such as systemic response, brain edema, inflammation, vasospasm, or changes in synaptic transmission and behavior must be evaluated in experimental animals. Against this background, it is necessary that such animal experiments are carefully developed imitations of actual components in the blast injury. This paper describes and discusses examples of different designs of experimental models relevant to BINT. PMID- 22485106 TI - Exercise effects on sleep physiology. AB - This mini-review focuses on the effects of exercise on sleep. In its early days, sleep research largely focused on central nervous system (CNS) physiology using standardized tabulations of several sleep-specific landmark electroencephalogram (EEG) waveforms. Though coarse, this method has enabled the observation and inspection of numerous uninterrupted sleep phenomena. The research on the effects of exercise on sleep began, in the 1960s, with a focus primarily on sleep related EEG changes (CNS sleep). Those early studies found only small effects of exercise on sleep. However, more recent sleep research has explored not only CNS functioning, but somatic physiology as well. Sleep should be affected by daytime exercise, as physical activity alters endocrine, autonomic nervous system (ANS), and somatic functions. Since endocrinological, metabolic, and autonomic changes can be measured during sleep, it should be possible to assess exercise effects on somatic physiology in addition to CNS sleep quality, evaluated by standard polysomnographic (PSG) techniques. Additional measures of somatic physiology have provided enough evidences to conclude that the auto-regulatory, global regulation of sleep is not the exclusive domain of the CNS, but it is heavily influenced by inputs from the rest of the body. PMID- 22485105 TI - REM Sleep Rebound as an Adaptive Response to Stressful Situations. AB - Stress and sleep are related to each other in a bidirectional way. If on one hand poor or inadequate sleep exacerbates emotional, behavioral, and stress-related responses, on the other hand acute stress induces sleep rebound, most likely as a way to cope with the adverse stimuli. Chronic, as opposed to acute, stress impairs sleep and has been claimed to be one of the triggering factors of emotional-related sleep disorders, such as insomnia, depressive- and anxiety disorders. These outcomes are dependent on individual psychobiological characteristics, conferring even more complexity to the stress-sleep relationship. Its neurobiology has only recently begun to be explored, through animal models, which are also valuable for the development of potential therapeutic agents and preventive actions. This review seeks to present data on the effects of stress on sleep and the different approaches used to study this relationship as well as possible neurobiological underpinnings and mechanisms involved. The results of numerous studies in humans and animals indicate that increased sleep, especially the rapid eye movement phase, following a stressful situation is an important adaptive behavior for recovery. However, this endogenous advantage appears to be impaired in human beings and rodent strains that exhibit high levels of anxiety and anxiety-like behavior. PMID- 22485107 TI - Intrinsic neuronal excitability: a role in homeostasis and disease. PMID- 22485110 TI - Ebolavirus Replication and Tetherin/BST-2. AB - Ebolavirus (EBOV) is an enveloped, non-segmented, negative-stranded RNA virus, which consists of five species: Zaire ebolavirus, Sudan ebolavirus, Tai Forest ebolavirus, Bundibugyo ebolavirus, and Reston ebolavirus. EBOV causes a lethal hemorrhagic fever in both humans and non-human primates. The EBOV RNA genome encodes seven viral proteins: NP, VP35, VP40, GP, VP30, VP24, and L. VP40 is a matrix protein and is essential for virus assembly and release from host cells. Expression of VP40 in mammalian cells is sufficient to generate extracellular virus-like particles, which resemble authentic virions. Tetherin/BST-2, which was identified as an effective cellular factor that prevents human immunodeficiency virus-1 release in the absence of viral accessory protein Vpu, has been reported to inhibit ZEBOV VP40-induced VLP release. Tetherin/BST-2 appears to inhibit virus release by physically tethering viral particles to the cell surface via its N-terminal transmembrane domain and C-terminal glycosylphosphatidylinositol anchor. Replication of ZEBOV is not inhibited by tetherin/BST-2 expression, although tetherin/BST-2 was expected to inhibit EBOV release as well as VLP release. Recently, it was reported that viral glycoprotein of EBOV, GP, antagonizes the antiviral effect of tetherin/BST-2. However, the mechanism by which GP antagonizes the antiviral activity of tetherin/BST-2 and whether GP of the other EBOV species function as antagonists of tetherin/BST-2 remain unclear. PMID- 22485111 TI - Characterization of Metabolically Active Bacterial Populations in Subseafloor Nankai Trough Sediments above, within, and below the Sulfate-Methane Transition Zone. AB - A remarkable number of microbial cells have been enumerated within subseafloor sediments, suggesting a biological impact on geochemical processes in the subseafloor habitat. However, the metabolically active fraction of these populations is largely uncharacterized. In this study, an RNA-based molecular approach was used to determine the diversity and community structure of metabolically active bacterial populations in the upper sedimentary formation of the Nankai Trough seismogenic zone. Samples used in this study were collected from the slope apron sediment overlying the accretionary prism at Site C0004 during the Integrated Ocean Drilling Program Expedition 316. The sediments represented microbial habitats above, within, and below the sulfate-methane transition zone (SMTZ), which was observed approximately 20 m below the seafloor (mbsf). Small subunit ribosomal RNA were extracted, quantified, amplified, and sequenced using high-throughput 454 pyrosequencing, indicating the occurrence of metabolically active bacterial populations to a depth of 57 mbsf. Transcript abundance and bacterial diversity decreased with increasing depth. The two communities below the SMTZ were similar at the phylum level, however only a 24% overlap was observed at the genus level. Active bacterial community composition was not confined to geochemically predicted redox stratification despite the deepest sample being more than 50 m below the oxic/anoxic interface. Genus-level classification suggested that the metabolically active subseafloor bacterial populations had similarities to previously cultured organisms. This allowed predictions of physiological potential, expanding understanding of the subseafloor microbial ecosystem. Unique community structures suggest very diverse active populations compared to previous DNA-based diversity estimates, providing more support for enhancing community characterizations using more advanced sequencing techniques. PMID- 22485112 TI - Multivariate analysis of flow cytometric data using decision trees. AB - Characterization of the response of the host immune system is important in understanding the bidirectional interactions between the host and microbial pathogens. For research on the host site, flow cytometry has become one of the major tools in immunology. Advances in technology and reagents allow now the simultaneous assessment of multiple markers on a single cell level generating multidimensional data sets that require multivariate statistical analysis. We explored the explanatory power of the supervised machine learning method called "induction of decision trees" in flow cytometric data. In order to examine whether the production of a certain cytokine is depended on other cytokines, datasets from intracellular staining for six cytokines with complex patterns of co-expression were analyzed by induction of decision trees. After weighting the data according to their class probabilities, we created a total of 13,392 different decision trees for each given cytokine with different parameter settings. For a more realistic estimation of the decision trees' quality, we used stratified fivefold cross validation and chose the "best" tree according to a combination of different quality criteria. While some of the decision trees reflected previously known co-expression patterns, we found that the expression of some cytokines was not only dependent on the co-expression of others per se, but was also dependent on the intensity of expression. Thus, for the first time we successfully used induction of decision trees for the analysis of high dimensional flow cytometric data and demonstrated the feasibility of this method to reveal structural patterns in such data sets. PMID- 22485109 TI - CTX-M Enzymes: Origin and Diffusion. AB - CTX-M beta-lactamases are considered a paradigm in the evolution of a resistance mechanism. Incorporation of different chromosomal bla(CTX-M) related genes from different species of Kluyvera has derived in different CTX-M clusters. In silico analyses have shown that this event has occurred at least nine times; in CTX-M-1 cluster (3), CTX-M-2 and CTX-M-9 clusters (2 each), and CTX-M-8 and CTX-M-25 clusters (1 each). This has been mainly produced by the participation of genetic mobilization units such as insertion sequences (ISEcp1 or ISCR1) and the later incorporation in hierarchical structures associated with multifaceted genetic structures including complex class 1 integrons and transposons. The capture of these bla(CTX-M) genes from the environment by highly mobilizable structures could have been a random event. Moreover, after incorporation within these structures, beta-lactam selective force such as that exerted by cefotaxime and ceftazidime has fueled mutational events underscoring diversification of different clusters. Nevertheless, more variants of CTX-M enzymes, including those not inhibited by beta-lactamase inhibitors such as clavulanic acid (IR-CTX-M variants), only obtained under in in vitro experiments, are still waiting to emerge in the clinical setting. Penetration and the later global spread of CTX-M producing organisms have been produced with the participation of the so-called "epidemic resistance plasmids" often carried in multi-drug resistant and virulent high-risk clones. All these facts but also the incorporation and co-selection of emerging resistance determinants within CTX-M producing bacteria, such as those encoding carbapenemases, depict the currently complex pandemic scenario of multi drug resistant isolates. PMID- 22485108 TI - Systems biology of fungal infection. AB - Elucidation of pathogenicity mechanisms of the most important human-pathogenic fungi, Aspergillus fumigatus and Candida albicans, has gained great interest in the light of the steadily increasing number of cases of invasive fungal infections. A key feature of these infections is the interaction of the different fungal morphotypes with epithelial and immune effector cells in the human host. Because of the high level of complexity, it is necessary to describe and understand invasive fungal infection by taking a systems biological approach, i.e., by a comprehensive quantitative analysis of the non-linear and selective interactions of a large number of functionally diverse, and frequently multifunctional, sets of elements, e.g., genes, proteins, metabolites, which produce coherent and emergent behaviors in time and space. The recent advances in systems biology will now make it possible to uncover the structure and dynamics of molecular and cellular cause-effect relationships within these pathogenic interactions. We review current efforts to integrate omics and image-based data of host-pathogen interactions into network and spatio-temporal models. The modeling will help to elucidate pathogenicity mechanisms and to identify diagnostic biomarkers and potential drug targets for therapy and could thus pave the way for novel intervention strategies based on novel antifungal drugs and cell therapy. PMID- 22485113 TI - Mineralogy of iron microbial mats from loihi seamount. AB - Extensive mats of Fe oxyhydroxides and associated Fe-oxidizing microbial organisms form in diverse geochemical settings - freshwater seeps to deep-sea vents - where ever opposing Fe(II)-oxygen gradients prevail. The mineralogy, reactivity, and structural transformations of Fe oxyhydroxides precipitated from submarine hydrothermal fluids within microbial mats remains elusive in active and fossil systems. In response, a study of Fe microbial mat formation at the Loihi Seamount was conducted to describe the physical and chemical characteristics of Fe-phases using extended X-ray absorption fine structure spectroscopy, powder X ray diffraction, synchrotron radiation X-ray total scattering, low-temperature magnetic measurements, and Mossbauer spectroscopy. Particle sizes of 3.5-4.6 nm were estimated from magnetism data, and coherent scattering domain (CSD) sizes as small as 1.6 nm are indicated by pair distribution function (PDF) analysis. Disorder in the nanostructured Fe-bearing phases results in limited intermediate range structural order: less than that of standard two-line ferrihydrite (Fh), except for the Pohaku site. The short-range ordered natural Fh (Fh(SRO)) phases were stable at 4 degrees C in the presence of oxygen for at least 1 year and during 400 degrees C treatment. The observed stability of the Fh(SRO) is consistent with magnetic observations that point to non-interacting nanoparticles. PDF analyses of total scattering data provide further evidence for Fh(SRO) particles with a poorly ordered silica coating. The presence of coated particles explains the small CSD for the mat minerals, as well as the stability of the minerals over time and against heating. The mineral properties observed here provide a starting point from which progressively older and more extensively altered Fe deposits may be examined, with the ultimate goal of improved interpretation of past biogeochemical conditions and diagenetic processes. PMID- 22485114 TI - Biogenic Amines Degradation by Lactobacillus plantarum: Toward a Potential Application in Wine. AB - Biogenic amines (BA) in wine represent a toxicological risk for the health of the consumer, with several trade implications. In this study 26 strains of Lactobacillus plantarum were analyzed for their ability to degrade BA commonly found during wine fermentation. Two strains of L. plantarum were selected in reason of their ability to degrade putrescine and tyramine. The degradation was assessed in vitro, both in presence of the BA and in presence of the specific chemical precursor and of producer bacteria. The two L. plantarum biotypes were found capable to work synergically. In addition, the survival in wine-like medium and the aptitude to degrade malic acid after alcoholic fermentation of the selected L. plantarum strains was analyzed. Our results suggest the potential application of wine L. plantarum strains to design malolactic starter cultures able to degrade BA in wine. PMID- 22485115 TI - Outcome of the 'Drip-and-Ship' Paradigm among Patients with Acute Ischemic Stroke: Results of a Statewide Study. AB - BACKGROUND: The 'drip-and-ship' paradigm denotes a treatment regimen in patients in whom intravenous (IV) recombinant tissue plasminogen activator (rt-PA) is initiated at the emergency department (ED) of a community hospital, followed by transfer within 24 h to a comprehensive stroke center. Although the drip-and-ship paradigm has the potential to increase the number of patients who receive IV rt PA, comparative outcomes have not been assessed at a population-based level. METHODS: Statewide estimates of thrombolysis, associated in-hospital outcomes, and hospitalization charges were obtained from 2008-2009 Minnesota Hospital Association data for all patients hospitalized with a primary diagnosis of ischemic stroke. Patients who were assigned the drip-and-ship code [International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) V45.88] were classified under the drip-and-ship paradigm. Patients who underwent thrombolysis (ICD-9-CM code 99.10) without drip-and-ship code were classified as primary ED arrival. Patient outcomes were analyzed after stratification into patients treated with IV rt-PA through primary ED arrival or drip-and-ship paradigm. RESULTS: Of the 21,024 admissions, 602 (2.86%) received IV rt-PA either through primary ED arrival (n = 473) or the drip-and-ship paradigm (n = 129). IV rt-PA was administered in 30 hospitals, of which 13 hospitals used the drip-and-ship paradigm; the number of patients treated with the drip-and-ship paradigm varied from 1 to 40 between the 13 hospitals. The rates of secondary intracerebral or subarachnoid hemorrhage were higher in patients treated with IV rt-PA through primary ED arrival compared with those treated with the drip-and ship paradigm (8.5 vs. 3.1%, respectively; p = 0.038). The in-hospital mortality rate was similar among ischemic stroke patients receiving IV rt-PA through primary ED arrival or the drip-and-ship paradigm (5.9 vs. 7.0%, respectively). The mean hospital charges were USD 65,669 for primary ED arrival and USD 47,850 for drip-and-ship-treated patients (p < 0.001). The rate of admission to a certified stroke center as final destination for acute hospitalization was higher in patients treated by drip-and-ship paradigm compared with those treated by primary ED arrival mode (p = 0.015). CONCLUSIONS: The results of the drip-and ship paradigm compare favorably with IV rt-PA treatment through primary ED arrival in this statewide study. Our results support the recommendations of various professional organizations that the drip-and-ship method of IV rt-PA administration for stroke may be an effective option for increasing the utilization of IV rt-PA on a large scale. PMID- 22485116 TI - Improving RNA-Seq Precision with MapAl. AB - With currently available RNA-Seq pipelines, expression estimates for most genes are very noisy. We here introduce MapAl, a tool for RNA-Seq expression profiling that builds on the established programs Bowtie and Cufflinks. In the post processing of RNA-Seq reads, it incorporates gene models already at the stage of read alignment, increasing the number of reliably measured known transcripts consistently by 50%. Adding genes identified de novo then allows a reliable assessment of double the total number of transcripts compared to other available pipelines. This substantial improvement is of general relevance: Measurement precision determines the power of any analysis to reliably identify significant signals, such as in screens for differential expression, independent of whether the experimental design incorporates replicates or not. PMID- 22485118 TI - Cardiac tamponade secondary to haemopericardium in a patient on warfarin. AB - Excessive anticoagulation with warfarin may contribute to certain complications, including bleeding into body cavities. Haemopericardiac tamponade secondary to warfarin is rare outside cardiac surgery. The present report describes an unusual presentation of spontaneous cardiac tamponade in a patient on warfarin and recently treated for chest infection with erythromycin. The patient was referred to the surgeons with acute abdominal pain and hypotension. Blood tests revealed an international normalised ratio (INR) of 16.9. An emergency abdominal computed tomography (CT) scan revealed pericardial effusion. Intravenous vitamin K and prothrombin complex concentrate were administered and urgent referral to a cardiologist was made for pericardiocentesis. Monitoring INR in patients on warfarin is paramount in avoiding the potential detrimental complications of excessive anticoagulation. Clinicians should be aware of drug interactions of warfarin and risk factors associated with its prolonged half-life. Internal bleeding, including haemorrhagic cardiac tamponade, should be ruled out in patients with unexplained hypotension and excessive anticoagulation. PMID- 22485117 TI - Genomics of behavioral diseases. PMID- 22485119 TI - An unusual cause of severe dyspnoea-papillary fibroelastoma of the tricuspid valve. PMID- 22485120 TI - Simultaneous distal radius and lunate fractures: a lesson for an unwary eye. AB - Simultaneous distal radius and carpus fractures are uncommon. They can be missed because of a diffused clinical picture and an inexperienced clinician reviewing the patient and radiographs. A 64-year-old woman presented to the emergency department (ED) with a clinically deformed left wrist after a fall. Plain radiographs were interpreted as a distal radius intra-articular fracture with volar angulation, both by the ED physician and the first on call for trauma and orthopaedics (T&O). Review of the radiographs in the trauma meeting revealed the possibility of an additional undisplaced lunate fracture. A computed tomography scan confirmed the distal radius fracture in addition to an undisplaced fracture of the lunate. Because of the unstable nature of the distal radius fracture, open reduction and internal fixation was performed. As the lunate fracture was undisplaced, it was managed conservatively. The patient was discharged home the next day and has been doing well at follow-up. PMID- 22485121 TI - The national pandemic flu service, oseltamivir, and a case of pancreatitis. AB - The recent outbreak of the influenza virus H1N1 continues to pose a serious public health threat at a population wide level. In response to this, the UK National Health Service has made antiviral medication available to the general public in a unique way. Individuals can receive treatment without having to consult a medical practitioner, by simply answering a set of questions online or over the telephone. We present the case of a 65-year-old woman who developed a case of acute pancreatitis shortly after taking oseltamivir. Extensive investigation revealed that she had no risk factors or other identifiable cause for developing pancreatitis, and the possible adverse drug reaction has been reported to the Medicines and Healthcare Products Regulatory Agency. Concerns regarding the strategy to provide antiviral medication to the population using this novel approach are discussed in light of patient safety and implications for health policy. PMID- 22485122 TI - An unusual way of diagnosing acute inferior myocardial infarction. PMID- 22485123 TI - Campylobacterjejuni cholecystitis: a rare but significant clinical entity. AB - Cholecystitis caused by Campylobacter is rare with only 14 cases found in the literature. This case describes a 71-year-old man who presented with right hypochondrial abdominal pain due to a gangrenous gallbladder identified at laparotomy. Culture of a bile sample identified a slow-growing gram-negative bacterium identified as Campylobacter jejuni. After a poor clinical response, this identification allowed targeted antibiotic treatment resulting in a slow but successful recovery and discharge 17 days postoperatively. This case demonstrates the importance of considering rare organisms in severe acute cholecystitis and ensuring appropriate cultures are performed, particularly in those who fail to respond to initial antimicrobial treatment. PMID- 22485124 TI - In Defence of Modest Doxasticism About Delusions. AB - Here I reply to the main points raised by the commentators on the arguments put forward in my Delusions and Other Irrational Beliefs (OUP, 2009). My response is aimed at defending a modest doxastic account of clinical delusions, and is articulated in three sections. First, I consider the view that delusions are in between perceptual and doxastic states, defended by Jacob Hohwy and Vivek Rajan, and the view that delusions are failed attempts at believing or not-quite beliefs, proposed by Eric Schwitzgebel and Maura Tumulty. Then, I address the relationship between the doxastic account of delusions and the role, nature, and prospects of folk psychology, which is discussed by Dominic Murphy, Keith Frankish, and Maura Tumulty in their contributions. In the final remarks, I turn to the continuity thesis and suggest that, although there are important differences between clinical delusions and non-pathological beliefs, these differences cannot be characterised satisfactorily in epistemic terms. PMID- 22485125 TI - Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis. AB - BACKGROUND: T-helper (Th) 22 is involved in the pathogenesis of inflammatory diseases. The roles of Th22 cells in the pathophysiological of ankylosing spondylitis (AS) and rheumatoid arthritis (RA) remain unsettled. So we examined the frequencies of Th22 cells, Th17 cells and Th1 cells in peripheral blood (PB) from patients with AS and patients with RA compared with both healthy controls as well as patients with osteoarthritis. DESIGN AND METHODS: We studied 32 AS patients, 20 RA patients, 10 OA patients and 20 healthy controls. The expression of IL-22, IL-17 and IFN-gamma were examined in AS, RA, OA patients and healthy controls by flow cytometry. Plasma IL-22 and IL-17 levels were examined by enzyme linked immunosorbent assay. RESULTS: Th22 cells, Th17 cells and interleukin-22 were significantly elevated in AS and RA patients compared with OA patients and healthy controls. Moreover, Th22 cells showed positive correlation with Th17 cells as well as interleukin-22 in AS and RA patients. However, positive correlation between IL-22 and Th17 cells was only found in AS patients not in RA patients. In addition, the percentages of both Th22 cells and Th17 cells correlated positively with disease activity only in RA patients not in AS patients. CONCLUSIONS: The frequencies of both Th22 cells and Th17 cells were elevated in PB from patients with AS and patients with RA. These findings suggest that Th22 cells and Th17 cells may be implicated in the pathogenesis of AS and RA, and Th22 cells and Th17 cells may be reasonable cellular targets for therapeutic intervention. PMID- 22485126 TI - The isolation and characterization of beta-glucogallin as a novel aldose reductase inhibitor from Emblica officinalis. AB - Diabetes mellitus is recognized as a leading cause of new cases of blindness. The prevalence of diabetic eye disease is expected to continue to increase worldwide as a result of the dramatic increase in the number of people with diabetes. At present, there is no medical treatment to delay or prevent the onset and progression of cataract or retinopathy, the most common causes of vision loss in diabetics. The plant Emblica officinalis (gooseberry) has been used for thousands of years as a traditional Indian Ayurvedic preparation for the treatment of diabetes in humans. Extracts from this plant have been shown to be efficacious against the progression of cataract in a diabetic rat model. Aldose reductase (ALR2) is implicated in the development of secondary complications of diabetes including cataract and, therefore, has been a major drug target for the development of therapies to treat diabetic disease. Herein, we present the bioassay-guided isolation and structure elucidation of 1-O-galloyl-beta-D-glucose (beta-glucogallin), a major component from the fruit of the gooseberry that displays selective as well as relatively potent inhibition (IC(50) = 17 uM) of AKR1B1 in vitro. Molecular modeling demonstrates that this inhibitor is able to favorably bind in the active site. Further, we show that beta-glucogallin effectively inhibits sorbitol accumulation by 73% at 30 uM under hyperglycemic conditions in an ex-vivo organ culture model of lenses excised from transgenic mice overexpressing human ALR2 in the lens. This study supports the continued development of natural products such as beta-glucogallin as therapeutic leads in the development of novel therapies to treat diabetic complications such as cataract. PMID- 22485127 TI - Seasonality in human zoonotic enteric diseases: a systematic review. AB - BACKGROUND: Although seasonality is a defining characteristic of many infectious diseases, few studies have described and compared seasonal patterns across diseases globally, impeding our understanding of putative mechanisms. Here, we review seasonal patterns across five enteric zoonotic diseases: campylobacteriosis, salmonellosis, vero-cytotoxigenic Escherichia coli (VTEC), cryptosporidiosis and giardiasis in the context of two primary drivers of seasonality: (i) environmental effects on pathogen occurrence and pathogen-host associations and (ii) population characteristics/behaviour. METHODOLOGY/PRINCIPAL FINDINGS: We systematically reviewed published literature from 1960-2010, resulting in the review of 86 studies across the five diseases. The Gini coefficient compared temporal variations in incidence across diseases and the monthly seasonality index characterised timing of seasonal peaks. Consistent seasonal patterns across transnational boundaries, albeit with regional variations was observed. The bacterial diseases all had a distinct summer peak, with identical Gini values for campylobacteriosis and salmonellosis (0.22) and a higher index for VTEC (Gini 0.36). Cryptosporidiosis displayed a bi-modal peak with spring and summer highs and the most marked temporal variation (Gini = 0.39). Giardiasis showed a relatively small summer increase and was the least variable (Gini = 0.18). CONCLUSIONS/SIGNIFICANCE: Seasonal variation in enteric zoonotic diseases is ubiquitous, with regional variations highlighting complex environment-pathogen-host interactions. Results suggest that proximal environmental influences and host population dynamics, together with distal, longer-term climatic variability could have important direct and indirect consequences for future enteric disease risk. Additional understanding of the concerted influence of these factors on disease patterns may improve assessment and prediction of enteric disease burden in temperate, developed countries. PMID- 22485128 TI - Frontal GABA levels change during working memory. AB - Functional neuroimaging metrics are thought to reflect changes in neurotransmitter flux, but changes in neurotransmitter levels have not been demonstrated in humans during a cognitive task, and the relationship between neurotransmitter dynamics and hemodynamic activity during cognition has not yet been established. We evaluate the concentration of the major inhibitory (GABA) and excitatory (glutamate + glutamine: Glx) neurotransmitters and the cerebral perfusion at rest and during a prolonged delayed match-to-sample working memory task. Resting GABA levels in the dorsolateral prefrontal cortex correlated positively with the resting perfusion and inversely with the change in perfusion during the task. Further, only GABA increased significantly during the first working memory run and then decreased continuously across subsequent task runs. The decrease of GABA over time was paralleled by a trend towards decreased reaction times and higher task accuracy. These results demonstrate a link between neurotransmitter dynamics and hemodynamic activity during working memory, indicating that functional neuroimaging metrics depend on the balance of excitation and inhibition required for cognitive processing. PMID- 22485129 TI - Low lipoprotein(a) concentration is associated with cancer and all-cause deaths: a population-based cohort study (the JMS cohort study). AB - BACKGROUND: Experimental studies support the anti-neoplastic effect of apo(a), but several clinical studies have reported contradictory results. The purpose of this study was to determine whether a low lipoprotein(a) [Lp(a)] concentration is related to mortality from major causes of death, especially cancer. METHODS: The subjects were 10,413 participants (4,005 men and 6,408 women) from a multi-center population-based cohort study in Japan (The Jichi Medical School cohort study). The average age at registration was 55.0 years, and the median observation period was 4,559 days. As the estimated hazard ratio was high for both the low and very high Lp(a) levels, we defined two Lp(a) groups: a low Lp(a) group [Lp(a)<80 mg/L] and an intermediate-to-high Lp(a) group [Lp(a) >= 80]. Participants who died from malignant neoplasms (n = 316), cardiovascular disease (202), or other causes (312) during the observation period were examined. RESULTS: Cumulative incidence plots showed higher cumulative death rates for the low Lp(a) group than for the intermediate-to-high Lp(a) group for all-cause, cancer, and miscellaneous-cause deaths (p<0.001, p = 0.03, and p = 0.03, respectively). Cox proportional hazards analyses with the sex and age of the participants, body mass index, and smoking and drinking histories as covariates showed that a low Lp(a) level was a significant risk for all-cause, cancer, and miscellaneous-cause deaths (p<0.001, p = 0.003, and p = 0.01, respectively). The hazard ratio (95% CI) [1.48, 1.15 1.92] of a low Lp(a) level for cancer deaths was almost the same as that for a male sex (1.46, 1.00-2.13). CONCLUSIONS: This is the first report to describe the association between a low Lp(a) level and all-cause or cancer death, supporting the anti-neoplastic effect of Lp(a). Further epidemiological studies are needed to confirm the present results. PMID- 22485130 TI - Old world monkeys compare to apes in the primate cognition test battery. AB - Understanding the evolution of intelligence rests on comparative analyses of brain sizes as well as the assessment of cognitive skills of different species in relation to potential selective pressures such as environmental conditions and social organization. Because of the strong interest in human cognition, much previous work has focused on the comparison of the cognitive skills of human toddlers to those of our closest living relatives, i.e. apes. Such analyses revealed that apes and children have relatively similar competencies in the physical domain, while human children excel in the socio-cognitive domain; in particular in terms of attention sharing, cooperation, and mental state attribution. To develop a full understanding of the evolutionary dynamics of primate intelligence, however, comparative data for monkeys are needed. We tested 18 Old World monkeys (long-tailed macaques and olive baboons) in the so-called Primate Cognition Test Battery (PCTB) (Herrmann et al. 2007, Science). Surprisingly, our tests revealed largely comparable results between Old World monkeys and the Great apes. Single comparisons showed that chimpanzees performed only better than the macaques in experiments on spatial understanding and tool use, but in none of the socio-cognitive tasks. These results question the clear cut relationship between cognitive performance and brain size and--prima facie- support the view of an accelerated evolution of social intelligence in humans. One limitation, however, is that the initial experiments were devised to tap into human specific skills in the first place, thus potentially underestimating both true nonhuman primate competencies as well as species differences. PMID- 22485131 TI - The role of mislocalized phototransduction in photoreceptor cell death of retinitis pigmentosa. AB - Most of inherited retinal diseases such as retinitis pigmentosa (RP) cause photoreceptor cell death resulting in blindness. RP is a large family of diseases in which the photoreceptor cell death can be caused by a number of pathways. Among them, light exposure has been reported to induce photoreceptor cell death. However, the detailed mechanism by which photoreceptor cell death is caused by light exposure is unclear. In this study, we have shown that even a mild light exposure can induce ectopic phototransduction and result in the acceleration of rod photoreceptor cell death in some vertebrate models. In ovl, a zebrafish model of outer segment deficiency, photoreceptor cell death is associated with light exposure. The ovl larvae show ectopic accumulation of rhodopsin and knockdown of ectopic rhodopsin and transducin rescue rod photoreceptor cell death. However, knockdown of phosphodiesterase, the enzyme that mediates the next step of phototransduction, does not. So, ectopic phototransduction activated by light exposure, which leads to rod photoreceptor cell death, is through the action of transducin. Furthermore, we have demonstrated that forced activation of adenylyl cyclase in the inner segment leads to rod photoreceptor cell death. For further confirmation, we have also generated a transgenic fish which possesses a human rhodopsin mutation, Q344X. This fish and rd10 model mice show photoreceptor cell death caused by adenylyl cyclase. In short, our study indicates that in some RP, adenylyl cyclase is involved in photoreceptor cell death pathway; its inhibition is potentially a logical approach for a novel RP therapy. PMID- 22485132 TI - Fstl1 antagonizes BMP signaling and regulates ureter development. AB - Bone morphogenetic protein (BMP) signaling pathway plays important roles in urinary tract development although the detailed regulation of its activity in this process remains unclear. Here we report that follistatin-like 1 (Fstl1), encoding a secreted extracellular glycoprotein, is expressed in developing ureter and antagonizes BMP signaling activity. Mouse embryos carrying disrupted Fstl1 gene displayed prominent hydroureter arising from proximal segment and ureterovesical junction defects. These defects were associated with significant reduction in ureteric epithelial cell proliferation at E15.5 and E16.5 as well as absence of subepithelial ureteral mesenchymal cells in the urinary tract at E16.5 and E18.5. At the molecular level, increased BMP signaling was found in Fstl1 deficient ureters, indicated by elevated pSmad1/5/8 activity. In vitro study also indicated that Fstl1 can directly bind to ALK6 which is specifically expressed in ureteric epithelial cells in developing ureter. Furthermore, Sonic hedgehog (SHH) signaling, which is crucial for differentiation of ureteral subepithelial cell proliferation, was also impaired in Fstl1(-/-) ureter. Altogether, our data suggest that Fstl1 is essential in maintaining normal ureter development by antagonizing BMP signaling. PMID- 22485133 TI - Contribution of cerebellar sensorimotor adaptation to hippocampal spatial memory. AB - Complementing its primary role in motor control, cerebellar learning has also a bottom-up influence on cognitive functions, where high-level representations build up from elementary sensorimotor memories. In this paper we examine the cerebellar contribution to both procedural and declarative components of spatial cognition. To do so, we model a functional interplay between the cerebellum and the hippocampal formation during goal-oriented navigation. We reinterpret and complete existing genetic behavioural observations by means of quantitative accounts that cross-link synaptic plasticity mechanisms, single cell and population coding properties, and behavioural responses. In contrast to earlier hypotheses positing only a purely procedural impact of cerebellar adaptation deficits, our results suggest a cerebellar involvement in high-level aspects of behaviour. In particular, we propose that cerebellar learning mechanisms may influence hippocampal place fields, by contributing to the path integration process. Our simulations predict differences in place-cell discharge properties between normal mice and L7-PKCI mutant mice lacking long-term depression at cerebellar parallel fibre-Purkinje cell synapses. On the behavioural level, these results suggest that, by influencing the accuracy of hippocampal spatial codes, cerebellar deficits may impact the exploration-exploitation balance during spatial navigation. PMID- 22485134 TI - Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients. AB - PURPOSE: Dendritic cell (DC) vaccines have recently emerged as an innovative therapeutic option for glioblastoma patients. To identify novel surrogates of anti-tumor immune responsiveness, we studied the dynamic expression of activation and inhibitory markers on peripheral blood lymphocyte (PBL) subsets in glioblastoma patients treated with DC vaccination at UCLA. EXPERIMENTAL DESIGN: Pre-treatment and post-treatment PBL from 24 patients enrolled in two Phase I clinical trials of dendritic cell immunotherapy were stained and analyzed using flow cytometry. A univariate Cox proportional hazards model was utilized to investigate the association between continuous immune monitoring variables and survival. Finally, the immune monitoring variables were dichotomized and a recursive partitioning survival tree was built to obtain cut-off values predictive of survival. RESULTS: The change in regulatory T cell (CD3(+)CD4(+)CD25(+)CD127(low)) frequency in PBL was significantly associated with survival (p = 0.0228; hazard ratio = 3.623) after DC vaccination. Furthermore, the dynamic expression of the negative co-stimulatory molecule, CTLA 4, was also significantly associated with survival on CD3(+)CD4(+) T cells (p = 0.0191; hazard ratio = 2.840) and CD3(+)CD8(+) T cells (p = 0.0273; hazard ratio = 2.690), while that of activation markers (CD25, CD69) was not. Finally, a recursive partitioning tree algorithm was utilized to dichotomize the post/pre fold change immune monitoring variables. The resultant cut-off values from these immune monitoring variables could effectively segregate these patients into groups with significantly different overall survival curves. CONCLUSIONS: Our results suggest that monitoring the change in regulatory T cell frequencies and dynamic expression of the negative co-stimulatory molecules on peripheral blood T cells, before and after DC vaccination, may predict survival. The cut-off point generated from these data can be utilized in future prospective immunotherapy trials to further evaluate its predictive validity. PMID- 22485137 TI - Some commonly used brominated flame retardants cause Ca2+-ATPase inhibition, beta amyloid peptide release and apoptosis in SH-SY5Y neuronal cells. AB - Brominated flame retardants (BFRs) are chemicals commonly used to reduce the flammability of consumer products and are considered pollutants since they have become widely dispersed throughout the environment and have also been shown to bio-accumulate within animals and man. This study investigated the cytotoxicity of some of the most commonly used groups of BFRs on SH-SY5Y human neuroblastoma cells. The results showed that of the BFRs tested, hexabromocyclododecane (HBCD), tetrabromobisphenol-A (TBBPA) and decabromodiphenyl ether (DBPE), all are cytotoxic at low micromolar concentrations (LC(50) being 2.7 +/- 0.7 uM, 15 +/- 4 uM and 28 +/- 7 uM, respectively). They induced cell death, at least in part, by apoptosis through activation of caspases. They also increased intracellular [Ca(2+)] levels and reactive-oxygen-species within these neuronal cells. Furthermore, these BFRs also caused rapid depolarization of the mitochondria and cytochrome c release in these neuronal cells. Elevated intracellular [Ca(2+)] levels appear to occur through a mechanism involving microsomal Ca(2+)-ATPase inhibition and this maybe responsible for Ca(2+)-induced mitochondrial dysfunction. In addition, uM levels of these BFRs caused beta-amyloid peptide (Abeta-42) processing and release from these cells with a few hours of exposure. These results therefore shows that these pollutants are both neurotoxic and amyloidogenic in-vitro. PMID- 22485136 TI - Skin regeneration in adult axolotls: a blueprint for scar-free healing in vertebrates. AB - While considerable progress has been made towards understanding the complex processes and pathways that regulate human wound healing, regenerative medicine has been unable to develop therapies that coax the natural wound environment to heal scar-free. The inability to induce perfect skin regeneration stems partly from our limited understanding of how scar-free healing occurs in a natural setting. Here we have investigated the wound repair process in adult axolotls and demonstrate that they are capable of perfectly repairing full thickness excisional wounds made on the flank. In the context of mammalian wound repair, our findings reveal a substantial reduction in hemostasis, reduced neutrophil infiltration and a relatively long delay in production of new extracellular matrix (ECM) during scar-free healing. Additionally, we test the hypothesis that metamorphosis leads to scarring and instead show that terrestrial axolotls also heal scar-free, albeit at a slower rate. Analysis of newly forming dermal ECM suggests that low levels of fibronectin and high levels of tenascin-C promote regeneration in lieu of scarring. Lastly, a genetic analysis during wound healing comparing epidermis between aquatic and terrestrial axolotls suggests that matrix metalloproteinases may regulate the fibrotic response. Our findings outline a blueprint to understand the cellular and molecular mechanisms coordinating scar free healing that will be useful towards elucidating new regenerative therapies targeting fibrosis and wound repair. PMID- 22485138 TI - Topological analysis of small leucine-rich repeat proteoglycan nyctalopin. AB - Nyctalopin is a small leucine rich repeat proteoglycan (SLRP) whose function is critical for normal vision. The absence of nyctalopin results in the complete form of congenital stationary night blindness. Normally, glutamate released by photoreceptors binds to the metabotropic glutamate receptor type 6 (GRM6), which through a G-protein cascade closes the non-specific cation channel, TRPM1, on the dendritic tips of depolarizing bipolar cells (DBCs) in the retina. Nyctalopin has been shown to interact with TRPM1 and expression of TRPM1 on the dendritic tips of the DBCs is dependent on nyctalopin expression. In the current study, we used yeast two hybrid and biochemical approaches to investigate whether murine nyctalopin was membrane bound, and if so by what mechanism, and also whether the functional form was as a homodimer. Our results show that murine nyctalopin is anchored to the plasma membrane by a single transmembrane domain, such that the LRR domain is located in the extracellular space. PMID- 22485135 TI - Circadian gene variants and susceptibility to type 2 diabetes: a pilot study. AB - BACKGROUND: Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs) in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants. METHODOLOGY/PRINCIPAL FINDINGS: The pilot study was performed using two genetically homogeneous Punjabi cohorts, one resident in the United Kingdom and one indigenous to Pakistan. Subjects with (N = 1732) and without (N = 1780) type 2 diabetes were genotyped for thirteen circadian variants using a competitive allele-specific polymerase chain reaction method. Associations between the SNPs and type 2 diabetes were investigated using logistic regression. The results were also combined with in silico data from other South Asian datasets (SAT2D consortium) and white European cohorts (DIAGRAM+) using meta-analysis. The rs7602358G allele near PER2 was negatively associated with type 2 diabetes in our Punjabi cohorts (combined odds ratio [OR] = 0.75 [0.66-0.86], p = 3.18 * 10(-5)), while the BMAL1 rs11022775T allele was associated with an increased risk of the disease (combined OR = 1.22 [1.07-1.39], p = 0.003). Neither of these associations was replicated in the SAT2D or DIAGRAM+ datasets, however. Meta-analysis of all the cohorts identified disease associations with two variants, rs2292912 in CRY2 and rs12315175 near CRY1, although statistical significance was nominal (combined OR = 1.05 [1.01 1.08], p = 0.008 and OR = 0.95 [0.91-0.99], p = 0.015 respectively). CONCLUSIONS/SIGNIFICANCE: None of the selected circadian gene variants was associated with type 2 diabetes with study-wide significance after meta-analysis. The nominal association observed with the CRY2 SNP, however, complements previous findings and confirms a role for this locus in disease susceptibility. PMID- 22485139 TI - Inhibition of mesothelin as a novel strategy for targeting cancer cells. AB - Mesothelin, a differentiation antigen present in a series of malignancies such as mesothelioma, ovarian, lung and pancreatic cancer, has been studied as a marker for diagnosis and a target for immunotherapy. We, however, were interested in evaluating the effects of direct targeting of Mesothelin on the viability of cancer cells as the first step towards developing a novel therapeutic strategy. We report here that gene specific silencing for Mesothelin by distinct methods (siRNA and microRNA) decreased viability of cancer cells from different origins such as mesothelioma (H2373), ovarian cancer (Skov3 and Ovcar-5) and pancreatic cancer (Miapaca2 and Panc-1). Additionally, the invasiveness of cancer cells was also significantly decreased upon such treatment. We then investigated pro oncogenic signaling characteristics of cells upon mesothelin-silencing which revealed a significant decrease in phospho-ERK1 and PI3K/AKT activity. The molecular mechanism of reduced invasiveness was connected to the reduced expression of beta-Catenin, an important marker of EMT (epithelial-mesenchymal transition). Ero1, a protein involved in clearing unfolded proteins and a member of the ER-Stress (endoplasmic reticulum-stress) pathway was also markedly reduced. Furthermore, Mesothelin silencing caused a significant increase in fraction of cancer cells in S-phase. In next step, treatment of ovarian cancer cells (OVca429) with a lentivirus expressing anti-mesothelin microRNA resulted in significant loss of viability, invasiveness, and morphological alterations. Therefore, we propose the inhibition of Mesothelin as a potential novel strategy for targeting human malignancies. PMID- 22485140 TI - Measuring adiposity in patients: the utility of body mass index (BMI), percent body fat, and leptin. AB - BACKGROUND: Obesity is a serious disease that is associated with an increased risk of diabetes, hypertension, heart disease, stroke, and cancer, among other diseases. The United States Centers for Disease Control and Prevention (CDC) estimates a 20% obesity rate in the 50 states, with 12 states having rates of over 30%. Currently, the body mass index (BMI) is most commonly used to determine adiposity. However, BMI presents as an inaccurate obesity classification method that underestimates the epidemic and contributes to failed treatment. In this study, we examine the effectiveness of precise biomarkers and duel-energy x-ray absorptiometry (DXA) to help diagnose and treat obesity. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study of adults with BMI, DXA, fasting leptin and insulin results were measured from 1998-2009. Of the participants, 63% were females, 37% were males, 75% white, with a mean age = 51.4 (SD = 14.2). Mean BMI was 27.3 (SD = 5.9) and mean percent body fat was 31.3% (SD = 9.3). BMI characterized 26% of the subjects as obese, while DXA indicated that 64% of them were obese. 39% of the subjects were classified as non-obese by BMI, but were found to be obese by DXA. BMI misclassified 25% men and 48% women. Meanwhile, a strong relationship was demonstrated between increased leptin and increased body fat. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate the prevalence of false negative BMIs, increased misclassifications in women of advancing age, and the reliability of gender-specific revised BMI cutoffs. BMI underestimates obesity prevalence, especially in women with high leptin levels (>30 ng/mL). Clinicians can use leptin-revised levels to enhance the accuracy of BMI estimates of percentage body fat when DXA is unavailable. PMID- 22485141 TI - Correlates of cooperation in a one-shot high-stakes televised prisoners' dilemma. AB - Explaining cooperation between non-relatives is a puzzle for both evolutionary biology and the social sciences. In humans, cooperation is often studied in a laboratory setting using economic games such as the prisoners' dilemma. However, such experiments are sometimes criticized for being played for low stakes and by misrepresentative student samples. Golden balls is a televised game show that uses the prisoners' dilemma, with a diverse range of participants, often playing for very large stakes. We use this non-experimental dataset to investigate the factors that influence cooperation when "playing" for considerably larger stakes than found in economic experiments. The game show has earlier stages that allow for an analysis of lying and voting decisions. We found that contestants were sensitive to the stakes involved, cooperating less when the stakes were larger in both absolute and relative terms. We also found that older contestants were more likely to cooperate, that liars received less cooperative behavior, but only if they told a certain type of lie, and that physical contact was associated with reduced cooperation, whereas laughter and promises were reliable signals or cues of cooperation, but were not necessarily detected. PMID- 22485142 TI - Methylsulfonylmethane suppresses breast cancer growth by down-regulating STAT3 and STAT5b pathways. AB - Breast cancer is the most aggressive form of all cancers, with high incidence and mortality rates. The purpose of the present study was to investigate the molecular mechanism by which methylsulfonylmethane (MSM) inhibits breast cancer growth in mice xenografts. MSM is an organic sulfur-containing natural compound without any toxicity. In this study, we demonstrated that MSM substantially decreased the viability of human breast cancer cells in a dose-dependent manner. MSM also suppressed the phosphorylation of STAT3, STAT5b, expression of IGF-1R, HIF-1alpha, VEGF, BrK, and p-IGF-1R and inhibited triple-negative receptor expression in receptor-positive cell lines. Moreover, MSM decreased the DNA binding activities of STAT5b and STAT3, to the target gene promoters in MDA-MB 231 or co-transfected COS-7 cells. We confirmed that MSM significantly decreased the relative luciferase activities indicating crosstalk between STAT5b/IGF-1R, STAT5b/HSP90alpha, and STAT3/VEGF. To confirm these findings in vivo, xenografts were established in Balb/c athymic nude mice with MDA-MB 231 cells and MSM was administered for 30 days. Concurring to our in vitro analysis, these xenografts showed decreased expression of STAT3, STAT5b, IGF-1R and VEGF. Through in vitro and in vivo analysis, we confirmed that MSM can effectively regulate multiple targets including STAT3/VEGF and STAT5b/IGF-1R. These are the major molecules involved in tumor development, progression, and metastasis. Thus, we strongly recommend the use of MSM as a trial drug for treating all types of breast cancers including triple-negative cancers. PMID- 22485143 TI - Long time to diagnosis of medulloblastoma in children is not associated with decreased survival or with worse neurological outcome. AB - BACKGROUND: The long time to diagnosis of medulloblastoma, one of the most frequent brain tumors in children, is the source of painful remorse and sometimes lawsuits. We analyzed its consequences for tumor stage, survival, and sequelae. PATIENTS AND METHODS: This retrospective population-based cohort study included all cases of pediatric medulloblastoma from a region of France between 1990 and 2005. We collected the demographic, clinical, and tumor data and analyzed the relations between the interval from symptom onset until diagnosis, initial disease stage, survival, and neuropsychological and neurological outcome. RESULTS: The median interval from symptom onset until diagnosis for the 166 cases was 65 days (interquartile range 31-121, range 3-457). A long interval (defined as longer than the median) was associated with a lower frequency of metastasis in the univariate and multivariate analyses and with a larger tumor volume, desmoplastic histology, and longer survival in the univariate analysis, but not after adjustment for confounding factors. The time to diagnosis was significantly associated with IQ score among survivors. No significant relation was found between the time to diagnosis and neurological disability. In the 62 patients with metastases, a long prediagnosis interval was associated with a higher T stage, infiltration of the fourth ventricle floor, and incomplete surgical resection; it nonetheless did not influence survival significantly in this subgroup. CONCLUSIONS: We found complex and often inverse relations between time to diagnosis of medulloblastoma in children and initial severity factors, survival, and neuropsychological and neurological outcome. This interval appears due more to the nature of the tumor and its progression than to parental or medical factors. These conclusions should be taken into account in the information provided to parents and in expert assessments produced for malpractice claims. PMID- 22485144 TI - Gene expression profile of adult human olfactory bulb and embryonic neural stem cell suggests distinct signaling pathways and epigenetic control. AB - Global gene expression profiling was performed using RNA from human embryonic neural stem cells (hENSC), and adult human olfactory bulb-derived neural stem cells (OBNSCs), to define a gene expression pattern and signaling pathways that are specific for each cell lineage. We have demonstrated large differences in the gene expression profile of human embryonic NSC, and adult human OBNSCs, but less variability between parallel cultures. Transcripts of genes involved in neural tube development and patterning (ALDH1A2, FOXA2), progenitor marker genes (LMX1a, ALDH1A1, SOX10), proliferation of neural progenitors (WNT1 and WNT3a), neuroplastin (NPTN), POU3F1 (OCT6), neuroligin (NLGN4X), MEIS2, and NPAS1 were up regulated in both cell populations. By Gene Ontology, 325 out of 3875 investigated gene sets were scientifically different. 41 out of the 307 investigated Cellular Component (CC) categories, 45 out of the 620 investigated Molecular Function (MF) categories, and 239 out of the 2948 investigated Biological Process (BP) categories were significant. KEGG Pathway Class Comparison had revealed that 75 out of 171 investigated gene sets passed the 0.005 significance threshold. Levels of gene expression were explored in three signaling pathways, Notch, Wnt, and mTOR that are known to be involved in NS cell fates determination. The transcriptional signature also deciphers the role of genes involved in epigenetic modifications. SWI/SNF DNA chromatin remodeling complex family, including SMARCC1 and SMARCE1, were found specifically up regulated in our OBNSC but not in hENSC. Differences in gene expression profile of transcripts controlling epigenetic modifications, and signaling pathways might indicate differences in the therapeutic potential of our examined two cell populations in relation to in cell survival, proliferation, migration, and differentiation following engraftments in different CNS insults. PMID- 22485145 TI - Quantitative X-ray tomography of the mouse cochlea. AB - Imaging with hard X-rays allows visualizing cochlear structures while maintaining intrinsic qualities of the tissue, including structure and size. With coherent X rays, soft tissues, including membranes, can be imaged as well as cells making use of the so-called in-line phase contrast. In the present experiments, partially coherent synchrotron radiation has been used for micro-tomography. Three-dimensional reconstructions of the mouse cochlea have been created using the EM3D software and the volume has been segmented in the Amira Software Suite. The structures that have been reconstructed include scala tympani, scala media, scala vestibuli, Reissner's membrane, basilar membrane, tectorial membrane, organ of Corti, spiral limbus, spiral ganglion and cochlear nerve. Cross-sectional areas of the scalae were measured. The results provide a realistic and quantitative reconstruction of the cochlea. PMID- 22485146 TI - Host shifts from Lamiales to Brassicaceae in the sawfly genus Athalia. AB - Plant chemistry can be a key driver of host shifts in herbivores. Several species in the sawfly genus Athalia are important economic pests on Brassicaceae, whereas other Athalia species are specialized on Lamiales. These host plants have glucosides in common, which are sequestered by larvae. To disentangle the possible direction of host shifts in this genus, we examined the sequestration specificity and feeding deterrence of iridoid glucosides (IGs) and glucosinolates (GSs) in larvae of five species which either naturally sequester IGs from their hosts within the Plantaginaceae (Lamiales) or GSs from Brassicaceae, respectively. Furthermore, adults were tested for feeding stimulation by a neo clerodane diterpenoid which occurs in Lamiales. Larvae of the Plantaginaceae feeders did not sequester artificially administered p-hydroxybenzylGS and were more deterred by GSs than Brassicaceae-feeders were by IGs. In contrast, larvae of Brassicaceae-feeders were able to sequester artificially administered catalpol (IG), which points to an ancestral association with Lamiales. In line with this finding, adults of all tested species were stimulated by the neo-clerodane diterpenoid. Finally, in a phylogenetic tree inferred from genetic marker sequences of 21 Athalia species, the sister species of all remaining 20 Athalia species also turned out to be a Lamiales-feeder. Fundamental physiological pre adaptations, such as the establishment of a glucoside transporter, and mechanisms to circumvent activation of glucosides by glucosidases are therefore necessary prerequisites for successful host shifts between Lamiales and Brassicaceae. PMID- 22485147 TI - Tanshinones inhibit the growth of breast cancer cells through epigenetic modification of Aurora A expression and function. AB - The objectives of this study were to evaluate the effects of tanshinones from a Chinese herb Salvia Miltiorrhiza on the growth of breast cancer cells, and to elucidate cellular and molecular mechanisms of action. Tanshinones showed the dose-dependent effect on the growth inhibition of breast cancer cells in vitro, with tanshinone I (T1) the most potent agent. T1 was also the only tanshinone to have potent activity in inhibiting the growth of the triple-negative breast cancer cell line MDA-MB231. T1 caused cell cycle arrests of both estrogen dependent and estrogen-independent cell lines associated with alterations of cyclinD, CDK4 and cyclinB, and induced breast cancer cell apoptosis associated with upregulation of c-PARP and downregulation of survivin and Aurora A. Among these associated biomarkers, Aurora A showed the most consistent pattern with the anti-growth activity of tanshinones. Overexpression of Aurora A was also verified in breast tumors. The gene function assay showed that knockdown of Aurora A by siRNA dramatically reduced the growth-inhibition and apoptosis-induction activities of T1, suggesting Aurora A as an important functional target of T1 action. On the other hand, tanshinones had much less adverse effects on normal mammary epithelial cells. Epigenetic mechanism studies showed that overexpression of Aurora A gene in breast cancer cells was not regulated by gene promoter DNA methylation, but by histone acetylation. T1 treatment significantly reduced acetylation levels of histone H3 associated with Aurora A gene. Our results supported the potent activity of T1 in inhibiting the growth of breast cancer cells in vitro in part by downregulation of Aurora A gene function. Our previous studies also demonstrated that T1 had potent anti-angiogenesis activity and minimal side effects in vivo. Altogether, this study warrants further investigation to develop T1 as an effective and safe agent for the therapy and prevention of breast cancer. PMID- 22485148 TI - Pitch enumeration: failure to subitize in audition. AB - BACKGROUND: Subitizing involves recognition mechanisms that allow effortless enumeration of up to four visual objects, however despite ample resolution experimental data suggest that only one pitch can be reliably enumerated. This may be due to the grouping of tones according to harmonic relationships by recognition mechanisms prior to fine pitch processing. Poorer frequency resolution of auditory information available to recognition mechanisms may lead to unrelated tones being grouped, resulting in underestimation of pitch number. METHODS, RESULTS AND CONCLUSION: We tested whether pitch enumeration is better for chords of full harmonic complex tones, where grouping errors are less likely, than for complexes with fewer and less accurately tuned harmonics. Chords of low familiarity were used to mitigate the possibility that participants would recognize the chord itself and simply recall the number of pitches. We found that accuracy of pitch enumeration was less than the visual system overall, and underestimation of pitch number increased for stimuli containing fewer harmonics. We conclude that harmonically related tones are first grouped at the poorer frequency resolution of the auditory nerve, leading to poor enumeration of more than one pitch. PMID- 22485149 TI - Blockade of fatty acid synthase triggers significant apoptosis in mantle cell lymphoma. AB - Fatty acid synthase (FASN), a key player in the de novo synthetic pathway of long chain fatty acids, has been shown to contribute to the tumorigenesis in various types of solid tumors. We here report that FASN is highly and consistently expressed in mantle cell lymphoma (MCL), an aggressive form of B-cell lymphoid malignancy. Specifically, the expression of FASN was detectable in all four MCL cell lines and 15 tumors examined. In contrast, benign lymphoid tissues and peripheral blood mononuclear cells from normal donors were negative. Treatment of MCL cell lines with orlistat, a FASN inhibitor, resulted in significant apoptosis. Knockdown of FASN expression using siRNA, which also significantly decreased the growth of MCL cells, led to a dramatic decrease in the cyclin D1 level. beta-catenin, which has been previously reported to be upregulated in a subset of MCL tumors, contributed to the high level of FASN in MCL cells, Interesting, siRNA knock-down of FASN in turn down-regulated beta-catenin. In conclusion, our data supports the concept that FASN contributes to the pathogenesis of MCL, by collaborating with beta-catenin. In view of its high and consistent expression in MCL, FASN inhibitors may hold promises for treating MCL. PMID- 22485150 TI - Regulation of expression of citrate synthase by the retinoic acid receptor related orphan receptor alpha (RORalpha). AB - The retinoic acid receptor-related orphan receptor alpha (RORalpha) is a member of the nuclear receptor superfamily of transcription factors that plays an important role in regulation of the circadian rhythm and metabolism. Mice lacking a functional RORalpha display a range of metabolic abnormalities including decreased serum cholesterol and plasma triglycerides. Citrate synthase (CS) is a key enzyme of the citric acid cycle that provides energy for cellular function. Additionally, CS plays a critical role in providing citrate derived acetyl-CoA for lipogenesis and cholesterologenesis. Here, we identified a functional RORalpha response element (RORE) in the promoter of the CS gene. ChIP analysis demonstrates RORalpha occupancy of the CS promoter and a putative RORE binds to RORalpha effectively in an electrophoretic mobility shift assay and confers RORalpha responsiveness to a reporter gene in a cotransfection assay. We also observed a decrease in CS gene expression and CS enzymatic activity in the staggerer mouse, which has a mutation of in the Rora gene resulting in nonfunctional RORalpha protein. Furthermore, we found that SR1001 a RORalpha inverse agonist eliminated the circadian pattern of expression of CS mRNA in mice. These data suggest that CS is a direct RORalpha target gene and one mechanism by which RORalpha regulates lipid metabolism is via regulation of CS expression. PMID- 22485151 TI - Mitochondrial bioenergetic alterations in mouse neuroblastoma cells infected with Sindbis virus: implications to viral replication and neuronal death. AB - The metabolic resources crucial for viral replication are provided by the host. Details of the mechanisms by which viruses interact with host metabolism, altering and recruiting high free-energy molecules for their own replication, remain unknown. Sindbis virus, the prototype of and most widespread alphavirus, causes outbreaks of arthritis in humans and serves as a model for the study of the pathogenesis of neurological diseases induced by alphaviruses in mice. In this work, respirometric analysis was used to evaluate the effects of Sindbis virus infection on mitochondrial bioenergetics of a mouse neuroblastoma cell lineage, Neuro 2a. The modulation of mitochondrial functions affected cellular ATP content and this was synchronous with Sindbis virus replication cycle and cell death. At 15 h, irrespective of effects on cell viability, viral replication induced a decrease in oxygen consumption uncoupled to ATP synthesis and a 36% decrease in maximum uncoupled respiration, which led to an increase of 30% in the fraction of oxygen consumption used for ATP synthesis. Decreased proton leak associated to complex I respiration contributed to the apparent improvement of mitochondrial function. Cellular ATP content was not affected by infection. After 24 h, mitochondria dysfunction was clearly observed as maximum uncoupled respiration reduced 65%, along with a decrease in the fraction of oxygen consumption used for ATP synthesis. Suppressed respiration driven by complexes I- and II-related substrates seemed to play a role in mitochondrial dysfunction. Despite the increase in glucose uptake and glycolytic flux, these changes were followed by a 30% decrease in ATP content and neuronal death. Taken together, mitochondrial bioenergetics is modulated during Sindbis virus infection in such a way as to favor ATP synthesis required to support active viral replication. These early changes in metabolism of Neuro 2a cells may form the molecular basis of neuronal dysfunction and Sindbis virus-induced encephalitis. PMID- 22485152 TI - EEG-fMRI based information theoretic characterization of the human perceptual decision system. AB - The modern metaphor of the brain is that of a dynamic information processing device. In the current study we investigate how a core cognitive network of the human brain, the perceptual decision system, can be characterized regarding its spatiotemporal representation of task-relevant information. We capitalize on a recently developed information theoretic framework for the analysis of simultaneously acquired electroencephalography (EEG) and functional magnetic resonance imaging data (fMRI) (Ostwald et al. (2010), NeuroImage 49: 498-516). We show how this framework naturally extends from previous validations in the sensory to the cognitive domain and how it enables the economic description of neural spatiotemporal information encoding. Specifically, based on simultaneous EEG-fMRI data features from n = 13 observers performing a visual perceptual decision task, we demonstrate how the information theoretic framework is able to reproduce earlier findings on the neurobiological underpinnings of perceptual decisions from the response signal features' marginal distributions. Furthermore, using the joint EEG-fMRI feature distribution, we provide novel evidence for a highly distributed and dynamic encoding of task-relevant information in the human brain. PMID- 22485153 TI - Shift work disorder in nurses--assessment, prevalence and related health problems. AB - BACKGROUND: This study investigates the prevalence of symptoms of shift work disorder in a sample of nurses, and its association to individual, health and work variables. METHODOLOGY/PRINCIPAL FINDINGS: We investigated three different shift work disorder assessment procedures all based on current diagnostic criteria and employing symptom based questions. Crude and adjusted logistic regression analyses were performed with symptoms of shift work disorder as the dependent variable. Participants (n = 1968) reported age, gender, work schedule, commuting time, weekly work hours, children in household, number of nights and number of shifts separated by less than 11 hours worked the last year, use of bright light therapy, melatonin and sleep medication, and completed the Bergen Insomnia Scale, Epworth Sleepiness Scale, Global Sleep Assessment Questionnaire, Diurnal Scale, Revised Circadian Type Inventory, Dispositional Resilience (Hardiness) Scale--Revised, Fatigue Questionnaire, questions about alcohol and caffeine consumption, as well as the Hospital Anxiety and Depression Scale. CONCLUSIONS/SIGNIFICANCE: Prevalence rates of symptoms of shift work disorder varied from 32.4-37.6% depending on the assessment method and from 4.8-44.3% depending on the work schedule. Associations were found between symptoms of shift work disorder and age, gender, circadian type, night work, number of shifts separated by less than 11 hours and number of nights worked the last year, insomnia and anxiety. The different assessment procedures yielded similar results (prevalence and logistic regression analyses). The prevalence of symptoms indicative of shift work disorder was high. We argue that three symptom-based questions used in the present study adequately assess shift work disorder in epidemiological studies. PMID- 22485154 TI - Diet-morphology correlations in the radiation of South American geophagine cichlids (Perciformes: Cichlidae: Cichlinae). AB - Genera within the South American cichlid tribe Geophagini display specialized feeding and reproductive strategies, with some taxa specialized for both substrate-sifting and mouth brooding. Several lineages within the clade also possess an epibranchial lobe (EBL), a unique pharyngeal structure that has been proposed to have a function in feeding and/or mouth brooding. A recently published genus-level phylogeny of Neotropical cichlids was used as the evolutionary framework for investigating the evolution of morphological features presumably correlated with diet and mouth brooding in the tribe Geophagini. We tested for possible associations between the geophagine epibranchial lobe and benthic feeding and mouth brooding. We also addressed whether the EBL may be associated with unique patterns of diversification in certain geophagine clades. Tests of binary character correlations revealed the EBL was significantly associated with mouth brooding. We also tested for a relationship between diet and morphology. We analyzed stomach contents and morphometric variation among 21 species, with data for two additional species obtained from the literature. Principal Components Analysis revealed axes of morphological variation significantly correlated with piscivory and benthivory, and both morphology and diet were significantly associated with phylogeny. These results suggest that the EBL could be an adaptation for either feeding or mouth brooding. The EBL, however, was not associated with species richness or accelerated rates of phyletic diversification. PMID- 22485155 TI - In search of critically endangered species: the current situation of two tiny salamander species in the Neotropical mountains of Mexico. AB - Worldwide, one in every three species of amphibian is endangered, 39 species have gone extinct in the last 500 years and another 130 species are suspected to have gone extinct in recent decades. Of the amphibians, salamanders have the highest portion of their species in one of the risk categories, even higher than the frogs. To date there have been few studies that have used recent field data to examine the status of populations of endangered salamanders. In this study we evaluate the current situation of two tiny salamanders, Parvimolge townsendi and Thorius pennatulus, both of which are distributed at intermediate elevations in the mountains of the northern Neotropics and are considered to be critically endangered; the first has been proposed as possibly extinct. By carrying out exhaustive surveys in both historical and potentially suitable sites for these two species, we evaluated their abundance and the characteristics of their habitats, and we estimated their potential geographic distribution. We visited 22 sites, investing 672 person-hours of sampling effort in the surveys, and found 201 P. townsendi salamanders in 11 sites and only 13 T. pennatulus salamanders in 5 sites. Both species were preferentially found in cloud forest fragments that were well conserved or only moderately transformed, and some of the salamanders were found in shade coffee plantations. The potential distribution area of both species is markedly fragmented and we estimate that it has decreased by more than 48%. The results of this study highlight the importance of carrying out exhaustive, systematic field surveys to obtain accurate information about the current situation of critically endangered species, and help us better understand the crisis that amphibians are facing worldwide. PMID- 22485156 TI - Development of a unique small molecule modulator of CXCR4. AB - BACKGROUND: Metastasis, the spread and growth of tumor cells to distant organ sites, represents the most devastating attribute and plays a major role in the morbidity and mortality of cancer. Inflammation is crucial for malignant tumor transformation and survival. Thus, blocking inflammation is expected to serve as an effective cancer treatment. Among anti-inflammation therapies, chemokine modulation is now beginning to emerge from the pipeline. CXC chemokine receptor-4 (CXCR4) and its ligand stromal cell-derived factor-1 (CXCL12) interaction and the resulting cell signaling cascade have emerged as highly relevant targets since they play pleiotropic roles in metastatic progression. The unique function of CXCR4 is to promote the homing of tumor cells to their microenvironment at the distant organ sites. METHODOLOGY/PRINCIPAL FINDINGS: We describe the actions of N,N'-(1,4-phenylenebis(methylene))dipyrimidin-2-amine (designated MSX-122), a novel small molecule and partial CXCR4 antagonist with properties quite unlike that of any other reported CXCR4 antagonists, which was prepared in a single chemical step using a reductive amination reaction. Its specificity toward CXCR4 was tested in a binding affinity assay and a ligand competition assay using (18)F labeled MSX-122. The potency of the compound was determined in two functional assays, Matrigel invasion assay and cAMP modulation. The therapeutic potential of MSX-122 was evaluated in three different murine models for inflammation including an experimental colitis, carrageenan induced paw edema, and bleomycin induced lung fibrosis and three different animal models for metastasis including breast cancer micrometastasis in lung, head and neck cancer metastasis in lung, and uveal melanoma micrometastasis in liver in which CXCR4 was reported to play crucial roles. CONCLUSIONS/SIGNIFICANCE: We developed a novel small molecule, MSX 122, that is a partial CXCR4 antagonist without mobilizing stem cells, which can be safer for long-term blockade of metastasis than other reported CXCR4 antagonists. PMID- 22485157 TI - Tract specific reproducibility of tractography based morphology and diffusion metrics. AB - INTRODUCTION: The reproducibility of tractography is important to determine its sensitivity to pathological abnormalities. The reproducibility of tract morphology has not yet been systematically studied and the recently developed tractography contrast Tract Density Imaging (TDI) has not yet been assessed at the tract specific level. MATERIALS AND METHODS: Diffusion tensor imaging (DTI) and probabilistic constrained spherical deconvolution (CSD) tractography are performed twice in 9 healthy subjects. Tractography is based on common space seed and target regions and performed for several major white matter tracts. Tractograms are converted to tract segmentations and inter-session reproducibility of tract morphology is assessed using Dice similarity coefficient (DSC). The coefficient of variation (COV) and intraclass correlation coefficient (ICC) are calculated of the following tract metrics: fractional anisotropy (FA), apparent diffusion coefficient (ADC), volume, and TDI. Analyses are performed both for proximal (deep white matter) and extended (including subcortical white matter) tract segmentations. RESULTS: Proximal DSC values were 0.70-0.92. DSC values were 5-10% lower in extended compared to proximal segmentations. COV/ICC values of FA, ADC, volume and TDI were 1-4%/0.65-0.94, 2-4%/0.62-0.94, 3-22%/0.53 0.96 and 8-31%/0.48-0.70, respectively, with the lower COV and higher ICC values found in the proximal segmentations. CONCLUSION: For all investigated metrics, reproducibility depended on the segmented tract. FA and ADC had relatively low COV and relatively high ICC, indicating clinical potential. Volume had higher COV but its moderate to high ICC values in most tracts still suggest subject differentiating power. Tract TDI had high COV and relatively low ICC, which reflects unfavorable reproducibility. PMID- 22485158 TI - Treatment with a substance P receptor antagonist is neuroprotective in the intrastriatal 6-hydroxydopamine model of early Parkinson's disease. AB - Neuroinflammation and blood brain barrier (BBB) dysfunction have been implicated in the pathogenesis of Parkinson's disease (PD). The neuropeptide substance P (SP) is an important mediator of both neuroinflammation and BBB dysfunction through its NK1 receptor in a process known as neurogenic inflammation. Increased SP content has previously been reported following 6-OHDA treatment in vitro, with the levels of SP correlating with cell death. The present study used an in vivo 6 OHDA lesion model to determine if dopaminergic degeneration was associated with increased SP in the substantia nigra and whether this degeneration could be prevented by using a SP, NK1 receptor antagonist. Unilateral, intrastriatal 6 OHDA lesions were induced and SP (10 ug/2 uL) or the NK1 receptor antagonists, N acetyl-L-tryptophan (2 uL at 50 nM) or L-333,060 (2 uL at 100 nM), administered immediately after the neurotoxin. Nigral SP content was then determined using immunohistochemical and ELISA methods, neuroinflammation and barrier integrity was assessed using Iba-1, ED-1, GFAP and albumin immunohistochemistry, while dopaminergic cell loss was assessed with tyrosine hydroxylase immunohistochemistry. Motor function in all animals was assessed using the rotarod task. Intrastriatal 6-OHDA lesioning produced an early and sustained increase in ipsilateral nigral SP content, along with a breakdown of the BBB and activation of microglia and astrocytes. Further exacerbation of SP levels accelerated disease progression, whereas NK1 receptor antagonist treatment protected dopaminergic neurons, preserved barrier integrity, reduced neuroinflammation and significantly improved motor function. We propose that neurogenic inflammation contributes to dopaminergic degeneration in early experimental PD and demonstrate that an NK1 receptor antagonist may represent a novel neuroprotective therapy. PMID- 22485159 TI - Structural insights into TIR domain specificity of the bridging adaptor Mal in TLR4 signaling. AB - MyD88 adaptor-like protein (Mal) is a crucial adaptor that acts as a bridge to recruit the MyD88 molecule to activated TLR4 receptors in response to invading pathogens. The specific assembly of the Toll/interleukin-1 receptor (TIR) domains of TLR4, Mal and MyD88 is responsible for proper signal transduction in the TLR4 signaling pathway. However, the molecular mechanism for the specificity of these TIR domains remains unclear. Here, we present the crystal structure of the TIR domain of the human Mal molecule (Mal-TIR) at a resolution of 2.4 A. Unexpectedly, Mal-TIR exhibits an extraordinarily long AB loop, but no alphaB helix or BB loop, distinguishing it from other TIR domains. More importantly, the Mal-TIR AB loop is capable of mediating direct binding to the TIR domains of TLR4 and MyD88 simultaneously. We also found that Mal-TIR can form a back-to-back dimer that may resemble the dimeric assembly of the entire Mal molecule. Our data demonstrate the bridge role of the Mal-TIR domain and provide important information about TIR domain specificity. PMID- 22485160 TI - SweetBac: a new approach for the production of mammalianised glycoproteins in insect cells. AB - Recombinant production of therapeutically active proteins has become a central focus of contemporary life science research. These proteins are often produced in mammalian cells, in order to obtain products with post-translational modifications similar to their natural counterparts. However, in cases where a fast and flexible system for recombinant production of proteins is needed, the use of mammalian cells is limited. The baculoviral insect cell system has proven to be a powerful alternative for the expression of a wide range of recombinant proteins in short time frames. The major drawback of baculoviral systems lies in the inability to perform mammalian-like glycosylation required for the production of therapeutic glycoproteins. In this study we integrated sequences encoding Caenorhabditis elegans N-acetylglucosaminyltransferase II and bovine beta1,4 galactosyltransferase I into the backbone of a baculovirus genome. The thereby generated SweetBac virus was subsequently used for the production of the human HIV anti-gp41 antibody 3D6 by integrating heavy and light chain open reading frames into the SweetBac genome. The parallel expression of target genes and glycosyltransferases reduced the yield of secreted antibody. However, the overall expression rate, especially in the recently established Tnao38 cell line, was comparable to that of transient expression in mammalian cells. In order to evaluate the ability of SweetBac to generate mammalian-like N-glycan structures on 3D6 antibody, we performed SDS-PAGE and tested for the presence of terminal galactose using Riccinus communis agglutinin I. The mammalianised variants of 3D6 showed highly specific binding to the lectin, indicating proper functionality. To confirm these results, PNGase A released N-glycans were analyzed by MALDI-TOF-MS and shown to contain structures with mainly one or two terminal galactose residues. Since the presence of specific N-glycans has an impact on antibodies ability to exert different effector functions, we tested the binding to human Fc gamma receptor I present on U937 cells. PMID- 22485161 TI - Characterisation of bovine leukocyte Ig-like receptors. AB - Leukocyte Immunoglobulin-like receptors (LILR) are innate immune receptors involved in regulating both innate and adaptive immune functions. LILR show more interspecies conservation than the closely related Killer Ig-like receptors, and homologues have been identified in rodents, primates, seals and chickens. The murine equivalents, paired Ig-like receptors (PIR), contain two additional immunoglobulin domains, but show strong sequence and functional similarities to human LILR. The bovine genome was recently sequenced, with preliminary annotations indicating that LILR were present in this species. We therefore sought to identify and characterize novel LILR within the Bos taurus genome, compare these phylogenetically with LILR from other species and determine whether they were expressed in vivo. Twenty six potential bovine LILR were initially identified using BLAST and BLAT software. Phylogenetic analysis constructed using the neighbour-joining method, incorporating pairwise deletion and confidence limits estimated from 1000 replicates using bootstrapping, indicated that 16 of these represent novel bovine LILR. Protein structures defined using protein BLAST predict that the bovine LILR family comprises seven putative inhibitory, four activating and five soluble receptors. Preliminary expression analysis was performed by mapping the predicted sequences with raw data from total transcript sequence generated using Genome Analyzer IIx (Illumina) to provide evidence that all 16 of these receptors are expressed in vivo. The bovine receptor family appears to contain receptors which resemble the six domain rodent PIR as well as the four domain LILR found in other species. PMID- 22485162 TI - Annotation of the M. tuberculosis hypothetical orfeome: adding functional information to more than half of the uncharacterized proteins. AB - The genome of Mycobacterium tuberculosis (H37Rv) contains 4,019 protein coding genes, of which more than thousand have been categorized as 'hypothetical' implying that for these not even weak functional associations could be identified so far. We here predict reliable functional indications for half of this large hypothetical orfeome: 497 genes can be annotated based on orthology, and another 125 can be linked to interacting proteins via integrated genomic context analysis and literature mining. The assignments include newly identified clusters of interacting proteins, hypothetical genes that are associated to well known pathways and putative disease-relevant targets. All together, we have raised the fraction of the proteome with at least some functional annotation to 88% which should considerably enhance the interpretation of large-scale experiments targeting this medically important organism. PMID- 22485164 TI - Stimulation of midbrain dopaminergic structures modifies firing rates of rat lateral habenula neurons. AB - Ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) are midbrain structures known to be involved in mediating reward in rodents. Lateral habenula (LHb) is considered as a negative reward source and it is reported that stimulation of the LHb rapidly induces inhibition of firing in midbrain dopamine neurons. Interestingly, the phasic fall in LHb neuronal activity may follow the excitation of dopamine neurons in response to reward-predicting stimuli. The VTA and SNpc give rise to dopaminergic projections that innervate the LHb, which is also known to be involved in processing painful stimuli. But it's unclear what physiological effects these inputs have on habenular function. In this study we distinguished the LHb pain-activated neurons of the Wistar rats and assessed their electrophysiological responsiveness to the stimulation of the VTA and SNpc with either single-pulse stimulation (300 uA, 0.5 Hz) or tetanic stimulation (80 uA, 25 Hz). Single-pulse stimulation that was delivered to either midbrain structure triggered transient inhibition of firing of ~90% of the LHb pain activated neurons. However, tetanic stimulation of the VTA tended to evoke an elevation in neuronal firing rate. We conclude that LHb pain-activated neurons can receive diverse reward-related signals originating from midbrain dopaminergic structures, and thus participate in the regulation of the brain reward system via both positive and negative feedback mechanisms. PMID- 22485163 TI - A membrane fusion protein alphaSNAP is a novel regulator of epithelial apical junctions. AB - Tight junctions (TJs) and adherens junctions (AJs) are key determinants of the structure and permeability of epithelial barriers. Although exocytic delivery to the cell surface is crucial for junctional assembly, little is known about the mechanisms controlling TJ and AJ exocytosis. This study was aimed at investigating whether a key mediator of exocytosis, soluble N-ethylmaleimide sensitive factor (NSF) attachment protein alpha (alphaSNAP), regulates epithelial junctions. alphaSNAP was enriched at apical junctions in SK-CO15 and T84 colonic epithelial cells and in normal human intestinal mucosa. siRNA-mediated knockdown of alphaSNAP inhibited AJ/TJ assembly and establishment of the paracellular barrier in SK-CO15 cells, which was accompanied by a significant down-regulation of p120-catenin and E-cadherin expression. A selective depletion of p120 catenin effectively disrupted AJ and TJ structure and compromised the epithelial barrier. However, overexpression of p120 catenin did not rescue the defects of junctional structure and permeability caused by alphaSNAP knockdown thereby suggesting the involvement of additional mechanisms. Such mechanisms did not depend on NSF functions or induction of cell death, but were associated with disruption of the Golgi complex and down-regulation of a Golgi-associated guanidine nucleotide exchange factor, GBF1. These findings suggest novel roles for alphaSNAP in promoting the formation of epithelial AJs and TJs by controlling Golgi-dependent expression and trafficking of junctional proteins. PMID- 22485165 TI - BF integrase genes of HIV-1 circulating in Sao Paulo, Brazil, with a recurrent recombination region. AB - Although some studies have shown diversity in HIV integrase (IN) genes, none has focused particularly on the gene evolving in epidemics in the context of recombination. The IN gene in 157 HIV-1 integrase inhibitor-naive patients from the Sao Paulo State, Brazil, were sequenced tallying 128 of subtype B (23 of which were found in non-B genomes), 17 of subtype F (8 of which were found in recombinant genomes), 11 integrases were BF recombinants, and 1 from subtype C. Crucially, we found that 4 BF recombinant viruses shared a recurrent recombination breakpoint region between positions 4900 and 4924 (relative to the HXB2) that includes 2 gRNA loops, where the RT may stutter. Since these recombinants had independent phylogenetic origin, we argue that these results suggest a possible recombination hotspot not observed so far in BF CRF in particular, or in any other HIV-1 CRF in general. Additionally, 40% of the drug naive and 45% of the drug-treated patients had at least 1 raltegravir (RAL) or elvitegravir (EVG) resistance-associated amino acid change, but no major resistance mutations were found, in line with other studies. Importantly, V151I was the most common minor resistance mutation among B, F, and BF IN genes. Most codon sites of the IN genes had higher rates of synonymous substitutions (dS) indicative of a strong negative selection. Nevertheless, several codon sites mainly in the subtype B were found under positive selection. Consequently, we observed a higher genetic diversity in the B portions of the mosaics, possibly due to the more recent introduction of subtype F on top of an ongoing subtype B epidemics and a fast spread of subtype F alleles among the B population. PMID- 22485166 TI - Genome-wide identification of polycomb target genes reveals a functional association of Pho with Scm in Bombyx mori. AB - Polycomb group (PcG) proteins are evolutionarily conserved chromatin modifiers and act together in three multimeric complexes, Polycomb repressive complex 1 (PRC1), Polycomb repressive complex 2 (PRC2), and Pleiohomeotic repressive complex (PhoRC), to repress transcription of the target genes. Here, we identified Polycomb target genes in Bombyx mori with holocentric centromere using genome-wide expression screening based on the knockdown of BmSCE, BmESC, BmPHO, or BmSCM gene, which represent the distinct complexes. As a result, the expressions of 29 genes were up-regulated after knocking down 4 PcG genes. Particularly, there is a significant overlap between targets of BmPho (331 out of 524) and BmScm (331 out of 532), and among these, 190 genes function as regulator factors playing important roles in development. We also found that BmPho, as well as BmScm, can interact with other Polycomb components examined in this study. Further detailed analysis revealed that the C-terminus of BmPho containing zinc finger domain is involved in the interaction between BmPho and BmScm. Moreover, the zinc finger domain in BmPho contributes to its inhibitory function and ectopic overexpression of BmScm is able to promote transcriptional repression by Gal4-Pho fusions including BmScm-interacting domain. Loss of BmPho expression causes relocalization of BmScm into the cytoplasm. Collectively, we provide evidence of a functional link between BmPho and BmScm, and propose two Polycomb related repression mechanisms requiring only BmPho associated with BmScm or a whole set of PcG complexes. PMID- 22485167 TI - Relationship between the composition of flavonoids and flower colors variation in tropical water lily (Nymphaea) cultivars. AB - Water lily, the member of the Nymphaeaceae family, is the symbol of Buddhism and Brahmanism in India. Despite its limited researches on flower color variations and formation mechanism, water lily has background of blue flowers and displays an exceptionally wide diversity of flower colors from purple, red, blue to yellow, in nature. In this study, 34 flavonoids were identified among 35 tropical cultivars by high-performance liquid chromatography (HPLC) with photodiode array detection (DAD) and electrospray ionization mass spectrometry (ESI-MS). Among them, four anthocyanins: delphinidin 3-O-rhamnosyl-5-O-galactoside (Dp3Rh5Ga), delphinidin 3-O-(2"-O-galloyl-6"-O-oxalyl-rhamnoside) (Dp3galloyl-oxalylRh), delphinidin 3-O-(6"-O-acetyl-beta-glucopyranoside) (Dp3acetylG) and cyanidin 3- O (2"-O-galloyl-galactopyranoside)-5-O-rhamnoside (Cy3galloylGa5Rh), one chalcone: chalcononaringenin 2'-O-galactoside (Chal2'Ga) and twelve flavonols: myricetin 7 O-rhamnosyl-(1 -> 2)-rhamnoside (My7RhRh), quercetin 7-O-galactosyl-(1 -> 2) rhamnoside (Qu7GaRh), quercetin 7-O-galactoside (Qu7Ga), kaempferol 7-O galactosyl-(1 -> 2)-rhamnoside (Km7GaRh), myricetin 3-O-galactoside (My3Ga), kaempferol 7-O-galloylgalactosyl-(1 -> 2)-rhamnoside (Km7galloylGaRh), myricetin 3-O-galloylrhamnoside (My3galloylRh), kaempferol 3-O-galactoside (Km3Ga), isorhamnetin 7-O-galactoside (Is7Ga), isorhamnetin 7-O-xyloside (Is7Xy), kaempferol 3-O-(3"-acetylrhamnoside) (Km3-3"acetylRh) and quercetin 3-O acetylgalactoside (Qu3acetylGa) were identified in the petals of tropic water lily for the first time. Meanwhile a multivariate analysis was used to explore the relationship between pigments and flower color. By comparing, the cultivars which were detected delphinidin 3-galactoside (Dp3Ga) presented amaranth, and detected delphinidin 3'-galactoside (Dp3'Ga) presented blue. However, the derivatives of delphinidin and cyanidin were more complicated in red group. No anthocyanins were detected within white and yellow group. At the same time a possible flavonoid biosynthesis pathway of tropical water lily was presumed putatively. These studies will help to elucidate the evolution mechanism on the formation of flower colors and provide theoretical basis for outcross breeding and developing health care products from this plant. PMID- 22485169 TI - A comparison of different approaches to unravel the latent structure within metabolic syndrome. AB - BACKGROUND: Exploratory factor analysis is a commonly used statistical technique in metabolic syndrome research to uncover latent structure amongst metabolic variables. The application of factor analysis requires methodological decisions that reflect the hypothesis of the metabolic syndrome construct. These decisions often raise the complexity of the interpretation from the output. We propose two alternative techniques developed from cluster analysis which can achieve a clinically relevant structure, whilst maintaining intuitive advantages of clustering methodology. METHODS: Two advanced techniques of clustering in the VARCLUS and matroid methods are discussed and implemented on a metabolic syndrome data set to analyze the structure of ten metabolic risk factors. The subjects were selected from the normative aging study based in Boston, Massachusetts. The sample included a total of 847 men aged between 21 and 81 years who provided complete data on selected risk factors during the period 1987 to 1991. RESULTS: Four core components were identified by the clustering methods. These are labelled obesity, lipids, insulin resistance and blood pressure. The exploratory factor analysis with oblique rotation suggested an overlap of the loadings identified on the insulin resistance and obesity factors. The VARCLUS and matroid analyses separated these components and were able to demonstrate associations between individual risk factors. CONCLUSIONS: An oblique rotation can be selected to reflect the clinical concept of a single underlying syndrome, however the results are often difficult to interpret. Factor loadings must be considered along with correlations between the factors. The correlated components produced by the VARCLUS and matroid analyses are not overlapped, which allows for a simpler application of the methodologies and interpretation of the results. These techniques encourage consistency in the interpretation whilst remaining faithful to the construct under study. PMID- 22485170 TI - Modulation of Wnt5a expression by periodontopathic bacteria. AB - Wingless proteins, termed Wnt, are involved in embryonic development, blood cell differentiation, and tumorigenesis. In mammalian hematopoiesis, Wnt signaling is essential for stem-cell homeostasis and lymphocyte differentiation. Recent studies have suggested that these molecules are associated with cardiovascular diseases, rheumatoid arthritis, and osteoarthritis. Furthermore, Wnt5a signaling is essential for the general inflammatory response of human macrophages. Periodontitis is a chronic inflammatory disease caused by gram-negative periodontopathic bacteria and the resultant host immune response. Periodontitis is characterized by loss of tooth-supporting structures and alveolar bone resorption. There have been no previous reports on Wnt5a expression in periodontitis tissue, and only few study reported the molecular mechanisms of Wnt5a expression in LPS-stimulated monocytic cells. Using RT-PCR, we demonstrated that Wnt5a mRNA expression was up-regulated in chronic periodontitis tissue as compared to healthy control tissue. P. gingivalis LPS induced Wnt5a mRNA in the human monocytic cell line THP-1 with a peak at 4 hrs after stimulation. P. gingivalis LPS induced higher up-regulation of Wnt5a mRNA than E. coli LPS. The LPS receptors TLR2 and TLR4 were equally expressed on the surface of THP-1 cells. P. gingivalis LPS induced IkappaBalpha degradation and was able to increase the NF-kappaB binding activity to DNA. P. gingivalis LPS-induced Wnt5a expression was inhibited by NF-kappaB inhibitors, suggesting NF-kappaB involvement. Furthermore, IFN-gamma synergistically enhanced the P. gingivalis LPS-induced production of Wnt5a. Pharmacological investigation and siRNA experiments showed that STAT1 was important for P. gingivalis LPS-induced Wnt5a expression. These results suggest that the modulation of Wnt5a expression by P. gingivalis may play an important role in the periodontal inflammatory process and serve a target for the development of new therapies. PMID- 22485171 TI - Metastasis of neuroendocrine tumors are characterized by increased cell proliferation and reduced expression of the ATM gene. AB - PURPOSE: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare group of tumors with a wide spectrum of clinical behavior. However, there are no known clinically relevant biomarkers to predict metastasis. EXPERIMENTAL DESIGN: To investigate differential gene expression signatures of metastatic vs non metastatic NETs, we studied cell cycle regulatory genes in 19 metastatic and 22 non-metastatic colorectal NETs by PCR arrays. Immunohistochemistry (IHC) and quantitative real-time RT-PCR were performed to verify the results and another set of 38 GEP-NETs were further studied for validation. RESULTS: We first delineated six candidate genes for metastasis including ATM, CCND2, RBL2, CDKN3, CCNB1, and GTSE1. ATM was negatively correlated with metastatic NETs (p<0.001) with more than 2-fold change compared to non-metastatic NETs. Overexpression of ATM protein by IHC was strongly correlated with high ATM mRNA levels and low Ki 67 labeling index. Patients with ATM-negativity by IHC showed significantly decreased overall survival than patients with ATM-positivity (median OS, metastatic vs non-metastatic NETs; 2.7 years vs not reached; p = 0.003) and 85.7% of metastatic NETs were ATM-negative. In another validation set of GEP-NETs, decreased mRNA of ATM gene was associated with metastasis and remained significant (p = 0.023). CONCLUSIONS: ATM down-regulation was strongly associated with metastatic NETs when compared with non-metastatic NETs and ATM may be a potential predictive marker for metastasis as well as a novel target in metastatic GEP-NETs. PMID- 22485168 TI - Multivariate protein signatures of pre-clinical Alzheimer's disease in the Alzheimer's disease neuroimaging initiative (ADNI) plasma proteome dataset. AB - BACKGROUND: Recent Alzheimer's disease (AD) research has focused on finding biomarkers to identify disease at the pre-clinical stage of mild cognitive impairment (MCI), allowing treatment to be initiated before irreversible damage occurs. Many studies have examined brain imaging or cerebrospinal fluid but there is also growing interest in blood biomarkers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) has generated data on 190 plasma analytes in 566 individuals with MCI, AD or normal cognition. We conducted independent analyses of this dataset to identify plasma protein signatures predicting pre-clinical AD. METHODS AND FINDINGS: We focused on identifying signatures that discriminate cognitively normal controls (n = 54) from individuals with MCI who subsequently progress to AD (n = 163). Based on p value, apolipoprotein E (APOE) showed the strongest difference between these groups (p = 2.3 * 10(-13)). We applied a multivariate approach based on combinatorial optimization ((alpha,beta)-k Feature Set Selection), which retains information about individual participants and maintains the context of interrelationships between different analytes, to identify the optimal set of analytes (signature) to discriminate these two groups. We identified 11-analyte signatures achieving values of sensitivity and specificity between 65% and 86% for both MCI and AD groups, depending on whether APOE was included and other factors. Classification accuracy was improved by considering "meta-features," representing the difference in relative abundance of two analytes, with an 8-meta-feature signature consistently achieving sensitivity and specificity both over 85%. Generating signatures based on longitudinal rather than cross-sectional data further improved classification accuracy, returning sensitivities and specificities of approximately 90%. CONCLUSIONS: Applying these novel analysis approaches to the powerful and well-characterized ADNI dataset has identified sets of plasma biomarkers for pre-clinical AD. While studies of independent test sets are required to validate the signatures, these analyses provide a starting point for developing a cost-effective and minimally invasive test capable of diagnosing AD in its pre-clinical stages. PMID- 22485172 TI - The promoter of Rv0560c is induced by salicylate and structurally-related compounds in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a major global health threat. During infection, bacteria are believed to encounter adverse conditions such as iron depletion. Mycobacteria synthesize iron sequestering mycobactins, which are essential for survival in the host, via the intermediate salicylate. Salicylate is a ubiquitous compound which is known to induce a mild antibiotic resistance phenotype. In M. tuberculosis salicylate highly induces the expression of Rv0560c, a putative methyltransferase. We identified and characterized the promoter and regulatory elements of Rv0560c. P(Rv0560c) activity was highly inducible by salicylate in a dose-dependent manner. The induction kinetics of P(Rv0560c) were slow, taking several days to reach maximal activity, which was sustained over several weeks. Promoter activity could also be induced by compounds structurally related to salicylate, such as aspirin or para-aminosalicylic acid, but not by benzoate, indicating that induction is specific to a structural motif. The -10 and -35 promoter elements were identified and residues involved in regulation of promoter activity were identified in close proximity to an inverted repeat spanning the -35 promoter element. We conclude that Rv0560c expression is controlled by a yet unknown repressor via a highly-inducible promoter. PMID- 22485173 TI - AMPA receptor activation causes silencing of AMPA receptor-mediated synaptic transmission in the developing hippocampus. AB - Agonist-induced internalization of transmembrane receptors is a widespread biological phenomenon that also may serve as a mechanism for synaptic plasticity. Here we show that the agonist AMPA causes a depression of AMPA receptor (AMPAR) signaling at glutamate synapses in the CA1 region of the hippocampus in slices from developing, but not from mature, rats. This developmentally restricted agonist-induced synaptic depression is expressed as a total loss of AMPAR signaling, without affecting NMDA receptor (NMDAR) signaling, in a large proportion of the developing synapses, thus creating AMPAR silent synapses. The AMPA-induced AMPAR silencing is induced independently of activation of mGluRs and NMDARs, and it mimics and occludes stimulus-induced depression, suggesting that this latter form of synaptic plasticity is expressed as agonist-induced removal of AMPARs. Induction of long-term potentiation (LTP) rendered the developing synapses resistant to the AMPA-induced depression, indicating that LTP contributes to the maturation-related increased stability of these synapses. Our study shows that agonist binding to AMPARs is a sufficient triggering stimulus for the creation of AMPAR silent synapses at developing glutamate synapses. PMID- 22485174 TI - In vitro studies on erythrosine-based photodynamic therapy of malignant and pre malignant oral epithelial cells. AB - Photodynamic Therapy (PDT) involves the administration of a tumor localizing photosensitizing agent, which upon activation with light of an appropriate wavelength leads to the destruction of the tumor cells. The aim of the present study was to determine the efficacy of erythrosine as a photosensitizer for the PDT of oral malignancies. The drug uptake kinetics of erythrosine in malignant (H357) and pre-malignant (DOK) oral epithelial cells and their susceptibility to erythrosine-based PDT was studied along with the determination of the subcellular localization of erythrosine. This was followed by initial investigations into the mechanism of cell killing induced following PDT involving both high and low concentrations of erythrosine. The results showed that at 37 degrees C the uptake of erythrosine by both DOK and H357 cells increased in an erythrosine dose dependent manner. However, the percentage of cell killing observed following PDT differed between the 2 cell lines; a maximum of ~80% of DOK cell killing was achieved as compared to ~60% killing for H357 cells. Both the DOK and H357 cell types exhibited predominantly mitochondrial accumulation of erythrosine, but the mitochondrial trans-membrane potential (DeltaPsi(m)) studies showed that the H357 cells were far more resistant to the changes in DeltaPsi(m) when compared to the DOK cells and this might be a factor in the apparent relative resistance of the H357 cells to PDT. Finally, cell death morphology and caspase activity analysis studies demonstrated the occurrence of extensive necrosis with high dose PDT in DOK cells, whereas apoptosis was observed at lower doses of PDT for both cell lines. For H357 cells, high dose PDT produced both apoptotic as well as necrotic responses. This is the first instance of erythrosine-based PDT's usage for cancer cell killing. PMID- 22485175 TI - Computed tomography imaging of primary lung cancer in mice using a liposomal iodinated contrast agent. AB - PURPOSE: To investigate the utility of a liposomal-iodinated nanoparticle contrast agent and computed tomography (CT) imaging for characterization of primary nodules in genetically engineered mouse models of non-small cell lung cancer. METHODS: Primary lung cancers with mutations in K-ras alone (Kras(LA1)) or in combination with p53 (LSL-Kras(G12D);p53(FL/FL)) were generated. A liposomal-iodine contrast agent containing 120 mg Iodine/mL was administered systemically at a dose of 16 ul/gm body weight. Longitudinal micro-CT imaging with cardio-respiratory gating was performed pre-contrast and at 0 hr, day 3, and day 7 post-contrast administration. CT-derived nodule sizes were used to assess tumor growth. Signal attenuation was measured in individual nodules to study dynamic enhancement of lung nodules. RESULTS: A good correlation was seen between volume and diameter-based assessment of nodules (R(2)>0.8) for both lung cancer models. The LSL-Kras(G12D);p53(FL/FL) model showed rapid growth as demonstrated by systemically higher volume changes compared to the lung nodules in Kras(LA1) mice (p<0.05). Early phase imaging using the nanoparticle contrast agent enabled visualization of nodule blood supply. Delayed-phase imaging demonstrated significant differential signal enhancement in the lung nodules of LSL Kras(G12D);p53(FL/FL) mice compared to nodules in Kras(LA1) mice (p<0.05) indicating higher uptake and accumulation of the nanoparticle contrast agent in rapidly growing nodules. CONCLUSIONS: The nanoparticle iodinated contrast agent enabled visualization of blood supply to the nodules during the early-phase imaging. Delayed-phase imaging enabled characterization of slow growing and rapidly growing nodules based on signal enhancement. The use of this agent could facilitate early detection and diagnosis of pulmonary lesions as well as have implications on treatment response and monitoring. PMID- 22485176 TI - Critical role of NADPH oxidase in neuronal oxidative damage and microglia activation following traumatic brain injury. AB - BACKGROUND: Oxidative stress is known to play an important role in the pathology of traumatic brain injury. Mitochondria are thought to be the major source of the damaging reactive oxygen species (ROS) following TBI. However, recent work has revealed that the membrane, via the enzyme NADPH oxidase can also generate the superoxide radical (O(2)(-)), and thereby potentially contribute to the oxidative stress following TBI. The current study thus addressed the potential role of NADPH oxidase in TBI. METHODOLOGY/PRINCIPAL FINDINGS: The results revealed that NADPH oxidase activity in the cerebral cortex and hippocampal CA1 region increases rapidly following controlled cortical impact in male mice, with an early peak at 1 h, followed by a secondary peak from 24-96 h after TBI. In situ localization using oxidized hydroethidine and the neuronal marker, NeuN, revealed that the O(2)(-) induction occurred in neurons at 1 h after TBI. Pre- or post treatment with the NADPH oxidase inhibitor, apocynin markedly inhibited microglial activation and oxidative stress damage. Apocynin also attenuated TBI induction of the Alzheimer's disease proteins beta-amyloid and amyloid precursor protein. Finally, both pre- and post-treatment of apocynin was also shown to induce significant neuroprotection against TBI. In addition, a NOX2-specific inhibitor, gp91ds-tat was also shown to exert neuroprotection against TBI. CONCLUSIONS/SIGNIFICANCE: As a whole, the study demonstrates that NADPH oxidase activity and superoxide production exhibit a biphasic elevation in the hippocampus and cortex following TBI, which contributes significantly to the pathology of TBI via mediation of oxidative stress damage, microglial activation, and AD protein induction in the brain following TBI. PMID- 22485177 TI - Identification of the inorganic pyrophosphate metabolizing, ATP substituting pathway in mammalian spermatozoa. AB - Inorganic pyrophosphate (PPi) is generated by ATP hydrolysis in the cells and also present in extracellular matrix, cartilage and bodily fluids. Fueling an alternative pathway for energy production in cells, PPi is hydrolyzed by inorganic pyrophosphatase (PPA1) in a highly exergonic reaction that can under certain conditions substitute for ATP-derived energy. Recombinant PPA1 is used for energy-regeneration in the cell-free systems used to study the zymology of ATP-dependent ubiquitin-proteasome system, including the role of sperm-borne proteasomes in mammalian fertilization. Inspired by an observation of reduced in vitro fertilization (IVF) rates in the presence of external, recombinant PPA1, this study reveals, for the first time, the presence of PPi, PPA1 and PPi transporter, progressive ankylosis protein ANKH in mammalian spermatozoa. Addition of PPi during porcine IVF increased fertilization rates significantly and in a dose-dependent manner. Fluorometric assay detected high levels of PPi in porcine seminal plasma, oviductal fluid and spermatozoa. Immunofluorescence detected PPA1 in the postacrosomal sheath (PAS) and connecting piece of boar spermatozoa; ANKH was present in the sperm head PAS and equatorial segment. Both ANKH and PPA1 were also detected in human and mouse spermatozoa, and in porcine spermatids. Higher proteasomal-proteolytic activity, indispensable for fertilization, was measured in spermatozoa preserved with PPi. The identification of an alternative, PPi dependent pathway for ATP production in spermatozoa elevates our understanding of sperm physiology and sets the stage for the improvement of semen extenders, storage media and IVF media for animal biotechnology and human assisted reproductive therapies. PMID- 22485178 TI - Skip the alignment: degenerate, multiplex primer and probe design using K-mer matching instead of alignments. AB - PriMux is a new software package for selecting multiplex compatible, degenerate primers and probes to detect diverse targets such as viruses. It requires no multiple sequence alignment, instead applying k-mer algorithms, hence it scales well for large target sets and saves user effort from curating sequences into alignable groups. PriMux has the capability to predict degenerate primers as well as probes suitable for TaqMan or other primer/probe triplet assay formats, or simply probes for microarray or other single-oligo assay formats. PriMux employs suffix array methods for efficient calculations on oligos 10-~100 nt in length. TaqMan(r) primers and probes for each segment of Rift Valley fever virus were designed using PriMux, and lab testing comparing signatures designed using PriMux versus those designed using traditional methods demonstrated equivalent or better sensitivity for the PriMux-designed signatures compared to traditional signatures. In addition, we used PriMux to design TaqMan(r) primers and probes for unalignable or poorly alignable groups of targets: that is, all segments of Rift Valley fever virus analyzed as a single target set of 198 sequences, or all 2863 Dengue virus genomes for all four serotypes available at the time of our analysis. The PriMux software is available as open source from http://sourceforge.net/projects/PriMux. PMID- 22485179 TI - Accounting for a quantitative trait locus for plasma triglyceride levels: utilization of variants in multiple genes. AB - BACKGROUND: For decades, research efforts have tried to uncover the underlying genetic basis of human susceptibility to a variety of diseases. Linkage studies have resulted in highly replicated findings and helped identify quantitative trait loci (QTL) for many complex traits; however identification of specific alleles accounting for linkage remains elusive. The purpose of this study was to determine whether with a sufficient number of variants a linkage signal can be fully explained. METHOD: We used comprehensive fine-mapping using a dense set of single nucleotide polymorphisms (SNPs) across the entire quantitative trait locus (QTL) on human chromosome 7q36 linked to plasma triglyceride levels. Analyses included measured genotype and combined linkage association analyses. RESULTS: Screening this linkage region, we found an over representation of nominally significant associations in five genes (MLL3, DPP6, PAXIP1, HTR5A, INSIG1). However, no single genetic variant was sufficient to account for the linkage. On the other hand, multiple variants capturing the variation in these five genes did account for the linkage at this locus. Permutation analyses suggested that this reduction in LOD score was unlikely to have occurred by chance (p = 0.008). DISCUSSION: With recent findings, it has become clear that most complex traits are influenced by a large number of genetic variants each contributing only a small percentage to the overall phenotype. We found that with a sufficient number of variants, the linkage can be fully explained. The results from this analysis suggest that perhaps the failure to identify causal variants for linkage peaks may be due to multiple variants under the linkage peak with small individual effect, rather than a single variant of large effect. PMID- 22485180 TI - Interaction of chandipura virus N and P proteins: identification of two mutually exclusive domains of N involved in interaction with P. AB - The nucleocapsid protein (N) and the phosphoprotein (P) of nonsegmented negative strand (NNS) RNA viruses interact with each other to accomplish two crucial events necessary for the viral replication cycle. First, the P protein binds to the aggregation prone nascent N molecules maintaining them in a soluble monomeric (N(0)) form (N(0)-P complex). It is this form that is competent for specific encapsidation of the viral genome. Second, the P protein binds to oligomeric N in the nucleoprotein complex (N-RNA-P complex), and thereby facilitates the recruitment of the viral polymerase (L) onto its template. All previous attempts to study these complexes relied on co-expression of the two proteins in diverse systems. In this study, we have characterised these different modes of N-P interaction in detail and for the first time have been able to reconstitute these complexes individually in vitro in the chandipura virus (CHPV), a human pathogenic NNS RNA virus. Using a battery of truncated mutants of the N protein, we have been able to identify two mutually exclusive domains of N involved in differential interaction with the P protein. An unique N-terminal binding site, comprising of amino acids (aa) 1-180 form the N(0)-P interacting region, whereas, C-terminal residues spanning aa 320-390 is instrumental in N-RNA-P interactions. Significantly, the ex-vivo data also supports these observations. Based on these results, we suggest that the P protein acts as N-specific chaperone and thereby partially masking the N-N self-association region, which leads to the specific recognition of viral genome RNA by N(0). PMID- 22485181 TI - Gene expression signature of DMBA-induced hamster buccal pouch carcinomas: modulation by chlorophyllin and ellagic acid. AB - Chlorophyllin (CHL), a water-soluble, semi-synthetic derivative of chlorophyll and ellagic acid (EA), a naturally occurring polyphenolic compound in berries, grapes, and nuts have been reported to exert anticancer effects in various human cancer cell lines and in animal tumour models. The present study was undertaken to examine the mechanism underlying chemoprevention and changes in gene expression pattern induced by dietary supplementation of chlorophyllin and ellagic acid in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model by whole genome profiling using pangenomic microarrays. In hamsters painted with DMBA, the expression of 1,700 genes was found to be altered significantly relative to control. Dietary supplementation of chlorophyllin and ellagic acid modulated the expression profiles of 104 and 37 genes respectively. Microarray analysis also revealed changes in the expression of TGFbeta receptors, NF-kappaB, cyclin D1, and matrix metalloproteinases (MMPs) that may play a crucial role in the transformation of the normal buccal pouch to a malignant phenotype. This gene expression signature was altered on treatment with chlorophyllin and ellagic acid. Our study has also revealed patterns of gene expression signature specific for chlorophyllin and ellagic acid exposure. Thus dietary chlorophyllin and ellagic acid that can reverse gene expression signature associated with carcinogenesis are novel candidates for cancer prevention and therapy. PMID- 22485182 TI - Shared resistance to aging and ALS in neuromuscular junctions of specific muscles. AB - Normal aging and neurodegenerative diseases both lead to structural and functional alterations in synapses. Comparison of synapses that are generally similar but respond differently to insults could provide the basis for discovering mechanisms that underlie susceptibility or resistance to damage. Here, we analyzed skeletal neuromuscular junctions (NMJs) in 16 mouse muscles to seek such differences. We find that muscles respond in one of three ways to aging. In some, including most limb and trunk muscles, age-related alterations to NMJs are progressive and extensive during the second postnatal year. NMJs in other muscles, such as extraocular muscles, are strikingly resistant to change. A third set of muscles, including several muscles of facial expression and the external anal sphinter, succumb to aging but not until the third postnatal year. We asked whether susceptible and resistant muscles differed in rostrocaudal or proximodistal position, source of innervation, motor unit size, or fiber type composition. Of these factors, muscle innervation by brainstem motor neurons correlated best with resistance to age-related decline. Finally, we compared synaptic alterations in normally aging muscles to those in a mouse model of amyotrophic lateral sclerosis (ALS). Patterns of resistance and susceptibility were strikingly correlated in the two conditions. Moreover, damage to NMJs in aged muscles correlated with altered expression and distribution of CRMP4a and TDP-43, which are both altered in motor neurons affected by ALS. Together, these results reveal novel structural, regional and molecular parallels between aging and ALS. PMID- 22485183 TI - Zfp296 is a novel, pluripotent-specific reprogramming factor. AB - Expression of the four transcription factors Oct4, Sox2, Klf4, and c-Myc (OSKM) is sufficient to reprogram somatic cells into induced pluripotent stem (iPSCs). However, this process is slow and inefficient compared with the fusion of somatic cells with embryonic stem cells (ESCs), indicating that ESCs express additional factors that can enhance the efficiency of reprogramming. We had previously developed a method to detect and isolate early neural induction intermediates during the differentiation of mouse ESCs. Using the gene expression profiles of these intermediates, we identified 23 ESC-specific transcripts and tested each for the ability to enhance iPSC formation. Of the tested factors, zinc finger protein 296 (Zfp296) led to the largest increase in mouse iPSC formation. We confirmed that Zfp296 was specifically expressed in pluripotent stem cells and germ cells. Zfp296 in combination with OSKM induced iPSC formation earlier and more efficiently than OSKM alone. Through mouse chimera and teratoma formation, we demonstrated that the resultant iPSCs were pluripotent. We showed that Zfp296 activates transcription of the Oct4 gene via the germ cell-specific conserved region 4 (CR4), and when overexpressed in mouse ESCs leads to upregulation of Nanog expression and downregulation of the expression of differentiation markers, including Sox17, Eomes, and T, which is consistent with the observation that Zfp296 enhances the efficiency of reprogramming. In contrast, knockdown of Zfp296 in ESCs leads to the expression of differentiation markers. Finally, we demonstrated that expression of Zfp296 in ESCs inhibits, but does not block, differentiation into neural cells. PMID- 22485184 TI - NESH regulates dendritic spine morphology and synapse formation. AB - BACKGROUND: Dendritic spines are small membranous protrusions on the neuronal dendrites that receive synaptic input from axon terminals. Despite their importance for integrating the enormous information flow in the brain, the molecular mechanisms regulating spine morphogenesis are not well understood. NESH/Abi-3 is a member of the Abl interactor (Abi) protein family, and its overexpression is known to reduce cell motility and tumor metastasis. NESH is prominently expressed in the brain, but its function there remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: NESH was strongly expressed in the hippocampus and moderately expressed in the cerebral cortex, cerebellum and striatum, where it co-localized with the postsynaptic proteins PSD95, SPIN90 and F-actin in dendritic spines. Overexpression of NESH reduced numbers of mushroom-type spines and synapse density but increased thin, filopodia-like spines and had no effect on spine density. siRNA knockdown of NESH also reduced mushroom spine numbers and inhibited synapse formation but it increased spine density. The N-terminal region of NESH co-sedimented with filamentous actin (F-actin), which is an essential component of dendritic spines, suggesting this interaction is important for the maturation of dendritic spines. CONCLUSIONS/SIGNIFICANCE: NESH is a novel F-actin binding protein that likely plays important roles in the regulation of dendritic spine morphogenesis and synapse formation. PMID- 22485185 TI - The effect of interocular phase difference on perceived contrast. AB - Binocular vision is traditionally treated as two processes: the fusion of similar images, and the interocular suppression of dissimilar images (e.g. binocular rivalry). Recent work has demonstrated that interocular suppression is phase insensitive, whereas binocular summation occurs only when stimuli are in phase. But how do these processes affect our perception of binocular contrast? We measured perceived contrast using a matching paradigm for a wide range of interocular phase offsets (0-180 degrees ) and matching contrasts (2-32%). Our results revealed a complex interaction between contrast and interocular phase. At low contrasts, perceived contrast reduced monotonically with increasing phase offset, by up to a factor of 1.6. At higher contrasts the pattern was non monotonic: perceived contrast was veridical for in-phase and antiphase conditions, and monocular presentation, but increased a little at intermediate phase angles. These findings challenge a recent model in which contrast perception is phase-invariant. The results were predicted by a binocular contrast gain control model. The model involves monocular gain controls with interocular suppression from positive and negative phase channels, followed by summation across eyes and then across space. Importantly, this model--applied to conditions with vertical disparity--has only a single (zero) disparity channel and embodies both fusion and suppression processes within a single framework. PMID- 22485186 TI - Nuclear factor kappa B activation occurs in the amnion prior to labour onset and modulates the expression of numerous labour associated genes. AB - BACKGROUND: Prior to the onset of human labour there is an increase in the synthesis of prostaglandins, cytokines and chemokines in the fetal membranes, particular the amnion. This is associated with activation of the transcription factor nuclear factor kappa B (NFkappaB). In this study we characterised the level of NFkappaB activity in amnion epithelial cells as a measure of amnion activation in samples collected from women undergoing caesarean section at 39 weeks gestation prior to the onset of labour. METHODOLOGY/PRINCIPAL FINDINGS: We found that a proportion of women exhibit low or moderate NFkappaB activity while other women exhibit high levels of NFkappaB activity (n = 12). This activation process does not appear to involve classical pathways of NFkappaB activation but rather is correlated with an increase in nuclear p65-Rel-B dimers. To identify the full range of genes upregulated in association with amnion activation, microarray analysis was performed on carefully characterised non-activated amnion (n = 3) samples and compared to activated samples (n = 3). A total of 919 genes were upregulated in response to amnion activation including numerous inflammatory genes such cyclooxygenase-2 (COX-2, 44-fold), interleukin 8 (IL-8, 6-fold), IL-1 receptor accessory protein (IL-1RAP, 4.5-fold), thrombospondin 1 (TSP-1, 3-fold) and, unexpectedly, oxytocin receptor (OTR, 24-fold). Ingenuity Pathway Analysis of the microarray data reveal the two main gene networks activated concurrently with amnion activation are i) cell death, cancer and morphology and ii) cell cycle, embryonic development and tissue development. CONCLUSIONS/SIGNIFICANCE: Our results indicate that assessment of amnion NFkappaB activation is critical for accurate sample classification and subsequent interpretation of data. Collectively, our data suggest amnion activation is largely an inflammatory event that occurs in the amnion epithelial layer as a prelude to the onset of labour. PMID- 22485187 TI - Hoxb1 controls anteroposterior identity of vestibular projection neurons. AB - The vestibular nuclear complex (VNC) consists of a collection of sensory relay nuclei that integrates and relays information essential for coordination of eye movements, balance, and posture. Spanning the majority of the hindbrain alar plate, the rhombomere (r) origin and projection pattern of the VNC have been characterized in descriptive works using neuroanatomical tracing. However, neither the molecular identity nor developmental regulation of individual nucleus of the VNC has been determined. To begin to address this issue, we found that Hoxb1 is required for the anterior-posterior (AP) identity of precursors that contribute to the lateral vestibular nucleus (LVN). Using a gene-targeted Hoxb1 GFP reporter in the mouse, we show that the LVN precursors originate exclusively from r4 and project to the spinal cord in the stereotypic pattern of the lateral vestibulospinal tract that provides input into spinal motoneurons driving extensor muscles of the limb. The r4-derived LVN precursors express the transcription factors Phox2a and Lbx1, and the glutamatergic marker Vglut2, which together defines them as dB2 neurons. Loss of Hoxb1 function does not alter the glutamatergic phenotype of dB2 neurons, but alters their stereotyped spinal cord projection. Moreover, at the expense of Phox2a, the glutamatergic determinants Lmx1b and Tlx3 were ectopically expressed by dB2 neurons. Our study suggests that the Hox genes determine the AP identity and diversity of vestibular precursors, including their output target, by coordinating the expression of neurotransmitter determinant and target selection properties along the AP axis. PMID- 22485188 TI - A novel enzymatic system against oxidative stress in the thermophilic hydrogen oxidizing bacterium Hydrogenobacter thermophilus. AB - Rubrerythrin (Rbr) is a non-heme iron protein composed of two distinctive domains and functions as a peroxidase in anaerobic organisms. A novel Rbr-like protein, ferriperoxin (Fpx), was identified in Hydrogenobacter thermophilus and was found not to possess the rubredoxin-like domain that is present in typical Rbrs. Although this protein is widely distributed among aerobic organisms, its function remains unknown. In this study, Fpx exhibited ferredoxin:NADPH oxidoreductase (FNR)-dependent peroxidase activity and reduced both hydrogen peroxide (H(2)O(2)) and organic hydroperoxide in the presence of NADPH and FNR as electron donors. The calculated K(m) and V(max) values of Fpx for organic hydroperoxides were comparable to that for H(2)O(2), demonstrating a multiple reactivity of Fpx towards hydroperoxides. An fpx gene disruptant was unable to grow under aerobic conditions, whereas its growth profiles were comparable to those of the wild-type strain under anaerobic and microaerobic conditions, clearly indicating the indispensability of Fpx as an antioxidant of H. thermophilus in aerobic environments. Structural analysis suggested that domain-swapping occurs in Fpx, and this domain-swapped structure is well conserved among thermophiles, implying the importance of structural stability of domain-swapped conformation for thermal environments. In addition, Fpx was located on a deep branch of the phylogenetic tree of Rbr and Rbr-like proteins. This finding, taken together with the wide distribution of Fpx among Bacteria and Archaea, suggests that Fpx is an ancestral type of Rbr homolog that functions as an essential antioxidant and may be part of an ancestral peroxide-detoxification system. PMID- 22485189 TI - The N2pc is increased by perceptual learning but is unnecessary for the transfer of learning. AB - BACKGROUND: Practice improves human performance in many psychophysical paradigms. This kind of improvement is thought to be the evidence of human brain plasticity. However, the changes that occur in the brain are not fully understood. METHODOLOGY/PRINCIPAL FINDINGS: The N2pc component has previously been associated with visuo-spatial attention. In this study, we used event-related potentials (ERPs) to investigate whether the N2pc component changed during long-term visual perceptual learning. Thirteen subjects completed several days of training in an orientation discrimination task, and were given a final test 30 days later. The results showed that behavioral thresholds significantly decreased across training sessions, and this decrement was also present in the untrained visual field. ERPs showed training significantly increased the N2pc amplitude, and this effect could be maintained for up to 30 days. However, the increase in N2pc was specific to the trained visual field. CONCLUSION/SIGNIFICANCE: Training caused spatial attention to be increasingly focused on the target positions. However, this process was not transferrable from the trained to the untrained visual field, which suggests that the increase in N2pc may be unnecessary for behavioral improvements in the untrained visual field. PMID- 22485190 TI - Myosin light-chain kinase is necessary for membrane homeostasis in cochlear inner hair cells. AB - The structural homeostasis of the cochlear hair cell membrane is critical for all aspects of sensory transduction, but the regulation of its maintenance is not well understood. In this report, we analyzed the cochlear hair cells of mice with specific deletion of myosin light chain kinase (MLCK) in inner hair cells. MLCK deficient mice showed impaired hearing, with a 5- to 14-dB rise in the auditory brainstem response (ABR) thresholds to clicks and tones of different frequencies and a significant decrease in the amplitude of the ABR waves. The mutant inner hair cells produced several ball-like structures around the hair bundles in vivo, indicating impaired membrane stability. Inner hair cells isolated from the knockout mice consistently displayed less resistance to hypoosmotic solution and less membrane F-actin. Myosin light-chain phosphorylation was also reduced in the mutated inner hair cells. Our results suggest that MLCK is necessary for maintaining the membrane stability of inner hair cells. PMID- 22485191 TI - Evaluation of an Emerging Research Center: Lessons Learned. AB - PROBLEM STATEMENT: Rigorous evaluation assures that research endeavors meet their purpose and achieve stated goals. This is especially true for federally funded exploratory research centers, which tend to be more complex due to the involvement of multiple, interdisciplinary investigators. This study provides an overview of the approach used to develop an evaluation strategy and reports the lessons learned during the initial development of the Center for Ohana Self Management of Chronic Illness (COSMCI) at the University of Hawai'i at Manoa School of Nursing and Dental Hygiene. The COSMCI is composed of an interdisciplinary team of researchers and practitioners and aims to advance knowledge in the field of self management of chronic disease in the community setting. APPROACH: A systematic approach was utilized that included formative and summative strategies for ongoing evaluation. The problem was solved by addressing five key concerns: (1) development of research structure, (2) observing the process of the research pilot projects, (3) scholarly activity of COSMCI faculty, (4) dissemination and translation and (5) sustainability prospects. The method of research included formulating process strategies and determine if the plans for developing the Center were followed and whether these plans were effective. Interviews were also conducted at year one and at mid-point though the project. RESULTS: Themes that emerged from our evaluation included inclusion, timelines, realistic expectations, ongoing evaluation and preparing for changes in the team. This provided timely recognition of successes and challenges and facilitated a rapid response for interventions especially during the early development stage of the center. CONCLUSION/RECOMMENDATIONS: Effective development of a successful Center is highly dependent upon having a strong evaluation process in place that can inform ongoing development. An exploratory research center requires ongoing evaluation that allows for celebration of successes, as well as early identification of problems and rapid response. PMID- 22485194 TI - Plasmon-Enhanced Enzymatic Reactions 2:Optimization of Enzyme Activity by Surface Modification of Silver Island Films with Biotin-Poly (Ethylene-glycol)-Amine. AB - Surface modification of silver island films (SIFs) was carried out with Biotin Poly (Ethylene-glycol)-Amine (BEA), which acts as a cross-linker between the silver surface and horse radish peroxidase (HRP) enzyme for optimum plasmon enhanced enzymatic activity. SIFs-deposited blank glass slides and SIFs-deposited 3-Aminopropyltriethoxysilane(APTES)-coated glass slides were used as our plasmonic surfaces.In this regard, three different extent of loading of SIFs were also prepared (low, medium and high) on APTES-coated glass slides. Streptavidin linked HRP enzyme was attached to SIFs-deposited blank glass slides and SIFs deposited APTES-coated glass slides through the well-known biotin-streptavidin interactions. The characterization of these surfaces was done using optical absorption spectroscopy. The loading of SIFs on glass slides was observed to have significant effect on the efficiency of plasmon-enhanced enzymatic activity, where an enhancement of 200% in the enzymatic activity was observed when compared to our previously used strategies for enzyme immobilization in our preceding work[1]. In addition, SIFs-deposited on APTES-coated glass slides were found to be re-usable for plasmon-enhanced enzymatic reactions unlike SIFs deposited on to blank glass slides. PMID- 22485192 TI - Physically facilitating drug-delivery systems. AB - Facilitated/modulated drug-delivery systems have emerged as a possible solution for delivery of drugs of interest to pre-allocated sites at predetermined doses for predefined periods of time. Over the past decade, the use of different physical methods and mechanisms to mediate drug release and delivery has grown significantly. This emerging area of research has important implications for development of new therapeutic drugs for efficient treatments. This review aims to introduce and describe different modalities of physically facilitating drug delivery systems that are currently in use for cancer and other diseases therapy. In particular, delivery methods based on ultrasound, electrical, magnetic and photo modulations are highlighted. Current uses and areas of improvement for these different physically facilitating drug-delivery systems are discussed. Furthermore, the main advantages and drawbacks of these technologies reviewed are compared. The review ends with a speculative viewpoint of how research is expected to evolve in the upcoming years. PMID- 22485193 TI - THE ROLE OF SPECIFIC IgG AND COMPLEMENT IN COMBATING A PRIMARY MUCOSAL INFECTION OF THE GUT EPITHELIUM. AB - The role of complement and complement-fixing IgG isotypes at mucosal surfaces is ill defined. Previous data have demonstrated that survival of an infection with the attaching and effacing pathogen Citrobacter rodentium requires production of systemic and CD4+ T cell-dependent IgG. We have found that both complement and complement-fixing IgG isotypes are needed to survive a C. rodentium infection. Our results indicate that both IgG and complement C3b enter the gut lumen and bind epithelially adherent, and fecally shed C. rodentium. Furthermore, C3 deficient mice demonstrate a profound survival defect, though means to replenish C3 in systemic or mucosal sites restores the protective capacity of complement in the host. Our data provide evidence that both IgG and complement interact constructively on both sides of the epithelium to fight colonizing mucosal infections. PMID- 22485195 TI - Rapid and Selective Crystallization of Acetaminophen using Metal-Assisted and Microwave-Accelerated Evaporative Crystallization. AB - In this paper, we demonstrate the application of Metal-Assisted and Microwave Accelerated Evaporative Crystallization (MA-MAEC) technique to rapid and selective crystallization of a small drug compound. i.e. acetaminophen. Subsequent characterization of the crystals by optical microscopy, powder X-ray diffraction (PXRD) and Raman spectroscopy showed quantitatively selective growth of different crystal forms at various experimental conditions. Acetaminophen crystals were grown predominantly as Form I (99%) on blank glass slides at room temperature. Form II crystals with 39% purity grown on SIFs using microwave energy. PMID- 22485196 TI - Modeling follicular thyroid cancer for future therapies. AB - Therapeutic choices are limited for undifferentiated metastatic thyroid carcinomas. Although implanted subcutaneous thyroid tumors are standard preclinical models to examine the efficacy of new therapeutic agents, these xenograft models frequently fail to predict the outcomes of clinical trials in patients with metastatic thyroid carcinomas. Genetically engineered mouse models with alterations similar to human cancers in their pathological progression and in an immunocompetent environment offer unparalleled opportunities for evaluating novel potential molecular targets. We review recent advances in the modeling of follicular thyroid carcinoma with distant metastasis and in the use of these mouse models in preclinical studies, emphasizing the significance of genetically engineered mouse models in clinical applications. PMID- 22485197 TI - Therapeutic implications of targeting the PI3Kinase/AKT/mTOR signaling module in melanoma therapy. AB - The PI3Kinase/AKT/mTOR signaling module is implicated in various cellular functions including cell survival, growth and proliferation, glucose metabolism, apoptosis, migration, and angiogenesis. Increased expression of AKT and its up- and downstream regulators is linked to several types of cancer. Aberrant expression of AKT is observed in nearly 60% of melanomas culminating in apoptosis resistance via deactivation of apoptotic molecules Bad and Cas-pase-9. Through cross-talk with NF-kappaB, ERK1/2, JNK and p38MAPK signaling pathways, AKT induces a plethora of cellular effects often leading to tumor development and progression. Due to frequently observed resistance to other common cancer treatments such as chemotherapy, immunotherapy, and radiation, and the detrimental consequences of constitutive activation of the PI3Kinase/AKT/mTOR signaling module, targeted inhibition of the effectors and substrates involved in this module has become a viable and attractive option for molecular targeted therapy in melanoma. Pharmacological inhibitors of various components of this module, either alone or in combination with other agents, have shown significant decrease in proliferation, tumorigenesis, cell growth and survival of various tumors in phases I and II clinical trials. Some inhibitors have even received their Food and Drug Administration (FDA) approval. This review summarizes the current knowledge on this module, its cross-talk with other major cell survival pathways and its targeted inhibition for therapeutic purposes in melanoma. PMID- 22485198 TI - Bcl-2:Beclin 1 complex: multiple, mechanisms regulating autophagy/apoptosis toggle switch. AB - Cancer cells have developed novel mechanisms for evading chemotherapy-induced apoptosis and autophagy-associated cell death pathways. Upon the discovery that chemotherapeutics could target these cell death pathways in a manner that was not mutually exclusive, new discoveries about the interrelationship between these two pathways are emerging. Key proteins originally thought to be "autophagy-related proteins" are now found to be involved in either inducing or inhibiting apoptosis. Similarly, apoptosis inhibiting proteins can also block autophagy associated cell death. One example is the complex formed by the autophagy protein, Beclin 1, and anti-apoptotic protein Bcl-2, which leads to inhibition of autophagy-associated cell death. Researchers have been investigating additional mechanisms that form/disrupt this complex in order to better design chemotherapeutics. This review will highlight the role Bcl-2 and Beclin 1 play in cancer development and drug resistance, as well as the role the Bcl-2:Beclin 1 complex in the switch between autophagy and apoptosis. PMID- 22485199 TI - Recrudescent wave of pandemic A/H1N1 influenza in Mexico, Winter 2011-2012: Age shift and severity. AB - BACKGROUND: A substantial recrudescent wave of pandemic influenza A/H1N1 that began in December 2011 is ongoing and has not yet peaked in Mexico, following a 2 year period of sporadic transmission. Mexico previously experienced three pandemic waves of A/H1N1 in 2009, associated with higher excess mortality rates than those reported in other countries, and prompting a large influenza vaccination campaign. Here we describe changes in the epidemiological patterns of the ongoing 4th pandemic wave in 2011-12, relative to the earlier waves in 2009. The analysis is intended to guide public health intervention strategies in near real time. METHODS: We analyzed demographic and geographic data on all hospitalizations with acute respiratory infection (ARI) and laboratory-confirmed A/H1N1 influenza, and inpatient deaths, from a large prospective surveillance system maintained by the Mexican Social Security medical system during 01-April 2009 to 10-Feb 2012. We characterized the age and regional patterns of A/H1N1 positive hospitalizations and inpatient-deaths relative to the 2009 A/H1N1 influenza pandemic. We also estimated the reproduction number (R) based on the growth rate of the daily case incidence by date of symptoms onset. RESULTS: A total of 5,795 ARI hospitalizations and 186 inpatient-deaths (3.2%) were reported between 01-December 2011 and 10-February 2012 (685 A/H1N1-positive inpatients and 75 A/H1N1-positive deaths). The nationwide peak of daily ARI hospitalizations in early 2012 has already exceeded the peak of ARI hospitalizations observed during the major fall pandemic wave in 2009. The mean age was 34.3 y (SD=21.3) among A/H1N1 inpatients and 43.5 y (SD=21) among A/H1N1 deaths in 2011-12. The proportion of laboratory-confirmed A/H1N1 hospitalizations and deaths was higher among seniors >=60 years of age (Chi-square test P<0.001) and lower among younger age groups (Chi-square test, P<0.03) for the 2011-2012 pandemic wave, compared to the earlier waves in 2009. The reproduction number of the winter 2011-12 wave in central Mexico was estimated at 1.2-1.3, similar to that reported for the fall 2009 wave, but lower than that of spring 2009. CONCLUSIONS: We have documented a substantial and ongoing increase in the number of ARI hospitalizations during the period December 2011-February 2012 and an older age distribution of laboratory confirmed A/H1N1 influenza hospitalizations and deaths, relative to 2009 A/H1N1 pandemic patterns. The gradual change in the age distribution of A/H1N1 infections in the post-pandemic period is reminiscent of historical pandemics and indicates either a gradual drift in the A/H1N1 virus, and/or a build-up of immunity among younger populations. PMID- 22485200 TI - ? AB - Reaction and activation energy barriers are calculated for the H abstraction reactions (C(6)H(5)SH + X(*) -> C(6)H(5)S + XH, X = H, OH and HO(2)) at the BB1K/GTLarge level of theory. The corresponding reactions with H(2)S and CH(3)SH are also investigated using the G3B3 and CBS-QB3 methods in order to demonstrate the accuracy of BB1K functional in finding activation barriers for hydrogen atom transfer reactions. Arrhenius parameters for the title reactions are fitted in the temperature range of 300 K-2000 K. The calculated reaction enthalpies are in good agreement with their corresponding experimental reaction enthalpies. It is found that H abstraction by OH radicals from the thiophenol molecule proceed in a much slower rate in reference to the analogous phenol molecule. [Formula: see text] of thiophenoxy radical is calculated to be 63.3 kcal/mol. Kinetic parameters presented herein should be useful in describing the decomposition rate of thiophenol; i.e., one of the major aromatic sulfur carriers, at high temperatures. PMID- 22485201 TI - Effect of peripheral administration of peptide ligands of delta-opioid receptors on anxiety level and locomotor activity of rats. AB - We studied the effect of intragastric administration of a peptide delta-opioid receptor agonist DADLE and peptide delta-opioid receptor antagonist ICI 174.864 on anxiety and locomotor activity of rats. Peripheral administration of ICI 174.864 produced an anxiolytic effect, but did not modulate locomotor activity of rats. Agonist DADLE in doses of 50 and 100 MUg/kg increased anxiety, but decreased locomotor activity of rats. Our results indicate that ICI 174.864 and DADLE produce opposite effects on anxiety in rats. These data support our hypothesis on the interaction between the central and peripheral compartments of the endogenous opioid system. PMID- 22485202 TI - Comparative analysis of the impact of alpha1-and alpha2-adrenoreceptor blockade on cardiac function in rats during postnatal ontogeny. AB - We compared the effects of alpha1-and alpha2-adrenoreceptor blockade on cardiac function in rats aged 1, 3, 6 and 20 weeks. Administration of alpha1 adrenoblocker prazosin decreased heart rate in 20- and 6-week-old rats; in 3-week old rats, this decrease was insignificant and in 1-week-old rats was absent. Blockade of alpha2-adrenoreceptors with yohimbine did not change heart rate in 6- and 20-week-old rats and induced bradycardia in 1- and 3-week old rats. PMID- 22485203 TI - Comparative analysis of the effects of various stress factors at the stage of early organogenesis on heart rate variability in pregnant female rats and their offspring. AB - We studied changes in the autonomic balance of heart regulation (by the parameters of heart rate variability) in non-pregnant female rats and rats on the days 10-11 of pregnancy on the next day after stress provoked by acute hypobaric hypoxia, intermittent normobaric hypoxia, or immobilization. The same parameters were assessed in 36-day-old offspring. In non-pregnant rats, the intermittent hypoxia resulted in a shift of the autonomic balance of heart regulation towards activation of the parasympathetic nervous system; in pregnant females, immobilization led to a shift of the autonomic balance towards the sympathetic nervous system. In the offspring, the changes also depended on the type of stress. PMID- 22485204 TI - Impact of amyloid-beta peptide (1-42) on voltage-gated ion currents in molluscan neurons. AB - Different types of voltage-gated ion currents were recorded in isolated neurons of snail Helix pomatia using the two-microelectrode voltage-clamp technique. Application of amyloid-beta peptide (1-42, 1-10 MUM) in the bathing solution did not change delayed rectifier K(+)-current and leakage current, but enhanced inactivation of Ca(2+)-current and blocked Ca(2+)-dependent K(+)-current. PMID- 22485205 TI - Activities of proline-specific peptidases in brain structures of rats with experimental anxiety-depressive state caused by administration of dipeptidyl peptidase IV inhibitor in the early postnatal period. AB - We studied the dynamics of activity of dipeptidyl peptidase IV (DP-IV) and prolyl endopeptidase (PEP) in the frontal cortex, hypothalamus, striatum, nucleus accumbens, and hippocampus of rats with experimental anxiety-depression state induced by administration of methionyl-2(s)-cyano-pyrrolidine, an inhibitor of DPP-IV, in the early postnatal period. In 1-month-old experimental males, PEP and DP-IV activities increased in the frontal cortex and hypothalamus, while in 1 month-old experimental females PEP activity increased in the hippocampus and DP IV activity increased in all studied brain structures. At the age of 3 months, increased PEP activity in the hypothalamus and nucleus accumbens was detected in males and decreased DP-IV activity in the nucleus accumbens and decreased PEP activity in the hippocampus were detected in females. At the age of 7 months, PEP activity increased in the frontal cortex and striatum and DP-IV activity increased in all studied brain structures in males; in 7-months-old females, activity of both enzymes increased in the striatum. PMID- 22485206 TI - Effect of coenzyme Q10 on proteomic profile of rat plasma under conditions of metabolic stress. AB - Proteomic profile of rat plasma was evaluated under conditions of metabolic stress (5-day starvation) and administration of coenzyme Q10 in doses of 10 and 100 mg/kg. This antioxidant and geroprotector plays a key role in cell metabolism. The expression of some low-molecular-weight proteins in response to treatment with coenzyme Q10 was observed. PMID- 22485207 TI - Albendazole and colchicine modulate LPS-induced secretion of inflammatory mediators by liver macrophages. AB - Colchicine and albendazole inhibited LPS-induced secretion of TNF-alpha and NO in a primary culture of rat Kupffer cells. Both agents potentiated the stimulating effect of this toxin on prostaglandin E2 secretion. The amount of prostaglandin D2 remained unchanged under these conditions. PMID- 22485208 TI - Effect of non-starch polysaccharide calcium pectate on the growth and colonization of normal and pathogenic microflora in vitro. AB - In vitro experiments showed that calcium pectate added to the culture medium produces a dose-dependent prebiotic effect on lacto-and bifidobacteria cultures and on non-pathogenic strain of Escherichia coli. Calcium pectate produced a pronounced bacteriostatic effect on Candida albicans strain; the effects was more pronounced in a concentration of 4%. PMID- 22485209 TI - Antiparkinsonian properties of a nerve growth factor dipeptide mimetic GK-2 in in vivo experiments. AB - An intraperitoneal injection of GK-2 (dipeptide mimetic of nerve growth factor, 0.01-5.00 mg/kg) 24 h before the adverse exposure reduced the severity of haloperidol-induced catalepsy in rats. This agent retained the activity after oral administration in a dose of 10 mg/kg. An intraperitoneal injection of GK-2 in a dose of 1 mg/kg reduced the severity of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced parkinsonian syndrome in mice. Administration of GK-2 45 min after haloperidol treatment was also followed by a decrease in the degree of catalepsy. The repeated intraperitoneal treatment with GK-2 in a dose of 1 mg/kg after intrastriatal injection of 6-hydroxydopamine was shown to prevent the development of apomorphine-induced rotations in rats. PMID- 22485210 TI - In vitro effect of combined hybrid molecules from vitamin E analogues and betulinic acid on macrophage activity. AB - Macrophage activity was studied after treatment with hybrid molecules obtained by condensation of terpenic acid residues (betulinic and betulonic acids) and alpha tocopherol analogues (alpha-tocopherol hemisuccinate and Trolox acid). As distinct from betulinic acid and alpha-tocopherol hemisuccinate, hybrid molecules did not exhibit cytotoxicity in relation to mouse peritoneal macrophages in the MTT test. Test substances inhibited the production of NO by mouse peritoneal macrophages. However, hybrid molecules had no effect on activity of macrophage arginase. Our results indicate that new molecules have anti-inflammatory activity. It can be hypothesized that these substances have immunomodulatory properties. PMID- 22485211 TI - Biological activity of some derivatives of beta-cyclodextrin. AB - New compounds of beta-cyclodextrin containing covalently bound (conjugated) residues of acetylsalicylic and 1-(4-isobutylphenyl)-propionic acids were synthesized in the reaction of chlorides of the corresponding acids with beta cyclodextrin. We studied antiplatelet and antiphlogistic properties of these substances. It was shown that new compounds are comparable and in some cases are superior to the reference drugs acetylsalicylic acid and ibuprofen by anti inflammatory and antiaggregant activities. PMID- 22485212 TI - Role of hydrogen sulfide in the regulation of cell apoptosis. AB - We studied the effect of a gas transmitter hydrogen sulfide (H(2)S) on the realization of apoptosis in Jurkat cells and mononuclear leukocytes from healthy donors. Treatment with H(2)S donor NaHS was accompanied by a dose-dependent intensification of cell death via apoptosis and necrosis. T-cell leukemia cells were more sensitive to H2S than mononuclear leukocytes from healthy donors. H(2)S induced cell apoptosis was accompanied by activation of caspase-3 and caspase-9. PMID- 22485213 TI - Damaging effects of lyticase on Candida albicans and changes in the response of rat alveolar macrophages to the contact with yeast-like fungi. AB - Changes in the cell wall of yeast-like fungi Candida albicans caused by bacterial enzyme lyticase were studied under an electron microscope. The results were compared with the findings on phagocytosis of lyticase-treated Candida albicans by rat alveolar macrophages. It was shown that destruction of the mannan and fibrous outer layers of the cell wall of yeast-like fungi treated with the enzyme led to the release of intracellular organelles and their content. Lyticase treatment reduced the resistance of Candida albicans to intracellular digestion by macrophages contributing to completion of phagocytosis. PMID- 22485214 TI - Investigation on genetic heterogeneity of alpha-subunit of the epithelial sodium channel in rat renal cortex. AB - Genotypic variability of alphaENaC mRNA in adult rat kidney caused by deletion at the 3'-end of alpha-subunit DNA was studied by real-time PCR using specific probes with a fluorescent dye (TaqMan). It was found that mRNA deletion forms (a and b), products of alternative splicing of aENaC gene, are absent in the cortex of adult rat kidney. PMID- 22485215 TI - Comparative study of the expression of ATF-3 and ATF-4 genes in vessels involved into atherosclerosis process and in psoriatic skin. AB - Expression of ATF-3 and ATF-4 genes was examined quantitatively by real-time PCR and changes in the expression of these genes in atherosclerotic lesions and in psoriatic skin were demonstrated. It was found that concomitant pathologies do not affect the expression of these genes. Opposite changes in the expression of ATF-3 and ATF-4 genes in atherosclerotic and psoriatic samples were revealed and a hypothesis was put forward that this parameter could be a criterion of pathological process in both diseases. PMID- 22485216 TI - Bifidobacterium longum modified recombinant HU protein as a vector for nonviral delivery of DNA to HEK293 human cell culture. AB - Creation of effective nontoxic highly specific systems for nonviral transportation of DNA is one of the priority problems in the development of genotherapeutic methods. Chimerical recombinant proteins consisting of Antp and Tat protein cell-penetrating domains and Bifidobacterium longum DNA-binding histone-like protein HU were obtained. The resultant recombinant proteins bind to plasmid DNA in vitro and provide intracellular delivery and expression of the reporter genetic construction with GFP gene in cultured HEK293 human cells. PMID- 22485217 TI - Effect of tripeptides on lymphoid and stem cells. AB - Tripeptides T-36 and, particularly, T-38 in concentrations of 0.1, 1, and 10 ng/ml inhibited proliferation of primary trypsinized embryonic mesenchymal stem cells, rat transplantable KF-1 fibroblasts, and human erythromyelosis K-562 cells. Inhibition of proliferation in embryonic and immortalized cells under the influence of tripeptides probably reflects antitumor activity of these substances. Tripeptides had no effect on lymphocyte survival and their adhesive, cytotoxic, and induced proliferative activities. T-36 did not modulate the proliferative properties of erythromyelosis K-562 cells. Tripeptides did not change engulfment activity and spontaneous and induced bactericidal activities of granulocytes. T-36 in a concentration of 0.1 ng/ml increased spontaneous proliferation of normal lymphocytes. These data suggest that tripeptides stimulate nontumor immune cells in adult people. PMID- 22485218 TI - Magnetic resonance imaging of endothelial cells with vectorized iron oxide nanoparticles. AB - We propose a method for obtaining superparamagnetic nanoparticles based on iron oxide and their water suspensions. The structure and size of nanoparticles were confirmed by transmission electron microscopy, dynamic light scattering, and X ray diffraction analysis. The nanoparticles also contained a fluorescent dye Dil C18. Cytotoxicity of obtained aqueous suspension was studied by MTT assay; low toxicity of nanoparticles was demonstrated. High T2-relaxivity of nanoparticles allows using them as a contrast agent for MRI. After incubation of cerebellar sections with nanoparticles vectorized with antibodies to antigen AMVB1, specific visualization of blood vessels was detected. PMID- 22485219 TI - Mutagenic effect of gold nanoparticles in the micronucleus assay. AB - Mutagenic activity of gold nanoparticles of different sizes were studied by micronucleus assay. Karyological analysis was performed and the count of micronucleoli in interphase bone marrow polychromatic erythrocytes in white outbred rats was determined. The animals orally received gold nanoparticles 16 and 55 nm in diameter and gold nanoshells 160 nm in diameter once a day for 7 days in a dose of 0.25 mg gold/kg. To ensure stability and biocompatibility, the surface of nanoparticles was functionalized with polyethylene glycol molecules. There were no significant differences in the number of micronucleoli in comparison with the control group, which suggests that gold nanoparticles of the specified size administered orally in the specified doses do not exhibit mutagenic activity. PMID- 22485220 TI - Etiologic structure of bacterial intestinal infections in monkeys of Adler breeding center. AB - We studied etiologic structure of bacterial intestinal infections in monkeys of Adler nursery. A total of 533 monkeys with diarrhea syndrome and monkeys dead from intestinal infections, as well as clinically healthy monkeys and animals dead from other pathologies were examined by bacteriological and molecular genetic methods. Pathogenic enterobacteria Shigella and Salmonella and microaerophile Campylobacter were found in 5 and 19%, respectively. A high percentage (49%) of intestinal diseases of unknown etiology was revealed in monkeys. The fact that the number of detected opportunistic enterobacteria did not differ in healthy and diseased monkeys suggests that they are not involved into the etiology of intestinal disease. PMID- 22485221 TI - Species variety of staphylococcal microflora of the skin in athletes engaged in water sports. AB - Staphylococcal flora of the skin was studied in athletes whose professional activity involved training in water. Inoculations were carried out by impressions in selective agar medium (yolk saline agar; YSA) in bacteriological signets. Drug sensitivity was studied by the disk diffusion method modified by Kerby-Bauer using standard disks with antibiotics. The study was carried out in 4 groups of athletes engaged in water sports (athletic and synchronous swimming, modern pentathlon, and water polo). Quantitative and qualitative characteristics of staphylococcal flora in water athletes are presented, MRSA strains are detected, and antibiotic sensitivity of staphylococcal microflora was evaluated. PMID- 22485222 TI - Relationship between CYP2E1 polymorphism and increase of ALT activity during therapy of patients with pulmonary tuberculosis. AB - Association of CYP2E1 polymorphism with ALT activity increase was studied in patients with pulmonary tuberculosis receiving therapy by intermittent and daily protocols. The greatest increment of ALT activity in the group receiving therapy by intermittent protocol was seen in the patients with CYP2E1*7632TA genotype. In patients with wild homozygotic 1C/1C (6/6) genotype, ALT activity significantly increased, but remained within the normal range (p=0.048). In the group on daily regimen, activity of ALT increased significantly in patients with all genotypes identified. A more pronounced elevation surpassing the median of the upper threshold of ALT norm was observed in patients with 7632TA genotype (p=0.0051) and in patients with 7632TA or -71GT or 1C/1D genotypes in combinations with wild type alleles by other detected polymorphisms (p=0.0277). Detection of the CYP2E1 gene 7632T0.5ng/ml). We discontinued the antibiotic therapy if clinical signs and symptoms of infection improved and PCT was <0.5ng/ml over 3 days. In the control group, antibiotic therapy was administrated for 2 weeks, or antibiotic therapy was continued because of confirmed infection until clinical signs and symptoms of infection disappeared over 3 days. RESULTS: In the study group (35 patients), the duration of antibiotic therapy and hospitalization was significantly shorter than the control group (36 patients) (10.89+/-2.85 versus 16.06+/-2.48 days, p<0.001, and 16.66+/-4.02 days versus 23.81+/-7.56 days, p<0.001) without negative clinical effects and the cost of hospitalization was significantly lower. CONCLUSION: Procalcitonin is a helpful and safe tool for guiding duration of antibiotic treatment in patients with severe acute pancreatitis. PMID- 22485233 TI - Comparison of proseal laryngeal mask and endotracheal tube for airway safety in pediatric strabismus surgery. AB - OBJECTIVE: To compare proseal laryngeal mask airway (PLMA) with an endotracheal tube (ET) for airway safety, maintained ease of insertion, and hemodynamic stability in pediatric strabismus surgery (PSS). METHODS: This prospective randomized clinical study was carried out in the Department of Anesthesiology, Faculty of Medicine, Gaziantep University, Turkey between April 2008 and July 2009. Eighty American Society of Anesthesiology (ASA) I-II children, weight 10-30 kg, aged between 1-12 years undergoing PSS were selected. The anesthesia was induced with 8% sevoflurane, 50% nitrous oxide/oxygen mixture, and a neuromuscular blockade with 0.5 mg/kg atracurium in both groups. After a sufficient dosage of anesthesia, the patients were randomized into 2 groups (Group P: PLMA, n= 40, Group T: ET, n=40) and an airway management device; either a PLMA or ET was inserted. The number of placement attempts, placement success or failure, success or failure of a gastric suction tube placement during the procedures and perioperative complications were assessed. RESULTS: Thirty-eight patients (95%) in the PLMA group, 39 (97.5%) patients in the ET group were successfully placed with a PLMA and ET on the first attempt (p>0.05). There were no statistically significant differences in the hemodynamic parameters, end-tidal carbon dioxide, and complications. CONCLUSION: This study revealed that PLMA may offer an alternative airway to ET wherein positive pressure ventilation was the preferred choice for children undergoing PSS. PMID- 22485234 TI - Outcomes of 3 hours part-time occlusion treatment combined with near activities among children with unilateral amblyopia. AB - OBJECTIVE: To evaluate the outcome of part-time occlusion therapy with or without near activities in monocular amblyopic patients. METHODS: One hundred and thirty patients who prescribed daily occlusion therapy (part-time occlusion) were followed-up for a 12-week period. The study was carried out in the Pediatric Ophthalmology and Orthoptics Clinics of King Abdul-Aziz University Hospital, Riyadh, Saudi Arabia for the period from January to November 2010. Sixty-five patients were recommended to undertake the 3 hours of near visual activities (such as reading a book during patching) while the other 65 patients were not advised to do any near activity. Main outcome measures were best corrected visual acuity (VA) for both groups and line improvement. RESULTS: The total line of VA improved from baseline by an average of 6.7+/-2.37 line log MAR (logarithm of the minimum angle of resolution) units in the group of patching with near activities and by an average of 5.3+/- 2.04 line log MAR units in the group of patching without near activities. All type of amblyopia (strabismic, anisometropic, and mixed types of amblyopia) improved significantly after patching with near activities. Both moderate and severe amblyopia improved significantly in the group of near activities compared with the group without near activities. CONCLUSION: Performing near activities while patching in the treatment of anisometropic, stabismic, or combined amblyopia improves the VA outcome more than patching alone. PMID- 22485235 TI - The importance of second opinion in surgical pathology referral material of lymphoma. AB - OBJECTIVE: To evaluate the importance of inter-institutional second opinion surgical pathology review of lymphoma, and identify the lymphoma pathologic mimics. METHODS: The surgical pathology material of patients referred to 2 tertiary care hospitals in the western region of Saudi Arabia (King Faisal Specialist Hospital and Research Centre and King Abdulaziz University Hospital, Jeddah, Saudi Arabia), for evaluation or therapy for lymphoma over a 10-year period (August 2001 to August 2011), were reviewed. This study included only cases in which the patient referred with a diagnosis previously made at the primary institution. RESULTS: Of 560 cases, the second opinion diagnosis differed significantly from the initial diagnosis in 39 cases (7%). These include changing the diagnoses from lymphoma to non-lymphoma lesions, change the type of lymphoma with major clinical impact, and change from reactive/non-diagnostic to lymphoma. CONCLUSION: Second opinion surgical pathology for lymphomas can result in major therapeutic and prognostic modifications. Thus, review of the original histologic material is recommended prior to a major therapeutic decision, and to maximize the discovery of clinically relevant major disagreements. Stringent adherence to institution's second opinion policy is an important quality assurance measure in surgical pathology. PMID- 22485236 TI - Is it feasible to perform coronary chronic total occlusion intervention with conventional angioplasty equipment. AB - OBJECTIVE: To demonstrate feasibility of coronary chronic total occlusion (CTO) procedures with conventional interventional equipment. METHODS: Ninety-five subsequent CTO patients were analyzed retrospectively. Patients who met the inclusion criteria were intervented with standard angioplasty catheters, guidewires, and balloon catheters. The procedural success rate of the interventions was discussed according to clinical and demographic characteristics of patients and equipment used for intervention. This study was carried out in Istanbul Medicine Hospital, Istanbul, Turkey between January 2007 and June 2011. RESULTS: Successful revascularization was achieved in 80% of patients, and all patients were discharged on the day after the procedure without complication. The success rate decreased to 60% in the CTOs of more than one year and approximately 90% in the shorter duration. Stent implantation was carried out in 82.9% of patients with a mean stent length of 42.7+/-21.4 mm. Occlusion duration was the major predictor of successful procedure on regression analysis (p=0.01). CONCLUSION: Coronary intervention for CTO with conventional equipment is still reasonable in the CTOs of short duration. Duration of coronary CTO over a year should be referred to a reference center where skilled operators and specialized equipment for CTOs are widely available. PMID- 22485237 TI - Gallstones in a group of Iraqi patients with type 2 diabetes mellitus. AB - OBJECTIVE: To find the frequency of gallstones in diabetic patients, and to study the relationship between the frequency of gallstones and state of control, and duration of diabetes mellitus (DM). METHODS: This case control study was carried out in the Department of Medicine, Al-Yarmook Teaching Hospital, Baghdad, Iraq from April 2008 to December 2008. We enrolled 100 patients with type 2 DM (60 females and 40 males) as a test group and 100 subjects with no DM (61 females and 39 males) as a control group. Both groups were comparable for gender, age, and body mass index (BMI) and examined by ultrasound to find the gallstones. Blood samples were taken for fasting blood glucose and the BMI was measured. Both groups were asked regarding age, gender, family history of gallstones, and parity for females. The tested groups were further divided into 2 subgroups: with gallstone and without gallstone. The association between duration of DM and hemoglobin A1c level with gallstone were assessed. RESULTS: Gallstones were found in 33% of diabetic and 17% of non-diabetic patients. There was no significant difference in age and family history of gallstone between diabetic and non diabetic groups. However, gallstones was higher in diabetic patients with BMI >25Kg/m2, with increased duration of DM, with increased HbA1C, and multiparous females. CONCLUSION: The frequency of gallstones in type 2 DM increases in obese patients, females with increased parity, increased level of HbA1c, and is positively correlated with the duration of DM. PMID- 22485238 TI - Ewing's sarcoma family tumors in the western region of Saudi Arabia. A pathological experience from 2 tertiary medical centers. AB - OBJECTIVE: To review the pattern of Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) in 2 medical centers in the western region of Saudi Arabia. METHODS: We retrospectively analyzed the pathological data of patients diagnosed with ES/PNET in 2 tertiary medical centers in the western region of Saudi Arabia (King Abdulaziz University Hospital, [March 1995 to November 2011], and King Faisal Specialized Hospital [April 2003 to 12 December 2010]). Age, gender, and site of tumors were analyzed. RESULTS: Sixty-nine cases were diagnosed as ES/PNET. The age range was 3-62 years (mean 22 years). Male cases were more than the female. Approximately 28.9% of cases presented within the skeleton, and 71.1% cases were presented as a soft tissue disease. Bone affection was higher in the iliac bone. Long bones were affected at a lower frequency. Soft tissue affection showed a higher incidence in the head and neck region followed by the lower limb. CONCLUSION: The current study represents a review of a large number of Ewing's sarcoma family of tumors in western Saudi Arabia. Cases showed clinicopathological features comparable to those reported from other locations worldwide apart from relatively higher soft tissue affection than skeletal affection and a higher incidence of head and neck involvement by soft tissue ES/PNET. Further, multicenter studies (epidemiological and genetic) are recommended to obtain profiling of the disease and effect on outcome and therapy. PMID- 22485239 TI - Presenting features of childhood-onset inflammatory bowel disease in the central region of Saudi Arabia. AB - OBJECTIVE: To investigate the presenting features of childhood-onset inflammatory bowel disease (IBD) in the central region of Riyadh, Saudi Arabia and to compare with those reported in the literature. METHODS: This is a retrospective review of medical records of children below 18 years of age at onset of symptoms with confirmed diagnosis of IBD for age, gender, family history, presenting clinical and laboratory findings in the Divisions of Pediatric and Adult Gastroenterology, King Khalid University Hospital (which provides free health care) and the Department of Gastroenterology Al Mofarreh Poly Clinic, Riyadh, Saudi Arabia, between January 1993 and December 2010. RESULTS: Two hundred and eighteen children diagnosed with IBD with predominance of males in Crohn's disease (CD) (56%) and females in ulcerative colitis (UC) (59%). There was no significant difference between UC and CD regarding age of onset of symptoms (p=0.347); however, the difference in the age at presentation and age at final diagnosis were significant (p=0.027 and p=0.008). There was a significant increase of IBD diagnosis from the period 1993-2001 to 2002-2010 (p<0.0001). The family history was positive in 15.3%. CONCLUSION: The presenting clinical features and laboratory abnormalities are similar to those reported in other populations. Further studies are needed to establish the incidence and prevalence. PMID- 22485240 TI - Poor hand function in diabetics. Its causes and effects on the quality of life. AB - OBJECTIVE: To find the possible causes of limited hand functions, and to investigate the subjective evaluation of hand functioning in patients with diabetes and its impact on the quality of life (QoL) in the physical and mental dimensions. METHODS: This study was conducted on 71 patients with type 1 and type 2 diabetes attending the Department of Endocrinology, Diabetes and Internal Diseases, Medical University of Bialystok, Poland from March to December 2009. Median nerve conduction and a questionnaire survey (Acceptance of Illness Scale, Hospital Anxiety and Depression Scale, functional capacity, and QoL SF-36v2 and Quality of Life Index) were employed for this study. RESULTS: Patients with damaged distal latency in the right (p=0.05) and left hand (p=0.004) had difficulty lifting objects. The QoL in relation to health (SF-36v2) and Quality of Life Index in patients with hand dysfunctions were significantly statistically lower compared with patients not experiencing these symptoms. These disorders also had a significant negative impact on Acceptance of Illness Scale, the incidence of depressive symptoms (p=0.001), and the patient's functional status (p=0.001). CONCLUSION: Impaired hand function affects lower acceptance of the disease, the occurrence of depression, and reduces patient's QoL. PMID- 22485241 TI - Breastfeeding practice and determinants among Arab mothers in Qatar. AB - OBJECTIVE: To assess the breastfeeding practices of Arab mothers by measuring breastfeeding indicators, and to identify the related determinants that affect maternal practices in Qatar. METHODS: Using interview administered questionnaires, we carried out this cross-sectional study with cluster sampling of 770 Arab mothers of children below 24 months of age attending primary health care centers in Qatar from June to October 2009. RESULTS: Early initiation of breastfeeding was found in 57%, exclusive breastfeeding under 6 months in 18.9%, and continued breastfeeding at one year in 49.9% of mothers. Children ever breastfed comprised 97.9%, continued breastfeeding at 2 years old comprised 45.4%, and predominant breastfeeding 11.9%. The proportion of children who were appropriately breastfed was 29%. The 'rooming in' rate was 43.9%. Receiving breast milk substitutes, exposure to advertisements for artificial teats, and employment status showed a significant relation with both early initiation and exclusive breastfeeding. On demand feeding was related to exclusive breastfeeding, and 'rooming in' and mode of delivery was related to early initiation. CONCLUSION: Breastfeeding practice among Arab mothers in Qatar is not at an acceptable level. Core indicators, optional indicators, and health facility indicators for breastfeeding practice are not at the desired World Health Organization recommended levels. PMID- 22485242 TI - Fetus-in-fetu. Imaging and pathology. AB - Fetus-in-fetu (FIF), also known as endoparasitic twin, is a form of asymmetric fetal duplication in which the abnormal developing embryo parasitizes the normal co-twin by attaching internally. Here, we report a case of FIF presented as an intra-abdominal cystic mass, which was first detected during an antenatal ultrasound examination of a 32-year-old Saudi mother. At 34 weeks and 4 days of gestation, she had spontaneous labor and delivered a baby boy. The x-ray and CT examination of the baby boy clearly suggested the presence of limbs, vertebral column, and anomalous blood supply to the mass. After laparotomy and surgical removal, the intra-abdominal mass was subjected to detailed pathological examination. Microscopic studies further showed the presence of brain tissue, gut like structures, fingers, and limbs. The mass was finally confirmed as FIF. PMID- 22485243 TI - Childhood penetrating eye trauma visits to the emergency room. Causes and outcomes. PMID- 22485244 TI - Towards active learning case study at the end of the physiology course in dental student. PMID- 22485245 TI - Congenital short femur. PMID- 22485246 TI - Kikuchi-Fujimoto disease, histiocytic necrotizing lymphadenitis. PMID- 22485247 TI - The reliability of an Arabic translation of the chronic obstructive pulmonary disease assessment test. PMID- 22485248 TI - Interleukin-12 inhibits cell invasion in choriocarcinoma. AB - Gestational trophoblastic disease (GTD) is a unique disease that arises from allografting of the conceptus, and has a characteristic morphology and biological behavior. It encompasses a spectrum of interrelated diseases, including hydatidiform mole, invasive mole, choriocarcinoma and placental-site trophoblastic tumor, but its pathogenesis remains unrevealed. Particularly, choriocarcinoma is a highly malignant tumor with poor prognosis. In this study, we cultured the human choriocarcinoma cell line JEG-3 in vitro. After treating the cells with different doses of interleukin (IL)-12, the cell invasion was observed. We also detected the expression of matrix metalloproteinases (MMP)-9 and tissue inhibitors of metalloproteinases (TIMP)-1 and the cell cycle of JEG-3 cells. Our data indicated that IL-12 inhibits cell invasion in a dose- and time dependent manner through regulating the expression of MMP-9 and TIMP-1. In addition, treatment with IL-12 redistributes the phases of the cell cycle in JEG 3 cells. These findings suggest an antitumor role of IL-12 in choriocarcinoma, with far reaching possibilities for understanding the mechanisms of IL-12. PMID- 22485249 TI - Inhibition of human topoisomerase I and activation of caspase-3 by aza angucyclinones and arylaminopyrimido[4,5-c]isoquinoline-7,10-quinones. AB - Cancer is the second cause of death in the world after cardiovascular diseases. Cancer cells acquire capacities not present in normal cells, such as self sufficiency, resistance to antiproliferative stimuli, evasion of apoptosis, unlimited replication, invasiveness and metastasis. Consequently, it is of major interest to explore and develop molecules with anticancer activity directed to specific targets. In this study, we aimed to evaluate two series of polycyclic quinones: aza-angucyclinone and arylaminopyrimido[4,5-c]isoquinoline-7,10 quinones, in their capacity to inhibit human topoisomerase I (TOP1) and to trigger apoptosis through activation of caspase-3. We evaluated the capacity of the two series of polycyclic quinones to inhibit TOP1, using a DNA supercoiled relaxation assay and their capacity to induce apoptosis through the activation of caspase-3 in HL60 cells. Both series of quinones inhibited TOP1 activity over 50%. When we evaluated the pro-apoptotic capacity of both series of quinones, at therapeutically relevant concentrations, the arylaminoquinones ADPA-1CC (methyl 7 (4-methoxyphenyl)amino-1,3-dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4 carboxylate), P4 (9-phenylamino-3,4-dihydrophenanthridine-1,7,10(2H)-trione) and the aza-angucyclinone OH-6H (8-hydroxy-2,4-dimethyl-2H,4H-benzo[g]pyrimido[4,5 c]isoquinoline-1,3,7,12-tetraone) increased the caspase-3 activity by approximately 2-fold over the control. The series of the arylaminoquinones and aza-angucyclinones showed differential antiproliferative capacity. We further identified a group of them that showed antiproliferative capacity possibly through inhibition of TOP1 and by activation of caspase-3. This group of molecules may represent a potential pharmacological tool in the treatment against cancer. PMID- 22485250 TI - ErbB3 expression predicts sensitivity to elisidepsin treatment: in vitro synergism with cisplatin, paclitaxel and gemcitabine in lung, breast and colon cancer cell lines. AB - Irvalec(r) (elisidepsin trifluoroacetate, PM02734) is a novel marine-derived cyclic peptide belonging to the Kahaladide family of compounds, currently in clinical trials with preliminary evidence of antitumor activity. Previous studies have shown a correlation between elisidepsin sensitivity and expression of the ErbB3 receptor in a panel of NSCLC cell lines. We have studied the effect of elisidepsin on the ErbB3 pathway, characterizing the expression of all members of the ErbB (HER) family of receptors and their main downstream signaling effectors, such as Akt and MAPK. Interestingly, we observed a downregulation of ErbB3 upon elisidepsin treatment that correlates with a reduction in the Akt phosphorylation levels in the most sensitive cell lines, whereas ErbB3 levels are not affected in the less sensitive ones. Also, we observed that the basal levels of ErbB3 protein expression show a significant correlation with cell viability response against elisidepsin treatment in 14 different cell lines. Furthermore, we analyzed the combination of elisidepsin with different chemotherapeutics agents, such as cisplatin, paclitaxel and gemcitabine, in a panel of different breast (MDA-MB 435, MDA-MB-231 and MCF7), lung (HOP62, DV90 and A549) and colorectal cancer cell lines (DLD1 and HT29). IC50 values for the different drugs were tested. We observed a synergistic effect in all cell lines tested with any chemotherapeutic agent. More importantly, the two in vitro elisidepsin-resistant cell lines (MDA MB-231 and HOP62) presented a synergistic effect in combination with cisplatin and paclitaxel, respectively. These results provide a rationale for further development of these combinations in an ongoing clinical trial. PMID- 22485251 TI - All-trans retinoic acid inhibits tumor growth of human osteosarcoma by activating Smad signaling-induced osteogenic differentiation. AB - Osteosarcoma (OS) is one of the most common malignant bone tumors. Despite the advancement of diagnosis and treatment for OS, the prognosis remains poor. We investigated the proliferation inhibitory effect of all-trans retinoic acid (ATRA) for human OS and the possible mechanism underlying this effect. We examined the proliferation inhibition and apoptosis-inducing effects of ATRA in 143B OS cells. We validated this effect by exogenously expressing the retinoic acid receptor alpha (RARalpha) in 143B OS cells and injecting the cells into nude mice. We explored the possible mechanism for the proliferation inhibitory effect of ATRA on OS cells and multipotential progenitor cells by detecting osteogenic markers. We demonstrated that the endogenous retinoic acid receptor and retinoid X receptor are all detectable in the commercially available OS cell lines and in primary osteosarcoma cells. ATRA inhibits the proliferation of OS cells in a concentration-dependent manner, as well as induces apoptosis in 143B OS cells. The exogenous expression of RARalpha inhibits the tumor growth and cell proliferation in vivo. The alkaline phosphatase activity, protein levels of osteopontin (OPN) and osteocalcin (OCN) are all promoted by ATRA in OS cells and mouse embryonic fibroblasts (MEFs), at least by activating the Smad signaling pathway. Collectively, our results strongly indicate that ATRA can inhibit the tumor growth of OS by promoting osteogenic differentiation in OS cells, which is mediated in part by activating Smad signaling. Therefore, combination of ATRA with other current chemotherapy agents may be a promising therapy strategy for OS treatment. PMID- 22485253 TI - Buying antibodies on the internet. PMID- 22485254 TI - Isolation of DNA fragments from polyacrylamide gels by the crush and soak method. PMID- 22485252 TI - Aryl hydrocarbon receptor activation by aminoflavone: new molecular target for renal cancer treatment. AB - Aminoflavone (AF; NSC 686288, AFP464, NSC710464) is a new anticancer drug that has recently entered phase II clinical trials. It has demonstrated antiproliferative effects in MCF-7 human breast cancer cells mediated by the aryl hydrocarbon receptor (AhR). AF also exhibits noteworthy evidence of antitumor activity in vitro and in vivo against neoplastic cells of renal origin. AF treatment of sensitive renal cells, in contrast to resistant cells, promotes the induction of CYP1A1, the covalent binding of AF-reactive intermediates and apoptosis. Based on this evidence, the aim of this study was to evaluate the role of AhR, the main transcriptional regulator of CYP1A1, in the antiproliferative effects of AF in human renal cancer cells. AF-cytoxicity in human renal cell lines and a renal cancer cell strain was assessed by MTS assay in the presence or absence of an Ahr inhibitor. Drug-induced AhR nuclear translocation was evaluated by western blotting of AhR in cytosolic and nuclear fractions and by measuring xenobiotic response element-driven luciferase activity. Apoptosis induced by the drug was evaluated by 4,6-diamidino-2-phenylindole and acridine orange/ethidium bromide staining and by measuring phosphorylated P53 (p-P53) and P21 levels, caspase 3 activation and poly(ADP-ribose) polymerase cleavage. AF inhibited cell growth in a dose-dependent manner in TK-10, Caki-1, SN12-C and A498 human renal cells but not in ACHN cells. The antiproliferative effect of AF was abrogated by pre-incubation of TK-10, Caki-1 and SN12-C cells with the AhR antagonist, alpha naphthoflavone. AF treatment also induced apoptosis in TK-10, Caki-1 and SN12-C cells, which was not observed in ACHN cells. AF induced time-dependent AhR nuclear translocation and AhR transcriptional activity in sensitive renal cancer cell lines. A renal cell strain derived from a human papillary tumor also showed sensitivity to AF, as well as AhR pathway activation and drug-induced apoptosis. AhR translocation could be included as a marker of sensitivity to AF in sensitive renal tumor cells of different histological origin, in ongoing phase II clinical trials. PMID- 22485255 TI - Ecdysone as regulator of inducible gene expression in Mammalian cells. PMID- 22485257 TI - Markers for Pulsed-field Gel Electrophoresis. PMID- 22485256 TI - Recovery of DNA from Agarose Gels: Electrophoresis onto DEAE-cellulose Membranes. PMID- 22485258 TI - Isolation of High-molecular-weight DNA from Mammalian Cells Using Formamide. PMID- 22485259 TI - Preparation of DNA for Pulsed-field Gel Electrophoresis: Isolation of Intact DNA from Yeast. PMID- 22485261 TI - Large-scale Preparation of Single-stranded and Double-stranded Bacteriophage M13 DNA. PMID- 22485260 TI - Preparation of Double-stranded (Replicative Form) Bacteriophage M13 DNA. PMID- 22485262 TI - Screening an Unamplified Cosmid Library by Hybridization: Plating the Library onto Filters. PMID- 22485263 TI - Working with yeast artificial chromosomes. PMID- 22485264 TI - Growth of S. cerevisiae and Preparation of DNA. PMID- 22485265 TI - Small-scale Preparations of Yeast DNA. PMID- 22485266 TI - Construction of cDNA libraries * stage 4: attachment of linkers or adaptors. PMID- 22485267 TI - Removal of Cross-reactive Antibodies from Antiserum: Affinity Chromatography. PMID- 22485268 TI - Rapid and Efficient Site-directed Mutagenesis by the Single-tube Megaprimer PCR Method. PMID- 22485269 TI - Site-specific Mutagenesis by Overlap Extension. PMID- 22485270 TI - Mixed Oligonucleotide-primed Amplification of cDNA (MOPAC). PMID- 22485271 TI - Inverse PCR. PMID- 22485272 TI - Purification of radiolabeled oligonucleotides by precipitation with ethanol. PMID- 22485273 TI - Rapid isolation of Mammalian DNA. PMID- 22485274 TI - Random priming: radiolabeling of purified DNA fragments by extension of random oligonucleotides. PMID- 22485275 TI - Random priming: radiolabeling of DNA by extension of random oligonucleotides in the presence of melted agarose. PMID- 22485276 TI - Synthesis of Single-stranded DNA Probes of Heterogeneous Length from Bacteriophage M13 Templates. PMID- 22485277 TI - Labeling 3' Termini of Double-stranded DNA Using the Klenow Fragment of E. coli DNA Polymerase I. PMID- 22485278 TI - Construction of cDNA Libraries * Stage 2: Second-strand Synthesis. PMID- 22485279 TI - Labeling of Synthetic Oligonucleotides Using the Klenow Fragment of E. coli DNA Polymerase I. PMID- 22485280 TI - Autoradiography and reading of sequencing gels. PMID- 22485281 TI - Generation of Bidirectional Sets of Deletion Mutants by Digestion with BAL 31 Nuclease. PMID- 22485282 TI - Expression of Cloned Genes in E. coli Using the Bacteriophage T7 Promoter. PMID- 22485283 TI - Assay for luciferase in extracts of Mammalian cells. PMID- 22485284 TI - Exon trapping and amplification * stage 5: analysis of clones. PMID- 22485285 TI - Expression of Secreted Foreign Proteins Using the Alkaline Phosphatase Promoter (phoA) and Signal Sequence. PMID- 22485286 TI - Purification of fusion proteins by affinity chromatography on glutathione agarose. PMID- 22485287 TI - Preparation of Single-stranded Bacteriophage M13 DNA. PMID- 22485288 TI - Isolation of DNA from Mammalian Cells Grown in 96-well Microtiter Plates. PMID- 22485290 TI - Northern hybridization. PMID- 22485289 TI - Detection of DNA in polyacrylamide gels by staining. PMID- 22485291 TI - Purification of Radiolabeled Oligonucleotides by Size-exclusion Chromatography. PMID- 22485292 TI - Construction of cDNA Libraries * Stage 5: Fractionation of cDNA by Gel Filtration through Sepharose CL-4B. PMID- 22485294 TI - Exon trapping and amplification * stage 3: harvesting the mRNA. PMID- 22485293 TI - Exon Trapping and Amplification * Stage 2: Electroporation of the Library into COS-7 Cells. PMID- 22485295 TI - Oligonucleotide-directed Mutagenesis by Elimination of a Unique Restriction Site (USE Mutagenesis). PMID- 22485296 TI - DNA transfection by electroporation. PMID- 22485297 TI - Detection of Protein-Protein Interactions Using the GST Fusion Protein Pulldown Technique. PMID- 22485299 TI - Removal of Cross-reactive Antibodies from Antiserum: Incubation with E. coli Lysate. PMID- 22485298 TI - Screening Expression Libraries Constructed in Bacteriophage lambda Vectors. PMID- 22485300 TI - Preparation of Lysates Containing Fusion Proteins Encoded by Bacteriophage lambda Lysogens: Lysis of Bacterial Colonies. PMID- 22485301 TI - Preparation of Lysates Containing Fusion Proteins Encoded by Bacteriophage lambda: Lytic Infections on Agar Plates. PMID- 22485302 TI - Preparation of Lysates Containing Fusion Proteins Encoded by Bacteriophage lambda: Lytic Infections in Liquid Medium. PMID- 22485304 TI - Identifying DNA-binding Proteins in Bacteriophage lambda Expression Libraries. PMID- 22485303 TI - Removal of Cross-reactive Antibodies from Antiserum: Pseudoscreening. PMID- 22485305 TI - Preparing Denatured Templates for Sequencing by Dideoxy-mediated Chain Termination. PMID- 22485306 TI - Cycle Sequencing: Dideoxy-mediated Sequencing Reactions Using PCR and End-labeled Primers. PMID- 22485307 TI - Preparation of denaturing polyacrylamide gels. PMID- 22485308 TI - Loading and running DNA sequencing gels. PMID- 22485309 TI - Preparation of electrolyte gradient gels. PMID- 22485310 TI - Dideoxy-mediated Sequencing Reactions Using Bacteriophage T7 DNA Polymerase (Sequenase). PMID- 22485311 TI - Dideoxy-mediated Sequencing Reactions Using the Klenow Fragment of E. coli DNA Polymerase I and Single-stranded DNA Templates. PMID- 22485312 TI - Dideoxy-mediated Sequencing of DNA Using Taq DNA Polymerase. PMID- 22485313 TI - Chemical sequencing. PMID- 22485314 TI - Preparation of denaturing polyacrylamide gels containing formamide. PMID- 22485315 TI - Preparation of Uracil-containing Single-stranded Bacteriophage M13 DNA. PMID- 22485316 TI - In Vitro Mutagenesis Using Double-stranded DNA Templates: Selection of Mutants with DpnI. PMID- 22485318 TI - Oligonucleotide-directed Mutagenesis of Single-stranded DNA. PMID- 22485317 TI - Detection of Mutations by Single-strand Conformational Polymorphism. PMID- 22485319 TI - Probing Protein Interactions Using GFP and FRET * Stage 3: FLIM-FRET Measurements. PMID- 22485320 TI - The basic polymerase chain reaction. PMID- 22485321 TI - Purification of PCR products in preparation for cloning. PMID- 22485322 TI - Removal of Oligonucleotides and Excess dNTPs from Amplified DNA by Ultrafiltration. PMID- 22485323 TI - Blunt-end Cloning of PCR Products. PMID- 22485324 TI - Cloning PCR products into T vectors. PMID- 22485325 TI - Cloning PCR products by addition of restriction sites to the termini of amplified DNA. PMID- 22485327 TI - Amplification of cDNA generated by reverse transcription of mRNA. PMID- 22485326 TI - Genetic engineering with PCR. PMID- 22485328 TI - Rapid Characterization of DNAs Cloned in Prokaryotic Vectors. PMID- 22485329 TI - Long PCR. PMID- 22485330 TI - Quantitative PCR. PMID- 22485331 TI - Differential Display-PCR. PMID- 22485332 TI - Synthesis of Single-stranded RNA Probes by In Vitro Transcription. PMID- 22485333 TI - Radiolabeling of DNA probes by the polymerase chain reaction. PMID- 22485334 TI - Labeling 3' Termini of Double-stranded DNA with Bacteriophage T4 DNA Polymerase. PMID- 22485335 TI - End Labeling Protruding 3' Termini of Double-stranded DNA with [alpha 32P]Cordycepin 5'-Triphosphate or [alpha-32P]dideoxyATP. PMID- 22485337 TI - Dephosphorylation of DNA fragments with alkaline phosphatase. PMID- 22485336 TI - Radiolabeling of subtracted cDNA probes by random oligonucleotide extension. PMID- 22485338 TI - Phosphorylation of DNA molecules with protruding 5'-hydroxyl termini. PMID- 22485339 TI - Rapid Amplification of 3' cDNA Ends (3'-RACE). PMID- 22485341 TI - Synthesis of Radiolabeled, Subtracted cDNA Probes Using Oligo(dT) as a Primer. PMID- 22485340 TI - Synthesis of cDNA probes from mRNA using random oligonucleotide primers. PMID- 22485342 TI - DNA transfection mediated by lipofection. PMID- 22485343 TI - Calcium-phosphate-mediated Transfection of Eukaryotic Cells with Plasmid DNAs. PMID- 22485344 TI - Calcium-phosphate-mediated Transfection of Cells with High-molecular-weight Genomic DNA. PMID- 22485345 TI - DNA transfection by biolistics. PMID- 22485346 TI - DNA transfection using polybrene. PMID- 22485347 TI - Transfection Mediated by DEAE-Dextran: High-efficiency Method. PMID- 22485348 TI - Phosphorylating the 5' termini of oligonucleotides. PMID- 22485349 TI - Purification of radiolabeled oligonucleotides by precipitation with cetylpyridinium bromide. PMID- 22485350 TI - Hybridization of oligonucleotide probes in aqueous solutions: washing in buffers containing quaternary ammonium salts. PMID- 22485351 TI - Empirical measurement of melting temperature. PMID- 22485352 TI - Two-hybrid Systems * Stage 2: Selecting an Interactor. PMID- 22485353 TI - Two-hybrid Systems. PMID- 22485355 TI - Analysis of Interacting Proteins with SPR Spectroscopy Using BIAcore * Stage 1: Preparation of the Capture Surface and Test Binding. PMID- 22485354 TI - Probing Protein Interactions Using GFP and FRET * Stage 2: Cell Preparation for FLIM-FRET Analysis. PMID- 22485356 TI - Two-hybrid Systems * Stage 1: Characterization of a Bait-LexA Fusion Protein. PMID- 22485357 TI - Identification of associated proteins by coimmunoprecipitation. PMID- 22485358 TI - Preparation of Plasmid DNA by Alkaline Lysis with SDS: Midipreparation. PMID- 22485359 TI - Preparation of Plasmid DNA by Small-scale Boiling Lysis. PMID- 22485360 TI - Preparation of Plasmid DNA: Toothpick Minipreparation. PMID- 22485361 TI - Preparation of Plasmid DNA by Lysis with SDS. PMID- 22485362 TI - Purification of plasmid DNA by precipitation with polyethylene glycol. PMID- 22485363 TI - Preparation of Plasmid DNA by Large-scale Boiling Lysis. PMID- 22485364 TI - Purification of Closed Circular DNA by Equilibrium Centrifugation in CsCl Ethidium Bromide Gradients: Discontinuous Gradients. PMID- 22485365 TI - Removal of ethidium bromide from DNA by extraction with organic solvents. PMID- 22485366 TI - Removal of Ethidium Bromide from DNA by Ion-exchange Chromatography. PMID- 22485367 TI - Removal of Small Fragments of Nucleic Acid from Preparations of Plasmid DNA by Centrifugation through NaCl. PMID- 22485368 TI - Removal of Small Fragments of Nucleic Acid from Preparations of Plasmid DNA by Chromatography through Sephacryl S-1000. PMID- 22485369 TI - Removal of small fragments of nucleic Acid from preparations of plasmid DNA by precipitation with lithium chloride. PMID- 22485370 TI - Directional cloning into plasmid vectors. PMID- 22485371 TI - Attaching adaptors to protruding termini. PMID- 22485372 TI - Blunt-ended Cloning into Plasmid Vectors. PMID- 22485373 TI - Dephosphorylation of plasmid DNA. PMID- 22485374 TI - Purification of plasmid DNA by chromatography. PMID- 22485375 TI - Purification of Closed Circular DNA by Equilibrium Centrifugation in CsCl Ethidium Bromide Gradients: Continuous Gradients. PMID- 22485376 TI - Ligating Plasmid and Target DNAs in Low-melting-temperature Agarose. PMID- 22485377 TI - Preparation and Transformation of Competent E. coli Using Calcium Chloride. PMID- 22485378 TI - Transformation of E. coli by Electroporation. PMID- 22485379 TI - Screening bacterial colonies by hybridization: small numbers. PMID- 22485380 TI - Screening bacterial colonies by hybridization: large numbers. PMID- 22485381 TI - Lysing colonies and binding of DNA to filters. PMID- 22485382 TI - Hybridization of bacterial DNA on filters. PMID- 22485383 TI - Addition of Synthetic Linkers to Blunt-ended DNA. PMID- 22485384 TI - The Hanahan Method for Preparation and Transformation of Competent E. coli: High efficiency Transformation. PMID- 22485385 TI - The inoue method for preparation and transformation of competent e. Coli: "ultra competent" cells. PMID- 22485386 TI - Screening Bacterial Colonies Using X-gal and IPTG: alpha-Complementation. PMID- 22485387 TI - Screening bacterial colonies by hybridization: intermediate numbers. PMID- 22485388 TI - Mapping Protein-binding Sites on DNA by DNase I Footprinting. PMID- 22485389 TI - Gel Retardation Assays for DNA-binding Proteins. PMID- 22485390 TI - Mapping DNase-I-hypersensitive Sites. PMID- 22485391 TI - Measurement of Chloramphenicol Acetyltransferase in Extracts of Mammalian Cells Using Thin-layer Chromatography. PMID- 22485392 TI - Assay for beta-galactosidase in Extracts of Mammalian Cells. PMID- 22485393 TI - Transcriptional Run-on Assays. PMID- 22485394 TI - Tetracycline as Regulator of Inducible Gene Expression * Stage 2: Stable Transfection of Inducible tTA-expressing NIH-3T3 Cells with Tetracycline regulated Target Genes. PMID- 22485395 TI - Tetracycline as regulator of inducible gene expression * stage 3: analysis of protein expression in transfected cells. PMID- 22485397 TI - Plating Bacteriophage lambda. PMID- 22485396 TI - Probing Protein Interactions Using GFP and FRET * Stage 1: Labeling Proteins with Fluorescent Dyes. PMID- 22485398 TI - Picking Bacteriophage lambda Plaques. PMID- 22485399 TI - Preparing Stocks of Bacteriophage lambda by Plate Lysis and Elution. PMID- 22485400 TI - Large-scale Growth of Bacteriophage lambda: Infection at Low Multiplicity. PMID- 22485401 TI - Precipitation of Bacteriophage lambda Particles from Large-scale Lysates. PMID- 22485402 TI - Assaying the DNA Content of Bacteriophage lambda Stocks and Lysates by Gel Electrophoresis. PMID- 22485403 TI - Purification of Bacteriophage lambda Particles by Isopycnic Centrifugation through CsCl Gradients. PMID- 22485404 TI - Purification of Bacteriophage lambda Particles by Centrifugation through a Glycerol Step Gradient. PMID- 22485405 TI - Purification of Bacteriophage lambda Particles by Pelleting/Centrifugation. PMID- 22485406 TI - Preparing Stocks of Bacteriophage lambda by Small-scale Liquid Culture. PMID- 22485407 TI - Extraction of Bacteriophage lambda DNA from Large-scale Cultures Using Proteinase K and SDS. PMID- 22485408 TI - Extraction of Bacteriophage lambda DNA from Large-scale Cultures Using Formamide. PMID- 22485409 TI - Preparation of Bacteriophage lambda DNA Cleaved with a Single Restriction Enzyme for Use as a Cloning Vector. PMID- 22485410 TI - Alkaline Phosphatase Treatment of Bacteriophage lambda Vector DNA. PMID- 22485411 TI - Partial digestion of eukaryotic DNA for use in genomic libraries: pilot reactions. PMID- 22485412 TI - Partial digestion of eukaryotic DNA for use in genomic libraries: preparative reactions. PMID- 22485413 TI - Ligation of Bacteriophage lambda Arms to Fragments of Foreign Genomic DNA. PMID- 22485414 TI - Amplification of genomic libraries. PMID- 22485416 TI - Hybridization of bacteriophage DNA on filters. PMID- 22485415 TI - Transfer of bacteriophage DNA from plaques to filters. PMID- 22485417 TI - Rapid Analysis of Bacteriophage lambda Isolates: Purification of lambda DNA from Plate Lysates. PMID- 22485418 TI - Rapid Analysis of Bacteriophage lambda Isolates: Purification of lambda DNA from Liquid Cultures. PMID- 22485419 TI - Tetracycline as Regulator of Inducible Gene Expression * Stage 1: Stable Transfection of Fibroblasts with pTet-tTAk. PMID- 22485421 TI - Rapid Amplification of 5' cDNA Ends (5'-RACE). PMID- 22485420 TI - Preparation of Bacteriophage lambda DNA Cleaved with Two Restriction Enzymes for Use as a Cloning Vector. PMID- 22485422 TI - Purification of Bacteriophage lambda Arms: Centrifugation through Sucrose Density Gradients. PMID- 22485423 TI - Plating bacteriophage m13. PMID- 22485425 TI - Analysis of recombinant bacteriophage m13 clones. PMID- 22485424 TI - Growing bacteriophage m13 in liquid culture. PMID- 22485426 TI - Construction of genomic DNA libraries in cosmid vectors. PMID- 22485427 TI - Amplification and storage of a cosmid library: amplification in liquid culture. PMID- 22485428 TI - Amplification and storage of a cosmid library: amplification on filters. PMID- 22485429 TI - Working with bacteriophage p1 and its cloning systems. PMID- 22485430 TI - Transferring Bacteriophage P1 Clones between E. coli Hosts. PMID- 22485431 TI - Isolation of BAC DNA from Small-scale Cultures. PMID- 22485432 TI - Isolation of BAC DNA from Large-scale Cultures. PMID- 22485434 TI - Working with bacterial artificial chromosomes. PMID- 22485433 TI - Isolating the Ends of Genomic DNA Fragments Cloned in High-capacity Vectors: Vectorette Polymerase Chain Reactions. PMID- 22485435 TI - Phosphorylation of DNA molecules with dephosphorylated blunt ends or recessed 5' termini. PMID- 22485436 TI - Phosphorylation of DNA molecules with protruding 5' termini by the exchange reaction. PMID- 22485437 TI - Screening Recombinant Clones for Site-directed Mutagenesis by Hybridization to Radiolabeled Oligonucleotides. PMID- 22485438 TI - Detection of Protein-Protein Interactions Using Far Western with GST Fusion Proteins. PMID- 22485439 TI - Analyzing yeast colonies by PCR. PMID- 22485440 TI - Cloning into bacteriophage m13 vectors. PMID- 22485441 TI - Producing Single-stranded DNA with Phagemid Vectors. PMID- 22485442 TI - Agarose gel electrophoresis. PMID- 22485443 TI - Detection of DNA in agarose gels. PMID- 22485444 TI - Recovery of DNA from agarose and polyacrylamide gels: electroelution into dialysis bags. PMID- 22485445 TI - Purification of DNA Recovered from Agarose and Polyacrylamide Gels by Anion exchange Chromatography. PMID- 22485446 TI - Recovery of DNA from Low-melting-temperature Agarose Gels: Organic Extraction. PMID- 22485447 TI - Recovery of DNA from Low-melting-temperature Agarose Gels: Enzymatic Digestion with Agarase. PMID- 22485448 TI - Alkaline agarose gel electrophoresis. PMID- 22485449 TI - Neutral polyacrylamide gel electrophoresis. PMID- 22485450 TI - Detection of DNA in polyacrylamide gels by autoradiography. PMID- 22485451 TI - Preparation of DNA for Pulsed-field Gel Electrophoresis: Isolation of DNA from Mammalian Cells and Tissues. PMID- 22485453 TI - Pulsed-field Gel Electrophoresis via Transverse Alternating Field Electrophoresis Gels. PMID- 22485452 TI - Restriction endonuclease digestion of DNA in agarose plugs. PMID- 22485454 TI - Pulsed-field Gel Electrophoresis via Contour-clamped Homogeneous Electric Field Gels. PMID- 22485455 TI - Retrieval of DNA Fragments from Pulsed-field Gels following DNA Concentration. PMID- 22485456 TI - Isolation of High-molecular-weight DNA from Mammalian Cells Using Proteinase K and Phenol. PMID- 22485457 TI - Isolation of DNA from Mammalian cells by spooling. PMID- 22485458 TI - Preparation of genomic DNA from mouse tails and other small samples. PMID- 22485459 TI - Rapid isolation of yeast DNA. PMID- 22485460 TI - Southern blotting: capillary transfer of DNA to membranes. PMID- 22485461 TI - Southern blotting: simultaneous transfer of DNA from a single agarose gel to two membranes. PMID- 22485463 TI - Purification of RNA from cells and tissues by Acid phenol-guanidinium thiocyanate chloroform extraction. PMID- 22485462 TI - Southern hybridization of radiolabeled probes to nucleic acids immobilized on membranes. PMID- 22485465 TI - Selection of poly(a)+ RNA by batch chromatography. PMID- 22485464 TI - Selection of Poly(A)+ RNA by Oligo(dT)-Cellulose Chromatography. PMID- 22485467 TI - Dot and slot hybridization of purified RNA. PMID- 22485466 TI - Separation of RNA According to Size: Electrophoresis of RNA through Agarose Gels Containing Formaldehyde. PMID- 22485468 TI - Mapping RNA with nuclease s1. PMID- 22485469 TI - Ribonuclease protection: mapping RNA with ribonuclease and radiolabeled RNA probes. PMID- 22485470 TI - Analysis of RNA by primer extension. PMID- 22485472 TI - Separation of RNA According to Size: Electrophoresis of Glyoxylated RNA through Agarose Gels. PMID- 22485471 TI - A Single-step Method for the Simultaneous Preparation of DNA, RNA, and Protein from Cells and Tissues. PMID- 22485473 TI - Transfer and fixation of denatured RNA to membranes. PMID- 22485474 TI - Synthesis of Single-stranded DNA Probes of Defined Length from Bacteriophage M13 Templates. PMID- 22485475 TI - Purification of synthetic oligonucleotides by polyacrylamide gel electrophoresis. PMID- 22485476 TI - Purification of radiolabeled oligonucleotides by chromatography on a sep-pak c18 column. PMID- 22485477 TI - Construction of cDNA Libraries Stage 1: Synthesis of First-strand cDNA Catalyzed by Reverse Transcriptase. PMID- 22485478 TI - Construction and screening of eukaryotic expression libraries * stage 1: construction of cDNA libraries in eukaryotic expression vectors. PMID- 22485479 TI - Construction and screening of eukaryotic expression libraries * stage 2: screening cDNA libraries constructed in eukaryotic expression vectors. PMID- 22485480 TI - Construction of cDNA libraries * stage 3: methylation of cDNA. PMID- 22485481 TI - Construction of cDNA Libraries * Stage 6: Ligation of cDNA to Bacteriophage lambda Arms. PMID- 22485482 TI - Exon trapping and amplification * stage 1: construction of the library. PMID- 22485483 TI - Exon Trapping and Amplification * Stage 4: Reverse Transcriptase-PCR. PMID- 22485484 TI - Direct Selection of cDNAs with Large Genomic DNA Clones. PMID- 22485486 TI - Screening expression libraries constructed in plasmid vectors. PMID- 22485485 TI - Generation of Sets of Nested Deletion Mutants with Exonuclease III. PMID- 22485487 TI - Generation of a library of randomly overlapping DNA inserts. PMID- 22485488 TI - Direct Retrieval of DNA Fragments from Pulsed-field Gels. PMID- 22485489 TI - Preparation of Plasmid DNA by Alkaline Lysis with SDS: Minipreparation. PMID- 22485491 TI - Expression of Cloned Genes in E. coli Using the Bacteriophage lambda pL Promoter. PMID- 22485490 TI - Expression of Cloned Genes in E. coli Using IPTG-inducible Promoters. PMID- 22485492 TI - Purification of Maltose-binding Fusion Proteins by Affinity Chromatography on Amylose Resin. PMID- 22485493 TI - Purification of Histidine-tagged Proteins by Immobilized Ni2+ Absorption Chromatography. PMID- 22485494 TI - Purification of expressed proteins from inclusion bodies. PMID- 22485496 TI - Dealing with Carryover Contamination in PCR: An Enzymatic Strategy. PMID- 22485495 TI - Preparation of Plasmid DNA by Alkaline Lysis with SDS: Maxipreparation. PMID- 22485497 TI - PCR Amplification of Highly GC-Rich Regions. PMID- 22485498 TI - Long and accurate PCR. PMID- 22485499 TI - Nonradioactive Cycle Sequencing of PCR-Amplified DNA. PMID- 22485500 TI - Purification of genomic DNA from whole blood: a solution-based method. PMID- 22485501 TI - A silica membrane-based method for the isolation of genomic DNA from tissues and cultured cells. PMID- 22485502 TI - DNA IQ Isolation of Genomic DNA from Stains and Buccal Swabs. PMID- 22485503 TI - A silica-based method for purifying PCR fragments from agarose gels. PMID- 22485504 TI - A magnetic particle-based method for purifying PCR products from solution. PMID- 22485505 TI - Dye terminator cleanup for automated DNA sequencing reactions. PMID- 22485506 TI - Preparation of RNA from plant tissue using guanidinium isothiocyanate/cesium chloride ultracentrifugation. PMID- 22485508 TI - Purification of RNA from animal cells using trizol. PMID- 22485507 TI - Preparation of RNA from paraffin-embedded fixed tissue using trizol. PMID- 22485509 TI - Preparation of RNA from plant tissue using trizol. PMID- 22485510 TI - Purification of RNA from plant tissue using the concert plant reagent. PMID- 22485511 TI - Laser Capture Microdissection (LCM): Preparation and Sectioning of Frozen Tissue Blocks and Purification of RNA from Isolated Cells. PMID- 22485512 TI - cDNA synthesis and real-time PCR using RNA from laser-captured cells. PMID- 22485513 TI - Relative RT-PCR: Determining the Linear Range of Amplification and Optimizing the Primers:Competimers Ratio. PMID- 22485515 TI - Competitive RT-PCR: Estimation of Copy Number. PMID- 22485514 TI - Competitive RT-PCR: Preparation of Competitor RNA. PMID- 22485516 TI - Real-time PCR. PMID- 22485517 TI - Multiplex real-time PCR. PMID- 22485518 TI - Real-Time RT-PCR: cDNA Synthesis. AB - INTRODUCTION This protocol uses the Superscript II First-Strand Synthesis System for the generation of cDNA from total RNA. PMID- 22485520 TI - Loss of heterozygosity: a multiplex PCR method to define a narrow deleted chromosomal region of a tumor genome. PMID- 22485519 TI - Amplification of RNA: High-Temperature Reverse Transcription and DNA Amplification with a Magnesium-Activated Thermostable DNA Polymerase. PMID- 22485521 TI - Single-strand conformation polymorphism analysis. PMID- 22485522 TI - Reverse transcriptase in situ PCR. PMID- 22485524 TI - Hybridization and Detection Using the HC ExpressArray Kit. PMID- 22485523 TI - Mutation detection by solid-phase chemical cleavage of mismatches using radioactive probes. PMID- 22485525 TI - Extraction and purification of RNA from tissue-cultured cells for fluorescent mRNA differential display. PMID- 22485526 TI - Extraction and purification of RNA from tissue samples for fluorescent mRNA differential display. PMID- 22485527 TI - Extraction and purification of RNA from blood samples for fluorescent mRNA differential display. PMID- 22485528 TI - Removal of genomic DNA from total RNA for use in fluorescent mRNA differential display. PMID- 22485529 TI - Preparation of a denaturing agarose gel for the analysis of RNA samples. PMID- 22485530 TI - FDD PCR, Identification and Analysis of Differentially Expressed cDNAs. PMID- 22485531 TI - PCR-Based Screening of DNA Libraries. PMID- 22485533 TI - 5'-End cDNA Amplification Using Classic RACE. PMID- 22485532 TI - 3'-End cDNA Amplification Using Classic RACE. PMID- 22485534 TI - 5'-End cDNA Amplification Using New RACE. PMID- 22485535 TI - Cap-Switching RACE. PMID- 22485536 TI - Use of PCR to prepare a double-stranded DNA library encoding random peptides. PMID- 22485538 TI - Use of PCR for quality control of a Peptide DNA library. PMID- 22485537 TI - Synthesis of DNA libraries: use of PCR to analyze ligation substrates and products. PMID- 22485539 TI - Use of PCR for quality control of a genomic DNA library. PMID- 22485540 TI - Bidirectional cloning of PCR products. PMID- 22485541 TI - Directional cloning of PCR products. PMID- 22485543 TI - Ribocloning: DNA cloning and gene construction using PCR primers terminated with a ribonucleotide. PMID- 22485542 TI - Colony PCR. PMID- 22485544 TI - Mutagenic PCR. PMID- 22485545 TI - Rapid PCR site-directed mutagenesis. PMID- 22485546 TI - High-efficiency transformation of yeast. PMID- 22485547 TI - "Quick and dirty" plasmid transformation of yeast colonies. PMID- 22485548 TI - Yeast DNA isolation: midiprep. PMID- 22485549 TI - Yeast DNA isolation: miniprep. PMID- 22485550 TI - Isolation of yeast genomic DNA for southern blot analysis. PMID- 22485551 TI - Isolation of plasmid DNA from yeast cells: a ten-minute preparation. PMID- 22485553 TI - Yeast protein extracts. PMID- 22485552 TI - Preparation of genomic DNA from yeast using glass beads. PMID- 22485554 TI - Tandem Affinity Protein (TAP) Purification from Yeast. PMID- 22485555 TI - Yeast RNA isolation: large-scale. PMID- 22485556 TI - Yeast RNA isolation: small-scale. PMID- 22485557 TI - Hydroxylamine mutagenesis of plasmid DNA. PMID- 22485558 TI - Assay of beta-Galactosidase in Yeast: Assay of Crude Extracts. PMID- 22485559 TI - Assay of beta-Galactosidase in Yeast: Permeabilized Cell Assay. PMID- 22485560 TI - Assay of beta-Galactosidase in Yeast: Freeze/Thaw Assay by Chemiluminescence in Microcentrifuge Tubes. PMID- 22485561 TI - Assay of beta-Galactosidase in Yeast: Freeze/Thaw Assay by Chemiluminescence in 96-Well Plates. PMID- 22485562 TI - Plate assay for carboxypeptidase y in yeast cells. PMID- 22485563 TI - Random spore analysis in yeast. PMID- 22485564 TI - Yeast Vital Stains: DAPI Stain of Nuclear and Mitochondrial DNA. PMID- 22485566 TI - Yeast Vital Stains: Visualizing Vacuoles and Endocytic Compartments with FM4-64. PMID- 22485565 TI - Yeast Vital Stains: Visualizing Mitochondria with DiOC6 or DiIC5(3). PMID- 22485567 TI - Yeast vital stains: calcofluor staining of chitin and bud scars. PMID- 22485568 TI - Yeast immunofluorescence. PMID- 22485569 TI - Actin staining in fixed yeast cells. PMID- 22485570 TI - PCR-Mediated Gene Disruption: One-Step Method. PMID- 22485571 TI - Yeast colony PCR. PMID- 22485572 TI - Inducing Yeast Cell Synchrony: alpha-Factor Arrest Using Low Cell Concentration. PMID- 22485573 TI - Inducing Yeast Cell Synchrony: alpha-Factor Arrest Using Low pH. PMID- 22485574 TI - Inducing Yeast Cell Synchrony: alpha-Factor Arrest Using bar1 Mutants. PMID- 22485575 TI - Inducing yeast cell synchrony: hydroxyurea arrest. PMID- 22485576 TI - Inducing yeast cell synchrony: nocodazole arrest. PMID- 22485578 TI - Chromatin immunoprecipitation in yeast. PMID- 22485577 TI - Inducing yeast cell synchrony: dilution of stationary-phase cultures. PMID- 22485579 TI - Preparation of yeast cells for flow cytometry. PMID- 22485580 TI - Logarithmic growth. PMID- 22485581 TI - Ethyl Methane Sulfonate (EMS) Mutagenesis. PMID- 22485582 TI - Tetrad dissection. PMID- 22485583 TI - Making a tetrad dissection needle. PMID- 22485584 TI - Picking zygotes. PMID- 22485585 TI - Determining plating efficiency in yeast: indirect method. PMID- 22485586 TI - Determining plating efficiency in yeast: direct method. PMID- 22485587 TI - Measuring yeast cell density by spectrophotometry. PMID- 22485588 TI - The tap-fill method for dry packing columns of rigid solids. PMID- 22485589 TI - Preparation of vectors for high-throughput screening of soluble recombinant proteins. PMID- 22485590 TI - Preparation of sticky-end PCR products and ligation into expression vectors for high-throughput screening of soluble recombinant proteins. PMID- 22485591 TI - Induction and screening of soluble fusion proteins in bacterial cells. PMID- 22485593 TI - Selection of an Ion Exchanger: Determining the pI of a Protein Using Isoelectric Focusing. PMID- 22485592 TI - Selection of an Ion Exchanger: Determining the pI of a Protein Using the Titration Curve Method. PMID- 22485594 TI - Selection of an Ion Exchanger: Determining the pI of a Protein Using the Test Tube Method. PMID- 22485595 TI - Selection of an Ion Exchanger: Determining the pI of a Protein Using the Trial and-Error Method. PMID- 22485597 TI - Separating proteins using ion-exchange chromatography. PMID- 22485596 TI - Preparation of an ion-exchange column. PMID- 22485598 TI - Packing a size-exclusion column. PMID- 22485599 TI - Preparative size-exclusion chromatography. PMID- 22485600 TI - Desalting and buffer exchange of proteins using size-exclusion chromatography. PMID- 22485601 TI - Standard Chromatographic Conditions for RP-HPLC of Proteins. PMID- 22485602 TI - Separation of proteins using hydrophobic interaction chromatography. PMID- 22485603 TI - Lectin-agarose affinity chromatography. PMID- 22485604 TI - Protein ligand affinity chromatography. PMID- 22485605 TI - Directed Orientation of Antibodies during Preparation of Antibody Affinity Resin. PMID- 22485606 TI - Preparation of DNA affinity resin. PMID- 22485608 TI - Preparation of affinity-ligand resins by immobilization of dyes on polyhydroxyl matrices using a direct coupling method. PMID- 22485607 TI - DNA affinity chromatography. PMID- 22485609 TI - Preparation of affinity-ligand resins by immobilization of dyes on polyhydroxyl matrices using a spacer arm. PMID- 22485610 TI - Screening Immobilized Dyes for their Ability to Bind a Target Protein. PMID- 22485611 TI - Optimization of adsorption conditions for dye-ligand affinity chromatography. PMID- 22485612 TI - Optimization of elution conditions for dye-ligand affinity chromatography. PMID- 22485613 TI - A Batch Test Tube Method for the Calculation of an Adsorbent's Available Capacity. PMID- 22485614 TI - Purification of protein using dye-ligand affinity chromatography. PMID- 22485615 TI - Preparation of a Prepacked IMAC Column. PMID- 22485616 TI - Packing an IMAC Column. PMID- 22485617 TI - Preparation of Clarified E. coli Extract Containing Histidine-Tagged Proteins. PMID- 22485619 TI - Purification of Histidine-Tagged Proteins under Denaturing Conditions Using IMAC. PMID- 22485618 TI - Purification of Histidine-Tagged Proteins Using IMAC Without Parameter Optimization. PMID- 22485620 TI - Chromatography using a crystalline powder form of hydroxyapatite. PMID- 22485621 TI - Extraction and solubilization of total protein from microorganisms. PMID- 22485622 TI - Extraction and solubilization of total protein from plant seeds. PMID- 22485623 TI - Extraction and solubilization of total protein from Mammalian tissue samples. PMID- 22485624 TI - Extraction and solubilization of mouse liver proteins enriched for alkaline proteins. PMID- 22485625 TI - Sequential extraction of wheat seed proteins. PMID- 22485626 TI - Prefractionation of mouse liver proteins with sephadex-isoelectric focusing. PMID- 22485627 TI - Isoelectric Focusing in Immobilized pH Gradient Strips Using the IPGphor Unit: Sample In-Gel Rehydration. PMID- 22485628 TI - Isoelectric Focusing in Immobilized pH Gradient Strips Using the IPGphor Unit: Sample Cup Loading. PMID- 22485629 TI - Multiple SDS-PAGE on Vertical Electrophoresis Units. PMID- 22485630 TI - Fluorescent difference gel electrophoresis. PMID- 22485631 TI - Fractionation of Human Plasma Proteins for Two-Dimensional Gel Electrophoresis Using a Multicompartment Electrolyzer (MCE). PMID- 22485632 TI - Fractionation of maize embryo proteins for two-dimensional gel electrophoresis using a multicompartment electrolyzer. PMID- 22485633 TI - Preparation of Polyclonal Antibodies from Plasma or Serum Using the Gradiflow BF400 Instrument. PMID- 22485634 TI - Concentration of Proteins from Tissue Culture Supernatant Using the Gradiflow BF400 Instrument. PMID- 22485635 TI - Albumin Depletion from Plasma Using the Gradiflow BF400 Instrument. PMID- 22485636 TI - Native Isoelectric Focusing Free-flow Electrophoresis (IEF-FFE) Fractionation of Crude Protein Mixtures. PMID- 22485637 TI - Denaturing Isoelectric Focusing Free-Flow Electrophoresis (IEF-FFE) Fractionation of Crude Protein Mixtures. PMID- 22485638 TI - Preparation of urea and guanidinium chloride stock solutions for measuring denaturant-induced unfolding curves. PMID- 22485639 TI - Determining a urea or guanidinium chloride unfolding curve. PMID- 22485640 TI - Determining a thermal unfolding curve. PMID- 22485641 TI - Measuring the conformational stability of a protein by NMR. PMID- 22485642 TI - Hydrogen fluoride deglycosylation of glycoproteins. PMID- 22485643 TI - Monosaccharide composition analysis: alditol acetates. PMID- 22485644 TI - Monosaccharide analysis by methanolysis. PMID- 22485645 TI - Monosaccharide analysis of phosphorylated sugars by methanolysis and diazomethane methylation. PMID- 22485646 TI - Linkage Analysis Using the NaOH Methylation Method. PMID- 22485647 TI - Measuring protein concentration by a280 using a single-beam spectrophotometer. PMID- 22485648 TI - Measuring protein concentration by a280 using a dual-beam spectrophotometer. PMID- 22485649 TI - Measuring protein concentration in the presence of nucleic acids by a280/a260: the method of warburg and christian. PMID- 22485650 TI - Estimating protein concentration by dot blotting of multiple samples. PMID- 22485651 TI - Rapid Measurement of Protein Concentration by Western Analysis Using Colorimetric Detection by BCIP-NBT. PMID- 22485653 TI - Western Analysis Using the Chemiluminescent Alkaline Phosphatase Substrate CSPD. PMID- 22485652 TI - Measuring protein concentration by Western analysis using enhanced chemiluminescence detection. PMID- 22485654 TI - Using trichloroacetic Acid to concentrate proteins and remove interfering substances. PMID- 22485655 TI - Using deoxycholate and trichloroacetic Acid to concentrate proteins and remove interfering substances. PMID- 22485657 TI - Using phenol and ether to concentrate proteins and remove interfering substances. PMID- 22485656 TI - Using acetone and trichloroacetic Acid to concentrate proteins and remove interfering substances. PMID- 22485658 TI - Optimization of imidazole concentrations for immobilized metal-ion affinity chromatography. PMID- 22485659 TI - Protein Purification Using Immobilized Metal-Ion Affinity Chromatography under Optimized Imidazole Concentrations. PMID- 22485661 TI - Purification of histidine-tagged proteins using stepwise elution with imidazole. PMID- 22485660 TI - Optimization of an imidazole gradient for purification of histidine-tagged proteins. PMID- 22485662 TI - Preparation of denatured protein samples from inclusion bodies. PMID- 22485663 TI - Preparation of denatured protein samples from cell paste or cell extract. PMID- 22485665 TI - Protein separation on ceramic hydroxyapatite using high-performance liquid chromatography. PMID- 22485664 TI - Packing ceramic hydroxyapatite columns for high-performance liquid chromatography. PMID- 22485666 TI - Staining immunoblots for total protein using ponceau s. PMID- 22485667 TI - Staining immunoblots for total protein using India ink. PMID- 22485669 TI - Immunoblotting: antigen detection using chromogenic methods. PMID- 22485668 TI - Immunoblotting: antigen detection using chemiluminescence. PMID- 22485670 TI - Stripping immunoblots for reprobing or storage. PMID- 22485671 TI - Immunoaffinity purification: binding of antigen to antibody-bead matrix in a column. PMID- 22485672 TI - Immunoaffinity purification: binding of antigen to antibody-bead matrix in a suspension. PMID- 22485673 TI - Immunoaffinity purification: eluting antigens from immunoaffinity columns. PMID- 22485674 TI - Storage of purified antibodies. PMID- 22485675 TI - Antibody purification on protein a or protein g columns. PMID- 22485676 TI - Purification of antibodies on an antigen column. PMID- 22485677 TI - Immunoblotting: semi-dry electrophoretic transfer of proteins from gels to membranes. PMID- 22485678 TI - Immunoblotting: submerged electrophoretic transfer of proteins from gels to membranes. PMID- 22485679 TI - Immunoaffinity purification: coupling antibodies to protein a or g bead columns. PMID- 22485680 TI - Immunoaffinity purification: coupling antibodies to activated beads. PMID- 22485681 TI - Preparing acetone powders. PMID- 22485682 TI - Protein quantitation: bradford spot test. PMID- 22485684 TI - Bulk precipitation of proteins by ammonium sulfate. PMID- 22485683 TI - Protein Quantitation: UV Detection. PMID- 22485686 TI - Precipitation of proteins by organic solvents. PMID- 22485685 TI - Fractional precipitation of proteins by ammonium sulfate. PMID- 22485687 TI - Precipitation of proteins by polyethylene glycol. PMID- 22485688 TI - Precipitation of proteins by polyethylenimine. PMID- 22485690 TI - Electrophoresis of Peptides (Tricine-SDS-PAGE). PMID- 22485689 TI - SDS-PAGE of Proteins. PMID- 22485691 TI - Introduction of Double-Stranded RNA in C. elegans by Injection. PMID- 22485692 TI - Introduction of Double-Stranded RNA in C. elegans by Soaking. PMID- 22485693 TI - Introduction of Double-Stranded RNA in C. elegans by Feeding. PMID- 22485694 TI - Cosuppression in C. elegans. PMID- 22485695 TI - Detection of siRNA in C. elegans Using RNase Protection. PMID- 22485696 TI - Detection of si/miRNA in C. elegans by Northern Blot. PMID- 22485697 TI - Isolation of RNA from C. elegans. PMID- 22485698 TI - An Assay for RNA-Dependent RNA Polymerase Activity. PMID- 22485699 TI - Assay for Primed RNA-Dependent RNA Polymerase Transcription. PMID- 22485700 TI - Preparation and Fractionation of Drosophila Embryo Extracts for the In Vitro Characterization of RNAi. PMID- 22485702 TI - Protocol for siRNA-Primed RNA Synthesis. PMID- 22485701 TI - Preparation of siRNAs from Drosophila Embryo Extracts. PMID- 22485703 TI - Delivery of dsRNA into Plants by VIGS Methodology. PMID- 22485704 TI - Preparing frozen tissue sections for immunostaining. PMID- 22485705 TI - Preparing paraffin tissue sections for immunostaining. PMID- 22485706 TI - Preparing cell smears from tissue samples for immunostaining. PMID- 22485707 TI - Binding antibodies to tissue sections. PMID- 22485708 TI - Detection of horseradish peroxidase-labeled reagents with diaminobenzidine/metal. PMID- 22485709 TI - Detection of horseradish peroxidase-labeled reagents with chloronaphthol. PMID- 22485711 TI - Detection of alkaline phosphatase-labeled reagents. PMID- 22485712 TI - Detection of beta-Galactosidase-Labeled Reagents. PMID- 22485710 TI - Detection of horseradish peroxidase-labeled reagents with aminoethylcarbazole. PMID- 22485713 TI - Detection of gold-labeled reagents. PMID- 22485715 TI - Selection of siRNA Sequences for Mammalian RNAi. PMID- 22485714 TI - Counterstains. PMID- 22485716 TI - Annealing siRNAs to Produce siRNA Duplexes. PMID- 22485717 TI - Mammalian Cell Culture and Preparation of Cells for RNAi in 24-Well Plates. PMID- 22485718 TI - Cotransfection of Luciferase Reporter Plasmids with siRNA Duplexes. PMID- 22485719 TI - Transfection of Mammalian Cells with siRNA Duplexes. PMID- 22485720 TI - Immunofluorescence Detection of RNAi-Induced Protein Knockdown in Mammalian Cells. PMID- 22485721 TI - Detection of RNAi-Induced Protein Knockdown in Mammalian Cells by Western Blotting. PMID- 22485722 TI - Serum testing for Mammalian cell culture. PMID- 22485723 TI - Trypsinization of cells grown in monolayer. PMID- 22485724 TI - Cryopreservation of Mammalian culture cells: preparation and recovery of samples. PMID- 22485725 TI - Detection of Mycoplasma in Mammalian cell cultures using fluorescence microscopy. PMID- 22485727 TI - Setting up microdrop cultures. PMID- 22485726 TI - Intraperitoneal (IP) Injection. PMID- 22485728 TI - Making pipettes from hard glass capillaries. PMID- 22485730 TI - Opening the abdominal cavity and locating female reproductive organs. PMID- 22485729 TI - Preparing siliconized pipettes. PMID- 22485731 TI - Quick and humane sacrifice of a mouse by cervical dislocation. PMID- 22485732 TI - Collecting zygotes and removing cumulus cells with hyaluronidase. PMID- 22485733 TI - Collecting two-cell- to compacted morula-stage embryos. PMID- 22485734 TI - Collecting blastocysts. PMID- 22485735 TI - Isolating postimplantation embryos: prestreak-stage. PMID- 22485736 TI - Isolating postimplantation embryos: early primitive-streak-stage. PMID- 22485737 TI - Isolating postimplantation embryos: late primitive-streak-stage. PMID- 22485738 TI - Isolating postimplantation embryos: early neural-fold-stage. PMID- 22485739 TI - Isolating postimplantation embryos: early somite-stage. PMID- 22485740 TI - Isolating extraembryonic membranes. PMID- 22485741 TI - Separating postimplantation germ layers. PMID- 22485742 TI - Germ layer explant recombination culture. PMID- 22485743 TI - Isolating germ cells from the genital ridge. PMID- 22485745 TI - Preparation of rat serum. PMID- 22485744 TI - Roller culture of postimplantation embryos. PMID- 22485746 TI - Static culture of postimplantation embryos. PMID- 22485747 TI - Electroporation. PMID- 22485748 TI - Ovariectomy for induction of blastocyst implantation delay. PMID- 22485749 TI - Simple, reliable steps for DNA fragment isolation and purification. PMID- 22485750 TI - Isolating Bacterial Artificial Chromosome (BAC) DNA from Bacterial Cultures Using the NucleoBond System. PMID- 22485751 TI - Purification of Bacterial Artificial Chromosome (BAC) DNA Prepared with the NucleoBond System. PMID- 22485752 TI - Large-scale preparation of agarose plugs of yeast DNA. PMID- 22485753 TI - Purification of Yeast Artificial Chromosome (YAC) DNA with Filtration Units. PMID- 22485754 TI - Making holding pipettes. PMID- 22485755 TI - Making injection pipettes. PMID- 22485756 TI - Microinjection setup. PMID- 22485757 TI - Microinjection of mouse zygotes. PMID- 22485758 TI - Preparing mouse embryo fibroblasts. PMID- 22485759 TI - Preparing Feeder Cell Layers from STO or Mouse Embryo Fibroblast (MEF) Cells: Treatment with Mitomycin C. PMID- 22485760 TI - Preparing Feeder Cell Layers from STO or Mouse Embryo Fibroblast (MEF) Cells: Treatment with gamma-Irradiation. PMID- 22485761 TI - Passage of Embryonic Stem (ES) Cells. PMID- 22485762 TI - Freezing and Thawing of Embryonic Stem (ES) Cells Using Cryovials. PMID- 22485763 TI - De Novo Isolation of Embryonic Stem (ES) Cell Lines from Blastocysts. PMID- 22485764 TI - Analysis of DNA fragmentation using agarose gel electrophoresis. PMID- 22485765 TI - Analysis of DNA Fragmentation Using Propidium Iodide (PI) Fluorescence of Individual Nuclei. PMID- 22485766 TI - Analysis of DNA Fragmentation Using Propidium Iodide (PI) Staining After Ethanol Fixation. PMID- 22485767 TI - Analysis of DNA Fragmentation Using the JAM Assay. PMID- 22485768 TI - TUNEL Staining of Adherent Cells to Detect Apoptosis. PMID- 22485769 TI - Biochemical analysis of cell death using colorimetric quantification of caspase activation. PMID- 22485770 TI - Measurement of DNA Content Using Propidium Iodide (PI) Staining of Fixed Whole Cells. PMID- 22485771 TI - Propidium Iodide (PI) or DAPI Staining of Unfixed Tissue Culture Cells for Flow Cytometry. PMID- 22485772 TI - Propidium Iodide (PI) or DAPI Staining of Unfixed Solid Tissues for Flow Cytometry. PMID- 22485773 TI - Fluorescent staining of cell surface antigens on viable cells using direct immunofluorescence. PMID- 22485775 TI - Concentrating hypotrichs. PMID- 22485774 TI - Fluorescent staining of cell surface antigens on viable cells using indirect immunofluorescence. PMID- 22485776 TI - Transfection of hippocampal neurons with plasmid DNA using calcium phosphate coprecipitation. AB - INTRODUCTION This protocol describes transfection of plasmid DNA into primary hippocampal neurons using DNA/calcium-phosphate (CaPO(4)) coprecipitation. The precise pH of the transfection medium and the incubation time of cells with the coprecipitate are critical for reproducible and efficient transfection. Once these parameters are optimized for a given plasmid, the method is easily adapted for transfection of other established cell lines and primary cell cultures. PMID- 22485777 TI - Gene delivery to skin using biolistics. AB - INTRODUCTION Biolistics ("biological ballistics") or particle bombardment provides a rapid and simple physical procedure for delivering genes into cells (Klein et al. 1987; Yang et al. 1990). The technique has many advantages-plasmids may be used for delivery, DNA theoretically can be delivered to any cell type, and genes may be delivered to cells in vitro, ex vivo, or in vivo. DNA-coated gold particles are distributed evenly along the length of the tubing, which is subsequently cut into short sections of cartridges to be used in a gene gun. The Helios Gene Gun uses a pulse of helium to launch the DNA-coated particles, spreading them onto the target cells. PMID- 22485778 TI - Micro in utero electroporation for efficient gene targeting in mouse embryos. AB - INTRODUCTION A mixture of DNA and tracking dye is microinjected into a precisely targeted area of the developing mouse embryo. A pulse generator is used to pass current into the tissue using needle electrodes placed on either side of the injection. Fiberoptic light is used to visualize the procedure. This method can be readily adapted for use on most parts of the embryo. It can be used with many different types of genes, as well as for simultaneously delivering multiple genes. PMID- 22485779 TI - Lipoplex and LPD Nanoparticles for In Vivo Gene Delivery. AB - INTRODUCTION Lipoplex (cationic liposome-DNA complex) is formed via electrostatic interaction of anionic nucleic acids with cationic liposomes. A thin film of lipids is dried on the bottom of a glass tube and rehydrated in an aqueous solution. The resulting liposome suspension is passed through polycarbonate filters of desired pore size. This protocol also describes the preparation, physical properties, and biological activity of liposome-polycation-DNA (LPD) nanoparticles. The LPD nanoparticles contain a highly condensed DNA core surrounded by lipid bilayers with an average size of ~100 nm. The nanoparticle complex is injected into mice, and expression of the transfected DNA is monitored with an appropriate assay. PMID- 22485780 TI - Optimizing electrotransfection of Mammalian cells in vitro. AB - INTRODUCTION This protocol describes transfection of plasmid DNA into mammalian cell lines using electroporation, a process whereby external application of electric pulses induce cell membrane permeability. A number of factors can affect electrotransfection efficiency. In general, cells in suspension and small volume cells are difficult to transfect, whereas adherent cells and large volume cells are relatively easy. Regardless of cell size or phenotype, transfection efficiency increases with a high concentration of cells in a small volume. The use of plasmid DNA larger than 13 kb reduces transfection efficiency. One important variable is the choice of electroporation buffer--the appropriate buffer can increase cell transfection efficiency 50-98%. Generally, buffers with low ionic constants enhance transfection efficiency. PMID- 22485781 TI - Bioresponsive targeted charge neutral lipid vesicles for systemic gene delivery. AB - INTRODUCTION This protocol describes a stepwise procedure to prepare nucleic acids encapsulated in a polyethylene glycol (PEG)-shielded nanolipoparticle (NLP) that contain a bioresponsive lipid and ligand. This process provides several advantages for systemic gene delivery. The in vivo circulation time is extended. Also, low pH-sensitive lipids enhance DNA unpacking and endosomal escape. Finally, ligands inserted into the NLP surface can target gene delivery to specific tissues or cells in vivo. PMID- 22485782 TI - PEI Nanoparticles for Targeted Gene Delivery. AB - INTRODUCTION This protocol describes the preparation of polyethylenimine (PEI)/DNA nanoparticles for targeted gene delivery. This delivery strategy improves the efficiency of gene transfer by enhancing the entry of gene vectors into the desired cells and reducing uptake by nontarget cells. We describe here methods for the conjugation of targeting peptides to PEIs, formation of DNA complexes using the conjugated PEIs or nonconjugated PEIs together with targeting peptides, and cell transfection using these complexes. The conjugation step involves the use of the succinimidyl-4-(N-maleimidomethyl)cyclohexane-1 carboxylate (SMCC), a heterobifunctional cross-linker, to form a stable bond between PEI and peptides containing thiol groups. PMID- 22485783 TI - Storage of bacterial cultures growing in liquid media. PMID- 22485785 TI - Estimation of cell number by hemocytometry counting. PMID- 22485784 TI - Storage of bacterial cultures growing on solid medium. PMID- 22485786 TI - Purification of nucleic acids by extraction with phenol:chloroform. PMID- 22485787 TI - Standard ethanol precipitation of DNA in microcentrifuge tubes. PMID- 22485789 TI - Fluorometric quantitation of DNA using hoechst 33258. PMID- 22485788 TI - Concentrating and desalting nucleic acids with microconcentrators. PMID- 22485791 TI - Mounting Samples in DPX. PMID- 22485790 TI - Static culture of postimplantation embryos for imaging. PMID- 22485792 TI - Mounting samples in gelvatol or mowiol. PMID- 22485793 TI - Epitope mapping by competition assay. PMID- 22485794 TI - Epitope mapping using synthetic biotin-labeled peptides. PMID- 22485795 TI - Storage of sera. PMID- 22485796 TI - Storage of tissue culture supernatants. PMID- 22485797 TI - Storage of ascitic fluid. PMID- 22485798 TI - Labeling antibodies with fluorochromes. PMID- 22485799 TI - Labeling antibodies with biotin. PMID- 22485800 TI - Labeling antibodies with iodine. PMID- 22485801 TI - Labeling monoclonal antibodies by biosynthesis. PMID- 22485802 TI - Visualizing early embryo implantation sites by dye injection. PMID- 22485803 TI - Vasectomy for Generation of Sterile Males: Access via Abdominal Wall. PMID- 22485804 TI - Vasectomy for Generation of Sterile Males: Access via Scrotal Sac. PMID- 22485805 TI - Oviduct transfer. PMID- 22485806 TI - Uterine transfer. PMID- 22485807 TI - Caesarean section and fostering. PMID- 22485808 TI - Transplantation of tissues under the kidney capsule. PMID- 22485809 TI - Subcutaneous Injection of Embryonic Stem (ES) Cells. PMID- 22485810 TI - Partial hepatectomy. PMID- 22485811 TI - Splenectomy. PMID- 22485812 TI - Nephrectomy. PMID- 22485813 TI - Castration. PMID- 22485814 TI - Blood collection by tail bleeding. PMID- 22485815 TI - Differentiating Embryonic Stem (ES) Cells into Embryoid Bodies. PMID- 22485816 TI - Culturing Trophoblast Stem (TS) Cell Lines. PMID- 22485817 TI - Derivation of Trophoblast Stem (TS) Cell Lines from Blastocysts. PMID- 22485818 TI - Electroporating DNA into Embryonic Stem (ES) Cells and Selection Methods. PMID- 22485819 TI - Isolating Individual Embryonic Stem (ES) Cell Colonies by Picking. PMID- 22485820 TI - Freezing Embryonic Stem (ES) Cells in 96-Well Plates. PMID- 22485821 TI - Rapid preparation of DNA from cells in 96-well tissue culture dishes. PMID- 22485822 TI - Preparation of DNA from cells in 24-well tissue culture plates. PMID- 22485823 TI - Microscopic Analysis of Mitochondrial Transmembrane Potential ({Delta}{Psi}m). PMID- 22485824 TI - Analysis of TUNEL Staining by Flow Cytometry to Detect Apoptosis. PMID- 22485825 TI - Isolation of fibroblasts from Mammalian embryos. PMID- 22485826 TI - Isolation of fibroblasts from chicken embryos. PMID- 22485827 TI - Lymphocyte isolation and culture. PMID- 22485828 TI - Epstein-barr virus transformation of lymphoblasts. PMID- 22485829 TI - Isolation and Freezing of Primary Mouse Embryonic Fibroblasts (MEF) For Feeder Plates. PMID- 22485830 TI - Preparation of Mouse Embryonic Fibroblast (MEF) Feeder Plates. PMID- 22485831 TI - Propagation of Pluripotent Mouse Embryonic Stem (ES) Cells. PMID- 22485832 TI - Differentiation of Embryonic Stem (ES) Cells Using the Hanging Drop Method. PMID- 22485833 TI - G1/S Phase Synchronization using Double Thymidine Synchronization. PMID- 22485834 TI - Cell synchronization using centrifugal elutriation. PMID- 22485835 TI - Propidium Iodide (PI) Uptake Assay to Detect Apoptosis. PMID- 22485837 TI - Growing adherent cells on coverslips or multiwell slides. PMID- 22485836 TI - TUNEL Staining of Tissue Sections to Detect Apoptosis. PMID- 22485838 TI - Growing adherent cells directly on tissue dishes. PMID- 22485839 TI - Attaching suspension cells to slides using a cytocentrifuge. PMID- 22485840 TI - Attaching suspension cells to slides using chemical linkers. PMID- 22485841 TI - Fixing attached cells in organic solvents. PMID- 22485842 TI - Fixing attached cells in paraformaldehyde. PMID- 22485843 TI - Fixing suspension cells with paraformaldehyde. PMID- 22485844 TI - Indirect detection using horseradish peroxidase-labeled reagents. PMID- 22485845 TI - Indirect detection using fluorochrome-labeled reagents. PMID- 22485846 TI - Immunoblotting: preparing protein solutions. PMID- 22485847 TI - Immunoblotting: preparing cell lysates. PMID- 22485848 TI - Immunoblotting: preparing immunoprecipitated proteins. PMID- 22485849 TI - Genotyping Embryonic Stem (ES) Cell Colonies Prior to Picking. PMID- 22485850 TI - Preparation of Embryonic Stem (ES) Cells for Injection. PMID- 22485851 TI - Breaking the Tips of Embryonic Stem (ES) Cell Injection Needles. PMID- 22485854 TI - Preparing the aggregation plate. PMID- 22485853 TI - Preparing Embryonic Stem (ES) Cells for Aggregation. PMID- 22485852 TI - Injecting blastocysts. PMID- 22485855 TI - Removal of zona pellucida. PMID- 22485856 TI - Production of tetraploid embryos. PMID- 22485857 TI - Assembling Aggregates between Diploid Embryos. PMID- 22485858 TI - Assembling Aggregates between Embryonic Stem (ES) Cells and Diploid Embryos. PMID- 22485859 TI - Assembling Aggregates between Diploid and Tetraploid Embryos. PMID- 22485860 TI - Assembling Aggregates between Embryonic Stem (ES) Cells and Tetraploid Embryos. PMID- 22485861 TI - Disaggregating Cleavage-Stage Embryos and the Inner Cell Mass (ICM) of Blastocysts into Individual Cells. PMID- 22485862 TI - Immunosurgery: Isolating the Inner Cell Mass (ICM) of Blastocysts. PMID- 22485863 TI - Growth and concentration of chlorogonium for culturing freshwater hypotrichs. PMID- 22485864 TI - Flow Cytometric Analysis of Mitochondrial Transmembrane Potential ({Delta}{Psi}m). PMID- 22485866 TI - Culturing marine euplotids using dunaliella as a food source. PMID- 22485865 TI - Mass culture of freshwater hypotrichs. PMID- 22485867 TI - Refeeding marine euplotids with bacteria. PMID- 22485868 TI - Maintenance of stocks of marine hypotrichs. PMID- 22485869 TI - Short-term storage of tetrahymena cultures. PMID- 22485870 TI - Long-term storage storage of unfrozen tetrahymena cultures in maintenance culture medium. PMID- 22485871 TI - Long-term storage of unfrozen tetrahymena cultures in soybean medium. PMID- 22485872 TI - Leukostat staining of cytospin preparations to detect apoptosis. PMID- 22485873 TI - Staining of suspension cells with hoechst 33258 to detect apoptosis. PMID- 22485874 TI - Acridine Orange/Ethidium Bromide (AO/EB) Staining to Detect Apoptosis. PMID- 22485875 TI - Detection of phosphatidylserine externalization during apoptosis. PMID- 22485876 TI - Preparation of dsRNA Molecules for RNAi in Mouse Oocytes and Early Embryos. PMID- 22485877 TI - Collection of Mouse Oocytes for RNAi. PMID- 22485879 TI - Microinjection of dsRNA into Mouse Oocytes and Early Embryos. PMID- 22485878 TI - Collection of Early Mouse Embryos for RNAi. PMID- 22485880 TI - Synthesis of dsRNA for RNAi in Drosophila: Plasmid Template Method. PMID- 22485881 TI - RNA Isolation and RT-PCR from dsRNA-Treated Mouse Oocytes and Early Embryos. PMID- 22485882 TI - Synthesis of dsRNA for RNAi in Drosophila: PCR Template Method. PMID- 22485884 TI - Microinjection of dsRNA into Drosophila Embryos. PMID- 22485883 TI - Synthesis of siRNA for RNAi in Drosophila. PMID- 22485885 TI - Delivery of dsRNA into Drosophila Embryos by Gene Gun. PMID- 22485886 TI - Semiquantitative RT-PCR for Phenotype Analysis of RNAi-Treated Drosophila Embryos. PMID- 22485887 TI - Transcript In Situ Hybridization of Whole-Mount Embryos for Phenotype Analysis of RNAi-Treated Drosophila. PMID- 22485888 TI - Troubleshooting and Limitations of the Tandem Affinity Purification (TAP) Method. PMID- 22485889 TI - G1 Synchronization of CHO Cells by Isoleucine Deprivation. AB - INTRODUCTIONThis protocol provides a method for the synchronization of a monolayer culture of CHO cells in G(1) using isoleucine deprivation. Since CHO cells can also be adapted to grow in suspension culture, this procedure can be used to obtain larger quantities of cells. When isoleucine is replaced, the cells resume growth and begin to enter S phase ~4 hours later. This method arrests almost 100% of the CHO cells in G(1), and upon reversal, leads to rapid recovery of cell growth and very high cell viability. This method has been used with other hamster cell lines, some transformed mouse cells, and some transformed human cell lines have also been used, but with varying effectiveness. PMID- 22485890 TI - G1/S phase synchronization using mimosine arrest. AB - INTRODUCTIONThis protocol uses the plant amino acid mimosine as a G(1)/S synchronizing agent. Cells are first treated with excess thymidine to accumulate the majority of them at G(1)/S; however, some cells will have stopped growth within the S phase. Thymidine is then removed to allow all the cells to proceed completely through the S phase. Mimosine is then added to arrest the cells at the G(1)/S border. When mimosine is removed, cells will begin to enter S phase within about 1 hour. PMID- 22485891 TI - Synchronization of Mammalian cell cultures in mitosis using selective detachment. AB - INTRODUCTIONThis protocol describes a method for synchronizing monolayer cells in mitosis using selective detachment from their substrate. During mitosis, cells become more spherical, causing them to become more loosely attached to their substrate. The "rounded up" cells are selectively detached by tapping the culture flask, resulting in a population in which as many as 90-98% of the cells are in mitosis. The drug nocodazole is used to increase the percentage of cells undergoing mitosis before detachment is performed. This procedure has been applied to mouse fibroblast and CHO (Chinese hamster ovary) cells. Since different cell types may attach differently, it will be necessary to determine the amount of force needed to remove loosely attached cells and the mitotic cells. PMID- 22485892 TI - Freezing and thawing tetrahymena cultures. AB - INTRODUCTIONThe method for freezing Tetrahymena has undergone major modifications over the years. The protocol given below was optimized by P.J. Bruns. PMID- 22485893 TI - Vegetative growth of tetrahymena. AB - INTRODUCTIONThis protocol describes initiating and maintaining cultures for vegetative growth of Tetrahymena. PMID- 22485894 TI - Induction of conjugation in tetrahymena. AB - INTRODUCTIONThe method to induce Tetrahymena conjugation described below is modified from that of Martindale et al. (1982). Mature Tetrahymena cells of opposite mating types are starved under appropriate salt conditions. The mating types are then combined to costimulate through cell-cell interaction. Loose pairs and then firm, irreversible pairs of cells of opposite mating types form. This method consistently results in a high percentage of pairing (usually greater than 80%) and good synchrony. PMID- 22485895 TI - Isolation and purification of tetrahymena nuclei. AB - INTRODUCTIONThe procedures described below allow the isolation of nuclei from all stages of the Tetrahymena life cycle in high yield with a high degree of purity. This method gives highly purified populations of both micronuclei and macronuclei. PMID- 22485896 TI - Transformation of Tetrahymena thermophila by Electroporation. AB - INTRODUCTIONThis protocol describes a method for transformation of the Tetrahymena using electroporation. The vector is electroporated into cells after mating, where it is incorporated into the DNA of developing macronuclei. Because T. thermophila can be propagated indefinitely without conjugation, transformation of the macronucleus provides a way to obtain stable somatic transformants. DNA vectors transformed using this protocol include those containing drug-resistant versions of Tetrahymena genes (which replace endogenous genes via homologous recombination) as well as those containing rDNA replication origins. Cotransformation using these two vector types is also possible: Electroporated cells are selected for drug resistance conferred by the replicating vector for 10 15 generations, then screened for the gene replacement using another drug resistant marker. Usually a few percent of the cells that are transformed by the replicating vector are cotransformed by the gene replacement vector. PMID- 22485897 TI - Production of dsRNA for RNAi in Avian Embryos. AB - INTRODUCTIONThis protocol describes the production of double-stranded RNA (dsRNA) from fragments of cDNAs of candidate genes. The cDNA fragments must be cloned in plasmids with a flanking SP6 and T7 promoter (e.g., pSP72 or pCRII). The plasmid is linearized and sense and antisense RNAs are produced separately by in vitro transcription. After purification, the RNA strands are annealed to yield a dsRNA molecule suitable for RNAi in avian embryos. PMID- 22485898 TI - Injection of dsRNA and Electroporation in Avian Embryos. AB - INTRODUCTIONThis protocol describes a method for in ovo transfection of avian embryos with double-stranded RNA (dsRNA). The dsRNA is injected into the spinal cord of the embryo. Subsequent electroporation facilitates the cellular uptake of the dsRNA molecules. It may be necessary to optimize the stage of the embryo and the electroporation procedure to improve the effectiveness of in ovo RNAi-cell competence changes with differentiation. The half-life of the target protein product may also affect the time point of injection and electroporation-proteins with slow turnover may require RNAi at earlier stages, preferably before the onset of expression. Check the quality of the dsRNA used for injections and make sure that the buffer used for injection does alter development or survival of the embryo. Tris buffers and buffers containing glycerol are not compatible with in vivo injections. Salt concentration and pH should be in the physiological range. Always use the same buffers for injection and electroporation of test and control embryos. PMID- 22485899 TI - Dissection of Spinal Cords for Analysis of Axonal Pathfinding in dsRNA-Treated Avian Embryos. AB - INTRODUCTIONThis protocol describes how to dissect spinal cords of dsRNA-treated avian embryos for analysis of commissural axon guidance. After fixation of the spinal cord with paraformaldehyde, commissural axons are stained with Fast-DiI. PMID- 22485900 TI - Whole-Mount Preparations for Analysis of Axonal Pathfinding in dsRNA-Treated Avian Embryos. AB - INTRODUCTIONThis protocol describes a method for staining nerve fibers in whole mount preparations of avian embryos using an antibody against the 160-kD subunit of neurofilaments. This allows the comparison of the branching pattern of motor and sensory neurons between control and experimental embryos. This protocol has been successfully applied for embryos at different stages up to about stage 33 (7 days of incubation). PMID- 22485901 TI - Staining of Tissue Slices for Analysis of Axonal Pathfinding in dsRNA-Treated Avian Embryos. AB - INTRODUCTIONThis protocol describes a method to stain nerve fibers in tissue slices of avian embryos using an antibody against the 160-kD subunit of neurofilaments. This allows the comparison of the branching pattern of motor and sensory neurons between control and experimental embryos. The tissue is cut in slices using a vibratome or tissue slicer. The protocol is suitable for older embryos after approximately stage 33 and regions that are not accessible by whole mount analysis. Slices can also be used for tracing axon tracts with lipophilic dyes rather than immunohistochemical detection of all neurites with anti neurofilament antibodies. PMID- 22485902 TI - Staining yeast. AB - INTRODUCTIONStaining yeast cells for the presence and localization of antigens has been particularly challenging because of several factors. The yeast cells are small, making the resolution of any antigen difficult; they have a thick cell wall that antibodies cannot penetrate and that is difficult to remove; and they grow in suspension, making handling difficult. Background problems can be especially severe, particularly with polyclonal antibodies, because many antisera contain antibodies to yeast cell-wall components. The difficulties encountered in localizing antigens in yeast can be overcome by using fluorochrome-labeled secondary antibodies, controlled enzymatic removal of the cell wall, and by binding the cells to a solid phase (e.g., poly-L-lysine-coated slides). PMID- 22485903 TI - Fixing Caenorhabditis elegans in Bouin's fixative. AB - INTRODUCTIONBouin's fixative is a particularly good choice for worms because it penetrates dense tissues well and is extremely good for fixing antigens. Like all strong fixatives, however, it is unsuitable for some antibody-antigen pairs. In such cases, the length of time in the Bouin's fixative can be shortened, or paraformaldehyde fixation can be used instead. PMID- 22485904 TI - Fixing Caenorhabditis elegans in Paraformaldehyde. AB - INTRODUCTIONAnother common method for fixing worms is to use paraformaldehyde. This method provides a gentler fixation than the Bouin's method, but often requires the use of collagenase. This method is particularly good for examining adult worms. PMID- 22485905 TI - Antibody Addition and Detection for Staining Caenorhabditis elegans. AB - INTRODUCTIONThe most common method of detection for staining worms is to use fluorochrome-labeled reagents, because of the desire for high resolution of the antigen location. Extreme care should be used to identify and verify positive reactions, however, because cross-reactions are common. Counterstaining is essential for examining worms by immunofluorescence and is used to identify the exact cell in which an antigen appears. Methods for counterstaining include labeling all cells with a fluorescent dye that is specific for nucleic acids (e.g., DAPI or propidium iodide) and using GFP driven by tissue-specific promoters. PMID- 22485906 TI - Preparing early whole-mount Drosophila embryos for immunostaining. AB - INTRODUCTIONThe choice of fixation and permeabilization methods for examining flies depends on their stage of development. Early embryos (0-17 hours or until cuticle formation) are treated with a mixture of organic solvents, formaldehyde, and alcohols, as described here. The cuticles of late-stage embryos are usually opened by sonication. Tissues from more advanced stages of development are normally dissected by hand and then fixed and stained in a standard paraformaldehyde/detergent combination. PMID- 22485907 TI - Preparing late whole-mount Drosophila embryos for immunostaining. AB - INTRODUCTIONThe choice of fixation and permeabilization methods for examining flies depends on the stage of development. Early and late embryos are treated with a mixture of organic solvents, formaldehyde, and alcohols. The cuticles of late-stage embryos (17-22 hours or until hatching) are usually opened by sonication, as described here. Tissues from later stages of development are normally dissected by hand and then fixed and stained in a standard paraformaldehyde/detergent combination. PMID- 22485908 TI - Antibody addition to Drosophila specimens and detection using enzyme-linked reagents. AB - INTRODUCTIONEnzyme-linked reagents give excellent sensitivity and use a simple light microscope for detection. A range of enzymes is available, but for staining in situ, horseradish peroxidase will suit most needs. Diaminobenzidine (DAB) is one of the most sensitive substrates for horseradish peroxidase. It yields an intense brown product that is insoluble in both water and alcohol. It can be made more sensitive by adding metal salts such as cobalt or nickel to the substrate solution. The reaction products are slate gray to black, and they are stable in both water and alcohol. DAB/metal staining is compatible with a wide range of common histological stains. PMID- 22485909 TI - Antibody addition to Drosophila specimens and detection using fluorochrome-linked reagents. AB - INTRODUCTIONFluorochrome-linked reagents should be used when high resolution is needed or if two antigens need to be localized simultaneously. Because of the thickness of fly specimens, detection requires access to a confocal microscope. PMID- 22485910 TI - Unmasking hidden epitopes with proteases. AB - INTRODUCTIONFixation can mask epitopes. However, it is often possible to re expose them using a gentle incubation with proteases, which removes obstructing structures and allows antibody access, as described here. Many proteases can be used for this procedure, including very crude preparations of proteases, such as pronase. However, using a better-characterized protease, such as trypsin, allows a more controlled reaction and better comparison between experiments. Be aware that any of the antigen retrieval methods should be avoided wherever possible, because they may introduce artifactual false-positive staining. Methods for antigen retrieval are specific for each antibody/antigen combination. No attempts to establish quantitative data following these methods should be considered. PMID- 22485911 TI - Unmasking hidden epitopes using the microwave oven. AB - INTRODUCTIONSeveral methods have been developed to "retrieve" antigens that have been masked by fixation. The principle behind using the microwave oven method described here is to use extended periods of heat to break some of the subcellular structures that block antibody access. Be aware that any of the antigen retrieval methods should be avoided wherever possible, because they may introduce artifactual false-positive staining. Methods for antigen retrieval are specific for each antibody/antigen combination. No attempts to establish quantitative data following these methods should be considered. PMID- 22485912 TI - Unmasking hidden epitopes using the pressure cooker. AB - INTRODUCTIONSeveral methods have been developed to "retrieve" antigens that have been masked by fixation. The principle behind the pressure cooker method described here is to use extended periods of heat to break some of the subcellular structures that block antibody access. This approach is appropriate for handling specimens on glass slides. The major advantages of the pressure cooker method are the ability to handle a large number of slides simultaneously, the convenience of using metal racks, and the avoidance of any hot spots that are found in the microwave. Be aware that any of the antigen retrieval methods should be avoided wherever possible, because they may introduce artifactual false positive staining. Methods for antigen retrieval are specific for each antibody/antigen combination. No attempts to establish quantitative data following these methods should be considered. PMID- 22485913 TI - Lysing tissue-culture cells for immunoprecipitation. AB - INTRODUCTIONFor cells grown in tissue culture, the most useful method of lysis is treating with detergents, as described in this protocol. Non-ionic detergents, such as NP-40, solubilize the plasma and intracellular membranes, break many weak intermolecular bonds, and solubilize most of the commonly studied protein antigens. RIPA lysis buffer, which contains non-ionic detergents mixed with ionic detergents, may be used as a more rigorous extraction buffer to release all but the insoluble proteins of the cell and to break most weak noncovalent interactions. The resulting lysate is ready for preclearing. PMID- 22485914 TI - Immunoprecipitation: lysing bacteria by sonication. AB - INTRODUCTIONIn this protocol, bacterial cells are lysed by being subjected to short, intense treatments with ultrasound, which breaks the cell walls and shears the DNA into sizes that will not affect the viscosity of the samples. Note that this method causes some denaturation of the samples. The resulting lysate is ready for preclearing. PMID- 22485915 TI - Immunoprecipitation: lysing yeast cells using glass beads. AB - INTRODUCTIONFor yeast, the preferred method of lysis is mechanical shearing by vortexing the cells in the presence of glass beads as described in this protocol. This is a powerful lysis method but imparts extensive energy into the lysis procedure and results in considerable denaturation of the samples. For this reason, yeast immunoprecipitations are not as powerful a technique as similar studies in mammalian cells and should not be relied upon for determination of protein properties that require authentic protein structure. The lysate prepared in this procedure is ready for preclearing. PMID- 22485916 TI - Immunoprecipitation: denaturing lysis. AB - INTRODUCTIONFor many sources of antigens, one useful method of lysis is to treat cells with harsh, denaturing solutions to release most of the protein antigens, as described here. The lysates are then diluted to reduce the denaturing conditions to levels that are suitable for the formation of antibody-antigen complexes. The resulting solution is precleared prior to immunoprecipitation. The major consideration in choosing this lysis method is that all noncovalent protein protein interactions will be lost and that denaturation-sensitive epitopes will be destroyed. Therefore, this is not an appropriate method for many types of final assays, but it is a good method for quantitation of the antigen, careful identification of the polypeptide band recognized by the antibody, and display of denaturation-resistant epitopes. PMID- 22485917 TI - Immunoprecipitation: preclearing the lysate. AB - INTRODUCTIONTo reduce backgrounds and to improve the signal-to-noise ratio, an antibody that does not recognize the antigen being studied can be added to the lysate and processed as for a normal immunoprecipitation. Any nonspecific proteins that might contaminate the final immunoprecipitation step are presumably removed with this irrelevant antibody. Rabbit serum collected from a healthy adult animal that has not been previously immunized is used because it provides a complex mixture of different antibody types. Fixed Staphylococcus aureus Cowan I (SAC), a relatively inexpensive, concentrated source of protein A is used to collect the rabbit antibodies. Precleared samples prepared according to this protocol are ready for the final immunoprecipitation step. PMID- 22485918 TI - Immunoprecipitation: purifying the immune complexes. AB - INTRODUCTIONIn this protocol, immune complexes are formed by the addition of antibodies to cell lysates. The antibodies bind to their cognate antigen from a lysate. Protein A or protein G beads are then added to the solution containing antibody-antigen complexes, and the proteins that do not bind to the beads are removed by washing. The correct controls for immunoprecipitation should include nonimmune antibodies that are as close as possible to the specific antibody; for example, polyclonal serum should be compared to polyclonal serum from the same species (ideally a prebleed from the same animal used for immunization). For monoclonal antibodies, the control must be from the same source as the specific antibody. Do not use tissue culture supernatants from parental myeloma cells as they do not contain antibodies. Suitable control hybridoma cell lines can be obtained from the American Type Culture Collection and the European Collection of animal cell cultures. PMID- 22485919 TI - Fragmentation of DNA by sonication. AB - INTRODUCTIONDNA fragmentation is often necessary prior to library construction or subcloning for DNA sequencing. This protocol describes a method for DNA fragmentation by sonication. During sonication, DNA samples are subjected to hydrodynamic shearing by exposure to brief periods of sonication. DNA that has been sonicated for excessive periods of time is extremely difficult to clone. Most sonicators will not shear DNA to a size of less than 300-500 bp, and it is tempting to continue sonication until the entire DNA population has been reduced in size. However, the yield of subclones is usually greater if sonication is stopped when the fragments of the target DNA first reach a size of ~700 bp. PMID- 22485920 TI - Fragmentation of DNA by nebulization. AB - INTRODUCTIONDNA fragmentation is often necessary prior to library construction or subcloning for DNA sequencing. This protocol describes a method for DNA fragmentation by nebulization, in which the fine mist created by forcing a DNA solution through a small hole in the nebulizer unit is collected. The size of the fragments obtained by nebulization is determined chiefly by the speed at which the DNA solution passes through the hole, altering the pressure of the gas blowing through the nebulizer, the viscosity of the solution, and the temperature. Nebulization is easy, quick, and requires only small amounts of DNA (0.5-5 MUg). The resulting DNA fragments are distributed over a narrow range of sizes (700-1330 bp). It requires ligation of DNA before nebulization and end repair afterward. PMID- 22485921 TI - SDS-Polyacrylamide Gel Electrophoresis of Proteins. AB - INTRODUCTIONThis protocol describes the separation of proteins by SDS polyacrylamide gel electrophoresis. SDS is used with a reducing agent and heat to dissociate the proteins. SDS-polypeptide complexes form and migrate through the gels according to the size of the polypeptide. By using markers of known molecular weight, the molecular weight of the polypeptide chain(s) can be estimated. PMID- 22485922 TI - Staining SDS-Polyacrylamide Gels with Silver Salts. AB - INTRODUCTIONA number of methods have been developed to stain polypeptides with silver salts after separation by SDS-polyacrylamide gel electrophoresis. It is somewhat more difficult to perform than staining with Coomassie Brilliant Blue R 250, but it is ~100-1000-fold more sensitive and is capable of detecting as little as 0.1-1.0 ng of polypeptide in a single band. PMID- 22485923 TI - Drying SDS-Polyacrylamide Gels. AB - INTRODUCTIONThis protocol describes a method for drying SDS-polyacrylamide gels. Gels containing proteins radiolabeled with (35)S-labeled amino acids must be dried before autoradiographic images can be obtained. Nonradioactive gels can also be preserved by drying. PMID- 22485924 TI - Chromatin Immunoprecipitation (ChIP) of Protein Complexes: Mapping of Genomic Targets of Nuclear Proteins in Cultured Cells. AB - INTRODUCTIONThis protocol describes the use of chromatin immunoprecipitation technology (ChIP) to analyze interactions of proteins or protein complexes with DNA in vivo. In this approach, the material is fixed with formaldehyde to preserve DNA-protein and protein-protein associations, the cells are lysed, and the chromatin is cut and solubilized. The chromatin suspension is immunoprecipitated with an antibody against the protein(s) of interest, and the coimmunoprecipitated DNA fragments are analyzed. The following protocol has been established for the cultured cell line Schneider 2 (S2) from Drosophila melanogaster. If other tissue is used, certain steps of the protocol may need to be optimized; the main variation is likely to be in the cross-linking step. PMID- 22485925 TI - Genome-Wide Analysis of Protein-Protein Interactions Using a Two-Hybrid Array: Amplification of ORFs. AB - INTRODUCTIONThe two-hybrid array method described in this protocol was applied to ~6000 open reading frames (ORFs) of the Saccharomyces cerevisiae genome, but it could be applied to any collection of ORFs, including the genome complements of other organisms or smaller sets of functionally related ORFs. The method relies on a spatially ordered set of yeast strains, each expressing a different protein fused to the Gal4 activation domain (AD). A mating strategy is used in which a strain expressing a protein fused to the Gal4 DNA-binding domain (BD) (the bait) is mated to each array strain (the prey). Construction of the array is achieved using polymerase chain reaction (PCR) and recombinational cloning in conjunction with high-throughput transformation of the appropriate yeast strain. To capitalize on the advantageous use of the mating procedure, the array strains must be haploid yeast. This allows the introduction of the Gal4 BD and AD fusions into the same diploid cell by mating of the haploid array strains with a haploid strain of the opposite mating type containing the BD. Diploid yeast strains expressing both of these protein fusions are selected using auxotrophic media, and subsequently, two-hybrid positives are selected for the activation of a reporter gene that allows their growth on the appropriate media. This protocol describes the first step in constructing an array: amplification of the predicted ORFs that are to be included in the array. Gene-specific primers containing vector-specific flanking sequences that facilitate recombinational cloning are used to amplify each ORF. A secondary amplification can be used to extend the length of the homologous vector sequence flanking the ORF. PMID- 22485926 TI - Genome-wide analysis of protein-protein interactions using a two-hybrid array: cloning by homologous recombination and high-throughput transformation. AB - INTRODUCTIONAlthough described here as a means of producing baits and preys, the generation of an array of ORFs fused to any moiety can be achieved using this protocol. This procedure capitalizes on the asexual/sexual reproductive cycle of yeast cells. Laboratory yeast strains can be maintained indefinitely by asexual reproduction as one of two haploid mating types, MATa or MATalpha. However, overlaying MATa and MATalpha cells allows them to fuse and form diploid cells. Hence, the strategy involves transforming MATalpha cells with the Gal4 BD (bait) fusion plasmids and transforming MATa cells with the Gal4 AD (prey) fusion plasmids. The transformants are then mixed on a plate, or in liquid, and diploids are selected by plating them onto media lacking the marker nutrients for both of the plasmids. In this way, the prey transformations need only be performed once, and each bait protein can then be tested against the array of prey-containing strains using only one transformation per bait. The protocol is easily adapted to small-scale transformation of single microcentrifuge tubes for bait transformations. PMID- 22485927 TI - Genome-wide analysis of protein-protein interactions using a two-hybrid array: high-density robotic screening procedure. AB - INTRODUCTIONThis protocol describes how to handle arrayed yeast using robotics. PMID- 22485928 TI - Genome-wide analysis of protein-protein interactions using a two-hybrid array: storage, maintenance, and working with living arrays. AB - INTRODUCTIONThe most difficult aspect of using an array approach for a high throughput study is maintaining the array's viability while avoiding contamination of the plates. This protocol describes three different storage methods for the array. Frozen stocks are the most permanent method and are an absolute requirement for maintaining a record of the array. Unfortunately, because thawing is necessary to access the strains from a 96-well format, the repeated use of the frozen stocks as a source is expected to eventually lead to loss of viability of the stock. (Generating frozen stocks of the array strains individually, as well as in the arrayed format, is essential.) Maintenance of a water stock provides a source that is more convenient and (relative to yeast cells in media) semi-permanent (~6 months). However, the water stock is fairly precarious because cross-transfer of strains between wells can occur quite easily if the plates are dropped or disturbed. The third method of storage, that of maintaining extra copies of the solid medium array plates, is the most convenient, but it is also the least stable. In short, the best option is to make several frozen stocks. For greater convenience in repeated use of the array, generate water stocks and additional copies of the solid medium plates. PMID- 22485930 TI - Experimental Design for In Vivo FRET Analysis. PMID- 22485929 TI - Analysis of protein interactions with immobilized Peptide arrays synthesized on membrane supports. AB - INTRODUCTIONThe following protocol describes the synthesis of short linear peptides, or peptide pools, on modified cellulose membranes, and the detection of their protein-binding partners. Peptides are synthesized from their carboxyl termini using Fmoc-amino acid derivatives. After completion of the synthesis and cleavage of all side-chain-protecting groups, the peptide array on the membrane is incubated with the potential interaction partners to identify their target sequences. PMID- 22485931 TI - Cultivation of Arabidopsis. PMID- 22485932 TI - Chromatographic conditions for the analytical separation of crude Peptide and protein mixtures. PMID- 22485934 TI - The use of mass spectrometry in proteomics: database searching. PMID- 22485933 TI - Chromatographic conditions for the preparative separation of peptides. PMID- 22485935 TI - Chromatographic conditions for the desalting of peptides and proteins. PMID- 22485936 TI - Equipment for In Vivo FRET Analysis. PMID- 22485937 TI - An Explanation of Symbols Used for Analysis of FRET Data. PMID- 22485938 TI - Staining membrane-bound proteins with ponceau s. AB - INTRODUCTIONBecause Ponceau S is relatively insensitive (~1 MUg of protein), only the most abundant proteins will be visible. However, it is a reversible stain that can be removed completely with H(2)O prior to processing the blots. After staining, a soft lead pencil can be used to record the presence of visible proteins and molecular-weight markers, which will help when aligning the proteins detected on the membrane by western analysis with those in a total protein stained gel or membrane. Ponceau S is compatible with both nitrocellulose and PVDF membranes. PMID- 22485939 TI - Staining membrane-bound proteins with coomassie blue r250. AB - INTRODUCTIONCoomassie Blue R250 permanently stains membrane-bound proteins and is compatible with PVDF and nitrocellulose membranes, but it is incompatible with nylon membranes. This technique is relatively insensitive, with a detection limit of ~1.5 MUg of protein. One drawback of Coomassie Blue staining is that it produces a high background that can make interpretation of results difficult. PMID- 22485940 TI - Staining membrane-bound proteins with colloidal gold. AB - INTRODUCTIONColloidal Gold is the most sensitive staining technique for proteins bound on membranes, detecting as little as 1-3 ng of protein. Protein spots are permanently stained a dark red after incubation with the Colloidal Gold solution. Colloidal Gold staining can detect proteins on both nitrocellulose and PVDF membranes, but it is not recommended for nylon membranes. PMID- 22485941 TI - Packing Capillary Columns for RP-HPLC. AB - INTRODUCTIONCapillary or microcolumn (<0.5-mm internal diameter [I.D.]) high performance liquid chromatography (HPLC) is an extremely powerful technique for separating small quantities of proteins and peptides. This protocol describes a procedure for adapting conventional HPLC systems to provide accurate low-flow rates (0.4-4 MUl/min) and gradients required to operate slurry-packed capillary columns. A key component of this system is a commercial axial-beam longitudinal flow cell that can be fitted to a number of commercial UV detectors. Procedures are described for the fabrication of 0.32-mm I.D. polyimide-coated fused-silica columns, slurry-packed with reversed-phase chromatographic supports. PMID- 22485942 TI - Purification of Large "Troublesome" Polypeptides by RP-HPLC. AB - INTRODUCTIONThis protocol addresses the group of large polypeptides that have proved to be troublesome to handle because of their low solubility or the presence of secondary structural elements that favor supramolecular self-self assembly. Included in this group are polypeptides with amphipathic alpha-helical or beta-sheet structures with extensive runs of nonpolar (hydrophobic) amino acid side chains or proline-rich sequences. RP-HPLC provides one avenue to purify such troublesome examples provided certain steps and precautions are taken. (Related procedures are equally germane to polypeptides that have been lipidated or subjected to chemical modifications with nonpolar moieties, as well as to some core cyanogen bromide fragments of large proteins.) RP-HPLC methods not only enable concomitant desalting, removal of additives that aid dissolution of the polypeptide or protein, but also permit resolution and maintenance of a reasonably high concentration of the solutes, due to the presence of the (often) low-pH, aquo-organic solvent conditions. PMID- 22485943 TI - Purification of Peptides from Solid-Phase Peptide Synthesis with RP-HPLC. AB - INTRODUCTIONPurification of peptides derived from solid-phase peptide synthesis (SPPS) requires the removal of deletion peptides resulting from incomplete coupling/deprotection steps, from racemization or side-chain rearrangement, and from various chemical substances introduced during the deprotection or cleavage stages of an SPPS procedure. This protocol details the purification and analysis of many synthetic peptides of 2-65 amino acid residues. These peptides contain a number of ionizable or polar side chains, but do not contain secondary structural elements (such as beta-sheets) that favor supramolecular assembly. PMID- 22485944 TI - Desalting of Peptides and Protein Mixtures by RP-HPLC Techniques. AB - INTRODUCTIONThe RP-HPLC technique can be used to "desalt" peptide or protein samples derived from extraction procedures, from chemical reactions such as reductive alkylation in the presence of urea or guanidine hydrochloride, citraconylation, iodination, or cyanogen bromide cleavage, or recovered from other chromatographic separation. The peptide or protein solution is injected onto a small RP-HPLC column. An aqueous buffer is used to elute the salts while the peptides or proteins are concentrated at the top of the column. After elution of the salts, monitored by UV detection, the peptides or proteins are eluted with H(2)O-acetonitrile or H(2)O-isopropanol mobile phases. PMID- 22485945 TI - Fragmentation of protein using trypsin. AB - INTRODUCTIONIn this protocol, the highly specific protease trypsin is used to hydrolyze a protein completely. Proteolysis is carried out with high levels of trypsin to ensure total proteolysis. (Trypsin is a robust enzyme; hence, proteolysis can also be carried out under denaturing conditions such as 2 M guanidine-HCl, 0.1% SDS, and >10% acetonitrile to ensure complete digestion.) Trypsin cleaves the peptide bond between the carboxyl group of arginine or the carboxyl group of lysine and the amino group of the adjacent amino acid. The rate of cleavage occurs more slowly when the lysine and arginine residues are adjacent to acidic amino acids in the sequence or cystine. Cleavage does not occur when lysine or arginine is followed by proline. The sites of trypsin cleavage can be limited to arginine peptide bonds by succinylation. or citraconylation prior to trypsin digestion. PMID- 22485946 TI - Modification of lysyl side chains using succinic anhydride. AB - INTRODUCTIONThe sites of trypsin cleavage can be restricted when the epsilon amino group of lysine is blocked, for example, by succinic anhydride. This can be useful for obtaining overlapping peptides during classical protein sequencing strategies. For example, in selective peptide cleavage with trypsin, it may be desirable to block the epsilon-amino groups of lysine so that the enzyme attacks only at arginine peptide bonds. Another advantage of succinylation is that the reagent places substantial negative charge on the protein because the positively charged lysine side chain is replaced by a negatively charged carboxyl group of the succinate half-amide. Hence, succinylation may be used to solubilize a protein while blocking its lysine groups (in general, succinylated proteins are soluble at pH >7). The attached succinyl moiety forms a stable linkage to most protein treatments, but may be cleaved off with 6 N HCl at 100oC. PMID- 22485947 TI - Modification of lysyl side chains using citraconic anhydride. AB - INTRODUCTIONReversible masking of epsilon-amino groups of lysine is a valuable procedure for limiting trypsin hydrolysis of proteins to arginine peptide bonds. Citraconic anhydride is a reversible blocking agent of lysyl side chains. A major advantage of citraconylation is the ease with which the blocking group can be removed under conditions that will not lead to protein denaturation. PMID- 22485948 TI - Analysis of Complex Protein Mixtures Using Nano-LC Coupled to MS/MS. AB - INTRODUCTIONNanoliter-LC coupled to tandem mass spectrometry (nano-LC-MS/MS) permits the rapid and sensitive determination of protein-protein interactions. By using a specific purification technique such as coimmunoprecipitation or affinity purification in conjunction with nano-LC-MS/MS, not only are proteins identified, but specific protein-protein interactions are elucidated as well. PMID- 22485949 TI - Tandem Mass Spectrometry Analysis Using the ThermoFinnigan LCQ System. AB - INTRODUCTIONThis protocol provides guidance for setting the parameters for a typical data-dependent MS/MS acquisition analysis using the ThermoFinnigan LCQ system. The method consists of a continual cycle beginning with one scan of MS (scan one), which records all of the m/z values of the ions present at that moment in the gradient, followed by two rounds of MS/MS. The initial MS/MS scan is of the first most-intense ion recorded from the MS scan. The second MS/MS scan is of the second most-intense ion recorded from scan one. Dynamic exclusion is activated to improve the protein identification capacity during the analysis. PMID- 22485950 TI - Analysis of Complex Protein Mixtures Using Multidimensional Protein Identification Technology (MuDPIT). AB - INTRODUCTIONThis protocol describes the analysis of a proteome using multidimensional protein identification technology (MuDPIT), which couples 2D-LC to MS/MS, to resolve and identify peptides from complex mixtures. In this method, a pulled capillary microcolumn is packed with two independent chromatography phases: a strong cation exchanger and reversed-phase matrix material. Once a complex peptide mixture is loaded onto the system, no additional sample handling is required, because, as the peptides elute from the column, they are directed into the ESI ion-trap mass spectrometer, where they are ionized, mass-selected, and fragmented. Finally, advanced search algorithms match the fragmented peptides to their respective proteins in a database. PMID- 22485951 TI - Digestion of Insoluble Protein Fractions for Multidimensional Protein Identification Technology (MuDPIT) Analysis. AB - INTRODUCTIONProteins associated with insoluble particulate matter from a whole cell lysate, or carefully prepared membrane samples, can be analyzed using MuDPIT analysis. However, the preliminary steps provided in this protocol are required to prepare a usable complex protein mixture from these types of samples. PMID- 22485952 TI - Using FLAG Epitope-Tagged Proteins for Coimmunoprecipitation of Interacting Proteins. AB - INTRODUCTIONThis protocol describes the use of FLAG-epitope-tagged proteins for both small-scale analysis and large-scale coimmunoprecipitation of interacting proteins. When examining protein interactions, it is sometimes possible to immunoprecipitate an endogenous protein X directly, without using an epitope tag, if antibodies are available. The advantage of examining interactions of endogenously expressed proteins is that these are more likely to be physiological and less likely to be an artifact of overexpression. However, when scaling up the procedure for protein isolation and identification, epitope-tagged overexpressed protein X (e.g., FLAG-protein X) may be necessary for sufficient coimmunoprecipitating protein to be isolated. PMID- 22485953 TI - Preparative 2D Gel Electrophoresis with Immobilized pH Gradients: SDS-PAGE of Proteins. AB - INTRODUCTIONFollowing first-dimension IEF and equilibration of the IPG gel strips, the proteins are separated on the basis of their molecular weight in the second dimension on an SDS-PAGE gel. Systems for this separation are available from a variety of suppliers and are commonly found in many protein chemistry laboratories. This protocol describes a method for placement of the IPG strip and gives some recommended electrophoresis conditions for these second-dimension gels. PMID- 22485954 TI - Fluorescent Staining of Proteins with SYPRO Ruby. AB - INTRODUCTIONSYPRO Ruby is a sensitive ruthenium-based fluorescent dye that, similar to silver stains, interacts with basic amino acids, including lysine, arginine, and histidine. Recent studies have shown that this dye is as sensitive as silver staining and completely compatible with matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy. The staining method has only three steps: fixation, staining, and destaining. Since SYPRO Ruby is very expensive, this dye might be limited to micropreparative gels, as the cost to run the large number of gels done in quantitative studies is prohibitive. PMID- 22485955 TI - Preparation of Eukaryotic Lysates for 2D Gel Electrophoresis. AB - INTRODUCTIONCultured mammalian cell lines are widely used as study models in biomedical research. The protocol described here has been used successfully for many human colon carcinoma cell lines and fibroblast cell lines. Although most cellular proteins can be extracted by this protocol, some DNA-binding proteins may not be recovered. If DNA-binding proteins are to be studied, a nuclease (e.g., Benzonase) should be included. Expression proteomic studies frequently require the detection of low-abundance proteins. PMID- 22485956 TI - Radioisotopic Labeling of Eukaryotic Cell Proteins Using 35S. AB - INTRODUCTIONRadioisotope labeling of proteins is an important technique in expression proteomics studies for detecting low-abundance proteins. The procedure given below describes (35)S labeling. After the labeling procedure described here, cell lysates can be prepared for analysis by 2D gel electrophoresis. PMID- 22485957 TI - Radioisotopic Labeling of Eukaryotic Cell Proteins Using 32P. AB - INTRODUCTIONRadioisotope labeling of proteins is an important technique in expression proteomics studies for detecting low-abundance proteins. The procedure given below describes a labeling technique using (32)P labeling. After the labeling procedure described here, cell lysates can be prepared for analysis by 2D gel electrophoresis. PMID- 22485958 TI - Preparative 2D Gel Electrophoresis with Immobilized pH Gradients: Rehydration of IPG Strips for Isoelectric Focusing of Proteins. AB - INTRODUCTIONThis protocol describes a method for rehydration of IPG gel strips in preparation for their use for isoelectric focusing (IEF) on immobilized pH gradient (IPG) gels. Following rehydration, IEF can be performed using either a flatbed unit or a self-contained instrument. PMID- 22485959 TI - Preparative 2D Gel Electrophoresis with Immobilized pH Gradients: Isoelectric Focusing of Proteins in a Multipurpose Flatbed Electrophoresis Unit. AB - INTRODUCTIONThis protocol describes a method for separating proteins based on their net charge using the technique of isoelectric focusing (IEF) on immobilized pH gradient (IPG) gels. This method serves as the first dimension of the 2D separation. The method described in this protocol utilizes a flatbed unit; however, self-contained instruments for IEF are also available. PMID- 22485960 TI - Preparative 2D Gel Electrophoresis with Immobilized pH Gradients: IEF of Proteins in an IEF-Dedicated Electrophoresis Unit. AB - INTRODUCTIONThis protocol describes a method for separating proteins based on their net charge using the technique of isoelectric focusing (IEF) on immobilized pH gradient (IPG) gels, providing the first dimension of the 2D separation. In this protocol, the IPG gels are focused using self-contained instruments for IEF. These high-voltage systems allow fewer manipulations of the IPG gels, resulting in less error, strip mix-up, contamination, air contact, or urea crystallization. Because rehydration and IEF can be performed consecutively within a single unit, these two steps can be performed unattended overnight. Finally, faster separations and sharper focusing are possible due to the higher voltage available in these instruments. PMID- 22485961 TI - Phosphoprotein Staining with the GelCode Phosphoprotein Staining Kit. AB - INTRODUCTIONThe phosphorylation state of a protein has an important role in the regulation of a wide variety of cellular processes. As a result, there has been a great deal of interest in detecting phosphorylated proteins. The method presented here uses the GelCode phosphoprotein staining kit (Pierce Chemical Company). This method depends on the hydrolysis of the phosphoprotein phosphoester linkage using sodium hydroxide in the presence of calcium ions. The gel containing the newly formed insoluble calcium phosphate is then treated with ammonium molybdate in dilute nitric acid. The resultant insoluble nitrophospho-molybdate complex is stained with Methyl Green. After destaining, the phosphoproteins are colored green to green-blue. The detection limit is in the nanogram range, but depends on the degree of phosphorylation of the protein. This method will detect the phosphoproteins phosvitin and beta-casein in the 40-80 ng/band and 80-160 ng/band range, respectively. The method presented here is for staining minigels. Volumes will need to be increased for larger gels. PMID- 22485962 TI - Analysis of Protein Interactions In Vivo with Fluorescence Resonance Energy Transfer (FRET). AB - INTRODUCTIONThe protocol presented here focuses on a standard microscope-based fluorescence resonance energy transfer (FRET) assay for budding yeast, but many aspects are applicable to other systems and assays. It provides information on experimental design and data analysis procedures that can be extended to FRET experiments in any system, including mammalian cell lines and other model organisms. The steps describing strain construction can be applied to studies in yeast using fluorimetry instead of microscopy. Although the data acquisition and analysis described in this protocol can be a daunting task, careful quantitative analysis is absolutely necessary because of a high degree of cross-talk and many unknown parameters that vary from cell to cell. PMID- 22485963 TI - Preparation of Vertical SDS Slab Gels: Casting a Single Homogeneous Gel. AB - INTRODUCTIONFollowing the separation of proteins by IEF, the second dimension is carried out by SDS-PAGE. This protocol details the method for casting single homogeneous SDS-PAGE gels. Homogeneous gels (with the same %T and %C throughout) offer the best resolution for a particular molecular-weight range and are commonly used because they are the easiest to pour reproducibly. The second dimension gels can be conveniently prepared in three different formats (i.e., sizes): minigels, for use with 7-cm IEF first-dimension gels; standard gels, for use with 11-, 13-, and 18-cm IEF first-dimension gels; and large-format gels, for use with 18- and 24-cm IEF first-dimension gels. All of the gels use a common set of reagents, listed below, but differ slightly in the equipment required. PMID- 22485964 TI - Preparation of Vertical SDS Slab Gels: Simultaneous Casting of Multiple-Gradient Gels. AB - INTRODUCTIONGradient SDS-PAGE gels provide the best resolution over a wide range of molecular weights, resulting in sharper protein spots, because diffusion is minimized by the decreasing pore size in the gel. However, gradient gels are more difficult to produce reproducibly; thus, they are commonly cast with multiple-gel casters, which allows for an identical set of gels to be produced for an experiment. Presented here is a method for casting gradient gels using a multiple gel casting system. PMID- 22485965 TI - Preparative 2D Gel Electrophoresis with Immobilized pH Gradients: IPG Strip Equilibration. AB - INTRODUCTIONThe equilibration step serves to saturate the IPG strip with the SDS buffer system required for the second-dimension separation. The equilibration solution consists of buffer, urea, glycerol, reductant, SDS, and dye. The buffer (50 mM Tris-HCl, pH 8.8) maintains the appropriate pH range for electrophoresis. Urea and glycerol are added to reduce the effects of electroendosmosis, thus helping improve protein transfer from the IPG strip to the second dimension. The reductant (dithiothreitol) ensures that disulfide bridges are broken. SDS ensures that the proteins are denatured and also provides a net negative charge to all proteins. Iodoacetamide, introduced during a second equilibration step, alkylates thiol groups on the proteins, preventing their reoxidation during electrophoresis, and thus reducing streaking and other artifacts in the second dimension separation. Iodoacetamide also alkylates residual dithiothreitol, preventing point streaking and other silver staining artifacts. Finally, a tracing dye (bromophenol blue) is added to allow the electrophoresis to be monitored during the run. PMID- 22485966 TI - Concentrating acrylamide gel spots. AB - INTRODUCTIONThis protocol describes a method for concentrating gel bands or spots excised from 1D or 2D acrylamide gels. Several replicate protein bands (or spots) are often required to provide sufficient material for sequencing. In these situations, it is necessary to excise several stained protein bands or spots from the gels and pre-concentrate them prior to electroblotting for amino-terminal sequencing or internal sequence analysis following in-gel proteolytic (or chemical) fragmentation. In the method described below, concentration is done by re-electrophoresis of the gel pieces in a simple SDS-PAGE gel poured in a single conventional glass Pasteur pipette. PMID- 22485967 TI - Gateway-compatible yeast one-hybrid screens. AB - INTRODUCTIONProtein-DNA interactions (PDIs) between transcription factors (TFs) and their target genes form the backbone of transcription regulatory networks. Such PDIs can be identified with either a TF or a gene as a starting point. The Gateway-compatible yeast one-hybrid (Y1H) system provides a high-throughput, gene centered method for the identification of interactions between a "DNA bait" (e.g., cis-regulatory DNA elements or gene promoters) and "protein preys" (e.g., TFs). The Y1H system is a genetic system to detect PDIs based on selection of reporter gene expression in yeast. DNA baits are fused by Gateway cloning to two reporter genes, HIS3 and lacZ, and the resulting DNA bait::reporter constructs are subsequently integrated into the genome of the host yeast strain. After integration, baits are examined for self-activation (i.e., their ability to drive reporter gene expression in the absence of an exogenous prey protein). Subsequently, each DNA bait is screened for interacting proteins by transforming a library of preys into the corresponding Y1H DNA bait yeast strain. Preys are hybrid proteins composed of a protein from the organism of interest and a heterologous transcription activation domain. When a prey protein binds to the DNA bait, the heterologous activation domain activates reporter gene expression. Thus, physical interactions between both repressors and activators and their DNA targets can be identified. PMID- 22485968 TI - EMS Mutagenesis of Arabidopsis Seed. AB - INTRODUCTIONEMS-mutagenized Arabidopsis seed collections can be purchased from companies or acquired from other researchers. But in some cases (e.g., mutagenesis of a specific genotype), it is necessary for an investigator to generate EMS-mutagenized seed. In this protocol, EMS is used at concentrations that induce multiple point mutations in each plant, such that mutant alleles of a specific locus are found at a rate of ~1 in 2000-5000 M(2) plants. This high rate of mutagenesis makes possible the screening of relatively few plants to find those with the phenotype of interest, a particular advantage if the screen is laborious or if only a small number of genes mutate to the required phenotype. PMID- 22485969 TI - Screening DNA Pools for T-DNA Insertions in Arabidopsis Genes. AB - INTRODUCTIONMany investigators are interested in studying the functions of genes whose sequences or expression patterns suggest roles in particular biological processes. A powerful way to identify a mutation in the gene of interest and to test mutant plants for phenotypes that are predicted to result from loss of function of that gene is by PCR screening. Pools of insertion lines are screened using one primer corresponding to the gene of interest and one primer corresponding to the end of the insertion element. The synthesis of a product indicates the presence of an insertion in the gene of interest. The pool is then repeatedly subdivided until a single plant carrying the desired insertion is identified. PMID- 22485970 TI - Setting up Arabidopsis crosses. AB - INTRODUCTIONThe inheritance of mutant phenotypes is most often analyzed in the progeny resulting from crosses between different parents. Because Arabidopsis naturally self-pollinates, the generation of cross-progeny requires some intervention by the investigator. This protocol describes the generation and collection of seeds by crossing suitable Arabidopsis parent plants. PMID- 22485971 TI - Forward Genetics in Arabidopsis: Finding Mutations that Cause Particular Phenotypes. PMID- 22485972 TI - Measuring FRET by sensitized emission. PMID- 22485973 TI - Measuring FRET by acceptor photobleaching. PMID- 22485974 TI - An experimental setup for frequency domain FLIM. PMID- 22485976 TI - Live imaging of Caenorhabditis elegans: observation of nematodes and data collection. PMID- 22485975 TI - FLIM measurements and frequency domain FLIM data analysis. PMID- 22485977 TI - Live imaging of Caenorhabditis elegans: examples. PMID- 22485978 TI - Fluorescent reagents for live cell imaging and their introduction into cells. AB - Most biological specimens, including Drosophila tissues, are relatively transparent, so details of internal and intracellular morphology are difficult to image in untreated living specimens using simple bright-field techniques. Although there are methods for improving contrast in bright-field imaging, fluorescence microscopy offers greater advantages and possibilities for increasing contrast and determining the specific localization of molecules in cells. Fluorescence microscopy has proven to be particularly well suited to the study of live material, now that an ever-increasing and bewildering array of different "vital" probes are available for tracking cellular components and activities, including some that have been applied to Drosophila. Here we outline the three methods most commonly used to introduce an appropriate label into Drosophila tissue without unduly perturbing the process. PMID- 22485979 TI - Selection of appropriate imaging equipment and methodology for live cell imaging in Drosophila. AB - The wide range of microscopy equipment and techniques are truly bewildering and ever-expanding. In the past two decades, there have been many revolutions in light microscopy techniques made possible by improvements in optics, detector technology, and computers. Furthermore, there is no indication that the rate of development of new equipment is slowing down. Here we attempt to provide an overview of available options and important considerations applicable to imaging Drosophila cells and tissues. PMID- 22485980 TI - Membrane trafficking and organelle reagents. PMID- 22485981 TI - Site-specific protein-DNA photo-cross-linking: analysis of structural organization of protein-DNA and multiprotein-DNA complexes. AB - Site-specific protein-DNA photo-cross-linking is able to define positions of proteins relative to DNA within large multiprotein-DNA complexes. Chemical and enzymatic reactions are used to prepare a DNA fragment containing a phenyl-azide photoactivatible cross-linking agent and an adjacent radiolabel incorporated at a single, defined DNA phosphate. The multiprotein-DNA complex of interest is formed using the site-specifically derivatized DNA fragment. The complex is then UV irradiated, initiating covalent cross-linking with proteins in direct physical proximity to the cross-linking agent. Extensive nuclease digestion is performed to eliminate uncross-linked DNA and convert cross-linked DNA to a cross-linked, radiolabeled nucleotide "tag." The "tagged" proteins are identified, usually by denaturing polyacrylamide gel electrophoresis followed by autoradiography. The procedure is performed in a systematic fashion: At least 10 derivatized DNA fragments, each having the cross-linking agent incorporated at a defined DNA phosphate within the region of interest, are analyzed. The results of the procedure define the translational positions of proteins relative to the DNA sequence. Plotted on a three-dimensional representation of a DNA helix, the results also define the rotational orientations of proteins relative to the DNA helix axis and the groove orientations of proteins relative to the DNA major and minor grooves. Here, we present a detailed protocol for the cross-linking of protein-DNA complexes immobilized on streptavidin-coated paramagnetic beads ("on bead" cross-linking). PMID- 22485982 TI - Split luciferase complementation assay for studying interaction of proteins x and y in living mice. AB - This protocol describes a split luciferase complementation assay that can be used to repetitively and noninvasively study the interaction of proteins in small living animals. After the expression of the appropriate vectors has been checked in cell culture in vivo, studies can be performed either by implanting transiently transfected cells for short-term analysis (maximum of 7 days), as described below, or with tumor models grown from tumor cells stably expressing the complete reporter system. For optical imaging, the number of cells implanted can be relatively low (~1-5 * 10(6)), and imaging can begin even before the tumors are palpable. When using a regulated reporter gene, it may be necessary to perform a dose-dependent pilot experiment with the inducer or repressor before performing the primary experiments. Animal models other than mice can be used, including rats and, in theory, transgenic animals in which the reporter constructs have been stably integrated into the genome. Animals larger than the rat would be difficult to image due to poor penetration of light. For these larger-animal models, the use of other imaging technologies such as microPET should be considered. PMID- 22485983 TI - Split luciferase complementation assay for studying interaction of proteins x and y in cells. AB - This protocol describes a split luciferase complementation assay used to study the interaction of proteins in cells. In the "split protein" strategy, a single reporter protein/enzyme (in this case, firefly luciferase [Fluc]) is cleaved into amino-terminal and carboxy-terminal halves; each half is fused to one of two interacting proteins, X and Y. Physical interactions between the two proteins, X and Y, reconstitute the functional reporter protein, leading to enzymatic activities that can be measured by in vitro or in vivo assays. It is important to perform the assay initially in cell culture before proceeding with animal imaging, not only to conserve animals, but also to establish the sensitivity of the assay. PMID- 22485984 TI - Imaging protein interactions by FRET microscopy: FRET measurements by sensitized emission. AB - This protocol describes a method for measuring fluorescence resonance energy transfer (FRET) by the detection of acceptor-sensitized emission. This approach is useful in situations where donor intensities are low and/or there is contamination with high background (auto) fluorescence in the donor channel. However, absorption spectra characteristically exhibit long tails in the higher energy, shorter-wavelength (blue) region, which may result in the direct excitation of the acceptor molecule in addition to that of the donor, thus resulting in mixing of direct and sensitized emission. Conversely, fluorescence emission tends to tail into the red part of the spectrum, causing donor fluorescence bleed-through into the acceptor detection channel. Corrections for these effects involve the acquisition of fluorescence images of samples containing the donor, the acceptor, and both of these for three different filter settings. The result is an estimation of the sensitized emission, i.e., the emission induced by FRET from the donor to the acceptor alone. Excitation of a donor fluorophore in a FRET pair leads to quenching of the donor fluorescence and increased emission from the acceptor (sensitized emission). This can be normalized using the acceptor emission, measured after specific excitation of the acceptor, to define apparent energy transfer efficiency in each pixel of the image. It is also proportional to the fraction of acceptor molecules that is bound to a donor-tagged molecule. Alternatively, an apparent energy transfer efficiency can also be defined that is proportional to the bound fraction of donor-tagged molecules. PMID- 22485985 TI - Imaging protein interactions by FRET microscopy: FRET measurements by acceptor photobleaching. AB - This protocol describes the detection of fluorescence resonance energy transfer (FRET) by measuring the quenching of donor emission alone. As opposed to sensitized emission measurements, photobleaching can be performed with high selectivity of the acceptor because absorption spectra are steep at their red edge, allowing the acceptor to be bleached without excitation of the donor. When using acceptor photobleaching FRET measurements, care should be taken that the photochemical product of the bleached acceptor does not have residual absorption at the donor emission and, more importantly, that it does not fluoresce in the donor spectral region. Because of mass movement of protein during the extended time required for photobleaching (typically 1-20 min), it is preferable to perform this type of FRET determination on fixed cell samples. Live-cell FRET measurements based only on donor fluorescence are more feasible using fluorescence lifetime imaging (FLIM), because lifetimes are independent of probe concentration and light path length. The former is not easy to determine in cells, and the latter means that cell shape is not a factor. PMID- 22485986 TI - Imaging protein interactions by FRET microscopy: FLIM measurements. AB - This image acquisition protocol is a basic plan for taking a fluorescence lifetime imaging (FLIM) series. FLIM makes live-cell FRET measurements based only on donor fluorescence more feasible, because lifetimes are independent of probe concentration and light path length. The former is not easy to determine in cells, and the latter means that cell shape is not a factor. PMID- 22485987 TI - Photoactivation-based labeling and in vivo tracking of RNA molecules in the nucleus. AB - This protocol describes a method for observing and measuring the movement of RNA molecules in the nucleus of living mammalian cells. Caged fluorescein-labeled DNA oligonucleotides are introduced into living mammalian cells, where they demonstrably hybridize to complementary RNA. After site-specific photoactivation at desired sites within the cell, the RNA movements away from those sites are followed and digitally recorded using a rapid acquisition microscopy system. PMID- 22485988 TI - Live Imaging of Caenorhabditis elegans: preparation of samples. AB - Caenorhabditis elegans, a small (adults are ~1 mm long), free-living soil nematode that feeds on bacteria, is an ideal organism for applying various live microscopy techniques. The organism is transparent, thus it is possible to microscopically analyze the whole animal throughout its entire life. Its complete cell lineage is known, making it possible to follow developmental and differentiation processes in real time. Furthermore, the development of transgenic techniques, as well as RNA interference (RNAi) methods and sophisticated genetic analyses, and the availability of a large collection of mutant lines all make C. elegans especially attractive for live microscopy. This protocol describes useful techniques for preparing C. elegans for live microscopic analysis. Details of sample preparation depend on the developmental stage of the worm to be studied. PMID- 22485989 TI - Time-lapse cinematography in living Drosophila tissues: preparation of material. AB - The fruit fly, Drosophila melanogaster, has been an extraordinarily successful model organism for studying the genetic basis of development and evolution. It is arguably the best-understood complex multicellular model system, owing its success to many factors. Recent developments in imaging techniques, in particular sophisticated fluorescence microscopy methods and equipment, now allow cellular events to be studied at high resolution in living material. This ability has enabled the study of features that tend to be lost or damaged by fixation, such as transient or dynamic events. Although many of the techniques of live cell imaging in Drosophila are shared with the greater community of cell biologists working on other model systems, studying living fly tissues presents unique difficulties in keeping the cells alive, introducing fluorescent probes, and imaging through thick hazy cytoplasm. This protocol outlines the preparation of major tissue types amenable to study by time-lapse cinematography and different methods for keeping them alive. PMID- 22485990 TI - Imaging of organelle membrane systems and membrane traffic in living cells. AB - Eukaryotic cells are composed of an intricate system of internal membranes that are organized into different compartments, including the endoplasmic reticulum, the nucleus, the Golgi apparatus, lysosomes, endosomes, mitochondria, and peroxisomes, with specialized roles within the cell. Only recently have the localization and dynamics of these organelles been studied in the context of the living cell because of the availability of green fluorescent protein (GFP) fusion proteins and recent advances in fluorescent microscope imaging systems. In this protocol, a confocal laser-scanning microscope (CLSM) and GFP fusion proteins are used in time-lapse imaging to visualize the behavior of organelles and to track membrane-bound transport intermediates that bud off from organelles. Practical issues related to the construction and expression of GFP fusion proteins are also discussed. These are essential for optimizing the brightness and expression levels of GFP fusion proteins so that intracellular membrane-bound structures containing these fusion proteins can be readily visualized. PMID- 22485991 TI - Detection of ubiquitylated proteins in mammalian cells. AB - This assay is performed to detect ubiquitylated proteins in transfected mammalian cells. Twenty-four to 40 hours after transfection, cells are harvested, total ubiquitylated proteins are recovered by nickel-affinity chromatography, and specific proteins are detected by Western blotting. PMID- 22485992 TI - Bradford assay. AB - This assay is used for protein quantitation. It is relatively accurate for most proteins, except for small basic polypeptides such as ribonuclease or lysozyme. It is also hampered by detergent concentrations over ~0.2%. PMID- 22485993 TI - Imaging protein interactions by FRET microscopy: labeling proteins with fluorescent dyes. AB - This protocol provides a method for labeling proteins, such as antibodies and purified recombinant proteins, with succinimide esters of sulfoindocyanine (Cy) dyes. Cy dyes covalently bind to free amino groups (the alpha-amino-terminal or epsilon-amino groups on lysine side chains). PMID- 22485994 TI - Imaging protein interactions by FRET microscopy: cell preparation for FRET analysis. AB - The following protocol describes the preparation of cells for FRET analysis on live and fixed cells. The reagents used have been optimized to minimize the quenching of GFP mutants and fluorescent dyes. PMID- 22485995 TI - Identification of positive GATEWAY expression clones when both the pENTRY and pDEST vectors contain the same marker for bacterial selection. AB - GATEWAY cloning technology (Invitrogen) takes advantage of bacteriophage lambda site-specific recombination. The life cycle of lambda alternates between the lytic and lysogenic stages. DNA can be inserted or excised from the Escherichia coli host genome by recombination between specific sites, AttB (bacterial) and AttP (phage). This process is mediated by the lambda proteins int (integrase) and xis (excisionase), and a host protein IHF (integration host factor). GATEWAY cloning technology uses this process to insert fragments of DNA directionally into specially adapted vectors. These vectors contain a negative selectable marker, the ccdB gene, to select against nonrecombinant clones. Promoter or gene fragments are made GATEWAY compatible with adapter primers and amplified by PCR. These fragments are used in a BP clonase reaction to create ENTRY clones. Usually the pDONR vector used to generate such ENTRY clones is chosen so that the antibiotic selection marker is different from that of the pDEST vector, which finally generates an expression clone. This favors the selection of the expression clone and selects against the pENTRY clone. Now that many pENTRY and pDEST vectors have been generated and made available in stock centers, the antibiotic resistance genes are predetermined and may not always be compatible with each other. This problem is frequently experienced by plant researchers, since many full-length cDNA libraries have been generated using the pDONR-TOPO, pDONR221, or pENTR1A vectors, which are all kanamycin resistant in bacteria, and many pDEST vectors have been adapted from conventional plant transformation vectors, which are also frequently kanamycin resistant in bacteria. The following protocol describes ways in which such difficult vector combinations can be used effectively to obtain the appropriate expression clone without having to convert the pENTRY clone or pDEST clone to vectors with compatible antibiotic resistances. PMID- 22485996 TI - Coding genes join the non-coding world. PMID- 22485997 TI - Overuse of stents in cardiology. PMID- 22485998 TI - The discovery of thrombolysis. PMID- 22485999 TI - Clearing the murky waters of cardiac biomarkers. PMID- 22486000 TI - The power of transparency. PMID- 22486001 TI - Turning point: Jessica Ware. Interviewed by Virginia Gewin. PMID- 22486002 TI - [Proceedings of the Quadrimed Congress Medicine: beyond the beaten path, January 26-29, 2012 Crans-Montana, Switzerland]. PMID- 22486003 TI - [50 years of publication in Vnitrni lekarstvi]. PMID- 22486005 TI - Regenerating battle wounds, together. PMID- 22486004 TI - The parasite-stress theory may be a general theory of culture and sociality. AB - In the target article, we presented the hypothesis that parasite-stress variation was a causal factor in the variation of in-group assortative sociality, cross nationally and across the United States, which we indexed with variables that measured different aspects of the strength of family ties and religiosity. We presented evidence supportive of our hypothesis in the form of analyses that controlled for variation in freedom, wealth resources, and wealth inequality across nations and the states of the USA. Here, we respond to criticisms from commentators and attempt to clarify and expand the parasite-stress theory of sociality used to fuel our research presented in the target article. PMID- 22486006 TI - Kitty breastfeeding. PMID- 22486007 TI - Milk boosters: naturally enhancing a mother's milk supply. PMID- 22486008 TI - Marion's message. Messages from Sorot, Uganda. PMID- 22486009 TI - Biological Nurturing: the laid-back breastfeeding revolution. PMID- 22486010 TI - Breastfeeding Milla. PMID- 22486011 TI - The role of the shy hormone in breastfeeding. PMID- 22486012 TI - Whatever turn my birthing may take. PMID- 22486013 TI - Midwives: guardians of nature's design. PMID- 22486014 TI - Adapting birth services for incarcerated mothers. PMID- 22486015 TI - Kangaroo care. PMID- 22486016 TI - The two faces of postdate pregnancies. PMID- 22486017 TI - Growth as an industry: how can we become our best selves? PMID- 22486018 TI - Meeting the need: building communities of lactation support. PMID- 22486019 TI - Compassion and empathy--a Doulas best friends. PMID- 22486020 TI - Engaging the senses as midwifery tools. PMID- 22486021 TI - The four pillars of safe breast milk sharing. PMID- 22486022 TI - Milk supply: you have enough. PMID- 22486023 TI - Rights and relationships. PMID- 22486024 TI - My nursing journey. PMID- 22486025 TI - A futuristic allegory of over-medicalization. PMID- 22486026 TI - Breastfeeding duration and mother-to-mother support. PMID- 22486027 TI - A mom's breastfeeding adventure. PMID- 22486028 TI - Gentle Hands Clinic, Philippines. PMID- 22486030 TI - Babin Den. PMID- 22486029 TI - Reasons why the Dutch system is changing. PMID- 22486031 TI - Breastfeeding and newborn survival. PMID- 22486032 TI - Midwifery in Toraja, Indonesia. PMID- 22486033 TI - Not in Kansas anymore: an unexpected birth in Sudan. PMID- 22486034 TI - A buddy near the crib: perinatal coaching for underprivileged families. PMID- 22486035 TI - Geographical variation of the furanocoumarin composition of the fruits of Icelandic Angelica archangelica. AB - Angelica archangelica fruits were collected from 64 locations around Iceland and analysed for furanocoumarins by high-performance liquid chromatography. The average furanocoumarin content was found to be 22.5 mg/g, ranging from 14.0 to 31.6 mg/g. Whereas imperatorin was the main compound in all samples, the order of other compounds was highly diverse. Considerable differences were observed between individuals from the same location and between neighbouring locations. However, strong geographical impact was observed on the composition, with isoimperatorin and bergapten being more pronounced in South Iceland, and oxypeucedanin and an unidentified compound being more pronounced in North Iceland and absent in many samples from South Iceland. PMID- 22486036 TI - Tropane alkaloids of Datura innoxia from Morocco. AB - Fifty three alkaloids were identified in the organs (roots, stems, leaves, flowers, and seeds) of Datura innoxia by GC/MS. Seventeen of them are reported for the first time for this species and one nor-derivative, 3 phenylacetoxynortropane (28), for the genus Datura. Furthermore, four new tropane esters were tentatively identified as 3-acetoxy-6,7-epoxytropane (acetylscopine) (10), 3-acetoxy-6-propionyloxy-7-hydroxytropane (15), 6,7-dehydro-3 phenylacetoxytropane (25), and 3-(2'-phenylpropionyloxy)-6,7-epoxynortropane (dihydroaponorscopolamine) (37) on the basis of their mass spectral data. Hyoscyamine (44) and scopolamine (48) figure as main alkaloids in the roots and aerial parts, respectively. PMID- 22486037 TI - Evaluation of the anti-inflammatory and antinociceptive properties of p-cymene in mice. AB - We attempted to identify the antinociceptive and anti-inflammatory actions of the monoterpene p-cymene. Firstly, behavioural screening was carried out to verify the influence of p-cymene [25, 50, and 100 mg/kg intraperitoneal (i.p.)] on the central nervous system (CNS) activity. The antinociceptive activity of p-cymene was evaluated by the acetic acid-induced writhing response, formalin, and hot plate test, respectively. The leukocyte migration induced by injection of carrageenan was used to assess the anti-inflammatory activity. p-Cymene showed depressant activity on CNS after 4 h of treatment and also a possible action on the autonomous nervous system (ANS), mainly at the dose of 100 mg/kg (i.p.). It was found that p-cymene (50 and 100 mg/kg, i.p.) significantly (p < 0.05) reduced the writhing responses induced by acetic acid. p-Cymene also decreased the licking time in the first and second phase, respectively, of the formalin test. The results of the hot-plate test showed that all doses of p-cymene increased significantly the latency time of the response to the thermal stimulus in both licking and jumping parameters. In addition, there was a significantly (p < 0.05) decreased leukocyte migration at all doses of p-cymene. The experimental data demonstrate that p-cymene possesses antinociceptive and anti-inflammatory activities. PMID- 22486038 TI - Chemical and antiviral study on alkaloids from Papaver pseudocanescens M. Pop. AB - The phytochemical investigation of the aerial parts of Papaver pseudocanescens M. Pop. of Mongolian origin resulted in the isolation and structural elucidation of 8 alkaloids of the isoquinoline and promorphinane type. 8,14-Dihydroamurine, 8,14 dihydroflavinantine, and flavinantine are promorphinanes. Alborine, mecambridine, and mecambridine methohydroxide are retroprotoberberines. Amurensinine is an isopavine alkaloid and O-methylarmepavine is a benzylisoquinoline alkaloid. O Methylarmepavine is a new alkaloid for the genus Papaver. Promorphinane-type alkaloids have been found for the first time in the species. All structures were established by physical and spectral analysis. As a first attempt to describe some of the biological activities of these alkaloids, the antiviral effect was tested against the in vitro replication of several viruses which belong to different taxonomic groups and represent significant human pathogens. Based on the results, the conclusion could be drawn that particular alkaloids from P. pseudocanescens possess selective antiviral effects against the replication of poliovirus 1 and human rhinovirus 14, two viruses from the Enterovirus genus of the Picornaviridae family. PMID- 22486039 TI - Antimicrobial and antioxidant activities of Gentianella multicaulis collected on the Andean Slopes of San Juan Province, Argentina. AB - The infusion of the aerial parts of Gentianella multicaulis (Gillies ex Griseb.) Fabris (Gentianaceae), locally known as 'nencia', is used in San Juan Province, Argentina, as stomachic and as a bitter tonic against digestive and liver problems. The bioassay-guided isolation of G. multicaulis extracts and structural elucidation of the main compounds responsible for the antifungal and free radical scavenging activities were performed. The extracts had strong free radical scavenging effects in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay (45-93% at 10 microg/mL) and ferric-reducing antioxidant power (FRAP) assay at 200 microg/mL. Demethylbellidifolin (4) had high antioxidant activity in the DPPH and FRAP assay. The dermatophytes Microsporum gypseum, Trichophyton mentagrophytes, and T. rubrum were moderately inhibited by the different extracts (MIC values of 125-250 microg/mL). Demethylbellidifolin (4), bellidifolin (5), and isobellidifolin (6) showed an antifungal effect (MIC values of 50 microg/mL), while swerchirin (3) was less active with a MIC value of 100 microg/mL. In addition, oleanolic acid (1) and ursolic acid (2) were also isolated. These findings demonstrate that Gentianella multicaulis collected in the mountains of the Province of San Juan, Argentina, is an important source of compounds with antifungal and antioxidant activities. PMID- 22486040 TI - The saponin-rich fraction of a Gymnema sylvestre R. Br. aqueous leaf extract reduces cafeteria and high-fat diet-induced obesity. AB - We examined the antiobesity effect of a saponin-rich fraction of a Gymnema sylvestre R. Br. aqueous leaf extract (SGE) using cafeteria and high-fat diet induced obese rats for a period of eight weeks. SGE was orally administered at a dose of 100 mg/kg body weight once a day to the treatment group. It significantly decreased the body weight, food consumption, visceral organs weight, and the levels of triglycerides, total cholesterol, low-density lipoproteins, very low density lipoproteins, atherogenic index, glucose, and increased the levels of high-density lipoproteins. There was no significant difference with respect to all parameters of the study in case of normal (N) diet and N diet + SGE rats. In vitro, SGE inhibited the pancreatic lipase activity. The present study gave clear evidence that the SGE has a significant antiobese action, supporting its use in traditional medicine, and can be used as a substitute for synthetic drugs. PMID- 22486041 TI - Protective and therapeutic effects of Argyreia speciosa against ethanol-induced gastric ulcer in rats. AB - The protective and therapeutic effects of Argyreia speciosa Sweet (Convolvulaceae) against ethanol-induced gastric ulcer in rats were evaluated. Ethanolic and water extracts of the aerial plant parts (200 mg/kg body weight) were orally administered daily for seven days prior to or after ulceration with one oral dose of 1 mL absolute ethanol on 24-h empty stomachs. Rats were divided into eleven groups. Group 1 served as control. To groups 2 and 3 each extract was administered. Groups 4 to 6 received each extract or ranitidine (100 mg/kg body weight) prior to ulcer induction. Groups 7 to 9 received each extract or ranitidine post ulcer induction. Groups 10 and 11 were gastric ulcerative rats after one hour and one week of ethanol induction. The evaluation was done through measuring ulcer indices: stomach acidity and volume, lesion counts, mucus, and prostaglandin E2 contents. Oxidative stress marker, i. e. malondialdehyde, glutathione, and superoxide dismutase, were estimated. Certain marker enzymes for different cell organelles, i. e. succinate and lactate dehydrogenases, glucose-6 phosphatase, acid phosphatase, and 5'-nucleotidase, were evaluated. The work was extended to determine the collagen content and the histopathological assessment of the stomach. Gastric ulcer exhibited a significant elevation of the ulcer index, antioxidant levels, collagen content, and the marker enzymes. The water extract attenuated these increments and was more potent as a protective agent, while the ethanol extract exhibited stronger therapeutic potency. In conclusion, A. speciosa acted as antiulcer agent. More detailed studies are required to identify the compounds responsible for the pharmacological effect. PMID- 22486042 TI - Accumulation of tetracoumaroyl spermine in Matricaria chamomilla during floral development and nitrogen deficiency. AB - The new natural polyamine conjugate 1N,5N,10N,14N-tetracoumaroyl spermine (tetracoumaroyl spermine) recently isolated from chamomile (Matricaria chamomilla L.) flower heads is applicable for the treatment of several human disorders such as depression and anxiety. High variability in the level of tetracoumaroyl spermine is found in commercial tisanes. Accumulation of tetracoumaroyl spermine was tested during floral development, and nitrogen deficiency was chosen as its putative limiting environmental factor. It was observed that tetracoumaroyl spermine is present mainly in tubular flowers, reaching its maximal content during the 3rd phase of flowering when the corollae of tubular flowers start to open. The later observed decrease could result from a release of pollen that also contains a considerable amount of tetracoumaroyl spermine. It is likely that tetracoumaroyl spermine plays an important role in pollen development, and so, despite overall N-deficiency in the plants, tetracoumaroyl spermine is accumulated at the same or even higher rate than in the flowers of the N sufficient control. PMID- 22486043 TI - Micropropagation of Cyclopia genistoides, an endemic South African plant of economic importance. AB - An efficient micropropagation protocol of Cyclopia genistoides (L.) Vent., an indigenous South African shrub of economic importance, was established. In vitro shoot cultures were obtained from shoot tip fragments of sterile seedlings cultured on solid Schenk and Hildebrandt (SH) medium supplemented with 9.84 microM 6-(gamma,gamma-dimethylallylamino)purine (2iP) and 1.0 microM thidiazuron (TDZ). Maximum shoot multiplication rate [(8.2 +/- 1.3) microshoots/explant)] was observed on this medium composition. Prior to rooting, the multiplied shoots were elongated for 60 days (two 30-days passages) on SH medium with one-half sucrose concentration, supplemented with 4.92 microM indole-3-butyric acid (IBA). The rooting of explants was only possible in the case of the elongated shoots. The highest root induction rate (54.8%) was achieved on solid SH medium with one-half sucrose and one-half potassium nitrate and ammonium nitrate concentration, respectively, supplemented with 28.54 microM indole-3-acetic acid (IAA) and 260.25 microM citric acid. The plantlets were acclimatized for 30 days in the glasshouse, with the use of peat/gravel/perlite substrate (1:1:1). The highest acclimatization rate (80%) was obtained for explants rooted with the use of IAA supplemented medium. The phytochemical profile of the regenerated plants was similar to that of the reference intact plant material. HPLC analyses showed that C. genistoides plantlets obtained by the micropropagation procedure kept the ability to produce xanthones (mangiferin and isomangiferin) and the flavanone hesperidin, characteristic of wild-growing shrubs. PMID- 22486044 TI - Flavonoids and antioxidative enzymes in temperature-challenged roots of Scutellaria baicalensis Georgi. AB - The active compounds in the roots of Scutellaria baicalensis Georgi, a traditional Chinese medicinal plant, are mainly flavonoids which have anti inflammatory, antitumour, and anti-HIV activity, respectively. The increasing annual average temperature has rendered the S. baicalensis plants grown in some ancient producing regions no longer suitable for their medicinal usage. Hydrogen peroxide plays an important role in root responses to abnormal temperature in S. baicalensis. Baicalin and baicalein and antioxidative enzymes were anticipated to detoxify H2O2 in S. baicalensis. Here, we show that abnormal temperatures (10 and 40 degrees C) decreased the content of flavonoids as compared with the normal temperature (30 degrees C), and the transcripts of UDP-glucuronate:baicalein 7-O glucuronosyltransferase and beta-glucuronidase involved in the interconversion between baicalin and baicalein were affected by the 40-degrees C treatment. High temperature also increased the activities of catalase and peroxidase. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that the transcript levels of peroxidase 2, peroxidase 3, monodehydroascorbate reductase 2, and dehydroascorbate reductase were significantly increased under high temperature conditions. The respective genes would be candidates for improvement of the adaptation of S. baicalensis plants to abnormal temperatures and for regulation of the contents of the active compounds. PMID- 22486045 TI - Major biological activities of the skin secretion of the Chinese giant salamander, Andrias davidianus. AB - Amphibian skin can produce abundant secretion which contains many bioactive compounds. In this work, skin secretion of the Chinese giant salamander (Andrias davidianus) was obtained by mild electrical stimulation of the dorsal skin surface, and the main physiopathological properties of the secretion were described. Intraperitoneal administration of the skin secretion caused lethal effects in mice. Low doses of the skin secretion induced significant systemic and local effects like edema and nociception in mice. The activities of phospholipase A2 and proteolytic enzyme were likely related to the physiopathological activities observed. The work proved the complex toxic effects of the Chinese giant salamander skin secretion and provided clues to study its physiological function further. PMID- 22486046 TI - Nonvolatile chemical cues affect host-plant ranking by gravid Polygonia c-album females. AB - In a multiple-choice test, the preference of egg-laying Polygonia c-album (comma butterfly) females was studied for oviposition on plants bearing surrogate leaves treated with crude methanol extracts obtained from leaves of seven host-plant species: Humulus lupulus, Urtica dioica, Ulmus glabra, Salix caprea, Ribes nigrum, Corylus avellana, and Betula pubescens. The ranking order of surrogate leaves treated with host-plant extracts corresponded well to that reported on natural foliage, except R. nigrum. Thus, host-plant choice in P. c-album seems to be highly dependent on chemical cues. Moreover, after two subsequent fractionations using reversed-phase chromatography the nonvolatile chemical cues residing in the most polar water-soluble fractions evidently provided sufficient information for egg-laying females to discriminate and rank between the samples of more and less preferred plants, since the ranking in these assays was similar to that for natural foliage or whole methanol extracts, while the physical traits of the surrogate leaves remained uniform. PMID- 22486047 TI - [The importance of disability insurance]. PMID- 22486048 TI - [Thyroid disorders]. AB - In Germany, thyroid disorders have a long history. A sufficient iodine supply has been achieved in recent years in Germany. Thyroid nodules are frequent and mostly benign findings. Autonomous adenomas are not self-curable findings and require a definitive therapy, especially in the case of concomitant functional abnormalities (subclinical or overt hyperthyroidism). Graves' disease is the other most frequent cause of overt hyperthyroidism. In Germany, Graves' disease is treated with thyrostatic medication usually over 1-1 1/2 years, resulting in a definitive cure in about 50% of patients. In the case of therapy failure or high risk of relapse according to initial findings or complications under thyrostatic medication (leucopenia), definitive treatment mostly by way of radioactive iodine 131 is advised. Radioiodine therapy is usually well tolerated with minimal side effects and is not associated with risks such as laryngeal nerve palsy and hypoparathyroidism. Alternatively, surgical treatment is indicated in case of suspected malignancy or large thyroid volumes with relevant tracheal compression. Hashimoto's thyroiditis is the most frequent reason for hypothyroidism requiring levothyroxine substitution. In Germany, about 3500 women and 1500 men are diagnosed with papillary or follicular thyroid carcinoma each year which can be cured in the vast majority of patients. Less than 10% develop metastases after initial thyroidectomy and ablative radioiodine therapy. These patients can be treated with further therapy cycles of radioiodine. In the case of development of dedifferentiated iodine-negative, FDG-PET-positive metastatic disease treatment options are limited. In this situation, tyrosinkinase-inhibitors are a new treatment option which are being evaluated in current and prospective randomised controlled trials. Thyroid carcinoma (C73) is the most frequent reason for medical pensions because of thyroid disease. The rare anaplastic thyroid carcinoma is one of the most malignant tumours overall being usually fatal within a few months after diagnosis. PMID- 22486049 TI - [From guilt and shame to professional handling of mistakes--risk management in surgical medicine]. AB - Medical advances in diagnosis and therapy, especially in medical technology, lead to differenciated and more complex strategies in therapy with higher risks. Patients show higher expectations concerning the results of a therapy and claim more often that a mistake in treatment has been made. This makes patients turn to arbitration boards more often. They may also want to bring civil action against physicians and hospitals, claiming for compensation and damages. Personal liability insurances have to pay more for damages. Medical insurances have more recourse demands due to mistake in treatment. Hospital and especially operative medicine do have high chances of risks and mistakes. The implementation of a modern risk management system in the hospitals is becoming more and more important, for patients as well as for the surgical departments. A structured reporting system of critical incidents can produce indicators of potential sources of mistakes, which appears to be a successful approach to reduce or avoid typical risks and mistakes in medical treatment. Risk management in medical treatment must be more than just a trendy word, because its roots are in the medical principles of "primum nihil nocere". It is a challenge to today's and tomorrow's medicine. This article is a general overview of current strategies for avoiding mistakes: It is meant to be the basis of a new culture of mistake avoidance as a part of a future quality competition. PMID- 22486050 TI - [Relevant aspects of the individual medical examination in SLAP lesion: traumatic versus degenerative/preexisting changes]. AB - In the case of SLAP-lesions the upper part of the labrum glenoidale is affected and the long tendon of the biceps muscle can be involved. In literature different types of the lesions are classified. In the case of an individual medical examination, it should be kept in mind that variations of normal anatomy exist and for that reason the examiner should analyse if there is a real pathological condition. He should also discuss the pathogenesis with special regard to the mechanisms of trauma as published in literature. With SLAP-lesions there should be a functional disabling symptomatology of the affected shoulder that occurs directly or at least shortly after the accident. Also the imaging modalities and, when available the findings of an operative treatment, should be analysed to see if other trauma-lesions exist. These aspects will be discussed in the following paper. PMID- 22486051 TI - [The medical specialist for insurance medicine--the Flemish residency]. AB - Insurance medicine is becoming more and more important. Currently, there are few countries in Europe where insurance medicine is recognised as an independent discipline; the Netherlands is one example. Since 2007 the "Specialist in Insurance Medicine and Medico-legal Expertise" is recognised in Belgium. This article will give an overview of the residency of Flemish physicians. By enactment, this consists of a theoretical and a practical section. This way of education should open broad possibilities in private and social insurance medicine, but also in the research sector. PMID- 22486052 TI - [Traditional Chinese medicine--quo vadis?]. PMID- 22486053 TI - [Asian medicine - from the perspective of consumer protection]. PMID- 22486054 TI - [Psychological evaluations in the BU-insurance - sound, comprehensible and plausible]. PMID- 22486056 TI - Postage stamp on TNAI: another feather on TNAI's cap. PMID- 22486055 TI - [Extensive check-up in a healthy person, including CT scans and MRI]. PMID- 22486057 TI - Practicing transcultural nursing care. PMID- 22486058 TI - Effect of health education programme on worm infestation in school children. PMID- 22486059 TI - Assessing and comparing the knowledge of nursing students regarding breast cancer. PMID- 22486060 TI - Cardiac surgery in a child with Jehovah's Witness faith--a case report. PMID- 22486061 TI - Design and operation of the 2010 National Survey of Residential Care Facilities. AB - OBJECTIVES: This methods report provides an overview of the National Survey of Residential Care Facilities (NSRCF) conducted in 2010. NSRCF is a first-ever national probability sample survey that collects data on U.S. residential care providers, their staffs and services, and their residents. Included are residential care facilities consisting of assisted living residences; board and care homes; congregate care; enriched housing programs; homes for the aged; personal care homes; and shared housing establishments that are licensed, registered, listed, certified, or otherwise regulated by a state. A survey specific definition was used to select residential care facilities into the study. This report discusses the need for and objectives of the survey, design process, survey methods, and data availability. METHODS: In 2008, a small pilot study and a pretest were conducted to test and refine the survey protocol, data collection procedures, and questionnaires. NSRCF was conducted between March and November 2010. The survey used a two-stage probability sampling design in which residential care facilities were sampled. Then, depending on facility size, three to six current residents were sampled. In-person interviews were conducted with facility directors and designated staffs; no interviews were conducted with residents. The survey instrument contained a facility screening module, facility- and resident-level modules, a resident sampling module, and a pre-interview worksheet. RESULTS: National data were collected on 2,302 facilities, and 8,094 current residents. The first-stage facility weighted response rate (for differential probabilities of selection) was 81%. The second-stage resident weighted response rate was 99%. Two public-use files will be released. The facility and resident files include sampling weights to generate national estimates, and design variables to calculate accurate standard errors. PMID- 22486062 TI - [Chronic renal failure causes bone fragility and blood vessel stiffening]. AB - Chronic renal failure results in disturbances of bone formation, degradation and mineralization and changes in bone volume. These bone changes as well as biochemical abnormalities of the blood have also been found to be associated with soft-tissue and blood vessel calcification. In fact, the patients suffer not only from skeletal problems but also from rapidly progressing arterial stiffening, which leads to early cardiovascular morbidity and mortality. Essential therapy consists of early management of hyperphosphatemia and supplementation of active vitamin D. PMID- 22486063 TI - [Medical treatment of juvenile idiopathic arthritis]. AB - Although etiology of juvenile idiopathic arthritis (JIA) is currently not known, better understanding of immunologic pathways of inflammation and the development of new therapies with biologic agents have remarkably improved the treatment of JIA. However, approximately 30% of the patients with JIA do not seem to response adequately to conventional anti-rheumatic drugs but the arthritis runs a continuously active course and may lead to the evolution of erosions. Such patients benefit from biologic agents, of which the longest clinical experience comes from anti-TNF therapies. Molecules targeting IL-1, IL-6 and B- and T lymphocytes are also used in the treatment of severe JIA. PMID- 22486064 TI - [Publication bias--the Achilles' heel of medical research]. AB - Overestimation of results that are positive or meet the expectations may lead to biased information and have an influence on treatment practices. Compared with positive research results, the publication delay of negative results may be longer by up to several years. The file drawer effect, grey literature, selective publication of results along with commercial interests or lack thereof also influence the selection of publications. Publication bias can be reduced by registering studies in databases, by agreeing upon rights to the results and by favoring open peer review. PMID- 22486065 TI - [How can we help a binge eater?]. AB - In primary health care, early recognition of a patient having a binge eating disorder is essential already before the development of overweight. The therapy aims at gaining control over eating, stopping radical attempts at weight reduction and guiding the binge eater to follow a regular meal rhythm and a well balanced diet. With the help of a regular meal rhythm, food volumes in binge eating episodes will decrease fairly quickly and the episodes become less frequent. The immediate prognosis of the patient is usually good, but the illness is characterized by a periodic and fluctuating course. PMID- 22486066 TI - [Marfan syndrome]. AB - This review on Marfan syndrome is focused on the clinical heterogeneity and variability, the new diagnostic criteria as delineated by an expert group in 2010, the current knowledge on the molecular and pathogenetic etiology, and the options of the medical and surgical treament. Defined clinical findings, family history and mutations in the FBN1 gene only differentiate Marfan syndrome from the other aortic syndromes. The involvement of the cellular TGF-beta-signaling in pathogenesis allows new approach for medical treatment with ATR-blockers for which, however, evidence based indications are still lacking. Finally, a suggestion is made how to arrange the diagnostic workup, appropriate treatment and follow-up of the Marfan patients in the Finnish health care. PMID- 22486067 TI - [Myocardial infarct during pregnancy]. AB - Acute myocardial infarction during pregnancy is a rare but potentially fatal complication. We describe a 43-year-old patient with non-ST-segment elevation myocardial infarction during late pregnancy. She underwent coronary angiography but was treated conservatively after an occlusion of mid-size left oblique marginal branch was observed. During pregnancy many medications normally used in the setting of acute coronary syndrome are contraindicated and use of radiation should be minimized. Thus treatment of acute coronary syndrome must be carefully tailored in this patient group. PMID- 22486068 TI - [Incarcerated Spigelian hernia]. AB - Incarcerated Spigelian hernia is a rare cause of abdominal pain requiring emergency surgery. It occurs in the lower abdomen between abdominal musculature in the region of Spigelian aponeurosis. On the basis of incidental findings in laparoscopy the frequency of this hernia is less than 2%. Spigelian hernias are often completely symptomless, but they are associated with the risk of intestinal incarceration. Owing to its rare occurrence, incarcerated Spigelian hernia is difficult to diagnose, which may delay the treatment. PMID- 22486069 TI - [Impaired vision-dependent performance due to posterior cortical atrophy]. AB - By causing problems in vision-dependent perception, posterior cortical atrophy (PCA) results in a significant impairment of functional ability. Most cases of PCA are atypical manifestations of Alzheimer's disease. PCA is a rare disease, and accurate data about its frequency are lacking. Disease symptoms begin typically under the age of 60 years. The prerequisites for a correct diagnosis are awareness and recognition of a special clinical picture and special investigations such as cerebrospinal fluid analysis and investigations of brain metabolism. A typical set of clinical characteristics and findings of special examinations in PCA are described. PMID- 22486070 TI - [Update on Current Care guidelines: ADHD (attention-deficit/hyperactivity disorder, children and adolescents)]. AB - The updated Current Care guideline for children and adolescents with ADHD covers both diagnosis and treatment. Psychosocial support is provided when hyperactivity problems arise, even before specific diagnosis. While psychosocial interventions are effective in the treatment of ADHD, the core symptoms are best treated with medication, such as methylphenidate, dexamphetamine, lisdexamphetamine or atomoxetine. Collaboration between families, primary health care services, specialist consultation services and day-care and school professionals is essential within the chain of care. PMID- 22486071 TI - [Asbestos in pre-industrial times: from natural wonder to subject of scientific investigation]. AB - The author proposes a reading of "Concerning incombustible flax or asbestos stone" which was published in 1696 by Giovanni Giustino Ciampini, who was a historian, a man of the church and scientist in Rome. The text, which was originally written in Latin, is an excellent and early description of the need felt by the majority of scientists in Europe at that time for a change in method: that is, to use scientific experiments to explain and control the natural phenomena observed and even perhaps mythologized right from antiquity. In the case of asbestos this was necessary to check the veracity and consistency of a series of recommendations handed down by the earliest authors but also to revive and reinvent the techniques that had largely been lost so as to be able to utilize and develop a substance that it was thought could be of great benefit to society. In the presentation of Ciampini's text an attempt is made to recall and contextualize the earliest knowledge on asbestos and follow its evolution over a long historical period, up to the first half of the nineteenth century. It can thus be seen how asbestos, once considered "a wonder of nature", became a raw material widely used in industrial applications. The most significant steps in this phase of transformation were taken thanks to Italian entrepreneurs and technicians and to the presence of asbestos in the Alpine valleys of Italy. PMID- 22486072 TI - Occupational nonasthmatic eosinophilic bronchitis: current concepts. AB - BACKGROUND: Nonasthmatic eosinophilic bronchitis (NAEB) is an important cause of chronic cough, since it is present in 10-15% of patients referred for specialist investigation. The syndrome is considered a variant of occupational asthma when it develops as a consequence of occupational exposure, hence it should be considered in the spectrum of work-related airway diseases. OBJECTIVES AND METHODS: The aim of this paper was to update and expand the previous reviews on the clinical and pathophysiological features of NAEB and analyze available data on the occupational causes of the disease. Literature on the topic between the years 1990 and 2010 was reviewed with a Med Line search. RESULTS: The disease is probably underdiagnosed and an occupational origin was demonstrated only in isolated cases, probably due to the rarity of the disease and the lack of systematic evaluation of bronchial inflammation. CONCLUSIONS: In view of the current knowledge on this condition and the development of techniques to evaluate bronchial inflammation, occupational NAEB cannot be neglected any more and has been rightly included in the spectrum of occupational respiratory disorders. PMID- 22486073 TI - Immunosurveillance for Mycobacterium tuberculosis of health care personnel in a third level care hospital. AB - BACKGROUND: Health care workers are at risk for Mycobacterium tuberculosis (MTB) infection. OBJECTIVES: To perform an occupational health survey among 621 employees of a 800-bed third level care hospital covered by MTB surveillance. METHODS: Statistical analysis was applied to results from tuberculin skin test (TST), QuantiFERON - TB Gold in tube assay (QFT), PPD-ELISA for serum antibodies, and occupational or vaccine data. RESULTS: 29.1% of subjects were TST positive, 18.5% were QFT positive. In 23% of subjects no correlation between these tests was found, presumably linked to BCG-vaccination, since TST positivity was 4 times higher among vaccinated subjects, whereas both tests correlated well in unvaccinated subjects. QFT values above 2 IU/ml were significantly associated with positive TST and age over 40 years. Working in MTB risk level 4 was significantly associated with QFT, TST and PPD-antibody levels, suggesting booster effects by repeated exposure. No clear correlation was observed with medical specializations but significantly higher QFTpositivity was found in subjects not assigned to the classical medical professions and originating from MTB high risk areas. CONCLUSIONS: These results shift the focus on maintenance personnel, who mostly worked in MTB risk level 2 areas. The less positive QFT results in vaccinated subjects highlight QFT's advantage as a screening tool and argue for a protective effect of the BCG-vaccine, although percentages of vaccinated persons varied largely between different medical professions. Interestingly, the percentage of QFT positive persons was lower among subjects reporting MTB exposure than those who were not aware of exposure events. PMID- 22486074 TI - [Screening of patient manual handling risk using the MAPO method]. AB - BACKGROUND: International standards draw attention to the steps that risk assessment should follow to first identify hazards, then proceed to risk evaluation and lastly, if necessary, risk assessment. The same logic also applies to risk assessment of manual patient handling. OBJECTIVES: To check appropriateness of approach to "risk evaluation" of manual patient handling using MAPO, a cross sectional study was carried out aimed at checking the relationship between this new risk assessment model (MAPO screening) and occurrence of acute low back pain. METHODS: After proper training the MAPO screening method was used to assess risk of manual handling of patients in 31 wards, covering 411 exposed subjects employed in geriatric hospitals belonging to the UNEBA (National Union Institutions and Social Welfare Initiatives) of the Veneto Region. At the same time health data were collected on the occurrence of low back pain episodes during the last year both in the group of exposed subjects and in an external reference group (237 subjects). Risk and clinical assessment data were verified and checked by the EPM research unit. Logistic analysis was used as a method to evaluate the relationship between MAPO screening risk index and acute low back pain. RESULTS: Investigating the relationship between acute low back pain episodes and levels of MAPO screening index, carried out only on exposed subjects who reported working for at least 30 hours per week (N=178), showed definitely positive trends: for MAPO screening index of exposure levels between 1.51 and 5, OR were double (OR=2.22; IC 95% 0.88-5.63) whereas for index levels exceeding 5, OR were about 4 (OR=3.77; IC 95% 1.33-10.74). These results did not show significant differences when correcting the analysis for confounding factors such as gender and age classes. CONCLUSIONS: The results of the study indicate that the proposed method, "MAPO screening", can be a useful tool to estimate risk due to manual handling of patients and can also be used to test the efficacy of preventive measures. PMID- 22486075 TI - [Risk assessment of biomechanical overload of limbs and spine in workers employed on stone paving roads, using a combination of different methods]. AB - BACKGROUND: Few data exist on the risk of musculoskeletal disorders in road paving workers, in addition methods for risk assessment of biomechanical overload of the lower limbs and the spine are also lacking. OBJECTIVES: The aim of this study was to assess the risk from biomechanical overload for the whole musculoskeletal system and manual handling involved in the activity of stone paving of roads. METHODS: In accordance with the guidelines of the Italian Society of Occupational Medicine and Industrial Hygiene various risk assessment methods were used. RESULTS: The Washington State checklist revealed the presence of biomechanical overload of the spine in flexion. The Turin checklist showed a risk score higher than the acceptable limit for the cervical and lumbar spine and limbs (risk level similar to that obtained from the OCRA checklist for the upper limbs). The assessment of risk from manual handling of loads carried out using the NIOSH method provided a synthetic risk index whereas evaluation conducted using the Washington State method was acceptable. CONCLUSIONS: Biomechanical risk assessment showed the presence of risk for use of force and awkward postures of the wrist and elbow, which agrees with literature data. The division of tasks among workers and the distribution of breaks helped to reduce the risk to an acceptable level for limbs. All methods however showed a risk for the spine. Health surveillance showed disorders of the spine in 28% of the workers and no disorders of the upper limbs, which agrees with the risk assessment. PMID- 22486076 TI - [Definition and validation of a comfort index calculation method for office seats]. AB - BACKGROUND: Among its other required features, a highly comfortable chair should adapt its contact surfaces, namely the seat and the back rest, to the shape of the body of the person sitting on it. However, "comfort" is not usually perceived as an absolute value, but is derived from a subjective comparison between two or more chairs. OBJECTIVES: The purpose of this research was the definition of an objective comfort index (IC), i.e., derived from instrumental measurements, and which would also represent an absolute comfort value. METHODS: Analytical evaluation of the distribution of body weight, by means of a barometric matrix, shows that a comfortable chair tends to minimize peak and average values of pressure at the level of the contact areas located between the body and the seat and the back of the chair. To define a comparison parameter for determining an absolute comfort value, a reference chair (SDR) was developed. The seat and the back of this chair are rigid, with poor compliance. A comfort value of zero was, by definition, assigned to this chair. Therefore, the Comfort index (IC) was obtained by the mathematical calculation of the ratios of averages, peaks and gradients of pressure, appropriately weighted, and the corresponding values measured on the tested chair and on the SDR. RESULTS: It is shown that the anthropometric characteristics of each subject are irrelevant to the assessment of the IC, which depends only on the compliance characteristics of the seat and back surfaces of the tested chair CONCLUSIONS: IC can be improved through analysis of a larger number of seats, which would thus constitute the basis for the use of an objective evaluation of seating comfort. PMID- 22486077 TI - [The right of self-determination in dealing with the physician and the employer between the obligations, prohibitions, obligations and rights related to health surveillance]. PMID- 22486078 TI - Asbestos exposure among hairdressers. PMID- 22486079 TI - [Scientific productivity of Italian Universities of Occupational Medicine in the decade 2001-2010]. PMID- 22486080 TI - Fungal endophytes directly increase the competitive effects of an invasive forb. AB - Competitive outcomes among plants can vary in different abiotic and biotic conditions. Here we tested the effects of two phylotypes of Alternaria endophytes on the growth, competitive effects, and competitive responses of the exotic invasive forb Centaurea stoebe. Centaurea stoebe was a better competitor against North American grass species than grasses from its European home range in the absence of endophytes. However, one endophyte both increased the biomass of C. stoebe and reduced the competitive effect of North American grasses on C. stoebe. The competitive effects of C. stoebe on grass species native to North America were enhanced by both fungal endophytes, but not for native European grasses. We do not know the mechanism by which endophytes increased C. stoebe's competitive ability, and particularly against biogeographically new neighbors, but one endophyte increased the competitive ability of C. stoebe without increasing its size, suggesting mechanisms unrelated to increased growth. We tested only a fraction of the different endophytic fungi that have been found in C. stoebe, only scratching the surface of understanding their indirect effects. However, our results are the first to demonstrate such effects of a fungal endophyte infecting an invasive forb, and one of the few to show that endophyte effects on competition do not have to be mediated through herbivory. PMID- 22486081 TI - Bottom-up multitrophic effects in resprouting plants. AB - Severe damage often provokes compensatory resprouting of plants, which commonly modify plant morphological and phenological traits. Rapid plant growth often results in poorly defended nutrient-rich foliage, which is more susceptible to foliar-chewing herbivores. It is less known how other guilds of arthropods are affected by plant regrowth. We tested the hypotheses that clipping-induced resprouting and nutrient availability, separately and in combination, would (1) influence plant traits, (2) benefit chewing herbivores, sap-suckers, gallers, and pre-dispersal seed predators, and (3) cascade up to the third trophic level by positively affecting herbivores. Resprouted plants were morphologically and phenologically different from undamaged plants; as a result, seed predation, infestation rate, richness, and diversity of seed predators increased, and species composition was altered. Leaf consumption by chewing herbivores was four times higher on resprouted plants. The number of galls decreased, whereas the abundance of sap-sucking and leaf-chewing insects was not affected. The incidence of predators and parasitoids was also higher on resprouted plants and on plants with nutrients added, but the increase was less pronounced compared to the herbivores they feed on. Thus, the effects of resprouting, contingent on nutrient availability, can propagate simultaneously through two independent tri-trophic level pathways. PMID- 22486082 TI - Experimental and environmental factors affect spurious detection of ecological thresholds. AB - Threshold detection methods are increasingly popular for assessing nonlinear responses to environmental change, but their statistical performance remains poorly understood. We simulated linear change in stream benthic macroinvertebrate communities and evaluated the performance of commonly used threshold detection methods based on model fitting (piecewise quantile regression [PQR]), data partitioning (nonparametric change point analysis [NCPA]), and a hybrid approach (significant zero crossings [SiZer]). We demonstrated that false detection of ecological thresholds (type I errors) and inferences on threshold locations are influenced by sample size, rate of linear change, and frequency of observations across the environmental gradient (i.e., sample-environment distribution, SED). However, the relative importance of these factors varied among statistical methods and between inference types. False detection rates were influenced primarily by user-selected parameters for PQR (tau) and SiZer (bandwidth) and secondarily by sample size (for PQR) and SED (for SiZer). In contrast, the location of reported thresholds was influenced primarily by SED. Bootstrapped confidence intervals for NCPA threshold locations revealed strong correspondence to SED. We conclude that the choice of statistical methods for threshold detection should be matched to experimental and environmental constraints to minimize false detection rates and avoid spurious inferences regarding threshold location. PMID- 22486083 TI - The role of chitin in the decomposition of ectomycorrhizal fungal litter. AB - Ectomycorrhizal fungal tissues comprise a significant forest-litter pool. Ectomycorrhizal (EM) fungi may also influence the decomposition of other forest litter components via competitive interactions with decomposer fungi and by ensheathing fine roots. Because of these direct and indirect effects of ectomycorrhizal fungi, the factors that control the decomposition of EM fungi will strongly control forest-litter decomposition as a whole and, thus, ecosystem nutrient and carbon cycling. Some have suggested that chitin, a component of fungal cell walls, reduces fungal tissue decomposition because it is relatively recalcitrant. We therefore examined the change in chitin concentrations of EM fungal tissues during decomposition. Our results show that chitin is not recalcitrant relative to other compounds in fungal tissues and that its concentration is positively related to the decomposition of fungal tissues. Variation existing among EM fungal isolates in chitin concentration suggests that EM fungal community structure influences C and nutrient cycling. PMID- 22486084 TI - Optimum swimming pathways of fish spawning migrations in rivers. AB - Fishes that swim upstream in rivers to spawn must navigate complex fluvial velocity fields to arrive at their ultimate locations. One hypothesis with substantial implications is that fish traverse pathways that minimize their energy expenditure during migration. Here we present the methodological and theoretical developments necessary to test this and similar hypotheses. First, a cost function is derived for upstream migration that relates work done by a fish to swimming drag. The energetic cost scales with the cube of a fish's relative velocity integrated along its path. By normalizing to the energy requirements of holding a position in the slowest waters at the path's origin, a cost function is derived that depends only on the physical environment and not on specifics of individual fish. Then, as an example, we demonstrate the analysis of a migration pathway of a telemetrically tracked pallid sturgeon (Scaphirhynchus albus) in the Missouri River (USA). The actual pathway cost is lower than 10(5) random paths through the surveyed reach and is consistent with the optimization hypothesis. The implication--subject to more extensive validation--is that reproductive success in managed rivers could be increased through manipulation of reservoir releases or channel morphology to increase abundance of lower-cost migration pathways. PMID- 22486085 TI - Life history theory predicts fish assemblage response to hydrologic regimes. AB - The hydrologic regime is regarded as the primary driver of freshwater ecosystems, structuring the physical habitat template, providing connectivity, framing biotic interactions, and ultimately selecting for specific life histories of aquatic organisms. In the present study, we tested ecological theory predicting directional relationships between major dimensions of the flow regime and life history composition of fish assemblages in perennial free-flowing rivers throughout the continental United States. Using long-term discharge records and fish trait and survey data for 109 stream locations, we found that 11 out of 18 relationships (61%) tested between the three life history strategies (opportunistic, periodic, and equilibrium) and six hydrologic metrics (two each describing flow variability, predictability, and seasonality) were statistically significant (P < or = 0.05) according to quantile regression. Our results largely support a priori hypotheses of relationships between specific flow indices and relative prevalence of fish life history strategies, with 82% of all significant relationships observed supporting predictions from life history theory. Specifically, we found that (1) opportunistic strategists were positively related to measures of flow variability and negatively related to predictability and seasonality, (2) periodic strategists were positively related to high flow seasonality and negatively related to variability, and (3) the equilibrium strategists were negatively related to flow variability and positively related to predictability. Our study provides important empirical evidence illustrating the value of using life history theory to understand both the patterns and processes by which fish assemblage structure is shaped by adaptation to natural regimes of variability, predictability, and seasonality of critical flow events over broad biogeographic scales. PMID- 22486086 TI - A test of the senses: fish select novel habitats by responding to multiple cues. AB - Habitat-specific cues play an important role in orientation for animals that move through a mosaic of habitats. Environmental cues can be imprinted upon during early life stages to guide later return to adult habitats, yet many species must orient toward suitable habitats without previous experience of the habitat. It is hypothesized that multiple sensory cues may enable animals to differentiate between habitats in a sequential order relevant to the spatial scales over which the different types of information are conveyed, but previous research, especially for marine organisms, has mainly focused on the use of single cues in isolation. In this study, we investigated novel habitat selection through the use of three different sensory modalities (hearing, vision, and olfaction). Our model species, the French grunt, Haemulon flavolineatum, is a mangrove/seagrass associated reef fish species that makes several habitat transitions during early life. Using several in situ and ex situ experiments, we tested the response of fish toward auditory, olfactory, and visual cues from four different habitats (seagrass beds, mangroves, rubble, and coral reef). We identified receptivity to multiple sensory cues during the same life phase, and found that different cues induced different reactions toward the same habitat. For example, early-juvenile fish only responded to sound from coral reefs and to chemical cues from mangroves/seagrass beds, while visual cues of conspecifics overruled olfactory cues from mangrove/seagrass water. Mapping these preferences to the ecology of ontogenetic movements, our results suggest sequential cue use would indeed aid successful orientation to novel key habitats in early life. PMID- 22486087 TI - Species diversity reduces parasite infection through cross-generational effects on host abundance. AB - With growing interest in the effects of biodiversity on disease, there is a critical need for studies that empirically identify the mechanisms underlying the diversity-disease relationship. Here, we combined wetland surveys of host community structure with mechanistic experiments involving a multi-host parasite to evaluate competing explanations for the dilution effect. Sampling of 320 wetlands in California indicated that snail host communities were strongly nested, with competent hosts for the trematode Ribeiroia ondatrae predominating in low-richness assemblages and unsuitable hosts increasingly present in more diverse communities. Moreover, competent host density was negatively associated with increases in snail species richness. These patterns in host community assembly support a key prerequisite underlying the dilution effect. Results of multigenerational mesocosm experiments designed to mimic field-observed community assemblages allowed us to evaluate the relative importance of host density and diversity in influencing parasite infection success. Increases in snail species richness (from one to four species) had sharply negative effects on the density of infected hosts (-90% reduction). However, this effect was indirect; competition associated with non-host species led to a 95% reduction in host density (susceptible host regulation), owing primarily to a reduction in host reproduction. Among susceptible hosts, there were no differences in infection prevalence as a function of community structure, indicating a lack of support for a direct effect of diversity on infection (encounter reduction). In monospecific conditions, higher initial host densities increased infection among adult hosts; however, compensatory reproduction in the low-density treatments equalized the final number of infected hosts by the next generation, underscoring the relevance of multigenerational studies in understanding the dilution effect. These findings highlight the role of interspecific competition in mediating the relationship between species richness and parasite infection and emphasize the importance of field-informed experimental research in understanding mechanisms underlying the diversity-disease relationship. PMID- 22486088 TI - Are lower-latitude plants better defended? Palatability of freshwater macrophytes. AB - Increased herbivory at lower latitudes is hypothesized to select for more effective plant defenses. Feeding assays with seaweeds and salt marsh plants support this hypothesis, with low-latitude plants experiencing greater damage in the field and being less palatable than higher-latitude plants. We tested this hypothesis for freshwater macrophytes because they offered an independent plant lineage and habitat type for testing this general hypothesis and because the patchiness of consumer occupancy across isolated water bodies might produce local variance in herbivory that would override geographic variance and produce different results for this habitat type. When we fed eight congeneric pairs of live plants from four sites in Indiana vs. four sites in South Florida (-215 and 0 frost days/yr respectively) to three species of crayfishes and one species of snail, three of the four herbivores significantly preferred high-latitude to low latitude plants. For two crayfishes that differed in feeding on live plants (one favoring high-latitude plants and one not), we retested feeding using foods composed of freeze-dried and finely ground plants, thus removing structural characteristics while retaining most chemical/nutritional traits. In this assay, both herbivores strongly preferred high-latitude plants, suggesting that lower latitude plants had been selected for more deterrent chemical traits. When we collected 22 pairs of congeneric plants from 9 sites throughout Indiana vs. 13 sites in Central Florida (-215 and -95 frost days/yr respectively) and tested these in feeding assays with three crayfishes using dried, ground, and reconstituted plant material, we found a significant effect of latitude for only one of three species of herbivore. Overall, our results suggest a preference for high-latitude plants, but the strength of this relationship varied considerably across small scales of latitude that differed considerably in numbers of frost free days. The difference in results suggests that large changes in frost frequency over small spatial scales may affect selection for plant defenses, that local variance in herbivory overrode differential selection at geographic scales, or that these possibilities interact when durations of cold weather periodically exclude herbivores from shallower habitats, producing heterogeneous selection for defenses at small spatial scales. PMID- 22486089 TI - Functional identity and functional structure change through succession in a rocky intertidal marine herbivore assemblage. AB - Despite the great interest in characterizing the functional structure and resilience of functional groups in natural communities, few studies have examined in which way the roles and relationships of coexisting species change during community succession, a fundamental and natural process that follows the release of new resources in terrestrial and aquatic ecosystems. Variation in algal traits that characterize different phases and stages of community succession on rocky shores are likely to influence the magnitude, direction of effects, and the level of redundancy and complementarity in the diverse assemblage of herbivores. Two separate field experiments were conducted to quantify per capita and population effects and the functional relationship (i.e., redundancy or complementarity) of four herbivore species found in central Chile during early and late algal succession. The first experiment examined grazer effects on the colonization and establishment of early-succession algal species. The second experiment examined effects on the late-successional, dominant corticated alga Mazzaella laminarioides. Complementary laboratory experiments with all species and under natural environmental conditions allowed us to further characterize the collective effects of these species. We found that, during early community succession, all herbivore species had similar effects on the ephemeral algae, ulvoids, but only during the phase of colonization. Once these algae were established, only a subset of the species was able to control their abundance. During late succession, only the keyhole limpet Fissurella crassa could control corticated Mazzaella. The functional relationships among these species changed dramatically from redundant effects on ephemeral algae during early colonization, to a more complementary role on established early-successional algae, to a dominant (i.e., keystone) effect on late succession. This study highlights that functional relationship within consumer assemblages can vary at different phases and times of community succession. Differentiation in herbivore roles emphasizes the need to evaluate consumer's impacts through different times of community succession, and through experimental manipulations to make even broad predictions about the resilience or vulnerability of diverse intertidal assemblages to human disturbances. PMID- 22486090 TI - Mechanisms mediating plant distributions across estuarine landscapes in a low latitude tidal estuary. AB - Understanding of how plant communities are organized and will respond to global changes requires an understanding of how plant species respond to multiple environmental gradients. We examined the mechanisms mediating the distribution patterns of tidal marsh plants along an estuarine gradient in Georgia (USA) using a combination of field transplant experiments and monitoring. Our results could not be fully explained by the "competition-to-stress hypothesis" (the current paradigm explaining plant distributions across estuarine landscapes). This hypothesis states that the upstream limits of plant distributions are determined by competition, and the downstream limits by abiotic stress. We found that competition was generally strong in freshwater and brackish marshes, and that conditions in brackish and salt marshes were stressful to freshwater marsh plants, results consistent with the competition-to-stress hypothesis. Four other aspects of our results, however, were not explained by the competition-to-stress hypothesis. First, several halophytes found the freshwater habitat stressful and performed best (in the absence of competition) in brackish or salt marshes. Second, the upstream distribution of one species was determined by the combination of both abiotic and biotic (competition) factors. Third, marsh productivity (estimated by standing biomass) was a better predictor of relative biotic interaction intensity (RII) than was salinity or flooding, suggesting that productivity is a better indicator of plant stress than salinity or flooding gradients. Fourth, facilitation played a role in mediating the distribution patterns of some plants. Our results illustrate that even apparently simple abiotic gradients can encompass surprisingly complex processes mediating plant distributions. PMID- 22486091 TI - Patch size-dependent community recovery after massive disturbance. AB - Massive anthropogenic and climate-related disturbances are now common in ecosystems worldwide, generating widespread die-off and subsequent community recovery dominated by remnant-patch dynamics rather than open-gap dynamics. Whether communities can recover and, if so, which factors mediate recolonization rate and extent remain unresolved. Here we evaluate recolonization dynamics of southern U.S. salt marshes that experienced extensive, drought-induced die-off of the foundation species Spartina alterniflora over the previous decade. Surveys of Georgia (USA) salt marshes showed little seedling recruitment in die-off areas but persistence of Spartina particularly in large, rather than small, remnant patches. Given this natural variation in remnant patch size, we conducted field experiments to test whether key plant-controlling biotic (grazing, plant neighbor presence) and abiotic (water availability) factors differentially impact Spartina recolonization at small and large-patch scales. In the small-patch (< 1 m2) experiment in 2009, removing grazers and plant neighbors prompted dramatically higher expansion and growth of Spartina relative to controls, while adding freshwater to reduce water limitation had little effect. In contrast, large-patch (> 20 m2 borders advanced significantly over the same time period regardless of grazer or neighbor removal. We continued the large-patch experiments in 2010, a year that experienced drought, and also added freshwater or salt to borders to modify ambient drought stress; overall, borders advanced less than the previous year but significantly more where neighbors were removed or freshwater added. Thus, water availability appears to mediate Spartina recovery by fueling large patch expansion during wet summers and intensifying interspecific competition during drought. Combined, these findings suggest ecosystems can recover from massive disturbance if remnant foundation species' patches are large enough to overcome biotic inhibition and successfully expand during periods of relaxed abiotic stress. PMID- 22486092 TI - Elevated land runoff after European settlement perturbs persistent foraminiferal assemblages on the Great Barrier Reef. AB - Coral reefs are under pressure from a variety of human-induced disturbances, but demonstration of ecosystem changes and identification of stressors are often difficult. We tested whether global change or increased agricultural runoff after European settlement of Northeast Australia (ca. 1860) has affected inshore reefs of the Great Barrier Reef. Eleven sediment cores were retrieved from inner reefs, intermediate reefs, and outer-island reefs, and benthic foraminiferal assemblages were analyzed in dated (14C, 210Pb, 137Cs) core sections (N = 82 samples). Data were grouped into six age bands (< 55, 55-150, 150-500, 500-1000, 1000-1500, and > 1500 yr). Principal component analysis and two-factor (Zone and Age) permutational analysis of variance (PERMANOVA) suggested that assemblages from the three zones were significantly different from each other over several millennia, with symbiont-bearing (mixotrophic) species dominating the outer reefs. A significant interaction term indicated that within-zone patterns varied. Assemblages in outer reefs unaffected from increased land runoff were persistent until present times. In both other zones, assemblages were also persistent until 150 yr ago, suggesting that benthic foraminiferal assemblages are naturally highly persistent over long (> 2000 yr) timescales. Assemblages in core sections < 55 yr old from inner reefs were significantly (post hoc t test) different from those older than 150 yr. Similarly, assemblages < 55 yr old from intermediate reefs were significantly different compared to older assemblages. A multivariate regression tree (environmental variables: Zone and Age) explained 56.8% of the variance in foraminiferal assemblages and confirmed patterns identified by PERMANOVA. With some exceptions, changes on the inner and intermediate reefs were consistent with a model predicting that increased nutrients and higher turbidity enhance relative abundance of heterotrophic species. Given that assemblages did not change in outer-island reefs (not impacted by runoff) we argue that changes in assemblages due to global change can be rejected as an explanation. Thus, the findings are more consistent with the hypothesis that agricultural runoff since European settlement altered foraminiferal assemblages than with the hypothesis that global forcing caused changes. PMID- 22486093 TI - Coexistence of oceanic predators on wintering areas explained by population-scale foraging segregation in space or time. AB - Ecological niche theory predicts segregation mechanisms that mitigate potential competition between closely related organisms. However, little is known outside the breeding season, when central-place foraging animals may move on larger scales. This study tested for segregation mechanisms within the same 2007 inter breeding period on three neighboring populations of avian predators from the southern Indian Ocean: Eastern Rockhopper Penguins Eudyptes filholi from Crozet and Kerguelen and Northern Rockhopper Penguins E. moseleyi from Amsterdam. Using state-of-the-art geolocation tracking and stable isotope analysis techniques, we quantified and compared the ecological niches in time, space, and diet. The three populations showed large-scale movements over deep oceanic waters near the Subantarctic Front, with generally little individual variation. The two neighboring populations of Eastern Rockhopper Penguins showed strikingly distinct distribution in space, while foraging in similar habitats and at the same trophic level (crustacean-eaters). In contrast, Northern Rockhoppers showed marked spatial overlap with birds of the sibling Eastern species, but their temporal delay of two months enabled them to effectively avoid significant overlap. Our results highlight parsimonious mechanisms of resource partitioning operating at the population level that may explain how animals from neighboring localities can coexist during the nonbreeding period. PMID- 22486094 TI - Incorporating temporally dynamic baselines in isotopic mixing models. AB - Stable isotopes (particularly C and N) are widely used to make inferences regarding food web structure and the phenology of consumer diet shifts, applications that require accurate isotopic characterization of trophic resources to avoid biased inferences of feeding relationships. For example, most isotope mixing models require that endmembers be adequately represented by a single probability distribution; yet, there is mounting evidence that the isotopic composition of aquatic organisms often used as mixing model endmembers can change over periods of weeks to months. A review of the literature indicated that the delta13C values of five aquatic primary consumer taxa, commonly used as proxies of carbon production sources (i.e., trophic baselines), express seasonally dynamic cycles characterized by an oscillation between summer maxima and winter minima. Based on these results, we built a dynamic baseline mixing model that allows a growing consumer to track temporal gradients in the isotopic baselines of a food web. Simulations showed that the ability of a consumer to maintain or approach isotopic equilibrium with its diet over a realistic growth season was strongly affected by both the rate of change of the isotopic baseline and equilibration rate of the consumer. In an empirical application, mixing models of varying complexity were used to estimate the relative contribution of benthic vs. pelagic carbon sources to nine species of juvenile fish in a fluvial lake of the St. Lawrence River system (Quebec, Canada). Estimates of p (proportion of carbon derived from benthic sources) derived from a static mixing model indicated broad interspecific variation in trophic niche, ranging from complete benthivory to > 95% reliance on pelagic food webs. Output from the more realistic dynamic baseline mixing model increased estimated benthivory by an average of 36% among species. Taken together, our results demonstrate that failing to identify dynamic baselines when present, and (or) matching consumers with baseline taxa that possess substantially different equilibration rates can seriously bias interpretation of stable isotope data. Additionally, by providing a formalized framework that allows both resources and consumers to shift their isotopic value through time, our model demonstrates a feasible approach for incorporating temporally dynamic isotope conditions in trophic studies of higher consumers. PMID- 22486095 TI - Cascading effects of long-term land-use changes on plant traits and ecosystem functioning. AB - There is much concern that the functioning of ecosystems will be affected by human-induced changes in biodiversity, of which land-use change is the most important driver. However, changes in biodiversity may be only one of many pathways through which land use alters ecosystem functioning, and its importance relative to other pathways remains unclear. In particular, although biodiversity ecosystem function research has focused primarily on grasslands, the increases in agricultural inputs (e.g., fertilization, irrigation) and grazing pressure that drive change in grasslands worldwide have been largely ignored. Here we show that long-term (27-year) manipulations of soil resource availability and sheep grazing intensity caused marked, consistent shifts in grassland plant functional composition and diversity, with cascading (i.e., causal chains of) direct, indirect, and interactive effects on multiple ecosystem functions. Resource availability exerted dominant control over above-ground net primary production (ANPP), both directly and indirectly via shifts in plant functional composition. Importantly, the effects of plant functional diversity and grazing intensity on ANPP shifted from negative to positive as agricultural inputs increased, providing strong evidence that soil resource availability modulates the impacts of plant diversity and herbivory on primary production. These changes in turn altered litter decomposition and, ultimately, soil carbon sequestration, highlighting the relevance of ANPP as a key integrator of ecosystem functioning. Our study reveals how human alterations of bottom-up (resources) and top-down (herbivory) forces together interact to control the functioning of grazing systems, the most extensive land use on Earth. PMID- 22486096 TI - Gradient forests: calculating importance gradients on physical predictors. AB - In ecological analyses of species and community distributions there is interest in the nature of their responses to environmental gradients and in identifying the most important environmental variables, which may be used for predicting patterns of biodiversity. Methods such as random forests already exist to assess predictor importance for individual species and to indicate where along gradients abundance changes. However, there is a need to extend these methods to whole assemblages, to establish where along the range of these gradients the important compositional changes occur, and to identify any important thresholds or change points. We develop such a method, called "gradient forest," which is an extension of the random forest approach. By synthesizing the cross-validated R2 and accuracy importance measures from univariate random forest analyses across multiple species, sampling devices, and surveys, gradient forest obtains a monotonic function of each predictor that represents the compositional turnover along the gradient of the predictor. When applied to a synthetic data set, the method correctly identified the important predictors and delineated where the compositional change points occurred along these gradients. Application of gradient forest to a real data set from part of the Great Barrier Reef identified mud fraction of the sediment as the most important predictor, with highest compositional turnover occurring at mud fraction values around 25%, and provided similar information for other predictors. Such refined information allows for more accurate capturing of biodiversity patterns for the purposes of bioregionalization, delineation of protected areas, or designing of biodiversity surveys. PMID- 22486097 TI - 13C-labeling shows the effect of hierarchy on the carbon gain of individuals and functional groups in dense field stands. AB - Measurements of resource capture by individuals, species, or functional groups coexisting in field stands improve our ability to investigate the ecophysiological basis of plant competition. But methodological and technical difficulties have limited the use of such measurements. Carbon capture, in particular, is difficult to asses in heterogeneous, dense field stands. Here we present a new approach to measure in situ daily gross carbon gain of individuals. It is based on measuring the 13C content of shoots after a few hours of continuous labeling of all assimilated CO2. The technique is simple and has few assumptions. A new, fully mobile facility was developed, capable of providing a labeling environment with a CO2 concentration close to atmospheric air and known, constant 13C-enrichment, while maintaining temperature and relative humidity within ambient values. This facility was used in seminatural grasslands of Germany and Argentina to explore the relationship between size and carbon gain of individuals of coexisting species growing in contrasting hierarchical positions, and to analyze the carbon gain of functional groups. In general, carbon gain per unit shoot mass increased with increasing size among small individuals, but it became independent of size among the largest ones. In consequence, competition appeared to be size asymmetric between subordinate individuals but size symmetric between dominant individuals. When comparing functional groups, the carbon gain per unit shoot mass of rosette dicots vs. grasses reflected not their relative contribution to stand biomass, but their hierarchical position: irrespectively of mass or growth form, being taller than neighbors was most important in determining carbon gain per unit shoot mass. We believe these results show that in situ measurements of carbon gain can provide valuable insight in field studies of plant competition. PMID- 22486098 TI - Interannual variability of growth and reproduction in Bursera simaruba: the role of allometry and resource variability. AB - Plants are expected to differentially allocate resources to reproduction, growth, and survival in order to maximize overall fitness. Life history theory predicts that the allocation of resources to reproduction should occur at the expense of vegetative growth. Although it is known that both organism size and resource availability can influence life history traits, few studies have addressed how size dependencies of growth and reproduction and variation in resource supply jointly affect the coupling between growth and reproduction. In order to understand the relationship between growth and reproduction in the context of resource variability, we utilize a long-term observational data set consisting of 670 individual trees over a 10-year period within a local population of Bursera simaruba (L.) Sarg. We (1) quantify the functional form and variability in the growth-reproduction relationship at the population and individual-tree level and (2) develop a theoretical framework to understand the allometric dependence of growth and reproduction. Our findings suggest that the differential responses of allometric growth and reproduction to resource availability, both between years and between microsites, underlie the apparent relationship between growth and reproduction. Finally, we offer an alternative approach for quantifying the relationship between growth and reproduction that accounts for variation in allometries. PMID- 22486099 TI - Multidimensional trade-offs in species responses to disturbance: implications for diversity in a subtropical forest. AB - Species employ diverse strategies to cope with natural disturbance, but the importance of these strategies for maintaining tree species diversity in forests has been debated. Mechanisms that have the potential to promote tree species coexistence in the context of repeated disturbance include life history trade offs in colonization and competitive ability or in species' ability to survive at low resource conditions and exploit the temporary resource-rich conditions often generated in the wake of disturbance (successional niche). Quantifying these trade-offs requires long-term forest monitoring and modeling. We developed a hierarchical Bayes model to investigate the strategies tree species employ to withstand and recover from hurricane disturbance and the life history trade-offs that may facilitate species coexistence in forests subject to repeated hurricane disturbance. Unlike previous approaches, our model accommodates temporal variation in process error and observations from multiple sources. We parameterized the model using growth and mortality data from four censuses of a 16-ha plot taken every five years (1990-2005), together with damage data collected after two hurricanes and annual seed production data (1992-2005). Species' susceptibilities to hurricane damage as reflected by changes in diameter growth and fecundity immediately following a storm were weak, highly variable, and unpredictable using traditional life history groupings. The lower crowding conditions (e.g., high light) generated in the wake of storms, however, led to greater gains in growth and fecundity for pioneer and secondary-forest species than for shade-tolerant species, in accordance with expectation of life history. We found moderate trade-offs between survival in high crowding conditions, a metric of competitive ability, and long-distance colonization. We also uncovered a strong trade-off between mean species fecundity in low crowding conditions, a metric of recovery potential, and competitive ability. Trade-offs in competitive and colonization ability, in addition to successional niche processes, are likely to contribute to species persistence in these hurricane-impacted forests. The strategies species employ to cope with hurricane damage depend on the degree to which species rely on sprouting, repair of adult damage, changes in demographic rates in response to enhanced resource availability after storms, or long distance dispersal as recovery mechanisms. PMID- 22486100 TI - Sex-based differences in density-dependent sociality: an experiment with a gregarious ungulate. AB - For animals living in natural or semi-natural settings, empirical data on how sociality changes in response to increasing population density are few, especially with respect to true conspecific density and not group size. However, insight into this line of research may be far-reaching--from understanding density dependence in sexual selection to improving models of disease transmission. Using elk (Cervus elaphus Linnaeus) held in enclosures, we conducted sex-stratified experiments to test how the frequency of dyadic pairings (interaction rate) and their quality (duration) responded to manipulations in exposure to density. Using proximity-logging radio collars we recorded when and for how long individuals shared a space within 1.4 m of each other. As predicted, males increased their interaction rate as density increased. Female interaction rates, however, increased initially as density increased but soon declined to become indistinguishable from rates at low density. Females interacted for longer periods at medium densities, whereas male interaction length clearly decreased as density increased. We highlight a sexually dichotomous, density-dependent response in sociality that has yet to be reported. In addition to furthering our understanding of sociobiology (e.g., implications of time constraints presented by density on dyadic interactions), our results have implications for managing communicable disease in gregarious species of livestock and wildlife. PMID- 22486101 TI - Who owns the past? PMID- 22486102 TI - What science wants to know. PMID- 22486104 TI - Scanning for E.T.'s calls. A giant telescope will soon begin its search for the first stars and galaxies. PMID- 22486103 TI - The Mind Recovery Act. Why Obama's "war on Alzheimer's" may pay off. PMID- 22486105 TI - Hopeful vision. Gene therapy restores human sight. PMID- 22486106 TI - Picky eaters club. Fungi that orchids need to grow are just as finicky as the exotic flowers themselves. PMID- 22486107 TI - Fast talkers. Some languages sound faster than others, but most convey information at the same rate. PMID- 22486108 TI - Blue bacteria in bloom. The proliferation of cyanobacteria in oceans may accelerate warming. PMID- 22486109 TI - Coffee mystery. An entomologist describes his efforts to stop Rwanda's coffee from tasting like potatoes. PMID- 22486110 TI - Swimming on Mars. The Red Planet may have once been home to an ocean. PMID- 22486111 TI - Cold call. What will scientists find in Antarctica's ancient Lake Vostok? PMID- 22486112 TI - Food poisoning's hidden legacy. PMID- 22486113 TI - Technology's friction problem. Make buying, voting and losing weight easier by blasting away unnecessary steps. PMID- 22486114 TI - First of our kind. Sensational fossils from South Africa spark debate over how we came to be human. PMID- 22486115 TI - Quantum gravity in flatland. PMID- 22486116 TI - This is your brain in meltdown. PMID- 22486117 TI - Bound for the moon. PMID- 22486118 TI - Polio's last act. PMID- 22486119 TI - Birth of a cold war vaccine. PMID- 22486120 TI - Time traveler. PMID- 22486121 TI - The limits of breath holding. PMID- 22486122 TI - Climbing mount immortality. How awareness of our mortality may be a major driver of civilization. PMID- 22486123 TI - Space age wasteland. Debris in orbit is here to stay. PMID- 22486124 TI - Aptitude test for students seeking admission to nursing institutes. PMID- 22486125 TI - Plagiarism: don't forget to acknowledge! PMID- 22486126 TI - Breastfeeding for the health of baby and mother. PMID- 22486127 TI - Role of breastfeeding in pain response during injectable immunisation among infants. PMID- 22486129 TI - Biopsychosocial wellbeing and family support for menopausal women in Karnataka. PMID- 22486130 TI - Happy learning, happy Teachers Day. PMID- 22486131 TI - Are nurses nothing more than doctor's helpers? PMID- 22486132 TI - Assessing mortality risk in very low birth weight infants. AB - INTRODUCTION: Preterm birth is the most important univariant risk factor of neonatal mortality. Assessment of risk factors affecting mortality in preterm infants with very low birth weight is important for the treatment of this highly vulnerable population. OBJECTIVE: Detection of risk factors for neonatal mortality in very low birth weight premature infants. METHODS: The current study was conducted in a tertiary research and educational hospital, NICU, Pediatric Clinic KCU Sarajevo, from January 2010 to December 2010. After admission CRIB score was determined to every hospitalized infant with birth weight < 1500 g, born before the full 31 weeks of gestation (30 weeks + 6 days). We also gathered information about the Apgar score in 5th minute, gender, presence of respiratory distress syndrome and hemodynamic stability. 67 infants fulfilled inclusion criteria. RESULTS: Mean birth weight was 1136.4 g +/- 250.9, range 550-1500 g. Mean gestational age was 27.29 weeks +/-1.97, range 22-30 weeks. Mean CRIB score was 3.22, range 0-18. Twenty VLBW infants out of 67 died (29.85%). There was significant difference between groups of survived and dead infants regarding gestational age, birth weight, Apgar score, Crib score, base excess, presence of respiratory distress syndrome and hemodynamic stability at the birth. CONCLUSION: CRIB score, birth weight, gestational age, base excess, Apgar score, respiratory distress syndrome and hemodynamic instability are valuable predictors for a neonatal mortality in population of preterm infants with very low birth weight. PMID- 22486133 TI - The effect of intravenous morphine on the level of spinal anesthesia with lidocaine. AB - One of the major concerns in spinal anesthesia with lidocaine is its short duration of action. Enhancement is necessary in some situations during surgery, because surgeons encounter with unexpected events and need more time. Therefore there is a need to increase anesthesia duration in these situations. Many studies investigated various additives with different administration routes to enhance spread and duration of spinal block with lidocaine. Because we only have morphine sulfate in our clinics and the sulfate compounds are neurotoxic, we cannot prescribe it by intrathecal route; for this reason we investigated effects of intravenous morphine on the spinal anesthesia with lidocaine. METHODS: This double blinded randomized clinical trial study was performed on 36 patients who were allocated to two groups. All patients underwent spinal anesthesia with lidocaine by the same method. Patients in the case group received morphine plus midazolam intravenously as the additive medication and in the control group received normal saline plus midazolam. Duration, spinal block level, recovery time, sedation score and adverse effects were compared between the two groups. RESULTS: This study showed that although intravenous morphine can provide better safe sedation (p-value < 0.01), it has no effect on the level (p-value: 0.42) and duration of spinal block (p-value: 0.26). Although heart rate and blood pressure had significant decrease in the case group (p-value < 0.01 and < 0.05 respectively) but the need for administration of ephedrine was completely similar in both groups. CONCLUSION: Although some studies had proved the efficacy of systemic use of other opioids including fentanyl and sufentanil, morphine had no effect on the level and duration of spinal block. It can be due to differences in the chemical structures of these substances. However, intravenous morphine as an additive to spinal anesthesia with lidocaine can provide acceptable sedation with no major side effects. PMID- 22486134 TI - Role of pentoxifylline in treatment of anemic patients suffering chronic hemodialysis: a randomized clinical trial. AB - BACKGROUND: Anemia is a major problem in patients with end-stage renal disease on chronic hemodialysis. rh-EPO is used mostly to elevate serum hemoglobin level and improve complaints caused by anemia, although in some patients it may not be totally effective for treating the disease. In this study, we aimed to evaluate pentoxifylline as a drug for treating anemia. METHODS AND MATERIAL: Fifty patients were enrolled in the study and divided into 2 groups. The case group took 400 mg of pentoxifylline daily for 6 months, while the control group took placebo for the same time. The levels of hemoglobin and serum albumin, TIBC, iron, ferritin, and PTH, and use of rh-EPO were estimated. The data were analyzed using SPSS-18 software. RESULTS: Of the 50 patients, 33 (66%) were male and 17 (34%) were female. Student paired t tests showed no significant difference in hemoglobin and serum albumin, TIBC, ferritin, and PTH levels, or use of rh-EPO between the case and control groups. However, iron level was significantly different in the 2 groups. CONCLUSION: In contrast to previous studies, our data do not support the concept that pentoxifylline elevates hemoglobin level and improves anemia, Further studies on a larger number of patients are required to assess whether or not pentoxifylline is useful in these patients. PMID- 22486135 TI - Quercetin in the treatment of dyslipidemia. AB - Dyslipidemia is a relatively common problem observed in clinical practice, seen both in instances when evaluating patients with subjective problems as well as among those coming to take a regular preventive exams. needless to say, discovery of any significant vascular disease necessitates initiation of proven medical therapy, which, ideally, besides its action on blood lipid values, sholud also exert effect on other, equally important parameters of vascular disease. STUDY GOAL: Goal of the sudy was to evaluate effects of regular consumption of quercetin on blood lipid values among healthy persons with dyslipidemia discovered on routine laboratory work up for different reasons. The study was designed as double blind, randomised study with two hunderd patients in each arm and total duration of the study being two months. RESULTS: Groups were randomized in accordance with age and sex of patients as well as degree of blood lipid elevations. Average cholesterol, triglycerides, HDL and LDL value in both groups were similar to statisticaly insignificant differences among groups. Test group A had average values of cholesterol 6,21 mmol/l, triglycerides 3,02 mmol/l, HDL 0,89 mmol/l and LDL 3,98 mmol/l. Control group had values of same parameters as follows 6,17 mmol/l, 3,14 mmol/l, 0,92 mmol/l and 3,84 mmol/l respectively. Upon completion of therapy, test group has demonstrated a decrease in cholesterol, triglyceride and LDL values with parallel increase in HDL. Average cholesterol values at the end of the study were 5,09 mmol/l, whereas HDL and LDL values changed to 1,29 mmol/l and 2,91 mmol/l respectively. DISCUSSION AND CONCLUSION: Patients rarely agree to start taking medications on a permanent basis, medications most of which are related to certain, not that infrequent, side effects. So these persons start using other means in an attempt to put blood lipids under control. Some of these means include lifestyle modification, exercise, but also use of food supplements that are proven to lower blood lipids. Among these available supplements, quercetin has recently attracted a lot of attention due to its strong antioxidant effects. PMID- 22486136 TI - Upper functional gastrointestinal disorders in young adults. AB - BACKGROUND: Functional Gastrointestinal disorders (FGID) are common disorders in gastroenterology which are common in young adults. The aim of this study is evaluating the prevalence of upper FGID in iranian young adults. METHODS AND MATERIAL: This was a cross-sectional study which was on 995 persons who were going to marry. A ROME III based questionnaire was used to determine the frequency of upper GI Syndromes among the sample population. RESULTS: Our results determined 74 subjects had functional dyspepsia (36 subjects diagnosed as postprandial distress syndrome patient and Epigastric pain syndrome was seen in 38 subjects). Functional heartburn was diagnosed in 52 participants. Globus was seen in 35 subjects and 41 had unspecified excessive belching. DISCUSSION: Many epidemiologic studies were done all around the world but there are different reports about prevalence and incidence of FGIDs. Our results were agreed with reported prevalence of FGIDs in Iran in adults. And our findings were agreed with some other Asian studies. PMID- 22486137 TI - Blood pressure evaluation at the workers exposed to lead. AB - INTRODUCTION: Biochemical and physiological mechanisms by which lead affects the cardiovascular system by increasing blood pressure are still unknown. But it is believed that the increased arterial pressure disturbance is caused as a result of the concentration of intracellular calcium ions (Ca). AIM OF THE STUDY: The study had the purposes of analyzing the effect of lead in blood pressure at the mine workers in "Trepca" Stan Terg comparing years worked in the mine. MATERIAL AND METHODS: The study included 55 workers at Stan Terg Trepca mine, out of which 44 are direct employees who work within the galleries of the mine and 11 workers outside the galleries of the mine, The Control Group. RESULTS: From the data provided in the study, it is noted an increase of arterial blood pressure value (Systolic and Diastolic) at workers who have worked directly in the mine gallery in comparison with The Control Group. DISCUSSION: Workers with the longest time worked in the mine have the most pronounced increase of arterial blood pressure values than those with less working experience. Lead affects the blood pressure and is closely dependent on the workplace and the years worked in the mine. CONCLUSION: Protective measures are necessary in prevention of lead poisoning in the workplace. PMID- 22486138 TI - Effect of preoperative volume loading on the intraoperative variability of blood pressure and postoperative nausea and vomiting. AB - INTRODUCTION: Preoperative volume loading (PVL) in addition to counteract the decreases in blood pressure during intraoperative period, also may decrease postoperative nausea and vomiting (PONV). This study was designed to investigate the effect of preoperative volume loading on the intraoperative blood pressure variability and postoperative nausea and vomiting. METHODS: Thirty subjects scheduled for elective orthopedic procedures randomly divided into case and control groups. The patients in the case group received lactated Ringer 10 ml/kg before induction of general anesthesia. Mean arterial blood pressure (MAP) and heart rate were recorded in two groups every 3 minutes from induction of anesthesia until five minutes after extubation. Variability of mean arterial blood pressure and heart rate were defined as the standard deviation (SD) of the measured values for each patient. Means of these individual SD values were compared between two groups using Mann-Whitney U test. RESULTS: The mean variability of mean arterial blood pressure and heart rate ware significantly lower in case group (8.3 +/- 3 mmHg and 8.4 +/- 2.5 bpm vs. 13 +/- 6 mmHg and 11 +/- 2.6 bpm in control group; p < 0.5). The severity of nausea (measured as a ten point visual analog scale) was significantly lower in case group (1.2 +/- 0.9 vs. 3.9 +/- 1.8 in control group; p < 0.05). No patients in case group developed postoperative vomiting (compared to 5 patients in control group). CONCLUSIONS: The results of this study shows that preoperative volume loading is associated with lower variability of blood pressure and heart rate during operative period and also reduces the severity and incidence of postoperative nausea and vomiting. PMID- 22486139 TI - Quality of life in patients after laparoscopic and open cholecystectomy. AB - BACKGROUND/AIM: The aim of this study was to establish Gastrointestinal Life Quality Index scores of patients before and after laparoscopic and open cholecystectomy comparing scores after both operations. SETTINGS AND DESIGN: The 120 patients were involved in this prospective study, 51 male and 69 female, 59 of patients were underwent by laparoscopic method and rest of them, 61, by open method on Surgery Clinic on Clinical university center in Tuzla in period from February 2006 to October 2006, chosen by consecutive method. This study evaluates patients life quality according to score of Gastrointestinal Life Quality Index. METHODS: Patients have been tested two weeks before the operation and in two, five and ten weeks of post-operative period. Except from Gastrointestinal Life Quality Index total score, established scores,a parts of life quality are: symptoms, physical function, emotional and mental status and also social activities. STATISTICAL ANALYSIS USED: For analysis of achieved results, SPSS (Statistical Package for Social Sciences, V 10.01) program with statistical parameters was used: average values and standard deviation. Out of statistical tests, we used Chi-square test and Student t-test. Values p < 0,05 have been accepted as statisticaly significant. RESULTS: The results of the study confirm a working hypothesis that patients life quality after two and five weeks of postoperative period is significantly better (p < 0.05) in laparoscopic method group versus open method group. Also, in domains Gastrointestinal Life Quality Index symptoms, physical function, emotional and menthal status and social activities results are significantly better (p < 0.05) in the laparoscopic cholecystectomy group than in open method cholecystectomy group. Ten weeks of post-operative period, results showed that these two groups have no difference in life quality in total score, also in domain score. CONCLUSION: This comparative study between laparoscopic and open cholecystectomy according to patients life quality aspects confirms advantages of laparoscopic technique in comparison to open cholecystectomy method. PMID- 22486140 TI - Accuracy of amniotic fluid lamellar body counting for evaluating fetal lung maturity. AB - BACKGROUND: Respiratory distress syndrome (RDS) is one of the important causes of mortality in neonates. This study was designed to assess the role of the amniotic fluid lamellar body counting in predicting fetal lung maturity. METHOD: This study was conducted during 2010, April to 2011, February, at Isfahan University of Medical Sciences, Isfahan, Iran. One hundred and twenty eight amniotic fluid samples were obtained during normal delivery, or before rupturing the membrane in cesarean, and lamellar body was assessed by cellular counter. The respiratory statuses of neonates were determined at delivery and the optimal cut-off point was assessed by receiver operating characteristic (ROC) curve. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were evaluated in optimal cut-off point. RESULTS: One hundred and twenty eight amniotic samples and 131 infants were evaluated. The means of maternal and gestational ages were 28.12 +/- 3.84 years and 32.56 +/- 2.72 weeks, respectively. The mean of lamellar body was 31266 +/- 15831 microl in matured lung infants compared to 63081 +/- 16966 microl in immature lung infants (p < 0.001). The optimal cut-off point was evaluated as 47500 microl in predicted pulmonary maturity with sensitivity of 85.1%, specificity of 91.2%, positive predictive value of 92.6% and negative predictive value of 82.5%. CONCLUSION: This study indicated that lamellar body counting test has a high positive predictive value with a good sensitivity, specificity and negative predictive value. Future studies for different cellular counters are warranted. PMID- 22486141 TI - The effect of sildenafil on respiratory weaning of patients with chronic obstructive pulmonary diseases admitted to intensive care unit. AB - INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) is a common disease that tends to occur worldwide and is a common cause of respiratory failure requiring mechanical ventilation and admission to the intensive care unit (ICU). The present study was carried out to investigate the efficacy of sildenafil in facilitating the weaning of COPD patients from the ventilator. METHODS: This randomized double blind clinical trial study was carried out with 40 patients suffering from COPD. The patients were divided in two study groups. 20 patients belonging to Group I received 20 mg sildenafil tablets twice a day for one week while 20 patients of the second group (Group II) received placebo tablets with the same dosage. Respiratory parameters like rapid shallow breathing index (RSBI), mixed venous oxygen pressure (PvO2) and plateau pressure were measured in both groups. Data were analyzed on the basis of student's t-test and Chi2 test using SPSS 16 software. RESULTS: The results are expressed as mean +/- SE and P < 0.05 is considered statistically significant. According to our findings RSBI was lower in Group I compared with Group II after one week of treatment (P = 0.032). PvO2 value was higher in sildenafil group compared with placebo group (P = 0.025). Plateau pressure was lower in first group than group II (P = 0.022). CONCLUSION: Sildenafil facilitated weaning of COPD patients from the ventilator by improving the respiratory parameters. PMID- 22486142 TI - Analgesic effects of ketamine infusion on postoperative pain after fusion and instrumentation of the lumbar spine: a prospective randomized clinical trial. AB - BACKGROUND: Intractable pain occurs as a result of extensive damage to soft tissue, bones and muscles after fusion of lumbar spondylolisthesis. Although different drugs and protocols have been suggested for postoperative pain management, the best method of treatment has not been proposed yet. Therefore, this study tried to compare the efficacy of ketamine infusion and routine opioid administration on postoperative pain. METHODS: A double-blind prospective randomized clinical trial was performed on 45 patients candidate for fusion of lumbar spondylolisthesis. Patients were divided into two groups of A (treatment) and B (control). In group A, pain was controlled by intravenous infusion of ketamine. Morphine was also administrated when the patients scored their pain above 4 on a visual analogue scale (VAS). In group B, intravenous infusions of morphine were performed every 6 hours. VAS and whole dosage of morphine were compared between two groups every 6 hours. RESULTS: Morphine and ketamine were both effective on pain control. Mean values of pain intensity at the first to fourth time points were 2.1, 1.8, 1.6, and 1.7 in group A and 3.9, 3.4, 3.5, and 3.5 in group B, respectively (p < 0.01 for all periods). However, ketamine was more efficient in pain reduction during the first 24 hours (p < 0.001). CONCLUSION: Ketamine could be a good alternative analgesic after fusion of lumbar spondylolisthesis. However, the probable side effects should also be considered. Ketamine infusion is more effective than morphine on postoperative pain control. In addition, tolerance to drug application is not a challenging problem at least during 24 hours after operation. PMID- 22486143 TI - Assessing intravenous ketamine and intravenous dexamethasone separately and in combination for early oral intake, vomiting and postoperative pain relief in children following tonsillectomy. AB - BACKGROUND: The aim of the present study is to evaluate the effect of preoperative 0.5 mg/kg i.v. dexamethasone in combination with 0.5 mg/kg i.v. ketamine on pain, early oral intake and vomiting in pediatric patients undergoing tonsillectomy during the first 24 hours of the postoperative period. METHODS: One hundred twenty children who were scheduled for tonsillectomy were randomly assigned to receive a single dose of dexamethasone 0.5 mg/kg i.v. as Group D (n = 30), receive ketamine 0.5 mg/kg i.v. as Group K (n = 30), receive dexamethasone 0.5 mg/kg i.v. and ketamine 0.5 mg/kg i.v. as Group KD (n = 30) and an equivalent volume of saline as Group C (n = 30) 15 minutes before the induction of anesthesia. Post-operative pain was evaluated using an observational pain score (OPS) on arrival to the post-anesthesia care unit (PACU), at 15, 30, 45, and 60 minutes after that and at 1, 2, 4, 6, 12, and 24 hours after arrival to the ward. RESULTS: OPS scores were significantly lower at the time of arrival to the PACU, and at 15, 30, 45, and 60 minutes in the Group KD compared with Group C (p < 0.05). Postoperative OPS scores were significantly lower at 1, 2, 4, 6, 12, and 24 hours after operation in Group KD compared with Group C (p < 0.05). CONCLUSION: A prophylactic preoperative single dose of i.v. 0.5 mg/kg dexamethasone in combination with a single dose of i.v. 0.5 mg/kg ketamine significantly decreased post-tonsillectomy pain compare with using i.v. ketamine or i.v. dexamehasone separately. PMID- 22486144 TI - Correlation of aggressiveness and anxiety in fighting sports. AB - INTRODUCTION: in fighting sports there are many opened issues related with levels of aggression and anxiety. MATERIAL AND METHODS: Our study is performed with healthy young athletes: kick boxers, karate fighters, and boxers. Examined group consisted of 55 members (45 male) with average age of 20.2 +/- 3.8 years. In analysis of level of aggression Questionnaire A-87 is used. Its purpose is assessment of aggressive behaviour in provoked situations, or measurement of impulsive aggression. Questionnaire A-87 consists of 15 items of different situations with five possible responses. RESULTS AND DISCUSSION: The possible responses or reactions are the five most frequent forms of aggressive responses: a) verbal manifest aggression (VM); b) physical manifest aggression (PHM); c) indirect aggression (IND); d) verbal latent aggression (VL), and e) physical latent aggression (PHL). In the analysis of anxiety is used Beck Anxiety Inventory, BAI. Average training period was 7.8 +/- 3.6 years. Even 37 athletes during sporting carriers were injured, and most of examiners (precisely 13) experienced 3 injuries. Average value of BAI was 12.7 +/- 8.7. Average value of total aggression was 152.2 +/- 40.9; highest levels were observed in VM (33.9) and VL (30.1). Significant positive correlations of all components of aggression with level of anxiety is observed (p < 0.05), most prominent IND (r = 0.4263; p = 0.0012), and VL (r = 0.4163; p = 0.0016), and also total aggression (r = 0.4822; p = 0.0002). Slightly significant positive correlation of total aggression with age of examiners is also observed (r = 0.2668, p = 0.0489). Positive correlation VM (r = 0.4928; p = 0.0001), PHL (r = 0.2761; p = 0.0413), and total aggression (r = 0.347; p = 0.0094) is observed with number of injuries of examined athletes. Also, positive correlation (r = 0.2927, p = 0.0301) is observed with level of anxiety and number of injuries. Higher level of aggression and anxiety might change attitude of some sports authorities (especially coaches), and additional psychological training of fight sports might be necessary. CONCLUSION: Assessment of basically levels of aggression and anxiety of athletes might be valuable not only in sport activities, but in overall aspects of life. PMID- 22486145 TI - Corelation between cytologic, colposcopic and pathohistological findings of cervical intraepithelial lesions. AB - AIM OF THIS STUDY was to examine the frequency of cervical cancer and cervical intraepithelial lesions of a different degree in women, corelation between cytologically diagnosed CIN I, CIN II and CIN III lesions and colposcopic findings and corelation between cytologic and pathohistologic findings of CIN III lesion. MATERIAL AND METHODS: Cytologic and colposcopic findings have been analysed retrospectively in 2652 women who went through systematic examinations in Women's Health Care Department at Health Center "Dr.Mustafa Sehovic" Tuzla in period 2008-2011. For 93.2% (N = 2475) cytology results were normal. Abnormal cytology result was found in 6.71% (N = 178): CIN I in 5.54% (147), CIN II in 0.67% (18) and CIN III in 0.49% (13) of women examined. RESULTS AND DISCUSSION: Colposcopy in women with cytology results CIN I, CIN II and CIN III showed abnormal result in women with CIN I in 29.9% (44/147), CIN II in 61.1% (11/18) and CIN III in 61.5% (8/13). Significant association between abnormal colposcopic and abnormal cytologic findings (Chi2 = 36.30, p < 0.0005). Abnormal colposcopic result is twice as often with CIN II and CIN III changes on cervix in relation to CIN I. Byopsy of cervix in 13 women with CIN III pathohistologicaly confirmed the diagnose in 46.1% (4/13), cervix lesion was of higher degree in 30.8%, and in 23.0% (3/13) lesion of cervix was of a lower degree. Abnormal colposcopic image is an indicator for the abnormal cytological result. CONCLUSION: Systematic examination of women represents an efficient way of organized screening and prevention of cervical cancer. PMID- 22486146 TI - Corneal astigmatism after micro-incision cataract operation. AB - GOALS: To evaluate the effect of micro-incision (2.2 mm) and small-incision (3.0 mm) coaxial phaco-emulsification on surgically induced astigmatism (SIA). METHODS: Cataract patients (n = 60, 60 eyes) were randomized into two groups: 30 eyes in the 2.2-mm incision group, 30 eyes in the 3,0-mm group. Phaco emulsification was followed by intraocular lens implantation via the Monarch II injector with the C cartridge (Alcon Laboratories Inc., Fort Worth, TX, USA). Uncorrected distance visual acuity, corneal keratometry and corneal astigmatism and SIA were assessed 1, 7 and 30 days after cataract surgery. RESULTS: At 1, 7 and 30 days postoperative, SIA of the 3.0-mm group was greater than SIA of the 2.2-mm (p < or = 0.05) only at first postoperative day, but SIA was similar between the 2.2-mm group and the 3,0-mm group at other follow-ups. Time wise, mean SIA at 30 days was greater than SIA at 90 days in the 3.0-mm group (p = 0.04), while SIA did less change with time for the 2.2-mm group. Postoperative uncorrected distance visual acuity tended to be better with the smaller incisions, but this trend did not reach statistical significance (p > or = 0.07) especially at letter follow-ups. CONCLUSION: Incision size contributed to postoperative corneal astigmatism especially at earlier postoperative period. When incision size was reduced from 3.0 mm to 2.2 mm, SIA was reduced and refractive stabilization was faster. In longer period of time difference between 3,0 mm and 2,2 mm incision size groups decreases. PMID- 22486147 TI - National plan of establishment and maintenance of the health management system in schools and grading for awarding stars. AB - INTRODUCTION: Addressing school health and safetyis an important public health issue. The aim of this study was to identify the status of safety and health (HSE) in Iranian schools, and to provide a monitoring and evaluation scoring system. MATERIAL AND METHODS: A 81-item checklist was applied to obtain data regarding the performance of HSE in 60 schools in five Iranian provinces to award health stars (15-level stars). In all provinces, inadequacies and limitations were documented in safety measures such as access to emergency exits, and the risk of firing. RESULTS AND DISCUSSION: By passing this pilot phase, now an agreement is signed between the Ministry of Health & Medical Education and the Ministry of Education & Training, and this plan is implemented as a national program in Iran for improvement of the safety in schools. We suggest that establishment and maintenance of the health management system in schools and ranking and granting stars to them is one of the most appropriate plans in this regard to be implemented in the region. CONCLUSION: An innovational plan is going to be executed for the first time in Iran and may be set forth as a successful pattern of institutionalization of health systematic and dynamic system in collective environments such as schools in the region. PMID- 22486148 TI - Design and implementation of a web directory for medical education (WDME): a tool to facilitate research in medical education. AB - BACKGROUND: Access to the medical resources on the web is one of current challenges for researchers and medical science educators. The purpose of current project was to design and implement a comprehensive and specific subject/web directory of medical education. METHODS: First, the categories to be incorporated in the directory were defined through reviewing related directories and obtaining medical education experts' opinions in a focus group. Then, number of sources such as (Meta) search engines, subject directories, databases and library catalogs searched/browsed for selecting and collecting high quality resources. Finally, the website was designed and the resources were entered into the directory. RESULTS: The main categories incorporating WDME resources are: Journals, Organizations, Best Evidence in Medical Education, and Textbooks. Each category is divided into sub-categories and related resources of each category are described shortly within it. The resources in this directory could be accessed both by browsing and keyword searching. WDME is accessible on http://medirectory.org. CONCLUSIONS: The innovative Web Directory for Medical Education (WDME) presented in this paper, is more comprehensive than other existing directories, and expandable through user suggestions. It may help medical educators to find their desirable resources more quickly and easily; hence have more informed decisions in education. PMID- 22486149 TI - Acrodermatitis enteropathica. AB - AIM: The aim of the work was the presentation of one case with Acrodermatitis enteropathica. METHODS: Acrodermatitis enteropathica is diagnosed based on the pedigree, typical clinical manifestations on the skin, laboratory results, small bowel biopsy, skin biopsy and kariotype. RESULTS: The patient was a two years old male toddler, hospitalized due to skin changes, chronic diarrhoea and total alopecia. Skin changes appeared on akral of the limbs, inguinal and perineal region, joints, perioral area and eyes. These changes appeared in different forms (erythematous, squamous, eczematiod, psoriasisforme and crusted). In the eyes were present these changes: blepharitis and conjunctivitis. Also total alopecia was prezent. Diarrhoea was chronic and specific. Laboratory findings showed the existence of sideropenic anemia, hypoproteinemia with hypoalbuminemia and low plasma zinc concentration (7.5 micromol/L). Hystopathological changes on the small bowel and skin biopsy were not typical for this disease. Following the beginning of treatment with zinc sulphate, all clinical skin manifestations disappeared within two months, but the disease itself was characterized with the periods of exarcerbation and remission. CONCLUSION: Acrodermatitis Enteropathica is a rare hereditary autosomal recessive disease. Mandatory clinical manifestations are: skin changes, chronic diarrhoea and alopecia. Treatment with zinc is obligatory for the life time. PMID- 22486150 TI - Bloodless off pump coronary artery bypass grafting treatment of choice for Jehova's witness patients. AB - Jehovah's witnesses (JW) belong to a religious group refusing to accept blood transfusion Surgical treatment remains a challenge in this subset of patients. From 1945, JW introduced a ban on accepting blood transfusions, even in life threatening situations while autologous blood must also be refused if it is predeposited-thus excluding preoperative autodonation. However, autologous blood is acceptable if it is not separated from the patients' circulation at any time. The invasive nature of coronary artery bypass grafting (CABG), the associated decrease of body temperature and the use of cardiopulmonary bypass (CPB) are major reasons for increased blood loss and high incidence for blood transfusions during and after this procedures. Allogenic blood transfusions are often given and considered necessary in such operations, in spite of increased mortality, morbidity and major adverse outcomes resulting from transfusion. Reduction in the use of blood products should therefore be a general desire for every patient due to the associated risk factors. The evolution of less invasive cardiac surgical approaches, such as CABG without CPB (OPCAB) may contribute to a further reduction of blood transfusion and although these minimally invasive techniques may benefit every patient, they might be particularly valuable for JW. In this report, we present our initial experience in JW patient undergoing OPCAB and the way to use patient blood management for improved surgical outcome in such patient. PMID- 22486151 TI - Pt nanoparticles@photoactive metal-organic frameworks: efficient hydrogen evolution via synergistic photoexcitation and electron injection. AB - Pt nanoparticles of 2-3 nm and 5-6 nm in diameter were loaded into stable, porous, and phosphorescent metal-organic frameworks (MOFs 1 and 2) built from [Ir(ppy)(2)(bpy)](+)-derived dicarboxylate ligands (L(1) and L(2)) and Zr(6)(MU(3)-O)(4)(MU(3)-OH)(4)(carboxylate)(12) secondary building units, via MOF mediated photoreduction of K(2)PtCl(4). The resulting Pt@MOF assemblies serve as effective photocatalysts for hydrogen evolution by synergistic photoexcitation of the MOF frameworks and electron injection into the Pt nanoparticles. Pt@2 gave a turnover number of 7000, approximately five times the value afforded by the homogeneous control, and could be readily recycled and reused. PMID- 22486152 TI - Effect of processing on recovery and variability associated with immunochemical analytical methods for multiple allergens in a single matrix: dark chocolate. AB - Immunodetection of allergens in dark chocolate is complicated by interference from the chocolate components. The objectives of this study were to establish reference materials for detecting multiple allergens in dark chocolate and to determine the accuracy and precision of allergen detection by enzyme-linked immunosorbent assay (ELISA) before and after chocolate processing. Defatted peanut flour, whole egg powder, and spray-dried milk were added to melted chocolate at seven incurred levels and tempered for 4 h. Allergen concentrations were measured using commercial ELISA kits. Tempering decreased the detection of casein and beta-lactoglobulin (BLG), but had no significant effect on the detection of peanut and egg. Total coefficients of variation were higher in tempered than untempered chocolate for casein and BLG, but total and analytical CVs were comparable for peanut and egg. These findings indicate that processing has a greater effect on recovery and variability of casein and BLG than peanut and egg detection in a dark chocolate matrix. PMID- 22486153 TI - Structure and dynamics of small soluble Abeta(1-40) oligomers studied by top-down hydrogen exchange mass spectrometry. AB - Abeta peptides can assemble into amyloid fibrils, which represent one of the hallmarks of Alzheimer's disease. Recent studies, however, have focused on the behavior of small soluble Abeta oligomers that possess a much greater neurotoxicity than mature fibrils. The structural characterization of these oligomers remains difficult because of their highly dynamic and polymorphic nature. This work explores the behavior of Abeta(1-40) in a slightly basic solution (pH 9.3) at a low salt concentration (10 mM ammonium acetate). These conditions lead to the formation of small oligomers, without any signs of fibrillation for several hours. The structure and dynamics of these oligomers were characterized by circular dichroism spectroscopy, size exclusion chromatography, and millisecond time-resolved hydrogen exchange mass spectrometry (MS). Our results reveal rapid interconversion between Abeta(1-40) oligomers and monomers. The mole fraction of monomeric molecules is on the order of 40%. Oligomers consist of ~4 Abeta(1-40) molecules on average, and the resulting assemblies have a predominantly beta-sheet secondary structure. Hydrogen exchange proceeds in the EX1 regime. This feature allows the application of conformer specific top-down MS. Electron capture dissociation is used for interrogating the deuteration behavior of the Abeta(1-40) oligomers. This approach provides a spatial resolution of ~2 residues. The backbone amide deuteration pattern uncovered in this way is consistent with a beta-turn-beta motif for L17-M35. The N-terminus is involved in hydrogen bonding, as well, whereas protection gradually tapers off for C-terminal residues 35-40. Our data are consistent with earlier proposals, according to which Abeta(1-40) oligomers adopt a beta-barrel structure. In general terms, this study demonstrates how top-down MS with precursor ion selection can be employed for structural studies of specific protein conformers within a heterogeneous mix. PMID- 22486154 TI - Mononuclear gold(I) acetylide complexes with urea group: synthesis, characterization, photophysics, and anion sensing properties. AB - A series of mononuclear gold(I) acetylide complexes with urea moiety, R'(3)PAuC=CC(6)H(4)-4-NHC(O)NHC(6)H(4)-4-R (R' = cyclohexyl, R = NO(2) (2a), CF(3) (2b), Cl (2c), H (2d), CH(3) (2e), (t)Bu (2f), OCH(3) (2g); R' = phenyl, R = NO(2) (3a), OCH(3) (3b); R' = 4-methoxyphenyl, R = H (4a), OCH(3) (4b)), have been synthesized and characterized. The crystal structures of Ph(3)PAuC=CC(6)H(4) 4-NHC(O)NHC(6)H(4)-4-NO(2) (3a) and (4-CH(3)OC(6)H(4))(3)PAuC=CC(6)H(4)-4 NHC(O)NHC(6)H(5) (4a) have been determined by X-ray diffraction. Complexes 2a-2g, 3b, and 4a-4b show intense luminescence both in the solid state and in degassed THF solution at 298 K. Anion binding properties of complexes 2a-2g, 3a-3b, and 4a 4b have been studied by UV-vis and (1)H NMR titration experiments. In general, the log K values of 2a-2g with the same anion in THF depend on the substituent R on the acetylide ligand of 2a-2g: R = NO(2) (2a) > CF(3) (2b) >= Cl (2c) > H (2d) > CH(3) (2e) ~ (t)Bu (2f) >= OCH(3) (2g). Complex 2a with NO(2) group shows the dramatic color change toward F(-) in DMSO, which provides an access of naked eye detection of F(-). PMID- 22486155 TI - A discrete lesion of the midpontine tegmentum causing migrainous headache and numbness. PMID- 22486156 TI - Experiences of using blood glucose targets when following an intensive insulin regimen: a qualitative longitudinal investigation involving patients with Type 1 diabetes. AB - AIMS: Use of blood glucose targets is considered essential to help patients with Type 1 diabetes achieve tight glycaemic control following structured education. To foster effective use of blood glucose targets, we explored patients' experiences and views of implementing clinically recommended blood glucose targets after attending a structured education programme promoting intensive insulin treatment. METHODS: Repeat, in-depth interviews with 30 patients with Type 1 diabetes recruited from Dose Adjustment for Normal Eating (DAFNE) courses in the UK. Data were analysed using an inductive, thematic approach. RESULTS: Patients found use of blood glucose targets motivational. Targets enabled patients to identify problems with blood glucose control and prompted them to make insulin dose adjustments independently, or with assistance. However, patients tended to adapt or simplify targets over time to: make them more attainable and easy to remember; reduce risk of hypoglycaemia; and, mitigate feelings of failure when attempts to attain clinically defined targets were unsuccessful. Some patients were advised to use elevated targets to counter hypoglycaemia unawareness and required help from health professionals to determine when/if these should be reduced. CONCLUSIONS: Although blood glucose targets are an important component of diabetes self-management, patients may adapt and personalize them over time, sometimes inadvertently, with a potentially detrimental impact on long-term glycaemic control. Blood glucose targets should be regularly revisited during clinical reviews and revised/new targets agreed to accommodate patients' concerns and difficulties. Other interventions may need to be considered to promote effective use of blood glucose targets. PMID- 22486157 TI - Catalytic alpha-allylation of unprotected amino acid esters. AB - Catalytic alpha-allylation of unprotected amino acid esters to produce alpha quaternary alpha-allyl amino acid esters is reported. Catalytic loadings of picolinaldehyde and Ni(II) salts induce preferential reactivity at the enolizable alpha-carbon of amino acid esters over the free nitrogen with electrophilic palladium pi-allyl complexes. Fourteen examples are given. Additionally, the use of chiral ligands to access enantioenriched alpha-quaternary amino acid esters from racemic precursors is demonstrated by the enantioselective synthesis of alpha-allyl phenylalanine methyl ester from racemic phenylalanine methyl ester. PMID- 22486158 TI - Ablation of a resistant right atrial appendage tachycardia using a magnetic navigation system. AB - The right atrial appendage is an uncommon site of origin for ectopic atrial tachycardia. Right atrial appendage tachycardia (RAAT) has been noted to be prevalent in young males and responds well to radiofrequency ablation. We report a case of RAAT resistant to multiple attempts of ablation that responded to ablation using Stereotaxis NiobeTM Magnetic Navigation System (RMN, Stereotaxis, St. Louis, MO, USA). PMID- 22486159 TI - Palatability of crushed beta-blockers, converting enzyme inhibitors and thiazides. AB - WHAT IS KNOWN AND OBJECTIVES: A problem that often affects antihypertensive drugs is the lack of formulations appropriate for childhood. Parents, therefore, crush tablets and administer the antihypertensive drug mixed with solid food or a palatable drink. Because palatability is a major modulator of adherence to prescribed medication, the palatability of crushed beta-blockers, converting enzyme inhibitors and thiazides was assessed among adult volunteers. METHODS: The palatability of crushed atenolol, bisoprolol, enalapril, lisinopril, ramipril, chlorthalidone and hydrochlorothiazide was evaluated by means of a facial hedonic scale among 20 volunteers. The calcium channel-blockers amlodipine and lercanidipine whose tastes are disliked and liked, respectively, by children were also tested. A concealed random allocation procedure was used. RESULTS: The palatability scores assigned to chlorthalidone, hydrochlorothiazide and lisinopril were superior (P < 0.002) to those assigned to atenolol, bisoprolol, enalapril and ramipril. As with children, the palatability score of lercanidipine was superior to that of amlodipine (P < 0.002). The scores assigned to the various agents were similar in women and in men and were age-independent. WHAT IS NEW AND CONCLUSION: Pulverized atenolol, bisoprolol, enalapril and ramipril are poor tasting. From the perspective of palatability, pulverized chlorthalidone, hydrochlorothiazide and lisinopril are preferable. PMID- 22486160 TI - Stability of gas-phase tartaric acid anions investigated by quantum chemistry, mass spectrometry, and infrared spectroscopy. AB - In an effort to understand the chemical factors that stabilize dianions, experimental and theoretical studies on the stability of the tartrate dianion were performed. Quantum chemical calculations at the coupled cluster level reveal only a metastable state with a possible decomposition pathway (O(2)C-CH(OH) CH(OH)-CO(2))(2-) -> (O(2)C-CH(OH)-CH(OH))(*-) + CO(2) + e(-) explaining the observed gas-phase instability of this dianion. Further theoretical data were collected for the bare dianion, this molecule complexed to water, sodium, and a proton, in both the meso and l forms as well as for the uncomplexed radical anion and neutral diradical. The calculations suggest that the l-tartrate dianion is more thermodynamically stable than the dianion of the meso stereoisomer and that either dianion can be further stabilized by association with a separate species that can help to balance the charge of the molecular complex. Mass spectrometry was then used to measure the energy needed to initiate collisionally induced dissociation of the racemic tartrate dianion and for the proton and sodium adducts of both the racemic and meso form of this molecule. Infrared action spectra of the dianion stereoisomers complexed with sodium were also acquired to determine the influence of the metal ion on the vibrations of the dianions and validate the computationally predicted structures. These experimental data support the theoretical conclusions and highlight the instability of the bare tartrate dianion. From the experimental work, it could also be concluded that the pathway leading to dissociation is under kinetic control because the sodium adduct of the racemic stereoisomer dissociated at lower collisional energy, although it was calculated to be more stable, and that decomposition proceeded via C-C bond dissociation as computationally predicted. Taken together, these data provide insight into the gas-phase stability of the tartrate dianion and highlight the role of adducts in stabilizing this species. PMID- 22486161 TI - Lineage-dependent ecological coherence in bacteria. AB - Bacteria comprise an essential element of all ecosystems, including those present on and within the human body. Understanding bacterial diversity therefore offers enormous scientific and medical benefit, but significant questions remain regarding how best to characterize that diversity and organize it into biologically meaningful units. Bacterial communities are routinely characterized based on the relative abundances of taxa at the genus or even the phylum level, but the ecological coherence of these high-level taxonomic units is uncertain. Using human microbiota from the skin and gut as our model systems, we tested the ecological coherence of bacteria by investigating the habitat associations of bacteria at all levels of the taxonomic hierarchy. We observed four distinct taxonomic patterns of habitat association, reflecting different levels of ecological coherence among taxa. Our results support the hypothesis that deep branch bacterial clades could be ecologically coherent and suggest that the phylogenetic depth of ecological coherence varies among the bacterial lineages and is an important factor to consider in studies of human microbiome associations. PMID- 22486162 TI - Effect of prenatal exposure to diclofenac sodium on the male rat arteries: a stereological and histopathological study. AB - In this study, we investigated the morphometric and histological alterations of the aorta, brachial, and femoral arteries in 4- and 20-week-old rats that were prenatally exposed to diclofenac sodium (DS). For this purpose, pregnant rats were divided into three groups: control, saline injected, and drug treated. Beginning from day 5 after mating through day 15 of pregnancy, saline or DS (1 mg/kg daily) was intraperitoneally injected into groups 2 and 3. No injection was given to the rats in the control group. After spontaneous delivery, male offspring were obtained. At the end of weeks 4 and 20, vessel samples were removed. After dissection and routine histological preparation, histopathological and stereological investigations were made. Our results indicate that both saline and DS application lead to a decrease in the mean volume fraction of tunica media in all vessel walls, but result in an increase of the same fraction of lumen to the whole vessel wall, especially in 4-week-old rats. Elastic fibers of the vessel wall were affected by DS treatment, because a decrease of the elastic fiber was observed in this group. Finally, in light of our findings, we suggest that DS or saline may lead to vascular changes (i.e., vasodilatation or vasoconstriction) in rats that are prenatally subjected to increased volume of maternal blood resulting from injection. PMID- 22486163 TI - Oral healthcare issues in rural residential aged care services in Victoria, Australia. AB - OBJECTIVES: To identify major issues in providing and accessing oral health care in Victorian rural residential aged care services from the perspectives of dentists, aged care staff and residents. METHODS: Structured interviews were conducted with five dentists, nine aged care staff and six residents. Three focus groups were conducted with aged care staff. These data were thematically analysed independently by two researchers. RESULTS: The challenges reported by dentists included complexity of care, infrastructure needs and need for skill development. Aged care staff reported lack of skills and confidence in providing oral hygiene care, especially in residents with natural teeth, and an increasing burden on their daily workload. Residents reported concern and shame regarding their declining oral health status and increased challenges accessing appropriate oral health care. CONCLUSION: These findings indicate the need to build and sustain aged care 'oral health teams' who are able to provide daily oral hygiene care for residents and mentor other staff. Rural dentists need access to gerodontic training, portable equipment and appropriate workspaces in aged care services. Aged care and oral health services need to establish clear referral and communication pathways. PMID- 22486164 TI - Kinase signaling dysfunction in Parkinson's disease: a reverse genetic approach in Drosophila. AB - Drosophila genetics is one of the most powerful tools in modern biology. For many years, the "forward genetic" approach using Drosophila has been extraordinarily successful in elucidating the molecular pathways of many physiological processes and behaviors. Recently, the "reverse genetic" approach in Drosophila is increasingly being developed as a major tool for research in biology, especially in the study of human diseases. Parkinson's disease (PD) is the second most common neurodegenerative disease. Kinase signaling has been directly implicated in PD pathogenesis. Mutations in PTEN-induced kinase 1 (PINK1) cause PARK6 type PD, in which mitochondrial deficits are at the center of pathogenesis. Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most prevalent genetic cause of both familial (PARK8 type with autosomal dominant inheritance) and sporadic PD. To understand the mechanism of PINK1- and LRRK2- mediated pathogenesis, reverse engineered Drosophila models have been critical tools. Here the authors will discuss the usage of Drosophila models in their and other laboratories, and share scientific insights that originate from these studies, and discuss their experimental results of the effect of PINK1 on proteasome function. The authors will also comment on the different approaches taken in these lines of investigation. PMID- 22486165 TI - Contribution of catalase to hydrogen peroxide resistance in Enterococcus faecalis. AB - Enterococcus faecalis exhibits high resistance to oxidative stress. Several enzymes are responsible for this trait. The role of alkyl hydroperoxide reductase (Ahp), thiol peroxidase (Tpx), and NADH peroxidase (Npr) in oxidative stress defense was recently characterized. Enterococcus faecalis, in contrast to many other streptococci, contains a catalase (KatA), but this enzyme can only be formed when the bacterium is supplied with heme. We have used this heme dependency of catalase activity and mutants deficient in KatA and Npr to investigate the role of the catalase in resistance against exogenous and endogenous hydrogen peroxide stress. The results demonstrate that in the presence of environmental heme catalase contributes to the protection against toxic effects of hydrogen peroxide. PMID- 22486166 TI - Inter-observer variability in the histological assessment of colorectal polyps detected through the NHS Bowel Cancer Screening Programme. AB - AIMS: Although effective clinical management of colorectal polyps detected through the National Health Service (NHS) Bowel Cancer Screening Programme (BCSP) is dependent on the quality of pathological diagnosis, there have been few attempts to formally evaluate inter-observer variability in histological assessment. The aim of this study was to examine the impact of inter-observer variability on the reported prevalence of prognostic features in a large series of screen-detected colorectal polyps. METHODS AND RESULTS: A retrospective series of 1329 screen-detected polyps (2008-10) was identified from computerized records at two histopathology departments participating in the NHS BCSP. Slides from a sample of 239 polyps were exchanged between centres for independent review and measurement of inter-observer (kappa) agreement. There were significant between centre differences in the prevalence of polyps with high-risk histological features. Diagnostic review demonstrated good reliability with respect to the assessment of adenomatous change (kappa = 0.83), excision margin status (kappa = 0.74), high-grade dysplasia (0.61) and invasive malignancy (kappa = 0.84). By contrast, there were significant inter-observer differences in the classification of villous lesions (0.18) despite recent efforts to standardize reporting practice. CONCLUSIONS: Inter-observer variability in the assessment of screen detected colorectal polyps limits the prognostic value of histological subtyping and highlights the need for clarification of existing diagnostic criteria. PMID- 22486167 TI - A role for genetic counsellors and clinical geneticists in pharmacogenetics? PMID- 22486168 TI - Biologic treatment or immunomodulation is not associated with postoperative anastomotic complications in abdominal surgery for Crohn's disease. AB - OBJECTIVES: There are concerns that biologic treatments or immunomodulation may negatively influence anastomotic healing. This study investigates the relationship between these treatments and anastomotic complications after surgery for Crohn's disease. PATIENTS AND METHODS: Retrospective study on 417 operations for Crohn's disease performed at four Danish hospitals in 2000-2007. Thirty-two patients were preoperatively treated with biologics and 166 were on immunomodulation. In total, 154 were treated with corticosteroids of which 66 had prednisolone 20 mg or more. RESULTS: Anastomotic complications occurred at 13% of the operations. There were no difference in patients on biologic treatment (9% vs. 12% (p = 0.581)) or in patients on immunomodulation (10% vs. 14% (p = 0.263)). Patients on 20 mg prednisolone or more had more anastomotic complications (20% vs. 11% (p = 0.04)). Anastomotic complications were more frequent after a colo-colic anastomosis than after an entero-enteric or entero colic (33% vs. 12% (p = 0.013)). Patients with anastomotic complications were older (40 years vs. 35 years (p = 0.014)), had longer disease duration (7.5 years vs. 4 years (p = 0.04)), longer operation time (155 min vs. 115 min (p = 0.018)) and more operative bleeding (200 ml vs. 130 ml (p = 0.029)). Multivariate analysis revealed preoperative treatment with prednisolone 20 mg or more, operation time and a colo-colic anastomosis as negative predictors of anastomotic complications. CONCLUSIONS: Preoperative biologic treatment or immunomodulation had no influence on anastomotic complications. The study confirms previous findings of corticosteroids and a colo-colic anastomosis as negative predictors and also that surgical complexity, as expressed by bleeding and operation time, may contribute to anastomotic complications. PMID- 22486169 TI - An unusual cause of unilateral hydronephrosis: invasive colonic amebiasis. AB - A 62-year-old man was admitted to our hospital with complaints of abdominal pain and rectal bleeding. Although the colonoscopic examination was highly suggestive of a carcinoma, the histopathological examinations were consistent with chronic inflammation. CT examination revealed a solid lesion from cecum to the ascending colon with right urethral invasion. Percutaneous right nephrostomy was performed for grade 2-3 hydronephrosis. Three days after hospitalization, ileus developed and right hemicolectomy was performed. During surgery we observed that the lesion had invaded the middle part of ureter. So the middle part of ureter was removed with side-to-side urethral anastomosis and 6F double-J catheter was placed. The histopathological findings of resected specimen were consistent with ameboma. Reviewing the literature unilateral hydronephrosis due to colonic amebiasis has not been reported. PMID- 22486170 TI - Downregulation of CD94/NKG2A inhibitory receptor on decreased gammadelta T cells in patients with systemic lupus erythematosus. AB - gammadelta T cells are characterized by recognizing conserved endogenous and stress-induced antigens without antigen presentation. It has been show that gammadelta T cells play an important role in anti-tumour/microbe responses, but their function in autoimmune diseases is yet not clear. Here, we reported the quantity and phenotype of peripheral blood gammadelta T cells from systemic lupus erythematosus (SLE). Both the percentages of gammadelta T cells in peripheral blood and among CD3(+) T cells of patients with SLE were significantly decreased, regardless of disease activity. However, activating marker CD69 and HLA-DR was upregulated, while inhibiting receptor CD94/NKG2A was downregulated in gammadelta T cells of patients with SLE. The expression of CD69 is negatively correlated with the quantity of gammadelta T cells. Moreover, the expression of CD94/NKG2A remained low even with antigen stimulation on those gammadelta T cells. Our results suggested that the low expression level of CD94/NKG2A upon gammadelta T cell activation might lead to the over-activation of gammadelta T cells in patients with SLE. These findings will be useful in elucidating the roles of gammadelta T cells in SLE pathogenesis. PMID- 22486171 TI - Progesterone prevents mitochondrial dysfunction in the spinal cord of wobbler mice. AB - In the Wobbler mouse, a mutation of the Vps54 protein increases oxidative stress in spinal motoneurons, associated to toxic levels of nitric oxide and hyperactivity of nitric oxide synthase (NOS). Progesterone neuroprotection has been reported for several CNS diseases, including the Wobbler mouse neurodegeneration. In the present study, we analyzed progesterone effects on mitochondrial-associated parameters of symptomatic Wobbler mice. The activities of mitochondrial respiratory chain complexes I, II-III and IV and protein levels of mitochondrial and cytosolic NOS were determined in cervical and lumbar cords from control, Wobbler and Wobbler mice receiving a progesterone implant for 18 days. We found a significant reduction of complex I and II-III activities in mitochondria and increased protein levels of mitochondrial, but not cytosolic nNOS, in the cervical cord of Wobbler mice. Progesterone treatment prevented the reduction of complex I in the cervical region and the increased level of mitochondrial nNOS. Wobbler motoneurons also showed accumulation of amyloid precursor protein immunoreactivity and decreased activity and immunostaining of MnSOD. Progesterone treatment avoided these abnormalities. Therefore, administration of progesterone to clinically afflicted Wobblers (i) prevented the abnormal increase of mitochondrial nNOS and normalized respiratory complex I; (ii) decreased amyloid precursor protein accumulation, a sign of axonal degeneration, and (iii) increased superoxide dismutation. Thus, progesterone neuroprotection decreases mitochondriopathy of Wobbler mouse cervical spinal cord. PMID- 22486172 TI - Gender-specific association of androgenetic alopecia with metabolic syndrome in a middle-aged Korean population. AB - BACKGROUND: Although several previous studies have investigated the association between metabolic syndrome (MetS) and androgenetic alopecia (AGA), the study results have been inconsistent. OBJECTIVES: The aim of this study was to investigate the relationship between the presence of MetS and AGA according to gender in a middle-aged Korean population. METHODS: A population-based cross sectional study was conducted on a sample from the Korean Genome Epidemiology Study. In total, 3408 subjects (1707 men and 1701 women) were enrolled between January 2008 and February 2010. The Norwood classification for men and Ludwig classification for women were used for assessment of the degree of hair loss. Information on components of MetS together with other possible risk factors was collected. RESULTS: In men, the risk of having Norwood type IV or greater was not increased for subjects with MetS compared with those without MetS. In women, the risk of having Ludwig type I or greater was significantly increased for subjects with MetS compared with those without MetS after controlling for age and smoking status (OR 1.68, 95% CI 1.14-2.48; P=0.01). Similar results were also observed for the number of fulfilled components of MetS [odds ratio (OR) 1.38, 95% confidence interval (CI) 1.00-1.91; P<0.05]. When each component of MetS was considered individually, associations between AGA and all five components of MetS (waist circumference, triglycerides, high-density lipoprotein-C, blood glucose, and blood pressure) were not statistically significant. When multiple regression was used to adjust for age, family history and smoking, there was no significant association between the prevalence of MetS and moderate to severe AGA in the male group. On the contrary, a statistically significant positive association was noted between the prevalence of MetS and AGA in the female group. CONCLUSIONS: Our analysis of AGA and the prevalence of MetS in a large population-based cohort demonstrated quite different findings compared with previous reports. The different results according to gender suggest that there may be different mechanisms that are yet to be defined between male and female AGA. PMID- 22486173 TI - Improving influenza vaccination coverage in pregnancy in Melbourne 2010-2011. AB - BACKGROUND: Seasonal influenza vaccination during pregnancy is effective in preventing serious maternal and infant respiratory illness, but published Australian audits are sparse concerning practice. AIMS: Guided by information gained from new mothers about obstacles to influenza vaccination in July 2010, an educational program for maternity staff and pregnant women was developed with the aim of improving vaccine uptake in 2011. METHODS: One hundred and ninety-nine new mothers in July 2010 and 240 new mothers in July 2011 on postnatal wards of a tertiary obstetric hospital were interviewed about whether influenza vaccine had been offered or given and about reasons why women chose for or against vaccination during pregnancy. RESULTS: Influenza vaccination increased from 30% in 2010 to 40% in 2011 (P = 0.03). Fewer women cited safety concerns for themselves or their babies after the 2011 educational campaign. Comments from 90 women in 2011 give grounds for speculation that the vaccination rate could have been as high as 78% if influenza vaccination had been integrated as part of hospital-based antenatal care. CONCLUSIONS: Influenza vaccine coverage during pregnancy is increasing but obstacles persist, especially absent or inconsistent advice from healthcare workers and lack of ready access during routine antenatal care. PMID- 22486174 TI - Alcohol exposure rate control through physiologically based pharmacokinetic modeling. AB - BACKGROUND: The instantaneous rate of change of alcohol exposure (slope) may contribute to changes in measures of brain function following administration of alcohol that are usually attributed to breath alcohol concentration (BrAC) acting alone. To test this proposition, a 2-session experiment was designed in which carefully prescribed, constant-slope trajectories of BrAC intersected at the same exposure level and time since the exposure began. This paper presents the methods and limitations of the experimental design. METHODS: Individualized intravenous infusion rate profiles of 6% ethanol (EtOH) that achieved the constant-slope trajectories for an individual were precomputed using a physiologically based pharmacokinetic model. Adjusting the parameters of the model allowed each infusion profile to account for the subject's EtOH distribution and elimination kinetics. Sessions were conducted in randomized order and made no use of feedback of BrAC measurements obtained during the session to modify the precalculated infusion profiles. In one session, an individual's time course of exposure, BrAC(t), was prescribed to rise at a constant rate of 6.0 mg% per minute until it reached 68 mg% and then descend at -1.0 mg% per minute; in the other, to rise at a rate of 3.0 mg% per minute. The 2 exposure trajectories were designed to intersect at a BrAC (t = 20 minutes) = 60 mg% at an experimental time of 20 minutes. RESULTS: Intersection points for 54 of 61 subjects were within prescribed deviations (range of +/- 3 mg% and +/- 4 minutes from the nominal intersection point). CONCLUSIONS: Results confirmed the feasibility of applying the novel methods for achieving the intended time courses of the BrAC, with technical problems limiting success to 90% of the individuals tested. PMID- 22486175 TI - Effect of processing on recovery and variability associated with immunochemical analytical methods for multiple allergens in a single matrix: sugar cookies. AB - Among the major food allergies, peanut, egg, and milk are the most common. The immunochemical detection of food allergens depends on various factors, such as the food matrix and processing method, which can affect allergen conformation and extractability. This study aimed to (1) develop matrix-specific incurred reference materials for allergen testing, (2) determine whether multiple allergens in the same model food can be simultaneously detected, and (3) establish the effect of processing on reference material stability and allergen detection. Defatted peanut flour, whole egg powder, and spray-dried milk were added to cookie dough at seven incurred levels before baking. Allergens were measured using five commercial enzyme-linked immunosorbent assay (ELISA) kits. All kits showed decreased recovery of all allergens after baking. Analytical coefficients of variation for most kits increased with baking time, but decreased with incurred allergen level. Thus, food processing negatively affects the recovery and variability of peanut, egg, and milk detection in a sugar cookie matrix when using immunochemical methods. PMID- 22486176 TI - Oscillatory template exchange in polyoxometalate capsules: a ligand-triggered, redox-powered, chemically damped oscillation. AB - The redox-controlled driven oscillatory template exchange between phosphate (P) and vanadate (V) anions enclosed in an {X(2)M(18)} cluster is reported. Extensive investigations using a range of techniques, including correlated ESI-MS, EPR, and UV-vis as a function of reaction time, showed that six complete oscillations interconverting the capsule species present in solution from {P(2)M(18)} to {V(2)M(18)} were possible, provided that a sufficient concentration of the TEA reducing agent was present in solution. PMID- 22486177 TI - Predictors of more cranial or caudal axillary vein location to facilitate blind venous cannulation. PMID- 22486178 TI - Construction of the azocane (azacyclooctane) moiety of the Lycopodium alkaloid lycopladine H via an intramolecular hydroaminomethylation strategy. AB - An efficient synthetic strategy has been developed for annulation of an azocane ring onto a bicyclo[2.2.2]octane scaffold via an intramolecular hydroaminomethylation protocol to generate an advanced intermediate bearing three of the four rings of the structurally unique Lycopodium alkaloid lycopladine H (1). PMID- 22486179 TI - Tryptophan stabilizes His-heme loops in the denatured state only when it is near a loop end. AB - We use a host-guest approach to evaluate the effect of Trp guest residues relative to Ala on the kinetics and thermodynamics of formation of His-heme loops in the denatured state of iso-1-cytochrome c at 1.5, 3.0, and 6.0 M guanidine hydrochloride (GdnHCl). Trp guest residues are inserted into an alanine-rich segment placed after a unique His near the N-terminus of iso-1-cytochrome c. Trp guest residues are either 4 or 10 residues from the His end of the 28-residue loop. We find the guest Trp stabilizes the His-heme loop at all GdnHCl concentrations when it is the 4th, but not the 10th, residue from the His end of the loop. Thus, residues near loop ends are most important in developing topological constraints in the denatured state that affect protein folding. In 1.5 M GdnHCl, the loop stabilization is ~0.7 kcal/mol, providing a thermodynamic rationale for the observation that Trp often mediates residual structure in the denatured state. Measurement of loop breakage rate constants, k(b,His), indicates that loop stabilization by the Trp guest residues occurs completely after the transition state for loop formation in 6.0 M GdnHCl. Under poorer solvent conditions, approximately half of the stabilization of the loop develops in the transition state, consistent with contacts in the denatured state being energetically downhill and providing evidence for funneling even near the rim of the folding funnel. PMID- 22486181 TI - Reaction pathway and rate-determining step of the Schmidt rearrangement/fragmentation: a kinetic study. AB - The Schmidt rearrangement of substituted 3-phenyl-2-butanone with trimethylsilyl azide in 90% (v/v) aqueous TFA gave two types of product, fragmentation and rearrangement, the ratio of which depends on the substituent: more fragmentation for a more electron-donating substituent. Rate measurements by azotometry indicated the presence of an induction period, and the pseudo-first-order rate constants showed saturation kinetics with respect to the azide concentration. It was indicated that the reaction proceeds through pre-equilibrium in the formation of iminodiazonium (ID) ion and that the N(2) liberation from the ID ion is rate determining. Under high azide concentration conditions, where the effective reactant is the ID ion, the reaction gave a linear Hammett plot with a rho value of -0.50. The observed substituent effects on the rate and the product selectivity imply that path bifurcation on the way from the rate-determining TS to the product states occurs, as suggested by previous molecular dynamics simulations, in a similar manner to the analogous Beckmann rearrangement/fragmentation reactions. PMID- 22486180 TI - HbA1c-based diabetes diagnosis among patients with glucokinase mutation (GCK MODY) is affected by a genetic variant of glucose-6-phosphatase (G6PC2). AB - AIMS: Genetic variation at the rs560887 locus of the glucose-6-phosphatase, catalytic 2 gene (G6PC2) is known to affect regulation of fasting glycaemia. We determined the rs560887 genotype of patients with monogenic diabetes and glucokinase gene mutations (GCK-MODY) and correlated the genotypes with HbA(1c) levels. METHODS: Patients from families with GCK-MODY were recruited from two large cohorts from Poland (n = 128) and the Czech Republic (n = 154). Genotypes at the rs560887 polymorphic site in G6PC2 were examined using real-time quantitative polymerase chain reaction. The effect of rs560887 genotype on age at diagnosis of GCK-MODY and initial HbA(1c) levels were evaluated separately within both cohorts. Following that, a meta-analysis of rs560887 genotype-HbA(1c) associations of both Polish and Czech cohorts was performed to confirm homogeneity of findings and validate cohort-specific results. RESULTS: GG homozygosity at rs560887 was associated with marginally elevated HbA(1c) levels (P = 0.07 in both cohorts). The effects observed in both groups were very homogeneous (Q = 0.18; P = 0.68). Meta-analysis showed that GG homozygosity at rs560887 was associated with mean HbA(1c) levels higher by 2.4 mmol/mol (0.24%), 95% CI 0.5-4.4 mmol/mol (0.05-0.44%) than in individuals with other genotypes. Additionally, meta-analysis of both cohorts showed that GG homozygous individuals had higher odds of reaching the 48 mmol/mol (6.5%) diagnostic threshold of diabetes; (odds ratio 1.90; 95% CI 1.07-3.36; P = 0.03). No such effects were observed for age at diagnosis of diabetes. CONCLUSIONS: Variation at the rs560887 locus of G6PC2 is associated with worse glycated haemoglobin levels in individuals with GCK mutations; GG homozygotes are more likely to meet diagnostic criteria for diabetes based on HbA(1c) level. PMID- 22486182 TI - Influence of genetics and non-genetic factors on acenocoumarol maintenance dose requirement in Moroccan patients. AB - WHAT IS KNOWN AND OBJECTIVE: Coumarin derivatives such as acenocoumarol represent the therapy of choice for the long-term treatment and prevention of thromboembolic diseases. Many genetic, clinical and demographic factors have been shown to influence the anticoagulant dosage. Our aim was to investigate the contribution of genetic and non-genetic factors to variability in response to acenocoumarol in Moroccan patients. METHODS: Our study included 114 adult Moroccan patients, receiving long-term acenocoumarol therapy for various indications. Tests for VKORC1 -1639G>A promoter polymorphism (rs9923231), CYP2C9*2 rs1799853, CYP2C9*3 rs1057910, and CYP4F2 rs2108622 alleles were undertaken using Taq Man((r)) Pre-Developed Assay Reagents for allelic discrimination. The statistical analysis was performed using the SAS V9 statistical package. RESULTS AND DISCUSSION: Genotyping showed that the allele frequencies for the SNPs studied were no different to those found in Caucasians population. A significant association was observed between the weekly maintenance dose and the VKORC1 (P = 0.0027) and CYP2C9 variant genotypes (P = 0.0082). A final multivariate regression model that included the target International Normalized Ratio, VKORC1 and CYP2C9 genotypes explained 36.2% of the overall interindividual variability in acenocoumarol dose requirement. WHAT IS NEW AND CONCLUSION: Our study shows large interindividual variability in acenocoumarol maintenance dose requirement in our population. VKORC1 and CYP2C9 variants significantly affected acenocoumarol dose, in-line with results in other populations. For the Moroccan population, the SNPs that have the largest effect on acecoumarol dose are CYP2C9 rs1799853, CYP2C9 rs1057910 and VKORC1 rs9923231. PMID- 22486183 TI - A genetic risk factor for low serum ferritin levels in Danish blood donors. AB - BACKGROUND: Iron deficiency is a frequent side effect of blood donation. In recent years, several studies have described genetic variants associated with iron concentrations. However, the impact of these variants on iron levels is unknown in blood donors. Knowledge of genetic variants that predispose donors to iron deficiency would allow bleeding frequency and iron supplementation to be tailored to the individual donor. STUDY DESIGN AND METHODS: The genotypes of five specific single-nucleotide polymorphisms (SNPs) in three genes that have been previously associated with iron status and/or restless leg syndrome (RLS) were investigated in two groups of female blood donors. The first group had low iron stores (serum ferritin <= 12 ug/L, n = 657), and the second group had normal to high iron stores (serum ferritin > 30 ug/L, n = 645). Genotype distribution for each of the SNPs was compared between the two groups. RESULTS: Homozygosity for the T-allele of BTBD9 rs9296249 was associated with lower serum ferritin. The odds ratio for low serum ferritin was 1.35 (95% confidence interval, 1.02-1.77; p = 0.03) when comparing donors with the TT genotype with donors with the CT genotype. CONCLUSION: A frequent polymorphism in BTBD9 was significantly associated with serum ferritin. This polymorphism has previously been associated with RLS, but not low iron stores in blood donors. PMID- 22486184 TI - Risk factors for injury in community-level football: a cohort study. AB - We investigated the independent effect of commonly postulated risk factors on injury incidence in amateur football (soccer), using a prospective cohort design with follow-up over two seasons. A total of 1702 male and female players aged 13 years or older contributed information on 21,797 player-matches. Confirmed, were the effect of male vs. female sex (injury rate ratios (IRR) = 0.81, 95% confidence interval (CI): 0.67-0.97), older age (increasing IRR gradient), New Zealand European ethnicity (IRR = 0.87, 95% CI: 0.74-1.01), being taller (180-189 cm: IRR = 1.32, 95% CI: 1.06-1.63), previous injury (IRR = 1.32, 95% CI: 1.12 1.57), playing against medical advice (IRR = 1.24, 95% CI: 1.03-1.49), playing while recovering from injury (IRR = 1.40, 95% CI: 1.20-1.49), history of cigarette smoking (IRR = 1.27, 95% CI: 1.00-1.61) and time of season (IRR = 0.97, 95% CI: 0.96-0.98). Female, adult, non-European and taller players could be paid particular attention in injury prevention programmes. The need for effective injury management is reinforced. Adding physical conditioning to pre-season training may be required. PMID- 22486185 TI - The acute, genetic, developmental and inhalation toxicology of trans-1,3,3,3 tetrafluoropropene (HFO-1234ze). AB - HFO-1234ze is being developed as a refrigerant, propellant, and foam-blowing agent because it has a very low global warming potential (less than 10), as contrasted to the hydrofluorocarbons with values of over 500. Several toxicology studies were conducted to develop a toxicology profile for this material. There was no lethality in mice and rats receiving single 4-hour exposures up to 103,300 or 207,000 ppm, respectively. Exposures up to 120,000 ppm did not induce cardiac sensitization to adrenalin. Rats were exposed to HFO-1234ze at levels of 5,000, 20,000, and 50,000 ppm 6 hours/day 5 days/week for 2 weeks. Predominate findings of increased liver and kidney weights and histopathological changes in the liver and heart suggested that these organs were the targets for HFO-1234ze toxicity. In a 4-week study at 1000, 5000, 10,000, and 15,000 ppm, the only organ showing treatment-related effects was the heart. In a 90-day study with exposures of 1500, 5000, and 15,000 ppm 6 hours/day 5 days/week, again, the heart was the only target organ. The findings consisted of focal and multifocal mononuclear cell infiltrates in the heart. There was no evidence of fibrosis, and, when compared to the 2- and 4-week studies, there did not appear to be an increase in severity with length of exposure. HFO-1234ze was inactive in a mouse and rat micronucleus assay, an Ames assay, and an unscheduled DNA synthesis assay and was not clastogenic in human lymphocytes. It was also not a developmental toxin in either the rat or rabbit, even at exposure levels up to15,000 ppm. PMID- 22486186 TI - Mast cell activation by conidia of Sporothrix schenckii: role in the severity of infection. AB - Mast cells are abundant in the skin and other peripheral tissues, where they are one of the first immune cells to make contact with invading pathogens. As a result of pathogen recognition, mast cells can be activated and release different preformed and de novo-synthesized mediators. Sporothrix schenckii is the fungus that causes sporotrichosis, a worldwide-distributed subcutaneous mycosis considered as an important emerging health problem. It remains unknown whether or not mast cells are activated by S. schenckii. Here, we investigated the in vitro response of mast cells to conidia of S. schenckii and their in vivo involvement in sporotrichosis. Mast cells became activated after interaction with conidia, releasing early response cytokines as TNF-alpha and IL-6. Although histamine release was not significantly stimulated by S. schenckii, we determined that conidia potentiate histamine secretion induced by compound 48/80. Furthermore, functional depletion of peritoneal mast cells before S. schenckii infection significantly reduced the severity of cutaneous lesions of the sporotrichosis. These data demonstrate that mast cells are important contributors in the host response to S. schenckii infection, suggesting a role of these cells in the progress of clinical manifestations in sporotrichosis. PMID- 22486187 TI - Mucosal cytokine gene expression profiles as biomarkers of response to infliximab in ulcerative colitis. AB - OBJECTIVE: Mucosal cytokine profile determines T cell differentiation and may play an important role in the clinical course of inflammatory bowel disease (IBD). Cytokines from different T helper (Th) cell subsets are elevated in inflamed mucosa of patients with ulcerative colitis (UC), contributing to the inflammation. The aim of this study was to determine the predictive value of pre treatment mucosal cytokine profile in response to therapy with the anti-TNF agent infliximab (IFX). MATERIAL AND METHODS: The expression of Th1, Th17, Th2 and T regulatory (Treg)-related cytokines was quantified by real-time PCR in mucosal biopsies from 74 UC patients before initiation of IFX induction therapy. Clinical and endoscopic effects were assessed after three infusions. Remission was defined as ulcerative colitis disease activity index (UCDAI) below 3. RESULTS: Higher gene expression levels of IL-17A and IFN-gamma were significantly associated with remission after three IFX infusions (OR = 5.4, p = 0.013 and OR = 5.5, p = 0.011, respectively). IL-17A and IFN-gamma mRNA expression showed positive correlation. Th2 and Treg-related mediators were not significantly associated with clinical outcome, but were expressed at higher levels in UC patients compared with the controls. Immunohistochemistry (IHC) confirmed the presence of cells expressing both IL-17A and IFN-gamma. CONCLUSIONS: High expression of Th1- and Th17-related cytokines in the mucosa of UC patients can potentially predict a favorable outcome of IFX induction therapy. Th2 and Treg-related mediators do not appear useful as predictive markers. PMID- 22486188 TI - Alpha-ketoglutarate (AKG) inhibits proliferation of colon adenocarcinoma cells in normoxic conditions. AB - BACKGROUND AND OBJECTIVE: Alpha-ketoglutarate (AKG), a key intermediate in Krebs cycle, is an important biological compound involved in the formation of amino acids, nitrogen transport, and oxidation reactions. AKG is already commercially available as a dietary supplement and its supplementation with glutamine, arginine, or ornithine alpha-ketoglutarate has been recently considered to improve anticancer immune functions. It is well documented that AKG treatment of Hep3B hepatoma cells in hypoxia induced HIF-alpha (hypoxia-inducible factor) degradation and reduced vascular endothelial growth factor (VEGF) synthesis. Moreover, AKG showed potent antitumor effects in murine tumor xenograft model, inhibiting tumor growth, angiogenesis, and VEGF gene expression. However, the mechanisms of its anticancer activity in normoxia have not been examined so far. RESULTS: Here, we report that in normoxia, AKG inhibited proliferation of colon adenocarcinoma cell lines: Caco-2, HT-29, and LS-180, representing different stages of colon carcinogenesis. Furthermore, AKG influenced the cell cycle, enhancing the expression of the inhibitors of cyclin-dependent kinases p21 Waf1/Cip1 and p27 Kip1. Moreover, expression of cyclin D1, required in G1/S transmission, was decreased, which accompanied with the significant increase in cell number in G1 phase. AKG affected also one the key cell cycle regulator, Rb, and reduced its activation status. CONCLUSION: In this study for the first time, the antiproliferative activity of AKG on colon adenocarcinoma Caco-2, HT-29, and LS-180 cells in normoxic conditions was revealed. Taking into consideration an anticancer activity both in hypoxic and normoxic conditions, AKG may be considered as a new potent chemopreventive agent. PMID- 22486191 TI - Development of a sequence typing scheme for differentiation of Salmonella Enteritidis strains. AB - A DNA sequence typing scheme based on the caiC and SEN0629 loci was developed for differentiation of Salmonella Enteritidis strains and validated using a diverse collection of 102 isolates representing 38 phage types from different sources, year of isolation, geographical locations and epidemiological backgrounds. caiC encodes a probable crotonobetaine/carnitine-CoA ligase, and SEN0629 is a pseudogene. Our system allowed for discrimination of 16 sequence types (STs) among the 102 isolates analysed and intraphage type differentiation. Our findings also suggested that the stability of phage typing may be adversely affected by the occurrence of phage type conversion events. During a confirmatory phage typing analysis performed by a reference laboratory, 13 of 31 S. Enteritidis strains representing nine phage types were assigned phage types that differed from the ones originally determined by the same reference laboratory. It is possible that this phenomenon passes largely unrecognized in reference laboratories performing routine phage typing analyses. Our results demonstrate that phage typing is an unstable system displaying limited reproducibility and that the two-loci sequence typing scheme is highly discriminatory, stable, truly portable and has the potential to become the new gold standard for epidemiological typing of S . Enteritidis strains. PMID- 22486192 TI - Preparation, structure, and properties of tetranuclear vanadium(III) and (IV) complexes bridged by diphenyl phosphate or phosphate. AB - Three novel tetranuclear vanadium(III) or (IV) complexes bridged by diphenyl phosphate or phosphate were prepared and their structures characterized by X-ray crystallography. The novel complexes are [{V(III)(2)(MU-hpnbpda)}(2){MU (C(6)H(5)O)(2)PO(2)}(2)(MU-O)(2)].6CH(3)OH (1), [{V(III)(2)(MU-tphpn)(MU-eta(3) HPO(4))}(2)(MU-eta(4)-PO(4))](ClO(4))(3).4.5H(2)O (2), and [{(V(IV)O)(2)(MU tphpn)}(2)(MU-eta(4)-PO(4))](ClO(4))(3).H(2)O (3), where hpnbpda and tphpn are alkoxo-bridging dinucleating ligands. H(3)hpnbpda represents 2-hydroxypropane-1,3 diamino-N,N'-bis(2-pyridylmethyl)-N,N'-diacetic acid, and Htphpn represents N,N,N',N'-tetrakis(2-pyridylmethyl)-2-hydroxy-1,3-propanediamine. A dinuclear vanadium(IV) complex without a phosphate bridge, [(VO)(2)(MU tphpn)(H(2)O)(2)](ClO(4))(3).2H(2)O (4), was also prepared and structurally characterized for comparison. The vanadium(III) center in 1 adopts a hexacoordinate structure while that in 2 adopts a heptacoordinate structure. In 1, the two dinuclear vanadium(III) units bridged by the alkoxo group of hpnbpda are further linked by two diphenylphosphato and two oxo groups, resulting in a dimer-of-dimers. In 2, the two vanadium(III) units bridged by tphpn are further bridged by three phosphate ions with two different coordination modes. Complex 2 is oxidized in aerobic solution to yield complex 3, in which two of the three phosphate groups in 2 are substituted by oxo groups. PMID- 22486193 TI - Short-term side effects of 0.2% alcohol-free chlorhexidine mouthrinse in geriatric patients: a randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: To determine the effects of a 0.2% alcohol-free chlorhexidine mouthwash applied twice a day during 30 days in patients over 65 years of age. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled study was made of 70 denture wearers over 65 years of age. The study subjects were randomly assigned to one of the two groups (chlorhexidine or placebo). The patients were instructed to complete a first whitening phase with a duration of 1 week, followed by a 30-day treatment period. The following data were collected: Silness and Loe plaque index, gingival index, the number of colony-forming units of Candida albicans at the start and end of treatment and the possible adverse effects of chlorhexidine. RESULTS: Significant differences were observed in the evolution of the Silness and Loe plaque index and gingival index in the two groups, as well as in the number of colony-forming units of C. albicans between the start and end of treatment. CONCLUSIONS: These results suggest that the clinical benefits of antiplaque, antigingivitis mouthrinses in both study groups. PMID- 22486194 TI - X-linked recessive ichthyosis: an impaired barrier function evokes limited gene responses before and after moisturizing treatments. AB - BACKGROUND: X-linked recessive ichthyosis (XLRI) is due to deletions or inactivating mutations in the steroid sulfatase (STS) gene. This results in an accumulation of cholesterol sulphate affecting the packing of intercorneocyte lipids. XLRI is characterized by dry, scaly skin and increased skin barrier permeability; patients are often dependent on daily use of moisturizers. OBJECTIVES: To examine the biophysical and molecular changes in the skin of patients with XLRI compared with healthy volunteers, and to analyse the effects of moisturizers on the patients' barrier function. METHODS: Patients with XLRI (n=14) and healthy controls (n=14) were included in the study. Skin dryness score, transepidermal water loss (TEWL) and skin surface pH were monitored at baseline, and punch biopsies were obtained for mRNA expression profiles determined by oligonucleotide arrays. Measurements were repeated in the patients with XLRI after a 4-week treatment with three different moisturizers on the volar forearms. RESULTS: Patients with XLRI showed, compared with healthy controls, increased dryness and TEWL, equal skin pH and altered expression of 27 genes. There were no signs of activation of inflammation or repair pathways. Five selected genes were significantly altered also on quantitative polymerase chain reaction analysis. Treatment with the moisturizers showed similar effects: they improved skin dryness but had no effect on TEWL, pH or expression of selected genes. CONCLUSIONS: Despite a dysfunctional skin barrier, the limited number of genes altered in XLRI skin suggests that no inflammatory or repair mechanisms are triggered. Treatment with moisturizers does not have any major impact on the skin barrier properties of patients with XLRI. PMID- 22486195 TI - HER-2/neu gene amplification in carcinoma ex pleomorphic adenoma in relation to progression and prognosis: a chromogenic in-situ hybridization study. AB - AIMS: The aim of this study was to investigate the potential role of HER-2/neu in the stepwise progression of carcinoma ex pleomorphic adenoma (CXPA) and to evaluate its prognostic significance in CXPA. METHODS AND RESULTS: We examined HER2 overexpression and HER2 amplification by immunohistochemistry and chromogenic in-situ hybridization in 31 cases of CXPA with ductal differentiation (eight intraductal, five intracapsular, and 18 extracapsular) and seven cases of atypical pleomorphic adenoma (PA). HER2 overexpression and HER2 amplification were found in 17 (54.8%) and 12 (38.7%) of the 31 CXPA cases, respectively. HER2 amplification was more prevalent in extracapsular CXPAs (9/18 cases; 50%) than intracapsular CXPAs (1/5 cases; 20%), intraductal CXPAs (2/8 cases; 25%), or atypical PAs (0/7 case; 0%). The status of HER2 amplification was essentially retained from the intraductal to the extracapsular component in individual extracapsular CXPAs. In addition, HER2 amplification was significantly associated with a worse prognosis (shorter disease-free survival time and shorter overall survival time) among extracapsular CXPAs (each P < 0.05). CONCLUSIONS: These results suggest that HER2 may play an important role in the progression of CXPA, and that HER2 amplification may be an additional prognostic indicator of CXPA. PMID- 22486196 TI - Early use of hemodialysis for active rewarming in severe hypothermia: a case report and review of literature. AB - Deep accidental hypothermia (body temperature below 28 degrees C) is rare. Even with modern supportive care of active external and internal rewarming techniques it is associated with a high mortality rate. We report the early and successful use of hemodialysis (HD) for active rewarming of a middle-aged alcoholic man with severe deep accidental hypothermia after failure of initial efforts of rewarming using conventional strategies. This case report and review of the literature highlights the advantages and the challenges of using HD in this setting and suggests a potential role for HD in the routine management of severe hypothermia in the absence of circulatory arrest. PMID- 22486197 TI - An intronic mutation causes severe LGMD2A in a large inbred family belonging to a genetic isolate in the Alps. PMID- 22486198 TI - Probing the pharmacological properties of distinct subunit interfaces within heteromeric glycine receptors reveals a functional betabeta agonist-binding site. AB - Synaptic glycine receptors (GlyRs) are hetero-pentameric chloride channels composed of alpha and beta subunits, which are activated by agonist binding at subunit interfaces. To examine the pharmacological properties of each potential agonist-binding site, we substituted residues of the GlyR alpha(1) subunit by the corresponding residues of the beta subunit, as deduced from sequence alignment and homology modeling based on the recently published crystal structure of the glutamate-gated chloride channel GluCl. These exchange substitutions allowed us to reproduce the betaalpha, alphabeta and betabeta subunit interfaces present in synaptic heteromeric GlyRs by generating recombinant homomeric receptors. When the engineered alpha(1) GlyR mutants were expressed in Xenopus oocytes, all subunit interface combinations were found to form functional agonist-binding sites as revealed by voltage clamp recording. The betabeta-binding site displayed the most distinct pharmacological profile towards a range of agonists and modulators tested, indicating that it might be selectively targeted to modulate the activity of synaptic GlyRs. The mutational approach described here should be generally applicable to heteromeric ligand-gated ion channels composed of homologous subunits and facilitate screening efforts aimed at targeting inter subunit specific binding sites. PMID- 22486199 TI - The impact of interferon beta and natalizumab on comorbid migraine in multiple sclerosis. AB - BACKGROUND: Some multiple sclerosis (MS)-specific therapies may exacerbate a comorbid migraine. Whereas data regarding the impact of interferon beta (IFNB) on this comorbidity have been reported, studies on the role of natalizumab (NTZ) are still lacking. PURPOSE: Our aim was to compare the impact of IFNB and NTZ on the frequency and disability of comorbid migraine in MS patients. METHODS: performed a longitudinal evaluation on MS patients with comorbid migraine previously assessed at our center and retested for the present study, by comparing data from 33 patients originally treated with IFNB and thereafter switched to NTZ vs 30 patients continued currently to receive IFNB. RESULTS: Longitudinal analysis showed a significant reduction of migraine frequency (from a mean value of 8.4 to 5.1 days per month; P = .034) and Migraine Disability Assessment Scale (MIDAS) score (from a mean value of 14.2 to 10.5; P = .045) in the subgroup patients switched from IFNB to NTZ but not in those remaining in the IFNB recipient, irrespective of level of fatigue, trait anxiety, depression, alexithymia, or other clinical variables. CONCLUSIONS: Our findings suggest that NTZ did not exacerbate comorbid migraine in MS patients and support the hypothesis that IFNB might represent an important trigger for migraine worsening. PMID- 22486200 TI - Adnexal masses in women with breast cancer. AB - BACKGROUND: Adnexal masses detected in breast cancer survivors are of particular concern because of the increased risk of ovarian malignancy. AIMS: This study was performed to analyse adnexal masses among women with breast cancer with regard to variables predictive of malignancy. METHODS: The study included women with breast cancer who had undergone surgery for an adnexal mass between 2002 and 2010 at Hacettepe University Hospital. A total of 45 consecutive women with a mean age of 47.3 years (range 25-76) were analysed retrospectively. RESULTS: Of 45 cases reviewed, benign ovarian pathology was found in 35 cases (77.8%) and malignant ovarian neoplasms were found in 10 cases (22.2%). A simple ovarian cyst was observed in 25 cases (71.4%) as the most common type of benign pathology. Of the 10 cases with malignancy, 5 (50%) had primary ovarian carcinoma, while the remaining five women had breast carcinoma metastases to the ovary. Complex mass at ultrasonography, increased CA 125 level and oestrogen receptor-negative tumour were found to be the significant predictors of ovarian malignancy. CONCLUSIONS: Although an adnexal mass in a woman with breast cancer is most commonly a benign ovarian cyst, the overall risk of ovarian malignancy is increased with breast cancer. An adnexal mass with complex architecture detected by ultrasonography and high CA 125 level were the strongest risk factors associated with increased risk of malignancy. PMID- 22486201 TI - Hazardous drinking and dimensions of impulsivity, behavioral approach, and inhibition in adult men and women. AB - INTRODUCTION: Hazardous drinking is characterized by decisions to engage in excessive or risky patterns of alcohol consumption. Levels of impulsivity and behavioral approach and inhibition may differ in hazardous drinkers and nonhazardous drinkers. A comparison of the relative levels of dimensions of impulsivity and behavioral inhibition and approach in adult men and women hazardous and nonhazardous drinkers may inform treatment and prevention efforts. METHODS: In the present research, 466 men and women from a community sample were administered the Alcohol Use Disorders Identification Test (AUDIT), the Behavioral Inhibition System/Behavioral Approach System (BIS/BAS) scale, and the Barratt Impulsiveness Scale, version 11 (BIS-11). Relations among the dimensions of these constructs were examined using multivariate analysis of covariance (MANCOVA), with age and race as covariates. RESULTS: There were main effects of hazardous drinking on all 3 dimensions of impulsivity, the behavioral inhibition system, and the behavioral activation system Reward Responsiveness, and Fun Seeking components, with hazardous drinkers scoring higher than nonhazardous drinkers. CONCLUSIONS: This research provides a better understanding of the manner in which impulsivity and behavioral inhibition and approach tendencies relate to hazardous alcohol use in men and women. The present results have implications for alcohol-related prevention and treatment strategies for adult men and women. PMID- 22486203 TI - Stereocontrolled synthesis of vicinal diamines by organocatalytic asymmetric Mannich reaction of N-protected aminoacetaldehydes: formal synthesis of (-) agelastatin A. AB - The 1,2-diamine (vicinal diamine) motif is present in a number of natural products with interesting biological activity and in many chiral molecular catalysts. The efficient and stereocontrolled synthesis of enantioenriched vicinal diamines is still a challenge to modern chemical methodology. We report here both syn- and anti-selective asymmetric direct Mannich reactions of N protected aminoacetaldehydes with N-Boc-protected imines catalyzed by proline and the axially chiral amino sulfonamide (S)-3. This organocatalytic process represents the first example of a Mannich reaction using Z- or Boc-protected aminoacetaldehyde as a new entry of alpha-nitrogen functionalized aldehyde nucleophile in enamine catalysis. The obtained optically active vicinal diamines are useful chiral synthons as exemplified by the formal synthesis of (-) agelastatin A. PMID- 22486204 TI - Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic review and meta-analysis. AB - AIMS: To systematically review the evidence for the effect of vitamin D supplementation on glycaemia, insulin resistance, progression to diabetes and complications of diabetes. METHODS: Systematic review and meta-analysis. We searched databases including MEDLINE, EMBASE and the Cochrane Library for randomized controlled trials comparing vitamin D or analogues with placebo. We extracted data on fasting glucose, glycaemic control, insulin resistance, insulin/C-peptide levels, micro- and macrovascular outcomes and progression from non-diabetes to diabetes. Studies were assessed independently by two reviewers according to a pre-specified protocol. RESULTS: Fifteen trials were included in the systematic review. Trial reporting was of moderate, variable quality. Combining all studies, no significant improvement was seen in fasting glucose, HbA(1c) or insulin resistance in those treated with vitamin D compared with placebo. For patients with diabetes or impaired glucose tolerance, meta-analysis showed a small effect on fasting glucose (-0.32 mmol/l, 95%CI -0.57 to -0.07) and a small improvement in insulin resistance (standard mean difference -0.25, 95%CI 0.48 to -0.03). No effect was seen on glycated haemoglobin in patients with diabetes and no differences were seen for any outcome in patients with normal fasting glucose. Insufficient data were available to draw conclusions regarding micro- or macrovascular events; two trials failed to show a reduction in new cases of diabetes in patients treated with vitamin D. CONCLUSIONS: There is currently insufficient evidence of beneficial effect to recommend vitamin D supplementation as a means of improving glycaemia or insulin resistance in patients with diabetes, normal fasting glucose or impaired glucose tolerance. PMID- 22486205 TI - Biochemical alterations and liver toxicity analysis with pioglitazone in healthy subjects. AB - Pioglitazone, a member of the thiazolidinediones, is a potent, highly selective agonist for peroxisome proliferator-activated receptor gamma and is an excellent insulin sensitizer used in treating type 2 diabetes mellitus. The present study investigated the effect of pioglitazone on glucose, total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol and high density lipoprotein (HDL) cholesterol, total proteins, albumin (ALB), alanine transaminase (ALT), and aspartate transaminase (AST) levels in 20 healthy Bengali male volunteers in a randomized, placebo-controlled study. Blood samples were collected before and 0.5-24.0 hours after a single oral dose of a 30 mg pioglitazone tablet. Plasma pioglitazone level was determined using a validated method of reverse-phase binary high-performance liquid chromatography. Blood lipid profile and levels of glucose, ALT, and AST were estimated using enzyme assay kits, plasma protein level was estimated by the biuret method, and plasma ALB level was determined colorimetrically. No significant change in blood glucose, total proteins, total cholesterol, triglyceride, HDL, and LDL levels was observed over the 24-hour assessment period, indicating no plasma biochemical alterations. There were no significant differences between baseline and 24-hour values of ALB, ALT, and AST levels, indicating a lack of liver toxicity. Our results indicate that a single dose of 30 mg of pioglitazone has no hypoglycemic or hypolipidemic effect or liver toxicity within 24 hours of treatment among healthy Bengali males. PMID- 22486206 TI - Courting controversy. PMID- 22486207 TI - Thermal unfolding of proteins probed at the single molecule level using nanopores. AB - The nanopore technique has great potential to discriminate conformations of proteins. It is a very interesting system to mimic and understand the process of translocation of biomacromolecules through a cellular membrane. In particular, the unfolding and folding of proteins before and after going through the nanopore are not well understood. We study the thermal unfolding of a protein, probed by two protein nanopores: aerolysin and alpha-hemolysin. At room temperature, the native folded protein does not enter into the pore. When we increase the temperature from 25 to 50 degrees C, the molecules unfold and the event frequency of current blockade increases. A similar sigmoid function fits the normalized event frequency evolution for both nanopores, thus the unfolding curve does not depend on the structure and the net charge of the nanopore. We performed also a circular dichroism bulk experiment. We obtain the same melting temperature (around 45 degrees C) using the bulk and single molecule techniques. PMID- 22486208 TI - Anti-biofilm activity of Quercus infectoria G. Olivier against methicillin resistant Staphylococcus aureus. AB - AIMS: To establish the effect of Quercus infectoria G. Olivier extract and its main constituent, tannic acid, on staphylococcal biofilm and their anti-biofilm mechanisms. METHODS AND RESULTS: Anti-biofilm activity of the plant materials on clinical isolated of methicillin-resistant Staphylococcus aureus and methicillin susceptible Staph. aureus was employed using a crystal violet-stained microtiter plate method. The extract at minimum inhibitory concentration (MIC; 0.25 mg ml( 1)) was significantly reduced the biofilm formation of the isolates (P < 0.05). The effect on staphylococcal cell surface hydrophobicity (CSH) of the test compounds was investigated as a possible mode of action of the anti-biofilm activity. The hydrophobicity index of all the bacterial isolates increased following treatment with supra-MIC, MIC and sub-MIC of the extract and tannic acid. Observation of the treated bacterial cells by electron microscopy revealed that the test compounds caused clumps of partly divided cocci with thickened and slightly rough cell wall. CONCLUSIONS: The results indicated that Q. infectoria extract and tannic acid affected staphylococcal biofilm formation and their effect on bacterial CSH and cell wall may involve in the anti-biofilm activity. SIGNIFICANCE AND IMPACT OF THE STUDY: This evidence highlighted the anti-biofilm potency of the natural products and clarified their anti-biofilm mechanisms. PMID- 22486209 TI - Water administration and the risk of syncope and presyncope during blood donation: a randomized clinical trial. AB - BACKGROUND: Blood centers rely heavily on adolescent donors to meet blood demand, but presyncope and syncope are more frequent in younger donors. Studies have suggested administration of water before donation may reduce syncope and/or presyncope in this group. STUDY DESIGN AND METHODS: We conducted a randomized, controlled trial to establish the effect of preloading with 500 mL of water on the rate of syncope and presyncope in adolescent donors. School collection sites in Eastern Cape Province of South Africa were randomized to receive water or not. Incidence of syncope and presyncope was compared between randomization groups using multivariable logistic regression. RESULTS: Of 2464 study participants, 1337 received water and 1127 did not; groups differed slightly by sex and race. Syncope or presyncope was seen in 23 (1.7%) of the treatment and 18 (1.6%) of the control arm subjects. After adjusting for race, sex, age, and donation history, there was no difference in outcome between the water versus no water arms (adjusted odds ratio [OR], 0.80; 95% confidence interval [CI], 0.42-1.53). Black donors had sevenfold lower odds of syncope or presyncope than their white counterparts (adjusted OR, 0.14; 95% CI, 0.04-0.47). CONCLUSION: Preloading adolescent donors with 500 mL of water did not have a major effect in reducing syncope and presyncope in South African adolescent donors. Our adolescent donors had lower overall syncope and presyncope rates than similar populations in the United States, limiting the statistical power of the study. We confirmed much lower rates of syncope and presyncope among young black donors. PMID- 22486210 TI - Angiogenic imbalance and plasma lipid alterations in women with preeclampsia from a developing country. AB - BACKGROUND: An imbalance between anti-angiogenic factors (e.g. soluble vascular endothelial growth factor receptor-1 (s-FLT1) and soluble endoglin (s-Eng)) and pro-angiogenic factors (e.g. placental growth factor (PlGF)) as well as increased oxidized low-density lipoprotein (ox-LDL) concentrations have been associated with preeclampsia (PE). Risk factors associated with the development of PE, however, are known to be different between developed and developing countries. The aim of the study was to determine the levels of s-FLT1, s-Eng, PIGF, and ox LDL in women with PE from a developing country. METHODS: A multi-center case control study was conducted. One hundred and forty three women with PE were matched by age and parity with 143 healthy pregnant women without cardiovascular or endocrine diseases. Before delivery, blood samples were taken and serum was stored until analysis. RESULTS: Women with PE had lower concentrations of PIGF (p<0.0001) and higher concentrations of s-Eng (p=0.001) than healthy pregnant women. There were no differences between the groups regarding ox-LDL or s-FLT1. Women with early onset PE had higher s-FLT1 concentrations (p=0.0004) and lower PIGF concentrations (p<0.0001) than their healthy pregnant controls. Women with late onset PE had higher concentrations of s-Eng (p=0.005). Women with severe PE had higher concentrations of s-Eng (p=0.0008) and ox-LDL (p=0.01), and lower concentrations of PIGF (p<0.0001). CONCLUSIONS: Women with PE from a developing country demonstrated an angiogenic imbalance and an increased rate of LDL oxidation. Findings from this study support the theory that PE is a multifactorial disease, and understanding differences in these subpopulations may provide a better target to approach future therapies. PMID- 22486211 TI - Immunoglobulin G4-positive multi-organ lymphoproliferative syndrome with antiphospholipid antibody syndrome. AB - We report immunoglobulin (Ig)G4-positive multi-organ lymphoproliferative syndrome (IgG4(+) -MOLPS) with antiphospholipid antibody syndrome (APS) in a 56-year-old Japanese man presenting with purpuric patches on his legs. Skin biopsy revealed leukocytoclastic vasculitis. Laboratory tests demonstrated high levels of serum IgG and IgG4, hypocomplementemia and anticardiolipin antibody. Echography of the lower limbs and pulmonary scintigraphy showed a thrombus in the left soleal vein and multiple emboli in the basal part of both inferior pulmonary arteries. Computed tomography revealed systemic lymphadenopathy. Histologically, there was reactive paracortical hyperplasia with proliferation of histiocytes and infiltration of IgG4-positive plasma cells. We made a diagnosis of IgG4(+) -MOLPS with APS. To our knowledge, this complication has not been reported previously. PMID- 22486212 TI - Serum levels of visfatin and omentin-1 in patients with psoriasis and their relation to disease severity. AB - BACKGROUND: The association of the novel adipokines visfatin and omentin-1 with psoriasis is still obscure. Data concerning other inflammatory diseases suggest a possible role of these adipokines in the pathophysiology of psoriasis. OBJECTIVES: To investigate serum levels of visfatin and omentin-1 in patients with psoriasis compared with healthy controls, and to consider their relation to disease duration, disease severity and obesity markers. METHODS: Visfatin and omentin-1 concentrations were measured in 46 patients with plaque-type psoriasis and 42 healthy controls by using specific enzyme-linked immunosorbent assays. RESULTS: Patients with psoriasis showed considerably higher serum levels of visfatin than healthy controls with significant positive correlation with disease severity and duration. They also showed lower levels of ominten-1 compared with healthy controls with significant inverse correlation with body mass index and waist circumference. CONCLUSIONS: Coordinated roles for visfatin and omentin-1 are suggested in the modulation of the inflammatory environment in patients with psoriasis. Given the significant relations of omentin-1 with obesity markers, the health consequences of excessive weight should be better communicated to patients with psoriasis. PMID- 22486213 TI - Low-temperature diffusion of oxygen through ordered carbon vacancies in Zr2C(x): the formation of ordered Zr2C(x)O(y). AB - Investigations are performed on low-temperature oxygen diffusion in the carbon vacancy ordered ZrC(0.6)and thus induced formation of the oxygen atom ordered ZrC(0.6)O(0.4). Theoretically, a superstructure of Zr(2)CO can be constructed via the complete substitution of carbon vacancies with O atoms in the Zr(2)C model. In the ordered ZrC(0.6), the consecutive arrangement of vacancies forms the vacancy channels along some zone axes in the C sublattice. Through these vacancy channels, the thermally activated oxygen diffusion is significantly facilitated. The oxygen atoms diffuse directly into and occupy the vacancies, producing the ordered ZrC(0.6)O(0.4). Relative to the ordered ZrC(0.6), the Zr positions are finely tuned in the ordered ZrC(0.6)O(0.4) because of the ionic Zr-O bonds. Because of this fine adjustment of Zr positions and the presence of oxygen atoms, the superstructural reflections are always observable in a selected area electron diffraction (SAED) pattern, despite the invisibility of superstructural reflections in ZrC(0.6) along some special zone axes. Similar to the vacancies in ordered ZrC(0.6), the ordering arrangement of O atoms in the ordered ZrC(0.6)O(0.4) is in nanoscale length, thus forming the nano superstructural domains with irregular shapes. PMID- 22486214 TI - Urinary platelet-derived growth factor-BB as an early marker of nephropathy in patients with type 2 diabetes: an Egyptian study. AB - BACKGROUND: Diabetic nephropathy (DN) is one of the most serious complications of diabetes worldwide. Strong evidence suggests that several growth factors may contribute to the initiation and progressive fibrosis of DN. Recently, there is an overexpression of platelet-derived growth factor (PDGF) in renal biopsies from patients with DN. This study aimed to investigate the clinical significance of urinary PDGF-BB level in type 2 diabetic patients with and without nephropathy and to evaluate its relationship with various clinical and laboratory parameters. METHODS: Urinary levels of PDGF-BB were measured in 60 Egyptian type 2 diabetic patients categorized into three equal groups (normo-, micro-, and macroalbuminuria), according to urinary albumin level. In addition, 20 healthy subjects were selected to serve as controls. RESULTS: The urinary PDGF-BB levels were significantly increased in type 2 diabetic patients as compared to controls (p < 0.001). Moreover, diabetics with micro- and macroalbuminuria had significantly higher levels than in those with normoalbuminuria (p < 0.001). Urinary PDGF-BB correlated positively with disease duration, low-density lipoprotein (LDL)-cholesterol, and urinary albumin and negatively with creatinine clearance in diabetic patients. In a multiple regression model, urinary PDGF-BB was strongly and independently associated with nephropathy in diabetic patients (beta = -0.03, p < 0.001). CONCLUSIONS: PDGF-BB may play an important role in the initiation and progression of DN. It is considered as a good predictor for early deterioration of renal function in DN. Thus, measurement of urinary PDGF-BB in type 2 diabetic patients could be used for early detection of diabetic renal disease. PMID- 22486215 TI - Ganglionated plexi ablation directed by high-frequency stimulation and complex fractionated atrial electrograms for paroxysmal atrial fibrillation. AB - BACKGROUND: The effectiveness of ganglionated plexi (GP) ablation in patients with atrial fibrillation (AF) is ambiguous. Some researchers had already suggested that additional identification of complex fractionated atrial electrograms (CFAE) around the areas with a positive reaction to high-frequency stimulation (HFS) might improve the accuracy of GP's boundaries location, then enhancing the success rate of ablation. The purpose of this study was to assess the safety and efficacy of GP ablation directed by HFS and CFAE in patients with paroxysmal AF (PAF). METHODS AND RESULTS: Sixty-two patients with PAF (age 57+/-8 years) underwent GP ablation. Ablation targets were the sites where vagal reflexes were evoked by HFS and additional extended ablation CFAE area around the areas where vagal reflexes were evoked. At 12 months, 71% of patients were free of symptomatic AF. At 3 months after ablation the root mean square successive differences and HF were significantly lower in patients without AF recurrence (P < 0.0001 and P = 0.004). The LF/HF ratio was significantly higher in patients without AF recurrence (P = 0.02). CONCLUSION: Enhanced GP ablation directed by HFS and CFAE can be safely performed and enables maintenance of sinus rhythm in the majority of patients with PAF for a 12-month period. Denervation of the intrinsic cardiac autonomic nervous system may be the preferable target of catheter ablation of AF. PMID- 22486216 TI - 15th International Headache Congress: basic science highlights. AB - The 15th Congress of the International Headache Society was held in Berlin from June 23rd to 26th of 2011. Interesting new data from several areas of the basic sciences of headache were presented. This is a review of some of the most exciting platform and poster presentations of the meeting. Research addressing 3 general areas of interest is presented in this review: pathophysiology, pharmacology, and genetics. PMID- 22486219 TI - Efficient alkyl ether synthesis via palladium-catalyzed, picolinamide-directed alkoxylation of unactivated C(sp3)-H and C(sp2)-H bonds at remote positions. AB - We report the efficient synthesis of alkyl ethers by the functionalization of unactivated sp(3)- and sp(2)-hybridized C-H bonds. In the Pd(OAc)(2)-catalyzed, PhI(OAc)(2)-mediated reaction system, picolinamide-protected amine substrates undergo facile alkoxylation at the gamma or delta positions with a range of alcohols, including t-BuOH, to give alkoxylated products. This method features a relatively broad substrate scope for amines and alcohols, inexpensive reagents, and convenient operating conditions. This method highlights the emerging value of unactivated C-H bonds, particularly the C(sp(3))-H bond of methyl groups, as functional groups in organic synthesis. PMID- 22486217 TI - Dopaminochrome induces caspase-independent apoptosis in the mesencephalic cell line, MN9D. AB - Parkinson's disease is characterized by a deficiency in motor cortex modulation due to degeneration of pigmented dopaminergic neurons of the substantia nigra projecting to the striatum. These neurons are particularly susceptible to oxidative stress, perhaps because of their dopaminergic nature. Like all catecholamines, dopamine is easily oxidized, first to a quinone intermediate and then to dopaminochrome (DAC), a 5-dihydroxyindole tautomer, that is cytotoxic in an oxidative stress-dependent manner. Here we show, using the murine mesencephalic cell line MN9D, that DAC causes cell death by apoptosis, illustrated by membrane blebbing, Annexin V, and propidium iodide labeling within 3 h. In addition, DAC causes oxidative damage to DNA within 3 h, and positive terminal deoxynucleotidyl transferase dUTP nick end labeling fluorescence by 24 h. DAC, however, does not induce caspase 3 activation and its cytotoxic actions are not prevented by the pan-caspase inhibitor, Z-VAD-fmk. DAC-induced cytotoxicity is limited by the PARP1 inhibitor, 5-aminoisoquinolinone, supporting a role for apoptosis-inducing factor (AIF) in the apoptotic process. Indeed, AIF is detected in the nuclear fraction of MN9D cells 3 h after DAC exposure. Taken together these results demonstrate that DAC induces cytotoxicity in MN9D cells in a caspase-independent apoptotic manner, likely triggered by oxidative damage to DNA, and involving the translocation of AIF from the mitochondria to the nucleus. PMID- 22486220 TI - A retrospective population-based data analyses of unintentional fall mortality and hospitalisation in Taiwan during 2005-2007. AB - The objective of this study is to describe the epidemiology of unintentional fall mortality and hospitalisation and to find the risk factors associated with inpatient mortality. We analysed mortality data from official publications which record the vital statistics and hospitalisation data from National Health Insurance (NHI) Research Database from 2005 to 2007 and fall injuries were classified in accordance with ICD-9-CM E-Codes, including 'falls on the same level (E885-E886)', 'falls on a different level (E880-E884)' and 'unspecified falls (E887-E888)'. We used SPSS 18.0 software. During 2005-2007 in Taiwan, there were 3555 deaths and 180,175 inpatients due to unintentional falls and the mortality rate was 5.19 per 100,000 and the hospitalisation rate was 236.14 per 100,000. With regards to deaths, different-level falls were the primary cause, and those aged 25 or more were high-risk groups; with regards to hospitalisation, same-level falls were the primary cause, and those aged 65 or more were the high risk group. Associated factors for inpatient mortality can be classified by patient characteristics (older age, catastrophic illness, higher Charlson Comorbidity Index (CCI) and head trauma) and hospital-related factors (geographic area, type of hospital, level of hospital and department of care). The high-risk groups were different between 'same-level' and 'different-level' falls and the findings of this study will be beneficial for concerned authorities to draft up appropriate prevention plans in the future. Moreover, future researchers can further explore different risk factors for injuries using questionnaire surveys or hospital emergency room data. PMID- 22486221 TI - Protein kinase B promotes radiation-induced regulatory T cell survival in bladder carcinoma. AB - Radiotherapy is an efficient remedy in the treatment for bladder carcinoma (BCa); still, some cancer cells can survive from the radiation; the therapeutic effect is to be improved. Regulatory T cell (Treg)-induced tumour tolerance and Akt expression play important roles in the tumour survival. This study aims to elucidate the role of radiation induces Akt expression in regulatory T cells (Tregs). The surgically removed BCa tissue was collected from 26 patients treated with or without radiotherapy. The frequency of Tregs and apoptotic Tregs in BCa tissue was assessed by flow cytometry. A cell culture model was employed to investigate the mechanism by which the tumour-infiltrating Tregs survive from radiation. After radiotherapy, the frequency of Treg was increased in the BCa tissue; the apoptotic Tregs were decreased; the expression of Akt was increased in remained Tregs. The results were reproduced in vitro with a cell culture model. The addition of Akt inhibitor blocked the radiation-induced Treg survival in culture. Akt plays an important role in the radiation-induced tumour infiltrating Treg survival in BCa. PMID- 22486222 TI - The curette prep: a modification of the traditional scabies preparation. AB - An accurate diagnosis of scabies is critical for proper treatment of this common infestation. In our clinic, we have developed a modification of the traditional method of performing a scabies preparation, called the curette prep, that substitutes a disposable curette for a scalpel blade when obtaining skin scrapings for examination. The major advantages of this technique are greater acceptability and safety for pediatric patients. PMID- 22486223 TI - Adolescence and parental history of alcoholism: insights from the sleep EEG. AB - BACKGROUND: Disrupted sleep is a common complaint of individuals with alcohol use disorder and in abstinent alcoholics. Furthermore, among recovering alcoholics, poor sleep predicts relapse to drinking. Whether disrupted sleep in these populations results from prolonged alcohol use or precedes the onset of drinking is not known. The aim of this study was to examine the sleep electroencephalogram (EEG) in alcohol-naive, parental history positive (PH+), and negative (PH-) boys and girls. METHODS: All-night sleep EEG recordings in 2 longitudinal cohorts (child and teen) followed at 1.5 to 3 year intervals were analyzed. The child and teen participants were 9/10 and 15/16 years old at the initial assessment, respectively. Parental history status was classified by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria applied to structured interviews (DIS-IV) resulting in 14 PH- and 10 PH+ children and 14 PH- and 10 PH+ teens. Sleep data were visually scored in 30-second epochs using standard criteria. Power spectra were calculated for EEG derivations C3/A2, C4/A1, O2/A1, O1/A2 for nonrapid eye movement (NREM) and rapid eye movement (REM) sleep. RESULTS: We found no difference between PH+ and PH- individuals in either cohort for any visually scored sleep stage variable. Spectral power declined in both cohorts across assessments for NREM and REM sleep in all derivations and across frequencies independent of parental history status. With regard to parental history, NREM sleep EEG power was lower for the delta band in PH+ teens at both assessments for the central derivations. Furthermore, power in the sigma band for the right occipital derivation in both NREM and REM sleep was lower in PH+ children only at the initial assessment. CONCLUSIONS: We found no gross signs of sleep disruption as a function of parental history. Modest differences in spectral EEG power between PH+ and PH- children and teens indicate that a marker of parental alcohol history may be detectable in teens at risk for problem drinking. PMID- 22486224 TI - Synthesis and pairing properties of oligodeoxynucleotides containing bicyclo-RNA and bicyclo-ANA modifications. AB - The synthesis of the ribo(bc-rT)- and arabino(bc-araT)-version of bicyclothymidine (bc-dT) has been achieved. A conformational analysis by X-ray and/or (1)H NMR spectroscopy on the corresponding 3',5'-benzyl-protected nucleosides featured a rigid C(2')-endo conformation for the furanose ring, irrespective of the configuration of the OH group at C(2'). The conformation of the carbocyclic ring in these nucleosides was found to be less defined and thus more flexible. Both nucleosides were converted into the corresponding phosphoramidites and incorporated into oligodeoxynucleotides by standard DNA chemistry. T(m)-data of duplexes with cDNA and RNA revealed that a bc-rT unit strongly destabilized duplexes with cDNA and RNA by 6-8 degrees C/mod, while bc araT was almost T(m) neutral. A rationale based on a previous structure of a bc DNA mini duplex suggests that the strong destabilization caused by a bc-rT unit arises from unfavorable steric interactions of the equatorial 2'-OH group with the sugar residue of the 3'-neighboring nucleotide unit. PMID- 22486225 TI - Monitoring of total type ii pyrethroid pesticides in citrus oils and water by converting to a common product 3-phenoxybenzoic acid. AB - Pyrethroids are a class of insecticides that are becoming increasingly popular in agricultural and home use applications. Sensitive assays for pyrethroid insecticides in complex matrices are difficult with both instrumental and immunochemical methods. Environmental analysis of the pyrethroids by immunoassay requires either knowing which pyrethroids contaminate the source or the use of nonspecific antibodies with cross-reactivities to a class of compounds. We describe an alternative method that converts the type II pyrethroids to a common chemical product, 3-phenoxybenzoic acid (3-PBA), prior to analysis. This method is much more sensitive than detecting the parent compound, and it is much easier to detect a single compound rather than an entire class of compounds. This is useful in screening for pyrethroids as a class or in situations where a single type of pyrethroid is used. We demonstrated this technique in both citrus oils and environmental water samples with conversion rates of the pyrethroid to 3-PBA that range from 45 to 75% and methods that require no extraction steps for either the immunoassay or the liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques. Limits of detection for this technique applied to orange oil are 5 nM, 2 MUM, and 0.8 MUM when detected by LC-MS/MS, gas chromatography-mass spectrometry, and immunoassay, respectively. The limit of detection for pyrethroids in water when detected by immunoassay was 2 nM. PMID- 22486226 TI - Adding pharmacists to primary care teams reduces predicted long-term risk of cardiovascular events in type 2 diabetic patients without established cardiovascular disease: results from a randomized trial. AB - AIM: To determine the impact of adding pharmacists to primary care teams on predicted 10-year risk of cardiovascular events in patients with Type 2 diabetes without established cardiovascular disease. METHODS: This was a pre-specified secondary analysis of randomized trial data. The main study found that, compared with usual care, addition of a pharmacist resulted in improvements in blood pressure, dyslipidaemia, and hyperglycaemia for primary care patients with Type 2 diabetes. In this sub-study, predicted 10-year risk of cardiovascular events at baseline and 1 year were calculated for patients free of cardiovascular disease at enrolment. The primary outcome was change in UK Prospective Diabetes Study (UKPDS) risk score; change in Framingham risk score was a secondary outcome. RESULTS: Baseline characteristics were similar between the 102 intervention patients and 93 control subjects: 59% women, median (interquartile range) age 57 (50-64) years, diabetes duration 3 (1-6.5) years, systolic blood pressure 128 (120-140) mmHg, total cholesterol 4.34 (3.75-5.04) mmol/l and HbA(1c) 54 mmol/mol (48-64 mmol/mol) [7.1% (6.5-8.0%)]. Median baseline UKPDS risk score was 10.2% (6.0-16.7%) for intervention patients and 9.5% (5.8-15.1%) for control subjects (P = 0.80). One-year post-randomization, the median absolute reduction in UKPDS risk score was 1.0% greater for intervention patients compared with control subjects (P = 0.032). Similar changes were seen with the Framingham risk score (median reduction 1.2% greater for intervention patients compared with control subjects, P = 0.048). The two risk scores were highly correlated (rho = 0.83; P < 0.001). CONCLUSION: Adding pharmacists to primary care teams for 1 year significantly reduced the predicted 10-year risk of cardiovascular events for patients with Type 2 diabetes without established cardiovascular disease. PMID- 22486227 TI - Respecting autonomy without disclosing information. AB - There is widespread agreement that it would be both morally and legally wrong to treat a competent patient, or to carry out research with a competent participant, without the voluntary consent of that patient or research participant. Furthermore, in medical ethics it is generally taken that that consent must be informed. The most widely given reason for this has been that informed consent is needed to respect the patient's or research participant's autonomy. In this article I set out to challenge this claim by considering in detail each of the three most prominent ways in which 'autonomy' has been conceptualized in the medical ethics literature. I will argue that whilst these accounts support the claim that consent is needed if the treatment of competent patients, or research on competent individuals, is to respect their autonomy, they do not support the claim that informed consent is needed for this purpose. PMID- 22486228 TI - Neoplastic spindle cells in nasopharyngeal carcinoma show features of epithelial mesenchymal transition. AB - AIM: To investigate whether the neoplastic spindle cells in nasopharyngeal carcinoma (NPC) are associated with the process of epithelial-mesenchymal transition (EMT). METHODS AND RESULTS: We used immunohistochemistry to analyse the expression of cytokeratin, E-cadherin, beta-catenin, vimentin, fibronectin, Snail1, Slug and aldehyde dehydrogenase 1 (ALDH1) in 115 cases of NPC in which there were neoplastic spindle cells; in 47 cases a neoplastic squamous cell component was also present. There was no significant difference in the expression of cytokeratin observed in the neoplastic spindle cells (P = 0.644), compared to the squamous component whereas E-cadherin expression was reduced. By contrast, the expression of beta-catenin, vimentin, fibronectin, Snail1, Slug and ALDH1 was up-regulated in the spindle cells (all P = 0.000). Furthermore, E-cadherin expression was associated negatively with beta-catenin (P < 0.001), vimentin (P < 0.001), fibronectin (P < 0.001), Slug (P < 0.001) and ALDH1 (P < 0.001) in neoplastic spindle cells, but did not correlate with Snail1 expression (P = 0.093). CONCLUSIONS: Our findings demonstrate for the first time that EMT might play an important role in the development of neoplastic spindle cells in NPC. PMID- 22486229 TI - Anastomotic stricture after minimally invasive radical prostatectomy: what should be expected from the Van Velthoven single-knot running suture? AB - BACKGROUND AND PURPOSE: Patients with localized prostate cancer (PCa) who are treated by radical prostatectomy (RP) have a good overall survival rate. Their quality of life, however, can deteriorate because of the incidence of bladder neck contracture (BNC). Our aim was to evaluate the incidence and the risk factors of BNC after minimally invasive radical prostatectomy (MIRP) with a single-knot running suture also known as the Van Velthoven technique (VVT). PATIENTS AND METHODS: From 2003 to 2010, 2115 patients underwent extraperitoneal, transperitoneal, or robot-assisted RP for localized PCa. A single-knot running suture according to the VVT was performed for the vesicourethral anastomosis. Follow-up was scheduled and standardized for all patients and recorded into a prospective database. BNC was defined by a reduction of the lumen that does not allow the passage of an 18F fibroscope. RESULTS: Mean follow-up of the patients was 43 (6-144) months. Of all, 1342, 241, and 532 had extraperitoneal, transperitoneal, and robot-assisted prostatectomy, respectively. BNC was diagnosed in 30 (1.4%) patients. Among them, 78% had the diagnosis within the first year of follow-up. Previous transurethral resection of the prostate (TURP) and external beam radiotherapy were independent risk factors of BNC. CONCLUSIONS: BNC incidence after MIRP using the single-knot running suture for the vesicourethral anastomosis is low. Previous TURP and external beam radiotherapy are identified as risk factors. This technique showed satisfying results regardless of the classic laparoscopic or robot-assisted approach. PMID- 22486230 TI - Effect of pH on protein distribution in electrospun PVA/BSA composite nanofibers. AB - We examine the protein distribution within an electrospun polymer nanofiber using polyvinyl alcohol and bovine serum albumin as a model system. We hypothesize that the location of the protein within the nanofiber can be controlled by carefully selecting the pH and the applied polarity of the electric field as the pH affects the net charge on the proteins. Using fluorescently labeled BSA and surface analysis, we observe that the distribution of BSA is affected by the pH of the electrospinning solution. Therefore, we further probe the relevant forces on the protein in solution during electrospinning. The role of hydrodynamic friction was assessed using glutaraldehyde and HCl as a tool to modify the viscosity of the solution during electrospinning. By varying the pH and the polarity of the applied electric field, we evaluated the effects of electrostatic forces and dielectrophoresis on the protein during fiber formation. We surmise that electrostatic forces and hydrodynamic friction are insignificant relative to dielectrophoretic forces; therefore, it is possible to separate species in a blend using polarizability contrast. A coaxial distribution of protein in the core can be obtained by electrospinning at the isoelectric point of the protein, whereas surface enrichment can be obtained when the protein carries a net charge. PMID- 22486231 TI - Avoiding surgical errors by referencing anatomical landmarks. PMID- 22486233 TI - Structure and dynamics of dodecaborate clusters in water. AB - We have studied using molecular dynamics simulations the interaction of the dodecaborate anion, B(12)H(12)(2-), and its amino, trimethyl, and triethyl derivatives with water molecules. We found peculiar organization of the water molecules in the first solvation shell with the formation of a dihydrogen bond between the hydrogen atoms of the anions and the hydrogen atoms of the water molecules. The simulations also show that the organization of the hydration shell is strongly influenced by the substituents in the anions. These differences are likely to play an important role in understanding the interaction of the anions with biological systems like membranes and proteins in aqueous environments. PMID- 22486232 TI - Protective effects of N-acetylcysteine amide (NACA) on gentamicin-induced apoptosis in LLC-PK1 cells. AB - AIM: Apoptosis plays a critical role in the pathogenesis of gentamicin (Gen) induced nephrotoxicity. However, the underlying molecular mechanisms still remain unclear. In this study, we addressed the role of p38 mitogen-activated protein kinase (MAPK)/inducible nitric oxide synthase (iNOS) signaling pathway in Gen induced nephrotoxicity and evaluated the protective effect of the free-radical scavenger N-acetylcysteine amide (NACA). METHODS: Pig kidney epithelial cells (LLC-PK1) cells were exposed to Gen for variable times and doses. Cytotoxicity was assessed by morphology and by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Protein expression was assessed by Western blotting. RESULTS: Exposure to Gen-induced apoptosis in a dose-dependent and time dependent manner was assessed by DNA content analysis and poly ADP ribose polymerase (PARP) cleavage. Gen caused increased phosphorylation of p38 MAPK and induction of iNOS. This was accompanied by a significant upregulation of Bax and nuclear factor kappaB (NF-kappaB) and a downregulation of Bcl-2 expression. Pretreatment with SB203580, aminoguanidine (AG), and NACA inhibited apoptosis. Furthermore, pretreatment with SB203580 and NACA not only attenuated the pro apoptotic effect of Gen, but also significantly reversed its effects on p38 MAPK phosphorylation and iNOS induction. The Gen-induced effects on Bcl-2, Bax, and NF kappaB expression were also reversed by SB203580, AG, and NACA. CONCLUSION: In conclusion, NACA can attenuate Gen-induced apoptotic injury in LLC-PK1 cells through inhibiting p38 MAPK/iNOS signaling pathway. PMID- 22486234 TI - Elemental determination of microsamples by liquid film dielectric barrier discharge atomic emission spectrometry. AB - In this study, a new liquid-film dielectric barrier discharge (LFDBD) atomic emission source was developed for microsample elemental determination. It consists of a copper electrode, a tungsten wire electrode, and a piece of glass slide between them, which serves as the dielectric barrier as well as the sample plate. The sample solution with 1 mol L(-1) nitric acid, when deposited onto the surface of the glass slide, forms a thin liquid film. The plasma is generated between the tip of the tungsten wire electrode and the liquid film surface when alternating-current (ac) high voltage (peak voltage ~3.7 kV, frequency ~30 kHz) is applied on the electrodes. Qualitative and quantitative determinations of metal ions in the sample solution were achieved by atomic emission measurements in the plasma and were demonstrated in this study with elements Na, K, Cu, Zn, and Cd. Detection limits were in the range from 0.6 ng (7 MUg L(-1)) for Na to 6 ng (79 MUg L(-1)) for Zn. Repeatability, expressed as relative standard deviation from seven repetitive analyses of samples with analyte concentrations at 1 mg L( 1), varied from 2.1% to 4.4%. Compared with other liquid discharge systems that operate at atmospheric pressure, the current system offers several advantages: First, it eliminates the use of a sample flow system (e.g., syringe or peristaltic pump); instead, a small aliquot of sample is directly pipetted onto the glass slide for analysis. Second, it is a microanalysis system and requires sample volume <=80 MUL, a benefit when a limited amount of sample is available. Third, because the sample is applied in aliquot, there is no washout time, and the analysis can be easily extended to sample array for high-throughput analysis. The proposed LFDBD is promising for in-field elemental determination because of its simplicity, cost effectiveness, low power supply, and no inert gas requirement. PMID- 22486235 TI - Buruli ulcer and current situation in Japan: a new emerging cutaneous Mycobacterium infection. AB - Buruli ulcer (BU) is a new emerging disease and the third most common chronic mycobacterial infection in humans, caused by Mycobacterium ulcerans. Approximately 5000 cases are reported annually from at least 33 countries around the globe, but more from the tropical nations. A total of 32 cases have been reported from Japan sporadically since 1980. None of the cases were related to international travel. Of the total reported, M. ulcerans ssp. shinshuense, a subspecies speculated to be domestic to Japan or in Asia, has been isolated from 23 cases. The mode of transmission and its incubation period remain unclear, despite several proposed hypotheses, including several vectors and cutaneous wound as port of entry for the pathogen. M. ulcerans invades the skin, subcutaneous tissue, fascia and eventually forms extensive ulceration. Smear, culture, histopathology and polymerase chain reaction are established diagnostic tools to identify M. ulcerans. Multiple antimicrobial therapy is a commonly used therapeutic method, but patients often need extensive debridement and, at times, skin grafting, especially when diagnosis is delayed. Thus, expanding a system for improved awareness and diagnosis in Japan and Asia is important, together with elucidating the candidate vector and the mode of transmission. Here, to establish a base for future progress in better understanding of this infectious disease, we reviewed the characteristics of the disease together with an update of reported cases in Japan. PMID- 22486236 TI - Annual scientific meeting--American Headache Society Washington 2011--highlights. AB - The 53rd Annual Scientific Meeting of the American Headache Society was held in Washington from June 2 to 5, 2011. Important clinical and basic science information was presented at this meeting. This is a review of the highlights of that meeting dealing in many areas of headache medicine. Once again, this meeting, which is the premier scientific meeting of the American Headache Society, provided lots of new and exciting information about multiple facets of migraine headache and other disorders. PMID- 22486237 TI - How to avoid development of AV block during RF ablation: anatomical and electrophysiological analyses at the time of AV node ablation. AB - BACKGROUND: With an aim to identify risk factors that can serve for prevention of atrioventricular (AV) block (AVB) during radiofrequency (RF) ablation, we conducted anatomical and electrophysiological investigations at the time of AV node ablation (AVNA). METHODS AND RESULTS: Ten patients who underwent AVNA were enrolled. RF energy was delivered from posterior region of septal annulus of the tricuspid valve to the His bundle potential (HBP) recording site using a stepwise approach. In each delivery, atrial/ventricle potential amplitude ratio (A/V ratio), HBP, and juctional ectopy (JE) that appeared during RF delivery were evaluated. Furthermore, fluoroscopic distance between ablation site and HBP recording site (anatomical H-ABL distance) and electrophysiological H-ABL interval were measured. HBP was recorded in 25 of total 70 RF deliveries. When HBP was recorded, the A/V ratio was significantly greater in the group with AVB than without AVB (1.6 +/- 2.3 mV vs 0.1 +/- 0.2 mV, P = 0.02). The minimum cycle length (CL) of JE was significantly shorter in the group with AVB than without AVB (438 +/- 112 ms vs 557 +/- 178, ms, P = 0.04). AVB developed frequently when H-ABL distance was less than 15 mm from right anterior oblique view 30 degrees and 12 mm from left anterior oblique view 45 degrees and when H-ABL interval was less than 10 ms. AVB did not develop over the above values. CONCLUSIONS: HBP with high A/V ratio, JE with short CL, short H-ABL distance, and short H-ABL interval of less than 10 ms should be avoided to prevent AVB during RF ablation at the near site of AV node. PMID- 22486238 TI - A case of pemphigus herpetiformis occurring in a 9-year-old boy. AB - Pemphigus herpetiformis (PH) is a rare autoimmune vesiculobullous disease. It clinically mimics dermatitis herpetiformis and has immunofluorescent findings typical of pemphigus. PH occurs in adults more commonly than children and is often effectively treated with dapsone. We report a case of PH occurring in a 9 year-old boy that was refractory to dapsone and to various other steroid-sparing medications but resolved with methotrexate. PMID- 22486239 TI - Structural correlations in heterogeneous electron transfer at monolayer and multilayer graphene electrodes. AB - As a new form of carbon, graphene is attracting intense interest as an electrode material with widespread applications. In the present study, the heterogeneous electron transfer (ET) activity of graphene is investigated using scanning electrochemical cell microscopy (SECCM), which allows electrochemical currents to be mapped at high spatial resolution across a surface for correlation with the corresponding structure and properties of the graphene surface. We establish that the rate of heterogeneous ET at graphene increases systematically with the number of graphene layers, and show that the stacking in multilayers also has a subtle influence on ET kinetics. PMID- 22486240 TI - Rat sperm immobilisation effects of a protein from Ricinus communis (Linn.): an in vitro comparative study with nonoxynol-9. AB - Previous study conducted in our department showed that 50% ethanolic extract of the root of Ricinus communis possess reversible antifertility effect and a 62-kDa protein (Rp) from this extract is responsible for the antifertility effects. In this study, we compared the spermicidal effect of this Rp with nonoxynol-9 (N-9) in vitro. The sperm immobilisation studies showed that 100 MUg ml(-1) of Rp was able to immobilise the sperms completely within 30 s. Sperm revival test revealed that the spermicidal effect was irreversible. There was also a significant reduction in sperm viability and hypo-osmotic swelling in Rp and N-9 treated groups in comparison with the control. In Rp and N-9 treated groups, the number of acrosome-reacted cells was found to be high and also caused agglutination of the spermatozoa, indicating the loss of intactness of the plasma membrane, which was further supported by the significant reduction in the activity of membrane bound 5'-nucleotidase, acrosomal acrosin. In short, the protein Rp possesses spermicidal activity in vitro and its effects are similar to that of nonoxynol 9. PMID- 22486241 TI - Stress distribution in implant-supported prosthesis with external and internal implant-abutment connections. AB - OBJECTIVE: This study aimed to investigate the stress distribution in screwed implant-supported prostheses with different implant-abutment connections by using a photoelastic analysis. MATERIALS AND METHODS: Four photoelastic models were fabricated in PL-2 resin and divided according to the implant-abutment connection (external hexagon (EH) and Morse taper (MT) implants (3.75 * 11.5 mm)) and the number crowns (single and 3-unit piece). Models were positioned in a circular polariscope and 100-N axial and oblique (45) loading were applied in the occlusal surface of the crowns by using a universal testing machine. The stresses were photographically recorded and qualitatively analyzed using software (Adobe Photoshop). RESULTS: Under axial loading, the MT implants exhibited a lower number of fringes for single-unit crowns than EH implants, whereas for a 3-unit piece the MT implants showed a higher number of fringes vs EH implants. The oblique loading increased the number of fringes for all groups. CONCLUSION: In conclusion, the MT implant-abutment connection reduced the amount of stress in single-unit crowns, for 3-unit piece crowns the amount of stress was lower using an external hexagon connection. The stress pattern was similar for all groups. Oblique loading promoted a higher stress concentration than axial loading. PMID- 22486242 TI - Growth and differentiation factors for periodontal regeneration: a review on factors with clinical testing. AB - BACKGROUND AND OBJECTIVE: A large body of evidence implies that growth and differentiation factors, based on their ability to regulate various functions of cells originating in the periodontal tissues, may support periodontal wound healing/regeneration, creating an environment conducive to and/or immediately inducing de novo tissue formation. This study presents a short systematic overview on growth and differentiation factor technologies evaluated in the clinic for their potential to enhance periodontal wound healing/regeneration. MATERIAL AND METHODS: Reports on growth and differentiation factor technologies evaluated in the clinic for their potential to enhance periodontal wound healing/regeneration were selected for review. RESULTS: Growth and differentiation factor technologies intended for periodontal wound healing/regeneration and evaluated clinically included platelet-derived growth factor, insulin-like growth factor-I and -II, basic fibroblast growth factor, bone morphogenetic protein-3 and growth differentiation factor-5; platelet derived growth factor was the only Food and Drug Administration-approved commercially available growth and differentiation factor technology. In general, enhanced periodontal regeneration was observed in sites receiving growth and differentiation factors compared with control(s). However, improvements of relatively limited clinical magnitude have been shown thus far. CONCLUSION: Although growth and differentiation factors project considerable appeal as candidate technologies in support of periodontal wound healing/regeneration, current candidate and commercially available technologies enhance treatment outcomes only to a limited extent in clinical settings. PMID- 22486243 TI - Concordance facilitates access in diabetes care--service provider perspectives of service improvement and cultural competency. AB - AIMS: Inequalities between different ethnic groups in diabetes care and outcomes are well documented in the UK. This research sought to explore and understand how national and local policy interventions impacted upon access and the development of culturally competent diabetes services from the care provider perspective. METHODS: This paper describes the care provider perspective of access to diabetes care in ethnically mixed populations from a thematic analysis of 14 semi structured interviews conducted with professionals, at three study sites, with different roles in the diabetes care pathway. RESULTS: National policy level initiatives to improve quality have led to quality improvements at a practical level. These achievements, however, have been unable to address all aspects of care that service providers identified as important in facilitating access for all patient groups. Concordance emerged as a key process in improving access to care within local systems and barriers to this exist at different levels and are greater for some groups of patients compared with others. CONCLUSIONS: Concordance is a key concept that underpins access and cultural competency in diabetes service improvement. A focus on concordance at different levels within local systems may improve access to quality diabetes care for ethnic minority groups. PMID- 22486244 TI - AAVrh.10-mediated expression of an anti-cocaine antibody mediates persistent passive immunization that suppresses cocaine-induced behavior. AB - Cocaine addiction is a major problem affecting all societal and economic classes for which there is no effective therapy. We hypothesized an effective anti cocaine vaccine could be developed by using an adeno-associated virus (AAV) gene transfer vector as the delivery vehicle to persistently express an anti-cocaine monoclonal antibody in vivo, which would sequester cocaine in the blood, preventing access to cognate receptors in the brain. To accomplish this, we constructed AAVrh.10antiCoc.Mab, an AAVrh.10 gene transfer vector expressing the heavy and light chains of the high affinity anti-cocaine monoclonal antibody GNC92H2. Intravenous administration of AAVrh.10antiCoc.Mab to mice mediated high, persistent serum levels of high-affinity, cocaine-specific antibodies that sequestered intravenously administered cocaine in the blood. With repeated intravenous cocaine challenge, naive mice exhibited hyperactivity, while the AAVrh.10antiCoc.Mab-vaccinated mice were completely resistant to the cocaine. These observations demonstrate a novel strategy for cocaine addiction by requiring only a single administration of an AAV vector mediating persistent, systemic anti-cocaine passive immunity. PMID- 22486247 TI - Empowering sibship analyses with reference pedigrees. AB - BACKGROUND: In sibship analysis, the usual comparison of an alleged (test) sibling's short tandem repeat (STR) types with those of a reference sibling may prove inconclusive. Increasing the number of examined STR loci may not change sibship probabilities very much. We increased the number of verified reference siblings to resolve problematic cases of alleged sibship. STUDY DESIGN AND METHODS: (A) Ten paternity cases were chosen in which there were three highly probable children of each alleged father. Pairs of the alleged father's children were analyzed for full sibship. The test sib with the lowest likelihood of sibship was reanalyzed by a comparison with two reference siblings combined. (B) Five problematic sibship cases are presented to demonstrate how two-person reference pedigrees can improve diagnosis over tests using one reference person. RESULTS: (A) Two-person pedigrees exponentially increased sibship probabilities of true siblings above those produced by one reference person. (B) In problem cases, reference pedigrees provided data that: (1) statistically verified some alleged sibships in which analyses using one reference person yielded inconclusive results, (2) allowed exclusion of some alleged sibships, or (3) suggested alternate blood relationships to the alleged one. CONCLUSIONS: Use of reference pedigrees often resolves sibship questions left unsettled by tests using reference individuals. Adding reference relatives is a far more powerful analytical strategy than adding test loci. Whenever possible, verified blood relatives should be incorporated into a reference pedigree to retest an alleged sibling whose initial results were unclear. PMID- 22486248 TI - Solid-phase synthesis of asymmetrically branched sequence-defined poly/oligo(amidoamines). AB - We present for the first time the synthesis of asymmetrically branched sequence defined poly/oligo(amidoamines) (PAAs) using solid-phase synthesis with the capability of introducing diversity at the side chains. We introduce two new versatile (diethylenetriamine) building blocks for solid-phase synthesis bearing Fmoc/Boc and Fmoc/Alloc protecting groups expanding recently used Fmoc/Boc protecting group strategy for linear PAAs to an Fmoc/Alloc/Boc strategy. This allows for orthogonal on-resin cleavage of Fmoc and Alloc protecting groups during solid-phase synthesis of PAAs with backbones differing in chain length and sequence. With these structures we then demonstrate the potential for generating asymmetrical branching by automated multiple on-resin cleavage of Alloc protecting groups as well as the introduction of side chains varying in length and number. Such systems have high potential as nonviral vectors for gene delivery and will allow for more detailed studies on the correlation between the degree of branching of PAAs and their resulting biological properties. PMID- 22486245 TI - Comparison of the effect of the GABABeta receptor agonist, baclofen, and the positive allosteric modulator of the GABAB receptor, GS39783, on alcohol self administration in 3 different lines of alcohol-preferring rats. AB - BACKGROUND: Administration of the GABA(B) receptor agonist, baclofen, and positive allosteric modulator, GS39783, has been repeatedly reported to suppress multiple alcohol-related behaviors, including operant oral alcohol self administration, in rats. This study was designed to compare the effect of baclofen and GS39783 on alcohol self-administration in 3 lines of selectively bred, alcohol-preferring rats: Indiana alcohol-preferring (P), Sardinian alcohol preferring (sP), and Alko Alcohol (AA). METHODS: Rats of each line were initially trained to respond on a lever, on a fixed ratio (FR) 4 (FR4) schedule of reinforcement, to orally self-administer alcohol (15%, v/v) in daily 30-minute sessions. Once responding reached stable levels, rats were exposed to a sequence of experiments testing baclofen (0, 1, 1.7, and 3 mg/kg; i.p.) and GS39783 (0, 25, 50, and 100 mg/kg; i.g.) on FR4 and progressive ratio (PR) schedules of reinforcement. Finally, to assess the specificity of baclofen and GS39783 action, rats were slightly food-deprived and trained to lever-respond for food pellets. RESULTS: The rank of order of the reinforcing and motivational properties of alcohol was P>sP>AA rats. Under both FR and PR schedules of reinforcement, the rank of order of potency and efficacy of baclofen and GS39783 in suppressing alcohol self-administration was P>sP>AA rats. Only the highest dose of baclofen reduced lever-responding for food pellets; this effect was common to all 3 rat lines. Conversely, no dose of GS39783 altered lever-responding for food in any rat line. CONCLUSIONS: These results suggest that: (i) the strength of the reinforcing and motivational properties of alcohol differ among P, sP, and AA rats; (ii) the reinforcing and motivational properties of alcohol in P, sP, and AA rats are differentially sensitive to treatment with baclofen and GS39783; (iii) the heterogeneity in sensitivity to baclofen and GS39783 of alcohol self administration in P, sP, and AA rats may resemble the differential effectiveness of pharmacotherapies among the different typologies of human alcoholics; and (iv) the GABA(B) receptor is part of the neural substrate mediating the reinforcing and motivational properties of alcohol. PMID- 22486249 TI - What does respect for the patient's autonomy require? AB - Personal autonomy presupposes the notion of rationality. What is not so clear is whether, and how, a compromise of rationality to various degrees will diminish a person's autonomy. In bioethical literature, three major types of threat to the rationality of a patient's medical decision are identified: insufficient information, irrational beliefs/desires, and influence of different framing effects. To overcome the first problem, it is suggested that patients be provided with information about their diseases and treatment choices according to the objective standard. I shall explain how this should be finessed. Regarding the negative impact of irrational beliefs/desires, some philosophers have argued that holding irrational beliefs can still be an expression of autonomy. I reject this argument because the degree of autonomy of a decision depends on the degree of rationality of the beliefs or desires on which the decision is based. Hence, to promote patient autonomy, we need to eliminate irrational beliefs by the provision of evidence and good arguments. Finally, I argue that the way to smooth out the framing effects is to present the same information in different perspectives: it is too often assumed that medical information can always be given in a complete and unadorned manner. This article concludes with a cautionary note that the protection of patient autonomy requires much more time and effort than the current practice usually allows. PMID- 22486246 TI - Minocycline: therapeutic potential in psychiatry. AB - Pharmacological interventions to treat psychiatric illness have previously focused on modifying dysfunctional neurotransmitter systems to improve symptoms. However, imperfect understanding of the aetiology of these heterogeneous syndromes has been associated with poor treatment outcomes for many individuals. Growing evidence suggests that oxidative stress, inflammation, changes in glutamatergic pathways and neurotrophins play important roles in many psychiatric illnesses including mood disorders, schizophrenia and addiction. These novel insights into pathophysiology allow new treatment targets to be explored. Minocycline is an antibiotic that can modulate glutamate-induced excitotoxicity, and has antioxidant, anti-inflammatory and neuroprotective effects. Given that these mechanisms overlap with the newly understood pathophysiological pathways, minocycline has potential as an adjunctive treatment in psychiatry. To date there have been promising clinical indications that minocycline may be a useful treatment in psychiatry, albeit from small trials most of which were not placebo controlled. Case reports of individuals with schizophrenia, psychotic symptoms and bipolar depression have shown serendipitous benefits of minocycline treatment on psychiatric symptoms. Minocycline has been trialled in open-label or small randomized controlled trials in psychiatry. Results vary, with findings supporting use in schizophrenia, but showing less benefit for nicotine dependence and obsessive-compulsive disorder. Given the limited data from rigorous clinical trials, further research is required. However, taken together, the current evidence suggests minocycline may be a promising novel therapy in psychiatry. PMID- 22486250 TI - NMR insights into dendrimer-based host-guest systems. PMID- 22486251 TI - Evidence for vitamin D deficiency and increased prevalence of fractures in autoimmune bullous skin diseases. AB - BACKGROUND: Vitamin D deficiency plays a role in autoimmune diseases and risk of fractures. No data are available on vitamin D levels and vertebral fractures in autoimmune bullous skin diseases. OBJECTIVES: To assess serum vitamin D levels and the prevalence of vertebral fractures in patients with pemphigus vulgaris (PV) and bullous pemphigoid (BP), potentially fatal autoimmune bullous disorders. METHODS: We studied 13 consecutive inpatients with untreated active PV (six men and seven women, mean +/- SD age 53.5 +/- 14.3 years), 15 with BP (seven men and eight women, mean +/- SD age 76.9 +/- 12.4 years) and 28 age-, body mass index- and sex-matched controls. The 25-hydroxyvitamin D (25-OHD) levels and presence of vertebral fractures on spinal X-ray were assessed in all subjects. RESULTS: In patients with PV, 25-OHD levels were lower (mean +/- SD 12 +/- 4.4 ng mL(-1) ) and prevalence of severe hypovitaminosis D higher (62%) than in controls (mean +/ SD 22.2 +/- 11.7 ng mL(-1) , P = 0.012; 23%, P = 0.0047, respectively). The prevalence of fractures was 54% and 31% in patients with PV and controls, respectively. Patients with BP showed lower 25-OHD levels (mean +/- SD 9.6 +/- 7.2 ng mL(-1) ) and higher prevalence of severe hypovitaminosis D (73%) than controls (mean +/- SD 22.6 +/- 18.7 ng mL(-1) , P = 0.022; 27%, P = 0.01, respectively). The prevalence of fractures tended to be higher in patients with BP than in controls (67% vs. 33%, respectively, P = 0.068). CONCLUSIONS: The low 25-OHD levels found in PV and BP may suggest a role for this agent in their pathogenesis. The increased prevalence of fractures should be taken into consideration in patients who must be given corticosteroids. PMID- 22486252 TI - Analysis of energy loss mediated by an alpha-1 blocker in patients with benign prostatic hyperplasia using a virtual urethra processed from an endoscopic video image. AB - PURPOSE: To examine the efficacy of an alpha-1 blocker and its correlation to structural alteration of the prostatic urethra and the loss of energy in the urine flow using a virtual urethra processed from an endoscopic video image. MATERIALS AND METHODS: Video images of the prostatic urethra were recorded during cystourethroscopy in 11 patients with benign prostatic hyperplasia (BPH) before and after treatment with an alpha-1 blocker, naftopidil. The three-dimensional (3D) structure of the prostatic urethra was reproduced from video files. Fluid dynamic analysis and hydraulic energy calculations were performed using the "virtual" 3D urethral images. RESULTS: In 9 of 11 patients studied, an 11% improvement in the loss of energy (range, 1%-82%) was seen. Alpha-1 blocker treatment mediated the disappearance or decrease of the bulky vortex formation in seven patients, which led to an improved urinary stream. A positive correlation was found between improved energy loss and residual urine volume (P=0.0312). CONCLUSION: Alpha-1 blocker therapy led to a decreased energy loss in the urine flow in the prostatic urethra in relation to the improvement of clinical symptoms. The cystourethroscopy could be a tool to assess the urethral resistance in patients with BPH using image processing methodology. PMID- 22486253 TI - Mechanism of water oxidation to molecular oxygen with osmocene as photocatalyst: a theoretical study. AB - In the present work, photoinduced O(2) evolution from the [Cp(2)Os-OH](+) complex in aqueous solution has been studied by the DFT, CASSCF, and CASPT2 methods. The CASPT2//CASSCF calculations predict that the S(3) state is initially populated and the subsequent deprotonation of [Cp(2)Os-OH](+) proceeds very easily along the T(1) pathway as a result of the efficient S(3) -> T(1) intersystem crossing. It is found that the O-O bond is formed via the acid-base mechanism, which is different from the direct oxo-oxo coupling mechanism suggested in the experimental study. Formation of the O-O bond is the rate-determining step and has an activation energy and activation free energy of 81.3 and 90.4 kcal/mol, respectively. This is consistent with the low quantum yield observed for generating molecular oxygen upon irradiation at 350 nm (~ 82 kcal/mol). The O(2) release from an intermediate complex has to overcome a small barrier on the triplet pathway first and then pass through the triplet-singlet intersection, generating the O(2) molecules in either the lowest singlet or triplet state. The formed (3)O(2) molecule can be converted into the (1)O(2) molecule by the heavy atom effect in the Os complexes, which is probably the reason only the (1)O(2) molecule was detected experimentally. PMID- 22486254 TI - Rational design of fluorescent phosgene sensors. AB - Phosgene is a very toxic gas, which was used as a chemical weapon in World War I, and is currently widely used in industrial processes. So far, no any phosgene fluorescent sensor has been reported. In this study, we report rational design of unimolecular fluorescent phosgene sensors for the first time. Phosgene was used to initiate intramolecular cyclization and convert nonfluorescent molecules to highly fluorescent products. Bright blue fluorescence of phosgene reaction products can be easily visualized by naked eye. The detection limit for phosgene is as low as 1 nM in solutions at room temperature. PMID- 22486255 TI - Magnetic silica nanotubes: synthesis, drug release, and feasibility for magnetic hyperthermia. AB - A new kind of silica nanotube with incorporated gamma-Fe(2)O(3) nanoparticles has been successfully prepared through sol-gel processes. Hematite particles supported on carbon nanotubes served as templates for the fabrication of the magnetic silica nanotubes. The obtained nanostructures consisting of magnetic Fe(2)O(3) nanoparticles protected by a silica shell were fully characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), N(2) sorption and desorption, and magnetization studies. The hollow inner space and the magnetic functionalization render the material promising for applications in biology and medicine. This is underlined by studies in alternating magnetic fields which show a significant heating effect, i.e., the feasibility for applications in hyperthermia therapies. In addition, the material exhibits enhanced drug-loading capacity which is demonstrated by loading with rhodamine B molecules as drugs and corresponding release experiments. The results show that magnetic silica nanotubes can be straightforwardly synthesized and have a great potential as a multifunctional drug carrier system. PMID- 22486256 TI - Molecular evidence in support of the neoplastic and precursor nature of microglandular adenosis. AB - AIMS: Microglandular adenosis (MGA) is a proliferative breast lesion, which has been proposed to be a potential precursor of triple-negative breast cancers. The aims of this study were to determine whether MGAs harbour genetic alterations and if any such genetic aberrations found in MGAs are similar to those found in matched invasive carcinomas. METHODS AND RESULTS: Twelve cases of MGA and/or atypical MGA (AMGA), 10 of which were associated with invasive carcinoma, were evaluated. Immunohistochemical profiling revealed that all invasive carcinomas were of triple-negative phenotype and expressed S100, cytokeratins 8/18 and 'basal' markers. The morphologically distinct components of each case (MGA, AMGA and/or invasive carcinoma) were microdissected and subjected to microarray comparative genomic hybridization. Apart from three typical MGAs, all samples harboured genetic alterations. The percentage of the genome affected by copy number aberrations in MGA/AMGA ranged from 0.5 to 61.9%, indicating varying levels of genetic instability. In three cases, MGA/AMGA displayed copy number aberrations similar to those found in matched invasive components, providing strong circumstantial evidence that MGA may constitute the substrate for the invasive carcinoma development. CONCLUSIONS: Our results support the contention that MGA can be a clonal lesion and non-obligate precursor of triple-negative breast cancer. PMID- 22486257 TI - Calcitonin gene-related peptide and size of the atrial septal defect in new-onset migraine after transcatheter closure: results of a preliminary study. AB - BACKGROUND: New-onset migraine headache attacks (MHAs) can occur after atrial septal device implantation in patients without previous migraine. Plasma calcitonin gene-related peptide (CGRP), which plays a crucial role in migraine pathophysiology, has shown to be released from specific cardiac tissues. METHODS AND RESULTS: We prospectively collected patients before and after closure and measured plasma CGRP levels using enzyme-linked immunosorbent assay. Forty atrial septal defect (ASD) patients who had no migraine previously were enrolled. Four (23.5%) of the 17 consecutive patients whose CGRP levels were checked before ASD closure had new-onset MHAs. The patients with MHAs had bigger ASD size (20 +/- 0.9 vs 16 +/- 1 mm, P = .009) and lower CGRP levels before closure (21.1 +/- 3.9 vs 90.1 +/- 27.1 pg/mL, P = .042) than those without. Among the 5 patients with blood samplings both during and between attacks, a paired comparison revealed a significantly increased level during attack (257.2 +/- 45.5 vs 45.6 +/- 25.5 pg/mL, P = .03). CONCLUSION: Bigger ASD size and lower plasma CGRP levels before closure can be a potential predictor of new-onset MHAs. Furthermore, a significant increase of CGRP levels during migraine attack implies that the occurrences of new-onset MHAs after ASD closure correlate with the release of CGRP. This suggests CGRP sensitization from a lower baseline may be involved in the occurrence of new-onset MHAs after ASD closure. PMID- 22486258 TI - Dichotomous long-term response to isotretinoin in two patients with fordyce spots. AB - Fordyce spots are benign, enlarged sebaceous glands that commonly present as tiny yellow papules on a variety of body surfaces, including the lips. Although these lesions are asymptomatic, in some patients, they are abundant and conspicuous, leading to concerns regarding their cosmetic appearance. The response of Fordyce spots to isotretinoin therapy is poorly documented in the literature, which contains only one case report of an affected patient treated with a short course of isotretinoin (35 mg/kg in total). Herein, we report dichotomous long-term response to a standard course of isotretinoin in two patients with Fordyce spots of the lips and concomitant acne. PMID- 22486259 TI - A presentation of glandular penile metastases from prostate adenocarcinoma. AB - Secondary tumours of the penis are rare; they most commonly arise from the prostate and the bladder. These lesions are often associated with disseminated malignancy and have a poor prognosis, with a 6-month mortality of up to 80% reported. Penile metastases have a variety of clinical manifestations including incidental penile nodules, cutaneous findings, urinary symptoms, pain and malignant priapism. Treatment options are mainly targeted at improving the patients' quality of life and are tailored to their clinical condition, but are primarily palliative. This study reports a case of a 92-year-old man with a presentation of glandular penile metastases from prostate adenocarcinoma treated conservatively. PMID- 22486260 TI - Quantitative polymerase chain reaction for Mycobacterium tuberculosis in so called Eales' disease. AB - PURPOSE: To report mycobacterial load in the vitreous of patients labeled as having Eales' disease. METHODS: Eighty-eight patients were prospectively enrolled into 3 groups: 28 patients with so-called Eales' disease (group A); 30 positive controls with specific uveitis syndromes (group B), and 30 negative controls (group C). The undiluted vitreous humor samples were collected and subjected to real-time PCR assay for MPB64 gene of Mycobacterium tuberculosis (MTB) and load quantified. RESULTS: Sixteen (57.14%) vitreous fluid samples in group A; 1 sample in group B, and none of the samples in group C were positive for MTB genome from the vitreous. The copies of MTB genomes in the positive samples in group A were 1.52 * 10(4) to 1.01 * 10(6). CONCLUSION: MTB genome was demonstrated in more than 50% of vitreous fluid samples with significant bacillary load, indicating that half of patients with so-called Eales' disease are indeed cases of tubercular vasculitis. PMID- 22486261 TI - Sclerochoroidal calcifications imaged using enhanced depth imaging optical coherence tomography. AB - PURPOSE: To report a case of sclerochoroidal calcifications and describe the appearance of these lesions using optical coherence tomography with enhanced depth imaging (EDI-OCT) technology. DESIGN: Case Report METHODS: An 85-year-old patient who presented with bilateral retinal lesions suspected to be metastases was evaluated with slit-lamp biomicroscopy, funduscopy, fluorescein angiography, B-scan ultrasonography (U/S), and EDI-OCT. RESULTS: B-scan U/S demonstrated echo dense consolidations in the choroid bilaterally with acoustic shadowing consistent with sclerochoroidal calcifications. EDI-OCT revealed hyper-reflective lesions with decreased reflectivity posterior to the lesion. CONCLUSIONS: Sclerochoroidal calcifications should be included in the differential of choroidal masses, given their unique appearance on EDI-OCT. PMID- 22486262 TI - An essential role for death receptor 3 in experimental autoimmune uveoretinitis. PMID- 22486263 TI - Ocular findings in a patient with virus-associated hemophagocytic syndrome. AB - PURPOSE: To describe a case of virus-associated hemophagocytic syndrome with ocular changes resembling Vogt-Koyanagi-Harada disease prior to the systemic changes. METHODS: A 51-year-old man presented with a sudden decline in vision. The patient was examined by fluorescein angiography, bone marrow biopsy, abdominal ultrasound, ocular examinations, and laboratory examinations. RESULTS: Fluorescein angiography revealed uveitis resembling Vogt-Koyanagi-Harada disease. Bone marrow biopsy specimen demonstrated histiocytic hyperplasia and some hemophagocytes. Abdominal ultrasound findings indicated hepato-splenomegaly. And ocular examinations revealed hematocytopenia and hypoproteinemia. CONCLUSION: The ocular changes resembling Vogt-Koyanagi-Harada disease observed in this study could be a kind of manifestation of virus-associated hemophagocytic syndrome in retina. PMID- 22486264 TI - Infliximab monotherapy versus infliximab and colchicine combination therapy in patients with Behcet's disease. AB - PURPOSE: To compare infliximab monotherapy with infliximab and colchicine combination therapy in Behcet's disease. METHODS: Clinical records of 14 Behcet's disease patients who were administered infliximab with or without colchicine were retrospectively reviewed. Patients who were given other immunosuppresants after initiation of infliximab therapy were excluded. The frequency of ocular attacks and best-corrected visual acuity were investigated. RESULTS: Seven patients received monotherapy and 7 received combination therapy. The mean frequency of ocular attacks significantly decreased from 2.14 to 0.22 per 6 months in monotherapy group and from 2.57 to 0.18 per 6 months in combination therapy group. No significant difference was observed between both groups in the frequency of ocular attacks and in changes in best-corrected visual acuity during 0 to 24 months. CONCLUSIONS: Infliximab is as efficacious as infliximab and colchicines together in Behcet's disease treatment. This study suggests that colchicine administration is not necessary in Behcet's disease patients receiving infliximab. PMID- 22486265 TI - Long-term efficacy and safety of infliximab in the treatment of Behcet's disease. AB - PURPOSE: To assess the long-term efficacy and safety of infliximab therapy for the treatment of Behcet's disease patients with ocular involvement who failed to respond or did not tolerate conventional treatment. METHODS: Retrospective study of 12 patients treated with infliximab at a starting dose of 5 mg/kg. RESULTS: Infliximab was infused during a mean of 31.43 months. The mean follow-up period was 35.77 months (range: 6-94). All patients achieved remission, 7 of whom did not need any adjuvant immunosuppressive therapy and 9 of whom were able to discontinue systemic corticosteroids. Visual acuity remained stable or improved in 20/21 eyes. Ten patients did not report any side effect of the medication or those were mild and tolerable. We observed two major adverse events requiring withdrawal of infliximab. CONCLUSIONS: Infliximab therapy is an effective biologic agent for the treatment of ocular inflammation in Behcet's disease unresponsive to the standard immunosuppressive therapy. PMID- 22486266 TI - Frosted branch angiitis in a woman with Mycobacterium tuberculosis infection. AB - PURPOSE: To describe a case of frosted branch angiitis in a patient with tuberculous meningitis. METHODS: Case report. RESULTS: A 27-year-old woman of tuberculous meningitis was referred to us complaining of blurred vision for 2 days. Prominent white sheathing of the retinal venules and, to a much lesser extent, arterioles, consistent with frosted branch angiitis were also observed in both eyes. And after treatment with systemic anti-tuberculosis medications and steroid, frosted branch angiitis showed resolution. CONCLUSIONS: Frosted branch angiitis can be caused by Mycobacterium tuberculosis. Systemic anti-tubercular therapy and steroids were effective. PMID- 22486267 TI - Validation of diagnostic assays to screen broodstock for Flavobacterium psychrophilum infections. AB - It is hypothesized that the frequency of bacterial coldwater disease outbreaks can be reduced through the detection of the aetiologic agent, Flavobacterium psychrophilum, in broodstock followed by culling of eggs from heavily infected broodstock. Before a culling programme can be instituted, however, it is necessary to determine the sensitivity and specificity of existing assays for the detection of F. psychrophilum. In this study, tissue and ovarian fluid samples were collected from 224 fish at five hatcheries and screened using an enzyme linked immunosorbent assay (ELISA), a membrane-filtration fluorescent antibody test (MF-FAT), bacteriological culture and nested PCR. Latent class analysis was used to estimate sensitivity and specificity of kidney culture, kidney ELISA, nested PCR and MF-FAT. Analytical sensitivity of the ELISA varied but was greatest when bacteria were cultured under iron-limiting conditions. Diagnostic sensitivity estimates ranged from 0.02 (kidney culture) to 0.97 (kidney ELISA). Specificity estimates ranged from 0.02 (MF-FAT) to 0.98 (kidney ELISA). In a separate challenge experiment, the ELISA confirmed the presence of F. psychrophilum in sub-clinically infected fish. Results from this study demonstrate that the ELISA is an appropriate tool to screen broodstock and provides an indication of infection severity, which is crucial for implementation of a screening/culling programme. PMID- 22486268 TI - Autonomics and ablation of paroxysmal atrial fibrillation. PMID- 22486269 TI - Coexpression of CCR6 and CD146 (MCAM) is a marker of effector memory T-helper 17 cells. AB - Effector memory T (T(EM)) cells are a subpopulation of memory T cells that express receptors mediating migration to inflamed tissues and produce various cytokines. Effector memory T-helper (Th)17 (Th17(EM)) cells are thought to be essential for inflammation in Th17-mediated diseases, but have not been studied in detail. To identify superior surface markers to isolate a homogeneous population of Th17(EM) cells from peripheral blood, CD4(+) T cells were isolated from the peripheral blood of healthy donors based on the expression of CCR7, CCR6 and CD146 using six-color flow cytometry. After 4days of culture in the presence of anti-CD3/28 beads, intracellular cytokines were determined by flow cytometric analysis. To investigate the relevance of Th17(EM) cells in Th17-mediated disease, the frequencies of T(EM) -cell subsets in psoriasis were quantified using six-color flow cytometry. An enzyme-linked immunosorbent assay was performed to confirm the interleukin (IL)-17-producing capacity of T(EM) -cell subsets from the peripheral blood of a patient with psoriasis. CCR6(+) CD146(+) T(EM) (CD4(+) CD45RA(-) CCR7(-)) cells had a greater capacity to produce IL-17 than CCR6(+) CD146(-) or CCR6(-) CD146(+) T(EM) cells. Although the percentage of CCR6(+) CD146(+) cells in T(EM) cells was not significantly different between patients with psoriasis and controls, three of eight patients had a higher percentage of CCR6(+) CD146(+) T(EM) cells than the mean +5 standard deviations of the controls. Coexpression of CCR6 and CD146 is a useful marker for Th17(EM) cells. Increasing the number of CCR6(+) CD146(+) Th17(EM) cells in peripheral blood may facilitate estimation of systemic Th17-cell activity in Th17-mediated diseases. PMID- 22486270 TI - Origins of enantioselectivity during allylic substitution reactions catalyzed by metallacyclic iridium complexes. AB - In depth mechanistic studies of iridium catalyzed regioselective and enantioselective allylic substitution reactions are presented. A series of cyclometalated allyliridium complexes that are kinetically and chemically competent to be intermediates in the allylic substitution reactions was prepared and characterized by 1D and 2D NMR spectroscopies and single-crystal X-ray difraction. The rates of epimerization of the less thermodynamically stable diastereomeric allyliridium complexes to the thermodynamically more stable allyliridium stereoisomers were measured. The rates of nucleophilic attack by aniline and by N-methylaniline on the isolated allyliridium complexes were also measured. Attack on the thermodynamically less stable allyliridium complex was found to be orders of magnitude faster than attack on the thermodynamically more stable complex, yet the major enantiomer of the catalytic reaction is formed from the more stable diastereomer. Comparison of the rates of nucleophilic attack to the rates of epimerization of the diastereomeric allyliridium complexes containing a weakly coordinating counterion showed that nucleophilic attack on the less stable allyliridium species is much faster than conversion of the less stable isomer to the more stable isomer. These observations imply that Curtin Hammett conditions are not met during iridium catalyzed allylic substitution reactions by eta(3)-eta(1)-eta(3) interconversion. Rather, these data imply that when these conditions exist for this reaction, they are created by reversible oxidative addition, and the high selectivity of this oxidative addition step to form the more stable diastereomeric allyl complex leads to the high enantioselectivity. The stereochemical outcome of the individual steps of allylic substitution was assessed by reactions of deuterium-labeled substrates. The allylic substitution was shown to occur by oxidative addition with inversion of configuration, followed by an outer sphere nucleophilic attack that leads to a second inversion of configuration. This result contrasts the changes in configuration that occur during reactions of molybdenum complexes studied with these substrates previously. In short, these studies show that the factors that control the enantioselectivity of iridium-catalyzed allylic substitution are distinct from those that control enantioselectivity during allylic substitution catalyzed by palladium or molybdenum complexes and lead to the unique combination of high regioselectivity, enantioselectivity, and scope of reactive nucleophile. PMID- 22486271 TI - Sigmund S. Socransky, D.D.S., 1934-2011. PMID- 22486272 TI - Influence of autogenous platelet concentrate on combined GTR/graft therapy in intrabony defects: a 7-year follow-up of a randomized prospective clinical split mouth study. AB - OBJECTIVES: To investigate the influence of autogenous platelet concentrate (APC) on the long-term regeneration outcome 7 years after guided tissue regeneration (GTR) in deep intrabony periodontal defects. MATERIAL AND METHODS: In 25 patients, two deep contra-lateral intrabony defects were treated according to GTR (randomized split-mouth-design). In the test defects, APC was additionally applied. After 7 years, healing results were assessed clinically by a blinded examiner and compared to baseline and 12-months results. Furthermore, a tooth survival analysis was performed. RESULTS: After 7 years, 23 patients were available for survival analysis and 16 patients for split-mouth analysis; 84% of the test and control teeth were still in situ. In both groups, the median attachment level of 10.5 mm [(25/75%): test 9.0/13.0, control 10.0/12.0] at baseline was significantly (p <= 0.05) reduced to 6.0 mm [test 4.0/6.8, control 5.0/7.0] after 1 year. Six years later, it had increased again to 7.0 mm in test sites [5.3/10.0] (p <= 0.05) and had remained stable in control sites [5.0/7.8] (p > 0.05). Bleeding on Probing (BOP) had increased in both groups. During the last 6 years, only 26% of the patients received a structured supportive periodontal therapy in the clinic. CONCLUSION: Within its limitations, the present study indicates that the clinical outcome of GTR therapy can be maintained over 7 years. However, the additional use of APC may even have a possibly negative influence on the long-term stability. PMID- 22486273 TI - Prevalence of peri-implant diseases. A cross-sectional study based on a private practice environment. AB - AIM: To determine the prevalence of peri-implant diseases in private practice patients enrolled in a periodontal maintenance programme. MATERIAL AND METHODS: A cross-sectional study was carried out in patients with dental implants attending the dental clinic to comply with a periodontal maintenance programme between January and June 2010. Implants with at least 1 year of loading time (range: 1-18 years) were included. A patient-based prevalence analysis of peri-implant diseases was carried out. Additionally, implants were classified into the following categories: healthy, clinically stable, mucositis and peri-implantitis. RESULTS: A total of 245 patients (964 dental implants) were analysed. Implant and patient-based peri-implantitis prevalences were 9.1% [95% confidence interval (95%CI): 7.5-11.1%] and 16.3% [95%CI: 12.2-21.5%] respectively. Mucositis affected 21.6% [95%CI: 19.1-24.5%] of the studied implants and 38.8% [95%CI: 33.3 45.4%] of the patients. CONCLUSIONS: The prevalence of peri-implantitis in private practice patients enrolled in a periodontal maintenance programme was estimated to be between 12% and 22%. Almost 40% of the patients had mucositis. These prevalences are similar to those published in University environment samples. PMID- 22486274 TI - A new tool to assess bleeding severity in patients with chemotherapy-induced thrombocytopenia. AB - BACKGROUND: Current scales to measure bleeding in clinical trials are inadequate. The aim of this study was to develop a simple, valid, and reliable measurement tool to categorize the severity of bleeding in patients with chemotherapy-induced thrombocytopenia (CIT). STUDY DESIGN AND METHODS: Measurement theory was used to develop the Bleeding Severity Measurement Scale (BSMS) in four steps: 1) identification of the patient population, 2) item generation and reduction, 3) reviewing the items and formatting the scale, and 4) evaluation of psychometric properties. Feasibility was tested in a pilot study. Content and face validity were assessed by expert review. Psychometric evaluation included determination of intra- and interrater reliability and construct and criterion validity. RESULTS: The final BSMS defined two grades of bleeding: not clinically significant (Grade 1) and clinically significant (Grade 2). Grade 2 bleeds were defined as bleeds resulting in morbidity, requiring interventions, or directly causing death. The BSMS had excellent interrater (intraclass correlation coefficient [ICC], 0.80) and intrarater (ICC, 1.0) reliability and good construct and criterion validity. The BSMS distinguished between patients with different bleeding severities. CONCLUSION: Using rigorous methods, we designed a simple bleeding assessment tool with excellent psychometric properties for patients with CIT. Use of this scale in clinical trials should provide valid and reliable assessments of bleeding. PMID- 22486275 TI - A prospective study in the rational design of efficient antisense oligonucleotides for exon skipping in the DMD gene. AB - Antisense oligonucleotide (AON)-mediated exon skipping to restore dystrophin expression in Duchenne muscular dystrophy (DMD) therapy shown promise in a number of human clinical trials. Current AON design methods are semi-empirical, involving either trial-and-error and/or preliminary experimentations. Therefore, a rational approach to design efficient AONs to address the wide spectrum of patients' mutations is desirable. Retrospective studies have extracted many AON design variables, but they were not tested prospectively to design AONs for skipping DMD exons. Not only did the variables differ among the various studies, no numerical cutoff for each variable was inferred, which makes their use in AON design difficult. The challenge is to thus select a minimal set of key independent variables that can consistently design efficient AONs. In this prospective study, a novel set of design variables with respective cutoff values was used to design 23 novel AONs, each to skip one of nine DMD exons. Nineteen AONs were found to be efficacious in inducing specific exon skipping (83% of total), of which 14 were considered efficient (61% of total), i.e., they induced exon skipping in >25% of total transcripts. Notably, the satisfactory success rates were achieved by using only three design variables; namely, co transcriptional binding accessibility of target site, presence of exonic splicing enhancers, and target length. Retrospective analyses revealed that the most efficient AON in every exon targeted has the lowest average cumulative position (ACP) score. Taking the prospective and retrospective studies together, we propose that design guidelines recommend using the ACP score to select the most efficient AON for each exon. PMID- 22486276 TI - Combination treatment with a tumour necrosis factor antagonist and an oral retinoid: efficacy in severe acral psoriasis? PMID- 22486277 TI - Effects of chronic treatment with metformin on dipeptidyl peptidase-4 activity, glucagon-like peptide 1 and ghrelin in obese patients with Type 2 diabetes mellitus. AB - AIMS: Studies investigating the acute effects of metformin have demonstrated actions on the incretin system and appetite regulatory hormones. There are limited data to support that these effects are sustained in the long term. We therefore studied the effects of chronic treatment with metformin on endogenous glucagon-like peptide 1, dipeptidyl peptidase-4 activity and active ghrelin (an orexigenic hormone) in obese patients with Type 2 diabetes mellitus. METHODS: Eight subjects [six male, age 58.7 +/- 2.6 years, BMI 41.1 +/- 2.9 kg/m(2) , HbA(1c) 69 +/- 6 mmol/mol (8.5 +/- 0.5%), mean +/- sem] with drug-naive Type 2 diabetes were studied for 6 h following a standard mixed meal, before and after at least 3 months of metformin monotherapy (mean dose 1.75 g daily). RESULTS: The area under the curve (AUC(0-6 h) ) for active glucagon-like peptide 1 was significantly higher on metformin (pre-metformin 1750.8 +/- 640 pmol l(-1) min( 1) vs. post-metformin 2718.8 +/- 1182.3 pmol l(-1) min(-1) ; P=0.01). The areas under the curves for dipeptidyl peptidase-4 activity and ghrelin were not significantly different pre- and post-treatment with metformin. CONCLUSION: Three months or more of metformin monotherapy in obese patients with Type 2 diabetes was associated with increased postprandial active glucagon-like peptide 1 levels. The effects of metformin on the enteroinsular axis may represent yet another important mechanism underlying its glucose-lowering effects. PMID- 22486278 TI - Metal-organic frameworks with phosphotungstate incorporated for hydrolytic cleavage of a DNA-model phosphodiester. AB - Five phosphotungstate-incorporated metal-organic frameworks {[Eu(4)(dpdo)(9)(H(2)O)(16)PW(12)O(40)]}(PW(12)O(40))(2).(dpdo)(3).Cl(3) (1); {ZnNa(2)(MU-OH)(dpdo)(4)(H(2)O)(4)[PW(12)O(40)]}.3H(2)O (2); {Zn(3)(dpdo)(7)}[PW(12)O(40)](2).3H(2)O (3); and [Ln(2)H(MU O)(2)(dpdo)(4)(H(2)O)(2)][PW(12)O(40)].3H(2)O (Ln = Ho for 4 and Yb for 5) (dpdo = 4,4'-bipyridine-N,N'-dioxide) have been synthesized through a one-step hydrothermal reaction and characterized by elemental analyses, infrared (IR) spectroscopy, photoluminescence, and single-crystal X-ray diffraction (XRD). The structural analyses indicate that 1-5 display diversity structure from one dimensional (1D) to three-dimensional (3D) series of hybrids. Kinetic experiments for the hydrolytic cleavage of DNA-model phosphodiester BNPP (bis(p nitrophenyl)phosphate) were followed spectrophotometrically for the absorbance increase at 400 nm in EPPS (4-(2-hydroxyethyl)piperazine-1-propane sulfonic acid) buffer solution, because of the formation of p-nitrophenoxide with 1-5 under conditions of pH 4.0 and 50 degrees C. Ultraviolet (UV) spectroscopy indicate that the cleavage of the phosphodiester bond proceeds with the pseudo-first-order rate constant in the range of 10(-7)-10(-6) s(-1), giving an inorganic phosphate and p-nitrophenol as the final products of hydrolysis. The results demonstrate that 1-5 have good catalytic activity and reusability for hydrolytic cleavage of BNPP. PMID- 22486279 TI - CuSO4-glucose for in situ generation of controlled Cu(I)-Cu(II) bicatalysts: multicomponent reaction of heterocyclic azine and aldehyde with alkyne, and cycloisomerization toward synthesis of N-fused imidazoles. AB - The catalytic efficiency of mixed Cu(I)-Cu(II) system in situ generated by partial reduction of CuSO(4) with glucose in ethanol (nonanhydrous) under open air has been explored. With this catalysis, the multicomponent cascade reaction of A(3)-coupling of heterocyclic amidine with aldehyde and alkyne, 5-exo-dig cycloisomerization, and prototropic shift has afforded an efficient and eco friendly synthesis of therapeutically important versatile N-fused imidazoles. Diverse heterocyclic amidines, several of which are known to be poorly reactive, and aldehydes are compatible in this catalytic process. PMID- 22486280 TI - Alcohol consumption among pregnant women in a Swedish sample and its effects on the newborn outcomes. AB - BACKGROUND: Little is known about the effects of low levels of maternal alcohol intake on the neuropsychological development of the child. This study is part of an ongoing investigation on maternal drinking and presents data on demographic variables, maternal alcohol use, and birth outcomes from that study. METHODS: The sample comprised 2,264 women from a Swedish antenatal clinic. Retrospective self report data were collected on alcohol consumption before and during pregnancy, using the Alcohol Use Disorders Identification Test (AUDIT), and on nicotine use. Specific alcohol biomarkers for excessive drinking, carbohydrate-deficient transferrin (CDT) in serum and phosphatidylethanol (PEth) in whole blood, were determined during mid-pregnancy in a subsample of the women. Data on labor and early characteristics of the child were also assessed. RESULTS: Before pregnancy, 89% of the women regularly consumed alcohol and 49% reported occasional or frequent binge drinking. Nicotine was used by 15% before and by 5% during pregnancy. During pregnancy, 12% continued using alcohol and 5% also admitted binge drinking. However, all alcohol biomarker values were below the reporting limits (CDT <= 1.7% disialotransferrin; total PEth < 0.1 MUmol/L). Self-reported drinking during pregnancy was associated with a higher AUDIT score before pregnancy, nicotine use at the time of the first prenatal visit, older age, and previous legal abortions. CONCLUSIONS: The AUDIT questionnaire and 2 specific alcohol biomarkers were used in routine maternity care to collect information about drinking during pregnancy and thereby to identify children at risk for alcohol-related complications. While the AUDIT results suggested that a significant number of women continued using alcohol during pregnancy, implying a risk for fetal disorders, the biomarkers showed negative test values thus indicating only modest drinking levels. PMID- 22486281 TI - Expression of 5alpha-reductase in apocrine carcinoma of the breast and its correlation with clinicopathological aggressiveness. AB - AIMS: Apocrine carcinomas of the breast frequently lack oestrogen and progesterone receptors and often express androgen receptor. However, little is known about the role of androgen in apocrine carcinoma. Androgen-producing enzymes, such as 5alpha-reductase (5alphaR), which converts testosterone locally to the potent androgen dihydrotestosterone, have recently gained attention in studies of the intratumoural actions of androgens. The goal of this study was to examine 5alphaR expression and its relationship to other clinicopathological factors in apocrine carcinoma. METHODS AND RESULTS: Of 48 cases of infiltrating apocrine carcinoma, 30 cases (62.5%) were immunopositive for 5alphaR. Twenty seven of the 5alphaR-positive cases were also positive for androgen receptor. In comparison to 5alphaR-negative cases, 5alphaR-positive cases showed clinicopathological aggressiveness characterized by significantly larger infiltrating tumour size (P = 0.001), higher frequency of lymphatic (P = 0.029) and vascular invasion (P = 0.009), higher histological grade (P = 0.048) and shorter recurrence-free survival time (P = 0.047). No significant differences in nuclear grade, hormonal receptors, human epidermal growth factor receptor 2 (HER2) or p53 protein were detected between two groups. All five cases of intraductal apocrine carcinoma lacked 5alphaR. CONCLUSION: Approximately 60% of infiltrating apocrine carcinomas were immunopositive for 5alphaR. The 5alphaR positive apocrine carcinomas were clinicopathologically more aggressive than 5alphaR-negative cases. Our findings suggest that autocrine androgen synthesis accelerates tumour aggressiveness in apocrine carcinoma. PMID- 22486282 TI - [The seroprevalence of HCV among injecting drug users in the years 2004-2008 in Slovakia]. AB - INTRODUCTION: Virus of hepatitis C (HCV) is the leading cause of chronic liver disease, including cirrhosis and cancer, and the most common indication for liver transplantation. In industrialised countries, injecting drug use is currently the most important risk factor for infection with hepatitis C, resulting in high prevalence of hepatitis C among injecting drug users (IDUs). The aim of the study was to assess the seroprevalence of HCV infection and distribution of genotypes among IDUs in the years 2004-2008. PROBANDS AND METHODS: A total number of 846 probands, both sexes (590 males and 256 females) with mean age from 24 to 29 years were investigated in the years 2004-2008. Standard virological tests were performed. RESULTS: The seroprevalence of anti-HCV positivity during the years 2004-2008 were in range 34-78% and positivity of HCV RNA assessed by PCR method were in range 17-71%. The genotypes distribution was in favour of genotype 3. CONCLUSIONS: In Slovakia IDUs represent risk group with high prevalence of hepatitis C. These results are comparable to those published in other European countries. PMID- 22486283 TI - [Blood pressure changes in chronically haemodialysed patients]. AB - BACKGROUND: Poor blood pressure control in chronically haemodialysed patients leads to increased cardiovascular morbidity and mortality. Information on valid values of blood pressure during haemodialysis and out of office is very important in order to set up adequate treatment. AIM: To measure blood pressure during the haemodialysis and the subsequent 24-hour period using an ambulatory blood pressure monitoring (ABPM) in patients with normal blood pressure (BP) and patients with high normal BP and hypertension. Relationship between time dependent blood pressure changes, ultrafiltration (UF) and interdialytic weight gain (IDWG) was analysed. PATIENTS AND METHODS: Fifty chronically haemodialysed (> 3 months) patients (males/females 33/18) aged 57.5 (53-63; median, interquartile interval) years were studied. Systolic and diastolic pressures (SP, DP) were measured during haemodialysis every hour (H0-H4) and over following 24 hours using Spacelab 90217 monitor. Pulse pressure (PP) values were calculated as a difference between SP and DP. The patients were stratified into two groups based on the cut-off-point calculated as the mean of two mean arterial pressure (MAP) values obtained at the beginning and after the first hour of HD: Group A (n = 25), MAP < 100 mm Hg; Group B (n = 25), MAP 100 mm Hg. Interdialytic weight gain was measured before HD (IDWG1) and after the ABPM (IDWG2); also ultrafiltration (UF) was obtained. The post-dialysis 24-h ABPM period was divided into eight 3-hour intervals (M1-8). RESULTS: During HD no significant change in SP, DP or PP was found in both group, but there was a significant difference (p = 0.01) between both groups in SP, DP and PP. Values of BP at the end of dialysis were in group A: SP 125 (120-130) mm Hg, DP 75 (60-80) mm Hg and PP 50 (40-60) mm Hg in group B: SP 150 (140-160) mm Hg, DP 80 (80-90) mm Hg a PP 60 (60-70) mm Hg. We did not find any influence of IDWG1 or IDWG2 on SP or DP in both groups. Relationship between UF 3 000 (2 500-4 300) ml and SP (Delta sTK -5 mm Hg) was confirmed only in group A (p = 0.04). In group A, we found a decrease in SP during the third and sixth 3-hour interval (p = 0.01; p = 0.02) including sleeping period, all compared to the end of HD (H4). In group B, such a decrease in SP was found only in the second sleep interval (p = 0.01) and in the sixth 3 hour interval (p = 0.03), all compared to the end of HD (H4). As to DP at the end of dialysis (H4) in group A, it differed only in the third 3-hour interval (p = 0.02), but not during the sleeping period. In group B, the decrease of DP compared to the end HD (H4) was recorded during the two sleep intervals (p = 0.01), and also in the sixth and seventh 3-hour intervals (p = 0.01; p = 0.03). In group A, PP was compared to the end of HD (PPH4) significantly decreased in the first 3-hour interval (p = 0.02) and in seventh and eight 3-hour interval (p = 0.03; p = 0.04). In group B, PP did not significant change from the end of HD. Difference in SP between both groups was maintained over the entire course of ABPM (p = 0.01). However, DP values in both groups were different in the first and third 3-hour intervals (p = 0.01) but in following intervals DP in group B decreased to the level of that in group A. There was no significant difference in the proportion of non-dippers and reverse dippers in both groups. CONCLUSION: Systolic, diastolic, mean arterial and pulse pressure pressures were not significantly changed during the haemodialysis in both groups. Relationship between ultrafiltration and systolic pressure was confirmed only in group A. No influence of interdialytic weight gain on blood pressure during 24 hours was seen in either group. Systolic pressure decreased in both groups during the nighttime compared to post-HD values, but diastolic pressure decreased only in group B. PP did not decrease during the night in any group. There was no significant difference in the proportion of non-dippers and reverse dippers in both groups. PMID- 22486284 TI - [The benefits of centralization of care for patients with acute upper gastrointestinal bleeding]. AB - INTRODUCTION: Acute upper gastrointestinal bleeding still remains one of the serious conditions that require a rapid diagnostic and therapeutic intervention. Such procedure is highly dependent on good interdisciplinary cooperation, which, when centralized, may positively influence mortality and economic costs. OBJECTIVE: To determine the benefits of centralization of care provided to patients with acute bleeding in the upper gastrointestinal tract. PATIENTS AND METHODS: A total of 632 patients with acute bleeding were enrolled in the study at two different health-care establishments of the same type, however with a different organisation of care. We have evaluated the influence of the organisation of care on the length of hospitalization stay, mortality and economic costs. RESULTS: Centralized treatment significantly shortens the interval from hospital admission to endoscopic examination and leads to a reduction in mortality, although not statistically significant. On the other hand, it does not affect the length of hospitalization, the distribution of patients between internal and surgical departments, and provides no guarantee of lower economic costs. Many other factors play an important role in that respect. It seems, that the importance of centralization plays the main role especially in the pre-hospital and early hospital period, when it accelerates and simplifies the diagnostic and therapeutic procedure. PMID- 22486285 TI - [Vitamin D -- remarks of known and overwiev of new facts]. AB - Vitamin D as one of liposolubile vitamins was related to children age and skeleton at the clinical practice until now. There is lot of new information considering rather more complicated connection of vitamin D into many functions of human body during last years. On the other hand we are able to measure the serum level of vitamin D, so we recognized the possibility of long term significantly low levels of vitamin D in tenths percent of population. This review shows actual information about relationship between vitamin D and organ systems and their disturbances. Long term low level of vitamin D potentiates cognitive deterioration in elderly, influences the mood up to depression appearance. The influence of vitamin D on immunity system and cancerogenesis appears to be of high importance too. From the seniors independence point of view the relationship between vitamin D and sarcopenia is very important especially in connection with osteoporosis prevention - the way how to reduce the danger of falls and osteoporotic fractures. Autoimmune diseases and diabetes mellitus are mentioned at the end of the review. PMID- 22486286 TI - [Oxidative stress in kidney disease patients]. AB - Patients with chronic kidney disease are exposed to oxidative stress (OS) that contributes to deterioration of health. Decrease in renal excretory capacity contributes to the accumulation of pro-oxidative substances that are detrimental not only to kidney but to the whole organism including the cardiovascular system. Components of antioxidant system play an important role in the elimination of the OS. The monitoring of antioxidant levels and products of oxidative damage in these patients and the correct interpretation of relationship between these markers and the function of kidney and other organs may contribute to the more effective treatment and health improvement of the patients. PMID- 22486287 TI - [FTO gene and his role in genetic determination of obesity]. AB - Obesity is a risk factor for development of cardiovascular disease, type 2 diabetes and some cancers. Substantial proportions of obese people die from diseases caused by complications of overweight. The incidence of obesity in different populations exceeds 15%. The emergence of obesity is influenced by external factors (especially excessive energy intake and reduced physical activity). Body Mass Index (BMI) is also influenced by genetic factors, estimates of the degree of inheritance of obesity, according to the type of study range from 30 to 70%. Newly detected genetic risk factor for body weight is the FTO gene ("fat mass and obesity associated"). Variants in the first (and in some populations also in the third) intron of this gene are associated with BMI values and the presence of one risk allele is associated with an increase of body weight by about 1.5-2 kg. Studies on the possible causality (impact on energy intake, basal metabolism, physical activity) did not show consistent results. Variants in the first intron are also associated with higher risk of type 2 diabetes, polycystic ovary syndrome, and cardiovascular disease and seem to play a role in the determination of certain types of cancer and are associated with higher mortality. The exact mechanism of the effect of FTO on BMI determination is not yet known, however, the FTO exhibit a DNA demethylase activity and its role is designed as a transcription coactivator. PMID- 22486288 TI - [Castlemans disease]. AB - Castlemans disease is a rare but potentially serious diagnosis and, therefore, this paper aims to enhance the medical community's knowledge of this diverse disease. This is a non-malignant angiofollicular nodular hyperplasia. There are three types according to the histological picture - hyalinvascular, plasmocellular and plasmablastic, and two types according to the clinical picture - unicentric and multicentric. The symptoms are rather heterogeneous, from an asymptomatic mass seen in the unicentric form, to life-threatening systemic inflammatory state with systemic symptoms in the multicentric form. Pathophysiological mechanism involves hypersecretion of IL-6 cytokin, although the process trigger is known only in a small proportion of cases. This is HHV-8 infection that, however, is not found in every patient with Castlemans disease. Aetiology in HHV-8 negative patients is unclear. The disease is associated with a range of autoimmune conditions and some haematological malignancies. Surgical resection, some-times followed with radiotherapy, is the gold standard in the treatment of the unicentric form. Anti-IL-6 monoclonal antibodies are the optimal therapy of the multicentric form, although other modalities, including corticosteroids, chemotherapy (CHOP, CVAD), immunomodulators and rituximab, given in monotherapy or in combination, are more accessible in real practice. PMID- 22486289 TI - [Secondary dyslipidemias]. AB - Dyslipidemias rank among the most important preventabile factors of atherogenesis and its progression. This topic is increasingly being discussed as e.g. more than 50% of Slovak population die on atherosclerotic complications. According to etiology we distinguish primary dyslipidemias with strictly genetic background and secondary ones with origin in other disease or pathological state. Secondary dyslipidemias accompany various diseases, from common (endocrinopathies, renal diseases etc) to rare ones (thesaurismosis etc.) and represents one of symptoms of these diseases. Apart from particular clinical follow up of diagnosed dysipidemias, basic screening and secondary causes as well as treatment due to updated guidelines is recuired. In this review we present the most frequent dyslipidemias of clinical practice. PMID- 22486290 TI - [Androgen deficit and diabetes]. AB - Low testosterone level is common in obese men and even more frequent in the presence of type 2 diabetes mellitus. Low testosterone level is probably not caused by increased aromatization of testosterone to estradiol in fat tissue. Increase of inflammation mediators, insulin and leptin resistance and low SHBG level may play more important role. Low testosterone level may manifest with low libido, erectile dysfunction, fatigue and depressive mood; it has a role in development of anaemia, osteoporosis, worsening of insulin resistance and it is probably marker of increased all-case and cardiovascular mortality. Routine investigation of testosterone level is indicated in every man with type 2 diabetes mellitus. As in non-diabetic men of middle and higher age substitution is indicated only in presence of clinical symptoms of hypogonadism. The substitution improves mainly libido, erectile dysfunction is influenced less. However, the phosphodiasterase-5 inhibitors efficiency is markedly improved. Metabolic changes during testosterone substitution are small. PMID- 22486291 TI - [Guidelines for alemtuzumab treatment in chronic lymphocytic leukaemia (CLL)]. AB - Alemtuzumab, the humanized monoclonal anti-CD52 antibody, is an effective agent in the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL). Due to many specific issues associated with alemtuzumab treatment, the Working Committee of Czech CLL Study Group developed these guidelines. SUMMARY OF RECOMMENDATIONS: (1) The main indication of alemtuzumab is fludarabine-refractory CLL. (2) Further possible indications include first-line treatment (in patients who cannot be treated by fludarabine-containing regimens), therapy of patients with del 17p, treatment of refractory autoimmune cytopenias and management of patients with severe cytopenias due to bone marrow infiltration. (3) The treatment should last 12 weeks and should not be terminated prematurely if there are no signs of CLL progression; bone marrow aspirate/biopsy can be performed after 12 weeks of treatment. (4) Subcutaneous administration of alemtuzumab seems to be equally effective with advantageous reduction of infusion-related adverse events. (5) Patients treated with alemtuzumab must receive combined antimicrobial prophylaxis against Pneumocystis jiroveci and herpetic viruses. Cytomegalovirus viremia should be monitored using weekly PCR from peripheral blood. (6) Use of alemtuzumab in combinations and consolidation/maintenance protocols must be considered experimental and needs optimization within prospective clinical trials. (7) Alemtuzumab treatment should be conducted by an experienced hematologist within a center of intensive hematology care. PMID- 22486292 TI - [Recommendations of care for patients with prediabetes]. PMID- 22486293 TI - [The role of PET-CT in decision making on the treatment of localized nodular form of pulmonary AL-amyloidosis]. AB - Depending on the extent of organism affected, there is a systemic (amyloid is deposited in the interstitial space of multiple tissues and organs) and localized (amyloid is deposited in one or a few solitary lesions) form of amyloidosis. Localized forms of amyloidosis have a significantly better prognosis than the systemic ones. The respiratory tract might be affected by diffuse interstitial involvement, associated with systemic AL-amyloidosis, as well as localised involvement of respiratory tract (localised laryngotracheobronchial amyloidosis) or pulmonary parenchyma called nodular form of localized pulmonary amyloidosis. Tracheobronchial form may affect larynx and bronchial tree, and forms plaques or nodules in the epithelium of the respiratory tract. Nodular form causes spherical or irregular lesions in the pulmonary parenchyma, indistinguishable from pulmonary parenchyma metastases. We describe a two-year follow up of a patient with nodular form of pulmonary amyloidosis. The patient had multiple lesions in both lungs, clearly visible on HRCT (High Resolution Computer Tomography) that intensively accumulated fluorodeoxyglucose (FDG) during the first PET-CT. At the time of diagnosis, the largest lesion SUV for FDG accumulation was 8.2. Histochemical analysis showed that amyloid consisted of the light lambda chains, i.e. AL-amyloid. Investigations to detect a systemic form of amyloidosis, if present, were negative. The patient had no monoclonal immunoglobulin either in the urine or serum (negative immunofixation) and had normal levels of free light chains in the serum. Her symptoms were previously suggestive of the Sjogrens syndrome. However, the rheumatologist consulted at the time of diagnosis of the nodular form of pulmonary amyloidosis did not find any signs of an active systemic connective tissue disorder. CRP was repeatedly normal. When systemic AL amyloidosis was excluded, we decided to only monitor lesion development with no treatment intervention. The patient had 3 PET-CTs. CT showed that no lesions enlarged, some lesions decreased in size slightly. It should be emphasized that follow-up PET-CTs did not show increased FDG accumulation. We assume that the increased FDG accumulation in pulmonary lesions seen during the first PET-CT was due to the activity of the cells that formed this amyloid and that this activity spontaneously ceased, leading to normalization of FDG accumulation in pulmonary nodules. PET-CT is useful for monitoring of the development of pulmonary nodular amyloidosis. Normalization of originally increased FDG accumulation in amyloid lesions suggests cessation of the process of amyloid formation and is a positive prognostic sign. PMID- 22486295 TI - Correlation of 2D parameters to lung and heart dose-volume in radiation treatment of breast cancer. PMID- 22486294 TI - Previous pregnancy is a favourable prognostic factor in women with localised cutaneous melanoma. AB - BACKGROUND: The influence of pregnancy on survival in melanoma has been a controversial issue. OBJECTIVE: In this retrospective study we investigated whether pregnancy (overall or temporally melanoma-related) has any effect on melanoma progression or patient outcome. METHODS: Patient data were collected from Turku University Hospital records concerning all women in fertile age (15-45 years) and diagnosed with melanoma between January 1, 1990 and December 31, 2009. We collected data on melanoma characteristics, treatment, pregnancies and patient outcomes. RESULTS: Of the 334 patients, 248 (74%) had been pregnant in some point during their life while 55 (17%) were nulliparous. The history of pregnancies could not be verified in 31 women (9%). Progression of melanoma to advanced stage was found in 58 (17%) of these women. Altogether, 35 women (14%) with at least one pregnancy had disease progression in contrast to 14 women (26%) with no pregnancies (p =0.049). Women with at least one pregnancy had a 94% probability to survive from melanoma compared to nulliparous women of whom only 83% survived (p =0.041). In Multivariate (COX) analysis pregnancy was a favourable factor for disease-specific survival (DSS) (HR 3.75; 95% CI 1.24-11.34; p =0.019) when adjusted for age (HR 1.064; 95% CI 1.00-1.13; p =0.50), localisation and stage (p =0.040), and Breslow (HR 1.32; 95% CI 1.10-1.58; p =0.002). However, when ulceration of the primary tumour was included in the multivariate model, Breslow remained as the only independent predictor of DSS (HR 1.58; 95% CI 1.34-1.86; p =0.0001) and pregnancy was dropped from the stepwise backward model in the step preceding the last one (p =0.081). CONCLUSION: Pregnancy is not a risk factor for disease recurrence or progression in melanoma patients, but instead can exert some favourable influence on prognosis. PMID- 22486296 TI - The rise of global warming skepticism: exploring affective image associations in the United States over time. AB - This article explores how affective image associations to global warming have changed over time. Four nationally representative surveys of the American public were conducted between 2002 and 2010 to assess public global warming risk perceptions, policy preferences, and behavior. Affective images (positive or negative feelings and cognitive representations) were collected and content analyzed. The results demonstrate a large increase in "naysayer" associations, indicating extreme skepticism about the issue of climate change. Multiple regression analyses found that holistic affect and "naysayer" associations were more significant predictors of global warming risk perceptions than cultural worldviews or sociodemographic variables, including political party and ideology. The results demonstrate the important role affective imagery plays in judgment and decision-making processes, how these variables change over time, and how global warming is currently perceived by the American public. PMID- 22486297 TI - From coarse-grained to atomic-level characterization of protein dynamics: transition state for the folding of B domain of protein A. AB - Atomic-level molecular dynamics simulations are widely used for the characterization of the structural dynamics of proteins; however, they are limited to shorter time scales than the duration of most of the relevant biological processes. Properly designed coarse-grained models that trade atomic resolution for efficient sampling allow access to much longer time-scales. In depth understanding of the structural dynamics, however, must involve atomic details. In this study, we tested a method for the rapid reconstruction of all atom models from alpha carbon atom positions in the application to convert a coarse-grained folding trajectory of a well described model system: the B domain of protein A. The results show that the method and the spatial resolution of the resulting coarse-grained models enable computationally inexpensive reconstruction of realistic all-atom models. Additionally, by means of structural clustering, we determined the most persistent ensembles of the key folding step, the transition state. Importantly, the analysis of the overall structural topologies suggests a dominant folding pathway. This, together with the all-atom characterization of the obtained ensembles, in the form of contact maps, matches the experimental results well. PMID- 22486298 TI - Novel fluorescence method for detection of alpha-L-fucosidase based on CdTe quantum dots. AB - The enzyme alpha-L-fucosidase (AFu) plays an important role in the diagnosis of hepatocellular carcinoma (HCC) and fucosidosis. In this paper, a simple, sensitive and precise method based upon measuring the fluorescence quenching of CdTe semiconductor quantum dots (QDs) was developed for detecting the enzymatic activity of AFu. The detection limit of AFu was 0.01 U/L (n = 3) and the linear relationship was 0.01-4 U/L. The selectivity experiment indicated excellent selectivity for AFu over a number of interfering species. We have also studied the detection mechanism of AFu by X-ray photoelectron spectroscopy (XPS) and found that the quenching effect was caused by the oxidation of tellurium by 2 chloro-4-nitrophenol (2-CNP) which produced in AFu catalytic reaction. Moreover, the AFu sensor based on QDs was used satisfactorily for the assessment of AFu activity in serum samples. It will most probably be applicable in assembling diagnostic microdevice to realize the rapid clinic analysis of AFu. PMID- 22486299 TI - Facile fabrication and magnetic properties of a one-dimensional magnetite peapod in a lipid nanotube. AB - Magnetite nanoclusters (MNCs) were aligned one-dimensionally in the hollow cavity of a lipid nanotube (LNT) as a peapod using a simple mixing method in an aqueous solution. The electrostatic interaction of the two materials was considerable enough to allow the preparation of a densely packed MNC-LNT peapod composite. The composite was formed at a pH 5.4-6.8, i.e., near the isoelectric point of the MNCs. At a pH 5.4-6.8, there was neither a strong attractive nor repulsive electrostatic interaction between the surface of the MNC and the LNT. The MNCs capped LNT composites were formed at basic conditions (above a pH 7.8) in which the MNCs and the LNT pushed each other because of their opposite surface charges. The magnetic property measurement revealed that the 1D aligned MNCs in the peapod structure had a much higher coercivity (10.6 Oe) than the bulk randomized MNCs (5.8 Oe). PMID- 22486300 TI - Adenosine and atrial arrhythmias: exploring electrophysiological mechanisms in vivo. PMID- 22486301 TI - Long-term comparison of video-assisted thoracic sympathectomy and clinical observation for the treatment of palmar hyperhidrosis in children younger than 14. AB - The results of video-assisted thoracic sympathectomy (VATS)in children are unknown. To investigate the improvement in quality of life (QOL) of a group of 45 children who did and did not undergo VATS for the treatment of palmar hyperhidrosis (PH) 4 years after the initial evaluation. Forty-five children with PH were initially evaluated. Children were divided into two groups: 30 in the VATS group and 15 in the control group. We studied the evolution of PH, negative effect of hyperhidrosis on the QOL before the treatment, and improvement in QOL after treatment. Twenty-five patients (83.4%) in the VATS group experienced great improvement in PH, and five (16.6%) experienced partial improvement; 12 (80.0%) children from the control group had some type of improvement, and three (20.0%) had partial improvement. Two (13.3%) children in the control group and 23 (76.7%) in the VATS group had great improvement in QOL. For children with PH and poor QOL, VATS is better than no treatment. It produces better results with regard to sweating and greater improvement in QOL. PMID- 22486303 TI - HCMV-encoded UL128 enhances TNF-alpha and IL-6 expression and promotes PBMC proliferation through the MAPK/ERK pathway in vitro. AB - Cytomegalovirus (CMV) infection enhances expression of several cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), granulocyte macrophage colony-stimulating factor (GM-CSF), and IL-8, to the benefit of virus replication and dissemination. However, the stimulus for certain cytokine production remains unclear. CMV encodes a series of proteins that alter and/or mimic functions of leukocyte migration, activation, and cytokine responses. Our study revealed that human CMV (HCMV)-encoded UL128 protein, which contains signal peptides and has similar amino acid sequences to the CC chemokine, recruits monocytes as human beta chemokine (microphage inflammatory protein 1alpha). Using RNA interference technology, we constructed an HCMV (UL128+/UL128-)-infected tissue cell (MRC-5) and peripheral blood mononuclear cell (PBMC) co-culture system. We measured 6 cytokine levels (IL-2, IL-4, IL-6, IL-10, TNF-alpha, and interferon-gamma [IFN-gamma]) in the supernatant, and found significantly elevated IL-6 and elevated TNF-alpha levels in the HCMV UL128+-infected group. Conversely, we observed decreased levels in the UL128-knockout supernatant. PBMCs presented with UL128 (50 ng/mL) demonstrated better cell viability than the UL128 absent group. Finally, the MAPK/ERK pathway was found to be involved in UL128 induction of cell proliferation. Selective induction of cytokine expression indicates that HCMV-encoded UL128 is a potent inducer of several inflammatory mediators. PMID- 22486304 TI - Interleukin-21 inhibits humoral response to an HIV DNA vaccine by enhancing Bcl-6 and Pax-5 expression. AB - Interleukin-21 (IL-21) is a T-cell-derived cytokine that modulates T-cell, B cell, and natural killer cell responses. It is not known if it could be used as an adjuvant for HIV DNA vaccination. In our study, we investigated if a DNA construct expressing IL-21 (designated as pVAX-IL-21) as a molecule adjuvant could enhance antigen-specific immune responses to an HIV DNA vaccine (pGX-EnvC). We found that a higher level of antigen-specific cytotoxic responses was induced in BALB/C mice immunized with pGX-EnvC with the pVAX-IL-21 via electroporation. The increased response was associated with higher expression of IFN-gamma in CD8+ T cells. In contrast, the administration of pVAX-IL-21 inhibited the antibody responses to HIV induced by the pGX-EnvC. The plasma cell inhibitory transcription factors B-cell lymphoma 6 protein (Bcl-6) and Pax-5 were increased in B cells from mice that had been immunized by HIV DNA vaccine plus pVAX-IL-21, suggesting that the expressed IL-21 may inhibit the differentiation from B cells to plasma cells. These results indicate that IL-21 could enhance CD8+ T-cell immunity, but inhibit humoral responses during HIV DNA vaccination. PMID- 22486305 TI - Human papillomavirus immunogen that provides protective tumor immunity and induces tumor regression. AB - Human papillomavirus (HPV) is associated with premalignant lesions such as high grade cervical intraepithelial neoplasia (CIN-III) with potential progression to cervical carcinoma. There are now preventive vaccines against HPV. However, no effective therapeutic vaccine or immunological treatment exists for individuals already infected or for the 470,000 women that develop high-grade dysplasia, carcinoma in situ, and cervical cancer each year. More than half of these women die from cervical cancer. Relative non-immunogenicity of HPV infection is one of the main reasons for the difficulty in designing a comprehensive therapeutic vaccine against HPV-induced premalignant lesions and cervical carcinoma. HPV E6 and E7 proteins, the major HPV oncogenes, are highly immunogenic but fail to induce cross-reactive and protective immune responses against heterologous strains. We designed and synthesized a therapeutic peptide vaccine comprised of multivalent peptide mixtures called hypervariable epitope constructs (HECs) that represent the major epitope variants of the oncogenic E7 structural protein, and assessed their immunogenicity and in vivo efficacy in mice. Our results show that this peptide vaccine can induce strong, HPV-specific, T-helper cell and CTL responses. More significantly, we have demonstrated that the vaccine is efficacious as a therapeutic agent in a mouse HPV tumor model. Therefore, the HPV HEC vaccine approach described herein can potentially prevent progression of HPV associated premalignant lesions, and may also be therapeutic against tumors associated with HPV. PMID- 22486306 TI - Structural salience and the nonaccidentality of a Gestalt. AB - We perceive structure through a process of perceptual organization. Here we report a new perceptual organization phenomenon-the facilitation of visual grouping by global curvature. Observers viewed patterns that they perceived as organized into collections of curves. The patterns were perceptually ambiguous such that the perceived orientation of the patterns varied from trial to trial. When patterns were sufficiently dense and proximity was equated for the predominant perceptual alternatives, observers tended to perceive the organization with the greatest curvature. This effect is tantamount to visual grouping by maximal curvature and thus demonstrates an unprecedented effect of global structure on perceptual organization. We account for this result with a model that predicts the perceived organization of a pattern as function of its nonaccidentality, which we define as the probability that it could have occurred by chance. Our findings demonstrate a novel relationship between the geometry of a pattern and the visual salience of global structure. PMID- 22486307 TI - Transurethral transvesical endoscopic management of a retrovesical hydatid cyst. AB - We present a technique of transurethral transvesical endoscopic management of an intraperitoneal retrovesical hydatid cyst. Cystoscopy is performed using a 20.8F nephroscope. The cyst is punctured using an 18-gauge, 36-cm needle through the nephroscope operating channel. Saline (20%) is used as scolicidal agent. After balloon tract dilation, the nephroscope is introduced into the cyst, and the hydatid material is evacuated. PMID- 22486308 TI - A nationwide descriptive study of obstetric claims for compensation in Norway. AB - OBJECTIVE: To describe causes of substandard care in obstetric compensation claims. DESIGN AND SETTING: A nationwide descriptive study in Norway. POPULATION: All obstetric patients who believed themselves inflicted with injuries by the Health Service and applying for compensation. METHODS: Data were collected from 871 claims to The Norwegian System of Compensation to Patients during 1994-2008, of which 278 were awarded compensation. MAIN OUTCOME MEASURES: Type of injury and cause of substandard care. RESULTS: Of 871 cases, 278 (31.9%) resulted in compensation. Of those, asphyxia was the most common type of injury to the child (83.4%). Anal sphincter tear (29.9%) and infection (23.0%) were the most common types of injury to the mother. Human error, both by midwives (37.1% of all cases given compensation) and obstetricians (51.2%), was an important contributing factor in inadequate obstetric care. Neglecting signs of fetal distress (28.1%), more competent health workers not being called when appropriate (26.3%) and inadequate fetal monitoring (17.3%) were often observed. System errors such as time conflicts, neglecting written guidelines and poor organization of the department were infrequent causes of injury (8.3%). CONCLUSIONS: Fetal asphyxia is the most common reason for compensation, resulting in large financial expenses to society. Human error contributes to inadequate health care in 92% of obstetric compensation claims, although underlying system errors may also be present. PMID- 22486309 TI - Safety and efficacy of emamectin benzoate to treat Anguillicoloides crassus (Kuwahara, Niimi & Itagaki) infections in American eels, Anguilla rostrata (Lesueur). PMID- 22486310 TI - Maturation of alveolar bone following implantation of an rhGDF-5/PLGA composite into 1-wall intra-bony defects in dogs: 24-week histometric observations. AB - OBJECTIVE: The aim of this study was to evaluate long-term (24 weeks) alveolar bone maturation following surgical application of recombinant human growth/differentiation factor-5 (rhGDF-5) in an injectable poly-lactide-co glycolide-acid (PLGA) composite carrier using an established periodontal defect model. METHODS: Routine, bilateral, 4 * 5 mm (width * depth), 1-wall, critical size, intra-bony periodontal defects were surgically created at the 2nd and 4th mandibular premolar teeth in 10 Beagle dogs. The animals were randomized to receive (split-mouth design; defect sites in the same jaw quadrant getting the same treatment) rhGDF-5/PLGA high dose (188 MUg/defect) versus sham-surgery control (5 animals), and rhGDF-5/PLGA low dose (37 MUg/defect) versus carrier control (5 animals). The animals were euthanized for histometric analysis following a 24-week healing interval. RESULTS: Clinical healing was uneventful. The rhGDF-5 high dose significantly increased bone formation compared with controls in terms of bone area (p < 0.05), and a high degree of bone maturation was observed in the rhGDF-5/PLGA high dose group. Root resorption/ankylosis or other aberrant healing events were not observed. CONCLUSION: The rhGDF-5/PLGA appears to support alveolar bone healing/regeneration and the rhGDF-5/PLGA high dose uniquely increased maturation of the regenerated bone. PMID- 22486311 TI - Protective B-cell epitopes of Francisella tularensis O-polysaccharide in a mouse model of respiratory tularaemia. AB - Antibodies to the lipopolysaccharide (LPS) of Francisella tularensis have been shown to be protective against respiratory tularaemia in mouse models, and we have previously described mouse monoclonal antibodies (mAbs) to non-overlapping terminal and internal epitopes of the F. tularensis LPS O-polysaccharide (OAg). In the current study, we used F. tularensis LPS oligosaccharides of defined OAg repeat length as molecular rulers in competition ELISA to demonstrate that the epitope targeted by the terminal OAg-binding mAb FB11 is contained within one tetrasaccharide repeat whereas the epitope targeted by the internal OAg-binding mAb Ab52 spans two tetrasaccharide repeats. Both mAbs conferred survival to BALB/c mice infected intranasally with the F. tularensis type B live vaccine strain and prolonged survival of BALB/c mice infected intranasally with the highly virulent F. tularensis type A strain SchuS4. The protective effects correlated with reduced bacterial burden in mAb-treated infected mice. These results indicate that an oligosaccharide with two OAg tetrasaccharide repeats covers both terminal and internal protective OAg epitopes, which may inform the design of vaccines for tularaemia. Furthermore, the FB11 and Ab52 mAbs could serve as reporters to monitor the response of vaccine recipients to protective B cell epitopes of F. tularensis OAg. PMID- 22486312 TI - DNA mobility shift assay as a tool for the detection of anti-dsDNA antibodies in sera from discoid lupus erythematosus patients. AB - Discoid lupus erythematosus (DLE) is a form of local inflammatory autoimmune disease limited to the skin, involving essentially the face, scalp and ear. DLE occurs in genetically predisposed individuals, sunlight being an identified trigger. Diagnosis is made by clinical examination and histopathology; laboratory tests occasionally performed include anti-nuclear antibodies titers and presence of circulating antibodies against dsDNA. DLE patients have about a 10% chance of developing systemic lupus erythematosus (SLE), a systemic inflammatory autoimmune disease affecting a range of internal organs. Although elevated titers of anti dsDNA antibodies is an earmark for lupus disease, they are detected in only 20 55% of DLE patients by routine laboratory tests such as enzyme-linked immunosorbent assay (ELISA). In this research, we applied an electrophoretic mobility shift assay (EMSA) in parallel with an ELISA for the detection of circulating anti-dsDNA in DLE patients. The assays were conducted on sera as well as on the immunoglobulin G fraction from sera of 24 DLE patients and of 24 healthy individuals. The EMSA was positive for all DLE patients while the ELISA was positive for only 36% of them; both assays were negative for the healthy individuals. EMSA conducted on the sera of 15 patients with lichen planus was negative in all cases. Results suggest that the EMSA is more sensitive than the routine tests used for the detection of anti-dsDNA in DLE, thus helping to improve early detection of the disease and, by extension, to better evaluate the factors triggering the disease. PMID- 22486313 TI - Visible light-mediated atom transfer radical addition via oxidative and reductive quenching of photocatalysts. AB - Herein, the development of visible light-mediated atom transfer radical addition (ATRA) of haloalkanes onto alkenes and alkynes using the reductive and oxidative quenching of [Ir{dF(CF(3))ppy}(2)(dtbbpy)]PF(6) and [Ru(bpy)(3)]Cl(2) is presented. Initial investigations indicated that the oxidative quenching of photocatalysts could effectively be utilized for ATRA, and since that report, the protocol has been expanded by broadening the scope of the reaction in terms of the photocatalysts, substrates, and solvents. In addition, further modifications of the reaction conditions allowed for the efficient ATRA of perfluoroalkyl iodides onto alkenes and alkynes utilizing the reductive quenching cycle of [Ru(bpy)(3)]Cl(2) with sodium ascorbate as the sacrificial electron donor. These results signify the complementary nature of the oxidative and reductive quenching pathways of photocatalysts and the ability to predictably direct reaction outcome through modification of the reaction conditions. PMID- 22486315 TI - beta-Technetium trichloride: formation, structure, and first-principles calculations. AB - A second polymorph of technetium trichloride, beta-TcCl(3), has been identified from the reaction between Tc metal and Cl(2) gas. The structure of beta-TcCl(3) consists of infinite layers of edge-sharing octahedra, similar to its MoCl(3) and RuCl(3) analogues. The Tc-Tc distance [2.861(3) A] between adjacent octahedra is indicative of metal-metal bonding. Earlier theoretical work predicted that beta TcCl(3) is less stable than alpha-TcCl(3). In agreement with the prediction, beta TcCl(3) slowly transforms into alpha-TcCl(3) (Tc(3)Cl(9)) over 16 days at 280 degrees C. PMID- 22486314 TI - AAV-mediated gene targeting is significantly enhanced by transient inhibition of nonhomologous end joining or the proteasome in vivo. AB - Recombinant adeno-associated virus (rAAV) vectors have clear potential for use in gene targeting but low correction efficiencies remain the primary drawback. One approach to enhancing efficiency is a block of undesired repair pathways like nonhomologous end joining (NHEJ) to promote the use of homologous recombination. The natural product vanillin acts as a potent inhibitor of NHEJ by inhibiting DNA dependent protein kinase (DNA-PK). Using a homology containing rAAV vector, we previously demonstrated in vivo gene repair frequencies of up to 0.1% in a model of liver disease hereditary tyrosinemia type I. To increase targeting frequencies, we administered vanillin in combination with rAAV. Gene targeting frequencies increased up to 10-fold over AAV alone, approaching 1%. Fah(-/-)Ku70( /-) double knockout mice also had increased gene repair frequencies, genetically confirming the beneficial effects of blocking NHEJ. A second strategy, transient proteasomal inhibition, also increased gene-targeting frequencies but was not additive to NHEJ inhibition. This study establishes the benefit of transient NHEJ inhibition with vanillin, or proteasome blockage with bortezomib, for increasing hepatic gene targeting with rAAV. Functional metabolic correction of a clinically relevant disease model was demonstrated and provided evidence for the feasibility of gene targeting as a therapeutic strategy. PMID- 22486316 TI - Rituximab maintenance for relapsed refractory thrombotic thrombocytopenic purpura. AB - BACKGROUND: Rituximab, an anti-CD20 chimeric monoclonal antibody, has been used successfully to treat patients with relapsed or refractory thrombotic thrombocytopenic purpura (TTP); however, the optimal dose and frequency and the role of rituximab maintenance remain uncertain. STUDY DESIGN AND METHODS: We describe a 45-year-old woman with chronic relapsing immune thrombocytopenia who responded to rituximab retreatment administered in four doses over the course of 12 months. Previously, she had received four doses of rituximab and sustained a remission for 19 months. During her latest TTP relapse, multiple treatments were administered including rituximab retreatment. After the first dose (375 mg/m2), she developed serum sickness requiring further doses to be deferred. Three subsequent doses were administered at 4-month intervals over the course of 12 months. ADAMTS13 activity was measured by von Willebrand factor (VWF) digestion. ADAMTS13 inhibition was measured by a modification of the VWF digestion assay and anti-ADAMTS13 antibodies were measured by enzyme-linked immunoassay (enzyme linked immunosorbent assay, American Diagnostica). RESULTS: Clinical and laboratory remission were achieved after one dose of rituximab, with normalization of ADAMTS13 activity and disappearance of ADAMTS13 inhibitor. Three subsequent doses of rituximab were given without incident and the patient remained in remission after 3.5 years of follow-up (2.5 years since her last dose of rituximab). CONCLUSION: Maintenance dosing of rituximab should be considered in some patients with relapsing TTP. PMID- 22486317 TI - Diabetes before and after lung transplantation in patients with cystic fibrosis and other lung diseases. AB - AIMS: The aims of the study are to investigate the prevalence of diabetes in patients with cystic fibrosis compared with patients without cystic fibrosis, and its impact on the outcome after lung transplantation. METHODS: Data were reviewed from 77 lung transplantation recipients in our centre between 2001 and 2010; 43 patients had cystic fibrosis and 34 patients had other lung diseases (no cystic fibrosis). To define diabetes, we used the American Diabetes Association definition. RESULTS: Before lung transplantation, diabetes was diagnosed in 63% of patients with cystic fibrosis and 6% of patients without cystic fibrosis (P<0.001). In both groups, approximately 60% of the patients at risk developed new-onset diabetes after transplantation. The mortality in patients with cystic fibrosis was higher in patients with diabetes diagnosed before lung transplantation compared with those without (44 vs. 6%, P=0.04). Diabetes remained an independent factor in multivariate analyses. CONCLUSIONS: Diabetes diagnosed before lung transplantation has a negative effect on survival after lung transplantation in patients with cystic fibrosis. Pre-existing diabetes is common in patients with cystic fibrosis, in contrast to patients without cystic fibrosis. Development of new-onset diabetes after transplantation is similar in both groups. PMID- 22486318 TI - Regulation of the activity and expression of aryl hydrocarbon receptor by ethanol in mouse hepatic stellate cells. AB - BACKGROUND: During the course of alcohol-induced liver damage, hepatic stellate cells are transformed into proliferative, fibrogenic, and contractile myofibroblasts. Aryl hydrocarbon receptor (AhR) is a transcription factor that controls the expression of genes involved in the metabolism of xenobiotics, inflammation, cell proliferation, and death. METHODS: Immortal mouse hepatic stellate cells (MHSCs) were isolated from transgenic mice that expressed a thermolabile SV40 tumor antigen. Quantitative real-time reverse transcription polymerase chain reaction assays, Western blot analysis, promoter activity assays, and chromatin immunoprecipitation analyses were performed for studying the effect of ethanol (EtOH) on AhR expression and transcriptional activity. RESULTS: Treatment of MHSCs with 50 to 200 mM EtOH for 6 hours induced AhR nuclear translocation, enhanced the promoter activity of cytochrome P450 (CYP) 1A1, increased the amount of AhR bound to the promoter of CYP1A1 and 1B1, and up regulated the mRNA expression of these AhR target genes in a dose-dependent manner. In contrast, EtOH exposure down-regulated AhR mRNA and protein expression. Similarly, benzo(a)pyrene (BaP) at 10 nM reduced AhR and increased CYP1A1 and 1B1 mRNAs. Pretreatment of MHSCs with 50 mM EtOH for 7 days diminished the capacity of MHSCs to express CYP1A1 and 1B1 induced by a 200 mM EtOH challenge, or by 10 nM BaP. However, the up-regulatory effect of EtOH on solute carrier family 16, member 6 (SLC16a6) was unaffected by EtOH pretreatment. Similar to EtOH, dimethyl sulfoxide (DMSO) at concentrations of 50 to 100 mM down regulated AhR and up-regulated CYP1A1 mRNA expression in a dose-dependent manner. CONCLUSIONS: These data, for the first time, demonstrate that EtOH activates MHSC AhR and down-regulates its expression. Chronic EtOH pretreatment lowers the availability of AhR, and specifically diminishes the inducibility of CYP genes. The effect on AhR appears to not be an EtOH-specific response, as DMSO alone (and possibly other organic solvents) was also able to activate AhR. PMID- 22486319 TI - Solitary, multifocal and generalized myofibromas: clinicopathological and immunohistochemical features of 114 cases. AB - AIMS: To report a large series of solitary and multiple myofibromas with systematic clinicopathological correlations. METHODS AND RESULTS: We report on 114 patients with myofibromas, 97 of which were solitary and 17 multifocal. The age at presentation ranged from newborn to 70 years. All multifocal myofibromas and 91% of solitary myofibromas occurred in children. The head and neck region was the most common site (n = 43), followed by the trunk (n = 24), lower limbs (n = 14), upper limbs (n = 11), and viscera (n = 4). Solitary and multifocal myofibromas stained positively for smooth muscle actin (SMA) in 95% and 92% of cases, muscle-specific actin (MSA) in 75% and 50% of cases, and desmin in 10% and 14% of cases, respectively. Regressive features were seen in 34 solitary myofibromas and in nine multifocal myofibromas. Most patients were treated with complete excision (n = 79) or partial excision (n = 12). There were no recurrences after treatment. CONCLUSIONS: Solitary and multiple myofibromas are benign tumours that predominantly occur in infancy and childhood. Myofibromas occur especially in the head and neck region, and are characterized by SMA and, to a lesser extent, MSA expression. The clinical course is self-limiting, and local excision appears to be sufficient. PMID- 22486320 TI - Brittle cornea without clinically-evident extraocular findings in an adult harboring a novel homozygous ZNF469 mutation. PMID- 22486321 TI - Ocular anomalies in an infant with Klinefelter Syndrome. AB - Klinefelter syndrome is caused by the presence of one or more additional X chromosomes in an affected male. Patients often exhibit gynecomastia, small testes, and infertility. Though the characteristics of Klinefelter have been well documented, associated ocular abnormalities have been only occasionally reported. Here we present a 2-month-old infant with Klinefelter syndrome and a unique combination of ocular abnormalities including microphthalmia, cataracts, and malformed pupils. PMID- 22486322 TI - Ophthalmic and systemic findings in interstitial deletions of chromosome 14q: a case report and literature review. AB - We report a patient with clinical anophthalmia, partial eyelid fusion and a hypoplastic socket on the right. The left eye has microphthalmia involving the anterior and posterior segments, microcornea, iris coloboma, chorioretinal dysgenesis, macular dysplasia, absence of retinal vessels, and optic nerve aplasia. Systemic abnormalities include microcephaly, bilateral hearing loss, and duodenal atresia. Electrophysiologic testing showed no response from either eye. Cytogenetic testing revealed a de novo interstitial deletion of chromosome 14q22.3q23.1. The literature of similar interstitial deletions and ongoing candidate gene studies are reviewed. PMID- 22486323 TI - Association of CFH Y402H polymorphism with both forms of advanced age-related macular degeneration in Turkish patients. AB - PURPOSE: The purpose of this study was to investigate the association between complement factor H Y402H polymorphism and age-related macular degeneration (AMD) development in a cohort of Turkish patients. METHODS: A total of 182 individuals, including 95 individuals with unrelated late age-related macular degeneration and 87 age-matched healthy individuals as a control group were genotyped with polymerase chain reaction followed by restriction enzyme digestion and direct sequence analysis. The statistical analysis was performed with statistical software R 2.9.2 and epicalc package. RESULTS: The Y402H variant in the CFH gene was found to be associated with late AMD in our study population. Genotypic frequencies were highly different between all patients and control individuals compared for the heterozygotes carrying the risk allele C (AMD patients (CT) 70.5%, control individuals (CT) 54.02%; chi(2)= 5.285, d.f. = 1, p = 0.02). When all AMD patients were compared with the healthy control group, TC heterozygotes showed a significantly increased risk of AMD (O.R = 2.32, CI% 1.23-4.35). CONCLUSION: This study suggests that the CFH Y402H polymorphism is associated with increased risk for both types of end-stage AMD in Turkish patients. PMID- 22486324 TI - GPR143 gene mutation analysis in pediatric patients with albinism. AB - BACKGROUND: X-linked ocular albinism type 1 is difficult to differentiate clinically from other forms of albinism in young patients. X-linked ocular albinism type 1 is caused by mutations in the GPR143 gene, encoding melanosome specific G-protein coupled receptor. Patients typically present with moderately to severely reduced visual acuity, nystagmus, strabismus, photophobia, iris translucency, hypopigmentation of the retina, foveal hypoplasia and misrouting of optic nerve fibers at the chiasm. MATERIALS AND METHODS: Following clinical ophthalmological evaluation, GPR143 gene mutational analyses were performed in a cohort of 15 pediatric male patients with clinical signs of albinism. RESULTS: Three different mutations in the GPR143 gene were identified in four patients, including a novel c.886G>A (p.Gly296Arg) mutation occurring "de novo" and a novel intronic c.360 + 5G>A mutation, identified in two related boys. CONCLUSIONS: Four patients with X-linked ocular albinism type 1 were identified from a cohort of 15 boys with clinical signs of albinism using mutation detection methods. Genetic analysis offers the possibility of early definitive diagnosis of ocular albinism type 1 in a significant portion of boys with clinical signs of albinism. PMID- 22486325 TI - Familial spherophakia with short stature caused by a novel homozygous ADAMTS17 mutation. AB - PURPOSE: Weill-Marchesani syndrome is characterized by spherophakia, short stature, short hands/feet, joint stiffness, and occasional cardiac abnormalities. The phenotype can be caused by recessive ADAMTS10 mutations or heterozygous fibrillin-1 mutation. In contrast, isolated spherophakia with short stature has been associated with three different homozygous ADAMTS17 mutations in three families from Saudi Arabia. The purpose of this report is to determine the genetic cause of isolated spherophakia with short stature in two siblings from a consanguineous Saudi family. METHODS: Clinical examination, homozygosity screen, and candidate gene analysis. RESULTS: A brother and sister with high myopia were referred for genetic counseling. Ophthalmic examination revealed spherophakia in both and narrow angles in the sister. Axial lengths were not elongated. Although both had short stature, neither had short hands, short feet, joint stiffness, or non-ocular congenital abnormalities. Homozygosity analysis suggested the candidate gene ADAMTS17, which was found to harbor a novel homozygous mutation (p.Asp218ThrfsX41) that segregated with the phenotype. CONCLUSIONS: Recessive ADAMTS17 mutations are a recurrent cause of isolated spherophakia with short stature. In Saudi Arabia this phenotype shows allelic heterogeneity rather than founder effect. PMID- 22486326 TI - Ophthalmologic abnormalities in Mowat-Wilson syndrome and a mutation in ZEB2. AB - Mowat-Wilson syndrome is a genetic disorder characterized by a distinct facial appearance, moderate-to-severe mental retardation, microcephaly, agenesis of the corpus callosum, Hirschsprung disease, congenital heart disease, and genital anomalies. Ophthalmological abnormalities have been rarely described in patients with this condition which is caused by mutations in the ZEB2 gene. We report a 9 year-old female with this syndrome who has severe ocular abnormalities including bilateral microphthalmia, cataract, and retinal aplasia. PMID- 22486327 TI - Salting-in and salting-out of water-soluble polymers in aqueous salt solutions. AB - To obtain further experimental evidence for the mechanisms of the salting effect produced by the addition of salting-out or sating-in inducing electrolytes to aqueous solutions of water-soluble polymers, systematic studies on the vapor liquid equilibria and liquid-liquid equilibria of aqueous solutions of several polymers are performed in the presence of a large series of electrolytes. Polymers are polyethylene glycol 400 (PEG400), polyethylene glycol dimethyl ether 250 (PEGDME250), polyethylene glycol dimethyl ether 2000 (PEGDME2000), and polypropylene glycol 400 (PPG400), and the investigated electrolytes are KCl, NH(4)Cl, MgCl(2), (CH(3))(4)NCl, NaCl, NaNO(3), Na(2)CO(3), Na(2)SO(4), and Na(3)Cit (tri-sodium citrate). Aqueous solutions of PPG400 form aqueous two-phase systems with all the investigated salts; however, other investigated polymers form aqueous two-phase systems only with Na(2)CO(3), Na(2)SO(4), and Na(3)Cit. A relation was found between the salting-out or sating-in effects of electrolyte on the polymer aqueous solutions and the slopes of the constant water activity lines of ternary polymer-salt aqueous solutions, so that, in the case of the salting out effect, the constant water activity lines had a concave slope, but in the case of the salting-in effects, the constant water activity lines had a convex slope. The effect of temperature, anion of electrolyte, cation of electrolyte, and type and molar mass of polymers were studied and the results interpreted in terms of the solute-water and solute-solute interactions. The salting-out effect results from the formation of ion (specially anion)-water hydration complexes, which, in turn, decreases hydration, and hence, the solubility of the polymer and the salting-in effect results from a direct binding of the cations to the ether oxygens of the polymers. PMID- 22486328 TI - Proton-in-flight mechanism for the spontaneous hydrolysis of N-methyl O-phenyl sulfamate: implications for the design of steroid sulfatase inhibitors. AB - The hydrolysis of N-methyl O-phenyl sulfamate (1) has been studied as a model for steroid sulfatase inhibitors such as Coumate, 667 Coumate, and EMATE. At neutral pH, simulating physiological conditions, hydrolysis of 1 involves an intramolecular proton transfer from nitrogen to the bridging oxygen atom of the leaving group. Remarkably, this proton transfer is estimated to accelerate the decomposition of 1 by a factor of 10(11). Examination of existing kinetic data reveals that the sulfatase PaAstA catalyzes the hydrolysis of sulfamate esters with catalytic rate accelerations of ~10(4), whereas the catalytic rate acceleration generated by the enzyme for its cognate substrate is on the order of ~10(15). Rate constants for hydrolysis of a wide range of sulfuryl esters, ArOSO(2)X(-), are shown to be correlated by a two-parameter equation based on pK(a)(ArOH) and pK(a)(ArOSO2XH). PMID- 22486329 TI - Attention deficit hyperactivity disorder and severity of substance use: the role of comorbid psychopathology. AB - Attention deficit hyperactivity disorder (ADHD) is a highly comorbid disorder, and, as such, there is much confusion surrounding the exact role it plays in increasing susceptibility to harmful behaviors. To date, no studies have examined the impact of adult ADHD on severity of substance use, while controlling for comorbid psychiatric disorders. Using a structured cross-sectional survey of 269 regular polysubstance users in Sydney, Australia, this study aimed to determine whether ADHD was a risk factor for more severity of substance use, and whether this effect remained when Borderline Personality Disorder (BPD) and Conduct Disorder (CD) diagnoses were controlled for. Rates of psychiatric disorders were high, with 45% meeting criteria for ADHD, 47% for BPD, and 64% for CD. While bivariate analyses showed that adult ADHD was significantly associated with all indicators of drug use severity, this effect did not remain once confounding factors were controlled. While ADHD accounted for very few differences in drug use severity, CD was found to independently predict all drug use severity indicators, including earlier onset, greater polydrug use, more frequent stimulant use, and greater risk for stimulant dependence. These results suggest that CD, rather than ADHD, is the strongest predictor of differences in patterns of drug use severity. The extensive comorbidity among this sample highlights the great potential for misattributing drug use risks to ADHD, and that it is important to account for psychiatric comorbidity to properly discern what underlying variables account for differences in harmful drug use behaviors. PMID- 22486330 TI - Abnormal affective decision making revealed in adolescent binge drinkers using a functional magnetic resonance imaging study. AB - The goal of this study was to investigate the neural correlates of affective decision making, as measured by the Iowa Gambling Task (IGT), which are associated with adolescent binge drinking. Fourteen adolescent binge drinkers (16 18 years of age) and 14 age-matched adolescents who had never consumed alcohol- never drinkers--were recruited from local high schools in Chengdu, China. Questionnaires were used to assess academic performance, drinking experience, and urgency. Brain regions activated by the IGT performance were identified with functional magnetic resonance imaging. Results showed that, compared to never drinkers, binge drinkers performed worse on the IGT and showed higher activity in the subcomponents of the decision-making neural circuitry implicated in the execution of emotional and incentive-related behaviors, namely, the left amygdala and insula bilaterally. Moreover, measures of the severity of drinking problems in real life, as well as high urgency scores, were associated with increased activity within the insula, combined with decreased activity within the orbitofrontal cortex. These results suggest that hyperreactivity of a neural system implicated in the execution of emotional and incentive-related behaviors can be associated with socially undesirable behaviors, such as binge drinking, among adolescents. These findings have social implications because they potentially reveal underlying neural mechanisms for making poor decisions, which may increase an individual's risk and vulnerability for alcoholism. PMID- 22486331 TI - The effect of desire thinking on craving: an experimental investigation. AB - Desire thinking is a voluntary cognitive process involving verbal and imaginal elaboration of a desired target. Recent research has revealed that desire thinking and craving are distinct constructs and that desire thinking may play a significant role in the escalation of craving. The goal of this study was to explore the effect of desire thinking induction on craving in a nonclinical sample. Forty-five volunteers with no current diagnosis of psychological disorders chose a desired activity and were randomly allocated to three thinking manipulation tasks: distraction, verbal reasoning, and desire thinking. Craving was measured before and after manipulation and during a 3-day period of abstinence from the desired activity. Findings showed that desire thinking had a significant effect on craving after manipulation. This effect appeared to be independent of baseline levels of craving and desire thinking as well as perceived stress changes during the manipulation. Both distraction and verbal reasoning inductions did not lead to a significant change in craving. Desire thinking impacts craving and is a risk factor for craving-related problems. PMID- 22486333 TI - Fitness supplements as a gateway substance for anabolic-androgenic steroid use. AB - Approximately 3.0% of young Americans have used anabolic-androgenic steroids (AAS). A traditional model of adolescent substance use, the gateway hypothesis, suggests that drug use follows a chronological, causal sequence, whereby initial use of a specific drug leads to an increased likelihood of future drug use. Therefore, the use of illicit appearance and performance enhancing drugs (APED), such as AASs, also follows an analogous progression, whereby legal APEDs, (e.g., nutritional supplements) precedes illicit APED use. We examined the relationship between nutritional supplement use, beliefs about APEDs, and APED use in 201 male (n = 100) and female (n = 101) undergraduates. Participants completed measures of muscle dysmorphia (MDDI), body checking (BCQ, MBCQ), eating disorder symptoms (EDE-Q), perfectionism (FMPS), positive beliefs about the efficacy-safety of AAS use and APED use patterns. A series of covariance structure models (CSM) showed body image disturbance, compulsive exercise, illicit drug use, and perfectionism, independent of gender, were significant predictors of positive beliefs about AAS. Those who used both fat burning and muscle building supplements reported the strongest beliefs in AAS efficacy-safety, which was associated with higher likelihood of current illicit APED use. There was evidence of significant indirect relationships between supplement use and illicit APED use through contact with other AAS users and beliefs about AAS. The potential role for nutritional supplement use in the initiation of illegal APED use is discussed. Future prevention efforts may benefit from targeting legal APED users in youth. PMID- 22486334 TI - Concurrent validity of an online version of the Timeline Followback assessment. AB - The Timeline Followback (TLFB) interview has been used extensively in the assessment of alcohol and other substance use. While this methodology has been validated in multiple formats for multiple behaviors, to date no systematic comparisons have been conducted between the traditional interview format and online versions. The present research employed a randomized within-subjects design to compare interview versus online-based TLFB assessments of alcohol and marijuana use among 102 college students. Participants were randomly assigned to receive either the online version first or the in-person interview format first. Participants subsequently completed the second format within 3 days. While we expected few overall differences between formats, we hypothesized that differences might emerge to the extent that participants are more comfortable and willing to answer honestly in an online format, which provides a degree of anonymity. Results were consistent with expectations in suggesting relatively few differences between the online version and the in-person version. Participants did report feeling more comfortable in completing the online version. Moreover, greater discomfort during the in-person assessment was associated with reporting more past-month marijuana use on the online assessment, but reported discomfort did not moderate differences between formats in reported alcohol consumption. PMID- 22486335 TI - A quantitative release assessment for the noncommercial movement of companion animals: risk of rabies reintroduction to the United kingdom. AB - In 2004, the European Union (EU) implemented a pet movement policy (referred to here as the EUPMP) under EU regulation 998/2003. The United Kingdom (UK) was granted a temporary derogation from the policy until December 2011 and instead has in place its own Pet Movement Policy (Pet Travel Scheme (PETS)). A quantitative risk assessment (QRA) was developed to estimate the risk of rabies introduction to the UK under both schemes to quantify any change in the risk of rabies introduction should the UK harmonize with the EU policy. Assuming 100 % compliance with the regulations, moving to the EUPMP was predicted to increase the annual risk of rabies introduction to the UK by approximately 60-fold, from 7.79 * 10(-5) (5.90 * 10(-5), 1.06 * 10(-4)) under the current scheme to 4.79 * 10(-3) (4.05 * 10(-3), 5.65 * 10(-3)) under the EUPMP. This corresponds to a decrease from 13,272 (9,408, 16,940) to 211 (177, 247) years between rabies introductions. The risks associated with both the schemes were predicted to increase when less than 100 % compliance was assumed, with the current scheme of PETS and quarantine being shown to be particularly sensitive to noncompliance. The results of this risk assessment, along with other evidence, formed a scientific evidence base to inform policy decision with respect to companion animal movement. PMID- 22486337 TI - In situ growth of Ni(x)Co(100-x) nanoparticles on reduced graphene oxide nanosheets and their magnetic and catalytic properties. AB - Ni(x)Co(100-x) (x = 0, 25, 50, 75, and 100) nanoparticles were uniformly in situ grown on reduced graphene oxide (RGO) nanosheets by a coreduction process for the first time. The as-synthesized products were characterized by X-ray powder diffraction (XRD), energy-dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), inductively coupled plasma optical emission spectrometry (ICP-OES), and transmission electron microscopy (TEM). It was found that RGO nanosheets can effectively prevent the aggregation of Ni(x)Co(100-x) nanoparticles. The size and morphology of the Ni(x)Co(100-x) nanoparticles on RGO nanosheets can be slightly adjusted by changing the Ni:Co atomic ratio. The magnetic properties of the RGO-Ni(x)Co(100-x) composites were investigated at 300 and 1.8 K, respectively. The results reveal that the composites have ferromagnetic characteristics and show composition dependent magnetic properties. In addition, these RGO-Ni(x)Co(100-x) nanocomposites also exhibit enhanced catalytic activities toward the reduction of 4-nitrophenol (4-NP) by NaBH(4) as compared with bare Ni(x)Co(100-x) alloy, and the RGO-Ni(25)Co(75) shows the highest catalytic activity among the obtained nanocomposites. This general and facile coreduction route can be extended to synthesize other alloy nanostructures on RGO nanosheets with various morphologies and functions, and provides a new opportunity for the application of graphene-based materials. PMID- 22486336 TI - In vivo quantitative study of sized-dependent transport and toxicity of single silver nanoparticles using zebrafish embryos. AB - Nanomaterials possess distinctive physicochemical properties (e.g., small sizes and high surface area-to-volume ratios) and promise a wide variety of applications, ranging from the design of high quality consumer products to effective disease diagnosis and therapy. These properties can lead to toxic effects, potentially hindering advances in nanotechnology. In this study, we have synthesized and characterized purified and stable (nonaggregation) silver nanoparticles (Ag NPs, 41.6 +/- 9.1 nm in average diameter) and utilized early developing (cleavage-stage) zebrafish embryos (critical aquatic and eco- species) as in vivo model organisms to probe the diffusion and toxicity of Ag NPs. We found that single Ag NPs (30-72 nm diameters) passively diffused into the embryos through chorionic pores via random Brownian motion and stayed inside the embryos throughout their entire development (120 hours-post-fertilization, hpf). Dose- and size-dependent toxic effects of the NPs on embryonic development were observed, showing the possibility of tuning biocompatibility and toxicity of the NPs. At lower concentrations of the NPs (<=0.02 nM), 75-91% of embryos developed into normal zebrafish. At the higher concentrations of NPs (>=0.20 nM), 100% of embryos became dead. At the concentrations in between (0.02-0.2 nM), embryos developed into various deformed zebrafish. Number and sizes of individual Ag NPs embedded in tissues of normal and deformed zebrafish at 120 hpf were quantitatively analyzed, showing deformed zebrafish with higher number of larger NPs than normal zebrafish and size-dependent nanotoxicity. By comparing with our previous studies of smaller Ag NPs (11.6 +/- 3.5 nm), we found striking size dependent nanotoxicity that, at the same molar concentration, the larger Ag NPs (41.6 +/- 9.1 nm) are more toxic than the smaller Ag NPs (11.6 +/- 3.5 nm). PMID- 22486338 TI - Scleral hemangioma: case report and response to propranolol. AB - Scleral infantile hemangiomas are rare. We describe a patient who presented at 3 months of age with an enlarging infantile hemangioma on the sclera of the left eye. He had two other hemangiomas on the left eyebrow and chest. Treatment with propranolol resulted in marked improvement of all of his hemangiomas. He did not develop any ocular complications. PMID- 22486339 TI - Editorial comment for Okhunov et al. PMID- 22486340 TI - Ligand-based virtual screening approach using a new scoring function. AB - In this study, we aimed to develop a new ligand-based virtual screening approach using an effective shape-overlapping procedure and a more robust scoring function (denoted by the HWZ score for convenience). The HWZ score-based virtual screening approach was tested against the compounds for 40 protein targets available in the Database of Useful Decoys (DUD; dud.docking.org/jahn/ ), and the virtual screening performance was evaluated in terms of the area under the receiver operator characteristic (ROC) curve (AUC), enrichment factor (EF), and hit rate (HR), demonstrating an improved overall performance compared to other popularly used approaches examined. In particular, the HWZ score-based virtual screening led to an average AUC value of 0.84 +/- 0.02 (95% confidence interval) for the 40 targets. The average HR values at the top 1% and 10% of the active compounds for the 40 targets were 46.3% +/- 6.7% and 59.2% +/- 4.7%, respectively. In addition, the performance of the HWZ score-based virtual screening approach is less sensitive to the choice of the target. PMID- 22486342 TI - Effects of resistance or aerobic exercise training on total and regional body composition in sedentary overweight middle-aged adults. AB - The purpose of this study was to examine the effects of 10 weeks of aerobic endurance training (AET), resistance exercise training (RET), or a control (CON) condition on absolute and relative fat mass (FM) or fat-free mass (FFM) in the total body (TB) and regions of interest (ROIs) of sedentary overweight middle aged males and females. Following prescreening, 102 subjects underwent anthropometric measurements, dual-energy X-ray absorptiometry, and strength and aerobic exercise testing. Randomized subjects (male RET, n = 16; female RET, n = 19; male AET, n = 16; and female AET, n = 25) completed supervised and periodized exercise programs (AET, 30-50 min cycling at 70%-75% maximal heart rate; RET, 2-4 sets * 8-10 repetitions of 5-7 exercises at 70%-75% 1 repetition maximum) or a nonexercising control condition (male CON, n = 13 and female CON, n = 13). Changes in absolute and relative TB-FM and TB-FFM and ROI-FM and ROI-FFM were determined. At baseline, and although matched for age and body mass index, males had greater strength, aerobic fitness, body mass, absolute and relative TB-FFM and ROI-FFM, but reduced absolute and relative TB-FM and ROI-FM, compared with females (p < 0.05). After training, both female exercise groups showed equivalent or greater relative improvements in strength and aerobic fitness than did the male exercise groups (p < 0.05); however, the male exercise groups increased TB FFM and reduced TB-FM more than did the female exercise groups (p < 0.05). Male AET altered absolute FM more than male RET altered absolute FFM, thus resulting in a greater enhancement of relative FFM. Despite equivalent or greater responses to RET or AET by female subjects, the corresponding respective increases in FFM or reductions in FM were lower than those in males, indicating that a biased dose response relationship exists between sexes following 10 weeks of exercise training. PMID- 22486343 TI - Comparison of the efficiency of sampling devices for aerosolized Burkholderia pseudomallei. AB - Previous studies have demonstrated that aerosol sampling devices can have deleterious effects on bacteria due to stresses intrinsic to the sampling processes. Although a significant amount of work has been carried out to develop animal models of inhalational melioidosis, little information has been reported on the effects of the aerosol sampling devices on the causative bacterium, Burkholderia pseudomallei. The aim of this study was to compare the efficiencies for collection of aerosolized bacteria in three sampling devices that have been used in studies utilizing aerosolized B. pseudomallei. The data from this study demonstrate the equivalence of the Mercer impactor, gelatin filter, and model 7541 AGI for sampling respirable aerosols containing B. pseudomallei across a range of aerosol concentrations. It was also determined that the retention efficiency of gelatin filters for culturable B. pseudomallei was near unity, suggesting that desiccation of collected material did not occur for the short sampling period tested. The retention efficiency of the model 7541 AGI for culturable B. pseudomallei was significantly less than unity, and it was determined that this decrease was likely due to the stresses associated with repetitive sampler bubbling. The results of this study also confirmed the results of previous studies on the deleterious effects of the Collison nebulizer on microorganisms and extended these data to include B. pseudomallei. PMID- 22486344 TI - Exposure to and deposition of fine and ultrafine particles in smokers of menthol and nonmenthol cigarettes. AB - INTRODUCTION: Research on the deposition of mainstream smoke particulate in the respiratory tract of smokers is needed to understand how exposure may vary based on cigarette menthol content. METHODS: We conducted a nine-participant crossover study in which smokers were randomly assigned to cigarettes differing primarily in menthol content. Participants smoked the test cigarettes ad libitum for one week, provided spot urine samples, and then smoked four test cigarettes in a laboratory session; this was repeated for the other test cigarette in week two. Fine and ultrafine particulate matter in exhaled breath were characterized, and smoking behavior was monitored. Participant-specific mainstream smoke, generated using each participant's topography data, was characterized. During home smoking, participants collected their spent test cigarette butts for estimates of mouth level exposures (MLE) to mainstream nicotine and 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK). RESULTS: Participant-specific mainstream smoke NNK was higher (39%) and daily MLE to NNK was also higher (52%) when participants smoked the menthol cigarette. Nicotine was not significantly different. Participants retained more ultrafine particulate (43%) and fine particulate benzo(a)pyrene (43%) when smoking the menthol cigarette. There were no significant differences in the levels of urinary biomarkers for nicotine, NNK, or pyrene. CONCLUSION: This study demonstrates the use of noninvasive real-time techniques to measure exposure differences between cigarettes differing primarily in menthol content. Differences between NNK exposure, ultrafine particle and benzo(a)pyrene deposition, and smoking behavior were observed. Additional research using these techniques with cigarettes that differ only in menthol content is required to unequivocally attribute the exposure differences to presence or absence of menthol. PMID- 22486345 TI - Identification of chemical components of combustion emissions that affect pro atherosclerotic vascular responses in mice. AB - Combustion emissions cause pro-atherosclerotic responses in apolipoprotein E deficient (ApoE/-) mice, but the causal components of these complex mixtures are unresolved. In studies previously reported, ApoE-/- mice were exposed by inhalation 6 h/day for 50 consecutive days to multiple dilutions of diesel or gasoline exhaust, wood smoke, or simulated "downwind" coal emissions. In this study, the analysis of the combined four-study database using the Multiple Additive Regression Trees (MART) data mining approach to determine putative causal exposure components regardless of combustion source is reported. Over 700 physical-chemical components were grouped into 45 predictor variables. Response variables measured in aorta included endothelin-1, vascular endothelin growth factor, three matrix metalloproteinases (3, 7, 9), metalloproteinase inhibitor 2, heme-oxygenase-1, and thiobarbituric acid reactive substances. Two or three predictors typically explained most of the variation in response among the experimental groups. Overall, sulfur dioxide, ammonia, nitrogen oxides, and carbon monoxide were most highly predictive of responses, although their rankings differed among the responses. Consistent with the earlier finding that filtration of particles had little effect on responses, particulate components ranked third to seventh in predictive importance for the eight response variables. MART proved useful for identifying putative causal components, although the small number of pollution mixtures (4) can provide only suggestive evidence of causality. The potential independent causal contributions of these gases to the vascular responses, as well as possible interactions among them and other components of complex pollutant mixtures, warrant further evaluation. PMID- 22486346 TI - Effects of fresh and aged vehicular exhaust emissions on breathing pattern and cellular responses--pilot single vehicle study. AB - The study presented here is a laboratory pilot study using diluted car exhaust from a single vehicle to assess differences in toxicological response between primary emissions and secondary products resulting from atmospheric photochemical reactions of gas phase compounds with O3, OH and other radicals. Sprague Dawley rats were exposed for 5 h to either filtered room air (sham) or one of two different atmospheres: (i) diluted car exhaust (P)+Mt. Saint Helens Ash (MSHA); (ii) P+MSHA+secondary organic aerosol (SOA, formed during simulated photochemical aging of diluted exhaust). Primary and secondary gases were removed using a nonselective diffusion denuder. Continuous respiratory data was collected during the exposure, and bronchoalveolar lavage (BAL) and complete blood counts (CBC) were performed 24 h after exposure. ANOVA models were used to assess the exposure effect and to compare those effects across different exposure types. Total average exposures were 363 +/- 66 MUg/m3 P+MSHA and 212 +/- 95 ug/m3 P+MSHA+SOA. For both exposures, we observed decreases in breathing rate, tidal and minute volumes (TV, MV) and peak and median flows (PIF, PEF and EF50) along with increases in breathing cycle times (Ti, Te) compared to sham. These results indicate that the animals are changing their breathing pattern with these test atmospheres. Exposure to P+MSHA+SOA produced significant increases in total cells, macrophages and neutrophils in the BAL and in vivo chemiluminescence of the lung. There were no significant differences in CBC parameters. Our data suggest that simulated atmospheric photochemistry, producing SOA in the P+MSHA+SOA exposures, enhanced the toxicity of vehicular emissions. PMID- 22486347 TI - Cardiovascular and thermoregulatory responses of unrestrained rats exposed to filtered or unfiltered diesel exhaust. AB - Diesel exhaust has been associated with adverse cardiovascular and pulmonary health effects. The relative contributions of the gas phase and particulate components of diesel exhaust are less well understood. We exposed telemetered Wistar-Kyoto rats to air or diesel exhaust that was either filtered (F) or unfiltered [gas-phase plus diesel exhaust particles (DEP)], containing ~1.9 mg/m3 of particulate matter for 5 h/day; 5 days/week for 4 consecutive weeks. Blood pressure (BP), core temperature (T(c)), heart rate (HR), and cardiac contractility (CC) estimated by the QA interval were monitored by radiotelemetry during exposure as well as during a 2-week period of recovery. Pulmonary injury and inflammation markers were analysed after 2-day, and 4 weeks of exposure, and 2-week recovery. Exposure to F or DEP was associated with a trend for a reduction in BP during weeks 1, 2 and 4. A reduction in HR in the DEP group was apparent during week 4. Exposure to DEP but not F was associated with significant reduction in CC over weeks 1-4. There was also a slight elevation in T(c) during DEP exposure. All telemetry parameters were normal during recovery at night and a 2-week recovery period. Neutrophilic inflammation in bronchoalveolar lavage fluid was evident after 2 days and 4 weeks of exposure to F and DEP. There were no signs of inflammation after 2-week recovery. We found a significant decrease in CC and slight reduction in BP. Exposure to DEP and F is associated with pulmonary inflammation, and mild effects on HR, BP, and T(c) but there is a marked effect of DEP on CC. PMID- 22486348 TI - Simulated downwind coal combustion emissions for laboratory inhalation exposure atmospheres. AB - Exposure atmospheres for rodent inhalation toxicology studies were generated to enable the evaluation of biological responses to a simulated downwind coal combustion atmosphere. A composition representing a single test case of emissions components as they may exist tens to hundreds of miles from a coal-fired power plant was developed. The particulate matter (PM) was 99% sulfate (partially neutralized) and 1% ash. Sulfate was present in equimolar concentrations to sulfur dioxide (SO2). Gaseous nitrogen species included nitrogen monoxide (NO), nitrogen dioxide (NO2), and nitric acid (HNO3). At the high-exposure level, the gaseous species target concentrations were 0.2 ppm SO2, 0.6 ppm NO, 0.3 ppm NO2, and 0.1 ppm HNO3. The test atmosphere was produced by combining effluent from a laboratory coal combustor with sulfate generated through an evaporation condensation generator. These atmospheres were used to conduct inhalation toxicology studies that have been previously reported. PMID- 22486351 TI - Two double heterozygotes in a South African Afrikaner family: implications for BRCA1 and BRCA2 predictive testing. PMID- 22486349 TI - Manufactured and airborne nanoparticle cardiopulmonary interactions: a review of mechanisms and the possible contribution of mast cells. AB - Human inhalation exposures to manufactured nanoparticles (NP) and airborne ultrafine particles (UFP) continues to increase in both occupational and environmental settings. UFP exposures have been associated with increased cardiovascular mortality and morbidity, while ongoing research supports adverse systemic and cardiovascular health effects after NP exposures. Adverse cardiovascular health effects include alterations in heart rate variability, hypertension, thrombosis, arrhythmias, increased myocardial infarction, and atherosclerosis. Exactly how UFP and NP cause these negative cardiovascular effects is poorly understood, however a variety of mediators and mechanisms have been proposed. UFP and NP, as well as their soluble components, are known to systemically translocate from the lung. Translocated particles could mediate cardiovascular toxicity through direct interactions with the vasculature, blood, and heart. Recent study suggests that sensory nerve stimulation within the lung may also contribute to UFP- and NP-induced acute cardiovascular alterations. Activation of sensory nerves, such as C-fibers, within the lung may result in altered cardiac rhythm and function. Lastly, release of pulmonary-derived mediators into systemic circulation has been proposed to facilitate cardiovascular effects. In general, these proposed pulmonary-derived mediators include proinflammatory cytokines, oxidatively modified macromolecules, vasoactive proteins, and prothrombotic factors. These pulmonary-derived mediators have been postulated to contribute to the subsequent prothrombotic, atherogenic, and inflammatory effects after exposure. This review will evaluate the potential contribution of individual mediators and mechanisms in facilitating cardiopulmonary toxicity following inhalation of UFP and NP. Lastly, we will appraise the literature and propose a hypothesis regarding the possible role of mast cells in contributing to these systemic effects. PMID- 22486352 TI - Treatment with the cancer drugs decitabine and doxorubicin induces human skin keratinocytes to express Oct4 and the OCT4 regulator mir-145. AB - Previously, we showed that transient transfection with OCT4 not only produced high expression of Oct4 in skin keratinocytes, but also caused a generalized demethylation of keratinocyte DNA. We hypothesized that DNA demethylation alone might allow expression of endogenous OCT4. Here, we report that treatment with the cancer drug decitabine results in generalized DNA demethylation in skin keratinocytes, and by 48 h after treatment, 96% of keratinocytes show expression of the endogenous Oct4 protein and the OCT4 repressor mir-145. This is true for keratinocytes only, as skin fibroblasts treated similarly show no OCT4 or mir-145 expression. Decitabine-treated keratinocytes also show increased mir-302c and proliferation similar to other Oct4(+) cells. Treatment with doxorubicin, another cancer drug, induces expression of mir-145 only in cells that already express OCT4, suggesting that Oct4 regulates its own repressor. Co-treatment with decitabine and doxorubicin results first in increased OCT4 and mir-145, then a decrease in both, suggesting that OCT4 and mir-145 regulate each other. The novel strategy presented here provides a regulatable system to produce Oct4(+) cells for transformation studies and provides a unique method to study the effects of endogenous Oct4 in cancer cells and the surrounding somatic cells. PMID- 22486355 TI - What predicts high risk acute graft-versus-host disease (GVHD) at onset?: identification of those at highest risk by a novel acute GVHD risk score. AB - To define high-risk acute graft-versus-host disease (GVHD) at onset, we examined the initial GVHD stage and grade of 864 patients at the University of Minnesota who received uniform therapy with prednisone 60 mg/m(2) per d. We compared the prognostic utility of the Minnesota (MN; modified from Consensus) versus Center for International Blood and Marrow Transplant Research (CIBMTR) GVHD organ stage derived grading systems. As neither GVHD grading system optimally predicted outcomes, a novel acute GVHD risk score was devised by combining the MN and CIBMTR systems. Using multiple regression analysis, we could dichotomize patients into high risk (HR, n = 86) acute GVHD with initial grade IIIC, IIID or IVD who were less likely to respond to steroid therapy by day 28 [relative risk (RR), 0.3, P < 0.001] and had a higher risk for transplant-related mortality (RR, 2.0, P < 0.001) than patients with standard risk (SR, initial grade IA-IIIB, n = 778) GVHD. Using this novel acute GVHD Risk Score, HR GVHD is either skin stage 4, lower gastrointestinal (GI) stage 3+, liver stage 3+, or skin stage 3 and lower GI or liver stage 2+ GVHD. Patients with HR acute GVHD have a poor prognosis, require alternative initial therapy and should be the focus of novel therapeutic trials. PMID- 22486356 TI - Assessing diabetes support in adolescents: factor structure of the modified Diabetes Social Support Questionnaire (DSSQ-Friends). AB - AIMS: To determine the underlying factor structure of friends' enacted support behaviours for adolescents with Type 1 diabetes, confirm it in a second sample, delineate distinctive aspects of friends' support and test the reliability of resulting scale. METHODS: The study included a total of 434 adolescents (54.8% girls), mean age 14.7 years, mean duration of diabetes 6.1 years. RESULTS: Results from the exploratory factor analysis, including data from a random half of the participants revealed a five-factor solution explaining approximately 48.4% of the item variance. The five factors emerged Guidance and Encouragement (13 items; alpha=0.91), Help in Critical Situations (7 items; alpha=0.92), Nourishment (11 items; alpha=0.88), Empathy (6 items; alpha=0.83) and Help in Exercise (5 items; alpha=0.76). Confirmatory factor analysis on the remainder of the sample showed good indices of model fit. Comparison of the factor structure across gender and age also presented an excellent fit. In a second-order factor analysis all five factors loaded on one overall factor, Diabetes Social Support Friends. Construct validity of the resulting scales was supported by predicted associations of Modified Diabetes Specific Support Questionnaire-Friends scale scores with HbA(1c) , treatment adherence and responsibility, and well-being. CONCLUSION: The 42-item Modified Diabetes Specific Support Questionnaire-Friends emerged as a reliable and valid scale for Dutch adolescents with Type 1 diabetes and measures five factors of diabetes-specific support from close friends. PMID- 22486354 TI - Dendritic cell-based immunity and vaccination against hepatitis C virus infection. AB - Hepatitis C virus (HCV) has chronically infected an estimated 170 million people worldwide. There are many impediments to the development of an effective vaccine for HCV infection. Dendritic cells (DC) remain the most important antigen presenting cells for host immune responses, and are capable of either inducing productive immunity or maintaining the state of tolerance to self and non-self antigens. Researchers have recently explored the mechanisms by which DC function is regulated during HCV infection, leading to impaired antiviral T-cell responses and so to persistent viral infection. Recently, DC-based vaccines against HCV have been developed. This review summarizes the current understanding of DC function during HCV infection and explores the prospects of DC-based HCV vaccine. In particular, it describes the biology of DC, the phenotype of DC in HCV infected patients, the effect of HCV on DC development and function, the studies on new DC-based vaccines against HCV infection, and strategies to improve the efficacy of DC-based vaccines. PMID- 22486357 TI - From lithium bis(trimethylsilyl)amide with cyanoamine into triazine compounds: synthesis and structures of lithium 6-((trimethylsilyl)amido)-2,4 bis(dimethylamino)[1,3,5]triazines and their manganese and cobalt complexes. AB - Addition reactions of lithium bis(trimethylsilyl)amide with dimethylcyanamide lead to novel lithium salts of 6-((trimethylsilyl)amido)-2,4 bis(dimethylamino)[1,3,5]triazines [LLi(D)](2) (L = NC(NMe(2))NC(NMe(2))NC(NSiMe(3)); D = Me(2)NCN (1), Et(2)O (2)) and to the Mn and Co complexes [LL'M] (L' = N{N(SiMe(3))C(NMe(2))}(2); M = Mn (3), Co (4)); the structures of crystalline 1, 3, and 4 are reported. Their formation involves trimethylsilyl shifts, ring formation, and unusual Me(2)NSiMe(3) elimination. PMID- 22486358 TI - Pharmacokinetics of ceftiofur crystalline free acid after single and multiple subcutaneous administrations in healthy alpacas (Vicugna pacos). AB - Six adult male alpacas received one subcutaneous administration of ceftiofur crystalline free acid (CCFA) at a dosage of 6.6 mg/kg. After a washout period, the same alpacas received three subcutaneous doses of 6.6 mg/kg CCFA at 5-day intervals. Blood samples collected from the jugular vein before and at multiple time points after each CCFA administration were assayed for ceftiofur- and desfuroylceftiofur-related metabolite concentrations using high-performance liquid chromatography. Pharmacokinetic disposition of CCFA was analyzed by a noncompartmental approach. Mean pharmacokinetic parameters (+/- SD) following single-dose administration of CCFA were Cmax (2.7 +/- 0.9 MUg/mL); Tmax (36 +/- 0 h); area under the curve AUC0->infinity (199.2 +/- 42.1 MUg.h/mL); terminal phase rate constant lambdaz (0.02 +/- 0.003/h); and terminal phase rate constant half life t1/2lambdaz (44.7 h; harmonic). Mean terminal pharmacokinetic parameters (+/ SD) following three administrations of CCFA were Cmax (2.0 +/- 0.4 MUg/mL); Tmax (17.3 +/- 16.3 h); AUC0->infinity (216.8 +/- 84.5 MUg.h/mL); lambdaz (0.01 +/- 0.003/h); and t1/2lambdaz (65.9 h; harmonic). The terminal phase rate constant and the Tmax were significantly different between single and multiple administrations. Local reactions were noted in two alpacas following multiple CCFA administrations. PMID- 22486359 TI - New approach for designing single-chain magnets: organization of chains via hydrogen bonding between nucleobases. AB - Two one-dimensional (1D) manganese complexes, [Mn(2)(naphtmen)(2)(L)](ClO(4)).2Et(2)O.2MeOH.H(2)O (1) and [Mn(2)(naphtmen)(2)(HL)](ClO(4))(2).MeOH (2), were synthesized by using a bridging ligand with a nucleobase moiety, 6-amino-9-beta-carboxyethylpurine, and a salen-type manganese(III) dinuclear complex, [Mn(2)(naphtmen)(2)(H(2)O)(2)](ClO(4))(2) (naphtmen(2-) = N,N'-(1,1,2,2 tetramethylethylene)bis(naphthylideneiminato) dianion). In 1 and 2, the carboxylate-bridged Mn(III) dinuclear units are alternately linked by two kinds of weak Mn...O interactions into 1D chains. As a result, canted antiferromagnetic and ferromagnetic interactions are alternately present along the chains, leading to a 1D chain with non-cancellation of anisotropic spins. Since the chains connected via H-bonds between nucleobase moieties are magnetically isolated, both 1 and 2 act as single-chain magnets (SCMs). More importantly, this result shows the smaller canting angles hinder long-range ordering in favor of SCM dynamics. PMID- 22486361 TI - Herbivore-induced plant volatiles mediate host selection by a root herbivore. AB - In response to herbivore attack, plants mobilize chemical defenses and release distinct bouquets of volatiles. Aboveground herbivores are known to use changes in leaf volatile patterns to make foraging decisions, but it remains unclear whether belowground herbivores also use volatiles to select suitable host plants. We therefore investigated how above- and belowground infestation affects the performance of the root feeder Diabrotica virgifera virgifera, and whether the larvae of this specialized beetle are able to use volatile cues to assess from a distance whether a potential host plant is already under herbivore attack. Diabrotica virgifera larvae showed stronger growth on roots previously attacked by conspecific larvae, but performed more poorly on roots of plants whose leaves had been attacked by larvae of the moth Spodoptera littoralis. Fittingly, D. virgifera larvae were attracted to plants that were infested with conspecifics, whereas they avoided plants that were attacked by S. littoralis. We identified (E)-beta-caryophyllene, which is induced by D. virgifera, and ethylene, which is suppressed by S. littoralis, as two signals used by D. virgifera larvae to locate plants that are most suitable for their development. Our study demonstrates that soil-dwelling insects can use herbivore-induced changes in root volatile emissions to identify suitable host plants. PMID- 22486360 TI - The role of complement in the trafficking of hematopoietic stem/progenitor cells. PMID- 22486363 TI - Just the two of us: misalignment of theory and methods in examining dyadic phenomena. AB - Many organizational phenomena such as leader-member exchange, mentoring, coaching, interpersonal conflict and cooperation, negotiation, performance appraisal, and the employment interview involve inherently dyadic relationships and interactions. Even when theories explicitly acknowledge the dyadic nature of such phenomena, it is not uncommon to observe a disconnection or misalignment between the level of theory and method. Our purpose in the current paper is to discuss how organizational scholars might better align these components of their research endeavors. We discuss how recent developments involving the actor partner interdependence model (APIM) and reciprocal one-with-many (OWM) models are applicable to studying dyadic phenomena in organizations. The emphasis is on preanalytic considerations associated with collecting and organizing reciprocal dyadic data, types of research questions that APIM and reciprocal OWM models can help answer, and specific analytic techniques involved in testing dyadic hypotheses. PMID- 22486362 TI - Selenium or selenium plus folic acid-supplemented diets ameliorate renal oxidation in ethanol-exposed pups. AB - BACKGROUND: Ethanol (EtOH) exposure during gestation and lactation induces an oxidative stress in offspring. In kidney, the oxidative damage is the primary pathway to alcohol-induced injury. In this study, we have demonstrated that a diet supplemented with selenium (Se) (0.5 ppm) or with Se (0.5 ppm) + folic acid (8 ppm) administered to EtOH-exposed (20% v/v) dams during gestation and lactation prevents the oxidative EtOH-provoked effects in their offspring's kidneys. METHODS: All the studies were performed on 21-day-old pups. Serum, urine, and kidney Se levels were assessed by graphite-furnace atomic absorption spectrometry. Se and creatinine clearance, antioxidant enzyme activities, and lipid and protein peroxidation were determined by a spectrophotometric method in kidney. RESULTS: Dietary supplementation treatments used could not improve the glomerular filtration function altered by EtOH exposure during gestation and lactation; however, they did improve renal Se deposits, renal development, and renal protein content while decreasing lipid and protein oxidation and modifying antioxidant enzymes' activity. CONCLUSIONS: Se or Se + folic acid supplementations improve renal development and protein content and modify antioxidant enzymes' activity, decreasing lipid and protein oxidation after EtOH exposure. In this context, a double-supplemented diet appears to reduce protein peroxidation more efficiently than the Se-only-supplemented one, probably via superoxide dismutase and catalase. PMID- 22486364 TI - Fairness at the collective level: a meta-analytic examination of the consequences and boundary conditions of organizational justice climate. AB - This article uses meta-analytic methods (k = 38) to examine the relationship between organizational justice climate and unit-level effectiveness. Overall, our results suggest that the relationship between justice and effectiveness is significant (rho = .40) when both constructs are construed at the collective level. Our results also indicate that distributive justice climate was most strongly linked with unit-level performance (e.g., productivity, customer satisfaction), whereas interactional justice was most strongly related to unit level processes (e.g., organizational citizenship behavior, cohesion). We also show that a number of factors moderate this relationship, including justice climate strength, the level of referent in the justice measure, the hierarchical level of the unit, and how criteria are classified. We elaborate on these findings and attempt to provide a clearer direction for future research in this area. PMID- 22486365 TI - The best laid plans: examining the conditions under which a planning intervention improves learning and reduces attrition. AB - Planning plays an instrumental role in prominent self-regulation theories (e.g., action regulation, control, goal setting), yet as a scientific community we know little about how people carry out their learning plans. Using an experimental field study, we implemented a repeated-measures intervention requiring trainees to create a plan for when, where, and how much time they intended to devote to training before each of 4 online modules and examined the conditions under which the planning intervention improved learning and reduced attrition. Trainees benefited from the planning intervention when it was paired with another intervention-prompting self-regulation-targeting self-regulatory processes that occur subsequent to planning (e.g., monitoring, concentration, learning strategies). Trainees' learning performance was highest and attrition lowest when they received both interventions. The planning intervention was also advantageous for enhancing learning and reducing attrition when trainees followed through on the amount of time that they planned to devote to training. Finally, the relationship between planned study time, time on task, and learning performance was cyclical. Planned study time had a positive effect on time on task, which, in turn, had a positive effect on learning performance. However, trainees planned to devote less time to training following higher rather than lower learning performance. The current study contributes to our theoretical understanding of self-regulated learning by researching one of the most overlooked components of the process-planning-and examining the conditions under which establishing a learning plan enhances training outcomes. PMID- 22486367 TI - Discotic triphenylene twins linked through thiophene bridges: controlling nematic behavior in an intriguing class of functional organic materials. AB - Substituted triphenylenes and similar discotic molecules have a strong tendency toward columnar organization. Nematic mesophases are much less commonly observed in discotic systems. We have demonstrated a general strategy whereby discotic triphenylenes can be twinned to form stable, boardlike materials that display only nematic mesophases. The dominant structural feature that leads to nematic behavior is an enforced void region in the center of the macrocycle that results from bridging through the triphenylene 3,6-positions. This precludes simple columnar assembly because it would lead to free space through the center of each stack. Selection of appropriate bridging units allows materials to be designed which combine molecular features, such as the optoelectronic properties of electron-rich triphenylenes and conjugated thiophene units, with the processability, self-healing, and alignment features inherent in nematic mesophases. In addition, communication across twinned structures can lead to additional enhancement of optoelectronic behavior. This is particularly apparent in fully conjugated, planar twin 12 which is formally expected to have some antiaromatic character. This character is manifested in its spectral properties, and particularly noteworthy is its strong, Stokes shifted emission at around 500 nm. PMID- 22486366 TI - Eye shape and retinal shape, and their relation to peripheral refraction. AB - PURPOSE: We provide an account of the relationships between eye shape, retinal shape and peripheral refraction. RECENT FINDINGS: We discuss how eye and retinal shapes may be described as conicoids, and we describe an axis and section reference system for determining shapes. Explanations are given of how patterns of retinal expansion during the development of myopia may contribute to changing patterns of peripheral refraction, and how pre-existing retinal shape might contribute to the development of myopia. Direct and indirect techniques for determining eye and retinal shape are described, and results are discussed. There is reasonable consistency in the literature of eye length increasing at a greater rate than height and width as the degree of myopia increases, so that eyes may be described as changing from oblate/spherical shapes to prolate shapes. However, one study indicates that the retina itself, while showing the same trend, remains oblate in shape for most eyes (discounting high myopia). Eye shape and retinal shape are not the same and merely describing an eye shape as being prolate or oblate is insufficient without some understanding of the parameters contributing to this; in myopia a prolate eye shape is likely to involve both a steepening retina near the posterior pole combined with a flattening (or a reduction in steepening compared with an emmetrope) away from the pole. SUMMARY: In the recent literature, eye and/or retinal shape have often been inferred from peripheral refraction, and, to a lesser extent, vice versa. Because both the eye's optics and the retinal shape contribute to the peripheral refraction, and there is large variation in the latter, this inference should be made cautiously. Recently retinal shape has been measured independent of optical methods using magnetic resonance imaging. For further work on retinal shape, determining the validity of cheaper alternatives to magnetic resonance techniques is required. PMID- 22486368 TI - Using novel descriptor accounting for ligand-receptor interactions to define and visually explore biologically relevant chemical space. AB - The definition and pragmatic implementation of biologically relevant chemical space is critical in addressing navigation strategies in the overlapping regions where chemistry and therapeutically relevant targets reside and, therefore, also key to performing an efficient drug discovery project. Here, we describe the development and implementation of a simple and robust method for representing biologically relevant chemical space as a general reference according to current knowledge, independently of any reference space, and analyzing chemical structures accordingly. Underlying our method is the generation of a novel descriptor (LiRIf) that converts structural information into a one-dimensional string accounting for the plausible ligand-receptor interactions as well as for topological information. Capitalizing on ligand-receptor interactions as a descriptor enables the clustering, profiling, and comparison of libraries of compounds from a chemical biology and medicinal chemistry perspective. In addition, as a case study, R-groups analysis is performed to identify the most populated ligand-receptor interactions according to different target families (GPCR, kinases, etc.), as well as to evaluate the coverage of biologically relevant chemical space by structures annotated in different databases (ChEMBL, Glida, etc.). PMID- 22486369 TI - Spectroscopic, molecular modeling, and NMR-spectroscopic investigation of the binding mode of the natural alkaloids berberine and sanguinarine to human telomeric G-quadruplex DNA. AB - G-quadruplex structures can be formed at the single-stranded overhang of telomeric DNA, and ligands able to stabilize this structure have recently been identified as potential anticancer drugs. Among the potential G-quadruplex binders, we have studied the binding ability of berberine and sanguinarine, two members of the alkaloid family, an important class of natural products long known for medicinal purpose. Our spectroscopic (CD, NMR, and fluorescence) studies and molecular modeling approaches revealed binding modes at ligand-complex stoichiometries >1:1 and ligand self-association induced by DNA for the interactions of the natural alkaloids berberine and sanguinarine with the human telomeric G-quadruplex DNA. PMID- 22486370 TI - Pleomorphic lobular carcinoma: a distinctive clinical and molecular breast cancer type. AB - AIMS: Pleomorphic lobular carcinoma (PLC) is an aggressive variant of invasive lobular carcinoma. The aim of this study was to redefine PLC in terms of molecular classification. METHODS AND RESULTS: Cases of PLC were selected between 1995 and 2010. Key clinicopathological features were recorded for most of the patients. A panel of immunohistochemical stains including E-cadherin, oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin (CK)5/6, CK14, CK17, anti-cytokeratin (CAM) 5.2, CD117, vimentin, epidermal growth factor receptor (EGFR), p53 and gross cystic disease fluid protein-15 (GCDFP-15) were performed. HER2 test by fluorescence in-situ hybridization (FISH) was also performed. The log-rank test was used for statistical analyses. Forty cases fulfilled the criteria for PLC (26 with available tissue). The median age was 61 years and median tumour size was 2.0 cm. There were five of 38 (13.2%) triple-negative cases. The basal type was seen in one of 25 cases (4%), which had a triple-negative phenotype. HER2 was amplified in 14 of 38 cases (35%). Older patients and negative hormonal receptor status correlated significantly with worse clinical outcome (P < 0.03). The 5-year recurrence-free and overall survival was 54.9% and 76.2%, respectively. CONCLUSIONS: Pleomorphic lobular carcinoma is a distinctive breast cancer subtype. It has hybrid clinicopathological characteristics of ductal and lobular carcinoma. PMID- 22486371 TI - Mobility of proteins in highly hydrated polyelectrolyte multilayer films. AB - The lateral diffusion of a protein (human serum albumin labeled with fluorescein isothiocyanate) within a highly hydrated polyelectrolyte film is studied. The film is built up with poly(L-lysine) as polycation and hyaluronate as polyanion. Fluorescence recovery after photobleaching is used to evaluate the mobility of the labeled protein. Spatial Fourier transformation is applied to the fluorescence intensity recorded at various times after bleaching of a narrow rectangular area within an image representative of the film. This approach necessitates no hypothesis on the intensity distribution at the end of the bleaching provided that the bleach has not appreciably changed the concentration ratios of the different diffusing species. Furthermore, under the hypothesis that molecules move according to Fick's law, we represent the Fourier transform by a weighted sum of exponentials each containing another diffusion coefficient and evaluate the proportion attached to each term of this sequence using the simulated annealing method. A criterion, combining goodness-of-fit and the entropy characterizing the diffusion coefficient spectrum, is proposed to avoid overinterpretation of the experimental data. The optimum spectrum of the diffusion coefficient is then extracted from the time evolution of the light intensity at various albumin concentrations within the films. It appears that the mobility, quantified by the amount of tracer molecules having a diffusion coefficient smaller than, e.g., 0.1 MUm(2)/s, undergoes a transition between 20 and 2000 MUg/mL of internal concentration. This suggests that the mutual interactions of the albumin molecules and the interactions between fluorescently labeled albumin and the film network become increasingly important in the reduction of the albumin mobility as the albumin concentration increases. PMID- 22486372 TI - Nanotoxicity of gold and gold-cobalt nanoalloy. AB - Nanotoxicology test of gold nanoparticles (Au NPs) and gold-cobalt (Au-Co) nanoalloy is an important step in their safety evaluation for biomedical applications. The Au and Au-Co NPs were prepared by reducing the metal ions using sodium borohydride (NaBH(4)) in the presence of polyvinyl pyrrolidone (PVP) as a capping material. The average size and shape of the nanoparticles (NPs) were characterized using high resolution transmission electron microscopy (HRTEM). Cobalt presence in the nanoalloy was confirmed by energy dispersive X-ray spectroscopy (EDX) analysis, and the magnetic properties of these particles were determined using a vibrating sample magnetometer (VSM). The Gold and gold-cobalt NPs of average size 15 +/- 1.5 nm were administered orally to mice with a dose of 80, 160, and 320 mg/kg per body weight (bw) using gavages. Samples were collected after 7 and 14 days of the treatment. The results indicated that the Au-Co NPs were able to induce significant alteration in the tumor-initiating genes associated with an increase of micronuclei (MNs) formation and generation of DNA adduct (8-hydroxy-2-deoxyguanosine, 8-OHdG) as well as a reduction in the glutathione peroxidase activity. This action of Au-Co NPs was observed using 160 and 320 mg/kg bw at both time intervals. However, Au NPs had much lower effects than Au-Co NPs on alteration in the tumor-initiating genes, frequency of MNs, and generation of 8-OHdG as well as glutathione peroxidase activity except with the highest dose of Au NPs. This study suggests that the potential to cause in vivo genetic and antioxidant enzyme alterations due to the treatment by Au-Co nanoalloy may be attributed to the increase in oxidative stress in mice. PMID- 22486374 TI - Left ventricular mechanics following restrictive mitral annuloplasty for functional mitral regurgitation: two-dimensional speckle tracking echocardiographic study. AB - BACKGROUND: Restrictive mitral annuloplasty (RMA) is widely employed for patients with functional mitral regurgitation (MR). Its improvement of left ventricular (LV) function has been demonstrated by only a gradual increase in LV ejection fraction (EF) in the chronic phase. However, the detailed evaluation of changes in LV function has not been fully elucidated in functional MR patients before and after RMA. Therefore, we performed two-dimensional speckle tracking echocardiography (2D-STE), which enables accurate evaluation of myocardial deformation and rotation that are undetectable by conventional echocardiography. METHODS: We studied 13 patients (mean age 61 +/- 10 years) with functional MR associated with cardiomyopathy undergoing RMA. In addition to conventional echocardiographic measurements, 2D-STE was performed to measure peak systolic radial (RS), circumferential (CS), and longitudinal (LS) strains and twist before and 4 +/- 2 weeks after surgery. LV twist was defined as the difference between the apical and basal rotations. RESULTS: After RMA, EF and LS remained unchanged, but RS and CS were significantly improved at the mid-LV (RS, 20.6 +/- 10.8 vs 24.5 +/- 11.6%; CS, -9.6 +/- 5.2 vs -12.8 +/- 5.6%) and at the apex (RS, 15.0 +/- 12.2 vs 18.7 +/- 8.6%; CS, -4.4 +/- 3.0 vs -7.8 +/- 4.8%). RS and CS were unchanged at the base. The apical and basal rotations changed significantly, from 3.5 degrees +/- 0.7 degrees to 9.2 degrees +/- 2.1 degrees , and -2.1 degrees +/ 0.7 degrees to -3.8 degrees +/- 1.0 degrees , respectively. Consequently, the LV twist increased significantly, from 5.6 degrees +/- 1.0 degrees to 13.0 degrees +/- 1.9 degrees . CONCLUSIONS: Radial and circumferential strains and LV twist increased significantly in the early postoperative period in functional MR patients after RMA and concomitant procedures. PMID- 22486377 TI - Editorial comment for Seideman et al. PMID- 22486378 TI - Staphylococcal superantigen-like protein 10 binds to phosphatidylserine and apoptotic cells. AB - Staphylococcal superantigen-like proteins (SSLs) are a family of exoproteins that have structural similarities to staphylococcal superantigens. Although SSLs do not have superantigenic activity, some of them have been reported to bind to host immune related molecules and they have been implicated in immune evasion by S. aureus. In this study, we showed that SSL10 is capable of binding to phospholipids. SSL10 bound to phosphatidylserine (PS) containing liposome, but not to phosphatidylcholine liposome. SSL10, but not SSL7, bound to PS containing liposome, suggesting that SSL10 specifically binds to PS. Analysis of PS binding ability among recombinant truncated SSL10 fragments revealed that the beta-barrel in the N-terminal oligonucleotide/oligosaccharide-binding (OB)-fold domain contributes to PS binding capacity. Fluorescein isothiocyanate labeled OB-fold of SSL10 stained hydrogen peroxide treated Jurkat cells. Annexin V is widely utilized for detection of apoptosis. Unlike annexin V, the OB-fold domain of SSL10 also bound to apoptotic cells in the presence of EDTA, suggesting that the OB-fold of SSL10 recognizes PS and apoptotic cells in a Ca(2+) independent manner. These findings suggest SSL10 and its derived peptides may be a novel detection tool for apoptotic cells. PMID- 22486380 TI - A comparison of Er:YAG laser and mechanical debridement for the non-surgical treatment of chronic periodontitis: a randomized, prospective clinical study. AB - AIMS: To compare a monotherapy of Er:YAG laser debridement (ERL), wavelength 2940 nm, with mechanical scaling and root planing (SRP) for the treatment of chronic periodontitis using clinical and patient-centred outcomes. METHODS: Twenty-eight participants had two randomly assigned quadrants treated with ERL and two with SRP. Full-mouth plaque index, probing depth, bleeding on probing, clinical attachment level and gingival recession were recorded at baseline and 6- and 12 weeks post therapy. A questionnaire was used to assess pain, discomfort and satisfaction during and after treatment. RESULTS: Twenty-two participants completed treatment and had 6- and 12-week clinical re-evaluations. SRP provided greater mean pocket depth reduction at 6- and 12-weeks (p = 0.01 and p = 0.003 respectively), and a greater reduction in pockets >= 4 mm at 6 weeks only (p = 0.03) compared with ERL. SRP also resulted in a significant reduction in bleeding on probing (BOP) sites at 12 weeks compared with ERL and a statistically significant greater reduction in mean clinical attachment level (CAL) at 6- (p = 0.02) and 12-weeks (p = 0.03). Patients expressed greater satisfaction with SRP on the day of treatment but were equally satisfied subsequently. CONCLUSION: SRP resulted in a statistically significant greater short-term improvement in clinical parameters and patient satisfaction compared with ERL. PMID- 22486379 TI - Exercise-induced vasodilation is associated with menopause stage in healthy middle-aged women. AB - Leg exercise hemodynamics during single-leg knee extensions were compared among healthy groups of early perimenopausal (n = 15), late perimenopausal (n = 12), and early postmenopausal (n = 11) women. Femoral blood flow (FBF) and vascular conductance (FVC) at rest and during very light work rates (0 and 5 W) were similar among all three menopause stage groups. Vascular responses at 10 W (FBF) and 20 W (FBF and FVC) were significantly higher (P < 0.05) in early perimenopausal compared with late perimenopausal women. At 15 and 25 W, FBF and FVC were similar between late perimenopausal and early postmenopausal groups but higher (P < 0.05) in early perimenopausal women as compared with the other two menopausal groups. In the combined sample of all three menopause stage groups, follicle-stimulating hormone was significantly correlated with vascular conductance during submaximal (15 W) exercise (R = -0.56, P < 0.001), even after adjustment for age, fitness, LDL cholesterol, and abdominal fat (R = -0.46, P = 0.005). Collectively, these findings suggest that in middle-aged women, there is an association between menopause stage and leg vascular responsiveness during exercise. PMID- 22486381 TI - Study on the electro-transformation conditions of improving transformation efficiency for Bacillus subtilis. AB - AIMS: To optimize the transformation conditions and improve the transformation efficiency of Bacillus subtilis WB800 and DB104. METHODS AND RESULTS: Trehalose, which could decrease the damage of electric shock to the cells, was added to the electroporation medium containing sorbitol and mannitol. The factors affecting the transformation efficiency, such as the growth phase of bacteria, cell concentration, electric field strength and plasmid variety, were examined and improved. The new method increased the transformation efficiency of B. subtilis by nearly 100-fold compared with the conventional one. CONCLUSIONS: With the optimized method, the transformation efficiency came up to 3.64 * 10(5) transformants MUg(-1) DNA for WB800, and 2.10 * 10(5) transformants MUg(-1) DNA for DB104. SIGNIFICANCE AND IMPACT OF THE STUDY: This improvement in transformation efficiency will be largely attributed to the research of expression of exogenous genes in B. subtilis, gene library construction for directed evolution and transformation of wild-type B. subtilis strains. PMID- 22486382 TI - Several components of SKP1/Cullin/F-box E3 ubiquitin ligase complex and associated factors play a role in Agrobacterium-mediated plant transformation. AB - * Successful genetic transformation of plants by Agrobacterium tumefaciens requires the import of bacterial T-DNA and virulence proteins into the plant cell that eventually form a complex (T-complex). The essential components of the T complex include the single stranded T-DNA, bacterial virulence proteins (VirD2, VirE2, VirE3 and VirF) and associated host proteins that facilitate the transfer and integration of T-DNA. The removal of the proteins from the T-complex is likely achieved by targeted proteolysis mediated by VirF and the plant ubiquitin proteasome complex. * We evaluated the involvement of the host SKP1/culin/F-box (SCF)-E3 ligase complex and its role in plant transformation. Gene silencing, mutant screening and gene expression studies suggested that the Arabidopsis homologs of yeast SKP1 (suppressor of kinetochore protein 1) protein, ASK1 and ASK2, are required for Agrobacterium-mediated plant transformation. * We identified the role for SGT1b (suppressor of the G2 allele of SKP1), an accessory protein that associates with SCF-complex, in plant transformation. We also report the differential expression of many genes that encode F-box motif containing SKP1 interacting proteins (SKIP) upon Agrobacterium infection. * We speculate that these SKIP genes could encode the plant specific F-box proteins that target the T complex associated proteins for polyubiquitination and subsequent degradation by the 26S proteasome. PMID- 22486383 TI - A simple method for asymmetric trifluoromethylation of N-acyl oxazolidinones via Ru-catalyzed radical addition to zirconium enolates. AB - A Ru-catalyzed direct thermal trifluoromethylation and perfluoroalkylation of N acyloxazolidinones has been developed. The reaction is experimentally simple and requires inexpensive reagents while providing good yields of products with good levels of stereocontrol. Preliminary studies have shown notable compatibility with functional groups, aromatics, and certain heteroaromatic substituents. The described method provides a useful alternative for the synthesis of fluorinated materials in an experimentally convenient manner. PMID- 22486385 TI - Adiposity in 277 young adult male offspring of women with diabetes compared with controls: a Danish population-based cohort study. AB - OBJECTIVE: To examine the associations of maternal diabetes, overall and stratified according to treatment of diabetes, with weight-related outcomes at the time of military conscription, at age 18-20 years. DESIGN AND SETTING: Cohort study of 277 Danish male offspring of mothers with recognized pre-gestational or gestational diabetes. As population-based controls we selected 870 men matched from the Civil Registration Office. METHODS: Data on weight-related outcomes were retrieved from the Danish military conscription registry. MAIN OUTCOME MEASURES: Military rejection due to adiposity and body mass index (BMI) at conscription. RESULTS: Army rejection rate due to adiposity was 5.8% (n= 16) among 277 diabetes mellitus-exposed men compared with 3.1% (n= 27) in 870 controls (risk difference 2.7 (95% confidence interval (CI) -0.3-5.7)) and mean BMI at conscription was 1.4 kg/m(2) (95%CI 0.8-2.0) higher among those diabetes mellitus-exposed men. In analyses adjusted for birthweight and gestational age, compared with controls, the BMI was 0.6 kg/m(2) (95%CI -0.3-1.5) higher in sons of mothers with pre gestational and 2.7 kg/m(2) (95% (CI): 0.9-4.5) higher with gestational diabetes. The greatest BMI difference was in offspring of mothers with gestational diabetes in whom insulin was initiated during pregnancy. We found no difference in conscript height. CONCLUSIONS: Compared with controls, male offspring of women with diabetes had a higher rejection rate due to adiposity and higher adult BMI. Subgroup analyses showed that the association was most pronounced in sons of mothers with gestational diabetes, whereas pre-gestational diabetes was only weakly associated with higher offspring BMI. PMID- 22486386 TI - What is your diagnosis? Fine-needle aspirate of a third eyelid mass in a Paint horse. PMID- 22486387 TI - Cost-effectiveness of prion filtration of red blood cells to reduce the risk of transfusion-transmitted variant Creutzfeldt-Jakob disease in the Republic of Ireland. AB - BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is a rare, progressive fatal noninflammatory neurodegenerative disease. Ireland has the second highest rate of vCJD in the world with an ongoing risk of vCJD transmission through blood transfusion. Prion-removing filters have been developed to reduce the risk of vCJD transmission. This study aimed to evaluate the cost-effectiveness of implementing a policy of prion filtration of red blood cells (RBCs) in the Republic of Ireland. STUDY DESIGN AND METHODS: A cost-effectiveness model was developed to simulate the likelihood of RBC recipients developing clinical vCJD as a result of being transfused with infected RBCs. Model variables were collected from published literature and expert opinion. Costs were estimated based on the processing changes required to implement prion filtration. RESULTS: In the absence of prion filtration, it is estimated that two individuals will develop clinical vCJD arising from RBC transfusions over a 10-year time horizon. The discounted life-years lost will be 18.5 years. With prion filtration, there will be no deaths or life-years lost. The discounted cost of universal prion filtration is ?68.2 million over 10 years with a corresponding incremental cost effectiveness ratio of ?3.7 million per life-year gained. In 25.3% of simulations there were no deaths from vCJD infection through infected blood transfusions, irrespective of prion filtration. CONCLUSION: Prion filtration is considered not cost-effective by traditional measures. Although numerous non-cost-effective blood safety strategies have been implemented in the past, consideration should be given to the most efficient use of finite resources in transfusion medicine. PMID- 22486388 TI - A competitive nucleotide binding inhibitor: in vitro characterization of Rab7 GTPase inhibition. AB - Mapping the functionality of GTPases through small molecule inhibitors represents an underexplored area in large part due to the lack of suitable compounds. Here we report on the small chemical molecule 2-(benzoylcarbamothioylamino)-5,5 dimethyl-4,7-dihydrothieno[2,3-c]pyran-3-carboxylic acid (PubChem CID 1067700) as an inhibitor of nucleotide binding by Ras-related GTPases. The mechanism of action of this pan-GTPase inhibitor was characterized in the context of the Rab7 GTPase as there are no known inhibitors of Rab GTPases. Bead-based flow cytometry established that CID 1067700 has significant inhibitory potency on Rab7 nucleotide binding with nanomolar inhibitor (K(i)) values and an inhibitory response of >=97% for BODIPY-GTP and BODIPY-GDP binding. Other tested GTPases exhibited significantly lower responses. The compound behaves as a competitive inhibitor of Rab7 nucleotide binding based on both equilibrium binding and dissociation assays. Molecular docking analyses are compatible with CID 1067700 fitting into the nucleotide binding pocket of the GTP-conformer of Rab7. On the GDP-conformer, the molecule has greater solvent exposure and significantly less protein interaction relative to GDP, offering a molecular rationale for the experimental results. Structural features pertinent to CID 1067700 inhibitory activity have been identified through initial structure-activity analyses and identified a molecular scaffold that may serve in the generation of more selective probes for Rab7 and other GTPases. Taken together, our study has identified the first competitive GTPase inhibitor and demonstrated the potential utility of the compound for dissecting the enzymology of the Rab7 GTPase, as well as serving as a model for other small molecular weight GTPase inhibitors. PMID- 22486389 TI - Decrease in frequency of ketoacidosis at diabetes onset over the past two decades - perspectives of a paediatric tertiary care centre. AB - AIMS: To determine whether the frequency and severity of diabetic ketoacidosis and the clinical characteristics of children at diagnosis of Type 1 diabetes mellitus have changed over the past decades among patients under surveillance of a tertiary paediatric centre. METHODS: In three time-periods, 75 (1986-1987), 86 (1996-1997) and 245 (2006-2007) patients at mean age 10.1 +/- 4.7 years (0.6 20.0) were diagnosed with new-onset Type 1 diabetes. Data on clinical characteristics and laboratory evaluation at diagnosis retrieved from the patients' files . Comparative analysis was performed between the three time periods. RESULTS: The frequency of diabetic ketoacidosis at diagnosis was 40% in 1986-1987, 41.8% in 1996-1997 and 29.4% in 2006-2007; the last rate was significantly lower (P=0.04). No significant differences in the proportions of patients with severe or moderate diabetic ketoacidosis were found over time. Mean weight standard deviation score significantly increased from -0.72 +/- 1.8 in 1986-1987 to -0.27 +/- 1.2 in 2006-2007 (P<0.05), while percentage weight loss (~6.5%) before diagnosis remained unchanged. In 2006-2007 a higher proportion of children had glucose testing at the community clinic before diagnosis, than in the earlier years (73.1 vs. 59.6%, P=0.003). CONCLUSIONS: The overall frequency of diabetic ketoacidosis in children with newly diagnosed Type 1 diabetes has decreased in the past decade, although the degree of metabolic decompensation has remained unchanged. PMID- 22486391 TI - Ectopic ureters in dogs: clinical features, surgical techniques and outcome. AB - OBJECTIVE: To compare clinical features of ectopic ureter (EU) in male and female dogs and outcome after neoureterostomy with resection restricted to the intravesical part of the ureter for intramural ectopic ureter (iEU) or of ureteroneocystostomy for extramural ectopic ureter (eEU). STUDY DESIGN: Retrospective case series. ANIMALS: Female dogs (n = 26) with 32 iEU and 8 eEU; male dogs (n = 24) with 25 iEU and 18 eEU. METHODS: Data were collected from medical records (1992-2008). Long-term follow-up information after surgical correction by modified neoureterostomy or ureteroneocystostomy was gathered by owner questionnaire. RESULTS: Median age at first occurrence of UI was significantly lower in females (<2 months) than in males with EU (8 months; P = 0.0015). Bilateral occurrence and an extramural course of the ureter were more common in males (n = 19 and n = 20, respectively) compared with females (14 and 12, respectively), but the outcome of surgical treatment was comparable in both genders. CONCLUSIONS: The prognosis after surgery is fair with a success rate of 72% and a complication rate of 26%. Resection of only the intravesicular ectopic ureter resulted in resolution of incontinence in a high percentage of dogs and thus is an acceptable alternative to removal of the entire ureteral remnant. PMID- 22486390 TI - In vivo biodistribution and small animal PET of (64)Cu-labeled antimicrobial peptoids. AB - Peptoids are a rapidly developing class of biomimetic polymers based on oligo-N substituted glycine backbones, designed to mimic peptides and proteins. Inspired by natural antimicrobial peptides, a group of cationic amphipathic peptoids has been successfully discovered with potent, broad-spectrum activity against pathogenic bacteria; however, there are limited studies to address the in vivo pharmacokinetics of the peptoids. Herein, (64)Cu-labeled DOTA conjugates of three different peptoids and two control peptides were synthesized and assayed in vivo by both biodistribution studies and small animal positron emission tomography (PET). The study was designed in a way to assess how structural differences of the peptidomimetics affect in vivo pharmacokinetics. As amphipathic molecules, major uptake of the peptoids occurred in the liver. Increased kidney uptake was observed by deleting one hydrophobic residue in the peptoid, and (64)Cu-3 achieved the highest kidney uptake of all the conjugates tested in this study. In comparison to peptides, our data indicated that peptoids had general in vivo properties of higher tissue accumulation, slower elimination, and higher in vivo stability. Different administration routes (intravenous, intraperitoneal, and oral) were investigated with peptoids. When administered orally, the peptoids showed poor bioavailability, reminiscent of that of peptide. However, remarkably longer passage through the gastrointestinal (GI) tract without rapid digestion was observed for peptoids. These unique in vivo properties of peptoids were rationalized by efficient cellular membrane permeability and protease resistance of peptoids. The results observed in the biodistribution studies could be confirmed by PET imaging, which provides a reliable way to evaluate in vivo pharmacokinetic properties of peptoids noninvasively and in real time. The pharmacokinetic data presented here can provide insight for further development of the antimicrobial peptoids as pharmaceuticals. PMID- 22486392 TI - Nitrogen-rich 5-(1-methylhydrazinyl)tetrazole and its copper and silver complexes. AB - Nitrogen-rich 5-(1-methylhydrazinyl)tetrazole (1, MHT) was synthesized by using a straightforward method. White plate crystals of 1 were isolated in acetonitrile and crystallized in the monoclinic system P2(1)/c (# 14) (a = 3.8713(18) A, b = 12.770(6) A, c = 9.974(5) A, alpha = 90 degrees , beta = 93.397(6) degrees , gamma = 90 degrees , V = 492.3(4) A(3), Z = 4). The reactions of Cu(II) and Ag(I) ions in aqueous solution with 1 were investigated and found to form two complexes under mild conditions. The crystal structures of 2 and 3 are discussed with respect to the coordination mode of the MHT anion. Thermal stabilities were determined from differential scanning calorimetry (DSC) combined with thermogravimetric analysis (TGA) tests. Impact sensitivity was determined by BAM standards showing that these MHT salts are insensitive to impact (>40 J) confirmed by UN standards. The energies of combustion of 1-3 were determined using oxygen bomb calorimetry values and were used to obtain the corresponding enthalpies of formation. Combined with these data above, the neutral MHT is an attractive nitrogen-rich ligand for metallic energetic materials. Its copper and silver coordinated complexes are of interest as potential "green" metal energetic materials with high thermal stability as well as low sensitivity to impact and a high molar enthalpy of formation. PMID- 22486394 TI - Exploring aromatic chemical space with NEAT: novel and electronically equivalent aromatic template. AB - In this paper, we describe a lead transformation tool, NEAT (Novel and Electronically equivalent Aromatic Template), which can help identify novel aromatic rings that are estimated to have similar electrostatic potentials, dipoles, and hydrogen bonding capabilities to a query template; hence, they may offer similar bioactivity profiles. In this work, we built a comprehensive heteroaryl database, and precalculated high-level quantum mechanical (QM) properties, including electrostatic potential charges, hydrogen bonding ability, dipole moments, chemical reactivity, and othe properties. NEAT bioisosteric similarities are based on the electrostatic potential surface calculated by Brood, using the precalculated QM ESP charges and other QM properties. Compared with existing commercial lead transformation software, (1) NEAT is the only one that covers the comprehensive heteroaryl chemical space, and (2) NEAT offers a better characterization of novel aryl cores by using high-evel QM properties that are relevant to molecular interactions. NEAT provides unique value to medicinal chemists quickly exploring the largely uncharted aromatic chemical space, and one successful example of its application is discussed herein. PMID- 22486393 TI - Exercise acts as a drug; the pharmacological benefits of exercise. AB - The beneficial effects of regular exercise for the promotion of health and cure of diseases have been clearly shown. In this review, we would like to postulate the idea that exercise can be considered as a drug. Exercise causes a myriad of beneficial effects for health, including the promotion of health and lifespan, and these are reviewed in the first section of this paper. Then we deal with the dosing of exercise. As with many drugs, dosing is extremely important to get the beneficial effects of exercise. To this end, the organism adapts to exercise. We review the molecular signalling pathways involved in these adaptations because understanding them is of great importance to be able to prescribe exercise in an appropriate manner. Special attention must be paid to the psychological effects of exercise. These are so powerful that we would like to propose that exercise may be considered as a psychoactive drug. In moderate doses, it causes very pronounced relaxing effects on the majority of the population, but some persons may even become addicted to exercise. Finally, there may be some contraindications to exercise that arise when people are severely ill, and these are described in the final section of the review. Our general conclusion is that exercise is so effective that it should be considered as a drug, but that more attention should be paid to the dosing and to individual variations between patients. PMID- 22486395 TI - The effect of head movement and head positioning on sound field audiometry. AB - OBJECTIVE: Positioning and maintaining the subject's head at the calibration point (CP) of the sound field (SF) during SF assessment remains a challenge. The purpose of this study was to investigate the sound pressure level (SPL) at head positions likely to be encountered in routine audiological practice. DESIGN: Eight National Health Service SF clinics were used to obtain SPL measurements. Part 1 of the study investigated SPL variability at positions around the CP (0.15 m and 0.30 m). Parts 2 and 3 of the study, investigated the SPL at two typical head heights of the infant population. STUDY SAMPLE: Only sound field measures were obtained. RESULTS: Part 1: 32% and 40% of measurements of SPL around the CP were >2 dB different from the SPL at the CP (0.15 m and 0.30 m). Parts 2 and 3: 55% and 38% of measurements of SPL, at the two infant head heights, were >2 dB from the SPL at the CP. CONCLUSIONS: Variability in SPL, due to head movement, is to be expected when performing SF audiometry. Furthermore, the typical head heights of infants will introduce additional variability, unless the position of the CP is chosen carefully. PMID- 22486396 TI - Differentiating cardiac amyloidosis and hypertrophic cardiomyopathy by use of three-dimensional speckle tracking echocardiography. AB - INTRODUCTION: Cardiac amyloidosis (CA) and hypertrophic cardiomyopathy (HCM) are important differential diagnosis of left ventricular hypertrophy. The aim of this study was to investigate if three-dimensional (3D) speckle tracking-derived functional parameters enabled differentiation of CA and HCM by a disease-specific pattern. METHODS: Twelve patients with CA and 12 patients with HCM were included. CA and HCM were diagnosed by contrast-enhanced cardiovascular magnetic resonance (CMR). Three-dimensional speckle tracking echocardiography with wall motion analysis was performed for strain (radial [RS(%)], longitudinal [LS (-%)], and circumferential [CS (-%)]), rotation (ROT [degree]), and twist (TWT [degree]). Intergroup comparison included normalized values from 49 healthy volunteers. RESULTS: Averaged RS, LS, CS, ROT, and TWT were investigated at basal, midventricular, and apical levels. With some exceptions, 3D speckle tracking function parameters were mostly lower in the HCM and minimal in the CA group as compared to controls. Comparing CA and HCM, basal RS was significantly reduced in patients with amyloidosis (7.5 +/- 19.7 vs. 22.3 +/- 22.7; P < 0.0001), furthermore the "physiological" gradient of basoapically decreasing RS, which was reduced, but still preserved in HCM, showed a clear "inverse pattern" in patients with amyloidosis, comprising a gradual increase from base to apex. Correlation analysis of 3D speckle tracking function and CMR late gadolinium enhancement (LGE) revealed high inverse correlation of RS and LGE in CA (r =-0.82) and only mild correlation in HCM, followed by CS as second best parameter. An increasing/decreasing basoapical RS gradient yielded a sensitivity of 83% versus the CMR-derived diagnosis "CA" and "HCM." CONCLUSIONS: Three-dimensional speckle tracking echocardiography demonstrated significant differences in CA and HCM. The basoapical RS gradient displayed oppositional characteristics in CA and HCM, suggesting a "function-pattern-based" differentiation of amyloidosis and HCM. PMID- 22486397 TI - Long-term care gets personal. PMID- 22486398 TI - Promoting personalization in social care services for older people. AB - This article presents findings on 4 themes associated with the personalization of social care for older people: integration of health and social care services; initiatives that prevent the need for more costly interventions; services to maintain people at home; and systems that promote choice, control, and flexibility. The quantitative study utilized data from a national postal survey conducted in England. Findings suggest variable progress regarding the range and style of support available to older people. These are discussed in the context of service integration, community-based services, and consumer-directed care. Implications for service development and future research are highlighted. PMID- 22486399 TI - From person-centered to relational care: expanding the focus in residential care facilities. AB - Long-term residential care facilities for older adults currently espouse a philosophy of person-centered care (PCC). However, these facilities operate according to a medical model with highly structured administration and regulation. As a result, there is tension between the priorities of the resident and the organization. A qualitative study conducted with 4 social workers and 1 physician employed in residential care facilities demonstrates not only the structural barriers to PCC, but also the importance of meaningful relationships to residents' socio-emotional well-being. The final section explores how organizational barriers might be mitigated through the complementary use of relational care. PMID- 22486400 TI - "Maintaining connections but wanting more": the continuity of familial relationships among assisted-living residents. AB - Social support is a key component of well-being for older adults, particularly for those who have moved from independent living to assisted living involving a transformation of roles, relationships, and responsibilities. Twenty-nine assisted-living facility residents were interviewed to understand the perceived continuity of relationships with family and friends. An inductive approach to thematic analysis revealed 1 main theme and 3 subthemes. The main theme that emerged was: maintaining connections but wanting more. Residents appreciated maintaining connections with family and friends, but often expressed feelings of discontentment with the continuity of former relationships. The subthemes included: appreciating family and friends, waiting for more, and losing control. Implications for research and practice are discussed. PMID- 22486401 TI - Expanding the role of long-term care social workers: assessment and intervention related to urinary incontinence. AB - Urinary incontinence (UI) is a common and stigmatizing problem faced by long-term care (LTC) residents. It is typically addressed by medical professionals, with social work rarely involved. The purpose of this article is to illustrate how social workers can address the psychosocial implications of UI while working with residents and their family members as part of an interdisciplinary team. Using a case example and the NASW objectives for LTC, recommendations on how the role of the LTC social workers can be expanded to better address both the needs of residents, families, and the larger LTC system are provided. PMID- 22486402 TI - A conceptual framework for differential use of mediation and family therapy interventions with older adults and their families. AB - The purpose of this article is to present a family-centered approach to working with older adults. This framework utilizes a differential use of family therapy and therapeutic mediation theoretical concepts and skills. This provides an effective approach to conceptualizing and intervening with these often complex situations regarding the decision-making processes related to care of older members. Family-centered mediators/clinicians must be skilled in both models to understand and intervene in the challenging issues presented by families. A case example is included in the article to illustrate the framework. PMID- 22486404 TI - Novel WDR35 mutations in patients with cranioectodermal dysplasia (Sensenbrenner syndrome). PMID- 22486405 TI - Peroxiredoxin-1, a possible target in modulating inflammatory cytokine production in macrophage like cell line RAW264.7. AB - Peroxiredoxin (PRX), a scavenger of H(2) O(2) and alkyl hydroperoxides in living organisms, protects cells from oxidative stress. Contrary to its known anti oxidant roles, the involvement of PRX-1 in the regulation of lipopolysaccharide (LPS) signaling is poorly understood, possible immunological functions of PRX-1 having been uncovered only recently. In the present study, it was discovered that the PRX-1 deficient macrophage like cell line (RAW264.7) has anti-inflammatory activity when stimulated by LPS. Treatment with LPS for 3 hrs resulted in increased gene expression of an anti-inflammatory cytokine, interleukin-10 (IL 10), in PRX-1 knock down RAW264.7 cells. Gene expression of pro-inflammatory cytokines IL-1beta and tumor necrosis factor- alpha (TNF-alpha) did not show notable changes under the same conditions. However, production of these cytokines significantly decreased in PRX-1 knock down RAW264.7 cells with 12 hrs of stimulation. Production of IL-10 was also increased in PRX-1 knock down RAW264.7 cells with 12 hrs of stimulation. We predicted that higher concentrations of IL 10 would result in decreased expression of IL-1beta and TNF-alpha in PRX-1 knock down cells. This was confirmed by blocking IL-10, which reestablished IL-1beta and TNF-alpha secretion. We also observed that increased concentrations of IL-10 do not affect the NF-kappaB pathway. Interestingly, STAT3 phosphorylation by LPS stimulation was significantly increased in PRX-1 knockdown RAW264.7 cells. Up regulation of IL-10 in PRX-1 knockdown cells and the resulting downregulation of proinflammatory cytokine production seem to involve the STAT3 pathway in macrophages. Thus, down-regulation of PRX-1 may contribute to the suppression of adverse effects caused by excessive activation of macrophages through affecting the STAT3 signaling pathway. PMID- 22486406 TI - Role of photoionization on the dynamics and mechanism of photoinduced electron transfer reaction of coumarin 307 in micelles. AB - The dynamics and mechanism of the photoinduced electron transfer (PET) reaction between coumarin 307 (C307) and aromatic amines in micelles have been studied by using steady-state (S-S) and time-resolved (T-R) absorption and fluorescence spectroscopy. Based on the fluorescence quenching time scale, PET in micelles is grouped into two types: (i) ultrafast electron transfer (ET) due to the close contact of the donor and acceptor in micelles and (ii) diffusion averaged dynamic electron transfer (DADET) which is controlled by the diffusion of the reactants in micellar Stern layer and diffusion of the micelles. The DADET does not affect the photoionization and solvation processes whereas ultrafast ET competes with the photoionization and faster than the solvation process. Both ultrafast and DADET shows Marcus inversion in the ET rates at the similar exergonicity and indicates that the role of diffusion and solvent reorganization is negligible toward the activation barrier for the ET reaction in micelles. The activation barrier for the ET reactions in micelles is mainly due to intramolecular reorganization energy. The intramolecular reorganization energy must be higher in CTAB due to the photoionization and subsequent recombination and also involvement of triplet state in the PET. The ET reaction between coumarin radical cation and amine is reported for the first time in the C307-amine systems in micelles which are confirmed by the effect on amine concentration of the decay of coumarin radical cation and the dynamics of the ground-state recovery of C307. A mechanism for the PET reaction between C307-amine systems is proposed in micelles including photoionization, ultrafast and dynamic ET, and solvation dynamics. PMID- 22486407 TI - Acute ethanol administration and reinforcer magnitude reduction both reduce responding and increase response latency in a go/no-go task. AB - BACKGROUND: Ethanol (EtOH) administration decreases behavioral inhibition in human subjects, assessed using cued Go/No-Go tasks, in which an unreliable cue suggests whether participants will be required to respond or not when a signal occurs. Few studies have examined EtOH's effects on behavioral inhibition in animals, and those that have done so have used Go/No-Go tasks in which no warning cue was provided. METHODS: Two cohorts of male Long-Evans rats were trained and tested on 2 different Go/No-Go procedures with differing ratios of Go to No-Go trials (25 to 75 and 50 to 50). Using a within-subjects design, each rat was administered 0.0, 0.63, 0.95, and 1.27 g/kg of EtOH (i.p.) on 3 separate occasions according to an incomplete Latin square. An additional experiment examined the effects of reducing the amount of sucrose given for correct responses to either the Go or the No-Go signal in the absence of EtOH administration. RESULTS: Acute intraperitoneal EtOH administration dose dependently decreased responding during the No-Go signal (false alarms), the Go signal (hits), and responding prior to the occurrence of either signal (precue response rate). These effects were more pronounced in rats with the 50 to 50 ratio. Reducing the amount of sucrose presented generally led to a decrease in responding, although this effect was also moderated by the Go to No-Go ratio employed and the contingency relationship (reduced sucrose for correct Go trial responding or for correct No-Go trial response withholding). CONCLUSIONS: Acute EtOH administration does not decrease behavioral inhibition in rats in this task. Rather EtOH appears to dose-dependently decrease behavior in general, possibly by reducing the efficacy of the sucrose reinforcer, as both EtOH administration and sucrose reduction for Go trials yielded similar patterns of behavioral responding in this task in rats. PMID- 22486409 TI - Light source spectrum strongly influences the in vitro estimation of sun protection factor. AB - Irradiation from an artificial solar simulator that matches the relative cumulative erythema effectiveness (RCEE) of sunlight is used for in vivo sun protection factor (SPF) testing, whereas irradiation that matches the spectrum of natural sunlight (NS) is generally used for in vitro SPF testing. This study was designed to clarify whether this difference is important. Eight sunscreens spread on artificial substrates and several optical filters as sunscreen mimics were used. Their in vitro SPF values were evaluated using RCEE-compliant and NS spectrum-matching light sources in calculation. The calculated in vitro SPF values obtained using NS light (SPF [NS]) were lower than those obtained using RCEE light (SPF [RCEE]). The in vitro SPF (RCEE) values showed a better correlation and better agreement with in vivo SPF values, as compared with the in vitro SPF (NS) values. A marked difference between in vitro SPF values obtained with the two light sources in calculation was found for sunscreens showing low transmittance in the ultraviolet B region. To obtain in vitro SPF values that correspond well to in vivo SPF values measured with currently accepted methodology, it is important to use an RCEE-compliant light source. PMID- 22486410 TI - In vitro glucuronidation of the angiotensin II receptor antagonist telmisartan in the cat: a comparison with other species. AB - Glucuronidation of telmisartan comprises nearly its entire metabolic clearance in several mammalian species including human. However, data were lacking for the cat, a species noted for its inability to glucuronidate some drugs. Therefore, the glucuronidation of telmisartan was investigated using feline liver microsomes and compared to liver microsomes of rats, dogs, and human, intestinal human microsomes and cell lines expressing human UDP-glucuronosyltransferases (UGT). Incubation of telmisartan with cat liver microsomes readily yielded telmisartan glucuronide, and pooled (N = 3 for each gender) cat liver microsomes even showed the highest glucuronidation rate (cat > dog >> human > rat). Michaelis Menten kinetics were observed with Km of 7.5 and 10 MUm and Vmax of 3.9 and 3.3 nmol/min/mg for male and female cats, respectively. Confirming the in vitro data, telmisartan glucuronide was detected as the major circulating metabolite in cat plasma. To elucidate which UGT enzymes are involved, telmisartan was incubated with cell lines expressing human UGTs. The highest glucuronidation activity was observed for UGT1A8, UGT1A7, and UGT1A9. In conclusion, telmisartan was effectively glucuronidated in cats. Defects of the UGT1A6 gene in cats do not affect the glucuronidation of telmisartan as it is not a substrate of human UGT1A6. PMID- 22486408 TI - Does fear reactivity during exposure predict panic symptom reduction? AB - OBJECTIVE: Fear reactivity during exposure is a commonly used indicator of learning and overall therapy outcome. The objective of this study was to assess the predictive value of fear reactivity during exposure using multimodal indicators and an advanced analytical design. We also investigated the degree to which treatment condition (cognitive training vs. respiratory skill training) moderated fear reactivity and therapeutic outcome. METHOD: Thirty-four patients with panic disorder and agoraphobia completed a total of 123 in-vivo exposure sessions, comprising 3 weekly sessions and a 4th session 2 months following therapy completion. Sessions varied in length and phobic stimuli. Cardiorespiratory physiology (heart rate, carbon dioxide partial pressure [PCO2], respiration rate) and experiential symptoms (panic symptoms and anxiety) were assessed repeatedly throughout exposure sessions, in addition to weekly assessments of panic cognitions, avoidance, and functioning. RESULTS: Panic symptomatology decreased substantially in both treatment conditions during therapy and follow-up. Significant cardiorespiratory and experiential reactivity was observed during all exposures, characterized by activation followed by reduction. Greater within-session activation of anxiety and panic symptoms was inversely related to improvement in panic symptoms severity, but neither physiological activation nor within- or between-session reduction of either physiological or experiential variables was predictive of outcome. No moderating effects of treatment condition were found. CONCLUSIONS: Fear activation and reduction during exposure are weak predictors of corrective learning and fear extinction. Clinical implications for exposure therapy and directions for future research are discussed. PMID- 22486411 TI - What is your diagnosis? Cytologic findings from a subcutaneous nodule over the left epaxial musculature in a dog. PMID- 22486412 TI - Recovery of E. coli O157 strains after exposure to acidification at pH 2. AB - AIMS: Rapid detection and selective isolation of E. coli O157:H7 strains have been difficult owing to the potential interference from background microflora present in high background food matrices. To help selectively isolate E. coli O157H7 strains, a useful plating technique that involved acidifying the cultures to pH 2 was evaluated with a large number of E. coli O157:H7 strains to ensure response to treatment was consistent across strains. METHODS AND RESULTS: Escherichia coli O157, 46 strains including ATCC 35150, were acidified to pH 2 following enrichment and plated onto Tryptic Soy Agar + 0.6% Yeast Extract (TSA YE) and Sorbitol MacConkey Agar + cefixime and tellurite (CT-SMAC). Samples were enumerated and modest decreases in plate counts were observed on TSA-YE media, with a greater reduction observed on CT-SMAC. CONCLUSIONS: The acid-resistant character of E. coli O157:H7 is a consistent trait and may be used for improved isolation of the organism from mixed cultures. SIGNIFICANCE AND IMPACT OF THE STUDY: There was little difference observed between the commonly used laboratory strain E. coli O157:H7 35150 and 45 other strains of E. coli O157 when subjected to acidifying conditions prior to plating, demonstrating that an acid rinse procedure was equally effective across a wide variety of E. coli O157 strains and broadly applicable for isolating unknown strains from food samples. PMID- 22486413 TI - Noble metal coated single-walled carbon nanotubes for applications in surface enhanced Raman scattering imaging and photothermal therapy. AB - Single-walled carbon nanotubes (SWNTs) with various unique optical properties are interesting nanoprobes widely explored in biomedical imaging and phototherapies. Herein, DNA-functionalized SWNTs are modified with noble metal (Ag or Au) nanoparticles via an in situ solution phase synthesis method comprised of seed attachment, seeded growth, and surface modification with polyethylene glycol (PEG), yielding SWNT-Ag-PEG and SWNT-Au-PEG nanocomposites stable in physiological environments. With gold or silver nanoparticles decorated on the surface, the SWNT-metal nanocomposites gain an excellent concentration and excitation-source dependent surface-enhanced Raman scattering (SERS) effect. Using a near-infrared (NIR) laser as the excitation source, targeted Raman imaging of cancer cells labeled with folic acid (FA) conjugated SWNT-Au nanocomposite (SWNT-Au-PEG-FA) is realized, with images acquired in significantly shortened periods of time as compared to that of using nonenhanced SWNT Raman probes. Owing to the strong surface plasmon resonance absorption contributed by the gold shell, the SWNTs-Au-PEG-FA nanocomposite also offers remarkably improved photothermal cancer cell killing efficacy. This work presents a facile approach to synthesize water-soluble noble metal coated SWNTs with a strong SERS effect suitable for labeling and fast Raman spectroscopic imaging of biological samples, which has been rarely realized before. The SWNT-Au-PEG nanocomposite developed here may thus be an interesting optical theranostic probe for cancer imaging and therapy. PMID- 22486414 TI - Subtle skin infiltration in hepatosplenic gammadelta T cell lymphoma. PMID- 22486415 TI - The diagnostic accuracy of two methods for E6&7 mRNA detection in women with minor cytological abnormalities. AB - OBJECTIVE: To examine the diagnostic accuracy of nucleic acid sequence based amplification (NASBA) and flow cytometry for E6&7 human papillomavirus (HPV) mRNA detection in the triage of minor cytological abnormalities. DESIGN: Prospective diagnostic accuracy study. SETTING: Gynecology outpatient clinics of a university hospital. POPULATION: 472 women with low-grade squamous intraepithelial lesion (LSIL) or atypical squamous cells of undetermined significance (ASCUS). METHODS: Residual material of the liquid-based smears was tested by NASBA and by flow cytometry for E6&E7 mRNA expression. Histological diagnosis was used as reference standard. MAIN OUTCOME MEASURES: Accuracy indices of the two techniques and of type 16-specific NASBA for the detection of cervical intraepithelial neoplasia (CIN) 2+ and CIN3+, accuracy indices at age >35 years, correlation between NASBA and flow, comparison between integrated and episomal high-risk HPV infection for risk of CIN2+. RESULTS: Both tests showed increased positivity rates with increasing severity of the lesion (p < 0.05, chi-squared test for trend). There was a positive correlation between NASBA and flow results (phi coefficient = 0.325). NASBA-positive cases were more likely to have CIN2+ than were NASBA negative/DNA-positive for types 16, 18, 31, 33, 45 (25/73 vs. 4/52, p= 0.0004; Fisher's exact test). In the LSIL group the NASBA accuracy indices for CIN3+ were: sensitivity 75%, specificity 78.7% and positivity rate 20.8%, and for flow 77.8%, 64.5% and 35.9%, respectively. CONCLUSIONS: NASBA has favorable specificity and positivity rates for triaging LSIL prior to colposcopy. A relatively low sensitivity warrants cytological surveillance of the NASBA negative LSILs. Flow cytometry does not perform as well overall. PMID- 22486418 TI - Cord blood banking activities at a university hospital in northeast Mexico: an 8 year experience. AB - BACKGROUND: Umbilical cord blood (UCB) represents an alternative source of stem cells for transplantation for the treatment of hematologic malignancies and genetic disorders. There is scarce information detailing cord blood bank (CBB) collection and transplantation activities from developing countries. We documented our experience at a public university hospital in northeast Mexico. STUDY DESIGN AND METHODS: We carried out a retrospective and descriptive analysis of our CBB activity during an 8-year period from May 2002 to September 2010. Collection, processing, and cryopreservation of CB were carried out following standard operating procedures. The minimum volume and total nucleated cell (TNC) content for cryopreservation were 80 mL and 8.0 * 10(8) , respectively. RESULTS: A total of 1256 UCB units were collected; 428 (34%) were banked and 828 (66%) were discarded. The main reason for exclusion was biologic: low volume and/or low number of TNC accounted for 84% of the total discarded units. Cryopreserved cord blood units (CBUs) had a median volume of 113.8 mL (range, 80-213.2 mL) and 13.0 * 10(8) (range, 8 * 10(8) -36.6 * 10(8) ) TNCs. Cell viability was 99.3% (88 100%). The median CD34+ cell content was 4.0 * 10(6) (0.46 * 10(6) -19.38 * 10(6) ). Sixteen units have been released for transplantation, leading to a utilization rate of 3.7%. CONCLUSION: CBB demands considerable human and financial resources; it is then essential for centers at developing countries to share their experience, results, and databases to increase the probability of finding matching units for their patients. Efforts to create and maintain CBBs allow to offer this therapeutic option at an affordable cost. PMID- 22486416 TI - Cyanoacetamides (IV): versatile one-pot route to 2-quinoline-3-carboxamides. AB - Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction (MCR) scaffolds. Herein, we describe scope of a valuable general protocol for the synthesis of arrays of 2-aminoquinoline-3-carboxamides from cyanoacetamides and 2-aminobenzaldehydes or heterocyclic derivatives via a Friedlander reaction variation. In many cases, the reactions involve a very convenient work up by simple precipitation and filtration. More than 40 new products are described. We foresee our protocol and the resulting derivatives becoming very valuable to greatly expanding the scaffold space of cyanoacetamide derivatives. PMID- 22486419 TI - Luminescent/magnetic hybrid nanoparticles with folate-conjugated peptide composites for tumor-targeted drug delivery. AB - We developed a novel chitosan-based luminescent/magnetic hybrid nanoparticles with folate-conjugated tetrapeptide composites (CLMNPs-tetrapeptide-FA) by conjugation in situ. First, chitosan, CdTe quantum dots (QDs), and superparamagnetic iron oxide were directly gelled into ternary hybrid nanogels. Subsequently, tetrapeptides (GFFG and LGPV) and folate were conjugated orderly into the hybrid nanoparticles. The morphology, composition, and properties of the as-prepared copolymers have also been characterized and determined using TEM, EDX, XRD, FTIR spectra, DLS, fluorescence spectroscopy, VSM, and fluorescence microscopy imaging studies. The size range of the end product CLMNPs-tetrapeptide FA copolymers was from 150 to 190 nm under simulated physiological environment. In vivo, the experimental results of magnetic accumulation showed that the copolymers could be trapped in the tumor tissue under magnetic guidance. Under the present experimental conditions, the loading efficiencies of CPT were approximately 8.6 wt % for CLMNPs-GFFG-FA and 1.1 wt % for CLMNPs-LGPV-FA, respectively. The CPT cumulative release under dialysis condition mainly occurred for the first 28 h, and could reach 55% at pH 5.3 and 46% at pH 7.4 from CPT loaded CLMNPs-GFFG-FA, and 69% at pH 5.3 and 57% at pH 7.4 from CPT-loaded CLMNPs LGPV-FA within 28 h, respectively. The hemolysis percentages (<2%) and coagulation properties of blank and CPT-loaded copolymers were within the scope of safe values. Compared to free CPT, the CPT-loaded CLMNPs-tetrapeptide-FA copolymers showed specific targeting to A549 cells in vitro. More than 75% viability in L02 cells were seen in CLMNPs-GFFG-FA and CLMNPs-LGPV-FA copolymer concentration of 500 MUg/mL, respectively. It was found that the two kinds of copolymers were transported into the A549 cells by a folate-receptor-mediated endocytosis mechanism. These results indicate that the multifunctional CLMNPs tetrapeptide-FA copolymers possess a moderate CPT loading efficiency, low cytotoxicity, and favorable biocompatibility, and are promising candidates for tumor-targeted drug delivery. PMID- 22486421 TI - Ferrocene-decorated nanocrystalline cellulose with charge carrier mobility. AB - Ferrocene-decorated cellulose nanowhiskers were prepared by the grafting of ethynylferrocene onto azide functionalized cotton-derived cellulose nanowhiskers using azide-alkyne cycloaddition. Successful surface modification and retention of the crystalline morphology of the nanocrystals was confirmed by elemental analysis, inductively coupled plasma-atomic emission spectroscopy, X-ray photoelectron spectroscopy, and X-ray diffraction. The coverage with ferrocenyl is high (approximately 1.14 * 10(-3) mol g(-1) or 4.6 * 10(13) mol cm(-2) corresponding to a specific area of 61 A(2) per ferrocene). Cyclic voltammetry measurements of films formed by deposition of ferrocene-decorated nanowhiskers showed that this small spacing of redox centers along the nanowhisker surface allowed conduction hopping of electrons. The apparent diffusion coefficient for electron (or hole) hopping via Fe(III/II) surface sites is estimated as Dapp = 10(-19) m(2)s(-1) via impedance methods, a value significantly less than nonsolvated ferrocene polymers, which would be expected as the 1,2,3-triazole ring forms a rigid linker tethering the ferrocene to the nanowhisker surface. In part, this is believed to be also due to "bottleneck" diffusion of charges across contact points where individual cellulose nanowhiskers contact each other. However, the charge-communication across the nanocrystal surface opens up the potential for use of cellulose nanocrystals as a charge percolation template for the preparation of conducting films via covalent surface modification (with applications similar to those using adsorbed conducting polymers), for use in bioelectrochemical devices to gently transfer and remove electrons without the need for a solution-soluble redox mediator, or for the fabrication of three dimensional self-assembled conducting networks. PMID- 22486422 TI - The effect of shock wave therapy on patellar ligament desmitis after tibial plateau leveling osteotomy. AB - OBJECTIVE: To determine if shock wave therapy (SWT) after tibial plateau leveling osteotomy (TPLO) has a beneficial effect on patellar ligament inflammation assessed by thickening of the ligament and ligament fiber disruption. STUDY DESIGN: Prospective, randomized, controlled clinical trial. ANIMALS: Dogs (n = 30). MATERIALS AND METHODS: Dogs that had TPLO (July 1, 2009 to June 1, 2010) were enrolled. The affected stifle was examined by radiographs and ultrasonography preoperatively and 4, 6, and 8 weeks after TPLO. At 4 and 6 weeks, dogs in the treatment group were briefly anesthetized and treated with SWT. Patellar ligament thickness on a lateral radiographic projection was measured at 1/4, 1/2, 3/4 of the distance from origin to insertion. Ultrasound images were evaluated for patellar ligament disruption and periligament edema. RESULTS: There was significant difference in thickness (P = .0264) only at the distal point; therefore, only this point was used to measure difference between the control and treatment groups. A significant difference between groups was reached at 6 and 8 weeks (P = .0059 and P = .0095, respectively) postoperatively. No significant ultrasonographic differences were found. CONCLUSION: Based on these results, SWT decreases the radiographic signs of patellar ligament desmitis. PMID- 22486423 TI - Liquid-crystalline zinc(II) and iron(II) alkyltriazoles one-dimensional coordination polymers. AB - Several series of unidimensional coordination polymers of formula [Zn(C(n)H(2n+1)trz)(3)](Cl)(2).xH(2)O (n = 18, 16, 13, 11, 10, trz = 4 substituted-1,2,4-triazole), [Zn(C(18)H(37)trz)(3)](ptol)(2).xH(2)O, [Fe(C(n)H(2n+1)trz)(3)](X)(2).xH(2)O (n = 18, 16, 13, 10; X = Cl(-) or ptol(-), where ptol(-) = p-tolylsulfonate anion), and [Fe(C(18)H(37)trz)(3)](X)(2).xH(2)O (X = C(8)H(17)PhSO(3)(-) and C(8)H(17)SO(3)(-)) are reported with their thermal, structural, and magnetic properties. Most of these materials exhibit thermotropic lamellar mesophases at temperatures as low as 410 K, as confirmed by textures observed by polarized optical microscopy. The corresponding phase diagrams deduced by differential scanning calorimetry are also reported. All iron containing materials present a spin crossover phenomenon that occurs at temperatures ranging from 242 to 360 K, only slightly below the mesophase temperature domain, and remains complete and cooperative, even for the longer alkyl substituents. The use of stable diamagnetic Zn(II) analogues proves to be very useful to characterize the comparatively less stable and less crystalline Fe(II) analogues. PMID- 22486424 TI - Cereal bran and wholegrain as a source of dietary fibre: technological and health aspects. AB - Interest in cereal bran as a source of dietary fibre (DF) and functional components has increased in recent years. Current studies actively focus on DF definition, analysis, formulation in consumer-friendly food products, processing and beneficial health effects. Although bran composition and its benefits to human physiology have been investigated, its technological role as an ingredient is still under study for a variety of cereal foodstuffs. This review provides an overview of cereal bran characterization, functional properties and technological features concerning the bread-making process. In addition, we review the evidence from recent studies indicating that cereal bran may be used as a functional ingredient to improve consumer perception. PMID- 22486425 TI - A large hemodynamically significant right coronary artery fistula to right ventricle: prenatal detection and progression. AB - Prenatal diagnosis of a congenital coronary artery fistula between the right coronary artery and right ventricle was made by two-dimensional and color Doppler echocardiography in a pregnant woman at 37 weeks of gestation. The right ventricle and right coronary artery were dilated with a fistula between them. A boy was delivered at 39 weeks' gestation. Progression of the fistula was monitored by serial echocardiography postnatally. Because there were severe symptoms associated with the fistula, the infant had an operation 6 months after he was born. Four years of follow-up examination showed that the boy is in good clinical condition. PMID- 22486426 TI - AIDS orphans and vulnerable children in India: problems, prospects, and concerns. AB - This article reviews and discusses the problems, responses, and concerns of orphans and vulnerable children in India. The article shows that HIV/AIDS programs and interventions are vital for survival and welfare of orphan and vulnerable children, but they have reached only to a small fraction of the most vulnerable children. The article suggests a number of measures that government and civil society could take to address the problems and emphasizes the need to learn from other countries' experience and initiatives in developing appropriate policy and programmes for orphan and vulnerable children. PMID- 22486427 TI - The medicine that might kill the patient: Structural Adjustment and its impacts on health care in Bangladesh. AB - Over the past decade, reforms of the health sector have evolved as a global phenomenon. There is, by now, a fair literature on the relationship between globalization and health. Within this literature, however, there is relatively little attention given to the Structural Adjustment Program (SAP), one aspect of globalization, and its impact on health. It can be observed that the SAP has had a dramatic impact on the status of education, health, the environment, and women and children in many developing countries. The restructuring of the health sector has led to the collapse of preventive and curative care due to the lack of medical equipment, supplies, poor working conditions, low pay of medical personnel, and the resulting low morale in Ghana, Philippines, and Zimbabwe. User fees in primary health care have led to the exclusion of a large section of the population from accessing health services as they are unable to pay. This article discusses the health specific impact of the SAP and the economic reforms initiated under it in Bangladesh. In particular, it will analyze how these policies affect the health care delivery system in Bangladesh in relation to geographic accessibility, affordability, quality of services, administrative efficiency, the rural urban service gap, public provision of health care, and donor influence on health policy. PMID- 22486428 TI - The impact of the process of deinstitutionalization of mental health services in Canada: an increase in accessing of health professionals for mental health concerns. AB - This research evaluates accessing of community-based mental health services in relation to the ongoing process of deinstitutionalization of mental health services in Canada. From 1998/1999 to 2002/2003, the process of deinstitutionalization decreased in intensity among the provinces that implemented deinstitutionalization earlier and increased in intensity among the provinces that implemented deinstitutionalization later. By 2002/2003, average days of care per 1,000 population in psychiatric units in general hospitals exceeded days of care in psychiatric hospitals (transinstitutionalization). Accessing of community-based mental health services by individuals with higher levels of psychological distress increased in all provinces from 1998/1999 to 2002/2003. PMID- 22486429 TI - Policy implications of Medicare Part D for adults with mental illness: a qualitative exploration. AB - The Medicare prescription drug benefit, introduced in January 2006, has had a substantial impact on the lives of adults disabled by mental illness. However, few studies have undertaken an exploration of the difference that this benefit has made to beneficiaries' access to medication. This study uses a qualitative approach to examine beneficiaries' experiences with the Medicare Part D benefit, and whether having Medicare prescription drug coverage is perceived as helpful. Twenty-six Medicare beneficiaries with mental illness were interviewed regarding their opinions of the Part D benefit, and the investigator found that most beneficiaries were highly satisfied with their prescription drug coverage. However, they would appreciate more information from the Medicare program about their benefits. In addition, beneficiaries were concerned about the possibility of increased future costs. Overall, however, these participants in the Medicare Part D program who had mental illness felt that their needs for psychotropic and other medications were met. PMID- 22486430 TI - Sedentarism: the effects of Internet use on human obesity in the United States. AB - This paper analyzes the impact of Internet use on human obesity in the United States. The United States is facing a skyrocketing obesity epidemic among adults and children. The authors hypothesize that the more individuals use the Internet, the more they increase their risks of becoming obese. The explanation is that Internet use may cause sedentarism, which refers to decreased energy expenditure or, simply, physical inactivity. Sedentarism, in turn, may increase obesity. PMID- 22486431 TI - The use of computer technology to reduce and prevent college drinking. AB - Underage drinking, or binge drinking, has become a major concern in U.S. society. At The University of Tennessee (UT) a computer-based intervention was put into place for the past 3 years with funding from the Substance Abuse and Mental Health Services Administration (SAMHSA). The intervention was provided to all college students via UT's computer network system and was completed mostly online. Students were given a computerized, standardized assessment of alcohol use, and then a brief intervention was given based on the students' information. The intervention targeted students who were at highest risk for developing unsafe alcohol behaviors and/or increasing prior alcohol consumption habits in their first year of college. More than 54,000 graduate and undergraduate students completed the program. Since the launch of the program binge drinking has dropped 27% on campus, frequent binge drinking dropped 44%, and the number of liquor law violations to 18- to 20-year-olds decreased from 542 in 2004 to approximately 158 in 2007. The use of a computer-based intervention was comprehensive, low cost, and required low maintenance. PMID- 22486432 TI - Gender-responsive programs in U.S. prisons: implications for change. AB - This research examines the need for programs that focus on mental health issues, parenting issues, and other unique needs of female offenders incarcerated throughout the United States. The Bureau of Justice Statistics showed that 84% of female offenders were living with their children prior to their arrest. This constitutes a crisis in our society today, which is manifest in overcrowded state and federal prisons, increased caseloads for the Department of Children and Family Services, the Foster Care System, and families of the offenders. The goal of this research is to determine what types of gender-responsive programs are effective in reducing recidivism. The methods used were qualitative data analysis, by comparing which programs are offered, either within the prison, or as a reentry postrelease program. A survey was used and interview data were analyzed by identifying and comparing common themes and patterns. The findings reveal the most effective gender-responsive programs are those that incorporate substance abuse treatment, education and job preparedness, parenting programs where contact with children is allowed and/or encouraged, and family reunification programs. PMID- 22486434 TI - Trichilemmomas show loss of PTEN in Cowden syndrome but only rarely in sporadic tumors. AB - BACKGROUND: Trichilemmoma (TL) can occur as a solitary sporadic lesion usually on the face or as multiple facial lesions almost invariably associated with Cowden syndrome (CS). CS is a multisystem disorder caused by a germline inactivating mutation in PTEN (10q23.31), a tumor suppressor gene. We sought to identify PTEN loss by immunohistochemistry (IHC) in sporadic and CS-associated TL to determine whether IHC is a useful tool to assess an individual for CS. METHODS: Six TL biopsies associated with CS and 33 biopsies without CS were retrieved. IHC for PTEN was performed. RESULTS were scored as positive (reactivity in TL cells) or negative (no reactivity in TL cells); normal squamous epithelium and vascular endothelium served as internal positive controls. RESULTS: Complete PTEN loss was noted in 5/6 (83%) CS-associated TL and 1/33 (3%) sporadic (non-CS) TL. CONCLUSION: Demonstration of complete PTEN loss in TL by IHC is strongly suggestive of association with CS, but retention of PTEN staining does not entirely exclude CS. Therefore, PTEN IHC in TLs may be helpful in screening TL for association with CS, but should be used in context with other established clinical criteria, and possibly germline PTEN genotyping to confirm a diagnosis of CS. PMID- 22486435 TI - Adaptability of large carnivores to changing anthropogenic food sources: diet change of spotted hyena (Crocuta crocuta) during Christian fasting period in northern Ethiopia. PMID- 22486436 TI - Progress in computational medicinal chemistry. PMID- 22486437 TI - Comparison of canine core bone marrow biopsies from multiple sites using different techniques and needles. AB - BACKGROUND: Commonly used 11 or 13ga needles are relatively large for collection of bone marrow (BM) biopsies from small dogs. OBJECTIVES: The aims of this study were to assess ease of BM collection and quality of specimens obtained from small dogs using 13 and 15ga needles and to determine if specimen encasement would improve quality. METHODS: Humeral and iliac biopsies obtained from 17 Beagle dogs with a 15ga needle and a power driver were compared with humeral biopsies obtained with a 13ga Jamshidi needle. Ease of collection (scored as 1 [very difficult] to 5 [very easy] for 3 components of collection with scores summed), section quality (scored as 1 [poor] to 5 [good]), and lesions at collection sites were scored. Quality of additional humeral biopsies obtained with a 15ga needle and wrapped in tissue paper prior to fixation was assessed. RESULTS: Use of a 15ga needle to obtain a humeral BM biopsy was significantly easier (mean score +/ SD = 13.6 +/- 1.7) than obtaining humeral BM using a 13ga needle (11.4 +/- 1.6; P < .001) or obtaining iliac BM using a 15ga needle (10.9 +/- 2.0, P < .001). Quality of humeral biopsies obtained with a 13ga needle (3.9 +/- 1.2) was better than for biopsies of the humerus (1.9 +/- 1.3, P < .001) or ilium (1.4 +/- 0.6, P < .001) using a 15ga needle. Only sites sampled with a 13ga needle were identifiable grossly after the procedure. In most biopsies, cell density and cellularity were lower when a 15ga needle was used. Paper-wrapping of biopsies did not improve quality. CONCLUSIONS: In small dogs, collection of humeral BM biopsies using a 15g needle is feasible and more easily accomplished than collection using a 13ga needle. Hematopoiesis may be underestimated in specimens collected using the smaller needle. PMID- 22486439 TI - Modulation of photochemical damage in normal and malignant cells by naturally occurring compounds. AB - Certain phytochemicals, such as the stilbene, resveratrol (RES, found in red grapes and berries), and the triterpenoid, ursolic acid (UA, found in waxy berries and herbs such as rosemary and oregano), have antioxidant, anti inflammatory and antiproliferative effects. Two human-derived cell lines, hTERT RPE with a nonmalignant phenotype derived from retinal pigment epithelium, and ATCC CRL-11147 derived from a malignant skin melanoma, were used as in vitro models of photooxidative stress produced by exposure to the broadband output of a 150 W Hg vapor arc lamp at an irradiance of 19-26 mW cm(-2). In untreated cells, UV-VIS broadband light exposure produced a loss of proliferative ability, an activation of NF-kappaB and an increase in protein carbonyl adducts at 24 h postexposure. Pretreatment of the cells with RES or UA at 1-2 MUmsignificantly reduced the amount of phosphorylated NF-kappaB at 24 h postexposure. RES pretreatment reduced the burden of light-induced protein carbonyl adducts by up to 25% in exposed cells. UA treatment markedly increased the sensitivity of melanoma cells to UV radiation, while conferring some photoprotection to RPE cells. These observations indicate that phytochemicals modulate the cellular response to photochemical stress by interacting with specific cell-signaling pathways. PMID- 22486440 TI - Herpes simplex virus US3 protein kinase regulates host responses and determines neurovirulence. AB - The US3 of HSV encodes a serine/threonine protein kinase that is highly conserved among members of the alphaherpesviruses. It is an accessory gene that is not required for viral replication in cultured cells but appears essential for viral survival in humans. Although accumulating in vitro evidence suggested that the viral protein kinase is multifunctional, little information is available about its functions in vivo. Several reports point out that, upon invasion into the peripheral nervous system, HSV blocks virus-induced neuronal apoptosis, while presumably subverting host immune responses, largely through actions of the US3 protein kinase. In addition, the US3 protein kinase confers the viral neurovirulence. In the present article, functions of the HSV US3 protein kinase are briefly reviewed, with special attention given to its role in regulating host responses and neurovirulence. PMID- 22486438 TI - Rapid temporal changes in the expression of a set of neuromodulatory genes during alcohol withdrawal in the dorsal vagal complex: molecular evidence of homeostatic disturbance. AB - BACKGROUND: Chronic alcohol exposure produces neuroadaptation, which increases the risk of cellular excitotoxicity and autonomic dysfunction during withdrawal. The temporal progression and regulation of the gene expression that contributes to this physiologic and behavioral phenotype is poorly understood early in the withdrawal period. Further, it is unexplored in the dorsal vagal complex (DVC), a brainstem autonomic regulatory structure. METHODS: We use a quantitative polymerase chain reaction platform to precisely and simultaneously measure the expression of 145 neuromodulatory genes in more than 100 rat DVC samples from control, chronically alcohol-exposed, and withdrawn rats. To gain insight into the dynamic progression and regulation of withdrawal, we focus on the expression of a subset of functionally relevant genes during the first 48 hours, when behavioral symptoms are most severe. RESULTS: In the DVC, expression of this gene subset is essentially normal in chronically alcohol-exposed rats. However, withdrawal results in rapid, large-magnitude expression changes in this group. We observed differential regulation in 86 of the 145 genes measured (59%), some as early as 4 hours into withdrawal. Time series measurements (4, 8, 18, 32, and 48 hours after alcohol removal) revealed dynamic expression responses in immediate early genes, gamma-aminobutyric acid type A, ionotropic glutamate, and G-protein coupled receptors and the Ras/Raf signaling pathway. Together, these changes elucidate a complex, temporally coordinated response that involves correlated expression of many functionally related groups. In particular, the expression patterns of Gabra1, Grin2a, Grin3a, and Grik3 were tightly correlated. These receptor subunits share overrepresented transcription factor binding sites for Pax-8 and other transcription factors, suggesting a common regulatory mechanism and a role for these transcription factors in the regulation of neurotransmission within the first 48 hours of alcohol withdrawal. CONCLUSIONS: Expression in this gene set is essentially normal in the alcohol-adapted DVC, but withdrawal results in immediate, large-magnitude, and dynamic changes. These data support both increased research focus on the biological ramifications of alcohol withdrawal and enable novel insights into the dynamic withdrawal expression response in this understudied homeostatic control center. PMID- 22486441 TI - Mesorhizobium ciceri LMS-1 expressing an exogenous 1-aminocyclopropane-1 carboxylate (ACC) deaminase increases its nodulation abilities and chickpea plant resistance to soil constraints. AB - AIMS: Our goal was to understand the symbiotic behaviour of a Mesorhizobium strain expressing an exogenous 1-aminocyclopropane-1-carboxylate (ACC) deaminase, which was used as an inoculant of chickpea (Cicer arietinum) plants growing in soil. METHODS AND RESULTS: Mesorhizobium ciceri LMS-1 (pRKACC) was tested for its plant growth promotion abilities on two chickpea cultivars (ELMO and CHK3226) growing in nonsterilized soil that displayed biotic and abiotic constraints to plant growth. When compared to its wild-type form, the M. ciceri LMS-1 (pRKACC) strain showed an increased nodulation performance of c. 125 and 180% and increased nodule weight of c. 45 and 147% in chickpea cultivars ELMO and CHK3226, respectively. Mesorhizobium ciceri LMS-1 (pRKACC) was also able to augment the total biomass of both chickpea plant cultivars by c. 45% and to reduce chickpea root rot disease susceptibility. CONCLUSIONS: The results obtained indicate that the production of ACC deaminase under free living conditions by Mesorhizobium strains increases the nodulation, plant growth abilities and biocontrol potential of these strains. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study regarding the use of a transformed rhizobial strain expressing an exogenous ACC deaminase in different plant cultivars growing in soil. Hence, obtaining Mesorhizobium strains with high ACC deaminase activity is a matter of extreme importance for the development of inoculants for field applications. PMID- 22486442 TI - Copper-free route to triazole-modified peptidomimetic by the combination of two multicomponent reactions in one pot. AB - An efficient copper-free protocol for the synthesis of 5-methyl-1H-1,2,3-triazole modified peptidomimetics through the combination of Ugi four-component reaction with a three-component cycloaddition, has been developed. The copper-free straightforward process is suitable for drug discovery. The chemoselective preparation of 1,4-disubstituted, triazole-modified peptidomimetics by using alkynyl substituted amines may have potential biological and synthetic application. At last, a "Lapinski type" analysis of the physical properties was performed, which is expected to help drug discovery. PMID- 22486443 TI - Cumulative risk and adolescent's internalizing and externalizing problems: the mediating roles of maternal responsiveness and self-regulation. AB - The purpose of the present study was to examine longitudinal associations among maternal responsiveness, self-regulation, and behavioral adjustment in adolescents. The authors used structural equation modeling to test a model that demonstrates that the effects of early cumulative risk on behavioral problems is mediated by maternal responsiveness and self-regulation. Furthermore, the authors examine the contributions of cumulative risk and maternal responsiveness on children's self-regulatory abilities. The study uses a 3-wave longitudinal design with multiple measures of risk and self-regulation from multiple observers. Data were collected from adolescents (N = 265, male = 140) and their parents at age 9, 13, and 17. Results suggest that the mediation hypothesis held true for externalizing, but not internalizing problems. Furthermore, cumulative risk and maternal responsiveness contributed uniquely to children's self-regulation abilities. (PsycINFO Database Record (c) 2012 APA, all rights reserved). PMID- 22486445 TI - Opioid analgesics in experimental sepsis: effects on physiological, biochemical, and haemodynamic parameters. AB - Cecal ligation and puncture (CLP) is the sepsis model that more closely resembles the human pathology, but it is likely to cause suffering to experimental animals. However, it is not clear whether the use of analgesia may affect some parameters evaluated in experimental sepsis research. Therefore, we investigated the effects of fentanyl and tramadol in experimental sepsis in the rat. The following parameters were evaluated: body temperature, body weight, water and food ingestion, mortality, analgesia, blood leukocytes, mean arterial blood pressure, vascular reactivity to phenylephrine, lung myeloperoxidase activity, and plasma levels of IL1-beta, glutamic-oxaloacetic, glutamic-pyruvic, lactate, creatinine and urea. While producing significant analgesia, the opioids modify minimally the parameters, with the exception of sepsis-induced hypotension and mortality. Although fentanyl and tramadol can minimize pain and the general suffering of animals submitted to CLP surgery, their effects on cardiovascular parameters as well as in the mortality indicate that their use in experimental sepsis must be done with caution and with all the proper control groups. PMID- 22486446 TI - Large variations of global functioning over five years in treated patients with personality traits and disorders. AB - The aim of this study was to examine the long-term course of global functioning in patients with personality disorders (PD) and investigate predictors of variation. The Global Assessment of Functioning (GAF) was repeated over five years in 352 patients with PDs of varying severity, all treated in psychotherapeutic day hospitals. Growth models were used for statistical analysis. Large variations in the long-term course of global functioning were evident in this clinical sample. At five-year follow-up, 46% reached a GAF-score above 60 with a mean GAF-score of 71. Their linear change-rate over the five years was estimated to be 4.4 GAF points per year. The average five-year GAF score for the remaining subgroup (54%) was 50 and their linear yearly change-rate was 0.8 GAF points. Greater relief of symptom distress and interpersonal problems was typical of patients with functional improvement. The number of avoidant PD criteria was associated with slower functional change. PMID- 22486447 TI - The utility of the cognitive-affective processing system in the diagnosis of personality disorders: some preliminary evidence. AB - The Cognitive-Affective Processing System (CAPS) suggests that personality is best understood as a collection of situationally consistent traits that are expressed contingent upon features of the situation that elicit them. This differs from the Five-Factor Model (FFM) of personality, in which personality is believed to be composed of five broad trait domains that are observed consistently across multiple situations. In this study, 202 licensed members of a state psychological association assigned diagnoses to written case studies that were created out of situationally specific descriptions of Axis II criteria. The accuracy of these diagnoses were compared to case studies written from FFM trait descriptions representative of the same Axis II disorders (schizoid, narcissistic, and obsessive compulsive) and to case studies taken from published DSM case books. Results demonstrated that cases constructed with the CAPS descriptions yielded more accurate diagnoses in two of the three cases compared to FFM trait description cases and equivalent diagnostic accuracy when using the DSM-IV. Based on these initial findings, it appears that clinicians may be able to judge personality disorders better with situationally specific, or context dependent, information than simple trait descriptions. PMID- 22486448 TI - Adult attachment to transitional objects and borderline personality disorder. AB - Borderline personality disorder (BPD) is characterized by tumultuous, unstable personal relationships, difficulty being alone, and an inability to self-soothe. This may explain why patients with BPD tend to develop strong attachments to transitional objects such as stuffed animals. Research in hospital settings has linked the use of transitional objects to the presence of BPD. Using a nonclinical community sample (N = 80) we explored the link between attachments to transitional objects and various aspects of personality pathology, as well as to childhood trauma, and parental rearing styles. People who reported intense current attachments to transitional objects were significantly more likely to meet criteria for a BPD diagnosis than those who did not; they also reported more childhood trauma, rated their early caregivers as less supportive, and had more attachment problems as adults. Heavy emotional reliance on transitional objects in adulthood may be an indicator of underlying pathology, particularly BPD. PMID- 22486449 TI - The course of adult experiences of abuse in patients with borderline personality disorder and Axis II comparison subjects: a 10-year follow-up study. AB - The first objective of this study was to assess the rates of adult experiences of verbal, emotional, physical, and sexual abuse reported by borderline patients and Axis II comparison subjects over 10 years of prospective follow-up. The second objective was to determine time-to-cessation, recurrence, and new onset of each type of abuse. The Abuse History Interview (AHI) was administered to 290 borderline patients and 72 Axis II comparison subjects at baseline. The AHI Follow-up Version (AHI-FUV) was administered at five contiguous follow-up waves. Over 10 years of follow-up, the rates of all four types of abuse declined significantly for borderline patients. For borderline patients, rates of cessation were high for all types of abuse (>90%). However, recurrences and new onsets of verbal and emotional abuse were relatively common (>60%). Contrastingly, they were relatively uncommon for physical and sexual abuse (<30%), suggesting that verbal and emotional abuse represent more stable forms of abuse. PMID- 22486450 TI - BIS and BAS interact with perceived parental affectionless control to predict personality disorder symptomatology. AB - The objective of this study was to examine if and how two basic dimensions of temperament-behavioral inhibition system (BIS) and behavioral approach system (BAS) sensitivity-might interact with exposure to perceived parental affectionless control (AFC) to predict personality disorder (PD) symptomatology. Measures of BIS, BAS, AFC, and PD symptomatology were administered to a large nonclinical sample (n = 318). As predicted, exposure to AFC was positively associated with PD symptoms in general, BIS was positively associated with Cluster A and C symptoms, and BAS was positively associated with Cluster B symptoms. BIS and BAS were also found to interact with each other to predict Cluster B symptomatology. In addition, BIS, BAS, and maternal AFC interacted to predict Cluster A symptomatology. In the latter case, it was found that individuals who reported high BIS, high BAS, and high maternal AFC reported the highest overall level of Cluster A symptoms. PMID- 22486451 TI - Psychopathy and traumatic stress. AB - This study examined the relationship between psychopathy and traumatic stress. First, a sample of 48 male patients in a security hospital was assessed using the Psychopathy Checklist (Hare, 2003) and the Stanford Acute Stress Reactions Questionnaire (SASRQ; Cardena, Classen, Koopman, & Spiegel, 1996). Linear regression analyses suggested that the affect deficit component of psychopathy was the best negative predictor of avoidance, dissociation, and re-experiencing symptoms. The 13 highest-scoring psychopathy participants were then compared to the 13 lowest-scoring participants. Psychopaths differed from controls in terms of number but not type of traumatic events. They obtained significantly lower SASRQ total score, reflecting a lower level of traumatic symptomatology. The results are discussed in connection with the emotional deficit component of psychopathy. PMID- 22486452 TI - The associations between non-suicidal self-injury and borderline personality disorder features among Chinese adolescents. AB - This study examined the relative importance of four major BPD features, that is, affective instability, disturbed interpersonal relationship, unstable sense of self, and behavioral impulsivity, in explaining the presence, initiation, repetition, and discontinuation of non-suicidal self-injury (NSSI) among a 2-year follow-up sample of 4,782 (68.5% girls) Hong Kong Chinese secondary school students. Affective instability, disturbed interpersonal relationship and behavioral impulsivity were significantly associated with the presence of NSSI both concurrently and longitudinally. These three BPD features were also related to the future initiation of NSSI. On the other hand, only behavioral impulsivity made a significant contribution to the repetition of NSSI. Additionally, a lower level of affective instability was also associated with quitting NSSI. We discussed some possible mechanisms underlying the effects of different BPD features on different developmental stages of NSSI. PMID- 22486453 TI - Childhood abuse in Chinese patients with borderline personality disorder. AB - This study examined (1) the relative prevalence of childhood abuse and other pathological childhood experiences in China reported by outpatients with borderline personality disorder (BPD), with other personality disorders, and without personality disorders; and, (2) whether the primary predictors of BPD in North America are associated with the development of BPD in China. The childhood experiences of 203 outpatients with BPD, 109 outpatients with other personality disorders, and 70 outpatients without Axis II diagnoses were assessed with the Chinese version of the Childhood Experience of Care and Abuse Questionnaire (CECA.Q). Patients with BPD reported significantly more physical, emotional, and sexual abuse than either comparison group. Four types of childhood experiences were significant predictors of BPD: maternal neglect, paternal antipathy, sexual abuse, and maternal physical abuse. The findings suggest that maternal physical abuse is as strong a predictor of BPD in China as sexual abuse, a finding not replicated in North America. PMID- 22486454 TI - Personality disorders in young adult survivors of pediatric burn injury. AB - OBJECTIVE: Life experience shapes personality and chronic trauma in childhood has been associated with risk for development of subsequent personality disorder. The purpose of this study is to determine the prevalence and character of personality disorders and traits in young adult survivors of severe pediatric burn injury. METHOD.: SCID-II and 16PF were completed by 98 young adult survivors of pediatric burn trauma. RESULTS: 48 (49%) met criteria for one or more personality disorders. The most frequent personality disorders were Paranoid (19.4%), Passive Aggressive (18.4%), Antisocial (17.3%), Depressive (11.2%), and Borderline (9.2%). Diagnosis with a personality disorder was associated with comorbid Axis I diagnoses and strongly correlated with personality traits as measured by the 16PF. CONCLUSIONS: Pediatric burn trauma is similar to other chronic traumas of childhood in significant correlation with subsequent personality disorder. PMID- 22486455 TI - Functions and timescale of self-cutting in participants suffering from borderline personality disorder. AB - The purpose of this study was to examine the meanings and timescale of self cuttings in a cohort of 22 outpatients suffering from borderline personality disorder. Sixty-one events were recorded using the newly developed self-cutting checklist (SCUC) designed to investigate the severity of self-cuttings, and intent to die, suicidal ideation, inner tension, sense of relief and anesthesia, and consequences associated with this behavior. We found that typical self cuttings were associated with a decrease in inner tension and suicidal ideation. Moreover self-cuttings associated with a desire to die differentiated from those associated with no desire to die by significantly less reduction in inner tension. Finally, self-cuttings occurred significantly more often during evenings and nights than during daytime. In conclusion, self-cuttings can be reasonably addressed by self-report. Attention to specific issues such as intent to die and the time of the self-cuttings may improve the outcome of these particularly high risk subjects. PMID- 22486456 TI - Predicting borderline personality disorder features from personality traits, identity orientation, and attachment styles in Italian nonclinical adults: issues of consistency across age ranges. AB - The aims of this study were to assess whether Borderline Personality Disorder (BPD) features could be predicted by Big Five traits, impulsivity, identity orientation, and adult attachment patterns in a sample of 1,192 adult nonclinical participants, and to evaluate the consistency of these regression models across four age groups (<30 years, 30-39 years, 40-49 years, and >50 years, respectively). In the full sample, measures of neuroticism (N), impulsivity, and anxious insecure attachment were substantial predictors of BPD features (adjusted R(2) = .38, p < .001). Attachment scales were significant predictors of BPD features across all age groups, but different scales were relevant in different age groups. Our results suggest that in nonclinical populations, BPD may represent a complex constellation of personality traits and disturbed attachment patterns. PMID- 22486457 TI - Personality disorder categories as combinations of dimensions: translating cooperative behavior in borderline personality disorder into the five-factor framework. AB - The authors examined the proposal that personality disorder categories may denote particular detrimental combinations of personality dimensions. A multiround economic exchange game (ten round trust game), conducted with university students pre-selected on basis of their personalities (N = 164), provided a framework within which to investigate inability to repair ruptured cooperation. This behavior, thought to be characteristic of patients diagnosed with DSM-IV borderline personality disorder, was predicted only by the combination of high Neuroticism and low Agreeableness. Our results highlight an advantage of the categorical approach, category labels being a much more economic means of description than the delineation of interactions between dimensions. PMID- 22486458 TI - Surgical-pathologic risk factors of pelvic lymph node metastasis in stage Ib1-IIb cervical cancer. AB - OBJECTIVE: To study the distribution characteristics and risk factors of cervical cancer lymph node metastasis (LNM). DESIGN: Retrospective study. SETTING: Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology and Affiliated Hospital to Zunyi Medical College. POPULATION: 404 women diagnosed with cervical cancer FIGO stage Ib1-IIa who underwent primary radical surgery and 104 women with Ib2-IIb tumors treated with neoadjuvant chemotherapy (NACT) before surgery. METHODS: Clinicopathological data were collected and analyzed. MAIN OUTCOME MEASURES: Incidence of infiltration, metastasis and pelvic LNM. RESULTS: In women without NACT, the incidence of infiltration, metastasis and LNM was 7.2, 17.6 and 15.8%, respectively. Metastasis and LNM were significantly associated with advanced FIGO stage and poorer histological grade. The incidence of multiple metastatic lymph nodes (MLNs), bilateral LNM, skip LNM, LNM in primary group and LNM in secondary group was 6.2, 3.0, 6.2%, 11.4 and 4.5%, respectively. Of the 111 MLNs, 13 (11.7%) were common iliac lymph nodes. In the NACT group, infiltration, metastasis and LNM were observed in 10 (9.6%), 24 (23.1%) and 21 (20.1%) of 104 women, respectively. Metastasis and LNM were significantly correlated with moderate cell differentiation. CONCLUSION: High LNM risk is expected in tumors of IIa stage or higher and in moderately differentiated tumors. Skip metastasis and common iliac LNM are relatively common and therefore should not be neglected. Our results suggest that standardized and complete pelvic lymph node dissection under surgery is an important measure to ensure a therapeutic effect. PMID- 22486459 TI - Strobes: an oscillatory combustion. AB - Strobe compositions belong to the class of solid combustions. They are mixtures of powdered ingredients. When ignited, the combustion front evolves in an oscillatory fashion, and flashes of light are produced by intermittence. They have fascinated many scientists since their discovery at the beginning of the 20th century. However, the chemical and physical processes involved in this curious oscillatory combustion remain unknown. Several theories have been proposed: One claims that two different reactions occur: one during the slow dark phase and another during the fast flash phase. The alternation between the phases is ascribed to heat variations. Other theories suggest that the formation of intermediate species during the dark phase and the change of phase are caused by variations in their concentration. A ternary strobe composition with ammonium perchlorate, magnalium, and barium sulfate is analyzed. The role of barium sulfate is studied by replacing it by other metal sulfates that have different physical properties (melting points), and the burning of the compositions is recorded with a high-speed camera and a spectrometer coupled with a charge coupled device (CCD) camera. Experimental results show noticeable differences in the physical and chemical processes involved in the strobe reactions. PMID- 22486460 TI - Comparison of squatting stress echocardiography and dobutamine stress echocardiography for the diagnosis of coronary artery disease. AB - BACKGROUND: Dobutamine stress echocardiography (DSE) is commonly used for the diagnosis for coronary artery disease (CAD). We previously demonstrated that squatting induces wall motion abnormalities (WMA) in areas subtended by stenotic coronary arteries. OBJECTIVE: This study was designed to test the hypothesis that dobutamine and squatting stress echocardiography are equally useful for the diagnosis of CAD. METHODS: We studied 39 patients who were scheduled to have coronary angiography for the evaluation of chest pain. Each patient had squatting stress echocardiography followed by DSE. For squatting stress echocardiography the echocardiogram in standard views was recorded in the standing position. The procedure was repeated during squatting for 2 minutes. Dobutamine echocardiography was performed using standard protocol. The squatting and dobutamine stress echocardiograms were interpreted by an observer blinded to the results of coronary angiography. RESULTS: During squatting, new or worsening WMA developed in 20 patients. Six patients developed WMA in the left anterior descending artery territory, three in circumflex territory, three in the right coronary artery territory, and eight in multiple coronary territories. The sensitivity, specificity, and accuracy of squatting echocardiography for diagnosis of CAD were 95%, 94%, and 94%, respectively. For DSE, the sensitivity, specificity, and accuracy for the diagnosis of CAD were 85%, 94%, and 90%, respectively. There was no significant difference between squatting and dobutamine stress echocardiography for the diagnosis of CAD (P = 0.702). CONCLUSION: These data indicate that squatting and dobutamine echocardiography are equally useful in the diagnosis of CAD. In selected patients, squatting echocardiography may be used in place of dobutamine echocardiography for the diagnosis of CAD. PMID- 22486461 TI - Pressure catalyzed bond dissociation in an anthracene cyclophane photodimer. AB - The anthracene cyclophane bis-anthracene (BA) can undergo a [4 + 4] photocycloaddition reaction that results in a photodimer with two cyclobutane rings. We find that the subsequent dissociation of the dimer, which involves the rupture of two carbon-carbon bonds, is strongly accelerated by the application of mild pressures. The reaction kinetics of the dimer dissociation in a Zeonex (polycycloolefin) polymer matrix were measured at various pressures and temperatures. Biexponential reaction kinetics were observed for all pressures, consistent with the presence of two different isomers of bis(anthracene). One of the rates showed a strong dependence on pressure, yielding a negative activation volume for the dissociation reaction of DeltaV(++) = -16 A(3). The 93 kJ/mol activation energy for the dissociation reaction at ambient pressure is lowered by more than an order of magnitude from 93 to 7 kJ/mol with the application of modest pressure (0.9 GPa). Both observations are consistent with a transition state that is stabilized at higher pressures, and a mechanism for this is proposed in terms of a two-step process where a flattening of the anthracene rings precedes rupture of the cyclobutane rings. The ability to catalyze covalent bond breakage in isolated small molecules using compressive forces may present opportunities for the development of materials that can be activated by acoustic shock or stress. PMID- 22486462 TI - Different lying positions and their effects on tissue blood flow and skin temperature in older adult patients. AB - AIM: To report a study to compare the effects of different lying positions on tissue blood flow and skin temperature in older adult patients. This article reports the evaluation of study design and procedures. BACKGROUND: To reduce risk of pressure ulcers, repositioning of immobile patients is a standard nursing practice; however, research into how different lying positions effect tissue microcirculation is limited. DESIGN: Descriptive comparative design. METHODS: From March-October 2010, 20 inpatients, aged 65 years or older, were included in the study. Tissue blood flow and skin temperature were measured over bony prominences and in gluteus muscle in four supine and two lateral positions. RESULTS: The blood flow over the bony prominence areas was most influenced in the superficial skin and especially in the 30 degrees lateral position, where the blood flow decreased significantly in comparison with the supine positions. There were significant individual differences in blood flow responses, but no common trend was identified among the patients considered at risk for pressure ulcer development. The study procedure worked well and was feasible to perform in an inpatient population. CONCLUSION: The lying positions seem to influence the tissue blood flow over the bony prominences in different ways in older adult inpatients, but further study is needed to confirm the results and to make recommendations to clinical practice. The study procedure worked well, although some minor adjustments with regard to heat accumulation will be made in future studies. PMID- 22486463 TI - Chemical descriptors for sensory and parental origin of commercial Coffea genotypes. AB - To attain chemical descriptors responsible for sensory characteristics linked to the botanical origin of five Brazilian coffee genotypes, a chemical survey was carried out. Highest and lowest amounts of caffeine were found in Apoata and Obata. Coffea dewevrei showed the lowest contents of 5-CQA and 3-CQA. 3,5-diCQA was higher for Apoata and minimum values were detected in Icatu. Apoata showed the highest contents of 3,4-diCQA and 4,5-diCQA, Catuai, Icatu and Obata revealed lower values of 4,5-diCQA. Among hydroxycinnamic acids ferulic acid prevailed in all genotypes, with lower values in Icatu and Obata. 3,4-DCA remained significantly higher in Apoata, C. dewevrei and Catuai. Caffeic acid and p coumaric acid did not vary significantly. It was concluded that Apoata was most adequate for the decaffeinated industry; Catuai, Icatu and Obata were identified as producers of good beverages. Apoata and C. dewevrei seemed to share closer parental origins to Coffea canephora cv. Robusta, whereas Icatu, Obata and Catuai showed higher similarities to Coffea arabica. PMID- 22486464 TI - Paradoxical downregulation of CXC chemokine receptor 4 induced by polyphemusin II derived antagonists. AB - CXC chemokine receptor 4 (CXCR4) is a G protein-coupled receptor implicated in cell entry of T-cell line-tropic HIV-1 strains. CXCR4 and its ligand stromal cell derived factor-1 (SDF-1)/CXCL12 play pivotal parts in many physiological processes and pathogenetic conditions (e.g., immune cell-homing and cancer metastasis). We previously developed the potent CXCR4 antagonist T140 from structure-activity relationship studies of the antimicrobial peptide polyphemusin II. T140 and its derivatives have been exploited in biological and biomedical studies for the SDF-1/CXCR4 axis. We investigated receptor localization upon ligand stimulation using fluorescent SDF-1 and T140 derivatives as well as a specific labeling technique for cellular-membrane CXCR4. Fluorescent T140 derivatives induced translocation of CXCR4 into the perinuclear region as observed by treatment with fluorescent SDF-1. T140 derivative-mediated internalization of CXCR4 was also monitored by the coiled-coil tag-probe system. These findings demonstrated that the CXCR4 antagonistic activity and anti-HIV activity of T140 derivatives were derived (at least in part) from antagonist mediated receptor internalization. PMID- 22486465 TI - Effects of calcining temperature on photocatalytic activity of Fe-doped sulfated titania. AB - Using industrial titanyl sulfate as a raw material, Fe-doped sulfated titania (FST) photocatalysts were prepared by using the one-step thermal hydrolysis method and characterized using XRD, SEM, TGA-DSC, FTIR, UV-Vis DRS and N(2) adsorption-desorption techniques. The effects of calcining temperature on the structure of the titania were investigated. The photocatalytic activity of the FST was evaluated using the photodegradation of methylene blue and photooxidation of phenol in aqueous solutions under UV and visible light irradiation, respectively. The results evinced that Ti(4+) is substituted by Fe(3+) in titania lattice and forms impurity level within the band gap of titania, which consequently induces the visible light absorption and visible-light-driven photocatalytic activity. The synergistic effects of Fe-doping and sulfation are beneficial to the efficient separation of the photogenerated carriers and also improve the quantum efficiency of photocatalysis. In addition, Bronsted acidity arisen from the strong inductive effect of sulfate is also conducive to enhancing the photocatalytic performance of FST. However, when the calcining temperature is higher than 800 degrees C, sulfur species and surface hydroxyl groups decompose and desorb from FST and the specific surface area decreases sharply. Moreover, severe sintering and rutile phase formation occur simultaneously. All these are detrimental to photocatalytic activity of FST. PMID- 22486466 TI - Breastfeeding--a public health issue, not just a matter of choice. PMID- 22486467 TI - Advocacy and support of breastfeeding: where do we stand? PMID- 22486468 TI - Allergic response to lactogenesis 2? PMID- 22486470 TI - A cross-over randomised clinical trial of eccentric occlusion in complete dentures. AB - The objective of this study is to compare the effects of canine guidance (CG) and bilateral balanced occlusion (BBO) on denture satisfaction and kinesiographic parameters of complete denture wearers, by means of a cross-over trial. Fifty edentulous patients received new maxillary and mandibular complete dentures. After the intra-oral adjustments and adaptation period, 44 participants were enrolled in the trial and randomly received a sequence of occlusal schemes: BBO followed by CG, or CG followed by BBO. Outcomes were assessed after 30 days of each occlusal scheme. Participants answered a denture satisfaction questionnaire and a kinesiograph instrument recorded mandibular physiologic movements and pattern of maxillary denture movement during chewing. Wilcoxon test and paired sample t-test were used to compare satisfaction levels and kinesiographic data for each occlusal scheme, respectively (alpha=0.05). The results showed no differences between occlusal schemes on participant's satisfaction and in any of the kinesiographic parameters studied, except for the vertical intrusion of the maxillary complete denture during chewing, which was lower with CG. It can be concluded that the occlusal scheme did not influence on satisfaction and kinesiographic parameters evaluated, as long as volume and resilience of residual edentulous ridges of the participants were normal. Clinical Trial Registration Identifier: NC.T01420536. PMID- 22486471 TI - West Nile virus infection in blood donors in the New York City area during the 2010 seasonal epidemic. AB - BACKGROUND: A uniform threshold strategy for converting from minipool (MP) nucleic acid testing (NAT) to individual donation (ID)-NAT screening for acute West Nile virus (WNV) infection among blood donors is lacking. We report on WNV screening at the New York Blood Center during the 2010 seasonal WNV epidemic, the most severe epidemic in that state since the original outbreak in 1999. STUDY DESIGN AND METHODS: Between July 1 and October 31, 2010, blood donations were screened by MP-NAT or ID-NAT and the presence of anti-WNV immunoglobulin (Ig)M and IgG was evaluated among NAT-positive donations. RESULTS: Twenty presumed viremic donations were identified for a frequency of 0.0129% (1 in 7752 donations). Nine donations that could have been missed by MP-NAT were identified. Two of these donations were both IgM and IgG negative, one of which would have been missed if more than one positive donation was required for initiating ID NAT. Retrospective ID-NAT revealed two positive donations. The majority of the NAT-positive donations in New York (16/19) were from donors who lived in counties that had the highest incidence of human WNV cases in the state. CONCLUSION: Our data details the identification of WNV NAT-positive blood donations during a severe seasonal epidemic in the New York area. By initiating ID-NAT after one positive donation, using retrospective testing, and triggering ID-NAT regionally, we were able to prevent the release of presumably infectious donations. The detection of NAT-positive donations with retrospective testing, however, may indicate the need for changes in our trigger criteria. PMID- 22486472 TI - Development of an in vitro antigen-detection test as an alternative method to the in vivo plaque reduction neutralization test for the quality control of Japanese encephalitis virus vaccine. AB - Japanese encephalitis virus (JEV) causes diseases that attack the human central nervous system. Traditionally, the quality control for JEV vaccines, in which the plaque reduction neutralization (PRN) titer is measured by the national control laboratories before the vaccine batches are marketed, has required laboratory animal testing. However, classical animal tests have inherent problems, including the very fact that animals are used, ethical issues, and the possibility of error. In this study, JEV antigen was measured in an in vitro assay to assess the feasibility of replacing in vivo assays that measure the PRN titers of JEV vaccines. We constructed a double-sandwich enzyme-linked immunosorbent assay (DS ELISA) that could detect JEV envelope (E). Initially, monoclonal antibodies (mAbs) directed against the JEV E protein were generated and characterized. We isolated 18 mAbs against JEV E protein, and most were the IgG1 or IgG2a isotype. The mAbs (5F15 and 7D71) were selected as the most suitable mAb pair to detect JEV E protein. DS-ELISA with this pair detected as little as approximately 3 MUg/mL JEV E protein and demonstrated a relationship between the amount of JEV E protein and the PRN titer. From these results, we surmise that this DS-ELISA may be useful, not only in terms of measuring the amount of JEV E protein, but also as a substitute for the PRN test for JEV vaccine evaluation. PMID- 22486473 TI - Journal of Women & Aging. From the editor. PMID- 22486474 TI - Health and cultural determinants of voluntary HIV testing and counseling among middle-aged and older Latina women. AB - The rate of cases of HIV/AIDS in older people is increasing; indeed one out of every four people with HIV/AIDS is over age 50. This study describes the correlates of HIV Voluntary Counseling and Testing (VCT) using structural equation modeling techniques for a sample of 135 middle-aged and middle-aged and older Latinas in South Florida. Over 60% of participants had been tested for HIV. Provider endorsement was found to be the strongest predictor of VCT (odds ratio [OR] = 6. 38), followed by having a clinic as a regular source of healthcare (OR = 3.88). Social work implications are provided. PMID- 22486475 TI - Driving in older age: a longitudinal study of women in urban, regional, and remote areas and the impact of caregiving. AB - This study uses data from the Australian Longitudinal Study on Women's Health to describe the trends in the proportion of older women who drive themselves as their main means of transport, factors associated with giving up driving, and the impact of women's caring roles on driving cessation. Compared to major cities, the odds of driving were 110% higher in outer regional areas, particularly for women carers. This highlights the importance of informed and responsive transport policies to address the needs of older women who are unable to continue driving, those living in rural areas, and women who are carers. PMID- 22486477 TI - Menopause symptoms' predictors: the influence of lifestyle, health- and menopause related, and sociodemographic characteristics. AB - This research explores a causal model of menopausal symptoms in peri- and postmenopausal women. A community sample of 710 women was assessed regarding menopausal symptoms, and sociodemographic, health- and menopause-related, and lifestyle characteristics. Structural equation modelling was used. Menopausal status predicted skin/facial hair changes (beta = .156; p <.001), vasomotor (beta = .122; p <.001) and sexual symptoms (beta = .158; p <.001). Age was significantly associated with cognitive impairment (beta = .087; p = .003), aches/pain (beta = .072; p = .006), urinary (beta = .115; p = .004) and also sexual symptoms (beta = .107; p = .021). Several menopausal symptoms are predicted, not only by menopausal status, but also by age progression, among other variables; this should be considered in the context of a well-adapted menopausal transition. PMID- 22486476 TI - Wearing the garment of widowhood: variations in time since spousal loss among community-dwelling older adults. AB - We examine how the passage of time since spousal loss varies by social and demographic characteristics, using data from the University of Alabama at Birmingham Study of Aging. In multivariate analyses, African American race, female sex, lower income, and higher risk of social isolation had significant and independent associations with variation in time since spousal loss. African American women were at highest risk for long-term widowhood. Accurate characterizations of widowhood among community-dwelling older adults must consider variation in the length of time individuals are living as widowed persons and socioeconomic concomitants of long-term widowhood. PMID- 22486478 TI - Personality, activities, and well-being: a study based on women in late adulthood. AB - The purpose of this study was to explore comparatively personality variables, subjective well-being variables, and participation in daily life activities in 150 women aged 50 to 82 years with different employment status. Moreover, we also analyzed the extent to which personality and participation in daily life activities accounted for life satisfaction, positive affect, and negative affect. Results from analyses of variance showed that there were significant differences between women with different working status. Multiple regression analyses revealed that self-esteem, optimism, and social activities accounted for a significant amount of variance in predicting life satisfaction and positive affect. PMID- 22486481 TI - Characterization of phospholipid bilayer formation on a thin film of porous SiO2 by reflective interferometric Fourier transform spectroscopy (RIFTS). AB - Classical methods for characterizing supported artificial phospholipid bilayers include imaging techniques such as atomic force microscopy and fluorescence microscopy. The use in the past decade of surface-sensitive methods such as surface plasmon resonance and ellipsometry, and acoustic sensors such as the quartz crystal microbalance, coupled to the imaging methods, have expanded our understanding of the formation mechanisms of phospholipid bilayers. In the present work, reflective interferometric Fourier transform spectrocopy (RIFTS) is employed to monitor the formation of a planar phospholipid bilayer on an oxidized mesoporous Si (pSiO(2)) thin film. The pSiO(2) substrates are prepared as thin films (3 MUm thick) with pore dimensions of a few nanometers in diameter by the electrochemical etching of crystalline silicon, and they are passivated with a thin thermal oxide layer. A thin film of mica is used as a control. Interferometric optical measurements are used to quantify the behavior of the phospholipids at the internal (pores) and external surfaces of the substrates. The optical measurements indicate that vesicles initially adsorb to the pSiO(2) surface as a monolayer, followed by vesicle fusion and conversion to a surface adsorbed lipid bilayer. The timescale of the process is consistent with prior measurements of vesicle fusion onto mica surfaces. Reflectance spectra calculated using a simple double-layer Fabry-Perot interference model verify the experimental results. The method provides a simple, real-time, nondestructive approach to characterizing the growth and evolution of lipid vesicle layers on the surface of an optical thin film. PMID- 22486483 TI - Parallel and modular synthesis of P-chirogenic P,O-ligands. AB - A modular synthesis of P-chirogenic alpha-alkoxyphosphine ligands has been developed, allowing for the variation of two of the three groups on phosphorus. Oxidation and concomitant desymmetrization of a prochiral alkyl- or aryldimethylphosphine borane afforded alpha-hydroxyphosphines, which were subsequently deprotonated and alkylated in a parallel fashion. The choice of base and temperature for the alkylation step was found to be crucial for the outcome of the reaction. Selected ligands were subsequently screened in palladium catalyzed allylic substitution, affording product in good to excellent yield but moderate enantioselectivity, indicating that further optimization of the ligand structures is desirable to increase the stereoselectivity. PMID- 22486484 TI - Nitric oxide turn-on fluorescent probe based on deamination of aromatic primary monoamines. AB - The stable, water-soluble, and nonfluorescent FA-OMe can sense nitric oxide (NO) and form the intensely fluorescent product dA-FA-OMe via reductive deamination of the aromatic primary amine. The reaction is accompanied by a notable increase of the fluorescent quantum yield from 1.5 to 88.8%. The deamination mechanism of FA OMe with NO was proposed in this study. The turn-on fluorescence signals were performed by suppression of photoinduced electron transfer (PeT), which was demonstrated by density functional theory (DFT) calculations of the components forming FA-OMe and dA-FA-OMe. Furthermore, FA-OMe showed water solubility and good stability at physiological pHs. Moreover, the selectivity study indicated that FA-OMe had high specificity for NO over other reactive oxygen/nitrogen species. In an endogenously generated NO detection study, increasing the incubation time of FA-OMe with lipopolysaccharide (LPS) pretreated Raw 264.7 murine macrophages could cause an enhanced fluorescence intensity image. In addition, a diffusion/localization cell imaging study showed that FA-OMe could be trapped in Raw 264.7 cells. These cell imaging results demonstrated that FA-OMe could be used as a turn-on fluorescent sensor for the detection of endogenously generated NO. PMID- 22486485 TI - Editorial commentary: challenges and potential of DSM-5 and ICD-11 revisions. PMID- 22486487 TI - India's environmental budget: will it benefit or backfire? PMID- 22486488 TI - How do children and their caregivers perceive the benefits of inhaled asthma therapy? AB - OBJECTIVE: Although well reported in adults, there is relatively little data on how children with asthma and their parents describe their attitudes to the disease, expectations of therapy, and perception of treatment benefit. We investigated this to determine if they differed from reports by adults with asthma. METHODS: We recruited families with an asthmatic child (4-11 years) who had recently been prescribed a change in treatment [starting inhaled corticosteroid monotherapy (ICS) or changing from ICS to inhaled corticosteroid/long-acting beta(2)-agonist combination therapy (ICS/LABA)]. Semi structured interviews were conducted with the parents and the children if aged 7 11 years. RESULTS: We interviewed 28 parents and 13 children. All children on ICS/LABA had been changed from ICS monotherapy because of poor asthma control. Pediatric asthma had a significant impact on the whole family and both parents and children hoped the new medication would improve symptoms, increase their participation in physical activities, and decrease unscheduled visits to the GP (General Practitioner)/hospital. Positive effects of treatment change were reported by both parents and children, particularly in those changing from ICS to ICS/LABA. The most commonly reported benefits were reduced cough and wheeze, increased participation in sport or play activities, and reduced rescue medication use. These effects resulted in fewer visits to the GP/hospital and better attendance at school. CONCLUSIONS: While asthma symptoms prevent adults and children from participating in different types of activities (e.g., school, employment), children and their parents report the same benefits as previously reported in adults with asthma. PMID- 22486489 TI - Troubled lives: chaos and trauma in the accounts of young people considered 'at risk' of diagnosis of personality disorder. AB - This study explores accounts provided by 27 young people who had contact with an early intervention service for young people considered to be 'at risk' of diagnosis of personality disorder. These accounts, developed from semi-structured interviews, focussed on their experiences prior to and since referral, which normally followed an episode of extremely risky behaviour such as self-harm or a suicide attempt. Analysis provided three themes. These focussed on the chaotic lifestyles of the young people, which were punctuated by episodes of self-harm and other risky behaviours; the unsupportive or traumatic relationships with parents and partners, which culminated in a toxic mix of isolation and self-blame and the role of case coordinators. The lack of stable adult relationships is evident. Findings suggest the establishment of stable, supportive adult relationships with a view to providing a problem-solving approach with the aim of guiding young people away from risky acts and their traumatic consequences may be fruitful. The challenge is to find a sustainable way of establishing such a model outside of paid relationships. The other challenge is to develop research approaches with similarly placed young people, which enable ongoing contact. PMID- 22486486 TI - Annual research review: re-thinking the classification of autism spectrum disorders. AB - BACKGROUND: The nosology of autism spectrum disorders (ASD) is at a critical point in history as the field seeks to better define dimensions of social communication deficits and restricted/repetitive behaviors on an individual level for both clinical and neurobiological purposes. These different dimensions also suggest an increasing need for quantitative measures that accurately map their differences, independent of developmental factors such as age, language level and IQ. METHOD: Psychometric measures, clinical observation as well as genetic, neurobiological and physiological research from toddlers, children and adults with ASD are reviewed. RESULTS: The question of how to conceptualize ASDs along dimensions versus categories is discussed within the nosology of autism and the proposed changes to the DSM-5 and ICD-11. Differences across development are incorporated into the new classification frameworks. CONCLUSIONS: It is crucial to balance the needs of clinical practice in ASD diagnostic systems, with neurobiologically based theories that address the associations between social communication and restricted/repetitive dimensions in individuals. Clarifying terminology, improving description of the core features of ASD and other dimensions that interact with them and providing more valid and reliable ways to quantify them, both for research and clinical purposes, will move forward both practice and science. PMID- 22486490 TI - Two-body wear of occlusal splint materials. AB - This study investigates the wear resistance of four different types of occlusal splint materials based on two-body wear simulations under wet and dry conditions. Twenty specimens of each splint material (Dentalon Plus, Orthoplast, Biocryl C, and Eclipse), each with a diameter of 16 mm and a thickness of 3 mm, were tested, half under wet and half under dry conditions. Each wear test was performed using a device called chewing simulator CS-4 (n=10; test load: 50 N; number of cycles: 10000, 20000, and 30000; continuous rinsing with 30 degrees C water for wet conditions); the antagonists were simulated using steel balls. Wear was determined using a 3D laser scanner and a surface analysis program. To detect significant statistical differences, wear data after 10000; 20000; and 30000 cycles were compared using the Kruskal-Wallis test and the Mann-Whitney U-test. The level of significance was set at 5%. Significant differences were found between the groups of different materials tested under wet conditions (P<0.05), whereas no differences between them were found under dry conditions (P>0.05). No significant difference was found between the wet and dry conditions for all materials and cycles (P>0.05). For groups of different materials tested under wet conditions, the degree of volume loss generated in the Chewing Simulator CS-4 was found to differ significantly for different numbers of cycles. The presence of water had no effect on the volume loss in the different material groups that were tested. PMID- 22486491 TI - Deficiency of the Y14 protein is a critical factor underlying the etiology of thrombocytopenia with absent radii syndrome. PMID- 22486493 TI - Why is cardiovascular risk stratification important in hypertensive patients? AB - BACKGROUND: The aim is to evaluate whether cardiovascular (CV) risk stratification in newly diagnosed hypertensive patients according to the European Society of Hypertension (ESH) guidelines, can predict the evolution of target organ damage (TOD) using routine examinations in clinical practice during 1 year. METHODS: Prospective study of recently diagnosed untreated hypertensives. At the moment of inclusion and 1 year later, urinary albumin excretion rate (UAER), blood analysis, electrocardiogram, retinography, self-monitored blood pressure (BP) and ambulatory BP measurement were performed. TOD was defined following the ESH guidelines and evaluated as having favorable or unfavorable evolution. RESULTS: Four hundred and seventy-nine hypertensive patients were included (58.8 years; 43.4% women). The baseline prevalence of TOD was: high UAER (2.4%), left ventricular hypertrophy (LVH) (20.7%), advanced lesion of the fundus oculi (FO) (10.2%). After 1 year, no differences were found between the final systolic and diastolic BP neither in the high/very high nor in the low/moderate CV risk groups. Patients with low/moderate CV risk had less unfavorable TOD evolution, LVH (9.2% vs 41.7%; p <0.001), FO advanced damage (0.99% vs 14.3%; p <0.001), high UAER (0.3% vs 5.1%; p <0.005) and amount of TOD (9.2% vs 44.0%; 0<0.001) than those with high/very high CV risk. The odds ratios of favorable TOD evolution adjusted for BP change and antihypertensive drug treatment were (low/moderate vs high/very high CV risk); 5.14 (95% confidence interval, CI, 3.99 6.64) for LVH; 12.42 (6.67-23.14) FO advanced damage; 10.71 (3.67-31.22) high UAER and 13.99 (10.18-19.22) for amount of TOD. CONCLUSIONS: It is possible to detect variations in TOD in hypertensive patients with a 1-year follow-up using the examinations available in routine clinic practice. The risk determined by the ESH guidelines predicts the evolution of TOD at 1 year. PMID- 22486492 TI - Pilot study of iPS-derived neural cells to examine biologic effects of alcohol on human neurons in vitro. AB - BACKGROUND: Studies of the effects of alcohol on N-methyl-d-aspartate (NMDA) receptor function and gene expression have depended on rodent or postmortem human brain models. Ideally, the effects of alcohol might better be examined in living neural tissue derived from human subjects. In this study, we used new technologies to reprogram human subject-specific tissue into pluripotent cell colonies and generate human neural cultures as a model system to examine the molecular actions of alcohol. METHODS: Induced pluripotent stem (iPS) cells were generated from skin biopsies taken from 7 individuals, 4 alcohol-dependent subjects, and 3 social drinkers. We differentiated the iPS cells into neural cultures and characterized them by immunocytochemistry using antibodies for the neuronal marker beta-III tubulin, glial marker s100beta, and synaptic marker synpasin-1. Electrophysiology was performed to characterize the iPS-derived neurons and to measure the effects of acute alcohol exposure on the NMDA receptor response in chronically alcohol exposed and nonexposed neural cultures from 1 nonalcoholic. Finally, we examined changes in mRNA expression of the NMDA receptor subunit genes GRIN1, GRIN2A, GRIN2B, and GRIN2D after 7 days of alcohol exposure and after 24-hour withdrawal from chronic alcohol exposure. RESULTS: Immunocytochemistry revealed positive staining for neuronal, glial, and synaptic markers. iPS-derived neurons displayed spontaneous electrical properties and functional ionotropic receptors. Acute alcohol exposure significantly attenuated the NMDA response, an effect that was not observed after 7 days of chronic alcohol exposure. After 7 days of chronic alcohol exposure, there were significant increases in mRNA expression of GRIN1, GRIN2A, and GRIN2D in cultures derived from alcoholic subjects but not in cultures derived from nonalcoholics. CONCLUSIONS: These findings support the potential utility of human iPS-derived neural cultures as in vitro models to examine the molecular actions of alcohol on human neural cells. PMID- 22486494 TI - Selective forces shaping diversity in the class I region of the major histocompatibility complex in dairy cattle. AB - The major histocompatibility complex (MHC) is one of the most diverse regions of the mammalian genome. Diversity in MHC genes is integral to their function in the immune system, and while pathogens play a key role in shaping this diversity, the contribution of other selective forces remains unclear. The controlled breeding of cattle offers an excellent model for the identification and exploration of these forces. We characterized the MHC class I genes present in a sample of Canadian Holstein A.I. bulls and compared the results with those obtained in an earlier study. No evidence for a reduction in MHC diversity over 20 years was observed, but the relative frequency of some haplotypes had changed: the formerly rare A12 (w12B) haplotype had become the most common, together with A15, while A19, which dominated the earlier sample, had significantly reduced in frequency. Only 7% of bulls in the current study were MHC homozygous compared with the 14% expected under Hardy-Weinberg. To identify the selective forces at work, a gene substitution model was used to calculate the effects of MHC on selection traits using estimated breeding values for each bull. Significant associations between MHC and production, disease and fertility traits were identified, suggesting that MHC diversity is not merely shaped by disease in this controlled breeding system. The decrease in a common haplotype, the reduced number of homozygous bulls and the associations with disease and production traits together indicate that MHC diversity in dairy cattle is maintained by heterozygote advantage. PMID- 22486495 TI - Haplotype variability in the bovine MITF gene and association with piebaldism in Holstein and Simmental cattle breeds. AB - Candidate gene analysis, quantitative trait locus mapping in outbreed and experimental cross-populations and a genomewide association study in Holstein have reported that a few chromosome regions contribute to great variability in the degree of white/black spotting in cattle. In particular, an important region affecting this trait was localized on bovine chromosome 22 in the region containing the microphthalmia-associated transcription factor (MITF) gene. We sequenced a total of 7258 bp of the MITF gene in 40 cattle of different breeds, including 20 animals from spotted breeds (10 Italian Holstein and 10 Italian Simmental) and 20 animals from solid coloured breeds (10 Italian Brown and 10 Reggiana), and identified 17 single nucleotide polymorphisms (SNPs). The allele frequencies of one polymorphism (g.32386957A>T) were clearly different between spotted (A = 0.875; T = 0.125) and non-spotted breeds (A = 0.125; T = 0.875) (P = 8.2E-12). This result was confirmed by genotyping additional animals of these four breeds (P < 1.0E-20). A total of 21 different haplotypes were inferred from the sequenced animals. Considering similarities among haplotypes, spotted and non spotted groups of cattle showed significant differences in their haplotype distribution (P = 0.001), which was further supported by the analysis of molecular variance (amova) of two genotyped SNPs in an enlarged sample of cattle. Variability in the MITF gene clearly explained the differences between spotted and non-spotted phenotypes but, at the same time, it is evident that this gene is not the only genetic factor determining piebaldism in Italian Holstein and Italian Simmental cattle breeds. PMID- 22486496 TI - Genetic diversity and admixture of indigenous cattle from North Ethiopia: implications of historical introgressions in the gateway region to Africa. AB - Microsatellite variation was surveyed to determine the genetic diversity, population structure and admixture of seven North Ethiopian cattle breeds by combining multiple microsatellite data sets of Indian and West African zebu, and European, African and Near-Eastern taurine in genetic analyses. Based on allelic distribution, we identified four diagnostic alleles (HEL1-123 bp, CSSM66-201 bp, BM2113-150 bp and ILSTS6-285 bp) specific to the Near-Eastern taurine. Results of genetic relationship and population structure analyses confirmed the previously established marked genetic distinction between taurine and zebu, and indicated further divergence among the bio-geographical groupings of breeds such as North Ethiopian, Indian and West African zebu, and African, European and Near-Eastern taurine. Using the diagnostic alleles for bio-geographical groupings and a Bayesian method for population structure inference, we estimated the genetic influences of major historical introgressions in North Ethiopian cattle. The breeds have been heavily (>90%) influenced by zebu, followed by African, European and the Near-Eastern taurine. Overall, North Ethiopian cattle show a high level of within-population genetic variation (e.g. observed heterozygosity = 0.659 0.687), which is in the upper range of that reported for domestic cattle and indicates their potential for future breeding applications, even in a global context. Rather low but significant population differentiation (F(ST) = 1.1%, P < 0.05) was recorded as a result of multiple introgression events and strong genetic exchanges among the North Ethiopian breeds. PMID- 22486497 TI - Identification of congenital muscular dystonia 2 associated with an inherited GlyT2 defect in Belgian Blue cattle from the United Kingdom. AB - Two newborn Belgian Blue calves from a farm in the United Kingdom exhibited lateral recumbency, low head carriage and transient muscle spasms following tactile or auditory stimulation. DNA sequence analysis indicated that both calves were homozygous for the recessive congenital muscular dystonia type 2 (CMD2) mutation (c.809T>C, p.Leu270Pro) in SLC6A5, encoding the neuronal glycine transporter GlyT2. Further testing of animals from the index farm and a sample of Belgian Blue sires revealed an unexpectedly high frequency of CMD2 carriers. This implies that linked quantitative trait loci may be influencing the prevalence of CMD2 in the estimated 55,000 Belgian Blue cattle in the United Kingdom. We have therefore developed new inexpensive tests for the CMD2 allele that can be used to confirm diagnosis, identify carriers and guide future breeding strategy, thus avoiding animal distress/premature death and minimizing the future economic impact of this disorder. PMID- 22486498 TI - Transcriptome analysis of muscle in horses suffering from recurrent exertional rhabdomyolysis revealed energetic pathway alterations and disruption in the cytosolic calcium regulation. AB - Recurrent exertional rhabdomyolysis (RER) is frequently observed in race horses like trotters. Some predisposing genetic factors have been described in epidemiological studies. However, the exact aetiology is still unknown. A calcium homeostasis disruption was suspected in previous experimental studies, and we suggested that a transcriptome analysis of RER muscles would be a possible way to investigate the pathway disorder. The purpose of this study was to compare the gene expression profile of RER vs. control muscles in the French Trotter to determine any metabolic or structural disruption. Total RNA was extracted from the gluteal medius and longissimus lumborum muscles after biopsies in 15 French Trotter horses, including 10 controls and 5 RER horses affected by 'tying-up' with high plasmatic muscular enzyme activities. Gene expression analysis was performed on the muscle biopsies using a 25K oligonucleotide microarray, which consisted of 24,009 mouse and 384 horse probes. Transcriptome analysis revealed 191 genes significantly modulated in RER vs. control muscles (P < 0.05). Many genes involved in fatty acid oxidation (CD36/FAT, SLC25A17), the Krebs cycle (SLC25A11, SLC25A12, MDH2) and the mitochondrial respiratory chain were severely down-regulated (tRNA, MT-ND5, MT-ND6, MT-COX1). According to the down-regulation of RYR1, SLC8A1 and UCP2 and up-regulation of APP and HSPA5, the muscle fibre calcium homeostasis seemed to be greatly affected by an increased cytosolic calcium and a depletion of the sarcoplasmic reticulum calcium. Gene expression analysis suggested an alteration of ATP synthesis, with severe mitochondrial dysfunction that could explain the disruption of cytosolic calcium homeostasis and inhibition of muscular relaxation. PMID- 22486499 TI - A genome-wide survey of copy number variation regions in various chicken breeds by array comparative genomic hybridization method. AB - The discovery of copy number variation (CNV) in the genome has provided new insight into genomic polymorphism. Studies with chickens have identified a number of large CNV segments using a 385k comparative genomic hybridization (CGH) chip (mean length >140 kb). We present a detailed CNV map for local Chinese chicken breeds and commercial chicken lines using an Agilent 400k array CGH platform with custom-designed probes. We identified a total of 130 copy number variation regions (CNVRs; mean length = 25.70 kb). Of these, 104 (80.0%) were novel segments reported for the first time in chickens. Among the 104 novel CNVRs, 56 (53.8%) of the segments were non-coding sequences, 65 (62.5%) showed the gain of DNA and 40 (38.5%) showed the loss of DNA (one locus showed both loss and gain). Overlapping with the formal selective sweep data and the quantitative trait loci data, we identified four loci that might be considered to be high-confidence selective segments that arose during the domestication of chickens. Compared with the CNVRs reported previously, genes for the positive regulation of phospholipase A2 activity were discovered to be significantly over-represented in the novel CNVRs reported here by gene ontology analysis. Availability of our results should facilitate further research in the study of the genetic variability in chicken breeds. PMID- 22486500 TI - Centromere mapping in the Pacific abalone (Haliotis discus hannai) through half tetrad analysis in gynogenetic diploid families. AB - Centromere mapping is an essential prerequisite for our understanding of the composition and structure of genomes. For centromere mapping, in two meiogynogenetic families of the Pacific abalone (Haliotis discus hannai), we screened 97 microsatellite markers that cover all linkage groups from a currently available abalone linkage map. Microsatellite analysis showed that no unique paternal allele was found in all gynogenetic progeny, which confirmed 100% success of induction of gynogenesis. In the control crosses, all 97 microsatellite loci were compatible with Mendelian inheritance, while in meiogynogenetic progeny, 5.2% of the microsatellite loci showed segregation distortions from an expected 1:1 ratio of two homozygote classes. The second division segregation frequency of the microsatellites ranged from 0.037 to 0.950 with a mean of 0.399, indicating the existence of interference. Heterogeneity among linkage groups in the crossover distribution was observed. Centromere location was mostly in accordance with the abalone karyotype, but differences in marker order between linkage and centromere maps occurred. Information on the positions of centromeres in relation to the microsatellite loci will represent a contribution towards assembly of genetic maps in the commercially important abalone species. PMID- 22486501 TI - Differential expression of genes characterizing myofibre phenotype. AB - Skeletal muscle is composed of metabolically heterogeneous myofibres that exhibit high plasticity at both the morphological and transcriptional levels. The objective of this study was to employ microarray analysis to elucidate the differential gene expression between the tonic-'red' anterior latissimus dorsi (ALD) muscle, the phasic-'white' posterior latissimus dorsi (PLD) and 'mixed' phenotype biceps femoris (BF) in 1-week-and 19-week-old male turkeys. A total of 170 differentially expressed genes were identified in the muscle samples analysed (P < 0.05). Gene GO analysis software was utilized to identify top gene networks and metabolic pathways involving differentially expressed genes. Quantitative real-time PCR for selected genes (BAT2D, CLU, EGFR and LEPROT) was utilized to validate the microarray data. The largest differences were observed between ALD and PLD muscles, in which 32 genes were over-expressed and 82 genes were under expressed in ALD1-PLD1 comparison, and 70 genes were over-expressed and 70 under expressed in ALD19-PLD19 comparison. The largest number of genes over-expressed in ALD muscles, as compared to other muscles, code for extracellular matrix proteins such as dystroglycan and collagen. The gene analysis revealed that phenotypically 'red' BF muscle has high expression of glycolytic genes usually associated with the 'white' muscle phenotype. Muscle-specific differences were observed in expression levels of genes coding for proteins involved in mRNA processing and translation regulation, proteosomal degradation, apoptosis and insulin resistance. The current findings may have large implications in muscle type-related disorders and improvement of muscle quality in agricultural species. PMID- 22486502 TI - An ABC estimate of pedigree error rate: application in dog, sheep and cattle breeds. AB - On the basis of correlations between pairwise individual genealogical kinship coefficients and allele sharing distances computed from genotyping data, we propose an approximate Bayesian computation (ABC) approach to assess pedigree file reliability through gene-dropping simulations. We explore the features of the method using simulated data sets and show precision increases with the number of markers. An application is further made with five dog breeds, four sheep breeds and one cattle breed raised in France and displaying various characteristics and population sizes, using microsatellite or SNP markers. Depending on the breeds, pedigree error estimations range between 1% and 9% in dog breeds, 1% and 10% in sheep breeds and 4% in cattle breeds. PMID- 22486503 TI - Mitochondrial DNA diversity patterns in Pakistani buffalo. AB - The Indian subcontinent is considered to be the likely centre of river buffalo domestication, based on population dynamics, archaeological evidence and genetic diversity. Recent studies on mitochondrial DNA diversity have drawn useful conclusions about the domestication history of Bubalus bubalis. The conclusions of these studies are, however, incomplete, unless samples can also be analysed from Pakistan, which contains the second largest buffalo population of the world. Here, we report the results of the first study on mitochondrial D-loop sequence diversity in five breeds of Pakistani buffalo. Analysis of sequence variations in 503-bp of the D-loop region of 123 animals revealed 52 haplotypes, including 40 singletons. Multidimensional display of breed pairwise F(ST) values revealed no strong clustering of breeds. Bayesian, maximum parsimony, neighbour joining and UPGMA trees revealed a topology consistent with domestication as well as subsequent introgression of multiple maternal lineages from the wild stocks. Reduced median network analysis provided evidence of population expansion from more than one set of haplotypes. The study also confirmed that Pakistani buffalo are of the river type. The observed mitochondrial D-loop sequence diversity suggests that Pakistani areas bordering India might have contributed to the initiation of domestication of the present-day river buffalo. PMID- 22486504 TI - Revisiting the quantitative trait loci for milk production traits on BTA6. AB - A parallel association study was performed in two independent cattle populations based on 41 validated, targeted single nucleotide polymorphisms (SNPs) and four microsatellite markers to re-evaluate the multiple quantitative trait loci (QTL) architecture for milk performance on bovine chromosome 6 (BTA6). Two distinct QTL located in the vicinity of the middle region of BTA6, but differing unambiguously regarding their effects on milk composition and yield traits were validated in the German Holstein population. A highly significant association of the protein variant ABCG2 p.Tyr581Ser with milk composition traits reconfirmed the causative molecular relevance of the ABCG2 gene in QTL region 1, whereas in QTL region 2, significant and tentative associations between gene variants RW070 and RW023 (located in the promoter region and exon 9 of the PPARGC1A gene for milk yield traits) were detected. For the German Fleckvieh population, only RW023 showed a tentative association with milk yield traits, whereas those loci with significant effects in German Holsteins (ABCG2 p.Tyr581Ser, RW070) showed fixed alleles. Even though our new data highlight two variants in the PPARGC1A gene (RW023, RW070) in QTL region 2, based on the results of our study, currently no unequivocal conclusion about the causal background of this QTL affecting milk yield traits can be drawn. Notably, the German Holstein and Fleckvieh populations, known for their divergent degree of dairy type, differ substantially in their allele frequencies for the growth-associated NCAPG p.Ile442Met locus. PMID- 22486505 TI - Susceptibility of piglets to enterotoxigenic Escherichia coli is not related to the expression of MUC13 and MUC20. AB - Enterotoxigenic Escherichia coli (ETEC) is one of the most frequently isolated enteropathogens in production animals, especially pigs and calves. Economically, the swine industry is by far the most affected by infections with ETEC because of mortality, morbidity and decreased growth rate of newborn and early-weaned piglets. After ingestion by the animal, these bacteria attach themselves to specific receptors on the small intestinal epithelium by means of proteinaceous surface appendages, the fimbriae. The F4 fimbriae, which attach to the F4 receptor, are the most studied. The aim of our study was to investigate gene expression in the small intestine of piglets of MUC13 and MUC20 in relation to animals with a different treatment towards or a different reaction on ETEC-F4ac by means of quantitative reverse transcription chain reaction (qRT/PCR). MUC13 and MUC20 are positional candidate genes for this F4ac receptor and are located in the region on SSC13q41 that segregates with the susceptibility to ETEC-F4ac. The condition of the small intestine is crucial when examining expression differences between different samples. Therefore, the expression of two genes, fatty-acid binding protein 2, intestinal (FABP2) and pancreatitis-associated protein (PAP), now known as regenerating islet-derived 3 alpha (REG3A) in the small intestine was simultaneously checked. FABP2, a standard for epithelial content, reflects the state of damage, whereas REG3A is a measure for inflammation in the small intestine. The four different substudies presented here suggest that expression of MUC13 and MUC20 is not related to the susceptibility of piglets to ETEC-F4ac. PMID- 22486506 TI - Identifying putative candidate genes and pathways involved in immune responses to porcine reproductive and respiratory syndrome virus (PRRSV) infection. AB - Differences in gene expression were compared between RNAs from lungs of high (HR) and low (LR) porcine reproductive and respiratory syndrome virus (PRRSV) burden pigs using the swine protein-annotated long oligonucleotide microarray, the Pigoligoarray. Pathway analyses were carried out to determine biological processes, pathways and networks that differ between the LR and HR responses. Differences existed between HR and LR pigs for 16 signalling pathways [P < 0.01/ log (P-value) >1.96]. Top canonical pathways included acute phase response signalling, crosstalk between dendritic cells and natural killer cells and tight junction signalling, with numerous immune response genes that were upregulated (SOCS1, SOD2, RBP4, HLA-B, HLA-G, PPP2R1A and TAP1) or downregulated (IL18, TF, C4BPA, C1QA, C1QB and TYROBP). One mechanism, regulation of complement activation, may have been blocked in HR (PRRSV-susceptible) pigs and could account for the poor clearance of PRRSV by infected macrophages. Multiple inhibiting signals may have prevented effective immune responses in susceptible HR pigs, although some protective genes were upregulated in these pigs. It is likely that in HR pigs, expression of genes associated with protection was delayed, so that the immune response was not stimulated early; thus, PRRSV infection prevented protective immune responses. PMID- 22486507 TI - Four genes located on a SSC2 meat quality QTL region are associated with different meat quality traits in Landrace * Chinese-European crossbred population. AB - Several quantitative trait loci (QTL) for different meat quality traits have been localized on the q arm of porcine chromosome 2 at position 55-78 cM. Association analyses were performed in a commercial Landrace * Chinese-European (LCE) crossbred population (n = 446) slaughtered at approximately 127 kg and an average age of 198 days with records for performance (growth, fat and meat accretion) and meat quality [intramuscular fat (IMF), Minolta L*, Minolta a*, Minolta b* and pH at 45 m]. Polymorphisms within positional candidate genes cloned from homologous regions on human chromosome 19, ubiquitin-like 5 (UBL5- AM950288:g.566G>A), resistin (RETN- AM157180:g.1473A>G causing substitution p.Ala36Thr), insulin receptor (INSR- AM950289:g.589T>C) and complement factor D (adipsin) (CFD- AM950287:g. 306C>T) were located at positions 62.1, 64.0, 68.0 and 70.7 cM respectively on the current USDA USMARC map of porcine chromosome 2 and had the following allele frequencies in the LCE: UBL5 566G - 0.57; RETN 1473G - 0.84; INSR 589C - 0.70; and CFD 306C - 0.73. The effects of alleles within the candidate genes on the recorded traits were estimated using an animal model. Significant effects (P < 0.05) were found for pH(45) in m. semimembranosus (m. sm.) (UBL5), IMF (RETN) and Minolta L* (RETN, CFD). Differences between phenotypic means of homozygotes at UBL5, RETN and either RETN or CFD explained 0.34 SD for pH(45) in m. sm., 0.47 SD for IMF and 0.68 SD for Minolta L* respectively. Suggestive effects (P < 0.10) on IMF (UBL5, CFD), Minolta a* (INSR, CFD) and Minolta b* (INSR) were also observed. Our results support the localization of further QTL for meat quality traits in this region and suggest that there are several genes affecting different meat quality traits. PMID- 22486508 TI - The identification of SNPs with indeterminate positions using the Equine SNP50 BeadChip. AB - We have used linkage disequilibrium (LD) to identify single nucleotide polymorphisms (SNPs) on the Illumina Equine SNP50 BeadChip, which may be incorrectly positioned on the genome map. A total of 1201 Thoroughbred horses were genotyped using the Illumina Equine SNP50 BeadChip. LD was evaluated in a pairwise fashion between all autosomal SNPs, both within and across chromosomes. Filters were then applied to the data, firstly to identify SNPs that may have been mapped to the wrong chromosome and secondly to identify SNPs that may have been incorrectly positioned within chromosomes. We identified a single SNP on ECA28, which showed low LD with neighbouring SNPs but considerable LD with a group of SNPs on ECA10. Furthermore, a cluster of SNPs on ECA5 showed unusually low LD with surrounding SNPs. A total of 39 SNPs met the criteria for unusual within-chromosome LD. The results of this study indicate that some SNPs may be misplaced. This finding is significant, as misplaced SNPs may lead to difficulties in the application of genomic methods, such as homozygosity mapping, for which SNP order is important. PMID- 22486509 TI - Inbreeding in the Thoroughbred horse. AB - Changes in the inbreeding coefficient, F, in the Thoroughbred horse over the past 45 years have been investigated by genotyping 467 Thoroughbred horses (born between 1961 and 2006) using the Illumina Equine SNP50 bead chip, which comprises 54,602 SNPs uniformly distributed across the equine genome. The Spearman rank correlation coefficient, r, between the year of birth and F was estimated. The results indicate that inbreeding in Thoroughbreds has increased over the past 40 years, with r = 0.24, P < 0.001 demonstrating that there is a highly significant, though relatively weak correlation between the year of birth and inbreeding coefficients. Interestingly, the majority of the increase in inbreeding is post 1996 and coincides with the introduction of stallions covering larger numbers of mares. PMID- 22486510 TI - Haplotypic variation and characteristics across the toll-like receptor 3 locus in chickens. AB - Toll-like receptor 3 (TLR3) has an important protective function against viral infection. The ability of an individual to respond properly to TLR ligands may be impaired by variants located in the TLR genes. By directly PCR sequencing four exons and their flanking sequence of chicken TLR3, a total of 50 nucleotide variants were identified from five breeds. Tibetan chickens and Silkies exhibited more abundant variation sites and rare alleles. Thirty haplotypes were reconstructed, with 31 variants whose minor allelic frequency was above 5% in five breeds, which revealed four divergent clades. Chicken TLR3 was partitioned into three haplotype blocks by the htSNPer program, and six tag SNPs could be used to distinguish these 30 haplotypes. Thirty variants were located in the coding sequence of chicken TLR3, and 16 of them were non-synonymous substitutions. It is predicted that p.Ser180Gly amino substitution could form an N-myristoylation site; the p.Lys240Thr amino substitution in chicken TLR3 could result in the loss of one protein kinase C phosphorylation site. These data provide a basic understanding of chicken TLR3 sequence variation and provide haplotypic markers for disease association studies. PMID- 22486511 TI - Structural analysis of MHC alleles in an RSV tumour regression chicken using a BAC library. AB - The chicken major histocompatibility complex (MHC-B locus) has a strong association with resistance and susceptibility to numerous diseases. We have found a B haplotype designated WLA that associated with the regression of tumours caused by Rous sarcoma virus J strain (RSV-J). Haplotype WLA was identical to the regressive B6 haplotype when partial genotyping was performed (Poultry Science, 89, 2010, 651). We then constructed a bacterial artificial chromosome (BAC) library from a WLA homozygote chicken to evaluate the structure of this regression haplotype and compared it to those of the B6 haplotype. Comparison between WLA and B6 above 59 kb within the 167 kb, including 14 genes from BG1 to BF2, revealed 75 SNPs and 14 indels. However, several genes were identical between WLA and B6, including the BF1 and BF2 genes, which encode a class I molecule previously suggested to be related to the regression phenotype. The BLB2 gene encoding the MHC class II beta chain showed the greatest diversity, with 19 non-synonymous SNPs. A comparison of WLA and B6 haplotpyes that are associated with tumour regression and RIRa and B24 haplotypes associated with tumour progression suggests that DMA1, DMA2, BRD2, TAPBP and BLB2 genes are not involved in the intensity of RSV J tumour regression. PMID- 22486512 TI - Genetic structure of Eurasian and North American mallard ducks based on mtDNA data. AB - To elucidate the origin and genetic structure of the domesticated duck in Eurasia and North America, we sequenced 114 duck D-loop sequences and retrieved 489 D loop sequences from GenBank. In total, 603 ducks including 50 duck breeds/populations from eight countries (China, France, Russia, India, Kazakhstan, Mongolia, Thailand and USA) were used in this study. One hundred and thirty-four haplotypes and 81 variable sites were detected. H49 was the predominant haplotype, which was considered to be the same dominant haplotype found in the previous studies, and was found in 309 birds. The smallest values for both genetic differentiation index (F(ST), 0.04156) and the number of the net nucleotide substitutions between two populations (D(A), 0.00018) were observed between Eurasian domestic ducks and Eurasian mallards. No geography, breed or population clusters were observed in the Eurasian domestic ducks and mallards. Five haplotypes were shared by USA mallards and Eurasian domestic duck/Eurasian mallards. Only one haplotype (H49) was shared by Eurasian domestic ducks and China spot-billed ducks. By combining phylogenetic analyses, haplotype network profile, genetic distances and shared haplotypes, we can draw two major conclusions: (i) Eurasian and North American mallards show a clear geographic distribution pattern; (ii) Eurasian domestic ducks are derived from the Eurasian mallards, not from the spot-billed ducks. PMID- 22486513 TI - Primary hyperoxaluria in Coton de Tulear. AB - Primary hyperoxaluria (PH) is a rare autosomal recessive disorder of glyoxylate metabolism in humans. It is characterized by the accumulation of oxalate and subsequent precipitation of calcium oxalate crystals, primarily in the kidneys. Deficiencies in glyoxylate-metabolizing enzymes alanine-glyoxylate aminotransferase (AGXT) or glyoxylate reductase/hydroxypyruvate reductase (GRHPR) occur in 95% of PH cases. Seven Coton de Tulear puppies from four apparently unrelated litters were examined owing to sudden illness at the age of 3-4 weeks. A complete necropsy was performed. The typical finding was tubular necrosis with extensive oxalate crystal deposition. Based on history and necropsy findings, PH was suspected. Eight microsatellite loci flanking AGXT and GRHPR were analysed, and based on segregation results, AGXT was suspected as to be the candidate gene. AGXT exon sequencing revealed a single base change (c.996G>A) that changed one conserved residue (p.Gly102Ser). The mutation was tested in of 118 Finnish Coton de Tulear dogs, ten (8.5%) of which were revealed as carriers. This preliminary study reports PH as a cause of neonatal death in Finnish Coton de Tulear and suggests that genetic testing of dogs be carried out before breeding to prevent the birth of affected offspring. PMID- 22486514 TI - Detection of mitochondrial DNA from domestic cattle in European bison (Bison bonasus) from the Altai Republic in Russia. PMID- 22486515 TI - Between-breed variation in frequency of five novel missense SNPs in porcine casein beta (CSN2) and casein kappa (CSN3) genes. PMID- 22486516 TI - Polymorphism within thyroid hormone responsive (THRSP) associated with weaning-to oestrus interval in swine. PMID- 22486517 TI - Development and characterization of 260 microsatellite loci in the domestic goat, Capra hircus. PMID- 22486518 TI - Electronic interactions in helical stacked arrays of the modified DNA base pyrrolocytosine. AB - The thermal stability and ultraviolet and circular dichroism spectra of nine synthetic DNA hairpins possessing one or more (P)C-G base pairs ((P)C = pyrrolocytosine) have been investigated. One group of hairpins possess 1-5 sequential (P)C-G base pairs while another group possess two (P)C-G base pairs separated by 1-3 A-T base pairs. The first group displays a nearly linear dependence of UV and exciton-coupled circular dichroism (EC-CD) band intensity upon the number of neighboring chromophores, whereas the second group shows weak EC-CD only at the shortest distances between non-neighboring chromophores. This result stands in marked contrast to the exciton coupling seen between stilbene chromophores separated by as many as a dozen base pairs. The weak exciton coupling between non-neighboring (P)C chromophores, like that of the natural nucelobases, is attributed to their relatively weak electronic transition dipoles. PMID- 22486519 TI - A two-step pH-dependent liquid-liquid extraction combined with HPLC-fluorescence method for the determination of 10-hydroxycamptothecin in mouse liver tissue. AB - CONTEXT: Liquid-liquid extraction (LLE) shows high efficiency in the plasma sample preparation. However, this extraction method is not optimal for the biological samples containing complex organic interferences, such as liver and brain tissues. Some plant secondary metabolites can be converted between water insoluble and water-soluble forms by pH adjustment. OBJECTIVE: A two-step pH dependent LLE method was introduced in this study to eliminate both water-soluble and lipidic interferences using the properties of pH-dependent interconvertible forms of analytes during sample preparation. A sensitive and reliable method using a reverse-phase HPLC coupled with a fluorescence detector was developed and validated. MATERIALS AND METHODS: 10-Hydroxycamptothecin (HCPT) with internal standard camptothecin and liver tissues were used as model compounds and biological samples. The lactone form of HCPT was converted to the water-soluble carboxylate form under moderate alkaline conditions, and the water-insoluble interferences were extracted with a nonpolar solvent. Afterward, the water insoluble lactone form of HCPT was regenerated by acidification and then extracted using an organic solvent in a second LLE step. RESULTS: The calibration curve was linear (r2 > 0.999) for HCPT concentrations ranging from 2.5 to 160 ng/mL. The mean recoveries of HCPT were 114.94 +/- 3.98, 104.30 +/- 2.44 and 95.90 +/- 1.40% (n = 6) at concentrations of 2.5, 10 and 80 ng/mL, respectively. The stability determination data showed that no significant degradation occurred under the experimental conditions. This method was successfully applied to liver tissue distribution study of HCPT in mice. DISCUSSION AND CONCLUSION: This two step LLE can be applied to distribution studies of compounds with pH-dependent interconvertible forms in other biological matrices. PMID- 22486520 TI - Oral contraception in Denmark 1998-2010. AB - BACKGROUND: Oral contraceptives (OC) are the most popular contraception in Denmark. Overall figures on use are well described, but more detailed use patterns according to type and age need to be updated. OBJECTIVES: To assess trends in the use of OC including progestogen-only pills among Danish women in 1998-2010 and to describe in detail use patterns in 2010. Design. Annual cross sectional prescription statistics. SETTING: Denmark. POPULATION: Danish women 10 49 years old. MATERIAL AND METHODS: Analysis of prescription data from the National Registry of Medicinal Products Statistics from 1 January 1998 through 31 December 2010. RESULTS: Combined OC (COC) with 50 MUg estrogen decreased their market share from 3% in 1998 to zero in 2010, and COC with 30-40 MUg estrogen decreased to 50% in 2010, in contrast, COC with 20 MUg estrogen increased to 46% in 2010. Progestogen-only pills accounted for 4%. COC with levonorgestrel decreased, while the use of pills with desogestrel and gestodene among two-thirds of current users was constant. CONCLUSION: Low-dose COCs gradually replaced middle-dose pills. Pills with newer progestogens are used primarily by young women, and 85% of users in 2010 were on products with desogestrel, gestodene, drospirenone or cyproteroneacetate. We still need low-dose pills with 1(st) and 2(nd) generation progestogens on the Scandinavian market. PMID- 22486521 TI - Inhibitory effects of sigma-1 ligands on handling-induced tachycardia in conscious tethered rats. AB - We used conscious tethered Sprague-Dawley rats to evaluate the cardiovascular effects of four sigma-1 (sigma1 ) agonists and five antagonists, given alone or in combination. All drugs were administered as a single intraperitoneal dose. The agonists were given at doses reported as efficacious in rodent cognition models, while the antagonists were administered at doses neutralizing agonist effects in vivo. Systolic blood pressure (SBP) and heart rate (HR) were continuously recorded for 20 min before and 60 min postadministration. Immediately after injection, a sudden, transitory increase in HR and SBP was noted in all animals, because of the stress induced by handling. For both parameters, a peak value (DeltaHRmax and DeltaSBPmax ) and an area under the curve of changes from baseline over the period 5-20 min postinjection (DeltaHR_AUC5-20 min and DeltaSBP_AUC5-20 min ) were calculated. Three of the four sigma1 agonists (SKF 10,047, dehydroepiandrosterone (DHEAS), Compound 14) significantly reduced DeltaHR_AUC5-20 min value without changing DeltaHRmax , while the fourth one, SA 4503, had no significant effect. None of the antagonists (haloperidol, rimcazole, NE-100, and BD1047) reduced, and even one (progesterone) enhanced the stress induced effects on HR. No changes in SBP were noted with any compound. When the antagonist NE-100 was administered just before SKF-10,047, it completely reversed the inhibitory effects of the sigma1 agonist on HR increase. In conclusion, we demonstrated for the first time the involvement of sigma1 receptors in the regulation of handling-induced tachycardia in the conscious rat. Although additional investigations are needed to fully understand this role, it might offer new therapeutic perspectives to sigma1 ligands in the cardiovascular sphere. PMID- 22486523 TI - Histomorphometric analysis and regional variations of full thickness skin grafts in dogs. AB - OBJECTIVE: To (1) compare thickness of the epidermis and dermis of anatomically different donor sites in dogs, and (2) evaluate hair follicle damage during full thickness skin grafts (FTSG) preparation from anatomically different donor sites. Another objective was to compare the extent of agreement between gross and histologic quality of graft preparation. STUDY DESIGN: Ex vivo study. ANIMALS: Healthy Beagle dogs (n = 12). METHODS: Skin samples were harvested from fresh cadavers free of gross dermatopathology and FTSG prepared. Regional, epidermal and dermal thickness, and hair follicle density in intact skin and FTSG specimens from different regions were determined by histomorphometric analysis. Hair follicle density in intact skin and FTSG specimens, and skin thickness measurements were compared among regions. RESULTS: Mean epidermis and dermis thickness of the dorsal lumbar and lateral neck regions were significantly greater when compared with other sites. Total hair follicle (superficial and deep dermis) densities were significantly less in prepared FTSG versus intact skin specimens. The dorsal lumbar region had the highest hair follicle density. CONCLUSIONS: Thickness of the epidermis and dermis is dependent on body region. Hair follicle density in the FTSG specimens was decreased compared with intact skin specimens, which may affect hair regrowth in FTSG. PMID- 22486522 TI - Analysis of copy number variation in Alzheimer's disease: the NIALOAD/ NCRAD Family Study. AB - Copy number variants (CNVs) are DNA regions that have gains (duplications) or losses (deletions) of genetic material. CNVs may encompass a single gene or multiple genes and can affect their function. They are hypothesized to play an important role in certain diseases. We previously examined the role of CNVs in late-onset Alzheimer's disease (AD) and mild cognitive impairment (MCI) using participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study and identified gene regions overlapped by CNVs only in cases (AD and/or MCI) but not in controls. Using a similar approach as ADNI, we investigated the role of CNVs using 794 AD and 196 neurologically evaluated control non-Hispanic Caucasian NIA-LOAD/NCRAD Family Study participants with DNA derived from blood/brain tissue. The controls had no family history of AD and were unrelated to AD participants. CNV calls were generated and analyzed after detailed quality review. 711 AD cases and 171 controls who passed all quality thresholds were included in case/control association analyses, focusing on candidate gene and genome-wide approaches. We identified genes overlapped by CNV calls only in AD cases but not controls. A trend for lower CNV call rate was observed for deletions as well as duplications in cases compared to controls. Gene-based association analyses confirmed previous findings in the ADNI study (ATXN1, HLA DPB1, RELN, DOPEY2, GSTT1, CHRFAM7A, ERBB4, NRXN1) and identified a new gene (IMMP2L) that may play a role in AD susceptibility. Replication in independent samples as well as further analyses of these gene regions is warranted. PMID- 22486524 TI - An orange fluorescent protein with a large Stokes shift for single-excitation multicolor FCCS and FRET imaging. AB - Multicolor imaging based on genetically encoded fluorescent proteins (FPs) is a powerful approach to study several dynamic processes in a live cell. We report a monomeric orange FP with a large Stokes shift (LSS), called LSSmOrange (excitation/emission at 437/572 nm), which fills up an existing spectral gap between the green-yellow and red LSSFPs. Brightness of LSSmOrange is five-fold larger than that of the brightest red LSSFP and similar to the green-yellow LSSFPs. LSSmOrange allows numerous multicolor applications using a single excitation wavelength that was not possible before. Using LSSmOrange we developed four-color single-laser fluorescence cross-correlation spectroscopy, solely based on FPs. The quadruple cross-correlation combined with photon counting histogram techniques allowed quantitative single-molecule analysis of particles labeled with four FPs. LSSmOrange was further applied to simultaneously image two Forster resonance energy transfer pairs, one of which is the commonly used CFP-YFP pair, with a single-excitation laser line. The combination of LSSmOrange-mKate2 and CFP YFP biosensors enabled imaging of apoptotic activity and calcium fluctuations in real time. The LSSmOrange mutagenesis, low-temperature, and isotope effect studies revealed a proton relay for the excited-state proton transfer responsible for the LSS phenotype. PMID- 22486525 TI - The role of comparative effectiveness research in transfusion medicine clinical trials: proceedings of a National Heart, Lung, and Blood Institute workshop. AB - Comparative effectiveness research (CER) is the study of existing treatments or ways to deliver health care to determine what intervention works best under specific circumstances. CER evaluates evidence from existing studies or generates new evidence, in different populations and under specific conditions in which the treatments are actually used. CER does not embrace one research design over another but compares treatments and variations in practice using methods that are most likely to yield widely generalizable results that are directly relevant to clinical practice. Treatments used in transfusion medicine (TM) are among the most widely used in clinical practice, but are among the least well studied. High quality evidence is lacking for most transfusion practices, with research efforts hampered by regulatory restrictions and ethical barriers. To begin addressing these issues, the National Heart, Lung, and Blood Institute convened a workshop in June 2011 to address the potential role of CER in the generation of high quality evidence for TM decision making. Workshop goals were to: 1) evaluate the current landscape of clinical research, 2) review the potential application of CER methods to clinical research, 3) assess potential barriers to the use of CER methodology, 4) determine whether pilot or vanguard studies can be used to facilitate planning of future CER research, and 5) consider the need for and delivery of training in CER methods for researchers. PMID- 22486526 TI - Impact of body mass index on left ventricular diastolic dysfunction. AB - BACKGROUND: The prevalence of obesity is increasing in the developed and developing world. It is an independent risk factor for heart failure. Left ventricular (LV) diastolic dysfunction has been demonstrated to be a strong predictor of heart failure. In the present study we aimed to assess the impact of body weight on LV diastolic function. METHODS: The study was conducted on 2,228 participants (1,424 women, 804 men with a mean age of 49). Traditional and tissue Doppler echocardiographic examination were performed in all of the participants. The demographic and echocardiographic data were compared. Multivariate logistic regression analysis was used to assess the independent predictors of association of LV diastolic function. The study sample was divided into four groups: group 1 (body mass index [BMI] < 25.0 kg/m(2) ), group 2 (BMI 25.0-29.9 kg/m(2)), group 3 (BMI >= 30-39.9 kg/m(2)), and group 4 (BMI >= 40 kg/m(2)). RESULTS: Septal E was significantly lower in groups 2 and 3 compared to group 1 (P = 0.003). Septal A and septal A' were significantly higher whereas septal E' and lateral E' were significantly lower in the groups 2, 3, and 4 compared to the normal weight group (P < 0.001). Lateral A', deceleration time, and ejection time were significantly higher in obese when compared to the normal weight (P = 0.025, P < 0.001, and P = 0.009, respectively). The E/E' ratio was significantly higher in groups 2, 3, and 4 compared to the group 1 (P < 0.001). Logistic regression analysis revealed that age, BMI (OR = 1.060 [95% CI = 1.040 and 1.080]; P < 0.001), hypertension, and diabetes mellitus were independent predictors of LV diastolic dysfunction. CONCLUSION: BMI is an independent predictor of LV diastolic dysfunction along with age, hypertension, and diabetes mellitus. PMID- 22486527 TI - Silica-graphene oxide hybrid composite particles and their electroresponsive characteristics. AB - Silica-graphene oxide (Si-GO) hybrid composite particles were prepared by the hydrolysis of tetraethyl orthosilicate (TEOS) in the presence of hydrophilic GO obtained from a modified Hummers method. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images provided visible evidence of the silica nanoparticles grafted on the surface of GO, resulting in Si-GO hybrid composite particles. Energy dispersive X-ray spectroscopy (EDX) and X-ray diffraction (XRD) spectra indicated the coexistence of silica and GO in the composite particles. The Si-GO hybrid composite particles showed better thermal stability than that of GO according to thermogravimetric analysis (TGA). The electrorheological (ER) characteristics of the Si-GO hybrid composite based ER fluid were examined further by optical microscopy and a rotational rheometer in controlled shear rate mode under various electric field strengths. Shear stress curves were fitted using both conventional Bingham model and a constitutive Cho Choi-Jhon model. The polarizability and relaxation time of the ER fluid from dielectric spectra measured using an LCR meter showed a good correlation with its ER characteristics. PMID- 22486528 TI - LPHN3 and attention-deficit/hyperactivity disorder: interaction with maternal stress during pregnancy. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous behavioral disorder, complex both in etiology and clinical expression. Both genetic and environmental factors have been implicated, and it has been suggested that gene-environment interactions may play a pivotal role in the disorder. Recently, a significant association was reported between ADHD and LPHN3 (which codes for latrophilin 3), and replicated in independent samples. METHODS: We have examined the association between tag single nucleotide polymorphisms (SNPs) in LPHN3 within the region previously implicated in ADHD. Family based association tests (FBAT) were conducted (n = 380 families) with the categorical diagnosis of ADHD, behavioral and cognitive phenotypes related to ADHD, and response to treatment (given a fixed dose of methylphenidate, 0.5 mg/day). Stratified FBAT analyses, based on maternal smoking and stress during pregnancy, was conducted. RESULTS: Whereas limited association was observed in the total sample, highly significant interaction between four LPHN3 tag SNPs (rs6551665, rs1947274, rs6858066, rs2345039) and maternal stress during pregnancy was noted. Analysis conducted in the sub-group of mothers exposed to minimal stress during pregnancy showed significant associations with ADHD, behavioral and cognitive dimensions related to ADHD, as well as treatment response. Although extensive association was observed with the candidate SNPs, the findings are partially inconsistent with previously published results with the opposite alleles over-transmitted in these studies. CONCLUSIONS: These results provide evidence for the interaction between a genetic and environmental factor independently shown to be associated with ADHD. If confirmed in independent large studies, they may present a step forward in unraveling the complex etiology of ADHD. PMID- 22486529 TI - Mechanisms of resistance to cephalosporin and emergence of O25b-ST131 clone harboring CTX-M-27 beta-lactamase in extraintestinal pathogenic Escherichia coli from dogs and cats in Japan. AB - Thirty-three cefazolin-resistant extraintestinal pathogenic Escherichia coli strains from companion animals were screened for bla(CMY-1) , bla(CMY-2) , bla(SHV) , bla(TEM) , and bla(CTX-M) genes. Extended-spectrum beta-lactamase producing strains were further characterized by O serotyping and multilocus sequence typing. It was found that 20 and 17 isolates harbored TEM-1 and CMY-2 beta-lactamases, respectively, and 13 isolates harbored both beta-lactamases. One isolate harbored DHA-1 beta-lactamase. Eleven isolates were found to possess CTX M beta-lactamases (CTX-M-27 [n= 6], CTX-M-14 [n= 3], CTX-M-15 [n= 1], and CTX-M 55 [n= 1]). Of 11 CTX-M-positive strains, four strains were O25b-ST131 clones harboring CTX-M-27, and the remaining seven strains belonged to O6-ST127, ONT ST354, O159-ST539, O1-ST648, O8-ST1642, O25b-ST2042, and ONT-ST2178. PMID- 22486530 TI - Simple models for stomatal conductance derived from a process model: cross validation against sap flux data. AB - Representation of stomatal physiology in models of plant-atmosphere gas exchange is minimal, and direct application of process-based models is limited by difficulty of parameter estimation. We derived simple models of stomatal conductance from a recent process-based model, and cross-validated them against measurements of sap flux (176-365 d in length) in 36 individual trees of two age classes for two Eucalyptus species across seven sites in the mountains of southeastern Australia. The derived models - which are driven by irradiance and evaporative demand and have two to four parameters that represent sums and products of biophysical parameters in the process model - reproduced a median 83 89% of observed variance in half-hourly and diurnally averaged sap flux, and performed similarly whether fitted using a random sample of all data or using 1 month of data from spring or autumn. Our simple models are an advance in predicting plant water use because their parameters are transparently related to reduced processes and properties, enabling easy accommodation of improved knowledge about how those parameters respond to environmental change and differ among species. PMID- 22486531 TI - Prevalence of sensitization to Blomia tropicalis among young adults in a temperate climate. AB - BACKGROUND: There are no previous population-based studies assessing the prevalence of Blomia tropicalis (BT). This investigation analyzes the prevalence of sensitization to BT and its contribution to asthma and related diseases among young adults in the Canary Islands. MATERIAL AND METHODS: From a random sample of 9506 adults, aged between 20 and 44, who had previously answered a short respiratory questionnaire, a further 20% random sample was drawn. All participants filled in an extensive questionnaire, and they underwent spirometry and bronchial hyperresponsiveness (BHR) test and skin testing to several allergens as well as the determination of total IgE and specific IgE. RESULTS: The prevalence of positive skin tests to BT was 13.8% (95% confidence interval [CI] 10.6-17.9%) and that of BT-specific IgE 17.9% (95% CI 14.2-24.5%). Sensitization to BT (positive skin tests or positive specific IgE) was 20.9% (95% CI 16.9-25.5%). Most of the subjects sensitized to BT were also sensitized to Dermatophagoides pteronissimus; however, only 7% displayed monosensitization to BT. Among subjects who exhibited BHR, sensitization to BT reached 46.7% (95% CI 32.7-60.9%), among those with asthma 50% (95% CI 26.8-73.2%), in subjects with rhinitis 37.2% (95% CI 28.1-47.6%), and in those suffering from dermatitis 25.9% (95% CI 18.7-34.5%). A strong association of BT sensitization with BHR and asthma before and after 15 years was found. CONCLUSION: The prevalence of sensitization to BT among young adults in the Canary Islands is high, and it displays a close relationship with allergic respiratory diseases and dermatitis. PMID- 22486532 TI - High TPMT enzyme activity does not explain drug resistance due to preferential 6 methylmercaptopurine production in patients on thiopurine treatment. AB - BACKGROUND: Up to 20% of patients on thiopurine therapy fail to achieve adequate drug response. Many of these patients preferentially produce the toxic 6 methylmercaptopurine metabolites (6-MMP) rather than the active 6-thioguanine nucleotides (6-TGN) resulting in a high 6-MMP/6-TGN ratio (>20) and increased risk of hepatotoxicity. AIM: To determine the prevalence of preferential 6-MMP producers and define the relationships between 6-TGN, 6-MMP and thiopurine methyltransferase (TPMT). METHODS: The database of 6-TGN, 6-MMP and TPMT measurements from patients throughout New Zealand was used to calculate patients' 6-MMP/6-TGN ratios and identify those with high (>20) or normal ratio (<=20).The TPMT enzyme activity was compared amongst the groups. RESULTS: Of 1879 patients with TPMT, 6-TGN and 6-MMP results, 349 (19%) had a 6-MMP/6-TGN ratio >20. The mean TPMT enzyme activity was slightly lower for those with a 6-MMP/6-TGN ratio <=20 vs. >20, which achieved statistical significance (12.2 vs. 13.2; P < 0.001). However, the distributions of TPMT enzyme activity were similar, with 97% of TPMT results falling between 5.0 and 17.6 IU/mL for both groups. In all, 17% of those with 6-MMP/6-TGN ratio <=20 were intermediate TPMT metabolisers (TPMT 5.0-9.2 IU/mL) vs. 7% in those with a ratio >20. CONCLUSIONS: In this patient population with measured 6-MMP/6-TGN ratios, 19% of patients were preferential 6-MMP producers. The results show that high TPMT enzyme activity is not the major reason for preferential 6-MMP production in most patients with a high metabolite ratio. This suggests that there are one or more important alternative mechanisms for preferentially producing 6-MMP. PMID- 22486533 TI - A review of the literature and latest advances in research of Piper sarmentosum. AB - CONTEXT: Piper sarmentosum Roxb. (Piperaceae) is a traditional medicinal as well as a culinary plant in South East Asian countries, whereby aerial parts of the plant are consumed as a vegetable in various forms and the whole plant or parts are used as folk remedies, alone or in combination with other herbs, to treat various ailments. The plant has extensively been investigated in a broad range of studies to provide scientific evidence for folklore claims or to find new therapeutic uses; however, heretofore, a summary of the data are not available. OBJECTIVE: In order to describe nutritional and therapeutic potential of P. sarmentosum and summarize scientific evidence that supports traditional claims, a literature review and latest advances in research of the plant are given herein. MATERIALS AND METHODS: The literature has been retrieved from a number of databases such as Google Scholar, PubMed, Medline, Science Direct and SciFinder. The articles related to synthetic work, ecology and agriculture have been excluded. RESULTS AND DISCUSSION: The review has not only revealed a number of pharmacological activities supporting the traditional claims but indicates new prospects for the plant. Antiangiogenic activity and toxicity studies suggest the usage of the plant in treating diseases involving neo-vascularization. The available efficacy, safety, pharmacokinetic and stability data urge clinical studies on extracts of the plant. CONCLUSION: The present review may be helpful to future researchers intending to investigate the plant and natural pharmaceutical industry for preparing evidence-based formulations. PMID- 22486534 TI - Insights into photoinduced sol-gel polymerization: an in situ infrared spectroscopy study. AB - Photoacid-catalyzed sol-gel polymerization is now recognized as a powerful single step synthetic approach to the synthesis of hybrid films, which can be distinguished from conventional sol-gel methods by higher reactivity and a solvent-free process. Despite its utility, the mechanism is not yet understood, in particular what chemical, physical, and photochemical parameters determine the precise sequence, kinetics, and advancement of this UV inorganic photopolymerization. Here, using mainly transmission real-time Fourier transformed infrared (RT-FTIR) spectroscopy, we characterize in situ the hydrolysis-condensation reactions of oligomeric silicon alkoxides and the formation of byproducts. Systematic review and assessment of numerous processing variables (relative humidity, film thickness, precursor structure, nature, and the concentration of photoacid generator) prove that the reaction kinetics are controlled by the two independent phenomena: the intrinsic chemical reaction rates and the water vapor permeation into the film. PMID- 22486535 TI - The dental occlusion as a suspected cause for TMDs: epidemiological and etiological considerations. AB - The relationship between the dental occlusion and temporomandibular disorders (TMDs) has been one of the most controversial topics in the dental community. In a large epidemiological cross-sectional survey - the Study of Health in Pomerania (Germany) - associations between 15 occlusion-related variables and TMD signs or symptoms were found. In other investigations, additional occlusal variables were identified. However, statistical associations do not prove causality. By using Hill's nine criteria of causation, it becomes apparent that the evidence of a causal relationship is weak. Only bruxism, loss of posterior support and unilateral posterior crossbite show some consistency across studies. On the other hand, several reported occlusal features appear to be the consequence of TMDs, not their cause. Above all, however, biological plausibility for an occlusal aetiology is often difficult to establish, because TMDs are much more common among women than men. Symptom improvement after insertion of an oral splint or after occlusal adjustment does not prove an occlusal aetiology either, because the amelioration may be due to the change of the appliance-induced intermaxillary relationship. In addition, symptoms often abate even in the absence of therapy. Although patients with a TMD history might have a specific risk for developing TMD signs, it appears more rewarding to focus on non-occlusal features that are known to have a potential for the predisposition, initiation or perpetuation of TMDs. PMID- 22486536 TI - Early trauma and familial risk in the development of the extended psychosis phenotype in adolescence. AB - OBJECTIVE: Both genetic and environmental factors are thought to play a role in the development of psychotic outcomes; however, their respective contributions over time, including possible developmental interactions, remain largely unknown. METHOD: The contribution of parental general and psychotic psychopathology as proxies of genetic risk to the development of subthreshold psychosis and its hypothesized interaction with childhood trauma were studied in a general population sample of 2230 adolescents, followed from age 10-16 years. Outcome measures were: i) level of psychotic experiences at age 16 years and ii) persistence of such experiences over the total follow-up period. RESULTS: General parental psychopathology was associated with CAPE score (OR = 1.08; P < 0.043 for highest quintile) and suggestively predicted psychosis persistence (OR, 1.16; P < 0.072). Psychotic parental psychopathology was suggestively associated with CAPE score (OR, 2.25; P < 0.063 for highest quintile), predicted membership of the Persistent group (OR, 3.72; P < 0.039) and suggestively predicted membership of the Decreasing group (OR 2.04; P < 0.051). Childhood trauma was associated with CAPE score and with all developmental trajectories of subclinical psychosis. No evidence was found for an interaction between trauma and parental psychopathology. CONCLUSION: The development and persistence of subthreshold psychotic symptoms may be conditional on non-interacting proxy genetic and environmental influences. PMID- 22486537 TI - Understanding the influences on self-confidence among first-year undergraduate nursing students in Ireland. AB - AIM: To report a mixed-methods study of the development of self-confidence in Irish nursing students undertaking the first year of an undergraduate nursing programme. BACKGROUND: Self-confidence underpins nurses' competence to carry out care effectively, yet there is little empirical evidence of how this attribute is fostered in pre-registration preparation. There is an assumption, however, that self-confidence develops independently and spontaneously. DESIGN: A sequential, mixed methods three-phase design was used. METHOD: The design involved pretest and posttest measurements of self-confidence, focus group interviews, a student self-evaluation questionnaire and analysis of the relevant curriculum content. Data were collected between September 2007-April 2008 and sampling was from three cohorts of students at three different Institutes of Technology in Ireland. Data collection matched the nature of the data, including descriptive, non-inferential statistics and qualitative content analysis. RESULTS: There was considerable variation in the amount and nature of theoretical preparation. Factors in clinical practice exerted the most influence. Self-confidence fluctuated during the first clinical placement and as students' self-confidence developed, simultaneously, motivation towards academic achievement increased. Conversely, self-confidence was quickly eroded by poor preceptor attitudes, lack of communication, and feeling undervalued. CONCLUSION: The development of self confidence is complex and multi-factorial. This study offers further understanding of facilitators and barriers that may be relevant elsewhere in promoting student nurses' developing self-confidence. The development of self confidence must be recognized as a central tenet for the design and delivery of undergraduate programmes. PMID- 22486538 TI - Quality of life in dementia care--differences in quality of life measurements performed by residents with dementia and by nursing staff. AB - OBJECTIVES: Quality of life (QoL) is a major outcome parameter in dementia care. Self-ratings are considered the best way to evaluate QoL, but staff-ratings also provide valid results. In particular, the discrepancies between self-ratings and staff-ratings are underrepresented. The aim was to identify characteristics of people with dementia that improve the probability of completing a self rating QoL instrument on the 'Quality of Life - Alzheimers' Disease' (QoL-AD). Additionally, a level of agreement was set between self-rated and staff-rated QoL-AD and possible influencing factors. METHOD: A cross-sectional study was conducted in 2010 in Berlin. Using the instrument QoL-AD, the self- and staff-rated QoL of people with dementia was assessed. RESULTS: 104 residents (73.1% female, mean age: 79.0 years, mean cognitive function (MMSE): 11.5) were included in this research project. 49 (47.1%) residents were able to complete the QoL-AD questionnaire. A predictor to complete the QoL-AD was the MMSE-part 'language'. Residents rated their QoL as significantly higher than the nursing staff did. If the primary nurse rated the QoL, a significantly better agreement was identified. CONCLUSION: The study generated new findings concerning a better understanding of QoL measurements. The results suggest the usefulness of performing self-ratings whenever possible. If proxy-ratings have to be used, these should be performed by primary nurses only in order to get reliable results. PMID- 22486539 TI - Higher serum free glycerol levels in a group of alcoholics than in controls. AB - BACKGROUND: The biomarkers of excessive alcohol intake reported thus far have not always been reliable. We discovered the presence of free glycerol (FG) by high performance liquid chromatography (HPLC) in the serum of alcoholic patients but not in healthy persons, and a higher percentage of the alcoholics were positive for serum FG than for gamma-glutamyl transpeptidase, mean corpuscular volume, or carbohydrate-deficient transferrin (%CDT). Therefore, in this study, we investigated whether the same results as with HPLC could be obtained by measuring FG with an easy-to-use autoanalyzer and whether the serum FG measured by this method would be useful as a biomarker of excessive alcohol intake. METHODS: First, the measurements of serum FG made by HPLC and by a biochemical method with an autoanalyzer were tested for a correlation, and then fasting serum FG was measured with the autoanalyzer in 3 groups: a group of Japanese male alcoholics who drank until just before admission, a group of Japanese male patients with chronic viral hepatitis, and a group of Japanese healthy male volunteers. RESULTS: There was a strong positive correlation between the serum FG values measured by HPLC and by the autoanalyzer in the alcoholic group. The values in the alcoholic group were significantly higher than in the viral hepatitis group and healthy control group. We set the cutoff serum FG value for discriminating between the alcoholic group and the other 2 groups in the receiver operating characteristic analysis at 0.9 mg/dl, and that cutoff value provided a sensitivity of 80% for identifying the alcoholic group and a specificity of 84 and 94% in relation to the viral hepatitis group and the healthy volunteer group, respectively. Among various clinical tests in the alcoholic group, serum FG showed the highest rate of abnormally high value. CONCLUSIONS: Measurement of serum FG with an autoanalyzer may be useful as a biomarker of excessive alcohol intake. PMID- 22486540 TI - Imatinib mesylate-induced neutrophilic folliculitis in a teenager. PMID- 22486543 TI - On the accessibility to conical intersections in purines: hypoxanthine and its singly protonated and deprotonated forms. AB - The dynamics following electronic excitation of hypoxanthine and its nucleoside inosine were studied by femtosecond fluorescence up-conversion. Our objective was to explore variants of the purinic DNA bases in order to determine the molecular parameters that increase or reduce the accessibility to ground state conical intersections. From experiments in water and methanol solution we conclude that both dominant neutral tautomers of hypoxanthine exhibit ultrashort excited state lifetimes (tau < 0.2 ps), which are significantly shorter than in the related nucleobase guanine. This points to a more accessible conical intersection for the fluorescent state upon removal of the amino group, present in guanine but absent in hypoxanthine. The excited state dynamics of singly protonated hypoxanthine were also studied, showing biexponential decays with a 1.1 ps component (5%) besides a sub-0.2 ps ultrafast component. On the other hand, the S(1) lifetimes of the singly deprotonated forms of hypoxanthine and inosine show drastic differences, where the latter remains ultrafast but the singly deprotonated hypoxanthine shows a much longer lifetime of 19 ps. This significant variation is related to the different deprotonation sites in hypoxanthine versus inosine, which gives rise to significantly different resonance structures. In our study we also include multireference perturbation theory (MRMP2) excited state calculations in order to determine the nature of the initial electronic excitation in our experiments and clarify the ordering of the states in the singlet manifold at the ground state geometry. In addition, we performed multireference configuration interaction calculations (MR-CIS) that identify the presence of low-lying conical intersections for both prominent neutral tautomers of hypoxanthine. In both cases, the surface crossings occur at geometries reached by out of plane opposite motions of C2 and N3. The study of this simpler purine gives several insights into how small structural modifications, including amino substitution and protonation site and state, determine the accessibility to conical intersections in this kind of heterocycles. PMID- 22486544 TI - Discordant impairment of multidirectional myocardial deformation in rats with Doxorubicin induced cardiomyopathy. AB - BACKGROUND: In doxorubicin-induced cardiomyopathy (DIC), the sequence of decrease in multidirectional myocardial deformation has not been clearly elucidated. OBJECTIVES: We investigated the sequence of myocardial deformations in rat DIC, using two-dimensional speckle tracking echocardiography (2DSTE). METHODS: Twenty rats were treated with doxorubicin (1.25 mg/kg * 16 times, intraperitoneal) for 4 weeks and compared with nine control rats. Myocardial strain analysis with 2DSTE, as well as conventional echocardiography, was obtained. RESULTS: Compared with baseline, longitudinal strain/strain rate (LS/LSr) decreased at week 2 (-15.7 +/- 1.5 to -14.1 +/- 1.4%, P = 0.01 for LS; -4.4 +/- 0.7 to -3.9 +/- 0.5 per second, P = 0.009 for LSr). Left ventricular ejection fraction (LVEF) and circumferential strain (CS) decreased at week 4 (80.3 +/- 3.2 to 78.1 +/- 3.3%, P = 0.031 for LVEF; -18.6 +/- 1.9 to -15.0 +/- 3.4%, P = 0.019 for CS). Circumferential strain rate (CSr) decreased at week 6 (-5.5 +/- 0.8 to -4.6 +/- 1.0 per second, P = 0.008). Radial strain/strain rate (RS/RSr) decreased at week 8 (54.8 +/- 9.4 to 43.7 +/- 10.6%, P = 0.005 for RS; 8.0 +/- 1.1 to 7.0 +/- 1.1 per second, P = 0.005 for RSr), while there was no significant change in LS/LSr, LVEF, CS/CSr, or RS/RSr in the control group. LVEF had the highest correlation with LS (r =-0.607, P = 0.000) and the lowest correlation with RSr (r = 0.357, P = 0.000). CONCLUSIONS: In DIC of rat hearts, LS/LSr decreased first, and then LVEF, CS, CSr, RS/RSr subsequently decreased. LS/LSr is considered to be a more sensitive predictor than LVEF in progressive rat DIC, and RS/RSr was preserved until the last stage. PMID- 22486545 TI - Development and application of a database of food ingredient fraud and economically motivated adulteration from 1980 to 2010. AB - Food ingredient fraud and economically motivated adulteration are emerging risks, but a comprehensive compilation of information about known problematic ingredients and detection methods does not currently exist. The objectives of this research were to collect such information from publicly available articles in scholarly journals and general media, organize into a database, and review and analyze the data to identify trends. The results summarized are a database that will be published in the US Pharmacopeial Convention's Food Chemicals Codex, 8th edition, and includes 1305 records, including 1000 records with analytical methods collected from 677 references. Olive oil, milk, honey, and saffron were the most common targets for adulteration reported in scholarly journals, and potentially harmful issues identified include spices diluted with lead chromate and lead tetraoxide, substitution of Chinese star anise with toxic Japanese star anise, and melamine adulteration of high protein content foods. High-performance liquid chromatography and infrared spectroscopy were the most common analytical detection procedures, and chemometrics data analysis was used in a large number of reports. Future expansion of this database will include additional publically available articles published before 1980 and in other languages, as well as data outside the public domain. The authors recommend in-depth analyses of individual incidents. PRACTICAL APPLICATION: This report describes the development and application of a database of food ingredient fraud issues from publicly available references. The database provides baseline information and data useful to governments, agencies, and individual companies assessing the risks of specific products produced in specific regions as well as products distributed and sold in other regions. In addition, the report describes current analytical technologies for detecting food fraud and identifies trends and developments. PMID- 22486546 TI - Transplantation of adipose-derived mesenchymal stem cells into a murine model of passive chronic immune thrombocytopenia. AB - BACKGROUND: Immune thrombocytopenia (ITP) is a bleeding disorder characterized by antibody-opsonized platelets (PLTs) being prematurely destroyed by macrophages in the reticuloendothelial system. T helper (Th) cells and different Th cytokines play an important role in the pathophysiology of ITP. As immunomodulators, adipose-derived mesenchymal stem cells (ADSCs) regulate Th cells and show therapeutic effects in autoimmune diseases. However, it is not clear how ADSCs affect ITP. In this study, we explored the specific effects of ADSCs on ITP in mice. STUDY DESIGN AND METHODS: BALB/c mice were randomly divided into three groups: normal controls, ITP controls, and ITP with ADSC transplantation. PLT levels were monitored by an automatic blood cell counter, and the cytokines interferon-gamma (IFN-gamma); interleukin (IL)-2, -4, -10, and -17; and transforming growth factor-beta1 (TGF-beta1) were analyzed by enzyme-linked immunosorbent assays. RESULTS: Compared to the untreated ITP mice, the PLT level of the ITP mice significantly increased after ADSC treatment. In the ADSC group, IFN-gamma, IL-2, and IL-17 significantly decreased, while IL-4, IL-10, and TGF beta1 increased. CONCLUSION: These findings constitute the first experimental evidence that ADSCs are efficacious in improving PLT levels and reducing the related Th cytokines mediating proinflammatory response in ITP mice, which may provide a scientific basis for using ADSCs as a new therapy for ITP. PMID- 22486547 TI - "Science is meant to be cumulative, but many scientists are not cumulating scientifically". PMID- 22486548 TI - Musculoskeletal disease and injury, now and in the future. Part 2: Tendon and ligament injuries. AB - Tendon and ligament injuries continue to be one of the most frequent causes of orthopaedic injury and early retirement in the Thoroughbred racehorse. In the UK, the Horserace Betting Levy Board has invested considerable research funding in the last decade in order to investigate aspects of tendon epidemiology, biology and therapy, in order to decrease both the welfare and economic consequence of such injuries. This review summarises key aspects of this research effort and identifies specific research directions for the future. PMID- 22486549 TI - Health care utilization and psychosocial factors in pediatric noncardiac chest pain. AB - OBJECTIVE: This study investigated factors related to health care utilization (HCU) among patients presenting to pediatric cardiologists with symptoms of chest pain later diagnosed as noncardiac chest pain (NCCP). METHODS: Participants included 67 children and adolescents diagnosed with NCCP and their parent. Measures of HCU, pain severity, and child self-report and parent self-report of anxiety and depression were collected at the cardiologist's office. The child's sex was examined as a moderator of HCU. RESULTS: Pain severity and maternal and child depression were significant contributors to the variance in child HCU. The relationship between depression and HCU was moderated by the child's sex, with boys higher in levels of maternal or child depression reporting greater HCU. CONCLUSIONS: Psychological factors are related to HCU for children with NCCP, with depression positively associated with HCU. The child's sex plays an important role in depression and HCU. Family-focused psychological screening of pediatric patients with NCCP may aid in identifying families who may benefit from referrals for psychological assessment and treatment. PMID- 22486551 TI - Novel immunomic technologies for schistosome vaccine development. AB - Schistosomiasis remains one of the most common human helminthiases, despite the availability of an effective drug against the causative parasites. Drug treatment programmes have several limitations, and it is likely that a vaccine is required for effective control. While decades of vaccine development have seen the discovery and testing of several candidate antigens, none have shown consistent and acceptable high levels of protection. The migrating larval stages are susceptible to immunity, however few larval-specific antigens have been discovered. Therefore, there is a need to identify novel larval-specific antigens, which may prove to be more efficacious than existing targets. Immunomics, a relatively new field developed to cope with the recent large influx of biological information, holds promise for the discovery of vaccine targets, and this review highlights some immunomic approaches to schistosome vaccine development. Firstly, a method to focus on the immune response elicited by the important and vulnerable larval stage is described, which allows a targeted study of the immunome at different tissue sites. Then, two high-throughput arrays are discussed for the identification of protein and carbohydrate antigens. It is anticipated that these approaches will progress vaccine development against the schistosomes, as well as other parasites. PMID- 22486550 TI - A longitudinal analysis of the relations among stress, depressive symptoms, leisure satisfaction, and endothelial function in caregivers. AB - OBJECTIVE: Stress and depressive symptoms have been associated with impaired endothelial function as measured by brachial artery flow-mediated dilation (FMD), possibly through repeated and heightened activation of the sympathetic nervous system. Behavioral correlates of depression, such as satisfaction with leisure activities (i.e., leisure satisfaction), may also be associated with endothelial function via their association with depressive symptoms. This study examined the longitudinal associations between stress, depressive symptoms, leisure satisfaction, and endothelial function as measured by FMD. METHOD: Participants were 116 older Alzheimer's caregivers (M age = 74.3 +/- 8.1; 68% women; 87% white) who underwent 3 yearly assessments of FMD, stress, depressive symptoms, and leisure satisfaction. Mixed-regression analyses were used to examine longitudinal relationships between constructs of interest. RESULTS: A significant and positive association was found between leisure satisfaction and FMD (p = .050), whereas a negative relationship was found for stress (p = .017). Depressive symptoms were not associated with FMD (p = .432). Time (p < .001) and the number of years caregiving (p = .027) were also significant predictors of FMD, suggesting that FMD decreased over time and was worse the longer a participant had been a caregiver prior to study enrollment. CONCLUSIONS: These results suggest that behavioral correlates of depression (i.e., engagement in pleasurable activities) may be related to endothelial function in caregivers, and behavioral treatments for depression may be particularly useful in improving cardiovascular outcomes in caregivers. PMID- 22486552 TI - Randomised clinical trial: sustained response to PPI treatment of symptoms resembling functional dyspepsia and irritable bowel syndrome in patients suffering from an overlap with erosive gastro-oesophageal reflux disease. AB - BACKGROUND: Gastro-oesophageal reflux disease (GERD), functional dyspepsia (FD) and irritable bowel syndrome (IBS) are highly prevalent gastrointestinal conditions with accumulating evidence of overlap in patients. Despite availability of a vast body of research related to individual disorders, major pharmacological breakthrough in treatment of the overlap condition is still lacking. AIM: To assess sustainability of GERD healing and whether known beneficial effects of proton pump inhibitor treatment on GERD also extend to symptoms suggestive of FD and IBS. METHODS: A total of 626 patients with reflux oesophagitis were treated with pantoprazole for up to 16 weeks depending on healing of GERD, followed by an observational phase of up to 6 months without treatment. Rates of patients suffering from GERD, FD or IBS were assessed at baseline, and at last visits of treatment and observational phase. RESULTS: Rates of patients with reflux oesophagitis and concomitantly with reflux symptoms, FD or IBS were each significantly lower after pantoprazole treatment (P < 0.0001). While rates of patients with reflux signs or symptoms increased again during observational phase, rates of FD and IBS were maintained at the low level after cessation of medication (P < 0.0001). CONCLUSIONS: Pantoprazole is efficacious in the treatment of patients suffering from signs and symptoms suggesting an overlap of GERD, FD and/or IBS, providing a sustained response post-treatment in FD and IBS symptom categories. Mechanisms underlying the beneficial effects of improvement in reflux oesophagitis on symptoms suggestive of FD or IBS still need to be determined. PMID- 22486553 TI - Children's pain perspectives. AB - BACKGROUND: Previous studies on children's pain perspectives remain limited to English-speaking populations. METHODS: An exploratory cross-sectional descriptive design was used to investigate the developmental progression of children's pain perspectives, including their pain experience, its definition and attributes, causality and coping. The Children's Pain Perspectives Inventory was applied to 180 healthy Spanish children. A coding system was developed following the content analysis method. Three age groups were compared: 4-6 years, corresponding to the Piagetian pre-operational stage of cognitive development; 7-11 years, corresponding to stage of concrete operations; and 12-14 years, corresponding to the period of early formal operations. RESULTS: In children between 4 and 6, the predominant narratives related to physical injuries, the notion of causality and the definition of pain. In children between 7 and 11, the predominant narratives were those in which pain was described as a sensation in one part of the body. The view of pain as having an emotional basis significantly increased with age and was more frequent in adolescents. In contrast, children between 4-6 and 7-11 indicated that pain occurs spontaneously. The denial of any positive aspects of pain significantly decreased with age; some children between 7 and 11 referred to the 'possibility of relief', while the view that pain is a 'learning experience' was significantly more frequent among adolescents aged between 12 and 14 years. The use of cognitive strategies to control pain significantly increased with age. Between 12 and 14 years of age, adolescents communicate pain by non-verbal behaviour and reported that they do not express demands for relief. CONCLUSIONS: There was a progression from concrete to more complex notions of pain as age increased. These results may be of use to health professionals and parents to understand how children at various developmental stages express and cope with pain and to develop tools that effectively assess and manage pain in children. PMID- 22486554 TI - Effects of drop-out on efficacy estimates in five Cochrane reviews of popular antipsychotics for schizophrenia. AB - OBJECTIVE: Our aim was to find out how Cochrane reviews of five popular or frequently prescribed second-generation antipsychotics in the UK (olanzapine, risperidone, quetiapine, amisulpride and aripiprazole) approached the problem of high drop-out in placebo-controlled trials. METHOD: We examined the following: (i) whether reviews included data from studies with a level of drop-out exceeding their stated exclusion criterion; (ii) the level of missing data each efficacy outcome in each review relied upon; and (iii) impact of excluding studies with high drop-out. RESULTS: All reviews included data they stated they would exclude because of unacceptable levels of attrition, four (risperidone, olanzapine, amisulpride, aripiprazole) without clear acknowledgement or justification. Several reviews also excluded data from a number of relatively low-attrition studies because of missing standard deviations. CONCLUSION: Cochrane reviews of five popular antipsychotics for schizophrenia misrepresented the available evidence on their efficacy. The impact of including high-attrition studies was difficult to quantify because of the exclusion of relevant low-attrition studies. Further analysis of the efficacy of these drugs in studies with acceptable rates of attrition is required. To reduce the problem of high attrition, trialists should gather follow-up data from people who leave the double-blind process early. PMID- 22486555 TI - Evaluation of cerebral activity in the prefrontal cortex in mood [affective] disorders during animal-assisted therapy (AAT) by near-infrared spectroscopy (NIRS): a pilot study. AB - OBJECTIVE: Previous studies have shown the possibility that animal-assisted therapy (AAT) is useful for promoting the recovery of a patient's psychological, social, and physiological aspect. As a pilot study, we measured the effect that AAT had on cerebral activity using near-infrared spectroscopy (NIRS), and examined whether or not NIRS be used to evaluate the effect of AAT biologically and objectively. METHODS: Two patients with mood [affective] disorders and a healthy subject participated in this study. We performed two AAT and the verbal fluency task (VFT). RESULTS: The NIRS signal during AAT showed great [oxy-Hb] increases in most of the prefrontal cortex (PFC) in the two patients. When the NIRS pattern during AAT was compared with that during VFT, greater or lesser differences were observed between them in all subjects. CONCLUSION: The present study suggested that AAT possibly causes biological and physiological changes in the PFC, and that AAT is useful for inducing the activity of the PFC in patients with depression who have generally been said to exhibit low cerebral activity in the PFC. In addition, the possibility was also suggested that the effect of AAT can be evaluated using NIRS physiologically and objectively. PMID- 22486556 TI - Antischistosomal effect of holothurin extracted from some Egyptian sea cucumbers. AB - CONTEXT: Holothuria polii (H. polii) Linnaeus (Holothuriidae), Actinopyga mauritiana (A. mauritiana) Quoy & Gaimard (Holothuriidae) and Bohadschia vitiensis (B. vitiensis) Semper (Holothuriidae) are sea cucumbers inhabiting the coasts of Egypt. Their tegument and the cuvierian gland contained a substance called holothurin that was used in traditional medicine. These three species are abundant in the Egyptian coast, however there are no reports about their efficacy as antiparasitic agent. OBJECTIVE: The antischistosomal effect of the holothurin extracted from the three species of sea cucumber is investigated. MATERIALS AND METHODS: The ethanol extract was made from the tegument of both H. polii and A. mauritiana while it was made from the cuvierian gland of B. vitiensis. The body wall (or cuvierian gland) of the sea cucumber was blended with 95% ethanol in a volume = 4 * tissue weight. Extraction was done at room temperature for one day then filtered. The ethanol was removed by evaporation using Rotavapour (BUCHI 461 water bath REIII) at 40 degrees C. Later the aqueous residue was placed in a vacuum oven at 20 degrees C for about 48 h to remove water. The resulting dried mass was then stored at -4 degrees C until use. The percentage yield and the LD50 were calculated for each extract. Each extract was administered orally to Shistosoma mansoni infected mice in acute and chronic phases of infection. The dose of one-tenth of LD50 of each extract was administrated to mice (5.4, 62.2, and 10 mg/kg body weight/mouse for H. polii extract (HPE), A. mauritiana extract (AME), and cuvierian gland of B. vitiensis, respectively) for 24 h. The effects of each extract on the worm burden and total egg count was studied. The effects of each extract on the worm tegument using scanning electron microscope (SEM) were investigated in vivo and in vitro. RESULTS: The percentage yield of cuvierian gland extract (CGE) was higher (70%) than the tegument AME (33.4%) and HPE (9.3%). The 24 h LD50 of investigated sea cucumber ethanol extracts were 54.46, 627, and 100 mg/kg body weight/mouse for HPE, AME, and CGE. Oral administration of HPE caused decrease in male and female worm burden of 30-day infected mice to reach 60 and 90%, respectively. HPE decreased the egg count significantly in those mice with 30-day (1.75 egg counts/g tissue, p < 0.05) and 45-day (3.25 egg counts/g tissue, p < 0.05) infections. SEM studies of recovered worms from treated mice with all extracts showed different tegumental changes like formation of blebs, wrinkling, formation of numerous pores, and rupturing of some tubercles. These effects were more pronounced in those worms treated in vitro represented by severe shrinkage of the tegument, deformation of spines, rupturing, and collapsing of tubercles. DISCUSSION AND CONCLUSION: Results support the hypothesis that holothurin is a promising antischistosomal agent. PMID- 22486557 TI - On the unexpected cation exchange behavior, caused by covalent bond formation between PEDOT and Cl- ions: extending the conception for the polymer-dopant interactions. AB - The ionic motion in connection with the redox transformation of poly(3,4 ethylenedioxythiophene) (PEDOT) conjugated polymer have been studied by both experimental-electrochemical (electrochemical quartz crystal nanobalance, EQCN) and spectroscopic (infrared spectroscopy, IR-ATR)-and theoretical methods. The observations have been completed by direct, semiquantitative analytical data, provided by energy dispersive X-ray (EDX) microanalysis. The EQCN results suggested an anomalous behavior, since only cationic movements have been observed for films deposited from chloride solutions. Chloride ions were proved to be immobile also when bulky tetrabutylammonium (Bu(4)N(+)) cations were substituted with even larger (hexadecyltrimethylammonium) cations. Since PEDOT films synthesized in the presence of other spherical, not too large anions-such as perchlorate and tetrafluoroborate-endowed mixed ion exchange behavior together with the Bu(4)N(+) cation, the possibility of a special interaction between chloride and the polymeric chain has been assumed. Semiempirical and DFT calculations indicated that chloride ions interact with the alpha carbon atoms of the thiophene rings of the oxidized EDOT oligomers, creating sp(3) type perturbations in the polymer chain. FTIR-ATR spectra evidenced the appearance of C-Cl bonds. Elementary analysis, performed by EDX spectroscopy with eight polymer samples at different doping levels clearly showed the permanent presence of constant amount of chlorine, independently of the oxidation state of the PEDOT layer. Finally, the presented observations call attention to the fact that unique dopant-polymer interactions during the electrochemical polymerization are of prime importance, being able to rule over conventions for the charge compensation of conjugated polymers, often solely based on steric parameters. PMID- 22486558 TI - Development of the permanent mandibular cheek teeth in fallow deer (Dama dama). AB - The study describes crown and root formation of the permanent mandibular cheek teeth of fallow deer from a gestational age of 22-23 weeks up to a post-natal age of 33 months. Tooth development was recorded using a scoring scheme based on morphological criteria ranging from crypt formation to completion of root growth. The morphological appearance of the enamel surface during three different stages (secretory-stage enamel, maturation-stage enamel and mature enamel) was described, and the approximate age at termination of the secretory stage of amelogenesis in the deciduous and permanent mandibular cheek teeth was determined. The data enable an age estimation of fallow deer up to 3 years of age and provide a basis for assessing the timing of stress episodes that affect tooth crown formation. This information is useful for the management of the species as well as in bioarchaeological and bioindication studies. PMID- 22486559 TI - Preparation of antibodies and development of an enzyme-linked immunosorbent assay (ELISA) for the determination of doxycycline antibiotic in milk samples. AB - This paper reports the development of an immunoassay for the specific analysis of doxycycline (DC), a congener of the tetracycline antibiotic family (TCs), in milk samples. This is the first time that DC antibody production is reported, based on a rationally designed and well-characterized immunizing hapten. The chemical structure of the immunizing hapten (13-[(2-carboxyethyl)thiol]-5-hydroxy-6-alpha deoxytetracycline, TC1) was designed to maximize recognition of the tetracycline characteristic moiety defined as lower periphery of the TCs plus the region of the upper periphery composed by the hydroxyl group at position C(5) (B ring) and the dimethylamino group in ring A. Polyclonal antibodies raised against TC1 coupled to horseshoe crab hemocianyn (HCH) were used to develop a homologous indirect competitive enzyme-linked immunosorbent assay (ELISA). The microplate ELISA can detect DC in buffer down to 0.1 MUg L(-1). The ELISA has been proven to tolerate a wide range of ionic strengths and pH values. The assay is very selective for DC with a minor recognition of methacycline (32% of cross reactivity). Experiments performed with whole milk samples demonstrate that samples can be directly analyzed after a simple treatment method, reaching detectability values below 5 MUg L(-1). PMID- 22486560 TI - Cure of a thyrotrophin (TSH)-secreting pituitary adenoma by medical therapy. PMID- 22486561 TI - Structural and cognitive social capital and depression among older adults in two Nordic regions. AB - OBJECTIVE: To study the association between structural and cognitive aspects of social capital and depression among older adults in two Nordic regions. METHOD: Data were retrieved from a postal survey targeting older adults aged 65, 70, 75 and 80 years (N=6 838, response rate=64%) residing in the Vasterbotten region (Sweden), and the Osterbotten region (Finland) in 2010. The associations between structural (measured by frequency of social contact with friends and neighbours) and cognitive (measured by experienced trust in friends and neighbours) aspects of social capital and depression (measured by Geriatric Depression Scale, GDS-4) were tested by logistic regression analyses. RESULTS: Both low structural and cognitive social capital as defined in the study showed statistically significant associations with depression in older adults. Only experienced trust in neighbours failed to show significant association with depression. In addition, being single and being 80 years of age indicated a higher risk of depression as defined by GDS-4. CONCLUSION: The findings underline the connection between adequate levels of both structural and cognitive individual social capital and mental health in later life. They also suggest that the connection differs depending on various network types; the cognitive aspect of relationships between friends was connected to depression, while the connection was not found for neighbours. Further, the oldest age group in the sample (80 years of age) is pointed out as a population especially vulnerable for depression that should not be overlooked in mental health promotion and depression prevention. PMID- 22486563 TI - STR melting curve analysis as a genetic screening tool for crime scene samples. AB - In this proof-of-concept study, high-resolution melt curve (HRMC) analysis was investigated as a postquantification screening tool to discriminate human CSF1PO and THO1 genotypes amplified with mini-STR primers in the presence of SYBR Green or LCGreen Plus dyes. A total of 12 CSF1PO and 11 HUMTHO1 genotypes were analyzed on the LightScanner HR96 and LS-32 systems and were correctly differentiated based upon their respective melt profiles. Short STR amplicon melt curves were affected by repeat number, and single-source and mixed DNA samples were additionally differentiated by the formation of heteroduplexes. Melting curves were shown to be unique and reproducible from DNA quantities ranging from 20 to 0.4 ng and distinguished identical from nonidentical genotypes from DNA derived from different biological fluids and compromised samples. Thus, a method is described which can assess both the quantity and the possible probative value of samples without full genotyping. PMID- 22486562 TI - Oxidative stress modulates KLF6Full and its splice variants. AB - BACKGROUND: Induction of reactive oxygen species (ROS) is a central mechanism in alcohol hepatotoxicity. Kruppel-like factor 6 (KLF6), a transcription factor and a tumor-suppressor gene, is an early-responsive gene to injury; however, the effect of ROS and alcohol on KLF6 induction is unknown. The aim of this study is to investigate the contribution of 2 sources of ROS, cytochrome P450 2E1 (CYP2E1), NAD(P)H quinone oxidoreductase (NQO1), and alcohol on the modulation of KLF6(Full) expression, splicing to KLF6_V1 and KLF6_V2, and the effect on TNFalpha, a downstream target. METHODS AND RESULTS: Endogenous ROS production in CYP2E1-expressing HepG2 cells induced mRNA and protein expression of KLF6(Full) and its splice variants compared to control cells. Incubation with pro-oxidants such as arachidonic acid (AA), beta-naphtoflavone, and H(2) O(2) further enhanced KLF6(Full) and its splice variants. The AA effects on KLF6(Full) and its splice forms were blocked by vitamin E-which prevents lipid peroxidation-and by diallylsulfide-a CYP2E1 inhibitor. Menadione and paraquat, 2 pro-oxidants metabolized via NQO1, induced KLF6(Full) mRNA in a thiol-dependent manner. Antioxidants and an NQO1 inhibitor suppressed the menadione-dependent increase in KLF6(Full) and its splice variants mRNA. Furthermore, primary hepatocytes and livers from chronic alcohol-fed rats, with elevated lipid peroxidation, H(2) O(2) and CYP2E1 but with low GSH, showed a ~2-fold increase in KLF6(Full) mRNA compared to controls. Inhibition of p38 phosphorylation further up-regulated the CYP2E1 and the AA effects on KLF6(Full) mRNA, whereas inhibition JNK and ERK1/2 phosphorylation decreased both. KLF6_V1 but not KLF6(Full) ablation markedly increased TNFalpha levels in macrophages; thus, TNFalpha emerges as a downstream target of KLF6_V1. CONCLUSIONS: The novel effect of ROS on modulating KLF6(Full) expression and its splice variants could play a relevant role in liver injury and in TNFalpha regulation. PMID- 22486565 TI - Sesquiterpene lactone mix as a diagnostic tool for Asteraceae allergic contact dermatitis: chemical explanation for its poor performance and Sesquiterpene lactone mix II as a proposed improvement. AB - BACKGROUND: Two preparations are currently in use for the diagnosis of allergic contact dermatitis caused by Asteraceae: (i) Sesquiterpene lactone (SL) mix [three pure sesquiterpene lactones (STLs)], whose use has been questioned, owing to an insufficient rate of true-positive results; and (ii) Compositae mix, consisting of five Asteraceae extracts, which is problematic because of lack of standardization and questionable reproducibility. OBJECTIVES: To analyse the reasons for the narrow sensitivity of SL mix from a chemoinformatic point of view, and to propose a solution by rational selection of alternative constituents for a new SL mix II covering a broader cohort of allergic patients. MATERIALS/METHODS: Structural and biological information on allergenic STLs was retrieved from databases and the literature, and molecular modelling and chemoinformatic computations were performed. RESULTS: An explanation for the insufficient hit rate of SL mix is that the three constituents possess extremely similar molecular structures/properties and do not represent well the structural diversity of allergenic STLs. STLs that are known as constituents of Compositae mix plants show much a wider diversity, which explains the higher positive rate. CONCLUSIONS: On the basis of their positions in chemical property space, a new collection of STLs that more evenly cover the overall structural diversity spectrum is proposed. SL mix II is likely to detect a larger number of patients sensitized to Asteraceae. PMID- 22486564 TI - Differential effects of procaspase-3 activating compounds in the induction of cancer cell death. AB - The evasion of apoptosis is a key characteristic of cancer, and thus strategies to selectively induce apoptosis in cancer cells hold considerable promise in personalized anticancer therapy. Structurally similar procaspase activating compounds PAC-1 and S-PAC-1 restore procaspase-3 activity through the chelation of inhibitory zinc ions in vitro, induce apoptotic death of cancer cells in culture, and reduce tumor burden in vivo. Ip or iv administrations of high doses of PAC-1 are transiently neurotoxic in vivo, while S-PAC-1 is safe even at very high doses and has been evaluated in a phase I clinical trial of pet dogs with spontaneously occurring lymphoma. Here we show that PAC-1 and S-PAC-1 have similar mechanisms of cell death induction at low concentrations (less than 50 MUM), but at high concentrations PAC-1 displays unique cell death induction features. Cells treated with a high concentration of PAC-1 have a distinctive gene expression profile, unusual cellular and mitochondrial morphology, and an altered intracellular Ca(2+) concentration, indicative of endoplasmic reticulum (ER) stress-induced apoptosis. These studies suggest strategies for anticancer clinical development, specifically bolus dosing for PAC-1 and continuous rate infusion for S-PAC-1. PMID- 22486566 TI - Patch testing with constituents of Compositae mixes. AB - BACKGROUND: The development of mixes containing Compositae plant extracts has improved the diagnosis of Compositae contact allergy, but none of them has fulfilled the criteria for an ideal European plant mix. OBJECTIVE: To evaluate which constituents of two commercial Compositae mixes were most useful as screening agents. PATIENTS: These comprised 76 patients testing positive to Compositae mix 6% in petrolatum and 29 patients testing positive to Compositae mix 5% pet., all of whom were tested with constituents of the respective mixes. RESULTS: The majority of patients tested positive to parthenolide or parthenolide containing extracts, followed by German chamomile, yarrow, and arnica. As German chamomile is a weak sensitizer, the results suggest cross-reactions or reactions to unknown allergens. No one was positive to Roman chamomile. CONCLUSIONS: Even though parthenolide seems to be a suitable supplement to the baseline series, the results emphasize that it is important to patch test with extracts of native or locally grown plants, not only because of the geographical variation, but also because of the potential unknown allergens contained in short ether preparations and the variability in the individual patient's exposure and cross-reaction patterns. PMID- 22486567 TI - Exposures related to hand eczema: a study of healthcare workers. AB - BACKGROUND: Hand eczema is common in healthcare workers, owing to intensive exposure to wet work and skin irritants. Targeted interventions and vocational guidance based on documented exposures and risk factors are needed. OBJECTIVES: The aims of the study were to investigate the relationship between exposures (domestic and at work) and prevalence and severity of hand eczema. METHODS: Self administered questionnaires were sent to 3181 healthcare workers in Denmark. RESULTS: Two thousand two hundred and sixty-nine (71%) workers responded to the questionnaire. Frequent hand washing was significantly related to the presence of hand eczema. Having children < 4 years old in the household was also related to the presence of hand eczema. A lower prevalence of hand eczema was found among those using moisturizers at work, and a higher prevalence was found among those using moisturizers at home. CONCLUSIONS: Although healthcare workers are recommended to use disinfectants when the hands are not visibly dirty, hand washing is still significantly related to hand eczema. Frequent hand washing may be a question of behavioural habits, and a focus for future guidance should be on changing hand washing habits. Attention should also be paid to healthcare workers with small children at home. The preventive effect of moisturizers used during working hours should be tested in future follow-up studies. PMID- 22486568 TI - Occupational food-related hand dermatoses seen over a 10-year period. AB - BACKGROUND. Protein contact dermatitis was originally defined in 1976 by Hjorth and Roed-Petersen as a distinct kind of dermatitis seen in patients with occupational food contact. Even though occupational skin diseases are frequent in Denmark, little attention has been paid to protein contact dermatitis, and the frequency is unknown. OBJECTIVES: To evaluate the frequency of occupational food related hand dermatoses and test results in patients occupationally exposed to foods. MATERIALS AND METHODS: This was a retrospective study based on examinations, including skin prick testing and patch testing, performed at the Department of Dermato-Allergology, Gentofte University Hospital, Denmark between 2001 and 2010. RESULTS: Of all patients (n = 372), 57.0% had irritant contact dermatitis, 22.0% had protein contact dermatitis, 2.4% had contact urticaria, and 1.8% had allergic contact dermatitis. A suggestion for diagnostic criteria is presented. Frequent risk occupations were cooking in restaurants, baking, and kitchen work. Substantially more patients reacted in skin prick testing with fresh foods than with food extracts. Conclusion. Protein contact dermatitis is a frequent disorder among patients who professionally handle foods, and should be considered to be a distinct clinical entity. When diagnosing protein contact dermatitis and in other food-related skin prick testing procedures, it is important to include fresh foods. PMID- 22486569 TI - Patch test characteristics of patients referred for suspected contact allergy of the feet--retrospective 10-year cross-sectional study of the IVDK data. AB - BACKGROUND: The warm und humid environment, friction and occlusion within shoes make the feet to a favorable body site to acquire allergic contact dermatitis. OBJECTIVES: To evaluate and compare patch test results in patients with suspected contact allergy of the feet with the results in those with concomitant involvement of the feet/legs, feet/hands, and all others tested (excluding secondary involvement of the feet in 'others'), with regard to specific patterns of clinical data and patch test results. METHODS: For the present cross-sectional study, data were collected by the 59 participating centres of the Information Network of Departments of Dermatology in Germany, Austria, and Switzerland, including 102 209 patients patch-tested between January 2001 and December 2010. RESULTS: Allergens that were significantly over-represented in the tested 2671 foot patients included potassium dichromate, colophonium, and p-tert-butylphenol formaldehyde resin. Among materials brought in by the patients, shoe pieces (27.5%), topical medications/pharmaceutical products (24.4%) and cosmetics (16.8%) played a major role. The final diagnoses of vesicular and hyperkeratotic dermatitis, as well as psoriasis, were significantly more common among foot patients. CONCLUSIONS: Chromium compounds and adhesives were the most common causes of allergic contact dermatitis among our foot patients. Psoriasis should be considered, particularly when the hands are concomitantly affected. PMID- 22486570 TI - Chromium in leather footwear - risk assessment of chromium allergy and dermatitis. AB - BACKGROUND: Chromium-tanned leather footwear, which releases >3 ppm hexavalent Cr(VI), may pose a risk of sensitizing and eliciting allergic dermatitis. OBJECTIVES: To determine the content and potential release of chromium in leather footwear and to discuss the prevention of chromium contact allergy and dermatitis. METHODS: Sixty pairs of leather shoes, sandals and boots (20 children's, 20 men's, and 20 women's) were purchased in Copenhagen and examined with X-ray fluorescence spectroscopy. Chromium was extracted according to the International Standard, ISO 17075. The detection level for Cr(VI) was 3 ppm. RESULTS: Chromium was identified in 95% of leather footwear products, the median content being 1.7% (range 0-3.3%). No association with store category or footwear category was found. A tendency for there to be a higher chromium content in footwear with high prices was shown (p(trend) = 0.001). Cr(VI) was extracted from 44% of 18 footwear products, and, in three items, more than 10 ppm was extracted. One shoe had 62 ppm Cr(VI) extracted. Sandals seemed to be over-represented among footwear with detectable Cr(VI). Cr(III) extraction reached a median value of 152 ppm. CONCLUSIONS: Most leather footwear contained chromium. Cr(VI) was extracted from a high proportion of leather footwear; this poses a risk of sensitization. PMID- 22486571 TI - Occupational hand dermatitis caused by benzoyl peroxide in transformer coil binding tape. PMID- 22486572 TI - Allergic contact dermatitis probably caused by mercaptobenzothiazole in thermal undergarments. PMID- 22486573 TI - Nomenclature and contact allergy to nickel and gold. PMID- 22486574 TI - Clinic value of two-dimensional speckle tracking combined with adenosine stress echocardiography for assessment of myocardial viability. AB - BACKGROUND: To evaluate whether myocardial strain under adenosine stress calculated from two-dimensional echocardiography by automatic frame-by-frame tracking of natural acoustic markers enables objective description of myocardial viability in clinic. METHODS AND RESULTS: Two-dimensional echocardiography and two-dimensional speckle tracking imaging (2D STI) at rest were performed first and once again after adenosine was infused at 140 ug/kg/min over a period of 6 minutes in 36 stable patients with previous myocardial infarction. Then radionuclide myocardial perfusion/metabolic imaging served as the "gold standard" to define myocardial viability was given in all patients within 1 day. Two dimensional speckle tracking images were acquired at rest and after adenosine administration. An automatic frame-by-frame tracking system of natural acoustic echocardiographic markers was used to calculate 2D strain variables including peak-systolic circumferential strain (CS(peak-sys)), radial strain (RS(peak sys)), and longitudinal strain (LS(peak-sys)). Those segments with abnormal motion from visual assessment of two-dimensional echocardiography were selected for further study. As a result, 126 regions were viable whereas 194 were nonviable among 320 abnormal motion segments in 36 patients according to radionuclide imaging. At rest, there were no significant changes of 2D strain between the viable and nonviable myocardium. After adenosine administration (140 ug/kg/min), CS(peak-sys) had a little change of the viable myocardium while RS(peak-sys) and LS(peak-sys) increased significantly compared with those at rest. In nonviable group, CS(peak-sys), RS(peak-sys), and LS(peak-sys) had no significant changes during adenosine administration. After adenosine administration, RS(peak-sys) and LS(peak-sys) in viable group increased significantly compared with nonviable group. Obtained strain data were highly reproducible and affected in small intraobserver and interobserver variabilities. A change of radial strain more than 9.5% has a sensitivity of 83.9% and a specificity of 81.4% for viable whereas a change of longitudinal strain more than 14.6% allowed a sensitivity of 86.7% and a specificity of 90.2%. CONCLUSIONS: 2D STI combined with adenosine stress echocardiography could provide a new and reliable method to identify myocardium viability. PMID- 22486575 TI - Mid-gestation pregnancy is not disrupted by a 5-day gastrointestinal mucosal cytoprotectant oral regimen of misoprostol. AB - REASONS FOR PERFORMING STUDY: To investigate effects of a 5-day oral misoprostol regimen recommended for use in horses as a gastrointestinal mucosal cytoprotectant during colic on mid-gestation pregnancies. OBJECTIVES: To monitor cervical tone, ultrasonographic characteristics of the uterus, cervix and conceptus, as well as serum progesterone and oestrone sulphate concentrations, and observations of general health, behaviour and comfort of mid-gestation mares given a 5-day course of misoprostol or control treatment. METHODS: Eleven light horse and pony mares with known breeding dates were administered 5 ug/kg bwt misoprostol orally, twice daily for 5 days. General health and pregnancy status were monitored daily during treatment via general physical examination, as well as palpation and ultrasonography per rectum of the uterus, cervix and conceptus. Jugular serum was obtained during and for 5 days following treatment for assay of progesterone and oestrone sulphate concentrations. Additionally, daily 12 h video samples of the mares were obtained to evaluate behaviour and comfort. RESULTS: All findings, including cervical tone, ultrasonographic characteristics of the uterus, cervix and conceptus, as well as progesterone and oestrone sulphate concentrations, and observations of general health, behaviour and comfort, were similar during misoprostol and control treatment. CONCLUSIONS: Treatment of pregnant mares with a gastrointestinal mucosal cytoprotectant regimen of oral misoprostol for 5 days did not disrupt pregnancy, nor adversely affect the general health and comfort of these mares. Additional investigation of treatment at earlier and later stages of gestation, for longer-term treatment, as well as evaluating neonates for developmental disturbances, would add further information on safety of misoprostol during gestation. POTENTIAL RELEVANCE: These results provide some assurance of safety of a 5-day gastrointestinal mucosal cytopretectant regimen of oral misprostol in mid-gestation pregnant mares. PMID- 22486576 TI - An SEM approach to continuous time modeling of panel data: relating authoritarianism and anomia. AB - Panel studies, in which the same subjects are repeatedly observed at multiple time points, are among the most popular longitudinal designs in psychology. Meanwhile, there exists a wide range of different methods to analyze such data, with autoregressive and cross-lagged models being 2 of the most well known representatives. Unfortunately, in these models time is only considered implicitly, making it difficult to account for unequally spaced measurement occasions or to compare parameter estimates across studies that are based on different time intervals. Stochastic differential equations offer a solution to this problem by relating the discrete time model to its underlying model in continuous time. It is the goal of the present article to introduce this approach to a broader psychological audience. A step-by-step review of the relationship between discrete and continuous time modeling is provided, and we demonstrate how continuous time parameters can be obtained via structural equation modeling. An empirical example on the relationship between authoritarianism and anomia is used to illustrate the approach. PMID- 22486577 TI - Endogenous galectin-3 controls experimental malaria in a species-specific manner. AB - Galectins are evolutionarily conserved glycan-binding proteins with pleiotropic roles in innate and adaptive immune responses. Galectin-3 has been implicated in several immunological processes as well as in pathogen recognition through specific binding to glycosylated receptors on the surface of host cells or microorganisms. In spite of considerable evidence supporting a role for galectin 3 in host-pathogen interactions, the relevance of this lectin in the regulation of the host defence mechanisms in vivo is poorly understood. In this study, we analysed the impact of galectin-3 deficiency during infection with three distinct species of rodent malaria parasites, Plasmodium yoelii 17XNL, Plasmodium berghei ANKA and Plasmodium chabaudi AS. We found that galectin-3 deficiency showed a marginal effect on the course of parasitaemia during P. chabaudi infection, but did not alter the course of parasitaemia during P. berghei infection. However, lack of galectin-3 significantly reduced P. yoelii parasitaemia. This reduced parasitaemia in Lgals3(-/-) mice was consistent with higher titres of anti-P. yoelii MSP1(19) IgG2b isotype antibodies when compared with their wild-type counterparts. Our results reflect the complexity and singularity of host-pathogen interactions, indicating a species-specific role of endogenous galectin-3 in the control of parasite infections and the modulation of antibody responses. PMID- 22486578 TI - The age-dependence of atrial arrhythmogenicity in Scn5a+/- murine hearts reflects alterations in action potential propagation and recovery. AB - 1. In the present study, we investigated the effect of age on atrial electrophysiological properties in Scn5a(+/-) hearts used to model corresponding increases in atrial arrhythmic tendency in human Brugada syndrome. 2. Atrial action potential initiation, propagation and recovery were compared in young (3 month old) and aged (12 month old), wild-type (WT) and Scn5a(+/-) hearts. Multielectrode array recordings assessed the spatial propagation of intrinsic electrical activity in superfused atrial preparations, whereas bipolar electrogram recordings measured basic cycle lengths (BCL) in Langendorff preparations. The duration of electrogram activity (EGD) during regular and extrasystolic stimulation with programmed electrical stimulation provided EGD ratios and atrial effective refractory periods (AERP). Monophasic recordings measured action potential durations (APD). 3. Systematic statistical explorations for independent and interacting effects of age and the Scn5a(+/-) condition demonstrated that both young and aged Scn5a(+/-) mice exhibited slowed propagation of atrial excitation relative to corresponding WT mice, with the greatest effects in aged Scn5a(+/-) mice, which additionally exhibited increased intrinsic BCL. 4. Young Scn5a(+/-) mice exhibited greater EGD and EGD ratios, as well as APD/AERP ratios, suggesting increased arrhythmic tendency compared with WT mice. 5. Aged Scn5a(+/-) mice exhibited normal EGD, EGD ratios and APD compared to aged WT and young Scn5a(+/-), and increased AERP and smaller APD/AERP ratios compared with young Scn5a(+/-). 6. These electrophysiological findings indicate increased atrial arrhythmogenicity with maximal effects on both conduction and repolarization characteristics in young compared with aged Scn5a(+/-) mice. PMID- 22486579 TI - Systematic review: the burden of disruptive gastro-oesophageal reflux disease on health-related quality of life. AB - BACKGROUND: About one-third of patients with gastro-oesophageal reflux disease (GERD) have frequent and/or severe reflux symptoms ('disruptive GERD'). The relative burden of disruptive GERD on health-related quality of life (HRQL) has not been systematically investigated. AIM: To assess the burden of disruptive vs. nondisruptive GERD on HRQL. METHODS: Systematic searches were conducted in PubMed and Embase. To be included, studies had to have used validated questionnaires to assess HRQL. RESULTS: Nineteen studies were included. Data on the comparative burden of frequent (ranging from daily to >=weekly) and severe reflux symptoms were provided in eight and 13 studies respectively; six reported on the additional burden of nocturnal symptoms. Compared with individuals with nondisruptive GERD, those with disruptive GERD had 2.4-times and 1.5-times higher mean rates of absenteeism and presenteeism respectively (five studies), 1.5-times lower sleep quality scores (three studies), 1.1-times lower mean summary scores for physical and mental health (five studies) and 1.3-times lower mean scores for psychological and general well-being (four studies). Increasing symptom frequency and severity both increased the burden of disease to a similar extent. The presence of nocturnal symptoms in addition to daytime symptoms led to worsening of physical health, but their effect on mental health and work productivity was less clear. CONCLUSIONS: Disruptive GERD is associated with a high burden of disease compared with occasional or mild reflux symptoms. Disease management needs to vary across the GERD spectrum and should be tailored to patients' requirements for optimal therapeutic outcomes. PMID- 22486580 TI - Antidepressant monotherapy compared with combinations of antidepressants in the treatment of resistant depressive patients: a randomized, open-label study. AB - OBJECTIVE: This randomized, 6-week, open-label study compared efficacy of CAD and antidepressant monotherapies (ADM) that had been chosen according to clinical judgment of the attending psychiatrist. METHODS: A total of 60 inpatients (intent to-treat analysis) with depressive disorder (>= 1 unsuccessful antidepressant treatment) were randomly assigned to the interventions. The responders who completed the acute phase of study, were evaluated for relapse within 2 months of follow-up treatment. The primary outcome measure was change in the Montgomery Asberg Depression Rating Scale (MADRS) and response was defined as a >= 50% reduction of MADRS score. RESULTS: Mean changes in total MADRS score from baseline to week 6 for patients in both treatment modalities were not different (ADM = 13.2 +/- 8.6 points; CAD = 14.5 +/- 9.5 points; P = 0.58). The analysis of covariance performed for significantly higher value of imipramine equivalent dose in CAD group showed only a non-significant between-group difference for total MADRS change (P = 0.17). There were also no differences between groups in response rate (ADM = 48%; CAD = 58%) and number of drop-outs in acute treatment as well as proportion of responders' relapses in the follow-up. CONCLUSION: Both treatment modalities produced clinically relevant reduction of depressive symptomatology in acute treatment of patients with resistant depression and their effect was comparable. PMID- 22486581 TI - Prevalence of adult attention deficit hyperactivity disorder in the relatives of patients with bipolar disorder. AB - OBJECTIVE: We hypothesized that relatives of bipolar patients would have increased rate of attention deficit hyperactivity disorder (ADHD) and subsyndromal manifestations compared to demographically matched relatives of healthy controls. METHOD: Forty consecutive patients with bipolar disorder were recruited from inpatient and outpatient units of Sisli Etfal Teaching and Research Hospital, Psychiatry Department. Seventy-three first-degree relatives of bipolar disorder group were included. A control group of first-degree relatives of individuals without DSM-IV Axis I psychopathology were also recruited. The Turkish version of the Structural Clinical Interview for DSM-IV, Wender Utah Rating Scale, Turgay's Adult ADD/ADHD DSM-IV based Diagnostic and Rating Scale were administered to participants. RESULTS: Overall rate of adult ADHD in RBD group was significantly higher than RC group (9.6 vs. 1.5%; P = 0.04). Participants with adult ADHD in the RBD group had significantly higher rate of alcohol abuse compared to those without adult ADHD (14.3 vs. 1.5%; P = 0.05). Rates of OCD and dysthimia were significantly higher in the subjects with ADHD in the RBD group than the subjects without ADHD (28.6 vs. 4.5%; P = 0.02, 14.3 vs. 1.5%; P = 0.05 respectively). CONCLUSION: Our findings indicate that relatives of bipolar patients have a risk for suffering from ADHD, and support the hypothesis that relatives of bipolar patients are at a risk for developing attentional and behavioral problems. PMID- 22486582 TI - A new labdane diterpene from Vitex negundo. AB - CONTEXT: Vitex negundo Linn. (Verbenaceae) seeds are pepper substitute and occasionally used as a condiment for edible purposes. The seeds also find use for analgesia, sedation, rheumatism and joint inflammation in folk medicine. OBJECTIVE: To isolate and characterize bioactive constituents from V. negundo seeds. MATERIALS AND METHODS: The ethanol extract of V. negundo seeds was subjected to repeated column chromatography. Chemical structures were elucidated by detailed spectroscopic analyses on the basis of NMR, IR, and MS data. Several pathogenic fungi isolates were employed to evaluate the antifungal activity of the isolated compound. RESULTS: Chemical investigations of the seed extract afforded a new labdane diterpenoid, named negundol (1a + 1b), as an inseparable mixture of two diastereoisomers in a 5:4 ratio. Their structures were identified as (rel 3S, 5S, 8R, 9R, 10S, 13S, 16S)-3-acetoxy-9, 13-epoxy-16-hydroxy-labda-15, 16-olide (1a), and (rel 3S, 5S, 8R, 9R, 10S, 13S, 16R)-3-acetoxy-9, 13-epoxy-16 hydroxy-labda-15, 16-olide (1b). Compound 1 was active as an antifungal agent with MIC80 values in the range of 16-64 MUg/mL. DISCUSSION AND CONCLUSION: The presence of compound 1 in V. negundo is of chemotaxonomic significance, since plants under the genus Vitex are chemically characterized with labdane diterpenoids. Compound 1 exhibited potential antifungal activity and may be considered a lead compound for promising antifungal agent. PMID- 22486583 TI - Primary sources and secondary formation of organic aerosols in Beijing, China. AB - Ambient aerosol samples were collected at an urban site and an upwind rural site of Beijing during the CAREBEIJING-2008 (Campaigns of Air quality REsearch in BEIJING and surrounding region) summer field campaign. Contributions of primary particles and secondary organic aerosols (SOA) were estimated by chemical mass balance (CMB) modeling and tracer-yield method. The apportioned primary and secondary sources explain 73.8% +/- 9.7% and 79.6% +/- 10.1% of the measured OC at the urban and rural sites, respectively. Secondary organic carbon (SOC) contributes to 32.5 +/- 15.9% of the organic carbon (OC) at the urban site, with 17.4 +/- 7.6% from toluene, 9.7 +/- 5.4% from isoprene, 5.1 +/- 2.0% from alpha pinene, and 2.3 +/- 1.7% from beta-caryophyllene. At the rural site, the secondary sources are responsible for 38.4 +/- 14.4% of the OC, with the contributions of 17.3 +/- 6.9%, 13.9 +/- 9.1%, 5.6 +/- 1.9%, and 1.7 +/- 1.0% from toluene, isoprene, alpha-pinene, and beta-caryophyllene, respectively. Compared with other regions in the world, SOA in Beijing is less aged, but the concentrations are much higher; between the sites, SOA is more aged and affected by regional transport at the urban site. The high SOA loading in Beijing is probably attributed to the high regional SOC background (~2 MUg m(-3)). The toluene SOC concentration is high and comparable at the two sites, implying that some anthropogenic components, at least toluene SOA, are widespread in Beijing and represents a major factor in affecting the regional air quality. The aerosol gaseous precursor concentrations and temperature correlate well with SOA, both affecting SOA formation. The significant SOA enhancement with increasing water uptake and acidification indicates that the aqueous-phase reactions are largely responsible SOA formation in Beijing. PMID- 22486584 TI - Physical exercise through mountain hiking in high-risk suicide patients. A randomized crossover trial. AB - OBJECTIVE: The following crossover pilot study attempts to prove the effects of endurance training through mountain hiking in high-risk suicide patients. METHOD: Participants (n = 20) having attempted suicide at least once and clinically diagnosed with hopelessness were randomly distributed among two groups. Group 1 (n = 10) began with a 9-week hiking phase followed by a 9-week control phase. Group 2 (n = 10) worked vice versa. Assessments included the Beck Hopelessness Scale (BHS), Beck Depression Inventory (BDI), Beck Scale of Suicide Ideation (BSI), and maximum physical endurance. RESULTS: Ten participants of Group 1 and seven participants of Group 2 completed the study. A comparison between conditions showed that, in the hiking phase, there was a significant decrease in hopelessness (P < 0.0001, d = -1.4) and depression (P < 0.0001, d = -1.38), and a significant increase in physical endurance (P < 0.0001, d = 1.0), but no significant effect for suicide ideation (P = 0.25, d = -0.29). However, within the hiking phase, there was a significant decrease in suicide ideation (P = 0.005, d = -0.79). CONCLUSION: The results suggest that a group experience of regular monitored mountain hiking, organized as an add-on therapy to usual care, is associated with an improvement of hopelessness, depression, and suicide ideation in patients suffering from high-level suicide risk. PMID- 22486585 TI - CCR5-targeted hematopoietic stem cell gene approaches for HIV disease: current progress and future prospects. AB - Despite substantial progress that has been made in understanding many aspects regarding biology and pathogenesis of human immunodeficiency virus type 1 (HIV 1), there is currently no vaccine or curative treatment available. HIV-1 continues to be a major global health problem. In this regard, new strategies are required for promoting a complete immune reconstitution and eradicating the virus from the body. The rationale for the use of hematopoietic stem cell (HSC)-based gene therapy against HIV infection is that, after transplantation, genetically modified HSCs carrying anti-HIV transgenes would engraft, divide and differentiate into large numbers of mature myeloid and lymphoid cells that express antiviral genes and thus are protected from HIV invasion or productive replication. HIV-1 attachment to susceptible cells involves binding of gp120 to CD4 receptor and subsequently to a HIV co-receptor, either CCR5 or CXCR4. The pivotal role of CCR5 in HIV-1 acquisition and disease progression has been established by the discovery of a naturally occurring 32-bp deletion in CCR5 (CCR5Delta 32) which generates a nonfunctional gene product. Homozygosity for CCR5Delta32 confers profound resistance against HIV infection, and heterozygous mutation that induces a decrease in CCR5 surface expression is associated with lower plasma viral load and delayed progression to acquired immune deficiency syndrome (AIDS). This, together with the fact of R5 dominance during the acute and asymptomatic phase, suggests that CCR5 is an attractive target for HIV gene therapeutics. The present review addresses recent advances of CCR5-targeted HSC gene approaches to treat HIV infection, discusses the future prospects and postulates potential strategies in the field. PMID- 22486586 TI - Is there sufficient evidence to consider the use of 11beta-hydroxysteroid dehydrogenase type 1 inhibition in children? AB - Manifestations of the metabolic syndrome [obesity, dyslipidaemia, hypertension, blood glucose derangements including prediabetes or type 2 diabetes mellitus (T2DM)] in juvenile populations are becoming increasingly prevalent throughout the world and are at the point of being a global public health concern. Derangements in cortisol regeneration seem to be involved in the pathophysiology. Treatment with selective 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) inhibitors could be a therapeutic strategy in paediatric patients with manifestations of the metabolic syndrome. Based on preclinical and clinical data regarding development of the 11beta-HSD1 enzyme, it appears that maturation occurs within the first year of life. Different changes in biomarkers for assessing the efficacy and safety of 11beta-HSD1 inhibitors are to be expected in paediatric patients compared to adults, reflecting differences in metabolism. The effect of 11beta-HSD1 treatment in children on bone differentiation and development as well as adrenocorticotropic hormone (ACTH), circulating and local cortisol tissue concentrations, androgens and respective stress response is not yet known. Based on current literature, the concept of inhibition of 11beta-HSD1 is considered a potentially effective mean to regulate local cortisol levels in the paediatric population, and 11beta-HSD1 inhibitors may provide a valuable target and treatment option for the metabolic syndrome in paediatric patients. However, the uncertainty over effects on the developing skeleton combined with mild increases in adrenal androgen levels raises potential concerns regarding growth as well as onset of puberty as to their future use in children. Future clinical studies are needed to thoroughly assess the risks and benefits of this new class of drugs in the paediatric population. PMID- 22486587 TI - The Pyramid Trough Wetland: environmental and biological diversity in a newly created Antarctic protected area. AB - The Pyramid Trough (Lat 78 degrees S) has recently gained protection under the Antarctic Treaty system, owing to its wetland values. Here, we describe the microbial diversity of this system, with emphasis on cyanobacteria, and evaluate environment-biota relationships. Geochemistry separates ponds along hydrological gradients receiving recent inflows of dilute meltwater, from a second group that is rarely inundated and where chemistry is dominated by evaporation. Cyanobacteria-based microbial mats dominated the biota throughout. Mats were characterized by light-microscopy, pigment analysis, automated ribosomal intergenic spacer analysis and 16S rRNA gene clone libraries. A total of 17 morphotypes and 21 ribotypes were identified, mostly Oscillatoriales and several taxa that are usually rare in continental Antarctica, including Chroococcales and scytomin-rich Calothrix/Dichothrix, were abundant. There was a general decline in cyanobacterial diversity with increasing conductivity, but weak support for either differences in community composition between the two groups of ponds or sorting of taxa along the hydrological gradients with the pond groups. This implies a broad environmental tolerance and a prevalence of neutral assembly mechanisms in cyanobacterial communities of Antarctic wetland ecosystems. PMID- 22486588 TI - Effect of the attachment of a penetration accelerating sequence and the influence of hydrophobicity on octaarginine-mediated intracellular delivery. AB - Arginine-rich cell-penetrating peptides (CPPs), including oligoarginine peptides, have been widely used as a tool for intracellular delivery of various molecules with low membrane permeability. We previously reported the enhanced cytosolic entry of arginine-rich CPPs by the attachment of a short peptide segment, the penetration accelerating sequence (Pas). In this study, the importance of hydrophobic sequences, especially phenylalanine residues, in the Pas segment was demonstrated for this enhanced translocation through cell membranes. The advantage of using Pas for intracellular delivery was particularly marked for delivering cargoes with a relatively small molecular weight, such as bioactive peptides. In addition, the results of this study indicate the important roles that the total hydrophobicity of the PasR8 conjugates play in cytosolic translocation and the eventual bioactivity thus attained. PMID- 22486590 TI - A case of severe mitral regurgitation due to an unusually long aberrant chorda tendinea straddling the anterior mitral leaflet. AB - We present a case of a 27-year-old female with severe mitral regurgitation caused by a single long aberrant chorda tendinea. This chorda extended from the base of the right coronary cusp of the aortic valve, through the A2 scallop of the mitral valve, and attached to the dome of the left atrium. Initial transthoracic echocardiogram (TTE) demonstrated a mildly redundant anterior mitral leaflet with thickened leaflet tip and moderate eccentric, posteriorly directed mitral regurgitation. Repeat TTE revealed a chord-like structure attached to the midportion of the anterior mitral leaflet and extending to the left ventricular outflow tract. Transesophageal echocardiography (TEE) suggested two aberrant chordae tendineae tethering the A2 scallop on both the left atrial and left ventricular side. Patient underwent surgical resection of the aberrant chorda. During the excision of the chorda the structural integrity of the A2 scallop was compromised, necessitating mitral valve repair with excellent results. PMID- 22486589 TI - Ethanol metabolism and osmolarity modify behavioral responses to ethanol in C. elegans. AB - BACKGROUND: Ethanol (EtOH) is metabolized by a 2-step process in which alcohol dehydrogenase (ADH) oxidizes EtOH to acetaldehyde, which is further oxidized to acetate by aldehyde dehydrogenase (ALDH). Although variation in EtOH metabolism in humans strongly influences the propensity to chronically abuse alcohol, few data exist on the behavioral effects of altered EtOH metabolism. Here, we used the nematode Caenorhabditis elegans to directly examine how changes in EtOH metabolism alter behavioral responses to alcohol during an acute exposure. Additionally, we investigated EtOH solution osmolarity as a potential explanation for contrasting published data on C. elegans EtOH sensitivity. METHODS: We developed a gas chromatography assay and validated a spectrophotometric method to measure internal EtOH in EtOH-exposed worms. Further, we tested the effects of mutations in ADH and ALDH genes on EtOH tissue accumulation and behavioral sensitivity to the drug. Finally, we tested the effects of EtOH solution osmolarity on behavioral responses and tissue EtOH accumulation. RESULTS: Only a small amount of exogenously applied EtOH accumulated in the tissues of C. elegans and consequently their tissue concentrations were similar to those that intoxicate humans. Independent inactivation of an ADH-encoding gene (sodh-1) or an ALDH-encoding gene (alh-6 or alh-13) increased the EtOH concentration in worms and caused hypersensitivity to the acute sedative effects of EtOH on locomotion. We also found that the sensitivity to the depressive effects of EtOH on locomotion is strongly influenced by the osmolarity of the exogenous EtOH solution. CONCLUSIONS: Our results indicate that EtOH metabolism via ADH and ALDH has a statistically discernable but surprisingly minor influence on EtOH sedation and internal EtOH accumulation in worms. In contrast, the osmolarity of the medium in which EtOH is delivered to the animals has a more substantial effect on the observed sensitivity to EtOH. PMID- 22486591 TI - Derivation of the short form of the Oral Health Impact Profile in Spanish (OHIP EE-14). AB - BACKGROUND AND OBJECTIVE: The Oral Health Impact Profile is the most frequently used and validated of the Oral Health Quality of Life instruments. Several short versions have been developed; and a validation of the OHIP-49 in Spanish has been published. The objective was to develop the short version of the Oral Health Impact Profile in Spanish (OHIP-EE-14). METHODS: Cross-sectional study. One hundred and thirty-one persons aged >=60 years attending a social centre for the elderly, residents of a nursing home and persons seeking dental care at a dental school in Mexico City were interviewed and examined. The validity of each of the 49 questions was evaluated, and, to construct the short version, 14 items were selected. The perceived need for dental treatment, number of teeth, presence of coronal caries, root caries, presence of dental plaque and utilisation of removable prosthesis were measured. Internal consistency, repeatability and discriminant validity were calculated. RESULTS: The OHIP-EE-14 was reliable (Cronbach's-alpha = 0.918, ICC = 0.825). Significant associations were found between OHIP-EE-14 and the number of teeth and perceived need for dental treatment. CONCLUSIONS: The OHIP-EE-14 is a reliable and valid instrument and can be used in subjects aged 60 years and over from Mexico City. PMID- 22486592 TI - Contact sensitization to tree moss (Evernia furfuracea extract, INCI) is heterogeneous. AB - BACKGROUND: Evernia prunastri (oak moss) and Evernia furfuracea (tree moss) are lichens from which natural extracts are obtained. OBJECTIVES: To identify possible subgroups of E. furfuracea-sensitized patients according to whether these are allergic to lichen components or to contaminants. METHODS: A retrospective analysis was performed of surveillance data collected by the Information Network of Departments of Dermatology (www.ivkd.org) in 2003-2010 with oak moss absolute (1% pet.), tree moss absolute (1% pet.), and colophonium (colophony, 20% pet.). RESULTS: In total, 3030 patients had been tested with all three allergens. Positive reactions to E. furfuracea were observed in 6.37%, to E. prunastri in 5.71%, and to colophonium in 4.82%. Concordance between positive reactions to E. prunastri and E. furfuracea was good only in patients not co sensitized to colophonium (Cohen's kappa = 0.681, 95% confidence interval 0.615 0.746). Moreover, E. furfuracea-sensitized patients showed (strong or extreme) concomitant reactions to colophonium significantly more often if not co sensitized to E. prunastri. CONCLUSIONS: Two subgroups of E. furfuracea sensitized patients are identifiable: (i) those with sensitization to (oxidized) resin acids, as indicated by positive patch test reactions also to colophonium, and (ii) those non-sensitized to resin acids, but sensitized to common constituents of E. prunastri and E. furfuracea. PMID- 22486594 TI - Nanotopography influences adhesion, spreading, and self-renewal of human embryonic stem cells. AB - Human embryonic stem cells (hESCs) have great potentials for future cell-based therapeutics. However, their mechanosensitivity to biophysical signals from the cellular microenvironment is not well characterized. Here we introduced an effective microfabrication strategy for accurate control and patterning of nanoroughness on glass surfaces. Our results demonstrated that nanotopography could provide a potent regulatory signal over different hESC behaviors, including cell morphology, adhesion, proliferation, clonal expansion, and self-renewal. Our results indicated that topological sensing of hESCs might include feedback regulation involving mechanosensory integrin-mediated cell-matrix adhesion, myosin II, and E-cadherin. Our results also demonstrated that cellular responses to nanotopography were cell-type specific, and as such, we could generate a spatially segregated coculture system for hESCs and NIH/3T3 fibroblasts using patterned nanorough glass surfaces. PMID- 22486595 TI - The Believability of Anxious Feelings and Thoughts Questionnaire (BAFT): a psychometric evaluation of cognitive fusion in a nonclinical and highly anxious community sample. AB - Cognitive fusion--or the tendency to buy into the literal meaning of thoughts, feelings, and bodily sensations--plays an important role in the etiology and maintenance of anxiety disorders and figures prominently in third-generation behavior therapies such as acceptance and commitment therapy (ACT). Nonetheless, there is a lack of validated self-report measures of cognitive fusion/defusion, particularly in the area of anxiety disorders. We attempted to fill this gap with the development and validation of a self-report cognitive fusion measure, the Believability of Anxious Feelings and Thoughts Questionnaire (BAFT), in both a healthy undergraduate sample (N = 432) and highly anxious community sample (N = 503) undergoing a 12-week online ACT intervention. Results suggested a hierarchical factor structure of the BAFT with three lower order factors and one hierarchical factor and excellent internal consistency for the total BAFT score (i.e., alphas = .90 and .91 for the undergraduate and highly anxious samples, respectively) and for its factors. Additionally, the BAFT and all of its factors consistently showed strong construct validity with other relevant process and outcome measures in both samples, strong 12-week test-retest reliability (r = .77) in our highly anxious waitlist control subsample and responsiveness to treatment in our highly anxious intervention subsample. These findings suggest that the BAFT is a reliable and valid measure of cognitive fusion in both healthy and clinical populations. PMID- 22486597 TI - A randomized, placebo-controlled trial of aripiprazole for the treatment of methamphetamine dependence and associated psychosis. AB - OBJECTIVES: The objectives of this study were to determine the efficacy and safety of aripiprazole for treatment of psychosis, retention and abstinence in patients with methamphetamine dependence. METHODS: This was a double-blind study where 37 methamphetamine dependent patients with history of psychosis were randomly assigned to receive aripiprazole (5-10 mg daily, N = 19) or placebo (N = 18) for 8 weeks. Follow-up evaluation was scheduled on day 7, 14, 28, 42 day 56 after enrolment. RESULTS: Participants on aripiprazole were retained significantly longer in treatment (48.7 days, SD =4.0) compared to placebo (37.1 days, SD =5.0). The Kaplan-Meier survival analysis showed that participants on aripiprazole were less likely to drop out of the study than the placebo group (P =0.02, chi(2) =5.3). Psychotic symptoms significantly decreased among those on aripiprazole as compared to placebo (P < 0.05). However, no statistically significance was found between the two groups in maintaining abstinence (generalised estimation equation (GEE) analysis, P = 0.41). No serious adverse events were reported in either group. CONCLUSION: Aripiprazole was no more effective than placebo in maintaining abstinence from methamphetamine use. However, it facilitated treatment retention and reduced the severity of psychotic symptoms. Aripiprazole was found to be generally safe and well tolerated. PMID- 22486596 TI - CD36 modulates proinflammatory cytokine responses to Plasmodium falciparum glycosylphosphatidylinositols and merozoites by dendritic cells. AB - Studies have shown that glycosylphosphatidylinositols (GPIs) of Plasmodium falciparum activate macrophages mainly through Toll-like receptor 2 (TLR2) mediated signalling and to certain extent through TLR4-mediated signalling to induce proinflammatory cytokine production. However, the ability of parasite GPIs to activate dendritic cells (DCs) has not been reported. Here, we show that parasite GPIs efficiently activate DCs through TLR2-mediated signalling mechanism and induce the production of TNF-alpha and IL-12. We also studied the role of scavenger receptor CD36 in P. falciparum GPI- and merozoite-induced cytokine responses by DCs. The results indicate that CD36 modulates the cytokine-inducing activity of the parasite GPIs by collaborating with TLR2 in DCs. Furthermore, our data reveal that CD36 modulates the activity of P. falciparum merozoites, likely by the contribution of phagocytosis-coupled CD36-mediated signalling to the signalling induced by merozoites. Altogether, these results contribute towards understanding of signalling mechanisms in malaria parasite-induced activation of the innate immune system. PMID- 22486598 TI - Exploiting modern cannabinoid pharmacology for therapeutic gain? PMID- 22486599 TI - A new taxonomy for describing and defining adherence to medications. AB - Interest in patient adherence has increased in recent years, with a growing literature that shows the pervasiveness of poor adherence to appropriately prescribed medications. However, four decades of adherence research has not resulted in uniformity in the terminology used to describe deviations from prescribed therapies. The aim of this review was to propose a new taxonomy, in which adherence to medications is conceptualized, based on behavioural and pharmacological science, and which will support quantifiable parameters. A systematic literature review was performed using MEDLINE, EMBASE, CINAHL, the Cochrane Library and PsycINFO from database inception to 1 April 2009. The objective was to identify the different conceptual approaches to adherence research. Definitions were analyzed according to time and methodological perspectives. A taxonomic approach was subsequently derived, evaluated and discussed with international experts. More than 10 different terms describing medication-taking behaviour were identified through the literature review, often with differing meanings. The conceptual foundation for a new, transparent taxonomy relies on three elements, which make a clear distinction between processes that describe actions through established routines ('Adherence to medications', 'Management of adherence') and the discipline that studies those processes ('Adherence-related sciences'). 'Adherence to medications' is the process by which patients take their medication as prescribed, further divided into three quantifiable phases: 'Initiation', 'Implementation' and 'Discontinuation'. In response to the proliferation of ambiguous or unquantifiable terms in the literature on medication adherence, this research has resulted in a new conceptual foundation for a transparent taxonomy. The terms and definitions are focused on promoting consistency and quantification in terminology and methods to aid in the conduct, analysis and interpretation of scientific studies of medication adherence. PMID- 22486600 TI - Multifactorial pharmacogenetic analysis in colorectal cancer patients receiving 5 fluorouracil-based therapy together with cetuximab-irinotecan. AB - AIM: To examine the predictive value of gene polymorphisms potentially linked to toxicity, clinical response, time to progression and overall survival, following cetuximab-tegafur-uracil (UFT)-irinotecan therapy. METHODS: Fifty-two patients with advanced colorectal cancer were enrolled in an ancillary pharmacogenetic study of the phase II CETUFTIRI trial. Treatment consisted of 21 day cycles of cetuximab (day 1-day 8-day 15, 250 mg m(-2) week(-1) following a 400 mg m(-2) initial dose) together with irinotecan (day 1, 250 mg m(-2)) and UFT-folinic acid (days 1-14, 250 mg m(-2) day(-1) UFT, 90 mg day(-1) folinic acid). Analysed gene polymorphisms (blood DNA) were as follows: EGFR (CA repeats in intron 1, -216G>T, -191C>A), EGF (61A>G), FCGR2A (131Arg>His), FCGR3A (158Phe>Val), UDP glycosyltransferase1-polypeptide A1 (TA repeats), TYMS (28 bp repeats, including the G>C mutation on the 3R allele, 6 bp deletion in 3' UTR) and MTHFR (677C>T, 1298A>C). RESULTS: Maximum toxicity grade was linked to EGFR-191C>A polymorphism, with 71.1% grade 3-4 toxicity in CC patients vs. 28.6% in other patients (P= 0.010). A tendency to a better response was observed in patients bearing the TYMS 3RG allele (P= 0.029) and those bearing the FCGR3A 158Val genotype (P= 0.020). The greater the score of favourable TYMS and FCGR3A genotypes, the better the response rate (P= 0.009) and the longer the overall survival (P= 0.007). In multivariate analysis, the score of favourable genotypes was a stronger survival predictor than the performance status. CONCLUSIONS: Present data suggest the importance of FCGR3A 158Phe>Val and TYMS 5' UTR polymorphisms in responsiveness and survival of patients receiving cetuximab-fluoropyrimidine-based therapy. PMID- 22486601 TI - Dose-response relationship between selective serotonin re-uptake inhibitors and injurious falls: a study in nursing home residents with dementia. AB - AIM: The contribution of selective serotonin re-uptake inhibitors (SSRIs) to injurious fall risk in patients with dementia has not been quantified precisely until now. Our objective was to determine whether a dose-response relationship exists for the use of SSRIs and injurious falls in a population of nursing home residents with dementia. METHODS: Daily drug use and daily falls were recorded in 248 nursing home residents with dementia from 1 January 2006 until 1 January 2008. For each resident and for each day of the study period, data on drug use were abstracted from the prescription database, and information on falls and subsequent injuries was retrieved from a standardized incident report system, resulting in a dataset of 85,074 person-days. RESULTS: We found a significant dose-response relationship between injurious falls and the use of SSRIs. The risk of an injurious fall increased significantly with 31% at 0.25 of the Defined Daily Dose (DDD) of a SSRI, 73% at 0.50 DDD, and 198% at 1.00 DDD (Hazard ratio = 2.98; 95% confidence interval 1.94, 4.57). The risk increased further in combination with a hypnotic or sedative. CONCLUSIONS: Even at low doses, SSRIs are associated with increased risk of an injurious fall in nursing home residents with dementia. Higher doses increase the risk further with a three-fold risk at 1.00 DDD. New treatment protocols might be needed that take into account the dose response relationship between SSRIs and injurious falls. PMID- 22486603 TI - Identifying outpatients with entrenched suicidal ideation following hospitalization. AB - The purpose of this study was to identify outpatients who experience entrenched suicidal ideation following inpatient psychiatric hospitalization. Our findings suggest that the use of a suicidal ambivalence index score was helpful at discriminating those who reported significantly greater ratings of suicidal ideation across a 1-year period of time, whereas splitting patients based upon suicide attempt history yielded nonsignificant results. Similar findings resulted from a dimensional analytic approach, as well. Application of the suicidal ambivalence index may help administrators identify patients who require more intensive clinical services to resolve their suicidal ideation. PMID- 22486604 TI - Rates and correlates of undetermined deaths among African Americans: results from the National Violent Death Reporting System. AB - Little is known about the factors associated with undetermined death classifications among African Americans. In this study, the rates of undetermined deaths were assessed, the prevalence of missing information was estimated, and whether the circumstances preceding death differ by race were examined. Data were derived from the 2005-2008 National Violent Death Reporting System. African Americans had higher prevalence of missing information than Whites. African Americans classified as undetermined deaths were more likely to be older, women, never married/single, to have had a blood alcohol content at or above the legal limit, and to have had a substance abuse problem. The results suggest that racial differences in the preponderance and the type of evidence surrounding the death may affect death classification. PMID- 22486605 TI - Nonsuicidal self-injury: relationship to behavioral and self-rating measures of impulsivity and self-aggression. AB - Previous research using self-report measures has shown an association between nonsuicidal self-injurious behavior (NSSI) and impulsive tendencies. However, self-injurers have not been shown to be different from comparison groups on laboratory tasks putatively assessing impulsive behavior. One explanation for these contradictory findings is that self-report and laboratory measures of impulsive behavior tap into distinct but related constructs. Moreover, performance on laboratory measures of impulsive behavior can be influenced by myriad contextual and affective factors not present during past self-reported NSSI events. Accordingly, a relationship between behavioral tasks of impulsivity and self-injurious behavior could emerge if both are assessed relatively close in time under controlled laboratory conditions. To test this possibility, both self ratings and laboratory task measures of self-injurious and impulsive behavior were employed in the current study. This multi-modal assessment approach revealed that self-rated impulsivity was associated with both self-report and behavioral measures of self-injurious behavior. Moreover, behavioral measures of impulsivity were associated with self-injurious behavior, but not NSSI history. These results provide support for the notion that a multi-modal approach to assessing self injurious behavior is important for better understanding the correlates of nonsuicidal self-injury. PMID- 22486606 TI - Linking quantitative microbial risk assessment and epidemiological data: informing safe drinking water trials in developing countries. AB - Intervention trials are used extensively to assess household water treatment (HWT) device efficacy against diarrheal disease in developing countries. Using these data for policy, however, requires addressing issues of generalizability (relevance of one trial in other contexts) and systematic bias associated with design and conduct of a study. To illustrate how quantitative microbial risk assessment (QMRA) can address water safety and health issues, we analyzed a published randomized controlled trial (RCT) of the LifeStraw Family Filter in the Congo. The model accounted for bias due to (1) incomplete compliance with filtration, (2) unexpected antimicrobial activity by the placebo device, and (3) incomplete recall of diarrheal disease. Effectiveness was measured using the longitudinal prevalence ratio (LPR) of reported diarrhea. The Congo RCT observed an LPR of 0.84 (95% CI: 0.61, 1.14). Our model predicted LPRs, assuming a perfect placebo, ranging from 0.50 (2.5-97.5 percentile: 0.33, 0.77) to 0.86 (2.5-97.5 percentile: 0.68, 1.09) for high (but not perfect) and low (but not zero) compliance, respectively. The calibration step provided estimates of the concentrations of three pathogen types (modeled as diarrheagenic E. coli, Giardia, and rotavirus) in drinking water, consistent with the longitudinal prevalence of reported diarrhea measured in the trial, and constrained by epidemiological data from the trial. Use of a QMRA model demonstrated the importance of compliance in HWT efficacy, the need for pathogen data from source waters, the effect of quantifying biases associated with epidemiological data, and the usefulness of generalizing the effectiveness of HWT trials to other contexts. PMID- 22486607 TI - Attitudes and perceptions towards substances among people with mental disorders: a systematic review. AB - OBJECTIVE: To develop effective interventions for people with coexisting mental disorders (MD) and substance use, it may be beneficial to understand their attitudes and perceptions of substances. METHOD: A systematic literature search regarding attitudes and perceptions towards tobacco, alcohol or cannabis among people with MD was conducted. Studies' methodological quality was assessed using the Newcastle-Ottawa Scale. RESULTS: Twenty-one papers were included in the review and found to have generally low methodological quality. Papers investigated reasons for substance use, substance use expectancies, substances' perceived effects and reasons for quitting. People with psychotic disorders reported using substances primarily for relaxation and pleasure. Among people with mood disorders, alcohol was used primarily for social motives and tobacco for negative affect reduction. CONCLUSION: For substance use interventions among people with MD to be more effective, it may be necessary to tailor interventions specifically for this population and customize by substance type. Gaps in the literature regarding attitudes and perceptions towards substance use among people with MD were identified, which future research should aim to address. These include designing and conducting methodologically rigorous research, investigating perceived harmfulness and knowledge of substances, and broadening recruitment of participants to include people with MD other than psychosis. PMID- 22486608 TI - Comparative genomic and physiological analysis provides insights into the role of Acidobacteria in organic carbon utilization in Arctic tundra soils. AB - Acidobacteria are among the most abundant bacterial phyla found in terrestrial ecosystems, but relatively little is known about their diversity, distribution and most critically, their function. Understanding the functional activities encoded in their genomes will provide insights into their ecological roles. Here we describe the genomes of three novel cold-adapted strains of subdivision 1 Acidobacteria. The genomes consist of a circular chromosome of 6.2 Mbp for Granulicella mallensis MP5ACTX8, 4.3 Mbp for Granulicella tundricola MP5ACTX9, and 5.0 Mbp for Terriglobus saanensis SP1PR4. In addition, G. tundricola has five mega plasmids for a total genome size of 5.5 Mbp. The three genomes showed an abundance of genes assigned to metabolism and transport of carbohydrates. In comparison to three mesophilic Acidobacteria, namely Acidobacterium capsulatum ATCC 51196, 'Candidatus Koribacter versatilis' Ellin345, and 'Candidatus Solibacter usitatus' Ellin6076, the genomes of the three tundra soil strains contained an abundance of conserved genes/gene clusters encoding for modules of the carbohydrate-active enzyme (CAZyme) family. Furthermore, a large number of glycoside hydrolases and glycosyl transferases were prevalent. We infer that gene content and biochemical mechanisms encoded in the genomes of three Arctic tundra soil Acidobacteria strains are shaped to allow for breakdown, utilization, and biosynthesis of diverse structural and storage polysaccharides and resilience to fluctuating temperatures and nutrient-deficient conditions in Arctic tundra soils. PMID- 22486610 TI - Saturation transfer difference NMR studies of the interaction of the proteinkinase CK2 with peptides. AB - Saturation Transfer Difference NMR (STD NMR) is used for the detection of the binding constant of the decapeptide RRRDDDSDDD with CK2alpha, the catalytic subunit of the proteinkinase CK2. For this work a valid irradiation frequency of the CK2alpha had to be found ensuring that no peptide resonance is affected by the irradiation. This is the principle problem for investigations of protein peptide interactions by STD NMR due to the similarity of protein and peptide resonances. It is shown that by careful selection of the irradiation point a KD value averaging to 1 mM can be found. In addition, preferred binding sites of the peptide are detected and it is shown that the side chains of serine and aspartate are closest to the protein surface. PMID- 22486611 TI - Cytokine production induced by marine algae lectins in BALB/c mice splenocytes. AB - Marine algae can serve as sources of bioactive compounds and currently have been shown their potential biological and pharmaceutical applications. Marine algae lectins have been shown to be effective at controlling inflammatory processes. This work aimed to analyze the immunostimulatory properties of lectins from the marine algae Solieria filiformis (SfL), Pterocladiella capillacea (PcL) and Caulerpa cupressoides (CcL). This analysis was performed on BALB/c mouse splenocytes by measuring cytokine and nitric oxide production and cellular damage using tests of cytotoxicity and cell viability. These lectins were not cytotoxic (1-100 MUg/mL), and were not able to induce IFN-gamma and IL-2 production. IL- 10 production was induced at high levels by all lectins tested. Treatment with SfL induced IL-6 production at higher levels at all experimental times, whereas treatment with PcL and CcL induced higher levels only in 24 and 72 h. Treatment with SfL did not result in nitrite oxide production, whereas treatment with PcL or CcL was able to induce nitrite release at high levels (after 24, 48 and 72 h). Lesser cellular damage (5%) was observed in splenocytes treated with these lectins (10 MUg/mL). Thus, the lectins from these algae were not cytotoxic, promoted increased in cell viability and induced Th2 immune responses in mouse splenocytes, indicating that they have anti-inflammatory effects. PMID- 22486609 TI - Development of an oral operant nicotine/ethanol co-use model in alcohol preferring (p) rats. AB - BACKGROUND: Alcohol abuse is frequently associated with nicotine (Nic) use. The current experiments were conducted to establish an oral operant ethanol + Nic (EtOH + Nic) co-use model and to characterize some aspects of EtOH + Nic co-use. METHODS: Rats were allowed to choose between EtOH alone or EtOH + Nic solutions. Additionally, alcohol-preferring (P) rats were allowed to concurrently self administer 3 distinct EtOH solutions (10, 20, and 30%) with varying amounts of Nic (0.07, 0.14, or 0.21 mg/ml) under operant conditions. P rats were also allowed to concurrently self-administer 2 distinct amounts of Nic (0.07 and 0.14 mg/ml) added to saccharin (Sacc; 0.025%) solutions. RESULTS: During acquisition, P rats responded for the EtOH + Nic solutions at the same level as for EtOH alone, and responding for EtOH + Nic solutions was present throughout all drinking conditions. P rats also readily maintained stable self-administration behaviors for Nic + Sacc solutions. The results demonstrated that P rats readily acquired and maintained stable self-administration behaviors for EtOH + 0.07 and EtOH + 0.14 mg/ml Nic solutions. Self-administration of EtOH + 0.21 mg/ml Nic was established in only 50% of the subjects. P rats readily expressed seeking behaviors for the EtOH + Nic solutions and reacquired EtOH + Nic self administration during relapse testing. In addition, tail blood samples indicated that EtOH + Nic co-use resulted in pharmacologically relevant levels of both EtOH and Nic in the blood. CONCLUSIONS: Overall, the results indicate that P rats readily consume EtOH + Nic solutions concurrently in the presence of EtOH alone, express drug-seeking behaviors, and will concurrently consume physiologically relevant levels of both drugs. These results support the idea that this oral operant EtOH + Nic co-use model would be suitable for studying the development of co-abuse and the consequences of long-term chronic co-abuse. PMID- 22486612 TI - Biophysical analysis of the transition of an all alpha-helical Greek-key protein into amyloid fibrils composed of beta-sheet structure. AB - Amyloidosis resulting from the deposition of aggregated protein has been linked to many debilitating degenerative diseases which include most notably Alzheimer's and Parkinson's. The tendency for a protein to alternatively form highly ordered amyloid fibrils is dependent on many biological factors. Mutations, temperature, concentration, translational motion and pH play a pivotal role in inducing fibril aggregate assembly in vitro. The key feature appears to be the need to destabilize the native state structure as a required first step. In this paper we report on the detailed conversion of the death domain of the human Fas-associated death domain, an all alpha-helical protein with a Greek-key topology, into an all beta-sheet amyloid fibril, using a comprehensive range of spectroscopic techniques that provide insight into this process. This transition from alpha helical to beta-sheet seems to require destabilization but not complete loss of the secondary structure to explore alternative conformations. This is a fascinating transition that supports the hypothesis that all proteins have the innate ability to form a fibril-like structure. Thus, the primary structure can encode two alternative three-dimensional structures: the native, functional state and the beta-amyloid state. The Fas-associated death domain does not appear to naturally form amyloid fibrils in vivo. Our results clearly indicate that proteins evolved to avoid amyloid fibril formation because we find that the conditions required for formation in our model system are very specific and far from physiological. PMID- 22486613 TI - Targeting the epidermal growth factor receptor: exploring the potential of novel inhibitor N-(3-ethynylphenyl)-6, 7-bis (2-methoxyethoxy) quinolin- 4-amine using docking and molecular dynamics simulation. AB - Head and neck squamous cell carcinoma (HNSCC) is a major cause of cancer related death. The epidermal growth factor receptor (EGFR) pathway is over expressed in HNSCC. EGFR regulates the HNSCC by inducing signalling events responsible for regulating key tumorigenic processes such as proliferation, inhibition of apoptosis, cell adhesion/ motility, growth and survival. Present study evaluates the potential of N-(3-Ethynylphenyl)-6, 7-bis (2-methoxyethoxy) quinolin-4-amine as a new inhibitor for EGFR. We have explored the binding and inhibitory potential of the compound using molecular docking, structural interactions fingerprinting and molecular dynamics studies. The inhibitor exhibits extensive interactions with the EGFR catalytic site in the form of hydrogen bonds, pi-pi bond and salt bridges. It shows high specificity and binding affinity towards the protein. The compound can further be explored for its potential to serve in the diagnosis and treatment of HNSCC. The quantitative prediction provides a scope for future experimental testing, facilitating the understanding of the crosstalks between signalling pathways. PMID- 22486614 TI - Predicting protein solubility by the general form of Chou's pseudo amino acid composition: approached from chaos game representation and fractal dimension. AB - Obtaining soluble proteins in sufficient concentrations is a major obstacle in various experimental studies. How to predict the propensity of targets in large scale proteomics projects to be soluble is a significant but not fairly resolved scientific problem. Chaos game representation (CGR) can investigate the patterns hiding in protein sequences, and can visually reveal previously unknown structure. Fractal dimensions are good tools to measure sizes of complex, highly irregular geometric objects. In this paper, we convert each protein sequence into a high-dimensional vector by CGR algorithm and fractal dimension, and then predict protein solubility by these fractal features together with Chou's pseudo amino acid composition features and support vector machine (SVM). We extract and study six groups of features computed directly from the primary sequence, and each group is evaluated by the 10-fold cross-validation test. As the results of comparisons, the group of 445-dimensional vector gets the best results, the average accuracy is 0.8741 and average MCC is 0.7358. The resulting predictor is also compared with existing methods and shows significant improvement. PMID- 22486615 TI - Site-directed mutagenesis study of the Ile140 in conserved hydrophobic core of Bcl-x(L). AB - The hydrophobic core in Bcl-x(L) composed of Trp137, Ile140, Trp181, Ile182, Trp188 and Phe191 is highly conserved and essential for protein folding, protein stability and binding affinity with BH3-peptide. 9 mutants of Ile140 residue were constructed and characterized in order to get better understanding of the effect of the hydrophobic core. Binding assay demonstrated that binding affinities between 4 charged mutants and BH3-peptide were significantly weakened or lost, suggesting that the integrity of the hydrophobic core has close relationship with binding. The CD spectroscopy results indicated that disruption of the hydrophobic core may affect local conformation within the protein and result in intrinsic inactivity. Further chemical-induced protein folding results on these 4 mutants revealed that the conserved hydrophobic core is also important for the protein stability. PMID- 22486616 TI - Binding of a bcl-2 family inhibitor to bovine serum albumin: fluorescence quenching and molecular docking study. AB - Both fluorescence spectroscopic and molecular docking methods were used to investigate the interaction between bovine serum albumin (BSA) and a known Bcl xl/Bcl-2 inhibitor HA 14-1. Based on the spectral overlap between the emission of BSA and absorption of HA 14-1, Forster energy transfer was proposed to be the possible quenching mechanism. The Stern-Volmer constants are 2.49 x 104, 2.04 x 104 and 0.90 x 104 M-1 at 293, 303 and 318 K, respectively, indicating that a static quenching process dominates. Thermodynamic parameters were further obtained. The derived negative Delta H (-27.51 kJ mol-1) and Delta S (-11.11 J mol-1 K-1) values suggest hydrogen bond interaction and van der Waals force are the main binding force. The docking study was performed on BSA model. According to the docking score and the number of hydrogen bonds, the potential binding site for HA 14-1 is proposed to be the site IIA, also known as drug site 1. PMID- 22486617 TI - Prediction of human genes' regulatory functions based on proteinprotein interaction network. AB - In systems biology, regulatory pathway is one of the most important research areas. However, regulatory pathway is so complicated that we still poorly understand this system. On the other hand, with rapid accumulated information on different organisms, it becomes more and more possible to in-depth investigate regulatory pathway. To understand regulatory pathway well, figuring out the components of each pathway is the most important step. In this study, a network- based method was proposed to classify human genes into corresponding pathways. The information of protein-protein interactions retrieved from STRING was used to construct a network and jackknife test was employed to evaluate the method. As a result, the first order prediction accuracy was 87.91%, indicating that interactive proteins always have similar biological regulatory functions. By comparing the predicted results obtained from other methods based on blast and amino acid composition, respectively, it implies that our prediction method is quite promising that may provide an opportunity to understand this complicated pathway system well. PMID- 22486618 TI - Machine learning study of classifiers trained with biophysiochemical properties of amino acids to predict fibril forming Peptide motifs. AB - It is important to understand the cause of amyloid illnesses by predicting the short protein fragments capable of forming amyloid-like fibril motifs aiding in the discovery of sequence-targeted anti-aggregation drugs. It is extremely desirable to design computational tools to provide affordable in silico predictions owing to the limitations of molecular techniques for their identification. In this research article, we tried to study, from a machine learning perspective, the performance of several machine learning classifiers that use heterogenous features based on biochemical and biophysical properties of amino acids to discriminate between amyloidogenic and non-amyloidogenic regions in peptides. Four conventional machine learning classifiers namely Support Vector Machine, Neural network, Decision tree and Random forest were trained and tested to find the best classifier that fits the problem domain well. Prior to classification, novel implementations of two biologically-inspired feature optimization techniques based on evolutionary algorithms and methodologies that mimic social life and a multivariate method based on projection are utilized in order to remove the unimportant and uninformative features. Among the dimenionality reduction algorithms considered under the study, prediction results show that algorithms based on evolutionary computation is the most effective. SVM best suits the problem domain in its fitment among the classifiers considered. The best classifier is also compared with an online predictor to evidence the equilibrium maintained between true positive rates and false positive rates in the proposed classifier. This exploratory study suggests that these methods are promising in providing amyloidogenity prediction and may be further extended for large-scale proteomic studies. PMID- 22486619 TI - Peptidoglycan hydrolase enterolysin a recognizes lipoteichoic acid chains in the cell walls of sensitive bacteria. AB - C-terminal domain of peptidoglycan hydrolase enterolysin A (EnlA) is involved in specific recognition and binding to the target cell envelopes and represents true cell wall binding (CWB) domain. Sensitivity/resistance to EnlA is dependent on binding ability/disability of its CWB domain. We assume that main mechanism of resistance against EnlA is absence of the specific receptor on the cell surface, which is necessary for binding of the enzyme molecule. Using competitive and enzymatic assays we have uncovered the chemical nature of the EnlA receptor, which is a lipoteichoic acid. PMID- 22486620 TI - Secreted nucleobindin-2 inhibits 3T3-L1 adipocyte differentiation. AB - Nucleobindin-2 is a 420 amino acid EF-hand Ca2+ binding protein that can be further processed to generate an 82 amino terminal peptide termed Nesfatin-1. To examine the function of secreted Nucleobindin-2 in adipocyte differentiation, cultured 3T3-L1 cells were incubated with either 0 or 100 nM of GST, GST Nucleobindin-2, prior to and during the initiation of adipocyte differentiation. Nucleobindin-2 treatment decreased neutral lipid accumulation (Oil-Red O staining) and expression of several marker genes for adipocyte differentiation (PPARgamma, aP2, and adipsin). When Nucleobindin- 2 was constitutively secreted into cultured medium, cAMP content and insulin stimulated CREB phosphorylation were significantly reduced. On the other hand, intracellularly overexpressed Nucleobindin-2 failed to affect cAMP content and CREB phosphorylation. Taken together, these data indicate that secreted Nucleobindin-2 is a suppressor of adipocyte differentiation through inhibition of cAMP production and insulin signal. PMID- 22486621 TI - A novel approach for secretion of heterologous proteins with correct n-terminal processing by using alpha-factor pre sequence in Pichia pastoris. AB - Numerous proteins have been secreted in P. pastoris by fusing the target gene with alpha-factor pre-pro sequence at Kex2 endopeptidase cleavage site. However, in some instances the product cannot be correctly processed due to aberrant cleavage by Kex2 endopeptidase such as aprotinin. In this study, an aprotinin gene was cloned into pPIC9K at the signal peptidase cleavage site through a single NheI restriction site designed at the 3'end of the alpha-factor signal sequence preregion, and transformed into GS115 host cell. By G418 resistance and ELISA assay, a high-yield recombinant was selected. After fed-batch cultivation in a 7-L bioreactor, the product was efficiently secreted into culture medium and accumulated up to ~4.7 mg L-1. MALDI-TOF/MS and N-terminal analyses confirmed its authenticity. Thus, a novel cloning strategy for secretion of aprotinin with correct N-terminal processing in P. pastoris has been developed which can be potentially applied to other proteins. PMID- 22486622 TI - The influence of social factors and health on depressive symptoms and worry: a study of older Vietnamese adults. AB - OBJECTIVES: Vietnam has a growing older population, many of whom experienced war and social upheavals in their lives. Prior research has described the health of the older population, but little work has explored mental health. The current study examines the frequency and correlates of two mental health indicators: depressive symptoms and worry. METHOD: A representative sample of 600 adults 55 and older stratified by gender (50% women), age (mean=70.33), and rural/urban (50% rural) was recruited in Da Nang, Vietnam and surrounding rural districts. Participants were interviewed in their homes by trained interviewers. Dependent variables were a Vietnamese version of the CES-D and a culturally specific worry scale. RESULTS: Forty-seven percent of the sample had scores above the cut-off for clinical depression and scores on the worry scale were high. Using multiple linear regressions we found that women, the less educated and individuals with more material hardship had higher depressive symptoms whereas rural residents, women, married, and young-old individuals were more worried. Pain, ADL assistance and emotional support were significant predictors of both depressive symptoms and worry, though the direction of the association for emotional support differed. Illnesses were only a predictor of depressive symptoms. CONCLUSION: The high reports of depressive symptoms and worry suggests the need for incorporating mental health screening as part of health programs for older adults in Vietnam. Attention to factors associated with depressive symptoms and worry, such as economic hardship, health problems and lack of emotional support, may contribute to alleviation of symptoms. PMID- 22486624 TI - Immunological pathways in virus-induced COPD exacerbations: a role for IL-15. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by high levels of antiviral type 1 cytokine interferon-gamma and activated CD8(+) T cells. COPD exacerbations are the major cause of morbidity and mortality, have a prolonged and intense effect on quality of life and may result in accelerated loss of lung function. Respiratory virus infections, frequently within a state of colonization by bacteria, are the major cause of COPD exacerbations, and there is also evidence of virus latency in 'stable' disease, suggesting that latent infection might be a cause of chronic inflammation in COPD. DESIGN: This is an update of current literature concerning the role of interleukin-15 and major histocompatibility complex class I-related chain A and B molecules in type 1 immune responses, particularly to respiratory virus infections, which are the main cause of COPD exacerbations. We also present data from our own group suggesting a role for interleukin-15 in virus-induced COPD exacerbations. RESULTS: Type 1 cytokine interleukin-15 is produced by resident airway cells (epithelial cells and macrophages) in response to virus infection and bacteria. Virus infections modulate major histocompatibility complex class I-related chain A and B molecules in respiratory epithelial cells. CONCLUSIONS: Interleukin-15 could play a major role in the airway inflammation in COPD directly, via its own receptors, by amplifying the type 1 immune responses and decreasing apoptosis or indirectly, via modulating molecules associated with cytotoxic activity of natural killer and CD8(+) T cells, such as major histocompatibility complex class I-related chain A and B. PMID- 22486623 TI - Enhanced delivery of chemotherapy to tumors using a multicomponent nanochain with radio-frequency-tunable drug release. AB - While nanoparticles maximize the amount of chemotherapeutic drug in tumors relative to normal tissues, nanoparticle-based drugs are not accessible to the majority of cancer cells because nanoparticles display patchy, near-perivascular accumulation in tumors. To overcome the limitations of current drugs in their molecular or nanoparticle form, we developed a nanoparticle based on multicomponent nanochains to deliver drug to the majority of cancer cells throughout a tumor while reducing off-target delivery. The nanoparticle is composed of three magnetic nanospheres and one doxorubicin-loaded liposome assembled in a 100 nm long chain. These nanoparticles display prolonged blood circulation and significant intratumoral deposition in tumor models in rodents. Furthermore, the magnetic particles of the chains serve as a mechanical transducer to transfer radio frequency energy to the drug-loaded liposome. The defects on the liposomal walls trigger the release of free drug capable of spreading throughout the entire tumor, which results in a widespread anticancer effect. PMID- 22486626 TI - A prospective study on the safety of sublingual immunotherapy in pregnancy. AB - BACKGROUND: The aim of this study was to determine the safety of sublingual immunotherapy in pregnancy, which has not yet been reported. METHODS: One hundred and fifty-five patients received sublingual immunotherapy with either house dust mite (D. farinae) or a mixture of up to five allergens during 185 pregnancies. Twenty-four patients received sublingual immunotherapy for the first time during pregnancy. Follow-up data were analysed with regard to abortion, perinatal mortality, prematurity, toxaemia and congenital malformation. Two control groups did not receive immunotherapy; group A (85 patients) received budesonide 400 MUg twice daily and group B (40 patients) received rescue salbutamol inhalation. All three groups were on appropriate avoidance measures. RESULTS: Six-year follow-up data for the sublingual immunotherapy group revealed an incidence of complications less than that in the general population and a higher incidence of complications in both control groups. CONCLUSIONS: This study concludes that sublingual immunotherapy is safe during pregnancy and is also safe when initiated for the first time in a pregnant patient. PMID- 22486627 TI - Oral health status in elders from South Brazil: a population-based study. AB - OBJECTIVE: To assess the oral health status of community-dwelling adults aged 60 years and older from southern Brazil and to determine demographics, socioeconomic, behavioural and dental risk indicators. MATERIALS AND METHODS: This cross-sectional study used a multistage, probability sampling method to draw a representative sample of the metropolitan area of Porto Alegre, Brazil. A subsample of 217 subjects was included in this analysis. Oral mucosal lesions, dental caries, tooth loss and periodontal status (full-mouth, six sites per tooth exam) were assessed by calibrated examiners. RESULTS: Prevalence of edentulism was 39.5%, and mean tooth loss was 20.2 (SE = 0.6). Older individuals [Odds Ratio (OR) = 2.2], women (OR = 2.3), white people (OR = 5.9), individuals of lower socioeconomic status (OR = 5.6) and smokers (OR = 3.5) had higher likelihood of being edentulous. Approximately 36% of dentate individuals had caries and/or restoration affecting, in average, 5.0 teeth. Periodontitis affected 79% of subjects, and it was associated with older age (OR = 4.0), men (OR = 3.4) and large amounts of supragingival plaque (OR = 3.0). CONCLUSION: Poor oral health was observed in this elderly population from South Brazil. Sociodemographic disparities accounted for most of the burden of disease and treatment needs. PMID- 22486628 TI - The clofibrate saga: a retrospective commentary. PMID- 22486629 TI - Three-dimensional echocardiographic imaging of biventricular false tendons mimicking hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is characterized by hypertrophy of the left ventricle, with variable clinical manifestations and morphologic and hemodynamic abnormalities. False tendons (FTs) are discrete, fibromuscular structures of varying length and thickness that tranverse either left and right ventricular cavities. Left and right ventricular FTs were giving a false impression of HCM. Misdiagnosis of HCM can lead to undue anxiety, unnecessary medication, and further evaluation. Three-dimensional (3D) transthoracic echocardiography is additive to conventional two-dimensional imaging in these patients in terms of 3D perspective and anatomically correct examination. We present a 32-year-old male who was misdiagnosed as asymetrical septal hypertrophy. PMID- 22486630 TI - Meta-analysis: vasoactive medications for the management of acute variceal bleeds. AB - BACKGROUND: Vasoactive medications such as vasopressin, somatostatin and their analogues (terlipressin, vapreotide and octreotide) are commonly used for the treatment of acute variceal bleeding. However, the risks and benefits of these interventions are not well understood. AIM: To undertake a meta-analysis of the efficacy of vasoactive medications in patients having acute variceal bleeds. METHODS: Randomised controlled trials (RCTs) of vasopressin, somatostatin and their analogues, administered to patients with acute variceal bleeds were identified based on systematic searches of nine electronic databases and multiple sources of grey literature. RESULTS: The search identified 3011 citations, and 30 trials with a total of 3111 patients met eligibility criteria. The use of vasoactive agents was associated with a significantly lower risk of 7-day mortality (RR 0.74; 95% CI 0.57-0.95; P = 0.02; I(2) = 0%; moderate quality of evidence), and a significant improvement in haemostasis (RR 1.21, 95% CI 1.13 1.30; P < 0.001; I(2) = 28%; very low quality of evidence), lower transfusion requirements (pooled mean difference -0.70 units of blood transfused, 95% CI 1.01 to -0.38; P < 0.001; I(2) = 82%; moderate quality of evidence), and a shorter duration of hospitalisation (pooled mean difference -0.71 days; 95% CI 1.23 to -0.19; P = 0.007; I(2) = 0%; low quality of evidence). Studies comparing different vasoactive agents did not show a difference in efficacy, although the quality of evidence was very low. CONCLUSIONS: The use of vasoactive agents was associated with a significantly lower risk of acute all-cause mortality and transfusion requirements, and improved control of bleeding and shorter hospital stay. Studies comparing different vasoactive medications failed to demonstrate a difference in efficacy. PMID- 22486631 TI - Chemical composition, antioxidant and antibacterial activities of two Spondias species from Northeastern Brazil. AB - CONTEXT: The leaves of Spondias tuberosa Arr. Cam. (Anacardiaceae) and Spondias mombin L. have been traditionally used for medicinal purposes. Some studies reveal their antibacterial, antimicrobial, and antiviral properties. OBJECTIVE: Determine the chemical composition, antioxidant, and antimicrobial activities of Spondias species to justify its ethnopharmacological use. MATERIALS AND METHODS: Spondias species extracts were prepared with methanol:water 80:20 and analyzed by silica gel column chromatography and reversed phase liquid chromatography (HPLC). The antioxidant activity was evaluated by scavenging the radicals 1,1-diphenyl-2 picrylhydrazyl radical (DPPH) and 2,2-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS*+) and measuring antimicrobial activity (agar well diffusion method, minimum inhibitory concentration and minimum bactericidal concentrations). RESULTS: The HPLC analysis of Spondias extracts demonstrated the occurrence of high yield of flavonoids. Found in S. mombin were quercetin (2.36 +/- 0.01 mg/g) and ellagic acid (41.56 +/- 0.01 mg/g) and in S. tuberosa species rutin (53.38 +/ 1.71 mg/g), quercetin (24.46 +/- 0.87 mg/g), and ellagic acid (169.76 +/- 0.17 mg/g). The antibacterial activity of the extracts against the various bacteria strains varied from 8.8 to 20.1 mm. MIC values from 62.5 to 125 ug/mL were satisfactory when compared with other plant products. Medium DPPH scavenging activity IC50 for Spondias extracts varied from 0.042 to 0.558 mg/mL and for ABTS from 0.089 to 0.465 mg/mL. DPPH scavenging activity for constituent ellagic acid IC50 = 0.042 mg/mL and for quercetin IC50 = 0.081 mg/mL. DISCUSSION AND CONCLUSION: The chemical study of Spondias leaf extracts showed the occurrence of quercetin, rutin and ellagic acid, substances with relevant antioxidant and antimicrobial activities. PMID- 22486632 TI - Pharmacokinetics and distribution of fluvoxamine to the brain in rats under oxidative stress. AB - The effects of oxidative stress (OS) on the pharmacokinetics of fluvoxamine (FLV), particularly on FLV distribution in the plasma, were studied in ferric nitrilotriacetate-induced OS rat models (OS rats). The study protocol involved a continuous FLV infusion (25.0 MUg/kg/min). The resulting mean plasma FLV concentration measured in steady state OS rats was 0.13 +/- 0.01 MUg/mL, which was significantly lower than plasma concentrations measured in control rats (0.19 +/- 0.01 MUg/mL). Moreover, the mean FLV concentration in the OS rat brain (0.51 +/- 0.08 MUg/g) was determined to be approximately half the concentration in control rat brains (0.95 +/- 0.11 MUg/g). The FLV concentrations in both the unbound fraction of plasma and erythrocytes of OS rats were significantly greater than that of control rats. These results suggest the potential attenuation of FLV's pharmacological effects in patients under OS. PMID- 22486633 TI - The use of vertebral osteoarthritis and osteophytosis in age estimation. AB - Previous research on age and vertebral degenerative change has focused on osteophytosis. The present study expands this research by examining the association between osteoarthritis and osteophytosis and by assessing their relationship to age. Researchers scored the bodies and facets in 104 individuals. Statistical analyses assessed relationships between age and degenerative change for the bodies and facets, both separately and combined, for all vertebrae collectively, and for subcategories of vertebral types. Separate analyses were conducted which included only regions that experience heavier stress loads. Results indicate that osteophytosis and osteoarthritis are not associated with each other for all subcategories of vertebrae. Also, the inclusion of osteoarthritis does not enhance the relationship between age and degenerative change, nor does limiting analyses to areas of heaver stress. Finally, although both conditions are significantly correlated with age, the relationship is not strong enough to yield predictive power for establishing age beyond a general estimate. PMID- 22486634 TI - Evaluation of vapor intrusion using controlled building pressure. AB - The use of measured volatile organic chemical (VOC) concentrations in indoor air to evaluate vapor intrusion is complicated by (i) indoor sources of the same VOCs and (ii) temporal variability in vapor intrusion. This study evaluated the efficacy of utilizing induced negative and positive building pressure conditions during a vapor intrusion investigation program to provide an improved understanding of the potential for vapor intrusion. Pressure control was achieved in five of six buildings where the investigation program was tested. For these five buildings, the induced pressure differences were sufficient to control the flow of soil gas through the building foundation. A comparison of VOC concentrations in indoor air measured during the negative and positive pressure test conditions was sufficient to determine whether vapor intrusion was the primary source of VOCs in indoor air at these buildings. The study results indicate that sampling under controlled building pressure can help minimize ambiguity caused by both indoor sources of VOCs and temporal variability in vapor intrusion. PMID- 22486636 TI - Antibiotic-resistant Escherichia coli in karstic systems: a biological indicator of the origin of fecal contamination? AB - Occurrences of antibiotic-resistant Escherichia coli in two springs of a karstic system (NW France) providing drinking water were determined to study the role of aquifers in the dissemination of the resistance genes. Water samples were collected during wet and dry periods and after a heavy rainfall event to investigate E. coli density, antibiotic resistance patterns, and occurrences of class 1, 2, and 3 integrons. By observing patterns of the resistant isolates (i.e. number and type of resistances) and their occurrences, we were able to define two resistant subpopulations, introduced in the aquifer via surface water: (1) R1-2, characterized by one or two resistance(s), essentially to chloramphenicol and/or tetracycline (96.5%), was always found during the heavy rainfall event; (2) R3-10, characterized by three or more resistances, mostly resistant to tetracycline (94.1%) and beta-lactams (86%), was found transiently. Class 1 and 2 integrons were detected, mostly in the R3-10 subpopulation for class 1 integrons. The characteristics of these two subpopulations strongly suggest that the contamination originates from pasture runoff for the R1-2 subpopulation and from wastewater treatment plant effluents for the R3-10 subpopulation. These two subpopulations of E. coli could be used as biological indicators to determine the origin of groundwater contamination. PMID- 22486635 TI - The heritability of avoidant and dependent personality disorder assessed by personal interview and questionnaire. AB - OBJECTIVE: Personality disorders (PDs) have been shown to be modestly heritable. Accurate heritability estimates are, however, dependent on reliable measurement methods, as measurement error deflates heritability. The aim of this study was to estimate the heritability of DSM-IV avoidant and dependent personality disorder, by including two measures of the PDs at two time points. METHOD: Data were obtained from a population-based cohort of young adult Norwegian twins, of whom 8045 had completed a self-report questionnaire assessing PD traits. 2794 of these twins subsequently underwent a structured diagnostic interview for DSM-IV PDs. Questionnaire items predicting interview results were selected by multiple regression, and measurement models of the PDs were fitted in Mx. RESULTS: The heritabilities of the PD factors were 0.64 for avoidant PD and 0.66 for dependent PD. No evidence of common environment, that is, environmental factors that are shared between twins and make them similar, was found. Genetic and environmental contributions to avoidant and dependent PD seemed to be the same across sexes. CONCLUSION: The combination of both a questionnaire- and an interview assessment of avoidant and dependent PD results in substantially higher heritabilities than previously found using single-occasion interviews only. PMID- 22486637 TI - Efficacy of food proteins as carriers for flavonoids. AB - Enrichment of flavonoids in food is often limited by their off-tastes, which might be counteracted by the use of food proteins as carriers of flavonoids. Various milk proteins, egg proteins, and gelatin hydrolysates were compared for their binding characteristics to two flavan-3-ols. Among the proteins tested for their affinities toward epigallocatechin gallate (EGCG), beta-casein and gelatin hydrolysates, in particular fish gelatin, were found to be the most promising carriers with an affinity on the order of 10(4) M(-1). A flexible open structure of proteins, as present in random coil proteins, was found to be important. The saturation of binding observed at high flavonoid/protein ratios was used to estimate the maximal binding capacity of each protein. To reach a daily intake of EGCG that has been associated with positive health effects, only 519 mg of gelatin B and 787 mg of beta-casein were required to complex EGCG on the basis of their maximal binding capacity. When the absence of turbidity is taken into account, beta-casein prevails as carrier. Three selected proteins were further investigated for their binding potential of representative flavonoids differing in their C-ring structure. An increase in hydrophobicity of flavonoids was related to a higher affinity for proteins, and the presence of a gallic acid ester on the C-ring showed an overall higher affinity. PMID- 22486638 TI - Evaluating the Cornell Scale for Depression in Dementia as a proxy measure in nursing home residents with and without dementia. AB - OBJECTIVES: We evaluated the use of the Cornell Scale for Depression in Dementia (CSDD) as a proxy measure. Study questions were: How do residents' self-reports on the CSDD compare with the nurse proxy CSDD ratings of the resident? How do characteristics of depression as rated by the resident CSDD and the nurse CSDD compare? To what extent are demographic and clinical variables associated with resident CSDD, nurse CSDD, and the discrepancy between resident and nurse CSDD scores? METHODS: Residents and nurse proxy pairs (n=395 pairs) from 28 nursing homes (NHs) participated. We calculated discrepancy scores for total and subscale CSDD scores, examined correlations between resident and nurse CSDD scores, and described rates of clinical depression using each of the scores. We conducted multivariate analyses to examine factors associated with resident and nurse CSDD and discrepancy scores. RESULTS: On average, participants had mild cognitive impairment, were White, and female. Associations between resident and nurse CSDD were low (r=0.16). The mean discrepancy score was -2.03 (SD=5.28, p<0.001), indicating that nurses evaluated residents as less depressed than residents evaluated themselves. Discrepancy scores were not associated with residents' cognitive status, but were associated with a measure of self-report reliability. Regression analyses indicated that depression diagnosis accounted for a small but significant association with resident CSDD, but was not significantly associated with nurse CSDD. CONCLUSION: These findings underscore the importance of obtaining resident input when assessing depression in NH residents with dementia, and educating NH nurses in the most effective ways to assess depression. PMID- 22486639 TI - Visualizing dynamics of sub-hepatic distribution of nanoparticles using intravital multiphoton fluorescence microscopy. AB - Nanoparticles that do not undergo renal excretion or in vivo degradation into biocompatible debris often accumulate in the reticuloendothelial system, also know as the mononuclear phagocyte system, with undesired consequences that limit their clinical utility. In this work, we report the first application of intravital multiphoton fluorescence microscopy to dynamically track the hepatic metabolism of nanoparticles with subcellular resolution in real time. Using fluorescently labeled mesoporous silica nanoparticles (MSNs) in mice as a prototypical model, we observed significant hepatocyte uptake of positively charged, but not negatively charged, moieties. Conversely, in vivo imaging of negatively charged, but not positively charged, MSNs reveals an overwhelming propensity for the former's rapid uptake by Kupffer cells in liver sinusoids. Since the only prerequisite for these studies was that nanoparticles are fluorescently labeled and not of a specific composition or structure, the techniques we present can readily be extended to a wide variety of nanoparticle structures and surface modifications (e.g., shape, charge, hydrophobicity, PEGylation) in the preclinical assessment and tailoring of their hepatotoxicities and clearances. PMID- 22486640 TI - Effect of primary percutaneous coronary intervention on stress hyperglycaemia in myocardial infarction. AB - AIM: To measure the effect of primary percutaneous coronary intervention on stress hyperglycaemia induced by ST segment elevation myocardial infarction. METHODS: We measured blood glucose before primary percutaneous coronary intervention and 1 h after intervention in all patients presenting with ST segment elevation myocardial infarction for 2 months in our unit. A paired t-test was used for a statistical analysis. RESULTS: From 157 patients accepted for primary percutaneous coronary intervention, 90 patients were included in the analysis. Blood glucose before intervention was 8.4 +/- 2.46 mmol/l (mean +/- SD) and after intervention was 7.9 +/- 2.0 mmol/l (mean +/- sd) (P = 0.003). In the subset of 15 patients with hyperglycaemia (glucose greater than 10 mmol/l), glucose before intervention was 12.7 +/- 2.62 mmol/l (mean +/- SD) and after intervention was 9.8 +/- 3.42 mmol/l (mean +/- sd) (P = 0.0002). CONCLUSIONS: Blood glucose in patients with ST segment elevation myocardial infarction is significantly lower after primary percutaneous coronary intervention and this reduction is most marked in patients with hyperglycaemia. Waiting for the stress response to diminish means that 11.1% of patients' glucose levels fell below the treatment threshold of 10 mmol/l. Using the post-intervention blood glucose level avoids the need for treatment with insulin in this population. Further randomized studies are warranted to investigate the impact on mortality and morbidity of administering insulin triggered by pre-invention blood glucose vs. post intervention blood glucose. PMID- 22486641 TI - Bimolecular reactions of vibrationally excited molecules. Roaming atom mechanism at low kinetic energies. AB - Quasiclassical trajectory calculations have been performed for the H + H'X(v) -> X + HH' abstraction and H + H'X(v) -> XH + H' (X = Cl, F) exchange reactions of the vibrationally excited diatomic reactant at a wide collision energy range extending to ultracold temperatures. Vibrational excitation of the reactant increases the abstraction cross sections significantly. If the vibrational excitation is larger than the height of the potential barrier for reaction, the reactive cross sections diverge at very low collision energies, similarly to capture reactions. The divergence is quenched by rotational excitation but returns if the reactant rotates fast. The thermal rate coefficients for vibrationally excited reactants are very large, approach or exceed the gas kinetic limit because of the capture-type divergence at low collision energies. The Arrhenius activation energies assume small negative values at and below room temperature, if the vibrational quantum number is larger than 1 for HCl and larger than 3 for HF. The exchange reaction also exhibits capture-type divergence, but the rate coefficients are larger. Comparisons are presented between classical and quantum mechanical results at low collision energies. At low collision energies the importance of the exchange reaction is enhanced by a roaming atom mechanism, namely, collisions leading to H atom exchange but bypassing the exchange barrier. Such collisions probably have a large role under ultracold conditions. The calculations indicate that for roaming to occur, long range attractive interaction and small relative kinetic energy in the chemical reaction at the first encounter are necessary, which ensures that the partners can not leave the attractive well. Large orbital angular momentum of the primary products (equivalent to large rotational excitation in a unimolecular reaction) is favorable for roaming. PMID- 22486642 TI - The role of Staphylococcal enterotoxin in atopic keratoconjunctivitis and corneal ulceration. AB - BACKGROUND: Patients with atopic eczema frequently experience colonization with Staphylococcus aureus that is directly correlated with the eczema severity. We hypothesized that S. aureus-secreted enterotoxins (SE) are involved in the pathophysiology of atopic keratoconjunctivitis (AKC). METHODS: A total of 45 subjects (18 with AKC, nine vernal keratoconjunctivitis (VKC), eight seasonal allergic conjunctivitis (SAC), and ten healthy volunteers) were enrolled. Slit lamp examinations, including fluorescein staining, were performed. Scraped samples were collected from the upper tarsal conjunctiva, lower conjunctival sacs, and the skin around the eyelid margins. Superantigen (SAg) genes were detected using polymerase chain reaction (PCR). RESULTS: Among 45 cases, S. aureus was detected significantly more in AKC patients than VKC patients (P = 0.026), SAC patients (P = 0.0003), and healthy volunteers (P = 0.0001). SAg genes were detected in 11 patients. SEB (2/11), SEG (8/11), and SEI (8/11) were detected, but no other SE. There was a significant difference in SE detection between AKC and SAC patients (P = 0.03). In severe types of ocular allergic disease such as AKC and VKC (N = 27), SE was detected in six of ten patients with corneal ulcers and two of 17 patients without corneal ulcers. SE was detected in significantly more patients with corneal ulcers (P = 0.025). CONCLUSIONS: In patients with AKC, S. aureus and SE were detected more frequently compared with other patients and healthy volunteers, especially in association with corneal ulceration suggesting a role of SE. So far, it is unknown whether SE leads to tissue damage of the cornea by initiating an immune response or has direct toxic effects. PMID- 22486643 TI - Differential kinetics and inhibition of purified recombinant tyrosine kinase 2 (TYK-2) and its catalytic domain JH-1. AB - The Janus kinase (JAK) family consists of four members: JAK-1, -2, -3 and tyrosine kinase 2 (TYK-2). Recent work suggests that cytokine signaling through TYK-2 may play a critical role in a number of inflammatory processes. We recently described the purification and characterization of phosphorylated isoforms of the TYK-2 kinase domain (TYK-2 KD) and its high resolution 3D structure in the presence of inhibitors. We now report the expression and a two-step purification procedure for the doubly tagged full-length construct, H6-FL-TYK-2-FLAG, and examine its properties compared to those of TYK-2 KD. In the presence of ATP and a peptide substrate, H6-FL-TYK-2-FLAG showed a marked lag in phosphopeptide product formation, while TYK-2 KD showed no such lag. This lag could be eliminated by ATP pretreatment, suggesting that the H6-FL-TYK-2-FLAG enzyme was activated by phosphorylation. The potencies of several nanomolar inhibitors were similar for TYK-2 KD and H6-FL-TYK-2-FLAG. However, these same inhibitors were about 1000 times less potent inhibiting the autophosphorylation of H6-FL-TYK-2 FLAG than they were inhibiting the phosphorylation of a peptide substrate modeled after the activation loop sequence of TYK-2. This intriguing result suggests that autophosphorylation and, thus, activation of H6-FL-TYK-2-FLAG is relatively insensitive to inhibition and that present inhibitors act to inhibit TYK-2 subsequent to activation. Inhibition of TYK-2 autophosphorylation may represent a new area of investigation for the JAK family. PMID- 22486644 TI - Predicting protein-protein interactions by combing various sequence- derived features into the general form of Chou's Pseudo amino acid composition. AB - Knowledge of protein-protein interactions (PPIs) plays an important role in constructing protein interaction networks and understanding the general machineries of biological systems. In this study, a new method is proposed to predict PPIs using a comprehensive set of 930 features based only on sequence information, these features measure the interactions between residues a certain distant apart in the protein sequences from different aspects. To achieve better performance, the principal component analysis (PCA) is first employed to obtain an optimized feature subset. Then, the resulting 67-dimensional feature vectors are fed to Support Vector Machine (SVM). Experimental results on Drosophila melanogaster and Helicobater pylori datasets show that our method is very promising to predict PPIs and may at least be a useful supplement tool to existing methods. PMID- 22486645 TI - Effects of compounds from Passiflora edulis Sims f. flavicarpa juice on blood coagulation and on proteolytic enzymes. AB - Passion fruit (Passiflora edulis Sims f. flavicarpa) is popularly known for its sedative and calming properties and is consumed as a fresh fruit or as a juice. The clinical observation of blood incoagulability associated with excessive consumption of passion fruit juice, in a patient treated with warfarin, prompted the current study to investigate in vitro the presence of blood clotting inhibitors in Passiflora edulis Sims f. flavicarpa extract. After purification process, two compounds of distinct molecular weight and inhibitory action were better characterized. One is a trypsin inhibitor similar to inhibitors from Bowman-Birk family, named PeTI-I12, and other is a compound active in coagulation that prolongs aPTT and PT, but does not change TT. The aim of this study is to provide evidence that passion fruit extract's components play a role on hemostasis and therefore may be relevant in the handling of patients treated with anticoagulants or suffering hemorrhagic diseases. PMID- 22486646 TI - Expression, purification and evaluation of diagnostic potential and immunogenicity of dengue virus type 3 domain III protein. AB - Dengue hemorrhagic fever and dengue shock syndrome are the severe manifestations of dengue infection. The quest for reliable dengue diagnostics and a dengue vaccine remained elusive for decades. Domain III of dengue virus envelope contains multiple conformation dependant neutralizing epitopes, thus making it an attractive diagnostic and vaccine candidate. In this report we show the expression of dengue virus type 3 envelope domain III protein (D3EDIII) and demonstrate its potential as a diagnostic and vaccine candidate. Accordingly, D3EDIII was expressed to high levels in Escherichia coli and purified by Ni-NTA affinity chromatography. The purified protein was used to develop an in-house plate ELISA and was further tested with a panel of 40 dengue infected serum samples previously characterized by commercially available serological tests. The in-house results were in excellent agreement with the commercial kits. D3EDIII was refolded by rapid dilution method and the refolded monomer protein was purified by Ion exchange chromatography. Further, the recombinant protein was biologically functional and found to inhibit dengue virus type 3 plaque formation on LLC-MK2 cells demonstrating its function of receptor interaction. Furthermore, D3EDIII in combination with Freund's complete adjuvant induced high antibody titers in BALB/c mice and these antibodies efficiently neutralized dengue 3 virus. Additionally, D3EDIII induced expression of Th1 cytokines that can inhibit the intracellular viral infections. Thus, our results demonstrate that D3EDIII protein has tremendous potential both in diagnosis of dengue infections and in vaccine development. PMID- 22486647 TI - Antimicrobial peptides from Adenanthera pavonina L. seeds: characterization and antifungal activity. AB - In this study, the antifungal activity of peptides extracted from Adenanthera pavonina seeds was assessed. Peptides were extracted and fractionated by DEAE Sepharose chromatography. The non-retained D1 fraction efficiently inhibited the growth of the pathogenic fungi. This fraction was later further fractionated by reversed-phase chromatography, resulting in 23 sub-fractions. All separation processes were monitored by tricine-SDS-PAGE. Fractions H11 and H22 strongly inhibited the growth of Saccharomyces cerevisiae and Candida albicans. Fraction H11 caused 100% death in S. cerevisiae in an antimicrobial assay. The complete amino acid sequence of the peptide in fraction P2 was determined, revealing homology to plant defensins, which was named ApDef1. Peptides from fraction H22 were also sequenced. PMID- 22486648 TI - Deletion mutant comprising 198 residues of BoNT/A toxin receptor binding domain retained gt1b binding property but failed to induce protective antibody response in a mouse model. AB - The most effective protection against toxin is inducing protective immune response through vaccination that will produce neutralizing antibodies. Antibodies will bind to and clear toxin from the circulation before it can enter nerve cells and block neurotransmission and can also be used for development of detection system. In the present study we constructed a deletion mutant of the binding domain (1098-1296) to produce smallest toxin fragment as vaccine candidate against BoNT/A. The BoNT/A-HCC protein was highly expressed in Escherichia coli SG13009 and found to form inclusion bodies. The purified inclusion bodies were solubilized in 6 M guanidine-HCl containing 10 mM beta mercaptoethanol and 20 mM imidazole and the rBoNT/A-HCC was purified and refolded in a single step on Ni2+ affinity column. The purified protein was ~98 % pure as assessed by SDS-polyacrylamide gel with the yield of 8 mg/L and showed binding to polysialoganglioside (GT1b). The rBoNT/A-HCC at dose of 40 MUg/mouse generated high IgG antibody titre with predominance of IgG1 subtype, but failed to protect animals against BoNT/A challenge. Antibody titre in serum was determined by enzyme linked immunosorbent assay and specific binding to rBoNT/A-HCC was demonstrated by surface plasmon resonance (SPR), with a dissociation constant of 0.8 pM. PMID- 22486649 TI - Isolation and characterization of novel tyrosinase from Laceyella sacchari. AB - We here describe the isolation and characterization of a tyrosinase from a newly isolated soil bacterium. 16S rDNA sequence analysis revealed that the bacterium most probably belongs to the species Laceyella sacchari (Ls) ( > 99.9 % identity). The tyrosinase extracellular enzymatic activity was induced in the presence of L-methionine and CuSO4. The crude enzyme was first purified by centrifugation followed by ammonium sulphate precipitation and ultrafiltration. After removal of a brown pigment, probably melanin, a purified enzyme was obtained by further separation of the crude protein mixture using size exclusion chromatography. Some 10.5 mg of pure tyrosinase (LsTyr) was isolated with a molecular mass of 30 910 Da, based on MALDI mass spectrometry. Together with the observed enzymatic activity, N-terminal chemical sequence analysis confirmed that the isolated enzyme is homologous to other tyrosinases. The kinetic parameters for the diphenol substrates L-DOPA and dopamine and for the monophenol substrate L-tyrosine were determined to be KM = 4.5 mM , 1.5 mM and 0.055 mM, and kcat/KM = 261.5 mM-1 s -1 , 30.6 mM-1 s-1 and 56.3 mM-1 s-1, respectively. Maximal activities of the purified enzyme were found to occur at pH 6.8. PMID- 22486650 TI - Detailed folding structures of kappa-conotoxin RIIIJ and its mutageneses obtained from 2-dimensional HP model. AB - Kappa-conotoxin RIIIJ is a conopeptide to inhibit voltage-gated potassium channels, however, its detailed folding structures have yet to be studied. With the advance in computing power, it is possible to use the HP model to analyze all its possible folding structures. In this study, the amino acid sequences of kappa conotoxin RIIIJ and its four mutageneses were converted into ten HP sequences according to the normalized hydrophobicity index. All 282 429 536 481 possible folding structures in each HP sequence were found using the 2-dimensional HP model, and the detailed folding structures at native state were studied. The results showed that kappa-conotoxin RIIIJ had 180 and 90 folding structures at their native state with minimal energy of -9 and -10 at pH 2 and pH 7; its mutagenesis (6-8) TPP - > SLN increased the numbers of the folding structures to 456 and 564 at pH 2 and pH 7; whereas its mutageneses (6-11) TPPKKH - > SLNLRL, (9- 11) KKH - > LRL, and (10-11) KH - > RL decreased the numbers of the folding structures to 60, 30 and 90 at both pH levels, respectively. Thereafter, the normalized hydrophobicity index was employed to distinguish those native states, and attempts were made to explain the effect of mutageneses on potassium channels in terms of the number of folding structures and numerical native states. PMID- 22486651 TI - Intravitreal pegaptanib sodium (Macugen(r)) for treatment of diabetic macular oedema: a morphologic and functional study. AB - AIMS: To study whether morphologic (foveal thickness, FT) variations of clinically significant macular oedema (CMO) in patients suffering from diabetes following intravitreal pegaptanib sodium (IVP) injection were associated with functional [macular sensitivity (MS) and colour discrimination (CD)] changes. METHODS: A longitudinal, interventional, non-randomized study was performed. FT was assessed by optical coherence tomography (OCT), MS by microperimetry, best corrected visual acuity (BCVA) by early treatment diabetic retinopathy study charts (ETDRS) and CD by Farnswoth-Munsell test. The treatment protocol consisted of three consecutive injections (0.3 mg/0.05 ml; baseline, week 6 and week 12). Follow-up checks were scheduled at 18, 24, 36 and 48 weeks, after injections. RESULTS: Thirty eyes of 30 patients with clinically significant CMO were included for analysis. After IVP a significant decrease of FT occurred with a mean reduction from baseline of 56.9% (P= 0.0001). An improvement of functional parameters was recorded in all patients (BCVA from 18.2 +/- 8.5 letters to 25.5 +/- 8.4 letters, P < 0.005, MS from 8.6 +/- 2.16 dB to 10.6 +/- 2.61 dB, P < 0.001, colour analysis from 376.1 +/- 125.6 TES to 116 +/- 34.6 TES, P= 0.0001). A statistically significant correlation between FT and BCVA as well as MS and CD was also found. Neither ocular nor systemic adverse events were reported. CONCLUSIONS: Intravitreal pegaptanib significantly reduced FT, with a concomitant improvement of MS and CD. This association emphasizes the efficacy of IVP in the treatment of CMO. PMID- 22486653 TI - The knowledge-learning-instruction framework: bridging the science-practice chasm to enhance robust student learning. AB - Despite the accumulation of substantial cognitive science research relevant to education, there remains confusion and controversy in the application of research to educational practice. In support of a more systematic approach, we describe the Knowledge-Learning-Instruction (KLI) framework. KLI promotes the emergence of instructional principles of high potential for generality, while explicitly identifying constraints of and opportunities for detailed analysis of the knowledge students may acquire in courses. Drawing on research across domains of science, math, and language learning, we illustrate the analyses of knowledge, learning, and instructional events that the KLI framework affords. We present a set of three coordinated taxonomies of knowledge, learning, and instruction. For example, we identify three broad classes of learning events (LEs): (a) memory and fluency processes, (b) induction and refinement processes, and (c) understanding and sense-making processes, and we show how these can lead to different knowledge changes and constraints on optimal instructional choices. PMID- 22486652 TI - Optimization of adenosine 5'-carboxamide derivatives as adenosine receptor agonists using structure-based ligand design and fragment screening. AB - Structures of G protein-coupled receptors (GPCRs) have a proven utility in the discovery of new antagonists and inverse agonists modulating signaling of this important family of clinical targets. Applicability of active-state GPCR structures to virtual screening and rational optimization of agonists, however, remains to be assessed. In this study of adenosine 5' derivatives, we evaluated the performance of an agonist-bound A(2A) adenosine receptor (AR) structure in retrieval of known agonists and then employed the structure to screen for new fragments optimally fitting the corresponding subpocket. Biochemical and functional assays demonstrate high affinity of new derivatives that include polar heterocycles. The binding models also explain modest selectivity gain for some substituents toward the closely related A(1)AR subtype and the modified agonist efficacy of some of these ligands. The study suggests further applicability of in silico fragment screening to rational lead optimization in GPCRs. PMID- 22486654 TI - Comparative analysis of yellow microbial communities growing on the walls of geographically distinct caves indicates a common core of microorganisms involved in their formation. AB - Morphologically similar microbial communities that often form on the walls of geographically distinct limestone caves have not yet been comparatively studied. Here, we analysed phylotype distribution in yellow microbial community samples obtained from the walls of distinct caves located in Spain, Czech Republic and Slovenia. To infer the level of similarity in microbial community membership, we analysed inserts of 474 16S rRNA gene clones and compared those using statistical tools. The results show that the microbial communities under investigation are composed solely of Bacteria. The obtained phylotypes formed three distinct groups of operational taxonomic units (OTUs). About 60% of obtained sequences formed three core OTUs common to all three sampling sites. These were affiliated with actinobacterial Pseudonocardinae (30-50% of sequences in individual sampling site libraries), but also with gammaproteobacterial Chromatiales (6-25%) and Xanthomonadales (0.5-2.0%). Another 7% of sequences were common to two sampling sites and formed eight OTUs, while the remaining 35% were site specific and corresponded mostly to OTUs containing single sequences. The same pattern was observed when these data were compared with sequence data available from similar studies. This comparison showed that distinct limestone caves support microbial communities composed mostly of phylotypes common to all sampling sites. PMID- 22486655 TI - Reducing the recruitment of sedimented algae and nutrient release into the overlying water using modified soil/sand flocculation-capping in eutrophic lakes. AB - The effect of simultaneously removing algal blooms from water and reducing the resuspension and nutrient release from the sediment was studied using modified local soil/sand flocculation-capping (MLS-capping) in simulated water-sediment systems. Twenty one sediment cores in situ with overlying water containing algal blooms were collected from Meiliang Bay of Lake Taihu (China) in July 2011. The algal cells in the water were flocculated and sunk to the sediment using chitosan modified local soils, and the algal flocs were capped with modified and nonmodified soil/sand and then incubated at 25 degrees C for 20 days. In the MLS capping treated systems, the TP concentration was reduced from 2.56 mg P L(-1) to 0.06-0.14 mg P L(-1) and TN from 14.66 mg N L(-1) to 6.03-9.56 mg N L(-1) throughout the experiment, whereas the sediment to water fluxes of TP, TN, PO(4) P, and NH(4)-N were greatly reduced or reversed and the redox potential remarkably increased compared to the control system. A capping layer of 1 cm chitosan-modified sand decreased the resuspension of the sediment by a factor of 5 compared to the clay/soil/sediment systems and the overlying water kept clear even under constant stirring conditions (200 rpm). The study suggested that by using MLS-capping technology it is possible to quickly reduce the nutrient and turbidity of water by flocculating and capping the algal cells into the sediment, where the resuspension of algal flocs is physically reduced and the diffusion of nutrients from sediment to the overlying water chemically blocked by the MLS capping layers. PMID- 22486656 TI - Arjunolic acid: beneficial role in type 1 diabetes and its associated organ pathophysiology. AB - In this review article, we describe the most recent development of the beneficial effect of arjunolic acid (AA) in reducing type 1 diabetic pathophysiology. Diabetic mellitus is a serious and growing health problem worldwide. Increasing evidence suggest that oxidative stress plays a pivotal role in the pathogenesis of diabetes and its associated complications. Use of antioxidant supplements as a complimentary therapeutic approach in diabetes has, therefore, been seriously considered worldwide. AA, a natural pentacyclic triterpenoid saponin, is well known for various biological functions including antioxidant activity. It could prevent the increased production of ROS, RNS, AGEs, and the 8OHdG/2dG ratio and increase the intracellular antioxidant defence system. Signal transduction studies showed that AA could prevent hyperglycaemia induced activation of MAPKs, PKC, NF-kappaB signalling cascades and apoptotic cell death. Combining, AA supplements could be regarded as beneficial therapeutics in the treatment of diabetes and its associated complications. PMID- 22486657 TI - Inhibitory effects of ERbeta on proliferation, invasion, and tumor formation of MCF-7 breast cancer cells--prognostication for the use of ERbeta-selective therapy. AB - CONTEXT: Estrogen is well-known as an important factor in the physiological functions and pathological processes of breast. Estrogen receptor beta (ERbeta) is expressed in the majority of breast cancers at lower levels compared with the normal breast tissue. OBJECTIVE: The effect of ERbeta on the characteristics of breast tumor cells and its prognostication for the use of ERbeta-selective therapy were investigated here for the first time. MATERIALS AND METHODS: ERbeta was overexpressed in ERalpha positive MCF-7 breast cancer cells by gene transfection. The proliferation, motility, and xenografts growth of MCF-7 cells were investigated by MTT assays, wound-healing assay and animal study. RESULTS: Results demonstrated that ERbeta-GFP localized in both the cytoplasm and the nucleus in the presence of 17beta-estradiol (E2), with stronger fluorescence signal intensity in the nucleus, 2.8-times higher than that in the cytoplasm. The ERbeta overexpressed MCF-7 cells resulted in a 38.7% decreased growth rate and motility in vitro. Furthermore, ERbeta overexpression enhanced the antiproliferative effects of phytoestrogen, antiestrogen, and histone deacetylase inhibitor. Exogenous ERbeta expression reduced tumor volume by 99% at 27 days postadministration, indicated that overexpression of ERbeta led to retardation of tumor formation and growth in immunodeficient mice. DISCUSSION AND CONCLUSION: This study provided a relatively new evidence to support that ERbeta is an important modulator of proliferation and motility of breast cancer cells, and implied for the first time a possibility for the use of novel ERbeta-selective therapies in breast cancer treatment. PMID- 22486658 TI - Attachment representations in people with dementia and their carers: implications for well-being within the dyad. AB - OBJECTIVES: The process of developing and living with dementia may activate attachment feelings and behaviours in people with dementia (PwD) and their carers. By obtaining information from both PwD and carer, we aimed to provide information on the nature and concordance of attachment patterns within the dyad and to examine the relative contribution of attachment representations in PwD and carers to the well-being of both parties. METHOD: Ninety-seven PwD and their carers completed categorical and dimensional ratings of attachment. PwD also rated their self-concept, mood and quality of life. Carers rated the functional ability of PwD and neuropsychiatric symptoms and measures of subjective well being. RESULTS: People with dementia reported more insecure than secure attachment, with the most frequently reported style being dismissive attachment. Attachment security for PwD was related to more positive self-concept and less symptoms of anxiety. Attachment was not related to quality of life in PwD, but mood and self-concept were strong predictors of quality of life. Carer attachment security was related to their psychological health. Distress at symptoms and MMSE score of the PwD were the strongest predictors of stress. There was no association between PwD and carer attachment styles; PwD working models of attachment did not predict carer well-being and vice versa. CONCLUSION: Attachment representations may be important for the psychological well-being of PwD and carers, but there was no evidence of the reciprocal nature of attachment within these dyads. PMID- 22486659 TI - Successful slow pathway ablation in a patient with a rare unroofed type coronary sinus. AB - We report a case of atrioventricular nodal reentrant tachycardia coexistent with a coronary sinus (CS) anomaly. During a standard electrophysiological study, the CS could not be cannulated despite several attempts. A persistent left superior vena cava angiogram through the left brachial vein confirmed an unroofed type CS. Successful slow pathway ablation from the right posterior paraseptum lesion was achieved using an anatomical approach. PMID- 22486660 TI - Determination of furaltadone and nifursol residues in poultry eggs by liquid chromatography-electrospray ionization tandem mass spectrometry. AB - The use of nitrofurans as veterinary drugs has been banned from intensive animal production in the European Union (EU) since 1993. The objective of the present study was to evaluate the accumulation and depletion of furaltadone and nifursol and their side-chain metabolites 5-methylmorpholino-3-amino-2-oxazolidinone (AMOZ) and 3,5-dinitrosalicylic acid hydrazide (DNSAH) in eggs after administration of therapeutic and subtherapeutic doses of the drugs to laying hens during three consecutive weeks. LC-MS/MS, with positive and negative electrospray ionization methods, was used for the determination of parent compounds and metabolites in yolk and egg white and was validated according to criteria established by Commission Decision 2002/657/EC. The decision limit (CCalpha) and the detection capability (CCbeta) of the analytical methodology for metabolites were 0.1 and 0.5 MUg/kg for AMOZ and 0.3 and 0.9 MUg/kg for DNSAH, respectively. For the parent compounds, CCalpha and CCbeta were 0.9 and 2.0 MUg/kg for furaltadone and 1.3 and 3.1 MUg/kg for nifursol, respectively. The data obtained show that the parent compounds are much less persistent than their side-chain metabolites in either yolk or egg white. Between the studied metabolites, AMOZ is the most persistent and could be detected in either yolk or egg white three weeks following withdrawal from treatment. PMID- 22486661 TI - Journal of Environmental Science and Health, Part A. Toxic/hazardous substances and environmental engineering. Foreword. PMID- 22486662 TI - Combined biological and physicochemical waste-gas cleaning techniques. AB - This review presents a general overview of physical, chemical and biological waste-gas treatment techniques such as adsorption, absorption, oxidation and biodegradation, focusing more extensively on combined processes. It is widely recognized that biological waste-gas treatment devices such as biofilters and biotrickling filters can show high performance, often reaching removal efficiencies above 90 % for pollutant concentrations below 5 g/m(3). However, for concentrations exceeding this limit and under transient shock-load conditions that are frequently encountered in industrial situations, a physicochemical gas cleaning process can sometimes be advantageously combined with a biological one. Besides improving the overall treatment efficiency, the non-biological, first stage process could also serve as a load equalization system by reducing the pollutant load during periodic shock-loads, to levels that can easily be handled in the second-stage bioreactor. This article reviews the operational advantages of integrating different non-biological and biological processes, i.e., adsorption pre-treatment+bioreactor, bioreactor+adsorption post-treatment, absorption pre-treatment+bioreactor, UV pre-treatment+bioreactor, and bioreactor/bioreactor combinations, for waste-gas treatment, where different gas phase pollutants have been tested. PMID- 22486663 TI - Characterization of artificially dried biofilms for air biofiltration studies. AB - One of the main problems associated with the operation of air biofilters is the loss of performance caused by drying of the bioactive support, as the removal capacity of contaminants by the microorganisms is dependent on their water content. In this work, biofilms from a microbial consortium adapted to toluene were grown on stainless steel slides. The biofilms were dried in stoppered flasks with saturated saline solutions to obtain final water activities of 97.4 %, 83.9 %, 74.8 % and 32 %. The biofilms were characterized by a sorption isotherm Type III with toluene; the water desorption isotherm was fitted to the BET model and the biofilm hydrophobicity was also determined. Specific oxygen consumption rates decreased at lower Aw from 60 MUg O(2)/mg protein/h to zero activity. Biofilm activity, represented by a toluene consumption rate, and others physical properties presented a critical point between Aw 0.84 and 0.97. Biological activity of dried biofilms was restored either partially or completely, depending on the extent of drying and rewetting method. PMID- 22486664 TI - Microbial monitoring and performance evaluation for H2S biological air emissions control at a wastewater lift station in South Texas, USA. AB - A pilot-scale biological sequential treatment system consisting of a biotrickling filter and two biofilters was installed at Waste Water Lift Station # 64 in Brownsville, Texas, USA to evaluate the performance of the system being loaded with variable concentrations of wastewater hydrogen sulfide (H(2)S) emissions. In this study, the effectiveness of sulfur oxidizing bacteria along with the distribution of various sulfur species and their correlation with the performance of the biofilters was evaluated. The biofilters were packed with engineered media consisting of plastic cylinders with compacted organic material which was supplied by Met-Pro Environmental Air Solutions (formerly Bio.Reaction Industries). The overall performance of the pilot-scale biological sequential treatment system with an Empty Bed Residence Time (EBRT) of 60s and the overall performance of the biofilter unit with an EBRT of 35s developed a removal efficiency of > 99% at H(2)S levels up to 500 ppm. A decrease in performance over time was observed in the first and second sections of the first biofilter unit with the third section of the biofilter unit ultimately becoming the most robust unit removing most of the pollutant. The second biofilter unit was not needed and subsequently removed from the system. The number of CFUs in sulfur oxidizing T.thioparus selective media grew significantly in all four sections of the biofilter over the two months of pilot operation of the biological unit. The sulfur oxidizer growth rates appeared to be highest at low total sulfur content and at slightly acidic pH levels. This study has implications for improving the understanding of the distribution of sulfur oxidizing bacteria throughout the length of the biofilter columns, which can be used to further optimize performance and estimate breakthrough at these very high H(2)S input loadings. PMID- 22486665 TI - Extremely acidophilic sulfur-oxidizing bacteria applied in biotechnological processes for gas purification. AB - Extreme acidophilic (pH ~ 0.25) microorganisms have been studied and applied to treat volatile sulfur emissions like carbon disulfide. These microorganisms provide opportunities for biomass control and recycling of sulfuric acid using extremely low pH operating conditions as shown in 70 L bench-scale bioreactors. Applying the extreme acidophilic bacteria in full-scale bioreactors treating carbon disulfide in combination with hydrogen sulfide emissions from industrial processes like the viscose industry was shown to be effective with average total sulfur removal efficiency above 90%. PMID- 22486666 TI - Hydrogen sulfide and odor removal by field-scale biotrickling filters: influence of seasonal variations of load and temperature. AB - Two biotrickling filters were set up at two wastewater treatment plants (WWTP) in The Netherlands to investigate their effectiveness for treatment of odorous waste gases from different sources. One biotrickling filter was installed at Nieuwe Waterweg WWTP in Hook of Holland to study the hydrogen sulfide removal from headworks waste air. The other reactor was installed at Harnaschpolder WWTP (treating wastewater of the city of The Hague) to remove mercaptans and other organic compounds (odor) coming from the emissions of the anaerobic tanks of the biological nutrient removal (BNR) activated sludge. The performance of both units showed a stable and highly efficient operation under seasonal variations of load and temperature over nearly one year of monitoring. The Nieuwe Waterweg unit achieved removals of up to 99%, corresponding to a maximum daily average elimination capacity (EC) of 55.8 g H(2)S/m(3)/h at an empty bed residence time (EBRT) as short as 8.5 s. Odor reduction at the Harnaschpolder unit was 95% at an EBRT of 18.9 s, with average outlet concentration lower than the objective value which was established as 1000 European Odor Units (OU(E)/m(3)). PMID- 22486667 TI - Parameters affecting HS emissions removal and re-circulating water quality in a pilot-scale sequential biological treatment system at a wastewater lift station in Brownsville, Texas, USA. AB - In this study, a pilot-scale sequential biological treatment system combining a biotrickling filter and biofilter was used to optimize the removal of variable emission H(2)S loadings ranging from 30 to 120 g m(-3) h(-1)at a wastewater lift station in Brownsville, Texas USA. The biotrickling filter recycle water pH remained between 2.0 to 3.0 during the four months of unit operation and the overall removal efficiency for H(2)S was >99%. The biotrickling filter removal efficiency was 70 +/- 8%, with an elimination capacity of 10 to 80 g m(-3) h(-1) while the biofilter elimination capacity ranged from 10 to 40 g m(-3) h(-1). The sequential treatment system was operated initially at an Empty Bed Residence Time (EBRT) of 120 s (50 s for the biotrickling filter and 70 s for biofilter) for two months and then at an EBRT of 60 s (25 s for biotrickling filter and 35s for biofilter) for the remainder of the operating period; remarkably, there was only a slight decrease in removal efficiency at 60 s EBRT. In order to qualitatively evaluate the changes in recycle water quality in the system on the performance of the unit in precipitating sulfur species, the equilibrium chemical model, Visual MINTEQ was employed. The model predicted speciation results based on the feed water quality and sulfur loadings, and also forecast some iron-sulfur complexes which have potential to form some complex precipitates. This research demonstrated that low pH re-circulating water quality in the biological treatment of H(2)S was possible without compromising the high removal efficiency, and that an improved understanding of the recycle water chemistry of the trickling unit of a sequential treatment system could be useful in the overall optimization of the process. PMID- 22486668 TI - Strategies for pH control in a biofilter packed with sugarcane bagasse for hydrogen sulfide removal. AB - The biological removal of hydrogen sulfide at low concentration (<120 ppmv) was studied in a laboratory-scale biofilter packed with sugarcane bagasse and inoculated with a sulfur-oxidizing bacterial consortium isolated from activated sludge from a wastewater treatment plant (WWTP). Inlet loads from 1.31 to 20.2 g Sm(-3) h(-1) were supplied to the biofilter, and empty bed residence times (EBRTs) of 30, 20 and 10 s were tested. In all cases, the removal efficiency was greater than 99%. Two methods for the pH control were tested: increasing the phosphate buffer capacity of the mineral medium (method I), and a new method, which involves the addition of solid CaCO(3) to the bagasse at the upper inlet of the biofilter (method II). For method I, pH increased gradually along the bed (from the bottom to the top), from a constant value of 3.0 to 7.0. For method II, pH was constant (2.4 +/- 0.8) along the bed, and then a steep increase of pH was observed at the top to 7.1. We suggest the use of CaCO(3) instead of phosphate buffer because the former is less expensive, it is a simple method and the results obtained with the two methods are similar. PMID- 22486669 TI - Preferences in removal of aliphatic and aromatic gasoline components by biofiltration under varied loading. AB - Removal of gasoline vapors from waste air was investigated in a bench-scale perlite biofilter for three aromatic-to-aliphatic mass ratios (62/38, 92/8 and 44/56) under different loads, varied by changing both the substrate inlet concentration and air flow rate. The measurement of concentration profiles along the bed height allowed for an assessment of interactions between the aromatic and aliphatic fractions of gasoline. Variations in both the inlet concentrations and empty bed residence time significantly influenced the removal of aliphatic gasoline components. Except for the lowest organic loads, the whole biofilter bed was required for achieving an acceptable removal efficiency of aliphatic hydrocarbons. The presence of large amounts of aromatics negatively impacted the removal of aliphatics. By contrast, the aromatic gasoline components were near completely removed from any mixtures; the bulk of them were degraded in the first (out of three) biofilter section, even at high concentrations of aliphatic hydrocarbons. The observed effect was shown to be due to competitive interactions of aliphatic and aromatic components, which is consistent with the biological steps being rate limiting. Mass transfer, particularly for aliphatic components due to their high Henry's law constants, was shown to be rate-limiting under extreme scenarios, such as low loading rates and EBRT. PMID- 22486670 TI - Biofiltration of gasoline and ethanol-amended gasoline vapors. AB - Assuming the projected increase in use of ethanol as a biofuel, the current study was conducted to compare the biofiltration efficiencies for plain and 25% ethanol containing gasoline. Two biofilters were operated in a downflow mode for 7 months, one of them being compost-based whereas the other using a synthetic packing material, granulated tire rubber, inoculated with gasoline-degrading microorganisms. Inlet concentrations measured as total hydrocarbon (TH) ranged from 1.9 to 5.8 g m(-3) at a constant empty bed retention time of 6.84 min. Contrary to the expectations based on microbiological considerations, ethanol amended gasoline was more readily biodegraded than plain hydrocarbons, with the respective steady state elimination capacities of 26-43 and 14-18 gTH m(-3) h(-1) for the compost biofilter. The efficiency of both biofilters significantly declined upon the application of higher loads of plain gasoline, yet immediately recovering when switched back to ethanol-blended gasoline. The unexpected effect of ethanol in promoting gasoline biodegradation was explained by increasing hydrocarbon partitioning into the aqueous phase, with mass transfer being rate limiting for the bulk of components. The tire rubber biofilter, after a long acclimation, surpassed the compost biofilter in performance, presumably due to the 'buffering' effect of this packing material increasing the accessibility of gasoline hydrocarbons to the biofilm. With improved substrate mass transfer, biodegradable hydrocarbons were removed in the tire rubber biofilter's first reactor stage, with most of the remaining poorly degradable smaller-size hydrocarbons being degraded in the second stage. PMID- 22486671 TI - Biodegradation of methyl tert-butyl ether by cometabolism with hexane in biofilters inoculated with Pseudomonas aeruginosa. AB - Biodegradation of methyl tert-butyl ether (MTBE) vapors by cometabolism with gaseous hexane (n-hexane > 95%) was investigated using Pseudomonas aeruginosa utilizing short chain aliphatic hydrocarbon (C(5)-C(8)). Kinetic batch experiments showed that MTBE was degraded even when hexane was completely exhausted with a cometabolic coefficient of 1.06 +/- 0.16 mg MTBE mg hexane(-1). Intermediate tert-butyl alcohol (TBA) accumulation was observed followed by its gradual consumption. A maximum MTBE elimination capacity (EC(MAX)) of 35 g m(-3) h(-1) and removal efficiency (RE) of 70% were attained in mineral medium amended biofilters having an empty bed residence time (EBRT) of 1 min. For these experimental conditions, a maximum hexane EC of approximately 60 g m(-3) h(-1) was obtained at a load of 75 g m(-3) h(-1). Experiments under transient conditions revealed a competitive substrate interaction between MTBE and hexane. Biomass densities between 5.8 and 12.6 g L(biofilter) (-1) were obtained. Nevertheless, production of biopolymers caused non-uniform distribution flow rates that reduced the performance. Residence time distribution profiles showed an intermediate dispersion flow rate with a dispersion coefficient of 0.8 cm(2) s(-1). PMID- 22486672 TI - Kinetics and simulations of substrate interactions during the biodegradation of benzene, toluene, p-xylene and styrene. AB - Air streams commonly emitted from industrial sources generally contain various mixtures of volatile organic compounds (VOCs), and these complex mixtures can present challenges with respect to bioreactor design and applications. In this study, therefore, a modified Monod-type model using interaction parameters was employed to describe the biodegradation kinetics of mixtures of aromatic compounds by a Pseudomonas isolate. In addition, the model and estimated parameters were utilized to predict the performance of a bubble-column bioreactor for the treatment of mixtures of benzene, toluene, p-xylene, and styrene (BTXS). Benzene, toluene and styrene, as individual substrates, were actively degraded by the bacterial culture, whereas p-xylene was not degraded as a single substrate. Relative to the single substrate experiments, the degradation of benzene and toluene was inhibited by the other compounds, while the degradation of styrene was significantly stimulated in the presence of the other BTXS compounds. The cometabolic degradation of p-xylene was observed in the presence of benzene and toluene. The estimated interaction parameters indicated that the degradation of benzene was substantially inhibited in the presence of styrene, whereas the degradation of styrene was strongly stimulated by toluene. The kinetic coefficients and interaction parameters were used to successfully predict the biodegradation kinetics and performance of a bioreactor subjected to the quaternary mixture. Overall, the model was able to provide reasonable predictions when substrate interactions, including inhibition, stimulation, and cometabolism, play significant roles in biodegradation processes. PMID- 22486673 TI - Biofiltration of paint solvent mixtures in two reactor types: overloading by polar components. AB - Steady-state performances of a trickle bed reactor (TBR) and a biofilter (BF) in loading experiments with increasing inlet concentrations of polar solvents, acetone, methyl ethyl ketone, methyl isobutyl ketone and n-butyl acetate, were investigated, along with the system's dynamic responses. Throughout the entire experimentation time, a constant loading rate of aromatic components of 4 g(c).m( 3).h(-1) was maintained to observe the interactions between the polar substrates and aromatic hydrocarbons. Under low combined substrate loadings, the BF outperformed TBR not only in the removal of aromatic hydrocarbons but also in the removal of polar substrates. However, increasing the loading rate of polar components above the threshold value of 31-36 g(c).m(-3).h(-1) resulted in a steep and significant drop in the removal efficiencies of both polar (except for butyl acetate) and hydrophobic components, which was more pronounced in the BF; so the relative TBR/BF efficiency became reversed under such overloading conditions. A step-drop of the overall OL(POLAR) (combined loading by polar air pollutants) from overloading values to 7 g(c).m(-3).h(-1) resulted in an increase of all pollutant removal efficiencies, although in TBR the recovery was preceded by lag periods lasting between 5 min (methyl ethyl ketone) to 3.7 h (acetone). The occurrence of lag periods in the TBR recovery was, in part, due to the saturation of mineral medium with water-soluble polar solvents, particularly, acetone. The observed bioreactor behavior was consistent with the biological steps being rate-limiting. PMID- 22486674 TI - Removal of gaseous trichloroethylene (TCE) in a composite membrane biofilm reactor. AB - A membrane biofilm reactor (MBfR) was investigated for the degradation of trichloroethylene (TCE) vapors inoculated by Burkholderia vietnamiensis G4. Toluene (TOL) was used as the primary substrate. The MBfR was loaded sequentially with TOL, TCE (or both) during 110 days. In this study, a maximum steady-state TCE removal efficiency of 23% and a maximum volumetric elimination capacity (EC) of 2.1 g m(-3) h(-1) was achieved. A surface area based maximum elimination capacity (EC(m)) of 4.2 * 10(-3) g m(-2) h(-1) was observed, which is 2-10 times higher than reported in other gas phase biological treatment studies. However, further research is needed to optimize the TCE feeding cycle and to evaluate the inhibiting effects of TCE and its intermediates on TOL biodegradation. PMID- 22486675 TI - Biofiltration of air polluted with methane at concentration levels similar to swine slurry emissions: influence of ammonium concentration. AB - An evaluation of the effect of ammonium on the performance of two up-flow inorganic packed bed biofilters treating methane was conducted. The air flow rate was set to 3.0 L min(-1) for an empty bed residence time of 6.0 min. The biofilter was fed with a methane concentration of 0.30% (v/v). The ammonium concentration in the nutrient solution was increased by small increments (from 0.01 to 0.025 gN-NH(4) (+) L(-1)) for one biofilter and by large increments of 0.05 gN-NH(4) (+) L(-1) in the other biofilter. The total concentration of nitrogen was kept constant at 0.5 gN-NH(4) (+) L(-1) throughout the experiment by balancing ammonium with nitrate. For both biofilters, the methane elimination capacity, carbon dioxide production, nitrogen bed retention and biomass content decreased with the ammonium concentration in the nutrient solution. The biofilter with smaller ammonium increments featured a higher elimination capacity and carbon dioxide production rate, which varied from 4.9 to 14.3 g m(-3) h(-1) and from 11.5 to 30 g m(-3) h(-1), respectively. Denitrification was observed as some values of the nitrate production rate were negative for ammonium concentrations below 0.2 gN-NH(4) (+) L(-1). A Michalelis-Menten-type model fitted the ammonium elimination rate and the nitrate production rate. PMID- 22486676 TI - Abatement of synthetic landfill gas including limonene by biotrickling filter and membrane biofiltration. AB - In this study, a single silicone rubber membrane biofilter was compared to a lava rock biotrickling filter to examine the aerobic biofiltration of synthetic landfill gas including odorous limonene. The membrane bioreactor and biotrickling filter showed, respectively, maximum elimination capacities of 17 g m(-3) h(-1) and 31.3 g m(-3) h(-1) for limonene and removal efficiencies of 11 % and 18 % for methane. The membrane bioreactor was apparently mass transfer-limited and the biotrickling filter was reaction-limited. PMID- 22486677 TI - Mental representations of attachment figures facilitate recovery following upsetting autobiographical memory recall. AB - A growing literature shows that even the symbolic presence of an attachment figure facilitates the regulation of negative affect triggered by external stressors. Yet, in daily life, pernicious stressors are often internally generated--recalling an upsetting experience reliably increases negative affect, rumination, and susceptibility to physical and psychological health problems. The present research provides the first systematic examination of whether activating the mental representation of an attachment figure enhances the regulation of affect triggered by thinking about upsetting memories. Using 2 different techniques for priming attachment figure representations and 2 types of negative affect measures (explicit and implicit), activating the mental representation of an attachment figure (vs. an acquaintance or stranger) after recalling an upsetting memory enhanced recovery--eliminating the negative effects of the memory recall (Studies 1-3). In contrast, activating the mental representation of an attachment figure before recalling an upsetting memory had no such effect (Studies 1 and 2). Furthermore, activating the mental representation of an attachment figure after thinking about upsetting memories reduced negative thinking in a stream of consciousness task, and the magnitude of the attachment induced affective recovery effects as assessed with explicit affect measures predicted mental and physical health in daily life (Study 3). Finally, a meta analysis of the 3 studies (Study 4) showed that the regulatory benefits conferred by the mental representation of an attachment figure were weaker for individuals high on attachment avoidance. The implications of these findings for attachment, emotion regulation, and mental and physical health are discussed. PMID- 22486678 TI - Beyond gains and losses: the effect of need on risky choice in framed decisions. AB - Substantial evidence suggests people are risk-averse when making decisions described in terms of gains and risk-prone when making decisions described in terms of losses, a phenomenon known as the framing effect. Little research, however, has examined whether framing effects are a product of normative risk sensitive cognitive processes. In 5 experiments, it is demonstrated that framing effects in the Asian disease problem can be explained by risk-sensitivity theory, which predicts that decision makers adjust risk acceptance on the basis of minimal acceptable thresholds, or need. Both explicit and self-determined need requirements eliminated framing effects and affected risk acceptance consistent with risk-sensitivity theory. Furthermore, negative language choice in loss frames conferred the perception of high need and led to the construction of higher minimal acceptable thresholds. The results of this study suggest that risk sensitivity theory provides a normative rationale for framing effects based on sensitivity to minimal acceptable thresholds, or needs. PMID- 22486679 TI - High normal HbA(1c) levels were associated with impaired insulin secretion without escalating insulin resistance in Japanese individuals: the Toranomon Hospital Health Management Center Study 8 (TOPICS 8). AB - AIMS: We aimed to characterize the association of insulin resistance, impaired insulin secretion and beta-cell dysfunction in relation to HbA(1c) levels in a non-diabetic range in Japanese individuals without clinically diagnosed diabetes. METHODS: This cross-sectional study included 1444 individuals without a history of outpatient treatment of diabetes or use of insulin or oral hypoglycaemic agents. The homeostasis model assessment of insulin resistance and beta-cell function, insulinogenic index, Matsuda index and disposition index were calculated using data from 75-g oral glucose tolerance tests and compared across quintile (Q) categories of HbA(1c) levels. RESULTS: Fasting plasma glucose and 30 min and 60-min plasma glucose (PG) levels were significantly higher when HbA(1c) exceeded 36 mmol/mol (5.4%). A HbA(1c) concentration of 36-37 mmol/mol (5.4-5.5%) (Q3) was significantly associated with a 15% lower homeostasis model assessment of beta-cell function value and 31% lower insulinogenic index value compared with HbA(1c) <= 32 mmol/mol (<= 5.1%) (Q1) (P <0.01). Further, a HbA(1c) concentration of 38-40 mmol/mol (5.6-5.8%) (Q4) was associated with 17% (P <0.01) and 24% (P <0.05) reductions in those indexes, respectively. However, the homeostasis model assessment of insulin resistance was not significantly elevated and the Matsuda index was not significantly lower unless HbA(1c) exceeded 41 mmol/mol (5.9%). Individuals with HbA(1c) >= 41 mmol/mol (>= 5.9%) (Q5) had a 69% lower disposition index than those with a HbA(1c) concentration of <= 32 mmol/mol (<= 5.1%) (Q1). CONCLUSIONS: Elevated HbA(1c) levels >= 41 mmol/mol (>= 5.9%) were associated with substantial reductions in insulin secretion, insulin sensitivity and beta-cell dysfunction in Japanese individuals not treated for diabetes. High normal HbA(1c) levels of 36-40 mmol/mol (5.4-5.8%) were also associated with impaired insulin secretion without marked insulin resistance in Japanese individuals. PMID- 22486680 TI - Two-dimensional liquid chromatography-tandem mass spectrometry coupled with isobaric tags for relative and absolute quantification (iTRAQ) labeling approach revealed first proteome profiles of pulmonary alveolar macrophages infected with porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome (PRRS) has devastated the pig industry worldwide for almost 25 years, and its virus (PRRSV) preferentially infects and replicates in pulmonary alveolar macrophages (PAMs). To discover cellular protein responses in PRRSV-infected PAMs, two-dimensional liquid chromatography-tandem mass spectrometry coupled with isobaric tags for relative and absolute quantification (iTRAQ) labeling was employed to quantitatively identify the differentially expressed proteins between the PRRSV-infected groups and the controls. A total of 160 cellular proteins in PAMs that were significantly altered post-infection were identified. These differentially expressed proteins are related to the biological processes of virus binding, cell structure, signal transduction, cell adhesion, etc., and their interactions. This is the first report that analyzed the cellular protein profile of PRRSV-infected PAMs using iTRAQ technology, and this data provides important information to help understand the host response to PRRSV and to define the cellular requirements for the underlying mechanism of PRRSV replication and pathogenesis. PMID- 22486681 TI - What uses are mating types? The "developmental switch" model. AB - Why mating types exist at all is subject to much debate. Among hypotheses, mating types evolved to control organelle transmission during sexual reproduction, or to prevent inbreeding or same-clone mating. Here I review data from a diversity of taxa (including ciliates, algae, slime molds, ascomycetes, and basidiomycetes) to show that the structure and function of mating types run counter the above hypotheses. I argue instead for a key role in triggering developmental switches. Genomes must fulfill a diversity of alternative programs along the sexual cycle. As a haploid gametophyte, an individual may grow vegetatively (through haploid mitoses), or initiate gametogenesis and mating. As a diploid sporophyte, similarly, it may grow vegetatively (through diploid mitoses) or initiate meiosis and sporulation. Only diploid sporophytes (and not haploid gametophytes) should switch on the meiotic program. Similarly, only haploid gametophytes (not sporophytes) should switch on gametogenesis and mating. And they should only do so when other gametophytes are ready to do the same in the neighborhood. As argued here, mating types have evolved primarily to switch on the right program at the right moment. PMID- 22486682 TI - Functional pleiotropy and mating system evolution in plants: frequency independent mating. AB - Mutations that alter the morphology of floral displays (e.g., flower size) or plant development can change multiple functions simultaneously, such as pollen export and selfing rate. Given the effect of these various traits on fitness, pleiotropy may alter the evolution of both mating systems and floral displays, two characters with high diversity among angiosperms. The influence of viability selection on mating system evolution has not been studied theoretically. We model plant mating system evolution when a single locus simultaneously affects the selfing rate, pollen export, and viability. We assume frequency-independent mating, so our model characterizes prior selfing. Pleiotropy between increased viability and selfing rate reduces opportunities for the evolution of pure outcrossing, can favor complete selfing despite high inbreeding depression, and notably, can cause the evolution of mixed mating despite very high inbreeding depression. These results highlight the importance of pleiotropy for mating system evolution and suggest that selection by nonpollinating agents may help explain mixed mating, particularly in species with very high inbreeding depression. PMID- 22486683 TI - Local selection underlies the geographic distribution of sex-ratio drive in Drosophila neotestacea. AB - "Selfish" genetic elements promote their own transmission to the next generation, often at a cost to the host individual. A sex-ratio (SR) driving X chromosome prevents the maturation of Y-bearing sperm, and as a result is transmitted to 100% of the offspring, all of which are female. Because the spread of a SR chromosome can result in a female-biased population sex ratio, the ecological and evolutionary consequences of harboring this selfish element can be severe. In this study, we show that the prevalence of SR drive in Drosophila neotestacea varies between 0% and 30% among populations, and is common in the south whereas rare in the north. The prevalence of SR is not associated with the presence of suppressors of drive, geographic distance, or genetic distance based on autosomal microsatellite loci. Instead, our results indicate that ecological selection on SR drive varies among populations, as the prevalence of SR is highly correlated with climatic factors, with the severity of winter the best determinant of SR frequency. Thus, ecological and demographic factors may have significant consequences for the short and long term evolutionary dynamics of selfish elements and the manner with which they coevolve with the rest of the genome. PMID- 22486684 TI - Does hybridization drive the transition to asexuality in diploid Boechera? AB - Gametophytic apomixis is a common form of asexual reproduction in plants. Virtually all gametophytic apomicts are polyploids, and some view polyploidy as a prerequisite for the transition to apomixis. However, any causal link between apomixis and polyploidy is complicated by the fact that most apomictic polyploids are allopolyploids, leading some to speculate that hybridization, rather than polyploidy, enables apomixis. Diploid apomixis presents a rare opportunity to isolate the role of hybridization, and a number of diploid apomicts have been documented in the genus Boechera (Brassicaceae). Here, we present the results of a microsatellite study of 1393 morphologically and geographically diverse diploid individuals, evaluating the hypothesis that diploid Boechera apomicts are hybrids. This genus-wide dataset was made possible by the applicability of a core set of microsatellite loci in 69 of the 70 diploid Boechera species and by our ability to successfully genotype herbarium specimens of widely varying ages. With few exceptions, diploid apomicts exhibited markedly high levels of heterozygosity resulting from the combination of disparate genomes. This strongly suggests that most apomictic diploid Boechera lineages are of hybrid origin, and that the genomic consequences of hybridization allow for the transition to gametophytic apomixis in this genus. PMID- 22486685 TI - Assessing adaptive phenotypic plasticity by means of conditional strategies from empirical data: the latent environmental threshold model. AB - Conditional strategies are the most common form of discrete phenotypic plasticity. In a conditional strategy, the phenotype expressed by an organism is determined by the difference between an environmental cue and a threshold, both of which may vary among individuals. The environmental threshold model (ETM) has been proposed as a mean to understand the evolution of conditional strategies, but has been surprisingly seldom applied to empirical studies. A hindrance for the application of the ETM is that often, the proximate cue triggering the phenotypic expression and the individual threshold are not measurable, and can only be assessed using a related observable cue. We describe a new statistical model that can be applied in this common situation. The Latent ETM (LETM) allows for a measurement error in the phenotypic expression of the individual environmental cue and a purely genetically determined threshold. We show that coupling our model with quantitative genetic methods allows an evolutionary approach including an estimation of the heritability of conditional strategies. We evaluate the performance of the LETM with a simulation study and illustrate its utility by applying it to empirical data on the size-dependent smolting process for stream-dwelling Atlantic salmon juveniles. PMID- 22486686 TI - Pervasive genetic integration directs the evolution of human skull shape. AB - It has long been unclear whether the different derived cranial traits of modern humans evolved independently in response to separate selection pressures or whether they resulted from the inherent morphological integration throughout the skull. In a novel approach to this issue, we combine evolutionary quantitative genetics and geometric morphometrics to analyze genetic and phenotypic integration in human skull shape. We measured human skulls in the ossuary of Hallstatt (Austria), which offer a unique opportunity because they are associated with genealogical data. Our results indicate pronounced covariation of traits throughout the skull. Separate simulations of selection for localized shape changes corresponding to some of the principal derived characters of modern human skulls produced outcomes that were similar to each other and involved a joint response in all of these traits. The data for both genetic and phenotypic shape variation were not consistent with the hypothesis that the face, cranial base, and cranial vault are completely independent modules but relatively strongly integrated structures. These results indicate pervasive integration in the human skull and suggest a reinterpretation of the selective scenario for human evolution where the origin of any one of the derived characters may have facilitated the evolution of the others. PMID- 22486687 TI - Morphological integration in the hominin dentition: evolutionary, developmental, and functional factors. AB - As the most common and best preserved remains in the fossil record, teeth are central to our understanding of evolution. However, many evolutionary analyses based on dental traits overlook the constraints that limit dental evolution. These constraints are diverse, ranging from developmental interactions between the individual elements of a homologous series (the whole dentition) to functional constraints related to occlusion. This study evaluates morphological integration in the hominin dentition and its effect on dental evolution in an extensive sample of Plio- and Pleistocene hominin teeth using geometric morphometrics and phylogenetic comparative methods. Results reveal that premolars and molars display significant levels of covariation; that integration is stronger in the mandibular dentition than in the maxillary dentition; and that antagonist teeth, especially first molars, are strongly integrated. Results also show an association of morphological integration and evolution. Stasis is observed in elements with strong functional and/or developmental interactions, namely in first molars. Alternatively, directional evolution (and weaker integration) occurs in the elements with marginal roles in occlusion and mastication, probably in response to other direct or indirect selective pressures. This study points to the need to reevaluate hypotheses about hominin evolution based on dental characters, given the complex scenario in which teeth evolve. PMID- 22486688 TI - Vertebral evolution and the diversification of squamate reptiles. AB - Taxonomic, morphological, and functional diversity are often discordant and independent components of diversity. A fundamental and largely unanswered question in evolutionary biology is why some clades diversify primarily in some of these components and not others. Dramatic variation in trunk vertebral numbers (14 to >300) among squamate reptiles coincides with different body shapes, and snake-like body shapes have evolved numerous times. However, whether increased evolutionary rates or numbers of vertebrae underlie body shape and taxonomic diversification is unknown. Using a supertree of squamates including 1375 species, and corresponding vertebral and body shape data, we show that increased rates of evolution in vertebral numbers have coincided with increased rates and disparity in body shape evolution, but not changes in rates of taxonomic diversification. We also show that the evolution of many vertebrae has not spurred or inhibited body shape or taxonomic diversification, suggesting that increased vertebral number is not a key innovation. Our findings demonstrate that lineage attributes such as the relaxation of constraints on vertebral number can facilitate the evolution of novel body shapes, but that different factors are responsible for body shape and taxonomic diversification. PMID- 22486689 TI - Body mass and foraging ecology predict evolutionary patterns of skeletal pneumaticity in the diverse "waterbird" clade. AB - Extensive skeletal pneumaticity (air-filled bone) is a distinguishing feature of birds. The proportion of the skeleton that is pneumatized varies considerably among the >10,000 living species, with notable patterns including increases in larger bodied forms, and reductions in birds employing underwater pursuit diving as a foraging strategy. I assess the relationship between skeletal pneumaticity and body mass and foraging ecology, using a dataset of the diverse "waterbird" clade that encompasses a broad range of trait variation. Inferred changes in pneumaticity and body mass are congruent across different estimates of phylogeny, whereas pursuit diving has evolved independently between two and five times. Phylogenetic regressions detected positive relationships between body mass and pneumaticity, and negative relationships between pursuit diving and pneumaticity, whether independent variables are considered in isolation or jointly. Results are generally consistent across different estimates of topology and branch lengths. "Predictive" analyses reveal that several pursuit divers (loons, penguins, cormorants, darters) are significantly apneumatic compared to their relatives, and provide an example of how phylogenetic information can increase the statistical power to detect taxa that depart from established trait correlations. These findings provide the strongest quantitative comparative support yet for classical hypotheses regarding the evolution of avian skeletal pneumaticity. PMID- 22486690 TI - Exploring patterns of interspecific variation in quantitative traits using sequential phylogenetic eigenvector regressions. AB - A number of metrics have been developed for estimating phylogenetic signal in data and to evaluate correlated evolution, inferring broad-scale evolutionary and ecological processes. Here, we proposed an approach called phylogenetic signal representation (PSR) curve, built upon phylogenetic eigenvector regression (PVR). In PVR, selected eigenvectors extracted from a phylogenetic distance matrix are used to model interspecific variation. In the PSR curve, sequential PVR models are fitted after successively increasing the number of eigenvectors and plotting their R(2) against the accumulated eigenvalues. We used simulations to show that a linear PSR curve is expected under Brownian motion and that its shape changes under alternative evolutionary models. The PSR area, expressing deviations from Brownian motion, is strongly correlated (r= 0.873; P < 0.01) with Blomberg's K statistics, so nonlinear PSR curves reveal if traits are evolving at a slower or higher rate than expected by Brownian motion. The PSR area is also correlated with phylogenetic half-life under an Ornstein-Uhlenbeck process, suggesting how both methods describe the shape of the relationship between interspecific variation and time since divergence among species. The PSR curve provides an elegant exploratory method to understand deviations from Brownian motion, in terms of acceleration or deceleration of evolutionary rates occurring at large or small phylogenetic distances. PMID- 22486691 TI - Direct benefits of genetic mosaicism and intraorganismal selection: modeling coevolution between a long-lived tree and a short-lived herbivore. AB - We model direct fitness benefits of genetic mosaicism for a long-lived tree in coevolution with a short-lived herbivore to test four hypotheses: that mosaicism reduces selection on the herbivore for resistance to plant defenses; that module level selection allows the individual tree to adapt to its herbivore; and that this benefits the tree population, increasing average tree fitness and reducing local adaptation of the herbivore. We show that: mosaicism does not sufficiently reduce selection for resistance in the herbivore to benefit the tree; that individual trees do benefit from module-level selection when somatic mutation introduces new defenses; and that mosaicism does reduce local adaptation in the herbivore, which increases average tree fitness. These results are robust to varying genetic assumptions of dominance and the somatic mutation rate, but only hold for sufficiently long-lived trees with relatively strong selection. We also show that a mixed reproductive strategy of primarily asexual reproduction interspersed with occasional sexual reproduction is effective in coevolving with the herbivore, as it maintains beneficial allele combinations. Finally, we argue that intraorganismal genetic heterogeneity need not threaten the integrity of the individual and may be adaptive when selection acts concordantly between levels. PMID- 22486692 TI - Specific interactions between host and parasite genotypes do not act as a constraint on the evolution of antiviral resistance in Drosophila. AB - Genetic correlations between parasite resistance and other traits can act as an evolutionary constraint and prevent a population from evolving increased resistance. For example, previous studies have found negative genetic correlations between host resistance and life-history traits. In invertebrates, the level of resistance often depends on the combination of the host and parasite genotypes, and in this study, we have investigated whether such specific resistance also acts as an evolutionary constraint. We measured the resistance of different genotypes of the fruit fly Drosophila melanogaster to different genotypes of a naturally occurring pathogen, the sigma virus. Using a multitrait analysis, we examine whether genetic covariances alter the potential to select for general resistance against all of the different viral genotypes. We found large amounts of heritable variation in resistance, and evidence for specific interactions between host and parasite, but these interactions resulted in little constraint on Drosophila evolving greater resistance. PMID- 22486693 TI - Exploring variation in fitness surfaces over time or space. AB - As the number of studies estimating selection on multiple traits has increased in recent years, fitness surfaces have become a fundamental tool for understanding multivariate selection and evolution. However, rigorous statistical comparisons of multivariate selection surfaces over time or space have been limited to parametric analyses of selection coefficients estimated using a quadratic regression model. Although parametric comparisons are useful when selection is approximately linear or quadratic in nature, they are limited when confronting the complex nature of rugged fitness surfaces. Here, I present a novel solution to comparing nonparametric fitness surfaces over time or space. Using a Tucker3 tensor decomposition, which is essentially a higher order principal components analysis, I show how major features of fitness surfaces can be compared statistically. Combined with a bootstrap algorithm, I develop three statistical tests that identify (1) differences in the shape of nonparametric fitness surfaces, (2) differences in the contribution of each surface to variation in fitness across time or space, and (3) specific areas of the surfaces (trait combinations) that vary significantly over time or space. I illustrate the tensor decomposition and statistical analyses using idealized fitness surfaces. PMID- 22486694 TI - Evidence for stabilizing selection and slow divergent evolution of male genitalia in a millipede (Antichiropus variabilis). AB - It is generally accepted that postcopulatory sexual selection drives rapid divergence of genital morphology among isolated populations. The mode of selection operating upon genitalia can be explored by comparing patterns of population divergence in genetic and genitalic traits. We collected Antichiropus variabilis millipedes from eight localities across the species range. Levels of among-population genetic divergence, at microsatellite loci, and the mitochondrial COI gene were very high. Following geometric morphometric analyses, genital morphology was also found to be highly divergent among the populations surveyed, whereas head morphology had not diverged as markedly. However, pairwise comparisons of F(ST) and P(ST) showed that among-population divergence in both genital and head shape was significantly lower than that experienced by neutral genetic markers. Our results suggest that the genitalia of A. variabilis are currently experiencing a period of stabilizing selection, the mode of selection expected for genitalia that function in species recognition via a "lock-and-key" mechanism. Our results demonstrate that although genital morphology can clearly diverge among genetically isolated populations, divergence is not necessarily as rapid as commonly argued, and continuous directional sexual selection may not always underpin the evolutionary divergence of male genitalia. PMID- 22486695 TI - Sexual, fecundity, and viability selection on flower size and number in a sexually dimorphic plant. AB - The evolution of sexual dimorphism will depend on how sexual, fecundity and viability selection act within each sex, with the different forms of selection potentially operating in opposing directions. We examined selection in the dioecious plant Silene latifolia using planted arrays of selection lines that differed in flower size (small vs. large). In this species, a flower size/number trade-off exists within each sex, and males produce smaller and more numerous flowers than females. Moreover, floral traits are genetically correlated with leaf physiology. Sexual selection favoring males in the small-flower line occurred via greater overlap in the timing of flower output between males from this line and females. Fecundity selection favored males with high flower production, as siring success was proportionate to pollen production. Viability selection opposed sexual selection, favoring males from the large-flower line. In females, fecundity and viability selection operated in the same direction, favoring those from the large-flower line via greater seed production and survival. These results concur with the pattern of floral sexual dimorphism. Together with previous results they suggest that the outcome of the different forms of selection will be environmentally dependent, and therefore help to explain variation among populations in sexually dimorphic traits. PMID- 22486696 TI - Positive feedback between ecological and reproductive character displacement in a young avian hybrid zone. AB - Character displacement can reduce costly interspecific interactions between young species. We investigated the mechanisms behind divergence in three key traits breeding habitat choice, timing of breeding, and plumage coloration-in Ficedula flycatchers. We found that male pied flycatchers became expelled from the preferred deciduous habitat into mixed forest as the superior competitor, collared flycatchers, increased in numbers. The peak in food abundance differs between habitats, and the spatial segregation was paralleled by an increased divergence in timing of breeding between the two species. Male pied flycatchers vary from brown to black with brown coloration being more frequent in sympatry with collared flycatchers, a pattern often proposed to result from selection against hybridization, that is, reinforcement. In contrast to this view, we show that brown male pied flycatchers more often hybridize than black males. Male pied flycatcher plumage coloration influenced the territory obtained in areas of co occurrence with collared flycatchers, and brown male pied flycatchers experienced higher relative fitness than black males when faced with heterospecific competition. We suggest that allopatric divergence in resource defense ability causes a feedback loop at secondary contact where male pied flycatchers with the most divergent strategy compared to collared flycatchers are favored by selection. PMID- 22486697 TI - Genetic variation for postzygotic reproductive isolation between Caenorhabditis briggsae and Caenorhabditis sp. 9. AB - The process of speciation is key to the origins of biodiversity, and yet the Caenorhabditis nematode model system has contributed little to this topic. Genetic studies of speciation in the genus are now feasible, owing to crosses between the recently discovered Caenorhabditis sp. 9 and the well-known C. briggsae producing fertile F(1) hybrid females. We dissected patterns of postzygotic reproductive isolation between these species by crossing eight isogenic strains of C. briggsae reciprocally with six strains of C. sp. 9. We determined that overall patterns of reproductive isolation are robust across these genetic backgrounds. However, we also quantified significant heritable variation within each species for interspecific hybrid incompatibilities for total adult progeny, egg-to-adult viability, and the percentage of male progeny. This demonstrates that intraspecific variation for interspecific hybrid incompatibility occurs despite extensive, albeit incomplete, reproductive isolation. Therefore, this emerging general phenomenon of variable reproductive isolation is not restricted to highly interfertile, early-stage incipient species, but also applies to species in the latest stages of the speciation process. Furthermore, we confirm Haldane's rule and demonstrate strongly asymmetric parent-of-origin effects (Darwin's corollary) that consistently manifest more extremely when hermaphroditic C. briggsae serves as maternal parent. These findings highlight Caenorhabditis as an emerging system for understanding the genetics of general patterns of reproductive isolation. PMID- 22486698 TI - Prezygotic isolation between Saccharomyces cerevisiae and Saccharomyces paradoxus through differences in mating speed and germination timing. AB - Although prezygotic isolation between sympatric populations of closely related animal and plant species is well documented, far less is known about such evolutionary phenomena in sexual microbial species, as most are difficult to culture and manipulate. Using the molecular and genetic tools available for the unicellular fungus Saccharomyces cerevisiae, and applying them to S. paradoxus, we tested the behavior of individual cells from sympatric woodland populations of both species for evidence of prezygotic isolation. First, we confirmed previous observations that vegetative cells of both species mate preferentially with S. cerevisiae. Next, we found evidence for mate discrimination in spores, the stage in which outcrossing opportunities are most likely to occur. There were significant differences in germination timing between the species: under the same conditions, S. paradoxus spores do not begin germinating until almost all S. cerevisiae spores have finished. When germination time was staggered, neither species discriminated against the other, suggesting that germination timing is responsible for the observed mate discrimination. Our results indicate that the mechanisms of allochronic isolation that are well known in plants and animals can also operate in sexual microbes. PMID- 22486700 TI - Reductions in prolonged swimming capacity following freshwater colonization in multiple threespine stickleback populations. AB - We compared ancestral anadromous-marine and nonmigratory, stream-resident threespine stickleback (Gasterosteus aculeatus) populations to examine the outcome of relaxed selection on prolonged swimming performance. We reared marine and stream-resident fish from two locations in a common environment and found that both stream-resident populations had lower critical swimming speeds (U(crits) ) than marine populations. F1 hybrids from the two locations displayed significant differences in dominance, suggesting that the genetic basis for variation in U(crit) differs between locations. To determine which traits evolved in conjunction with, and may underlie, differences in performance capacity we measured a suite of traits known to affect prolonged swimming performance in fish. Although some candidate traits did not evolve (standard metabolic rate and two body shape traits), multiple morphological (pectoral fin size, shape, and four body shape measures) and physiological (maximum metabolic rate; MMR) traits evolved in the predicted direction in both stream-resident populations. However, data from F1 hybrids suggested that only one of these traits (MMR) had dominance effects similar to those of U(crit) in both locations. Overall, our data suggest that reductions in prolonged swimming performance were selected for in nonmigratory populations of threespine stickleback, and that decreases in MMR may mediate these reductions in performance. PMID- 22486701 TI - Convergence of life-history phenotypes in a Trinidadian killifish (Rivulus hartii). AB - Convergent evolution is characterized by the independent evolution of similar phenotypes within similar selective environments. Previous work on Trinidadian killifish, Rivulus hartii, demonstrated repeatable life-history differences across communities that differ in predation intensity. These studies were performed in rivers located on the south slope of Trinidad's Northern Range Mountains. There exists a parallel series of rivers on the north slope of these mountains. As on the south slope, Rivulus is found across a gradient of fish predation. However, the predatory fish species in north-slope rivers are derived from marine families, whereas south-slope rivers contain a predatory fish fauna characteristic of the South American mainland. If predator-induced mortality and the associated indirect effects are the causal factors selecting for life-history patterns in Rivulus, and these are similar in north- and south-slope rivers, then the specific predatory species should be interchangeable and we would expect convergence of life-history phenotypes across slopes. Here, we characterize the life-history phenotypes of Rivulus from north-slope communities by measuring number of eggs, egg weight, reproductive allotment, reproductive tissue weight, and size at maturity. We find similar patterns of life-history divergence across analogous predator communities. Between slopes, minor differences in Rivulus life history traits exist and one potential cause of these differences is the abundance of Macrobrachium prawns in north-slope rivers. PMID- 22486703 TI - Tragedy of the commons among antibiotic resistance plasmids. AB - As social interactions are increasingly recognized as important determinants of microbial fitness, sociobiology is being enlisted to better understand the evolution of clinically relevant microbes and, potentially, to influence their evolution to aid human health. Of special interest are situations in which there exists a "tragedy of the commons," where natural selection leads to a net reduction in fitness for all members of a population. Here, I demonstrate the existence of a tragedy of the commons among antibiotic resistance plasmids of bacteria. In serial transfer culture, plasmids evolved a greater ability to superinfect already-infected bacteria, increasing plasmid fitness when evolved genotypes were rare. Evolved plasmids, however, fell victim to their own success, reducing the density of their bacterial hosts when they became common and suffering reduced fitness through vertical transmission. Social interactions can thus be an important determinant of evolution for the molecular endosymbionts of bacteria. These results also identify an avenue of evolution that reduces proliferation of both antibiotic resistance genes and their bacterial hosts. PMID- 22486702 TI - Reconstructing the origins of high-alpine niches and cushion life form in the genus Androsace S.L. (Primulaceae). AB - Relatively, few species have been able to colonize extremely cold alpine environments. We investigate the role played by the cushion life form in the evolution of climatic niches in the plant genus Androsace s.l., which spreads across the mountain ranges of the Northern Hemisphere. Using robust methods that account for phylogenetic uncertainty, intraspecific variability of climatic requirements and different life-history evolution scenarios, we show that climatic niches of Androsace s.l. exhibit low phylogenetic signal and that they evolved relatively recently and punctually. Models of niche evolution fitted onto phylogenies show that the cushion life form has been a key innovation providing the opportunity to occupy extremely cold environments, thus contributing to rapid climatic niche diversification in the genus Androsace s.l. We then propose a plausible scenario for the adaptation of plants to alpine habitats. PMID- 22486704 TI - The expression of self-incompatibility in angiosperms is bimodal. AB - Self-incompatibility is expressed by nearly one-half of all angiosperms. A large proportion of the remaining species are self-compatible, and they either outcross using various contrivances or self-fertilize to some extent. Because of the common occurrence of populations and individuals with intermediate levels of self incompatibility, categorization of the expression of self-incompatibility as an approximately binary trait has become controversial. We collect a widely reported index (index of self-incompatibility [ISI]) used to asses the strength and variation of self-incompatibility from over 1200 angiosperm taxa. Its distribution is bimodal and positively associated with outcrossing rate, albeit with a weak relationship within self-compatible taxa. A substantial fraction of species has intermediate mean values of ISI. Their occurrence can be caused by segregating ephemeral self-compatible mutations, averaging artifacts, and experimental biases, in addition to the often invoked stabilizing selection acting on the expression of self-incompatibility. Selection may also generally favor taxa with high ISI values through increased lineage birth and death rates, and it may counter lower level selection advantages within taxa expressing intermediate and low values of ISI. Such a null hypothesis is nearly universally overlooked, despite the fact that it could adequately explain the observed distribution of mating and breeding systems. PMID- 22486699 TI - Tempo and mode of mating system evolution between incipient Clarkia species. AB - Mating systems are among the most labile characteristics of flowering plants, with transitions frequently occurring among populations or in association with speciation. The frequency of mating system shifts has made it difficult to reconstruct historical evolutionary dynamics unless transitions have been very recent. Here, we examine molecular and phenotypic variation to determine the polarity, timescale, and causes of a transition between outcrossing and self fertilization in sister subspecies of Clarkia xantiana. Phylogenetic analyses and coalescent-based estimates of the time to most recent common ancestor indicated that outcrossing is ancestral to selfing and that there has been a single origin of selfing. Estimates of divergence time between outcrossing and selfing subspecies were 10,000 (95% CI [credible interval]: 3169-66,889) and 65,000 years ago (95% CI: 33,035-151,448) based on two different methods, suggesting a recent and rapid evolutionary transition. Population genetic data indicated that the transition to selfing was associated with a 80% reduction in molecular diversity, which is much greater than the 50% reduction expected under a shift from obligate outcrossing to obligate self-fertilization alone. Our data also suggest that this severe loss of diversity was caused by colonization bottlenecks. Together with previous studies, evidence for reproductive assurance in C. xantiana now connects variation in plant-pollinator interactions in the field to phenotypic and molecular evolution. PMID- 22486705 TI - Evolution of premating reproductive isolation among conspecific populations of the sea rock-pool beetle Ochthebius urbanelliae driven by reinforcing natural selection. AB - How natural selection might be involved in speciation remains a fundamental question in evolutionary biology. When two or more species co-occur in the same areas, natural selection may favor divergence in mating traits. By acting in sympatric but not allopatric populations, natural selection can also affect mate choice within species and ultimately initiate speciation among conspecific populations. Here, we address this potential effect in the sea rock-pool beetles Ochthebius quadricollis and O. urbanelliae. The two species, which inhabit the Mediterranean coasts, co-occurr syntopically in an area along the Italian Tyrrhenian coast and completed reproductive isolation by reinforcement. In this article, through mating trials under laboratory conditions between conspecific populations, we found in O. quadricollis no deviations from random mating. Conversely, in O. urbanelliae, we found a clear pattern of premating isolation between the reinforced populations sympatric with O. quadricollis and those nonreinforced allopatric. This pattern is consistent with the view that natural selection, which completed the reproductive isolation between the two species in sympatry, led incidentally also to partial premating reproductive isolation (I(PSI) estimator from 0.683 to 0.792) between conspecific populations of O. urbanelliae. This case study supports an until recently underappreciated role of natural selection resulting from species interactions in initiating speciation. PMID- 22486706 TI - Low-energy H+ + H2 reactive collisions: mean-potential statistical model and role of permutation symmetry. AB - Statistical theory based on a mean isotropic potential deduced from a full potential energy surface is applied to the complex-forming, reactive H(+) + H(2) system in the interval of collision energies E(c) = 10(-3) to 0.5 eV. We present expressions for the reaction probabilities that incorporate the full permutation symmetry of the protons and compare our results with other statistical models and full quantum mechanical approaches that take account this symmetry correctly, approximately, or erroneously for the exchange rearrangement mechanism of the reaction. PMID- 22486707 TI - A questionnaire study to derive information on the working environment, clinical training, use of ancillary staff and optimization of patient radiation dose within UK dental practice. AB - AIM: To evaluate the working environment of GDPs and Endodontists and the methods used to optimize patient radiation dose. METHODOLOGY: A total of 857 GDPs and 170 specialist Endodontists were contacted. The responders, 603 of the former and 132 of the latter, completed a questionnaire covering practitioner demographics, pattern of practice, the use of radiographic techniques and the optimization of dose. Chi-squared tests were used to compare groups at the P=0.05 level of significance. For nonparametric data, the Mann-Whitney U-test was employed. RESULTS: A response rate of 73% was achieved. Overall, 79.5% of endodontic specialists used film holders compared with 65.9% of GDPs (P=0.001). One hundred and thirty (98.5%) endodontists and 581 (96.3%) GDPs reported that they were well prepared or adequately prepared in radiographically assessing the presence of apical pathosis. The study found significant differences (P<0.001) between the use of digital radiography by specialist endodontists 93 (70.5%) compared with general dental practitioners 167 (27.7%). Significant differences (P=0.004) were also observed in the use of rectangular collimation between endodontic specialists 55 (42%) and GDPs 223 (37%). With regard to the use of film holders in diagnostic radiography, 105 (79.5%) of endodontic specialists employed these devices compared with 396 (65.7%) GDPs; this finding was significant (P=0.005). For working length estimation, significant differences (P=0.001) were noted in the use of a film holder between endodontic specialists 105 (79.5%) and GDPs 386 (64%). CONCLUSIONS: Both Endodontists and GDPs demonstrated compliance with guidelines relating to radiation protection being more significant amongst those clinicians working within specialist clinical practice. PMID- 22486708 TI - Time-resolved indirect nanoplasmonic sensing spectroscopy of dye molecule interactions with dense and mesoporous TiO2 films. AB - Indirect nanoplasmonic sensing (INPS) is an experimental platform exploiting localized surface plasmon resonance (LSPR) detection of processes in nanomaterials, molecular assemblies, and films at the nanoscale. Here we have for the first time applied INPS to study dye molecule adsorption/impregnation of two types of TiO(2) materials: thick (10 MUm) mesoporous films of the kind used as photoanode in dye-sensitized solar cells (DSCs), with particle/pore size in the range of 20 nm, and thin (12-70 nm), dense, and flat films. For the thick-film experiments plasmonic Au nanoparticles were placed at the hidden, internal interface between the sensor surface and the mesoporous TiO(2). This approach provides a unique opportunity to selectively follow dye adsorption locally in the hidden interface region inside the material and inspires a generic and new type of nanoplasmonic hidden interface spectroscopy. The specific DSC measurement revealed a time constant of thousands of seconds before the dye impregnation front (the diffusion front) reaches the hidden interface. In contrast, dye adsorption on the dense, thin TiO(2) films exhibited much faster, Langmuir-like monolayer formation kinetics with saturation on a time scale of order 100 s. This new type of INPS measurement provides a powerful tool to measure and optimize dye impregnation kinetics of DSCs and, from a more general point of view, offers a generic experimental platform to measure adsorption/desorption and diffusion phenomena in solid and mesoporous systems and at internal hidden interfaces. PMID- 22486709 TI - Regulation and expression of IL-32 in chronic rhinosinusitis. AB - BACKGROUND: Activated T lymphocytes and their interaction with resident tissue cells, particularly epithelium, play important roles in inflammatory processes in chronic rhinosinusitis (CRS). IL-32 is a recently described cytokine, which is expressed in a variety of tissue cells and involved in the pathogenesis of several chronic inflammatory diseases. METHODS: Human sinus epithelial cells were isolated from biopsies and stimulated with different cytokines, which play a role in the pathogenesis of CRS. IL-32 mRNA expression was analyzed using real-time PCR, IL-32 protein was determined by Western blot and flow cytometry as well as immunofluorescent staining in primary sinus epithelial cells and nasal biopsies from patients with CRS and healthy controls. RESULTS: IL-32 mRNA was upregulated by TNF-alpha and IFN-gamma in primary sinus epithelial cells, whereas IL-1 beta, IL-4, IL-13, and IL-17 did not influence IL-32 expression. IL-32 mRNA expression was significantly higher in human primary sinonasal epithelial cells (HSECs) cocultured with Th1 cells compared with HSECs cocultured with Th0 or Th2 cells. IL-32 mRNA expression was significantly higher in biopsies from sinus epithelial tissue of CRS patients with nasal polyps compared with healthy subjects (P = 0.01). IL-32 was detected in biopsies from patients with CRS, whereas it was scarcely present in control tissues. CONCLUSION: The induction of IL-32 by TNF alpha, IFN-gamma and Th1 cells as well as its increased expression in sinus tissues from CRS patients with nasal polyps demonstrated a potential role for IL 32 in the pathogenesis of CRS. PMID- 22486711 TI - Dental implications of bisphophonate-related osteonecrosis. AB - OBJECTIVES: The aim is to explore the current theories about clinical , pathological and dental management of bisphosphonate related osteonecrosis of the jaws. Also discussed are the actions of bisphosphonates, pathogenesis related to the susceptibility of jaws, the predisposing risk factors for the development of bisphosphonate-related osteonecrosis of the jaws (BRONJ) and diagnostic criteria based on the literature review. DISCUSSION: Osteoporosis is a disease that generally affects the mineral status of both cortical and trabecular bone in post menopausal women. Bisphosphonates are a group of drugs that preserve and increase bone mass. Bisphosphonate drugs are classified according to use and method of delivery. The bisphosphonates used for the treatment of osteoporosis are taken orally. Little is known about the side effects and dangers of the long-term use of therapeutic doses of Bisphosphonates. A recent complication reported is osteonecrosis of jaws. The use of IV bisphosphonates for multiple myeloma and metastatic bone diseases suggests that dosage, length of treatment, and route of administration, as well as cofactors such as use of glucocorticoids and immunosuppressive agents, and dental surgery, could all be related to the incidence of BRONJ. This review provides an update on current knowledge about clinical, pathological and management aspects of BRONJ. CONCLUSIONS: Little evidence exists to direct the prosthodontic management of patients with a history of bisphosphonate use. Patients with active osteonecrosis related to bisphosphonate use have reduced tissue tolerance to function with removable prostheses and decreased potential for osseointegration of dental implants. Decisions should be based on clinical judgment tempered by the presenting conditions, medical profile, and patient needs. A better understanding would help in a dental setting to prevent any complication and help to improve the prognosis for those being treated for osteoradionecrosis.Until further evidence emerges regarding management of patients with active bisphosphonate- related osteonecrosis, conservative prosthodontic treatment is reasonable and prudent. PMID- 22486710 TI - Head-to-head prenyl tranferases: anti-infective drug targets. AB - We report X-ray crystallographic structures of three inhibitors bound to dehydrosqualene synthase from Staphylococcus aureus: 1 (BPH-651), 2 (WC-9), and 3 (SQ-109). Compound 2 binds to the S2 site with its -SCN group surrounded by four hydrogen bond donors. With 1, we report two structures: in both, the quinuclidine headgroup binds in the allylic (S1) site with the side chain in S2, but in the presence of PPi and Mg(2+), the quinuclidine's cationic center interacts with PPi and three Mg(2+), mimicking a transition state involved in diphosphate ionization. With 3, there are again two structures. In one, the geranyl side chain binds to either S1 or S2 and the adamantane headgroup binds to S1. In the second, the side chain binds to S2 while the headgroup binds to S1. These results provide structural clues for the mechanism and inhibition of the head-to-head prenyl transferases and should aid future drug design. PMID- 22486712 TI - Active energy harvesting from microbial fuel cells at the maximum power point without using resistors. AB - Microbial fuel cell (MFC) technology offers a sustainable approach to harvest electricity from biodegradable materials. Energy production from MFCs has been demonstrated using external resistors or charge pumps, but such methods can only dissipate energy through heat or receive electrons passively from the MFC without any controllability. This study developed a new approach and system that can actively extract energy from MFC reactors at any operating point without using any resistors, especially at the peak power point to maximize energy production. Results show that power harvesting from a recirculating-flow MFC can be well maintained by the maximum power point circuit (MPPC) at its peak power point, while a charge pump was not able to change operating point due to current limitation. Within 18-h test, the energy gained from the MPPC was 76.8 J, 76 times higher than the charge pump (1.0 J) that was commonly used in MFC studies. Both conditions resulted in similar organic removal, but the Coulombic efficiency obtained from the MPPC was 21 times higher than that of the charge pump. Different numbers of capacitors could be used in the MPPC for various energy storage requirements and power supply, and the energy conversion efficiency of the MPPC was further characterized to identify key factors for system improvement. This active energy harvesting approach provides a new perspective for energy harvesting that can maximize MFC energy generation and system controllability. PMID- 22486713 TI - Detection of BRCA1/2 mutations in breast cancer patients from Thailand and Pakistan. PMID- 22486714 TI - Yoga in schizophrenia: a systematic review of randomised controlled trials. AB - OBJECTIVE: The objective of this systematic review was to assess the effectiveness of yoga as a complementary treatment on general psychopathology, positive and negative symptoms and health-related quality of life (HRQL) for people with schizophrenia. METHOD: Randomised controlled trials (RCTs) were considered whether they investigated a yoga intervention in patients with schizophrenia. The selection of studies, data extraction and quality assessment were performed independently by two reviewers. RESULTS: Only three RCTs met the inclusion criteria. Lower Positive and Negative Syndrome Scale (PANSS) total scores and subscale scores for positive and negative symptoms were obtained after yoga compared with exercise or waiting list control conditions. In the same way, the physical, psychological, social and environmental HRQL as measured with the abbreviated version of the World Health Organization Quality of Life questionnaire (WHOQOL-BREF) increased more significantly after yoga than after exercise or waiting list control conditions. None of the RCTS encountered adverse events. Dose-response relationships could, however, not be determined. CONCLUSION: Although the number of RCTs included in this review was limited, results indicated that yoga therapy can be an useful add-on treatment to reduce general psychopathology and positive and negative symptoms. In the same way, HRQL improved in those antipsychotic-stabilised patients with schizophrenia following yoga. PMID- 22486715 TI - Polygonum sachalinense alters the balance between capacities of regeneration and carboxylation of ribulose-1,5-bisphosphate in response to growth CO2 increment but not the nitrogen allocation within the photosynthetic apparatus. AB - The limiting step of photosynthesis changes depending on CO(2) concentration and, in theory, photosynthetic nitrogen use efficiency at a respective CO(2) concentration is maximized if nitrogen is redistributed from non-limiting to limiting processes. It has been shown that some plants increase the capacity of ribulose-1,5-bisphoshate (RuBP) regeneration (evaluated as J(max) ) relative to the RuBP carboxylation capacity (evaluated as V(cmax) ) at elevated CO(2) , which is in accord with the theory. However, there is no study that tests whether this change is accompanied by redistribution of nitrogen in the photosynthetic apparatus. We raised a perennial plant, Polygonum sachalinense, at two nutrient availabilities under two CO(2) concentrations. The J(max) to V(cmax) ratio significantly changed with CO(2) increment but the nitrogen allocation among the photosynthetic apparatus did not respond to growth CO(2) . Enzymes involved in RuBP regeneration might be more activated at elevated CO(2) , leading to the higher J(max) to V(cmax) ratio. Our result suggests that nitrogen partitioning is not responsive to elevated CO(2) even in species that alters the balance between RuBP regeneration and carboxylation. Nitrogen partitioning seems to be conservative against changes in growth CO(2) concentration. PMID- 22486717 TI - Scan patterns predict sentence production in the cross-modal processing of visual scenes. AB - Most everyday tasks involve multiple modalities, which raises the question of how the processing of these modalities is coordinated by the cognitive system. In this paper, we focus on the coordination of visual attention and linguistic processing during speaking. Previous research has shown that objects in a visual scene are fixated before they are mentioned, leading us to hypothesize that the scan pattern of a participant can be used to predict what he or she will say. We test this hypothesis using a data set of cued scene descriptions of photo realistic scenes. We demonstrate that similar scan patterns are correlated with similar sentences, within and between visual scenes; and that this correlation holds for three phases of the language production process (target identification, sentence planning, and speaking). We also present a simple algorithm that uses scan patterns to accurately predict associated sentences by utilizing similarity based retrieval. PMID- 22486716 TI - Radiological response predicts survival following transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma. AB - BACKGROUND: It remains unclear whether initial compact lipiodol uptake after transarterial chemoembolisation (TACE) is associated with improved survival in patients with hepatocellular carcinoma (HCC). AIM: To reveal the clinical relevance of compact lipiodolisation after TACE. METHODS: We studied 490 patients with unresectable HCC who had first been treated with TACE. Compact lipiodolisation was defined as the absence of an arterial enhancing lesion, reflecting complete lipiodol uptake, as assessed by dynamic computed tomography (CT) 1 month after treatment. The rate of initial compact lipiodolisation was analysed according to multiplicity and size of tumour, and survival of patients who achieved compact lipiodolisation was compared to that of patients who did not. RESULTS: Of the 490 patients, 409 (83.5%) were in Child-Pugh class A and 81 (16.5%) in class B. The rate of initial compact lipiodolisation in single HCCs was higher than that in multinodular HCCs (33.7% vs. 14.6%, P < 0.001). Among single HCCs, the rate of compact lipiodolisation in tumours <=5, 5-10 and >10 cm was 46.6%, 13.6%, and 0% respectively. The 1-, 3- and 5-year survival rates of patients with compact uptake were 92.7%, 70.7% and 52.4% compared to 60.8%, 28.0% and 16.9% in patients with noncompact lipiodolisation. Multivariate analysis revealed that Child-Pugh class, alpha-fetoprotein level, tumour node metastasis stage, portal vein thrombosis and initial compact lipiodolisation were independent predictors of survival. CONCLUSIONS: Initial compact lipiodol uptake after transarterial chemoembolisation is associated with improved survival in patients with unresectable hepatocellular carcinoma. Accordingly, initial complete lipiodolisation should be considered a relevant therapeutic target. PMID- 22486718 TI - Expression of aquaporins in rat liver regeneration. AB - OBJECTIVE: The remarkable ability of liver to regenerate after insults has been harnessed by surgeons when designing techniques for liver resection or transplantation. However, the underlying mechanisms of liver regeneration are not fully clarified. On the other hand, aquaporins (AQPs) are small transmembrane proteins with unexpected physiological roles in addition to water transport. For example, they play pivotal roles in cell migration, angiogenesis, and cell proliferation, events that are also occurred during liver regeneration. We thus examined the possible involvement of AQPs in this regenerative process. MATERIAL AND METHODS: A two-thirds partial hepatectomy (PH) rat model was employed. The temporal expression of various AQPs in the liver following PH was determined by semiquantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. The localization of AQPs was evaluated by immunohistochemistry. RESULTS: As anticipated, AQP0, 8, 9, and 11 were detected mainly in hepatocytes; unexpectedly, Kupffer cells were observed to express AQP8 during a specific period of time in the regenerative process. AQP9 protein was shown to be expressed in a progressively enhanced pattern at early time points after PH. A transient expression of AQP11 in the nucleus of hepatocytes was observed. CONCLUSION: These findings suggest the possibility that AQP might be involved in the PH-induced liver regeneration. PMID- 22486720 TI - Recognition of heteropolysaccharide alginate by periplasmic solute-binding proteins of a bacterial ABC transporter. AB - Alginate is a heteropolysaccharide that consists of beta-D-mannuronate (M) and alpha-L-guluronate (G). The Gram-negative bacterium Sphingomonas sp. A1 directly incorporates alginate into the cytoplasm through the periplasmic solute-binding protein (AlgQ1 and AlgQ2)-dependent ABC transporter (AlgM1-AlgM2/AlgS-AlgS). Two binding proteins with at least four subsites strongly recognize the nonreducing terminal residue of alginate at subsite 1. Here, we show the broad substrate preference of strain A1 solute-binding proteins for M and G present in alginate and demonstrate the structural determinants in binding proteins for heteropolysaccharide recognition through X-ray crystallography of four AlgQ1 structures in complex with saturated and unsaturated alginate oligosaccharides. Alginates with different M/G ratios were assimilated by strain A1 cells and bound to AlgQ1 and AlgQ2. Crystal structures of oligosaccharide-bound forms revealed that in addition to interaction between AlgQ1 and unsaturated oligosaccharides, the binding protein binds through hydrogen bonds to the C4 hydroxyl group of the saturated nonreducing terminal residue at subsite 1. The M residue of saturated oligosaccharides is predominantly accommodated at subsite 1 because of the strict binding of Ser-273 to the carboxyl group of the residue. In unsaturated trisaccharide (DeltaGGG or DeltaMMM)-bound AlgQ1, the protein interacts appropriately with substrate hydroxyl groups at subsites 2 and 3 to accommodate M or G, while substrate carboxyl groups are strictly recognized by the specific residues Tyr-129 at subsite 2 and Lys-22 at subsite 3. Because of this substrate recognition mechanism, strain A1 solute-binding proteins can bind heteropolysaccharide alginate with different M/G ratios. PMID- 22486719 TI - Population pharmacokinetics of clindamycin orally and intravenously administered in patients with osteomyelitis. AB - AIMS: This study was performed to describe clindamycin, administered either orally or intravenously, concentration-time courses to patients with osteomyelitis, to study the effects of different covariates on clindamycin pharmacokinetics and to simulate an optimized administration scheme. METHODS: Clindamycin concentrations were measured in 50 patients. A total of 122 plasma concentrations were available (58 from oral administration and 64 from i.v. infusion). A population pharmacokinetic model was developed with MONOLIX 4 software. RESULTS: A one compartment model adequately described the data. Clindamycin clearance increased significantly with body weight (BW). The typical population estimates (interindividual variability) for clearance, volume of distribution and absorption rate constant were 16.2 l h(-1) (0.39), 70.2 l and 0.92 h(-1) , respectively. The bioavailability of the oral form was estimated to be 87.6%. According to BW, theoretical doses needed to reach a C(min) of 2 mg l( 1) were then calculated. CONCLUSIONS: The current recommendation of 600 mg three times daily seems to be effective up to 75 kg but the dose should be raised to 900 mg three times daily thereafter. These assumptions should be prospectively confirmed. PMID- 22486721 TI - A protective coat of microorganisms on macroalgae: inhibitory effects of bacterial biofilms and epibiotic microbial assemblages on barnacle attachment. AB - Effects of epibiotic bacteria associated with macroalgae on barnacle larval attachment were investigated. Eight bacterial isolates obtained from samples of three macroalga species were cultured as monospecies bacterial films and tested for their activity against barnacle (Amphibalanus improvisus) attachment in field experiments (Western Baltic Sea). Furthermore, natural biofilm communities associated with the surface of the local brown alga, Fucus vesiculosus, which were exposed to different temperatures (5, 15 and 20 degrees C), were harvested and subsequently tested. Generally, monospecies bacterial biofilms, as well as natural microbial assemblages, inhibited barnacle attachment by 20-67%. denaturing gradient gel electrophoresis fingerprints showed that temperature treatment shifted the bacterial community composition and weakened the repellent effects at 20 degrees C. Repellent effects were absent when settlement pressure of cyprids was high. Nonviable bacteria tended to repel cyprids when compared to the unfilmed surfaces. We conclude that biofilms can have a repellent effect benefiting the host by preventing heavy fouling on its surface. However, severe settlement pressure, as well as stressful temperature, may reduce the protective effects of the alga's biofilm. Our results add to the notion that the performance of F. vesiculosus may be reduced by multiple stressors in the course of global warming. PMID- 22486723 TI - Explain the A-V relationship. PMID- 22486722 TI - Effect of the novel low molecular weight hydrolyzed chicken sternal cartilage extract, BioCell Collagen, on improving osteoarthritis-related symptoms: a randomized, double-blind, placebo-controlled trial. AB - Osteoarthritis (OA) is a significant source of pain and disability. Current medical and surgical treatments can be costly and have serious side effects. The aim of this randomized, double-blind, placebo-controlled trial was to investigate the tolerability and efficacy of BioCell Collagen (BCC), a low molecular weight dietary supplement consisting of hydrolyzed chicken sternal cartilage extract, in the treatment of OA symptoms. Patients (n = 80) in the study had physician verified evidence of progressive OA in their hip and/or knee joint. Joint pain had been present for 3 months or longer at enrollment, and pain levels were 4 or higher at baseline as assessed by Physician Global Assessment scores. Subjects were divided into two groups and administered either 2 g of BCC or placebo for 70 days. Other outcome measurements included visual analogue scale (VAS) for pain and Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores taken on days 1, 35, and 70. The tolerability profile of the treatment group was comparable to that of the placebo. Intent-to-treat analysis showed that the treatment group, as compared to placebo, had a significant reduction of VAS pain on day 70 (p < 0.001) and of WOMAC scores on both days 35 (p = 0.017) and 70 (p < 0.001). The BCC group experienced a significant improvement in physical activities compared to the placebo group on days 35 (p = 0.007) and 70 (p < 0.001). BCC was well tolerated and found to be effective in managing OA associated symptoms over the study period, thereby improving patient's activities of daily living. BCC can be considered a potential complement to current OA therapies. PMID- 22486724 TI - Efficacy of low-level laser therapy (LLLT) in oral mucositis: what have we learned from randomized studies and meta-analyses? PMID- 22486725 TI - INPPL1 is associated with the metabolic syndrome in men with Type 1 diabetes, but not with diabetic nephropathy. AB - AIMS: The metabolic syndrome is a frequent phenomenon in people with Type 1 diabetes and is associated with diabetic nephropathy. The aim of this study was to investigate if the INPPL1 (inositol polyphosphate phosphatase-like 1) gene encoding lipid phosphatase SHIP2 is associated with the metabolic syndrome and diabetic nephropathy in Finnish people with Type 1 diabetes. METHODS: Participants were selected from the FinnDiane study for this cross-sectional study. The individuals were divided into controls without the metabolic syndrome (n = 1074) and cases with the metabolic syndrome (n = 1328), or into groups based upon their albumin excretion rate. Nine single-nucleotide polymorphisms covering the INPPL1 gene +/- 20 kb were genotyped. The associations between the single nucleotide polymorphisms and outcome variables were analysed with the chi(2) test and logistic regression. RESULTS: Two INPPL1 single-nucleotide polymorphisms, rs2276048 (silent mutation) and rs2276047 (intronic), were associated with the metabolic syndrome in men with odds ratios of 0.23 (95% CI 0.11-0.45, P = 2.1 * 10(-5) ), and 0.37 (0.21-0.65, P = 0.001), adjusted for age, duration of diabetes and history of smoking. When both sexes were included, these associations were less significant. No association between the genotyped single-nucleotide polymorphisms and diabetic nephropathy was observed. CONCLUSIONS: INPPL1 gene variants may contribute to susceptibility to the metabolic syndrome in men with Type 1 diabetes, but not to diabetic nephropathy. PMID- 22486727 TI - Low temperature stress modulated secretome analysis and purification of antifreeze protein from Hippophae rhamnoides, a Himalayan wonder plant. AB - Plants' distribution and productivity are adversely affected by low temperature (LT) stress. LT induced proteins were analyzed by 2-DE-nano-LC-MS/MS in shoot secretome of Hippophae rhamnoides (seabuckthorn), a Himalayan wonder shrub. Seedlings were subjected to direct freezing stress (-5 degrees C), cold acclimation (CA), and subzero acclimation (SZA), and extracellular proteins (ECPs) were isolated using vacuum infiltration. Approximately 245 spots were reproducibly detected in 2-DE gels of LT treated secretome, out of which 61 were LT responsive. Functional categorization of 34 upregulated proteins showed 47% signaling, redox regulated, and defense associated proteins. LT induced secretome contained thaumatin like protein and Chitinase as putative antifreeze proteins (AFPs). Phase contrast microscopy with a nanoliter osmometer showed hexagonal ice crystals with 0.13 degrees C thermal hysteresis (TH), and splat assay showed 1.5 fold ice recrystallization inhibition (IRI), confirming antifreeze activity in LT induced secretome. A 41 kDa polygalacturonase inhibitor protein (PGIP), purified by ice adsorption chromatography (IAC), showed hexagonal ice crystals, a TH of 0.19 degrees C, and 9-fold IRI activity. Deglycosylated PGIP retained its AFP activity, suggesting that glycosylation is not required for AFP activity. This is the first report of LT modulated secretome analysis and purification of AFPs from seabuckthorn. Overall, these findings provide an insight in probable LT induced signaling in the secretome. PMID- 22486726 TI - Models of verbal working memory capacity: what does it take to make them work? AB - Theories of working memory (WM) capacity limits will be more useful when we know what aspects of performance are governed by the limits and what aspects are governed by other memory mechanisms. Whereas considerable progress has been made on models of WM capacity limits for visual arrays of separate objects, less progress has been made in understanding verbal materials, especially when words are mentally combined to form multiword units or chunks. Toward a more comprehensive theory of capacity limits, we examined models of forced-choice recognition of words within printed lists, using materials designed to produce multiword chunks in memory (e.g., leather brief case). Several simple models were tested against data from a variety of list lengths and potential chunk sizes, with test conditions that only imperfectly elicited the interword associations. According to the most successful model, participants retained about 3 chunks on average in a capacity-limited region of WM, with some chunks being only subsets of the presented associative information (e.g., leather brief case retained with leather as one chunk and brief case as another). The addition to the model of an activated long-term memory component unlimited in capacity was needed. A fixed capacity limit appears critical to account for immediate verbal recognition and other forms of WM. We advance a model-based approach that allows capacity to be assessed despite other important processing contributions. Starting with a psychological-process model of WM capacity developed to understand visual arrays, we arrive at a more unified and complete model. PMID- 22486728 TI - Fracture resistance and mode of failure of various types of root filled teeth. AB - AIM: To investigate ex vivo the influence of the post system on fracture resistance and failure mode of root filled incisor, canine, premolar and molar teeth. METHODOLOGY: Eighty human teeth were divided into eight groups (n = 10) resulting from the interaction between the two study factors: post system (glass fibre post; cast Ni-Cr alloy post and core) and type of tooth (maxillary incisors, maxillary canines, maxillary premolars and mandibular molars). All roots were prepared with a 2-mm ferrule and restored with metal crown. Fracture resistance (N) was assessed in a mechanical testing device, and the data were analysed by two-way anova (4 * 2) followed by Tukey's test (alpha = 0.05). The failure mode was evaluated using an optical stereomicroscope and classified according to the location of the failure. Failure mode data were analysed by two factor anova and Student-Newman-Keuls (SNK) tests (alpha = 0.05). Correlation between fracture resistance and failure mode was analysed by linear regression. RESULTS: Glass fibre and cast posts and cores had similar fracture resistance, regardless of the type of tooth. Canines and molars had significantly higher fracture resistance (P < 0.001) than premolars. Incisors teeth had significantly lower fracture resistance (P < 0.001) than premolars. The fracture mode for incisors, premolars and molars was more amenable to restoration when the teeth were restored with glass fibre posts. Fracture resistance had no correlation with fracture mode, regardless of the post system and type of tooth analysed. CONCLUSIONS: Post system had no significant effect on fracture resistance, regardless of the type of tooth. The mode of fracture was more restorable with glass fibre posts. PMID- 22486729 TI - Evaluation of satisfaction with masticatory efficiency of new conventional complete dentures in edentulous patients--a survey. AB - BACKGROUND: Knowing how patients really feel after treatment is, very often, as relevant as the success rate of the conventional dentures and it can even be the measurement of masticatory function. AIM AND OBJECTIVES: This questionnaire survey aimed to analyse the satisfaction level and masticatory efficiency of patients treated with conventional complete dentures. DESIGN AND SETTING: Thirty edentulous patients were considered in the study. Satisfaction level and masticatory efficiency were analysed based on specific questionnaires for edentulous patients and by a likert rating scale from 0 to 5, at three moments: Prior to treatment (edentulous period), after the insertion of the new dentures and at 30-45 days follow-up. MATERIALS AND METHODS: Thirty patients including 12 male and 18 female patients (mean age 65 years), who voluntarily came for the services. T-test was applied at three different levels. RESULTS: The rehabilitation with conventional complete dentures produced an improvement (p < 0.05) in satisfaction level and masticatory efficiency. CONCLUSION: Thus, those patients who were edentulous previously and dissatisfied with their masticatory ability showed improvement after receiving a new set of conventional complete dentures. PMID- 22486730 TI - Non-Helicobacter pylori gastritis is common among paediatric patients with inflammatory bowel disease. AB - BACKGROUND: Helicobacter-negative gastritis and duodenitis occur more often in patients with inflammatory bowel disease (IBD) than in non-IBD controls. Preliminary evidence suggests that they are particularly common among children. AIM: To study the age-specific occurrence of gastritis and duodenitis among paediatric IBD patients. METHODS: From a computerised database of surgical pathology reports, we selected 344 IBD patients and 4241 non-IBD controls between the age 0 and 21 years, who underwent colonoscopy and oesophago-gastro duodenoscopy with biopsy results from both procedures. RESULTS: Helicobacter negative chronic active gastritis was found in 2% of controls and 20% of IBD patients (Crohn's disease (CD) 26%, ulcerative colitis (UC) 13%). Duodenitis was found in 2% of controls and 17% of IBD patients (Crohn's disease 28%, UC 8%). Similar prevalence rates were observed in male and female patients. The most striking age-specific patterns were seen in Crohn's disease, with chronic active gastritis being highest in the 5-9 years age-group and declining in all subsequent age-groups. The age-specific rise and fall of duodenitis appeared more protracted, reaching a peak at age 10-14 years and then gradually declining. CONCLUSIONS: Helicobacter-negative gastritis and duodenitis occur significantly more often in paediatric IBD patients than in non-IBD controls, as well as in adult IBD patients. Such upper gastrointestinal inflammation appears to be particularly common in patients with Crohn's disease. PMID- 22486731 TI - Subclinical mucosal inflammation in diarrhea-predominant irritable bowel syndrome (IBS) in a tropical setting. AB - BACKGROUND AND AIMS: There is evidence for low-grade inflammation in the pathophysiology of post-infectious irritable bowel syndrome (IBS). We assessed the degree of subclinical intestinal mucosal inflammation in diarrhea-predominant IBS (IBS-D) in a tropical setting. MATERIAL AND METHODS: In a prospective study over 1 year, we investigated 49 patients with IBS-D (cases; median age 34 years (range 18-59); M:F 36:13), diagnosed on Rome III criteria. 14 individuals with a family history of colon cancer (median age 46.5 years (range 23-56); M:F 6:8) were selected as controls. Stools of cases and controls were tested for calprotectin. During colonoileoscopy, serial biopsies were obtained. Mucosal mast cells, neutrophils, eosinophils and lymphocytes/plasma cell infiltrate were quantified. Tissue expression of IL-8 and IL-10 was assessed in biopsies by semi quantitative RT-PCR. RESULTS: A history suggestive of an episode of infectious diarrhea (ID) was present in 16/49 cases and 0/14 controls (p = 0.013). In cases, there were significantly more mucosal mast cells in the ileum and all segments of colon and significantly more eosinophils in the cecum. Tissue expression of IL-8 was significantly higher and IL-10 significantly lower in cases compared with controls (target/standard cDNA ratio, median (range) IL-8: 1.25 (0.75-2) vs. 0.85 (0.63-1.3), p < 0.0001, Mann-Whitney U test; IL-10: 0.33 (0-0.63) vs. 0.55 (0.5 0.7), p < 0.0001). There was a significant inverse correlation between IL-8 and IL-10 expression (Pearson correlation, (-) 0.509; p < 0.01). CONCLUSION: There was evidence of subclinical intestinal mucosal inflammation in patients with IBS D. The finding of increased eosinophils is novel, and may be of special relevance to IBS-D in the tropics. PMID- 22486732 TI - Hypoxic stress triggers a programmed cell death pathway to induce vascular cavity formation in Pisum sativum roots. AB - Flooding at warm temperatures induces hypoxic stress in Pisum sativum seedling roots. In response, some undifferentiated cells in the primary root vascular cylinder start degenerating and form a longitudinal vascular cavity. Changes in cellular morphology and cell wall ultrastructure detected previously in the late stages of cavity formation suggest possible involvement of programmed cell death (PCD). In this study, cytological events occurring in the early stages of cavity formation were investigated. Systematic DNA fragmentation, a feature of many PCD pathways, was detected in the cavity-forming roots after 3 h of flooding in situ by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay and in isolated total DNA by gel electrophoresis. High molecular weight DNA fragments of about 20-30 kb were detected by pulse-field gel electrophoresis, but no low-molecular weight internucleosomal DNA fragments were detected by conventional gel electrophoresis. Release of mitochondrial cytochrome c protein into the cytosol, an integral part of mitochondria-dependent PCD pathways, was detected in the cavity-forming roots within 2 h of flooding by fluorescence microscopy of immunolabeled cytochrome c in situ and in isolated mitochondrial and cytosolic protein fractions by western blotting. DNA fragmentation and cytochrome c release remained confined to the undifferentiated cells in center of the root vascular cylinders, even after 24 h of flooding, while outer vascular cylinder cells and cortical cells maintained cellular integrity and normal activity. These findings confirm that hypoxia-induced vascular cavity formation in P. sativum roots involves PCD, and provides a chronological model of cytological events involved in this rare and understudied PCD system. PMID- 22486733 TI - Marginal emissions factors for the U.S. electricity system. AB - There is growing interest in reducing emissions from electricity generation in the United States (U.S.). Renewable energy, energy efficiency, and energy conservation are all commonly suggested solutions. Both supply- and demand-side interventions will displace energy-and emissions-from conventional generators. Marginal emissions factors (MEFs) give a consistent metric for assessing the avoided emissions resulting from such interventions. This paper presents the first systematic calculation of MEFs for the U.S. electricity system. Using regressions of hourly generation and emissions data from 2006 through 2011, we estimate regional MEFs for CO(2), NO(x), and SO(2), as well as the share of marginal generation from coal-, gas-, and oil-fired generators. Trends in MEFs with respect to system load, time of day, and month are explored. We compare marginal and average emissions factors (AEFs), finding that AEFs may grossly misestimate the avoided emissions resulting from an intervention. We find significant regional differences in the emissions benefits of avoiding one megawatt-hour of electricity: compared to the West, an equivalent energy efficiency measure in the Midwest is expected to avoid roughly 70% more CO(2), 12 times more SO(2), and 3 times more NO(x) emissions. PMID- 22486734 TI - QRISK or Framingham? PMID- 22486735 TI - Identification of four novel alleles of the BoLA-DRB3 upstream regulatory region in Chinese yellow cattle. AB - The sequence of upstream regulatory region (URR) of BoLA-DRB3 gene was amplified with polymerase chain reaction followed by DNA sequencing from six animals of Chinese yellow cattle. A total of five alleles including four newly identified ones, named BoLA-DRB3*R-03-U2, BoLA-DRB3*R-06-U2, BoLA-DRB3*R-07-U and BoLA DRB3*R-12-U for the BoLA-DRB3 URR were found. Result of sequence analysis showed that the regulatory elements W, X, Y, CCAAT and TATA-like boxes existed in such URRs and 16 polymorphic sites (11 transitions, 3 transversions, 1 deletion and 1 insertion) located in the spacers between the conserved consensus boxes and 1 insertion within X box, while no new polymorphic site within the consensus boxes. PMID- 22486737 TI - Directed self-assembly of epitaxial CoFe2O(4)-BiFeO3 multiferroic nanocomposites. AB - CoFe(2)O(4) (CFO)-BiFeO(3) (BFO) nanocomposites are an intriguing option for future memory and logic technologies due to the magnetoelectric properties of the system. However, these nanocomposites form with CFO pillars randomly located within a BFO matrix, making implementation in devices difficult. To overcome this, we present a technique to produce patterned nanocomposites through self assembly. CFO islands are patterned on Nb-doped SrTiO(3) to direct the self assembly of epitaxial CFO-BFO nanocomposites, producing square arrays of CFO pillars. PMID- 22486736 TI - Physical activity and physical function in older adults: the 45 and up study. AB - OBJECTIVES: To determine the strength of the relationship between physical activity and physical function in older adults. DESIGN: Cross-sectional. SETTING: The 45 and Up Study baseline questionnaire, New South Wales, Australia. PARTICIPANTS: Ninety-one thousand three hundred seventy-five Australian men and women aged 65 and older from the 45 and Up Study. MEASUREMENTS: Physical activity engagement (Active Australia Survey), physical function (Medical Outcomes Study Physical Functioning), psychological distress (Kessler-10), and self-reported age, smoking history, education, height, and weight were all measured. RESULTS: Higher levels of physical activity were associated with better physical function in older adults (correlation coefficient = 0.166, P < .001). Participants engaging in higher levels of physical activity had progressively lower likelihoods of functional limitation (middle tertile: odds ratio (OR) = 0.39, 95% confidence interval (CI) = 0.38-0.41; highest tertile: OR = 0.28, 95% CI = 0.27 0.29). This relationship remained significant, but weakened slightly, when adjusted for age, sex, body mass index, smoking history, psychological distress, and educational attainment (middle tertile: adjusted OR (AOR) = 0.48, 95% CI = 0.46-0.50; highest tertile: AOR = 0.36, 95% CI = 0.34-0.37). CONCLUSION: There is a significant, positive relationship between physical activity and physical function in older adults, with older adults who are more physically active being less likely to experience functional limitation than their more-sedentary counterparts. Level of engagement in physical activity is an important predictor of physical function in older adults. PMID- 22486738 TI - Guaiane sesquiterpenes from Biscogniauxia nummularia featuring potent antigerminative activity. AB - Xylaranone, a previously unreported guaiane sesquiterpene along with the known terpenoid xylaranol B and the two mellein derivatives 3,5-dimethyl-8-methoxy-3,4 dihydroisocoumarin and 3,5-dimethyl-8-hydroxy-3,4-dihydroisocoumarin were isolated from Biscogniauxia nummularia. Pogostol was also isolated from this fungus, and in light of our spectroscopic data, its structure was revised and corrected. This fungus, which was isolated as an endophyte from the plum yew Cephalotaxus harringtonia, is also suspected of being a pathogen. Interestingly, we report here the potent antigerminative activity of xylaranone and xylaranol B against seeds of Raphanus sativus at concentrations comparable to glyphosate, a commonly used herbicide. This effect suggests a role for these metabolites in the latent fungal pathogenesis of B. nummularia. PMID- 22486740 TI - The development of a survey to measure completeness of response to migraine therapy. AB - OBJECTIVE: To assess the psychometric properties of a new patient-reported migraine instrument, the Completeness of Response Survey (CORS), which measures a comprehensive set of factors important to patients' decisions regarding the initiation and continuation of treatment. BACKGROUND: Traditionally, migraine treatments and the instruments used to demonstrate their efficacy have focused on the relief of headache pain. As new treatments emerge with the potential for more complete and consistent migraine relief, more comprehensive tools are needed to demonstrate these benefits. The CORS includes 2 modules, the static CORS, which comprehensively evaluates one treatment at one time point, and the comparative CORS, which provides a more global comparison between 2 treatments at one time point. Together, the 2 modules can measure unmet treatment needs and improvements over the course of a clinical study. METHODS: Data from an 8-site study comparing 147 patients' recent experiences with their current triptan therapy and 2 months of study treatment with a single-tablet formulation of sumatriptan/naproxen sodium were used to conduct a preliminary psychometric evaluation of the CORS. The study included both modules of the CORS, the Headache Impact Test, the revised Patient Perception of Migraine Questionnaire, and a migraine diary. RESULTS: The CORS response categories in both the static and comparative modules demonstrated limited floor or ceiling effects and few missing values (<3%). Inter item correlations, principal components analysis (component loading range: 0.62 to 0.95), and high estimates of internal consistency (alpha range: 0.88 to 0.94) for each composite score supported the structure and proposed scoring algorithm for the static module. The pattern of correlations between the CORS static and comparative items and composites with the revised Patient Perception of Migraine Questionnaire items and subscales, as well as the relationships between responses to selected static CORS items and the migraine diary, supported the construct validity of the CORS. CONCLUSIONS: The CORS is capable of demonstrating advantages of more comprehensive migraine therapies over traditional therapies, which are primarily focused on the resolution of headache pain, by addressing the frequency and speed with which the most common migraine symptoms are resolved and patients' return to normal functioning. This research shows evidence for the value and utility for the CORS static and comparative items and components, and further evaluation is underway. PMID- 22486741 TI - The University of Alabama Interregional Headache School Study: anatomy of a failure. PMID- 22486742 TI - What happens to the old headache medicines? AB - Old headache medicines never die; they either fade away or come back in disguise. The disguise is often a new route of administration, which may work better, faster, more completely, with fewer adverse events, and/or have certain other advantages. The clinical aspects of 3 of the oldest headache medicines (ergotamine tartrate, dihydroergotamine, and methysergide) will be discussed here. Sumatriptan will then be discussed as the prototype of the newest category of acute care therapy (triptans) for migraine. It will be compared with the older medications, and the new forms being developed will be briefly discussed. Diclofenac potassium for oral solution will be mentioned as the newest drug approved for migraine by the Food and Drug Administration, and a possible alternative to triptans in patients with frequent headaches or those with contraindications to vasoconstrictors. PMID- 22486743 TI - Botox-A for suppression of chronic migraine: commonly asked questions. PMID- 22486744 TI - Structure and dynamics of calmodulin (CaM) bound to nitric oxide synthase peptides: effects of a phosphomimetic CaM mutation. AB - Nitric oxide synthase (NOS) plays a major role in a number of key physiological and pathological processes. Knowledge of how this is regulated is important. The small acidic calcium binding protein, calmodulin (CaM), is required to fully activate the enzyme. The exact mechanism of how CaM activates NOS is not fully understood. Studies have shown CaM to act like a switch that causes a conformational change in NOS to allow for the transfer of an electron between the reductase and oxygenase domains through a process that is thought to be highly dynamic. To investigate the dynamic properties of CaM-NOS interactions, we determined the solution structure of CaM bound to the inducible NOS (iNOS) and endothelial NOS (eNOS) CaM binding region peptides. In addition, we investigated the effect of CaM phosphorylation. Tyrosine 99 (Y99) of CaM is reported to be phosphorylated in vivo. We have produced a phosphomimetic Y99E CaM to investigate the structural and functional effects that the phosphorylation of this residue may have on nitric oxide production. All three mammalian NOS isoforms were included in the investigation. Our results show that a phosphomimetic Y99E CaM significantly reduces the maximal synthase activity of eNOS by 40% while having little effect on nNOS or iNOS activity. A comparative nuclear magnetic resonance study between phosphomimetic Y99E CaM and wild-type CaM bound to the eNOS CaM binding region peptide was performed. This investigation provides important insights into how the increased electronegativity of a phosphorylated CaM protein affects the binding, dynamics, and activation of the NOS enzymes. PMID- 22486745 TI - Insulin initiation and management in people with Type 2 diabetes in an ethnically diverse population: the healthcare provider perspective. AB - AIM: To explore barriers to prescribing of insulin, particularly delays in initiation, from the perspective of healthcare professionals involved in managing Type 2 diabetes in a multi-ethnic setting. METHODS: The study was carried out in a UK population with high numbers of people of South Asian (mainly Indian) origin. Semi-structured interviews were conducted with 14 healthcare professionals from primary and secondary care. Analysis involved exploring interview transcripts in terms of themes and sub-themes identified through a process of progressive focusing. RESULTS: Initiation of insulin therapy was described as challenging in all patients irrespective of ethnicity, but some barriers were perceived to be accentuated because of language needs and lower levels of understanding about diabetes and insulin. Additionally, some South Asians were viewed as more likely than their white European counterparts to be influenced by negative observations and experiences about insulin therapy within community networks. Time restrictions were seen as a barrier that was accentuated in the management of South Asian patients. Participants suggested strategies for overcoming patient barriers; with South Asians these included involvement of families and patient peers and availability of South Asian healthcare providers. CONCLUSION: The challenge for healthcare providers is to how to address the tension between the optimal clinical time for commencing insulin therapy and the time when the patient feels psychologically ready. To help make these two time points coincide, our findings suggest the need to adopt a holistic approach involving consideration of the cultural context of patients, including their ethnic background. PMID- 22486746 TI - Effect of triethylene glycol dimethacrylate on the cytotoxicity, cyclooxygenase-2 expression and prostanoids production in human dental pulp cells. AB - AIM: To evaluate the effect of TEGDMA on cell cycle progression as well as alterations of cell cycle-related gene and protein expression. METHODOLOGY: Human dental pulp cells were exposed to 0-5 mmol L(-1) TEGDMA for 24 h. Cytotoxicity was evaluated by 3-(4, 5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. Cell cycle progression was analysed by propidium iodide (PI) flow cytometry. Cell death pathway was surveyed by annexin V/PI dual-staining flow cytometry. The mRNA expression of cell cycle-related genes (cdc2, cyclinB1 and p21) and COX-2 was evaluated by reverse transcriptase-polymerase chain reaction, and their protein expression was evaluated by Western blotting. The production of PGE(2) and PGF(2alpha) in the culture medium was determined by enzyme-linked immunosorbent assay. RESULTS: Triethylene glycol dimethacrylate inhibited cellular growth and induced cell cycle deregulation in dental pulp cells. High dose exposure provoked both necrotic and apoptotic cell death. The gene and protein expression of cdc2, cyclin B1 and cdc25C declined obviously whilst cells treated with 2.5 mmol L(-1) TEGDMA concurrent with the elevated expression of p21. The mRNA and protein expression of COX-2, along with production of PGE(2) and PGF(2alpha), are drastically raised by 2.5-5 mmol L(-1) TEGDMA. CONCLUSIONS: Triethylene glycol dimethacrylate induced cytotoxicity, cell cycle arrest and apoptosis in dental pulp cells, which was associated with the decline of cdc2, cyclin B1, cdc25C expression and elevation of p21 expression. Concomitantly, COX 2 expression, PGE(2) and PGF(2alpha) production increased. These effects may contribute to explain the pulpal damage and inflammation induced by TEGDMA after operative procedures. PMID- 22486747 TI - A case of focal segmental glomerulosclerosis with myeloid bodies. AB - The presence of myeloid bodies in electron microscopy is a characteristic finding of Fabry's disease. Here, we present a male patient, whose renal biopsy findings suggested the coexistence of focal segmental glomerulosclerosis and Fabry's disease, because of the presence of segmental hyalinosis and/or sclerosis in glomeruli and myeloid bodies in electron microscopy. But finally, Fabry's disease was excluded as a diagnosis because the alpha-galactosidase A activity in leukocyte and plasma in this patient was within normal limits. After renal biopsy, although he received medication including steroid therapy, his renal function gradually decreased to end-stage renal failure and hemodialysis was initiated. Until now, he does not exhibit any specific symptoms. In conclusion, our case suggests that occasional myeloid bodies in renal biopsy specimens should be interpreted with caution. PMID- 22486748 TI - Casein micelles: size distribution in milks from individual cows. AB - The size distribution and protein composition of casein micelles in the milk of Holstein-Friesian cows was determined as a function of stage and number of lactations. Protein composition did not vary significantly between the milks of different cows or as a function of lactation stage. Differences in the size and polydispersity of the casein micelles were observed between the milks of different cows, but not as a function of stage of milking or stage of lactation and not even over successive lactations periods. Modal radii varied from 55 to 70 nm, whereas hydrodynamic radii at a scattering angle of 73 degrees (Q2 = 350 MUm 2) varied from 77 to 115 nm and polydispersity varied from 0.27 to 0.41, in a log normal distribution. Casein micelle size in the milks of individual cows was not correlated with age, milk production, or lactation stage of the cows or fat or protein content of the milk. PMID- 22486750 TI - Coordination and spin states in vanadium carbonyl complexes (V(CO)n+, n = 1-7) revealed with IR spectroscopy. AB - The vibrational spectra of vanadium carbonyl cations of the form V(CO)(n)(+), where n = 1-7, were obtained via mass-selected infrared laser photodissociation spectroscopy in the carbonyl stretching region. The cations and their argon and neon "tagged" analogues were produced in a molecular beam via laser vaporization in a pulsed nozzle source. The relative intensities and frequency positions of the infrared bands observed provide distinctive patterns from which information on the coordination and spin states of these complexes can be obtained. Density functional theory is carried out in support of the experimental spectra. Infrared spectra obtained by experiment and predicted by theory provide evidence for a reduction in spin state as the ligand coordination number increases. The octahedral V(CO)(6)(+) complex is the fully coordinated experimental species. A single band at 2097 cm(-1) was observed for this complex red-shifted from the free CO vibration at 2143 cm(-1). PMID- 22486751 TI - Decreased serum LL-37 and vitamin D3 levels in atopic dermatitis: relationship between IL-31 and oncostatin M. AB - BACKGROUND: Skin lesions with atopic dermatitis (AD) are associated with dysregulated expression of LL-37 and enhanced expression of IL-22, thymic stromal lymphopoietin (TSLP), IL-25, IL-31, and oncostatin M. Vitamin D3 enhances LL-37 production in keratinocytes. This study aimed to examine the serum levels of LL 37 and vitamin D3 and their regulation of cytokine production in patients with AD. METHODS: Serum levels of LL-37 and 25-hydroxyvitamin D3 were analyzed by ELISA. The effects of 1,25-dihydroxyvitamin D3 or LL-37 on cytokine production in T cells or keratinocytes were analyzed by ELISA and real-time PCR. RESULTS: Serum levels of LL-37 and 25-hydroxyvitamin D3 were decreased in patients with AD compared to normal donors and were correlated in both groups. Serum levels of LL 37 correlated with those of oncostatin M and IL-31 in normal donors and patients with AD, while 25-hydroxyvitamin D3 levels did so only in normal donors. 1,25 dihydroxyvitamin D3 increased LL-37 production in human keratinocytes and neutrophils. 1,25-dihydroxyvitamin D3 and LL-37 enhanced the oncostatin M and IL 31 production in CD3/28-stimulated T cells, but did not alter IL-25 and TSLP production in TNF-alpha-stimulated keratinocytes. In CD3/28-stimulated T cells, 1,25-dihydroxyvitamin D3 reduced the IL-22 production, while LL-37 enhanced it. These effects of 1,25-dihydroxyvitamin D3 and LL-37 were suppressed by vitamin D receptor antagonist and pertussis toxin, respectively. CONCLUSIONS: Systemic vitamin D3 levels are reduced in patients with AD, which may contribute to decreased systemic LL-37 levels. LL-37 may systemically potentiate the oncostatin M and IL-31 production in normal donors and patients with AD, while vitamin D3 may do so only in normal donors. PMID- 22486752 TI - Cloning, purification, and characterization of a cold-adapted esterase produced by Psychrobacter cryohalolentis K5T from Siberian cryopeg. AB - A psychrotrophic gram-negative bacterium Psychrobacter cryohalolentis K5(T) was previously isolated from a cryopeg within Siberian permafrost and its genome has been completely sequenced. To clone and characterize potential cold-active lipases/esterases produced by P. cryohalolentis K5(T) , we have identified their potential genes by alignment with amino acid sequences of lipases/esterases from related bacteria. One of the targets, EstPc, was cloned and overexpressed in Escherichia coli BL21 (DE3) cells. The recombinant protein was produced with a 6x histidine tag at its C-terminus and purified by nickel affinity chromatography. Purified recombinant protein displayed maximum esterolytic activity with p nitrophenyl butyrate (C4) as a substrate at 35 degrees C and pH 8.5. Activity assay conducted at different temperatures revealed that EstPc is a cold-adapted esterase which displayed more than 90% of its maximum activity at 0-5 degrees C. In contrast to many known cold-active enzymes, it possesses relatively high thermostability, preserving more than 60% of activity after incubation for 1 h at 80 degrees C. It was activated by Ca(2+) , Mn(2+) , and EDTA whereas Zn(+2) , Cu(+2) , Co(+2) , Ni(+2) , and Mg(+2) inhibited it. Various organic solvents (ethanol, methanol and others) inhibited the enzyme. Most non-ionic detergents, such as Triton X-100 and Tween 20 increased the lipase activity while SDS completely inhibited it. PMID- 22486753 TI - Pacemaker optimization in nonresponders to cardiac resynchronization therapy: left ventricular pacing as an available option. AB - BACKGROUND: Echocardiographic (ECHO)-guided pacemaker optimization (PMO) in cardiac resynchronization therapy (CRT) nonresponders acutely improves left ventricular (LV) function. However, the chronic results of LV pacing in this group are less understood. METHODS: We retrospectively studied 28 CRT nonresponders optimized based on ECHO to LV pacing and compared them to 28 age- and gender-matched patients optimized to biventricular (BiV) pacing. ECHOs with tissue Doppler imaging assessed LV hemodynamics before, immediately after, and 29 +/- 16 months after PMO. Also, 56 age- and gender-matched CRT responders were included for comparison of clinical outcomes. RESULTS: PMO resulted in acute improvements in longitudinal LV systolic function and several measures of dyssynchrony, with greater improvements in the LV paced group. Chronic improvements in ejection fraction (EF) (3.2 +/- 7.7%), and left ventricle end systolic volume (LVESV) (-11 +/- 36 mL) and one dyssynchrony measure were seen in the combined group. Chronically, both LV and BiV paced patients improved some measures of systolic function and dyssynchrony although response varied between the groups. Survival at 3.5 years was similar (P = 0.973) between the PMO (58%) and nonoptimized groups (58%) but survival free of cardiovascular hospitalization was significantly (P = 0.037) better in the nonoptimized group. CONCLUSIONS: CRT nonresponders undergoing PMO to either LV or BiV pacing have acute improvements in longitudinal systolic function and some measures of dyssynchrony. Some benefits are sustained chronically, with improvements in EF, LVESV, and dyssynchrony. A strategy of ECHO-guided PMO results in survival for CRT nonresponders similar to that of CRT patients not referred for PMO. PMID- 22486754 TI - Re-assessing causal accounts of learnt behavior in rats. AB - Rats received either a common-cause (i.e., A->B, A->food) or a causal-chain training scenario (i.e., B->A, A->food) before their tendency to approach the food magazine during the presentation of B was assessed as a function of whether it was preceded by a potential alternative cause. Causal model theory predicts that the influence of an alternative cause should be restricted to the common cause scenario. In Experiment 1, responding to B was reduced when it occurred after pressing a novel lever during the test phase. This effect was not influenced by the type of training scenario. In Experiment 2, rats were familiarized with the lever prior to test by training it as a potential cause of B. After this treatment, the lever now failed to influence test responding to B. In Experiment 3, rats given common-cause training responded more to B when it followed a cue that had previously been trained as a predictor of B, than when it followed another stimulus. This effect was not apparent in rats that received causal-chain training. This pattern of results is the opposite of that predicted by causal model theory. Thus, in three experiments, the presence of an alternative cause failed to influence test responding in manner consistent with causal model theory. These results undermine the application of causal model theory to rats, but are consistent with associative analyses. PMID- 22486755 TI - The fate of redundant cues during blocking and a simple discrimination. AB - In each of three experiments animals received blocking, A+ AX+, in which food was always presented after one stimulus, A, that was occasionally accompanied by another stimulus, X. They also received a simple discrimination, AX+ BX-, in which the presence and absence of food was signaled by two compounds that contained one unique cue, A or B, and one common cue, X. In each of these designs, X can be said to be redundant relative to A as a signal for food. Test trials at the end of training revealed that responding during X was stronger after blocking than after the simple discrimination. These results contradict predictions from theories of learning that assume changes in associative strength of a stimulus are determined by a global error term based on the outcome predicted by all the stimuli that are present for a conditioning trial. The results are interpreted, instead, by assuming either that animals store a memory of every trial to which they have been exposed, or that learning is governed by an error term based on the significance of individual stimuli. PMID- 22486756 TI - The curious case of the refrigerator-TV: similarity and hybridization. AB - This article examines the role of similarity in the hybridization of concepts, focusing on hybrid products as an applied test case. Hybrid concepts found in natural language, such as singer songwriter, typically combine similar concepts, whereas dissimilar concepts rarely form hybrids. The hybridization of dissimilar concepts in products such as jogging shoe mp3 player and refrigerator TV thus poses a challenge for understanding the process of conceptual combination. It is proposed that models of conceptual combination can throw light on the judged future success and desirability of hybrid products in general. The composite prototype model proposes two stages of conceptual combination. In the first stage, the concepts are aggregated into an additive hybrid, simply by forming the union of the two sets of attributes. In the second stage, any conflicting attributes are identified and resolved, often with the introduction of emergent attributes, resulting in an integrative hybrid. Across four studies that varied the similarity and type of hybrid products, similar and integrative hybrids were valued more than dissimilar and additive hybrids. Critically, though, dissimilar hybrids were also highly valued if they were integrative. Results supported the two stages proposed by the composite prototype model, and implications for other models of hybrid formation are discussed. PMID- 22486757 TI - Perchlorate and thiocyanate exposure and thyroid function in first-trimester pregnant women from Greece. AB - OBJECTIVE: Thyroid hormone, requiring adequate maternal iodine intake, is critical for neurodevelopment in utero. Perchlorate and, less so, thiocyanate decrease uptake of iodine into the thyroid gland by competitively inhibiting the sodium/iodide symporter (NIS). It remains unclear whether environmental perchlorate exposure adversely affects thyroid function in first-trimester pregnant women. DESIGN: Cross-sectional. PATIENTS: 134 pregnant women from Athens, Greece, at mean +/- SD 10.9 +/- 2.3 weeks' gestation. MEASUREMENTS: Urinary iodide, perchlorate, and thiocyanate and thyroid function tests were measured. RESULTS: The median urinary iodide was 120 MUg/l. Urinary perchlorate levels were detectable in all women: median (range) 4.1 (0.2-118.5) MUg/l. Serum thyroperoxidase antibodies (TPO Ab) were detectable in 16% of women. Using Spearman's rank correlation analyses, there was no correlation between urinary perchlorate concentrations and serum TSH, although inverse correlations were seen between urine perchlorate and free T3 and free T4 values. In univariate analyses, urine thiocyanate was positively correlated with serum TSH, but was not associated with serum free T3 or free T4. Urine perchlorate was positively correlated with gestational age. In multivariate analyses adjusting for urinary iodide concentrations, urine thiocyanate, gestational age, maternal age and TPO Ab titres, urine perchlorate was not a significant predictor of thyroid function. CONCLUSIONS: Low-level perchlorate and thiocyanate exposure is ubiquitous, but, in adjusted analyses, is not associated with alterations in thyroid function tests among mildly iodine-deficient Greek women in the first trimester of pregnancy. PMID- 22486758 TI - Effects of the peracetic acid and sodium hypochlorite on the colour stability and surface roughness of the denture base acrylic resins polymerised by microwave and water bath methods. AB - OBJECTIVE: This study evaluated the surface roughness (Ra) and color stability of acrylic resin colors (Lucitone 550, QC-20 and Vipi-Wave) used for fabricating bases for complete, removable dentures, overdentures and prosthetic protocol after immersion in chemical disinfectants (1% sodium hypochlorite and 2% peracetic acid) for 30 and 60 minutes. MATERIAL AND METHODS: Sixty specimens were made of each commercial brand of resin composite, and divided into 2 groups according to the chemical disinfectants. Specimens had undergone the finishing and polishing procedures, the initial color and roughness measurements were taken (t=0), and after this, ten test specimens of each commercial brand of resin composite were immersed in sodium hypochlorite and ten in peracetic acid, for 30 and 60 minutes, with measurements being taken after each immersion period. These data were submitted to statistical analysis. RESULTS: There was evidence of an increase in Ra after 30 minutes immersion in the disinfectants in all the resins, with QC-20 presenting the highest Ra values, and Vipi-Wave the lowest. After 60 minutes immersion in the disinfectants all the resins presented statistically significant color alteration. CONCLUSIONS: Disinfection with 1% sodium hypochlorite and peracetic acid altered the properties of roughness and color of the resins. PMID- 22486759 TI - Editorial comment from Dr Chancellor to periurethral injection of autologous adipose-derived regenerative cells for the treatment of male stress urinary incontinence: report of three initial cases. PMID- 22486760 TI - Development and calibration of a passive sampler for perfluorinated alkyl carboxylates and sulfonates in water. AB - Perfluorinated chemicals (PFCs) are emerging environmental contaminants with a global distribution. Due to their moderate water solubility, the majority of the environmental burden is assumed to be in the water phase. This work describes the application of the first passive sampler for the quantitative assessment of concentrations of perfluorinated alkylcarboxylates (PFCAs) and sulfonates (PFSAs) in water. The sampler is based on a modified Polar Organic Chemical Integrative Sampler (POCIS) with a weak anion exchange sorbent as a receiving phase. Sampling rates were between 0.16 and 0.37 L d(-1), and the duration of the kinetic sampling stage was between 2.2 and 13 d. A field deployment in the most urbanized estuary in Australia (Sydney Harbour) showed trace level concentrations from passive samplers (0.1-12 ng L(-1)), in good agreement with parallel grab sampling (0.2-16 ng L(-1)). A separate field comparison of the modified POCIS with standard POCIS suggests the latter may have application for PFC sampling, but with a more limited range of analytes than the modified POCIS which contains a sorbent with a mixed mode of action. PMID- 22486761 TI - Reference ranges for thromboelastography (TEG((r)) ) and traditional coagulation tests in term parturients undergoing caesarean section under spinal anaesthesia*. AB - There has been little published work defining 'normal' thromboelastography (TEG((r)) ) values in healthy parturients, and few large studies defining reference ranges for traditional coagulation tests in this patient group. Our aim was to establish peri-operative reference ranges for TEG and for standard laboratory coagulation tests in our pregnant population. Fifty healthy term parturients presenting for elective caesarean section under spinal anaesthesia had blood samples taken pre-operatively, on arrival in the recovery room and, in a subset of 33 women, 4 h after routine thromboprophylaxis with enoxaparin 40 mg. All three samples had TEG analysis, the first and second having standard laboratory coagulation tests in addition. Reference ranges for our pregnant population were established, demonstrating a hypercoagulable state in term parturients and a significant effect of enoxaparin. The standard coagulation reference ranges were within 98% of the local non-pregnant ranges. These reference ranges provide a useful comparator for peri-operative TEG and routine coagulation analysis in term parturients. PMID- 22486762 TI - Guidance on the diagnosis and clinical management of acne. AB - This article discusses the effects of acne (sometimes referred to as acne vulgaris), how to diagnose it confidently and how to distinguish it from rosacea, and the options available for treatment, especially in primary care. We also suggest when referral to dermatology should be considered, and try to anticipate some frequently asked questions. PMID- 22486763 TI - Guidance on the diagnosis and clinical management of atopic eczema. AB - This article discusses the effects of atopic eczema, how to diagnose it confidently, and the options available for treatment, especially in primary care. We also suggest when referral to dermatology departments in secondary care should be considered, and try to anticipate some frequently asked questions. PMID- 22486764 TI - Guidance on the diagnosis and clinical management of psoriasis. AB - This article discusses the effects of psoriasis, how to diagnose it confidently, and the options available for treatment, especially in primary care. We also suggest when referral to dermatology should be considered, and try to anticipate some frequently asked questions. PMID- 22486765 TI - Detection and quantification of mast cell, vascular endothelial growth factor, and microvessel density in human inflammatory periapical cysts and granulomas. AB - AIM: To identify and quantify mast cell (MC), vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) in human periapical cysts and granulomas. METHODOLOGY: Archived samples of cysts (n = 40) and granulomas (n = 28) were sectioned and stained with toluidine blue. MCs were identified and counted. Immunohistochemical reactions were employed to evaluate the tissue expression of VEGF and vessels. MVD was estimated by determining the areas of tissue labelled with CD31 antibody. The data were analysed using the Mann-Whitney test (P < 0.05). RESULTS: MCs were observed in the peripheral regions of both lesion types, whilst VEGF and MVD were distributed in the stroma. The presence of MCs was higher in cysts than in granulomas (P < 0.05). VEGF and MVD expression were similar in these lesions. CONCLUSIONS: The highest number of MCs was observed in cysts. Moreover, the identification of VEGF and MVD was consistent with the immune mechanisms involved in the lesions. PMID- 22486766 TI - Pelvic floor dysfunction predicts abdominal bloating and distension in eating disorder patients. AB - OBJECTIVE: Little is known about the symptoms of abdominal bloating and distension in women with eating disorders (EDs). This study aimed to explore the prevalence and predictors of these symptoms in patients with EDs, by examining correlations with functional gastrointestinal disorders (FGIDs) including pelvic floor symptoms and other clinical features. MATERIAL AND METHODS: 184 ED inpatients, 16-55 years, completed on admission to hospital the ROME II symptom questionnaire, additional questions about abdominal bloating and distension, and psychological questionnaires. Prediction of abdominal bloating and distension was modeled using logistic regression analyses with individual FGIDs, psychological variables, ED type, and clinical features as the potential predictors. RESULTS: Bloating (78%) was more common than distension (58%) in each ED type. In the final multivariate models, after controlling for BMI, the number of Rome II symptoms of pelvic floor dyssynergia (i.e., having to strain to pass a stool, feeling unable to empty the rectum, and having difficulty relaxing to evacuate the stool) was a significant predictor of both abdominal distension (p < 0.001) and bloating (p < 0.005). The presence of irritable bowel syndrome (IBS, 46%) was a significant predictor of bloating (p < 0.001) but not distension. CONCLUSIONS: Symptoms of pelvic floor dysfunction, but not IBS, appear to be especially important in the genesis of abdominal distension in patients with ED. PMID- 22486767 TI - Genic DNA methylation changes during in vitro organogenesis: organ specificity and conservation between parental lines of epialleles. AB - During differentiation, in vitro organogenesis calls for the adjustment of the gene expression program toward a new fate. The role of epigenetic mechanisms including DNA methylation is suggested but little is known about the loci affected by DNA methylation changes, particularly in agronomic plants for witch in vitro technologies are useful such as sugar beet. Here, three pairs of organogenic and non-organogenic in vitro cell lines originating from different sugar beet (Beta vulgaris altissima) cultivars were used to assess the dynamics of DNA methylation at the global or genic levels during shoot or root regeneration. The restriction landmark genome scanning for methylation approach was applied to provide a direct quantitative epigenetic assessment of several CG methylated genes without prior knowledge of gene sequence that is particularly adapted for studies on crop plants without a fully sequenced genome. The cloned sequences had putative roles in cell proliferation, differentiation or unknown functions and displayed organ-specific DNA polymorphism for methylation and changes in expression during in vitro organogenesis. Among them, a potential ubiquitin extension protein 6 (UBI6) was shown, in different cultivars, to exhibit repeatable variations of DNA methylation and gene expression during shoot regeneration. In addition, abnormal development and callogenesis were observed in a T-DNA insertion mutant (ubi6) for a homologous sequence in Arabidopsis. Our data showed that DNA methylation is changed in an organ-specific way for genes exhibiting variations of expression and playing potential role during organogenesis. These epialleles could be conserved between parental lines opening perspectives for molecular markers. PMID- 22486768 TI - Component-resolved in vitro diagnosis of carrot allergy in three different regions of Europe. AB - BACKGROUND: Carrot is a frequent cause of food allergy in Europe. The objective of this study was to evaluate a panel of carrot allergens for diagnosis of carrot allergy in Spain, Switzerland and Denmark. METHODS: Forty-nine carrot allergic patients, 71 pollen allergic but carrot-tolerant patients and 63 nonatopic controls were included. Serum IgE to carrot extract, recombinant carrot allergens (rDau c 1.0104; rDau c 1.0201; rDau c 4; the isoflavone reductase-like proteins rDau c IFR 1, rDau c IFR 2; the carrot cyclophilin rDau c Cyc) were analyzed by ImmunoCAP. RESULTS: The sensitivity of the carrot extract-based test was 82%. Use of the recombinant allergens increased the sensitivity to 90%. The Dau c 1 isoforms were major allergens for Swiss and Danish carrot allergic patients, the profilin rDau c 4 for the Spanish patients. The rDau c IFR 1 and rDau c IFR 2 were recognized by 6% and 20% of the carrot allergics, but did not contribute to a further increase of sensitivity. Among pollen allergic controls, 34% had IgE to carrot extract, 18% to each of rDau c 1.0104, rDau c 1.0201 and rDau c 4, 8% to rDau c IFR 1 and 7% to rDau c IFR 2. Sensitization to rDau c Cyc occurred in one carrot allergic patient and one nonatopic control. CONCLUSION: Component-resolved in vitro analyses revealed a significant difference in IgE sensitization pattern between geographical regions and in the prevalence of sensitization to carrot components between carrot allergic and carrot-tolerant but pollen sensitized patients. PMID- 22486769 TI - Porous doped silicon nanowires for lithium ion battery anode with long cycle life. AB - Porous silicon nanowires have been well studied for various applications; however, there are only very limited reports on porous silicon nanowires used for energy storage. Here, we report both experimental and theoretical studies of porous doped silicon nanowires synthesized by direct etching of boron-doped silicon wafers. When using alginate as a binder, porous silicon nanowires exhibited superior electrochemical performance and long cycle life as anode material in a lithium ion battery. Even after 250 cycles, the capacity remains stable above 2000, 1600, and 1100 mAh/g at current rates of 2, 4, and 18 A/g, respectively, demonstrating high structure stability due to the high porosity and electron conductivity of the porous silicon nanowires. A mathematic model coupling the lithium ion diffusion and the strain induced by lithium intercalation was employed to study the effect of porosity and pore size on the structure stability. Simulation shows silicon with high porosity and large pore size help to stabilize the structure during charge/discharge cycles. PMID- 22486770 TI - Endometrial phospholipase A2 activity during the oestrous cycle and early pregnancy in mares. AB - The aim of this study was to determine phospholipase A2 (PLA2) kinetics and activity in the mare's endometrium during the oestrous cycle and early pregnancy. Phospholipase A2 is responsible for the liberation of arachidonic acid from phospholipids, which is the first limiting step in prostaglandins synthesis. Phospholipase A2 activity was measured using an assay based on the liberation of oleic acid from 1-palmitoyl-2-[(14) C] oleoyl phosphatidylcholine. The enzyme was shown to be calcium dependent, to have an optimum pH of 8 and an apparent Michaelis constant of 127 MUM. Enzyme activity was low in the endometrium of early luteal phase tissue but increased significantly (p < 0.001) during the late luteal phase (5.39 +/- 0.16; 3.48 +/- 0.33, 6.85 +/- 0.59, and 9.96 +/- 1.23 nmol oleic acid released/mg protein at oestrus, and Days 3, 8 and 14 after ovulation, respectively). The mean PLA2 activity in endometrial tissue from pregnant mares (4.23 +/- 0.74) was significantly lower (p < 0.01) than from cyclic animals during late dioestrus (9.96 +/- 1.23). The results indicate that PLA2 activity in equine endometrium changes with the stage of the oestrous cycle and thus may be influenced by systemic hormone concentrations. The inhibitory effects of conceptus products on secretion of prostaglandin during early pregnancy were associated with a competitive inhibitor that decreased endometrial PLA2 activity. PMID- 22486772 TI - Wide QRS tachycardia: what is the mechanism? PMID- 22486773 TI - Estimating the prevalence of infections in vector populations using pools of samples. AB - Several statistical methods have been proposed for estimating the infection prevalence based on pooled samples, but these methods generally presume the application of perfect diagnostic tests, which in practice do not exist. To optimize prevalence estimation based on pooled samples, currently available and new statistical models were described and compared. Three groups were tested: (a) Frequentist models, (b) Monte Carlo Markov-Chain (MCMC) Bayesian models, and (c) Exact Bayesian Computation (EBC) models. Simulated data allowed the comparison of the models, including testing the performance under complex situations such as imperfect tests with a sensitivity varying according to the pool weight. In addition, all models were applied to data derived from the literature, to demonstrate the influence of the model on real-prevalence estimates. All models were implemented in the freely available R and OpenBUGS software and are presented in Appendix S1. Bayesian models can flexibly take into account the imperfect sensitivity and specificity of the diagnostic test (as well as the influence of pool-related or external variables) and are therefore the method of choice for calculating population prevalence based on pooled samples. However, when using such complex models, very precise information on test characteristics is needed, which may in general not be available. PMID- 22486775 TI - Provitamin A carotenoids are independently associated with matrix metalloproteinase-9 in plasma samples from a general population. AB - BACKGROUND AND AIM: Carotenoids in plasma are inversely associated with cardiovascular risk. Low levels can be explained by low dietary intake but also by a number of other factors including inflammatory activity. Given that matrix metalloproteinase (MMP)-9 has an important role in inflammation and cardiovascular disease, we hypothesized that circulating MMP-9 levels would be inversely related to total or single carotenoids in a general population cohort. METHODS: A well-characterized population-based cohort of 285 Swedish men and women (45-69 years) was used for the present study. The intake of carotenoid-rich fruits and vegetables was estimated from a food frequency questionnaire. Levels of MMP-9, C-reactive protein (CRP), interleukin (IL)-6 and six major carotenoids [beta-cryptoxanthine, alpha-carotene, beta-carotene, lutein (+zeaxanthin) and lycopene] were determined in plasma. RESULTS: Lower plasma levels of total and single carotenoids were associated with lower dietary intake of carotenoids, older age, male sex, lower physical activity, higher alcohol consumption, higher body mass index (BMI), higher systolic and diastolic blood pressures, lower levels of total cholesterol and HDL cholesterol and higher levels of CRP, IL-6 and MMP-9. After multivariate adjustments, plasma levels of total carotenoids and provitamin A carotenoids (beta-cryptoxanthine, alpha-carotene and beta-carotene) remained independently associated with sex, dietary intake of carotenoids, BMI, HDL cholesterol and MMP-9, whilst associations with CRP and IL-6 were not maintained. Neither dietary intake of carotenoid-rich fruits and vegetables, nor vitamin supplement use was associated with MMP-9, CRP or IL-6 levels. CONCLUSION: Plasma carotenoids were associated with a variety of factors including age, sex, dietary intake and metabolic variables. A new finding was the independent relationship in plasma between low provitamin A carotenoids and high MMP-9, suggesting a link between these carotenoids, matrix turnover and arterial remodelling. PMID- 22486774 TI - Extensive p-tau pathology and SDS-stable p-tau oligomers in Alzheimer's cortical synapses. AB - Like amyloid beta (Abeta) oligomers, tau aggregates are increasingly recognized as potential key toxic intermediates in Alzheimer's disease (AD) and as therapeutic targets. P-tau co-localizes with Abeta in cortical AD synapses and may contribute to synapse dysfunction and loss. Flow cytometry analysis of synaptosomes from AD compared with aged cognitively normal cortex demonstrates increased immunolabeling for three p-tau antibodies (AT8, PHF-1 and pS422), indicating phosphorylation at multiple tau epitopes. Sequential extraction experiments show increased soluble p-tau in AD synapses, but a sizable pool of p tau requires detergent solubilization, suggesting endosomal/lysosomal localization. P-tau is co-localized with Abeta in individual synaptosomes in dual labeling experiments, and flow cytometry sorting of Abeta-positive synaptosomes from an AD case reveals a marked enrichment of p-tau aggregates. The p-tau enrichment, a 76-fold increase over the initial homogenate, is consistent with sequestration of p-tau in internal synaptic compartments. Western analysis of a series of AD and normal cases shows SDS-stable tau oligomers in the dimer/trimer size range in AD samples. These results indicate that widespread synaptic p-tau pathology accompanies Abeta accumulations in surviving synaptic terminals, particularly in late-stage AD. PMID- 22486776 TI - Novel roles of SUMO in pancreatic beta-cells: thinking outside the nucleus. AB - The endocrine pancreas is critically important in the regulation of energy metabolism, with defective insulin secretion from pancreatic islet beta-cells a major contributing factor to the development of type 2 diabetes. Small ubiquitin like modifier (SUMO) proteins have been demonstrated to covalently modify a wide range of target proteins, mediating a broad range of cellular processes. While the effects of SUMOylation on beta-cell gene transcription have been previously reviewed, recent reports indicate roles for SUMO outside of the nucleus. In this review we shall focus on the reported non-nuclear roles of SUMOylation in the regulation of beta-cells, including SUMOylation as a novel signaling pathway in the acute regulation of insulin secretion. PMID- 22486777 TI - Proteasomal degradation of the metabotropic glutamate receptor 1alpha is mediated by Homer-3 via the proteasomal S8 ATPase: Signal transduction and synaptic transmission. AB - The metabotropic glutamate receptors (mGluRs) fine-tune the efficacy of synaptic transmission. This unique feature makes mGluRs potential targets for the treatment of various CNS disorders. There is ample evidence to show that the ubiquitin proteasome system mediates changes in synaptic strength leading to multiple forms of synaptic plasticity. The present study describes a novel interaction between post-synaptic adaptors, long Homer-3 proteins, and one of the 26S proteasome regulatory subunits, the S8 ATPase, that influences the degradation of the metabotropic glutamate receptor 1alpha (mGluR1alpha). We have shown that the two human long Homer-3 proteins specifically interact with human proteasomal S8 ATPase. We identified that mGluR1alpha and long Homer-3s immunoprecipitate with the 26S proteasome both in vitro and in vivo. We further found that the mGluR1alpha receptor can be ubiquitinated and degraded by the 26S proteasome and that Homer-3A facilitates this process. Furthermore, the siRNA mediated silencing of Homer-3 led to increased levels of total and plasma membrane-associated mGluR1alpha receptors. These results suggest that long Homer 3 proteins control the degradation of mGluR1alpha receptors by shuttling ubiquitinated mGluR-1alpha receptors to the 26S proteasome via the S8 ATPase which may modulate synaptic transmission. PMID- 22486778 TI - Evolution in transvenous extraction of pacemaker and implantable cardioverter defibrillator leads using a mechanical dilator sheath. AB - BACKGROUND: With developing technology, transvenous lead extraction (TLE) has undergone an explosive evolution due to incremental problems related to lead infection and malfunction. OBJECTIVE: We aimed to present our experience in TLE with the Evolution(r)Mechanical Dilator Sheath (Cook Medical, Grandegrift, PA, USA). METHODS: Between June 2009 and July 2011, the Evolution(r)mechanical dilator sheath was used for the extraction of 140 pacemaker (PM) and implantable cardioverter-defibrillator (ICD) leads in 66 patients. Indications for extraction, procedural success, and complications were defined according to Heart Rhythm Society Guidelines. RESULTS: Indications for TLE were infection in 39 patients (59.1%), lead malfunction in 26 patients (39.4%), and lead displacement in one patient (1.5%). Extracted devices were PM in 28 cases (42.3%), ICD in 26 cases (39.4%), and biventricular cardioverter defibrillator in 12 cases (18.2%). Among 140 leads, 31 (22.1%) were right ventricular, 49 (35.0%) were defibrillator coil, 47 (33.6%) were atrial, and 13 (9.3%) were coronary sinus electrodes. The median time interval from the lead implantation to lead extraction was 85 months (range 22-240 months). Complete procedural success with the Evolution(r)system alone was achieved in 58 (87.9%) patients and overall clinical success was 98.5%. Four leads were completely removed with the help of a femoral snare and partial success was achieved in three leads with a remaining small ventricular tip. Major complication was observed in only one (1.5%) patient without any mortality. CONCLUSIONS: Our experience confirms that the hand-powered Evolution system is an effective extraction tool for chronically implanted PM/ICD leads. Randomized controlled studies are required to evaluate success and complication rates in comparison to other techniques. PMID- 22486779 TI - Posterior reversible encephalopathy syndrome: a syndrome not present in the ICHD II. PMID- 22486780 TI - Matched false-belief performance during verbal and nonverbal interference. AB - Language has been shown to play a key role in the development of a child's theory of mind, but its role in adult belief reasoning remains unclear. One recent study used verbal and nonverbal interference during a false-belief task to show that accurate belief reasoning in adults necessarily requires language (Newton & de Villiers, 2007). The strength of this inference depends on the cognitive processes that are matched between the verbal and nonverbal inference tasks. Here, we matched the two interference tasks in terms of their effects on spatial working memory. We found equal success on false-belief reasoning during both verbal and nonverbal interference, suggesting that language is not specifically necessary for adult theory of mind. PMID- 22486782 TI - Editorial comment to safety and tolerability of intermittent androgen deprivation therapy: a literature review. PMID- 22486781 TI - Multiple Vibrio fischeri genes are involved in biofilm formation and host colonization. AB - Biofilms are increasingly recognized as being the predominant form for survival for most bacteria in the environment. The successful colonization of Vibrio fischeri in its squid host Euprymna tasmanica involves complex microbe-host interactions mediated by specific genes that are essential for biofilm formation and colonization. Here, structural and regulatory genes were selected to study their role in biofilm formation and host colonization. We have mutated several genes (pilT, pilU, flgF, motY, ibpA and mifB) by an insertional inactivation strategy. The results demonstrate that structural genes responsible for synthesis of type IV pili and flagella are crucial for biofilm formation and host infection. Moreover, regulatory genes affect colony aggregation by various mechanisms, including alteration of synthesis of transcriptional factors and regulation of extracellular polysaccharide production. These results reflect the significance of how genetic alterations influence communal behavior, which is important in understanding symbiotic relationships. PMID- 22486783 TI - Stroke patients' functions in personal activities of daily living in relation to sleep and socio-demographic and clinical variables in the acute phase after first time stroke and at six months of follow-up. AB - AIMS AND OBJECTIVES: To explore first-time stroke patients' degree of independence in activities of daily life in relation to sleep and other essential variables that might influence activities of daily life. BACKGROUND: Sleep has received little attention in rehabilitation of activities of daily life in stroke patients. DESIGN: This is a longitudinal survey and observational study design from the acute phase to six months poststroke. METHODS: First-time stroke patients (n = 90) were recruited from two hospitals in eastern Norway in 2007 and 2008. Data were collected by survey interview, medical records and wrist actigraphy in the first two weeks at the hospital and at six months of follow-up. Actigraph measures patient activity and estimates sleep during the day and night. RESULTS: Linear regression showed that high dependence in personal activities of daily living was directly related to low estimated sleep time at night and higher estimated sleep during the day in the acute phase, controlling for socio demographic and clinical variables. Furthermore, high estimated numbers of awakenings in the acute phase were related to lower activities of daily life functioning at six months of follow-up after controlling for socio-demographic and clinical variables. Stronger pain and a lower physical functioning showed direct relationships with lower independency level of in activities of daily life both in the acute phase and after six months. CONCLUSIONS: Sleep patterns in the acute phase may influence the patients' activities of daily life functioning up to six months poststroke. Furthermore, pain in the acute phase may influence the level of activities of daily life functioning in stroke patients. RELEVANCE TO CLINICAL PRACTICE: Nurses should pay attention to stroke patients' sleep quality and pain in the rehabilitation period after a stroke. Facilitating good sleep conditions and screening for pain should be an integral part of the rehabilitation programme. PMID- 22486784 TI - Isolated complete tubular esophageal duplication in a neonate. PMID- 22486785 TI - Increased prospective memory interference in normal and pathological aging: different roles of motor and verbal processing speed. AB - This is a study on prospective memory (PM) and the PM interference effect in normal and pathological aging. One hundred and seven subjects, including 41 healthy young adults, 40 non-demented older adults and 26 patients with mild Alzheimer's disease (AD) participated in this study using a laboratory event based PM task. PM task performance was comparable between the non-demented older and young adults, but impaired in the AD patients. The PM interference effect increased progressively from the healthy young adults, the non-demented older adults, to the AD patients. Path analysis revealed that the possible mechanism mediating the increased PM interference was the slow motor processing speed in normal aging, while it was the slow verbal speed in pathological aging. It is suggested that different neuropsychological mechanisms may underpin the affected performance of PM task in normal and pathological aging. PMID- 22486786 TI - Monocytoid B cells: an enigmatic B cell subset showing evidence of extrafollicular immunoglobulin gene somatic hypermutation. AB - Monocytoid B cells are IgM(+) , IgD(-/+) , CD27(-) B cells, localized in the perisinusoidal area of the lymph node. These cells are especially prominent in infections such as those caused by toxoplasma and HIV. The ontogeny of monocytoid B cells with respect to B cell maturation is incompletely known. We analysed clonal expansion, somatic hypermutation and expression of activation-induced cytidine deaminase (AID) in monocytoid B cells. Sequence analysis of the rearranged immunoglobulin heavy chain genes amplified from microdissected monocytoid B cell zones with a high proportion of proliferating cells reveals the presence of multiple clones with low-level ongoing mutations (mean frequency: 0.46 * 10(-2) per bp). Mutation analysis of these ongoing mutations reveals strand bias, a preference of transitions over transversions as well as the occurrence of small deletions, as observed for somatically mutated immunoglobulin genes in the human germinal centre. Proliferation, ongoing mutation as well as expression of AID, combined, is evidence that monocytoid B cells acquire the mutations in the extrafollicular perisinusoidal area of the lymph node and pleads against a postgerminal centre B cell origin. PMID- 22486787 TI - High-efficiency solid-state dye-sensitized solar cells based on TiO(2)-coated ZnO nanowire arrays. AB - Replacing the liquid electrolytes in dye-sensitized solar cells (DSCs) with solid state hole-transporting materials (HTMs) may solve the packaging challenge and improve the long-term stability of DSCs. The efficiencies of such solid-state DSCs (ss-DSCs), however, have been far below the efficiencies of their counterparts that use liquid electrolytes, primarily due to the challenges in filling HTMs into thick enough sensitized films based on sintered TiO(2) nanoparticles. Here we report fabrication of high-efficiency ss-DSCs using multilayer TiO(2)-coated ZnO nanowire arrays as the photoanodes. The straight channel between the vertically aligned nanostructures combined with a newly developed multistep HTM filling process allows us to effectively fill sensitized films as thick as 50 MUm with the HTMs. The resulting ss-DSCs yield an average power conversion efficiency of 5.65%. PMID- 22486788 TI - Does increasing mortality change the response of fish populations to environmental fluctuations? AB - Fluctuations of fish populations abundances are shaped by the interplay between population dynamics and the stochastic forcing of the environment. Age-structured populations behave as a filter of the environment. This filter is characterised by the species-specific life cycle and life-history traits. An increased mortality of mature individuals alters these characteristics and may therefore induce changes in the variability of populations. The response of a generic age structured model was analysed to investigate the expected changes in the fluctuations of fish populations in response to decreased adult survival. These expectations were then tested on an extensive dataset. In accordance with theory, the analyses revealed that decreased adult survival and mean age of spawners were linked to an increase in the relative importance of short-term fluctuations. It suggests that intensive exploitation can lead to a change in the variability of fish populations, an issue of central interest from both conservation and management perspectives. PMID- 22486789 TI - Characterization of HLA-E polymorphism in four distinct populations in Mainland China. AB - In this study, human leukocyte antigen (HLA)-E allelic typing was performed for 690 individuals from two southern Chinese Han populations (Hunan Han and Guangdong Han) and two northern Chinese populations (Inner Mongolia Han and Inner Mongolia Mongol) using polymerase chain reaction-sequence-specific priming (PCR SSP) method. Our data showed that (1) HLA-E*01:01 and HLA-E*01:03, but not E*01:04 allele, were detected in the four populations, HLA-E distribution differed significantly between each of the two southern Chinese Han populations and the Inner Mongolia Mongol population, and between Hunan Han population and Inner Mongolia Han population; (2) HLA-G*01:05N-A*30-E*01:01-C*06-B*13:02-DRB1*07 was a conserved extended haplotype in the Chinese Han populations; (3) five HLA-A E haplotypes showed significant linkage disequilibrium (LD) in at least one population, including HLA-A*02-E*01:03 in populations except for the Inner Mongolia Mongol group, HLA-A*01-E*01:01 and HLA-A*30-E*01:01 in the Hunan Han and the Inner Mongolia Han populations, HLA-A*33-E*01:01 in the two southern Chinese Han populations and HLA-A*03-E*01:03 in the Inner Mongolia Mongol group; and (4) Ewens-Watterson homozygosity test showed a trend for balancing selection at the HLA-E locus in each of the four populations. Our data unraveled the peculiarity in terms of HLA-E allelic and haplotypic repertoire in four main ethnic groups in Mainland China, findings shown here are valuable for future studies of the potential role of HLA-E in allogeneic organ transplantation and HLA-linked disease association in related ethnic groups. PMID- 22486790 TI - Economic impact on US Medicare of a new diagnosis of myelodysplastic syndromes and the incremental costs associated with blood transfusion need. AB - BACKGROUND: Recent retrospective studies suggest myelodysplastic syndromes (MDSs) are more common than previously recognized and patients who develop transfusional dependence may be at risk for increased comorbid complications. STUDY DESIGN AND METHODS: A retrospective review was undertaken of Medicare claims focusing on costs associated with patients with a new claim listing ICD-9-CM Diagnosis Code 238.7 in first quarter of 2003. Patients were followed until 2005 to assess resource use and costs. RESULTS: A total of 512 patients aged 65 years or more with newly diagnosed MDS were identified. Forty percent had received red blood cell transfusions between 2003 and 2005. During the 3-year follow-up, transfused patients experienced increased prevalence of cardiac diseases, dyspnea, and infections. Cumulative 3-year mean Medicare costs for MDS patients were $49,156. Transfused patients had greater use of hospital inpatient and outpatient services and incurred significantly higher mean costs than nontransfused patients ($88,824 vs. $29,519, p < 0.001). After adjustment for baseline characteristics and clinical complications, transfusion was independently associated with a 48% increase in monthly costs in addition to the cost of transfusion administration. CONCLUSION: MDS places a significant economic burden on the US Medicare system. MDS patients requiring transfusions experience higher prevalence of new comorbid conditions and incur significantly higher Medicare costs than nontransfused patients during the initial 3 years after diagnosis. PMID- 22486791 TI - Bartholin's gland leiomyoma: a diagnostic and management dilemma. AB - There are limited reports in the literature about Bartholin's gland leiomyoma, mainly due to its rare occurrence. This case report describes a 56-year-old woman presenting with a lump in her vulva. The initial suspicion was that of a Bartholin's gland carcinoma based on her clinical signs and symptoms. The mass was excised and the histopathology report described a leiomyoma. Differentiating between benign and malignant tumors by inspection alone can pose a diagnostic dilemma. There are no clear management guidelines but some authorities recommend that enlarged Bartholin's gland in postmenopausal women should be completely excised so as to exclude adenocarcinoma of the gland. However, other case reports and reviews have tried to justify an initial biopsy before considering complete excision to avoid unnecessary intervention in women whose biopsy confirms a benign lesion. In the case described, surgical excision was necessary and beneficial to the patient to provide symptom control. PMID- 22486792 TI - A need for biomarkers of operational tolerance in liver and kidney transplantation. AB - Both kidney and particularly liver recipients can occasionally discontinue all immunosuppressive drugs without undergoing rejection. These patients, who maintain stable graft function off immunosuppressive drugs without clinically significant detrimental immune responses and/or immune deficits, are conventionally termed operationally tolerant and offer a unique paradigm of tolerance in humans. The immune characterization of operationally tolerant transplant recipients has recently received substantial attention. Operationally tolerant patients might exhibit a signature of tolerance that could potentially be useful to select recipients amenable to drug minimization or withdrawal. Furthermore, elucidation of the molecular pathways associated with the operational tolerance phenotype could provide novel targets for therapy. Particular emphasis has been placed on the use of blood samples and high throughput transcriptional profiling techniques. In liver transplantation, natural killer related transcripts seem to be the most robust markers of operational tolerance, whereas enrichment in B cell-related gene expression markers has been consistently found in blood samples from operationally tolerant kidney recipients, suggesting that different mechanisms operate in the two situations. In this minireview, we summarize the main achievements of recently published reports focused on the identification of transcriptional markers of operational tolerance, we highlight their mechanistic and clinical implications and describe their methodological limitations. PMID- 22486793 TI - Reading to children. PMID- 22486794 TI - A case of Cyrano-nose haemangioma. nasal tip infantile haemangioma. PMID- 22486796 TI - Treatment of allergic rhinitis in children: what's new? PMID- 22486797 TI - T-cell lymphoma masquerading as juvenile rheumatoid arthritis. PMID- 22486798 TI - Teleconference etiquette: job interview. PMID- 22486799 TI - Teleconference etiquette. PMID- 22486801 TI - A paper that changed my practice: the question cube. PMID- 22486802 TI - Association between liver insulin resistance and cardiovascular risk factors. AB - OBJECTIVES: The objective of this study was to examine the associations between indices of liver insulin resistance (IR) and whole-body insulin sensitivity and different cardiovascular disease (CVD) risk factors. DESIGN AND SUBJECTS: A total of 8750 nondiabetic men (age 57.2 +/- 7.1 years, body mass index 26.8 +/- 3.8 kg m(-2) ) were included in this study from the population-based cross-sectional Metabolic Syndrome In Men (METSIM) cohort. Liver IR index and Matsuda insulin sensitivity index (ISI) were used as markers of liver IR and whole-body insulin sensitivity, respectively. Pearson correlation analysis was performed to examine the associations between these indices and various CVD risk factors. RESULTS: Total cholesterol (r = -0.088 vs. r = 0.020; P < 0.0019), high-sensitivity C reactive protein (CRP) (r = 0.284 vs. r = -0.219; P < 0.0019) and total triglycerides (r = 0.507 vs. r = -0.477; P < 0.05) were more highly correlated with liver IR index than with Matsuda ISI. By contrast, Matsuda ISI was nominally more highly correlated with systolic and diastolic blood pressure (r = -0.234 and r = -0.275 vs. r = 0.202 and r = 0.239, respectively) compared to liver IR index. Furthermore, the variance explained by liver IR index was larger than that explained by Matsuda ISI for the majority of CVD risk factors measured. CONCLUSIONS: Liver IR index correlated more strongly than Matsuda ISI with levels of total cholesterol, CRP and triglycerides. Therefore, liver IR might be a significant indicator of CVD risk amongst men. PMID- 22486803 TI - Turnover intention among hospital-based registered nurses in the Eastern Caribbean. AB - PURPOSE: Vacancy rates for nurses in the English-speaking Caribbean are estimated at 30% with turnover typically associated with migration. The purpose of this study was to describe the characteristics of hospital-based registered nurses (RNs) in the sub-region, their practice environment and turnover intention in two and five years, respectively, and to determine the relationships among practice environment characteristics and turnover intention. DESIGN: A descriptive correlational design was used with self-reported questionnaires from a convenience sample of 301 RNs working in hospitals in four English speaking Eastern Caribbean countries. Single-item visual analog scales (VAS) were used to measure turnover intention in 2 years and 5 years. The Practice Environment Scale of the Nursing Work Index (PES-NWI) measured the characteristics in the practice environment. FINDINGS: The mean age of the nurses was 32.5 (SD = 6.75) years. Most nurses (58.8%) were single and 91.4% had relatives living abroad. Nurses scored three PES-NWI subscales < 2.5, indicating a less positive practice environment: resource adequacy, nurse participation in hospital affairs, and nurse managers' ability, leadership, and support. The subscale for collegial nurse-physician relations received the best rating (mean = 2.61, SD = .62). For 2 year intention to leave, the mean rating on the 100-mm VAS was 63.2, while that for the 5-year intention to leave was 65.6. No significant correlations were found among four of the five PES-NWI subscales and turnover intention in 2 and 5 years. CONCLUSIONS: The practice environment, while generally unfavorable, is not associated with the nurses' intention to leave their jobs. These findings support the current policy position that calls for managing turnover among nurses. Nursing and health system administrators should assess, plan, and implement workforce policies to slow the outflow of nurses. CLINICAL RELEVANCE: Initiatives to improve the work environment and the delivery of high-quality care are important to RNs in the Eastern Caribbean. Managing the negative impact of continuous outflow of nurses through turnover requires long-term coordinated policy and human resource development and management initiatives to sustain the supply of RNs in the subregion. PMID- 22486804 TI - Atrioesophageal fistula after cryoballoon pulmonary vein isolation. AB - The risk of atrioesophageal fistula after cryoballoon pulmonary vein isolation is thought to be much lower than after radiofrequency ablation, seeing that no data exist on this complication so far. We report for the first time on the occurrence of an atrioesophageal fistula 4 weeks after cryoballoon ablation at the site of the left inferior pulmonary vein. We suggest that even when using cryothermal ablation technique, an imaging modality to assess the proximity of esophagus and left atrium should be routinely performed to avoid this fatal complication. PMID- 22486805 TI - Decontamination efficacy of photon-initiated photoacoustic streaming (PIPS) of irrigants using low-energy laser settings: an ex vivo study. AB - AIM: To assess ex vivo, the antibacterial effectiveness of photon-initiated photoacoustic streaming (PIPS) of irrigants using an Er:YAG laser equipped with a newly designed, stripped and tapered tip in extracted teeth with infected root canals. METHODOLOGY: One hundred and forty-eight single-rooted extracted teeth were prepared to a size 25, 0.06 taper. The specimens were sterilized, and all teeth except ten (negative control group) were inoculated with Enterococcus faecalis and incubated in a CO(2) chamber at 37 degrees C for 15 days in Eppendorf tubes filled with trypticase soy broth medium changed every 2 days. Infected teeth were then randomly divided into four test groups (n = 32 for each): pulsed erbium/YAG laser at nonablative settings for 30 s with sterile bi distilled water (Group A) or 5% sodium hypochlorite (NaOCl) (Group B); without laser-activated sterile bi-distilled water irrigation for 30 s (Group C) or 5% NaOCl irrigation for 30 s (Group D); the positive control group received no treatment in infected teeth (n = 10). Colony-forming units (CFUs) were counted from bacteriologic samples taken before (S1) and after treatment (S2). Data were analysed by Kruskal-Wallis and post hoc Dunn's multiple comparison tests. RESULTS: CFU counts were significantly lower in 5% NaOCl groups with or without laser activation than in sterile bi-distilled water without laser activation group (P < 0.001). Moreover, there was a significant difference between bi distilled water groups with or without laser activation (P < 0.001). Sodium hypochlorite with laser activation group had the greatest CFU reduction, which was significantly greater than that evident in bi-distilled water groups with or without laser activation (P < 0.001). There were no significant differences between 5% NaOCl groups with or without laser activation (P > 0.05). None of the four groups generated negative samples predictably. CONCLUSIONS: Under the conditions of this ex vivo study, there were no significant differences in bacterial reduction between the laser and NaOCl or NaOCl alone groups. [Correction added after online publication, 18th April 2012: The following statement has been deleted: 'Thus, the use of a laser did not improve microbial killing over and above use of NaOCI alone.']. PMID- 22486806 TI - Comparison of quality of recovery from anaesthesia in cats induced with propofol or alfaxalone. AB - OBJECTIVE: To assess the quality and length of recovery from anaesthesia induced with either propofol or alfaxalone and maintained with isoflurane, in cats undergoing short procedures in private veterinary practice. STUDY DESIGN: Prospective, blinded, randomized study. ANIMALS: Ninety-three healthy mixed breed cats. METHODS: After premedication with intramuscular acepromazine (0.05 mg kg( 1)) and buprenorphine (0.01 mg kg(-1)), cats were randomly allocated to receive either propofol (Group P) or alfaxalone (Group A) for induction of anaesthesia. Following endotracheal intubation, anaesthesia was maintained with isoflurane vaporized in oxygen. The quality of induction, physiological parameters throughout anaesthesia and the duration of both surgery and anaesthesia were recorded. The level of ambient noise, recovery times, number of attempts to stand, reaction of the cat to touch 15 minutes after extubation, and other relevant characteristics of the recovery period were noted and a video recording of the recovery was made. The videos were assessed by a second, blinded anaesthetist, using simple descriptive and visual analogue scales. RESULTS: No statistically significant differences between groups with respect to preoperative data, premedication, surgery, anaesthesia and recovery times and scores were observed. There was a statistically significant difference in the number of patients paddling and trembling on recovery in Group A (p = 0.032) even though there was no statistically significant difference in the level of ambient noise in the recovery ward or in the overall quality of recovery. CONCLUSIONS: Both propofol and alfaxalone provide good recovery characteristics in premedicated cats undergoing short procedures in clinical settings. Alfaxalone induction was associated with more episodes of paddling and trembling during recovery. CLINICAL RELEVANCE: Both agents would appear appropriate for induction of anaesthesia in cats for short procedures. PMID- 22486807 TI - The prognostic value of plasma fibrinogen concentrations of patients with ST elevation myocardial infarction and treated by primary percutaneous coronary intervention: a cautionary message. AB - BACKGROUND: Fibrinogen elevation is associated with a worse prognosis in patients with acute coronary syndrome (ACS). The aim of the present study was to assess the prognostic value of increased fibrinogen concentrations in ST-elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PCI). METHODS: A total of 428 STEMI patients treated with primary PCI were retrospectively selected (median age: 62 years; 82.5% males) from a continuous case series of 832 ACS patients. Plasma fibrinogen concentrations were measured before PCI and after 24, 48, and 72 hours. In the 4-year follow-up, one major adverse cardiovascular event (MACE) occurred in 111 patients (40%): 17 re STEMI (7%), 64 re-PCI (22%), 22 cardiac deaths (7%), and eight non ST-elevated acute coronary syndromes (NSTEACS, 4%). RESULTS: According to the reference change value, fibrinogen concentrations increased in 25% of patients at 24 h, 64% at 48 h and 19% at 72 h. Only fibrinogen concentrations at 48 h showed a mild association with overall MACEs (p = 0.036): the risk increased, starting from a concentration of 4 g/L. However a further multivariate model did not confirm any prognostic value. No association with specific MACEs emerged. CONCLUSIONS: In contrast to NSTEACS patients, fibrinogen concentrations increased slightly in STEMI patients after primary PCI, however, they were not as prognostic as for MACEs. PMID- 22486808 TI - Plasma adiponectin is related to the progression of kidney disease in type 2 diabetes patients. AB - BACKGROUND: Adiponectin, an anti-inflammatory and insulin-sensitizing cytokine, has been shown to reduce proteinuria and glomerulosclerosis in experimental models. We assessed the relationship of plasma adiponectin to the progression of kidney disease in type 2 diabetes (T2D) patients. METHODS: T2D nonnephrotic patients with glomerular filtration rate (GFR) >30 ml/min and without acute cardiovascular/inflammatory conditions were included. Laboratory standard evaluation, urinary albumin/creatinine ratio (UACR), total plasma adiponectin, and CRP (C-reactive protein) were determined at inclusion and the end of study. RESULTS: Eighty-six patients (62.79% male) were followed up for 20.53+/-5.46 months. Baseline GFR was 72.85+/-26.29 ml/min and UACR was 20.53 (interquartile range 6.82-86.39) mg/g. At baseline adiponectin was significantly correlated to UACR (r =0.40, p =0.0001), HDL cholesterol (r =0.30, p =0.005), GFR (r =- 0.23, P =0.04), body mass index (BMI) (r =- 0.26, P =0.02) and waist circumference (r = 0.27, p =0.01). In multiple regression UACR (p =0.0003) and BMI (p =0.03) were significantly related to baseline adiponectin. The progression of kidney disease was estimated as the difference (D) between end and baseline UACR/month and between end and baseline GFR/month. None of the baseline parameters correlated to DeltaGFR, but adiponectin inversely (r =- 0.26, p =0.02) correlated to DeltaUACR. In multiple regression only adiponectin (p <0.0001) predicted DeltaUACR. A computed progression index (PI) resulting from a linear combination of GFR and UACR was also used to assess progression. Baseline adiponectin was significantly correlated to DeltaPI between end of study and baseline (r =- 0.43, p <0.0001), and predicted DeltaPI in multiple regression (p =0.009). CONCLUSION: Low plasma adiponectin predicts progression of kidney disease in T2D patients. PMID- 22486809 TI - Multi-tier regulation of the streptomycete morphogenetic peptide SapB. AB - Streptomyces coelicolor is a morphologically complex bacterium requiring the secretion of surface-active proteins to progress through its life cycle. SapB represents an important class of these biosurfactants, as illustrated by its ability to restore aerial hyphae formation when applied exogenously to developmental mutants. However, such aerial hyphae fail to sporulate, exemplifying the need to co-ordinate the timing of SapB production with other developmental events. SapB has an unusual lantibiotic structure. Its structural gene, ramS, is only 38 nucleotides downstream of the gene encoding its putative modification enzyme, RamC. Transient, co-ordinated expression of the operon was thought to be controlled by the response regulator RamR. However, we show that ramS is transcribed throughout the cell cycle with a dual expression profile dissimilar to the tightly controlled ramC expression. Surprisingly, post translational modification relies on prior membrane localization of the precursor peptide, RamS, as demonstrated by the absence of RamS modification in S. coelicolor hyphae treated with the Bacillus subtilis lipoprotein surfactin. Our results demonstrate that interspecies interaction can also be mediated by interference of post-translational events. Further, temporal and spatial regulation of irreversible post-translational modification of a surface-active morphogenetic peptide suggests a new model for the control of key developmental events. PMID- 22486810 TI - Aspirin's effect on platelet inhibition in migraineurs. AB - OBJECTIVE: To assess the effect of aspirin on platelet reactivity in migraineurs. BACKGROUND: Migraineurs, particularly women with aura and high monthly migraine frequency, are at risk for ischemic stroke and myocardial infarction (MI). High on-aspirin platelet reactivity (HAPR), or aspirin resistance, has been reported in females and patients with coronary artery disease, and is associated with adverse outcomes. METHODS: Using a single group, pretest/posttest design, 50 migraineurs without prior history of stroke or MI were prospectively treated for 14 to 21 consecutive days with 325 mg generic enteric-coated aspirin, after undergoing a 14-day aspirin washout. Platelet reactivity was measured after aspirin washout and following aspirin treatment. Subjects were screened for HAPR using the VerifyNowTM Aspirin Assay (Accumetrics, San Diego, CA, USA). HAPR was defined as >= 460 Aspirin Reaction Units (ARU; primary endpoint). RESULTS: Fifty subjects, 44 (88%) female, aged (mean +/- standard deviation) 43 +/- 12 years were enrolled. Twelve (24%; 95% CI 12-36%) subjects, all female, had HAPR and were classified as aspirin resistant. Subjects with HAPR had lower baseline hemoglobin levels than those without HAPR (P = .03). Baseline hemoglobin was significantly correlated with final ARU (r = -0.39, P = .005). CONCLUSIONS: Findings of this exploratory study suggest that migraineurs have a higher prevalence of HAPR than healthy volunteers or patients with coronary artery disease taking aspirin 325 mg. The clinical implications of HAPR in migraine warrant further exploration due to the risk of stroke and MI and the potential need for antiplatelet therapy in this population. PMID- 22486811 TI - Gene expression changes in melanoma metastases in response to high-dose chemotherapy during isolated limb perfusion. AB - Despite recent advances in melanoma therapy, disseminated melanoma still lacks effective treatment, and recurrence of the tumor frequently occurs, even after high-dose chemotherapy. The mechanisms responsible for this chemoresistance or for the formation of new relapses remain poorly understood. Using a human 'model', in which the isolated limb is perfused with high doses of the chemotherapeutic melphalan (ILP), we identified a five-gene set (ATF3, CYR61, IER5, IL6, and PTGS2) of stress-induced genes that was consistently upregulated after ILP in all in-transit metastatic melanoma samples as well as in three melphalan-treated melanoma cell lines. Early post-ILP relapses retained these elevated expressions, whereas the expression of these genes returned to their original levels in late post-ILP recurrences. In addition, we identified upregulation of these genes in the A375 cell line's side population (SP) and melanospheres, established methods to enrich for candidate cancer stem cells (CSCs), which are considered chemoresistant and tumorigenic, and thus proposed to be responsible for tumor relapse. Our data identify an immediate and short-term upregulation of early stress-responsive genes that are potentially linked to chemoresistance and CSCs. PMID- 22486812 TI - Coronary sinus isolation: no myth but reality. AB - Coronary sinus (CS) has muscular connections with atria and is often targeted to complete left atrial ablation for curing atrial fibrillation; however, complete CS isolation is difficult to achieve with hard end points. We present a distinctive case of complete isolation of CS that had an unusual muscular connection. PMID- 22486813 TI - Sorting nexin 5 of a new diagnostic marker of papillary thyroid carcinoma regulates Caspase-2. AB - Papillary thyroid carcinoma (PTC) is a well-differentiated endocrine malignant tumor that develops from thyroid follicular epithelium. The tumor represents the most common type of endocrine malignancy; however, its tumorigenesis is not fully elucidated. The aim of this study was to address the functional role of the sorting nexin (SNX) family in PTC because of recent experimental evidence suggesting that the SNX family members actively control endocytotic transportation as well as cell fate. Expression profiles of SNX family members of PTC showed a significant quantity of transcripts of SNX5. Further immunohistochemical analysis with an SNX5-specific monoclonal antibody established in this study consistently demonstrated the preferential expression of SNX5 in PTC (94.2%, 113/120 cases) as indicated by studies on 440 cases of various tumors. In contrast, other major carcinomas originating from the lung (2.6%, 1/38 cases), breast (5.1%, 2/39 cases), and intestine (4.2%, 1/24 cases) scarcely expressed SNX5. When we investigated models of murine thyroid tumors induced by the administration of carcinogens, high expression of Snx5 was also observed in well-differentiated thyroid tumors, further implying that the tumorigenesis of the thyroid gland was tightly associated with the abundance of SNX5/Snx5. Moreover epithelial cells expressing excess SNX5 showed high levels of Caspase-2 of an initiator caspase. Collectively these findings suggest that the evaluation of SNX5 expression would support pathological diagnosis of primary and secondary PTC. PMID- 22486815 TI - Five-year results of a randomized trial comparing de novo sirolimus and cyclosporine in renal transplantation: the SPIESSER study. AB - Calcineurin inhibitors improve acute rejection rates and short-term graft survival in renal transplantation, but their continuous use may be deleterious. We evaluated the 5-year outcomes of sirolimus (SRL) versus cyclosporine (CsA) immunosuppressive treatment. This observational study was an extension of the SPIESSER study where deceased donor kidney transplant recipients were randomized before transplantation to a SRL- or CsA-based regimen and followed up 1 year. Data from 131 (63 SRL, 68 CsA) out of 133 patients living with a functional graft at 1 year were collected retrospectively at 5 years posttransplant. Seventy percent of CsA patients versus 54% of SRL patients were still on the allocated treatment at 5 years (p = 0.091), most discontinuations in each group being due to safety issues. In intent-to-treat, mean MDRD eGFR was higher with SRL: 54.2 versus 45.3 mL/min with CsA (p = 0.019); SRL advantage was greater in on treatment analyses. There were no differences for patient survival (p = 0.873), graft survival (p = 0.121) and acute rejection (p = 0.284). Adverse events were more frequent with SRL (80% vs. 60%, p = 0.015). Results confirmed the high SRL discontinuation rate due to adverse events. Nevertheless, a benefit was evidenced on renal function in patients (more than 50%) still on treatment at 5 years. PMID- 22486817 TI - Outcome of SurePathTM cervical samples reported as borderline nuclear change by cytological subtype and high-risk HPV status. AB - BACKGROUND: The average borderline rate in cervical cytology samples for English laboratories was 3.8% with the range being 2.0-6.8% at the time of the present study, which was undertaken in order to determine the association between different subtypes of borderline nuclear change (BNC), high-grade cervical intraepithelial neoplasia (CIN) and high-risk human papillomavirus (hrHPV) status. MATERIALS AND METHODS: Of 68,551 SurePath(TM) cervical samples reported in one laboratory over a period of 2 years, 2335 (3.4%) were reported as BNC. hrHPV status was known in 1112 cases (47.6%). The outcome was known only for women with hrHPV-positive BNC, who were recommended for colposcopy under the National Health Service Cervical Screening Programme sentinel site protocol. Women with hrHPV-negative BNC were returned to 3-yearly recall. The cases were subdivided into BNC, high-grade dyskaryosis cannot be excluded (B-HG; 105 cases); BNC with koilocytosis (B-K; 421 cases); BNC with other features of HPV (B-HPV; 160 cases); and BNC, not otherwise specified (B-NOS; 426 cases) and were correlated with the histological outcome where available. RESULTS: The study population age ranged from 23 to 65 years. Cases that tested positive for hrHPV by Qiagen HCII assay comprised 78.1%, 81.0%, 73.1% and 67.8% of B-HG, B-K, B-HPV and B-NOS categories, respectively. CIN2 or worse (CIN2+) was found in 64.6%, 10.0%, 19.7% and 20.1% of hrHPV-positive cases of B-HG, B-K, B-HPV and B-NOS, respectively, which was significantly higher in the B-HG category (P < 0.001) and lower in the B-K category compared with B-NOS (p < 0.001) and B-HPV (p = 0.006) respectively. CIN3+ comprised 55.6%, 6.3%, 26.3% and 19.1% of biopsies in the same categories, respectively. CONCLUSIONS: Subtyping BNC is useful, especially B K and B-HG, which, respectively, had the lowest and highest rates of detection of both CIN2+ and CIN3+, confirming that koilocytosis is likely to be associated with transient HPV infection. Women with B-HG should be referred to colposcopy in the absence of HPV triage. PMID- 22486816 TI - Ecotin-like serine peptidase inhibitor ISP1 of Leishmania major plays a role in flagellar pocket dynamics and promastigote differentiation. AB - Leishmania ISPs are ecotin-like natural peptide inhibitors of trypsin-family serine peptidases, enzymes that are absent from the Leishmania genome. This led to the proposal that ISPs inhibit host serine peptidases and we have recently shown that ISP2 inhibits neutrophil elastase, thereby enhancing parasite survival in murine macrophages. In this study we show that ISP1 has less serine peptidase inhibitory activity than ISP2, and in promastigotes both are generally located in the cytosol and along the flagellum. However, in haptomonad promastigotes there is a prominent accumulation of ISP1 and ISP2 in the hemidesmosome and for ISP2 on the cell surface. An L. major mutant deficient in all three ISP genes (Deltaisp1/2/3) was generated and compared with Deltaisp2/3 mutants to elucidate the physiological role of ISP1. In in vitro cultures, the Deltaisp1/2/3 mutant contained more haptomonad, nectomonad and leptomonad promastigotes with elongated flagella and reduced motility compared with Deltaisp2/3 populations, moreover it was characterized by very high levels of release of exosome-like vesicles from the flagellar pocket. These data suggest that ISP1 has a primary role in flagellar homeostasis, disruption of which affects differentiation and flagellar pocket dynamics. PMID- 22486818 TI - Allergen sensitivity pattern in Kuwaiti children with atopic dermatitis. PMID- 22486819 TI - Environmental DNA. PMID- 22486820 TI - Next-generation sequencing technologies for environmental DNA research. AB - Since 2005, advances in next-generation sequencing technologies have revolutionized biological science. The analysis of environmental DNA through the use of specific gene markers such as species-specific DNA barcodes has been a key application of next-generation sequencing technologies in ecological and environmental research. Access to parallel, massive amounts of sequencing data, as well as subsequent improvements in read length and throughput of different sequencing platforms, is leading to a better representation of sample diversity at a reasonable cost. New technologies are being developed rapidly and have the potential to dramatically accelerate ecological and environmental research. The fast pace of development and improvements in next-generation sequencing technologies can reflect on broader and more robust applications in environmental DNA research. Here, we review the advantages and limitations of current next generation sequencing technologies in regard to their application for environmental DNA analysis. PMID- 22486821 TI - New environmental metabarcodes for analysing soil DNA: potential for studying past and present ecosystems. AB - Metabarcoding approaches use total and typically degraded DNA from environmental samples to analyse biotic assemblages and can potentially be carried out for any kinds of organisms in an ecosystem. These analyses rely on specific markers, here called metabarcodes, which should be optimized for taxonomic resolution, minimal bias in amplification of the target organism group and short sequence length. Using bioinformatic tools, we developed metabarcodes for several groups of organisms: fungi, bryophytes, enchytraeids, beetles and birds. The ability of these metabarcodes to amplify the target groups was systematically evaluated by (i) in silico PCRs using all standard sequences in the EMBL public database as templates, (ii) in vitro PCRs of DNA extracts from surface soil samples from a site in Varanger, northern Norway and (iii) in vitro PCRs of DNA extracts from permanently frozen sediment samples of late-Pleistocene age (~16,000-50,000 years bp) from two Siberian sites, Duvanny Yar and Main River. Comparison of the results from the in silico PCR with those obtained in vitro showed that the in silico approach offered a reliable estimate of the suitability of a marker. All target groups were detected in the environmental DNA, but we found large variation in the level of detection among the groups and between modern and ancient samples. Success rates for the Pleistocene samples were highest for fungal DNA, whereas bryophyte, beetle and bird sequences could also be retrieved, but to a much lesser degree. The metabarcoding approach has considerable potential for biodiversity screening of modern samples and also as a palaeoecological tool. PMID- 22486822 TI - Bioinformatic challenges for DNA metabarcoding of plants and animals. AB - Almost all empirical studies in ecology have to identify the species involved in the ecological process under examination. DNA metabarcoding, which couples the principles of DNA barcoding with next generation sequencing technology, provides an opportunity to easily produce large amounts of data on biodiversity. Microbiologists have long used metabarcoding approaches, but use of this technique in the assessment of biodiversity in plant and animal communities is under-explored. Despite its relationship with DNA barcoding, several unique features of DNA metabarcoding justify the development of specific data analysis methodologies. In this review, we describe the bioinformatics tools available for DNA metabarcoding of plants and animals, and we revisit others developed for DNA barcoding or microbial metabarcoding. We also discuss the principles and associated tools for evaluating and comparing DNA barcodes in the context of DNA metabarcoding, for designing new custom-made barcodes adapted to specific ecological question, for dealing with PCR and sequencing errors, and for inferring taxonomical data from sequences. PMID- 22486823 TI - The future of environmental DNA in ecology. AB - The contributions of environmental DNA to ecology are reviewed, focusing on diet, trophic interactions, species distributions and biodiversity assessment. Environmental DNA has the potential to dramatically improve quantitative studies in these fields. Achieving this, however, will require large investments of time and money into developing the relevant databases, models, and software. PMID- 22486824 TI - Towards next-generation biodiversity assessment using DNA metabarcoding. AB - Virtually all empirical ecological studies require species identification during data collection. DNA metabarcoding refers to the automated identification of multiple species from a single bulk sample containing entire organisms or from a single environmental sample containing degraded DNA (soil, water, faeces, etc.). It can be implemented for both modern and ancient environmental samples. The availability of next-generation sequencing platforms and the ecologists' need for high-throughput taxon identification have facilitated the emergence of DNA metabarcoding. The potential power of DNA metabarcoding as it is implemented today is limited mainly by its dependency on PCR and by the considerable investment needed to build comprehensive taxonomic reference libraries. Further developments associated with the impressive progress in DNA sequencing will eliminate the currently required DNA amplification step, and comprehensive taxonomic reference libraries composed of whole organellar genomes and repetitive ribosomal nuclear DNA can be built based on the well-curated DNA extract collections maintained by standardized barcoding initiatives. The near-term future of DNA metabarcoding has an enormous potential to boost data acquisition in biodiversity research. PMID- 22486825 TI - Synthesis and immunomodulatory activities of Helicobacter pylori lipophilic terminus of lipopolysaccharide including lipid A. AB - Helicobacter pylori, a Gram-negative bacterium, causes gastroduodenal inflammatory diseases such as chronic gastritis and peptic ulcers, and is also a risk factor for gastric carcinogenesis. In this article, we review recent developments and findings in the chemical synthesis and immunomodulatory activities of H. pylori lipid A and 3-deoxy-D-manno-2-octulosonic acid (Kdo) lipid A, to clarify the structural basis for the inflammatory response to H. pylori LPS. The synthetic methods include a new divergent synthetic approach with a widely applicable key intermediate for other types of lipid A structures, as well as a selective alpha-glycosylation reaction between Kdo and lipid A. Cytokine induction assays of the chemically synthesized lipid A structures showed selective cytokine induction depending on the patterns of acyl groups and phosphate groups. The results of cytokine induction assay suggested that H. pylori LPS can modulate the immune response during infection, and also plays a role in chronic inflammatory responses. PMID- 22486826 TI - A novel water-soluble beta-D-glucan isolated from the spores of Ganoderma lucidum. AB - Ganoderma lucidum is an edible and medicinal mushroom used widely in East Asia. In recent years, its spores have been used as a supplement in combination with other forms of antitumor therapies. The cell wall of Ganoderma lucidum spores contains a high amount of polysaccharides. In this study, a neutral polysaccharide, GLSA50-1B, was isolated from sporoderm-broken spores of Ganoderma lucidum, by hot-water extraction, graded ethanol precipitation, anion-exchange chromatography, and gel permeation chromatography. Using sugar compositional analysis, methylation analysis, partial acid hydrolysis, acetolysis, and NMR and ESI-MS spectroscopy, GLSA50-1B was elucidated to be a novel beta-D-glucan featured by a 1,6-linked beta-D-Glcp backbone with different length of branches consisting of terminal and 1,4-linked Glcp residues, attached to O-4 of alternative Glc residues in the backbone. PMID- 22486827 TI - Trehalose glycolipids--synthesis and biological activities. AB - A variety of trehalose glycolipids have been isolated from natural sources, and several of these glycolipids exhibit important biological properties. These molecules also represent challenging synthetic targets due to their highly amphiphilic character, their large number of functional groups and additional chiral centres. This review highlights some of the recent advances made in the synthesis of trehalose glycolipids, and their associated biological activities. PMID- 22486828 TI - Synthesis of heparan sulfate tetrasaccharide as a substrate for human heparanase. AB - Regiospecifically sulfated heparan sulfate tetrasaccharide, GlcAbeta GlcN(NS6S)alpha-GlcAbeta-GlcN(NS6S)alpha was first synthesized as an octyl glycoside. Total synthesis was achieved effectively by coupling the corresponding disaccharide units in short steps. PMID- 22486829 TI - Vacuolar degradation of two integral plasma membrane proteins, AtLRR84A and OsSCAMP1, is cargo ubiquitination-independent and prevacuolar compartment mediated in plant cells. AB - In plant cells, how integral plasma membrane (PM) proteins are degraded in a cargo ubiquitination-independent manner remains elusive. Here, we studied the degradative pathway of two plant PM proteins: AtLRR84A, a type I integral membrane protein belonging to the leucine-rich repeat receptor-like kinase protein family, and OsSCAMP1 (rice secretory carrier membrane protein 1), a tetraspan transmembrane protein located on the PM and trans-Golgi network (TGN) or early endosome (EE). Using wortmannin and ARA7(Q69L) mutant that could enlarge the multivesicular body (MVB) or prevacuolar compartment (PVC) as tools, we demonstrated that, when expressed as green fluorescent protein (GFP) fusions in tobacco BY-2 or Arabidopsis protoplasts, both AtLRR84A and OsSCAMP1 were degraded in the lytic vacuole via the internal vesicles of MVB/PVC in a cargo ubiquitination-independent manner. Such MVB/PVC-mediated vacuolar degradation of PM proteins was further supported by immunocytochemical electron microscopy (immunoEM) study showing the labeling of the fusions on the internal vesicles of the PVC/MVB. Thus, cargo ubiquitination-independent and PVC-mediated degradation of PM proteins in the vacuole is functionally operated in plant cells. PMID- 22486830 TI - Benign esophagorespiratory fistula: a case series and a novel technique of definitive management. AB - Benign esophagorespiratory fistula is a relatively rare condition in adults that poses a technical challenge to manage. This case series describes our experience in the treatment of benign esophagorespiratory fistula in 12 adults. A retrospective review of case records of 12 patients with benign esophagorespiratory fistula was done. There were eight tracheoesophageal fistulae and four bronchoesophageal fistulae. Among them, four fistulae were congenital, one was secondary to corrosive injury, three were due to foreign body (dentures), one was secondary to erosion because of prolonged endotracheal intubation, one was secondary to penetrating trauma, and two were infective in etiology. Of the 12 patients, there were nine males and three females. The mean age of presentation was 30.16 years (range 15-53 years). Nine patients had a definitive surgical intervention. The esophageal end of the fistula was managed by primary closure of the esophageal defect and reinforcement with pleural or intercostal muscle flap or a subtotal esophagectomy. The respiratory end of the fistula was dealt with by primary closure of the defect or by a novel technique of neomembranous airway formation, whereby the tracheal defect was closed with the help of a vascularized patch of the esophageal wall. The technique of this neomembranous airway formation is described in detail, and to our knowledge, this is the first time that this technique is being reported in the English literature. This technique is a novel method for definitive repair and can be considered as an option for repair of esophagorespiratory fistula with large defects. PMID- 22486831 TI - An intervention to change the approach to colorectal cancer screening in primary care. AB - PURPOSE: The purpose of this project was to increase colorectal cancer screening (CRC) rates in the state of Nevada. Research has shown that there are several interventions for providers to use to increase CRC screening rates in practice. The Nevada Colon Cancer Partnership (NCCP) has created a toolkit to assist providers to implement these interventions in practice. DATA SOURCES: Research has repeatedly shown that CRC screening has a great impact on the morbidity and mortality of CRC. Studies have shown that a fecal occult blood test can detect 60 85% of CRCs and a colonoscopy with polyp removal can reduce mortality by 60-90%. Multiple studies have shown that a provider's recommendation is the most consistently influential factor in cancer screening. Furthermore, offering patients a choice and encouraging active participation in health care decision making has proven to increase CRC screening rates. CONCLUSIONS: The NCCP has collaborated with the American Cancer Society to create a web based toolkit for use by providers to change practice and screen all eligible patients for CRC. The toolkit is designed to encourage providers to decrease the morbidity and mortality of CRC and other cancers. The toolkit is useful to facilitate efforts of office-based clinicians to reduce disparities by applying screening guidelines on a universal basis to the age-appropriate population. A team approach to screening is encouraged to promote an opportunistic or global approach to assure all eligible patients are reached. IMPLICATIONS FOR PRACTICE: As healthcare reform continues to evolve, Nurse Practitioners (NPs) will assume much of the primary care needs of our country. A preventive care model is an important aspect of the future of healthcare. NPs are in a perfect position to change the health of patients in a global way. The strategies and tools presented in this toolkit are designed to improve preventive care and assist the NP in assuring that every eligible patient receives the screening tests they need. PMID- 22486832 TI - The dangers of iron overload: bring in the iron police. AB - PURPOSE: To increase awareness of nurse practitioners (NPs) about the dangers of iron overload and to review common hematologic conditions where transfusions are essential, iron mechanism and transport within the body, effects of iron overload on the body, and treatment options available. Finally, the process for development of a protocol for monitoring such patients will be introduced. DATA SOURCES: Review of existing literature, myelodysplastic syndrome guidelines, sickle cell guidelines, thalassemia guidelines. CONCLUSIONS: Transfusions of packed red blood cells save lives. There are many hematologic conditions for which packed red blood cell transfusions are required as a result of bone marrow suppression. However, extended exposure to red blood cell transfusions places the patient at an additional risk of iron overload. Iron overload is a real concern for patients who become transfusion dependent, with increased risks of liver cirrhosis and cardiac arrhythmias. IMPLICATIONS FOR PRACTICE: NPs in all areas of practice can increase awareness of the dangers of transfusional iron overload, and become familiar with the treatment options available. Additionally, NPs can institute a monitoring program based on the protocol suggested here within their own practices to prevent poor outcomes for patients with transfusion-related iron overload. PMID- 22486833 TI - Fibromyalgia: diagnosing and managing a complex syndrome. AB - PURPOSE: The purpose of this clinical review is to clarify and discuss the diagnosis and management of fibromyalgia. This includes typical signs and symptoms, pathophysiology, concomitant disease states, differential diagnoses, and recommended pharmacologic and nonpharmacologic treatment modalities. DATA SOURCES: The search included Evidence Based Medicine Reviews, Ovid MEDLINE, PubMed, and CINAHL. Search terms used: fibromyalgia diagnosis, fibromyalgia pathophysiology, incidence of fibromyalgia, fibromyalgia comorbidities, etiology of fibromyalgia, fibromyalgia treatment, American College of Rheumatology criteria. Search limited to sources from 1990 to 2010. CONCLUSIONS: Fibromyalgia is a complex muscular rheumatism that is not fully understood and often misdiagnosed. Signs and symptoms may overlap with many other conditions that must be properly ruled out to prevent diagnosis based upon arbitrary clinical judgment. Treatment is most beneficial when tailored to individual patient presentation, and further research is warranted, particularly in the domains of pathophysiology and efficacy of treatment options. IMPLICATIONS FOR PRACTICE: An accurate knowledge of current research will aid the nurse practitioner in effectively prescribing evidence-based clinical interventions. Optimal fibromyalgia management can be achieved through a multifaceted treatment approach and is enhanced with early identification of the disease process. PMID- 22486834 TI - Ensuring a nurse practitioner workforce prepared to care for older adults: findings from a national survey of adult and geriatric nurse practitioner programs. AB - PURPOSE: To present the findings from a needs assessment of adult primary care (ANP), gerontological (GNP), and adult acute care (ACNP) nurse practitioner faculty regarding the transition to adult-gerontology NP (A-GNP) programs. DATA SOURCES: Data were obtained from two sources: (a) an online survey to identify the faculty's primary needs in order to facilitate success in this transition and (b) telephone focus groups to explore survey responses in greater depth. CONCLUSIONS: The survey and the focus group findings indicate that there is a strong need for (a) access to a set of nationally recognized competencies for A GNPs; (b) teaching/learning resources to support faculty in implementation of A GNP programs; and (c) formal faculty development opportunities to facilitate faculty efforts to engage in curricular redesign and innovations and assure that NP students acquire strong competence in gerontology content. IMPLICATIONS FOR PRACTICE: The transition to A-GNP has implications not only for NP faculty but also for practicing NPs. Almost all NPs care for older adults in a variety of settings. However, most of these NPs are not specialists in geriatrics. This article provides a context for self-assessment by these NPs of their own needs related to this transition. PMID- 22486835 TI - Application of appropriate use criteria for stress myocardial perfusion imaging at two academic medical centers: compliance and association with image findings. AB - PURPOSE: Explore the extent to which stress myocardial perfusion imaging (MPI) studies for coronary heart disease detection met published appropriate use criteria (AUC), and the association between AUC classification and image findings. DATA SOURCES: Retrospective, descriptive review of stress studies performed at the University of Washington Medical Center (UWMC n= 1377) and the Veterans Health Administration of Puget Sound (VA n= 1445) in the 31 months following AUC publication. CONCLUSIONS: At UWMC and VA, 69% and 89% of MPI studies, respectively, were classified as appropriate, 16% and 3% as inappropriate, and 15% and 8% as uncertain. All differences were significant, p < .001. At UWMC, 11% of appropriate studies and 10% of inappropriate or uncertain studies were abnormal (demonstrating myocardial ischemia or myocardial infarction), p= .93; these analyses were not performed on VA studies. IMPLICATIONS FOR PRACTICE: Most studies at both sites were classified as appropriate. At UWMC, the likelihood of a study classified as appropriate demonstrating an abnormality was not significantly different from a study classified as uncertain or inappropriate. AUC are imperfect tools but are increasingly created and referenced; as such, it is vital that practicing nurse practitioners are knowledgeable about their creation, application, and evaluation. PMID- 22486836 TI - Factors associated with physical activity levels in African-American women with type 2 diabetes. AB - PURPOSE: To examine how family/friend social support, exercise self-efficacy, physical environment, sense of community, social issues and roles, socioeconomic status, and body image discrepancy influence physical activity levels in African American females with type 2 diabetes. DATA SOURCES: A sample of 50 African American females with type 2 diabetes was recruited from a Midwest diabetes center for this descriptive, cross-sectional, correlational study. A series of self-report instruments were administered to examine the relationships between the independent study variables and physical activity levels. CONCLUSIONS: Results of the study suggested that higher levels of exercise self-efficacy, family social support for exercise, and a decrease in physical environmental barriers may serve to increase physical activity levels in this population. No significant relationships were observed between the other study variables and physical activity levels. IMPLICATIONS FOR PRACTICE: Nurse practitioners working with African American females with type 2 diabetes need to assess family social support, exercise self-efficacy, and physical environmental barriers and plan interventions that incorporate family support and the principles of self-efficacy while minimizing environmental barriers. Further exploration is warranted to examine the relationship between body image discrepancy and physical activity in this population. PMID- 22486837 TI - Health literacy: the sixth vital sign. AB - PURPOSE: The purpose of this project was to describe the concept of health literacy, and to assess health literacy levels in diabetic patients receiving care in primary care settings. DATA SOURCES: Health literacy was measured by the Newest Vital Sign (NVS), an assessment tool that was developed for use in primary care settings. The sample consisted of 54 participants of whom 22% were Caucasian, 43% Black, and 35% Latino/Latina. Health literacy scores ranged from 0 6, with a mean of 2.87. Nearly 2/3 of the participants obtained scores of 3 or less, indicating a strong possibility of limited literacy. Significant correlations were obtained between health literacy and educational level, and between health literacy and ethnicity/race. CONCLUSIONS: Limited health literacy is so common that health literacy assessment needs to be considered in all clinical practice settings. Health literacy is considered the sixth vital sign- along with temperature, pulse, respiration, blood pressure, and pain level. IMPLICATIONS FOR PRACTICE: The NVS takes about three minutes to administer and the assessment is easily accomplished during the initial visit for each patient. Healthcare providers will then be aware of the health literacy level of each patient and base their communication appropriately. PMID- 22486838 TI - Cardiovascular effects of cis-atracurium overdose in a dog following misplacement of neuromuscular monitoring electrodes. PMID- 22486839 TI - Supplemental nutrition assistance program and body weight outcomes: the role of economic contextual factors. AB - We explored the extent to which economic contextual factors moderated the association of Supplemental Nutrition Assistance Program (SNAP) participation with body mass index (BMI) among low-income adults whose family income (adjusted for family size) is less than 130% of the federal poverty guideline. We drew on individual-level data from the Panel Study of Income Dynamics in the United States, including three waves of data in 1999, 2001, and 2003. Economic contextual data were drawn from the American Chamber of Commerce Researchers Association for food prices and Dun & Bradstreet for food outlet measures. In addition to cross-sectional estimation, a longitudinal individual fixed effects model was used to control for permanent unobserved individual heterogeneity. Our study found a statistically significant joint moderating effect of the economic contextual factors in longitudinal individual fixed effects model for both women (BMI only) and men (both BMI and obesity). For both women and men, SNAP participants' BMI was statistically significantly lower if they faced increased numbers of available supermarkets/grocery stores in the longitudinal model. A simulated 20% reduction in the price of fruits and vegetables resulted in a larger decrease in BMI among SNAP participants than non-participants for women and men, whereas a simulated 20% increase in the availability of supermarkets and grocery stores resulted in a statistically significant difference in the change in BMI by SNAP participation for women but not for men. Policies related to economic contextual factors, such as subsidies for fruits and vegetables or those that would improve access to supermarkets and grocery stores may enhance the relationship between SNAP participation and body mass outcomes among food assistance program participants. PMID- 22486840 TI - Towards a differentiated understanding of active travel behaviour: using social theory to explore everyday commuting. AB - Fostering physical activity is an established public health priority for the primary prevention of a variety of chronic diseases. One promising population approach is to seek to embed physical activity in everyday lives by promoting walking and cycling to and from work ('active commuting') as an alternative to driving. Predominantly quantitative epidemiological studies have investigated travel behaviours, their determinants and how they may be changed towards more active choices. This study aimed to depart from narrow behavioural approaches to travel and investigate the social context of commuting with qualitative social research methods. Within a social practice theory framework, we explored how people describe their commuting experiences and make commuting decisions, and how travel behaviour is embedded in and shaped by commuters' complex social worlds. Forty-nine semi-structured interviews and eighteen photo-elicitation interviews with accompanying field notes were conducted with a subset of the Commuting and Health in Cambridge study cohort, based in the UK. The findings are discussed in terms of three particularly pertinent facets of the commuting experience. Firstly, choice and decisions are shaped by the constantly changing and fluid nature of commuters' social worlds. Secondly, participants express ambiguities in relation to their reasoning, ambitions and identities as commuters. Finally, commuting needs to be understood as an embodied and emotional practice. With this in mind, we suggest that everyday decision-making in commuting requires the tactical negotiation of these complexities. This study can help to explain the limitations of more quantitative and static models and frameworks in predicting travel behaviour and identify future research directions. PMID- 22486841 TI - Childhood family income and life outcomes in adulthood: findings from a 30-year longitudinal study in New Zealand. AB - The aims of this study were to use data gathered over the course of a 30-year longitudinal study to examine the linkages between economic circumstances in childhood and subsequent developmental outcomes spanning educational achievement; economic circumstances; crime; mental health; and teenage pregnancy. All of these outcomes have been linked with childhood economic conditions and it is frequently argued that reducing income inequalities will mitigate psychosocial risks of children reared in families facing economic hardship. Alternatively it may be suggested that the associations between childhood family economic circumstances and later outcomes are mediated by individual, family and social factors that are correlated with low family income and contribute to later outcomes. To examine these issues, data were drawn from a birth cohort of New Zealand children born in 1977 and followed to age 30. Declining childhood family income was associated with a range of negative outcomes in adulthood, including: lower educational achievement; poorer economic circumstances; higher rates of criminal offending; higher rates of mental health problems; and higher rates of teenage pregnancy. After covariate adjustment, childhood family income remained significantly associated with educational achievement and economic circumstances, but was no longer significantly associated with the mental health, offending and teenage pregnancy outcomes. These findings suggest that, after due allowance has been made for social, family and individual contextual factors, low family income during childhood is associated with a range of educational and economic disadvantages in adulthood but is not directly related to increased risks of crime, mental health problems or teen pregnancy. PMID- 22486842 TI - Reaction based fluorescent probes for hydrogen sulfide. AB - A reaction based fluorescence turn-on strategy for hydrogen sulfide (H(2)S) was developed. This strategy was based on a H(2)S-specific Michael addition cyclization sequence. Other biological thiols such as cysteine and glutathione did not pursue the reaction and therefore did not turn on the fluorescence/consume the substrates. The probes showed good selectivity and sensitivity for hydrogen sulfide. PMID- 22486843 TI - Alternative pathway activation of complement in laparoscopic and open rectal surgery. AB - The study was designed to investigate whether complement is activated in patients subject to rectal surgery and whether the choice of surgical technique (open or laparoscopic) has any impact on the activation of complement. Our hypothesis is that laparoscopic surgery leads to a lower-level activation of complement than open surgery. Patients (n = 24) subject to rectal surgery owing to rectal cancer were included. The study was prospective and randomized. The patients were randomized to either laparoscopic surgery (n = 12) or open surgery (n = 12). Blood samples for determination of complement activation (C4d, Bb, C3bc and the terminal C5b-9 complex TCC) were drawn before start of surgery (T0) and at the following time-points after start of surgery: 180 min (T1), 360 min (T2), 24 h (T3) and 3-5 days (T4). A significant increase in the alternative pathway activation product Bb and in the terminal pathway activation product TCC was seen over time in both groups (P < 0.001). Bb peaked early (T1) and returned to baseline levels post-operatively, whereas TCC increased steadily with maximum values in the late post-operative period. The plasma concentrations of C4d and C3bc decreased significantly in both groups at T1 and T2 and returned to baseline levels at T4. There was no significant difference between the groups. Rectal surgery causes activation of the complement system. Complement is activated through the alternative pathway. Results mostly showed no significant differences between laparoscopic and open rectal surgery apart from lower levels of factor Bb in the former group in the perioperative period. PMID- 22486844 TI - UVA irradiation following treatment with topical 8-methoxypsoralen improves bleomycin-induced scleroderma in a mouse model, by reducing the collagen content and collagen gene expression levels in the skin. AB - BACKGROUND: Recent studies have demonstrated that systemic or topical PUVA therapy, i.e., ultraviolet A (UVA) irradiation following treatment with 8 methoxypsoralen (8-MOP), is effective against the sclerotic skin lesions in systemic sclerosis. However, the mechanisms still remain unknown. OBJECTIVE: To clarify the mechanisms of this therapy, we created a mouse model of bleomycin (BLM) injection-induced scleroderma and evaluated the effects of PUVA on the fibrotic lesions of scleroderma in this mouse model. METHODS: BLM was injected subcutaneously once a day into the mice for 24 days. During the injection period, one group of mice was irradiated with UVA following local application of 8-MOP. Control groups were also set up, which were injected with phosphate-buffered saline, instead of BLM. Skin tissue samples examined histopathologically changes, measured of the content of hydroxyproline, and checked for the expression of genes encoding type I collagen, type III collagen, and transforming growth factor beta1 (TGF-beta1). RESULTS: The mouse models of scleroderma was found to show an increase in the density of the collagen fibers and thickening of the dermis and increased expressions of type I collagen, type III collagen, and TGF-beta1. However, the combination of BLM treatment and topical PUVA treatment mice appeared reduced the dermal thickness and hydroxyproline content, down-regulation of expressions of the type I and type III collagen genes was observed while the expression of the TGF-beta1 gene remained unchanged. CONCLUSION: These results suggest that the effectiveness of topical PUVA therapy is attributable to the down-regulation of the expressions of the collagen genes by this treatment. The results additionally suggest that is not mediated by down-regulated expression of the TGF-beta1. PMID- 22486845 TI - Root canal debridement efficacy of different final irrigation protocols. AB - AIM: To compare the smear layer and debris removal effectiveness of four root canal irrigation protocols as well as their effectiveness in removing remaining soft tissues in curved root canals. METHODOLOGY: The mesiobuccal and mesial root canals of 107 extracted human maxillary and mandibular molars were instrumented using Mtwo rotary NiTi instruments then randomly divided into four groups according to a final rinse protocol: Group 1 (n = 28) - manual agitation of 1% NaOCl and 15% EDTA; Group 2 (n = 26) - CanalBrush agitation of 1% NaOCl and 15% EDTA; Group 3 (n = 26) - 3% H(2) O(2) alternated with 1% NaOCl; Group 4 (n = 27) passive ultrasonic agitation of 1% NaOCl and 15% EDTA. All irrigation protocols were performed in a closed system. Eleven roots per group were prepared and histologically stained (H&E) to assess percentage of remaining pulpal tissues in the apical thirds. The remaining specimens were split longitudinally and examined under scanning electron microscope at *2000 magnification to assess smear layer and debris removal. Image Pro Plus 6.0 software was used to analyse smear layer and remaining pulp tissue. Debris presence was scored by two blinded investigators using a five-point scale. Data were analysed using Univariate analysis of variance (GenStat 13, alpha = 0.05). RESULTS: CanalBrush and passive ultrasonic irrigation were equally effective with significantly less smear layer and debris than manual agitation and H(2) O(2) alternated with NaOCl (P < 0.05). The H(2) O(2) alternated with NaOCl protocol was significantly more effective in removing pulp tissue remnants in the apical level than manual agitation (P = 0.009) and passive ultrasonic irrigation (P = 0.01). CONCLUSIONS: CanalBrush was as effective as passive ultrasonic irrigation in smear layer and debris removal. Alternating H(2) O(2) with NaOCl was effective in removing soft tissues from root canal complexities. Further studies are required to evaluate effectiveness of this regimen taking into account irrigant volume differences and effect of root canal system configuration. PMID- 22486848 TI - Efficacy of aripiprazole in comorbid addiction in bipolar disorder. PMID- 22486847 TI - Risperidone enhances the vulnerability to stroke in hypertensive rats. AB - BACKGROUND: Stroke is the second most common cause of death and a major cause of disability worldwide. Risperidone is an atypical antipsychotic drug that may increase the risk of stroke. The present work examined whether risperidone enhances the vulnerability to stroke in hypertensive rats and the potential mechanisms underlying such action. METHODS: Experiment 1: Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs) and stroke-prone SHRs (SHR-SPs) were treated with risperidone (0.8 and 2.4 mg/kg/d) or vehicle for 30 consecutive days. Tissue damage in response to middle cerebral artery occlusion (MCAO) was measured microscopically. The activity of superoxide dismutase, glutathione peroxidase, the levels of malondialdehyde were also determined. Experiment 2: Survival data were recorded in SHR-SPs that received daily risperidone perpetually. Experiment 3: Effect of risperidone on interleukin-6 and tumor necrosis factor-alpha was examined in quiescent or LPS-activated cortical microglias from WKY rats. Experiment 4: Potential damage of risperidone exposure to neurons was examined in primary neuronal culture obtained from WKY rats, SHRs, and SHR-SPs. RESULTS: Risperidone increased infarct areas upon MCAO in SHR-SPs and SHRs, but not in WKY rats. Survival time in SHR-SPs was shortened by risperidone. Apoptosis was augmented by risperidone through enhanced Bax. Risperidone also increased endothelial injury. CONCLUSIONS: Risperidone enhances the vulnerability to stroke in hypertensive rats through increasing neuronal apoptosis and endothelial injury. PMID- 22486849 TI - Effects of three target-controlled concentrations of sufentanil on MAC(BAR) of sevoflurane. PMID- 22486851 TI - Are the ICHD-II criteria for hemicrania continua too restrictive? PMID- 22486852 TI - Discovery of the novel HLA-DRB1*03:77 allele in a Taiwanese unrelated hematopoietic stem cell donor by a sequence-based typing method and identification of the probable HLA haplotype in association with DRB1*03:77. AB - Here, we report a novel human leucocyte antigen (HLA)-DRB1 allele, DRB1*03:77, discovered in a Taiwanese unrelated volunteer hematopoietic stem cell donor by a sequence-based typing (SBT) method. The DNA sequence of DRB1*03:77 is identical to the DNA sequence of DRB1*03:01:01 in exon 2 except one nucleotide at position 223 (G->C). The nucleotide substitution caused an amino acid replacement at residue 46 (E->Q). The formation of DRB1*03:77 was thought as the result of a nucleotide point mutation. The probable HLA-A, HLA-B and HLA-DRB1 haplotype in association with DRB1*03:77 may be deduced as A*33-B*58-DRB1*03:77. The donor was a Minna Taiwanese whose ancestors came from mainland China. PMID- 22486853 TI - Impact of human T cell leukemia virus type 1 in living donor liver transplantation. AB - Human T cell leukemia virus type 1 (HTLV-1) is an endemic retrovirus in southwestern Japan, which causes adult T cell leukemia (ATL) or HTLV-1 associated myelopathy in a minority of carriers. Here, we investigated the impact of HTLV-1 status in living donor liver transplantation (LDLT). Twenty-six of 329 (7.9%) HTLV-1 carriers underwent primary LDLT. One recipient negative for HTLV-1 before LDLT received a graft from an HTLV-1 positive donor. Eight donors were HTLV-1 positive. Twenty-seven recipients (13 male and 14 female; mean age 52.5 years) were reviewed retrospectively. ATL developed in four recipients who ultimately died. The intervals between LDLT and ATL development ranged from 181 to 1315 days. Of the four ATL recipients, two received grafts from HTLV-1 positive donors and two from negative donors. The 1-, 3- and 5-year HTLV-1 carrier survival rates were 91.3%, 78.3% and 66.3%, respectively. Fulminant hepatic failure as a pretransplant diagnosis and a pretransplant MELD score >= 15 was identified as risk factors for ATL development in this study (p = 0.001 and p = 0.041, respectively). In conclusion, LDLT can be performed for HTLV-1 positive recipients. However, when fulminant hepatic failure is diagnosed, LDLT should not be performed until further studies have revealed the mechanisms of ATL development. PMID- 22486854 TI - Hedgehog inhibitor decreases chemosensitivity to 5-fluorouracil and gemcitabine under hypoxic conditions in pancreatic cancer. AB - Pancreatic cancer is one of the deadliest types of cancer. Previously, we showed that hypoxia increases invasiveness through upregulation of Smoothened (Smo) transcription in pancreatic ductal adenocarcinoma (PDAC) cells. Here, we first evaluated whether hypoxia-induced increase in Smo contributes to the proliferation of PDAC cells. We showed that Smo, but not Gli1, inhibition decreases proliferation significantly under hypoxic conditions. To further investigate the effects of Smo on PDAC growth, cell cycle analysis was carried out. Inhibition of Smo under hypoxia led to G(0) /G(1) arrest and decreased S phase. As 5-fluorouracil (5-FU) and gemcitabine, which are first-line drugs for pancreatic cancer, are sensitive to S phase, we then evaluated whether cyclopamine-induced decreased S phase under hypoxia affected the chemosensitivity of 5-FU and gemcitabine in PDAC cells. Cyclopamine treatment under hypoxia significantly decreased chemosensitivity to 5-FU and gemcitabine under hypoxia in both in vitro and in vivo models. In contrast, cis-diamminedichloroplatinum, which is cell cycle-independent, showed significant synergistic effects. These results suggest that hypoxia-induced increase of Smo directly contributes to the proliferation of PDAC cells through a hedgehog/Gli1-independent pathway, and that decreased S phase due to the use of Smo inhibitor under hypoxia leads to chemoresistance in S phase-sensitive anticancer drugs. Our results could be very important clinically because a clinical trial using Smo inhibitors and chemotherapy drugs will begin in the near future. PMID- 22486855 TI - Serum alanine aminotransferase is correlated with hematocrit in healthy human subjects. AB - BACKGROUND: Serum alanine aminotransferase (ALT) activity is a widely-used surrogate marker for liver injury. However, mild elevation of serum ALT is frequently observed in apparently healthy individuals, making it sometimes challenging to interpret whether this laboratory abnormality is medically benign or serious. To obtain a better understanding of the factors influencing ALT levels, we examined the relation between ALT and a number of anthropometric and biochemistry measurements in humans. METHODS: We assessed the associations of ALT with hematocrit (HCT) in 1,200 apparently healthy adults from an Amish population. Multivariate analyses were carried out to determine whether observed associations were independent of other factors known to modulate ALT and HCT, including body mass index (BMI) and sex. The correlation detected in the Amish was then replicated in an independent population sample (N = 9,842) from the National Health and Nutrition Examination Survey (NHANES) III. RESULTS: ALT levels were positively correlated with HCT (r = 0.33, p < 0.0001) in both Amish and NHANES III. The magnitude of association was unchanged after adjustment for BMI, but was reduced by age/sex adjustment to r = 0.18 (p < 0.0001) and r = 0.17 (p < 0.0001) in the Amish and NHANES populations, respectively. HCT accounts for about 3% of the population variation in ALT, which is smaller than the contributions of gender and BMI, but larger than individual blood pressure and cholesterol components. CONCLUSIONS: We observed a correlation between ALT and HCT, suggesting that HCT may be a newly identified modulator of ALT in humans. PMID- 22486856 TI - Inequality and infection in China. PMID- 22486857 TI - Epidemiology and predictors of a poor outcome in elderly patients with candidemia. AB - BACKGROUND: Candidemia affects patient populations from neonates to the elderly. Despite this, little information is available about the epidemiology of candidemia in elderly patients. METHODS: We performed a retrospective analysis of 987 episodes of candidemia in adults (>14 years of age) from the databases of three laboratory-based surveys of candidemia performed at 14 tertiary care hospitals. Patients aged >=60 years were considered elderly (group 1, n=455, 46%) and were compared to younger patients (group 2, n=532, 54%) regarding demographics, underlying diseases, comorbidities, exposure to medical procedures, species, treatment, and outcome. RESULTS: The median APACHE II score was significantly higher in the elderly patients (19 vs. 15, p=0.03). Variables that were observed significantly more frequently in elderly patients included admission to an intensive care unit, diabetes mellitus, renal failure, cardiac disease, lung disease, receipt of antibiotics or H2 blockers, insertion of a central venous catheter, mechanical ventilation, and candidemia due to Candida tropicalis. The 30-day mortality of elderly patients was significantly higher than that of younger patients (70% vs. 45%, p<0.001). Factors associated with higher mortality by multivariate analysis included APACHE II score and being in group 1 (elderly). Factors associated with mortality in elderly patients were lung disease and the receipt of mechanical ventilation. CONCLUSIONS: Elderly patients account for a substantial proportion of patients with candidemia and have a higher mortality compared to younger patients. PMID- 22486858 TI - The effect of metformin on the efficacy of antiviral therapy in patients with genotype 1 chronic hepatitis C and insulin resistance. AB - OBJECTIVES: Insulin resistance (IR) affects sustained virological response (SVR) in chronic hepatitis C (CHC). The aim of this study was to investigate the effect of adding metformin to peginterferon alfa-2a and ribavirin on the efficacy in patients with genotype 1 CHC and IR. METHODS: Ninety-eight patients with genotype 1 CHC and IR were randomized into the treatment group (n=49) and the control group (n=49). Patients in the control group received peginterferon alfa-2a and ribavirin, and patients in the treatment group received metformin in addition to peginterferon alfa-2a and ribavirin. The rate of virological response, changes in the homeostasis model assessment of insulin resistance (HOMA-IR) index, and the incidence of side effects were compared between the two groups. Factors influencing the SVR were studied by multivariate analysis. RESULTS: The SVR rate of the treatment group was significantly higher than that of the control group (59.2%, 29/49 vs. 38.8%, 19/49; Chi-square=4.083, p=0.043). The HOMA-IR index of patients in the treatment group was lower than that of patients in the control group at weeks 12, 24, and 48 of the treatment period, and at week 24 of follow up (3.00+/-0.65 vs. 3.50+/-0.72, 1.90+/-0.45 vs. 2.90+/-0.64, 1.75+/-0.40 vs. 2.74+/-0.48, and 1.60+/-0.35 vs. 2.60+/-0.55, respectively; t=3.610, 8.947, 11.091, and 10.738, respectively; p<0.01). Diarrhea was more often seen in the treatment group (28.6%, 14/49 vs. 10.2%, 5/49; Chi-square=5.288, p=0.021). In the multivariate logistic regression analysis, the independent factors associated with SVR were treatment method (p=0.009) and HOMA-IR <2 at week 24 (p=0.011). CONCLUSIONS: A combination of metformin, peginterferon alfa-2a, and ribavirin improved insulin sensitivity and increased the SVR rate of patients with hepatitis C genotype 1 and IR, with a good safety profile. PMID- 22486859 TI - Signet-ring cell carcinoma of the breast with uterine metastasis treated with extensive cytoreductive surgery: a case report and brief review of the literature. AB - Primary signet-ring cell carcinoma (SRCC) of the breast is an uncommon variant, accounting for 2-4.5% of all primary breast cancers. Secondary SRCC of the endometrium is very rare and usually originates from the breast or gastrointestinal tract. A 54-year-old, postmenopausal woman with a past history of breast cancer four years previously was admitted with abnormal uterine bleeding. An endometrial biopsy revealed undifferentiated adenocarcinoma with signet-ring cells. The patient underwent laparotomy and cytoreductive surgery was performed. Pathological analysis and immunohistochemical tests demonstrated a uterine (endomyometrial) metastasis of breast SRCC. Omentum, peritoneal surfaces and retroperitoneal lymph nodes also included tumoral tissue with signet-ring cell morphology. The patient received adjuvant systemic chemotherapy with adriamycin, cyclophosphamide and paclitaxel. This case report discusses the patient's clinical characteristics and the role of cytoreductive surgery on patient survival in SRCC of the breast metastasizing to the uterus. PMID- 22486860 TI - Cactin is essential for G1 progression in Toxoplasma gondii. AB - Toxoplasma gondii is an obligate intracellular protozoan parasite whose rapid lytic replication cycles define its pathogenicity. We identified a temperature sensitive growth mutant, FV-P6, which irreversibly arrests before the middle of the G1 stage of the tachyzoite cell cycle. This arrest is caused by a point mutation in a gene conserved across eukaryotes, Cactin, whose product localizes to the nucleus. To elucidate the role of TgCactin we performed genome-wide expression profiling. Besides the expected G1 expression profile, many genes associated with the extracellular state as well as with the bradyzoite cyst stage were identified. Consistent with these profiles were the expression of AP2 transcription factors typically associated with extracellular and bradyzoite stage parasites. This suggests a role for TgCactin in control of gene expression. As TgCactin does not contain any functionally defined domains we reasoned TgCactin exerts its function through interactions with other proteins. In support of this model we demonstrated that TgCactin is present in a protein complex and can oligomerize. Taken together, these results suggest that TgCactin acts as a pivotal protein potentially regulating gene expression at several transition points in parasite development. PMID- 22486863 TI - Preface. PMID- 22486861 TI - A novel class of cysteine protease receptors that mediate lysosomal transport. AB - The transport of lysosomal proteins is, in general, mediated by mannose 6 phosphate receptors via carbohydrate modifications. Here, we describe a novel class of receptors that regulate the transport of lysosomal hydrolases in the enteric protozoan Entamoeba histolytica, which is a good model organism to investigate membrane traffic. A novel 110 kDa cysteine protease (CP) receptor (CP binding protein family 1, CPBF1) was initially discovered by affinity co precipitation of the major CP (EhCP-A5), which plays a pivotal role in the pathogenesis of E. histolytica. We demonstrated that CPBF1 regulates EhCP-A5 transport from the endoplasmic reticulum to lysosomes and its binding to EhCP-A5 is independent of carbohydrate modifications. Repression of CPBF1 by gene silencing led to the accumulation of the unprocessed form of EhCP-A5 in the non acidic compartment and the mis-secretion of EhCP-A5, suggesting that CPBF1 is involved in the trafficking and processing of EhCP-A5. The CPBF represents a new class of transporters that bind to lysosomal hydrolases in a carbohydrate independent fashion and regulate their trafficking, processing and activation and, thus, regulate the physiology and pathogenesis of E. histolytica. PMID- 22486864 TI - Therapeutic options for refractory gastroesophageal reflux disease. AB - Refractory gastroesophageal reflux disease may affect up to one-third of the patients that consume proton pump inhibitor (PPI) once daily. Treatment in clinical practice has been primarily focused on doubling the PPI dose, despite lack of evidence of its value. In patients who failed PPI twice daily, medical treatment has been primarily focused on reducing transient lower esophageal sphincter relaxation rate or attenuating esophageal pain perception using visceral analgesics. In patients with evidence of reflux as the direct trigger of their symptoms, endoscopic treatment or antireflux surgery may be helpful in remitting symptoms. The role of psychological interventions, as well as non traditional therapeutic strategies remains to be further elucidated. PMID- 22486865 TI - Risk and preventive factors of low-dose aspirin-induced gastroduodenal injuries: a comprehensive review. AB - The risk of peptic ulcer complications, particularly bleeding, is increased in association with the use of low-dose aspirin (LDA). Risk factors for upper gastrointestinal (GI) ulcer or bleeding among LDA users include a history of prior GI events, older age, chronic renal failure, combined antithrombotic therapy and nonsteroidal anti-inflammatory drugs (NSAIDs). Helicobacter pylori and aspirin seem to be independent risk factors for peptic ulcer and bleeding. The studies report conflicting findings about the effect of H. pylori infection on NSAID-related ulcers, and proton-pump inhibitors (PPIs) seem to be superior to eradication only to prevent recurrent ulcer bleeding with LDA. Previous studies indicate that hypoacidity related to corpus atrophy, as well as taking PPIs and co-treatment with angiotensin type 1 receptor blockers (ARBs) and statins seem to reduce peptic ulcer among LDA users. In addition, the interleukin-1beta (IL 1beta)-511 T allele and angiotensinogen (AGT)-20 CC, which work as the high producer allele of IL-1beta and AGT, are significantly associated with ulcer or ulcer bleeding. The SLCO1B1*1b haplotype, which has the highest transport activity, may diminish the preventive effect of statins or ARBs. The data are still lacking and further prospective studies are needed to identify the specific risk or protective factors for upper GI ulcer and its complications associated with LDA. PMID- 22486866 TI - Attenuation of cysteamine-induced duodenal ulcer with Cochinchina momordica seed extract through inhibiting cytoplasmic phospholipase A2/5-lipoxygenase and activating gamma-glutamylcysteine synthetase. AB - BACKGROUND AND AIM: Cysteamine is a reducing aminothiol used for inducing duodenal ulcer through mechanisms of oxidative stress related to thiol-derived H(2)O(2) reaction. Cochinchina momordica saponins have been suggested to be protective against various gastric diseases based on their cytoprotective and anti-inflammatory mechanisms. This study was aimed to document the preventive effects of Cochinchina momordica seed extract against cysteamine-induced duodenal ulcer as well as the elucidation of its pharmacological mechanisms. METHODS: Cochinchina momordica seed extract (50, 100, 200 mg/kg) was administrated intragastrically before cysteamine administration, after which the incidence of the duodenal ulcer, ulcer size, serum gastrin level, and the ratio of reduced glutathione (GSH)/oxidized glutathione disulfide (GSSG) as well as biochemical and molecular measurements of cytoplasmic phospholipase A(2) (cPLA(2)), cyclooxygenase-2 (COX-2), 5-lipoxygenase and the expression of proinflammatory genes including IL-1beta, IL-6, COX-2 were measured in rat model. Additional experiments of electron spin resonance measurement and the changes of glutathione were performed. RESULTS: Cochinchina momordica seed extract effectively prevented cysteamine-induced duodenal ulcer in a dose-dependent manner as reflected with significant decreases in either duodenal ulcerogenesis or perforation accompanied with significantly decreased in serum gastrin in addition to inflammatory mediators including cPLA(2), COX-2, and 5-lipoxygenase. Cochinchina momordica seed extract induced the expression of gamma-glutamylcysteine synthetase (gamma GCS)-related glutathione synthesis as well as significantly reduced the expression of cPLA(2). Cochinchina momordica seed extract preserved reduced glutathione through increased expressions of gamma-GCS. CONCLUSION: Cochinchina momordica seed extracts exerted significantly protective effect against cysteamine-induced duodenal ulcer by either cPLA2 inhibition or glutathione preservation. PMID- 22486867 TI - Characterization and usefulness of stool antigen tests using a monoclonal antibody to Helicobacter pylori catalase. AB - BACKGROUND AND AIM: Two types of stool antigen tests have been used in the management of Helicobacter pylori infection. Testmate Pylori Antigen enzyme immunoassay (TPAg EIA) is a direct sandwich enzyme immunoassay (EIA) while Testmate Rapid Pylori Antigen (Rapid TPAg) is performed using immunochromatography. The aim of this study was to study the characterization and usefulness of these tests. METHODS: Accuracy of both tests was studied using 111 fecal samples obtained from H. pylori-positive or -negative patients. Cross reactivity was examined with four other Helicobacter spp. and five fecal bacteria in humans. To estimate the sensitivity of both kits, we tested H. pylori clinical strains. We also examined the diagnostic performances of both tests after the storage for 12 months. RESULTS: The accuracy of both Testmate kits was 100% in fecal samples from 111 patients. No cross-reactivity was observed in both Testmate kits in five fecal bacteria and four other Helicobacter spp. TPAg EIA and Rapid TPAg showed positive results in 1342 of 1344, and 483 of 485 clinical strains, respectively. Diagnostic performances was maintained for 12 months when TPAg EIA was stored at 4 degrees C and Rapid TPAg at 30 degrees C. CONCLUSIONS: We examined the details of high accuracy of TPAg EIA and Rapid TPAg. The diagnostic performance of both kits was maintained after storage for up to 1 year. The two types of tests would be useful in the management of H. pylori infection. PMID- 22486868 TI - Indocyanine green injection for detecting sentinel nodes using color fluorescence camera in the laparoscopy-assisted gastrectomy. AB - BACKGROUND AND AIM: We seek for the accurate and simple method for detecting sentinel nodes of gastric cancer which can be popularized in community hospitals. The indocyanine green (ICG) fluorescence-guided method is reported to be sensitive. However, the ordinal fluorescence cameras have gray scale imaging and require a dark room. We have developed a new device, Hyper Eye Medical System (HEMS) which can simultaneously detect color and near-infrared rays and can be used under room light. This study was planned to examine whether submucosal injection of 0.5 mL * 4 of 50 ug/mL ICG on the day before operation is the adequate administration for detecting sentinel nodes using HEMS in the gastric cancer surgery. METHODS: The patients underwent gastrectomy for clinical T1a (mucosa)-T2 (muscularis propria) and clinical N0 were enrolled in the present study. As a preliminary trial, one case each of the ICG 25 and 100 ug/mL, injected on the day before operation and intraoperative injection, was examined. Then, 10 cases injected 50 ug/mL ICG on the day before operation were examined. RESULTS: The ICG fluorescence of the patient injected 100 ug/mL was too intense and that of the patient injected 25 ug/mL was too faint. Sentinel lymph nodes were detected in all of 10 cases injected 50 ug/mL, the day before operation and number of sentinel lymph nodes per patient was 3.6 +/- 2.1. Metastasis was observed in one case. All of ICG fluorescence-positive sentinel nodes were positive for the metastasis. In the patient who underwent intraoperative injection, sentinel lymphatic basins could be identified. CONCLUSION: The present study shows that HEMS-guided abdominal surgery is feasible under room light. Submucosal injection of 0.5 mL * 4 of 50 ug/mL ICG on the day before operation is the adequate administration for detecting sentinel nodes using HEMS in the gastric cancer surgery. PMID- 22486869 TI - Narrow-band imaging on screening of esophageal lesions using an ultrathin transnasal endoscopy. AB - BACKGROUND AND AIM: Ultrathin transnasal endoscopy, used extensively in Japan, is considered to have inferior image quality and suction performance, and questionable diagnostic performance. So the aim of the present study was to compare the diagnostic performance of white light (WL) examination and non magnified narrow-band imaging (NBI) examination in screening for esophageal disorders with ultrathin transnasal endoscopy. METHODS: A prospective case study of 105 consecutive patients screened for upper gastrointestinal disorders at a single clinic in Tokyo Medical University Hospital. All subjects were diagnosed using WL, NBI and Lugol-staining examinations. Areas >= 5 mm clearly not a Lugol staining lesion were defined as esophageal disorders and the rates of detection of the two examination methods (WL vs NBI) were compared. RESULTS: For WL examination, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy (concordance rate) for esophageal disorders were 19.6%, 98.1%, 90.9%, 55.4%, and 59.2%, respectively, versus 60.8% 96.2%, 93.9%, 71.4%, and 78.6% for NBI. CONCLUSION: A useful level of diagnostic performance for esophageal disorders can be achieved with non-magnified narrow band NBI ultrathin transnasal endoscopy. PMID- 22486870 TI - Topical application of acetic acid in cytoreduction of gastric cancer. A technical report using mouse model. AB - BACKGROUND AND AIM: Application of acetic acid topically to the mucosal or serosal side of the stomach has been well used to create a chronic gastric ulcer model. The aim of the present study was to apply it as a new cytoreductive approach in a mouse model of gastric cancer. METHODS: A total of 43 genetically engineered mice, the so-called (INS-GAS) mice that develop spontaneously gastric cancer at 10-14 months of age, were included. Acetic acid-induced ulcer method was applied to mice under isofluran anesthesia. The ulcer at the cancer side was made by exposing either the anterior serosal or posterior mucosal side of gastric wall to 0.1 mL of 60% or 100% acetic acid for 30 or 60 s with a cylindrical metal mold (4 mm ID). Route to the serosal side was intra-abdominal and one to the mucosal side was through a small hole made in the forestomach. The opposite side of gastric wall (no treatment with acetic acid) was used as the corresponding control. After the mice were sacrificed, the stomachs were collected 1, 3, 6 h or 1, 3 and 7 days, postoperatively, and evaluated by visual inspection and histology. RESULTS: Gastric cancer was found in both the anterior and posterior walls of the corpus in all 43 mice. Intraluminal pH value was between 11 and 13. Severe necrosis in the cancer was observed in the side exposing to acetic acid, but not in the control side, shortly after the treatment (i.e. within 30 or 60 min). The muscularis mucosa and muscle layers were less damaged, regardless of the side of the treatment. Ulcer formation in the cancer took place 1, 3 or 7 days later. The ulcer depth was sometimes at the muscularis mucosa and muscle layers. At 3 and 7 days, regeneration of epithelial cells was clearly observed in the ulcer margin in the stomach of mice. CONCLUSIONS: Topical application of acetic acid either from mucosal or serosal surface promptly caused the necrosis of tumor, suggesting the potential approach of this simple and reliable method as a cytoreductive treatment of gastric cancer in patients through endoscopy or laparoscopy. PMID- 22486871 TI - Analysis of brain activity during visceral stimulation. AB - BACKGROUND AND AIM: Functional magnetic resonance imaging (fMRI) is a useful technology for investigating regional metabolic activity in the brain. Many experiments using fMRI have been performed, but because of variations in protocols and analytic techniques, the results vary. When a priori information of the task is known, a model-based technique, such as statistical parametric mapping, is often used for analysis. In the case of acid stimulation of the esophagus the task model is unclear, so we analyzed brain activity during an acid or isotonic saline infusion to the esophagus using independent component analysis (ICA), which does not depend on a priori information of the task. METHODS: Six healthy male volunteers (29-45 years) participated in the study. A multi-lumen catheter was inserted transnasally and side-hole infusions ports were approximately 15 cm proximal to the lower esophageal sphincter. The experimental protocol was 5-min interval, 5-min saline infusion, 5-min interval, 5-min 0.1 N HCl, and a final 5-min interval. After magnetic resonance scanning, fMRI image data were analyzed using group ICA. RESULTS: The cerebral regions activated during the first interval, saline infusion, and HCl infusion were the thalamus, insula, cingulate gyri, temporal pole and some parts of the frontal, parietal, temporal and occipital lobes. Activation of the postcentral and precentral gyri occurred during both infusions, but was not observed during the first interval. CONCLUSION: ICA, which can show the cerebral areas activated in relation to liquid in the esophagus, may be a powerful technique for studying the brain's response to visceral stimulation. PMID- 22486872 TI - Clinical feature of asymptomatic reflux esophagitis in patients who underwent upper gastrointestinal endoscopy. AB - BACKGROUND AND AIM: Prevalence of gastroesophageal reflux disease (GERD) varies in regions, but few reports on clinical features and quality of life (QOL) of asymptomatic GERD exist in Japan. METHODS: Endoscopy was performed in our department between April 2008 and September 2010. Among 6409 cases answering Frequency of Scale for the Symptoms of GERD (FSSG) and SF8 QOL (PCS: physical component summary; MCS: mental component summary), proton pump inhibitor or histamine 2 receptor antagonist users were excluded, and 388 cases diagnosed as reflux esophagitis (RE) (Los Angeles Classification grade A, B, C, D) were analyzed. Asymptomatic cases with FSSG total score = 0 were defined as asymptomatic RE (AsymRE) and FSSG total score >= 1 as symptomatic RE (SymRE). Each clinical feature was analyzed. RESULTS: The frequency of AsymRE was 11.6% of RE (AsymRE, n = 45; SymRE, n = 343). Patient characteristics in AsymRE, SymRE were male/female = 35/10; 239/104 (not significant), mean age (year) = 63.5 +/- 14.3; 58.3 +/- 12.7 (P < 0.01), body mass index = 23.9 +/- 4.3; 23.5 +/- 3.7 (ns), respectively. Regarding the grade of RE, grade A 80.0%, B 17.8%, C 2.2% and D 0% in AsymRE, and grade A 72.6%, B 24.8%, C 2.0% and D 0.6% in SymRE (ns). PCS in SF8 was AsymRE; SymRE = 51.8 +/- 9.8; 49.0 +/- 7.7 (P < 0.01) and MCS in SF8 was AsymRE; SymRE = 51.4 +/- 9.4; 48.2 +/- 7.6 (P < 0.01), respectively. CONCLUSION: The prevalence of asymptomatic RE was high, particularly in elderly subjects. Unlike symptomatic RE, QOL was not impaired at all with asymptomatic RE. No differences were seen between groups in clinical features such as endoscopic severity of RE, indicating that asymptomatic RE is a condition that should not be overlooked clinically. PMID- 22486873 TI - Pathogenesis of proton-pump inhibitor-refractory non-erosive reflux disease according to multichannel intraluminal impedance-pH monitoring. AB - BACKGROUND AND AIM: Proton-pump inhibitor (PPI) therapy is the first-line treatment for gastroesophageal reflux disease; however, there are some reports of PPI failure in cases of non-erosive reflux disease (NERD). Among the pathogenic factors associated with PPI-refractory NERD, reflux other than acid reflux can not be detected by conventional pH monitoring. The purpose of this study was to clarify the usefulness of multichannel intraluminal impedance-pH (MII-pH) monitoring for PPI-refractory NERD patients and examine the pathogenesis. METHODS: We used MII-pH monitoring to examine 29 PPI-refractory NERD patients on PPI treatment. Reflux parameters, symptom index (SI: positive if >= 50%), and proximal migration were analyzed. The acidity of the reflux was divided into acid (nadir pH <= 4) and non-acid (nadir pH > 4). Subjects were classified into reflux related disease (abnormal reflux parameters or positive SI) and non-reflux related disease (normal reflux parameters and negative SI). RESULTS: Of the 29 subjects, 21 were diagnosed with reflux-related disease, including 6 with acid reflux type and 15 with non-acid reflux type, and 8 were diagnosed with non reflux-related disease. Of the total 1816 liquid reflux episodes, 834 showed proximal migration, which was more common in symptomatic reflux than in asymptomatic reflux. CONCLUSIONS: MII-pH monitoring could distinguish reflux related disease (especially non-acid type) from PPI-refractory NERD. Proximal migration was associated with symptomatic reflux in PPI-refractory NERD patients. PMID- 22486874 TI - Utility and problems of endoscopic submucosal dissection for early gastric cancer in elderly patients. AB - BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) is reported to be a safe and reliable procedure for the elderly, but these reports could have already had a bias at the time ESD was performed. However, the reports have not clearly stated the criteria of indications. In the present study, we retrospectively elucidated the usefulness and problems of ESD for early gastric cancer in elderly patients (>= 65 years) in comparison with non-elderly patients. METHODS: The subjects were selected from 412 consecutive patients with early gastric cancer (515 lesions) for which ESD was performed between June 2002 and February 2010. The following were used for analysis between groups: pre- and postoperative performance status (PS) of subjects, prevalence rates of pre-existing comorbidities, characteristics of lesions, treatment outcomes, durations of hospitalization, operating times, incidence rates of complications and durations of hospitalization, and postoperative hemorrhage rates, and duration of hospitalization in patients with anticoagulant therapy. RESULTS: Of the lesions in the elderly, four patients (1.0%) were elderly with a PS of 3. The PS increased to six patients (1.6%) after the procedure. None of the non-elderly had a PS of 3 before or after the procedure. The ratio of patients with a pre existing comorbidity was higher in the elderly than in the non-elderly. There were no differences between the two groups in the characteristics of the lesions, their duration of hospitalization, their operating times, or the incidence rates of complications. However, the elderly with perforations had a significantly longer hospitalization than the comparable non-elderly. The percentage of the patients taking anticoagulant drugs was significantly higher among the elderly. Of the patients on anticoagulant therapy, the duration of hospitalization tended to be longer in the elderly but no significant difference was found. None of the non-elderly with postoperative hemorrhage had received anticoagulant therapy. In the elderly with postoperative hemorrhage, 15.8% of the lesions were in those who had received anticoagulant therapy, indicating a significantly higher percentage of such lesions in the elderly group. CONCLUSION: We conclude that ESD is useful in elderly patients because there is a similar risk as for the non-elderly if the approach is individualized, and the following are taken into consideration when making the final decision of performing ESD in an elderly patient: patients should have a PS of 0, 1, or 2; determine whether or not anticoagulant therapy can be discontinued and whether or not treatment can be performed reliably without complications. PMID- 22486875 TI - Hemopexin is upregulated in rat intestinal mucosa injured by indomethacin. AB - BACKGROUND AND AIMS: Recent advancements in capsule endoscopy and double-balloon endoscopy have revealed that non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, can induce small intestinal mucosal damage. However, the precise pathogenesis and therapeutic strategy have not been fully revealed. The aim of the present study was to determine the upregulated proteins in the small intestine exposed to indomethacin. METHODS: Indomethacin (10 mg/kg) was administered subcutaneously to male Wistar rats to induce small intestinal damage and the severity of the intestinal injury was evaluated by measuring the area of visible ulcerative lesions. The intestinal mucosal tissue samples were collected and then analyzed by two-dimensional gel electrophoresis, with matrix-assisted laser desorption/ionization time-of-flight spectrometer peptide mass fingerprinting being used to determine the differentially expressed proteins between normal and injured intestinal mucosa. RESULTS: Among several protein spots showing differential expression, one, hemopexin (HPX), was identified as upregulated in indomethacin-induced injured intestinal mucosa using the MASCOT search engine. CONCLUSION: HPX was identified as upregulated protein in the small intestine exposed to indomethacin. HPX may be responsible for the development of the intestinal inflammation induced by NSAIDs. PMID- 22486876 TI - Correlation between Helicobacter pylori infection and low-dose aspirin use on damage of the upper gastrointestinal tract. AB - BACKGROUND AND AIM: Low-dose aspirin (LDA), and Helicobacter pylori (HP) infection are considered the two primary causes of peptic ulceration. The interaction between HP infection and non-steroidal anti-inflammatory drugs is, however, a matter of considerable discussion and controversy. In this study, we investigated possible synergistic or negative interactions between HP infection and LDA in gastric mucosal lesions, according to lesion site. METHODS: The subjects were 120 patients attending the Cardiology Outpatients Department (average age, 67.1 +/- 8.9 years; male : female ratio 2.9:1). Endoscopic findings were graded using the Modified Lanza score. Lesions were scored for the antral, body and fundal regions. Ulcers were defined as mucosal defects >= 5 mm in size. RESULTS: There were 55 HP-positive and 65 HP-negative subjects, and 91 subjects on LDA therapy. The gastric antral Lanza scores were HP(-) LDA(-): 0.2 +/- 1.6, HP(-) LDA(+): 1.8 +/- 1.5, HP(+) LDA(-): 0.3 +/- 0.7, and HP(+) LDA(+): 0.5 +/- 1.0. The gastric body and fundal Lanza scores were 0.0 +/- 0.0, 0.8 +/- 0.9, 0.4 +/- 1.1, and 1.0 +/- 1.5, respectively, and 0.1 +/- 0.3, 0.5 +/- 0.9, 0.1 +/- 0.3, and 0.1 +/- 0.3, respectively. Variance analysis of the correlation between HP infection and LDA by regional Lanza scores identified both HP infection and LDA use as factors that significantly influence the antral Lanza score. However, LDA was an aggressive factor, and HP infection a protective factor. In the gastric body, LDA was a non-significant, and HP infection a significant, aggressive factor. In the gastric fundus, neither HP infection nor LDA was a significant factor (LDA was an aggressive factor, and HP infection a protective factor). CONCLUSIONS: LDA had aggressive effects in all gastric lesions; on the other hand, HP infection had protective effects in the antrum and fundus in the stomach, and aggressive effects in the body in the stomach. PMID- 22486877 TI - Endoscopic characteristics of short-segment Barrett's esophagus, focusing on squamous islands and mucosal folds. AB - BACKGROUND AND AIM: Endoscopic definitions of Barrett's esophagus (BE) vary among countries, mainly because of the difficulty in diagnosing short-segment BE (SSBE) endoscopically. The aim of this study was to investigate whether the endoscopic identification of squamous islands and the specific position of columnar epithelium helps improve the diagnosis of SSBE. METHODS: First, we prospectively enrolled 100 consecutive patients with SSBE and evaluated the number of identified squamous islands in the columnar epithelium with different modalities: white light (WL), narrow band imaging (NBI), and iodine chromoendoscopy. Second, in another group of 100 consecutive patients with tongue-like SSBE, the correlation of the location of Barrett's mucosa to the esophageal longitudinal folds (ridge or valley) was evaluated endoscopically. RESULTS: It was possible to detect squamous islands in 48, 71, and 75 patients by WL, NBI, and iodine chromoendoscopy, respectively. The detection rate of squamous islands by NBI or iodine chromoendoscopy was significantly superior to that by WL. Tongue-like SSBEs were predominantly found on the ridge of mucosal folds (71%), similar to the location of mucosal breaks (84%). CONCLUSIONS: Squamous islands in the columnar epithelium were efficiently observed by NBI or iodine chromoendoscopy. SSBE was found more frequently on the ridges but not in the valleys of esophageal longitudinal mucosal folds. NBI endoscopic observation focusing on columnar epithelium with squamous islands on the ridges of distal esophageal folds may improve endoscopic detection of SSBE. PMID- 22486878 TI - Utility of preoperative chemoradiotherapy for advanced esophageal carcinoma. AB - BACKGROUND AND AIMS: The most effective treatment would be neoadjuvant chemoradiotherapy (NACRT) plus surgery with three-field lymphadenectomy, if tolerability and complications are acceptable. The aim of this prospective study was to evaluate the tolerability of NACRT+ systematic three-field lymphadenectomy. METHODS: A total of 127 cases of advanced esophageal carcinoma were objected, among which 32 had NACRT, being the cases suspected to cT3-T4 or, < cT3 with multiple lymph node metastasis. >= T2 of 95 cases were treated by surgery alone (NACRT [-] case). The effect of NACRT was evaluated by histological examination and corrected with the clinicopathologic factors, including postoperative prognosis. After reports JCOG9907, we treated eight cases with neoadjuvant chemotherapy at stages II and III. We examined Musashi-1 staining for these eight cases. RESULTS: Histological good response to NACRT group showed good prognosis. Lymph node metastasis is a predictive factor for prognosis. In this additional study, Musashi-1 was positive after neoadjuvant chemotherapy in three cases. The histological response was grade 1 in all of them and recurrence was observed within a short period of time. Two cases of grade 3 were negative staining to Musashi-1 and showed no recurrence. CONCLUSIONS: This study shows that NACRT plus surgery with three-field lymphadenectomy is a feasible therapeutic approach for the cases with multiple lymph node metastases. Prognosis was significantly better in cases with marked histological improvement. It is important to find the predictive factors of histological improvement. Musashi-1 might be a candidate maker for histological response and prognosis, and further studies are needed to prove it. PMID- 22486879 TI - Genomic copy number of a carcinogenic single nucleotide polymorphism at 8q24 in non-risk allele colorectal cancer associated with insulin growth factor 2 receptor expression. AB - BACKGROUND AND AIM: The incidence of both diabetes mellitus and hyperlipidemia is increasing and they are risk factors for colorectal cancer (CRC). On the other hand, the carcinogenic significance of the single nucleotide polymorphism (SNP), rs6983267 at 8q24, in CRC has been reported. The association between the SNP genotype and genes associated with diabetes or hyperlipidemia was investigated in cases of CRC. METHODS: In 107 cases of CRC diagnosed in eight institutes from 2003 to 2008, array-CGH and cDNA microarray was performed and the data analyzed from two groups subdivided according to SNP genotype. RESULTS: In the array-CGH data, we selected 38 genes related to diabetes or fat metabolism, and of these 10 had a correlation coefficient between the genome copy number at 8q24 locus and that of each gene. Of the 10 genes, insulin growth factor 2 receptor (IGF2R) was the only one with an expression level significantly associated with the 8q24 genotype. IGF2R expression was significantly lower in non-risk allele than in risk allele cases (P = 0.012). There was neither a diabetes- nor a fat metabolism related gene that was significantly associated with CRC cases with the risk allele at 8q24. CONCLUSIONS: SNP at 8q24 makes diabetes a risk factor of CRC via IGF2R, especially in genetically non-risk allele cases. We speculate that the risk allele of 8q24 might be risky enough that diabetes is not necessary to worsen the risk for CRC. PMID- 22486880 TI - Effect of ecabet sodium treatment on urea breath test and stool antigen tests in volunteers with Helicobacter pylori infection. AB - BACKGROUND AND AIM: Ecabet sodium is reported to have a bactericidal effect on Helicobacter pylori and inhibit urease activity in vitro. METHODS: Seven male volunteers (mean age, 51.3 years; range, 45-55 years) with H. pylori infection were medicated with 1 g ecabet sodium t.i.d. for 4 weeks. The urea breath test (UBT) was performed 10 times per person: before medication, seven times in 2 weeks, and once in the third and fourth weeks. Stool antigen tests (HpSA PLUS and Testmate pylori antigen) were performed five times per person: before medication and weekly during medication. RESULTS: The premedication UBT value ranged from 4.9 0/00 to 77.4 0/00 and from 2.9 0/00 to 44 0/00 at the end of the treatment period. Not one of the subjects had a negative UBT result during medication. The optical densities of the HpSA and Testmate pylori antigen tests ranged from 0.4 to > 3.0 premedication and from 0.0 to > 3.0 at the end of treatment. HpSA and Testmate pylori antigen were negative in two cases. CONCLUSIONS: In this study, ecabet sodium did not effect the results of UBT in volunteers with H. pylori infection. Ecabet sodium may influence stool antigens because in two of seven cases the H. pylori stool antigen tests returned negative results. PMID- 22486881 TI - Intestinal cancers occurring in patients with Crohn's disease. AB - BACKGROUND AND AIMS: The number of patients with Crohn's disease (CD) and the number of cases of intestinal cancer associated with CD have both been increasing in Japan. However, the number of reported cases is lower than for ulcerative colitis-associated cancer. The aim of this study was to identify the clinical picture of CD-associated intestinal cancer in a consecutive series of patients with CD and to stress the importance of surveillance. METHODS: We enrolled 174 consecutive patients (130 men, 44 women, mean age 25 years) diagnosed with CD and investigated the development of intestinal cancer from October 1998 to July 2010. There were 104 cases of the ileocolitis type, 47 of ileitis, and 23 of colitis. RESULTS: Intestinal cancer developed in two male patients (1.5% of the total), whose respective ages at onset of CD were 41 and 19 years, and 55 and 37 years at onset of cancer. Both cases were of ileocolitis-type CD; one cancer developed in the rectum and the other in the small bowel, and both were accompanied by severe stricture. Histopathological results revealed well and moderately differentiated adenocarcinoma, respectively. CONCLUSIONS: Intestinal cancer developed in patients with ileocolitis-type CD of more than 10 years' duration. Our findings suggest that patients with chronic, widespread CD should be under cancer surveillance. PMID- 22486882 TI - Multiple-antibiotic-resistant Helicobacter pylori infection eradicated with a tailor-made quadruple therapy. AB - In 2008, a 44-year-old woman with mild epigastralgia diagnosed as having Helicobacter pylori-positive chronic gastritis without peptic ulcer underwent eradication therapy with lansoprazole (LPZ), amoxicillin (AMPC) and clarithromycin (CAM) for 7 days, but it failed, so treatment with rabeprazole, AMPC, and metronidazole (MNZ) for another 7 days was given, but it also failed. She was then prescribed a modified, 14-day sequential therapy of LPZ and AMPC with an increased dose of CAM followed by MNZ supplement, but the infection was still not eradicated. The H. pylori was cultured and examined for antibiotic susceptibility with the agar dilution method and was found to be resistant to CAM, MNZ, and levofloxacin, and non-sensitive to AMPC, namely multiple-antibiotic resistant, although sensitive to minocycline. The CYP2C19 genotype of the patient was an extensive metabolizer (G681A: G/A, G636A: G/G). In 2010, she gave informed consent for a 14-day, tailor-made, modified classical (or modified high-dose PPI + AMPC) quadruple therapy comprising 30 mg LPZ, 500 mg AMPC and 500 mg bismuth subnitrate, qid, and 100 mg minocycline, bid. Two months later, her urea breath test was negative. Histology and bacterial culture were still negative 1 year after the therapy. She did not have any adverse events during or after the novel therapy, nor did she feel any further epigastralgia. PMID- 22486883 TI - Reflectance confocal microscopy accurately discriminates between benign and malignant melanocytic lesions exhibiting a 'dermoscopic island'. AB - BACKGROUND: The 'dermoscopic island' is a term that was recently proposed to design an area of a pigmented lesion with a uniform dermoscopic pattern different from the remainder of the lesion. The positive predictive value of this sign for the diagnosis of melanoma is about 50%. OBJECTIVE: The purpose of our study was to see if reflectance confocal microscopy (RCM) permitted to accurately distinguish between nevi and melanoma in such lesions. METHODS: Five lesions of five consecutive unselected patients, with a dermoscopic island but no feasible clear cut diagnosis on the basis of dermoscopy alone were examined by RCM before excision for histopathological evaluation. RESULTS: Two lesions corresponded to nevi, and three lesions were early melanomas arising on a benign naevus in one case, and on a dysplastic naevus in two cases. In all five cases, RCM permitted to make the correct diagnosis, with a very good correlation with conventional histopathology. CONCLUSION: Reflectance confocal microscopy appears as a promising tool not only to enhance the early diagnosis of melanoma but also to avoid unnecessary excisions of lesions with a dermoscopic island. PMID- 22486884 TI - Decoupling of genetic and phenotypic divergence in a headwater landscape. AB - In stream organisms, the landscape affecting intraspecific genetic and phenotypic divergence is comprised of two fundamental components: the stream network and terrestrial matrix. These components are known to differentially influence genetic structure in stream species, but to our knowledge, no study has compared their effects on genetic and phenotypic divergence. We examined how the stream network and terrestrial matrix affect genetic and phenotypic divergence in two stream salamanders, Gyrinophilus porphyriticus and Eurycea bislineata, in the Hubbard Brook Watershed, New Hampshire, USA. On the basis of previous findings and differences in adult terrestriality, we predicted that genetic divergence and phenotypic divergence in body morphology would be correlated in both species, but structured primarily by distance along the stream network in G. porphyriticus, and by overland distance in E. bislineata. Surprisingly, spatial patterns of genetic and phenotypic divergence were not strongly correlated. Genetic divergence, based on amplified DNA fragment length polymorphisms, increased with absolute geographic distance between sites. Phenotypic divergence was unrelated to absolute geographic distance, but related to relative stream vs. overland distances. In G. porphyriticus, phenotypic divergence was low when sites were close by stream distance alone and high when sites were close by overland distance alone. The opposite was true for E. bislineata. These results show that small differences in life history can produce large differences in patterns of intraspecific divergence, and the limitations of landscape genetic data for inferring phenotypic divergence. Our results also underscore the importance of explicitly comparing how terrestrial and aquatic conditions affect spatial patterns of divergence in species with biphasic life cycles. PMID- 22486885 TI - The use of trauma transfusion pathways for blood component transfusion in the civilian population: a systematic review and meta-analysis. AB - This study was undertaken to determine if, amongst civilian trauma patients requiring massive transfusion (MT), the use of a formal trauma transfusion pathway (TTP), in comparison with transfusion without a TTP, is associated with a reduction in mortality, or changes in indices of coagulation, blood product utilisation and complications. A systematic review of three bibliographic databases, reference lists and conference proceedings was conducted. Studies were included if comparisons were made between patients receiving transfusion with and without a TTP. Data were extracted by two independent reviewers on population characteristics, transfusion strategies, blood product utilisation, indices of coagulation, clinical outcomes and complications. Data were pooled using a random effects model and heterogeneity explored. Seven observational studies met all eligibility criteria. Amongst 1801 patients requiring MT, TTPs were associated with a significant reduction in mortality (RR 0.69, 95% CI 0.55, 0.87). No significant increase in the mean number of PRBC transfused between TTP and control patients was seen (MD -1.17 95% CI -2.70, 0.36). When studies assessing only trauma patients were considered, TTPs were associated with a reduction in the mean number of units of plasma transfused (MD -2.63, 95% CI -4.24, -1.01). In summary, the use of TTPs appears to be associated with a reduction in mortality amongst trauma patients requiring MT without a clinically significant increase in the number of PRBC transfused and a potential reduction in plasma transfusion. Effects of TTPs on platelet transfusion, indices of coagulation and complications remain unclear. A randomised controlled trial is warranted. PMID- 22486886 TI - Pancuronium dose refinement in experimental pigs used in cardiovascular research. AB - OBJECTIVE: To quantify the dose of pancuronium required to obtain moderate neuromuscular blockade as monitored by acceleromyography (NMB(mod) : train-of four count of <=2) as a part of a balanced anaesthetic protocol in pigs used in cardiovascular research. STUDY DESIGN: Prospective cross-sectional study. ANIMALS: Five pigs (median body weight: 60 (range 60-63) kg). METHODS: Anaesthesia was induced with xylazine, ketamine, atropine and midazolam and maintained with isoflurane in O(2) :air and fentanyl. Pigs received 0.1 mg kg(-1) pancuronium initial bolus to reach NMB(mod) followed by 0.1 mg kg(-1) hour(-1) constant rate infusion (CRI). During anaesthesia a twitch count of 3 or measureable T4/T1 ratio indicated unsatisfactory NMB. In this case additional 0.4 mg boluses of pancuronium were administered IV to effect in addition to the CRI. Descriptive statistical analysis was performed to express the median and range of the bolus and CRI dose of pancuronium in pigs. Cardiovascular parameters were analyzed at selected time points with Friedman Repeated Measures Analysis on Ranks. Spearman Rank test was used to evaluate correlation between parameters. RESULTS: Acceleromyographic monitoring of NMB is feasible in anaesthetized pigs. The median initial dose and rate of pancuronium required to achieve NMB(mod) were 0.10 (range 0.10-0.13) mg kg(-1) and 0.11 (range 0.10-0.21) mg kg(-1) hour(-1) , respectively. The administration rate showed considerable individual variation. CONCLUSIONS AND CLINICAL RELEVANCE: These pancuronium doses can be used as a guideline to achieve NMB(mod) in pigs as part of a balanced anaesthetic protocol. Instrumental NMB monitoring is essential because of individual kinetic variations and compliance to monitoring guidelines. PMID- 22486888 TI - The impact of prior radiotherapy on fatal complications after self-expandable metallic stents (SEMS) for malignant dysphagia due to esophageal carcinoma. AB - The esophageal stent has been demonstrated to serve as a safe and effective palliative treatment for advanced inoperable esophageal carcinoma. However, the safety of esophageal stents in patients with prior radiotherapy (RT) remains debated. This article aims to investigate the impact of prior RT on the incidence of fatal complications after self-expandable metallic stents for palliation of malignant dysphagia because of esophageal carcinoma. Between January 2007 and July 2010, 93 patients with malignant dysphagia because of esophageal carcinoma underwent placement of self-expandable metallic stents in our hospital. Patients were retrospectively separated into two groups: patients with RT before stent placement (RT group, n=57) and patients with no treatment before stent placement (no RT group, n=35).The median survival after stent placement was 77 days (7-842 days) in the RT group and 246 days (15-878 days) in the no RT group. Improvement in dysphagia score was similar in both groups. The fatal complications included fatal gastrointestinal hemorrhage and uncontrolled pneumonia. The incidence of fatal gastrointestinal hemorrhage and uncontrolled pneumonia were 28.1% and 5.7% (P=0.009), 28.1% and 5.7% (P=0.009), respectively. Logistic regression analysis showed a significant interaction between prior RT and fatal gastrointestinal hemorrhage (relative risk 7.82, 95% confidence interval 1.54-39.61; P=0.013). Mortality of massive hemorrhage was 5.7% (2/35), 0% (0/4), 12.5% (3/24), and 44.8% (13/29), respectively, in patients who received 0, 1Gy~49Gy, 50Gy~60Gy, and >60Gy (chi(2) =17.761; P=0.000). Logistic regression analysis disclosed prior RT did not significantly increase the risk of uncontrolled pneumonia (relative risk 1.47, 95% confidence interval 0.21-10.12; P=0.697). PMID- 22486887 TI - Interaction with a kinesin-2 tail propels choline acetyltransferase flow towards synapse. AB - Bulk flow constitutes a substantial part of the slow transport of soluble proteins in axons. Though the underlying mechanism is unclear, evidences indicate that intermittent, kinesin-based movement of large protein-aggregates aids this process. Choline acetyltransferase (ChAT), a soluble enzyme catalyzing acetylcholine synthesis, propagates toward the synapse at an intermediate, slow rate. The presynaptic enrichment of ChAT requires heterotrimeric kinesin-2, comprising KLP64D, KLP68D and DmKAP, in Drosophila. Here, we show that the bulk flow of a recombinant Green Fluorescent Protein-tagged ChAT (GFP::ChAT), in Drosophila axons, lacks particulate features. It occurs for a brief period during the larval stages. In addition, both the endogenous ChAT and GFP::ChAT directly bind to the KLP64D tail, which is essential for the GFP::ChAT entry and anterograde flow in axon. These evidences suggest that a direct interaction with motor proteins could regulate the bulk flow of soluble proteins, and thus establish their asymmetric distribution. PMID- 22486889 TI - Ratiometric fluorescent chemosensor for Hg(2+) based on heptamethine cyanine containing a thymine moiety. AB - Based on a T-Hg(2+)-T binding mode, a sensitive ratiometric fluorescent chemosensor for aqueous Hg(2+) was developed with a heptamethine cyanine chromophore containing a thymine moiety. PMID- 22486890 TI - Anatomical distribution of striated pattern of contrast media during conventional chemical lumbar sympathectomy using X-ray fluoroscopic guidance. PMID- 22486891 TI - T helper type 17 cells expand in patients with myasthenia-associated thymoma. AB - Myasthenia gravis (MG) is a prototypical CD4(+) T cell-dependent autoimmune disease mediated by anti-acetylcholine receptor autoantibodies (AChR-Abs). Certain subsets of helper T cells are suggested to be involved in the pathogenesis of MG, including Th1 and regulatory T cells (Treg). However, whether the recently identified Th17 cells play a role in the development of MG and its prognosis is still unknown. Here, we demonstrated that Th17 cells and their associated cytokines are increased, while the Treg cells are decreased in the peripheral blood mononuclear cells (PBMCs) from MG patients with thymomas (TM), but not from those with normal thymus (NT) or thymic hyperplasia (TH). Furthermore, the quantity of Th17 cells correlates with the quantitative myasthenia gravis (QMG) score in patients with TM. We also found a significant positive relationship between the frequency of Th17 cells (%) and the concentration of AChR antibodies in patients with MG. Therefore, the Th17/Treg imbalance in TM may suggest MG with certain pathological subtype, and the increase in Th17 cells may reveal the severity of the disease, which is valuable in the diagnosis and choice of therapeutic strategy for patients with MG. PMID- 22486892 TI - The protein import pore Tom40 in the microsporidian Nosema bombycis. AB - Microsporidia, an unusual group of unicellular parasites related to fungi, possess a highly reduced mitochondrion known as the mitosome. Since mitosomes lack an organellar genome, their proteins must be translated in the cytosol before being imported into the mitosome via translocases. We have identified a Tom40 gene (NbTom40), the main component of the translocase of the outer mitochondrial membrane, in the genome of the microsporidian Nosema bombycis. NbTom40 is reduced in size, but it is predicted to form a beta-barrel structure composed of 19 beta-strands. Phylogenetic analysis confirms that NbTom40 forms a clade with Tom40 sequences from other species, distinct from a related clade of voltage-dependent anion channels (VDACs). The NbTom40 contains a beta-signal motif that the polar residue is substituted by glycine. Furthermore, we show that expression of NbTom40, as a GFP fusion protein within yeast cells, directs GFP to mitochondria of yeast. These findings suggest that NbTom40 may serve as an import channel of the microsporidian mitosome and facilitate protein translocation into this organelle. PMID- 22486893 TI - Discovery of the novel HLA-DRB1*16:16 allele in a Taiwanese unrelated bone marrow stem cell donor by a sequence-based typing method and the probable haplotype associated with DRB1*16:16. AB - We report here a de novo HLA-DRB1 allele, DRB1*16:16, discovered in a Taiwanese unrelated volunteer bone marrow stem cell donor by a sequence-based typing (SBT) method. In exon 2, the DNA sequence of DRB1*16:16 is identical to the sequence of DRB1*16:02:01 except the nucleotides at positions 258 (C->T), 260 (C->A) and 261 (T->G). The nucleotide substitution produced an amino acid replacement at residue 58 (A->E). The formation of DRB1*16:16 was probably generated by a DNA sequence recombination event involving DRB1*11:01:01 and DRB1*16:02:01. The probable HLA A, -B and -DRB1 haplotype in association with DRB1*16:16 may be deduced as A*02 B*38-DRB1*16:16. PMID- 22486894 TI - The effect of using an alternative irrigant between sodium hypochlorite and chlorhexidine to prevent the formation of para-chloroaniline within the root canal system. AB - AIM: To determine if the formation of para-chloroaniline (PCA) can be avoided by using an alternative irrigant following sodium hypochlorite but before chlorhexidine. METHODOLOGY: Fifty-five single-rooted teeth were decoronated, instrumented to size 40, .06 taper whilst being irrigated with 14% ethylene diamine-tetra-acetic acid (EDTA) and 6% NaOCl. Samples were then randomly divided into three experimental and two control groups. Group 1 was irrigated with saline followed by 2% chlorhexidine gluconate (CHX). Group 2 was irrigated with 50% citric acid (CA) followed by 2% CHX. Group 3 was irrigated with 14% EDTA followed by 2% CHX. The chemical identity and quantification of the PCA in the formed precipitate was determined using gas chromatography/mass spectrometry (GC/MS). RESULTS: All experimental groups contained PCA. The mean level of PCA for group 1 (sterile saline) was 229 ng mL(-1), group 2 (citric acid) 72 ng mL(-1) and group 3 (EDTA) 400 ng mL(-1), respectively. A significant difference was found between the saline and EDTA groups and the negative control (P < 0.05). Although no statistical significance was found between the negative control and citric acid group, PCA was still present in this experimental group. CONCLUSIONS: Citric acid used as the intermittent irrigant had the least amount of PCA formation in the canal system. Until the threshold required to cause biological damage in humans is determined, the combination of NaOCl and CHX in root canal treatment should be avoided. PMID- 22486895 TI - Inhibition and inactivation of cytochrome P450 2A6 and cytochrome P450 2A13 by menthofuran, beta-nicotyrine and menthol. AB - Nicotine is the primary addictive agent in tobacco products and is metabolized in humans by CYP2A6. Decreased CYP2A6 activity has been associated with decreased smoking. The extrahepatic enzyme, CYP2A13 (94% identical to CYP2A6) also catalyzes the metabolism of nicotine, but is most noted for its role in the metabolic activation of the tobacco specific lung carcinogen, 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In this study, the inhibition and potential inactivation of CYP2A6 and CYP2A13 by two tobacco constituents, 1 methyl-4-(3-pyridinyl) pyrrole (beta-nicotyrine) and (-)-menthol were characterized and compared to the potent mechanism based inactivator of CYP2A6, menthofuran. The effect of these compounds on CYP2A6 and CYP2A13 activity was significantly different. (-)-Menthol was a more efficient inhibitor of CYP2A13 than of CYP2A6 (KI, 8.2 MUM and 110 MUM, respectively). beta-Nicotyrine was a potent inhibitor of CYP2A13 (KI, 0.17 MUM). Neither menthol nor beta-nicotyrine was an inactivator of CYP2A13. Whereas, beta-nicotyrine was a mechanism based inactivator of CYP2A6 (KI(inact), 106 MUM, kinact was 0.61 min(-1)). Similarly, menthofuran, a potent mechanism based inactivator of CYP2A6 did not inactivate CYP2A13. Menthofuran was an inhibitor of CYPA13 (KI, 1.24 MUM). The inactivation of CYP2A6 by either beta-nicotyrine or menthofuran was not due to modification of the heme and was likely due to modification of the apo-protein. These studies suggest that beta-nicotyrine, but not menthol may influence nicotine and NNK metabolism in smokers. PMID- 22486896 TI - Time course and prognostic implications of QT interval in patients with coronary artery disease undergoing coronary bypass surgery. AB - INTRODUCTION: The aim of the present study was to determine the prognostic implication of preoperative QT interval in relation to overall death and sudden cardiac death after coronary bypass surgery and to investigate the course of QT interval after surgery. METHODS AND RESULTS: Of 812 consecutive patients undergoing isolated off-pump coronary surgery, 656 were retrospectively analyzed after excluding the 48 patients who were taking QT prolonging drugs and the 108 patients who had any of the following electrocardiographic findings: atrial fibrillation, pacemaker, QRS of >120 milliseconds, bundle branch block. QT intervals were corrected for heart rate (QTc) using Bazett's formula. Prolonged QTc was defined as QTc of >=450 milliseconds in men (n = 144) and >=470 milliseconds in women (n = 36). The 5-year cumulative rate of sudden cardiac death in patients with prolonged QTc was 25% against 4% for those with normal QTc (P = 0.01). The risk-adjusted hazard ratio (95% confidence interval) for the association between preoperative QTc and overall death was 1.47 (1.21-1.74) per 1 SD increase in QTc; and 2.38 (1.50-3.45) for prolonged versus normal QT. For sudden cardiac death, the respective ratios were 1.63 (1.32-2.25) per 1-SD increase in QTc; and 3.32 (2.14-4.23). QTc interval did not change during the first year after surgery, but increased significantly during the subsequent years. Patients with prolonged QTc before surgery had consistently longer QTc even after revascularization than those with normal QTc. CONCLUSION: Preoperative QT interval was an independent predictor of overall death and sudden cardiac death after isolated coronary bypass surgery. PMID- 22486897 TI - Use of response surface methodology to optimize protease synthesis by a novel strain of Bacillus sp. isolated from Portuguese sheep wool. AB - AIMS: To investigate the influence of yeast extract, peptone, temperature and pH upon protease productivity by Bacillus sp. HTS102--a novel wild strain isolated from wool of a Portuguese sheep breed (Merino). METHODS AND RESULTS: A 2(4) full factorial, central composite design together with response surface methodology was used to carry out the experiments and analyse the results, respectively. Among the individual parameters tested, temperature and peptone concentration produced significant effects upon protease productivity. A high correlation coefficient (R(2 ) = 0.994, P < 0.01) indicated that the empiric second-order polynomial model postulated was adequate to predict said productivity, with the optimum loci characterized by: temperature of 43 degrees C, peptone content of 1.4 g l(-1) , pH of 5.1 and yeast extract concentration of 10.0 g l(-1) . CONCLUSIONS: Protease synthesis depends chiefly on temperature and peptone level. The maximum protease activity was more than twice that obtained with the basal medium, so the experimental design and analysis undertaken were effective towards process optimization. SIGNIFICANCE AND IMPACT OF THE STUDY: Rational choice of processing conditions for maximum protease productivity will be relevant if an economically feasible fermentation process based on Bacillus sp. HTS102 is intended. PMID- 22486898 TI - Expression of CA-IX is associated with advanced stage tumors and poor survival in oral squamous cell carcinoma patients. AB - INTRODUCTION: Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including tumorigenicity. Specifically, CA-IX has been primarily found in hypoxic tumor tissues. MATERIAL AND METHODS: This is a retrospective study of tumors from the Tissue Bank of the Pathology Department of the University Hospital of Santiago de Compostela. We selected 50 oral squamous cell carcinomas (OSCCs) using Tissue Microarray (TMA) technology. The immunohistochemical study was performed to determine CA-IX expression. The resulting data were subject to statistical analysis and survival curves. RESULTS: Of the 50 cases, 23 were detected in early stages (I and II) and 27 in advanced stages (III and IV). In the first year, almost 50% of patients in stages III-IV died, which contrasted with those patients in initial stages who registered a survival rate of 80% (P = 0.019). Regarding the expression of CA-IX, nine cases (18%) were negative, 18 cases (36%) were moderate, while 23 cases (46%) were intense. Tumors in stages I II showed a positivity of 52.6%; however, in advanced stages, the percentage reached 95.5% (P = 0.002). Regarding CA-IX expression and survival, patients with tumors with strong staining had a lower average survival time (13.8 months) than patients with negative or weak-moderate staining (33.4 and 32.8 months, respectively), log-rank=6.1, P value=0.0484. CONCLUSIONS: Early diagnosis of these tumors is essential to improve patient survival. CA-IX expression augments with increasing tumor stage, probably related with the degree of hypoxia; thus, its measurement can be used as a prognostic factor. PMID- 22486899 TI - Inpatient verbal aggression: content, targets and patient characteristics. AB - Verbally aggressive behaviour on psychiatric wards is more common than physical violence and can have distressing consequences for the staff and patients who are subjected to it. Previous research has tended to examine incidents of verbal aggression in little detail, instead combining different types of aggressive behaviour into a single measure. This study recruited 522 adult psychiatric inpatients from 84 acute wards. Data were collected from nursing and medical records for the first 2 weeks of admission. Incidents of verbal aggression were categorized and associations with patient characteristics examined. There were 1398 incidents of verbal aggression in total, reported for half the sample. Types of verbal aggression were, in order of prevalence: abusive language, shouting, threats, expressions of anger and racist comments. There were also a large number of entries in the notes which did not specify the form of verbal aggression. Staff members were the most frequent target of aggression. A history of violence and previous drug use were consistently associated with verbal aggression. However, there were also some notable differences in patient variables associated with specific types of verbal aggression. Future studies should consider using multidimensional measures of verbal aggression. PMID- 22486900 TI - Psychiatric morbidity in gynecological outpatients. AB - AIM: To assess the prevalence of depression and anxiety in women presenting with gynecological symptoms, to determine how many women with these disorders were receiving treatment for them, and to investigate risk factors for these disorders. METHOD: Two hundred and sixty-four women seeking medical care from gynecology clinics at a specialist women's hospital completed a self-report questionnaire asking about sociodemographics, physical and mental health, personality (neuroticism) and psychosocial stressors. RESULTS: A total of 91 women met the diagnostic criteria for one or more Patient Health Questionnaire (PHQ) diagnosis. Forty-six (17.4%) met criteria for major depressive disorder (MDD), 15 (5.7%) for panic disorder (PD) and 73 (27.7%) for generalized anxiety disorder (GAD). Thirty-nine (42.9%) of the 91 women met criteria for two or more disorders. An additional 23 (8.7%) met DSM-IV-TR criteria for minor (sub threshold) depression. Fifty percent with MDD, 4% with minor depression, 53% with PD and 22% with GAD reported they were receiving treatment. Psychosocial stressors and the neuroticism score were risk factors for both anxiety and depression. CONCLUSIONS: Anxiety and depression are common amongst women attending a gynecology clinic. Clinicians should be alert to the possibility of these disorders and make specific enquiries about their emotional wellbeing. PMID- 22486901 TI - Laser confocal microscopy is a valuable, non-invasive tool for early diagnosis and characterisation of epithelial nests. AB - A 22-year-old woman presented with blurred vision and glare in the right eye, which had been present for three months. The patient had undergone laser-assisted in situ keratomileusis nine months previously and enhancement three months thereafter. On ophthalmological examination, visual acuity was 6/8.6 in the right eye and 6/6 in the left eye. An opaque epithelial nest below the flap with a visible demarcation line was detected along the pupil margin in the right eye. Subsequent laser confocal microscopy revealed the presence of epithelial cells in a whorled pattern with irregular astigmatism on corneal topography. Three months later, the clinical symptoms had worsened and a denser and larger wedge-shaped epithelial nest was observed. The nest was scraped. Six months later, the patient exhibited restored visual acuity (6/6) without glare. Laser confocal microscopy is a valuable, non-invasive tool and provides in vivo pathological images for early diagnosis and localisation of lesion depth in epithelial nests to guide appropriate surgical management. PMID- 22486903 TI - The DSL1 complex: the smallest but not the least CATCHR. AB - The DSL1 complex is a conserved tethering complex at the endoplasmic reticulum that recognizes Golgi-derived COPI vesicles and hands them over to the fusion machinery. The DSL1 complex is the simplest tethering complex of the complexes associated with tethering containing helical rods (CATCHR) family. CATCHR tethering complexes play a role at compartments along the exocytic and endocytic pathways. In this review, different functions of the DSL1 complex are discussed, some open questions with the seemingly straightforward picture are pointed out and alternative functions of the DSL1 complex members are mentioned. PMID- 22486904 TI - Alpha-2 adrenoceptor agonists as adjuncts to Peripheral Nerve Blocks in Children- is there a mechanism of action and should we use them? PMID- 22486902 TI - Salmonella chemoreceptors McpB and McpC mediate a repellent response to L cystine: a potential mechanism to avoid oxidative conditions. AB - Chemoreceptors McpB and McpC in Salmonella enterica have been reported to promote chemotaxis in LB motility-plate assays. Of the chemicals tested as potential effectors of these receptors, the only response was towards L-cysteine and its oxidized form, L-cystine. Although enhanced radial migration in plates suggested positive chemotaxis to both amino acids, capillary assays failed to show an attractant response to either, in cells expressing only these two chemoreceptors. In vivo fluorescence resonance energy transfer (FRET) measurements of kinase activity revealed that in wild-type bacteria, cysteine and cystine are chemoeffectors of opposing sign, the reduced form being a chemoattractant and the oxidized form a repellent. The attractant response to cysteine was mediated primarily by Tsr, as reported earlier for Escherichia coli. The repellent response to cystine was mediated by McpB/C. Adaptive recovery upon cystine exposure required the methyl-transferase/-esterase pair, CheR/CheB, but restoration of kinase activity was never complete (i.e. imperfect adaptation). We provide a plausible explanation for the attractant-like responses to both cystine and cysteine in motility plates, and speculate that the opposing signs of response to this redox pair might afford Salmonella a mechanism to gauge and avoid oxidative environments. PMID- 22486905 TI - The placement of an intravenous cannula is always necessary during general anesthesia in children: a pro-con debate. The case against. PMID- 22486906 TI - Anesthetic approach to a patient with multiple pterygium (Escobar) syndrome. PMID- 22486907 TI - Reply to article: An optimum time for intravenous cannulation after induction with sevoflurane in children. PMID- 22486908 TI - Anesthetic challenges in lamellar ichthyosis. PMID- 22486909 TI - Submental intubation: another anesthetic option for maxillofacial trauma. PMID- 22486910 TI - Difficult intubation in an infant with Hallermann-Streiff syndrome-easy with Airtraq laryngoscope. PMID- 22486911 TI - Difficult tracheal intubation in a child born small for gestational age and receiving growth hormone therapy for short stature. PMID- 22486912 TI - The air-Q((r)) intubating laryngeal airway for endotracheal intubation in children with difficult airway: our experience. PMID- 22486913 TI - Lightwand for confirming tracheal intubation in the presence of severe postintubation bronchospasm. PMID- 22486914 TI - Endotracheal tube connector defect as a cause of high airway pressure. PMID- 22486915 TI - Current state of malignant hyperthermia in China mainland: a less optimistic reality. PMID- 22486916 TI - Bilateral ultrasound-guided axillary plexus anesthesia in a child with dystrophic epidermolysis bullosa. PMID- 22486917 TI - Supraclavicular subclavian vein approach for central venous catheterization is a safe and preferable method also in pediatric patients. PMID- 22486919 TI - Anaerobic photosynthetic ecosystems. PMID- 22486920 TI - Variability of physicochemical properties of an epoxy resin sealer taken from different parts of the same tube. AB - AIM: To analyse several physicochemical properties of AH Plus (Dentsply DeTrey, Konstanz, Germany), including setting time, flow, radiopacity and the degree of conversion (DC); and to correlate the results with the source of the material: from the beginning, middle or end of the tubes in which they were supplied. METHODOLOGY: Three experimental groups were established for each property investigated. Group 1 corresponded to material taken from the beginning of tubes A and B; Group 2 corresponded to material taken from the middle of each tube; and group 3 corresponded to that from the end of each tube. The setting time, flow and radiopacity were studied according to American National Standards Institute/American Dental Association (ANSI/ADA) Specification 57. DC was determined from infrared spectra, which were recorded at 1-h intervals for the first 6 h; then, at 2-h intervals for the next 14 h; then, at 24 and 30 h. Data were analysed statistically by analysis of variance (anova), Tukey-Kramer, Kruskal-Wallis and Dunn tests, with a significance level of 5%. RESULTS: Group 1 had a significantly longer setting time (2303 +/- 1058 min) (P < 0.05). Group 3 had the lowest flowability (30.0 +/- 0.7 mm) and the highest radiopacity (14.85 +/- 1.8 mm Al) (P < 0.05). No differences were found for the DC test (P > 0.05). CONCLUSION: The results suggest that segregation occurs between the organic and inorganic components of AH Plus sealer, thereby changing the setting time, flow and radiopacity. PMID- 22486918 TI - Environmental and ecological factors that shape the gut bacterial communities of fish: a meta-analysis. AB - Symbiotic bacteria often help their hosts acquire nutrients from their diet, showing trends of co-evolution and independent acquisition by hosts from the same trophic levels. While these trends hint at important roles for biotic factors, the effects of the abiotic environment on symbiotic community composition remain comparably understudied. In this investigation, we examined the influence of abiotic and biotic factors on the gut bacterial communities of fish from different taxa, trophic levels and habitats. Phylogenetic and statistical analyses of 25 16S rRNA libraries revealed that salinity, trophic level and possibly host phylogeny shape the composition of fish gut bacteria. When analysed alongside bacterial communities from other environments, fish gut communities typically clustered with gut communities from mammals and insects. Similar consideration of individual phylotypes (vs. communities) revealed evolutionary ties between fish gut microbes and symbionts of animals, as many of the bacteria from the guts of herbivorous fish were closely related to those from mammals. Our results indicate that fish harbour more specialized gut communities than previously recognized. They also highlight a trend of convergent acquisition of similar bacterial communities by fish and mammals, raising the possibility that fish were the first to evolve symbioses resembling those found among extant gut fermenting mammals. PMID- 22486921 TI - Enantioselective activation of stable carboxylate esters as enolate equivalents via N-heterocyclic carbene catalysts. AB - The first N-Heterocyclic Carbene (NHC) mediated activation of stable carboxylate esters to generate enolate intermediates is disclosed. The catalytically generated arylacetic ester enolates undergo enantioselective reactions with alpha,beta-unsaturated imines. PMID- 22486922 TI - Monitoring of the Bagaza virus epidemic in wild bird species in Spain, 2010. AB - By the end of August 2010, high mortalities in red-legged partridges (Alectoris rufa) and pheasants (Phasianus colchicus) were detected in several hunting states in the province of Cadiz (southern Spain). Retrospective epidemiological studies revealed that the first clinical signs had been observed in late July-early August. The most common clinical signs were incoordination, disorientation and ataxia. The estimated mean morbidity rates were 37% in partridges and 11% in pheasants. The estimated mean mortality rates were 23% in partridges and 6% in pheasants. The estimated mean case-fatality rates were 38% and 8% in partridges and pheasants, respectively. A total of 19 clinically affected birds from 18 affected hunting states were analysed between August and November 2011. Histopathological analyses revealed encephalitis, myocarditis, leiomyositis, meningoencephalitis and neuritis as the most frequently observed lesions. Molecular analyses identified Bagaza virus (BAGV) as the causative agent of the epidemic. Further studies are needed to determine the source of introduction of the virus into Europe and to elucidate whether wild birds play a role in the epidemiology of BAGV. Surveillance in susceptible bird species, including partridges and pheasants, may be useful for the early detection of BAGV in an area. PMID- 22486923 TI - Increase in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis. AB - AIMS: It remains uncertain if differences in mortality risk exist among the sulfonylureas, especially in patients with documented coronary artery disease (CAD). The purpose of this study was to assess the overall mortality risk of the individual sulfonylureas versus metformin in a large cohort of patients with type 2 diabetes. METHODS: A retrospective cohort study was conducted using an academic health centre enterprise-wide electronic health record (EHR) system to identify 23 915 patients with type 2 diabetes who initiated monotherapy with metformin (N = 12774), glipizide (N = 4325), glyburide (N = 4279) or glimepiride (N = 2537), >= 18 years of age, with and without a history of CAD, and not on insulin or a non-insulin injectable at baseline. The patients were followed for mortality by documentation in the EHR and Social Security Death Index. Multivariable Cox models with propensity analysis were used to compare cohorts. RESULTS: An increase in overall mortality risk was observed in the entire cohort with glipizide (HR 1.64; 95% CI 1.39-1.94), glyburide (HR 1.59; 95% CI 1.35-1.88), and glimepiride (HR 1.68; 95% CI 1.37-2.06) versus metformin; however, in those patients with documented CAD, a statistically significant increase in overall mortality risk was only found with glipizide (HR 1.41; 95% CI 1.07-1.87) and glyburide (HR 1.38; 95% CI 1.04-1.83) versus metformin. CONCLUSIONS: Glipizide, glyburide and glimepiride are associated with an increased risk of overall mortality versus metformin. Our results suggest that if a sulfonylurea is required to obtain glycaemic control, glimepiride may be the preferred sulfonylurea in those with underlying CAD. PMID- 22486924 TI - Genotyping of HPA-1 to -7 and -15 in the Thai population using multiplex PCR. AB - BACKGROUND: Different polymerase chain reaction (PCR) techniques for human platelet antigens (HPA) genotyping have been implemented, in order to diagnose the clinical syndromes of patients with thrombocytopaenia and provide effective HPA-matched platelet donors. OBJECTIVES: The aim of this study is to develop an in-house multiplex PCR for HPA-1 to -7 and -15 genotyping in the Thai population. METHODS: One hundred DNA samples of known HPA genotyping by the PCR with sequence specific primers (PCR-SSP), as previously described, were tested with the multiplex PCR. Additionally, 300 DNA samples of group O donors were tested for HPA-1 to -7 and -15 genotyping using multiplex PCR. RESULTS: The comparison of HPA-1 to -7 and -15 genotype results between multiplex PCR and PCR-SSP technique was in 100% concordance. Interestingly, HPA-2b2b genotype was found in two samples; however, other low-incidence genotypes such as HPA-1b1b, HPA-5b5b, HPA 6b6b and HPA-7b7b were not found in this study. Moreover, 30 samples were randomly tested twice for HPA genotyping using the multiplex PCR and demonstrated reproducible results. CONCLUSIONS: This study shows that the in-house multiplex PCR is simple, cost-effective and suitable for HPA genotyping for routine laboratories in other developing countries. Nevertheless, a large-scale evaluation of this technique through multicentre analysis is suggested. PMID- 22486925 TI - Mesotherapy using dutasteride-containing preparation in treatment of female pattern hair loss: photographic, morphometric and ultrustructural evaluation. AB - BACKGROUND: Treatment of female pattern hair loss (FPHL) is frustrating for both patients and doctors. Mesotherapy is a novel treatment for hair fall and its efficacy in FPHL has not been evaluated. OBJECTIVE: Evaluation of the efficacy and safety of mesotherapy using dutasteride-containing preparation in treatment of FPHL. METHODS: This study included 126 female patients with FPHL. They were classified into two groups; group I (86 patients) injected with dutasteride containing preparation and group II (40 control patients) injected with saline. Patients received 12 sessions and were evaluated at the 18th week by: photographic assessment, hair pull test, hair diameter and patient self assessment. Ultrastructural evaluation was done for three patients. RESULTS: After mesotherapy with dutasteride-containing preparation, photographic improvement occurred in 62.8% of patients compared with 17.5% in control group (P < 0.05), mean number of epilated hairs was significantly decreased (P < 0.05), mean hair diameter was significantly increased (P < 0.05). Patient self assessment showed statistically significant improvement compared with the controls (P < 0.05). There was a negative correlation between degree of improvement and duration of FPHL (P < 0.05). Side effects were minimal with no statistically significant difference between the two groups (P > 0.05). Ultrastructural examination of pretreated hairs revealed absent cuticle in one patient and focal destruction of the cuticle in the second patient, which reappeared in both after therapy. CONCLUSION: We concluded that mesotherapy with dutasteride-containing preparation was effective, tolerable and minimally invasive treatment modality in FPHL with better response for shorter duration of the disease. PMID- 22486926 TI - Islet cell transplantation in type 1 diabetes: an analysis of efficacy outcomes and considerations for trial designs. AB - To estimate treatment effect size and other parameters required for planning the designs and analyses of future phase 3 islet transplant trials, we analyzed key clinical and laboratory outcomes of 347 allogeneic islet transplant recipients, using data from the Collaborative Islet Transplant Registry (CITR). At 1 year, approximately 59% of all transplant recipients were free of severe hypoglycemic events and maintained hemoglobin A1c (HbA1c) level of <= 6.5%. The Kaplan-Meier (KM) survival analyses showed that 69%, 54% and 44% of these 1-year responders maintained this composite endpoint at 2, 3 and 4 years, respectively. Ninety-one percent of all recipients were free of severe hypoglycemic episodes at 1 year. Furthermore, the KM survival estimates showed that 91%, 85% and 80% of these subjects maintained this clinical benefit at 2, 3 and 4 years, respectively. These results can be very useful in developing framework for study designs, sample size estimates, and statistical analysis plans for future pivotal trials of islet cell transplantation in type 1 diabetes. PMID- 22486927 TI - Polyunsaturated fatty acid supplements modulate mast cell membrane microdomain composition. AB - In the present study, the lipid raft composition of a canine mastocytoma cell line (C2) was analyzed. Lipid rafts were well separated from non-raft plasma membranes using a detergent-free isolation technique. To study the influence of n 3 and n-6 polyunsaturated fatty acids (PUFA) on raft fatty acid composition in comparison to non-raft cell membrane, C2 were supplemented with one of the following: alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid or arachidonic acid. Enrichment of the culture medium with a specific PUFA resulted in an increase in the content of this fatty acid both in rafts and non-raft membranes. Contents of cholesterol and protein were found not to be affected by the changes in the fatty acid profiles. In conclusion, our data provide strong evidence that PUFA modulate lipid composition and physiological properties of membrane micro domains of mast cells which in turn may have effects on mast cell function. PMID- 22486928 TI - Characterization of a mobile and multiple resistance plasmid isolated from swine manure and its detection in soil after manure application. AB - AIMS: To isolate and characterize multiple antibiotic resistance plasmids found in swine manure and test for plasmid-associated genetic markers in soil following manure application to an agricultural field. METHODS AND RESULTS: Plasmids were isolated from an erythromycin enrichment culture that used liquid swine manure as an inoculant. Plasmids were transformed into Escherichia coli DH10beta for subsequent characterization. We isolated and DNA sequenced a 22 102-bp plasmid (pMC2) that confers macrolide, and tetracycline resistances, and carries genes predicted to code for mercury and chromium resistance. Conjugation experiments using an pRP4 derivative as a helper plasmid confirm that pMC2 has a functional mobilization unit. PCR was used to detect genetic elements found on pMC2 in DNA extracted from manure amended soil. CONCLUSIONS: The pMC2 plasmid has a tetracycline-resistant core and has acquired additional resistance genes by insertion of an accessory region (12 762 bp) containing macrolide, mercury and chromium resistance genes, which was inserted between the truncated DDE motifs within the Tn903/IS102 mobile element. SIGNIFICANCE AND IMPACT OF THE STUDY: Liquid swine manure used for manure spreading contains multiple antibiotic resistance plasmids that can be detected in soil following manure application. PMID- 22486929 TI - When is it safe to stop for safety? PMID- 22486930 TI - Modified C-reactive protein selectively binds to immunoglobulins. AB - Modified C-reactive protein (mCRP) has been reported to non-specifically bind to immunoglobulins; notwithstanding, the nature of these interactions is not clear. The aim of this study was to investigate the binding of antibodies directed against HSA and IgG to mCRP, fibrinogen (Fg), IgG, fibronectin (Fn) and C1q and its contaminants. We also studied the binding of mCRP to the antibodies directed towards receptors involved in CRP signalling (anti-CD32, anti-CD16). For the analysis of such interactions, a combination of ELISA and Western immunoblotting has been applied. The tested antibodies powerfully bound to either the contaminations of purified proteins (Fg, IgG, Fn and mCRP) or interacted directly with some of these proteins (C1q, mCRP, Fg). The effectiveness of anti-HSA binding to immobilized proteins was influenced by the antigenic specificity of the antibody, the content of various protein fractions in the contaminants of a given protein (albumin augmented the interactions), overall protein purity and a natural avidity of a given protein towards immunoglobulins. The relative binding of anti-HSA or anti-IgG to immobilized mCRP was considerably lower than that observed for plasma proteins. Furthermore, the strength of the direct interaction between immunoglobulins and mCRP varied from the lack of response (anti-HSA) or a negligible response (anti-IgG) to the relatively high signal (human IgG, anti CD16, anti-CD32), as compared to the control. Based on these observations, we conclude that the binding of mCRP to immunoglobulins cannot be easily generalized as a kind of some universal phenomenon. PMID- 22486932 TI - Severe deformation of right atrium and tricuspid annulus due to compression by tortuous aorta. PMID- 22486931 TI - Evaluation of the efficacy and safety of high dose short duration enrofloxacin treatment regimen for uncomplicated urinary tract infections in dogs. AB - BACKGROUND: Uncomplicated urinary tract infections (UTI) in dogs usually are treated with antimicrobial drugs for 10-14 days. Shorter duration antimicrobial regimens have been evaluated in human patients. HYPOTHESIS: A high dose short duration (HDSD) enrofloxacin protocol administered to dogs with uncomplicated UTI will not be inferior to a 14-day treatment regimen with amoxicillin-clavulanic acid. ANIMALS: Client-owned adult, otherwise healthy dogs with aerobic bacterial urine culture yielding >= 10(3) CFU/mL of bacteria after cystocentesis. METHODS: Prospective, multicenter, controlled, randomized blinded clinical trial. Enrolled dogs were randomized to group 1 (enrofloxacin 18-20 mg/kg PO q24h for 3 days) or group 2 (amoxicillin-clavulanic acid 13.75-25 mg/kg PO q12h for 14 days). Urine cultures were obtained at days 0, 10, and 21. Microbiologic and clinical cure rates were evaluated 7 days after antimicrobial treatment was discontinued. Lower urinary tract signs and adverse events also were recorded. RESULTS: There were 35 dogs in group 1 and 33 in group 2. The microbiologic cure rate was 77.1 and 81.2% for groups 1 and 2, respectively. The clinical cure rate was 88.6 and 87.9% for groups 1 and 2, respectively. Cure rates between groups did not differ according to the selected margin of noninferiority. CONCLUSIONS AND CLINICAL IMPORTANCE: HDSD enrofloxacin treatment was not inferior to a conventional amoxicillin clavulanic acid protocol for the treatment of uncomplicated bacterial UTI in dogs. Further research is warranted to determine if this protocol will positively impact owner compliance and decrease the emergence of antimicrobial resistance. PMID- 22486933 TI - Effectiveness of ProTaper, D-RaCe, and Mtwo retreatment files with and without supplementary instruments in the removal of root canal filling material. AB - AIM: To assess the efficacy of different retreatment rotary files in removing gutta-percha and endodontic sealer from canals. METHODOLOGY: Ninety straight single-rooted premolars were prepared up to a size 30 and filled with gutta percha and sealer and then randomly assigned to six retreatment groups (n = 15). Groups I, III, and V were retreated using rotary systems ProTaper Universal Retreatment (PTUR), D-RaCe, and Mtwo Retreatment, respectively. Groups II, IV, and VI were retreated using the additional instruments F4, size 40, .04 taper RaCe, and size 40, .04 taper Mtwo, respectively. The roots were split vertically, and images of the halves were obtained using a high-resolution scanner and evaluated with AutoCAD software to calculate the percentage of residual material. Data were analyzed with Kruskal-Wallis and Student-Newman-Keuls tests using a 5% significance cutoff (P < 0.05). RESULTS: There were no statistically significant differences (P > 0.05) between groups when additional instruments were used. The percentage of residual material was lowest in the PTUR group and was statistically significant only when compared to the D-RaCe system (P = 0.0038). CONCLUSIONS: All root canals had residual filling material after retreatment even when additional instruments were used. PMID- 22486935 TI - A novel approach for intracellular 3D immuno-labeling for electron tomography. AB - Electron tomography (ET) is an indispensable high-resolution tool for three dimensional (3D) imaging in cell biology. When applied to immuno-labeled cells, ET can provide essential insights in both the cellular architecture and the dynamics. Current protocols for 3D immuno-labeling of intracellular antigens include permeabilization steps that cause random, extensive cell membrane disruption. This permeabilization results in a poor cell ultrastructure, limiting the usefulness of the specimens for high-resolution studies. Here we describe a novel method, based on a well-controlled permeabilization by targeted laser cell perforation, that allows for the 3D immuno-localization of cytoplasmic antigens in cultured cells. The approach is unique since it is applicable to both chemically and cryo-fixed cells and leads to a superior ultrastructural preservation for electron microscopy and tomography. PMID- 22486934 TI - Agrobacterium tumefaciens can obtain sulphur from an opine that is synthesized by octopine synthase using S-methylmethionine as a substrate. AB - Agrobacterium tumefaciens incites plant tumours that produce nutrients called opines, which are utilized by the bacteria during host colonization. Various opines provide sources of carbon, nitrogen and phosphorous, but virtually nothing was previously known about how A. tumefaciens acquires sulphur during colonization. Some strains encode an operon required for the catabolism of the opine octopine. This operon contains a gene, msh, that is predicted to direct the conversion of S-methylmethionine (SMM) and homocysteine (HCys) to two equivalents of methionine. Purified Msh carried out this reaction, suggesting that SMM could be an intermediate in opine catabolism. Purified octopine synthase (Ocs, normally expressed in plant tumours) utilized SMM and pyruvate to produce a novel opine, designated sulfonopine, whose catabolism by the bacteria would regenerate SMM. Sulfonopine was produced by tobacco and Arabidopsis when colonized by A. tumefaciens and was utilized as sole source of sulphur by A. tumefaciens. Purified Ocs also used 13 other proteogenic and non-proteogenic amino acids as substrates, including three that contain sulphur. Sulfonopine and 11 other opines were tested for induction of octopine catabolic operon and all were able to do so. This is the first study of the acquisition of sulphur, an essential element, by this pathogen. PMID- 22486936 TI - Ichthyosporidium weissii n. sp. (Microsporidia) infecting the arrow goby (Clevelandia ios). AB - Gonadal infections by a novel microsporidium were discovered in 34% (13/38) of arrow gobies, Clevelandia ios, sampled over a 3-yr period from Morro Bay Marina in Morro Bay, California. Gonadal tumors had been reported in arrow gobies from this geographic area. The infected gonads, found primarily in females, typically appeared grossly as large, white-gray firm and lobulated masses. Histological examination revealed large, multilobate xenomas within the ovaries and no evidence of neoplasia. Typical of the genus Ichthyosporidium, the large xenomas were filled with developmental stages and pleomorphic spores. Wet mount preparations showed two general spore types: microspores with mean length of 6.2 (7.0-4.9, SD = 0.6, N = 20) MUm and mean width of 4.3 (5.3-2.9, SD = 0.8) MUm; and less numerous macrospores with mean length of 8.5 (10.1-7.1, SD = 1.0, N = 10) MUm and mean width of 5.5 (6.2-4.8, SD = 0.5) MUm. Transmission electron microscopy demonstrated stages consistent with the genus and 35-50 turns of the polar filament. Small subunit rDNA gene sequence analysis revealed that the parasite from arrow gobies was most closely related to, but distinct from Ichthyosporidium sp. based on sequences available in GenBank. We conclude that this microsporidium represents a new species of Ichthyosporidium, the first species of this genus described from a member of the family Gobiidae and from the Pacific Ocean. PMID- 22486937 TI - Is ethnicity associated with morphine's side effects in children? Morphine pharmacokinetics, analgesic response, and side effects in children having tonsillectomy. AB - OBJECTIVES/AIMS: To examine whether morphine pharmacokinetics (PK) and/or genetic polymorphisms in opioid-related genes, underlie differences in analgesic response and side effects to morphine in Latino (L) vs non-Latino Caucasian (NL) children. BACKGROUND: Morphine has high interindividual variability in its analgesic response and side effects profile. Earlier studies suggest that morphine response may vary by race and ethnicity. METHODS: Prospective cohort study in L and NL children, 3-17 years of age comparing pain scores, occurrence of side effects, plasma morphine, morphine-6- and morphine-3-glucuronide concentrations measured after a single morphine IV bolus administration. Noncompartmental pharmacokinetic analysis and genotyping for 28 polymorphisms in eight genes (UGT1A8, UGT2B7, ABCB1, COMT, STAT6, MC1R, OPRM1, and ARRB2) were performed. RESULTS: We enrolled 68 children (33 L, 35 NL). There were no differences in pain scores or need for rescue analgesia. Statistically significant differences in the occurrence of side effects were documented: While 58% of L children experienced at least one side effect only 20% of NL did (P = 0.001). Pruritus was four times (P = 0.006) and emesis seven times (P = 0.025) more frequent in L compared with NL. PK parameters were similar between groups. None of the assessed polymorphisms mediated the association between ethnicity and side effects. CONCLUSIONS: We found statistically significant differences in the occurrence of side effects after morphine administration between L and NL children. Neither differences in morphine or metabolite concentrations, nor the genetic polymorphisms examined explain these findings. Studies are needed to further investigate reasons for the increase in morphine side effects by Latino ethnicity. PMID- 22486938 TI - Aggression in a high secure hospital: staff and patient attitudes. AB - Responding to aggressive behaviour is a key activity for nurses and other care staff in high secure hospitals. The attitudes and beliefs of staff regarding patient aggression will influence the management strategies they adopt. Patients will also hold attitudes regarding the causes of and best ways to respond to aggressive behaviour. This study measured the attitudes towards aggression of staff (n= 109) and patients (n= 27) in a high secure hospital in the UK using the Management of Aggression and Violence Attitude Scale (MAVAS). There was considerable concordance of views, staff and patients disagreeing on only two items on the MAVAS. Aggression was felt to have a range of causes, embracing factors internal to the person, factors in the external environment and situational or interactional factors. Interpersonal means of managing aggression were supported, but both staff and patients also advocated the use of controlling management strategies such as medication, seclusion and restraint. The implications of these findings for aggression management in high secure settings are discussed in the light of best practice guidelines that promote interpersonal approaches over controlling strategies. PMID- 22486940 TI - A proteomics approach reveals divergent molecular responses to salinity in populations of European whitefish (Coregonus lavaretus). AB - Osmoregulation is a vital physiological function for fish, as it helps maintain a stable intracellular concentration of ions in environments of variable salinities. We focused on a primarily freshwater species, the European whitefish (Coregonus lavaretus), to investigate the molecular mechanisms underlying salinity tolerance and examine whether these mechanisms differ between genetically similar populations that spawn in freshwater vs. brackishwater environments. A common garden experiment involving 27 families in two populations and five salinity treatments together with a large-scale, high-resolution mass spectrometry experiment that quantified 1500 proteins was conducted to assess phenotypic and proteomic responses during early development, from fertilization until hatching, in the studied populations. The populations displayed drastically different phenotypic and proteomic responses to salinity. Freshwater-spawning whitefish showed a significantly higher mortality rate in higher salinity treatments. Calcium, an ion involved in osmotic stress sensing, had a central role in the observed proteomic responses. Brackishwater-spawning fish were capable of viable osmoregulation, which was modulated by cortisol, an important seawater-adaptation hormone in teleost fish. Several proteins were identified to play key roles in osmoregulation, most importantly a highly conserved cytokine, tumour necrosis factor, whereas calcium receptor activities were associated with salinity adaptation. These results imply that individuals from these populations are most likely adapted to their local environments, even though the baseline level of genetic divergence between them is low (F(ST)=0.049). They also provide clues for choosing candidate loci for studying the molecular basis of salinity adaptation in other species. Further, our approach provides an example of how proteomic methods can be successfully used to obtain novel insights into the molecular mechanisms behind adaptation in non-model organism. PMID- 22486939 TI - An important role for autoimmunity in the immunopathogenesis of chronic allograft rejection. AB - Organ transplantation is the treatment of choice for patients with end-stage organ dysfunction. In spite of advances in understanding of donor and recipient physiology, organ preservation, operative techniques and immunosuppression, long term graft survival still remains a major problem primarily due to chronic rejection. Alloimmune responses to mismatched major histocompatibility antigens have been implicated as an important factor leading to rejection. However, there is increasing evidence pointing towards cross-talk between the alloimmune and autoimmune responses creating a local inflammatory milieu, which eventually leads to fibrosis and occlusion of the lumen in the transplanted organ i.e. chronic rejection. In this review, we will discuss recent studies and emerging concepts for the interdependence of alloimmune and autoimmune responses in the immunopathogenesis of chronic allograft rejection. The role of autoimmunity in the development of chronic rejection is an intriguing and exciting area of research in the field of solid-organ transplantation with a significant potential to develop novel therapeutic strategies towards preventing chronic allograft rejection. PMID- 22486942 TI - Meticillin-resistant Staphylococcus pseudintermedius: clinical challenge and treatment options. AB - Meticillin-resistant Staphylococcus pseudintermedius (MRSP) has emerged as a major therapeutic challenge for small animal veterinarians over the past 10 years and continues to spread worryingly in many countries. This review focuses on the clinical aspects of MRSP infections seen in patients with skin disease and on currently available treatment options. In addition, it discusses the implications for in-contact people, other animals and the environment, because infection control strategies are likely to have a significant impact on treatment success and prevention of spread. There is currently no indication that MRSP is more virulent than meticillin-susceptible S. pseudintermedius, and reported infections have mostly been treated successfully, although possibly with a longer time to resolution than infections with more susceptible S. pseudintermedius. However, in vitro testing of MRSP isolates indicates resistance to most or all antibacterial agents licensed for use in pets. Based on susceptibility results, the most useful systemic antimicrobials may include chloramphenicol, rifampicin, amikacin, clindamycin and/or minocycline. Adverse effects of some of these medications may limit their usefulness. While in vitro susceptibility to vancomycin and linezolid is reported by some laboratories, use of these drugs in animals is strongly discouraged because of ethical considerations. Aggressive topical therapy has been effective as the only treatment in certain cases. Awareness, continued research and comprehensive management of infections are required by veterinary practitioners not only to help treat infected animals but also to limit the spread and prevent the establishment of this highly drug-resistant and zoonotic pathogen in veterinary facilities and in the community. PMID- 22486941 TI - Immunohistochemical detection of piscine reovirus (PRV) in hearts of Atlantic salmon coincide with the course of heart and skeletal muscle inflammation (HSMI). AB - Aquaculture is the fastest growing food production sector in the world. However, the increased production has been accompanied by the emergence of infectious diseases. Heart and skeletal muscle inflammation (HSMI) is one example of an emerging disease in farmed Atlantic salmon (Salmo salar L). Since the first recognition as a disease entity in 1999 it has become a widespread and economically important disease in Norway. The disease was recently found to be associated with infection with a novel reovirus, piscine reovirus (PRV). The load of PRV, examined by RT-qPCR, correlated with severity of HSMI in naturally and experimentally infected salmon. The disease is characterized by epi-, endo- and myocarditis, myocardial necrosis, myositis and necrosis of the red skeletal muscle. The aim of this study was to investigate the presence of PRV antigens in heart tissue of Atlantic salmon and monitor the virus distribution in the heart during the disease development. This included target cell specificity, viral load and tissue location during an HSMI outbreak. Rabbit polyclonal antisera were raised against putative PRV capsid proteins MU1C and sigma1 and used in immunohistochemical analysis of archived salmon heart tissue from an experimental infection. The results are consistent with the histopathological changes of HSMI and showed a sequential staining pattern with PRV antigens initially present in leukocyte-like cells and subsequently in cardiomyocytes in the heart ventricle. Our results confirm the association between PRV and HSMI, and strengthen the hypothesis of PRV being the causative agent of HSMI. Immunohistochemical detection of PRV antigens will be beneficial for the understanding of the pathogenesis of HSMI as well as for diagnostic purposes. PMID- 22486943 TI - Interrelationships among physical activity, depression, homocysteine, and metabolic syndrome with special considerations by sex. AB - OBJECTIVE: Examine the interrelationships among physical activity, depression, homocysteine and metabolic syndrome, and to examine the association between physical activity and the simultaneous presence of metabolic syndrome, depression, and high homocysteine. METHODS: Data from the 2005-2006 National Health and Nutrition Examination Survey were used. 1146 participants were included in the analyses. Physical activity was objectively measured using accelerometry. RESULTS: With respect to the association between physical activity and the simultaneous presence of these three co-morbidities, women, compared to men, had a greater strength of association. For women, compared to those participants not having metabolic syndrome or at least mild depression or high homocysteine (reference groups), the odds ratio values for participants with 1) only depression, 2) only metabolic syndrome, 3) only high homocysteine, 4) metabolic syndrome and mild depression, and 5) metabolic syndrome, mild depression and high homocysteine, respectively, were 0.74 (95% confidence interval: 0.57-0.96, 0.77 (95% confidence interval: 0.61-0.97), 1.08 (95% confidence interval: 0.66-1.76), 0.43 (95% confidence interval: 0.32-0.58), and 0.15 (95% confidence interval: 0.05-0.44), respectively. CONCLUSION: Promotion of physical activity in the adult population, especially among women, who were found to be less moderately- to vigorously-physically active than their male counterparts, may play an important role in reducing these deleterious conditions. PMID- 22486944 TI - Effect of magnetite nanoparticles on living rate of MCF-7 human breast cancer cells. AB - Superparamagnetic and ferromagnetic magnetite nanoparticles, with diameters of approximately 13 and 44 nm, respectively, were synthesized and their uptake amount and heating efficiency were evaluated for application to magnetic hyperthermia. Both nanoparticles had almost the same zeta-potential (+10.2 mV) and hydrodynamic size (~1 MUm) and there was no significant difference in their uptake amount 18 h after they were added to the medium. After internalization, the ferromagnetic nanoparticles incorporated in human breast cancer cells (MCF-7) showed a higher heating efficiency than the superparamagnetic nanoparticles when an external magnetic field (4 kW, 250 kHz) high enough to produce heat by hysteresis loss was applied, followed by cellular death of MCF-7 with high ferromagnetic nanoparticle content. PMID- 22486945 TI - Ectopic production of hair keratin constitutes Rushton's hyaline bodies in association with hematogenous deposits. AB - A Rushton's hyaline body (HB) is a concretion occasionally found in odontogenic cysts. Unspecified substances produced by the lining epithelium or derived from blood components have been suggested as possible causes of HB formation, but the origin of HBs is still elusive. This study aimed to clarify the origin of HBs. Ten specimens with HBs were obtained from 400 odontogenic cysts. HBs were stained by orcein and Congo red. Immunohistochemical examination revealed that HBs were positive for hair keratin and keratin 17. Hair keratin was concentrated in HBs, and cells with hair keratin expression were hardly seen, while cells with keratin 17 expression were observed near HBs. HBs were also positive for hemoglobin alpha chain. The presence of hair keratin in HBs was confirmed by Western blot analysis. The present study suggests that HBs are formed as a consequence of two independent events: unusual alteration of epithelial differentiation so as to provide hair keratin, and hemorrhage so as to provide erythrocytic substances. Although the ectopic production of hair keratin appears more essential, our results reconcile the long-standing debate between two theories, the keratin theory versus the hematogenous theory, concluding that both substances are required for the genesis of HBs, and also suggesting that they might be novel non pathological amyloidogenic proteins. PMID- 22486946 TI - Predictors of PTSD trajectories following captivity: a 35-year longitudinal study. AB - Although war captivity is a potent pathogen for psychiatric illness, little is known about the long-term trajectories of post-traumatic stress disorder (PTSD) among ex-prisoners of wars (ex-POWs). This study aimed to assess the long-term trajectories of PTSD and their predictors following war captivity. Three follow ups (1991, 2003, 2008) were conducted over 35 years of 164 Israeli ex-POWs and185 comparable combatants from the 1973 Yom Kippur War. Ex-POWs reported higher PTSD rates than controls at all three assessments. Four trajectories of PTSD were identified: chronic PTSD, delayed PTSD, recovery and resilience. The majority of POWs reported delayed PTSD, while the majority of controls were classified as resilient. While PTSD rates remained relatively stable over time among controls, a steep increase in rates was observed among POWs between 1991 and 2003, followed by stabilization in rates between 2003 and 2008. Finally, subjective experience of captivity was the variable that best distinguished between the resilience and PTSD groups of ex-POWs, followed by participation in previous wars and negative life events during childhood. War captivity carries long-lasting psychiatric implications, even decades after release. Aging processes, as well as unique stressors that exist in Israel, may account for the elevated PTSD rates found here. PMID- 22486947 TI - Twice versus thrice weekly ECT in a clinical population: an evaluation of patient outcomes. AB - Increasing demand on electroconvulsive therapy (ECT) services led to a recommendation that low risk patients be considered for twice weekly ECT rather than the usual thrice weekly. We evaluated whether practice changed and compared patient clinical outcomes for twice and thrice weekly ECT. Medical records for all patients receiving ECT in the 2-year study period (1/9/08 to 30/8/10) were reviewed to determine ECT protocol, diagnosis, admission duration and readmission rates. During the study period, 119 patients received 150 treatment courses. Patient outcomes were compared for twice weekly ECT and thrice weekly ECT protocols, as well as for 1 year before and after the recommendation (1/9/09). Twice weekly ECT courses increased (8-20) after the recommendation while thrice weekly ECT courses decreased (64-30). The recommendation had no significant effect on patient outcomes. Comparing twice and thrice weekly ECT, patient clinical outcomes were similar between the two groups, though non-affective twice weekly patients waited longer before starting ECT. In the context of resource constraints, psychiatrists can be influenced to examine and change their ECT prescribing practice. This bodes well for the implementation of evidence-based treatment into mental health services. Secondly, for adults, there appear to be no significant differences in clinical outcomes for twice versus thrice weekly ECT. PMID- 22486948 TI - A randomized, placebo-controlled trial of vitamin D supplementation to improve glycaemia in overweight and obese African Americans. AB - AIMS: Vitamin D deficiency may increase the risk for type 2 diabetes. African Americans tend to have poor vitamin D status and increased risk of diabetes, but effects of vitamin D supplementation on components of diabetes risk have not been tested in this group. This study was conducted to determine whether vitamin D supplementation improves insulin secretion, insulin sensitivity and glycaemia in African Americans with prediabetes or early diabetes. METHODS: In this randomized, placebo-controlled trial, we examined the effect of 4000 IU/day vitamin D(3,) on glycaemia and contributing measures including insulin secretion, insulin sensitivity and the disposition index over 12 weeks in 89 overweight or obese African Americans with prediabetes or early diabetes. Outcome measures were derived from oral glucose tolerance testing. RESULTS: Mean plasma 25 hydroxyvitamin D was about 40 nmol/l in the placebo and vitamin D groups at baseline and increased to 81 nmol/l with supplementation. Insulin sensitivity decreased by 4% in the vitamin D group compared with a 12% increase in the placebo group (p = 0.034). Insulin secretion increased by 12% in the vitamin D group compared with a 2% increase in the placebo group (p = 0.024), but changes in the disposition index were similar across groups. There was no effect of supplementation on post-load glucose or other measures of glycaemia. CONCLUSIONS: Supplementation with 4000 IU/day vitamin D(3) successfully corrected vitamin D insufficiency and had divergent effects on insulin secretion and sensitivity with no overall effect on disposition index or glycaemia. In this study, vitamin D supplementation for 3 months did not change the pathophysiology of prediabetes in overweight and obese African Americans. PMID- 22486949 TI - Intra- and inter-observer reliability of the application of the cellulite severity scale to a Spanish female population. AB - BACKGROUND: 'Hexsel, dal'Forno and Hexsel Cellulite Severity Scale' (CSS) was developed to evaluate cellulite with an objective and easy to apply tool. Objective Study CSS intra- and inter-observer reliability in a Spanish female population by evaluating patients' cellulite through photographs of their overall gluteofemoral zone as opposed to its creators who distinguished between buttocks and thigh. METHODS: Cellulite Severity Scale was applied to 27 women, evaluating gluteofemoral cellulite, differentiating between left and right. Evaluations were made by three expert examiners each at three times with a 1-week separation. Variables were the five CSS dimensions (number of evident depressions; depth of depressions; morphological appearance of skin surface alterations; grade of laxity, flaccidity, or sagging skin; and the Nurnberger and Muller classification scale), and the overall CSS score. Cronbach's alpha, intra-class correlation and item total correlation were analysed. RESULTS: Cronbach's alpha values were 0.951 (right) and 0.944 (left). In the intra-observer reliability analysis, intra-class correlation coefficient ranged from 0.993 to 0.999 (P < 0.001) and in the inter observer analysis were 0.937 (right) and 0.947 (left) (P < 0.001). Item total correlation showed all dimensions to be needed except grade of laxity, flaccidity or sagging skin (0.959 right; 0.955 left). CONCLUSION: Cellulite Severity Scale has excellent reliability and internal consistency when used to evaluate cellulite on the buttocks and back of the thighs considered together. Nevertheless, the dimension grade of laxity, flaccidity or sagging skin does not contribute positively to the final consistency of the scale. This dimension needs to be analysed in greater depth in future studies. PMID- 22486950 TI - Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients. AB - Voriconazole is commonly used for prophylaxis and treatment of invasive aspergillosis in lung transplant recipients. However, the use of voriconazole may at times be limited by the development of hepatotoxicity. Our goal is to determine predictors of voriconazole-associated hepatotoxicity in lung transplant recipients. We conducted a single center retrospective cohort study of lung transplant recipients from 2006 to 2010 who received voriconazole therapy. We compared characteristics of patients who developed hepatotoxicity and those who did not. One hundred five lung transplant recipients received voriconazole. Hepatotoxicity occurred in 51% (54/105) of patients and lead to discontinuation in 34% (36/105). In univariate analysis, age less than 40 years, cystic fibrosis, use of azathioprine, history of liver disease and early initiation of voriconazole were associated with hepatotoxicity. In multivariable logistic regression analysis, perioperative initiation of voriconazole (within 30 days of transplantation) was independently associated with hepatotoxicity (OR 4.37, 95% CI: 1.53-12.43, p = 0.006). The five risk factors identified in the univariate analysis were used to build a K-nearest neighbor algorithm predictive model for hepatotoxicity. This model predicted hepatotoxicity with an accuracy of 70%. Voriconazole therapy initiated within the first 30 days of transplantation is associated with a greater risk of developing hepatotoxicity. PMID- 22486951 TI - Importance of the effective strong ion difference of an intravenous solution in the treatment of diarrheic calves with naturally acquired acidemia and strong ion (metabolic) acidosis. AB - BACKGROUND: The effect of sodium bicarbonate on acid-base balance in metabolic acidosis is interpreted differently by Henderson-Hasselbalch and strong ion acid base approaches. Application of the traditional bicarbonate-centric approach indicates that bicarbonate administration corrects the metabolic acidosis by buffering hydrogen ions, whereas strong ion difference theory indicates that the co-administration of the strong cation sodium with a volatile buffer (bicarbonate) corrects the strong ion acidosis by increasing the strong ion difference (SID) in plasma. OBJECTIVE: To investigate the relative importance of the effective SID of IV solutions in correcting acidemia in calves with diarrhea. ANIMALS: Twenty-two Holstein-Friesian calves (4-21 days old) with naturally acquired diarrhea and strong ion (metabolic) acidosis. METHODS: Calves were randomly assigned to IV treatment with a solution of sodium bicarbonate (1.4%) or sodium gluconate (3.26%). Fluids were administered over 4 hours and the effect on acid-base balance was determined. RESULTS: Calves suffered from acidemia owing to moderate to strong ion acidosis arising from hyponatremia and hyper-D-lactatemia. Sodium bicarbonate infusion was effective in correcting the strong ion acidosis. In contrast, sodium gluconate infusion did not change blood pH, presumably because the strong anion gluconate was minimally metabolized. CONCLUSIONS: A solution containing a high effective SID (sodium bicarbonate) is much more effective in alkalinizing diarrheic calves with strong ion acidosis than a solution with a low effective SID (sodium gluconate). Sodium gluconate is ineffective in correcting acidemia, which can be explained using traditional acid base theory but requires a new parameter, effective SID, to be understood using the strong ion approach. PMID- 22486952 TI - [Analysis of experience in the use of dynamic pelvic magnetic resonance imaging in the assessment of obstructive defaecation syndrome]. AB - INTRODUCTION: The aetiological diagnosis of obstructive defaecation syndrome (ODS) requires, among others, imaging tests. The purpose of this study is to descriptively analyse and compare the findings of dynamic pelvic magnetic resonance imaging (DPMRI) with the clinical examinations in patients with ODS. MATERIAL AND METHODS: A prospective comparative study was made between the physical examination and the DPMRI, with a descriptive analysis of the results. A total of 30 patients were included (2 males and 28 females), with a median age of 60 (range 23-76) years, with symptoms of ODS. An anamnesis and detailed physical examination and a DPMRI were performed on all of them. Functional (anismus) and morphological changes (rectocele, enterocele, intussusception, etc.), were analysed. RESULTS: The physical examination did not detect anomalies in 6 (20%) patients. A rectocele was diagnosed in 21 (70%) of the cases, and 2 (6.7%) a rectal mucosal prolapse. The DPMRI showed evidence of pelvic floor laxity in 22 (73.3%) cases, an enterocele in 4 (13.3%), a sigmoidocele in 2 (6.7%), intussusception in 8 (26.7%), rectal mucosal prolapse in 4 (13.3%), anismus in 3 (10%), and a cystocele in 4 (13.3%). The rectocele was the most frequent diagnosis, being given in 26 (86.6%) patients. CONCLUSIONS: Magnetic resonance imaging provides an overall pelvic assessment with good definition of the tissues, and does not use ionising radiation, is well tolerated, and provides us with complementary information to arrive at the diagnosis, and establish the best treatment for ODS. Larger studies comparing videodefaecography (VD), currently considered the Gold Standard technique, are needed to be able to demonstrate whether it is superior or not to DPMRI. PMID- 22486953 TI - Penetration and release studies of positively and negatively charged nanoemulsions--is there a benefit of the positive charge? AB - The surface of all tissues, including the stratum corneum, carries a negative charge. Following that fact it is assumed that a positively charged topical formulation could lead to an enhanced penetration because of an increased interaction with the negative charge of the membrane. The intention of this study is to prove an enhanced penetration of a positively charged nanoemulsion compared to a negatively charged nanoemulsion, both containing prednicarbate. The release and penetration of these nanoemulsions, produced with the high pressure homogenization method, were investigated. Regarding these results reveals that the release of the negatively charged formulation is higher compared to the positively charged nanoemulsion, while the penetration of the positively charged nanoemulsion is enhanced compared to the negatively charged formulation. The results of the investigated positively charged nanoemulsion containing prednicarbate show that its topical use could be advantageous for the therapy of atopic dermatitis, especially regarding phytosphingosine, which was responsible for the positive charge. PMID- 22486954 TI - A biorelevant in vitro release/permeation system for oral transmucosal dosage forms. AB - This research describes the development and validation of a biorelevant in vitro release/permeation system to predict the in vivo performance of oral transmucosal dosage forms. The system is a biorelevant bidirectional transmucosal apparatus which allows better simulation of oral cavity physiological variables in comparison to compendial dissolution apparatuses and therefore may be a better predictor of in vivo behavior. The feasibility of the bidirectional apparatus was studied using smokeless tobacco (snus) as a model oral transmucosal product. In this research, nicotine release and permeation was investigated from commercially available snus using a modified USP IV flow-through apparatus, a commercially available vertical diffusion cell and a fabricated novel bidirectional transmucosal apparatus. The percent nicotine released/permeated was utilized as an input function for the prediction of in vivo plasma nicotine profiles by back calculation based on the Wagner-Nelson method. The prediction errors in C(max) and AUC(0-infinity) with the USP IV flow-through device, vertical diffusion cell and novel apparatus were 4.03, 22.85 and 1.59 and -5.85, 5.85 and -9.27% respectively. This work demonstrated the suitability of the novel bidirectional transmucosal apparatus for predicting the in vivo behavior of oral transmucosal products. PMID- 22486956 TI - On the size and shape dependence of the solubility of nano-particles in solutions. AB - The general equation is derived for the equilibrium of a small solid particle and a large solution, being consistent with the thermodynamics of Gibbs. This equation can be solved in a closed form for solubility if an ideal (or an infinitely diluted) solution is considered, if the interfacial energy is independent of the composition of the solution and if all physical parameters (other than the solubility itself) are taken size independent. The solubility of the particles is found to increase with increasing its specific surface area, i.e. if non-spherical particles are applied. This simplified solution further simplifies if the shape of the solid is supposed to be spherical. This latter equation, however, is found to be in contradiction with the Ostwald-Freundlich equation, widely used in chemistry, biology and materials science to describe the size dependence of solubility of a spherical crystal. The reason for its incorrectness is shown to be due to the incorrect application of the Laplace equation. It is found that the solubility increases with decreasing the size of the dissolving phase not due to the increased curvature of the phase (Kelvin and Freundlich), but rather due to the increased specific surface area of the phase (Gibss, Ostwald). Equations are also derived for the case, when the size effect of the interfacial energy is taken into account, and when the crystal is surrounded by several planes of different interfacial energies. The role of wettability is discussed on the size dependence of solubility. PMID- 22486955 TI - Characterisation of protein stability in rod-insert vaginal rings. AB - A major goal in vaccine development is elimination of the 'cold chain', the transport and storage system for maintenance and distribution of the vaccine product. This is particularly pertinent to liquid formulation of vaccines. We have previously described the rod-insert vaginal ring (RiR) device, comprising an elastomeric body into which are inserted lyophilised, rod-shaped, solid drug dosage forms, and having potential for sustained mucosal delivery of biomacromolecules, such as HIV envelope protein-based vaccine candidates. Given the solid, lyophilised nature of these insert dosage forms, we hypothesised that antigen stability may be significantly increased compared with more conventional solubilised vaginal gel format. In this study, we prepared and tested vaginal ring devices fitted with lyophilised rod inserts containing the model antigen bovine serum albumin (BSA). Both the RiRs and the gels that were freeze-dried to prepare the inserts were evaluated for BSA stability using PAGE, turbidimetry, microbial load, MALDI-TOF and qualitative precipitate solubility measurements. When stored at 4 degrees C, but not when stored at 40 degrees C/75% RH, the RiR formulation offered protection against structural and conformational changes to BSA. The insert also retained matrix integrity and release characteristics. The results demonstrate that lypophilised gels can provide relative protection against degradation at lower temperatures compared to semi-solid gels. The major mechanism of degradation at 40 degrees C/75% RH was shown to be protein aggregation. Finally, in a preliminary study, we found that addition of trehalose to the formulation significantly reduces the rate of BSA degradation compared to the original formulation when stored at 40 degrees C/75% RH. Establishing the mechanism of degradation, and finding that degradation is decelerated in the presence of trehalose, will help inform further development of RiRs specifically and polymer based freeze-dried systems in general. PMID- 22486957 TI - Ambiguous effect of dendrimer PAMAM G3 on rat heart respiration in a model of an experimental diabetes - Objective causes of laboratory misfortune or unpredictable G3 activity? AB - Poly(amido)amine (PAMAM) dendrimer G3 was investigated for its ability to support the proper functioning of rat heart mitochondria exposed to hyperglycemia, in both the in vitro and in vivo experiments. The main aims of this study were to check whether PAMAM G3 dendrimer improves the efficiency of the impaired respiration of rat heart mitochondria. This study showed that mitochondria isolated from animals studied in different seasons respond to G3 (100 MUM) exposure to a different extent. Probably, seasonal variations had the impact on rat metabolism and consequently on the received data. The used biological samples formed a heterogenous group and therefore the obtained results were not pooled together but treated separately. Nevertheless, the in vitro part of this study revealed that PAMAM G3 could be successfully used in the protection of heart mitochondria against MG-induced impaired respiratory activity. Despite these promising data, the protective effect of G3 was not confirmed in the in vivo experiment. This study revealed that dendrimer G3 (20 mg/kgbw) is toxic and very high mortality among the animals administered with G3 did not allow to perform a reliable data analysis. PMID- 22486958 TI - The fractal hologram and elucidation of the structure of liposomal carriers in aqueous and biological media. AB - The present study deals with the physicochemical characterization (size, polydispersity, zeta-potential) of dipalmitoylphosphatidylcholine (DPPC) liposomes and DPPC:cholesterol (chol) (9:1 molar ratio) liposomes, and the determination of their fractal dimension (mass fractal (d(f)) and surface fractal (d(s))), in an aqueous (HPLC grade water) and in a biological (fetal bovine serum - FBS) medium. Dynamic, static and electrophoretic light scattering and fluorescence spectroscopy are used as experimental techniques to elucidate the structure and physicochemical parameters of liposomes in an ageing study in two different media, as well as their structural response in changes in concentration and temperature. The extended DLVO theory would be the tool to explain the phenomenology of the colloidal behavior in these systems and of their aggregation process. The fractal dimensionality of DPPC liposomes was decreased while for DPPC:cholesterol (9:1) it remained unaffected in the two dispersion media. The structure of the liposomal systems, the process kinetics, and the fractal dimension are consistent with the diffusion-limited cluster aggregation (DLCA) and reaction-limited cluster aggregation (RLCA) models. On the contrary, hydrodynamic radius (R(h)) was found to be stable during the variations of colloidal system conditions, especially due to concentration changes. Finally, we suggest that this study can be a rational road map to design advanced Drug Delivery nano Systems (aDDnSs) with improved pharmacokinetic profile which could be considered as crucial for their effectiveness. PMID- 22486959 TI - Enhancement and restriction of chain motion in polymer networks. AB - Sevelamer carbonate, a polymeric drug, adsorbs phosphate ions from the gastro intestine of patients suffering from chronic kidney disease. Polymer chain mobility becomes critical during its manufacture and storage. How the polymer chain mobility in sevelamer carbonate is quantitatively controlled by small molecular species, in this case by water molecules and bicarbonate anions, is demonstrated here. Spin-lattice relaxation times of the protons in the hydrogel, detected by solid state NMR, are indicative of mobility within the polymer. They decreased with increasing water content but increased as the bicarbonate anion content increased. As the water content increased, the glass transition temperature decreased but increasing the bicarbonate anion content had the opposite effect. FTIR analysis indicated that the anions were involved in bonding while the water molecules were not. The stability and physicochemical properties of polymers during storage and formulation depend on the polymeric structure and the dynamic behaviour of the polymer chains. PMID- 22486960 TI - Fabrication of inhalable spore like pharmaceutical particles for deep lung deposition. AB - An innovative strategy of fabricating uniform spore like drug particles to improve pulmonary drug delivery efficiency was disclosed in the present study. Spore like particles were prepared through combination of high gravity controlled precipitation and spray drying process with insulin as model drug first, showing rough surface and hollow core. The shell of such spore-like particle was composed of nanoparticles in loose agglomerate and could form nanosuspension upon contacting antisolvent. Further characterization confirmed secondary structure and bio-activity was well preserved in spore like particles of insulin. Stable aerosol performance at different dosages with fine powder fraction (FPF) of 80% and comparable FPF (69-76%) for formulated powder were achieved, significantly higher than marketed product Exubera. On the other hand spore like particles of bovine serum albumin, lysozyme and salbutamol sulfate showed similar high FPF of 80%, regardless of different shape of primary nanoparticles, indicating various application of this new process in significant improvement of pulmonary drug delivery. PMID- 22486961 TI - The development and registration of topical pharmaceuticals. AB - From our own experience we have seen that over the past 60 years topical delivery of drugs with its advantages and disadvantages has become much more widely understood and much more is now known about the disposition of drugs in the skin. Today, pharmaceutical scientists produce dermatological vehicles which are tailored to patients' needs and better appreciate how the formulation may affect rates of drug delivery, and ultimately, efficacy and safety. The guidelines for developing a New Chemical Entity (NCE) to be administered by the topical route are rather straightforward. What appears to be less well understood are the pathways for development, and the regulatory routes for topical formulations of a known established Active Pharmaceutical Ingredient (API) either in a new formulation, at a different concentration, or with APIs where topical administration is an alternative route of administration. This article provides guidance, on the regulatory routes which can help achieve marketing approval in Europe for topical formulations, with particular emphasis on clinical development. Some comments on NCE's will be given, and further detail is provided in cases where the topical route is a new method of administration for delivering a known API. PMID- 22486962 TI - Development of a quercetin-loaded nanostructured lipid carrier formulation for topical delivery. AB - The main objective of this study was to evaluate the potential of quercetin loaded nanostructured lipid carriers (QT-NLCs) as a topical delivery system. QT NLCs were prepared by the method of emulsion evaporation-solidification at low temperature. The average entrapment efficiency and drug loading of the optimized QT-NLCs were 89.95 +/- 0.16% and 3.05 +/- 0.01%, respectively. Under the transmission electron microscope, the nanoparticles were spherically shaped. The average particle size was 215.2 nm, the zeta potential was -20.10 +/- 1.22 mV and pH value of QT-NLCs system was 4.65. Topical delivery of QT in the form of NLCs was investigated in vitro and in vivo. The results showed that QT-NLCs could promote the permeation of QT, increase the amount of QT retention in epidermis and dermis, and enhance the effect of anti-oxidation and anti-inflammation exerted by QT. Then the mechanism of NLCs for facilitating drug penetration was further investigated through histological sections. In conclusion, NLCs could be a promising vehicle for topical delivery of QT. PMID- 22486963 TI - Self-assembled drug delivery systems. Part 6: in vitro/in vivo studies of anticancer N-octadecanoyl gemcitabine nanoassemblies. AB - The nanoassemblies were prepared from N-octadecanoyl gemcitabine (NOG)/cholesteryl succinyl poly(ethylene glycol) 1500 (CHS-PEG(1500)) (5:1, mol/mol). They showed higher cytotoxicity than gemcitabine on HpG2 cell model. The amphiphilicity of NOG may improve permeation of prodrugs and destruction of cell membrane. The nanoassemblies were rapidly eliminated from circulation after bolus intravenous administration to healthy and tumor-bearing mice. The in vivo distribution sites of NOG were mainly liver and spleen though the distribution in tumor was not high. The non-spherical shape and high surface charge of the nanoassemblies may affect distribution. The nanoassemblies had similar anticancer efficacy to free gemcitabine solutions when the former contained about 1/3 dose of the latter in gemcitabine form. The nanoassemblies would be a promising anticancer nanomedicine. PMID- 22486964 TI - Temozolomide loaded PLGA-based superparamagnetic nanoparticles for magnetic resonance imaging and treatment of malignant glioma. AB - Polysorbate 80 coated temozolomide-loaded PLGA-based superparamagnetic nanoparticles (P80-TMZ/SPIO-NPs) were successfully synthesized and characterized as drug carriers and diagnosis agent for malignant brain glioma. The mean size of P80-TMZ/SPIO-NPs was 220 nm with narrow hydrodynamic particle size distribution. The superparamagnetic characteristic of P80-TMZ/SPIO-NPs was proved by vibration simple magnetometer. P80-TMZ/SPIO-NPs exhibited high drug loading and encapsulation efficiency as well as good sustained drug release performance for 15 days. MTT assay demonstrated the antiproliferative effect of P80-TMZ/SPIO-NPs for C6 glioma cells. Significant cellular uptake of P80-TMZ/SPIO-NPs was evaluated in C6 glioma cells by fluorescence microscopy, Prussian blue staining, and atomic absorption spectrophotometer (AAS) for qualitative and quantitative study, respectively. MRI scanning analyses in vitro indicated that P80-TMZ/SPIO NPs could be used as a good MRI contrast agent. Polysorbate 80 coated temozolomide-loaded PLGA-based superparamagnetic nanoparticles could be able to promise a multifunctional theragnostic carrier of brain cancer. PMID- 22486965 TI - Characterization of agglomerated carvedilol by hot-melt processes in a fluid bed and high shear granulator. AB - The purpose of this study was to prepare and characterize granulated carvedilol by melt-in and spray-on melt granulation in a fluid bed and a high shear granulator. Granulates having comparable particle size distribution and good flow properties were obtained with proper adjustment of process parameters for each binder (poloxamer 188, polyethylene glycol 4000, and gliceryl monosterate), procedure (spray-on and melt-in) and equipment (fluid bed and high shear granulator). In-line probes for particle size measurements proved to be a useful tool for determining the end point of melt granulation. The product temperature during melt granulation was found to be the critical process parameter for achieving appropriate granulate particle size distribution. The results showed that melt granulation using hydrophilic binders is an effective method to improve the dissolution rate of carvedilol. The method of binder addition to the powders (melt-in or spray-on procedure) was found to strongly influence the dissolution rate of carvedilol. The highest dissolution rates were obtained when the spray-on procedure is used, independently from the type of granulator used. The results also suggest that the most probable explanation for the increase in the dissolution rate of granulated carvedilol is improvement of the wettability through intimate contact between hydrophilic binder and hydrophobic drug. PMID- 22486966 TI - Osteoprotegerin levels are increased in patients with venous thromboembolic disease. PMID- 22486967 TI - Improvement of A21978C production in Streptomyces roseosporus by reporter-guided rpsL mutation selection. AB - AIMS: Daptomycin, one of the A21978C factors produced by Streptomyces roseosporus, is an acidic cyclic lipopeptide antibiotic with potent activity against a variety of Gram-positive pathogens. To increase the titre of this extensively used and clinically important antibiotic, we applied a reported guided rpsL mutation selection system to generate strains producing high levels of A21978C. METHODS AND RESULTS: In the reporter design, dptE was chosen as the overexpressing target, and neo-encoding neomycin phosphotransferase as the reporter. Using this reporter-guided selection system, 20% of the selected, streptomycin-resistant mutants produced greater amounts of A21978C than the starting strain. The selection system increased the screening efficiency about 10 fold with a frequency of 1.7% A21978C overproducing strains among str(r) mutants. A21978C production was increased approximately 2.2-fold in the rpsL K43N mutant. CONCLUSIONS: The combination of ribosome engineering and reporter-guided mutant selection generated an A21978C overproducing strain that produced about twice as much A21978C as the parental strain. SIGNIFICANCE AND IMPACT OF THE STUDY: The strategies presented here, which integrated the advantages of both ribosome engineering and reporter-guided mutation selection, could be applied to other bacteria to improve their yield of secondary metabolites. PMID- 22486968 TI - Large-scale study of the interactions between proteins involved in type IV pilus biology in Neisseria meningitidis: characterization of a subcomplex involved in pilus assembly. AB - The functionally versatile type IV pili (Tfp) are one of the most widespread virulence factors in bacteria. However, despite generating much research interest for decades, the molecular mechanisms underpinning the various aspects of Tfp biology remain poorly understood, mainly because of the complexity of the system. In the human pathogen Neisseria meningitidis for example, 23 proteins are dedicated to Tfp biology, 15 of which are essential for pilus biogenesis. One of the important gaps in our knowledge concerns the topology of this multiprotein machinery. Here we have used a bacterial two-hybrid system to identify and quantify the interactions between 11 Pil proteins from N. meningitidis. We identified 20 different binary interactions, many of which are novel. This represents the most complex interaction network between Pil proteins reported to date and indicates, among other things, that PilE, PilM, PilN and PilO, which are involved in pilus assembly, indeed interact. We focused our efforts on this subset of proteins and used a battery of assays to determine the membrane topology of PilN and PilO, map the interaction domains between PilE, PilM, PilN and PilO, and show that a widely conserved N-terminal motif in PilN is essential for both PilM-PilN interactions and pilus assembly. Finally, we show that PilP (another protein involved in pilus assembly) forms a complex with PilM, PilN and PilO. Taken together, these findings have numerous implications for understanding Tfp biology and provide a useful blueprint for future studies. PMID- 22486969 TI - Y chromosome microdeletions in Mexican males of couples with idiopathic recurrent pregnancy loss. AB - AIM: To analyze the presence of Y chromosome microdeletions in males of Mexican couples with idiopathic recurrent pregnancy losses (RPL). METHODS: Seventy-one males from couples with RPL and 66 fertile males as controls were studied. DNA was isolated from peripheral lymphocytes and used to run multiplex polymerase chain reactions. Regions AZFa (sY84, sY86), AZFb (sY127, sY134) and AZFc (sY254, sY255) of the Y chromosome were analyzed according to valid guidelines recommended by the European Academy of Andrology and the European Molecular Genetics Quality Network. Also, the sequence tagged sites (STSs): DYS262 (sY67), DYS220 (sY129), DYF85S1 (sY150), DYF86S1 (sY152) and DYF87S1 (sY153) were included in order to analyze STSs previously reported as deleted. A power analysis to support our simple size was performed. RESULTS: Results show an absence of Y chromosome microdeletions in males of couples with RPL and controls with an acceptable statistical power. CONCLUSION: The study did not show an association of recurrent pregnancy loss and Y chromosome microdeletions in Mexican male partners. Based on the results, the study of Y chromosome microdeletions in couples with RPL is not considered clinically relevant. PMID- 22486970 TI - Late potentials abolition as an additional technique for reduction of arrhythmia recurrence in scar related ventricular tachycardia ablation. AB - RATIONALE: To evaluate the efficacy of radiofrequency ventricular tachycardia (VT) ablation targeting complete late potential (LP) activity. METHODS AND RESULTS: Sixty-four consecutive patients (pts) with recurrent VTs and coronary artery disease or idiopathic dilated cardiomyopathy were evaluated. Fifty patients (47 male; 66.2 +/- 10.1 years) had LPs at electroanatomical mapping; 35 patients had at least 1 VT inducible at basal programmed stimulation. After substrate mapping, radiofrequency ablation was performed with the endpoint of all LPs abolition. LPs could not be abolished in 5 patients despite extensive ablation, in 1 patient because of localization near an apical thrombus, and in 2 patients because of possible phrenic nerve injury. At the end of procedure, prevention of VT inducibility was achieved in 25 of 35 patients (71.4%) with previously inducible VT; VT was still inducible in 5 of 8 patients with incomplete LP abolition; and in 5 of 42 patients (16.1%) with complete LP abolition (P < 0.01). After a follow-up of 13.4 +/- 4.0 months, 10 patients (20.0%) had VT recurrences and one of them died after surgical VT ablation; VT recurrence was 9.5% in patients with LPs abolition (4/42 pts) and 75.0% (6/8 pts) in those with incomplete abolition [positive predictive value (PPV): 75%, negative predictive value (NPV): 90.4%, sensibility: 60.0%, and specificity: 95.0%, P < 0.0001); although it was 12.5% (5/40 pts) in patients without inducibility VT after the ablation, and 50% (5/10 pts) in those with inducible VT (PPV: 50%, NPV: 87.5%, sensitivity: 50.0%, and specificity: 87.5%, P = 0.008). CONCLUSIONS: LP abolition is an effective endpoint of VT ablation and its prognostic value compares favorably to that achieved by programmed electrical stimulation. PMID- 22486971 TI - Pex19p contributes to peroxisome inheritance in the association of peroxisomes to Myo2p. AB - During budding of yeast cells peroxisomes are distributed over mother cell and bud, a process that involves the myosin motor protein Myo2p and the peroxisomal membrane protein Inp2p. Here, we show that Pex19p, a peroxin implicated in targeting and complex formation of peroxisomal membrane proteins, also plays a role in peroxisome partitioning. Binding studies revealed that Pex19p interacts with the cargo-binding domain of Myo2p. We identified mutations in Myo2p that specifically reduced binding to Pex19p, but not to Inp2p. The interaction between Myo2p and Pex19p was also reduced by a mutation that blocked Pex19p farnesylation. Microscopy revealed that the Pex19p-Myo2p interaction is important for peroxisome inheritance, because mutations that affect this interaction hamper peroxisome inheritance in vivo. Together these data suggest that both Inp2p and Pex19p are required for proper association of peroxisomes to Myo2p. PMID- 22486972 TI - Correlated evolution of senescence and ephemeral substrate use in the Sordariomycetes. AB - Evolutionary theory predicts that senescence--a decline in reproduction and survival with increasing age--can evolve as a trade-off between investment in reproduction on one side and in somatic maintenance and repair on the other. The ecology of a species is crucial because it provides the external causes of death that determine the statistical limit to a species' lifespan. Filamentous fungi are generally believed to be nonsenescent, and there are indeed spectacular examples of very old fungal individuals in nature. However, some fungi utilize ephemeral resources, and therefore, senescence is expected to have evolved, like in the coprophilic Podospora anserina, the only well-studied filamentous fungus with intrinsic senescence. Here, we hypothesize that rapid senescence is more common in fungi than generally believed and that the phylogenetic distribution of senescence correlates with ecology. We collected lifespan data for a set of Sordariomycetes and constructed phylogenies based on several nuclear sequences. Several of the strains were from the CBS culture collection, originally isolated from various substrates, some of which ephemeral. In addition, we isolated new strains from short-lived substrates. Senescence was observed throughout the phylogeny. Correlation tests support the hypothesis that in the Sordariomycetes, senescence is a trait that has arisen in response to ephemeral substrates, and that it has evolved repeatedly and independently along the phylogeny. PMID- 22486973 TI - Smallpox eradication after 30 years: lessons, legacies and innovations. Proceedings of a Symposium held at the Oswaldo Cruz Foundation, Rio de Janeiro, Brazil. Foreword. PMID- 22486974 TI - "IDEAL" vaccines for resource poor settings. AB - In developing countries, immunization delivery would be more efficient, safer and economical if all vaccines could elicit long-term protection following needle free administration of just a single dose and without need for a cold chain, and if immunization left an indelible (e.g., serologic) marker that would identify immunized persons. A few existing vaccines (e.g., yellow fever, measles) confer long-term protection following a single dose. To accomplish the same with less immunogenic live vaccines and with non-living antigens, potent (parenteral and mucosal) adjuvants are required. Emerging knowledge of how the innate immune system modulates adaptive immune responses is guiding development of modern adjuvants that can markedly enhance immune responses to vaccines by selective stimulation of components of the innate immune system. Needle-free immunization can be accomplished by administering vaccines via mucosal (oral or nasal) or transcutaneous routes or by parenteral injection using needle-free injection devices. Technologies such as vitrification (treatment with trehalose followed by drying) render vaccines resistant to temperature extremes. Ideally, immunization would lead to a biomarker such as a specific vaccine-derived antibody that allows differentiation of successfully immunized persons from susceptibles. PMID- 22486975 TI - Surveillance in eradication and elimination of infectious diseases: a progression through the years. AB - During the years since certification of smallpox eradication, the power of infectious disease surveillance has been greatly increased by new biotechnical and electronic technologies. These technologies have transformed the way that surveillance can be used to contribute to public health, and to infectious disease eradication and elimination. In addition to permitting precise geographical placement of infections by incorporating the most up to date geographical positioning systems, infectious disease surveillance can now also provide more comprehensive understanding of the spread and risks of infections because of genomic sequencing that leads to more meaningful epidemiological analysis. These new technologies have made infectious disease surveillance an even more powerful and timely tool than it was during the period of smallpox eradication. Future surveillance will continue to refine these technologies, and adapt newer ones such as rapid point of care diagnostics and hand held communication devices that will lead to more timely and accurate reporting from health facilities. These technologies will also lead to the possibility of direct participation in surveillance by individuals who will be able to report their own disease syndromes, those of their neighbors, or those of domestic and wild animals at the animal/human interface. PMID- 22486976 TI - The Jenner Society and the Edward Jenner Museum: tributes to a physician scientist. AB - Dr. Edward Jenner's discovery and application of vaccination against smallpox was one of the most important medical advances of all time. In the modern era many millions of lives are saved each year by vaccines that work essentially on the same scientific principles established by Jenner more than 200 years ago. Jenner's country home in Berkeley, Gloucestershire, UK, where he carried out his work and where he spent most of his life, is now a museum and something of a shrine for vaccinologists. Jenner's house is also now the focal point of a new international learned society dedicated to advancing modern vaccinology. The aims of the new Jenner Society are to engage, support, and sustain the professional goals of vaccinologists, and to perpetuate the memory of Dr. Edward Jenner. Ultimately it is hoped that the Jenner Society will be recognized as one of the leading academic societies representing and promoting vaccine science around the world. We invite readers to consider joining the society (http://www.edwardjennersociety.org/). PMID- 22486977 TI - Lessons from smallpox eradication campaign in Bihar state and in India. AB - Following several key breakthroughs during the mid-1960s under the global smallpox eradication programme namely, development of a thermo-stable vaccine, efficient and acceptable technique of it's delivery by bifurcated needle and evolution of a strategy (in lieu of mass vaccination) of active case search and containment, an intensified campaign of smallpox eradication from India was successfully implemented during 1973-1975. A formidable battle was fought, particularly in Bihar state leading to the occurrence of last indigenous case on 17 May 1975. The rapid achievement of eradication of the scourge from India in a record time was hailed as unprecedented in public health history. The single key factor in the achievement was the sustained efforts of a band of national and international epidemiologists, supported by young medical interns heading mobile containment teams, working under trying field conditions. Through the campaign several important lessons were learnt and innovations made. Important among these were: (i) need for refinement of tools, techniques, and strategies for attaining the objective; (ii) implementation of a time and target oriented campaign; (iii) support of adequate and dedicated short term personnel to supplement supervision and field activities; (iv) providing of flexible funding and a convenient disbursement procedure; (v) building private-public partnership; (vi) devising of simple innovations, based on feedback from field, to support activities; (vii) development of political commitment; (viii) improved communication from field to higher levels to enable action on recent information; (ix) regular periodic staff meetings at each administrative level to facilitate early recognition and correction of deficiencies; (x) mobilization of support from international community, whenever required. PMID- 22486978 TI - Smallpox eradication after 30 years: lessons, legacies, and innovations. Introduction: meeting objectives, summary and final statement. PMID- 22486979 TI - Experiences with smallpox eradication in Ethiopia. AB - The smallpox eradication campaign operated in Ethiopia from 1970 until 1977. During this time Ethiopia had only 84 hospitals, 64 health centres and fewer than 400 physicians in a country of 25 million people. In 1970 smallpox vaccination was relatively unknown in the country, and the government actually contested the fact that smallpox was present in the country. Most of the resources of the Ministry of Health were used for malaria eradication. Initial pessimism from the Ministry of Health and others was eventually overcome as the smallpox eradication campaign continued to pick up steam but many remained unenthusiastic. Ethiopia was the first country in the world to start its smallpox eradication campaign from day one with the strategy of "Surveillance and Containment". Establishing a surveillance system in a country with a limited health infrastructure was a daunting challenge. At the end of the first year of the programme in 1971, 26,000 cases of smallpox had been registered through the growing surveillance system. Throughout revolution of 1974 the smallpox campaign was the only UN program to operate in the country; in fact it expanded with the hire of many locals leading to a "nationalized" program. This development ushered in the most successful final phase of the program. As the program progressed cases were diminishing in most regions, however transmission continued in the Ogaden desert. Over the course of the campaign approximately 14.3 million US dollars was spent. Working conditions were extremely challenging and a variety of chiefs, guerrillas, landowners and governments had to be appeased. The programme was successful due to the dedicated national and international staff on the ground and by having the full support of the WHO HQ in Geneva. PMID- 22486980 TI - The expanded programme on immunization: a lasting legacy of smallpox eradication. AB - Since the mid-1970s, the widespread establishment and implementation of the Expanded Programme on Immunization (EPI) has led to remarkable achievements in controlling vaccine preventable diseases worldwide. Today, more children than ever are being reached with immunization; interruption of poliomyelitis transmission has occurred in most countries; mortality due to measles, tetanus, diphtheria and pertussis has been reduced to record low levels. In addition, increasing numbers of vaccines are being used for infants and older age persons, such as vaccines against hepatitis A and hepatitis B, Haemophilus influenzae type b, rotavirus, pneumococcus, meningococcus, human papilloma virus (HPV) and varicella. The design of EPI reflects in large part the experience accumulated during the implementation of the intensified campaign for smallpox eradication during the period 1966-1977. At that time, the existing health infrastructure and network was found inadequate to reach most individuals with community wide immunization programmes in most countries. Thus, efforts were made to train dedicated health personnel and allocate specific resources for programme coordination and implementation. With the establishment of EPI, there was a gradual shift in emphasis from vaccination campaign strategies using mobile teams to the delivery of immunization services as part of routine health services of health facilities. Both the campaign and the outreach strategies are nevertheless required to reach those segments of the population not reached by the routine health services and to accelerate the achievement of disease control initiatives such as polio eradication and measles elimination. Whilst the campaign for smallpox eradication was set up as special and time-limited effort, the EPI requires long-term sustainable approaches to protect new cohorts of susceptible persons with vaccination and monitor trends and progress towards disease control with high quality surveillance. PMID- 22486981 TI - The global polio eradication initiative: lessons learned and prospects for success. AB - Following the rapid progress towards interrupting indigenous wild poliovirus transmission in the Americas in the early 1980s, the Global Polio Eradication Initiative (GPEI) was launched with a resolution of the World Health Assembly (WHA) in 1988. The GPEI built on many lessons learned from smallpox eradication, including the large-scale deployment of technical assistance, implementing agendas of innovation and research and the use of professionally planned and guided advocacy. By the year 2000, the incidence of polio globally had decreased by 99% compared with the estimated >350,000 cases reported from 125 endemic countries in 1988. By 2002, three WHO Regions (the Americas, Western Pacific and European Regions) had been certified polio-free. By 2005, transmission of indigenous wild poliovirus (WPV) had been interrupted in all but 4 'endemic' countries: India, Nigeria, Pakistan and Afghanistan, where eradication efforts effectively stalled. WPV exported from northern Nigeria and northern India subsequently caused >50 outbreaks and paralysed >1500 children in previously polio-free countries across Asia and Africa. In each of the four remaining polio endemic countries different challenges, or a combination of factors, prevented to build up sufficient levels of population immunity to stop transmission. Consequently, specific strategies were increasingly tailored to each setting. A new 2010-2012 GPEI Strategic Plan was developed which brought together several approaches to overcome the remaining hurdles to eradication, including the large scale use of bivalent oral poliovaccine (bOPV) in supplementary immunization activities (SIAs). By the end of 2010, the impact of the new GPEI Strategic Plan 2010-2012 was apparent. Compared to 2009, the number of new polio cases in 2010 fell by 95% in both northern Nigeria and northern India, the world's largest remaining reservoirs of indigenous WPVs. By mid-2011, India had not reported a polio case for more than 5 months, and in Nigeria, endemic transmission appeared to be restricted to the north-east and north-west corners of the country. While polio cases due to WPV type 3 were still being detected in west and central Africa, the overall level of WPV3 transmission globally was at an all-time low. Uncontrolled WPV transmission appeared to be restricted to Chad and Pakistan, which increasingly represented the greatest risks to the GPEI. Although insufficient financing continued to be a major concern, political support for completing polio eradication in polio-infected countries was stronger than ever by mid-2011. While continued transmission in some areas, particularly in Pakistan and Chad, still had to be controlled as a matter of urgency, there were real opportunities to achieve new landmarks in polio eradication, especially in the key WPV reservoirs of India and Nigeria, setting the stage for polio to soon follow smallpox into the history books. PMID- 22486982 TI - Proteomic analysis of sputum in patients with active pulmonary tuberculosis. AB - The protein composition of sputum most faithfully reflects the state of the lungs. The aim of this study was to determine whether relative qualitative and quantitative differences in protein expression of sputum could be related to active pulmonary tuberculosis. Sputum samples were collected from 65 patients with active pulmonary tuberculosis and 38 healthy controls. Comprehensive proteomic approaches were used to profile the proteome changes of host sputum in response to Mycobacterium tuberculosis infection using two-dimensional electrophoresis in combination with matrix-assisted laser desorption ionization time-of-flight/time-of-flight mass spectrometry. Mascot software was used to identify proteins from protein databases. Enzyme-linked immunosorbent assay was used to confirm the proteomic results. A total of 62 differentially expressed proteins were identified, among which, 15 proteins were up-regulated and 47 proteins were down-regulated in the tuberculosis sputum compared with the controls. Bacterial protein UqhC was the most increased protein, whereas serum albumin was the most decreased protein in the tuberculosis sputum compared with the controls. The enzyme-linked immunosorbent assay analysis was consistent with proteomic data. Bioinformatics analysis suggested that multiple host cell pathways were involved in the tuberculosis infection processes, including acute phase response, signal transduction, cytoskeleton structure, immune response and so on. In all, for the first time, our results revealed that a number of proteins were differentially expressed during active pulmonary tuberculosis infection. These data will provide valuable clues for further investigation of tuberculosis pathogenesis and biomarkers for detection of active pulmonary tuberculosis infection. PMID- 22486983 TI - PM2.5 and ultrafine particles emitted during heating of commercial cooking oils. AB - Seven commercial cooking oils were investigated to determine the PM(2.5) mass and ultrafine particle (UFP) emission rates and emission fluxes (rates per area). The results of this study showed that at 197 degrees C soybean, safflower, canola, and peanut oils produced lower PM(2.5) emission fluxes (6.1 * 10(5), 3.0 * 10(5), 5.4 * 10(5), and 3.9 * 10(5) MUg/min/m(2), respectively) than corn, coconut, and olive oils (2.7 * 10(6), 2.9 * 10(6), and 5.7 * 10(6) MUg/min/m(2), respectively). Similarly, the total particle number flux at 197 degrees C was lower for soybean, safflower, and canola oils (3.5 * 10(13), 8.6 * 10(13), and 1.0 * 10(14) #/min/m(2), respectively) than the corn, coconut, olive, and peanut oils (2.4 * 10(14), 1.4 * 10(14), 1.7 * 10(14), and 3.8 * 10(14) #/min/m(2), respectively). In general, oils with a higher smoke temperature resulted in lower particle concentrations over the measured temperature range (131-197 degrees C). The percentage of UFP (particle diameter D(p) 10-100 nm) to total particles (D(p) 10-500 nm) ranged from 76 to 99% for this temperature range. Particles below 10 nm in diameter were not measured. The particle number size distribution showed a polydisperse behavior with major mode sizes ranging from 25 nm (for peanut oil) to 82 nm (for soybean oil) at an oil temperature of 197 degrees C. PRACTICAL IMPLICATIONS: The study presents particle number and mass concentrations, size distributions, emission rates, and emission fluxes from heating common cooking oils. The emission rates and emission fluxes can be used as inputs to models for indirect exposure analysis studies. The study may also be used to provide guidance on choosing oils that result in lower emission rates when heated. PMID- 22486984 TI - Platelet proteome and clopidogrel response in patients with stable angina undergoing percutaneous coronary intervention. AB - OBJECTIVES: We analyzed the platelet proteome of circulating platelets during the onset of clopidogrel therapy in patients with stable angina underwent percutaneous coronary intervention in order to investigate the mechanisms that control platelet reactivity and clopidogrel response in this context. DESIGN & METHODS: Twenty patients were enrolled in this study. Blood samples were collected before coronary angiography (T0), 12 h after 600 mg of clopidogrel (T1) and 24 h after percutaneous coronary intervention (PCI) (T2). Platelet reactivity, Clopidogrel response and proteomic analysis were examined. RESULTS: Clopidogrel loading dose produced a significant inhibition in all markers of platelet activation in both flow cytometry and aggregation tests. Among the proteins found differentially expressed, eighteen were identified by MS/MS analysis and they resulted involved in the cytoskeleton rearrangement (profilin 1, calpain, alpha-soluble NSF attachment protein, thrombospondin), in the energetic metabolism (ubiquitin-like modifier-activating enzyme 1, protein-L isoaspartate-(D-aspartate) O-methyltransferase and nucleoside diphosphate kinase B) and in the oxidative stress (heat shock 70 kDa protein 5 and anti-stress induced phosphoprotein 1. CONCLUSIONS: The present study provides novel information on platelet proteome changes associated with platelet activation and clopidogrel response. This investigation supports the development of further proteomic studies for the identification of novel platelet biomarkers. PMID- 22486985 TI - Insulin-like growth factor-II and heparin are anti-apoptotic survival factors in human villous cytotrophoblast. AB - OBJECTIVE: This study aimed to determine the effects of insulin-like growth factors (IGF-I and IGF-II), heparin, aspirin and vitamin C on the proliferation and apoptosis of human villous cytotrophoblast from first trimester and term placentae. STUDY DESIGN: Villous cytotrophoblast cells were isolated from uncomplicated first trimester (n=12) and term placental tissues (n=12) using negative immunoselection with an antibody to HLA class I antigens. Cells were incubated with IGF-I, IGF-II, heparin, aspirin and vitamin C either alone, or in combination with either TNF-alpha/IFN-gamma or staurosporine. Proliferation was determined by measurement of Ki67 expression using immunocytochemistry. Trophoblast apoptosis was determined by TUNEL staining. Finally RT-PCR was carried out to identify IGF-binding insulin receptor isoforms. Data were expressed as means+/-SEM. One way analysis of variance (ANOVA) with Bonferroni correction was used to determine if differences between groups were statistically significant. RESULTS: Following negative immunoselection >98% of cells were positively stained for cytokeratin 7, a marker for cytotrophoblasts, and <1% were vimentin positive. First trimester and term trophoblasts underwent spontaneous apoptosis which was inhibited by approximately 50% in the presence of IGF-II or heparin. Apoptosis was significantly increased following incubation with a combination of TNF-alpha and IFN-gamma or staurosporine. Apoptosis was decreased to basal levels following coincubation with IGF-II or heparin. Incubation with IGFs or heparin resulted in a small, but significant increase in Ki67 expression. Insulin receptor isoform A, which binds IGF-II with high affinity, was present in all trophoblast samples tested. CONCLUSION: These results suggest that heparin and IGF-II, but not IGF-I are important regulators of villous cytotrophoblast survival in early and late pregnancy. PMID- 22486986 TI - Reducing the social gradient in smoking: initiatives in the United Kingdom. AB - ISSUES: To describe initiatives aiming to reduce the social gradient of smoking in the UK. APPROACH: A description of government initiatives to support smokers from low socioeconomic and other key groups, including National Health Service Stop Smoking Services and how they are seeking to support smokers to quit. KEY FINDINGS: The UK is employing a number of strategies to reduce smoking prevalence and is currently top of the Tobacco Control Scale in Europe but the health gap does not yet appear to be decreasing (in relation to smoking prevalence in deprived and higher income groups). More recently, efforts have been made to target smokers in more deprived groups to draw more of these smokers into the quitting process. IMPLICATIONS: While Stop Smoking Services are a key part of the UK's comprehensive tobacco control strategy and are reaching smokers from low socioeconomic groups, wider population strategies, such as ensuring all contacts with health-care professionals include advice to stop and the prohibition of remaining channels of tobacco marketing, are required to maximise the impact on deprived smokers. CONCLUSION: While smoking prevalence decreases among the general population are important, reducing smoking among disadvantaged groups is imperative to reduce health inequalities. It is too soon to say whether the new measures recently adopted in the UK will help to achieve this. PMID- 22486987 TI - Successful spontaneous pregnancy after pelvic chemoradiotherapy for anal cancer. PMID- 22486988 TI - Feasibility of conjunctival hemodynamic measurements in rabbits: reproducibility, validity, and response to acute hypotension. AB - OBJECTIVE: To evaluate the feasibility of conjunctival hemodynamic measurements based on assessment of reproducibility, validity, and response to acute hypotension. METHODS: Image sequences of the conjunctival microvasculature of rabbits were captured using a slit lamp biomicroscope under a steady-state condition, after topical administration of phenylephrine, and after intravenous administration of esmolol. Venous hemodynamic parameters (diameter, blood velocity, blood flow, and wall shear stress) were derived. RESULTS: Conjunctival venous diameters ranged from 9 to 34 MUm and blood velocities ranged from 0.08 to 0.95 mm/s. Coefficients of variation of venous diameter and blood velocity measurements were, on average, 6% and 14%, respectively. Automated and manual measurements of venous diameter and velocity were highly correlated (R = 0.97; p < 0.001; n = 16). With phenylephrine administration, diameter and velocity were reduced by 21% and 69%, respectively. Following esmolol administration, blood pressure was reduced with a concomitant decrease in velocity, followed by recovery to baseline. Venous blood velocity, flow, and WSS were correlated with blood pressure (R >= 0.52; p <= 0.01). CONCLUSIONS: The feasibility of quantifying alterations in microvascular hemodynamics in the bulbar conjunctiva was established. The method is of potential value in evaluating microcirculatory hemodynamics related to cardiovascular function. PMID- 22486990 TI - Effect of antidiabetic agents added to metformin on glycaemic control, hypoglycaemia and weight change in patients with type 2 diabetes: a network meta analysis. AB - AIM: Most guidelines recommend metformin as first-line therapy in patients with type 2 diabetes. However, the choice of a second-line drug lacks consistent consensus. We aimed to assess available information of antidiabetic drugs added to metformin on the change in glycated haemoglobin A1c (A1C), risk of hypoglycaemia and change in body weight. METHODS: PubMed and Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) written in English through December 2011. We analysed direct and indirect comparisons of different treatments using Bayesian network meta-analysis. RESULTS: Thirty-nine RCTs involving 17 860 individuals were included. Glucagon like peptide-1 (GLP-1) analogues resulted in greater decrease in A1C compared with sulfonylureas, glinides, thiazolidinediones, alpha-glucosidase inhibitors and DPP-4 inhibitors [-0.20% (95% CI -0.34 to -0.04%), -0.31% (95% CI -0.61 to 0.02%), -0.20% (95% CI -0.38 to -0.00), -0.36% (95% CI -0.64 to -0.07%), -0.32% (95% CI -0.47 to -0.17%), respectively] and was comparable with basal insulin and biphasic insulin. A1C decrease was greater for sulfonylureas compared with DPP-4 inhibitors [-0.12% (-0.23 to -0.03%)], and for biphasic insulin compared with glinides (-0.36%; 95% CI -0.82 to -0.11%). Compared with placebo, the risk of hypoglycaemia was increased in the sulfonylureas, glinides, basal insulin and biphasic insulin. Weight increase was seen with sulfonylureas, glinides, thiazolidinediones, basal insulin and biphasic insulin, and weight loss was seen with alpha-glucosidase inhibitors and GLP-1 analogues. CONCLUSIONS: Biphasic insulin, GLP-1 analogues and basal insulin were ranked the top three drugs in terms of A1C reduction. GLP-1 analogues did not increase the risk of hypoglycaemia and resulted in a significant decrease in body weight. Most oral antidiabetic drugs had similar effects on A1C, but some agents had a lower risk of hypoglycaemia and body weight gain. PMID- 22486989 TI - Laterality, frequency and replication of rTMS treatment for chronic tinnitus: pilot studies and a review of maintenance treatment. AB - This manuscript reports on findings of three open-label, pilot studies and it reviews studies using rTMS as a maintenance treatment for any disorder. The first pilot study examined whether a patient's original treatment response to 1 Hz rTMS over temporal cortex could be replicated by stimulating a homologous region of the opposite hemisphere. The second study examined whether a patient's response to 1 Hz rTMS could be replicated by applying 10 Hz rTMS over the same treatment site. The third study applied a 3-day course of maintenance rTMS, either at 1 or 10 Hz, when subjects indicated that the benefit of their last course of treatment was waning. Patients with bilateral subjective tinnitus of at least 6 months duration were recruited from a prior, sham controlled study with treatment crossover that applied 1 Hz rTMS over temporal cortex. Both treatment responders and non-responders were recruited. Results indicated, first, that the original treatment response, both positive and negative, is replicated after stimulating a homologous region of the opposite hemisphere; second, patients respond similarly to 1 and 10 Hz stimulation of the same treatment site (an exception was one patient who initially failed 1 Hz stimulation but responded positively to 10 Hz stimulation); and, third, maintenance rTMS had a sustained and additive benefit for tinnitus among treatment responders. Conclusions are that rTMS-induced effects on tinnitus are neither hemisphere specific nor frequency dependent; although, different frequencies of rTMS may have greater potency for a given subject. Maintenance treatment is a well tolerated approach with demonstrated feasibility for managing chronic tinnitus in persons who respond positively to an initial course of treatment. PMID- 22486991 TI - Relative expression of gammadelta T-cell receptor gene families detected by RT PCR and capillary electrophoresis. AB - gammadelta T cells are intensively studied because their function in infection, allergy, autoimmune disease, cancer and post-transplant period is not yet fully understood. PCR-based techniques were established to study the gamma variable (Vgamma) and delta variable (Vdelta) gene families. PCR product evaluation is routinely carried out by Southern blot analysis or the third complementarity determining region spectratyping, but a fast and simple assessment of Vgamma and Vdelta gene family expression is missing. The aim of our study was to test capillary electrophoresis as a potential method for evaluating the composition of the gammadelta T-cell population. This report provides optimized PCR conditions for gammadelta T-cell receptor amplification. Further, it describes the utilization of capillary electrophoresis in the Agilent 2100 Bioanalyzer to evaluate the relative expression of Vgamma and Vdelta gene families after their amplification. An application of the methodology to peripheral blood mononuclear cell samples from patients during haemato-oncological treatment is shown. The described methodology is fast and simple to operate and is therefore suitable as a first screening of the gammadelta T-cell population composition in tissues of interest. PMID- 22486992 TI - Assessing reader performance in radiology, an imperfect science: lessons from breast screening. AB - The purpose of this article is to review the limitations associated with current methods of assessing reader accuracy in mammography screening programmes. Clinical audit is commonly used as a quality-assurance tool to monitor the performance of screen readers; however, a number of the metrics employed, such as recall rate as a surrogate for specificity, do not always accurately measure the intended clinical feature. Alternatively, standardized screening test sets, which benefit from ease of application, immediacy of results, and quicker assessment of quality improvement plans, suffer from experimental confounders, thus questioning the relevance of these laboratory-type screening test sets to clinical performance. Four key factors that impact on the external validity of screening test sets were identified: the nature and extent of scrutiny of one's action, the artificiality of the environment, the over-simplification of responses, and prevalence of abnormality. The impact of these factors on radiological and other contexts is discussed, and although it is important to acknowledge the benefit of standardized screening test sets, issues relating to the relevance of test sets to clinical activities remain. The degree of correlation between performance based on real-life clinical audit and performances at screen read test sets must be better understood and specific causal agents for any lack of correlation identified. PMID- 22486993 TI - Adrenal neoplasms. AB - Adenoma, myelolipoma, phaeochromocytoma, metastases, adrenocortical carcinoma, neuroblastoma, and lymphoma account for the majority of adrenal neoplasms that are encountered in clinical practice. A variety of imaging methods are available for evaluating adrenal lesions including ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine techniques such as meta iodobenzylguanidine (MIBG) scintigraphy and positron-emission tomography (PET). Lipid-sensitive imaging techniques such as unenhanced CT and chemical shift MRI enable detection and characterization of lipid-rich adenomas based on an unenhanced CT attenuation of <= 10 HU and signal loss on opposed-phase compared to in-phase T1-weighted images, respectively. In indeterminate cases, an adrenal CT washout study may differentiate adenomas (both lipid-rich and lipid-poor) from other adrenal neoplasms based on an absolute percentage washout of >60% and/or a relative percentage washout of >40%. This is based on the principle that adenomas show rapid contrast washout while most other adrenal neoplasms including malignant tumours show slow contrast washout instead. 18F-2-fluoro-2-deoxy-d glucose-PET (18FDG-PET) imaging may differentiate benign from malignant adrenal neoplasms by demonstrating high tracer uptake in malignant neoplasms based on the increased glucose utilization and metabolic activity found in most of these malignancies. In this review, the multi-modality imaging appearances of adrenal neoplasms are discussed and illustrated. Key imaging findings that facilitate lesion characterization and differentiation are emphasized. Awareness of these imaging findings is essential for improving diagnostic confidence and for reducing misinterpretation errors. PMID- 22486994 TI - Effect of pulsed electric fields on the activity of neutral trehalase from beer yeast and RSM analysis. AB - The trehalase activity plays an important role in extraction of trehalose from beer yeast. In this study, the effect of pulsed electric field processing on neutral trehalase activity in beer yeast was investigated. In order to develop and optimize a pulsed electric field (PEF) mathematical model for activating the neutral trehalase, we have investigated three variables, including electric field intensity (10-50 kV/cm), pulse duration (2-10 MUs) and liquid-solid ratio (20-50 ml/g) and subsequently optimized them by response surface methodology (RSM). The experimental data were fitted to a second-order polynomial equation and profiled into the corresponding contour plots. Optimal condition obtained by RSM is as follows: electric field intensity 42.13 kV/cm, liquid-solid ratio 30.12 ml/g and pulse duration 5.46 MUs. Under these conditions, with the trehalose decreased 8.879 mg/L, the PEF treatment had great effect on activating neutral trehalase in beer yeast cells. PMID- 22486995 TI - Arthrospira platensis biomass with high protein content cultivated in continuous process using urea as nitrogen source. AB - AIMS: Arthrospira platensis has been studied for single-cell protein production because of its biomass composition and its ability of growing in alternative media. This work evaluated the effects of different dilution rates (D) and urea concentrations (N(0)) on A. platensis continuous culture, in terms of growth, kinetic parameters, biomass composition and nitrogen removal. METHODS AND RESULTS: Arthrospira platensis was continuously cultivated in a glass-made vertical column photobioreactor agitated with Rushton turbines. There were used different dilution rates (0.04-0.44 day(-1)) and urea concentrations (0.5 and 5 mmol l(-1)). With N(0) = 5 mmol l(-1), the maximum steady-state biomass concentration was 1415 mg l(-1), achieved with D = 0.04 day(-1), but the highest protein content (71.9%) was obtained by applying D = 0.12 day(-1), attaining a protein productivity of 106.41 mg l(-1) day(-1). Nitrogen removal reached 99% on steady-state conditions. CONCLUSIONS: The best results were achieved by applying N(0) = 5 mmol l(-1); however, urea led to inhibitory conditions at D >= 0.16 day( 1), inducing the system wash-out. The agitation afforded satisfactory mixture and did not harm the trichomes structure. SIGNIFICANCE AND IMPACT OF THE STUDY: These results can enhance the basis for the continuous removal of nitrogenous wastewater pollutants using cyanobacteria, with an easily assembled photobioreactor. PMID- 22486996 TI - Trends and distribution of oral and pharyngeal lymphoma in Israel. AB - OBJECTIVES: To describe the distribution and trends of oral and pharyngeal lymphoma cases in Israel. METHODS: Incidence rates were derived from the Israel National Cancer Registry and included all registered data from 1970 to 2006. Oral lymphoma included the tongue, mouth, salivary glands, tonsils, and pharynx. Morphological description was according to WHO classification of lymphoid neoplasms. RESULTS: A total of 670 cases were diagnosed, mean age 59.5 years, half were over 65 years old. Tonsils were the most prevalent site of involvement (36.0%), followed by the pharyngeal region and salivary glands. Over the years, the prevalence of lymphoma in salivary glands increased by 49%, whereas in tonsils lymphoma decreased by 28.6%. The overall 5-year survival rate was 57% with best rates among young people. CONCLUSION: The correlation of survival, type of lymphoma and age, was similar to extra-oral lymphoma. A trend of increased cases in the parotid region, dissimilar to other oral sites, raises a question of possible external factors or an increase in autoimmune diseases. Head and neck clinicians should be aware of different sites, types, and prognoses for the different age groups. PMID- 22486997 TI - Molecular pathogenesis of bovine paratuberculosis and human inflammatory bowel diseases. AB - Paratuberculosis (Ptb), caused by Mycobacterium avium subsp. paratuberculosis (Map), is a chronic enteritis that affects many ruminants and other wild animals worldwide. Ptb is a great concern in animal health and in etiology of human Crohn's disease (CD). In the present study, we detected Map-specific insertion sequence IS900 of DNA in tissue sections surgically removed from lesions of patients with CD (29 samples), ulcerative colitis (UC) (17 samples), and non inflammatory bowel disease (IBD) (20 samples). We then compared the histopathological findings of 29 CD and 17 UC cases with those of 35 cases of bovine Ptb, since few comparative pathological studies of human IBD and Ptb have been conducted. The QPCR examination indicated positive results in 13.37% of CD cases, 3.57% of UC cases, and 10% of non-IBD cases. Human CD tissues typically exhibited destructive full thickness enteritis with severe lympho-plasma infiltration and scattered additional granulomas; UC lesions exhibited much less inflammation than CD lesions. Non-IBD control samples did not exhibit pathological changes. Human CD and UC lesions were very different from Ptb lesions that are characterized by predominant granuloma formation. Immunohistochemistry for Map antigen and acid-fast staining were negative in all human IBD cases but were always positive in Ptb cases. Our present comparative study strongly suggests that we reconsider the previous hypothesis that "Map infection" causes CD, even though human intestines were considered to have been exposed to the Map antigen containing the DNA. PMID- 22486999 TI - Effects of non-steroidal antiinflammatory drugs on D-serine-induced oxidative stress in vitro. AB - Inflammation is deleterious for organs with reduced capacity of regeneration, such as the brain. Recently, studies have focused on investigating the therapeutic effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Excitotoxicity is the pathological process when receptors for the excitatory neurotransmitter glutamate, such as the N-methyl-D-aspartate (NMDA), receptors are overactivated. This process may be involved in neurodegenerative diseases. D-serine is one of the coagonist of NMDA receptors, and increased levels of D-serine are associated with excitotoxicity. In our study, the potential neuroprotective effects of mefenamic acid, acetaminophen, and naproxen sodium were investigated against D-serine-induced oxidative stress in the rat brain in vitro. To show their potential neuroprotective properties, NSAIDs were incubated with D-serine and reactive oxygen species (ROS), malondialdehyde, and protein carbonyl content of the brain after different treatments were measured. Our results demostrate that NSAIDs used in the present study significantly reduced ROS production, lipid peroxidation, and protein oxidation against D serine treatment. PMID- 22486998 TI - Arteriovenous fistula creation using the Optiflow vascular anastomosis device: a first in man pilot study. AB - Although arteriovenous fistulae are the preferred form of dialysis vascular access they continue to have significant problems with maturation failure. The Optiflow device is a sutureless anastomotic conduit which could potentially reduce surgical time and also standardize the surgical procedure. We report herein on the "First in Man" experience with the Optiflow device. PMID- 22487000 TI - Spermatocele following kidney transplant. AB - Lymphocele following kidney transplant is a common occurrence, but on occasion, what appears to be a lymphocele is not. We present an unusual case of a kidney transplant recipient whose presumed lymphocele was actually a spermatocele. Our patient is a 60-year-old man who is 11 years status post his second deceased donor kidney transplant. The original cause of his renal failure was poststreptococcal glomerulonephritis. He was followed with this nonobstructing lymphocele for years, but wished to have it addressed at the time of sigmoidectomy for recurrent diverticulitis. Preoperative imaging included CT scan, which showed a 12 cm * 6 cm collection, of greater density than simple fluid, adjacent to the bladder, and causing mass effect on the bladder. Intraoperatively, the collection was somewhat atypical for a lymphocele, and located posterior to the bladder. Cultures were negative, but evaluation of the fluid revealed it to be a spermatocele. Postoperative ultrasound demonstrated full resolution of the collection. PMID- 22487001 TI - A randomized double-blind study of low-molecular-weight heparin (parnaparin) for superficial vein thrombosis: STEFLUX (Superficial ThromboEmbolism and Fluxum). AB - BACKGROUND: Optimal doses and duration of low-molecular-weight heparin (LMWH) for the treatment of superficial vein thrombosis (SVT) are still uncertain. OBJECTIVES: To compare the efficacy and safety of different doses and durations of LMWH parnaparin for symptomatic lower limb SVT. PATIENTS AND METHODS: Outpatients with at least a 4-cm-long SVT of long or short saphenous veins or their collaterals were randomized to receive parnaparin either 8500 UI once daily ( o.d.) for 10 days followed by placebo for 20 days (group A) or 8500 UI o.d. for 10 days followed by 6400 UI once daily (o.d.) for 20 days (group B) or 4250 UI o.d. for 30 days (group C) in a double-blind fashion in 16 clinics. Primary outcome was the composite of symptomatic and asymptomatic deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE) and relapse and/or symptomatic or asymptomatic SVT recurrence in the first 33 days with 60 days follow-up. RESULTS: Among 664 patients, primary outcome occurred in 33/212 (15.6%), 4/219 (1.8%) and 16/217 (7.3%) subjects in groups A, B and C, respectively (B vs. A: absolute risk reduction [ARR]: 13.7%, 95% confidence intervals [CI]: 8-18.9 P<0.001; B vs. C: ARR: 5.5%; 95% CI: 1.6-9.4 P= 0.011; C vs. A: ARR: 8.2%, 95% CI: 2-14 P=0.012). During days 0-93, the event rate was higher in group A (22.6%) than either in group B (8.7%; P=0.001) or C (14.3%, P=0.034). No major hemorrhages occurred. CONCLUSIONS: An intermediate dose of parnaparin for 30 days is superior to either a 30-day prophylactic dose or a 10-day intermediate dose for lower limb SVT treatment. PMID- 22487002 TI - The distinct category of healthcare associated bloodstream infections. AB - BACKGROUND: Bloodstream infections (BSI) have been traditionally classified as either community acquired (CA) or hospital acquired (HA) in origin. However, a third category of healthcare-associated (HCA) community onset disease has been increasingly recognized. The objective of this study was to compare and contrast characteristics of HCA-BSI with CA-BSI and HA-BSI. METHODS: All first episodes of BSI occurring among adults admitted to hospitals in a large health region in Canada during 2000-2007 were identified from regional databases. Cases were classified using a series of validated algorithms into one of HA-BSI, HCA-BSI, or CA-BSI and compared on a number of epidemiologic, microbiologic, and outcome characteristics. RESULTS: A total of 7,712 patients were included; 2,132 (28%) had HA-BSI, 2,492 (32%) HCA-BSI, and 3,088 (40%) had CA-BSI. Patients with CA-BSI were significantly younger and less likely to have co-morbid medical illnesses than patients with HCA-BSI or HA-BSI (p < 0.001). The proportion of cases in males was higher for HA-BSI (60%; p < 0.001 vs. others) as compared to HCA-BSI or CA-BSI (52% and 54%; p = 0.13). The proportion of cases that had a poly-microbial etiology was significantly lower for CA-BSI (5.5%; p < 0.001) compared to both HA and HCA (8.6 vs. 8.3%). The median length of stay following BSI diagnosis 15 days for HA, 9 days for HCA, and 8 days for CA (p < 0.001). Overall the most common species causing bloodstream infection were Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae. The distribution and relative rank of importance of these species varied according to classification of acquisition. Twenty eight day all cause case-fatality rates were 26%, 19%, and 10% for HA-BSI, HCA-BSI, and CA-BSI, respectively (p < 0.001). CONCLUSION: Healthcare-associated community onset infections are distinctly different from CA and HA infections based on a number of epidemiologic, microbiologic, and outcome characteristics. This study adds further support for the classification of community onset BSI into separate CA and HCA categories. PMID- 22487003 TI - Effect of the Fukushima nuclear power plant accident on radioiodine (131 I) content in human breast milk. AB - BACKGROUND: Environmental pollution with radioiodine (iodine-131, (131) I) occurred after an accident at the Fukushima nuclear power plant (FNP) on March 11, 2011, in Japan. Whether environmental pollution with (131) I can contaminate human breast milk has not been documented. METHODS: The (131) I content was determined in 126 breast milk samples from 119 volunteer lactating women residing within 250 km of the FNP, between April 24 and May 31, 2011. The degree of environmental pollution was determined based on the data released by the Japanese government. RESULTS: An (131) I content of 210 Bq/kg in the tap water in Tokyo, which is located 230 km south of the FNP, on March 22 and of 3500 Bq/kg in spinach sampled in a city located 140 km southwest of the FNP on March 19 decreased over time to <21 Bq/kg on March 27 and 12 Bq/kg on April 26, respectively. Seven of the 23 women who were tested in April secreted a detectable level of (131) I in their breast milk. The concentrations of (131) I in the breast milk of the seven women were 2.3 Bq/kg (on April 24), and 2.2, 2.3, 2.3, 3.0, 3.5 and 8.0 (on April 25); the concentrations of (131) I in the tap water available for these seven women at the same time were estimated to be <1.3 Bq/kg. None of the remaining 96 women tested in May exhibited a detectable concentration of (131) I in their breast milk samples. CONCLUSIONS: The contamination of breast milk with (131) I can occur even when only mild environmental (131) I pollution is present. PMID- 22487005 TI - Self-injurious behaviour in people with intellectual disability. PMID- 22487004 TI - Akt/PKB controls the activity-dependent bulk endocytosis of synaptic vesicles. AB - Activity-dependent bulk endocytosis (ADBE) is the dominant SV endocytosis mode during intense neuronal activity. The dephosphorylation of Ser774 on dynamin I is essential for triggering of ADBE, as is its subsequent rephosphorylation by glycogen synthase kinase 3 (GSK3). We show that in primary cultures of cerebellar granule neurons the protein kinase Akt phosphorylates GSK3 during intense neuronal activity, ensuring that GSK3 is inactive during intense stimulation to aid dynamin I dephosphorylation. Furthermore, when a constitutively active form of Akt was overexpressed in primary neuronal cultures, ADBE was inhibited with no effect on clathrin-mediated endocytosis. Thus Akt has two major regulatory roles (i) to ensure efficient dynamin I dephosphorylation via acute activity-dependent inhibition of GSK3 and (ii) to negatively regulate ADBE when activated in the longer term. This is the first demonstration of a role for Akt in SV recycling and suggests a key role for this protein kinase in modulating synaptic strength during elevated neuronal activity. PMID- 22487006 TI - 'If you listen to me properly, I feel good': a qualitative examination of patient experiences of dietetic consultations. AB - BACKGROUND: There is considerable interest in healthcare research regarding communication skills and some debate surrounding the effectiveness of a patient centred approach to care. Understanding patient experiences of consultations can help indicate how consultations can be modified to improve effectiveness. At present, there is little research exploring patient experience of dietetic consultations. The present study aimed to achieve a better understanding of patients' experiences of dietetic consultations using qualitative analysis. METHODS: Patients undergoing consultations with a dietitian were invited to discuss their experience of the consultation with a research dietitian who was not involved in their care. Individual interviews and focus groups were conducted and analysed using the Framework approach. RESULTS: Seventeen patients participated and described their experiences of consultations, which were varied and influenced by factors such as information given (resources, explanation, repetition, consistency); their dietitian's approach (prescriptive or nonprescriptive, use of behaviour change skills), behaviour (listening skills, body language) and appointment (expectations, involvement of the multidisciplinary team, length of time); and their own internal experience (confidence, guilt, frustration). Patients agreed that certain factors, such as good communication and rapport, receiving effective and reliable information and resources, and nonjudgmental, regular support, were important factors in creating a positive experience of their consultation. However, they differed in what they believed constituted these factors. CONCLUSIONS: Patients like dietitians to adopt a patient-centred approach, which might be either patient- or practitioner led, and to take account of what they wanted from consultations, adapting these to meet their individual requirements. PMID- 22487007 TI - Isolated subtricuspid low-voltage segment in arrhythmogenic right ventricular cardiomyopathy: structural characterization by intracardiac echocardiography. PMID- 22487008 TI - Role for direct electronic verification of pharmaceutical ingestion in pharmaceutical development. AB - Identifying a dosing regimen for recommended use is one of the more difficult tasks in pharmaceutical development and has major therapeutic and economic consequences. In the clinical phase of pharmaceutical development, pharmacokinetic-pharmacodynamic (PK/PD) models are used to characterize the relationship between drug exposure and clinical outcome. When adherence to the prescribed drug dosage is known, true dose-response can be validly estimated, while non-compliance with the nominal prescribed dosage causes unintended variability in actual drug exposure and ensuing difficulty in determining dose response. The purpose of this manuscript is to provide an overview of the important role that adherence plays in the interpretation of clinical studies for pharmaceutical development, to summarize the challenges in utilizing currently available tools for assessing adherence, to characterize the attributes of an ideal adherence marker, and to describe the utilization of a networked system having an ingestible sensor for direct confirmation of pharmaceutical utilization in drug development studies. The positive detection accuracy of this networked system when compared to direct ingestion is 99.3% [95%CI: 0.977, 0.999]. A direct measure of pharmaceutical utilization in pharmaceutical studies provides the means to examine the temporal patterns of drug response that are engendered by patients' actual dosing patterns, and to characterize more accurately exposure response relationships. Materials and methods are available to accomplish these goals. PMID- 22487009 TI - Switch on or switch off: an optical DNA sensor based on poly(p-phenylenevinylene) grafted magnetic beads. AB - There has been an enormous demand for commercial label-free DNA sensors in a diverse range of fields including pre-emptive medicine, diagnostics, environmental monitoring, and food industry. Addressing the need for sensitive, selective and facile DNA sensors, we demonstrate a novel switch on/off sensor design that utilizes sandwich hybridization between photoluminescent anionic conjugated polyelectrolyte (CPE) bound captureprobe coated onto magnetic beads, target and the signaling probe. The hybridization-readout in our sensor was monitored by either fluorescence resonance energy transfer (FRET, switch-on) or superquenching (switch-off) depending on the type of signaling probe used. Moreover recent designs that utilize beads for sensing DNA have been limited towards using electrostatic interactions or intercalation of dyes to observe FRET. To our knowledge this is the first report of a switch on/off sensor utilizing either FRET or superquenching thus providing flexibility for future development of such rapid, facile and sensitive DNA sensors. The FRET-based sensor was investigated by optimizing the reaction parameters and selectivity. A low detection limit of 240 fmol in 2 mL of SSC buffer was achieved. PMID- 22487010 TI - A simple, post-additional antioxidant capacity assay using adenosine triphosphate stabilized 2,2'-azinobis(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) radical cation in a G-quadruplex DNAzyme catalyzed ABTS-H2O2 system. AB - The scavenging of 2,2'-azinobis(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) radical cation (ABTS(+)) by antioxidants has been widely used in antioxidant capacity assay. Because of ABTS(+) disproportionation, however, this radical cannot be prepared on a large scale and stored long-term, making it unsuitable for high-throughput detection and screening of antioxidants. We developed a modified "post-additional" antioxidant capacity assay. This method possessed two remarkable features: First, instead of natural peroxidases, an artificial enzyme, G-quadruplex DNAzyme, was used for the preparation of ABTS(+), thus greatly reducing the cost of the assay, and eliminating the strict demand for the storage of enzymes. Second, an ABTS(+) stabilizer, adenosine triphosphate (ATP), was used. In the presence of ATP, the disproportionation of ABTS(+) was effectively inhibited, and the lifetime of this radical cation was prolonged about 6-fold (12 days versus 2 days), making the large-scale preparation of ABTS(+) possible. Utilizing this method, the antioxidant capacities of individual antioxidants and real samples can be quantified and compared easily. In addition, this method can be developed as a high-throughput screening method for antioxidants. The screening results could even be judged by the naked eye, eliminating the need for expensive instruments. PMID- 22487011 TI - Carbon nanospheres-promoted electrochemical immunoassay coupled with hollow platinum nanolabels for sensitivity enhancement. AB - Two nanostructures including carbon nanospheres-graphene hybrid nanosheets (CNS GNS) and hollow platinum nanospheres (HPtNS) were first synthesized by using direct electrolytic reduction and wet chemistry methods, respectively. Thereafter, a specific sandwich-type electrochemical immunoassay was designed for determination of carcinoembryonic antigen (CEA) by using HPtNS-labeled horseradish peroxidase-anti-CEA conjugates (HRP-anti-CEA) as molecular tags and anti-CEA-assembled CNS-GPS as sensing probes. Compared with pure graphene nanosheets, the presence of carbon nanospheres on the graphene increased the surface coverage of the substrate, and enhanced the immobilized amount of primary antibodies. Several labeling protocols, such as HRP-anti-CEA, solid platinum nanoparticle-labeled HRP-anti-CEA, and hollow platinum nanospheres-labeled HRP anti-CEA, were investigated for determination of CEA and improved analytical features were obtained with hollow platinum nanosphere labeling. With the HPtNS labeling method, the effects of incubation time and pH on the current responses of the immunosensors were also studied. The strong attachment of biomolecules to the CNS-GPS and HPtNS resulted in a good repeatability and intermediate precision down to 10.2%. The dynamic concentration range spanned from 0.001 ng mL(-1) to 100 ng mL(-1) CEA with a detection limit of 1.0 pg mL(-1) at the 3S(blank) level. No significant differences at the 0.05 significance level were encountered in the analysis of 10 clinical serum samples between the developed immunoassay and the commercially available electrochemiluminescent method for determination of CEA. PMID- 22487012 TI - The Sun Exposure and Behaviour Inventory (SEBI): validation of an instrument to assess sun exposure and sun protective practices. AB - BACKGROUND: Skin cancer is the most common cancer worldwide. Sun exposure is the most important risk factor for its development. The amount of exposure required to cause skin cancer has not been quantified, and the impact of sun protective practices is unknown. OBJECTIVES: To develop a brief self-administered questionnaire to estimate past and current sun exposure, sun protective practices, and assess the questionnaire's reliability and validity. METHODS: The study had three stages: (1) questionnaire formulation, (2) internal reliability and construct validity testing and questionnaire refinement, (3) test-retest and further internal reliability testing. The final Sun Exposure and Behaviour Inventory (SEBI) is composed of 15 questions assessing three domains; current sun behaviour, current sun exposure and prior sun exposure. RESULTS: A total of 251 subjects completed Stage 2 testing and 57 completed Stage 3. Final Cronbach's alpha-scores ranged from 0.71 to 0.84 and k-scores demonstrated excellent to fair/good agreement, indicating acceptable internal consistency and test-retest reliability. Construct validity was evidenced by significantly higher prior sun exposure scores and lower current sun behaviour scores in subjects with a history of non-melanoma skin cancer. LIMITATIONS: Self-reported questionnaires, though efficient and low cost, may be subject to recall error and bias. Further work remains to determine if the SEBI maintains its reliability and validity in different populations. CONCLUSION: The SEBI is a brief self-administered questionnaire, which appears to be reliable and valid. It may provide useful measures of past and present sun exposure and current sun behaviour, which may be useful in studies of skin cancer incidence and risk modification. PMID- 22487013 TI - Regulatory volume decrease in COS-7 cells at 22 degrees C and its influence on the Boyle van't Hoff relation and the determination of the osmotically inactive volume. AB - Cryobiological analyses assume that the direction and rate of water movements across cell membranes and equilibrium cell volumes are determined solely by differences in the chemical potentials of intra- and extra-cellular water. A consequence of this assumption is that cells obey the Boyle van't Hoff (BvH) law which states that cell volumes are a linear function of reciprocal osmolality. Extrapolation of the BvH plot to infinite osmolality yields a quantity b, the fractional volume of the cell occupied by solids. In many cells, however, a cell volume excursion above the isotonic volume initiates an energy-requiring response that causes the swollen cells to shrink back to or towards isotonic volume. It is referred to as regulatory volume decrease (RVD). We have observed a strong RVD in COS-7 cells. If not eliminated by keeping exposure times short, this RVD produces a b that is 60% too high (0.48 vs. 0.30). These results indicate the importance of examining cells for volume regulatory mechanisms before performing measurements to determine their osmotic parameters. PMID- 22487014 TI - Re: Stephan Madersbacher. After three randomised controlled trials comparing 120 W high-performance-system potassium-titanyl-phosphate laser vaporisation to transurethral resection of the prostate (TURP), is this procedure finally first line, outdated, or still not surpassing TURP? Eur Urol 2012;61:1174-6. PMID- 22487015 TI - Re: Camillo Porta, Emiliano Calvo, Miguel A. Climent, et al. Efficacy and safety of everolimus in elderly patients with metastatic renal cell carcinoma: an exploratory analysis of the outcomes of elderly patients in the RECORD-1 Trial. Eur Urol 2012;61:826-33. PMID- 22487017 TI - Preoperative staging with magnetic resonance imaging, with confirmatory biopsy, improves surgical outcomes in women with breast cancer without increasing rates of mastectomy. AB - Needle biopsy to evaluate findings on MRI that could alter surgical planning has been recommended. This study is a retrospective review to evaluate MRI preoperative staging with biopsy confirmation of suspicious findings. A total of 184 women were diagnosed with breast cancer between January 2004 and June 2008. Of these, 79 underwent bilateral MRI before definitive surgery and 105 did not. Suspicious findings on MRI, mammography, or clinical exam underwent additional needle biopsy at the discretion of the surgeon. A retrospective chart review was performed to compare the two groups with respect to rates of reoperative surgery, successful breast conservation, and confirmatory biopsies. Sensitivity and specificity of MRI for preoperative staging is 0.81 and 0.84, respectively. There were no significant differences in demographics or cancer characteristics between the MRI and non-MRI groups. Fewer women who underwent preoperative MRI staging required repeat breast surgery (11% versus 26%, p = .04) or repeat axillary surgery (10% versus 20%, p = .05). There is no difference in the proportion of women who successfully completed conservative therapy and those treated radically (52% versus 53%), but there is a significant increase in women who undergo additional needle biopsy to confirm suspicious findings after initial diagnosis in the MRI group (25% versus 11% p = .04). In this study, mastectomy rates are not increased; suggesting that women who undergo mastectomy following staging would undergo mastectomy following failed conservative therapy if they were not staged. The downside of this improvement is a 14% increase in women who require confirmatory biopsy. PMID- 22487018 TI - The influence of the cementation margin position on the amount of undetected cement. A prospective clinical study. AB - OBJECTIVE: To evaluate the amount of undetected cement after cementation and cleaning of implant-supported restorations. MATERIALS AND METHODS: Fifty three patients were treated with 53 single implant-supported metal-ceramic restorations. The subgingival location of the margin of each implant was measured with a periodontal probe mesially, distally, buccaly, and lingually(,) resulting in 212 measurements. The data were divided into four groups: equally with tissue level (14 samples), 1 mm subgingivally (56), 2 mm (74), and 3 mm (68) below tissues contour. Metal-ceramic restorations were fabricated with occlusal openings and cemented on standard abutments with resin-reinforced glass-ionomer. After cleaning, a radiograph was taken to assess if all cement had been removed. Then the abutment/crown unit was unscrewed for evaluation. All quadrants of the specimens and peri-implant tissues were photographed and analyzed with Adobe Photoshop. Two proportions were calculated: (1) the relation between the cement remnants area and the total area of the abutment/restoration and (2) the relation between the cement remnants and the total area of implant soft tissue contour. Significance set to 0.05. RESULTS: Excess on the crown groups: 1 (0.002 +/- 0.001); 2 (0.024 +/- 0.005); 3 (0.036 +/- 0.004); 4 (0.055 +/- 0.007). Undetected excess increased when the margin was located deeper subgingivally (P = 0.000), significant difference was found among all groups (P <= 0.05). Remnants in the soft tissue groups: 1 (0.014 +/- 0.006); 2 (0.052 +/- 0.011); 3 (0.057 +/- 0.009); 4 (0.071 +/- 0.012). The increase of the remnants was statistically reliable (P = 0.0045), significant difference was found between group 1 and 2 (P <= 0.05). Radiographic evaluation showed that cement remnants mesially were visible in four cases of 53 or 7.5%, and in six cases of 53 distally (11.3%). CONCLUSIONS: The deeper the position of the margin, the greater amount of undetected cement was discovered. Dental radiographs should not be considered as a reliable method for cement excess evaluation. PMID- 22487016 TI - Categorisation of complications and validation of the Clavien score for percutaneous nephrolithotomy. AB - BACKGROUND: Although widely used, the validity and reliability of the Clavien classification of postoperative complications have not been tested in urologic procedures, such as percutaneous nephrolithotomy (PCNL). OBJECTIVE: To validate the Clavien score and categorise complications of PCNL. DESIGN, SETTING, AND PARTICIPANTS: Data for 528 patients with complications after PCNL were used to create a set of 70 unique complication-management combinations. Clinical case summaries for each complication-management combination were compiled in a survey distributed to 98 urologists, who rated each combination using the Clavien classification. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Interrater agreement for Clavien scores was estimated using Fleiss' kappa (kappa). The relationship between Clavien score and the duration of postoperative hospital stay was analysed using multivariate nonlinear regression models that adjusted for operating time, preoperative urine microbial culture, presence of staghorn stone, and use of postoperative nephrostomy tube. RESULTS AND LIMITATIONS: Overall interrater agreement in grading postoperative complications was moderate (kappa=0.457; p<0.001). Agreement was highest for Clavien score 5 and decreased with lower Clavien scores. Higher agreement was found for Clavien scores 3 and 4 than in subcategories of these scores. Postoperative stay increased with higher Clavien scores and was unaffected by inherent differences between study centres. A standard list of post-PCNL complications and their corresponding Clavien scores was created. CONCLUSIONS: Although the Clavien classification demonstrates high validity, interrater reliability is low for minor complications. To improve the reliability and consistency of reporting adverse outcomes of PCNL, we have assigned Clavien scores to complications of PCNL. PMID- 22487019 TI - How to define 'best practice' for use in Knowledge Translation research: a practical, stepped and interactive process. AB - OBJECTIVES: Defining 'best practice' is one of the first and crucial steps in any Knowledge Translation (KT) research project. Without a sound understanding of what exactly should happen in practice, it is impossible to measure the extent of existing gaps between 'desired' and 'actual' care, set implementation goals, and monitor performance. The aim of this paper is to present a practical, stepped and interactive process to develop best practice recommendations that are actionable, locally applicable and in line with the best available research-based evidence, with a view to adapt these into process measures (quality indicators) for KT research purposes. METHODS: Our process encompasses the following steps: (1) identify current, high-quality clinical practice guidelines (CPGs) and extract recommendations; (2) select strong recommendations in key clinical management areas; (3) update evidence and create evidence overviews; (4) discuss evidence and produce agreed 'evidence statements'; (5) discuss the relevance of the evidence with local stakeholders; and (6) develop locally applicable actionable best practice recommendations, suitable for use as the basis of quality indicators. CONCLUSIONS: Actionable definitions of local best practice are a prerequisite for doing KT research. As substantial resources go into rigorously synthesizing evidence and developing CPGs, it is important to make best use of such available resources. We developed a process for efficiently developing locally applicable actionable best practice recommendations from existing high quality CPGs that are in line with current research evidence. PMID- 22487020 TI - Factors associated with antenatal smoking among Aboriginal and Torres Strait Islander women in two jurisdictions. AB - INTRODUCTION AND AIMS: Smoking rates are three times as high for pregnant Indigenous women relative to non-Indigenous women, in Australia. This paper describes Indigenous women's self-reported antenatal smoking behaviour and compares knowledge and attitudes of those who: (i) smoke and don't smoke during pregnancy; and (ii) quit or continued to smoke since the beginning of pregnancy. DESIGN AND METHODS: Cross-sectional surveys with 264 pregnant Indigenous women in two states collected data on smoking status, antenatal changes, risk knowledge, attitudes to smoking and sociodemographic characteristics. Multivariable logistic regression analyses assessed associations between knowledge and attitude variables and smoking status and antenatal changes in smoking status. RESULTS: Forty-six per cent of the women (n = 121) reported currently smoking. The majority (68%) who smoked at the beginning of pregnancy reported quitting (21%) or reducing (47%). Relative to smokers, non-smokers had more schooling (P = 0.002), more post-secondary education (P = 0.023), lower parity (P = 0.003), better understanding of smoking-related risks (miscarriage P = 0.01; low birth weight P = 0.003; infant illness P < 0.001; childhood behavioural problems P = 0.007), and less frequently expressed attitudes indicating that quitting was very difficult given other problems they faced. Similar patterns were found for women who quit during pregnancy compared to those who continued smoking. DISCUSSION AND CONCLUSIONS: Increasing awareness of antenatal smoking risks and the benefits of quitting may motivate women to attempt to quit. However, knowledge alone is unlikely to be sufficient considering the life circumstances of many Indigenous women. Addressing the social environment and daily stressors, particularly those exacerbated by pregnancy, may be critical to supporting quit attempts. PMID- 22487021 TI - Bifocal intestinal gastric heterotopia involving the duodenum and colon: a case report. PMID- 22487023 TI - Analysis of KIR gene frequencies and HLA class I genotypes in prostate cancer and control group. AB - Prostate cancer is the second most common cancer in men, with a significant increase in incidence and mortality in men over 50 years of age. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study is to evaluate the association between the KIR genes and HLA alleles in patients with prostate cancer and healthy controls. Two hundred patients with prostate cancer and 185 healthy controls were typed for HLA class I and KIR genes by PCR-SSP. When both groups were compared, no significant differences were found for HLA-C group 1 and group 2, HLA-Bw4, HLA-A3 and A11. No difference was seen either in KIR frequency between patients with prostate cancer and controls. In conclusion, our data suggest no potential role for the KIR gene system in prostate cancer. PMID- 22487022 TI - Characterization of antimicrobial resistance of Pseudomonas aeruginosa isolated from canine infections. AB - AIMS: To determine the prevalence of Pseudomonas aeruginosa among dogs with suspected soft tissue infections and to characterize these isolates. METHODS AND RESULTS: Swabs were taken from infected soft tissues of 402 dogs. Pseudomonas aeruginosa strains were confirmed phenotypically and tested for susceptibility to 11 antimicrobial agents and genotyped by SpeI pulsed-field gel electrophoresis (PFGE). The genetic basis of fluoroquinolone (FQ) resistance and the presence of integrons were also characterized. A total of 27 (6.7%) dogs tested positive for Ps. aeruginosa. Fourteen different SpeI patterns were observed in 25 typeable strains. Among the beta-lactams, three isolates presented resistance to ticarcillin and carbenicillin, while only one isolate exhibited resistance to ceftazidime. Among the aminoglycosides (AGs), three strains showed resistance to amikacin, and four strains exhibited resistance to gentamicin and tobramycin. Four strains with mutations that led to the substitution of Thr at position 83 with Ile in GyrA and the exchange of Ser at position 87 with Leu in ParC displayed resistance to all tested FQs. These strains also carried class 1 integrons and showed resistance to between 6 and 10 antimicrobials. These integrons included four different gene cassettes (aacA4-aadA1, bla(OXA-31) aadA2, aadA1-arr-3-catB3 and cmlA5-cmlA-aadA1). CONCLUSIONS: A small proportion of infected dogs treated in two animal hospitals in Beijing, China carried Ps. aeruginosa isolates. Low levels of resistance to anti-pseudomonal agents were observed in these strains. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first report on the antimicrobial resistance profiles of Ps. aeruginosa isolated from infected canine origin in China. Additionally, this is the first report of the oxacillin resistance gene bla(OXA-31) in a canine Ps. aeruginosa isolate. PMID- 22487024 TI - Fistula first breakthrough initiative: targeting catheter last in fistula first. AB - An arteriovenous fistula (AVF) is the optimal vascular access for hemodialysis (HD), because it is associated with prolonged survival, fewer infections, lower hospitalization rates, and reduced costs. The AVF First breakthrough initiative (FFBI) has made dramatic progress, effectively promoting the increase in the national AVF prevalence since the program's inception from 32% in May 2003 to nearly 60% in 2011. Central venous catheter (CVC) use has stabilized and recently decreased slightly for prevalent patients (treated more than 90 days), while CVC usage in the first 90 days remains unacceptably high at nearly 80%. This high prevalence of CVC utilization suggests important specific improvement goals for FFBI. In addition to the current 66% AVF goal, the initiative should include specific CVC usage target(s), based on the KDOQI goal of less than 10% in patients undergoing HD for more than 90 days, and a substantially improved initial target from the current CVC proportion. These specific CVC targets would be disseminated through the ESRD networks to individual dialysis facilities, further emphasizing CVC avoidance in the transition from advanced CKD to chronic kidney failure, while continuing to decrease CVC by prompt conversion of CVC based hemodialysis patients to permanent vascular access, utilizing an AVF whenever feasible. PMID- 22487026 TI - The strange case of Dr Jekyll and Mr Hyde (about surgery and basic research). A perspective for a new approach for pursuing an academic career (also in Italy). PMID- 22487025 TI - Safety of catheter-delivered plasmin in patients with acute lower extremity arterial or bypass graft occlusion: phase I results. AB - BACKGROUND: Current treatment of acute peripheral artery or bypass graft occlusion utilizes catheter-directed thrombolysis of a plasminogen activator (PA). Plasmin is a direct-acting thrombolytic with a striking safety advantage over PA in preclinical models. OBJECTIVES: To report the first use of purified plasmin for acute lower extremity arterial or bypass graft thrombosis in a phase I dose-escalation study of a catheter-delivered agent. METHODS: Eighty-three patients with non-embolic occlusion of infrainguinal native arteries or bypass grafts were enrolled (safety population) into seven sequential dose cohorts to receive 25-175 mg of plasmin by intrathrombus infusion over 5 h. Arteriograms were performed at baseline, 2 h, and 5 h, and subjects were monitored for 30 days for clinical outcomes and laboratory parameters of systemic fibrinolysis. RESULTS: Major bleeding occurred in four patients (4.8%), and minor bleeding alone in 13 (15.7%), with no trend towards more bleeding at higher dosages of plasmin. There was a trend towards lower plasma concentrations of fibrinogen, alpha(2) -antiplasmin and alpha(2) -macroglobulin with increasing doses of plasmin, but the nadir fibrinogen concentration was > 350 mg dL(-1) at the highest plasmin dose. Individual nadir values were above 200 mg dL(-1) in 82 of 83 subjects, and were not different in patients with or without bleeding. Thrombolysis (>= 50%) occurred in 79% of subjects receiving 125-175 mg of plasmin, as compared with 50% who received 25-100 mg. CONCLUSIONS: Catheter delivered plasmin can be safely administered to patients with acute lower extremity arterial occlusion at dosages of 25-175 mg. PMID- 22487027 TI - The incidence of type 1 diabetes in young Czech children stopped rising. AB - AIMS: The aim was to assess trends in incidence of pediatric type 1 diabetes (T1D) using data recorded by the population-based Czech Childhood Diabetes Register over 1989-2009. METHODS: New cases of childhood-onset T1D aged 0-14.9 yr were recorded using the EURODIAB protocol by two independent sources with the combined estimated completeness of 98.6%. The incidence was modeled by Poisson regression, and the effects of age and calendar time on incidence were assessed using piecewise linear functions. RESULTS: A total of 5155 cases was ascertained over 1989-2009 from an average pediatric population of 1.76 million. Two points of change in the incidence trend were identified by the modeling: in 1995 the incidence accelerated, while in 2001 the growth in incidence significantly slowed down in all ages up to 10 yr. In the youngest age category, 0-4 yr at onset, the rapid average annual rise of 15% over 1996-2001 suddenly changed into stagnation over 2002-2009. CONCLUSIONS: Our data contribute to the notion that long- and intermediate-term predictions from the past incidence developments of incidence are difficult, as abrupt changes in the trend can occur. Caution should be exercised against too far-reaching incidence predictions, even if the population has experienced a previous history of a very fast rise in T1D incidence. PMID- 22487028 TI - Hyperactivation of right inferior frontal cortex in young binge drinkers during response inhibition: a follow-up study. AB - AIMS: The objective of this study was to examine brain activity, with particular attention to prefrontal function, during response execution and inhibition in youths who have engaged in binge drinking (BD) for at least 2 years. DESIGN: Event-related potentials (ERPs) were recorded twice within 3 years, during performance of a Go/NoGo task. SETTING: The study was part of a longitudinal study of the neurocognitive effects of BD. PARTICIPANTS: A total of 48 undergraduate students, 25 controls (14 females) and 23 binge drinkers (10 females), with no personal or family history of alcoholism or psychopathological disorders. MEASUREMENTS: The Go-P3 and NoGo-P3 components of the ERPs were examined by principal component analysis and exact low-resolution tomography analysis (eLORETA). FINDINGS: Binge drinkers showed larger Go-P3 amplitudes than controls in the first and second evaluations (P = 0.019). They also showed larger NoGo-P3 amplitude in the second evaluation (P = 0.002). eLORETA analyses in the second evaluation revealed significantly greater activation of the right inferior frontal cortex (rIFC) in binge drinkers than in controls during successful inhibition (P < 0.05). CONCLUSIONS: Young binge drinkers appear to show abnormal brain activity as measured by event-related potentials during response execution and inhibition which may represent a neural antecedent of difficulties in impulse control. PMID- 22487029 TI - Beyond simple reinforcement learning: the computational neurobiology of reward learning and valuation. AB - Neural computational accounts of reward-learning have been dominated by the hypothesis that dopamine neurons behave like a reward-prediction error and thus facilitate reinforcement learning in striatal target neurons. While this framework is consistent with a lot of behavioral and neural evidence, this theory fails to account for a number of behavioral and neurobiological observations. In this special issue of EJN we feature a combination of theoretical and experimental papers highlighting some of the explanatory challenges faced by simple reinforcement-learning models and describing some of the ways in which the framework is being extended in order to address these challenges. PMID- 22487030 TI - Model-based learning and the contribution of the orbitofrontal cortex to the model-free world. AB - Learning is proposed to occur when there is a discrepancy between reward prediction and reward receipt. At least two separate systems are thought to exist: one in which predictions are proposed to be based on model-free or cached values; and another in which predictions are model-based. A basic neural circuit for model-free reinforcement learning has already been described. In the model free circuit the ventral striatum (VS) is thought to supply a common-currency reward prediction to midbrain dopamine neurons that compute prediction errors and drive learning. In a model-based system, predictions can include more information about an expected reward, such as its sensory attributes or current, unique value. This detailed prediction allows for both behavioral flexibility and learning driven by changes in sensory features of rewards alone. Recent evidence from animal learning and human imaging suggests that, in addition to model-free information, the VS also signals model-based information. Further, there is evidence that the orbitofrontal cortex (OFC) signals model-based information. Here we review these data and suggest that the OFC provides model-based information to this traditional model-free circuitry and offer possibilities as to how this interaction might occur. PMID- 22487031 TI - Re-evaluating the role of the orbitofrontal cortex in reward and reinforcement. AB - The orbitofrontal cortex and adjacent ventromedial prefrontal cortex carry reward representations and mediate flexible behaviour when circumstances change. Here we review how recent experiments in humans and macaques have confirmed the existence of a major difference between the functions of the ventromedial prefrontal cortex and adjacent medial orbitofrontal cortex (mOFC) on the one hand and the lateral orbitofrontal cortex (lOFC) on the other. These differences, however, may not be best accounted for in terms of specializations for reward and error/punishment processing as is commonly assumed. Instead we argue that both lesion and functional magnetic resonance imaging studies reveal that the lOFC is concerned with the assignment of credit for both reward and error outcomes to the choice of specific stimuli and with the linking of specific stimulus representations to representations of specific types of reward outcome. By contrast, we argue that the ventromedial prefrontal cortex/mOFC is concerned with evaluation, value guided decision-making and maintenance of a choice over successive decisions. Despite the popular view that they cause perseveration of behaviour and inability to inhibit repetition of a previously made choice, we found that lesions in neither orbitofrontal subdivision caused perseveration. On the contrary, lesions in the lOFC made animals switch more rapidly between choices when they were finding it difficult to assign reward values to choices. Lesions in the mOFC caused animals to lose their normal predisposition to repeat previously successful choices, suggesting that the mOFC does not just mediate value comparison in choice but also facilitates maintenance of the same choice if it has been successful. PMID- 22487032 TI - Dissociating hippocampal and striatal contributions to sequential prediction learning. AB - Behavior may be generated on the basis of many different kinds of learned contingencies. For instance, responses could be guided by the direct association between a stimulus and response, or by sequential stimulus-stimulus relationships (as in model-based reinforcement learning or goal-directed actions). However, the neural architecture underlying sequential predictive learning is not well understood, in part because it is difficult to isolate its effect on choice behavior. To track such learning more directly, we examined reaction times (RTs) in a probabilistic sequential picture identification task in healthy individuals. We used computational learning models to isolate trial-by-trial effects of two distinct learning processes in behavior, and used these as signatures to analyse the separate neural substrates of each process. RTs were best explained via the combination of two delta rule learning processes with different learning rates. To examine neural manifestations of these learning processes, we used functional magnetic resonance imaging to seek correlates of time-series related to expectancy or surprise. We observed such correlates in two regions, hippocampus and striatum. By estimating the learning rates best explaining each signal, we verified that they were uniquely associated with one of the two distinct processes identified behaviorally. These differential correlates suggest that complementary anticipatory functions drive each region's effect on behavior. Our results provide novel insights as to the quantitative computational distinctions between medial temporal and basal ganglia learning networks and enable experiments that exploit trial-by-trial measurement of the unique contributions of both hippocampus and striatum to response behavior. PMID- 22487033 TI - How much of reinforcement learning is working memory, not reinforcement learning? A behavioral, computational, and neurogenetic analysis. AB - Instrumental learning involves corticostriatal circuitry and the dopaminergic system. This system is typically modeled in the reinforcement learning (RL) framework by incrementally accumulating reward values of states and actions. However, human learning also implicates prefrontal cortical mechanisms involved in higher level cognitive functions. The interaction of these systems remains poorly understood, and models of human behavior often ignore working memory (WM) and therefore incorrectly assign behavioral variance to the RL system. Here we designed a task that highlights the profound entanglement of these two processes, even in simple learning problems. By systematically varying the size of the learning problem and delay between stimulus repetitions, we separately extracted WM-specific effects of load and delay on learning. We propose a new computational model that accounts for the dynamic integration of RL and WM processes observed in subjects' behavior. Incorporating capacity-limited WM into the model allowed us to capture behavioral variance that could not be captured in a pure RL framework even if we (implausibly) allowed separate RL systems for each set size. The WM component also allowed for a more reasonable estimation of a single RL process. Finally, we report effects of two genetic polymorphisms having relative specificity for prefrontal and basal ganglia functions. Whereas the COMT gene coding for catechol-O-methyl transferase selectively influenced model estimates of WM capacity, the GPR6 gene coding for G-protein-coupled receptor 6 influenced the RL learning rate. Thus, this study allowed us to specify distinct influences of the high-level and low-level cognitive functions on instrumental learning, beyond the possibilities offered by simple RL models. PMID- 22487034 TI - Habits, action sequences and reinforcement learning. AB - It is now widely accepted that instrumental actions can be either goal-directed or habitual; whereas the former are rapidly acquired and regulated by their outcome, the latter are reflexive, elicited by antecedent stimuli rather than their consequences. Model-based reinforcement learning (RL) provides an elegant description of goal-directed action. Through exposure to states, actions and rewards, the agent rapidly constructs a model of the world and can choose an appropriate action based on quite abstract changes in environmental and evaluative demands. This model is powerful but has a problem explaining the development of habitual actions. To account for habits, theorists have argued that another action controller is required, called model-free RL, that does not form a model of the world but rather caches action values within states allowing a state to select an action based on its reward history rather than its consequences. Nevertheless, there are persistent problems with important predictions from the model; most notably the failure of model-free RL correctly to predict the insensitivity of habitual actions to changes in the action-reward contingency. Here, we suggest that introducing model-free RL in instrumental conditioning is unnecessary, and demonstrate that reconceptualizing habits as action sequences allows model-based RL to be applied to both goal-directed and habitual actions in a manner consistent with what real animals do. This approach has significant implications for the way habits are currently investigated and generates new experimental predictions. PMID- 22487035 TI - A theoretical account of cognitive effects in delay discounting. AB - Although delay discounting, the attenuation of the value of future rewards, is a robust finding, the mechanism of discounting is not known. We propose a potential mechanism for delay discounting such that discounting emerges from a search process that is trying to determine what rewards will be available in the future. In this theory, the delay dependence of the discounting of future expected rewards arises from three assumptions. First, that the evaluation of outcomes involves a search process. Second, that the value is assigned to an outcome proportionally to how easy it is to find. Third, that outcomes that are less delayed are typically easier for the search process to find. By relaxing this third assumption (e.g. by assuming that episodically-cued outcomes are easier to find), our model suggests that it is possible to dissociate discounting from delay. Our theory thereby explains the empirical result that discounting is slower to episodically-imagined outcomes, because these outcomes are easier for the search process to find. Additionally, the theory explains why improving cognitive resources such as working memory slows discounting, by improving searches and thereby making rewards easier to find. The three assumptions outlined here are likely to be instantiated during deliberative decision-making, but are unlikely in habitual decision-making. We model two simple implementations of this theory and show that they unify empirical results about the role of cognitive function in delay discounting, and make new neural, behavioral, and pharmacological predictions. PMID- 22487036 TI - Decision value computation in DLPFC and VMPFC adjusts to the available decision time. AB - It is increasingly clear that simple decisions are made by computing decision values for the options under consideration, and then comparing these values to make a choice. Computational models of this process suggest that it involves the accumulation of information over time, but little is known about the temporal course of valuation in the brain. To examine this, we manipulated the available decision time and observed the consequences in the brain and behavioral correlates of choice. Participants were scanned with functional magnetic resonance imaging while they chose to eat or not eat basic food items, in two conditions differing in the amount of time provided for choice. After identifying valuation-related regions with unbiased whole-brain general linear models, we analyzed two regions of interest: ventromedial prefrontal cortex (VMPFC) and dorsolateral prefrontal cortex (DLPFC). Finite impulse response models of the upsampled estimated neural activity from those regions allowed us to examine the onset, duration and termination of decision value signals, and to compare across regions. We found evidence for the immediate onset of value computation in both regions, but an extended duration with longer decision time. However, this was not accompanied by behavioral changes in either the accuracy or determinants of choice. Finally, there was modest evidence that DLPFC computation correlated with, but lagged behind, VMPFC computation, suggesting the sharing of information across these regions. These findings have important implications for models of decision value computation and choice. PMID- 22487038 TI - Category representation and generalization in the prefrontal cortex. AB - Categorization is a function of the brain that serves to group together items and events in our environments. Here we review the following important issues related to category representation and generalization: namely, where categories are presented in the brain, and how the brain utilizes categorical membership to generate new information. Accumulated experimental evidence shows that the prefrontal cortex (PFC) plays a critical role in category formation and generalization. We propose that prefrontal neurons abstract the commonality beyond individual stimuli, and categorize these based on their common meaning by ignoring their physical properties and learning to represent the boundaries between behaviorally significant categories. We also claim that a subgroup of prefrontal neurons simultaneously receives the category-related information and specific property information (e.g. reward) associated with an exemplar, to form a category-based representation of that property, and propagates it among stimuli of the same category, possibly reflecting a neural basis for category generalization in the PFC. These results suggest that the PFC is involved in representing abstract rules, and generating new information on the basis of previously acquired knowledge. PMID- 22487037 TI - Strategic control in decision-making under uncertainty. AB - Complex economic decisions - whether investing money for retirement or purchasing some new electronic gadget - often involve uncertainty about the likely consequences of our choices. Critical for resolving that uncertainty are strategic meta-decision processes, which allow people to simplify complex decision problems, evaluate outcomes against a variety of contexts, and flexibly match behavior to changes in the environment. In recent years, substantial research has implicated the dorsomedial prefrontal cortex (dmPFC) in the flexible control of behavior. However, nearly all such evidence comes from paradigms involving executive function or response selection, not complex decision-making. Here, we review evidence that demonstrates that the dmPFC contributes to strategic control in complex decision-making. This region contains a functional topography such that the posterior dmPFC supports response-related control, whereas the anterior dmPFC supports strategic control. Activation in the anterior dmPFC signals changes in how a decision problem is represented, which in turn can shape computational processes elsewhere in the brain. Based on these findings, we argue for both generalized contributions of the dmPFC to cognitive control, and specific computational roles for its subregions depending upon the task demands and context. We also contend that these strategic considerations are likely to be critical for decision-making in other domains, including interpersonal interactions in social settings. PMID- 22487039 TI - Generalization of value in reinforcement learning by humans. AB - Research in decision-making has focused on the role of dopamine and its striatal targets in guiding choices via learned stimulus-reward or stimulus-response associations, behavior that is well described by reinforcement learning theories. However, basic reinforcement learning is relatively limited in scope and does not explain how learning about stimulus regularities or relations may guide decision making. A candidate mechanism for this type of learning comes from the domain of memory, which has highlighted a role for the hippocampus in learning of stimulus stimulus relations, typically dissociated from the role of the striatum in stimulus-response learning. Here, we used functional magnetic resonance imaging and computational model-based analyses to examine the joint contributions of these mechanisms to reinforcement learning. Humans performed a reinforcement learning task with added relational structure, modeled after tasks used to isolate hippocampal contributions to memory. On each trial participants chose one of four options, but the reward probabilities for pairs of options were correlated across trials. This (uninstructed) relationship between pairs of options potentially enabled an observer to learn about option values based on experience with the other options and to generalize across them. We observed blood oxygen level-dependent (BOLD) activity related to learning in the striatum and also in the hippocampus. By comparing a basic reinforcement learning model to one augmented to allow feedback to generalize between correlated options, we tested whether choice behavior and BOLD activity were influenced by the opportunity to generalize across correlated options. Although such generalization goes beyond standard computational accounts of reinforcement learning and striatal BOLD, both choices and striatal BOLD activity were better explained by the augmented model. Consistent with the hypothesized role for the hippocampus in this generalization, functional connectivity between the ventral striatum and hippocampus was modulated, across participants, by the ability of the augmented model to capture participants' choice. Our results thus point toward an interactive model in which striatal reinforcement learning systems may employ relational representations typically associated with the hippocampus. PMID- 22487040 TI - Different dorsal striatum circuits mediate action discrimination and action generalization. AB - Generalization is an important process that allows animals to extract rules from regularities of past experience and apply them to analogous situations. In particular, the generalization of previously learned actions to novel instruments allows animals to use past experience to act faster and more efficiently in an ever-changing environment. However, generalization of actions to a dissimilar instrument or situation may also be detrimental. In this study, we investigated the neural bases of action generalization and discrimination in mice trained on a lever-pressing task. Using specific schedules of reinforcement known to bias animals towards habitual or goal-directed behaviors, we confirmed that action generalization is more prominent in animals using habitual rather than goal directed strategies. We discovered that selective excitotoxic lesions of the dorsolateral and dorsomedial striatum have opposite effects on the generalization of a previously learned action to a novel lever. Whereas lesions of the dorsolateral striatum impair action generalization, dorsomedial striatum lesions affect action discrimination and bias subjects towards action generalization. Importantly, these lesions do not affect the ability of animals to explore or match their lever-pressing rate to the reinforcement rate, or the ability to distinguish between different levers. The data presented here reveal that dorsolateral and dorsomedial striatal circuits have opposing roles in the generalization of previously learned actions to novel instruments, and suggest that these circuits compete for the expression of generalization in novel situations. PMID- 22487041 TI - Neural control of dopamine neurotransmission: implications for reinforcement learning. AB - In the past few decades there has been remarkable convergence of machine learning with neurobiological understanding of reinforcement learning mechanisms, exemplified by temporal difference (TD) learning models. The anatomy of the basal ganglia provides a number of potential substrates for instantiation of the TD mechanism. In contrast to the traditional concept of direct and indirect pathway outputs from the striatum, we emphasize that projection neurons of the striatum are branched and individual striatofugal neurons innervate both globus pallidus externa and globus pallidus interna/substantia nigra (GPi/SNr). This suggests that the GPi/SNr has the necessary inputs to operate as the source of a TD signal. We also discuss the mechanism for the timing processes necessary for learning in the TD framework. The TD framework has been particularly successful in analysing electrophysiogical recordings from dopamine (DA) neurons during learning, in terms of reward prediction error. However, present understanding of the neural control of DA release is limited, and hence the neural mechanisms involved are incompletely understood. Inhibition is very conspicuously present among the inputs to the DA neurons, with inhibitory synapses accounting for the majority of synapses on DA neurons. Furthermore, synchronous firing of the DA neuron population requires disinhibition and excitation to occur together in a coordinated manner. We conclude that the inhibitory circuits impinging directly or indirectly on the DA neurons play a central role in the control of DA neuron activity and further investigation of these circuits may provide important insight into the biological mechanisms of reinforcement learning. PMID- 22487043 TI - Decomposing effects of dopaminergic medication in Parkinson's disease on probabilistic action selection--learning or performance? AB - Dopamine has long been implicated in reward-based learning and the expression of such learned associations on performance. Robust evidence supports its effects on learning and performance, but teasing these apart has proved challenging. Here we have adapted a classic test of value-based learning, the probabilistic selection task, to disentangle effects of dopamine on value-based performance from effects on value-based learning. Valence-specific effects of dopamine on this specific task cannot be accounted for by modulation of learning, and therefore must reflect modulation of performance. We found that dopaminergic medication, consisting of levodopa and/or dopamine agonists taken at own dose, in 18 patients with mild Parkinson's disease (Hoehn and Yahr < 2.5) potentiated reward-based approach in terms of both accuracy and reaction times, while leaving punishment based avoidance unaffected. These data demonstrate that the effects of dopamine on probabilistic action selection are at least partly mediated by effects on the expression of learned associations rather than on learning itself, and help refine current models of dopamine's role in reward. PMID- 22487044 TI - Instrumental vigour in punishment and reward. AB - Recent notions about the vigour of responding in operant conditioning suggest that the long-run average rate of reward should control the alacrity of action in cases in which the actual cost of speed is balanced against the opportunity cost of sloth. The average reward rate is suggested as being reported by tonic activity in the dopamine system and thereby influencing all actions, including ones that do not themselves lead directly to the rewards. This idea is syntactically problematical for the case of punishment. Here, we broaden the scope of the original suggestion, providing a two-factor analysis of obviated punishment in a variety of operant circumstances. We also consider the effects of stochastically successful actions, which turn out to differ rather markedly between appetitive and aversive cases. Finally, we study how to fit these ideas into nascent treatments that extend concepts of opponency between dopamine and serotonin from valence to invigoration. PMID- 22487042 TI - From prediction error to incentive salience: mesolimbic computation of reward motivation. AB - Reward contains separable psychological components of learning, incentive motivation and pleasure. Most computational models have focused only on the learning component of reward, but the motivational component is equally important in reward circuitry, and even more directly controls behavior. Modeling the motivational component requires recognition of additional control factors besides learning. Here I discuss how mesocorticolimbic mechanisms generate the motivation component of incentive salience. Incentive salience takes Pavlovian learning and memory as one input and as an equally important input takes neurobiological state factors (e.g. drug states, appetite states, satiety states) that can vary independently of learning. Neurobiological state changes can produce unlearned fluctuations or even reversals in the ability of a previously learned reward cue to trigger motivation. Such fluctuations in cue-triggered motivation can dramatically depart from all previously learned values about the associated reward outcome. Thus, one consequence of the difference between incentive salience and learning can be to decouple cue-triggered motivation of the moment from previously learned values of how good the associated reward has been in the past. Another consequence can be to produce irrationally strong motivation urges that are not justified by any memories of previous reward values (and without distorting associative predictions of future reward value). Such irrationally strong motivation may be especially problematic in addiction. To understand these phenomena, future models of mesocorticolimbic reward function should address the neurobiological state factors that participate to control generation of incentive salience. PMID- 22487045 TI - How can a Bayesian approach inform neuroscience? AB - In this review we consider how Bayesian logic can help neuroscientists to understand behaviour and brain function. Firstly, we review some key characteristics of Bayesian systems - they integrate information making rational use of uncertainty, they apply prior knowledge in the interpretation of new observations, and (for several reasons) they are very effective learners. Secondly, we illustrate how some well-known psychological phenomena including visual illusions, categorical perception and attention can be understood in terms of Bayesian inference. We also consider how formal models can clarify our understanding of psychological constructs, by giving a truly computational definition of psychological processes. Finally, we consider how probabilistic representations and hence Bayesian algorithms could be implemented by neural populations. In particular, we explore how different types of population coding may lead to different predictions about activity in both single-unit and imaging studies, and draw a distinction in this context between the representation of parameters and implementation of computations. PMID- 22487046 TI - Uncertainty in action-value estimation affects both action choice and learning rate of the choice behaviors of rats. AB - The estimation of reward outcomes for action candidates is essential for decision making. In this study, we examined whether and how the uncertainty in reward outcome estimation affects the action choice and learning rate. We designed a choice task in which rats selected either the left-poking or right-poking hole and received a reward of a food pellet stochastically. The reward probabilities of the left and right holes were chosen from six settings (high, 100% vs. 66%; mid, 66% vs. 33%; low, 33% vs. 0% for the left vs. right holes, and the opposites) in every 20-549 trials. We used Bayesian Q-learning models to estimate the time course of the probability distribution of action values and tested if they better explain the behaviors of rats than standard Q-learning models that estimate only the mean of action values. Model comparison by cross-validation revealed that a Bayesian Q-learning model with an asymmetric update for reward and non-reward outcomes fit the choice time course of the rats best. In the action-choice equation of the Bayesian Q-learning model, the estimated coefficient for the variance of action value was positive, meaning that rats were uncertainty seeking. Further analysis of the Bayesian Q-learning model suggested that the uncertainty facilitated the effective learning rate. These results suggest that the rats consider uncertainty in action-value estimation and that they have an uncertainty-seeking action policy and uncertainty-dependent modulation of the effective learning rate. PMID- 22487048 TI - Bioengineering natural product biosynthetic pathways for therapeutic applications. AB - With the advent of next-generation DNA sequencing technologies, the number of microbial genome sequences has increased dramatically, revealing a vast array of new biosynthetic gene clusters. Genomics data provide a tremendous opportunity to discover new natural products, and also to guide the bioengineering of new and existing natural product scaffolds for therapeutic applications. Notably, it is apparent that the vast majority of biosynthetic gene clusters are either silent or produce very low quantities of the corresponding natural products. It is imperative therefore to devise methods for activating unproductive biosynthetic pathways to provide the quantities of natural products needed for further development. Moreover, on the basis of our expanding mechanistic and structural knowledge of biosynthetic assembly-line enzymes, new strategies for re programming biosynthetic pathways have emerged, resulting in focused libraries of modified products with potentially improved biological properties. In this review we will focus on the latest bioengineering approaches that have been utilised to optimise yields and increase the structural diversity of natural product scaffolds for future clinical applications. PMID- 22487047 TI - Surprise! Neural correlates of Pearce-Hall and Rescorla-Wagner coexist within the brain. AB - Learning theory and computational accounts suggest that learning depends on errors in outcome prediction as well as changes in processing of or attention to events. These divergent ideas are captured by models, such as Rescorla-Wagner (RW) and temporal difference (TD) learning on the one hand, which emphasize errors as directly driving changes in associative strength, vs. models such as Pearce-Hall (PH) and more recent variants on the other hand, which propose that errors promote changes in associative strength by modulating attention and processing of events. Numerous studies have shown that phasic firing of midbrain dopamine (DA) neurons carries a signed error signal consistent with RW or TD learning theories, and recently we have shown that this signal can be dissociated from attentional correlates in the basolateral amygdala and anterior cingulate. Here we will review these data along with new evidence: (i) implicating habenula and striatal regions in supporting error signaling in midbrain DA neurons; and (ii) suggesting that the central nucleus of the amygdala and prefrontal regions process the amygdalar attentional signal. However, while the neural instantiations of the RW and PH signals are dissociable and complementary, they may be linked. Any linkage would have implications for understanding why one signal dominates learning in some situations and not others, and also for appreciating the potential impact on learning of neuropathological conditions involving altered DA or amygdalar function, such as schizophrenia, addiction or anxiety disorders. PMID- 22487049 TI - Synaesthesia and colour constancy. AB - Grapheme-colour synaesthesia is an atypical condition characterized by the perception of colours when reading achromatic text. We investigated the level of colour processing responsible for these experiences. To do so, we tapped a central characteristic of colour perception. In different lighting conditions the same wavelength of light can prompt the perception of different colours. This helps humans recognize distinctive coloured objects despite changes in illumination. We wanted to see if synaesthetic colours were generated at a neural locus that was susceptible to colour constancy analyses. We used colour matching and naming tasks to examine interactions between simulated coloured illuminants and synaesthetic colours. Neither synaesthetic colour matching or naming was impacted. This contrasted with non-synaesthetic control participants, who performed the colour-matching task with graphemes physically coloured to mimic synaesthesia. Our data suggest that synaesthetic colour signals are not generated at lower-levels of colour processing, but are introduced at higher levels of analysis and are therefore not impacted by the processes responsible for perceptual constancy. PMID- 22487050 TI - Noninvasive electrocardiographic mapping for prediction of tachycardia mechanism and origin of atrial tachycardia following bilateral pulmonary transplantation. AB - This is a case of atrial tachycardia 2 years after pulmonary transplantation. After excluding right atrial involvement, tachycardia origin was located in a scar region medial to the anastomosis of the left inferior pulmonary donor vein. Tachycardia mechanism was microreentry. Noninvasive electrocardiographic mapping performed before the ablation procedure matched with results of invasive Carto mapping and predicted both tachycardia mechanism and origin. We discuss arrhythmia mechanism found after pulmonary transplantation and benefit of noninvasive electrocardiographic mapping for procedure planning. PMID- 22487051 TI - Interferon-gamma release assays for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis. AB - Interferon -gamma release assays (IGRAs) provide a new diagnostic method for Mycobacterium tuberculosis (TB) infection. However, the diagnostic value of IGRAs for extrapulmonary TB (EPTB) has not been clarified. We searched several databases and selected papers with strict inclusion criteria, evaluated the evidence of commercially available IGRAs (QuantiFERON((r)) -TB Gold QFT-G or QFT GIT and T-SPOT((r)) .TB) on blood and the tuberculin skin test (TST) using random effects models. Twenty studies with 1711 patients were included. After excluding indeterminate results, pooled sensitivity for the diagnosis of EPTB was 72% [95% confidence interval (CI) 65-79%] for QFT-G or GIT and 90% (95% CI, 86-93%) for T SPOT; in high-income countries the sensitivity of QFT-G or GIT (79%, 95% CI 72 86%) was much higher than that (29%, 95% CI 14-48%) in low/middle-income countries. Pooled specificity for EPTB was 82% (95% CI 78-87%) for QFT-G or GIT and 68% (95% CI 64-73%) for T-SPOT. Pooled sensitivity of TST from four studies in high-income countries was lower than that of IGRAs. T-SPOT was more sensitive in detecting EPTB than QFT-G or GIT and TST. However, both IGRAs and TST have similar specificity for EPTB. IGRAs have limited value as diagnostic tools to screen and rule out EPTB, especially in low/middle-income countries. The immune status of patients does not affect the diagnostic accuracy of IGRAs for EPTB. PMID- 22487052 TI - First detection of VIM-4 metallo-beta-lactamase-producing Escherichia coli in Russia. AB - An Escherichia coli isolate co-producing VIM-4 metallo-beta-lactamase and CTX-M 15 extended spectrum beta-lactamase was recovered from the urine of a patient with head trauma in Moscow, Russia. The bla(VIM-4) and bla(CTX-M-15) genes were carried, respectively, by transmissible plasmids of IncW and IncI1 groups. The nucleotide sequence of the VIM-4-encoding integron was nearly identical to that of In416, which represent a large group of structurally related integrons previously found in Enterobacteriaceae all around the Mediterranean basin. This is the first report of a metallo-beta-lactamase-producing E. coli in Russia. PMID- 22487053 TI - Unilateral pallidal stimulation in a patient with truncal dystonia. PMID- 22487054 TI - Metabolic monosaccharides altered cell responses to anticancer drugs. AB - Metabolic glycoengineering has been used to manipulate the glycochemistry of cell surfaces and thus the cell/cell interaction, cell adhesion, and cell migration. However, potential application of glycoengineering in pharmaceutical sciences has not been studied until recently. Here, we reported that Ac(4)ManNAc, an analog of N-acetyl-D-mannosamine (ManNAc), could affect cell responses to anticancer drugs. Although cells from different tissues and organs responded to Ac(4)ManNAc treatment differently, treated cells with increased sialic acid contents showed dramatically reduced sensitivity (up to 130 times) to anti-cancer drugs as tested on various drugs with distinct chemical structures and acting mechanisms. Neither increased P-glycoprotein activity nor decreased drug uptake was observed during the course of Ac(4)ManNAc treatment. However, greatly altered intracellular drug distributions were observed. Most intracellular daunorubicin was found in the perinuclear region, but not the expected nuclei in the Ac(4)ManNAc treated cells. Since sialoglycoproteins and gangliosides were synthesized in the Golgi, intracellular glycans affected intracellular signal transduction and drug distributions seem to be the main reason for Ac(4)ManNAc affected cell sensitivity to anticancer drugs. It was interesting to find that although Ac(4)ManNAc treated breast cancer cells (MDA-MB-231) maintained the same sensitivity to 5-Fluorouracil, the IC(50) value of 5-Fluorouracil to the same Ac(4)ManNAc treated normal cells (MCF-10A) was increased by more than 20 times. Thus, this Ac(4)ManNAc treatment enlarged drug response difference between normal and tumor cells provides a unique opportunity to further improve the selectivity and therapeutic efficiency of anticancer drugs. PMID- 22487055 TI - Cationic liposomes as adjuvants for influenza hemagglutinin: more than charge alone. AB - Cationic liposomes are known as potent adjuvants for subunit vaccines. The purpose of this work was to study whether the content and the physicochemical properties of the positively charged compound affect the adjuvanticity of cationic liposomes. Cationic liposomes containing a cationic compound (DDA, DPTAP, DC-Chol, or eDPPC) and a neutral phospholipid (DPPC) were prepared by the film hydration-extrusion method and loaded with influenza hemagglutinin (HA) by adsorption. The liposomes were characterized (hydrodynamic diameter, zeta potential, membrane fluidity, HA loading) and their adjuvanticity was tested in mice. The formulations were administered twice subcutaneously and mouse sera were analyzed for HA-specific antibodies by ELISA and for HA-neutralizing antibodies by hemagglutination inhibition (HI) assay. First, the influence of cationic lipid concentration in the DC-Chol/DPPC liposomes (10 vs. 50 mol%) was investigated. The DC-Chol/DPPC (50:50) liposomes showed a higher zeta potential and HA loading, resulting in stronger immunogenicity of the HA/DC-Chol/DPPC (50:50) liposomes compared to the corresponding (10:90) liposomes. Next, we used liposomes composed of 50 mol% cationic lipids to investigate the influence of the nature of the cationic compound on the adjuvant effect. Liposomes made of the four cationic compounds showed similar hydrodynamic diameters (between 100 and 170 nm), zeta potentials (between +40 and +50 mV), HA loading (between 55% and 76%) and melting temperatures (between 40 and 55 degrees C), except for the DC-Chol liposomes, which did not show any phase transition. HA adjuvanted with the DC-Chol/DPPC (50:50) liposomes elicited significantly higher total IgG1 and IgG2a titers compared to the other liposomal HA formulations and non-adjuvanted HA. A similar trend was observed for the HI titers. These results show that the adjuvanticity of cationic liposomes depends on both the content and the physicochemical properties of the charged compound. PMID- 22487056 TI - PEGylation of supercooled smectic cholesteryl myristate nanoparticles. AB - Supercooled smectic cholesterol ester nanoparticles are under investigation as a new carrier system for lipophilic drugs. The smectic thermotropic liquid crystalline state of the matrix lipid is expected to lead to advantages with respect to physicochemical stability and drug loading capacity. Such nanoparticles can be prepared by high-pressure melt homogenization in the presence of emulsifiers. The purpose of this study was to develop PEGylated supercooled smectic cholesteryl myristate nanoparticles for parenteral administration and to provide evidence of the successful PEGylation by detecting the alterations of particle properties due to the insertion of PEGylated phospholipid into the surface layer of the particles. To achieve PEGylation, MPEG(2000)-DSPE was processed together with the phospholipids used as emulsifiers during particle preparation. The influence of the PEGylated phospholipid on the size, zeta potential, phase behavior and recrystallization tendency of the nanoparticles indicated the insertion of MPEG(2000)-DSPE into the surface layer of the particles. Evidence of the PEGylation was also obtained by (1)H NMR measurements, and the steric stabilization was verified by neutralizing the particle surface charge with calcium chloride or adjusting the pH value. As sterility is an important aspect with regard to parenteral administration of the dispersions their stability upon autoclaving was a further point of interest in the present study. The results indicate that PEGylated particles can be sterilized by autoclaving. In conclusion, the PEGylated particles are a promising formulation with respect to small particle size, stability against recrystallization and upon autoclaving. PMID- 22487057 TI - Single nucleotide polymorphisms of RAD51 G135C, XRCC2 Arg188His and XRCC3 Thr241Met homologous recombination repair genes and the risk of sporadic endometrial cancer in Polish women. AB - BACKGROUND: The genes RAD51, XRCC2 and XRCC3 encode proteins that are important for the repair of double-strand DNA breaks by homologous recombination. Therefore, genetic variability in these genes may contribute to the occurrence and progression of endometrial cancer. METHODS: The subject of investigation in the reported study was the distribution of genotypes and the prevalence of alleles of the RAD51 G135C, XRCC2 Arg188His and XRCC3 Thr241Met polymorphism in 230 cases of sporadic endometrial cancer; the polymorphisms were determined by polymerase chain reaction-restriction fragment-length polymorphism methods. RESULTS: The obtained results demonstrated a significant positive association between the RAD51 C/C genotype and endometrial carcinoma, with an adjusted odds ratio (OR) of 3.75 (P < 0.0001). The homozygous C/C genotype was found in 72% of endometrial cancer cases and in 19% of the used controls. The variant 135C allele of RAD51 increased the cancer risk (OR = 1.64 [1.28-2.10]P < 0.0001). There were no significant differences between the distribution of G135C, Arg188His and Thr241Met genotypes in the subgroups assigned to histological grades. CONCLUSIONS: The obtained results indicate that the polymorphism of RAD51, but not of either XRCC2 or XRCC3 genes, may be positively associated with the incidence of endometrial carcinoma in the population of Polish women. Further studies, including those on a larger group of patients, are required to further clarify this point. PMID- 22487058 TI - Neuroimaging, biochemical and cellular evidence of protection by mycophenolate mofetil on middle cerebral artery occlusion induced injury in rats. AB - Stroke is a major cause of mortality and disability worldwide. Presently, recombinant tissue plasminogen activator is the only approved drug for the management of acute ischemic stroke. However, it has limitations like narrow therapeutic window and increased risk of intracranial hemorrhage. In previous studies, immunosuppressive agents such as cyclosporine A and tacrolimus have shown neuroprotection by improving neurological functions and infarct volume in models of ischemic stroke. Therefore, the present study was designed to evaluate the effect of mycophenolate mofetil (MMF) on the cerebral ischemic injury in the middle cerebral artery occlusion (MCAo) model in rats. MCAo was carried out in male Wistar rats by inserting an intraluminal thread. One hour after MCAo, the animals were treated with MMF (50, 100, 200mg/kg, i.p.). Reperfusion was done after 2h of occlusion. Thirty minutes after reperfusion, animals were subjected to diffusion-weighted magnetic resonance imaging for assessment of neuroprotective effect of MMF. Twenty four hours after MCAo, motor performance was assessed and the animals were euthanized for estimation of brain malondialdehyde, glutathione, myeloperoxidase and nitric oxide levels. The effect of MMF on apoptosis was also evaluated. MMF significantly attenuated the percent infarct area, apparent diffusion coefficient and signal intensity as compared to a vehicle treated group. Treatment with MMF prevented the motor impairment and significantly reversed the changes in levels of malondialdehyde, glutathione, myeloperoxidase and nitric oxide. MMF treatment significantly reduced the apoptosis. Data of the present study indicate neuroprotective effect of MMF in the experimental model of ischemic stroke. PMID- 22487059 TI - Anxiolytic effect of clonazepam in female rats: grooming microstructure and elevated plus maze tests. AB - Grooming behavior is an adaptation to a stressful environment that can vary in accordance with stress intensity. Direct and indirect GABA(A) receptor agonists decrease duration, frequency, incorrect transitions and uninterrupted bouts of grooming. Hormonal variation during the different phases of the estrous cycle of female rats also changes the grooming behavior. It is known that GABA(A) agonists and endogenous hormones change anxiety-like behaviors observed in the elevated plus maze test, a classical animal model of anxiety. This study was designed to determine the anxiolytic effect of clonazepam in female rats in different estrous phases and to correlate anxiety behaviors in the elevated plus maze and grooming microstructure tests. Our results show that female rats displayed higher anxiety like behavior scores during the estrus and proestrus phases in the elevated plus maze and that clonazepam (0.25 mg/kg; i.p.) had an anxiolytic effect that was independent of the estrous phase. Grooming behaviors were higher in the proestrus phase but were decreased by clonazepam administration, independent of the estrous phase, demonstrating the anxiolytic effect of this drug in both animal models. Grooming behaviors were moderately associated with anxiolytic-like behaviors in the elevated plus maze test. Here, we describe the anxiolytic effect of clonazepam and the influence of estrous phase on anxiety. Moreover, we show that the grooming microstructure test is a useful tool for detecting anxiolytic-like behaviors in rats. PMID- 22487060 TI - Clinical features and prognostic factors in patients with carcinomatous meningitis secondary to breast cancer. AB - Prognosis in patients with carcinomatous meningitis (CM) is poor, and numerous prognostic factors for response and survival have been described, but remain controversial. In general, series are small and involve a heterogeneous type of solid neoplasms. The purpose of this study was to describe a series of patients with breast cancer-associated CM to determine the clinical features and prognostic factors associated with survival. We conducted a retrospective study on 49 patients diagnosed between January 2003 and December 2007 at the Instituto Nacional de Cancerologia in Mexico City. CSF cytopathology samples were re reviewed to confirm the diagnosis. Overall survival (OS) for patients with breast cancer with CM was 7 weeks. Factors independently associated with better OS included absence of encephalopathy at diagnosis (11 weeks versus 1 week; p = .036), low CSF protein content (15 versus 5 weeks; p = .022), and nontriple negative receptor status in the primary breast cancer tumor (13 versus 3 weeks; p = .015). According to multivariate analysis, patients were divided into favorable and poor prognostic groups, with OS of 14 weeks and 2 weeks, respectively (p < .001). These factors can identify a subgroup of patients who are candidates for an intensive management approach. PMID- 22487061 TI - Vaccine-derived NSP2 segment in rotaviruses from vaccinated children with gastroenteritis in Nicaragua. AB - Rotavirus (RV) vaccination programs have been established in several countries using the human-attenuated G1P[8] monovalent vaccine Rotarix (GlaxoSmithKline) and/or the human-bovine reassortant G1, G2, G3, G4, P[8] pentavalent vaccine RotaTeq (Merck). The efficacy of both vaccines is high (~90%) in developed countries, but can be remarkably lower in developing countries. For example, a vaccine efficacy against severe diarrhea of only 58% was observed in a 2007-2009 Nicaraguan study using RotaTeq. To gain insight into the significant level of vaccine failure in this country, we sequenced the genomes of RVs recovered from vaccinated Nicaraguan children with gastroenteritis. The results revealed that all had genotype specificities typical for human RVs (11 G1P[8], 1 G3P[8]) and that the sequences and antigenic epitopes of the outer capsid proteins (VP4 and VP7) of these viruses were similar to those reported for RVs isolated elsewhere in the world. As expected, nine of the G1P[8] viruses and the single G3P[8] virus had genome constellations typical of human G1P[8] and G3P[8] RVs: G1/3-P[8]-I1-R1 C1-M1-A1-N1-T1-E1-H1. However, two of the G1P[8] viruses had atypical constellations, G1-P[8]-I1-R1-C1-M1-A1-N2-T1-E1-H1, due to the presence of a genotype-2 NSP2 (N2) gene. The sequence of the N2 NSP2 gene was identical to the bovine N2 NSP2 gene of RotaTeq, indicating that the two atypical viruses originated via reassortment of human G1P[8] RVs with RotaTeq viruses. Together, our data suggest that the high level of vaccine failure in Nicaraguan is probably not due to antigenic drift of commonly circulating virus strains nor the emergence of new antigenetically distinct virus strains. Furthermore, our data suggest that the widespread use of the RotaTeq vaccine has led to the introduction of vaccine genes into circulating human RVs. PMID- 22487062 TI - Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity. AB - BACKGROUND: Primary osteoporosis is a rare childhood-onset skeletal condition whose pathogenesis has been largely unknown. We have previously shown that primary osteoporosis can be caused by heterozygous missense mutations in the Low density lipoprotein receptor-related protein 5 (LRP5) gene, and the role of LRP5 is further investigated here. METHODS: LRP5 was analyzed in 18 otherwise healthy children and adolescents who had evidence of osteoporosis (manifested as reduced bone mineral density i.e. BMD, recurrent peripheral fractures and/or vertebral compression fractures) but who lacked the clinical features of osteogenesis imperfecta (OI) or other known syndromes linked to low BMD. Also 51 controls were analyzed. Methods used in the genetic analyses included direct sequencing and multiplex ligation-dependent probe amplification (MLPA). In vitro studies were performed using luciferase assay and quantitative real-time polymerase chain reaction (qPCR) to examine the effect of two novel and three previously identified mutations on the activity of canonical Wnt signaling and on expression of tryptophan hydroxylase 1 (Tph1) and 5-hydroxytryptamine (5-Htr1b). RESULTS: Two novel LRP5 mutations (c.3446 T > A; p.L1149Q and c.3553 G > A; p.G1185R) were identified in two patients and their affected family members. In vitro analyses showed that one of these novel mutations together with two previously reported mutations (p.C913fs, p.R1036Q) significantly reduced the activity of the canonical Wnt signaling pathway. Such reductions may lead to decreased bone formation, and could explain the bone phenotype. Gut-derived Lrp5 has been shown to regulate serotonin synthesis by controlling the production of serotonin rate limiting enzyme, Tph1. LRP5 mutations did not affect Tph1 expression, and only one mutant (p.L1149Q) reduced expression of serotonin receptor 5-Htr1b (p < 0.002). CONCLUSIONS: Our results provide additional information on the role of LRP5 mutations and their effects on the development of juvenile-onset primary osteoporosis, and hence the pathogenesis of the disorder. The mutations causing primary osteoporosis reduce the signaling activity of the canonical Wnt signaling pathway and may therefore result in decreased bone formation. The specific mechanism affecting signaling activity remains to be resolved in future studies. PMID- 22487063 TI - Does the choice of baseline liver imaging influence patient outcome after resection of colorectal liver metastases? PMID- 22487064 TI - Resectability of colorectal liver metastases: an evolving definition. PMID- 22487065 TI - Systematic review of actual 10-year survival following resection for hepatocellular carcinoma. AB - BACKGROUND: Hepatic resection is a potentially curative therapy for hepatocellular carcinoma (HCC), but recurrence of disease is very common. Few studies have reported 10-year actual survival rates following hepatic resection; instead, most have used actuarial measures based on the Kaplan-Meier method. This systematic review aims to document 10-year actual survival rates and to identify factors significant in determining prognosis. METHODS: A comprehensive search was undertaken of MEDLINE and EMBASE. Only studies reporting the absolute number of patients alive at 10 years after first resection for HCC were included; these figures were used to calculate the actual 10-year survival rate. A qualitative review and analysis of the prognostic factors identified in the included studies were performed. RESULTS: Fourteen studies, all of which were retrospective case series, including data on 4197 patients with HCC were analysed. Ten years following resection, 303 of these patients were alive. The 10-year actual survival rate was 7.2%, whereas the actuarial survival quoted from the same studies was 26.8%. Positive prognostic factors included better hepatic function, a wider surgical margin and the absence of satellite lesions. CONCLUSIONS: The actual long-term survival rate after resection of HCC is significantly inferior to reported actuarial survival rates. The Kaplan-Meier method of actuarial survival analysis tends to overestimate survival outcomes as a result of censorship of data and subgroup analysis. PMID- 22487066 TI - Evaluating agreement regarding the resectability of colorectal liver metastases: a national case-based survey of hepatic surgeons. AB - BACKGROUND: The resectability of colorectal liver metastases is in part largely based on the surgeon's assessment of cross-sectional imaging. This process, while guided by principles, is subjective. The objective of the present study was to assess agreement between hepatic surgeons regarding the resectability of colorectal liver metastases. METHODS: Forty-six hepatic surgeons across Canada were invited. A patient with biologically favourable disease was presented after having received neoadjuvant chemotherapy. The scenario was matched with 10 different scrollable abdominal CT scans representing a maximum response after six cycles of chemotherapy. Surgeons were asked to offer an opinion on resectability of liver metastases, and whether they would use adjunct modalities to hepatic resection. RESULTS: Twenty-six surgeons participated. Twenty responses were complete. The median number of scenarios deemed resectable was 6/10 (range 3-8). Two control scenarios demonstrated perfect agreement. Agreement on resectability was poor for 4/8 test scenarios, of which one scenario demonstrated complete disagreement. Among resectable cases, the pattern of use of adjunct modalities was variable. A median ratio of 0.87 adjunct modality per resectable scenario per surgeon was used (range 0.25-1.75). CONCLUSION: A significant lack of agreement was identified among surgeons on the resectability and use of adjunct modalities in the treatment of colorectal liver metastases. PMID- 22487067 TI - Detailed liver-specific imaging prior to pre-operative chemotherapy for colorectal liver metastases reduces intra-hepatic recurrence and the need for a repeat hepatectomy. AB - BACKGROUND: Neoadjuvant chemotherapy for colorectal liver metastases (CRLM) reduces the accuracy of liver imaging which may understage patients pre operatively. Retrospective review of a prospective database to determine whether liver-specific magnetic resonance imaging (MRI) prior to pre-operative chemotherapy affects intra-hepatic recurrence and long-term outcome after hepatectomy. PATIENTS AND METHODS: Between 2003 and 2009, 242 patients with CRLM underwent a hepatectomy after >=3 cycles of oxaliplatin or irinotecan-based chemotherapy. All had a liver-specific MRI immediately pre-operatively. The outcome of patients who had a liver-specific MRI prior to chemotherapy (PCI group, n= 92) was compared with those who did not (non-PCI group, n= 150). RESULTS: A liver-specific MRI pre-chemotherapy changed the staging in 56% of patients. At a median (range) follow-up of 55 (6-94) months, there was a higher incidence of intra-hepatic recurrence at a new site in the non-PCI group (65% vs. 48% in the PCI group, P= 0.041) and an increased rate of recurrence in patients with the same number of lesions pre- and post-chemotherapy [hazard ratio (HR) 2.02, 1:10-3.37, P= 0.024]. The non-PCI group underwent more repeat hepatectomies than the PCI group (24.7% vs. 13%, P= 0.034), achieving similar long-term survival. CONCLUSIONS: A liver-specific MRI prior to chemotherapy reduces intra hepatic recurrence and avoids a repeat hepatectomy. PMID- 22487068 TI - Determination of factors predictive of outcome for patients undergoing a pancreaticoduodenectomy of pancreatic head ductal adenocarcinomas. AB - INTRODUCTION: A pancreaticoduodenectomy is the reference treatment for a resectable pancreatic head ductal adenocarcinoma. The probability of 5-year survival in patients undergoing such treatment is 5-25% and is associated with relatively high peri-operative morbidity and mortality. The objective of the present study was to evaluate risk factors predictive of outcome for patients undergoing a pancreaticoduodenectomy for a pancreatic adenocarcinoma. METHODS: This retrospective analysis incorporated data from the Vancouver General Hospital and the British Columbia Cancer Agency (BCCA) from 1999-2007. RESULTS: The 5-year survival of 100 patients was 12% with a median survival of 16.5 months. Ninety day mortality was 7%. Predictors of 90-day mortality included age >= 80 years (P < 0.001) and an American Society of Anesthesiologists (ASA) score = 3 (P= 0.012) by univariate analysis and age >=80 years (P < 0.001) by multivariate analysis. The identifiable predictive factor for poor 5-year survival was an ASA score = 3 (P= 0.043) whereas a Dindo-Clavien surgical complication grade >= 3 was associated with a worse outcome (P= 0.013). Referral to the BCCA was associated with a favourable 5-year survival (P= 0.001). CONCLUSIONS: The present study identifies risk factors for patient selection to enhance survival benefit in this patient population. PMID- 22487069 TI - Outcome of hepatectomy for hepatocellular carcinoma in patients with renal dysfunction. AB - OBJECTIVES: There are few reports on the efficacy of hepatectomy for hepatocellular carcinoma (HCC) in patients with renal dysfunction (RD). This study aimed to clarify the validity of hepatectomy for treating HCC in RD patients, and to compare postoperative courses in RD and non-RD patients. METHODS: The clinical features of 722 HCC patients who underwent curative hepatectomy between 1986 and 2009 were retrospectively reviewed. Seventeen patients (2.4%) with preoperative serum creatinine levels of >2.0 mg/dl were defined as the RD group, and, of these, seven who did not receive preoperative haemodialysis were defined as borderline patients. Clinicopathological characteristics and postoperative outcomes were compared between the RD group (n= 17) and the non-RD group (n= 705). The postoperative courses of borderline patients were reviewed in detail. RESULTS: Overall survival (P= 0.177) and disease-free survival (P= 0.942) after hepatectomy did not differ significantly between the groups. Incidences of massive ascites (35.3% vs. 14.3%; P= 0.034) and pleural effusion (52.9% vs. 17.6%; P= 0.001), defined as massive effusion (ME), were significantly higher in the RD group than in the non-RD group. Hypoalbuminaemia (<=2.8 g/dl; P= 0.031), heavy blood loss (>=1000 ml; P= 0.012) and intraoperative blood transfusion (P= 0.007) were risk factors for ME. Among the borderline patients, serum creatinine values were not increased immediately after surgery and four patients underwent haemodialysis. CONCLUSIONS: Preoperative hypoalbuminaemia, heavy blood loss and blood transfusion are independent risk factors for ME in RD patients. Preoperative improvement of anaemia and reduction of blood loss by meticulous surgical techniques may prevent ME in RD patients who require hepatectomy for HCC. PMID- 22487070 TI - Loco-regional therapy in patients with Milan Criteria-compliant hepatocellular carcinoma and short waitlist time to transplant: an outcome analysis. AB - OBJECTIVES: Liver transplantation (LT) in Milan Criteria (MC) hepatocellular carcinoma (HCC) has excellent outcomes. Pre-transplant loco-regional therapy (LRT) has been used to downstage HCC to meet the MC. However, its benefit in patients with a brief waiting time to transplant remains unclear. This study evaluated outcomes in patients with short waitlist times to LT for MC-compliant HCC. METHODS: Patients undergoing LT for MC HCC at either of two transplant centres between 2002 and 2009 were retrospectively evaluated for outcome. Patients for whom post-transplant follow-up amounted to <12 months were excluded. RESULTS: A total of 225 patients were included, 93 (41.3%) of whom received neoadjuvant LRT. The median waiting time to transplant was 48 days. Mean post transplant follow-up was 32.2 months. Overall and disease-free survival at 1 year, 3 years and 5 years were 93.1%, 82.4% and 72.6%, and 91.3%, 79.3% and 70.6%, respectively. There was no difference in overall (P= 0.94) and disease free survival (P= 0.94) between groups who received and did not receive pre-LT LRT. There were also no disparities in survival or tumour recurrence among categories of patients (with single tumours measuring <3 cm, with single tumours measuring 3-5 cm, with multiple tumours). CONCLUSIONS: Loco-regional therapy followed by rapid transplantation in MC HCC appears not to have an impact on post transplant outcome. PMID- 22487071 TI - Correlations between histopathological diagnosis of chemotherapy-induced hepatic injury, clinical features, and perioperative morbidity. AB - BACKGROUND: Chemotherapy has in some series been linked with increased morbidity after a hepatectomy. Hepatic injuries may result from the treatment with chemotherapy, but can also be secondary to co-morbid diseases. The aim of the present study was to draw correlations between clinical features, treatment with chemotherapy and injury phenotypes and assess the impact of each upon perioperative morbidity. PATIENTS AND METHODS: Retrospective samples (n= 232) were scored grading steatosis, steatohepatitis and sinusoidal injury (SI). Clinical data were retrieved from medical records. Correlations were drawn between injury, clinical features and perioperative morbidity. RESULTS: Injury rates were 18%, 4% and 19% for steatosis, steatohepatitis and SI, respectively. High-grade steatosis was more common in patients with diabetes [odds ratio (OR) = 3.33, P= 0.01] and patients with a higher weight (OR/kg = 1.04, P= 0.02). Steatohepatitis was increased with metabolic syndrome (OR = 5.88, P= 0.02). Chemotherapy overall demonstrated a trend towards an approximately doubled risk of high-grade steatosis and steatohepatitis although not affecting SI. However, pre-operative chemotherapy was associated with an increased SI (OR = 2.18, P= 0.05). Operative morbidity was not increased with chemotherapy, but was increased with steatosis (OR = 2.38, P= 0.02). CONCLUSIONS: Diabetes and higher weight significantly increased the risk of steatosis, whereas metabolic syndrome significantly increased risk of steatohepatitis. The presence of high-grade steatosis increases perioperative morbidity, not administration of chemotherapy per se. PMID- 22487073 TI - Monitoring for post-transplant hepatocellular carcinoma recurrence. PMID- 22487072 TI - Quality of life and survival analysis of patients undergoing transarterial chemoembolization for primary hepatic malignancies: a prospective cohort study. AB - INTRODUCTION: Transarterial chemoembolization (TACE) is indicated for primary hepatic tumours when resection or local ablation are not feasible. Patients undergoing TACE have a better survival than best supportive therapy. However, there is paucity of prospective studies on the quality of life (QOL) after TACE for primary hepatic malignancies, especially in the Western world. PURPOSE: The primary aim of the present study was to determine if TACE impacts on the QOL of patients affected by primary hepatic tumours, and to assess treatment efficacy in a prospective cohort of patients treated at a tertiary Canadian university medical centre. METHODS: From September 2005 to December 2010, 48 candidates for TACE underwent at least one TACE session. Data on their QOL, tumour response, serum alpha fetoprotein (AFP) and survival were prospectively collected every 3-4 months. RESULTS: The overall QOL of patients undergoing TACE did not decline during the first 12 months after treatment. A decline was observed in the physical health domain after the third TACE that coincided with the increasing size of the largest tumour and a rise in the serum AFP levels. Psychological, social and environmental domains remained stable throughout the treatment period. Multivariate analysis revealed that tumour focality, AFP levels and model of end stage liver disease (MELD) scores were associated with long-term survival (P= 0.001, P= 0.01, P= 0.02, respectively). The overall survival at 12, 36 and 48 months were 72%, 28% and 12%, respectively. CONCLUSION: TACE is an effective palliative intervention for unresectable and non-ablatable primary liver tumours without affecting the QOL of patients even when repeated interventions are performed. PMID- 22487077 TI - The impact of tax policies on living organ donations in the United States. AB - In an effort to increase living organ donation, fifteen states passed tax deductions and one a tax credit to help defray potential medical, lodging and wage loss costs between 2004 and 2008. To assess the impact of these policies on living donation rates, we used a differences-in-differences strategy that compares the pre- and postlegislation change in living donations in states that passed legislation against the same change in those states that did not. We found no statistically significant effect of these tax policies on donation rates. Furthermore, we found no evidence of any lagged effects, differential impacts by gender, race or donor relationship, or impacts on deceased donation. Possible hypotheses to explain our findings are: the cash value of the tax deduction may be too low to defray costs faced by donors, lack of public awareness about the existence of these policies, and that states that were proactive enough to pass tax policy laws may have already depleted donor pools with previous interventions. PMID- 22487078 TI - Systematic review of the use of topical diltiazem compared with glyceryltrinitrate for the nonoperative management of chronic anal fissure. AB - AIM: The study analyzed clinical trials investigating the effectiveness of diltiazem (DTZ) and glyceryltrinitrate (GTN) for the nonsurgical management of chronic anal fissure (CAF). METHOD: Randomized trials on the effectiveness of DTZ and GTN were analyzed systematically using RevMan((r)) where combined outcome was expressed as risk ratio (RR). RESULTS: Seven randomized controlled trials that included 481 patients were analyzed. Two-hundred and thirty-eight patients were treated with DTZ and 243 patients were treated with GTN. There was significant heterogeneity [Tau(2) = 0.24, chi2 = 13.16, d.f. = 6 (P < 0.05); I(2) = 54%] among the included trials. In the random-effects model, DTZ was associated with a lower incidence of side effects (RR = 0.48; 95% CI = 0.27, 0.86; z = 2.46; P < 0.01), headache (RR = 0.39; 95% CI = 0.24, 0.66; z = 3.54; P < 0.004) and recurrence (RR = 0.68; 95% CI = 0.52, 0.89; z = 2.77; P < 0.006) of CAF. Both GTN and DTZ were equally effective (RR = 1.10; 95% CI = 0.90, 1.34; z = 0.92; P = 0.36) in the nonsurgical management of CAF. CONCLUSION: This systematic review of seven trials validates and strengthens the finding of a previously published meta analysis of two randomized trials. Both DTZ and GTN are equally effective in the management of CAF. However, DTZ is associated with a lower incidence of headache and recurrent fissure. Therefore DTZ should be the preferred first line of treatment for CAF. PMID- 22487079 TI - Sensor augmented pump therapy from onset of type 1 diabetes: late follow-up results of the Pediatric Onset Study. AB - AIM: To evaluate the metabolic control and beta-cell function 1 yr after the end of the European multicentre randomized Pediatric Onset Study. METHODS: Of 154 study patients, 131 were re-examined 24 months after type 1 diabetes onset (49.6% boys, age at onset 8.9 +/- 4.3 yrs). Of which, 62 patients belonged to the primary group of the main study applying a sensor-augmented pump system during the first yr and 69 patients to the control group performing conventional insulin pump therapy with self-monitoring blood glucose. HbA1c, fasting blood glucose, and C-peptide were centrally measured (Clinical Trail Registration Number: ISRCTN05450731). RESULTS: At 24 months, i.e., 1 yr after the end of the interventional study, 52.4% of the patients used the sensor-augmented pump system, 46.0% conventional pump, and 1.6% multiple daily injections. HbA1c was 7.6 +/- 1.3% in the primary and 7.7 +/- 1.2% in the control group (p = 0.493). Frequent sensor use during the first yr was associated with statistically insignificant lowering of the HbA1c at 24 months (p = 0.236) as compared with irregular or no sensor use (7.4 +/- 1.0% vs. 7.7 +/- 1.3%). Although fasting C peptide was not clearly different between the primary and control group (0.13 +/- 0.17 vs. 0.09 +/- 0.10 nmol/L, p = 0.121), patients with frequent sensor use had significantly less C-peptide loss within 24 months (C-peptide reduction 0.02 +/- 0.18 vs. 0.07 +/- 0.11 nmol/L, p = 0.046). There was no difference between the groups regarding daily insulin requirements. CONCLUSION: Sensor-augmented pump therapy from onset of diabetes may lead to better long-term glycemic control and help to preserve endogenous beta-cell function, if patients comply with frequent use of continuous glucose monitoring. PMID- 22487080 TI - Development of an IPTG inducible expression vector adapted for Bacteroides fragilis. AB - The genus Bacteroides are gram-negative, obligate anaerobes indigenous to the gastrointestinal tract of humans and animals. The Bacteroides and other members of the Bacteroidetes phylum have diverged from the Proteobacteria. These organisms evolved a unique promoter structure for the initiation of transcription, hence common genetic tools are of limited use in the Bacteroides. An expression vector that can control gene expression in the Bacteroides was constructed by engineering the lacO1,3 repressor binding sites into the promoter of the cfxA beta-lactamase gene. The gene for the LacI repressor was placed under control of the Bacteroides tetQ gene promoter for constitutive expression and inserted into the vector. Studies utilizing the xylosidase reporter gene, Xa, showed that the gene was induced by Isopropyl beta-d-1-thiogalactopyransoide (IPTG) in a time and concentration dependent manner from 10 to 250 MUM over a 10 240 min time frame. The utility of the vector was demonstrated by insertion of the Bacteroides fragilis trxA gene into the plasmid. TrxA synthesis was monitored by Western hybridization and the results indicated that it was regulated by the presence of IPTG in the media. This is the first transcriptional regulatory system developed for the Bacteroides that has incorporated components from the Proteobacteria and demonstrates the feasibility of modifying existing genetic tools for use in these organisms. PMID- 22487081 TI - rctB mutations that increase copy number of Vibrio cholerae oriCII in Escherichia coli. AB - RctB serves as the initiator protein for replication from oriCII, the origin of replication of Vibrio cholerae chromosome II. RctB is conserved between members of Vibrionaceae but shows no homology to known replication initiator proteins and has no recognizable sequence motifs. We used an oriCII based minichromosome to isolate copy-up mutants in Escherichia coli. Three point mutations rctB(R269H), rctB(L439H) and rctB(Y381N) and one IS10 insertion in the 3'-end of the rctB gene were obtained. We determined the maximal C-terminal deletion that still gave rise to a functional RctB protein to be 165 amino acids. All rctB mutations led to decreased RctB-RctB interaction indicating that the monomer is the active form of the initiator protein. All mutations also showed various defects in rctB autoregulation. Loss of the C-terminal part of RctB led to overinitiation by reducing binding of RctB to both rctA and inc regions that normally serve to limit initiation from oriCII. Overproduction of RctB(R269H) and RctB(L439H) led to a rapid increase in oriCII copy number. This suggests that the initiator function of the two mutant proteins is increased relative to the wild-type. PMID- 22487082 TI - Antimalarial drugs and drug targets specific to fatty acid metabolic pathway of Plasmodium falciparum. AB - Plasmodium falciparum, a causitive agent of malaria, is the third most prevalent factor for mortility in the world. Falciparum malaria is an example of evolutionary and balancing selection. Because of mutation and natural selection, the parasite has developed resistance to most of the existing drugs. Under such circumstances, there is a growing need to develop new molecular targets in P. falciparum. A four membrane bound organelles called apicoplast, very much similar to that of chloroplast of plants, have been found in parasite. Therefore, the proteins involved in metabolic pathways of apicoplasts are important drug targets. Among the pathways in apicoplast, fatty acid biosynthetic pathway is the most important metabolic pathway in P. falciparum. Several studies have explored the role of different proteins involved in this pathway and antimalarial compounds against this target. In this review, we have studied the role of different proteins in fatty acid metabolism and designing, synthesis and evaluation of compounds against the targets identified in fatty acid metabolic pathway. PMID- 22487083 TI - Progressive widening of the QRS complex during tachycardia: what are the underlying rhythms? PMID- 22487084 TI - Differential sensitivity of von Willebrand factor (VWF) 'activity' assays to large and small VWF molecular weight forms: a cross-laboratory study comparing ristocetin cofactor, collagen-binding and mAb-based assays. AB - BACKGROUND: von Willebrand disease (VWD), the most common inherited bleeding disorder, is caused by deficiencies and/or defects in von Willebrand factor (VWF). An effective diagnostic and VWD typing strategy requires plasma testing for factor VIII, and VWF antigen plus one or more VWF 'activity' assays. VWF activity is classically assessed by using VWF ristocetin cofactor activity (VWF:RCo), although VWF collagen-binding (VWF:CB) and VWF mAb-based (VWF activity [VWF:Act]) assays are used by some laboratories. OBJECTIVE: To perform a cross laboratory study to specifically evaluate these three VWF activity assays for comparative sensitivity to loss of high molecular weight (HMW) VWF, representing the form of VWF that is most functionally active and that is absent in some types of VWD, namely 2A and 2B. METHODS: A set of eight samples, including six selectively representing stepwise reduction in HMW VWF, were tested by 51 different laboratories using a variety of assays. RESULTS: The combined data showed that the VWF:CB and VWF:RCo assays had higher sensitivity to the loss of HMW VWF than did the VWF:Act assay. Moreover, within-method analysis identified better HMW VWF sensitivity of some VWF:CB assays than of others, with all VWF:CB assays still showing better sensitivity than the VWF:Act assay. Differences were also identified between VWF:RCo methodologies on the basis of either platelet aggregometry or as performed on automated analyzers. CONCLUSIONS: We believe that these results have significant clinical implications for the diagnosis of VWD and monitoring of its therapy, as well as for the future diagnosis and therapy monitoring of thrombotic thrombocytopenic purpura. PMID- 22487085 TI - Identification and characterization of 4-[4-(3-phenyl-2-propen-1-yl)-1 piperazinyl]-5H-pyrimido[5,4-b]indole derivatives as Salmonella biofilm inhibitors. AB - A screening of a small-molecule library was conducted, in search of Salmonella biofilm inhibitors active in a broad temperature range, both in prevention and in eradication of biofilms. Moreover, the inhibitors were selected not to influence the planktonic growth of Salmonella to diminish the selective pressure and to prevent or slow down resistance development. Out of the 20,014 compounds screened at 16 and 37 degrees C, 140 hits were identified. After characterization of the most promising hits at a broader set of temperatures (16, 25, 30 and 37 degrees C), we identified 7-methoxy-4-[4-(3-phenyl-2-propen-1-yl)-1-piperazinyl]-5H pyrimido[5,4-b]indole as an interesting preventive anti-biofilm compound. A first structure-activity relationship of this compound was delineated, revealing 8 fluoro-4-[4-(3-phenyl-2-propen-1-yl)-1-piperazinyl]-5H-pyrimido[5,4-b]indole as a promising analogue in the prevention of Salmonella biofilms. PMID- 22487086 TI - Functional and laminar dissociations between muscarinic and nicotinic cholinergic neuromodulation in the tree shrew primary visual cortex. AB - Acetylcholine is an important neuromodulator involved in cognitive function. The impact of cholinergic neuromodulation on computations within the cortical microcircuit is not well understood. Here we investigate the effects of layer specific cholinergic drug application in the tree shrew primary visual cortex during visual stimulation with drifting grating stimuli of varying contrast and orientation. We describe differences between muscarinic and nicotinic cholinergic effects in terms of both the layer of cortex and the attribute of visual representation. Nicotinic receptor activation enhanced the contrast response in the granular input layer of the cortex, while tending to reduce neural selectivity for orientation across all cortical layers. Muscarinic activation modestly enhanced the contrast response across cortical layers, and tended to improve orientation tuning. This resulted in highest orientation selectivity in the supra- and infragranular layers, where orientation selectivity was already greatest in the absence of pharmacological stimulation. Our results indicate that laminar position plays a crucial part in functional consequences of cholinergic stimulation, consistent with the differential distribution of cholinergic receptors. Nicotinic receptors function to enhance sensory representations arriving in the cortex, whereas muscarinic receptors act to boost the cortical computation of orientation tuning. Our findings suggest close homology between cholinergic mechanisms in tree shrew and primate visual cortices. PMID- 22487087 TI - Examination of mortality rates in a retrospective cohort of patients treated with oral or implant naltrexone for problematic opiate use. AB - AIMS: To examine and compare mortality rates in patients treated with oral and implant naltrexone. DESIGN: A retrospective cohort study. SETTING: A community not-for-profit drug treatment clinic. PARTICIPANTS: Patients treated with oral naltrexone (n = 2155, 17 207 patient-years) and implant naltrexone (n = 2389, 11 678 patient-years) for problematic opiate use between August 1997 and December 2009. MEASUREMENTS: Crude gender, age, treatment period and cause-specific mortality rates were calculated using data obtained from the National Death Index. FINDINGS: Crude mortality rates for patients treated with oral naltrexone [8.78 deaths per 1000 patient-years (ptpy), 95% confidence interval (CI): 7.38 10.17] were significantly different to those treated with implant naltrexone (6.59 ptpy, 95% CI: 5.13-8.06) (P = 0.0339). During the first 4 months following treatment, differences in the two groups were particularly apparent, with a mortality rate of 26.28 ptpy in patients treated with oral naltrexone compared to 7.34 ptpy in patients treated with implant naltrexone (P = 0.0003). Differences in initial mortality rates following treatment were associated predominantly with high rates of opiate overdoses in oral naltrexone patients during the first 4 months following treatment (17.22 ptpy compared with 0.67 ptpy in implant naltrexone patients) (P < 0.0001). CONCLUSIONS: The use of implant naltrexone can reduce all-cause mortality and opiate overdose during the first 4 months following treatment compared with patients treated with oral naltrexone. PMID- 22487088 TI - OSVZ progenitors in the human cortex: an updated perspective on neurodevelopmental disease. AB - Recent discoveries concerning the architecture and cellular dynamics of the developing human brain are revealing new differences between mouse and human cortical development. In mice, neurons are produced by ventricular radial glial (RG) cells and subventricular zone intermediate progenitor (IP) cells. In the human cortex, both ventricular RG and highly motile outer RG cells generate IP cells, which undergo multiple rounds of transit amplification in the outer subventricular zone before producing neurons. This creates a more complex environment for neurogenesis and neuronal migration, adding new arenas in which neurodevelopmental disease gene mutation could disrupt corticogenesis. A more complete understanding of disease mechanisms will involve use of emerging model systems with developmental programs more similar to that of the human neocortex. PMID- 22487090 TI - Are dialysate sodium levels too high? AB - Universal lower dialysate [Na+] is often advocated as a means of improving the dire cardiovascular plight of our dialysis patients. However, there is evidence associating lower dialysate [Na+] and increased morbidity and mortality especially in frailer patients, probably as a result of more frequent intra dialytic hypotension. In this editorial, we summarize arguments for and against lower dialysate [Na+], and provide recommendations around selecting the most appropriate dialysate [Na+] for specific clinical subsets that may benefit from manipulation of salt and water balance. The lack of overall clarity on relative benefits and risks of lower dialysate [Na+] does not support the case for empirical "across the board" change, and experimental testing in clinical trials is required to determine safe and effective use. PMID- 22487089 TI - FoxO inhibits juvenile hormone biosynthesis and vitellogenin production in the German cockroach. AB - The transcription factor Forkhead-box O (FoxO) is the main transcriptional effector of the Insulin Receptor/Phosphatidylinositol 3-kinase (InR/PI3K) pathway. In a situation of nutrient restriction, the pathway is inactive and FoxO translocates to the nucleus to exert its transcriptional action. In starved females of the cockroach Blattella germanica, the reproductive processes, and in particular the synthesis of juvenile hormone in the corpora allata and that of vitellogenin in the fat body, are arrested. In the present report we examine the possible role of FoxO in the transduction of the nutritional signals to these reproductive events. We first cloned FoxO cDNA from B. germanica (BgFoxO), and showed that its expression is not nutritionally regulated. BgFoxO knockdown using systemic RNAi in vivo in starved females elicited an increase of juvenile hormone biosynthesis, although without modifying mRNA levels of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) synthase-1, HMG-CoA synthase-2, HMG-CoA reductase or methyl farnesoate epoxidase (CYP15A1) in corpora allata. In addition, BgFoxO RNAi treatment produced a remarkable increase of vitellogenin mRNA levels in fat body and of vitellogenin protein in the haemolymph. Our results indicate that BgFoxO plays an inhibitory role on juvenile hormone biosynthesis and vitellogenin production in a situation of nutrient shortage. PMID- 22487091 TI - Impact of donor site for bone graft harvesting for dental implants on health related and oral health-related quality of life. AB - OBJECTIVES: To assess and compare changes in health-related quality of life (HRQoL) and oral health-related quality of life (OHRQoL) after bone graft harvesting for dental implants with respect to the donor site. MATERIAL AND METHODS: Autologous bone grafts were harvested in a consecutive sample of 23 patients (mean age: 46.1 years; 52% female) either from an intra-oral (IO; N = 8; chin, ascending ramus, buttress region) or an extra-oral (EO; N = 15; anterior iliac crest) donor site, followed by implant placements. HRQoL was self administered by the patients using the Short-Form 36 (SF-36) and OHRQoL was assessed using the Oral Health Impact Profile (OHIP-49) preoperatively, 3 days and 4 weeks after surgery. Impact of donor site on changes in both concepts of QoL was determined in multiple linear regression analyses. RESULTS: Patients with extra-oral donor sites reported a substantial deterioration in the physical component (PC) of HRQoL indicated by an increase in the PC score of the SF-36 (P < 0.001), whereas this score did not significantly change in patients with intra oral donor sites. The mental health component (MC) of HRQoL (MC score of the SF 36) remained virtually identical in both groups. OHRQoL deteriorated from baseline (67.7 OHIP points) to first follow-up (76.6 OHIP points) in both groups, however, changes were not statistically significant. CONCLUSION: In clinical decision-making regarding donor site for bone graft harvesting, patients and clinicians should be aware of the expected decrease in HRQoL if deciding to use extra-oral donor sites. Whenever possible, intra-oral donor sites should be preferred. PMID- 22487092 TI - Review of the pandemic (H1N1) 2009 among pregnant Japanese women. AB - Pregnant women are prone to serious complications when they contract influenza, and a considerable number of pregnant women died from the pandemic (H1N1) 2009 worldwide; however, no maternal mortality occurred in Japan during this pandemic. This review explores the reasons why maternal mortality did not occur in Japan. Two studies conducted during and soon after the pandemic (H1N1) 2009 in Japan suggested the following: 40,000-50,000 pregnant Japanese women took antiviral medicines for prophylaxis after close contact with an infected person; 40% of them (16,000-20,000) contracted the novel influenza and accounted for a half of all 30,000-40,000 pregnant patients with the novel influenza; at least 181 of them required hospitalization; and at least 17 of them developed pneumonitis. Hospitalized women had a 2.5 times higher risk of preterm delivery (at <37 weeks) compared with the general population. The two studies suggested that the following may have contributed to the lack of maternal mortality in Japan: (i) more than 60% of candidates were vaccinated within 1.5 months after the availability of a vaccine against the novel virus; (ii) vaccination reduced the infection rate by 89%; (iii) a large number of women took antiviral drugs before symptom onset after close contact with an infected person; and (iv) approximately 90% of hospitalized pregnant patients took antiviral drugs within 48 hours after symptom onset. PMID- 22487093 TI - The membrane anchor of penicillin-binding protein PBP2a from Streptococcus pneumoniae influences peptidoglycan chain length. AB - The pneumococcus is an important Gram-positive pathogen, which shows increasing resistance to antibiotics, including beta-lactams that target peptidoglycan assembly. Understanding cell-wall synthesis, at the molecular and cellular level, is essential for the prospect of combating drug resistance. As a first step towards reconstituting pneumococcal cell-wall assembly in vitro, we present the characterization of the glycosyltransferase activity of penicillin-binding protein (PBP)2a from Streptococcus pneumoniae. Recombinant full-length membrane anchored PBP2a was purified by ion-exchange chromatography. The glycosyltransferase activity of this enzyme was found to differ from that of a truncated periplasmic form. The full-length protein with its cytoplasmic and transmembrane segment synthesizes longer glycan chains than the shorter form. The transpeptidase active site was functional, as shown by its reactivity towards bocillin and the catalysis of the hydrolysis of a thiol-ester substrate analogue. However, PBP2a did not cross-link the peptide stems of glycan chains in vitro. The absence of transpeptidase activity indicates that an essential component is missing from the in vitro system. PMID- 22487094 TI - Time-course of arm lymphedema and potential risk factors for progression of lymphedema after breast conservation treatment for early stage breast cancer. AB - The objective of this study was to describe the progression of arm lymphedema (ALE) after the initial presentation among patients receiving breast conservation therapy for early stage breast cancer and to identify potential risk factors contributing to ALE progression. The study sample was the 266 stage I or II breast cancer patients with documented ALE who underwent breast conservation therapy that included lumpectomy, axillary staging followed by radiation therapy. ALE were graded according to a difference of 0.5-2 cm (mild), 2.1-3 cm (moderate), and >3 cm (severe) in the circumference between the upper extremities for the treated and untreated sides. ALE at presentation was scored as mild, moderate, and severe in 109 (41%), 125 (47%), and 32 (12%) patients, respectively. One third of patients with ALE progressed to a more severe grade of lymphedema at 5 years of follow-up. Age older than 65 years at the time of breast cancer treatment was associated with higher risk of ALE progression when compared 65 year age or younger (p = 0.04). The patients who had regional lymph node irradiation including posterior axillary boost were at higher risk of lymphedema progression than the patients treated with whole breast irradiation only (p = 0.001). Progression of ALE is a common occurrence. The current study provides support for the utility of routine arm measurements after breast cancer treatment to facilitate timely diagnosis and treatment of ALE. PMID- 22487095 TI - The spatial regulation of meiotic recombination hotspots: are all DSB hotspots crossover hotspots? AB - A key step for the success of meiosis is programmed homologous recombination, during which crossovers, or exchange of chromosome arms, take place. Crossovers increase genetic diversity but their main function is to ensure accurate chromosome segregation. Defects in crossover number and position produce aneuploidies that represent the main cause of miscarriages and chromosomal abnormalities such as Down's syndrome. Recombination is initiated by the formation of programmed double strand breaks (DSBs), which occur preferentially at places called DSB hotspots. Among all DSBs generated, only a small fraction is repaired by crossover, the other being repaired by other homologous recombination pathways. Crossover maps have been generated in a number of organisms, defining crossover hotspots. With the availability of genome-wide maps of DSBs as well as the ability to measure genetically the repair outcome at several hotspots, it is becoming more and more clear that not all DSB hotspots behave the same for crossover formation, suggesting that chromosomal features distinguish different types of hotspots. PMID- 22487096 TI - Separation anxiety: stress, tension and cytokinesis. AB - Cytokinesis, the physical separation of a mother cell into two daughter cells, progresses through a series of well-defined changes in morphology. These changes involve distinct biochemical and mechanical processes. Here, we review the mechanical features of cells during cytokinesis, discussing both the material properties as well as sources of stresses, both active and passive, which lead to the observed changes in morphology. We also describe a mechanosensory feedback control system that regulates protein localization and shape progression during cytokinesis. PMID- 22487097 TI - Loss of cancer drug activity in colon cancer HCT-116 cells during spheroid formation in a new 3-D spheroid cell culture system. AB - Clinically relevant in vitro methods are needed to identify new cancer drugs for solid tumors. We report on a new 3-D spheroid cell culture system aimed to mimic the properties of solid tumors in vivo. The colon cancer cell lines HCT-116 wt and HCT-116 wt/GFP were grown as monolayers and for 3 or 6 days on 96-well NanoCulture(r) plates to form spheroids. Expression of surface markers, genes and hypoxia were assessed to characterize the spheroids and drug induced cytotoxicity was evaluated based on fluorescein diacetate (FDA) conversion by viable cells to fluorescent fluorescein or by direct measurement of fluorescence of GFP marked cells after a 72 h drug incubation. The cells reproducibly formed spheroids in the NanoCulture(r) plates with tight cell-attachment after 6 days. Cells in spheroids showed geno- and phenotypical properties reminiscent of hypoxic stem cells. Monolayer cultured cells were sensitive to standard and investigational drugs, whereas the spheroids gradually turned resistant. Similar results for cytotoxicity were observed using simplified direct measurement of fluorescence of GFP marked cells compared with FDA incubation. In conclusion, this new 3-D spheroid cell culture system provides a convenient and clinically relevant model for the identification and characterization of cancer drugs for solid tumors. PMID- 22487098 TI - Heterogeneous minimal surface porous scaffold design using the distance field and radial basis functions. AB - This paper presented an effective method for the 3D heterogeneous porous scaffold design of human tissue using triply periodic minimal surface (TPMS) internal pore architectures. First, an implicit solid representing the smooth 3D scalar field for the porosity distribution was reconstructed by interpolating the geometric positions of control points and porosity values defined at those points using an implicit interpolation algorithm based on the thin-plate radial basis function. After generating the implicit solid representing the smooth 3D scalar field for the porosity distribution, a functionally graded tissue scaffold with accurately controlled porosity distribution was designed using the TPMS-based unit cell libraries. Numerical results showed that the proposed scaffold design method has the potential benefits for accurately controlling the spatial porosity distribution within an arbitrarily shaped scaffold while keeping the advantage of the TPMS-based unit cell libraries. PMID- 22487099 TI - Chromosome rearrangements during domestication of cucumber as revealed by high density genetic mapping and draft genome assembly. AB - Cucumber, Cucumis sativus L. is the only taxon with 2n = 2x = 14 chromosomes in the genus Cucumis. It consists of two cross-compatible botanical varieties: the cultivated C. sativus var. sativus and the wild C. sativus var. hardwickii. There is no consensus on the evolutionary relationship between the two taxa. Whole genome sequencing of the cucumber genome provides a new opportunity to advance our understanding of chromosome evolution and the domestication history of cucumber. In this study, a high-density genetic map for cultivated cucumber was developed that contained 735 marker loci in seven linkage groups spanning 707.8 cM. Integration of genetic and physical maps resulted in a chromosome-level draft genome assembly comprising 193 Mbp, or 53% of the 367 Mbp cucumber genome. Strategically selected markers from the genetic map and draft genome assembly were employed to screen for fosmid clones for use as probes in comparative fluorescence in situ hybridization analysis of pachytene chromosomes to investigate genetic differentiation between wild and cultivated cucumbers. Significant differences in the amount and distribution of heterochromatins, as well as chromosomal rearrangements, were uncovered between the two taxa. In particular, six inversions, five paracentric and one pericentric, were revealed in chromosomes 4, 5 and 7. Comparison of the order of fosmid loci on chromosome 7 of cultivated and wild cucumbers, and the syntenic melon chromosome I suggested that the paracentric inversion in this chromosome occurred during domestication of cucumber. The results support the sub-species status of these two cucumber taxa, and suggest that C. sativus var. hardwickii is the progenitor of cultivated cucumber. PMID- 22487101 TI - Changing trends in rectal cancer surgery in Ontario: 2002-2009. AB - AIM: The safety and efficacy of laparoscopic surgery for colon cancer have been demonstrated in large, multicentre clinical trials. The study aimed to determine the use of laparoscopic surgery for rectal cancer in Ontario over a 7-year period. METHOD: We conducted a retrospective study examining rates of elective rectal cancer surgery among 10.5 million adults in Ontario, Canada, from 1 April 2002 to 31 March 2009. We linked the Canadian Institute for Health Information Discharge Abstract Database, the Registered Persons Database and the database of the Ontario Cancer Registry to assess procedures used over the period. Data on demographics were collected. Trends were assessed using time series analysis. RESULTS: Over the 7-year period, 8189 open and 1079 laparoscopic elective operations for rectal cancer were identified. The annual rate of laparoscopic rectal cancer procedures increased from 0.60 per 100,000 population in 2003 to 2.24 per 100,000 population in 2008 (P < 0.01). Laparoscopic patients were similar to open with respect to age (66.5 +/- 11.8 vs 66.2 +/- 12.1 years; standardized difference 0.02), gender (63.2%vs 59.4%; standardized difference 0.08), Charlson Comorbidity Index score (standardized difference < 0.1) and socioeconomic status (standardized difference < 0.1). CONCLUSION: Laparoscopic rectal cancer surgery rates are increasing in Ontario. Ongoing research regarding the long-term safety and effectiveness of the laparoscopic approach for rectal cancer surgeries may lead to greater increases in its utilization. PMID- 22487102 TI - Clinical and pathological progression of non-alcoholic steatohepatitis to hepatocellular carcinoma. AB - AIM: Non-alcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to examine the clinical and pathological course of how NASH progresses to HCC. METHODS: In this retrospective multicenter study conducted in Japan, we examined 19 patients (53% female), who had been previously diagnosed with histologically proven NASH and developed HCC during the follow-up period. The median age of the patients at the time of initial diagnosis of NASH was 65 years. RESULTS: NASH progressed to HCC after a median follow-up period of 3.8 years (range: 0.5-11.6 years). All patients had been identified as having HCC during screening, which included 12 patients assessed by ultrasound, four patients assessed with computerized tomography, two patients that underwent serum des-gamma-carboxy prothrombin testing and one patient that underwent serum alpha fetoprotein testing. The median diameter of HCC tumors was 1.8 cm (range: 0.8-3.0 cm). The majority of patients (n = 13; 68%) presented with only one HCC tumor. The stage of liver fibrosis was significantly more advanced at the time of diagnosis of HCC than at the time of initial diagnosis of NASH, whereas there were no significant differences in the degree of steatosis. CONCLUSION: Screening for HCC with imaging is necessary not only in NASH patients with advanced fibrosis, but also in those with less advanced forms of fibrosis, particularly if they are old men. Liver fibrosis progresses to a more advanced stage during the development of HCC in NASH patients. PMID- 22487100 TI - The molecular dynamics of Trypanosoma brucei UDP-galactose 4'-epimerase: a drug target for African sleeping sickness. AB - During the past century, several epidemics of human African trypanosomiasis, a deadly disease caused by the protist Trypanosoma brucei, have afflicted sub Saharan Africa. Over 10 000 new victims are reported each year, with hundreds of thousands more at risk. As current drug treatments are either highly toxic or ineffective, novel trypanocides are urgently needed. The T. brucei galactose synthesis pathway is one potential therapeutic target. Although galactose is essential for T. brucei survival, the parasite lacks the transporters required to intake galactose from the environment. UDP-galactose 4'-epimerase (TbGalE) is responsible for the epimerization of UDP-glucose to UDP-galactose and is therefore of great interest to medicinal chemists. Using molecular dynamics simulations, we investigate the atomistic motions of TbGalE in both the apo and holo states. The sampled conformations and protein dynamics depend not only on the presence of a UDP-sugar ligand, but also on the chirality of the UDP-sugar C4 atom. This dependence provides important insights into TbGalE function and may help guide future computer-aided drug discovery efforts targeting this protein. PMID- 22487103 TI - Objective and perceived arousal during performance of tasks with elements of social threat: the influence of anxiety sensitivity. AB - BACKGROUND AND OBJECTIVES: Physiological arousal serves to maintain social anxiety disorder by skewing self-perception. Anxiety sensitivity is associated with the disorder and exaggerated perceptions of arousal, but has not been tested as explaining exaggerated perceived arousal in social contexts. The aim of this investigation was to address this issue. METHODS: A total of 42 individuals participated in three tasks associated with potential social threat (i.e., a speech, typing task, hyperventilation) and completed measures of trait social anxiety and anxiety sensitivity. State anxiety, perceived arousal, and objective arousal were assessed during each task. RESULTS: Trait social anxiety and anxiety sensitivity were correlated with state anxiety and perceived arousal, but not objective arousal, during the tasks. Anxiety sensitivity mediated the relationships between trait social anxiety and perceived arousal and between trait social anxiety and state anxiety for the typing and hyperventilation tasks. LIMITATIONS: Although the sample likely included a number of individuals with social anxiety disorder, the sample was mostly comprised of individuals without a diagnosis. The current results can be extended to clinical presentations to some extent, but future research is needed to further explore the demonstrated relationships in samples of individuals with social anxiety disorder. CONCLUSIONS: Anxiety sensitivity may play a crucial role in perceptions of arousal and state anxiety in the context of potential social threats, warranting attention from researchers and clinicians focussing on social anxiety disorder. PMID- 22487105 TI - Asthma diagnosis and management. AB - Asthma is a chronic inflammatory airway disease that is commonly seen in the emergency department (ED). This article provides an evidence-based review of diagnosis and management of asthma. Early recognition of asthma exacerbations and initiation of treatment are essential. Treatment is dictated by the severity of the exacerbation. Treatment involves bronchodilators and corticosteroids. Other treatment modalities including magnesium, heliox, and noninvasive ventilator support are discussed. Safe disposition from the ED can be considered after stabilization of the exacerbation, response to treatment and attaining peak flow measures. PMID- 22487104 TI - Epigenetic rejuvenation. AB - Induced pluripotent stem (iPS) cells have provided a rational means of obtaining histo-compatible tissues for 'patient-specific' regenerative therapies (Hanna et al. 2010; Yamanaka & Blau 2010). Despite the obvious potential of iPS cell-based therapies, there are certain problems that must be overcome before these therapies can become safe and routine (Ohi et al. 2011; Pera 2011). As an alternative, we have recently explored the possibility of using 'epigenetic rejuvenation', where the specialized functions of an old cell are rejuvenated in the absence of any change in its differentiated state (Singh & Zacouto 2010). The mechanism(s) that underpin 'epigenetic rejuvenation' are unknown and here we discuss model systems, using key epigenetic modifiers, which might shed light on the processes involved. Epigenetic rejuvenation has advantages over iPS cell techniques that are currently being pursued. First, the genetic and epigenetic abnormalities that arise through the cycle of dedifferentiation of somatic cells to iPS cells followed by redifferentiation of iPS cells into the desired cell type are avoided (Gore et al. 2011; Hussein et al. 2011; Pera 2011): epigenetic rejuvenation does not require passage through the de-/redifferentiation cycle. Second, because the aim of epigenetic rejuvenation is to ensure that the differentiated cell type retains its specialized function it makes redundant the question of transcriptional memory that is inimical to iPS cell-based therapies (Ohi et al. 2011). Third, to produce unrelated cell types using the iPS technology takes a long time, around three weeks, whereas epigenetic rejuvenation of old cells will take only a matter of days. Epigenetic rejuvenation provides the most safe, rapid and cheap route to successful regenerative medicine. PMID- 22487106 TI - Acute exacerbations of chronic obstructive pulmonary disease in the emergency department. AB - Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality worldwide. Acute exacerbations of COPD (AECOPDs) are a common presentation to emergency departments and are an important cause of respiratory failure. This article discusses the disease process and diagnosis of COPD and AECOPD. A further in-depth discussion is undertaken of evidence-based treatments, palliation, and disposition of patients who present to emergency departments with AECOPD. PMID- 22487107 TI - Pneumonia in adults: the practical emergency department perspective. AB - In those patients who are hospitalized with pneumonia, mortality is 15%. Close to 90% of deaths attributed to pneumonia are in patients older than 65 years. This article provides the emergency physician with an understanding of how to make the diagnosis, initiate early and appropriate antibiotic therapy, risk stratify patients with respect to the severity of illness, and recognize indications for admission. The discussion is balanced with an emphasis on cost-effective management, an understanding of the changing spectrum of pathogenesis, and a cognizance toward variable and less common presentations. PMID- 22487108 TI - Evaluation and management of seasonal influenza in the emergency department. AB - Seasonal influenza causes significant morbidity and mortality, primarily due to increased complication rates among the elderly population and patients with chronic diseases. Timely diagnosis of influenza and early recognition of an influenza outbreak or epidemic are key components in preventing influenza-related complications, hospitalizations, and deaths. Emergency departments are the most frequent points of entry for most influenza cases and are well positioned to identify and manage influenza community outbreaks and epidemics. Emergency departments need specific infection control measures to curb the spread of influenza in the Emergency Department and hospital during the influenza season. PMID- 22487109 TI - Acute aortic dissection in the emergency department: diagnostic challenges and evidence-based management. AB - Acute aortic dissection in the emergency department (ED) remains one of the riskiest clinical and medicolegal challenges facing ED physicians. The variability in clinical presentations and mimics, the unreliability of clinical assessments and initial screening tools, and the need for advanced imaging all present obstacles in making an accurate and timely diagnosis for this entity. This article reviews available information and evidence regarding pathophysiology, risk factors, clinical variations in presentation, the usefulness of different diagnostic testing modalities, and management options in the ED when considering this diagnosis. Key recommendations from recent guidelines are reviewed in the context of ED practice. PMID- 22487110 TI - Pulmonary embolism. AB - Pulmonary embolism (PE) remains one of the most challenging medical diseases in the emergency department. PE is a potentially life threatening diagnosis that is seen in patients with chest pain and/or dyspnea but can span the clinical spectrum of medical presentations. In addition, it does not have any particular clinical feature, laboratory test, or diagnostic modality that can independently and confidently exclude its possibility. This article offers a review of PE in the emergency department. It emphasizes the appropriate determination of pretest probability, the approach to diagnosis and management, and special considerations related to pregnancy and radiation exposure. PMID- 22487111 TI - Initial management and resuscitation of severe chest trauma. AB - Severe chest trauma, blunt or penetrating, is responsible for up to 25% of traumatic deaths in North America. Respiratory compromise is the most frequent dramatic presentation in blunt trauma, while injuries to the heart and great vessels pose the greatest risk of immediate death following penetrating trauma. More than 80% of patients will be managed with interventions that can be performed in the emergency department. This article reviews the presentation, diagnosis, and management of the most important thoracic injuries. A structured approach to the acutely unstable patient is proposed to guide resuscitation decisions. PMID- 22487112 TI - Emergency airway management: the difficult airway. AB - Patients requiring airway management in the emergency department present an enormous challenge. It requires not only a firm concept of techniques for securing the airway but also of dealing with the potential difficult airway (DA) in which establishing a definite airway is not possible with techniques routinely used. This article highlights the importance of recognition and management of the DA in emergent situations. Both awake and nonawake intubation are discussed, and indications and guidelines are given for the use of nonsurgical and surgical airway interventions. PMID- 22487113 TI - Invasive and noninvasive ventilation in the emergency department. AB - This article reviews invasive and noninvasive ventilation for emergency physicians. It presents an overview of respiratory physiology principles that will help emergency physicians adapt their ventilation strategies to any clinical situation. The basic modes of ventilation are summarized. The advantages and limitations of certain novel modes of ventilation are presented. This review highlights a variety of ventilation strategies to be used for patients with normal lung mechanics and gas exchange, acute hypoxemic respiratory failure, decreased lung compliance, airflow obstruction, and weakness or restriction of the chest wall. This article will help clinicians prevent, recognize, and treat complications of mechanical ventilation. PMID- 22487114 TI - Thoracic ultrasound. AB - Dyspnea and hypotension often present a diagnostic challenge to the emergency physician. With limitations on traditional methods of evaluating these patients, lung ultrasound has become an essential assessment tool. With the sensitivity of lung ultrasound approaching that of CT scan for many indications, it is quickly becoming a fundamental technique in assessing patients with thoracic emergencies. This article reviews the principles of thoracic ultrasound; describes the important evidence-based sonographic features found in pneumothorax, pleural effusion, pneumonia, and pulmonary edema; and provides a framework of how to use thoracic ultrasound to aid in assessing a patient with severe dyspnea. PMID- 22487115 TI - Pleural disease in the emergency department. AB - Emergency department presentations of pleural-based diseases are common, with severity ranging from mild to life threatening. The acute assessment, diagnosis, and treatment of pleural disease are critical as urgent invasive maneuvers such as thoracocentesis and thoracostomy may be indicated. The emergency physician must have a systematic approach to these conditions that allows for rapid recognition, diagnosis, and definitive management. This article focuses on nontraumatic pleural disease, including diagnostic and treatment considerations of pleural effusion, empyema, primary spontaneous pneumothorax, secondary spontaneous pneumothorax, pediatric pneumothorax, spontaneous hemothorax, and spontaneous tension pneumothorax. PMID- 22487116 TI - Diagnosis and management of environmental thoracic emergencies. AB - Physiologic sequelae from increasing ambient pressure in underwater activities, decreasing ambient pressure while at altitude, or the consequences of drowning present a unique set of challenges to emergency physicians. In addition, several environmental toxins cause significant respiratory morbidity, whether they be pulmonary irritants, simple asphyxiants, or systemic toxins. It is important for emergency physicians to understand the pathophysiology of these illnesses as well as to apply this knowledge to the clinical arena either in the prehospital setting or in the emergency department. Current treatment paradigms and controversies within these regimens are discussed. PMID- 22487117 TI - Common pediatric respiratory emergencies. AB - Pediatric respiratory illnesses are a huge burden to emergency departments worldwide. This article reviews the latest evidence in the epidemiology, assessment, management, and disposition of children presenting to the emergency department with asthma, croup, bronchiolitis, and pneumonia. PMID- 22487118 TI - Thoracic emergencies in immunocompromised patients. AB - With the increasing prevalence of human immunodeficiency virus/AIDS patients and patients receiving chemotherapy for various malignancies, the numbers of immunosuppressed patients who present to the emergency department is on the increase. Thoracic-related emergencies in these vulnerable patients are serious and challenging to diagnose for the emergency physician, due mainly to atypical presentations, atypical pathogens, and to the often tenuous state of health of the patient. This article addresses a variety of cardiovascular, pulmonary, and esophageal emergencies that are seen specifically in immunocompromised patients presenting to the emergency department. Epidemiology, clinical presentation, investigations, prognosis, management, and evidence-based recommendations are discussed. PMID- 22487119 TI - Thoracic emergencies. Foreword. PMID- 22487120 TI - Thoracic emergencies. Preface. PMID- 22487121 TI - Clinical assessment of the pathogenicity of unknown variants in long-QT syndrome: does the pendulum swing back? PMID- 22487122 TI - Obesity and clustering of cardiovascular disease risk factors are associated with elevated plasma complement C3 in children and adolescents. AB - OBJECTIVES: To investigate the relationship among obesity, cardiovascular disease risk factors (CVDRFs), and plasma complement C3 concentration in children and adolescents. METHODS: In a nationwide survey conducted between 1992 and 2000, all school children aged 6-18 yr with abnormal results in repeated urine samples, including hematuria, proteinuria, and glucosuria (n = 97 312; 36 557 boys and 60 755 girls), were investigated for their body mass index (BMI), blood pressure, fasting plasma glucose, total cholesterol, and plasma complement C3 concentrations. RESULTS: Children in the higher percentile groups for BMI or having more CVDRFs, namely, hypertension, diabetes, and hypercholesterolemia, had higher plasma C3 concentrations independently (p for both trends <0.05, adjusted for age and gender). The odds ratios (ORs) for having one, two, or three CVDRFs in obese children were 4.74 [95% confidence interval (CI) = 4.47-5.03], 19.8 (95% CI = 17.8-22.0), and 139 (95% CI = 96.6-200), respectively, adjusted for age, gender, and family history of diabetes, which were substantially reduced after adjustment for plasma C3 concentrations. The ORs for children with plasma C3 concentrations in the highest quartile to have one, two, or three CVDRFs were 2.32 (95% CI = 2.21-2.44), 5.68 (95% CI = 4.83-6.67), and 58.6 (95% CI = 19.7 174), respectively, adjusted for age, gender, family history of diabetes, and BMI. CONCLUSION: Obesity is associated with clustering of CVDRFs in children and adolescents. Obesity and clustering of CVDRFs are associated with elevated plasma complement C3. Children and adolescents with higher plasma C3 concentrations have higher risk of clustering of CVDRFs independent of obesity. PMID- 22487123 TI - Enhanced exercise performance and survival associated with evidence of autonomic reinnervation in pediatric heart transplant recipients. AB - Following heart transplantation (HTx), loss of autonomic input to the allograft results in elevated resting heart rate (HR) and decreased chronotropic reserve. As enhanced exercise capacity and HR recovery post exercise are suggestive of reinnervation in pediatric cohorts, we used heart rate variability (HRV) analysis to assess autonomic reinnervation in pediatric HTx recipients. Pediatric patients transplanted between 1996 and 2010 and with serial 24-hour Holter recordings post HTx were analyzed for HRV using time and frequency domain measures. Of 112 patients, 68 (57%) showed evidence of autonomic reinnervation that was not associated with age at HTx. Evidence of reinnervation was associated with a significant increase in low-frequency power spectrum (p<0.001), suggesting sympathetic reinnervation. Patients with evidence of reinnervation showed higher percent-predicted maxVO(2) on performing an exercise test (+10.2 +/- 3.6%, p = 0.006) and improved HR recovery at 3 minutes (-11.4 +/- 3.9 bpm, p = 0.004), but no difference in percent-predicted maximal HR. Cox hazards modeling using presumed sinus reinnervation criteria at last Holter recording as a time dependent covariate was associated with decreased hazard of mortality and/or retransplantation (HR: 0.2, 95% CI 0.04-1.0, p = 0.05). In conclusion, a majority of pediatric HTx recipients demonstrate evidence of reinnervation that is associated with functional outcomes. Studies to assess graft reinnervation as a marker of long-term prognosis are warranted. PMID- 22487124 TI - Pathway-specific plasticity in the human spinal cord. AB - The aim of the present study was to artificially induce plasticity in the human spinal cord and evaluate whether this plasticity is pathway specific. For this purpose, a technique called paired associative stimulation (PAS) was applied. Volleys evoked by transcranial magnetic stimulation over the primary motor cortex and peripheral nerve stimulation of the nervus tibialis in the popliteal fossa were timed to coincide at the spinal level. The transmission of different corticospinal projections was assessed before and after PAS using conditioned H reflexes. Different groups of healthy volunteers (28 +/- 5 years) were tested; intervention groups 1 (n = 9) and 2 (n = 8) received spinal PAS (360 paired stimuli) and the induced effects were evaluated using cortical (group 1) or cervicomedullary (group 2) conditioning of musculus soleus H-reflexes. After spinal PAS, the conditioned H-reflexes were significantly facilitated when tested with cortical and cervicomedullary stimulation. The effect of the latter technique is independent of changes in the excitability of cortical neurons. Therefore, the finding that conditioned H-reflexes were increased after spinal PAS when tested with both cortical and cervicomedullary stimulation suggests that neural plasticity was induced within the spinal cord. The facilitation could only be observed for specific inter-stimulus intervals between volleys induced by peripheral nerve stimulation and transcranial magnetic stimulation. As the specific inter-stimulus intervals were assumed to relate to transmission within specific motor pathways, it is argued that changes in the corticospinal transmission were pathway-specific. These findings may be helpful in inducing and assessing neural plasticity in pathological conditions like spinal cord injuries. PMID- 22487126 TI - Comparison of immunomodulatory effects of placenta mesenchymal stem cells with bone marrow and adipose mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are powerful sources for cell therapy in regenerative medicine because they can be isolated from various tissues, expanded, and induced into multiple-lineages. Of note, their immunomodulatory effects maximize the therapeutic effects of stem cells engrafted on host, making them an especially attractive choice. Recently, several varieties of placenta derived stem cells (PDSCs) including chorionic plate-derived MSCs (CP-MSCs) have been suggested as alternative sources of stem cells. However, comparative studies of immunomodulatory effects for CP-MSCs among various MSCs are largely lacking. We examined and compared immunomodulatory function of CP-MSCs with that of BM MSCs and AD-MSCs using co-culture system with activated T-cells derived from human umbilical cord blood (UCB) exposed to anti-CD3 and anti-CD28 which are T cell activating monoclonal antibodies. All MSCs expressed markers of stem cells and three germ layers by RT-PCR. These cells also exhibited comparable immunomodulatory effects when they were co-cultured with activated T-cells in dose-dependent manner. However, expression of HLA-ABC and HLA-G was highly positive in CP-MSCs compared to other MSCs, and higher levels of cytokines of IL 2, IL-4, IL-13, and GM-CSF were detected in dose-dependent manner in CP-MSCs. Taken together, the results of the present study suggest that while CP-MSCs, BM MSCs, and AD-MSCs all have immunomodulatory effects, CP-MSCs may have additional advantage over the other MSCs in terms of immunomodulation. In conjunction with other previous studies, CP-MSCs are suggested to be a useful stem cell source in cell therapy. PMID- 22487127 TI - Involvement of histamine receptors in SAPK/JNK phosphorylation. AB - Histamine is a mediator of inflammation in allergic disease and asthma. Stress activated protein kinases/c-jun N-terminal kinases (SAPK/JNK) are involved in asthma. This study examined the role of histamine receptors on the phosphorylation of SAPK/JNK in splenocytes. C57BL/6 mice splenocytes were treated with histamine (10-4 M to 10-11 M), and its selective receptor agonists, phorbol 12 myristate 13-acetate (PMA) was used as a positive control, and phosphorylation of SAPK/JNK was determined. Histamine (10-4 M-10-8 M) inhibited phosphorylation of SAPK/JNK. H1R agonist betahistine (10-5 M) decreased SAPK/JNK phosphorylation and H2R agonist amthamine (10-5 M) did not show any significant effect. However, H3R agonist methimepip (10-6 M) and H4R agonist 4-methyl histamine (10-6 M), increased SAPK/JNK phosphorylation. We used TNFalpha knockout mice to determine if histamine regulated SAPK/JNK phosphorylation via TNFalpha. While the effects of histamine and H1 agonists were similar to that of wild type mice in inhibiting the phosphorylation of SAPK/JNK, the effects of H3 and H4 agonists differed in TNFalpha knockout mice splenocytes. Activation of H3 receptors decreased SAPK/JNK phosphorylation in TNFalpha knockout mice, as opposed to an increase in wild type mice, whereas H4 agonist did not show any significant effect on the phosphorylation of SAPK/JNK. This data showed that histamine acting through H4 receptors caused the phosphorylation of SAPK/JNK via TNFalpha. The role of H4 receptors in pro-inflammatory response is intriguing. PMID- 22487128 TI - Characterization of laccase isoforms produced by Pleurotus ostreatus in solid state fermentation of sugarcane bagasse. AB - Laccases are oxidative enzymes linked to biological degradation of lignin. The aim of this work was to evaluate the effect of inducers and different concentrations of nitrogen on production level of total laccase activity and pattern of laccase isoforms, produced in solid state fermentation of sugarcane bagasse by a selected strain of Pleurotus ostreatus. The addition of yeast extract 5 g/L, copper sulfate 150 MUM and ferulic acid 2 mM provided highest enzymatic activity (167 U/g) and zymograms indicated the presence of six laccase isoforms (POXA1b, POXA3, POXC and three other isoforms). Results of protein identification by mass spectrometry confirmed the presence of POXC and POXA3 as the main isoenzymes, and also identified a glyoxal oxidase and three galactose oxidases. The fact that the isoenzyme POXA1b was not identified in the analyzed samples can be possibly explained by its sensitivity to protease degradation. PMID- 22487129 TI - Biological conversion of carbon monoxide to ethanol: effect of pH, gas pressure, reducing agent and yeast extract. AB - A two-level full factorial design was carried out in order to investigate the effect of four factors on the bioconversion of carbon monoxide to ethanol and acetic acid by Clostridium autoethanogenum: initial pH (4.75-5.75), initial total pressure (0.8-1.6 bar), cysteine-HCl.H(2)O concentration (0.5-1.2 g/L) and yeast extract concentration (0.6-1.6 g/L). The maximum ethanol production was enhanced up to 200% when lowering the pH and amount yeast extract from 5.75 to 4.75 g/L and 1.6 to 0.6 g/L, respectively. The regression coefficient, regression model and analysis of variance (ANOVA) were obtained using MINITAB 16 software for ethanol, acetic acid and biomass. For ethanol, it was observed that all the main effects and the interaction effects were found statistically significant (p<0.05). The comparison between the experimental and the predicted values was found to be very satisfactory, indicating the suitability of the predicted model. PMID- 22487130 TI - Coproduction of hydrogen and methane via anaerobic fermentation of cornstalk waste in continuous stirred tank reactor integrated with up-flow anaerobic sludge bed. AB - A 10 L continuous stirred tank reactor (CSTR) system was developed for a two stage hydrogen fermentation process with an integrated alkaline treatment. The maximum hydrogen production rate reached 218.5 mL/L h at a cornstalk concentration of 30 g/L, and the total hydrogen yield and volumetric hydrogen production rate reached 58.0 mL/g-cornstalk and 0.55-0.57 L/L d, respectively. A 10 L up-flow anaerobic sludge bed (UASB) was used for continuous methane fermentation of the effluents obtained from the two-stage hydrogen fermentation. At the optimal organic loading rate of 15.0 g-COD/Ld, the COD removal efficiency and volumetric biogas production rate reached 83.3% and 4.6L/Ld, respectively. Total methane yield reached 200.9 mL/g-cornstalk in anaerobic fermentation with the effluents and alkaline hydrolysate. As a result, the total energy recovery by coproduction of hydrogen and methane with anaerobic fermentation of cornstalk reached 67.1%. PMID- 22487131 TI - Fast start-up and stable performance coupled to sulfate reduction in the nitrobenzene bio-reduction system and its microbial community. AB - Three laboratory-scale sequence batch reactors were set up in this study. It was found that a successfully established sulfate-reducing system - operating at COD/SO42- ratio of 5.0 - could speed up the start-up process, leading to a high performance. It took about 100 and 60 days, respectively, for a non-sulfate reducing system and a sulfate-reducing control system to achieve stable and high removal of NB. However, it maintained a complete NB removal in sulfate-reducing system throughout the study. Rapid and stable NB reduction was coupled to the on going sulfate reducing process. Denaturing gradient gel electrophoresis profile demonstrated that the predominant bacterial groups in the non-sulfate-reducing system and the sulfate-reducing control system were affiliated to Deltaproteobacterium and Acinetobacter, while in the sulfate-reducing system were sulfate-reducing and sulfur-oxidizing bacteria. PMID- 22487132 TI - Isolation and characterization of hemicelluloses extracted by hydrothermal pretreatment. AB - The dewaxed sample from Triploid of Populus tomentosa Carr. was extracted by using organic alkaline solvent (Dimethylformamide, DMF) via hydrothermal pretreatment. Neutral sugar compositions and molecular weight analysis demonstrated that the hemicellulosic fractions with a higher Uro/Xyl ratio, namely the more branched hemicelluloses, had higher molecular weights. Interestingly, these results were different from the previous report, in which the ratio of Uro/Xyl in the water-soluble hemicellulosic fraction was more than that of the alkali-soluble hemicellulosic fraction. Spectroscopy (FTIR, (1)H NMR, (13)C NMR, and HSQC) analysis indicated that the hemicellulosic fractions were mainly composed of (1->4)-linked alpha-D-glucan from starch and (1->4)-linked beta-D-xylan attached with minor amounts of branched sugars from hemicelluloses. In addition, thermal analysis implied that linear hemicelluloses showed more thermal stability than the branched ones during pyrolysis. PMID- 22487133 TI - Enhanced nitrogen removal in a wastewater treatment process characterized by carbon source manipulation with biological adsorption and sludge hydrolysis. AB - An innovative adsorption/nitrification/denitrification/sludge-hydrolysis wastewater treatment process (ENRS) characterized by carbon source manipulation with a biological adsorption unit and a sludge hydrolysis unit was developed to enhance nitrogen removal and reduce sludge production for municipal wastewater treatment. The system presented good performance in pollutants removal, yielding the effluent with average COD, NH(4)(+)-N, TN and TP of 48.5, 0.6, 13.2 and 1.0 mg/L, respectively. Sixty percent of the total carbon source in the influent was concentrated and separated by the quick adsorption of activated sludge, providing the possibilities of reusing waste carbon source in the denitrification tank and accumulating nitrobacteria in the nitrification tank. Low temperature of 6-15 degrees C and high hydraulic loading rate of 3.0-15.0 m(3)/d did not affect NH(4)(+)-N removal performance, yielding the NH(4)(+)-N of lower 1.0 mg/L in the effluent. Furthermore, 50% of the residual sludge in the ENRS system could be transformed into soluble COD (SCOD) by alkaline thermal hydrolysis with temperature of 60 degrees C and pH of 11, and the hydrolyzed carbon could completely substitute methanol as a good quality carbon to support high efficient denitrification. PMID- 22487134 TI - Improved procedural results after CoreValve implantation with the new AccuTrak delivery system. AB - AIMS OF THE STUDY: Transcatheter aortic valve implantation (TAVI) has become an established treatment for severe aortic stenosis in patients with unacceptable high-surgical risk. Recently, the new AccuTrak delivery system for improved deliverability of the CoreValve aortic bioprosthesis was launched. It has not yet been shown if the new delivery catheter leads to optimized positioning and improved procedural outcomes. METHODS AND RESULTS: We conducted a retrospective single-center analysis and evaluated 70 consecutive patients (35 with the original delivery catheter and 35 with the new AccuTrak catheter) for anatomic positioning and related outcome parameters like postinterventional aortic regurgitation (AR) and the need for permanent pacemaker insertion, after CoreValve implantation. The use of the AccuTrak delivery catheter resulted in significantly higher positioning of the CoreValve prosthesis in the left ventricular outflow tract (distance from annulus to lower edge of prosthesis 7.0 mm [5.5 to 9.4 mm] for the AccuTrak group vs. 8.8 mm [7.1 to 11.2 mm] for the original system; median [interquartile range]; P = 0.0068). Moreover, the optimized positioning resulted in reduced rates of significant (>=grade 2) AR assessed by postinterventional aortography and echocardiography (P = 0.044 and P = 0.0275, respectively). Despite improved positioning, no differences in the need for permanent pacemaker implantation were observed. CONCLUSIONS: Our retrospective analysis indicates improved positioning with reduced postinterventional AR with the new CoreValve AccuTrak delivery system. Whether this may also affect the need for permanent pacemaker insertion or long-term outcome after TAVI needs to be evaluated in larger studies. PMID- 22487135 TI - Malnutrition and brain development: an analysis of the effects of inadequate diet during different stages of life in rat. AB - Protein malnutrition or undernutrition can result in abnormal development of the brain. Depending on type, age at onset and duration, different structural and functional deficits can be observed. In the present review, we discuss the neuroanatomical, behavioral, neurochemical and oxidative status changes associated with protein malnutrition or undernutrition at different ages during prenatal and immediately postnatal periods as well as in adult rat. Analysis of all data suggests that protein malnutrition as well as undernutrition induced impaired learning and retention when imposed during the immediately postnatal period and in adulthood, whereas hyperactivity including increased impulsiveness and greater reactivity to aversive stimuli occurred when malnutrition or undernutrition was imposed either pre or postnatally. This general state of hyperreactivity may be linked essentially to an alteration in dopaminergic system. Hence, the present review shows that in spite of the attention devoted in the literature to prenatal effects, cognitive deficits are more serious following malnutrition or undernutrition after birth. We thus clearly establish a special vulnerability to malnutrition after weaning in rats. PMID- 22487137 TI - Hydrothermal sulfidation and floatation treatment of heavy-metal-containing sludge for recovery and stabilization. AB - This study focuses on the application of hydrothermal sulfidation and floatation to treat the heavy-metal-containing sludge for recovery and stabilization. After the hydrothermal sulfidation, the sulfidation percentage of zinc and lead reach up to 85.0% and 75.4%, respectively. 33.3% of Zn, 58.9% of Pb and 68.8% of Cu can be recovered from the sludge by floatation. The lower recovery of ZnS attributes to its surface and structural characteristics. To compare these characteristics, three types of synthetic metal sulfide (ZnS, PbS and CuS) were prepared and examined with XRD, SEM and TEM. The poor floatability of the finely dispersed, round shape of ZnS can be improved by crystal modification in hydrothermal condition. With increasing the temperature and reaction time, the grain size of the ZnS increased from 7.95 nm to 44.28 nm and the recovery of Zn increased to from 33.3% to 72.8%. The TCLP results indicate that all the leached heavy metal concentrations of floatation tailings are under the allowable limit. No obvious increase of heavy metal concentration was observed in continuous leaching procedure. The presence of alkaline compounds after hydrothermal sulfidation might act as mineralogical scavengers of dissolved heavy metal released by sulfide oxidation to avoid the heavy metal pollution. PMID- 22487136 TI - How transparent is behavioral intervention research on pathological gambling and other gambling-related disorders? A systematic literature review. AB - AIMS: To review the transparency of reports of behavioral interventions for pathological gambling and other gambling-related disorders. METHODS: We used the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) Statement to develop the 59-question adapted TREND questionnaire (ATQ). Each ATQ question corresponds to a transparency guideline and asks how clearly a study reports its objectives, research design, analytical methods and conclusions. A subset of 23 ATQ questions is considered particularly important. We searched PubMed, PsychINFO and Web of Science to identify experimental evaluations published between 2000 and 2011 aiming to reduce problem gambling behaviors or decrease problems caused by gambling. Twenty-six English-language reports met the inclusion criteria and were reviewed by three abstractors using the ATQ. RESULTS: The average report adhered to 38.4 (65.1%) of the 59 ATQ transparency guidelines. Each of the 59 ATQ questions received positive responses from an average of 16.9 (63.8%) of the reports. The subset of 23 particularly relevant questions received an average of 15.3 (66.5%) positive responses. Thirty-two of 59 (54%) ATQ questions were answered positively by 75% or more of the study reports, while 12 (20.3%) received positive responses by 25% or fewer. Publication year did not affect these findings. CONCLUSIONS: Gambling intervention reports need to improve their transparency by adhering to currently neglected and particularly relevant guidelines. Among them are recommendations for comparing study participants who are lost to follow-up and those who are retained, comparing study participants with the target population, describing methods used to minimize potential bias due to group assignment, and reporting adverse events or unintended effects. PMID- 22487138 TI - Advanced oxidation treatment and photochemical fate of selected antidepressant pharmaceuticals in solutions of Suwannee River humic acid. AB - Antidepressant pharmaceuticals have recently been detected at low concentrations in wastewater and surface water. This work reports studies of the direct and indirect photochemical fate and treatment by advanced oxidation of three antidepressant compounds (duloxetine, venlafaxine and bupropion) in solutions of humic acid in order to elucidate their behavior in the natural environment prior to reaching a water treatment facility and potentially entering a potable water supply. Humic acid solution was prepared by adding to distilled water a known amount of organic matter as a photosensitizer. All three antidepressants react very rapidly with hydroxyl radicals (.OH) and hydrated electrons (e(-)(aq)) with rate constants of ~10(8) to 10(10)M(-1)s(-1), but significantly slower with singlet oxygen ((1)DeltaO(2)) (~10(3) to 10(5)M(-1)s(-1)). The steady-state concentrations of .OH and (1)DeltaO(2), in a sample of humic acid solution were measured and used with the second order rate constants to show that the hydroxyl radical was an order of magnitude more effective than the singlet oxygen in the solar-induced photochemical degradation of the antidepressants. Excited state dissolved organic matter also accounted for a substantial portion of degradation of duloxetine, decreasing its half-life by 27% under solar irradiation. Several reaction pathways and by-products arising from the photodegradation were identified using gamma-irradiation followed by LC-MS analysis. PMID- 22487139 TI - Pneumocystis jirovecii multilocus genotyping in pooled DNA samples: a new approach for clinical and epidemiological studies. AB - Specific single-nucleotide polymorphisms (SNPs) are recognized as important DNA sequence variations influencing the pathogenesis of Pneumocystis jirovecii and the clinical outcome of Pneumocystis pneumonia, which is a major worldwide cause of illness among immunocompromised patients. Genotyping platforms for pooled DNA samples are promising methodologies for genetic characterization of infectious organisms. We have developed a new typing strategy for P. jirovecii, which consisted of DNA pools prepared according to clinical data (HIV diagnosis, microscopic and molecular detection of P. jirovecii, parasite burden, clinical diagnosis and follow-up of infection) from individual samples using quantitative real-time PCR followed by multiplex-PCR/single base extension (MPCR/SBE). The frequencies of multiple P. jirovecii SNPs (DHFR312, mt85, SOD215 and SOD110) encoded at three distinct loci, the dihydrofolate reductase (DHFR), the mitochondrial large-subunit rRNA (mtLSU rRNA) and the superoxide dismutase (SOD) loci, were estimated in seven DNA pooled samples, representing a total of 100 individual samples. The studied SNPs were confirmed to be associated with distinct clinical parameters of infection such as parasite burden and follow-up. The MPCR/SBE-DNA pooling methodology, described in the present study, was demonstrated to be a useful high-throughput procedure for large-scale P. jirovecii SNPs screening and a powerful tool for evaluation of clinically relevant SNPs potentially related to parasite burden, clinical diagnosis and follow-up of P. jirovecii infection. In further studies, the candidate SNPs mt85, SOD215 and SOD110 may be used as molecular markers in association with MPCR/SBE DNA pooling to generate useful information for understanding the patterns and causes of Pneumocystis pneumonia. PMID- 22487140 TI - Intercepting neoplastic progression in lung malignancies via the beta adrenergic (beta-AR) pathway: implications for anti-cancer drug targets. AB - The understanding of signaling cascades involved in the induction, promotion, and progression of cancer, although advanced in recent years, is still incomplete. Tracing the imbalance of the impaired, physiologically-essential cellular signaling that drives the neoplastic process is a complex issue. This review discusses the role of the regulator of the fight or flight response, the beta adrenergic signaling cascade, as a mediator of cancer growth and progression in in vitro and in vivo cancer models. We review a series of experiments from our own laboratory and those of others examining the contribution of this signaling network to lung and other human malignancies and thereby identifying potential targets for chemotherapeutic interventions. The stimulation of the beta adrenergic receptor by lifestyle and environmental factors, as well as a preexisting risk for neoplasm, activates downstream effector molecules (adenylyl cyclase/cAMP/PKA/CREB) concomitant to the transactivation of related pathways (EGFR) that lead to pro-oncogenic signaling; this beta-adrenergic pathway thereby encourages cancer growth by evasion of apoptosis, invasion, angiogenesis, and metastasis. GABAergic signaling acts as an antagonist to the beta-adrenergic cascade by intercepting adenylyl cyclase activation, and thereby neutralizing the pro-oncogenic effects of beta-adrenergic stimulation. The regulation of cancer cell growth by neurobiological signals expands the possibilities for pharmacological interventions in cancer therapy. PMID- 22487141 TI - The open abdomen and temporary abdominal closure systems--historical evolution and systematic review. AB - AIM: Several techniques for temporary abdominal closure have been developed. We systematically review the literature on temporary abdominal closure to ascertain whether the method can be tailored to the indication. METHOD: Medline, Embase, the Cochrane Central Register of Controlled Trials and relevant meeting abstracts until December 2009 were searched using the following headings: open abdomen, laparostomy, VAC (vacuum assisted closure), TNP (topical negative pressure), fascial closure, temporary abdominal closure, fascial dehiscence and deep wound dehiscence. The data were analysed by closure technique and aetiology. The primary end-points included delayed fascial closure and in-hospital mortality. The secondary end-points were intra-abdominal complications. RESULTS: The search identified 106 papers for inclusion. The techniques described were VAC (38 series), mesh/sheet (30 series), packing (15 series), Wittmann patch (eight series), Bogota bag (six series), dynamic retention sutures (three series), zipper (15 series), skin only and locking device (one series each). The highest facial closure rates were seen with the Wittmann patch (78%), dynamic retention sutures (71%) and VAC (61%). CONCLUSION: Temporary abdominal closure has evolved from simple packing to VAC based systems. In the absence of sepsis Wittmann patch and VAC offered the best outcome. In its presence VAC had the highest delayed primary closure and the lowest mortality rates. However, due to data heterogeneity only limited conclusions can be drawn from this analysis. PMID- 22487142 TI - Calculation of protein and energy requirements in beluga sturgeon (Huso huso) using a factorial approach. AB - This study tried to determine the protein and energy requirements of growing beluga sturgeon Huso huso using a factorial approach. The experiment was composed of four small-scale growth trails covering different weight ranges. The fish fed at 0, 20, 40, 60, 80 and 100% of satiation. DWG had a steady increase throughout the experiment following a non-linear equation as Y = 1.433 (+/-0.056) * Ln(X) 2.740 (+/-0.261); r(2) = 0.99, p < 0.001, where Y = weight gain (g/day) and X = fish weight (g). The daily requirement of digestible energy (DE) for maintenance amounted to 79.09 kJ * BW (kg)(0.8) . The daily requirement of DP for maintenance calculated as 0.93 g * BW (kg)(0.7) . The relationship between DE intake (X) and DE gain (Y) expressed as Y = -0.0004 (+/-0.000) X(2) + 0.600 (+/-0.082) X -44.95 (+/- 6.72). Also, the relationship between DP intake (X) and protein gain (Y) was expressed as Y = -0.019 (+/-0.006) X(2) + 0.548 (+/-0.062) X - 0.498 (+/-0.121). The daily requirements of energy and protein were estimated as 79.09 kJ * BW (kg)(0.8) + 2.94 * DE gain and 0.93 g * BW (kg)(0.7) + 2.63 * DP gain. Apparently, beluga sturgeon is inefficient in converting energy and protein into body tissue. Therefore, energy content of the diet should be sufficiently high to satisfy large energy demands in beluga sturgeon and also to reduce the catabolism of protein. PMID- 22487144 TI - Do hepatitis B virus and hepatitis C virus co-infections increase hepatocellular carcinoma occurrence through synergistically modulating lipogenic gene expression? AB - Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections cause a wide range of liver diseases including hepatocellular carcinoma (HCC). Because of the similar modes of transmission, HBV HCV co-infections are found in approximately 7 20 million people globally. Compared with HBV or HCV mono-infections, co infections are associated with more severe liver diseases and higher risk of HCC. Abnormal lipid biosynthesis and metabolism has been increasingly recognized as a cause for cancer. While HBV infection does not seem to significantly increase the risk of developing hepatic steatosis, steatosis is a prominent feature of chronic hepatitis C (CHC). In addition, steatosis in HBV or HCV mono-infections is a significant and independent risk factor for HCC. However, whether and how HBV HCV co-infections synergistically increase the risk of HCC development through modulating lipid metabolism is not well understood. Possible mechanisms by which steatosis causes HCC include: activation of sterol regulatory element-binding protein-mediated lipogenesis through the PI3K-Akt pathway, abnormal activation of peroxisome proliferator-activated receptors and endoplasmic reticulum stress. Here, we review the potential mechanisms by which HBV HCV co-infections may increase HCC risk through modulation of lipogenic gene expression. We begin with reviewing the impact of HBV and HCV on host lipogenic gene expression and carcinogenesis. We then discuss the potential mechanisms by which HBV and HCV can increase carcinogenesis through synergistically activating lipid biosynthesis and metabolism. We end by sharing our thoughts on future research directions in this emerging paradigm with an ultimate goal of developing effective therapeutics. PMID- 22487143 TI - Pfatp6 molecular profile of Plasmodium falciparum isolates in the western Brazilian Amazon. AB - BACKGROUND: Anti-malarial drug resistance has emerged as one of the biggest challenges confronting the worldwide effort to control malaria. The appearance of chloroquine and multi-drug resistance had devastating effects on therapeutic efficacy of former first-line agents. Artemisinin has proven to be an excellent therapeutic alternative to fill the void in chemotherapeutic options left by resistance mechanisms. At the time of introduction, no resistance to artemisinins had been recorded, and artemisinins demonstrated excellent parasite reduction rates. In an attempt to protect artemisinin efficacy, the World Health Organization (WHO) made artemisinin-based combination therapy (ACT) its official first-line treatment recommendation for uncomplicated Plasmodium falciparum in 2006. In Brazil, artemether/lumefantrine became the Brazilian Malaria Control Programme's official treatment recommendation in 2007. The sarco/endoplasmic reticulum Ca2+ - ATPase ortholog of P. falciparum (pfatp6) has been suggested as one of the targets of artemisinins. Consequently, pfatp6 gene polymorphisms are being investigated as markers of artemisinin resistance elsewhere. The goal of this work was to describe the molecular profile of pfatp6 in P. falciparum isolates from different localities in the Amazonas State. METHODS: DNA polymorphisms of the pfatp6 gene in 80 P. falciparum isolates from 11 municipalities of the Amazonas State (Western Brazilian Amazon), before and after the introduction of ACT in the Brazilian anti-malarial guidelines, were analysed by automatic sequencing. Mutations in the pfatp6 gene were searched using Mutation Surveyor v3.25 software. RESULTS: The P. falciparum pfatp6 gene presented polymorphisms at codons 37, 630 and 898. The R37K mutation was found in 16% of the samples, A630S in 32% and I898I in 52%. No S769N mutation, however, was detected in the analysed samples. CONCLUSION: Despite the small number of samples, data presented here provide baseline information about polymorphisms of pfatp6 gene before and after exposure to ACT in a low transmission area, which will help to infer drug selection pressure in this area in the future. PMID- 22487145 TI - Disulfide bond formation network in the three biological kingdoms, bacteria, fungi and mammals. AB - Almost all organisms, from bacteria to humans, possess catalytic systems that promote disulfide bond formation-coupled protein folding, i.e. oxidative protein folding. These systems are necessary for the biosynthesis of many secretory and membrane proteins, such as antibodies, major histocompatibility complex molecules, growth factors, and insulin. Over the last decade, structural studies have made striking progress in this field of research, identifying how oxidative systems operate in a specific and regulated manner to maintain redox and protein homeostasis within cells. Interestingly, more and more novel catalysts that promote disulfide bond formation have been discovered in mammals, suggesting that the oxidative protein folding network is even more complicated in higher eukaryotes than previously thought. This review highlights the physiological roles and molecular bases of the disulfide bond formation pathways that have evolved in the bacterial periplasm and the endoplasmic reticulum of fungi and mammals. Accumulating knowledge about disulfide bond formation networks widely distributed throughout the biological kingdom has significantly advanced our understanding of the cellular mechanisms dedicated to protein quality control. PMID- 22487147 TI - A simpler alternative to the Sengstaken-Blakemore tube: cervix-holding by forceps to control hemorrhage after cesarean section for placenta previa. PMID- 22487146 TI - Differentiation of endosperm transfer cells of barley: a comprehensive analysis at the micro-scale. AB - Barley endosperm cells differentiate into transfer cells (ETCs) opposite the nucellar projection. To comprehensively analyse ETC differentiation, laser microdissection-based transcript and metabolite profiles were obtained from laser microdissected tissues and cell morphology was analysed. Flange-like secondary wall ingrowths appeared between 5 and 7 days after pollination within the three outermost cell layers. Gene expression analysis indicated that ethylene signalling pathways initiate ETC morphology. This is accompanied by gene activity related to cell shape control and vesicle transport, with abundant mitochondria and endomembrane structures. Gene expression analyses indicate predominant formation of hemicelluloses, glucuronoxylans and arabinoxylans, and transient formation of callose, together with proline and 4-hydroxyproline biosynthesis. Activation of the methylation cycle is probably required for biosynthesis of phospholipids, pectins and ethylene. Membrane microdomains involving sterols/sphingolipids and remorins are potentially involved in ETC development. The transcriptional activity of assimilate and micronutrient transporters suggests ETCs as the main uptake organs of solutes into the endosperm. Accordingly, the endosperm grows maximally after ETCs are fully developed. Up regulated gene expression related to amino acid catabolism, C:N balances, carbohydrate oxidation, mitochondrial activity and starch degradation meets high demands for respiratory energy and carbohydrates, required for cell proliferation and wall synthesis. At 10 days after pollination, ETCs undergo further differentiation, potentially initiated by abscisic acid, and metabolism is reprogrammed as shown by activated storage and stress-related processes. Overall, the data provide a comprehensive view of barley ETC differentiation and development, and identify candidate genes and associated pathways. PMID- 22487148 TI - Relationship between depression and loneliness in elderly and examination of influential factors. AB - This study was planned and conducted for the purpose of examining the relationship between depression and loneliness in elderly people and the influencing factors. The study was a descriptive and correlational study and its population consisted of 17,080 older individuals aged sixty and over who were registered at six Family Healthcare Centers (FHCs) located in the provisional center of Malatya. The sample of the study comprised of 913 elderly people who were chosen from the elderly people registered at the FHCs first by cluster sampling and then by simple random sampling from the clusters in proportion to the population. The data was collected between April and June 2011 using a questionnaire developed by the investigators in line with the literature, the Geriatric Depression Scale (GDS) and the UCLA Loneliness Scale (ULS). They had a mean score of 13.83 +/- 7.4 from the GDS and 40.50 +/- 12.1 from the ULS. A positive correlation was found between Geriatric Depression and loneliness (r=0.608, p<0.001). It was observed that there was a significant correlation between loneliness and depression in the elderly people living in a community, presence of social security and higher income, on the other hand, led to lower mean scores. In view of these results, it can be advised that a minimum income should be secured for elderly people whether they have social security or not, their families and the society should be trained not to leave elderly people alone. PMID- 22487150 TI - Effect of exercise intensity on oxygen consumption kinetics in non-exercising muscle during exercise. AB - This study examined the effect of exercise intensity on the kinetics of muscle oxygen consumption in non-exercising forearm flexor muscles (VO(2mf)) during exercise. Seven healthy male subjects performed cycling exercise for 60 min at 30% of maximal oxygen consumption (%VO(2max)) and 30 min at 50% VO(2max) on separate days. The VO(2mf) values at rest and during exercise were measured by near-infrared spectroscopy. The VO(2mf) at 30% VO(2max) significantly increased to 1.2 +/- 0.1-fold over resting value at 20 min after the beginning of exercise (P<0.05) and remained constant within 1.2- to 1.3-fold over resting value until 60 min during exercise. The VO(2mf) at 50% VO(2max) significantly increased to 1.2 +/- 0.1-fold over resting value at 15 min after the beginning of exercise (P<0.05). Subsequently, the VO(2mf) at 50% VO(2max) increased with time to 1.3 +/ 0.1-fold over resting value at 20 min after the beginning of exercise and to 1.5 +/- 0.2-fold over resting value at 30 min. The VO(2mf) 15-30 min of exercise at 50% VO(2max) was significantly higher than that at 30% VO(2max) (P<0.05). These data suggest that the increase in VO(2mf) has a time lag from the beginning of exercise, and the kinetics of VO(2mf) during exercise differs with exercise intensity. Therefore, we conclude that the kinetics of VO(2mf) during exercise is dependent on exercise intensity. PMID- 22487149 TI - Decreased aerobic capacity 4 years after aortic valve replacement in male patients operated upon for chronic aortic regurgitation. AB - Exercise testing is underutilized in patients with valve disease. We have previously found a low physical work capacity in patients with aortic regurgitation 6 months after aortic valve replacement (AVR). The aim of this study was to evaluate aerobic capacity in patients 4 years after AVR, to study how their peak oxygen uptake (peakVO(2)) had changed postoperatively over a longer period of time. Twenty-one patients (all men, 52+/-13 years) who had previously undergone cardiopulmonary exercise testing (CPET) pre- and 6 months postoperatively underwent maximal exercise testing 49 +/- 15 months postoperatively using an electrically braked bicycle ergometer. Breathing gases were analysed and the patients' physical fitness levels categorized according to Astrand's and Wasserman's classifications. Mean peakVO(2) was 22.8 +/- 5.1 ml * kg(-1) * min(-1) at the 49-month follow-up, which was lower than at the 6-month follow-up (25.6 +/- 5.8 ml * kg(-1) * min(-1), P = 0.001). All but one patient presented with a physical fitness level below average using Astrand's classification, while 13 patients had a low physical capacity according to Wasserman's classification. A significant decrease in peakVO(2) was observed from six to 49 months postoperatively, and the decrease was larger than expected from the increased age of the patients. CPET could be helpful in timing aortic valve surgery and for the evaluation of need of physical activity as part of a rehabilitation programme. PMID- 22487151 TI - Dissociated time course recovery between rate of force development and peak torque after eccentric exercise. AB - This study investigated the association between isokinetic peak torque (PT) of quadriceps and the corresponding peak rate of force development (peak RFD) during the recovery of eccentric exercise. Twelve untrained men (aged 21.7 +/- 2.3 year) performed 100 maximal eccentric contractions for knee extensors (10 sets of 10 repetitions with a 2-min rest between each set) on isokinetic dynamometer. PT and peak RFD accessed by maximal isokinetic knee concentric contractions at 60 degrees s(-1) were obtained before (baseline) and at 24 and 48 h after eccentric exercise. Indirect markers of muscle damage included delayed onset of muscle soreness (DOMS) and plasma creatine kinase (CK) activity. The eccentric exercise resulted in elevated DOMS and CK compared with baseline values. At 24 h, PT ( 15.3%, P = 0.002) and peak RFD (-13.1%, P = 0.03) decreased significantly. At 48 h, PT (-7.9%, P = 0.002) was still decreased but peak RFD have returned to baseline values. Positive correlation was found between PT and peak RFD at baseline (r = 0.62, P = 0.02), 24 h (r = 0.99, P = 0.0001) and 48 h (r = 0.68, P = 0.01) after eccentric exercise. The magnitude of changes (%) in PT and peak RFD from baseline to 24 h (r = 0.68, P = 0.01) and from 24 to 48 h (r = 0.68, P = 0.01) were significantly correlated. It can be concluded that the muscle damage induced by the eccentric exercise affects differently the time course of PT and peak RFD recovery during isokinetic concentric contraction at 60 degrees s(-1). During the recovery from exercise-induced muscle damage, PT and peak RFD are determined but not fully defined by shared putative physiological mechanisms. PMID- 22487152 TI - Comparison of low-intensity blood flow-restricted training-induced muscular hypertrophy in eumenorrheic women in the follicular phase and luteal phase and age-matched men. AB - The purpose of this study was to compare the muscle hypertrophic response in women during both the follicular (FP) and the luteal phase (LP) of their menstrual cycles following short-term, low-intensity resistance training combined with blood flow restriction (BFR). Eight eumenorrheic women and five men, all previously untrained, performed unilateral low-intensity (30% of 1 repetition maximum) dumbbell curl training with BFR once a day for 6 days. The opposite arm served as an untrained control. This 6-day training programme was conducted during both menstrual cycle phases: the early FP and the mid LP. MRI-measured biceps muscle volume (MV) and isometric elbow flexion strength were measured in both arms before and 2 days after the final training bout. Significantly (P<0.05) greater muscle hypertrophy was observed in the LP (5.7%) than in the FP (3.7%). The absolute and relative changes in serum hormone concentrations between the two phases did not correlate (P>0.05) with the percentage change in MV between the LP and FP. There was no change in MV in the control arm for both cycle phases. Following training, isometric strength increased (P<0.01) in the LP, but not in the FP (P = 0.17). Relative strength (strength per unit MV) was similar pre- and post-training in both phases. The percentage changes in MV and strength were similar between the women (average of LP and FP) and men. Our results indicate that muscle hypertrophy and strength gain are higher in the LP than in the FP following 6 days of BFR training, although the sex difference in the training response is non-existent. PMID- 22487153 TI - A suggestion of reference data for flow distribution at ankle and foot level using quantitative 99Tc-HDP three-phase bone scintigraphy. AB - AIM: To determine reference intervals for quantitative 99mTc-hydroxymethylene diphosphonate (99mTc-HDP) three-phase bone scintigraphy regarding flow distribution at ankle and mid-foot level. MATERIALS AND METHODS: Fifty patients referred to bone scintigraphy without known or suspected pathology in the legs or hips were included. Quantitative three-phase bone scintigraphy was performed in all patients. A processing protocol with standardized size regions of interests (ROIs) was used to quantify the distribution of flow and blood pool at ankle and level mid-foot levels. Patients were divided into three groups: <60 years (n = 20), 60 years or older (n = 17) and finally a group (n = 13) with pedal foci (PF). RESULTS: Blood pool distribution varied between the two age groups, with younger having the narrowest confidence interval at mid-foot level but the widest at ankle level. Blood flow distribution confidence intervals were wider in the presence of PF, whereas blood pool distribution intervals were independent of PF. Both blood flow distribution and blood pool at ankle and mid-foot level were independent of gender and referral status being either cancer or skeletal complaints. CONCLUSION: As there was no evident increase in blood flow distribution at ankle and mid-foot level with age, we suggest the use of pooled data from both age groups. Subsequently, the confidence interval for the relative distribution of blood flow at ankle level is 37/63 and 33/67 at mid-foot level. For blood pool, the corresponding intervals are 43/57 and 40/60, respectively. Blood flow distribution appears to be influenced by the presence of PF, whereas blood pool distribution is not. PMID- 22487154 TI - Evaluating abdominal oedema during experimental sepsis using an isotope technique. AB - PURPOSE: Abdominal oedema is common in sepsis. A technique for the study of such oedema may guide in the fluid regime of these patients. PROCEDURES: We modified a double-isotope technique to evaluate abdominal organ oedema and fluid extravasation in 24 healthy or endotoxin-exposed ('septic') piglets. Two different markers were used: red blood cells (RBC) labelled with Technetium-99m ((99m)Tc) and Transferrin labelled with Indium111 ((111)In). Images were acquired on a dual-head gamma camera. Microscopic evaluation of tissue biopsies was performed to compare data with the isotope technique. RESULTS: No (99m)Tc activity was measured in the plasma fraction in blood sampled after labelling. Similarly, after molecular size gel chromatography, (111)In activity was exclusively found in the high molecular fraction of the plasma. Extravasation of transferrin, indicating the degree of abdominal oedema, was 4.06 times higher in the LPS group compared to the healthy controls (P<0.0001). Abdominal free fluid, studied in 3 animals, had as high (111)In activity as in plasma, but no (99m)Tc activity. Intestinal lymphatic vessel size was higher in LPS (3.7 +/- 1.1 MUm) compared to control animals (0.6 + 0.2 MUm; P<0.001) and oedema correlated to villus diameter (R(2) = 0.918) and lymphatic diameter (R(2) = 0.758). A correlation between a normalized index of oedema formation (NI) and intra abdominal pressure (IAP) was also found: NI = 0.46*IAP-3.3 (R(2) = 0.56). CONCLUSIONS: The technique enables almost continuous recording of abdominal oedema formation and may be a valuable tool in experimental research, with the potential to be applied in the clinic. PMID- 22487155 TI - The effect of interval training combined with thigh cuffs pressure on maximal and submaximal exercise performance. AB - The purpose of the study was to investigate the effect of interval training combined with a thigh cuffs pressure of +90 mmHg on maximal and submaximal cycling performance. Twenty untrained individuals were assigned either to a control (CON) or to an experimental (CUFF) training group. Both groups trained 3 days per week for 6 weeks at the same relative intensity; each training session consisted of 2-min work bout at 90% of VO(2max): 2-min active recovery bout at 50% of VO(2max). An incremental exercise test to exhaustion, a 6-min constant power test at 80% of VO(2max) (Sub(80)) and a maximal constant-power test to exhaustion (TF(150)) were performed pre- and post-training. Despite the unchanged VO(2max), both groups significantly increased peak power output (CON: ~12%, CUFF: ~20%) that was accompanied by higher deoxygenation (DeltaStO(2)) measured with near-infrared muscle spectroscopy. These changes were more pronounced in the CUFF group. Moreover, both groups reduced VO(2) during the Sub(80) test without concomitant changes in DeltaStO(2). TF(150) was enhanced in both groups. Thus, an interval exercise training protocol under moderate restricted blood flow conditions does not provide any additive effect on maximal and submaximal cycling performance. However, it seems to induce peripheral muscular adaptations, despite the lower absolute training intensity. PMID- 22487156 TI - Free-living energy expenditure reduced after deep brain stimulation surgery for Parkinson's disease. AB - BACKGROUND: The clinical picture in Parkinson's disease (PD) is characterized by bradykinesia, rigidity, resting tremor and postural instability. In advanced stages of the disease, many patients will experience reduced efficacy of medication with fluctuations in symptoms and dyskinesias. Surgical treatment with deep brain stimulation in the subthalamic nucleus (STN-DBS) is now considered the gold standard in fluctuating PD. Many patients experience a gain of weight following the surgery. The aim of this study was to identify possible mechanisms, which may contribute to body weight gain in patients with PD following bilateral STN-DBS surgery. METHODS: Ten patients with PD were studied before bilateral STN DBS surgery, and seven patients were studied again 3 and 12 months postoperatively. Clinical examination and resting metabolic rate with and without medical treatment was measured before and after STN-DBS. Furthermore, free-living energy expenditure, body composition, energy intake, peak oxygen consumption, maximal workload and leisure time physical activity were measured before and 3 and 12 months after surgery. RESULTS: The STN-DBS operated patients had a significant weight gain of 4.7 +/- 1.6 kg (mean +/- SE) 12 months postoperatively, and the weight gain was in the fat mass. The free-living energy expenditure decreased postoperatively 13 +/- 4% even though the reported dietary intake was reduced. A decreased energy expenditure took place in the non-resting energy expenditure. The reported daily leisure time activity, peak oxygen consumption and maximal workload were unchanged. CONCLUSION: The STN-DBS operated patients have a significant postoperative weight gain, as a result of a decrease in free-living energy expenditure concomitant with an insufficient decrease in energy intake. PMID- 22487157 TI - Reliability of the rectus femoris muscle cross-sectional area measurements by ultrasonography. AB - The skeletal muscle system can adapt to an external stimulus from either physiological or pathological conditions. This plasticity is measured by imaging techniques such as magnetic resonance imaging or ultrasound. The anatomical cross sectional area of a muscle is one of the muscle architecture parameters that relates to the maximum muscle strength. The aim of this study was to determine the reliability of anatomical cross-sectional area rectus femoris measurements, obtained by ultrasound, with two different protocols. Acquisition of four anatomical cross-sectional area images of the right rectus femoris in two distinct regions (15 cm above the patella and 50% of the thigh length) was performed in 2 days, from a group of 15 young healthy subjects. The cross sectional area of each image was measured five times. The reliability of the anatomical cross-sectional area measures was determined by the coefficient of variation (CV), intraclass correlation coefficient (ICC) and typical error of measurement (TEM). In each protocol, there were no significant differences between the means of anatomical cross-sectional area in measurements, images and days (P>0.05). The CVs were 8.53% and 8.9%, the ICCs 0.88 and 0.87 and the TEMs 65.59 and 94.25 between the 2 days in the regions of 15 cm and 50% of the thigh length, respectively. The average values of the cross-sectional area at 50% of the thigh length were significantly higher than those for at 15 cm above the patella (P<0.001). The measurement of rectus femoris anatomical cross-sectional area by ultrasound proved reliable. PMID- 22487158 TI - Brachial artery hyperaemic blood flow velocity in relation to established indices of vascular function and global atherosclerosis: the Prospective Investigation of the Vasculature in Uppsala Seniors study. AB - BACKGROUND: Systolic to diastolic blood flow velocity (SDFV) ratio in the brachial artery recently proved to be related to cardiovascular risk and carotid atherosclerosis. We hypothesized that the SDFV ratio was related to established markers of vascular function and global atherosclerosis. METHODS: Established markers of endothelial function in forearm resistance vessels, flow-mediated vasodilation and arterial stiffness were assessed in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study including 1016 individuals aged 70. Whole-body magnetic resonance angiography was performed in a random 306 of the participants. Atherosclerotic lesions were summarized in a total atherosclerotic score (TAS). Before and during hyperaemia of the brachial artery, systolic and diastolic blood flow velocities were measured by Doppler. RESULTS: The SDFV ratio was positively related to endothelium-independent vasodilatation, while inverse relations were found to flow-mediated dilation, common carotid artery distensibility and the stroke volume to pulse pressure ratio. Endothelium-dependent vasodilatation and total peripheral resistance index were not significantly related to the SDFV ratio. The SDFV ratio (P = 0.015) and the blood flow increase (BFI) during hyperaemia (P = 0.020) were both significantly related to TAS after gender adjustment. When adjusted for the Framingham risk score, both the SDFV ratio (P = 0.057) and BFI (P = 0.078) lost somewhat in significance. CONCLUSION: The SDFV ratio was related to established markers of both vasodilation and arterial compliance, and to global atherosclerosis. Future larger studies have to evaluate whether the SDFV ratio is related to global atherosclerosis independently of traditional risk factors. PMID- 22487159 TI - A comparison of postexercise shear rate patterns following different intensities and durations of running in healthy men. AB - PURPOSE: We tested the hypothesis that high-intensity exercise would elicit the greatest alterations in postexercise shear rate (SR) patterns when compared to moderate intensity exercise, and moderate duration exercise would produce similar postexercise SR patterns as long-duration exercise. METHODS: On separate days, ten healthy men completed three acute treadmill exercise sessions at different intensities and/or durations. Sessions were 80% VO(2peak) for 30 min (HIGH), 50% VO(2peak) for 30 min (MOD) and 50% VO(2peak) for 60 min (MOD(L) . SR in the brachial artery was assessed at baseline, immediately postexercise, 1 and 2 h postexercise using Doppler ultrasound. RESULTS: Oscillatory and retrograde SR decreased immediately following all exercise sessions (P<0.01) and returned to baseline at 1 h postexercise; however, there were no differences between sessions (P>0.08). Antegrade and mean SR were elevated immediately following all exercise sessions (P<0.01), and the greatest elevations were observed following the HIGH session (P<0.05). Antegrade and mean SR declined below baseline values at 1 h (P<0.05) and 2 h (P<0.05) after the MOD(L) session and 2 h following the HIGH session (P<0.05). CONCLUSION: Antegrade and mean SR immediately following running exercise are dependent upon exercise intensity. Reductions in oscillatory and retrograde SR after treadmill running are not dependent on exercise intensity or duration and appear to last <1 h. Collectively, SR profiles following exercise are differentially altered based on the dose of exercise performed. PMID- 22487161 TI - Concurrent protracted febrile myalgia syndrome in a child with diabetic ketoacidosis. AB - Familial Mediterranean Fever (FMF), characterized by recurrent attacks of inflammation in predominantly serosal and synovial membranes, is caused by MEFV gene mutations resulting in abnormal pyrin. Protracted febrile myalgia syndrome (PFMS), a kind of vasculitis requiring corticosteroid treatment, is associated with M694V mutation of MEFV gene. Here, we report a case where the patient developed PFMS leading to the diagnosis of FMF concurrently at the time of treatment for diabetic ketoacidosis (DKA) of new-onset type 1 diabetes mellitus and discuss the possible mechanisms of simultaneous DKA and FMF-associated PFMS. DKA-associated cytokine release may be a predisposing factor or trigger for FMF associated PFMS. PMID- 22487160 TI - Functional assessment of high-grade ICA stenosis with duplex ultrasound and transcranial Doppler. AB - BACKGROUND: Duplex ultrasound (DUS) has shown a >90% accuracy compared to angiography, concerning the degree of internal carotid artery (ICA) stenosis. However, uncertainty may occur in a severe stenosis, in which peak systolic velocity (PSV) may decrease owing to high flow resistance or high backward pressure. We investigated intracranial collateral flows using transcranial Doppler (TCD) to further evaluate the hemodynamic significance of high-grade ICA stenosis. METHODS: In this retrospective study, 320 consecutive symptomatic patients were examined. The degree of ICA stenosis and collateral capacity in the circle of Willis was investigated by DUS and TCD. In addition, magnetic resonance angiography (MRA) was added in a subgroup of 204 patients. The criterion for hemodynamic significant ICA stenosis was established collateral flow. RESULTS: In 91% of all symptomatic vessels (291 vessels), an ICA stenosis of >=70% was found. Established collateral flow always indicated precerebral carotid artery disease of >=70%. Furthermore, in 11% of the whole study material, collateral reserve capacity was found despite high-grade (>=70%) ICA stenosis. PSV in ICA <2.5 m s( 1) was combined with established collateral flow and MRA stenosis of >=70% in 9% (19 arterial systems). In 4%, doubt existed concerning the degree of stenosis after DUS. CONCLUSION: Transcranial Doppler helps to determine whether an ICA stenosis is of hemodynamic significance and to assess collateral patterns. Established collateral blood flow will help to identify patients with >=70% (ECST) carotid artery disease. TCD might be of value when flow velocity criteria combined with plaque assessment by DUS are inclusive. Other diagnostic methods may also be considered. PMID- 22487162 TI - Breast cancer detection method among 20- to 49-year-old patients at a community based cancer center: 1990-2008. AB - Our research goal is to report on method of breast cancer detection among young women from a prospective cohort study of primary breast cancer patients, aged 20 49 years, 1990-2008 (n = 2579). Clinical presentation characteristics including race, TNM stage, first degree relative family history, histologic type and method of detection by patient (PtD), physician (PhysD), or mammography (MamD) were chart abstracted. Forward conditional stepwise regression was used to for association with detection method and Kaplan-Meier for relapse free survival (RFS) analysis. Among 20- to 39-year olds (n = 602) no change in detection method occurred over time with 12% MamD, 7% PhysD, and 81% PtD. Among 40- to 49-year olds, MamD BC increased over time (28% to 58%) and PtD BC decreased (63-36%) (Pearson X(2) = 72.72, p < .001). Among 20-39/40- to 49-year old MamD cases 31%/32% were stage 0 versus 2%/6% of the PhysD/PtD cases. In two separate conditional logistic regression models, older age at diagnosis and first degree relative BC history were associated with MamD BC for 20- to 39- and 40- to 49 year olds. Five-year MamD BC RFS was superior for both age groups (20-39: 94%, 40 49: 94%) compared to PtD BC rates (20-39: 80%, p = .016; 40-49: 88%, p < .001). For PtD BC 20- to 39-year olds had worse RFS (5 year 80%, 10 year 75%) than 40- to 49-year olds (5 year 88%, 10 year 82%) (p = .002) but RFS was equivalent for MamD cases by age. The majority of breast cancers among women 20-49 years were patient detected and mammography detection occurred rarely among youngest women. Lower stage and superior survival among MamD patients support mammography for detecting disease in high risk women aged 30-39 years and 40-49 years. PMID- 22487163 TI - What's new in resuscitation strategies for the patient with multiple trauma? AB - The last decade has seen a sea change in the management of major haemorrhage following traumatic injury. Damage control resuscitation (DCR), a strategy combining the techniques of permissive hypotension, haemostatic resuscitation and damage control surgery has been widely adopted as the preferred method of resuscitation in patients with haemorrhagic shock. The over-riding goals of DCR are to mitigate metabolic acidosis, hypothermia and coagulopathy and stabilise the patient as early as possible in a critical care setting. This narrative review examines the background to these changes in resuscitation practice, discusses the central importance of traumatic coagulopathy in driving these changes particularly in relation to the use of high FFP:RBC ratio and explores methods of predicting, diagnosing and treating the coagulopathy with massive transfusion protocols as well as newer coagulation factor concentrates. We discuss other areas of trauma haemorrhage management including the role of hypertonic saline and interventional radiology. Throughout this review we specifically examine whether the available evidence supports these newer practices. PMID- 22487164 TI - Utility of interim ROTEM((r)) values of clot strength, A5 and A10, in predicting final assessment of coagulation status in severely injured battle patients. AB - BACKGROUND: Proactive management of trauma-related coagulopathy requires early identification and rapid assessment in order to allow targeted resuscitation. This study determined whether early (interim) ROTEM((r)) (TEM International GmbH, Munich, Germany) values could predict hypocoagulopathy in seriously injured military patients. METHODS: Normal ranges for ROTEM((r)) values were obtained from 50 volunteers. 108 samples were collected during the early phase of clinical management from 48 severe trauma patients. The blood was subject to EXTEM analysis and compared to the 95% tolerance limits from the volunteers. Coagulopathy (was deemed to be present if EXTEM MCF was below 40 mm, which is in the range indicating clinical concern defined by the ROTEM((r)) Expert Working Group. RESULTS: The normal range data was broadly similar to ROTEM((r)) published data. Admission samples were available from 31 battlefield casualties, and 39% of these were coagulopathic 51% of the samples from all 48 patients were coagulopathic (EXTEM MCF<40 mm) and interim EXTEM values of these at 5 and 10 min (A5 and A10) predicted coagulopathy with sensitivities/specificities of 0.96/0.58 (A5) and 1.00/0.70 (A10). In addition, statistical comparison of clotting domains between normal volunteers and trauma patients suggests a difference in clot strengths due to a difference in platelet function rather than platelet number (mean 142 * 10(9)l(-1)). CONCLUSIONS: The A10 value of ROTEM((r)) provides an early sensitive and specific assessment of coagulopathy after military trauma and may be of utility in guiding bespoke resuscitation. We found some speculative evidence that in major trauma platelet function is particularly affected. PMID- 22487165 TI - The V-A-V response to ventricular entrainment during atrial tachycardia: what is the mechanism? PMID- 22487166 TI - Estimating the costs of rearing young dairy cattle in the Netherlands using a simulation model that accounts for uncertainty related to diseases. AB - The costs of rearing young dairy cattle are a part of the cost of the price of milk, as rearing produces the future dairy cows. As most dairy farmers are not aware of the rearing costs, the rearing of dairy replacements often does not get the attention it deserves. Calculating the distribution of the rearing costs throughout the rearing process is difficult as the costs are correlated with biological processes, such as variation in growth rate and disease uncertainty. In this study, a calf level simulation model was built to estimate the rearing costs and their distribution from 2 weeks of age until first calving in the Netherlands. The uncertainties related to calf diseases (calf scours and bovine respiratory disease) were included, in which both the probabilities of disease and the effects of diseases (growth reduction) differ at different ages. In addition, growth was modeled stochastically and in a detailed manner using a two phase growth function. The total cost of rearing young dairy cattle was estimated as ?1567 per successfully reared heifer and varied between ?1423 and ?1715. Reducing the age of first calving by 1 month reduced the total cost between 2.6% and 5.7%. The difference in the average cost of rearing between heifers that calved at 24 months and those calving at 30 months was ?400 per heifer reared. Average rearing costs were especially influenced by labor efficiency and cost of feed. The rearing costs of a heifer that experienced disease at least once (20% of the simulated heifers) were on average ?95 higher than those of healthy heifers. Hence, for an individual diseased heifer, disease costs can be rather high, while the relative contribution to the average rearing cost for a standard Dutch dairy farm is low (approx. 3%). Overall, the model developed proved to be a useful tool to investigate the total cost of rearing young dairy cattle, providing insights to dairy farmers with respect to the cost-efficiency of their own rearing management. PMID- 22487167 TI - Evaluation of the Salmonella surveillance program in Belgian pig farms. AB - Since July 2007, Belgium has implemented a national surveillance and control program for Salmonella in pigs. Pig farms are designated as Salmonella high risk farms based on serological profiles and are obliged to subsequently take part in a Salmonella specific action plan (SSAP). The SSAP was evaluated and potential risk factors for the persistence of Salmonella on the farm were investigated. First, the Kaplan-Meier method was used in order to study the period during which a farm maintains a Salmonella high risk status. Farms recovered more slowly from their high risk status before the SSAP was implemented compared to after the program was implemented (p<0.001). However, results showed that 29% of the farms were withdrawn from the program possibly only because of sampling error. The program should thus be adapted to accommodate for this. Secondly, the influence of several risk factors (type of farm, season of entrance into the SSAP, size of farm and farm density of the municipality) on the time to withdrawal from the high risk status was evaluated using univariable methods and a Cox multiple regression model for survival data. A statistically significant association was identified between the type of farm and the time to withdrawal from the high risk status. At any point in time after the onset of the SSAP, withdrawals from the high risk status occurred at a 39% and 28% higher rate in mixed (p=0.01) and fattening farms (p=0.05), respectively, compared to closed farms. The risk attributed to closed pig farms is related to the presence of sows in this particular type of structure, which underlines the importance of implementing control measures in this category of animals. PMID- 22487168 TI - Pig producers' perceptions of the Influenza Pandemic H1N1/09 outbreak and its effect on their biosecurity practices in Australia. AB - The Influenza Pandemic (H1N1/09) virus was first reported in humans in Mexico in April 2009 and a pandemic level was declared on 11th of June 2009 by the World Health Organization (Chan, 2009; WHO, 2009a). Public misconceptions about the transmission of H1N1/09 were caused by the inadequate naming of the disease as 'swine influenza'. This cross-sectional study was conducted at the height of the outbreak in the Australian human population and before the virus was reported in the first piggery in Australia in July 2009 (OIE, 2009b; Holyoake et al., 2011). The aims of this study were to evaluate pig producers' perceptions about the virus and the outbreak financial impact and influence on on-farm biosecurity practices. A questionnaire was designed and posted to Australian Pork Limited (APL) members (n=460), obtaining responses from 182 producers (39.6%). Pig producers had good general knowledge on potential transmission pathways for H1N1/09 between people, with direct or close contact with a sick person perceived as the most likely pathways. Changes on biosecurity practices, such as asking visitors if they had recently been overseas (27.8%) and not allowing any visitor to inspect their pigs (18.3%), were reported among respondents. In addition, approximately 40% of producers asked their employees to notify flu like symptoms, consulted a veterinarian on H1N1/09 and visited websites to seek information on H1N1/09. A higher adoption of these practices was observed among large (>100 sows) than small herds. Only 2.9% of respondents reported a reduction in pig sales during the outbreak. However, approximately one third of producers reported being financially and emotionally stressed, 38.2% were distressed about the health of their pigs and 16.7% about their own health. The most important sources of information were APL (93%), veterinarians (89%) and the state Department of Primary Industries (DPI) (75%). The first two considered the most trusted sources of information. Television, radio and other farmers were considered more important sources of information by small herds and veterinarians by larger herds. Producers believed that the H1N1/09 outbreak was better managed by the pork industry (89.9%) than by the health authorities (58.8%), and the on-going communication with APL was the main strength of the outbreak management. Communication and extension programs in future outbreaks should consider the needs of all sectors of the pig industry to increase their effectiveness. PMID- 22487169 TI - Artificially depleted plasmas are not necessarily commutable with native patient plasmas for International Sensitivity Index calibration and International Normalized Ratio derivation: a rebuttal. PMID- 22487170 TI - Motor skills and school performance in children with daily physical education in school--a 9-year intervention study. AB - The aim was to study long-term effects on motor skills and school performance of increased physical education (PE). All pupils born 1990-1992 from one school were included in a longitudinal study over nine years. An intervention group (n = 129) achieved daily PE (5 * 45 min/week) and if needed one extra lesson of adapted motor training. The control group (n = 91) had PE two lessons/week. Motor skills were evaluated by the Motor Skills Development as Ground for Learning observation checklist and school achievements by marks in Swedish, English, Mathematics, and PE and proportion of pupils who qualified for upper secondary school. In school year 9 there were motor skills deficits in 7% of pupils in the intervention group compared to 47% in the control group (P < 0.001), 96% of the pupils in the intervention group compared to 89% in the control group (P < 0.05) qualified for upper secondary school. The sum of evaluated marks was higher among boys in the intervention group than in the control group (P < 0.05). The sum of marks was also higher in pupils with no motor skills deficit than among pupils with motor skills deficits (P < 0.01), as was the proportion of pupils who qualified for upper secondary school (97% vs 81%, P < 0.001). Daily PE and adapted motor skills training during the compulsory school years is a feasible way to improve not only motor skills but also school performance and the proportion of pupils who qualify for upper secondary school. PMID- 22487171 TI - Noradrenaline-induced enhancement of oscillatory local field potentials in the mouse accessory olfactory bulb does not depend on disinhibition of mitral cells. AB - The olfactory bulb differs from other brain regions by its use of bidirectional synaptic transmission at dendrodendritic reciprocal synapses. These reciprocal synapses provide tight coupling of inhibitory feedback from granule cell interneurons to mitral cell projection neurons in the accessory olfactory bulb (AOB), at the first stage of vomeronasal processing. It has been proposed that both the mGluR2 agonist DCG-IV and noradrenaline promote mate recognition memory formation by reducing GABAergic feedback on mitral cells. The resultant mitral cell disinhibition is thought to induce a long-lasting enhancement in the gain of inhibitory feedback from granule to mitral cells, which selectively gates the transmission of the learned chemosensory information. However, we found that local infusions of both noradrenaline and DCG-IV failed to disinhibit AOB neural activity in urethane-anaesthetised mice. DCG-IV infusion had similar effects to the GABA(A) agonist isoguvacine, suggesting that it increased GABAergic inhibition in the AOB rather than reducing it. Noradrenaline infusion into the AOB also failed to disinhibit mitral cells in awake mice despite inducing long term increases in power of AOB local field potentials, similar to those observed following memory formation. These results suggest that mitral cell disinhibition is not essential for the neural changes in the AOB that underlie mate recognition memory formation in mice. PMID- 22487173 TI - Epidemiological aspects of pandemic influenza A(H1N1) virus from 2009 to 2011 in Iran. PMID- 22487172 TI - RNA plasticity and selectivity applicable to therapeutics and novel biosensor development. AB - Aptamers are short, single-stranded nucleic acid sequences that are selected in vitro from large oligonucleotide libraries based on their high affinity to a target molecule. Hence, aptamers can be thought of as a nucleic acid analog to antibodies. However, several viewpoints hold that the potential of aptamers arises from interesting characteristics that are distinct from, or in some cases, superior to those of antibodies. This review summarizes the recent achievements in aptamer programs developed in our laboratory against basic and therapeutic protein targets. Through these studies, we became aware of the remarkable conformational plasticity and selectivity of RNA, on which the published report has not shed much light even though this is evidently a crucial feature for the strong specificity and affinity of RNA aptamers. PMID- 22487174 TI - Isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors: SAR and pharmacokinetic evaluation. AB - The synthesis and structure-activity relationship studies of isothiazole and isoxazole fused pyrimidones as PDE7 inhibitors are discussed. The pharmacokinetic profile of 10 and 21 with adequate CNS penetration, required for in vivo Parkinson's disease models, are disclosed. PMID- 22487175 TI - A conformationally restricted uniconazole analogue as a specific inhibitor of rice ent-kaurene oxidase, CYP701A6. AB - The plant growth retardant uniconazole (UNI), which has been used as an effective inhibitor of ent-kaurene oxidase (CYP701A) involved in gibberellin biosynthesis, also strongly inhibits ABA 8'-hydroxylase (CYP707A), a key enzyme in abscisic acid catabolism. Azole P450 inhibitors bind to the P450 active site by both coordinating to the heme-iron atom via an sp(2) nitrogen and interacting with surrounding protein residues through a lipophilic region. We hypothesized that poor selectivity of UNI may result from its small molecular size and flexible conformation that allows it to fit into active sites differing in size and shape. To find a selective inhibitor of CYP701A based on this hypothesis, we examined inhibitory activities of three types of UNI analogues, which were conformationally constrained, enlarged in width, and enlarged in length, against recombinant rice CYP701A6 and Arabidopsis CYP707A3. Conformationally restricted analogues, UFAP2 and UFAP2N, inhibited CYP701A6 as strongly as UNI, whereas it inhibited CYP707A3 less than UNI. PMID- 22487176 TI - Flavones and structurally related 4-chromenones inhibit carbonic anhydrases by a different mechanism of action compared to coumarins. AB - An inhibition study of several carbonic anhydrase (CA, EC 4.2.1.1) isoforms with flavones and aminoflavones, compounds possessing a rather similar scaffold with the coumarins, recently discovered inhibitors of this enzyme, is reported. The natural product flavone and some of its hydroxylated derivatives did not show time-dependent inhibition of the CAs, sign that they are not hydrolyzed within the enzyme active site as the (thio)coumarins and lactones. These compounds were low micromolar inhibitors of hCA I, II, IX and XII, with K(I)s in the range of 1.88-9.07 MUM. A series of substituted 2-amino-3-phenyl-4H-chromen-4-ones, incorporating chloro- and methoxy substituents in various positions of the heterocycle, were then prepared and assayed as hCA I and II inhibitors, showing activity in the micromolar range. Some of these derivatives, as well as cis+trans resveratrol, were then assayed for the inhibition of all catalytically active mammalian CA isoforms, hCA I, II, III, IV, VA, VB, VI, VII, IX, XII, XIII, XIV and mCA XV (h=human, m=murine enzyme). These derivatives inhibited these CAs in the submicromolar-low micromolar range. Flavones, although not as active as the coumarins, may be considered as interesting leads for the design of non sulfonamide CA inhibitors. PMID- 22487177 TI - Blocking HIV-1 entry by a gp120 surface binding inhibitor. AB - We report the mode of action of a proteomimetic compound that binds to the exterior surface of gp120 and blocks HIV-1 entry into cells. Using a one cycle time-of-addition study and antibody competition binding studies, we have determined that the compound blocks HIV-1 entry through modulation of key protein protein interactions mediated by gp120. The compound exhibits anti-HIV-1 replication activities against several pseudotype viruses derived from primary isolates and the resistant strains isolated from existing drug candidates with equal potency. Together, these data provide evidence that the proteomimetic compound represents a novel class of HIV-1 viral entry inhibitor that functions through protein surface recognition in analogy to an antibody. PMID- 22487178 TI - Pyronepolyene C-glucosides with NF-kappaB inhibitory and anti-influenza A viral (H1N1) activities from the sponge-associated fungus Epicoccum sp. JJY40. AB - A new pyronepolyene C-glucoside, named iso-D8646-2-6 (1) together with the known related compound D8646-2-6 (2), was isolated from the sponge-associated fungus Epicoccum sp. JJY40. They showed NF-kappaB inhibitory and anti-influenza A viral (H1N1) activities. PMID- 22487179 TI - Synthesis and SAR of 1,3-thiazolyl thiophene and pyridine derivatives as potent, orally active and S1P3-sparing S1P1 agonists. AB - We have previously disclosed 1,2,4-oxadiazole derivative 3 as a potent S1P(3) sparing S1P(1) agonist. Although compound 3 exhibits potent and manageable immunosuppressive efficacy in various in vivo models, recent studies have revealed that its 1,2,4-oxadiazole ring is subjected to enterobacterial decomposition. As provisions for unpredictable issues, a series of alternative compounds were synthesized on the basis of compound 3. Extensive SAR studies led to the finding of 1,3-thiazole 24c with the EC(50) value of 3.4 nM for human S1P(1), and over 5800-fold selectivity against S1P(3). In rat on host versus graft reaction (HvGR), the ID(50) value of 24c was determined at 0.07 mg/kg. The pharmacokinetics in rat and monkey is also reported. Compared to compound 3, 24c showed excellent stability against enterobacteria. PMID- 22487180 TI - Design, synthesis and anticonvulsant activities of novel 1 (substituted/unsubstituted benzylidene)-4-(4-(6,8-dibromo-2-(methyl/phenyl)-4 oxoquinazolin-3(4H)-yl)phenyl) semicarbazide derivatives. AB - Novel quinazolinone derivatives 5a-5n were designed, synthesized and screened for antiepileptic activity using MES and scPTZ seizures tests. Neurotoxicity study was performed by rotorod test. Compounds 5c, 5d, 5g, 5j and 5k were found active in the preliminary screening in MES model and/or scPTZ model. Further all these five compounds were administered to rats, 5c and 5d showed better activity than Phenytoin in oral route. Among all the title compounds tested, the most active one was 5c that revealed protection in MES at a dose of 30 mg/kg (ip) after 0.5 and 4h. This molecule also provided protection in the scPTZ at a dose of 100mg/kg (0.5h) and 300 mg/kg (4h). PMID- 22487181 TI - Inhibition of quorum sensing regulated biofilm formation in Serratia marcescens causing nosocomial infections. AB - Serratia marcescens is an opportunistic pathogen causing severe urinary tract infections in hospitalized individuals. Infections of S. marcescens are of great concern because of its increasing resistance towards conventional antibiotics. Quorum sensing (QS)-a cell to cell communication-system of S. marcescens acts as a global regulator of almost all the virulence factors and majorly its biofilm formation. Since, the QS system of S. marcescens directly accords to its pathogenesis, targeting QS system will provide an improved strategy to combat drug resistant pathogens. In the present study, QS system of S. marcescens has been used as target and its inhibition has been studied upon exposure to bioactives from coral associated bacteria (CAB). This study also emphasises the potential of CAB in producing bioactive agents with anti-QS and antibiofilm properties. Two CAB isolates CAB 23 and 41 have shown to inhibit biofilm formation and the production of QS dependent virulence factors like prodigiosin, protease, lipase and swarming motility. The study, on the whole explicates the potential of QS system as a target to treat drug resistant bacterial infections. PMID- 22487182 TI - Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists. AB - Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the beta2-adrenergic receptor, including extracellular loops, were developed and used to guide the design. PMID- 22487184 TI - Strategies for immunophenotyping and purifying classical Hodgkin lymphoma cells from lymph nodes by flow cytometry and flow cytometric cell sorting. AB - Flow cytometry is an established technique to immunophenotype hematopoietic neoplasms. While the diagnosis of classical Hodgkin lymphoma (CHL) has commonly been made using paraffin sections, we have recently demonstrated that the neoplastic Hodgkin and Reed-Sternberg (HRS) cells of CHL can be identified by flow cytometry. Using 6- and 9-color flow cytometric assays, CHL can be immunophenotyped with 85-90% sensitivity and nearly 100% specificity. Analysis of this data requires using established gating strategies to help in the identification of putative HRS cell populations. Interestingly, HRS cells bind to reactive T cells (HRS-T cell rosetting) and this phenomenon can be identified and utilized diagnostically by flow cytometry. In addition, the reactive T cells of CHL show characteristic immunophenotypic changes by flow cytometry and these changes can suggest a diagnosis of CHL. Finally, these principles can be employed to rapidly purify HRS cells using flow cytometric cell sorting. This manuscript provides experimental protocols for immunophenotyping CHL by flow cytometry as well as purifying the HRS cells via flow cytometric cell sorting. PMID- 22487183 TI - Single-molecule investigation of G-quadruplex using a nanopore sensor. AB - This review article introduces the nanopore single-molecule method for the study of G-quadruplex nucleic acid structures. Single G-quadruplexes can be trapped into a 2 nm protein pore embedded in the lipid bilayer membrane. The trapped G quadruplex specifically blocks the current through the nanopore, creating a signature event for quantitative analysis of G-quadruplex properties, from cation determined folding and unfolding kinetics to the interactions with the protein ligand. The nanopore single-molecule method is simple, accurate, and requires no labels. It can be used to evaluate G-quadruplex mechanisms and it may have applications in G-quadruplex-based biosensors, nanomachines, and nanostructure assembly. PMID- 22487185 TI - How far has the pendulum swung in the surgical management of sigmoid volvulus? Experience from the KwaZulu-Natal Teaching Hospitals and review of the literature. AB - AIM: Sigmoid volvulus is common in sub-Saharan Africa. The aim of the study was to document the clinicopathological patterns of sigmoid volvulus in KwaZulu Natal. METHOD: Analysis was performed of prospectively collected data of patients presenting with sigmoid volvulus at the KwaZulu-Natal Teaching Hospitals from 2000 to 2009. Data collected included demographics, clinical presentation, operative findings, management and outcome. RESULTS: There were 135 patients (122 male) of mean age 39.3 +/- 17 years. Management was by emergency surgery (103), elective surgery (23), no surgery (9). The level of the twist was at the pelvic brim. Fifty-four patients had gangrenous bowel and 81 had viable bowel. Resection was accompanied by primary anastomosis (80) and Hartmann's procedure (46). Complication and mortality rates were 47% and 17% respectively. Mortality rates for emergency and elective surgery were 19% and 9% (P = 0.330), and those for primary anastomosis and Hartmann's procedure were 14% and 24% respectively (P = 0.305). Mortality rates for gangrenous and viable bowel were 21% and 15% respectively (P = 0.624). Twenty-eight (22%) patients required intensive care in the intensive care unit (ICU) with an ICU stay of 8.8 +/- 8 days. Hospital stay was 10.5 +/- 14.4 days. CONCLUSION: The clinicopathological picture of sigmoid volvulus resembles that in the rest of Africa in that it affects predominantly young African males. The level of the twist is at the pelvic brim. The timing of surgery, the type of anastomosis and the viability of the bowel does not influence outcome. PMID- 22487186 TI - Decomposing the brain: components and modes, networks and nodes. AB - Smith and colleagues recently presented a temporal independent component analysis (tICA) decomposition of resting-state functional MRI data. Compared to the widely used spatial ICA (sICA), tICA better allows for a brain region to engage in multiple, independent interactions with other regions and will potentially offer new insights into brain function. PMID- 22487187 TI - HSP60 is transported through the secretory pathway of 3-MCA-induced fibrosarcoma tumour cells and undergoes N-glycosylation. AB - There is increasing evidence localizes the mitochondrial chaperone heat shock protein (HSP)60, outside the cell, where it mediates interactions between immune cells and other body tissues. However, the mechanisms by which HSP60 is secreted into the extracellular environment are not fully understood. Recent studies have shown that HSP60 is actively released by a nonconventional secretion mechanism, the lipid raft-exosome pathway. In the present study, we show for the first time that HSP60, produced by 3-methylcholantrene-induced fibrosarcoma tumour cells, is secreted through the conventional endoplasmic reticulum-Golgi secretory pathway. Confocal microscopy using anti-TGN38 and anti-HSP60 antibodies together with monensin, a Golgi transport inhibitor, demonstrated the relocation of HSP60 to the Golgi of malignant cells but not primary fibroblast cells subjected to heat shock or fibroblast cell lines. Transmission electron microscopy, flow cytometry and cell fractionation of cell treated with brefeldin A, an inhibitor of endoplasmic reticulum to Golgi protein transport, further indicated that HSP60 is present both in the endoplasmic reticulum and the Golgi complex of malignant cells. We found a single mRNA with a mitochondrial targeting sequence encoding for HSP60 in the malignant cells but two HSP60 translation products, namely the native unmodified protein and a protein post-translationally modified by N glycosylation. The N-glycans observed were composed of high-mannose structures and bi-, tri- and tetra-antennary complex type structures occupying sites of the three potential glycosylation sites present on HSP60. Accordingly, we propose that HSP60 in malignant cells is transported through the endoplasmic reticulum Golgi secretion pathway, where it acquires N-glycans, and thus can affect the immunological properties of the proteins in the tumour microenvironment. PMID- 22487188 TI - The use of megavoltage radiation therapy in the treatment of thymomas in rabbits: 19 cases. AB - An overall median survival time (MST) and prognostic factors in rabbits with thymomas treated with megavoltage radiation therapy (RT) were determined in this multi-institutional retrospective case analysis. Medical records for 19 rabbits with suspected or confirmed thymomas treated with RT were evaluated for data including signalment, haematological and serum biochemistry abnormalities, presence of pleural effusion, radiation plan, body weight, total radiation dose and institution administering RT. Statistical significance of these factors related to overall survival was assessed. An overall MST for all 19 rabbits was 313 days; exclusion of 3 rabbits that died acutely during the first 14 days of RT yielded a MST of 727 days. The only factor associated with a significantly decreased survival time was having a body weight lower than mean body weight of 1.57 kg. Radiation treatment-associated complications were infrequent and included radiation-induced myocardial failure, radiation pneumonitis and alopecia. PMID- 22487190 TI - Analysis of 100 pharmaceuticals and their degradates in water samples by liquid chromatography/quadrupole time-of-flight mass spectrometry. AB - A straightforward methodology for the chromatographic separation and accurate mass identification of 100 pharmaceuticals including some of their degradation products was developed using liquid chromatography/quadrupole time-of-flight mass spectrometry (LC/Q-TOF-MS). A table compiling the protonated or deprotonated exact masses for all compounds, as well as the exact mass of several fragment ions obtained by MS-MS is included. Excellent chromatographic separation was achieved by using 3.5 MUm particle size columns and a slow and generic 30-min gradient. Isobaric and isomeric compounds (same nominal mass and same exact mass, respectively) were distinguished by various methods, including chromatography separation, MS-MS fragmentation, and isotopic signal identification. Method reporting limits of detection ranged from 1 to 1000 ng/L, after solid-phase extraction of 100mL aqueous samples. The methodology was successfully applied to the analysis of surface water impacted by wastewater effluent by identifying many of the pharmaceuticals and metabolites included in the list. Examples are given for some of the most unusual findings in environmental samples. This paper is meant to serve as a guide for those doing analysis of pharmaceuticals in environmental samples, by providing exact mass measurements of several well known, as well as newly identified and environmentally relevant pharmaceuticals in water samples. PMID- 22487191 TI - Efficacy of the regimen using twice-daily beta-interferon followed by the standard of care for chronic hepatitis C genotype 1b with high viral load. AB - AIM: In patients with refractory genotype 1b chronic hepatitis C with high viral loads, we retrospectively compared the efficacy of standard of care treatment (SOC: combined PEG-IFN-alpha-2b/ribavirin for 48 weeks) and a regimen in which 2 weeks of SOC induction was replaced by twice-daily beta-interferon alone (IFN-beta induction therapy). METHODS: Seventeen patients received the IFN-beta induction therapy plus SOC (IFN-beta induction group) and 13 patients received SOC alone (SOC group). RESULTS: In the IFN-beta induction group and SOC group, early virological response (EVR) rates were 88.2% and 53.8%, respectively. The end of treatment rates were 100.0% and 92.3%, and sustained virological response (SVR) rates were 70.6% and 53.8%, respectively. By induction with IFN-beta, even in refractory cases, the high virus negative conversion rate in the early treatment phase and actions of pegylated IFN-alpha-2b and ribavirin in the maintenance treatment phase led to an additive effect. In the analysis of contributing factors, only the achievement of EVR was associated with a significant difference in SVR (P = 0.0011). The univariate logistic regression analysis showed that only IFN-beta treatment was associated with a significant difference in EVR (P = 0.0492, odds ratio = 6.248, 95% confidence interval = 1.026-40.252), whereas no significant factors were found in the multivariate analysis due to small samples. CONCLUSION: IFN-beta induction therapy with higher EVR might be beneficial for protease inhibitor-refractory chronic hepatitis C patients. PMID- 22487189 TI - Primary biliary cirrhosis and the nuclear pore complex. AB - Experimental models of autoimmune diseases have led to the conclusion that an immune response to nuclear antigens is a sentinel marker for loss of tolerance and potential tissue damage. Various proteins are targets of antinuclear antibodies in a variety of autoimmune diseases, ranging from systemic rheumatologic disorders to diseases affecting specific organs such as the liver. Autoantibodies against specific nuclear constituents have also been used as probes to understand the structure and the function of the targeted components and their relevance to disease pathogenesis. Approximately a quarter of patients with primary biliary cirrhosis (PBC) have antibodies targeting proteins of the nuclear pore complex (NPC), a multi-protein structure that mediates molecular transport across the nuclear envelope. Autoantibodies against the integral membrane glycoprotein gp210 and nucleoporin p62 appear to be highly specific for PBC, an autoimmune disease characterized by progressive destruction of intrahepatic biliary epithelial cells. This review discusses the diagnostic and clinical relevance of anti-NPC antibodies in PBC and the possibility that this autoimmune response may arise as a result of molecular mimicry. PMID- 22487192 TI - CK2-defective Arabidopsis plants exhibit enhanced double-strand break repair rates and reduced survival after exposure to ionizing radiation. AB - The multifunctional protein kinase CK2 is involved in several aspects of the DNA damage response (DDR) in mammals. To gain insight into the role of CK2 in plant genome maintenance, we studied the response to genotoxic agents of an Arabidopsis CK2 dominant-negative mutant (CK2mut plants). CK2mut plants were hypersensitive to a wide range of genotoxins that produce a variety of DNA lesions. However, they were able to activate the DDR after exposure to gamma irradiation, as shown by accumulation of phosphorylated histone H2AX and up-regulation of sets of radio modulated genes. Moreover, functional assays showed that mutant plants quickly repair the DNA damage produced by genotoxins, and that they exhibit preferential use of non-conservative mechanisms, which may explain plant lethality. The chromatin of CK2mut plants was more sensitive to digestion with micrococcal nuclease, suggesting compaction changes that agreed with the transcriptional changes detected for a number of genes involved in chromatin structure. Furthermore, CK2mut plants were prone to transcriptional gene silencing release upon genotoxic stress. Our results suggest that CK2 is required in the maintenance and control of genomic stability and chromatin structure in plants, and that this process affects several functions, including the DNA damage response and DNA repair. PMID- 22487193 TI - Hybrid cells derived from breast epithelial cell/breast cancer cell fusion events show a differential RAF-AKT crosstalk. AB - BACKGROUND: The biological phenomenon of cell fusion has been linked to several characteristics of tumour progression, including an enhanced metastatogenic capacity and an enhanced drug resistance of hybrid cells. We demonstrated recently that M13SV1-EGFP-Neo breast epithelial cells exhibiting stem cell characteristics spontaneously fused with MDA-MB-435-Hyg breast cancer cells, thereby giving rise to stable M13MDA435 hybrid cells, which are characterised by a unique gene expression profile and migratory behaviour. Here we investigated the involvement of the PLC-beta/gamma1, PI3K/AKT and RAS-RAF-ERK signal transduction cascades in the EGF and SDF-1alpha induced migration of two M13MDA435 hybrid cell clones in comparison to their parental cells. RESULTS: Analysis of the migratory behaviour by using the three-dimensional collagen matrix migration assay showed that M13SV1-EGFP-Neo cells as well as M13MDA435 hybrid cells, but not the breast cancer cell line, responded to EGF stimulation with an increased locomotory activity. By contrast, SDF-1alpha solely stimulated the migration of M13SV1-EGFP-Neo cells, whereas the migratory activity of the other cell lines was blocked. Analysis of signal transduction cascades revealed a putative differential RAF-AKT crosstalk in M13MDA435-1 and -3 hybrid cell clones. The PI3K inhibitor Ly294002 effectively blocked the EGF induced migration of M13MDA435-3 hybrid cells, whereas the EGF induced locomotion of M13MDA435-1 hybrid cells was markedly increased. Analysis of RAF-1 S259 phosphorylation, being a major mediator of the negative regulation of RAF-1 by AKT, showed decreased pRAF-1 S259 levels in LY294002 treated M13MDA435-1 hybrid cells. By contrast, pRAF-1 S259 levels remained unaltered in the other cell lines. Inhibition of PI3K/AKT signalling by Ly294002 relieves the AKT mediated phosphorylation of RAF-1, thereby restoring MAPK signalling. CONCLUSIONS: Here we show that hybrid cells could evolve exhibiting a differential active RAF-AKT crosstalk. Because PI3K/AKT signalling has been chosen as a target for anti cancer therapies our data might point to a possible severe side effect of AKT targeted cancer therapies. Inhibition of PI3K/AKT signalling in RAF-AKT crosstalk positive cancer (hybrid) cells could result in a progression of these cells. Thus, not only the receptor (activation) status, but also the activation of signal transduction molecules should be analysed thoroughly prior to therapy. PMID- 22487194 TI - Shoulder kinematics during pitching: comparing the slide step and traditional stretch deliveries. AB - Although studies have investigated the traditional stretch delivery, there is little biomechanical data describing the slide step delivery in baseball pitchers. Thus, the purpose of this study was to compare shoulder kinematics across the traditional stretch and slide step deliveries. To collect kinematic data from thirty-seven high school baseball pitchers, electromagnetic sensors recording at 140 Hz were affixed to various body segments. The average of those data from the three fastest pitches passing through the strike-zone were analyzed for each delivery. At the instances of front foot contact and ball release, no differences were observed between the two deliveries. At the instant of maximum shoulder external rotation, differences were observed between the two deliveries with regard to plane of elevation (t(72)=4.19, p<.001), elevation (t(72)=-3.38, p<.001), and axial rotation (t(72)=2.49, p=.015). The mechanical differences observed between the two delivery styles may have the potential to impact both performance and injury. Also, based on these results there may be a tradeoff between injury risk and performance. Thus, further study is warranted in an effort to identify the interrelationships between injury risk, performance, and pitching kinematics when throwing from the stretch position. PMID- 22487195 TI - Effect of donor animals and their diet on in vitro nutrient degradation and microbial protein synthesis using grass and corn silages. AB - Two nonlactating cows and two wether sheep, all fitted with a permanent cannula into the rumen, were fed either hay plus concentrate, grass silage or corn silage to study the effect of the donor animal and its diet on in vitro fermentation and microbial protein synthesis. Rumen inoculum was obtained before the morning feeding. Grass silage or corn silage was incubated in a semi-continuous rumen simulation system for 14 days. Four replicated vessels were used per treatment. Degradation of crude nutrients and detergent fibre fractions as well as microbial protein synthesis and the production of volatile fatty acids were studied. Additionally, total gas and methane production was measured with a standard in vitro gas test. Gas production and methane concentration was higher when the inoculum used was from sheep than that from cows. The donor animal also affected the degradation of organic matter and ether extract as well as the amount of propionate and butyrate, and the acetate-to-propionate ratio. The effect of the diet fed to the donor animal on fermentation was much greater than the effect of the donor animal itself. Feeding hay plus concentrate resulted in higher gas production and degradation of acid detergent fibre, but in lower degradation of ether extract and reduced microbial protein synthesis. Additionally, the pattern of volatile fatty acids changed significantly when the diet of the donor animals was hay plus concentrate or one of the silages. These results show that in vitro fermentation and microbial protein synthesis is different when based on inoculum from either cattle or sheep. The diet fed to the donor animal is more important than the animal species and is probably mediated by an adjusted microbial activity. With regard to standardized feed evaluations, these results further support the need to harmonize in vitro approaches used in different laboratories. PMID- 22487196 TI - Decreased expression of elastin, fibulin-5 and lysyl oxidase-like 1 in the uterosacral ligaments of postmenopausal women with pelvic organ prolapse. AB - AIM: Pelvic organ prolapse is associated with defects in connective tissues, including elastic fibers. The purpose of this study was to investigate the expression of fibulin-5 and lysyl oxidase-like 1 (LOXL1), which play an essential role in the synthesis and assembly of elastic fibers, in the uterosacral ligaments of women with advanced pelvic organ prolapse (POP) compared with controls. METHOD: Specimens were obtained prospectively during transvaginal or abdominal hysterectomy from 30 women with advanced pelvic organ prolapse and 30 controls matched to the POP group for age and parity among postmenopausal women with benign gynecologic diseases. The expressions of elastin, fibulin-5 and LOXL1 in uterosacral ligaments were measured by immunohistochemistry. RESULTS: We detected a decreased, sometimes absent, expression of fibulin-5 and LOXL1 in the uterosacral ligaments of women with POP, despite a positive expression of elastin. There was a decrease in positive percentage of LOXL1 in the POP group (23.3%) compared with the controls (60%) (P = 0.004). With immunolabeling intensity classified as negative, weak, moderate or strong, there was a decrease in the expression of fibulin-5 in the POP group (P = 0.049). We also detected a significantly decreased expression of LOXL1 in the POP group (P = 0.001). CONCLUSIONS: There was decreased expression of fibulin-5 and LOXL1 in the uterosacral ligaments of patients with pelvic organ prolapse, while the elastin expression was equivalent, which may suggest the possibility of defects in elastic fiber remodeling in the postpartum period and contribute to POP. PMID- 22487197 TI - Vitamin D deficiency in Tasmania: a whole of life perspective. AB - AIM: This study aims to describe the lifetime picture of vitamin D deficiency, as measured by serum 25(OH)D concentration, in Tasmania (latitude 43 degrees S). METHODS: Five cross-sectional studies were used: a sample of primary schoolchildren (n = 201, aged 7-8 years), two samples of adolescents (sample 1: n = 374, aged 15-18 years; sample 2: n = 136, aged 16-19 years), a sample of young to middle-aged adults (n = 262, aged 19-59 years) and a sample of older adults (n = 1092, aged 50-80 years). RESULTS: In winter/spring, approximately two-thirds of the adolescents and adults (young, middle-aged and older) had 25(OH)D levels <=50 nmol/L, and around 10% had 25(OH)D levels <=25 nmol/L. The prevalence of vitamin D deficiency was much lower for primary schoolchildren (11.5% < 50 nmol/L, 0.5% <= 25 nmol/L). In summer/autumn, approximately one-third of the adolescents and adults had 25(OH)D levels <=50 nmol/L, and very few had 25(OH)D levels <=25 nmol/L. For the adolescents and adults, even among those who reported the highest category of sun exposure, approximately 45% had 25(OH)D levels <=50 nmol/L in winter/spring. CONCLUSIONS: Vitamin D deficiency was uncommon among our sample of primary school children but increased substantially during the teenage years and seemed to remain high throughout the rest of life, suggesting that mild vitamin D deficiency is endemic in Tasmania apart from in the very young. PMID- 22487198 TI - Invasive lobular carcinoma of the nipple. PMID- 22487199 TI - Wireless peripheral nerve stimulation increases pain threshold in two neuropathic rat models. AB - Neurostimulation approaches including spinal cord and peripheral nerve stimulation are typically used to treat intractable chronic pain in individuals who are refractory to pain medications. Our earlier studies have shown that a voltage controlled capacitive discharge (VCCD) method of stimulation of nerve activation is able to selectively recruit activity in large myelinated nerve fibers. In this study, we were able to wirelessly activate the sciatic nerve using the VCCD waveform. The purpose of this study was to determine whether this waveform can effectively improve two of the most troublesome pain symptoms experienced by patients with chronic neuropathic pain mechanical and cold hyperalgesia. Neuropathic mechanical hyperalgesia was reproduced using the Spinal Nerve Ligation (SNL) rat model whereas cold allodynia was reproduced using the Chronic Constriction Injury (CCI) model in male rats. Von Frey and cold plate tests were used to evaluate paw withdrawal threshold and latency to withdrawal before and after stimulation in experimental and control rats. Paw withdrawal threshold increased significantly compared to post-lesion baseline after VCCD stimulation in SNL rats. We also observed a significant improvement in cold allodynia in the active implant CCI rats after stimulation. These results suggest that the VCCD stimulation using a wireless microstimulator may be effective in the treatment of neuropathic pain. PMID- 22487200 TI - Cutaneous inputs from the back abolish locomotor-like activity and reduce spastic like activity in the adult cat following complete spinal cord injury. AB - Spasticity is a condition that can include increased muscle tone, clonus, spasms, and hyperreflexia. In this study, we report the effect of manually stimulating the dorsal lumbosacral skin on spontaneous locomotor-like activity and on a variety of reflex responses in 5 decerebrate chronic spinal cats treated with clonidine. Cats were spinalized 1 month before the terminal experiment. Stretch reflexes were evoked by stretching the left triceps surae muscles. Crossed reflexes were elicited by electrically stimulating the right tibial or superficial peroneal nerves. Wind-up of reflex responses was evoked by electrically stimulating the left tibial or superficial peroneal nerves. We found that pinching the skin of the back abolished spontaneous locomotor-like activity. We also found that back pinch abolished the rhythmic activity observed during reflex testing without eliminating the reflex responses. Some of the rhythmic episodes of activity observed during reflex testing were consistent with clonus with an oscillation frequency greater than 3 Hz. Pinching the skin of the back effectively abolished rhythmic activity occurring spontaneously or evoked during reflex testing, irrespective of oscillation frequency. The results are consistent with the hypothesis that locomotion and clonus are produced by common central pattern-generators. Stimulating the skin of the back could prove helpful in managing undesired rhythmic activity in spinal cord-injured humans. PMID- 22487201 TI - Survival, migration and differentiation of mouse tau-GFP embryonic stem cells transplanted into the rat auditory nerve. AB - Stem cells have been investigated as treatment for a variety of diagnoses such as Parkinson's disease, Alzheimer's disease and spinal cord injuries. Here, we investigated the possibility of using stem cells as a replacement therapy for lesions of the auditory nerve (AN). We transplanted tau-GFP mouse embryonic stem cells into the AN either by the internal auditory meatus or via the modiolus in rats that had been previously deafened by application of beta-bungarotoxin to the round window niche. We investigated the effect of brain derived neurotrophic factor (BDNF) on cell transplant survival and differentiation. Additionally chondroitinase ABC (ChABC), a digestive enzyme that cleaves the core chondroitin sulfate proteoglycans, was used in order to promote possible migration of cells and axons through the transitional zone. A bioactive isoleucine-lysine-valine alanine-valine (IKVAV) peptide amphiphile (PA) nanofiber gel was applied around the cell injection site. This nanofiber gel has been shown to promote neural differentiation and other similar gels have been used to encapsulate and release proteins. Three weeks after injection, transplanted cells were found in the scala tympani, the modiolus, the AN trunk and the brain stem. As compared to cell transplantation and gel only, BDNF content in the PA gel increased cell survival and neuronal differentiation. In the animals treated with ChABC we observed extensive migration of cells through the transitional zone to or from the CNS. PMID- 22487202 TI - Regarding protamine, ACT and sheath removal. PMID- 22487203 TI - Enterococci of animal origin and their significance for public health. AB - Enterococci are commensal bacteria in the intestines of humans and animals, but also cause infections in humans. Most often, Enterococcus faecium isolates from clinical outbreaks belong to different types than E. faecium from animals, food, and humans in the community. The same variants of the vanA gene cluster (Tn1546) encoding vancomycin resistance can be detected in enterococci of both human and animal origin. This could indicate horizontal transfer of Tn1546 between enterococci of different origin. E. faecium isolates of animal origin might not constitute a human hazard in themselves, but they could act as donors of antimicrobial resistance genes for other pathogenic enterococci. Enterococcus faecalis of animal origin seems to be a human hazard, as the same types can be detected in E. faecalis from animals, meat, faecal samples from humans in the community, and patients with bloodstream infections. PMID- 22487204 TI - Pneumonia and risk of venous thrombosis: results from the MEGA study. PMID- 22487205 TI - Sex differences in social investigation: effects of androgen receptors, hormones and test partner. AB - We examined the role of the androgen receptor (AR) in the investigatory behaviour of conspecifics using mice carrying the testicular feminisation mutation (X(Tfm) Y). Responses to members of the same and opposite sex were evaluated in a habituation/dishabituation task. Adult mice were gonadectomised and treated with oestradiol (E(2) ) or testosterone. After E(2) treatment, regardless of the sex of the stimulus mouse, wild-type (WT) males engaged in significantly more investigation than WT females. X(Tfm) Y males treated with E(2) showed 'male like' behaviour in response to a male but behaved 'female-like' when the stimulus was a female. Because WT and X(Tfm) Y males behaved the same in response to another male, we used two additional mouse models to ask whether sex chromosomes were responsible for this phenomenon. Regardless of sex chromosome complement, gonadal males displayed high levels of investigation. When mice were treated with testosterone, investigation by WT females was enhanced, which eliminated the sex differences. Most strikingly, X(Tfm) Y males receiving testosterone-treatment increased the investigation of females to levels equal to those shown by WT mice. Given that testosterone, but not its metabolite E(2) , caused X(Tfm) Y males to investigate female conspecifics at high levels, it is plausible that nonclassical actions of AR, and/or activation of a novel AR, may be involved in this behaviour. Taken together, our data show that AR activation during adulthood is not required for males to investigate mice of either sex. However, 'male-like' levels of investigation of a female stimulus may depend on neonatal activation of the classic nuclear AR. PMID- 22487206 TI - Survival and clinicopathological characteristics of breast cancer patient according to different tumour subtypes as determined by hormone receptor and Her2 immunohistochemistry. a single institution survey spanning 1998 to 2010. AB - As far as recent breast cancer molecular subtype classification is concerned, much work has dealt with clinical outcomes for triple negative and Her2 patients. Less is known about the course of patients in the remaining subtypes. Molecular classification based on immunohistochemistry is widely available and correlates well with genetic microarray assessment, but at a lower cost. The aim of our investigation was to correlate immunohistochemical subtypes of breast cancer with clinical characteristics and patient outcomes. Since 1998, 1167 patients operated for 1191 invasive breast tumours were included in our database. Patients were regularly followed up until March 2010. Disease-free survival, overall mortality, and breast cancer-specific mortality at 5 years were calculated for the cohort. 72% of tumours were ER+PR+/-HER2- group, 13% triple negative (ER-PR-HER2-), 10% ER+PR+/-HER2+ group, and 5% Her2 (ER-PR-HER2+). Cancer-specific survival was 94.2% for the ER+PR+HER2- subtype, 84.8% for the Her2 subtype, 83.3% for the ER+PR-HER2- subtype, and 78.6% for triple negatives. Distant metastases prevalence ranged from 7% to 22% across subtypes, increasing stepwise from ER+PR+HER2-, ER+PR+HER2+, ER+PR-HER2-, ER+PR-HER2+, ER-PR-HER2+ through triple negative. Small, low-grade tumours with low axillary burden were more likely to belong to the ER+PR+/-HER2- group. Conversely, larger high-grade tumours with significant axillary burden were more likely to belong to Her2 or triple negative groups. ER+PR+/-HER2- group patients with negative PR receptors performed more like Her2 or triple negative than like the rest of ER+PR+/-HER2+/- groups patients. Molecular classification of breast tumours based only on immunohistochemistry is quite useful on practical clinical grounds, as expected. ER+PR+/-HER2- group patients with negative PR receptors seem to be at high risk and deserve further consideration. PMID- 22487207 TI - Patterns of male fitness conform to predictions of evolutionary models of late life. AB - We studied lifetime male virility, a male fitness component, in five populations of Drosophila melanogaster. Virility was measured as the number of females, of eight total, that a male could fertilize in 24 h. Individual males were measured at weekly intervals until they died. Virility declined in an approximately linear fashion for the first 3 weeks of adult life. It then stayed low but relatively constant for another 3 weeks, exhibiting a clear plateau. These observations are consistent with the evolutionary theories of late life. The results were not consistent with a simple heterogeneity theory of late life. This is the first demonstration of a late-life plateau for a male fitness component. We also found that the virility of males that were within 7 days of death was significantly lower than that of similarly aged males that were not about to die. This rapid deterioration of virility prior to death, or death spiral, is similar to a decline in fecundity that we had previously documented. PMID- 22487208 TI - Natural compounds inhibiting the replication of Porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is an economically important pathogenic virus in the swine production. Current vaccines against PRRSV do not induce sterile immunity and the virus evolves at a rapid rate with frequent appearances of new strains. In this study, we screened a library of 502 highly purified natural product compounds to identify specific inhibitors of PRRSV replication cycle. Our observations showed that many of the inhibitory compounds identified have activity on the cellular ion transport mechanisms. We identified for the first time, four compounds which inhibit the PRRSV replication cycle at micro molar concentration or less, namely, 12-deoxyphorbol 13 phenylacetate 20-acetate, ouabain, bufalin and valinomycin. Further, we have identified 15 other compounds which can inhibit the PRRSV replication at the concentration of 8MUM. This study provides a basis for further development of pharmacological agents to inhibit PRRSV replication. PMID- 22487209 TI - Rapid death after admission to palliative care. AB - BACKGROUND: Palliative care units provide non-curative treatment and support to patients with terminal illness. Brief end-of-life admissions are disruptive for patients and their families, and increase staff stress. Extremely rapid deaths (survival <24 h from admission) are particularly challenging for all involved. From 1 January 2010 to 23 August 2011, 256 patients died on the Palliative Care Unit (Caritas Christi) at St Vincent's Hospital Melbourne. Forty-two died within 24 h (16%), while 214 survived beyond 24 h (84%). AIMS: A retrospective chart audit was conducted, aiming to identify factors characterising those patients who died within 24 h. METHODS: Groups were compared for age, gender, country of birth, preferred language, ward of origin, primary pathology, time trends, whether an emergency code was called, Palliative Care Outcomes Collaboration (PCOC) phase, modified Karnofsky score and commencement of a syringe driver for medication. RESULTS: Results showed that admission from neurosurgery (P= 0.0001), a vascular or infective pathology (P= 0.0001), PCOC phase >= 3 (P= 0.0001), modified Karnofsky score <= 20% (P= 0.0001), and commencement of a syringe driver prior to or at admission (P= 0.0001) were all significantly associated with death within 24 h of admission. On binary logistic regression, the only independent predictor of patients likely to die in <24 h from admission was PCOC phase >= 3 (P= 0.002). PMID- 22487210 TI - Response-guided peginterferon-alpha-2b plus ribavirin therapy for chronic hepatitis C patients with genotype 2 and high viral loads. AB - AIMS: Optimization of the duration of peginterferon-alpha/ribavirin therapy in patients with hepatitis C virus (HCV) genotype 2 and high viral loads remains to be established. We sought to prospectively optimize the treatment duration based on their virological responses. METHODS: Serum HCV RNA levels of less than 50 IU/mL at weeks 2 and 4, and of 50 IU/mL or more at week 4, were defined as a super-rapid virological response (SRVR), rapid virological response (RVR) and late virological response (LVR), respectively. Treatment for 12, 24 or 48 weeks was assigned to the patients with an SRVR, RVR or LVR, respectively. However, patients with an LVR who expressed a desire to receive the standard therapy duration were given the 24-week therapy. RESULTS: The overall sustained virological response (SVR) rate was 78.1% (118/151). The SVR rate in the SRVR group was 93.8% (15/16), which was comparable to the 93.0% (66/71) SVR rate in the RVR group. In the LVR patients, the 48-week treatment slightly increased the SVR rate to 76.5% (13/17) compared with the 51.1% (24/47) SVR rate in LVR patients who underwent the standard 24-week treatment. The relapse rate in LVR patients was significantly decreased in patients treated for 48 weeks compared with patients treated for 24 weeks. Multivariate analysis identified the predictive factors for SVR as RVR, prior interferon therapy and total peginterferon-alpha-2b adherence in patients treated for 24 weeks. CONCLUSION: Response-guided therapy may be effective and useful for optimization of the treatment duration. PMID- 22487211 TI - Immunoprotective effect of cysteine proteinase fractions from two Haemonchus contortus strains adapted to sheep and goats. AB - A preliminary analysis of the significance of genetic diversity in cysteine proteinase genes has been performed simultaneously in sheep and goats, with regard to the immunological control using these enzymes against haemonchosis. For this purpose, we have studied the cross-immunoprotective effect of cysteine protease-enriched protein fractions (CPFs) in adult worms of two Haemonchus contortus strains from North America and Spain that are adapted to sheep and goats, respectively. Previous genetic analysis of cysteine proteinase genes in both strains has shown that some of loci are polymorphic and these differences are translated into changes in the amino acid sequences. However, our results show that CPFs from H. contortus adult worms have a protective effect against the parasite in both sheep and goats. These results are similar regardless of whether they were obtained from sheep or goat-adapted H. contortus strains, which could be very important in case H. contortus CPFs were commercially used in different countries, as vaccines to prevent the negative effects of this parasite. Interestingly, this experimental inoculation of both species with a heterologous strain of H. contortus contributes to the idea shown in previous studies about how difficult is the interpretation and the comparison of vaccination where strains not adapted to a specific host are used. Therefore, the challenger of using heterologous strains could provide similar results to those observed in immunised animals. This study suggests the possibility of exploring the mechanisms involved in natural protection against non-adapted strains, in order to develop strategies to control haemonchosis. PMID- 22487212 TI - Reducing the use of seclusion for mental disorder in a prison: implementing a high support unit in a prison using participant action research. AB - BACKGROUND: Vulnerable prisoners and mentally disordered offenders who present with risk of harm to self or others were accommodated in Special Observation Cells (SOCs) isolated from others for considerable periods of time. This practice has been criticised by the Council of Europe Committee for the Prevention of Torture. The objective of this initiative was to reduce the use of seclusion within the prison and to improve the care of vulnerable and mentally ill prisoners within the prison. RESULTS: The prison studied is a committal centre for sentenced prisoners with an official bed capacity of 630. The forensic mental health in-reach team, in co-operation with the prison health service followed the 'spiral' of planning, action and fact finding about the results of the action. In December 2010 a 10 bed High Support Unit (HSU) was established within the prison. During the first year, 96 prisoners were admitted. A third (35%) reported psychotic symptoms, 28% were referred due to the immediate risk of self-harm, 17% were accommodated for medical treatments and increased observation, 13% received specialised treatment by the Addiction Psychiatry team, 6% presented with emotional distress. One prisoner was accommodated on the HSU due to the acute risk he posed to others. A major mental illness was diagnosed in 29%, 20% required short-term increased support for crisis intervention and were found not to have a mental illness. A further 10% were deemed to be feigning symptoms of mental illness to seek refuge in the HSU. 7% had personality disorder as their primary diagnosis and 4% had a learning disability. Stratifying risk within the prison population through the provision of the HSU decreased the total episodes of seclusion in the prison by 59% (p < 0.001) in addition to providing a more effective psychiatric in-reach service to the prison. Pathways between the prison and the forensic psychiatric hospital saw no change in activity but improved continuity of care. CONCLUSIONS: The next step is to further stratify risk by establishing a low support unit to serve as a step-down from the high support unit. PMID- 22487213 TI - Identification and characterization of a new xylanase from Gram-positive bacteria isolated from termite gut (Reticulitermes santonensis). AB - Termites are world champions at digesting lignocellulosic compounds, thanks to cooperation between their own enzymes and exogenous enzymes from microorganisms. Prokaryotic cells are responsible for a large part of this lignocellulolytic activity. Bacterial enzyme activities have been demonstrated in the higher and the lower termite gut. From five clones of Gram-positive bacteria isolated and identified in a previous work, we constructed a genomic DNA library and performed functional screening for alpha-amylase, beta-glucosidase, and xylanase activities. One candidate, Xyl8B8, showed xylanase activity. Sequence analysis of the genomic insert revealed five complete ORFs on the cloned DNA (5746bp). Among the encoded proteins were a putative endo-1,4-beta-xylanase (XylB8) belonging to glycoside hydrolase family 11 (GH11). On the basis of sequence analyses, genomic DNA organization, and phylogenetic analysis, the insert was shown to come from an actinobacterium. The mature xylanase (mXylB8) was expressed in Escherichia coli and purified by affinity chromatography and detected by zymogram analysis after renaturing. It showed maximal xylanase activity in sodium acetate buffer, pH 5.0 at 55 degrees C. Its activity was increased by reducing agents and decreased by Cu(2+), some detergents, and chelating agents. Its substrate specificity appeared limited to xylan. PMID- 22487215 TI - Nitric oxide and guanylate cyclase signalling are differentially involved in gonadotrophin (LH) release responses to two endogenous GnRHs from goldfish pituitary cells. AB - Nitric oxide synthase (NOS) immunoreactivity is present in goldfish gonadotrophs. The present study investigated whether two native goldfish gonadotrophin releasing hormones (GnRHs), salmon (s)GnRH and chicken (c)GnRH-II, use NOS/nitric oxide (NO) and soluble guanylate cyclase (sGC)/cyclic (c)GMP/protein kinase G (PKG) signalling to stimulate maturational gonadotrophin [teleost gonadotrophin II, luteinising hormone (LH)] release. In cell column perifusion experiments with dispersed goldfish pituitary cells, the application of three NOS inhibitors (aminoguanidine hemisulphate, 1400W and 7-nitroindazole) and two NO scavengers [2 phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) and rutin hydrate] reduced sGnRH-elicited, but not cGnRH-II-induced, LH increases. The NO donor sodium nitroprusside (SNP) increased NO production in goldfish pituitary cells in static incubation. SNP-stimulated LH release in column perifusion was attenuated by PTIO and the sGC inhibitor 1H-(1,2,4)oxadiazolo[4,3-a]quinoxalin-1-oneon (ODQ), and additive to responses elicited by cGnRH-II, but not sGnRH. ODQ and the PKG inhibitor KT5823 decreased sGnRH- and cGnRH-II-stimulated LH release. Similarly, the LH response to dibutyryl cGMP was reduced by KT5823. These results indicate that, although only sGnRH uses the NOS/NO pathway to stimulate LH release, both GnRHs utilise sGC/PKG to increase LH secretion. PMID- 22487214 TI - Expressed protein ligation-mediated template protein extension. AB - Expressed protein ligation (EPL) was performed to investigate sequence requirements for a variant human apolipoprotein A-I (apoA-I) to adopt a folded structure. A C-terminal truncated apoA-I, corresponding to residues 1-172, was expressed and isolated from Escherichia coli. Compared to full length apoA-I (243 amino acids), apoA-I(1-172) displayed less alpha-helix secondary structure and lower stability in solution. To determine if extension of this polypeptide would confer secondary structure content and/or stability, 20 residues were added to the C-terminus of apoA-I(1-172) by EPL, creating apoA-I(Milano)(1-192). The EPL product displayed biophysical properties similar to full-length apoA-I(Milano). The results provide a general protein engineering strategy to modify the length of a recombinant template polypeptide using synthetic peptides as well as a convenient, cost effective way to investigate the structure/function relations in apolipoprotein fragments or domains of different size. PMID- 22487216 TI - Phosphotyrosine enrichment identifies focal adhesion kinase and other tyrosine kinases for targeting in canine hemangiosarcoma. AB - Canine hemangiosarcoma (HSA) is an endothelial cell malignancy driven, in part, by activating mutations in receptor and non-receptor tyrosine kinases. Proteomics, Western blots and a tyrosine kinase inhibitor were used to elucidate activating mechanisms in HSA cell lines. Phosphotyrosine peptides from focal adhesion kinase (FAK) STAT3, Lyn, Fyn and other signal transduction kinases were identified by mass spectrometry. FAK was constitutively activated at tyrosine 397, the autophosphorylation site, and this was reversible with high concentrations of a FAK inhibitor. FAK inhibitor-14 suppressed migration and phosphorylation of FAK tyrosine 397 and tyrosines 576/577 and was cytotoxic to HSA cells suggesting FAK signalling may be an important contributor to canine HSA survival. PMID- 22487217 TI - Pleiotropic functions of pre-B-cell colony-enhancing factor (PBEF) revealed by transcriptomics of human pulmonary microvascular endothelial cells treated with PBEFsiRNA. AB - This study profiled transcriptomes of human pulmonary microvascular endothelial cells (HMVEC-L) treated with pre-B-cell colony-enhancing factor (PBEF) siRNA or scrambled RNA to gain insight into transcriptional regulations of PBEF on the endothelial function using the Affymetrix GeneChips HG-U133 plus 2. Several important themes are emerged from this study. First, PBEF affected expressions of multiple genes in the endothelium. Expression of 373 genes was increased and 64 genes decreased by at least 1.3-fold in the PBEFsiRNA-treated HMVEC-L versus the scramble RNA control. Second, the microarray results confirmed previous reports of PBEF-mediated gene expressions in some pathways but provided a more complete repertoire of molecules in those pathways. Third, most of the affected canonical pathways have not previously been reported to be PBEF responsive. Fourth, network analysis supports that PBEF has pleiotropic functions. Our first transcriptome analysis of human pulmonary microvascular endothelial cells treated with PBEFsiRNA has provided important insights into the transcriptional regulation of gene expression in HMVEC-L cells by PBEF. Further in-depth analysis of these transcriptional regulations may shed light on molecular mechanisms underlying PBEF-mediated endothelial functions and dysfunctions in various diseases and provide new leads of therapeutic targets to those diseases. PMID- 22487219 TI - Concentrations of haptoglobin in bovine plasma determined by ELISA or a colorimetric method based on peroxidase activity. AB - The objective was to compare different procedures for determination of haptoglobin in bovine plasma. Nine Angus steers were vaccinated against Mannheimia haemolytica to stimulate an acute-phase response. Blood samples were collected immediately prior to vaccination (day 0), and on days 1, 3, 5, 7 and 10. Plasma samples were frozen in duplicates at -80 degrees C. One set of the duplicates was analysed for haptoglobin concentrations using a commercial ELISA kit. A day effect was detected (p < 0.01) because haptoglobin peaked on day 3 and returned to baseline on day 7 relative to vaccination. The second duplicate was analysed using a procedure that measures haptoglobin-haemoglobin complexing by estimating differences in peroxidase activity (CPPA) with results expressed as optical density. Further, based on the ELISA results, the plasma sample with the greatest haptoglobin concentration was also serially diluted into a plasma sample with negligible haptoglobin concentration from the same steer (1:1 through 1:1024 dilution). These dilutions were used within the CPPA method to generate a standard curve and estimate plasma haptoglobin concentrations (CPPA + STD). A linear standard curve was generated (r(2) = 0.99). A day effect similar to the ELISA method was detected for the CPPA and CPPA + STD methods (p < 0.01). Results obtained from CPPA and ELISA methods were positively correlated (r = 0.97; p < 0.01). The values generated by the CPPA + STD procedure were similar (p = 0.38) compared to the values generated by the ELISA method. In conclusion, assessing concentrations of haptoglobin in bovine plasma using the CPPA and CPPA + STD methods generate highly correlated or similar results, respectively, compared to ELISA. Therefore, the CPPA + STD and CPPA methods can be used as a less expensive alternative to ELISA to determine concentrations or monitor changes in plasma haptoglobin in bovine samples. PMID- 22487218 TI - Altered arterial stiffness in male-to-female transsexuals undergoing hormonal treatment. AB - AIM: Male-to-female (MTF) transsexuals are treated with estrogen with and without progestin through a variety of routes. The aim of this study is to evaluate the arterial stiffness in MTF transsexuals undergoing hormonal treatment. METHODS: We evaluated the arterial stiffness in 156 MTF transsexuals (22 untreated and 129 treated with estrogen only or plus progestin) using a volume-plethysmographic apparatus equipped with a multi-element applanation tonometry sensor. RESULTS: MTF transsexuals treated with parenteral estrogen were significantly older than untreated MTF transsexuals. Hematocrit, uric acid and activated partial thromboplastin time in treated MTF transsexuals were significantly lower than in untreated MTF transsexuals. The level of high-density lipoprotein cholesterol in MTF transsexuals treated with oral estrogen was significantly higher than in untreated MTF transsexuals or those treated with parenteral estrogen with and without progestin. The systolic blood pressure in MTF transsexuals treated with estrogen only is significantly lower than that in untreated MTF transsexuals. The brachial-ankle pulse wave velocity was significantly decreased in MTF transsexuals treated with estrogen compared to that in untreated MTF transsexuals or in those treated with estrogen plus progestin. The carotid augmentation index in MTF transsexuals treated with oral estrogen was significantly lower than that in MTF transsexuals treated with parenteral estrogen or oral estrogen plus progestin. CONCLUSIONS: Estrogen treatment is likely to have some beneficial effects on lipid metabolism and vascular function in MTF transsexuals; however, progestin administered with estrogen may have adverse effects on arterial stiffness. PMID- 22487220 TI - Role of vesicle-inducing protein in plastids 1 in cpTat transport at the thylakoid. AB - VIPP1 has been shown to be required for the proper formation of thylakoid membranes. However, studies on VIPP1 itself, as well as on PspA, its bacterial homolog, suggests that this protein may be involved in a number of additional functions, including protein translocation. The role of VIPP1 in protein translocation in the chloroplast has not been investigated. To this end, we conducted in vitro thylakoid protein transport assays to look at the effect of VIPP1 on the cpTat pathway, which is one of three translocation pathways found in both the chloroplast and its bacterial progenitor. We found that VIPP1 does indeed enhance protein transport through the cpTat pathway by up to 100%. The VIPP1 effect on cpTat activity occurs without interacting with the substrates or components of the translocon, and does not alter the energy potentials driving this translocation pathway. Instead, VIPP1 greatly enhances the amount of substrate bound productively to the thylakoids. Moreover, the presence of increasing VIPP1 concentrations in the reactions resulted in greater interactions between thylakoid membranes. Taken together, these results demonstrate a stimulatory role for VIPP1 in cpTat transport by enhancement of substrate binding, probably to the membrane lipid regions of the thylakoid. We propose a model in which VIPP1 facilitates reorganization of the thylakoid structure to increase substrate access to productive binding regions of the membrane as an early step in the cpTat pathway. PMID- 22487221 TI - Atovaquone versus trimethoprim-sulfamethoxazole as Pneumocystis jirovecii pneumonia prophylaxis following renal transplantation. AB - Pneumocystis pneumonia (PCP) is associated with significant morbidity and mortality in renal transplant recipients (RTR). Trimethoprim-sulfamethoxazole (TMP-SMZ) is considered the prophylactic agent-of-choice. Some patients require an alternative owing to TMP-SMZ intolerance. This is the first evaluation of full dose atovaquone vs. TMP-SMZ for PCP prevention in RTR. One hundred and eighty five RTR were evaluated in this single-center, retrospective analysis. Patients received either single-strength TMP-SMZ daily (group I; n = 160) or 1500 mg/d of atovaquone and of a fluoroquinolone for one month (group II; n = 25). The primary endpoint was the incidence of PCP at 12 months post-transplant. There were no cases of PCP in either group. There were comparable rates of infections from bacterial pathogens and cytomegalovirus, but rates of BK viremia were significantly higher in group I (22.5%) vs. group II (4%; p = 0.03). The incidence of leukopenia was similar in both groups. Higher mean potassium levels were seen in group I at three months post-transplant but were comparable at all other time points. The need for dose reduction and/or premature discontinuation of therapy secondary to adverse events was more prevalent in TMP-SMZ-treated patients. In our experience, atovaquone appears to be effective in preventing PCP post-renal transplant and also demonstrates good tolerability. PMID- 22487222 TI - Risk of residual breast tissue after skin-sparing mastectomy. AB - Skin-sparing mastectomy (SSM) is an accepted surgical option for breast cancer treatment. SSM allows for preservation of the skin envelope and improved cosmesis. Despite initial concerns, large series have not revealed higher recurrence rates. There is, however, a paucity of data regarding the rates of residual breast tissue (RBT) left behind after SSM, what factors influence this, and the oncologic implications of RBT. Retrospective review identified 288 total mastectomies. Patients who had undergone SSM with excision of additional skin for reconstructive purposes, either at the initial oncologic surgery or at subsequent revision, were included in the final study group. Pathologic analysis was performed to evaluate excised skin. Data regarding demographics, tumor type, and treatment were collected. Comparison between patients who had pathologically confirmed RBT in the excised skin and those who did not was performed. Of 288 total mastectomies, 92 were SSM's, and 66 had skin specimens removed for nononcologic reasons, of these, 4 (6%) had RBT. Age at diagnosis (p = 0.806), BMI (p = 0.531), tumor size (p = 0.922), and estrogen receptor status (p > 0.999) did not contribute to increased RBT risk. At median follow-up of 33.5 months, there have been no recurrences. In addition, cost analysis reveals it is likely not cost-effective to perform pathologic evaluation of these specimens. SSM, performed at an academic medical center by fellowship-trained surgeons, has a very low rate of RBT, and does not compromise oncologic outcomes. Routine pathologic assessment of these skin specimens, removed for nononcologic reasons, may not be required. PMID- 22487224 TI - The role of technology in enhancing evidence-based practice, education, heathcare quality, and patient outcomes: a call for randomized controlled trials and comparative effectiveness research. PMID- 22487223 TI - The impact of bacterial and viral co-infection in severe influenza. AB - BACKGROUND: Many questions remain concerning the burden, risk factors and impact of bacterial and viral co-infection in patients with pandemic influenza admitted to the intensive care unit (ICU). OBJECTIVES: To examine the burden, risk factors and impact of bacterial and viral co-infection in Australian patients with severe influenza. PATIENTS/METHODS: A cohort study conducted in 14 ICUs was performed. Patients with proven influenza A during the 2009 influenza season were eligible for inclusion. Demographics, risk factors, clinical data, microbiological data, complications and outcomes were collected. Polymerase chain reaction for additional bacterial and viral respiratory pathogens was performed on stored respiratory samples. RESULTS: Co-infection was identified in 23.3-26.9% of patients with severe influenza A infection: viral co-infection, 3.2-3.4% and bacterial co-infection, 20.5-24.7%. Staphylococcus aureus was the most frequent bacterial co-infection followed by Streptococcus pneumoniae and Haemophilus influenzae. Patients with co-infection were younger [mean difference in age = 8.46 years (95% CI: 0.18-16.74 years)], less likely to have significant co morbidities (32.0% versus 66.2%, P = 0.004) and less frequently obese [mean difference in body mass index = 6.86 (95% CI: 1.77-11.96)] compared to those without co-infection. CONCLUSIONS: Bacterial or viral co-infection complicated one in four patients admitted to ICU with severe influenza A infection. Despite the co-infected patients being younger and with fewer co-morbidities, no significant difference in outcomes was observed. It is likely that co-infection contributed to a need for ICU admission in those without other risk factors for severe influenza disease. Empiric antibiotics with staphylococcal activity should be strongly considered in all patients with severe influenza A infection. PMID- 22487225 TI - Unusual substrate underlying Brugada syndrome and early repolarization syndrome revealed in unusual circadian and seasonal patterns. PMID- 22487226 TI - Combined adsorption and oxidation mechanisms of hydrogen sulfide on granulated coal ash. AB - Hydrogen sulfide is highly toxic to benthic organisms and may cause blue tide with depletion of dissolved oxygen in water column due to its oxidation. The purpose of this study is to reveal the combined adsorption and oxidation mechanisms of hydrogen sulfide on granulated coal ash that is a byproduct from coal electric power stations to apply the material as an adsorbent for hydrogen sulfide in natural fields. Sulfur species were identified in both liquid and solid phases to discuss removal mechanisms of the hydrogen sulfide with the granulated coal ash. Batch experiments revealed that hydrogen sulfide decreased significantly by addition of the granulated coal ash and simultaneously the sulfate ion concentration increased. X-ray absorption fine structure analyses showed hydrogen sulfide was adsorbed onto the granulated coal ash and successively oxidized by manganese oxide (III) contained in the material. The oxidation reaction of hydrogen sulfide was coupling with reduction of manganese oxide. On the other hand, iron containing in the granulated coal ash was not involved in hydrogen sulfide oxidation, because the major species of iron in the granulated coal ash was ferrous iron that is not easily reduced by hydrogen sulfide. PMID- 22487227 TI - Immobilization of fluorescein isothiocyanate on magnetic polymeric nanoparticle using chitosan as spacer. AB - The nanoparticle with simultaneous combination of magnetic and fluorescent properties was prepared by immobilization of fluorescein isothiocyanate (FITC) onto magnetic polymeric nanoparticle (MPNP). The MPNP with 41% magnetic content was obtained from incorporating Fe(3)O(4) magnetic nanoparticles (MNPs) into poly(styrene/divinyl benzene/acrylic acid) via the miniemulsion polymerization. Before labeling with FITC, the carboxylated MPNP was coated with chitosan (CS) having low, medium, or high molecular weight (MW) in order to avoid quenching of the fluorescent by iron oxide. Data obtained from TEM, size and zeta potential measurements clearly indicated the presence of CS as a shell surrounding the superparamagnetic MPNP core. The zeta potential, FTIR, and fluorescent spectroscopies confirmed the attachment of FITC to the MPNP-CS via covalent bonding. The higher MW or longer chains of CS (300kDa) offered the larger spacer with multiple sites for the FITC binding and, thus, provided the higher fluorescent emission intensity. The MPNP-CS immobilized with FITC would be useful for cell-labeling application. PMID- 22487228 TI - Competitive adsorption of surfactants and hydrophilic silica particles at the oil water interface: interfacial tension and contact angle studies. AB - The effect of surfactants' type and concentration on the interfacial tension and contact angle in the presence of hydrophilic silica particles was investigated. Silica particles have been shown to have an antagonistic effect on interfacial tension and contact angle in the presence of both W/O and O/W surfactants. Silica particles, combined with W/O surfactant, have no effect on interfacial tension, which is only dictated by the surfactant concentration, while they strongly affect interfacial tension when combined with O/W surfactants. At low O/W surfactant, both particles and surfactant are adsorbed at the interface, modifying the interface structure. At higher concentration, interfacial tension is only dictated by the surfactant. By increasing the surfactant concentration, the contact angle that a drop of aqueous phase assumes on a glass substrate placed in oil media decreases or increases depending on whether the surfactant is of W/O or O/W type, respectively. This is due to the modification of the wettability of the glass by the oil or water induced by the surfactants. Regardless of the surfactant's type, the contact angle profile was dictated by both particles and surfactant at low surfactant concentration, whereas it is dictated by the surfactant only at high concentration. PMID- 22487229 TI - Fabrication of Co(OH)2 coated Pt nanoparticles as an efficient catalyst for chemoselective hydrogenation of halonitrobenzenes. AB - Co(OH)(2) coated platinum nanoparticles Pt/Co(OH)(2) were prepared by microwave assistance and hydrothermal method, and the prepared samples were composed of Pt nanoparticles with an average size of 1.8 nm coated uniformly in the thin Co(OH)(2) leaves based on the results of X-ray diffraction, transmission electron microscopy, scanning electron microscopy and X-ray photoelectron spectroscopy. The Pt/Co(OH)(2) presented excellent catalytic performance in the chemoselective hydrogenation of halonitrobenzenes such as chloronitrobenzenes, bromonitrobenzene and iodonitrobenzene, and above 99.6% selectivity to haloanilines was achieved at complete conversion irrespective of the substrates used, even for iodonitrobenzene to which the dehalogenation is more easily to occur. Co(OH)(2) was confirmed to prohibit the dehalogenation effectively, and the Pt/Co(OH)(2) catalyst could be recycled for several times. PMID- 22487230 TI - Crystallization of CaCO3 in the presence of sulfate and additives: experimental and molecular dynamics simulation studies. AB - The effects of sulfate and BHTPMP (Bis (hexamethylene) triaminepentakis (methylene phosphonic acid)) on the crystallization rate, phase composition and morphology of calcium carbonate have been studied. It was observed that sulfate reduces the nucleation rate and favors the formation of aragonite form in the calcium carbonate precipitate. Moreover, in the presence of sulfate the rhombohedral morphology of the calcite crystals is modified, and during the formation of calcite, the development of {104} faces are more significantly prohibited than {110} faces. In the presence of sulfate together with BHTPMP, the crystallization process is inhibited and the modified morphology and the dominant calcite form are observed in the solid. The results from molecular dynamics simulations show the more strong combination of sulfate with calcite surface, in particular the {104} face, in comparison with the aragonite surface. The strong interaction of BHTPMP with sulfate and the aragonite surface favors the formation of the dominant calcite phase in the precipitate. PMID- 22487231 TI - Efficient synthesis and sulfonation of ordered mesoporous carbon materials. AB - Ordered mesoporous carbons (OMCs) with hexagonal structure were efficiently synthesized via cooperative self-assembly of phenol/formaldehyde resol and surfactant F127 under acidic aqueous conditions. Induced by HCl, a gel phase mainly containing phenol/formaldehyde resol and F127 was obtained within several hours. X-ray diffraction (XRD), transmission electron microscope (TEM) and nitrogen adsorption isotherms indicated that the synthesized samples possess 2-D hexagonal mesostructure. The influence of the synthesis conditions, including acid concentration and mass ratio of resol to F127, was investigated. When the acid concentration was fixed in the range of 0.6-2.0 M and the mass ratio of resol to F127 in the range of 3.5-4.0, highly ordered mesoporous carbon could be synthesized. The synthesized OMCs could be easily sulfonated in concentrated sulfuric acid at elevated temperature. The results indicate that the mesostructural stability and the content of the surface sulfonic acid (SO(3)H) groups depend mainly on the pyrolysis temperature of the OMCs and the sulfonation temperature, suggesting that the combination of pyrolysis and sulfonation temperature is essential for developing OMCs with high densities of SO(3)H groups. PMID- 22487232 TI - Spontaneous liquid-gas imbibition for characterization of carbon molecular sieves. AB - Spontaneous liquid-gas imbibition at 293.2K and 0.1 MPa was conducted to assess the micropore size and size-exclusion property of carbon molecular sieves (CMS). The CMS were firstly saturated with N(2) and then immersed into water. The volume of gas recovered by the water imbibition was measured and applied to evaluate the density of the N(2) adsorbed in the CMS. The micropore size of the CMS was determined by comparing the N(2) density from the water-N(2) imbibition with that calculated by grand canonical simulation. The micropore size evaluated by the liquid-gas imbibition coincides with that obtained by N(2) adsorption at ambient temperature. The size-exclusion property of the CMS was estimated through comparing the N(2) recovery by imbibition of liquids with increasing molecular dimensions, that is, water, benzene, and cyclohexane. The amount of N(2) recovered from benzene imbibition is dramatically less than that from the water imbibition, showing that the dominated micropore size of the CMS is smaller than 0.37 nm. Furthermore, the effect of chemical vapor deposition treatment on the porous texture of the CMS was revealed by the liquid-gas imbibition. PMID- 22487233 TI - Visible light induced CO2 reduction and Rh B decolorization over electrostatic assembled AgBr/palygorskite. AB - AgBr/palygorskite composite was prepared by an in situ electrostatic adsorption deposition-precipitation method and characterized by field emission scanning electron microscope (FE-SEM), X-ray diffraction (XRD), UV-Vis diffuse reflection, and BET surface measurements techniques. The layer negative charge and larger specific surface area of palygorskite, along with the poor cation-exchange ability of tetra-n-butyl ammonium cation (N(CH(2)CH(2)CH(2)CH(3))(4)(+)) due to its larger ion radius, could mainly account for high dispersity of AgBr on the surface of fibrous palygorskite. The rate of Rh B decolorization and CO(2) reduction with H(2) as a proton donor and reductant over AgBr/palygorskite was about three and two times faster than that of the corresponding bare AgBr, respectively. The strategy reported in this work can be easily extended to synthesize other palygorskite-based heterostructure catalysts. PMID- 22487234 TI - Capillary rise in Hele-Shaw models of disordered media. AB - We study the capillary rise of a viscous liquid in large Hele-Shaw models of disordered media, both analytically and experimentally. Compared to the Fries Dreyer and Lucas-Washburn solutions for capillary rise with and without gravity, our experimental data reveal a systematic deviation at short and intermediate times. The original pressure balance equation leading to Washburn's results is reformulated in order to include an additional resisting term, proportional to the mean velocity of the front h, which appears naturally as a result of the geometry of the cell. Analytical solutions h(t) are found for displacements with and without gravity. These new solutions reproduce the experimental results very accurately in Hele-Shaw cells of constant gap thickness, where the capillary pressure can be approximated by a constant. In cells of fluctuating gap thickness, where the capillary pressure fluctuates in space, a small additional pressure contribution is required. This correction that depends on h is also studied. PMID- 22487235 TI - Formation of supramolecular systems via directed Nucleoside-Lipid recognition. AB - We report the synthesis of a new series of Ketal Nucleoside Lipids (KNLs) featuring saturated hydrophobic double chains and either adenosine or uridine as nucleosides (KNL(A) and KNL(U), respectively). Physicochemical studies (differential scanning calorimetry, small angle X ray scattering, transmission electronic microscopy, atomic force microscopy, Langmuir isotherm, infrared spectroscopy) show that the KNLs form hydrogels below the main phase transition temperature (Tm), whereas fluid lamellar phases are obtained above T(m). Mixing complementary KNLs affords a new stable Combined Supramolecular Systems (CSSs) due to complementary A-U recognition. Molecular modeling calculations of the bilayers in a fluid state exhibit a merging of the bilayers partially due to base base interactions. PMID- 22487236 TI - Molecular dynamics simulation of TCDD adsorption on organo-montmorillonite. AB - In this work, molecular dynamics simulation was applied to investigate the adsorption of Tetrachlorodibenzo-p-Dioxin (TCDD) on tetramethylammonium (TMA) and tetrapropylammonium (TPA) modified montmorillonite, with the aim of providing novel information for understanding the adsorptive characteristics of organo montmorillonite toward organic contaminants. The simulation results showed that on both outer surface and interlayer space of TPA modified montmorillonite (TPA mont), TCDD was adsorbed between the TPA cations with the molecular edge facing siloxane surface. Similar result was observed for the adsorption on the outer surface of TMA modified montmorillonite (TMA-mont). These results indicated that TCDD had stronger interaction with organic cation than with siloxane surface. While in the interlayer space of TMA-mont, TCDD showed a coplanar orientation with the siloxane surfaces, which could be ascribed to the limited gallery height within TMA-mont interlayer. Comparing with TMA-mont, TPA-mont had larger adsorption energy toward TCDD but smaller interlayer space to accommodate TCDD. Our results indicated that molecular dynamics simulation can be a powerful tool in characterizing the adsorptive characteristics of organoclays and provided additional proof that for the organo-montmorillonite synthesized with small organic cations, the available interlayer space rather than the attractive force plays the dominant role for their adsorption capacity toward HOCs. PMID- 22487237 TI - MMP-8 polymorphism is genetic marker to tendinopathy primary posterior tibial tendon. AB - Posterior tibial tendon is particularly vulnerable and is responsible for much morbidity in sportspersons. Some patients have a predisposition without a clinically recognized cause, suggesting that individual characteristics, inclusive genetic inheritance, play an important role in tendinopathy. Matrix metalloproteinase (MMP)-8 is a proteinase capable of degrading a large amount of extracellular proteins, and influence degradation and remodeling of collagen. To determine whether the -799 polymorphism in the promoter of MMP-8 gene is associated with tendinopathy in posterior tibial tendon, 50 patients undergoing surgical procedures and anatomopathological diagnosis of degenerative lesions of the posterior tibial tendon and 100 control patients with posterior tibial tendon integrity and without signs of degeneration in magnetic resonance imaging were evaluated for the -799 MMP-8 polymorphism. There was a significant difference in the presence of the different alleles (P = 0.001) and genotype (P = 0.003) between the control group and the test group for the MMP-8 gene. The polymorphism at position -799 of the gene for MMP-8 is associated with tendinopathy primary posterior tibial tendon in the population studied. The results suggest that individuals with the T allele are at greater risk of developing tendinopathy. PMID- 22487238 TI - Impact of metabolic syndrome on the incidence of chronic kidney disease: a Chinese cohort study. AB - AIM: Metabolic syndrome (MetS) is a major culprit in cardiovascular disease and chronic kidney disease (CKD) in Western populations. We studied the longitudinal association between MetS and incident CKD in Chinese adults. METHODS: A cohort study was conducted in a nationally representative sample of 4248 Chinese adults in Taiwan. The MetS was defined according to a unified criteria set by several major organizations and CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m(2). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for sex, age, body mass index (BMI) and serum levels of total cholesterol. RESULTS: The prevalence of MetS among participants at baseline recruitment was 15.0% (637/4248). During a median follow-up period of 5.40 years, 208 subjects (4.9%) developed CKD. The multivariate-adjusted HR of CKD in participants with MetS compared with those without was 1.42 (95% CI = 1.03, 1.73). Additionally, there was a significantly graded relationship between the number of the MetS components and risk of CKD. Further, the relation between MetS and incident CKD was more robust in subjects with BMI >27.5 kg/m(2) than in those with lower BMI. CONCLUSION: The results suggest that the presence of MetS was significantly associated with increased risk of incident CKD in a Chinese population. These findings warrant future studies to test the impact of preventing and treating MetS on the reduction of the occurrence of CKD. PMID- 22487239 TI - Functional analysis of the Notch ligand Jagged1 missense mutant proteins underlying Alagille syndrome. AB - Heterozygous mutations in the JAG1 gene, encoding Notch ligand Jagged1, cause Alagille syndrome (ALGS). As most of the mutations are nonsense or frameshift mutations producing inactive truncated proteins, haplo-insufficiency is considered the major pathogenic mechanism of ALGS. However, the molecular mechanisms by which the missense mutations cause ALGS remain unclear. Here we analyzed the functional properties of four ALGS missense mutant proteins, P163L, R184H, G386R and C714Y, using transfected mammalian cells. P163L and R184H showed Notch-binding activities similar to that of the wild-type when assessed by immunoprecipitation. However, their trans-activation and cis-inhibition activities were almost completely impaired. These mutant proteins localized mainly to the endoplasmic reticulum (ER), suggesting that the mutations induced improper protein folding. Furthermore, the mutant proteins bound more strongly to the ER chaperone proteins calnexin and calreticulin than the wild-type did. C714Y also localized to the ER, but possessed significant trans-activation activity and lacked enhanced binding to the chaperones, indicating a less severe phenotype. The properties of G386R were the same as those of the wild-type. Dominant negative effects were not detected for any mutant protein. These results indicate that accumulation in the ER and binding to the chaperones correlate with the impaired signal-transduction activities of the missense mutant proteins, which may contribute to the pathogenic mechanism of ALGS. Our findings, which suggest the requirement for cell-surface localization of Jagged1 for cis-inhibition activities, also provide important information for understanding the molecular basis of Notch-signaling pathways. PMID- 22487240 TI - Refractive state of the Spanish Thoroughbred horse: a comparison with the Crossbred horse. AB - OBJECTIVE: To assess the refractive state of the equine eye utilizing retinoscopy. To compare the refractive state of Spanish Thoroughbred horses with the refractive state of Crossbred horses. PROCEDURES: The refractive state of 135 horses (264 eyes) was assessed utilizing streak retinoscopy. Two perpendicular meridians were examined in order to assess astigmatism at a working distance of approximately 67 cm. A group of 81 Spanish Thoroughbred horses was compared with a group of 54 Crossbred horses. Cyclopentolate ophthalmic solution was instilled in the eyes of a group of 18 horses to determine if accommodation has any influence on the assessment of the refractive state. RESULTS: Mean +/- SE refractive state of all horses examined was -0.17 +/- 0.04 D. The mean refractive state of the Spanish Thoroughbred was -0.28 +/- 0.06 D while that of the Crossbred was -0.01 +/- 0.05 D. The refractive state of the Spanish Thoroughbred was found to be statistically different to that of the Crossbred. The most prevalent refractive state was emmetropia in all cases, followed by hyperopia for the Crossbred, and myopia for the Spanish Thoroughbred. Astigmatism >=0.50 D present in both eyes from the same individual was found in 21.7% of all horses examined. Anisometropia >=1.00 D was diagnosed in 4 out of 129 horses with both visual eyes. Cycloplegia did not statistically affect the refractive state of the evaluated eyes. CONCLUSIONS: The equine eye has a refractive state close to emmetropia. Myopia is higher among Spanish Thoroughbred horses than among Crossbred horses. PMID- 22487241 TI - Using non-steroidal anti-inflammatory drugs around calving: maximizing comfort, productivity and fertility. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) have analgesic, anti-inflammatory, anti-endotoxic and anti-pyretic effects in cattle. As such, they could be expected to have significant effects in cows and calves in the post-calving period. This review evaluates the published data on the use of NSAIDs in the dam and its calf after dystocia, the impact of NSAIDs on uterine involution, the restoration of ovarian function and prevention and treatment of the metritis complex, and the benefits of using NSAIDs in the recumbent cow. Overall, the published data are very limited, despite frequent use of NSAIDs by veterinarians in the post-calving cow, and the small number of published studies focus on blanket treatment of calving cows rather than targeted treatment after dystocia. Blanket treatment had no economic benefit; indeed, some studies reported adverse effects, such as pyrexia and increased risk of metritis. There is even less information on the value of treating calves with NSAIDs after dystocia, despite significant tissue damage which may benefit from NSAID use. Appreciably more studies have evaluated the influence of NSAIDs on uterine and ovarian function, but clinical relevance is limited. In cows with a normal puerperium, prolonged treatment with NSAIDs may slow the restoration of normal function, but most reported studies are small and use NSAIDs more frequently and for longer periods than is common in general practice. The evidence of a clinical benefit in cows with puerperal disease is limited and equivocal, and the evidence base for the use of NSAIDs in the treatment of recumbent cows is also small, even though an expert panel concluded that NSAIDs were a key aspect of veterinary treatment of downer cows. The lack of evidence identified by this review supports the contention that NSAIDs are likely to be under-used and sub-optimally prescribed in the post calving period. Further research on the use of NSAIDs in the post calving cow and calf is required. PMID- 22487242 TI - Machine learning identifies specific habitats associated with genetic connectivity in Hyla squirella. AB - The goal of this study was to identify and differentiate the influence of multiple habitat types that span a spectrum of suitability for Hyla squirella, a widespread frog species that occurs in a broad range of habitat types. We collected microsatellite data from 675 samples representing 20 localities from the southeastern USA and used machine-learning methodologies to identify significant habitat features associated with genetic structure. In simulation, we confirm that our machine-learning algorithm can successfully identify landscape features responsible for generating between-population genetic differentiation, suggesting that it can be a useful hypothesis-generating tool for landscape genetics. In our study system, we found that H. squirella were spatially structured and models including specific habitat types (i.e. upland oak forest and urbanization) consistently explained more variation in genetic distance (median pR(2) = 47.78) than spatial distance alone (median pR(2) = 23.81). Moreover, we estimate the relative importance that spatial distance, upland oak and urbanized habitat have in explaining genetic structure of H. squirella. We discuss how these habitat types may mechanistically facilitate dispersal in H. squirella. This study provides empirical support for the hypothesis that habitat use can be an informative correlate of genetic differentiation, even for species that occur in a wide range of habitats. PMID- 22487243 TI - Evaluation of the morphological changes in the lungs of BALB/c mice after inhalation of spherical and rod-shaped titanium nanoparticles. AB - Titanium nanoparticles are widely used by industry in consumer products such as sunscreens and some cosmetic products due to their specifically engineered properties. Some of these properties may, however, increase the toxicity of the nanoparticles which in turn may affect human and environmental health. Therefore, it is of utmost importance to study the possible effects of these particles through in vivo studies, which might produce different results than in vitro cell studies. The current study aimed to investigate the possible remodelling in the lungs of BALB/c mice by means of light and transmission electron microscopy after inhalation of spherical and rod-shaped titanium nanoparticles at two different concentrations. The focus of this paper was to demonstrate whether whole body exposure to different concentrations of the said nanoparticles could induce an inflammatory response in the lungs and no inter particle comparison was done or retention investigated. Animals were divided into five experimental groups: control, high and low concentration groups exposed to the spherical-shaped particles, as well as high and low concentration groups exposed to the rod-shaped particles. Histological and ultrastructural changes, typical of an inflammatory response, were noted in the lungs of the exposed animals. These changes were not observed in the lungs of the control animals. It can be concluded from this study that titanium nanoparticles may cause inflammatory reactions in the lungs of animals exposed through inhalation, as indicated by the presence of inflammatory cells and congestion of inter-alveolar areas. This has implications for individuals who may be potentially exposed during the production and use of titanium nanoparticles. PMID- 22487244 TI - Recent trends in Victorian risk-adjusted in-hospital mortality: 1999-2009. AB - BACKGROUND: The background of the study is a comparison of risk-adjusted mortality across hospitals from different jurisdictions is now common worldwide. AIM: To examine temporal trends in risk-adjusted mortality in Victoria over the last decade. METHODS: Retrospective cohort study of 6.89 million adult (>14 years) patient episodes from 23 major Victorian public hospitals between 1999 and 2009. The primary outcome was in-hospital death. Three measures were calculated: the crude mortality rate, risk-adjusted mortality rate and standardised mortality ratio (SMR). The Hospital Outcome Prediction Equation (HOPE) was applied to generate estimates of predicted mortality that were used to compute the SMR and risk-adjusted mortality rates. The HOPE model includes 26 exogenous risk factors for which providers have no influence. The model was calibrated using the 2004 2005 data. Temporal mortality trends from 1999-2009 were evaluated using negative binomial regression for crude mortality and SMR estimates and random-intercept hierarchical logistic regression for risk-adjusted mortality. RESULTS: The study population included 84 423 in-hospital deaths (1.2%). Crude mortality risk declined from 1.5% in 2000 to 1.1% in 2005-2009 (incidence rate ratio (IRR): 0.96; 95% confidence interval (CI): 0.95-0.97; P < 0.001). There were 1.39 million episodes in the HOPE calibration cohort. Between 1999 and 2009, the SMR decreased from 1.4 to 0.9 (IRR = 0.91; 95% CI: 0.90-0.97; P < 0.001) and adjusted mortality risk declined from 2.1% to 0.9% (odds ratio = 0.94, 95% CI: 0.94-0.94, P < 0.001). Declining mortality trends were evident in the tertiary, metropolitan and regional peer groups (P < 0.001). CONCLUSION: Analysis of in-hospital risk adjusted mortality trends using the HOPE model indicates significant improvement in patient outcomes in the State of Victoria over the past decade. PMID- 22487245 TI - Linezolid-induced pure red cell aplasia in a patient with Staphylococcus epidermidis infection after allogeneic stem cell transplantation. AB - Linezolid (LZD) is the first oxazolidinone antibiotic that is effective against drug-resistant gram-positive organisms. Hematological toxicities such as thrombocytopenia, anemia, and leukocytopenia are common in LZD therapy. However, LZD-induced pure red cell aplasia (PRCA) is very rare. A 56-year-old man with myelodysplastic syndrome underwent allogeneic bone marrow transplantation from a human leukocyte antigen-matched and ABO blood type-matched unrelated male donor. He had bacteremia caused by Staphylococcus epidermidis after engraftment of neutrophils and red blood cells. We first administered vancomycin, but then changed to intravenous LZD because of kidney damage. Two weeks after LZD therapy, the patient's hemoglobin and reticulocyte levels were 6.8 g/dL and 0.3%, respectively. Bone marrow examination revealed red blood cell aplasia (myeloid/erythroid ratio was 402). The patient showed rapid recovery of normal erythropoiesis within 2 weeks of LZD cessation. It is important to be aware of the hematological effects associated with LZD in the setting of stem cell transplantation,particularly for those with pre-existing myelosuppression, renal insufficiency, and those receiving concomitant drugs that produce bone marrow suppression. We advocate that a reticulocyte count be performed periodically for detecting bone marrow suppression, including PRCA, during LZD therapy. PMID- 22487246 TI - Acute restraint differently alters defensive responses and fos immunoreactivity in the rat brain. AB - Results from a previous study show that rats exposed to acute restraint display anxiogenic-like behavior, evidenced by facilitation of avoidance responses in the elevated T-maze (ETM) model of anxiety. In contrast, escape responses were unaltered by stress exposure. Since ETM avoidance and escape tasks seem to activate distinct sets of brain structures, it is possible that the differences observed with acute restraint are due to particularities in the neurobiological mechanisms which modulate these responses. In the present study, analysis of fos protein immunoreactivity (fos-ir) was used to map areas activated by exposure of male Wistar rats to restraint stress (30 min) previously (30 min) to the ETM. Corticosterone levels were also measured in stressed and non-stressed animals. Confirming previous observations restraint facilitated avoidance performance, an anxiogenic result, while leaving escape unaltered. Performance of the avoidance task increased fos-ir in the frontal cortex, intermediate lateral septum, basolateral amygdala, basomedial amygdala, lateral amygdala, anterior hypothalamus and dorsal raphe nucleus. In contrast, performance of escape increased fos-ir in the ventromedial hypothalamus, dorsolateral periaqueductal gray and locus ceruleus. Both behavioral tasks also increased fos-ir in the dorsomedial hypothalamus. Restraint significantly raised corticosterone levels. Additionally after restraint, fos-ir was predominantly seen in the basolateral amygdala and dorsal raphe of animals submitted to the avoidance task. This data confirms that different sets of brain structures are activated by ETM avoidance and escape tasks and suggests that acute restraint differently alters ETM behavior and the pattern of fos activation in the brain. PMID- 22487248 TI - Attenuating the effect of Ghrelin on memory storage via bilateral reversible inactivation of the basolateral amygdale. AB - Previous studies have shown that Ghrelin increases memory retention. They have also indicated that amygdale is involved in memory storage. The present study examined the role of basolateral amygdala (BLA) in Ghrelin-induced retention improvement, using reversible inactivation of this region with lidocaine. Rats were bilaterally implanted with cannulae at the BLA. One week later, they received intra-BLA injection of lidocaine, saline or Ghrelin with 5 min interval immediately after training. 24-72 h after training, step-through latency (STL) was measured as learning and memory index. The results showed that injection of Ghrelin into the BLA produced a significant enhancement in retention, which was attenuated by injection of lidocaine into BLA. These finding indicate that the BLA is involved in mediating the memory-modulating effect of Ghrelin. PMID- 22487247 TI - Pharmacological enhancement of calcium-activated potassium channel function reduces the effects of repeated stress on fear memory. AB - Repeated stress impacts emotion, and can induce mood and anxiety disorders. These disorders are characterized by imbalance of emotional responses. The amygdala is fundamental in expression of emotion, and is hyperactive in many patients with mood or anxiety disorders. Stress also leads to hyperactivity of the amygdala in humans. In rodent studies, repeated stress causes hyperactivity of the amygdala, and increases fear conditioning behavior that is mediated by the basolateral amygdala (BLA). Calcium-activated potassium (K(Ca)) channels regulate BLA neuronal activity, and evidence suggests reduced small conductance K(Ca) (SK) channel function in male rats exposed to repeated stress. Pharmacological enhancement of SK channels reverses the BLA neuronal hyperexcitability caused by repeated stress. However, it is not known if pharmacological targeting of SK channels can repair the effects of repeated stress on amygdala-dependent behaviors. The purpose of this study was to test whether enhancement of SK channel function reverses the effects of repeated restraint on BLA-dependent auditory fear conditioning. We found that repeated restraint stress increased the expression of cued conditioned fear in male rats. However, 1-Ethyl-2 benzimidazolinone (1-EBIO, 1 or 10 mg/kg) or CyPPA (5 mg/kg) administered 30 min prior to testing of fear expression brought conditioned freezing to control levels, with little impact on fear expression in control handled rats. These results demonstrate that enhancement of SK channel function can reduce the abnormalities of BLA-dependent fear memory caused by repeated stress. Furthermore, this indicates that pharmacological targeting of SK channels may provide a novel target for alleviation of psychiatric symptoms associated with amygdala hyperactivity. PMID- 22487249 TI - Maternal immune activation in late gestation enhances locomotor response to acute but not chronic amphetamine treatment in male mice offspring: role of the D1 receptor. AB - Exposure to elevated levels of maternal cytokines can lead to functional abnormalities of the dopaminergic system in the adult offspring, including enhanced amphetamine (AMPH)-induced locomotion. Therefore, it seems reasonable to consider that offspring of challenged mothers would behave differently in models of addictive behavior, such as behavioral sensitization. Thus, we sought to evaluate the effects of prenatal exposure to lipopolysaccharide (LPS) on the locomotor response to acute and chronic AMPH treatment in male mice offspring. For this purpose, LPS (Escherichia coli 0127:B8; 120 MUg/kg) was administered intraperitoneally to pregnant Swiss mice on gestational day 17. At adulthood, male offspring were studied under one of the following conditions: (1) locomotor response to acute AMPH treatment (2.5 or 5.0 mg/kg) in an open field test; (2) behavioral sensitization paradigm, which consists of a daily injection of AMPH (1.0 mg/kg) for 10 days and observation of locomotion in the open field on days 1, 5, 10 (development phase), 15 and 17 (expression phase). The LPS stimulated offspring showed enhancement of the locomotor-stimulant effect after an acute AMPH challenge in comparison to baseline and saline pre-treated mice. They also showed development of behavioral sensitization earlier than the saline pre treated group, although no changes between saline and LPS pre-treated groups were observed on development or expression of locomotor behavioral sensitization to AMPH. Furthermore, there was up-regulation of D1 receptor protein level within striatum in the LPS-stimulated offspring which was strongly correlated with increased grooming behavior. Taken together, our results indicate that motor and dopaminergic alterations caused by maternal immune activation are restricted to the acute AMPH challenge, mostly due to up-regulation of the D1 receptor within the mesolimbic and nigrostriatal pathways, but no locomotor differences were observed for behavioral sensitization to AMPH. PMID- 22487250 TI - Near-infrared imaging of the effects of glucose ingestion and regulation on prefrontal activation during dual-task execution in healthy fasting older adults. AB - RATIONALE: Glucose enhancing effects in older adults have mostly been observed for episodic memory, but have recently been found for attentional control performance. Yet, brain activation patterns underlying these effects are still unknown. OBJECTIVE: The present study examined the acute effects of glucose ingestion on prefrontal brain activation during the execution of a divided attention task in fasting non-diabetic older adults. METHODS: Twenty older adults (60 years and older) took part in the study that included two experimental sessions. After an overnight fast, participants received either a glucose drink (50 g) or a placebo (saccharin) drink, following which they completed a dual task. During task execution, prefrontal activation was recorded with functional near-infrared spectroscopy (fNIRS). A repeated-measures design was used such that each participant served as his or her own control. The two experimental sessions were counterbalanced among participants and were performed two weeks apart. RESULTS: When participants were in the glucose condition, they showed similar dual-task costs for both tasks, whereas in the placebo condition they prioritized one task over the other, with a significantly larger dual-task cost for the non prioritized task (p<0.01). Differential brain activation was also observed in right ventral-lateral prefrontal regions for oxygenated hemoglobin and deoxygenated hemoglobin, with more activation apparent in the glucose condition (p<0.05). Furthermore, behavioral and activation data were influenced by individual differences in glucose regulation. CONCLUSIONS: Glucose ingestion appears to momentarily enhance fasting seniors' capacity to coordinate more equally two concurrent tasks and this is reflected in brain activation patterns. PMID- 22487251 TI - Synthesis, characterization and biological activity of ferrocene-based Schiff base ligands and their metal (II) complexes. AB - Metal (II) complexes derived from S-benzyl-N-(1-ferrocenyl-3-(4 methylbenzene)acrylketone) dithiocarbazate; HL(1), S-benzyl-N-(1-ferrocenyl-3-(4 chlorobenzene)acrylketone)dithiocarbazate; HL(2), all the compounds were characterized using various spectroscopic techniques. The molar conductance data revealed that the chelates were non-electrolytes. IR spectra showed that the Schiff bases were coordinated to the metal ions in a bidentate manner with N, S donor sites. The ligands and their metal complexes have been screened for in vitro antibacterial, antifungal properties. The result of these studies have revealed that zinc (II) complexes 6 and 13 of both the ligands and copper (II) complexes 9 of the HL(2) were observed to be the most active against all bacterial strains, antifungal activity was overall enhanced after complexation of the ligands. PMID- 22487252 TI - Developmental expression of sex steroid- and thyroid hormone-related genes and their regulation by triiodothyronine in the gonad-mesonephros of a Neotropical frog, Physalaemus pustulosus. AB - Gonadal differentiation in frogs is affected by sex steroids and thyroid hormones (THs); however, the genes controlling differentiation and the molecular effects of THs in the gonad are not clear and have only been investigated in a few anuran species. In this study, we established developmental profiles and TH regulation of sex steroid- and TH-related genes in the gonad-mesonephros complex (GMC) of the tungara frog (Physalaemus pustulosus), and compared the results to our previous research in another tropical frog, Silurana tropicalis. The developmental profiles allowed us to identify three genes as markers of ovarian development. During metamorphosis, aromatase (cyp19), estrogen receptor alpha, and steroid 5alpha-reductase 1 (srd5alpha1) were higher in the GMC of putative and morphological females. Acute exposure to triiodothyronine (T3) decreased GMC expression of srd5alpha1 and cyp19, while increasing TH-related genes in premetamorphic tadpoles. The regulation of sex steroid-related genes differed significantly from our previous study in S. tropicalis. P. pustulosus and S. tropicalis share ecological, developmental, and reproductive characteristics; however, they are not closely related. These results along with our previous research in the tadpole brain support the hypothesis that evolutionary convergence is not important in understanding differences in the effects of TH on sex steroid-related genes in frogs. Finally, we propose that T3 induces male gonadal development but this can be achieved through different mechanisms depending on the species. PMID- 22487253 TI - Voluntary feed intake and leptin sensitivity in ad libitum fed obese ponies following a period of restricted feeding: a pilot study. AB - The relation between plasma leptin and daily ad libitum roughage intake was evaluated during a 14-day period in eight obese Shetland ponies. When the feeding strategy was changed from maintenance feeding to ad libitum feeding, feed intake increased the first day, decreased the second day and increased again during the following days to reach a constant level after 8 days. Plasma leptin concentration increased during the first 2 days, but remained constant afterwards. Although the same pattern was found in all ponies, the magnitude of the increase in leptin on day 1 and the resulting decrease in feed intake on day 2 differed between ponies. A lower anorectic effect was seen in ponies with higher initial leptin concentration, suggesting the presence of different degrees in leptin sensitivity in obese ponies. High leptin production in a attempt to compensate for the decrease in leptin sensitivity might explain large variations in plasma leptin among obese ponies with similar body condition score. Further research is necessary to clarify whether the reduced leptin sensitivity precedes obesity in equines or vice versa. PMID- 22487255 TI - Estimating the risks of acquiring a kidney abroad: a meta-analysis of complications following participation in transplant tourism. AB - A meta-analysis of odds ratios comparing the risks of participating in transplant tourism by acquiring a kidney abroad to the risks associated with domestic kidney transplant was undertaken. Comparison across 12 medical outcomes indicates transplant tourists are significantly more likely to contract cytomegalovirus, hepatitis B, HIV, post-transplantation diabetes mellitus, and wound infection than those receiving domestic kidney transplant. Results also indicate that domestic kidney transplant recipients experience significantly higher one-yr patient- and graft-survival rates. Analyses are supplemented by independent comparisons of outcomes and provide practitioners with weighted estimates of the proportion of transplant recipients experiencing 15 medical outcomes. Practitioners are encouraged to caution patients of the medical risks associated with transplant tourism. Despite the illegal and unethical nature of transplant tourism, additional efforts are indicated to eliminate the organ trade and to educate wait-listed patients about the risks of transplant tourism. PMID- 22487254 TI - Heterosis manifestation during early Arabidopsis seedling development is characterized by intermediate gene expression and enhanced metabolic activity in the hybrids. AB - Heterosis-associated cellular and molecular processes were analyzed in seeds and seedlings of Arabidopsis thaliana accessions Col-0 and C24 and their heterotic hybrids. Microscopic examination revealed no advantages in terms of hybrid mature embryo organ sizes or cell numbers. Increased cotyledon sizes were detectable 4 days after sowing. Growth heterosis results from elevated cell sizes and numbers, and is well established at 10 days after sowing. The relative growth rates of hybrid seedlings were most enhanced between 3 and 4 days after sowing. Global metabolite profiling and targeted fatty acid analysis revealed maternal inheritance patterns for a large proportion of metabolites in the very early stages. During developmental progression, the distribution shifts to dominant, intermediate and heterotic patterns, with most changes occurring between 4 and 6 days after sowing. The highest incidence of heterotic patterns coincides with establishment of size differences at 4 days after sowing. In contrast, overall transcript patterns at 4, 6 and 10 days after sowing are characterized by intermediate to dominant patterns, with parental transcript levels showing the largest differences. Overall, the results suggest that, during early developmental stages, intermediate gene expression and higher metabolic activity in the hybrids compared to the parents lead to better resource efficiency, and therefore enhanced performance in the hybrids. PMID- 22487256 TI - Incidence of seizures associated with the use of acepromazine in dogs undergoing myelography. AB - OBJECTIVE: To investigate the frequency of seizures associated with acepromazine administration when used as a premedicant with methadone for dogs undergoing myelography. DESIGN: Retrospective clinical case study. SETTING: University veterinary teaching hospital. ANIMALS: Sixty-six dogs (mixed and pure breeds), aged between 4 months and 15 years, weighing between 3.5-61 kg. All animals were classified as ASA score I or II. INTERVENTIONS: Forty-three animals were premedicated with methadone (0.1-0.5 mg/kg) and acepromazine (0.01-0.05 mg/kg) intramuscularly. Twenty-three animals were premedicated with methadone alone (0.1 0.5 mg/kg) intramuscularly. Anesthesia was induced with propofol intravenously and maintained with isoflurane delivered in 100% oxygen. All animals received a balanced isotonic crystalloid solution intravenously at a rate of 10 mL/kg/h. Blood pressure, end-tidal CO(2) , oxygen saturation, respiratory rate, and heart rate were monitored throughout anesthesia. Animals requiring surgery immediately following myelography were excluded from the study. MEASUREMENTS AND MAIN RESULTS: The frequency of seizures was 14% (CI: 3.6-24.3%) and 13.0% (CI: 0.7 27%) in dogs that received methadone/acepromazine and methadone alone, respectively. There was no significant difference in the frequency of seizures between dogs receiving methadone/acepromazine or methadone alone (P = 1). Analysis of the association of site of injection of the contrast and the frequency of seizures in dogs receiving methadone/acepromazine showed no significant difference in the frequency of seizures following cervical injection (25%; CI: 0.5-24.5%) or lumbar injection (9.7%; CI: -0.7-20.1%). CONCLUSIONS: The administration of acepromazine combined with methadone as a premedicant used with propofol and isoflurane anesthesia did not significantly increase the frequency of seizures following myelography compared to dogs who received methadone alone. PMID- 22487258 TI - Hypothalamic gene expression rapidly changes in response to photoperiod in juvenile Siberian hamsters (Phodopus sungorus). AB - Siberian hamsters are seasonal mammals that survive a winter climate by making adaptations in physiology and behaviour. This includes gonadal atrophy, reduced food intake and body weight. The underlying central mechanisms responsible for the physiological adaptations are not fully established but involve reducing hypothalamic tri-iodthyronine (T3) levels. Juvenile Siberian hamsters born or raised in short days (SD) respond in a similar manner, although with an inhibition of gonadal development and growth instead of reversing an established long day (LD) phenotype. Using juvenile male hamsters, the present study aimed to investigate whether the central mechanisms are similar before the establishment of the mature LD phenotype. By in situ hybridisation, we examined the response of genes involved in thyroid hormone (Dio2 and Dio3, which determine hypothalamic T3 levels) and glucose/glutamate metabolism in the ependymal layer, histamine H3 receptor and VGF as representatives of the highly responsive dorsomedial posterior arcuate nucleus (dmpARC), and somatostatin, a hypothalamic neuropeptide involved in regulating the growth axis. Differential gene expression of type 2 and type 3 deiodinase in the ependymal layer, histamine H3 receptor in the dmpARC and somatostatin in the ARC was established by the eighth day in SD. These changes are followed by alterations in glucose metabolism related genes in the ependymal layer by day 16 and increased secretogranin expression in the dmpARC by day 32. In conclusion, our data demonstrate similar but rapid and highly responsive changes in gene expression in the brain of juvenile Siberian hamsters in response to a switch from LD to SD. The data also provide a temporal definition of gene expression changes relative to physiological adaptations of body weight and testicular development and highlight the likely importance of thyroid hormone availability as an early event in the adaptation of physiology to a winter climate in juvenile Siberian hamsters. PMID- 22487259 TI - Genome editing in induced pluripotent stem cells. AB - The discovery of induced pluripotent stem (iPS) cells has broadened the promises of regenerative medicine through the generation of syngeneic replacement cells or tissues via the differentiation of patient-specific iPS cells. To apply iPS cell mediated therapy to patients with genetic disorders, however, genome-editing technologies with high efficiency and specificity are needed. Recently, several targeted genome-editing strategies mediated by zinc finger nuclease and transcription activator-like effector nuclease have been applied to human and mouse iPS cells. Furthermore, spontaneous homologous recombination can restore genotype to wild type in mouse iPS cells heterozygous for genetic mutations. Through genome editing, the clinical application of patient-specific genetic mutation-free iPS cells to genetic disorders can finally be realized. PMID- 22487257 TI - Quantification of dust-borne transmission of highly pathogenic avian influenza virus between chickens. AB - BACKGROUND: Understanding the transmission of highly pathogenic avian influenza virus (HPAIv) between poultry flocks is essential to prevent and control epidemics. Dust, produced in infected chicken flocks, has been hypothesized to be an important mechanical vector for between-flock transmission of HPAIv. OBJECTIVES: The aim of our study was to quantify the amount of virus shed by infected birds and its relation to deposition of virus in the environment and the rate of dust-borne transmission between groups of chickens. METHODS: Four replicate experiments were performed, each replicate with two groups of 14 chickens housed in two separate rooms. In one group, chickens were inoculated with HPAIv. Ventilation forced the air from that room to the second (recipient) group through a tube. Deceased birds in the inoculated group were replaced with new susceptible birds up to day 10 p.i. Dust samples were collected daily. Trachea and cloaca swabs were collected daily to determine virus shedding and virus spread to the recipient group. RESULTS: The amount of virus detected in dust samples in the recipient room was, on average, 10(3.7) EID(50) /m(3) . Virus transmission from the inoculated to the recipient group occurred in two experiments. The transmission rate parameter for dust-borne transmission was estimated at 0.08 new infections/infectious chicken/day. CONCLUSIONS: The results of this study are a first step to elucidate the importance of dust-borne transmission of HPAIv between flocks and help interpret environmental samples. PMID- 22487260 TI - Two versus one repeat freeze-thaw cycle(s) after cryoballoon pulmonary vein isolation: the alster extra pilot study. AB - BACKGROUND: Repeated freezing (bonus applications) during cryoballoon pulmonary vein isolation (PVI) has been suggested to improve lesion durability. However, the long-term clinical effects of repeated freezing have not been investigated. METHODS AND RESULTS: A total of 51 patients (pts) with paroxysmal atrial fibrillation (AF) underwent PVI using the single big (28 mm) cryoballoon technique. One (27 pts, group I) or 2 bonus applications (24 pts, group II) were performed at all PVs subsequent to PVI. Clinical follow-up consisted of continuous rhythm monitoring by an implantable cardiac monitor (ICM, 24 pts) and serial 7-day Holter-ECG recording (7DH, 27 pts). The primary endpoint was defined as recurrent AF or atrial tachycardia. Acute PVI of all PVs was obtained in 50/51 pts (98%). The median (Q1;Q3) follow-up duration in this study was 384 (213;638) days. The primary endpoint occurred in 48% (group I, 15 pts ICM, 12 pts 7DH) and 46% (group II, 9 pts ICM, 15 pts 7DH), P = 0.84. Procedure- and fluoroscopy-time for group I versus group II was 193 +/- 56 minutes versus 207 +/- 27 and 33 +/- 13 minutes versus 34 +/- 11 minutes, respectively. Right phrenic nerve palsy (PNP) occurred in 3 pts (all group II, time to resolution: 128 +/- 112 days). In 2 of these pts, PNP occurred during the second bonus application. CONCLUSION: Application of 2 when compared to 1 freeze-thaw cycle(s) following cryoballoon PVI did not result in improved clinical success but was associated with a higher complication rate. PMID- 22487261 TI - Can the Kattan nomogram still accurately predict prognosis in renal cell carcinoma using the revised 2010 tumor-nodes-metastasis reclassification? AB - The Kattan nomogram has been used in renal cell cancer to predict progression free survival after nephrectomy. Tumor-nodes-metastasis staging is essential for the calculation of this score. The effect of the recent 2010 revision to the tumor-nodes-metastasis classification on the predictive ability of the Kattan nomogram was studied. All patients having radical nephrectomy for renal cell cancer in the 5-year period of 2004-2008 at a tertiary referral center were included. Pathological and radiological records were reviewed to identify tumor nodes-metastasis stage (2002 and 2010 classifications). Kattan scores were calculated for the 2002 and 2010 tumor-nodes-metastasis stages, and the effect on survival predictions were compared with actual outcomes. A total of 291 patients with non-metastatic renal cell cancer were identified. Revision of the tumor nodes-metastasis staging from the 2002 to 2010 classification resulted in an increase in the number of patients with stage pT3a (from 30 to 75), a reduction in the patients with stage pT3b (from 57 to 10) and a small increase in stage pT4 cases (1 to 3). This altered the proportion of patients in the Kattan prognostic of "good" (from 61% to 69%), "intermediate" (from 29% to 22%) and "poor" (from 10% to 8%). The overall median predicted 5-year progression-free survival was 79.8% with 2002 tumor-nodes-metastasis, and 81.8% with 2010 tumor-nodes metastasis. Actual 5-year progression-free survival was 83.0%, which was not significantly different from that predicted using either tumor-nodes-metastasis classification (P = 0.66). On comparing the new 2010 and old 2002 tumor-nodes metastasis classification in our cohort, we showed the predictive ability of the Kattan nomogram remained unaltered. PMID- 22487262 TI - A chemical method for investigating disulfide-coupled peptide and protein folding. AB - Investigations of protein folding have largely involved studies using disulfide containing proteins, as disulfide-coupled folding of proteins permits the folding intermediates to be trapped and their conformations determined. Over the last decade, a combination of new biotechnical and chemical methodology has resulted in a remarkable acceleration in our understanding of the mechanism of disulfide coupled protein folding. In particular, expressed protein ligation, a combination of native chemical ligation and an intein-based approach, permits specifically labeled proteins to be easily produced for studies of protein folding using biophysical methods, such as NMR spectroscopy and X-ray crystallography. A method for regio-selective formation of disulfide bonds using chemical procedures has also been established. This strategy is particularly relevant for the study of disulfide-coupled protein folding, and provides us not only with the native conformation, but also the kinetically trapped topological isomer with native disulfide bonds. Here we review recent developments and applications of biotechnical and chemical methods to investigations of disulfide-coupled peptide and protein folding. Chemical additives designed to accelerate correct protein folding and to avoid non-specific aggregation are also discussed. PMID- 22487263 TI - Exposure of Sebastiscus marmoratus embryos to pyrene results in neurodevelopmental defects and disturbs related mechanisms. AB - Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants, which are known to be carcinogenic and teratogenic. These compounds cause a range of macroscopic malformations, particularly to the craniofacial apparatus and cardiovascular system during vertebrate development. However, little is known concerning microscopic effects, especially on the sensitive early life stages or on the molecular basis of developmental neurotoxicity. Using the rockfish (Sebastiscus marmoratus), we explored the neurodevelopmental defects caused by early-life exposure to environmentally relevant concentrations of pyrene, a 4-ring PAH. The results showed that pyrene substantially disrupted the cranial innervation pattern and caused deficiency of motor nerves. The expression of a protein associated with axon growth, growth associated protein 43, was decreased in the central nervous system after treatment with pyrene. N-methyl-D aspartate receptor (NMDAR) plays a vital role in a variety of processes, including neuronal development, synaptic plasticity, and neuronal survival and death. Our results showed that the expression of Ca2+/calmodulin dependent kinase II and cAMP-response element-binding, which belong to the NMDAR pathway, were increased in a dose-dependent manner after exposure to pyrene. Acetylcholine, an important neurotransmitter which is known to suppress retinal cells neurite outgrowth, was increased by pyrene exposure. Nitric oxide (NO) acts as an activity-dependent retrograde signal that can coordinate axonal targeting and synaptogenesis during development. The level of NO was decreased in a dose dependent manner following exposure to pyrene. Taken together, the defects in neurodevelopment and the damage to related mechanisms provided the basis for a better understanding of the neurotoxic effects of pyrene. PMID- 22487264 TI - A population-based study of breast cancer-specific survival following mastectomy and immediate or early-delayed breast reconstruction. AB - Immediate breast reconstruction allows for improved patient psychosocial outcomes after mastectomy. We used the Surveillance, Epidemiology, and End Results (SEER) database to study the breast cancer-specific survival of patients treated with immediate or early-delayed breast reconstruction after mastectomy. Population level de-identified data was abstracted from the SEER database. All female patients treated with mastectomy for a diagnosis of ductal and/or lobular breast cancer between 1998 and 2002 were included. Breast cancer-specific survival was reported as hazard ratios using multivariate analysis to control for patient demographic and oncologic covariates. Demographic covariates included age, race, marital status, income, education, and county metropolitan status; oncologic covariates included tumor stage, histology, grade, lymph node status, hormone receptor status, receipt of radiation therapy, and unilateral or bilateral mastectomy. A total of 52,249 patients were included in the study. Patients treated with mastectomy and reconstruction had a significantly lower hazard of death (HR 0.73, p < 0.0001) compared with patients treated with mastectomy only. Black patients had a significantly increased hazard of death (HR 1.42, p < 0.0001) compared with white patients. Receipt of radiotherapy did not significantly associate with hazard of death (HR 1.03, p = 0.3494). Additionally, bilateral mastectomy did not significantly associate with hazard of death (HR 0.98, p = 0.763). Our analysis shows that patients who undergo breast reconstruction after mastectomy have a higher breast cancer-specific survival than those undergoing mastectomy alone, when controlling for demographic and oncologic covariates. Further research is required to understand the nature of this relationship. PMID- 22487265 TI - Evolutionary engineering of Saccharomyces cerevisiae for efficient aerobic xylose consumption. AB - Industrial biotechnology aims to develop robust microbial cell factories, such as Saccharomyces cerevisiae, to produce an array of added value chemicals presently dominated by petrochemical processes. Xylose is the second most abundant monosaccharide after glucose and the most prevalent pentose sugar found in lignocelluloses. Significant research efforts have focused on the metabolic engineering of S. cerevisiae for fast and efficient xylose utilization. This study aims to metabolically engineer S. cerevisiae, such that it can consume xylose as the exclusive substrate while maximizing carbon flux to biomass production. Such a platform may then be enhanced with complementary metabolic engineering strategies that couple biomass production with high value-added chemical. Saccharomyces cerevisiae, expressing xylose reductase, xylitol dehydrogenase and xylulose kinase, from the native xylose-metabolizing yeast Pichia stipitis, was constructed, followed by a directed evolution strategy to improve xylose utilization rates. The resulting S. cerevisiae strain was capable of rapid growth and fast xylose consumption producing only biomass and negligible amount of byproducts. Transcriptional profiling of this strain was employed to further elucidate the observed physiology confirms a strongly up-regulated glyoxylate pathway enabling respiratory metabolism. The resulting strain is a desirable platform for the industrial production of biomass-related products using xylose as a sole carbon source. PMID- 22487266 TI - Patent foramen ovale, dialysis and microembolization. AB - BACKGROUND: Haemodialysis (HD) circuits are known to produce microemboli. Patent foramen ovale (PFO) may be important in HD patients by allowing right to left intracardiac shunting of microemboli (blood clots or microbubbles), which may pass into the cerebral circulation. METHODS: We undertook bubble contrast transthoracic echocardiography to identify PFO in HD patients and in a control population of peritoneal dialysis patients. We interrogated draining arteriovenous fistulae to confirm that microemboli are created during HD. We then undertook transcranial Doppler scanning of the middle cerebral artery before and during dialysis, with and without Valsalva augmentation, to detect cerebral microemboli in HD patients and in the control group. RESULTS: Eighty patients (age 60.4 +/- 15.0 years) were recruited to the study. In 12 of 51 HD patients and five of 29 peritoneal dialysis patients a PFO was found (21.3%). Ultrasound scanning of draining arteriovenous fistulae showed a significant difference in the number of microemboli before (1.63 +/- 3.47 hits per 5 min) and during (31.6 +/- 28.9 hits per 5 min) HD (P = 0.012). However, there was no evidence of microembolization to the middle cerebral artery before or during HD in the study or control groups. CONCLUSIONS: Although microemboli are detectable in the draining arteriovenous fistulae of patients undergoing HD, there was no evidence of cerebral microembolization in the middle cerebral artery during HD in those with or without a PFO. The results contrast with previous reports demonstrating microemboli in the carotid circulation during HD. PMID- 22487267 TI - The protective effects of Lycium barbarum and Chrysanthemum morifolum on diabetic retinopathies in rats. AB - The effects of Lycium barbarum and Chrysanthemum morifolum extracts on diabetic retinopathy were evaluated. The diabetes model was induced by streptozotocin. Animals were divided into six groups: the control group received only vehicle; diabetic animal models received no treatment, insulin treatment, Lycium extract, Chrysanthemum extract, or a combination of Lycium and Chrysanthemum extracts, respectively. Retinal function was evaluated by electroretinography, and the diabetic progression was monitored by blood test for hyperglycemia. In addition, retinal histopathology and retinal glial reactivity were also investigated. The electroretinographic amplitudes of the a- and b-waves were significantly decreased in the diabetic animals, and the implicit time of the b-wave was also delayed, compared to the control group. However, reductions in the a- and b-wave amplitudes were not observed in the Lycium-treated group. Histopathological studies showed no significant differences between the Lycium-treated, Chrysanthemum-treated, Lycium/Chrysanthemum-treated groups, and the control group. The results of this study suggest that L. barbarum may have protective effects in diabetic retinopathy. PMID- 22487268 TI - Fluorescence correlation spectroscopy, combined with bimolecular fluorescence complementation, reveals the effects of beta-arrestin complexes and endocytic targeting on the membrane mobility of neuropeptide Y receptors. AB - Fluorescence correlation spectroscopy (FCS) and photon counting histogram (PCH) analysis are powerful ways to study mobility and stoichiometry of G protein coupled receptor complexes, within microdomains of single living cells. However, relating these properties to molecular mechanisms can be challenging. We investigated the influence of beta-arrestin adaptors and endocytosis mechanisms on plasma membrane diffusion and particle brightness of GFP-tagged neuropeptide Y (NPY) receptors. A novel GFP-based bimolecular fluorescence complementation (BiFC) system also identified Y1 receptor-beta-arrestin complexes. Diffusion co efficients (D) for Y1 and Y2-GFP receptors in HEK293 cell plasma membranes were 2.22 and 2.15 * 10(-9)cm(2)s(-1) respectively. At a concentration which promoted only Y1 receptor endocytosis, NPY treatment reduced Y1-GFP motility (D 1.48 * 10( 9)cm(2)s(-1)), but did not alter diffusion characteristics of the Y2-GFP receptor. Agonist induced changes in Y1 receptor motility were inhibited by mutations (6A) which prevented beta-arrestin recruitment and internalisation; conversely they became apparent in a Y2 receptor mutant with increased beta arrestin affinity. NPY treatment also increased Y1 receptor-GFP particle brightness, changes which indicated receptor clustering, and which were abolished by the 6A mutation. The importance of beta-arrestin recruitment for these effects was illustrated by reduced lateral mobility (D 1.20-1.33 * 10(-9)cm(2)s(-1)) of Y1 receptor-beta-arrestin BiFC complexes. Thus NPY-induced changes in Y receptor motility and brightness reflect early events surrounding arrestin dependent endocytosis at the plasma membrane, results supported by a novel combined BiFC/FCS approach to detect the underlying receptor-beta-arrestin signalling complex. PMID- 22487269 TI - Epidermal choristoma arising on the midline gingiva as a congenital epulis: a case report. AB - We report an extremely rare case of epidermal choristoma in the midline of the maxillary gingiva. A 2-month-old Japanese boy presented with a polypoid mass in the midline of the maxillary gingiva. The initial clinical diagnosis was congenital epulis. Microscopic examination revealed a granular cell layer and melanin pigmentation within the basal cell layer. Furthermore, sebaceous glands and hair follicles were observed within the connective tissue. The histological diagnosis was therefore epidermal choristoma, based on clinical microscopic observations. PMID- 22487270 TI - Management of mandibular interforaminal fractures using 3 dimensional locking and standard titanium miniplates - a comparative preliminary report of 10 cases. AB - PURPOSE: The aim of this follow up clinical study was to compare and evaluate the effectiveness of 2mm 4 holed 3-dimensional (3D) locking titanium miniplates over standard miniplate fixation using Champy's technique in the management of interforaminal mandibular fractures. PATIENTS AND METHODS: A prospective randomized double blind clinical trial was carried out in patients with well defined inclusion and exclusion criteria. Patients were followed for a period of 2 months at the intervals of 1 week, 2 weeks, 4 weeks, 6 weeks and 2 months by a blinded senior oral surgeon for wound dehiscence, infection, postoperative occlusion, significant postoperative complications, need for post-operative inter maxillary fixation and radiological evaluation of reduction, fixation. RESULT: 10 patients were enrolled in both the groups in this preliminary report with no case of clinically significant postoperative complications. In comparison, 3D locking plates were economical, easy to adapt, required less operating time, and provided better stability. However, 2 patients in group 1 (3D locking plates) with severely displaced unfavourable fractures required 6 holed plates or more for adequate stability. CONCLUSION: Because of its added advantages and encouraging results in comparison to standard miniplate, we suggest use of 3D 4 holed locking 2mm titanium miniplate for the management of isolated moderately displaced mandibular fractures in inter mental foramen region. PMID- 22487271 TI - Density-dependent investment in costly anti-predator defences: an explanation for the weak survival benefit of group living. AB - A central explanation for group living across animal taxa is the reduced rate of attack by predators. However, many field observations show a weak or non-existent effect of group size on per capita mortality rates. Herein we resolve this apparent paradox. We found that Pieris brassicae larvae defended themselves less readily when in groups than when alone, in that they were more reluctant to regurgitate in response to simulated attacks and produced less regurgitant. Furthermore, a simple model demonstrates that this reluctance was sufficient to cancel out the benefit from being in a group. This conditional strategy can be understood in terms of the costs and benefits of defences. For grouped individuals, defence is less often required because attack rates are lower and the costs of defence may be higher due to competition for resources. These phenomena are likely to be widespread in facultatively gregarious species that utilise anti-predator defences. PMID- 22487272 TI - Demodicidosis simulating acute graft-versus-host disease after allogeneic stem cell transplantation in one patient with acute lymphoblastic leukemia. AB - One important differential diagnosis of facial erythema in a patient receiving an allogeneic bone marrow transplant (BMT) is acute graft-versus-host disease (GVHD). Demodex folliculorum has been rarely implicated in the development of facial rashes in immunosuppressed patients, including BMT recipients. We report the case of a patient, suffering from acute lymphoblastic leukemia, who after bone marrow transplantation developed a facial rash due to D. folliculorum mimicking GVHD. Differential diagnosis of facial rashes and demodicidosis after BMT is reviewed. PMID- 22487273 TI - Assessment of exposure to metals in lead processing industries. AB - Inhalation of particulate matter in industrial environments has been associated with respiratory symptoms and lung diseases, which continues to lead to long- and short-term hazardous health effects on exposed subjects. The main objectives of this study were (a) to determine the dust exposure of workers from the lead industry in different operations and (b) to evaluate if the Exhaled Breath Condensate (EBC) can be used as a non-invasive tool to evaluate this exposure. Therefore, this cross-sectional study not only measured the exposure to Airborne Particulate Matter (APM) and to the associated elements but also analysed the EBC elemental composition. APM was collected in Ind1, Ind2, Offices and outdoor with Gent samplers, which delivers two size fractions: fine particulate matter (< 2.5 MUm), and coarse particulate matter (between 2.5 and 10 MUm). EBC samples were collected from the workers and from a non-exposed group working in Offices. The techniques INAA and PIXE were used for the APM element characterization and ICP MS for EBC elemental content. The PM2.5 and PM2.5-10 mass concentrations were significantly higher in the industries studied than in Offices and in the environment. At the industrial sites surveyed the coarse fraction dominated and both factories had different fingerprints: APM elements with higher expression were Pb, Sb, Na, Cl and Fe in Ind1 and Pb, Si, Br, Ca, Al, Cl and Na in Ind2. Most of these elements revealed a gradient of concentration where Ind.1 > Ind.2 > Offices and EBC revealed a clear translation of this exposure, suggesting the latter to be a potential good indicator of exposure to metals in occupational settings. Pb in EBC presented the most representative results. Even though EBC was found to reflect predominantly the inhaled coarser fraction it is more related to concentration levels of exposure than to the predominance of APM fraction. The present study demonstrated not only the ability of EBC to reflect environmental exposure to metals but also the importance of measuring and characterizing different fractions of APM for a correct assessment. PMID- 22487274 TI - Multiple chemical sensitivity: on the scent of central sensitization. AB - BACKGROUND: Multiple Chemical Sensitivity (MCS) is a chronic condition characterized by recurrent, non-specific symptoms in response to chemically unrelated exposures in non-toxic concentrations. Although the pathophysiology of MCS remains unknown, central sensitization may be an important factor contributing to the clinical manifestations. PURPOSE: To use quantitative sensory testing (QST) to study central hyperexcitability and multiple aspects of central sensory processing in MCS patients without comorbid overlapping disorders and to compare the results with those among matched controls. METHODS: 15 MCS patients and 15 healthy matched controls underwent QST to assess the following aspects of pain: capsaicin-induced secondary punctate hyperalgesia, stimulus response function (SRF) to punctate mechanical stimuli before and after capsaicin injection, temporal summation to punctate stimuli post capsaicin injection, pressure pain thresholds, heat pain thresholds, tonic heat stimulation and conditioning pain modulation (CPM: formerly known as diffuse noxious inhibitory control or DNIC). RESULTS: The mean area of capsaicin-induced secondary punctate hyperalgesia was significantly larger in MCS patients than in controls at 5, 30 and 60 min post capsaicin injection (p=0.01). In addition MCS patients reported higher ratings in response to punctate mechanical stimuli assessed by SRF compared with controls (p<0.001). The CPM test induced significantly higher pain ratings in patients than in controls (p=0.002). We found no group differences in pressure pain and heat pain thresholds, temporal summation to punctate stimuli post capsaicin injection, capsaicin and tonic heat pain ratings or CPM effect. CONCLUSION: Increased capsaicin-induced secondary punctate hyperalgesia was demonstrated in MCS patients without comorbid, overlapping disorders, suggesting facilitated central sensitization in MCS. PMID- 22487275 TI - Application of classic epidemiological studies and proteomics in research of occupational and environmental exposure to lead, cadmium and arsenic. AB - The metals/metaloids lead (Pb), cadmium (Cd), and arsenic (As) are among the leading toxic agents in the environment. They represent an important source of dangerous exposure in humans, particularly in industry workers. The most serious consequences of exposure to those heavy metals are cancers and cardiovascular diseases. In studies of human exposure to Pb, Cd, and As alone and in a mixture markers signaling the subtle, early lesions that occur in the human body are still lacking. It is appropriate to develop high throughput techniques and use non-invasive materials. The techniques currently used in classic epidemiological studies allow selection of single markers of changes of exposure to chronic low dose levels of metal/metaloids mixtures. However, application of proteomic techniques in such studies may allow the selection of new biomarkers of environmental and occupational exposure to heavy metals characterized by high sensitivity and specificity. As presented in our review paper, proteomic techniques in combination with appropriate statistical methods allow the selection of potential markers to estimate the changes in the human body when exposed to those heavy metals. PMID- 22487278 TI - Inflammatory cell patterns in the nasal mucosa of patients with idiopathic rhinitis. AB - BACKGROUND: Nonallergic rhinitis comprises many subgroups of rhinitis (vasomotor rhinitis, nonallergic rhinitis with eosinophilia syndrome, occupational rhinitis, idiopathic rhinitis, etc. in which its main feature is known to be free of allergy. We evaluate the cellular infiltrate of subjects with idiopathic rhinitis and compare them with allergic and control counterparts for detecting underlying pathophysiology. METHODS: Subjects selected from patients admitted to Istanbul University Medical Faculty between 2006 and 2009 were classified into idiopathic rhinitis (n = 16; mean age, 26.5 years), allergic rhinitis (n = 17; mean age, 31.1 years), and the control (n = 25, mean age, 28.8 years) groups. Inferior turbinate specimens were collected using Gerritsma forceps. Skin-prick testing was performed. Immunohistochemical detection was performed using B7 (chymase, clone CC1) and G3 (tryptase, clone AA1) primary antibodies for mast cells, human eosinophil major basic protein (clone BMK-13) for eosinophils, and immunoglobulin E (IgE) Ab-1 for mast and plasma cells in epithelium, superficial, and deep submucosa. RESULTS: We found significantly higher levels of mast cells within the different sites of nasal mucosa of allergic and idiopathic subjects compared with normal mucosa (p < 0.05). Additionally, a significant increase was observed in IgE(+) cells of the patients with allergic and idiopathic rhinitis compared with the controls (p < 0.05 for each) Eosinophils were significantly increased within the epithelium of allergic patients' mucosa. CONCLUSION: We seem to have supportive data about possible mechanisms of "idiopathic rhinitis" that suggests local allergic inflammation. The study results provided important information for further provocation and immunohistochemical studies analyzing the shared mechanism of allergic and idiopathic rhinitis. PMID- 22487276 TI - Indoor factors and behavioural problems in children: the GINIplus and LISAplus birth cohort studies. AB - Indoor microbial agents exposure is associated to depressive symptoms in adults and persistent exposure to indoor mould is associated to poorer cognitive function in children. In our study, we aimed to assess the effects of the exposure to indoor factors associated with increased microbial exposure (mould, dampness and pets) on behavioural problems in children aged 10 years, participating in two German birth cohorts. A total of 4860 children were followed until the age of 10 years, and the strengths and difficulties questionnaire (SDQ) was administered to the parents. Indoor factors were assessed through parental reported questionnaires in periodical surveys. Logistic and multinomial regressions adjusting for potential confounders were performed. Prevalences of borderline/abnormal total scores in the SDQ at 10 years of age were higher in children exposed to mould (aOR=1.23, 95%CI=1.00-1.56), dampness (aOR=1.51, 95%CI=1.10-2.07), and pets (aOR=1.48, 95%CI=1.20-1.94). The dimension "emotional symptoms" showed statistically significant risk estimates for mould and pets, meanwhile "conduct problems" and "hyperactivity/inattention" dimensions only did for pets. No significant associations were found for the "peer relationship problems" dimension. We found a significant strong interaction between dampness and pet, the risk of borderline/abnormal scores in the "total difficulties" scale and the "emotional symptoms" dimension for pets' was at least twice the risk in children with reported dampness than in children without. Our findings point to a potential effect of microbial exposure on children's behavioural problems, especially on emotional disorders, probably mediated through neurotoxicity and immune system activation. PMID- 22487277 TI - Comparison of orally exhaled nitric oxide in allergic versus nonallergic rhinitis. AB - BACKGROUND: Fractional exhaled nitric oxide (FeNO), a well-known marker of airway inflammation, is rarely evaluated in rhinitis of different etiology. We aimed to compare the eNO levels in allergic rhinitis (AR) and nonallergic rhinitis (NAR) with/without asthma, as well as the contributing factors that interfere with elevated FeNO. METHODS: Patients were enrolled based on chronic nasal symptoms. Orally exhaled NO was measured with the single exhalation method at 50 mL/s. All subjects underwent a panel of tests: skin-prick tests, asthma control test, blood sampling, spirometry, and health-related quality-of-life questionnaires. RESULTS: The study group consisted of mainly women (130 women/41 men), with a mean age of 32.6 +/- 13.2 years. AR was diagnosed in 122 (78.2%), NAR in 34 (21.8%), and 15 subjects were healthy controls. FeNO was insignificantly higher in patients with AR compared with patients with NAR and controls (32.2 parts per billion [ppb] versus 27 and 19.4 ppb), with no difference between genders. NAR + asthma had higher FeNO than those without asthma (40.5 ppb versus 14.9 ppb; p < 0.03), whereas accompanying asthma did not affect FeNO levels in the AR group. AR +/- asthma had significantly higher FeNO levels than the NAR-only group (p < 0.01). Among AR + asthma, perennial sensitization caused higher FeNO levels than did seasonal allergens (48.5 +/- 33.9 and 19.5 +/- 13.6' p = 0.003), whereas FeNO was significantly higher during the allergen season. Nasally inhaled corticosteroids insignificantly reduced FeNO levels in all groups. Severity and seasonality of rhinitis, asthma, and ocular symptoms, but not gender, age, body mass index, Total IgE, forced expiratory volume in 1 second, and smoking, were associated with FeNO. CONCLUSION: Rhinitis and comorbid asthma are responsible for increased FeNO, irrespective of atopy. However, NAR without asthma may not be considered as a strong risk factor for airway inflammation. PMID- 22487279 TI - Orbital involvement in Pott's puffy tumor: a systematic review of published cases. AB - BACKGROUND: Pott's puffy tumor (PPT) is a frontal subperiosteal abscess associated with underlying frontal bone osteomyelitis. It represents a well-known source of sinogenic intracranial infection, but the orbital complications related to this entity are rarely reported. The goal of this study was to characterize the orbital involvement in PPT. METHODS: We performed a systematic review through a Medline search (1950-2010). The authors reviewed all cases of PPT, selecting those explicitly describing orbital complications associated with PPT. RESULTS: We screened 139 articles, of which 93 reported cases of PPT. Of these, 35 articles described a total of 42 cases presenting simultaneous orbital complications. Eyelid and/or periorbital edema was the most common finding in patients with orbital involvement, and preseptal cellulitis is by far the most prevalent orbital complication in PPT. Postseptal involvement (orbital cellulitis, subperiosteal abscess of the orbit, and orbital abscess) is much rarer. Although treatment of the classic PPT is surgical, only a minority of patients with orbital infection required orbital drainage. Most reported patients made a full recovery, without permanent sequelae. CONCLUSION: Orbital infections are possible in patients with PPT. In contrast to surgical treatment of the frontal subperiosteal abscess, the orbital complications can be treated conservatively most of the time. Early diagnosis and aggressive therapy of the underling PPT are essential to avoid severe local or systemic complications. PMID- 22487280 TI - The effect of topical FK506 (tacrolimus) in a mouse model of allergic rhinitis. AB - BACKGROUND: The management of allergic rhinitis (AR) encompasses education, pharmacotherapy, immunotherapy, and surgery. FK506 (tacrolimus) is an immunosuppressant that inhibits allergic reactions. The purpose of this study was to reveal whether FK506 treatment reduces allergic inflammation in an AR mouse model and to elucidate the mechanisms. METHODS: Forty mice were divided into four groups: control, AR, FK (FK506), and dexamethasone (DEX). All mice except for the control group were sensitized by an i.p. injection of ovalbumin (OVA). After sensitization, the FK and DEX groups were treated with FK506 and DEX intranasally. All sensitized mice were challenged intranasally with OVA. Allergic symptoms and tissue eosinophil counts were recorded. Interleukin (IL)-5, interferon gamma, and IL-10 levels in nasal lavage fluid (NALF) and serum OVA specific IgE levels were measured. T-bet, GATA-3, and Foxp3 mRNA expression in splenic mononuclear cells were determined by real-time polymerase chain reaction. RESULTS: In the FK group and DEX group, allergic symptoms, serum OVA-specific IgE, tissue eosinophil counts, IL-5 in NALF, and GATA-3 mRNAs expression decreased (p < 0.05), and IL-10 in NALF and Foxp3 mRNAs expression increased compared with the AR group (p < 0.05). No significant difference was observed between the FK group and the DEX group. CONCLUSION: These results suggest that topical FK506 may reduce allergic inflammation and have potency equal to DEX in the AR model. This mechanism may involve not only Th2 cells but also regulatory T cells. Additional studies are needed on FK506, but in the future, we can consider FK506 as an alternative to topical steroids in the treatment of AR. PMID- 22487281 TI - Surfactant protein A and D in chronic rhinosinusitis with nasal polyposis and corticosteroid response. AB - BACKGROUND: Corticosteroids are a mainstay of treatment for chronic rhinosinusitis with nasal polyposis (CRSwNP). Data related to the effect of systemic methylprednisolone on surfactant protein (SP) expression in CRSwNP is limited. This study aimed to reveal the consequences of systemic methylprednisolone treatment on levels of SP-A and SP-D, which play a role in innate immunity, in patients with CRSwNP. METHODS: Twenty-one patients with CRSwNP were included in the study, along with 15 control patients scheduled for dacryocystorhinostomy. A polypoid tissue biopsy was taken under local anesthesia, and 15 CRSwNP patients were scheduled for endoscopic sinus surgery after 3 weeks of oral methylprednisolone. Posttreatment biopsies were performed perioperatively. Pre- and posttreatment endoscopic polyp grades were determined, as were symptom scores regarding nasal obstruction, headache, and nasal discharge using a visual analog scale (VAS). SP-A and SP-D levels were measured using enzyme-linked immunosorbent assay and the results were compared. RESULTS: All patients reported relief from clinical symptoms through VAS after methylprednisolone treatment. The posttreatment polyp grade was reduced (p < 0.0001). SP-A and SP-D levels did not yield a significant difference between CRSwNP patients and controls (p = 0.25 and p = 0.13, respectively). Statistically significant up-regulation was detected in SP-A and SP-D levels after oral methylprednisolone (p = 0.0002 and p = 0.0004, respectively). CONCLUSION: In this study, significant up-regulation of SP-A and SP-D was revealed in patients with CRSwNP after systemic steroid treatment. The role of SP-A and SP-D up-regulation in CRSwNP pathogenesis and therapeutic outcomes of corticosteroids have potential importance for the introduction of new therapeutic modalities that are more effective and produce fewer adverse effects. PMID- 22487282 TI - Effects of statins on the recovery of olfactory function in a 3-methylindole induced anosmia mouse model. AB - BACKGROUND: Despite the importance of olfactory function, no effective medications have been identified to treat olfactory disorders. This study was performed to evaluate the functional recovery of olfaction damaged by 3 methylindole (3MI) in a mouse model with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins). METHODS: In a randomized placebo-controlled trial, 24 healthy female BALB/c mice (aged 9-10 weeks and weighing 18-20 g each) were randomly allocated to statin-treated or control groups. Olfactory loss was induced by i.p. injections of 3MI. Atorvastatin (10 mg/kg) or normal saline was then administered per os with a gastric tube for 3 weeks. The effects of treatment were evaluated by food-finding tests and Western blot analysis. RESULTS: Both groups showed complete losses of olfactory function 1 week after 3MI injection. Three weeks after 3MI injection, 9 of the 12 mice in the statin treated group (75%) passed a food-finding test, in which they were able to find the food within 3 minutes, at least two times out of three trials. However, only two mice in the control group (16.6%) passed the food-finding test, and this difference was statistically significant (p = 0.004; chi-square test). The expression level of the olfactory marker protein was also elevated in the statin treated group (p = 0.030; Wilcoxon rank sum test). CONCLUSION: Statins are associated with recovery of olfaction after 3MI injection in a mouse model. PMID- 22487283 TI - Management of the nasolacrimal system during transnasal endoscopic medial maxillectomy. AB - BACKGROUND: During transnasal endoscopic medial maxillectomy (TEMM) for sinonasal tumors, the nasolacrimal duct (NLD) is resected as it forms part of the medial wall of the maxillary sinus. This disrupts the nasolacrimal drainage system. To ensure that epiphora does not develop after such resection, an endoscopic dacryocystorhinostomy (DCR) is traditionally performed. This is based primarily on prior experience with open medial maxilloethmoidectomy. It is unclear whether a concurrent DCR during endoscopic medial maxillectomy is necessary, however. This study was designed to compare patients undergoing TEMM with or without concurrent DCR for postoperative patency of the NLD. METHODS: This is a prospective cohort study comparing12 patients undergoing TEMM, 5 with concurrent DCR and 7 without, to assess for patency of the NLD system. In the group that underwent a concurrent DCR, a Jones silastic stent was inserted for 2-3 months. Patients were followed for a minimum of 1 year for assessment of epiphora. The patency of the NLD was judged by clinical and qualitative evidence for epiphora. RESULTS: None of the patients in either group developed epiphora. All were completely symptom free for epiphora during the follow-up period. CONCLUSION: It appears that after TEMM, patients do not develop epiphora, whether or not a concurrent DCR is performed. Hence, a concurrent DCR does not seem necessary during TEMM. PMID- 22487284 TI - Immunological parameters associated with the development of allergic rhinitis: a preliminary prospective study. AB - BACKGROUND: Many subjects are sensitized to Japanese cedar pollen but do not develop allergic rhinitis (AR). The aim of this study was to examine the immunologic parameters related to the development of AR in sensitized subjects. METHODS: The subjects were 33 adults who were sensitized to Japanese cedar pollen, but had not developed as of 2007. Cedar pollen-specific IgE (sIgE) and total IgE (tIgE) in serum, cedar pollen antigen (Cry j 1) Cry j-specific memory Th2 cell clone size, and the Cry j-specific induced regulatory T cell (iTreg) level were examined before and after the season in 2008. RESULTS: Eight of the 33 subjects developed cedar pollinosis. The sIgE titers before the season in these eight subjects did not differ from those in the subjects who did not develop pollinosis, but the titers after the season were significantly higher in the group that developed pollinosis. The sIgE/tIgE ratio increased in almost all subjects, but the ratio was significantly higher before the season in the subjects who developed pollinosis. Cry j-specific Th2 cells were detected in all subjects, but the clone size only increased in those that developed pollinosis. The Cry j-specific iTreg population did not differ between the two groups. CONCLUSION: A high sIgE/tIgE ratio before the season may be predictive of development of pollinosis, and an increase in the allergen-specific Th2 clone size during the pollen season could be a biomarker for pollinosis. The role of allergen-specific iTreg cells in the development of pollinosis could not be clarified in this preliminary study. PMID- 22487285 TI - Effect of [6]-gingerol on myofibroblast differentiation in transforming growth factor beta 1-induced nasal polyp-derived fibroblasts. AB - BACKGROUND: [6]-Gingerol is one of the major pungent principles of ginger and has diverse effects, including anti-inflammatory, and antioxidative effects. Reactive oxygen species (ROS) are released during the phenotypic transformation of fibroblasts to myofibroblasts, a process that is involved in the growth of nasal polyps by inducing extracellular matrix (ECM) accumulation. The purpose of this study was to determine the effect of [6]-gingerol on myofibroblast differentiation and collagen production of nasal polyp-derived fibroblasts (NPDFs) and to determine if the effect of [6]-gingerol is linked to an antioxidant effect. METHODS: NPDFs were incubated and treated with transforming growth factor (TGF) beta 1. The ROS generated by NPDFs were determined using 2",7"-dichlorfluorescein-diacetate. The fluorescence was captured by a fluorescent microscope and measured using a fluorometer. The expression of alpha smooth muscle actin (SMA) and collagen type IV mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of alpha-SMA protein and pSmad2/3 was determined by immunofluorescence microscopy and or Western blotting. The amount of total soluble collagen production was analyzed by the SirCol collagen dye-binding assay. RESULTS: TGF-beta 1 stimulation increased ROS production by NPDFs. [6]-Gingerol decreased the production of ROS in TGF-beta 1 induced NPDFs. Myofibroblast differentiation, collagen production, and phosphorylation of Smad2/3 were prevented by [6]-gingerol and inhibition of ROS generation with antioxidant such as diphenyliodonium, N-acetylcysteine, and ebselen. CONCLUSION: These results suggest the possibility that [6]-gingerol may play an important role in inhibiting the production of the ECM in the development of nasal polyps through an antioxidant effect. PMID- 22487286 TI - Chronic rhinosinusitis, race, and ethnicity. AB - BACKGROUND: Little is known regarding the epidemiology of chronic rhinosinusitis (CRS) in racial and ethnic minorities in the United States. This study was designed to comprehensively evaluate the current prevalence of CRS across various treatment settings to identify possible disparities in health care access and use between racial and ethnic populations. METHODS: The National Health Interview Survey (NHIS), National Ambulatory Medical Care Survey (NAMCS), and National Hospital Ambulatory Medical Care Survey (NHAMCS) database registries were extracted to identify the national prevalence of CRS in race/ethnic populations and resource use in ambulatory care settings. Systematic literature review identified studies reporting treatment outcomes in minority patients electing endoscopic sinus surgery (ESS). Data were supplemented using a multi institutional cohort of patients undergoing surgical treatment. RESULTS: National survey data suggest CRS is a significant health condition for all major race/ethnic groups in the United States, accounting for a sizable portion of office, emergency, and outpatient visits. Differences in insurance status, work absenteeism, and resource use were found between race/ethnic groups. Despite its prevalence, few published studies include information regarding minority patients with CRS. Most (90%) cohort studies did not provide details of race/ethnicity for ESS outcomes. Prospective cohort analysis indicated that minority surgical patients accounted for only 18%, when compared with national census estimates (35%). CONCLUSION: CRS is an important health condition for all major race/ethnic groups in the United States. Significant differences may exist across racial and ethnic categories with regard to CRS health status and health care use. Given current demographic shifts in the United States, specific attention should be given to understanding CRS within the context of racial and ethnic populations. Public clinical trial registration (www.clinicaltrials.gov) I.D. No. NCT00799097. PMID- 22487287 TI - The significance of computed tomographic findings in the diagnosis of fungus ball in the paranasal sinuses. AB - BACKGROUND: Sinus fungus ball (SFB), previously termed mycetoma of the paranasal sinus is a type of noninvasive fungal rhinosinusitis and the treatment of choice for this condition is functional endoscopic sinus surgery. Predicting the possibility of SFB by performing preoperative computed tomography (CT) is important to ensure appropriate treatment. Various studies have reported the CT findings of SFB. We aimed to investigate the relationship between CT features and SFB to increase the preoperative diagnostic accuracy of CT. METHODS: Based on a literature review, we selected six CT features of SFB including calcification, erosion of the inner wall of the sinus, sclerosis of sinus lateral wall, heterogeneous opacification of sinus, absence of an air-fluid level, and sinus mucosal thickening. From January 2004 to February 2010, 96 SFB patients and 72 unilateral chronic rhinosinusitis (CRS) patients were enrolled in this study. Preoperative CT images of all of the patients were interpreted by a radiologist and an otolaryngologist. RESULTS: All of the CT features except mucosal thickening showed statistically significant differences between SFB and CRS group patients. After adjusting for these CT features in a multiple logistic regression model, only the two features, viz., calcification and erosion of the inner wall of the sinus, were found to have a significant positive association with SFB. CONCLUSION: We found that five CT features, particularly calcification and erosion of the inner wall of the sinus, increase the diagnostic accuracy of CT for SFB, and this ensures that the patient receives appropriate treatment. PMID- 22487288 TI - Functional limitations and workdays lost associated with chronic rhinosinusitis and allergic rhinitis. AB - BACKGROUND: Chronic rhinosinusitis (CRS) and allergic rhinitis are associated with functional limitations, but these impacts are not known on a population basis. Our objective was to epidemiologically determine functional limitations and workdays lost that are associated with CRS and allergic rhinitis in adults. METHODS: The Medical Expenditure Panel Survey for calendar year 2007 was examined to identify cases of CRS and allergic rhinitis. Functional limitation variables for activity limitation, work limitation, social limitation, and cognitive limitation determined by the survey also were extracted. Using multivariate models adjusting for age, gender, race, ethnicity, education level, insurance status, geographic region, as well as the Charlson comorbidity index, incremental differences in workdays lost and these functional limitations were determined for patients with and without CRS and allergic rhinitis. RESULTS: Among 225.1 million adults, the prevalences of CRS and allergic rhinitis were 4.9 +/- 0.2% and 7.9 +/- 0.3%, respectively. Patients with CRS demonstrated an incremental 1.04 +/- 0.3 workdays lost per year along with significant increased adjusted odds ratios for activity limitation (odds ratio, 1.54), work limitation (1.50), and social limitation (1.49, all p < .005) but not cognitive limitation (1.05, p = .213). Patients with allergic rhinitis demonstrated an incremental 0.60 +/- 0.45 workdays lost along with significant increased adjusted odds ratios for activity limitation (1.42), work limitation (1.43), social limitation (1.47), and cognitive limitation (1.32, all p < .019). CONCLUSIONS: Both CRS and allergic rhinitis impart significantly increased odds ratios for activity, work, and social limitations. Allergic rhinitis also carries with it statistically significant odds of functional cognitive limitation. The total aggregate workdays missed in the United States may be estimated at 11.5 million workdays and 10.7 million workdays for CRS and allergic rhinitis, respectively. PMID- 22487289 TI - Pilot evaluation of the nasal nitric oxide response to humming as an index of osteomeatal patency. AB - BACKGROUND: Paranasal sinuses are reservoirs for nitric oxide (NO), and humming facilitates nasal diffusion of NO. The nasal NO response to humming has previously been shown to be blunted with chronic sinusitis and nasal polyposis. We hypothesized that the nasal NO response to humming will be proportional to radiographic osteomeatal patency when comparing allergic rhinitis (AR) patients (without chronic sinusitis) with normal controls. METHODS: Nonsmoking subjects completed questionnaires and skin-prick testing. Subjects underwent sinus CT scanning, followed by exhaled (oral) and nasal NO sampling (with and without humming). Humming-to-quiet (H/Q) nasal NO ratios were calculated. Three dimensional reconstructions were used to trace the osteomeatal complex (OMC) and measure minimum cross-sectional area. Lund-Mackay scores were also documented. RESULTS: A total of 33 subjects (22 women; mean age, 35.5 years) completed the study. Seventeen AR patients (5 IAR and 12 PAR) participated, as did 16 nonallergic controls. Among controls, quiet nasal NO levels--corrected for fractional exhaled NO--rose significantly with OMC area and fell significantly with Lund-Mackay scores (p < 0.05). However, we observed no proportionality between H/Q ratio and radiographic OMC patency. CONCLUSION: Analysis of nasal NO samples taken under quiet conditions from normal controls was consistent with the paranasal sinuses acting as a reservoir of nasal NO and with OMC patency acting as a significant factor in NO diffusion. However, our results did not support a relationship between the nasal NO response to humming and radiographic OMC patency in a sample excluding subjects with severe rhinosinusitis. PMID- 22487290 TI - A comparison of the psychometric properties of the Mini-Rhinitis Quality of Life Questionnaire and the Rhinitis Control Assessment Test. AB - BACKGROUND: The relationships between validated quality of life tools and control tools have not been explored for rhinitis. This study was designed to determine relationships of the Mini-Rhinitis Quality of Life Questionnaire (MiniRQLQ) and the Rhinitis Control Assessment Test (RCAT) to each other regarding content and predictive abilities. METHODS: Participants were adult members of a large integrated care organization with an encounter diagnosis of rhinitis in the prior 2 years. Patients completed mailed questionnaires at baseline that contained the MiniRQLQ and the RCAT and three follow-up questionnaires that contained those tools as well as questions regarding missed work or school because of rhinitis and frequency and effectiveness of medications used for rhinitis. Medications dispensed during the follow-up year were obtained from computerized pharmacy records. Results of allergy tests were retrieved for patients seen in the Allergy Department. RESULTS: The final cohort included 1051 patients. Baseline RCAT scores were strongly correlated with baseline MiniRQLQ scores in both allergic (r = -0.80) and nonallergic (r = -0.84) patients. Baseline MiniRQLQ and RCAT scores were significantly related to patient reports of missed school/work, medication use, and effectiveness over the next 3 months and to dispensing during the following year of total and some individual rhinitis medications. Test retest reliability, responsiveness, and a preliminary minimal important difference (>2.5) were shown for the RCAT, using the MiniRQLQ as an anchor. CONCLUSION: The MiniRQLQ and RCAT are strongly related to each other and both predict subsequent rhinitis outcomes. Determining the comparative usefulness of these tools will require further study. PMID- 22487291 TI - Immunomodulatory treatments for aspirin exacerbated respiratory disease. AB - BACKGROUND: Aspirin triad is a subclass of chronic sinusitis characterized by nasal polyposis, nonallergic induced asthma, and aspirin sensitivity. Also known as Samter's triad or aspirin-exacerbated respiratory disease, aspirin triad commonly affects the adult population and is seldom found in pediatric patients. METHODS: This rhinosinusitis has multiple layers of pathological process, but the ultimate predicament is caused by cysteinyl leukotrienes (cysLTs). RESULTS: Pharmacotherapies include oral steroid, lipoxygenase inhibitor, and cysLT receptor inhibitor drugs, which can provide some relief for these patients. CONCLUSION: Immunomodulation via aspirin desensitization is considered when pharmacotherapy has failed. When aspirin triad is unmanageable with medical treatment alone, endoscopic sinus surgery with polypectomy can alleviate the patient's symptoms, allowing for a better response to postoperative medical management such as topical medication as well as delivery of topical medications. PMID- 22487292 TI - Antifungal therapy in the treatment of chronic rhinosinusitis: a meta-analysis. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is an inflammatory disorder of the nose and sinuses. Because fungi were postulated as a potential cause of CRS in the late 1990s, contrasting articles have advocated and refuted the use of antifungal agents in its management. Although good research shows an interaction of the immune system with fungus in CRS, e.g., allergic fungal sinusitis (AFS), this does not imply that fungi are the cause of CRS or that antifungals will be effective in management. This study was designed to assess the potential advantage of either topical or systemic antifungal therapy in the symptomatic treatment of CRS to aid physicians in making informed decisions about treating patients with CRS. METHODS: A systematic review of the literature was performed with meta-analysis. All studies obtained from searches were reviewed and trials meeting the eligibility criteria were selected. CRS was defined using either the European Position Paper on Rhinosinusitis and Nasal Polyps or American Academy of Otolaryngology-Head and Neck Surgery criteria. Authors were contacted and original data were used for data analysis. RESULTS: Five studies investigating topical antifungals and one investigating systemic antifungals met the inclusion criteria. All trials were double blinded and randomized. Pooled meta-analysis showed no statistically significant benefit of topical or systemic antifungals over placebo. Symptoms scores statistically favored the placebo group for this outcome. Adverse event reporting was higher in the antifungal group. CONCLUSION: Reported side-effects of antifungal therapies may outweigh any potential benefits of treatment based on this meta-analysis and the authors therefore do not advocate the use antifungal treatment in the management of CRS. PMID- 22487293 TI - Endoscopic frontal sinus drainage Draf type III with mucosal transplants. AB - BACKGROUND: This study was designed to evaluate the extent of restenosis that occurs after an endoscopic frontal sinus drainage Draf type III (Draf III; modified Lothrop procedure) using a modified technique with reconstruction of the frontal sinus drainage pathway with mucosal transplants, in combination with occlusive postoperative care. METHODS: Retrospective case series was performed with 24 consecutive patients undergoing Draf III drainage between 2005 and 2010 using the modified technique of covering the bare bone with mucosal transplants from the nasal septum. To ensure optimal moist wound healing, occlusion of the nose was realized by taping the nose for 2 weeks postoperatively. Frontal ostium measurements were done intraoperatively and at follow-up visits for a minimum of 12 months. Data on patient history, demographics, comorbidities, and computed tomography scans were collected. RESULTS: Mean follow-up was 25.6 months. Eight patients were lost to follow-up. Ninety-four percent of frontal sinus neo-ostia remained open. One patient needed revision surgery using an osteoplastic flap with obliteration. The frontal neo-ostium narrowed by an average of 36.9% from 20.5 * 12.5 to 15 * 9.6 mm. On average, three visits were needed for postoperative care. The patients did not experience significant pain throughout the postoperative healing time. CONCLUSION: The modified Lothrop procedure is a well-established technique in endoscopic sinus surgery to handle difficult frontal sinus drainage pathways or revision surgeries. The modified technique provides good results in combination with minimized postoperative care and morbidity. A comparative study would be necessary to show superiority to the standard method of Draf III. PMID- 22487296 TI - Clinical analysis of deep cutaneous mycoses: a 12-year experience at a single institution. AB - Deep cutaneous mycoses can cause significant morbidity and mortality, especially in immunocompromised patients. There have been few studies focusing on deep cutaneous mycoses and there are no data from Asian countries. This study aimed to investigate clinical characteristics, underlying predisposing factors, aetiological organisms and outcomes in patients with deep cutaneous mycoses. A retrospective medical record review of patients with deep cutaneous mycoses treated at a tertiary referral centre in Korea from 1999 to 2010. Forty-one cases of deep cutaneous mycosis were identified (median age: 49). Most patients (32/41) had impaired immunological status, and seven of the remaining nine had a history of physical trauma. Neutropenia and long-term use of antibiotics were detected in 13 and 12 patients respectively. Nodular skin lesions were the most common type (17/41) and the morphology of the lesions varied. Fungal organisms were identified by culture and histopathology of skin specimens. Candida (16/41) was the most common organism, followed by Aspergillus, Alternaria, Fusarium (4/41 each). Systemic antifungal treatment was successful in 28 patients, while nine patients died from the fungal infection. Our study may lead to improved insights into deep cutaneous mycoses as their incidence is increasing and they vary in different clinical settings. PMID- 22487294 TI - Inverted papillomas and benign nonneoplastic lesions of the nasal cavity. AB - BACKGROUND: Benign lesions of the nasal cavity represent a diverse group of pathologies. Furthermore, each of these disorders may present differently in any given patient as pain and discomfort, epistaxis, headaches, vision changes, or nasal obstruction. Although these nasal masses are benign, many of them have a significant capacity for local tissue destruction and symptomatology secondary to this destruction. Advances in office-based endoscopic nasendoscopy have equipped the otolaryngologist with a safe, inexpensive, and rapid means of directly visualizing lesions within the nasal cavity and the initiation of appropriate treatment. METHODS: The purpose of this study is to review the diagnosis, management, and controversies of many of the most common benign lesions of the nasal cavity encountered by the primary care physician or otolaryngologist. RESULTS: This includes discussion of inverted papilloma (IP), juvenile angiofibroma, squamous papilloma, pyogenic granuloma, hereditary hemorrhagic telangiectasia, schwannoma, benign fibro-osseous lesions, and other benign lesions of the nasal cavity, with particular emphasis on IP and juvenile angiofibroma. CONCLUSION: A diverse array of benign lesions occur within the nasal cavity and paranasal cavities. Despite their inability to metastasize, many of these lesions have significant capability for local tissue destruction and recurrence. PMID- 22487297 TI - Characterization of alpha-smooth muscle actin positive cells during multilineage differentiation of dental pulp stem cells. AB - OBJECTIVES: Dental pulp tissue contains stem cells that can differentiate into multiple lineages under specific culture conditions; the origin of these dental pulp stem cells, however, is still unknown. MATERIALS AND METHODS: Here we have utilized an alpha-SMA-GFP transgenic mouse model to characterize expression of a smooth muscle actin (SMA)-GFP in subpassages of pulp-tissue-derived dental pulp cells, as perivascular cells express alpha-SMA. RESULTS: During subculturing, percentages of cells expressing a-SMA increased significantly from passage 1 to 3. alpha-SMA-GFP-positive cells expanded faster than alpha-SMA-GFP-negative cells. The dental pulp cells at passage 3 were induced towards osteogenic, adipogenic or chondrogenic differentiation. All three differentiated cell lines expressed high levels of alpha-SMA (mineralized nodules, lipid droplets and chondrocyte pellets). GFP expression colocalized with differentiated osteoblasts, adipocytes and chondrocytes. Co-culturing the alpha-SMA-GFP-positive cells with human endothelial cells promoted formation of tube-like structures and robust vascular networks, in 3-D culture. CONCLUSIONS: Taken together, the a-SMA-GFP positive cells were shown to have multilieange differentiation ability and to promote vascularization in a co-culture system with endothelial cells. PMID- 22487299 TI - 25 hydroxyvitamin D serum levels influence adequate response to bisphosphonate treatment in postmenopausal osteoporosis. AB - It remains unclear whether vitamin D sufficiency optimizes response to bisphosphonate (BP) treatment in postmenopausal osteoporosis. We evaluated the role and possible mechanisms of vitamin D in adequate response to standard BP treatment for postmenopausal osteoporosis. METHODS: We included 120 postmenopausal osteoporotic women (aged 68 +/- 8 years) receiving BP (alendronate or risedronate) at their annual follow-up, performing complete anamnesis, including treatment adherence, use of vitamin D supplements, and previous falls and fractures during the last year. We analyzed the evolution of bone mineral density (BMD) during this period and serum PTH and 25 hydroxyvitamin D (25(OH)D) and urinary NTx levels. Patients were classified as inadequate responders to antiosteoporotic treatment based on BMD loss>2% and/or the presence of fragility fractures during the last year. RESULTS: Thirty percent of patients showed inadequate response to BP treatment, with significantly lower levels of 25(OH)D (22.4 +/- 1.3 vs. 26.6 +/- 0.3 ng/ml, p=0.01), a higher frequency of 25(OH)D levels<30 ng/ml (91% vs. 69%, p=0.019) and higher urinary NTx values (42.2 +/- 3.9 vs. 30.9 +/- 2.3 nM/mM, p=0.01). Patients with 25(OH)D>30 ng/ml had a greater significant increase in lumbar BMD than women with values <30 ng/ml (3.6% vs. 0.8%, p<0.05). The probability of inadequate response was 4-fold higher in patients with 25(OH)D<30 (OR, 4.42; 95% CI, 1.22-15.97, p=0.02). CONCLUSIONS: Inadequate response to BP treatment is frequent in postmenopausal women with osteoporosis as is vitamin D insufficiency, despite vitamin D supplementation. Maintenance of 25(OH)D levels >30 ng/ml is especially indicated for adequate response to BP treatment. PMID- 22487300 TI - Effect of venipuncture quality on thromboelastography. AB - OBJECTIVE: To determine if the quality of venipuncture impacts thromboelastography (TEG) results and if an initial discard tube mitigates any effects of traumatic venipuncture. DESIGN: Prospective, observational study. SETTING: Veterinary teaching hospital. ANIMALS: Fifteen privately owned and research colony adult dogs. MEASUREMENTS: Samples were collected from each jugular vein using 1 of 2 venipuncture techniques per vein. The venipuncture technique was randomized to the vein as follows: (1) "clean" venipuncture (CV) from 1 jugular vein, and (2) suboptimal venipuncture (SOV) from the opposite jugular vein. CV was defined as a direct entry into the vein on the first attempt. SOV was defined as needle insertion adjacent to the vein with redirection at least once to enter the vein. Two consecutive samples were collected from each venipuncture without removal of the needle, yielding 4 samples: CV1, CV2, SOV1, and SOV2. TEG was performed on each blood sample and the TEG parameters R, K, alpha, and MA were recorded. RESULTS: Mean +/- SD of R for the SOV1 group (4.1 +/- 1.3 s) was significantly shorter than that of the CV1 group (5.7 +/- 1.4 s) and the SOV2 group (5.5 +/- 1.9 s), P< 0.05. There was no difference in R between CV1 and CV2 groups, or between SOV2 and either CV1 or CV2. There was no significant difference in alpha, K, or MA among groups. CONCLUSIONS: Mild-to-moderate venipuncture trauma had little effect on TEG overall, but R was significantly affected. Poorer quality collection resulted in a more rapid initiation of clot formation. However, the effect was mild and mitigated by testing samples in a second collection tube after discard of an initial sample. PMID- 22487298 TI - Effects of aging on articular cartilage homeostasis. AB - This review is focused on aging-related changes in cells and extracellular matrix of the articular cartilage. Major extracellular matrix changes are a reduced thickness of cartilage, proteolysis, advanced glycation and calcification. The cellular changes include reduced cell density, cellular senescence with abnormal secretory profiles, and impaired cellular defense mechanisms and anabolic responses. The extracellular and cellular changes compound each other, leading to biomechanical dysfunction and tissue destruction. The consequences of aging related changes for joint homeostasis and risk for osteoarthritis are discussed. This article is part of a Special Issue entitled "Osteoarthritis". PMID- 22487301 TI - Live attenuated H5N1 vaccine with H9N2 internal genes protects chickens from infections by both highly pathogenic H5N1 and H9N2 influenza viruses. AB - BACKGROUND: The highly pathogenic H5N1 and H9N2 influenza viruses are endemic in many countries around the world and have caused considerable economic loss to the poultry industry. Objectives We aimed to study whether a live attenuated H5N1 vaccine comprising internal genes from a cold-adapted H9N2 influenza virus could protect chickens from infection by both H5N1 and H9N2 viruses. METHODS: We developed a cold-adapted H9N2 vaccine virus expressing hemagglutinin and neuraminidase derived from the highly pathogenic H5N1 influenza virus using reverse genetics. RESULTS AND CONCLUSIONS: Chickens immunized with the vaccine were protected from lethal infections with homologous and heterologous H5N1 or H9N2 influenza viruses. Specific antibody against H5N1 virus was detected up to 11 weeks after vaccination (the endpoint of this study). In vaccinated chickens, IgA and IgG antibody subtypes were induced in lung and intestinal tissue, and CD4+ and CD8+ T lymphocytes expressing interferon-gamma were induced in the splenocytes. These data suggest that a live attenuated H5N1 vaccine with cold adapted H9N2 internal genes can protect chickens from infection with H5N1 and H9N2 influenza viruses by eliciting humoral and cellular immunity. PMID- 22487302 TI - Overexpression of cannabinoid CB2 receptor in the brain induces hyperglycaemia and a lean phenotype in adult mice. AB - It is well known that the endocannabinoid system, through cannabinoid CB1 receptor activation, has an important role in the main aspects of energy balance (i.e. food intake, energy expenditure and glucose and fat metabolism), orchestrating all the machinery involved in body weight control and energy homeostasis. A number of studies have revealed a crucial role of brain CB1 receptors in these processes. However, functional cannabinoid CB2 receptors have also been described in the brain, with no studies addressing their putative role in body weight control and glucose homeostasis. We have tested this hypothesis by analysing fasting-induced feeding, body weight, some hypothalamic neuropeptides, glucose tolerance and plasma hormones in an animal model specifically overexpressing CB2 receptors in the central nervous system. We found that specific overexpression of CB2 receptors in the brain promoted higher basal glucose levels, decreased fasting-induced feeding and, eventually, led to a lean phenotype and glucose intolerance. These findings could not be attributed to decreased locomotor activity, increased anxiety or depressive-like behaviours. The expression of relevant neuropeptides such as pro-opiomelanocortin and galanin in the arcuate nucleus of the hypothalamus was altered but not those of the CB1 receptor. Indeed, no changes in CB1 expression were found in the liver, skeletal muscle and adipose tissue. However, cannabinoid CB1 and CB2 receptor expression in the endocrine pancreas and glucagon plasma levels were decreased. No changes in plasma adiponectin, leptin, insulin and somatostatin were found. Taken together, these results suggest a role for central cannabinoid CB2 receptors in body weight control and glucose homeostasis. PMID- 22487303 TI - Metabolic, mental health, behavioural and socioeconomic characteristics of migrants with Chagas disease in a non-endemic country. AB - OBJECTIVES: Chronic Chagas disease causes cardiopathy in 20-40% of the 8-10 million people affected. The prevalence of atherogenic factors increases rapidly in Latin America. Somatic, mental, behavioural and social characteristics of the 80,000 Latino migrants with Chagas disease in Europe are not known. We postulate that they may accumulate these factors for poor health--notably cardiovascular outcomes. METHODS: This study took place at the Geneva University Hospitals in 2011. Latin American migrants with Chagas disease diagnosed in Geneva since 2008 were contacted. Interviews and blood tests assessed behavioural, socioeconomic, metabolic and cardiovascular factors. RESULTS: One hundred and thirty-seven patients (women: 84.7%; median age: 43 years) with chronic Chagas disease were included in the study. The majority were Bolivians (94.2%), undocumented (83.3%), uninsured (72.3%) and living below the Swiss poverty line (89.1%). Prevalence of obesity was 25.5%, of hypertension 17.5%, of hypercholesterolemia 16.1%, of impaired fasting glucose 23.4%, of diabetes 2.9%, of metabolic syndrome 16.8%, of anxiety 58.4%, of depression 28.5%, of current smoking 15.4% and of sedentary lifestyle 62.8%. High (>10%) 10-year cardiovascular risk affected 12.4%. CONCLUSIONS: Latin American migrants with Chagas disease accumulate pathogenic chronic conditions of infectious, non-transmissible, socioeconomic and behavioural origin, putting them at high risk of poor health, notably cardiovascular, outcomes. This highlights the importance of screening for these factors and providing interventions to tackle reversible disorders; facilitating access to care for this hard-to-reach population to prevent delays in medical interventions and poorer health outcomes; and launching prospective studies to evaluate the long-term impact of these combined factors on the natural course of Chagas disease. PMID- 22487304 TI - Epidemiology of Aspergillus keratitis at a tertiary care eye hospital in South India and antifungal susceptibilities of the causative agents. AB - In recent years, Aspergillus species are reported frequently as aetiological agents of fungal keratitis in tropical countries such as India. Our aim was to evaluate the epidemiological features of Aspergillus keratitis cases over a 3 year period in a tertiary eye care hospital and to determine the antifungal susceptibilities of the causative agents. This study included culture proven Aspergillus keratitis cases diagnosed between September 2005 and August 2008. Data including prevalence, predisposing factors and demography were recorded, the isolates were identified by morphological and molecular methods and the minimum inhibitory concentration values of antifungal agents towards the isolates were determined by the microdilution method. Two hundred Aspergillus isolates were identified among 1737 culture proven cases. Most of the aspergilli (75%) proved to be A. flavus, followed by A. fumigatus (11.5%). Sixteen (8%) isolates belonged to species that are recently identified causative agents of mycotic keratitis. Most of the infected patients (88%) were adults ranging from 21 to 70 years of age. Co-existing ocular disease was confirmed in 16.5% of the patients. Econazole, clotrimazole and ketoconazole were notably active against A. flavus. Aspergillus keratitis is a significant problem in patients with ocular lesions in South-Indian States, warranting early diagnosis and initiation of specific antifungal therapy to improve outcome. PMID- 22487305 TI - Localized neurofibromatosis of the female genital system: a case report and review of the literature. AB - Neurofibromatosis within the female genital tract is uncommon. The vulva is the most frequent genital location, but it has rarely been reported in the context of the vagina, uterine cervix or ovaries. In spite of its rarity, neurofibroma is a neoplasm that should be considered in the differential diagnosis of pelvic masses, especially in patients with neurofibromatosis. In this paper we describe the case of a 71-year-old patient with pelvic pain and a uterine mass who underwent a hysterectomy after having been diagnosed with an 11-cm neurofibroma occupying the myometrium of the entire uterine corpus. There were no neurofibromas in the endometrium, serosa, fallopian tubes or ovaries. The patient had an unknown von Recklinghausen's disease. PMID- 22487306 TI - Malfunction of the da Vinci robotic system in urology. AB - OBJECTIVES: To analyze the incidence of malfunction of the da Vinci robotic system in a single center and to provide potential solutions. METHODS: A total of 400 patients underwent da Vinci robotic urological surgery at Taichung Veterans General Hospital in Taichung, Taiwan, from December 2005 to April 2011. Episodes of malfunction of the robotic system were analyzed by period of operation, type of procedure, type of malfunction and management of the event. RESULTS: Overall, 14 cases of malfunction occurred (3.5% of the entire series). Among them, five (1.25%) occurred before the surgery and nine (2.25%) intraoperatively. Operative procedures included radical prostatectomy, bilateral pelvic lymph node dissection, dismembered pyeloplasty, partial nephrectomy, nephroureterectomy, and radical and partial cystectomies. Areas of malfunctions included the robotic arm system and joint (11/14), optical system (1/14), power system and connector (1/14), endoscopic instrument (1/14), and software (1/14). In 10 cases, the failure was recoverable, whereas in four cases there was a critical failure, requiring a conversion to standard laparoscopy in three of them, and the rescheduling of the surgery in one case. CONCLUSIONS: The da Vinci robotic system is extremely reliable for use in urology. Malfunction is rare and the risk of critical failure is very low. Managing mechanical failure before or during the surgery is the key to maintaining the safety of patients undergoing robotic surgical procedures. PMID- 22487307 TI - A S-adenosylmethionine methyltransferase-like domain within the essential, Fe-S containing yeast protein Dre2. AB - Yeast Dre2 is an essential Fe-S cluster-containing protein that has been implicated in cytosolic Fe-S protein biogenesis and in cell death regulation in response to oxidative stress. Its absence in yeast can be complemented by the human homologous antiapoptotic protein cytokine-induced apoptosis inhibitor 1 (also known as anamorsin), suggesting at least one common function. Using complementary techniques, we have investigated the biochemical and biophysical properties of Dre2. We show that it contains an N-terminal domain whose structure in solution consists of a stable well-structured monomer with an overall typical S-adenosylmethionine methyltransferase fold lacking two alpha-helices and a beta strand. The highly conserved C-terminus of Dre2, containing two Fe-S clusters, influences the flexibility of the N-terminal domain. We discuss the hypotheses that the activity of the N-terminal domain could be modulated by the redox activity of Fe-S clusters containing the C-terminus domain in vivo. PMID- 22487308 TI - Enhancing the copy number of episomal plasmids in Saccharomyces cerevisiae for improved protein production. AB - 2 MUm-based episomal expression vectors are widely used in Saccharomyces cerevisiae for recombinant protein production and synthetic pathway optimization. In this study, we report a new approach to increase the plasmid copy number (PCN) and thus improve the expression of plasmid-encoded proteins. This was achieved by combining destabilization of the marker protein with decreasing the marker gene transcription level. Destabilization of the marker protein alone by fusing a ubiquitin/N-degron tag (ubi-tag) to the N-terminus of the Ura3 marker protein could increase the PCN and activity of LacZ expressed from the same vector. When arginine was exposed at the N-terminus of the marker protein after cleavage of ubiquitin, the PCN and LacZ activity were increased by 70-80%. Replacement of the native URA3 promoter with the HXT1, KEX2 or URA3-d promoter resulted in an increase in the PCN and LacZ activity by about 30-100%. Combining the ubi-tag and promoter modification of the marker gene, increased the PCN and LacZ activity by threefold. We also demonstrated that this new expression vectors can be used to increase enzyme activity by improving patchoulol production by threefold. PMID- 22487309 TI - Tuberculosis and advances in the online delivery of scientific research. PMID- 22487310 TI - Detection of members of the Secoviridae in the Tallgrass Prairie Preserve, Osage County, Oklahoma, USA. AB - Viruses are most frequently discovered because they cause disease. To expand knowledge of plant-associated viruses beyond these narrow constraints, non cultivated plants of the Tallgrass Prairie of the United States were systematically surveyed for evidence of viruses. This report discusses putative viruses of the family Secoviridae identified by the survey. Sequence analysis suggests the presence of at least six viruses in the study site, including Bean pod mottle virus, Maize chlorotic dwarf virus, three previously undescribed viruses within the subfamily Comovirinae and one unclassifiable virus. PMID- 22487311 TI - Do the same factors predict outcome in schizophrenia and non-schizophrenia syndromes after first-episode psychosis? A two-year follow-up study. AB - OBJECTIVE: The aim of this two-year longitudinal study was to identify the best baseline predictors of functional outcome in first-episode psychosis (FEP). We tested whether the same factors predict functional outcomes in two different subsamples of FEP patients: schizophrenia and non-schizophrenia syndrome groups. METHODS: Ninety-five patients with FEP underwent a full clinical evaluation (i.e., PANSS, Mania, Depression and Insight). Functional outcome measurements included the WHO Disability Assessment Schedule (DAS-WHO), Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI). Estimation of cognition was obtained by a neuropsychological battery which included attention, processing speed, language, memory and executive functioning. RESULTS: Greater severity of visuospatial functioning at baseline predicted poorer functional outcome as measured by the three functional scales (GAF, CGI and DAS-WHO) in the pooled FEP sample (explaining ut to the 12%, 9% and 10% of the variance, respectively). Negative symptoms also effectively contributed to predict GAF scores (8%). However, we obtained different predictive values after differentiating sample diagnoses. Processing speed significantly predicted most functional outcome measures in patients with schizophrenia, whereas visuospatial functioning was the only significant predictor of functional outcomes in the non-schizophrenia subgroup. CONCLUSIONS: Our results suggest that processing speed, visuospatial functioning and negative symptoms significantly (but differentially) predict outcomes in patients with FEP, depending on their clinical progression. For patients without a schizophrenia diagnosis, visuospatial functioning was the best predictor of functional outcome. The performance on processing speed seemed to be a key factor in more severe syndromes. However, only a small proportion of the variance could be explained by the model, so there must be many other factors that have to be considered. PMID- 22487313 TI - Neoadjuvant gemcitabine-taxane chemotherapy for radiation-induced angiosarcoma of the breast: a case report. PMID- 22487312 TI - Natural selection. IV. The Price equation. AB - The Price equation partitions total evolutionary change into two components. The first component provides an abstract expression of natural selection. The second component subsumes all other evolutionary processes, including changes during transmission. The natural selection component is often used in applications. Those applications attract widespread interest for their simplicity of expression and ease of interpretation. Those same applications attract widespread criticism by dropping the second component of evolutionary change and by leaving unspecified the detailed assumptions needed for a complete study of dynamics. Controversies over approximation and dynamics have nothing to do with the Price equation itself, which is simply a mathematical equivalence relation for total evolutionary change expressed in an alternative form. Disagreements about approach have to do with the tension between the relative valuation of abstract versus concrete analyses. The Price equation's greatest value has been on the abstract side, particularly the invariance relations that illuminate the understanding of natural selection. Those abstract insights lay the foundation for applications in terms of kin selection, information theory interpretations of natural selection and partitions of causes by path analysis. I discuss recent critiques of the Price equation by Nowak and van Veelen. PMID- 22487314 TI - Microfluidic bead-based enzymatic primer extension for single-nucleotide discrimination using quantum dots as labels. AB - This study reports the development of an on-chip enzyme-mediated primer extension process based on a microfluidic device with microbeads array for single nucleotide discrimination using quantum dots as labels. The functionalized microbeads were independently introduced into the arrayed chambers using the loading chip slab. A single channel was used to generate weir structures to confine the microbeads and make the beads array accessible by microfluidics. The applied allele-specific primer extension method employed a nucleotide-degrading enzyme (apyrase) to achieve specific single-nucleotide detection. Based on the apyrase-mediated allele-specific primer extension with quantum dots as labels, on chip single-nucleotide discrimination was demonstrated with high discrimination specificity and sensitivity (0.5 pM, signal/noise > 3) using synthesized target DNA. The chip-based signal enhancement for single-nucleotide discrimination resulted in 200 times higher sensitivity than that of an off-chip test. This microfluidic device successfully achieved simultaneous detection of two disease associated single-nucleotide polymorphism sites using polymerase chain reaction products as target. This apyrase-mediated microfluidic primer extension approach combines the rapid binding kinetics of homogeneous assays of suspended microbeads array, the liquid handling capability of microfluidics, and the fluorescence detection sensitivity of quantum dots to provide a platform for single-base analysis with small reagent consumption, short assay time, and parallel detection. PMID- 22487315 TI - On the use of size exclusion chromatography for the resolution of mixed amyloid aggregate distributions: I. equilibrium partition models. AB - In this study, we investigated the theoretical potential of size exclusion chromatography (SEC) for resolving mixtures of protein aggregates (of various sizes and shapes) produced in the generation of amyloid fibrils. We present our findings in the form of an equilibrium partition model. We first review the general characteristics of SEC and discuss the physicochemical features affecting solute transport and partition. We then develop new methods for estimating the transport and partition coefficients of protein aggregates on the basis of their molecular dimensions and the SEC column properties. We detail how these calculated properties can be used to estimate the likely resolving power of an SEC column. Model predictions were found to be in general agreement with experimental data gained from the measurement of the elution profile of sheared amyloid fibrils prepared from bovine insulin and passed through a Superose 6 precision SEC column. Our formalism should provide a basic appreciation of the competing factors at work and allow an informed choice to be made for optimal selection of SEC column medium to separate a desired size range of aggregate. PMID- 22487316 TI - How closely does stem growth of adult beech (Fagus sylvatica) relate to net carbon gain under experimentally enhanced ozone stress? AB - The hypothesis was tested that O(3)-induced changes in leaf-level photosynthetic parameters have the capacity of limiting the seasonal photosynthetic carbon gain of adult beech trees. To this end, canopy-level photosynthetic carbon gain and respiratory carbon loss were assessed in European beech (Fagus sylvatica) by using a physiologically based model, integrating environmental and photosynthetic parameters. The latter were derived from leaves at various canopy positions under the ambient O(3) regime, as prevailing at the forest site (control), or under an experimental twice-ambient O(3) regime (elevated O(3)), as released through a free-air canopy O(3) fumigation system. Gross carbon gain at the canopy-level declined by 1.7%, while respiratory carbon loss increased by 4.6% under elevated O(3). As this outcome only partly accounts for the decline in stem growth, O(3) induced changes in allocation are referred to and discussed as crucial in quantitatively linking carbon gain with stem growth. PMID- 22487317 TI - General practitioners' preferences for the organisation of primary care: a discrete choice experiment. AB - OBJECTIVES: To examine GPs' preferences for organisational characteristics in general practice with focus on aspects that can potentially mitigate problems with GP shortages. METHODS: A simple random sample of 1823 GPs (corresponding to half of all GPs in Denmark) was drawn at the beginning of 2010, and a response rate of 68% was obtained. A discrete choice experiment (DCE) is applied, and attributes included are: practice type (solo/shared), number of GPs in general practice, collaboration with other practices (yes/no), change in weekly working hours (administrative versus patient related) and change in yearly surplus. Multinomial logit analyses (with and without interaction variables) are used, and marginal rates of substitution are calculated. RESULTS: GPs working in solo practices have different preferences for the organisational attributes compared to GPs in shared practices. The compensation needed for GPs to re-organise from solo to shared practice is associated with the size of the practice. GP characteristics such as age, working hours and surplus affect their willingness to undergo organisational changes. CONCLUSIONS: Our results are of relevance to decision makers in designing policies aimed at influencing GPs' organisation in order to overcome problems related to shortages. PMID- 22487318 TI - In vivo receptor occupancy assay of histamine H3 receptor antagonist in rats using non-radiolabeled tracer. AB - INTRODUCTION: Rapid and reliable preclinical receptor occupancy measurement at the target organ in relevant species is critical in accelerating the drug hunting process. The aim of this study was to develop in vivo receptor occupancy assay for histamine H3 receptors (H3R) using the non-radiolabeled GSK189254 as a tracer and to correlate the occupancy-exposure relationship for H3R antagonists in the rats. METHODS: In vivo tracer characterization studies like brain regional distribution, dose and time dependent uptake were carried out for GSK189254 in the male Wistar rats after intravenous administration. The tracer specificity was validated by pretreatment with H3 antagonists like ciproxifan, thioperamide, and GSK334429. The brain regional tracer levels and H3R antagonist concentrations in plasma and brain were quantified using liquid chromatography tandem mass spectrometry. Receptor occupancy was calculated using the ratio of total binding (striatum or frontal cortex) to the nonspecific binding (cerebellum) of the tracer in animals pretreated with H3R antagonist. RESULTS: High degree of selective distribution of GSK189254 was found in striatum, frontal cortex, and low level in the cerebellum. Regional distribution of GSK189254 in the rat brain was consistent to that of H3R distribution mapped using 3H or 11C-GSK189254 in human, porcine, and rat. The calculated occupancy ED50 values in the frontal cortex were 0.14, 1.58, and 0.14 mg/kg for ciproxifan, thioperamide, and GSK334429, respectively. The plasma EC50 values (ng/mL) were found to be 2.33, 292.2, and 3.54 for ciproxifan, thioperamide and GSK334429, respectively. DISCUSSION: Results from mass spectroscopy based approach to determine H3R occupancy in rat brain is comparable with reported radiolabeled method by scintillation spectroscopy. In conclusion, non-radiolabeled GSK189254 was successfully employed as a tracer for assessing the H3R occupancy in rats and it can be used as a preclinical tool for evaluation of novel H3R ligands in the drug discovery. PMID- 22487319 TI - Skin lesions, malaise, and heart failure in a renal transplant recipient. AB - A male Caucasian patient developed nodular erythematous skin lesions, malaise, and clinical signs of progressive heart failure 4 months after renal transplantation. Bronchoscopy with bronchoalveolar lavage performed for a small infiltrate seen on a computed tomography scan revealed Trypanosoma, which had at this point not been suspected as a cause. Parasitemia was present, and reactivation rather than transmission of Chagas' disease was established by performing polymerase chain reaction and serology in the donor and recipient. Treatment with benznidazole and allopurinol successfully reduced parasitemia, but the clinical course was fatal owing to progression of severe myocarditis. The patient had never lived in an endemic area, but had an extensive travel history in South America. The last visit was more than 5 years before transplantation. In non-endemic countries (United States, Europe), reactivation after transplantation has only been very rarely reported. Given the rising numbers of transplantations in patients with a migration background and extensive travel histories, specific screening procedures have to be considered. PMID- 22487320 TI - Evaluation of transvesical intra-abdominal pressure measurement in hospitalized dogs. AB - OBJECTIVES: To (1) evaluate intra-abdominal pressure (IAP) measurements in dogs with possible risk factors for the development of intra-abdominal hypertension (IAH); (2) determine intra-observer variability of IAP measurements; and (3) determine interobserver variability of IAP measurements. DESIGN: Prospective, observational, pilot study. SETTING: Veterinary teaching hospital. ANIMALS: Fourteen client-owned dogs, requiring urinary catheterization, admitted to the ICU. INTERVENTIONS: Using the risk factors for IAH established for human patients as defined by the World Society of Abdominal Compartment Syndrome, dogs were assigned to either an IAH risk or no risk group. A commercially available IAP monitoring system was used to obtain 3 direct, transvesical IAP measurements. The primary investigator obtained the first 2 IAP measurements. A secondary investigator obtained the third IAP measurement. MEASUREMENTS AND MAIN RESULTS: Dogs in the IAH risk group (n = 9/14) had significantly higher mean IAPs (9.4 +/- 3.4 mm Hg) than dogs in the no risk group (n = 5/14; 4.1 +/- 0.9 mm Hg) (P < 0.05). Measurements recorded by the primary investigator were compared to determine intra-observer variability. Pearson's correlation coefficient was 0.98 (P < 0.0001). Bland-Altman analysis determined a mean difference in IAP measurements of -0.3 mm Hg (95% confidence interval from 0.13 to -0.71 mm Hg) indicating an intra-observer variability of less than 0.8 mm Hg. Measurements recorded by the primary and secondary investigator were compared to determine interobserver variability. Pearson's correlation coefficient was 0.95 (P < 0.0001). Bland-Altman analysis determined a mean difference in IAP measurements of 0 mm Hg (95% confidence interval from 1.1 to -1.1 mm Hg) indicating an interobserver variability of less than 2.0 mm Hg. CONCLUSIONS: Dogs with predefined human risk factors for IAH had higher IAP than dogs without risk factors. IAP monitoring appears to have low variability within and across observers. PMID- 22487321 TI - CD73: a potent suppressor of antitumor immune responses. AB - Tumors use several strategies to evade immunosurveillance. One such mechanism is the generation of adenosine within the tumor microenvironment, which potently suppresses antitumor T cell responses. Adenosine within the tumor is generated by CD73, a membrane-bound nucleotidase that is expressed by tumor cells, suppressive immune subsets such as T regulatory cells (Tregs) and myeloid-derived suppressor cells and endothelial cells. Recent evidence suggests that targeted inhibition of CD73 has the potential to reduce tumorigenesis and metastasis, as well as enhancing the potency of T-cell-directed therapies. This review outlines the impact of adenosine on suppressing the antitumor response and the evidence supporting the rationale for CD73 targeting in the treatment of cancer. PMID- 22487322 TI - Serological evidence of swine influenza in Brazil. AB - The aim of this work was to detect serum antibodies specific to influenza viruses in swine in Brazil. Serum samples of 355 pigs from 17 herds in Minas Gerais state were tested by hemagglutination inhibition (HI) for antibodies against H1N1 swine (SIV) and human influenza viruses, and H3N2 SIV. HI revealed that 158 animals (44.5%) and 11 herds (64.7%) were positive for H1N1 SIV, 36 animals (10.1%) and four herds (23.5%) were positive for H3N2 SIV, and 136 animals (38.3%) and 10 herds (58.8%) were positive for H1N1 human. This study indicates that swine influenza is disseminated throughout Minas Gerais state, Brazil. PMID- 22487323 TI - Caring for elders: the role of registered nurses in nursing homes. AB - Gerontological care in nursing homes receives little interest from students and newly qualified nurses alike. Yet, this population does have ever-more complex needs that call for a wide array of nursing competencies. This article highlights the essential contributions of registered nurses in the context of nursing homes and is part of a research study aimed at grasping the nature of caring for elders. The researchers used the methodology inspired from activity analysis using focus groups. Situations identified by the respondents as being disruptive have been looked at in cross-perspective. The results show that the work carried out by the registered nurses constitutes the linchpin of institutional functioning. Their contribution consists of coordinating all the activities that take place, while striving to make them relevant to the caretakers, residents, and their relatives. This key role comprises three fields of activities: organizational and innovative activities; autonomous, person-centered activities; and ethical tension management activities. By helping to meet the daily challenges pertaining to the care and monitoring of very old people and by dealing with situations that are often tragic, they carry out tasks that are stimulating on human, intellectual, and relational levels. PMID- 22487324 TI - The value of coordinated management of interacting ecosystem services. AB - Coordinating decisions and actions among interacting sectors is a critical component of ecosystem-based management, but uncertainty about coordinated management's effects is compromising its perceived value and use. We constructed an analytical framework for explicitly calculating how coordination affects management decisions, ecosystem state and the provision of ecosystem services in relation to ecosystem dynamics and socio-economic objectives. The central insight is that the appropriate comparison strategy to optimal coordinated management is optimal uncoordinated management, which can be identified at the game theoretic Nash equilibrium. Using this insight we can calculate coordination's effects in relation to uncoordinated management and other reference scenarios. To illustrate how this framework can help identify ecosystem and socio-economic conditions under which coordination is most influential and valuable, we applied it to a heuristic case study and a simulation model for the California Current Marine Ecosystem. Results indicate that coordinated management can more than double an ecosystem's societal value, especially when sectors can effectively manipulate resources that interact strongly. However, societal gains from coordination will need to be reconciled with observations that it also leads to strategic simplification of the ecological food web, and generates both positive and negative impacts on individual sectors and non-target species. PMID- 22487325 TI - Health Statistics NSW: getting the right balance between privacy and small numbers in a web-based reporting system. AB - Health Statistics NSW is a new web-based application developed by the Centre for Epidemiology and Research at the NSW Ministry of Health. The application is designed to be an efficient vehicle for the timely delivery of health statistics to a diverse audience including the general public, health planners, researchers, students and policy analysts. The development and implementation of this web application required the consideration of a series of competing demands such as: the public interest in providing health data while maintaining the privacy interests of the individuals whose health is being reported; reporting data at spatial scales of relevance to health planners while maintaining the statistical integrity of any inferences drawn; the use of hardware and software systems which are publicly accessible, scalable and robust, while ensuring high levels of security. These three competing demands and the relationships between them are discussed in the context of Health Statistics NSW. PMID- 22487326 TI - Utilisation of the Medicare Teen Dental Plan in NSW, 2008-2010. AB - AIM: To examine the use of the Medicare Teen Dental Plan in NSW, its uptake in the private and public dental sectors and to map the geographical pattern of program use. METHODS: Data describing the use of the Medicare Teen Dental Plan were assembled from a variety of sources including Medicare, the NSW Oral Health Data Collection and the NSW Teen Dental Survey 2010. RESULTS: In 2010, use of the Medicare Teen Dental Plan across the entire NSW eligible aged population ranged from 20 to 25.5%, with the average usage across all ages being 20.2%. For the period 2002 to 2010, the average utilisation rate for teenagers accessing public dental care was approximately 6.8%. CONCLUSION: As a single Dental Benefits Schedule item is used for service provided under the Plan, it is difficult to evaluate the mix of dental treatment items and the comparative value of the service provided unless these services are provided in a public dental service with a data collection that can flag care provided under a Medicare Teen Dental Plan voucher. PMID- 22487327 TI - Development of a maternity hospital classification for use in perinatal research. AB - We aimed to develop a maternity hospital classification, using stable and easily available criteria, that would have wide application in maternity services research and allow comparison across state, national and international jurisdictions. A classification with 13 obstetric groupings (12 hospital groups and home births) was based on neonatal care capability, urban and rural location, annual average number of births and public/private hospital status. In a case study of early elective birth we demonstrate that neonatal morbidity differs according to the maternity hospital classification, and also that the 13 groups can be collapsed in ways that are pragmatic from a clinical and policy decision making perspective, and are manageable for analysis. PMID- 22487328 TI - Reporting of Aboriginal and Torres Strait Islander peoples on the NSW Admitted Patient Data Collection: the 2010 data quality survey. AB - The reporting of Aboriginal and Torres Strait Islander peoples on the NSW Admitted Patient Data Collection was ascertained using a stratified purposive sample of NSW public hospital patients in 2010. Information was collected by interviewing patients and compared with patient information obtained on admission. The study used the methods used in the national survey by the AIHW in 2007 and the study results were compared to the AIHW survey results. The level of correct reporting was 90.7% (95% CI 84.6-94.2). These results, while indicative, should be interpreted with caution as some people may not have identified themselves as Aboriginal or Torres Strait Islander either on hospital admission or in the survey, and non-random sampling can produce non-representative samples. PMID- 22487329 TI - Non-intentional farm injury fatalities in Australia, 2003-2006. AB - AIM: To describe the pattern of non-intentional farm-related fatalities in Australia for 2003-2006 and examine trends. METHODS: Data from the National Coroners Information System were analysed to define all non-intentional farm injury fatalities for the period. RESULTS: The incidence of farm fatalities has declined by 44% over the past 20 years from an average of 146 deaths per year to 82 deaths per year. For adults there are high numbers of fatalities related to tractors, quad bikes and farm utilities. Children aged under 15 years account for 17% of fatalities, with dams or other water bodies and quad bikes remaining the most common causes of non-intentional farm fatalities. Almost half of all on-farm non-intentional fatalities are non-work-related. CONCLUSION: Future interventions targeting these priority areas are required to reduce the incidence of non intentional farm-related fatalities within Australia. PMID- 22487330 TI - Developing an environmentally sustainable NHS: outcomes of implementing an educational intervention on sustainable health care with UK public health registrars. AB - Environmental sustainability is a new and fast moving field in health. There is little evidence about how to teach it effectively to health professionals. METHODS: We conducted a pilot study of an educational intervention with more than 200 UK public health registrars. The intervention consisted of a day-long workshop with the aim of training participants to help make the UK's National Health Service more environmentally sustainable. RESULTS: We measured outcomes in three areas: awareness, advocacy and actions. Comparison of baseline and post intervention questionnaire scores showed statistically significant improvements in the awareness and advocacy scores. Actions were assessed qualitatively. Our findings suggest that, while there are some pockets of good practice, many health professionals are yet to engage with sustainability in the workplace. DISCUSSION: We propose reasons why health professionals are yet to become involved in sustainability issues despite the related opportunities for health and health services. PMID- 22487331 TI - EpiReview: notifications of Q fever in NSW, 2001-2010. AB - Q fever is the most frequently notified zoonotic infection in NSW residents. The past decade has seen the introduction of a targeted national Q fever vaccination program. METHODS: We undertook a descriptive analysis of Q fever notifications in NSW, for the period 2001-2010. RESULTS: A total of 1912 cases of Q fever were notified in NSW between 2001 and 2010 (average 2.8 per 100 000 persons per annum). The majority of Q fever cases were reported in men, aged 40-59 years, living in rural NSW and working in agricultural related occupations. CONCLUSION: The results suggest changes in the epidemiology of Q fever in response to the targeted vaccination program. PMID- 22487332 TI - Bug breakfast in the Bulletin: meningococcal disease. PMID- 22487333 TI - Bug breakfast in the Bulletin: antimicrobial resistance: moving forward to the past. PMID- 22487334 TI - Communicable diseases report, NSW, November and December 2011. PMID- 22487335 TI - Editorial comment to management trends, angioembolization performance and multiorgan injury indicators of renal trauma from Japanese administrative claims database. PMID- 22487336 TI - Reported use of intravesical therapy for non-muscle-invasive bladder cancer (NMIBC): results from the Bladder Cancer Advocacy Network (BCAN) survey. AB - Study Type - Therapy (patterns of practice) Level of Evidence 2b. What's known on the subject? and What does the study add? Claims-based analyses suggest unexplained and potentially problematic variation in treatment intensity adherence to guidelines-recommended care in NMIBC. Previous physician surveys prior to the contemporary Clinical Practice Guidelines (CPGs) reported associations between variation in NMIBC care and practice type, years in practice, and other physician-related factors. In the largest physician survey addressing the management of NMIBC, and the first to examine these questions after the promulgation of contemporary CPGs, US urologists report grade-specific utilization consistent with CPG recommendations, at rates higher than suggested by recent claims-based analyses. As with prior studies, practice type and years in practice were significantly associated with variation in practices. Further research is needed to reconcile these findings with administrative claims data. OBJECTIVES: To determine self-reported practices of use of intravesical chemo- and immunotherapy for patients with non-muscle-invasive bladder cancer (NMIBC) * To evaluate the extent to which respondent characteristics were associated with any observed variation. Guidelines recommend intravesical therapy (IVT) in the management of NMIBC, but recent claims-based analyses suggest exceedingly low rates of use of some of these therapies. MATERIALS AND METHODS: An electronic survey was developed by members of the Bladder Cancer Advocacy Network (BCAN) to elicit self-reported use of management strategies for NMIBC. * The survey was circulated to urologists via the American Urological Association, Society for Urologic Oncology and Large Urology Group Practice Association distribution lists. * In all, 512 respondents completed the survey. RESULTS: In all, 63% reported routine perioperative mitomycin-c (MMC) after transurethral resection of bladder tumour (80% academic vs 54% private practice, P < 0.001). * Whereas 5% of respondents reported routine induction therapy with all new low-grade (LG) diagnoses, 99% reported routinely doing so in new high-grade (HG) cases; most commonly with single-agent bacille Calmette-Guerin (BCG) (94% vs 9% BCG/interferon and 5% MMC). * Reported induction therapy was higher in the setting of high-volume (77%) or frequently recurrent (44%) LG disease. * In all, 89% reported routinely using maintenance therapy for HG vs 29% for LG disease. * Routine biopsy after BCG, even with normal cystoscopy, was endorsed by 28% (39% academic vs 22% private practice, P < 0.001). CONCLUSIONS: Urologists report grade-specific use of IVT for NMIBC, at rates higher than suggested in some claims-based analyses. * Further study is needed to corroborate these self reported patterns of care with lower rates of use suggested by claims-based analyses. PMID- 22487339 TI - An April Fool joke or were you serious? PMID- 22487340 TI - Public health and climate change. PMID- 22487337 TI - The Breast Cancer Quality of Care Study (BQUAL): a multi-center study to determine causes for noncompliance with breast cancer adjuvant therapy. AB - In oncology, quality of care is a major issue for patients and providers. Significant variations in care, including nonreceipt of adjuvant systemic therapy, nonadherence to therapy, and/or early discontinuation of therapy, occur frequently and may impact survival. Reasons for these variations are not well understood, but may play a role in the prominent disparity in breast cancer survival between blacks and whites. Since May 2006, the Breast Cancer Quality of Care Study (BQUAL) has recruited 1158 women with nonmetastatic breast cancer from several centers across the country, with completed data on 1057 participants to date. Detailed information on demographic, behavioral, biomedical, and emotional factors related to chemotherapy use was collected on each participant at baseline and at two follow-up interviews during the first 6 months. In addition, for women with ER+ tumors, further questionnaires were completed every 6 months regarding hormonal therapy use. Each participant was also asked to provide a DNA sample, and to allow medical record review. We surveyed physicians providing care to the study participants regarding attitudes toward adjuvant treatment. The mean age of participants was 58 years (SD 11.6), and 15% (n = 160) were black. The majority had an annual household income <$90,000 (n = 683), had college education or higher (n = 802), 55.9% were married, and 57.9% were not currently employed. Seventy-six percent had hormone-receptor-positive tumors, 49.9% initiated chemotherapy and 82.7% started hormonal therapy. Blacks were more likely to have lower annual household income (p < 0001), less education (p = 0.0005), ER negative tumor status (p = 0.02), and poorly differentiated cancer (p = 0.0002). The main endpoints of the study are noninitiation of chemotherapy or hormonal therapy, nonadherence to therapy and early discontinuation of therapy. Treatment and outcomes will be compared on the 15% of participants who are black versus other participants. The BQUAL Study will be a rich ongoing source of information regarding reasons for differences in receipt of both adjuvant chemotherapy and hormonal therapy. This information may be useful in planning interventions to improve quality of care. PMID- 22487341 TI - In the 21st Century, what is an acceptable response rate? PMID- 22487342 TI - Alcohol and tobacco. PMID- 22487343 TI - A priority list of occupational carcinogenic agents for preventative action in Australia. AB - OBJECTIVE: To develop a list of carcinogens to guide decisions on priorities for preventive action in Australian workplaces. APPROACH: The following criteria provided the assessment framework to establish a list of priority carcinogens: evidence of carcinogenicity using International Agency for Research on Cancer (IARC) criteria; use in occupational circumstances; and use in Australia industry. Literature from national and international agencies relating to carcinogens and industrial practice informed the assessment. CONCLUSION: The final priority list contained 38 established or probable carcinogenic agents that are present in Australian workplaces. Agents were grouped into the following categories: combustion products, inorganic dusts, organic dusts, metals, radiation, other industrial chemicals and non-chemical agents. The priorities are based primarily on the potential for occupational exposure and evidence of use in Australian industry because there is limited information on the prevalence and level of exposure to occupational carcinogens in Australia. IMPLICATIONS: The priority list of agents can provide direction for future disease burden studies to establish the prevalence and levels of exposure to carcinogens amongst Australian workers. From a policy viewpoint, a priority list will allow regulators to focus on activities such as setting exposure standards and restricting importation and use. PMID- 22487344 TI - Workplace bullying a risk for permanent employees. AB - OBJECTIVE: We tested the hypothesis that the risk of experiencing workplace bullying was greater for those employed on casual contracts compared to permanent or ongoing employees. METHODS: A cross-sectional population-based telephone survey was conducted in South Australia in 2009. Employment arrangements were classified by self-report into four categories: permanent, casual, fixed-term and self-employed. Self-report of workplace bullying was modelled using multiple logistic regression in relation to employment arrangement, controlling for sex, age, working hours, years in job, occupational skill level, marital status and a proxy for socioeconomic status. RESULTS: Workplace bullying was reported by 174 respondents (15.2%). Risk of workplace bullying was higher for being in a professional occupation, having a university education and being separated, divorced or widowed, but did not vary significantly by sex, age or job tenure. In adjusted multivariate logistic regression models, casual workers were significantly less likely than workers on permanent or fixed-term contracts to report bullying. Those separated, divorced or widowed had higher odds of reporting bullying than married, de facto or never-married workers. CONCLUSIONS: Contrary to expectation, workplace bullying was more often reported by permanent than casual employees. It may represent an exposure pathway not previously linked with the more idealised permanent employment arrangement. IMPLICATIONS: A finer understanding of psycho-social hazards across all employment arrangements is needed, with equal attention to the hazards associated with permanent as well as casual employment. PMID- 22487345 TI - Under-use of migrants' employment skills linked to poorer mental health. AB - OBJECTIVE: Since the mid-1990s Australia's immigration program has focused on encouraging skilled migration. This study investigated skill usage in three longitudinal studies of immigrants to Australia and examined if there is an association with mental health status. METHODS: Three Longitudinal Surveys of Immigrants to Australia (LSIA), with multiple data collection waves, were conducted between 1994 and 2006. Some 5,192 primary applicants participated in LSIA1, 3,124 in LSIA2 and 9,865 in LSIA3. Data collected included demographics and employment history in all surveys as well as mental health in LSIA1 and 2. RESULTS: Among migrants in LSIA 1, 49% reported working in jobs in which they used their skills sometimes, rarely or never, 31/2 years after immigrating. This was not solely explained by English language proficiency as 47% of migrants who reported speaking English well or very well did not use their qualifications in their job. Migrants who did not use their job qualifications at wave three had a worse GHQ-12 score at wave three after adjusting for age, sex, country of birth and highest educational qualification. There was no difference in wave one or wave two GHQ-12 score between those who did or did not use their job qualifications at wave three. The pattern was similar for those migrants in LSIA 2. CONCLUSIONS AND IMPLICATIONS: There is a large under-utilisation of employment skills in the migrant population in Australia up to 31/2 years after immigrating. This is associated with poorer mental health. PMID- 22487346 TI - Afghan and Kurdish refugees, 8-20 years after resettlement, still experience psychological distress and challenges to well being. AB - OBJECTIVE: To examine the resettlement experiences and provide data of well being and psychological distress for Afghan and Kurdish refugees settled between eight and 20 years in New Zealand and Australia. METHODS: Participants completed the Kessler-10 Psychological Distress Scale (K10) and Personal Well Being Index (PWI) for subjective well being. A mixed methods approach was used, with participants also discussing during interview resettlement difficulties, quality of life (QOL) and sources of stress. RESULTS: Data from 81 Muslim participants is reported; all spoke English, were generally well educated with 88% having secondary or tertiary level education, and the majority of those resettled before 2001 lived in Perth. Although psychological distress levels were mostly within the low-moderate risk range, significant differences were observed by gender and employment status. Participants identified a range of ongoing stressors with unemployment of particular concern. Social isolation and a sense that they would never really 'fit in' was also reported by some. Participants particularly valued the safety and improved quality of life in their host communities. CONCLUSIONS: Despite their appreciation of the overall resettlement experience, too much time to introspect, separation from family, status dissonance and still occasionally feeling overwhelmed by resettlement challenges is a long-term ongoing reality for some former refugees. IMPLICATIONS: Former refugees continue to struggle with unemployment, possible discrimination and loss of status long-term. PMID- 22487347 TI - Combining food records with in-depth probing interviews improves quality of dietary intake reporting in a group of South Asian women. AB - OBJECTIVE: To investigate if the addition of an in-depth interview focused on cultural dietary practices could improve the quality of dietary data from food records among South Asian women in New Zealand. METHODS: Cross-sectional data were collected from 134 South Asian women (>=20 years), living in Auckland. Dietary data were collected using four-day food records. Nutritional analysis revealed 33.6% under-reporting of energy intakes. All women were recalled for an in-depth probing interview focused on culture-specific foods and dietary practices. RESULTS: The interview revealed extensive use of dairy products and plant oils. The nutrient content of the food record alone and the food record plus interview were compared; median energy intakes were 6,852 kJ vs 7,246 kJ (p<0.001); under-reporting decreased by 14.2%, and total fat and protein intakes (g/day) increased (p<0.001). Estimates of poly- and mono-unsaturated fatty acids increased significantly (p<0.001) due to greater use of plant oils due to greater use of plant oils replacing saturated fatty acid-rich fats in food preparation. A significant increase (17%) (p<0.001) in calcium intake reflects the higher dairy intake identified with the interview. CONCLUSION: The addition of an in-depth probing interview to a four-day food record enhanced food intake reporting. Self reported dietary assessments in immigrant population groups require quality control for accuracy. IMPLICATIONS: Methods to ensure high-quality dietary data are essential to assess health outcomes and to inform public health interventions, especially in immigrant populations. PMID- 22487348 TI - Markedly different clustering of CVD risk factors in New Zealand Indian and European people but similar risk scores (PREDICT-14). AB - OBJECTIVE: To compare the cardiovascular disease (CVD) risk profiles of Indian and European patients from routine primary care assessments in the northern region of New Zealand. METHOD: Anonymous CVD risk profiles were extracted from PREDICT (a web-based decision support program) for Indian and European patients aged 35-74 years. Linear regression models were used to obtain mean differences adjusted for age, gender and deprivation. RESULTS: At recruitment, Indian participants (n=8,830) were younger than Europeans (n=47,091), in keeping with national guidelines that recommend earlier CVD risk assessment for Indians. Compared with Europeans, a greater proportion of Indian participants lived in areas of higher deprivation and had a two to four-fold greater burden of diabetes in all age groups. Indian participants had a significantly lower proportion of smokers and a lower mean systolic blood pressure. The respective cardiovascular risk factor profiles lead to similar age-adjusted Framingham five-year CVD risk scores. CONCLUSIONS AND IMPLICATIONS: National data sources indicate that there are higher rates of hospitalisations and deaths from CVD in Indians compared with Europeans. Our study found similar predicted CVD risk in these two populations despite markedly different clustering of risk factors, suggesting that the Framingham risk equation may underestimate risk in Indians. There is a need for better ethnicity coding to identify all South Asian ethnicities. PMID- 22487349 TI - Sports betting marketing during sporting events: a stadium and broadcast census of Australian Football League matches. AB - OBJECTIVE: Using Australian Football League (AFL) matches as a case study, we investigated the frequency, length and content of marketing strategies for sports betting during two specific settings: 1) at stadiums during four live matches; and 2) during eight televised broadcasts of matches. METHODS: Census of sports betting marketing during Round 12 of the 2011 AFL premiership season. RESULTS: Per match, there was an average of 58.5 episodes (median 49.5, s.d 27.8) and 341.1 minutes (median 324.1 minutes and s.d 44.5) of sports betting marketing at stadiums, and 50.5 episodes (median 53.5, s.d 45.2) and 4.8 minutes (median 5.0 minutes, s.d 4.0) during televised broadcasts. A diverse range of marketing techniques were used to: a) embed sports betting within the game; b) align sports betting with fans' overall experience of the game; and c) encourage individuals to bet live during the game. There were very few visible or audible messages (such as responsible gambling or Gambler's Help messages) to counter-frame the overwhelmingly positive messages that individuals received about sports betting during the match. CONCLUSIONS AND IMPLICATIONS: This study raises important questions about the impacts of saturation, integrated and impulse gambling marketing strategies in sporting matches. Future research should explore: 1) how wagering industry marketing strategies may affect the attitudes and behaviours of community sub-groups (e.g. young male sports fans, and children); and 2) which public health and policy strategies, including regulation and harm minimisation messaging, will be effective in responding to wagering industry marketing strategies during sporting matches. PMID- 22487350 TI - Knowledge, views and experiences of gambling and gambling-related harms in different ethnic and socio-economic groups in New Zealand. AB - OBJECTIVE: To describe survey findings which measure broader gambling harms and provide benchmark data to evaluate an awareness and education program to minimise harm; part of NZ's public health approach to problem gambling. To assess whether previously reported ethnic and socio-economic disparities are evident when researching broader gambling harms. METHODS: An in-home, nationwide survey captured data from a multi-stage, random probability sample of 1,774 adults and 199 15-17-year-olds. Oversampling Maori (NZ's indigenous people), Pacific and Asian peoples, and people in areas of deprivation, allowed analysis by ethnicity and socio-economic status. RESULTS: Data show high participation levels; around 8 out of 10 people took part in at least one gambling activity in the previous 12 months. Type and frequency of activities was used to define four groups: infrequent gamblers (60.9%); frequent, non-continuous gamblers (17.6%); frequent, continuous gamblers (4%); and non-gamblers (17.5%). Self-reported knowledge of the signs of gambling harm was high. Arguments about gambling and people going without/unpaid bills provided two indicators of broader gambling harm. Around one sixth of New Zealanders experienced each of these harms. Impacts were greatest for low-income groups, Maori, and Pacific peoples. CONCLUSIONS: The proportion of New Zealander's experiencing broader gambling harms is much higher than the prevalence for problem gambling. Consistent with other research, results show the flow-on impacts of problem gambling - on family, friends and communities. IMPLICATIONS: Measures can be developed to benchmark the wider harms of gambling and evaluate public health programs addressing harm at population and sub population levels. PMID- 22487351 TI - Young adults' gambling and its association with mental health and substance use problems. AB - OBJECTIVE: To examine the socio-demographic characteristics of young adults' gambling and its association with mental health and substance use behaviour. METHODS: The study is based on 3,512 young adults (1648 males) for whom data from the Mater-University of Queensland Study of Pregnancy (MUSP) were available on self-report gambling, gambling expenditure, Achenbach's Young Adult Self Report and substance use at the 21-year follow-up of the MUSP. The participants' age ranged between 18.2 and 23.6 (mean = 20.6, standard deviation = 0.8) years. RESULTS: Two-fifths of the young adults reported gambling. Males reported more money spent on gambling and were significantly more likely to be at risk of problem gambling. Gambling and problem gambling were significantly more common in less-educated individuals, those who had higher income or those who had a paid job. Individuals who reported gambling were more likely to smoke cigarettes, drink more than a glass of alcohol per day, use illicit drugs, or exhibit high levels of externalising behaviour than non-gamblers. CONCLUSIONS: The findings confirm the high prevalence of gambling and gambling expenditure in young adults. Individuals who are involved in gambling are more likely to report cigarette smoking, alcohol consumption, and use of illicit drugs. There is a need for further research to explore the mechanisms of association between gambling behaviour and individuals' mental health and substance use. IMPLICATIONS: Substance abuse and mental health services are recommended to consider co-morbid gambling problems in treatment-seeking patients. PMID- 22487352 TI - From strength to strength: an 18-year comparison of New Zealand adolescents' self perceived strengths. AB - OBJECTIVE: To examine whether self-views of New Zealand (NZ) adolescents have become more positive or negative over time. METHOD: We compared the self perceptions of 609 adolescents in 1987, with 499 adolescents in 2005 using a 22 item measure of perceived strengths. RESULTS: The mean scores for total strengths fell by 2.4 (0.5sd) from 1987 to 2005. Endorsement of most strengths decreased over time, with especially marked decreases in perceptions of being 'healthy', 'careful', 'good with pets', and 'popular'. There were increases among the girls in perceptions of being 'attractive' and 'confident' while boys showed decreases in these strengths. Boys also showed an especially marked decrease in being 'good at sport'. CONCLUSIONS: The findings point to significant changes in self perceived strengths among NZ adolescents over time. An examination of changes in other critical variables suggests reasons why this may be occurring. PMID- 22487353 TI - Community blood lead survey with emphasis on preschool children following lead dust pollution in Esperance, Western Australia. AB - OBJECTIVE: To assess the impact of airborne lead dust on blood lead levels in residents of Esperance, a regional Western Australian town, with particular reference to preschool children. METHODS: Following identification of significant airborne lead contamination, residents were notified that a blood lead clinic was available to all, with testing of preschool children encouraged. About 40% (333 children) of the preschool group and about 20% of the remaining population were tested. The main measures were blood lead levels, prevalence of elevated results and comparisons to other Western Australian surveys. RESULTS: In preschoolers, 2.1% (seven children) had blood lead levels exceeding the current 10 MUg/dL level of concern. This was not significantly different to two previous community-based surveys elsewhere in Western Australia. However, at a lower cut-off of 5 MUg/dL, the prevalence of elevated lead levels was 24.6%, significantly higher than children tested in a previous Western Australian survey. The prevalence of blood lead levels of 10 MUg/dL or greater in adults was 1.3% (26 adults), not significantly different from a previous Western Australian survey. CONCLUSIONS: The prevalence of preschool children with blood lead levels exceeding the current level of concern was not significantly increased. However, the increased prevalence of children with lead levels at or above 5 MUg/dL demonstrates exposure to lead dust pollution. IMPLICATIONS: This episode of lead dust contamination highlights the need for strict adherence to environmental controls and effective monitoring processes to ensure the prevention of future events. PMID- 22487354 TI - Lower well-being of young Australian adults with self-reported disability reflects their poorer living conditions rather than health issues. AB - OBJECTIVE: To determine the extent to which the lower well-being of young Australians with disabilities could be accounted for by increased rates of exposure to adversity and reduced access to personal, economic, social and community resources. METHODS: Secondary analysis of data extracted from Waves 1 (2001) to 8 (2008) of the annual longitudinal survey of Household Income and Labour Dynamics in Australia. RESULTS: Self-reported disability was associated with significantly lower scores on all indicators of psychological well-being. However, people self-reporting disability were more likely to be exposed to adversity and less likely to have access to a range of personal, economic, material, social and community resources. When these between-group differences in social context were controlled for, the between-group differences in psychological well-being were largely eliminated. CONCLUSION: Our results suggest that, among younger adults in Australia, the association between disability and lower psychological well-being largely reflects their increased risk of exposure to adversity and reduced access to resources, rather than the presence of health conditions or impairments per se. IMPLICATIONS: Public health interventions aimed at improving the well-being of young adults with a disability need to address the predominantly social determinants of well-being in this group. PMID- 22487355 TI - Social and emotional outcomes of Australian children from Indigenous and culturally and linguistically diverse backgrounds. AB - OBJECTIVES: 1) profile the living environments and 2) examine the social and emotional outcomes of Australian children from Indigenous and cultural and linguistically diverse (CALD) backgrounds at school entry. METHOD: Secondary analysis of cross-sectional data collected in Wave 1 of the Longitudinal Study of Australian Children (n=4,735). Child mental-health outcomes were measured using parent report of the Strengths and Difficulties Questionnaire (SDQ). RESULTS: Significant differences in family and neighbourhood characteristics, including parental income, maternal education, maternal parenting quality and neighbourhood safety, were found in children of Indigenous and CALD backgrounds compared to the reference group of Australian-born, English-speaking children. After controlling for family and neighbourhood characteristics, significant differences in parent reported SDQ total difficulties were found for Indigenous children. Significant differences in emotional difficulties and peer problems subscales were found for children with overseas-born mothers regardless of English proficiency. CONCLUSIONS: Children from Indigenous and CALD backgrounds experience poorer mental health outcomes at school entry than their Australian-born English speaking peers. They are also more likely to be exposed to risk factors for poor child mental-health outcomes within their family and neighbourhood environments. PMID- 22487356 TI - Differences between landline and mobile-only respondents in a dual-frame mental health literacy survey. PMID- 22487357 TI - Promoting car safety behaviours should not stigmatise cycling as an alternative mode of transportation. PMID- 22487358 TI - Adequacy of handwashing facilities in public toilets in Dunedin, New Zealand. PMID- 22487359 TI - Human papillomavirus and head and neck cancers: emerging trends and improving survival. PMID- 22487360 TI - Brain processing of duodenal and portal glucose sensing. AB - Peripheral and central glucose sensing play a major role in the regulation of food intake. Peripheral sensing occurs at duodenal and portal levels, although the importance of these sensing sites is still controversial. The present study aimed to compare the respective influence of these sensing pathways on the eating patterns; plasma concentrations of glucose, insulin and glucagon-like peptide-1 (GLP-1); and brain activity in juvenile pigs. In Experiment 1, we characterised the changes in the microstructure as a result of a 30-min meal in eight conscious animals after duodenal or portal glucose infusion in comparison with saline infusion. In Experiment 2, glucose, insulin and GLP-1 plasma concentrations were measured during 2 h after duodenal or portal glucose infusions in four anaesthetised animals. In Experiment 3, single photon emission computed tomography brain imaging was performed in five anaesthetised animals receiving duodenal or portal glucose or saline infusions. Both duodenal and portal glucose decreased the amount of food consumed, as well as the ingestion speed, although this effect appeared earlier with the portal infusion. Significant differences of glucose and GLP-1 plasma concentrations between treatments were found at the moment of brain imaging. Both duodenal and portal glucose infusions activated the dorsolateral prefrontal cortex and primary somatosensory cortex. Only duodenal glucose infusion was able to induce activation of the prepyriform area, orbitofrontal cortex, caudate and putamen, as well as deactivation of the anterior prefrontal cortex and anterior entorhinal cortex, whereas only portal glucose infusion induced a significant activation of the insular cortex. We demonstrated that duodenal and portal glucose infusions led to the modulation of brain areas that are known to regulate eating behaviour, which probably explains the decrease of food intake after both stimulations. These stimulation pathways induced specific systemic and central responses, suggesting that different brain processing matrices are involved. PMID- 22487361 TI - Liver histology as predictor of outcome in patients with acute liver failure. AB - Acute liver failure (ALF) is a clinical syndrome associated with significant morbidity and mortality with a highly unpredictable outcome. We retrospectively analyzed 71 ALF patients (53 males; mean age = 27.5 +/- 15.6 years) that underwent transjugular liver biopsy (TJLB) at our institution. The aims of this study are (i) to report our experience with TJLB in these patients, and (ii) to examine the role of liver histology in predicting their outcome. We also compared the histopathological findings between TJLB and explanted liver specimens in 31 patients who underwent liver transplantation (LT). Biopsy specimens were satisfactory for histopathological analyses in 69 (97.1%) patients, confirmed the clinical diagnosis in 56 (81.2%) patients, and altered the diagnosis in 13 (18.8%) patients. Minor complications were encountered in four (5.6%) patients. Percentage of hepatocyte necrosis was the only histological parameter that has significant discriminatory prognostic value, with no survivors having >75% necrosis without LT. In conclusions, TJLB is a safe technique for obtaining liver tissue in both adult and pediatric patients with ALF. Histological characteristics, mainly etiological diagnosis and degree of hepatocyte necrosis may assist in clinical decision-making for need of LT in these patients. PMID- 22487362 TI - Community participation and voice mechanisms under performance-based financing schemes in Burundi. AB - OBJECTIVE: Community participation is often described as a key for primary health care in low-income countries. Recent performance-based financing (PBF) initiatives have renewed the interest in this strategy by questioning the accountability of those in charge at the health centre (HC) level. We analyse the place of two downward accountability mechanisms in a PBF scheme: health committees elected among the communities and community-based organizations (CBOs) contracted as verifiers of health facilities' performance. METHOD: We evaluated 100 health committees and 79 CBOs using original data collected in six Burundi provinces (2009-2010) and a framework based on the literature on community participation in health and New Institutional Economics. RESULTS: Health committees appear to be rather ineffective, focusing on supporting the medical staff and not on representing the population. CBOs do convey information about the concerns of the population to the health authorities; yet, they represent only a few users and lack the ability to force changes. PBF does not automatically imply more 'voice' from the population, but introduces an interesting complement to health committees with CBOs. However, important efforts remain necessary to make both mechanisms work. More experiments and analysis are needed to develop truly efficient 'downward' mechanisms of accountability at the HC level. PMID- 22487363 TI - Synthesis of chlorin-based unsaturated fatty acid conjugates: their in vitro phototoxicity on TC-1 cancer cell line. AB - Chlorin-based photosensitizers in photodynamic therapy are the promising anticancer agents, but some of their properties such as specific-targeting to tumor need to be improved. The aim of this study was to synthesize chlorin-based unsaturated fatty acid conjugates to obtain an optimal photosensitizers. Thus four chlorin-based fatty acid conjugates were successfully synthesized through an esterification reaction using carbodiimide coupling reagents in enough yields. Then, structures of these conjugates were confirmed by (1)H NMR, MALDI-MS, and UV vis spectroscopy. Furthermore, their in vitro phototoxicity and cellular uptake were evaluated on TC-1 lung cancer cell line and HeLa cell line. PMID- 22487364 TI - Economics of facial fracture reductions in the United States over 12 months. AB - OBJECTIVE: The face is a complex architectural structure in the body and is a high-risk site for fractures. Hospitalization is necessary for adequate treatment. The objective of this study is to examine hospitalization outcomes associated with reduction in facial fractures in the United States. METHODS: The Nationwide Inpatient Sample (NIS) of the health care cost and utilization project for 2008 was used. This database provides weighted estimates of all hospitalizations in the United States, which approximates 39.88 million admissions in the entire United States. Hospital discharges with primary procedure ICD-9-CM codes for reduction in facial fractures were selected. Outcomes examined included hospitalization charges, length of stay, and causes of injuries. All estimates obtained from the sample were projected to national levels. RESULTS: Reduction in facial fractures was performed as primary procedure in 21,244 hospitalizations. The total hospitalization charges were about $1.06 billion, and total hospitalization days was 93,808. About 80% of all hospitalizations occurred among men. The frequently occurring external causes of injuries leading to hospitalization for reduction in facial fractures include assault (36.5% of all hospitalizations), motor vehicle traffic accidents (16%), falls (15%), and other transportation accidents (3.5%). The frequently performed procedures were open reduction in mandibular fractures (52.2%), open reduction in facial fractures including those of orbital rim or wall (14.7%), closed reduction in mandibular fractures (12.1%), and open reduction in malar and zygomatic fractures (11.8%). CONCLUSIONS: National hospitalization outcomes related to reduction in facial fractures indicate an extensive consumption of hospital resources. If hospital emergency room protocols and inpatient protocols relating to the most expensive fractures and longest hospital stays that we have identified can improve, this may lead to improved outcomes and a reduction in hospital charges for facial fractures. PMID- 22487365 TI - C957T polymorphism of the dopamine D2 receptor gene is associated with motor learning and heart rate. AB - Genetic variants that are related to the dopaminergic system have been frequently found to be associated with various neurological and mental disorders. Here, we studied the relationships between some of these genetic variants and some cognitive and psychophysiological processes that are implicated in such disorders. Two single nucleotide polymorphisms were chosen: one in the dopamine D2 receptor gene (rs6277-C957T) and one in the catechol-O-methyltransferase gene (rs4680-Val158Met), which is involved in the metabolic degradation of dopamine. The performance of participants on two long-term memory tasks was assessed: free recall (declarative memory) and mirror drawing (procedural motor learning). Heart rate (HR) was also monitored during the initial trials of the mirror-drawing task, which is considered to be a laboratory middle-stress generator (moderate stress), and during a rest period (low stress). Data were collected from 213 healthy Caucasian university students. The C957T C homozygous participants showed more rapid learning than the T allele carriers in the procedural motor learning task and smaller differences in HR between the moderate- and the low-stress conditions. These results provide useful information regarding phenotypic variance in both healthy individuals and patients. PMID- 22487366 TI - Catching Sunbeams: reflecting the living dynamic in our data sets. PMID- 22487367 TI - Homeopathy in chronic sinusitis: a prospective multi-centric observational study. AB - OBJECTIVE: The primary objective was to ascertain the therapeutic usefulness of homeopathic medicine in the management of chronic sinusitis (CS). MATERIALS AND METHODS: Multicentre observational study at Institutes and Units of the Central Council for Research in Homoeopathy, India. Symptoms were assessed using the chronic sinusitis assessment score (CSAS). 17 pre-defined homeopathic medicines were shortlisted for prescription on the basis of repertorisation for the pathological symptoms of CS. Regimes and adjustment of regimes in the event of a change of symptoms were pre-defined. The follow-up period was for 6 months. Statistical analysis was done using SPSS version 16. RESULTS: 628 patients suffering from CS confirmed on X-ray were enrolled from eight Institutes and Units of the Central Council for Research in Homoeopathy. All 550 patients with at least one follow-up assessment were analyzed. There was a statistically significant reduction in CSAS (P = 0.0001, Friedman test) after 3 and 6 months of treatment. Radiological appearances also improved. A total of 13 out of 17 pre defined medicines were prescribed in 550 patients, Sil. (55.2% of 210), Calc. (62.5% of 98), Lyc. (69% of 55), Phos. (66.7% of 45) and Kali iod. (65% of 40) were found to be most useful having marked improvement. 4/17 medicines were never prescribed. No complications were observed during treatment. CONCLUSION: Homeopathic treatment may be effective for CS patients. Controlled trials are required for further validation. PMID- 22487368 TI - Effects of Calendula officinalis on human gingival fibroblasts. AB - BACKGROUND: Calendula officinalis is commonly called the marigold. It is a staple topical remedy in homeopathic medicine. It is rich in quercetin, carotenoids, lutein, lycopene, rutin, ubiquinone, xanthophylls, and other anti-oxidants. It has anti-inflammatory properties. Quercetin, one of the active components in Calendula, has been shown to inhibit recombinant human matrix metalloproteinase (MMP) activity and decrease the expression of tumor necrosis factor-alpha, interleukin-1beta (IL), IL-6 and IL-8 in phorbol 12-myristate 13-acetate and calcium ionophore-stimulated human mast cells. OBJECTIVES: To examine the effects of Calendula on human gingival fibroblast (HGF) mediated collagen degradation and MMP activity. MATERIAL AND METHODS: Lactate dehydrogenate assays were performed to determine the non-toxic concentrations of Calendula, doxycycline and quercetin. Cell-mediated collagen degradation assays were performed to examine the inhibitory effect on cell-mediated collagen degradation. Gelatin zymography was performed to examine their effects on MMP-2 activity. The experiments were repeated three times and ANOVA used for statistical analyses. RESULTS: Calendula at 2-3% completely inhibited the MMP-2 activity in the zymograms. Doxycycline inhibited HGF-mediated collagen degradation at 0.005, 0.01, 0.02 and 0.05%, and MMP-2 activity completely at 0.05%. Quercetin inhibited HGF-mediated collagen degradation at 0.005, 0.01 and 0.02%, and MMP-2 activity in a dose-dependent manner. Calendula inhibited HGF-mediated collagen degradation and MMP-2 activity more than the same correlated concentration of pure quercetin. CONCLUSION: Calendula inhibits HGF-mediated collagen degradation and MMP-2 activity more than the corresponding concentration of quercetin. This may be attributed to additional components in Calendula other than quercetin. PMID- 22487369 TI - Effects of two homeopathic complexes on bovine sperm mitochondrial activity. AB - OBJECTIVES: This study was conducted to evaluate the effect of two homeopathic complexes Ubichinon compositum(r) (Ubi comp) and Coenzyme compositum ad us. vet.(r) (CoQ10 comp) on bovine sperm mitochondrial activity. METHODS: Sperm viability, acrosomal integrity and sperm chromatin structure were estimated to detect the possible side effect of complexes on other sperm parameters. RESULTS: Mitochondrial activity was significantly enhanced by both Ubi comp (P<0.01) and CoQ10 comp (P<0.05). No effects were detected in other tested sperm parameters. CONCLUSION: The tested homeopathic complex medicines stimulate the mitochondrial activity of bovine sperm without effects on their viability, acrosomal integrity or chromatin structure. The possibility that this translates into improved fertilization capacity in artificial insemination should investigated. PMID- 22487370 TI - Frequently occurring polar symptoms assessed by successful cases. AB - BACKGROUND: Frequently occurring symptoms with opposite poles like 'Cold ameliorates/aggravates' are regarded valuable for homeopathic practice, but are insufficiently assessed and impossible to handle with conventional repertorisation. METHOD: In a pilot study 30 questions out of a standard questionnaire in 102 cases responding well to five medicines were analysed and compared with a control group of 100 consecutive new cases. Outcomes of a pivot table, Likelihood Ratio (LR) calculations and Multivariate Analysis (MVA) were compared. RESULTS: Some questions were less useful than expected. With an average of 4.8 useful answers per patient and moderate LRs this questionnaire provided substantial information. MVA was useful in emphasising differences between medicines and for differential diagnosis. CONCLUSION: The value of frequently occurring symptoms could be much enhanced by scientific assessment. We propose further research with an improved questionnaire. PMID- 22487371 TI - Homeopathic aggravation with Quinquagintamillesimal potencies. AB - INTRODUCTION: Homeopathic aggravation is the exacerbation of some symptoms or the whole pathological situation, followed by improvement of the patient's conditions. AIM: To evaluate the typology, intensity and frequency of homeopathic aggravation, especially with Quinquagintamillesimal (Q, LM) potencies and its prognostic value. METHODS: The homeopathic prescription strategy evaluated consists in the administration of a single homeopathic medicine in Q dilutions, starting with 6Q, then a progressive scale of Q potencies. Patients whose symptoms could be attributed to a wrong and inappropriate prescription, according to the criteria previously described, were excluded. RESULTS: Data was collected on 1108 patients consecutively visited from 3rd October 2002 to 31st December 2007, and 441 cases followed for at least 2 months (40% of total cases). 63 of these cases (14%) reported homeopathic aggravation: 7% reported 'slight', 5% 'medium', 2% 'intense' and 0.4% 'very intense' aggravation. Homeopathic aggravation was present in 21% of paediatric patients (<= 14 years). About 50% of the cases manifested homeopathic aggravation 1 or 2 days after the prescription and for 67% of patients the symptoms lasted 1 week or less. Patients with aggravation of the original disease had significantly greater improvement than those patients showing the aggravation of other, new or different, symptoms or conditions, or no aggravation. CONCLUSIONS: These data show that homeopathic aggravation with Q potencies is quite frequent in homeopathic clinical practice and seems to be associated with better treatment outcome. PMID- 22487372 TI - The biopsychosocial model and its potential for a new theory of homeopathy. AB - Since the nineteenth century the theory of conventional medicine has been developed in close alignment with the mechanistic paradigm of natural sciences. Only in the twentieth century occasional attempts were made to (re)introduce the 'subject' into medical theory, as by Thure von Uexkull (1908-2004) who elaborated the so-called biopsychosocial model of the human being, trying to understand the patient as a unit of organic, mental, and social dimensions of life. Although widely neglected by conventional medicine, it is one of the most coherent, significant, and up-to-date models of medicine at present. Being torn between strict adherence to Hahnemann's original conceptualization and alienation caused by contemporary scientific criticism, homeopathy today still lacks a generally accepted, consistent, and definitive theory which would explain in scientific terms its strength, peculiarity, and principles without relapsing into biomedical reductionism. The biopsychosocial model of the human being implies great potential for a new theory of homeopathy, as may be demonstrated with some typical examples. PMID- 22487373 TI - The science of high dilutions in historical context. AB - This paper begins from a discussion of the terms currently applied to the preparations used in homeopathic practice and relates them to the names given to them by Hahnemann, the founder of homeopathy. The latter were directly related to the notion of matter Hahnemann held, this is discussed as it evolved from the earliest sources to the sixth and final edition of the Organon of Medicine, through all the editions of this work as well as many other hitherto rarely explored sources. This review shows that Hahnemann moved conceptually within the field of concepts of late 18th- early 19th century science. This is only natural, and, a legitimate object for studies of the history of science and medicine. PMID- 22487375 TI - Galactomannan: testing the same sample twice? PMID- 22487374 TI - Enhancers as information integration hubs in development: lessons from genomics. AB - Transcriptional enhancers are the primary determinants of tissue-specific gene expression. Although the majority of our current knowledge of enhancer elements comes from detailed analyses of individual loci, recent progress in epigenomics has led to the development of methods for comprehensive and conservation independent annotation of cell type-specific enhancers. Here, we discuss the advantages and limitations of different genomic approaches to enhancer mapping and summarize observations that have been afforded by the genome-wide views of enhancer landscapes, with a focus on development. We propose that enhancers serve as information integration hubs, at which instructions encoded by the genome are read in the context of a specific cellular state, signaling milieu and chromatin environment, allowing for exquisitely precise spatiotemporal control of gene expression during embryogenesis. PMID- 22487376 TI - Antiarrhythmic effects of vasostatin-1 in a canine model of atrial fibrillation. AB - BACKGROUND: We examined the antiarrhythmic effects of vasostatin-1, a recently identified cardioregulatory peptide, in canine models of atrial fibrillation (AF). METHODS AND RESULTS: In 13 pentobarbital-anesthetized dogs bilateral thoracotomies allowed the attachment of multielectrode catheters to superior and inferior pulmonary veins and atrial appendages (AA). Rapid atrial pacing (RAP) was maintained for 6 hours. Each hour, programmed stimulation was performed to determine the window of vulnerability (WOV), a measure of AF inducibility, at all sites. During the last 3 hours, vasostatin-1, 33 nM, was injected into the anterior right (AR) ganglionated plexus (GP) and inferior right (IR) GP every 30 minutes (n = 6). Seven dogs underwent 6 hours of RAP only (controls). At baseline, acetylcholine, 100 mM, was applied on the right AA and AF duration was recorded before and after injection of vasostatin-1, 33 nM, into the ARGP and IRGP. In separate experiments (n = 8), voltage-sinus rate response curves (surrogate for GP function) were constructed by applying high-frequency stimulation to the ARGP with incremental voltages with or without vasostatin-1. Vasostatin-1 significantly decreased the duration of acetylcholine-induced AF (11.0 +/- 4.1 vs 5.5 +/- 2.6 min, P = 0.02). The cumulative WOV (the sum of individual WOVs) significantly increased (P < 0.0001) during the first 3 hours and decreased toward baseline in the presence of vasostatin-1 (P < 0.0001). Cumulative WOV in controls steadily increased. Vasostatin-1 blunted the slowing of sinus rate with increasing stimulation voltage of ARGP. CONCLUSIONS: Vasostatin-1 suppresses AF inducibility, likely by inhibiting GP function. These data may provide new insights into the role of peptide neuromodulators for AF therapy. PMID- 22487377 TI - Laparostomy management using the ABTheraTM open abdomen negative pressure therapy system in a grade IV open abdomen secondary to acute pancreatitis. AB - Wound control in laparostomy for the treatment of intra-abdominal hypertension remains challenging and numerous techniques have been described. We report the first UK experience with a new commercially available device specifically designed to facilitate management of the open abdomen. A 44-year-old gentleman presented with a 3-day history of constant severe epigastric pain and associated vomiting. Amylase was markedly elevated and he was admitted for supportive management of pancreatitis, with subsequent transfer to intensive care due to severe systemic inflammatory syndrome. The patient decompensated, developing intra-abdominal hypertension with renal and respiratory failure. This was successfully managed by performing a laparostomy and using an ABTheraTM Open Abdomen Negative Pressure Therapy System (KCI, San Antonio, TX). We describe its use to facilitate wound control, including enteroatmospheric fistula, allowing granulation and eventual restoration of gastrointestinal continuity 383-days after admission. We found the ABTheraTM System proved to be a useful treatment adjunct, protecting intra-abdominal contents while removing large volumes of exudate and infected material from within the abdominal cavity. Complex cases such as this remain infrequent and this article provides a summary of our experience, including a review of indications for laparostomy and the underlying basic science in this difficult area. PMID- 22487378 TI - Breast cancer in central Tunisia: an earlier age at diagnosis and incidence increase over a 15-year period. PMID- 22487379 TI - Impact of renal function on cardiovascular events in patients undergoing radical nephrectomy for renal cancer. AB - OBJECTIVE: To examine the actual impact of renal dysfunction on cardiovascular events in Japanese patients undergoing radical nephrectomy for renal cancer. METHODS: This retrospective study included 178 Japanese patients who underwent radical nephrectomy between 1980 and 2010. Kaplan-Meier survival curves with a log-rank test and the Cox proportional hazards model were used to investigate the impact of the estimated glomerular filtration rate at 1 month after the radical nephrectomy on cardiovascular-event-free, cancer-specific and overall survivals. RESULTS: During a median follow up of 68 months, 23 patients experienced cardiovascular events and 32 died. Postoperative renal dysfunction (estimated glomerular filtration rate <45 mL/min/1.73 m(2) 1 month after radical nephrectomy) was a significant risk factor for postoperative cardiovascular events in addition to age and history of cardiovascular disease. After adjustment for preoperative characteristics, postoperative renal dysfunction increased the risk of cardiovascular events by 3.48-fold (95% confidence interval 1.28-8.66). For overall and cancer-specific survivals, postoperative renal dysfunction did not represent an independent risk factor. CONCLUSION: Renal dysfunction has a significant impact on cardiovascular events in patients undergoing radical nephrectomy for renal cancer. PMID- 22487380 TI - Comparison of five point-of-care D-dimer assays with the standard laboratory method. AB - INTRODUCTION: D-dimer (DD) assays are effective for the exclusion of deep-vein thrombosis (DVT), but point-of-care (POC) DD assays have not been fully evaluated. METHODS: We have compared five POC DD assays (Pathfast, Cardiac, Vidas, Stratus and NycoCard) with our routine DD method (Tinaquant), testing 60 samples from patients with suspected DVT. RESULTS: Using 0.5 MUg/mL as a cut-off value, four samples tested negative with Tinaquant were positive with Pathfast. There were no Tinaquant-positive samples tested negative with Pathfast, while the overall agreement (k = 0.81) was very good. Four samples were discrepant between Tinaquant and Cardiac (cut-off, 0.4 MUg/mL), while k = 0.72. One of two Tinaquant negative samples was shown to be positive for either Vidas (cut-off, 0.5 MUg/mL) or Stratus (cut-off, 0.4 MUg/mL), respectively. The agreement with Tinaquant was excellent for both Vidas (k = 0.92) and Stratus (k = 0.94). Total CV was <10% for all four assays. Eight samples (of 27) were negative with NycoCard although they were positive with Tinaquant, while CV was 41%. CONCLUSION: Vidas cannot be considered a POC assay because the sample has to be centrifuged before testing. Our findings have also shown that the use of NycoCard is inappropriate. Stratus and Pathfast have a similar analytical profile in comparison with the Tinaquant method. Cardiac is potentially less sensitive but may still be acceptable for use. It seems that the employment of these three assays for rapid bed-side analysis offers a possibility to adequately rule out DVT in outpatients within minutes after admission. PMID- 22487382 TI - Magnesium sulfate inhibits the secretion of high mobility group box 1 from lipopolysaccharide-activated RAW264.7 macrophages in vitro. AB - BACKGROUND: High mobility group box 1 (HMGB1) is an important inflammatory factor that is closely related to mortality in patients with sepsis. High magnesium therapy has been proved to reduce sepsis-related mortality and sepsis-induced pathologic complications. These effects result from reduced expression and release of many inflammatory cytokines, although it is not clear whether high magnesium affects the expression and release of HMGB1. In the present study, we explored the effect of magnesium sulfate on the expression and release of HMGB1 in lipopolysaccharide (LPS)-activated macrophages. METHODS: RAW264.7 cells were incubated with LPS in the presence or absence of various concentrations of magnesium sulfate. An enzyme-linked immunosorbent assay was used to detect the levels of HMGB1 in the culture supernatant. Real-time polymerase chain reaction was used to assess the expression of HMGB1 mRNA. The nuclear/cytoplasm extraction kit was used to extract the nuclear and cytoplasmic proteins. Western blotting was used to observe the changes in the translocation of HMGB1 from the nucleus to the cytoplasm. The nuclear factor (NF)-kappaB p50/p65 Transcription Factor Assay Kit was used to analyze NF-kappaB activity in the nuclear extract. RESULTS: We found that magnesium sulfate inhibited translocation of HMGB1 from the nucleus to the cytoplasm and its extracellular release in LPS-activated macrophages and also suppressed the expression of HMGB1 mRNA. Furthermore, magnesium sulfate inhibited the translocation of NF-kappaB from the cytoplasm to the nucleus in LPS-activated macrophages in a dose-dependent manner. CONCLUSIONS: Our study has demonstrated that magnesium sulfate inhibits the translocation of HMGB1 from the nucleus to the cytoplasm and the expression of HMGB1 mRNA in a dose-dependent manner. The mechanism responsible for these effects involves the NF-kappaB signaling pathway. PMID- 22487381 TI - PKA phosphorylation of cardiac ryanodine receptor modulates SR luminal Ca2+ sensitivity. AB - During physical exercise and stress, the sympathetic system stimulates cardiac contractility via beta-adrenergic receptor activation, resulting in protein kinase A (PKA)-mediated phosphorylation of the cardiac ryanodine receptor, RyR2, at Ser2808. Hyperphosphorylation of RyR2-S2808 has been proposed as a mechanism contributing to arrhythmogenesis and heart failure. However, the role of RyR2 phosphorylation during beta-adrenergic stimulation remains controversial. We examined the contribution of RyR2-S2808 phosphorylation to altered excitation contraction coupling and Ca(2+) signaling using an experimental approach at the interface of molecular and cellular levels and a transgenic mouse with ablation of the RyR2-S2808 phosphorylation site (RyR2-S2808A). Experimentally challenging the communication between L-type Ca(2+) channels and RyR2 led to a spatiotemporal de-synchronization of RyR2 openings, as visualized using confocal Ca(2+) imaging. beta-Adrenergic stimulation re-synchronized RyR2s, but less efficiently in RyR2 S2808A than in control cardiomyocytes, as indicated by comprehensive analysis of RyR2 activation. In addition, spontaneous Ca(2+) waves in RyR2-S2808A myocytes showed significantly slowed propagation and complete absence of acceleration during beta-adrenergic stress, unlike wild type cells. Single channel recordings revealed an attenuation of luminal Ca(2+) sensitivity in RyR2-S2808A channels upon addition of PKA. This suggests that phosphorylation of RyR2-S2808 may be involved in RyR2 modulation by luminal (intra-SR) Ca(2+) ([Ca(2+)](SR)). We show here by three independent experimental approaches that PKA-dependent RyR2-S2808 phosphorylation plays significant functional roles at the subcellular level, namely, Ca(2+) release synchronization, Ca(2+) wave propagation and functional adaptation of RyR2 to variable [Ca(2+)](SR). These results indicate a direct mechanistic link between RyR2 phosphorylation and SR luminal Ca(2+) sensing. PMID- 22487383 TI - Hyperbaric oxygen therapy in necrotizing soft tissue infections. AB - BACKGROUND: Surgical debridement and antibiotics are the mainstays of therapy for patients with necrotizing soft tissue infections (NSTIs), but hyperbaric oxygen therapy (HBO) is often used as an adjunctive measure. Despite this, the efficacy of HBO remains unclear. We hypothesized that HBO would have no effect on mortality or amputation rates. METHODS: We performed a retrospective analysis of our institutional experience from 2005 to 2009. Inclusion criteria were age > 18 y and discharge diagnosis of NSTI. We abstracted baseline demographics, physiology, laboratory values, and operative course from the medical record. The primary endpoint was in-hospital mortality; the secondary endpoint was extremity amputation rate. We compared baseline variables using Mann-Whitney, chi-square, and Fisher's exact test, as appropriate. Significance was set at P < 0.05. RESULTS: We identified 80 cases over the study period. The cohort was 54% male (n = 43) and 53% white (n = 43), and had a mean age of 55 +/- 16 y. There were no significant differences in demographics, physiology, or comorbidities between groups. In-hospital mortality was not different between groups (16% in the HBO group versus 19% in the non-HBO group; P = 0.77). In patients with extremity NSTI, the amputation rate did not differ significantly between patients who did not receive HBO and those who did (17% versus 25%; P = 0.46). CONCLUSIONS: Hyperbaric oxygen therapy does not appear to decrease in-hospital mortality or amputation rate after in patients with NSTI. There may be a role for HBO in treatment of NSTI; nevertheless, consideration of HBO should never delay operative therapy. Further evidence of efficacy is necessary before HBO can be considered the standard of care in NSTI. PMID- 22487384 TI - Cysteinyl leukotriene receptor antagonism alleviates renal injury induced by ischemia-reperfusion in rats. AB - BACKGROUND: Renal inflammation has an important role in the development of ischemia-reperfusion injury of the kidney. Cysteinyl leukotrienes have been implicated in many inflammatory conditions. The aim of this study was to investigate the ability of the cysteinyl leukotriene receptor blocker, zafirlukast, to alleviate renal dysfunction and injury in a rat model of renal ischemia-reperfusion injury. METHODS: We induced renal ischemia for 45 min, followed by 24 h reperfusion. We gave zafirlukast at a dose of 20 mg/kg/d for 3 d before ischemia-reperfusion. At the end of the reperfusion (24 h), we collected blood samples to measure blood urea nitrogen, creatinine, tumor necrosis factor alpha, intercellular adhesion molecule-1, and nitrite/nitrate. We took kidney samples for histological and immunohistochemical assessment, and to measure malondialdehyde, glutathione content, and myeloperoxidase activity. RESULTS: Induction of renal ischemia-reperfusion resulted into renal dysfunction, as indicated by elevated levels of blood urea nitrogen and serum creatinine, serum nitrite and nitrate, serum tumor necrosis factor-alpha, and intercellular adhesion molecule-1. An oxidative stress marker, renal malondialdehyde concentration, was increased, whereas renal reduced glutathione content was decreased. Myeloperoxidase activity, suggestive of neutrophil infiltration, was elevated in renal tissues. Histological changes confirmed these biochemical changes, as did P-selectin overexpression in renal tissues subjected to ischemia reperfusion. Administration of zafirlukast before ischemia-reperfusion improved renal functions and reduced serum levels of nitrite and nitrate, tumor necrosis factor-alpha, and intercellular adhesion molecule-1, renal concentration of myeloperoxidase activity, and malondialdehyde concentration, whereas increased renal reduced glutathione concentration. Moreover, zafirlukast reduced histopathological features of tubular injury and P-selectin overexpression in both cortex and medulla. CONCLUSIONS: These results demonstrate that zafirlukast significantly reduces the severity of ischemic acute renal failure, probably via anti-inflammatory action, reduction of neutrophil infiltration into renal tissues, and oxidative stress subsequent to an attenuation of P-selectin expression. PMID- 22487385 TI - Fasudil, a Rho-kinase inhibitor, attenuates lipopolysaccharide-induced vascular hyperpermeability and colonic muscle relaxation in guinea pigs. AB - BACKGROUND: Rho-associated coiled coil-forming protein kinase (Rho-kinase), a downstream target effector of the small GTP-binding protein Rho, plays a key role in cell adhesion, motility, and contraction. The goal of the present study was to determine the role of the Rho/Rho-kinase signal pathway in the pathogenesis of lipopolysaccharide (LPS)-induced vascular hyperpermeability using the Rho-kinase inhibitor fasudil. METHODS: To evaluate plasma leakage, fasudil (3 or 10 mg/kg) or saline was intravenously administered 30 min before LPS injection. LPS (100, 300, and 1,000 MUg/0.1 mL/site) and saline (0.1 mL/site) were administered intracutaneously in the dorsum of guinea pigs. Vascular permeability was measured on the dorsal skin by the local accumulation of Evans Blue dye after intracutaneous injection of LPS (100-1000 MUg/site) from Escherichia coli. For the measurement of colonic muscle tension, fasudil (3 mg/kg) or saline was intravenously administered 30 min before LPS injection. LPS (1 mg/kg) was administered intravenously. RESULTS: Dye leakage in the skin increased significantly 2 h after the injection of LPS. This LPS-induced dye leakage was significantly suppressed by fasudil (3 and 10 mg/kg). LPS caused a transient decrease in colonic muscle tension, which peaked 2.5 h after the injection. This decrease in muscle tension was significantly suppressed by pretreatment with fasudil (3 mg/kg). CONCLUSIONS: The Rho/Rho-kinase pathway might play an important role in the pathogenesis of LPS-induced endotoxemia, and fasudil could attenuate LPS-induced microvascular permeability, leading to inhibition of endotoxemia. PMID- 22487386 TI - Changes in morphology and function in small intestinal mucosa after Roux-en-Y surgery in a rat model. AB - BACKGROUND: Currently there is no an appropriate model to study intestinal mucosal atrophy in vivo that preserves the nutritional status of the organism. MATERIALS AND METHODS: We created a defunctionalized segment of jejunum via a dead-end Roux-en-Y anastomosis in rats. We compared tissue morphometric parameters in the intestinal mucosa of the defunctionalized bowel with that of the mucosa proximal and distal to the anastomosis. We further measured extracellular signal-regulated kinase (ERK) activation within the mucosa as well as sucrase-isomaltase and dipeptidyl peptidase-4 levels as markers of intestinal mucosal differentiation by Western blotting of mucosal scrapings. RESULTS: Three days after anastomosis, the defunctionalized bowel exhibited decreased diameter and thickness of both the mucosa and the fibromuscular layer compared with adjacent bowel in continuity for luminal nutrient flow or with bowel from control animals. Sucrase-isomaltase and dipeptidyl peptidase-4 levels also were decreased. Furthermore, mucosal ERK activation, assessed as the ratio of phosphorylated to total ERK, also was reduced. Animal weights did not differ between bypassed and control animals. CONCLUSIONS: Deprivation of nutrient flow in a segment of bowel by defunctionalizing Roux-en-anastomosis produces mucosal atrophy as indicated by altered histology, differentiation marker expression, and ERK signaling, in animals that are otherwise able to maintain enteral nutrition. PMID- 22487387 TI - Milk fat globule--EGF factor VIII ameliorates liver injury after hepatic ischemia reperfusion. AB - BACKGROUND: Hepatic ischemia-reperfusion (I/R) injury is a serious clinical complication that may compromise liver function because of extensive hepatocyte loss. Therefore, the development of novel and effective therapies for hepatic I/R is critical for the improvement of patient outcome. It has been previously shown that administration of milk fat globule-EGF factor VIII (MFG-E8), a membrane associated secretory glycoprotein, exerts significant beneficial effects under acute inflammatory conditions through multiple physiological processes associated with tissue remodeling. METHODS: To determine whether administration of recombinant human (rh) MFG-E8 attenuates liver injury in an animal model of hepatic I/R, male adult rats were subjected to 70% hepatic ischemia for 90 min, followed by reperfusion. At the beginning of reperfusion, rats were treated intravenously with normal saline (vehicle) or rhMFG-E8 (160 MUg/kg) over a period of 30 min. MFG-E8 levels and various measurements were assessed 4 h after reperfusion. In addition, survival study was conducted in MFG-E8(-/-) and rhMFG E8-treated wild-type (WT) mice using a total hepatic ischemia model. RESULTS: Liver and plasma MFG-E8 protein levels were significantly decreased after hepatic I/R. Administration of rhMFG-E8 significantly improved liver injury, suppressed apoptosis, attenuated inflammation and oxidative stress, and downregulated NF kappaB pathway. We also noticed that rhMFG-E8 treatment restored the downregulated PPAR-gamma expression after hepatic I/R. MFG-E8(-/-) mice showed deterioration on survival and, in contrast, rhMFG-E8-treated WT mice showed a significant improvement of survival compared with vehicle-treated WT mice. CONCLUSIONS: MFG-E8-mediated multiple physiological events may represent an effective therapeutic option in tissue injury following an episode of hepatic I/R. PMID- 22487388 TI - Dexmedetomidine attenuates tourniquet-induced hyperdynamic response in patients undergoing lower limb surgeries: a randomized controlled study. AB - BACKGROUND: Activation of sympathetic nervous system has a crucial role in mediating the pneumatic tourniquet inflation induced hyperdynamic response. Dexmedetomidine, a selective alpha(2)-adrenergic receptor agonist, has potent sympatholytic effects. We conducted this prospective, randomized, placebo controlled, double-blinded study to elucidate the effects of dexmedetomidine on attenuating the tourniquet-induced hyperdynamic response during general anesthesia. MATERIALS AND METHODS: We included a total of 72 healthy adult patients undergoing elective lower limb surgery. Under general anesthesia, patients were randomized to the dexmedetomidine or the control group (n = 36 in each group). The dexmedetomidine group received a loading dose of dexmedetomidine (0.8 MUg.kg(-1) over 10 min) followed by continuous infusion of dexmedetomidine (0.4 MUg.kg(-1).h(-1)) until tourniquet deflation. The control group received normal saline instead. We compared tourniquet-induced changes in hemodynamic parameters between groups to elucidate the effects of dexmedetomidine. RESULTS: Tourniquet inflation induced significant increases in hemodynamic parameters, including heart rate, systolic arterial pressure, mean arterial pressure, diastolic arterial pressure, rate pressure product, cardiac output, and stroke volume in the control group. The effects of tourniquet inflation on increasing hemodynamic parameters were significantly attenuated by dexmedetomidine: heart rate (P < 0.001), systolic arterial pressure (P = 0.002), mean arterial pressure (P = 0.042), diastolic arterial pressure (P = 0.012), rate pressure product (P < 0.001), and cardiac output (P = 0.001) of the dexmedetomidine group were significantly lower than those of the control group. However, the stroke volume of these groups was comparable. CONCLUSIONS: Dexmedetomidine attenuates tourniquet-induced hyperdynamic response in general anesthesia patients undergoing lower limb surgeries. PMID- 22487389 TI - Centhaquin improves resuscitative effect of hypertonic saline in hemorrhaged rats. AB - BACKGROUND: We observed that centhaquin, a cardiovascular active agent, reduces blood lactate levels. Because blood lactate is an important indicator of end organ perfusion, we determined the resuscitative effect of centhaquin in hemorrhaged rats. MATERIALS AND METHODS: Male, adult Sprague-Dawley rats (Harlan, Indianapolis, IN) were anesthetized with urethane, and a pressure catheter SPR 320 was placed in the left femoral artery, and a pressure-volume catheter SPR-869 was placed into the left ventricle through carotid artery. Hemorrhage was induced by withdrawing blood from the right femoral artery, and mean arterial pressure was maintained between 35 and 40 mm Hg for 30 min after which resuscitation was performed using normal saline (control), 3% hypertonic saline, or centhaquin dissolved in 3% hypertonic saline. Arterial blood pH, pO(2), pCO(2), lactate, hematocrit, and cardiovascular parameters were measured before the induction of hemorrhage (baseline), 30 min after induction of hemorrhagic shock, and every 60 min thereafter until the animal expired. RESULTS: Hypertonic saline was effective in reducing blood lactate levels and improving cardiac output (CO) of hemorrhaged rats. Centhaquin dissolved in hypertonic saline produced a significantly greater decrease in blood lactate and increase in mean arterial pressure and CO compared with hypertonic saline in hemorrhaged rats. Fraction survival at 250 min was 0 when resuscitated with hypertonic saline, whereas it was 0.8 with centhaquin. CONCLUSIONS: Centhaquin significantly improved the resuscitative effect of hypertonic saline by increasing CO, reducing blood lactate, and improving survival time of hemorrhaged rats. PMID- 22487390 TI - Anti-human leukocyte antigen-DR (MHC class II) humanized monoclonal antibody, IMMU-114, suppresses human to bovine cellular responses. AB - The effect of an anti-human leukocyte antigen-DR (MHC class II) humanized monoclonal antibody, IMMU-114, against the human to bovine cellular response was investigated. METHODS: Human peripheral mononuclear cells (PBMCs) were cocultured with inactivated self-PBMCs (Self), bovine PBMCs with control antibody (Xeno), or bovine PBMCs with IMMU-114 (IMMU-114). Cellular responses were investigated by thymidine incorporation assay, CFSE (carboxyfluorescein diacetate succinimidyl ester)-mixed lymphocyte reaction, and cytokine production in culture medium. RESULTS: Thymidine incorporation rates at a 1:1 responder to stimulator ratio for Xeno + control antibody, Xeno + IMMU-114, Self + control antibody, and Self + IMMU-114 were 14201.3 +/- 1968.4, 513.0 +/- 49.5, 952.7 +/- 128.7, and 423.3 +/- 138.8 cpm, respectively (P = 0.032). Those at a 1:2 ratio were 6518.0 +/- 690.1, 896.6 +/- 92.9, 1051.0 +/- 123.6, and 736.0 +/- 35.6 cpm, respectively (P = 0.036). CFSE-mixed lymphocyte reaction demonstrated that the frequencies of CFSE low, CD4(+), and CD25(+) activating T cells in Self, Xeno, and IMMU-114 were 0.27 +/- 0.04%, 3.65 +/- 0.53%, and 1.23 +/- 0.15%, respectively (P = 0.027). Cytokine production in culture medium indicated that IMMU-114 decreased Th1-type cytokines, including interleukin-2, interferon-gamma, and tumor necrosis factor alpha. CONCLUSION: IMMU-114 effectively suppresses human to bovine cellular responses. The mechanism involves direct inhibition of the interaction between class II human leukocyte antigen-DR-positive cells and CD4(+) T cells, and indirect suppression of Th1 cytokine production. PMID- 22487391 TI - Physiologic responses to severe hemorrhagic shock and the genesis of cardiovascular collapse: can irreversibility be anticipated? PMID- 22487392 TI - Use of mobile learning module improves skills in chest tube insertion. AB - BACKGROUND: Just-In-Time Learning is a concept increasingly applied to medical education, and its efficacy must be evaluated. MATERIALS AND METHODS: A 3-minute video on chest tube insertion was produced. Consenting participants were assigned to either the video group, which viewed the video on an Apple(r) iPod Touch immediately before chest tube insertion, or the control group, which received no instruction. Every participant filled out a questionnaire regarding prior chest tube experience. A trained clinician observed participants insert a chest tube on the TraumaMan(r) task simulator, and assessed performance using a 14-item skills checklist. RESULTS: Overall, 128 healthcare trainees participated, with 50% in the video group. Participants included residents (34.4%, n = 44), medical students (32.8%, n = 42), and U.S. Army Forward Surgical Team members (32.8%, n = 42). Sixty-nine percent of all participants responded that they had never placed a chest tube, but 7% had placed more than 20. Only 25% of the participants had previously used TraumaMan(r). Subjects who viewed the video scored better on the skills checklist than the control group (11.09 +/- 3.09 versus 7.17 +/- 3.56, P < 0.001, Cohen's D = 1.16). Medical students (9.33 +/- 2.65 versus 4.52 +/- 3.64, P < 0.001), Forward Surgical Team members (10.07 +/- 2.52 versus 8.57 +/- 3.22, P < 0.001), anesthesia residents (8.25 +/- 2.56 versus 5.9 +/- 2.23, P = 0.017), and subjects who had placed fewer than 10 chest tubes (9.7 +/- 3 versus 6.6 +/- 3.9, P < 0.001) performed significantly better with the video. CONCLUSIONS: The procedural animation video is an effective medium for teaching procedural skills. Embedding the video on a mobile device, and allowing trainees to access it immediately before chest tube insertion, may enhance and standardize surgical education for civilians and military personnel. PMID- 22487393 TI - Association between tumor necrosis factor-alpha gene -308A/G polymorphism and the risk of acute pancreatitis: a meta-analysis. AB - BACKGROUND: Epidemiologic studies have evaluated the association between tumor necrosis factor-alpha (TNF-alpha) gene -308A/G polymorphism and the risk of acute pancreatitis (AP), but the results are inconsistent. In order to derive a more precise estimation of the associations, a meta-analysis was performed. MATERIALS AND METHODS: Systematic searches of electronic databases PubMed, Embase, and Web of Science, as well as hand searching of the references of identified articles, were performed. All case-control studies investigating the association between TNF-alpha gene -308A/G polymorphism and AP risk were included. The association was assessed by odds ratio (OR) with 95% confidence intervals (CIs). Publication bias was analyzed by Begg's funnel plot and Egger's regression test. RESULTS: The initial search revealed 818 potentially eligible studies. Having read the title, abstract, or full text, we included six relevant studies in the final meta analysis, which contained 1,006 AP cases and 782 controls. Overall, no significant association was found between TNF-alpha gene -308A/G polymorphism and AP risk when all studies were pooled into the meta-analysis (for A/A+A/G versus G/G: OR = 1.03, 95% CI = 0.83-1.28, P = 0.79; for A/A versus A/G+G/G: OR = 0.97, 95% CI = 0.65-1.45, P = 0.87; for A/A versus G/G: OR = 1.23, 95% CI = 0.79-1.91, P = 0.37; for A allele versus G allele: OR = 0.99, 95% CI = 0.83-1.18, P = 0.90). In addition, the similar results were obtained in the subgroup analysis based on the ethnicity and subtype of AP. CONCLUSIONS: The present meta-analysis reveals that the TNF-alpha gene -308A/G polymorphism is not associated with AP risk. However, due to the small number of subjects included in analysis and the selection bias in some studies, the results should be interpreted with caution. PMID- 22487394 TI - Risedronate inhibits bone marrow mesenchymal stem cell adipogenesis and switches RANKL/OPG ratio to impair osteoclast differentiation. AB - BACKGROUND: Osteoporosis is accompanied by an increase in bone marrow adipose tissue. Bone marrow adipogenesis has emerged as a therapeutic target for prevention of bone loss. Amino-bisphosphonates have been widely used for treatment of osteoporosis, but the mechanism through which amino-bisphosphonates inhibit osteoporosis remains unclear. The purpose of this study is to investigate the effects of bisphosphonates on bone marrow adipogenesis and the pro osteoclastic factors produced by adipocytes in bone marrow microenvironment. MATERIALS AND METHODS: Human mesenchymal stem cells were obtained and purified from six volunteer donors. Each sample of cells was treated by increasing concentrations of risedronate with or without adipogenic induction for 14 d, and then droplets of the differentiated adipocytes were analyzed. The level of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin, as well as pro-osteoclastic inflammatory factors interleukin-1, interleukin-6, and tumor necrosis factor alpha produced by adipocytes were evaluated by Western blot and ELISA assay. Moreover, the effect of risedronate on the activity of mammalian target of rapamycin complex 1, a key Ser/Thr kinase for initiation of adipocyte differentiation, was investigated. RESULTS: Risedronate not only dose-dependently inhibited the bone marrow adipogenesis from human mesenchymal stem cells but also suppressed receptor activator of nuclear factor-kappaB ligand, not osteoprotegerin, expression in differentiated adipocytes, as well as pro osteoclastic inflammatory factors. Furthermore, the activity of mammalian target of rapamycin complex 1 was suppressed by risedronate. CONCLUSION: Our findings that risedronate influences the crosstalk between bone marrow adipocyte osteoclast represent a novel mechanism for the anti-osteoporotic effects of risedronate. PMID- 22487395 TI - "Pre-hospital intubation is associated with increased mortality after traumatic brain injury". PMID- 22487396 TI - Remote ischemic preconditioning promotes early liver cell proliferation in a rat model of small-for-size liver transplantation. AB - BACKGROUND: The size of the liver donor graft is a major concern in living donor liver transplantation. Rapid regeneration is essential for the survival of these grafts. The purpose of this study was to investigate the effect of remote ischemic preconditioning (RIPC) on liver regeneration in a rat small-for-size liver transplantation model. METHODS: We established rat models of small-for-size liver transplantation (30%) in the presence or absence (control) of remote ischemic preconditioning. We observed liver mass regeneration, serum alanine aminotransferase, hepatic pathologic alterations, flow cytometry, and Ki-67 antigen immunohistochemistry. In addition, using Western blotting and reverse transcriptase-polymerase chain reaction, we assessed the activation of cell cycle progression as well as tumor necrosis factor-alpha and interleukin-6 expression. RESULTS: Compared with the control group, serum alanine aminotransferase activity was significantly lower and histopathology changes were significantly attenuated in the RIPC group. Remote ischemic preconditioning induced a high level of interleukin-6 mRNA in small grafts, but suppressed the expression of tumor necrosis factor-alpha. The proliferation index, indicated by the S-phase and G2/M phase ratio [(S+G2/M)/(G0/G1+S+G2/M)], was significantly increased in the RIPC group at 24 h (58.25% +/- 0.506% versus 53.405% +/- 1.25%; P = .007). Meanwhile, cell cycle progression and regeneration (Ki-67) were initiated early in liver grafts treated with RIPC. CONCLUSIONS: These results suggest that RIPC can protect liver cells against ischemia reperfusion injury in the small grafts and enhance liver regeneration. Interleukin-6 may be a critical mediator in the stimulatory effect on liver cell regeneration, which may make RIPC valuable as a hepatoprotective modality. PMID- 22487398 TI - Multiple approaches to valuation of conservation design and low-impact development features in residential subdivisions. AB - Residents, developers and civic officials are often faced with difficult decisions about appropriate land uses in and around metropolitan boundaries. Urban expansion brings with it the potential for negative environmental impacts, but there are alternatives, such as conservation subdivision design (CSD) or low impact development (LID), which offer the possibility of mitigating some of these effects at the development site. Many urban planning jurisdictions across the Midwest do not currently have any examples of these designs and lack information to identify public support or barriers to use of these methods. This is a case study examining consumer value for conservation and low-impact design features in one housing market by using four different valuation techniques to estimate residents' willingness to pay for CSD and LID features in residential subdivisions. A contingent valuation survey of 1804 residents in Ames, IA assessed familiarity with and perceptions of subdivision development and used an ordered value approach to estimate willingness to pay for CSD and LID features. A majority of residents were not familiar with CSD or LID practices. Residents indicated a willingness to pay for most CSD and LID features with the exception of clustered housing. Gender, age, income, familiarity with LID practices, perceptions of attractiveness of features and the perceived effect of CSD and LID features on ease of future home sales were important factors influencing residents' willingness to pay. A hypothetical referendum measured willingness to pay for tax-funded conservation land purchases and estimated that a property tax of around $50 would be the maximum increase that would pass. Twenty-seven survey respondents participated in a subsequent series of experimental real estate negotiations that used an experimental auction mechanism to estimate willingness to pay for CSD and LID features. Participants indicated that clustered housing (with interspersed preserved forest or open space areas), rain gardens, and neighborhood streams with a forested buffer were the features they were most willing to pay for. Participants were not willing to pay for neighborhood streams without buffers. Finally, a spatial hedonic price model using 2093 homes in Ames, IA was used to estimate the effect of public and private open space on housing values. The model indicated that presence of neighborhood association-owned forest and water features as well as proximity to public parks had significant positive effects on housing prices. However, proximity to a public lake had a negative effect on home values. The four methods used in this study include both stated and revealed preference techniques. Although the relative magnitude of value expressed varied, all methods indicated that residents value CSD and LID subdivision features. Subdivision features that included explicit environmental benefits were also consistently preferred over features that did not. Familiarity with alternative designs was an important factor influencing resident willingness to pay for neighborhood features, and developers and civic officials should consider ways to educate citizens about CSD and LID development techniques to increase interest in these designs. PMID- 22487399 TI - Degradation of UV filters in sewage sludge and 4-MBC in liquid medium by the ligninolytic fungus Trametes versicolor. AB - Ultraviolet (UV) filters are xenobiotic compounds that can enter the environment through the liquid effluent of wastewater treatment plants (WWTPs) and through adsorption in the sludge by-product because of their high hydrophobicity, as the sludge is subsequently applied as a fertiliser. A solid-state treatment of WWTP sludge with the white-rot fungus Trametes versicolor is reported in the present work as a feasible method for UV filter degradation, with reductions ranging from 87% in the case of 3-(4'-methylbenzylidene) camphor (4-MBC) to 100% for benzophenone-3 (BP3) and its metabolite 4,4'-dihydroxybenzophenone (4DHB). This study represents a first step in the development of a future fungal treatment for UV filters; thus, it is essential to prove that elimination is due only to the action of the fungus and not that of other microorganisms. To this end, the sludge was sterilised prior to fungal treatment. Biological assays indicate that T. versicolor readily eliminates oestrogenic activity, although it may be inefficient at eliminating other compounds, including some with dioxin-like activity. Degradation studies of 4-MBC in liquid media were also performed, and complete removal was achieved in less than 24 h. The main metabolites were identified, and the first steps of the transformation pathway were elucidated: a mono- or di-hydroxylation by cytochrome P450 and a subsequent conjugation with a pentose. None of 4-MBC transformation products was found to be responsible for increased dioxin-like activity in the sludge. PMID- 22487397 TI - Major liver resection stimulates stromal recruitment and metastasis compared with repeated minor resection. AB - BACKGROUND: The present study examined the effects of types of liver resection on the growth of liver and lung metastases. METHODS: Experimental liver metastases were established by spleen injection of the Colon 26 murine adenocarcinoma cell line expressing green fluorescent protein (GFP) into transgenic nude mice expressing red fluorescent protein. Experimental lung metastases were established by tail-vein injection with Colon 26-GFP. Three days after cell injection, groups of mice underwent (35% + 35% repeated minor resection versus 70% major resection versus 35% minor resection). Metastatic tumor growth was measured by color-coded fluorescence imaging of the GFP-expressing cancer cells and red fluorescent protein-expressing stroma. RESULTS: Although major and repeated minor resection removed the same total volume of liver parenchyma, the 2 procedures had very different effects on metastatic tumor growth. Major resection stimulated liver and lung metastatic growth and recruitment of host-derived stroma compared with repeated minor resection. Repeated minor resection did not stimulate metastasis or stromal recruitment. No significant difference was found in liver regeneration between the 2 groups. Host-derived stroma density, which was stimulated by major resection compared with repeated minor resection, might stimulate growth in the liver-metastatic tumor. Transforming growth factor-beta is also preferentially stimulated by major resection and might play a role in stromal and metastasis stimulation. CONCLUSIONS: The results of the present study indicate that when liver resection is necessary, repeated minor liver resection will be superior to major liver resection, because major resection, unlike repeated minor resection, stimulates metastasis. This should be taken into consideration in clinical situations that require liver resection. PMID- 22487400 TI - Inadequate environmental monitoring around offshore oil and gas platforms on the Grand Bank of Eastern Canada: are risks to marine birds known? AB - Petroleum exploration and production on the Grand Bank of eastern Canada overlaps with productive marine habitat that supports over 40 million marine birds annually. Environmental assessments for oil and gas projects in the region predict insignificant adverse effects on marine birds from oil spills, incineration in platform flares and collisions. Limited baseline data on seasonal occupancies and a failure to quantify the nature and extent of marine bird attraction to platforms and related mortality undermines these assessments. We conducted 22 surveys to offshore platforms on the Grand Bank during 1999-2003 to measure avian associations with platforms and to determine the level of monitoring needed to assess the risks to marine birds. We document seasonal shifts in marine bird occurrences and higher densities of auks (fall) and shearwaters (summer) around platforms relative to surrounding areas. The limited temporal and spatial coverage of our surveys is more robust than existing industry monitoring efforts, yet it is still inadequate to quantify the scale of marine bird associations with platforms or their associated mortality risks. Systematic observations by independent biologists on vessels and platforms are needed to generate reliable assessments of risks to marine birds. Instead, the regulatory body for offshore oil and gas in eastern Canada (Canada - Newfoundland and Labrador Offshore Petroleum Board; C-NLOPB) supports industry self-reporting as the accepted form of environmental monitoring. Conflicting responsibilities of oil and gas regulatory agencies for both energy development and environmental monitoring are major barriers to transparency, unbiased scientific inquiry and adequate environmental protection. Similar conflicts with the oil and gas regulatory body in the United States, the former Minerals and Management Service (MMS) were identified by the U.S. President as a major contributor to the Deepwater Horizon disaster in the Gulf of Mexico. The MMS has since been restructured into the Bureau of Ocean Energy Management, (BOEM) with separate departments responsible for drilling leases and the regulation of drilling activities. Similar restructuring of the oil and gas regulatory bodies in Canada is needed for better public information, scientific investigation and environmental protection in the offshore. PMID- 22487401 TI - Treating renal calculi 1-2 cm in diameter with minipercutaneous or retrograde intrarenal surgery: a prospective comparative study. AB - OBJECTIVE: To plan a prospective comparative case-control designed study aiming to compare minipercutaneous (miniperc) and retrograde intrarenal surgery (RIRS) for a renal calculus of size 1-2 cm. PATIENTS AND METHODS: A total of 64 cases (32 in each arm) underwent miniperc and RIRS during the study period from March 2009 to April 2011. The primary and secondary outcome objective was stone-free rate and retreatment rate, complications, operation duration, patient visual pain scores, analgesic requirement, haemoglobin drop and hospital stay, respectively. RESULTS: Miniperc and RIRS had stone clearance rates of 100% and 96.88%, respectively. In the RIRS group, one patient required retreatment at 1 month. Hospital stay (0.24) and intra-operative (0.99) and postoperative complications (0.60) were similar in both groups. Operation duration (P = 0.003) was lower in the miniperc group. Haemoglobin drop (P < 0.001), patient pain and visual analogue scale score (each P < 0.001) at 6, 24 and 48 h, as well as analgesic requirement (P < 0.003), were all lower in the RIRS group. CONCLUSIONS: The stone clearances in both modalities are high and complications are low. RIRS requires a larger operation duration, although it is associated with favourable pain scores and a lower haemoglobin drop. PMID- 22487402 TI - Tracheo-neo-esophageal fistula caused by exposed metallic staples erosion. PMID- 22487403 TI - There is more than one way to skin a G matrix. AB - Because of its importance in directing evolutionary trajectories, there has been considerable interest in comparing variation among genetic variance-covariance (G) matrices. Numerous statistical approaches have been suggested but no general analysis of the relationship among these methods has previously been published. In this study, we used data from a half-sib experiment and simulations to explore the results of applying eight tests (T method, modified Mantel test, Bartlett's test, Flury hierarchy, jackknife-manova, jackknife-eigenvalue test, random skewers, selection skewers). Whereas a randomization approach produced acceptable estimates, those from a bootstrap were typically unacceptable and we recommend randomization as the preferred method. All methods except the jackknife eigenvalue test gave similar results although a fine-scale analysis suggested that the former group can be subdivided into two or possibly three groups, hierarchical tests, skewers and the rest (jackknife-manova, modified Mantel, T method, probably Bartlett's). An advantage of the jackknife methods is that they permit tests of association with other factors, such as in this case, temperature and sex. We recommend applying all the tests described in this article, with the exception of the T method, and provide R functions for this purpose. PMID- 22487404 TI - An inherited virus influences the coexistence of parasitoid species through behaviour manipulation. AB - The potential role of pathogens or parasites in maintaining species coexistence is well documented. However, the impact of vertically transmitted symbionts, that can markedly modify their host's biology, is largely unknown. Some females of the Drosophila parasitoid Leptopilina boulardi are infected with an inherited virus (LbFV). The virus forces females to lay supernumerary eggs in already parasitised hosts, thus allowing its horizontal transmission. Using two independent experimental procedures, we found that LbFV impacts inter-specific competition between L. boulardi and the related L. heterotoma. While L. boulardi rapidly outcompetes L. heterotoma in the absence of the virus, L. heterotoma was able to maintain or even to eliminate L. boulardi in the presence of LbFV. By forcing females to superparasitise, LbFV induced egg wastage in L. boulardi thus explaining its impact on the competition outcome. We conclude that this symbiont whose transmission is L. boulardi-density-dependant may affect the coexistence of Leptopilina species. PMID- 22487405 TI - [Increased effort is required to meet the course program for chronic obstructive pulmonary disease]. PMID- 22487406 TI - [Knee pain]. PMID- 22487407 TI - [Unsatisfactory long-term prognosis of conservative treatment of patellofemoral pain syndrome]. AB - This review overviews the long-term prognosis of conservatively treated patients with patellofemoral pain syndrome (PFPS). Median values of the 16 included studies show that 29% of soldiers, 27.8% of sports active and 24,7% of the general public will become pain free after they are diagnosed with PFPS. 21.5% of sports active and 23% of the general public diagnosed with PFPS will stop participating in sports because of knee pain. There is an indication that around one third diagnosed with PFPS will become pain free and one fourth will stop participating in sports because of knee pain. PMID- 22487408 TI - [A practical treatment of hyponatraemia]. AB - Hyponatraemia with cerebral symptoms is a medical emergency. Prompt management of airway, breathing and circulation together with repeated boluses of 2 ml/kg 3% NaCl constitute a rational treatment. The goal is remission of symptoms. After the initial correction, the main concern is to avoid overcorrection, thus reducing the risk of osmotic demyelination. P-[Na(+)] and diuresis must be measured frequently together with diuresis. Definitive treatment should be directed toward the aetiology. PMID- 22487409 TI - [Diagnostics and new treatment methods of syndrome of inappropriate antidiuretic hormone secretion (SIADH)]. AB - New treatment methods of syndrome of inappropriate antidiuretic hormone secretion (SIADH) has emerged with the oral vasopressin V2-receptor antagonist (VV2RA) tolvaptan, but its therapeutic window remains to be defined. We present the scientific data and describe treatment possibilities of SIADH while raising the questions: "Does the present evidence enable us to identify who to treat with VV2RAs?" and "is VV2RAs justified as first-line treatment?". PMID- 22487410 TI - [Necrotizing fasciitis caused by Salmonella Enteritidis]. AB - A 73 year-old immunocompromised male was admitted to the intensive care unit with signs of necrotising fasciitis and septic shock. Prompt surgery was performed. Cultures showed Salmonella Enteritidis. Relevant antibiotics were given in a course of 14 days. A few weeks later the patient had a relapse of fever. Again blood cultures showed S. Enteritidis. This case presents a rare manifestation of extraintestinal infection with S. Enteritidis, and implicates the need for long term antibiotic therapy to prevent relapse. PMID- 22487411 TI - [Liquorice-induced hypertension and hypokalaemia]. AB - Consumption of large amounts of liquorice can cause hypertension and hypokalaemia. Liquorice contains glycyrrhetinic acid, which inhibits the enzyme 11 beta-hydroxysteroid dehydrogenase type 2, and ultimately leads to an apparent mineralocorticoid excess syndrome. This case report describes a 50 year-old woman presenting with hypertension and hypokalaemia-induced limb paresis due to chronic liquorice ingestion. The patient was treated with potassium supplementation and spironolactone. Her blood pressure and electrolyte status normalised within a month after cessation of liquorice intake. PMID- 22487412 TI - [Endoscopic ultrasound-guided rendezvous manoeuvre following unsuccessful endoscopic retrograde cholangiopancreatography]. AB - In this case report we describe an alternative method of cholangiography. Endoscopic retrograde cholangiopancreatography (ERCP) was not successful in a patient with choledocolithiasis. A combined endoscopic ultrasound (EUS) and ERCP procedure was performed and a stent was inserted in the common bile duct. PMID- 22487413 TI - [Cardiac tamponade and purulent pericarditis caused by Streptococcus pneumoniae]. AB - Purulent pericarditis is a rare entity in the modern antibiotic era. Despite advances in treatment and diagnostics, purulent pericarditis remains a life threatening disease. We present a case with cardiac tamponade due to purulent pericarditis caused by Streptococcus pneumoniae. A 67 year-old woman was admitted with massive pericardial fluid. The patient was treated successfully with drainage and intravenous penicillin. Due to the high mortality of this disease, early diagnosis, aggressive pericardial drainage and appropriate antibiotic therapy are essential. PMID- 22487414 TI - [Picture of the month: fibromuscular dysplasia]. PMID- 22487415 TI - Impairment of fear-conditioning responses and changes of brain neurotrophic factors in diet-induced obese mice. AB - Recent epidemiological studies demonstrate that obesity is related to a high incidence of cognitive impairment. In the present study, cognitive behaviours in diet-induced obese (DIO) mice fed 60% high-fat diet for 16 weeks were compared with those in mice fed a control diet (CD) in fear-conditioning tests including both contextual and cued elements that preferentially depend on the hippocampus and amygdala, respectively. Furthermore, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) content in the brain areas was examined in both CD and DIO mice. In fear-conditioning tests, the freezing percentages of both contextual fear and cued fear responses in DIO mice were significantly lower than in CD mice. BDNF content in the cerebral cortex and hippocampus of DIO mice was significantly lower than that in CD mice. Its receptor, full-length TrkB, in the amygdala of DIO mice was significantly decreased compared to that in CD mice, although not in the cerebral cortex, hippocampus and hypothalamus. By contrast, NT-3 content in the hippocampus, amygdala and hypothalamus of DIO mice was significantly higher than that in CD mice. Its receptor, full-length TrkC, was not significantly different between CD and DIO mice. The present study demonstrates that DIO mice show impairment of both hippocampus-dependent contextual and amygdala-dependent cued responses in the fear-conditioning tests, as well as an imbalance in the interaction between the BDNF and NT-3 systems in the cerebral cortex, hippocampus and amygdala related to cognition and fear. PMID- 22487416 TI - Co-existence of other copy number variations with 22q11.2 deletion or duplication: a modifier for variable phenotypes of the syndrome? AB - BACKGROUND: The phenotype in patients with a 22q11.2 deletion or duplication can be extremely variable, and the causes of such as variations are not well known. RESULTS: We observed additional copy number variations (CNVs) in 2 of 15 cases with a 22q11.2 deletion or duplication. Both cases were newborn babies referred for severe congenital heart defects. The first case had a deletion with a size of approximately 1.56 Mb involving multiple genes including STS in the Xp22.31 region along with a 22q11.2 deletion. The second case had a duplication of 605 kb in the 15q13.3 region encompassing CHRNA7 and a deletion of 209 kb involving the RBFOX1 gene in the 16p13.2 region, in addition to 22q11.2 duplication. DISCUSSION: Our observations have shown that additional CNVs are not rare (2/15, 13%) in patients with a 22q11.2 deletion or duplication. We speculate that these CNVs may contribute to phenotype variations of 22q11.2 microdeletion/duplication syndromes as genomic modifiers. PMID- 22487417 TI - Association between initial type of hemodialysis access used in the elderly and mortality. AB - We hypothesized that certain subpopulations (elderly and those with greater comorbidity) may not have significant benefit from "fistula first" initiative. A cohort of incident hemodialysis patients from 2005 to 2007, who were >=70 years old, was derived from the United States Renal Data System. Primary variable of interest was type of vascular access used at first outpatient hemodialysis (i.e., fistula, graft, or central catheter), with primary outcome of all-cause mortality (time to death measured from the first outpatient hemodialysis). A cohort of 82,202 patients was stratified by age (70 to <=80, 81 to <=90, and >90). Each group demonstrated a survival benefit with the use of an arterio-venous fistula compared with catheter (hazard ratio [HR] 0.56 [P < 0.001], HR 0.55 [P < 0.001], and HR 0.69 [P = 0.007], respectively). Comparing graft to with a catheter, both groups, 70 to <=80 and 81 to <=90, had significant benefit compared with catheter (HR 0.73, P < 0.001 and HR 0.74, P < 0.001, respectively). However, significance was lost in those >=90 (HR 0.83, P = 0.354). When substratified by comorbidity, those 81 to <=90 years old with a history of malignancy or peripheral vascular disease also did not reach significant benefit compared with a catheter (HR 0.88, P = 0.423 and HR 0.85, P = 0.221, respectively). While specific subgroups in the hemodialysis population exist where use of fistulas and grafts at time of dialysis initiation is not of proven statistical benefit to survival, elderly hemodialysis patients with comorbidities still appear to benefit from the use of fistulas and grafts. PMID- 22487418 TI - Statistical methodology to determine kinetically derived maximum tolerated dose in repeat dose toxicity studies. AB - Several statistical approaches were evaluated to identify an optimum method for determining a point of nonlinearity (PONL) in toxicokinetic data. (1) A second order least squares regression model was fit iteratively starting with data from all doses. If the second order term was significant (alpha<0.05), the dataset was reevaluated with successive removal of the highest dose until the second-order term became non-significant. This dose, whose removal made the second order term non-significant, is an estimate of the PONL. (2) A least squares linear model was fit iteratively starting with data from all doses except the highest. The mean response for the omitted dose was compared to the 95% prediction interval. If the omitted dose falls outside the confidence interval it is an estimate of the PONL. (3) Slopes of least squares linear regression lines for sections of contiguous doses were compared. Nonlinearity was suggested when slopes of compared sections differed. A total of 33 dose-response datasets were evaluated. For these toxicokinetic data, the best statistical approach was the least squares regression analysis with a second-order term. Changing the alpha level for the second-order term and weighting the second-order analysis by the inverse of feed consumption were also considered. This technique has been shown to give reproducible identification of nonlinearities in TK datasets. PMID- 22487419 TI - Menthol smoking in relation to time to first cigarette and cotinine: results from a community-based study. AB - Smokers who have their first cigarette shortly after waking, an indicator of nicotine dependence, have substantially higher cotinine levels. There is controversy regarding the role of menthol in nicotine dependence. We hypothesized that menthol smokers have a shorter time to first cigarette (TTFC), and tested whether any statistical association actually reflects increased dependence by measuring nicotine uptake (e.g. cotinine) in the same group of smokers. A cross sectional community-based study was conducted that included 495 black and white daily cigarette smokers. Results showed a trend between menthol smoking and a shorter TTFC (P < 0.04 in blacks). Menthol was not an independent predictor of cotinine or an effect modifier with TTFC on cotinine levels in blacks and whites. These results show that while menthol in tobacco is associated with an indicator of nicotine dependence in blacks, menthol was not associated with biological uptake of nicotine in black and white smokers. PMID- 22487420 TI - Co-infection with Toxoplasma gondii and Clostridium perfringens in a postpartum woman with uterine gas gangrene: a case report. AB - Toxoplasmosis is a protozoan infection caused by Toxoplasma gondii. We report a case of Toxoplasma gondii and Clostridium perfringens co-infection complicating uterine gas gangrene following a term pregnancy. The histological examination of the necrotic uterine tissues and uterine swab cultures obtained at laparotomy revealed T. gondii and C. perfringens, respectively. Treatment was administered with bactericidal activity against both pathogens and the patient had an uneventful post-operative recovery. Although there have been some cases that have documented an association between toxoplasmosis and non-uterine C. perfringens infection, such a relationship has not been established. It is of interest to determine if the presence of both organisms can explain the severe myonecrosis that occurs in some cases of uterine gas gangrene. PMID- 22487421 TI - Support group participation during the post-operative radiotherapy period increases levels of coping resources among women with breast cancer. AB - r Being diagnosed with breast cancer is a traumatic experience that can elevate levels of distress and cause depletion of coping resources in many of the disease's victims. This non-randomised case-control study among breast cancer patients undergoing radiotherapy indicates that participation in a support group that focuses on communication and mutual sharing between its member's has positive effects and increases levels of coping resources assessed with the Coping Resources Inventory (CRI). Results of the CRI showed a significant difference between the study group and control group in the social domain at the second occasion of measurement (P= 0.007) and in the emotional domain at the third occasion (P= 0.028). Within the study group, over time, increased levels of coping resources reached significant levels concerning the emotional domain at the second occasion (P= 0.025). Conversely, coping resources were decreased in the same domain within the control group over time, at the third occasion (P= 0.053). Additionally, anxiety and depression were assessed using the Hospital Anxiety and Depression Scale, showing no difference between the groups. This study shows that participation in a support group during post-operative radiotherapy can be socially and emotionally strengthening because of the opportunity for the patients to mutually share experiences. PMID- 22487422 TI - Auxiliary reno-portal anastomosis in living donor liver transplantation: a technique for recipients with low portal inflow. PMID- 22487423 TI - The expanding options for front-line treatment in patients with newly diagnosed CML. AB - The past decade has seen remarkable advances in the treatment of chronic myeloid leukemia (CML). The discovery of the underlying cause of CML, a chromosomal translocation resulting in the expression of an aberrant tyrosine kinase, has enabled the rational development of targeted therapy with tyrosine kinase inhibitors (TKIs). The first available TKI, imatinib, dramatically improved survival rates and demonstrated the potential for long-term treatment. A number of additional strategies have been tested to further maximize outcomes in patients with newly diagnosed CML, including newer TKIs, imatinib dose escalation, and combination therapy. The advanced, more potent TKIs, nilotinib and dasatinib, have proven effective for newly diagnosed patients and for those who experience inadequate response or intolerance to imatinib. Randomized phase 3 studies have shown that nilotinib and dasatinib are more efficacious than imatinib in achieving primary study endpoints. Nilotinib was superior to imatinib in the rate of major molecular response at 12 months; dasatinib was superior to imatinib in the rate of complete cytogenetic response by 12 months. These phase 3 studies are ongoing to further define longer-term efficacy and safety. Research on additional contributing signaling pathways in CML, T315I mutations, and other causes of treatment resistance has identified additional potential treatments that are now in early stages of clinical development, with encouraging preliminary results. With continued advances, it is conceivable that the ultimate goal - a cure for CML - is in our sights. PMID- 22487424 TI - Pol kappa partially rescues MMR-dependent cytotoxicity of O6-methylguanine. AB - To maintain genomic integrity cells have to respond properly to a variety of exogenous and endogenous sources of DNA damage. DNA integrity is maintained by the coordinated action of DNA damage response mechanisms and DNA repair. In addition, there are also mechanisms of damage tolerance, such as translesion synthesis (TLS), which are important for survival after DNA damage but are potentially error-prone. Here, we investigate the role of DNA polymerase kappa (pol kappa) in TLS across alkylated lesions by silencing this polymerase (pol) in human cells using transient small RNA interference. We show that human pol kappa has a significant protective role against methyl nitrosourea (MNU)-associated cytotoxicity without affecting significantly mutagenicity. The increase in MNU induced cytotoxicity when pol kappa is down-regulated was affected by the levels of O6-methylguanine DNA methyltransferase and fully abolished when mismatch repair (MMR) was defective. Following MNU treatment, the cell cycle profile was unaffected by the pol kappa status. The downregulation of pol kappa caused a severe delay in the onset of the second mitosis that was fully dependent on the presence of O6-methylguanine ( O6-meGua) lesions. After MNU exposure, in the absence of pol kappa, the frequency of sister chromatid exchanges was unaffected whereas the induction of RAD 51 foci increased. We propose that pol kappa partially protects human cells from the MMR-dependent cytotoxicity of O6-meGua lesions by restoring the integrity of replicated duplexes containing single stranded gaps generated opposite O6-meGua facilitated by RAD 51 binding. PMID- 22487425 TI - Species determination and characterization of developmental stages of ticks by whole-animal matrix-assisted laser desorption/ionization mass spectrometry. AB - Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) of crude bacterial samples has been introduced as a very cost-efficient and rapid, yet highly informative tool to identify and classify bacteria. The potential of this approach to characterize whole animals, so far preferentially insects, is only evolving. Here, a simple protocol was developed to perform MALDI-MS analysis on extracts from whole ticks of 7 species and 4 developmental stages. Using commercially available software designed for the identification of bacteria, a reference database of spectra was constructed that allowed the species determination of ticks using larvae, nymphs, or adult individuals as starting material. Cluster analysis on the basis of MALDI mass spectra indicated that the primary determinant for the mass spectra was the species, followed by the developmental stages, which formed distinct clusters within the given species. With certain limitations, species identification was also possible using body parts and engorged animals. Spectra of developing Ixodes ricinus eggs showed dramatic changes with time, suggesting that, beyond its usefulness for species determination, MALDI-typing may have applications in developmental biology. PMID- 22487426 TI - Prevalence of Rickettsia spp., Anaplasma phagocytophilum, and Coxiella burnetii in adult Ixodes ricinus ticks from 29 study areas in central and southern Sweden. AB - A total of 887 adult Ixodes ricinus ticks (469 females and 418 males) from 29 different localities in Sweden were screened for Rickettsia, Anaplasma, and Coxiella DNA using PCR and then subjected to gene sequencing. Rickettsial DNA was detected in 9.5-9.6% of the ticks. Most of the positive ticks were infected with Rickettsia helvetica. One tick harbored another spotted fever rickettsia, closely related to or identical with R. sibirica not previously found in I. ricinus nor in Sweden. Six of the ticks (0.7%) were infected with an Anaplasma sp., presumably A. phagocytophilum. Coxiella burnetii DNA was not detected in any of the ticks. The detection of R. helvetica and A. phagocytophilum in several of the localities sampled suggests that these potentially human-pathogenic agents are common in Sweden. PMID- 22487428 TI - Distribution assessment comparing continuous and periodic wound instillation in conjunction with negative pressure wound therapy using an agar-based model. AB - Negative pressure wound therapy (NPWT) is a widely accepted and effective treatment for various wound types, including complex wounds. Negative pressure with instillation was initially used as a gravity-fed system whereby reticulated, open-cell foam in the wound bed was periodically exposed to cycles of soaking with instillation solution followed by NPWT. Recent publications have alluded to positive outcomes with continuous instillation, where fluid is delivered simultaneously with negative pressure. To evaluate the distribution of instillation solutions to wound beds in conjunction with negative pressure, agar based models were developed and exposed to coloured instillation solutions to identify exposure intensity via agar staining. This model allowed comparison of continuous- versus periodic-instillation therapy with negative pressure. Continuous instillation at a rate of 30 cc/hour with negative pressure showed isolated exposure of instillation fluid to wound beds in agar wound models with and without undermining and tunnelling. In contrast, periodic instillation illustrated uniform exposure of the additive to the entire wound bed including undermined and tunnel areas, with increased staining with each instillation cycle. These findings suggest that periodic instillation facilitates more uniform exposure throughout the wound, including tunnels and undermining, to instillation solutions, thereby providing therapy consistent with the clinician-ordered treatment. PMID- 22487427 TI - Absence of selenoprotein P but not selenocysteine lyase results in severe neurological dysfunction. AB - Dietary selenium restriction in mammals causes bodily selenium to be preferentially retained in the brain relative to other organs. Almost all the known selenoproteins are found in brain, where expression is facilitated by selenocysteine (Sec)-laden selenoprotein P. The brain also expresses selenocysteine lyase (Scly), an enzyme that putatively salvages Sec and recycles the selenium for selenoprotein translation. We compared mice with a genetic deletion of Scly to selenoprotein P (Sepp1) knockout mice for similarity of neurological impairments and whether dietary selenium modulates these parameters. We report that Scly knockout mice do not display neurological dysfunction comparable to Sepp1 knockout mice. Feeding a low-selenium diet to Scly knockout mice revealed a mild spatial learning deficit without disrupting motor coordination. Additionally, we report that the neurological phenotype caused by the absence of Sepp1 is exacerbated in male vs. female mice. These findings indicate that Sec recycling via Scly becomes limiting under selenium deficiency and suggest the presence of a complementary mechanism for processing Sec. Our studies illuminate the interaction between Sepp1 and Scly in the distribution and turnover of body and brain selenium and emphasize the consideration of sex differences when studying selenium and selenoproteins in vertebrate biology. PMID- 22487429 TI - Retrograde trans bioprosthetic aortic valve His ablation. PMID- 22487430 TI - VEGF and sVEGFR-1 in malignant pleural effusions: association with survival and pleurodesis outcomes. AB - VEGF is a key mediator of tumour growth and metastasis and is considered central to the formation of exudative pleural effusions. This study examined the relationship between levels of VEGF and its soluble receptor, sVEGFR-1 in the pleural fluid and plasma of patients with malignant pleural effusions and their association with pleurodesis outcomes and survival. 103 patients with malignant pleural effusions were recruited at their first presentation. Follow-up was to 6 months or death. Survival and pleurodesis outcomes were robustly ascertained. VEGF and sVEGFR-1 were measured in pleural fluid and plasma by ELISA. VEGF and sVEGFR-1 were present in significantly higher concentrations in pleural fluid than plasma. There was no significant correlation between mediators within or between sample types. There was no association between baseline pleural fluid VEGF or sVEGFR-1 levels and pleurodesis failure. In both sample types, survival was inversely associated with sVEGFR-1 and within the non-small cell lung cancer sub-group (n=26), a highly significant association between increased pleural fluid VEGF and sVEGFR-1 and reduced survival was demonstrated (p=0.02 and 0.004 respectively). In conclusion, we have shown for the first time that sVEGFR-1 can be reproducibly measured in pleural fluid from malignant effusions. High levels at presentation in those with non-small cell carcinoma are strongly associated with poor outcomes. PMID- 22487431 TI - Thymoma and solid-organ transplantation. AB - Solid-organ-transplant recipients are at high risk of developing cancer, including thoracic malignancies. Herein, we report on two cases of thymoma in solid-organ recipients. One case was a female kidney-transplant recipient who had a type B2, Masaoka stage IVA thymoma that was treated by extended surgical resection followed by postoperative radiation therapy. The second case was type A Masaoka II thymoma that occurred after a liver transplant. The role of EBV in the oncogenesis of thymoma is controversial. We suggest that viruses may induce neoplasms in this specific population, as observed in post-transplant lymphoproliferative disorders. However, Epstein-Barr-encoded RNA (EBER) was negative in both patients. PMID- 22487432 TI - Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung Cancer Study Group. AB - OBJECTIVE: We examined the prognosis of patients with leptomeningeal metastasis (LM) from non-small cell lung cancer (NSCLC) and that stratified by epidermal growth factor receptor (EGFR) mutation status in LM patients receiving EGFR tyrosine kinase inhibitors (TKIs). METHODS: We retrospectively analyzed a series of 91 consecutive NSCLC patients with LM between 2001 and 2010. RESULTS: Most of the LM patients had adenocarcinoma histology and a poor performance status (PS). The median survival time (MST) for all patients was 3.6 months. Adenocarcinoma and TKI treatment were associated with a better prognosis. Among the patients, 51 received EGFR-TKIs. Of these, the EGFR mutation status was assessed in 30 patients; 7 (23%) showed no mutation (group 1), 10 (33%) had a mutation in exon 21 (group 2), and 13 (43%) had deletions in exon 19 (group 3). Interestingly, PS was significantly improved in groups 2 and 3 but not in group 1. The MST in these subgroups was 1.4, 7.1, and 11.0 months in groups 1, 2, and 3, respectively (p<0.001). The median time to progression or symptom deterioration was 0.9, 2.0, and 7.8 months for groups 1, 2, and 3, respectively (p<0.001). A multivariate analysis showed that EGFR-mutant tumors were associated with a better prognosis in patients receiving EGFR-TKIs. CONCLUSIONS: The prognosis for patients with LM from NSCLC was still poor. Survival after the initiation of EGFR-TKI treatment differed according to the type of EGFR mutation, suggesting the potential benefit of TKIs for patients with EGFR mutations, even though they suffered from LM. PMID- 22487433 TI - Human safety controversies surrounding nitrate and nitrite in the diet. AB - Nitrate and nitrite are part of the human diet as nutrients in many vegetables and part of food preservation systems. In the 1950s and 1960s the potential for formation of nitrosamines in food was discovered and it ignited a debate about the safety of ingested nitrite which ultimately focused on cured meats. Nitrate impurities in salt used in the drying of meat in ancient times resulted in improved protection from spoilage during storage. This evolved into their deliberate modern use as curing ingredient responsible for 'fixing' the characteristic color associated with cured meats, creating a unique flavor profile, controlling the oxidation of lipids, and serving as an effective antimicrobial. Several critical reports and comprehensive reviews reporting weak associations and equivocal evidence of nitrite human health safety have fostered concerns and debate among scientists, regulators, press, consumer groups, and consumers. Despite periodic controversy regarding human health concerns from nitrite consumption, a building base of scientific evidence about nitrate, nitrite, heme chemistry, and the overall metabolism of nitrogen oxides in humans has and continues to affirm the general safety of nitrate/nitrite in human health. As nitrite based therapeutics emerge, it is important to consider the past controversies and also understand the beneficial role in the human diet. PMID- 22487434 TI - Surgical cryoablation for ventricular tachyarrhythmia in patients undergoing surgical ventricular restoration: lessons learned from radiofrequency ablation. PMID- 22487435 TI - Aortic valve repair by sinotubular junctional remodeling to eliminate aortic regurgitation in donor cardiac allograft. PMID- 22487436 TI - Cardiac extension of an intravascular leiomyomatosis 43 years after hysterectomy. PMID- 22487438 TI - Partial anomalous pulmonary venous connection with anomalous connection of the superior vena cava to the left atrium. PMID- 22487437 TI - Using contracting band to improve right ventricle ejection fraction for patients with repaired tetralogy of Fallot: a modeling study using patient-specific CMR based 2-layer anisotropic models of human right and left ventricles. AB - OBJECTIVE: Patients with repaired tetralogy of Fallot account for most cases of late-onset right ventricle failure. The current surgical approach, which includes pulmonary valve replacement/insertion, has yielded mixed results. A new surgical option of placing an elastic band in the right ventricle is proposed to improve right ventricular cardiac function as measured by the ejection fraction. METHODS: A total of 20 computational right ventricular/left ventricular/patch/band combination models using cardiac magnetic resonance imaging from a patient with tetralogy of Fallot were constructed to investigate the effect of band material stiffness variations, band length, and active contraction. These models included 4 different band material properties, 3 band length, 3 active contracting band materials, and models with patch and scar replaced by contracting tissue. RESULTS: Our results indicated that the band insertion, combined with active band contraction and tissue regeneration techniques that restore right ventricular myocardium, has the potential to improve right ventricular ejection fraction by 7.5% (41.63% ejection fraction from the best active band model to more than 34.10% ejection fraction from baseline passive band model) and 4.2% (41.63% from the best active band model compared with cardiac magnetic resonance imaging measured ejection fraction of 37.45%). CONCLUSIONS: The cardiac magnetic resonance imaging-based right ventricular/left ventricular/patch/band model provides a proof of concept for using elastic bands to improve right ventricular cardiac function. Band insertion, combined with myocardium regeneration techniques and right ventricular remodeling surgical procedures, has the potential to improve ventricular function in patients with repaired tetralogy of Fallot and other similar forms of right ventricular dysfunction after surgery. Additional investigations using in vitro experiments, animal models, and, finally, patient studies are warranted. PMID- 22487439 TI - Reversible reduction of cardiac sympathetic innervation after coronary artery bypass graft surgery: an observational study using serial iodine 123-labeled meta iodobenzyl-guanidine (MIBG) imaging. AB - OBJECTIVES: Various types of surgical and interventional procedures have been reported to cause cardiac sympathetic denervation. We aimed at evaluating the effects of coronary artery bypass grafting (CABG) in cardiac sympathetic innervation through meta-iodobenzyl-guanidine (MIBG) imaging. METHODS: MIBG imaging was performed in 21 patients with coronary artery disease (CAD) 1 day before and 1 week and 6 months after CABG with concomitant measurements of corrected QT interval. In each study we evaluated MIBG defect score in a 16 segment left ventricular model, MIBG-defect size (percent) from generated polar maps, and heart/mediastinum ratio. RESULTS: Mean MIBG defect score and size were increased (32 +/- 9.5 vs 24 +/- 5, P < .0001, and 49.5% +/- 20.4% vs 37% +/- 8.7%, P = .004, respectively) and mean heart/mediastinum ratio was reduced (1.5 +/- 0.4 vs 1.9 +/- 0.3, P < .0001) at 1 week after CABG. At 6 months these indices had no significant differences compared with their pre-CABG values. Mean corrected QT interval demonstrated no significant changes. Increase in MIBG score in the second imaging was associated with adverse events related to arrhythmia and myocardial dysfunction during the 6-month follow-up period in a binary logistic regression model. CONCLUSIONS: CABG is associated with clinically important but reversible reduction in cardiac sympathetic nerve function, with periprocedural effects (cardioplegia, hypothermia, ischemia, direct nerve injury) being possible mechanisms for this finding. PMID- 22487440 TI - Effects of bone morphogenetic protein 2 on human umbilical vein endothelial cells. AB - Bone morphogenetic proteins (BMPs) and their receptors play important roles in cellular processes such as proliferation, differentiation, migration and cell survival. It was also demonstrated that BMPs are involved in vasculogenesis and angiogenesis. In this study, we investigated the expression profile of BMP receptors in human umbilical vein endothelial cells (HUVECs) and determined the effect of BMP-2 on proliferation, migration, invasion, cell survival and tube formation. HUVECs express the type I BMP receptors ALK2, ALK3 and ALK6 and the type II receptor BMPR-II. Treatment of HUVECs with recombinant human BMP-2 induced migration, invasion and tube formation of HUVECs without affecting proliferation and apoptosis. Our data suggest that BMP-2 represents a chemoattractant and proangiogenic factor for HUVECs. PMID- 22487441 TI - Radical prostatectomy represents an effective treatment in patients with specimen confined high pathological Gleason score prostate cancer. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: To date, only a few studies have addressed the long-term oncological outcomes of radical prostatectomy (RP) in patients with pathological Gleason score >= 8 prostate cancer. According to these reports, some individuals with pathological Gleason score >= 8 may benefit from RP, with cancer-control outcomes comparable with those of patients with low- and intermediate-risk prostate cancer. The presence of pathological Gleason score 8-10 represents a poor prognostic factor in the outcome of men with prostate cancer. However, in patients with specimen-confined disease, RP and bilateral PLND provided long-term cancer-control outcomes similar to those of patients with more favourable disease characteristics. OBJECTIVES: To evaluate the outcomes of patients with pathological Gleason score 8-10 prostate cancer subjected to radical prostatectomy (RP). To determine the prognostic factors associated with cancer-specific survival (CSS) in this subset of patients. PATIENTS AND METHODS: The study included 580 consecutive patients with pathological Gleason sum 8-10 prostate cancer treated with RP and pelvic lymph node dissection (PLND) at a single European institution between July 1988 and April 2010. All patients had detailed pathological and follow-up data. Pathological Gleason score was determined by a single expert genitourinary pathologist. Biochemical recurrence (BCR) was defined PSA concentration of >= 0.2 ng/mL and rising. Kaplan-Meier plots were used to graphically explore BCR-free survival as well as CSS and overall survival (OS) rates. Moreover, univariable and multivariable Cox regression models were fitted to test the predictors of CSS. RESULTS: The mean (median, range) age at surgery was 66.1 (66.4, 41-85) years. The mean (median, range) total PSA concentration was 29.6 (11.1, 0.5-1710) ng/mL. Pathological Gleason score was 8 in 238 (41.0%), 9 in 330 (56.9%) and 10 in 12 (2.1%) patients. Overall, 119 (20.5%), 124 (21.4%), 281 (48.4%) and 56 (9.7%) patients had pT2, pT3a, pT3b and pT4 prostate cancer, respectively. Overall, 275 (47.4%) had LN invasion, while 150 (25.1%) patients had specimen confined disease (defined as pT2cR0 pN0 or pT3aR0 pN0 prostate cancer). The mean (median, range) follow-up was 53 (47, 1-226) months. At 5 and 10 years after RP, BCR-free survival was 76.7% and 49.6%, respectively. Similarly, the 5- and 10 year CSS rates were 87.3% and 69.5%, respectively. Patients with specimen confined disease (P < 0.001) and patients with negative LNs (P = 0.012) had significantly better CSS rates than their counterparts with less favourable pathological characteristics. In multivariable Cox regression models, only the presence of specimen-confined disease achieved independent predictor status (P = 0.001). CONCLUSION: Presence of high Gleason score at RP represents a poor prognostic factor in the outcome of patients with prostate cancer. However, RP provides excellent long-term cancer control outcomes in the subset of patients with specimen-confined disease. PMID- 22487442 TI - Association of prostate-specific antigen doubling time and cancer in men undergoing repeat prostate biopsy. AB - OBJECTIVES: To analyze the association between prostate-specific antigen doubling time with prostate cancer risk and grade among men with prostate-specific antigen levels >=4.0 ng/mL undergoing repeat prostate biopsy. METHODS: A total of 286 patients with prostate-specific antigen >=4 ng/mL and available prostate-specific antigen doubling time data, who underwent repeat prostate biopsy from 1996-2009, were included in this analysis. Prostate-specific antigen doubling time was divided into three groups: >9 years, 3-9 years and <3 years. Multivariate analyses of prostate-specific antigen doubling time with cancer risk and grade (<=3 + 4 vs >=4 + 3) were carried out using logistic regression adjusting for prebiopsy prostate-specific antigen, race, age, digital rectal examination, year of biopsy and number of prior negative biopsies. RESULTS: The median prostate specific antigen doubling time before biopsy was 4.5 years (interquartile range = 2.5-10). Shorter prostate-specific antigen doubling time was associated with higher prostate-specific antigen (P < 0.001), but it was unrelated to age, digital rectal examination or race. Shorter prostate-specific antigen doubling time as a continuous variable was associated with greater prostate cancer risk in both uni- (hazard ratio = 0.99, 95% confidence interval = 0.98-0.99, P = 0.001) and multivariate analysis (hazard ratio = 0.99, 95% confidence interval = 0.98 0.99, P = 0.004). The prevalence of cancer among prostate-specific antigen doubling time groups (>9, 3-9, <3 years) was 17%, 37% and 40%, respectively. Shorter prostate-specific antigen doubling time groups were associated with higher cancer risk (P = 0.001). Stratified by grade, short prostate-specific antigen doubling time as a continuous variable significantly predicted both low- (P = 0.010) and high-grade disease (P = 0.049). The inclusion of prostate specific antigen doubling time groups in a multivariate model to predict biopsy positivity increased its accuracy from 0.69 to 0.74. CONCLUSION: Prostate specific antigen doubling time seems to provide further cancer risk assessment in men undergoing repeat biopsy for prostate-specific antigen >=4.0 ng/mL. If validated in future studies, the present findings support the use of prostate specific antigen doubling time in the risk stratification of this patient population. PMID- 22487443 TI - Cecropins as a marker of Spodoptera frugiperda immunosuppression during entomopathogenic bacterial challenge. AB - An antimicrobial peptide (AMP) of the cecropin family was isolated by HPLC from plasma of the insect pest, Spodoptera frugiperda. Its molecular mass is 3910.9 Da as determined by mass spectrometry. Thanks to the EST database Spodobase, we were able to describe 13 cDNAs encoding six different cecropins which belong to the sub-families CecA, CecB, CecC and CecD. The purified peptide identified as CecB1 was chemically synthesized (syCecB1). It was shown to be active against Gram positive and Gram-negative bacteria as well as fungi. Two closely related entomopathogenic bacteria, Xenorhabdus nematophila F1 and Xenorhabdus mauleonii VC01(T) showed different susceptibility to syCecB1. Indeed, X. nematophila was sensitive to syCecB1 whereas X. mauleonii had a minimal inhibitory concentration (MIC) eight times higher. Interestingly, injection of live X. nematophila into insects did not induce the expression of AMPs in hemolymph. This effect was not observed when this bacterium was heat-killed before injection. On the opposite, both live and heat-killed X. mauleonii induced the expression of AMPs in the hemolymph of S. frugiperda. The same phenomenon was observed for another immune related protein lacking antimicrobial activity. Altogether, our data suggest that Xenorhabdus strains have developed different strategies to supplant the humoral defense mechanisms of S. frugiperda, either by increasing their resistance to AMPs or by preventing their expression during such host-pathogen interaction. PMID- 22487444 TI - 1,450-nm diode laser in combination with the 1550-nm fractionated erbium-doped fiber laser for the treatment of steatocystoma multiplex: a case report. AB - Steatocystoma multiplex (SM) is a rare condition characterized by multiple, small, asymptomatic dermal cysts. Treatment options are limited, with varying degrees of success; these include oral isotretinoin, surgical excision or drainage, and liquid nitrogen cryotherapy. The most effective method is excision, but cosmetic considerations, time, overall cost, and pain must be considered, because patients tend to have multiple cysts. Lasers, especially nonablative devices, have not frequently been used to treat SM. Herein, we present the case of a patient with isolated steatocystoma multiplex on the abdomen and lower chest with substantial clearance after two laser treatment sessions using two complementary lasers: a 1,450-nm diode laser to target the abnormal sebaceous glands and a 1,550-nm fractionated erbium-doped fiber laser to target the dermal cysts. PMID- 22487445 TI - Does phylogeny matter? Assessing the impact of phylogenetic information in ecological meta-analysis. AB - Meta-analysis is increasingly used in ecology and evolutionary biology. Yet, in these fields this technique has an important limitation: phylogenetic non independence exists among taxa, violating the statistical assumptions underlying traditional meta-analytic models. Recently, meta-analytical techniques incorporating phylogenetic information have been developed to address this issue. However, no syntheses have evaluated how often including phylogenetic information changes meta-analytic results. To address this gap, we built phylogenies for and re-analysed 30 published meta-analyses, comparing results for traditional vs. phylogenetic approaches and assessing which characteristics of phylogenies best explained changes in meta-analytic results and relative model fit. Accounting for phylogeny significantly changed estimates of the overall pooled effect size in 47% of datasets for fixed-effects analyses and 7% of datasets for random-effects analyses. Accounting for phylogeny also changed whether those effect sizes were significantly different from zero in 23 and 40% of our datasets (for fixed- and random-effects models, respectively). Across datasets, decreases in pooled effect size magnitudes after incorporating phylogenetic information were associated with larger phylogenies and those with stronger phylogenetic signal. We conclude that incorporating phylogenetic information in ecological meta-analyses is important, and we provide practical recommendations for doing so. PMID- 22487446 TI - Parasitological, serological and clinical evidence for high prevalence of podoconiosis (non-filarial elephantiasis) in Midakegn district, central Ethiopia. AB - OBJECTIVE: To determine whether the elephantiasis in Midakegn district, central Ethiopia, is filarial or non-filarial (podoconiosis) using serological, parasitological and clinical examinations, and to estimate its prevalence. METHODS: At house-to-house visits in 330 randomly selected households, all household members who had elephantiasis were interviewed and clinically examined at the nearby health centre to confirm the presence of elephantiasis, check the presence of scrotal swelling and rule out the other causes of lymphoedema. A midnight blood sample was obtained from each participant with elephantiasis for microscopic examination of Wuchereria bancrofti microfilaria. A daytime blood sample was obtained from half of the participants for serological confirmation using the immuno-chromatographic test card. RESULTS: Consistent with the features of podoconiosis, none of the elephantiasis cases had consistently worn shoes since childhood; 94.3% had bilateral swelling limited below the level of the knees; no individual had thigh or scrotal elephantiasis; parasitological test for microfilariae and serological tests for W. bancrofti antigen were negative in all samples. The prevalence of the disease was 7.4% and it peaked in the third decade of life, the most economically active age. CONCLUSION: Midakegn District has a high prevalence of podoconiosis and no filarial elephantiasis. Prevention, treatment and control of podoconiosis must be among the top priorities of public health programmes. PMID- 22487447 TI - Panthenyl triacetate transformation, stimulation of metabolic pathways, and wound healing properties in the human skin. AB - Vitamin B5 and its derivatives are well known in personal care applications and are often used in wound healing and soothing compositions. However, little is known about the biochemical pathways involved. A better knowledge of these pathways would help to understand some of the mechanisms of action and suggest further applications. We have investigated the transformation of D-panthenyl triacetate (PTA) into D-panthenol (PAN) and its skin diffusion on human volunteers by Raman spectroscopy. Additionally, we have utilized human skin biopsies and quantitative RT-PCR to demonstrate the effect of PTA compared to PAN on 27 metabolic markers when introduced at 2% in a cosmetic emulsion. Then we conducted a double-blind clinical study to measure the effect of PTA compared to PAN on wound healing, measured by transepidermal water loss (TEWL), when incorporated at 3% in a cosmetic emulsion. Results show de-acetylation of PTA into PAN and an increased activity of PTA compared to PNA over time in the skin. Metabolic marker analysis demonstrates stimulation of energetic pathways such as glycolysis and the citric acid cycle, but also of synthesis pathways such as isoprenoids and lipid synthesis, by PTA and PAN. Finally, the clinical study demonstrates a statistically significant effect by PTA on wound healing after 72 hours when compared to a saline treatment. Statistical significance was not achieved by PAN or a placebo treatment. Due to the differences between PTA and PAN action, different applications in personal care products can be suggested. Moreover, PTA seems more effective than PAN for a long-lasting wound healing action. PMID- 22487448 TI - Effects of oxidative treatments on human hair keratin films. AB - The effects of hydrogen peroxide and commercial bleach on hair and human hair keratin films were examined by protein solubility, scanning electron microscopy (SEM), immunofluorescence microscopy, immunoblotting, and Fourier-transform infrared spectroscopy. Protein solubility in solutions containing urea decreased when the keratin films were treated with hydrogen peroxide or bleach. Oxidative treatments promoted the urea-dependent morphological change by turning films from opaque to transparent in appearance. Immunofluorescence microscopy and immunoblotting showed that the oxidation of amino acids and proteins occurred due to the oxidative treatments, and such occurrence was more evident in the bleach treated films than in the hydrogen peroxide-treated films. Compared with hair samples, the formation of cysteic acid was more clearly observed in the keratin films after the oxidative treatments. PMID- 22487449 TI - Quantitative measurement of the penetration of coconut oil into human hair using radiolabeled coconut oil. PMID- 22487450 TI - Differential wetting characterization of hair fibers. AB - Surface wetting is one of the key properties of human hair used to indicate the extent of chemical/mechanical damage and the outcome of conditioning treatment. Characterization of hair wetting property is a challenging task due to the non homogeneous nature of hair fibers and the requirement for sensitive equipment. Motivated by these considerations, we developed a new methodology, termed a differential wetting characterization (DWC), which would allow rapid and reliable characterization of the wetting property of hair fibers. This method is based on observation of a number of droplets suspended on a pair of parallel fibers stretched in a horizontal plane. The wetting behavior of the fibers can be deduced from the shape assumed by the droplets. When the wetting properties of the two hair fibers are identical, the droplets suspended between the fibers assume a symmetric configuration. In contrast, on the fibers with dissimilar wetting characteristics, the droplets will assume a skewed configuration towards a more hydrophilic fiber. This makes it possible to differentiate the hydrophobicities of the tested fibers. In this paper it is demonstrated that the proposed DWC method is capable of differentiating the changes in wetting property of hair surfaces in response to either chemical or physical treatment. Results of the paper indicate that the DWC method is applicable for broad wetting differentiation of various fibers. PMID- 22487451 TI - Fairness via formulations: a review of cosmetic skin-lightening ingredients. AB - Skin-lightening cosmetics are in big demand across Asia, and the quest for fairness has led to identification of many new ingredients. The mechanisms underlying pigmentation have been researched extensively and the knowledge is being updated regularly. This review serves to list the ingredients that are commercially available for that purpose and the modes of action through which the lightening is effected. Skin-lightening ingredients are also classified based on their sources; it is significant that far more botanicals have made the list than have synthesized compounds. Tyrosinase inhibition as a means of skin lightening is still the most reported method, followed by other methods such as Mitf inhibition, down regulation of MC1R activity, interference with melanosomal transfer, and melanocyte loss. PMID- 22487453 TI - Patients' quality of life after allogeneic haematopoietic stem cell transplantation: mixed-methods study. AB - Allogeneic haematopoietic stem cell transplantation (HSCT) is an increasingly widespread therapy method. It is associated with many socio-psychological and physical risks. Forty-four subjects, who were clinically monitored at the Bolzano BMT Centre including a follow-up period of at least 3 months, completed the questionnaire Functional Assessment of Chronic Illness Therapy-Bone Marrow Transplantation (version 4). Semi-structured, problem-oriented interviews were conducted with seven randomly selected subjects, the results of which were subjected to a summarising content analysis according to Mayring. The results from the quantitative and qualitative parts were compared based on triangulation. In the random sample, 22.7% stated that they were highly satisfied with their current quality of life (QOL). Throughout all dimensions of the questionnaire, women showed lower scores than men. The results revealed a positive correlation between the post-HSCT period and QOL (r(s)=0.338, P=0.025), especially regarding the social/family (r(s)=0.411, P=0.006) and emotional well-being (r(s)=0.306, P=0.043). The interviews primarily revealed dependence and inability to work. The support received from family, friends and hospital staff and the shift in priorities because of the transplantation were perceived as positive. The comparison mainly leads to corresponding results of the quantitative and qualitative parts of the study. Patient self-rating using questionnaires and interviews plays a direct and relevant role in the assessment of the QOL after allogeneic HSCT. PMID- 22487455 TI - Effect of marbofloxacin on Haemophilus parasuis nasal carriage. AB - Haemophilus parasuis is a colonizer of the upper respiratory tract and the causative agent of Glasser's disease in swine. This study focused on the nasal carriage of H. parasuis after treatment with marbofloxacin. Three marbofloxacin treatments (three doses of 2mg/kg body weight [bw] every 24h, two doses of 4 mg/kg bw every 48 h and 8 mg/kg bw in one single shot) were used and all of them reduce significantly (p<0.05) the nasal carriage of H. parasuis as compared to control animals. Moreover, H. parasuis was not detected in the nasal cavities of piglets after administering the highest dose. The effect of a dose of 8 mg marbofloxacin/kg bw in one shot was further studied in a farm with clinical cases of Glasser's disease using a longitudinal study. Statistically significant reduction of nasal carriage of H. parasuis was detected during the first week after treatment in comparison with the control group. However, a clear relationship between the minimum inhibitory concentration (MIC) of the different strains, their putative virulence or the treatment group (antibiotic or control) from which they were isolated was not detected. Finally, the effect induced by the antibiotic treatment on the bacterial strains seemed to be transitory, since diverse H. parasuis strains (with high and low marbofloxacin MICs) were observed 7 days after finishing the treatment. PMID- 22487456 TI - Changes in the caecal microflora of chickens following Clostridium perfringens challenge to induce necrotic enteritis. AB - Necrotic enteritis is a disease of considerable economic importance to the global poultry industry. Clostridium perfringens has long been recognised as the etiological agent of the disease. However, disease initiation and progression is complex and appears to be precipitated by a range of predisposing factors. The present study investigated microbial interactions in the caecum of birds challenged with C. perfringens that developed necrotic enteritis. Bacterial populations of healthy and diseased birds, across two independent animal trials, were characterised by pyrosequencing of the V1-V3 region of 16S rRNA genes. Significant changes in the microbiota of infected birds were detected. Most of the affected bacterial species, including a number of butyrate producers, were reduced in abundance in infected birds compared to uninfected controls and a number of phylotypes, classified as Weissella species, were also more abundant in healthy birds. Conversely, some bacterial groups were more abundant in the C. perfringens-infected birds, for example, members of an unclassified order of Mollicutes showed a 3.7-fold increase in abundance in infected birds. Representative sequences from this novel order shared 99% identity with sequences previously detected in intestinal microbiota of chickens and humans, and have previously been shown to be represented in a number of samples originating from irritable bowel syndrome disease patients. We speculate that these newly identified perturbations in the composition of caecal microflora may play a role in the development and manifestation of necrotic enteritis. PMID- 22487454 TI - Loss of glutathione homeostasis associated with neuronal senescence facilitates TRPM2 channel activation in cultured hippocampal pyramidal neurons. AB - BACKGROUND: Glutathione (GSH) plays an important role in neuronal oxidant defence. Depletion of cellular GSH is observed in neurodegenerative diseases and thereby contributes to the associated oxidative stress and Ca2+ dysregulation. Whether depletion of cellular GSH, associated with neuronal senescence, directly influences Ca2+ permeation pathways is not known. Transient receptor potential melastatin type 2 (TRPM2) is a Ca2+ permeable non-selective cation channel expressed in several cell types including hippocampal pyramidal neurons. Moreover, activation of TRPM2 during oxidative stress has been linked to cell death. Importantly, GSH has been reported to inhibit TRPM2 channels, suggesting they may directly contribute to Ca2+ dysregulation associated with neuronal senescence. Herein, we explore the relation between cellular GSH and TRPM2 channel activity in long-term cultures of hippocampal neurons. RESULTS: In whole cell voltage-clamp recordings, we observe that TRPM2 current density increases in cultured pyramidal neurons over time in vitro. The observed increase in current density was prevented by treatment with NAC, a precursor to GSH synthesis. Conversely, treatment of cultures maintained for 2 weeks in vitro with L-BSO, which depletes GSH by inhibiting its synthesis, augments TRPM2 currents. Additionally, we demonstrate that GSH inhibits TRPM2 currents through a thiol independent mechanism, and produces a 3.5-fold shift in the dose-response curve generated by ADPR, the intracellular agonist for TRPM2. CONCLUSION: These results indicate that GSH plays a physiologically relevant role in the regulation of TRPM2 currents in hippocampal pyramidal neurons. This interaction may play an important role in aging and neurological diseases associated with depletion of GSH. PMID- 22487457 TI - Prevalence of ESBLs and PMQR genes in fecal Escherichia coli isolated from the non-human primates in six zoos in China. AB - The aim of this study is to characterize the prevalence of extended-spectrum beta lactamases (ESBLs) and plasmid-mediated quinolone resistance (PMQR) genes in Escherichia coli from captive non-human primates. A total of 206 E. coli isolates were collected from primates in six zoos in China in 2009 and their susceptibility to 10 antimicrobials were tested by broth microdilution. The susceptibility patterns of E. coli strains varied greatly among different zoos reflecting different backgrounds of antimicrobial usage. Both the ESBL-encoding genes and the PMQR genes were detected by PCR. Of the 206 strains, 65 (32%) were confirmed as phenotypic ESBL producers with bla(CTX-M) (27%, bla(CTX-M-15), n=31, bla(CTX-M-3), n=23 and bla(CTX-M-14), n=2) mainly mediating the ESBL phenotype. qnrS1 (18%, n=36) and oqxAB (15%, n=31) were the predominant PMQR genes and the prevalence of PMQR genes was much higher among phenotypic ESBL producers than that among phenotypic non-ESBL producers from any zoo. Notably, the PMQR genes qnrS1 and oqxAB and beta-lactamase genes bla(TEM-1) and bla(CTX-M-3) were found together in 23 E. coli isolates in two zoos in Shanghai. PFGE analysis of these 23 isolates demonstrated nearly identical PFGE profiles (similarity matrix >97%) indicating this specific E. coli genotype was prevalent in these two zoos. To the best of our knowledge, this is the first report of these four genes coexisting in an E. coli genotype and the first report of antimicrobial resistance profiles in E. coli isolated from primates in China. PMID- 22487458 TI - Expression of aromatase and two isozymes of 5alpha-reductase in the developing green anole forebrain. AB - Neural steroids, as well as the enzymes that produce these hormones, are important for sexual differentiation of the brain during development. Aromatase converts testosterone into oestradiol. 5alpha-reductase converts testosterone to 5alpha-dihydrotestosterone and occurs in two isozymes: type 1 (5alphaR1) and type 2 (5alphaR2). Each of these enzymes is present in the developing brain in many species, although no work has been carried out examining the expression of all three enzymes in non-avian reptiles with genetic sex determination. In the present study, we evaluated mRNA expression of neural aromatase, 5alphaR1 and 5alphaR2, on the day of hatching and at day 50 in one such lizard, the green anole. We describe the distribution of these enzymes throughout the brain and the quantification of mRNA expression in three regions that control adult sexual behaviours: the preoptic area (POA) and ventromedial amygdala (AMY), which are involved in male displays, as well as the ventromedial hypothalamus, which regulates female receptivity. Younger animals had a greater number (POA) and density (AMY) of 5alphaR1 mRNA expressing cells. We detected no effects of sex or age on aromatase or 5alphaR2. In comparison with data from adults, the present results support the idea that the green anole forebrain has not completely differentiated by 50 days after hatching and that 5alphaR1 may play a role in the early development of regions important for masculine function. PMID- 22487459 TI - Three-year outcome of isolated glomerulitis on 3-month protocol biopsies of donor HLA antibody negative patients. AB - Transplant glomerulitis (TG) can lead to the diagnosis of acute humoral rejection when associated with C4d. Recent data have shown that, in patients with donor specific antibodies, TG is a sign of humoral rejection, even in the absence of C4d. However, the clinical significance of isolated TG, i.e. TG without C4d deposition or morphological evidence of rejection, has not been specifically studied in protocol biopsies of recipients without donor-specific antibodies. We compared 20 isolated TG-patients with 44 selected recipients without TG or any rejection-associated change. The two groups had similar baseline characteristics. After a 3 year follow-up, renal function, acute rejection rate, and development of HLA antibodies were not significantly different between the two groups. Isolated TG had no deleterious consequences on the 3 year graft outcome. Eleven patients of the glomerulitis-group had another allograft biopsy during follow-up: glomerular lesions returned to normal in six patients whereas the persistence of glomerulitis or features consistent with chronic transplant glomerulopathy were noticed in the remaining five patients. Four of these five patients had pretransplant non-donor specific HLA antibodies. In conclusion, although isolated TG had no impact on allograft function at 3 year, histological outcome could be related to patient sensitization. PMID- 22487460 TI - An experimental comparison of two different clinically used implant designs and surfaces. AB - BACKGROUND: Various designs of dental implants representing different geometries and surface technologies are commercially available and clinically used in patients. However, data with regard to bone tissue responses and stability for comparison of their biologic performances are rare. PURPOSE: The aim of the present experimental investigation was to compare the bone tissue responses and implant stability between two commonly used dental implants representing different geometries and surface characteristics. MATERIALS AND METHODS: A total of 90 dental implants (4.3 mm in diameter, 10 mm long) with an oxidized surface (Replace Select Tapered, TiUnite, Nobel Biocare AB, Gothenburg, Sweden) (OX) and 90 implants (4.1 mm in diameter, 10 mm total length) with a hydrophilic sand blasted and acid etched surface (Standard Plus, SLActive, Institut Straumann AG, Basel, Switzerland) (HSBA) were placed in the distal femur (n = 1) and tibia (n = 2) of 30 rabbits. The implants were analyzed with implant stability quotient (ISQ) measurements, removal torque (RTQ) and histomorphometry (bone-implant contact, BIC) after 10 days, 3, and 6 weeks. Moreover, RTQ values were corrected for differences in surface area by calculating the shear strength for each implant. RESULTS: RTQ and ISQ measurements showed an increase with time for both implant types. A significantly higher RTQ value was observed for the HSBA implant at 3 weeks (p = .05). A lower ISQ value was seen for HSBA than for OX implants at placement in the tibia (p < 0.001). HSBA implants showed higher shear strength values than OX implants after 3 weeks (p < .001), and 6 weeks (p < .01). The morphometric measurements showed significantly higher BIC for HSBA implants after 10 days (p < .01), similar values after 3 weeks and significantly higher BIC for OX implants after 6 weeks (p < .001). CONCLUSIONS: Both HSBA and OX implants were well integrated in bone and showed firm and increased stability from placement to after 6 weeks of healing. The HSBA implant showed more BIC after 10 days and the OX implant more BIC after 6 weeks of healing. The HSBA implant showed significantly higher shear strength after 3 and 6 weeks and higher RTQ values after 3 weeks than the OX implant. The results may be due to differences in surface roughness and hydrophilic properties. PMID- 22487461 TI - If steatosis is the atherosclerosis of the liver, are statins the "aspirin" for steatosis? PMID- 22487462 TI - Risk of infant mortality with weekend versus weekday births: a population-based study. AB - AIM: To examine the association between infant mortality, the day of birth and sociodemographic factors. METHODS: This population-based retrospective study analyzed all singleton live births in the state of Missouri during the period 1989 to 1997. The main outcome of interest was infant survival after birth. Hazard ratios (HR) and 95% confidence intervals (CI) for the association between infant mortality and the day of birth were obtained through parametric time to event models. RESULTS: The neonatal mortality rate was higher on weekends (3.25/1000) compared to weekdays (2.87/1000) (P = 0.042). Cesarean section delivery increased the risk of neonatal death by a magnitude of 31.5 compared to vaginal births (HR = 31.47, 95% CI: 15.79, 62.74). Adolescent females (age <18) were more likely to experience neonatal (HR = 2.20, 95% CI: 1.47, 3.31), post neonatal (HR = 2.20, 95% CI: 1.47, 3.30) and infant mortality (HR = 4.06, CI: 2.02, 8.14). CONCLUSIONS: Cesarean section delivery heightens the risk of all infant death, including neonatal and post-neonatal death, regardless of the day of birth, underscoring the need for multi-tiered strategies to reduce the occurrence of medically unnecessary cesarean sections. Furthermore, the elevated risk of infant mortality among adolescent mothers highlights the importance of enhanced preconception care and age-appropriate pregnancy prevention interventions. PMID- 22487463 TI - Amelioration of oxidative stress in bio-membranes and macromolecules by non-toxic dye from Morinda tinctoria (Roxb.) roots. AB - Plant dyes have been in use for coloring and varied purposes since prehistoric times. A red dye found in the roots of plants belonging to genus Morinda is a well recognized coloring ingredient. The dye fraction obtained from the methanolic extract of the roots of Morinda tinctoria was explored for its role in attenuating damages caused by H(2)O(2)-induced oxidative stress. The antioxidant potential of the dye fraction was assessed through DPPH radical scavenging, deoxyribose degradation and inhibition of lipid peroxidation in mice liver. It was subsequently screened for its efficiency in extenuating damage incurred to biomembrane (using erythrocytes and their ghost membranes) and macromolecules (pBR322 DNA, lipids and proteins) from exposure to hydrogen peroxide. In addition, the non-toxic nature of the dye was supported by the histological evaluation conducted on the tissue sections from the major organs of Swiss Albino mice as well as effect on Hep3B cell line (human hepatic carcinoma). The LC-MS confirms the dye fraction to be morindone. Our study strongly suggests that morindone present in the root extracts of M. tinctoria, in addition to being a colorant, definitely holds promise in the pharmaceutical industry. PMID- 22487464 TI - Storage media enhance osteoclastogenic potential of human periodontal ligament cells via RANKL-independent signaling. AB - BACKGROUND: Hank's balanced salt solution (HBSS) and milk have gained wide acceptance as storage media for avulsed tooth. However, the effect of the media and storage time on the periodontal ligament (PDL) cells involvement in the development of root resorption is still unclear. The purpose of this study was to evaluate whether precultured PDL cells in HBSS, milk, or modified Eagle's medium alpha (alpha-MEM) would affect osteoclastogenesis. MATERIALS AND METHODS: PDL cells were precultured in HBSS, milk, or alpha-MEM for 1 h or 6 h before being co cultured with RAW 264.7 cells for an additional 3 days for mRNA analysis and 11 days for osteoclastogenesis assay. RESULTS: Cyclooxygenase-2 (COX-2) mRNA was detected immediately in PDL cells precultured in the three storage media. The expression was up-regulated markedly in all co-cultures when compared with RAW cells alone. As a result of the co-culture, interleukin-1beta (IL-1beta) expression was detectable in both PDL and RAW cells. TRAP+ multinucleated, osteoclast-like cells developed in all co-cultures; the number of TRAP+ cells was highest (P < 0.05) in the co-cultures that PDL cells precultured in milk for 6 h. The mRNA level of receptor activator of nuclear factor-kappa B ligand (RANKL) was not detected in PDL cells. Osteoprotegerin (OPG) mRNA expression reduced with increased preculture time, but the difference was not significant (P > 0.05). CONCLUSIONS: PDL cells kept in the three storage media led to TRAP+ multinucleated, osteoclast-like cells formation via RANKL-independent signaling. The ability to induce osteoclastogenesis may be considered as one of the factors to evaluate the ability of storage medium to maintain PDL viability after tooth avulsion. PMID- 22487465 TI - Congenic dissection of a major QTL for methamphetamine sensitivity implicates epistasis. AB - We previously used the C57BL/6J (B6) * A/J mouse chromosome substitution strain (CSS) panel to identify a major quantitative trait locus (QTL) on chromosome 11 influencing methamphetamine (MA)-induced locomotor activity. We then made an F(2) cross between CSS-11 and B6 and narrowed the locus (Bayes credible interval: 79 109 Mb) which was inherited dominantly and accounted for 14% of the phenotypic variance in the CSS panel. In the present study, we created congenic and subcongenic lines possessing heterozygous portions of this QTL to narrow the interval. We identified one line (84-96 Mb) that recapitulated the QTL, thus narrowing the region to 12 Mb. This interval also produced a small decrease in locomotor activity following prior saline treatment. When we generated subcongenic lines spanning the entire 12-Mb region, the phenotypic difference in MA sensitivity abruptly disappeared, suggesting an epistatic mechanism. We also evaluated the rewarding properties of MA (2 mg/kg, i.p.) in the 84- to 96-Mb congenic line using the conditioned place preference (CPP) test. We replicated the locomotor difference in the MA-paired CPP chamber yet observed no effect of genotype on MA-CPP, supporting the specificity of this QTL for MA-induced locomotor activity under these conditions. Lastly, to aid in prioritizing candidate genes responsible for this QTL, we used the Affymetrix GeneChip((r)) Mouse Gene 1.0ST Array to identify genes containing expression QTLs (eQTL) in the striatum of drug-naIve, congenic mice. These findings highlight the difficulty of using congenic lines to fine map QTLs and illustrate how epistasis may thwart such efforts. PMID- 22487466 TI - Chemotherapy and autophagy-mediated cell death in pancreatic cancer cells. AB - Autophagy is an evolutionarily preserved degradation process of cytoplasmic cellular constituents and plays important physiological roles in human health and disease. It has been proposed that autophagy plays an important role both in tumor progression and in promotion of cancer cell death, although the molecular mechanisms responsible for this dual action of autophagy in cancer have not been elucidated. Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies with 2-3% five-year survival rate. Its poor prognosis has been attributed to the lack of specific symptoms and early detection tools, and its relatively refractory to traditional cytotoxic agents and radiotherapy. Experimental evidence pointed at autophagy as a pancreatic cancer cell mechanism to survive under adverse environmental conditions, or as a defective programmed cell death mechanism that favors pancreatic cancer cell resistance to treatment. Here, we consider several phenotypical alterations that have been related to increase or decrease the autophagic process in pancreatic tumor cells. We specially review autophagy as a cell death mechanism in response to chemotherapeutic drugs. PMID- 22487467 TI - Direct histological processing of EUS biopsies enables rapid molecular biomarker analysis for interventional pancreatic cancer trials. AB - OBJECTIVE: Current practice to diagnose pancreatic cancer is accomplished by endoscopic ultrasound guided fine needle aspiration (EUS-FNA) using a cytological approach. This method is time consuming and often fails to provide suitable specimens for modern molecular analyses. Here, we compare the cytological approach with direct formalin fixation of pancreatic EUS-FNA micro-cores and evaluate the potential to perform molecular biomarker analysis on these specimen. METHODS: 130 specimens obtained by EUS-FNA with a 22G needle were processed by the standard cytological approach and compared to a separate cohort of 130 specimens that were immediately formalin fixed to preserve micro-cores of tissue prior to routine histological processing. RESULTS: We found that direct formalin fixation significantly shortened the time required for diagnosis from 3.6 days to 2.9 days (p<0.05) by reducing the average time (140 vs 33 min/case) and number of slides (9.65 vs 4.67 slides/case) for histopathological processing. Specificity and sensitivity yielded comparable results between the two approaches (82.3% vs 77% and 90.9% vs 100%). Importantly, EUS-FNA histology preserved the tumour tissue architecture with neoplastic glands embedded in stroma in 67.89% of diagnostic cases compared to 27.55% with the standard cytological approach (p < 0.001). Furthermore, micro-core samples were suitable for molecular studies including the immunohistochemical detection of intranuclear Hes1 in malignant cells, and the laser-capture microdissection-mediated measurement of Gli-1 mRNA in tumour stromal myofibroblasts. CONCLUSIONS: Direct formalin fixation of pancreatic EUS-FNA micro-cores demonstrates superiority regarding diagnostic delay, costs, and specimen suitability for molecular studies. We advocate this approach for future investigational trials in pancreatic cancer patients. PMID- 22487468 TI - Losses at chromosome 4q are associated with poor survival in operable ductal pancreatic adenocarcinoma. AB - Here we tested the prognostic impact of genomic alterations in operable localized pancreatic ductal adenocarcinoma (PDAC). Fifty-two formalin-fixed and paraffin embedded primary PDAC were laser micro-dissected and were investigated by comparative genomic hybridization after whole genome amplification using an adapter-linker PCR. Chromosomal gains and losses were correlated to clinico pathological parameters and clinical follow-up data. The most frequent aberration was loss on chromosome 17p (65%) while the most frequent gains were detected at 2q (41%) and 8q (41%), respectively. The concomitant occurrence of losses at 9p and 17p was found to be statistically significant. Higher rates of chromosomal losses were associated with a more advanced primary tumor stage and losses at 9p and 18q were significantly associated with presence of lymphatic metastasis (chi square: p = 0.03, p = 0.05, respectively). Deletions on chromosome 4 were of prognostic significance for overall survival and tumor recurrence (Cox multivariate analysis: p = 0.026 and p = 0.021, respectively). In conclusion our data suggest the common alterations at chromosome 8q, 9p, 17p and 18q as well as the prognostic relevant deletions on chromosome 4q as relevant for PDAC progression. Our comprehensive data from 52 PDAC should provide a basis for future studies with a higher resolution to discover the relevant genes located within the chromosomal aberrations identified. PMID- 22487469 TI - Intraductal polypoid growth variant of pancreatic acinar cell carcinoma metastasizing to the intrahepatic bile duct 6 years after surgery: a case report and literature review. AB - We present the first reported case of intraductal polypoid growth (IPG) variant of pancreatic acinar cell carcinoma (ACC) metastasizing to the intrahepatic bile duct. A 58-year-old Japanese woman had previously presented with obstructive jaundice and a 7.0 cm mass in the pancreatic head. She underwent biliary drainage for 2 months followed by pancreatectomy. Histological examination revealed a carcinoma with acinar pattern, immunohistochemically positive for trypsin, and acinar cell carcinoma was diagnosed. IPGs were prominent in the main pancreatic duct and its tributaries, extending into the intrapancreatic bile duct with tumor casts in the lumen. Imaging examinations 6 years later revealed a growing lesion within the intrahepatic bile duct. Needle biopsy examination suggested metastasis of ACC, and she underwent chemoradiation therapy and partial hepatectomy. Histological examination demonstrated ACC confined to the intrahepatic bile duct. The localization of metastasis and slow growth may indicate indolent biologic behavior of the IPG variant. PMID- 22487470 TI - Gene expression signature of advanced pancreatic ductal adenocarcinoma using low density array on endoscopic ultrasound-guided fine needle aspiration samples. AB - AIMS: The purpose of this study was to investigate the clinical feasibility and utility of low-density array analysis on samples obtained from endoscopic ultrasound-guided fine needle aspiration biopsy in locally advanced and/or metastatic pancreatic ductal adenocarcinoma and chronic pancreatitis. PATIENTS AND METHODS: In this prospective multicenter study, we quantified candidate gene expression in biopsies sampled from 44 locally advanced and/or metastatic pancreatic carcinoma and from 17 pseudotumoural chronic pancreatitis using dedicated low-density array microfluidic plates. RESULTS: We first demonstrated that 18S gene expression is stable and comparable in normal pancreas and pancreatic cancer tissues. Next, we found that eight genes (S100P, PLAT, PLAU, MSLN, MMP-11, MMP-7, KRT7, KRT17) were significantly over expressed in pancreatic cancer samples when compared to pseudotumoural chronic pancreatitis (p value ranging from 0.0007 to 0.0215): Linear discriminative analysis identified S100P, PLAT, MSLN, MMP-7, KRT7 as highly explicative variables. The area under receiver operating curve establishes the clinical validity of the potential diagnostic markers identified in this study (values ranging from 0.69 to 0.76). In addition, combination of S100P and KRT7 gave better diagnosis performances (Area Under Receiver Operating Curve 0.81, sensitivity 81%, specificity 77%). CONCLUSION: We demonstrate that molecular studies on EUS-guided FNA material are feasible for the identification and quantification of markers in PDAC patients diagnosed with non-resectable tumours. Using low-density array, we isolated a molecular signature of advanced pancreatic carcinoma including mostly cancer invasion related genes. This work stems for the use of novel biomarkers for the molecular diagnosis of patient with solid pancreatic masses. PMID- 22487471 TI - Locally advanced anaplastic pancreatic adenocarcinoma with initial response to FOLFIRINOX and rapid progression after five months. AB - Anaplastic pancreatic carcinoma (APC) is a rare, aggressive variant of pancreatic ductal adenocarcinoma. Surgery is the preferred treatment whenever possible, however APC is often unresectable at presentation and prognosis remains poor. We present a case of APC which showed a marked initial response to FOLFIRINOX with decreased size and increased cystic change, however then rapidly progressed with innumerable hepatic metastases after five months of FOLFIRINOX treatment. Although there is limited data on use of FOLFIRINOX in locally advanced pancreatic adenocarcinoma, it remains an attractive option in comparison to radiotherapy and 5-fluorouracil. PMID- 22487472 TI - Opie's hypothesis revisited: acute pancreatitis due to bile reflux into the pancreas. PMID- 22487473 TI - Pain-related gene expression profile during the onset and resolution of caerulein induced acute pancreatitis in mice. PMID- 22487474 TI - Serum lipid and fatty acid profiles are highly changed in patients with alcohol induced acute pancreatitis. AB - BACKGROUND/AIMS: Hyperlipidemia is one known etiology of acute pancreatitis. Alcohol use is known to induce changes in lipid metabolism and might alter the serum lipid and fatty acid profile. We hypothesized that these changes may explain individual susceptibility of developing acute pancreatitis. We compared lipid and fatty acid profiles of patients with acute alcoholic pancreatitis and alcoholic controls. METHODS: 19 patients with their first alcoholic pancreatitis and 20 controls were included. Late follow-up samples were obtained from 16 patients. Serum lipids were analyzed enzymatically and the fatty acid profile using gas chromatography. RESULTS: The concentrations of serum total cholesterol, LDL-cholesterol and HDL-cholesterol were markedly lower in patients than in controls during the acute disease but normalized after follow-up. Patients had statistically significantly lower fatty acid proportions of saturated C14:0, polyunsaturated C18:2, C18:3 and C20:3 of the n-6-series and C18:3 of the n-3 series than controls. In contrast, patients had higher percentages of saturated C16:0 and monounsaturated C18:1n9 fatty acids than controls. Mead acid, C20:3n9, marker of essential fatty acid deficiency, was lower in patients than in controls. C14:0, C20:3n6, C18:3n3 and C20:3n9 remained altered after follow-up. CONCLUSION: Serum lipid and fatty acid levels were significantly altered during the acute disease and returned toward normal after 18-24 months, suggesting that the changes are secondary to acute pancreatitis. They are unlikely to be the much sought 'trigger factor' of pancreatic necro-inflammation. However, further studies are warranted to fully establish this point. PMID- 22487475 TI - Lung injury in acute pancreatitis: mechanisms underlying augmented secondary injury. AB - Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are common complications of acute pancreatitis (AP). ALI/ARDS contribute to the majority of AP-associated deaths, particularly in the setting of secondary infection. Following secondary pulmonary infection there can be an exacerbation of AP-associated lung injury, greater than the sum of the individual injuries alone. The precise mechanisms underlying this synergism, however, are not known. In this review we discuss the main factors contributing to the development of augmented lung injury following secondary infection during AP and review the established models of AP in regard to the development of associated ALI. PMID- 22487476 TI - A novel tissue for islet transplantation in diabetics. AB - BACKGROUND: Islet transplantation for diabetes therapy has remained a challenge. None of the currently used transplantation sites have provided satisfactory results as islets seem to require a specific tissue for survival and growth. Since the submandibular gland (SMG) shares physiological and anatomical similarities with the pancreas, we attempted to use this tissue as the transplantation site. METHODS: In Experiment 1, a group of 10 female Syrian Golden hamsters' (SGH) received isolated and purified homologous islets transplanted into their right SMG. In Experiment 2, 15 female SGH received islet transplant into their left SMG as above, except that the recipient hamsters were made diabetic by streptozotocin (STZ) before islet transplantation. In Experiment 3, isolated and purified human islets were transplanted into the SMG of 10 female hamsters. RESULTS: In 8 out of 10 hamsters in Experiment 1 the islets survived and showed the same morphological structure and endocrine cell content, as intrapancreatic islets and presented signs of rapid growth and distribution. Also, as in Experiment 1, well-established islets were present in Experiment 2. Ten of the 15 hamsters pretreated with STZ had blood glucose values between 96 and 125 mg/dl, whereas three hamsters remained hyperglycemic (glucose levels between 194 and 417 mg/dl). Remarkably, the islets in the pancreas of 10 STZ treated hamsters with functioning SMG islets remained atrophic even after 12 weeks. In two hamsters transplanted islets showed degeneration and remained diabetic until their pancreatic islets regenerated. In Experiment 3, transplanted human islets were completely destroyed. CONCLUSIONS: SMG appears to be the most suitable site for islet transplantation for the treatment of diabetes. PMID- 22487477 TI - Association between lymphoepithelial cysts of the pancreas and HIV infection. AB - BACKGROUND & AIMS: To report the association of lymphoepithelial cysts (LEC) of the pancreas with Human Immunodeficiency Virus (HIV) infection. An association between LEC and HIV infection is already established in the parotid gland (PG). METHODS: Report of the first two cases of LEC of the pancreas associated with HIV infection and comparison of the clinical and histopathological aspects of LECs of the pancreas and of the PG. RESULTS: LECs of the pancreas were discovered by CT imaging in 2 patients with a history of HIV infection. Notably, LEC completely resolved in one patient after initiation of antiretroviral therapy. CONCLUSION: This is the first report of an association of LEC of the pancreas and HIV infection. In the presence of LEC of the pancreas, we propose a systematic screening for HIV infection and associated lesions in the PG. Antiretroviral therapy should be initiated in untreated patients. Surgery should be reserved for symptomatic patients in whom medical therapy has failed. PMID- 22487478 TI - Interferon gamma and glycemic status in diabetes associated with chronic pancreatitis. AB - BACKGROUND/AIMS: Although the role of cytokines in the etiopathology of chronic pancreatitis (CP) is well recognized, information on pancreatic tissue cytokines in CP with/without associated diabetes is unavailable. The aim of the present study was to identify the differences in pancreatic cytokines and observe their correlations with the glycemic status in CP. METHODS: Pancreata were obtained from CP patients (n = 44), with/without associated diabetes and non-diabetic control subjects (n= 20). Patients with CP were classified into two groups after ascertaining their diabetic status. Pancreatic cytokines (IL 1beta, IL 6, IL 8, IL 10, IL 12P70, TNF alpha, IFN gamma) were analyzed by flow cytometer. The influence of individual and cocktail of cytokines on glucose stimulated insulin release (GSIR) was examined by challenging the islets from control subjects. RESULTS: The pancreatic IFN gamma levels in diabetic and non diabetic CP patients were significantly higher in comparison to controls. The glucose stimulated insulin release (GSIR) in response to high glucose concentration in control islets, islets from non-diabetic and diabetic CP patients was 8.2, 5.67 and 3.15 MUU * 10(-3)/min/islet equivalent respectively. IFN gamma resulted in 82.35% decrease in GSIR from the control islet cells at a concentration of >20 pg/ml which was reversed by epigallocatechin-3-gallate (EGCG). CONCLUSION: These results suggest that IFN gamma among other cytokines, play a major role in beta cell dysfunction associated with CP. PMID- 22487479 TI - Patients with exocrine insufficiency due to chronic pancreatitis are undertreated: a Dutch national survey. AB - BACKGROUND: Treating exocrine pancreatic insufficiency with pancreatic enzymes is challenging because there is no fixed dose regimen. The required dose varies per patient, depending on the residual pancreatic function, the gut lumen physiology, and the fat content of each meal. Using a sufficient dose of enzymes is crucial to prevent weight loss, nutritional deficiencies, and to ameliorate steatorrhea related symptoms. Data regarding the practise of enzyme replacement therapy are lacking. Therefore, we evaluated if patients with exocrine insufficiency caused by chronic pancreatitis receive proper treatment in the Netherlands. METHODS: An anonymous survey was distributed to the members of the Dutch Association of Patients with Pancreatic Disorders. The survey focused on enzyme use, steatorrhea related symptoms, dietary consultation, and food restrictions. Responding patients were included if they had chronic pancreatitis and were treated for exocrine insufficiency with pancreatic enzymes. RESULTS: The survey was returned by 178 members who suffered from chronic pancreatitis, 161 of whom (90%) met the inclusion criteria. The mean age was 56 years and 53% were male. The median enzyme intake was 6 capsules per day and 25% of patients took 3 or less capsules. Remarkably, 70% of patients still reported steatorrhea-related symptoms, despite treatment. Only 25% of cases were referred to a dietician and 58% kept a restriction of fat (either instructed by a dietician or self-imposed). CONCLUSION: Many patients with exocrine insufficiency caused by chronic pancreatitis are under-treated in the Netherlands, a country with a well organized healthcare system. To improve treatment efficacy, patients should be educated in adjusting the enzyme dosage according to steatorrhea-related symptoms and dietary fat intake. Moreover, patients should be referred to a well-trained, specialized dietician. PMID- 22487480 TI - A novel animal model for studying pancreatic regeneration by employing photochemical reaction. AB - PURPOSE: We present photochemical-induced pancreatic necrosis (PIPN) as a novel induction method for studying pancreatic regeneration in an animal model. METHODS: Photosensitive Rose Bengal was injected through the femoral vein in rats, followed by illumination of the surface of the pancreas with a cool halogen light for a period of 20 min. At 3, 6, and 24 h, and 7, 10, 14, and 20 days, experimental animals were sacrificed; all the animals received intravenous injection with 5-bromo-2-deoxyuridine (BrdU) 1 h prior to sacrifice. RESULTS: At 3-6 h of induction of PIPN, pancreatic necrosis was superficially observed in the illuminated field. At 24 h, there was a slight increase in the depth and width of the lesion along with appearance of vascular congestion and thrombosis in the lesion. On days 7-10, the area of illumination was totally replaced by necrotic pancreatic tissue, inflammatory cell infiltrates, and newly appearing cellular components, including mesenchymal and epithelial cells, which formed tubular complexes. On day 14, clusters of tubular complexes intermingled with acinar cells, which were proven as newly formed acinar tissue by BrdU staining. On day 20, all the lesions had returned to a normal state of pancreatic tissue. CONCLUSION: This study demonstrates the potential of PIPN as a valuable method for production of an animal model for studying healing processes or regeneration of pancreatic tissue after injury. PMID- 22487481 TI - Role of radiation-induced granulocyte colony-stimulating factor in recovery from whole body gamma-irradiation. AB - The purpose of this study was to further elucidate the radioprotective role of granulocyte colony-stimulating factor (G-CSF) induced in response to irradiation. The induction of G-CSF and interleukin-6 (IL-6) in response to radiation exposure was evaluated in mice. The level of cytokine in serum was determined by multiplex Luminex. The role of G-CSF on survival and tissue injury after total body gamma irradiation was evaluated by administration of neutralizing antibody to G-CSF before radiation exposure. An isotype control was used for comparison and survival was monitored for 30 d after irradiation. Jejunum samples were used for immunohistochemistry. Ionizing radiation exposure induced significant levels of the hematopoietic cytokines G-CSF and IL-6, in mice receiving 9.2 Gy radiation. Maximal levels of G-CSF were observed in peripheral blood of mice 8h after irradiation. IL-6 levels were maximum at 12h after irradiation. Administration of G-CSF antibody significantly enhanced mortality in irradiated mice. G-CSF antibody-treated mice had higher numbers of CD68(+) cells and apoptotic cells in intestinal villi. Our results confirm that radiation exposure induces elevations of circulating G-CSF and IL-6. Neutralizing antibody to G-CSF exacerbates the deleterious effects of radiation, indicating that G-CSF induced in response to irradiation plays an important role in recovery. PMID- 22487482 TI - Recruitment and degeneration of mitochondrion-rich cells in the gills of Mozambique tilapia Oreochromis mossambicus during adaptation to a hyperosmotic environment. AB - Cellular recruitment and degeneration of branchial mitochondrion-rich (MR) cells were examined in Mozambique tilapia transferred from hypoosmotic to hyperosmotic water. To examine apoptosis in the gills associated with salinity change, tilapia were directly transferred from freshwater to 70% seawater. The TUNEL assay showed that apoptotic cells in the gills were significantly increased at 1 day after transfer, which was supported by an electron-microscopic observation that gill MR cells underwent morphological changes characteristic of apoptosis such as an irregularly shaped electron-dense nucleus and distension of the tubular system. To further examine MR-cell recruitment, freshwater-acclimated tilapia were transferred either to freshwater or to 70% seawater after BrdU injection. Immunohistochemical detection of BrdU-labeled nuclei and Na(+)/K(+)-ATPase-rich MR cells allowed us to classify BrdU-labeled MR cells into two subtypes: a single MR cell and an MR-cell complex. Although newly generated single MR cells were observed similarly in both freshwater and 70% seawater-transferred fish, the density of MR-cell complexes was much higher in 70% seawater than in freshwater. Our findings indicated that transfer from hypoosmotic to hyperosmotic water enhanced apoptosis of freshwater-type MR cells, resulting in reduction in hyperosmoregulatory ability for freshwater adaptation, and stimulated the recruitment of MR-cell complexes to develop hypoosmoregulatory ability for seawater adaptation. PMID- 22487483 TI - High prevalence of cataracts in birds with pheomelanin-based colouration. AB - The crystalline lens of the eyes of vertebrates focuses light on the retina. Therefore, maintaining the lens clear is necessary for proper visual function. However, oxidative damage to proteins of the lens leads to opacification and lens dysfunction, termed cataract. Antioxidants thus have a role in avoiding the development of cataracts through their reduction of oxidative stress, and glutathione (GSH), a key intracellular antioxidant, belongs to the primary antioxidant defence mechanism of the lens. Other physiological mechanisms that require GSH may compete with the antioxidant mechanism of the eye. Pheomelanin is a main type of melanin, the most common pigment in vertebrates, and its synthesis consumes GSH. Here, we use data on 81 bird species to test the hypothesis that species producing large amounts of pheomelanin should have diminished capacity to use GSH to protect their eyes and, as a consequence, higher prevalence of cataracts. As predicted, the proportion of pheomelanic plumage was positively associated with the proportion of individuals with cataracts across species, suggesting that production of pheomelanin may have profound fitness consequences, as birds with cataracts have limited ability to perform vital activities. This constitutes the first comparative study of cataracts in wild animals. PMID- 22487484 TI - Summer and winter torpor use by a free-ranging marsupial. AB - Torpor is usually associated with low ambient temperatures (T(a)) in winter, but in some species it is also used in summer, often in response to limited food availability. Since the seasonal expression of torpor of both placental and marsupial hibernators in the wild is poorly documented by quantitative data, we investigated torpor and activity patterns of the eastern pygmy-possum Cercartetus nanus (17.4 g) over two seasons. We used radio telemetry to track animals during winter (n=4) and summer (n=5) in a warm-temperate habitat and found that torpor was used in both seasons. In winter all animals entered periods of short-term hibernation (from 5 to 20 days) containing individual torpor bouts of up to 5.9 days. In summer, torpor bouts were always <1 day in duration, only used by males and were not related to daily mean T(a). Pygmy-possums entered torpor at night as T(a) cooled, and rewarmed during the afternoon as T(a) increased. Individuals interspersed torpor bouts with nocturnal activity and the percentage of the night animals were active was the same in summer and winter. Our study provides the first information on torpor patterns in free-ranging C. nanus, and shows that the use of torpor throughout the year is important for energy management in this species. PMID- 22487485 TI - Group adaptation, formal darwinism and contextual analysis. AB - We consider the question: under what circumstances can the concept of adaptation be applied to groups, rather than individuals? Gardner and Grafen (2009, J. Evol. Biol.22: 659-671) develop a novel approach to this question, building on Grafen's 'formal Darwinism' project, which defines adaptation in terms of links between evolutionary dynamics and optimization. They conclude that only clonal groups, and to a lesser extent groups in which reproductive competition is repressed, can be considered as adaptive units. We re-examine the conditions under which the selection-optimization links hold at the group level. We focus on an important distinction between two ways of understanding the links, which have different implications regarding group adaptationism. We show how the formal Darwinism approach can be reconciled with G.C. Williams' famous analysis of group adaptation, and we consider the relationships between group adaptation, the Price equation approach to multi-level selection, and the alternative approach based on contextual analysis. PMID- 22487486 TI - Two highly informative dinucleotide SSR multiplexes for the conifer Larix decidua (European larch). AB - We have designed two highly polymorphic microsatellite multiplexes for Larix decidua Mill (European larch), a coniferous tree species with a fragmented distribution across Europe. The multiplexes combine microsatellites previously designed for the sister species L. kaempferi and newly identified microsatellites obtained by pyrosequencing of an enriched microsatellite library and subsequent marker candidate selection. As we wanted to target highly polymorphic markers, only microsatellite motifs with a high number of repeats (>= 12) were selected. An important proportion of the marker candidates presented multiple bands, bad amplification or insufficient polymorphism. Such difficulties were expected owing to the large genome size of the studied species. Our strategy for marker validation followed most recent recommendations for microsatellite development, for example verifying marker quality in terms of polymorphism and accurate allele binning before multiplexing. The most promising loci were combined in two multiplexes, a 7-plex and a 6-plex. These were tested on a sample of 413 individuals from 18 populations distributed across the natural range. The 13 loci had from 9 to 36 alleles. Markers were successfully tested in another laboratory, confirming robustness of the marker protocols. We also tested transferability on six other larch species from Asia and North America. Overall, this study shows that, even in species with large genome size and relatively low overall polymorphism, microsatellites can be successfully developed using next-generation sequencing technologies, provided that some additional precautions are taken compared to species lacking these characteristics. PMID- 22487487 TI - Is the clinical malignant phenotype of prostate cancer a result of a highly proliferative immune-evasive B7-H3-expressing cell population? AB - OBJECTIVES: To assess the expression of the cell surface protein B7-H3 in prostate cancer, and its association to clinically relevant parameters after radical prostatectomy and to the proliferation marker Ki-67. METHODS: Radical prostatectomy specimens from a cohort of 130 patients with a median clinical follow up of 8 years were used for the analysis. The expression of B7-H3 and the proliferation marker Ki-67, as well as other standard clinicopathological parameters, were evaluated. RESULTS: A high expression of B7-H3 was associated with pathological stage T3a and T3b, high Gleason score, extraprostatic extension, seminal vesicle invasion and high proliferative activity. Univariable analysis showed that a high expression level of B7-H3 was also correlated with biochemical failure and clinical relapse, and with the expression of Ki-67. A high expression level of Ki-67 was associated with clinical progression and a tendency towards higher rates of prostate-specific antigen relapse in multivariate analyses. CONCLUSIONS: Our findings show that a high expression level of B7-H3 in prostate cancer correlates with the expression of the proliferation marker Ki-67, biochemical failure and clinical relapse. Thus, expression of the cell surface molecule B7-H3 adds to the malignant phenotype of prostate cancer cells expressing high levels of Ki-67. The impact of B7-H3 function on prostate cancer and its potential role in immunotherapy should be explored further. PMID- 22487489 TI - Molecular dynamics studies of beta-hairpin folding with the presence of the sodium ion. AB - Metal ions are ubiquitous in protein systems and play a significant role during their folding processes. Nineteen independent structures were determined for the Na(+)/beta-hairpin interacting systems, and their folding pathways are different. (i) For Na(S47), the turn is rapidly shaped with the help of Na(+) and acts as the folding nucleus for the rest regions. Two intermediate states are observed and the resulted structure is the most folded. (ii) For Na(B41), Na(B52), Na(B54), Na(S55) and Na(B56), the inclusive Na(+) ions are anchored by beta strands. The local structures around the Na(+) ions and the turn regions fold simultaneously and serve as two independent folding nuclei. (iii) The other systems have no folding nuclei and correspond to low-folded structures. Long range electrostatic interactions contribute a lot to the folding, especially from the four negatively charged residues (Glu42, Asp46, Asp47 and Glu56). The initial positions of the Na(+) ions are largely responsible for the different folding behaviors. The interactions with sidechain- rather than backbone-O atoms generally lead to more compact structures. Another factor affecting the folding is whether the O atoms are associated with native H-bonds, and those involved show decreased affinities to metal ions. The addition of water solvent does not induce obvious folding and conformational transitions to the Na(+)/beta-hairpin interacting systems. PMID- 22487490 TI - Dual utility of adenosine during focal AF. PMID- 22487491 TI - Co-producing novel wound care products for Epidermolysis bullosa; an empirical case study of the use of surrogates in the design and prototype development process. AB - The Woundcare for Epidermolysis bullosa (WEB) project aims to enable people with Epidermolysis bullosa (EB), their carers and clinicians to co-produce wound care products to meet their needs. EB is an inherited disorder causing extensive, painful skin blistering and wounds. It is relatively rare, with approximately 300 000 patients worldwide, but it incurs high costs (up to L50 000 per month on products alone). During the course of four workshops, adults with EB, their carers and specialist nurses gave detailed accounts of their experiences with pre sized, pre-shaped dressings, including the need to patchwork individual dressings over large areas of broken skin. Five themes were identified from the workshop data relating to the limitations of existing products for EB wounds: dressing fit, stability, comfort, temperature and exudate. Novel designs were generated from these themes and although the intention was to develop the designs iteratively with the workshop participants, issues arose necessitating the interim use of surrogates. Our account of the design process is given, presenting the arguments for and against the use of surrogates, with suggestions for incorporating surrogate input into product development in a way that does not undermine the integrity of patient experiences or the co-production process. PMID- 22487492 TI - What makes a healthier nurse, workplace or leisure physical activity? Informed by the Australian and New Zealand e-Cohort Study. AB - AIM AND OBJECTIVE: To investigate health differences between nurses who report meeting the daily physical activity recommendations in or away from the workplace. BACKGROUND: Adhering to the national physical activity recommendations has known health benefits. Whilst often considered a workplace active profession, data are emerging of poor health amongst nurses. However, health differences between workplace or leisure-time physically active nurses are understudied. DESIGN: The investigation is an observation study of Australian and New Zealand nurses. Data were generated from the longitudinal, population-based, observational e-Cohort nursing survey. METHODS: Data were informed and groups defined by the self-reported minutes per day of moderate physical activity collected from a large international survey of practicing nurses (n = 2264). Groups were: Group (G) 1--high workplace (>=30 minutes/day)/high leisure (>=30 minutes/day), G2--high workplace/low leisure (<30 minutes/day), G3--low workplace/low leisure (<30 minutes/day) and G4--low workplace/high leisure. RESULTS: G2 had a high BMI and were younger than G4. G4 were significantly more active away from work and more likely to report cycling to work than G2. In contrast, G2 were most likely to have taken sick days because of their health (chi(2) = 19.101), have difficulty sleeping most of the time and have a medical history of diagnosed anxiety and depression. CONCLUSIONS: This study shows that improved well-being can be achieved in nursing cohort through leisure-time physical activity. RELEVANCE TO CLINICAL PRACTICE: This research shows that nurse should consider leisure-time physical activity necessary to maintain and prolong health and that workplace activity is not a sufficient stimulus. This has important implications for workforce planners and administrators. PMID- 22487494 TI - Age-dependent regulation of tumor-related microRNAs in the brain of the annual fish Nothobranchius furzeri. AB - MicroRNAs are regulators of gene expression. We used miRNA-seq by the Illumina platform to quantify and compare the temporal miRNA expression profiles in the brain of a short-lived (GRZ) and a longer-lived strain (MZM) of the annual fish Nothobranchius furzeri. We used fuzzy-c-means clustering to group miRNAs with similar profiles. In MZM, we found tumor suppressors with known negative interactions with MYC and/or positive interactions with TP53 among up-regulated miRNAs (e.g. miR-23a, miR-26a/b, miR-29a/b and miR-101a) in aged animals. Conversely, we found oncogenes which are MYC targets among down-regulated miRNAs (miR-7a, members of miR cluster 17~92). These latter were previously shown to be regulated in human replicative aging. In addition, three regulated miRNAs (miR 181c, miR-29a and miR-338) are known to be age-regulated and to globally contribute to regulation of their targets in the human brain. Therefore, there appears to be a degree of evolutionarily conservation in age-dependent miRNA expression between humans and N. furzeri. GRZ showed specific regulation of some miRNAs, notably a marked up-regulation of miR-124, a miRNA important for neuronal differentiation. The two strains differ in their miRNA expression profiles already at sexual maturity. Short lifespan in GRZ could therefore be--at least partially--due to dysregulated miRNA expression. PMID- 22487495 TI - A consolidated biovigilance system for blood, tissue and organs: one size does not fit all. AB - Biovigilance systems to assess and analyze risks for disease transmission through the transfer of organs, tissue, cells and blood between people is part of administrative oversight and has impact upon clinical practice and policy. In 2009, a formal recommendation by the Public Health Service requested that Health and Human Services fund and support efforts to consolidate national biovigilance efforts. There are differences in the biovigilance issues involved in organ and tissue donation/transplantation. If disease avoidance is made the dominant principle guiding organ donor testing, an unintended consequence may be an increase in deaths on the waiting list. We propose that overall benefit for the organ transplant recipient, tempered by patient informed awareness of limited organ availability and assessment processes, should be the guiding principle of such a system. PMID- 22487493 TI - Notch signals in the endothelium and cancer "stem-like" cells: opportunities for cancer therapy. AB - Anti-angiogenesis agents and the identification of cancer stem-like cells (CSC) are opening new avenues for targeted cancer therapy. Recent evidence indicates that angiogenesis regulatory pathways and developmental pathways that control CSC fate are intimately connected, and that endothelial cells are a key component of the CSC niche. Numerous anti-angiogenic therapies developed so far target the VEGF pathway. However, VEGF-targeted therapy is hindered by clinical resistance and side effects, and new approaches are needed. One such approach may be direct targeting of tumor endothelial cell fate determination. Interfering with tumor endothelial cells growth and survival could inhibit not only angiogenesis but also the self-replication of CSC, which relies on signals from surrounding endothelial cells in the tumor microenvironment. The Notch pathway is central to controlling cell fate both during angiogenesis and in CSC from several tumors. A number of investigational Notch inhibitors are being developed. Understanding how Notch interacts with other factors that control endothelial cell functions and angiogenesis in cancers could pave the way to innovative therapeutic strategies that simultaneously target angiogenesis and CSC. PMID- 22487496 TI - Global catastrophizing vs catastrophizing subdomains: assessment and associations with patient functioning. AB - OBJECTIVE: The primary objectives of the current study were to 1) confirm the three-factor model of the Pain Catastrophizing Scale (PCS) items in a Japanese sample and 2) identify the catastrophizing subdomain(s) most closely associated with measures of pain and functioning in a sample of individuals with chronic pain. DESIGN: This was based on a cross-sectional observational study. SETTING: This study was conducted in a university-based clinic. PATIENTS: One hundred and sixty outpatients with chronic pain participated in this study. OUTCOME MEASURES: Patients completed the PCS, the Brief Pain Inventory, and the Hospital Anxiety and Depression Scale; 30 patients completed the PCS again between 1 and 4 weeks later. RESULTS: Confirmatory factor analysis supported a three-factor structure of the Japanese version of the PCS, and univariate and multivariate associations with validity criterion supported the validity of the measure. Catastrophic helplessness was shown to make a unique contribution to the prediction of pain intensity, pain interference and depression, and catastrophic magnification made a unique contribution to the prediction of anxiety. CONCLUSIONS: The findings support the cross-cultural generalizability of the three-factor structure of the PCS and indicate that the PCS-assessed catastrophizing subdomains provide greater explanatory power than the PCS total score for understanding pain-related functioning. PMID- 22487497 TI - Need to reform the remuneration system to initiate a system approach to the health sector in resource-poor countries. PMID- 22487498 TI - Diversity-dependent stability under mowing and nutrient addition: evidence from a 7-year grassland experiment. AB - Anthropogenic perturbations may affect biodiversity and ecological stability as well as their relationships. However, diversity-stability patterns and associated mechanisms under human disturbances have rarely been explored. We conducted a 7 year field experiment examining the effects of mowing and nutrient addition on the diversity and temporal stability of herbaceous plant communities in a temperate steppe in northern China. Mowing increased population and community stability, whereas nutrient addition had the opposite effects. Stability exhibited positive relationships with species richness at population, functional group and community levels. Treatments did not alter these positive diversity stability relationships, which were associated with the stabilising effect of species richness on component populations, species asynchrony and portfolio effects. Despite the difficulty of pinpointing causal mechanisms of diversity stability patterns observed in nature, our results suggest that diversity may still be a useful predictor of the stability of ecosystems confronted with anthropogenic disturbances. PMID- 22487499 TI - [Reform Act on safety of drug and health products in France: announcement effect, strengthening or upheaval?]. AB - In France, the Mediator((r)) scandal and the trauma it has created, are the source of Law n degrees 2011-2012 of 29 December 2011 on strengthening safety of drug and health products, intended by the Ministry of Labour, Employment and Health, adopted by the National Assembly and promulgated in order to restore confidence and enhance safety of drug and health products. This new law affects all stakeholders and health professionals impacts key points in the life cycle of the drug: MA, reimbursement, advertising, promotion, distribution, prescription, dispensing, and pharmacovigilance. It also provides for financial, administrative or criminal penalties, which are intended deterrent. Beyond strengthening constraints on safety of health products, this new law in France foreshadowed a revolution in behaviour, attitudes and overall scenery of the health system and no one today knows exactly the outline. PMID- 22487500 TI - [A manual of good professional practices for the Clinical Investigation Centres]. AB - Clinical Investigation Centres (CICs) are academic organisations for performing clinical studies. They are a part of a national network which is co-ordinated by French national institute for health and medical research (Inserm), and the head office of healthcare provision (DGOS). There are working groups and specialised networks within the overall CIC network. The Harmonisation of CIC Procedures (HPCIC) group wrote a manual of good professional practices for clinical research. This manual is described here. This manual was written by consensus. It was approved by the coordinators of all CICs, external experts, and validated by representatives of both Inserm and the General directorate of healthcare provision (DGOS). The CIC Good Professional Practices manual is a guide divided into two sections. The first section covers the general management of a CIC (common to all CICs). The second section covers the core activities of CICs, running clinical studies (clinical study coordination, clinical investigation, data management, statistical analysis, valorisation). This manual is available for all CICs and any other clinical research organisations. It will serve as a basis for CIC self-quality evaluation, audits between CICs, and external audits. This manual shows how much the CICs want to standardise practices and procedures nationwide to offer their partners the best quality in performing clinical studies. PMID- 22487501 TI - [Sulphur mineral water and SPA therapy in osteoarthritis]. AB - OBJECTIVE: Osteoarthritis (OA), the most common degenerative osteoarticular disease, is cause of pain and limitations in physical function with high disability that can conduct to a state of psycological stress, not always considered adequately, with negative impact on the quality of life. The mud and bath therapy can improve this aspect. However, these studies are insufficient. The objective of our research was to evaluate the impact of SPA therapy cycle on safety, efficacy and psychosocial disability in osteoarthritis. MATERIALS AND METHODS: The study was carried out on 99 subjects suffering from OA. The patients has treated for 12 days with applications of sulphurous mud-bath therapy from "Terme di Telese" (Benevento, Italy). At the beginning and at the end of the SPA therapy considered has assessed: 1) the adverse reactions; 2) the efficacy on the pain and functional limitations; c) the impact on the psychosocial function using the VAS scale, the SF-36 questionnaire, the WOMAC index and the SDS-Zung test. Statistical analysis of the data was performed by determining the mean +/- SD. The results were compared with the Student "t" test or Wilcoxon test. A p value < 0.05 was considered significant. RESULTS: In comparison to the basal values, this investigation has demonstrated that sulphurous mud and bath therapy has induced a significant (p < 0.01) improvement of overall quality of life with reduction of pain at rest (2.1 +/- 1.5 -> 1.2 +/- 1.3) and during daily activities (2.3 +/- 1.3 -> 1.4 +/- 1.3). This has facilitated the physical function and psychosocial disability as shown by the questionnaires SF-36, WOMAC and SDS Zung. CONCLUSIONS: In conclusion our data suggest that mud-bath therapy with sulphurous mineral water can be considered as an important phase of the therapeutic strategy in OA. PMID- 22487502 TI - [Treatment of psoriasis by methotrexate in the era of biotherapies: a study in 21 Tunisian patients]. AB - INTRODUCTION: We present here results of methotrexate, in term of efficacy and tolerance, administrated in 21 Tunisian patients with severe psoriasis. METHODS: It was a retrospective study conducted between january 2002 and december 2009 in the department of dermatology of Charles Nicolle Hospital of Tunis. We have included 21 patients with severe psoriasis treated by methotrexate. RESULTS: Patients were 53 year-middle aged with a sex-ratio = 6. Psoriasis evolved for a mean of 10 years (1month-60 years). Patients had: plaque psoriasis (n = 18, 85.8%) with 63% body surface involvement, erythrodermic psoriasis (n = 2, 9.5%) and psoriatic arthritis (n = 1, 4.7%). Methotrexate was orally administrated at an initial dose of 5-7.5 mg/week. The maximum dose was of 7.5 mg-12.5 mg/week. Complete remission was achieved in 62% of cases and partial remission in 28.5% of cases. Haematological and hepatic toxicities were observed in 2 patients (9.5%). Mean remission period was of 14 months (3 months-3 years). Seven patients had severe relapses. CONCLUSION: Our study concluded to the efficacy of methotrexate in severe psoriasis with a high rate and long term remission, despite lower doses than those classically used in the literature. PMID- 22487503 TI - [Peganum harmala L. poisoning in Morocco: about 200 cases]. AB - AIM OF THE STUDY: Peganum harmala L. is commonly used in traditional medicine in Morocco for its sedative and emmenagogue properties but expose to the risk of overdose and poisoning. The aim of our study was to analyze a series of 200 cases of poisoning collected in poison control and pharmacovigilance center of Morocco in order to describe the epidemiological, clinical, therapeutic features and outcome of patients and indicate the toxicity of this plant used primarily for therapeutic purposes. METHODS: This retrospective study performed over a period of twenty four years from January 1984 to December 2008. RESULTS: The mean age of patients was 24.4+/-16.8 years with a female predominance (167 women against 33 men). Therapeutic circumstance was found in 32.5%, followed by suicide (28.5%) and abortion (13.5%). The symptomatology was dominated by neurological, gastrointestinal and cardiovascular signs respectively 34.4%, 31.9 % and 15.8%. The evolution has been specified in 114 cases, 7 deaths have been deplored with a fatality rate of 6.2%. PMID- 22487504 TI - [Misuse of a salbutamol inhaler causing skin burns]. PMID- 22487505 TI - [Mechanisms of digoxin-induced gynecomastia: a case report and literature review]. PMID- 22487506 TI - [Rhabdomyolysis and acute renal failure secondary to ciprofloxacin therapy]. PMID- 22487507 TI - Assessing the relevance of in vitro studies in nanotoxicology by examining correlations between in vitro and in vivo data. AB - There is an urgent need for in vitro screening assays to evaluate nanoparticle (NP) toxicity. However, the relevance of in vitro assays is still disputable. We administered doses of TiO(2) NPs of different sizes to alveolar epithelial cells in vitro and the same NPs by intratracheal instillation in rats in vivo to examine the correlation between in vitro and in vivo responses. The correlations were based on toxicity rankings of NPs after adopting NP surface area as dose metric, and response per unit surface area as response metric. Sizes of the anatase TiO(2) NPs ranged from 3 to 100 nm. A cell-free assay for measuring reactive oxygen species (ROS) was used, and lactate dehydrogenase (LDH) release, and protein oxidation induction were the in vitro cellular assays using a rat lung Type I epithelial cell line (R3/1) following 24 h incubation. The in vivo endpoint was number of PMNs in bronchoalveolar lavage fluid (BALF) after exposure of rats to the NPs via intratracheal instillation. Slope analyses of the dose response curves shows that the in vivo and in vitro responses were well correlated. We conclude that using the approach of steepest slope analysis offers a superior method to correlate in vitro with in vivo results of NP toxicity and for ranking their toxic potency. PMID- 22487508 TI - Expression pattern of PLUNC proteins as an auxiliary tool for the diagnosis of high-grade mucoepidermoid carcinoma of the salivary gland. AB - BACKGROUND: Mucoepidermoid carcinomas are the most frequent malignant neoplasia of the salivary glands and are histologically classified as low, intermediate, and high grade. At present, histochemical stains such as periodic acid-Schiff or mucicarmine are useful tools in making a diagnosis. Recently, expression of the PLUNC proteins has been described in mucin-producing salivary gland tumors, with the suggestion that they could provide a powerful tool for the diagnosis of difficult cases. METHODS: This study evaluates the expression of PLUNC proteins in 30 cases of salivary gland mucoepidermoid carcinomas. Tumors were reviewed and classified according to histological grade. Periodic acid-Schiff, mucicarmine, and immunohistochemical staining for SPLUNC1, LPLUNC1, SPLUNC2, and LPLUNC2 were carried out. Immunostaining was classified as positive or negative. RESULTS: The majority of the tumors (63%) were classified as low grade, 13% were intermediate grade, and 23% were high grade. SPLUNC1 (90%) and LPLUNC1 (93%) were positive in the majority of cases, mainly in mucous cells, mucin plugs, and intermediate cells. SPLUNC2 and LPLUNC2 did not present significative expression within the tumors; however, LPLUNC2 was found to stain positively in mast cells in 83% of the samples. CONCLUSIONS: SPLUNC1 and LPLUNC1 showed a similar pattern of expression and could prove useful in the diagnosis of high-grade cases because of the differential staining in intermediate and epidermoid cells. The expression of LPLUNC2 in mast cells has not previously been reported, but further studies are necessary to validate this finding and to determine its significance. PMID- 22487509 TI - How can we utilize livers from advanced aged donors for liver transplantation for hepatitis C? AB - Advanced age donors have inferior outcomes of liver transplantation for Hepatitis C (HCV). Aged donors grafts may be transplanted into young or low model for end stage liver disease (MELD) patients in order to offset the effect of donor age. However, it is not well understood how to utilize liver grafts from advanced aged donors for HCV patients. Using the UNOS database, we retrospectively studied 7508 HCV patients who underwent primary liver transplantation. Risk factors for graft failure and graft survival using advanced aged grafts (donor age >= 60 years) were analyzed by Cox hazards models, donor risk index (DRI) and organ patient index (OPI). Recipient's age did not affect on graft survival regardless of donor age. Advanced aged grafts had significant inferior survival compared to younger aged grafts regardless of MELD score (P < 0.0001). Risk factors of HCV patients receiving advanced aged grafts included donation after cardiac death (DCD, HR: 1.69) and recent hospitalization (HR: 1.43). Advanced aged grafts showed significant difference in graft survival of HCV patients with stratification of DRI and OPI. In conclusion, there was no offsetting effect by use of advanced aged grafts into younger or low MELD patients. Advanced aged grafts, especially DCD, should be judiciously used for HCV patients with low MELD score. PMID- 22487510 TI - Lemierre's syndrome in a patient with habitual toothpick usage. AB - Lemierre's syndrome is characterized by septic thrombophlebitis of the internal jugular vein that is complicated by metastatic infections. The disease usually presents after oropharyngeal infection. In rare cases, odontogenic infection has been implicated as culprit. Here, we report a case of Lemierre's syndrome that most likely developed secondary to toothpick usage. The patient had an uneventful recovery after the timely administration of the appropriate antibiotics. PMID- 22487511 TI - Proximal epithelioid sarcoma of the vulva: a case report and review of current medical literature. AB - Proximal-type epithelioid sarcoma (PES) of the vulva is an exceedingly rare soft tissue tumor with an unpredictable symptom pattern and frequent recurrences. Information on management is limited. This report describes a 51-year-old woman with proximal-type epithelioid sarcoma of the vulva which was resected surgically and reviewed the current medical literature regarding the diagnosis and management of this disease. PMID- 22487512 TI - Immediate radical cystectomy vs conservative management for high grade cT1 bladder cancer: is there a survival difference? AB - OBJECTIVE: To determine whether a survival difference exists between patients with high grade (HG) cT1 urothelial cell carcinoma (UCC) receiving immediate radical cystectomy (IRC) as opposed to those choosing bladder-sparing therapy. PATIENTS AND METHODS: Between January 1990 and August 2010, 349 patients were retrospectively identified with a diagnosis of HG cT1 UCC of the bladder. Patients were divided into two groups: those who underwent IRC and those treated with conservative management (CM), consisting of transurethral resection of the bladder tumour (TURBT) and intravesical therapy. IRC was defined as surgery within 90 days of HG cT1 diagnosis with no intervening transurethral resection (TUR) or intravesical therapy (IVT). Trends in patient selection and cancer specific survival (CSS) were analyzed over consecutive decades. The primary outcome was to compare CSS among patients during consecutive decades whereby management paradigms shifted from IRC to CM. The secondary outcome was to examine whether patient selection changed over time for each respective intervention. RESULTS: One hundred and thirteen patients underwent IRC and 236 had CM. From 1990 to 1999, only 90 patients were diagnosed with HG cT1 disease, and a majority of patients (n= 54) underwent IRC. From 2000 to 2010, only 23% (59/259) of the patients with HG cT1 underwent IRC. Despite 42.3% more patients successfully maintaining their bladder in the long-term, no difference in 5 year bladder CSS was noted between decades (77% vs 80% consecutively, P= 0.566). A subset analysis of risk factors for bladder cancer progression/recurrence demonstrated more patients with lymphovascular invasion (LVI) on TUR underwent IRC in the current era (13/59 (22.0%) vs 13/200 (6.5%), P < 0.001). These findings remain to be validated in prospective work at other institutions. CONCLUSION: Conservative management strategies are a viable treatment option within a well selected subset of patients with HG cT1 UCC. PMID- 22487513 TI - Evaluation of the clinical efficacy of fractional radiofrequency microneedle treatment in acne scars and large facial pores. AB - BACKGROUND: Fractional technology overcomes the problems of ablative lasers, such as inaccurate depth control and damage to the epidermis. Minimally invasive fractional radiofrequency microneedle devices allow for more-selective heating of the dermis. OBJECTIVE: To evaluate the clinical efficacy of fractional radiofrequency microneedle (ERM) treatment in acne scars and large facial pores. MATERIALS AND METHODS: Thirty patients with acne scars and large facial pores were enrolled. Bipolar radiofrequency energy was delivered to the skin through the electrodes of the FRM device. Skin lesions were evaluated according to grade of acne scars, Investigator Global Assessment of large pores, skin surface roughness, transepidermal water loss (TEWL), dermal density, microscopic and composite image, sebum measurement, and questionnaires regarding patient satisfaction. RESULTS: The grade of acne scars and Investigator Global Assessment of large pores improved in more than 70% of all patients. Skin surface roughness, dermal density, and microscopic and composite images also improved, whereas TEWL and sebum measurement did not change. CONCLUSION: Clinical improvement from FRM treatment appeared to be related to dermal matrix regeneration. FRM treatment may be effective in improving acne scars and facial pores. PMID- 22487514 TI - A new model of Pde4d deficiency: genetic knock-down of PDE4D enzyme in rats produces an antidepressant phenotype without spatial cognitive effects. AB - Phosphodiesterases (PDEs) are a superfamily of intracellular second messenger cyclic nucleotide hydrolyzing enzymes composed of 12 families. The Pde4 family has been implicated in depression and cognition, and PDE4 inhibitors have been evaluated as antidepressants and possible cognitive enhancers. Pde4d(-/-) mice show an antidepressant phenotype and learning enhancement on some tests, but not others as do mice treated with PDE4 inhibitors. Here, we report for the first time the behavioral phenotype of a new Pde4d knock-down (KD) rat model of PDE4D deficiency. Consistent with other data on PDE4D deficiency, Pde4d KD rats showed depression resistance in the Porsolt forced swim test and hyperreactivity of the acoustic startle response with no differential response on prepulse inhibition, suggesting no sensorimotor gating defect. Pde4d KD rats also exhibited a small exploratory activity reduction but no difference following habituation, and no enhanced spatial learning or reference memory in the Morris water maze. A selective improvement in route-based learning in the Cincinnati water maze was seen as well as enhanced contextual and cued fear conditioning and a more rapid rate of cued extinction from their higher freezing level that declined to wild type (WT) levels only after ~20 extinction trials. The rat model confirms Pde4d's role in depression but not in spatial learning or memory enhancement and shows for the first time higher fear conditioning and altered extinction compared with controls. The new model provides a tool by which to better understand the role of PDE4D in neuropsychiatric disorders and for the development of alternate treatment approaches. PMID- 22487515 TI - The sixth nationwide epidemiological survey of chronic pancreatitis in Japan. AB - OBJECTIVES: A nationwide survey was conducted to clarify the epidemiological features of patients with chronic pancreatitis (CP) in Japan. METHODS: Two sequential surveys were conducted. In the first survey, both the prevalence and incidence of CP in Japan in 2007 were estimated by a questionnaire, which was mailed to 3027 randomly chosen Japanese facilities. In the second survey, the second questionnaire was then mailed to 1110 facilities selected by the first survey to clarify the clinicoepidemiological features of the patients. RESULTS: The estimated annual prevalence of CP was 36.9 per 100,000; 53.2 in males and 21.2 in females. The estimated annual incidence was 11.9 per 100,000. The prevalence and the incidence of CP gradually increased in Japan as compared to former surveys. The sex ratio (male/female) of definitive and probable CP patients was 4.5, with a mean age of 59.4 years; 59.2 years in males and 60.2 years in females. Alcoholic (69.7%) was most the common and idiopathic (21.0%) was the second most common cause of CP. The proportion of alcoholic CP increased as compared to the 55.5% found in 1994. The clinical features of overall Japanese patients with CP were: abdominal pain (60.6%), malabsorbtion (12.2%), diabetes mellitus (39.7%) and pancreatolithiasis (75.7%). Alcoholic patients were characterized by high morbidity as compared to nonalcoholic patients: abdominal pain (alcoholic 65.0% vs nonalcoholic 53.0%, p < 0.0001), diabetes mellitus (44.8% vs 31.4%, p < 0.0001) and pancreatolithiasis (84.0% vs 60.8%, p < 0.0001). CONCLUSION: The prevalence and the incidence of CP, especially alcoholic CP, have been increasing in Japan. PMID- 22487516 TI - Pancreatic pseudocysts: prognostic factors for their development and their spontaneous resolution in the setting of acute pancreatitis. AB - BACKGROUND AND AIM: Previous studies on the development of pancreatic pseudocysts following acute pancreatitis were monocentric, mostly retrospective, did not fulfil the Atlanta criteria, and featured a mixture of patients with post-acute and chronic pancreatitis. Therefore, the natural course of pancreatic pseudocysts after acute pancreatitis and the reasons for their spontaneous resolution remain unknown. METHODS: This prospective study of 369 patients investigated the prognostic factors for development of pancreatic pseudocysts and for their spontaneous resolution after a first episode of acute pancreatitis. RESULTS: On discharge, 124 (34%) patients still had pancreatic fluid collections. The prognostic factor for these fluid collections was severe acute pancreatitis. Follow-up examination 3 and 6 months later showed pancreatic pseudocysts in 36 (10%) patients (30 with and 6 without prior fluid collection), and in 27 (7%) patients (25 with and 2 without pancreatic pseudocyst after 3 months), respectively. The prognostic factors for their development were alcohol abuse and an initial severe course of the disease. Spontaneous complete resolution of the pancreatic pseudocysts occurred in 11 (31%) of the 36 patients. Prognostic factors for the spontaneous resolution were no or mild symptoms (nausea, vomiting, abdominal pain) and a maximal cyst diameter of <4 cm. CONCLUSIONS: Patients with a first severe attack of acute pancreatitis and fluid collections at discharge should be checked by ultrasonography for pancreatic pseudocysts 3 months later. In patients with a small pseudocyst and mild symptoms therapy may be postponed for a further 3 months, since spontaneous resolution is possible. PMID- 22487517 TI - miR-15b and miR-16 induce the apoptosis of rat activated pancreatic stellate cells by targeting Bcl-2 in vitro. AB - OBJECTIVES: Activated pancreatic stellate cells (PSCs) play a pivotal role in the development of pancreatic diseases, especially chronic pancreatitis and pancreatic cancer. MicroRNAs have become a focal point of interest as post transcriptional regulators of gene expression via their interaction with the 3' untranslated region of target mRNAs, which results in gene silencing. We examined the relative expression of microRNAs (miR-15b and miR-16) and their target gene, Bcl-2, during activation of rat PSCs, and determined their effects on apoptosis of rat PSCs in vitro. METHODS: miR-15b and miR-16 expression levels were analyzed in quiescent and activated PSCs by stem-loop RT-PCR. In addition, the effects of miR-15b and miR-16 on apoptosis of activated PSCs were investigated by immunofluorescence microscopy with Hoechst 33342 staining, and flow cytometry with annexin-V/propidium (PI) co-labeling. Bcl-2 and Bcl-xl were also analyzed by real-time RT-PCR and Western blotting. RESULTS: During activation of PSCs, from the quiescent stage to activated stage, miR-15b and miR_16 were downregulated, while Bcl-2 expression was upregulated. Restoring intracellular miRNA levels by miR-15b and miR-16 administration greatly reduced Bcl-2 protein levels, and significantly induced apoptosis in activated PSCs. CONCLUSIONS: miR-15b and miR 16 could induce apoptosis of rat PSCs by targeting Bcl-2. PMID- 22487518 TI - Improved glycemic control in pancreatic diabetes through intensive conservative insulin therapy. AB - OBJECTIVE: The aim of this study was to evaluate the effectivity and safety of insulin therapy in patients with DM secondary to underlying chronic pancreatitis with initially inappropriate glycemic control. METHODS: Pancreatic DM patients treated with oral antidiabetics (OAD) or pre-mixed insulin (PMI) with HbA1c >=7.0% were recruited. Intensive conservative insulin treatment (ICT) (Group A, n = 16) or PMI (Group B, n = 8) was introduced instead of OAD, or the initial PMI therapy was switched to ICT (Group C, n = 10). The changes in HbA1c, fasting plasma glucose, body weight and hypoglycemic events from baseline to 2 years were followed. RESULTS: The patients in Group A and B had been treated with oral antidiabetics for 55 +/- 68 months before switching to insulin therapy. The level of HbA1c had worsened from 8.3 +/- 1.5% to 9.8 +/- 1.7% during this period. The ICT had reduced HbA1c significantly from 9.7 +/- 1.8% to 7.6 +/- 1.4% after 12 weeks, in Group A, and five patients had HbA1c<7.0%. The introduction of PMI in Group B reduced HbA1c from 10.0 +/- 1.4% to 9.0 +/- 0.6% by 12 weeks. None of the patients had HbA1c<7.0%. By 12 weeks, the introduction of ICT in Group C had reduced the level of HbA1c from 8.8 +/- 1.7% to 7.7 +/- 1.2%. Two patients reached HbA1c<7.0%. There were two severe hypoglycemic episodes during the 2 years, one-one case in Group A and B. CONCLUSIONS: Oral medication becomes insufficient early in pancreatic DM. Long-term improvement of glycemic control can be achieved through intensified insulin therapy and in selected cases through PMI with a low risk of hypoglycemia. PMID- 22487519 TI - Pancreatic nociception--revisiting the physiology and pathophysiology. AB - BACKGROUND: Pain management of many pancreatic diseases remains a major clinical concern. This problem reflects our poor understanding of pain signaling from the pancreas. OBJECTIVES: This review provides an overview of our current knowledge, with emphasis on current pain management strategies and recent experimental findings. METHODS: A systematic search of the scientific literature was carried out using EMBASE, PubMed/MEDLINE, and the Cochrane Central Register of Controlled Trials for the years 1965-2011 to obtain access to all publications, especially randomized controlled trials, systematic reviews, and meta-analyses exploring pain and its management in disease states such as acute pancreatitis (AP), chronic pancreatitis (CP) and pancreatic cancer (PC). RESULTS: Over the last decade, numerous molecular mediators such as nerve growth factor and the transient receptor potential (TRP) cation channel family have been implicated in afferent nerve signaling. More recent animal studies have indicated the location of the receptive fields for the afferent nerves in the pancreas and shown that these are activated by agents including cholecystokinin octapeptide, 5 hydroxytryptamine and bradykinin. Studies with PC specimens have shown that neuro immune interactions occur and numerous agents including TRP cation channel V1, artemin and fractalkine have been implicated. Experimental studies in the clinical setting have demonstrated impairment of inhibitory pain modulation from supraspinal structures and implicated neuropathic pain mechanisms. CONCLUSIONS: Our knowledge in this area remains incomplete. Characterization of the mediators and receptors/ion channels on the sensory nerve terminals are required in order to facilitate the development of new pharmaceutical treatments for AP and CP. PMID- 22487520 TI - TNF-alpha gene (TNFA) variants increase risk for multi-organ dysfunction syndrome (MODS) in acute pancreatitis. AB - BACKGROUND/OBJECTIVES: Acute pancreatitis (AP) is a complex inflammatory syndrome with unpredictable progression to systemic inflammation and multi-organ dysfunction syndrome (MODS). Tumor necrosis factor alpha (TNF-alpha) is a cytokine that may link inflammation to the systemic inflammatory response syndrome (SIRS), which usually precedes MODS. Small genetic cohort studies of the TNFA promoter in AP produced ambiguous results. We performed a comprehensive evaluation of TNFA promoter variants to assess both susceptibility to AP and risk of progression to MODS. METHODS: We prospectively ascertained 401 controls and 211 patients with AP that were assessed for persistent SIRS (>48 h) and MODS. MODS was defined as failure of >=2 organ systems (cardiovascular, pulmonary, and/or renal) persisting more than 48 h. Subjects were genotyped by DNA sequencing and analyzed for SNPs at -1031 C/T (rs1799964), -863 A/C (rs1800630), 857 C/T (rs1799724), -308 A/G (rs1800629), and -238 A/G (rs361525). RESULTS: Twenty-three of 211 AP patients (11%) developed MODS. TNFA promoter variants were not associated with susceptibility to AP, but progression to MODS was associated with the minor allele at -1031C (56.5% vs. 32.4% P = 0.022, OR: 2.7; 95%CI: 1.12 6.51) and -863A (43.5% vs. 21.8% P = 0.022, OR: 2.76; 95%CI: 1.12-6.74). CONCLUSION: TNFA promoter variants do not alter susceptibility to AP, but rather the TNF-alpha expression-enhancing -1031C and -863A alleles significantly increased the risk of AP progression to MODS. These data, within the context of previous studies, clarify the risk of specific genetic variants in TNFA and therefore the role of TNF-alpha in the overall AP syndrome. PMID- 22487521 TI - Recombinant human activated protein C as a disease modifier in severe acute pancreatitis: systematic review of current evidence. AB - BACKGROUND: The severity of organ failure caused by acute pancreatitis (AP) is the most important determinant of mortality in the disease. Recombinant human activated protein C (Drotrecogin Alfa; Xigris, APC, rhAPC) is the first drug to show a decrease in all-cause mortality due to multiple organ failure caused by sepsis. As the systemic inflammatory response syndrome (SIRS) that causes organ failure in early AP is similar to that caused by severe sepsis, the use of rhAPC in the management of AP has been investigated in experimental and clinical studies which are collated in this review. METHODS: A literature review of published material identified from MEDLINE and EMBASE databases, for the period from January 1985 to January 2011, reporting rhAPC usage in AP. RESULTS: 3 of 4 experimental studies reported an improvement in outcome in animals with AP given rhAPC. The clinical randomized trial showed no improvement in outcome in the treatment arm. CONCLUSION: The experimental evidence of disease amelioration in AP following intervention with rhAPC has not translated to the small clinical RCT. Given that there were only 16 patients in the treatment arm, further clinical evaluation is justified. PMID- 22487522 TI - Discovery of diagnostic biomarkers for pancreatic cancer in immunodepleted serum by SELDI-TOF MS. AB - MOTIVATION: Reports of serum pancreatic cancer (PC) biomarkers using SELDI-TOF MS have been inconsistent because different chip surfaces and interference with high abundant proteins. This study examines the influence of these factors on the detection of discriminating diagnostic biomarkers. METHODS: Serum from fourteen from patients with PC, disease controls (DC, n = 14) and healthy volunteers (HV, n = 14) were evaluated by SELDI using H50, IMAC, Q10 and CM10 chips. A further evaluation was undertaken after depletion of seven high-abundant proteins using spin cartridges. RESULTS: More protein peaks were detected in whole serum than in depleted serum for IMAC, H50 and Q10 chips: 60 vs 39, 56 vs 48 and 69 vs 65, respectively, while the CM10 found less peaks in serum (27 vs 47 peaks). However, there were more differentially expressed peaks in the depleted serum samples for PC vs DC and PC vs HV samples using the H50, Q10 and CM10 ProteinChip arrays, whereas for IMAC arrays, more discriminating peaks were seen in non-depleted serum. The highly significant peaks observed on Q10, CM10 and H50 are consistent with the previous finding of ApoA-I (m/z 27,910-28000) and ApoA-II (m/z 8758 and 17,240). In addition, a number of new discriminating protein peaks were found on different ProteinChip arrays, notably peaks at m/z 4280 and 7763 on IMAC arrays. CONCLUSION: This study confirms the diagnostic value of ApoA-I&II and identifies further potential diagnostic biomarkers for pancreatic cancer when multiple chip surfaces are used with depletion of the most highly-abundant proteins. PMID- 22487523 TI - Invasive markers identified by gene expression profiling in pancreatic cancer. AB - BACKGROUND: Molecular profiling has proven utility as a diagnostic and predictive tool in clinical oncology. However, a clinically relevant gene expression profile in pancreatic cancer remains elusive. METHODS: Primary and metastatic pancreatic cancer cell lines (BxPC-3 and AsPC-1), were stimulated with phorbol-12-myristate 13-acetate (PMA), a known inducer of cell invasion. Affymetrix gene expression microarray analysis was performed, comparing gene expression to unstimulated controls. Differential expression was identified using ArrayAssist, and confirmed using quantitative real-time PCR. Bioinformatic analysis was performed using Pathway Studio and GOstat. The derived gene expression was further validated in fresh frozen pancreatic tumour samples. The ability of the derived 3 gene expression markersto differentiate between pancreatic adenocarcinoma (PDAC) and other neoplasms, and its association with clinicopathological variables was examined. RESULTS: PMA-induced significant changes in cell line gene expression, from which distinctive 3 potential invasive markers were derived. Expression of these genes, uPA, MMP-1 and IL1-R1 was confirmed in human pancreatic tumours, and was found to differentiate PDAC from other pancreatic neoplasms. The expression of IL1-R1 in PDAC is a novel finding. We found that the expression of MMP-1 was associated with high-grade PDAC (p = 0.035, Wilcoxon rank sum). CONCLUSION: We have identified three potential invasive markers, uPA, MMP-1 and IL1-R1, whose gene expression may differentiate PDAC from other pancreatic neoplasms, and potentially reflect a more invasive phenotype. PMID- 22487524 TI - Endoscopic ultrasonographic findings predict the risk of carcinoma in branch duct intraductal papillary mucinous neoplasms of the pancreas. AB - BACKGROUND: The preoperative diagnosis of branch duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas can be very difficult, since low-risk and high-risk lesions can be difficult to differentiate even after cytological analysis. The purpose of this study was to evaluate the preoperative diagnostic value of endoscopic ultrasonography (EUS) in differentiating low-risk and high risk IPMNs. METHODS: We retrospectively identified 36 patients who underwent preoperative EUS for branch duct IPMNs. The pathological diagnosis after surgical resection was low-grade dysplasia (n = 26), moderate dysplasia (n = 1), high grade dysplasia or carcinoma in situ (n = 5), and invasive carcinoma (n = 4). We divided the patients into two groups: low risk (low-grade dysplasia or moderate dysplasia) and high risk (high-grade dysplasia or carcinoma). We focused on the diameter of the cystic dilated branch duct, the main pancreatic duct, and the mural nodule as measured using the EUS findings. RESULTS: The cystic dilated branch duct diameter (31.5 mm vs. 41.9 mm, P = 0.0225) was significantly correlated with low-risk and high-risk IPMNs, but the main pancreatic duct diameter (5.37 mm vs. 5.44 mm, P = 0.9418) was not significantly correlated with the low-risk and high-risk IPMNs. The mural nodule diameter of the papillary protrusions (4.3 mm vs. 16.4 mm, P < 0.0001) and the width diameter of the mural nodule (5.7 mm vs. 23.2 mm, P < 0.0001) were significantly correlated with low risk and high-risk IPMNs. CONCLUSIONS: The mural nodule of papillary protrusions diameter and width diameter observed using EUS was a reliable preoperative diagnostic finding capable of distinguishing low-risk and high-risk IPMNs. PMID- 22487525 TI - HDAC gene expression in pancreatic tumor cell lines following treatment with the HDAC inhibitors panobinostat (LBH589) and trichostatine (TSA). AB - BACKGROUND: In this study, the effect of LBH589 and trichostatin (TSA), a standard histone deacetylase inhibitor (HDACi) toward the growth of pancreatic cancer cell lines was studied. Thus, we examined for the first time, the HDAC family gene expression levels before and after drug treatment. METHODS: Several human pancreatic cancer cell lines (Panc-1, BxPC-3, SOJ-6) and a normal human pancreatic duct immortalized epithelial cell line (HPDE/E6E7) were used as target cells. The cell growth was measured by MTT assay, cell cycle alteration, membrane phosphatidylserine exposure, DNA fragmentation, mitochondrial membrane potential loss, RT-PCR and Western blots were done using standard methods. The effect of drugs on tumor growth in vivo was studied using subcutaneous xenograft model. RESULTS: Except in the case of certain HDAC gene/tumor cell line couples: (SIRT1/HPDE-SOJ6/TSA- or LBH589-treated cells; LBH589-treated Panc-1 Cells; HDAC2/BxPC-3/LBH589-treated cells or TSA-treated SOJ-6-1 cells), there were no major significant changes of HDACs genes transcription in cells upon drug treatment. However, significant variation in HDACs and SIRTs protein expression levels could be seen among individual cell samples. The in vivo results showed that LBH589 formulation exhibited similar tumor reduction efficacy as the commercial drug gemcitabine. CONCLUSION: Our data demonstrate that LBH589 induced the death of pancreatic tumor cell by apoptosis. In line with its in vitro activity, LBH589 achieved a significant reduction in tumor growth in BxPC-3 pancreatic tumor cell line subcutaneous xenograft mouse model. Furthermore, exploring the impact of LBH589 on HDACs encoding genes expression revealed for the first time that some of them, depending on the cell line considered, seem to be regulated during translation. PMID- 22487526 TI - New-onset diabetes in pancreatic cancer: a study in the primary care setting. AB - BACKGROUND: Onset of diabetes mellitus (DM) is often first noted by primary care physicians. New-onset DM (duration <36 months before PaC diagnosis) can be a harbinger of pancreatic cancer (PaC). However, its clinical significance remains unclear. METHODS: To determine the prevalence, onset, and delay in diagnosis of DM in PaC patients in the primary care setting, we retrospectively reviewed the records of consecutive patients followed in Mayo Clinic's primary care clinics (at least one visit in the preceding 2 years) from 1995 to 2009 who were eventually diagnosed with PaC. Onset of DM was the first date the fasting blood glucose was >=126 mg/dl. RESULTS: Of the 111 PaC patients (59 male, median age 74 years), 52 (47%) had DM of whom 30 (58%) had new-onset DM. Among the 30 with new onset DM, 24 (80%) were asymptomatic (no cancer-specific symptoms), at DM onset. In these 24 patients, median duration of DM prior to PaC diagnosis was 6.5 (0.5 35) months, and median delay between onset and physician diagnosis of DM was 2.5 (0.25-14) months, which decreased from 8.8 (3.5-14) months in patients with DM onset between 1995 and 1999 to 0 (0-2) months, in patients with DM onset between 2004 and 2009. However, the proportion of patients with undiagnosed DM (~33%) remained unchanged. CONCLUSIONS: Diabetes is very common (~50%) in PaC. In over a fifth of PaC, the onset of DM occurs when the cancer is asymptomatic, providing a potential window-of-opportunity to diagnose early PaC. However, nearly a third of new-onset DM in PaC remains undiagnosed. PMID- 22487527 TI - Adjuvant chemotherapy, with or without postoperative radiotherapy, for resectable advanced pancreatic adenocarcinoma: continue or stop? AB - AIMS: The aim of the article is to perform a focused review of adjuvant chemotherapy with or without radiotherapy for the treatment of resectable pancreatic adenocarcinoma (PAC). METHODS: We performed a Medline database search from 1965 to 2010 using the terms "adjuvant," "trial" and "pancreatic cancer". RESULTS: Adding adjuvant chemotherapy to patients with resectable PAC was associated with significantly increased median overall survival (OS) (odds ratio[OR]: 1.98, p < 0.001), disease-free survival (DFS) (OR: 2.12, p < 0.001), two-year survival (OR: 1.38, p = 0.04) and five-year survival (OR: 2.16, p = 0.007) compared to surgery alone. There was no statistically significant difference observed with regard to OS (OR:0.99, p = 0.93), DFS (OR:0.99, p = 0.95), and two-year survival (OR: 0.90, p = 0.57) between adjuvant chemoradiotherapy and surgery alone. The further analysis showed that single agent gemcitabine was as active as combined chemotherapy or chemoradiation, which was reflected by an OR of 1.13 (p = 0.26) for OS and1.08 (p = 0.47) for DFS. CONCLUSIONS: A significant benefit with regard to DFS and median OS for adjuvant chemotherapy after PAC resection was demonstrated by this analysis. These results do not support the use of adjuvant radiotherapy for PAC. PMID- 22487528 TI - Hypoxia-inducible factor-1 up-regulates the expression of Toll-like receptor 4 in pancreatic cancer cells under hypoxic conditions. AB - BACKGROUND & AIMS: Hypoxia is a common characteristic of solid tumors. Recent studies confirmed that Toll-like receptor 4 (TLR4) plays a significant role in cancer invasion and progression. In this study, the correlation between the expression of TLR4 and the change of the protein level of Hypoxia-inducible factor-1 alpha (HIF-1alpha) was studied. METHODS: We examined 84 human pancreatic cancer tissues for expression of HIF-1alpha and TLR4 proteins. Panc-1 cells were exposed to normoxia (20% O(2)) or hypoxia (<1% O(2)) or treated with CoCl(2). TLR4 protein was analyzed by flow cytometry and immunostaining. Growth studies were conducted on cells with the HIF-1alpha inhibition isolated from stable transfected cell lines. Finally, TLR4 protein was detected by immunohistochemistry in vivo tumors. RESULTS: There was a positive correlation between TLR4 and HIF-1alpha protein in pancreatic cancer tissues. Hypoxic stress induced TLR4 mRNA and protein expression in Panc-1 cells. Cells transfected with HIF-1alpha siRNA showed attenuation of hypoxia stress-induced TLR4 expression. In vivo growth decreased in response to TLR4 and HIF-1alpha inhibiton. Transient HIF 1alpha siRNA treatment could effectively curb tumor growth in vivo. CONCLUSION: These results suggest that TLR4 expression in pancreatic cancer cells is up regulated via HIF-1alpha in response to hypoxic stress and underscore the crucial role of HIF-1alpha-induced TLR4 in tumor growth. PMID- 22487529 TI - Humidity affects genetic architecture of heat resistance in Drosophila melanogaster. AB - Laboratory experiments on Drosophila have often demonstrated increased heritability for morphological and life-history traits under environmental stress. We used parent-offspring comparisons to examine the impact of humidity levels on the heritability of a physiological trait, resistance to heat, measured as knockdown time at constant temperature. Drosophila melanogaster were reared under standard nonstressful conditions and heat-shocked as adults at extreme high or low humidity. Mean knockdown time was decreased in the stressful dry environment, but there was a significant sex-by-treatment interaction: at low humidity, females were more heat resistant than males, whereas at high humidity, the situation was reversed. Phenotypic variability of knockdown time was also lower in the dry environment. The magnitude of genetic correlation between the sexes at high humidity indicated genetic variation for sexual dimorphism in heat resistance. Heritability estimates based on one-parent-offspring regressions tended to be higher under desiccation stress, and this could be explained by decreased environmental variance of heat resistance at low humidity. There was no indication that the additive genetic variance and evolvability of heat resistance differed between the environments. The pattern of heritability estimates suggests that populations of D. melanogaster may have a greater potential for evolving higher thermal tolerance under arid conditions. PMID- 22487530 TI - The design and cross-population application of a genome-wide SNP chip for the great tit Parus major. AB - The vast amount of phenotypic information collected in some wild animal populations makes them extremely valuable for unravelling the genetics of ecologically important traits and understanding how populations adapt to changes in their environment. Next generation sequencing has revolutionized the development of large marker panels in species previously lacking genomic resources. In this study, a unique genomics toolkit was developed for the great tit (Parus major), a model species in ecology and behavioural biology. This toolkit consists of nearly 100,000 SNPs, over 250 million nucleotides of assembled genomic DNA and more than 80 million nucleotides of assembled expressed sequences. A SNP chip with 9193 SNP markers expected to be spaced evenly along the great tit genome was used to genotype 4702 birds from two of the most intensively studied natural vertebrate populations [Wytham Woods/Bagley Woods (United Kingdom) and de Hoge Veluwe/Westerheide (The Netherlands)]. We show that (i) SNPs identified in either of the two populations have a high genotyping success in the other population, (ii) the minor allele frequencies of the SNPs are highly correlated between the two populations and (iii) despite this high correlation, a large number of SNPs display significant differentiation (F(ST) ) between the populations, with an overrepresentation of genes involved in cardiovascular development close to these SNPs. The developed resources provide the basis for unravelling the genetics of important traits in many long-term studies of great tits. More generally, the protocols and pitfalls encountered will be of use for those developing similar resources. PMID- 22487531 TI - Living in dressings and bandages: findings from workshops with people with Epidermolysis bullosa. AB - Epidermolysis bullosa (EB) is an inherited disorder causing extensive, painful skin blistering and wounds. Currently, there is no cure and the focus of care is on the clinical management of the skin and other affected body systems, together with supportive care to individuals and families. The wound care for Epidermolysis bullosa (WEB) project is a collaboration with adults with EB, carers, clinical nurse specialists, a designer and manufacturers to develop novel products for EB wound care. This article reports the findings from workshops with adults with EB, their carers and clinical nurse specialists, together with observations of dressing changes. A cluster of significant limitations were revealed in the performance of wound care products, designed to cover a single wound, when they are used to cover extensive and whole body wounds. A working hypothesis for EB wound care was developed from the findings, together with design concepts and new products for EB wound care. In addition, a model of user engagement in medical device development and evaluation has been tested. PMID- 22487532 TI - Editorial comment to can the Kattan nomogram still accurately predict prognosis in renal cell carcinoma using the revised 2010 tumor-nodes-metastasis reclassification? PMID- 22487533 TI - Integrating tracer-based metabolomics data and metabolic fluxes in a linear fashion via Elementary Carbon Modes. AB - Constraints-based modeling is an emergent area in Systems Biology that includes an increasing set of methods for the analysis of metabolic networks. In order to refine its predictions, the development of novel methods integrating high throughput experimental data is currently a key challenge in the field. In this paper, we present a novel set of constraints that integrate tracer-based metabolomics data from Isotope Labeling Experiments and metabolic fluxes in a linear fashion. These constraints are based on Elementary Carbon Modes (ECMs), a recently developed concept that generalizes Elementary Flux Modes at the carbon level. To illustrate the effect of our ECMs-based constraints, a Flux Variability Analysis approach was applied to a previously published metabolic network involving the main pathways in the metabolism of glucose. The addition of our ECMs-based constraints substantially reduced the under-determination resulting from a standard application of Flux Variability Analysis, which shows a clear progress over the state of the art. In addition, our approach is adjusted to deal with combinatorial explosion of ECMs in genome-scale metabolic networks. This extension was applied to infer the maximum biosynthetic capacity of non-essential amino acids in human metabolism. Finally, as linearity is the hallmark of our approach, its importance is discussed at a methodological, computational and theoretical level and illustrated with a practical application in the field of Isotope Labeling Experiments. PMID- 22487534 TI - The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival. AB - Apolipoprotein L-1 (APOL1) gene variants are associated with end-stage renal disease in African Americans (AAs). Here we investigate the impact of recipient APOL1 gene distributions on kidney allograft outcomes. We conducted a retrospective analysis of 119 AA kidney transplant recipients, and found that 58 (48.7%) carried two APOL1 kidney disease risk variants. Contrary to the association seen in native kidney disease, there is no difference in allograft survival at 5-year posttransplant for recipients with high-risk APOL1 genotypes. Thus, we were able to conclude that APOL1 genotypes do not increase risk of allograft loss after kidney transplantations, and carrying 2 APOL1 risk alleles should not be an impediment to transplantation. PMID- 22487535 TI - A qualitative study of the pre-operative preparation of children, young people and their parents' for planned continence surgery: experiences and expectations. AB - AIM: The aim of this study is to explore children's, young people's and parents' pre-operative experiences of continent stoma formation. BACKGROUND: Current research investigating continent stoma surgery focuses on surgical outcomes including complication rates, adherence to management regimes, self-management practices and levels of continence achieved. Despite reports of pre-operative anxiety in families undergoing continent stoma surgery, there has been a lack of research exploring pre-operative experiences, information needs or decision making processes in this group. DESIGN: A qualitative study. METHODS: Forty-nine semi-structured interviews were conducted with 17 children, young people and their parents. Data were collected at key points in the surgical process that aimed to represent a longitudinal perspective of continent stoma formation. RESULTS: The interviews suggested that children's, young people's and parents' information needs in relation to the long-term implications of surgery and for their day-to-day lives were not being adequately met. The preparation process was described as being positively influenced by contact with a nurse specialist, being given time to make the decision and having access to different sources of information. CONCLUSION: Decisions regarding life-long planned surgery can be challenging. The individual involvement and information needs of children, young people and their parents need to be recognised during pre-operative preparation. RELEVANCE TO CLINICAL PRACTICE: Health professionals need to discuss the holistic implications of continent stoma surgery and provide families with the time and opportunity to consider surgery and access relevant sources of information pre operatively. PMID- 22487536 TI - Sequential bevacizumab and oral cyclophosphamide for recurrent ovarian cancer. AB - OBJECTIVE: Test the safety and efficacy of sequentially blocking angiogenesis by adding oral cyclophosphamide to bevacizumab following cancer progression on bevacizumab in patients with recurrent ovarian cancer. METHODS: Eligibility included <= 2 lines of treatment for recurrence and measurable cancer by RECIST 1.0. Patients received bevacizumab (15 mg/kg every 3 weeks IV) and upon RECIST progression, oral cyclophosphamide (50mg orally daily) was added. Objectives included safety, toxicities, 3- and 6-month PFS rates, response rate, PFS, and OS. RESULTS: 20 patients were enrolled. Overall response rate was 10%, and 65% of patients had confirmed stable disease (SD). Thirteen of 20 patients received oral cyclophosphamide added to bevacizumab upon bevacizumab progression. Of these 13 patients, 1 patient subsequently achieved a PR (this patient had SD as best response during bevacizumab) and 3 patients had a confirmed SD. For all patients, median PFS was 8.41 months, 6 month PFS rate was 65%, duration of response (DOR) was 7.3 months, and median OS was 22.72 months. Median DOR for patients receiving both bevacizumab and cyclophosphamide was 8.4 months. Most toxicities were grades 1 and 2 and manageable. Grades 3 and grade 4 toxicities included 1 myocardial infarction, 1 gastrointestinal perforation (GIP), and 12/20 patients (60%) developed grade 3 HTN. CONCLUSIONS: Addition of oral cyclophosphamide to bevacizumab at the time of cancer progression on bevacizumab appears to have continued anti-cancer effects in a subgroup of patients and appears to be safe. Randomized trials testing combination versus sequential anti-angiogenic therapy for recurrent ovarian cancer are warranted. PMID- 22487537 TI - Immunohistochemical expression of Annexin A2 and S100A proteins in patients with bulky stage IB-IIA cervical cancer treated with neoadjuvant chemotherapy. AB - OBJECTIVE: Abnormal expression of Annexin A2 and S100A proteins has been reported to induce sensitivity/resistance to chemotherapy in a variety of cancers. The aim of this study was to evaluate the significance of Annexin A2 and S100A protein expression to predict response to neoadjuvant chemotherapy and prognostic significance of these protein expressions in bulky stage IB-IIA cervical cancer patients. METHODS: Paired tumor samples (pre- and post-chemotherapy) were obtained from 68 patients who were treated with cisplatin-based neoadjuvant chemotherapy and radical hysterectomy at our hospital from 2006 to 2011. The expression of Annexin A2 and S100A proteins was analyzed by immunohistochemistry. RESULTS: Thirty-six patients were identified as chemotherapy-response and 32 were non-response. (a). Protein expression in tumor cells: (1). Exposure of tumor cells to chemotherapy results in a change of Annexin A2 and S100A expression (P<0.05). (2). Annexin A2, S100A8 and S100A9 protein expression correlates with tumor response to chemotherapy (P<0.05). (b). Protein expression in stromal cells: (1). Expression of Annexin A2, S100A8 and S100A9 was increased, but S100A2 and S100A4 was decreased after exposure to chemotherapy (P<0.05). (2). Only S100A4 expression was associated with response to chemotherapy (P<0.05). Multivariate analysis revealed that tumor size (P=0.022), differentiation (P=0.000), Annexin A2 expression in stromal cells (P=0.009), and S100A8 expression in tumor cells (P=0.008) were independent prognostic factors for progression-free survival of cervical cancer patients. CONCLUSIONS: Expression of some of the measured proteins in tumor and stromal cells correlates with chemotherapy exposure, response to therapy, and progression-free survival. PMID- 22487538 TI - Second primary malignancies among women with uterine sarcoma. AB - OBJECTIVE: Uterine sarcomas (US) are rare malignancies with unclear aetiology. Studies on uterine sarcomas in the setting of second primary malignant tumours can provide clues to aetiology and identify side effects of different treatments. METHODS: A cohort of 8606 cases of US was extracted from the data from 13 cancer registries and followed for second primary cancers within the period 1943-2000. Standardized incidence ratios (SIRs) were calculated, and Poisson regression analyses were performed. RESULTS: There were 499 cancer cases observed after a first diagnosis of US (SIR 1.26, 95%CI 1.16-1.38). SIRs were elevated for cancers of the mouth and pharynx (2.16, 95%CI 1.15-3.69), colorectum (1.60, 95%CI 1.28 1.98), lung (1.73, 95%CI 1.27-2.29), breast (1.25, 95%CI 1.05-1.49), urinary bladder (1.74, 95%CI 1.02-2.79), kidney (2.00, 95%CI 1. 24-3.06), thyroid gland (2.74, 95%CI 1.42-4.79), and soft tissue sarcoma (5.23, 95%CI 2.51-9.62). The risk of breast cancer increased along with increasing age of US diagnosis (p trend 0.040). The risk of kidney cancer increased along with decreasing age of US diagnosis (p trend 0.004) and short time since the US diagnosis (p trend 0.018). CONCLUSIONS: Our study demonstrated increased risk of certain cancers following a diagnosis of US. The elevated risk for breast cancer may indicate shared hormonal aetiology, while the increased risk of colorectal and bladder cancers after US may be caused by radiation therapy of US. The clustering of smoking-related cancers after US is worth exploring in the future. PMID- 22487540 TI - Simple extrafascial trachelectomy and pelvic bilateral lymphadenectomy in early stage cervical cancer. AB - OBJECTIVE: To determine the feasibility and safety of simple extra-fascial trachelectomy plus pelvic lymphadenectomy in young patients affected by early stage cervical cancer. METHODS: We have prospectively identified all patients with early-stage cervical cancer (stages IA2-IB1) referred to our department. Inclusion criteria were: age <= 38 years, strong desire to maintain fertility, FIGO stage <= IB1, tumor size<2 cm, no LVSI, no evidence of nodal metastasis. Surgical technique included two steps: laparoscopic pelvic lymphadenectomy and vaginal simple extrafascial trachelectomy. Patients were followed up for oncological and obstetrical outcomes. RESULTS: Fourteen patients were enrolled in the study. Median age was 32 years (range 28-37); histotype was squamous in 11/14 (79%) cases and adenocarcinoma in 3/14 cases (21%); FIGO stage was IA2 in 5/14 (36%) patients, IB1 in 9/14 (64%) patients; median tumor size was 17 mm (range 14 19); median operative time was 120 min (range 95-210). No severe intraoperative complications were recorded. Postoperative complications were observed in two patients. No recurrences were detected. One patient died for other disease. Eight patients became pregnant and 3 of them had a term delivery. CONCLUSION: Low risk early-cervical cancer patients could be safely treated by simple extrafascial trachelectomy in order to maintain fertility. More studies are needed to better define the role of conservative and ultraconservative surgical approaches (i.e. conization) in this setting, either for fertility purposes or to minimize surgical complications. PMID- 22487539 TI - Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer. AB - OBJECTIVES: On the basis of reversal of taxane resistance with AKT inhibition, we initiated a phase I trial of the AKT inhibitor perifosine with docetaxel in taxane and platinum-resistant or refractory epithelial ovarian cancer. METHODS: Patients with pathologically confirmed high-grade epithelial ovarian cancer (taxane resistant, n=10; taxane refractory, n=11) were enrolled. Peripheral blood samples and tumor biopsies were obtained and (18)F-FDG-PET and DCE-MRI scans were performed for pharmacodynamic and imaging studies. RESULTS: Patients received a total of 42 treatment cycles. No dose-limiting toxicity was observed. The median progression-free survival and overall survival were 1.9 months and 4.5 months, respectively. One patient with a PTEN mutation achieved a partial remission (PR) for 7.5 months, and another patient with a PIK3CA mutation had stable disease (SD) for 4 months. Two other patients without apparent PI3K pathway aberrations achieved SD. Two patients with KRAS mutations demonstrated rapid progression. Decreased phosphorylated S6 correlated with (18)F-FDG-PET responses. CONCLUSIONS: Patients tolerated perifosine 150 mg PO daily plus docetaxel at 75 mg/m(2) every 4 weeks. Further clinical evaluation of effects of perifosine with docetaxel on biological markers and efficacy in patients with ovarian cancer with defined PI3K pathway mutational status is warranted. PMID- 22487541 TI - Biatrial fibrillation originating from different sources. PMID- 22487542 TI - Exploration of the relationship between disability perception, preference for death over disability, and suicidality in patients with acute and chronic pain. AB - HYPOTHESIS: Passive, active, and historical suicidality are associated with preference for death over disability. DESIGN: Community nonpatients without pain, community patients with pain, and patients with acute and chronic pain were compared for endorsement of disability perception and preference for death over disability. Phi correlations and chi-square analyses were calculated between preference for death over disability and six suicidality items representing passive, active, and historical suicidality. Logistic regression was used to predict preference for death over disability in patients with acute and chronic pain. RESULTS: For patients with acute and chronic pain, endorsement of preference for death over disability correlated significantly with all six suicidality items. The logistic regression models identified the following variables as predictors for preference for death over disability in patients with acute pain: the Behavior Health Inventory (BHI 2) family dysfunction scale, history of wanting to die, and disability perception. For patients with chronic pain, predictors were the BHI 2 Borderline scale, history of wanting to die, treated fairly by family item, frequent suicide ideation, people I trust turn on me item, and disability perception. Preference for death over disability was a statistically significant predictor in patients with chronic pain for disability perception, recent suicide ideation, having a suicidal plan, and a history of wanting to die but was not a significant predictor for any suicide items in patients with acute pain. CONCLUSION: Preference for death over disability is associated with passive and active suicide ideation and historical suicidality in patients with chronic pain. PMID- 22487543 TI - Water quality sample collection, data treatment and results presentation for principal components analysis--literature review and Illinois River Watershed case study. AB - Comprehensive water quality investigations to characterize large watersheds include collection of surface water samples over time at various locations within the watershed and analyses of the samples for multiple chemical and biological constituents. The size and complexity of the resulting dataset make overall evaluations difficult, and as a result, multivariate statistical methods can be useful to evaluate environmental patterns and sources of contamination. The most commonly applied multivariate method in watershed studies is principal components analysis (PCA), which uses correlation among multiple water quality constituents to effectively reduce the number of variables. The reduced set of variables may assist in the identification and description of spatial patterns in water quality that result from hydrologic and geochemical processes and from sources of contamination. The utility of PCA for identifying important environmental factors in a given study is obviously affected by sampling design, constituents analyzed, data quality, data treatment prior to PCA, methods of interpreting PCA results, and other factors. Unfortunately no comprehensive evaluations have been performed and no standard procedures exist for dealing with these issues. This paper examines and evaluates the current state-of-the-science by review of 49 published papers dealing with multivariate (typically PCA) techniques to evaluate watershed water quality. Additionally an example PCA for a surface water quality study in the Illinois River Watershed (IRW) is provided to illustrate methods to address the above issues and to evaluate the sensitivity of results to alternative methods. The example PCA evaluations were consistent with two dominant sources of surface water contamination in the IRW: 1) discharge to the streams from municipal wastewater treatment plants and 2) runoff and infiltration from fields with land applied poultry waste. PMID- 22487544 TI - The functional human neuroanatomy of food pleasure cycles. AB - Food ensures our survival and is a potential source of pleasure and general well being. In order to survive, the human brain is required to optimize the resource allocation such that rewards are pursued when relevant. This means that food intake follows a similar cyclical time course to other rewards with phases related to expectation, consummation and satiety. Here we develop a multilevel model for the full cycle of eating behavior based on the evidence for the brain networks and mechanisms initiating, sustaining and terminating the various phases of eating. We concentrate on how the underlying reward mechanisms of wanting, liking and learning lead to how human food intake is governed by both hedonic and homeostatic principles. We describe five of the main processing principles controlling food intake: hunger and attentional signal processing; motivation independent discriminative processing; reward representations; learning-dependent multimodal sensory representations and hedonic experience. Overall, the evidence shows that while human food intake is complex, we are making progress in understanding the underlying mechanisms and that the brain networks supporting the food pleasure cycle are remarkably similar to those underlying the processing of other rewards. PMID- 22487545 TI - Environment-dependent selection on mate choice in a natural population of birds. AB - Female mate choice acts as an important evolutionary force, yet the influence of the environment on both its expression and the selective pressures acting upon it remains unknown. We found consistent heritable differences between females in their choice of mate based on ornament size during a 25-year study of a population of collared flycatchers. However, the fitness consequences of mate choice were dependent on environmental conditions experienced whilst breeding. Females breeding with highly ornamented males experienced high relative fitness during dry summer conditions, but low relative fitness during wetter years. Our results imply that sexual selection within a population can be highly variable and dependent upon the prevailing weather conditions experienced by individuals. PMID- 22487546 TI - Cost-benefit analysis of laparoscopic surgery versus laparotomy for patients with endometrioid endometrial cancer: experience from an institute in China. AB - AIM: To compare the clinical outcomes and associated costs between laparoscopic and abdominal surgery for patients with endometrioid endometrial cancer. METHODS: From 2003 to 2008, 115 patients who underwent laparoscopically-assisted surgery for endometrioid endometrial cancers were enrolled in this retrospective study. Another 123 patients who had abdominal surgery for the same histological type of endometrial cancer were included as the control group. The clinico-pathological variables, surgical outcome, costs, death and case recurrence of the two groups were compared. RESULTS: There was no difference in the patients' age, body mass index, FIGO stage, histological grade or surgical types between the two groups. The patients in the laparoscopy group had less blood loss (P = 0.010), a shorter hospital stay (P < 0.001), less postoperative pain (P < 0.001) and lower complication rates (P < 0.001) than those treated by laparotomy. The total costs in the laparoscopy group were higher than that in the laparotomy group ($2073 vs $1638, P < 0.001). Patients in the laparoscopy group returned to usual activity more quickly (P = 0.001) and went back to work earlier (P = 0.013) than those in laparotomy group. With a median follow-up of 42 months for the laparoscopy group and 40 months for the laparotomy group, there was no significant difference in the number of cases with respect to death (P = 1.000) or recurrence (P = 1.000). CONCLUSIONS: Laparoscopically-assisted surgery is as effective as the laparotomy approach for the treatment of early-stage and advanced-stage endometrial cancer. The relatively higher cost of the laparoscopic surgery may be compensated by its benefits. In developing countries such as China, laparoscopically-assisted surgery is also an attractive alternative for selected patients with endometrial cancer. PMID- 22487547 TI - Quantitative imaging of energy expenditure in human brain. AB - Despite the essential role of the brain energy generated from ATP hydrolysis in supporting cortical neuronal activity and brain function, it is challenging to noninvasively image and directly quantify the energy expenditure in the human brain. In this study, we applied an advanced in vivo(31)P MRS imaging approach to obtain regional cerebral metabolic rates of high-energy phosphate reactions catalyzed by ATPase (CMR(ATPase)) and creatine kinase (CMR(CK)), and to determine CMR(ATPase) and CMR(CK) in pure gray mater (GM) and white mater (WM), respectively. It was found that both ATPase and CK rates are three times higher in GM than WM; and CMR(CK) is seven times higher than CMR(ATPase) in GM and WM. Among the total brain ATP consumption in the human cortical GM and WM, 77% of them are used by GM in which approximately 96% is by neurons. A single cortical neuron utilizes approximately 4.7 billion ATPs per second in a resting human brain. This study demonstrates the unique utility of in vivo(31)P MRS imaging modality for direct imaging of brain energy generated from ATP hydrolysis, and provides new insights into the human brain energetics and its role in supporting neuronal activity and brain function. PMID- 22487549 TI - Multimodal human communication--targeting facial expressions, speech content and prosody. AB - Human communication is based on a dynamic information exchange of the communication channels facial expressions, prosody, and speech content. This fMRI study elucidated the impact of multimodal emotion processing and the specific contribution of each channel on behavioral empathy and its prerequisites. Ninety six video clips displaying actors who told self-related stories were presented to 27 healthy participants. In two conditions, all channels uniformly transported only emotional or neutral information. Three conditions selectively presented two emotional channels and one neutral channel. Subjects indicated the actors' emotional valence and their own while fMRI was recorded. Activation patterns of tri-channel emotional communication reflected multimodal processing and facilitative effects for empathy. Accordingly, subjects' behavioral empathy rates significantly deteriorated once one source was neutral. However, emotionality expressed via two of three channels yielded activation in a network associated with theory-of-mind-processes. This suggested participants' effort to infer mental states of their counterparts and was accompanied by a decline of behavioral empathy, driven by the participants' emotional responses. Channel specific emotional contributions were present in modality-specific areas. The identification of different network-nodes associated with human interactions constitutes a prerequisite for understanding dynamics that underlie multimodal integration and explain the observed decline in empathy rates. This task might also shed light on behavioral deficits and neural changes that accompany psychiatric diseases. PMID- 22487550 TI - Monolignol biosynthesis is associated with resistance to Sclerotinia sclerotiorum in Camelina sativa. AB - The ascomycete Sclerotinia sclerotiorum is a necrotrophic plant pathogen with an extremely broad host range. It causes stem rot in Camelina sativa, a crucifer with great potential as an alternative oilseed crop. Lignification is a common phenomenon in the expression of resistance against necrotrophs, but the molecular mechanisms underlying this defence response are poorly understood. We present histochemical, gene expression and biochemical data investigating the role of monolignols in the resistance of C. sativa to S. sclerotiorum. Comparative studies with resistant and susceptible lines of C. sativa revealed substantial differences in constitutive transcript levels and gene regulation patterns for members of the gene family encoding cinnamoyl-CoA reductase (CCR), the first enzyme specifically committed to the synthesis of lignin monomers. These differences were associated with anatomical and metabolic factors. While the induction of CsCCR2 expression after inoculation with S. sclerotiorum was associated with the deposition of lignin mainly derived from guaiacyl monomers, high constitutive levels of CsCCR4 paralleled a high syringyl lignin content in healthy stems of resistant plants. The results provide evidence that plant cell wall strengthening plays a role in the resistance of C. sativa to S. sclerotiorum, and that both constitutive and inducible defence mechanisms contribute to reduced symptom development in resistant germplasm. This study provides the first characterization of quantitative resistance in C. sativa to S. sclerotiorum. PMID- 22487548 TI - Diminished performance on neuropsychological testing in late life depression is correlated with microstructural white matter abnormalities. AB - BACKGROUND: Traditional T2 weighted MR imaging results are non-specific for the extent of underlying white matter structural abnormalities present in late life depression (LLD). Diffusion tensor imaging provides a unique opportunity to investigate the extent and nature of structural injury, but has been limited by examining only a subset of regions of interest (ROI) and by confounds common to the study of an elderly population, including comorbid vascular pathology. Furthermore, comprehensive correlation of diffusion tensor imaging (DTI) measurements, including axial and radial diffusivity measurements, has not been demonstrated in the late life depression population. METHODS: 51 depressed and 16 non-depressed, age- and cerebrovascular risk factor-matched elderly subjects underwent traditional anatomic T1 and T2 weight imaging, as well as DTI. The DTI data were skeletonized using tract based spatial statistics (TBSS), and both regional and global analyses were performed. RESULTS: Widespread structural abnormalities within white matter were detected in the LLD group, accounting for age, gender and education and matched for cerebrovascular risk factors and global T2 white matter hyperintensities (T2WMH). Regional differences were most prominent in uncinate and cingulate white matter and were generally characterized by an increase in radial diffusivity. Age-related changes particularly in the cingulate bundle were more advanced in individuals with LLD relative to controls. Regression analysis demonstrated significant correlations of regional fractional anisotropy and radial diffusivity with five different neuropsychological factor scores. TBSS analysis demonstrated a greater extent of white matter abnormalities in LLD not responsive to treatment, as compared to controls. CONCLUSIONS: White matter integrity is compromised in late life depression, largely manifested by increased radial diffusivity in specific regions, suggesting underlying myelin injury. A possible mechanism for underlying myelin injury is chronic white matter ischemia related to intrinsic cerebrovascular disease. In some regions such as the cingulate bundle, the white matter injury related to late life depression appears to be independent of and compounded by age-related changes. The correlations with neuropsychological testing indicate the essential effects of white matter injury on functional status. Lastly, response to treatment may depend on the extent of white matter injury, suggesting a need for intact functional networks. PMID- 22487551 TI - Abstracts of the Meeting of the Associazione Italiana Sistema Nervoso Periferico and Gruppo Neuroscienze e Dolore della Societa Italiana di Neurologia. April 12 14, 2012. Pisa, Italy. PMID- 22487552 TI - Determinants of pancreatic islet development in mice and men: a focus on the role of transcription factors. AB - The development of the endocrine pancreas is regulated by several cell-matrix interactions that generate a diverse array of intracellular signals determining the progression of a multipotent progenitor to a mature endocrine cell. This process involves interactions between the epithelium, mesenchyma, and endothelial cells. Later in development, coordinated signaling contributes to the maintenance of the differentiated endocrine cell phenotype. It has been demonstrated that key factors as well as the sequence of events involved in mouse pancreatic development is conserved in humans. This review will discuss our current knowledge in mouse as well as human pancreatic development and highlights some important transcription factors associated with human disease. PMID- 22487553 TI - Ensuring HIV-infected pregnant women start antiretroviral treatment: an operational cohort study from Lilongwe, Malawi. AB - OBJECTIVES: HIV-infected women identified through antenatal care (ANC) often fail to access antiretroviral treatment (ART), leaving them and their infants at risk for declining health or HIV transmission. We describe results of measures to improve uptake of ART among eligible pregnant women. METHODS: Between October 2006 and December 2009, interventions implemented at ANC and ART facilities in urban Lilongwe aimed to better link services for women with CD4 counts <250/MUl. A monitoring system followed women referred for ART to examine trends and improve practices in referral completion, on-time ART initiation and ART retention. RESULTS: Six hundred and twelve women were ART eligible: 604 (99%) received their CD4 result, 344 (56%) reached the clinic, 286 (47%) started ART while pregnant and 261 (43%) were either alive on ART or transferred out after 6 months. Between 2006 and 2009, the median (IQR) time between CD4 blood draw and ART initiation fell from 41 days (17, 349) to 15 days (7,42) (P = 0.183); the proportion of eligible individuals starting ART while pregnant and retained for 6 months improved from 17% to 65% (P < 0.001). Delays generally shortened within the continuum of care from 2006 to 2009; however, time from CD4 blood draw to ART referral increased from 7 to 14 days. CONCLUSIONS: Referrals between facilities and delays through CD4 count measurements create bottlenecks in patient care. Retention improved over time, but delays within the linkage process remained. ART initiation at ANC plus use of point-of-care CD4 tests may further enhance ART uptake. PMID- 22487554 TI - The tyrosine kinase inhibitor masitinib blunts airway inflammation and improves associated lung mechanics in a feline model of chronic allergic asthma. AB - BACKGROUND: Blockade of tyrosine kinase signaling by masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, can modulate allergic airway inflammation, but effects on lung mechanics have not been well characterized. We hypothesized masitinib would decrease airway eosinophilia and consequently improve pulmonary mechanics in a feline allergic asthma model. METHODS: Asthma was induced in 12 cats using Bermuda grass allergen (BGA). Cats received 50 mg/day oral masitinib or placebo. Bronchoalveolar lavage fluid (BALF) was analyzed for eosinophils, total protein (TP) and BGA-specific IgE. Ventilator-acquired mechanics after methacholine (MCh) challenge determined MCh concentration needed to increase baseline airway resistance by 200% (EC(200)R(aw)), positive end expiratory occlusion pressure (PEEP) and end inspiratory breath hold pressure (P(plat)). An inverse correlate of respiratory system compliance P(plat)-PEEP was also calculated. Data were analyzed using the Wilcoxon test, with one-tailed significance set at p < 0.1. RESULTS: After 4 weeks, percent eosinophils in BALF was lower in masitinib-treated cats (7 +/- 9%) versus controls (30 +/- 27%, p = 0.023). BALF TP significantly differed (p = 0.047) between groups, decreasing with masitinib and increasing with placebo. BALF BGA-specific IgE was unaffected by masitinib. Both groups showed an improvement in EC(200)R(aw) (masitinib, p = 0.015; control, p = 0.078) but no significant change in PEEP after 4 weeks. Masitinib-treated cats demonstrated decreased P(plat) (p = 0.033) and P(plat) PEEP (p = 0.075) at week 4, suggesting an improvement in respiratory compliance. CONCLUSIONS: Masitinib reduced BALF eosinophilia and TP, indicating improved airway inflammation and edema, and improved P(plat) and P(plat)-PEEP, suggesting benefit to respiratory compliance influenced by airway inflammation/edema. Masitinib deserves further study in humans with chronic allergic asthma. PMID- 22487555 TI - Call to develop a standard acquisition charge model for kidney paired donation. AB - We propose a Medicare Demonstration Project to develop a standard acquisition charge for kidney paired donation. A new payment strategy is required because Medicare and commercial insurance companies may not directly pay living donor costs intended to lead to transplantation of a beneficiary of a different insurance provider. Until the 1970s, when organ procurement organizations were empowered to serve as financial intermediaries to pay the upfront recovery expenses for deceased donor kidneys before knowing the identity of the recipient, there existed similar limitations in the recovery and placement of deceased donor organs. Analogous to the recovery of deceased donor kidneys, kidney paired donation requires the evaluation of living donors before identifying their recipient. Tissue typing, crossmatching and transportation of living donors or their kidneys represent additional financial barriers. Finally, the administrative expenses of the organizations that identify and coordinate kidney paired donation transplantation require reimbursement akin to that necessary for organ procurement organizations. To expand access to kidney paired donation for more patients, we propose a model to reimburse paired donation expenses analogous to the proven strategy used for over 30 years to pay for deceased donor solid organ transplantation in America. PMID- 22487556 TI - Robustness of the outcome of adult bumblebee infection with a trypanosome parasite after varied parasite exposures during larval development. AB - The outcome of defence by the invertebrate immunity has recently been shown to be more complex than previously thought. In particular, the outcome is affected by biotic and abiotic environmental variation, host genotype, parasite genotype and their interaction. Knowledge of conditions under which environmental variation affects the outcome of an infection is one important question that relates to this complexity. We here use the model system of the bumblebee, Bombus terrestris, infected by the trypanosome, Crithidia bombi, combined with a split colony design to test the influence of the parasite environment during larval rearing on adult resistance. We find that genotype-specific interactions are maintained and adult resistance is not influenced. This demonstrates that environmental dependence of bumblebee-trypanosome interactions is not ubiquitous, and yet unknown constraints will maintain standard coevolutionary dynamics under such environmental deviations. PMID- 22487557 TI - Nanotoxicology. Preface. PMID- 22487558 TI - Differential fumarate binding to Arabidopsis NAD+-malic enzymes 1 and -2 produces an opposite activity modulation. AB - Arabidopsis mitochondria contain two NAD(+)-malic enzymes, NAD-ME1 and NAD-ME2. These proteins have similar affinity for their substrates but display opposite regulation by fumarate, which strongly stimulates NAD-ME1 but inhibits NAD-ME2 activity. Here, the interaction of NAD-ME1 and -2 with fumarate was investigated by kinetic approaches, urea denaturation assays and intrinsic fluorescence quenching, in the absence and presence of NAD(+). Fumarate inhibited NAD-ME2 at saturating, but not at low, levels of NAD(+), and it behaved as competitive inhibitor with respect to L-malate. In contrast, NAD-ME1 fumarate activation was higher at suboptimal NAD(+) concentrations. In the absence of cofactor, the fluorescence of both NAD-ME1 and -2 is quenched by fumarate. However, for NAD-ME2 the quenching arises from a collisional phenomenon, while in NAD-ME1 the fluorescence decay can be explained by a static process that involves fumarate binding to the protein. Furthermore, the residue Arg84 of NAD-ME1 is essential for fumarate binding, as the mutant protein R84A exhibits a collisional quenching by this metabolite. Together, the results indicate that the differential fumarate regulation of Arabidopsis NAD-MEs, which is further modulated by NAD(+) availability, is related to the gaining of an allosteric site for fumarate in NAD ME1 and an active site-associated inhibition by this C(4)-organic acid in NAD ME2. PMID- 22487559 TI - Use of acronyms in the patient dental record. AB - The patient dental record is a legal document that captures the history of patient care for a particular patient. This article references the American Dental Association's listing of common dental abbreviations, symbols and acronyms, which aid in establishing uniformity for clinicians. PMID- 22487560 TI - Editorial comment from Dr Matsumoto to periurethral injection of autologous adipose-derived regenerative cells for the treatment of male stress urinary incontinence: report of three initial cases. PMID- 22487561 TI - Genotoxicity of sediment extracts of the Berre lagoon (France). AB - To evaluate the genotoxic risk that contaminated sediment could constitute for benthic organisms, three contaminated (VA, VC and VN) and one uncontaminated (RN) sediment samples were collected in the Berre lagoon (France). Potentially bioavailable contaminants in sediments were obtained using sediment extraction with synthetic seawater adjusted to pH 4 or pH 6, simulating the range of pH prevailing in the digestive tract of benthic organisms. The genotoxic activities of these extracts were evaluated by three short-term bioassays: the Salmonella mutagenicity test using the Salmonella typhimurium strain TA102, the alkaline comet assay and the micronucleus assay on the Chinese Hamster Ovary cells CHO-K1. Results of the Salmonella mutagenicity assay detected a mutagenic response for RN extract at pH 6, and for VA extract at pH 4. Results of the comet and micronucleus assays detected low genotoxic/clastogenic activities for VA and VC extracts at pH 6 and higher activities for RN, VA and VC extracts at pH 4. To identify if metals (Al, Fe, Mn, As, Cd, Co, Cr, Cu, Hg, Ni, Pb and Zn) were involved in these genotoxic activities, their concentrations were determined in the extracts, and their speciation was assessed by thermodynamic calculations. Results showed that extracts from sites VA, VC and VN generally presented the highest trace metal contents for both extractants, while the site RN presented lower trace metal contents but the highest Fe and Mn contents. Thermodynamic calculations indicated that Fe, Mn, As and in a lower extend Co, Ni and Zn were mainly present under free forms in extracts, and were consequently, more likely able to induce a genotoxic effect. Results globally showed no correspondence between free metal contents and genotoxic activities. They suggested that these positive results could be due to uncharacterized compounds, acting as direct genotoxic agents or enhancing the genotoxic properties of analyzed metals. PMID- 22487562 TI - Dietary exposure to polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans and polychlorinated biphenyls of the French population: Results of the second French Total Diet Study. AB - Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) bioaccumulate through the food chain and are therefore of public health concern. Exposure to these compounds was assessed in the second French Total Diet Study (TDS). Food samples (n=583) were collected to be representative of the whole diet of the population, prepared as consumed, and analyzed. Contamination data were combined with national individual food consumption data. Mean exposure (95th percentile) to PCDD/F+DL-PCBs was assessed to be 0.57 (1.29) pg TEQ(WHO-98) (kg bw)(-1) d(-1) in the adult population and 0.89 (2.02) pg TEQ(WHO-98) (kg bw)(-1) d(-1) in the child and teenager population. Less than 4% of the population exceeded the health-based guidance value for PCDD/F+DL-PCBs. Mean exposure (95th percentile) to the six indicator PCBs (PCB 28, 52, 101, 138, 153, 180) was estimated at 2.71 (7.90) ng (kg bw)(-1) d(-1) in the adult population and 3.77 (11.7) ng (kg bw)(-1) d(-1) in the child and teenager population. Only 2.6% of the adults [CI(95%): 1.9; 3.3] and 6.5% of the children and teenagers [5.2; 7.8] exceeded the health-based guidance value for total PCBs. These results show that the contamination levels in food and therefore the exposure of the general French population to PCDD/Fs and PCBs have declined (by a factor of 3.2 for PCDD/F+DL-PCBs and about three for total PCBs) since the last evaluation, which was conducted using another methodology in 2005 and 2007, and show the efficiency of the European risk management measures which came into force after these evaluations. PMID- 22487563 TI - Discrimination of hybrid classes using cross-species amplification of microsatellite loci: methodological challenges and solutions in Daphnia. AB - Microsatellite markers are important tools in population, conservation and forensic studies and are frequently used for species delineation, the detection of hybridization and introgression. Therefore, marker sets that amplify variable DNA regions in two species are required; however, cross-species amplification is often difficult, as genotyping errors such as null alleles may occur. To estimate the level of potential misidentifications based on genotyping errors, we compared the occurrence of parental alleles in laboratory and natural Daphnia hybrids (Daphnia longispina group). We tested a set of 12 microsatellite loci with regard to their suitability for unambiguous species and hybrid class identification using F(1) hybrids bred in the laboratory. Further, a large set of 44 natural populations of D. cucullata, D. galeata and D. longispina (1715 individuals) as well as their interspecific hybrids were genotyped to validate the discriminatory power of different marker combinations. Species delineation using microsatellite multilocus genotypes produced reliable results for all three studied species using assignment tests. Daphnia galeata * cucullata hybrid detection was limited due to three loci exhibiting D. cucullata-specific null alleles, which most likely are caused by differences in primer-binding sites of parental species. Overall, discriminatory power in hybrid detection was improved when a subset of markers was identified that amplifies equally well in both species. PMID- 22487564 TI - A new approach to the side chain formation of 24-alkyl-22-hydroxy steroids: application to the preparation of early brassinolide biosynthetic precursors. AB - A new synthetic route to 22S-hydroxy-24R-methyl steroids has been developed and applied for the preparation of cathasterone, (22S)-hydroxycampesterol, and 6 deoxocathasterone, which are precursors in the early stages of the biosynthesis of brassinolide. The construction of the steroid side chain with the correct stereochemistry at C-24 is based on the use of Claisen rearrangement. The introduction of the 22-hydroxyl group has been achieved by epoxidation of the Delta(22)-double bond, nucleophilic opening of the intermediate mesyl epoxide with sodium sulfide, and desulfurization of the formed tetrahydrothiophenes with Raney nickel. PMID- 22487565 TI - Water channel proteins in bile formation and flow in health and disease: when immiscible becomes miscible. AB - An essential function of the liver is the formation and secretion of bile, a complex aqueous solution of organic and inorganic compounds essential as route for the elimination of body cholesterol as unesterified cholesterol or as bile acids. In bile, a considerable amount of otherwise insoluble cholesterol is solubilized by carriers including two other classes of lipids, namely phospholipid and bile acids. Formation of bile and generation of bile flow are driven by the active secretion of bile acids, lipids and electrolytes into the canalicular and bile duct lumens followed by the parallel movement of water. Thus, water has to cross rapidly into and out of the cell interior driven by osmotic forces. Bile as a fluid, results from complicated interplay of hepatocyte and cholangiocyte uptake and secretion, concentration, by involving a number of transporters of lipids, anions, cations, and water. The discovery of the aquaporin water channels, has clarified the mechanisms by which water, the major component of bile (more than 95%), moves across the hepatobiliary epithelia. This review is focusing on novel acquisitions in liver membrane lipidic and water transport and functional participation of aquaporin water channels in multiple aspects of hepatobiliary fluid balance. Involvement of aquaporins in a series of clinically relevant hepatobiliary disorders are also discussed. PMID- 22487566 TI - Nervous system involvement of connective tissue disease: mechanisms and diagnostic approach. AB - PURPOSE OF REVIEW: Connective tissue diseases can present with a wide spectrum of neurological symptoms. The present review summarizes the neurological involvement in connective tissue diseases and highlights recent findings on the diagnosis of neurological manifestations and potential underlying mechanisms. RECENT FINDINGS: The wide range in the prevalence of neurological manifestations in systemic lupus erythematosus (SLE) and Sjogren's syndrome reveals the necessity of clear decision algorithms for the association of neurological symptoms with a systemic autoimmune disease. For this purpose new recommendations for the diagnosis and treatment of neuropsychiatric SLE have been published. Recent studies identified potential paraclinical markers for the diagnosis of nervous system involvement in connective tissue diseases. Antiaquaporin-4 antibodies occur highly specifically in those patients with connective tissue diseases that present with symptoms typical for neuromyelitis optica. SUMMARY: To date there is no specific marker available to prove neurological manifestation of connective tissue diseases. However, some progress has been achieved in characterizing typical clinical features and potential disease associated autoantibodies, which may lead to a better management of these patients. PMID- 22487567 TI - Neuron-directed autoimmunity in the central nervous system: entities, mechanisms, diagnostic clues, and therapeutic options. AB - PURPOSE OF REVIEW: The human central nervous system (CNS) can mistakenly be the target of adaptive cellular and humoral immune responses causing both functional and structural impairment. We here provide an overview of neuron-directed autoimmunity as a novel class of inflammatory CNS disorders, their differential diagnoses, clinical hallmarks, imaging features, characteristic laboratory, electrophysiological, cerebrospinal fluid and neuropathological findings, cellular and molecular disease mechanisms, as well as therapeutic options. RECENT FINDINGS: A growing number of immune-mediated CNS disorders of both autoimmune and paraneoplastic origin have emerged, in which neurons seem to be the target of the immune response. Antibodies binding to a variety of synaptic and extrasynaptic antigens located on the neuronal surface membrane can define distinct entities. Clinically, these disorders are characterized by subacute CNS related [and sometimes peripheral nervous system (PNS)-related] symptoms involving a variety of cortical and subcortical gray matter areas, which often reflect the expression pattern and function of the respective target antigen. Antibodies seem to be pathogenic and cause (reversible) disturbance of synaptic transmission and neuronal excitability by selective functional inhibition or crosslinking and internalization of their antigen in the absence of overt cytotoxicity, at least at early disease stages. Whether at later disease stages antibody-mediated cytotoxicity, cytotoxic CD8+ T cells, or other detrimental immune mechanisms contribute to neuronal impairment is unclear at present. SUMMARY: Adaptive humoral autoimmunity directed to neuronal cell-surface antigens offers first and unique insights and provokes further investigation into the systemic, cellular, and molecular consequences of immune-mediated disruption of distinct neuronal signaling pathways within the living human CNS. PMID- 22487568 TI - Neuromyelitis optica: not a multiple sclerosis variant. AB - PURPOSE OF REVIEW: The discovery of neuromyelitis optica (NMO)-immunoglobulin (Ig)G and its target antigen aquaporin 4 (AQP4) redefined NMO, historically considered a multiple sclerosis (MS) variant, as a specific disease entity. NMO and MS have divergent responses to immunotherapy and it is important to distinguish the conditions at disease onset. In this article, we review new pathological, imaging and clinical trial data pertaining to NMO, and discuss emerging concepts of molecular immunopathogenesis in NMO that can inform the development of targeted therapies. RECENT FINDINGS: Recent studies illustrate the range of brain lesions associated with NMO, and the importance of diagnostic biomarkers in patients with atypical or limited presentations. Neuropathological studies showing perivascular astrocyte destruction and preserved myelin in early NMO lesions indicate a pathogenesis distinct from MS. Characterisation of NMO-IgG binding to AQP4 isoforms and the development of novel disease models have elucidated complement-mediated and cell-mediated mechanisms of astrocyte injury. SUMMARY: NMO-IgG positive NMO is not an MS variant. Further work is required to delineate the pathogenesis of NMO syndromes without antibodies to AQP4. Methodological flaws inherent to small, open label trials of current NMO therapies limit extrapolation to clinical practice. In the coming years, NMO will be treated with targeted therapies that are emerging from an enhanced understanding of the molecular immunopathogenesis of the disease. PMID- 22487569 TI - Neuroinflammation: the world is not enough. PMID- 22487571 TI - Identifying autoantigens in demyelinating diseases: valuable clues to diagnosis and treatment? AB - PURPOSE OF REVIEW: Identification of autoantigens in demyelinating diseases is essential for the understanding of the pathogenesis. Immune responses against these antigens could be used as biomarkers for diagnosis, prognosis and treatment responses. Knowledge of antigen-specific immune responses in individual patients is also a prerequisite for antigen-based therapies. RECENT FINDINGS: A proportion of patients with demyelinating disease have antibodies to aquaporin 4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG). Patients with anti-AQP4 have the distinct clinical presentation of neuromyelitis optica (NMO), and these patients often also harbour other autoimmune responses. In contrast, anti-MOG is seen in patients with different disease entities such as childhood multiple sclerosis (MS), acute demyelinating encephalomyelitis (ADEM), anti-AQP4 negative NMO, and optic neuritis, but hardly in adult MS. A number of new candidate autoantigens have been identified and await validation. Antigen-based therapies are mainly aimed at tolerizing T-cell responses against myelin basic protein (MBP) and have shown only modest or no clinical benefit so far. SUMMARY: Currently, only few patients with demyelinating diseases can be characterized based on their autoantibody profile. The most prominent antigens in this respect are MOG and AQP4. Further research has to focus on the validation of newly discovered antigens as biomarkers. PMID- 22487570 TI - Migraine changes the brain: neuroimaging makes its mark. AB - PURPOSE OF REVIEW: This review summarizes key findings of the current literature on functional neuroimaging in migraine and describes how these studies have changed our view of the disorder. RECENT FINDINGS: Recent studies have started not only to investigate the global cerebral activation pattern during migraine attacks, but to address specific aspects of migraine attacks such as photophobia, osmophobia as well as pain perception with the aim of disentangling the underlying mechanisms. There is also more and more evidence that the migraine brain is abnormal even outside of attacks and that repeated attacks are leading to functional and structural alterations in the brain, which may in turn drive the transformation of migraine to its chronic form. Some new results are pinpointing toward a potential role of interesting new brain areas in migraine pathophysiology such as the temporal cortex or the basal ganglia. SUMMARY: Neuroimaging studies are beginning to shed light on the mechanisms underlying the development and evolution of migraine and its specific symptoms. Future studies have the potential to also improve our understanding of established and upcoming treatment approaches and to monitor treatment effects in an objective and noninvasive way. PMID- 22487572 TI - Obesity: Weight loss after Roux-en-Y gastric bypass is associated with SNPs in ghrelin receptor gene. PMID- 22487573 TI - Microbiota: Tolerating gluten--a role for gut microbiota in celiac disease? PMID- 22487574 TI - Genetics: Genetic susceptibility has a role in the development of diverticular disease. PMID- 22487575 TI - Celiac disease: Obesity in celiac disease. PMID- 22487576 TI - Quantitative analysis of cystoid macular edema using scanning laser ophthalmoscope in modified dark-field imaging. AB - PURPOSE: To quantitatively analyze cystoid macular edema (CME) using scanning laser ophthalmoscope in the modified dark-field imaging. METHODS: We studied 37 eyes with CME associated with different diseases before and after treatment. The CME area was measured with the modified dark-field imaging and fluorescein angiography. The best-corrected visual acuity, mean deviation and macular sensitivity measured by Humphrey automated perimetry, and foveal thickness and macular volume determined by optical coherence tomography were investigated. RESULTS: The CME area could be clearly outlined in 50% with the fluorescein angiography and in 100% with the modified dark-field imaging (P < 0.0001). The CME area calculated using the modified dark-field imaging was significantly correlated with that using the fluorescein angiography (P = 0.0001). Before treatment, the CME area calculated using the modified dark-field imaging was significantly correlated with only the macular volume (P = 0.0230). Three months after treatment, decrease in the CME area was significantly correlated with improvement in the best-corrected visual acuity, mean deviation, macular sensitivity, foveal thickness, and macular volume (P < 0.05 for all). CONCLUSION: Our findings indicate that scanning laser ophthalmoscope in the modified dark field imaging can measure the CME area and is useful in analyzing CME quantitatively. The findings can also be used to evaluate the effectiveness of treatment. PMID- 22487577 TI - Genotype-phenotype associations in neovascular age-related macular degeneration. AB - PURPOSE: To examine associations between recognized genetic susceptibility loci and angiographic subphenotypes of the neovascular variant of age-related macular degeneration (nvAMD). METHODS: Participants (247 nvAMD, 52 early age-related macular degeneration [AMD], and 103 controls) were genotyped (complement factor H and ARMS2/HTRA1). nvAMD participants were assigned to one of two subcategories: mainly classic or mainly occult (based on the proportions of classic and occult choroidal neovascularization). nvAMD and early AMD were reassigned to two groups based on the extent and severity of drusen (retinal pigment epithelium dysfunction or not). Univariate and multivariate analysis were used to examine for associations between participant characteristics and genetic loci after adjusting for age, smoking status, and history of cardiovascular disease. RESULTS: Univariate analysis confirmed the known significant associations between AMD stage and age, hypertension, and a history of cardiovascular disease. Those with retinal pigment epithelium dysfunction (F = 5.46; P = 0.02) or a positive smoking history (F = 3.89; P = 0.05) were more likely to have been classified as having mainly an occult rather than a mainly classic lesion. Multivariate analysis showed that significant associations were noted with the number of ARMS2/HTRA1 risk alleles (P < 0.001), smoking (ever vs. never) (P = 0.03), and cardiovascular disease (P = 0.01). With early AMD as the reference category, the mainly classic group exhibited significant associations with the number of ARMS2/HTRA1 risk alleles present (P < 0.001) and cardiovascular disease (P = 0.02). When mainly classic was compared with mainly occult, the latter was associated with the ARMS2/HTRA1 locus (P = 0.02). CONCLUSION: ARMS2/HTRA1 risk genotype may play a role in determining neovascular subphenotype, whereas genetics/demographics, smoking, and systemic health factors contribute to the development of advanced AMD in the presence of early AMD. PMID- 22487578 TI - Association of glutathione S-transferase pi isoform single-nucleotide polymorphisms with exudative age-related macular degeneration in a Chinese population. AB - PURPOSE: To investigate the association between single-nucleotide polymorphisms in the pi isoform of glutathione S-transferase (GSTP1) gene and the risk of exudative age-related macular degeneration (AMD) in a Chinese case-control cohort. METHODS: A total of 131 Chinese patients with exudative AMD and 138 control individuals were recruited. Genomic DNA was extracted from venous blood leukocytes. Two common nonsynonymous single-nucleotide polymorphisms in GSTP1 (rs1695 and rs1138272) were genotyped by polymerase chain reaction followed by allele-specific restriction enzyme digestion and direct sequencing. RESULTS: Significant association with exudative AMD was detected for single-nucleotide polymorphism, rs1695 (P = 0.019). The risk G allele frequencies were 21.8% in AMD patients and 12.7% in control subjects (P = 0.007). Compared with the wild-type AA genotype, odds ratio for the risk of AMD was 1.91 (95% confidence interval, 1.09-3.35) for the heterozygous AG genotype and 2.52 (95% confidence interval, 0.6-10.61) for the homozygous GG genotype. In contrast, rs1138272 was not associated with exudative AMD (P = 1.00). The risk G allele frequencies of rs1138272 were 0.4% in AMD patients and 0.4% in control subjects (P = 1.00). CONCLUSION: Our data suggest that the GSTP1 variant rs1695 moderately increases the risk of exudative AMD. The variant rs1138272 was rare and was not associated with exudative AMD in this Chinese cohort. PMID- 22487579 TI - Comparison of intraocular pressure elevation after anterior versus posterior subtenon triamcinolone acetonide acetate injection: a retrospective study. AB - PURPOSE: To compare the profiles of elevated intraocular pressure (IOP) after anterior and posterior subtenon injections (PSTIs) of triamcinolone. METHODS: In this retrospective case series, 131 patients (131 eyes) with a single anterior subtenon injection (ASTI) of triamcinolone acetonide acetate (20 mg in 0.5 mL) and 49 patients (49 eyes) with a single PSTI of triamcinolone acetonide acetate (40 mg in 0.4 mL) were studied for changes in IOP. Changes in IOP compared with the baseline and fellow eyes were analyzed for both the ASTI and PSTI groups. RESULTS: The study revealed that ASTI was 2.4 times more likely (95% confidence interval, 1.02-5.9) to have an IOP elevation >21 mmHg when compared with the PSTI (P = 0.0389). Twenty-one percent (28 of 131) of eyes having an IOP >21 mmHg were found in the ASTI group, while only 12% (6 of 49) were found in the PSTI group. Similarly, ASTI was 5.3 times more likely (95% confidence interval, 1.2-22.5) to have an IOP >30 mmHg compared with the PSTI (P = 0.03, one-tailed). Anterior subtenon injection had 7% (9 of 131) of eyes with IOP >30 mmHg, while only 2% (1 of 49) were present in the PSTI group. Age was negatively associated with IOP elevation (P < 0.05), and the baseline IOP was positively associated with IOP elevation (P < 0.05). The mean IOP elevation from the baseline was also found to be greater in ASTI (3.1 mmHg) than in PSTI (1.8 mmHg; P = 0.02, generalized estimating equation). CONCLUSION: An ASTI of triamcinolone acetonide may bear a higher risk of developing elevated IOP than a PSTI of triamcinolone acetonide. PMID- 22487580 TI - Radiation dose to the surgeon during plaque brachytherapy. AB - PURPOSE: To evaluate the radiation dose to a surgeon's hands during I eye plaque procedures. METHODS: Sixteen consecutive patients with uveal melanomas were scheduled for eye plaque brachytherapy. The same surgeon wore thermoluminescent dosimeters on the dominant index finger and thumb while placing and removing the eye plaque to measure radiation dose. Additional laboratory experiments were performed to measure unobstructed (by surgical gloves or other parts of the hand) radiation exposure from a plaque. RESULTS: Hand radiation doses during eye plaque brachytherapy are very low, but measurable, with plaques containing an average of 1.3 GBq of 125I. CONCLUSION: Using these data, a surgeon would need to perform more than 1,000 cases each year to approach or exceed the annual regulatory radiation dose limits for the extremities. PMID- 22487581 TI - Retinal structural alterations and macular sensitivity in idiopathic macular telangiectasia type 1. AB - PURPOSE: To evaluate the relationship between the abnormalities of retinal structures showed on spectral-domain optical coherence tomography and the changes in the macular sensitivity measured by microperimetry in eyes with idiopathic macular telangiectasia type 1. METHODS: Eleven eyes of 11 patients with macular telangiectasia type 1 were reviewed. Morphologic changes in the retina and retinal sensitivity of eyes with macular telangiectasia type 1 were studied using spectral-domain optical coherence tomography and microperimetry. RESULTS: Spectral-domain optical coherence tomographic images revealed disruptions in the photoreceptor inner segment-outer segment (IS/OS) junction in all the eyes and intraretinal cystoid spaces in 10 eyes. In the points that had intraretinal cystoid spaces, the mean retinal sensitivity was 6.8 +/- 5.5 dB where the IS/OS was disrupted and 13.4 +/- 4.0 dB where the IS/OS was intact (P < 0.001). In the points that had intact IS/OS and no cystoid spaces, the mean retinal sensitivity was 15.3 +/- 4.3 dB, which was better than that of points that had intact IS/OS with cystoid spaces (P < 0.001). CONCLUSION: Retinal sensitivity is influenced not only by intraretinal cystoid spaces but also by IS/OS disruptions, and the IS/OS alterations reduce the visual function more severely. PMID- 22487583 TI - Second free flaps in head and neck reconstruction. AB - INTRODUCTION: Ablative surgery for head and neck cancer often results in defects that require free flap reconstruction. Improved survival after refined oncologic and adjuvant techniques has led to an increase in the number of patients undergoing a second free flap reconstruction. The objective of this study was to assess outcomes following a second free flap in head and neck reconstruction. MATERIALS AND METHODS: Following ablative defects in the head and neck, 1475 patients underwent reconstructive surgery over a period of 17 years. A second free flap for reconstruction was performed on 123 of these patients. In Group 1, 93 patients had a reconstruction for either tumour recurrence, second primary tumour or reconstructive complications (fractured plate, osteoradionecrosis, orocutaneous fistula). In Group 2, 30 patients had a second free flap following primary free flap reconstructive failure. RESULTS: Flap success for Group 1 patients was 86/90 (96%) compared to group 2 patients, 22/30 (73%) (p < 0.05). In Group 1, partial necrosis occurred in four patients whereas in Group 2, there was only one partial necrosis (NS; p > 0.05). CONCLUSION: A second free flap may be required for reconstruction of head and neck defects following complications of the initial reconstruction, presence of a second primary or tumour recurrence. Success rates for second free flap reconstructions were significantly lower in those patients with initial free flap failure. PMID- 22487582 TI - Choroidal imaging using spectral-domain optical coherence tomography. AB - BACKGROUND: A structurally and functionally normal choroidal vasculature is essential for retinal function. Therefore, a precise clinical understanding of choroidal morphology should be important for understanding many retinal and choroidal diseases. METHODS: PUBMED (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed) was used for most of the literature search for this article. The criterion for inclusion of an article in the references for this review was that it included materials about both the clinical and the basic properties of choroidal imaging using spectral-domain optical coherence tomography. RESULTS: Recent reports show successful examination and accurate measurement of choroidal thickness in normal and pathologic states using spectral-domain optical coherence tomography systems. This review focuses on the principles of the new technology that make choroidal imaging using optical coherence tomography possible and on the changes that subsequently have been documented to occur in the choroid in various diseases. Additionally, it outlines future directions in choroidal imaging. CONCLUSION: Optical coherence tomography is now proven to be an effective noninvasive tool to evaluate the choroid and to detect choroidal changes in pathologic states. Additionally, choroidal evaluation using optical coherence tomography can be used as a parameter for diagnosis and follow-up. PMID- 22487584 TI - A modified method of labia minora reduction: the de-epithelialised reduction of the central and posterior labia minora. AB - OBJECTIVE: The aim of this study was to introduce a new method of labiaplasty. Here we describe the surgical procedure, outcomes and the advantages and disadvantages of this method. METHOD: The medical records of 167 patients aged between 20 and 43 years who underwent reduction of the labia minora from May 2006 to March 2011 were reviewed. The procedures performed in these studies used de epithelialised reduction of the middle and posterior sections of the labia minora. RESULTS: All the surgeries were performed successfully, and 164 patients experienced an uneventful postoperative period. A minor dehiscence occurred in one patient, who recovered with no requirement for additional treatment. Another two women felt that the reduction was not fully achieved. All of the patients were satisfied with the eventual aesthetic appearance. CONCLUSIONS: The de epithelialised reduction of the middle and posterior portion of the labia minora is a simple and safe method that is associated with satisfactory outcomes. PMID- 22487585 TI - Development of a clinical screening index predictive of incident HIV infection among men who have sex with men in the United States. AB - BACKGROUND: To implement biomedical and other intensive HIV prevention interventions cost-effectively, busy care providers need validated, rapid, risk screening tools for identifying persons at highest risk of incident infection. METHODS: To develop and validate an index, we included behavioral and HIV test data from initially HIV-uninfected men who have sex with men who reported no injection drug use during semiannual interviews in the VaxGen VAX004 study and Project Explore HIV prevention trials. Using generalized estimating equations and logistic regression analyses, we identified significant predictors of incident HIV infection, then weighted and summed their regression coefficients to create a risk index score. RESULTS: The final logistic regression model included age, and the following behaviors reported during the past 6 months: total number of male sex partners, total number of HIV-positive male sex partners, number of times the participant had unprotected receptive anal sex with a male partner of any HIV status, number of times the participant had insertive anal sex with an HIV positive male partner, whether the participant reported using poppers, and whether they reported using amphetamines. The area under the receiver operating characteristic curve was 0.74, possible scores on index range from 0 to 47 and a score >=10 had as sensitivity of 84% and a specificity of 45%, levels appropriate for a screening tool. CONCLUSIONS: We developed an easily administered and scored 7-item screening index with a cutoff that is predictive of HIV seroconversion in 2 large prospective cohorts of US men who have sex with men. The index can be used to prioritize patients for intensive HIV prevention efforts (eg, preexposure prophylaxis). PMID- 22487587 TI - Symptom screen for identification of highly infectious tuberculosis in people living with HIV in Southeast Asia. AB - BACKGROUND: Tuberculosis (TB) is the leading cause of death among people living with HIV and frequently transmitted among this susceptible group. Transmission can be reduced by infection control practices. Simple evidence-based methods to identify patients who should be isolated are not well described in the literature. We sought to identify a simple, sensitive symptom or symptom combination that healthcare providers in resource-limited settings can use to identify and isolate persons living with HIV with highly infectious TB. METHODS: Participants from 8 outpatient facilities in Cambodia, Thailand, and Vietnam underwent an extensive evaluation for TB. Patients with >=1 positive sputum smear and Mycobacterium tuberculosis culture growth from a pulmonary site were defined as having highly infectious TB. We calculated sensitivity and prevalence of individual symptoms and >1000 symptom combinations. RESULTS: Of 1980 participants, 272 (14%) had TB. Forty percent (n = 109) were highly infectious. Sensitivity for detecting highly infectious TB was highest for having the following symptoms in the past month as follows: weight loss (84%), cough (83%), fever (81%), and fatigue (78%); however, these symptoms were found in 46%-54% of all participants. Having 2 or 3 of 4 symptoms (prevalence, 26%-47%)-weight loss, fever, current cough, and night sweats-was 72%-90% sensitive for highly infectious TB. CONCLUSIONS: The 2 or 3 of 4 symptom combinations of weight loss, fever, current cough, and night sweats, which are the same symptoms comprising the current World Health Organization-recommended TB diagnostic screen, are sensitive for detecting highly infectious TB in people living with HIV. PMID- 22487586 TI - Prevalent pregnancy, biological sex, and virologic response to antiretroviral therapy. AB - OBJECTIVE: Pregnancy is a common indication for initiation of highly active antiretroviral therapy (HAART) in sub-Saharan Africa. Our objective was to evaluate how pregnancy at treatment initiation predicts virologic response to HAART. METHODS: We evaluated an open cohort of 9173 patients who initiated HAART between April 2004 and September 2009 in the Themba Lethu Clinic in Johannesburg, South Africa. Risk ratios were estimated using log-binomial regression; hazard ratios were estimated using Cox proportional hazards models; time ratios were estimated using accelerated failure time models. We controlled for calendar date, age, ethnicity, employment status, history of smoking, tuberculosis, WHO stage, weight, body mass index, hemoglobin, CD4 count and CD4 percent, and whether clinical care was free. Extensive sensitivity and secondary analyses were performed. RESULTS: During follow-up, 822 nonpregnant women and 70 pregnant women experienced virologic failure. In adjusted analyses, pregnancy at baseline was associated with reduced risk of virologic failure by 6 months [risk ratio 0.66, 95% confidence limits (CL): 0.35 to 1.22] and with reduced hazard of virologic failure over follow-up (hazard ratio: 0.69, 95% CL: 0.50 to 0.95). The adjusted time ratio for failure was 1.44 (95% CL: 1.13 to 1.84), indicating 44% longer time to event among women pregnant at baseline. Sensitivity analyses generally confirmed main findings. CONCLUSIONS: Pregnancy at HAART initiation is not associated with increased risk of virologic failure at 6 months or during longer follow-up. PMID- 22487588 TI - Changes in pediatric HIV-related hospital admissions and mortality in Soweto, South Africa, 1996-2011: light at the end of the tunnel? AB - BACKGROUND: With widespread availability of pediatric antiretroviral therapy and improved access to prevention of mother-to-child transmission (PMTCT), it is important to monitor the impact on pediatric HIV-related hospital admissions and in-hospital mortality in South Africa. METHODS: Over a 15-year period, 4 independent surveillance studies were conducted in the pediatric wards at Chris Hani Baragwanath Hospital in Soweto, South Africa (1996, 2005, 2007, and late 2010 to early 2011). Trends in HIV prevalence and HIV-related mortality were evaluated. RESULTS: HIV prevalence was similar during the first 3 periods: 26.2% (1996), 31.7% (2005), and 29.5% (2007) P > 0.10, but was lower in 2010-2011 (19.3%; P = 0.0005). Median age of the children admitted with HIV increased in the latter periods from 9.13 (interquartile range 3.6-28.8) months to 10.0 (3.0 44.5) months (P > 0.10) and 18.0 (6.2-69.8) months (P = 0.048). Median admission weight-for-age z-scores were similar (< -3 SD) for the latter 3 periods. Admission CD4 percentage increased from 0.0% (0.0-9.4) in 2005 to 15.0% (8.2 22.8) in 2007 (P < 0.0001) and was 18.7% (9.6-24.7) in 2010-2011 (P > 0.10). Mortality among all vs. HIV-infected admissions was 63 of 565 (11.2%) and 43 of 179 (24.0%) in 2005, 91 of 1510 (6.0%) and 53 of 440 (12.0%) in 2007, and 18 of 429 (4.2%) and 9 of 73 (12.3%) in 2010-2011. CONCLUSIONS: HIV prevalence and mortality among pediatric admissions is decreasing. This is likely a result of improved PMTCT and wider antiretroviral therapy coverage. Continued effort to improve PMTCT coverage and identify and treat younger and older HIV-infected children is required to further reduce HIV-related morbidity and mortality. PMID- 22487589 TI - The reliability of point-of-care CD4 testing in identifying HIV-infected pregnant women eligible for antiretroviral therapy. AB - OBJECTIVE: Point-of-care (POC) CD4 testing may play an important role in identifying individuals who require antiretroviral therapy (ART), particularly during pregnancy. However, there have been no evaluations of POC CD4 testing in pregnant women. We compared the performance of the PIMA POC analyzer with laboratory-based testing in identifying pregnant women eligible for ART. DESIGN AND METHODS: Participants were 296 consecutive HIV-infected pregnant women in a prevention of mother-to-child transmission of HIV service in Johannesburg, South Africa. Parallel CD4 cell count testing was done using capillary specimens for the PIMA analyzer and venous samples for flow cytometry. RESULTS: The median age was 28 years, and the median gestation was 19 weeks (interquartile range, IQR, 16 24). The median PIMA and laboratory CD4 cell counts were 352 cells (IQR, 251-491) cells per cubic millimeter and 367 (IQR, 251-524) cells per cubic millimeter, respectively. The mean difference between the PIMA and the laboratory CD4 results was 20.5 (95% confidence interval: 11.7 to 29.3) cells per cubic millimeter with limits of agreement from -133.9 to 175.0. The PIMA correctly identified 93% of women who were ART eligible based on a laboratory CD4 <=350 cells per cubic millimeter. There was no evidence of variability in the agreement of PIMA and laboratory-based CD4 testing by participant age or gestation. CONCLUSIONS: These data show good agreement between the PIMA analyzer and laboratory-based CD4 enumeration, comparable to levels in nonpregnant HIV-infected adults. The reliability of the PIMA did not vary with gestation despite the hemodilution of pregnancy. POC CD4 technologies may be used to identify ART-eligible women in prevention of mother-to-child transmission of HIV settings to help promote the rapid initiation of ART. PMID- 22487590 TI - Genetic explorations of recent human metabolic adaptations: hypotheses and evidence. AB - Since humans and chimpanzees split from a common ancestor over 6 million years ago, human metabolism has changed dramatically. This change includes adaptations to a high-quality diet, the evolution of an energetically expensive brain, dramatic increases in endurance abilities, and capacity for energy storage in white adipose tissue. Human metabolism continues to evolve in modern human populations in response to local environmental and cultural selective forces. Understanding the nature of these selective forces and the physiological responses during human evolution is a compelling challenge for evolutionary biologists. The complex genetic architecture surrounding metabolic phenotypes indicates that selection probably altered allelic frequencies across many loci in populations experiencing adaptive metabolic change to fit their environment. A recent analysis supports this hypothesis, finding that classic selective sweeps at single loci were rare during the past 250,000 years of human evolution. Detection of selective signatures at multiple loci, as well as exploration of physiological adaptation to environment in humans, will require cross disciplinary collaboration, including the incorporation of biological pathway analysis. This review explores the Thrifty Genotype Hypothesis, high-altitude adaptation, cold-resistance adaptation, and genetic evidence surrounding these proposed metabolic adaptations in an attempt to clarify current challenges and avenues for future progress. PMID- 22487591 TI - Charged aerosol detection in pharmaceutical analysis. AB - Due to its wide field of application, sensitivity, wide range of linearity and the applicability to gradient elution, the most common detection technique for HPLC nowadays is UV/vis spectrophotometry. However, UV/vis detection comes to its limits when the analytes are lacking suitable chromophors or exhibit very different UV responses. In the past years, different types of evaporation/aerosol based HPLC detectors have been developed to fill this gap in HPLC detection. Amongst those, the corona-charged aerosol detector (CAD) is one of the most powerful and versatile representatives. In the recent past a variety of papers have been published, demonstrating the potential of the CAD in different fields of analytical chemistry. This paper is intended to provide an overview of the key performance characteristics and manifold applications for HPLC-CAD in the field of pharmaceutical analysis. PMID- 22487592 TI - Enantiomeric resolution of albendazole sulfoxide by semipreparative HPLC and in vitro study of growth inhibitory effects on human cancer cell lines. AB - Analytical and semipreparative high performance liquid chromatography methods using polysaccharide-based chiral stationary phases were developed for the enantiomeric resolution of albendazol sulfoxide. The enantioseparation of this compound was evaluated with four chiral stationary phases: cellulose and amylose tris(3,5-dimethylphenylcarbamate), amylose tris[(S)-1-phenylethylcarbamate] and amylose tris(3,5-dimethoxyphenylcarbamate), under three elution conditions: normal, reversed-phase and polar organic mode. The influences of the mobile phase and of the structure of the chiral stationary phase on the enantiomeric separation are discussed. The best chiral performances were achieved on an amylose tris(3,5-dimethylphenylcarbamate) phase under normal (R(s)=4.96) and polar organic mode (R(s)=2.60 and 3.09). A polar organic condition using methanol as mobile phase offered shorter retention factors (k(1)=0.34) and was scaled up to semipreparative HPLC to obtain milligram quantities of both albendazole sulfoxide enantiomers for further in vitro studies. Optical rotation and circular dichroism of both enantiomers of albendazole sulfoxide was determined. The compounds ABZ, ABZ-SO, (R)-(+)-ABZ-SO and (S)-(-)-ABZ-SO were all evaluated regarding their capacity to inhibit the in vitro growth of three human tumor cell lines: MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and A375-C5 (melanoma). In addition, the effect of the (R)-(+)-ABZ-SO compound in the cell cycle profile and apoptosis of MCF-7 cells were also studied. Results indicated that compound ABZ was the most potent regarding cell growth inhibition and that the (+)-(R)-ABZ was a more potent inhibitor of cell growth than the (S) (-)-ABZ-SO, particularly in the MCF-7 cell line. In addition, the (R)-(+)-ABZ-SO significantly increased the levels of apoptosis of the MCF-7 cells. PMID- 22487593 TI - Is tissue augmentation a reality in biosurgery? An experimental study of endothelial cell invasion into tissue filler. AB - New therapeutic approaches for wound treatment are evolving. Non healing wounds in oncology and after trauma may be cured by a novel technique of tissue augmentation with soft tissue fillers. The principle resides in filling the wound with collagen filler in order to seal the defect and promote healing. Successful angiogenesis forms the basis of tissue filler survival and determines the outcome of the healing process. During this study, basic data about endothelial cell invasion into collagen-made substratum was collected that could be used for neoangiogenesis studies in tissue augmentation techniques for large wound defect treatment. In the in vitro assay, the human umbilical vein endothelial cells (HUVEC) grow into a three-dimensional framework of collagenous tissue fillers, forming the basic step for angiogenesis. After heparins were used as chemotactic agents, a typical bell-shaped relationship between chemotaxis and agent concentrations was found. Significant cell infiltration was present in the assays with chemotactic agents. These observations support the potential for tissue augmentation with soft tissue fillers that could be used in acute and chronic non healing traumatic and oncology wounds after extensive surgical resections and radiotherapy. PMID- 22487594 TI - Furnishing hypnotic instructions with implementation intentions enhances hypnotic responsiveness. AB - Forming implementation intentions has been consistently shown to be a powerful self-regulatory strategy. As the self-regulation of thoughts is important for the experience of involuntariness in the hypnotic context, investigating the effectiveness of implementation intentions on the suppression of thoughts was the focus of the present study. Participants were randomly assigned to one of four conditions (hypnotic instruction plus implementation intention, hypnotic instruction, implementation intention, and control condition). Results showed that participants who received information included in the "Carleton Skill Training Program" and in addition formed implementation intentions improved their hypnotic responsiveness as compared to all of the other three groups on measures of objective responding and involuntary responding. Thus, in line with the nonstate or cognitive social-psychological view of hypnosis stating that an individual's hypnotic suggestibility is not dispositional but modifiable, our results suggest that hypnotic responsiveness can be heightened by furnishing hypnotic instructions with ad hoc implementation intentions. PMID- 22487595 TI - Olean-18-ene triterpenoids from Celastraceae species inhibit HIV replication targeting NF-kB and Sp1 dependent transcription. AB - In the present study we report the isolation of nine new olean-18-ene triterpenes (1-9), along with three known ones (10-12), from Cassine xylocarpa and Maytenus jelskii. Their stereostructures have been elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques (COSY, ROESY, HSQC and HMBC), and spectrometric methods. The natural compounds and derivatives 13-15 have been tested for their potential as inhibitors of human immunodeficiency virus type 1 replication. Five compounds from this series displayed potent antiviral activity with IC(50)s in the micromolar range (1, 3, 4, 7 and 8) being 1 and 8 the most active compounds. The target of these compounds was different from antiretroviral drugs currently licensed as they act as inhibitors of enhancer-dependent transcription. The structure-activity relationships were established based on the regiosubstitution and oxidation degree of the triterpene scaffold, revealing that these aspects were able to modulate the selectivity and intensity of HIV inhibition. PMID- 22487596 TI - The extinction of comprehensive pain management: a casualty of the medical industrial complex or an outdated concept? PMID- 22487597 TI - Neurotech report. PMID- 22487599 TI - Reflections on a lifetime in cytogenetics. AB - This review traces the history of cytogenetic studies on the induction of chromosomal alterations by chemicals and radiation as observed by a single investigator over half a century. The work begins with early studies using traditional plant cytogenetics and extends through the integration of molecular methodology into cytogenetic studies in mammalian cells. It also highlights the importance of international collaboration in this field of research. PMID- 22487600 TI - Objective assessment of olfactory function using functional magnetic resonance imaging. AB - OBJECTIVE: To show the results of a device that generates automated olfactory stimuli suitable for functional magnetic resonance imaging (fMRI) experiments. MATERIAL AND METHODS: Ten normal volunteers, 5 women and 5 men, were studied. The system allows the programming of several sequences, providing the capability to synchronise the onset of odour presentation with acquisition by a trigger signal of the MRI scanner. The olfactometer is a device that allows selection of the odour, the event paradigm, the time of stimuli and the odour concentration. The paradigm used during fMRI scanning consisted of 15-s blocks. The odorant event took 2s with butanol, mint and coffee. RESULTS: We observed olfactory activity in the olfactory bulb, entorhinal cortex (4%), amygdala (2.5%) and temporo-parietal cortex, especially in the areas related to emotional integration. CONCLUSIONS: The device has demonstrated its effectiveness in stimulating olfactory areas and its capacity to adapt to fMRI equipment. PMID- 22487601 TI - Dermoscopy of Merkel cell carcinoma. AB - INTRODUCTION: Merkel cell carcinoma (MCC) is an aggressive cutaneous tumor whose clinical presentation, usually a pink nodule, is not specific. We aimed in this study to determine the dermoscopic criteria encountered in MCC. METHODS: From our image database we selected the patients diagnosed with MCC and scored the dermoscopic criteria shown by these tumors. RESULTS: Ten patients coming from three different academic hospitals were studied. Vascular structures were the more relevant dermoscopic features. In 8 out of 10 (80%) patients a polymorphic vascular pattern was seen, composed of milky-red clods/areas in association with one or more additional vascular structures. CONCLUSION: Although an overlap existed between the dermoscopic features observed in MCC and amelanotic melanoma, the presence of a polymorphous vascular pattern may constitute an additional clinical clue to accurately diagnose this rare tumor. PMID- 22487602 TI - Substrate modification by pulmonary vein isolation and left atrial linear ablation in patients with persistent atrial fibrillation: its impact on complex fractionated atrial electrograms. AB - PV and Linear Ablation for CFAEs. INTRODUCTION: Linear ablations in the left atrium (LA), in addition to pulmonary vein (PV) isolation, have been demonstrated to be an effective ablation strategy in patients with persistent atrial fibrillation (PsAF). This study investigated the impact of LA linear ablation on the complex-fractionated atrial electrograms (CFAEs) of PsAF patients. METHODS AND RESULTS: A total of 40 consecutive PsAF patients (age: 54 +/- 10 years, 39 males) who underwent catheter ablation were enrolled in this study. Linear ablation of both roofline between the right and left superior PVs and the mitral isthmus line joining from the mitral annulus to the left inferior PV were performed following PV isolation during AF. High-density automated CFAE mapping was performed using the NAVX, and maps were obtained 3 times during the procedure (prior to ablation, after PV isolation, and after linear ablations) and were compared. PsAF was terminated by ablation in 13 of 40 patients. The mean total LA surface area and baseline CFAEs area were 120.8 +/- 23.6 and 88.0 +/- 23.5 cm(2) (74.2%), respectively. After PV isolation and linear ablations in the LA, the area of CFAEs area was reduced to 71.6 +/- 22.6 cm(2) (58.7%) (P < 0.001) and 44.9 +/- 23.0 cm(2) (39.2%) (P < 0.001), respectively. The LA linear ablations resulted in a significant reduction of the CFAEs area percentage in the region remote from ablation sites (from 56.3 +/- 20.6 cm(2) (59.6%) to 40.4 +/- 16.5 cm(2) (42.9%), P < 0.0001). CONCLUSION: Both PV isolation and LA linear ablations diminished the CFAEs in PsAF patients, suggesting substrate modification by PV and linear ablations. (J Cardiovasc Electrophysiol, Vol. 23, pp. 962-970, September 2012). PMID- 22487603 TI - Growth of silicene layers on Ag(111): unexpected effect of the substrate temperature. AB - The deposition of one silicon monolayer on the silver (111) substrate in the temperature range 150-300 degrees C gives rise to a mix of (4 * 4), (2?3 * 2?3)R30 degrees and (?13 * ?13)R13.9 degrees superstructures which strongly depend on the substrate temperature. We deduced from a detailed analysis of the LEED patterns and the STM images that all these superstructures are given by a quasi-identical silicon single layer with a honeycomb structure (i.e. a silicene like layer) with different rotations relative to the silver substrate. The morphologies of the STM images are explained from the position of the silicon atoms relative to the silver atoms. A complete analysis of all possible rotations of the silicene layer predicts also a (?7 * ?7)R19.1 degrees superstructure which has not been observed so far. PMID- 22487604 TI - Accuracy of Kubelka-Munk reflectance theory for dental resin composite material. AB - OBJECTIVE: The objective of this study is to determine the effect of interfacial reflection correction (IRC) on the accuracy of this reflectance model for contemporary dental resin composite materials. METHODS: Visible reflectance spectra were obtained for varying thicknesses (~0.3-1.2mm) of five shades of each of two brands (Herculite Ultra and Kalore) of dental resin composite materials on black, gray and white backings. For each shade and brand, K-M theory was fit (SAS non-linear fit) for each of three IRC methods: (1) no IRC (No), (2) an IRC method which uses a theoretical value of the internal reflection for translucent materials (Tr), and (3) an IRC method which uses a derived value of the internal reflection for opaque materials (Op). The errors were subjected to repeated measures analysis of variance and Bonferroni corrections were applied to selected pairwise comparisons. RESULTS: The Op method had a statistically lower error than the No method at wavelengths from 460 to 560nm, and the Tr method had this lower error at wavelengths from 440 to 780nm. SIGNIFICANCE: Corrected K-M reflectance theory may be used to accurately quantify the optical K-M absorption and scattering coefficients for contemporary dental resin composite materials, and this theory may be used to calculate accurately the reflectance spectrum for a clinically relevant thickness value and for a backing that is low, mid-range or high in lightness. Both color and translucency information of resin composite materials may be accurately predicted using corrected Kubelka-Munk reflectance model. PMID- 22487605 TI - Smoking prevention and cessation in the Africa and Middle East region: a consensus draft guideline for healthcare providers--executive summary. AB - Despite the abundance of scientific evidence confirming the health consequences of smoking and other forms of tobacco use, the tobacco epidemic remains an important public health problem and by 2030 it is predicted that more than 80% of tobacco deaths will be in developing countries. In Africa and the Middle East, many local factors contribute to the initiation and maintenance of tobacco use. Although efforts to reduce the mortality and morbidity associated with smoking and tobacco dependence are underway, there is a need for guidance on how to utilize appropriate tobacco control policies and psychology- and pharmacology based therapies to counter tobacco dependence as recommended by the Framework Convention on Tobacco Control (FCTC). A group of tobacco cessation experts from public health services and/or academic institutions in Africa and the Middle East participated in a series of four meetings held in Cairo, Cape Town, and Dubai between May 2008 and February 2011 to develop a draft guideline tailored to their region. This article provides the background to the development of this draft smoking cessation guideline and discusses how the recommendations can be implemented and progress monitored to promote both primary prevention and cessation of tobacco use within our countries. The draft guideline for Africa and the Middle East provides an important resource in combating the devastating effects of tobacco use in these regions which can be further localized through engagement with local stakeholders in the countries of the region. PMID- 22487606 TI - Docosahexaenoic acid exerts anti-inflammatory action on human eosinophils through peroxisome proliferator-activated receptor-independent mechanisms. AB - BACKGROUND: Despite the fact that previous studies have indicated the significant roles of polyunsaturated fatty acids (PUFAs) in the immune system through peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma, the biological functions and the mechanisms of action in eosinophils are poorly understood. METHODS: We investigated the functional effects of docosahexaenoic acid (DHA, n-3 PUFA) on human peripheral blood eosinophils, using in vitro systems to test the hypothesis that DHA negatively regulates eosinophil mechanisms through PPARalpha and PPARgamma. RESULTS: Eosinophil apoptosis that spontaneously occurs under normal culture conditions was accelerated in the presence of DHA. In addition, eotaxin-directed eosinophil chemotactic responses were inhibited by pretreatment with DHA, disturbing both the velocity and the directionality of the cell movement. Pharmacological manipulations with specific antagonists indicated that the effects of DHA were not mediated through PPARalpha and PPARgamma, despite the presence of these nuclear receptors. DHA also induced Fas receptor expression and caspase-3 activation that appears to be associated with a proapoptotic effect of DHA. Further, DHA rapidly inhibited the expression of eotaxin receptor C-C chemokine receptor 3 and eotaxin-induced calcium influx and phosphorylation of extracellular signal-regulated kinase. Interestingly, these inhibitory effects were not observed with linoleic acid (n-6 PUFA). CONCLUSIONS: The data might explain one of the mechanisms found in previous research showing the favorable effects of n-3 PUFA supplementation on allergic diseases, and provide novel therapeutic strategies to treat eosinophilic disorders. PMID- 22487607 TI - Scale-up of TB and HIV programme collaborative activities in Zambia - a 10-year review. AB - OBJECTIVE: To review the activities, progress, achievements and challenges of the Zambia Ministry of Health tuberculosis (TB)/HIV collaborative activities over the past decade. METHODS: Analysis of Zambia Ministry of Health National TB and HIV programme documents and external independent programme review reports pertaining to 2000-2010. RESULTS: The number of people testing for HIV increased from 37 557 persons in 2003 to 1 327 995 persons in 2010 nationally. Those receiving anti retroviral therapy (ART) increased from 143 in 2003 to 344 304 in 2010. The national HIV prevalence estimates declined from 14.3% in 2001 to 13.5% in 2009. The proportion of TB patients being tested for HIV increased from 22.6% in 2006 to 84% in 2010 and approximately 70% were HIV positive. The proportion of the HIV infected TB patients who: (i) started on ART increased from 38% in 2006 to 50% in 2010; (ii) commenced co-trimoxazole preventive therapy (CPT) increased from 31% in 2006 to 70% in 2010; and (iii) were successfully treated increased to an average of 80% resulting in decline of deaths from 13% in 2006 to 9% in 2010. CONCLUSIONS: The scale-up of TB/HIV collaborative programme activities in Zambia has steadily increased over the past decade resulting in increased testing for TB and HIV, and anti-retroviral (ARV) rollout with improved treatment outcomes among TB patients co-infected with HIV. Getting service delivery points to adhere to WHO guidelines for collaborative TB/HIV activities remains problematic, especially those meant to reduce the burden of TB in people living with HIV/AIDS (PLWHA). PMID- 22487609 TI - Quantifying circular-linear associations: hippocampal phase precession. AB - When a rat crosses the place field of a hippocampal pyramidal cell, this cell typically fires a series of spikes. Spike phases, measured with respect to theta oscillations of the local field potential, on average decrease as a function of the spatial distance traveled. This relation between phase and position of spikes might be a neural basis for encoding and is called phase precession. The degree of association between the circular phase variable and the linear spatial variable is commonly quantified through, however, a linear-linear correlation coefficient where the circular variable is converted to a linear variable by restricting the phase to an arbitrarily chosen range, which may bias the estimated correlation. Here we introduce a new measure to quantify circular linear associations. This measure leads to a robust estimate of the slope and phase offset of the regression line, and it provides a correlation coefficient for circular-linear data that is a natural analog of Pearson's product-moment correlation coefficient for linear-linear data. Using surrogate data, we show that the new method outperforms the standard linear-linear approach with respect to estimates of the regression line and the correlation, and that the new method is less dependent on noise and sample size. We confirm these findings in a large data set of experimental recordings from hippocampal place cells and theta oscillations, and we discuss remaining problems that are relevant for the analysis and interpretation of phase precession. In summary, we provide a new method for the quantification of circular-linear associations. PMID- 22487611 TI - Current world literature. PMID- 22487613 TI - Combined surgical treatment for localized prostate cancer and incidental ureteral duplication with ectopic ureter inserting into the prostatic urethra. PMID- 22487610 TI - Fibroblast growth factor 23 and adverse clinical outcomes in chronic kidney disease. AB - PURPOSE OF REVIEW: The aim is to review data on the epidemiology of fibroblast growth factor 23 (FGF23) and adverse clinical outcomes in chronic kidney disease (CKD) and introduce recent insights into the pathophysiology behind the observed relationships. RECENT FINDINGS: End-stage renal disease and cardiovascular disease are frequent events in patients with CKD, in whom cardiovascular disease is the leading cause of death. Elevated levels of FGF23, a phosphate and vitamin D-regulating hormone, have been associated with risks of end-stage renal disease, cardiovascular disease and mortality. FGF23 excess has also been linked with left ventricular hypertrophy, and innovative translational experiments have recently established direct end-organ toxicity of FGF23, which induced left-ventricular hypertrophy in animals. SUMMARY: FGF23 is emerging as a novel risk factor in CKD. Future studies should determine whether interventions that lower FGF23 levels improve clinical outcomes in CKD. PMID- 22487614 TI - Can individuals participating in cardiac rehabilitation achieve recommended exercise training levels following stroke? AB - PURPOSE: Cardiac rehabilitation (CR) has been recommended to provide exercise guidance poststroke. However, it has not been established whether minimal exercise training levels, sufficient for obtaining health benefits, can be attained in CR. Therefore, we assessed the ability of stroke patients to achieve recommended exercise levels during a single standard CR session following completion of CR. METHODS: Sixteen patients (10 males and 6 females) with mild/moderate motor impairments who had completed CR participated in the study. Resting metabolic rate and oxygen uptake during 30 minutes each of aerobic and resistance training (AT, RT, respectively) were assessed by ambulatory oxygen monitor. Obtained values were compared with recommended minimal levels, that is, 20 or more minutes of exercise at 40% or more of peak oxygen uptake (VO(2peak)), 30 or more minutes of exercise at 3 or more metabolic equivalents (METs) (multiples of resting metabolic rate), and an energy expenditure of approximately 200 kcal per session. RESULTS: Mean time sustaining 40% or more of VO(2peak) was 47.6 +/- 9 minutes, exceeding the minimal target of 20 minutes (P < .001). Time sustaining 3 or more METs was 30.8 +/- 12.2 minutes, matching the target of 30 minutes (P = .8). Total energy expenditure (252 +/- 49.9 kcal) was significantly greater than the target value of 200 kcal (P = .001). CONCLUSIONS: Chronic stroke patients with mild/moderate motor impairments are able to meet or exceed minimal recommended exercise target levels for intensity, duration, and energy expenditure during a typical exercise session consisting of 30 minutes of AT combined with 30 minutes of RT after completing CR. These data contribute to the evidence promoting the efficacy and feasibility of CR for people following stroke. PMID- 22487615 TI - Effect of exercise training in patients with chronic obstructive pulmonary disease compared with healthy elderly subjects. AB - PURPOSE: Exercise training in patients with chronic obstructive pulmonary disease (COPD) can be challenging because whole-body exercise often elicits disabling symptoms of dyspnea before the exercising muscles reach their critical limits. The extent that this factor limits training has not been totally defined. The purpose of this study was to compare the response to training of patients with moderate to severe COPD with that achieved by healthy elderly subjects who were exercising using an identical program. METHODS: Eight healthy subjects and 20 patients with COPD (forced expiratory volume in 1 second 42 +/- 13% predicted) exercised 3 times a week for 8 weeks. Outcome measures included 6-minute walk distance, maximal exercise capacity (Wmax) during an incremental cycle ergometer test, and submaximal constant workload (60%-70% of subject Wmax) exercise time. RESULTS: Six-minute walk distance and Wmax increased after training to a significantly greater extent in the healthy controls compared with the patients with COPD; 65 +/- 24 versus 32 +/- 50 m, P = .03; and 25.1+/-13.9 versus 11.5+/ 13.1 watts, P = .025, respectively. However, these differences disappeared when data were expressed as percent improvement, 12.1 +/- 5.3% versus 10.0 +/- 15.8%, and 25.6 +/- 13.5% versus 23.1 +/- 33.3%. Improvement in submaximal constant workload exercise time after training was similar in healthy controls 21.6 +/- 6.1 versus patients with COPD 18.8 +/- 11.2 minutes. CONCLUSIONS: Patients with COPD can show similar relative improvements in exercise capacity compared with healthy elderly subjects. The difference in absolute values reflects, at least in part, the greater baseline exercise capacity. PMID- 22487608 TI - Utility of the DNA barcoding gene fragment for parasitic wasp phylogeny (Hymenoptera: Ichneumonoidea): data release and new measure of taxonomic congruence. AB - The enormous cytochrome oxidase subunit I (COI) sequence database being assembled from the various DNA barcoding projects as well as from independent phylogenetic studies constitutes an almost unprecedented amount of data for molecular systematics, in addition to its role in species identification and discovery. As part of a study of the potential of this gene fragment to improve the accuracy of phylogenetic reconstructions, and in particular, exploring the effects of dense taxon sampling, we have assembled a data set for the hyperdiverse, cosmopolitan parasitic wasp superfamily Ichneumonoidea, including the release of 1793 unpublished sequences. Of approximately 84 currently recognized Ichneumonoidea subfamilies, 2500 genera and 41,000 described species, barcoding 5'-COI data were assembled for 4168 putative species-level terminals (many undescribed), representing 671 genera and all but ten of the currently recognized subfamilies. After the removal of identical and near-identical sequences, the 4174 initial sequences were reduced to 3278. We show that when subjected to phylogenetic analysis using both maximum likelihood and parsimony, there is a broad correlation between taxonomic congruence and number of included sequences. We additionally present a new measure of taxonomic congruence based upon the Simpson diversity index, the Simpson dominance index, which gives greater weight to morphologically recognized taxonomic groups (subfamilies) recovered with most representatives in one or a few contiguous groups or subclusters. PMID- 22487617 TI - Minimally invasive myotomy for the treatment of esophageal achalasia: evolution of the surgical procedure and the therapeutic algorithm. AB - Achalasia is a rare disease of the esophagus, characterized by the absence of peristalsis in the esophageal body and incomplete relaxation of the lower esophageal sphincter, which may be hypertensive. The cause of this disease is unknown; therefore, the aim of the therapy is to improve esophageal emptying by eliminating the outflow resistance caused by the lower esophageal sphincter. This goal can be accomplished either by pneumatic dilatation or surgical myotomy, which are the only long-term effective therapies for achalasia. Historically, pneumatic dilatation was preferred over surgical myotomy because of the morbidity associated with a thoracotomy or a laparotomy. However, with the development of minimally invasive techniques, the surgical approach has gained widespread acceptance among patients and gastroenterologists and, consequently, the role of surgery has changed. The aim of this study was to review the changes occurred in the surgical treatment of achalasia over the last 2 decades; specifically, the development of minimally invasive techniques with the evolution from a thoracoscopic approach without an antireflux procedure to a laparoscopic myotomy with a partial fundoplication, the changes in the length of the myotomy, and the modification of the therapeutic algorithm. PMID- 22487616 TI - Patients with heart failure in the "intermediate range" of peak oxygen uptake: additive value of heart rate recovery and the minute ventilation/carbon dioxide output slope in predicting mortality. AB - PURPOSE: While patients with heart failure who achieve a peak oxygen uptake (peak VO2) of 10 mL.kg(-1).min(-1) or less are often considered for intensive surveillance or intervention, those achieving 14 mL.kg(-1).min(-1) or more are generally considered to be at lower risk. Among patients in the "intermediate" range of 10.1 to 13.9 mL.kg(-1).min(-1), optimally stratifying risk remains a challenge. METHODS: Patients with heart failure (N = 1167) referred for cardiopulmonary exercise testing were observed for 21 +/- 13 months. Patients were classified into 3 groups of peak VO2 (<=10, 10.1-13.9, and >=14 mL.kg( 1).min(-1)). The ability of heart rate recovery at 1 minute (HRR1) and the minute ventilation/carbon dioxide output (VE/VCO2) slope to complement peak VO2 in predicting cardiovascular mortality were determined. RESULTS: Peak VO2, HRR1 (<16 beats per minute), and the VE/VCO2 slope (>34) were independent predictors of mortality (hazard ratio 1.6, 95% CI: 1.2-2.29, P = .006; hazard ratio 1.7, 95% CI: 1.1-2.5, P = .008; and hazard ratio 2.4, 95% CI: 1.6-3.4, P < .001, respectively). Compared with those achieving a peak VO2 >= 14 mL.kg(-1).min(-1), patients within the intermediate range with either an abnormal VE/VCO2 slope or HRR1 had a nearly 2-fold higher risk of cardiac mortality. Those with both an abnormal HRR1 and VE/VCO2 slope had a higher mortality risk than those with a peak VO2 <= 10 mL.kg(-1).min(-1). Survival was not different between those with a peak VO2 <= 10 mL.kg(-1).min(-1) and those in the intermediate range with either an abnormal HRR1 or VE/VCO2 slope. CONCLUSIONS: HRR1 and the VE/VCO2 slope effectively stratify patients with peak VO2 within the intermediate range into distinct groups at high and low risk. PMID- 22487618 TI - Single-incision laparoscopic right colectomy: an efficient technique. AB - PURPOSE: Laparoscopic right colectomy has an established patient benefit. We sought to demonstrate that a single-incision approach to laparoscopic right colectomy is safe, reproducible, and efficient. METHODS: Photographs were acquired from cases to depict a step-by-step approach. We collected operative, pathologic, and postoperative outcomes from 8 patients who underwent a single incision laparoscopic right colectomy. RESULTS: There were no intraoperative complications nor deaths and 3 complications postoperatively. The average return of bowel function and length of stay was 3 and 5 days, respectively. Pathologic assessment revealed negative margins and an average of 17 lymph nodes harvested from the specimens. CONCLUSIONS: Single-incision laparoscopic right colectomy is an evolving technique and likely to supplant conventional laparoscopic colectomy because of its equivalent and reproducible outcomes and the ease of the procedure. We depict our preferred method and review the current literature of single-incision right colectomy. PMID- 22487619 TI - Linear-stapled versus circular-stapled laparoscopic gastrojejunal anastomosis in morbid obesity: meta-analysis. AB - BACKGROUND: The study aims to provide a pooled analysis of individual small trials comparing linear-stapled versus circular-stapled laparoscopic gastrojejunal (GJ) anastomosis in morbid obesity surgery. METHODS: A systematic literature search of Medline, Embase, and Cochrane library databases was performed. Primary outcomes were GJ leak and stricture. Secondary outcomes were operative time, length of hospital stay, postoperative bleeding, wound infection, marginal ulcers, and estimated weight loss. Pooled odds ratios were calculated for categorical outcomes and weighted mean differences for continuous outcomes. RESULTS: Nine trials were included comprising 9374 patients (2946 linear vs. 6428 circular). Primary outcome analysis revealed a statistically significant increase in the rate of GJ stricture associated with circular-stapled anastomosis. A significantly reduced rate of wound infection, bleeding, and operative time associated with linear stapling was also found. No significant differences appeared for the other outcomes. CONCLUSIONS: This pooled analysis recommends the preferential use of the linear stapling technique over circular stapling. PMID- 22487620 TI - Postpolypectomy bleeding: incidence, risk factors, prevention, and management. AB - Endoscopic polypectomy is at the forefront of colorectal cancer (CRC) prevention. However, endoscopic polypectomy is not completely free of complications, with bleeding being one of the most common complications encountered. In view of the ongoing campaign to introduce colorectal cancer screening to the population, addressing the issue of colonoscopic complications, and postpolypectomy bleeding (PPB) in particular is becoming more important. Despite the fact that the overall incidence of PPB is low, predisposing factors need to be elucidated to further decrease the frequency of this complication. Furthermore, the role of various techniques of PPB prophylaxis remains controversial. We review recent studies on the incidence, risk factors, prophylaxis, and management of PPB. PMID- 22487621 TI - Single-incision laparoscopic cholecystectomy: comparison analysis of feasibility and safety. AB - To maintain operative safety, patient selection criteria for single-incision laparoscopic cholecystectomy (SILC) are more stringent than that for traditional laparoscopic cholecystectomy (TLC). No other method could demonstrate the same feasibility and safety as TLC because the patient selection criteria were too restrictive for SILC to compare with TLC. In this study, we conducted a comparative study between our original SILC and TLC for demonstrating similar feasibility and safety among patients who had the same selection criteria as that for TLC. A statistical comparison between 114 patients of SILC and 201 patients of TLC was conducted during the same time period. The preoperative patient characteristics for SILC and TLC showed no statistical difference. In the operative result analysis, a significant disadvantage of SILC was the prolongation of operative time by only 15 minutes. The original SILC was as feasible and safe as TLC and virtually scarless cholecystectomy could be performed without any selection criteria. This was performed using only 2 trocars from an umbilical incision and 2 incisionless extracorporeal retraction devices. PMID- 22487622 TI - Single-incision laparoscopic cholecystectomy learning curve experience seen in a single institution. AB - INTRODUCTION: Single-incision laparoscopic surgery (SILS) is laparoscopic surgery done by one incision through the umbilicus. Cholecystectomy lends itself well to a SILS approach. As these procedures have become more widely adapted, it is important to determine the approximate learning curve to decrease two surgical endpoints: (1) time to completion of the procedure; and (2) decreased incidence of conversion. METHODS: We prospectively reviewed our series of 50 cholecystectomies done using the SILS approach between May 2008 to September 2008. All cases were performed by two advanced laparoscopic surgeons at a single institution. Data was collected immediately after the case and entered into an Excel database. Cases were performed by insufflating the abdomen with a Veress needle through the umbilicus followed by placement of 5-mm ports at the umbilicus. RESULTS: Patient ages ranged between 21 and 82 years with a median age of 45 years. Body mass index (BMI) range was 21 to 42 kg/m with a mean of 30 kg/m. Average length of time for cases was 1 hour 9 minutes with a range between 55 minutes and 120 minutes. The average length of time for the first 25 cases was 80 minutes. When compared with cases 26 to 50 the average length of time was 60 minutes (P<0.05). The conversion rate to conventional laparoscopic cholecystectomy was 10%. Conversion was accomplished through the addition of a 5 mm port elsewhere on the abdominal cavity. After the tenth case, the incidence of conversion went down to zero. When conversions were further stratified, they occurred within each individual surgeon's first ten cases. CONCLUSIONS: The learning curve for successful consistent completion of SILS cholecystectomy cases appears to be after 25 cases. In addition, conversion rates drop dramatically after the first ten cases. PMID- 22487623 TI - Benefits of a straight laparoscopic restorative proctocolectomy with ileal pouch anal anastomosis for ulcerative colitis: a retrospective case-matched study. AB - PURPOSES: The aim of this study was to evaluate the benefit of straight laparoscopic restorative proctocolectomy (sLRP) with ileal pouch anal anastomosis for ulcerative colitis (UC). METHODS: Twenty patients underwent sLRP or open restorative proctocolectomy. The 2 groups were retrospectively well matched with respect to sex, body mass index, and American Society of Anesthesiologists' score. RESULTS: The median operative time was longer in the sLRP group (P=0.0003). The median operative blood loss was significantly less in the sLRP group (P=0.0054). The median analgesic drug usage during the first 7 days after surgery was lower in the sLRP group (P=0.038). There were no differences in morbidity rates and long-term functional outcome measures between the groups. CONCLUSIONS: An sLRP for UC has the advantage over an open restorative proctocolectomy of better short-term outcomes, and both groups have similar long term outcomes. This procedure is acceptable for minimally invasive surgery in patients with UC. PMID- 22487624 TI - The applicability of laparoscopic gastrectomy in the surgical treatment of giant duodenal ulcer perforation. AB - PURPOSE: The present study aims to provide an applicability of laparoscopic gastrectomy used in the treatment of giant duodenal ulcer perforation. METHODS: Between July 2010 and April 2011, laparoscopic distal gastrectomy with ROUX-EN-Y gastrojejunostomy and truncal vagotomy was performed in consecutive 5 patients with giant duodenal ulcer perforation. RESULTS: There was no conversion to open surgery. There was no severe postoperative complication. The days of normalization of leukocytosis were 3, 1, 2, 2, and 5, respectively. The times to first flatus were postoperative days 2, 3, 5, 2, and 3. The days of commencement of a soft diet were postoperative days 5, 5, 6, 5, and 5. They were discharged on postoperative days 9, 11, 20, 10, and 11. CONCLUSIONS: We suggest that laparoscopic surgery may be a good surgical method to improve surgical outcomes and is worth a try in experts. PMID- 22487626 TI - Results from a consecutive series of laparoscopic incisional and ventral hernia repairs. AB - INTRODUCTION: Incisional hernia is a problematic complication of abdominal surgery and both late and early outcomes can be unsatisfactory. Laparoscopic repair has been gaining popularity for both incisional and ventral herniae. However, the perceived benefits have not been convincingly demonstrated by randomized-controlled studies or meta-analyses. METHODS: Case notes from 54 patients undergoing consecutive laparoscopic repairs of the abdominal wall hernia at a single center were reviewed. Demographic data, postoperative complications, length of stay, and recurrence rates were all recorded. RESULTS: The majority of the patients had incisional hernia, with de novo ventral hernia comprising 7.4% of the total. Forty percent of patients had undergone at least 1 previous repair of their incisional hernia. The median recorded diameter of the hernia defect was 5 cm. No recurrences were recorded over a median follow-up of 26 months. Complications were all minor and included seroma formation, hematoma, and wound infection (n=5 patients). Median operative duration was 45 minutes and median length of stay postoperatively was 1 day. CONCLUSIONS: The results compare well with those in the published literature and would support the continued use of laparoscopic incisional/ventral hernia repair. Any benefits from this approach, however, are likely to be operator dependent. As a result, all units undertaking such repairs should regularly review their results and compare them with the reported standard. PMID- 22487625 TI - The value of a laparoscopic interval appendectomy for treatment of a periappendiceal abscess: experience of a single medical center. AB - BACKGROUND: Interval appendectomy has been known to be an effective and safe treatment for a periappendiceal abscess, but there is no study on a laparoscopic approach for the treatment of a periappendiceal abscess. The aim of this study is to investigate the value of laparoscopic interval appendectomy. MATERIALS AND METHODS: We retrospectively studied 56 patients who had been admitted due to a periappendiceal abscess to Chungbuk National University Hospital from July 2005 to June 2010. Fifteen patients underwent an initial conservative treatment and interval appendectomy. Medical records were reviewed for the postoperative hospital course such as complications, time of initiation of diet, time since stopping antibiotics, symptoms' relief period, and length of hospital stay. RESULTS: All patients received initial conservative treatment [percutaneous drainage insertion (1 case failed) and intravenous antibiotics], and the initial length of hospital stay was 11.6+/-4.3 days. Percutaneous drainage was removed a mean of 21.7+/-9.4 days after the initial treatment. Interval appendectomy was performed at a mean of 64.0+/-17.8 days after initial admission. The duration of use of intravenous antibiotics was a mean of 4.1+/-1.8 days after laparoscopic interval appendectomy. The complication rate was 1 (6.7%) and the open conversion rate was 1 (6.7%). CONCLUSIONS: Our study revealed that initial conservative treatment and laparoscopic interval appendectomy represented a feasible and effective treatment for patients with a periappendiceal abscess. PMID- 22487627 TI - Laparoscopic splenectomy: ligasure or clip ligation? AB - Laparoscopic splenectomy (LS) is frequently performed for spleen removal under pathologic conditions. The aim of this study was to evaluate whether ligasure is superior to clip ligation during LS. In a simple randomized prospective study, 40 patients who were candidates for splenectomy were randomly assigned to 2 groups of clip and ligasure. Operating time, need for transfusion, intraoperative and postoperative bleeding, open conversion, and postoperative complications were evaluated. Operating time was 115.4 min (SD 15.24) in the clip group and 100.6 min (SD 16.05) in the ligasure group (P=0.005). Bleeding volume was 150.9 mL (SD 26.2) in the clip group and 131.7 mL (SD 25.1) in the ligasure group (P=0.025). In both groups, there was no need for transfusion and no conversion to the open approach. Although both clip and ligasure can be used for vascular control in LS, hemostasis is simply and easily achieved with little dissection using the ligasure method. Therefore, ligasure is superior to clip in cases of LS. PMID- 22487628 TI - Laparoscopic cholecystectomy in children with sickle cell anemia and the role of ERCP. AB - BACKGROUND: Patients with sickle cell anemia (SCA) have a high incidence of cholelithiasis and choledocholithiasis. This report is an analysis of our experience with laparoscopic cholecystectomy (LC) for children with SCA and the role of endoscopic retrograde cholangiopancreatography (ERCP). PATIENTS AND METHODS: The records of children with SCA who had cholecystectomy were retrospectively reviewed for age, sex, hemoglobin level, hemoglobin electrophoresis, indication for cholecystectomy, operative time, hospital stay, and postoperative complications. They were divided into 2 groups, open cholecystectomy (OC) group and LC group, and the 2 were compared in terms of operative time, hospital stay, and postoperative complications. RESULTS: Over a period of 15 years (January 1995 and December 2009), 94 children with SCA had cholecystectomy. Thirty-five (19 males and 16 females) had OC, 52 (28 males and 24 females) had LC, and 7 (4 males and 3 females) had LC and splenectomy. Their age ranged from 4 to 15 years (mean, 11.4 y). The indications for cholecystectomy were biliary dyspepsia and biliary colic (55), acute cholecystitis (7), obstructive jaundice (17), asymptomatic (12), and biliary pancreatitis (3). All those who had OC underwent intraoperative cholangiogram, 9 of them (25.7%) had common bile duct (CBD) exploration and 2 transduodenal sphincterotomy. Of those who had LC, 13 (25%) underwent preoperative ERCP, which was normal in 1, showed dilated CBD with no stones in 2, and dilated CBD with stones in 7. In 3, ERCP showed dilated CBD with enlarged, inflammed papilla suggestive of recent stone passage. Nine underwent endoscopic sphincterotomy and stone extraction followed by LC. There was no mortality; 1 (2.1%) required conversion to OC and another underwent postoperative exploration because of bleeding from an accessory cystic artery. In the LC group, 4 (7.7%) developed minor postoperative complications, whereas 8 (22.9%) in the OC group developed complications. CONCLUSIONS: With proper perioperative management, LC is feasible, safe, and superior to OC in children with SCA with regard to postoperative complications, duration of hospital stay, cosmetic appearance, and postoperative recovery. LC should be the treatment of choice for both symptomatic and asymptomatic cholelithiasis in children with SCA. ERCP is a valuable diagnostic and therapeutic investigation both preoperatively and postoperatively. The sequential approach of endoscopic sphincterotomy and stone extraction followed by LC is a safe and effective approach for the management of cholelithiasis and choledocholithiasis in children with SCA. PMID- 22487629 TI - Laparoscopic management of obturator nerve schwannomas: experiences with 6 cases and review of the literature. AB - OBJECTIVES: To present our experiences in management of obturator nerve schwannomas by laparoscopy. PATIENTS AND METHODS: Six patients who were diagnosed preoperatively with pelvic tumors and histologically with obturator nerve schwannomas were treated by laparoscopy in our hospital between 1998 and 2009. Clinical data were obtained by a retrospective review of all the patients' medical records, radiologic reports, pathologic reports, and operation videos. RESULTS: A total of 6 tumors were found in 6 patients, none of which was correctly, preoperatively diagnosed as a schwannoma. In 5 of them, obturator nerve roots were identified to be associated with the tumors during the operation. All of the tumors were resected successfully by laparoscopy, including 2 resected by enucleation. Postoperatively, 2 patients developed a permanent neurological deficit, 2 patients developed transient nerve neuropathy but complete resolution within 8 weeks, and the other 2 developed no neurological deficit. Pathologic examination showed that all the tumors were benign schwannoma. At a mean follow-up of 24 months (range, 12 to 48 mo) postresection, all the patients remained free from recurrence. CONCLUSIONS: Pelvic schwannomas are rare and difficult to diagnose preoperatively. The intraoperative observation of the nerve running through the tumor may aid the diagnosis. Although obturator nerve injury does not seem to be associated with severe impairments, efforts should be made to preserve the integrity of the nerve. Laparoscopic surgery is a safe and feasible method for approaching benign schwannoma in the obturator fossa. PMID- 22487630 TI - Endoanal ultrasonography-assisted percutaneous transperineal management of anorectal sepsis. AB - PURPOSE: We aimed to analyze the feasibility and efficacy of a new transperineal access to treat anorectal sepsis (fistulae and abscesses) under endoanal ultrasonography guidance. METHODS: Twenty-five patients (80% Crohn disease) were included retrospectively. Twenty-one patients had fistulae (perianal, urethroanal, and anovaginal) treated by injection of heterologous fibrin glue and cyanoacrylate. Four patients with abscesses were treated by irrigation-injection of normal saline solution and an aminoglycoside antibiotic. RESULTS: Twenty-five patients underwent 32 treatment sessions. At 4 weeks' evaluation, 19 patients (90.5%) with anal fistulae ultimately achieved a 4-week short-term success. Of these, 5 patients (26%) showed resolution of symptoms and persistent occlusion of the fistula track at long-term follow-up (>6 mo). At 4-week follow-up, the treatment of abscesses was successful in 3 of 4 cases. However, a relapse was observed in 2 cases after a mean period of 3 months. No serious adverse events were observed. CONCLUSIONS: Endoanal ultrasonography-assisted percutaneous transperineal injection represents a sphincter-sparing alternative to the surgical route, with interesting outcomes and excellent tolerability for the treatment of anorectal sepsis. PMID- 22487631 TI - Are short-term focused training courses on a phantom model using porcine gall bladder useful for trainees in acquiring basic laparoscopic skills? AB - The best training method in laparoscopic surgery has not been defined. We evaluated the efficacy of laparoscopic skills acquisition in a short-term focused program. Two hundred fifty-six participants undergoing training on a phantom model were divided into 2 groups. Group 1 had no exposure and group 2 had performed a few laparoscopic surgeries. Acquisition of laparoscopic skills was assessed by operation time and the modified Global Operative Assessment of Laparoscopic Skills (GOALS) scale. A questionnaire was sent to the participants after 3 to 6 months for assessment of impact of training. There was a statistically significant improvement in the assessed parameters and in the mean score of all 5 domains of GOALS. The participants in group 2 performed better than those in group 1 in the first case. The difference between both the groups disappeared after the training. Participants who responded to the questionnaire felt that training helped them in improving their performance in the operation theater. PMID- 22487632 TI - Feasibility of the novel 3-step protocol for biliary cannulation--a prospective analysis. AB - Traditionally, a 2-step protocol has been used for deep biliary cannulation. The purpose of the present prospective study was to find out the feasibility and safety of the novel sequential 3-step protocol (traditional cannula with guidewire, double-guidewire, and needle-knife techniques) for deep biliary cannulation. All consecutive patients admitted for endoscopic retrograde cholangiopancreatography (ERCP) to a single, very experienced ERCP endoscopist during the year 2009 with intended biliary cannulation and with unhindered access to a native papilla (n=105) were included in the present study. The overall success rate for deep biliary cannulation was 99% (104/105). Cannulation with cannula and guidewire was attempted in all patients and proved successful in 80% (84/105) of the attempts, the double-guidewire technique was applied in 19% (20/105) and was successful in 65% (13/20) of the cases, and the needle-knife technique was applied in 7% (7/105) with success in all cases. The median cannulation time was 1 minute (range, 0 to 27 min). The rate of post-ERCP pancreatitis was 3% (3/105) and post-ERCP cholangitis 2% (2/105). We conclude that in experienced hands, the novel sequential 3-step protocol for biliary cannulation tested herein proved to be an effective cannulation protocol with the overall success rate of 99%. The complication rate of these ERCP procedures (5%) was within acceptable limits. PMID- 22487633 TI - Laparoscopic splenectomy for the treatment of wandering spleen in a pregnant woman: a case report. AB - Laparoscopic splenectomy became the gold standard recently for the removal of spleen. One of its rare indication is wandering spleen (WS). WS is characterized by incomplete fixation of the spleen. Patients usually have an asymptomatic abdominal mass. When they are symptomatic, abdominal pain with a mobile mass is the major finding. Laboratory data are nonspecific, but the diagnosis can be confirmed by imaging studies; computed tomography, magnetic resonance imaging, and ultrasonography are preferred modalities. It can predispose one to life threatening complications such as splenic infarction, portal hypertension, pancretitis, and hemorrhage, due to torsion of its vascular pedicle. Herein, we present a female patient, a 24-year-old, 18-week primigravida. She was admitted with an intra-abdominal mass and lower abdominal pain. Ultrasonography revealed a mass behind the uterus. Magnetic resonance imaging was planned, and the spleen was seen at this area. We performed laparoscopic splenectomy for the treatment of a WS, which would be dangerous for pregnancy. The patient was discharged without any postoperative complication on the third day postoperatively. A healthy baby was delivered at term. Minimally invasive procedures should also be the primary choice in the treatment of such pregnant women. This is the first case of laparoscopic splenectomy in a pregnant woman for WS in the English literature. PMID- 22487634 TI - Combined intraperitoneal monitoring and total extraperitoneal repair of McBurney's incisional hernia. AB - BACKGROUND: McBurney's incisional hernia after appendectomy is rare. Although the open surgical approach, either through direct suturing or through mesh repairs, mostly achieves a satisfactory outcome, postoperative wound pain usually impedes patient's early ambulation. Accordingly, laparoscopic ventral hernia repair has emerged as a minimally invasive technique in modern surgical practice. We described a different approach of laparoscopic incisional hernia repair. CASE REPORT: A 76-year-old woman with a history of appendectomy presenting with a bulging mass over the right lower quadrant of the abdomen beneath the operation scar was admitted to our hospital. Computed tomography revealed defects in the abdominal muscle layers without evidence of bowel incarceration. The patient was diagnosed with postappendectomy incisional hernia for which laparoscopic hernia repair was performed through a combined intraperitoneal and extraperitoneal approach. The patient's postoperative course was excellent. CONCLUSIONS: Combined extraperitoneal approach and intraperitoneal monitoring for McBurney's incisional hernia is feasible in selected cases. PMID- 22487635 TI - Late umbilical port-site recurrence of a gastrointestinal stromal tumor with an acquired PDGFRalpha mutation after laparoscopic resection: report of a case. AB - A 71-year-old man underwent laparoscopic partial gastrectomy for a gastric submucosal tumor in 1997; subsequently, he underwent follow-up without therapy. In December 2008, he noticed a mass at the umbilical wound. Computed tomography and physical examination of the umbilical mass indicated suspected recurrence of the gastric submucosal tumor at the port site. Because the lesion was locally confined, surgery was performed, including resection of the greater omentum; peritoneum; rectus abdominis; and the navel, including the skin. Histologic analysis of the tumor yielded positive results for c-kit, thereby indicating a gastrointestinal stromal tumor (GIST). Mutation analysis of c-kit and platelet derived growth factor receptor alpha (PDGFRalpha) revealed an acquired mutation in exon 18 of PDGFRalpha in the recurrent tumor. To date, only 4 cases of port site recurrence after laparoscopic resection of GIST have been reported. This is the first study to report an acquired PDGFRalpha mutation in port-site recurrence after laparoscopic resection of a GIST. PMID- 22487636 TI - Laparoscopic sleeve gastrectomy in a pediatric patient. AB - Laparoscopic sleeve gastrectomy (LSG) is a novel technique in pediatric bariatric surgery. The patient reported here participated in our pediatric weight management clinic for 2 years. His obesity was complicated by obstructive sleep apnea, acanthosis nigricans, and hypertension. His past medical history included 2 small bowel resections, bilateral nephrectomy and kidney transplantation for multicystic renal dysplasia, and 2 peritoneal dialysis-catheter infections. Gastric banding was contraindicated because of previous foreign body infections and chronic need of immunosuppression and steroids. Roux-en-Y gastric bypass was of higher risk given his previous abdominal operations and the resulting medication absorption issues. He underwent LSG without any complications. Five trocars were utilized and a gastroscope was placed during gastric resection. Presurgical body mass index was 44.8 kg/m. At 18 months follow-up body mass index was 26.5 kg/m. We concur that LSG can be a safe and effective alternative in bariatric surgery in well-selected adolescents. PMID- 22487637 TI - Autolysis: a plausible finding suggestive of long ESD procedure time. AB - Autolysis is the enzymatic digestion of cells by the action of its own enzymes, and it mostly occurs in dying or dead cells. It has previously been suggested that prolonged procedure time could lead to autolytic changes from the periphery of the endoscopic submucosal dissection specimens. Recently, the authors have experienced a case of autolysis; due to the presence of ulcer, fibrosis, and frequent bleeding from the cut surface, it took 6 hours to complete the resection. More than halfway through the resection; bluish purple discoloration of the part of the dissected flap where the dissection was initiated was noticed. Histologic examination of this site showed diffuse distortion of epithelial lining and cellular architectures along with loss of cell components, compatible with autolysis. Because autolysis could theoretically pose a potential problem regarding the evaluation of resection margin, endoscopists and pathologists should communicate with each other for a reliable pathologic decision. PMID- 22487638 TI - Laparoscopic introduction of a center rod using a Nelaton catheter during laparoscopic esophagogastrostomy. AB - During laparoscopic proximal gasterctomy, the difficulty associated with the use of a circular stapler for esophagogastrectomy is not only the fixation of the anvil, but also the laparoscopic manipulation of the body of the circular stapler. We have developed a new approach to the laparoscopic introduction of the center rod using a Nelaton catheter. After transection of the esophagus, the stomach is pulled out through an umbilical minilaparotomy. The proximal gastrectomy is performed extracorporeally, and a Nelaton catheter is passed through a small incision at the lower body of the stomach and a small penetrating wound at the point of the esophagogastrostomy. The Nelaton catheter is attached to the center rod of the circular stapler. The center rod can be guided to the appropriate point laparoscopically by the Nelaton catheter. Between January 2009 and May 2010, 11 patients underwent this procedure, successfully. This technique was useful for laparoscopic proximal gastrectomy. PMID- 22487639 TI - Laparoscopic insertion of antegrade continence enema catheter: a technique enabling early postoperative usage. AB - AIMS: The Chait Trapdoor Caecostomy catheter was developed to allow the use of antegrade continence enemas without using the appendix. We describe a technique for its insertion under laparoscopic guidance. METHODS: Bowel is secured to the abdominal wall using nonabsorbable sutures. Technical details of the procedure are described. RESULTS: Five children underwent the procedure. Four had a left sided procedure and tolerated the procedure well without complications. They have good results with daily antegrade enemas. One child who had a cecostomy had postoperative abdominal distension. He has ongoing soiling and constipation, but has problems with compliance. CONCLUSIONS: We have used the technique in a small number of patients, but results have been favorable. The sutures prevent the risk of the bowel segment slipping from the tube when distended with fluid, provide a good seal around the tube to avoid leakage, and keep a smooth alignment of bowel without angulation. PMID- 22487640 TI - Laparoscopic sleeve gastrectomy for a large gastrointestinal stromal tumor. AB - The biological behavior of gastrointestinal stromal tumor (GIST) makes resection of the tumor with adequate margins, a mode of curative treatment. GIST does not have lymphatic permeation. Hence, the goal of therapy is complete resection of visible and microscopic disease, which can be achieved by adequate tumor-free margins. Laparoscopic management of large GIST tumors is discouraged because of the fear of spillage of the tumor or rupture of the tumor capsule while handling a large tumor and thus causing metastasis. PMID- 22487641 TI - How to meet the challenge of flexible exposure of the Calot triangle in SILS cholecystectomy. AB - Single-incision laparoscopy was developed to further reduce the operative trauma in routine laparoscopic procedures. However, the method remains challenging because the exposure of the Calot triangle is more difficult as the use of a singular traction device does not allow the flexible 3-dimensional mounting of the structures. We introduce a technical improvement involving both exposure and traction. After installation of the technical devices for single-incision laparoscopy cholecystectomy, as usual, a suture on a Keith needle is inserted subcostally from the right side of the patient, passed midway through the infundibulum, and extracted subcostally on the left side of the patient. The suture is fixed with 2 metal clips on each side of the gallbladder. The gallbladder can be tilted both medially and laterally on a horizontal line and the Calot triangle can be dissected from medial and lateral aspects following the "critical view of safety" criteria used in conventional laparoscopy. PMID- 22487642 TI - Laparoscopic transcutaneous closure of central defects in laparoscopic incisional hernia repair. AB - PURPOSE: The aim of this technical report is to investigate the safety, efficacy, and outcome of transcutaneous closure of central defects (TCCD) for laparoscopic incisional hernia repair (LIHR). METHODS: Twenty-two patients with incisional hernias underwent a LIHR-TCCD repair. After clearance of the abdominal wall from adhesions, laparoscopic central closures were performed transcutaneously with 0 polypropelene sutures placed every 1 cm of the defect starting at the cranial most edge of the hernia and ending at the caudal-most edge of the hernia. A standard LIHR was performed with coated polyester mesh placed with at least 6 cm of overlap with mesh on all borders. Transfascial sutures with 0-polypropelene sutures were placed every 4 cm circumferentially, and titanium tacks were used to secure the mesh to the peritoneum every 1 cm. RESULTS: The mean age was 52 years and the mean body mass index was 35 kg/m. The mean hernia defect was 4.7 cm*7.2 cm with a mean area of 37 cm. There were no mortalities and no major perioperative morbidities. Minor complications included 2 (9%) cases of pneumonia/pneumonitis. There were no clinically significant seromas, no radiographic or clinical eventrations, and no hernia recurrences with a mean follow-up of 21 months. CONCLUSIONS: LIHR-TCCD is safe and technically feasible in incisional hernias of width <10 cm. By closing the central defect, seromas and eventrations can be reduced. PMID- 22487644 TI - Incidental fetoscopy during laparoscopy in pregnancy: management of perforation of the gravid uterus. AB - INTRODUCTION: Laparoscopy during pregnancy is safe and effective, but poses unique challenges because of alterations in the intra-abdominal anatomy induced by the gravid uterus. CASE: A 33-year-old female with an intrauterine pregnancy at 19 weeks' gestation presented with symptoms of appendicitis. Diagnostic laparoscopy resulted in incidental uterine perforation and insufflation. Transition to midline laparotomy was made to suture uterine puncture sites from the trocar and Veress needle. Preterm premature rupture of membranes and abruption were diagnosed at 32 weeks' gestation, and the patient was delivered. The child was alive and well at 12 months of age. CONCLUSIONS: Lessons from the emerging field of minimally invasive fetal surgery regarding the management of surgical entry into the gravid uterus can be applied to the rare case of incidental uterine perforation at the time of laparoscopy during pregnancy. PMID- 22487643 TI - Laparoscopic treatment for median arcuate ligament syndrome: the usefulness of intraoperative Doppler ultrasound to confirm the decompression of the celiac artery. AB - The median arcuate ligament syndrome is an unusual disease associated with postprandial epigastric pain, and the optimal treatment of this syndrome remains to be established. A 52-year-old woman manifested in our hospital postprandial epigastric pain, and extrinsic compression of the celiac trunk revealed by an abdominal computed tomography. After the induction of general anesthesia, the celiac artery origin was completely skeletonized using a laparoscopic dissector and vessel sealing system. Intraoperative Doppler ultrasound demonstrated that, after surgery, the stenosis of the celiac artery, and poststenotic dilatation observed before the release of the median arcuate ligament, had completely disappeared. In conclusion, the laparoscopic release of the median arcuate ligament is a minimally invasive treatment for median arcuate ligament syndrome. The intraoperative Doppler ultrasound is useful for confirming the decompression of the celiac artery, although long-term follow-up is mandatory. PMID- 22487645 TI - Simultaneous laparoscopic subtotal colectomy and pancreaticoduodenectomy for colonic FAP and ampullary cancer. AB - BACKGROUND: Laparoscopic surgery has extended its applications to resection of malignancies with favorable results. We report the first successful simultaneous laparoscopic subtotal colectomy and pancreaticoduodenectomy (PD) in a patient with familial adenomatous polyposis (FAP). CASE REPORT: A 37-year-old man presented with obstructive jaundice. Gastroscopy and biopsies revealed a large ampullary tubulovillous adenoma with mild dysplasia (Spigelman stage III). A colonoscopy for suspicion of FAP revealed numerous right-sided polyps with left sided sparing. Computed tomography showed a double duct sign. A simultaneous laparoscopic subtotal colectomy and PD was performed successfully. The operative time was 225 minutes for the colectomy and 390 minutes for the PD. Histology showed an R0 resection of ampullary adenocarcinoma (20 negative nodes) and colonic polyps with low-grade dysplasia. Genetic screening confirmed a diagnosis of FAP. CONCLUSIONS: A simultaneous laparoscopic subtotal colectomy and PD in patients with FAP and ampullary neoplasia seems safe with favorable clinical and oncologic outcomes. PMID- 22487646 TI - Single-port laparoscopic appendectomy during pregnancy. AB - As a result of the increased demand for minimally invasive surgery, single-port laparoscopic surgery performed via a single incision was introduced and has been performed in various fields. Herein, we report our initial experience with single port laparoscopic appendectomy (SP-LA) using Gelport access for the treatment of acute appendicitis in 2 pregnant women. SP-LA using Gelport access was performed successfully in these pregnant women without prolongation of operation time, and there was no need for ancillary trocar insertions or conversion to conventional laparoscopy. One woman spontaneously delivered at 39 weeks' gestation approximately 20 weeks after the surgery and the other has maintained a healthy pregnancy. SP-LA can be considered a minimally invasive alternative to conventional laparoscopic appendectomy in pregnant women (Supplemental Digital Content 1, http://links.lww.com/SLE/A55). PMID- 22487647 TI - Robot-assisted low anterior resection for situs inversus totalis: a novel technical approach for an uncommon condition. AB - INTRODUCTION: Situs inversus totalis (SIT) is an uncommon condition, with an incidence of 1 in 10,000. Surgery for SIT patients is more difficult because of the uncommon anatomy. Experience in laparoscopic surgery for patients with SIT is very limited. Only a few cases of laparoscopic colorectal resections have been reported in the literature. We present the first robot-assisted low anterior resection for rectal cancer in a patient with SIT. PATIENT: A 70-year-old woman with SIT who presented with rectal bleeding underwent a colonoscopy and barium enema. This workup revealed a rectal cancer 10 cm from the anal verge. The magnetic resonance imaging scan revealed a T3/4 tumor in the rectum with perirectal lymph node involvement, whereas the computed tomography positron emission tomography scan did not reveal any distal metastasis. She underwent neoadjuvant chemoradiotherapy 6 weeks before surgery. Postoperatively, she made an uneventful recovery and was discharged on day 6. SURGICAL TECHNIQUE: After laparoscopic examination and displacement of the small bowel, 4 robot trocars were inserted into 4 quadrants of the abdomen. A fifth port was inserted and used by the assistant. The robot cart was docked from the right side with arms 1, 2, and 3 in the right upper quadrant (Cadiere grasper), left lower quadrant (bipolar Maryland grasper), and left upper quadrant (monopolar scissors), respectively, for colonic mobilization without splenic flexure takedown. For pelvic dissection, arms 1 and 3 were moved to the right upper quadrant and right lower quadrant, respectively. After adequate pelvic dissection, the robot cart was undocked, and a laparoscopic articulating linear stapler was used to transect the rectum from the left lower quadrant port. Bowel continuity was restored with a circular stapler. A loop ileostomy was created through the extraction site in the right lower quadrant. CONCLUSIONS: Robot-assisted low anterior resection for SIT patients can be performed safely and confers the benefits of laparoscopic low anterior resection with additional advantages unique to the da Vinci system. PMID- 22487648 TI - Major bile duct injuries during cholecystectomy in children: conservative laparoscopic approach is possible. AB - Major bile duct injury is an inherent complication in cases of both open and laparoscopic cholecystectomies. In case of choledochal lesion, conservative treatment or internal derivation by a Roux-en-Y can be proposed. We report the case of a 5-year-old boy referred to our center for an iatrogenic choledochal ligation after open cholecystectomy (performed 20 d before) for asymptomatic gallbladder stone. We performed a laparoscopic conservative treatment with a consistent good result 5 years after the procedure. PMID- 22487649 TI - Perforated appendicitis caused by foreign body ingestion. AB - Most ingested foreign bodies pass through the gastrointestinal tract without any incident. However, foreign bodies lodged in the appendix can cause an inflammatory reaction with or without perforation. Here, we present a case of a 54-year-old woman with perforated appendicitis who consumed wild game containing a shot pellet. Five months before admission, she had eaten the meat of a pheasant that had been shot with a shotgun. Abdominal computed tomography confirmed the diagnosis of perforated appendicitis with abscess due to a foreign body. Subsequently, a laparoscopic appendectomy was performed. Follow-up radiographs obtained after the surgery did not identify the foreign body. Histolopathologic examination confirmed appendiceal perforation with focal inflammation secondary to a foreign body. PMID- 22487650 TI - Laparoscopic TME for rectal cancer: a case series. AB - PURPOSE: Laparoscopic colonic resection for cancer is becoming well established within the surgical community. However, the current evidence for laparoscopic total mesorectal excision (TME) is scanty but does point toward a potential for improved short-term outcomes and oncological equivalency to open resection. METHODS: Patients undergoing laparoscopic TME for rectal cancer in 1 hospital between October 2003 and December 2010 were analyzed. Data were collated from a prospective database. Survival analysis was calculated using the Kaplan-Meier method. RESULTS: 79 patients were analyzed (96.3% of all TMEs). There was a median length of stay of 5 days, with no postoperative mortality. The 5-year overall survival was 70% and the 5-year disease-free survival was 65.5%. There was a conversion rate of 10.1%. The 5-year overall survival for completed laparoscopic cases was 70.6% versus 62.5% for converted cases (P=0.041). CONCLUSIONS: There seems to be increasing evidence that laparoscopic TME is equivalent to open TME for rectal cancer. Conversion may be deleterious to overall survival. PMID- 22487651 TI - Scarf versus chevron osteotomy for the correction of 1-2 intermetatarsal angle in hallux valgus: a systematic review and meta-analysis. AB - The chevron and scarf osteotomies are commonly used for the surgical management of hallux valgus (HV). However, there is debate as to whether one osteotomy provides more 1-2 intermetatarsal (1-2 IMA) correction than the other. The objective of this systematic review and meta-analysis was to compare the effectiveness of 3 types of first metatarsal osteotomy for reducing the 1-2 IMA in HV correction: the chevron osteotomy, the long plantar arm (modified) chevron osteotomy, and the scarf osteotomy. A systematic search for eligible studies was performed of the following databases: Medline, Embase (Ovid), CINAHL (EBSCO Host), and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials. Only English-language studies previous to May 2010 were included in the review. Additional hand and electronic content searches of relevant foot and orthopaedic journals were performed. Criteria for inclusion in this analysis included systematic reviews of randomized controlled trials, prospective and retrospective cohort studies, and case-control studies, as well as case-series studies involving the chevron, scarf, or long plantar arm chevron osteotomy of >20 participants with a minimum of 80% follow-up. Quality of evidence of the included studies was assessed with the Grading of Recommendations Assessment, Development and Evaluation system. All pooled analyses were based on a fixed effects model. There was a total of 1351 participants who underwent either a chevron (n = 1028), scarf (n = 300), or long plantar arm chevron osteotomy (n = 23). Only one study for the long plantar arm chevron group fitted the eligibility criteria for this review; however, it was not amenable to meta analysis. The chevron osteotomy was associated with a mean reduction of 1-2 IMA from preoperative to postoperative of 5.33 degrees (95% confidence interval, 5.12 to 5.54, p < .001), and the scarf osteotomy was associated with a mean reduction of 6.21 degrees (95% confidence interval, 5.70 to 6.72, p < .001). There was a statistically significant 0.88 degrees increase in the correction of the 1-2 IMA in favor of the scarf osteotomy compared with the chevron osteotomy. The studies included in this review were of very low- to low-quality evidence. Our findings indicate that the scarf osteotomy provides greater correction of the 1-2 IMA when used for HV correction. However, only a weak recommendation in favor of the scarf osteotomy can be made based on the low quality of evidence of the studies included in this analysis. PMID- 22487653 TI - The storm has cleared: lessons from the CD28 superagonist TGN1412 trial. AB - The life-threatening cytokine-release syndrome suffered by six volunteers in a Phase I clinical trial following administration of the CD28 superagonist antibody TGN1412 (developed by TeGenero) in March 2006 was completely unpredicted by the preclinical studies. Here, Thomas Hunig, main founder of TeGenero, describes the recent investigations into what went wrong and discusses the lessons learnt for future clinical trials. PMID- 22487655 TI - Aging and human sexual behavior: biocultural perspectives - a mini-review. AB - In this mini-review, we consider an evolutionary biocultural perspective on human aging and sexuality. An evolutionary approach to senescence highlights the energetic trade-offs between fertility and mortality. By comparing humans to other primates, we situate human senescence as an evolutionary process, with shifts in postreproductive sexual behavior in this light. Age-related declines in sexual behavior are typical for humans but also highly contingent on the sociocultural context within which aging individuals express their sexuality. We briefly review some of the most comprehensive studies of aging and sexual behavior, both from the USA and cross-culturally. We frame these patterns with respect to the long-term relationships within which human sexual behavior typically occurs. Because sexuality is typically expressed within pair-bonds, sexual behavior sometimes declines in both members of a couple with age, but also exhibits sex-specific effects that have their roots in evolved sex differences. PMID- 22487654 TI - Fine-tuning of dendritic cell biology by the TNF superfamily. AB - Members of the tumour necrosis factor (TNF) superfamily have been implicated in a wide range of biological functions, and their expression by cells of the immune system makes them appealing targets for immunomodulation. One common theme for TNF superfamily members is their coordinated expression at the interface between antigen-specific T cells and antigen-presenting dendritic cells and, by virtue of this expression pattern, TNF superfamily members can shape T cell immune responses. Understanding how to manipulate such functions of the TNF superfamily may allow us to tip the balance between immunity and tolerance in the context of human disease. PMID- 22487656 TI - Lipid signaling in Drosophila photoreceptors. AB - Drosophila photoreceptors are sensory neurons whose primary function is the transduction of photons into an electrical signal for forward transmission to the brain. Photoreceptors are polarized cells whose apical domain is organized into finger like projections of plasma membrane, microvilli that contain the molecular machinery required for sensory transduction. The development of this apical domain requires intense polarized membrane transport during development and it is maintained by post developmental membrane turnover. Sensory transduction in these cells involves a high rate of G-protein coupled phosphatidylinositol 4,5 bisphosphate [PI(4,5)P(2)] hydrolysis ending with the activation of ion channels that are members of the TRP superfamily. Defects in this lipid-signaling cascade often result in retinal degeneration, which is a consequence of the loss of apical membrane homeostasis. In this review we discuss the various membrane transport challenges of photoreceptors and their regulation by ongoing lipid signaling cascades in these cells. This article is part of a Special Issue entitled Lipids and Vesicular Transport. PMID- 22487657 TI - [Conn adenoma complicated by tetraparesia]. PMID- 22487658 TI - [Sudden death caused by a less lethal weapon chest-wall injury (Commotio cordis)]. AB - Less lethal weapons, like Flashball, are more and more used since 1995 in law enforcement, even by the local police to neutralize combative individuals and to disperse riot crowds. This gun fires large rubber bullets and has been incriminated many times in cases of face injuries with functional consequences. In this case report, we mention a case of sudden death from cardiac arrest due to low energy chest wall impact of a rubber bullet shot with the Flashball. Commotio cordis is potentialized by a lethal set of three including, a certain impact velocity, an exact location of the hit over the cardiac silhouette, and a precise timing 15 m/s prior to the peak of the T-wave. This case report highlights the fact that such impacts can cause significant injury to internal organs, in particular circonstances, implying the necessity of a raising awareness of the medical staff, in ordre to not underestimate the severity of such injuries. PMID- 22487659 TI - Periodontal status and post-transplantation complications following intensive periodontal treatment in patients underwent allogenic hematopoietic stem cell transplantation conditioned with myeloablative regimen. AB - OBJECTIVES: Evaluation of the periodontal status is necessary prior to management with high-dose chemotherapy before hematopoietic stem cell therapy (HSCT). During medical therapy, pre-existing periodontal conditions may exacerbate and cause local and systemic complications. When possible, maximal oral health should be achieved prior to engraftment. In this study, we aimed to determine the alterations occurred in the periodontal status of the patients after periodontal treatment and allogenic HSCT and evaluate the effect of intensive periodontal approach on the short-term complications of HSCT. METHODS: The alterations occurred in the periodontal tissues 3-4 weeks after periodontal treatment and after HSCT periods of 3 months for 29 patients treated with full-mouth periodontal treatment completed in 24 h in addition to eradication of dental foci, and oral hygiene status were evaluated using pocket depth measurements, presence of bleeding on probing and plaque and gingival indices. The incidence and severity of acute graft-versus-host disease (GVHD) and oral mucositis (OM) were recorded. Duration of engraftment period and the episode of febrile neutropenia were also evaluated. RESULTS: There were significant improvements in periodontal status after periodontal treatment (P<0.001). There were 14 (48.3%) patients without acute GVHD and 17 (58.6%) patients with no sign of OM. The majority of OM was at grade II level. There was a negative relation that exists between the percentage of BOP (+) sites and presence of OM (r=-0.518, P<0.05). CONCLUSIONS: Together with a significant reduction in gingival inflammation and maintenance of the improvement in periodontal health, remarkable decrease in the incidence and severity of OM were observed. PMID- 22487660 TI - Telephone triage is not the answer to ED overcrowding. PMID- 22487661 TI - Review article: Part two: Goal-directed resuscitation--which goals? Perfusion targets. AB - Haemodynamic targets, such as cardiac output, mean arterial blood pressure and central venous oxygen saturations, remain crude predictors of tissue perfusion and oxygen supply at a cellular level. Shocked patients may appear adequately resuscitated based on normalization of global vital signs, yet they are still experiencing occult hypoperfusion. If targeted resuscitation is employed, appropriate use of end-points is critical. In this review, we consider the value of directing resuscitation at the microcirculation or cellular level. Current technologies available include sublingual capnometry, video microscopy of the microcirculation and near-infrared spectroscopy providing a measure of tissue oxygenation, whereas base deficit and lactate potentially provide a surrogate measure of the adequacy of global perfusion. The methodology and evidence for these technologies guiding resuscitation are considered in this narrative review. PMID- 22487662 TI - Pain management in Australian emergency departments: current practice, enablers, barriers and future directions. AB - OBJECTIVE: To explore current pain management practice in Australian EDs and identify enablers and barriers for best-practice pain management. METHODS: Five focus groups and two in-depth interviews were held with ED clinical staff (n= 47) from six hospitals in three states. Participants were asked open-ended questions to determine current pain management practices, enablers and barriers to implementing best-practice pain management, and understand change in practice within the ED setting. RESULTS: Emergency department staff identified a gap between evidence-based pain management recommendations and everyday practice. Perceived barriers to improving pain management included a lack of time and resources, a greater number of urgent and serious presentations that place pain management as a lower priority, organizational protocols and legislative issues. All groups noted difficulty in applying pain management guidelines in the context of competing priorities in the challenging ED environment. A culture of learning clinical practice from respected senior staff and peers was perceived to be a key enabler. Participants consistently expressed the view that evidence-based practice improvement should be championed by senior clinical staff, and that evidence to demonstrate the benefits of change must be presented to support the need for change. CONCLUSIONS: Effective and sustainable system change requires a strategy that is initiated within the ED, targets opinion leaders, is supported by evidence, and engages all levels of ED staff. PMID- 22487663 TI - Butylscopolammonium bromide does not provide additional analgesia when combined with morphine and ketorolac for acute renal colic. AB - OBJECTIVE: To evaluate the effect of adding butylscopolammonium bromide (BB) to morphine and ketorolac in the treatment of acute renal colic in the ED. METHODS: A prospective, double-blind, randomized controlled trial of i.v. triple therapy (morphine, ketorolac and BB) versus double therapy (morphine and ketorolac) in adult ED patients with a clinical diagnosis of acute renal colic and a pain rating greater than five on a 10 cm visual analogue scale (VAS). VAS was recorded at time 0, 20 and 40 min. Patients received rescue morphine at 20 or 40 min according to the protocol if needed. We compared pain reduction and the need for rescue analgesia at 4 min between two groups. RESULTS: Eighty-nine patients were randomized over a 13 month period. A total of 46 (51.7%) patients received BB in addition to morphine and ketorolac. The mean difference in change in pain score in the triple therapy group and double therapy group was 7.1 cm (95% CI 6.4-7.8) and 5.9 cm (95% CI 5.1-6.7), respectively (P= 0.024). Rescue morphine was required by 7/46 (15.2% [95% CI 4.4-20.6]) patients in the triple therapy group and 14/43 (32.6% [95% CI 18.0-47.1]) in the double therapy group (OR 0.37 [95% CI 0.133-1.038]). CONCLUSIONS: Although the addition of BB to morphine and ketorolac appeared to show a statistically significant reduction in pain compared with morphine and ketorolac alone, a reduction of 1.2 cm on VAS is unlikely to be clinically significant. PMID- 22487664 TI - Cardiac troponin I does not independently predict mortality in critically ill patients with severe sepsis. AB - OBJECTIVE: Patients with sepsis often have elevated cardiac troponin I even in the absence of coronary artery disease. The prognostic value of cardiac troponins in critically ill patients with sepsis remains debatable. Our objective was to evaluate the prognostic value of cardiac troponin I in critically ill patients with severe sepsis. METHODS: In this retrospective study, we included patients with severe sepsis who had troponin assayed within 12 h of admission to intensive care over a 6 year period. Patients who had myocardial infarction at intensive care admission in the setting of sepsis were excluded. Included patients were classified into two groups based on their serum troponin I levels: low troponin group (troponin <= 0.1 ug/L) and elevated troponin group (troponin > 0.1 ug/L). The primary outcome of interest was hospital mortality. The secondary outcome measures included intensive care mortality, intensive care and hospital length of stay. RESULTS: A total of 382 patients were admitted to intensive care with sepsis. Of these, 293 patients were included in analyses. There was a statistically significant difference in hospital (15% vs 36.1%; P < 0.01) and intensive care (11% vs 25%; P < 0.01) mortality, but not in intensive care and hospital duration of stay. Logistic regression analysis revealed temperature, simplified acute physiology score II and serum lactate to be independent predictors of hospital mortality. Cardiac troponin I was not an independent predictor of hospital mortality. CONCLUSION: Critically ill patients with severe sepsis who had elevated troponin had increased hospital and intensive care mortality. However, cardiac troponin I did not independently predict hospital mortality. PMID- 22487665 TI - Pandemic (H1N1 influenza 2009 and Australian emergency departments: implications for policy, practice and pandemic preparedness. AB - OBJECTIVE: To describe the reported impact of Pandemic (H(1)N(1) ) 2009 on EDs, so as to inform future pandemic policy, planning and response management. METHODS: This study comprised an issue and theme analysis of publicly accessible literature, data from jurisdictional health departments, and data obtained from two electronic surveys of ED directors and ED staff. The issues identified formed the basis of policy analysis and evaluation. RESULTS: Pandemic (H(1)N(1) ) 2009 had a significant impact on EDs with presentation for patients with 'influenza like illness' up to three times that of the same time in previous years. Staff reported a range of issues, including poor awareness of pandemic plans, patient and family aggression, chaotic information flow to themselves and the public, heightened stress related to increased workloads and lower levels of staffing due to illness, family care duties and redeployment of staff to flu clinics. Staff identified considerable discomfort associated with prolonged times wearing personal protective equipment. Staff believed that the care of non-flu patients was compromised during the pandemic as a result of overwork, distraction from core business and the difficulties associated with accommodating infectious patients in an environment that was not conducive. CONCLUSIONS: This paper describes the breadth of the impact of pandemics on ED operations. It identifies a need to address a range of industrial, management and procedural issues. In particular, there is a need for a single authoritative source of information, the re-engineering of EDs to accommodate infectious patients and organizational changes to enable rapid deployment of alternative sources of care. PMID- 22487666 TI - Prosthetic hip dislocations: is relocation in the emergency department by emergency medicine staff better? AB - OBJECTIVE: Prosthetic hip dislocation is common. This study compares prosthetic hip relocations attempted within the ED by emergency doctors and those under orthopaedic care in the ED or operating theatre (OT). METHODS: Retrospective cohort study of patients presenting to Auckland City Hospital Adult Emergency Department with prosthetic hip dislocations between 1 January 2003 and 14 April 2008. Primary outcomes were proportion of successful relocation attempts and length of hospital stay. Secondary outcomes were: time to relocation, complications, post-procedural advice, representation rate and long-term outcomes for first-time dislocations. There were 410 eligible presentations during the study period. RESULTS: Emergency medicine (EM) was successful in 254/323 attempts (79%, 95% confidence interval [CI] 74-83). Orthopaedics were successful in 25/35 reductions in the ED (71%, 95% CI 55-84) and 49/51 OT attempts (96%, 95% CI 86 100), P = 0.004 for location OT versus ED. Median times to discharge were 8.8 h for EM, 28.3 h for orthopaedics in the ED and 81 h for orthopaedics in the OT, P < 0.001 for EM versus orthopaedics. Mechanical complications of procedures and early redislocations were infrequent. Complication of sedation were more often seen in OT compared to ED (23/47 [49%, 95% CI 35-63]vs 37/318 [12%, 95% CI 9 16]). CONCLUSION: There was no difference between EM and orthopaedics in the proportion of hips successfully relocated or complications in the ED; however, EM patients were discharged much sooner, with important resource implications. Procedures carried out in the OT were more successful than in the ED but resulted in prolonged hospital stays and were associated with more complications. PMID- 22487667 TI - Patient satisfaction and outcome using emergency care practitioners in New Zealand. AB - OBJECTIVE: A patient satisfaction survey was undertaken in the Kapiti District of the Wellington Region to ascertain patients' experience and opinions of New Zealand's first extended care paramedic (ECP) service before consideration is given to extending it to other locations within the region. Patient outcomes were also analysed for 1 week following ECP care. METHODS: One hundred patients, 50 attended by ECPs and 50 by standard emergency ambulance service paramedics, were interviewed by an independent assessor, either in person or by phone according to patient preference. The questionnaire was aimed at comparing the experience of both groups of patients, dividing them into those treated at home and those transferred to the ED. ED and general practice records were then reviewed to determine whether the ECP-treated patients attended either facility within 7 days and why. RESULTS: Patients were very satisfied with their experience of both groups of paramedics but expressed a clear desire to be treated at home if possible. Of the 50 ECP-treated patients, 11 were transferred directly to the ED. Only one clinical complication arose over the next 7 days in those treated in the community: a seizure in a patient with refractory epilepsy. CONCLUSION: The avoidance of unnecessary transfers to hospital is beneficial to patients, the ambulance service and the ED. This study demonstrates that patients are very satisfied with their assessment and treatment by ECPs, endorsing the proposal that the scheme should be extended across the Wellington Region, and perhaps New Zealand. PMID- 22487668 TI - Burn size estimation in children: still a problem. AB - BACKGROUND: Accurate determination of burn size and depth forms an integral part of the initial assessment of any burn injury. Errors might lead to inaccurate fluid resuscitation and inappropriate transfer of patients to specialized burns units (BUs). Although recent data suggest some improvement in the estimation of burn injury in adults, this has not been shown in children. METHODS: A retrospective review of children with burn injuries referred to the BU of our institution was performed. Data were collected from all patients presenting to the BU during the calendar year 2009. The total body surface area burned (TBSA-B) estimated by the referring centre was compared with the actual TBSA determined measured on arrival at the BU. RESULTS: Of the 71 paediatric patients referred during the study period, 10 did not have any TBSA-B estimation documented by the referring hospital. Inaccurate estimation of burn area was noted in 48 out of 61 patients (79%). Burn size was more likely to be overestimated than underestimated by a ratio of 2.2 to 1, especially in burns >10% TBSA-B (P= 0.002). CONCLUSIONS: Inaccurate estimation of burn size remains a problem in children. The persistent miscalculation of burn size might be a result of the various methods employed in assessing burn area, the inclusion of simple erythema and inadequate training or exposure of first responders. Accurate assessment of TBSA-B and burn depth in children remains elusive and would appear to require additional training and education. PMID- 22487669 TI - Disaster triage tags: is one better than another? AB - OBJECTIVE: To determine which of the disaster triage tag systems in use in Australia and New Zealand is better in terms of the time taken to complete the triage and the ease of use. METHODS: A disaster scenario was created. Mock patients were provided with clinical information to allow them to be triaged in a disaster sieve. Six different triage tag systems available in Australia and New Zealand were trialled. Participants triaged 10 patients with each triage tag system. The 10 patients used were different for each of the tag systems and were standardized for acuity and triage category. The time to complete the triage of the 10 patients with each different tag system was measured. The participants then completed a questionnaire with regards to the ease of use of the different tags and were asked to nominate their most preferred tag. RESULTS: The Victorian cruciate fold up tag was the quickest to complete, with an average of 6.6 min to triage 10 patients, compared with an average time for all systems of 7.8 min. New Zealand tags were found to be the easiest to use, easiest to fill in and were considered the most preferred tag. CONCLUSION: The Victorian style of tag was found to be the most efficient in terms of the time to complete a triage. The New Zealand tags were the easiest to use, easiest to fill in and the most preferred tag by the participants. We recommend that one of these tags be adapted for use as a nationwide system. PMID- 22487670 TI - Comparison of intubation performance by junior emergency department doctors using gum elastic bougie versus stylet reinforced endotracheal tube insertion techniques. AB - OBJECTIVE: Endotracheal intubation is a challenging procedure in emergency medicine. Junior doctors lack experience and confidence in this task. The use of a gum elastic bougie (GEB) to facilitate intubation may improve success rates, especially in difficult situations. METHODS: Junior doctors working in the ED were studied. Endotracheal intubation was simulated using part-task trainers in "easy" positioning and "difficult" positioning modes. Intubation was attempted in both positions using either an endotracheal tube, with re-enforcing stylet (ETT S), or insertion of a gum elastic bougie (GEB), with subsequent passage of the endotracheal tube over the bougie. Success rates and time to complete intubation were measured with GEB, and with ETT-S. Participants were asked to record the perceived ease of intubation. RESULTS: One hundred and four intubations were performed by 26 study subjects. Overall, mean time to intubation with ETT-S technique was 16.14 s (14.49-17.98 95% CI), and was faster than with GEB 24.18 (21.45-27.25 95% CI) in both airway difficulty grades (P < 0.01). The success rate for intubation using the GEB was 100%, compared with 92.9% with ETT-S. This difference was not statistically significant. Perceived ease of intubation was similar for GEB and ETT-S (VAS 6.808 vs 6.904). CONCLUSION: The use of a GEB marginally increases the time taken to perform endotracheal intubation. Success rates for junior doctors attempting endotracheal intubation were not significantly different between the two techniques. Success rates for novice practitioners using a GEB were high after even limited instruction and practice. PMID- 22487671 TI - The developing challenge of clinical longevity. AB - Twenty-five years on from the first fellowship examination of the College, it is timely to reflect on the issue of clinical longevity. The pressures of the emergency medicine workplace are relatively unique among the medical specialties, and might require unique solutions if emergency physicians are to continue clinical practice in the latter stages of their careers. PMID- 22487672 TI - Case report on vertebral artery dissection in mixed martial arts. AB - A 41-year-old man presented to the ED with severe vertigo 2 days after a grappling injury while training in mixed martial arts. Imaging revealed a cerebellar infarct with complete occlusion of the right vertebral artery secondary to dissection. Management options are discussed as is the ongoing controversy regarding the safety of the sport. PMID- 22487673 TI - Angiotensin-converting enzyme inhibitor and visceral angio-oedema. AB - Abdominal pain can be a challenging presenting complaint with a broad differential diagnosis. Medication side-effect must always be considered. Visceral angio-oedema secondary to angiotensin-converting enzyme inhibitor use can cause abdominal pain. The association of angiotensin-converting enzyme inhibitor and visceral angio-oedema is not well recognized partly because the onset of angio-oedema might be delayed for months or years after commencement of an angiotensin-converting enzyme inhibitor. The epidemiology of angio-oedema is now changing in parallel with the increasing use of angiotensin-converting enzyme inhibitors. We present a case of visceral angio-oedema secondary to perindopril. This diagnosis requires a high index of suspicion because if not recognized early patients undergo extensive and expensive negative evaluation. PMID- 22487674 TI - Australasian College for Emergency Medicine trainee research project bar is not too high. PMID- 22487676 TI - Expression of SOCS1 and SOCS3 is altered in the nasal mucosa of patients with mild and moderate/severe persistent allergic rhinitis. AB - BACKGROUND: The aim of this study was to evaluate the role of suppressor of cytokine signaling (SOCS) molecules, SOCS1 and SOCS3, which act as negative regulators of cytokine signaling in various allergic diseases, in patients with mild and moderate/severe persistent allergic rhinitis. METHODS: The expression and distribution pattern of SOCS1 and SOCS3 were analyzed in nasal mucosa and peripheral blood mononuclear cells (PBMC) of healthy controls, and patients with mild and moderate/severe persistent allergic rhinitis using RT-PCR, immunohistochemistry and Western blotting. IL-4, IL-13, IL-15 and IFN-gamma expression was also analyzed in the nasal mucosa of each individual using RT-PCR and Western blotting. RESULTS: SOCS1 and SOCS3 mRNA and protein expression was significantly increased in the nasal mucosa and PBMC of patients with mild and moderate/severe persistent allergic rhinitis compared with healthy controls. In healthy and allergic nasal mucosa, they were commonly localized to the epithelium, submucosal glands and endothelium, showing stronger staining intensity in mild and moderate/severe persistent allergic nasal mucosa than in healthy nasal mucosa. Tissue levels of IL-4 and IL-13 were increased in moderate/severe persistent allergic nasal mucosa whereas IL-15 and IFN-gamma were decreased in moderate/severe persistent allergic nasal mucosa. CONCLUSIONS: Upregulation of SOCS1 and SOCS3 in mild and moderate/severe persistent allergic rhinitis suggests that SOCS proteins may be important regulators in the pathogenesis of allergic rhinitis and play a role as molecular determinants of allergic rhinitis persistence. PMID- 22487677 TI - Diffusion-weighted imaging-based probabilistic segmentation of high- and low proliferative areas in high-grade gliomas. AB - The apparent diffusion coefficient (ADC) derived from diffusion-weighted imaging (DWI) correlates inversely with tumor proliferation rates. High-grade gliomas are typically heterogeneous and the delineation of areas of high and low proliferation is impeded by partial volume effects and blurred borders. Commonly used manual delineation is further impeded by potential overlap with cerebrospinal fluid and necrosis. Here we present an algorithm to reproducibly delineate and probabilistically quantify the ADC in areas of high and low proliferation in heterogeneous gliomas, resulting in a reproducible quantification in regions of tissue inhomogeneity. We used an expectation maximization (EM) clustering algorithm, applied on a Gaussian mixture model, consisting of pure superpositions of Gaussian distributions. Soundness and reproducibility of this approach were evaluated in 10 patients with glioma. High- and low-proliferating areas found using the clustering correspond well with conservative regions of interest drawn using all available imaging data. Systematic placement of model initialization seeds shows good reproducibility of the method. Moreover, we illustrate an automatic initialization approach that completely removes user-induced variability. In conclusion, we present a rapid, reproducible and automatic method to separate and quantify heterogeneous regions in gliomas. PMID- 22487678 TI - A possible role for oxidation stress in lymphoid leukaemias and therapeutic failure. AB - The aim of this study was to evaluate the role of oxidative stress in the pathobiology of lymphoid leukaemias and its involvement in leukaemic relapse. For this purpose the generation of peroxides by mononuclear cells, the erythrocyte activity of superoxide-dismutase (SOD) and glutathione peroxidase (GL-PX), and the plasma levels of reduced glutathione (GSH) and vitamin E (VIT E) were determined in 52 patients with two different types of lymphoid leukaemias, chronic lymphocytic leukaemia (CLL) and acute lymphoblastic leukaemia (ALL), 36 prior to chemotherapy and 16 treated patients. A decrease in SOD and GL-PX activities was observed in ALL patients prior to therapy, while a decrease in GSH and VIT E plasma levels was observed in untreated CLL, as compared to age-matched controls. An increase in peroxides formation occurred in both types of leukaemia, as compared to age-matched controls. There are significant differences for GSH, VIT E and peroxides generation between the different types of leukaemias. In relapsed ALL patients a decrease in peroxides generation was observed which may be due to the increase of the non-enzymatic defences GSH and VIT E. These data suggest the involvement of oxidative stress in acute and chronic lymphoid leukaemias and leukaemic relapse. PMID- 22487679 TI - Optineurin: a new vision of cell division control. PMID- 22487680 TI - The p53 isoforms are differentially modified by Mdm2. AB - The discovery that the single p53 gene encodes several different p53 protein isoforms has initiated a flurry of research into the function and regulation of these novel p53 proteins. Full-length p53 protein level is primarily regulated by the E3-ligase Mdm2, which promotes p53 ubiquitination and degradation. Here, we report that all of the novel p53 isoforms are ubiquitinated and degraded to varying degrees in an Mdm2-dependent and -independent manner, and that high-risk human papillomavirus can degrade some but not all of the novel isoforms, demonstrating that full-length p53 and the p53 isoforms are differentially regulated. In addition, we provide the first evidence that Mdm2 promotes the NEDDylation of p53beta. Altogether, our data indicates that Mdm2 can distinguish between the p53 isoforms and modify them differently. PMID- 22487681 TI - PHF19 and Akt control the switch between proliferative and invasive states in melanoma. AB - Melanoma tumor cells shift between proliferative and invasive states based on their plasticity and microenvironmental conditions. Our team has shown that melanoma cells, grown as spheroids in a neural cell crest medium, polarize toward an invasive phenotype, characterized by a higher motility, a poor proliferation rate and a gain of pluripotency gene expression (Nanog and Oct4) when compared with cells grown in two dimensions in a serum-contaning medium. In agreement with the phenotypic switching hypothesis, most of these features are reversible. Microarray studies comparing two- vs. three-dimensional cultures revealed the downregulation of a polycomb-like protein, PHF19 (PHD finger protein 19), in the spheroids. As Polycomb proteins are involved in the epigenetic control of gene expression, we hypothesized that PHF19 might play a role in the switch between proliferative and invasive phenotypes. In this report, we show that PHF19 silencing reduces the cell proliferation rate and increases the transendothelial migration capacities of melanoma cell lines. However, PHF19 does not modulate the transcription level of Oct4 and Nanog. In the search of an upstream transcriptional regulator of the above genes, we identified the Akt signaling cascade as an inhibitor of Oct4 and Nanog expression and an activator for PHF19 expression. Through chromatin immunoprecipitation, we further provide evidence that phospho-Akt is part of the transcriptional complex associated to the promoters of all three genes. Our data therefore indicate the role of PHF19 and its upstream regulator, Akt, in the phenotype switch of melanoma cells from proliferative to invasive states. PMID- 22487683 TI - Understanding telomerase in cancer stem cell biology. PMID- 22487682 TI - Methylation of death-associated protein kinase is associated with cetuximab and erlotinib resistance. AB - Anti-EGFR therapy is among the most promising molecular targeted therapies against cancer developed in the past decade. However, drug resistance eventually arises in most, if not all, treated patients. Emerging evidence has linked epigenetic changes, such as DNA methylation at CpG islands, to the development of resistance to multiple anticancer drugs. In addition, genes that are differentially methylated have increasingly been appreciated as a source of clinically relevant biomarker candidates. To identify genes that are specifically methylated during the evolution of resistance to anti-EGFR therapeutic agents, we performed a methylation-specific array containing a panel of 56 genes that are commonly known to be regulated through promoter methylation in two parental non small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) cell lines and their resistant derivatives to either erlotinib or cetuximab. We found that death-associated protein kinase (DAPK) was hypermethylated in drug resistant derivatives generated from both parental cell lines. Restoration of DAPK into the resistant NSCLC cells by stable transfection re-sensitized the cells to both erlotinib and cetuximab. Conversely, siRNA-mediated knockdown of DAPK induced resistance in the parental sensitive cells. These results demonstrate that DAPK plays important roles in both cetuximab and erlotinib resistance, and that gene silencing through promoter methylation is one of the key mechanisms of developed resistance to anti-EGFR therapeutic agents. In conclusion, DAPK could be a novel target to overcome resistance to anti-EGFR agents to improve the therapeutic benefit, and further evaluation of DAPK methylation as a potential biomarker of drug response is needed. PMID- 22487685 TI - The fight of the Tudor domain "Royal family" for a broken DNA throne. PMID- 22487684 TI - ATP analog-sensitive Pat1 protein kinase for synchronous fission yeast meiosis at physiological temperature. AB - To study meiosis, synchronous cultures are often indispensable, especially for physical analyses of DNA and proteins. A temperature-sensitive allele of the Pat1 protein kinase (pat1-114) has been widely used to induce synchronous meiosis in the fission yeast Schizosaccharomyces pombe, but pat1-114-induced meiosis differs from wild-type meiosis, and some of these abnormalities might be due to higher temperature needed to inactivate the Pat1 kinase. Here, we report an ATP analog sensitive allele of Pat1 [Pat1(L95A), designated pat1-as2] that can be used to generate synchronous meiotic cultures at physiological temperature. In pat1-as2 meiosis, chromosomes segregate with higher fidelity, and spore viability is higher than in pat1-114 meiosis, although recombination is lower by a factor of 2 3 in these mutants than in starvation-induced pat1(+) meiosis. Addition of the mat-Pc gene improved chromosome segregation and spore viability to nearly the level of starvation-induced meiosis. We conclude that pat1-as2 mat-Pc cells offer synchronous meiosis with most tested properties similar to those of wild-type meiosis. PMID- 22487686 TI - Patterns of Y-STR variation in Italy. AB - The 17 Y-chromosomal short tandem repeats (STRs) included in the AmpFlSTR Yfiler Amplification Kit (AB Applied Biosystems) (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635 and GATA H4.1) were typed in 292 samples from seven Italian regions. Population comparisons with other European samples were undertaken; for this purpose, two databases were collated from the literature: (a) 19 population samples including >2900 Yfiler profiles, and (b) 67 population samples including >15,000 minimum haplotype profiles. A total of 276 different Yfiler haplotypes were observed in Italy, and only one of them was shared among our seven population samples. The overall haplotype diversity (0.9996) was comparable to other European samples. AMOVA indicates that among population variance depends on the amount of Y-STRs used, being higher when using minimal haplotypes. This is probably due to the fact that Yfiler profiles are represented by singleton haplotypes in all the population samples raising the diversity values to the maximum theoretical value. AMOVA results seems to depend even more strongly on the amount of population samples used, the among population variance in Italy ranging from 2.82% to 11.03% (using 15 and 32 Italian populations samples, respectively). Variance is not as strongly stratified geographically within Italy, although it is notorious that latitude is more important than longitude in the distribution of variance. The results also indicated that Italy is less stratified than other European samples. The present study contributes to enrich the Y-chromosome databases regarding high-resolution Y-chromosome data sets and demonstrates that extended Y-STR profiles substantially increases the discriminatory capacity in individual identification for forensic purposes. PMID- 22487687 TI - The global role of kidney transplantation. AB - World Kidney Day on 8 March 2012 provides a chance to reflect on the success of kidney transplantation as a therapy for end-stage kidney disease that surpasses dialysis treatments both for the quality and quantity of life that it provides and for its cost-effectiveness. Anything that is both cheaper and better, but is not actually the dominant therapy, must have other drawbacks that prevent replacement of all dialysis treatment by transplantation. The barriers to universal transplantation as the therapy for end-stage kidney disease include the economic limitations which in some countries place transplantation, appropriately, at a lower priority than public health fundamentals such as clean water, sanitation, and vaccination. Even in high-income countries, the technical challenges of surgery and the consequences of immunosuppression restrict the number of suitable recipients, but the major finite restrictions on kidney transplantation rates are the shortage of donated organs and the limited medical, surgical, and nursing workforces with the required expertise. These problems have solutions which involve the full range of societal, professional, governmental, and political environments. World Kidney Day is a call to deliver transplantation therapy to the one million people a year who have a right to benefit. PMID- 22487688 TI - IgG4-related kidney disease. AB - PURPOSE OF REVIEW: IgG4-related disease (IgG4-RD) is a recently recognized systemic autoimmune disease that has received increased attention in the literature in the past several years. Renal involvement can take several forms, which are described in this review. RECENT FINDINGS: IgG4-RD may affect the kidney in various patterns. IgG4-related tubulointerstitial nephritis (TIN), presenting as either a mass lesion, renal failure, or both, has become an accepted manifestation of IgG4-RD. Two large series with biopsies and one clinical series of IgG4-related TIN have been published in the past two years; these series further delineate the clinical, laboratory, and pathologic features of this entity and propose diagnostic criteria. Glomerular disease in IgG4-RD, most commonly membranous glomerulonephritis (MGN), is becoming recognized as well. The first international conference on IgG4-RD was held in Boston, Massachusetts, USA, in October 2011; nomenclature and pathology consensus statements from this conference are forthcoming. In addition to better-defined clinical features of this autoimmune disease, in-vivo and in-vitro characteristics of the unusual IgG4 molecule have been studied further. SUMMARY: IgG4-RD should be considered as a cause of TIN or MGN in the appropriate clinical setting. An unresolved question is the role of the IgG4 antibody, if any, in the pathogenesis of this disease. PMID- 22487689 TI - Early HIV viral load determination after initiating first-line antiretroviral therapy for indentifying patients with high risk of developing virological failure: data from a cohort study in a resource-limited setting. AB - OBJECTIVES: To evaluate the performance of a single determination of HIV viral load (VL) 6-12 months after starting antiretroviral therapy (ART) for identifying patients who will subsequently develop virological failure. METHODS: We selected HIV-infected patients with at least two VL determinations after 6 months of ART from an HIV cohort study in India. Patients were divided in two groups depending on whether the first VL was below (Group 1) or above (Group 2) 1000 copies/ml. Cut-off for virological failure was defined according to World Health Organization recommendation (>5000 copies/ml). RESULTS: The study included 584 patients and 560.1 person-years of follow-up. Of all virological failures, 83% were diagnosed at the first VL determination. The cumulative incidence of virological failure after 1 and 2 years since the first VL was 0.9% [95% confidence interval (CI), 0.3-2.7] and 1.7% (95% CI, 0.6-5), respectively, for Group 1, and 58.2% (95% CI, 47-69.7) and 63.1% (95% CI, 49.8-76.4), respectively, for Group 2. Compared with Group 1, patients from Group 2 had a hazard ratio for virological failure of 78.3 (95% CI, 27.8-220.2). CONCLUSIONS: A single VL determination after 6 months of ART was able to identify patients with high risk of virological failure. PMID- 22487690 TI - Grass pollen counts, air pollution levels and allergic rhinitis severity. AB - BACKGROUND: Little is known about the relation between allergic rhinitis severity and airborne pollen in combination with air pollutants. OBJECTIVE: To model the risk of suffering from severe seasonal allergic rhinitis (SAR) as a function of both pollen count and air pollution levels in a large nationwide sample of patients whose SAR was diagnosed by a physician and confirmed by skin prick test positivity or specific immunolglobulin E to common aeroallergens. METHODS: The severity of SAR symptoms was estimated with the Symptomatic Global Score (SGS) among 36,397 patients suffering from an untreated and uncomplicated SAR between May and August 2004 in metropolitan France. Patients who had an SGS in the upper third quartile were classified as suffering from severe SAR. A multilevel model relating SAR severity, pollen and air pollution was used to take into account the hierarchical data structure. RESULTS: 18.9% of the 17,567 urban patients retained for the analysis suffered from severe rhinitis. At the Lag0 (day of the visit), a rise of 60 grass pollen grains/m(3) increased the risk of suffering from a severe SAR form by 8% in the multileveled model after adjusting for potential confounders and air pollution levels. Results were also confirmed in the subsample of individuals with documented sensitization to grass pollen. CONCLUSION: Grass pollen count aggravated SAR in terms of symptoms in our nationwide sample. These findings confirm the need for proper treatment and preventive measures in SAR patients sensitized to grass pollen. PMID- 22487691 TI - Editorial comment to overall mortality after radical nephrectomy in patients aged over 80 years with renal cancer: a retrospective study on preoperative prognostic factors. PMID- 22487692 TI - Re: Impact of coding errors on departmental income: an audit of coding of microvascular free transfer cases using OPCS-4 in UK. PMID- 22487693 TI - Platelet-rich plasma stimulates cytokine expression and alkaline phosphatase activity in osteoblast-derived osteosarcoma cells. AB - OBJECTIVE: The aim of this study was to investigate the effects of PRP on SAOS-2 cells in terms of cytokine expression, cell activity and oxidative stress. DESIGN: Cell line SAOS-2 (1*10(5)cells/mL) were grown in culture medium alpha-MEM with 10% FBS for 24h and stimulated (or not) with PRP at concentrations of 3, 10 and 20%, LPS (E. coli, 10g/mL) and IL-1beta (1mg/mL) for 24h. The supernatant was collected and analyzed for the expression of cytokines in a panel array, ALP using a commercial kit and NO(2)(-) with Griess reaction method. Also, the cells were analyzed using Western blot for RANKL and slot blotting for nitrotyrosine expression. RESULT: There were no significant differences amongst the groups in terms of NO(2)(-), protein nitrotyrosine content and RANKL expression. However, all stimuli increased ALP activity and in case of PRP, it was in a dose-dependent manner (p<0.001). Also, all stimuli induced an increase in cytokines and chemokines expression, but only PRP promoted an increase of component C5, sICAM-1 and RANTES expression. Whilst IL-1 receptor antagonist (IL-1ra) expression was down-regulated by PRP, both LPS and IL-1beta caused up-regulation of this cytokine. CONCLUSIONS: PRP can stimulate osteoblast activity and cytokine/chemokine release, as well as indicate some of the mediators that can (and cannot) be involved in this activation. PMID- 22487694 TI - Contact allergy to dental materials. AB - The oral mucosa is constantly exposed to a large number of potentially irritating and sensitizing dental materials. Dental materials used for fillings and fixed or removable replacements must have a good biocompatibility. Metals including palladium are used in alloys for the production of the core of crowns, onto which porcelain is bonded for the generation of an artificial tooth to which the patient can develop an allergic contact dermatitis. The clinical manifestations of contact allergy to dental materials are not uniform. Objective symptoms of a contact allergy include a stomatitis and lichenoid reactions. However, patients may present with more subjective affections of the oral mucosa including burning, pain and dryness which need to be differentiated from a real contact allergic reaction. In this article we focus on the management of contact allergy to dental materials. PMID- 22487695 TI - Late-preterm birth by delivery circumstance and its association with parent reported attention problems in childhood. AB - OBJECTIVE: Late-preterm birth (LPB, 34-36 wk) has been associated with an increased risk of attention problems in childhood relative to full-term birth (FTB, >=37 wk), but little is known about factors contributing to this risk. The authors investigated the contributions of clinical circumstances surrounding delivery using follow-up data from the Pregnancy Outcomes and Community Health (POUCH) Study. METHODS: Women who delivered late preterm or full term and completed the sex- and age-referenced Conners' Parent Rating Scales-Short Form: Revised were included in the present analysis (N = 762; children's age, 3-9 y). The Conners' Parent Rating Scales-Short Form: Revised measures dimensions of behavior linked to attention problems, including oppositionality, inattention, hyperactivity, and a global attention problem index. Using general linear models, the authors evaluated whether LPB subtype (medically indicated [MI] or spontaneous) was associated with these dimensions relative to FTB. RESULTS: After adjustment for parity, sociodemographics, child age, and maternal symptoms of depression and serious mental illness during pregnancy and at the child survey, only MI LPB was associated with higher hyperactivity and global index scores (mean difference from FTB = 3.8 [95% confidence interval {CI}: 0.5, 7.0] and 3.1 [95% CI 0.0, 6.2]). These findings were largely driven by children between 6 and 9 years. Removal of women with hypertensive disorders during pregnancy (N = 85) or placental findings related to hypertensive conditions (obstruction, decreased maternal spiral artery conversion; N = 134) reduced the differences below significance thresholds. CONCLUSIONS: Among LPBs, only MI LPB was associated with higher levels of parent-reported childhood attention problems, suggesting that complications motivating medical intervention during the late-preterm period mark increased risk for such problems. Hypertensive disorders seem to play a role in these associations. PMID- 22487697 TI - Factors associated with severe skin infections in patients treated with biologic therapies for inflammatory rheumatic diseases. AB - BACKGROUND: The incidence of severe infections is increased under biologic therapies and the skin is the second localization. OBJECTIVE: To appraise the factors associated with severe skin infections (SSI) in patients under biologic therapies for inflammatory rheumatic diseases (IRD). METHODS: We performed a case control (ratio 1:3) study nested in a prospective cohort of patients with IRD. SSI was defined as requiring hospitalization or intravenous anti-infectious therapy. We defined two imbedded periods: period A was the time window between the first biologic therapy and the SSI; period B was the last 3 or 12 months (for tumor necrosis factor blockers or rituximab, respectively) before the SSI. RESULTS: Among 4,361 patients with IRD, 29 had a SSI under biologic therapy. In multivariate analyses, SSI were significantly associated with smoking, baseline C reactive protein and gammaglobulinemia, non-steroidal anti-inflammatory drugs before biologic therapy, cumulative dose of steroids, concomitant steroids during period A, number of different biologic therapies during period A, treatment with infliximab during period A, period B or as first biologic therapy and treatment at high dose during period B. CONCLUSION: In patients under biologic therapies for IRD, the risk of SSI is associated with several factors including tobacco, treatment with infliximab or high dose range. PMID- 22487696 TI - Psychopathology and special education enrollment in children with prenatal cocaine exposure. AB - OBJECTIVE: This study evaluated how enrollment in special education services in 11-year-old children relates to prenatal cocaine exposure (PCE), psychopathology, and other risk factors. METHODS: Participants were 498 children enrolled in The Maternal Lifestyle Study, a prospective, longitudinal, multisite study examining outcomes of children with PCE. Logistic regression was used to examine the effect of PCE and psychopathology on enrollment in an individualized education plan (IEP; a designation specific to children with special education needs), with environmental, maternal, and infant medical variables as covariates. RESULTS: PCE, an interaction of PCE and oppositional defiant disorder, child attention deficit hyperactivity disorder, parent-reported internalizing behaviors, and teacher-reported externalizing behaviors, predicted enrollment in an IEP. Other statistically significant variables in the model were male gender, low birth weight, being small for gestational age, white race, caregiver change, low socioeconomic status, low child intelligence quotient, caregiver depression, and prenatal marijuana exposure. CONCLUSIONS: PCE increased the likelihood of receiving an IEP with adjustment for covariates. Psychopathology also predicted this special education outcome, in combination with and independent of prenatal cocaine exposure. PMID- 22487701 TI - Acute kidney injury: AKI in acute myocardial infarction--are we making progress? PMID- 22487702 TI - Biocompatible fluid for PD--hanging in the balANZ? PMID- 22487698 TI - Interventional therapies for hepatocellular carcinoma. AB - Hepatocellular carcinoma is the third most common cause of cancer-related death. In the past few years, staging systems have been developed that enable patients to be stratified into treatment algorithms in a multidisciplinary setting. Several of these treatments involve minimally invasive image-guided therapy that can be performed by radiologists. PMID- 22487705 TI - Glomerular disease: Eculizumab for the treatment of MPGN. PMID- 22487703 TI - Considerations in the optimal preparation of patients for dialysis. AB - Every year, more than 110,000 Americans are newly diagnosed with end-stage renal disease and in the overwhelming majority, maintenance dialysis therapy is initiated. However, most patients, having received no predialysis nephrology care or dietary counseling, are inadequately prepared for starting treatment; furthermore, the majority of patients do not have a functioning permanent dialysis access. Annualized mortality in the USA in the first 3 months after starting dialysis treatment is approximately 45%; this high rate is possibly in part due to inadequate preparation for renal replacement therapy. Data from the Dialysis Outcomes and Practice Patterns study suggest that similar challenges exist in many parts of the world. Implementation of strategies that mitigate the risk of adverse consequences when starting dialysis are urgently needed. In this Review we present a step-by-step approach to tackling inadequate patient preparation, which includes identifying individuals with chronic kidney disease (CKD) who are most likely to need dialysis in the future, referring patients for education, timely placement of dialysis access and timely initiation of dialysis therapy. Treatment with dialysis might not be appropriate for some patients with progressive CKD; these individuals can be optimally managed with nondialytic, maximum conservative management. PMID- 22487707 TI - Educating about HIV: prevention, impact mitigation and care. AB - Since very early in the epidemic, education has been identified as central to an effective response. Three different kinds of education can be distinguished: education for HIV prevention, education about treatment, and education to prevent or mitigate the negative effects of the epidemic. This article also considers three different contexts in which education takes place: in schools, at the level of specific groups and across society as a whole. Some 30 years into the epidemic, it is vital that the potential of education is more fully recognized and embraced, not only by agencies and individuals with special expertise in the field (although this is essential), but also by everyone seeking to contribute to the ambitious goals of zero new infections, zero discrimination and zero AIDS related deaths. PMID- 22487708 TI - B-cell activation induced microRNA-21 is elevated in circulating B cells preceding the diagnosis of AIDS-related non-Hodgkin lymphomas. AB - We show that microRNA-21 is significantly elevated in peripheral B cells of HIV infected individuals who go on to develop AIDS-related non-Hodgkin lymphoma (n=13, <3 years prior to diagnosis) when compared with HIV-negative (n=18) or HIV positive controls (n=21) (P<0.01). Moreover, miR-21 is overexpressed in activated B cells and can be induced by interleukin 4 alone, or with CD40 or immunoglobulin M co-stimulation, and lipopolysaccharides, suggesting that miR-21 may help maintain B-cell hyperactivation, contributing to lymphomagenesis. PMID- 22487709 TI - Hysteroscopic resection of uterine septum and reproductive outcome in women with unexplained infertility. AB - BACKGROUND/AIMS: To investigate the reproductive outcome after hysteroscopic resection of uterine septum in women with septate uterus and otherwise idiopathic primary infertility. METHODS: Sixty-eight patients with septate uterus and idiopathic primary infertility were included in this prospective observational study. All patients underwent hysteroscopic metroplasty with scissors under general anesthesia. Main outcome measures were clinical pregnancy rate, live birth and abortion rate at 12 months' follow-up and at mean follow-up time. RESULTS: At 12 months' follow-up, the clinical pregnancy rate, the live birth rate and the abortion rate were 44% (30/68), 36.8% (25/68) and 16.6% (5/30), respectively. At total follow-up time, the overall pregnancy rate, the live birth rate and the abortion rate were 53.8% (35/65), 41.5% and 14.2% (7/35), respectively, while the stillbirth rate was 2.8% (1/35). CONCLUSION: Hysteroscopic metroplasty in women with septate uterus and unexplained infertility could improve clinical pregnancy rate and live birth rate in patients with otherwise unexplained infertility. If such a patient is looking for a spontaneous pregnancy, this is more likely to occur during the first 15 months following the procedure. PMID- 22487710 TI - Epidemiology of degenerative lumbar scoliosis: a community-based cohort study. AB - STUDY DESIGN: A 12-year prospective study of pre-existing and de novo degenerative lumbar scoliosis (DLS) among community-based female volunteers. OBJECTIVE: To investigate serial entire spine radiographs of healthy female volunteers and to clarify radiographical characteristics and predictors of pre existing and de novo DLS. SUMMARY OF BACKGROUND DATA: DLS is among the most frequent spinal defomities in the aging spine; however, the onset or the natural course of this condition has not been elucidated. METHODS: A total of 144 female volunteers were recruited from population register. Radiographical measurements using entire spine radiographs included thoracic kyphosis (T4-12), lumbar lordosis (LL) (L1-5), sacral inclination angle, pelvic incidence, sagittal balance (C7 plumb), coronal L4 endplate angle (L4 tilt), and scoliotic angle by Cobb method. More than 10 degrees of scoliosis was diagnosed as DLS. L4 vertebral size was measured (divided by body height) as well as lateral osteophyte formation and lateral disc wedge angle. RESULTS: Mean baseline age and follow-up period were 54.4 years and 12.1 years, respectively. Pre-existing DLS (pre-DLS) was found in 42 subjects (29.2%) at baseline. Among pre-DLS, 11 subjects (26%) showed more than 5 degrees progression in scoliosis. De novo DLS has developed in 30 subjects (29.4%) among those without baseline scoliosis.Cox proportional hazards models revealed younger age, smaller L4 size, lower LL, greater DLS angle, and L4 tilt at baseline to be the risk factors of progression of pre-DLS and smaller L4 size, unilateral osteophyte formation, and lateral disc wedging to the risk of development of de novo DLS. CONCLUSION: This study indicated that younger age, smaller L4 size, lower LL, greater DLS angle, and L4 tilt at baseline should be evaluated as predictors of progression of pre-DLS. Early signs of asymmetric disc degeneration and smaller L4 size should also be evaluated as predictors of development of de novo DLS. PMID- 22487711 TI - Use of chiropractic spinal manipulation in older adults is strongly correlated with supply. AB - STUDY DESIGN: Retrospective cross-sectional analysis of administrative data. OBJECTIVE: To examine the relationship between regional chiropractic supply and both use and utilization intensity of chiropractic services among Medicare beneficiaries. SUMMARY OF BACKGROUND DATA: Numerous studies have documented trends and patterns in the utilization of chiropractic services in the United States, but little is known about geographic variation in the relationship between chiropractic supply and utilization. METHODS: We analyzed Medicare claims data for services provided by chiropractic physicians in 2008. We aggregated the data to the hospital referral region level and used small area analysis techniques to generate descriptive statistics. We mapped geographic variations in chiropractic supply, use and utilization intensity (treatments per user), and quantified the variation by coefficient of variation and extremal ratio. We used Spearman rank correlation coefficient to correlate use with supply. We used a logistic regression model for chiropractic use and a multiple linear regression model for chiropractic utilization intensity. RESULTS: The average regional supply of chiropractic physicians was 21.5 per 100,000 adult capita. The average percentage of beneficiaries who used chiropractic was approximately 7.6 (SD, 3.9). The average utilization intensity was 10.6 (SD, 1.8). Regional chiropractic supply varied more than 14-fold, and chiropractic use varied more than 17-fold. Chiropractic supply and use were positively correlated (Spearman rho, 0.68; P < 0.001). A low back or cervical spine problem was strongly associated with chiropractic use (odds ratios, 21.6 and 14.3, respectively). Increased chiropractic supply was associated with increased chiropractic use (odds ratio, 1.04) but not with increased chiropractic utilization intensity. CONCLUSION: Both the supply of chiropractors and the utilization of chiropractic by older US adults varied widely by region. Increased chiropractic supply was associated with increased chiropractic use but not with increased chiropractic utilization intensity. Utilization of chiropractic care is likely sensitive to both supply and patient preference. PMID- 22487712 TI - Development of the Italian Version of the Neck Disability Index: cross-cultural adaptation, factor analysis, reliability, validity, and sensitivity to change. AB - STUDY DESIGN: Evaluation of the psychometric properties of a translated and culturally adapted questionnaire. OBJECTIVE: Translating, culturally adapting, and validating the Italian version of the Neck Disability Index (NDI-I) to allow its use with Italian-speaking patients with neck pain (NP). SUMMARY OF BACKGROUND DATA: More attention is being given to standardized outcome measures to improve interventions for NP. A translated form of the NDI has never been validated in Italian patients with NP. METHODS: The NDI-I was developed by forward-backward translation, a final review by an expert committee, and a test of the prefinal version to establish its correspondence with the original English version. The psychometric testing included factor analysis, reliability by internal consistency (Cronbach alpha) and test-retest reliability (intraclass coefficient correlation), construct validity by comparing NDI-I with the Neck Pain and Disability Scale, a numerical rating scale, the Hospital Anxiety and Depression Scale, and the 36-Item Short Form Health Survey (Spearman correlation), and sensitivity to change by calculating the smallest detectable change. RESULTS: The questionnaire was administered to 101 subjects with chronic NP and proved to be acceptable. Factor analysis revealed a 2-factor 10-item solution (explained variance: 56%). The questionnaire showed good internal consistency (alpha = 0.842) and test-retest reliability (intraclass coefficient correlation = 0.846). Construct validity showed a good correlation with Neck Pain and Disability Scale (rho = 0.687), moderate correlations with the numerical rating scale (rho = 0.545), and Hospital Anxiety and Depression Scale (rho = 0.422 for the Anxiety score and rho = 0.546 for the Depression score), and poor correlations with the 36-Item Short Form Health Survey subscales (rho = 0.066 to -0.286). The psychometric analyses of the subscales and total scale were similar. The smallest detectable change of the NDI-I was 3. CONCLUSION: The NDI was successfully translated into Italian and proved to have a good factorial structure and psychometric properties that replicated the results of other versions. Its use is recommended for research purposes. PMID- 22487713 TI - A comparison of perioperative costs and outcomes in patients with and without workers' compensation claims treated with minimally invasive or open transforaminal lumbar interbody fusion. AB - STUDY DESIGN: A nonrandomized, nonblinded prospective review. OBJECTIVE: To analyze intraoperative, immediate postoperative, and financial outcomes in worker's compensation (WC) and non-WC patients undergoing either an open or a minimally invasive surgery (MIS) transforaminal lumbar interbody fusion (TLIF). SUMMARY OF BACKGROUND DATA: Few studies have analyzed outcomes in a WC population of MIS TLIFs. METHODS: A total of 66 consecutive patients undergoing a single level TLIF (open/MIS) were analyzed (33 open and 33 MIS). Twenty-four total WC patients were identified (11 MIS and 13 open). Patients in either cohort (MIS/open) were matched according to insurance status (WC) and medical comorbidities (Charleston disability index). Every patient in this study had a diagnosis of either degenerative disc disease or spondylolisthesis and stenosis. Operative time (min), length of stay (d), estimated blood loss (mL), anesthesia time (min), visual analogue scale scores, and hospital cost/payment amount were assessed (MIS/open and work-comp versus non-work comp). RESULTS: There were no statistically significant differences between MIS WC and non-WC TLIFs with respect to surgical time, length of stay, estimated blood loss, visual analogue scale scores, and anesthesia time. There were no statistically significant differences between open WC and non-WC TLIF patients in all of the same above mentioned parameters. There were significant differences between MIS (WC and non WC) and open (WC and non-WC) TLIFs in clinical outcomes. There were statistically significant differences in total costs amounts between WC MIS TLIF and WC open TLIF ($28,060 vs. $33,862, respectively; P = 0.0311) and non-WC MIS TLIF versus non-WC open TLIF groups ($29,429 vs. $32,998, respectively; P = 0.0001). CONCLUSION: Contrary to popular belief, immediate outcomes and hospitalizations between non-WC and WC populations did not differ regardless of surgical technique (MIS/open). Differences occurred in improved outcomes with an MIS TLIF versus an open TLIF even in a WC environment. MIS TLIF WC and non-WC patient hospital costs were lower than their open TLIF counterparts. PMID- 22487714 TI - Evidence from cluster analysis for differentiation of antisaccade performance groups based on speed/accuracy trade-offs. AB - Anti and pro-saccade performance in single or mixed contexts was explored in a large sample of young adults (n=281). ANOVAs were first conducted to evaluate trial type, context and gender effects. A cluster analysis was then used to determine whether subgroups could be identified based on saccadic performance variables. Increased antisaccade errors were observed among females and during mixed-saccade runs. Cluster analysis identified two groups: 1) increased errors clustered with faster latencies and 2) decreased errors clustered with slower latencies. These data offer justification for examining subgroups based on saccadic performance and may help elucidate mechanisms underlying response variability within and between different populations. PMID- 22487715 TI - [From drug cost to drug price: steps and decisional processes]. PMID- 22487716 TI - [Medicoeconomic data on rare disease drugs: a move towards more transparency?]. PMID- 22487717 TI - Drug-induced blood consumption: the impact of adverse drug reactions on demand for blood components in German departments of internal medicine. AB - Therapy for adverse drug reactions (ADRs) often results in the application of blood components. This study aims to assess the demand for blood components and the resulting economic burden (hospital perspective) in German hospitals induced by ADRs leading to admissions to departments of internal medicine. In this prospective study, ADRs leading to hospitalization were surveyed in four regional pharmacovigilance centres in Germany during the years 2000-2007. ADRs assessed as 'possible', 'likely' or 'very likely' were included. Market prices for blood components and hospitalization data were determined by desktop research. A probabilistic sensitivity analysis was performed. A total of 6099 patients were admitted to internal medicine departments because of an outpatient ADR of whom 1165 patients (19.1%; mean age, 73.0 +/- 13.0 years) required treatment with blood components owing to major bleeding events. Overall consumption was 4185 erythrocyte concentrates (EC), 426 fresh frozen plasma (FFP) and 48 thrombocyte (TC) units. On the basis of statistical hospital data, we estimated a nationwide demand of approximately 132,020 EC, 13,440 FFP and 1515 TC units, resulting in total costs of ?12.66 million per year for all German hospitals. Some 19.2% of all ADR cases were assessed as preventable. Theoretically, a nationwide decreased demand for blood components and a savings potential of ?2.43 million per year could be achieved by preventing ADRs in Germany. Blood components are used in one fifth (mainly gastrointestinal bleeding) of all ADRs, leading to hospitalizations in internal medicine departments. Both blood demand and hospital procurement costs can be significantly lowered by preventing ADRs. PMID- 22487718 TI - Reconsidering Yarbus: a failure to predict observers' task from eye movement patterns. AB - In 1967, Yarbus presented qualitative data from one observer showing that the patterns of eye movements were dramatically affected by an observer's task, suggesting that complex mental states could be inferred from scan paths. The strong claim of this very influential finding has never been rigorously tested. Our observers viewed photographs for 10s each. They performed one of four image based tasks while eye movements were recorded. A pattern classifier, given features from the static scan paths, could identify the image and the observer at above-chance levels. However, it could not predict a viewer's task. Shorter and longer (60s) viewing epochs produced similar results. Critically, human judges also failed to identify the tasks performed by the observers based on the static scan paths. The Yarbus finding is evocative, and while it is possible an observer's mental state might be decoded from some aspect of eye movements, static scan paths alone do not appear to be adequate to infer complex mental states of an observer. PMID- 22487719 TI - Dichoptic difference thresholds for chromatic stimuli. AB - We have investigated the properties of binocular color vision using a new measure: the Dichoptic Color Difference Threshold (DCDT). The DCDT is the smallest detectable difference in color between two dichoptically superimposed stimuli. DCDTs differ from conventional measures of binocular rivalry in that they are performance--not appearance-based. The dependency of DCDTs on (a) color direction and (b) color contrast was measured. The colors (chromaticities) of the stimuli were defined according to a scaled version of the MacLeod-Boynton color space, and the luminance and color contrasts of the stimulus pairs were equated using a matching procedure. DCDTs were measured using a forced-choice procedure in which subjects had to chose which of two stimuli had a between-eye-difference in color. DCDTs ranged from 9 degrees to 22 degrees of color angle depending on color direction. DCDTs were lower than binocular rivalry thresholds but higher than thresholds for discriminating the color pairs when placed side-by-side. There were no minima at either the cardinal color or unique hues directions, suggesting that DCDTs are not mediated by these mechanisms. DCDTs were however positively correlated with the measured perceived color difference between the color pairs when placed side-by-side. PMID- 22487720 TI - Measuring the accommodative response with a double-pass system: comparison with the Hartmann-Shack technique. AB - The current study aims at analysing the suitability of the double-pass technique in measuring the accommodative response. A custom-built setup which allowed simultaneous double-pass and Hartmann-Shack measurements was used. Several metrics to assess the accommodative response were tested and compared. In order to validate double-pass based measurements, the accommodative response was measured in 10 young adults under monocular viewing conditions with an open field fixation test. Accommodation was stimulated with the push up method in the 0 5diopters (D) range with a 1-D step. We found no significant differences among accommodative response measurements obtained with the several metrics compared in the double-pass and the Hartmann-Shack technique. In addition, differences between the double-pass and Hartmann-Shack techniques were not statistically significant. However, we obtained slightly higher values in the measured accommodative response with the double-pass system than those usually reported by other authors. The double-pass technique takes into account all factors influencing retinal image quality. Consequently, we consider this technique as a potential powerful candidate for the analysis of accommodation. PMID- 22487721 TI - Structural basis for high selectivity of anti-CCL2 neutralizing antibody CNTO 888. AB - Human CC chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), is a member of the beta chemokine family whose actions are mediated through the G-protein-coupled receptor CCR2. Binding of CCL2 to its receptor CCR2 triggers calcium mobilization and chemotaxis. CCL2 is implicated in the pathogenesis of certain inflammatory diseases and cancer. CNTO 888, a neutralizing human anti-CCL2 antibody, was derived by antibody phage display. The antibody binds human CCL2 with high affinity (K(D)=22 pM) and inhibits CCL2 binding to its receptor. The crystal structure of the CNTO 888 Fab alone and in complex with the monomeric form of CCL2 (P8A variant) was determined at 2.6 A and 2.8 A resolution, respectively. CNTO 888 recognizes a conformational epitope encompassing residues 18-24 and 45-51 that overlaps the mapped receptor binding site. The epitope of CNTO 888 does not overlap with the dimerization site of CCL2, and thus its inhibitory activity is not expected to result from interference with the oligomeric state of CCL2. Comparison of the X-ray determined epitopes of CNTO 888 and another CCL2-neutralizing antibody, 11K2, provides insight into the molecular basis of antibody selectivity and functional inhibition. PMID- 22487723 TI - Clinical outcome in the use of cephalosporins in pediatric patients with a history of penicillin allergy. AB - BACKGROUND: The risk of cephalosporin administration in patients with a history of penicillin allergy is unclear. Few studies have looked at the risk of cephalosporin administration in children following penicillin skin testing for suspected penicillin allergy. The goal of this study was to determine whether children with penicillin allergy were at increased risk for adverse drug reactions when administered a cephalosporin. METHODS: A retrospective chart review was conducted in pediatric patients (<=18 years) with a history of penicillin allergy and a positive or negative penicillin skin test who were administered a cephalosporin after testing. Charts were reviewed for adverse drug reactions to the cephalosporin. RESULTS: A total of 173 patients (91 males) were included in this study. The mean age of the patients was 4.1 +/- 3.1 years. Twenty-one patients (12%) tested positive in a penicillin skin test and 152 patients (88%) tested negative. One patient with a negative penicillin skin test (0.7%) had an adverse drug reaction (eye swelling) to cephalexin. None of the patients with a positive penicillin skin test who received a course of cephalosporin had an adverse drug reaction. CONCLUSION: Among all patients with a history of penicillin allergy (penicillin skin test positive and negative), only 1 person had an adverse drug reaction. Further large prospective studies examining the safety of administering cephalosporins in pediatric patients with confirmed penicillin allergy are needed. PMID- 22487722 TI - Distinct subunit pairing criteria within the heterodimeric IL-12 cytokine family. AB - The heterodimeric IL-12 cytokine family is characterized by the sharing of three alpha (p19, p28, p35) and two beta (p40 and Ebi3) subunits, and includes IL-12 (p35/p40), IL-23 (p19/p40), IL-27 (p28/Ebi3) and IL-35 (p35/Ebi3). In this study, the dimerization interfaces of IL-12 family members were characterized, with emphasis on IL-35. Ebi3 and p35 subunits from human and mouse paired effectively with each other, indicating there is no species barrier to IL-35 dimerization and suggesting a conserved dimerization interface. Specific p35 residues that contribute to formation of the IL-12 interface were assessed for their contribution to the IL-35 interface, and candidate Ebi3 residues were screened for their contribution to both IL-27 and IL-35 interfaces. Several residues were identified as critical to the IL-12 or IL-27 interfaces. Conversely, no single mutation was identified that completely disrupts p35/Ebi3 pairing. Linear alanine scanning mutagenesis on both p35 and Ebi3 subunits was performed, focusing on residues that are conserved between the mouse and human proteins. Additionally, a structure-based alanine-scanning approach in which mutations were clustered based on proximitiy was performed on the p35 subunit. Both approaches suggest that IL 35 has distinct criteria for subunit pairing and is remarkabley less sensitive to structural perturbation than IL-12 and IL-27. Additionally, studies using a panel of anti-p35 and anti-Ebi3 antibodies indicate differential availability of epitopes within IL-12 family members that share these subunits, suggesting that IL-35 has distinct structural features, relative to IL-12 and IL-27. These results may be useful in future directed therapeutic targeting of IL-12 family members. PMID- 22487724 TI - PFO closuRE and CryptogenIc StrokE (PRECISE) registry: a multi-center, international registry. AB - BACKGROUND: The PremereTM PFO closure device has a special design for closure of patent foramen ovale (PFO) including a flexible distance and angulation between the right and left disc providing minimal septal distortion. The primary objective of the study was to determine the degree of risk for stroke or transient ischemic attack (TIA) in patients after PremereTM PFO closure device implantation. METHODS: In this multicenter, prospective observational registry, patients with a clinical indication for PFO closure were included. Patients had a history of stroke or TIA with right to left shunt. Follow-up visits were scheduled according to routine clinical practice. RESULTS: In 23 centers from 10 countries, 267 patients with successful device implantation were included. Assessment of right to left shunt after device implantation revealed no residual shunt in 71 %, small shunts in 16.8 %, and moderate or large residual shunts in 5.6 and 6.5 %. With common clinical practice, use of Coumadin or heparin decreased from 27 % pre- to 3 % post-implantation, while use of acetylsalicylic acid or thienopyridines increased from 64 to 95 % and 27 to 80 %, respectively; 18 % of patients were discharged with anti-platelet monotherapy. Mean follow-up was 11 +/- 9 months (range 1-24 months). There was no stroke or TIA. During follow-up, there was one sudden death. Atrial fibrillation occurred in five (1.9 %) patients. One (0.4 %) patient with a thrombophilic diathesis developed a thrombus. CONCLUSIONS: In this prospective, international, multicenter PRECISE registry, the use of the PremereTM PFO closure device for closure of PFO after stroke or TIA resulted in good clinical results with no recurrent event. PMID- 22487725 TI - Is the measurement of anti-Mullerian hormone essential? AB - PURPOSE OF REVIEW: Over the past decade, a large number of studies examining the multiple roles of anti-Mullerian hormone (AMH) have been published. The purpose of this article is to focus on the clinical usefulness of AMH in the fields of current gynecological clinical practice. RECENT FINDINGS: AMH has entered clinical practice in terms of poor ovarian response definition. It prevents folliculogenesis by reducing follicle sensitivity to follicle-stimulating hormone (FSH), and leads to anovulation when secreted in excess amounts in polycystic ovary syndrome (PCOS). Better results might be obtained in the assisted reproductive technique cycle in the presence of high AMH levels even though FSH is increased in women diagnosed with diminished ovarian reserve. In a more recently published study it has been reported that AMH can also predict the outcome of pregnancy in assisted reproduction. SUMMARY: AMH levels accurately reflect the ovarian follicular reserve and might, therefore, be considered as a sensitive marker of ovarian aging and ovarian reserve. Evaluation of the level of AMH has clinical value in predicting the success of in-vitro fertilization (IVF). Hyper-response/ovarian hyperstimulation syndrome (OHSS) might be anticipated as about 3.5 ng/ml or above. The cycle stability and operator independency make AMH a most appealing single marker of ovarian reserve. Use of AMH to paint tailored stimulation protocol could result in a reduced risk of OHSS, optimized treatment burden and maintained pregnancy rates. Cost-effectiveness of the use of AMH as a single test before initiating an IVF program should be determined. PMID- 22487726 TI - Embryo assessment strategies and their validation for clinical use: a critical analysis of methodology. AB - PURPOSE OF REVIEW: A multitude of novel embryo assessment strategies using genomics, transcriptomics, proteomics, and metabolomics approaches are being developed in order to improve upon the currently utilized embryo assessment methods based on morphology and cleavage rate. Although these novel technologies promise significant improvements in clinical outcome for women undergoing infertility treatment with in-vitro fertilization, their validation poses significant challenges. In this review, we discuss the appropriate steps to be taken in clinical validation of an embryo assessment test. We then provide a critical analysis of the studies evaluating embryo assessment strategies from a methodological perspective. RECENT FINDINGS: Validation of a novel embryo assessment test requires the determination of appropriate performance parameters (such as sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve), followed by clinical validation using appropriate study design. Finally, benefit from a test, alone or in combination with currently used methods, needs to be tested using a prospective randomized controlled trial study design. Few studies on existing or novel embryo assessment methods provide these parameters. SUMMARY: Validation of a test is a rigorous process that needs to be handled meticulously, using appropriate performance parameters determined by the inherent characteristics of the test and clinical studies with appropriate design. PMID- 22487727 TI - The impact of preconceptual diet on the outcome of reproductive treatments. AB - PURPOSE OF REVIEW: To discuss the dietary factors that influence the reproductive outcomes in patients undergoing fertility treatment. RECENT FINDINGS: Recent studies have found that a woman's nutritional status and dietary intake can play a role in her reproductive health. In addition to weight, specific dietary patterns rich in omega-3 fatty acids and micronutrients such as vitamin D have all been shown to impact fertility. Although data regarding diet and fertility treatment are limited with many studies lacking the statistical power to validate findings, recent studies corroborate the importance of a balanced diet and appropriate weight management program while undergoing fertility treatment. SUMMARY: The growing reliance on assisted reproductive technologies in conjunction with the increase in the general population's weight and poor nutritional status has raised questions as to the effects of dietary status and weight on fertility treatment outcome. A review of findings thus far indicates potential avenues for future research to further elucidate cytotoxic and genotoxic dietary factors as well as dietary elements that may improve oocyte quality, aid implantation, as well as pregnancy maintenance during the periconception period. PMID- 22487728 TI - Does syntax contribute to the function of duets in a parrot, Amazona auropalliata? AB - Complex acoustic signals in many animal species are characterized by a syntax that governs how different notes are combined, but the importance of syntax to the communicative function of signals is not well understood. Mated pairs of yellow-naped amazons, Amazona auropalliata, produce coordinated vocal duets that are used for territory maintenance and defense. These duets follow rules that specify the ordering of notes within duets, such as a strict alternation of sex specific notes and a defined progression of note types through each duet. These syntactical rules may function to define sex-specific roles, improve coordination, and allow individuals to combine calls into meaningful sequences. As a first step toward understanding the functional significance of syntax, we conducted two separate audio playback experiments in which we presented nesting pairs with normal duets and duets with broken syntax (i.e., one of the syntactic rules was broken). In Experiment One, we reversed the order of female and male notes within note pairs while retaining the typical progression of note types through a duet. In Experiment Two we reversed the order of note types across a whole duet while retaining the typical female-male ordering within note pairs. We hypothesized that duets with broken syntax would be less-effective signals than duets with normal syntax and predicted that pairs would respond less to broken syntax than to normal duets. Contrary to predictions, we did not observe differences in response between treatments for any variables except latency to approach the speaker. After we combined data across experiments post hoc, we observed longer latencies to approach the speakers after playbacks of broken syntax duets, suggesting that pairs could differentiate between playbacks. These responses suggest that breaking one rule of duet syntax at a time does not result in detectable loss of signal efficacy in the context of territorial intrusions. PMID- 22487729 TI - Dextromethorphan inhibition of voltage-gated proton currents in BV2 microglial cells. AB - Dextromethorphan, an antitussive drug, has a neuroprotective property as evidenced by its inhibition of microglial production of pro-inflammatory cytokines and reactive oxygen species. The microglial activation requires NADPH oxidase activity, which is sustained by voltage-gated proton channels in microglia as they dissipate an intracellular acid buildup. In the present study, we examined the effect of dextromethorphan on proton currents in microglial BV2 cells. Dextromethorphan reversibly inhibited proton currents with an IC(50) value of 51.7 MUM at an intracellular/extracellular pH gradient of 5.5/7.3. Dextromethorphan did not change the reversal potential or the voltage dependence of the gating. Dextrorphan and 3-hydroxymorphinan, major metabolites of dextromethorphan, and dextromethorphan methiodide were ineffective in inhibiting proton currents. The results indicate that dextromethorphan inhibition of proton currents would suppress NADPH oxidase activity and, eventually, microglial activation. PMID- 22487731 TI - Working hours, sleep, salivary cortisol, fatigue and neuro-behavior during Mars analog mission: five crews study. AB - The buoyancy of humans in exploring extreme space environments has been established during missions to the moon. Long duration missions like mission to Mars however, requires humans to adapt to systemic and complex environments beyond the human body's capacity. Astronauts will encounter both physiological and psychological extremes during this trip. Very few studies are conducted on effect of long duration work and sleepiness on cognitive performance. So, this study was planned to find out effects of leadership responsibility, sleepiness and long duration working hours on cognitive performance. The 30 members (leadership: normal; 10:20) were selected from MDRS crews (Mars Desert Research Station, USA). Neurobehavioral test performance, self-ratings of fatigue and sleepiness, and salivary cortisol levels were evaluated during first day, mid and end day of mission. The leadership group did not show any signs of reduced test performance, even in elevated fatigue and sleepiness. The leadership group had faster reaction times on end of mission as compared to first and after 7 day of mission. Salivary cortisol levels were significantly higher in leadership group as compared to normal group. The results suggest that long duration work and sleepiness does not affect the cognitive performance of crew member. Further study is required while taking into account all factors and large sample size to prove this fact. PMID- 22487730 TI - Nicotine-induced dendritic remodeling in the insular cortex. AB - The insular cortex has emerged as a novel target for nicotine addiction research. One unresolved question about the insular cortex is whether its neurons exhibit nicotine-induced dendritic remodeling similar to other brain regions implicated in nicotine addiction. To test this question, Long-Evans rats were administered nicotine via osmotic pump for two weeks. Thirty-seven days following the end of nicotine dosing, rats were sacrificed for Golgi-Cox staining and pyramidal neurons from the rostral agranular insular cortex were digitally reconstructed in three dimensions. Results from morphometric analyses revealed an increased complexity of dendrites in the insular cortex following nicotine. Increases were found for both total dendrite length and number of bifurcations. Sholl analyses revealed these changes depended on the distance from the soma, with the most prominent changes distributed at distal points along the dendritic tree. A follow up comparison of length and bifurcation measurements from Sholl analyses suggested that new dendritic branches, rather than growth of existing dendrites, most likely contributed to overall changes in complexity. No change in dendrite morphology was found for apical dendrites. Together, these results show the insular cortex is a target for neuroplasticity following nicotine exposure. PMID- 22487732 TI - Influence of COX-2 and OXTR polymorphisms on treatment outcome in treatment resistant depression. AB - Inflammatory pathways play a crucial role in the pathomechanisms of antidepressant efficacy. The aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within cyclooxygenase-2 (COX-2, rs5275 and rs20417) and oxytocin receptor (OXTR, rs53576 and rs2254298) genes was associated with antidepressant treatment resistance, response or remission. Three hundred seventy-two patients were recruited in the context of a multicenter resistant depression study. They were genotyped for COX-2 and OXTR SNPs. Treatment resistance (according to two different definitions), response and remission were recorded. We did not observe any association between the genotypes or alleles of the selected SNPs within COX-2 and OXTR genes and treatment resistance, response and remission in the whole sample. Our results are consistent with those of some studies but not with those of other ones. Indeed, several factors could be involved in the discrepancy observed across studies. They include sample size, environmental factors, differences in ethnicity, different study designs, and different definitions of treatment resistance. PMID- 22487733 TI - Methadone does not alter key parameters of adult hippocampal neurogenesis in the heroin-naive rat. AB - Methadone is a synthetic opiate that is useful in a variety of clinical settings, including in maintenance therapy of heroin dependence and as an analgesic. However, methadone can have negative effects on cognition in humans and in rodents. The mechanisms underlying methadone-induced disruption in cognition are unknown. One possibility is that methadone disrupts adult hippocampal neurogenesis, a form of hippocampal plasticity involved in cognition that is disrupted by other opiates, like morphine. The goal of this study was to determine if methadone alters key parameters of hippocampal neurogenesis in the adult rat. Four groups of male rats were injected with saline (Saline, n=11) or methadone (Escalating, Short Term, Acute, n=10-11/group) over the course of three weeks. Weight gain, locomotor activity, and neurogenesis data were collected. Consistent with prior results, Escalating rats had slower weight gain (-4% vs. Saline). Also consistent with prior results, methadone did not alter locomotor activity over the course of a 90 min test. However, closer analysis revealed that methadone - irrespective of the dose or duration - led to a decrease in locomotor activity (-11 to -20% vs. saline) when examined during the first 5 min of the locomotor test. Surprisingly, methadone did not alter any of three quantified parameters relevant to adult hippocampal neurogenesis (number of Ki67-, doublecortin-, or BrdU-immunoreactive cells [BrdU given prior to saline/methadone exposure]). These results suggest that - unlike other opiates such as morphine - experimenter-delivered methadone does not alter hippocampal plasticity by decreasing the number of adult-generated neurons. PMID- 22487734 TI - Impact of obesity on incident hypertension independent of weight gain among nonhypertensive Japanese: the Ibaraki Prefectural Health Study (IPHS). AB - OBJECTIVE: The aim of this study was to examine the association between BMI and risk of incident hypertension among Japanese men and women who are middle-aged and older. DESIGN: Prospective, population-based cohort study. PATIENTS: A total of 68 205 nonhypertensive adults (18 336 men and 49 869 women) aged 40-79 years who completed health check-ups in the Ibaraki prefecture, Japan, in 1993 were followed up through 2006. To exclude the impact of BMI change during the follow up period, a time-dependent covariate Cox proportional hazards model was used to compute the hazard ratios of incident hypertension according to BMI categories. Incident hypertension was defined as a SBP of at least 140 mmHg, a diastolic BP of at least 90 mmHg, and/or hypertensive medication use. RESULTS: A total of 30 982 adults (45.4%) developed hypertension (9331 men and 21 651 women) during a mean of 3.9 years of follow-up. Compared with a BMI of less than 19.0, time dependent covariates adjusted hazard ratios [95% confidence interval (CI)] for hypertension among participants with a BMI of at least 25.0 were 1.42 (1.17-1.73) for men aged 40-59 years, 1.34 (1.19-1.51) for men aged 60-79 years, 1.47 (1.33 1.62) for women aged 40-59 years, and 1.29 (1.18-1.41) for women aged 60-79 years. CONCLUSION: The baseline BMI is associated with future risk for incident hypertension even after accounting for weight change during the follow-up period. Weight loss may be recommended to nonhypertensive obese adults to prevent the development of hypertension. PMID- 22487735 TI - Increased mean platelet volume in cervicocephalic artery dissections. AB - AIM: We aimed to investigate the role of platelets in the pathogenesis of cervicocephalic artery dissections by measuring the mean platelet volume (MPV) and platelet count. METHODS: Thirty-four patients with evidence of cervicocephalic artery dissection were included in the study. Cervicocephalic artery dissection patients were divided into two subgroups as vertebral artery dissections and carotid artery dissections. There were 30 control subjects with similar baseline characteristics. The platelet count and MPV were compared between groups. RESULTS: The analysis showed a significant difference between the MPV values of the cervicocephalic artery dissection group and the control group (p < 0.05). However, when we compared subgroups with controls, we found a significantly higher MPV values only in the vertebral artery dissection group. We did not find any significant difference for total platelet count between the cervicocephalic artery dissection groups and controls. CONCLUSIONS: MPV is a marker of platelet function and activation. Increased MPV may be a result of dissection. In addition, it may be a risk factor for dissection-related stroke. Our study supports the notion that platelet reactivity is important in the pathogenesis of the cervicocephalic artery dissections, especially in vertebral artery dissections. PMID- 22487737 TI - Modeling and management of variation in the operating rooms helps to improve patient outcome. PMID- 22487736 TI - Protective effect of Panax ginseng against serum biochemical changes and apoptosis in kidney of rats treated with gentamicin sulphate. AB - The protective effects of Panax ginseng (PG) on gentamicin sulphate (GS) induced acute nephrotoxicity were investigated in rats. A total of 32 adult Sprague Dawley rats were randomly divided into 4 equal groups and treated by intraperitoneous route for 10 days with: 0.5 mL of isotonic saline (group C), GS 100 mg/kg/day (group GS), co treatment PG (100 and 200 mg/kg/day) plus GS (100 mg/kg/day). After the last injection, kidney markers (urea, creatinine and blood urea nitrogen-BUN) and hepatic markers (aspartate aminotransferase-AST, alanine aminotransferase-ALT, gama glutamil transferase-GGT), and biochemical parameters were analyzed using diagnostic kits. Also, kidney changes were evaluated by immunohistochemical and stereological methods. GS treatment induced significant elevation (P < 0.05) in kidney and hepatic markers, most of biochemical parameters, and Bax immunoreactivity as well. However, co treatments with both doses of PG (100 and 200 mg/kg/day) significantly alleviated (P < 0.05) the GS induced elevations and have partially protected rats from nephrotoxicity (reduction of kidney damage, and of urea, creatinine and BUN concentrations, and of apoptotic index). Both biochemical results and immunohistochemical evidence showed that administration of PG reduced the gentamicin-induced nephrotoxicity. PMID- 22487738 TI - Epidemiological characteristic of acute pancreatitis in Trzebnica district. AB - Acute pancreatitis is one of the most common surgical disease, and thus cause of hospitalization. Incidence and etiology of this condition demonstrates large regional differences. This situation is a substantial financial burden forhospital district, and changes in organization structure and funding medical service should be taken under consideration.The aim of the study was to record the epidemiology with etiology, diagnosis and treatment of acute pancreatitis in large district (77 000 inhabitants).Material and methods. A meta-analysis study of all 298 patients admitted to Hospital St Hedwig in Trzebnica, in the six-year period from 2005 to 2010, with acute pancreatitis was performed.Results. Acute pancreatitis was diagnosed in 298 patients in the six - year period, giving an estimated incidence of 64.4 per 100 000. Among the group of 441 admissions for acute pancreatitis in 298 patients was confirmed. Severe acute pancreatitis developed in 22.5% (67/298) of patients, more often in males 56/208 (27%) than in females 11/90 (12%). Gallstones were found as an etiological factor in 27% (80/298), and alcohol intake in 49% of patients. 211/298 (70%) patients had only one attack, whereas 29% (87/298) were readmitted with 230 relapses. The risk of recurrent pancreatitis was 48% in alcohol induced and 6,25% in gallstone induced pancreatitis. 53/298 patients (17%) were operated, ERCP procedures were performed in 24.Performed operations: necrosectomy in 25/53 (47%), elective cholecystectomy in 16/53 (30%), open drainage of abdominal abscess in 5/53 (9%), open drainage of cysts in 5/53 (9%), Jurasz's operation in 2/53 (3%). Majority surgical treatment was carried out in 68% cases with severe acute pancreatitis. Mortality due to acute pancreatitis was 3% (10/298); 15% in severe pancreatitis.Conclusions. 1. Acute pancreatitis continues to be an important clinical problem. 2. Severe, necrotic acute pancreatitis is associated with high mortality rates. 3. The ethanol-intake-related episodes of acute pancreatitits are much more prevalent than the gall-stone-related ones. 4. After the exclusion of ethanol- and gall stones-related etiologies, the subsequent diagnostic process should aim at excluding neoplastic process of the head of pancreas. PMID- 22487739 TI - The strategies of coping with stress in workplace used by surgeons working in different hospitals: a pilotage research. AB - THE AIM OF THE STUDY: was an evaluating the frequency for adapting different strategies within the group of surgeons to cope up with stress and determining the differentiation on their usage depending on the type of the hospital unit and social-demographic variables. MATERIAL AND METHODS: The samples were 40 surgeons from hospitals. Following research methods were applied: 1. Latack Coping Scale was used to investigate the strategies of coping with stress; 2. Personal questionnaire was used to obtain general social-demographic data about subjects. RESULTS: The Latack scale is a reliable tool for testing work related stress coping strategies within a group of surgeons. Active strategies are more common than avoiding strategies. Surgeons mostly use Direct action and Positive thinking strategy in coping with stress at work. In turn, Alcohol use strategy is rarely use by subjects to solve difficult professional situations. The lack of significant differences in frequency of usage of particular strategies in correlation with the hospital type was observed. There is positive correlation which is statistically significant between analyzed social-demographic variables and usage of Avoidance/Resignation strategy within examined surgeons. The more experienced, older people are, the more likely it is that they will use this strategy in stressful situations. CONCLUSIONS: Surgeons usually use adaptive strategies in coping with stress at work. PMID- 22487740 TI - Omphalocele, gastroschisis: epidemiology, survival, and mortality in Imam Khomeini hospital, Ahvaz-Iran. AB - Gastroschisis and omphalocele are the most common malformation of the anterior abdominal wall.The aim of the study was to determine the abdominal wall defect frequencies, survival, and mortalities in Ahvaz, Khuzestan province of Iran.Material and methods. All cases born with omphalocele or gastroschisis whom born in Imam Khomeini hospital, were included in this study. Duration of study was 3 years from April 2005. All patients treated at Imam Khomeini hospital in Ahwaz, Iran.Results. Among 15321 consecutive births, 42 patients had abdominal wall deformity. Overall incidence was 27.41 per 10,000 live births. Of all cases, 18 (42.9%) of cases were male and 24 (57.1%) were female. Of all cases, 21.7% of patients with omphalocele and 10% patients with gastroschisis had other anomalies. Of all cases, 71.8% of patients with omphalocele and 60% with gastroschisis underwent surgery. The type of anomaly (omphalocele and gastroschisis) had correlation with post operation prognosis significantly (p<0.001). Of 66.7% of patients under went surgery, 46.4% with mesh and 53.6% without mesh performed. 80% of patients with omphalocele and 20% with gastroschisis were lived. CONCLUSIONS: In our study, mortality was significantly higher in cases with gastroschisis than cases with omphalocele. PMID- 22487741 TI - The evaluation of diagnostic value of the tumor markers: CCSA-2 and CEA in colorectal cancer. AB - Finding the biomarker or biomarkers with high sensitivity and specificity in colorectal cancer, and thus a high diagnostic value will determine their clinical usefulness in clinical practice. An effective noninvasive blood test would be an ideal method to detect colorectal cancer. Discovered in 2007 a novel tumor marker CCSA-2 showes a promising results in patients with colorectal cancer. THE AIM OF THE STUDY was the evaluation of diagnostic and clinical value of a novel marker - colon cancer specific antigen-2 (CCSA-2) in colorectal adenocarcinoma in comparison to carcinoembryonic antigen (CEA) in patients operated during the years 2008 to 2010 at Wroclaw Medical University 1st Department and Clinic of General, Gastroenterological and Endocrinologic Surgery. MATERIAL AND METHODS: The study was performed on 40 patients with colorectal cancer and 40 patients in control group consisted of healthy subjects who had colonoscopy examinations with negative results (no pathology in the colon was found). The obtained results were statistically analyzed using nonparametric tests - Mann Whitney U and Kruskal Wallis and Spearman's rank correlation coefficients. To determine the clinical value of CCSA-2 and CEA in those groups, their sensitivity and specifity was evaluated using ROC analysis. This analysis determines the accuracy and diagnostic value of both tests. RESULTS: There was a positive correlation between markers in patients with colorectal cancer and a statistically significant relationship according to which respondents with higher concentrations of CCSA-2 also have higher concentrations of CEA (R=0.754, p<0,001). Concentrations of tumor markers increase and correlate with the clinical progression of the disease. Accuracy of CCSA-2 test using ROC analysis showed a slightly lower measurement of antigen CCSA-2 as diagnostic value in colorectal cancer in comparison to measurement of antigen CEA (accuracy of tests: CCSA-2 - 52%, CEA - 60%). CONCLUSIONS: CCSA-2 as a single tumor marker has a low diagnostic value in colorectal cancer because of low sensitivity and specifity. The diagnostic value of novel marker is slightly lower than previously understood and accepted in clinical practice - CEA. PMID- 22487742 TI - C-reactive protein as a marker of postoperative septic complications. AB - THE AIM OF THE STUDY: was to answer the question whether or not determination of C-reactive protein in patients after serious abdominal surgeries can be prognostic of septic complications. MATERIAL AND METHODS: 36 patients who underwent elective surgeries were included in the study. The patients were included either in the group where no postoperative SIRS developed or in the group where postoperative SIRS did occur. In the seven-day period after the surgery, in 26 patients SIRS was found, and in 10 - sepsis was suspected (according to the ACCP/SCCM definitions). In patients who underwent abdominal surgeries blood concentration of C-reactive protein was determined prior to the surgery (measurement '0'), and then on postoperative days 1, 2, 3, 5 and 7. RESULTS: The test for two variables (C-reactive protein on postoperative days five and seven) showed statistically significant difference, and for one variable (C-reactive protein on day three) - difference at the limit of significance. Thus, it was found that in the postoperative SIRS group the level of C-reactive protein is higher than in the non-SIRS group. CONCLUSIONS: Serial measurements of C-reactive protein are useful in the first week after surgery, as they can be prognostic of postoperative septic complications. Such complications can be anticipated if CRP on postoperative day 5 is higher than 1/2 of the maximum CRP concentration on day 2 or day 3, or CRP > 150 mg/L as of postoperative day 3. Unfortunately, the severity of the disease cannot be projected based on C reactive protein level. PMID- 22487743 TI - The use of three free flaps in the simultaneous reconstruction of the nose after extensive resection due to malignant cancer. AB - Reconstructive techniques for extended posttraumatic or post-resectional nose defects are well described. Small defects can usually be closed using local flaps with a good esthetic result. Extended resections in the mentioned area require more complex reconstruction methods, including microvascular techniques. The Authors' presented a case of whole nose and partial cheek simultaneous reconstruction using three free flaps. Two auricular free flaps and one radial forearm free flap were used to cover the defect. Meticulous preoperative planning and harvesting of flaps enabled to achieve good esthetic and functional results. PMID- 22487744 TI - Prolapse of submucous lipoma of the sigmoid colon. AB - Lipomas of the colon are rare and usually presenting in the later ages of life. This case describes and discusses the symptoms and signs of lipomas, recommendations and rationale for treatment. PMID- 22487745 TI - "Sportsman's hernia". part two: multispecialist differentia diagnosis of most common disorders. PMID- 22487746 TI - Motor neuron disease: the C9orf72 hexanucleotide repeat expansion in FTD and ALS. PMID- 22487747 TI - Neurodegenerative disease: Establishing a clinical trial battery for Huntington disease. PMID- 22487748 TI - Neurodevelopmental disorders: Transplantation therapy in a mouse model of Rett syndrome. PMID- 22487750 TI - Neuro-oncology: Identification of novel glioblastoma-associated antigens reveals targets for immunotherapy. PMID- 22487749 TI - Assessment and treatment of pain in people with dementia. AB - Many elderly people experience pain and regularly take analgesic medication. Pain is also frequent in people with dementia, particularly those with severe disease. As no robust clinical guidelines are available for the treatment of pain in the context of dementia, the risk of inadequate treatment in individuals with this condition is high. Furthermore, our understanding of the aetiology of pain and the potential role of dementia-associated neuropathology in pain is limited. These issues are important in the clinical management of individuals with dementia, as untreated pain is a major contributor to reduced quality of life and disability, and can lead to increased behavioural and psychological symptoms. Assessment scales to identify pain in people with dementia have been highlighted in recent studies, but there is little evidence for consistency between these tools. Numerous studies have evaluated various approaches for the treatment of pain, including stepped-care protocols and/or administration of paracetamol and opioid medications. In this Review, we summarize the best-available evidence regarding the aetiology, assessment and treatment of pain in people with dementia. Further validation of assessment tools and large-scale trials of treatment approaches in people with dementia are needed to improve clinical guidance for the treatment of pain in these individuals. PMID- 22487751 TI - Prion disease: New approaches to CJD diagnosis. PMID- 22487752 TI - Epilepsy: Surgical therapy should not be considered a last resort for pharmacoresistant epilepsy. PMID- 22487753 TI - Evaluating the efficiency of participatory epidemiology to estimate the incidence and impacts of foot-and-mouth disease among livestock owners in Cambodia. AB - The economic and social impacts of foot-and-mouth disease (FMD) for livestock owners of developed countries have been extensively documented over the past few years. In developing countries such as Cambodia, this evaluation is often lacking due to the scarcity of accurate data. In the present study, we used a range of participatory tools to infer farmers' knowledge and perception, and the relative incidence of FMD from January 2009 to June 2010 in fifty-one villages of Svay Rieng province, Cambodia. In addition, the detection of non-structural protein at village level was used to cross-validate the results from the participatory epidemiology (PE) study. A quantitative assessment using Bayesian modeling was carried out to assess the ability of PE to retrospectively determine the FMD infected status of a village in Cambodia. Our study shows that even if FMD is ranked second in the list of priority diseases, livestock owners did not see any benefit in reporting it since the disease entailed low direct losses. The average clinical incidence rates at individual level for cattle-buffaloes and pigs in infected villages were assessed by proportional piling at 18% and 11%, respectively for the year 2009. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PE study were estimated at 87%, 30%, 51% and 74%, respectively. This approach seems to largely overestimate the presence of the disease but proves useful in evaluating the impact of FMD at household level and in understanding the reasons for not reporting it. This information may be important in establishing well-adapted disease prevention and control strategies in Cambodia. PMID- 22487754 TI - In vivo efficacy of the anthelmintic tribendimidine against the cestode Hymenolepis microstoma in a controlled laboratory trial. AB - Tribendimidine has been registered for the treatment of human soil transmitted helminthiases in China. In the model nematode Caenorhabditis elegans it is an agonist of L-subtype nicotinic acetylcholine receptors and therefore shares its mode of action with levamisole and pyrantel. Besides its broad spectrum of nematicidal efficacy, tribendimidine is efficacious against several trematodes and has been attributed to have anti-cestodal effects. However, there are few published data available for the latter. The efficacy of tribendimidine and its nematicidal metabolite deacylated amidantel against Hymenolepis microstoma were examined for their anti-cestodal potential. Doses of 50 and 100mg/kg body weight deacylated amidantel and 10, 25, 50, and 100mg/kg tribendimidine were administered orally on three consecutive days to mice experimentally infected with eight cysticercoids. Necropsy was performed and the worm burdens were determined one day after the last treatment. Furthermore, levamisole was used in combination with tribendimidine (100mg/kg levamisole plus 10 and 25mg/kg tribendimidine, respectively) and alone (50 and 100mg/kg) to investigate any possible interactions of the partner compounds against cestodes. Tribendimidine showed a very high efficacy at dosages of 50mg/kg or higher. Surprisingly, deacylated amidantel led to no reduction of the worm burden in any of the treatments. Combinations of levamisole with tribendimidine did not augment the effects of tribendimidine alone and as expected levamisole alone also showed no anti-cestodal activity. To our knowledge, this study shows for the first time activity of tribendimidine against a cestode in a controlled laboratory study. Due to the excellent cure rates observed here, multiple tribendimidine treatments might be considered as useful scheme for treatments of cestode, nematode and trematode infections although this would significantly increase both costs and management efforts. Moreover, the differences between tribendimidine and deacylated amidantel indicate at least a strong difference in sensitivity of H. microstoma or a strong difference in drug availability. PMID- 22487755 TI - Disaster preparedness in home health and personal-care agencies: are they ready? AB - BACKGROUND: The use of home health care and personal-care agencies in the United States has increased by nearly 1,000% in less than 20 years. Despite the numerous advantages of keeping older and disabled people at home and fairly independent, new concerns have emerged about how to keep home health care and personal-care clients safe during emergencies and large-scale disasters. To date, little is known about the disaster preparedness activities of home health and personal-care agencies, including what oversight they have for their patients and what capabilities they sustain for preparing their clients for disasters. OBJECTIVE: The purpose of this study was to explore the disaster preparedness policies and practices of these agencies and to identify opportunities for coordination with disaster preparedness officials. METHODS: Semi-structured interviews were conducted by phone and in person with 21 home health and personal-care administrators across Georgia and Southern California. Transcripts from the interviews were analyzed for disaster preparedness themes. RESULTS: We found that most agencies have very limited disaster plans and capabilities. Despite this, most stated either their intentions or outlined past experience which demonstrated their commitment to provide services to clients on a case-by-case basis throughout a large-scale emergency or disaster. CONCLUSION: The findings from our study help to contribute to the growing interest in disaster preparedness among home health and personal-care agencies and point to the fact that these agencies need assistance to properly lay out their disaster preparedness plans. PMID- 22487756 TI - Histologic variants of renal cell carcinoma: does tumor type influence outcome? AB - Each histologic type of renal cell carcinoma (RCC) has different pathologic and clinical parameters; however, the independent role of histologic type in outcome prediction remains contested. Most studies show relevance for outcome of each histologic type when correlated with survival by univariate analysis, whereas few studies show differences in outcome once other key prognostic factors, such as stage and grade, are considered. These studies highlight the challenges to prove outcome relevance. Despite the contested independent value of type for outcome prediction, separation of RCC into types is well accepted and can be substantiated on clinical, pathologic, molecular, and general outcome differences. PMID- 22487757 TI - The surgical approach to multifocal renal cancers: hereditary syndromes, ipsilateral multifocality, and bilateral tumors. AB - Although the management of sporadic renal tumors is challenging enough, dealing with those with bilateral, multifocal, and hereditary kidney cancer adds an additional level of complexity. A clinician managing this patient population must understand the hereditary syndromes and the genetic testing available. Treating physicians must be familiar with enucleative surgery, complex or multiple tumor partial nephrectomy, complex renal reconstruction, re-operative renal surgery, and active surveillance strategies. With proper management, most patients affected with bilateral, multifocal, or hereditary RCC can have a long life expectancy while maintaining adequate renal function. PMID- 22487758 TI - Current practice patterns in the surgical management of renal cancer in the United States. AB - Over the last two decades, there has been a rising incidence of renal tumors, particularly, small renal masses (<4 cm) resulting in a downward size and stage migration. This has brought about a paradigm shift in the management of newly diagnosed renal masses, such that nephron-sparing surgery, minimally invasive techniques, and active surveillance are frequently considered preferable to the historical gold standard of open radical nephrectomy. Population-based cohort studies indicate, however, that the widespread adoption of these techniques has been relatively slow and incomplete leading to significant disparities in the delivery of care throughout the country. Further investigation is required to determine the barriers to diffusion of new techniques and technology as well as to ensure equal access to quality care in the United States. PMID- 22487759 TI - Contemporary imaging of the renal mass. AB - Contemporary imaging techniques for renal mass evaluation are essential to clinical management and surgical planning. Ultrasonography can be used to distinguish cystic from solid lesions but is less sensitive and accurate in renal mass characterization than computed tomography (CT) and magnetic resonance imaging (MRI). Multiphase CT imaging before and after administration of contrast is the primary imaging modality for characterization and staging of renal lesions. MRI is increasingly used as a problem solving tool. Advanced MRI techniques such as diffusion-weighted imaging and perfusion-weighted imaging are being explored in assessment of renal lesions. These techniques are discussed in this article. PMID- 22487760 TI - Approach to the small renal mass: to treat or not to treat. AB - Accurately conveying the benefits and risks of treatment interventions to patients diagnosed with small renal masses (SRMs) is essential to appropriately identify which patients will achieve better oncologic outcomes and confer a survival advantage from primary therapy. Treatment decisions to determine the ideal management with nephrectomy, thermal ablation, or active surveillance for patients diagnosed with an SRM remain highly complex. Existing prediction tools that incorporate various key clinical variables may facilitate an informed decision about the best management of SRM by more appropriately selecting treatment individualized to the characteristics of the SRM and the patient's clinical characteristics. PMID- 22487761 TI - Does renal mass ablation provide adequate long-term oncologic control? AB - Renal ablation (RA) is no longer used exclusively in patients with limited life expectancy. There are few studies reporting a minimum follow-up of 5 years. Biases and discrepancies within the literature are abundant. The outcomes of any series must be interpreted in the context of median follow-up time, reported tumor characteristics, ablation technique and training background of the practitioner, and the definition of tumor recurrence. The long-term oncologic efficacy of radiofrequency ablation (RFA) and cryoablation appear similar, although the percutaneous RFA technique may necessitate reablation in more cases. RA is associated with slightly higher rates of local recurrence compared to surgical excision. PMID- 22487762 TI - The influence of surgical approach to the renal mass on renal function. AB - The National Kidney Foundation estimates that 26 million Americans are living with chronic kidney disease (CKD). The high prevalence of obesity, heart disease, hypertension, and diabetes places millions more at risk for developing CKD. Although long-term sufficient renal function is routine in screened kidney donors, CKD is present in more than 30% of patients with a newly diagnosed renal mass and develops in most patients who undergo radical nephrectomy and a portion of those who undergo nephron-sparing approaches. Herein, the authors review the effect of the surgical approach on renal function for patients presenting with a renal mass. PMID- 22487763 TI - Partial nephrectomy: contemporary outcomes, candidate selection, and surgical approach. AB - Localized kidney cancer is ideally managed with surgical extirpation. Historically renal cell carcinoma has been treated with radical nephrectomy, but partial nephrectomy has become increasingly used because of a growing body of evidence demonstrating equivalent oncologic control and a potential benefit in overall survival. In this article, the authors demonstrate that partial nephrectomy carries excellent oncologic efficacy. They additionally review the growing indications for partial nephrectomy and factors influencing candidate selection. The authors also compare the relative outcomes of open and minimally invasive techniques. Several factors influence outcome, and surgeon experience should dictate the choice of technique. PMID- 22487764 TI - Integration of surgery and systemic therapy for renal cell carcinoma. AB - Proper integration of surgery and systemic therapy is essential for improving outcomes in renal cell carcinoma (RCC). There is no current role for adjuvant therapy after nephrectomy for clinically localized disease. The potential benefits of neoadjuvant therapy for locally advanced nonmetastatic disease are in need of further study. In metastatic disease, the proper integration of cytoreductive surgery and systemic therapy remains to be elucidated. Presurgical targeted therapy is feasible and may be beneficial. Pending the results of randomized controlled trials, upfront cytoreductive nephrectomy in appropriate patients will likely continue as the paradigm of choice in metastatic RCC. PMID- 22487765 TI - Defining an individualized treatment strategy for metastatic renal cancer. AB - Treatment of metastatic renal cell carcinoma (mRCC) has evolved dramatically within the past 10 years with the advent of therapy targeting the angiogenesis and mammalian target of rapamycin (mTOR) pathways. These therapies rapidly supplanted immunotherapy as a first-line systemic treatment option. Response rates, however, continue to vary, largely due to mRCC's clinical and molecular heterogeneity. This article reviews current understanding of mRCC biology and available treatments, discusses novel biomarkers that improve prognostication and may be able to predict response, and integrates available literature on surgical and systemic therapies into an individualized strategy. PMID- 22487766 TI - Foreword. Evolving treatment paradigms for renal cancer. PMID- 22487767 TI - Evolving treatment paradigms for renal cancer. PMID- 22487768 TI - Full-field optical coherence tomography: a new technology for 3D high-resolution skin imaging. AB - BACKGROUND/AIMS: Full-field optical coherence tomography (FFOCT) is a new imaging technology that can provide 3D micron-level resolution and is suited for high resolution imaging of biological tissue. The aim of this study was to evaluate its capacity and potential for imaging human epidermis and dermis and various skin pathologies in ex vivo and in vivo conditions. METHODS: Non-fixed and fixed samples of normal and pathological skin and normal in vivo skin were imaged with a FFOCT system and compared to histological slides. RESULTS: The epidermis and adnexae, the collagen bundles of the dermis and the hypodermis could be identified through architectural and cellular details. The pathological structures were distinguished from the normal structures and corresponded to their histopathological organization. CONCLUSION: FFOCT is a novel technology in the field of skin imaging that has the potential to be a relevant complement to existing non-invasive imaging modalities for clinical and cosmetic applications. PMID- 22487769 TI - kappa opioid regulation of anxiety-like behavior during acute ethanol withdrawal. AB - Withdrawal is one of the defining characteristics of alcohol dependence, and is often characterized by impaired physiological function and enhanced negative affect. Recent evidence suggests that the dynorphin (DYN)/kappa opioid receptor (KOR) system may be a key mediator in the negative affect often associated with drugs of abuse. The objective of the present experiments was to determine the role of the DYN/KOR system in the regulation of anxiety-related behavior during acute withdrawal from ethanol. Rats were fed an ethanol liquid diet and following removal, the ability of the KOR antagonist nor-BNI to attenuate the increased anxiogenic-like response characteristic of ethanol withdrawal was investigated using the elevated plus maze. A comparison study was also conducted examining anxiety-related behavior following direct activation of KORs via injections of the KOR agonist U50,488. Rats experiencing ethanol withdrawal showed a significant decrease in open arm exploration compared to controls, an effect that was blocked by nor-BNI. Similar decreases in open arm exploration were observed following injections with the KOR agonist, U50,488, an effect also reversed by pretreatment with nor-BNI. These results suggest that similar mechanisms are involved in the regulation of ethanol withdrawal- and KOR agonist-induced changes in behavior. Given the potential role of enhanced negative affect in persistent ethanol drinking, understanding the role of the DYN/KOR system in regulating anxiety associated with withdrawal may be critical in understanding the factors associated with the nature of alcohol dependence. PMID- 22487770 TI - Blockade of metabotropic glutamate receptors inhibits cognition and neurodegeneration in an MPTP-induced Parkinson's disease rat model. AB - Hyperactivity of the glutamatergic system is involved in excitotoxicity and neurodegeneration in Parkinson's disease (PD). Metabotropic glutamate receptor subtype 5 (mGluR5) modulates glutamatergic transmission and thus has been proposed as a potential target for neuroprotective drugs. The aim of this study was to determine the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), an mGluR5 antagonist, on working memory, object recognition, and neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats were stereotaxically injected with MPTP into the substantia nigra pars compacta (SNc). Starting 1 day after lesioning (day 1), the rats were treated daily with MPEP (2mg/kg/day, i.p.) for 14 days and rats underwent a T maze test on days 8-10 and an object recognition test on days 12-14. MPTP lesioned rats showed impairments of working memory in the T-maze test and of recognition function in the object recognition test and both effects were prevented by MPEP treatment. Furthermore, MPTP lesion-induced dopaminergic degeneration in the nigrostriatal system, microglial activation in the SNc, and cell loss in the hippocampal CA1 area were all inhibited by MPEP treatment. These data provide support for a role of mGluR5s in the pathophysiology of PD and suggest that MPEP is a promising pharmacological tool for the development of new treatments for dementia associated with PD. PMID- 22487772 TI - Decreased plasma methionine-enkephalin levels in cluster headache patients. AB - Results from a longitudinal study (blood drawn at days 29, 64, 89,124, 142, and 182 of the protocol) shows that the concentration of platelet-poor plasma (PPP) methionine(5)-enkephalin (MET) in healthy, drug-free, white male individuals (n = 5) remains within a relatively narrow range, well within the experimental error of the analytical procedures used. Interindividual differences fail to reach statistical significance [x +/- SD and range (MET picograms per mL of PPP) of 91.2 +/- 15.1, 67.1-113.5; 69.6 +/- 7.5, 66.1-90.1; 76.6 +/- 12.6, 58.5-93.1; 86.8 +/- 10.9, 76.3-107.4; and 84.5 +/- 11.4, 68.9-103.4; for subjects 1-5, respectively]. MET levels were similar to those recorded from single samples obtained from a group of 24 white male, age-comparable, drug-free healthy volunteers [x +/- SD and range (picograms of MET per mL of PPP) of 83.3 +/- 15.1 and 57.4-119.1]. The controls' range for all the subjects (n = 29) was 57.4-119.1 pgMET/mL PPP. Compared with the controls, individual patients with cluster headache (CH) show a much wider variation in PPP MET levels (blood drawn at different time intervals, at least 10 samples per patient, over a period of 221 298 days), with many (slightly over half) of single values below the controls range; no single MET level was above the controls range [x +/- SD and range (picograms of MET per mL of PPP) of 56.4 +/- 27.7, 6.1-100.5; 72.6 +/- 20.5, 43.0 113.0; 46.0 +/- 28.5, 10.0-92.6; 53.6 +/- 27.5, 13.0-101.0; 52.0 +/- 26.1, 17.5 83.6; 63.5 +/- 22.3, 21.7-91.3 for individuals A-F, respectively]. Although interindividual differences within the patients' group were not statistically significant, their peptide levels were significantly lower than those of controls. Neither the presence of unspecified "headaches between clinic visits" and "daily headaches" (patients E and F, respectively), nor the use of a number of drugs known to lack inhibitory activity upon the aminopeptidase-MET degradation reaction, seemed to significantly influence MET concentration. The results could lead to a better understanding of the etiology of the pain associated with CH, with the relative changes in plasma peptide perhaps reflecting the patients' vulnerability to such a condition. Pharmacological modulation of MET function may prove useful in the treatment of CH-associated pain, whether the development of such drugs could find useful pharmacological applications remains to be explored. PMID- 22487773 TI - Expanding the Evidence Base: Comparing Randomized Controlled Trials and Observational Studies of Statins. AB - It is widely accepted that randomized controlled trials (RCTs) are the gold standard for demonstrating the efficacy of a given therapy (results under ideal conditions). Observational studies, on the other hand, can complement this by demonstrating effectiveness (results under real-world conditions). To examine the role that observational studies can play in complementing data from RCTs, we reviewed published studies for statins, a class of drugs that have been widely used to reduce the risk of cardiovascular (CV) events by lowering low-density lipoprotein cholesterol levels. RCTs have consistently demonstrated the benefits of statin treatment in terms of CV risk reduction and have demonstrated that more intensive statin therapy has incremental benefits over less intensive treatment. Observational studies of statin use in 'real-world' populations have served to augment the evidence base generated from statin RCTs in preselected populations of patients who are often at high CV risk and have led to similar safety and efficacy findings. They have also raised questions about factors affecting medication adherence, under-treatment, switching between statins, and failure to reach low-density lipoprotein cholesterol target levels, questions for which the answers could lead to improved patient care. PMID- 22487771 TI - Differences in the locomotor-activating effects of indirect serotonin agonists in habituated and non-habituated rats. AB - The indirect serotonin (5-HT) agonist 3,4-methylenedioxymethamphetamine (MDMA) produces a distinct behavioral profile in rats consisting of locomotor hyperactivity, thigmotaxis, and decreased exploration. The indirect 5-HT agonist alpha-ethyltryptamine (AET) produces a similar behavioral profile. Using the Behavioral Pattern Monitor (BPM), the present investigation examined whether the effects of MDMA and AET are dependent on the novelty of the testing environment. These experiments were conducted in Sprague-Dawley rats housed on a reversed light cycle and tested during the dark phase of the light/dark cycle. We found that racemic MDMA (RS-MDMA; 3 mg/kg, SC) increased locomotor activity in rats tested in novel BPM chambers, but had no effect on locomotor activity in rats habituated to the BPM chambers immediately prior to testing. Likewise, AET (5 mg/kg, SC) increased locomotor activity in non-habituated animals but not in animals habituated to the test chambers. These results were unexpected because previous reports indicate that MDMA has robust locomotor-activating effects in habituated animals. To further examine the influence of habituation on MDMA induced locomotor activity, we conducted parametric studies with S-(+)-MDMA (the more active enantiomer) in habituated and non-habituated rats housed on a standard or reversed light cycle. Light cycle was included as a variable due to reported differences in sensitivity to serotonergic ligands during the dark and light phases. In confirmation of our initial studies, rats tested during the dark phase and habituated to the BPM did not show an S-(+)-MDMA (3 mg/kg, SC)-induced increase in locomotor activity, whereas non-habituated rats did. By contrast, in rats tested during the light phase, S-(+)-MDMA increased locomotor activity in both non-habituated and habituated rats, although the response in habituated animals was attenuated. The finding that habituation and light cycle interact to influence MDMA- and AET-induced hyperactivity demonstrates that there are previously unrecognized complexities associated with the behavioral effects of these drugs. PMID- 22487774 TI - The efficacy of rivaroxaban in patients with atrial fibrillation. AB - Atrial fibrillation (AF), the most common form of cardiac arrhythmia, is a major risk factor for cardioembolic stroke. Dose-adjusted warfarin has been the gold standard for stroke prophylaxis in moderate- to high-risk patients with AF. However, the use of warfarin therapy is greatly limited by its narrow therapeutic window, numerous dietary restrictions, and drug-drug interactions, and an increased risk of hemorrhage. As a result, great emphasis has been placed on developing a new anticoagulant agent with fewer risks and limitations. Current data suggest that the oral direct factor Xa inhibitor rivaroxaban is a safe and effective alternative to warfarin. Furthermore, rivaroxaban does not require routine coagulation monitoring, which may improve patient compliance to anticoagulant therapy. The ROCKET AF trial demonstrated that 20-mg oral rivaroxaban taken once daily was noninferior to dose-adjusted warfarin in the prevention of stroke and non-central nervous system systemic embolism and had a comparable risk of bleeding. Based primarily on the ROCKET AF trial results, the US Food and Drug Administration recently approved the use of rivaroxaban for stroke prophylaxis in patients with nonvalvular AF. However, additional postmarketing studies on its safety and cost effectiveness are needed before it can be widely accepted as a sound alternative to warfarin. PMID- 22487776 TI - Methicillin-resistant Staphylococcus infections. AB - Methicillin-resistant Staphylococcus aureus infection is currently the most common skin infection identified in human emergency rooms, and the development of methicillin resistance is increasing in veterinary medicine. This article reviews the current knowledge about methicillin-resistant Staphylococcus infections in human medicine as well as the limited information available in veterinary medicine, including options for diagnosis, treatment, and prevention. PMID- 22487775 TI - Diffuse lamellar keratitis after laser in situ keratomileusis with femtosecond laser flap creation. AB - PURPOSE: To identify possible associations with the development of diffuse lamellar keratitis (DLK) after laser in situ keratomileusis (LASIK) with femtosecond laser flap creation. SETTING: University-based academic practice, Ann Arbor, Michigan, USA. DESIGN: Case-control study. METHODS: Myopic LASIK was performed between October 2006 and December 2010 using an Intralase 60 kHz femtosecond laser for flap creation. Preoperative clinical characteristics, treatment parameters, and intraoperative and postoperative complications were recorded. Statistical comparisons were made using t, chi-square, and Fisher exact tests and repeated-measures logistic regression to adjust for inter-eye dependency. RESULTS: The study enrolled 801 eyes (419 patients). Ninety-nine eyes (12.4%) of 70 patients developed DLK; most cases comprised mild flap interface inflammation and were treated with a routine postoperative antiinflammatory regimen. Twenty-two eyes (2.7%) required more than 1 week of antiinflammatory treatment. There was a statistically significant increase in the incidence of DLK with larger flap diameter (P=.0171), higher side-cut energy (P=.0037), and higher raster energy (P=.0033). Patients with DLK were less likely to achieve corrected distance visual acuity of 20/20 or better 1 day postoperatively (P=.0453). The difference in acuity was no longer present at 1 week. There were no significant associations between the incidence of DLK and preoperative refractive error, flap thickness, ablation depth, or other treatment parameters. CONCLUSIONS: Diffuse lamellar keratitis after LASIK with femtosecond laser flap creation tended to be mild with little effect on visual acuity. Higher energy level for flap creation and larger flap diameter were associated with an increased risk for DLK. PMID- 22487777 TI - Equine laparoscopy: equipment and basic principles. AB - Laparoscopic techniques for veterinary surgery are growing in popularity for the same reason the use of minimally invasive procedures has increased tremendously in human surgery. Compared with open surgery, the benefits of laparoscopic surgery include smaller incisions, reduced postoperative morbidity and pain, shorter hospitalization, a more rapid return to normal activities, and, in some instances, superior access. Laparoscopic surgery is different from open surgery in equipment/instrumentation and psychomotor skills. This first article in a series on equine laparoscopic surgery introduces the necessary equipment and reviews basic techniques (e.g., triangulation, optimal coaxial alignment, ergonomics, instrument use) common to all procedures. PMID- 22487778 TI - Hyperbaric oxygen therapy. AB - Hyperbaric oxygen therapy (HBOT) is emerging in veterinary medicine as an effective treatment or adjunct therapy for a variety of disorders in which improving oxygen delivery to tissues is a priority. The primary mechanisms of action of HBOT are (1) immediate hyperoxygenation of plasma and tissues and (2) decreased gas bubble (air embolus) size. With each hyperbaric 'dive,' secondary physiologic effects are set into motion. This article provides an introduction to HBOT, as well as its benefits, potential indications, contraindications, complications, and future directions in small animal veterinary medicine. PMID- 22487779 TI - Promoter hypermethylation of Ras-related GTPase gene RRAD inactivates a tumor suppressor function in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is endemic in southern China. In a genome-wide screen for genes inactivated by promoter hypermethylation, we identified Ras related associated with diabetes (RRAD). Expression of RRAD was down-regulated in 83.3% (30/36) of the biopsies from NPC patients. RRAD was aberrantly methylated in 74.3% (26/35) of primary tumors, but not in normal nasopharyngeal epithelium. Ectopic RRAD expression in NPC cell lines inhibited the cell growth, colony formation, and cell migration. These results indicate that RRAD might act as a functional tumor suppressor and its epigenetic inactivation may play an important role in NPC development. PMID- 22487780 TI - Endovascular aortic aneurysm repair--still a failed experiment? PMID- 22487781 TI - Electromagnetic tracking for registration and navigation in endovascular aneurysm repair: a phantom study. AB - OBJECTIVE: To assess the feasibility of using an electromagnetic tracking for both registration and navigation in endovascular aneurysm repair. MATERIALS AND METHODS: A registration process was implemented to align computed tomography (CT) data and electromagnetic tracking data. Two abdominal aortic aneurysm (AAA) phantoms were used, a rigid plastic AAA model (phantom A) and a soft silicon AAA model (phantom B). A pre-procedural CT volume was acquired for each phantom. Intra-operative simulation was performed by placing each phantom in the magnetic field of the tracking device. Using a modified electromagnetic catheter, a set of three-dimensional positions was acquired in the phantom's aortic lumen. Pre procedural CT images and intra-procedural tracked positions were registered. Four reference points were used to calculate the registration accuracy of phantom A. Three surgeons simulated catheterisation of the left renal artery with phantom B using only image-guided procedure software. RESULTS: The mean registration error was 1.3 mm (range 0.88-1.89). The median time for left renal catheterisation was 22 s (range 15-59). CONCLUSION: Registration of CT data and electromagnetic tracking data is feasible using catheter positions in the aorto-iliac structure as landmark. This navigation system could reduce X-ray exposure time and the use of contrast medium injections. PMID- 22487782 TI - Association between plaque echogenicity and embolic material captured in filter during protected carotid angioplasty and stenting. AB - OBJECTIVES/DESIGN: The aim of the study was to investigate debris captured in filter embolic protection devices (EPDs) during carotid artery stenting (CAS) and its possible correlation with plaque echogenicity and other risk factors. MATERIALS/METHODS: Between June 2010 and March 2011, 51 consecutive CAS patients (11 females, mean age 71.2 +/- 7, 10 symptomatic) who underwent 53 procedures were included in this prospective study. Ultrasonographic Gray-Weale plaque type (I-V, echolucent to echogenic) characterisation was obtained in all cases. The same type of stent and filter EPD was used. Filters were collected and, after macroscopic evaluation, they were examined using the Thin-Prep((r)) liquid-based cytology (LBC) technique. RESULTS: Technical success was 100%. Thirty-day stroke and death rates were 1.8% (1/53) and 0%, respectively. Visible debris was detected in eight (15%) filters, whereas LBC revealed the presence of embolic material particles in 30 filters (56.6%). The presence of embolic material into the filter EPD was 2.38-fold increased for every category change from type IV to type I carotid plaques (OR = 2.38, 95%CI = 1.15-4.93). This association remained robust even after adjustment for age, gender and known atherosclerotic disease risk factors (OR = 2.26, 95%CI = 1.02-5.02). In multivariate analysis for risk factors, hypertension was associated with increased presence of embolic material detection in filter EPD (OR = 20.4, 95%CI = 1.28-326.1). The time distance from symptom to CAS was inversely correlated with debris quantity in EPD (Spearman rho -0.716; p = 0.02). CONCLUSIONS: Echolucent plaques, smaller time frame from last symptom and hypertension were associated with increased presence of embolic material. PMID- 22487783 TI - The burden associated with ocular symptoms in allergic rhinitis. AB - BACKGROUND: Ocular symptoms remain widely neglected while they concern the majority of subjects with allergic rhinitis (AR) and impair their daily activities. We describe the characteristics of ocular symptoms in subjects suffering from AR in the French INSTANT study and their impact on daily activities. METHODS: This cross-sectional observational survey was carried out in November 2006 using face-to-face interviews. RESULTS: 31.7% of the population based sample (n = 4,019) suffered from AR and 52.0% of AR subjects (n = 663) described ocular symptoms. Men had significantly less ocular symptoms than women (odds ratio 0.71, 95% CI 0.57-0.89). 57.5% of subjects suffered from ocular symptoms for >5 years, 30.2% for >6 months in the past 12 months, and 92.2% during the pollen season. The troublesome ocular symptoms were itching eyes (51.1%), watery eyes (38.6%), red eyes (6.6%) and swollen eyelids (3.6%). The trigger factors were pollens (51.3%), household dust and mites (34.8%), pets (12.2%) and air pollution (3.8%). Ocular symptoms had a negative impact on daily activities (blurred sight 47.8%, reduction in daily activities 38.8%, reduction in efficacy at work 25.8%, sleep disturbances 16.3%, and sick leave 12.9%). They were diagnosed in 38.9% of subjects and followed up in 34.8%. Treatment for ocular symptoms was prescribed to 35.4% of subjects and to 61.9% of subjects with a regular follow-up care. CONCLUSIONS: This survey confirms the impact of ocular symptoms on AR patients' lives and suggests that they are still neglected and undertreated. PMID- 22487784 TI - Myasthenia, spondylitis and Enterococcus faecalis endocarditis. AB - Parasympathomimetics, immunosuppression and plasmapheresis have considerably improved management and prognosis of myasthenia gravis. Side effects of these measures, however, may complicate the course of the disease. In a 66-year-old male with myasthenia gravis and lower back pain, blood cultures, echocardiography and magnetic resonance imaging led to the diagnosis of endocarditis and spondylodiscitis. Enterococcus faecalis grew in the blood cultures as well as on the aortic and tricuspid valve vegetations which were resected during cardiac surgery. Possible sources of the infection might be E. faecalis infections of catheter tips during a 46-day stay in the intensive care unit 11 months earlier where he had undergone plasmapheresis, hemodiafiltration and mechanical ventilation, or recurrent diarrheas since 18 months. Infection was favored by immunosuppression with glucocorticoids and azathioprine which received the patient because of myasthenia gravis and hypothyroidism. Patients with myasthenia gravis require close follow up, including infection parameters, especially when they receive immunosuppressive therapy and when microorganisms known to cause endocarditis, are identified. PMID- 22487785 TI - Aminopyridine treatment in a patient with bilateral vestibular failure and cryptogenic downbeat nystagmus. PMID- 22487786 TI - Surgical options for the allergic rhinitis patient. AB - PURPOSE OF REVIEW: Allergic rhinitis is a very common disorder that affects millions of patients annually and the hallmark complaint of nasal obstruction significantly impacts the quality of life. Many surgical options exist for the treatment of allergic rhinitis, directed primarily at the underlying nasal obstructive component. The purpose of this review is to highlight and discuss the various surgical modalities and their historical efficacy. RECENT FINDINGS: Much of the literature has focused on reduction of the inferior turbinate for symptomatic improvement in patients afflicted with allergic rhinitis. Endoscopic sinus surgery and septoplasty play little role in the management of allergic rhinitis, unless when seen in conjunction with other conditions such as rhinosinusitis. SUMMARY: Although no single modality has evolved as the gold standard for the treatment of allergic rhinitis, the mainstay of surgical intervention targets the inferior turbinate. It is very important for the otolaryngologist to be familiar with an armamentarium of surgical techniques. PMID- 22487787 TI - Practical clinical management strategies for the allergic patient with chronic rhinosinusitis. AB - PURPOSE OF REVIEW: Allergic rhinitis often coexists with chronic rhinosinusitis (CRS). The purpose of this review is to provide a practical algorithm for the treatment of patients with allergic rhinitis and CRS. RECENT FINDINGS: Despite conflicting literature on the causative association of allergic rhinitis with CRS, recent research shows a higher incidence of allergic rhinitis in CRS patients refractory to medical therapy. Local IgE is hypothesized to play a role in the inflammation characteristic of both disorders, even in patients who test negative for inhalant allergies. SUMMARY: As allergic rhinitis and CRS symptoms overlap, medications appropriate for one disorder may also be appropriate for the other. The exception would be allergen immunotherapy in the absence of allergy and antibiotics in the absence of infection. Given these principles, we have developed and provide a personalized management strategy for patients with symptoms of allergic rhinitis and CRS based on the individual's response to therapy. PMID- 22487788 TI - Beyond voice: perceptions of gender in male-to-female transsexuals. AB - PURPOSE OF REVIEW: This review covers recent research findings that demonstrate the effectiveness of speech pathology intervention in enabling male-to-female transsexual individuals to portray their gender identity through speech. Research reports that extend our understanding of communication characteristics that contribute to perceptions of sex in male-to-female transsexuals are identified. Current issues related to the measurement of therapy effectiveness are also presented. RECENT FINDINGS: Earlier studies confirmed that an increase in voice pitch is achievable for many transsexuals. However, it is now accepted that pitch is not the sole contributor to perceptions of gender. Recently, modification of vocal resonance has been shown to increase perceptions of a speaker as female. There is evidence that encouraging precise articulation results in increased perceptions of the speaker as female. Evidence for the contribution of voice quality and loudness to perceptions of gender is inconclusive. Speech rate does not appear to contribute significantly to gender perceptions.Ecologically valid measures of the individual's vocal functioning and its impact on everyday life in clinical assessment of male-to-female transsexuals are needed to provide meaningful measures of therapy outcome. SUMMARY: There continues to be a need for ongoing research into communication characteristics that contribute to perceptions of gender. It is essential to include the perspective of the individual when evaluating therapy outcome. PMID- 22487789 TI - Environmental pollutants and allergic rhinitis. AB - PURPOSE OF REVIEW: To review the current knowledge of the pathophysiology, epidemiology, and management of environmental pollutants and allergic rhinitis. RECENT FINDINGS: Both active cigarette smoking and passive exposure to cigarette smoke are associated with chronic rhinitis and sinusitis. Matrix metalloproteinase 9, which is thought to contribute to the pathophysiology of allergy, is elevated in children with passive cigarette smoke exposure compared with controls. Ground-level ozone and particulate matter exposure is associated with an allergic-type response and may increase sensitization to other allergens. Certain occupational exposures can cause nasal irritation and local cytotoxic effects. Evidence suggests that rhinitis symptomatology may often precede the development of occupational asthma. SUMMARY: Environmental factors have been noted to induce sinonasal mucosal irritation and often contribute to the multifactorial cause of chronic rhinitis and allergic rhinitis. Cigarette smoke is a common irritant that impacts the innate immune function of the sinonasal epithelial cells, and creates local irritation and cytotoxic effects. Both active smoking and exposure to second-hand smoke increase the risk of chronic rhinitis. Many other environmental pollutants are associated with chronic rhinitis, including ozone, particulate matter, and occupational irritants. The management of chronic rhinitis associated with environmental exposures is similar to the management of other types of chronic rhinitis. Although often not feasible, avoidance is probably the most effective course. PMID- 22487790 TI - 'Otolaryngic allergy in a changing environment'. PMID- 22487791 TI - The management of drooling in adults with neurological conditions. AB - PURPOSE OF REVIEW: Drooling is a distressing symptom for adults with neurological conditions and can be challenging for health professionals. This review will consider the physical and psychosocial impact of drooling and will discuss the current management options including behavioural, pharmacological and surgical approaches. RECENT FINDINGS: A number of studies describe the use of botulinum toxin injections and irradiation of the salivary glands but no conclusive guidelines exist to recommend the most efficient dose or technique. The majority of saliva management studies focus on children with physical and/or cognitive disabilities and this evidence cannot be generalized to adults. There are relatively few studies that focus on saliva management in the adult neurological population. SUMMARY: Drooling is distressing for patients and their families. Ideally an individual would have easy access to the most efficient treatment with the fewest side effects. More evidence is now available but a lack of consensus on management approach, treatment dose and administration technique still exists. The symptom of drooling is best managed by a multidisciplinary team, starting with a conservative approach and then leading to more invasive procedures as appropriate. PMID- 22487792 TI - N-n-Butyl haloperidol iodide inhibits the augmented Na+/Ca2+ exchanger currents and L-type Ca2+ current induced by hypoxia/reoxygenation or H2O2 in cardiomyocytes. AB - N-n-butyl haloperidol iodide (F(2)), a novel quaternary ammonium salt derivative of haloperidol, was reported to antagonize myocardial ischemia/reperfusion injuries. To investigate its mechanisms, we characterized the effects of F(2) on Na(+)/Ca(2+) exchanger currents (I(NCX)) and the L-type Ca(2+) channel current (I(Ca,L)) of cardiomyocytes during either hypoxia/reoxygenation or exposure to H(2)O(2). Using whole-cell patch-clamp techniques, the I(NCX) and I(Ca,L) were recorded from isolated rat ventricular myocytes. Exposure of cardiomyocytes to hypoxia/reoxygenation or H(2)O(2) enhanced the amplitude of the inward and outward of I(NCX) and I(Ca,L). F(2) especially inhibited the outward current of Na(+)/Ca(2+) exchanger, as well as the I(Ca,L), in a concentration-dependent manner. F(2) inhibits cardiomyocyte I(NCX) and I(Ca,L) after exposure to hypoxia/reoxygenation or H(2)O(2) to antagonize myocardial ischemia/reperfusion injury by inhibiting Ca(2+) overload. PMID- 22487793 TI - Analysis of gene expression levels in individual bacterial cells without image segmentation. AB - Studies of stochasticity in gene expression typically make use of fluorescent protein reporters, which permit the measurement of expression levels within individual cells by fluorescence microscopy. Analysis of such microscopy images is almost invariably based on a segmentation algorithm, where the image of a cell or cluster is analyzed mathematically to delineate individual cell boundaries. However segmentation can be ineffective for studying bacterial cells or clusters, especially at lower magnification, where outlines of individual cells are poorly resolved. Here we demonstrate an alternative method for analyzing such images without segmentation. The method employs a comparison between the pixel brightness in phase contrast vs fluorescence microscopy images. By fitting the correlation between phase contrast and fluorescence intensity to a physical model, we obtain well-defined estimates for the different levels of gene expression that are present in the cell or cluster. The method reveals the boundaries of the individual cells, even if the source images lack the resolution to show these boundaries clearly. PMID- 22487794 TI - Selective death of cancer cells by preferential induction of reactive oxygen species in response to (-)-epigallocatechin-3-gallate. AB - (-)-Epigallocatechin-3-gallate (EGCG) induces apoptosis in cancer cells without adversely affecting normal cells. Understanding the cancer-specific cytotoxic activity of EGCG is very important in defining the mechanism of tumorigenesis and identifying superb chemotherapeutic agents against cancer. We comparatively assayed human telomerase reverse transcriptase (hTERT)-mediated apoptosis by EGCG induced reactive oxygen species (ROS) in normal cells and cancer cells. EGCG showed differential levels of ROS induction between the cell types; ROS, especially hydrogen peroxide, was highly induced in cancer cells, while it was not in normal cells. In addition, the higher level of ROS down-regulated hTERT via binding of CCCTC binding factor (CTCF) to the core promoter region of hTERT, which repressed hTERT expression. CTCF binding was epigenetically controlled by the demethylation of the previously hypermethylated site for CTCF, which was induced by down-regulation of DNA methyltransferase 1 (DNMT1). In contrast, hTERT down-regulation was not observed in normal cells. These results suggest that preferential death of cancer cells by EGCG could be caused by the cancer-specific induction of ROS and epigenetic modulation of expression of apoptosis-related genes, such as hTERT. PMID- 22487795 TI - Depletion of mitochondrial fission factor DRP1 causes increased apoptosis in human colon cancer cells. AB - Mitochondria play a critical role in regulation of apoptosis, a form of programmed cell death, by releasing apoptogenic factors including cytochrome c. Growing evidence suggests that dynamic changes in mitochondrial morphology are involved in cellular apoptotic response. However, whether DRP1-mediated mitochondrial fission is required for induction of apoptosis remains speculative. Here, we show that siRNA-mediated DRP1 knockdown promoted accumulation of elongated mitochondria in HCT116 and SW480 human colon cancer cells. Surprisingly, DRP1 down-regulation led to decreased proliferation and increased apoptosis of these cells. A higher rate of cytochrome c release and reductions in mitochondrial membrane potential were also revealed in DRP1-depleted cells. Taken together, our present findings suggest that mitochondrial fission factor DRP1 inhibits colon cancer cell apoptosis through the regulation of cytochrome c release and mitochondrial membrane integrity. PMID- 22487796 TI - Genetics of spondyloarthritis--beyond the MHC. AB - Ankylosing spondylitis (AS), psoriasis and inflammatory bowel disease (IBD) often coexist in the same patient and in their families. In AS, genes within the MHC region, in particular HLA-B27, account for nearly 25% of disease hereditability, with additional small contributions from genes outside of the MHC locus, including those involved in intracellular antigen processing (that is, ERAP1, which interacts with HLA-B27) and cytokine genes such as those involved in the IL 17-IL-23 pathway. Similar to AS, the strongest genetic signal of susceptibility to psoriasis and psoriatic arthritis also emanates from the MHC region (attributable mostly to HLA-C(*)06:02 although other genes have been implicated), and gene-gene interaction of HLA-C with ERAP1. The remaining hereditary load is from genes involved in cytokine production, specifically genes in the IL-17-IL-23 pathway, the NFkappaB pathway and the type 2 T-helper pathway. In IBD, similar genetic influences are operative. Indeed, genes important in the regulation of the IL-17-IL-23 pathway and, in Crohn's disease, genes important for autophagy (that is, NOD2 and ATG16L1 and IRGM) have a role in conferring susceptibility of individuals to these diseases. Thus, AS, psoriasis and IBD seem to share similar pathogenic mechanisms of aberrant intracellular antigen processing or elimination of intracellular bacteria and cytokine production, especially in the IL-17-IL-23 pathway. PMID- 22487797 TI - Referral strategies for early diagnosis of axial spondyloarthritis. AB - The spectrum of HLA-B27-associated inflammatory spine diseases is referred to as axial spondyloarthritis (axSpA). AxSpA encompasses established ankylosing spondylitis (AS) but also nonradiographic axSpA, and can be classified according to the Assessment of SpondyloArthritis international Society classification criteria for axSpA. Specific and effective therapy for axSpA includes education, physiotherapy, NSAIDs and biologic agents, as appropriate. Patients with axSpA, however, are often diagnosed late in the course of the disease. As specific therapy is available, the effective identification of those individuals who are likely to have axSpA among patients with chronic back pain in primary care and their subsequent referral to a rheumatologist for establishing a correct diagnosis is worth pursuing. Candidate referral parameters that can easily be applied to patients with chronic back pain and age at onset <= 45 years (the target population) include inflammatory back pain (IBP) and positivity for HLA B27. Following diagnostic work-up by a rheumatologist, these referral parameters, either alone or in combination, have led to the diagnosis of as many as 33-45% of patients within this target population with axSpA, 41-62% of whom had undiagnosed AS. Thus, educating primary care physicians on the value of IBP and HLA-B27 testing within this target population, and referral to a rheumatologist if one of these parameters is positive, is a promising approach to reduce the long delay in diagnosing patients with axSpA. PMID- 22487799 TI - Spondyloarthritis: Evidence from animal studies supports the 'entheseal stress' hypothesis of ankylosing spondylitis. PMID- 22487800 TI - Bone: Safer glucocorticoid therapy--Bax to the future? PMID- 22487798 TI - Developments in therapies for spondyloarthritis. AB - First-line therapy for spondyloarthritis (SpA) has not yet altered in the wake of new classification criteria; NSAIDs and physical therapy are recommended. Anti TNF agents can be used when NSAIDs fail, but their efficacy has potentially been limited in previous trials by inclusion criteria requiring the presence of established, active disease. Now, not only patients with axial SpA (axSpA) with radiographic signs of sacroiliitis (that is, with ankylosing spondylitis), but also patients in whom structural damage is not-yet-visible radiographically (non radiographic axSpA) can be included in trials of therapy for axSpA. TNF blockers, it seems already, are at least similarly effective in patients with non radiographic axSpA as in those with established AS. Short symptom duration and a positive C-reactive protein test at baseline are currently the best predictors for a good response to TNF-blocking agents. Biologic agents besides anti-TNF therapies have so far failed in the treatment of axSpA. New bone formation seems currently to be best prevented by NSAIDs, not by TNF blockers. Whether earlier effective treatment of bony inflammation with anti-TNF therapy will be able to prevent ossification at a later stage has yet to be determined. New classification criteria for peripheral SpA will also allow treatment trials to be conducted more systematically than has previously been possible in this subgroup of patients. PMID- 22487802 TI - Surgical management and clinical prognosis of adrenocortical carcinoma. AB - OBJECTIVE: To study the relationship between surgical management and prognosis of adrenocortical carcinoma (ACC) in order to guide the surgical management of ACC. METHODS: Clinical data of 45 cases of ACC treated in our hospital were retrospectively analyzed. The 45 cases included 3 cases in stage I, 12 cases in stage II, 7 cases in stage III, and 23 cases in stage IV. 17 cases underwent complete excision, 14 cases underwent palliative excision, 8 cases had non operative treatment and 6 cases gave up treatment. All patients were followed up from 2 to 141 months. RESULTS: The average survival time of 31 patients with surgery was 32.46 months, and the average survival time of 14 patients without surgery was 4.75 months. There were statistically significant differences between the two groups (p < 0.01). There were no statistically significant differences between the two groups in survival time in stage III and stage IV (p > 0.05). CONCLUSIONS: Surgery is considered to be the only method to cure ACC. For ACC in stage I and II, tumor resection is the most effective treatment, and second surgical operation is recommended for local recurrence. For ACC in stage III, extensive surgical operation is recommended, and for ACC in stage IV, surgical operation has no effect on the prognosis. PMID- 22487801 TI - New advances in juvenile spondyloarthritis. AB - Juvenile spondyloarthritis (SpA) is a distinct disease to adult SpA, and usually manifests as peripheral arthritis and enthesitis. Importantly, many patients with juvenile SpA continue to be at risk of developing ankylosing spondylitis during their disease course. In this Review, the classification and diagnostic criteria, clinical manifestations and treatment guidelines for juvenile SpA will be discussed. Advances in the diagnosis of and management strategies for juvenile SpA will lead to earlier recognition, appropriate treatment and improved rates of inactive disease, which should lead to improved patient outcomes and quality of life. PMID- 22487803 TI - TT-301 inhibits microglial activation and improves outcome after central nervous system injury in adult mice. AB - BACKGROUND: Microglial inhibition may reduce secondary tissue injury and improve functional outcome following acute brain injury. Utilizing clinically relevant murine models of traumatic brain injury and intracerebral hemorrhage, neuroinflammatory responses and functional outcome were examined in the presence of a potential microglial inhibitor, TT-301. METHODS: TT-301 or saline was administered following traumatic brain injury or intracerebral hemorrhage, and then for four subsequent days. The effect of TT-301 on neuroinflammatory responses and neuronal viability was assessed, as well as short-term vestibulomotor deficit (Rotorod) and long-term neurocognitive impairment (Morris water maze). Finally differential gene expression profiles of mice treated with TT-301 were compared with those of vehicle. RESULTS: Reduction in F4/80+ staining was demonstrated at 1 and 10 days, but not 28 days, after injury in mice treated with TT-301 (n = 6). These histologic findings were associated with improved neurologic function as assessed by Rotorod, which improved by 52.7% in the treated group by day 7, and Morris water maze latencies, which improved by 232.5% as a function of treatment (n = 12; P < 0.05). Similar benefit was demonstrated following intracerebral hemorrhage, in which treatment with TT-301 was associated with functional neurologic improvement of 39.6% improvement in Rotorod and a reduction in cerebral edema that was independent of hematoma volume (n = 12; P < 0.05). Differential gene expression was evaluated following treatment with TT 301, and hierarchical cluster analysis implicated involvement of the Janus kinase Signal Transducer and Activator of Transcription pathway after administration of TT-301 (n = 3/group). CONCLUSIONS: Modulation of neuroinflammatory responses through TT-301 administration improved histologic and functional parameters in murine models of acute neurologic injury. PMID- 22487804 TI - Difficult tracheal intubation: looking to the past to determine the future. PMID- 22487805 TI - Awake fiberoptic or awake video laryngoscopic tracheal intubation in patients with anticipated difficult airway management: a randomized clinical trial. AB - BACKGROUND: Awake flexible fiberoptic intubation (FFI) is the gold standard for management of anticipated difficult tracheal intubation. The purpose of this study was to compare awake FFI to awake McGrath(r) video laryngoscope, (MVL), (Aircraft Medical, Edinburgh, Scotland, United Kingdom) intubation in patients with an anticipated difficult intubation. The authors examined the hypothesis that MVL intubation would be faster than FFI. METHODS: Ninety-three adult patients with anticipated difficult intubation were randomly allocated to awake FFI or awake MVL, patients were given glycopyrrolate, nasal oxygen, topical lidocaine orally, and a transtracheal injection of 100 mg lidocaine. Remifentanil infusion was administered intravenously to a Ramsay sedation score of 2-4. Time to tracheal intubation was recorded by independent assessors. The authors also recorded intubation success on the first attempt, investigators' evaluation of ease of the technique, and patients reported intubation-discomfort evaluated on a visual analog scale. RESULTS: Eighty-four patients were eligible for analysis. Time to tracheal intubation was median [interquartile range, IQR] 80 s [IQR 58 117] with FFI and 62 s [IQR 55-109] with MVL (P = 0.17). Intubation success on the first attempt was 79% versus 71% for FFI and MVL, respectively. The median visual analog scale score for ease of intubation was 2 (IQR 1-4) versus 1 (IQR 1 6) for FFI and MVL, respectively. The median visual analog scale score for patients' assessment of discomfort for both techniques was 2, FFI (IQR 0-3), MVL (IQR 0-4). CONCLUSIONS: The authors found no difference in time to tracheal intubation between awake FFI and awake MVL intubation performed by experienced anesthesiologists in patients with anticipated difficult airway. PMID- 22487806 TI - Arthroscopic electrothermal capsulorrhaphy for the treatment of recurrent temporomandibular joint dislocation. AB - Acute temporomandibular joint dislocation is a common occurrence that is generally treated by conservative therapy. In some patients, this can become a chronic recurrent condition. This recurrent temporomandibular joint dislocation (RTD) can significantly decrease the patient's quality of life and require some form of surgical intervention for correction. The purpose of this study is to present a minimally invasive alternative treatment for RTD using operative arthroscopy. 11 patients treated for recurrent temporomandibular dislocation between 2004 and 2010 were retrospectively analyzed. Electrothermal capsulorrhaphy was performed using a standard double puncture operative arthroscopy with a Hol:YAG laser and/or electrocautery. Postoperatively the patients were monitored for 6 months to 6 years. Of the 11 subjects, 2 suffered a recurrence of temporomandibular dislocation and required open arthrotomy for correction. The other 9 patients had no signs of recurrence or any significant postoperative loss of function. Electrothermal capsulorrhaphy is an effective and minimally invasive method for the treatment of RTD. PMID- 22487807 TI - The influence of pore size on osteoblast phenotype expression in cultures grown on porous titanium. AB - This study investigated the effect of pore size on osteoblastic phenotype development in cultures grown on porous titanium (Ti). Porous Ti discs with three different pore sizes, 312 MUm (Ti 312), 130 MUm (Ti 130) and 62 MUm (Ti 62) were fabricated using a powder metallurgy process. Osteoblastic cells obtained from human alveolar bone were cultured on porous Ti samples for periods of up to 14 days. Cell proliferation was affected by pore size at day 3 (p=0.0010), day 7 (p=0.0005) and day 10 (p=0.0090) in the following way: Ti 62C (p.L366P) missense mutation, which resulted in a compound heterozygote status. CONCLUSION: The fetus was diagnosed with Morquio A syndrome and a genotype similar to the proband. Termination of the pregnancy was recommended. Combined ARMS, DHPLC and DNA sequencing are effective for rapid and accurate prenatal diagnosis for fetus with a high risk for Morquio A syndrome. Such methods are particularly suitable for early diagnosis when pathogenesis is clear. Furthermore, combined ARMS and DHPLC are suitable for rapid processing of large numbers of samples for the identification of new mutations. PMID- 22487818 TI - [Correlation between RARbeta gene promoter methylation and P53 gene mutations in non-small cell lung cancer]. AB - OBJECTIVE: To investigate the correlation between RARbeta gene promoter methylation and P53 gene mutations in non-small cell lung cancer (NSCLC). METHODS: Promoter methylation of RARbeta and P53 mutations of exons 5 through 9 in 198 resected primary NSCLC tissues were determined by methylation-specific PCR and direct sequencing. RESULTS: RARbeta gene promoter methylation and P53 mutation were detected in 58.1% and 36.4% of tumors, respectively. Both were higher in males than in females and in smokers than in nonsmokers. A higher prevalence of RARbeta promoter methylation was found in patients with advanced stage tumors than those with TNM stage I. P53 gene mutations were more frequent in squamous cell carcinoma and adeno-squamous carcinoma than adenocarcinoma. All such differences were statistically significant (P< 0.05). Frequencies of P53 mutations, including G:C>T:A mutations, transversions and missense mutations were significantly higher in tumors with RARbeta methylation than in those without (P< 0.05). A significantly higher prevalence of RARbeta methylation was found in tumors with only G:C>T:A mutation in P53 gene than those without P53 mutations (P< 0.05). This difference (OR=3.737, 95%CI: 1.414-9.873) was still statistically significant (P< 0.05) in smokers (OR=4.020, 95%CI: 1.263-12.800), squamous cell carcinomas (OR=5.480, 95%CI: 1.400-21.446) or patients with advanced tumors (OR=3.446, 95%CI: 1.054-11.267) after adjusting for age and sex. CONCLUSION: RARbeta methylation is associated with G:C>T:A mutations in P53 gene in NSCLC. PMID- 22487819 TI - [Clinical and molecular cytogenetic studies of a case of B-lineage acute lymphoblastic leukemia with t(14;14)(q11;q32)]. AB - OBJECTIVE: To report on a rare case of B-lineage acute lymphoblastic leukemia (B ALL) with t(14;14) (q11;q32) and clarify its clinical and molecular cytogenetic features. METHODS: Clinical data of a B-ALL patient with t(14;14) (q11;q32) were analyzed. After 24 hour of unstimulated culturing, chromosome specimens of bone marrow cells were prepared with regular method, and R-banding was used for karyotype analysis. Fluorescence in situ hybridization (FISH) analysis was performed on fixed bone marrow cells using IGH dual-color break-apart probe, CEBPE dual-color break-apart probe, whole chromosome paint (WCP) probe for chromosome 4, and Chromoprobe Multiprobe-ALL System probe. RESULTS: The 39-year old female was diagnosed with B-ALL based on morphologic and immunophenotypic analyses. Conventional cytogenetic analysis showed a karyotype of 47, XX, +4, t(14;14) (q11;q32) [20], which was confirmed by FISH analysis. FISH using IGH dual-color break-apart probe confirmed involvement of IGH gene in t(14;14) (q11;q32), and FISH using CEBPE dual-color break-apart probe indicated that CEBPE is the partner gene involved in t(14;14) (q11; q32). The patient achieved complete remission (CR) after a round of combined chemotherapy. At the time of follow-up, she had remained CR for more than 6 months. CONCLUSION: t(14;14) (q11;q32) simultaneously involving IGH and CEBPE genes in B-ALL is a rare but recurrent genetic abnormality that may identify a new subgroup of B-ALL. In B-ALL patients, t(14; 14) (q11; q32) involving IGH/CEBPE translocation may indicate a better prognosis. PMID- 22487820 TI - [Identification of a mutation in exon 4 of apolipoprotein E gene in a family affected with lipoprotein glomerulopathy]. AB - OBJECTIVE: To identify potential mutation of apolipoprotein E (apoE) gene in a male patient affected with lipoprotein glomerulopathy (LPG), his mother and his sister. METHODS: The patient and his mother both had histologically confirmed LPG. His sister and his father were asymptomatic. Genomic DNA was extracted from peripheral blood samples. PCR products of the coding region of exons 3 and 4 of the apoE gene were cloned into a pTA2 vector and sequenced. Genetic variations of the apoE gene were detected using PCR and restriction fragment length polymorphism (RFLP). RESULTS: An apoE gene mutation was identified in the patient's family. Sequence analysis confirmed a 9-bp deletion in the exon 4 of apoE gene from nt 484 to 492. The 9-bp deletion resulted in loss of 3 amino acids at positions 143-145. The sister of the propositus carried the same mutation, though she had neither proteinuria nor elevated plasma apoE. Sequence analysis of exon 3 showed no abnormality. No abnormalities were found in the father's apoE gene sequence. Analysis of genetic variations of the apoE gene by PCR and RFLP confirmed a 57 bp fragment consistent with the 9-bp deletion in exon 4. The father had a normal epsilon 3 epsilon 3 genotype. CONCLUSION: The 9 bp deletion of apoE may be associated with the pathogenesis of LPG. PMID- 22487821 TI - [Mutation analysis of pathogenic genes in a Henan family affected with congenital stationary night blindness]. AB - OBJECTIVE: To detect genetic mutations associated with autosomal dominant congenital stationary night blindness (ADCSNB) in a family from Henan province. METHODS: Genomic DNA was extracted from peripheral blood samples of 14 family members. Based on 3 genes reported previously, PCR primers were designed and corresponding exons containing the mutation sites were amplified with PCR. PCR products were purified and directly sequenced. RESULTS: A c.281C>T heterozygous missense mutation was detected in RHO gene in all of the patients. This mutation can cause a change of the protein structure (p.Thr94Ile). The same mutation was not detected in normal individuals from the family and 50 normal controls. CONCLUSION: A c.281C>T mutation in RHO gene is responsible for the onset of ADCSNB in this Chinese family and results in symptoms of night blindness. PMID- 22487822 TI - [Association between polymorphism of IRF6 rs2235371 locus and nonsyndromic cleft lip with or without cleft palate]. AB - OBJECTIVE: To assess the association between polymorphism of interferon regulatory factor 6 (IRF6) gene rs2235371 locus and nonsyndromic cleft lip with or without cleft palate in Chinese population. METHODS: Blood samples from 106 patients and their parents and 129 controls and their parents were collected. The polymorphism of IRF6 rs2235371 locus was determined with PCR-restriction fragment length polymorphism (PCR-RFLP) method. Case-control analysis, transmission disequilibrium test(TDT), haplotype-based haplotype relative risk analysis (HHRR) and family-based association test (FBAT) were carried out. RESULTS: By case control analysis, no significant difference was found in the frequencies of GG, GA and AA genotypes of rs2235371 locus between the patient group and control group (P> 0.05), but there was a significant difference in allelic frequencies (P< 0.05). There was also a significant difference in genotype and gene frequencies of rs2235371 variant between family members from cleft lip only group and control group. However, in cleft lip with cleft palate group, no such difference was observed. TDT analysis suggested a linkage in the presence of disequilibrium (chi-square=5.56, P=0.024). Results of HHRR analysis (chi square=5.115, P=0.024) and FBAT (Z=2.218, P=0.027) also indicated an association between IRF6 rs2235371 variant and the risk of NSCL with or without cleft palate. CONCLUSION: Genetic polymorphism of IRF6 gene rs2235371 locus is associated with NSCL with or without cleft palate. PMID- 22487823 TI - [Association study of brain-derived neurotrophic factor Val66Met polymorphism and clinical characteristics of first episode schizophrenia]. AB - OBJECTIVE: To assess the association between brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism and clinical characteristics of first episode schizophrenia in a Chinese Han population. METHODS: Genotyping of BDNF Val66Met polymorphism was carried out for 135 schizophrenic patients and 483 healthy controls with TaqMan probe technology. The patients' psychotic symptoms were assessed using the positive and negative syndrome scale (PANSS). RESULTS: A significant difference was found in genotype distribution and allelic frequency of the Val66Met polymorphism between the two groups (P< 0.01). In patients, Met homozygotes had a significantly higher score in anxiety/depression factor, cognitive factor and total score of PANSS than Val carriers. CONCLUSION: BDNF gene Val66Met polymorphism is associated with the pathogenesis of schizophrenia. The Met/Met genotype of BDNF Val66Met variant may be a risk factor for symptoms in first episode schizophrenia patients. PMID- 22487824 TI - [Expression of RAS protein in glioma and its effect on the growth of human glioma cells]. AB - OBJECTIVE: To study the expression of RAS protein in human glioma tissues and its influence on tumor growth. METHODS: RAS protein expression in glioma tissues was determined by immunohistochemical (IHC) staining. Subsequently, MTT cell proliferation assay, flow cytometry and Western blotting were used to assay U251 cells with reduced RAS expression. RESULTS: The expression of RAS in glioma was increased and strongly correlated with pathological grade. Downregulation of RAS resulted in glioma cells growth suppression and increased apoptosis. CONCLUSION: The expression level of RAS protein in human glioma was increased. Downregulation of RAS can inhibit glioblastoma cell growth through the RAS signal pathway. PMID- 22487825 TI - [Establishment of a rapid and easy method for simultaneous detection of FLT3-ITD and NPM1 gene mutations in acute myeloid leukemia]. AB - OBJECTIVE: To establish a stable, rapid multiplex PCR assay combined with PAGE gel electrophoresis for simultaneously detecting FLT3-ITD and NPM1 mutations in acute myeloid leukemia (AML). METHODS: Capillary electrophoresis (CE) and PAGE gel electrophoresis were simultaneously used to analyze FLT3-ITD and NPM1 mutations in 117 de novo AML patients with normal cytogenetic findings. RESULTS: For certain mutations, the length of mutated double-stranded DNA is longer than wild-type DNA. Since FLT3-mut (420 bp) is longer than FLT3-wt (327-332 bp), and NPM1-mut (172 bp) is longer than NPM1-wt (168 bp), heteroduplex will move more slowly during PAGE gel electrophoresis than homoduplex. Therefore the mutations may be detected. A total of 117 CN-AML patients were analyzed with CE and PAGE gel electrophoresis, and the results were identical, which included 18 (15.4%) patients with FLT3-ITD+/NPM1-, 19 (16.2%) patients with FLT3-ITD+/NPM1+, 25 (21.4%) patients with FLT3-ITD-/NPM1+, and 55 (47.0%) patients with FLT3-ITD /NPM1-. CONCLUSION: Both types of electrophoresis assays may provide a rapid and handy assay for simultaneous detection of FLT3-ITD and NPM1 mutations. CE is relatively sensitive, stable; while PAGE electrophoresis is relatively simple, cheap, and reliable, which may be suitable for primary hospitals and preliminary screening. PMID- 22487826 TI - [Utilization of high-resolution melting analysis to screen patients with neonatal intrahepatic cholestasis caused by citrin deficiency]. AB - OBJECTIVE: To assess the feasibility of high-resolution melting (HRM) analysis for screening patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). METHODS: Based on previous studies on SLC25A13 gene in Chinese patients with NICCD, four hotspot mutations (851del4, 1638ins23, IVS6+5G>A and IVS16ins3kb) were selected. Results of the HRM analysis was validated using 50 negative controls and 20 patients with NICCD whose genotypes were confirmed previously by direct sequencing. With the established protocol, 171 suspected patients were enrolled. Samples with abnormal melting curves were further validated by DNA sequencing. RESULTS: HRM analysis can accurately determine the genotypes of all negative controls and patients. The sensitivity and specificity of the technique reached 100% (70/70). The melting curves of samples with the same genotype were highly reproducible. In 171 suspected patients, seven NICCD patients were detected by HRM. Identified mutations have included one case of 851del4 homozygote, one case of IVS6+5G>A heterozygote, 3 cases of 851del4 heterozygotes, one case of [IVS6+5G>A]+[ 851del4] and one case of [1638ins23+IVS16ins3kb]+[1638ins23]. All mutations were subsequently confirmed by DNA sequencing. CONCLUSION: HRM analysis is a convenient, high-throughput and rapid technique for the screening of NICCD patients. PMID- 22487827 TI - [Progress in research on the biological reason of male homosexuality]. AB - Male homosexuality is a complex phenomenon which is universal and with unknown causes. Researchers believe that both biological and environmental factors have played a role in its pathogenesis. Researches focusing on genetics, neurobiology, development and endocrinology have made certain progress. In this paper, we have reviewed the biological causes of male homosexuality, which may provide clues for further research in this field. PMID- 22487828 TI - [A versatile role of transcription regulator CTCF in epigenetics and diseases]. AB - CTCF as a multivalent eukaryotic transcription factor plays a diverse range of roles in regulation of various genes through the binding of its 11 zinc fingers to CTCF consensus sites or various proteins. CTCF is involved in multiple aspects of epigenetic regulation including regulation of chromatin remodeling and genomic imprinting. Deregulation of these processes result in a group of diseases are characterized by growth, development, and neurological dysfunction. This paper reviews recent researches that highlight the links between CTCF, epigenetics and diseases. PMID- 22487830 TI - [Screening and clinical phenotype analysis of microdeletions of azoospermia factor region on Y chromosome in 1011 infertile men]. AB - OBJECTIVE: To investigate the prevalence and subtypes of microdeletions in azoospermia factor (AZF) region in infertile men from Sichuan in order to correlate genotypes with phenotypes. METHODS: Multiplex-PCR was used to detect sequence tagged sites (STS) of AZF microdeletions in 1011 infertile men including 713 cases of non-obstructive azoospermia and 298 cases of severe oligospermia. RESULTS: The overall prevalence of microdeletions was 10.48% (106/1011), and the deletion rates were 11.08% (79/713) in non-obstructive azoospermia and 9.06% (27/298) in severe oligospermia. Complete AZFa or AZFb deletions were associated with azoospermia, whereas AZFc deletion (60.38%) was the most frequent deletion. The deletions were associated with variable spermatogenic phenotypes, and 37.50% of the patients with a deletion had sperms in the ejaculate. A mild decline in sperm concentration was found in two cases with partial AZFb deletion and one case with partial AZFb-c deletion. CONCLUSION: Deletions of the AZFc region were most commonly found in our patients. All cases with complete AZFa or AZFb deletions and a proportion of cases with AZFc deletion were associated with azoospermia. Our study has provided more insight into the genotype-phenotype correlation, and confirmed that Yq microdeletion screening has a significant value for the diagnosis for male infertility. PMID- 22487829 TI - [Prognostic value of t(11; 18) (q21; q21) for gastric mucosa-associated lymphoid tissue lymphoma]. AB - OBJECTIVE: To investigate the prognostic value of t(11; 18) (q21; q21) in gastric mucosa-associated lymphoid tissue lymphoma. METHODS: A cohort of thirty-six gastric mucosa-associated lymphoid tissue lymphoma patients who were pathologically identify diagnosis from January 1994 to June 2004 were followed up retrospectively and studied using fluorescence in situ hybridization(FISH) technique to detect t(11; 18) (q21; q21) chromosomal translocation on preservative paraffin specimen. RESULTS: Among thirty-six patients, fifteen (41.67%) were positive for t (11; 18) (q21; q21). All but one were followed up to March 2010, general median survival time (MST) was 87 months. The MST were 43 and 130 months for t(11; 18) positive and negative patients, respectively. The MST between these two groups was notably different (chi-square=29.57, P< 0.01). CONCLUSION: t(11; 18) (q21; q21) is important prognostic factor for gastric mucosa-associated lymphoid tissue lymphoma. PMID- 22487832 TI - [Association between plasma lipid, glucose, cortisol and adrenocorticotropic hormone levels and GR and ACTHR gene polymorphisms]. AB - OBJECTIVE: To explore the association between plasma fat and glucose, cortisol and adrenocorticotropic hormone (ACTH) levels and genotypes of GR and ACTHR genes in healthy Chinese Han subjects. METHODS: Two hundred healthy subjects were analyzed for GR and ACTHR gene polymorphisms using PCR-restriction fragment length polymorphism method. Plasma lipid, glucose, cortisol, ACTH levels were determined and correlated with the genotypes. RESULTS: No significant difference was found between plasma lipid and glucose levels and various GR and ACTHR genotypes. Subjects with AG genotype of GR 5556A/G polymorphism had lower plasma cortisol levels than AA genotype. Compared with subjects with GG genotype of GR 4534-4536GAG/AAA [GAGAGG (GluArg)>GAAAAG(GluLys)] polymorphism, those with AG genotype had significantly lower plasma cortisol levels. Subjects with CC and CG genotypes of GR 6294C/G polymorphism also had significantly lower plasma cortisol levels compared with those with GG genotype. With regard to plasma ACTH levels, those with TT genotype of ACTHR 2T/C polymorphism were significantly lower than CC and CT genotypes, and those with AG genotype for GR 5556 A/G polymorphism were also significantly lower than AA genotype. CONCLUSION: There was no difference in plasma cortisol and glucose levels between subjects with GR and ACTHR gene variants. GR gene variants (5556A/G, 4534-4536GAG/AAA and 6294C/G polymorphisms) may influence plasma cortisol level, and ACTHR 2T/C, GR 5556A/G polymorphisms may decrease plasma ACTH level. PMID- 22487833 TI - [Association analysis of genetic polymorphisms of TCF7L2, CDKAL1, SLC30A8, HHEX genes and microvascular complications of type 2 diabetes mellitus]. AB - OBJECTIVE: To study the associations of single nucleotide polymorphisms (SNPs) of TCF7L2, CDKAL1, SLC30A8, HHEX with diabetic retinopathy (DR) and nephropathy (DN) in type 2 diabetes mellitus. METHODS: A total of 479 subjects with DR,248 with DN and 650 without DR or DN were recruited to assess the associations between SNPs of TCF7L2 (rs7903146, rs6585205, rs11196218), CDKAL1 (rs10946398,rs4712527), SLC30A8 (rs13266634, rs3802177, rs11558471) and HHEX (rs1111875, rs7923837) and the development of DR and DN. RESULTS: There were significant differences in genotypic and allele frequencies of rs11558471 (SLC30A8) between DR and control groups (P< 0.05), the odds ratio (OR) values of A and AA were 1.27 and 1.68. The distributions of genotype and allele frequency for rs11196218 (TCF7L2) were significantly different between DN and control group (P=0.0051,OR=1.37). However, the P value after Bonferroni correction showed no significant difference. No significant differences were found in the distributions of rs13266634 and rs3802177 (SLC30A8), rs10946398 (CDKAL1), rs6585205, rs7903146 and rs11196218 (TCF7L2) and rs7923837 (HHEX) between DR and control groups, and nor significant differences were found in distributions of rs6585205 (TCF7L2), rs4712527 (CDKAL1), rs13266634, rs3802177 and rs11558471 (SLC30A8), and 7923837 (HHEX) between DN and control groups, though for all comparison the OR values were greater than 1. CONCLUSION: Polymorphisms of SLC30A8 and TCF7L2 genes may be associated with the development of DR and DN, respectively. Association between the polymorphisms of CKDAL1, TCF7L2 and HHEX genes and DR, and between the polymorphisms of SLC30A8, HHEX and CDKAL1 genes and DN, cannot be excluded. PMID- 22487834 TI - [Association between polymorphisms of inflammatory factor genes and coronary heart disease]. AB - OBJECTIVE: To investigate the association between genetic polymorphisms of inflammatory factors and susceptibility to coronary heart disease(CHD) in southern Chinese Han population. METHODS: Using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) method, the genotypes of five inflammatory factors (BRCA1-associated protein, a disintegrin and metalloproteinase 8, inter-alpha-trypsin inhibitor H3, interleukin-15, cyclooxygenase-2) were anaylzed in 283 CHD patients diagnosed by angiography and 176 controls. RESULTS: In these inflammatory factors, the 270T/C and 90A/G polymorphisms of the BRAP gene showed a significant association with CHD. The allele and genotype frequencies of BRAP gene were consistent with those predicted by Hardy-Weinberg equilibrium (chi-square=0.878, P> 0.05; chi-square=0.776, P> 0.05, respectively). The frequencecies of 270C and 90G alleles in CHD patients was significantly higher than those of the control group (29.51% vs. 21.31%, P=0.006; 30.04% vs. 21.31%, P=0.004, respectively). Compared with 270TT and 90AA, 270CC and 90GG genotypes had a significantly increased CHD risk by Logistic regression analysis (OR=4.51, 95%CI: 1.41-14.45, P=0.011; OR=5.09, 95%CI: 1.60 16.26, P=0.006, respectively). This association was still signifcant after adjustment for the sex, age, smoke, hypertension, diabetes, plasma total cholesterol and low density lipoprotein levels. No evidence of association was found for other single nucleotide polymorphisms. CONCLUSION: The 270T/C and 90A/G polymorphisms in the BRAP gene may contribute to an increased risk of CHD among southern Chinese Han population. PMID- 22487835 TI - [Correlation between serum anti-P53 and familial clustering of hepatocellular carcinoma in Guangxi]. AB - OBJECTIVE: To assess the correlation between familial clustering of hepatocellular carcinoma (HCC) and the level of anti-P53 in human serum in Guangxi. METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to detect anti-P53 in 164 members from 20 HCC families and 164 members from non-cancer control families. Univariate analysis was performed to assess the correlation between seral level of P53 antibody and familial clustering of HCC. RESULTS: The level of P53 antibody was significantly higher in the members of HCC families than controls (Z=-3.04, P=0.002). After eliminating the interference of hepatitis B virus infection, this tendency still remains (P=0.011). And there was a significant difference between relatives of different degrees from HCC families (chi-square=11.593, P=0.021), with the expression of anti-P53 declining along with decrease in relationship coefficient. Furthermore, the number of individuals with high anti-P53 expression was also significantly greater in HCC families (95/164) than controls (71/164) (P=0.006). And the expression was rising along with the increasing HCC numbers (chi-square=16.068, P=0.000). Anti-P53 level was also greater in HCC families featuring sibling affection than parental affection (chi-square=12.679, P=0.002). Univariate analysis indicated that high expression of anti-P53 is a risk factor for development of HCC (OR=2.087, 95%CI: 1.270 3.431). CONCLUSION: High level of anti-P53 expression may be a factor for the clustering of HCC families in Guangxi, China. PMID- 22487836 TI - [Association between rs6658835 polymorphism of transforming growth factor beta 2 gene and congenital heart diseases in Chinese Han population]. AB - OBJECTIVE: To assess the association between a tag single nucleotide polymorphism (rs6658835) of transforming growth factor beta 2 (TGF beta2) gene and congenital heart disease (CHD) in Chinese Han population. METHODS: A total of 324 CHD cases including 144 atrial septal defects (ASD), 88 patent ductus arteriosus (PDA), 92 ventricular septal defects (VSD) and 158 healthy controls were enrolled. The genotype of rs6658835 was determined by polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS: The genotypic and allelic frequencies of rs6658835 were associated with VSD (P< 0.05), but not with ASD or PDA (P> 0.05). CONCLUSION: The rs6658835 polymorphism of TGF beta 2 gene is associated with the susceptibility of VSD in Chinese Han population. PMID- 22487837 TI - [Cytogenetic analysis of a complex chromosomal imbalance 14q+ in a fetus featuring multiple congenital defects]. AB - OBJECTIVE: To analyze chromosomal imbalance in a fetus presenting with congenital heart disease and mild lateral ventriculomegaly, and to investigate the correlation between genotype and phenotype. The etiology of the fetal congenital diseases was determined, and the feasibility of array-based comparative genomic hybridization (array-CGH) application in molecular cytogenetic diagnosis was evaluated. METHODS: Following conventional G-banding analysis, array-based comparative genomic hybridization (array-CGH) was applied to delineate the precise location and size of genomic imbalance. RESULTS: A de novo 46, XY, -14, +der14(q31)? karyotype was identified in the fetus by G-banding analysis. Array CGH has verified the chromosomal imbalance to be 46, XY, -14, +der(12; 14) (p13; q32.33)del(14) (q32.33-> qter). CONCLUSION: del(14)(q32.33-> qter) is probably the predominant cause of the fetal congenital disease. For its high resolution and accuracy, array-CGH has provided a powerful tool for prenatal diagnosis and genetic counseling. PMID- 22487838 TI - [Genotypic and clinical features of spinal muscular atrophy type 3]. AB - OBJECTIVE: To explore the genotypic and clinical features and laboratory examinations of spinal muscular atrophy type 3 (SMA III). METHODS: Results of genetic testing and laboratory exams of 18 SMA III patients were collected and analyzed. RESULTS: The average age of onset of patients was 6.1 years, with the course of disease lasting from 13 months to 28 years. All patients became symptomatic with lower extremity muscle weakness. The symptoms gradually aggregated, with proximal lower limb muscle becoming atrophic and proximal upper limb muscle becoming weak. Genetic testing indicated that all subjects possessed homozygous deletions of SMN1 gene. Electromyography (EMG) of 15 subjects indicated neurogenic damage. Whilst younger patients had normal level of creatine kinase (CK), elder patients had higher level of CK, though no linear correlation was found. CONCLUSION: Full understanding of Clinical, especially the growth features of SMA III, in combination with genetic testing, can facilitate diagnosis and early intervention of the disease. PMID- 22487839 TI - [Association between Alu insertion polymorphisms and HLA class I alleles in Chinese Lisu and Nu ethnic populations]. AB - OBJECTIVE: To investigate the frequencies of HLA-Alu repeat polymorphisms (AluMICB, AluTF, AluHJ, AluHG and AluHF) in Chinese Lisu and Nu ethnic populations. METHODS: The frequencies of HLA-Alu repeat polymorphisms in above populations were determined with polymerase chain reaction (PCR). The associations between HLA-Alu repeat polymorphisms and HLA-A, HLA-B and HLA-C alleles were also analyzed. Phylogenetic trees were constructed with genetic distance calculated from the frequencies of HLA-Alu repeat polymorphisms. RESULTS: Frequencies of AluTF*2 and AluHF*2 were different between the two populations (P< 0.05), while those of other three insertions were similar. The strength of association between HLA-Alus and HLA alleles were different (P< 0.05) in the two populations. Although AluMICB*2 were associated with HLA-B*56:01 in both populations, the association was stronger in Lisu population (74.0%) but moderate in Nu population (30.7%). HLA-Alus were associated with particular HLA subtypes, e.g., AluHG*2 with certain HLA-A*02 subtypes. By phylogenetic analysis, Lisu and Nu were clustered together with southern Chinese and Thai populations. CONCLUSION: The distribution of HLA-Alus and the strength of associations between HLA-Alus and HLA class I alleles have varied between the two populations. Study of this association may facilitate identification of origins, evolution, progenitor haplotypes and recombination within the HLA class I region. PMID- 22487840 TI - [Analysis of HLA-A, B, and DRB1 polymorphism and genetic distance in Han population living in Yantai and Weihai regions of Shandong province]. AB - OBJECTIVE: To investigate allelic and haplotypic polymorphisms of human leukocyte antigen(HLA) genes at A, B and DRB1 loci in Yantai and Weihai Han population and analyze the genetic relationship between Yantai, Weihai Han population and other populations. METHODS: A total of 4062 unrelated Han ethnic individual from Yantai and Weihai regions were genotyped by polymerase chain reaction-sequence specific olignucleotide probe(PCR-SSOP) for HLA-A, B and DRB1 loci. Allelic and haplotypic frequencies were estimated by maximum likelihood estimation method using Arlequin 3.5 software. Genetic distances were computed, and phylogenetic tree was constructed using Mega5.0 software. RESULTS: Respectively 18, 33 and 13 alleles were observed at HLA-A, B and DRB1 loci. The most frequent alleles were HLA A*02(0.2935), HLA-B*15(0.1485) and HLA-DRB1*15(0.1621). And the most common three loci haplotype was A*30-B*13-DRB1*07(0.0649). A*33-B*58, A*66-DRB1*13 and B*08 DRB1*03 showed the strongest linkage disequilibrium. Yantai and Weihai Han population has the shortest genetic distance with Jilin Han population (0.0034). CONCLUSION: The HLA-A, B and DRB1 loci are highly polymorphic in Han population from Yantai and Weihai, and this population has closest relationship with Han population from Jilin province. PMID- 22487846 TI - Mindfulness meditation-related pain relief: evidence for unique brain mechanisms in the regulation of pain. AB - The cognitive modulation of pain is influenced by a number of factors ranging from attention, beliefs, conditioning, expectations, mood, and the regulation of emotional responses to noxious sensory events. Recently, mindfulness meditation has been found attenuate pain through some of these mechanisms including enhanced cognitive and emotional control, as well as altering the contextual evaluation of sensory events. This review discusses the brain mechanisms involved in mindfulness meditation-related pain relief across different meditative techniques, expertise and training levels, experimental procedures, and neuroimaging methodologies. Converging lines of neuroimaging evidence reveal that mindfulness meditation-related pain relief is associated with unique appraisal cognitive processes depending on expertise level and meditation tradition. Moreover, it is postulated that mindfulness meditation-related pain relief may share a common final pathway with other cognitive techniques in the modulation of pain. PMID- 22487848 TI - IL-2-inducible T-cell kinase deficiency with pulmonary manifestations due to disseminated Epstein-Barr virus infection. AB - IL-2-inducible T-cell kinase (ITK) deficiency is a rare inherited immunodeficiency disease characterized by homozygous mutations in the ITK gene and the inability to control Epstein-Barr virus (EBV) infection leading to EBV associated lymphoproliferative disorders of B cell origin. Many aspects of its clinical presentation and immunologic phenotype are still unclear to clinicians. We report on a 14-year-old female patient with complaints of an 8-month history of cough and fever. Imaging studies revealed diffuse pulmonary nodules and mediastinal lymphadenopathy. Transbronchial lung biopsy showed nonmalignant polyclonal B cell proliferation. High titers of EBV DNA were detected by PCR analysis in bronchoalveolar lavage fluid, bone marrow, and blood. Genomic analysis revealed a homozygous single base pair deletion in exon 5 of the ITK gene (c.468delT) in this patient. Treatment with rituximab (anti-CD20 mab) resulted in complete clinical remission with resolution of pulmonary lesions and a negative EBV titer in serum. All patients with EBV-associated lymphoproliferative disorders should be analyzed for mutations in ITK. PMID- 22487847 TI - Why HURT? A review of clinical instruments for headache management. AB - The Global Campaign against Headache, directed by the non-governmental organization Lifting The Burden (LTB) in official relations with the World Health Organization (WHO), aspires to reduce the global burden of headache. Ultimately this calls for improvements in headache management, largely in primary care, where most people with headache receive medical care. In support, LTB is developing a range of headache management aids for primary care. Presently, no single instrument covers the range of assessment and decision-making necessary for successful headache management, and few make the important link between assessment and clinical advice. Expressly to fill this gap, LTB has developed a new instrument: the Headache Under-Response to Treatment (HURT) Questionnaire, an eight-item, self-administered questionnaire addressing headache frequency, disability, medication use and effect, perceptions of headache "control" and knowledge of diagnosis. This instrument is intended not only to evaluate current headache outcomes and assess the need for and response to treatment, but also to provide guidance on appropriate actions towards treatment optimization. The first draft of the HURT was created by an expert consensus group, meeting at WHO headquarters in Geneva, Switzerland. The final version came about through multiple refinements following psychometric testing. Assessment of clinical utility is ongoing in multiple countries. PMID- 22487849 TI - Surgical treatment and prognosis in patients with high-grade soft tissue malignant fibrous histiocytoma of the extremities. AB - BACKGROUND: Malignant fibrous histiocytoma (MFH) of soft tissue is one of the most common sarcoma in adulthood. However, only a few series have separately studied the clinical behavior and prognosis of this malignancy. METHODS: We retrospectively reviewed 61 patients treated for extremity soft tissue high-grade MFH. Four patients had a history of another malignancy and were excluded from analysis. In 12 referred patients with incomplete excision, re-excision of the tumor bed was offered. Clinical and treatment variables were analyzed for their impact on treatment complications, local recurrence (LR), metastatic disease (MD) and overall survival (OS). RESULTS: Four patients underwent primary amputation. Twenty-three patients necessitated a primary reconstructive procedure for wound closure. Wound healing complication (WHC) developed in 28.3 % of the limb sparing group of patients. LR developed in 11 patients (19.3 %), while 6 of them had second LR. Eighteen patients (31.5 %) developed MD, involving lung at least. Patients who developed MD <12 vs >12 months, died within 19.3 vs 8 months mean time (p < 0.05). Overall survivorship was 66.7 % at 5 years. No statistically significant variables were identified for LR, while multivariate analysis for MD revealed tumor size >5 cm as the only statistically significant variable. For OS, development of MD and age >70 years emerged as independent prognostic factors. CONCLUSIONS: The overall prognosis is poor. LR, although can be managed with tumor re-excision, has high second recurrence rate. Increased tumor size is associated with shorter metastasis-free interval which significantly decreases survival. PMID- 22487850 TI - Inflammation induced by phytomodulatory proteins from the latex of Calotropis procera (Asclepiadaceae) protects against Salmonella infection in a murine model of typhoid fever. AB - OBJECTIVE AND DESIGN: Laticifer proteins (LP) of Calotropis procera were fractionated by ion-exchange chromatography, and the influence of a sub-fraction (LP(PI)) on the inflammatory response of Swiss mice challenged by Salmonella enterica Ser. Typhimurium was investigated. METHODS: Mice (n = 10) received LP(PI) (30 or 60 mg/kg) in a single inoculum by the intraperitoneal route 24 h before infection. To investigate the relevance of the proteolytic activity, three additional groups were included: the first one received heat-treated LP (30 mg/kg 30 min at 100 degrees C), the second received LP (30 mg/kg) inactivated by iodoacetamide, and a control group received only phosphate-buffered saline (PBS). RESULTS: The survival rate reached 100 % in mice treated with LP(PI) and was also observed with the other treatment, whereas the PBS group died 1-3 days after infection. The neutrophil infiltration into the peritoneal cavity of pretreated mice was enhanced and accompanied by high bacterial clearance from the bloodstream. Tumor necrosis factor-alpha mRNA transcripts, but not interferon gamma, were detected early in spleen cells of pretreated mice after infection; however, the nitric oxide contents in the bloodstream were decreased in comparison to the PBS group. CONCLUSIONS: The inflammatory stimulus of C. procera proteins increased phagocytosis and balanced the nitric oxide release in the bloodstream, preventing septic shock induced by Salmonella infection. PMID- 22487851 TI - Modelling experimental uveitis: barrier effects in autoimmune disease. AB - OBJECTIVE AND DESIGN: A mathematical analysis of leukocytes accumulating in experimental autoimmune uveitis (EAU), using ordinary differential equations (ODEs) and incorporating a barrier to cell traffic. MATERIALS AND SUBJECTS: Data from an analysis of the kinetics of cell accumulation within the eye during EAU. METHODS: We applied a well-established mathematical approach that uses ODEs to describe the behaviour of cells on both sides of the blood-retinal barrier and compared data from the mathematical model with experimental data from animals with EAU. RESULTS: The presence of the barrier is critical to the ability of the model to qualitatively reproduce the experimental data. However, barrier breakdown is not sufficient to produce a surge of cells into the eye, which depends also on asymmetry in the rates at which cells can penetrate the barrier. Antigen-presenting cell (APC) generation also plays a critical role and we can derive from the model the ratio for APC production under inflammatory conditions relative to production in the resting state, which has a value that agrees closely with that found by experiment. CONCLUSIONS: Asymmetric trafficking and the dynamics of APC production play an important role in the dynamics of cell accumulation in EAU. PMID- 22487852 TI - Anti-inflammatory effects of arbutin in lipopolysaccharide-stimulated BV2 microglial cells. AB - OBJECTIVES AND DESIGN: Arbutin, which is found in the genus Arctostaphylos, is an anti-oxidant and a depigmenting agent. The present study was designed to validate the anti-inflammatory effect of arbutin. MATERIALS AND METHODS: The anti inflammatory properties of arbutin were studied using a lipopolysaccharide (LPS) stimulated murine BV2 microglial cells model. As inflammatory parameters, the production of nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) were evaluated. We also examined the expression of ninjurin1 (Ninj1) and the adhesion activity of BV2 cells. Finally, we analyzed the activation of the nuclear factor kappaB (NF-kappaB) signaling pathway. RESULTS: Arbutin suppressed LPS-induced production of NO and expression of iNOS and COX-2 in a dose-dependent manner without causing cellular toxicity. Arbutin also significantly reduced generation of proinflammatory cytokines, including IL-1beta and TNF-alpha, and other inflammation-related genes such as MCP-1 and IL-6. Additionally, arbutin suppressed the adhesion activity of BV2 cells and the expression of an important adhesion molecule, Ninj1, in LPS-stimulated murine BV2 cells. Furthermore, arbutin inhibited nuclear translocation and the transcriptional activity of NF kappaB. CONCLUSIONS: Taken together, our results suggest that arbutin might be useful for treating the inflammatory and deleterious effects of BV2 microglial cells activation in response to LPS stimulation. PMID- 22487853 TI - Current world literature. PMID- 22487855 TI - Unmet need for corrective eyeglasses: results from a Los Angeles County Hospital survey. AB - To investigate the socioeconomic challenges encountered by patients from Los Angeles County Ophthalmology Clinic, California, United States, in obtaining prescription eyeglasses. A retrospective survey study. Patients sent for refraction in June 2009 were asked to rate their satisfaction with their eyeglasses. If they did not obtain eyeglasses, they were asked the reason e.g., cost, lost prescription, etc. Fifty-five percent (54/99) of patients who received a prescription did not obtain eyeglasses. The most common reason was cost (67 %). Eighty-eight percent of patients had some form of health insurance; however, 100 % were lacking eyeglasses coverage. The mean visual acuity pre-refraction was 20/80 versus 20/30 post-refraction (p < 0.001). It is well known that refractive error is a major cause of blindness worldwide, which negatively impacts the patient and their community. However, it is infrequently addressed that these conditions persist in parts of the develop world, including the United States. Los Angeles County Hospital is an example of an environment with many low-income patients in need of refractive correction who are limited mainly by cost in attaining eyeglasses. Furthermore, insurance organizations that cover low-income patients provide minimal or no coverage for prescription eyeglasses. PMID- 22487858 TI - Acute rejection of myofibers in nonhuman primates: key histopathologic features. AB - The aim of this study was to define the histologic features of acute rejection of myofibers, particularly in the context of therapeutic myogenic cell transplantation. Myoblasts expressing or not expressing beta-galactosidase were transplanted into 13 macaques that were divided into 3 protocols: withdrawal of immunosuppression, low immunosuppression, and progressive reduction of immunosuppression. The biopsy samples were obtained from cell-grafted sites at different intervals, and cryostat sections of biopsies were analyzed. The grafts were lost in all the monkeys at different periods after transplantation depending on the protocol and in association with low blood levels of tacrolimus. In all cases, graft loss was associated with the presence of dense focal accumulations of CD8-positive and CD4-positive lymphocytes and a component of macrophages. The lymphocyte accumulations totally or partially surrounded some myofibers and often invaded them; they were mainly endomysial. These histopathologic patterns in nonhuman primates and their similarity with preliminary observations in humans may facilitate the translation of these results to the histologic diagnosis of acute rejection of myofibers in human clinical trials of myogenic cell transplantation and probably gene therapy. PMID- 22487859 TI - Laforin and malin deletions in mice produce similar neurologic impairments. AB - Lafora disease is a progressive myoclonus epilepsy caused by mutations in the EPM2A gene encoding laforin or in the EPM2B gene encoding malin. It is characterized by the presence of polyglucosan intracellular inclusion bodies (Lafora bodies) in brain and other tissues. Targeted disruption of Epm2a or Epm2b genes in mice produced widespread neuronal degeneration and accumulation of Lafora bodies in neuronal and nonneuronal tissues. Here we analyzed the neurologic alterations produced by disruption of the laforin gene in Epm2a mice and compared them to those in malin-deficient mice. Both Epm2a and Epm2b mice showed altered motor activity, impaired motor coordination, abnormal hind limb clasping, and episodic memory deficits. Epm2a mice also had tonic-clonic seizures, whereas both Epm2a and Epm2b mice had spontaneous single spikes, spike wave, polyspikes, and polyspike-wave complexes with correlated myoclonic jerks. Neurologic alterations observed in the mutants were comparable and correlated with the accumulation of abundant Lafora bodies in the cerebral cortex, the hippocampus, the basal ganglia, the cerebellum, and the brainstem, suggesting that these inclusions could cause cognitive and behavioral deterioration. Thus, both Epm2a and Epm2b mice exhibit many pathologic aspects seen in patients with Lafora disease and may be valuable for the study of this disorder. PMID- 22487857 TI - Differences between the pattern of developmental abnormalities in autism associated with duplications 15q11.2-q13 and idiopathic autism. AB - The purposes of this study were to identify differences in patterns of developmental abnormalities between the brains of individuals with autism of unknown etiology and those of individuals with duplications of chromosome 15q11.2 q13 (dup[15]) and autism and to identify alterations that may contribute to seizures and sudden death in the latter. Brains of 9 subjects with dup(15), 10 with idiopathic autism, and 7 controls were examined. In the dup(15) cohort, 7 subjects (78%) had autism, 7 (78%) had seizures, and 6 (67%) had experienced sudden unexplained death. Subjects with dup(15) autism were microcephalic, with mean brain weights 300 g less (1,177 g) than those of subjects with idiopathic autism (1,477 g; p<0.001). Heterotopias in the alveus, CA4, and dentate gyrus and dysplasia in the dentate gyrus were detected in 89% of dup(15) autism cases but in only 10% of idiopathic autism cases (p < 0.001). By contrast, cerebral cortex dysplasia was detected in 50% of subjects with idiopathic autism and in no dup(15) autism cases (p<0.04). The different spectrum and higher prevalence of developmental neuropathologic findings in the dup(15) cohort than in cases with idiopathic autism may contribute to the high risk of early onset of seizures and sudden death. PMID- 22487860 TI - Mice devoid of Tau have increased susceptibility to neuronal damage in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. AB - The abundant axonal microtubule-associated protein tau regulates microtubule and actin dynamics, thereby contributing to normal neuronal function. We examined whether mice deficient in tau (Tau(-/-)) or with high levels of human tau differ from wild-type (WT) mice in their susceptibility to neuroaxonal injury in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. After sensitization with MOG35-55, there was no difference in clinical disease course between human tau and WT mice, but Tau mice had more severe clinical disease and significantly more axonal damage in spinal cord white matter than those in WT mice. Axonal damage in gray matter correlated with clinical severity in individual mice. By immunoblot analysis, the early microtubule-associated protein-1b was increased 2-fold in the spinal cords of Tau mice with chronic experimental autoimmune encephalomyelitis versus naive Tau mice. This difference was not detected in comparable WT animals, which suggests that there was compensation for the loss of tau in the deficient mice. In addition, levels of the growth arrest-specific protein 7b, a tau-binding protein that is stabilized when bound to tau, were higher in WT than those in Tau(-/-) spinal cord samples. These data indicate that loss of tau exacerbates experimental autoimmune encephalomyelitis and suggest that maintaining tau integrity might reduce the axonal damage that occurs in inflammatory neurodegenerative diseases such as multiple sclerosis. PMID- 22487862 TI - Airway simulators and mannequins: a case of high infidelity? PMID- 22487861 TI - Miglustat improves purkinje cell survival and alters microglial phenotype in feline Niemann-Pick disease type C. AB - Niemann-Pick disease type C (NPC disease) is an incurable cellular lipid trafficking disorder characterized by neurodegeneration and intralysosomal accumulation of cholesterol and glycosphingolipids. Treatment with miglustat, a small imino sugar that reversibly inhibits glucosylceramide synthase, which is necessary for glycosphingolipid synthesis, has been shown to benefit patients with NPC disease. The mechanism(s) and extent of brain cellular changes underlying this benefit are not understood. To investigate the basis of the efficacy of miglustat, cats with disease homologous to the juvenile-onset form of human NPC disease received daily miglustat orally beginning at 3 weeks of age. The plasma half-life of miglustat was 6.6 +/- 1.1 hours, with a tmax, Cmax, and area under the plasma concentration-time curve of 1.7 +/- 0.6 hours, 20.3 +/- 4.6 MUg/mL, and 104.1 +/- 16.6 MUg hours/mL, respectively. Miglustat delayed the onset of neurological signs and increased the lifespan of treated cats and was associated with decreased GM2 ganglioside accumulation in the cerebellum and improved Purkinje cell survival. Ex vivo examination of microglia from the brains of treated cats revealed normalization of CD1c and class II major histocompatibility complex expression, as well as generation of reactive oxygen species. Together, these results suggest that prolonged Purkinje cell survival, reduced glycosphingolipid accumulation, and/or the modulation of microglial immunophenotype and function contribute to miglustat-induced neurological improvement in treated cats. PMID- 22487856 TI - Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. AB - Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. beta-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Abeta plaques and neurofibrillary tangles. Although Abeta plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles. PMID- 22487863 TI - Patient blood management. PMID- 22487866 TI - The potential role of alpha(2) agonists for noncardiac surgery. PMID- 22487867 TI - Injectable and biodegradable poly(organophosphazene) gel containing silibinin: its physicochemical properties and anticancer activity. AB - The biodegradable poly(organophosphazene) hydrogels were developed as a locally injectable drug carrier for a hydrophobic silibinin to overcome its limited bioavailability. The aqueous solution of poly(organophosphazene) enhanced the solubility of silibinin up to 2000 times compared with that of phosphate buffered saline (0.0415 vs. 84.55 mg/mL). Both aqueous polymer solutions with and without silibinin showed a sol-gel transition as a function of temperature. A faster in vitro degradation rate of the gel and drug release rate from the gel at pH 6.8 than those at pH 7.4 were observed when the degradation and release study on hydrogels were conducted at 37 degrees C. Silibinin was sustainedly released from the hydrogel mainly by a diffusion-controlled mechanism. The silibinin released from the hydrogel was shown to be effective considering the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In the HT-29 xenografted mice model, the intratumorally injected hydrogel containing silibinin exhibited a good antitumor effect in comparison with the control groups. The Western blotting indicated that one of the reasons for the enhanced antitumor effect of the hydrogel system was the sustained antiangiogenic effect of silibinin. The poly(organophosphazene) gels are expected to be an effective candidate of the locally injectable drug carrier for silibinin. PMID- 22487864 TI - Gabapentin inhibits gamma-amino butyric acid release in the locus coeruleus but not in the spinal dorsal horn after peripheral nerve injury in rats. AB - BACKGROUND: Gabapentin reduces acute postoperative and chronic neuropathic pain, but its sites and mechanisms of action are unclear. Based on previous electrophysiologic studies, the authors tested whether gabapentin reduced gamma amino butyric acid (GABA) release in the locus coeruleus (LC), a major site of descending inhibition, rather than in the spinal cord. METHODS: Male Sprague Dawley rats with or without L5-L6 spinal nerve ligation (SNL) were used. Immunostaining for glutamic acid decarboxylase and GABA release in synaptosomes and microdialysates were examined in the LC and spinal dorsal horn. RESULTS: Basal GABA release and expression of glutamic acid decarboxylase increased in the LC but decreased in the spinal dorsal horn after SNL. In microdialysates from the LC, intravenously administered gabapentin decreased extracellular GABA concentration in normal and SNL rats. In synaptosomes prepared from the LC, gabapentin and other alpha2delta ligands inhibited KCl-evoked GABA release in normal and SNL rats. In microdialysates from the spinal dorsal horn, intravenous gabapentin did not alter GABA concentrations in normal rats but slightly increased them in SNL rats. In synaptosomes from the spinal dorsal horn, neither gabapentin nor other alpha2delta ligands affected KCl-evoked GABA release in normal and SNL rats. DISCUSSION: These results suggest that peripheral nerve injury induces plasticity of GABAergic neurons differently in the LC and spinal dorsal horn and that gabapentin reduces presynaptic GABA release in the LC but not in the spinal dorsal horn. The current study supports the idea that gabapentin activates descending noradrenergic inhibition via disinhibition of LC neurons. PMID- 22487868 TI - Effect of mild hypothermia on glutamate receptor expression after status epilepticus. AB - Hypothermia has been shown to have neuroprotective effects in various models of neurological damage. However, its therapeutic effect on pediatric status epilepticus (SE) is still unknown. We conducted a study to investigate whether hypothermia can have an adjuvant effect on pilocarpine-induced status epilepticus in immature rats when combined with diazepam treatment. Pilocarpine-induced status epilepticus was maintained for either 30 min or 60 min, which was followed by injection with diazepam (10mg/kg body weight) and/or treatment with mild hypothermia (core temperature to 33 degrees C). We found that the spike-wave amplitude and frequency after SE during treatment with diazepam and hypothermia was significantly lower than treatment with diazepam alone. Mild hypothermia significantly reduced the number of cells undergoing necrosis and apoptosis. In addition, alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor subunit GluR1 was shown to be up-regulated by SE, while GluR2 was shown to be down-regulated. However, after combination therapy with diazepam and mild hypothermia for 8h, the expression of GluR1 was decreased and GluR2 was increased relative to the levels of diazepam alone treated juveniles. We also found that the expression of mGluR-1a was also decreased relative to diazepam alone. These findings suggest that mild hypothermia might further protect against pilocarpine induced status epilepticus in immature rats by regulating glutamate receptor expression. This study was conducted using a pediatric model of SE so as to gain a better understanding of the role of hypothermia in the developing brain. PMID- 22487869 TI - A large deletion/insertion-induced frameshift mutation of the androgen receptor gene in a family with a familial complete androgen insensitivity syndrome. AB - Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic disorder with a normal 46, XY karyotype caused by abnormality of the androgen receptor (AR) gene. One Chinese family consisting of the proband and 5 other members with complete androgen insensitivity syndrome (CAIS) was investigated. Mutation analysis by DNA sequencing on all 8 exons and flanking intron regions of the AR gene revealed a unique large deletion/insertion mutation in the family. A 287 bp deletion and 77 bp insertion (c.933_1219delins77) mutation at codon 312 resulted in a frameshift which caused a premature stop (p.Phe312Aspfs*7) of polypeptide formation. The proband's mother and grandmother were heterozygous for the mutant allele. The proband's father, uncle and grandfather have the normal allele. From the pedigree constructed from mutational analysis of the family, it is revealed that the probably pathogenic mutation comes from the maternal side. PMID- 22487870 TI - Characterization of the chloroplast genome sequence of oil palm (Elaeis guineensis Jacq.). AB - Oil palm (Elaeis guineensis Jacq.) is an economically important crop, which is grown for oil production. To better understand the molecular basis of oil palm chloroplasts, we characterized the complete chloroplast (cp) genome sequence obtained from 454 pyrosequencing. The oil palm cp genome is 156,973 bp in length consisting of a large single-copy region of 85,192 bp flanked on each side by inverted repeats of 27,071 bp with a small single-copy region of 17,639 bp joining the repeats. The genome contains 112 unique genes: 79 protein-coding genes, 4 ribosomal RNA genes and 29 tRNA genes. By aligning the cp genome sequence with oil palm cDNA sequences, we observed 18 non-silent and 10 silent RNA editing events among 19 cp protein-coding genes. Creation of an initiation codon by RNA editing in rpl2 has been reported in several monocots and was also found in the oil palm cp genome. Fifty common chloroplast protein-coding genes from 33 plant taxa were used to construct ML and MP phylogenetic trees. Their topologies are similar and strongly support for the position of E. guineensis as the sister of closely related species Phoenix dactylifera in Arecaceae (palm families) of monocot subtrees. PMID- 22487871 TI - The effect of ethnicity and sexual preference on prostate-cancer-related quality of life. AB - In general, patients with prostate cancer are able to maintain a relatively high quality of life (QOL), commonly reporting improvements in physical, emotional, and social functioning within 1 year of treatment. However, certain subpopulations of patients are susceptible to significant reductions in QOL during the course of their treatment. Data suggest that ethnic background and sexual preference both have significant effects on QOL for patients with prostate cancer. These parameters are often poorly documented and addressed by medical practitioners. Greater attention is needed to identify patients who are at increased risk of QOL reduction as a result of these factors. PMID- 22487874 TI - Assessment of biophysical skin properties at different body sites in hospitalized old patients: results of a pilot study. AB - BACKGROUND: Skin aging is a risk factor for a decubitus and biophysical skin properties could help to identify persons at risk. Whether such biophysical properties of aged human skin differ between areas is undetermined. OBJECTIVE: To investigate whether viscoelasticity, hydration or friction differ between important areas for decubitus risk. METHODS: Pilot study in 32 (18 female, 14 male) acute and subacute old patients aged 81.9 +/- 5.9 years (+/-SD), without active skin disease after an average of 10 days of stay. Assessment of skin resilience/viscoelasticity (E) and hydration (H) at the volar forearm (VF), trochanter (TR) and the sacrum (SA), nutrition by a Mini Nutritional Assessment (MNA), total body water (TBW), lean body mass (LBM), % body fat (%F) by bioimpedance and routine laboratory parameters (hemoglobin, hematocrit, leukocytes, C-reactive protein, serum proteins and creatinine). RESULTS: Mean body mass index (27 +/- 4.2), MNA (22.5 +/- 2.9), Braden score (20 +/- 2.5), E (68.5 +/- 6.0%) and H (38.3 +/- 6.7) at any site and laboratory parameters did not differ by sex. Men had more TBW (+12 +/- 1.5 liters), LBM (+9 +/- 2 kg), less %F (-8.8 +/- 2.1%), increased H-TR (+7.11 +/- 2.8) and H-SA (+5.68 +/- 2.5). Overall E-VF correlated significantly with E-TR (r(2) = 0.40, p < 0.0001) and E SA (r(2) = 0.40, p < 0.0001). In contrast, skin hydration was not correlated. CONCLUSION: Results of forearm elasticity experiments can be used as a model for other body sites at risk for the development of pressure ulcers. PMID- 22487872 TI - Perioperative chemotherapy for upper tract urothelial cancer. AB - Upper tract urothelial cancer (UTUC) is an aggressive disease associated with significant morbidity and mortality. Radical nephroureterectomy (RNU) with bladder cuff removal is considered the standard of care for most invasive UTUCs but distant relapses after surgery for locally advanced, high-grade disease are common. Although multimodality treatment with perioperative chemotherapy has been investigated thoroughly in recent years, adjuvant chemotherapy has primarily been analyzed in small retrospective uncontrolled studies and a clear benefit for this treatment modality is yet to be established. It is likely that the high incidence of renal insufficiency after surgery substantially limits the applicability of adjuvant chemotherapy with cisplatin-based regimens. Neoadjuvant cisplatin-based chemotherapy has several practical advantages over adjuvant therapy, including better patient tolerance in the preoperative setting when a patient has two kidneys rather than one and the obtainment of prognostic information from pathological downstaging. Although, some academic centers have adopted neoadjuvant chemotherapy as a de facto treatment standard for patients with high grade locally advanced UTUC, this treatment approach has not been prospectively validated or adopted in general urologic practice. A multicenter trial of neoadjuvant chemotherapy for locally advanced high-grade UTUC could further define the role of neoadjuvant chemotherapy in treating UTUC. PMID- 22487875 TI - Tetrasomy 9p mosaicism associated with a normal phenotype in two cases. AB - Tetrasomy 9p is a rare chromosomal syndrome and about 30% of known cases exhibit mosaicism. Approximately 50 of the reported cases with tetrasomy 9p mosaicism show a characteristic facial appearance, growth failure, and developmental delay. However, 3 patients with mosaicism for isochromosome 9p and a normal phenotype have also been reported. We report 2 additional cases of clinically normal young females with tetrasomy 9p mosaicism, one of whom also exhibited X chromosome aneuploidy mosaicism leading to an overall of 6 different cell lines. STR analysis performed on this complex mosaic case indicated that the extra isochromosome was of maternal origin while the X chromosome aneuploidy was of paternal origin, indicating a postzygotic event. PMID- 22487876 TI - 25-hydroxyvitamin D levels and vascular calcification in predialysis and dialysis patients with chronic kidney disease. AB - BACKGROUND/AIMS: The role of vitamin D in the process of vascular calcification is unclear in patients with chronic kidney disease. We investigated whether serum 25-hydroxyvitamin D [25(OH)D] is associated with vascular calcification in predialysis and dialysis patients. METHODS: We included 86 predialysis and 139 dialysis patients. The simple vascular calcification score (SVCS) was evaluated by examining plain X-rays of the pelvis and hands as described previously. The carotid-to-femoral pulse wave velocity (CF-PWV) was assessed with a commercially available device. RESULTS: We found a high prevalence of vitamin D deficiency in our population (78.2%). Vascular calcification was present in 46.2% of all patients. Higher calcification (SVCS >3) was significantly associated with lower 25(OH)D levels in predialysis and dialysis patients. Multiple logistic regression analysis for SVCS >3 showed that 25(OH)D levels were negative independent predictors in predialysis (OR: 0.781; 95% CI: 0.623-0.908, p = 0.019) and dialysis patients (OR: 0.805; 95% CI: 0.749-0.853, p = 0.009). Lower 25(OH)D levels were associated with higher CF-PWV in predialysis patients, but this inverse relationship was no longer present in multivariate analysis. CONCLUSION: We showed an independent relationship between low serum 25(OH)D levels and vascular calcification in both predialysis and dialysis patients. PMID- 22487877 TI - Influence of the presence of monoglyceride on the interfacial properties of soy protein isolate. AB - BACKGROUND: This study focused on the contribution of soy protein isolate (SPI), in the absence or presence of monostearin (ME), to surface and interfacial properties as a function of protein concentration and pH, which is relevant to the physical stability of a variety of food systems. RESULTS: An increase in protein content always yielded a rapid decrease in surface tension followed by an evolution towards an asymptotic value. Addition of ME gave rise to mixed SPI/ME films, although the interface became dominated by SPI above the concentration for interfacial saturation. The relative interfacial shear viscosity of SPI films showed a marked dependence on: aging time, which may be attributed to a reorganisation of protein species at the interface with some penetration of hydrophobic parts into the oil phase; shear forces, which may partially reverse this reorganisation, leading to shear-thickening behaviour; and pH, which is the key factor controlling which SPI species is predominant at the interface. The effect of adding ME also depends on pH, favouring a reinforcement of SPI/ME films only at low pH, at which 3S and 7S fractions are dominant. CONCLUSION: The results obtained indicate that SPI shows excellent potential to favour stabilisation of air/water and oil/water interfaces in food systems. PMID- 22487878 TI - Identification and mapping of a major dominant quantitative trait locus controlling seeds per silique as a single Mendelian factor in Brassica napus L. AB - One putative quantitative trait locus (QTL) for seeds per silique (SS), cqSS.A8, was identified using a double haploid (DH) population in Brassica napus, and near isogenic lines (NILs; BC(3)F(1)) for cqSS.A8 were developed. However, the flanking markers from cqSS.A8 showed no significant difference using single marker analysis, even though the frequency distribution of SS in the BC(3)F(1) was bimodal, suggesting that one novel locus existed. In this study, we characterized the effects of this locus in the NILs and used a published linkage map to determine its location. A three-step approach was designed for mapping the locus in the NILs (BC(3)F(2)): (1) determining the individual BC(3)F(2) genotype at the locus using a progeny test; (2) identifying amplified fragment length polymorphism (AFLP) markers linked to the locus using a combination of AFLP and bulked segregant analysis; and (3) determining the location and effects of this locus. QTL analysis in the BC(3)F(2) revealed that this locus explained 85.8 and 55.7 % of phenotypic variance for SS and SL, respectively. Its additive and dominant effects on SS were 6.1 and 5.7, respectively. The locus was validated using a DH population by composite interval mapping and located to linkage group C9 (designated as qSS.C9). Mapping qSS.C9 was undertaken using 230 extremely low SS plants of a BC(4)F(1) population containing 807 plants. We found that qSS.C9 delimited a 1.005-Mb interval including 218 predicted genes in the reference Brassica rapa (Chiifu-401). These results will greatly facilitate map-based cloning of qSS.C9 and seed yield improvement in rapeseed. PMID- 22487879 TI - Critically assessing the Haiti earthquake response and the barriers to quality orthopaedic care. AB - BACKGROUND: Although numerous authors have described surgical experiences following major disasters, little is known regarding the needs of and barriers to care faced by surgeons during such disasters. QUESTIONS/PURPOSES: We therefore (1) identified and compared recurrent interview themes essential to the disaster response following the 2010 Haiti earthquake; (2) determined the difference in reported disaster equipment management task difficulty between disaster-trained and untrained volunteers; and (3) approximated the quantity of various procedures performed. METHODS: We conducted 14 interviews with selected orthopaedic surgeon volunteers. We also invited the 504 members of the American Academy of Orthopaedic Surgeons (AAOS), who registered as Haiti earthquake volunteers, to complete an online survey; 174 (35%) completed the survey and 131 (26%) were present in Haiti during the 30 days after the earthquake. Recurrent interview themes were identified, quantified, and compared using Poisson regression analysis. The difference in disaster equipment management difficulty scores was determined with a Wilcoxon rank-sum test. RESULTS: Of 10 recurrent interview themes, group organization (31 occurrences) was mentioned much more often than all but two of the remaining nine themes. Compared with disaster-untrained respondents, equipment management tended to be less challenging for disaster trained respondents. Transporting to the treatment site and security during storage at the site were less challenging (19.5% and 16.5% decreases, respectively). Revision surgeries, guillotine amputations, fasciotomies, and internal fixations, suggestive of inappropriate disaster care, were frequently reported. CONCLUSIONS: Organizational and training barriers obstructed orthopaedic care delivery immediately after the Haiti earthquake. Disaster training and outcomes require further study to improve care in future catastrophes. PMID- 22487881 TI - Parsing out reality from genetically engineered mouse models of neurologic diseases. PMID- 22487880 TI - Clinical stability of slipped capital femoral epiphysis does not correlate with intraoperative stability. AB - BACKGROUND: The most important objective of clinical classifications of slipped capital femoral epiphysis (SCFE) is to identify hips associated with a high risk of avascular necrosis (AVN)--so-called unstable or acute slips; however, closed surgery makes confirmation of physeal stability difficult. Performing the capital realignment procedure in SCFE treatment we observed that clinical estimation of physeal stability did not always correlate with intraoperative findings at open surgery. This motivated us to perform a systematic comparison of the clinical classification systems with the intraoperative observations. QUESTIONS/PURPOSES: We asked: (1) Is the classification of an acute versus chronic slip based on the duration of symptoms sensitive and specific in detecting intraoperative disrupted physes in patients with SCFE? (2) Is the stable/unstable classification system based on clinical symptoms sensitive and specific in detecting intraoperative disrupted physes in patients with SCFE? METHODS: We retrospectively reviewed 82 patients with SCFE treated by open surgery between 1996 and 2009. We classified the clinical stability of all hips using the classifications based on onset of symptoms and on function. We classified intraoperative stability as intact or disrupted. We determined the sensitivity and specificity of two classification systems to determine intraoperative stability. RESULTS: Complete physeal disruption at open surgery was seen in 28 of the 82 hips (34%). With classification as acute, acute-on-chronic, and chronic, the sensitivity for disrupted physes was 82% and the specificity was 44%. With the classification of Loder et al., the values were 39% and 76%, respectively. CONCLUSION: Current clinical classification systems are limited in accurately diagnosing the physeal stability in SCFE. LEVEL OF EVIDENCE: Level III, retrospective diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22487883 TI - Advances in quality-of-life and the financial independence of patients. PMID- 22487882 TI - Sialyldisaccharide conformations: a molecular dynamics perspective. AB - Sialyldisaccharides are significant terminal components of glycoconjugates and their negative charge and conformation are extensively utilized in molecular recognition processes. The conformation and flexibility of four biologically important sialyldisaccharides [Neu5Acalpha(2-3)Gal, Neu5Acalpha(2-6)Gal, Neu5Acalpha(2-8)Neu5Ac and Neu5Acalpha(2-9)Neu5Ac] are studied using Molecular Dynamics simulations of 20 ns duration to deduce the conformational preferences of the sialyldisaccharides and the interactions which stabilize the conformations. This study clearly describes the possible conformational models of sialyldisaccharides deduced from 20 ns Molecular Dynamics simulations and our results confirm the role of water in the structural stabilization of sialyldisaccharides. An extensive analysis on the sialyldisaccharide structures available in PDB also confirms the conformational regions found by experiments are detected in MD simulations of 20 ns duration. The three dimensional structural coordinates for all the MD derived sialyldisaccharide conformations are deposited in the 3DSDSCAR database and these conformational models will be useful for glycobiologists and biotechnologists to understand the biological functions of sialic acid containing glycoconjugates. PMID- 22487884 TI - Preference-based comparative effectiveness and cost-effectiveness: a review and relevance of value-based medicine for vitreoretinal interventions. AB - PURPOSE OF REVIEW: This analysis discusses the comparative effectiveness and cost effectiveness of vitreoretinal interventions, measured in quality-adjusted life years (QALYs) and percentage patient value (PPV gain, or improvement in quality of life and/or length of life). The material is relevant since the Patient Protection and Affordable Care Act enacted by Congress with the support of the President has emphasized the critical importance of patient-based preferences. RECENT FINDINGS: The majority of preference-based, comparative effectiveness and cost-effectiveness vitreoretinal interventions assessed in the US healthcare literature are Value-Based Medicine analyses, thus comparable. These interventions confer a mean patient (human) value gain (improvement in quality of life) of 8.3% [SD 6.3%, 95% confidence interval (CI) + 2.6%]. The average cost utility of these vitreoretinal interventions is US$23 026/QALY (SD US$24 508, 95% CI + US$8770). Most vitreoretinal interventions are very cost effective using a conventional US standard of US$50 000/QALY as the upper anchor for a very cost effective intervention, and the World Health Organization of approximately US$142 200/QALY as the upper anchor for a cost-effective intervention. CONCLUSIONS: Most vitreoretinal interventions confer considerable patient value and are very cost effective. Further standardization across healthcare is needed in the preference based, comparative and cost-utility (cost-effectiveness) arena. The metrics of PPV (percentage patient value) gain and US$/PPV (dollars expended per percentage patient value gain) or financial value gain may be more user-friendly than the QALY. PMID- 22487885 TI - An unusual mode of delivery. PMID- 22487886 TI - TVT-Secur for the treatment of female stress urinary incontinence: a 24-month follow-up retrospective study. AB - PURPOSE: To evaluate the mid-term efficacy and safety of the TVT-Secur device in the treatment of stress urinary incontinence. STUDY DESIGN: Retrospective study evaluating 68 women affected by stress urinary incontinence treated with TVT Secur procedure with hammock approach who attended the 24-month follow-up visit. Stress test, urodynamics, patient functional and quality of life questionnaires, visual analog scale pain score, and post-operative complications were evaluated. Data distribution was evaluated using the Shapiro-Wilk's test. Data were analyzed by the Student's t test for parametric variables, the Wilcoxon test for non parametric variables, and the Chi-squared test for categorized variables. RESULTS: Objective cure rate 24 months after surgery was 80.8 %. Incontinence quality of life and patient global impression of severity scores showed significant improvement. The only intra-operative complications were a vaginal wall tear and a case of severe bleeding, while post-operative complications were de novo urgency in five cases (7.3 %), one acute urinary retention (1.4 %), and one tape exposure (1.4 %). The study is limited by the retrospective design and the heterogeneity of patients. CONCLUSIONS: TVT-Secur seems to be an effective and safe procedure for stress urinary incontinence. PMID- 22487887 TI - Diffusion of innovations in social interaction systems. An agent-based model for the introduction of new drugs in markets. AB - The existence of imitative behavior among consumers is a well-known phenomenon in the field of Economics. This behavior is especially common in markets determined by a high degree of innovation, asymmetric information and/or price-inelastic demand, features that exist in the pharmaceutical market. This paper presents evidence of the existence of imitative behavior among primary care physicians in Galicia (Spain) when choosing treatments for their patients. From this and other evidence, we propose a dynamic model for determining the entry of new drugs into the market. To do this, we introduce the structure of the organization of primary health care centers and the presence of groups of doctors who are specially interrelated, as well as the existence of commercial pressure on doctors. For modeling purposes, physicians are treated as spins connected in an exponentially distributed complex network of the Watts-Strogatz type. The proposed model provides an explanation for the differences observed in the patterns of the introduction of technological innovations in different regions. The main cause of these differences is the different structure of relationships among consumers, where the existence of small groups that show a higher degree of coordination over the average is particularly influential. The evidence presented, together with the proposed model, might be useful for the design of optimal strategies for the introduction of new drugs, as well as for planning policies to manage pharmaceutical expenditure. PMID- 22487888 TI - Mitochondrial genome diversity in the Tubalar, Even, and Ulchi: contribution to prehistory of native Siberians and their affinities to Native Americans. AB - To fill remaining gaps in mitochondrial DNA diversity in the least surveyed eastern and western flanks of Siberia, 391 mtDNA samples (144 Tubalar from Altai, 87 Even from northeastern Siberia, and 160 Ulchi from the Russian Far East) were characterized via high-resolution restriction fragment length polymorphism/single nucleotide polymorphisms analysis. The subhaplogroup structure was extended through complete sequencing of 67 mtDNA samples selected from these and other related native Siberians. Specifically, we have focused on the evolutionary histories of the derivatives of M and N haplogroups, putatively reflecting different phases of settling Siberia by early modern humans. Population history and phylogeography of the resulting mtDNA genomes, combined with those from previously published data sets, revealed a wide range of tribal- and region specific mtDNA haplotypes that emerged or diversified in Siberia before or after the last glacial maximum, ~18 kya. Spatial distribution and ages of the "east" and "west" Eurasian mtDNA haploclusters suggest that anatomically modern humans that originally colonized Altai derived from macrohaplogroup N and came from Southwest Asia around 38,000 years ago. The derivatives of macrohaplogroup M, which largely emerged or diversified within the Russian Far East, came along with subsequent migrations to West Siberia millennia later. The last glacial maximum played a critical role in the timing and character of the settlement of the Siberian subcontinent. PMID- 22487891 TI - Using model organism Saccharomyces cerevisiae to evaluate the effects of ELF-MF and RF-EMF exposure on global gene expression. AB - The potential health hazard of exposure to electromagnetic fields (EMF) continues to cause public concern. However, the possibility of biological and health effects of exposure to EMF remains controversial and their biophysical mechanisms are unknown. In the present study, we used Saccharomyces cerevisiae to identify genes responding to extremely low frequency magnetic fields (ELF-MF) and to radiofrequency EMF (RF-EMF) exposures. The yeast cells were exposed for 6 h to either 0.4 mT 50 Hz ELF-MF or 1800 MHz RF-EMF at a specific absorption rate of 4.7 W/kg. Gene expression was analyzed by microarray screening and confirmed using real-time reverse transcription-polymerase chain reaction (RT-PCR). We were unable to confirm microarray-detected changes in three of the ELF-MF responsive candidate genes using RT-PCR (P > 0.05). On the other hand, out of the 40 potential RF-EMF responsive genes, only the expressions of structural maintenance of chromosomes 3 (SMC3) and aquaporin 2 (AQY2 (m)) were confirmed, while three other genes, that is, halotolerance protein 9 (HAL9), yet another kinase 1 (YAK1) and one function-unknown gene (open reading frame: YJL171C), showed opposite changes in expression compared to the microarray data (P < 0.05). In conclusion, the results of this study suggest that the yeast cells did not alter gene expression in response to 50 Hz ELF-MF and that the response to RF-EMF is limited to only a very small number of genes. The possible biological consequences of the gene expression changes induced by RF-EMF await further investigation. PMID- 22487893 TI - Fabrication of thermoplastics chips through lamination based techniques. AB - In this work, we propose a novel strategy for the fabrication of flexible thermoplastic microdevices entirely based on lamination processes. The same low cost laminator apparatus can be used from master fabrication to microchannel sealing. This process is appropriate for rapid prototyping at laboratory scale, but it can also be easily upscaled to industrial manufacturing. For demonstration, we used here Cycloolefin Copolymer (COC), a thermoplastic polymer that is extensively used for microfluidic applications. COC is a thermoplastic polymer with good chemical resistance to common chemicals used in microfluidics such as acids, bases and most polar solvents. Its optical quality and mechanical resistance make this material suitable for a large range of applications in chemistry or biology. As an example, the electrokinetic separation of pollutants is proposed in the present study. PMID- 22487892 TI - 25-Hydroxyvitamin D3 suppresses hepatitis C virus production. AB - Because the current interferon (IFN)-based treatment for hepatitis C virus (HCV) infection has a therapeutic limitation and side effects, a more efficient therapeutic strategy is desired. Recent studies show that supplementation of vitamin D significantly improves sustained viral response via IFN-based therapy. However, mechanisms and an active molecular form of vitamin D for its anti-HCV effects have not been fully clarified. To address these questions, we infected HuH-7 cells with cell culture-generated HCV in the presence or absence of vitamin D(3) or its metabolites. To our surprise, 25-hydroxyvitamin D(3) [25(OH)D(3) ], but not vitamin D(3) or 1,25-dihydroxyvitamin D(3) , reduced the extra- and intracellular levels of HCV core antigen in a concentration-dependent manner. Single-cycle virus production assay with a CD81-negative cell line reveals that the inhibitory effect of 25(OH)D(3) is at the level of infectious virus assembly but not entry or replication. Long-term 25(OH)D(3) treatment generates a HCV mutant with acquired resistance to 25(OH)D(3) , and this mutation resulting in a N1279Y substitution in the nonstructural region 3 helicase domain is responsible for the resistance. CONCLUSION: 25(OH)D(3) is a novel anti-HCV agent that targets an infectious viral particle assembly step. This finding provides insight into the improved efficacy of anti-HCV treatment via the combination of vitamin D(3) and IFN. Our results also suggest that 25(OH)D(3) , not vitamin D(3) , is a better therapeutic option in patients with hepatic dysfunction and reduced enzymatic activity for generation of 25(OH)D(3) . PMID- 22487894 TI - Hypogonadism related to crizotinib therapy: implications for patient care. PMID- 22487895 TI - Technical skills improve after practice on virtual-reality temporal bone simulator. AB - OBJECTIVES/HYPOTHESIS: To assess whether practice on a virtual-reality (VR) temporal bone simulator improves acquisition of technical skills in mastoid surgery. STUDY DESIGN: Prospective blinded study. METHODS: Using a previously validated objective structured assessment of technical skills (OSATS) tool, performance was assessed in 12 residents for two tasks of cortical mastoidectomy: 1) identifying and defining the tegmen and 2) defining the sigmoid sinus and sinodural angle. These surgical tasks were chosen as key steps in mastoid dissection because they were of intermediate complexity. Videos of virtual dissections were captured at baseline and again after practicing each task four to six times. RESULTS: OSATS scores for the tegmen task increased from 2.125 +/- 1.25 to 3.1 +/- 0.85 (P = .026), whereas for the sigmoid task scores increased from 2 +/- 0.45 to 2.75 +/- 1.125 (P = .0098). The time to complete the tasks decreased from 8.37 +/- 4.78 minutes to 5.39 +/- 3.06 minutes (P = .018) for the tegmen task and from 8.99 +/- 6.7 minutes to 8.68 +/- 5.98 minutes (P = .594) for the sigmoid task. There was a decline in number of injuries from 0.5 +/- 1.5 to 0 +/- 0.5 (P = .594) for the tegmen task and from 2.5 +/- 4 to 0.5 +/- 1 (P = .029) for the sigmoid task. CONCLUSIONS: Technical skills in mastoidectomy surgery can be acquired during even brief practice on the VR temporal bone simulator. It is anticipated that longer periods of practice presented within the fundamentals of comprehensive curriculum will facilitate procedural learning. Further studies are required to elucidate evidence of transference of these skills to the operating room and to procedures of greater complexity. PMID- 22487896 TI - The thrombophilic state in cancer part II: cancer outcomes, occult malignancy, and cancer suppression. AB - The association between malignancy and thrombosis has long been appreciated but remains incompletely understood. This is the second of a two-part review of the complex, integral relationship between these two entities, and addresses the specifics of cancer outcomes, occult malignancy in the presence of thrombosis, and the possibilities of cancer suppression by modulating thrombogenesis. PMID- 22487897 TI - Clinical follow-up and histopathology of the temporal bones in Nathalie syndrome. AB - The Nathalie syndrome (OMIM 255990) comprises a combination of features that do not resemble any other known syndrome and is as such an independent, rare entity. It is characterized by sensorineural hearing impairment, juvenile cataract, spinal muscular atrophy, skeletal abnormalities, retardation of growth, underdeveloped secondary gender characteristics and cardiomyopathy. Worldwide, only one family with this syndrome is known. An update of the clinical follow-up in this family and the results of autopsy are given. Audiometry showed a downsloping configuration that corresponded to the findings at histopathological examination of the cochlea: a diffuse atrophy of the organ of Corti, severe and diffuse atrophy of the stria vascularis and moderate loss of cochlear neurons in all turns. Another new striking feature is that individuals with the Nathalie syndrome have a shortened life expectancy with a risk of sudden death or death from heart failure resulting from (dilated) cardiomyopathy. PMID- 22487898 TI - Age-related changes in spectral transmittance of the human crystalline lens in situ. AB - AIMS: It was the aim of this study to measure spectral transmission of the human crystalline lens in situ. METHOD: The crystalline lens was illuminated by one of four light-emitting diodes of different colors. The relative spectral transmittance of the human crystalline lens was measured with the Purkinje-Sanson mirror images over a wide range of ages. RESULT: The study evaluated 36 crystalline lenses of 28 subjects aged 21-76 years. There was a significant correlation between the age and spectral transmittance for blue light. CONCLUSION: Spectral transmittance of the crystalline lens in situ could be measured with Purkinje-Sanson mirror images. PMID- 22487899 TI - Iontophoresis across the proximal nail fold to target drugs to the nail matrix. AB - The main objective of the present study was to investigate the plausibility of iontophoretic delivery of drugs to the nail matrix via proximal nail fold. The in vitro drug transport studies were performed in Franz diffusion cells across folded epidermis, which is used as a model for the proximal nail fold. The amount of drug transported into the receiver compartment following iontophoresis for 3 h at 0.5 mA/cm(2) was 150-fold higher than the control (0.008 +/- 0.002 MUg/cm(2)). The amount of drug present in the skin after iontophoresis (0.45 +/- 0.12 MUg/mg) was approximately fivefold higher as compared with that of the control (0.08 +/- 0.01 MUg/mg). Iontophoresis of terbinafine across the proximal nail fold was assessed using excised cadaver toe model as well. A custom-designed foam-pad-type patch system was used for iontophoresis in cadaver toes. The amount of the drug delivered into the nail matrix following iontophoresis for 3 h was significantly higher than the minimum inhibition concentration of terbinafine. However, on the contrary, passive delivery for about 24 h did not result in any detectable drug levels in the nail matrix. Iontophoresis across the proximal nail fold could be developed as a potential method to target drugs to nail matrix. PMID- 22487900 TI - Negative pressure wound therapy reduces deep infection rate in open tibial fractures. AB - OBJECTIVES: To evaluate the effect of negative pressure wound therapy (NPWT) on deep infection rate in open tibial fractures. DESIGN: Retrospective cohort study. Data was collected from medical records and radiographs. SETTING: Two level-1 trauma centers. PATIENTS/PARTICIPANTS: Patients who sustained an open tibial fracture which underwent delayed soft tissue coverage between January 2002 and December 2007 were included. Exclusion criteria included open fractures receiving a combination of NPWT and conventional dressings, fractures which were treated with a primary amputation, and fractures associated with mortality. INTERVENTION: : NPWT with reticulated open cell foam or conventional dressings at surgeon's discretion. MAIN OUTCOME MEASUREMENT: Deep infection rate. RESULTS: A total of 229 open tibial fractures in 220 patients met the inclusion criteria and received either NPWT (166/229-72%) or conventional dressings (63/229-28%). There was a decreased rate of deep infection in the NPWT group compared with the conventional dressing group [8.4% (14/166) vs. 20.6% (13/63); P = 0.01]. Univariate predictors of deep infection included Gustilo type {odds ratio (OR): 3.13 [95% confidence interval (CI): 1.74-5.64]; P < 0.001} and use of NPWT [OR: 0.35 (95% CI: 0.16 0.80); P = 0.01]. When adjustment was performed for Gustilo type with multivariate analysis, use of NPWT was found to reduce the risk of deep infection by almost 80% [OR: 0.22 (95% CI: 0.09-0.55); P = 0.001]. CONCLUSIONS: These results suggest that NPWT reduces the rate of deep infection when used for the dressing of traumatic wounds in open tibial fractures. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 22487901 TI - Incidence and radiologic outcome of intraoperative lateral wall fractures in OTA 31A1 and A2 fractures treated with cephalomedullary nailing. AB - OBJECTIVES: To determine the incidence of intraoperative lateral wall fracture in OTA 31A1 and A2 fractures treated with a cephalomedullary nail and to determine whether this contributed to the failure of treatment. DESIGN: Retrospective review. SETTING: University hospital. PATIENTS/PARTICIPANTS: A cohort of 291 patients (31.A1/A2-231, A3-60) was assessed with pre- and postoperative radiographs. Patients with intact lateral wall fractures were included in the study. One hundred sixty-five of 231 patients (77%) completed radiologic follow up. They were divided into 2 groups. Group 1 (129 patients, 78%) consisted of patients with an intact lateral wall postoperatively. Group 2 (36 patients, 22%) consisted of patients who sustained lateral wall fracture intraoperatively (FLW). INTERVENTION: Closed reduction and intramedullary nail insertion. MAIN OUTCOME MEASUREMENTS: Rate of failure/reoperation and collapse were compared between the groups. RESULTS: The incidence of intraoperative lateral wall fracture was 21% (48 of 165). Fracture collapse and failure rate were not statistically significant in either groups (group 1: 1%, group 2: 5%). CONCLUSIONS: The incidence of intraoperative lateral wall fracture in OTA 31A1 and A2 pertrochanteric fractures after cephalomedullary nailing is similar to sliding hip screws. The presence of lateral wall fracture did not adversely affect healing of pertrochanteric fractures. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 22487902 TI - Is reconstruction nailing of all femoral shaft fractures cost effective? A decision analysis. AB - OBJECTIVES: Femoral shaft fractures are usually treated with anterograde or retrograde nails that typically do not provide femoral neck fixation. Ipsilateral femoral neck fractures occur with 2.5%-10% of femoral shaft fractures; 19%-55% of associated femoral neck fractures are missed with plain films and 5%-22% with computed tomography (CT). This study was performed to determine if routine reconstruction nailing of all femoral shaft fractures with or without occult femoral neck fractures is cost effective. METHODS: A decision tree model examined the cost effectiveness of reconstruction nailing over standard intramedullary nailing for all femoral shaft fractures in which an associated femoral neck fracture was not identified on plain radiographs. As a base model, we assumed that 5% of shaft fractures had an ipsilateral femoral neck fracture, and 37% were missed and required further surgery. We assigned a small morbidity and additional cost ($680) for the use of a reconstruction nail and 2 screws. Model inputs including costs, clinical outcome probabilities, and health utilities were derived from the literature, estimated from institutional data, or assumed by the authors. Sensitivity analyses evaluated the effect of the rate of associated femoral neck fracture, the rate of missed femoral neck fracture, the complication rate of reconstruction screws, the cost of the extra reconstruction screws, and the utilities of each outcome on the incremental cost effectiveness (ICER) of both strategies. Current practice in cost-effectiveness analysis uses a threshold of $100,000 per quality-adjusted life year gained as cost effective. A secondary analysis of the use CT scans to reduce missed femoral neck fractures was also performed. RESULTS: The base model showed that the placement of reconstruction nails in all isolated femur fractures was not cost effective. Sensitivity analysis demonstrated that the ICER was most sensitive to the cost of the reconstruction nail, hemiarthroplasty, and a missed femoral neck fracture. The ICER was affected by the rate of femoral neck fracture and the rate of missed femoral neck fracture. If the rate of missed femoral neck fractures was >38%, then reconstruction nailing was a cost-effective strategy. If the probability of an ipsilateral femoral neck fracture was >7%, then reconstruction nailing was cost effective. Protocolized CT scans had an ICER >$100,000. If the additional cost of the reconstruction nails was <$650, then it was cost effective to perform reconstruction nailing for all femoral shaft fractures. CONCLUSIONS: Reconstruction nailing of femoral shaft fractures can be a cost-effective method to reduce the risks and morbidity of missed femoral neck fractures if the incremental implant costs are <$650. Routine reconstruction nailing is cost effective if the rate of associated femoral neck fracture is >7% or the rate of missed femoral neck fracture is >38%. CT scans are not a cost-effective strategy to reduce the risk and morbidity of missed femoral neck fractures if the cost is >$243. Weaknesses of this study include the reliance on low-powered studies and on estimations of some utilities and costs. To prevent the morbidity of missed or occult femoral neck fractures, the use of reconstruction nails for femoral shaft fractures is cost effective when the incremental costs of implants are <$650. LEVEL OF EVIDENCE: Economic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 22487904 TI - Outcomes of high-grade open calcaneus fractures managed with open reduction via the medial wound and percutaneous screw fixation. AB - OBJECTIVE: To determine the clinical and functional outcomes of high-grade (types II and III) open calcaneus fractures managed with a protocol of modern wound care, open reduction via the medial hindfoot wound, and percutaneous screw fixation. DESIGN: Retrospective clinical series of consecutively treated patients. SETTING: Regional trauma center (level 2). PATIENTS/PARTICIPANTS: Seventeen consecutive patients with open type II and III calcaneus fractures treated with fracture repair by a single surgeon. INTERVENTION: Soft tissue debridement and modern wound care, reduction of calcaneus fractures through the open medial wound, and percutaneous screw fixation. MAIN OUTCOME MEASUREMENTS: Patient demographics and injury data, radiographic analyses, complications of treatment, and hindfoot outcomes assessed with American Orthopaedic Foot and Ankle Surgeon and Maryland Foot Scores and general health with the Short Form 36 measurement at a minimum of 12 months post injury. RESULTS: Seventeen patients were available for follow-up at >12 months, with 15 completing all outcome measures. Four fractures were graded as type II, 9 as type IIIA, and 4 as type IIIB. There was 1 deep infection, and 1 wound dehiscence, both in type III open injuries; both were successfully treated with local wound care, delayed closure, and appropriate antibiotics. Overall, 7 of 17 (41%) patients required secondary surgical procedures, including 4 hindfoot fusions (23.5%). The average American Orthopaedic Foot and Ankle Surgeon score was 77 (range, 32-95), and the Maryland Foot Score was 64 (range, 16-93). The physical and mental components of the Short Form 36 averaged 44.4 and 49.1, respectively. CONCLUSIONS: Limb-threatening catastrophic complications are uncommon for high-grade open calcaneus fractures treated with modern soft-tissue care, fracture reduction using the medial open fracture wound, and percutaneously placed screw fixation. Limb and whole body functional outcomes are comparable to previously published reports of both closed and open calcaneus fractures. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22487905 TI - Internal fixation of diaphyseal fractures of the forearm: a retrospective comparison of hybrid fixation versus dual plating. AB - OBJECTIVES: To compare open reduction and internal fixation using dual plating to a hybrid fixation construct with intramedullary nailing of the ulna and plate fixation of the radius in both-bone forearm fractures. DESIGN: Retrospective comparison study. SETTING: Level I trauma center. PATIENTS: A total of 56 skeletally mature individuals treated surgically for acute both-bone forearm fractures between July 2005 and December 2009. Monteggia, Galeazzi, and pathologic fractures, patients treated with external fixation and patients with traumatic brain injuries were excluded. INTERVENTION: Twenty-seven patients were treated with dual plate fixation, and 29 patients were treated using a hybrid fixation construct. MAIN OUTCOME MEASURES: Time to union, range of motion as assessed using a Grace and Eversmann score, and presence of complications. RESULTS: There was no significant difference in either time to union or Grace and Eversmann scores between the 2 groups. There was 1 nonunion in each of the 2 groups. Nine overall complications, outside nonunions, were reported: 5 in the dual plating group and 4 in the hybrid fixation group. CONCLUSIONS: Hybrid fixation, using open reduction and internal fixation with a plate-and-screw construct on the radius and closed--or minimally open--reduction and interlocked intramedullary fixation of the ulna, is an acceptable method for treating both bone diaphyseal forearm fractures in skeletally mature patients. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 22487906 TI - Metabolomic changes and protective effect of (L)-carnitine in rat kidney ischemia/reperfusion injury. AB - BACKGROUND: Although great progress has been made in the pathogenesis and treatment of acute kidney injury (AKI), it still has high incidence and poor prognosis. The present study was performed in order to further understand the metabolomic changes of ischemia/reperfusion (I/R)-induced AKI and the protective effect of L-carnitine on AKI. METHODS: Kidney tissues and serum samples were collected at different time points from three groups of rats including control group, I/R group and L-carnitine-pretreated group. High-performance liquid chromatography coupled with mass spectrometry-based metabolomics approach was applied to investigate the characteristic of I/R-induced AKI and the protective effects of L-carnitine in rat kidney I/R model. Antioxidant enzymatic activity and phospholipase A(2) activity were determined to validate the metabolic outcomes. RESULTS: Changes in the pattern of endogenous metabolites as a result of kidney I/R injury were readily detected as early as 2 h after reperfusion, and earlier than the increase in blood urea nitrogen and serum creatinine. Twenty eight differential endogenous metabolites were discovered and structurally identified by MS(n) analysis. After I/R injury, lysophospholipids, free fatty acids and nitrotyrosine significantly increased, while carnitine and acetyl carnitine significantly decreased compared to control. Phospholipase A(2) activity and malondialdehyde level also increased, while superoxide dismutase activity decreased in kidney I/R injury rats. Treatment of L-carnitine 30 min prior to reperfusion significantly relieved I/R-induced metabolomic changes. CONCLUSION: I/R-induced AKI could be characterized by oxidative stress and changes in lipid metabolism through metabolomic investigation, and L-carnitine treatment 30 min before reperfusion had protective effects against I/R-induced AKI. PMID- 22487907 TI - Response-guided telaprevir therapy in prior relapsers? The role of bridging data from treatment-naive and experienced subjects. AB - The purpose of this report is to illustrate the US Food and Drug Administration's rationale for approving response-guided therapy (RGT) for telaprevir (TVR) in combination with pegylated interferon-alpha and ribavirin (P/R) for the treatment of adults with genotype 1 chronic hepatitis C who were prior relapsers. RGT was prospectively evaluated in two registration trials of treatment-naive subjects. In these studies, RGT allowed subjects who achieved undetectable hepatitis C virus RNA from weeks 4 and 12, known as extended rapid virologic response (eRVR), to stop all treatments at 24 weeks. A patient without eRVR received an additional 36 weeks of P/R after 12 weeks of a TVR triple regimen (total of 48 weeks). However, RGT in prior P/R relapsers was not prospectively evaluated. Empirical cross-trial data indicated high sustained virologic response rates (>90%) in prior relapsers achieving eRVR, irrespective of P/R duration (24 or 48 weeks). Further analyses demonstrated that interferon responsiveness does not change in P/R-experienced subjects with a second round of P/R. The comparability in interferon responsiveness across treatment courses allowed us to bridge data between treatment-naive and P/R-experienced subjects to support the approval of RGT in prior relapse subjects. PMID- 22487908 TI - Powered versus conventional endoscopic sinus surgery instruments in management of sinonasal polyposis. AB - To conduct a prospective randomized controlled trial investigating the efficacy and safety of powered versus conventional endoscopic sinus surgery instruments in the management of sinonasal polyposis. Two hundred patients with sinonasal polyposis who failed conservative therapy were included in the study. They were equally randomized into powered and conventional instruments groups. A subjective visual analogue scale (VAS), endoscopic examination, saccharine clearance time and coronal CT were done preoperatively. Intraoperatively, the operative time, the surgical conditions and degrees of dryness of the operative field were carefully rated and recorded. Postoperatively, VAS, polyp grades, saccharine clearance time, the number of endoscopic debridement and time to mucosalization were recorded. Complications, smoothness of postoperative course were reported. Both groups experienced a significant improvement in the VAS with no statistically significant difference in symptom improvement between the two groups except for olfaction where there was significant improvement in the powered group. Similarly, the two groups demonstrated a significant improvement in the objective parameters including polyp grade and saccharine clearance time changes, but no significant difference between the two groups was found. The operative time as well as the surgical conditions and dryness of the operative field score were significantly better in the powered group. There was a tendency for improvement in the number of endoscopic debridement and time to mucosalization in powered group when compared to conventional instruments group, but this did not reach statistical significance. The incidence of postoperative synechiae was significantly lower in powered endoscopic group. Powered endoscopic sinus surgery offers a better therapeutic approach for patients with sinonasal polyposis when compared to endoscopic surgery with the conventional instruments. It provides a bloodless dry operative field with better visualization for a more precise, less traumatic procedure with minimal intraoperative complications and shorter operative time. Additionally, patients have a smoother postoperative course, less incidence of synechiae, with a tendency for a faster healing. PMID- 22487909 TI - Complete high-intensity focused ultrasound in prostate cancer: outcome from the @-Registry. AB - BACKGROUND: To analyze data on patients with localized prostate cancer who were treated with complete high-intensity focused ultrasound (HIFU) prospectively captured within a voluntary HIFU user database (@-Registry). METHODS: The @ Registry includes data from consecutive patients treated with Ablatherm (EDAP TMS) HIFU at nine European Centres during the period 1994 and 2009. For this analysis, the data repository was reviewed for information on patients with localized prostate cancer (T1 -- T2) treated with complete (whole-gland) HIFU on the basis of an anterior-posterior prostate height of <=24 mm and a treated volume >120% of the prostate volume. Patients were regularly followed with PSA measurement and biopsy. Biochemical failure was defined for this study as PSA nadir +2 ngml(-1) (Phoenix definition). Disease-free survival was based on a biopsy, retreatment and biochemical data. Patients were risk group-stratified using the D'Amico classification system. RESULTS: The median follow-up was 2.8 years for the 356 patients included in the analysis. The majority could be classified as either low (44.9%) or intermediate risk (39.6%); 14.6% patients were classified as high risk. The median (mean, s.d.) PSA nadir was 0.11 ng ml( 1) (0.78 and 3.6), achieved at a mean (s.d.) of 14.4 (11.6) weeks after HIFU. Follow-up biopsies on 226/356 (63.5%) patients revealed an overall negative biopsy rate of 80.5% (182/226); there was no statistically significant difference in positive biopsy rate by risk group-stratification. Actuarial freedom from biochemical recurrence at 5 and 7 years according to the Phoenix definition was 85% and 79%, respectively. Disease-free progression rates at 5 and 7 years were 64% and 54%, respectively. CONCLUSIONS: Whole-gland prostate HIFU as primary monotherapy for localized prostate cancer achieves a recurrence-free survival in short-term analysis as assessed by prostate biopsy and serum PSA endpoints in a majority of patients. PMID- 22487910 TI - Better prognosis in newborns with trisomy 13 who received intensive treatments: a retrospective study of 16 patients. AB - Intensive treatment for newborns with trisomy 13 is controversial because of their lethal prognosis. We report the better life prognosis of patients with trisomy 13 who received intensive treatment. At our hospital, we provided an intensive management to such patients including resuscitation and surgical procedures as required. Herein, we present the results of a retrospective study (1989-2010) of 16 trisomy 13 cases who received an intensive treatment. None was diagnosed to have trisomy 13 before birth; 9 were delivered by C-section and oxygen was administered to all patients during postpartum resuscitation. Mechanical ventilation was used in 9 patients after tracheal intubation and tracheotomy was performed in 2 patients when withdrawing of extubation was difficult. Regarding prognosis, 9 patients died, 3 were referred to another hospital, and 4 were discharged from the hospital. Four and 7 patients died within 7 and 30 days after birth, respectively. Nine patients survived for >1 month, 7 for >180 days, and 5 for >3 years. Median survival for 16 patients was 733 days. The patients who received intensive treatments survived longer compared to the previous data. This study provides useful information concerning genetic counseling, especially from an ethical point of view, before providing intensive management to newborns with trisomy 13. PMID- 22487911 TI - MDM2 SNP285 does not antagonize the effect of SNP309 in lung cancer. AB - Conflicting reports exist regarding the contribution of SNP309 in MDM2 to cancer risk. Recently, SNP285 was shown to act as an antagonist to SNP309 by overriding the effect of SNP309 on SP1-mediated transcription. Moreover, SNP285 modified the relationship between SNP309 and risk of breast, ovarian and endometrial cancer. We assessed whether SNP285 confounded the effect of SNP309 in lung cancer in a cohort of 720 controls and 556 cases. Our cohort included both Caucasians and African Americans. Neither SNP309 nor SNP285 was associated with lung cancer risk or survival. In addition, removal of individuals who carried the variant C allele of SNP285 did not modify the association between SNP309 with either lung cancer risk or survival. Although an effect of SNP285 has been demonstrated in breast, ovarian and endometrial cancer, our findings do not support a role for this SNP in lung cancer and raise the possibility that the effect of SNP285 is restricted to cancers in women. PMID- 22487912 TI - Cholecystectomy through single access endoscopic surgery: where do we stand? AB - Single access endoscopic surgery, also called laparoendoscopic single site surgery, single port access or single incision laparoscopic surgery has rapidly emerged in clinical practice for some specific indications. Among them single access cholecystectomy is rapidly diffusing in an attempt to improve cosmetic results, reduce parietal trauma, fasten recovery and answer patient's demand of this frequent surgery. While this approach is diffusing some limitations still persist in its feasibility, which have to be overcome by new development in instrumentations and refinement in techniques. And, on the other hand safety principle of minimally invasive cholecystectomy should be strictly respected to ensure our patients safe surgeries. Recent experiences and reports have shown that all these points can be respected, at least by experienced teams, while offering patients the first steps towards routine clinical scarless surgery. In this paper we will review the current status of cholecystectomy through single access endoscopic surgery regarding techniques, indications and results. PMID- 22487913 TI - Endoluminal approaches to bariatric surgery. AB - The practice of surgery is in a constant flux with evolving technology as new techniques are continually being developed. Obesity is a major health problem worldwide and is the second most common preventable cause of death in North America. Currently, bariatric surgery is the only modality that results in a sustained weight loss along with reversal of the comorbidities. The purpose of this manuscript is to review the current endoluminal options for the treatment of morbid obesity. Procedures such as intragastric balloons, endoluminal vertical gastroplasty, transoral gastroplasty and transluminal sleeve are discussed and their efficacy is analyzed. PMID- 22487914 TI - The evidence for single-incision laparoscopic colectomy: is it time to adopt? AB - Laparoscopic colorectal surgery has advantages over open surgery including shorter postoperative length of hospital stay, early return of bowel function, decreased complications and reduced postoperative pain. Innovative minimally invasive surgery techniques such as single-incision laparoscopic surgery (SIL) have emerged to further enhance outcomes of conventional laparoscopy. This technique uses a single small incision for access of all instruments and specimen extraction. This concept has been proposed to improve cosmesis and enhance recovery. Technological advances have been introduced to overcome the challenges of co-axial instrument movement and collision that is inherent to SIL surgery. The application of SIL techniques to colorectal surgery is in its infancy, but gaining significant momentum. Early case reports and series have shown feasibility and safety. Emerging comparative studies of SIL colectomy to standard laparoscopic techniques are providing evidence of equivalency with potential benefit in outcomes such as reduced early postoperative pain and shortened length of hospital stay. The application of the SIL platform to robotics and transanal surgery demonstrates the broadening scope of this innovative field. However, we must be cognizant of the impact on surgeon training and resident education. In this review we present the current evidence supporting the application of SIL to colorectal surgery. PMID- 22487915 TI - Diagnostic transgastric endoscopic peritoneoscopy for staging of pancreatic and esophageal cancer. AB - Pancreatic and esophageal cancers are both gastrointestinal malignancies with relatively low long term survival. In part, the aggressiveness of these tumors is related to local and distant metastatic potential, subsequently affecting prognosis and treatment modalities. Currently, the mainstay of staging involves in-depth radiographic imaging with surgery offered for potentially curative tumors. As a result, staging becomes a key determinant in the role of surgical resection. As minimally invasive approaches continue to gain popularity, the idea of natural orifice surgery has been raised as a possible adjunct to staging neoplasias. Currently, the insertion of a perioral endoscope to gain access to the peritoneal cavity via a transgastric incision has been investigated, with demonstration of feasibility and efficacy in several animal studies and limited clinical studies. Similar techniques have been employed to gain access to the thoracic cavity via a transesophageal incision in early animal studies. This article aims to outline the advantages and limitations of natural orifice endoscopic surgery, and review the use of endoscopic techniques to assess the intraperitoneal cavity via a transgastric incision for determining local and widespread metastases with reference to pancreatic carcinoma. The method of transesophageal staging for esophageal carcinoma will also be discussed. PMID- 22487916 TI - Laparoscopic gastric banding. AB - Laparoscopic adjustable gastric banding is a highly effective treatment for obesity, with the broadest indications and lowest rate of early complications among the various bariatric surgeries commonly performed in the United States. Weight loss is accompanied by improvement or resolution of multiple comorbid conditions in addition to improvements in quality of life. The technique of band insertion has evolved over time, resulting in dramatic improvements of outcomes. As with any bariatric surgery, optimal results require evidence-based perioperative management, long-term routine followup, and the participation of committed patients both before and after surgery. This review encompasses the indications, technique, outcomes, and complications associated with this operation. PMID- 22487917 TI - An update on sleeve gastrectomy. AB - Laparoscopic sleeve gastrectomy (LSG) has emerged as the first step of a two staged operation in biliopancreatic diversion with duodenal switch (DS) or laparoscopic Roux-en-Y gastric bypass (LRYGB) for superobese high-risk patients. Due to the good short-term outcomes in weight loss and resolution of comorbidities and its technical simplicity, LSG has been increasingly applied as a definitive operation for morbidly obese patients. As LSG can be considered easier and faster to perform compared to LRYGB, it could become the procedure of choice in treating morbid obesity providing that long-term results of LSG were comparable with LRYGB regarding weight loss, the resolution of comorbidities and the quality of life improvement. A PubMed literature search was done, identifying over 2000 abstracts. Of these studies 74 original articles were selected as relevant studies for the topic and a secondary analysis. The operation is poorly standardized. There is no general agreement regarding the number of trocars used, the distance from pylorus to start the resection, bougie size, or staple line reinforcement among bariatric surgeons. The mechanisms by which LSG induces favourable metabolic changes and weight loss are not yet completely understood. As obesity is a lifelong disease, longer term comparative effectiveness data are most critical, and are yet to be determined. There is an obvious need for methodologically sound randomized studies concerning long-term results of LSG as a stand-alone operation compared to LRYGB and the effects on comorbidities of obesity. In conclusion, the quantity, quality, and consistency of evidence concerning LSG for obesity is low. Most of the current evidence comes from poorly designed nonrandomized controlled trials and case series and therefore, there is not yet enough evidence supporting the recommendation of LSG as a definitive, stand-alone procedure for morbid obesity. PMID- 22487918 TI - Gastrointestinal stromal tumors treatment in the Imatinib era. The role of fair indication. AB - AIM: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Surgery remains the elective treatment. We retrospectively compared two group of patients, who underwent surgery for GIST before and after Imatinib advent in order to analyze the recurrence and survival rate. METHODS: Two patient groups who underwent surgery for GIST, from January 1997 to December 2002 (Pre-Imatinib group) and from January 2003 to December 2008 (Post-Imatinib group) were compared. Patients were evaluated on the base of gender, age, clinical manifestations, primary location and metastasis positivity, tumor size, mitotic index, immunoreactivity for CD117 and the outcome, including date of death. RESULTS: In the Pre-IM group only one patient died for prostate cancer, 12 months after operation, the other died because of GIST with a 24.6 months of median survival rate (range 15-51). In the remaining 12 patients the median follow up period was 55 months (range 6-152 months). In the Post-IM group the mean follow up was 50.7 months (range 26-74) and they are still being assessed for oncological as well as surgical treatment. CONCLUSION: Early diagnosis and radical resection remain the standard of cure for GISTs. To date, the use of Imatinib lead to its utilization as adjuvant and neo-adjuvant therapy in adults. Our experience suggests that there is a correlation between the mutational status of KIT and clinical outcome. These aspects should be explored for targeted therapy that can effectively combine biological therapy to surgery. PMID- 22487919 TI - Clinical-pathological features of gastrointestinal stromal tumors presenting associated with other neoplasms: a brief report. AB - AIM: Over the past 10 years, few authors reported the synchronous detection of gastrointestinal stromal tumors (GISTs) and other neoplasms in the 9-33% of GISTs series. The primary aim of the present study was of investigating the features of GISTs detected in patients with other malignancies. METHODS: From 1999 to 2010 the GISTs detected at surgical exploration or preoperative assessment for other malignancies plus primary-GISTs, were recorded and reviewed. RESULTS: All synchronous GISTs were positive for kit/CD34, resulting smaller in size, with a lower mitotic index and occurring in elderly patients, comparing with primary GISTs (P<0.05). Moreover a prevalence of males and of lower-risk classifications were noted, not reaching, however, a statistical value. CONCLUSION: According with our findings, the synchronous GISTs are mainly asymptomatic/incidentally detected and display some of the low malignant features; we recommend, however, the surgical excision of GISTs occurring in patients with other malignancies in order to define the histology and risk features and since it might result in an incorrect management if misdiagnosed as a metastases. PMID- 22487920 TI - A randomized, placebo controlled study: EMLA in minor breast surgery. AB - AIM: Patients undergoing excision for breast lumps prefer general anesthesia or local anesthesia plus sedation, because of the fear of pain for local anesthesia alone. The aim of this study is to show the efficacy of an eutectic mixture of local anesthetic lignocaine and prilocaine (EMLA(r)) in these patients. METHODS: This study has been designed randomized, placebo-controlled. Forty five patients undergoing excision for breast lumps were divided into three groups. The first group was administered local EMLA cream preoperatively (Group I, N.=15), the second group (Group II, N.=15) had no preoperative preparation and the third group was placebo group (Group III, N.=15). All groups underwent the operation under local anesthesia. Pain during the local anesthesia and three hours after the operation were assessed using the visual analog scale. The amount of local anesthetic used during the operation and the anesthetic need of patients after the operation were assessed. RESULTS: When the three groups were compared, it was found that the intensity of pain in the group with EMLA was considerably lower during and after the operation (P<0.05). The amount of local anesthetic used during the operation was lower (P<0.05) and the need for post-operative analgesic was also less than the usual (P<0.05). CONCLUSION: Topical EMLA use decreases the pain, provides per-operative and postoperative patient and physician comfort, improved patient's compliance, and simplifies the surgical procedure. This is the first study demonstrating that a topical anesthetic provides a non-invasive analgesia during benign breast mass excision. PMID- 22487921 TI - The comparative study of former and latest FIGO staging of vulva cancer. AB - AIM: By means of comparing the 2009 staging with the 1994 staging for vulva carcinoma on prognostic predicting, the essay aims to investigate the alterations of clinical decision due to the staging changing. METHODS: A retrospective analysis was adopted which involves 100 patients with primary squamous cell carcinoma of the vulva treated at Sun Yat-sen University Cancer Center from January 1980 to December 2005. Meanwhile, survival rate was calculated by life table method. In addition, Kaplan-Meirer method was used to evaluate the prognostic factors in univariate analysis. And the independent prognostic factors were provided through COX regression model. RESULTS: Univariate analysis indicated that the prognostic factors of vulva squamous cell carcinoma were: age (P=0.018), lymph node metastasis (P=0.010), the 1988 staging (P=0.031), the 2009 staging (P=0.001), the number of positive lymphnodes (P<0.001), treatment method (P=0.011), recurrence site (P=0.024). COX regression model indicated that the independent prognostic factor was: the number of positive lymph nodes (P<0.001). Here was not significant difference in overall survival rate (P=0.454) between unilateral or bilateral lymph node metastasis. Also, lesion diameter was not an independent prognostic factor (P=0.380). CONCLUSION: Compared with the 1994 staging, the 2009 staging made some modifications in lesion size, extension, lymph node status and so on. The 2009 staging is better than the 1994 staging on prognostic predicting and, which could guide the clinical treatment more accurately. PMID- 22487922 TI - Transjugular Intrahepatic Portosystemic Shunt and Laparoscopic Colorectal Resection: the ideal minimally-invasive management for the treatment of colorectal cancer in severe cirrhotic patients. A case report and literature review. AB - Surgical interventions on gastrointestinal tract are often not well tolerated by patients with cirrhosis and severe portal hypertension, impairing their prognosis if suffering from malignant disease. Combining the benefits of two minimally invasive techniques such as Transjugular intrahepatic portosystemic shunt (TIPS) and Laparoscopic Colorectal Resection (LCR), the complications related to surgical intervention might be reduced and thus, it allows patients with liver disease, to undergo a curative intervention. One patient with cirrhosis and portal hypertension diagnosed with a rectal cancer underwent a meticulous preoperative preparation through placement of TIPS before laparoscopic surgery. TIPS placement was performed without intraprocedure complications. The patient was successfully operated by laparoscopic technique 36 days after TIPS placement without intraoperative bleeding or postoperative complications. Our experience, despite being based on one case, allows us to conclude that decompression of portal system by TIPS, already used in open surgery, may be applicable as a preoperative laparoscopic procedure with equally satisfactory results. PMID- 22487923 TI - Critical lower limb ischemia in a patient with atheroembolism from aortic source in systemic lupus erythematosus and antiphospholipid antibody syndrome. PMID- 22487924 TI - Laparoscopic cholecystectomy in adult with ventriculo-peritoneal shunt: report of a case and review of the literature. PMID- 22487925 TI - Acceleration of diabetes development in CXC chemokine receptor 3 (CXCR3) deficient NOD mice. AB - AIMS/HYPOTHESIS: The aim of this study was to understand the role of CXC chemokine receptor 3 (CXCR3), a T-helper 1(Th1) type chemokine receptor, in the pathogenesis of type 1 diabetes. METHODS: We observed the incidence of diabetes in Cxcr3 homozygous knockout mice. We compared the expression pattern of various cytokines and chemokines and the frequency of FOXP3(+) cells in the pancreas and pancreatic lymph nodes from Cxcr3 ( -/- ) NOD mice and wild-type NOD mice. In addition, we observed the migration ability of CXCR3(+)CD4(+) cells to pancreatic islets upon adoptive transfer. Finally, we examined whether Cxcr3 (+) regulatory T cells (Tregs) actually suppressed the onset of diabetes in vivo. RESULTS: Cxcr3 ( -/- ) NOD mice developed spontaneous diabetes earlier than did wild-type NOD mice. In Cxcr3 ( -/- ) NOD mice, Tregs were more frequent in pancreatic lymph nodes and less frequent in pancreatic islets than in wild-type NOD mice. While transferred CXCR3(-)CD4(+) cells from wild-type NOD mice did not infiltrate pancreatic islets of NOD-severe combined immunodeficiency (SCID) mice, CXCR3(+)CD4(+) cells from the same mice migrated into the recipient islets and contained Forkhead box P3 (FOXP3) upon adoptive transfer. Moreover, CD4(+)CD25(+) cells from wild-type NOD mice suppressed and delayed the onset of diabetes compared with those from Cxcr3 ( -/- ) NOD mice in a cyclophosphamide-induced diabetes model system. CONCLUSIONS/INTERPRETATION: The mechanism of accelerated diabetes onset in Cxcr3 ( -/- ) NOD mice was considered to be due to the lack of hybrid Tregs (CXCR3(+)FOXP3(+)CD4(+) cells), which could effectively migrate into and regulate Th1 inflammation in local lesions under Cxcr3 knockout conditions. PMID- 22487926 TI - Cerebral venous sinus thrombosis associated with spontaneous intermittent cerebrospinal fluid rhinorrhea: a case report. AB - OBJECTIVES: To present a rare case of cerebral venous sinus thrombosis (CVST). CLINICAL PRESENTATION AND INTERVENTION: A 43-year-old woman presented with coma and was diagnosed as a case of CVST. She recovered in a few days with heparin treatment. Many possible risk factors for CSVT were negative in the patient but intermittent cerebrospinal fluid (CSF) rhinorrhea was accidentally noticed. Cerebral computed tomography and magnetic resonance imaging were done. The patient was diagnosed as having spontaneous intermittent CSF rhinorrhea due to a defect in the base of the skull. CONCLUSIONS: This case showed the importance of being aware that a defect in the base of the skull may lead to intermittent CSF rhinorrhea in patients with CVST. PMID- 22487927 TI - A bioabsorbable microclip for laryngeal microsurgery: design and evaluation. AB - Epithelial flaps created during laryngeal microsurgery require apposition to facilitate proper healing. Current technologies are restricted by minimal access of the surgical site, posing various limitations in application. In this paper, we propose a novel magnesium-based bioabsorbable microclip, discuss our design considerations and evaluate the microclip's feasibility as a miniature wound closure device. Ex vivo experiments demonstrate that the microclip fastens securely to the vocal fold, while in vivo studies show bioabsorbability and a lack of adverse side effects, suggesting that the microclips are viable as implantable devices. PMID- 22487928 TI - Antibacterial and biological characteristics of silver containing and strontium doped plasma sprayed hydroxyapatite coatings. AB - Infection in primary total joint prostheses is estimated to occur in up to 3% of all surgery. As a measure to improve the antimicrobial properties of implant materials silver (Ag) was incorporated into plasma sprayed hydroxyapatite (HA) coatings. To offset potential cytotoxic effects of Ag in the coatings strontium (Sr) was also added as a binary dopant. HA powder was doped with 2.0 wt.% Ag(2)O, 1.0 wt.% SrO and was then heat treated at 800 degrees C. Titanium substrates were coated using a 30 kW plasma spray system equipped with a supersonic nozzle. X-ray diffraction confirmed the phase purity and high crystallinity of the coatings. Samples were evaluated for mechanical stability by adhesive bond strength testing. The results show that the addition of dopants did not affect the overall bond strength of the coatings. The antibacterial efficacies of the coatings were tested against Pseudomonas aeruginosa. Samples that contained the Ag(2)O dopant were found to be highly effective against bacterial colonization. In vitro cell-material interactions using human fetal osteoblast cells were characterized by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay for cell viability, field emission scanning electron microscopy for cell morphology and confocal imaging for the important differentiation marker alkaline phosphatase (ALP). Our results showed evidence of cytotoxic effects of the Ag-HA coatings, characterized by poor cellular morphology and cell death and nearly complete loss of functional ALP activity. The addition of SrO to the Ag-HA coatings was able to effectively offset these negative effects and improve performance compared with pure HA-coated samples. PMID- 22487929 TI - HSP47 siRNA conjugated with cationized gelatin microspheres suppresses peritoneal fibrosis in mice. AB - Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is essential for the biosynthesis and secretion of collagen and is expressed in the fibrotic peritoneum. In the present study, we evaluated the efficacy of HSP47 small interfering RNA (siRNA) to suppress the development of peritoneal fibrosis induced by chlorhexidine gluconate in mice. We initially confirmed that biodegradable cationized gelatin microspheres (CGMs) containing HSP47 siRNA could continuously release siRNA over 21 days as a result of microsphere degradation. We then determined that a single injection of CGMs incorporating HSP47 siRNA suppressed collagen expression and macrophage infiltration, thereby preventing peritoneal fibrosis. Therefore, we suggest that this controlled-release technology using HSP47 siRNA is a potential treatment for peritoneal fibrosis. Additionally, RNA interference combined with CGMs as a drug-delivery system may lead to new strategies for knocking down specific genes in vivo. PMID- 22487930 TI - The effect of pore geometry on the in vitro biological behavior of human periosteum-derived cells seeded on selective laser-melted Ti6Al4V bone scaffolds. AB - The specific aim of this study was to gain insight into the influence of scaffold pore size, pore shape and permeability on the in vitro proliferation and differentiation of three-dimensional (3-D) human periosteum-derived cell (hPDC) cultures. Selective laser melting (SLM) was used to produce six distinct designed geometries of Ti6Al4V scaffolds in three different pore shapes (triangular, hexagonal and rectangular) and two different pore sizes (500 MUm and 1000 MUm). All scaffolds were characterized by means of two-dimensional optical microscopy, 3-D microfocus X-ray computed tomography (micro-CT) image analysis, mechanical compression testing and computational fluid dynamical analysis. The results showed that SLM was capable of producing Ti6Al4V scaffolds with a broad range of morphological and mechanical properties. The in vitro study showed that scaffolds with a lower permeability gave rise to a significantly higher number of cells attached to the scaffolds after seeding. Qualitative analysis by means of live/dead staining and scanning electron micrography showed a circular cell growth pattern which was independent of the pore size and shape. This resulted in pore occlusion which was found to be the highest on scaffolds with 500 MUm hexagonal pores. Interestingly, pore size but not pore shape was found to significantly influence the growth of hPDC on the scaffolds, whereas the differentiation of hPDC was dependent on both pore shape and pore size. The results showed that, for SLM-produced Ti6Al4V scaffolds with specific morphological and mechanical properties, a functional graded scaffold will contribute to enhanced cell seeding and at the same time can maintain nutrient transport throughout the whole scaffold during in vitro culturing by avoiding pore occlusion. PMID- 22487931 TI - In vivo performance of microstructured calcium phosphate formulated in novel water-free carriers. AB - Osteoinductive calcium phosphate (CaP) ceramics can be combined with polymeric carriers to make shapeable bone substitutes as an alternative to autologous bone; however, carriers containing water may degrade the ceramic surface microstructure, which is crucial to bone formation. In this study five novel tricalcium phosphate (TCP) formulations were designed from water-free polymeric binders and osteoinductive TCP granules of different particle sizes (500-1000 MUm for moldable putty forms, and 150-500 MUm for flowable paste forms). The performance of these novel TCP formulations was studied and compared with control TCP granules alone (both 150-500 and 500-1000 MUm). In vitro the five TCP formulations were characterized by their carrier dissolution times and TCP mineralization kinetic profiles in simulated body fluid. In vivo the formulations were implanted in the dorsal muscle and a unicortical femoral defect (O=5 mm) of dogs for 12 weeks. The TCP formulation based on a xanthan gum-glycerol carrier exhibited fast carrier dissolution (1 h) and TCP mineralization (7 days) in vitro, but induced inflammation and showed little ectopic bone formation. This carrier chemistry was thus found to disrupt the early cellular response related to osteoinduction by microstructured TCP. TCP formulations based on carboxymethyl cellulose-glycerol and Polyoxyl 15-hydroxystearate-Pluronic((r)) F127 allowed the in vitro surface mineralization of TCP by day 7 and produced the highest level of orthotopic bone bridging and ectopic bone formation, which was equivalent to the control. These results demonstrate that water-free carriers can preserve the chemistry, microstructure, and performance of osteoinductive CaP ceramics. PMID- 22487932 TI - A new injectable radiopaque chitosan-based sclerosing embolizing hydrogel for endovascular therapies. AB - Endovascular repair of abdominal aortic aneurysms with a stent graft is limited by the persistence or recurrence of endoleaks. These are believed to be related to the recanalization of the aneurismal sac by endothelialized neochannels, which could lead to late type I and II endoleaks. Embolization has been proposed to treat or prevent endoleaks, but presently commercialized embolizing materials have several drawbacks and do not fully prevent endoleak recurrence. A novel chitosan hydrogel that is injectable, radiopaque and contains sodium tetradecyl sulfate (STS), a well-known sclerosing agent, was developed in order to combine blood flow occlusion and endothelium ablation properties. chitosan/STS hydrogels were characterized and optimized using rheometry, scanning electron microscopy, swelling and ex vivo embolization assay. They were shown to exhibit rapid gelation and good mechanical properties, as well as sclerosing properties. Their potential for the embolization of aneurysms was subjected to preliminary in vivo evaluation in a bilateral iliac aneurysm model (three dogs) reproducing persistent endoleaks after endovascular aneurysm repair (EVAR). At 3 months no endoleak was detected in any of the three aneurysms treated with chitosan/STS hydrogels. In contrast, type I endoleaks were detected in two of the three aneurysms treated with chitosan hydrogels. Generally, chitosan/STS hydrogels have great potential as embolizing and sclerosing agents for EVAR and possibly other endovascular therapies. PMID- 22487933 TI - Osteostatin improves the osteogenic activity of fibroblast growth factor-2 immobilized in Si-doped hydroxyapatite in osteoblastic cells. AB - Si-doped hydroxyapatite (Si-HA) is a suitable ceramic for the controlled release of agents to improve bone repair. We recently showed that parathyroid hormone related protein (PTHrP) (107-111) (osteostatin) has remarkable osteogenic features in various in vitro and in vivo systems. Fibroblast growth factor (FGF) 2 modulates osteoblastic function and induces angiogenesis, and can promote osteoblast adhesion and proliferation after immobilization on Si-HA. In the present study we examined whether osteostatin might improve the biological efficacy of FGF-2-coated Si-HA in osteoblastic MC3T3-E1 cells in vitro. We found that Si-HA/FGF-2 in the presence or absence of osteostatin (100 nM) similarly increased cell growth (by about 50%). However, addition of the latter peptide to Si-HA/FGF-2 significantly enhanced gene expression of Runx2, osteocalcin, vascular endothelial growth factor (VEGF) and the VEGF receptors 1 and 2, without significantly affecting that of FGF receptors in these cells. Moreover, secreted VEGF in the MC3T3-E1 cell conditioned medium, which induced the proliferation of pig endothelial-like cells, was also enhanced by these combined factors. The synergistic action of osteostatin and Si-HA/FGF-2 on the VEGF system was abrogated by a mitogen-activated protein kinase inhibitor (U0126) and by the calcium antagonist verapamil. This action was related to an enhancement of alkaline phosphatase activity and matrix mineralization in MC3T3-E1 cells, and also in primary human osteoblastic cells. These in vitro data show that osteostatin increases the osteogenic efficacy of a Si-HA/FGF-2 biomaterial by a mechanism involving mitogen-activated protein kinases and intracellular Ca(2+). These findings provide an attractive strategy for bone tissue engineering. PMID- 22487934 TI - Comprehensive analysis of head-shaking nystagmus in patients with vestibular neuritis. AB - Although biphasic head-shaking nystagmus (HSN) is a basic response to head shaking in patients with unilateral vestibular loss, monophasic HSN is commonly seen in patients with dizziness of undetermined etiology. Since the clinical significance of HSN remains unclear, we sought to characterize different types of HSN in patients with vestibular neuritis (VN) during the acute stage (within 7 days after the onset of vertigo) and at follow-up (about 2 months after the onset of vertigo), and to compare HSN and caloric responses. We analyzed HSN, spontaneous nystagmus and caloric tests in 66 patients with VN. Overall, HSN showed high abnormal rates (94 and 89%) during the acute and follow-up stages and could detect vestibular hypofunction even when canal paresis (CP) had normalized at follow-up. All patients in the acute stage and most patients at follow-up showed HSN with the slow phase to the lesioned side (paretic). Biphasic HSN was common at follow-up, and many patients with a monophasic paretic pattern during the acute stage had evolved to a biphasic paretic pattern at follow-up. Initial slow-phase eye velocities (SPVs) in biphasic HSN were larger than those in monophasic HSN at follow-up. Absence of HSN or reversal of its direction was closely related to normalized caloric responses, but SPVs of HSN did not correlate with the severity of CP. These findings indicate that the HSN test is a sensitive detector of vestibular hypofunction upon 2-Hz head rotation. HSN may reveal previous vestibular hypofunction in the 2-Hz frequency range even at follow-up, when caloric responses detecting vestibular hypofunction in the low frequency range had normalized. The two tests utilize different mechanisms to assess vestibular hypofunction and are complementary. Biphasic paretic HSN is the most common pattern at follow-up and occurs when the initial SPVs induced by head rotation are large enough to induce the adaptation of primary vestibular afferent activity. Monophasic HSN, which is commonly found in dizzy patients, indicates less severe vestibular hypofunction than biphasic HSN in the 2-Hz frequency range, and the caloric tests can provide further information about the side and presence of vestibular hypofunction at lower frequencies. PMID- 22487935 TI - Convenient method for resolving degeneracies due to symmetry of the magnetic susceptibility tensor and its application to pseudo contact shift-based protein protein complex structure determination. AB - Pseudo contact shifts (PCSs) induced by paramagnetic lanthanide ions fixed in a protein frame provide long-range distance and angular information, and are valuable for the structure determination of protein-protein and protein-ligand complexes. We have been developing a lanthanide-binding peptide tag (hereafter LBT) anchored at two points via a peptide bond and a disulfide bond to the target proteins. However, the magnetic susceptibility tensor displays symmetry, which can cause multiple degenerated solutions in a structure calculation based solely on PCSs. Here we show a convenient method for resolving this degeneracy by changing the spacer length between the LBT and target protein. We applied this approach to PCS-based rigid body docking between the FKBP12-rapamycin complex and the mTOR FRB domain, and demonstrated that degeneracy could be resolved using the PCS restraints obtained from two-point anchored LBT with two different spacer lengths. The present strategy will markedly increase the usefulness of two-point anchored LBT for protein complex structure determination. PMID- 22487936 TI - The effects of long-term exposure to extremely low-frequency magnetic fields on bone formation in ovariectomized rats. AB - The effects of long-term extremely low-frequency magnetic field (ELF-MF) exposure on bone formation and biochemical markers were investigated in ovariectomized rats. Sixty mature female Sprague-Dawley rats were randomly divided into four different groups (n = 15): (i) unexposed control (CTL); (ii) ovariectomized only (OVX); (iii) non-ovariectomized, exposed (SHAM + ELF-MF); and (iv) ovariectomized, exposed (OVX + ELF-MF). The third and fourth groups were exposed to 1.5 mT ELF-MF for 4 h a day for 6 months. Bone mineral density (BMD) was determined using dual energy X-ray absorption (DEXA) measurements. The formation and resorption of bone were evaluated using bone-specific alkaline phosphatase (BAP), osteocalcin, osteoprotogerin, and N-telopeptide. After 6 months of ELF-MF therapy, BMD values were significantly lower in the OVX group and higher in the OVX + ELF-MF and SHAM + ELF-MF groups than they were before therapy (P < 0.001). Although there was no significant difference in BMD values among the groups before therapy, the BMD values increased significantly after 6 months in the OVX + ELF-MF and SHAM + ELF-MF groups and were reduced in the OVX group compared to the CTL group (P < 0.001). The concentrations of BAP, osteocalcin, osteoprotogerin, and N-telopeptide in the three experimental groups also changed in a significant way compared to the CTL group. The results of the present study suggest that osteoporosis can be inhibited by ELF-MF stimulation treatments. It was also concluded that ELF-MF may be useful in the prevention of osteoporosis in ovariectomized rats. PMID- 22487937 TI - Differential expression of long non-coding RNAs during genotoxic stress-induced apoptosis in HeLa and MCF-7 cells. AB - Long non-coding RNAs (lncRNAs) are emerging as new players in cancer as they are implicated in diverse biological processes and aberrantly expressed in a variety of human cancers. No data are available on their function under genotoxic stress induced apoptosis. In this work, we assessed the behavior of some candidate lncRNAs (HOTAIR, MALAT1, TUG1, lincRNA-p21, GAS5, MEG3, PANDA, UCA1, ANRIL, and CCND1) during DNA damage-induced cell death in HeLa and caspase-3-deficient MCF-7 cells using bleomycin (BLM) and gamma-radiation to induce DNA damage. Cells were incubated in the presence of BLM for 24 h or irradiated. Apoptosis was analyzed by measurement of oligonucleosomal fragmentation of nuclear DNA. Our results reveal that basal RNA expression levels as well as the changes in the lncRNA expression rates during genotoxic stress-induced apoptosis were cell-type and/or DNA-damaging agent-specific. Generally, we found that some of the RNA molecules (HOTAIR and MALAT1) are down-regulated while many of them (lincRNA-p21, GAS5, MEG3, ANRIL, and ncRNA-CCND1) are up-regulated and some others (TUG1, UCA1, and PANDA) not affected. The decline in the expression of HOTAIR (approx. twofold, p < 0.01) and MALAT1 (approx 1.6-fold, p < 0.01) was clearly evident in BLM-treated HeLa and MCF cells (only HOTAIR, fivefold, p < 0.01). For lincRNA-p21, ncRNA CCND1, and MEG3, a similar up-regulation pattern was obvious in both cell lines where the increase was generally more pronounced in BLM-treated cells. Interestingly, the induction of ANRIL and GAS5 was mainly restricted to irradiated cells. In conclusion, our findings reveal a differential regulation of individual lncRNAs during genotoxic stress-induced apoptosis. PMID- 22487938 TI - Association between bone mineral density and C-reactive protein in a large population-based sample. AB - OBJECTIVE: Several studies suggest that bone mineral density (BMD) is reduced in chronic inflammatory diseases. Higher serum levels of C-reactive protein (CRP) have been associated with lower BMD in women and older adults. However, it is not clear whether this association holds in a representative sample of the general population. The purpose of this study was to examine the relationship between BMD and CRP level in a large representative US population-based sample from the National Health and Nutrition Examination Survey (NHANES). METHODS: We included participants age >=20 years with BMD (total and subregions) measured by dual x ray absorptiometry scans and complete information on covariates from NHANES. The association between CRP level and BMD was evaluated using multivariate linear regression models, adjusting for potential confounders and further adjusting for comorbid diseases, medications, and serum vitamin D levels. RESULTS: The study sample included 10,475 participants (53% Caucasian, 22% Mexican American, 18% African American, and 7% other races). Men had higher BMD and lower CRP concentrations than women. BMD (total body BMD as well as subtotal BMD and BMD of the extremities, ribs, and trunk subregions) was inversely associated with quintiles of CRP concentration both in men and in women in a dose-dependent manner (for total BMD, P for trend < 0.0001 for men, P for trend = 0.0005 for women). The associations were independent of medications, comorbidities, and other potential confounders. The results remained largely unchanged with further adjustment for serum vitamin D levels. CONCLUSION: Among men and women in a large representative population-based sample, the CRP level was inversely and independently associated with total BMD in a dose-dependent manner. PMID- 22487940 TI - On the other hand: overflow movements of infants' hands and legs during unimanual object exploration. AB - Motor overflow is extraneous movement in a limb not involved in a motor action. Typically, overflow is observed in people with neurological impairments and in healthy children and adults during strenuous and attention-demanding tasks. In the current study, we found that young infants produce vast amounts of motor overflow, corroborating claims of symmetry being the default state of the motor system. While manipulating an object with one hand, all 27 of the typically developing 4.5- to 7.5-month-old infants who we observed displayed overflow movements of the free hand (on 4/5 of unimanual actions). Mirror-image movements of the hands occurred on 1/8 of unimanual actions, and the hands and legs moved in synchrony on 1/3 of unimanual acts. Motor overflow was less frequent when infants were in a sitting posture and when infants watched their acting hand, suggesting that upright posture and visual examination may help to alleviate overflow and break obligatory symmetry in healthy infants. PMID- 22487942 TI - Attachment security and HPA axis reactivity to positive and challenging emotional situations in child-mother dyads in naturalistic settings. AB - This study investigated adrenocortical activity in response to different challenging and positive affect emotional contexts in child-mother dyads, as function of attachment security (children's secure base behaviors and mothers' attachment representations). Fifty-one children ranging in age from 18 to 26 months and their mothers participated in this study. Secure children showed significant increases in their cortisol levels after fear episodes and significant decreases, after positive affect ones. No significant changes were found for frustration/anger episodes. Insecure children did not show significant differences in cortisol levels in any of the episodes, which suggests that insecure attachment may be related to hypothalamic-pituitary-adrenal axis suppression in response to challenging and positive contexts. Mothers of insecure children showed significantly higher cortisol concentrations in pre- and post session samples, than mothers of secure children. Mothers' personal attachment representations influenced their own cortisol responses, as well as their children's (in a marginal significant way). PMID- 22487941 TI - Focused attention, heart rate deceleration, and cognitive development in preterm and full-term infants. AB - The majority of children who are born very preterm escape major impairment, yet more subtle cognitive and attention problems are very common in this population. Previous research has linked infant focused attention during exploratory play to later cognition in children born full-term and preterm. Infant focused attention can be indexed by sustained decreases in heart rate (HR). However there are no preterm studies that have jointly examined infant behavioral attention and concurrent HR response during exploratory play in relation to developing cognition. We recruited preterm infants free from neonatal conditions associated with major adverse outcomes, and further excluded infants with developmental delay (Bayley Mental Development Index [MDI < 70]) at 8 months corrected age (CA). During infant exploratory play at 8 months CA, focused attention and concurrent HR response were compared in 83 preterm infants (born 23-32 weeks gestational age [GA]) who escaped major impairment to 46 full-term infants. Focused attention and HR response were then examined in relation to Bayley MDI, after adjusting for neonatal risk. MDI did not differ by group, yet full-term infants displayed higher global focused attention ratings. Among the extremely preterm infants born <29 weeks, fewer days on mechanical ventilation, mean longest focus, and greater HR deceleration during focused attention episodes, accounted for 49% of adjusted variance in predicting concurrent MDI. There were no significant associations for later-born gestational age (29-32 weeks) or full term infants. Among extremely preterm infants who escape major impairment, our findings suggest unique relationships between focused attention, HR deceleration, and developing cognition. PMID- 22487943 TI - Foxp3+ regulatory T cells protect the liver from immune damage and compromise virus control during acute experimental hepatitis B virus infection in mice. AB - The strength of antiviral T cell responses correlates with clearance of hepatitis B virus (HBV) infection, but the immunological mechanisms mitigating or suppressing HBV-specific T cells are still poorly understood. In this study, we examined the role of CD4(+) Foxp3(+) regulatory T cells (Tregs) in a mouse model of acute HBV infection. We initiated HBV infection via an adenoviral vector transferring a 1.3-fold overlength HBV genome (AdHBV) into transgenic DEREG mice, where Tregs can be transiently but selectively depleted by injection of diphtheria toxin. The effect of Treg depletion on the outcome of HBV infection was characterized by detailed virological, immunological, and histopathological analysis. Numbers of Tregs increase in the liver rapidly after initiation of HBV replication. Initial depletion of Tregs revealed their complex regulatory function during acute infection. Tregs mitigated immunomediated liver damage by down-regulating the antiviral activity of effector T cells by limiting cytokine production and cytotoxicity, but did not influence development of HBV-specific CD8 T cells or development of memory T cells. Furthermore, Tregs controlled the recruitment of innate immune cells such as macrophages and dendritic cells to the infected liver. As a consequence, Tregs significantly delayed clearance of HBV from blood and infected hepatocytes. CONCLUSION: Tregs limit immunomediated liver damage early after an acute infection of the liver, thereby contributing to conservation of tissue integrity and organ function at the cost of prolonging virus clearance. PMID- 22487944 TI - Intrapleural agents for pleural infection: fibrinolytics and beyond. AB - PURPOSE OF REVIEW: Pleural infection is a common, increasing clinical problem with a high morbidity and mortality. Medical management of pleural infection often fails, requiring invasive thoracic surgery to drain infected pleural collections, and for many years intrapleural agents have been assessed to reduce the need for surgical drainage and improve clinical outcomes. Randomized trials assessing intrapleural fibrinolytic agents have given conflicting results, and recent evidence provides important information on the role of intrapleural agents in the treatment of pleural infection, and the possible biology associated with infection progression in these patients. RECENT FINDINGS: Pleural infection is increasing in both the adult and paediatric populations. The combined previous evidence assessing intrapleural fibrinolytics alone in pleural infection suggests lack of efficacy for clinically important outcomes. The Multi-Centre Intrapleural Sepsis Trial 2 (MIST2) study provides the first evidence of a novel treatment combination [intrapleural tissue plasminogen activator (tPA) combined with intrapleural deoxyribonuclease (DNase)], which significantly improves the chest radiograph compared with either agent alone or placebo, and has potentially important benefits to important clinical outcomes (need for surgery and hospital stay). The precise mechanism of action of combination fibrinolytic and DNase in pleural infection is speculative. SUMMARY: Fibrinolytic therapy alone has not been proven to be of use in the treatment of pleural infection. The MIST2 study provides clear-cut evidence demonstrating improved chest radiographs, and highly suggestive secondary outcomes suggesting improved clinically important outcomes, using a combination of intrapleural tPA and DNase. This novel treatment combination may represent an important step in our understanding and treatment of pleural infection; however, larger clinical studies specifically addressing important clinical outcomes and further laboratory research describing the potential mechanisms of action are now required. PMID- 22487945 TI - The post-pericardiotomy syndrome. AB - PURPOSE OF REVIEW: The postpericardiotomy syndrome (PPS) is a relatively common complication following cardiac surgery, whose epidemiology is not well known because there are no standardized definitions. The aim of the present study is to review more recent updates on the diagnosis, therapy, prognosis, and especially prevention of the PPS. RECENT FINDINGS: Recent studies suggest that it is time to develop standardized criteria for the diagnosis of the PPS to allow early recognition and treatment. Limited knowledge is still available on the pathogenesis of the syndrome, but it is now clear that the presumptive immune mediated origin is not able to explain all cases. Treatment is largely empirical and based on antiinflammatory drugs either nonsteroidal or corticosteroids with the possible adjunct of colchicine, that has been demonstrated as a promising well tolerated and efficacious means to prevent several postoperative complications, including the PPS, pericardial and pleural effusions, and atrial fibrillation. SUMMARY: Contemporary series of the PPS are scarce. About 20% of patients are affected by the syndrome after cardiac surgery with a significant increase in hospital stay, readmissions, and management costs. The overall short term and middle-term prognosis is relatively good but constriction may develop in a long-term follow-up in a minority of patients. Therapeutic and preventive strategies, especially based on the use of colchicine, are worthy of further investigations to develop a more evidence-based approach to treatment and prevention. PMID- 22487946 TI - Twelve-month clinical outcomes after coronary stenting with the Genous Bio engineered R Stent in patients with a bifurcation lesion: from the e-HEALING (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth) registry. AB - BACKGROUND: The e-Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth (e-HEALING) registry was designed to capture clinical data on the use of the endothelial progenitor cell capture stent (ECS) in routine clinical practice. In this analysis, we investigated the 12-month clinical outcomes in patients treated with an ECS for a bifurcation lesion. METHODS: The worldwide, prospective, nonrandomized e-HEALING registry aimed to enroll 5000 patients treated for coronary artery disease with one or more ECS between October 2005 and October 2007. Clinical follow-up was obtained at 1, 6, and 12 months. The primary endpoint was target vessel failure (TVF), defined as the composite of cardiac death, myocardial infarction, and target vessel revascularization at 12 months. RESULTS: A total of 573 patients were treated for at least one bifurcation lesion and were assessed in the current analysis. Baseline characteristics showed a median age of 65 years; 21% were diabetic patients and 36% had unstable angina. A total of 63% of the bifurcation lesions were located in the left artery descending and the mean stent length was 20.7+/-12.6 mm. At 12 months, TVF was 12.7% and target lesion revascularization was 7.5%. Definite or probable stent thrombosis occurred in 1.7% of the patients. Moreover, one or more stents per lesion [hazard ratio (HR): 2.79, 95% confidence interval (CI): 1.60-4.86, P<0.001], predilatation (HR: 0.39, 95% CI: 0.17-0.87, P=0.023), and lesions located in the right coronary artery (HR: 4.56, 95% CI: 1.07-19.5, P=0.041) were independent predictors of TVF. CONCLUSION: In the e-HEALING registry, coronary bifurcation stenting with the ECS results in favorable clinical outcomes and low incidences of repeat revascularization and stent thrombosis. PMID- 22487947 TI - The Lebanese allele at the LDLR in normocholesterolemic people merits reconsideration of genotype phenotype correlations in familial hypercholesterolemia. PMID- 22487948 TI - Effects of combined endothelin A receptor and renin-angiotensin system blockade on the course of end-organ damage in 5/6 nephrectomized Ren-2 hypertensive rats. AB - Our previous studies in rats with ablation nephrectomy have shown similar cardiorenal protective effects of renin-angiotensin system (RAS)-dependent treatment (combination of angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker) and RAS-independent treatment (combination of alpha- and beta-adrenoreceptor antagonist and diuretics). Moreover, selective blockade of endothelin (ET) receptor type A (ET(A)) improved survival rate and attenuated hypertension and organ damage in Ren-2 transgenic rats. Therefore, we were interested in whether ET(A) receptor blockade could have additive effects to the classical blockade of the RAS. Transgenic rats underwent 5/6 renal ablation at the age of 2 months and were treated for 20 weeks with RAS blockers alone (angiotensin II receptor blocker - losartan, and angiotensin-converting enzyme inhibitor - trandolapril), ET(A) receptor blocker alone (atrasentan) or with the combination of RAS and ET(A) receptor blockade. RAS blockade normalized blood pressure and improved survival. It decreased cardiac hypertrophy and proteinuria as well as tissue angiotensin II and ET-1 levels. In contrast, ET(A) receptor blockade only partially improved survival rate, reduced blood pressure, attenuated the development of cardiac hypertrophy and transiently reduced proteinuria. However, no additive cardio- and renoprotective effects of ET(A) and RAS blockade were noted at the end of the study. PMID- 22487949 TI - Exercise-induced muscle damage and inflammation: re-evaluation by proteomics. AB - Using proteomics combined with immunohistochemistry (IHC), we re-evaluated our previous hypothesis that voluntary eccentric exercise does not result in inflammation or necrosis while it does lead to muscular adaptation/remodeling through Z-band related proteins. Muscle biopsies from m. vastus lateralis were taken from five control and five exercised subjects 48 h after 45 min of downhill running. General muscle morphology was examined using histology and histochemistry. Proteomics was used to reveal protein profiles and novel proteins. IHC with specific antibody against three Z-band related proteins identified by proteomics was also performed. General morphology showed no muscle degeneration or inflammation in any exercised biopsy. Proteomics revealed that out of 612 individual protein spots, the exercised biopsy presented three proteins with significant (p < 0.05) higher expression ratio and four proteins of lower ratio compared to controls. Four of the proteins desmin, actin, Rab-35 and LDB3 are Z-band related; the former two have long been the focus of interest and were found to be up-regulated in the study; the latter two are Z-band assembly/stabilization protein and were for the first time observed to be down regulated in exercised muscles. The other three proteins are related with either cellular metabolism or calcium homeostasis and none is related with muscle necrosis or inflammation. IHC observations that both desmin and actin were increased whereas LDB3 was completely absent in some focal areas are consistent with proteomic results and with our previous observations. The results of the study confirmed our previous findings and therefore strengthened the hypothesis that voluntary eccentric exercise does not cause human muscle necrosis or inflammation; instead, muscular remodeling occurs specifically through Z-band related proteins. PMID- 22487950 TI - NASPGHAN practice guidelines: Diagnosis and management of hepatitis C infection in infants, children, and adolescents. AB - Hepatitis C virus (HCV) is an RNA virus that affects >180 million individuals worldwide with a high propensity for chronic infection. Children with HCV infection differ from adults in several ways including some modes of transmission, rates of clearance, progression of fibrosis, and the duration of potential chronic infection when acquired at birth. Since the discovery of HCV in 1989, there have been significant advances in the understanding of the virology and natural history of chronic HCV infection in children. In addition, there are now several treatment options for children with chronic hepatitis C infection and many new therapies on the horizon. As a consequence, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition brought together experts in pediatric hepatology to review the available data in children and provide clinicians with approaches to the diagnosis, management, and prevention of HCV infection in children and adolescents. The guideline details the epidemiology and natural history of HCV infection in children, the diagnostic workup, monitoring and treatment of disease, and provides an update on future treatment options and areas of research. PMID- 22487951 TI - Influence of shielding TPN from photooxidation on the number of early blood transfusions in ELBW premature neonates. AB - OBJECTIVES: The smallest premature neonates often receive blood transfusions early in life. Nonrestrictive transfusion policies are linked to deleterious outcomes. Exposure of total parenteral nutrition (TPN) to ambient light generates oxidation products associated with haemolysis in vitro. Shielding TPN from light limits oxidation. Our hypothesis was protecting TPN from light decreases haemolysis and therefore the need for early blood transfusions. METHODS: Comparison of haemolysis between animals fed enterally and those receiving TPN, and exploratory case-control retrospective analysis of transfusion counts in premature infants receiving light-exposed or light-protected TPN. The statistical analysis was analysis of variance and longitudinal binomial regression model adjusting for potential covariables of transfusion counts. RESULTS: In animals, TPN is associated with higher (P<0.05) haemolysis compared with enteral feeds; photoprotection induces lower peroxide load with no effect on the level of haemolysis. In premature infants, light-exposed (n=76) or light-protected (n=57) populations exhibited similar clinical characteristics. Initial haematocrit, gestational age, and index of disease severity had a significant effect on the number of transfusions. When adjusting for these covariables, photoprotection was no longer significant. CONCLUSIONS: Even though peroxides are associated in vitro with haemolysis, shielding TPN from light to reduce infused peroxides does not significantly decrease the need for early transfusions in premature infants. PMID- 22487952 TI - Crowning pancreatic stone in a pediatric patient. PMID- 22487953 TI - Opportunities for research to improve employment for people with spinal cord injuries. AB - OBJECTIVES: This paper reviews the literature pertaining to the employment of people who experience spinal cord injury (SCI) in the United States and recommending future research. METHODS: The literature was reviewed with search terms such as SCI, employment, working from home and telework using databases in EBSCO, including Academic Search Complete and the American Psychological Association's databases. RESULTS: Literature and findings on key factors related to employment illustrate the multiple dimensions of work environments, and health demands, that effect employment outcomes for people with SCI. CONCLUSION: Employment is important for people with SCI and valued in society. The literature reviewed indicates that researchers understand the work demands for people with SCI and may help to identify suitable supports, training and job opportunities. There remains a need for research focus on understanding future employment demands, necessary work skills, differing work environments and methods for increasing and preserving employment. PMID- 22487954 TI - Muscle perfusion of posterior trunk and lower-limb muscles at rest and during upper-limb exercise in spinal cord-injured and able-bodied individuals. AB - STUDY DESIGN: Nonrandomized-controlled trial. OBJECTIVES: To assess muscle perfusion at rest and during arm-cranking exercise (ACE) in upper and lower posterior trunk and vastus lateralis (VL) muscles in individuals with spinal cord injury (SCI) and controls (C). SETTING: Exercise Physiology-Biochemistry Laboratory. METHODS: Eight SCI with thoracic lesion and eight C received injections of radioactive tracer to trapezius (TRAP), latissimus dorsi (LAT) and VL. Radioactive counts were recorded with a gamma-camera for 10 min at rest and during ACE (60% VO(2max) for 20 min). Time-count curves were generated and the isotope clearance rate, expressed as half-life time (T(1/2),min), was calculated to assess muscle perfusion. RESULTS: Resting T(1/2) was lower in TRAP and LAT vs VL (P<0.05) in SCI, however, there were no differences among muscles in C. Arm cranking increased (P<0.001) the isotope clearance in TRAP and LAT in SCI and C, whereas no effect was found on T(1/2) in VL in both groups. T(1/2) was longer (P<0.05) in SCI vs C in VL at rest and during ACE, whereas there were no differences between groups in posterior trunk muscles. CONCLUSIONS: Resting muscle perfusion was reduced in the paralyzed limbs of SCI compared with C, whereas there was no evidence of impaired microcirculation in upper and lower back muscles in SCI. Although ACE did not induce a hyperemic response in VL, it increased hyperemia in upper and lower posterior trunk muscles in SCI, suggesting beneficial effects of this type of activity on muscle microvasculature in this region. PMID- 22487955 TI - Factors associated with early onset post-traumatic syringomyelia. AB - STUDY DESIGN: Retrospective study. OBJECTIVES: To identify factors associated with the development of early onset post-traumatic syringomyelia within 5 years of spinal cord injury. SETTING: Department of Rehabilitation Medicine, Pusan National University School of Medicine, Korea. METHODS: We retrospectively examined the records of 502 patients with traumatic cervical or thoracic spinal cord injury who underwent follow-up magnetic resonance imaging (MRI) examinations more than once a year for at least 5 years. Patients were assessed in terms of the neurological level of injury, the severity of initial spinal cord injury, the use of surgery and the extent of spinal canal involvement. The latter was evaluated by calculating the shortest antero-posterior diameter of the injured vertebral canal and the spinal reserve capacity as shown on MRI at the time of trauma onset and at the time of diagnosis of syringomyelia. RESULTS: Syringomyelia developed within 5 years in 37 (7.3%) of the 502 patients. The mean age of these 37 patients was 44.6 years (range, 17-67 years) and the mean interval from spinal cord injury to onset of syringomyelia was 38.8 months (range, 2-54 months). The development of post-traumatic syringomyelia within 5 years was not significantly related to the severity or level of injury, the use of spinal surgery or the extent of spinal canal encroachment (P>=0.05 for each comparison). CONCLUSION: Early onset syringomyelia occurring within 5 years after spinal cord injury was not associated with neurological injury level, severity of injury, the use of spinal surgery or canal encroachment. PMID- 22487956 TI - Validity of the mental health subscale of the SF-36 in persons with spinal cord injury. AB - STUDY DESIGN: Cross-sectional study 5 years after discharge from inpatient rehabilitation. OBJECTIVE: To examine the psychometric properties of the Mental Health subscale (MHI-5) of the 36-Item Short Form Health Survey (SF-36) in persons with spinal cord injury (SCI). SETTING: Eight Dutch rehabilitation centres with specialised SCI units. METHODS: Possible floor and ceiling effects were assessed, and Cronbach's alpha coefficient was calculated to assess internal consistency. Concurrent and divergent validity were assessed using Spearman correlations between the MHI-5 and measures of life satisfaction, neuroticism, vitality, general health, functional independence, participation, lesion characteristics and demographics. RESULTS: There were no floor or ceiling effects, but the total MHI-5 score was slightly skewed (-1.15). Internal consistency was good (alpha=0.79). Concurrent validity was shown by significant Spearman correlations between the MHI-5 and life satisfaction (0.53), neuroticism (-0.55), vitality (0.53) and general health (0.37). Divergent validity was shown by weak and, in part, non-significant correlations between the MHI-5 and functional independence (0.09), participation (-0.28) and lesion characteristics (range -0.01-0.19). CONCLUSION: The MHI-5 showed reliability and validity as a measure of mood in persons with SCI, and is a promising measurement instrument to assess mental health problems in this population. PMID- 22487957 TI - Re: Participation and conflict in the decision-making process for endoscopic resection or surgical gastrectomy for early gastric cancer. PMID- 22487958 TI - Mechanism of nanoparticle formation from ternary coground phenytoin and its derivatives. AB - The mechanism of drug nanoparticle formation of phenytoin (DPH) and its derivatives monomethylphenytoin (MDPH) and dimethylphenytoin (DMDPH) was investigated. The drug, polyvinylpyrrolidone K17 (PVP), and sodium dodecyl sulfate were coground to obtain the ground mixture (GM). The DPH GM was amorphous; however, MDPH and DMDPH GMs contained drug crystals. Spectral changes in infrared and (13)C solid-state nuclear magnetic resonance were observed in the DPH GM, partially observed in the MDPH GM, and hardly observed in the DMDPH GM. Mean particle sizes of the DPH, MDPH, and DMDPH GM nanosuspension were almost the same; however, stability after storage differed in the order of DPH > MDPH > DMDPH. The intermolecular interaction between the drug and PVP reflected not only the crystallinity of the drug in the GM but also the stability of the GM suspension. The size and stiffness of drug nanoparticles were evaluated using atomic force microscopy. Crystallization of the amorphous GM and agglomeration of the primary nanocrystals were observed in the DPH GM suspension. In contrast, primary nanocrystals were observed in the DMDPH GM suspension. The size of the drug nanocrystals formed from the different molecular states of the drug in the GM reflects the agglomerated states in water and stability. PMID- 22487960 TI - The puzzle of forebrain evolution. PMID- 22487959 TI - Clinical features, DYT1 mutation screening and genotype-phenotype correlation in patients with dystonia from Iran. AB - OBJECTIVE: To test Iranian patients with primary torsion dystonia to determine the frequency of 904-906 del GAG mutation in the DYT1 (TOR1A) gene and to investigate the genotype-phenotype association for this disease. SUBJECTS AND METHODS: Sixty-three patients with primary dystonia were investigated. DNA was extracted from peripheral blood and these samples were subjected to PCR sequencing for exon 5 of the DYT1 gene. RESULTS: Of the 63 patients, 10 (15.9%) carried the triplet GAG deletion mutation; this is a high DYT1-positive rate in comparison with other populations and the type of dystonia in this positive group was generalized in all except 1. In our patients, limbs were the most severely involved site at the time of onset and in most cases it developed to generalized form. The majority of DYT1-positive cases showed higher leg onset (5 patients, 62.5%) in comparison with higher arm onset in negative patients (20 patients, 50%). Also, the progression to generalized dystonia in DYT1-positive patients was significantly higher than in DYT1-negative patients. The mean age at onset was 8.6 +/- 1.6 years (7-12 years) in DYT1-positive patients, while mean age at onset in patients with no GAG deletion mutation was higher (15.7 +/- 11.5 years). CONCLUSIONS: The DYT1 904-906 del GAG mutation is responsible for some of Iranian dystonia patients, and screening for the DYT1 deletion is significant in cases with the generalized type of primary dystonia. Also, patients with leg or arm onset at a younger age are more likely to be DYT1-positive among primary torsion dystonia cases. PMID- 22487961 TI - Direct estimation of carbaryl by gas liquid chromatography with nitrogen phosphorus detection. AB - A simple and efficient analytical method was standardized for the estimation of residues of carbaryl in various substrates comprising grape berries, kinnow pulps, kinnow rind and soil. The samples were refluxed using mixture of methanol: 0.5 N HCl (1:1 v/v); diluted with brine solution, partitioned into chloroform and dried over anhydrous sodium sulfate. Further the samples were treated with anhydrous magnesium sulfate and primary secondary amine. Final clear extracts were concentrated under vacuum and reconstituted the volume into acetone. The residues were estimated directly on gas liquid chromatograph equipped with nitrogen phosphorus detection system equipped with a capillary column packed with 5 % diphenyl 95 % dimethyl polysiloxane non-polar phase. A consistent recovery from 82 % to 97 % for carbaryl was observed when samples were spiked at levels ranging from 0.05 to 1.00 mg kg(-1). The limit of quantification of the method was worked out to be 0.05 mg kg(-1) for grape berries, kinnow pulp, kinnow rind and soil. PMID- 22487962 TI - Assessment of the levels of hexachlorocyclohexane in blood samples from Mexico. AB - The aim of this study was to evaluate hexachlorocyclohexane (HCH) exposure in children living in nine hot spots in four Mexican states. We analyzed HCH (alpha, beta, and gamma-isomers) in blood using gas chromatography/mass spectrometry. HCH exposure level in 261 children was assessed and approximately 75 % of the children studied had detectable levels of HCH. These levels ranged from 188 to 40,096.7 ng/g lipid. The highest mean levels were found in Lacanja (5,446.9 ng/g lipid), an indigenous community in Chiapas, Mexico. Our data indicate high exposure to HCH in children living in these communities. PMID- 22487963 TI - Comparison of metal accumulation in fish species from the southeastern Black sea. AB - In this study, it was aimed to determine accumulation of the metal concentrations in fish species in different regions which are Surmene and Yomra bay at southeastern Black sea in Trabzon-Turkey. For this purpose, concentrations of metals (Cr, Co, Ni, Cu, Zn, As, Se, Cd, Sb, Hg, Pb) were measured by inductively coupled plasma mass spectrometry (ICP-MS) in muscle of red mullet (Mullus barbatus ponticus) and whiting (Merlangius merlangus euxinus). Metal concentrations were found for whiting ranged as follows; 0.35-1.64 (Cr), 0.01 0.09 (Co), 0.01-0.71 (Ni), 0.71-1.45 (Cu), 18.64-68.06 (Zn), 2.05-9.66 (As), 0.15 14.16 (Se), 0.01-0.22 (Cd), 0.01-0.01 (Sb), 0.01-0.15 (Hg), 0.01-0.25 (Pb) and for red mullet as 0.43-1.04 (Cr), 0.05-0.23 (Co), 0.02-0.67 (Ni), 0.74-2.32 (Cu), 19.89-43.50 (Zn), 6.04-24.82 (As), 0.02-9.83 (Se), 0.01-0.11 (Cd), 0.01-0.01 (Sb), 0.07-0.18 (Hg), 0.01-0.20 (Pb) MUg g(-1) dry weight. Metal concentrations in samples were found to be lower than legal limits proposed by Turkish Food Codex (2008), Food and Agricultural Organization (1983), and European Commission (Off J Eur Union L364-5-L364-24, 2006) for human consumption. PMID- 22487964 TI - Occurrence of (anti)estrogenic effects in surface sediment from an e-waste disassembly region in East China. AB - Because of the report on the abnormal local fertility rate at Taizhou area, which is a famous e-waste disassembly center in China, the hormone-like effects in the surface sediment from the local river was investigated. Compared to the control site DG, significant estrogenic effects (p < 0.01) were observed at e-waste recycling sites ranging from 6.01 to 29.31 nmol/kg dw E2 equivalents by water extraction while ranging from 20.47 to 135.02 nmol/kg dw by organic extraction. When coincubated with E2, the water and the organic extractions displayed significant (p < 0.01) synergistic and anti-estrogenic effects respectively. PMID- 22487965 TI - A rapid UHPLC method for the simultaneous determination of drugs from different therapeutic groups in surface water and wastewater. AB - A SPE-UHPLC-UV method for the determination of 13 pharmaceuticals from different therapeutic groups in surface water and wastewater samples was proposed. The following three solid-phase-extraction (SPE) columns with polymeric sorbents were used as a pre-concentration step: the Oasis HLB (average recoveries 93.8 %), the Nexus (84.0 %) and the Bond Elut ENV (88.3 %). A reverse-phase UHPLC with a C(18e) monolithic column and gradient elution program was used to obtain the best separations for all 13 drugs in short analysis time (3.4 min). The LOD range for determined drugs was 0.02-0.18 MUg L(-1), and the concentration range for drugs found in water samples was 0.06-0.90 MUg L(-1). The proposed method was used to analyze different water samples, mostly from rivers, and can be used as a monitoring tool for environmental pollution. PMID- 22487966 TI - Attitudinal familism predicts weight management adherence in Mexican-American women. AB - Adherence to behavioral weight management programs is often limited, especially among ethnic minority populations. The current study examined whether attitudinal familism, or attention to the needs of family above those of the self, predicted poorer adherence to a behavioral weight management program in Mexican-American women. One-hundred overweight or obese Mexican-American women from the southwestern United States were enrolled in a group-based weight loss treatment. Zero-order correlations indicated that general commitment to attitudinal familism, as measured by the Attitudinal Familism Scale, was significantly negatively associated with calorie and physical activity goal completion and marginally negatively associated with session attendance. The results of the current study indicate that researchers may consider addressing familism when developing tailored weight management interventions for Mexican-American women. PMID- 22487967 TI - 15-deoxy-Delta12,14 -prostaglandin J2 inhibits human immunodeficiency virus-1 tat induced monocyte chemoattractant protein-1/CCL2 production by blocking the extracellular signal-regulated kinase-1/2 signaling pathway independently of peroxisome proliferator-activated receptor-gamma and heme oxygenase-1 in rat hippocampal slices. AB - Human immunodeficiency virus (HIV)-induced inflammation, and its consequences within the central nervous system (CNS), must be countered by multiple pharmacologic agents, and 15-deoxy-Delta(12,14) -prostaglandin J(2) (15d-PGJ2) may hold promise in the treatment of pathologies associated with this inflammatory response. 15d-PGJ2 can repress the inflammatory response by means of peroxisome proliferator-activated receptor-gamma (PPARgamma)-dependent and independent mechanisms. However, its precise role and antiinflammatory mechanism in the hippocampus remain poorly understood. In the present study, rat hippocampal slices were stimulated with full-length HIV-1 Tat protein to investigate the role of 15d-PGJ2 8in the hippocampal inflammatory response. Pretreatment of slices with 15d-PGJ2 markedly reduced Tat-induced monocyte chemoattractant protein-1 (MCP-1/CCL2) production. Interestingly, the PPARgamma antagonist GW9662 did not inhibit action of 15d-PGJ2, confirming the latter's PPARgamma-independent mechanism of mediating antiinflammatory effects. Despite 15d-PGJ2's increasing the expression of heme oxygenase-1 (HO-1), its action was not abrogated by the HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX), nor was it recapitulated by HO-1 inducers such as cobalt protoporphyrin (CoPP). Moreover, short interfering RNA (siRNA)-directed knockdown of HO-1 did not abolish the antiinflammatory action of 15d-PGJ2 against Tat-induced MCP-1 production in human microglia-like THP-1 cells. Conversely, 15d-PGJ2 suppressed Tat-induced ERK1/2 activation, decreasing MCP-1 production upon Tat stimulation. The NADPH oxidase inhibitors DPI and apocynin also abrogated Tat-stimulated ERK1/2 activation, reducing MCP-1 production. Collectively, these data demonstrate that the antiinflammatory effects of 15d-PGJ2 on the hippocampus are exerted through inhibition of Tat-mediated ERK1/2 activation, coupled with that of a redox sensitive pathway, independent of PPARgamma and HO-1. PMID- 22487969 TI - Multidisciplinary management of skeletal metastases: a work in progress. PMID- 22487968 TI - Calcium efflux of plasma membrane vesicles exposed to ELF magnetic fields--test of a nuclear magnetic resonance interaction model. AB - The question whether very weak, low frequency magnetic fields can affect biological matter is still under debate. The theoretical possibility of such an interaction is often questioned and the site of interaction in the cell is unknown. In the present study, the influence of extremely weak 60 Hz magnetic fields on the transport of Ca(2+) was studied in a biological system consisting of highly purified plasma membrane vesicles. We tested a newly proposed quantum mechanical model postulates that polarization of hydrogen nuclei can elicit a biological effect. Vesicles were exposed for half an hour at 32 degrees C and the calcium efflux was studied using radioactive (45) Ca(2+) as a tracer. A static magnetic field of 26 uT and time-varying magnetic fields with a frequency of 60 Hz and amplitudes between 0.6 and 6.3 uT were used. The predictions of the model, proposed by Lednev, that at a frequency of 60 Hz the biological effect under investigation would significantly be altered at the amplitudes of 1.3 and 3.9 uT could not be confirmed. PMID- 22487970 TI - Overview of diagnosis and management of metastatic disease to bone. AB - BACKGROUND: Bone metastases occur frequently in patients with advanced cancer and are a serious complication of cancer. The decision to treat is often individualized, based on each patient's clinical presentation, life expectancy, and quality of life. METHODS: We reviewed the current literature pertaining to management of metastatic disease to bone, and the medical, radiotherapeutic, and surgical treatment options for management of bone metastasis are discussed. RESULTS: Current management of skeletal metastasis includes analgesia, systemic therapy, radiation therapy, and surgery. We propose treatment algorithms for management of vertebral and nonvertebral bone metastases and suggest individualized interventions based on clinical presentation. CONCLUSIONS: Management of bone metastases is complex and requires a multidisciplinary approach. The goal of treatment is often palliative, and intervention and treatment regimens should be individualized based on the specific clinical presentation of each patient. PMID- 22487971 TI - Biology of bone metastases. AB - BACKGROUND: Bone metastases cause morbidity and mortality in multiple malignancies. In addition to portending a dire prognosis, bone metastases cause bone pain, fractures, hypercalcemia, spinal cord compression, and other nerve compression syndromes. Improved understanding of the mechanisms that predispose tumor metastases to bone is needed to improve patients' therapeutic options, maintain their quality of life, and improve their survival. METHODS: This review discusses selected preclinical and clinical data regarding bone metastasis development and cytokine/molecular interactions predisposing to bone metastases formation. Potential interventions for reducing bone metastases are also described. RESULTS: Biologic mechanisms resulting in metastases of tumor cells to bone are being studied. Among these are the RANKL pathway, osteoclast activation via cytokines (produced by tumor cell and cells in the bone microenvironment), interactions with transient and stromal cells in the bone microenvironment, and molecules such as PTHrP and endothelin-1. These molecules offer important opportunities for targeted interventions to decrease bone metastases-associated morbidity. CONCLUSIONS: Knowledge of the pathophysiology of bone and cancer is developing rapidly. Relationships among cancer cells, bone-derived cells, and cytokines provide opportunities for the development of new interventions. Therapy targeting osteoclast/osteoblast interactions has proven benefit for patients with bone metastases. PMID- 22487972 TI - Diagnostic imaging and image-guided therapy of skeletal metastases. AB - BACKGROUND: The high incidence of skeletal metastases in cancer patients warrants careful detection with imaging and follow-up. Efforts are needed to manage pain associated with skeletal metastases as part of overall patient management. METHODS: This article reviews the current methods of diagnostic imaging in the evaluation of skeletal metastases and image-guided treatment of bone metastases for the palliation of pain based primarily on the assessment of imaging and interventional radiologic literature. RESULTS: Approaches to diagnostic imaging of skeletal metastases are summarized. Skeletal scintigraphy provides high sensitivity for detecting skeletal metastases, but targeted computed tomography (CT) or magnetic resonance imaging (MRI) may be needed to increase specificity. Newer imaging modalities, such as positron emission tomography (PET)/CT, improve detection of both lytic and blastic metastases. Minimally invasive percutaneous ablative treatment techniques, including radiofrequency ablation, microwave ablation, and cryoablation, are examined. They provide alternative approaches to radiation therapy to effectively palliate pain of bone metastases. Preliminary results of MR-guided focused ultrasound surgery (MRgFUS) demonstrate its effectiveness in palliating pain from skeletal metastases. CONCLUSIONS: Skeletal scintigraphy is the most common imaging modality for detecting skeletal metastases. Additional imaging may be required based on the type of tumor, the disease state, or treatment options. External-beam radiation therapy remains the mainstay for palliation of pain from bone metastases. Alternative minimally invasive and noninvasive image-guided treatment options can provide effective pain palliation. PMID- 22487973 TI - Surgical intervention of nonvertebral osseous metastasis. AB - BACKGROUND: Nonvertebral osseous metastases can result in pain and disability. The goals of surgical intervention are to reduce pain and to improve function if nonsurgical treatment fails. The indications for proceeding with surgical intervention depend on anatomic location, amount of local destruction, extent of skeletal and visceral disease and, most important, the patient's performance status and life expectancy. METHODS: This article reviews the evaluation and treatment of metastatic nonvertebral osseous lesions from the perspective of the orthopedic surgeon, based mainly on an assessment of the surgical literature. RESULTS: This article summarizes the approaches to preoperative evaluation, patient selection, and medical optimization. Guidelines for estimating osseous stability and fracture risk are discussed, and surgical implants and their relation to postoperative outcomes are examined. This review also describes less invasive ablative procedures currently available. CONCLUSIONS: The surgical management of nonvertebral osseous metastases involves multidisciplinary collaboration. The surgical construct must be a stable, reliable, and durable intervention that is individually tailored and matched to a patient's prognosis and performance status. PMID- 22487974 TI - Surgical management of metastatic spinal tumors. AB - BACKGROUND: The spine is the most common site of skeletal metastases. The evolution of surgical methods, medical treatment, and radiation therapy has led to improved survival, functional status, and quality of life for patients with cancer. The role of surgery in the treatment of patients with spinal metastases has evolved over time. METHODS: A review of publications describing the role of open surgery and vertebroplasty was performed and the results are summarized. RESULTS: The treatment goals of spinal metastases include the preservation and restoration of neurologic function and spinal stability. Modern imaging modalities provide accurate methods of tumor diagnosis. A variety of approaches and stabilization techniques are available and should be tailored to the location of the tumor and systemic comorbidities. CONCLUSIONS: As part of multidisciplinary treatment that includes radiation therapy and chemotherapy, surgery provides an effective method of restoration and preservation of neurologic function and spinal stability for patients with metastatic spinal tumors. PMID- 22487975 TI - Beyond the conventional role of external-beam radiation therapy for skeletal metastases: new technologies and stereotactic directions. AB - BACKGROUND: Radiation therapy is a common and effective treatment modality in the management of skeletal metastases. Recent advances in technology permitting delivery of an ablative radiation dose with an image-guided stereotactic approach improve the therapeutic threshold. METHODS: The authors reviewed the literature on conventional external-beam radiation therapy and summarized the emerging data about image-guided stereotactic body radiation therapy (SBRT) for vertebral oligometastasis. RESULTS: Pain control can be achieved effectively with conventional external-beam radiation therapy and may be further improved with image-guided spinal SBRT. Image-guided SBRT allows delivery of an ablative radiation dose with minimal toxicity, may potentially improve local tumor control, and may enhance clinical outcomes for histologies that are considered radioresistant. However, further understanding of long-term normal tissue toxicity is lacking. CONCLUSIONS: Radiotherapy options are expanding for patients with skeletal metastases. Image-guided spinal SBRT can deliver a safe ablative radiation dose to improve pain control and potentially local tumor control. Randomized clinical trials are ongoing to assess clinical benefits and outcome with spinal SBRT. PMID- 22487976 TI - The role of bone-seeking radionuclides in the palliative treatment of patients with painful osteoblastic skeletal metastases. AB - BACKGROUND: Pain from skeletal metastases represents a major burden of advanced disease from solid tumors. Analgesic medications, bisphosphonates, hormonal agents, cytotoxic chemotherapy, and external beam radiotherapy are all effective treatments. However, patients often suffer from diffuse painful metastases and respond poorly to these standard therapies. Bone-seeking radionuclides can specifically target osteoblastic lesions to offer palliation of pain. METHODS: This article offers a narrative review of bone-seeking radionuclides, examines the evidence of safety and efficacy for the treatment of painful skeletal metastases, and presents guidelines for their appropriate use in this patient population. RESULTS: Seven bone-seeking radionuclides have shown evidence of both safety and efficacy in reducing pain from diffuse skeletal metastases. 153Sm EDTMP and 89Sr are most commonly used in the United States and have been safely utilized for both repeat dosing as well as concurrent dosing with cytotoxic chemotherapy. CONCLUSIONS: Targeted bone-seeking radionuclides are underutilized in the treatment of painful diffuse osteoblastic metastases. Several new agents are in active clinical investigation, and the pending approval of the first alpha emitting radionuclide (223Ra) may offer a new class of agents that provide greater efficacy and less toxicity than those currently available for routine clinical use. PMID- 22487977 TI - Systemic therapy for bone metastases. AB - BACKGROUND: Accelerated bone loss in patients with cancer is a frequent problem that may result from invasion of the cancer to bone, paraneoplastic tumor proteins, and/or hormonal therapies utilized for cancer treatment. Patients with osteolytic bone disease from multiple myeloma and bone metastases from solid tumors may develop a vicious cycle of bone destruction involving both osteolytic and osteoblastic effects. Consequently, a variety of skeletal-related events (SREs) may occur, including pathological fractures, hypercalcemia, spinal cord compression, and the need for surgical intervention and radiation therapy. METHODS: This article reviews the results of trials that investigated the safety and efficacy of pharmacologic agents, including bisphosphonates and denosumab, for treatment of bone metastases. This analysis is derived from an assessment of the medical literature. RESULTS: Beneficial systemic therapies for bone metastases have been developed to decrease SREs. Possible antitumor effects of the bisphosphonates are explored. In addition, the utility of markers of bone turnover in relation to response to therapy and survival, the safety and toxicity of bone-targeted therapies, treatment guidelines, and economic considerations are also discussed. CONCLUSIONS: Effective systemic therapies for metastatic bone disease are available. Ongoing and future research projects in this field are also presented. PMID- 22487978 TI - The management of pain in metastatic bone disease. AB - BACKGROUND: Metastatic bone disease is a common cause of pain in cancer patients. A multidisciplinary approach to treatment is often necessary because simplified analgesic regimens may fail in the face of complex pain generators, especially those involved in the genesis of neuropathic pain. From the origins of formalized guidelines by the World Health Organization (WHO) to recent developments in implantable therapies, great strides have been made to meet the needs of these patients. METHODS: The authors review the existing literature on the pathophysiology and treatment options for pain generated by metastatic bone disease and summarize classic and new approaches. RESULTS: Relatively recent animal models of malignant bone disease have allowed a better understanding of the intimate mechanisms involved in the genesis of pain, resulting in a mechanistic approach to its treatment. Analgesic strategies can be developed with specific targets in mind to complement the classic, opioid-centered WHO analgesic ladder obtaining improved outcomes and quality of life. Unfortunately, high quality evidence is difficult to produce in pain medicine, and these concepts are evolving slowly. CONCLUSIONS: Treatment options are expanding for the challenging clinical problem of painful metastatic bone disease. Efforts are concentrated on developing alternative nonopioid approaches that appear to increase the success rate and improve patients' quality of life. PMID- 22487980 TI - Multilayer adaptive linear predictors for real-time tracking. AB - Enlarging or reducing the template size by adding new parts or removing parts of the template according to their suitability for tracking requires the ability to deal with the variation of the template size. For instance, real-time template tracking using linear predictors, although fast and reliable, requires using templates of a fixed size and does not allow online modification of the predictor. To solve this problem, we propose the Adaptive Linear Predictors (ALPs), which enable fast online modifications of prelearned linear predictors. Instead of applying a full matrix inversion for every modification of the template shape, as standard approaches to learning linear predictors do, we just perform a fast update of this inverse. This allows us to learn the ALPs in a much shorter time than standard learning approaches while performing equally well. Additionally, we propose a multilayer approach to detect occlusions and use ALPs to effectively handle them. This allows us to track large templates and modify them according to the present occlusions. We performed an exhaustive evaluation of our approach and compared it to standard linear predictors and other state-of the-art approaches. PMID- 22487979 TI - CCN5/WISP-2: A micromanager of breast cancer progression. AB - The gain of plasticity by a subset of cancer cells is a unique but common sequence of cancer progression from epithelial phenotype to mesenchymal phenotype (EMT) that is followed by migration, invasion and metastasis to a distant organ, and drug resistance. Despite multiple studies, it is still unclear how cancer cells regulate plasticity. Recent studies from our laboratory and others' proposed that CCN5/WISP-2, which is found intracellularly (in the nucleus and cytoplasm) and extracellularly, plays a negative regulator of plasticity. It prevents the EMT process in breast cancer cells as well as pancreatic cancer cells. Multiple genetic insults, including the gain of p53 mutations that accumulate over the time, may perturb CCN5 expression in non-invasive breast cancer cells, which ultimately helps cells to gain invasive phenotypes. Moreover, emerging evidence indicates that several oncogenic lesions such as miR-10b upregulation and activation of TGF-beta-signaling can accumulate during CCN5 crisis in breast cancer cells. Collectively, these studies indicate that loss of CCN5 activity may promote breast cancer progression; application of CCN5 protein may represent a novel therapeutic intervention in breast cancer and possibly pancreatic cancer. PMID- 22487981 TI - A hybrid multiview stereo algorithm for modeling urban scenes. AB - We present an original multiview stereo reconstruction algorithm which allows the 3D-modeling of urban scenes as a combination of meshes and geometric primitives. The method provides a compact model while preserving details: Irregular elements such as statues and ornaments are described by meshes, whereas regular structures such as columns and walls are described by primitives (planes, spheres, cylinders, cones, and tori). We adopt a two-step strategy consisting first in segmenting the initial meshbased surface using a multilabel Markov Random Field based model and second in sampling primitive and mesh components simultaneously on the obtained partition by a Jump-Diffusion process. The quality of a reconstruction is measured by a multi-object energy model which takes into account both photo-consistency and semantic considerations (i.e., geometry and shape layout). The segmentation and sampling steps are embedded into an iterative refinement procedure which provides an increasingly accurate hybrid representation. Experimental results on complex urban structures and large scenes are presented and compared to state-of-the-art multiview stereo meshing algorithms. PMID- 22487982 TI - Pose and Expression Independent Facial Landmark Localization Using Dense-SURF and the Hausdorff Distance. AB - We present an approach to automatic localization of facial feature points which deals with pose, expression, and identity variations combining 3D shape models with local image patch classification. The latter is performed by means of densely extracted SURF-like features, which we call DU-SURF, while the former is based on a multiclass version of the Hausdorff distance to address local classification errors and nonvisible points. The final system is able to localize facial points in real-world scenarios, dealing with out of plane head rotations, expression changes, and different lighting conditions. Extensive experimentation with the proposed method has been carried out showing the superiority of our approach with respect to other state-of-the-art systems. Finally, DU-SURF features have been compared with other modern features and we experimentally demonstrate their competitive classification accuracy and computational efficiency. PMID- 22487983 TI - Human pose co-estimation and applications. AB - Most existing techniques for articulated Human Pose Estimation (HPE)consider each person independently. Here we tackle the problem in a new setting,coined Human Pose Coestimation (PCE), where multiple people are in a common,but unknown pose. The task of PCE is to estimate their poses jointly and toproduce prototypes characterizing the shared pose. Since the poses of the individual people should be similar to the prototype, PCE has less freedom compared to estimating each pose independently, which simplifies the problem.We demonstrate our PCE technique on two applications. The first is estimating the pose of people performing the same activity synchronously, such as during aerobics, cheerleading, and dancing in a group. We show that PCE improves pose estimation accuracy over estimating each person independently. The second application is learning prototype poses characterizing a pose class directly from an image search engine queried by the class name (e.g., "lotus pose"). We show that PCE leads to better pose estimation in such images, and it learns meaningful prototypes which can be used as priors for pose estimation in novel images. PMID- 22487984 TI - Robust recovery of subspace structures by low-rank representation. AB - In this paper, we address the subspace clustering problem. Given a set of data samples (vectors) approximately drawn from a union of multiple subspaces, our goal is to cluster the samples into their respective subspaces and remove possible outliers as well. To this end, we propose a novel objective function named Low-Rank Representation (LRR), which seeks the lowest rank representation among all the candidates that can represent the data samples as linear combinations of the bases in a given dictionary. It is shown that the convex program associated with LRR solves the subspace clustering problem in the following sense: When the data is clean, we prove that LRR exactly recovers the true subspace structures; when the data are contaminated by outliers, we prove that under certain conditions LRR can exactly recover the row space of the original data and detect the outlier as well; for data corrupted by arbitrary sparse errors, LRR can also approximately recover the row space with theoretical guarantees. Since the subspace membership is provably determined by the row space, these further imply that LRR can perform robust subspace clustering and error correction in an efficient and effective way. PMID- 22487985 TI - State-of-the-art in visual attention modeling. AB - Modeling visual attention--particularly stimulus-driven, saliency-based attention -has been a very active research area over the past 25 years. Many different models of attention are now available which, aside from lending theoretical contributions to other fields, have demonstrated successful applications in computer vision, mobile robotics, and cognitive systems. Here we review, from a computational perspective, the basic concepts of attention implemented in these models. We present a taxonomy of nearly 65 models, which provides a critical comparison of approaches, their capabilities, and shortcomings. In particular, 13 criteria derived from behavioral and computational studies are formulated for qualitative comparison of attention models. Furthermore, we address several challenging issues with models, including biological plausibility of the computations, correlation with eye movement datasets, bottom-up and top-down dissociation, and constructing meaningful performance measures. Finally, we highlight current research trends in attention modeling and provide insights for future. PMID- 22487988 TI - CSD homomorphisms between phylogenetic networks. AB - Since Darwin, species trees have been used as a simplified description of the relationships which summarize the complicated network N of reality. Recent evidence of hybridization and lateral gene transfer, however, suggest that there are situations where trees are inadequate. Consequently it is important to determine properties that characterize networks closely related to N and possibly more complicated than trees but lacking the full complexity of N. A connected surjective digraph map (CSD) is a map f from one network N to another network M such that every arc is either collapsed to a single vertex or is taken to an arc, such that f is surjective, and such that the inverse image of a vertex is always connected. CSD maps are shown to behave well under composition. It is proved that if there is a CSD map from N to M, then there is a way to lift an undirected version of M into N, often with added resolution. A CSD map from N to M puts strong constraints on N. In general, it may be useful to study classes of networks such that, for any N, there exists a CSD map from N to some standard member of that class. PMID- 22487987 TI - Effects of heat acclimation on endurance capacity and prolactin response to exercise in the heat. AB - We examined the effect of heat acclimation (HA) on endurance capacity and blood prolactin (PRL) response to moderate intensity exercise in the heat in young male subjects (n = 21). Three exercise tests (ET) were completed on a treadmill: H1 (walk at 60% VO(2)peak until exhaustion at 42 degrees C), N (walk at 22 degrees C; duration equal to H1) and H2 (walk until exhaustion at 42 degrees C after a 10 day HA program). Heart rate (HR), skin (T (sk)) and core (T (c)) temperatures and body heat storage (HS) were measured. Blood samples were taken immediately before, during and immediately after each ET. HA resulted in lower HR, T (sk), T (c) and HS rate (P < 0.05) during ET, whereas endurance capacity increased from 88.6 +/- 27.5 min in H1 to 162.0 +/- 47.8 min in H2 (P < 0.001). Blood PRL concentration was lower (P < 0.05) during exercise in H2 compared to H1 but the peak PRL level observed at the time of exhaustion did not differ in the two trials. Blood PRL concentration at 60 min of exercise in H1 correlated with time to exhaustion in H1 (r = -0.497, P = 0.020) and H2 (r = -0.528, P = 0.014). In conclusion, HA slows down the increase in blood PRL concentration but does not reduce the peak PRL level occurring at the end of exhausting endurance exercise in the heat. Blood PRL response to exercise in the heat in non-heat-acclimated subjects is associated with their endurance capacity in the heat in a heat acclimated state. PMID- 22487989 TI - Synthesis of novel heterobimetallic copper(I) hydrazone Schiff base complexes: a comparative study on the effect of heterocyclic hydrazides towards interaction with DNA/protein, free radical scavenging and cytotoxicity. AB - Two new copper(I) hydrazone complexes have been synthesised from bivalent copper precursor [CuCl(2)(PPh(3))(2)] and ferrocene containing bidentate hydrazone ligands HL(1) (1) or HL(2) (2). Based on the elemental analyses and spectroscopic data, the complexes are best formulated as [CuL(1)(PPh(3))(2)] (3) and [CuL(2)(PPh(3))(2)] (4) of the monovalent copper ion. Solid state structures of ligand 2 and its corresponding complex 4 were also determined. The DNA/albumin interactions of all the synthesised compounds were investigated using absorption, emission and synchronous fluorescence studies. Further, antioxidant properties of all the compounds have also been checked against ABTS, O(2)(-) and OH radicals. Additionally, the in vitro cytotoxic activity of compounds 1-4 was assessed using tumour (HeLa, A431) and non-tumour (NIH 3T3) cell lines. PMID- 22487990 TI - A case of a patient with protein C deficiency presenting with concurrent thromboses in the pulmonary arteries and innominate artery: a suggestive computed tomographic finding of thrombophilia. AB - The incidence of arterial thrombosis in patients with protein C deficiency is relatively low compared with that of venous thrombosis. To our knowledge, there is no previously published report of a protein C deficiency patient with simultaneous thromboses in the pulmonary artery and innominate artery in the English literature. We present a case of a protein C deficiency in which the presence of concurrent clots in the pulmonary arteries and innominate artery demonstrated on a pulmonary computed tomographic angiography provided an important clue permitting diagnosis of the deficiency. PMID- 22487991 TI - Nonsuppressing normal thymus on chemical shift magnetic resonance imaging in a young woman. AB - A previously healthy 21-year-old woman presented with syncope and arrhythmia. A computed tomographic coronary angiogram was solely remarkable for an anterior mediastinal mass. Mediastinal magnetic resonance imaging of the reported mass revealed mildly prominent thymic tissue for age, with no suppression on out-of phase chemical shift magnetic resonance imaging. Thymoma and lymphoma could not be excluded. After diagnosis and stabilization of her arrhythmia, the patient underwent median sternotomy and radical thymectomy, with pathology revealing normal thymus. This case suggests that nonsuppression of mildly prominent, homogenous thymic soft tissue in young women may not be sufficient to warrant diagnostic intervention and instead may warrant close follow-up. PMID- 22487992 TI - Evaluation of discrete upper septal thickening on 64-slice coronary computed tomographic angiography. AB - PURPOSE: Discrete upper septal thickening (DUST) has been well described in the echocardiology literature. To our knowledge, the computed tomography findings of DUST, however, have not been previously described. MATERIALS AND METHODS: Five hundred consecutive coronary computed tomography angiograms were evaluated by 2 cardiothoracic radiologists for the presence of DUST. RESULTS: Of the 500 studies reviewed, 23 cases had features consistent with DUST (23/500 = 5%). The average systolic blood pressure of patients with DUST (150/77 mm Hg) was higher than that of patients without DUST (133/75 mm Hg). Patients with DUST were older (mean 63 y) than patients without DUST (mean 50 y). None of these patients had evidence of abnormal systolic anterior motion of the mitral valve on cine imaging. CONCLUSIONS: DUST is seen on coronary computed tomography angiograms and has imaging characteristics distinct from significant pathology, such as hypertrophic cardiomyopathy. Recognizing DUST is important because, unlike hypertrophic cardiomyopathy, previous studies have not found an associated adverse prognosis with DUST. PMID- 22487993 TI - High-pitch dual-source computed tomography pulmonary angiography in freely breathing patients. AB - PURPOSE: To investigate pulmonary arterial (PA) enhancement, image noise, and artifacts related to breathing and heart motion in patients with suspected pulmonary embolism. MATERIALS AND METHODS: Seventy-six consecutive patients underwent computed tomographic pulmonary angiography (CTPA) in dual-source high pitch mode (pitch 3.0, 100 kV, 180 mAs, 50 mL contrast material) without breathing commands. PA enhancement, image noise, signal to noise ratio, overall image quality, incidence of total or partial interruption of the contrast column in the PAs, and heart motion-related and breathing-related artifacts of the diaphragm and pulmonary structures were recorded. RESULTS: Mean central and peripheral PA attenuation was 404 +/- 104 and 453 +/- 119 HU; mean image noise was 11 +/- 2 HU; mean examination time was 0.67 +/- 0.09 s; and mean dose-length product was 142 +/- 31 mGy cm. There were no motion artifacts of the diaphragm or pulmonary vessels related to breathing or heart motion. There was no case of partial or total interruption of the contrast column in the PA tree. No examination was rated nondiagnostic. CONCLUSIONS: High-pitch dual-source CTPA in freely breathing patients effectively produces images that are free of artifacts related to breathing and cardiac motion. Hence, Valsalva-related artifacts can be eliminated using this technique. PMID- 22487994 TI - Effect of aging on lung structure in vivo: assessment with densitometric and fractal analysis of high-resolution computed tomography data. AB - PURPOSE: To test the hypothesis that there is a difference between the lung computed tomography (CT) microstructure of asymptomatic older individuals and that of young individuals as evaluated by objective indices of complexity and density. MATERIALS AND METHODS: Two study groups of nonsmoking urban-dwelling individuals over 75 years and under 55 years were prospectively identified. Thirty-three consecutive volunteers (21 older than 75 y and 12 less than 55 y) were included, and CTs were performed with concurrent pulmonary function testing. Pulmonary regions of interest (ROIs) were evaluated with fractal dimension (FD) analysis (an index of complexity), mean lung density (MLD), and percentage of pixels with lung density (LD) less than thresholds of -910 HU and -950 HU. The Student t test and the Mann-Whitney test were used to evaluate for differences in mean values between groups. The Pearson correlation coefficient was used to correlate mean FD value and LD data with pulmonary function. RESULTS: Significant correlations of ROI MLD, LD -910 HU, and LD -950 HU with age and sex were shown (P = 0.029-0.003). The ROI mean FD value was greater in younger individuals compared with older individuals (76.5 +/- 1.7 vs. 70.3 +/- 1.2; P = 0.004). There was a correlation between Kco (gas-diffusing capacity adjusted for alveolar volume) and mean FD value (P = 0.006) and MLD (P = 0.015). CONCLUSION: The lung parenchyma of nonsmoking older urban-dwelling asymptomatic individuals has significantly different CT density and complexity compared with younger individuals. PMID- 22487995 TI - Assessing the credibility of the "YouTube approach" to health information on acute myocardial infarction. AB - BACKGROUND: This study was designed to assess the credibility of YouTube video information on acute myocardial infarction by exploring the relationship between accuracy of information on the topic, source of expertise, and perceived credibility of the message. HYPOTHESIS: Health information videos in YouTube possess a diverse mix of information and can easily mislead online information seekers. METHODS: The Web site http://www.YouTube.com was queried for the following search terms: "acute myocardial infarction," "heart attack," "acute coronary syndrome," and "ST-elevation myocardial infarction." The resulting videos were categorized according to the source of the video and content was analyzed for discussion of different aspects of disease, ranging from pathophysiology to treatment. RESULTS: Only 6% of videos touched upon all aspects of acute myocardial infarction. These were mostly from professional societies, were of long duration, and were among the least viewed. Videos that described personal experiences were "liked" or "disliked" most and had the majority of comments. Only 17% of the videos discussed the preventive aspects of the disease and stressed weight-loss and exercise programs. Videos that stressed prevention were advertisements for specific weight-loss programs (45%) and diet pills (30%). Very few videos stressed other risk factors. A large number of videos were irrelevant. CONCLUSIONS: YouTube is a popular platform across the globe for sharing video information, including videos related to health and disease. However, the information on this platform is not regulated and can easily mislead those seeking it. We suggest that authoritative videos should come from reputable sources such as professional societies and/or academic institutions and should provide unbiased and accurate information on all aspects of diseases like acute myocardial infarction. PMID- 22487996 TI - Mild therapeutic hypothermia in cardiogenic shock syndrome. AB - OBJECTIVE: Mortality in patients with cardiogenic shock after out-of-hospital cardiac arrest remains high despite advances in resuscitation and early revascularization strategies. Recent studies suggest a reduced mortality in survivors of cardiac arrest subjected to mild therapeutic hypothermia, but the underlying mechanisms are not yet clear. Because positive hemodynamic effects of mild therapeutic hypothermia have been suggested, we aimed at testing the hypothesis that patients in cardiogenic shock might benefit from mild therapeutic hypothermia. METHODS: Hemodynamic effects of mild therapeutic hypothermia in 20 consecutive patients admitted in cardiogenic shock after successful resuscitation from out-of-hospital cardiac arrest were investigated. A historic normothermic control group was matched (one-to-one) by means of a propensity score. Patients were cooled to 33 degrees C for 24 hrs using an endovascular cooling device and hemodynamic variables were continuously recorded by means of pulse contour analysis. Cardiac performance was determined by echocardiography. RESULTS: Mild therapeutic hypothermia induced a significant decrease in heart rate from 74 to 64 beats per minute. Despite the reduction in heart rate, cardiac index remained unchanged under mild therapeutic hypothermia likely due to an increase in ejection fraction from 43 +/- 4% to 55 +/- 4%. Mean arterial pressure increased rapidly from 75 +/- 2 mm Hg to 84 +/- 3 mm Hg (p = .001) upon induction of hypothermia paralleled by an initial increase in systemic vascular resistance. Accordingly, patients with mild therapeutic hypothermia required lower cumulative doses of vasopressors and inotropes. CONCLUSIONS: We conclude that in cardiogenic shock mild therapeutic hypothermia provides circulatory support and an increase in systemic vascular resistance that leads to reduced vasopressor use and may result in lower oxygen consumption. These findings suggest that mild therapeutic hypothermia could be a therapeutic option in hemodynamically unstable patients independent of cardiac arrest and further randomized clinical studies are needed. PMID- 22487997 TI - Improved cerebral perfusion pressures and 24-hr neurological survival in a porcine model of cardiac arrest with active compression-decompression cardiopulmonary resuscitation and augmentation of negative intrathoracic pressure. AB - OBJECTIVE: Generation of negative intrathoracic pressure during the decompression phase of cardiopulmonary resuscitation enhances the refilling of the heart. We tested the hypothesis that when compared with closed-chest manual compressions at 80 chest compressions per min, treatment with active compression-decompression cardiopulmonary resuscitation at 80 chest compressions/min combined with augmentation of negative intrathoracic pressure would lower intracranial pressure and increase cerebral perfusion, thereby improving neurologically intact survival rates following prolonged untreated cardiac arrest. DESIGN: Prospective, randomized animal study. SETTING: Animal laboratory facilities. SUBJECTS: A total of 26 female farm pigs in two different protocols (n = 17 and n = 9). INTERVENTIONS, MEASUREMENTS, AND MAIN RESULTS: Seventeen pigs were subjected to 8.5 mins of untreated ventricular fibrillation and prospectively randomized to cardiopulmonary resuscitation at 80 chest compressions/min or active compression decompression cardiopulmonary resuscitation at 80 chest compressions/min plus an impedance threshold device. Coronary perfusion pressures (29.5 +/- 2.7 mm Hg vs. 22.4 +/- 1.6 mm Hg, p = .03), carotid blood flow (44.0 +/- 12.2 vs. 30.9 +/- 10.4, p = .03), and 24-hr neurological survival (88% vs. 22%, p = .015) were higher with active compression-decompression cardiopulmonary resuscitation + an impedance threshold device. Cerebral perfusion pressures, measured in nine additional pigs, were improved with active compression-decompression cardiopulmonary resuscitation + an impedance threshold device (21.9 +/- 1.2 mm Hg vs. 8.9 +/- 0.8 mm Hg, p < .0001). With active compression-decompression cardiopulmonary resuscitation + impedance threshold device, mean diastolic intracranial pressure during decompression was lower (12.2 +/- 0.2 mm Hg vs. 16.6 +/- 1.2 mm Hg, p = .02) and the downward slope of the decompression phase intracranial pressure curve was steeper (-60.3 +/- 12.9 mm Hg vs. -46.7 +/- 11.1 mm Hg/sec, p < .001). CONCLUSIONS: Active compression-decompression cardiopulmonary resuscitation + an impedance threshold device increased cerebral perfusion pressures and lowered diastolic intracranial pressure and intracranial pressure rate during the decompression phase. These mechanisms may underlie the observed increase in cerebral perfusion pressure, carotid blood flow, and survival rates with favorable neurologic outcomes in this pig model of cardiac arrest. PMID- 22487999 TI - Measurement of renal blood flow by phase-contrast magnetic resonance imaging during septic acute kidney injury: a pilot investigation. AB - OBJECTIVE: In septic patients, decreased renal perfusion is considered to play a major role in the pathogenesis of acute kidney injury. However, the accurate measurement of renal blood flow in such patients is problematic and invasive. We sought to overcome such obstacles by measuring renal blood flow in septic patients with acute kidney injury using cine phase-contrast magnetic resonance imaging. DESIGN: Pilot observational study. SETTING: University-affiliated general adult intensive care unit. PATIENTS: Ten adult patients with established septic acute kidney injury and 11 normal volunteers. INTERVENTIONS: Cine phase contrast magnetic resonance imaging measurement of renal blood flow and cardiac output. MEASUREMENTS AND MAIN RESULTS: The median age of the study patients was 62.5 yrs and eight were male. At the time of magnetic resonance imaging, eight patients were mechanically ventilated, nine were on continuous hemofiltration, and five required vasopressors. Cine phase-contrast magnetic resonance imaging examinations were carried out without complication. Median renal blood flow was 482 mL/min (range 335-1137) in septic acute kidney injury and 1260 mL/min (range 791-1750) in healthy controls (p = .003). Renal blood flow indexed to body surface area was 244 mL/min/m2 (range 165-662) in septic acute kidney injury and 525 mL/min/m2 (range 438-869) in controls (p = .004). In patients with septic acute kidney injury, median cardiac index was 3.5 L/min/m2 (range 1.6-8.7), and median renal fraction of cardiac output was only 7.1% (range 4.4-10.8). There was no rank correlation between renal blood flow index and creatinine clearance in patients with septic acute kidney injury (r = .26, p = .45). CONCLUSIONS: Cine phase-contrast magnetic resonance imaging can be used to noninvasively and safely assess renal perfusion during critical illness in man. Near-simultaneous accurate measurement of cardiac output enables organ blood flow to be assessed in the context of the global circulation. Renal blood flow seems consistently reduced as a fraction of cardiac output in established septic acute kidney injury. Cine phase-contrast magnetic resonance imaging may be a valuable tool to further investigate renal blood flow and the effects of therapies on renal blood flow in critical illness. PMID- 22487998 TI - Cross-talk between the calpain and caspase-3 proteolytic systems in the diaphragm during prolonged mechanical ventilation. AB - OBJECTIVE: Diaphragmatic weakness, due to both atrophy and contractile dysfunction, is a well-documented response following prolonged mechanical ventilation. Evidence indicates that activation of the proteases calpain and caspase-3 is essential for mechanical ventilation-induced diaphragmatic weakness to occur. We tested the hypothesis that a regulatory cross-talk exists between calpain and caspase-3 in the diaphragm during prolonged mechanical ventilation. To test this prediction, we determined whether selective pharmacological inhibition of calpain would prevent activation of caspase-3 and conversely whether selective inhibition of caspase-3 would abate calpain activation. DESIGN: Animal study. SETTING: University Research Laboratory. SUBJECTS: Female Sprague Dawley rats. INTERVENTIONS: Animals were randomly divided into control or one of three 12-hr mechanical ventilation groups that were treated with/without a selective pharmacological protease inhibitor: 1) control, 2) mechanical ventilation, 3) mechanical ventilation with a selective caspase-3 inhibitor, and 4) mechanical ventilation with a selective calpain inhibitor. MEASUREMENTS AND MAIN RESULTS: Compared to control, mechanical ventilation resulted in calpain and caspase-3 activation in the diaphragm accompanied by atrophy of type I, type IIa, and type IIx/IIb fibers. Independent inhibition of either calpain or caspase-3 prevented this mechanical ventilation-induced atrophy. Pharmacological inhibition of calpain prevented mechanical ventilation-induced activation of diaphragmatic caspase-3 and inhibition of caspase-3 prevented activation of diaphragmatic calpain. Furthermore, calpain inhibition also prevented the activation of caspase 9 and caspase-12, along with the cleavage of Bid to tBid, all upstream signals for caspase-3 activation. Lastly, caspase-3 inhibition prevented the mechanical ventilation-induced degradation of the endogenous calpain inhibitor, calpastatin. CONCLUSIONS: Collectively, these results indicate that mechanical ventilation induced diaphragmatic atrophy is dependent on the activation of both calpain and caspase-3. Importantly, these findings provide the first experimental evidence in diaphragm muscle that calpain inhibition prevents the activation of caspase-3 and vice versa and caspase-3 inhibition prevents the activation of calpain. These findings support our hypothesis that a regulatory calpain/caspase-3 cross-talk exists whereby calpain can promote caspase-3 activation and active caspase-3 can enhance calpain activity in diaphragm muscle during prolonged mechanical ventilation. PMID- 22488000 TI - Isoflurane delays the development of early brain injury after subarachnoid hemorrhage through sphingosine-related pathway activation in mice. AB - OBJECTIVE: Isoflurane, a volatile anesthetic agent, has been recognized for its potential neuroprotective properties and has antiapoptotic effects. We examined whether isoflurane posttreatment is protective against early brain injury after subarachnoid hemorrhage and determined whether this effect needs sphingosine related pathway activation. DESIGN: Controlled in vivo laboratory study. SETTING: Animal research laboratory. SUBJECTS: One hundred seventy-nine 8-wk-old male CD-1 mice weighing 30-38 g. INTERVENTIONS: Subarachnoid hemorrhage was induced in mice by endovascular perforation. Animals were randomly assigned to sham-operated, subarachnoid hemorrhage-vehicle, and subarachnoid hemorrhage+2% isoflurane. Neurobehavioral function and brain edema were evaluated at 24 and 72 hrs. The expression of sphingosine kinase, phosphorylated Akt, and cleaved caspase-3 was determined by Western blotting and immunofluorescence. Neuronal cell death was examined by terminal deoxynucleotidyl transferase-mediated uridine 5' triphosphate-biotin nick end-labeling staining. Effects of a sphingosine kinase inhibitor N, N-dimethylsphingosine or a sphingosine 1 phosphate receptor inhibitor VPC23019 on isoflurane's protective action against postsubarachnoid hemorrhage early brain injury were also examined. MEASUREMENTS AND MAIN RESULTS: Isoflurane significantly improved neurobehavioral function and brain edema at 24 hrs but not 72 hrs after subarachnoid hemorrhage. At 24 hrs, isoflurane attenuated neuronal cell death in the cortex, associated with an increase in sphingosine kinase 1 and phosphorylated Akt, and a decrease in cleaved caspase-3. The beneficial effects of isoflurane were abolished by N, N-dimethylsphingosine and VPC23019. CONCLUSIONS: Isoflurane posttreatment delays the development of postsubarachnoid hemorrhage early brain injury through antiapoptotic mechanisms including sphingosine-related pathway activation, implying its use for anesthesia during acute aneurysm surgery or intervention. PMID- 22488001 TI - Factors influencing intracranial pressure monitoring guideline compliance and outcome after severe traumatic brain injury. AB - OBJECTIVE: To determine adherence to Brain Trauma Foundation guidelines for intracranial pressure monitoring after severe traumatic brain injury, to investigate if characteristics of patients treated according to guidelines (ICP+) differ from those who were not (ICP-), and whether guideline compliance is related to 6-month outcome. DESIGN: Observational multicenter study. PATIENTS: Consecutive severe traumatic brain injury patients (>=16 yrs, n = 265) meeting criteria for intracranial pressure monitoring. MEASUREMENTS AND MAIN RESULTS: Data on demographics, injury severity, computed tomography findings, and patient management were registered. The Glasgow Outcome Scale Extended was dichotomized into death (Glasgow Outcome Scale Extended = 1) and unfavorable outcome (Glasgow Outcome Scale Extended 1-4). Guideline compliance was 46%. Differences between the monitored and nonmonitored patients included a younger age (median 44 vs. 53 yrs), more abnormal pupillary reactions (52% vs. 32%), and more intracranial pathology (subarachnoid hemorrhage 62% vs. 44%; intraparenchymal lesions 65% vs. 46%) in the ICP+ group. Patients with a total intracranial lesion volume of ~150 mL and a midline shift of ~12 mm were most likely to receive an intracranial pressure monitor and probabilities decreased with smaller and larger lesions and shifts. Furthermore, compliance was low in patients with no (Traumatic Coma Databank score I -10%) visible intracranial pathology. Differences in case-mix resulted in higher a priori probabilities of dying (median 0.51 vs. 0.35, p < .001) and unfavorable outcome (median 0.79 vs. 0.63, p < .001) in the ICP+ group. After correction for baseline and clinical characteristics with a propensity score, intracranial pressure monitoring guideline compliance was not associated with mortality (odds ratio 0.93, 95% confidence interval 0.47-1.85, p = .83) nor with unfavorable outcome (odds ratio 1.81, 95% confidence interval 0.88-3.73, p = .11). CONCLUSIONS: Guideline noncompliance was most prominent in patients with minor or very large computed tomography abnormalities. Intracranial pressure monitoring was not associated with 6-month outcome, but multiple baseline differences between monitored and nonmonitored patients underline the complex nature of examining the effect of intracranial pressure monitoring in observational studies. PMID- 22488004 TI - Matching positive end-expiratory pressure to intra-abdominal pressure prevents end-expiratory lung volume decline in a pig model of intra-abdominal hypertension. AB - OBJECTIVE: Intra-abdominal hypertension is common in critically ill patients and is associated with increased morbidity and mortality. In a previous experimental study, positive end-expiratory pressures of up to 15 cm H2O did not prevent end expiratory lung volume decline caused by intra-abdominal hypertension. Therefore, we examined the effect of matching positive end-expiratory pressure to the intra abdominal pressure on cardio-respiratory parameters. DESIGN: Experimental pig model of intra-abdominal hypertension. SETTING: Large animal facility, University of Western Australia. SUBJECTS: Nine anesthetized, nonparalyzed, and ventilated pigs (48 +/- 7 kg). INTERVENTIONS: Four levels of intra-abdominal pressure (baseline, 12, 18, and 22 mm Hg) were generated in a randomized order by inflating an intra-abdominal balloon. At each level of intra-abdominal pressure, three levels of positive end-expiratory pressure were randomly applied with varying degrees of matching the corresponding intra-abdominal pressure: baseline positive end-expiratory pressure (= 5 cm H2O), moderate positive end-expiratory pressure (= half intra-abdominal pressure in cm H2O + 5 cm H2O), and high positive end-expiratory pressure (= intra-abdominal pressure in cm H2O). MEASUREMENTS: We measured end-expiratory lung volume, arterial oxygen levels, respiratory mechanics, and cardiac output 5 mins after each new intra-abdominal pressure and positive end-expiratory pressure setting. MAIN RESULTS: Intra abdominal hypertension decreased end-expiratory lung volume and PaO2 (-49% [p < .001] and -8% [p < .05], respectively, at 22 mm Hg intra-abdominal pressure compared with baseline intra-abdominal pressure) but did not change cardiac output (p = .5). At each level of intra-abdominal pressure, moderate positive end expiratory pressure increased end-expiratory lung volume (+119% [p < .001] at 22 mm Hg intra-abdominal pressure compared with 5 cm H2O positive end-expiratory pressure) while minimally decreasing cardiac output (-8%, p < .05). High positive end-expiratory pressure further increased end-expiratory lung volume (+233% [p < .001] at 22 mm Hg intra-abdominal pressure compared with 5 cm H2O positive end expiratory pressure) but led to a greater decrease in cardiac output (-26%, p < .05). Neither moderate nor high positive end-expiratory pressure improved PaO2 (p = .7). Intra-abdominal hypertension decreased end-expiratory transpulmonary pressure but did not alter end-inspiratory transpulmonary pressure. Intra abdominal hypertension decreased total respiratory compliance through a decrease in chest wall compliance. Positive end-expiratory pressure decreased the respiratory compliance by reducing lung compliance. CONCLUSIONS: In a pig model of intra-abdominal hypertension, positive end-expiratory pressure matched to intra-abdominal pressure led to a preservation of end-expiratory lung volume, but did not improve arterial oxygen tension and caused a reduction in cardiac output. Therefore, we do not recommend routine application of positive end-expiratory pressure matched to intra-abdominal pressure to prevent intra-abdominal pressure induced end-expiratory lung volume decline in healthy lungs. PMID- 22488002 TI - A double-blind, randomized clinical trial comparing soybean oil-based versus olive oil-based lipid emulsions in adult medical-surgical intensive care unit patients requiring parenteral nutrition. AB - OBJECTIVE: Parenteral nutrition has been associated with metabolic and infectious complications in intensive care unit patients. The underlying mechanism for the high risk of complications is not known but may relate to the proinflammatory effects of soybean oil-based lipid emulsions, the only Food and Drug Administration-approved lipid formulation for clinical use. DESIGN: Prospective, double-blind, randomized, controlled trial. SETTING: Medical-surgical intensive care units from a major urban teaching hospital and a tertiary referral university hospital. PATIENTS: Adult medical-surgical intensive care unit patients. INTERVENTION: Parenteral nutrition containing soybean oil-based (Intralipid) or olive oil-based (ClinOleic) lipid emulsions. MEASUREMENTS: Differences in hospital clinical outcomes (nosocomial infections and noninfectious complications), hospital length of stay, glycemic control, inflammatory and oxidative stress markers, and granulocyte and monocyte functions between study groups. RESULTS: A total of 100 patients were randomized to either soybean oil-based parenteral nutrition or olive oil-based parenteral nutrition for up to 28 days. A total of 49 patients received soybean oil-based parenteral nutrition (age 51 +/- 15 yrs, body mass index 27 +/- 6 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.5 +/- 7 [+/-SD]), and a total of 51 patients received olive oil-based lipid emulsion in parenteral nutrition (age 46 +/- 19 yrs, body mass index 27 +/- 8 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.1 +/- 6 [+/-SD]) for a mean duration of 12.9 +/- 8 days. The mean hospital blood glucose concentration during parenteral nutrition was 129 +/- 14 mg/dL, without differences between groups. Patients treated with soybean oil-based and olive oil-based parenteral nutrition had a similar length of stay (47 +/- 47 days and 41 +/- 36 days, p = .49), mortality (16.3% and 9.8%, p = .38), nosocomial infections (43% vs. 57%, p = .16), and acute renal failure (26% vs. 18%, p = .34). In addition, there were no differences in inflammatory and oxidative stress markers or in granulocyte and monocyte functions between groups. CONCLUSION: The administration of parenteral nutrition containing soybean oil-based and olive oil-based lipid emulsion resulted in similar rates of infectious and noninfectious complications and no differences in glycemic control, inflammatory and oxidative stress markers, and immune function in critically ill adults. PMID- 22488003 TI - Dressing disruption is a major risk factor for catheter-related infections. AB - OBJECTIVE: Major catheter-related infection includes catheter-related bloodstream infections and clinical sepsis without bloodstream infection resolving after catheter removal with a positive quantitative tip culture. Insertion site dressings are a major mean to reduce catheter infections by the extraluminal route. However, the importance of dressing disruptions in the occurrence of major catheter-related infection has never been studied in a large cohort of patients. DESIGN: A secondary analysis of a randomized multicenter trial was performed in order to determine the importance of dressing disruption on the risk for development of catheter-related bloodstream infection. MEASUREMENTS AND MAIN RESULTS: Among 1,419 patients (3,275 arterial or central-vein catheters) included, we identified 296 colonized catheters, 29 major catheter-related infections, and 23 catheter-related bloodstream infections. Of the 11,036 dressings changes, 7,347 (67%) were performed before the planned date because of soiling or undressing. Dressing disruption occurred more frequently in patients with higher Sequential Organ Failure Assessment scores and in patients receiving renal replacement therapies; it was less frequent in males and patients admitted for coma. Subclavian access protected from dressing disruption. Dressing cost (especially staff cost) was inversely related to the rate of disruption. The number of dressing disruptions was related to increased risk for colonization of the skin around the catheter at removal (p < .0001). The risk of major catheter related infection and catheter-related bloodstream infection increased by more than three-fold after the second dressing disruption and by more than ten-fold if the final dressing was disrupted, independently of other risk factors of infection. CONCLUSION: Disruption of catheter dressings was common and was an important risk factor for catheter-related infections. These data support the preferential use of the subclavian insertion site and enhanced efforts to reduce dressing disruption in postinsertion bundles of care. PMID- 22488005 TI - Unlike arginine vasopressin, the selective V1a receptor agonist FE 202158 does not cause procoagulant effects by releasing von Willebrand factor. AB - OBJECTIVE: To compare the effects on von Willebrand factor release of the mixed vasopressin type 1a and type 2 receptor agonist arginine vasopressin and the selective vasopressin type 1a receptor agonist FE 202158, [Phe2,Ile3,Hgn4,Orn(iPr)8]vasopressin, at doses required for the treatment of septic shock. DESIGN: Prospective, randomized, controlled laboratory experiment. SETTING: University animal research facility. SUBJECTS: Twenty-four chronically instrumented sheep. INTERVENTIONS: After a 5-day recovery from instrumentation, sheep were randomly assigned to receive a single intravenous bolus of the selective vasopressin type 2 receptor agonist desmopressin (1 nmol.kg(-1)) or continuous intravenous infusions of arginine vasopressin (3 pmol.kg(-1).min(-1)), the selective vasopressin type 1a receptor agonist FE 202158 (10 pmol.kg(-1).min( 1)), or vehicle (0.9% NaCl) (n = 6 each). MEASUREMENTS AND MAIN RESULTS: The von Willebrand factor antigen activity relative to hemoglobin concentration (vWF:Ag/Hb ratio) was measured at different time points during the 120-min study period. Maximal vWF:Ag/Hb ratio expressed as percentage of baseline level was significantly increased compared to vehicle-infused animals (3 +/- 2%) in the desmopressin (40 +/- 6%, p < .001) and arginine vasopressin groups (25 +/- 4%, p < .001). The ratio for the FE 202158 group was not statistically different from the sham group (9 +/- 2%, p = .208). Notably, maximal vWF:Ag/Hb ratio was lower in the FE 202158 than the arginine vasopressin group (p < .005). CONCLUSIONS: Unlike the mixed vasopressin type 1a receptor/vasopressin type 2 receptor agonist arginine vasopressin, the selective vasopressin type 1a receptor agonist FE 202158 does not release von Willebrand factor. Because von Willebrand factor is involved in coagulatory and inflammatory pathways during septic shock, future studies should clarify the role of the vasopressin type 2 receptor-mediated von Willebrand factor increase by arginine vasopressin and the potential benefit of selective vasopressin type 1a receptor-agonists like FE 202158. PMID- 22488006 TI - Heparin or 0.9% sodium chloride to maintain central venous catheter patency: a randomized trial. AB - OBJECTIVE: To compare heparin (3 mL, 10 units/mL) and 0.9% sodium chloride (NaCl, 10 mL) flush solutions with respect to central venous catheter lumen patency. DESIGN: Single-center, randomized, open label trial. SETTING: Medical intensive care unit and Surgical/Burn/Trauma intensive care unit at Barnes-Jewish Hospital, St. Louis, MO. PATIENTS: Three hundred forty-one patients with multilumen central venous catheters. Patients with at least one lumen with a minimum of two flushes were included in the analysis. INTERVENTIONS: Patients were randomly assigned within 12 hrs of central venous catheter insertion to receive either heparin or 0.9% sodium chloride flush. MEASUREMENTS AND MAIN RESULTS: The primary outcome was lumen nonpatency. Secondary outcomes included the rates of loss of blood return, inability to infuse or flush through the lumen (flush failure), heparin induced thrombocytopenia, and catheter-related blood stream infection. Assessment for patency was performed every 8 hrs in lumens without continuous infusions for the duration of catheter placement or discharge from intensive care unit. Three hundred twenty-six central venous catheters were studied yielding 709 lumens for analysis. The nonpatency rate was 3.8% in the heparin group (n = 314) and 6.3% in the 0.9% sodium chloride group (n = 395) (relative risk 1.66, 95% confidence interval 0.86-3.22, p = .136). The Kaplan-Meier analysis for time to first patency loss was not significantly different (log rank = 0.093) between groups. The rates of loss of blood return and flush failure were similar between the heparin and 0.9% sodium chloride groups. Pressure-injectable central venous catheters had significantly greater rates of nonpatency (10.6% vs. 4.3%, p = .001) and loss of blood return (37.0% vs. 18.8%, p <.001) compared to nonpressure injectable catheters. The frequencies of heparin-induced thrombocytopenia and catheter-related blood stream infection were similar between groups. CONCLUSION: 0.9% sodium chloride and heparin flushing solutions have similar rates of lumen nonpatency. Given potential safety concerns with the use of heparin, 0.9% sodium chloride may be the preferred flushing solution for short-term use central venous catheter maintenance. PMID- 22488007 TI - In the critically ill patient, diabetes predicts mortality independent of statin therapy but is not associated with acute lung injury: a cohort study. AB - OBJECTIVES: Patients with diabetes mellitus form 23%-30% of published cohorts of critically ill patients. Conflicting published evidence links diabetes mellitus to both higher and lower mortality. Other cohort studies suggest that diabetes mellitus protects against acute lung injury. We hypothesized that diabetes mellitus is an independent risk factor for mortality. We further hypothesized that diabetes mellitus is a risk factor for cardiac overload and not for acute lung injury. DESIGN: Retrospective cohort study. SETTING: The intensive care unit of a tertiary referral hospital. PATIENTS: From November 1, 2004, to October 1, 2007, a cohort of patients admitted >=48 hrs to the intensive care unit. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 2,013 patients, 317 had diabetes mellitus. Ninety-day mortality was higher in the diabetes mellitus patients compared to patients without diabetes mellitus (hazard ratio 1.53, 95% confidence interval 1.29-1.80). This association strengthened after adjusting for confounders and for medication (hazard ratio 1.53, 95% confidence interval 1.07 2.17).We found no association between diabetes mellitus and acute lung injury (relative risk ratio 1.01, 95% confidence interval 0.78-1.32; adjusted relative risk ratio 0.99, 95% confidence interval 0.75-1.31), but diabetes mellitus was a risk factor for cardiac overload (relative risk ratio 1.91, 95% confidence interval 1.30-2.81; adjusted relative risk ratio 1.45, 95% confidence interval 0.97-2.18). Statins were associated with both a reduced risk of mortality (hazard ratio 0.74, 95% confidence interval 0.63-0.87; adjusted hazard ratio 0.53, 95% confidence interval 0.44-0.64) and a decreased risk of developing acute lung injury (relative risk ratio 0.71, 95% confidence interval 0.56-0.89; adjusted relative risk ratio 0.61, 95% confidence interval 0.47-0.79). CONCLUSIONS: Diabetes mellitus is an independent risk factor for mortality in critically ill patients and failure to adjust for statins underestimates the size of this association. Diabetes mellitus is not associated with acute lung injury but is associated with cardiac overload. A diagnosis of cardiac overload excludes a diagnosis of acute lung injury. Investigators who do not account for cardiac overload as a competing alternative outcome may therefore falsely conclude that diabetes mellitus protects from acute lung injury. PMID- 22488008 TI - Can early cardiac troponin I measurement help to predict recent coronary occlusion in out-of-hospital cardiac arrest survivors? AB - OBJECTIVE: Recent guidelines recommend the immediate performance of a coronary angiography when an acute myocardial infarction is suspected as a cause of out-of hospital cardiac arrest. However, prehospital factors such as postresuscitation electrocardiogram pattern or clinical features are poorly sensitive in this setting. We searched to evaluate if an early measurement of cardiac troponin I can help to detect a recent coronary occlusion in out-of-hospital cardiac arrest. DESIGN: Retrospective analysis of a prospective electronic registry database. SETTING: University cardiac arrest center. PATIENTS: Between January 2003 and December 2008, 422 out-of-hospital cardiac arrest survivors without obvious extra cardiac cause have been consecutively studied. An immediate coronary angiography has been systematically performed. The primary outcome was the finding of a recent coronary occlusion. INTERVENTION: First, blood cardiac troponin I levels at admission were analyzed to assess the optimum cutoff for identifying a recent coronary occlusion. Second, a logistic regression was performed to determine early predictive factors of a recent coronary occlusion (including cardiac troponin I) and their respective contribution. MEASUREMENTS AND MAIN RESULTS: An ST-segment elevation was present in 127 of 422 patients (30%). During coronary angiography, a recent occlusion has been detected in 193 of 422 patients (46%). The optimum cardiac troponin I threshold was determined at 4.66 ng.mL(-1) (sensitivity 66.7%, specificity 66.4%). In multivariate analyses, in addition of smoking and epinephrine initial dose, cardiac troponin I (odds ratio 3.58 [2.03 6.32], p < .001) and ST-segment elevation (odds ratio 10.19 [5.39-19.26], p < .001) were independent predictive factors of a recent coronary occlusion. CONCLUSIONS: In this large cohort of out-of-hospital cardiac arrest patients, isolated early cardiac troponin I measurement is modestly predictive of a recent coronary occlusion. Furthermore, the contribution of this parameter even in association with other factors does not seem helpful to predict recent occlusion. As a result and given the high benefit of percutaneous coronary intervention for such patients, the dosage of cardiac troponin I at admission could not help in the decision of early coronary angiogram. PMID- 22488009 TI - S-guanylation of human serum albumin is a unique posttranslational modification and results in a novel class of antibacterial agents. AB - 8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) is a nitric oxide metabolite and an important second messenger. 8-Nitro-cGMP reacts with sulfhydryl groups forming a novel posttranslational modification, namely, S-guanylation. In this work, we found, by using a quantitative competition enzyme-linked immunosorbent assay procedure, that S-guanylated human serum albumin (S-cGMP-HSA) is a component of normal plasma, and that hemodialysis patients decrease its concentration, on an average, from 68 to 34 nM. End-stage renal disease is often accompanied by septicemia, and we found that S-cGMP-HSA possesses an in vitro antibacterial effect with half maximal inhibitory concentration of approximately 2 MUM against Escherichia coli American Type Culture Collection. Our findings indicate that S-cGMP-HSA can be regarded as an endogenous antibacterial agent in healthy conditions and as a useful new class of antibacterial agents with a circulation time sufficient for in vivo biological activity. The clinical development of S-cGMP-HSA as a safe and strong antibacterial agent arisen from endogenous posttranslational modification would be expected. PMID- 22488010 TI - Neonatal activation of the nuclear receptor CAR results in epigenetic memory and permanent change of drug metabolism in mouse liver. AB - Aberrant epigenetic alterations during development may result in long-term epigenetic memory and have a permanent effect on the health of subjects. Constitutive androstane receptor (CAR) is a central regulator of drug/xenobiotic metabolism. Here, we report that transient neonatal activation of CAR results in epigenetic memory and a permanent change of liver drug metabolism. CAR activation by neonatal exposure to the CAR-specific ligand 1,4-bis[2-(3,5 dichloropyridyloxy)] benzene (TCPOBOP) led to persistently induced expression of the CAR target genes Cyp2B10 and Cyp2C37 throughout the life of exposed mice. These mice showed a permanent reduction in sensitivity to zoxazolamine treatment as adults. Compared with control groups, the induction of Cyp2B10 and Cyp2C37 in hepatocytes isolated from these mice was more sensitive to low concentrations of the CAR agonist TCPOBOP. Accordingly, neonatal activation of CAR led to a permanent increase of histone 3 lysine 4 mono-, di-, and trimethylation and decrease of H3K9 trimethylation within the Cyp2B10 locus. Transcriptional coactivator activating signal cointegrator-2 and histone demethylase JMJD2d participated in this CAR-dependent epigenetic switch. CONCLUSION: Neonatal activation of CAR results in epigenetic memory and a permanent change of liver drug metabolism. PMID- 22488011 TI - MR imaging of anterior knee pain: a pictorial essay. AB - Anterior knee pathology is a frequent cause of joint pain and limitation of function and mobility among patients presenting to an orthopaedic department. Proper recognition and treatment of pathologic conditions depend on the knowledge of normal anatomy and of the various abnormalities, which affect this area of the knee and may present with anterior knee pain. A broad array of benign and malignant processes may be manifested as anterior knee discomfort, and this common clinical entity is among the most frequent indications for MR imaging of the lower extremities. Clinical history and physical examination are also of paramount importance. The disorders can be categorized and differentiated primarily according to their location. Traumatic or non-traumatic disorders of the patella, patellar retinacula, quadriceps and patellar tendons and supra or infrapatellar fat pad can be the source of symptoms. This article includes a comprehensive pictorial essay of the characteristic MR features of common and uncommon disorders causing anterior knee pain. For accurate assessment of the aforementioned clinical problem, a radiologist should be able to identify typical MR imaging patterns that contribute in establishing the correct diagnosis and thus tailoring the appropriate therapy. Level of evidence IV. PMID- 22488012 TI - Platelet-rich plasma: does it help reduce tunnel widening after ACL reconstruction? AB - PURPOSE: The purpose of this study was to evaluate the efficacy of platelet-rich plasma (PRP) in reducing femoral and tibial tunnel enlargement in patients operated on for anterior cruciate ligament reconstruction with hamstrings. METHODS: Forty male patients, in which both femoral and tibial 9-mm tunnels were performed because of the graft size, were enrolled in this prospective study. They were randomly assigned to group A (20 patients, PRP group) and group B (20 patients, control group). All patients were followed up at a median of 14.7 months (range 10-16 months), with a physical examination, the Tegner, Lysholm and objective IKDC scoring scales, and with the KT-1000 arthrometer. Moreover, they underwent a CT evaluation in order to assess the amount of tunnel enlargement. RESULTS: Femoral tunnel diameter increased from 9.0 +/- 0.1 mm to 9.8 +/- 0.3 mm in group A (p = 0.032) and from 9.0 +/- 0.1 mm to 9.4 +/- 0.5 mm in group B (p = 0.043). Tibial tunnel diameter increased from 9.0 +/- 0.2 mm to 10.9 +/- 0.2 mm in group A (p = 0.029) and from 9.1 +/- 0.1 mm to 10.1 +/- 0.4 mm in group B (p = 0.028). Physical examination as well as the evaluation scales used showed no differences between the two groups. CONCLUSIONS: The use of PRP does not seem to be effective in preventing tunnel enlargement. PMID- 22488013 TI - Increased chondrocyte seeding density has no positive effect on cartilage repair in an MPEG-PLGA scaffold. AB - PURPOSE: This study investigates the effect of cell seeding density on cartilage repair in matrix-assisted chondrocyte implantation in vitro and in vivo. METHODS: In vitro: Four different cell seeding densities of human chondrocytes were seeded onto a porous methoxy-polyethylene glycol-polylactic-co-glycolic acid scaffold (MPEG-PLGA) polymer scaffold ASEEDTM (1.2 * 10(6), 4.0 * 10(6), 1.2 * 10(7) and 2.0 * 10(7) cells/cm(3)). The cartilage repair response was evaluated by relative gene expression of the chondrogenic markers sox9, collagen types I, II and X, and aggrecan, total DNA content and sulphated glycosaminoglycan synthesis. In vivo: Using a New Zealand white rabbit intercondylar osteochondral defect model, three different cell seeding densities (1.2 * 10(6), 4.0 * 10(6) and 1.2 * 10(7) cells/cm(3)) were tested with an empty scaffold as control. The cartilage repair response was evaluated using O'Driscoll score. RESULTS: In vitro: A significant difference (p < 0.05) in total DNA content was found at day 2 but not at day 7. The low cell seeding densities yielded the highest GAG content (p < 0.001) at day 7. Collagen type I was highest (p < 0.01) at the lowest density at day 7. In vivo: No significant difference was found between the 4 groups. CONCLUSIONS: No positive effect on cartilage repair was found using increased cell seeding density. LEVEL OF EVIDENCE: Controlled experimental study, Level II. PMID- 22488014 TI - No allergic reaction after TKA in a chrome-cobalt-nickel-sensitive patient: case report and review of the literature. AB - Hypersensitivity to metallic implants remains relatively unpredictable and poorly understood. Although 20-25 % of total joint arthroplasty patients develop metal sensitivity, only a few highly susceptible persons (<1 %) exhibit symptoms. We present a case report of a fifty-two-year-old woman with a preoperatively documented metal allergy who underwent bilateral total knee arthroplasty using a titanium-niobium-coated implant on one side and a chrome-cobalt implant on the other side because of a logistics problem. At 2-year follow-up, no clinical symptoms of allergy or loosening of the implant were observed. Level of evidence IV. PMID- 22488016 TI - Salivary cortisol measurement in developmental research: where do we go from here? AB - Salivary cortisol has been measured extensively in developmental research over the last three decades. The purpose of this article is to summarize the contributions to and limitations of salivary cortisol measurement in developmental research and propose future directions for research that includes salivary cortisol measurement. The properties of cortisol, the history of its burgeoning popularity, and the utility and limitations of (a) cortisol as a biological indicator, (b) saliva as a source of cortisol, and (c) various saliva collection methodologies are described. The current state of understanding about what is and is not reliably predictable from cortisol is summarized and the value of salivary cortisol measurement in developmental research is discussed, addressing whether methodology could be driving research design. Recommendations are made for streamlining study design and reporting within developmental research. PMID- 22488015 TI - Long-term results of arthroscopically assisted anatomical single-bundle anterior cruciate ligament reconstruction using patellar tendon autograft: are there any predictors for the development of osteoarthritis? AB - PURPOSE: The primary purpose of our study was to analyse the long-term outcome of patients treated for anterior cruciate ligament (ACL) tears by anatomical single bundle ACL reconstruction with patellar tendon autograft. The secondary purpose was to identify predictive factors for good outcome and occurrence of osteoarthritis. METHODS: Sixty-three patients (m:f = 54:9; mean age at surgery, 27 +/- 7 years) treated by ACL reconstruction were evaluated with a mean follow up of 16 +/- 1 years using IKDC2000, the SF36, Lysholm and Tegner score, Knee Society score, visual analogue scale for pain and satisfaction and KOOS. The femoral tunnel position was evaluated according to Sommer. It was also assessed in percentage of the Blumensaat line and the tibial tunnel position in percentage of the total anterior-posterior plateau length. The extent of osteoarthritis was graded according to the Kellgren-Lawrence score. RESULTS: The total IKDC2000 was normal in 20 (32 %), nearly normal in 29 (46 %), abnormal in 12 (19 %) and severely abnormal in 3 (5 %) of patients. The mean total SF-36 was 89 +/- 13, the Lysholm score 95 +/- 12, the Knee Society score 191 +/- 16 and the total KOOS 84 +/- 19. The Tegner score decreased from pre-injury 7(4-10) to 6 (2-10) at follow up. The Kellgren-Lawrence score was normal in 17 (27 %), suspected osteoarthritis in 25 (40 %), minimal osteoarthritis in 5 (8 %), moderate osteoarthritis in 9 (14 %) and severe osteoarthritis in 3 patients (5 %). The femoral tunnel was in zone A in 43 patients (68 %), in zone B in 16 (25 %) and in zone C in 4 patients (7 %). The femoral tunnel position in percentage of the Blumensaat line was 49 +/- 3 (range, 44-57), and the tibial tunnel position in percentage of the total anterior-posterior plateau length was 32 +/- 6 (range, 21-46). Patients with meniscal lesion at the time of ACL tear showed significantly less favourable outcomes than those without. CONCLUSIONS: Patients treated by the proposed ACL reconstruction technique showed on average good to excellent long-term results. A meniscal lesion at the time of ACL tear was highly predictive for less favourable outcome. PMID- 22488017 TI - Response criteria can be misleading when drawing conclusion regarding neoadjuvant chemotherapy in advanced ovarian cancer. PMID- 22488018 TI - Biomarkers of inflammation and endothelial dysfunction in stroke with and without sleep apnea. AB - OBJECTIVE: Although sleep apnea (SA) is a risk factor for ischemic stroke and an important prognostic factor in affected patients, the exact pathophysiological link between SA and stroke is unknown. We investigated whether the plasma concentration of biomarkers of inflammation and endothelial dysfunction, including soluble tumor necrosis factor receptor-1 and -2 (sTNF-R1 and sTNF-R2), tumor necrosis factor-beta (TNF-beta), soluble intercellular cell adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) are increased in patients with acute stroke and SA compared with stroke patients without SA. DESIGN/METHODS: In total, 76 patients with ischemic stroke admitted to the stroke unit were included in this study. Plasma concentrations of biomarkers were determined after CT scans on admission. All patients received cardiorespiratory polygraphy within the first 72 h after admission. In all patients, demographic data, National Institutes of Health Stroke Scale scores and cerebrovascular risk factors were assessed. RESULTS: An apnea-hypopnea index (AHI) >=10/h was found in 37 of our patients (48.7%). In these patients with SA, sTNF-R1 and sTNF-R2 levels were significantly higher than in patients with an AHI lower than 10/h. TNF-beta, however, showed no significant difference between both groups, just like the soluble intercellular and vascular cell adhesion molecules sICAM-1 and sVCAM-1. CONCLUSIONS/RELEVANCE: SA is associated with raised levels of sTNF-R1 and sTNF-R2 in patients with acute ischemic stroke. Taking into account the established impact of these two markers on the causation and course of cerebrovascular disease, these proteins may be part of the pathophysiological pathway linking SA to stroke. PMID- 22488019 TI - What's new in the development of tuberculosis vaccines. PMID- 22488020 TI - Facile synthesis of a flexible tethered porphyrin dimer that preferentially complexes fullerene C70. AB - A simple, high yield, two-step synthesis yields a porphyrin dimer linked by a flexible dithiol tether that preferentially binds fullerene C(70) over C(60) in toluene solution. The complex forms stable aggregates when cast on glass. PMID- 22488021 TI - Improving control of chemotherapy-induced nausea and vomiting. PMID- 22488022 TI - Evolving treatment paradigms for chemotherapy-induced nausea and vomiting. AB - BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is one of the most debilitating toxicities associated with cancer treatment. Although effective antiemetic agents are available, their use in practice often is suboptimal. METHODS: The author reviews the pathophysiology of CINV as well as the drug classes and cost considerations that should be incorporated into treatment planning. RESULTS: Several drug classes, including 5-hydroxytryptamine-3 receptor antagonists, neurokinin-1 receptor antagonists, and corticosteroids, are effective, especially when used in combination. Older antiemetic agents, such as prochlorperazine and metoclopramide, as well as olanzapine may provide reasonable alternatives in certain settings. CONCLUSIONS: Interventions for CINV should include standard-of-care antiemetics combined with corticosteroids. The cost of using older, less expensive antiemetics may be outweighed by the expenditures to rescue patients after suboptimal prophylaxis, as well as the indirect costs of missed work and lost productivity. PMID- 22488023 TI - Patient-centered management of chemotherapy-induced nausea and vomiting. AB - BACKGROUND: Oncology providers frequently underestimate the incidence of chemotherapy-induced nausea and vomiting (CINV), and patients often are reluctant to report symptoms. Inadequate patient-provider communication is a significant barrier to optimal management of this debilitating toxicity. METHODS: The author reviews relevant published data and methods to optimize the clinical care of patients receiving chemotherapy with moderate-to-high emetogenic potential. RESULTS: Patient reticence plus physician expectations that patients will report symptoms accurately lead to lapses in communication and suboptimal clinical care. CONCLUSIONS: Communication strategies should serve to encourage patients to share the responsibility for establishing goals of therapy and understanding the risks and benefits of their selected antiemetic regimen, thereby becoming active participants in their own cancer care. PMID- 22488024 TI - Orthotopic model of SHG-44 in the enhanced green fluorescent protein nude mouse. AB - Naturally fluorescent proteins have been widely used in biological research. In this study, we found that the simple and effective way to obtain enhanced green fluorescent protein (EGFP) nude mice is to cross transgenic EGFP C57BL/6J mice with nude (nu/nu) mice. EGFP expression is identified by tail genotyping. Establishment of the orthotopic EGFP nude mouse model used surgical orthotopic implantation. The morphology and human glioma cell markers, such as glial fibrillary acidic protein (GFAP) and S-100, remain unchanged in this mouse model. The tumor blood vessels obtained from the orthotopic model show brilliant EGFP fluorescence as observed by fluorescence microscopy. These findings suggested that this is an ideal mouse model with which to study interaction among host, tumor, and tumor microenvironment; the findings also suggested that the host (EGFP nude mouse) was involved in tumor angiogenesis. PMID- 22488025 TI - Self-reported oral hygiene habits among dental patients in Italy. AB - OBJECTIVE: The objective of this survey was to assess oral hygiene habits and compliance with guidelines for good oral health set forth by the Italian Ministry of Health (IMH). SUBJECTS AND METHODS: A sample of 2,200 self-administered questionnaires was sent to four dental clinics across Italy to assess sociodemographic information, oral hygiene habits, frequency of dental visits and services received at previous visits among a population of adult patients. RESULTS: Of the 2,200 questionnaires, 1,201 (54.6%) were returned. Findings showed that full compliance with the IMH recommendations was low (12%): a small number of patients (n = 223, 18.6%) visited a dentist every 6 months and only 256 (23.5%) brushed their teeth at least twice a day. CONCLUSION: Our data showed that regular attendance (at least 1 visit/year) at dental clinics for routine check-up and brushing teeth at least twice a day were poor. Therefore, we recommend that clinicians educate and motivate their patients about the benefits of healthy oral hygiene practices. PMID- 22488026 TI - Systems for the provision of oral health care in the Black Sea countries part 10: Greece. AB - This paper describes the complex Greek health insurance system in 2011 and how it funds some aspects of oral health care for the population. It explains how different aspects of oral health care for different groups in Greek society are funded by insurance schemes or the national health system (ESY) or purely by direct (out-of-pocket) payments from patients to dentists. It then describes the Greek oral health care workforce and explains that relative to the population there are more dentists than in any other European country. However, few work with chair-side assistance from dental nurses and there are no dental hygienists. There are two dental schools, whose intake may well be reduced in the near future. There are also only two recognised dental specialties (orthodontics and oral surgery). Some epidemiological data and costs are then presented. The paper finishes with a consideration of problems in oral health care in Greece and suggests how some may be overcome. PMID- 22488027 TI - Use of dental implants to retain finger prostheses: a case report. AB - Fingers as organs of manipulation have an important role in function and aesthetics. Moreover, for the majority of patients, the loss of the finger can lead to psychological problems. This case report presents the use of osseointegrated dental implants for the retention of finger prostheses. The possibility of using osseointegrated implant-retained prostheses offers a real alternative for the reconstruction of fingers in cases where other techniques are not applicable. PMID- 22488028 TI - In vitro evaluation of microleakage under a glass ionomer surface protector cement after different enamel treatment procedures. AB - AIM: The aim of this in vitrostudy was to evaluate the microleakage of a glass ionomer surface-protector cement (GC Fuji Triage) placed onto the fissure surfaces of extracted human molars prepared using six different treatment procedures. METHODS: Ninety-six extracted non-carious human molar teeth were divided into five enamel treatment groups: (Gp1) air-abraded (Micadent II, Medidenta); (Gp2) air-abraded and conditioned with 10% polyacrylic acid (GC dentin conditioner); (Gp3) prepared by a bur designed for enameloplasty (#8833 Komet); (Gp4) prepared with a bur and conditioned; (Gp5) conditioned; and (Gp6) no treatment (control). The teeth were then sealed with GC Fuji Triage. The teeth were thermocycled and left in distilled water or artificial saliva for one week, coated twice with nail varnish, and stained in a dye. They were sectioned and scored for microleakage. RESULTS: All groups showed microleakage. Samples that were kept in saliva had better results than those that were kept in distilled water (P<0.05). Samples conditioned before the treatment were also better than non-conditioned groups (P<0.05). In distilled water and artificial saliva, the range of the groups was, from the best, Gp2= 2 fatigue and of body weight loss >= 5% was two and threefold higher, respectively, in patients with disrupted circadian rhythm on chemotherapy. Chemotherapy disrupted circadian activity rhythm in nearly 50% of the patients. Circadian disruption on chemotherapy predicted for shorter overall survival. The prevention of chemotherapy-induced circadian disruption might reduce toxicity and improve efficacy in cancer patients. PMID- 22488039 TI - The need to compare rilonacept against active treatment for prevention of gout flares: comment on the article by Schumacher et al. PMID- 22488040 TI - In vivo antigenotoxic activity of watercress juice (Nasturtium officinale) against induced DNA damage. AB - The present study was carried out to investigate the genotoxicity as well as possible protective activity against damage induced by cyclophosphamide (CP) of the aqueous juice of watercress (Nasturtium officinale, W.T. Aiton) in vivo. Male and female Swiss mice 7-8 weeks old (N = 48) were treated by gavage with 1 g kg( 1) body weight and 0.5 g kg(-1) body weight of watercress juice during 15 consecutive days. Genotoxicity and its possible protective effect were tested by the comet assay in peripheral blood cells and the micronucleus test in bone marrow. In addition, biopsies of the bladder, epididymis and testicles of mice were performed to extend the experimental design. Watercress juice per se did not induce genetic damage according to the comet assay and micronucleus study, exhibiting a protective activity against CP (P < 0.05 and P < 0.001, respectively). The comparative analysis of bladder histological changes obtained in the watercress plus CP group against those treated with CP alone suggests a probable protective effect. Further studies are needed in order to establish the protective role of watercress juice against DNA damage. PMID- 22488041 TI - The triad of pain, fatigue and depression in ischemic stroke patients: the Bergen Stroke Study. AB - BACKGROUND: Many patients with cerebral infarction suffer from symptoms such as pain, fatigue and depression. Most studies focus on single symptoms, but these symptoms often occur together. Whereas symptom clusters have been studied in cancer patients, little is known about different symptom clusters in patients with cerebral infarction. The aim was to evaluate clusters of co-occurring symptoms in the long term. We hypothesized that patients with cerebral infarction display distinct symptom clusters. Furthermore, we hypothesized that multiple co occurring symptoms have an adverse effect on patients. METHODS: All consecutive patients with acute stroke (the index stroke) admitted to the Stroke Unit, Department of Neurology, Haukeland University Hospital, between February 2006 and July 2008, were prospectively registered in a database. Prior risk factors (including diabetes mellitus, hypertension, smoking, coronary heart disease, atrial fibrillation and prior stroke), prior depression and stroke severity (modified Rankin Scale (mRS) score on day 7) were registered. Patients with cerebral infarction were sent a questionnaire including a visual analogue pain scale (VAS), Fatigue Severity Scale (FSS), depression subscale of the Hospital Anxiety, Depression Scale (HADS-D) and Barthel Index at least 6 months after stroke onset. RESULTS: The questionnaire was returned by 328 patients (response rate 60%). All three symptoms were reported by 10.1%. Pain and fatigue among nondepressed patients were reported by 19.6%. Pain and depression among nonfatigued patients were reported by 2.0%. Depression and fatigue, and no pain were reported by 4.4%. Single symptoms were reported by 31% whereas 33% reported no symptoms. VAS, FSS and HADS-D score severity increased with the number of co occurring symptoms. Logistic regression analyses showed that two or three symptoms (versus no symptoms) was associated with high mRS score on day 7 (p = 0.02), prior stroke (p = 0.002), prior diabetes mellitus (p = 0.005) and prior depression (p < 0.001). CONCLUSIONS: Symptom clusters are frequent in patients with cerebral infarction. Fatigue was associated with pain and depression whereas there was little association between depression and pain in nonfatigue patients, indicating distinct symptom clusters. The severity of symptoms increased with the number of co-occurring symptoms. PMID- 22488042 TI - The expression of p-STAT3 in stage IV melanoma: risk of CNS metastasis and survival. AB - PURPOSE: The signal transducer and activator of transcription 3 (STAT3) is a key molecular hub of tumorigenesis and immune suppression. The expression of phosphorylated STAT3 (p-STAT3) has been shown to be higher in melanoma metastasis to the central nervous system (CNS) relative to distant metastasis in the rest of the body (systemic). We sought to determine whether the increased expression of p STAT3 in non-CNS systemic melanoma metastasis is associated with an increased risk of developing CNS metastasis and is a negative prognostic factor for overall survival time. METHODS: We retrospectively identified 299 patients with stage IV melanoma. In a tissue microarray of systemic non-CNS metastasis specimens from these patients, we used immunohistochemical analysis to measure the percentage of cells with p-STAT3 expression and Kaplan-Meier survival estimates to analyze the association of p-STAT3 expression with median survival time, time to first CNS metastasis, and development of CNS metastasis. RESULTS: Lung metastases exhibited the highest level of p-STAT3 expression while spleen lesions had the lowest. The p-STAT3 expression was not associated with an increased risk of developing CNS metastasis or time to CNS metastasis. However, p-STAT3 expression was a negative prognostic factor for overall survival time in patients that did not develop CNS metastasis. CONCLUSIONS: Stage IV melanoma patients without CNS metastasis treated with p-STAT3 inhibitors in efficacy studies should be stratified based on tumor expression of p-STAT3; however since p-STAT3 expression is not associated with the risk of CNS disease, increased MRI surveillance of the brain is not likely necessary. PMID- 22488043 TI - Novel potassium N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhex-1-yl]-L-amino acid dichloroplatinates(II) with high anti-tumor activity and low side reaction. AB - To discover whether novel anti-tumor platinum agents are capable of selectively accumulating in tumor tissue, three novel potassium N-[(2S,3R,4R,5R)-2,3,4,5,6 pentahydroxylhex-1-yl]-L-amino acid dichloroplatinates(II) were prepared. At a dose of 1.67 MUmol kg(-1) the in vivo anti-tumor potencies of two of the compounds were higher than that of oxaliplatin. The mortality analysis indicated that these compounds resulted in a 100% survival rate, whereas oxaliplatin lead to an 80% survival rate. The organ damage examination indicated that these compounds induced less damage than oxaliplatin. The platinum accumulation in the organs, blood and bone was significantly lower than that of oxaliplatin treated mice, while the platinum accumulation in the tumor tissue was significantly higher than that of the oxaliplatin treated mice. PMID- 22488044 TI - Effects of brief stress exposure during early postnatal development in balb/CByJ mice: I. Behavioral characterization. AB - Early life stress has been linked to the etiology of mental health disorders. Rodent models of neonatal maternal separation stress frequently have been used to explore the long-term effects of early stress on changes in affective and cognitive behaviors. However, most current paradigms risk metabolic deprivation, due to prolonged periods of pup removal from the dam. We have developed a new paradigm in Balb/CByJ mice, that combines very brief periods of maternal separation with temperature stress to avoid the confound of nutritional deficiencies. We have also included a within-litter control group of pups that are not removed from the dam. The present experiments provide an initial behavioral characterization of this new model. We show that neonatally stressed mice display increased anxiety and aggression along with increased locomotion but decreased exploratory behavior. In contrast, littermate controls show increased exploration of novelty, compared to age-matched, colony-reared controls. Behavioral changes in our briefly stressed mice substantially concur with the existing literature, except that we were unable to observe any cognitive deficits in our paradigm. However, we show that within litter control pups also sustain behavioral changes suggesting complex and long-lasting interactions between different environmental factors in early postnatal life. PMID- 22488045 TI - Arsenic modulates heme oxygenase-1, interleukin-6, and vascular endothelial growth factor expression in endothelial cells: roles of ROS, NF-kappaB, and MAPK pathways. AB - Chronic arsenic exposure has been linked to an increased risk of vascular diseases. To clarify the molecular mechanisms through which arsenic causes injuries to blood vessels, we analyzed the effects of arsenic trioxide on the cytotoxicity, intracellular reactive oxygen species (ROS), the expression of related genes, and signaling pathways involved in the SVEC4-10 mouse endothelial cells. Arsenic dose-dependently caused SVEC4-10 cell death, which is completely inhibited by alpha-lipoic acid (LA), a thioreductant, but partially ameliorated by Tiron, a potent superoxide scavenger. The mRNA levels of heme oxygenase-1 (HO 1), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) were significantly increased by arsenic. The up-regulation of these can be blocked by LA instead of Tiron, suggesting ROS is not important in their increase. HO-1 competitive inhibitor zinc protoporphyrin improved the cytotoxicity of arsenic in an inverted-U dose response curve, indicating the biphasic hormetic effect of HO-1. HO-1 siRNA decreased VEGF expression in response to arsenic. Arsenic exposure also enhanced NF-E2-related factor 2 (Nrf2) expression and increased activation of nuclear factor-kappaB (NF-kappaB). NF-kappaB inhibitor Bay 11-7082 reduced arsenic mediated expression of HO-1 and IL-6. Selective blocking of the MAPK pathways with p38 inhibitor SB203580 significantly decreased arsenic-induced HO-1 and VEGF expression, while JNKs inhibitor SP600125 increased IL-6 expression. These results suggest that in arsenic-treated SVEC4-10 cells, HO-1 expression is mediated through Nrf2-, NF-kappaB-, and p38 MAPK-dependent signaling pathways and serves as an upstream regulator of VEGF. IL-6 expression is regulated by NF kappaB and JNKs. In conclusion, oxidative stress may be associated with arsenic induced cytotoxicity and endothelial gene up-regulation, but signaling transduction dominates the direct effects of ROS. PMID- 22488046 TI - End-to-end distance distribution in fluorescent derivatives of bradykinin in interaction with lipid vesicles. AB - Cellular membranes have relevant roles in processes related to proteases like human kallikreins and cathepsins. As enzyme and substrate may interact with cell membranes and associated co-factors, it is important to take into account the behavior of peptide substrates in the lipid environment. In this paper we report an study based on energy transfer in two bradykinin derived peptides labeled with the donor-acceptor pair Abz/Eddnp (ortho-aminobenzoic acid/N-[2,4-dinitrophenyl] ethylenediamine). Time-resolved fluorescence experiments were performed in phosphate buffer and in the presence of large unilamelar vesicles of phospholipids, and of micelles of sodium dodecyl sulphate (SDS). The decay kinetics were analyzed using the program CONTIN to obtain end-to-end distance distribution functions f(r). Despite of the large difference in the number of residues the end-to-end distance of the longer peptide (9 amino acid residues) is only 20 % larger than the values obtained for the shorter peptide (5 amino acid residues). The proline residue, in position 4 of the bradykinin sequence promotes a turn in the longer peptide chain, shortening its end-to-end distance. The surfactant SDS has a strong disorganizing effect, substantially broadening the distance distributions, while temperature increase has mild effects in the flexibility of the chains, causing small increase in the distribution width. The interaction with phospholipid vesicles stabilizes more compact conformations, decreasing end-to-end distances in the peptides. Anisotropy experiments showed that rotational diffusion was not severely affected by the interaction with the vesicles, suggesting a location for the peptides in the surface region of the bilayer, a result consistent with small effect of lipid phase transition on the peptides conformations. PMID- 22488047 TI - Clinical outcomes of percutaneous interventions in saphenous vein grafts using drug-eluting stents compared to bare-metal stents: a comprehensive meta analysisof all randomized clinical trials. AB - BACKGROUND: Clinical outcomes of percutaneous coronary intervention (PCI) in patients with saphenous vein grafts (SVGs) remain poor despite the use of drug eluting stents (DES). There is a disparity in clinical outcomes in SVG PCI based on various registries, and randomized clinical data remain scant. We conducted a meta-analysis of all existing randomized controlled trials (RCTS) comparing bare metal stents (BMS) and DES in SVGPCIs. HYPOTHESIS: PCI in patients with SVG disease using DES may reduce need for repeat revascularization without an excess mortality when compared to BMS. METHODS: An aggregate data meta-analysis of clinical outcomes in RCTs comparing PCI with DES vs BMS for SVGs reporting at least 12 months of follow-up was performed. A literature search between Janurary 1, 2003 and September 30, 2011 identified 4 RCTs (812 patients; DES = 416, BMS = 396). Summary odds ratio (OR) and 95% confidence interval (CI) were calculated using the random-effects model. The primary endpoint was all-cause mortality. Secondary outcomes included nonfatal myocardial infarction (MI), repeat revascularization, and major adverse cardiac events (MACE). These outcomes were assessed in a cumulative fashion at 30 days, 18 months, and 36 months. RESULTS: There were no intergroup differences in baseline clinical and sociodemographic characteristics. At a median follow-up of 25 months, patients in the DES and BMS group had similar rates of death (OR: 1.63, 95% CI: 0.45-5.92), MI (OR; 0.83, 95% CI: 0.27-2.60), and MACE (OR: 0.58, 95% CI: 0.25-1.32). Patients treated with DES had lower rates of repeat revascularization (OR: 0.40, 95% CI: 0.22-0.75). CONCLUSIONS: In this comprehensive meta-analysis of all RCTs comparing clinical outcomes of PCI using DES vs BMS in patients with SVG disease, use of DES was associated with a reduction in rate of repeat revascularization and no difference in rates of all-cause death and MI. Clin. Cardiol. 2012 DOI: 10.1002/clc.21984 Dr. Virani is supported by a Department of Veterans Affairs Health Services Research and Development Service (HSR&D) Career Development Award (CDA-09-028), and has research support from Merck and National Football League Charities (all grants to the institution and not individual). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. The authors have no other funding, financial relationships, or conflicts of interest to disclose. PMID- 22488048 TI - "Evaluation of additional cooking procedures to achieve lethality microbiological performance standards for large, intact meat products," a comment on: J. Food Prot. 74(10):1741-1745 (2011). PMID- 22488049 TI - Rapid and sensitive detection of Salmonella Typhimurium on eggshells by using wireless biosensors. AB - This article presents rapid, sensitive, direct detection of Salmonella Typhimurium on eggshells by using wireless magnetoelastic (ME) biosensors. The biosensor consists of a freestanding, strip-shaped ME resonator as the signal transducer and the E2 phage as the biomolecular recognition element that selectively binds with Salmonella Typhimurium. This ME biosensor is a type of mass-sensitive biosensor that can be wirelessly actuated into mechanical resonance by an externally applied timevarying magnetic field. When the biosensor binds with Salmonella Typhimurium, the mass of the sensor increases, resulting in a decrease in the sensor's resonant frequency. Multiple E2 phage-coated biosensors (measurement sensors) were placed on eggshells spiked with Salmonella Typhimurium of various concentrations (1.6 to 1.6 * 10(7) CFU/cm(2)). Control sensors without phage were also used to compensate for environmental effects and nonspecific binding. After 20 min in a humidity-controlled chamber (95%) to allow binding of the bacteria to the sensors to occur, the resonant frequency of the sensors was wirelessly measured and compared with their initial resonant frequency. The resonant frequency change of the measurement sensors was found to be statistically different from that of the control sensors down to 1.6 * 10(2) CFU/cm(2), the detection limit for this work. In addition, scanning electron microscopy imaging verified that the measured resonant frequency changes were directly related to the number of bound cells on the sensor surface. The total assay time of the presented methodology was approximately 30 min, facilitating rapid detection of Salmonella Typhimurium without any preceding sampling procedures. PMID- 22488050 TI - Prevalence and antimicrobial susceptibility of Salmonella isolated from a variety of raw meat sausages in Gaborone (Botswana) retail stores. AB - The objective of the study was to provide baseline data on the prevalence and antimicrobial susceptibility of Salmonella in different types of raw meat sausages directly accessible to the consumers in Gaborone, Botswana. A total of 300 raw sausages comprising 79 beef, 78 pork, 72 chicken, and 71 mutton samples were concurrently analyzed for the presence of Salmonella using a conventional culture method and a validated PCR method. The PCR assay results were in full concordance with those of the conventional culture method for the detection of Salmonella. Sixty-five (21.7%) of 300 samples were positive for Salmonella by both the conventional culture method and PCR assay. Even though more chicken samples contained Salmonella than did any other sausage type, the difference in the presence of Salmonella among the four sausages types was not significant. Eleven serotypes were identified, and Salmonella enterica subsp. salamae II was most prevalent in all the sausage types. Beef sausages generally had higher mesophilic bacterial counts than did the other three sausage types. However, higher microbial counts were not reflective of the presence of salmonellae. Susceptibility of the Salmonella enterica serotypes to 20 antimicrobial agents was determined, and Salmonella Muenchen was resistant to the widest array of agents and was mostly isolated from chicken sausages. Regardless of the meat of origin, all 65 Salmonella isolates were resistant to at least four antimicrobial agents: amikacin, gentamicin, cefuroxime, and tombramycin. This resistance profile group was the most common in all four sausage types, comprising 90% of all Salmonella isolates from beef, 71% from pork, 63% from mutton, and 35% from chicken. These results suggest that raw sausages pose a risk of transmitting multidrug-resistant Salmonella isolates to consumers. PMID- 22488051 TI - Rapid and reliable detection of Shiga toxin-producing Escherichia coli by real time multiplex PCR. AB - Escherichia coli O26, O45, O103, O111, O121, O145, and O157 are the predominant Shiga toxin-producing E. coli (STEC) serogroups implicated in outbreaks of human foodborne illness worldwide. The increasing prevalence of these pathogens has important public health implications. Beef products have been considered a main source of foodborne human STEC infections. Robust and sensitive methods for the detection and characterization of these pathogens are needed to determine prevalence and incidence of STEC in beef processing facilities and to improve food safety interventions aimed at eliminating STEC from the food supply. This study was conducted to develop Taqman real-time multiplex PCR assays for the screening and rapid detection of the predominant STEC serogroups associated with human illness. Three serogroup-specific assays targeted the O-antigen gene clusters of E. coli O26 (wzy), O103 (wzx), and O145 (wzx) in assay 1, O45 (wzy), O111 (manC), and O121 (wzx) in assay 2, and O157 (rfbE) in assay 3. The uidA gene also was included in the serogroup-specific assays as an E. coli internal amplification control. A fourth assay was developed to target selected virulence genes for Shiga toxin (stx(1) and stx(2)), intimin (eae), and enterohemolysin (ehxA). The specificity of the serogroup and virulence gene assays was assessed by testing 100 and 62 E. coli strains and non-E. coli control strains, respectively. The assays correctly detected the genes in all strains examined, and no cross-reactions were observed, representing 100 % specificity. The detection limits of the assays were 10(3) or 10(4) CFU/ml for pure cultures and artificially contaminated fecal samples, and after a 6-h enrichment period, the detection limit of the assays was 10(0) CFU/ml. These results indicate that the four real-time multiplex PCR assays are robust and effective for the rapid and reliable detection of the seven predominant STEC serogroups of major public health concern and the detection of their virulence genes. PMID- 22488052 TI - Prevalence and molecular characterization of Vibrio cholerae from ice and beverages sold in Jakarta, Indonesia, using most probable number and multiplex PCR. AB - Vibrio cholerae is well recognized as the causative agent of cholera, an acute intestinal infection characterized by watery diarrhea that may lead to dehydration and death in some cases. V. cholerae is a natural inhabitant of the aquatic environment in the tropical regions. Jakarta has the highest percentage of individuals affected by sporadic diarrheal illness compared with other areas in Indonesia. Inadequate safety measures for drinking water supplies, improper sanitation, and poor hygiene can increase the risk of cholera outbreaks. Few studies have been conducted on the prevalence of these bacteria in ice and beverages that are popularly sold and consumed in Jakarta. In this study, we detected and quantified V. cholerae from ice and beverages collected from several areas in five regions of Jakarta. Levels of V. cholerae in both ice and beverages were determined with the three-tube most-probable-number (MPN) method and ranged from < 0.3 to > 110 MPN/ml. The presence of regulatory and virulence gene sequences was determined by using uniplex and multiplex PCR assays. Of 110 samples tested, 33 (30%) were positive for V. cholerae; 21 (64%) were ice samples and the remaining 12 (36%) were beverages. A total of 88 V. cholerae strains were isolated, based on the presence of the toxR gene sequence identified by PCR. Other genetic markers, such as hlyA (59%), ompU (16%), and ctxA (19%), also were found during the search for potential pathogenic strains. The detection and isolation of potentially harmful V. cholerae from ice and beverages in Jakarta indicate that these products pose a health risk from choleragenic vibrios, particularly because of the emergence of classical biotypes of V. cholerae O1 and potentially harmful non-O1 serovars of this species. PMID- 22488053 TI - Novel genomic tools for specific and real-time detection of biothreat and frequently encountered foodborne pathogens. AB - The bacterial genera Escherichia, Salmonella, Shigella, Vibrio, Yersinia, and Francisella include important food safety and biothreat agents. By extensive mining of the whole genome and protein databases of diverse, closely and distantly related bacterial species and strains, we have identified novel genome regions, which we utilized to develop a rapid detection platform for these pathogens. The specific genomic targets we have identified to design the primers in Francisella tularensis subsp. tularensis, F. tularensis subsp. novicida, Shigella dysenteriae, Salmonella enterica serovar Typhimurium, Vibrio cholerae, Yersinia pestis, and Yersinia pseudotuberculosis contained either known genes or putative proteins. Primer sets were designed from the target regions for use in real-time PCR assays to detect specific biothreat pathogens at species or strain levels. The primer sets were first tested by in silico PCR against whole-genome sequences of different species, subspecies, or strains and then by in vitro PCR against genomic DNA preparations from 23 strains representing six biothreat agents (Escherichia coli O157:H7 strain EDL 933, Shigella dysenteriae, S. enterica serovar Typhi, F. tularensis subsp. tularensis, V. cholerae, and Y. pestis) and six foodborne pathogens (Salmonella Typhimurium, Salmonella Saintpaul, Shigella sonnei, F. tularensis subsp. novicida, Vibrio parahaemolyticus, and Y. pseudotuberculosis). Each pathogen was specifically identifiable at the genus and species levels. Sensitivity assays performed with purified DNA showed the lowest detection limit of 128 fg of DNA/MUl for F. tularensis subsp. tularensis. A preliminary test to detect Shigella organisms in a milk matrix also enabled the detection of 6 to 60 CFU/ml. These new tools could ultimately be used to develop platforms to simultaneously detect these pathogens. PMID- 22488054 TI - Insight into the prevalence and distribution of microbial contamination to evaluate water management in the fresh produce processing industry. AB - This study provided insight into the degree of microbial contamination in the processing chain of prepacked (bagged) lettuce in two Belgian fresh-cut produce processing companies. The pathogens Salmonella and Listeria monocytogenes were not detected. Total psychrotrophic aerobic bacterial counts (TPACs) in water samples, fresh produce, and environmental samples suggested that the TPAC is not a good indicator of overall quality and best manufacturing practices during production and processing. Because of the high TPACs in the harvested lettuce crops, the process water becomes quickly contaminated, and subsequent TPACs do not change much throughout the production process of a batch. The hygiene indicator Escherichia coli was used to assess the water management practices in these two companies in relation to food safety. Practices such as insufficient cleaning and disinfection of washing baths, irregular refilling of the produce wash baths with water of good microbial quality, and the use of high product/water ratios resulted in a rapid increase in E. coli in the processing water, with potential transfer to the end product (fresh-cut lettuce). The washing step in the production of fresh-cut lettuce was identified as a potential pathway for dispersion of microorganisms and introduction of E. coli to the end product via cross-contamination. An intervention step to reduce microbial contamination is needed, particularly when no sanitizers are used as is the case in some European Union countries. Thus, from a food safety point of view proper water management (and its validation) is a critical point in the fresh-cut produce processing industry. PMID- 22488056 TI - Survival of Bacillus cereus vegetative cells and spores during in vitro simulation of gastric passage. AB - The enteric pathogen Bacillus cereus must survive gastric passage in order to cause diarrhea by enterotoxin production in the small intestine. The acid resistance and the survival after gastric passage were assessed by in vitro experiments with acidified growth medium and gastric simulation medium with B. cereus NVH 1230-88 vegetative cells and spores. First, batch incubations at constant pH values for 4 h, which represented different physiological states of the stomach, showed that spores were resistant to any gastric condition in the pH range of 2.0 to 5.0, while vegetative cells were rapidly inactivated at pH values of <=4.0. Second, a dynamic in vitro gastric experiment was conducted that simulated the continuously changing in vivo conditions due to digestion dynamics by gradually decreasing the pH from 5.0 to 2.0 and fractional emptying of the stomach 30 to 180 min from the start of the experiment. All of the B. cereus spores and 14% (+/- 9%) of the vegetative cells survived the dynamic simulation of gastric passage. PMID- 22488055 TI - Survival and germination of Clostridium perfringens spores during heating and cooling of ground pork. AB - The effect of heating rate on the heat resistance, germination, and outgrowth of Clostridium perfringens spores during cooking of cured ground pork was investigated. Inoculated cured ground pork portions were heated from 20 to 75 degrees C at a rate of 4, 8, or 12 degrees C/h and then held at 75 degrees C for 48 h. No significant differences (P > 0.05) in the heat resistance of C. perfringens spores were observed in cured ground pork heated at 4, 8, or 12 degrees C/h. At heating rates of 8 and 12 degrees C/h, no significant differences in the germination and outgrowth of spores were observed (P > 0.05). However, when pork was heated at 4 degrees C/h, growth of C. perfringens occurred when the temperature of the product was between 44 and 56 degrees C. In another set of experiments, the behavior of C. perfringens spores under temperature abuse conditions was studied in cured and noncured ground pork heated at 4 degrees C/h and then cooled from 54.4 to 7.2 degrees C within 20 h. Temperature abuse during cooling of noncured ground pork resulted in a 2.8-log CFU/g increase in C. perfringens. In cured ground pork, C. perfringens decreased by 1.1 log CFU/g during cooling from 54.4 to 36.3 degrees C and then increased by 0.9 log CFU/g until the product reached 7.2 degrees C. Even when the initial level of C. perfringens spores in cured ground pork was 5 log CFU/g, the final counts after abusive cooling did not exceed 3.4 log CFU/g. These results suggest that there is no risk associated with C. perfringens in cured pork products under the tested conditions. PMID- 22488057 TI - Heat shock and cold shock treatments affect the survival of Listeria monocytogenes and Salmonella Typhimurium exposed to disinfectants. AB - The foodborne pathogens Listeria monocytogenes and Salmonella Typhimurium were subjected to heat shock at 48 degrees C for 10 and 30 min, respectively, and then cold shocked at 15 degrees C for 3 h. The effect of these shocks on the viability of test organisms exposed to chlorine dioxide and quaternary ammonium compounds was then determined. After exposure to the disinfectants, the viable population of each test organism, regardless of heat shock or cold shock treatment, decreased as the exposure period was extended. Both heat shock and cold shock treatments reduced the susceptibility of L. monocytogenes to both disinfectants at 25 degrees C. However, for Salmonella Typhimurium, exposure to the chlorine dioxide disinfectant or quaternary ammonium compounds at 25 degrees C significantly reduced (P < 0.05) survival of heat-shocked cells but significantly increased (P < 0.05) survival of cold-shocked cells compared with control cells. Survival of both L. monocytogenes and Salmonella Typhimurium generally was reduced after exposure to disinfectants at 40 degrees C compared with 25 degrees C. PMID- 22488058 TI - Antimicrobial effects of silver nanoparticles against bacterial cells adhered to stainless steel surfaces. AB - Given the increasing number of antibiotic-resistant bacteria and the need to synthesize new antimicrobials, silver has attracted interest in the scientific community because of its recognized antimicrobial activity. This study aimed to evaluate the antimicrobial effects of silver nanoparticles (NP) obtained by a new method and tested at concentrations of 6 MUg/ml and 60 MUg/ml against the species Staphylococcus aureus, Listeria innocua, Salmonella Choleraesuis, Pseudomonas aeruginosa, Escherichia coli, and Bacillus cereus. The ability of these nanoparticles to remove or kill vegetative cells adhered to stainless steel surfaces was also evaluated. We observed that the NP obtained with the new method, concentrated silver nanoparticles (CNP), and silver nanoparticles with added sodium chloride (NPNaCl) had high antimicrobial activities (P < 0.05). We also verified that the most effective condition for the removal of P. aeruginosa cells on stainless steel coupons (10 by 10 mm) was immersion of the surfaces in CNP. The CNP treatment produced a 5-log reduction of the microbial population after 30 to 60 min of immersion. The CNP treatment also performed better than water and sodium carbonate, a compound commonly applied in clean-in-place procedures in the food industry, in removing adherent B. cereus cells from stainless steel cylinders. Therefore, these results suggest that NP synthesized by a new procedure may be used as antimicrobials in the food industry, for example, for the sanitization of utensils that come into contact with foods. PMID- 22488059 TI - Microbiological performance of a food safety management system in a food service operation. AB - The microbiological performance of a food safety management system in a food service operation was measured using a microbiological assessment scheme as a vertical sampling plan throughout the production process, from raw materials to final product. The assessment scheme can give insight into the microbiological contamination and the variability of a production process and pinpoint bottlenecks in the food safety management system. Three production processes were evaluated: a high-risk sandwich production process (involving raw meat preparation), a medium-risk hot meal production process (starting from undercooked raw materials), and a low-risk hot meal production process (reheating in a bag). Microbial quality parameters, hygiene indicators, and relevant pathogens (Listeria monocytogenes, Salmonella, Bacillus cereus, and Escherichia coli O157) were in accordance with legal criteria and/or microbiological guidelines, suggesting that the food safety management system was effective. High levels of total aerobic bacteria (>3.9 log CFU/50 cm(2)) were noted occasionally on gloves of food handlers and on food contact surfaces, especially in high contamination areas (e.g., during handling of raw material, preparation room). Core control activities such as hand hygiene of personnel and cleaning and disinfection (especially in highly contaminated areas) were considered points of attention. The present sampling plan was used to produce an overall microbiological profile (snapshot) to validate the food safety management system in place. PMID- 22488060 TI - Patulin reduction in apple juice from concentrate by UV radiation and comparison of kinetic degradation models between apple juice and apple cider. AB - Patulin, a mycotoxin produced by several genera of fungi, including Byssochlamys, Aspergillus, and Penicillium, has been an important concern in apple cider and apple juice due to its toxicity and health consequences. In this study, the effects of UV on the patulin level, physical and chemical properties, and sensory attributes in apple juice from concentrate were investigated. Kinetic modeling of patulin reduction by UV radiation in apple juice from concentrate was calculated and compared with the degradation rate observed previously in apple cider. From an initial patulin contamination of approximately 1,000 ppb (MUg/liter), the UV exposure, ranging from 14.2 mJ/cm(2) (one pass) to 99.4 mJ/cm(2) (seven passes), was successful in reducing patulin levels by 72.57% +/- 2.76% to 5.14% +/- 0.70%, respectively. Patulin reduction by UV radiation followed first-order kinetic modeling in a fashion similar to first-order microbial inactivation. An exponential correlation between UV exposure and the percentage of patulin remaining was observed, giving an r(2) value of 0.9950. Apple juice was repeatedly exposed to 14.2 mJ/cm(2) for each treatment, and patulin levels were significantly decreased when compared with the level obtained with the previous UV exposure treatment. While there were no significant differences in the percentages of titratable acidity and ascorbic acid (P > 0.05), there were minor yet random sampling differences in pH and degrees Brix (1 degrees Brix is 1 g of sucrose in 100 g of solution; the degrees Brix represents the soluble solids content of the solution as percentage by weight [%, wt/wt]) (P <= 0.05). A significant difference (P <= 0.05) in sensory perception for the finished apple juice was detected between the control and the full seven pass UV radiation treatment using an experienced consumer panel and a triangle test. Patulin reduction by UV radiation from both the current study and a previous study involving apple cider was compared, which showed that both matrices strongly fit a first-order kinetic degradation model. However, the kinetic constant for degradation in apple juice was approximately 5.5 times greater than that observed in an apple cider matrix. PMID- 22488061 TI - Mercury and cadmium concentrations in farmed bluefin tuna (Thunnus orientalis) and the suitability of using the caudal peduncle muscle tissue as a monitoring tool. AB - Three regions (cephalic, central, and caudal) of the dorsal and ventral muscle tissue (R1 through R6) and the caudal peduncle muscle tissue (CPMT) of 20 farmed bluefin tuna (Thunnus orientalis) were analyzed for mercury (Hg) and cadmium (Cd) concentrations. Region 1 (cephalic-ventral) had significantly lower concentrations of Hg but significantly higher concentrations of Cd than did the other regions. However, average metal concentrations of all regions (R1 through R6) were only 6% lower for Hg and were not significantly different for Cd from those in the CPMT. Therefore, the CPMT was used to monitor the concentrations of these two metals in more than 100 farmed tuna collected from July 2004 to January 2009 under the assumption that the Cd concentrations in the CPMT would be representative of the Cd concentration in the whole body and that the Hg concentrations would be, in the worst case, overestimated by approximately 6%. The Hg and Cd concentrations in these tuna were inversely related to the condition index, i.e., the tuna in better condition had the lowest concentrations of these metals. The mean concentrations in the CPMT of all fish analyzed were 0.31 +/- 0.17 MUg/g wet weight for Hg and 0.007 +/- 0.006 MUg/g wet weight for Cd. These concentrations were below the limits established by Mexican regulations for seafood (1.0 and 0.5 MUg/g for Hg and Cd, respectively) and Japan (0.4 MUg/g for Hg). PMID- 22488062 TI - Brown and black grease suitability for incorporation into feeds and suitability for biofuels. AB - Waste grease lipids used in animal feeds have been the cause of food recalls in Europe, where such materials were incorporated into animal feedstuffs. This resulted in unwanted residues in human food. The composition of such lipid sources has been lacking. Seventeen composite trap grease and isolated brown grease samples were analyzed. Analytes included nutrients, metals, and volatile organic compounds. Analytes were selected for relevance to wastewater treatment and resource reuse potential. Moisture averaged 89.4% and the pH was 3.8. The 5 day biological oxygen demand was 32,531 mg/liter, solids were 7.5%, and fats, oil, and grease were 48,970 mg/liter. Non-polychlorinated biphenyl volatile organic compounds were surveyed. In the 17 grease samples, 14 contained an average of 102.5 MUg/liter chloroform; 11 samples contained acetone, averaging 369 MUg/liter; 9 samples contained 2-butanone, with an average of 484 MUg/liter; and 8 contained an average of 710 MUg/liter methylene chloride and toluene at 311 MUg/liter. The mean concentration of copper in 17 composite samples ranged from 15 to 239 mg/liter, iron averaged 314 mg/liter, lead means ranged from 2.5 to 24 mg/liter, and magnesium averaged 975 mg/liter. It is hypothesized that food preparation facility cleaning and chlorinated cleaning-disinfection agents combined with the organics in the low-pH environment of the traps produce potentially carcinogenic compounds. It is recommended that these waste grease materials be used as a feedstock for biofuel. PMID- 22488063 TI - An outbreak of salmonella chester infection in Canada: rare serotype, uncommon exposure, and unusual population demographic facilitate rapid identification of food vehicle. AB - Salmonella Chester infection has rarely been reported in the literature. In 2010, 33 case patients were reported in 2 months in four Canadian provinces. We conducted an outbreak investigation in collaboration with public health agencies, food safety specialists, regulatory agencies, grocery store chains, and the product distributor. We used case patient interviews, customer loyalty cards, and microbiological testing of clinical and food samples to identify nationally distributed head cheese as the food vehicle responsible for the outbreak. The rare serotype, a limited affected demographic group, and an uncommon exposure led to the rapid identification of the source. Control measures were implemented within 9 days of notification of the outbreak. PMID- 22488064 TI - Comparison of a real-time PCR method with a culture method for the detection of Salmonella enterica serotype enteritidis in naturally contaminated environmental samples from integrated poultry houses. AB - Conventional culture methods have traditionally been considered the "gold standard" for the isolation and identification of foodborne bacterial pathogens. However, culture methods are labor-intensive and time-consuming. A Salmonella enterica serotype Enteritidis-specific real-time PCR assay that recently received interim approval by the National Poultry Improvement Plan for the detection of Salmonella Enteritidis was evaluated against a culture method that had also received interim National Poultry Improvement Plan approval for the analysis of environmental samples from integrated poultry houses. The method was validated with 422 field samples collected by either the boot sock or drag swab method. The samples were cultured by selective enrichment in tetrathionate broth followed by transfer onto a modified semisolid Rappaport-Vassiliadis medium and then plating onto brilliant green with novobiocin and xylose lysine brilliant Tergitol 4 plates. One-milliliter aliquots of the selective enrichment broths from each sample were collected for DNA extraction by the commercial PrepSEQ nucleic acid extraction assay and analysis by the Salmonella Enteritidis specific real-time PCR assay. The real-time PCR assay detected no significant differences between the boot sock and drag swab samples. In contrast, the culture method detected a significantly higher number of positive samples from boot socks. The diagnostic sensitivity of the real-time PCR assay for the field samples was significantly higher than that of the culture method. The kappa value obtained was 0.46, indicating moderate agreement between the real-time PCR assay and the culture method. In addition, the real-time PCR method had a turnaround time of 2 days compared with 4 to 8 days for the culture method. The higher sensitivity as well as the reduction in time and labor makes this real-time PCR assay an excellent alternative to conventional culture methods for diagnostic purposes, surveillance, and research studies to improve food safety. PMID- 22488065 TI - Glucose decreases virulence gene expression of Escherichia coli O157:H7. AB - Escherichia coli O157:H7 is responsible for a human toxico-infection that can lead to severe complications such as hemolytic uremic syndrome. Inside the intestine, E. coli O157:H7 forms typical attaching-effacing lesions and produces Shiga toxins. The genes that are responsible for these lesions are located in a pathogenicity island called the locus of enterocyte effacement (LEE). LEE gene expression is influenced by quorum sensing through the luxS system. In this study, the effect of glucose on the expression of several genes from LEE, on the expression of Shiga toxin genes, and on the expression of luxS was assessed with real-time, reverse transcription PCR. All concentrations of glucose (from 0.1 to 1%) were able to down-regulate genes from the LEE operon. A slight down regulation of genes implicated in Shiga toxin expression was also observed but was significant for low doses of glucose (0.1 to 0.5%) only. A slight but significant increase in luxS expression was observed with 1% glucose. This confirms that in addition to quorum sensing, the presence or absence of nutrients such as glucose has an impact on the down- or upregulation of LEE-encoded virulence genes by the bacterium. The influence of glucose on the virulence of E. coli O157:H7 has received little attention, and these results suggest that glucose can have an important effect on the virulence of E. coli O157:H7. PMID- 22488066 TI - Aqueous extracts of yerba mate (Ilex paraguariensis) as a natural antimicrobial against Escherichia coli O157:H7 in a microbiological medium and pH 6.0 apple juice. AB - Ilex paraguariensis is popularly used in the preparation of a tea infusion (yerba mate), most commonly produced and consumed in the South American countries of Uruguay, Paraguay, Argentina, and Brazil. In this study, aqueous extracts of commercial tea, derived from the holly plant species I. paraguariensis were evaluated for their ability to inhibit or inactivate Escherichia coli O157:H7 in a microbiological medium and modified apple juice. Dialyzed, lyophilized aqueous extracts were screened for antimicrobial activity against E. coli O157:H7 strains ATCC 43894 and 'Cider' in tryptic soy broth (TSB) and apple juice (adjusted to pH 6.0 to allow for growth of the bacterium). A mixture of the two strains was used as the inoculum when apple juice was used as the medium. MBCs were determined to be ca. 5 and 10 mg/ml for ATCC 43894 and 'Cider', respectively, in TSB. Higher concentrations of the extract were required to inactivate E. coli O157:H7 in pH-adjusted apple juice. An approximate 4.5-log reduction was observed for E. coli O157:H7 treated with 40 mg/ml extract. It was concluded that aqueous extracts from commercial yerba mate have potential to be used as antimicrobials in foods and beverages against pathogenic E. coli O157:H7. PMID- 22488067 TI - Effect of thymol or diphenyliodonium chloride on performance, gut fermentation characteristics, and campylobacter colonization in growing swine. AB - Food producing animals can be reservoirs of Campylobacter, a leading bacterial cause of human foodborne illness. Campylobacter spp. utilize amino acids as major carbon and energy substrates, a process that can be inhibited by thymol and diphenyliodonium chloride (DIC). To determine the effect of these potential additives on feed intake, live weight gain, and gut Campylobacter levels, growing pigs were fed standard grower diets supplemented with or without 0.0067 or 0.0201% thymol or 0.00014 or 0.00042% DIC in a replicated study design. Diets were offered twice daily for 7 days, during which time daily feed intake (mean +/- SEM, 2.39 +/- 0.06 kg day(-1)) and daily gain (0.62 +/- 0.04 kg day(-1)) were unaffected (P > 0.05) by treatment. Pigs treated with DIC but not thymol tended to have lower rectal Campylobacter levels (P ~ 0.07) (5.2 versus 4.2 and 4.4 log CFU g(-1) rectal contents for controls and 0.00014% DIC and 0.00042% DIC, respectively; SEM ~ 0.26). However, DIC or thymol treatments did not affect (P > 0.05) ileal or cecal Campylobacter (1.6 +/- 0.17 and 4.5 +/- 0.26 log CFU g(-1), respectively), cecal total culturable anaerobes (9.8 +/- 0.10 log CFU g(-1)), or accumulations of major fermentation end products within collected gut contents. These results suggest that thymol and DIC were appreciably absorbed, degraded, or otherwise made unavailable in the proximal alimentary tract and that encapsulation technologies will likely be needed to deliver effective concentrations of these compounds to the lower gut to achieve in vivo reductions of Campylobacter. PMID- 22488068 TI - Vibrio mimicus infection associated with crayfish consumption, Spokane, Washington, 2010. AB - We report a cluster of severe diarrheal disease caused by Vibrio mimicus infection among four persons who had consumed leftover crayfish the day after a private crayfish boil. Gastrointestinal illness caused by Vibrio mimicus has not been reported previously in Washington State. Three cases were laboratory confirmed by stool culture; using PCR, isolates were found to have ctx genes that encode cholera toxin (CT). Two of the cases were hospitalized under intensive care with a cholera-like illness. The illnesses were most likely caused by cross contamination of cooked crayfish with uncooked crayfish; however, V. mimicus was not isolated nor were CT genes detected by PCR in leftover samples of frozen crayfish. Clinicians should be aware that V. mimicus can produce CT and that V. mimicus infection can cause severe illness. PMID- 22488069 TI - Effect of anolyte on background microflora, Salmonella, and Listeria monocytogenes on catfish fillets. AB - Near-neutral electrolyzed water (anolyte), having a pH of 6.0 to 6.5 +/- 0.02, oxidation reduction potential of greater than 700 mV, and a residual chlorine level of 10 to 200 ppm, was reported to have a potential use to decontaminate food surfaces. An electrolyzing cell was developed that is capable of producing neutral electrolyzed water containing a chlorine level of greater than 700 ppm in the form of hypochlorous acid (anolyte). Anolyte with a chlorine level of 300 ppm was used to determine its effect on Salmonella and Listeria monocytogenes cells after a 3-min contact. Transmission electron micrograph results showed disruption of the outer cellular membrane for both bacteria. The anolyte (300 ppm) was used as a washing solution to decontaminate catfish fillets inoculated with either Salmonella or L. monocytogenes. After a 3-min contact time with the anolyte, there was a 1-log reduction for Salmonella, and after 8 days of refrigerated storage (4 degrees C), this bacterial reduction was maintained. There was no reduction of L. monocytogenes on the catfish fillet surfaces. The anolyte was an effective wash solution for Salmonella reduction on the catfish fillet surfaces. PMID- 22488070 TI - Total and inorganic arsenic in rice and rice bran purchased in Thailand. AB - Concentrations of total and inorganic arsenic were determined in 180 samples of polished and brown rice of three rice types, namely white, jasmine, and sticky, and 44 samples of rice bran from these three rice types purchased in Thailand. Concentrations (expressed in nanograms per gram) of inorganic arsenic in polished white, jasmine, and sticky rice were 68.3 +/- 17.6 (with a range of 45.0 to 106), 68.4 +/- 15.6 (41.7 to 101), and 75.9 +/- 24.8 (43.5 to 156), respectively, while those in the three brown rice samples were 124 +/- 34.4 (74.5 to 193), 120 +/- 31.6 (73.1 to 174), and 131 +/- 35.6 (78.0 to 188), respectively. Inorganic arsenic concentrations (expressed in nanograms per gram) in rice bran produced from the three rice types were 633 +/- 182 (375 to 919), 599 +/- 112 (447 to 824), and 673 +/- 195 (436 to 1,071), respectively. Rice bran contained concentrations of total and inorganic arsenic approximately seven and nine times higher, respectively, than those found in the corresponding polished rice. The levels of inorganic arsenic in the three rice types of both polished and brown rice were within the only published regulatory limit of 200 ng/g. PMID- 22488071 TI - Parametric distributions of underdiagnosis parameters used to estimate annual burden of illness for five foodborne pathogens. AB - Estimates of the burden of bacterial foodborne illness are used in applications ranging from determining economic losses due to a particular pathogenic organism to improving our understanding of the effects of antimicrobial resistance or changes in pathogen serotype. Estimates of the total number of illnesses can be derived by multiplying the number of observed illnesses, as reported by a specific active surveillance system, by an underdiagnosis factor that describes the relationship between observed and unobserved cases. The underdiagnosis factor can be a fixed value, but recent research efforts have focused on characterizing the inherent uncertainty in the surveillance system with a computer simulation. Although the inclusion of uncertainty is beneficial, re-creating the simulation results for every application can be burdensome. An alternative approach is to describe the underdiagnosis factor and its uncertainty with a parametric distribution. The use of such a distribution simplifies analyses by providing a closed-form definition of the underdiagnosis factor and allows this factor to be easily incorporated into Bayesian models. In this article, we propose and estimate parametric distributions for the underdiagnosis multipliers developed for the FoodNet surveillance systems in the United States. Distributions are provided for the five foodborne pathogens deemed most relevant to meat and poultry. PMID- 22488072 TI - Clostridium sporogenes PA 3679 and its uses in the derivation of thermal processing schedules for low-acid shelf-stable foods and as a research model for proteolytic Clostridium botulinum. AB - The putrefactive anaerobe Clostridium sporogenes PA 3679 has been widely used as a nontoxigenic surrogate for proteolytic Clostridium botulinum in the validation of thermal processes for low-acid shelf-stable foods, as a target organism in the derivation of thermal processes that reduce the risk of spoilage of such foods to an acceptable level, and as a research model for proteolytic strains of C. botulinum. Despite the importance of this organism, our knowledge of it has remained fragmented. In this article we draw together the literature associated with PA 3679 and discuss the identity of this organism, the phylogenetic relationships that exist between PA 3679 and various strains of C. sporogenes and proteolytic C. botulinum, the heat resistance characteristics of PA 3679, the advantages and limitations associated with its use in the derivation of thermal processing schedules, and the knowledge gaps and opportunities that exist with regard to its use as a research model for proteolytic C. botulinum. Phylogenetic analysis reviewed here suggests that PA 3679 is more closely related to various strains of proteolytic C. botulinum than to selected strains, including the type strain, of C. sporogenes. Even though PA 3679 is demonstrably nontoxigenic, the genetic basis of this nontoxigenic status remains to be elucidated, and the genetic sequence of this microorganism appears to be the key knowledge gap remaining to be filled. Our comprehensive review of comparative heat resistance data gathered for PA 3679 and proteolytic strains of C. botulinum over the past 100 years supports the practice of using PA 3679 as a (typically fail-safe) thermal processing surrogate for proteolytic C. botulinum. PMID- 22488073 TI - Meta-analysis of food safety training on hand hygiene knowledge and attitudes among food handlers. AB - Research has shown that traditional food safety training programs and strategies to promote hand hygiene increases knowledge of the subject. However, very few studies have been conducted to evaluate the impact of food safety training on food handlers' attitudes about good hand hygiene practices. The objective of this meta-analytical study was to assess the extent to which food safety training or intervention strategies increased knowledge of and attitudes about hand hygiene. A systematic review of food safety training articles was conducted. Additional studies were identified from abstracts from food safety conferences and food science education conferences. Search terms included combinations of "food safety," "food hygiene," "training," "education," "hand washing," "hand hygiene," "knowledge," "attitudes," "practices," "behavior," and "food handlers." Only before- and after-training approaches and cohort studies with training (intervention group) and without training (control group) in hand hygiene knowledge and including attitudes in food handlers were evaluated. All pooled analyses were based on a random effects model. Meta-analysis values for nine food safety training and intervention studies on hand hygiene knowledge among food handlers were significantly higher than those of the control (without training), with an effect size (Hedges' g) of 1.284 (95% confidence interval [CI] ~ 0.830 to 1.738). Meta-analysis of five food safety training and intervention studies in which hand hygiene attitudes and self-reported practices were monitored produced a summary effect size of 0.683 (95% CI ~ 0.523 to 0.843). Food safety training increased knowledge and improved attitudes about hand hygiene practices. Refresher training and long-term reinforcement of good food handling behaviors may also be beneficial for sustaining good hand washing practices. PMID- 22488074 TI - Radiographic progression in ankylosing spondylitis/axial spondyloarthritis: how fast and how clinically meaningful? AB - PURPOSE OF REVIEW: Radiographic progression in the axial skeleton is considered as an important outcome in ankylosing spondylitis (AS) and in the whole group of axial spondyloarthritis (SpA). Recently new data on the rates and predictors of radiographic progression from observational cohorts have become available. Here we summarize recent data and discuss their clinical relevance and directions for further investigations. RECENT FINDINGS: Nonradiographic axial SpA progresses to AS with a rate of about 12% over 2 years; elevated C-reactive protein (CRP) is an important predictor of such a progression. The rate of radiographic progression in the spine is strongly dependent on the presence of the following risk factors: syndesmophytes at baseline, elevated acute phase reactants (CRP and/or erythrocyte sedimentation rate) and smoking. The presence of radiographic damage in the spine has a strong impact on spinal mobility and functional status, although the association of radiographic sacroiliitis progression with the functional status remains unclear. SUMMARY: Radiographic progression in the spine and, to a lesser extent, in the sacroiliac joint represents a clinically relevant clinical outcome and treatment target in AS/axial SpA. PMID- 22488075 TI - Update on coxsackievirus B3 myocarditis. AB - PURPOSE OF REVIEW: To present recent findings on the pathogenesis of coxsackievirus B3 (CVB3) myocarditis based on animal models, with a focus on the role of T helper (Th) immune responses in disease progression. RECENT FINDINGS: Acute CVB3 myocarditis is known to be increased by Th1 immune responses, but recent findings indicate that Th1-type immunity protects against acute myocarditis by reducing viral replication and prevents the progression to chronic myocarditis and dilated cardiomyopathy (DCM) by inhibiting Th2 responses. Th2 responses reduce acute myocarditis by inhibiting Th1 responses via regulatory T cells and anti-inflammatory cytokines, but can be deleterious when they induce acute cardiac remodeling leading to chronic myocarditis/DCM. Th2-skewed immune responses allow resistant strains of mice to progress from myocarditis to DCM. In contrast, Th17 responses are elevated during acute and chronic myocarditis and have been found to contribute to cardiac remodeling and DCM. SUMMARY: Recent data indicate that elevated Th2 and Th17 responses during acute CVB3 myocarditis are critical for the progression from myocarditis to DCM and heart failure because of their ability to induce cardiac remodeling. Th1 responses protect against CVB3 myocarditis by inhibiting Th2 responses and viral replication, but increase acute inflammation. PMID- 22488076 TI - Pathogenesis of spondyloarthritis: autoimmune or autoinflammatory? AB - PURPOSE OF REVIEW: Spondyloarthritis (SpA) is a chronic immune-mediated inflammatory disease of unknown origin. Here we aim to review whether SpA is driven by T-cell and/or B-cell autoreactivity or by abnormal innate immune responses. RECENT FINDINGS: SpA does not share genetic risk factors, female predominance, presence of disease-specific autoantibodies and response to T-cell or B-cell-targeted therapies with prototypical autoimmune diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Growing evidence indicates that increased responsiveness of innate immune cells such as macrophages, mast cells and neutrophils drives inflammation in SpA. The altered innate immune response may be related to nonantigen-presenting functions of HLA B27, including the induction of an unfolded protein response, and can be triggered by bacterial and mechanical stress. Innate immune cells appear to be the main producers of both pro-inflammatory (tumor necrosis factor, IL-1, IL-23, IL-17) and anti-inflammatory (IL-10) cytokines in SpA. SUMMARY: The predominance of myeloid above lymphoid alterations suggests an autoinflammatory rather than autoimmune origin of inflammation in SpA. Therefore, targeting innate cells or their inflammatory mediators may be more effective than T-cell or B-cell-directed therapies. PMID- 22488077 TI - Food choice as a key management strategy for functional gastrointestinal symptoms. AB - Recognition of food components that induce functional gut symptoms in patient's functional bowel disorders (FBD) has been challenging. Food directly or indirectly provides considerable afferent input into the enteric nervous system. There is an altered relationship between the afferent input and perception/efferent response in FBD. Defining the nature of food-related stimuli may provide a means of minimizing such an input and gut symptoms. Using this premise, reducing the intake of FODMAPs (fermentable oligo-, di-, and mono saccharides and polyols)--poorly absorbed short-chain carbohydrates that, by virtue of their small molecular size and rapid fermentability, will distend the intestinal lumen with liquid and gas--improves symptoms in the majority of patients. Well-developed methodologies to deliver the diet via dietician-led education are available. Another abundant source of afferent input is natural and added food chemicals (such as salicylates, amines, and glutamates). Studies are needed to assess the efficacy of the low food chemical dietary approach. A recent placebo-controlled trial of FODMAP-poor gluten provided the first valid evidence that non-celiac gluten intolerance might actually exist, but its prevalence and underlying mechanisms require elucidation. Food choice via the low FODMAP and potentially other dietary strategies is now a realistic and efficacious therapeutic approach for functional gut symptoms. PMID- 22488078 TI - Endotherapy for Barrett's esophagus. AB - Endotherapy is now the mainstay of therapy for Barrett's associated neoplasia. The approach should begin with confirmation of neoplasia by a gastrointestinal pathologist, patient counseling, and appropriate endoscopic work up. Detailed examination with high-resolution white light endoscopy is the most important tool for detection of neoplasia. Further validation studies are needed for many enhanced imaging modalities before being recommended as part of the standard work up and assessment of patients with Barrett's esophagus (BE). Endoscopic mucosal resection is required for any visible lesion in the setting of dysplasia for accurate histological diagnosis. The remainder of the epithelium may be treated with resection or ablative therapy, followed by adequate surveillance. Patients with nondysplastic Barrett's require further risk stratification before incorporation of ablative therapy for this population. The future will fortify the endoscopic role in Barrett's with validation trials for endoscopic assessment, further long-term results for each of the treatment modalities, potential risk stratification for patients with BE, and improved guidelines for surveillance after therapy. PMID- 22488079 TI - Acupuncture for irritable bowel syndrome: systematic review and meta-analysis. AB - OBJECTIVES: Evidence-based treatment guidelines have been unable to provide evidence-based guidance on the effects of acupuncture for irritable bowel syndrome (IBS) because the only previous systematic review included only small, heterogeneous, and methodologically unsound trials. We conducted a new systematic review and meta-analysis of randomized controlled trials (RCTs) to estimate the effects of acupuncture for treating IBS. METHODS: MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, Cumulative Index to Nursing and Allied Health, and the Chinese databases Sino-Med, CNKI, and VIP were searched through November 2011. Eligible RCTs compared acupuncture with sham acupuncture, other active treatments, or no (specific) treatment, and evaluated acupuncture as an adjuvant to another treatment. Our outcomes were overall IBS symptom severity and health-related quality of life. Dichotomous data were pooled to provide a relative risk (RR) of substantial improvement after treatment, and continuous data were pooled to provide a standardized mean difference (SMD) in post treatment scores between groups. RESULTS: A total of 17 RCTs (N=1,806) were included. We found no evidence of an improvement with acupuncture relative to sham acupuncture on symptom severity (SMD=-0.11, 95% confidence interval (95% CI): -0.35 to 0.13; 4 RCTs) or quality of life (SMD=-0.03, 95% CI: -0.27 to 0.22; 3 RCTs). Because of the homogeneity of the results of the sham-controlled trials, results were unaffected by restriction to the four sham-controlled RCTs that used adequate randomization, blinding, and had few withdrawals/dropouts. Among RCTs that did not use a placebo control, acupuncture was more effective than pharmacological therapy (RR of symptom improvement=1.28, 95% CI: 1.12 to 1.45; 5 RCTs) and no (specific) treatment (RR = 2.11, 95% CI: 1.18 to 3.79; 2 RCTs). There was no difference between acupuncture and Bifidobacterium (RR=1.07, 95% CI: 0.90 to 1.27; 2 RCTs) or between acupuncture and psychotherapy (RR=1.05, 95% CI: 0.87 to 1.26; 1 RCT). Acupuncture as an adjuvant to another Chinese medicine treatment was statistically significantly better than the other treatment alone, in trials with a high risk of bias (RR=1.17, 95% CI: 1.02 to 1.33; 4 RCTs). CONCLUSIONS: Sham-controlled RCTs have found no benefits of acupuncture relative to a credible sham acupuncture control on IBS symptom severity or IBS-related quality of life. In comparative effectiveness Chinese trials, patients reported greater benefits from acupuncture than from pharmacological therapies. Future trials may help clarify whether or not these reportedly greater benefits of acupuncture relative to pharmacological therapies are due entirely to patients' preferences for acupuncture or patients' greater expectations of improvement on acupuncture relative to drugs. PMID- 22488080 TI - Mucosal immune cell numbers and visceral sensitivity in patients with irritable bowel syndrome: is there any relationship? AB - OBJECTIVES: Repeated exposure to stress leads to mast cell degranulation, microscopic inflammation, and subsequent visceral hypersensitivity in animal models. To what extent this pathophysiological pathway has a role in patients with the irritable bowel syndrome (IBS) has not been properly investigated. The objective of this study was to assess the relationship between visceral hypersensitivity, microscopic inflammation, and the stress response in IBS. METHODS: Microscopic inflammation of the colonic mucosa was evaluated by immunohistochemistry in 66 IBS patients and 20 healthy volunteers (HV). Rectal sensitivity was assessed by a barostat study using an intermittent pressure controlled distension protocol. Salivary cortisol to a psychological stress was measured to assess the stress response. RESULTS: Compared with HV, mast cells, T cells, and macrophages were decreased in IBS patients. Similarly, lambda-free light chain (FLC)-positive mast cells were decreased but not immunoglobulin E (IgE)- and IgG-positive mast cells. There were no differences between hypersensitive and normosensitive IBS patients. No relation was found between any of the immune cells studied and the thresholds of discomfort, urge, first sensation, or IBS symptoms (e.g., abdominal pain, stool-related complaints, bloating). Finally, stress-related symptoms and the hypothalamic-pituitary adrenal-axis response to stress were not correlated with the number of mast cells or the presence of visceral hypersensitivity. CONCLUSIONS: Although the number of mast cells, macrophages, T cells, and lambdaFLC-positive mast cells is decreased in IBS compared with HV, this is not associated with the presence of visceral hypersensitivity or abnormal stress response. Our data question the role of microscopic inflammation as an underlying mechanism of visceral hypersensitivity, but rather suggest dysregulation of the mucosal immune system in IBS. PMID- 22488083 TI - Visual changes after encircling band removal. AB - AIMS: Visual changes over 1 year in 40 eyes were studied in 40 patients after removing scleral encircling bands. METHODS: Encircling bands in 20 eyes were cut and removed. The fellow eyes of the above patients and the eyes of another 20 patients with encircling bands that were not removed over the same period served as controls. Intraocular pressure, best-corrected visual acuity, axial length, microperimetry and corneal topography were evaluated preoperatively and at 1 week and 1, 3 and 6 months postoperatively. RESULTS: Both best-corrected visual acuity and astigmatism were significantly improved at 6 months postoperatively (p < 0.05 for each). Microperimetry examination showed that 2 degrees fixation stability increased by 52.6% (p < 0.01), 4 degrees fixation stability increased by 17.65% (p < 0.01) and 10 degrees mean sensitivity increased by 30% (p < 0.05). However, the pre- and postoperative axial length showed no significant difference. CONCLUSION: These results suggest that removing scleral encircling bands within the desired time postoperatively may give better visual outcomes due to decreased corneal astigmatism and improved average macular retinal light sensitivity. Removal of the encircling band is a safe, simple and feasible operation. PMID- 22488082 TI - Inhibition by morphine and its analogs of action potentials in adult rat dorsal root ganglion neurons. AB - Although opioids inhibit action potential (AP) conduction in primary-afferent fibers, this has not yet been fully examined. We investigated by using the sharp glass microelectrode technique how opioids (morphine, codeine, and ethylmorphine) affect APs recorded from adult rat dorsal root ganglion (DRG) neurons in response to sciatic nerve stimulation. The DRG neurons were classified into three types, Aalpha/beta, Adelta, and C, according to AP characteristics, including the fiber conduction velocity (CV) of the neuron. AP of the Aalpha/beta neuron was reduced in peak amplitude by each of the opioids in a reversible and concentration dependent manner. The potency sequence was ethylmorphine > codeine = morphine (IC(50) = 0.70, 2.5, and 2.9 mM, respectively), indicating that this AP inhibition is related to the chemical structure of the opioid. Each of the Adelta and C neuron APs was also inhibited by the opioids; ethylmorphine had a tendency to inhibit APs more effectively than codeine and morphine. This inhibition was variable in extent among neurons and was either comparable to or greater than that of the Aalpha/beta neuron AP. The opioid-induced AP inhibitions were unaffected by nonspecific opioid-receptor antagonist naloxone; opioid-receptor agonists did not affect APs. In conclusion, the opioids inhibited APs in DRG neurons without opioid-receptor activation; this inhibition was different among neurons having different primary-afferent fiber CVs and also among the three kinds of opioid. The inhibition by opioid of primary-afferent fiber AP conduction is suggested to be distinct in extent among fibers conveying distinct types of nociceptive information. PMID- 22488084 TI - Absence of evidence is not evidence of absence - does structural quality not matter in colorectal cancer patients' satisfaction and quality of life? PMID- 22488085 TI - Quality of life of colorectal cancer patients in certified centers versus non certified hospitals. AB - BACKGROUND: Since 2006, in Germany colorectal cancer patients can be treated in certified colorectal cancer centers. The aim of this explorative study was to investigate whether there are differences in the quality of life (QoL) of colorectal cancer patients who were treated in certified versus noncertified centers. PATIENTS AND METHODS: A total of 284 colorectal cancer patients participated in the study: 184 patients from certified colorectal cancer centers and 100 patients from noncertified centers. Data on QoL (using the Quality of Life Questionnaire of the European Organization for Research and Treatment of Cancer (EORTC-QLQ C30)), patient satisfaction, mental distress and sociodemographic data were assessed with a questionnaire in a written survey after the hospital stay. The moderating influence of patientrelated characteristics (e.g. age, sex, patient satisfaction, and psychological distress) and cancerrelated factors (Union internationale contre le cancer (UICC) stage) were tested. RESULTS: On a descriptive level, patients from noncertified centers had a higher QoL in 5 subdimensions (higher physical and role functioning and less insomnia, appetite loss and financial difficulties). After adjustment, only 2 differences remained significant: physical functioning (p < 0.01) and role functioning (p = 0.02). CONCLUSION: Structural improvements in the oncological care are not necessarily reflected in a better QoL of the patients treated in certified colorectal cancer centers. The findings are discussed in the context of the applied study design. PMID- 22488081 TI - The risk of lymph-node metastases in patients with high-grade dysplasia or intramucosal carcinoma in Barrett's esophagus: a systematic review. AB - OBJECTIVES: Endoscopic eradication therapy is used to treat mucosal neoplasms in Barrett's esophagus, but cannot cure cancers that have metastasized to lymph nodes. The risk of such metastases has been proposed as a reason to consider esophagectomy rather than endoscopic therapy for esophageal mucosal neoplasia. The objective of our study was to determine the frequency of lymph-node metastases in patients with high-grade dysplasia (HGD) and intramucosal carcinoma in Barrett's esophagus. METHODS: We performed a systematic review using the PRISMA guidelines to identify studies that included patients who had esophagectomy for HGD or intramucosal carcinoma in Barrett's esophagus, and that reported final pathology results after examination of esophagectomy specimens. RESULTS: We identified 70 relevant reports that included 1,874 patients who had esophagectomy performed for HGD or intramucosal carcinoma in Barrett's esophagus. Lymph-node metastases were found in 26 patients (1.39 % , 95 % CI 0.86 - 1.92). No metastases were found in the 524 patients who had a final pathology diagnosis of HGD, whereas 26 (1.93 % , 95 % CI 1.19 - 2.66 %) of the 1,350 patients with a final pathology diagnosis of intramucosal carcinoma had positive lymph nodes. CONCLUSIONS: The risk of unexpected lymph-node metastases for patients with mucosal neoplasms in Barrett's esophagus is in the range of 1 - 2 %. Esophagectomy has a mortality rate that often exceeds 2 %, with substantial morbidity and no guarantee of curing metastatic disease. Therefore, the risk of lymph node metastases alone does not warrant the choice of esophagectomy over endoscopic therapy for HGD and intramucosal carcinoma in Barrett's esophagus. PMID- 22488086 TI - Clinical test of masticatory efficacy in patients with maxillary/mandibular defects due to tumors. AB - BACKGROUND: The goal of the study was to evaluate the masticatory efficacy in patients who had been provided with resection prostheses after tumor removal in the maxillary/ mandibular region. These patients complained of impairment of masticatory function. PATIENTS AND METHODS: 3 groups of patients were compared under clinical-experimental conditions. A uniform chewing material was masticated by the participants under standardized conditions. A sieving procedure was used to evaluate the masticatory efficacy. Analysis of the particle sizes and particle masses obtained was performed with the aid of computers. RESULTS: The results showed that the masticatory efficacy of the patients with resection prostheses was the lowest of the 3 groups compared. The number of existing supporting zones and the location of the defect were found to be important influencing factors. Recording of the dietary habits of all patients was performed using a standardized dietary questionnaire. These data were analyzed using the corresponding software of the German Nutrition Society. With regard to the patients with resection prostheses, it was revealed that they often switched to food that did not require mastication. CONCLUSIONS: A nutritional guideline for patients with resection prostheses was developed, which is available for downloading free of charge on the Internet. PMID- 22488087 TI - The impact of cross-resistance between paclitaxel and docetaxel for metastatic gastric cancer. AB - BACKGROUND: Paclitaxel and docetaxel show similar anticancer mechanisms, but cross-resistance for gastric cancer chemotherapy remains unclear. PATIENTS AND METHODS: Among 484 patients with metastatic gastric cancer, who had received chemotherapy in 4 Japanese hospitals, we identified 28 patients who had received either paclitaxel- or docetaxel-containing chemotherapy and who were refractory to the other taxane. RESULTS: The median age was 65 years, and target lesions were present in 20 patients and absent in 8. The first taxane was administered to 16 patients as first-line chemotherapy and to 12 patients as second-line chemotherapy, while the second taxane was administered to 5 patients as second line, 13 as third-line, and 10 as fourth-line or beyond. The median survival time was 456 days (95% confidence interval (CI) 145-767 days), and the median survival time and median progression-free survival after the second taxane were 119 days (95% CI 85-153 days) and 50 days (95% CI 42-58 days), respectively. The second taxane chemotherapy achieved a response rate of 5% (1/20 patients) and an overall disease control rate of 17.9% (5/28 patients). CONCLUSIONS: Paclitaxel and docetaxel might show a large degree of cross-resistance for gastric cancer. Paclitaxel and docetaxel should not be routinely administered for metastatic gastric cancer after failure of the other taxane. PMID- 22488088 TI - Management of diffuse hepatocellular carcinoma (? 10 Lesions) with doxorubicin loaded DC beads is a safe and effective treatment option. AB - BACKGROUND: Multinodular hepatocellular carcinoma (HCC; >= 10 lesions) has been considered a controversial indication for transarterial chemoembolization (TACE) based on the extent of disease and the belief that no clinical benefit can be achieved. The aim of this study was to assess the safety and efficacy of chemoembolization with doxorubicin-eluting beads (DEBDOX) in the treatment of multinodular HCC. PATIENTS AND METHODS: A 503-patient prospective multinational DC Bead registry database from 6/2007 to 2/2010 identified 176 patients treated for HCC with DEBDOX. RESULTS: There were 42 patients with multinodular HCC compared to 134 with non-multinodular HCC. After a median follow-up of 12 months, the multinodular group response rate according to modified RECIST criteria was 56% and median overall survival was 7.6 months, compared to 57% and 15 months in the non-multinodular group (p = 0.08). CONCLUSIONS: Multinodular HCC represents a more advanced stage of disease; however, DEBDOX treatment is safe and effective when compared to historical controls and current best systemic therapy. Continued hepatic arterial therapy and evaluation is needed in this clinical subset to further confirm these results. PMID- 22488089 TI - Radiation recall pneumonitis caused by erlotinib after palliative definitive radiotherapy. AB - BACKGROUND: Radiation recall pneumonitis (RRP) occurs in a previously irradiated field and is triggered by certain cytotoxic drugs, principally chemotherapeutic agents such as erlotinib. Erlotinib is a reversible epidermal growth factor receptor tyrosine kinase inhibitor (TKI) and is an effective second-line treatment for patients with advanced-stage non-squamous-cell lung cancer. Previously, only 2 cases of radiation recall after erlotinib treatment have been reported. Here, we report a case of RRP caused by treatment with erlotinib 4 months after palliative definitive hypofractionated radiation therapy (RT). PATIENT AND METHODS: A 58-year-old male patient with non-small cell lung cancer (adenocarcinoma) was treated with polychemotherapy, palliative RT (30 Gy in 10 fractions), and erlotinib thereafter. RESULTS: Dosimetric analysis obtained from a 3-dimensional conformal RT planning system revealed that the volume of lung receiving at least 20 Gy (V20) was 21.2% and the mean lung dose was 12.7 Gy. These data indicate that systemic administration of a TKI, even after palliative RT, may lead to unexpected toxicity when the radiation field encompasses visceral organs. CONCLUSION: We conclude that the use of a TKI after RT may trigger radiation pneumonitis. Although evidence is limited, we advise clinicians to be cautious of RRP after erlotinib treatment. PMID- 22488090 TI - Penile metastasis from primary bladder cancer: a study of 8 cases and review of the literature. AB - BACKGROUND: Penile metastases from primary bladder cancer are extremely rare. CASE REPORT: The medical records of 8 patients who presented with metastatic penile carcinoma originating from bladder between 2002 and 2010 were analyzed. The main complaint was a painless nodule (6 cases), priapism (1 case), and penile pain (1 case). All of the penile metastases were metachronous. The interval between primary cancer and penile metastases ranged from 1 to 100 months (mean 26.4 months). Total penectomy combined with systemic chemotherapy was the treatment of choice in 4 cases. 1 patient only accepted external beam radiotherapy, and 3 patients only accepted chemotherapy due to disseminated disease. The time interval between penile metastases and death ranged from 4 to 23 months (mean 11.4 months). CONCLUSION: Penile metastases secondary to primary bladder cancer are rare and represent a challenging problem. The common mode of spread to the penis is by retrograde venous route. The overall outcome is very poor, and most patients will die within 1 year despite systemic chemotherapy and supportive care. Radical ablative surgery is justified only for symptomatic relief. PMID- 22488091 TI - Peritoneal cystic mesothelioma: are surgery and HIPEC optimal first-line treatments? AB - BACKGROUND: Peritoneal cystic mesothelioma (PCM) is an uncommon clinical pathology. Its high rate of recurrence following partial or total resection as well as its spontaneous onset of malignancy have been well documented in a series of case studies. The medical community has yet to define standardized treatment guidelines for PCM. CASE REPORTS: This study reviews the case of 2 patients admitted and treated for PCM. Recent studies have reported improved recurrence and survival rates achieved by means of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), especially when used as first line treatments. However, whether or not the use of CRS and HIPEC is more effective than a surgical regimen of multiple debulking procedures, is still the subject of debate. CONCLUSION: CRS and HIPEC as first-line treatments have lower morbidity and mortality rates than regimens of multiple back-to-back surgical procedures, and as such, the CRS/HIPEC method appears to be the more successful approach. PMID- 22488092 TI - Advanced gastroesophageal carcinoma: an update on the current therapeutic landscape. AB - Gastroesophageal cancers are usually diagnosed in an advanced stage, and effective treatment options remain limited. The discovery of new drugs to treat these diseases has been slow for decades. An occasional favorable outcome, trastuzumab, in patients with HER2 protein-overexpressing tumors, is welcome but not sufficient. For advanced gastroesophageal adenocarcinoma (AGC), fluoropyrimidines (given orally or intravenously) plus a platinum compound (usually cisplatin) have been accepted as a global reference to streamline new drug development. The addition of a third cytotoxic (docetaxel or epirubicin) can produce modest prolongation of overall survival. In some European countries, the irinotecanbased regimen is considered as an alternative to platinum-based first line therapy. Selecting a safe, effective, and convenient regimen is desirable and is the focus of current research. Additionally, it appears that survival differences by regions (e.g., Asians survive longer compared to Western and South American patients) are likely due to second- and third-line therapies, differences in tumor biology, or unknown reasons. Future progress could come from 1 of 2 approaches: (1) conducting many empiric phase III trials in unselected patients or (2) through detailed studies of molecular biology to develop rational therapies. We provide a brief update on the treatment of AGC. PMID- 22488093 TI - Primary hepatic leiomyosarcoma in adults: analysis of prognostic factors. AB - Primary hepatic leiomyosarcoma (LMS) is a rare malignancy of the liver in adults, with variable overall survival (OS). The main purpose of this study was to identify prognostic factors of improved survival. Relevant data were abstracted from MEDLINE, EMBASE, and Academic Search Premiere (ASP), and from the medical records of a patient treated at our institution. Multivariate analysis was conducted by generating Cox proportional hazard ratios. We identified 109 patients with primary hepatic LMS; 95 were included for basic description, and 84 for OS analysis. Median age was 58 years (range 19-86 years), 45.0% of the patients were female, and 21.1% were AJCC stage IV. The primary treatment for all 95 patients was as follows: 61.1% had surgery, 13.7% had chemotherapy, 5.3% had liver transplantation, 2.1% received radiotherapy, and 14.7% were managed conservatively. Median OS was 19 months (range 0-181 months) with 1-, 2-, and 5 year survival rates of 61.2, 41.1, and 14.5%, respectively. In a multivariate analysis, smaller size of the largest hepatic lesion (p = 0.038) and negative resection margin (p = 0.0004) were associated with improved survival. Complete surgical resection with clear margin is necessary to improve survival of patients with primary hepatic LMS. PMID- 22488094 TI - Curative resection of double primary lung cancer after 15-month bortezomib administration. PMID- 22488095 TI - The role of radiation therapy in the management of adrenal carcinoma and adrenal metastases. AB - The use of radiation therapy (RT) to treat adrenal tumors has historically been limited by the risk of normal tissue toxicity, given the proximity of the adrenals to radiosensitive structures, such as the kidney, stomach, intestine, and spinal cord. However, contemporary techniques have made RT safe and effective for use in the management of adrenal carcinoma and adrenal metastases. Data on recent advances in the use of RT to treat adrenocortical carcinoma and adrenal metastases are reviewed, in both surgical and non-surgical settings. PMID- 22488097 TI - Development of a novel composite material with carbon nanotubes assisted by self assembled peptides designed in conjunction with beta-sheet formation. AB - A novel composite material is developed with single-walled carbon nanotubes (SWCNTs) and artificially designed peptides, and its chemical and physicochemical characteristics are evaluated with an aim toward biomedical application. The peptides were designed to form a beta-sheet structure that would be suitable for wrapping SWCNTs. The complex of SWCNTs and peptide (SWCNT-peptide) showed good dispersibility in aqueous media and was considerably stable even in the absence of an excess amount of peptide in the media. The formation of SWCNT-peptide was confirmed by its performance in water, atomic force microscopy and transmission electron microscopy observation, and molecular modeling. The possibility of introducing various functions to SWCNT-peptide was also demonstrated by several methods, such as introduction of special amino acids, chemical modification, and additional complex formation based on electrostatic interaction. These results suggest the potential of the SWCNT-peptide complex as a molecular platform on which a desirable structure and/or function can be constructed for biomedical and industrial application. PMID- 22488098 TI - Clinical outcomes of breast-conserving surgery in patients using a modified method for cavity margin assessment. AB - BACKGROUND: This study describes a modified intraoperative method for cavity margin (CM) assessment in place of lumpectomy margin assessment in patients undergoing breast-conserving surgery (BCS). METHODS: This is a retrospective review of 422 breast cancer patients undergoing BCS with intraoperative CM assessment. After an initial lumpectomy with intent to obtain >=1-cm margins, separate specimens 1 * 1 cm, 0.5-cm thick were taken from the cavity margin circumferentially. These were frozen without reference to the side of the new margin as a time-saving measure, and parallel sections of the resected surface were evaluated. RESULTS: After a median follow-up of 55.5 months, a cumulative 5 year locoregional recurrence-free survival rate of 95.3%, metastasis-free survival rate of 97.8%, disease-free survival rate of 88.3%, and overall survival rate of 96.0%, was achieved. The CM positivity rates were of no statistical difference when <7, 7-8, and >8 CMs were assessed. The second operation rate was 3.5% because of the false-negative results of the frozen section analysis on CMs. Univariate and multivariate analysis revealed that a higher pN stage and cT stage as well as a lack of adjuvant chemotherapy or radiation demonstrated significantly worse clinical outcomes. Locoregional recurrences and metastasis are both correlated with worse overall survival. The number of the CMs assessed was not associated with clinical outcomes. CONCLUSIONS: The modified CM assessment presented here is a rapid, accurate, and oncologically safe approach for margin evaluation in BCS patients. Lumpectomy margin assessment might be spared when this method is used. PMID- 22488096 TI - Cytoarchitectonical analysis and probabilistic mapping of two extrastriate areas of the human posterior fusiform gyrus. AB - The human extrastriate visual cortex comprises numerous functionally defined areas, which are not identified in the widely used cytoarchitectonical map of Brodmann. The ventral part of the extrastriate cortex is particularly devoted to the identification of visual objects, faces and word forms. We analyzed the region immediately antero-lateral to hOc4v in serially sectioned (20 MUm) and cell body-stained human brains using a quantitative observer-independent cytoarchitectonical approach to further identify the anatomical organization of the extrastriate cortex. Two novel cytoarchitectonical areas, FG1 and FG2, were identified on the posterior fusiform gyrus. The results of ten postmortem brains were then registered to their MRI volumes (acquired before histological processing), 3D reconstructed, and spatially normalized to the Montreal Neurological Institute reference brain. Finally, probabilistic maps were generated for each cytoarchitectonical area by superimposing the areas of the individual brains in the reference space. Comparison with recent functional imaging studies yielded that both areas are located within the object-related visual cortex. FG1 fills the gap between the retinotopically mapped area VO-1 and a posterior fusiform face patch. FG2 is probably the correlate of this face patch. PMID- 22488099 TI - The glasgow prognostic score as a predictor of survival in patients with potentially resectable pancreatic adenocarcinoma. AB - BACKGROUND: Survival rates after resection of pancreatic adenocarcinoma are poor; however, several tumor-related prognostic factors have been identified. There is increasing evidence that additional patient-related prognostic factors, such as ongoing systemic inflammatory response, are associated with poor outcomes in patients with common solid tumors. The purpose of this study was to evaluate the prognostic significance of the modified glasgow prognostic score (mGPS) in resected pancreatic ductal adenocarcinoma. METHODS: Data were collected from 101 patients who had undergone pancreatic resection for ductal adenocarcinoma. Tumor and host factors were analyzed by Kaplan-Meier and Cox proportional hazard models to evaluate their potential prognostic effects. RESULTS: An elevated mGPS was associated with lower overall survival rate after pancreatic resection. The median actuarial survival rate for patients with an mGPS of 0, 1, or 2 was 37.2, 11.5, and 7.3, respectively (p = 0.0001). The Cox proportional hazards model, including all the parameters statistically significant at univariate analysis, demonstrated that mGPS, lymph node ratio (LNR), and positive resection margins were independent negative prognostic factors CONCLUSIONS: Margin involvement, LNR, and the preoperative mGPS were identified as independent predictors of survival in patients undergoing potentially curative pancreatic resection. Based on the present results and existing validation literature, the mGPS should be included in the routine assessment of patients with pancreatic cancer to better stratify patients for entry into therapeutic trials. PMID- 22488101 TI - Instructive reconstruction: a new role for apoptosis in pattern formation. Instructive apoptotic patterning establishes de novo tissue generation via the apoptosis linked production of morphogenic signals. AB - Apoptosis is not only involved in patterning by removal of tissue (destructive apoptotic patterning), but it can also function in signalling the site of de novo tissue generation via morphogenic signals (instructive apoptotic patterning). PMID- 22488100 TI - Effects of brief stress exposure during early postnatal development in Balb/CByJ mice: II. Altered cortical morphology. AB - Early life experience can significantly determine later mental health status and cognitive function. Neonatal stress, in particular, has been linked to the etiology of mental health disorders as divergent as mood disorder, schizophrenia, and autism. Our study uses a Balb/CByJ mouse model to test the hypothesis, that neonatal stress will alter development and subsequent environmental modulation of neocortex. Using a split litter design, we generated stressed mice (STR) and within litter controls (LMC) along with age-matched, untreated animals (AMC), to serve as across litter controls. Short, daily exposure to a psychosocial/physical stressor, during the first week of life, resulted by adulthood in significant changes in neocortical thickness and architecture, which were further modulated by exposure to behavioral testing. Surprisingly, cortical size in LMC mice was also affected. These observations were compared to the effects of environmental enrichment in the same mouse strain. Our data indicate that LMC and STR males share with environmentally enriched males, an increase in thickness in infra granular cortical layers, while STR also display a stress selective decrease in supragranular layers, in response to behavioral training as adults. PMID- 22488102 TI - Choroidal thickness in open-angle glaucoma measured by spectral-domain scanning laser ophthalmoscopy/optical coherence tomography. AB - AIMS: To measure macular choroidal thickness in healthy and glaucomatous eyes using spectral-domain scanning laser ophthalmoscopy/optical coherence tomography. METHODS: Choroidal thickness was measured in 21 healthy eyes and 16 glaucomatous eyes. Choroidal thickness was measured under the fovea and at 500-um intervals from the foveal center to 4 mm in the nasal and temporal directions. Vessels were counted in a macular area of 8,000 um(2). Only choroidal vessels with a horizontal diameter of at least 155 um and a vertical diameter of at least 50 um were considered. RESULTS: The mean choroidal thickness was greatest below the fovea, i.e. 343.8 um (SD +/- 29.06) in controls and 411.56 um (SD +/- 33.60; p < 0.001) in the glaucomatous group. The mean vertical diameter was significantly greater (p = 0.008) in glaucomatous eyes (112.18 +/- 37.64 um) than in healthy eyes (103.98 +/- 25.67 um), whereas the luminal area of vessels was significantly larger (p = 0.3) in glaucomatous eyes (39,157.34 +/- 21,657.23 um(2)) than in healthy eyes (43,779.84 +/- 22,874.87 um(2)). CONCLUSIONS: We show that choroidal thickness is increased in glaucomatous eyes due to an increase in both the vertical diameter and the luminal area of the vessels. This seems to implicate the choroid in the pathogenesis of open-angle glaucoma. PMID- 22488103 TI - Functional properties of Lactobacillus strains isolated from dairy products. AB - Twenty-four acid- and bile-tolerant lactobacilli isolates from dairy products were identified and further in vitro characterized for the presence of functional traits potentially useful for probiotic applications, which included desirable and undesirable traits, such as biofilm formation, ability to inhibit intestinal pathogens, antibiotic susceptibility, and enzyme activity. The majority of examined strains were susceptible to certain antimicrobial agents (streptomycin, gentamicin, clindamycin, erythromycin, tetracycline, quinupristin-dalfopristin), except for three strains of Lactobacillus rhamnosus with minimal inhibitory concentration levels for streptomycin higher than the microbiological breakpoints (>=32 MUg/mL), which are considered as resistant. Undesirable traits such as alpha-chymotrypsin or N-acetyl-beta-glucosaminidase activities were not detected, but low beta-glucuronidase, and moderate and high beta-glucosidase activities were recorded in nine strains, which were eliminated from further examination together with three isolates showing unsuitable antibiotic resistance. Of the remaining 12 isolates, 4 (Lactobacillus fermentum 202, Lactobacillus gallinarum 7001, L. rhamnosus 183, and Lactobacillus plantarum L2-1) manifested an outstanding potential to inhibit selected intestinal pathogens in an agar spot test, including Escherichia coli and Salmonella spp., and simultaneously demonstrated strong biofilm-forming capacity. In conclusion, the results of our in vitro experiments showed that the above four strains had a potential probiotic value and met the criteria to be identified as a possible probiotic microorganism, with the necessity of verification through well-designed in vivo experimental, clinical, and technological studies before the strains can be used as probiotics or as starter probiotic cultures. PMID- 22488104 TI - Production of lignocellulose-degrading enzymes employing Fusarium solani F-552. AB - In this work, capability of Fusarium solani F-552 of producing lignocellulose degrading enzymes in submerged fermentation was investigated. The enzyme cocktail includes hydrolases (cellulases, xylanases, and proteinases) as well as ligninolytic enzymes: manganese-dependent peroxidase (MnP), lignin peroxidase (LiP), and laccase (Lac). To our knowledge, this is the first report on production of MnP, LiP, and Lac together by one F. solani strain. The enzyme productions were significantly influenced by application of either lignocellulosic material or chemical inducers into the fermentation medium. Among them, corn bran significantly enhanced especially productions of cellulases and xylanases (248 and 170 U/mL, respectively) as compared to control culture (11.7 and 29.2 U/mL, respectively). High MnP activity (9.43 U/mL, control 0.45 U/mL) was observed when (+)-catechin was applied into the medium, the yield of LiP was maximal (33.06 U/mL, control 2.69 U/mL) in gallic acid, and Lac was efficiently induced by, 2,2'-azino-bis-[3-ethyltiazoline-6-sulfonate] (6.74 U/mL, not detected in control). Finally, in order to maximize the ligninolytic enzymes yields, a novel strategy of introduction of mild oxidative stress conditions caused by hydrogen peroxide into the fermentation broth was tested. Hydrogen peroxide significantly increased activities of MnP, LiP, and Lac which may indicate that these enzymes could be partially involved in stress response against H(2)O(2). The concentration of H(2)O(2) and the time of the stress application were optimized; hence, when 10 mmol/L H(2)O(2) was applied at the second and sixth day of cultivation, the MnP, LiP, and Lac yields reached 21.67, 77.42, and 12.04 U/mL, respectively. PMID- 22488105 TI - Egg oral immunotherapy. AB - PURPOSE OF REVIEW: Egg allergy is one of the most common food allergies of childhood and no interventional therapy is currently approved by the Food and Drug Administration. Much recent research has focused on the safety, efficacy, and mechanism of oral immunotherapy (OIT) as a disease-modifying treatment. RECENT FINDINGS: Small pilot studies with varying protocol designs have shown egg OIT to be relatively well tolerated, and efficacy is suggested but not formally demonstrated. At this time, no placebo-controlled randomized trial has been published confirming desensitization and no published study has convincingly demonstrated the development of OIT-induced tolerance to egg. SUMMARY: Egg OIT is a promising modality for providing temporary protection from reactions caused by accidental egg exposure. However, the overall strength of the evidence in favor of egg OIT is limited by small sample sizes and the lack of controls, both of which are important considerations given the spontaneous resolution expected in egg allergy. More high-quality studies are necessary before egg OIT can be recommended as a viable treatment option. PMID- 22488106 TI - Design, simulation and experimental validation of a novel flexible neural probe for deep brain stimulation and multichannel recording. AB - An implantable micromachined neural probe with multichannel electrode arrays for both neural signal recording and electrical stimulation was designed, simulated and experimentally validated for deep brain stimulation (DBS) applications. The developed probe has a rough three-dimensional microstructure on the electrode surface to maximize the electrode-tissue contact area. The flexible, polyimide based microelectrode arrays were each composed of a long shaft (14.9 mm in length) and 16 electrodes (5 um thick and with a diameter of 16 um). The ability of these arrays to record and stimulate specific areas in a rat brain was evaluated. Moreover, we have developed a finite element model (FEM) applied to an electric field to evaluate the volume of tissue activated (VTA) by DBS as a function of the stimulation parameters. The signal-to-noise ratio ranged from 4.4 to 5 over a 50 day recording period, indicating that the laboratory-designed neural probe is reliable and may be used successfully for long-term recordings. The somatosensory evoked potential (SSEP) obtained by thalamic stimulations and in vivo electrode-electrolyte interface impedance measurements was stable for 50 days and demonstrated that the neural probe is feasible for long-term stimulation. A strongly linear (positive correlation) relationship was observed among the simulated VTA, the absolute value of the SSEP during the 200 ms post stimulus period (SigmaSSEP) and c-Fos expression, indicating that the simulated VTA has perfect sensitivity to predict the evoked responses (c-Fos expression). This laboratory-designed neural probe and its FEM simulation represent a simple, functionally effective technique for studying DBS and neural recordings in animal models. PMID- 22488107 TI - A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease. AB - Abnormal blood flow accounts for most of the clinical morbidity of sickle cell disease (SCD) [1,2]. Most notably, occlusion of flow in the microvasculature causes the acute pain crises [3] that are the commonest cause for patients with SCD to seek medical attention [4] and major determinants of their quality of life [5]. Based on evidence that endothelial P-selectin is central to the abnormal blood flow in SCD we provide results from four of our studies that are germane to microvascular blood flow in SCD. A proof-of-principle study established that doses of heparin lower than what are used for anticoagulation but sufficient to block P-selectin improved microvascular blood flow inpatients with SCD. An in vitro study showed that Pentosan Polysulfate Sodium (PPS) had greater P-selectin blocking activity than heparin. A Phase I clinical study demonstrated that a single oral dose of PPS increased microvascular blood flow in patients with SCD. A Phase II clinical study that was not completed documented that daily oral doses of PPS administered for 8 weeks lowered plasma levels of sVCAM-1 and tended to improve microvascular blood flow in patients with SCD. These data support the concept that P-selectin on the microvascular endothelium is critical to both acute vascular occlusion and chronically impaired microvascular blood flow in SCD. They also demonstrate that oral PPS is beneficial to microvascular sickle cell blood flow and has potential as an efficacious agent for long-term prophylactic therapy of SCD. PMID- 22488109 TI - Biomedical mass spectrometry. PMID- 22488108 TI - Runt-related transcription factor 3 reverses epithelial-mesenchymal transition in hepatocellular carcinoma. AB - Loss or decreased expression of runt-related transcription factor 3 (RUNX3), a tumor suppressor gene involved in gastric and other cancers, has been frequently observed in hepatocellular carcinoma (HCC). The objective of this study was to identify the regulatory mechanism of the epithelial-mesenchymal transition (EMT) by RUNX3 in HCC. Human HCC cell lines, Hep3B, Huh7, HLF and SK-Hep1, were divided into low- and high-EMT lines, based on their expression of TWIST1 and SNAI2, and were used in this in vitro study. Ectopic RUNX3 expression had an anti-EMT effect in low-EMT HCC cell lines characterized by increased E-cadherin expression and decreased N-cadherin and vimentin expression. RUNX3 expression has previously been reported to reduce jagged-1 (JAG1) expression; therefore, JAG1 ligand peptide was used to reinduce EMT in RUNX3-expressing low-EMT HCC cells. Immunohistochemical analyses were performed for RUNX3, E-cadherin, N-cadherin and TWIST1 in 33 human HCC tissues, also divided into low- and high-EMT HCC, based on TWIST1 expression. E-cadherin expression was correlated positively and N-cadherin expression was correlated negatively with RUNX3 expression in low-EMT HCC tissues. Correlations between EMT markers and RUNX3 mRNA expression were analyzed using Oncomine datasets. Similarly, mRNA expression of E-cadherin was also significantly correlated with that of RUNX3 in low-EMT HCC, while mRNA expression of JAG1 was negatively correlated with that of RUNX3. These results suggest a novel mechanism by which loss or decreased expression of RUNX3 induces EMT via induction of JAG1 expression in low-EMT HCC. PMID- 22488110 TI - High-resolution mass spectrometry. PMID- 22488111 TI - Current bioanalytical methods for detection of penicillins. AB - With the worldwide use of penicillin antibiotics comes the need for tighter controls. Bacterial resistance is a genuine problem and governmental and international bodies, for example the European Medicines Agency (EMA) and the World Health Organization (WHO), have designed strategies to overcome this unfortunate consequence of antibiotic use. Foodstuffs are monitored to ensure they contain very low quantities of antibiotics, so they are not prejudicial to health and the environment. Detection is based on chromatographic methods. However, screening can be performed by use of simpler, rapid methods of detection, e.g. microbial inhibition test, lateral flow assays, immunoassays, and use of biosensors, to reduce the final number of samples to be analyzed by chromatography. In this review, we have gathered information regarding all such screening methods for the penicillins and have critically assessed their capability and specificity for detection of penicillins. PMID- 22488112 TI - Chromosome painting of the pygmy tree shrew shows that no derived cytogenetic traits link primates and scandentia. AB - We hybridized human chromosome paints on metaphases of the pygmy tree shrew (Tupaia minor, Scandentia). The lack of the ancestral mammalian 4/8 association in both Primates and Scandentia was long considered a cytogenetic landmark that phylogenetically linked these mammalian orders. However, our results show that the association 4/8 is present in Tupaia along with not previously reported associations for 1/18 and 7/10. Altogether there are 11 syntenic associations of human chromosome segments in the pygmy tree shrew karyotype: 1/18, 2/21, 3/21, 4/8, 7/10, 7/16, 11/20, 12/22 (twice), 14/15 and 16/19. Our data remove any cytogenetic evidence that Scandentia has a preferential phylogenetic relationship with Primates. PMID- 22488113 TI - Fast and slow versus strong and weak metal-DNA binding: consequences for anti cancer activity. AB - The binding of transition metal compounds to nucleic acids is discussed in the perspectives of kinetics and their anticancer activity. Kinetics of ligand exchange is primarily determined by the intrinsic properties of the metal ions, and to a lesser degree by the ligands coordinated already to the metal ion. Metal compounds having ligand-exchange rates of the same order of magnitude as cell division processes, e.g. many Pt(iIIi), Ru(II) and Ru(III) compounds, are in use as chemotherapeutic drugs. Detailed knowledge of ligand exchange in such compounds is important for design of derivative and entirely new compounds. Metal coordination compounds of metal ions with much faster ligand-exchange reactions interact with DNA in a quite different way, namely primarily by compensation of negative charge of the polyanionic chain and are usually not active as anticancer agents. Examples of our recent work are presented in relation with experiments performed by others on new generations of platinum anti-cancer drugs. PMID- 22488114 TI - Effect of donor and recipient factors on corneal graft rejection. AB - PURPOSE: To assess the relationship between donor and recipient factors and corneal allograft rejection in eyes that underwent penetrating keratoplasty in the Cornea Donor Study. METHODS: Overall, 1090 subjects undergoing corneal transplantation for a moderate risk condition (principally Fuchs dystrophy or pseudophakic corneal edema) were followed for up to 5 years. Associations of baseline recipient and donor factors with the occurrence of a probable or definite rejection event were assessed in univariate and multivariate proportional hazards models. RESULTS: Eyes with pseudophakic or aphakic corneal edema (n = 369) were more likely to experience a rejection event than eyes with Fuchs dystrophy (n = 676) [34% +/- 6% vs. 22% +/- 4%; hazard ratio = 1.56; 95% confidence interval (CI), 1.21-2.03]. Among eyes with Fuchs dystrophy, a higher probability of a rejection event was observed in phakic posttransplant eyes compared with those that underwent cataract extraction with or without intraocular lens implantation during penetrating keratoplasty (29% vs. 19%; hazard ratio = 0.54; 95% CI, 0.36-0.82). Female recipients had a higher probability of a rejection event than male recipients (29% vs. 21%; hazard ratio = 1.42; 95% CI, 1.08-1.87) after controlling for the effect of preoperative diagnosis and lens status. Donor age and donor recipient ABO compatibility were not associated with rejection. CONCLUSIONS: There was a substantially higher graft rejection rate in eyes with pseudophakic or aphakic corneal edema compared to that in eyes with Fuchs dystrophy. Female recipients were more likely to have a rejection event than male recipients. Graft rejection was not associated with donor age. PMID- 22488115 TI - An examination of early childhood perfectionism across anorexia nervosa subtypes. AB - OBJECTIVE: To examine childhood perfectionism in anorexia nervosa (AN) restricting (RAN), purging (PAN), and binge eating with or without purging (BAN) subtypes. METHOD: The EATATE, a retrospective assessment of childhood perfectionism, and the eating disorder inventory (EDI-2) were administered to 728 AN participants. RESULTS: EATATE responses revealed general childhood perfectionism, 22.3% of 333 with RAN, 29.2% of 220 with PAN, and 24.8% of 116 with BAN; school work perfectionism, 31.2% with RAN, 30.4% with PAN, and 24.8% with BAN; childhood order and symmetry, 18.7% with RAN, 21.7% with PAN, and 17.8% with BAN; and global childhood rigidity, 42.6% with RAN, 48.3% with PAN and 48.1% with BAN. Perfectionism preceded the onset of AN in all subtypes. Significant associations between EDI-2 drive for thinness and body dissatisfaction were present with four EATATE subscales. DISCUSSION: Global childhood rigidity was the predominate feature that preceded all AN subtypes. This may be a risk factor for AN. PMID- 22488116 TI - Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. AB - OBJECTIVE: From an immunologic standpoint, the mechanisms by which treatment with tocilizumab (TCZ), a humanized anti-interleukin-6 (anti-IL-6) receptor antibody, results in improvement in rheumatoid arthritis (RA) patients are still not fully understood. In vitro studies and studies in mouse models have demonstrated the critical role of IL-6 in Th17 cell differentiation. Th17 lymphocytes have been shown to be strongly involved in RA pathogenesis, and the purpose of this study was to investigate the effect of IL-6 blockade on the balance between Th17 cells and Treg cells in patients with active RA. METHODS: Patients with active RA for whom TCZ had been prescribed by a rheumatologist were enrolled in this study. Phenotypic analyses of T cell populations were performed, and the Disease Activity Score in 28 joints (DAS28) was assessed. Serum cytokine levels and other parameters of inflammation were measured before the first infusion and after the third infusion of TCZ (8 mg/kg). RESULTS: Compared to controls, levels of Th17 cells (CD4+IL-17+) were increased and Treg cells (CD4+CD25(high) FoxP3+) were decreased in the peripheral blood of patients with active RA. The suppressive function of circulating Treg cells was not impaired in patients with active RA. TCZ treatment induced a significant decrease in the DAS28 associated with a significant decrease in the percentage of Th17 cells (from a median of 0.9% to 0.45%; P = 0.009) and an increase in the percentage of Treg cells (from a median of 3.05% to 3.94%; P = 0.0039) in all patients. CONCLUSION: This study demonstrates for the first time that inhibition of IL-6 function by TCZ corrects the imbalance between Th17 cells and Treg cells in patients with RA. PMID- 22488117 TI - The relationship of language acculturation (English proficiency) to current self rated health among African immigrant adults. AB - Although over 1.5 million African immigrants live in the US, few studies have examined the relationship of language acculturation to health outcomes among African immigrant adults. The primary objective of this research was to investigate the relationship between English proficiency and current self-rated health among African immigrant adults. Using a cross-sectional design, a secondary data analysis was performed on baseline data from the African immigrant adult subsample (n = 763) of the 2003 New Immigrant Survey, a longitudinal study of lawful permanent residents. Limited English proficiency (LEP), increased duration of US residence, older age at immigration, being male, less than 12 years of education, poor pre-migration health, and chronic disease were associated with good/fair/poor current self-rated health. Findings support consideration of pre-migration health and chronic disease in future acculturation and health studies, and provision of linguistically competent interventions for LEP African immigrants at risk for poor health outcomes. PMID- 22488118 TI - Osseointegration technique in patients with acquired auricular deformities and failed previous reconstruction: a retrospective study of long-term follow-up and Chinese experience. AB - OBJECTIVES: To evaluate the complication rate and patient satisfaction of reconstruction of acquired auricular deformities and failed previous reconstruction by the osseointegration technique. METHODS: The study enrolled 24 patients from January 2002 to December 2005. Data collected included demographic information, success rate of auricular prostheses, site of implants, survival rate of implants, occurrence of skin reaction and condition of the prosthetic ear. RESULTS: Twenty-five ears (24 patients) were implanted. All ears were healing well with a lifelike appearance, stable fixation and natural color; except for 2 instances of implants dislocated by trauma, the rest survived well by first intention; skin reaction was the most troublesome complication, no patient was able to maintain a consistent level of soft-tissue health for the whole follow-up period, but the ratio and degree of skin reaction decreased gradually. The time of wearing prosthetic ears was more than 8 h/day. The average time length until prosthetic ear replacement was 3.5 years. There were no intracranial or systemic complications. CONCLUSION: The osseointegration technique can be the method of choice for acquired auricular defects and failed reconstructions. Follow-up management is important to the health of the implants and the surrounding soft tissue and to preserve the prosthesis and its retention mechanism. PMID- 22488119 TI - Neonatal cholinergic lesion alters the acoustic structure of infant rat vocalization but not the early cognitive development. AB - Cholinergic innervation is critically required for cytoarchitectonic maturation of the cerebral cortex as well as functional assembling of neuronal networks and their behavioral readout. Selective lesion of cortically projecting cholinergic neurons initiated immediately after birth by the immunotoxin 192 IgG-saporin (SAP) led to abnormal wiring of prefrontal-hippocampal networks, yet the neurobehavioral and cognitive consequences of this impairment are still poorly understood. Here, we show that partial cholinergic depletion initiated at birth did not impact the general development of rat pups during the first 2 postnatal weeks, their homing behavior, and the maturation of recognition memory. However, the acoustic structure of infant ultrasonic vocalization was significantly affected by SAP, indicating that early neurobehavioral development relies on intact cholinergic drive. This altered vocalization did not elicit differential maternal care, suggesting that the previously reported SAP-induced behavioral deficits at adulthood are the direct result of cholinergic depletion rather than of abnormal mother-pup interactions. PMID- 22488120 TI - Absorption and bioavailability of glucosamine in the rat. AB - The objective of this study was to determine reasons behind the low oral (p.o.) bioavailability of glucosamine. By using male Sprague-Dawley rats, the movement of glucosamine through everted gut, the effect of dose and glucose, and inhibition of a glucose transporter (GLUT2) by quercetin were studied. Glucosamine pharmacokinetics and the effect of dosing, route of administration, food and antibiotic to eradicate gut microflora was also studied. Both in vitro and in vivo studies demonstrated linear absorption kinetics for glucosamine. Absorption from duodenum was the greatest. Glucose had no effect on the transport, whereas quercetin significantly reduced the extent of glucosamine transport. Intraperitoneal doses were completely absorbed, whereas p.o. doses demonstrated low bioavailability, indicating the gut as the site of presystemic loss. Food had no significant effect on glucosamine pharmacokinetics. Antibiotic treatment resulted in strong trends towards increased bioavailability with significant increase in fecal recovery. Incubation of glucosamine with faeces resulted in a significant loss. Glucosamine's low bioavailability is, at least in part, due to its dependence on a transport-facilitated absorption and presystemic loss brought about by the gut microflora. PMID- 22488121 TI - A lectin-based gold nanoparticle assay for probing glycosylation of glycoproteins. AB - We report a glycoanalysis method in which lectins are used to probe the glycans of therapeutic glycoproteins that are adsorbed on gold nanoparticles. A model mannose-presenting glycoprotein, ribonuclease B (RNase B), and the therapeutic monoclonal antibody (mAb) rituximab, were found to adsorb spontaneously and non specifically to bare gold nanoparticles such that glycans were accessible for lectin binding. Addition of a multivalent binding lectin, such as concanavalin A (Con A), to a solution of the modified gold nanoparticles resulted in cross linking of the nanoparticles. This phenomenon was evidenced within 1 min by a change in the hydrodynamic diameter, D(H), measured by dynamic light scattering (DLS) and a shift and increase in absorbance of the plasmon resonance band of the gold nanoparticles. By combining the sugar-binding specificity and the cross linking capabilities of lectins, the non-specific adsorption of glycoproteins to gold surfaces, and the unique optical reporting properties of gold nanoparticles, a glycosylation pattern of rituximab could be generated. This assay provides advantages over currently used glycoanalysis methods in terms of short analysis time, simplicity of the conjugation method, convenience of simple spectroscopic detection, and feasibility of providing glycan characterization of the protein drug product by using a variety of binding lectins. PMID- 22488122 TI - beta-Blockers in heart failure: benefits of beta-blockers according to varying male proportions of study patients. AB - BACKGROUND: In patients with heart failure (HF), b-blockers reduce mortality. It's not known whether the beneficial effects of the b-blockers were associated with the differing male proportions of study patients. It also remains to be clarified regarding the true beneficial effects of the 3 b-blockers recommended by the guideline on mortality in the real world. HYPOTHESIS: The benefits of b blockers in HF patients were sex-related different. METHODS: Randomized, placebo controlled clinical trials were included if they evaluated the beneficial effects of the three b-blockers on mortality and on hospital admissions on an intention to-treat basis, and lasted at least 3 months. RESULTS: Twenty-eighty trials with 14,829 patients were included. The b-blockers significantly reduced all cause mortality by 29.6%, cardiac death by 29.8%, sudden death by 49.4%, respectively. The magnitude of benefits of b-blockers in HF patients was increased with the increased male proportion. A similar magnitude of reduction in all cause mortality was observed among the three b blockers. A trend toward to reduced cardiac death was observed among the three b blockers, but only in bisoprolol was this statistically different (RR, 0.72; 95%CI, [0.59-0.87]). Metoprolol was significantly superior to carvedilol (P = 0.008) or bisoprolol (P = 0.034) in reduced sudden death. CONCLUSIONS: In patients with HF, the 3 commonly used b blockers significantly reduced mortality. Greater benefits of b-blockers were observed in the higher male proportion studies. The metoprolol was significantly superior to carvedilol or bisoprolol in reduced sudden death. Additional trials are required to determine whether the benefits of b-blockers will be observed in female HF patients. PMID- 22488123 TI - Waddington's epigenetic landscape and post-Darwinian biology. PMID- 22488124 TI - Preoperative evaluation, premedication, and induction of anesthesia in infants and children. AB - PURPOSE OF REVIEW: Preparation for and induction of anesthesia in children has evolved significantly over the last decade, with particular reference to the reduction of perioperative anxiety reduction by nonpharmacologic and pharmacologic means. Several new large population studies and meta-analyses further scrutinize the current techniques. RECENT FINDINGS: Many nonpharmacologic methods to reduce anxiety are effective lambdaU similar to sedative premedications, with the exception of parent present induction of anesthesia. Healthcare providers can be taught to increase anxiety-reducing behaviors through an educational intervention. Clonidine and dexmedetomidine have many similar or superior qualities to midazolam. SUMMARY: Larger studies still need to be conducted before wide-scale application of many nonpharmalogical interventions such as parental acupuncture. Similarly, more investigation should be done on outcomes such as onset, emergence, and discharge times, as well as the postoperative response with reference to emergence delirium and postoperative nausea and vomiting prevention to outline the differences among sedative premedications such as midazolam, clonidine, and dexmedetomidine. PMID- 22488125 TI - Cardiovascular medications in angiogenesis--how to avoid the sting in the tail. AB - Cancer and cardiovascular disease are the leading causes of death worldwide. Cardiovascular medications have recently been found to have favorable effects also for the treatment of noncardiovascular diseases, including cancer. In this review, we use a reverse bedside-to-bench approach to investigate the effects of common cardiovascular medications on tumor angiogenesis and vascular angiogenesis. Aspirin seems to reduce the risk of developing cancer, particularly colon cancer. However, whether the protective influence of aspirin is due to antiangiogenesis effect is still unclear. beta-Blockers, which are normally used to reduce heart rate and prolong diastole, trigger an increase in stretch associated release of proangiogenic growth factors thereby inducing angiogenesis. However, according to other studies beta-blockers are able to inhibit angiogenesis via multiplicate mechanisms. Similarly, angiotensin converting enzyme inhibitor and angiotensin II type 1 receptor blocker have controversial effects for the regulation of cell proliferation and angiogenesis. Statins can augment collateral vascular growth in ischemic tissues and restrict the development of cancer. So this topical anti-inflammatory drug seems to be of high value for further therapy. Finally, suggestions on how this pilot experience may guide the conduct of future preclinical investigations, and clinical trials are discussed. PMID- 22488127 TI - Prospective study of foveal thickness alterations after cataract surgery assessed by optical coherence tomography. AB - BACKGROUND/AIMS: To evaluate the alterations of mean foveal thickness (MFT) and visual acuity (VA) outcomes after uncomplicated cataract surgery in different groups of patients. METHODS: This study included eyes of consecutive patients who underwent cataract surgery between November 2007 and June 2009. The patients included in the study were divided into 4 groups, as follows: history-free patients, patients with diabetes mellitus without macular involvement at baseline, patients with glaucoma, and patients with epiretinal membrane (ERM). Preoperatively and at 1, 3 and 6 months postoperatively, patients were evaluated for MFT by optical coherence tomography at the central 1-mm macular zone and for logarithm of the minimum angle of resolution best spectacle-corrected VA (BSCVA). RESULTS: A total of 202 eyes were included in the study. MFT values demonstrated a statistically significant increase (p < 0.01) after cataract surgery in all groups at the first and third postoperative month. The history-free (p = 0.09) and glaucoma (p = 0.19) groups did not demonstrate a statistically significant difference in MFT values between the preoperative and 6-month measurements. MFT values 6 months after cataract surgery in the diabetes and ERM groups remained significantly higher (p < 0.01). Despite these findings, VA increased significantly (p < 0.01) in all groups at all postoperative follow-ups. CONCLUSIONS: MFT values increased significantly in all groups at the first and third months after cataract surgery. At 6 months, MFT values returned to preoperative levels in the history-free and glaucoma patients, while they remained significantly higher in the diabetic and ERM patients. Despite these macular alterations, BSCVA improved significantly after cataract surgery in all groups at all postoperative follow-ups. PMID- 22488126 TI - Sexual risk, serostatus and intimate partner violence among couples during pregnancy in rural South Africa. AB - The aim of this study was to describe sexual risk behavior among 239 couples during pregnancy and to examine the relationship of sexual risk behavior with HIV serostatus and intimate partner violence. One-third (31.8 %) of pregnant women and 20.9 % of male partners were HIV positive. HIV risk factors included lack of knowledge of partners' HIV serostatus, unprotected sexual intercourse and multiple sexual partners. Among men, multivariate logistic regression identified awareness of HIV negative partner status, multiple sexual partners and low levels of partner violence and among women Zulu or Swati ethnicity were associated with unprotected intercourse. HIV positive concordance was associated with protected sex and in multilevel analysis of couples HIV positive status and awareness of the partner's HIV positive status were associated with protected sex. High levels of HIV risk behaviour was found among couples during pregnancy calling for HIV risk reduction interventions. PMID- 22488128 TI - Decoding with limited neural data: a mixture of time-warped trajectory models for directional reaches. AB - Neuroprosthetic devices promise to allow paralyzed patients to perform the necessary functions of everyday life. However, to allow patients to use such tools it is necessary to decode their intent from neural signals such as electromyograms (EMGs). Because these signals are noisy, state of the art decoders integrate information over time. One systematic way of doing this is by taking into account the natural evolution of the state of the body--by using a so called trajectory model. Here we use two insights about movements to enhance our trajectory model: (1) at any given time, there is a small set of likely movement targets, potentially identified by gaze; (2) reaches are produced at varying speeds. We decoded natural reaching movements using EMGs of muscles that might be available from an individual with spinal cord injury. Target estimates found from tracking eye movements were incorporated into the trajectory model, while a mixture model accounted for the inherent uncertainty in these estimates. Warping the trajectory model in time using a continuous estimate of the reach speed enabled accurate decoding of faster reaches. We found that the choice of richer trajectory models, such as those incorporating target or speed, improves decoding particularly when there is a small number of EMGs available. PMID- 22488129 TI - Incidence of liver abnormalities in Fanconi anemia patients. AB - Patients with Fanconi anemia (FA) are prone to liver tumors, especially after androgen treatment, but other liver abnormalities have not been described for these patients. Here, we systematically reviewed liver manifestations in a cohort of 64 adult and pediatric patients with FA followed in a single center. "Significant biological liver abnormalities(SBLA)" in the absence of any androgen treatment were found in five patients, including two children, belonging to rare FA groups; these two patients presented with a very severe chronic cytolysis pattern which may be classified as a new FA phenotype. Liver radiological abnormalities, which include hepatic tumors (n 5 4), hepatomegaly(n 5 1), hyperechogenicity (n 5 2), and a previously undescribed biliary duct dilatation as demonstrated by magnetic resonance cholangiopancreatography(MRCP) (n 5 2), were found in eight patients who received androgen treatment or who had iron overload. Lastly, we found no correlation between cytolysis intensity and high levels of alpha-fetoprotein (AFP); this common finding in FA patients cannot therefore be explained by hepatocyte regeneration. PMID- 22488130 TI - Increased attentiveness is associated with hemispheric asymmetry measured with lateral tympanic membrane temperature in humans and dogs. AB - In this study, we examined the relationship between a measure of cerebral lateralization--differences in tympanic temperature (T(Ty))--and questionnaire measures of inattentiveness and hyperactivity in both people and dogs. Theories of cerebral lateralization indicate that cerebral asymmetry may improve attentive behaviour. In people, greater left than right T(Ty) was related to increased self reports of inattentiveness. There was no relationship between lateralized T(Ty) and hyperactivity. In dogs, there was quadratic relationship between lateralized T(Ty) and handler reports of inattentiveness. Increased T(Ty) asymmetry, regardless of direction, was related to more attentiveness. There was no discernable relationship between hyperactivity and lateralized T(Ty). Differences in T(Ty) may be an useful tool for investigating species comparisons of cerebral lateralization. PMID- 22488131 TI - Hip kinematics during a stop-jump task in patients with chronic ankle instability. AB - CONTEXT: Chronic ankle instability (CAI) commonly develops after lateral ankle sprain. Movement pattern differences at proximal joints may play a role in instability. OBJECTIVE: To determine whether people with mechanical ankle instability (MAI) or functional ankle instability (FAI) exhibited different hip kinematics and kinetics during a stop-jump task compared with "copers." DESIGN: Cross-sectional study. SETTING: Sports medicine research laboratory. PATIENTS OR OTHER PARTICIPANTS: Sixty-three recreational athletes, 21 (11 men, 10 women) per group, matched for sex, age, height, mass, and limb dominance. All participants reported a history of a moderate to severe ankle sprain. The participants with MAI and FAI reported 2 or more episodes of giving way at the ankle in the last year and decreased functional ability; copers did not. The MAI group demonstrated clinically positive anterior drawer and talar tilt tests, whereas the FAI group and copers did not. INTERVENTION(S): Participants performed a maximum-speed approach run and a 2-legged stop jump followed by a maximum vertical jump. MAIN OUTCOME MEASURE(S): An electromagnetic tracking device synchronized with a force plate collected data during the stance phase of a 2-legged stop jump. Hip motion was measured from initial contact to takeoff into the vertical jump. Group differences in hip kinematics and kinetics were assessed. RESULTS: The MAI group demonstrated greater hip flexion at initial contact and at maximum (P = .029 and P = .017, respectively) and greater hip external rotation at maximum (P = .035) than the coper group. The MAI group also demonstrated greater hip flexion displacement than both the FAI (P = .050) and coper groups (P = .006). No differences were noted between the FAI and coper groups in hip kinematic variables or among any of the groups in ground reaction force variables. CONCLUSIONS: The MAI group demonstrated different hip kinematics than the FAI and coper groups. Proximal joint motion may be affected by ankle joint function and laxity, and clinicians may need to assess proximal joints after repeated ankle sprains. PMID- 22488132 TI - Commentary. PMID- 22488133 TI - Knee separation distance and lower extremity kinematics during a drop land: implications for clinical screening. AB - CONTEXT: Excessive knee valgus during dynamic tasks is thought to contribute to lower extremity overuse and traumatic injuries. Clinically, assessments of frontal-plane knee motion typically include measures of the distance between the knees during landing. However, it is not clear how this clinical assessment relates to knee-abduction angle or how it is influenced by the position of the lower extremities in the transverse and frontal planes. OBJECTIVE: To determine whether normalized knee separation distance (NKSD) is a predictor of knee abduction angles and to assess the influence of lower extremity transverse-plane and frontal-plane angles on NKSD during a drop land. DESIGN: Cross-sectional study. SETTING: Motion analysis laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty-five healthy female athletes. INTERVENTION(S): The frontal-plane distance between the 2-dimensional coordinates of markers over the greater trochanters (intertrochanteric distance), lateral femoral epicondyles (knee separation distance), and lateral malleoli (stance width) bilaterally was calculated during a drop land. The knee separation distance was normalized by intertrochanteric distance (NKSD). Concurrently, 3-dimensional lower extremity transverse-plane and frontal-plane kinematics were obtained. MAIN OUTCOME MEASURE(S): We assessed NKSD, stance width, and bilateral average knee and hip transverse plane and frontal-plane angles and ankle frontal-plane angles. Linear regression was used to determine the association between NKSD and bilateral average knee frontal plane angles. Stepwise multiple regression was used to identify the best predictors of NKSD during the drop land. RESULTS: After we controlled for stance width, NKSD explained 52% of the variance in the knee frontal-plane angle. When we took lower extremity kinematics into account, after controlling for stance width, the average hip frontal-plane angle was the best predictor of NKSD, explaining 97% of the variance. CONCLUSIONS: Although NKSD is a predictor of knee abduction angle, frontal-plane hip angle and stance width are strongly related to NKSD. Caution must be taken when interpreting NKSD as knee abduction. PMID- 22488135 TI - Risk of injury in basketball, football, and soccer players, ages 15 years and older, 2003-2007. AB - CONTEXT: A major challenge in the field of sports injury epidemiology is identifying the appropriate denominators for injury rates. OBJECTIVE: To characterize risk of injury from participation in basketball, football, and soccer in the United States, using hours of participation as the measure of exposure, and to compare these rates with those derived using population estimates in the denominator. DESIGN: Descriptive epidemiology study. SETTING: United States, 2003-2007. PARTICIPANTS: People ages 15 years and older who experienced an emergency department-treated injury while playing basketball, football, or soccer. MAIN OUTCOME MEASURE(S): Rates of emergency department treated injuries resulting from participation in basketball, football, or soccer. Injury rates were calculated for people ages 15 and older for the years 2003-2007 using the U.S. population and hours of participation as the denominators. The risk of injury associated with each of these sports was compared for all participants and by sex. RESULTS: From 2003 through 2007, annual injury rates per 1000 U.S. population were as follows: 1.49 (95% confidence interval [CI] = 1.30, 1.67) in basketball, 0.93 (95% CI = 0.82, 1.04) in football, and 0.43 (95% CI = 0.33, 0.53) in soccer. When the denominator was hours of participation, the injury rate in football (5.08 [95% CI = 4.46, 5.69]/10 000 hours) was almost twice as high as that for basketball (2.69 [95% CI = 2.35, 3.02]/10 000 hours) and soccer (2.69 [95% CI = 2.07, 3.30]/10 000 hours). CONCLUSIONS: Depending on the choice of denominator, interpretation of the risk of an emergency department treated injury in basketball, football, or soccer varies greatly. Using the U.S. population as the denominator produced rates that were highest in basketball and lowest in soccer. However, using hours of participation as a more accurate measure of exposure demonstrated that football had a higher rate of injury than basketball or soccer for both males and females. PMID- 22488134 TI - Neuromuscular changes after aerobic exercise in people with anterior cruciate ligament-reconstructed knees. AB - CONTEXT: Anterior cruciate ligament (ACL) reconstructions are common, especially in young, active people. The lower extremity neuromuscular adaptations seen after aerobic exercise provide information about how previously injured patients perform and highlight deficits and, hence, areas for focused treatment. Little information is available about neuromuscular performance after aerobic exercise in people with ACL reconstructions. OBJECTIVE: To compare dynamic balance, gluteus medius muscle activation, vertical jump height, and hip muscle strength after aerobic exercise in people with ACL-reconstructed knees. DESIGN: Case control study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Of 34 recreationally active volunteers, 17 had a unilateral primary ACL reconstruction at least 2 years earlier and 17 were matched controls. INTERVENTION(S): All participants performed 20 minutes of aerobic exercise on a treadmill. MAIN OUTCOME MEASURE(S): We recorded dynamic, single-legged balance electromyographic gluteus medius muscle activation, single-legged vertical jump height, and maximum isometric strength for hip abduction, extension, and external rotation preexercise and postexercise. RESULTS: Participants with ACL reconstructions exhibited shorter reach distances during dynamic balance tasks, indicating poorer dynamic balance, and less gluteus medius muscle electromyographic activation. Reductions in hip abduction and extension strength after exercise were noted in all participants; however, those with ACL reconstructions displayed greater hip extensor strength loss after aerobic exercise than did the control group. CONCLUSIONS: Neuromuscular changes after aerobic exercise exist in both patients with ACL reconstructions and controls. The former group may experience greater deficits in hip extensor strength after aerobic exercise. Reduced reach distances in people with ACL reconstructions may represent a protective mechanism against excessive tibiofemoral rotation during dynamic balance. Clinicians should identify weaknesses in the resting state and after aerobic exercise in recreationally active patients and those with ACL reconstructions. PMID- 22488136 TI - Validity of soccer injury data from the National Collegiate Athletic Association's Injury Surveillance System. AB - CONTEXT: Few validation studies of sport injury-surveillance systems are available. OBJECTIVE: To determine the validity of a Web-based system for surveillance of collegiate sport injuries, the Injury Surveillance System (ISS) of the National Collegiate Athletic Association's (NCAA). DESIGN: Validation study comparing NCAA ISS data from 2 fall collegiate sports (men's and women's soccer) with other types of clinical records maintained by certified athletic trainers. SETTING: A purposive sample of 15 NCAA colleges and universities that provided NCAA ISS data on both men's and women's soccer for at least 2 years during 2005-2007, stratified by playing division. PATIENTS OR OTHER PARTICIPANTS: A total of 737 men's and women's soccer athletes and 37 athletic trainers at these 15 institutions. MAIN OUTCOME MEASURE(S): The proportion of injuries captured by the NCAA ISS (capture rate) was estimated by comparing NCAA ISS data with the other clinical records on the same athletes maintained by the athletic trainers. We reviewed all athletic injury events resulting from participation in NCAA collegiate sports that resulted in 1 day or more of restricted activity in games or practices and necessitated medical care. A capture-recapture analysis estimated the proportion of injury events captured by the NCAA ISS. Agreement for key data fields was also measured. RESULTS: We analyzed 664 injury events. The NCAA ISS captured 88.3% (95% confidence interval = 85.9%, 90.8%) of all time-lost medical-attention injury events. The proportion of injury events captured by the NCAA ISS was higher in Division I (93.8%) and Division II (89.6%) than in Division III (82.3%) schools. Agreement between the NCAA ISS data and the non NCAA ISS data was good for the majority of data fields but low for date of full return and days lost from sport participation. CONCLUSIONS: The overall capture rate of the NCAA ISS was very good (88%) in men's and women's soccer for this period. PMID- 22488137 TI - Value of sonography combined with clinical assessment to evaluate muscle injury severity in athletes. AB - CONTEXT: Predicting when an athlete can return to sport after muscle injury is a major concern. OBJECTIVE: To determine whether combining objective clinical and ultrasound findings at presentation accurately predicted time to sport resumption in athletes with muscle injuries. DESIGN: Cohort study. SETTING: Sports medicine clinic. PATIENTS OR OTHER PARTICIPANTS: A total of 93 consecutive patients, 87 male and 6 female, were seen over a 1-year period for sudden-onset muscle pain while engaging in a sporting activity within the last 5 days and inability to continue the training session or game. INTERVENTION(S): Standardized physical examination and sonogram. MAIN OUTCOME MEASURE(S): Statistical associations between clinical and sonographic features at presentation and time to sport resumption (<40 days or >= 40 days) were evaluated using multivariate models. Correlations between time to sport resumption predicted by a sports medicine specialist and actual time to sport resumption were evaluated using the Spearman rank correlation coefficient. RESULTS: The 93 patients had 95 injuries, caused by muscle contraction in 86 cases and impact in 9 cases. Only 7 injuries had normal sonogram findings. Late sport resumption was associated with 4 clinical criteria (bruising, tenderness to palpation, range-of-motion limitation compared with the other limb, and increased pain with isometric contraction during passive limb straightening) and 4 sonographic criteria (disorganized fibrous tissue, intramuscular hematoma, intermuscular hematoma, and power Doppler signal). The Spearman rank correlation coefficient between predicted and actual times was 0.669 (P < .0001) for mild exercise resumption and 0.804 (P < .0001) for full sport resumption. CONCLUSION: A combination of physical and sonographic data collected during the acute phase of sport-related muscle injury was effective in predicting time to sport resumption. PMID- 22488138 TI - Reliability of fitness tests using methods and time periods common in sport and occupational management. AB - CONTEXT: Fitness testing is used frequently in many areas of physical activity, but the reliability of these measurements under real-world, practical conditions is unknown. OBJECTIVE: To evaluate the reliability of specific fitness tests using the methods and time periods used in the context of real-world sport and occupational management. DESIGN: Cohort study. SETTING: Eighteen different Cirque du Soleil shows. PATIENTS OR OTHER PARTICIPANTS: Cirque du Soleil physical performers who completed 4 consecutive tests (6-month intervals) and were free of injury or illness at each session (n = 238 of 701 physical performers). INTERVENTION(S): Performers completed 6 fitness tests on each assessment date: dynamic balance, Harvard step test, handgrip, vertical jump, pull-ups, and 60 second jump test. MAIN OUTCOME MEASURE(S): We calculated the intraclass coefficient (ICC) and limits of agreement between baseline and each time point and the ICC over all 4 time points combined. RESULTS: Reliability was acceptable (ICC > 0.6) over an 18-month time period for all pairwise comparisons and all time points together for the handgrip, vertical jump, and pull-up assessments. The Harvard step test and 60-second jump test had poor reliability (ICC < 0.6) between baseline and other time points. When we excluded the baseline data and calculated the ICC for 6-month, 12-month, and 18-month time points, both the Harvard step test and 60-second jump test demonstrated acceptable reliability. Dynamic balance was unreliable in all contexts. Limit-of-agreement analysis demonstrated considerable intraindividual variability for some tests and a learning effect by administrators on others. CONCLUSIONS: Five of the 6 tests in this battery had acceptable reliability over an 18-month time frame, but the values for certain individuals may vary considerably from time to time for some tests. Specific tests may require a learning period for administrators. PMID- 22488139 TI - Overcoming barriers to implementation of evidence-based practice concepts in athletic training education: perceptions of select educators. AB - CONTEXT: The need to include evidence-based practice (EBP) concepts in entry level athletic training education is evident as the profession transitions toward using evidence to inform clinical decision making. OBJECTIVE: To evaluate athletic training educators' experience with implementation of EBP concepts in Commission on Accreditation of Athletic Training Education (CAATE)-accredited entry-level athletic training education programs in reference to educational barriers and strategies for overcoming these barriers. DESIGN: Qualitative interviews of emergent design with grounded theory. SETTING: Undergraduate CAATE accredited athletic training education programs. PATIENTS OR OTHER PARTICIPANTS: Eleven educators (3 men, 8 women). The average number of years teaching was 14.73 +/- 7.06. DATA COLLECTION AND ANALYSIS: Interviews were conducted to evaluate perceived barriers and strategies for overcoming these barriers to implementation of evidence-based concepts in the curriculum. Interviews were explored qualitatively through open and axial coding. Established themes and categories were triangulated and member checked to determine trustworthiness. RESULTS: Educators identified 3 categories of need for EBP instruction: respect for the athletic training profession, use of EBP as part of the decision-making toolbox, and third-party reimbursement. Barriers to incorporating EBP concepts included time, role strain, knowledge, and the gap between clinical and educational practices. Suggested strategies for surmounting barriers included identifying a starting point for inclusion and approaching inclusion from a faculty perspective. CONCLUSIONS: Educators must transition toward instruction of EBP, regardless of barriers present in their academic programs, in order to maintain progress with other health professions' clinical practices and educational standards. Because today's students are tomorrow's clinicians, we need to include EBP concepts in entry-level education to promote critical thinking, inspire potential research interest, and further develop the available body of knowledge in our growing clinical practice. PMID- 22488140 TI - Evidence-based practice and the recognition and treatment of exertional heat stroke, part I: a perspective from the athletic training educator. AB - CONTEXT: Athletic trainers (ATs) know to diagnose exertional heat stroke (EHS) via rectal thermometry (T(re)) and to treat EHS via cold-water immersion (CWI) but do not implement these recommendations in clinical practice. OBJECTIVE: To gain an understanding of educational techniques used to deliver content regarding EHS. DESIGN: Qualitative study. SETTING: In-person focus groups at the National Athletic Trainers' Association (NATA) Annual Meeting in June 2009 and 2 follow-up telephone interviews to confirm emergent themes. PATIENTS OR OTHER PARTICIPANTS: Thirteen AT educators (11 men, 2 women) from programs accredited by the Commission on Accreditation of Athletic Training Education, with an average of 22 +/- 9 years of clinical experience and 16 +/- 10 years of experience as educators. Five NATA districts were represented. DATA COLLECTION AND ANALYSIS: Data were analyzed using inductive content analysis. Peer review and data source triangulation also were conducted to establish trustworthiness. RESULTS: Four themes emerged from the analysis: educational techniques, educational competencies, previous educational training, and privacy/public opinion. Educational techniques highlighted the lack of hands-on training for T(re) and CWI. Educational competencies referred to the omission of T(re) and CWI as psychomotor skills. Previous educational training addressed educators not having the skills or comfort with the skills necessary to properly educate students. Privacy/public opinion comprised external inputs from various groups (parents and coaches), legal considerations, and social bias. CONCLUSIONS: Educators supplied students with the appropriate didactic knowledge about EHS, but their lack of training and misgivings about T(re) prevented them from allowing students to gain competence with this skill. Until the NATA competencies state the need to teach T(re) and CWI and until educators are provided with their own learning opportunities, evidence-based practice regarding EHS will be lacking. PMID- 22488141 TI - Evidence-based medicine and the recognition and treatment of exertional heat stroke, part II: a perspective from the clinical athletic trainer. AB - CONTEXT: Exertional heat stroke (EHS) is one of the leading causes of death in athletes. Certified athletic trainers (ATs) demonstrate strong knowledge of recommended practices with EHS but are apprehensive in implementing 2 basic procedures: rectal temperature assessment and cold water immersion. This apprehension might lead to deaths from EHS that could have been prevented. OBJECTIVE: To investigate why collegiate and high school ATs do not implement best practices for the recognition and treatment of EHS. DESIGN: Qualitative study. SETTING: In-person focus groups consisting of 3 to 6 collegiate or high school ATs. PATIENTS OR OTHER PARTICIPANTS: A total of 19 ATs (9 men, 10 women; age = 36 +/- 10 years, length of certification = 12 +/- 9 years) employed at either the collegiate (n = 10) or high school (n = 9) level participated in the study. DATA COLLECTION AND ANALYSIS: Interviews were transcribed verbatim, and data were analyzed using deductive data analysis. Peer review and multiple analyst data triangulation were conducted to establish trustworthiness of the data. RESULTS: Five emergent themes explained the lack of evidence-based practice (EBP) regarding recognition and treatment of EHS. Three themes (lack of knowledge, comfort level, lack of initiative) were common in both the collegiate and high school settings, and 2 separate themes (liability concerns, lack of resources) were present in the high school setting. CONCLUSIONS: Our findings are consistent with those in the literature on EBP and EHS. Regardless of clinical setting, ATs have basic information on recognition and treatment of EHS, but 5 themes act as barriers to implementing proper management in the clinical setting. Workshops or hands-on training sessions need to be made available to improve students' comfort levels so ATs will implement EBP into everyday settings. PMID- 22488142 TI - Evaluation of electromyographic biofeedback for the quadriceps femoris: a systematic review. AB - OBJECTIVE: To critically review evidence for the effectiveness of electromyographic biofeedback (EMGB) of the quadriceps femoris muscle in treating various knee conditions. DATA SOURCES: Databases used to locate randomized controlled trials included PubMed (1980-2010), Cumulative Index of Nursing and Allied Health Literature (CINAHL, 1995-2007), Web of Science (1986-2010), SPORTDiscus (1990-2007), and Physiotherapy Evidence Database (PEDro). Key words were knee and biofeedback. STUDY SELECTION: The criteria for selection were clinical randomized controlled trials in which EMGB of the quadriceps femoris was used for various knee conditions of musculoskeletal origin. Trials were excluded because of research designs other than randomized controlled trials, articles published in a non-English language, inclusion of healthy research participants, inability to identify EMGB as the source of clinical improvement, and lack of pain, functional outcome, or quadriceps torque as outcome measures. DATA EXTRACTION: Twenty specific data points were abstracted from each clinical trial under the broad categories of attributes of the patient and injury, treatment variables for the EMGB group, treatment variables for the control group, and attributes of the research design. DATA SYNTHESIS: Eight trials yielded a total of 319 participants with patellofemoral pain syndrome (n = 86), anterior cruciate ligament reconstruction (n = 52), arthroscopic surgery (n = 91), or osteoarthritis (n = 90). The average methodologic score of the included studies was 4.6/10 based on PEDro criteria. Pooled analyses demonstrated heterogeneity of the included studies, rendering the interpretation of the pooled data inappropriate. The EMGB appeared to benefit short-term postsurgical pain or quadriceps strength in 3 of 4 postsurgical investigations but was ineffective for chronic knee conditions such as patellofemoral pain and osteoarthritis in all 4 studies. Because the findings are based on limited data, caution is warranted until more randomized controlled trials are conducted to support or refute the general trends observed in this report. PMID- 22488143 TI - Epidemiology of adolescent rugby injuries: a systematic review. AB - OBJECTIVE: Despite recent increases in the volume of research in professional rugby union, there is little consensus on the epidemiology of injury in adolescent players. We undertook a systematic review to determine the incidence, severity, and nature of injury in adolescent rugby union players. DATA SOURCES: In April 2009, we performed a computerized literature search on PubMed, Embase, and Cochrane Controlled Trials Register (via Ovid). Population-specific and patient-specific search terms were combined in the form of MEDLINE subject headings and key words (wound$ and injur$, rugby, adolescent$). These were supplemented with related-citation searches on PubMed and bibliographic tracking of primary and review articles. STUDY SELECTION: Prospective epidemiologic studies in adolescent rugby union players. DATA SYNTHESIS: A total of 15 studies were included, and the data were analyzed descriptively. Two independent reviewers extracted key study characteristics regarding the incidence, severity, and nature of injuries and the methodologic design. CONCLUSIONS: Wide variations existed in the injury definitions and data collection procedures. The incidence of injury necessitating medical attention varied with the definition, from 27.5 to 129.8 injuries per 1000 match hours. The incidence of time-loss injury (>7 days) ranged from 0.96 to 1.6 per 1000 playing hours and from 11.4/1000 match hours (>1 day) to 12-22/1000 match hours (missed games). The highest incidence of concussion was 3.3/1000 playing hours. No catastrophic injuries were reported. The head and neck, upper limb, and lower limb were all common sites of injury, and trends were noted toward greater time loss due to upper limb fractures or dislocations and knee ligament injuries. Increasing age, the early part of the playing season, and the tackle situation were most closely associated with injury. Future injury-surveillance studies in rugby union must follow consensus guidelines to facilitate interstudy comparisons and provide further clarification as to where injury-prevention strategies should be focused. PMID- 22488144 TI - Is oral temperature an accurate measurement of deep body temperature? A systematic review. AB - CONTEXT: Oral temperature might not be a valid method to assess core body temperature. However, many clinicians, including athletic trainers, use it rather than criterion standard methods, such as rectal thermometry. OBJECTIVE: To critically evaluate original research addressing the validity of using oral temperature as a measurement of core body temperature during periods of rest and changing core temperature. DATA SOURCES: In July 2010, we searched the electronic databases PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL), SPORTDiscus, Academic Search Premier, and the Cochrane Library for the following concepts: core body temperature, oral, and thermometers. Controlled vocabulary was used, when available, as well as key words and variations of those key words. The search was limited to articles focusing on temperature readings and studies involving human participants. DATA SYNTHESIS: Original research was reviewed using the Physiotherapy Evidence Database (PEDro). Sixteen studies met the inclusion criteria and subsequently were evaluated by 2 independent reviewers. All 16 were included in the review because they met the minimal PEDro score of 4 points (of 10 possible points), with all but 2 scoring 5 points. A critical review of these studies indicated a disparity between oral and criterion standard temperature methods (eg, rectal and esophageal) specifically as the temperature increased. The difference was -0.50 degrees C +/- 0.31 degrees C at rest and -0.58 degrees C +/- 0.75 degrees C during a nonsteady state. CONCLUSIONS: Evidence suggests that, regardless of whether the assessment is recorded at rest or during periods of changing core temperature, oral temperature is an unsuitable diagnostic tool for determining body temperature because many measures demonstrated differences greater than the predetermined validity threshold of 0.27 degrees C (0.5 degrees F). In addition, the differences were greatest at the highest rectal temperatures. Oral temperature cannot accurately reflect core body temperature, probably because it is influenced by factors such as ambient air temperature, probe placement, and ingestion of fluids. Any reliance on oral temperature in an emergency, such as exertional heat stroke, might grossly underestimate temperature and delay proper diagnosis and treatment. PMID- 22488145 TI - Conservative treatment of an acute traumatic extensor carpi ulnaris tendon subluxation in a collegiate basketball player: a case report. AB - OBJECTIVE: To present the case of an acute traumatic extensor carpi ulnaris (ECU) subluxation in a National Collegiate Athletic Association Division II female basketball player. BACKGROUND: The ECU tendon is stabilized in the ulnar groove by a subsheath located inferior to the extensor retinaculum. The subsheath can be injured with forced supination, ulnar deviation, and wrist flexion, resulting in the ECU tendon subluxing in the palmar and ulnar directions during wrist circumduction. Several methods of intervention exist, but controversy remains on how to best treat this condition. DIFFERENTIAL DIAGNOSIS: Distal ulnar fracture, ulnar collateral ligament sprain, triangular fibrocartilage complex lesion, lunotriquetral instability, distal radioulnar joint injury, pisotriquetral joint injury, ECU tendinopathy or subluxation. TREATMENT: The wrist was placed in a short-arm cast in slight extension and radial deviation for 4 weeks. At that time, the patient was still able to actively sublux the ECU tendon, so a long-arm cast was applied with the wrist in slight extension, radial deviation, and pronation for an additional 4 weeks. The ECU tendon was then found to be stable. She wore a rigid wrist brace for 3 more weeks while she pursued rehabilitation. At the final follow-up appointment, the ECU tendon remained stable, and the wrist was asymptomatic. UNIQUENESS: Subluxations of the ECU are rare. If the patient does not improve with conservative measures, surgical intervention is warranted to repair the sixth dorsal compartment. CONCLUSIONS: A long-arm cast with the elbow flexed to 90 degrees and the wrist in approximately 30 degrees of extension, radial deviation, and pronation was appropriate treatment for this type of injury. PMID- 22488146 TI - Synthetic studies towards the mulberry Diels-Alder adducts: H-bond accelerated cycloadditions of chalcones. AB - The methyl ether derivatives 2, 4 and 6 of the mulberry Diels-Alder adducts chalcomoracin (1) and mulberrofuran C (3) and kuwanon J (5) respectively have been synthesized by a thermal [4 + 2]-cycloaddition reaction between a chalcone and dehydroprenyl diene. A H-bonded ortho OH substituent on the chalcone was found to be essential for Diels-Alder reactivity. Density functional theory calculations show that the OH group lowers the barrier for the Diels-Alder reaction by 2-3 kcal mol(-1) compared with OMe. The acceleration by the OH group is traced to two transition-state effects: a stronger diene-chalcone interaction and better planarity of the aryl-diene unit. PMID- 22488147 TI - Short-chain fatty acids induce apoptosis in colon cancer cells associated with changes to intracellular redox state and glucose metabolism. AB - BACKGROUND: Short-chain fatty acids (SCFA) are undergoing increased scrutiny as chemotherapeutics for colon cancer, although a comprehensive understanding of their mode of action is lacking. We investigated candidate SCFA for their capability to modulate apoptosis, cell cycle, intracellular redox state and glucose metabolism in the Caco-2 human colon cancer cell line. METHODS: Caco-2 cells were incubated with butyrate, propionate or a combination of these SCFA (1:1) and assessed by flow cytometry, enzyme activity analysis or by isotope ratio mass spectrometry. RESULTS: Butyrate and the SCFA combination induced apoptosis and G2-M arrest to a greater extent than propionate alone (p < 0.05). SCFA treatment led to time-dependent alterations to the oxidative pentose pathway, reductions in glutathione availability and increases in levels of reactive oxygen species (p < 0.05) compared with untreated controls. The rate of D-glucose metabolism was increased by all SCFA, although to the greatest extent by butyrate (p < 0.05). CONCLUSIONS: These results suggest that butyrate, or the combination of both SCFA, induced rapid and extensive apoptosis and G2-M arrest associated with changes to redox state and D-glucose metabolism. These results support the potential for butyrate and propionate to act as adjuncts to conventional chemotherapy regimens for colon cancer. PMID- 22488151 TI - A curative cryosurgical technique for advanced cancer of sacrococcygeal pilonidal sinuses. AB - BACKGROUND AND OBJECTIVE: Malignant degeneration of pilonidal sinuses of the sacrococcygeal region is rare but quite serious, as the tumor soon perforates the sacral fascia and becomes adherent to the irregular posterior aspect of the sacrum, making it very difficult, if not impossible, to remove all neoplastic tissue by conventional surgery, hence the high recurrence rate and poor prognosis. A new cryosurgical technique to treat advanced sacrococcygeal pilonidal cancer is herein presented. MATERIALS AND METHODS: Seven men aged 30-75 (mean: 54.4 years) with advanced squamous-cell carcinomas (four primary, three recurrent) arising in sacrococcygeal pilonidal sinuses were treated with open and thick liquid nitrogen spray-two freeze-thaw cycles. Temperature monitoring was made by thermocouples. RESULTS: Local eradication was achieved in all cases; one patient, however, died of metastatic disease 10 months after treatment, without local recurrence. One patient had a recurrence, or a new tumor, 8 years after treatment and was again submitted to aggressive cryosurgery followed by plastic surgery. He was followed for 14 years without recurrence. The follow-up of the remaining six patients ranges between 7 and 18 years. CONCLUSION: To the author's knowledge, this is the first series of carcinomas of sacrococcygeal pilonidal sinuses successfully treated by cryosurgery. PMID- 22488148 TI - Microbiota evaluation of patients with a Boston type I keratoprosthesis treated with topical 0.5% moxifloxacin and 5% povidone-iodine. AB - PURPOSE: To evaluate the efficacy of a prophylactic regimen of daily topical 0.5% moxifloxacin and 5% povidone-iodine (PI) in patients with Boston type I keratoprosthesis (KPro) and to assess the applicability of a novel molecular diagnostic technique to analyze the ocular surface microbiota in these patients. METHODS: Ten patients had their inferior conjunctival fornix sampled for standard culture methods before the addition of topical 5% PI to the prophylactic regimen and were considered the control group (group 1). The inferior conjunctival fornix and the KPro-donor cornea interface of 10 patients treated with the mentioned prophylactic regimen were sampled and analyzed by standard culture methods and using a polymerase chain reaction/electrospray ionization mass spectrometry assay (group 2). RESULTS: Samples from the inferior conjunctival fornix were positive for coagulase-negative staphylococcus in 3 patients and for Aerobasidium pullulans in 1 patient in group 1. The inferior conjunctival fornix and the KPro donor cornea interface scrapings were positive for coagulase-negative staphylococcus in 2 patients and 1 patient, respectively, in group 2. No bacteria and fungi growth were detected in any patient from group 2 with the molecular diagnostic approach. None of the patients with culture-positive results developed keratitis or endophthalmitis during the study. CONCLUSIONS: Topical 0.5% moxifloxacin associated with topical 5% PI is an effective prophylactic regimen in patients with Boston type I KPro. The molecular diagnostic approach using serial polymerase chain reaction and mass spectrometry was comparable with standard microbiologic techniques as a surveillance tool in these patients. PMID- 22488152 TI - LARP7 is a potential tumor suppressor gene in gastric cancer. AB - We previously reported frequent truncating mutations of the RNA-binding protein gene, La ribonucleoprotein domain family, member-7 (LARP7) in gastric cancers (GCs) with frequent microsatellite instability. LARP7 negatively regulates positive transcription elongation factor-b (p-TEFb) by binding to and stabilizing 7sk RNA. p-TEFb has been linked to proliferation and de-differentiation in various tissues. Therefore, we reasoned that loss of LARP7 may contribute to gastric tumorigenesis. In this study, we evaluated LARP7 mRNA expression in 18 GCs, their corresponding non-neoplastic gastric tissues (N(GC)), and 18 normal gastric tissues from healthy individuals (N(N)). We also assessed the effects of transient small interfering (siRNA)-mediated LARP7 knockdown in immortalized non neoplastic gastric epithelial cells. LARP7 mRNA was significantly decreased in GCs (median 2.5) relative to N(N)s (median 14.9, P<0.01) as well as relative to their corresponding N(GC)s (median 8.1, P<0.01). Transfection of an siRNA directed against LARP7 (anti-LARP7 siRNA) into non-neoplastic gastric epithelial cells decreased 7sk levels by 72% relative to a control siRNA (P<0.01). Furthermore, anti-LARP7 siRNA transfection increased cell proliferation by 23% (P<0.01) and cell migration by 22% (P<0.001) relative to control siRNA transfection. Taken together, these findings suggest that LARP7 downregulation occurs early during gastric tumorigenesis and may promote gastric tumorigenesis via p-TEFb dysregulation. PMID- 22488154 TI - Passion for leadership--pass it on! PMID- 22488153 TI - Alterations in Brca1 expression in mouse ovarian granulosa cells have short-term and long-term consequences on estrogen-responsive organs. AB - Incessant menstrual cycle activity, uninterrupted by either pregnancy or oral contraceptive use, is the most important risk factor for sporadic ovarian cancer. Menstrual cycle progression is partly controlled by steroid hormones such as estrogens and others that are secreted by the ovarian granulosa cells. We showed earlier that mice carrying a homozygous granulosa cell-specific knockout of Brca1, the homolog of BRCA1 that is associated with familial ovarian cancer predisposition in humans, develop benign epithelial tumors in their reproductive tract. These tumors are driven, at least in part, by a prolongation of the proestrus phase of the estrus cycle (equivalent to the follicular phase of the menstrual cycle) in Brca1 mutant mice, resulting in prolonged unopposed estrogen stimulation. Mutant mice synchronized in proestrus also showed increased circulating estradiol levels, but the possibility that this change also has a role in tumor predisposition was not investigated. We sought to determine whether these changes in hormonal stimulation result in measurable changes in tissues targeted by estrogen outside the ovary. Here we show that mice carrying a Brca1 mutation in their ovarian granulosa cells show increased endometrial proliferation during proestrus, implying that the effects of Brca1 inactivation on estrogen stimulation have short-term consequences, at least on this target organ. We further show that mutant mice develop increased femoral trabecular thickness and femoral length, which are well-known consequences of chronic estrogen stimulation. Estrogen biosynthesis by granulosa cells was increased not only in mice carrying a homozygous Brca1 mutation, but also in heterozygous mutants mimicking the mutational status in granulosa cells of human BRCA1 mutation carriers. The results suggest that human germline BRCA1 mutations, although associated with increased cancer risk, may also have beneficial consequences, such as increased bone strength, that may have contributed to the maintenance of mutated BRCA1 alleles in the human gene pool. PMID- 22488155 TI - Surviving posttraumatic stress disorder. PMID- 22488156 TI - The upper airway evaluation of habitual snorers and obstructive sleep apnea patients. AB - OBJECTIVE: To investigate the relationship between the Apnea Hypopnea Index (AHI) and upper airway examination findings of habitual snorers and obstructive sleep apnea (OSA) patients. MATERIALS AND METHODS: This study included 264 patients whose tonsils were evaluated in 4 grades. The Mallampati classification was used to determine the relationship between tongue and palate. All patients performed the Muller maneuver in a sitting position. The Fujita classification was used to define the type of obstruction. All patients had polysomnography and were divided into 4 groups according to AHI. Statistical analysis was performed to evaluate the relationship between examination findings and AHI. RESULTS: Of the patients, 133 (50.4%) were habitual snorers, 66 (25%) were mild OSA, 40 (15.2%) were moderate OSA and 25 (9.5%) were severe OSA patients. There was a positive correlation between neck circumference, BMI and AHI in males (p < 0.001). There was a significant difference between patient groups according to Mallampati classification, collapse at the velopharyngeal level and hypopharyngeal level and Fujita classification (all p < 0.001). There were significant relationships between tonsil size, Fujita classification, Mallampati classification, collapse ratios and AHI. CONCLUSION: We saw that hypopharyngeal area often contributes to obstruction and some examination methods correlate more with AHI. This can aid sleep physicians in the evaluation of OSA patients. PMID- 22488157 TI - Transient recombinant protein expression in a human amniocyte cell line: the CAP T(r) cell system. AB - The impact of transient gene expression approaches (TGE) on the rapid production of recombinant proteins is undisputed, despite that all efforts are currently relying on two host cell families only, namely HEK293 derivatives and CHO cell line(s). Yet, the increasing complexity of biological targets calls for more than two host cell types to meet the challenges of difficult-to-express proteins. For this reason, we evaluated the more recently established novel CAP-T(r) cell line derived from human amniocytes for its performance and potential in transient gene expression. Upon careful analyses and adaptation of all process parameters we show here that indeed the CAP-T(r) cells are extremely amenable to transient gene expression and recombinant protein production. Additionally, they possess inherent capabilities to express and secrete complex and difficult target molecules, thus adding an attractive alternative to the repertoire of existing host cell lines used in transient production processes. PMID- 22488158 TI - Leisure-time physical activity patterns and correlates among pregnant women in Ontario, Canada. AB - Physical activity significantly impacts public health as it reduces the risk of chronic diseases and provides numerous protective factors during pregnancy. Although Canadian guidelines recommend regular physical activity for healthy pregnant women, little is known about their leisure-time physical activity patterns. This study compared the physical activity levels of pregnant and non pregnant women and examined socio-demographic and health correlates of physical activity during pregnancy. Canadian Community Health Survey data (2005-2008) from 623 pregnant women and 20,392 non-pregnant women aged 15-49 years in Ontario, Canada were examined. The prevalence of regular physical activity (15 or more minutes on at least 3 days of the week) was 58.3 % [95 % CI 52.9, 63.4], among pregnant women and 66.9 % [95 % CI 65.8, 68.0] among non-pregnant women. However, the prevalence of meeting Canadian guidelines for physical activity during pregnancy (30 or more minutes on at least 4 days of the week) was only 23.3 %, [95 % CI 19.4, 27.7] among pregnant women and 33.6 % [95 % CI 32.7, 34.6] among non-pregnant women. Pregnant women were less likely to be meeting guidelines if they were single, divorced, separated or widowed, a visible minority, had a household income between $20,000 and $79,999, and reported being in good or fair/poor health; when it came to education, women who had completed high school were more likely to be meeting guidelines. Few pregnant women in Ontario are meeting guidelines for physical activity during pregnancy. Results indicate that promoting physical activity during pregnancy should remain a public health priority. PMID- 22488159 TI - Factors promoting or potentially impeding school success: disparities and state variations for children with special health care needs. AB - School success predicts many pathways for health and well-being across the life span. Factors promoting or potentially impeding school success are critical to understand for all children and for children with special health care needs (CSHCN), whose life course trajectories are already impacted by their chronic health problems. The 2007 National Survey of Children's Health was used (1) to estimate national and state prevalence and within and across states disparities in factors promoting school success (engagement, participation, safety) or potentially impeding success (missing school, grade repetition, school identified problems) for all children and CSHCN and (2) to evaluate associations with CSHCN service need complexity and presence of emotional, behavioral or developmental problems (EBD) as well as with school case management policies in states. Among school age children, 60 % experienced all three factors promoting school success (49.3-73.8 % across states), dropping to 51.3 % for CSHCN (39.4-64.7 % across states) and to 36.2 % for the 40 % of all CSHCN who have both more complex service needs and EBD. CSHCN were more likely to experience factors potentially impeding school success. After accounting for child factors, CSHCN living in states requiring case management in schools for children with disabilities were less likely to experience grade repetition (OR 0.65). Within-state disparities between non-CSHCN and CSHCN varied across states. Threats to school success for US children are pervasive and are especially pronounced for CSHCN with more complex needs and EBD. Findings support broad, non-condition specific efforts to promote school success for CSHCN and consideration of state school policies, such as case management. PMID- 22488160 TI - Seafood consumption and blood mercury concentrations in Jamaican children with and without autism spectrum disorders. AB - Mercury is a toxic metal shown to have harmful effects on human health. Several studies have reported high blood mercury concentrations as a risk factor for autism spectrum disorders (ASDs), while other studies have reported no such association. The goal of this study was to investigate the association between blood mercury concentrations in children and ASDs. Moreover, we investigated the role of seafood consumption in relation to blood mercury concentrations in Jamaican children. Based on data for 65 sex- and age-matched pairs (2-8 years), we used a General Linear Model to test whether there is an association between blood mercury concentrations and ASDs. After controlling for the child's frequency of seafood consumption, maternal age, and parental education, we did not find a significant difference (P = 0.61) between blood mercury concentrations and ASDs. However, in both cases and control groups, children who ate certain types of seafood (i.e., salt water fish, sardine, or mackerel fish) had significantly higher (all P < 0.05) geometric means blood mercury concentration which were about 3.5 times that of children living in the US or Canada. Our findings also indicate that Jamaican children with parents who both had education up to high school are at a higher risk of exposure to mercury compared to children with at least one parent who had education beyond high school. Based on our findings, we recommend additional education to Jamaican parents regarding potential hazards of elevated blood mercury concentrations, and its association with seafood consumption and type of seafood. PMID- 22488162 TI - Neonatal DSP-4 treatment modifies antinociceptive effects of the CB1 receptor agonist methanandamide in adult rats. AB - To study the influence of the central noradrenergic system on antinociceptive effects mediated by the CB(1)-receptor agonist methanandamide, intact rats were contrasted with rats in which noradrenergic nerves were largely destroyed shortly after birth with the neurotoxin DSP-4 [N-(-2-chloroethyl)-N-ethyl-2 bromobenzylamine (50 mg/kg sc * 2, P1 and P3); zimelidine (10 mg/kg sc, 30 min pretreatment, selective serotonin reuptake inhibitor). When rats attained 10 weeks of age, monoamine and their metabolite concentrations were determined in the frontal cortex, thalamus, and spinal cord by an HPLC/ED method. Antinociceptive effects after methanandamide (10 mg/kg ip) apply were evaluated by a battery of tests. In addition, immunohistochemistry and densitometric analysis of the cannabinoid CB(1) receptor in the rat brain was performed. DSP-4 lesioning was associated with a reduction in norepinephrine content of the frontal cortex (>90 %) and spinal cord (>80 %) with no changes in the thalamus. Neonatal DSP-4 treatment produced a significant reduction in the antinociceptive effect of methanandamide in the tail-immersion test, hot-plate test and writhing tests. In the paw pressure and formalin hind paw tests results were ambiguous. These findings indicate that the noradrenergic system exerts a prominent influence on analgesia acting via the cannabinoid system in brain, without directly altering CB(1) receptor density in the brain. PMID- 22488163 TI - Pathology associated with optical coherence tomography macular bending due to either dome-shaped macula or inferior staphyloma in myopic patients. AB - PURPOSE: To evaluate the prevalence of and describe the pathology associated with macular bending (MB) defined as a smooth macular elevation found in optical coherence tomography (OCT) of patients with high myopia related to either dome shaped macula (DSM) or the border of an inferior staphyloma. PROCEDURES: We reviewed the 330 files of all highly myopic patients in our database that had had an OCT performed in the last 5 years. Main outcome measures were MB prevalence and its associated pathology. RESULTS: Sixty-eight eyes from 45 patients (13.63%) presented MB; 23 bilateral, 40 in a posterior pole or macular staphyloma and 21 in an inferior staphyloma. Eighteen eyes presented choroidal neovascularization (CNV), 7 subretinal fluid without CNV, 11 retinoschisis and 3 a macular hole which had been stable for years. No differences were found in the rate of complications between patients with DSM or inferior staphyloma. CONCLUSIONS: MB is not an uncommon clinical feature. Associated pathology prevalence in MB was elevated and similar in posterior and inferior staphylomas. PMID- 22488161 TI - Nitric oxide-mediated oxidative damage and the progressive demise of motor neurons in ALS. AB - Oxidative damage is a common and early feature of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and other neurodegenerative disorders. Dr. Mark Smith and his colleagues have built the case for oxidative stress being a primary progenitor rather than a secondary end stage epiphenomenon of neurodegeneration. They proposed that reactive oxygen species contribute to the "age-related cascade of neurodegeneration," whereby accumulative oxidative damage with age promotes other characteristic pathological changes in afflicted brain regions, including protein aggregation, metabolic deficiencies, and inflammation. Nitric oxide (NO) likely plays a critical role in this age-related cascade. NO is a major signaling molecule produced in the central nervous system to modulate neurological activity through stimulating cyclic GMP synthesis. However, the same physiological concentrations of NO, relevant in cellular signaling, may also initiate and amplify oxidative damage by diffusion-limited reactions with superoxide (O(2)(*-)) to produce peroxynitrite (ONOO(-)). This is perhaps best illustrated in ALS where physiological levels of NO promote survival of motor neurons, but the same concentrations can stimulate motor neuron apoptosis and glial cell activation under pathological conditions. While these changes represent a complex mechanism involving multiple cell types in the pathogenesis of ALS, they also reveal general processes underlying neurodegeneration. PMID- 22488164 TI - The influences of perinatal challenge persist into the adolescent period in socially housed bonnet macaques (Macaca radiata). AB - Social challenges during the perinatal period influence the mother-infant relationship in nonhuman primates and may affect the offspring's response to later social challenge(s). Relocation of a breeding colony of monkeys (Macaca radiata) created two groups of infants: one group experienced social group relocation to a new housing facility during the perinatal period (ATYPICAL) and the second group developed within a constant environment (TYPICAL). At a mean age of 25 months, all animals were removed from their natal group and placed in same sex adolescent social groups. Behavioral observations were collected after group formation or introduction to a new group. ATYPICAL subjects showed increased aggression and reduced affiliation compared to TYPICAL subjects. Hair cortisol in male subjects collected 6 months after introduction was elevated in the ATYPICAL subjects compared to TYPICAL subjects. These findings demonstrate that early life challenges affect behavior as well as stress hormone responses to social challenge in adolescence. PMID- 22488165 TI - An existential approach to oncology: meeting the needs of our patients. AB - PURPOSE OF REVIEW: Patients with cancer face both physical and psychological challenges. In the past, oncologists often limited themselves to the medical aspects of cancer care and delegated psychosocial interventions to professionals from other disciplines. In this review, we explore the methods by which oncologists can expand their role in treating cancer patients. RECENT FINDINGS: Recent studies have shown that individuals with cancer are not always satisfied with the care that they are receiving and believe that their existential needs are not being met. A model is suggested for improving the interaction between oncologists and their patients that involves focusing on the existential needs of an individual with cancer. Specific interventions and their appropriateness are discussed. SUMMARY: Oncologists should consider expanding their role and involving themselves in the more holistic aspects of cancer care. As a result of the bonds that they develop with patients, these professionals often find themselves in a position of being able to help and counsel cancer patients who are coping with feelings of isolation, loneliness, and fear. PMID- 22488166 TI - Molecular "light switch" for G-quadruplex DNA: cycling the switch on and off. AB - We report a new G-quadruplex DNA "light switch", where the light switch can be cycled on and off through the successive introduction of G-quadruplex DNA and [Fe(CN)(6)](4-) ions. PMID- 22488167 TI - Heterogeneity of high-grade cervical intraepithelial neoplasia related to HPV16: implications for natural history and management. AB - Factors associated with progression from cervical intraepithelial neoplasia (CIN) grades 2 and 3 to invasive cancer are not well understood; most CIN2 and CIN3 do not progress to cancer. Among carcinogenic human papillomavirus (HPV) types, infections with HPV16 have the highest risk of progressing to cancer. We evaluated the heterogeneity of risk factors, lesion size, colposcopic impression and colposcopic biopsy results in relation to HPV16 status among 627 women with CIN2 or CIN3 in women referred to colposcopy at the University of Oklahoma. Loop excision specimens were evaluated in 12 radial segments to estimate lesion size. The mean age at CIN3 was 27.7 years for HPV16-positive women (n = 225) and 33.6 years for HPV16-negative women (n = 104). The average lesion size did not differ by HPV16 status (p = 0.83). Among HPV16-positive women with CIN3, lesions were significantly larger in women 30 years and older (p = 0.03). Colposcopic impression was worse in women with HPV16 infections (p = 0.009), but the detection of CIN3 at the preceding biopsy was not improved in HPV16-positive women. CIN3 is detected at the same lesion size, but at much younger age in women with HPV16 infections, suggesting faster growth. CIN2 lesion size in women without HPV16 peaks below 30 years and then decreases, suggesting frequent regression, whereas HPV16-related CIN2 is more likely to persist. Lesion size seems to be an important determinant of colposcopy and biopsy performance. Genotyping for HPV16 in cervical cancer screening can improve risk stratification but may pose challenges to finding small lesions in colposcopy. PMID- 22488168 TI - Clinical characteristics, sex hormones, and long-term follow-up in Swiss postmenopausal women presenting with Takotsubo cardiomyopathy. AB - BACKGROUND: The overwhelming majority of patients with stress cardiomyopathy (SC) are postmenopausal women, suggesting an important pathophysiologic role of the female sex hormones. Preliminary data suggest that myocardial stunning might be provoked by estrogen deficiency. HYPOTHESIS: We hypothesized that, compared with age- and gender-matched patients with myocardial infarction (MI) or patients with normal coronary arteries, patients with SC would exhibit altered levels of sex hormones. Furthermore, we aimed to describe the clinical course and the pattern of sex hormones of the SC patients during long-term follow-up. METHODS: Blood samples obtained on hospital admission were analyzed for estradiol (E2), progesterone (P), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in women with SC (n = 17), age-matched women with acute MI (n = 16), and women with normal coronary arteries (n = 15). Six years after the initial event, SC patients underwent a clinical and echocardiographic follow-up and reassessment of sex hormones. RESULTS: Estrogen concentrations at hospital admission were significantly higher in the SC group compared with the MI and the control groups, with no difference in P, FSH, and LH concentrations. Follow-up E2 after 6 years in SC patients was lower than during the acute SC episode. Follow-up P in these patients was lower than P in the MI and control groups during the acute event, with a similar trend for E2. After a median follow-up of 6.4 years, 1 sudden cardiac death occurred and 2 patients suffered from SC recurrence. CONCLUSIONS: During the acute event, E2 concentrations are elevated in postmenopausal SC patients compared with women with acute MI or with normal coronary arteries. The higher E2 concentrations might have exerted atheroprotective effects and thus diverted the stress response to SC rather than MI. Recurrence and/or sudden cardiac death remains a potential risk of SC. PMID- 22488170 TI - GDF3 inhibits the growth of breast cancer cells and promotes the apoptosis induced by Taxol. AB - PURPOSE: The aim of this study is to investigate whether GDF3 is related to the progression of human breast cancer and the effects of GDF3 on breast cancer cells. METHODS: The expression of GDF3 in 24 breast cancer specimens paired with corresponding neighboring nontumorous tissue was studied by Western blot. Breast cancer cells were treated with different concentrations of recombinant human GDF3 protein. Using lentivirus containing sh-RNA, we knocked down the expression of GDF3. Soft agar assay was performed to explore the effects of GDF3 on colony formation. Different anti-tumor drugs dealt with MCF-7 cells stably expressing GDF3. RESULTS: We found that GDF3 expression level was significantly down regulated in breast cancer tissues compared to the surrounding nontumorous tissues. GDF3 proteins could inhibit the proliferation of MCF-7 and T47D cells. We also found that the knockdown of GDF3 resulted in the promotion of colony formation and enhanced the ability of anchorage-independent cell growth in soft agar. Furthermore, overexpression of GDF3 could promote the apoptosis induced by Taxol. CONCLUSIONS: Our data indicated that GDF3 expression is significantly decreased in human breast cancer tissues, and reconstitution of GDF3 in breast cancer may be a potential therapeutic approach to inhibit aggressive growth of breast cancer. PMID- 22488169 TI - Chemoaffinity capture of pre-targeted prostate cancer cells with magnetic beads. AB - BACKGROUND: Prostate circulating tumor cells (PCTCs) in circulation are shed from either a primary tumor or metastases, which are directly responsible for most prostate cancer deaths. Quantifying exfoliated PCTCs may serve as an indicator for the clinical management of prostate cancer, isolating and removing of PCTCs could potentially reduce prostate cancer metastasis, and culturing and characterizing captured PCTCs could facilitate the development of personalized treatment options. Prostate-specific membrane antigen (PSMA) is an established biomarker for prostate cancer being strongly expressed on prostate tumor cells associated with high-grade primary, androgen independent, and metastatic tumors. METHODS: Suspensions of PSMA+ (LNCaP) cells were pre-targeted with the irreversible PSMA inhibitor biotin-PEG(12)-CTT-54 to serve as a bait to capture PSMA+ cells using streptavidin-coated magnetic beads. Decreasing numbers of LNCaP cells were spiked into blood to determine the cell captured efficiency, recovery and viability. RESULTS: High selectivity, recovery, and viability were achieved for the capture of PSMA+ cells in both model experiments with mixtures of LNCaP cells and WBCs as well as blood samples spiked with LNCaP cells. As low as 10 cells were captured from 1 ml of blood with nearly 90% viability. More importantly, captured cells could be subsequently propagated in vitro. CONCLUSIONS: This methodology for the detection, isolation, and culture of PCTCs from peripheral blood can serve as an effective tool for the detection of metastatic prostate cancer, treatment monitoring, and the development of personalized therapy based on the responsiveness of PCTCs to chemotherapeutic strategies. PMID- 22488171 TI - FAK and Src expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients survival. AB - PURPOSE: Focal adhesion kinase (FAK) and Src are protein tyrosine kinases, localized in the focal adhesions, which, upon activation interacts each other, regulate several cellular signaling pathways implicated in malignant transformation and disease progression. The present study aimed to evaluate the clinical significance of FAK and Src protein expression in mobile tongue squamous cell carcinoma (SCC). METHODS: FAK and Src protein expression was assessed immunohistochemically on 48 mobile tongue SCC tissue samples and was analyzed in relation with clinicopathological characteristics, overall and disease-free patients' survival. RESULTS: FAK positivity was noted in 32 (66.67 %) and Src positivity in 45 (93.75 %) out of 48 mobile tongue SCC cases. FAK and Src protein expression was significantly increased in well-differentiated tumors compared to poorly differentiated ones (p = 0.0455 and p = 0.0301, respectively). Mobile tongue SCC patients presenting elevated Src expression showed longer overall and disease-free survival (log-rank test, p = 0.0145 and p = 0.0388, respectively). In multivariate analysis, the depth of invasion proved to be an independent prognostic factor of both overall and disease-free patients' survival (Cox regression, p = 0.0313 and p = 0.0481, respectively), whereas Src expression did not remain significant. CONCLUSIONS: The present study supported evidence for a potential role of FAK and Src signaling in mobile tongue SCC, rendering their small-molecule tyrosine kinase inhibitors as possible treatment strategy in tongue cancer chemoprevention. PMID- 22488172 TI - Prognostic value of nuclear matrix protein expression in localized prostate cancer. AB - PURPOSE: The aim of the study was to correlate nuclear matrix (NM) protein expression profiles with the risk of PSA progression or death in early prostate cancer (PCa). METHODS: High-resolution two-dimensional gel electrophoresis (2D PAGE) was used to identify tumor-associated NM proteins in the PCa specimens obtained from 94 patients. The association between the expression of each protein and the probability of PSA progression or death was studied through univariate analysis. Unsupervised hierarchical clustering analysis was then used to generate patient clusters showing comparable outcomes by including the proteins that were predictive at univariate analysis. PSA-free and overall survival curves relative to each cluster were constructed by means of the Kaplan-Meier method and curves compared by the log-rank test. Multi-parametric models were constructed according to Cox proportional hazard technique. RESULTS: After a median follow-up of 11.7 years (range, 6.5-16.2), 50 patients progressed and 22 died. Of the eight NM proteins identified through 2D-PAGE, proteins NM-6, NM-7 and NM-8 were confirmed to be individually associated with a higher risk of PSA progression at univariate analysis. Proteins NM-6 and NM-8 were also predictive of survival probability. Hierarchical clustering analysis of these proteins allowed to identify one cluster of tumors co-expressing the three proteins or proteins NM-6 and NM-8, characterized by a very poor outcome, suggesting a specific role for these proteins in PCa progression. The predictive value of this mini-signature in respect to PSA-free survival was confirmed by multivariate analysis. CONCLUSIONS: Changes in NM scaffolding are strongly associated with the clinical outcome of patients following radical prostatectomy. PMID- 22488173 TI - Individual dose and scheduling determine the efficacy of combining cytotoxic anticancer agents with a kinase inhibitor in non-small-cell lung cancer. AB - PURPOSE: To investigate the combination of conventional cytotoxic anticancer agents and a small molecule kinase inhibitor in preclinical models of non-small cell lung cancer (NSCLC). METHODS: We compared the induction of apoptosis by DNA damaging anticancer drugs and PKC412, a predominantly protein kinase C (PKC) specific small molecule inhibitor, in six NSCLC cell lines of different histologic and genetic backgrounds. The outcome of various combinations and schedules of DNA-damaging agents and PKC412 was studied, and isobolograms were calculated. Conditional expression of pro-apoptotic BAK was applied to specifically target apoptotic signal transduction in combination with drug therapy. RESULTS: Resistance of NSCLC cells to DNA damage-induced apoptosis was mainly determined at the mitochondrial step of the intrinsic pathway of caspase activation. PKC412 effectively inhibited the growth factor signal transduction, but failed to induce apoptosis in NSCLC cells resistant to DNA-damaging agents. Combining conventional anticancer drugs with PKC412 at different doses and schedules resulted in unpredictable outcomes, including synergistic, additive, and antagonistic interactions. In contrast, conditional expression of BAK reliably sensitized drug-resistant NSCLC cells to apoptosis induced by cytotoxic agents or PKC412. CONCLUSIONS: Combining DNA-damaging anticancer drugs with a pharmacologic inhibitor of growth and survival factor signaling in NSCLC may result in unpredictable treatment outcomes. In contrast, targeting specific death effector mechanisms, such as apoptotic signal transduction, is a promising strategy to sensitize NSCLC to cytotoxic agents or kinase inhibitors. PMID- 22488174 TI - Molecular nanomedicine towards cancer: 111In-labeled nanoparticles. AB - Nanomedicine is the medical application of materials, devices, or systems in the nanometer scale and is currently undergoing explosive development. Molecular imaging of cancer using nanosized materials comprises an important part in diagnosis, therapy, and drug discovery in medical nanosciences. Radiopharmaceuticals are a key tool of molecular imaging in the field of nuclear medicine. The in vivo administration of radiolabeled nanoparticles (NPs) can provide an accurate biodistribution profile of the nanoformulations, as well as visualization of their route in vivo. Surface modifications of NPs with antibodies, peptides, or other small molecules that bind to tumor cell receptors have resulted in the development of sensitive and specific targeted imaging and diagnostic modalities for in vitro and in vivo applications. Radiometals are the most favorable of all radionuclides for labeling applications and they have the most suitable properties for single-photon emission computed tomography imaging. Indium-111((111)In), specifically, is a readily available gamma-emitting radiometal, which is widely used in clinical practice for diagnosis and/or therapy. Herein, we will overview the latest evolvement on (111)In-labeled nanoparticles for biodistribution assessment and/or imaging evaluation of nanocarriers, as well as therapy in cancer. PMID- 22488175 TI - Hyposplenism: comparison of different methods for determining splenic function. AB - Asplenic patients are at risk for pneumococcal sepsis. Patients with hyposplenic function, such as associated with sickle cell disease (SCD), are also at risk. However, tests to assess splenic function are either unavailable or lacking standardization. The aim of this study was to compare different methods for determining splenic function. Eighteen patients with SCD (i.e., 10 heterozygous (SC) and 8 homozygous (SS) SCD patients), and eight splenectomized patients were compared to 10 controls. All subjects underwent spleen scintigraphy, after which functional splenic volumes (FSV) were calculated. FSV was compared to immunological function and B cell-subsets, as well as phagocytic function represented by the presence of Howell Jolly bodies (HJB) and percentages of pitted red cells (PIT). Heterozygous SCD (SC) patients had increased splenic volumes, but diminished FSV, homozygous SCD (SS) patients were asplenic. Splenectomized and SS patients had a strongly reduced phagocytic and immunological function. SC patients had reduced anti-polysaccharide responses without an increase in PIT. FSV correlated significantly with phagocytic and immunological function. HJB were indicative of splenic dysfunction, HJB absence was not indicative of normal functioning splenic tissue. Although visualizing HJB is methodologically advantageous to PIT, both are valid biomarkers of splenic dysfunction. The amount of non-switched memory B cells is strongly correlated to FSV. PMID- 22488176 TI - Risk of fracture with thiazolidinediones: disease or drugs? AB - The use of thiazolidinediones (TZDs) has been associated with an increased fracture risk. In addition, type 2 diabetes mellitus (T2DM) has been linked with fracture. We evaluated to what extent the association between TZD use and fracture risk is related to the drug or to the underlying disease. We conducted a population-based cohort study using the Danish National Health Registers (1996 2007), which link pharmacy data to the national hospital registry. Oral antidiabetic users (n = 180,049) were matched 1:3 by year of birth and sex to nonusers. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture. Time-dependent adjustments were made for age, comorbidity, and drug use. We created a proxy indicator for the severity of disease. The first stage was defined as current use of either a biguanide or a sulfonyluerum, the second stage as current use of a biguanide and a sulfonyluerum at the same time, the third stage as patients using TZDs, and the fourth stage as patients using insulin. The risk of osteoporotic fracture was increased 1.3-fold for stages 3 and 4 compared with controls. Risk with current TZD use (stage 3 HR = 1.27, 95 % CI 1.06-1.52) and risk with current use of insulin (stage 4 HR = 1.25, 95 % CI 1.20-1.31) were similar. In the first (HR = 1.15, 95 % CI 1.13-1.18) and second (HR = 1.00, 95 % CI 0.96-1.04) stages risks were lower. Risk of osteoporotic fracture was similar for TZD users and insulin users. When studying fracture risk with TZDs, the underlying T2DM should be taken into account. PMID- 22488177 TI - Progression of double-hit lymphoma in the midst of R-hyper CVAD. PMID- 22488178 TI - Prolyl hydroxylase domain enzyme 2 is the major player in regulating hypoxic responses in rheumatoid arthritis. AB - OBJECTIVE: Rheumatoid arthritis (RA) is characterized by hypoxia and the expression of hypoxia-inducible transcription factors (HIFs), which coordinate cellular responses to hypoxia. The objective of this study was to analyze the expression and regulation of prolyl hydroxylase domain (PHD) enzymes and factor inhibiting HIF-1alpha (FIH-1), which regulate cellular HIF levels, and to study the roles of these enzymes in RA fibroblast-like synoviocytes (RA FLS). METHODS: The expression of PHD and FIH and downstream target genes was assessed by quantitative polymerase chain reaction and Western blotting. A small interfering RNA (siRNA) approach and an in vitro endothelial cell angiogenesis assay were used to analyze the roles of HIF hydroxylases. RESULTS: In human RA FLS, knockdown of PHD-2, but not knockdown of PHD-1 or FIH-1, dramatically augmented HIF-1alpha expression, modestly increased HIF-2alpha protein expression under normoxic conditions, and up-regulated HIF-dependent gene expression. In contrast, silencing of PHD-3 up-regulated HIF-2alpha but reduced HIF-1alpha, thereby decreasing the expression of HIF-regulated genes. A similar effect of PHD-2 knockdown was observed in osteoarthritis FLS (OA FLS) but not in nondiseased primary human dermal fibroblasts. These findings correlated with the induction of in vitro angiogenesis by supernatants from RA FLS and OA FLS transfected with siPHD-2 but not by supernatants from nondiseased fibroblasts or from siPHD-3 transfected cells. CONCLUSION: Our data suggest that PHD-2 is the major hydroxylase regulating HIF levels and the expression of angiogenic genes in arthritic cells. PHD-2 appears to regulate responses relevant to arthritis via HIF-alpha, highlighting the major importance of this enzyme in hypoxia- and angiogenesis-dependent inflammatory diseases such as RA. PMID- 22488179 TI - In vivo analysis of Saccharomyces cerevisiae plasma membrane ATPase Pma1p isoforms with increased in vitro H+/ATP stoichiometry. AB - Plasma membrane H(+)-ATPase isoforms with increased H(+)/ATP ratios represent a desirable asset in yeast metabolic engineering. In vivo proton coupling of two previously reported Pma1p isoforms (Ser800Ala, Glu803Gln) with increased in vitro H(+)/ATP stoichiometries was analysed by measuring biomass yields of anaerobic maltose-limited chemostat cultures expressing only the different PMA1 alleles. In vivo H(+)/ATP stoichiometries of wildtype Pma1p and the two isoforms did not differ significantly. PMID- 22488180 TI - On the genesis of heterogeneous photocatalysis: a brief historical perspective in the period 1910 to the mid-1980s. AB - The concept Photocatalysis and, of greater import here, Heterogeneous Photocatalysis were first introduced in the second decade (1910-1920) of the 20th century according to the CAPLUS and MEDLINE databases (SciFinder). This review reports a brief historical perspective on the origins of the two concepts, whether implied or explicitly stated, in some detail up to about the mid-1980s when heterogeneous photocatalysis witnessed the beginning of an exponential growth, with particular emphasis on the use of nanosized TiO(2) particles in powdered form as the (so-called) photocatalyst of choice in environmental applications because of its inherent properties of abundance and chemical stability in acidic and alkaline aqueous media (in the dark), in contrast to ZnO that had been the metal oxide of choice in the early days. The early workers in this area often used the term photosensitization rather than the current popular term photocatalysis, used since the early 1980s. The term Photocatalysis appeared in the literature as early as 1910 in a book by Plotnikow (Russia) and a few years later it was introduced in France by Landau. The review also reports on contributions during the early years by Terenin at the University of St. Petersburg (previously Leningrad, Soviet Union), and in the decade spanning 1975 1985 contributions by Bard's group at the University of Texas at Austin (USA) as well as those of other groups. Some activities into the conversion of light energy to chemical fuels (e.g. H(2)) during the 1975-1985 decade are also considered. PMID- 22488182 TI - Half-marathon and full-marathon runners' hydration practices and perceptions. AB - CONTEXT: The behaviors and beliefs of recreational runners with regard to hydration maintenance are not well elucidated. OBJECTIVE: To examine which beverages runners choose to drink and why, negative performance and health experiences related to dehydration, and methods used to assess hydration status. DESIGN: Cross-sectional study. SETTING: Marathon registration site. PATIENTS OR OTHER PARTICIPANTS: Men (n = 146) and women (n = 130) (age = 38.3 +/- 11.3 years) registered for the 2010 Little Rock Half-Marathon or Full Marathon. INTERVENTION(S): A 23-item questionnaire was administered to runners when they picked up their race timing chips. MAIN OUTCOME MEASURE(S): Runners were separated into tertiles (Low, Mod, High) based on z scores derived from training volume, expected performance, and running experience. We used a 100-mm visual analog scale with anchors of 0 (never) and 100 (always). Total sample responses and comparisons between tertile groups for questionnaire items are presented. RESULTS: The High group (58+/-31) reported greater consumption of sport beverages in exercise environments than the Low (42 +/- 35 mm) and Mod (39 +/- 32 mm) groups (P < .05) and perceived sport beverages to be superior to water in meeting hydration needs (P < .05) and improving performance during runs greater than 1 hour (P < .05). Seventy percent of runners experienced 1 or more incidents in which they believed dehydration resulted in a major performance decrement, and 45% perceived dehydration to have resulted in adverse health effects. Twenty percent of runners reported monitoring their hydration status. Urine color was the method most often reported (7%), whereas only 2% reported measuring changes in body weight. CONCLUSIONS: Greater attention should be paid to informing runners of valid techniques to monitor hydration status and developing an appropriate individualized hydration strategy. PMID- 22488183 TI - Self-paced exercise performance in the heat after pre-exercise cold-fluid ingestion. AB - CONTEXT: Precooling is the pre-exercise reduction of body temperature and is an effective method of improving physiologic function and exercise performance in environmental heat. A practical and effective method of precooling suitable for application at athletic venues has not been demonstrated. OBJECTIVE: To confirm the effectiveness of pre-exercise ingestion of cold fluid without fluid ingestion during exercise on pre-exercise core temperature and to determine whether pre exercise ingestion of cold fluid alone without continued provision of cold fluid during exercise can improve exercise performance in the heat. DESIGN: Randomized controlled clinical trial. SETTING: Environmental chamber at an exercise physiology laboratory that was maintained at 32 degrees C, 60% relative humidity, and 3.2 m/s facing air velocity. PATIENTS OR OTHER PARTICIPANTS: Seven male recreational cyclists (age = 21 +/- 1.5 years, height = 1.81 +/- 0.07 m, mass = 78.4 +/- 9.2 kg) participated. INTERVENTION(S): Participants ingested 900 mL of cold (2 degrees C) or control (37 degrees C) flavored water in 3 300-mL aliquots over 35 minutes of pre-exercise rest. MAIN OUTCOME MEASURE(S): Rectal temperature and thermal comfort before exercise and distance cycled, power output, pacing, rectal temperature, mean skin temperature, heart rate, blood lactate, thermal comfort, perceived exertion, and sweat loss during exercise. RESULTS: During rest, a greater decrease in rectal temperature was observed with ingestion of the cold fluid (0.41 +/- 0.16 degrees C) than the control fluid (0.17 +/- 0.17 degrees C) over 35 to 5 minutes before exercise (t(6) = -3.47, P = .01). During exercise, rectal temperature was lower after ingestion of the cold fluid at 5 to 25 minutes (t(6) range, 2.53-3.38, P <= .05). Distance cycled was greater after ingestion of the cold fluid (19.26 +/- 2.91 km) than after ingestion of the control fluid (18.72 +/- 2.59 km; t(6) = -2.80, P = .03). Mean power output also was greater after ingestion of the cold fluid (275 +/- 27 W) than the control fluid (261 +/- 22 W; t(6) = -2.13, P = .05). No differences were observed for pacing, mean skin temperature, heart rate, blood lactate, thermal comfort, perceived exertion, and sweat loss (P > .05). CONCLUSIONS: We demonstrated that pre-exercise ingestion of cold fluid is a simple, effective precooling method suitable for field-based application. PMID- 22488184 TI - Validity and reliability of limits-of-stability testing: a comparison of 2 postural stability evaluation devices. AB - CONTEXT: A lack of published comparisons between measures from commercially available computerized posturography devices and the outcome measures used to define the limits of stability (LOS) makes meaningful interpretation of dynamic postural stability measures difficult. OBJECTIVES: To compare postural stability measures between and within devices to establish concurrent and construct validity and to determine test-retest reliability for LOS measures generated by the NeuroCom Smart Balance Master and the Biodex Balance System. DESIGN: Cross sectional study. SETTING: Controlled research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 23 healthy participants with no vestibular or visual disabilities or lower limb impairments. INTERVENTION(S): The LOS were assessed during 2 laboratory test sessions 1 week apart. MAIN OUTCOME MEASURE(S): Three NeuroCom LOS variables (directional control, endpoint excursion, and movement velocity) and 2 Biodex LOS variables (directional control, test duration). RESULTS: Test-retest reliability ranged from high to low across the 5 LOS measures (intraclass correlation coefficient [2,k] = 0.82 to 0.48). Pearson correlations revealed 4 significant relationships (P < .05) between and within the 2 computerized posturography devices (r = 0.42 to -0.65). CONCLUSIONS: Based on the wide range of intraclass correlation values we observed for the NeuroCom measures, clinicians and researchers alike should establish the reliability of LOS testing for their own clinics and laboratories. The low to moderate reliability outcomes observed for the Biodex measures were not of sufficient magnitude for us to recommend using the LOS measures from this system as the gold standard. The moderate Pearson interclass correlations we observed suggest that the Biodex and NeuroCom postural stability systems provided unique information. In this study of healthy participants, the concurrent and construct validity of the Biodex and NeuroCom LOS tests were not definitively established. We recommend that this study be repeated with a clinical population to further explore the matter. PMID- 22488185 TI - Lower extremity neuromuscular control immediately after fatiguing hip-abduction exercise. AB - CONTEXT: Fatigue of the gluteus medius (GMed) muscle might be associated with decreases in postural control due to insufficient pelvic stabilization. Men and women might have different muscular recruitment patterns in response to GMed fatigue. OBJECTIVE: To compare postural control and quality of movement between men and women after a fatiguing hip-abduction exercise. DESIGN: Descriptive laboratory study. SETTING: Controlled laboratory. PATIENTS OR OTHER PARTICIPANTS: Eighteen men (age = 22 +/- 3.64 years, height = 183.37 +/- 8.30 cm, mass = 87.02 +/- 12.53 kg) and 18 women (age = 22 +/- 3.14, height = 167.65 +/- 5.80 cm, mass = 66.64 +/- 10.49 kg) with no history of low back or lower extremity injury participated in our study. INTERVENTION(S): Participants followed a fatiguing protocol that involved a side-lying hip-abduction exercise performed until a 15% shift in electromyographic median frequency of the GMed was reached. MAIN OUTCOME MEASURE(S): Baseline and postfatigue measurements of single-leg static balance, dynamic balance, and quality of movement assessed with center-of-pressure measurements, the Star Excursion Balance Test, and lateral step-down test, respectively, were recorded for the dominant lower extremity (as identified by the participant). RESULTS: We observed no differences in balance deficits between sexes (P > .05); however, we found main effects for time with all of our postfatigue outcome measures (P <= .05). CONCLUSIONS: Our findings suggest that postural control and quality of movement were affected negatively after a GMed fatiguing exercise. At similar levels of local muscle fatigue, men and women had similar measurements of postural control. PMID- 22488186 TI - Quadriceps function after exercise in patients with anterior cruciate ligament reconstructed knees wearing knee braces. AB - CONTEXT: Knee braces and neoprene sleeves are commonly worn by people with anterior cruciate ligament reconstructions (ACLRs) during athletic activity. How knee braces and sleeves affect muscle activation in people with ACLRs is unclear. PURPOSE: To determine the effects of knee braces and neoprene knee sleeves on the quadriceps central activation ratio (CAR) before and after aerobic exercise in people with ACLRs. DESIGN: Crossover study. PATIENTS OR OTHER PARTICIPANTS: Fourteen people with a history of ACLR (9 women, 5 men: age = 23.61 +/- 4.44 years, height = 174.09 +/- 9.82 cm, mass = 75.35 +/- 17.48 kg, months since ACLR = 40.62 +/- 20.41). INTERVENTION(S): During each of 3 sessions, participants performed a standardized aerobic exercise protocol on a treadmill. The independent variables were condition (brace, sleeve, or control) and time (baseline, pre-exercise with brace, postexercise with brace, postexercise without brace). MAIN OUTCOME MEASURE(S): Normalized torque measured during a maximal voluntary isometric contraction (T(MVIC)) and CAR were measured by a blinded assessor using the superimposed burst technique. The CAR was expressed as a percentage of full muscle activation. The quadriceps CAR and T(MVIC) were measured 4 times during each session: baseline, pre-exercise with brace, postexercise with brace, and postexercise without brace. RESULTS: Immediately after the application of the knee brace, T(MVIC) decreased (P = .01), but no differences between bracing conditions were observed. We noted reduced T(MVIC) and CAR (P < .001) after exercise, both with and without the brace. No differences were seen between bracing conditions after aerobic exercise. CONCLUSIONS: The decrease in T(MVIC) immediately after brace application was not accompanied by differences between bracing conditions. Wearing a knee brace or neoprene sleeve did not seem to affect the deterioration of quadriceps function after aerobic exercise. PMID- 22488187 TI - Electrode type and placement configuration for quadriceps activation evaluation. AB - CONTEXT: The ability to accurately estimate quadriceps voluntary activation is an important tool for assessing neuromuscular function after a variety of knee injuries. Different techniques have been used to assess quadriceps volitional activation, including various stimulating electrode types and electrode configurations, yet the optimal electrode types and configurations for depolarizing motor units in the attempt to assess muscle activation are unknown. OBJECTIVE: To determine whether stimulating electrode type and configuration affect quadriceps central activation ratio (CAR) and percentage-of-activation measurements in healthy participants. DESIGN: Crossover study. SETTING: Research laboratory. PATIENTS AND OTHER PARTICIPANTS: Twenty participants (13 men, 7 women; age = 26 +/- 5.3 years, height = 173.85 +/- 7.3 cm, mass = 77.37 +/- 16 kg) volunteered. INTERVENTION(S): All participants performed 4 counter-balanced muscle activation tests incorporating 2 different electrode types (self-adhesive, carbon-impregnated) and 2 electrode configurations (vastus, rectus). MAIN OUTCOME MEASURE(S): Quadriceps activation was calculated with the CAR and percentage-of activation equations, which were derived from superimposed burst and resting torque measurements. RESULTS: No differences were found between conditions for CAR and percentage-of-activation measurements, whereas resting twitch torque was higher in the rectus configuration for both self-adhesive (216 +/- 66.98 Nm) and carbon-impregnated (209.1 +/- 68.22 Nm) electrodes than in the vastus configuration (209.5 +/- 65.5 Nm and 204 +/- 62.7 Nm, respectively) for these electrode types (F(1,19) = 4.87, P = .04). In addition, resting twitch torque was greater for both electrode configurations with self-adhesive electrodes than with carbon-impregnated electrodes (F(1,19) = 9.33, P = .007). Bland-Altman plots revealed acceptable mean differences for agreement between electrode type and configuration for CAR and percentage of activation, but limits of agreement were wide. CONCLUSIONS: Although these electrode configurations and types might not necessarily be able to be used interchangeably, differences in electrode type and configuration did not seem to affect CAR and percentage-of-activation outcome measures. PMID- 22488188 TI - Evaluation of persistent antimicrobial effects of an antimicrobial formulation. AB - CONTEXT: Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is becoming more prevalent in healthy athletic populations. Various preventive measures have been proposed, but few researchers have evaluated the protective effects of a prophylactic application of a commercially available product. OBJECTIVE: To compare the persistent antimicrobial properties of a commercially available antimicrobial product containing 4% chlorhexidine gluconate (Hibiclens) with those of a mild, nonmedicated soap (Dr. Bronner's Magic Soap). DESIGN: Cross sectional study. SETTING: Microbiology laboratory, contract research organization. PATIENTS OR OTHER PARTICIPANTS: Twenty healthy human volunteers. INTERVENTION(S): The test and control products were randomly assigned and applied to both forearms of each participant. Each forearm was washed for 2 minutes with the test or control product, rinsed, and dried. At, 1, 2, and 4 hours after application, each forearm was exposed to MRSA for approximately 30 minutes. MAIN OUTCOME MEASURE(S): Differences in numbers of MRSA recovered from each forearm, test and control, at each post-application time point were compared. RESULTS: Fewer MRSA (P < .0001) were recovered from the forearms treated with the test product (4% chlorhexidine gluconate) than from the forearms treated with the control product (nonmedicated soap). CONCLUSIONS: The 4% chlorhexidine gluconate product demonstrated persistent bactericidal activity versus MRSA for up to 4 hours after application. PMID- 22488189 TI - Functional ankle instability and health-related quality of life. AB - CONTEXT: To our knowledge, no authors have assessed health-related quality of life (HR-QOL) in participants with functional ankle instability (FAI). Furthermore, the relationships between measures of ankle functional limitation and HR-QOL are unknown. OBJECTIVE: To use the Short Form-36v2 Health Survey (SF 36) to compare HR-QOL in participants with or without FAI and to determine whether HR-QOL was related to functional limitation. DESIGN: Cross-sectional study. SETTING: Sports medicine research laboratory. PATIENTS OR OTHER PARTICIPANTS: Sixty-eight participants with FAI (defined as at least 1 lateral ankle sprain and 1 episode of giveway per month) or without FAI were recruited (FAI group: n = 34, age = 25 +/- 5 years, height = 1.71 +/- 0.08 m, mass = 74.39 +/- 12.78 kg, Cumberland Ankle Instability Tool score = 19.3 +/- 4; uninjured [UI] group: n = 34, age = 23 +/- 4 years, height = 1.69 +/- 0.08 m, mass = 67.94 +/- 11.27 kg, Cumberland Ankle Instability Tool score = 29.4 +/- 1). MAIN OUTCOME MEASURE(S): All participants completed the SF-36 as a measure of HR-QOL and the Foot and Ankle Ability Measure (FAAM) and the FAAM Sport version (FAAMS) as assessments of functional limitation. To compare the FAI and UI groups, we calculated multiple analyses of variance followed by univariate tests. Additionally, we correlated the SF-36 summary component scale and domain scales with the FAAM and FAAMS scores. RESULTS: Participants with FAI had lower scores on the SF-36 physical component summary (FAI = 54.4 +/- 5.1, UI = 57.8 +/- 3.7, P = .005), physical function domain scale (FAI = 54.5 +/- 3.8, UI = 56.6 +/- 1.2, P = .004), and bodily pain domain scale (FAI = 52.0 +/- 6.7, UI = 58.5 +/- 5.3, P < .005). Similarly, participants with FAI had lower scores on the FAAM (FAI = 93.7 +/- 8.4, UI = 99.5 +/- 1.4, P < .005) and FAAMS (FAI = 84.5 +/- 8.4, UI = 99.8 +/ 0.72, P < .005) than did the UI group. The FAAM score was correlated with the physical component summary scale (r = 0.42, P = .001) and the physical function domain scale (r = 0.61, P < .005). The FAAMS score was correlated with the physical function domain scale (r = 0.47, P < .005) and the vitality domain scale (r = 0.36, P = .002). CONCLUSIONS: Compared with UI participants, those with FAI had less HR-QOL and more functional limitations. Furthermore, positive correlations were found between HR-QOL and functional limitation measures. This suggests that ankle impairment may reduce overall HR-QOL. PMID- 22488190 TI - Active stiffness and strength in people with unilateral anterior shoulder instability: a bilateral comparison. AB - CONTEXT: Active muscle stiffness might protect the unstable shoulder from recurrent dislocation. OBJECTIVE: To compare strength and active stiffness in participants with unilateral anterior shoulder instability and to examine the relationship between active stiffness and functional ability. DESIGN: Cross sectional study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: Participants included 16 males (age range, 16-40 years; height = 179.4 +/- 6.1 cm; mass = 79.1 +/- 6.8 kg) with 2 or more episodes of unilateral traumatic anterior shoulder instability. MAIN OUTCOME MEASURE(S): Active stiffness and maximal voluntary strength were measured bilaterally in participants. In addition, quality of life, function, and perceived instability were measured using the Western Ontario Stability Index, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form, and Single Alpha Numeric Evaluation, respectively. RESULTS: We found less horizontal adduction strength (t(15) = -4.092, P = .001) and less stiffness at 30% (t(14) = -3.796, P = .002) and 50% (t(12) = -2.341, P = .04) maximal voluntary strength in the unstable than stable shoulder. Active stiffness was not correlated with quality of life, function, or perceived instability (r range, 0.0-0.25; P > .05). CONCLUSIONS: The observed reduction in stiffness in the unstable shoulder warrants inclusion of exercises in the rehabilitation program to protect the joint from perturbations that might lead to dislocation. The lack of association between active stiffness and quality of life, function, or perceived instability might indicate that stiffness plays a less direct role in shoulder stability. PMID- 22488191 TI - Incidence of injuries in high school softball and baseball players. AB - CONTEXT: Participation in high school sports has grown 16.1% over the last decade, but few studies have compared the overall injury risks in girls' softball and boys' baseball. OBJECTIVE: To examine the incidence of injury in high school softball and baseball players. DESIGN: Cohort study. SETTING: Greenville, South Carolina, high schools. PATIENTS OR OTHER PARTICIPANTS: Softball and baseball players (n = 247) from 11 high schools. MAIN OUTCOME MEASURE(S): Injury rates, locations, types; initial or subsequent injury; practice or game setting; positions played; seasonal trends. RESULTS: The overall incidence injury rate was 4.5/1000 athlete-exposures (AEs), with more injuries overall in softball players (5.6/1000 AEs) than in baseball players (4.0/1000 AEs). Baseball players had a higher initial injury rate (75.9/1000 AEs) than softball players (66.4/1000 AEs): rate ratio (RR) = 0.88, 95% confidence interval (CI) = 0.4, 1.7. The initial injury rate was higher than the subsequent injury rate for the overall sample (P < .0001) and for softball (P < .0001) and baseball (P < .001) players. For both sports, the injury rate during games (4.6/1000 AEs) was similar to that during practices (4.1/1000 AEs), RR = 1.22, 95% CI = 0.7, 2.2. Softball players were more likely to be injured in a game than were baseball players (RR = 1.92, 95% CI = 0.8, 4.3). Most injuries (77%) were mild (3.5/1000 AEs). The upper extremity accounted for the highest proportion of injuries (63.3%). The incidence of injury for pitchers was 37.3% and for position players was 15.3%. The rate of injury was highest during the first month of the season (7.96/1000 AEs). CONCLUSIONS: The incidence of injury was low for both softball and baseball. Most injuries were minor and affected the upper extremity. The injury rates were highest in the first month of the season, so prevention strategies should be focused on minimizing injuries and monitoring players early in the season. PMID- 22488192 TI - Approved clinical instructors' perspectives on implementation strategies in evidence-based practice for athletic training students. AB - CONTEXT: Understanding implementation strategies of Approved Clinical Instructors (ACIs) who use evidence-based practice (EBP) in clinical instruction will help promote the use of EBP in clinical practice. OBJECTIVE: To examine the perspectives and experiences of ACIs using EBP concepts in undergraduate athletic training education programs to determine the importance of using these concepts in clinical practice, clinical EBP implementation strategies for students, and challenges of implementing EBP into clinical practice while mentoring and teaching their students. DESIGN: Qualitative study. SETTING: Telephone interviews. PATIENTS OR OTHER PARTICIPANTS: Sixteen ACIs (11 men, 5 women; experience as a certified athletic trainer = 10 +/- 4.7 years, experience as an ACI = 6.8 +/- 3.9 years) were interviewed. DATA COLLECTION AND ANALYSIS: We interviewed each participant by telephone. Interview transcripts were analyzed and coded for common themes and subthemes regarding implementation strategies. Established themes were triangulated through peer review and member checking to verify the data. RESULTS: The ACIs identified EBP implementation as important for validation of the profession, changing paradigm shift, improving patient care, and improving student educational experiences. They promoted 3 methods of implementing EBP concepts with their students: self-discovery, promoting critical thinking, and sharing information. They assisted students with the steps of EBP and often faced challenges in implementation of the first 3 steps of EBP: defining a clinical question, literature searching, and literature appraisal. Finally, ACIs indicated that modeling the behavior of making clinical decisions based on evidence was the best way to encourage students to continue using EBP. CONCLUSIONS: Athletic training education program directors should encourage and recommend specific techniques for EBP implementation in the clinical setting. The ACIs believed that role modeling is a strategy that can be used to promote the use of EBP with students. Training of ACIs should include methods by which to address the steps of the EBP process while still promoting critical thinking. PMID- 22488193 TI - Factors of persistence among graduates of athletic training education programs. AB - CONTEXT: Previous researchers have indicated that athletic training education programs (ATEPs) appear to retain students who are motivated and well integrated into their education programs. However, no researchers have examined the factors leading to successful persistence to graduation of recent graduates from ATEPs. OBJECTIVE: To determine the factors that led students enrolled in a postprofessional education program accredited by the National Athletic Trainers' Association (NATA) to persist to graduation from accredited undergraduate ATEPs. DESIGN: Qualitative study. SETTING: Postprofessional education program accredited by the NATA. PATIENTS OR OTHER PARTICIPANTS: Fourteen graduates (12 women, 2 men) of accredited undergraduate entry-level ATEPs who were enrolled in an NATA accredited postprofessional education program volunteered to participate. DATA COLLECTION AND ANALYSIS: We conducted semistructured interviews and analyzed data through a grounded theory approach. We used open, axial, and selective coding procedures. To ensure trustworthiness, 2 independent coders analyzed the data. The researchers then negotiated over the coding categories until they reached 100% agreement. We also performed member checks and peer debriefing. RESULTS: Four themes emerged from the data. Decisions to persist to graduation from ATEPs appeared to be influenced by students' positive interactions with faculty, clinical instructors, and peers. The environment of the ATEPs also affected their persistence. Participants thought they learned much in both the clinic and the classroom, and this learning motivated them to persist. Finally, participants could see themselves practicing athletic training as a career, and this greatly influenced their eventual persistence. CONCLUSIONS: Our study gives athletic training educators insight into the reasons students persist to graduation from ATEPs. Specifically, athletic training programs should strive to develop close knit learning communities that stress positive interactions between students and instructors. Athletic training educators also must work to present the athletic training field as exciting and dynamic. PMID- 22488194 TI - Characterizations of a quality certified athletic trainer. AB - CONTEXT: Didactic proficiency does not ensure clinical aptitude. Quality athletic health care requires clinical knowledge and affective traits. OBJECTIVE: To develop a grounded theory explaining the constructs of a quality certified athletic trainer (AT). DESIGN: Delphi study. SETTING: Interviews in conference rooms or business offices and by telephone. PATIENTS OR OTHER PARTICIPANTS: Thirteen ATs (men = 8, women = 5) stratified across the largest employment settings (high school, college, clinical) in the 4 largest districts of the National Athletic Trainers? Association (2, 3, 4, 9). DATA COLLECTION AND ANALYSIS: Open-ended interview questions were audio recorded, transcribed, and reviewed before condensing. Two member checks ensured trustworthiness. Open coding reduced text to descriptive adjectives. RESULTS: We grouped adjectives into 5 constructs (care, communication, commitment, integrity, knowledge) and grouped these constructs into 2 higher-order constructs (affective traits, effective traits). CONCLUSIONS: According to participants, ATs who demonstrate the ability to care, show commitment and integrity, value professional knowledge, and communicate effectively with others can be identified as quality ATs. These abilities facilitate the creation of positive relationships. These relationships allow the quality AT to interact with patients and other health care professionals on a knowledgeable basis that ultimately improves health care delivery. Our resulting theory supported the examination of characteristics not traditionally assessed in an athletic training education program. If researchers can show that these characteristics develop ATs into quality ATs (eg, those who work better with others, relate meaningfully with patients, and improve the standard of health care), they must be cultivated in the educational setting. PMID- 22488195 TI - Preferences for and barriers to formal and informal athletic training continuing education activities. AB - CONTEXT: Our previous research determined the frequency of participation and perceived effect of formal and informal continuing education (CE) activities. However, actual preferences for and barriers to CE must be characterized. OBJECTIVE: To determine the types of formal and informal CE activities preferred by athletic trainers (ATs) and barriers to their participation in these activities. DESIGN: Cross-sectional study. SETTING: Athletic training practice settings. PATIENTS OR OTHER PARTICIPANTS: Of a geographically stratified random sample of 1000 ATs, 427 ATs (42.7%) completed the survey. MAIN OUTCOME MEASURE(S): As part of a larger study, the Survey of Formal and Informal Athletic Training Continuing Education Activities (FIATCEA) was developed and administered electronically. The FIATCEA consists of demographic characteristics and Likert scale items (1 = strongly disagree, 5 = strongly agree) about preferred CE activities and barriers to these activities. Internal consistency of survey items, as determined by Cronbach alpha, was 0.638 for preferred CE activities and 0.860 for barriers to these activities. Descriptive statistics were computed for all items. Differences between respondent demographic characteristics and preferred CE activities and barriers to these activities were determined via analysis of variance and dependent t tests. The alpha level was set at .05. RESULTS: Hands-on clinical workshops and professional networking were the preferred formal and informal CE activities, respectively. The most frequently reported barriers to formal CE were the cost of attending and travel distance, whereas the most frequently reported barriers to informal CE were personal and job-specific factors. Differences were noted between both the cost of CE and travel distance to CE and all other barriers to CE participation (F(1,411) = 233.54, P < .001). CONCLUSIONS: Overall, ATs preferred formal CE activities. The same barriers (eg, cost, travel distance) to formal CE appeared to be universal to all ATs. Informal CE was highly valued by ATs because it could be individualized. PMID- 22488196 TI - Personal food systems of male collegiate football players: a grounded theory investigation. AB - CONTEXT: Factors that affect food choices include the physical and social environments, quality, quantity, perceived healthfulness, and convenience. The personal food choice process was defined as the procedures used by athletes for making food choices, including the weighing and balancing of activities of daily life, physical well-being, convenience, monetary resources, and social relationships. OBJECTIVE: To develop a theoretical model explaining the personal food choice processes of collegiate football players. DESIGN: Qualitative study. SETTING: National Collegiate Athletic Association Division II football program. PATIENTS OR OTHER PARTICIPANTS: Fifteen football players were purposefully sampled to represent various positions, years of athletic eligibility, and ethnic backgrounds. DATA COLLECTION AND ANALYSIS: For text data collection, we used predetermined, open-ended questions. Data were analyzed using the constant comparison method. The athletes' words were used to label and describe their interactions and experiences with the food choice process. Member checks and an external audit were conducted by a qualitative methodologist and a nutrition specialist, and the findings were triangulated with the current literature to ensure trustworthiness of the text data. RESULTS: Time was the core category and yielded a cyclic graphic of a theoretical model for the food choice system. Planning hydration, macronutrient strategies, snacks, and healthful food choices emerged as themes. CONCLUSIONS: The athletes planned meals and snacks around their academic and athletic schedules while attempting to consume foods identified as healthful. Healthful foods were generally lower in fat but high in preferred macronutrients. High-protein foods were the players' primary goal; carbohydrate consumption was secondary. The athletes had established plans to maintain hydration. Professionals may use these findings to implement educational programs on food choices for football players. PMID- 22488197 TI - Overexpression of CDC20 predicts poor prognosis in primary non-small cell lung cancer patients. AB - BACKGROUND: This study examined the expression of CDC20 in human non-small cell lung cancer (NSCLC), explored its clinicopathological significance, and evaluated as a potential prognostic marker. METHODS: A total of 362 cases of NSCLCs were analyzed immunohistochemically on tissue microarrays (TMAs). Additionally, the immunoreactivity of mitotic arrest defective protein 2 (MAD2) was also studied. The clinicopathological implications of these molecules were analyzed statistically. RESULTS: High-level CDC20 protein expression (CDC20-H) was detected in 71 cases (19.6%). Additionally, CDC20-H was correlated with male sex, pT status, pleural invasion, and non-adenocarcinoma (non-ADC) histology. Significant correlation between CDC20 and MAD2 expression was found. NSCLC patients with tumor exhibiting CDC20-H showed significantly shorter 5-year overall survival (P=0.0007). According to subset analyses, CDC20-H was associated with shorter survival than CDC20-L only among ADC patients (P=0.0008), and not among squamous cell carcinoma (SCC) patients (P=0.5100). Importantly, CDC20-H was also identified as an independent prognostic factor in multivariate analysis (P=0.0065). CONCLUSIONS: CDC20 was a negative prognostic marker with significance in patients with resected NSCLC, particularly those with ADC histology. These results provide additional information for determining postoperative adjuvant treatment. PMID- 22488198 TI - Estrogen receptor-beta protects against colitis-associated neoplasia in mice. AB - Estrogen receptor-beta (ERbeta) has been suggested to exert anti-inflammatory and anti-tumorigenic effects in the colon, providing a translational potential to prevent and/or treat inflammatory bowel disease (IBD) and its progression to colitis-associated colorectal cancer (CAC). However, the specific direct role of ERbeta in CAC has not yet been tested. We assessed the effects of ERbeta deficiency in the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC model using ERbeta knockout (betaERKO) mice and wild-type (WT) littermates. These mice were injected with AOM followed by 1 week of DSS treatment, and sacrificed on weeks 9 or 16. betaERKO mice developed more severe clinical colitis compared to WT mice, as evidenced by significantly higher disease activity index after DSS treatment, weight to length ratio of the colons, inflammation score and grade of dysplasia. ERbeta-deficient colons presented greater number and size of polyps at weeks 9 and 16, respectively, and were characterized by a significant increase in interleukin (IL)-6, IL-17, tumor necrosis factor alpha and interferon-gamma mRNA levels. Furthermore, higher protein expression levels of nuclear factor-kappa B, inducible nitric oxide synthase, beta-catenin, proliferating cell nuclear antigen, mucin-1 and significantly lower caveolin-1 and mucin-2 protein levels were shown in betaERKO mice compared to WT mice. These data suggest a possible anti-inflammatory and anti-neoplastic mechanism of action of ERbeta in CAC. These results demonstrate for the first time that ERbeta provides protection in the AOM/DSS-induced CAC model in mice, suggesting a preventive and/or therapeutic potential for the use of ERbeta-selective agonists in IBD. PMID- 22488199 TI - Improving knowledge and screening for colorectal cancer among Hispanics: overcoming barriers through a PROMOTORA-led home-based educational intervention. AB - In the U.S., nearly 67 % of Hispanics ages 50 and older report that they have never had a screening colonoscopy. Barriers to screening include cost, lack of health insurance, anticipation of pain, embarrassment, mistrust of medical/healthcare systems and institutions, a fatalistic belief system, as well as fear and lack of knowledge regarding cancer survival. These barriers are significantly more problematic among Hispanics who are poor and those who live in underserved rural and border communities. This study addressed barriers by using promotoras and a home-based educational intervention to improve knowledge of cancer and screening for colorectal cancer (CRC) among Hispanics in Yakima Valley, Washington. Study participants attended a promotora led home-based educational intervention consisting of home-health parties (HHPs) and completed baseline and follow-up surveys on general cancer knowledge and knowledge specific to CRC and related screening practices. Results suggest increase in knowledge of cancer and participation in screening for CRC. Promotora facilitated home-based interventions offer culturally appropriate ways to reach Hispanics in rural and other underserved communities to reduce barriers and improve access to CRC and other cancer screenings. PMID- 22488200 TI - Ultrastructural study of the spermatozoon of the digenean Enodiotrema reductum Looss, 1901 (Platyhelminthes, Plagiorchioidea, Plagiorchiidae), parasite of the green turtle Chelonia mydas (Linnaeus, 1758) in Senegal. AB - This study describes the ultrastructural organisation of the spermatozoon of a digenean Enodiotrema reductum (Pligiorchiida: Plagiorchiidae) from the green turtle Chelonia mydas (Linnaeus, 1758). This is the first report of E. reductum from Senegal. The mature spermatozoon of E. reductum is filiform and exhibits two axonemes of the 9 + "1" pattern of the Trepaxonemata, a nucleus, parallel cortical microtubules, an extramembranar ornamentation associated with spine-like bodies and granules of glycogen, among other ultrastructural features. The spermatozoon of E. reductum is distinguished by the presence of a moniliform mitochondrion composed of a bulge associated with a long cord and of a central cytoplasmic expansion. This work represents the first utrastructural study of any representative of the large family Plagiorchiidae. Our results are compared with previously published data on spermatozoa of other digenean taxa. PMID- 22488201 TI - Trypanorhyncha cestodes of hygienic-sanitary importance infecting flounders Paralichthys patagonicus Jordan, 1889 and Xystreurys rasile (Jordan, 1891) of the Neotropical region, Brazil. AB - From February 2007 to July 2010, 27 specimens of Paralichthys patagonicus, and from September to December 2010, 30 specimens of Xystreurys rasile were purchased from fish markets in the municipalities of Cabo Frio and Rio de Janeiro, State of Rio de Janeiro, Brazil. The fishes were measured, necropsied, filleted, and further had their organs investigated. In P. patagonicus, 19 (70, 3 %) were parasitized with metacestodes of Trypanorhyncha species: Nybelinia erythraea, N. lingualis, Heteronybelinia nipponica, Pterobothrium crassicolle, Grillotia carvajalregorum, and Callitetrahynchus gracilis. In X. rasile, 17 (56, 6 %) were parasitized with metacestodes: N. erythraea, N. lingualis, H. nipponica, and G. carvajalregorum. The parasitological indices of prevalence, intensity, mean intensity, abundance, mean abundance, range of infection, and infection sites of each parasite species are presented. This is the first report of Trypanorhyncha cestodes parasitizing specimens of P. patagonicus and X. rasile. These cestodes were studied due to their importance during fish sanitary inspection, if one considers the harm that the repulsive aspect of infected meat causes to consumers. PMID- 22488202 TI - Higher attack rate of fish-borne trematodes (Heterophyidae) in common carp fingerlings (Cyprinus carpio) at lower fish weight. AB - Fish-borne zoonotic trematodes (FZTs) can cause pathology in humans. Fish weight was reported as important risk factor for transmission from snail to fish. However, in fingerlings, the relation between fish weight and infection is unknown. Aim was quantifying the effect of fish weight on infection probability, attack rate, and metacercariae burden of FZTs in common carps (Cyprinus carpio) between 1 and 20 g. Fish were either used as controls (n = 66) or exposed to 250 parapleurolophocercous cercariae (n = 254). Fish weight was analysed as continuous explanatory variable or classified in four categories with average weights of 0.7 g (n = 116), 4.0 g (n = 58), 8.2 g (n = 57) and 14.2 g (n = 23). The inverse relation between percentage of fish with metacercariae and fish weight is reflected in lower percentages of infected fish at higher weights [%infected = 100/(1 + e([-2.02+0.15 fish weight (g)])); p < 0.01], i.e. 89 %, 85 %, 63 % and 61 %, respectively, in the four groups. Control fish did not get infected. Attack rates were 0.0087, 0.0073, 0.0040 and 0.0033 fish infected per cercariae, respectively; the first two attack rates being significantly higher than the latter two. Mean number of metacercariae per weight group was 5, 5, 2 and 1, respectively, (p < 0.05), with an inverse relation using weight as continuous explanatory variable [p < 0.01; number metacercariae = e(1.76-0.13fish weight(g))]. Concluding, an inverse relation exists between fish weight and probability of infection, attack rate and parasite burden in common carp fingerlings. Reducing transmission to fingerlings might be an effective intervention method to improve food safety, reduce the absolute amount of FZTs in the environment and eventually reduce incidence in humans. PMID- 22488203 TI - Sensory feedback alters spontaneous limb movements in newborn rats: effects of unilateral forelimb weighting. AB - Perinatal mammals show spontaneous movements that often appear random and uncoordinated. Here, we examined if spontaneous limb movements are responsive to a proprioceptive manipulation by applying a weight unilaterally to a forelimb of postnatal day 0 (P0; day of birth) and P1 rats. Weights were calibrated to approximate 0%, 25%, 50%, or 100% of the average mass of a forelimb, and were attached at the wrist. P0 and P1 pups showed different levels of activity during the period of limb weighting, in response to weight removal, and during the period after weighting. Pups exposed to 50% and 100% weights showed proportionately more activity in the nonweighted forelimb during the period of weighting, suggesting a threshold for evoking proprioceptive changes. Findings suggest that newborn rats use movement-related feedback to modulate spontaneous motor activity, and corroborate studies of human infants that have suggested a role for proprioception during early motor development. PMID- 22488204 TI - A new method for measuring meal intake in humans via automated wrist motion tracking. AB - Measuring the energy intake (kcal) of a person in day-to-day life is difficult. The best laboratory tool achieves 95 % accuracy on average, while tools used in daily living typically achieve 60-80 % accuracy. This paper describes a new method for measuring intake via automated tracking of wrist motion. Our method uses a watch-like device with a micro-electro-mechanical gyroscope to detect and record when an individual has taken a bite of food. Two tests of the accuracy of our device in counting bites found that our method has 94 % sensitivity in a controlled meal setting and 86 % sensitivity in an uncontrolled meal setting, with one false positive per every 5 bites in both settings. Preliminary data from daily living indicates that bites measured by the device are positively related to caloric intake illustrating the potential of the device to monitor energy intake. Future research should seek to further explore the relationship between bites taken and kilocalories consumed to validate the device as an automated measure of energy intake. PMID- 22488205 TI - A lower prevalence of self-reported fear of falling is associated with memory decline among older adults. AB - BACKGROUND: In spite of a number of reports about various factors associated with the fear of falling (FoF) among older adults (such as age and physical function), the relationship between FoF and cognitive decline remains unclear. OBJECTIVE: To determine which cognitive function is related with the prevalence of FoF in older adults. METHODS: Participants were 101 older adults (mean age 75.1 years; 48.5% males). Of these, 54 older adults (53.4%) were classified as the fear group on the basis of the presence of FoF. Age, gender, the Timed Up and Go test (TUG), fall history, the Alzheimer's Disease Assessment Scale, the Wechsler Memory Scale Revised-Logical Memory I (WMS-LM I), the delayed memory test, digit symbol coding, digit span and verbal fluency were measured as potential relevant factors. RESULTS: Logistic regression analysis revealed that TUG [odds ratio (OR) 1.43, 95% confidence interval (CI) 1.12-1.83; p = 0.004], WMS-LM I (OR 1.20, 95% CI 1.07-1.35; p = 0.002) and fall history (OR 4.38, 95% CI 1.53-12.51; p = 0.006) were independently associated with FoF. CONCLUSIONS: The results suggest that a lower prevalence of self-reported FoF is associated with memory decline among older adults. Insensitivity to FoF may be one of the characteristics of psychological change with memory decline. PMID- 22488206 TI - Three medication pathways for bipolar disorder. PMID- 22488207 TI - Malignant hyperthermia: turn down the heat. PMID- 22488208 TI - Remineralisation by chewing sugar-free gums in a randomised, controlled in situ trial including dietary intake and gauze to promote plaque formation. AB - Remineralisation has been shown to be an effective mechanism of preventing the progression of enamel caries. The aim of this double-blind, randomised, cross over in situ study was to compare enamel remineralisation by chewing sugar-free gum with or without casein phosphopeptide amorphous calcium phosphate (CPP-ACP) where the enamel lesions were exposed to dietary intake and some were covered with gauze to promote plaque formation. Participants wore removable palatal appliances containing 3 recessed enamel half-slabs with subsurface lesions covered with gauze and 3 without gauze. Mineral content was measured by transverse microradiography, and plaque composition was analysed by real-time polymerase chain reaction. For both the gauze-free and gauze-covered lesions, the greatest amount of remineralisation was produced by the CPP-ACP sugar-free gum, followed by the gum without CPP-ACP and then the no-gum control. Recessing the enamel in the appliance allowed plaque accumulation without the need for gauze. There was a trend of less remineralisation and greater variation in mineral content for the gauze-covered lesions. The cell numbers of total bacteria and streptococci were slightly higher in the plaque from the gauze-covered enamel for 2 of the 3 treatment legs; however, there was no significant difference in Streptococcus mutans cell numbers. In conclusion, chewing sugar-free gum containing CPP-ACP promoted greater levels of remineralisation than a sugar-free gum without CPP-ACP or a no-gum control using an in situ remineralisation model including dietary intake irrespective of whether gauze was used to promote plaque formation or not. PMID- 22488209 TI - The alphabet soup of perfusion CT and MR imaging: terminology revisited and clarified in five questions. AB - The five questions answered in this article revolve around the different parameters resulting from perfusion imaging processing, and this clarifies the frequently confusing terminology used to describe these parameters. More specifically, the article discusses the different imaging techniques and main mathematical models behind perfusion imaging, reviews the perfusion attributes of brain tissue, and proposes a standardized parameter terminology to facilitate understanding and avoid common misinterpretations. PMID- 22488210 TI - Follow-up after embolization of ruptured intracranial aneurysms: a prospective comparison of two-dimensional digital subtraction angiography, three-dimensional digital subtraction angiography, and time-of-flight magnetic resonance angiography. AB - INTRODUCTION: To prospectively compare of the diagnostic value of digital subtraction angiography (DSA) and time-of-flight magnetic resonance angiography (TOF-MRA) in the follow-up of intracranial aneurysms after endovascular treatment. METHODS: Seventy-two consecutive patients were examined 3 months after the embolization. The index tests included: two-dimensional DSA (2D-DSA), three dimensional DSA (3D-DSA), and TOF-MRA. The reference test was a retrospective consensus between 2D-DSA images, 3D-DSA images, and source rotational DSA images. The evaluation included: detection of the residual flow, quantification of the flow, and validity of the decision regarding retreatment. Intraobserver agreement and interobserver agreement were determined. RESULTS: The sensitivity and specificity of residual flow detection ranged from 84.6 % (2D-DSA and TOF-MRA) to 92.3 % (3D-DSA) and from 91.3 % (TOF-MRA) to 97.8 % (3D-DSA), respectively. The accuracy of occlusion degree evaluation ranged from 0.78 (2D-DSA) to 0.92 (3D DSA, Cohen's kappa). The 2D-DSA method presented lower performance in the decision on retreatment than 3D-DSA (P < 0.05, ROC analysis). The intraobserver agreement was very good for all techniques (kappa = 0.80-0.97). The interobserver agreement was moderate for TOF-MRA and very good for 2D-DSA and 3D-DSA (kappa = 0.72-0.94). CONCLUSION: Considering the invasiveness of DSA and the minor difference in the diagnostic performance between 3D-DSA and TOF-MRA, the latter method should be the first-line modality for follow-up after aneurysm embolization. PMID- 22488211 TI - Inhaled low-dose iloprost for pulmonary hypertension: a prospective, multicenter, open-label study. AB - BACKGROUND: Inhaled iloprost (average >30 ug/d) has been considered an effective treatment for severe pulmonary hypertension (PH). Further evidence also showed that low-dose iloprost given intravenously was equally effective as high-dose iloprost in the therapy of systemic sclerosis. HYPOTHESIS: Patients with pulmonary hypertension will benefit from inhalation of low-dose iloprost. METHODS: Sixty-two patients with PH were enrolled and initiated with neubulizedlow-dose iloprost (2.5 ug per inhalation, 6* daily) for 24 weeks in 13 medical centers in China. Efficacy endpoints included changes in 6-minute walk distance (6MWD), World Health Organization functional class (WHO-FC), and hemodynamic parameters. RESULTS: Fourteen patients (22.6%) prematurely discontinued the study: 8 due to clinical worsening (6 in WHO-FCIII-IV at baseline), 4 because of protocol change, and 2 patients lost during follow-up. In the remaining 48 patients, 6MWD was increased from 356 +/- 98 meters to 414 +/- 99 meters (P < 0.001) and WHO-FC improved significantly (P = 0.006) after 24-week inhalation therapy. Cardiac output, cardiac index, and mixed venous oxygen saturation improved significantly compared with baseline (n = 34, P < 0.05). Most of the hemodynamic parameters improved significantly in patients in WHO-FC II (P < 0.05) but not in patients in WHO-FCIII-IV. CONCLUSIONS: Low-dose iloprost inhalation significantly improved exercise capacity and functional status in patients with PH. It was well tolerated. The improvement of hemodynamics was confirmed in patients with WHO-FCI-II but not in patients with WHO-FCIII-IV, suggesting the importance of early treatment in patients with advanced disease stages. PMID- 22488212 TI - SMARTER crystallography of the fluorinated inorganic-organic compound Zn3Al2F12.[HAmTAZ]6. AB - We present in this paper the structure resolution of a fluorinated inorganic organic compound--Zn(3)Al(2)F(12).[HAmTAZ](6)--by SMARTER crystallography, i.e. by combining powder X-ray diffraction crystallography, NMR crystallography and chemical modelling of crystal (structure optimization and NMR parameter calculations). Such an approach is of particular interest for this class of fluorinated inorganic-organic compound materials since all the atoms have NMR accessible isotopes ((1)H, (13)C, (15)N, (19)F, (27)Al, (67)Zn). In Zn(3)Al(2)F(12).[HAmTAZ](6), (27)Al and high-field (19)F and (67)Zn NMR give access to the inorganic framework while (1)H, (13)C and (15)N NMR yield insights into the organic linkers. From these NMR experiments, parts of the integrant unit are determined and used as input data for the search of a structural model from the powder diffraction data. The optimization of the atomic positions and the calculations of NMR parameters ((27)Al and (67)Zn quadrupolar parameters and (19)F, (1)H, (13)C and (15)N isotropic chemical shifts) are then performed using a density functional theory (DFT) based code. The good agreement between experimental and DFT-calculated NMR parameters validates the proposed optimized structure. The example of Zn(3)Al(2)F(12).[HAmTAZ](6) shows that structural models can be obtained in fluorinated hybrids by SMARTER crystallography on a polycrystalline powder with an accuracy similar to those obtained from single crystal X-ray diffraction data. PMID- 22488213 TI - Transcriptional regulation of platelet-derived growth factor-B chain by thrombin in endothelial cells: involvement of Egr-1 and CREB-binding protein. AB - Thrombin and platelet-derived growth factor-B chain (PDGF-B) are key factors in the stimulation of atherosclerosis. The effect of thrombin on PDGF-B production has been characterized. However, the underlying mechanism is still far clear. Here, we investigate the transcription factors and regulators that are involved in PDGF-B production caused by thrombin in endothelial cells (ECs). Levels of PDGF were analyzed by real-time RT-PCR and ELISA, while levels of early growth response-1 (Egr-1) were analyzed by real-time RT-PCR and western blot. To evaluate the function of CBP and Egr-1 involved in regulation of PDGF-B, small interfering RNA (siRNA) were used to down-regulate their expression in mRNA and protein level. Interaction of Egr-1 and CBP was measured with immunoprecipitation and western blot. Thrombin induced an early and transient up-regulation of transcription factor early Egr-1, which was followed by a delayed increase of PDGF-B. siRNA against Egr-1-inhibited thrombin-induced PDGF-B production. Furthermore, thrombin could enhance the interaction of Egr-1 with its co activator CREB-binding protein (CBP). CBP knockdown attenuated this interaction, and led to a reduction of PDGF-B expression induced by thrombin. Our results suggest that CBP might be one of the main interaction targets for Egr-1, and the transient activation of Egr-1 and recruitment of CBP are required for thrombin induced PDGF-B in ECs. PMID- 22488215 TI - Mastoid obliteration with concha cartilage graft and temporal muscle fascia. AB - AIM: The aim of our study was to describe an effective technique for mastoid cavity obliteration in canal wall down tympanomastoidectomy for chronic otitis media and to review its efficacy in producing a dry, low-maintenance, small mastoid cavity. MATERIAL AND METHOD: A retrospective clinical study of 56 consecutive patients undergoing procedures for active chronic otitis media with cholesteatoma has been carried out. All surgical interventions involved partial mastoid obliteration and restoration of the middle ear space by use of cartilage reconstruction of the tympanic membrane. Ossicular reconstruction was achieved with either a partial or total ossicular replacement prosthesis. RESULTS: A completely dry cavity was achieved in 49 of 56 patients (approx. 88%, 95% confidence interval 77-95%). An overall statistically significant improvement in hearing (p < 0.05) was obtained, with the mean pure-tone average air-bone gap decreasing from 33.4 +/- 8.2 dB (average +/- SD) to 18.3 +/- 9.7 dB. There were no residual or recurrent cholesteatomas. CONCLUSION: Cartilage reconstruction of the tympanic membrane proved to be a useful adjunct in the surgical management of the chronically draining cavity. PMID- 22488214 TI - Transplantation of microencapsulated Schwann cells and mesenchymal stem cells augment angiogenesis and improve heart function. AB - Because of their plasticity and availability, bone-marrow-derived mesenchymal stem cells (MSC) are a potential cell source for treating ischemic heart disease. Schwann cells (SC) play a critical role in neural remodeling and angiogenesis because of their secretion of cytokines such as vascular endothelial growth factor (VEGF). Cell microencapsulation, surrounding cells with a semipermeable polymeric membrane, is a promising tool to shelter cells from the recipient's immune system. We investigated whether transplantation of microencapsulated SC (MC-SC) and MSC together could improve heart function by augmenting angiogenesis in acute myocardial infarction (AMI). Sprague-Dawley rats with ligation of the left anterior descending artery to induce AMI were randomly divided for cell transplantation into four groups-MC-SC+MSC, MC+MSC, MSC, MC-SC, and controls. Echocardiography was performed at 3 days and 2 and 4 weeks after AMI. Rat hearts were harvested on day 28 after transplantation and examined by immunohistochemistry and western blot analysis. Echocardiography revealed differences among the groups in fractional shortening and end-systolic and end diastolic dimensions (P < 0.05). The number of BrdU-positive cells was greater with MC-SC+MSC transplantation than the other groups (P < 0.01). The vessel density and VEGF level in the infarcted zone was significantly increased with MC SC+MSC transplantation (P < 0.05). These results show that transplanting a combination of MC-SC and MSC could augment angiogenesis and improve heart function in AMI. PMID- 22488216 TI - Cloning, mutagenesis, and characterization of the microalga Parietochloris incisa acetohydroxyacid synthase, and its possible use as an endogenous selection marker. AB - Parietochloris incisa is an oleaginous fresh water green microalga that accumulates an unusually high content of the valuable long-chain polyunsaturated fatty acid (LC-PUFA) arachidonic acid within triacylglycerols in cytoplasmic lipid bodies. Here, we describe cloning and mutagenesis of the P. incisa acetohydroxyacid synthase (PiAHAS) gene for use as an herbicide resistance selection marker for transformation. Use of an endogenous gene circumvents the risks and regulatory difficulties of cultivating antibiotic-resistant organisms. AHAS is present in plants and microorganisms where it catalyzes the first essential step in the synthesis of branched-chain amino acids. It is the target enzyme of the herbicide sulfometuron methyl (SMM), which effectively inhibits growth of bacteria and plants. Several point mutations of AHAS are known to confer herbicide resistance. We cloned the cDNA that encodes PiAHAS and introduced a W605S point mutation (PimAHAS). Catalytic activity and herbicide resistance of the wild-type and mutant proteins were characterized in the AHAS deficient E. coli, BUM1 strain. Cloned PiAHAS wild-type and mutant genes complemented AHAS-deficient bacterial growth. Furthermore, bacteria expressing the mutant PiAHAS exhibited high resistance to SMM. Purified PiAHAS wild-type and mutant proteins were assayed for enzymatic activity and herbicide resistance. The W605S mutation was shown to cause a twofold decrease in enzymatic activity and in affinity for the Pyruvate substrate. However, the mutant exhibited 7 orders of magnitude higher resistance to the SMM herbicide than that of the wild type. PMID- 22488217 TI - Direct asymmetric Mannich reaction of phthalides: facile access to chiral substituted isoquinolines and isoquinolinones. AB - The first Mannich reaction employing phthalides using a quinidine-based multifunctional catalyst has been developed. The reported method led to the synthesis of 3,3-disubstituted phthalide derivatives in excellent yields, with good diastereo- and enantioselectivities. Convenient synthesis of chiral isoquinolinones and isoquinolines has also been demonstrated. PMID- 22488219 TI - Pretransplant HLA mistyping in diagnostic samples of acute myeloid leukemia patients due to acquired uniparental disomy. AB - Although acquired uniparental disomy (aUPD) has been reported in relapse acute myeloid leukemia (AML), pretransplant aUPD involving chromosome 6 is poorly documented. Such events could be of interest because loss of heterozygosity (LOH) resulting from aUPD in leukemic cells may lead to erroneous results if HLA typing for hematopoietic stem cell donor searches is performed on blood samples drawn during blastic crisis. We report here six AML patients whose HLA typing was performed on DNA extracted from peripheral blood obtained at diagnosis. We observed LOH involving the entire HLA region (three patients), HLA-A, B, C (two patients) and HLA-A only (one patient). An array-comparative genomic hybridization showed that copy number was neutral for all loci, thus revealing partial aUPD of chromosome 6p21. When HLA typing was performed on remission blood samples both haplotypes were detected. A 3-4% LOH incidence was estimated in AML patients with high blast counts. Based on DNA mixing experiments, we determined by PCR sequence-specific oligonucleotide hybridization on microbeads arrays a detection threshold for HLA-A, B, DRB1 heterozygosity in blood samples with <80% blasts. Because aUPD may be partial, any homozygous HLA result should be confirmed by a second typing performed on buccal swabs or on blood samples from the patient in remission. PMID- 22488218 TI - Autoimmune epididymoorchitis is essential to the pathogenesis of male-specific spondylarthritis in HLA-B27-transgenic rats. AB - OBJECTIVE: Male rats transgenic for HLA-B27 and human beta(2) -microglobulin (hbeta(2) m) spontaneously develop epididymoorchitis (EO) preceding the development of spondylarthritis (SpA). In the specific B27/hbeta(2) m-transgenic rat cross-strain (21-3 * 382-2)F(1) , only the males develop SpA, and neither sex develops gut inflammation. This study was undertaken to determine whether EO and SpA in male (21-3 * 382-2)F(1) rats are causally related. In addition, the primary characteristics of EO in this rat arthritis model were assessed. METHODS: Male B27/hbeta(2) m-transgenic (21-3 * 382-2)F(1) rats underwent bilateral, unilateral, or sham epididymoorchiectomy between ages 36 and 125 days. The castrated rats were given testosterone replacement. Alternatively, the 21-3 and 283-2 transgene loci were crossed with a transgene inducing aspermatogenesis. Rats were observed for the development of EO, arthritis, and spondylitis. RESULTS: In unmanipulated transgenic rats, inflammation was first evident in the ductuli efferentes (DE; ducts linking the rete testis to epididymis) as early as age 30 days. The inflammation was initially neutrophilic, and later became granulomatous. Antisperm and anti-testis cell antibodies appeared in the rat serum after age 70 days. Cells infiltrating the testes were predominantly CD4+ T cells and CD68+ or CD163+ macrophages. Quantitative polymerase chain reaction of the DE, epididymis, and testis showed elevations in the levels of interferon gamma, interleukin-10 (IL-10), and IL-17A. In addition, levels of IL-12A, IL-22, IL-23A, and IL-23 receptor were found to be elevated in the DE. Remarkably, castration of the rats before age 91 days completely prevented the subsequent onset of arthritis and spondylitis, as did transgene-induced azospermia. CONCLUSION: Autoimmune EO develops spontaneously in HLA-B27/hbeta(2) m-transgenic (21-3 * 283-2)F(1) rats at age 30 days, the age when antigen-positive meiotic germ cells first exit the testis. Persistent testicular inflammation and/or antigenic stimulation are essential prerequisites for the subsequent development of SpA. Thus, dysregulated innate immunity at immune-privileged sites may be an essential mechanism triggering the onset of SpA. PMID- 22488220 TI - Reducing postpartum depressive symptoms among black and Latina mothers: a randomized controlled trial. AB - OBJECTIVE: To estimate the effectiveness of a behavioral educational intervention to reduce postpartum depressive symptoms among minority mothers. METHODS: We recruited 540 self-identified black and Latina mothers during their postpartum hospital stay and randomized them to receive a behavioral educational intervention or enhanced usual care. Those in the intervention arm received a two step behavioral educational intervention that prepares and educates mothers about modifiable factors associated with symptoms of postpartum depression (physical symptoms, low social support, low self-efficacy, and infant factors), bolsters social support, enhances management skills, and increases participants' access to resources. Enhanced usual care participants received a list of community resources and received a 2-week control call. Participants were surveyed before randomization and, 3 weeks, 3 months, and 6 months later to assess depressive symptoms. The primary outcome, depression, was assessed using the Edinburgh Postnatal Depression Scale (score of 10 or greater). RESULTS: Positive depression screens were less common among intervention compared with enhanced usual care posthospitalization: 3 weeks (8.8% compared with 15.3%, P=.03), 3 months (8.4% compared with 13.24%, P=.09), and 6 months (8.9% compared with 13.7%, P=.11). An intention-to-treat repeated-measures analysis for up to 6 months of follow-up demonstrated that mothers in the intervention group were less likely to screen positive for depression compared with enhanced usual care (odds ratio 0.67, 95% confidence interval [CI] 0.47-0.97; number needed to treat 16, 95% CI 9-112). CONCLUSION: An action-oriented behavioral educational intervention reduced positive depression screens among black and Latina postpartum mothers. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, www.clinicaltrials.gov, NCT01312883. LEVEL OF EVIDENCE: I. PMID- 22488221 TI - Mechanisms of endothelial dysfunction in obesity-associated hypertension. AB - Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular function and a better understanding of how vascular function can be influenced by these systems would facilitate the development of new therapies for treatment of obesity-associated hypertension. PMID- 22488222 TI - Human sepsis-associated Escherichia coli (SEPEC) is able to adhere to and invade kidney epithelial cells in culture. AB - The adhesins of extraintestinal pathogenic Escherichia coli are essential for mediating direct interactions between the microbes and the host cell surfaces that they infect. Using fluorescence microscopy and gentamycin protection assays, we observed that 49 sepsis-associated E. coli (SEPEC) strains isolated from human adults adhered to and invaded Vero cells in the presence of D-mannose (100%). In addition, bacteria concentrations of approximately 2 x 10(7) CFU/mL were recovered from Vero cells following an invasion assay. Furthermore, PCR analysis of adhesin genes showed that 98.0% of these SEPEC strains tested positive for fimH, 69.4% for flu, 53.1% for csgA, 38.8% for mat, and 32.7% for iha. Analysis of the invasin genes showed that 16.3% of the SEPEC strains were positive for tia, 12.3% for gimB, and 10.2% for ibeA. Therefore, these data suggest that SEPEC adhesion to cell surfaces occurs through non-fimH mechanisms. Scanning electron microscopy showed the formation of microcolonies on the Vero cell surface. SEPEC invasiveness was also confirmed by the presence of intracellular bacteria, and ultrastructural analysis using electron transmission microscopy revealed bacteria inside the Vero cells. Taken together, these results demonstrate that these SEPEC strains had the ability to adhere to and invade Vero cells. Moreover, these data support the theory that renal cells may be the predominant pathway through which SEPEC enters human blood vessels. PMID- 22488223 TI - Analysis of acylcarnitine profiles in umbilical cord blood and during the early neonatal period by electrospray ionization tandem mass spectrometry. AB - Acylcarnitine profiling by electrospray ionization tandem mass spectrometry (ESI MS/MS) is a potent tool for the diagnosis and screening of fatty acid oxidation and organic acid disorders. Few studies have analyzed free carnitine and acylcarnitines in dried blood spots (DBS) of umbilical cord blood (CB) and the postnatal changes in the concentrations of these analytes. We have investigated these metabolites in healthy exclusively breastfed neonates and examined possible effects of birth weight and gestational age. DBS of CB were collected from 162 adequate for gestational age neonates. Paired DBS of heel-prick blood were collected 4-8 days after birth from 106 of these neonates, the majority exclusively breastfed. Methanol extracts of DBS with deuterium-labeled internal standards were derivatized before analysis by ESI-MS/MS. Most of the analytes were measured using a full-scan method. The levels of the major long-chain acylcarnitines, palmitoylcarnitine, stearoylcarnitine, and oleoylcarnitine, increased by 27, 12, and 109%, respectively, in the first week of life. Free carnitine and acetylcarnitine had a modest increase: 8 and 11%, respectively. Propionylcarnitine presented a different behavior, decreasing 9% during the period. The correlations between birth weight or gestational age and the concentrations of the analytes in DBS were weak (r <= 0.20) or nonsignificant. Adaptation to breast milk as the sole source of nutrients can explain the increase of these metabolites along the early neonatal period. Acylcarnitine profiling in CB should have a role in the early detection of metabolic disorders in high-risk neonates. PMID- 22488224 TI - Lymphatic fluctuation in the parenchymal remodeling stage of acute interstitial pneumonia, organizing pneumonia, nonspecific interstitial pneumonia and idiopathic pulmonary fibrosis. AB - Because the superficial lymphatics in the lungs are distributed in the subpleural, interlobular and peribroncovascular interstitium, lymphatic impairment may occur in the lungs of patients with idiopathic interstitial pneumonias (IIPs) and increase their severity. We investigated the distribution of lymphatics in different remodeling stages of IIPs by immunohistochemistry using the D2-40 antibody. Pulmonary tissue was obtained from 69 patients with acute interstitial pneumonia/diffuse alveolar damage (AIP/DAD, N = 24), cryptogenic organizing pneumonia/organizing pneumonia (COP/OP, N = 6), nonspecific interstitial pneumonia (NSIP/NSIP, N = 20), and idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP, N = 19). D2-40+ lymphatic in the lesions was quantitatively determined and associated with remodeling stage score. We observed an increase in the D2-40+ percent from DAD (6.66 +/- 1.11) to UIP (23.45 +/- 5.24, P = 0.008) with the advanced process of remodeling stage of the lesions. Kaplan-Meier survival curves showed a better survival for patients with higher lymphatic D2-40+ expression than 9.3%. Lymphatic impairment occurs in the lungs of IIPs and its severity increases according to remodeling stage. The results suggest that disruption of the superficial lymphatics may impair alveolar clearance, delay organ repair and cause severe disease progress mainly in patients with AIP/DAD. Therefore, lymphatic distribution may serve as a surrogate marker for the identification of patients at greatest risk for death due to IIPs. PMID- 22488225 TI - Acute lower extremity running kinematics after a hamstring stretch. AB - CONTEXT: Limited passive hamstring flexibility might affect kinematics, performance, and injury risk during running. Preactivity static straight-leg raise stretching often is used to gain passive hamstring flexibility. OBJECTIVE: To investigate the acute effects of a single session of passive hamstring stretching on pelvic, hip, and knee kinematics during the swing phase of running. DESIGN: Randomized controlled clinical trial. SETTING: Biomechanics research laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-four male (age = 21.2 +/- 1.4 years) and female (age = 21.3 +/- 2.0 years) recreational athletes. INTERVENTION(S): Participants performed treadmill running pretests and posttests at 70% of their age-predicted maximum heart rate. Pelvis, hip, and knee joint angles during the swing phase of 5 consecutive gait cycles were collected using a motion analysis system. Right and left hamstrings of the intervention group participants were passively stretched 3 times for 30 seconds in random order immediately after the pretest. Control group participants performed no stretching or movement between running sessions. MAIN OUTCOME MEASURE(S): Six 2-way analyses of variance to determine joint angle differences between groups at maximum hip flexion and maximum knee extension with an alpha level of .008. RESULTS: Flexibility increased between pretest and posttest in all participants (F(1,30) = 80.61, P < .001). Anterior pelvic tilt (F(1,30) = 0.73, P = .40), hip flexion (F(1,30) = 2.44, P = .13), and knee extension (F(1,30) = 0.06, P = .80) at maximum hip flexion were similar between groups throughout testing. Anterior pelvic tilt (F(1,30) = 0.69, P = .41), hip flexion (F(1,30) = 0.23, P = .64), and knee extension (F(1,30) = 3.38, P = .62) at maximum knee extension were similar between groups throughout testing. Men demonstrated greater anterior pelvic tilt than women at maximum knee extension (F(1,30) = 13.62, P = .001). CONCLUSIONS: A single session of 3 straight-leg raise hamstring stretches did not change pelvis, hip, or knee running kinematics. PMID- 22488226 TI - Hip muscle activity during 3 side-lying hip-strengthening exercises in distance runners. AB - CONTEXT: Lower extremity overuse injuries are associated with gluteus medius (GMed) weakness. Understanding the activation of muscles about the hip during strengthening exercises is important for rehabilitation. OBJECTIVE: To compare the electromyographic activity produced by the gluteus medius (GMed), tensor fascia latae (TFL), anterior hip flexors (AHF), and gluteus maximus (GMax) during 3 hip-strengthening exercises: hip abduction (ABD), hip abduction with external rotation (ABD-ER), and clamshell (CLAM) exercises. DESIGN: Controlled laboratory study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty healthy runners (9 men, 11 women; age = 25.45 +/- 5.80 years, height = 1.71 +/- 0.07 m, mass = 64.43 +/- 7.75 kg) participated. INTERVENTION(S): A weight equal to 5% body mass was affixed to the ankle for the ABD and ABD-ER exercises, and an equivalent load was affixed for the CLAM exercise. A pressure biofeedback unit was placed beneath the trunk to provide positional feedback. MAIN OUTCOME MEASURE(S): Surface electromyography (root mean square normalized to maximal voluntary isometric contraction) was recorded over the GMed, TFL, AHF, and GMax. RESULTS: Three 1-way, repeated-measures analyses of variance indicated differences for muscle activity among the ABD (F(3,57) = 25.903, P < .001), ABD ER (F(3,57) = 10.458, P < .001), and CLAM (F(3,57) = 4.640, P = .006) exercises. For the ABD exercise, the GMed (70.1 +/- 29.9%), TFL (54.3 +/- 19.1%), and AHF (28.2 +/- 21.5%) differed in muscle activity. The GMax (25.3 +/- 24.6%) was less active than the GMed and TFL but was not different from the AHF. For the ABD-ER exercise, the TFL (70.9 +/- 17.2%) was more active than the AHF (54.3 +/- 24.8%), GMed (53.03 +/- 28.4%), and GMax (31.7 +/- 24.1%). For the CLAM exercise, the AHF (54.2 +/- 25.2%) was more active than the TFL (34.4 +/- 20.1%) and GMed (32.6 +/- 16.9%) but was not different from the GMax (34.2 +/- 24.8%). CONCLUSIONS: The ABD exercise is preferred if targeted activation of the GMed is a goal. Activation of the other muscles in the ABD-ER and CLAM exercises exceeded that of GMed, which might indicate the exercises are less appropriate when the primary goal is the GMed activation and strengthening. PMID- 22488227 TI - Lumbopelvic joint manipulation and quadriceps activation of people with patellofemoral pain syndrome. AB - CONTEXT: Quadriceps weakness and inhibition are impairments associated with patellofemoral pain syndrome (PFPS). Lumbopelvic joint manipulation has been shown to improve quadriceps force output and inhibition, but the duration of the effect is unknown. OBJECTIVE: To determine whether quadriceps strength and activation are increased and maintained for 1 hour after high-grade or low-grade joint mobilization or manipulation applied at the lumbopelvic region in people with PFPS. DESIGN: Randomized controlled clinical trial. SETTING: University laboratory. PATIENTS OR OTHER PARTICIPANTS: Forty-eight people with PFPS (age = 24.6 +/- 8.9 years, height = 174.3 +/- 11.2 cm, mass = 78.4 +/- 16.8 kg) participated. INTERVENTION(S): Participants were randomized to 1 of 3 groups: lumbopelvic joint manipulation (grade V), side-lying lumbar midrange flexion and extension passive range of motion (grade II) for 1 minute, or prone extension on the elbows for 3 minutes. MAIN OUTCOME MEASURE(S): Quadriceps force and activation were measured using the burst superimposition technique during a seated isometric knee extension task. A 2-way repeated-measures analysis of variance was performed to compare changes in quadriceps force and activation among groups over time (before intervention and at 0, 20, 40, and 60 minutes after intervention). RESULTS: We found no differences in quadriceps force output (F(5.33,101.18) = 0.65, P = .67) or central activation ratio (F(4.84,92.03) = 0.38, P = .86) values among groups after intervention. When groups were pooled, we found differences across time for quadriceps force (F(2.66,101.18) = 5.03, P = .004) and activation (F(2.42,92.03) = 3.85, P = .02). Quadriceps force was not different at 0 minutes after intervention (t(40) = 1.68, P = .10), but it decreased at 20 (t(40) = 2.16, P = .04), 40 (t(40) = 2.87, P = .01) and 60 (t(40) = 3.04, P = .004) minutes after intervention. All groups demonstrated decreased quadriceps activation at 0 minutes after intervention (t(40) = 4.17, P < .001), but subsequent measures were not different from preintervention levels (t(40) range, 1.53-1.83, P > .09). CONCLUSIONS: Interventions directed at the lumbopelvic region did not have immediate effects on quadriceps force output or activation. Muscle fatigue might have contributed to decreased force output and activation over 1 hour of testing. PMID- 22488228 TI - Two different fatigue protocols and lower extremity motion patterns during a stop jump task. AB - CONTEXT: Altered neuromuscular control strategies during fatigue probably contribute to the increased incidence of noncontact anterior cruciate ligament injuries in female athletes. OBJECTIVE: To determine biomechanical differences between 2 fatigue protocols (slow linear oxidative fatigue protocol [SLO-FP] and functional agility short-term fatigue protocol [FAST-FP]) when performing a running-stop-jump task. DESIGN: Controlled laboratory study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A convenience sample of 15 female soccer players (age = 19.2 +/- 0.8 years, height = 1.67 +/- 0.05 m, mass = 61.7 +/- 8.1 kg) without injury participated. INTERVENTION(S): Five successful trials of a running stop-jump task were obtained prefatigue and postfatigue during the 2 protocols. For the SLO-FP, a peak oxygen consumption (Vo(2)peak) test was conducted before the fatigue protocol. Five minutes after the conclusion of the Vo(2)peak test, participants started the fatigue protocol by performing a 30-minute interval run. The FAST-FP consisted of 4 sets of a functional circuit. Repeated 2 (fatigue protocol) * 2 (time) analyses of variance were conducted to assess differences between the 2 protocols and time (prefatigue, postfatigue). MAIN OUTCOME MEASURE(S): Kinematic and kinetic measures of the hip and knee were obtained at different times while participants performed both protocols during prefatigue and postfatigue. RESULTS: Internal adduction moment at initial contact (IC) was greater during FAST-FP (0.064 +/- 0.09 Nm/kgm) than SLO-FP (0.024 +/- 0.06 Nm/kgm) (F(1,14) = 5.610, P = .03). At IC, participants had less hip flexion postfatigue (44.7 degrees +/- 8.1 degrees ) than prefatigue (50.1 degrees +/- 9.5 degrees ) (F(1,14) = 16.229, P = .001). At peak vertical ground reaction force, participants had less hip flexion postfatigue (44.7 degrees +/- 8.4 degrees ) than prefatigue (50.4 degrees +/- 10.3 degrees ) (F(1,14) = 17.026, P = .001). At peak vertical ground reaction force, participants had less knee flexion postfatigue (-35.9 degrees +/- 6.5 degrees ) than prefatigue (-38.8 degrees +/- 5.03 degrees ) (F(1,14) = 11.537, P = .001). CONCLUSIONS: Our results demonstrated a more erect landing posture due to a decrease in hip and knee flexion angles in the postfatigue condition. The changes were similar between protocols; however, the FAST-FP was a clinically applicable 5-minute protocol, whereas the SLO-FP lasted approximately 45 minutes. PMID- 22488229 TI - Can a rescuer or simulated patient accurately assess motion during cervical spine stabilization practice sessions? AB - CONTEXT: Health care providers must be prepared to manage all potential spine injuries as if they are unstable. Therefore, most sport teams devote resources to training for sideline cervical spine (C-spine) emergencies. OBJECTIVE: To determine (1) how accurately rescuers and simulated patients can assess motion during C-spine stabilization practice and (2) whether providing performance feedback to rescuers influences their choice of stabilization technique. DESIGN: Crossover study. SETTING: Training studio. PATIENTS OR OTHER PARTICIPANTS: Athletic trainers, athletic therapists, and physiotherapists experienced at managing suspected C-spine injuries. INTERVENTION(S): Twelve lead rescuers (at the patient's head) performed both the head-squeeze and trap-squeeze C-spine stabilization maneuvers during 4 test scenarios: lift-and-slide and log-roll placement on a spine board and confused patient trying to sit up or rotate the head. MAIN OUTCOME MEASURE(S): Interrater reliability between rescuer and simulated patient quality scores for subjective evaluation of C-spine stabilization during trials (O = best, 10 = worst), correlation between rescuers' quality scores and objective measures of motion with inertial measurement units, and frequency of change in preference for the head-squeeze versus trap-squeeze maneuver. RESULTS: Although the weighted kappa value for interrater reliability was acceptable (0.71-0.74), scores varied by 2 points or more between rescuers and simulated patients for approximately 10% to 15% of trials. Rescuers' scores correlated with objective measures, but variability was large: 38% of trials scored as 0 or 1 by the rescuer involved more than 10 degrees of motion in at least 1 direction. Feedback did not affect the preference for the lift-and-slide placement. For the log-roll placement, 6 of 8 participants who preferred the head squeeze at baseline preferred the trap squeeze after feedback. For the confused patient, 5 of 5 participants initially preferred the head squeeze but preferred the trap squeeze after feedback. CONCLUSIONS: Rescuers and simulated patients could not adequately assess performance during C-spine stabilization maneuvers without objective measures. Providing immediate feedback in this context is a promising tool for changing behavior preferences and improving training. PMID- 22488230 TI - Reliability of thoracic spine rotation range-of-motion measurements in healthy adults. AB - CONTEXT: The reliability of clinical techniques to quantify thoracic spine rotation range of motion (ROM) has not been evaluated. OBJECTIVE: To determine the intratester and intertester reliability of 5 thoracic rotation measurement techniques. DESIGN: Descriptive laboratory study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: Forty-six healthy volunteers (age = 23.6 +/- 4.3 years, height = 171.0 +/- 9.6 cm, mass = 71.4 +/- 16.7 kg). MAIN OUTCOME MEASURE(S): We tested 5 thoracic rotation ROM techniques over 2 days: seated rotation (bar in back and front), half-kneeling rotation (bar in back and front), and lumbar-locked rotation. On day 1, 2 examiners obtained 2 sets of measurements (sessions 1, 2) to determine the within-session intertester reliability and within-day intratester reliability. A single examiner obtained measurements on day 2 (session 3) to determine the intratester reliability between days. Each technique was performed 3 times per side, and averages were used for data analysis. Reliability was determined using intraclass correlation coefficients, standard error of measurement (SEM), and minimal detectable change (MDC). Differences between raters during session 1 were determined using paired t tests. RESULTS: Within-session intertester reliability estimates ranged from 0.85 to 0.94. Ranges for the SEM were 1.0 degrees to 2.3 degrees and for the MDC were 2.8 degrees to 6.3 degrees . No differences were seen between examiners during session 1 for seated rotation (bar in front, both sides), half-kneeling rotation (bar in front, left side), or the lumbar locked position (both sides) (all values of P > .05). Within-day intratester reliability estimates ranged from 0.86 to 0.95. Ranges for the SEM were 0.8 degrees to 2.1 degrees and for the MDC were 2.1 degrees to 5.9 degrees . Between-days intratester reliability estimates ranged from 0.84 to 0.91. Ranges for the SEM were 1.4 degrees to 2.0 degrees and for the MDC were 3.9 degrees to 5.6 degrees . CONCLUSIONS: All techniques had good reliability and low levels of measurement error. The seated rotation, bar in front, and lumbar-locked rotation tests may be used reliably when more than 1 examiner is obtaining measurements. PMID- 22488231 TI - Whey protein addition to a carbohydrate-electrolyte rehydration solution ingested after exercise in the heat. AB - CONTEXT: Many active people finish exercise hypohydrated, so effective rehydration after exercise is an important consideration. OBJECTIVE: To determine the effects of a rehydration solution containing whey protein isolate on fluid balance after exercise-induced dehydration. DESIGN: Randomized controlled clinical trial. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: Twelve healthy men (age = 21 +/- 1 years, height = 1.82 +/- 0.08 m, mass = 82.71 +/- 10.31 kg) participated. INTERVENTION(S): Participants reduced body mass by 1.86% +/- 0.07% after intermittent exercise in the heat and rehydrated with a volume of drink in liters equivalent to 1.5 times their body mass loss in kilograms of a solution of either 65 g/L carbohydrate (trial C) or 50 g/L carbohydrate and 15 g/L whey protein isolate (trial CPl. Solutions were matched for energy density and electrolyte content. Urine samples were collected before and after exercise and for 4 hours after rehydration. MAIN OUTCOME MEASURE(S): We measured urine volume, drink retention, net fluid balance, urine osmolality, and subjective responses. Drink retention was calculated as the difference between the volume of drink ingested and urine produced. Net fluid balance was calculated from fluid gained through drink ingestion and fluid lost through sweat and urine production. RESULTS: Total cumulative urine output after rehydration was not different between trial C (1173 +/- 481 mL) and trial CP (1180 +/- 330 mL) (F(1) = 0.002, P = .96), and drink retention during the study also was not different between trial C (50% +/- 18%) and trial CP (49% +/- 13%) (t(11) = -0.159, P =.88). At the end of the study, net fluid balance was negative compared with baseline for trial C (-432 +/- 436 mL) (t(11) = 3.433, P = .03) and trial CP (-432 +/- 302 mL) (t(11) = 4.958, P = .003). CONCLUSIONS: When matched for energy density and electrolyte content, a solution of carbohydrate and whey protein isolate neither increased nor decreased rehydration compared with a solution of carbohydrate. PMID- 22488232 TI - Incidence and risk factors associated with meniscal injuries among active-duty US military service members. AB - CONTEXT: Few population-based studies have examined the incidence of meniscal injuries, and limited information is available on the influence of patient's demographic and occupational factors. OBJECTIVE: To examine the incidence of meniscal injuries and the influence of demographic and occupational factors among active-duty US service members between 1998 and 2006. DESIGN: Cohort study. SETTING: Using the International Classification of Diseases (9th revision) codes 836.0 (medial meniscus), 836.1 (lateral meniscus), and 836.2 (meniscus unspecified), we extracted injury data from the Defense Medical Surveillance System to identify all acute meniscal injuries among active-duty military personnel. PATIENTS OR OTHER PARTICIPANTS: Active-duty military personnel serving in all branches of military service during the study period. MAIN OUTCOME MEASURE(S): Incidence rate (IR) per 1000 person-years at risk and crude and adjusted rates by strata for age, sex, race, rank, and service. RESULTS: During the study period, 100201 acute meniscal injuries and 12115606 person-years at risk for injury were documented. The overall IR was 8.27 (95% confidence interval [CI] = 8.22, 8.32) per 1000 person-years. Main effects were noted for all demographic and occupational variables (P < .001), indicating that age, sex, race, rank, and service were associated with the incidence of meniscal injuries. Men were almost 20% more likely to experience an acute meniscal injury than were women (incidence rate ratio = 1.18, 95% CI = 1.15, 1.20). The rate of meniscal injury increased with age; those older than 40 years of age experienced injuries more than 4 times as often as those under 20 years of age (incidence rate ratio = 4.25, 95% CI=4.08,4.42). CONCLUSIONS: The incidence of meniscal injury was substantially higher in this study than in previously reported studies. Male sex, increasing age, and service in the Army or Marine Corps were factors associated with meniscal injuries. PMID- 22488233 TI - Menstrual irregularity and musculoskeletal injury in female high school athletes. AB - CONTEXT: The female athlete triad describes the interrelatedness of energy availability, menstrual function, and bone density. Although associations between triad components and musculoskeletal injury (INJ) have been reported in collegiate athletes, limited information exists about menstrual irregularity (MI) and INJ in the high school population. OBJECTIVE: To determine the prevalence of and relationship between MI and INJ in high school athletes. DESIGN: Cross sectional study. SETTING: High schools. PATIENTS OR OTHER PARTICIPANTS: The sample consisted of 249 female athletes from 3 high schools who competed in 33 interscholastic, school-sponsored sport teams, dance teams, and cheerleading or pom-pon squad during the 2006-2007 school year. Each athlete remained on the roster throughout the season. MAIN OUTCOME MEASURE(S): Participants completed a survey regarding injury type, number of days of sport participation missed, and menstrual history in the past year. RESULTS: The prevalences of M I and INJ were 19.7% and 63.1 %, respectively. Athletes who reported MI sustained a higher percentage of severe injuries (missing >= 22 days of practice or competition) than did athletes who reported normal menses. Although the trend was not significant, athletes with MI were almost 3 times more likely to sustain an injury resulting in 7 or more days of time lost from sport (odds ratio = 2.7, 95% confidence interval = 0.8, 8.8) than those who sustained an injury resulting in 7 or fewer days of time lost. CONCLUSIONS: The incidences of MI and INJ in this high school population during the study period were high. Athletes who reported MI sustained a higher percentage of severe injuries than did athletes who reported normal menses. Education programs to increase knowledge and improve management of MI and its potential effects on injury in female high school athletes are warranted. PMID- 22488234 TI - Arch height and maximum rearfoot eversion during jogging in 2 static neutral positions. AB - CONTEXT: Clinically, lowering of the medial longitudinal arch is believed to be closely related to rearfoot eversion. However, the relationship between arch height and rearfoot eversion during gait is unclear. OBJECTIVES: (1) To examine the influence of 2 reference positions (weight-bearing neutral position [WBNP] and subtalar neutral position [STNP]) on maximum rearfoot eversion, tibial internal rotation, knee flexion, knee internal rotation, and dorsiflexion-plantar flexion of ankle joint measures during jogging and (2) to compare the relationships among static arch height, navicular drop, and the 2 maximum rearfoot eversion measures. DESIGN: Crossover study. SETTING: Gait laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-three volunteers between 18 and 40 years of age. INTERVENTION(S): Each participant stood on the treadmill in 2 static positions: WBNP and STNP. Kinematic data were obtained using a 10-camera motion analysis system (120 Hz) when participants jogged at 2.65 m/s on the treadmill in bare feet. MAIN OUTCOME MEASURE(S): Rearfoot and shank angular kinematics, navicular drop, and static arch height. RESULTS: Maximum rearfoot eversion was greater (WBNP: 4.03 degrees +/- 2.58 degrees , STNP: 10.91 degrees +/- 5.34 degrees ) when STNP was the static reference (P < .001). A strong correlation was seen between maximum STNP eversion and navicular drop (r = 0.842) but not between WBNP and navicular drop (r = 0.216). Differences were noted in dorsiflexion and knee kinematics during gait between the static references; however, the effect sizes were low, and the mean differences were smaller than 2 degrees , which was less than 5% of total excursion during gait. CONCLUSIONS: Using STNP rather than WBNP as the reference position affects estimates of frontal-plane rearfoot movement but not other ankle or knee motions in jogging. PMID- 22488235 TI - The level of medical services and secondary school-aged athletes. AB - CONTEXT: Medical organizations have recommended that administrators, parents, and community leaders explore every opportunity to make interscholastic athletic programs safe for participation, including employing athletic trainers at practices and competitive events. OBJECTIVE: To determine the overall level of medical services provided for secondary school-aged athletes at high school athletic events in a rural southern state, to evaluate the employment of athletic trainers in the provision of medical services in secondary schools, and to compare athletic training medical services provided at athletic events among schools of various sizes. DESIGN: Cross-sectional study. SETTING: Questionnaires were sent to administrators at 199 secondary schools. PATIENTS OR OTHER PARTICIPANTS: A total of 144 administrators, including interscholastic athletic directors and school principals, from 199 secondary schools participated (72% response rate). MAIN OUTCOME MEASURE(S): Participants completed the Self Appraisal Checklist for Health Supervision in Scholastic Athletic Programs from the American Academy of Pediatrics, which has been demonstrated to be valid and reliable. The Kruskal-Wallis and Mann-Whitney tests were used to measure differences in groups. RESULTS: We found differences in cumulative scores when measuring between institutional classifications (P <= .05). Cumulative scores for the Event Coverage section of the instrument ranged from 80.5 to 109.6 out of a total possible score of 126. We also found differences in several factors identified in the Event Coverage section (P <= .05). CONCLUSIONS: The number of coaching staff certified in cardiopulmonary resuscitation or first aid was minimal. Most schools did not have a plan for providing minimal emergency equipment, ice, or water for visiting teams. We found that 88% (n = 7) of the 8 essential Event Coverage components that the American Academy of Pediatrics deems important were not addressed by schools represented in our study. PMID- 22488237 TI - Tumor-associated macrophages promote angiogenesis and lymphangiogenesis of gastric cancer. AB - BACKGROUND AND OBJECTIVES: This study was conducted to investigate whether and how macrophages recruited to tumor microenvironments (tumor-associated macrophages, TAMs) were involved in angiogenesis and lymphangiogenesis of gastric cancer (GC). METHODS: TAMs, microvessel density (MVD), and lymphatic vessel density (LVD) in 115 cases of GC tissue were assessed by immunohistochemistry (IHC) staining of CD68, CD34, and D2-40, respectively. Preoperative blood samples from 43 patients were obtained to detect serum levels of vascular endothelial growth factor (VEGF) and VEGF-C. A co-culture system was also developed to study effects and underlying mechanisms of THP-1 macrophages on SGC7901 GC cells. RESULTS: TAMs numbers were closely related to serosa invasion, lymph node metastasis and tumor, nodes, and metastases stage and a positive correlation existed between the TAMs count and MVD and LVD. Additionally, TAMs were associated with preoperative serum levels of VEGF and VEGF-C, the expression of VEGF and VEGF-C protein in macrophages was up-regulated in the co-culture system, and inhibition of the NF-kappaB pathway in macrophages induced a significant reduction in the expression of VEGF and VEGF-C in both macrophages and GC cells (all P<0.05). CONCLUSIONS: TAMs may promote angiogenesis and lymphangiogenesis of GC, possibly by enhancing VEGF and VEGF-C expression. PMID- 22488236 TI - National athletic trainers' association position statement: preventing sudden death in sports. AB - OBJECTIVE: To present recommendations for the prevention and screening, recognition, and treatment of the most common conditions resulting in sudden death in organized sports. BACKGROUND: Cardiac conditions, head injuries, neck injuries, exertional heat stroke, exertional sickling, asthma, and other factors (eg, lightning, diabetes) are the most common causes of death in athletes. RECOMMENDATIONS: These guidelines are intended to provide relevant information on preventing sudden death in sports and to give specific recommendations for certified athletic trainers and others participating in athletic health care. PMID- 22488238 TI - A sampling procedure for quantifying mites in soybeans. AB - To control phytophagous mites on soybean crops in an economically viable way, it is necessary to quantify the occurrence of the mites on the leaflets. Estimating the number of mites cm(-2) on leaflets is more difficult because of their irregular distribution on the leaflet surface. Therefore, the aim of this study was to determine the count-area/leaflet and the number of soybean leaflets to quantify the mites. One hundred infested plants were randomly collected. One leaflet was removed from each plant and divided into 32 sections (1.0 cm(2) per section), arranged in four columns and eight rows, to count the mites (adults, nymphs and eggs). The ideal count-area size per leaflet (Xo) was estimated by the maximum curvature of the coefficient of variation method for each of the 100 leaflets. For a count-area of Xo size, we obtained the number of mites cm(-2) per leaflet and, using the bootstrap resampling method, we estimated the point and interval averages as well as the sample size for a pre-established error. We suggest that the determination of the evaluated area size on each soybean leaflet (20 cm(2) in this case) and the bootstrap resampling estimate of the appropriate number of leaflets (12 in this case) for a bootstrap confidence interval of four mites (adults + nymphs) cm(-2) is sufficient to standardize the sampling procedures for quantifying mites on soybean leaflets. PMID- 22488242 TI - Enhanced thermotolerance and ethanol tolerance in Saccharomyces cerevisiae mutated by high-energy pulse electron beam and protoplast fusion. AB - To increase thermotolerance and ethanol tolerance in Saccharomyces cerevisiae strain YZ1, the strategies of high-energy pulse electron beam (HEPE) and three rounds of protoplast fusion were explored. The YF31 strain had the characteristics of resistant to high-temperature, high-ethanol tolerance, rapid growth and high yield. The YF31 could grow on plate cultures up to 47 degrees C, containing 237.5 g L(-1) of ethanol. In particular, the mutant strain YF31 generated 94.2 +/- 4.8 g L(-1) ethanol from 200 g glucose L(-1) at 42 degrees C, which was 2.48 times the production of the wild strain YZ1. Results demonstrated that the variant phenotypes from the strains screening by HEPE irradiation could be used as parent stock for yeast regeneration and the protoplast fusion technology is sufficiently powerful in combining suitable characteristics in a single strain for ethanol fermentation. PMID- 22488240 TI - An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease. AB - OBJECTIVE: A workgroup commissioned by the Alzheimer's Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer disease (AD). We performed a preliminary assessment of these guidelines. METHODS: We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis, and (18) fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cutpoints. A group of 450 cognitively normal (CN) subjects from a population-based sample was used to develop cognitive cutpoints and to assess population frequencies of the different preclinical AD stages using different cutpoint criteria. RESULTS: The new criteria subdivide the preclinical phase of AD into stages 1 to 3. To classify our CN subjects, 2 additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected non-AD pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cutpoints corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0, 16% stage 1, 12 % stage 2, 3% stage 3, and 23% SNAP. INTERPRETATION: This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1-3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving only 3% unclassified. Future longitudinal validation of the criteria will be important. PMID- 22488243 TI - The expression of heparanase and microRNA-1258 in human non-small cell lung cancer. AB - This study aims to discuss the correlation between miR-1258 and the expression of heparanase (HPSE) in the cancer cells of the patients with non-small cell lung cancer (NSCLC) and the inhibition mechanism of miR-1258 on the invasion of lung cancer cell. The expression level of miR-1258 was detected by TaqMan real-time PCR assay, the expression of HPSE was detected by immunohistochemistry, and the expression level of HPSE in the cancer tissue of each case was detected by western blot and in its adjacent tissue of 53 patients with NSCLC. The influence of miR-1258 on the invasion potential of the lung cancer cell line A549 was studied with lentivirus system including cloned miR-1258 fragments subsequently. The expression of HPSE and miR-1258 in NSCLC tissue was not obviously related to patient's gender, age, differentiation extent of cancer tissue, cancer types, etc., but also staging and lymph node metastasis, and the difference was significant. Further studies showed that the relationship between the expression level of miR-1258 and the expression of HPSE was closer. The relative expression level of miR-1258 was 0.58 +/- 0.07 in HPSE positive sample and 1.58 +/- 0.11 in HPSE negative sample, and the difference of which was notably significant (P < 0.0001). Western blot showed that the expression level of HPSE was highly negatively related to the expression level of miR-1258. The invasion potential of A549 was notably lowered when transfected by miR-1258. The miR-1258 regulates the expression level of HPSE to influence the morbidity and metastasis of NSCLC. The miR-1258 is likely to become the key to the treatment of lung cancer metastasis. PMID- 22488244 TI - Effects of SASH1 on lung cancer cell proliferation, apoptosis, and invasion in vitro. AB - The purposes of this study were to investigate the effects of the SASH1 gene on the growth, proliferation, apoptosis, invasiveness, and metastatic potential of lung cancer cells and explore the potential use of SASH1 for the treatment of human lung cancer. The SASH1 gene was cloned into the pcDNA3.1 eukaryotic expression vector, and SASH1 shRNA were designed and constructed. The resulting constructs were transfected into A549 human lung cancer cells, and the changes in the relevant biological characteristics of the cells overexpressing SASH1 and cells with downregulated expression of SASH1 were analyzed using the MTT assay, transwell invasion assay, and flow cytometry. The effects of the SASH1 gene on the expression of cyclin D1, Bcl-2, and MMP-2/9 were also concurrently examined. In the A549 cells from the pcDNA3.1-SASH1 transfected group, cell viability, proliferation, and migration were significantly reduced compared to the control cells (p = 0.039, p = 0.013), and a cell cycle arrest in G1 was observed. The A549 cells transfected with the SASH1 shRNA demonstrated significantly higher cell viabilities, proliferation, and migration compared to the control cells (p = 0.012, p = 0.045). Additionally, the percentage of A549 cells undergoing apoptosis was significantly higher in the pcDNA3.1-SASH1 transfected cells and significantly lower in the SASH1 shRNA transfected cells compared to the control cells (p = 0.010, p = 0.000). The cyclin D1, Bcl-2, and MMP-9/2 protein expression levels were significantly lower in the pcDNA3.1-SASH1-transfected cells and were significantly higher in the SASH1 shRNA-transfected cells than that in the control cells. The SASH1 gene may inhibit A549 cell growth and proliferation as well as promote cellular apoptosis. The overexpression of the SASH1 gene may also be related to the decreased migration of A549 human lung cancer cells. PMID- 22488245 TI - Maternal depression and infant daytime cortisol. AB - The effect of maternal depressive disorder on infant daytime cortisol production was studied in three groups of infants; one group with mothers with comorbid depression and anxiety (n = 19), a second group with mothers with depression only (n = 7), and a third group with non-depressed mothers (n = 24). The infants' cortisol production pattern was measured when they were 6, 12, and 18 months old in combination with repeated measures of parenting stress and depression symptoms. Multilevel modeling analyses showed that infants of mothers with comorbid depression and anxiety had relatively higher cortisol production from morning to bedtime and higher bedtime values as compared to infants of non depressed mothers and infants of depressed only mothers when they were 6 and 12 months old, but not when 18 months old. The results were interpreted in light of possible changes in the infants' stress regulatory capacities or changes in maternal coping strategies at infant age 18 months. PMID- 22488246 TI - A manganese oxido complex bearing facially coordinating trispyridyl ligands--is coordination geometry crucial for water oxidation catalysis? AB - In this work the synthesis of the novel manganese complex [Mn(2)(III,III)(tpdm)(2)(MU-O)(MU-OAc)(2)](2+) (1) is reported, containing two manganese centres ligated to the unusual, facially coordinating, all-pyridine ligand tpdm (tris(2-pyridyl)methane). The geometric and electronic properties of complex 1 were characterised by X-ray crystallography, vibrational (IR and Raman) and optical spectroscopy (UV/Vis and MCD). Cyclic voltammograms of 1 showed a quasi-reversible oxidation event at 950 mV and an irreversible reduction wave at 250 mV vs. Ag/Ag(+). The redox behaviour of the compound was investigated in detail by UV/Vis- and X-band EPR-spectroelectrochemistry. Both electrochemical (+1200 mV) and chemical (tBuOOH) oxidations transform 1 into the singly oxidized di-MU-oxido species [Mn(2)(III,IV)(tpdm)(2)(MU-O)(2)(MU-OAc)](2+). Further electrochemical oxidation at the same potential results in the removal of a second electron to obtain a Mn(2)(IV,IV)-species. The ability of compound 1 to evolve O(2) was studied using different reaction agents. While reactions with both hydrogen peroxide and peroxomonosulfate yield O(2), homogeneous water oxidation using Ce(IV) was not observed. Nevertheless, the oxidation reactions of 1 are very interesting model processes for oxidation state (S-state) transitions of the natural manganese water-oxidation catalyst in photosynthesis. However, despite its favourable coordination geometry and multielectron redox chemistry, complex 1 fails to be a catalytically active model for natural water-oxidation. PMID- 22488247 TI - Evolution of the B7 family: co-evolution of B7H6 and NKp30, identification of a new B7 family member, B7H7, and of B7's historical relationship with the MHC. AB - The B7 family of genes is essential in the regulation of the adaptive immune system. Most B7 family members contain both variable (V)- and constant (C)-type domains of the immunoglobulin superfamily (IgSF). Through in silico screening of the Xenopus genome and subsequent phylogenetic analysis, we found novel genes belonging to the B7 family, one of which is the recently discovered B7H6. Humans and rats have a single B7H6 gene; however, many B7H6 genes were detected in a single large cluster in the Xenopus genome. The B7H6 expression patterns also varied in a species-specific manner. Human B7H6 binds to the activating natural killer receptor, NKp30. While the NKp30 gene is single-copy and maps to the MHC in most vertebrates, many Xenopus NKp30 genes were found in a cluster on a separate chromosome that does not harbor the MHC. Indeed, in all species so far analyzed from sharks to mammals, the number of NKp30 and B7H6 genes correlates well, suggestive of receptor-ligand co-evolution. Furthermore, we identified a Xenopus-specific B7 homolog (B7HXen) and revealed its close linkage to B2M, which we have demonstrated previously to have been originally encoded in the MHC. Thus, our study provides further proof that the B7 precursor was included in the proto MHC. Additionally, the comparative analysis revealed a new B7 family member, B7H7, which was previously designated in the literature as an unknown gene, HHLA2. PMID- 22488248 TI - Lipoprotein(a), interleukin-10, C-reactive protein, and 8-year outcome after percutaneous coronary intervention. AB - BACKGROUND: This prospective study investigated the association between preprocedural biomarker levels and incident major adverse cardiac events (MACE) in complex patients undergoing percutaneous coronary intervention (PCI) with sirolimus-eluting stenting. HYPOTHESIS: Lipoprotein(a) (Lp[a]), interleukin-10 (IL-10), and high-sensitivity C-reactive protein (CRP) have long-term prognostic value in patients undergoing PCI. METHODS: Between April 2002 and February 2003, 161 patients were included in the study. Blood was drawn before the procedure, and biomarkers were measured. Patients were followed-up for MACE (death, nonfatal myocardial infarction, and repeat revascularization). Cox proportional hazard models were used to determine risk of MACE for tertiles of biomarkers. Both 1 year and long-term follow-up (median, 6 years; maximum, 8 years) were evaluated. RESULTS: Mean age was 59 years, and 68% were men. During long-term follow-up, 72 MACE occurred (overall crude cumulative incidence: 45% [95% confidence interval (CI): 37%-52%]). Lp(a) was associated with a higher 1-year risk of MACE, with an adjusted hazard ratio (HR) of 3.1 (95% CI: 1.1-8.6) for the highest vs the lowest tertile. This association weakened and lost significance with long-term follow up. IL-10 showed a tendency toward an association with MACE. The 1-year HR was 2.1 (95% CI: 0.92-5.0). Long-term follow-up rendered a similar result. The association of CRP with MACE did not reach statistical significance at 1-year follow-up. However, CRP was associated with long-term risk of MACE, with an HR of 1.9 (95% CI: 1.0-3.5). CONCLUSIONS: In this prospective study, preprocedural Lp(a) level was associated with short-term prognosis after PCI. The preprocedural CRP level was associated with long-term prognosis after PCI. PMID- 22488249 TI - Targeting Aurora A kinase activity with the investigational agent alisertib increases the efficacy of cytarabine through a FOXO-dependent mechanism. AB - Novel therapies are urgently needed to improve clinical outcomes for patients with acute myeloid leukemia (AML). The investigational drug alisertib (MLN8237) is a novel Aurora A kinase inhibitor being studied in multiple Phase I and II studies. We investigated the preclinical efficacy and pharmacodynamics of alisertib in AML cell lines, primary AML cells and mouse models of AML. Here, we report that alisertib disrupted cell viability, diminished clonogenic survival, induced expression of the FOXO3a targets p27 and BIM and triggered apoptosis. A link between Aurora A expression and sensitivity to ara-C was established, suggesting that Aurora A inhibition may be a promising strategy to increase the efficacy of ara-C. Accordingly, alisertib significantly potentiated the antileukemic activity of ara-C in both AML cell lines and primary blasts. Targeted FOXO3a knockdown significantly blunted the pro-apoptotic effects of the alisertib/ara-C combination, indicating that it is an important regulator of sensitivity to these agents. In vivo studies demonstrated that alisertib significantly augmented the efficacy of ara-C without affecting its pharmacokinetic profile and led to the induction of p27 and BIM. Our collective data indicate that targeting Aurora A with alisertib represents a novel approach to increase the efficacy of ara-C that warrants further investigation. PMID- 22488250 TI - Methicillin-resistant Staphylococcus aureus laryngitis: a report of two cases with different clinical presentations. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) infection has been described in multiple areas of the head and neck. Recently, otolaryngologists have recognized MRSA infection in the glottis. We describe 2 cases of MRSA laryngitis with divergent clinical presentations: acute airway obstruction and recalcitrant hoarseness. METHODS: Report of 2 cases and review of the literature. RESULTS: In the first case, a 44-year-old woman presented with near aphonia despite maximal medical therapy. Examination showed diffuse erythema and edema of the endolarynx with yellowish plaques lining the glottis and supraglottis. Complete resolution was achieved with long-term trimethoprim-sulfamethoxazole. In the second case, a 54-year-old woman presented with recent-onset hoarseness with rapid progression to respiratory distress and biphasic stridor. Endoscopy revealed exuberant granulation tissue in the glottis with a narrowed airway. Treatment required prolonged courses of antibiotics and steroids. Diagnosis in both cases was confirmed with biopsies taken during direct laryngoscopy. CONCLUSIONS: MRSA treatment is a growing part of otolaryngologic practice and should be included in the differential diagnosis of hoarseness and stridor. PMID- 22488252 TI - Fluoride-supplemented milk inhibits acid tolerance in root caries biofilms. AB - In this study we investigated the effect of fluoride on plaque acid tolerance. The test group consumed 200 ml of milk supplemented with 5 mg F/l as NaF once a day, the milk control group drank 200 ml of unsupplemented milk, and the no-milk control group did not consume milk in this manner. Plaque samples were taken at baseline and after 15 months. The proportion of acid-tolerant bacteria in plaque was estimated using LIVE/DEAD(r) BacLightTM staining after exposure to pH 3.5 for 2 h. The fluoride group showed a statistically significant decrease in plaque acid tolerance compared to baseline. This study shows that daily intake of fluoride in milk reduces plaque acid tolerance. PMID- 22488251 TI - Lymph node macrophages. AB - Lymph node (LN) macrophages have long been known for their efficient uptake of lymph-borne antigens. A convergence of studies on innate and adaptive immune responses has led to exciting recent advances in understanding their more specialized properties: presenting antigens to B cells, dendritic cells and T cells, producing trophic factors and cytokines, and, remarkably, being permissive for viral infection, a property critical for mounting anti-viral responses. LN macrophages have been traditionally divided into subsets based on their subcapsular sinus and medullary locations. Here, we classify LN macrophages into three subsets: subcapsular sinus macrophages, medullary sinus macrophages and medullary cord macrophages. We review the literature regarding the roles of these cells in innate and adaptive immune responses and requirements for their development. We also discuss challenges associated with their purification as well as the existence of additional heterogeneity among LN macrophages. PMID- 22488253 TI - Continuous microalgae cultivation in a photobioreactor. AB - New biomass sources for alternative fuels has become a subject of increasing importance as the nation strives to resolve the economic and strategic impacts of limited fossil fuel resources on our national security, environment, and global climate. Algae are among the most promising non-food-crop-based biomass feedstocks. However, there are currently no commercially viable microalgae-based production systems for biofuel production that have been developed, as limitations include less-than optimal oil content, growth rates, and cultivation techniques. While batch studies are critical for determining basic growth phases and characteristics of the algal species, steady-state studies are necessary to better understand and measure the specific growth parameters. This study evaluated the effects of dilution rate on microalgal biomass productivity, lipid content, and fatty acid profile under steady-state conditions with continuous illumination and carbon dioxide supplemention for two types of algae. Continuous cultures were conducted for more that 3 months. Our results show that the productivity of Chlorella minutissima varied from 39 to 137 mg/L/day (dry mass) when the dilution rate varied from 0.08 to 0.64 day(-1). The biomass productivity of C. minutissima reached a maximum value (137 mg/L/day) at a dilution rate of 0.33 day(-1), while the productivity of Dunaliella tertiolecta varied from 46 to 91 mg/L/day at a dilution rate of 0.17 to 0.74 day(-1). The biomass productivity of D. tertiolecta reached a maximum value of 91 mg/L/day at a dilution rate of 0.42 day(-1). Moreover, the lipid content had no significant change with various dilution rates. PMID- 22488254 TI - Counterintuitive compaction behavior of clopidogrel bisulfate polymorphs. AB - Being a density violator, clopidogrel bisulfate (CLP) polymorphic system (forms I and II) allows us to study individually the impact of molecular packing (true density) and thermodynamic properties such as heat of fusion on the compaction behavior. These two polymorphs of CLP were investigated for in-die and out-of-die compaction behavior using CTC profile, Heckel, and Walker equations. Compaction studies were performed on a fully instrumented rotary tabletting machine. Detailed examinations of the molecular packing of each form revealed that arrangement of the sulfate anion differs significantly in both crystal forms, thus conferring different compaction behavior to two forms. Close cluster packing of molecules in form I offers a rigid structure, which has poor compressibility and hence resists deformation under compaction pressure. This results into lower densification, higher yield strength, and mean yield pressure, as compared with form II at a given pressure. However, by virtue of higher bonding strength, form I showed superior tabletability, despite its poor compressibility and deformation behavior. Form I, having higher true density and lower heat of fusion showed higher bonding strength. Hence, true density and not heat of fusion can be considered predictor of bonding strength of the pharmaceutical powders. PMID- 22488255 TI - The effect of the serotonin transporter polymorphism (5-HTTLPR) on amygdala function: a meta-analysis. AB - The 5-HTTLPR polymorphism has been widely regarded as a potential genetic risk factor for affective disorders. Consistent with this, this polymorphism has been associated with altered amygdala responses at rest and in response to aversive stimuli. However, the strength of this association remains uncertain. We sought to synthesize existing data on the association between the 5-HTTLPR polymorphism and amygdala activation and ascertain the strength of evidence for this association. Meta-analytic techniques were applied to data from relevant published studies and unpublished data sets to obtain an estimate of the likely magnitude of effect of any association. The large number of studies allowed us to apply a formal test of publication bias, as well as explore the impact of various study-level characteristics on the magnitude of the observed effect size. Our meta-analysis indicated that there is a statistically significant but small effect of 5-HTTLPR on left and right amygdala activity. However, there was considerable between-study heterogeneity, which could not be fully accounted for by the study design and sample characteristics that we investigated. In addition, there was evidence of excess statistical significance among published studies. These findings indicate that the association between the 5-HTTLPR and amygdala activation is smaller than originally thought, and that the majority of previous studies have been considerably under powered to reliably demonstrate an effect of this size. PMID- 22488256 TI - Role of folate receptor autoantibodies in infantile autism. PMID- 22488258 TI - Eicosapentaenoic acid appears to be the key omega-3 fatty acid component associated with efficacy in major depressive disorder: a critique of Bloch and Hannestad and updated meta-analysis. PMID- 22488259 TI - Ethylene glycol: properties, synthesis, and applications. AB - Ethylene glycol (EG) is an important organic compound and chemical intermediate used in a large number of industrial processes (e.g. energy, plastics, automobiles, and chemicals). Indeed, owing to its unique properties and versatile commercial applications, a variety of chemical systems (e.g., catalytic and non catalytic) have been explored for the synthesis of EG, particularly via reaction processes derived from fossil fuels (e.g., petroleum, natural gas, and coal) and biomass-based resources. This critical review describes a broad spectrum of properties of EG and significant advances in the prevalent synthesis and applications of EG, with emphases on the catalytic reactivity and reaction mechanisms of the main synthetic methodologies and applied strategies. We also provide an overview regarding the challenges and opportunities for future research associated with EG. PMID- 22488257 TI - Neurodevelopmental model of schizophrenia: update 2012. AB - The neurodevelopmental model of schizophrenia, which posits that the illness is the end state of abnormal neurodevelopmental processes that started years before the illness onset, is widely accepted, and has long been dominant for childhood onset neuropsychiatric disorders. This selective review updates our 2005 review of recent studies that have impacted, or have the greatest potential to modify or extend, the neurodevelopmental model of schizophrenia. Longitudinal whole population studies support a dimensional, rather than categorical, concept of psychosis. New studies suggest that placental pathology could be a key measure in future prenatal high-risk studies. Both common and rare genetic variants have proved surprisingly diagnostically nonspecific, and copy number variants (CNVs) associated with schizophrenia are often also associated with autism, epilepsy and intellectual deficiency. Large post-mortem gene expression studies and prospective developmental multi-modal brain imaging studies are providing critical data for future clinical and high-risk developmental brain studies. Whether there can be greater molecular specificity for phenotypic characterization is a subject of current intense study and debate, as is the possibility of neuronal phenotyping using human pluripotent-inducible stem cells. Biological nonspecificity, such as in timing or nature of early brain development, carries the possibility of new targets for broad preventive treatments. PMID- 22488261 TI - Dkk-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice. AB - OBJECTIVE: Dkk is a family of canonical Wnt antagonists with 4 members (Dkk-1, Dkk-2, Dkk-3, and Dkk-4). We undertook this study to explore the roles of Dkk-1 and Dkk-2 in osteoarthritic (OA) cartilage destruction in mice. METHODS: Expression of Dkk and other catabolic factors was determined at the messenger RNA and protein levels in human and mouse OA cartilage. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM) or by intraarticular injection of Epas1 adenovirus (AdEPAS-1). The role of Dkk in OA pathogenesis was examined by intraarticular injection of AdDkk-1 or by using chondrocyte-specific Dkk1 (Col2a1-Dkk1)-transgenic mice and Dkk2 (Col2a1-Dkk2)-transgenic mice. Primary culture mouse chondrocytes were also treated with recombinant Dkk proteins. RESULTS: We found opposite patterns of Dkk1 and Dkk2 expression in human and mouse experimental OA cartilage: Dkk1 was up-regulated and Dkk2 was down-regulated. Overexpression of Dkk1 by intraarticular injection of AdDkk-1 significantly inhibited DMM-induced experimental OA. DMM-induced OA was also significantly inhibited in Col2a1-Dkk1-transgenic mice compared with their wild type littermates. However, Col2a1-Dkk2-transgenic mice showed no significant difference in OA pathogenesis. Wnt-3a, which activates the canonical Wnt pathway, induced Mmp13 and Adamts4 expression in primary culture chondrocytes, an effect that was significantly inhibited by Dkk-1 pretreatment or Dkk1 overexpression. CONCLUSION: Our findings indicate that expression of Dkk1, but not Dkk2, in chondrocytes inhibits OA cartilage destruction. The protective effect of Dkk-1 appears to be associated with its capacity to inhibit Wnt-mediated expression of catabolic factors, such as Mmp13, providing evidence that Dkk-1 might serve as a therapeutic target for OA treatment. PMID- 22488262 TI - Pediatric, elderly, and emerging adult-onset peaks in Burkitt's lymphoma incidence diagnosed in four continents, excluding Africa. AB - Burkitt's lymphoma (BL) in the general population and immunosuppressed persons with AIDS in the United States was characterized by three age-specific incidence peaks near 10, 40, and 70 years. We hypothesized that BL from different geographical areas may exhibit pediatric, adult, and elderly age incidence peaks. We investigated this hypothesis using data on 3,403 cases obtained from the International Agency for Research on Cancer (1963-2002). Data from Africa were sparse or incomplete, and thus were excluded. Age-standardized rates (ASRs) and age-specific incidence rates were calculated, supplemented with the calculations performed using age-period-cohort (APC) models. The ASR rose 5.3% (95% confidence interval [CI], 5.0-5.6) per year in males and 4.6% (95% CI, 4.5-4.8) in females. The ASR increased gradually in children, steeply in adults and most rapidly in the elderly both in males and in females. Overall, BL male/female ASR ratio was 2.5, but it declined from 3.1 (95% CI, 3.0-3.3) for pediatric BL to 2.3 (95% CI, 2.2-2.4) for adult BL and 1.5 (95% CI, 1.4-1.6) for elderly BL. Age-specific incidence peaks occurred near 10 and 70 years in all regions and periods. A peak near 40 years of age emerged in the mid-1990s, particularly in men. Findings using APC models confirmed those based on the standard analyses. Our findings, based on the international BL cases, support our hypothesis that BL is multimodal and that BL peaks at different ages may be clues to differences in the etiology and/or biology of BL at those ages. PMID- 22488263 TI - Prognosis and treatment of micrometastatic breast cancer sentinel lymph node: a population-based study. AB - BACKGROUND AND OBJECTIVES: Major concern of sentinel lymph node (SLN) biopsy (SLNB) regards the prognosis of micrometastasis (Nmic) in SLN. The purpose of this study is to determine the adequate surgical treatment and prognosis of Nmic in a population-based series of breast cancer patients. METHODS: All non metastatic breast cancer patients registered by the Modena Cancer Registry (MCR), from January 2000 to December 2008, were evaluated for SLNB. Information on patients' characteristics, treatment and follow-up was collected. RESULTS: Among 2,078 patients treated with SLNB, 28.5% (590) showed a positive SLN, subdivided in N0i+ 6.3% (31), Nmic 28.8% (176), N1 64.1% (378), and N2 0.8% (5). Of 176 Nmic, 80% (142) received an axillary lymph node dissection (ALND). Only three patients had >= 4 SLN involved. No axillary recurrence occurred in Nmic patients. The overall and disease-free survival rates were N0 99.2% and 97.7%, N0i+ 100% and 100%, Nmic 96% and 93.2%, N+ (N1 + N2) 96.1% and 92.4%, respectively (N0 vs. Nmic P<0.001). CONCLUSIONS: This study suggests that patients with Nmic have a similar prognosis to N+ (N1 + N2) patients, and a low risk of local recurrence, questioning the necessity of ALND for Nmic SLN. PMID- 22488264 TI - Advantages and disadvantages of etomidate use for intubation of patients with sepsis. AB - Etomidate is a potent imidazole hypnotic used widely in single doses in the rapid sequence intubation of critically ill patients with sepsis due to its presumed hemodynamic safety, fast onset, and short duration of action. However, the literature is conflicting regarding the hemodynamic advantages of etomidate over other induction agents, and its safety in this population is a matter of strong debate in the critical care community as the drug is associated with suppression of adrenal steroidogenesis, which can last up to 72 hours after a single dose, primarily through potent inhibition of the 11beta-hydroxylase enzyme. However, the clinical impact of this adrenal suppressive effect is not certain. The use of continuous-infusion etomidate in critically ill patients was abandoned more than 20 years ago due to reports of increased mortality. Nevertheless, mortality data of single-dose etomidate are still controversial, with no strong evidence of benefit over other agents and a tendency toward harm (keeping in mind the limitations of the available literature). Proponents of single-dose etomidate use in patients with sepsis suggest that the increased mortality associated with etomidate is merely a reflection of the patients' severity of illness and not related to the drug itself, whereas others believe that the drug causes true harm and increases mortality in this population. In view of the lack of a clear clinical advantage of etomidate over other agents used in rapid sequence intubation, it would be prudent to favor other agents until further conclusive evidence of etomidate safety is available in critically ill patients with sepsis. PMID- 22488266 TI - Clinical application of ocular imaging. AB - The broadening frontier of technology used in ocular imaging is continuously affecting the landscape of clinical eye care. With each wave of enhanced imaging modalities, the field faces the difficulties of optimally incorporating these devices into the clinic. Ocular imaging devices have been widely incorporated into clinical management after their diagnostic capabilities have been documented in a wide range of ocular disease. In this review, we are presenting the main commercially available devices for imaging of the posterior segment of the eye. PMID- 22488267 TI - Precise thickness measurements of Bowman's layer, epithelium, and tear film. AB - PURPOSE: To visualize corneal microstructure such as tear film, epithelium, and Bowman's layer in three dimensions with spectral domain optical coherence tomography (SDOCT) exhibiting 1.3 MUm axial resolution at 100,000 A-scans/s. This enables measurement of epithelial and Bowman layer thickness across an area of 8.4 mm * 8.4 mm and measuring the tear film thickness at the central cornea. METHODS: We designed a high-performance SDOCT system, which uses a broad bandwidth TiSapph Laser and a high-speed complementary metal-oxide-semiconductor detector technology, providing a resolution in tissue of 1.3 MUm and an acquisition speed of 100,000 A-scans/s. Such speed and resolution is a prerequisite if precise anatomy is to be determined. The high resolution gives access to corneal microstructure such as the epithelium layer as well as the boundaries of Bowman's layer and stroma. Even more interestingly, the tear film can be distinguished on the surface of the cornea. The Bowman's layer and epithelial thickness for both eyes of nine subjects have been measured out of which two subjects underwent photorefractive keratectomy treatment. RESULTS: Three-dimensional volumes of the human cornea have been recorded in vivo at an A scan rate of 100,000 scans/s. Epithelial thickness was measured to be 55.8 +/- 3.3 MUm and Bowman's layer thickness 18.7 +/- 2.5 MUm in normal eyes. Epithelial thickness in the eyes after refractive surgery was measured to be 68.2 +/- 5.0 MUm. The Bowman layer was degenerated in these eyes. The average tear film thickness of four eyes was 5.1 +/- 0.5 MUm. CONCLUSIONS: Using a high-performance SDOCT system with high-imaging speed and ultrahigh resolution, we produced precise thickness maps of the epithelium and for the first time of the Bowman's layer. Such a system will give insight into high-fidelity three-dimensional corneal microstructure helping to precisely plan refractive surgery. It may furthermore yield new perspectives on studying and understanding tear film dynamics. PMID- 22488265 TI - Optical coherence tomography: future trends for imaging in glaucoma. AB - Optical coherence tomography captures a major role in clinical assessment in eye care. Innovative hardware and software improvements in the technology would further enhance its usefulness. In this review, we present several promising initiatives currently in development or early phase of assessment that we expect to have a future impact on optical coherence tomography. PMID- 22488268 TI - A review of meibography. AB - Meibomian gland dysfunction is one of the most common causes of dry eye resulting in morphology changes to the meibomian glands. Meibography provides an in vivo means to assess the structure of the meibomian gland. Over the past 40 years, meibography has undergone significant development regarding its application to research and clinical practice. This review describes the evolution of the various meibography techniques, grading methods, and their diagnostic relevance. PMID- 22488269 TI - A clinical planning module for adaptive optics SLO imaging. AB - PURPOSE: To develop a clinical planning module (CPM) to improve the efficiency of imaging subjects with a steerable wide-field adaptive optics scanning laser ophthalmoscope (AOSLO) and to evaluate the performance of this module by imaging the retina in healthy and diseased eyes. METHODS: We developed a software-based CPM with two submodules: a navigation module and a montage acquisition module. The navigation module guides the AOSLO to image identified retinal regions from a clinical imaging platform using a matrix-based mapping between the two. The montage acquisition module systematically moves the AOSLO steering mirrors across the retina in predefined patterns. The CPM was calibrated using a model eye and tested on five normal subjects and one patient with a retinal nerve fiber layer defect. RESULTS: Within the central +/-7 degrees from the fixation target, the CPM can direct the AOSLO beam to the desired regions with localization errors of <0.3 degrees . The navigation error increases with eccentricity, and larger errors (up to 0.8 degrees ) were evident for regions beyond 7 degrees . The repeatability of CPM navigation was tested on the same locations from two subjects. The localization errors between trials on different days did not differ significantly (p > 0.05). The region with a size of approximately 13 degrees * 10 degrees can be imaged in about 30 min. An approximately 12 degrees * 4.5 degrees montage of the diseased region from a patient was imaged in 18 min. CONCLUSIONS: We have implemented a clinical planning module to accurately guide the AOSLO imaging beam to desired locations and to quickly acquire high resolution AOSLO montages. The approach is not only friendly for patients and clinicians but also convenient to relate the imaging data between different imaging platforms. PMID- 22488270 TI - Advancement flap in the management of chronic anal fissure: a prospective study. AB - Lateral internal sphincterotomy is the surgical treatment of choice of chronic anal fissure after failure of conservative measures. Several randomized trials identified an overall risk of incontinence of 10 % mostly for flatus. Fissurectomy is the most commonly used procedure to preserve the integrity of the anal sphincters. However, a possible complication is keyhole defect that may lead to faecal soiling. In this study, chronic anal fissure (CAF) was treated by fissurectomy and anal advancement flap to preserve the anatomo-functional integrity of sphincters and to reduce healing time and the risk of anal stenosis. In patients with hypertonia, surgical treatment was combined with chemical sphincterotomy by injection of botulinum toxin to enhance tissue perfusion. Forty eight patients with CAF underwent fissurectomy and anal advancement flap. In 22 subjects with hypertonia of the internal anal sphincter, intrasphincter injection of 30 UI of botulinum toxin at the completion of the surgical operation was used. All patients were followed up to 24 months. Since the first defecation, the intensity and duration of pain were significantly reduced. Two patients had urinary retention, five had infections and three had partial breakdowns. No anal stenosis, keyhole deformity or necrosis flap was recorded. At the 24 months follow-up visit, anal incontinence was similar to those detected preoperatively. Only four recurrences were detected at 18 and 20 months. After medical treatment failure, fissurectomy with advancement flap is a valid sphincter-conserving procedure for treatment of anterior or posterior CAF, regardless of hypertonia of the internal anal sphincter. PMID- 22488272 TI - Hydrocarbon solvent exposure and Parkinson disease. PMID- 22488271 TI - Ferguson hemorrhoidectomy: is still the gold standard treatment? AB - Hemorrhoidectomy remains the most definitive procedure to treat symptomatic grades III and IV hemorrhoids. However, over the years, several modifications have been made to the original operation to improve the outcomes. A total of 693 consecutive patients with grade III and IV hemorrhoids underwent Ferguson hemorrhoidectomy. Our results serve as a standard for comparison conventional hemorrhoidectomy (Ferguson's technique) with recent methods such as stapled hemorrhoidopexy and LigaSure hemorrhoidectomy. We have obtained a very low rate of post-operative pain after Ferguson hemorrhoidectomy (VAS pain score was 2.47 +/- 1.1 after a day, 1.34 +/- 0.7 after 7 days and 0.51 +/- 0.1 after 2 weeks) as to for stapler and LigaSure procedure in the literature. Moreover, long-term results demonstrate high levels of patient satisfaction (the satisfaction was good in 624 patients after 2 weeks and in 658 patients after 1 year) with a low recurrence rates (7 patients had recurrence after 1 year and 21 patients after 2 years). We believe that Ferguson-closed hemorrhoidectomy could still be, at the moment, the gold standard to which other techniques are compared. PMID- 22488273 TI - Regulation of mesenchymal stem cell differentiation and insulin secretion by differential expression of Pdx-1. AB - In recent years, major effort has been made to differentiate embryonic stem cells, pancreatic ductal epithelial multipotent progenitor cells, and bone marrow stem cells into insulin secreting cells. Our previous work has also demonstrated the feasibility of inducing mesenchymal stem cells (MSC) to insulin secreting cells through overexpression of Pdx-1, a pancreas and islet-specific transcription factor that plays a major role in differentiation of islet beta cells during development (Yuan et al. in Mol Biol Rep 37:4023-4031, 2010). However, the levels of insulin secretion among these differentiated MSC were quite variable. The purpose of this study is to address the issue whether the insulin secretion level from the differentiated MSC lines are determined by the expression level of the Pdx-1 transgene. To do so, we have generated several differentiated MSC lines with stable transfection of the Pdx-1 gene. Using RT-PCR analysis and insulin secretion assay, we have analyzed Pdx-1 mRNA levels and insulin secretion from these stable MSC lines. Our results showed that Pdx-1 expression is absolutely required for the differentiation of MSC lines to insulin secreting cell lines. Furthermore, we demonstrated that the level of Pdx-1 expression is closely correlated with level of insulin mRNA and insulin secretion level in differentiated MSC stable cell lines. These findings suggest that the level of Pdx-1 expression plays a key role in induction of MSCs to insulin secreting cells. PMID- 22488275 TI - Tumor microenvironment and lymphocyte infiltration. AB - There is ample evidence that the presence of tumor-infiltrating T lymphocytes is associated with a favorable prognostic in patients. These observations suggest that a limiting step to immune resistance and immunotherapy could be the capacity of tumor-specific T cells to reach tumor bed. In this article, we review some factors that may influence this infiltration, and in particular the nature of the vasculature, the expression of chemokines or tumor antigens and the presence of dendritic cells and CD4+ T lymphocytes. PMID- 22488274 TI - Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and antitumor effects. AB - We recently demonstrated that Venezuelan equine encephalitis virus-based replicon particle (VRPs) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP-expressing interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and antitumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)), and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12, and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP-IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing antitumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL 12 at the VRP-CEA(6D) injection site provided more potent activation of CEA specific immune responses than that of VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted. PMID- 22488276 TI - A methodologic approach for normalizing angular work and velocity during isotonic and isokinetic eccentric training. AB - CONTEXT: Resistance exercise training commonly is performed against a constant external load (isotonic) or at a constant velocity (isokinetic). Researchers comparing the effectiveness of isotonic and isokinetic resistance-training protocols need to equalize the mechanical stimulus (work and velocity) applied. OBJECTIVE: To examine whether the standardization protocol could be adjusted and applied to an eccentric training program. DESIGN: Controlled laboratory study. SETTING: Controlled research laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty one sport science male students (age = 20.6 +/- 1.5 years, height = 178.0 +/- 4.0 cm, mass = 74.5 +/- 9.1 kg). INTERVENTION(S): Participants performed 9 weeks of isotonic (n = 11) or isokinetic (n = 10) eccentric training of knee extensors that was designed so they would perform the same amount of angular work at the same mean angular velocity. MAIN OUTCOME MEASURE(S): Angular work and angular velocity. RESULTS: The isotonic and isokinetic groups performed the same total amount of work (-185.2 +/- 6.5 kJ and -184.4 +/- 8.6 kJ, respectively) at the same angular velocity (21 +/- 1 degrees /s and 22 degrees /s, respectively) with the same number of repetitions (8.0 and 8.0, respectively). Bland-Altman analysis showed that work (bias = 2.4%) and angular velocity (bias = 0.2%) were equalized over 9 weeks between the modes of training. CONCLUSIONS: The procedure developed allows angular work and velocity to be standardized over 9 weeks of isotonic and isokinetic eccentric training of the knee extensors. This method could be useful in future studies in which researchers compare neuromuscular adaptations induced by each type of training mode with respect to rehabilitating patients after musculoskeletal injury. PMID- 22488277 TI - Orthotic intervention and postural stability in participants with functional ankle instability after an accommodation period. AB - CONTEXT: Most protocols established to treat patients with functional ankle instability (FAI) have focused on taping the ankle. Orthotic intervention is a different treatment protocol that may have a positive effect on these patients, especially after an accommodation period. OBJECTIVE: To determine whether the use of a prefabricated orthotic affects postural stability in patients with FAI and a control group. DESIGN: Randomized controlled clinical trial. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Forty patients with unilateral FAI. INTERVENTION(S): Postural stability was measured on both limbs using a force plate on 3 occasions. Participants were instructed to balance on 1 limb with their eyes closed for 20 seconds. In session 1, postural stability was measured with the patient wearing his or her own athletic shoes. The control group repeated this procedure in sessions 2 and 3. When those in the orthotic group returned for session 2, they received prefabricated, full-length Quick Comfort Insoles for both feet, immediately placed the orthotics in their shoes, and were tested for postural stability. Patients in the orthotic group were instructed to wear the inserts daily and return 2 weeks later for session 3 and repeat postural stability testing. MAIN OUTCOME MEASURE(S): Center of pressure. RESULTS: In the orthotic group, postural stability improved between sessions 1 and 2 and sessions 1 and 3. In session 3, postural stability was different for the orthotic and control groups. We also identified a difference between the limbs such that the FAI ankle displayed worse postural stability than did the healthy ankle. CONCLUSIONS: Prefabricated orthotics improved postural stability in participants with FAI. Similar to the findings of previous researchers, we found that postural stability was worse in FAI ankles than in healthy ankles. PMID- 22488278 TI - Discriminating between copers and people with chronic ankle instability. AB - CONTEXT: Differences in various outcome measures have been identified between people who have sprained their ankles but have no residual symptoms (copers) and people with chronic ankle instability (CAI). However, the diagnostic utility of the reported outcome measures has rarely been determined. Identifying outcome measures capable of predicting who is less likely to develop CAI could improve rehabilitation protocols and increase the efficiency of these measures. OBJECTIVE: To determine the diagnostic utility and cutoff scores of perceptual, mechanical, and sensorimotor outcome measures between copers and people with CAI by using receiver operating characteristic curves. DESIGN: Case-control study. SETTING: Sports medicine research laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty-four copers (12 men, 12 women; age = 20.8 +/- 1.5 years, height = 173 +/- 11 cm, mass = 78 +/- 27 kg) and 24 people with CAI (12 men, 12 women; age = 21.7 +/- 2.8 years, height = 175 +/- 13 cm, mass = 71 +/- 13 kg) participated. INTERVENTION(S): Self-reported disability questionnaires, radiographic images, and a single-legged hop stabilization test. MAIN OUTCOME MEASURE(S): Perceptual outcomes included scores on the Foot and Ankle Disability Index (FADI), FADI Sport, and a self-report questionnaire of ankle function. Mechanically, talar position was quantified by measuring the distance from the anterior tibia to the anterior talus in the sagittal plane. Sensorimotor outcomes were the dynamic postural stability index and directional indices, which were calculated during a single-legged hop stabilization task. RESULTS: Perceptual outcomes demonstrated diagnostic accuracy (range, 0.79-0.91), with 95% confidence intervals ranging from 0.65 to 1.00. Sensorimotor outcomes also were able to discriminate between copers and people with CAI but with less accuracy (range, 0.69-0.70), with 95% confidence intervals ranging from 0.37 to 0.86. The mechanical outcome demonstrated poor diagnostic accuracy (0.52). CONCLUSIONS: The greatest diagnostic utility scores were achieved by the self-assessed disability questionnaires, which indicated that perceptual outcomes had the greatest ability to accurately predict people who became copers after their initial injuries. However, the diversity of outcome measures that discriminated between copers and people with CAI indicated that the causal mechanism of CAI is probably multifactorial. PMID- 22488279 TI - Sex differences, hormone fluctuations, ankle stability, and dynamic postural control. AB - CONTEXT: Hormonal fluctuation as a risk factor in anterior cruciate ligament injury has been investigated with conflicting results. However, the influence of hormone fluctuations on ankle laxity and function has not been thoroughly examined. OBJECTIVE: To examine the potential hormone contributions to ankle laxity and dynamic postural control during the preovulatory and postovulatory phases of the menstrual cycle using an ankle arthrometer and the Star Excursion Balance Test in healthy women. The cohort group consisted of male control participants. DESIGN: Cohort study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty healthy women (age = 23.8 +/- 6.50 years, height = 163.88 +/- 8.28 cm, mass = 63.08 +/- 12.38 kg) and 20 healthy men (age = 23.90 +/ 4.15 years, height = 177.07 +/- 7.60 cm, mass = 80.57 +/- 12.20 kg). INTERVENTION(S): Ankle stability was assessed with anterior-posterior and inversion-eversion loading. Dynamic postural control was assessed with the posteromedial reaching distance of the Star Excursion Balance Test. MAIN OUTCOME MEASURE(S): Female participants used ovulation kits for 3 months to determine the time of ovulation; during their preovulatory and postovulatory phases, they were tested in the laboratory with an ankle arthrometer and the Star Excursion Balance Test. Male participants were tested on similar dates as controls. For each dependent variable, a time by side by sex repeated-measures analysis of variance was performed. Statistical significance was set a priori at P < .05. RESULTS: For anterior-posterior laxity, a side main effect was noted (F1,38 = 10.93, P = .002). For inversion-eversion laxity, a sex main effect was seen (F1,38 = 10.75, P = .002). For the posteromedial reaching task, a sex main effect was demonstrated (F1,38 = 8.72, P = .005). No influences of time on the dependent variables were evident. CONCLUSIONS: Although women presented with more ankle inversion-eversion laxity and less dynamic postural control, hormonal fluctuations during the menstrual cycle (preovulatory compared with postovulatory) did not affect ankle laxity or dynamic postural control, 2 factors that are associated with ankle instability. PMID- 22488280 TI - Risk factors associated with shoulder pain and disability across the lifespan of competitive swimmers. AB - CONTEXT: The prevalence of shoulder pain among competitive swimmers is high, but no guidelines exist to reduce shoulder injuries. Elucidating differences between swimmers with and without shoulder pain can serve as a basis for the development of a program to prevent shoulder injury that might lead to pain and dysfunction. OBJECTIVE: To determine whether physical characteristics, exposure, or training variables differ between swimmers with and without shoulder pain or disability. DESIGN: Cross-sectional study. SETTING: Multisite swimming centers. PATIENTS OR OTHER PARTICIPANTS: A total of 236 competitive female swimmers aged 8 to 77 years. DATA COLLECTION AND ANALYSIS: Participants completed the Penn Shoulder Score and underwent testing of core endurance, range of motion, muscle force production, and pectoralis minor muscle length and the Scapular Dyskinesis Test. Swimmers were grouped by age for analysis: ages 8 to 11 years (n = 42), 12 to 14 years (n = 43), 15 to 19 years (high school, n = 84), and 23 to 77 years (masters, n = 67). Comparisons were made between groups with and without pain and disability using independent t tests for continuous data and chi2 analyses and Fisher exact tests for categorical data. RESULTS: Nine (21.4%) swimmers aged 8 to 11 years, 8 (18.6%) swimmers aged 12 to 14 years, 19 (22.6%) high school swimmers, and 13 (19.4%) masters swimmers had shoulder pain and disability. Differences that were found in 2 or more age groups between athletes with and without shoulder pain and disability included greater swimming exposure, a higher incidence of previous traumatic injury and patient-rated shoulder instability, and reduced participation in another sport in the symptomatic groups (P < .05). Reduced shoulder flexion motion, weakness of the middle trapezius and internal rotation, shorter pectoralis minor and latissimus, participation in water polo, and decreased core endurance were found in symptomatic females in single varying age groups (P < .05). CONCLUSIONS: Female competitive swimmers have shoulder pain and disability throughout their lives. Given that exposure and physical examination findings varied between athletes with and without substantial pain and disability, a program to prevent shoulder injury that might lead to pain and dysfunction appears warranted and might include exposure reduction, cross training, pectoral and posterior shoulder stretching, strengthening, and core endurance training. PMID- 22488281 TI - Identifying multiplanar knee laxity profiles and associated physical characteristics. AB - CONTEXT: A single measure of knee laxity (ie, measurement of laxity in a single plane of motion) is probably inadequate to fully describe how knee joint laxity is associated with anterior cruciate ligament injury. OBJECTIVE: To characterize interparticipant differences in the absolute and relative magnitudes of multiplanar knee laxity (ie, sagittal, frontal, and transverse planes) and examine physical characteristics that may contribute to these differences. DESIGN: Descriptive laboratory study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: 140 participants (90 women, 50 men). MAIN OUTCOME MEASURE(S): Using cluster analysis, we grouped participants into distinct multiplanar knee laxity profiles based on the absolute and relative magnitudes of their anterior knee laxity (AKL), genu recurvatum (GR), and varusvalgus (VV) and internal-external rotation (IER) knee laxity. Using multinomial logistic regression, we then examined associations between the different laxity profile clusters and physical characteristics of sex, age, activity level, general joint laxity, body mass index, thigh strength, and 8 measures of lower extremity anatomical alignment. RESULTS: Six clusters were identified: low (LOW), moderate (MOD) and high (HIGH) laxity overall and disproportionally higher VV/IER (MOD(VV/IER)), GR (HIGH(GR)), and AKL (HIGH(AKL)) laxity. Once all other physical characteristics were accounted for, the LOW cluster was more likely to be older, with longer femur length. Clusters with greater magnitudes of VV and IER laxity were more likely to be younger and to have lower body mass index, smaller Q angle, and shorter femur length (MOD, HIGH, MOD(VV/IER)) and less thigh strength (HIGH). The HIGH(GR) cluster was more likely to be female and to have a smaller tibiofemoral angle and longer femur length. The HIGH(AKL) cluster was more likely to have greater hip anteversion and navicular drop. CONCLUSIONS: The absolute and relative magnitudes of a person's multiplanar knee laxity are not always uniform across planes of motion and can be influenced by age, body composition, thigh strength, and structural alignment. Except in HIGH(GR), sex was not a significant predictor of cluster membership once other physical characteristics were taken into account. PMID- 22488282 TI - Skinfold thickness at 8 common cryotherapy sites in various athletic populations. AB - CONTEXT: Researchers have observed slower cooling rates in thigh muscle with greater overlying adipose tissue, suggesting that cryotherapy duration should be based on the adipose thickness of the treatment site. Skinfold data do not exist for other common cryotherapy sites, and no one has reported how those skinfolds might vary because of physical activity level or sex. OBJECTIVE: To determine the variability in skinfold thickness among common cryotherapy sites relative to sex and activity level (National Collegiate Athletic Association Division I athletes, recreationally active college athletes). DESIGN: Descriptive laboratory study. SETTING: Field. PATIENTS OR OTHER PARTICIPANTS: Three hundred eighty-nine college students participated; 196 Division I athletes (157 men, 39 women) were recruited during preseason physicals, and 193 recreationally active college athletes (108 men, 85 women) were recruited from physical education classes. INTERVENTION(S): Three skinfold measurements to within 1 mm were taken at 8 sites (inferior angle of the scapula, middle deltoid, ulnar groove, midforearm, midthigh, medial collateral ligament, midcalf, and anterior talofibular ligament [ATF]) using Lange skinfold calipers. MAIN OUTCOME MEASURE(S): Skinfold thickness in millimeters. RESULTS: We noted interactions among sex, activity level, and skinfold site. Male athletes had smaller skinfold measurements than female athletes at all sites except the ATF, scapula, and ulnar groove (F7,2702 = 69.85, P < .001). Skinfold measurements were greater for recreationally active athletes than their Division I counterparts at all sites except the ATF, deltoid, and ulnar groove (F7,2702 = 30.79, P < .001). Thigh skinfold measurements of recreationally active female athletes were the largest, and their ATF skinfolds were the smallest. CONCLUSIONS: Skinfold thickness at common cryotherapy treatment sites varied based on level of physical activity and sex. Therefore, clinicians should measure skinfold thickness to determine an appropriate cryotherapy duration. PMID- 22488283 TI - Limb blood flow after class 4 laser therapy. AB - CONTEXT: Laser therapy is purported to improve blood flow in soft tissues. Modulating circulation would promote healing by controlling postinjury ischemia, hypoxia, edema, and secondary tissue damage. However, no studies have quantified these responses to laser therapy. OBJECTIVE: To determine a therapeutic dose range for laser therapy for increasing blood flow to the forearm. DESIGN: Crossover study. SETTING: Controlled laboratory setting. PATIENTS OR OTHER PARTICIPANTS: Ten healthy, college-aged men (age = 20.80 +/- 2.16 years, height = 177.93 +/- 3.38 cm, weight = 73.64 +/- 9.10 kg) with no current history of injury to the upper extremity or cardiovascular conditions. INTERVENTION(S): A class 4 laser device was used to treat the biceps brachii muscle. Each grid point was treated for 3 to 4 seconds, for a total of 4 minutes. Each participant received 4 doses of laser therapy: sham, 1 W, 3 W, and 6 W. MAIN OUTCOME MEASURE(S): The dependent variables were changes in blood flow, measured using venous occlusion plethysmography. We used a repeated-measures analysis of variance to analyze changes in blood flow for each dose at 2, 3, and 4 minutes and at 1, 2, 3, 4, and 5 minutes after treatment. The Huynh-Feldt test was conducted to examine differences over time. RESULTS: Compared with baseline, blood flow increased over time with the 3-W treatment (F(3,9) = 3.468, P < .011) at minute 4 of treatment (2.417 +/- 0.342 versus 2.794 +/- 0.351 mL/min per 100 mL tissue, P = .032), and at 1 minute (2.767 +/- 0.358 mL/min per 100 mL tissue, P < .01) and 2 minutes (2.657 +/- 0.369 mL/min per 100 mL tissue, P = .022) after treatment. The sham, 1 W, and 6-W treatment doses did not change blood flow from baseline at any time point. CONCLUSIONS: Laser therapy at the 3-W (360-J) dose level was an effective treatment modality to increase blood flow in the soft tissues. PMID- 22488284 TI - Heat stress and cardiovascular, hormonal, and heat shock proteins in humans. AB - CONTEXT: Conditions such as osteoarthritis, obesity, and spinal cord injury limit the ability of patients to exercise, preventing them from experiencing many well documented physiologic stressors. Recent evidence indicates that some of these stressors might derive from exercise-induced body temperature increases. OBJECTIVE: To determine whether whole-body heat stress without exercise triggers cardiovascular, hormonal, and extracellular protein responses of exercise. DESIGN: Randomized controlled trial. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty-five young, healthy adults (13 men, 12 women; age = 22.1 +/- 2.4 years, height = 175.2 +/- 11.6 cm, mass = 69.4 +/- 14.8 kg, body mass index = 22.6 +/- 4.0) volunteered. INTERVENTION(S): Participants sat in a heat stress chamber with heat (73 degrees C) and without heat (26 degrees C) stress for 30 minutes on separate days. We obtained blood samples from a subset of 13 participants (7 men, 6 women) before and after exposure to heat stress. MAIN OUTCOME MEASURE(S): Extracellular heat shock protein (HSP72) and catecholamine plasma concentration, heart rate, blood pressure, and heat perception. RESULTS: After 30 minutes of heat stress, body temperature measured via rectal sensor increased by 0.8 degrees C. Heart rate increased linearly to 131.4 +/- 22.4 beats per minute (F6,24 = 186, P < .001) and systolic and diastolic blood pressure decreased by 16 mm Hg (F6,24 = 10.1, P < .001) and 5 mm Hg (F6,24 = 5.4, P < .001), respectively. Norepinephrine (F1,12 = 12.1, P = .004) and prolactin (F1,12 = 30.2, P < .001) increased in the plasma (58% and 285%, respectively) (P < .05). The HSP72 (F1,12 = 44.7, P < .001) level increased with heat stress by 48.7% +/- 53.9%. No cardiovascular or blood variables showed changes during the control trials (quiet sitting in the heat chamber with no heat stress), resulting in differences between heat and control trials. CONCLUSIONS: We found that whole-body heat stress triggers some of the physiologic responses observed with exercise. Future studies are necessary to investigate whether carefully prescribed heat stress constitutes a method to augment or supplement exercise. PMID- 22488285 TI - Injuries in Portuguese youth soccer players during training and match play. AB - CONTEXT: Epidemiologic information on the incidence of youth soccer injuries in southern Europe is limited. OBJECTIVE: To compare the incidence, type, location, and severity of injuries sustained by male subelite youth soccer players over the 2008-2009 season. DESIGN: Descriptive epidemiology study. SETTING: Twenty-eight Portuguese male youth soccer teams. PATIENTS OR OTHER PARTICIPANTS: A total of 674 youth male subelite soccer players in 4 age groups: 179 U-13 (age range, 11 12 years), 169 U-15 (age range, 13-14 years), 165 U-17 (age range, 15-16 years), and 161 U-19 (age range, 17-18 years). MAIN OUTCOME MEASURE(S): Injuries that led to participation time missed from training and match play prospectively reported by medical or coaching staff of the clubs. RESULTS: In total, 199 injuries reported in 191 players accounted for 14.6 +/- 13.0 days of absence from practice. The incidence was 1.2 injuries per 1000 hours of exposure to soccer (95% confidence interval [CI] = 0.8, 1.6), with a 4.2-fold higher incidence during match play (4.7 injuries per 1000 hours of exposure; 95% CI = 3.0, 6.5) than during training (0.9 injuries per 1000 hours of exposure; 95% CI = 0.6, 1.3) (F1,673 = 17.592, P < .001). The overall incidence of injury did not increase with age (F1,673 = 1.299,P = .30), and the incidence of injury during matches (F1,673 = 2.037, P = .14) and training (F1,673 = 0.927, P = .44) did not differ among age groups. Collisions accounted for 57% (n = 113) of all injuries, but participation time missed due to traumatic injury did not differ among age groups (F3,110 = 1.044, P = .38). Most injuries (86%, n = 172) involved the lower extremity. The thigh was the most affected region (30%, n = 60) in all age groups. Muscle strains were the most common injuries among the U-19 (34%, n = 26), U-17 (30%, n = 17), and U-15 (34%, n = 14) age groups, whereas contusions and tendon injuries were the most common injuries in U-13 players (both 32%, n = 8). The relative risk of injury slightly increased with the age of the competitors. CONCLUSIONS: The higher incidence of injury during matches than training highlights the need for education and prevention programs in youth soccer. These programs should focus on coach education aimed at improving skills, techniques, and fair play during competitions with the goal of reducing injuries. PMID- 22488286 TI - Epidemiology of overuse and acute injuries among competitive collegiate athletes. AB - CONTEXT: Although overuse injuries are gaining attention, epidemiologic studies on overuse injuries in male and female collegiate athletes are lacking. OBJECTIVE: To report the epidemiology of overuse injuries sustained by collegiate athletes and to compare the rates of overuse and acute injuries. DESIGN: Descriptive epidemiology study. SETTING: A National Collegiate Athletic Association Division I university. PATIENTS OR OTHER PARTICIPANTS: A total of 1317 reported injuries sustained by 573 male and female athletes in 16 collegiate sports teams during the 2005-2008 seasons. MAIN OUTCOME MEASURE(S): The injury and athlete-exposure (AE) data were obtained from the Sports Injury Monitoring System. An injury was coded as either overuse or acute based on the nature of injury. Injury rate was calculated as the total number of overuse (or acute) injuries during the study period divided by the total number of AEs during the same period. RESULTS: A total of 386 (29.3%) overuse injuries and 931 (70.7%) acute injuries were reported. The overall injury rate was 63.1 per 10 000 AEs. The rate ratio (RR) of acute versus overuse injuries was 2.34 (95% confidence interval [CI] = 2.05, 2.67). Football had the highest RR (RR = 8.35, 95% CI = 5.38, 12.97), and women's rowing had the lowest (RR = 0.75, 95% CI = 0.51, 1.10). Men had a higher acute injury rate than women (49.8 versus 38.6 per 10 000 AEs). Female athletes had a higher rate of overuse injury than male athletes (24.6 versus 13.2 per 10,000 AEs). More than half of the overuse injuries (50.8%) resulted in no time loss from sport. CONCLUSIONS: Additional studies are needed to examine why female athletes are at greater risk for overuse injuries and identify the best practices for prevention and rehabilitation of overuse injuries. PMID- 22488287 TI - Sports nutrition knowledge among collegiate athletes, coaches, athletic trainers, and strength and conditioning specialists. AB - CONTEXT: Coaches, athletic trainers (ATs), strength and conditioning specialists (SCSs), and registered dietitians are common nutrition resources for athletes, but coaches, ATs, and SCSs might offer only limited nutrition information. Little research exists about sports nutrition knowledge and current available resources for nutrition information for athletes, coaches, ATs, and SCSs. OBJECTIVE: To identify resources of nutrition information that athletes, coaches, ATs, and SCSs use; to examine nutrition knowledge among athletes, coaches, ATs, and SCSs; and to determine confidence levels in the correctness of nutrition knowledge questions within all groups. DESIGN: Cross-sectional study. SETTING: National Collegiate Athletic Association Division I, II, and III institutions across the United States. PATIENTS AND OTHER PARTICIPANTS: The 579 participants consisted of athletes (n = 185), coaches (n = 131), ATs (n = 192), and SCSs (n = 71). MAIN OUTCOME MEASURE(S): Participants answered questions about nutrition resources and domains regarding basic nutrition, supplements and performance, weight management, and hydration. Adequate sports nutrition knowledge was defined as an overall score of 75% in all domains (highest achievable score was 100%). RESULTS: Participants averaged 68.5% in all domains. The ATs (77.8%) and SCSs (81.6%) had the highest average scores. Adequate knowledge was found in 35.9% of coaches, 71.4% of ATs, 83.1% of SCSs, and only 9% of athletes. The most used nutrition resources for coaches, ATs, and SCSs were registered dietitians. CONCLUSIONS: Overall, we demonstrated that ATs and SCSs have adequate sports nutrition knowledge, whereas most coaches and athletes have inadequate knowledge. Athletes have frequent contact with ATs and SCSs; therefore, proper nutrition education among these staff members is critical. We suggest that proper nutrition programming should be provided for athletes, coaches, ATs, and SCSs. However, a separate nutrition program should be integrated for ATs and SCSs. This integrative approach is beneficial for the continuity of care, as both categories of professionals might be developing and integrating preventive or rehabilitative programs for athletes. PMID- 22488288 TI - Perceived frequency of peer-assisted learning in the laboratory and collegiate clinical settings. AB - CONTEXT: Peer-assisted learning (PAL) has been recommended as an educational strategy to improve students' skill acquisition and supplement the role of the clinical instructor (CI). How frequently students actually engage in PAL in different settings is unknown. OBJECTIVE: To determine the perceived frequency of planned and unplanned PAL (peer modeling, peer feedback and assessment, peer mentoring) in different settings. DESIGN: Cross-sectional study. SETTING: Laboratory and collegiate clinical settings. PATIENTS OR OTHER PARTICIPANTS: A total of 933 students, 84 administrators, and 208 CIs representing 52 (15%) accredited athletic training education programs. INTERVENTION(S): Three versions (student, CI, administrator) of the Athletic Training Peer Assisted Learning Survey (AT-PALS) were administered. Cronbach alpha values ranged from .80 to .90. MAIN OUTCOME MEASURE(S): Administrators' and CIs' perceived frequency of 3 PAL categories under 2 conditions (planned, unplanned) and in 2 settings (instructional laboratory, collegiate clinical). Self-reported frequency of students' engagement in 3 categories of PAL in 2 settings. RESULTS: Administrators and CIs perceived that unplanned PAL (0.39 +/- 0.22) occurred more frequently than planned PAL (0.29 +/- 0.19) regardless of category or setting (F(1,282) = 83.48, P < .001). They perceived that PAL occurred more frequently in the collegiate clinical (0.46 +/- 0.22) than laboratory (0.21 +/- 0.24) setting regardless of condition or category (F(1,282) = 217.17, P < .001). Students reported engaging in PAL more frequently in the collegiate clinical (3.31 +/- 0.56) than laboratory (3.26 +/- 0.62) setting regardless of category (F(1,860) = 13.40, P < .001). We found a main effect for category (F(2,859) = 1318.02, P < .001), with students reporting they engaged in peer modeling (4.01 +/- 0.60) more frequently than peer mentoring (2.99 +/- 0.88) (P < .001) and peer assessment and feedback (2.86 +/- 0.64) (P < .001). CONCLUSIONS: Participants perceived that students engage in unplanned PAL in the collegiate clinical setting with a stronger inclination toward engagement in peer modeling. Educators should develop planned PAL activities to capitalize on the inherent desire of the students to collaborate with their peers. PMID- 22488289 TI - Psychometric properties of self-report concussion scales and checklists. AB - REFERENCE/CITATION: Alla S, Sullivan SJ, Hale L, McCrory P. Self-report scales/checklists for the measurement of concussion symptoms: a systematic review. Br J Sports Med. 2009;43 (suppl 1):i3-i12. CLINICAL QUESTION: Which self report symptom scales or checklists are psychometrically sound for clinical use to assess sport-related concussion? DATA SOURCES: Articles available in full text, published from the establishment of each database through December 2008, were identified from PubMed, Medline, CINAHL, Scopus, Web of Science, SPORTDiscus, PsycINFO, and AMED. Search terms included brain concussion, signs or symptoms, and athletic injuries, in combination with the AND Boolean operator, and were limited to studies published in English. The authors also hand searched the reference lists of retrieved articles. Additional searches of books, conference proceedings, theses, and Web sites of commercial scales were done to provide additional information about the psychometric properties and development for those scales when needed in articles meeting the inclusion criteria. STUDY SELECTION: Articles were included if they identified all the items on the scale and the article was either an original research report describing the use of scales in the evaluation of concussion symptoms or a review article that discussed the use or development of concussion symptom scales. Only articles published in English and available in full text were included. DATA EXTRACTION: From each study, the following information was extracted by the primary author using a standardized protocol: study design, publication year, participant characteristics, reliability of the scale, and details of the scale or checklist, including name, number of items, time of measurement, format, mode of report, data analysis, scoring, and psychometric properties. A quality assessment of included studies was done using 16 items from the Downs and Black checklist1 and assessed reporting, internal validity, and external validity. MAIN RESULTS: The initial database search identified 421 articles. After 131 duplicate articles were removed, 290 articles remained and were added to 17 articles found during the hand search, for a total of 307 articles; of those, 295 were available in full text. Sixty articles met the inclusion criteria and were used in the systematic review. The quality of the included studies ranged from 9 to 15 points out of a maximum quality score of 17. The included articles were published between 1995 and 2008 and included a collective total of 5864 concussed athletes and 5032 nonconcussed controls, most of whom participated in American football. The majority of the studies were descriptive studies monitoring the resolution of concussive self-report symptoms compared with either a preseason baseline or healthy control group, with a smaller number of studies (n = 8) investigating the development of a scale. The authors initially identified 20 scales that were used among the 60 included articles. Further review revealed that 14 scales were variations of the Pittsburgh Steelers postconcussion scale (the Post-Concussion Scale, Post-Concussion Scale: Revised, Post-Concussion Scale: ImPACT, Post Concussion Symptom Scale: Vienna, Graded Symptom Checklist [GSC], Head Injury Scale, McGill ACE Post-Concussion Symptoms Scale, and CogState Sport Symptom Checklist), narrowing down to 6 core scales, which the authors discussed further. The 6 core scales were the Pittsburgh Steelers Post-Concussion Scale (17 items), Post-Concussion Symptom Assessment Questionnaire (10 items), Concussion Resolution Index postconcussion questionnaire (15 items), Signs and Symptoms Checklist (34 items), Sport Concussion Assessment Tool (SCAT) postconcussion symptom scale (25 items), and Concussion Symptom Inventory (12 items). Each of the 6 core scales includes symptoms associated with sport-related concussion; however, the number of items on each scale varied. A 7-point Likert scale was used on most scales, with a smaller number using a dichotomous (yes/no) classification. Only 7 of the 20 scales had published psychometric properties, and only 1 scale, the Concussion Symptom Inventory, was empirically driven (Rasch analysis), with development of the scale occurring before its clinical use. Internal consistency (Cronbach alpha) was reported for the Post-Concussion Scale (.87), Post-Concussion Scale: ImPACT 22-item (.88-.94), Head Injury Scale 9-item (.78), and Head Injury Scale 16-item (.84). Test-retest reliability has been reported only for the Post-Concussion Scale (Spearman r = .55) and the Post Concussion Scale: ImPACT 21-item (Pearson r = .65). With respect to validity, the SCAT postconcussion scale has demonstrated face and content validity, the Post Concussion Scale: ImPACT 22-item and Head Injury Scale 9-item have reported construct validity, and the Head Injury Scale 9-item and 16-item have published factorial validity. Sensitivity and specificity have been reported only with the GSC (0.89 and 1.0, respectively) and the Post-Concussion Scale: ImPACT 21-item when combined with the neurocognitive component of ImPACT (0.819 and 0.849, respectively). Meaningful change scores were reported for the Post-Concussion Scale (14.8 points), Post-Concussion Scale: ImPACT 22item (6.8 points), and Post Concussion Scale: ImPACT 21-item (standard error of the difference = 7.17; 80% confidence interval = 9.18). CONCLUSIONS: Numerous scales exist for measuring the number and severity of concussion-related symptoms, with most evolving from the neuropsychology literature pertaining to head-injured populations. However, very few of these were created in a systematic manner that follows scale development processes and have published psychometric properties. Clinicians need to understand these limitations when choosing and using a symptom scale for inclusion in a concussion assessment battery. Future authors should assess the underlying constructs and measurement properties of currently available scales and use the ever-increasing prospective data pools of concussed athlete information to develop scales following appropriate, systematic processes. PMID- 22488290 TI - Left ventricle fibrosis associated with nonsustained ventricular tachycardia in an elite athlete: is exercise responsible? A case report. AB - OBJECTIVE: To emphasize the potentially harmful effects of high-intensity exercise on cardiac health and the fine line between physiologic and pathologic adaptation to chronic exercise in the elite athlete. This case also highlights the crucial need for regular evaluation of symptoms that suggest cardiac abnormality in athletes. BACKGROUND: Sudden cardiac death (SCD) of young athletes is always a tragedy because they epitomize health. However, chronic, high intensity exercise sometimes has harmful effects on cardiac health, and pathologic changes, such as myocardial fibrosis, have been observed in endurance athletes. In this case, a highly trained 30-year-old cyclist reported brief palpitations followed by presyncope feeling while exercising. Immediate investigations revealed nonsustained ventricular tachycardia originating from the left ventricle on a stress test associated with myocardial fibrosis of the left ventricle as shown with magnetic resonance imaging. Despite complete cessation of exercise, life-threatening arrhythmia and fibrosis persisted, leading to complete restriction from competition. Differential Diagnosis: Hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, myocarditis, postmyocarditis, use of drugs and toxic agents, doping, and systemic disease. TREATMENT: The arrhythmia could not be treated with catheter ablation procedure or drug suppression. Therefore, the athlete was instructed to withdraw completely from sport participation and to have a medical follow-up twice each year. UNIQUENESS: To our knowledge, no other report of left ventricle exercise induced fibrosis associated with life-threatening arrhythmia in a living young elite athlete exists. Only postmortem evidence supports such myocardial pathologic adaptation to exercise. CONCLUSIONS: To prevent SCD in young athletes, careful attention must be paid to exercise-related symptoms that suggest a cardiac abnormality because they more often are linked to life-threatening cardiovascular disease. PMID- 22488292 TI - Application of statistics in establishing diagnostic certainty. AB - The examination and assessment of injured and ill patients leads to the establishment of a diagnosis. However, the tests and procedures used in health care, including procedures performed by certified athletic trainers, are individually and collectively imperfect in confirming or ruling out a condition of concern. Thus, research into the utility of diagnostic tests is needed to identify the procedures that are most helpful and to indicate the confidence one should place in the results of the test. The purpose of this report is to provide an overview of selected statistical procedures and the interpretation of data appropriate for assessing the utility of diagnostic tests with dichotomous (positive or negative) outcomes, with particular attention to the interpretation of sensitivity and specificity estimates and the reporting of confidence intervals around likelihood ratio estimates. PMID- 22488291 TI - Exertional rhabdomyolysis in a collegiate american football player after preventive cold-water immersion: a case report. AB - OBJECTIVE: To describe a case of exertional rhabdomyolysis in a collegiate American football player after preventive coldwater immersion. BACKGROUND: A healthy man (19 years old) participated in full-contact football practice followed by conditioning (2.5 hours). After practice, he entered a coach-mandated postpractice cold-water immersion and had no signs of heat illness before developing leg cramps, for which he presented to the athletic training staff. After 10 minutes of repeated stretching, massage, and replacement of electrolyte filled fluids, he was transported to the emergency room. Laboratory tests indicated a creatine kinase (CK) level of 2545 IU/L (normal range, 45-260 IU/L), CK-myoglobin fraction of 8.5 ng/mL (normal < 6.7 ng/mL), and CK-myoglobin relative index of 30% (normal range, 25%-30%). Myoglobin was measured at 499 ng/mL (normal = 80 ng/mL). The attending physician treated the athlete with intravenous fluids. DIFFERENTIAL DIAGNOSIS: Exercise-associated muscle cramps, dehydration, exertional rhabdomyolysis. TREATMENT: The patient was treated with rest and rehydration. One week after the incident, he began biking and swimming. Eighteen days later, the patient continued to demonstrate elevated CK levels (527 IU/L) but described no other symptoms and was allowed to return to football practice as tolerated. Two months after the incident, his CK level remained high (1900 IU/L). UNIQUENESS: The athlete demonstrated no signs of heat illness upon entering the cold-water immersion but experienced severe leg cramping after immersion, resulting in a diagnosis of exertional rhabdomyolysis. Previously described cases have not linked cold-water immersion with the pathogenesis of rhabdomyolysis. CONCLUSIONS: In this football player, CK levels appeared to be a poor indicator of rhabdomyolysis. Our patient demonstrated no other signs of the illness weeks after the incident, yet his elevated CK levels persisted. Cold water immersion immediately after exercise should be monitored by the athletic training staff and may not be appropriate to prevent muscle damage, given the lack of supporting evidence. PMID- 22488293 TI - Validity and reliability of the EQ-5D for cancer patients in Korea. AB - PURPOSE: The purpose of this study was to assess the validity and reliability of the Korean version of the EQ-5D health questionnaire for use in patients with cancer in Korea. METHODS: Patients with colorectal cancer were recruited from one ambulatory cancer center. Each participant consecutively self-administered the EQ 5D, the EORTC QLQ-C30, and the Short Form-36 (SF-36). Discriminatory ability was evaluated by comparing the SF-36 subscales with their corresponding EQ-5D dimensions. Convergent validity was assessed by examining the correlations between the EQ-5D index, EORTC QLQ-C30 subscales, and SF-36 scale and summary scores. Test-retest reliability was also evaluated. RESULTS: Subjects reporting problems in each EQ-5D dimension showed lower scores on all SF-36 subscales. As expected, the relationships were stronger between the EQ-5D functional dimensions and physical function on the EORTC QLQ-C30 and between the EQ-5D anxiety/depression dimension and emotional function on the EORTC QLQ-C30. The EQ 5D index and SF-36 scales were moderately or highly correlated. intraclass correlation coefficient of the EQ-5D index was 0.45. CONCLUSIONS: The Korean version of the EQ-5D may be a valid tool for assessing the health-related quality of life of patients with cancer. However, further research is needed to determine the reliability of the Korean EQ-5D over different time intervals and disease conditions. PMID- 22488294 TI - Quantitative analysis of the functionalization of gallium phosphide with organic azides. AB - Gallium phosphide (GaP) surfaces were functionalized with two different molecules that contain an azide moiety at their terminus. Compound 4-azidophenacyl bromide (4AB) is an aryl azide with a bromine group at its opposite terminus that provides easy identification of the molecule's presence on the surface with x-ray photoelectron spectroscopy (XPS). O-(2-aminoethyl)-O'-(2-azidoethyl)pentaethylene glycol (AAP) is a small poly(ethylene glycol) molecule with an amine group at its opposite terminus. Atomic force microscopy was used to identify the uniformity of the clean and functionalized GaP surfaces. Water contact angle revealed a more hydrophobic surface with AAP functionalization (33 degrees ) and even more hydrophobic (53 degrees ) with the 4AB functionalized surface compared to a clean surface (16 degrees ). XPS confirmed the presence of each of the organic azides on the surface. XPS was further used to calculate the adlayer thickness of each functionalization. This analysis revealed an adlayer thickness of about 8 A for the 4AB functionalized surfaces compared to 1 A for the AAP adlayer, which led to the conclusion that AAP functionalization only provided partial coverage. A stability study using 4AB-functionalized surfaces showed good stability in saline solutions with varying concentrations of hydrogen peroxide. Finally, inductively coupled plasma mass spectrometry was used to evaluate the gallium concentration in the stability solutions. While the functionalization with the organic azides did not provide complete suppression of gallium leaching, both of the azides decreased the leaching by 10-50%. PMID- 22488295 TI - Simultaneous treatment of renal cysts and stones with single-session retroperitoneoscopic renal cyst decortication and retroperitoneoscopy-assisted percutaneous nephrolithotomy. AB - INTRODUCTION: To determine the safety and efficacy of single-session retroperitoneoscopic renal cyst decortication in conjunction with retroperitoneoscopy-assisted percutaneous nephrolithotomy (PCNL) for simultaneous treatment of renal cysts and stones. PATIENTS AND METHODS: We enrolled 15 patients (10 men and 5 women, mean age 41 years), who underwent one-stage retroperitoneoscopic renal cyst decortication and retroperitoneoscopy-assisted PCNL between January 2008 and May 2009 for symptomatic renal cysts and concomitant large kidney stones (mean stone area 6.6 cm(2)). Intraoperative blood loss, duration of operation, and postoperative complications were evaluated. Median follow-up time was 22 months (range 12-26). RESULTS: Average total operative time was 83 +/- 12 min and mean duration of PCNL was 45 +/- 5 min. Mean estimated blood loss was 80 +/- 21 ml. A plain abdominal radiograph revealed an absence of residual stones in all cases. No cyst recurrence occurred within the follow-up period. The mean pre- and postoperative pain score was 7.3 +/- 0.8 and 2.8 +/- 0.6, respectively. All patients resumed ambulatory activities on the first postoperative day. No severe complications related to the procedure were encountered. CONCLUSION: The combined laparoscopic approach for simultaneous treatment of renal cysts and stones is safe and feasible. These results encourage further studies to determine long-term outcomes of this combined surgery. PMID- 22488296 TI - Development of active controlled retrieval during middle childhood. AB - The aim of this study was to examine the development of active controlled memory retrieval in children. Active retrieval is an effortful retrieval required to disambiguate information stored in memory. Brain imaging studies and monkey experiments have shown that the ventrolateral prefrontal cortex (VLPFC) is specifically engaged in this retrieval in both adult humans and monkeys. Three groups of 6-, 8-, and 11-year-old children and adults were tested on an active retrieval task. Results showed a marked difference in performance between 6-year olds, who made more errors and had longer response time, and 8- and 11-year olds, who had performance similar to adults. These results provide evidence that the VLPFC and the network supporting its top-down modulation undergo substantial maturational changes between 6 and 8 years old, giving children better active control of visual memory. PMID- 22488297 TI - Epithelial-mesenchymal transition: a hallmark in metastasis formation linking circulating tumor cells and cancer stem cells. AB - The occurrence of either regional or distant metastases is an indicator of poor prognosis for cancer patients. The mechanism of their formation has not yet been fully uncovered, which limits the possibility of developing new therapeutic strategies. Nevertheless, the discovery of circulating tumor cells (CTCs), which are responsible for tumor dissemination, and cancer stem cells (CSCs), required for tumor growth maintenance, shed light on the metastatic cascade. It seems that CTCs and CSCs are not necessarily separate populations of cancer cells, as CTCs generated in the process of epithelial-mesenchymal transition (EMT) can bear features characteristic of CSCs. This article describes the mechanisms of CTC and CSC formation and characterizes their molecular hallmarks. Moreover, we present different types of EMT occurring in physiological and pathological conditions, and we demonstrate its crucial role in providing CTCs with a CSC phenotype. The article delineates molecular changes acquired by cancer cells undergoing EMT that facilitate metastasis formation. Deeper understanding of those processes is of fundamental importance for the development of new strategies of early cancer detection and effective cancer treatment approaches that will be translated into clinical practice. PMID- 22488298 TI - Association between black stains and dental caries in primary teeth: findings from a Brazilian population-based birth cohort. AB - Lower dental caries experience has been observed in children and teenagers with the presence of black stains on dental structures. However, none of the previous investigations were population-based studies or adjusted the analysis for potential confounders. This study assessed the prevalence of black stains at the age of 5 in a population-based birth cohort from Pelotas, Brazil and investigated the association between black stains and dental caries. A total of 1,129 children from the 2004 Pelotas birth cohort were examined at age 5, and their mothers were interviewed at their households. Dental examinations included a search for black stains and dental caries on the primary dentition through the dmf-s index. The mothers' questionnaire comprised data on demographic, social, and behavior aspects. Prevalence of black stains was 3.5% (95% CI 2.5-4.7) and the prevalence of dental caries was 48.4% (95% CI 45.4-51.4). Multivariable logistic regression analysis was performed to assess the association between black stains and dental caries. Adjusted analysis revealed that the presence of black stains was associated with lower levels of dental caries (OR = 0.51; 95% CI 0.26-0.99). The results of the present study suggest that black stains are a protective factor for dental caries development. PMID- 22488299 TI - Accelerated stability studies of abatacept formulations: comparison of freeze thawing- and agitation-induced stresses. AB - Accelerated degradation studies are frequently used to screen for formulation conditions that confer adequate shelf life for therapeutic proteins. To speed development cycles, degradation is often accelerated by application of conditions that expose proteins to elevated temperatures, dynamic air-water interfaces created by agitation, or stresses induced by freeze-thaw cycling. The purpose of this case study was to compare freeze-thaw- and agitation-induced aggregations with aggregation previously studied at elevated temperatures (Fast J, Cordes AA, Carpenter JF, Randolph TW. 2009. Biochemistry 48:11724-11736) using the therapeutic fusion protein abatacept as a model. The stability of abatacept against aggregation induced by the freeze-thaw and agitation degradation methods was assessed by size-exclusion chromatography (SEC) and microflow imaging (MFI) analysis. pH conditions that were previously found to increase conformational stability of abatacept and reduce aggregation during incubation at elevated temperature (Fast J, Cordes AA, Carpenter JF, Randolph TW. 2009. Biochemistry 48:11724-11736) also reduced aggregation induced by freeze-thaw cycling and by agitation in this study. Especially in the case of the freeze-thaw cycling, wherein the formation of aggregates was not readily detectable by SEC, MFI proved to be a useful method to characterize the stability of the formulations against aggregation. PMID- 22488300 TI - A genome wide shRNA screen identifies alpha/beta hydrolase domain containing 4 (ABHD4) as a novel regulator of anoikis resistance. AB - Acquisition of resistance to anchorage dependant cell death, a process termed anoikis, is a requirement for cancer cell metastasis. However, the molecular determinants of anoikis resistance and sensitivity are poorly understood. To better understand resistance to anoikis we conducted a genome wide lentiviral shRNA screen to identify genes whose knockdown render anoikis-sensitive RWPE-1 prostate cells resistant to anoikis. RWPE-1 cells were infected with a pooled lentiviral shRNA library with 54,021 shRNA targeting 11,255 genes. After infection, an anoikis-resistant cell population was selected and shRNA sequences were amplified and sequenced. Thirty-four shRNA sequences reproducibly protected RWPE-1 cells from anoikis after culture under suspension conditions including the top validated hit, alpha/beta hydrolase domain containing 4 (ABHD4). In validation studies, ABHD4 knockdown inhibited anoikis in RWPE-1 cells as well as anoikis sensitive NP69 nasopharyngeal and OVCAR3 ovarian cancer cells, while over expression of the gene increased sensitivity. Induction of anoikis after ABHD4 knockdown was associated with cleavage of PARP and activation of caspases-3, but was independent in changes of FLIP, FAK and Src expression. Interestingly, induction of anoikis after ABHD4 knockdown was independent of the known role of ABHD4 in the anandamide synthesis pathway and the generation of glycerophospho-N acyl ethanolamines. Thus, ABHD4 is a novel genetic regulator of anoikis sensitivity. PMID- 22488301 TI - Proposal of new classification for stage III breast cancer on the number and ratio of metastatic lymph nodes. AB - BACKGROUND: The objective of the retrospective study was to confirm whether the current staging system of stage III was appropriate for breast cancer. METHODS: Four hundred fifteen patients with breast cancer in stage III were analyzed. The survival analysis was performed by Kaplan-Meier. RESULTS: Survival time of the patients with T1N3M0 was significantly better than the patients with other subgroups of stage IIIC (T2,3,4N3M0) and similar that of patients with T4N0,1,2M0 who formed the stage IIIB group based on pN stage. Tumor size, number of positive lymph nodes and lymph node ratio (LNR) were associated with overall survival (OS). The greatest survival difference was found when 0.60 as the cutoff point of LNR for the patients with current stage IIIC (pN3). rN1 included the patients in pN3 with LNR <= 0.60 and rN2 included the patients in pN3 with LNR >0.60. Survival time of the patients with T1,2,3,4N3(rN1)M0 and T1N3(rN2)M0 was differently better than the patients with T2,3,4N3(rN2)M0 and similar that of patients with T4N0,1,2M0. CONCLUSION: We suggested current staging system should be modified combining pN with rN. We presumed the patients with T1N3M0 and T2,3,4N3(rN1)M0 disease were excluded from the current stage IIIC and included in stage IIIB group. PMID- 22488303 TI - Evaluation of vancomycin dosing regimens in preterm and term neonates using Monte Carlo simulations. AB - STUDY OBJECTIVE: To compare four common dosing regimens for vancomycin in preterm and term neonates by assessing the probability that each regimen would achieve the widely used therapeutic target serum trough concentrations of 5-15 mg/L and the newly suggested target of 15-20 mg/L. DESIGN: Retrospective population pharmacokinetic analysis using therapeutic drug monitoring data obtained from 1990-2007, with a subsequent simulation study performed on the pharmacokinetic model. SETTING: Tertiary-care children's hospital. PATIENTS: One hundred thirty four preterm (66%) and term (34%) neonates, with a postnatal age of 1-121 days and postmenstrual age of 24.6-44 weeks. MEASUREMENTS AND MAIN RESULTS: Therapeutic drug monitoring data for vancomycin were used to develop a population pharmacokinetic model in the target population. Parameter estimates for the derived pharmacostatistical model were used to perform Monte Carlo simulations for four recommended dosing regimens: a standard dose for all neonates, postmenstrual age-based dosing, postmenstrual and postnatal age-based dosing, and serum creatinine-based dosing. Multivariate age-weight distributions were established for term and preterm neonates using Centers for Disease Control and Prevention growth charts and intrauterine and postnatal growth charts from the literature, respectively. Each dosing regimen was treated as a separate scenario in which 200 replicates with 100 patients/replicate were simulated. The 5-15-mg/L target trough serum concentration was achieved in 34% (90% confidence interval [CI] 20-53%), 42% (90% CI 31-55%), 52% (90% CI 43-60%), and 63% (90% CI 54-72%) of patients receiving the standard dose, postmenstrual age-based dose, postmenstrual and postnatal age-based dose, and serum creatinine-based dose, respectively. Serum creatinine-based dosing produced trough concentrations predominantly in the 5-15-mg/L target range, with the smallest variability in both term and preterm neonates. As expected, when the target range was narrow and higher (15-20 mg/L), only 13-21% of patients were within the range across the four dosing regimens. CONCLUSION: Monte Carlo simulations based on our population pharmacokinetic model suggest that vancomycin dosing guidelines based on serum creatinine concentration have a greater likelihood of achieving trough concentrations in the 5-15-mg/L range compared with other evaluated dosing regimens. None of the four dosing regimens is suitable to produce target trough concentration of 15-20 mg/L in an acceptable number of patients. PMID- 22488302 TI - Large-scale analysis of tumor necrosis factor alpha levels in systemic lupus erythematosus. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) disease manifestations are highly variable among patients, and the prevalence of individual clinical features differs significantly by ancestry. Serum tumor necrosis factor alpha (TNFalpha) levels are elevated in some SLE patients and may play a role in disease pathogenesis. The aim of this study was to look for associations between serum TNFalpha levels, clinical manifestations of SLE, autoantibodies, and serum interferon-alpha (IFNalpha) levels in a large multiancestral SLE cohort. METHODS: We studied serum TNFalpha levels in 653 SLE patients (214 African Americans, 298 European Americans, and 141 Hispanic Americans). TNFalpha was measured using an enzyme-linked immunosorbent assay, and IFNalpha was measured with a functional reporter cell assay. Stratified and multivariate analyses were used to detect associations in each ancestral background separately, with meta-analysis when appropriate. RESULTS: Serum TNFalpha levels were significantly higher in SLE patients than in non-autoimmune disease controls (P < 5.0 * 10(-3) for each ancestral background). High serum TNFalpha levels were positively correlated with high serum IFNalpha levels when tested in the same sample across all ancestral backgrounds (odds ratio range 1.76-1.86, P = 4.8 * 10(-3) by Fisher's combined probability test). While serum TNFalpha levels alone did not differ significantly among SLE patients of different ancestral backgrounds, the proportion of patients with concurrently high levels of TNFalpha and IFNalpha was highest in African Americans and lowest in European Americans (P = 5.0 * 10(-3) ). Serum TNFalpha levels were not associated with autoantibodies, clinical criteria for the diagnosis of SLE, or age at the time of sampling. CONCLUSION: Serum TNFalpha levels are high in many SLE patients, and we observed a positive correlation between serum TNFalpha and IFNalpha levels. These data support a role for TNFalpha in the pathogenesis of SLE across all ancestral backgrounds and suggest important cytokine subgroups within the disease. PMID- 22488304 TI - Babesia and red cell invasion. AB - PURPOSE OF REVIEW: Babesiosis is a zoonosis, a disease communicable from animals to humans and an important blood-borne human parasitic infection. Despite its public health impact, its study has largely been neglected. The objective of this review is to present up-to-date information on both parasite and red blood cell molecules that function at the host-parasite interface to facilitate successful invasion. RECENT FINDINGS: In the last few years, a number of parasite proteins have been identified from genome projects and from functional red cell-binding assays. However, their cognate receptors as well as the precise function these ligands perform in the cascade of invasive events remain umknown. There also appears to be a significant overlap in the structural and functional aspects of the invasion machinery between malaria and Babesia. SUMMARY: Recognizing that Babesia is an expanding blood safety threat, there should be rapid progress in the development of viable interventions to detect and halt transmission of these pathogens via blood transfusions. By developing a detailed mechanistic understanding of invasion, we can then exploit the participating molecules to procure much needed reagents for diagnosis, epidemiology, treatment and prevention of human babesiosis. PMID- 22488306 TI - Vascular lumen formation. AB - PURPOSE OF REVIEW: The lumen of a blood vessel is essential for providing blood to any given tissue. Here, we discuss the molecular and cellular mechanisms underlying vascular lumen formation in invertebrates and vertebrates and highlight a new hypothesis describing oxygen transport in human malignant tumors. RECENT FINDINGS: Several cellular mechanisms exist for blood vessel formation, that is vasculogenesis, intercellular and intracellular sprouting angiogenesis, and intussusceptive angiogenesis, all of which might follow common molecular principles to form a vascular lumen. The latter includes junctional remodeling and generation of apical endothelial cell surfaces, electrostatic deadhesion of these cell surfaces to create a small lumen between two or more apposing endothelial cells or a cavity within an endothelial cell, and force-dependent expansion or extension of the vascular lumen. Whereas these events require endothelial cells, vascular lumen formation in invertebrates mostly occurs in their absence. As therapeutically targeting endothelial cells alone does not prevent vascular supply and growth of human malignant tumors, the possibility exists that some tumors employ invertebrate-like mechanisms of vascular lumen formation. SUMMARY: Whereas the molecular mechanisms of endothelial cell-based vascular lumen formation are beginning to be understood, it is still largely unknown how invertebrates and some malignant tumors establish a circulatory system in the absence of endothelium. PMID- 22488307 TI - The future of the Brazilian Unified National Health System. PMID- 22488305 TI - Integrin signaling in vascular function. AB - PURPOSE OF REVIEW: In the current review, we summarize recent progress on vasculature-specific function and regulation of integrins and integrin-associated proteins, including advances in our understanding of inside-out integrin activation. The studies on regulation of integrin activation received new impulse in 2009 with the identification of kindlin protein family members as crucial mediators of integrin inside-out signaling. In the current review, we outline the recent findings on the role of kindlins in the vascular system, as well as new studies that have begun shaping the mechanistic model of kindlins' function. RECENT FINDINGS: Several tissue-specific knockout models for integrins and genes associated with the integrin functions have been recently presented, including smooth muscle-specific integrin-linked kinase and endothelial-specific focal adhesion kinase and talin-1 ablation. In the heterozygous animal knockout model, kindlin-2 has been demonstrated as a crucial modulator of angiogenesis and vascular permeability. As a number of articles have advanced our understanding of kindlin function, they are reviewed and discussed in further detail. New findings include an additional lipid-binding site within the kindlin molecule and preferential binding of the nonphosphorylated form of beta-integrins. SUMMARY: The role of integrins in angiogenesis has been demonstrated to include, in addition to cell adhesion and mechanotransduction, specific signaling functions. The importance of integrin inside-out pathway in vascular physiology has been unequivocally proven, and endothelial permeability is directly regulated by this process. Inhibition of kindlin-dependent steps in the inside-out pathway as an approach to block platelet aggregation should be paralog-specific, as it may have adverse effects on vascular permeability. PMID- 22488308 TI - [The use of management contracts and professional incentives in the public health sector]. AB - Results-based management is a cornerstone of reform in public administration, including the health field, and has become the basis for other innovations such as the institutionalization of management contracts and the use of professional incentives. This review article aims to introduce and discuss the use of such management contracts in the public health sector. Management by results has developed means and tools that highlight the importance of shared responsibility and mutual commitment between workers and management-level directors. Thus, preset goals are negotiated among all the stakeholders and are evaluated periodically in order to grant professional incentives. It is necessary to improve the mechanisms for control and observation, to more precisely determine the healthcare and management indicators and their patterns, to train stakeholders in designing the plan, and to improve the use of professional incentives in order to effectively increase accountability vis-a-vis the desired results. PMID- 22488309 TI - [Public hospital emergency department visits due to burns in Brazil, 2009]. AB - The objective was to analyze the characteristics of burn injuries treated in emergency departments (ED) and associated factors. This was a cross-sectional study of 761 ED visits collected through the National Injury Surveillance System in 2009. The majority of patients were males (58.6%), and the most prevalent age brackets were 30-49 years (23.1%) and 0-4 years (23%). Most burns occurred at home (62.1%), especially among females and children, and in commerce/services/industry/construction (19.1%), mainly among males 20-49 years. Work-related burns comprised 29.1% of the overall sample. Alcohol use prior to the injury was reported in 5.1% of cases. Causal agents across all age brackets were: contact with hot substances (43.6%) and exposure to fire and flames (24.2%); among the economically productive age groups, association with chemicals substances was common. Burns in children 0-14 years were associated with injuries at home, contact with heat and hot substances, and subsequent hospitalization; burns in the 15-49-year bracket were associated with exposure to fire/flames and electrical current, injuries occurring in public places, and outpatient treatment and discharge. The study highlights the importance of burn prevention strategies targeting children and workers. PMID- 22488310 TI - [Factors associated with early breastfeeding cessation: a birth cohort study in two municipalities in the Reconcavo region, Bahia State, Brazil]. AB - This study aimed to identify the median duration of breastfeeding and associated factors in a cohort of 531 infants in two municipalities in the Reconcavo region, Bahia State, Brazil. Breastfeeding duration was estimated by survival analysis and its associations by the Cox multivariate model. Median duration of exclusive breastfeeding, mixed breastfeeding with complementary feeding, and total breastfeeding was 74.73, 211.25, and 432.63 days, respectively. Lack of prenatal care increased the risk of shortening exclusive breastfeeding by 173% (HR = 2.73; 95%CI: 1.89-3.93), [corrected] of adopting mixed breastfeeding with complementary feeding by 83% (HR = 1.83; [corrected] 95%CI: 1.06-3.16), and of discontinuing breastfeeding entirely by 38% (HR = 1.38; 95%CI: 1.06-1.81). Both maternal employment and residence in an urban area increased the risk of early breastfeeding cessation. Expansion of access to prenatal care and the safety network for employed mothers living in urban areas could increase breastfeeding duration in the target region. PMID- 22488311 TI - Teenage pregnancy contextualized: understanding reproductive intentions in a Brazilian shantytown. AB - This paper presents the results of a socio-anthropological study with women from a low-income community in Belo Horizonte, Minas Gerais State, Brazil. Through the use of qualitative methods it looks at teenage pregnancy from the young mothers' perspective and the contribution of their socioeconomic environment. It shows the importance of different actors in their fertility decision and identifies contradictory cultural norms that recriminate teenage sexual activity while seeing motherhood as a ritual of passage to adulthood. Following criticisms of insufficient family planning programs and negative health and economic outcomes for the lives of youngsters, the paper argues that motherhood stands as a successful activity through which they fulfill the collectively recognized ideal of womanhood, also carrying a sense of achievement in an environment where lack of opportunities prevail long before pregnancy occurs. Improving formal knowledge and economic well-being are possible solutions to provide these girls with goals that go beyond parenthood while within reach of their economic reality. PMID- 22488312 TI - [Firearm mortality in Argentina, 1990-2008]. AB - This is a descriptive epidemiological study of firearm mortality in Argentina, 1990-2008. The study compared the firearm mortality percentages and rates between the country's jurisdictions. The data are from the Office of Health Statistics and Information, Ministry of Health. From 1990 to 2008 there were 358,484 deaths from external causes, of which 16.6% (59,339) were caused by firearms. The Province of Buenos Aires showed the highest percentage and crude and adjusted rates. The jurisdictions in the Pampeana region (including the Province of Buenos Aires) showed a more homogeneous profile, similar to that of the country as a whole, with an increase in the rates from 1999 to 2002 and a decrease from 2003 to 2006. These findings are partially explained by the country's deteriorating socioeconomic conditions in the late 20th century, with a greater impact on Buenos Aires, one of the provinces of Argentina with the greatest development and economic dynamism. The situation in Buenos Aires was aggravated by the fact that the Province has one of the country's most repressive police forces. PMID- 22488313 TI - [Adolescent substance use and family problems]. AB - This study aimed to evaluate the association between substance use (alcohol, tobacco, and illicit drugs) and family problems among 965 adolescents from 50 public schools in two cities in Sao Paulo State, Brazil, in 2007. The Drug Use Screening Inventory (DUSI) was used for data collection. Use of alcohol, tobacco, and illicit drugs was associated with a negative assessment of the family relationship, lack of monitoring/support, and psychoactive substance use by family members (p < 0.05). Adolescents that reported having used alcohol, tobacco, and illicit drugs had more family problems than those who did not consume any substance (p < 0.001). Adolescents that used alcohol and tobacco (p = 0.028) and illicit drugs (p < 0.001) reported having more family problems than those who used only alcohol. The results highlight the importance of awareness of alcohol and tobacco use by adolescents, since such use was associated with significant family impairments, similar to illicit drug use. PMID- 22488314 TI - [Asthma prevalence and risk factors in adolescents 13 to 14 years of age in Cuiaba, Mato Grosso State, Brazil]. AB - The objective of this study was to estimate the prevalence of active asthma and identify associated risk factors in adolescents 13 to 14 years of age in Cuiaba, Mato Grosso State, Brazil. A cross-sectional population-based and a subsequently a nested case-control study was conducted in 2008 using the protocol of the International Study of Asthma and Allergies in Childhood (ISAAC). Risk factor analysis used the chi-square test, Fisher's exact test, and binary logistic regression. Variables with p < 0.20 in the bivariate analysis entered the logistic regression model, with six variables remaining in the final model (p < 0.05). Prevalence of active asthma was 19.1%. Risk factors for active asthma (p = 0.01) were: smoking during pregnancy, exclusive breastfeeding < 6 months, family income < 3 minimum wages, female gender, pets currently in the home, and absence of fish in the diet. Prevalence of active asthma was high, but with a significant reduction compared to 1998. PMID- 22488315 TI - Hepatotoxicity induced by antituberculosis drugs among patients coinfected with HIV and tuberculosis. AB - Hepatotoxicity due to antituberculosis drugs limits treatment in patients coinfected with HIV and tuberculosis. We conducted a case-control study to identify risk factors for hepatotoxicity among patients coinfected with tuberculosis and HIV in two hospitals in Recife, Pernambuco State, Brazil. The sample consisted of 57 patients (36.5% of the total) who developed hepatotoxicity and a control group of 99 patients (63.5% of the total), who did not present this effect. Hepatotoxicity consisted of jaundice or a high concentration of AST/ALT or total bilirubinemia. Multivariate logistic regression showed that a T CD4+ count of < 200 cells/mm(3) increased the risk of hepatotoxicity by a factor of 1.233 (p < 0.001) and that coinfection with hepatitis B or C virus increased this risk by a factor of 18.187 (p = 0.029). Discharge occurred among 66.1% of the case group (p = 0.026). The absence of hepatotoxicity was a protective factor against death (OR = 0.42; 95%CI: 0.20-0.91). Coinfection with the B and C hepatitis virus and a T CD4+ cell count below 200 cells/mm(3) were independent risk factors for hepatotoxicity in these patients. PMID- 22488316 TI - Unsafe abortion: social determinants and health inequities in a vulnerable population in Sao Paulo, Brazil. AB - This cross-sectional population-based study in a peripheral low-income community in Sao Paulo, Brazil, aimed to estimate the prevalence of unsafe abortion and identify the socio-demographic characteristics associated with it and its morbidity. The article discusses the study's results, based on univariate and multiple multinomial logistic regression analyses. The final regression models included: age at first intercourse < 16 years (OR = 4.80); > 2 sex partners in the previous year (OR = 3.63); more live born children than the woman's self reported ideal number (OR = 3.09); acceptance of the abortion due to insufficient economic conditions (OR = 4.07); black ethnicity/color (OR = 2.67); and low schooling (OR = 2.46), all with p < 0.05. The discussion used an approach to social determinants of health based on the concept and model adopted by the WHO and the health inequities caused by such determinants in the occurrence of unsafe abortion. According to the findings, unsafe abortion and socio-demographic characteristics are influenced by the social determinants of health described in the study, generating various levels of health inequities in this low-income population. PMID- 22488317 TI - [The vulnerable male, or the sex ratio among fetal deaths in Brazil]. AB - Some studies indicate the existence of innate male vulnerabilities, especially during the perinatal period. The current study is a cross-sectional analysis of fetal mortality in Brazil according to sex from 2000 to 2009, stratified by maternal characteristics (age, schooling, and gestational age), using Ministry of Health data (DATASUS). The analysis included all fetal deaths from 2000 to 2009, except when the sex of the fetus was not recorded. The male/female sex ratio (SR) for all fetal deaths was 1.188. Analysis of maternal characteristics showed that the SR was statistically higher (p < 0.01) in mothers that were younger (10-14 years), had no formal schooling, and with gestational age < 22 weeks. The study showed a statistically higher-than-expected SR (p < 0.01) for 13 underlying causes of death and a lower SR for two others. The results suggest a potential innate male vulnerability. PMID- 22488318 TI - [Incentives to attract and retain the health workforce in rural areas of Peru: a qualitative study]. AB - The study aimed to identify the main incentives for attracting and retaining health workers in rural and remote health facilities in Ayacucho, Peru. In-depth interviews were performed with 80 physicians, obstetricians, nurses, and nurse technicians in the poorest areas (20 per group), plus 11 health managers. Ayacucho lacks systematic policies for attracting and retaining human resources. The main incentives, in order of relevance, were higher wages, opportunities for further training, longer/permanent contracts, better infrastructure and medical equipment, and more staff. Interviewees also mentioned improved housing conditions and food, the opportunity to be closer to family, and recognition by the health system. Health workers and policymakers share perceptions on key incentives to encourage work in rural areas. However, there are also singularities to be considered when designing specific strategies. Public initiatives thus need to be monitored and evaluated closely in order to ensure the intended impact. PMID- 22488319 TI - [Hospital costs related to streptococcal meningitis among children in Sao Jose dos Campos, Sao Paulo State, Brazil]. AB - Knowledge of hospital costs is highly important for public health decision making. This study aimed to estimate direct hospital costs related to pneumococcal meningitis in children 13 years or younger in the city of Sao Jose dos Campos, Sao Paulo State, Brazil, from January 1999 to December 2008. Data were obtained from medical records. Hospital costs were calculated according to the mixed method for measurement of quantities of items with identified costs and value attribution to items consumed (micro-costing and gross-costing). All costs were calculated according to monetary values for November 2009 and in Brazilian currency (Real). Epi Info 3.5.1 was used for frequencies and means analysis. Forty-one cases were reported. Direct hospital costs varied from R$ 1,277.90 to R$ 19,887.56 (mean = R$ 5,666.43), or 10 to 20 times the mean cost of hospitalization for other diseases. Hospital staff labor was the highest cost, followed by medication, procedures, supplies, and lab tests. PMID- 22488320 TI - The effects of air pollution on respiratory health in susceptible populations: a multilevel study in Bucaramanga, Colombia. AB - We conducted a cohort study to investigate the association between exposure to three different levels of outdoor air pollution and incidence of respiratory symptoms in a population with chronic cardiovascular and respiratory disease. We accompanied 756 participants for a period of six months through the maintenance of a daily record of symptoms and clinic visits. The symptoms with highest incidence rates were sneezing and hacking cough. Multivariate analysis showed that incidence of total symptoms was 60% and 74% lower in areas with medium and low levels of pollution compared to areas with high levels of pollution. These results suggest that negative respiratory effects occur at concentrations of particulate matter PM10 > 60 ug/m(3). PMID- 22488321 TI - [Labor market structure and access to private health insurance in Brazil]. AB - This paper aims to describe health insurance coverage among different types of workers in Brazil. Health insurance coverage and labor market insertion are used to define homogeneous groups of workers. The Grade of Membership method is used to build a typology of workers. The database was the Brazilian National Household Survey (PNAD) for 1998 and 2003, including a health survey. Five worker profiles were defined. The key variables were: health insurance coverage, schooling, and work status. The main findings show a positive association between health insurance coverage, income from work, and trade union membership. PMID- 22488322 TI - [Self-rated health in the elderly: a population-based study in Campinas, Sao Paulo, Brazil]. AB - This study analyzed self-rated health in the elderly according to demographic, socioeconomic, and health-related behavior. This was a cross-sectional, population-based study with a cluster sample using data from a survey in Campinas, Sao Paulo State, Brazil (ISACamp 2008-2009). Adjusted prevalence ratios were estimated using multiple Poisson regression. The study enrolled 1,432 elderly. Prevalence of excellent/very good health was 24.6% and was significantly higher in the elderly with more schooling, higher income, no religion, living alone, home computer, alcohol consumption 1-4 times a month, physical activity during leisure-time, no obesity, and fruit and vegetable consumption >= 4 times a week. Some of the findings are scarce in the literature and indicate relevant topics for further investigation. The results highlight the need for greater attention to socially vulnerable groups and the development of strategies to promote healthy habits in the elderly. PMID- 22488323 TI - [Lumbar hyperlordosis in children and adolescents at a privative school in southern Brazil: occurrence and associated factors]. AB - Posture assessment during childhood and adolescence allows early detection of postural disorders and adoption of preventive measures. This study evaluated the occurrence of lumbar hyperlordosis and associated factors in 467 children and adolescents aged 10 to 16 years at a school in Porto Alegre, Rio Grande do Sul State, Brazil. Lumbar hyperlordosis was defined as increased lumbar curvature evaluated by photography. Prevalence of lumbar hyperlordosis was 78%. Factors positively associated with lumbar hyperlordosis were female gender (PR = 1.08; 95%CI: 1.03; 1.13), abdominal strength below the 20th percentile (PR = 1.10; 95%CI: 1.05; 1.15), and flexibility below the 20th percentile (PR = 1.07; 95%CI: 1.01; 1.12). Lumbar hyperlordois was negatively associated with lumbar mobility (PR = 0.90; 95%CI: 0.85; 0.96) and height (PR = 0.995; 95%CI: 0.99; 0.999). Effective strategies to improve physical fitness in schoolchildren are necessary, because low abdominal strength and low flexibility were associated with lumbar hyperlordosis. PMID- 22488324 TI - [Quality of prenatal care: traditional primary care and Family Health Strategy units in a city in southern Brazil]. AB - Prenatal care in traditional primary care units (UBS) and Family Health Strategy units (ESF) was evaluated by a cross-sectional study from July 2009 to February 2010 in Santa Maria, Rio Grande do Sul State, Brazil. Seven hundred and ninety five postpartum women who had received prenatal care in either of the two types of units were interviewed. Four quality levels were used: level 1 (Kessner index modified by Takeda); level 2, which adds clinical obstetric procedures to level 1; level 3, which adds laboratory tests to level 1; and level 4, which includes all the above parameters. Prenatal care in the Family Health Strategy was superior to that of traditional primary care at all levels, with statistically significant differences in levels 1 and 2. Pregnant women received more guidance and prenatal care was superior in the Family Health Strategy. The study favored the Family Health Strategy, but improvement is still needed in the performance of procedures and laboratory tests in order to enhance prenatal care and strengthen primary care. PMID- 22488325 TI - One-year mortality among elderly people after hospitalization due to fall-related fractures: comparison with a control group of matched elderly. AB - Fall-related fractures among the elderly represent an important public health problem. Severe fractures have been related to increased risk of death. In order to investigate the mortality profile of elderly individuals with severe fractures, 250 patients aged 60 years and over, hospitalized due to fall-related fractures and 250 elderly without fractures living in the local community were followed-up for one year. They were matched according to sex, age, time of hospitalization and neighborhood. Deaths were identified using probabilistic linkage of the research dataset and the local mortality registry. The one-year cumulative mortality was 25.2% in the case of individuals with severe fractures and 4% for those individuals without. The mortality distribution was not homogeneous across the follow-up period. Two-thirds of deaths among the elderly individuals hospitalized due to fracture occurred within the first 3 months, whereas mortality among those individuals without fractures took place later. Heart disease, pneumonia, GI bleeding, sepsis, and pulmonary embolism, diabetes and stroke were important causes of one-year mortality. PMID- 22488326 TI - [Semantic and conceptual equivalences of the Portuguese version of the National College Health Assessment II]. AB - The objective of this study was to describe the semantic and conceptual equivalences of the National College Health Assessment II (NCHA II). The original version of the NCHA II was translated into Portuguese and back-translated into English. A committee of experts analyzed the different versions of the questionnaire. The version of the translated NCHA II questionnaire was experimentally administered to a sample of 64 university students of both sexes. After minor changes identified in the translation process, the committee of experts concluded that the Portuguese version of the NCHA II showed semantic and conceptual equivalences. In conclusion, the initial stages of the process of cross-cultural adaptation of the NCHA II questionnaire were satisfactory. Future studies are necessary to identify psychometric properties and validation indicators prior to the effective recommendation of the instrument for safe use. PMID- 22488327 TI - Biochemical profile and outcomes in trauma patients subjected to open cardiopulmonary resuscitation: a prospective observational pilot study. AB - BACKGROUND: The predictive factors to regain a heartbeat following emergency department resuscitative thoracotomy (EDT) for trauma are poorly understood. The objective of the present study was to prospectively assess the electrolyte profile, coagulation parameters, and acid-base status from intracardiac blood samples in trauma patients subjected to open cardiopulmonary resuscitation (CPR) in the presence of established cardiac arrest. METHODS: All patients who underwent EDT following trauma were considered for inclusion. Prior to the injection of any resuscitative medications, a sample of intracardiac blood from the right ventricle was obtained for analysis. RESULTS: During the study period, a total of 22 patients had intracardiac blood samples obtained and were eligible for analysis. Twelve patients never regained cardiac activity, and 10 patients transiently regained a heartbeat for a mean of 51 +/- 69 min, but ultimately died. Some 91 % (20/22) of patients presented with severe acidosis (pH < 7.20). The pCO(2) was <45 mmHg in 68 % (15/22) of patients, and the pO(2) level was >75 mmHg in 77 % (17/22) of patients. Patients who never regained cardiac activity had a significantly higher lactate level than those with a return of cardiac rhythm (17.1 +/- 2.6 vs. 10.6 +/- 4.9 mmol/L, p = 0.018). The sodium and potassium levels were higher for those who never regained a rhythm than for those who did regain a pulse (sodium: 155 +/- 14 vs. 147 +/- 9 mmol/L, p = 0.094; potassium: 6.0 +/- 1.1 vs. 4.6 +/- 1.0 mmol/L, p = 0.014). Severe hyperkalemia (potassium > 5.5 mmol/L) occurred significantly more often in patients who did not regain a heart beat (p = 0.030). Coagulopathy (INR > 1.2 and/or prothrombin time >15 s and/or platelet count <100,000/MUL) was noted in 96 % of patients. CONCLUSIONS: Most patients undergoing open CPR have normal blood gas levels. Severe lactic acidosis, hyperkalemia, and hypernatremia are associated with decreased probability for return of cardiac function. Calcium and magnesium levels were not significantly different between the two groups, making the therapeutic role of these electrolytes very questionable. PMID- 22488328 TI - Surgery, fame, and misfortune: the life of Bronislaw Kader. AB - Bronislaw Kader (1863-1937) introduced one of the traditional methods of gastrostomy. He was a Polish doctor who had been trained by such eminent surgeons as Ernst von Bergmann, Otto E. Kustner, Jan Mikulicz, and Eduard von Wahl. The Kader method implies blunt division of the left rectus muscle and opening of the stomach by a very small incision. A drainage tube is then inserted and fastened to the stomach wall by a stitch. Next, the stomach wall is sutured to the abdominal wall in a manner that places the tube in a tunnel surrounded by serosa. In comparison to others, Kader's method of gastrostomy was considered simpler, cheaper (fewer stitches), speedy, and safe. Although recommendations to perform gastric fistula were limited at the time, the value of gastrostomy remains undisputable. This is a method of choice for securing alimentation in cases of intractable stenosis of the pharynx or esophagus, which are usually due to cancer, chemical burns, trauma, or congenital defects. Nowadays, it is performed endoscopically or laparoscopically. This article presents the life history of Bronislaw Kader, the eponymous of this method and a gifted surgeon who lost his eyesight at the height of his fame. PMID- 22488329 TI - A tool and index to assess surgical capacity in low income countries: an initial implementation in Sierra Leone. AB - BACKGROUND: A first step toward improving surgical care in many low and middle income countries is to document the need. To facilitate the collection and analysis of surgical capacity data and measure changes over time, Surgeons OverSeas (SOS) developed a tool and index based on personnel, infrastructure, procedures, equipment, and supplies (PIPES). METHODS: A follow-up assessment of 10 government hospitals in Sierra Leone was completed 42 months after an initial survey in 2008 using the PIPES tool. An index based on number of operating rooms, personnel, infrastructure, procedures, equipment, and supplies was calculated. An index was also calculated, using the 2008 data for comparison. RESULTS: Most hospitals demonstrated an increased index that correlated with site visits that verified improved conditions. Connaught Hospital in Sierra Leone had the highest score (9.2), consistent with its being the best equipped and staffed Ministry of Health and Sanitation facility. Makeni District Hospital had the greatest increase, from 3.8 to 7.5, consistent with a newly constructed facility. DISCUSSION: The PIPES tool was easily administered at hospitals in Sierra Leone and an index was found useful. Surgical capacity in Sierra Leone improved between 2008 and 2011, as demonstrated by an increase in the overall PIPES indices. PMID- 22488330 TI - Ganglioside biosynthesis in developing brains and apoptotic cancer cells: X. regulation of glyco-genes involved in GD3 and Sialyl-Lex/a syntheses. AB - Gangliosides, the acidic glycosphingolipids (GSLs) containing N acetylgalactosamine and sialic acid are ubiquitous in the central nervous system. At least six DSL-glycosyltransferase activities (GLTs Gangliosides, the acidic glycosphingolipids (GSLs) containing N-acetylgalactosamine and sialic acid (or NAc-Neuraminic acid) are ubiquitous in the central nervous system. At least six GSL-glycosyltransferase activities (GLTs) of Basu-Roseman pathway catalyzing the biosynthesis of these gangliosides have been characterized in developing chicken brains. Most of these glyco-genes are expressed in the early stages (7-17 days) of brain development and lowered in the adult stage, but the cause of reduction of enzymatic activities of these GLTs in the adult stages is not known. In order to study glyco-gene regulation we used four clonal metastatic cancer cells of colon and breast cancer tissue origin (Colo-205, SKBR-3, MDA-468, and MCF-3). The glyco-genes for synthesis of SA-LeX and SA-LeA (which contain N acetylglucosamine, sialic acid and fucose) in these cells were modulated differently at different phases (between 2 and 48 h) of apoptotic inductions. L PPMP, D-PDMP (inhibitor of glucosylceramide biosynthesis), Betulinic Acid (a triterpinoid isolated from bark of certain trees and used for cancer treatment in China), Tamoxifen a drug in use in the west for treatment of early stages of the disease in breast cancer patients), and cis-platin (an inhibitor of DNA biosynthesis used for testicular cancer patients) were used for induction of apoptosis in the above-mentioned cell lines. Within 2-6 h, transcriptional modulation of a number of glyco-genes was observed by DNA-micro-array (containing over 300 glyco genes attached to the glass cover slips) studies. Under long incubation time (24-48 h) almost all of the glyco-genes were downregulated. The cause of these glyco-gene regulations during apoptotic induction in metastatic carcinoma cells is unknown and needs future investigations for further explanations. These apoptotic agents could be employed as a new generation of anti-cancer drugs after properly delivered to the patients. PMID- 22488331 TI - Essential roles of gangliosides in the formation and maintenance of membrane microdomains in brain tissues. AB - Gangliosides are considered to be involved in the maintenance and repair of nervous tissues. Recently, novel roles of gangliosides in the regulation of complement system were reported. Here we summarized roles of gangliosides in the formation and maintenance of membrane microdomains in brain tissues by comparing complement activation, inflammatory reaction and disruption of glycolipid enriched microdomain (GEM)/rafts among several mutant mice of ganglioside synthases. Depending on the defects in ganglioside compositions, corresponding up regulation of complement-related genes, proliferation of astrocytes and infiltration of microglia were found with gradual severity. Immunoblotting of fractions separated by sucrose density gradient ultracentrifugation revealed that DAF and NCAM having GPI-anchors tended to disappear from the raft fraction with intensities of DKO > GM2/GD2 synthase KO > GD3 synthase KO > WT. The lipid raft markers tended to disperse from the raft fractions with similar intensities. Phospholipids and cholesterol also tended to decrease in GEM/rafts in GM2/GD2 synthase KO and DKO, although total amounts were almost equivalent. All these results indicate that GEM/rafts architecture is destroyed by ganglioside deficiency with gradual intensity depending on the degree of defects of their compositions. Implication of inflammation caused by deficiency of gangliosides in various neurodegenerative diseases was discussed. PMID- 22488335 TI - Low-dose droperidol (<=1 mg or <=15 MUg kg-1) for the prevention of postoperative nausea and vomiting in adults: quantitative systematic review of randomised controlled trials. AB - CONTEXT: Droperidol is widely used for the prevention of postoperative nausea and vomiting (PONV) in European countries. It is unclear how efficacious low-dose droperidol is in the prevention of PONV. OBJECTIVES: To test the efficacy of low dose droperidol in the prevention of PONV in adults and to test for dose responsiveness. DESIGN: Systematic review of randomised controlled trials with meta-analyses. DATA SOURCES: Comprehensive search in electronic databases (Medline, Embase, Central) up to June 2011. Additional trials were obtained from bibliographies of retrieved reports. No language restriction was applied. ELIGIBILITY CRITERIA: Randomised trials testing prophylactic intravenous droperidol <=1 mg or <=15 MUg kg compared with placebo (or no treatment) in adults undergoing general anaesthesia and reporting on PONV. RESULTS: We analysed 25 trials (2957 patients). Doses varied from 0.25 to 1.0 mg. For prevention of early nausea (within 6 h postoperatively), relative risk (RR) was 0.45 (95% CI, 0.35 to 0.58); number needed to treat (NNT) was 7, 4, and 2 for low, medium and high baseline risk (i.e. control event rate 25, 50, 75%). For prevention of early vomiting, RR was 0.65 (95% CI, 0.57 to 0.74), NNT 11, 6, and 4. For prevention of late nausea (within 24 h), RR was 0.74 (95% CI, 0.62 to 0.87), NNT 15, 8, and 5. For prevention of late vomiting, RR was 0.61 (95% CI, 0.47 to 0.80), NNT 10, 5, and 3. Droperidol decreased the risk of headache but increased the risk of restlessness. For these outcomes there was no evidence of dose-responsiveness. There were no differences in the incidences of sedation or dizziness. Two patients receiving droperidol 0.625 mg had extrapyramidal symptoms. Cardiac toxicity data were not reported. CONCLUSION: Prophylactic doses of droperidol of 1 mg or below are antiemetic. Because adverse drug reactions are likely to be dose-dependent, there is an argument to stop using doses of more than 1 mg. PMID- 22488336 TI - Successful ultrasound guidance for transversus abdominis plane blocks improves postoperative analgesia after open appendicectomy in children. PMID- 22488332 TI - Roles of glutamine synthetase inhibition in epilepsy. AB - Glutamine synthetase (GS, E.C. 6.3.1.2) is a ubiquitous and highly compartmentalized enzyme that is critically involved in several metabolic pathways in the brain, including the glutamine-glutamate-GABA cycle and detoxification of ammonia. GS is normally localized to the cytoplasm of most astrocytes, with elevated concentrations of the enzyme being present in perivascular endfeet and in processes close to excitatory synapses. Interestingly, an increasing number of studies have indicated that the expression, distribution, or activity of brain GS is altered in several brain disorders, including Alzheimer's disease, schizophrenia, depression, suicidality, and mesial temporal lobe epilepsy (MTLE). Although the metabolic and functional sequelae of brain GS perturbations are not fully understood, it is likely that a deficiency in brain GS will have a significant biological impact due to the critical metabolic role of the enzyme. Furthermore, it is possible that restoration of GS in astrocytes lacking the enzyme could constitute a novel and highly specific therapy for these disorders. The goals of this review are to summarize key features of mammalian GS under normal conditions, and discuss the consequences of GS deficiency in brain disorders, specifically MTLE. PMID- 22488337 TI - Is a determination of medical futility ethical? AB - Medical futility is a timely topic and one fraught with ethical implications. Medical futility is a term used to describe medical interventions that are expected to result in little or no benefit to a patient. This Editorial examines some considerations and applications of medical futility to a specific patient or treatment, the ramifications of the use of the term futility, and its effects on physician-patient communication and the role of the health care administrator. Invoking medical futility is fraught with areas of vulnerability and implications in ethical decision making. Of concern is whether the treatment will cause more harm than good (nonmaleficence), whether it respects patients' goals and desires (autonomy), and whether the interests of patients, society, and the organization are served (justice). PMID- 22488338 TI - News from the National Case Management Network of Canada: A systems-level approach to safe and effective transitions. PMID- 22488339 TI - Reducing chronic obstructive pulmonary disease readmissions: the role of the durable medical equipment provider. AB - PURPOSE/OBJECTIVES: Exacerbation and frequent rehospitalization in chronic obstructive pulmonary disease exacts a heavy toll on the US health care system. To address these issues, new initiatives have been proposed that are largely based on financial penalties to promote patient education and postdischarge care. However, as laudable as these goals are, improving outcomes in the chronic obstructive pulmonary disease population is more confounding than it may first appear. Chronic hypoxia, cognitive dysfunction, poor nutrition, and economic disadvantage are just a few of the challenges that require creative solutions and ongoing support. Case managers need to utilize all the potential products and services that can assist in improving outcomes for these patients. Durable medical equipment providers are often viewed as purveyors of medical equipment that offer little in the form of clinical support. However, in many cases these providers represent an overlooked resource that provides individualized, highly structured patient education and ongoing support programs. The challenge is in identifying those durable medical equipment providers that offer patients contemporary technology, and have both the resources and the commitment to provide patient support that is amenable to the goals of the hospital. This article reviews many of the confounding issues that contribute to the frequent rehospitalization of chronic obstructive pulmonary disease patients. Recommendations to improve patient education and oxygen therapy outcomes are provided along with suggestions to aid in the vetting of durable medical equipment providers. PRIMARY PRACTICE SETTING: Acute care hospitals, long-term acute care hospitals, extended care facilities, integrated delivery systems. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: 1. An understanding of the complex variables that play in the management of chronic obstructive pulmonary disease will help the case manager to plan an effective course of care. 2. Case managers need to ensure that patients receive long-term oxygen technology that supports their lifestyle, promotes compliance, and ultimately achieves the desired outcomes. 3. Case managers must advocate for coordinated, ongoing patient education and stress the need for continuing reinforcement. 4. Case managers must ensure that patients under their care be matched with durable medical equipment providers that provide the technology and support that favors positive clinical outcomes. PMID- 22488341 TI - Hospital to home: a transition program for frail older adults. AB - PURPOSE OF STUDY: This study describes a social-worker navigator transitional care model for at-risk seniors being discharged from hospital to home. The model is designed to prevent rehospitalizations so as to improve quality of life and patient outcomes. This model is different from others with its focus on the psychosocial aspects of care transitions, medical needs, and individualized needs with the provision of nonreimbursable services. PRIMARY PRACTICE SETTING: Care begins in the acute care hospital or inpatient rehabilitation facility and continues in the postdischarge home environment. Participants are connected to community services to support their independent living at home. METHODOLOGY AND SAMPLE: Case managers, physicians, or others refer potential participants to the navigator. Criteria for inclusion include the following: age 65 years or older, Medicare and/or Medicaid recipient, living in the same county as the hospital, and having at least 2 of a list of 11 criteria that predict readmission. After the participant agrees to enroll, the navigator recommends in-home services at discharge. Within the first 72 hr, the navigator makes a home visit to evaluate the home environment, assess medical management, and make referrals for other services. Follow-up phone calls and other home visits are made by the navigator during the participant's enrollment, which is from 30 days to 4 months. RESULTS: Hospital readmissions were decreased by 61% for this high-risk population. Cost savings by preventing readmissions correlated to a cost savings of $628,202 per year. The 36-Item Short-Form Health Survey showed statistically significant improvements in quality-of-life scores for both physical and mental health summary scales and for all 8 subscales (p < .004). Almost all (99%) of respondents were satisfied with the overall Hospital to Home program. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: The results of this study demonstrate the importance of extending social support and health education into the home after discharge from the hospital. Access to immediate in-home care services such as transportation, housekeeping, laundry, and light meal preparation allows patients not to experience gaps in care that could result in a readmission. The assigned navigator reinforces medical management and connects participants to appropriate community resources in order to remain safe at home. PMID- 22488343 TI - Pneumonia rehospitalization of the Medicare fee-for-service patient: a state level analysis: exploring 30-day readmission factors. AB - PURPOSE OF THE STUDY: Pneumonia hospitalization and subsequent readmission among the elderly are frequent and costly both to patient and to the Medicare trust fund. In this study, we explored the factors that are associated with states having pneumonia readmission rates that are higher than the U.S. national rate. PRIMARY PRACTICE SETTING(S): Acute inpatient hospital settings. METHODOLOGY AND SAMPLE: Fifty state-level data and multivariate regression analysis were used. The dependent variable pneumonia 30-day readmission worse than U.S. rate was based on adult Medicare fee-for-service patients hospitalized with a primary discharge diagnosis of pneumonia and for which a subsequent inpatient readmission occurred within 30 days of their last discharge. RESULTS: Two key variables- discharge information given to the patient and giving correct initial antibiotic(s)--explain a decreased chance for states ranking "worse" on pneumonia 30-day readmission. States with a higher percentage of White Medicare enrollees, a higher median income, more total days of care, and more Medicare enrollees with prescription drug coverage have a greater chance for pneumonia 30-day readmission to be worse than the U.S. national rate. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Case management interventions targeting (1) inpatient clinical processes on antibiotic treatment and (2) patient discharge instructions may be more effective than other factors to improve state-level hospital performance on pneumonia 30-day readmission. Improving patient access to postdischarge medication(s) may not be as important a factor as are antibiotic treatment and patient discharge preparedness. Hospital programs aimed to prevent readmission disparities should not overlook nonminority and higher income population groups. PMID- 22488344 TI - The next half of the battle: workforce readiness for board-certified case managers. PMID- 22488345 TI - Bounce-backs. PMID- 22488346 TI - Standards of practice: the essence of a profession. PMID- 22488347 TI - Managing the return to work issues after a concussion. PMID- 22488348 TI - Staying stuck! The case manager's predicament, part 2. PMID- 22488350 TI - Helicobacter species and liver disease. PMID- 22488351 TI - Anti-inflammatory gallic Acid and wedelolactone are G protein-coupled receptor-35 agonists. AB - G protein-coupled receptor-35 (GPR35) has been shown to be a target of the asthma drugs cromolyn disodium and nedocromil sodium. Gallic acid and caffeic acids are reported to modulate allergic reactions via unknown mode(s) of action. Here we attempt to elucidate whether both phenolic acids share a common mode of action with the two asthma drugs. Label-free dynamic mass redistribution (DMR) assays showed that both phenolic acids triggered robust DMR signals in HT-29 cells, whose characteristics were similar to that of cromolyn disodium. Both phenolic acids resulted in detectable beta-arrestin translocation signals in an engineered U2OS cell line stably expressing a C-terminal-modified GPR35, but with lower efficacy than cromolyn disodium. Antiallergic wedelolactone was found to be a potent beta-arrestin-biased GPR35 agonist. These results suggest that certain anti-inflammatory phytochemicals including gallic acid and wedelolactone may modulate inflammatory allergic action via their agonism at GPR35. GPR35 may represent a target for the treatment of allergic disorders including asthma. PMID- 22488349 TI - Timeline for development of autologous bone marrow infusion (ABMi) therapy and perspective for future stem cell therapy. AB - Liver cirrhosis patients generally progress to liver failure. To cure this progressive disease, we developed a novel cell therapy using bone marrow cells; autologous bone marrow cell infusion (ABMi) therapy. We previously described the possible action mechanism of ABMi therapy in the cirrhotic liver, and showed the timeline and results of clinical studies of ABMi therapy. We have also carried out other clinical studies using bone marrow cells and granulocyte colony stimulating factor. Here, we report a new randomized clinical trial to evaluate the effects of ABMi therapy. However, ABMi therapy may not be possible in patients who are unable to undergo general anesthesia; therefore, we have started to develop a next-generation stem cell therapy using cultured mesenchymal stem cells. PMID- 22488352 TI - Cytokines in induced sputum: a role for the ratio of IL-6/IL-13 in the differentiation of asthma and chronic obstructive pulmonary disease? PMID- 22488353 TI - Design of donors with broad absorption regions and suitable frontier molecular orbitals to match typical acceptors via substitution on oligo(thienylenevinylene) toward solar cells. AB - A series of oligo(thienylenevinylene) derivatives with or without thieno[3,2 b]thiophene analogs as cores and three types substituent has been investigated at the PBE0/6-31G(d) and the TD-PBE0/6-31+G(d,p) levels to design materials with high performance such as suitable frontier molecular orbital (FMO) energies to match those of [6,6]-phenyl-C(61)-butyric acid methyl ester (PCBM) and its derivatives, broad absorption spectra, higher and balance transfer property, and better stability. The results reveal that fused cores have slight effects on photophysical properties of investigated derivatives. The electron-withdrawing or push-pull substituents result in red shifts of absorption spectra and better stabilities for investigated derivatives. The calculated reorganization energies of designed derivatives suggest them to be good potential ambipolar transport materials under the proper operating conditions. The promising donors for PCBM, bisPCBM, PC70BM, and indene-C(60) bisadduct (ICBA) as acceptors are recommended theoretically for solar cells based on the proper match for FMOs between donors and acceptors. Moreover, we have also predicted the mobility of designed molecule with better performance. PMID- 22488354 TI - Rise to power: a case study of male fecal androgen and cortisol levels before and after a non-aggressive rank change in a group of wild white-faced capuchins (Cebus capucinus). AB - We examined fecal androgen and cortisol levels in three adult male white-faced capuchin monkeys (Cebus capucinus) before and after a non-aggressive rank increase in one habituated group residing in the Santa Rosa Sector of the Area de Conservacion Guanacaste, Costa Rica. Fecal samples (n = 116) were collected opportunistically between July 2006 and July 2007. Alpha males had higher mean androgen levels than subordinates, and acquisition of the alpha position was linked to an immediate increase in mean androgens. Cortisol levels also increased in the alpha male after acquisition of his new rank, though this increase was delayed relative to the change in rank. These results indicate that, during a non aggressive rank change, androgen and cortisol levels in male white-faced capuchins are physiological responses to dominance rank, rather than precursors that facilitate rank acquisition. PMID- 22488355 TI - Multiplex fluorometric assessment of nutrient limitation as a strategy for enhanced lipid enrichment and harvesting of Neochloris oleoabundans. AB - Detailed in this study are the results of fluorometric assays used to assess the impact of gradual nutrient limitation versus punctuated nitrate limitation on the lipid content and morphology of Neochloris oleoabundans cells in batch culture. Punctuated nitrate limitation was imposed during pre-log, log, late-log, stationary, and senescent growth phases, and the cells were analyzed by bulk fluorescence emission, flow cytometry, and hyperspectral fluorescence imaging. In addition to intrinsic spectroscopic signatures provided by scatter and endogenous fluorescence, Nile Red staining was employed to monitor relative changes in lipid concentration. Analysis of the fluorescence images and temporal data sets was performed using multivariate curve resolution and fitting to logistic growth models to extract parameters of interest. The spectral components independently isolated from the image and temporal data sets showed close agreement with one another, especially relating to chlorophylls and Nile Red in polar and neutral lipid fractions, respectively. The fastest accumulation and highest total neutral lipid per cell and per chlorophyll were obtained with punctuated nitrate limitation during log phase growth on day 4 of culture. The presence of unbound chlorophyll in the resulting lipid bodies supports a membrane recycling TAG accumulation mechanism mediated by chloropolast-ER lipid exchange. Furthermore, an increase in cell size, indicated by forward scatter, was also found to correlate with increased neutral lipid, providing a size selection mechanism for passive harvest of algal cells at peak lipid enrichment. PMID- 22488357 TI - Immunology for the Balkans. PMID- 22488359 TI - An additional piece in the puzzle of neutrophil-derived IL-1beta: the NLRP3 inflammasome. AB - The notion that neutrophils play a pivotal role in orchestrating ongoing inflammatory immune responses has been bolstered by several fairly newly described effector mechanisms, particularly their capacity to serve as a source of cytokines. This frequently neglected phenomenon is acquiring more and more credit and, as a result, our understanding of the molecular basis of neutrophil derived cytokines has grown tremendously in the past 20 years. It is now clear that cytokine secretion by neutrophils is controlled by sophisticated regulatory mechanisms. In this issue of the European Journal of Immunology, Mankan et al. (Eur. J. Immunol. 42: 710-715) further extend our knowledge by reappraising the role of the inflammasome pathway, specifically the NLRP3 sensor, in the secretion of mature IL-1beta by murine neutrophils. Accordingly, Mankan et al. (Eur. J. Immunol. 42: 710-715) identify the neutrophil expression of the NLRP3 inflammasome complex, and by using specific knockout mice, they also show that, in LPS-primed neutrophils, the NLRP3/ASC/caspase-1 axis plays a nonredundant role for IL-1beta processing in response to typical NLRP3 inflammasome stimuli. PMID- 22488360 TI - Fulfilling the dream: tolerogenic dendritic cells to treat multiple sclerosis. AB - Autoimmune diseases including multiple sclerosis (MS) are the result of an imbalanced immune tolerance network. Dendritic cells (DCs) are key players in both initiating immunity (immunogenic DCs) and regulating immune responses (tolerogenic DCs = tolDCs) and are potential targets for the treatment of MS. While the immunogenic potential of DCs in fighting infection and cancer has been well established, approaches that exploit their tolerogenic features to promote transplantation tolerance and autoimmunity have emerged only more recently. TolDCs usually maintain antigen-specific T-cell tolerance either directly by inducing anergy, apoptosis, or phenotype skewing or indirectly by induction of regulatory T (Treg) cells. The use of ex vivo-generated tolDCs is an experimental approach to achieve tolerance towards myelin-antigen-specific CD4(+) T cells. In the article by Raiotach-Regue and colleagues (Eur. J. Immunol. 2011. 42:772-783) in this issue of the European Journal of Immunology, advances in human tolDC preparation and promise for autologous therapy are described. These findings raise hopes of achieving the "ideal" of a highly-specific, causally-oriented immune intervention for central nervous system (CNS) autoimmunity in MS. However, recent experience with antigen-specific immune interventions in MS and some general caveats associated with cell-based-therapies highlight the challenges for clinical translation of the "immunologist's dream" of treating autoimmunity as discussed in this Commentary. PMID- 22488361 TI - PACSIN1 regulates the TLR7/9-mediated type I interferon response in plasmacytoid dendritic cells. AB - Plasmacytoid dendritic cells (pDCs) are the professional interferon (IFN) producing cells of the immune system. pDCs specifically express Toll-like receptor (TLR)7 and TLR9 molecules and produce massive amounts of type I IFN by sensing microbial nucleic acids via TLR7 and TLR9. Here we report that protein kinase C and casein kinase substrate in neurons (PACSIN) 1, is specifically expressed in human and mouse pDCs. Knockdown of PACSIN1 by short hairpin RNA (shRNA) in a human pDC cell line significantly inhibited the type I IFN response of the pDCs to TLR9 ligand. PACSIN1-deficient mice exhibited normal levels of conventional DCs and pDCs, demonstrating that development of pDCs was intact although PACSIN1-deficient pDCs showed reduced levels of IFN-alpha production in response to both cytosine guanine dinucleotide (CpG)-oligonucleotide (ODN) and virus. In contrast, the production of proinflammatory cytokines in response to those ligands was not affected in PACSIN1-deficient pDCs, suggesting that PACSIN1 represents a pDC-specific adaptor molecule that plays a specific role in the type I IFN signaling cascade. PMID- 22488362 TI - Cytip regulates dendritic-cell function in contact hypersensitivity. AB - Cytohesin-interacting protein (Cytip) is induced during dendritic cell (DC) maturation and in T cells upon activation. It has also been shown to be involved in the regulation of immune responses. Here, we evaluated the functional consequences of Cytip deficiency in DCs using Cytip knockout (KO) mice. No difference in DC subpopulations in the skin draining lymph nodes (LNs) was found between Cytip KO mice and their wild-type counterparts, excluding a role in DC development. To investigate the function of Cytip in DCs in vivo, we used 2,4,6 trinitrochlorobenzene (TNCB)-induced contact hypersensitivity (CHS) as a model system. In the sensitization as well as in the elicitation phase, DCs derived from Cytip KO mice induced an increased inflammatory reaction indicated by more pronounced ear swelling. Furthermore, IL-12 production was increased in Cytip KO bone marrow-derived DCs (BMDCs) after CpG stimulation. Additionally, Cytip deficient DCs loaded with ovalbumin induced stronger proliferation of antigen specific CD4(+) and CD8(+) T cells in vitro. Finally, migration of skin DCs was not altered after TNCB application due to Cytip deficiency. Taken together, these data suggest a suppressive function for Cytip in mouse DCs in limiting immune responses. PMID- 22488363 TI - Circulating specific antibodies enhance systemic cross-priming by delivery of complexed antigen to dendritic cells in vivo. AB - Increasing evidence suggests that antibodies can have stimulatory effects on T cell immunity. However, the contribution of circulating antigen-specific antibodies on MHC class I cross-priming in vivo has not been conclusively established. Here, we defined the role of circulating antibodies in cross presentation of antigen to CD8(+) T cells. Mice with hapten-specific circulating antibodies, but naiotave for the T-cell antigen, were infused with haptenated antigen and CD8(+) T-cell induction was measured. Mice with circulating hapten specific antibodies showed significantly enhanced cross-presentation of the injected antigen compared with mice that lacked these antibodies. The enhanced cross-presentation in mice with circulating antigen-specific antibodies was associated with improved antigen capture by APCs. Importantly, CD11c(+) APCs were responsible for the enhanced and sustained cross-presentation, although CD11c(-) APCs had initially captured a significant amount of the injected antigen. Thus, in vivo formation of antigen-antibody immune complexes improves MHC class I cross-presentation, and CD8(+) T-cell activation, demonstrating that humoral immunity can aid the initiation of systemic cellular immunity. These findings have important implications for the understanding of the action of therapeutic antibodies against tumor-associated antigens intensively used in the clinic nowadays. PMID- 22488364 TI - T cells interact with T cells via CD40-CD154 to promote autoimmunity in type 1 diabetes. AB - We have investigated the role of CD40 signaling in islet-reactive, diabetogenic CD4(+) Th1 T-cell clones. Using multispectral flow cytometry, we showed that CD40 and CD154 are co-expressed and form complexes on the surface of activated T cells. We also demonstrate that activated Tcells can transactivate CD4(+) CD40(+) T cells through the CD40-CD154 pathway. To investigate the role of CD40 signaling on Th1 cells, we used the diabetogenic clone BDC-5.2.9 retrovirally transduced with a truncated form of the CD40 molecule to produce a CD40 dominant negative T-cell clone. Upon challenge with antigen in vitro, the production of IFN-&#x003B3; by BDC-5.2.9 CD40DN was greatly reduced and, in vivo, the dominant-negative variant was unable to induce diabetes. Transduction with the CD40DN vector was also effective in preventing transfer of disease by primary NOD CD4(+) T cells. Ex vivo analysis of pancreatic infiltrates after transfer of BDC 5.2.9 CD40DN cells revealed an overall reduction of cell numbers and cytokine production by both T cells and macrophages. These data indicate that CD40 is an important signaling molecule on autoreactive CD4(+) T cells and contributes to their pathogenic effector function. PMID- 22488365 TI - Stable antigen-specific T-cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients. AB - Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease of the central nervous system. Current therapies decrease the frequency of relapses and limit, to some extent, but do not prevent disease progression. Hence, new therapeutic approaches that modify the natural course of MSneed to be identified. Tolerance induction to self-antigens using monocyte-derived dendritic cells (MDDCs) is a promising therapeutic strategy in autoimmunity. In this work, we sought to generate and characterize tolerogenic MDDCs (tolDCs) from relapsing remitting (RR) MSpatients, loaded with myelin peptides as specific antigen, with the aim of developing immunotherapeutics for MS. MDDCs were generated from both healthy-blood donors and RR-MSpatients, and MDDCmaturation was induced with a proinflammatory cytokine cocktail in the absence or presence of 1alpha,25 dihydroxyvitamin-D(3) , a tolerogenicity-inducing agent. tolDCs were generated from monocytes of RR-MSpatients as efficiently as from monocytes of healthy subjects. The RR-MStolDCs expressed a stable semimature phenotype and an antiinflammatory profile as compared with untreated MDDCs. Importantly, myelin peptide-loaded tolDCs induced stable antigen-specific hyporesponsiveness in myelin-reactive T cells from RR-MS patients. These results suggest that myelin peptide-loaded tolDCs may be a powerful tool for inducing myelin-specific tolerance in RR-MS patients. PMID- 22488368 TI - Clinical impact of tumor infiltration at the transected surgical margin during gastric cancer surgery. AB - BACKGROUND: When transected surgical margins are involved by tumor cells during gastrectomy for gastric cancer, dissemination of tumor cells to the peritoneal cavity may be a concern. OBJECTIVES: The aim of this study is to evaluate the prognostic value of tumor infiltration at the transected surgical margin during gastrectomy. METHODS: A total of 1,717 patients with gastric cancer who underwent R0 gastrectomy were included. The relationship between positive margins on frozen biopsy during gastrectomy and clinicopathologic data was examined. The prognostic impact of this intraoperative event was evaluated by univariate and multivariate analysis. RESULTS: The intraoperative positive resection margin occurred in 69 patients (4.01%). Tumor size >5 cm, tumor located in the upper third or whole stomach, Bormann type IV gastric cancer, and signet ring cell histology were independent factors associated with that intraoperative event. pT and pN stages were significant prognostic factors associated with locoregional and/or peritoneal recurrence and overall recurrence. Tumor infiltration at the transected margin was not an independent prognostic factor associated with any recurrence. CONCLUSIONS: Microscopic tumor involvement at the margin during gastric cancer surgery does not increase locoregional and/or peritoneal recurrence or overall recurrence independently if R0 resection is achieved by re resection of the margin. PMID- 22488367 TI - Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression. AB - Signal transducers and activators of transcription (STAT) 1 plays a pivotal role in cell-cycle and cell-fate determination, and vascular endothelial growth factor (VEGF) also contributes tumor growth. Recently, interferon (IFN) alpha has been reported to be effective for prevention of hepatocellular carcinomas (HCCs) recurrence, but the detailed mechanisms remain elusive. In vitro, cobalt chloride treated VEGF induction and hypoxia responsive element (HRE) promoter activity were inhibited by IFNs and this abrogation was cancelled by introduction of small interfering RNA for STAT1. Immunoprecipitation/chromatin immunoprecipitation analyses showed STAT1 bound to hypoxia-inducible factor (HIF)-1alpha and dissociated HIF-complex from HRE promoter lesion. In a xenograft model using Balb/c nude mice, tumor growth was suppressed by IFNalpha through inhibition of VEGF expression and it was oppositely enhanced when STAT1-deleted cells were injected. This augmentation was due to upregulation of VEGF and hyaluronan synthase 2. In human samples, 29 HCCs were resected, divided into two groups based on STAT1 activation in tumor and the clinical features were investigated. Patients with suppressed STAT1 activity had a shorter recurrence-free survival. Histological and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses showed portal vein microinvasion and increased VEGF levels in tumors from suppressed STAT1 group. These human samples also showed a reverse correlation between VEGF and STAT1-regulated genes expression. These results in vitro and in vivo suggested that IFNalpha are potential candidates for prevention of vessel invasion acting through inhibition of VEGF expression and need to be properly used when STAT1 expression is suppressed. PMID- 22488370 TI - The trans-sphenoidal resection of pituitary adenomas in elderly patients and surgical risk. AB - In western countries, the process of "ageing of the population" is increasingly forcing clinical medicine to find answers for pathologies affecting the elder segments of our community. In this respect, pituitary adenomas often raise difficult questions on surgical indications, since little is known about postoperative morbidity and mortality in elderly patients. The transsphenoidal endonasal approach (TNS), which is considered the gold standard for surgical resection of the majority of functioning and non-functioning pituitary adenomas, is supposed to be a low morbidity and mortality procedure in adult patients. However, only a few contradicting data are available in the literature about elderly patients. In this paper we retrospectively analyze a cohort of 43 consecutive patients aged more than 65 years, operated on for pituitary adenomas at our Institution in the years 1998-2007. These patients were treated by transsphenoidal endonasal approach (TNS) for resection of non-functioning pituitary adenomas (n = 31), GH-secreting adenomas (n = 4) and ACTH-secreting adenomas (n = 8). Clinical records reported a macroadenoma with tumour-related mass symptoms in about 80 % of patients; single or multiple pituitary deficits were present in 44 % of patients. Regarding comorbidities, cardiac disease was the most frequently observed (86 %); assessment of anaesthesiological risk indicated a moderate to severe ASA score in most patients, 11 % showing a 4-5 score. On the basis of current criteria, our retrospective analysis revealed that cure was achieved in 54 % of patients. The outcome was similar to that observed in the general population of patients undergoing transphenoidal surgery in our centre, without differences in the rate of surgical and endocrinological cure, minor and major surgical complications and hospitalization duration. In particular, no significant anaesthesiological complications were observed and no patient developed either permanent diabetes insipidus or cerebrospinal fluid rhinorrhea. In conclusion, in specialized centres the surgical treatment of pituitary adenomas via the transsphenoidal route can be a safe and effective procedure even in elderly patients. PMID- 22488371 TI - Plasma renin activity-guided strategy for the management of hypertension. AB - Despite the wide array of antihypertensive agents and the availability of national guidelines regarding treatment for hypertension, the disease remains uncontrolled in nearly 50% of affected patients. Furthermore, the number of patients with resistant hypertension continues to increase. For patients with resistant hypertension, the American Heart Association has advocated for clinical studies to determine appropriate pharmacologic treatment strategies. One proposed strategy involves ambulatory measurement of plasma renin activity (PRA) to guide the selection of antihypertensive therapy. Patients with low PRA would be prescribed natriuretic volume-mediated therapies (e.g., diuretics and calcium channel blockers), whereas those with high PRA would receive antirenin system therapies (e.g., beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers). This review focuses on the principles of PRA guided therapy, its historical development, alternative approaches to classifying patients into categories of response to antihypertensive agents, and recent data supporting the use of plasma renin activity-guided hypertension management. PMID- 22488372 TI - Editor note. PMID- 22488373 TI - The weight of pathological: bio-politics and bare life. AB - This article analyzes the historical formation of the idea of obesity as illness, starting from the differentiation between the normal and the pathological so as to show the replacement, in present times, of the ancient view of self care by a medicalization of life. In the light of a bio-political interpretation, there is an exposition of how obesity shows, in a paradigmatic way, the play of the various forces within contemporary power mechanisms which have a direct effect on the body, aiming for the control and management of life. From this perspective we develop a criticism of the treatment of obesity bearing in mind the increasing custodianship over life which can be observed in modern states, where the exception has become the rule. PMID- 22488374 TI - The objectives of the U.S. Exploring Expedition's circumnavigation (1838-1842): longitude, nautical charting and the establishment of modern geographic coordinates. AB - This article analyzes the main objectives of the scientific voyage to circumnavigate the earth, undertaken by the United States from 1838 to 1842. Charting was one of the most important of the scientific and strategic goals of the exploratory voyage. The initiative for the undertaking was the search for exact positioning on the high seas after the establishment of the longitude system, when nautical charts and maps from various countries were compared, and other, new ones were drawn. The United States participated in this international effort, leading to the creation of its own cartographic system. PMID- 22488375 TI - [Stem cell research: a case study on the dynamics of one segment of a scientific field]. AB - Based on a case study conducted at a public institution for higher education, the article investigates the dynamics of the scientific field of stem cell research. Basic research projects with adult and embryonic stem cells (experiments in cell culture or an animal model) and tissue bioengineering were surveyed. Fieldwork included ethnographic observation and interviews with researchers (graduate students and professors). Project researchers were observed to be part of a scientific network displaying a marked division of labor and workflows of material and symbolic resources. A dynamic of alliances and exchanges was found to underlie collaborative relations between peers and students. When recapping the history of stem cell research at the institute, interviewees showed the organization of the field. PMID- 22488376 TI - [From miasmas to mosquitoes: medical thought on yellow fever in Yucatan, 1890 1920]. AB - Yellow fever has been a public health concern since colonial days because of its frequent epidemics and high mortality rate. This analysis of medical thought about "the black vomit" in the Yucatan and the evolution of this thinking from 1890 through 1921 first addresses some of the disease's antecedents and preponderant ideas prior to 1881 as well as Carlos Finlay's efforts to convince the medical community that his theory was right. The article goes on to analyze the co-existence of miasmatic and bacterial ideas and to show how medical initiatives began focusing on eradication of the mosquito transmitter once Finlay's postulates had been demonstrated. PMID- 22488377 TI - [Counting to cure: statistics and the medical community in Argentina, 1880-1940]. AB - The article analyzes the links between the professional medical community and the institutionalization of statistics in Argentina in 1880-1940. It begins with the initial period of medical and demographic statistics in Argentina, which bore ties to late nineteenth-century hygienist ideals and projects. It then describes the later organization and consolidation of a state agency responsible for producing these data, which, interestingly enough, was headed by a woman for several decades. The challenges encountered in training technical staff to produce public statistics are also examined. Based on information found in specialized magazines, the analysis likewise explores the tensions and controversies that arose within the medical community over the use of the numerical method. PMID- 22488378 TI - Colombian initiatives in the Social Appropriation of Science and Technology: tendencies and challenges for a broader understanding of these dynamics. AB - Is aimed at broadening Colombia's understanding of the social appropriation of science and technology, particularly the types of actors who promote initiatives in this sphere. Using a chain referral sampling methodology, a hundred such initiatives in Colombia were identified and documented, which were promoted by civil society, the State, business, the research community and mediators. The article further analyzes these iniciatives and indicates the challenges they represent, especially in breaking down the traditional approach to the social appropriation of science and technology in Colombia and replacing it with more participative strategies. PMID- 22488379 TI - [The formation of the field of psychiatry: two opposing perspectives]. AB - The article analyzes two opposing views of the formation of the psychiatric field: the Foucauldian perspective, which holds sway in Brazil, and the perspective of Gauchet and Swain. Two works by Foucault (History of Madness and Psychiatric Power) are contrasted with Madness and Democracy, by the latter authors. It is argued that a society's political and assistance strategies about madness are shaped by the conceptual bases defining what constitutes the field of psychiatric theory and how it was formed. The article calls attention to the diverse consequences that these two approaches may have on the reform of Brazilian psychiatry. PMID- 22488380 TI - [Eating education and the making of strong, robust, productive workers: an analysis of scientific scholarship on nutrition in Brazil, 1934-1941]. AB - In exploring the emergence of scientific scholarship on the field of eating and nutrition in Brazil, the article examines works produced and published from 1934 to 1941 that disseminated and sought to encourage application of the conceptual and methodological bases of rational eating. Employing theory on the social genesis of a field, the investigation reveals that intellectuals in the area relied on a standardized approach and modus operandi: the indication of interventionist practices in eating and nutritional education which targeted large numbers of people and were influenced by the era's social and educational ideas and by the notion of education as a tool for social redemption. PMID- 22488381 TI - [On the autonomy of the mouth: curricular practices, professional identity, and the emergence of dental teaching in Brazil]. AB - The article analyzes how the separation of the teaching of medicine and of dentistry occurred in Brazil. It highlights the role that the institutionalization of dental teaching policies played in shaping a professional identity. Relations are drawn between teaching policies and professional practices to show how their relationships and meanings have changed historically. It is argued that the teaching of dentistry became autonomous because of the need to comply with the formation of a system to regulate healing practices in Brazil and that the process of its institutionalization transpired under the inspiration of positivist policies about free teaching. Curricular practices produced the subjectivity of the modern dental surgeon and his clinical practices. PMID- 22488382 TI - ["Is a shot alone enough?": concepts of health, hygiene, and nutrition and the Program to Eradicate Yaws in Brazil, 1956-1961]. AB - The article analyzes the Program to Eradicate Yaws, enforced in Brazil from 1956 through 1961. Following World War II, when antibiotics first came into use, it seemed there might be a method for eradicating treponematosis in a short time: a single-dose injection of penicillin. At a moment when priority was being placed on fighting rural endemic disease in Brazil, it became possible to organize a campaign against yaws. The article explores the initiatives undertaken by the National Department of Rural Endemic Diseases that revealed a malnourished, starving population, and called into question the very intentions behind the campaign and the day's concepts of health and development. PMID- 22488383 TI - [Family health through the lens of mental hygiene]. AB - The article is meant to stimulate debate about the social and historical determinants that shape the construction of public mental health policy within the context of the Brazilian family. Current policies have emphasized the family as a strategic target of initiatives aimed at social transformation, with the intervention of different actors, including psychologists. An examination of some ideas from the field of mental hygiene suggests that this discourse is nothing new in the history of Brazilian health. While today's times, families, and professionals are different, the search for a solution to the so-called crisis of society still focuses on the individual. The family, as the expression of this individual, has been called upon to assume responsibilities that push society towards 'order' and 'progress' for the Nation. PMID- 22488384 TI - ["Pregnant belly showing": the vicissitudes and valorization of the reproductive body in the construction of images of pregnancy]. AB - This analysis of images of maternity and pregnancy seeks to identify the values and social conduct behind their creation. Through transformations of identities, the representations of the pregnant body that circulate in the media reflect a peculiar combination of values which, while affirming freedom of choice and self realization, also suggest that a female nature exists. Scientific conceptions of problems related to biological reproduction are widely conveyed as a biological problem attributable to the individual or couple. Historical analyses, however, show that the way we view reproductive events has changed, reflecting how modern medicine has intervened in our bodies and in the family and how female identity has been affirmed. PMID- 22488385 TI - The utopian Darcy Ribeiro archive. AB - The project in memory of anthropologist, writer and politician Darcy Ribeiro is analyzed, with emphasis on the relationship he had with his personal archives and the creation of the Darcy Ribeiro Foundation, established to give continuity to his 'legacy.' It highlights the influences present in the formation of his archive and presents an ethnography that seeks to restore the historicity of the archive. It reveals the significance attributed to it by the creator himself, and after his death, by those responsible for his memory. From this study, an attempt is made to evaluate the analytical return from socio-historical approaches to the archives. PMID- 22488386 TI - Photographs in archives: the production and meaning of visual records. AB - Based on discussions dealing with archival theory and methodology, the intention is to discuss the status of the photograph as an archival record. By means of the analysis of some attributes and characteristics of the photographic record, its specificity as a record is highlighted, as well as the need for a contextual approach to its production and its roles in the process of constituting the archives per se. The scope of this work is to question traditional methods of organizing photographs into archives, which perceive these records as being removed from the remaining documentation and which value the factual content of the images above any other elements of meaning. PMID- 22488387 TI - An archival approach: the documents of a biomedical sciences laboratory. AB - This article addresses archival methods, techniques, and practices for managing documents generated by scientific activity, using field research carried out at an Instituto Oswaldo Cruz laboratory at the Fundacao Oswaldo Cruz as a reference. Based on an analysis combining an archival studies approach with elements of the sociology of science, we believe that the models and instruments of archival knowledge are subordinate to the assumptions of historical research or social memory. They also serve a technical rationality aligned with empirical organization practices that confront the more complex archival reality, leading archival science to negate its foundations and theoretical principles. PMID- 22488388 TI - [A look through the Mexican Department of Health's film archive]. AB - Since the late 1920s, cinema has been a popular tool in health education in Mexico; over the years, it functioned as an efficient means of propaganda through which the State and public health authorities promoted their projects and re created the image of a healthy, modern country on screen. The article presents the results of an effort to recover and catalogue the Mexican Department of Health's film archive, an endeavor that allowed for the reconstruction of a list of national and international films screened and produced in Mexico from 1943 to 1960, especially from the United States. PMID- 22488389 TI - [Reversal of crime: hostile norms, a cruel society, and subjective escape through violence]. PMID- 22488390 TI - [Sanitation versus environment: engineering and politics at the end of the Empire and under the First Republic]. PMID- 22488391 TI - [Theory, critical analysis, and the challenge of interdisciplinary thought at the crossroads of collective health, the environment, and geography]. PMID- 22488392 TI - [Not Available]. PMID- 22488393 TI - A novel polyoxovanadium borate incorporating an organic amine ligand: synthesis and structure of [V12B16O50(OH)7(en)]7-. AB - A novel 1D chain organic-inorganic hybrid polyoxovanadium borate Na[V(12)B(16)O(50)(OH)(7)(en)](2)(enH(2))(6)(enH)(2)(OH)(H(2)O)(19) (1, en = ethylenediamine), based on a [V(12)B(16)O(50)(OH)(7)(en)](7-) cluster unit, has been hydrothermally synthesized and characterized. Interestingly, organic amine is incorporating into the V(12)B(16) clusters. PMID- 22488394 TI - Socioeconomic disparities in emerging adult weight and weight behaviors. AB - OBJECTIVES: To explore weight, weight behaviors, and tobacco and alcohol use among emerging adults by parental education and financial strain. METHODS: Cross sectional analyses of 2010 survey data from an urban Minnesota public 4-year university and 2-year community college (n=1201). RESULTS: Low parental education was associated with lower fruit/vegetable consumption and physical activity and more fast food and unhealthy weight control. Financial strain was associated with less physical activity and more unhealthy weight control, binge drinking, and tobacco use. CONCLUSIONS: Unique relationships exist between socioeconomic indicators and emerging adult health behaviors. Additional research is needed to understand financial context among emerging adults. PMID- 22488395 TI - Free alcohol use and consequences: gender differences among undergraduates. AB - OBJECTIVE: To examine gender differences in obtaining free alcohol, high-risk drinking, and consequences. METHODS: Web-based surveys were administered annually (2003-2005) to random samples of undergraduates (N=10,729). RESULTS: Gender, race, age under 21, sorority/fraternity membership, lower disposable income, and relationship status were significant predictors of obtaining free alcohol. Frequent obtainers had greater odds of heavy episodic drinking and consequences compared to infrequent obtainers. Females were less likely to report heavy episodic drinking; however, frequently obtaining females were more likely to report heavy episodic drinking. CONCLUSIONS: Approximately 25% of undergraduates frequently obtained free alcohol. Females obtained more often, had higher odds of high-risk drinking, and experienced fewer consequences compared to males. PMID- 22488396 TI - Sexual and substance use behaviors of college students with disabilities. AB - OBJECTIVES: To identify the substance use and the sexual behaviors of college students with disabilities. METHODS: A secondary data analysis was conducted of the spring 2009 administration of the ACHA-NCHA II. RESULTS: College students with disabilities tended to be 24 or more years old; of an ethnic minority; and bisexual, gay, or lesbian. They consistently reported engaging in both substance use and sexual risk behaviors more than those of students without disabilities. CONCLUSIONS: Substance use and sexuality programs on college campuses should be physically, socially, and intellectually accessible for students with disabilities while considering their multiple identities. Efforts should be made to recruit or target these students for such programming. PMID- 22488397 TI - Predictors of the intention to prevent excessive weight gain in youth. AB - OBJECTIVES: To examine psychosocial factors, BMI, perceived weight, and demographics as correlates of adolescents' intentions to prevent excessive weight gain. METHODS: Students (12-13 years) completed questionnaires at baseline and 4 month follow-up. Regression analyses were performed (n=345). RESULTS: Sixty percent showed a positive intention towards the prevention of excessive weight gain. A positive change in attitude and perceived internal control and higher perceived weight were related to a positive change in intention. CONCLUSION: A small majority of adolescents had a positive intention to prevent gaining excessive weight. A positive attitude and higher perceived internal control were related to a positive intention. PMID- 22488398 TI - Determinants of physical activity in young adult cancer survivors. AB - OBJECTIVES: To examine the determinants of physical activity (PA) in young adult cancer survivors (YACS). METHODS: A survey of 588 YACS in Alberta, Canada, assessed PA, medical and demographical factors, and theory of planned behavior variables. RESULTS: Path analysis explained 38% (P<.001) of the variance in PA with significant contributions from intention, planning, affective attitude, education, and general health. In turn, 56% (P<.001) of the variance in intention was explained by perceived behavioral control, instrumental attitude, and affective attitude. CONCLUSION: PA interventions in YACS should focus on developing strong intentions by targeting perceived behavioral control, instrumental attitude, and affective attitude. PMID- 22488399 TI - Prostate cancer screening among chinese american men: a structural model. AB - OBJECTIVE: To test the Sociocultural Health Behavior Model in relation to the health behavior of prostate cancer (PCa) screening among Chinese American men. METHODS: Confirmatory factor analysis and structural equation model analyses were conducted among Chinese American men. RESULTS: The path analysis supported the components of the sociocultural model and indicated a positive and significant relationship between PCa screening and the enabling factors; between cultural factors and predisposing, enabling, and access/satisfaction with health care factors; and between enabling factors and access/satisfaction with health care. CONCLUSIONS: The model highlights the significance that sociocultural factors play in relation to PCa screening. PMID- 22488400 TI - Smoking as a risk factor for STI diagnosis among African American females. AB - OBJECTIVES: To examine the relationship of smoking to sexual risk outcomes among African American adolescent females. METHODS: We analyzed baseline data from an HIV intervention trial, including sexual risk (older sex partners, number of vaginal sex partners, sex while high on drugs/alcohol, STI diagnosis) and smoking status among 715 participants. RESULTS: Smoking prevalence was 23.1%. Controlling for covariates, smoking predicted having older partners (P=.001), having sex while high on alcohol or drugs (P<.001), and STI diagnosis (P=.046), after including other sexual risk outcomes in the model. CONCLUSIONS: Smoking is an independent risk factor for sexual risk behaviors and STI diagnosis. PMID- 22488401 TI - Investigating race, gender, and access to cigarettes in an adolescent population. AB - OBJECTIVE: To examine race and gender as potential predictors for access to cigarettes and purchasing behaviors among an adolescent population. METHODS: Data were collected from a survey administered to 4336 high school students. The significance was examined using the chi-square test, with a P-value <=.05. RESULTS: Noncommercial outlets were the primary source of cigarette acquisition for white students; African American students were more likely than white students to use commercial sources to acquire cigarettes; females were more likely to report not being asked to show proof of age. CONCLUSIONS: Interventions designed to reduce youth access to tobacco must address racial and gender differences. PMID- 22488402 TI - Impact of diagnosing metabolic syndrome on risk perception. AB - OBJECTIVES: To determine the effect of using the diagnosis of metabolic syndrome (MetSx) on risk perception. METHODS: We randomized 74 participants to receive either the diagnosis of MetSx or the diagnosis of individual cardiovascular risk factors. The MetSx group was subdivided into those receiving written patient education material or written patient education plus educational videos. RESULTS: At 6 weeks, participants receiving the diagnosis of MetSx were more likely to increase their health concerns, perceived risk of myocardial infarction, and their motivation toward health behavior. CONCLUSION: Sharing the diagnosis of MetSx increases risk perception and motivation toward a healthier behavior. PMID- 22488403 TI - Self-image differences as related to body image of students in a middle school. AB - OBJECTIVE: To examine whether gender and ethnic self-image differences exist among Asian and white adolescents within the context of body image. METHODS: One hundred seventy-seven students in a Midwestern US middle school were surveyed on self-image. Analyzed using 2-way ANOVA by gender and race. RESULTS: Asian students have lower self-image compared to white students, including the subcomponents of self-esteem, identity, and integrity. CONCLUSIONS: Asian students have more critical feelings about themselves, base their identities on a few sources rather than on diverse sources, and choose unrealistic standards. However, Asian girls scored better on the image-consciousness subscale. PMID- 22488404 TI - Predicting young adulthood smoking among adolescent smokers and nonsmokers. AB - OBJECTIVE: To examine predictors of smoking in young adulthood among (1) adolescent nonsmokers and (2) adolescent smokers. METHODS: Data were analyzed from a longitudinal study of adolescents to young adulthood in 1988-1998. RESULTS: Predictors of smoking in young adulthood among adolescent nonsmokers included less education, being unmarried in adulthood, lower family social support, non-smoking parents, and increased alcohol use over time. Predictors of smoking in young adulthood among adolescent smokers included lower family social support, more adolescent friends who used drugs, and slower decreases in depressive symptoms over time. CONCLUSIONS: Distinct factors predict smoking initiation versus maintenance among young adults. PMID- 22488405 TI - The community-based participatory intervention effect of "HIV-RAAP". AB - OBJECTIVES: To design and test HIV-RAAP (HIV/AIDS Risk Reduction Among Heterosexually Active African American Men and Women: A Risk Reduction Prevention Intervention) a coeducational, culture- and gender-sensitive community-based participatory HIV risk reduction intervention. METHODS: A community-based participatory research process included intervention development and implementation of a 7-session coeducational curriculum conducted over 7 consecutive weeks. RESULTS: The results indicated a significant intervention effect on reducing sexual behavior risk (P=0.02), improving HIV risk knowledge (P=0.006), and increasing sexual partner conversations about HIV risk reduction (P= 0.001). CONCLUSIONS: The HIV-RAAP intervention impacts key domains of heterosexual HIV transmission. PMID- 22488406 TI - Prognostic significance of combined MN1, ERG, BAALC, and EVI1 (MEBE) expression in patients with myelodysplastic syndromes. AB - Overexpression of MN1, ERG, BAALC, and EVI1 (MEBE) genes in cytogenetically normal acute myeloid leukemia (AML) patients is associated with poor prognosis, but their prognostic effect in patients with myelodysplastic syndromes (MDS) has not been studied systematically. Expression data of the four genes from 140 MDS patients were combined in an additive score, which was validated in an independent patient cohort of 110 MDS patients. A high MEBE score, defined as high expression of at least two of the four genes, predicted a significantly shorter overall survival (OS) (HR 2.29, 95 % CI 1.3-4.09, P= .005) and time to AML progression (HR 4.83, 95 % CI 2.01-11.57, P< .001) compared to a low MEBE score in multivariate analysis independent of karyotype, percentage of bone marrow blasts, transfusion dependence, ASXL1, and IDH1 mutation status. In a validation cohort of 110 MDS patients, a high MEBE score predicted shorter OS (HR 1.77; 95 % CI 1.04-3.0, P= .034) and time to AML progression (HR 3.0, 95 % CI 1.17-7.65, P= .022). A high MEBE expression score is an unfavorable prognostic marker in MDS and is associated with an increased risk for progression to AML. Expression of the MEBE genes is regulated by FLI1 and c-MYC, which are potential upstream targets of the MEBE signature. PMID- 22488407 TI - Reduced-intensity conditioning in unrelated donor cord blood transplantation for familial hemophagocytic lymphohistiocytosis. AB - Familial hemophagocytic lymphohistiocytosis (FHL) is a disorder of immune homeostasis characterized by fever, cytopenias, hepatosplenomegaly, and coagulopathy. We studied the outcomes of 13 FHL patients who underwent the first unrelated cord blood transplantation (UCBT) after non-myeloablative conditionings. The major regimen consisted of fludarabine (FLU; n = 12)+melphalan (MEL; n = 11)+/- low-dose total body irradiation (TBI 2-4 Gy; n = 6). The median age at presentation and period to UCBT were 6 and 5 months, respectively. Central nervous system (CNS) disease developed in one infant at diagnosis, and in two others until UCBT. HLH activity was controlled in all but one at the time of UCBT. Ten patients had early engraftment on median day 21 with no grade >2 treatment-related toxicity and two controllable grade >2 acute GVHD. Two patients with early rejection successfully underwent subsequent UCBT after myeloablative conditioning. Two others had late graft failure following mixed donor chimerism. Two deaths occurred from HLH; early liver failure and late CNS disease. Of 11 FLU+MEL-conditioned patients, the frequency of disease-free complete engraftment was higher for MEL (>=120 mg/m(2) )+TBI, or high-dose MEL (180 mg/m(2) ) than for others (83% vs. 25%, p = 0.036). The FLU+MEL-based non-myeloablative regimen was acceptable for FHL infants undergoing UCBT, although further studies will be needed for confirmation. PMID- 22488408 TI - Brief report: first identification of H4 histamine receptor in healthy salivary glands and in focal sialadenitis in Sjogren's syndrome. AB - OBJECTIVE: The conventional H(1) and H(2) histamine receptors have >10,000-fold lower avidity for histamine than H(4) histamine receptor, which has been implicated in autoimmune diseases. This study was undertaken to compare H(4) histamine receptor levels in the salivary glands (SGs) of healthy controls with those in the SGs of patients with primary Sjogren's syndrome (SS). METHODS: H(4) histamine receptor messenger RNA (mRNA) was analyzed using real-time quantitative polymerase chain reaction, and the receptor protein was examined using immunostaining. Effects of the H(4) histamine receptor agonist ST-1006 on cytokine synthesis by human SG (HSG) cells were analyzed using xMAP technology and enzyme-linked immunosorbent assay. RESULTS: Healthy SGs contained H(4) histamine receptor mRNA. The receptor protein was localized to the acinar and ductal epithelial cells. H(4) histamine receptor agonist stimulated HSG cells to produce the cytokines interleukin-8 and vascular endothelial growth factor. SS patients had low H(4) histamine receptor levels. CONCLUSION: H(1) and H(2) histamine receptor antagonists are not effective in the treatment of autoimmune diseases. However, such antagonists do not affect the newly discovered H(4) histamine receptor. Dendritic cells and lymphocytes are nonprofessional histamine producing cells, which produce histamine at 100-1,000-fold lower rates than mast cells do. Saliva contains only 0.31-12.4 ng/ml histamine, which is too low to stimulate H(1) or H(2) histamine receptor, but stimulates H(4) histamine receptor half maximally. Our findings show that H(4) histamine receptor is strongly expressed in tubuloacinar SG cells, which emphasizes the role of these cells in the pathogenesis of SS. PMID- 22488409 TI - N-(4-hydroxyphenyl)retinamide inhibits breast cancer cell invasion through suppressing NF-KB activation and inhibiting matrix metalloproteinase-9 expression. AB - Synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) has been reported to exhibit anti-invasive and anti-metastatic activities by suppressing the enzymatic activity of matrix metalloproteinase (MMP)-9, but the underlying mechanism remains unclear. Here, we show that 4-HPR blocks the activity of MMP-9 in two ways: by reducing phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 secretion and by suppressing cell invasion through the downregulation of MMP-9 gene transcription in MCF-7 breast cancer cells. 4-HPR inhibits the transcriptional activity of MMP-9 by reducing the DNA-binding activity of NF-kappaB on the MMP-9 promoter as well as by inhibiting the degradation of IkappaBalpha, leading to cytoplasmic accumulation of NF-kappaB. We also found that 4-HPR inhibits invasion and MMP-9 expression in the highly metastatic breast cancer cell line MDA-MB-231. Thus, 4-HPR might be a potent anti-invasive agent that works by suppressing MMP-9 expression via the NF-kappaB signaling pathway. PMID- 22488410 TI - Psychiatric disorder as a risk factor for cancer: different analytic strategies produce different findings. AB - BACKGROUND: Reported associations between psychiatric disorders and cancer incidence are inconsistent, with cancer rates in psychiatric patients that are variously higher than, similar to, or lower than the general population. Understanding these associations is complicated by difficulties in establishing the timing of onset of psychiatric disorders and cancer, and by the possibility of reverse causality. Some studies have dealt with this problem by excluding patients with cancers predating their psychiatric illness; others have not considered the issue. METHODS: We examined associations between psychiatric hospitalization and cancer incidence in a cohort of 1,165,039 Swedish men, and we explored the impact of different analytic strategies on these associations using real and simulated data. RESULTS: Relative to men without psychiatric hospitalization, we observed consistent increases in smoking-related cancers in those with psychiatric hospitalizations, regardless of analytic approach (eg, hazard ratio = 1.73 [95% confidence interval = 1.52-1.96]). However, associations with cancers unrelated to smoking were highly dependent on analytic strategy. In analyses based on the full cohort, we observed no association or a modest increase in cancer incidence in those with psychiatric hospitalizations (1.14 [1.07-1.22]). In contrast, when men whose cancer predated their psychiatric hospitalizations were excluded, future cancer incidence was lower in psychiatric patients (0.72 [0.67-0.78]). Results from simulated data suggest that even modest exclusions of this type can lead to strong artifactual associations. CONCLUSIONS: Psychiatric disorder-cancer incidence associations are complex and influenced by analytic strategy. A better understanding of the temporal relationship between psychiatric disorder and cancer incidence is required. PMID- 22488411 TI - Grade three disc degeneration is a critical stage for anterior spondylolisthesis in lumbar spine. AB - INTRODUCTION: Little is known about when and how progressive spondylolisthesis occurs. In this report segmental motion related to age and disc degeneration at L4/5 disc was investigated. MATERIALS AND METHODS: 637 patients with low back and/or leg pain underwent radiologic and MRI examinations simultaneously. Because 190 patients with conditions which might impede accurate measurement were excluded, 447 patients, comprising 268 men and 179 women, were included; age range, was 10-86 (mean: 53) years. Three radiologic parameters slip in neutral position (mm), sagittal translation (mm), and segmental angulation (degrees) were examined at the L4/5 segment. On T2-weighted MRI, severity of disc degeneration at L4/5 was classified by Pfirrmann's criteria, grade 1-5. RESULTS: Results showed stage of disc degeneration that progressed according to aging with significant differences except for between grades 4 and 5. Amount of anterior slip was small among grades 1 to 3; however, it greatly increased between grades 3 and 4 and between grades 4 and 5, suggesting that grade 3 disc degeneration has a potential risk of future progression of anterior slip. This finding may also suggest that once significant slip occurs, it will progress to the final grade. Furthermore, the grade 3 degeneration group exhibited large amounts of motion in both angulation and translation, suggesting it was the most unstable group. CONCLUSION: Our results with radiography and MRI indicate that grade 3 disc degeneration is a critical stage for the progression of lumbar spondylolisthesis at L4/5 segment. PMID- 22488412 TI - Multiplex Ligation-dependent Probe Amplification improves the detection rate of NKX2.1 mutations in patients affected by brain-lung-thyroid syndrome. AB - BACKGROUND: NKX2.1 mutations have been identified in patients displaying complete or partial brain-lung-thyroid syndrome, which can include benign hereditary chorea (BHC), hypothyroidism and/or lung disease. AIMS AND METHODS: We evaluated the recently developed Multiplex Ligation-dependent Probe Amplification (MLPA) method to assess the relative copy number of genes. The goal was to determine if MLPA could improve, in addition to direct sequencing, the detection rate of NKX2.1 mutations in a phenotype-selected cohort of 24 patients affected by neurological, thyroid and/or pulmonary disorders. RESULTS: Direct sequencing revealed two heterozygous mutations. Using MLPA, we identified two further heterozygous NKX2.1 gene deletions. MLPA increased the detection rate by 50%. All patients with gene deletions identified were affected by BHC and congenital hypothyroidism. CONCLUSION: MLPA should be considered as a complementary tool in patients with partial or total brain-lung-thyroid syndrome when direct sequencing failed to identify NKX2.1 mutations. All patients with an NKX2.1 mutation had BHC and congenital hypothyroidism, emphasizing the high prevalence of these signs associated with defective NKX2.1 alleles. PMID- 22488413 TI - HolT Hunter: software for identifying and characterizing low-strain DNA Holliday Triangles. AB - Synthetic DNA nanostructures are most commonly held together via Holliday junctions. These junctions allow for a wide variety of different angles between the double helices they connect. Nevertheless, only constructs with a very limited selection of angles have been built, to date, because of the computational complexity of identifying structures that fit together with low strain at odd angles. I have developed an algorithm that finds over 95% of the possible solutions by breaking the problem down into two portions. First, there is a problem of how smooth rods can form triangles by lying across one another. This problem is easily handled by numerical computation. Second, there is the question of how distorted DNA double helices would need to be to fit onto the rod structure. This strain is calculated directly. The algorithm has been implemented in a Mathematica 8 notebook called Holliday Triangle Hunter. A large database of solutions has been identified. Additional interface software is available to facilitate drawing and viewing models. PMID- 22488414 TI - Quercetin induces rapid eNOS phosphorylation and vasodilation by an Akt independent and PKA-dependent mechanism. AB - Consumption of the flavonoid quercetin exerts beneficial effects on many chronic diseases. The mechanisms involved in the vasorelaxant effect of quercetin remain uncertain. In the present study, we examined the role of quercetin in vasodilation and rapid endothelial nitric oxide synthase (eNOS) activity in endothelial cells. Quercetin induced a rapid, dose-dependent phosphorylation of eNOS at serine 1179. PKA, Akt and ERK1/2 were all quickly phosphorylated in the process too, but not AMPK and CaMK II. The specific kinase inhibitors for Akt or ERK1/2 could not abolish the quercetin-induced eNOS phosphorylation at Ser1179, which, however, was significantly abolished by H89, an inhibitor of PKA. Concomitantly, intracellular cAMP production was quickly increased by quercetin stimulation and an adenylate cyclase activator, forskolin, also induced eNOS phosphorylation at Ser1179. Quercetin enhanced nitric oxide (NO) production, which was abolished by an eNOS inhibitor, L-NAME or H89. Quercetin exerted a vasodilatory effect on rings with an intact endothelium but not on endothelium deprived rings, and also inhibited vascular contractility induced by angiotensin II or phenylephrine in rat aortic rings. We conclude that quercetin quickly phosphorylates eNOS at Ser1179 via an Akt-independent, cAMP/PKA-mediated pathway to enhance the production of NO and to promote vasodilation. PMID- 22488416 TI - Should intranasal corticosteroids be used for the treatment of ocular symptoms of allergic rhinoconjunctivitis? A review of their efficacy and safety profile. AB - Allergic rhinoconjunctivitis (ARC) presents as nasal symptoms, eye watering and additional signs of ocular allergy (e.g. itchy/burning eyes). Intranasal corticosteroids (INSs) are the most effective treatment for the nasal symptoms of seasonal allergic rhinitis (SAR; based on 4 meta-analyses) and are considered first-line therapy when nasal congestion forms a substantial component of the patient's rhinitis symptoms. Clinical trial evidence shows that INSs also provide some relief from ocular symptoms of SAR and seasonal ARC in adults. INSs probably alleviate eye watering, the main ocular symptom of SAR, by relieving nasal congestion. Other ocular symptoms also improve with INSs. The mechanism for this effect is unknown, but might relate to naso-ocular reflex reduction. There are limited data on ocular safety with INSs. However, the literature supports the use of INSs over several months as there appears to be no considerable increase in the risk of ocular hypertension or glaucoma. PMID- 22488415 TI - Molecular combination of the dopamine and serotonin scaffolds yield in novel antipsychotic drug candidates - characterization by in vivo experiments. AB - Serotonin and dopamine play an important role in the aetiology of schizophrenia. Combination of the structural scaffolds of both neurotransmitters in a single molecule lead to aromatic [d,g]-bisannelated azecine derivatives, which have been shown to be nanomolar to subnanomolar dopamine D1-D5 receptor antagonists with a preference for the D1 family. In this work the potential antipsychotic activity of some azecine derivatives was predicted by their dopamine receptor affinities obtained in vitro from radioligand binding experiments and conclusively confirmed in vivo (rats) by applying a conditioned avoidance model. Furthermore, the compounds were tested in vivo for the development of catalepsy, which is a predictive parameter for extra-pyramidal side-effects caused by many antipsychotics. The investigated azecines displayed low cytotoxicity, and the affinities for human dopamine D1-D5 and serotonin 5-HT2 A receptors were in a nanomolar range. In vivo, their antipsychotic activities in the rat model were comparable with those of haloperidol and risperidone, but revealed a 2-5 times better therapeutic range with regard to catalepsy. Preliminary tests for oral bioavailability also revealed promising results for this new class of potential antipsychotic compounds. In conclusion, our in vivo experiments show that aromatic [d,g]-annelated azecines represent a novel and advantageous class of potential atypical neuroleptics. PMID- 22488417 TI - Effective palliation of malignant esophageal strictures. PMID- 22488418 TI - In vitro 3D human small intestinal villous model for drug permeability determination. AB - We present a novel method for testing drug permeability that features human cells cultured on hydrogel scaffolds made to accurately replicate the shape and size of human small intestinal villi. We compared villous scaffolds to more conventional 2D cultures in paracellular drug absorption and cell growth experiments. Our results suggest that 3D villous platforms facilitate cellular differentiation and absorption more similar to mammalian intestines than can be achieved using conventional culture. To the best of our knowledge, this is the first accurate 3D villus model offering a well-controlled microenvironment that has strong physiological relevance to the in vivo system. PMID- 22488419 TI - Investigation of the susceptibility of acid-deamidated wheat gluten to in vitro enzymatic hydrolysis using Raman spectra and free amino acid analysis. AB - BACKGROUND: The number and surface nature of amino acids (AAs) in substrate proteins available to hydrolytic enzymes are critical. Among them, the micro environmental properties of specific AAs in substrates before hydrolysis would probably dominate the susceptibility of substrates to enzymatic hydrolysis. Fundamental knowledge concerning this regard is lacking. The objective of this work was to investigate the relationship between the exposure level of AAs in acid-deamidated wheat gluten and their susceptibilities to in vitro enzymatic hydrolysis by pancreatin through both high-performance liquid chromatography and Raman spectra. Wheat gluten deamidated with HCl (HDWG), citric acid (CDWG), succinic acid (SDWG) and acetic acid (ADWG) at the same degree of deamidation under the same heat treatment were chosen as the substrates. Substrate characterisations including degree of hydrolysis, surface hydrophobicity and structural characteristics before hydrolysis, together with analysis of free AAs of the corresponding hydrolysates during hydrolysis, were investigated. RESULTS: Hydrolysates from SDWG had the highest value for the degree of hydrolysis. The susceptibility of CDWG to pancreatin hydrolysis was the lowest, lower than native wheat gluten (CK) after the initial 36 h. Compared with free AAs, the mole increase profiles of CK, Arg production levelled off in HDWG after 12 h whereas it was inhibited in ADWG. For SDWG, Arg release was dramatically inhibited after 12 h and was replaced by Trp. Investigations using Raman spectra of the micro environment of Cys, Trp, Tyr and His and the mole increase trend of them indicated that the exposure level of these amino acids in substrates was positively related to their susceptibilities to pancreatin hydrolysis especially after 24 h of hydrolysis. CONCLUSION: Deamidation by four acids has a distinct influence on the structural characteristics of wheat gluten substrates. Although the substrates were selected at the same level of deamidation by the same heat treatment, their resultant conformational differences significantly influenced the exposure level of amino acids for binding to enzymes and the susceptibility of substrates to in vitro enzymatic hydrolysis. Therefore, it had an influence on changing enzyme cutting sites of pancreatin. This information will provide a better understanding of specific behaviour of AAs in wheat gluten during enzymatic hydrolysis from a new perspective. PMID- 22488421 TI - Linking [M(III)3] triangles with "double-headed" phenolic oximes. AB - Strapping two salicylaldoxime units together with aliphatic alpha,Omega aminomethyl links in the 3-position gives ligands which allow the assembly of the polynuclear complexes [Fe(7)O(2)(OH)(6)(H(2)L1)(3)(py)(6)](BF(4))(5).6H(2)O.14MeOH (1.6H(2)O.14MeOH), [Fe(6)O(OH)(7)(H(2)L2)(3)](BF(4))(3).4H(2)O.9MeOH (2.4H(2)O.9MeOH) and [Mn(6)O(2)(OH)(2)(H(2)L1)(3)(py)(4)(MeCN)(2)](BF(4))(5)(NO(3)).3MeCN.H(2)O.5py (3.3MeCN.H(2)O.5py). In each case the metallic skeleton of the cluster is based on a trigonal prism in which two [M(III)(3)O] triangles are tethered together via three helically twisted double-headed oximes. The latter are present as H(2)L(2-) in which the oximic and phenolic O-atoms are deprotonated and the amino N-atoms protonated, with the oxime moieties bridging across the edges of the metal triangles. Both the identity of the metal ion and the length of the straps connecting the salicylaldoxime units have a major impact on the nuclearity and topology of the resultant cluster, with, perhaps counter-intuitively, the longer straps producing the "smallest" molecules. PMID- 22488420 TI - Klebsiella pneumoniae carbapenemases in Enterobacteriaceae: history, evolution, and microbiology concerns. AB - Since the discovery of penicillin 80 years ago, gram-negative bacteria have become proficient at evading the lethal activity of beta-lactam antibiotics, principally through the production of beta-lactamases. The rapid emergence of penicillinases in both gram-positive and gram-negative bacteria led to the development of cephalosporin beta-lactam antibiotics, but production of plasmid mediated extended-spectrum cephalosporinases (or extended-spectrum beta lactamases) and AmpC enzymes resulted in resistance to this drug class. Because carbapenems were the only beta-lactam agents active against such extended spectrum beta-lactamase-producing strains, appropriate and inappropriate use soon resulted in Enterobacteriaceae resistance. As a result, two distinct types of carbapenemases-the metallo-beta-lactamases and Klebsiella pneumoniae carbapenemases (KPCs)-were soon identified. The KPCs comprise 10 variants that differ from one another by one to three amino acid substitutions (KPC-2 to KPC 11). The KPC-producing Enterobacteriaceae are not only multidrug resistant but are also difficult to detect routinely in the clinical microbiology laboratory. Tigecycline, polymyxins (colistin and polymyxin B), and aminoglycosides are possible candidate therapies for infections caused by KPC-producing organisms, although well-conducted clinical trials are required to fully define their roles in patient management. The shortage of new antimicrobial agents on the immediate horizon suggests that enhanced adherence with infection prevention procedures and antimicrobial stewardship programs are needed to curb patient-to-patient transmission and to reduce the selection of multidrug-resistant bacteria. PMID- 22488422 TI - Next-generation sequencing fails to identify human virus sequences in cutaneous squamous cell carcinoma. AB - Nonmelanoma skin cancer (NMSC) shows a strongly increased incidence in solid organ transplant recipients (OTRs) and AIDS patients, suggesting an infectious etiology. The role of certain viruses, i.e., cutaneous human papillomaviruses (HPVs), in NMSC in immunosuppressed patients remains controversial. Merkel cell polyomavirus (MCPyV), which was recently identified using high-throughput sequencing, has been linked to cutaneous proliferations. Here, we aimed to identify novel or known viral sequences at the transcript level in cutaneous squamous cell carcinomas (SCCs) from OTR by using 454 high-throughput pyrosequencing, which can produce long reads (~400 bp) and thus is better suited for the analysis of unknown sequences than other sequencing platforms. cDNA libraries from three OTR SCC biopsies were generated and submitted to next generation sequencing using a 454 platform. Bioinformatic analysis included digital transcriptome subtraction and--in parallel-reference mapping as an alternative way for depleting human sequences. All control sequences introduced for bioinformatics analysis were recovered correctly. Among 717,029 454-sequenced transcripts, nearly all identified viral reads were derived from phages. Bacterial sequences originated from the skin flora or environmental sources. Our study did not reveal any transcripts of known oncogenic or related unknown human viruses. These findings suggest that there is no abundant expression of known human viruses, or viruses with a high degree of homology to known human viruses, in cutaneous SCCs of OTR. Further studies are required to exclude the presence of viruses in NMSC, which cannot easily be identified on the basis of sequence homology to known viruses. PMID- 22488423 TI - The role of cholesterol efflux in mechanisms of endothelial protection by HDL. AB - PURPOSE OF REVIEW: HDL and their main apolipoprotein (apo) constituent apoA-I are antiatherogenic. This has been predominantly attributed to the ability of apoA I/HDL to efflux cholesterol from macrophages within atherosclerotic plaques. It is now emerging that a number of the protective properties of HDL may be due to their effects on the endothelium. RECENT FINDINGS: In addition to their well characterized anti-inflammatory and antioxidant effects, apoA-I and HDL regulate several other key biological pathways known to preserve endothelial function and promote vascular repair. The ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, and the scavenger receptor B type 1 mediate multiple intracellular signaling pathways as well as the efflux of cholesterol and/or oxysterols in response to apoA-I/HDL. Although cholesterol efflux triggers a host of signaling events in endothelial cells, there is evidence that some of the beneficial actions of HDL may occur independently of efflux. SUMMARY: Current data suggest that in endothelial cells ABCA1 and ABCG1 mediate the activation of intracellular signaling pathways primarily through the efflux of cholesterol and oxysterols to apoA-I/HDL. Interaction between HDL and scavenger receptor B type 1 initiates the greatest number of known signaling pathways and there is evidence that some of these are activated independent of efflux. PMID- 22488424 TI - Parkin in the regulation of fat uptake and mitochondrial biology: emerging links in the pathophysiology of Parkinson's disease. AB - PURPOSE OF REVIEW: Perturbations in fatty acid levels and in regulatory proteins linked to fat and mitochondrial homeostasis are associated with modifying the risk of Parkinson's disease . Findings, that are not surprising, based on the high fat content of the brain, the myriad of neurological functions dependent on polyunsaturated fatty acids and the role of mitochondria in energy supply and stress amelioration. Nevertheless, dissecting out the molecular links between lipid biology, mitochondrial regulation and Parkinson's disease is complicated by the divergent causes underpinning Parkinson's disease pathophysiology. Here, we summarize aspects of fatty acid biology relevant to Parkinson's disease; the known links between the modulation of fat and Parkinson's disease and introduce mechanisms whereby the E3-ubiquitin ligase, Parkin known to be mutated as a genetic predisposing factor in Parkinson's disease, modulates fat uptake and mitochondrial control. RECENT FINDINGS: Prior evidence supports that Parkin, under mitochondrial stress conditions, plays a pivotal role in the mitophagy mitochondrial housekeeping program. Recent evidence now demonstrates a broader role of Parkin in controlling fat uptake and mitochondrial regulatory programs. SUMMARY: The identification that Parkin has a multifunctional role in modulating cellular fatty acid uptake and mitochondrial biology further strengthens the pathophysiologic link between fat metabolism, mitochondria and Parkinson's disease. PMID- 22488426 TI - MicroRNAs: emerging roles in lipid and lipoprotein metabolism. AB - PURPOSE OF REVIEW: MicroRNAs (miRNAs) regulate gene expression by binding to target mRNAs and control a wide range of biological functions. Recent reports have identified specific miRNAs as major regulators of fatty acid and cholesterol homeostasis. This review examines the biological function of various miRNAs and the emerging evidence linking specific miRNAs to critical pathways in lipid metabolism. RECENT FINDINGS: Disruption of lipid balance can lead to metabolic disturbances and thus tight regulation is required to maintain lipid homeostasis. Recent studies have shown key roles for miR-33 and miR-122 in regulation of lipid metabolism, and further evidence implicates miR-370 in regulation of miR-122. In addition, miRNAs involved in adipogenesis (miR-378/378* and miR-27) as well as newly discovered miRNAs such as miR-613, miR-302a, and miR-168 have now been implicated in regulation of lipid metabolism. SUMMARY: Growing evidence support key roles for miRNAs in regulating both cholesterol and fatty acid metabolism, leading to considerable interest in miRNAs as potential drug targets to modulate lipid and lipoprotein metabolism. MiRNA-based therapeutics hold considerable promise in the fight to curtail the growing epidemic of obesity and type 2 diabetes and the associated risk of atherosclerosis. PMID- 22488425 TI - Hepatic ABC transporters and triglyceride metabolism. AB - PURPOSE OF REVIEW: Elevated plasma triglyceride and reduced HDL concentrations are prominent features of metabolic syndrome and type 2 diabetes. Individuals with Tangier disease also have elevated plasma triglyceride concentrations and very low HDL, resulting from mutations in ATP-binding cassette transporter A1 (ABCA1), an integral membrane protein that facilitates nascent HDL particle assembly. Past studies attributed the inverse relationship between plasma HDL and triglyceride to intravascular lipid exchange and catabolic events. However, recent studies also suggest that hepatic signaling and lipid mobilization and secretion may explain how HDL affects plasma triglyceride concentrations. RECENT FINDINGS: Hepatocyte-specific ABCA1 knockout mice have markedly reduced plasma HDL and a two-fold increase in triglyceride due to failure to assemble nascent HDL particles by hepatocytes, causing increased catabolism of HDL apolipoprotein A-I and increased hepatic production of triglyceride-enriched VLDL. In-vitro studies suggest that nascent HDL particles may induce signaling to decrease triglyceride secretion. Inhibition of microRNA 33 expression in nonhuman primates augments hepatic ABCA1, genes involved in fatty acid oxidation, and decreases expression of lipogenic genes, causing increased plasma HDL and decreased triglyceride levels. SUMMARY: New evidence suggests potential mechanisms by which hepatic ABCA1-mediated nascent HDL formation regulates VLDL-triglyceride production and contributes to the inverse relationship between plasma HDL and triglyceride. PMID- 22488427 TI - Host-parasite relationships of Rhabdochona kidderi Pearse, 1936 (Nematoda: Rhabdochonidae) in fishes of the Lacantun River in the Lacandon rain forest of Chiapas State, southern Mexico, with a key to Mexican species of Rhabdochona Railliet, 1916. AB - For the first time, the nematode Rhabdochona kidderi kidderi Pearse, 1936 (Rhabdochonidae) was recorded from fishes of the Lacantun River (Usumacinta River basin) in the Lacandon rain forest, Chiapas State, southern Mexico. Amphilophus nourissati (Allgayer) and Theraps irregularis Gunther (both Perciformes: Cichlidae) were found to be the only definitive hosts in the locality, whereas Eugerres mexicanus (Steindachner) (Perciformes: Gerreidae), Ariopsis sp., Cathorops aguadulce (Meek) and Potomarius nelsoni (Evermann & Goldsborough) (all Siluriformes: Ariidae), Ictalurus furcatus (Valenciennes) (Siluriformes: Ictaluridae) and Strongylura hubbsi Collette (Beloniformes: Belonidae) all harboured the nematode's fourth-stage larva and only served as paratenic hosts. All these fish species represent new host records for this parasite. The morphology of both adults and larvae was studied in detail by light and scanning electron microscopy, and some conspecific museum specimens from three other host species were also examined for comparison. Rhabdochona ictaluri Aguilar-Aguilar, Rosas-Valdez & Perez-Ponce de Leon, 2010 is considered here to be a junior synonym of R. kidderi kidderi. A high degree of the variability of some morphological and biometrical features (deirid shape, left spicule length) and an unusually wide range of hosts suggest that R. kidderi may represent a species complex, but further studies are necessary in this respect. A key to Rhabdochona species and subspecies occurring in Mexico is provided. PMID- 22488428 TI - Studies on the life-cycle of Ganeo tigrinus Mehra & Negi, 1928 (Digenea). AB - The life-history stages of Ganeo tigrinus Mehra & Negi, 1928 infecting the Indian bull frog Hoplobatrachus tigerinus (Daudin) are described, those from cercaria to egg-producing adult having been established in the laboratory. Non-virgulate xiphidiocercariae are released by the planorbid snail Indoplanorbis exustus (Deshayes). Metacercariae occur in the haemocoel of dragonfly nymphs and become infective to the frog H. tigerinus within 15 days. The pre-patent period is 45 days. Growth and development of both metacercariae and adults are described in detail. Comments on the systematic position of Ganeo Klein, 1905 are included. PMID- 22488429 TI - Protospirura siamensis n. sp. (Nematoda: Spiruridae) from rodents in Thailand. AB - A large number (828) of rodents belonging to nine genera (Bandicota, Berylmys, Chiropodomys, Hapalomys, Leopoldamys, Maxomys, Mus, Niviventer and Rattus) were trapped in four Thai provinces between 2008 and 2010. A new species of Protospirura (Nematoda: Spiruridae) was identified and described. Protospirura siamensis n. sp. was found in 10 rodent species from the four Thai provinces surveyed. The new species can be distinguished from known species of the genus by the arrangement of the papillae on the male and the morphology and length of the spicules. This is the first species of Protospirura to be described from South East Asia. PMID- 22488430 TI - A new species of cestode, Vampirolepis muraiae n. sp. (Cyclophyllidea: Hymenolepididae), from a Chinese bat. AB - Vampirolepis muraiae n. sp. (Cestoda: Cyclophyllidea: Hymenolepididae) is described on the basis of a single specimen from a mouse-eared bat, Myotis sp., from Yunnan Province, China. It is distinguished from its congeners on the basis of the size and shape of the rostellar hooks, which have a blade shorter than the guard, the tubular structure of the initial stage of the developing uterus and eggs with a thick outer coat. PMID- 22488431 TI - Goezia nankingensis Hsu, 1933 (Nematoda: Raphidascarididae) from the critically endangered Chinese paddlefish Psephurus gladius (Martens) (Acipenseriformes: Polyodontidae). AB - Goeziine nematodes identified as Goezia nankingensis Hsu, 1933 were collected from the Chinese paddlefish Psephurus gladius (Martens) (Acipenseriformes: Polyodontidae), a critically endangered freshwater fish, from the Yangtze River in China. Their examination, using light microscopy and, for the first time, scanning electron microscopy, revealed some erroneous and previously unreported morphological features, necessitating the redescription of this poorly known species. Goezia nankingensis is easily distinguished from its congeners by the morphology and arrangement of its cuticular spines, the short intestinal caecum and long ventricular appendix (ratio of intestinal caecum to ventricular appendix 1:10.0-18.3), the short spicules (0.34-0.49 mm long, representing 6.09-10.1% of the body length), the number and arrangement of male caudal papillae [14-16 pairs in total, approximately arranged: precloacal 7-10 pairs, paracloacal 2 pairs and postcloacal 4-6 pairs (one pair double)], and the presence of a particular medio ventral, precloacal papilla in the male. PMID- 22488432 TI - Phylogenetic relationships of the anoplocephaline cestodes of Australasian marsupials and resurrection of the genus Wallabicestus Schmidt, 1975. AB - A phylogenetic analysis was carried out on rDNA of 45 species of anoplocephaline cestodes from marsupial hosts. The exclusively Australasian genera Progamotaenia Nybelin, 1917, Triplotaenia Boas, 1902, Paramoniezia Maplestone & Southwell, 1923 and Phascolotaenia Beveridge, 1976 formed a monophyletic clade, and the previously suggested relationship between the Australasian species of the cosmopolitan genus Bertiella Stiles & Hassall, 1902 and species of Progamotaenia was supported. A low degree of phyletic co-evolution was detected within endemic Australasian clades. Colonisation rather than co-speciation appeared to be the principal means of diversification within the Australasian anoplocephaline radiation. The clade of bile duct-inhabiting Progamotaenia species emphasises the role of microhabitat rather than host species as a driver of speciation. Triplotaenia undosa Beveridge, 1976 described from a wide variety of macropodid hosts was found to be polyphyletic and a proposition was made to resurrect Wallabicestus Schmidt, 1975, with W. ewersi Schmidt, 1975 as the type-species and including W. ualabati (Beveridge, 2009) n. comb. [previously Progamotaenia ualabati Beveridge, 2009]. PMID- 22488433 TI - Morphological characteristics of a new species of Haemogregarina Danilewsky, 1885 (Apicomplexa: Adeleorina) in naturally infected Acanthodactylus boskianus (Daudin) (Sauria: Lacertidae) in Egypt. AB - This paper describes the morphological characteristics of a new species of Haemogregarina Danilewsky, 1885, from naturally infected Acanthodactylus boskianus (Daudin) in Egypt, based on both blood and tissue stages. The prevalence of infection was found to be 66% (33/50). The blood stages were found to be confined to the erythrocytes and could be differentiated into small and large forms. The small form (trophozoites) measures 8 * 3.5 MUm, whereas the large form (mature gamonts) measures 12 * 5 MUm. The tissue stages were observed only in the liver. Meronts occurred within parasitophorous vacuoles in hepatocytes and ranged from mononucleate forms to mature forms that contained c.10-15 merozoites. PMID- 22488434 TI - Sagum posteli Delamare-Deboutteville & Nunes-Ruivo, 1954 (Copepoda: Siphonostomatoida: Lernanthropidae) parasitic on Epinephelus aeneus (Geoffroy Saint-Hilaire) in Turkish waters, with a key to the species of Sagum Wilson, 1913. AB - Sagum posteli Delamare-Deboutteville & Nunes-Ruivo, 1954 (Copepoda: Lernanthropidae) is reported from the white grouper Epinephelus aeneus Geoffroy Saint-Hilaire caught off the Turkish Mediterranean coast. This documents the first discovery of this species in the Mediterranean and is only the second record. The species is redescribed from adult females and the cephalothoracic limbs are described for the first time. The valid species of the genus Sagum Wilson, 1913 are reviewed, and the poorly described species S. poeyi Ortiz, Lalana & Suarez, 2003 is relegated as a junior synonym of S. texanum Pearse, 1952, described from the same host. A key is provided to females of the ten valid species of Sagum and the known hosts for all species are summarised. PMID- 22488437 TI - Pathway engineering strategies for production of beneficial carotenoids in microbial hosts. AB - Carotenoids, such as lycopene, beta-carotene, zeaxanthin, canthaxanthin and astaxanthin have many benefits for human health. In addition to the functional role of carotenoids as vitamin A precursors, adequate consumption of carotenoids prevents the development of a variety of serious diseases. Biosynthesis of carotenoids is a complex process and it starts with the common isoprene precursors. Condensation of these precursors and subsequent modifications, by introducing hydroxyl- and keto-groups, leads to the generation of diversified carotenoid structures. To improve carotenoid production, metabolic engineering has been explored in bacteria, yeast, and algae. The success of the pathway engineering effort depends on the host metabolism, specific enzymes used, the enzyme expression levels, and the strategies employed. Despite the difficulty of pathway engineering for carotenoid production, great progress has been made over the past decade. We review metabolic engineering approaches used in a variety of microbial hosts for carotenoid biosynthesis. These advances will greatly expedite our efforts to bring the health benefits of carotenoids and other nutritional compounds to our diet. PMID- 22488438 TI - A femto-injection technique for dynamic analysis of protein function in living embryonic stem cells. AB - The potential of a femto-injection technique for use in analyzing protein dynamics in embryonic stem (ES) cells was investigated. First, we showed that fluorescent proteins could be injected in a quantitative fashion into individual mouse ES cells. Second, we demonstrated that the technique could identify functional differences between proteins by analyzing the effect of a nuclear localization signal on the behavior of glutathione S-transferase conjugated to green fluorescent protein. The analysis showed a clear difference in the distribution of the protein when the nuclear localization signal was present. Our results confirm that the non-destructive, quantitative and time controllable aspects of the technique provide considerable advantages for the analysis of protein behavior in living ES cells. To the best of our knowledge, this is the first report of the successful introduction of proteins into living ES cells by an injection technique. PMID- 22488439 TI - Development of broad-spectrum insect-resistant tobacco by expression of synthetic cry1Ac and cry2Ab genes. AB - Efficacy of two newly synthesized cry1Ac and cry2Ab genes was checked in tobacco before their expression in cotton. Both genes were artificially synthesized and codon optimized with respect to cotton-preferred codon usage. These genes were cloned in a plant expression vector and then transformed into tobacco. Fifty eight putative transgenic plants were recovered from the selected explants. Successful integration of both genes in plant genome was confirmed by PCR amplification. Expression of transgenes was confirmed by PCR amplification from total plant RNA. Detached leaf insect bioassays were conducted with Helicoverpa armigera and Spodoptera exigua larvae. About 12 % of the transgenic plants showed significantly high resistance to S. exigua. Significant mortality (62 %) of H. armigera was recorded within 24 h of bioassays. Both toxins showed synergistic effect in tobacco and broadened the spectrum of plant activity against insects. PMID- 22488440 TI - Alkyl-substituted methoxysilanes enhance the activity and stability of D-amino acid oxidase encapsulated in biomimetic silica. AB - Several alkyl-substituted methoxysilanes were evaluated as potential activity and stability enhancing agents for biomimetic silicification of Rhodosporidium toruloides D-amino acid oxidase (RtDAO). When methyl-substituted silanes along with tetramethoxysilane were used as silicic acid precursors for polyallylamine (PAA)--or R5 peptide-catalyzed silicic encapsulation, the RtDAO activity increased with the degree of substitution and the molar ratio up to 15 % of methyl-substituted silanes added. In the presence of 15 mol% trimethylmethoxysilane, the specific activities of encapsulated RtDAO catalyzed by PAA and R5 increased by 1.4- and 4.8-fold, respectively. For PAA-catalyzed encapsulation, a 2.4-fold increase occurred with 30 mol% n propyltrimethoxysilane; this modification increased the T (m) value by 10 degrees C and gave a threefold longer half-life in the presence of 10 mM H(2)O(2) as compared to the encapsulation using tetramethoxysilane only. PMID- 22488441 TI - SK-HEP cells and lentiviral vector for production of human recombinant factor VIII. AB - Hemophilia A is caused by a deficiency in coagulation factor VIII. Recombinant factor VIII can be used as an alternative although it is unavailable for most patients. Here, we describe the production of a human recombinant B-domain deleted FVIII (rBDDFVIII) by the human cell line SK-HEP-1, modified by a lentiviral vector rBDDFVIII was produced by recombinant SK-HEP cells (rSK-HEP) at 1.5-2.1 IU/10(6) in 24 h. The recombinant factor had increased in vitro stability when compared to commercial pdFVIII. The functionality of rBDDFVIII was shown by its biological activity and by tail-clip challenge in hemophilia A mice. The rSK HEP cells grew in a scalable system and produced active rBDDFVIII, indicating that this platform production can be optimized to meet the commercial production scale needs. PMID- 22488442 TI - Distinct contribution of human cord blood-derived endothelial colony forming cells to liver and gut in a fetal sheep model. AB - Although the vasculogenic potential of circulating and cord blood (CB)-derived endothelial colony-forming cells (ECFC) has been demonstrated in vitro and in vivo, little is known about the inherent biologic ability of these cells to home to different organs and contribute to tissue-specific cell populations. Here we used a fetal sheep model of in utero transplantation to investigate and compare the intrinsic ability of human CB-derived ECFC to migrate to the liver and to the intestine, and to define ECFC's intrinsic ability to integrate and contribute to the cytoarchitecture of these same organs. ECFCs were transplanted by an intraperitoneal or intrahepatic route (IH) into fetal sheep at concentrations ranging from 1.1-2.6 * 10(6) cells/fetus. Recipients were evaluated at 85 days posttransplant for donor (human) cells using flow cytometry and confocal microscopy. We found that, regardless of the route of injection, and despite the IH delivery of ECFC, the overall liver engraftment was low, but a significant percentage of cells were located in the perivascular regions and retained the expression of hallmark endothelial makers. By contrast, ECFC migrated preferentially to the intestinal crypt region and contributed significantly to the myofibroblast population. Furthermore, ECFC expressing CD133 and CD117 lodged in areas where endogenous cells expressed those same phenotypes. CONCLUSION: ECFC inherently constitute a potential source of cells for the treatment of intestinal diseases, but strategies to increase the numbers of ECFC persisting within the hepatic parenchyma are needed in order to enhance ECFC therapeutic potential for this organ. PMID- 22488443 TI - Efficacy of lenalidomide plus dexamethasone for POEMS syndrome relapsed after autologous peripheral stem-cell transplantation. AB - POEMS syndrome is a rare paraneoplastic condition associated to an underlying plasmacellular dyscrasia. The pathogenesis of POEMS is poorly understood, but overproduction of VEGF, probably secreted by clonal plasma cells, is thought to be responsible for the signs and symptoms of the syndrome, and it seems to be useful for the monitoring of the response to therapy. At present, an effective therapeutic option for the patients is represented by autologous peripheral blood stem-cell transplantation (aPBSCT), although relapses have been described, and there is an important morbidity associated with this procedure. Before the implementation of aPBSCT, the clinical course of POEMS syndrome was characterized by progressive polyneuropathy potentially leading to death for respiratory failure. Given the high serum and plasma levels of VEGF observed in POEMS patients, the use of anti-angiogenetic drugs such as thalidomide and lenalidomide and other drugs with anti-VEGF and anti-TNF effect such as bortezomib have been considered to treat this syndrome. There are evidences of lenalidomide benefit in both front-line and previously treated patients, but scanty data are available about its use for relapse after aPBSCT. Here, we report the successful use of lenalidomide in a patient who relapsed after aPBSCT. PMID- 22488444 TI - Cerebrospinal fluid levels of complement proteins C3, C4 and CR1 in Alzheimer's disease. AB - Alzheimer's disease (AD) is strongly associated with loss of synapses. The complement system has been shown to be involved in synaptic elimination. Several studies point to an association between AD and the complement system. The purpose of this study was to examine the association of cerebrospinal fluid (CSF) levels of complement components 3 and 4 (C3 and C4, respectively), and complement receptor 1 (CR1) with AD in 43 patients with AD plus dementia, 42 patients with mild cognitive impairment (MCI) who progressed to AD during follow-up (MCI-AD), 42 patients with stable MCI and 44 controls. Complement levels were also applied in a multivariate model to determine if they provided any added value to the core AD biomarkers Abeta42, T-tau and P-tau. We found elevated CSF levels of C3 and C4 in AD compared with MCI without progression to AD, and elevated CSF levels of CR1 in MCI-AD and AD when these groups were merged. These results provide support for aberrant complement regulation as a part in the AD process, but the changes are not diagnostically useful. PMID- 22488446 TI - Association between circadian rhythms, sleep and cognitive impairment in healthy older adults: an actigraphic study. AB - There is increasing evidence for the relationship between circadian rhythm disturbance and cognitive decline in the older adult. This study measured circadian activity rhythms in a small group of healthy community-dwelling older adults (n = 26). Each participant completed a battery of neuropsychological tests and completed sleep diaries and 6 days of actigraphy. Ten participants were identified as having very early signs of cognitive decline as indicated by their performance on the memory tests. Results showed minimal differences on the sleep/activity and circadian parameters across the two groups (declined vs. intact), although there was a significant difference in the acrophase between the declined and intact groups. These findings, although exploratory, suggest that very subtle changes in circadian rhythm may be detected in older adults showing pre-clinical changes in cognitive performance. PMID- 22488445 TI - The effects of shift work on physical and mental health. AB - Occupational engagement is a pre-requisite for continuous income opportunities. Among the changing social circumstances work-related conditions play an increasingly eminent role in psychological and mental well-being. The public discusses the question of a possible association between the demands of modern work life and the increases of psychological, psychosomatic and cardiovascular disorders. Given the socioeconomic implications of psychiatric and psychosomatic suffering in the general population, there is a need to further elucidate the causes of their increasing incidence. From a medical point of view, any organization of work disrupting the phased circadian rhythms for bio-psycho social processes and functioning of the individual are interesting against the background of clock genes and certain biological functions that are organized in a circadian fashion. The authors review the influence of shift work as a form of systematic desynchronization of inner clock systems on the endocrine, the physical, and the mental level. The significance of the findings in the field is discussed along with future directions of conclusive research. PMID- 22488448 TI - Insulator-metal transition driven by pressure and B-site disorder in double perovskite La2CoMnO6. AB - The ground state of double perovskite oxide La2CoMnO6 (LCMO) and how it is influenced by external pressure and antisite disorder are investigated systematically by first-principles calculations. We find, on the consideration of both the electron correlation and spin-orbital coupling effect, that the LCMO takes on insulating nature, yet is transformed to half metallicity once the external pressure is introduced. Such tuning is accompanied by a spin-state transition of Co(2+) from the high-spin state (t(5)2ge(2)g) to low-spin state (t(6)2ge(1)g) because of the enhancement of crystal-field splitting under pressure. Using mean-field approximation theory, Curie temperature of LCMO with Co(2+) being in low-spin state is predicted to be higher than that in high-spin state, which is attributed to the enhanced ferromagnetic double exchange interaction arising from the shrinkage of Co-O and Mn-O bonds as well as to the increase in bond angle of Co-O?Mn under pressure. We also find that antisite disorder in LCMO enables such transition from insulating to half-metallic state as well, which is associated with the spin-state transition of antisite Co from high to low state. It is proposed that the substitution of La(3+) for the rare earth (RE) ions with smaller ionic radii could open up an avenue to induce a spin state transition of Co, rendering thereby the RE2CoMnO6 a promising half-metallic material. PMID- 22488447 TI - Pathogenesis of multiple sclerosis via environmental and genetic dysregulation of N-glycosylation. AB - Autoimmune diseases such as multiple sclerosis (MS) result from complex and poorly understood interactions of genetic and environmental factors. A central role for T cells in MS is supported by mouse models, association of the major histocompatibility complex region, and association of critical T cell growth regulator genes such as interleukin-2 receptor (IL-2RA) and interleukin-7 receptor (IL-7RA). Multiple environmental factors (vitamin D(3) deficiency and metabolism) converge with multiple genetic variants (IL-7RA, IL-2RA, MGAT1, and CTLA-4) to dysregulate Golgi N-glycosylation in MS, resulting in T cell hyperactivity, loss of self-tolerance and in mice, a spontaneous MS-like disease with neurodegeneration. Here, we review the genetic and biological interactions that regulate MS pathogenesis through dysregulation of N-glycosylation and how this may enable individualized therapeutic approaches. PMID- 22488449 TI - Maintenance plasma exchange therapy for steroid-refractory neuromyelitis optica. AB - Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease of the central nervous system with exacerbations involving the optic nerves, spinal cord, or both. This study explores the utility of maintenance plasma exchange (mTPE) as a therapy in patients with relapsing, corticosteroid-refractory, NMO. This retrospective case series presents data on patients who were diagnosed with NMO using currently accepted criteria. These patients were refractory to high dose corticosteroids and received mTPE. Seven patients met the criteria for NMO diagnosis and all were positive for antibodies against aquaporin-4. Over a mean of 7.1 years (range, 2-16), these patients received between 21 and 154 TPE treatments (mean, 76). Although treated with mTPE, five out of the seven patients improved by more than one point on the Expanded Disability Status Scale. Interruption in mTPE in five patients resulted in clinical worsening. When mTPE was restarted in three out of the five patients who experienced a cessation of mTPE, these patients either stabilized or improved. The two patients who did not restart the mTPE protocol died. Patients treated with mTPE also experienced a reduction in the number of NMO exacerbations. Finally, stabilization of the retinal nerve fiber layer thickness was observed while on mTPE. In this preliminary study, mTPE appeared safe and may bring about improvement in disability and sustained stabilization of the clinical course in patients with steroid-refractory relapsing forms of NMO. PMID- 22488451 TI - Functional perfusion imaging using pseudocontinuous arterial spin labeling with low-flip-angle segmented 3D spiral readouts. AB - Arterial spin labeling (ASL) provides quantitative and reproducible measurements of regional cerebral blood flow, and is therefore an attractive method for functional MRI. However, most existing ASL functional MRI protocols are based on either two-dimensional (2D) multislice or 3D spin-echo and suffer from very low image signal-to-noise ratio or through-plane blurring. 3D ASL with multishot (segmented) readouts can improve the signal-to-noise ratio efficiency relative to 2D multislice and does not suffer from T(2)-blurring. However, segmented readouts require lower imaging flip-angles and may increase the susceptibility to temporal signal fluctuations (e.g., due to physiology) relative to 2D multislice. In this article, we characterize the temporal signal-to-noise ratio of a segmented 3D spiral ASL sequence, and investigate the effects of radiofrequency phase cycling scheme and flip-angle schedule on image properties. We show that radiofrequency spoiling is essential in segmented 3D spiral ASL, and that 3D ASL can improve temporal signal-to-noise ratio 2-fold relative to 2D multislice when using a simple polynomial (cubic) flip-angle schedule. Functional MRI results using the proposed optimized segmented 3D spiral ASL protocol show excellent activation in the visual cortex. PMID- 22488450 TI - Fibroblast growth factor-2 promotes catabolism via FGFR1-Ras-Raf-MEK1/2-ERK1/2 axis that coordinates with the PKCdelta pathway in human articular chondrocytes. AB - Fibroblast growth factor 2 (FGF-2) has been found to play an anti-anabolic and/or a catabolic role in adult human articular cartilage via regulation of multiple signaling pathways. Upon FGF-2 stimulation, a molecular crosstalk between the mitogen activated protein kinase (MAPK) and protein kinase C delta (PKCdelta) pathways are initiated, where PKCdelta positively regulates downstream MAPK signaling. In this study, we explored the relationship between fibroblast growth factor receptor 1 (FGFR1), Ras, and PKCdelta in FGF-2 signaling in human articular chondrocytes. Pathway-specific inhibition using both chemical inhibitors and siRNA targeting FGFR1 demonstrated that, upon FGF-2 stimulation, FGFR1 controlled both Ras and PKCdelta activation, which converged on the Raf MEK1/2-ERK1/2 axis. No crosstalk was observed between Ras and PKCdelta. Quantitative PCR analyses revealed that both Ras and PKCdelta contributed to FGF 2-mediated upregulation of MMP-13, ADAMTS5, and repression of aggrecan gene. Correspondingly, FGF-2-mediated proteoglycan loss was effectively reversed by individual pathway-specific inhibitor of Ras, PKCdelta, and ERK1/2 in both 3 dimensional alginate bead culture and cartilage organ culture systems. Our findings suggest that FGFR1 interacts with FGF-2 and then activates Ras and PKCdelta, which concertedly drive MAPK signaling to mediate biological effects of FGF-2. Such an integration of dual inputs constitutes a novel mechanism of FGF-2 signaling cascade in human articular chondrocytes. PMID- 22488452 TI - Introduction to the 4th National Conference on Genomics and Public Health. PMID- 22488453 TI - The impact of genomics on public health practice: the case for change. AB - Public health practice will not be able in the 21st century to ignore the impact of genomics, cell and molecular biology. It will need to take into consideration issues that include, among others: the complementary nature of social and biological models of disease, genetic exceptionalism, the readiness of public and patient to respond to genomic information, the relationship between individuals and populations, and concepts of population stratification. Health systems will need to adapt their practice and organisation to include new sequencing technologies, bioinformatic expertise and proper evaluation of genetic and molecular tests. Links with the commercial sector will increase in importance. The impact on developing countries cannot be ignored and will require special attention. PMID- 22488454 TI - Advancing the post-genomic era agenda: contributions from public health. AB - As the science and practice of genomics increasingly turns attention to its role in common chronic illness prevention and treatment, contributions from public health become more visible. Integration of genomics into health care and public health is often framed by principles such as equity and utility, and the accompanying need to translate findings into interventions. This paper will discuss the ways the discipline of public health is in position to lead the way in promoting these principles. This can only occur with the support of an educated workforce and informed consumer base. Recommendations from the Secretary's Advisory Committee on Genetics, Health, and Society address the issues of education and training these groups, and are summarized. PMID- 22488455 TI - The public health genomics translation gap: what we don't have and why it matters. AB - Understanding the human genome and its interaction with the environment has the potential to change medical care by tailoring interventions to the precise needs of the individual patient. Little of this knowledge is currently being used in care. There are well recognized barriers to its use including lack of sufficient evidence of benefit, inadequate education of the provider workforce, concerns about privacy and reimbursement. However, there are also gaps in the current healthcare delivery system, particularly between traditional public health departments and clinical care that impede the translation of knowledge into practice. While this problem is not limited to genomics, the purpose of this article is to identify these gaps and propose potential solutions using examples from genomic medicine from the perspective of the United States healthcare system. PMID- 22488456 TI - The role of genomics in health behavior change: challenges and opportunities. AB - The most common causes of morbidity and mortality in the western world can be accounted for by unhealthy patterns of behavior (e.g. smoking, sedentary lifestyle, unhealthy diet, and alcohol consumption). Interventions to improve health behavior are sorely needed. To fully realize the potential of health behavior change interventions, be they individual level, community level, social structural, or policy-based, a greater understanding of the extent to which genomics can inform efforts at health behavior change is warranted. In this commentary, we explore three relatively novel possible routes to the integration of genomics and health behavior: (1) genomics may influence health behavior indirectly through intermediate phenotypes, requiring well-defined theory-based and mechanistic models of health behavior, (2) genomics may moderate response to interventions to change health behavior, and (3) genomics, specifically epigenetic variation, may be influenced by health behavior. The integration of genomics into research on interventions to change health behavior is not without challenges and will certainly require transdisciplinary collaborative science to succeed. We provide specific action points for moving the science forward to explore the extent to which genomic information can be harnessed to ultimately decrease morbidity and mortality associated with unhealthy behavior. PMID- 22488457 TI - Michigan BioTrust for Health: public support for using residual dried blood spot samples for health research. AB - PURPOSE: Focus groups were utilized as a mechanism to solicit input from the public in developing the Michigan BioTrust for Health, a program of the Michigan Department of Community Health to improve storage conditions and promote use of residual newborn screening dried blood spots in health research. METHODS: In 2008 2009, 10 diverse communities representative of the general public that might have special concerns as stakeholders in the BioTrust were identified, and 4 discussion questions were developed for use with a standard agenda. Focus group discussions were audio-recorded and transcribed by department staff. Qualitative conclusions resulting from the group discussions were compared with written, quantitative pre- and post-survey responses completed by individual participants. RESULTS: Overall, there was considerable concurrence of opinion across the focus groups. Participants were generally positive about the BioTrust; a sentiment that held true across different demographic populations with over 85% of participants stating they would support use of residual dried blood spots in health research. CONCLUSION: The focus group process and findings played an important role for public health policy makers in affirming the importance of engaging and informing the public and led to concrete steps to foster community support. PMID- 22488458 TI - Finding a place for genomics in health disparities research. AB - The existence of pronounced differences in health outcomes between US populations is a problem of moral significance and public health urgency. Pursuing research on genetic contributors to such disparities, despite striking data on the fundamental role of social factors, has been controversial. Still, advances in genomic science are providing an understanding of disease biology at a level of precision not previously possible. The potential for genomic strategies to help in addressing population-level disparities therefore needs to be carefully evaluated. Using 3 examples from current research, we argue that the best way to maximize the benefits of population-based genomic investigations, and mitigate potential harms, is to direct research away from the identification of genetic causes of disparities and instead focus on applying genomic methodologies to the development of clinical and public health tools with the potential to ameliorate healthcare inequities, direct population-level health interventions or inform public policy. Such a transformation will require close collaboration between transdisciplinary teams and community members as well as a reorientation of current research objectives to better align genomic discovery efforts with public health priorities and well-recognized barriers to fair health care delivery. PMID- 22488459 TI - Genetic service delivery: infrastructure, assessment and information. AB - Identification of genomic determinants of complex disorders such as cancer, diabetes and cardiovascular disease has prompted public health systems to focus on genetic service delivery for prevention of these disorders, adding to their previous efforts in birth defects prevention and newborn screening. This focus is consistent with previously identified obligations of the public health system as well as the core functions of public health identified by the Institute of Medicine. Models of service delivery include provision of services by the primary care provider in conjunction with subspecialists, provision of services through the medical home with co-management by genetics providers, provision of services in conjunction with disorder-specific treatment centers, and provision of services through a network of genetics clinics linked to medical homes. Whatever the model for provision of genetic services, tools to assist providers include facilities for outreach and telemedicine, information technology, just-in-time management plans, and emergency management tools. Assessment tools to determine which care is best are critical for quality improvement and development of best practices. Because the workforce of genetics providers is not keeping pace with the need for services, an understanding of the factors contributing to this lag is important, as is the development of an improved knowledge base in genomics for primary care providers. PMID- 22488461 TI - Family history tools in primary care: does one size fit all? AB - Family health history (FHH) has potential value in many health care settings. This review discusses the potential uses of FHH information in primary care and the need for tools to be designed accordingly. We developed a framework in which the attributes of FHH tools are mapped against these different purposes. It contains 7 attributes mapped against 5 purposes. In considering different FHH tool purposes, it is apparent that different attributes become more or less important, and that tools for different purposes require different implementation and evaluation strategies. The context in which a tool is used is also relevant to its effectiveness. For FHH tools, it is unlikely that 'one size fits all', although appreciation of different purposes, users and contexts should facilitate the development of different applications from single FHH platforms. PMID- 22488460 TI - Efficient identification and referral of low-income women at high risk for hereditary breast cancer: a practice-based approach. AB - BACKGROUND: Identification of low-income women with the rare but serious risk of hereditary cancer and their referral to appropriate services presents an important public health challenge. We report the results of formative research to reach thousands of women for efficient identification of those at high risk and expedient access to free genetic services. External validity is maximized by emphasizing intervention fit with the two end-user organizations who must connect to make this possible. This study phase informed the design of a subsequent randomized controlled trial. METHODS: We conducted a randomized controlled pilot study (n = 38) to compare two intervention models for feasibility and impact. The main outcome was receipt of genetic counseling during a two-month intervention period. Model 1 was based on the usual outcall protocol of an academic hospital genetic risk program, and Model 2 drew on the screening and referral procedures of a statewide toll-free phone line through which large numbers of high-risk women can be identified. In Model 1, the risk program proactively calls patients to schedule genetic counseling; for Model 2, women are notified of their eligibility for counseling and make the call themselves. We also developed and pretested a family history screener for administration by phone to identify women appropriate for genetic counseling. RESULTS: There was no statistically significant difference in receipt of genetic counseling between women randomized to Model 1 (3/18) compared with Model 2 (3/20) during the intervention period. However, when unresponsive women in Model 2 were called after 2 months, 7 more obtained counseling; 4 women from Model 1 were also counseled after the intervention. Thus, the intervention model that closely aligned with the risk program's outcall to high-risk women was found to be feasible and brought more low-income women to free genetic counseling. Our screener was easy to administer by phone and appeared to identify high-risk callers effectively. The model and screener are now in use in the main trial to test the effectiveness of this screening and referral intervention. A validation analysis of the screener is also underway. CONCLUSION: Identification of intervention strategies and tools, and their systematic comparison for impact and efficiency in the context where they will ultimately be used are critical elements of practice-based research. PMID- 22488462 TI - The effect of chronic disease family history on healthcare provider practice and patient behavior among Oregonians. AB - Family history is an independent risk factor for many chronic conditions. Therefore, efforts to prevent these diseases among asymptomatic people at high familial risk are justified to reduce the health burden of these chronic conditions. We analyzed 2006-2009 Oregon Behavioral Risk Factor Surveillance System data to examine associations between family history of diabetes, cardiovascular disease (CVD), colorectal cancer (CRC), breast cancer (BC), and: (1) patient-reported clinician recommendations, (2) adoption of preventive and screening behaviors, and (3) chronic disease risk factors among respondents without a personal history of the condition. A positive family history was associated with a higher likelihood of reported discussion by clinicians of CRC and BC screening and a greater likelihood of respondents having cholesterol and CRC screening. The combination of family history and clinician recommendations significantly increased the odds of CRC and BC screening compared to family history alone. A positive family history was also associated with respondents reporting lifestyle changes to prevent diabetes, CVD, and CRC, but not BC. Awareness of family history prompts clinicians to recommend screening and may motivate patients to be screened. Understanding positive family history may also motivate patients to adopt healthy lifestyles. PMID- 22488464 TI - Science and the sources of hype. AB - It has been suggested that genomic research is frequently inappropriately hyped, in both the popular press and the scientific literature, and that this hype has the potential to create a range of social concerns. This paper maps the complex array of social forces that contribute to the phenomenon of hype, including the pressure to publish, the increasingly intense commercialization agenda, the messaging emanating from research institutions, the news media and, even, the public itself. These numerous and interrelated factors create a 'hype pipeline' that will be difficult to counter without the utilization of a wide range of policy strategies. PMID- 22488463 TI - Implications of Internet availability of genomic information for public health practice. AB - Tensions in the field have emerged over how best to communicate to the public about genomic discoveries in an era of direct-to-consumer (DTC) DNA testing services available through the Internet. Concerns over what the psychological and behavioral response might be to a nuanced, multiplex risk message have spurred some to offer caution in communicating to the public about personalized risk until the necessary research has been completed on how to communicate effectively. The popularization of DTC testing services, along with a spreading Internet culture on transparency for personal data, may make 'waiting to communicate' a moot point. To steer communication efforts in the midst of increasing access to personal genomic information, a self-regulation framework is presented. The framework emphasizes the importance of presenting a coherent message in all communiques about public health genomics. Coherence should be based on an evidence-based model of how the public processes information about health conditions and an emphasis on risk-to-action links. Recommendations from the President's Council of Advisors for Science and Technology are reviewed as a way of identifying targets of opportunity for structured communications both within the healthcare system and in the broader external ecosystem of publicly available health information technologies. PMID- 22488465 TI - Genetics blogs as a public health tool: assessing credibility and influence. AB - The Internet is becoming an important source of information about genetics and holds promise for public health applications. However, the public has concerns about the credibility of online genetics information. We conducted a content analysis of genetics blogs (n = 94). Specifically, we assessed the prevalence of various genetics-related topics and perceived credibility indicators. The relationship between content indicators, credibility indicators, and blog influence, measured as links between blogs, was evaluated. Coverage of issues related to health or self-knowledge (31%) and life science (26%) was most common among genetics blogs. In terms of credibility indicators, most blogs disclosed authors' full names (81%) and biographical information (67%). Many blog authors reported having genetics (67%) or life science expertise (59%). However, only 7% of blogs were affiliated with educational or medical institutions. Overall, blogs that focused on ancestry, that had authors with life science expertise, and that posted more frequently tended to be more influential. Findings suggest that life scientists and those who blog frequently may figure more centrally in shaping the genetics information available to the public via blogs. There is room for institutions that are likely to be perceived as credible sources of genetics information to assume a greater presence through blogs. PMID- 22488466 TI - Clinical image: The Harlequin sign--benign blush or the bearer of bad news? PMID- 22488468 TI - [Perceptions of the local government about the primary care physicians shortage - a survey among mayors in the Federal State of Baden-Wuerttemberg]. AB - BACKGROUND: Local governments have a crucial role in dealing with the primary care physicians shortage (PS). The aim of this study is to evaluate the perspectives and experiences of the local mayors on this issue. METHODS: In May 2011, all 1101 mayors in the Federal State of Baden-Wuerttemberg (BW) were invited to participate in the study by filling out a survey developed by the authors. Data were analysed descriptively. RESULTS: Of the contacted mayors in BW, 63% (n=698) responded. More than 90% of the participants consider it their duty to ensure future primary care. 16% experienced local practice closures due to PS. The infrastructure provided by the communities seems to be at a high level, whereas emergency practices exist in only 15% of the communities at present. Supportive actions to attract new GPs are evaluated as appropriate by almost half of the participants. CONCLUSIONS: The PS topic is of high relevance for communities in BW. In order to gain future physicians for their region, the majority of the communities are maintaining a high level of infrastructure and are willing to offer more actions. The young generation physicians need to be informed about these existing conditions. Innovative ideas should be implemented in individual communities as pilot projects. PMID- 22488467 TI - Multi-LZerD: multiple protein docking for asymmetric complexes. AB - The tertiary structures of protein complexes provide a crucial insight about the molecular mechanisms that regulate their functions and assembly. However, solving protein complex structures by experimental methods is often more difficult than single protein structures. Here, we have developed a novel computational multiple protein docking algorithm, Multi-LZerD, that builds models of multimeric complexes by effectively reusing pairwise docking predictions of component proteins. A genetic algorithm is applied to explore the conformational space followed by a structure refinement procedure. Benchmark on eleven hetero multimeric complexes resulted in near-native conformations for all but one of them (a root mean square deviation smaller than 2.5A). We also show that our method copes with unbound docking cases well, outperforming the methodology that can be directly compared with our approach. Multi-LZerD was able to predict near native structures for multimeric complexes of various topologies. PMID- 22488469 TI - Living with rotationplasty--quality of life in rotationplasty patients from childhood to adulthood. PMID- 22488471 TI - Coronary embolism and calcified aortic valve: is there a correlation? AB - Coronary artery embolism is an uncommon cause of myocardial infarction. We report a case of acute ST-segment elevation myocardial infarction due to a coronary embolism that originated from a calcified aortic valve. Coronary angiography demonstrated complete occlusion of the left anterior descending coronary artery. Primary percutaneous coronary intervention was successfully performed, with aspiration of the valve tissue and complete restoration of the coronary artery blood flow. This was followed by aortic valve replacement a few days later. PMID- 22488472 TI - Identification of a new genotype of bovine leukemia virus. AB - To investigate the degree of genetic variability of bovine leukemia virus (BLV) strains circulating in Croatia, 29 isolates from the six largest dairy farms were examined by PCR for a segment of the gp51 env gene, followed by DNA sequencing and phylogenetic analysis. The nucleotide sequences were compared with other previously characterized BLV strains from different geographical areas, comprising all seven known BLV genotypes. The Croatian sequences showed six to eight nucleotide substitutions: six silent substitutions and two amino acid changes. Four of those substitutions were within epitopes. In comparison to the sequences of other BLV genotypes, our isolates showed the closest relationship to genotype 1 isolates PL-3252 (FJ808585) and AL-148 (FJ808573) from Argentina. The degree of variation between our sequences and those of genotype 1 was 0.2- 4.6 %. In phylogenetic trees based on 400-nt and 519-nt sequences, all of the Croatian sequences clustered separately from the other sequences, revealing a new genotype. PMID- 22488473 TI - Histone methyltransferase ASH1 orchestrates fibrogenic gene transcription during myofibroblast transdifferentiation. AB - Transdifferentiation of hepatic stellate cells (HSCs) to a myofibroblast-like phenotype is the pivotal event in liver fibrosis. The dramatic change in phenotype associated with transdifferentiation is underpinned by a global change in gene expression. Orchestrated changes in gene expression take place at the level of chromatin packaging which is regulated by enzymatic activity of epigenetic regulators that in turn affect histone modifications. Using expression profiling of epigenetic regulators in quiescent and activated primary HSCs we found a number of histone methyltransferases including MLL1, MLL5, Set1 and ASH1 to be highly up-regulated during transdifferentiation of HSCs. All of these histone methyltransferases regulate methylation of lysine 4 of histone H3, which is a signature of actively transcribed genes. We therefore postulated that one or more of these enzymes may be involved in positively influencing expression of profibrogenic genes. CONCLUSION: We find that ASH1 directly binds to the regulatory regions of alpha smooth muscle actin (alphaSMA), collagen I, tissue inhibitor of metalloproteinase-1 (TIMP1) and transforming growth factor beta1 (TGFbeta1) in activated HSCs while depletion of ASH1 caused broad suppression of fibrogenic gene expression. We also discovered that MeCP2 positively regulates ASH1 expression and therefore identify ASH1 as a key transcriptional activator component of the MeCP2 epigenetic relay pathway that orchestrates coordinated induction of multiple profibrogenic genes. PMID- 22488474 TI - Hemopericardium in a patient treated with dabigatran etexilate. AB - Dabigatran etexilate is a new oral anticoagulant used for the prevention of systemic thromboembolism in patients with atrial fibrillation. Acute bleeding episodes are known to occur with dabigatran etexilate therapy; however, only a few case reports in the literature describe such events. We describe a 70-year old man treated with dabigatran etexilate for newly diagnosed, nonvalvular atrial fibrillation who developed a large hemopericardium that appeared to be temporally related to dabigatran etexilate administration. One month after starting the drug, an incidental finding of a small pericardial effusion was found on echocardiography. One month later, the patient came to his pulmonologist's office complaining of shortness of breath; a large pericardial effusion was found on a noncontrast computed tomographic scan, and the patient was admitted to the hospital. Laboratory monitoring of his coagulation status was limited due to the lack of assays available to directly monitor the therapeutic effects of dabigatran. The internal laboratory was able to perform a dilute thrombin time (DTT) test as part of a quality improvement project aiming to validate an assay for monitoring patients receiving dabigatran therapy. A DTT was therefore performed in conjunction with routine coagulation assays to evaluate the patient's coagulation status. After pericardiocentesis, the patient recovered without incident and was discharged without anticoagulant therapy. Although the Naranjo adverse reaction probability scale only indicated a possible relationship (score of 1) between the patient's development of hemopericardium and dabigatran etexilate therapy, investigation into the patient's clinical course, comorbidities, and laboratory results led us to conclude that dabigatran etexilate was responsible for the hemopericardium. To our knowledge, this report is the first to describe a case of potentially life-threatening pericardial bleeding that was temporally related to starting dabigatran etexilate therapy. Although we found that the DTT was a viable method of monitoring coagulation status in a patient receiving dabigatran etexilate therapy, the assay lacks approval by the United States Food and Drug Administration, which limits its clinical utility and widespread use at this time. Clinicians should be aware of the potential for life-threatening bleeding with use of this agent and the difficulty associated with monitoring and reversing this therapy in the setting of acute bleeding. PMID- 22488481 TI - Acute coronary syndromes: Abciximab delivered to the MI lesion reduces infarct size. PMID- 22488482 TI - Stem cells: FOCUSing on outcomes in chronic ischemic heart failure. PMID- 22488483 TI - Antiplatelet therapy: Vorapaxar beneficial in setting of prior MI, but not in patients who have experienced a stroke. PMID- 22488484 TI - Surgery: Overall safety of on-pump and off-pump CABG surgery is similar. PMID- 22488485 TI - Lipids: Monoclonal antibody therapy lowers LDL-cholesterol levels. PMID- 22488486 TI - Valvular disease: TAVR outcomes maintained 2-years after the PARTNER trial. PMID- 22488487 TI - Benjamin Alcock (1801-?) and his canal. AB - Benjamin Alcock (1801-?) was a prominent anatomist from Ireland who is remembered most for his description of the pudendal canal. He was privileged to train under the great Irish anatomist, Abraham Colles. Following his training and several early teaching engagements, he was appointed as the first Professor of Anatomy and Physiology at Queen's College, Cork. He became a Fellow of the Royal College of Surgeons in Ireland. After several years of teaching at Queen's College, Alcock was forced to resign after a dispute over the Anatomy Act of 1832, during which he conveyed his disapproval of participation in the procurement of corpses for the school. Several years after his resignation, he left for the United States and removed himself from the view of the profession. His anatomical contributions were published in The Cyclopaedia of Anatomy and Physiology. The description he gave of the sheath enclosing the pudendal nerve and internal pudendal vessels is his most famous contribution to the literature. He is remembered eponymously for Alcock's canal. This article's intent is to clearly and concisely depict the life and contribution of Benjamin Alcock. PMID- 22488488 TI - The impact of PLCO control arm contamination on perceived PSA screening efficacy. AB - PURPOSE: To quantify the extent to which a clinically significant prostate cancer mortality reduction due to screening could have been masked by control arm screening (contamination) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial. METHODS: We used three independently developed models of prostate cancer natural history to conduct a virtual PLCO trial. Simulated participants underwent pre-trial screening based on population patterns. The intervention arm followed observed compliance during the trial then resumed population screening. A contaminated control arm followed observed contamination during the trial then resumed population screening, while an uncontaminated control arm discontinued screening upon entry. We assumed a clinically significant screening benefit, applied population treatments and survival patterns, and calculated mortality rate ratios relative to the contaminated and uncontaminated control arms. RESULTS: The virtual trial reproduced observed incidence, including stage and grade distributions, and control arm mortality after 10 years of complete follow up. Under the assumed screening benefit, the three models found that contamination increased the mortality rate ratio from 0.68-0.77 to 0.86-0.91, increased the chance of excess mortality in the intervention arm from 0-4 % to 15 28 %, and decreased the power of the trial to detect a mortality difference from 40-70 % to 9-25 %. CONCLUSIONS: Our computer simulation models indicate that contamination substantially limited the ability of the PLCO to identify a clinically significant screening benefit. While the trial shows annual screening does not reduce mortality relative to population screening, contamination prevents concluding whether screening reduces mortality relative to no screening. PMID- 22488489 TI - Molecular characterization of mercury resistant bacteria inhabiting polluted water bodies of different geographical locations in India. AB - Mercury pollution is a major environmental problem that arises as a result of natural processes as well as from anthropogenic sources. In response to toxic mercury compounds, microbes have developed astonishing array of resistance systems to detoxify them. To address this challenge, this study was aimed in screening bacterial isolates for their tolerance against varied concentrations of phenylmercuric acetate. Mercury transformation by bacteria being sensitive to factors such as available carbon source, etc. that affect mer-mediated transformation, screened mercury tolerant bacteria were also studied for their tolerance to different antimicrobials and carbon sources, followed by identification using biochemical as well as 16S rRNA approach. Following identification, gene encoding organomercurial lyase catalyzing protonolytic cleavage of C-Hg bond of organic mercury was amplified using gene specific primers, cloned in pGEMT((r)) easy vector and sequenced. Microbe-based approach using organomercurial lyase encoded by merB gene being potentially economic, provides foundation to facilitate genetic manipulation of this environmentally important enzyme to remove high concentrations of obstinate mercury using holistic, multifaceted approach for use in bioremediation through generation of transgenics or as catalyst for use in bioreactors. PMID- 22488491 TI - [Use of insulin sensitizers in the treatment of infertility in patients with polycystic ovary syndrome (POS)]. PMID- 22488490 TI - Chemical shift-induced phase errors in phase-contrast MRI. AB - Phase-contrast magnetic resonance imaging is subject to numerous sources of error, which decrease clinical confidence in the reported measures. This work outlines how stationary perivascular fat can impart a significant chemical shift induced phase-contrast magnetic resonance imaging measurement error using computational simulations, in vitro, and in vivo experiments. This chemical shift error does not subtract in phase difference processing, but can be minimized with proper parameter selection. The chemical shift induced phase errors largely depend on both the receiver bandwidth and the TE. Both theory and an in vivo comparison of the maximum difference in net forward flow between vessels with and without perivascular fat indicated that the effects of chemically shifted perivascular fat are minimized by the use of high bandwidth (814 Hz/px) and an in phase TE (high BW-TE(IN)). In healthy volunteers (N = 10) high BW-TE(IN) significantly improves intrapatient net forward flow agreement compared with low bandwidth (401 Hz/px) and a mid-phase TE as indicated by significantly decreased measurement biases and limits of agreement for the ascending aorta (1.8 +/- 0.5 mL vs. 6.4 +/- 2.8 mL, P = 0.01), main pulmonary artery (2.0 +/- 0.9 mL vs. 11.9 +/- 5.8 mL, P = 0.04), the left pulmonary artery (1.3 +/- 0.9 mL vs. 5.4 +/- 2.5 mL, P = 0.003), and all vessels (1.7 +/- 0.8 mL vs. 7.2 +/- 4.4 mL, P = 0.001). PMID- 22488492 TI - [Profile of gestational and metabolic risk in the prenatal care service of a public maternity in the Brazilian Northeast]. AB - PURPOSE: To assess the prevalence of obstetric risk factors and their association with unfavorable outcomes for the mother and fetus. METHODS: A longitudinal, descriptive and analytical study was conducted on 204 pregnant women between May 2007 and December 2008. Clinical and laboratory assessments followed routine protocols. Risk factors included socio-demographic aspects; family, personal and obstetric history; high pre-gestational body mass index (BMI); excessive gestational weight gain and anemia. Adverse outcomes included pre-eclampsia (4.5%), gestational diabetes mellitus (3.4%), premature birth (4.4%), caesarian birth (40.1%), high birth weight (9.8%) and low birth weight (13.8%). RESULTS: The average age was 26+/-6.4 years; the mothers were predominantly non-white (84.8%), 51.8% had incomplete or complete secondary level schooling, 67.2% were in a stable marital relationship and 51.0% had a regular paid job; 63.7% were admitted to the prenatal clinic during the second trimester and 16.7% during the first, with 42.6% being primiparous. A past history of chronic hypertension was reported by 2.9%, pre-eclampsia by 9.8%, excessive gestational weight gain by 15.2% and former gestational diabetes mellitus by 1.0%. In the current pregnancy, elevated pre-gestational BMI was found in 34.6%; 45.5% presented with excessive gestational weight gain, 25.3% with anemia and 47.3% with dyslipidemia. Of the 17.5% of cases with altered blood glucose, gestational diabetes mellitus was confirmed in 3.4% and proteinuria occurred in 16.4% of all cases. Adverse maternal fetal outcomes included pre-eclampsia (4.5%), gestational diabetes mellitus (3.4%), premature birth (4.4%), caesarean birth (40.1%) and high and low birth weight (9.8% and 13.8%, respectively). Independent predictors of adverse maternal fetal outcomes were identified by Poisson multivariate regression analysis: pre-gestational BMI>25 kg/m2 was a predictor for pre-eclampsia (RR=17.17; 95%CI 2.14-137.46) and caesarian operation (RR=1.79; 95%CI 1.13-2.85), previous caesarean was a predictor for present caesarean operation (RR=2.28; 95%CI 1.32-3.92) and anemia and high gestational weight gain were predictors for high birth weight (RR=3.38; 95%CI 1.41-8.14 and RR=4.68; 95%CI 1.56-14.01, respectively). CONCLUSION: Pre-gestational overweight/obesity, previous caesarean, excessive weight gain and anemia were major risk factors for pre eclampsia, caesarean operations and high birth weight. PMID- 22488493 TI - [Influence of maternal nutritional status, weight gain and energy intake on fetal growth in high-risk pregnancies]. AB - PURPOSE: To analyze the influence of maternal nutritional status, weight gain and energy consumption on fetal growth in high-risk pregnancies. METHODS: A prospective study from August 2009 to August 2010 with the following inclusion criteria: puerperae up to the 5th postpartum day; high-risk singleton pregnancies (characterized by medical or obstetrical complications during pregnancy); live fetus at labor onset; delivery at the institution; maternal weight measured on the day of delivery, and presence of medical and/or obstetrical complications characterizing pregnancy as high-risk. Nutritional status was assessed by pregestational body mass index and body mass index in late pregnancy, and the patients were classified as: underweight, adequate, overweight and obese. A food frequency questionnaire was applied to evaluate energy consumption. We investigated maternal weight gain, delivery data and perinatal outcomes, as well as fetal growth based on the occurrence of small for gestational age and large for gestational age neonates. RESULTS: We included 374 women who were divided into three study groups according to newborn birth weight: adequate for gestational age (270 cases, 72.2%), small for gestational age (91 cases, 24.3%), and large for gestational age (13 cases, 3.5%). Univaried analysis showed that women with small for gestational age neonates had a significantly lower mean pregestational body mass index (23.5 kg/m2, p<0.001), mean index during late pregnancy (27.7 kg/m2, p<0.001), and a higher proportion of maternal underweight at the end of pregnancy (25.3%, p<0.001). Women with large for gestational age neonates had a significantly higher mean pregestational body mass index (29.1 kg/m2, p<0.001), mean index during late pregnancy (34.3 kg/m2, p<0.001), and a higher proportion of overweight (30.8%, p=0.02) and obesity (38.5%, p=0.02) according to pregestational body mass index, and obesity at the end of pregnancy (53.8%, p<0.001). Multivariate analysis revealed the index value during late pregnancy (OR=0.9; CI95% 0.8-0.9, p<0.001) and the presence of hypertension (OR=2.6; 95%CI 1.5-4.5, p<0.001) as independent factors for small for gestational age. Independent predictors of large for gestational age infant were the presence of diabetes mellitus (OR=20.2; 95%CI 5.3-76.8, p<0.001) and obesity according to body mass index during late pregnancy (OR=3.6; 95%CI 1.1-11.7, p=0.04). CONCLUSION: The maternal nutritional status at the end of pregnancy in high-risk pregnancies is independently associated with fetal growth, the body mass index during late pregnancy is a protective factor against small for gestational age neonates, and maternal obesity is a risk factor for large for gestational age neonates. PMID- 22488494 TI - [Maternal complications related to the mode of delivery in pregnant women with heart disease in a specialist high risk delivery hospital in Fortaleza, CE]. AB - PURPOSE: To determine the association between maternal complications and type of delivery in women with heart disease and to identify the possible clinical and obstetrical factors implicated in the determination of the route of delivery. METHODS: This was a retrospective and descriptive study of the medical records of pregnant women with heart disease admitted to a tertiary reference hospital in the municipality of Fortaleza, Ceara, from 2006 to 2007. The study population included all pregnant women with an antepartum diagnosis of heart disease admitted for delivery, while women who received a diagnosis of heart disease after delivery were excluded, regardless of age and gestational week. A semi structured questionnaire regarding sociodemographic, clinical and obstetrical variables was used. A descriptive analysis was first performed based on simple frequencies and proportions of the sociodemographic variables. Next, possible associations between clinical and obstetrical aspects and type of delivery were analyzed, with the verification of association between maternal complications and type of delivery. The Fisher exact test was applied for this analysis, with the level of significance set at p<0.05. The collected data were processed and analyzed using the Epi-InfoTM software version 6.04 (Atlanta, USA). RESULTS: Seventy-three pregnant women with heart disease were included in the study. Interatrial communication was the condition most frequently observed among congenital diseases (11.0%) and mitral calcification among the acquired ones (24.6%). The proportion of cesarean deliveries was higher than the proportion of vaginal deliveries, except for women with acquired heart disease. An association was detected between type of heart disease and type of delivery (p=0.01). There were 13 cases of maternal complications (17.8%). Among them, ten (76.9%) occurred during cesarean section and three during vaginal delivery. No association mas detected between maternal complications and type of delivery in pregnant women with heart disease (p=0.74). CONCLUSIONS: There was no association between the occurrence of maternal complications and route of delivery among pregnant women with heart disease. PMID- 22488495 TI - [Treating ectopic pregnancy with colpotomy]. AB - PURPOSE: To report the use of colpotomy for the treatment of ectopic pregnancies. METHODS: This was a retrospective cross-sectional study conducted on all women hospitalized with a clinical-laboratory suspicion of ectopic pregnancy who did not fulfill the criteria for drug treatment with methothrexate, during the period from February 2007 to August 2008. Demographic variables, gynecologic history and characteristics associated with treatment were obtained by reviewing the medical records. RESULTS: Eighteen women were included in the study. Mean age was 27+/ 5.2 years. All patients presented ruptured ectopic pregnancy and all were submitted to partial salpingectomy. Surgical time ranged from 30 to 120 minutes (mean: 64.5 minutes) calculated from the moment when the patient entered the operating room to the moment when she left it. No patient presented postoperative infection. Mean time of hospitalization was 40+/-14.3 hours. The medications used during the postoperative period were similar in all cases, being based on nonsteroid anti-inflammatory drugs, dipyrone, paracetamol and meperidine, as needed. The diet was reintroduced 8 hours after the end of surgery. CONCLUSIONS: The use of colpotomy in the treatment of ectopic pregnancy showed good results, with the absence of important complications and a short hospitalization time. The basic surgical instruments needed for this procedure are relatively common to all hospitals, and the surgical technique is reproducible. PMID- 22488496 TI - [Sonohysterography accuracy versus transvaginal ultrasound in infertile women candidate to assisted reproduction techniques]. AB - PURPOSE: To compare the diagnostic accuracy of sonohysterography (HSN) and conventional transvaginal ultrasound (USG) in assessing the uterine cavity of infertile women candidate to assisted reproduction techniques (ART). METHODS: Comparative cross-sectional study with 120 infertile women candidate to ART, assisted at Centro de Reproducao Assistida (CRA) of Hospital Regional da Asa Sul (HRAS), Brasilia - DF, from August 2009 to November 2010. Sonohysterography was performed with saline solution infusion in a close system. The sonohysterography finding was compared to previous USG results. The uterine cavity was considered abnormal when the endometrium was found to be thicker than expected during the menstrual cycle and when an endometrial polyp, a submucous myoma and an abnormal shape of the uterine cavity were observed. The statistical analysis was done using absolute frequencies, percentage values and the chi2, with the level of significance set at 5%. RESULTS: HSN revealed that 92 (76.7%) infertile women candidate to ART had a normal uterine cavity, while 28 (23.3%) had the following abnormalities: 15 polyps (12.5%), 9 cases of abnormal shape of the uterine cavity (7.5%), 6 submucous myomas (5%), 4 cases of inadequate endometrial thickness for the menstrual cycle phase (3.3%), and 2 cases of uterine septum (1.7%); 5 women presented more than one abnormality (4.2%). While USG showed alteration in the cavity only in 5 (4.2%) women, the sonohysterography confirmed 4 out of the 5 abnormalities shown by USG and detected an abnormal uterine cavity in 24 other women, who had not been detected by USG. This means that sonohysterography was able to detect more abnormalities in the uterine cavity than USG, with a statistically significant difference (p=0.002). CONCLUSION: The sonohysterography was more accurate than USG in the assessment of the uterine cavity of this cohort of infertile women candidate to ART. The sonohysterography can be easily incorporated into the investigation of these women and contribute to reducing embryo implantation failures. PMID- 22488497 TI - [The importance of oral glucose tolerance test in diagnosis of glucose intolerance and type 2 diabetes mellitus in women with polycystic ovary syndrome]. AB - PURPOSE: To evaluate the importance of the oral glucose tolerance test for the diagnosis of glucose intolerance (GI) and type 2 diabetes mellitus (DM-2) in women with PCOS. METHODS: A retrospective study was conducted on 247 patients with PCOS selected at random. The diagnosis of GI was obtained from the two-hour oral glucose tolerance test with 75 g of glucose according to the criteria of the World Health Organization (WHO) (GI: 120 minutes for plasma glucose >140 mg/dL and <200 mg/dL), and the diagnosis of DM-2 was obtained by both the oral glucose tolerance test (DM: 120 minutes for plasma glucose >200 mg/dL) and fasting glucose using the criteria of the American Diabetes Association (impaired fasting glucose: fasting plasma glucose >100 and <126 mg/dL; DM: fasting glucose >126 mg/dL). A logistic regression model for repeated measures was applied to compare the oral glucose tolerance test with fasting plasma glucose. ANOVA followed by the Tukey test was used for the analysis of the clinical and biochemical characteristics of patients with and without GI and/or DM-2. A p<0.05 was considered statistically significant. RESULTS: PCOS patients had a mean age of 24.8+/-6.3, and body mass index (BMI) of 18.3 to 54.9 kg/m2 (32.5+/-7.6). The percentage of obese patients was 64%, the percentage of overweight patients was 18.6% and 17.4% had healthy weight. The oral glucose tolerance test identified 14 cases of DM-2 (5.7%), while fasting glucose detected only three cases (1.2%), and the frequency of these disorders was higher with increasing age and BMI. CONCLUSIONS: The results of this study demonstrate the superiority of the oral glucose tolerance test in relation to fasting glucose in diagnosing DM-2 in young women with PCOS and should be performed in these patients. PMID- 22488498 TI - [Atipical form of Mayer-Rokitansky-Kuster-Hauser syndrome with renal malformation and skeletal abnormalities (MURCS association)]. AB - The atypical and more severe form of Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) or MRKH type II is also known as MURCS association, an acronym meaning aplasia/hypoplasia of Mullerian ducts (MU), congenital renal dysplasia (R) and cervico-thoracic dysplasia (CS). It affects female patients with normal karyotype and ovarian function, evolving to primary amenorrhea. It has an incidence of 1:50,000, but it is underestimated due to late diagnosis and undefined etiology. We describe the cases of a child and an adolescent in order to predict the diagnosis even in childhood, before the onset of amenorrhea. Patients had in common renal malformation, agenesis or hypoplasia of Mullerian derivatives and vertebral anomalies, establishing the diagnosis of MURCS. The relevance of this paper is to show the importance of further investigation when some of pathologic signs are present, researching correlated abnormalities in order to establish an early diagnosis and consequently to provide guidance to the patients and their families about the best way to conduct the case, including genetic counseling. PMID- 22488499 TI - Quantification of changes in detrusor function and pressure-flow parameters after radical prostatectomy: relation to postoperative continence status and the impact of intensity of pelvic floor muscle exercises. AB - OBJECTIVES: We aim to quantify changes in detrusor function and pressure-flow parameters after radical retropubic prostatectomy (RRP) and to determine the impact of the level of intensity of pelvic floor muscle exercises (PFME) on these changes. We also tried to identify preoperative urodynamic factors, predictive of postoperative continence status. METHODS: Sixty-six patients were included in the study. An urodynamic examination was performed before surgery and 26 weeks after catheter removal. All patients were instructed in PFME. However the intensity of PFME varied between instructions based on an information folder only (F-PFME) and intensive guidance by a physiotherapist, in addition to the folder (PG-PFME). RESULTS: In 66 men pre- as well as postoperative urodynamic studies were available for analysis. Overall, Q(max) increased, p(det.Qmax) and the urethral resistance factor URA decreased significantly after surgery. At baseline, detrusor overactivity (DOA) was found in 34% and 5.3% of the men who were still incontinent 6 months postoperatively and those who regained continence, respectively (P = 0.015). Postoperatively, Q(max) was significantly higher (P = 0.04) and URA significantly lower (P = 0.047) in the physiotherapist-guided group. No prognostic standard urodynamic factors for post-RP incontinence (PRPI) were identified. CONCLUSION: In univariate analysis, preoperative DOA is associated with a higher risk of remaining incontinent after surgery. However, in multivariate analysis, urodynamic parameters predictive of PRPI could not be identified. Therefore, standard preoperative filling cystometry and pressure-flow studies seem to have no role as preoperative predictors of PRPI in patients with localized prostate cancer. More intensive PFME might have a lowering effect on bladder outflow resistance after RRP. PMID- 22488500 TI - Acute toxicity of cadmium, lead, zinc, and their mixtures to stream-resident fish and invertebrates. AB - The authors conducted 150 tests of the acute toxicity of resident fish and invertebrates to Cd, Pb, and Zn, separately and in mixtures, in waters from the South Fork Coeur d'Alene River watershed, Idaho, USA. Field-collected shorthead sculpin (Cottus confusus), westslope cutthroat trout (Oncorhynchus clarkii lewisi), two mayflies (Baetis tricaudatus and Rhithrogena sp.), a stonefly (Sweltsa sp.), a caddisfly (Arctopsyche sp.), a snail (Gyraulus sp.), and hatchery rainbow trout (Oncorhynchus mykiss), were tested with all three metals. With Pb, the mayflies (Drunella sp., Epeorus sp., and Leptophlebiidae), a Simuliidae black fly, a Chironomidae midge, a Tipula sp. crane fly, a Dytiscidae beetle, and another snail (Physa sp.), were also tested. Adult westslope cutthroat trout were captured to establish a broodstock to provide fry of known ages for testing. With Cd, the range of 96-h median effect concentrations (EC50s) was 0.4 to >5,329 ug/L, and the relative resistances of taxa were westslope cutthroat trout ~ rainbow trout ~ sculpin << other taxa; with Pb, EC50s ranged from 47 to 3,323 ug/L, with westslope cutthroat trout < rainbow trout < other taxa; and with Zn, EC50s ranged from 21 to 3,704 ug/L, with rainbow trout < westslope cutthroat trout ~ sculpin << other taxa. With swim-up trout fry, a pattern of decreasing resistance with increasing fish size was observed. In metal mixtures, the toxicities of the three metals were less than additive on a concentration-addition basis. PMID- 22488501 TI - Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. AB - OBJECTIVE: Allopurinol is the most commonly used urate-lowering therapy in gout. Allopurinol hypersensitivity syndrome (AHS) is a rare but potentially fatal adverse event. Dosing guidelines based on creatinine clearance have been proposed based on the recognition that dosages of >=300 mg/day may be associated with AHS, particularly in patients with renal impairment. However, the relationship between the allopurinol starting dose and AHS is unknown. This study was undertaken to determine the relationship between allopurinol dosing and AHS. METHODS: A retrospective case-control study of patients with gout who developed AHS between January 1998 and September 2010 was undertaken. For each case, 3 controls with gout who were receiving allopurinol but did not develop AHS were identified. Controls were matched with cases for sex, diuretic use at the time of initiating allopurinol, age (+/-10 years), and estimated glomerular filtration rate (estimated GFR). Starting dose and dose at the time of the reaction in cases were compared between cases and controls. RESULTS: Fifty-four AHS cases and 157 controls were identified. There was an increase in the risk of AHS as the starting dose of allopurinol corrected for the estimated GFR increased. For the highest quintile of starting dose per estimated GFR, the odds ratio was 23.2 (P < 0.01). Receiver operating characteristic analysis indicated that 91% of AHS cases and 36% of controls received a starting dose of allopurinol of >=1.5 mg per unit of estimated GFR (mg/ml/minute). CONCLUSION: Our findings indicate that starting allopurinol at a dose of 1.5 mg per unit of estimated GFR may be associated with a reduced risk of AHS. In patients who tolerate allopurinol, the dose can be gradually increased to achieve the target serum urate level. PMID- 22488502 TI - Development of nanoparticle stabilized polymer nanocontainers with high content of the encapsulated active agent and their application in water-borne anticorrosive coatings. AB - A novel method for the encapsulation of organic active agents in nanoparticle armored polymer composite nanocontainers (analog of Pickering emulsions) is introduced. The multifunctionality of the constituents allows a fabrication path that does not require auxiliary materials. Embedding the composite nanocontainers into a water-based alkyd resin and subsequent film formation yields a homogeneous polymer film doped with highly disperse composite nanocontainers. The resistance and self-healing of such a film on aluminium is enhanced. PMID- 22488504 TI - Compensatory redistribution of neuroligins and N-cadherin following deletion of synaptic beta1-integrin. AB - beta1-containing integrins are required for persistent synaptic potentiation in hippocampus and regulate hippocampal-dependent learning. Based largely on indirect evidence, there is a prevailing assumption that beta1-integrins are localized at synapses, where they contribute to synapse adhesion and signaling, but this has not been examined directly. Here we investigate the fine localization of beta1-integrin in adult mouse hippocampus using high-resolution immunogold labeling, with a particular emphasis on synaptic labeling patterns. We find that beta1-integrins localize to synapses in CA1 and are concentrated postsynaptically. At the postsynaptic membrane, beta1-integrins are found more commonly clustered near active zone centers rather than at the peripheral edges. In mice harboring a conditional deletion of beta1-integrins, labeling for N cadherin and neuroligins increases. Western blots show increased levels of N cadherin in total lysates and neuroligins increase selectively in synaptosomes. These data suggest there is a dynamic, compensatory adjustment of synaptic adhesion. Such adjustment is specific only for certain cell adhesion molecules (CAMs), because labeling for SynCAM is unchanged. Together, our findings demonstrate unequivocally that beta1-integrin is an integral synaptic adhesion protein, and suggest that adhesive function at the synapse reflects a cooperative and dynamic network of multiple CAM families. PMID- 22488506 TI - The statistical significance of selected sense-antisense peptide interactions. AB - Sense and antisense peptides, encoded by sense and corresponding antisense DNA strands, are capable of specific interactions that could be a driving force to mediate protein-protein or protein-peptide binding associations. The complementary residue hypothesis suggests that these interactions are founded upon the sum of pairwise interactions between amino acids encoded by corresponding sense and antisense codons. Despite many successful experimental results obtained with the hypothesis, however, the physicochemical basis for these interactions is poorly understood. We examined the potential of the hypothesis for general identification of protein-protein interaction sites, and the possible role of the hypothesis in determining folding in a broad set of protein structures. In addition, we performed a structural study to investigate the binding of a complementary peptide to IL-1F2. Our results suggest that complementary residue pairs are no more frequent or conserved than average in protein-protein interfaces, and are statistically under-represented amongst contacting residue pairs in folded protein structures. Although our structural results matched experimental observations of binding between the peptide and IL 1F2, complementary residue interactions do not appear to be dominant in the bound structure. Overall, our data do not allow us to conclude that the complementary residue hypothesis accounts for specific sense-antisense peptide interactions. PMID- 22488507 TI - The negative predictive value of D-dimer on the risk of recurrent venous thromboembolism in patients with multiple previous events: a prospective cohort study (the PROLONG PLUS study). AB - The optimal duration of anticoagulation after recurrent venous thromboembolism(VTE) is poorly established [1,2]. Recent studies suggested that D dimer may identify patients at low risk of recurrence after a first VTE [3,4]. In a pilot, prospective, cohort study we aimed to assess the negative predictive value of D-dimer in patients with recurrent VTE. Patients with negative D-dimer while on treatment stopped anti coagulation and underwent repeated testing after 7, 15, and 30 days; treatment was resumed if D-dimer turned positive and permanently stopped if it remained negative. The study was interrupted after the enrolment of 75 patients. At that time, treating physicians decided treatment resumption in 12.2% of the patients, but the majority of events were distal or superficial vein thromboses. The rate of objectively documented recurrent proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE) was 2.56% (95% CI 0.13, 15.07%) in the 39 patients with persistently negative D-dimer at 30 days, for an annual incidence of VTE of 5.65 events/100 patient/years. These preliminary findings suggest that negative D-dimer may identify patients with history of previous VTE at low risk of recurrences, but this approach should be tested in larger trials in highly selected patients. PMID- 22488508 TI - Impact of iso- and low-osmolar iodinated contrast agents on BOLD and diffusion MRI in swine kidneys. AB - PURPOSE: To assess whether functional MR imaging using blood-oxygenation level dependent (BOLD) imaging and diffusion-weighted imaging demonstrate changes in renal oxygenation and apparent diffusion coefficient (ADC) in a pig model. MATERIALS AND METHODS: After administration of either 1-g iodine/kg body weight low-osmolar iopromide or iso-osmolar iodixanol, 8 mini pigs underwent a series of repeated BOLD measurements (TR/TE 106/5.9-48.7 ms, slice thickness 4 mm) and diffusion-weighted imaging measurements (TR/TE 3900/79 ms, slice thickness 4 mm) for 1 hour at 1.5 T. In this intraindividual cross over study, the second contrast agent injection with the other iodinated contrast agent was performed at least 24 hours after the initial contrast agent injection. BOLD-based R2* values as indirect measures of the renal oxygenation were determined for the cortex, the inner medulla, and the outer medulla. ADC values were measured for the cortex and the whole kidney. RESULTS: For both contrast agents, a drop in R2* was found in the cortex, which normalized after 55 minutes. In the outer medulla and particularly in the inner medulla, a decreased initial drop of R2* was encountered with both contrast agents, with a slow increase toward the baseline R2*. In the inner medulla, elevated R2* values were found with the iso-osmolar contrast agent only. The ADC revealed an initial increase, which slowly decayed over the measurement period. This finding was more pronounced for the cortex compared with the whole-kidney analysis. CONCLUSION: Functional MR imaging of the kidneys demonstrates increased R2* in the inner medulla only after the administration of the iodixanol potentially indicating hypoxia and thus a pathomechanism of contrast-induced nephropathy. PMID- 22488509 TI - Flat-panel CT arthrography: feasibility study and comparison to multidetector CT arthrography. AB - OBJECTIVES: To show the feasibility of flat-panel computed tomography (FPCT) arthrography and quantitatively and qualitatively compare different FPCT protocols with standard multidetector computed tomography (MDCT). MATERIALS AND METHODS: First, a phantom simulating joint space with increasing iodine concentrations was scanned using a standard MDCT and 3 different FPCT protocols. Quantitative analyses were performed by measuring CT numbers of iodine dilutions, radiation dose, and image noise as well as signal-to-noise ratio and contrast-to noise ratio. Second, FPCT arthrographies of 4 animal joint specimens were performed and analyzed qualitatively by 2 independent readers who evaluated image artifacts, image noise, overall image quality and anatomic depiction of bone, cartilage, and soft tissue. Kappa values were calculated for inter-reader agreement. Pearson's correlation coefficient (r) and Wilcoxon signed-ranks test with Bonferroni corrections for multiple comparisons were used to compare MDCT and FPCT. RESULTS: In phantoms, all CT scans showed a linear correlation between increasing iodine concentrations and mean HU values of contrast media and radiation dose, respectively (r = 0.98-0.99, P < 0.01). Dose-length product remained constant for MDCT scans. Signal-to-noise ratio for phantom water linearly decreased in all FPCT scans with increasing iodine concentrations. Contrast-to-noise ratio curves showed reduced slope at iodine concentrations higher than 75 mg/mL. FPCT arthrography after intra-articular administration of 5 to 6 mL of a 25% dilution of iopromide (Ultravist 300 mg/mL, Bayer HealthCare, Berlin, Germany) was successfully performed in all 4 animal joint specimens. Kappa values for inter-reader agreement of qualitative image analyses were 0.62 to 0.91. Image and depiction quality of 20-s FPCT scans were similar or superior compared with standard MDCT (P < 0.005). CONCLUSION: FPCT arthrography is feasible and may allow similar image quality compared with standard MDCT arthrography. PMID- 22488503 TI - Connections of the lateral hypothalamic area juxtadorsomedial region in the male rat. AB - The connections of the lateral hypothalamic area juxtadorsomedial region (LHAjd) were investigated in a series of pathway-tracing experiments involving iontophoretic co-injection of the tracers Phaseolus vulgaris-leucoagglutinin (PHA L; for outputs) and cholera toxin B subunit (CTB; for inputs). Results revealed that the LHAjd has connections with some 318 distinct gray matter regions encompassing all four subsystems-motor, sensory, cognitive, and behavioral state included in a basic structure-function network model of the nervous system. Integration of these subsystems is necessary for the coordination and control of emotion and behavior, and in that regard the connections of the LHAjd indicate that it may have a prominent role. Furthermore, the LHAjd connections, together with the connections of other LHA differentiations studied similarly to date, indicate a distinct topographic organization that suggests each LHA differentiation has specifically differing degrees of involvement in the control of multiple behaviors. For the LHAjd, its involvement to a high degree in the control of defensive behavior, and to a lesser degree in the control of other behaviors, including ingestive and reproductive, is suggested. Moreover, the connections of the LHAjd suggest that its possible role in the control of these behaviors may be very broad in scope because they involve the somatic, neuroendocrine, and autonomic divisions of the nervous system. In addition, we suggest that connections between LHA differentiations may provide, at the level of the hypothalamus, a neuronal substrate for the coordinated control of multiple themes in the behavioral repertoire. PMID- 22488510 TI - Value of in vivo T2 measurement for myocardial fibrosis assessment in diabetic mice at 11.75 T. AB - OBJECTIVE: The aim of the study was to assess the value of in vivo T2 measurements to noninvasively quantify myocardial fibrosis in diabetic mice at 11.75 T. Diabetic cardiomyopathy is characterized by extracellular matrix alteration and microcirculation impairment. These conditions might provide electrical heterogeneity, which is a substrate for arrhythmogenesis. T1 mapping has been proposed to quantify diffuse myocardial fibrosis in cardiac diseases but has several limitations. T2 measurement may represent an alternative for fibrosis quantification at high magnetic field. MATERIALS AND METHODS: A magnetic resonance imaging protocol including in vivo T2 measurements at 11.75 T was performed in 9 male C57BL/6J mice after 8 weeks of streptozotocin-induced diabetes and in 9 control mice. Programmed ventricular stimulation was performed in both groups. T2 measurements were compared with histologic quantification of fibrosis using picrosirius red staining. RESULTS: Myocardial T2 was significantly lower in diabetic mice (13.8 +/- 2.8 ms) than in controls (18.9 +/- 2.3 ms, P < 0.001). There was a good correlation between T2 and fibrosis area obtained by histopathology (R = 0.947, P < 0.001). During programmed ventricular stimulation, 3 nonsustained ventricular tachycardias were induced in diabetic mice versus none in the control group. CONCLUSIONS: The in vivo T2 relaxation time strongly correlated with myocardial fibrosis area assessed with histologic staining in diabetic mice. PMID- 22488511 TI - Effects of thermal processing and various chemical substances on formaldehyde and dimethylamine formation in squid Dosidicus gigas. AB - BACKGROUND: Trimethylamine oxide (TMAO) in squid is demethylated to dimethylamine (DMA) and formaldehyde (FA) during storage and processing. This study examined the effects of thermal processing and various chemical substances on FA and DMA formation in squid. RESULTS: The thermal conversion of TMAO was assessed by analysing four squid and four gadoid fish species, which revealed that FA, DMA and trimethylamine (TMA) were gradually produced in squid, whereas TMA increased and FA decreased in gadoid fish. A significant increase in both FA and DMA levels was observed in the supernatant of jumbo squid with increased heating temperature and extended heating time at pH 6-7. Ferrous chloride combined with cysteine and/or ascorbate had a significantly positive effect on FA formation in the heated supernatant of jumbo squid. No significant difference was observed in the levels of Cu and Fe in squid and gadoid fish. The capability of Fe(2+) to promote the formation of FA and DMA was not completely attributable to its reducing power in squid. CONCLUSION: Non-enzymatic decomposition of TMAO was a key pathway during the thermal processing of jumbo squid, and Fe(2+) was a crucial activator in the formation of FA and DMA. PMID- 22488512 TI - Use of home telehealth monitoring with active medication therapy management by clinical pharmacists in veterans with poorly controlled type 2 diabetes mellitus. AB - STUDY OBJECTIVE: To compare the effect of medication therapy management by a clinical pharmacy specialist who used the Care Coordination Home Telehealth (CCHT) program with the effect of medication therapy management by a clinical pharmacy specialist who did not use the CCHT program in a cohort of patients with poorly controlled type 2 diabetes mellitus. DESIGN: Nonrandomized, parallel, control group study. SETTING: Four outpatient primary care clinics within a Veterans Affairs health care system in which diabetes management services were provided by three clinical pharmacy specialists. PATIENTS: One hundred three patients with type 2 diabetes and a hemoglobin A(1c) (A1C) of greater than 7% who were receiving insulin therapy between October 1, 2008, and April 1, 2010; 36 patients were enrolled in the CCHT group, and 67 patients were in the non-CCHT group. Patients enrolled in the CCHT group were initially seen by a clinical pharmacy specialist and had two follow-up visits within a 6-month period. The CCHT program predominantly used a messaging device as a means of communication between providers and clinical pharmacy specialists and patients in the time intervals between their face-to-face visits. The clinical pharmacy specialist evaluated the transmitted data and made clinical decisions with respect to medication therapy management and diabetes management; a registered nurse communicated this information to the patients by telephone. MEASUREMENTS AND MAIN RESULTS: Data from medical records were reviewed for both groups. Baseline demographics were similar between the groups, with an initial A1C of 9% and 9.1% in the CCHT and non-CCHT groups, respectively (p=0.6201). The primary outcome was the change in A1C from baseline to 6 months. Secondary outcomes included the percentage of patients meeting American Diabetes Association (ADA) treatment goals for A1C, total amount of time spent/patient, and number of antidiabetic drug changes. A statistically significant difference in mean A1C was noted in the CCHT versus the non-CCHT group at 3 months (7.2% vs 8.0%, p=0.0002) and 6 months (6.9% vs 7.5%, p=0.0066); however, the mean reduction in A1C from baseline to 6 months was not significant between groups (p=0.1987). Sixty-nine percent of the CCHT group versus 36% in the non-CCHT group achieved the ADA A1C goal of less than 7% (p=0.0011). More time was spent (p<0.001) and more antidiabetic drug changes were made (p<0.0001) in the CCHT group. CONCLUSION: Management of patients with diabetes who are receiving insulin may be optimized by clinical pharmacy specialist use of the CCHT program. Although no statistically significant difference was demonstrated with respect to change in A1C from baseline to 6 months, the CCHT group did show significantly greater differences than the non-CCHT group in A1C at 3 and 6 months, coupled with higher achievement of ADA A1C goals after 6 months. PMID- 22488513 TI - The impact of lifetime alcohol use on hepatitis C treatment outcomes in privately insured members of an integrated health care plan. AB - Treatment of chronic hepatitis C infection (HCV(+) ) has historically been shown to be less effective in patients with a heavy drinking history. The effect of moderate and heavy alcohol use on treatment with pegylated interferon-alpha and ribavirin (P/R) in an insured household population has not been previously reported. We investigated the effect of alcohol on treatment outcome in a cohort of 421 treatment-naive HCV(+) patients, members of an integrated health care plan treated with P/R between January 2002 and June 2008. A detailed drinking history was obtained for 259 (61.5%) eligible patients. Regular drinking was reported by 93.1% of patients before HCV diagnosis, by 30.9% between HCV diagnosis and treatment, by 1.9% during treatment, and 11.6% after the end of treatment. Heavy drinking patterns were reported by 67.9%, 63.5% of patients drank more than 100 kg of ethanol before initiating HCV treatment, and 29.3% reported abstaining less than the required 6 months before treatment. Despite these reports of heavy drinking, sustained virological responses (SVRs) were obtained in 80.2% of patients with HCV genotypes 2 or 3 and 45.1% of patients with genotypes 1, 4, or 6. Pretreatment drinking patterns and total alcohol intake were both unrelated to SVR rates. Abstaining less than 6 months before treatment was related to lower SVR rates in moderate, but not heavy, drinkers. HCV treatment relapse was unrelated to drinking after treatment ended. CONCLUSION: The amount of alcohol consumed before HCV treatment did not have a negative effect on treatment outcomes in our population. A history of heavy drinking should not be considered a deterrent to HCV treatment in members of an integrated health care plan who are closely monitored. PMID- 22488515 TI - Exploring the optimal treatment strategy for surgically resected T4 esophageal tumors. PMID- 22488514 TI - Repair of dental resin-based composites. AB - OBJECTIVES: The study analyzed the reparability and compatibility of light-curing resin-based composites (RBCs) of the categories "microhybrid," "nanohybrid," and "packable." MATERIALS AND METHODS: Six RBCs with different matrix and filler formulation--purely methacrylate-based composites (MBCs), ormocer-based composites (OBCs), and silorane-based composites (SBCs)--were used for the specimens. Every material was combined with itself and with the other five RBCs, resulting in a total of 36 combination groups (n = 20). The specimens were polymerized, aged for 8 weeks in distilled water at 37 degrees C, and then repaired by means of a repair kit. Shear bond strength and fracture mode were measured after aging of the specimens, undergoing storage for 24 h in distilled water at 37 degrees C followed by thermocycling (5,000 cycles, 5-55 degrees C) and an additional 4-week storage in distilled water at 37 degrees C. RESULTS: Data were statistically analyzed using ANOVA with TUKEY HSD post hoc test (alpha = 0.05). On average, the OBC Admira reached the highest value as a substrate material (30.41 MPa), and the SBC Filtek Silorane reached the lowest value (8.14 MPa). Filtek Silorane was identified as the repair material with the highest bond strength value (28.70 MPa), while a packable composite reached the lowest bond strength value (15.55 MPa). The analysis of the break modes showed that adhesive breaks are typical when strength is at its lowest (6.27 MPa). A large number of cohesive fractures are conspicuous when identical materials are used for repair, except Filtek Silorane (2 % cohesive fractures). CONCLUSIONS: The study demonstrated that the effect of the different materials on bond strength varies strongly, depending on whether the material is used as filling or as repair material. CLINICAL RELEVANCE: It is generally advisable but not compulsory to combine identical RBCs. PMID- 22488516 TI - Applicability and safety of autologous fat for reconstruction of the breast. AB - BACKGROUND: Autologous fat grafting to the breast for cosmetic and reconstructive purposes is still controversial with respect to its safety and efficacy. The objective of this study was to conduct a systematic review of the clinical applicability and safety of the technique. METHODS: An online search of the Cochrane Library, MEDLINE, Embase and SciELO was conducted from July 1986 to June 2011. Studies included in the review were original articles of autologous liposuctioned fat grafting to the female breast, with description of clinical complications and/or radiographic changes and/or local breast cancer recurrence. RESULTS: This review included 60 articles with 4601 patients. Thirty studies used fat grafting for augmentation and 41 for reconstructive procedures. The incidence of clinical complications, identified in 21 studies, was 3.9 per cent (117 of 3015); the majority were induration and/or palpable nodularity. Radiographic abnormalities occurred in 332 (13.0 per cent) of 2560 women (17 studies); more than half were consistent with cysts. Local recurrence of breast cancer (14 of 616, 2.3 per cent) was evaluated in three studies, of which only one was prospective. CONCLUSION: There is broad clinical applicability of autologous fat grafting for breast reconstruction. Complications were few and there was no evidence of interference with follow-up after treatment for breast cancer. Oncological safety remains unclear. PMID- 22488517 TI - The potential effect of TNF-alpha antagonist therapy in rheumatoid arthritis may depend on the degree and severity of insulin resistance before the onset of this therapy. PMID- 22488518 TI - Proliferative effects of estradiol- or ethinylestradiol-progestogen combinations on human breast cancer cells in an intermitted and a long-term regimen. AB - Currently the use of natural estradiol as estrogenic component in oral contraceptives is more and more extended. It is unknown whether the application of this estrogen is associated with a different breast cancer risk as compared to the common use of the synthetic ethinylestradiol. In addition with the intention to reduce menstruation associated symptoms and bleeding periods an extended-cycle regimen is currently considered. In the present in vitro work, we have compared the effect of these different estrogenic compounds and the different treatment regimens on breast cancer risk. Human breast cancer cells (ZR75-1 and HCC1500) were incubated with equimolar concentrations of estradiol or ethinylestradiol combined with various progestogens, dienogest, drospirenone, keto-desogestrel, levonorgestrel, and nomegestrel. Usual and extended cycle was mimicked by incubation periods of 3 days with 1 day hormones off and 4 days, respectively. Molecular markers for proliferation and apoptosis were investigated by Western blot. In both cell lines estradiol and ethinylestradiol elicited a significant increase in the proliferation rate without difference between the 2 estrogens. The effect in the long-term cycle tended to be more pronounced than in the intermitted cycle. Progestogen addition most significantly reduced the estrogen induced proliferation rate. The molecular markers were influenced by the progestogens mostly in the same manner, reducing the proliferation/apoptosis rate. Our results indicate that both estrogenic based combinations with progestogens may not increase breast cancer risk independent from the regimen, intermitted or long-term cycle. However clinical studies are necessary to prove these in vitro results. PMID- 22488519 TI - The vasculature within the paraventricular nucleus of the hypothalamus in mice varies as a function of development, subnuclear location, and GABA signaling. AB - The paraventricular nucleus of the hypothalamus (PVN) is a cell group that plays important roles in regulating sympathetic vasomotor tone, food intake, neuroendocrine and autonomic stress responses, and cardiovascular function. The developing PVN is surrounded by neuronal elements containing, and presumably secreting, gamma-aminobutyric acid (GABA). The vasculature of the adult PVN is notably denser than in other brain regions or in the PVN during perinatal development. To characterize the postnatal angiogenic process in mice, blood vessels were analyzed at P8, 20, and 50 in rostral, mid, and caudal divisions of the PVN in males and females. Vascular changes relative to disruption of the R1 subunit of the GABA(B) receptor were evaluated at P8 and P20. For defined regions of interest within the PVN there were age dependent increases in blood vessel lengths and branching from P8 to 20 to 50 with the most notable increases in the middle region. Loss of GABA(B) receptors did not influence vascular characteristics at P8 in any region, but by P20 there was significantly (20%) less blood vessel length and branching in the mid-PVN region vs. wild type. These findings suggest that the loss of GABA(B) signaling may lead to a late developing defect in angiogenesis. The loss of vascularity with defective GABA(B) signaling suggests that neurovascular relationships in the PVN may be an important locus for understanding disorders of the hypothalamic-pituitary-adrenal axis with potential impact for psychiatric mood disorders along with other comorbid disorders that may be regulated by cells in the PVN. PMID- 22488520 TI - GLUT4 in the endocrine pancreas--indicating an impact in pancreatic islet cell physiology? AB - The glucose transporter GLUT4 is well known to facilitate the transport of blood glucose into insulin-sensitive muscle and adipose tissue. In this study, molecular, immunohistochemical, and Western blot investigations revealed evidence that GLUT4 is also located in the mouse, rat, and human endocrine pancreas. In addition, high glucose decreased and insulin elevated the GLUT4 expression in pancreatic alpha-cells. In contrast, high glucose increased GLUT4 expression, whereas insulin led to a reduced expression level of the glucose transporter in pancreatic beta-cells. In vivo experiments showed that in pancreatic tissue of type 2 diabetic rats as well as type 2 diabetic patients, the GLUT4 expression is significantly increased compared to the nondiabetic control group. Furthermore, type 1 diabetic rats exhibited reduced GLUT4 transcript levels in pancreatic tissue, whereas insulin treatment of type 1 diabetic animals enhanced the GLUT4 expression back to control levels. These data provide evidence for the existence of GLUT4 in the endocrine pancreas and indicate a physiological relevance of this glucose transporter as well as characteristic changes in diabetic disease. PMID- 22488521 TI - Attenuation of PTEN perturbs genomic stability via activation of Akt and down regulation of Rad51 in human embryonic kidney cells. AB - To address the involvement of PTEN/Akt signaling in DNA repair and genomic stability, we developed a shRNA-mediated PTEN knockdown cell line from HEK293T cells and evaluated its response to etoposide by analyzing gammaH2AX and Rad51 foci formation, cell cycle analysis, and chromosome damage. HEK PTEN knockdown cells were impaired in DNA repair associated with loss of G2/M checkpoint and reduced Rad51 foci formation. Furthermore, inhibition of Akt did not restore etoposide-induced G2/M arrest in PTEN knockdown cells, suggesting that loss of G2/M checkpoint in PTEN knockdown cells is Akt-independent. On the other hand, these cells become sensitive to etoposide when Akt was inhibited. Thus, loss of G2/M checkpoint and reduction of Rad51-mediated homologous recombination is responsible for the genomic instability of PTEN knockdown cells where activated Akt additionally contribute to strong survival signal. PMID- 22488522 TI - Generic inhibition of amyloidogenic proteins by two naphthoquinone-tryptophan hybrid molecules. AB - Amyloid formation is associated with several human diseases including Alzheimer's disease (AD), Parkinson's disease, Type 2 Diabetes, and so forth, no disease modifying therapeutics are available for them. Because of the structural similarities between the amyloid species characterizing these diseases, (despite the lack of amino acid homology) it is believed that there might be a common mechanism of toxicity for these conditions. Thus, inhibition of amyloid formation could be a promising disease-modifying therapeutic strategy for them. Aromatic residues have been identified as crucial in formation and stabilization of amyloid structures. This finding was corroborated by high-resolution structural studies, theoretical analysis, and molecular dynamics simulations. Amongst the aromatic entities, tryptophan was found to possess the most amyloidogenic potential. We therefore postulate that targeting aromatic recognition interfaces by tryptophan could be a useful approach for inhibiting the formation of amyloids. Quinones are known as inhibitors of cellular metabolic pathways, to have anti- cancer, anti-viral and anti-bacterial properties and were shown to inhibit aggregation of several amyloidogenic proteins in vitro. We have previously described two quinone-tryptophan hybrids which are capable of inhibiting amyloid-beta, the protein associated with AD pathology, both in vitro and in vivo. Here we tested their generic properties and their ability to inhibit other amyloidogenic proteins including alpha-synuclein, islet amyloid polypeptide, lysozyme, calcitonin, and insulin. Both compounds showed efficient inhibition of all five proteins examined both by ThT fluorescence analysis and by electron microscope imaging. If verified in vivo, these small molecules could serve as leads for developing generic anti-amyloid drugs. PMID- 22488524 TI - Relationships between work organisation and size of dairy farms: a case study based in Vietnam. AB - In Vietnam, livestock farming policy is designed to develop milk production to increase the country's dairy self-sufficiency. However, workload is one of the main constraints limiting the potential for increasing production and herd sizes on family-run farms. The aim of this paper was to explore the relationships connecting work organisation forms and durations to herd sizes in order to understand the impacts of rationalising work by increasing herd numbers. A work organisation survey was carried on 19 dairy farmers in two regions of northern Vietnam. Statistical analysis was run to identify relationships between herd size, work organisation forms and work durations. A cluster analysis was used to establish a typology. The results show that the volume of routine work is higher in large herds but is also more efficient. Farmers running large herds lighten their family workload by mechanising routine tasks and by employing permanent contract workers. The paper concludes on a set of guidance strategies to help dairy farms develop their activity, such as hiring farm labour and mechanising farm tasks. PMID- 22488527 TI - Alternatively spliced variants of gamma-subunit of muscle-type acetylcholine receptor in fetal and adult skeletal muscle of mouse. AB - Gamma-subunit of nicotinic acetylcholine receptor is encoded by chrng gene of mouse. This gene is located on chromosome 1, spans 6.5 kb, and contains 12 exons and 11 introns. Previous studies have reported three transcript variants (C1-3) produced by alternative splicing; C1 contains all the 12 reported exons, C2 uses an in-frame alternate splice site in exon-2, and C3 produced by exon-5 skipping. These variants differ in their channel kinetics and opening times. In our study, we report the presence of two new transcript variants (T1 and T2) of chrng expressed in mouse postnatal day 3 and adult skeletal muscles. These transcripts contain novel first coding exon either N1 or N2. N1 is located in the 5' UTR, while N2 is an extended exon-2. 5' extension of exon-2 contains an initiation codon which produces a novel transcript variant. Either of the two exons can splice with the internal exons to produce mature transcripts making different 5' ends of the transcripts. Consequently, the proteins encoded by these two transcripts differ at N-termini. The presence of N2 exon containing transcript was further supported by the availability of EST from the database. These new variants display heterogeneous properties. They differ in the presence of signal peptide, phosphorylation, and acetylation of their amino acid residues of the new N-termini of the gamma subunit. PMID- 22488525 TI - Sex differences in molecular and cellular substrates of stress. AB - Women are twice as likely as men to suffer from stress-related psychiatric disorders, like unipolar depression and post-traumatic stress disorder. Although the underlying neural mechanisms are not well characterized, the pivotal role of stress in the onset and severity of these diseases has led to the idea that sex differences in stress responses account for this sex bias. Corticotropin releasing factor (CRF) orchestrates stress responses by acting both as a neurohormone to initiate the hypothalamic-pituitary-adrenal (HPA) axis and as a neuromodulator in the brain. One target of CRF modulation is the locus coeruleus (LC)-norepinephrine system, which coordinates arousal components of the stress response. Hypersecretion of CRF and dysregulation of targets downstream from CRF, such as the HPA axis and LC-norepinephrine system, are characteristic features of many stress-related psychiatric diseases, suggesting a causal role for CRF and its targets in the development of these disorders. This review will describe sex differences in CRF and the LC-norepinephrine system that can increase stress sensitivity in females, making them vulnerable to stress-related disorders. Evidence for gonadal hormone regulation of hypothalamic CRF is discussed as an effect that can lead to increased HPA axis activity in females. Sex differences in the structure of LC neurons that create the potential for hyperarousal in response to emotional stimuli are described. Finally, sex differences at the molecular level of the CRF(1) receptor that make the LC-norepinephrine system more reactive in females are reviewed. The implications of these sex differences for the treatment of stress-related psychiatric disorders also will be discussed. PMID- 22488528 TI - The blood-brain barrier permeability of 18beta-glycyrrhetinic acid, a major metabolite of glycyrrhizin in Glycyrrhiza root, a constituent of the traditional Japanese medicine yokukansan. AB - 18beta-Glycyrrhetinic acid (GA) is a major metabolite of glycyrrhizin (GL), which is one of the components of glycyrrhiza root, a constituent herb of the traditional Japanese medicine yokukansan. It is well known that most GL is metabolized to GA in the intestine by bacteria. A previous in vitro study using cultured rat cortical astrocytes suggested that GA activates glutamate transport, which is a putative mechanism of the psychotropic effect of yokukansan. To activate the glutamate transport in the brain, GA must be absorbed into the blood after oral administration of yokukansan and then cross the blood-brain barrier (BBB) to reach the brain. However, there is no data on the BBB permeability of GA derived from yokukansan. In the present study, the BBB permeability of GA was investigated in both in vivo and in vitro studies. In the in vivo study, GA was detected in the plasma, brain, and cerebrospinal fluid of rats orally administered yokukansan. In the in vitro study using a BBB model composed of co culture of endothelial cells, pericytes, and astrocytes, the permeability rate and apparent permeability coefficient of GA were found to be 13.3 +/- 0.5 % and 16.5 +/- 0.7 * 10(-6) cm/s. These in vivo and in vitro results suggest that GL in orally administered yokukansan is absorbed into the blood as GA, and then reaches the brain through the BBB. This evidence further supports the possibility that GA is an active component in the psychotropic effect of yokukansan. PMID- 22488529 TI - Analysis of bladder vascular resistance before and after prostatic surgery in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. AB - AIMS: To evaluate bladder vascular resistance before and after transurethral resection of the prostate (TURP). METHODS: Thirty-three patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction were prospectively studied. We analyzed correlations of bladder vascular resistance with various factors including age, vascular risk factors, symptom score, prostate volume (PV), and urodynamic parameters before and 3 months after TURP. Using contrast-enhanced color Doppler ultrasonography for measuring bladder vascular resistance, resistive index (RI) of vesical arteries was calculated. RESULTS: Compared with healthy young male (n = 10) and age-matched controls (n = 10), the study patients had a higher preoperative RI (0.403 +/- 0.100, 0.436 +/- 0.042, and 0.561 +/- 0.089, respectively; P < 0.01). Preoperative RI was significantly higher in patients with PV >= 60 ml versus <60 ml (0.604 +/- 0.078 vs. 0.525 +/- 0.082; P < 0.01), and in patients with severe obstruction versus mild/moderate obstruction (0.615 +/- 0.087 vs. 0.534 +/- 0.078; P = 0.017). Overall RI decreased significantly after TURP (from 0.561 +/- 0.089 to 0.450 +/- 0.086; P < 0.001). In patients with persistent urgency after TURP, RI was less improved than in those without urgency after TURP (change of RI 0.068 +/- 0.098 vs. 0.135 +/- 0.090; P < 0.05). This study was limited by a small sample size. CONCLUSIONS: Bladder vascular resistance in patients with LUTS was elevated in correlation with PV and severity of obstruction. Although bladder vascular resistance decreased significantly after TURP in overall patients, less reduction of vascular resistance was related to persistent urgency after TURP, implying that persistent urgency after TURP might be caused by persistent bladder ischemia. PMID- 22488526 TI - Mapping molecular memory: navigating the cellular pathways of learning. AB - A consolidated map of the signalling pathways that function in the formation of short- and long-term cellular memory could be considered the ultimate means of defining the molecular basis of learning. Research has established that experience-dependent activation of these complex cellular cascades leads to many changes in the composition and functioning of a neuron's proteome, resulting in the modulation of its synaptic strength and structure. However, although generally accepted that synaptic plasticity is the mechanism whereby memories are stored in the brain, there is much controversy over whether the site of this neuronal memory expression is predominantly pre- or postsynaptic. Much of the early research into the neuromolecular mechanisms of memory performed using the model organism, the marine snail Aplysia, has focused on the associated presynaptic events. Recently however, postsynaptic mechanisms have been shown to contribute definitively to long term memory processes, and are in fact critical for persistent learning-induced synaptic changes. In this review, in which we aimed to integrate many of the early and recent advances concerning coordinated neuronal signaling in both the pre- and postsynaptic neurons, we have provided a detailed account of the diverse cellular events that lead to modifications in synaptic strength. Thus, a comprehensive synaptic model is presented that could explain a few of the shortcomings that arise when the presynaptic and postsynaptic changes are considered separately. Although it is clear that there is still much to be learnt and that the exact nature of many of the signalling cascades and their components are yet to be fully understood, this still incomplete but integrated illustrative map of the cellular pathways involved provides an overview which expands understanding of the neuromolecular mechanisms of learning and memory. PMID- 22488530 TI - Prolapse surgery in octogenarians: are we pushing the limits too far? AB - PURPOSE: To report our experience with pelvic reconstructive surgery with transobturator mesh implants in elderly women. MATERIALS AND METHODS: A total of 32 women aged >75 years with pelvic organ prolapse receiving anterior and/or posterior repair using transobturator mesh implants were included. Concomitant mid-urethral sling procedure was performed in 78 % women. Postoperative outcome data and quality-of-life measurements were recorded prospectively. Patients were followed for up to 24 months. RESULTS: Mean age at surgery was 82.8 +/- 3.1 years. A total of 15 anterior repairs, 8 posterior repairs, and 9 posterior and anterior repairs were performed using transobturator mesh implants. Concomitant synthetic mid-urethral transobturator sling procedure was performed in 25 women (78 %). Mean operating time was 47.2 +/- 22.3 min, and the mean hospitalization period was 5.9 +/- 1.6 days. There were no systemic complications related to anesthesia or surgery. Two patients required intraoperative bladder suturing due to iatrogenic bladder lesion. There were no rectal injuries, no bleeding necessitating transfusion, voiding dysfunction, or erosions of synthetic implants. Pelvic floor testing at 24 months postoperatively showed 15 % of the patients presenting with stage II vaginal wall prolapse. Further, quality-of-life parameters, as measured by SF-36 questionnaire, were improved compared to baseline values. CONCLUSIONS: Pelvic reconstructive surgery in elderly women is safe and enhances the quality of life. However, special caution should be paid to risks and benefits of such surgery in this patient population. PMID- 22488531 TI - Plasma carotenoid levels are not directly related to heavy metal exposure or reproductive success in three insectivorous passerines. AB - The authors measured plasma carotenoid levels in three insectivorous bird species, the pied flycatcher (Ficedula hypoleuca), the blue tit (Cyanistes caeruleus), and the great tit (Parus major) in metal-polluted and unpolluted sites around a copper smelter. Their aim was to determine whether there was interspecific, age-related, or yearly variation in carotenoid levels and their responses to the ambient pollution level. The three bird species showed qualitatively and quantitatively similar carotenoid profiles, with lutein being always the predominant plasma carotenoid. Ficedula hypoleuca nestlings showed higher plasma carotenoid levels in the unpolluted than in the polluted area, whereas no significant differences were found in F. hypoleuca females or in nestlings or females of the Parids. Yearly comparison of plasma concentrations (only for P. major nestlings) showed, however, that levels varied nonsynchronously between polluted and unpolluted sites among the breeding seasons, with the yearly variation being higher in the polluted area. The survival of nestlings did not depend on their plasma carotenoid concentrations. The two Parid species showed lower nestling survival at sites with high metal exposure levels. The authors conclude that plasma carotenoid levels showed a marked spatial, temporal, and age-related variation, but were not directly related to heavy metal exposure or the reproductive success of birds. PMID- 22488532 TI - Rapid measurement and correction of phase errors from B0 eddy currents: impact on image quality for non-Cartesian imaging. AB - Non-Cartesian imaging sequences and navigational methods can be more sensitive to scanner imperfections that have little impact on conventional clinical sequences, an issue which has repeatedly complicated the commercialization of these techniques by frustrating transitions to multicenter evaluations. One such imperfection is phase errors caused by resonant frequency shifts from eddy currents induced in the cryostat by time-varying gradients, a phenomenon known as B(0) eddy currents. These phase errors can have a substantial impact on sequences that use ramp sampling, bipolar gradients, and readouts at varying azimuthal angles. We present a method for measuring and correcting phase errors from B(0) eddy currents and examine the results on two different scanner models. This technique yields significant improvements in image quality for high-resolution joint imaging on certain scanners. This result suggests that correcting short time B(0) eddy currents that do not affect conventional clinical sequences may simplify the adoption of non-Cartesian methods. PMID- 22488533 TI - Direct synthesis of anatase TiO2 nanowires with enhanced photocatalytic activity. PMID- 22488534 TI - Limitations of currently available Chagas disease chemotherapy. PMID- 22488535 TI - [Invasive fungal infection in critically ill patient: role of micafungin]. AB - The invasive fungal infections (IFIs) have increased in critically ill patients in recent years and are a serious complication that determine the evolution and prognosis of critically ill patients, especially invasive candidiasis (IC)and candidemia. Fortunately, treatment options for these infections have increased and there is a large arsenal of antifungal agents. This review of the literature, using PubMed and Cochrane databases, assesses the situation of the IFIs in critically ill patients and discusses the role of micafungin in this context. The broader spectrum of this candin, which gets the antifungal effect with lower MICs and that translates into greater clinical efficacy with a lower rate of adverse effects and easier to use, with proven cost-effectiveness compared with other antifungal, position micafungin as a useful therapeutic option for the management of invasive candidiasis / candidemia in critically ill patients. PMID- 22488536 TI - Macrolides and staphylococcal biofilms. AB - Medical device-associated infections represent a growing problem with limited or no therapeutic options beyond implant removal. Bacterial biofilm is the major and the final determinant of the poor prognosis of these difficult-to-treat infections. Due to the high antimicrobial resistance level of bacteria organized in biofilms, combination therapy is most often recommended, and macrolides may represent antibiotics of choice. Their anti-biofilm activity has been successfully used in-vitro and in-vivo against biofilm-associated infections caused by Pseudomonas aeruginosa and other Gram-negative bacilli. However there is only little data regarding their clinical interest against infections involving staphylococcal biofilms. Despite controversial reports, there is growing in-vitro and in-vivo evidences of anti-staphylococcal biofilm activity of macrolides that could represent a significant advance in the battle against implant-related infections. PMID- 22488537 TI - [Liposomal amphotericin B: a unique pharmacokinetic profile. An unfinished story]. AB - Amphotericin B in its lipid formulation continues to be the reference drug in the treatment of systemic fungal infections despite the time elapse since the development of this compound. The absence of fungal resistance, pharmacokinetics, and the better tolerability profile as compared with the remaining formulations of amphotericin B are sufficient reasons to justify its prominent therapeutic role. The liposome containing liposomal amphotericin B is very stable in relation to the presence of cholesterol and phospholipids are not thermolabile, so that free amphotericin B is almost inexistent (<1%), which explains the reduced incidence of effects related to the drug administration, and a reduction in the incidence of nephrotoxicity (half than that with amphotericin B lipid complex) and that even in some studies at doses of 1 mg/kg has been shown to be negligible. This profile explains the very high plasma drug concentrations and the reduced distribution volume and clearance, with a very prolonged elimination half-life. There are evidences showing that the liposome through amphotericin B is capable of binding to ergosterol present in the fungal membrane and only at this moment would be the antifungal released to exert its pharmacological effects. PMID- 22488538 TI - [Activity of vancomycin, teicoplanin and linezolid in methicillin resistant coagulase-negative Staphylococci isolates from paediatric blood cultures]. AB - INTRODUCTION: Coagulase-negative-Staphylococci (CNS) are the major cause of bacteraemia and sepsis in newborns. CNS methicillin resistance and its loss of sensitivity to glycopeptide antibiotics, make treatment significantly more difficult in positive cocci infections. OBJECTIVE: To study MIC vancomycin, teicoplanin and linezolid in different species of CNS methicillin resistant isolates from blood cultures from paediatric patients. METHODS: Clinically relevant CNS methicillin resistant isolates from paediatric blood cultures from different hospitalization wards were tested. The isolates were identified by biochemical tests by means in the Combo panels 31 of MicroScan (Dade Behring, Siemens). Resistance to oxacillin and susceptibility to vancomycin, teicoplanin and linezolid were tested by microdilution panels as cited above. We also tested teicoplanin and linezolid sensitivity using Etest. RESULTS: 50 methicillin resistant strains were isolated: 37 (74%)S. epidermidis, 7 (14%) S. hominis, 4 (8%) S. haemolyticus and 2 (4%) Staphylococcus spp. 26 strains were observed with reduced susceptibility to vancomycin MIC = 2 mg/L, (22 S. epidermidis, 2 S. haemolyticus and 2 Staphylococcus spp.) and 21 strains with loss of susceptibility to teicoplanin, MIC = 4-16 mg/L (20 S. epidermidis and 1 S. haemolyticus). No CNS linezolid resistant was found. CONCLUSIONS: There is a linear correlation between increased vancomycin MIC and teicoplanin MIC. There is a statistically significant difference (p <0.001) in the MIC of teicoplanin in the vancomycin group = 2 mg/L with respect to the vancomycin group <= 1 mg/L. We also observed very low levels of linezolid MIC for all strains. PMID- 22488539 TI - [Respiratory infections: etiology and patterns of resistance in the hospital general of Ciudad Real]. AB - OBJECTIVES: Understanding the impact on our work place of increasing antibiotic resistance in respiratory infections. MATERIAL AND METHODS: We have performed a retrospective observational study on patients with significant sputum culture admitted to Internal Medicine Service Hospital General in Ciudad Real from January to December 2008. Information has been collected on the epidemiological, microbiological features, resistance patterns and treatment. RESULTS: The total number of patients included in this study was 60. In 83.3% there was a predisposing factor. In 43 cases the diagnosis was made in spring and summer months. The exacerbation of COPD was the most frequent diagnosis (61.7%). The most frequently isolated organism was Pseudomonas spp. (41.7%). In our hospital the most commonly used antimicrobials in the initial treatment are levofloxacin (36.7%) and amoxicillinclavulanate (26.7%). The antibiotics with the highest percentage of antibiotic resistance were ciprofloxacin in E. coli (66.7%) and Pseudomonas spp. (60%), penicillin for S. pneumoniae (100%). CONCLUSIONS: The results of this study demonstrate the significant presence of resistance to most commonly used antibiotics in microorganisms which cause respiratory infections. PMID- 22488540 TI - [Antimicrobial resistance in clinical patterns of Pseudomonas aeruginosa]. AB - Pseudomonas aeruginosa is an opportunistic microorganism that is frequently the cause of nosocomial infections. Multiple mechanisms are involved in its natural and acquired resistance to many of the antimicrobial agents commonly used in clinical practice. We performed an antibiotic resistance study on P. aeruginosa isolated from intrahospitalary and extrahospitalary samples between 2005 and 2010 years. We included in the study a global amount of 3,029 P. aeruginosa isolates from clinical samples received at University Hospital Reina Sofia. Microbiology Service in Cordoba (Spain). Semiautomatic system WIDER I for strains identification and sensibility testing was employed. We considered susceptibility and resistance criteria recommended by MENSURA group. Results of the analysis showed that P. aeruginosa maintanied similar levels of antimicrobial susceptibility during the period 2005-2010, with increased susceptibility to amikacin, gentamicin and cefalosporins. There were also important differences in the degree of susceptibility between intrahospital and extrahospital strains during 2010 year, except for tobramicin and fosfomycin. The intrahospital difference in susceptibility was also evaluated, emphasizing the importance of periodically surveillance of susceptibility and resistance patterns of P. aeruginosa, in each setting in order to evaluate different therapeutic guidelines, because it is not always advisable to extrapolate data from different regions. PMID- 22488541 TI - [Phenotypes and mechanisms of resistance to macrolides and lincosamides in Streptococcus agalactiae isolates with clinical significance in an eight-year period (2002-2010)]. AB - INTRODUCTION: Streptococcus agalactiae is the most prevalent agent of invasive disease in the newborn (sepsis, pneumonia, and meningitis), as well as an important cause of puerperal fever, urinary tract infection and surgical site infection. The aim of our study was to know the evolution of macrolide and lincosamide resistance in this microorganism. METHODS: Resistance phenotypes were established according to the erythromycin-clindamycin induction test: M (efflux pump) or MLSB (methylase). Genetic mechanisms were detected by PCR for the following genes: ermB, ermA, ermTR, and mefA/E. Molecular typing was based on chromosomal DNA macrorestriction and detection of fragments using pulsed-field gel electrophoresis. RESULTS: During 8 years, 300 isolates of S. agalactiae were recovered. Seventy-eight (26%) were resistant to macrolides, and seventy (23%) were resistant to lincosamides. Constitutive MLSB was observed in 21% of the isolates (all but one carrying the ermB gene), with a erythromycin MIC90 >= 256 mg/L. Inducible MLSB was observed in 2.3% of the isolates (all carrying the ermTR gene), with a MIC90 of 6 mg/L. M phenotype was observed in 2.7% of the isolates (all carrying the mefA/E gene), with a MIC90 of 6 mg/L. Molecular typing revealed the presence of two major clones (A and B) comprising 56.6% of the isolates. Most of the isolates (90.5%) belonging to clon A carried the ermB gene. CONCLUSIONS: Macrolide resistance in our area is similar to that observed in the rest of Spain, but there has been no increase in the incidence rate along the study period. PMID- 22488542 TI - Effect of protein binding on the activity of voriconazole alone or combined with anidulafungin against Aspergillus spp. using a time-kill methodology. AB - OBJECTIVES: the aims of the study were to explore the activity of total and free (according to protein binding) maximal concentrations achieved in serum after multiple doses of voriconazole 400/200 mg and anidulafungin 200/100 mg against Aspergillus fumigatus and Aspergillus flavus and the human albumin or serum effects on antifungal activity. MATERIAL AND METHODS: Time-kill curves were performed with two A. fumigatus and two A. flavus strains at voriconazole and anidulafungin Cmax concentrations using different media: a) RPMI broth (Cmax RPMI); b) RPMI with human serum (Cmax-HS), and c) RPMI with human albumin (Cmax HAlb). In parallel, free-drug (fCmax) concentrations considering theoretical protein binding were performed in RPMI broth. Aspergillus metabolic activity was measured by the XTT reduction assay. RESULTS: Voriconazol or voriconazole plus anidulafungin reduced >88.4% the metabolic activity of Aspergillus sp. at Cmax RPMI and fCmax after 48 h of exposition. Anidulafungin alone showed poor metabolic reductions (<80.1% at Cmax- RPMI and <15% at fCmax). Anidulafungin activity, but not voriconazole activity alone or combined decreased in presence of HS or HAlb (more pronounced in A. flavus strains and HAlb). However, anidulafungin Cmax-HS or Cmax-HAlb against A. fumigatus strains were significantly more active (p<0.05) than fCmax in RPMI. These species and culture medium-dependent impact of human protein binding in the activity of anidulafungin was related to macroscopic and microscopic differences among mycelial mat grown in RPMI, HS or HAlb in whose XTT retention was different. CONCLUSIONS: Synergism could not be demonstrated due to the high activity showed by voriconazole. Protein binding has not impact on voriconazole activity and this impact is considerably less than predicted by free concentration extrapolated from theoretical binding rate on anidulafungin. The XTT colorimetric assay needs to be standardized for use with Aspergillus spp. since without DMSO extraction the activity of echinocandins in a free-human protein RPMI medium could be overestimated. PMID- 22488543 TI - Clinical characteristics and outcome of patients with pandemic 2009 Influenza A(H1N1)v virus infection admitted to hospitals with different levels of health care. AB - BACKGROUND: The outcome of patients with influenza A 2009 (H1N1)v virus infection taking into account hospital type has not been elucidated. OBJECTIVES: To compare risk factors, clinical features and outcome of patients admitted to 3 public hospitals with different levels of health-care. METHODS: Prospective study of all non-pregnant adult patients admitted to 3 hospitals with pandemic H1N1 infection, from June 1 to December 31 and followed up until 1 month after discharge. RESULTS: During the study period, 111 patients with a mean age of 49 years (15 89) were hospitalized: 52 in hospital 1 (900-bed tertiary-teaching-hospital), 33 in hospital 2 (315-beds secondary-hospital) and 26 in hospital 3 (150-beds primary-care-hospital).Overall 80% of patients had at least 1 comorbid condition with no differences between hospitals. Symptoms or signs on admission were similar except for cough (P=0.01) more frequent in patients in hospital 1 and dyspnea (P=0.05), myalgia, arthralgia (P=0.04) and hypoxemia (P=0.009) present in more patients in hospital 2. In-hospital mortality rates were not statistically different between hospitals. In the stepwise analysis, independent predictors of mortality were pneumonia on admission (adjusted OR=8.68, 95%CI 1.0-82.43) and cardiac complications during hospitalization (adjusted OR=13.2, 95%CI 1.67 103.98). CONCLUSIONS: Mortality of patients with pandemic H1N1 infection was influenced by patients underlying conditions, severity of disease (pneumonia) on admission and complications during hospitalization. Hospital-characteristics do not appear to have influenced severe outcome. PMID- 22488544 TI - [Analysis of treatments used in infections caused by gram-positive multiresistant cocci in critically ill patients admitted to the ICU]. AB - The appearance of new antimicrobials with activity against Gram-positive multiresistant cocci and knowledge of the limitations of glycopeptides has represented an important change in the use of these antibiotics. OBJECTIVE: To analyze at the national level changes in the use of antibiotics with specific activity against Gram-positive multiresistant cocci in critically ill patients admitted to the ICU as well as the characteristics of patients treated with these agents and the forms of administration. MATERIAL AND METHODS: Retrospective cohort study of patients admitted to the ICU for more than 24 hours between 2008 and 2010 in the ENVIN-HELICS national registry. Cases were defined as patients who had received one or more of the following antibiotics: vancomycin, teicoplanin, linezolid or daptomycin. The characteristics of patients who used one or more of these agents were compared with those treated with other antibiotics. Indications and forms of use of each antibiotic were assessed. Descriptive results are presented. RESULTS: A total of 45,757 patients, 27,982 (61.2%) of whom received 63,823 antimicrobials were included in the study. In 6,368 (13.9%) patients, one or more antibiotics specifically active against Gram positive multiresistant cocci were given. There was a predominance of the use of vancomycin and linezolid and an important increase in the prescription of daptomycin (+320%) and linezolid (+22.4%). In more than 95% of cases, linezolid and daptomycin were prescribed for the treatment of infections, whereas vancomycin and teicoplanin were used for prophylaxis in 20-25% of cases. Between 75% and 80% of indications for treating infections, antibiotics were used empirically except for daptomycin which was used as a directed treatment in 43% of the cases. Only in one third of the indications for empirical treatment, susceptible microorganisms were identified (appropriate treatment). CONCLUSIONS: The use of antibiotics with activity against Gram-positive multiresistant cocci remained stable around 14% of all indications. The use of vancomycin and linezolid predominated and there was a clear trend towards an increase in the use of daptomycin and linezolid and a decrease in the use of glycopeptides. Empirical treatments were considered appropriate in only one third of cases. PMID- 22488545 TI - Nifurtimox chemotherapy: collateral effects in treated Trypanosoma cruzi infected patients. PMID- 22488546 TI - [Fungemia caused by Rhodotorula mucilaginosa. Report of two cases]. PMID- 22488547 TI - [Prevention of perinatal group B Streptococcal disease. Updated Spanish recommendations 2012]. AB - It has been a significant reduction in neonatal group B streptococcus (GBS) infection in Spain following the widespread application of intrapartum antibiotic prophylaxis. In 2010, new recommendations have been published by the CDC and this fact, together with the new knowledge and experience available, has driven to the participating scientific societies publishing these new recommendations. In these recommendations is advised to study all pregnant women at 35-37 gestation weeks' to determine if they are colonized by GBS and to administer intrapartum antibiotic prophylaxis (IAP) to all colonized mothers. Microbiological methods to identify pregnant GBS carriers are updated and intrapartrum antibiotic prophylaxis in preterm labour and premature rupture of membranes and the management of the newborn in relation to GBS carrier status of the mother are also revised. PMID- 22488548 TI - Simulation of multiphase systems utilizing independent force fields to control intraphase and interphase behavior. AB - Fixed-charge empirical force fields have been developed and widely used over the past three decades for all-atom molecular simulations. Most simulation programs providing these methods enable only one set of force field parameters to be used for the entire system. Whereas this is generally suitable for single-phase systems, the molecular environment at the interface between two phases may be sufficiently different from the individual phases to require a different set of parameters to be used to accurately represent the system. Recently published simulations of peptide adsorption to material surfaces using the CHARMM force field have clearly demonstrated this issue by revealing that calculated values of adsorption free energy substantially differ from experimental results. Whereas nonbonded parameters could be adjusted to correct this problem, this cannot be done without also altering the conformational behavior of the peptide in solution, for which CHARMM has been carefully tuned. We have developed a dual force-field approach (Dual-FF) to address this problem and implemented it in the CHARMM simulation package. This Dual-FF method provides the capability to use two separate sets of nonbonded force field parameters within the same simulation: one set to represent intraphase interactions and a separate set to represent interphase interactions. Using this approach, we show that interfacial parameters can be adjusted to correct errors in peptide adsorption free energy without altering peptide conformational behavior in solution. This program thus provides the capability to enable both intraphase and interphase molecular behavior to be accurately and efficiently modeled in the same simulation. PMID- 22488551 TI - Ion-pair recognition of tetramethylammonium salts by halogenated resorcinarenes. AB - The non-covalent interactions of different upper-rim-substituted C(2) resorcinarenes with tetramethylammonium salts were analyzed in the gas phase in an Electrospray Ionization Fourier-transform ion-cyclotron-resonance (ESI-FTICR) mass spectrometer and by (1)H NMR titrations. The order of binding strengths of the hosts towards the tetramethylammonium cation in the gas phase reflects the electronic nature of the substituents on the upper rim of the resorcinarene. In solution, however, a different trend with particularly high binding constants for halogenated resorcinarenes has been observed. This trend can be explained by a synergetic effect originating from the interaction of the halogenated resorcinarenes with the counter anions through hydrogen bonding. This study highlights the importance of weak interactions in recognition processes and points out the benefits of comparing the gas-phase data with results obtained from solution experiments. PMID- 22488549 TI - Antiinflammatory functions of p38 in mouse models of rheumatoid arthritis: advantages of targeting upstream kinases MKK-3 or MKK-6. AB - OBJECTIVE: Inhibitors of p38 demonstrate limited benefit in rheumatoid arthritis (RA), perhaps due to the antiinflammatory functions of p38alpha. This study was performed to determine if selective deletion of p38alpha in macrophages affects the severity of arthritis and whether blocking upstream kinases in the p38 pathway, such as MKK-3 or MKK-6, avoids some of the limitations of p38 blockade. METHODS: Wild-type (WT) mice and mice with selective deletion of p38alpha in macrophages (p38alpha(DeltaLysM) ) were injected with K/BxN sera. Antigen-induced arthritis was also induced in p38alpha(DeltaLysM) mice. Mouse joint extracts were evaluated by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction (qPCR), and Western blot analysis. Bone marrow-derived macrophages (BMMs) were stimulated with lipopolysaccharide (LPS) and were evaluated by qPCR and Western blotting. Bone marrow chimeras were generated using MKK-3(-/-) and MKK-6(-/-) mice, and K/BxN serum was administered to induce arthritis. RESULTS: Compared to WT mice, p38alpha(DeltaLysM) mice had increased disease severity and delayed resolution of arthritis, which correlated with higher synovial inflammatory mediator expression and ERK phosphorylation. In contrast to WT BMMs cultured in the presence of a p38alpha/beta inhibitor, LPS-stimulated MKK-6- and MKK-3-deficient BMMs had suppressed LPS-mediated interleukin-6 (IL-6) expression but had normal IL-10 production, dual-specificity phosphatase 1 expression, and MAPK phosphorylation. WT chimeric mice with MKK-6- and MKK-3-deficient bone marrow had markedly decreased passive K/BxN arthritis severity. CONCLUSION: Inhibiting p38alpha in a disease that is dominated by macrophage cytokines, such as RA, could paradoxically suppress antiinflammatory functions and interfere with clinical efficacy. Targeting an upstream kinase that regulates p38 could be more effective by suppressing proinflammatory cytokines while preventing decreased IL 10 expression and increased MAPK activation. PMID- 22488550 TI - Taller women are at greater risk of recurrent venous thromboembolism: the Iowa Women's Health Study. AB - Venous thromboembolism (VTE) recurs frequently. Greater height is associated with increased risk of incident VTE, but it is unclear whether height is related to risk of VTE recurrence. Recurrent VTE is associated with substantial morbidity and mortality, thus identifying individuals at greatest risk of experiencing a recurrent event, who may benefit from extended anticoagulant therapy, is vitally important. Using data from the Iowa Women,s Health Study, we explored whether greater height was associated with increased risk of VTE recurrence.Among 1,691 women who experienced an initial VTE event, 286(16.9%) experienced a recurrent event. Risk of recurrence was 76%(95% CI: 16% -186%) higher among women >66 inches [168 cm] tall relative to those <=62 inches [158 cm] tall, after adjustment for age and waist circumference. Future research should evaluate whether body height improves clinical prediction of VTE recurrence risk. PMID- 22488552 TI - Solution processed MoO3 interfacial layer for organic photovoltaics prepared by a facile synthesis method. AB - An MoO(3) film spin-coated from a solution prepared by an extremely facile and cost-effective synthetic method is introduced as an anode buffer layer of bulk heterojunction polymer photovoltaic devices. The device efficiency using the MoO(3) anode buffer layer is comparable to that using a conventional PEDOT:PSS layer without annealing at an elevated temperature. PMID- 22488553 TI - Clinical and functional significance of loss of caveolin-1 expression in breast cancer-associated fibroblasts. AB - Loss of caveolin-1 (Cav-1) expression in breast cancer-associated fibroblasts (CAFs) is predictive of poor prognosis in breast cancer, but its function has not been established. Our study tested the hypotheses that loss of Cav-1 expression in breast fibroblasts was associated with poor prognosis in breast cancer, through promotion of breast cancer cell invasion. Cav-1 stromal expression was immunohistochemically assessed in 358 breast cancers. Cav-1 expression in primary breast fibroblasts was analysed by western blot. Modified Boyden chamber assays determined fibroblast ability to promote invasion of breast cancer cells. The impact of siRNA silencing of Cav-1 in fibroblasts was evaluated using invasion assays and 3D co-culture assays. Loss of Cav-1 expression in breast stroma was significantly associated with decreased breast cancer-specific and disease-free survival (p = 0.01). Mean survival was 72 months (Cav-1(+) group) versus 29.5 months (Cav-1(-) group). This was confirmed in multivariate analysis. Cav-1 expression was significantly decreased in CAFs compared to normal fibroblasts (p = 0.01) and was associated with increased invasion-promoting capacity. Cav-1 siRNA-treated fibroblasts promoted significantly increased invasion of MDA-MB-468 and T47D breast cancer cells from 27% (control) to 67% (p = 0.006) and from 37% to 56%, respectively (p = 0.01). 3D co-cultures of MDA-MB-468 cells with myoepithelial cells led to the formation of organized cohesive structures when cultured with conditioned media from fibroblasts but resulted in a disorganized appearance in the presence of conditioned media from Cav-1 siRNA-treated fibroblasts, accompanied by loss of E-cadherin expression in tumour cells. Our data confirm that loss of stromal Cav-1 in breast cancer predicts poor outcome. At a functional level, Cav-1-deficient CAFs are capable of significantly increasing the invasive capacity of breast cancer cells. PMID- 22488554 TI - Severe prolonged sedation associated with coadministration of protease inhibitors and intravenous midazolam during bronchoscopy. AB - STUDY OBJECTIVE: To determine whether human immunodeficiency virus (HIV)-positive patients who received intravenous midazolam during an inpatient bronchoscopy procedure were more likely to experience severe prolonged sedation if they were taking antiretroviral therapy that included a protease inhibitor versus those who were not taking any antiretroviral therapy. DESIGN: Retrospective cohort study. SETTING: Tertiary care academic medical center. PATIENTS: Two hundred forty-one HIV-positive adults who received intravenous midazolam while undergoing bronchoscopy between January 1, 2003, and December 31, 2006, were analyzed; 51 patients were taking an antiretroviral regimen that included a protease inhibitor (exposed group), whereas 190 patients were not taking any antiretroviral agents (nonexposed group). MEASUREMENTS AND MAIN RESULTS: Patient demographics, medication administration records, and bronchoscopy data were collected from electronic databases and patient medical records. The exposed and nonexposed groups had similar demographic characteristics except that patients in the exposed group had lower HIV viral loads and were less likely to have altered mental status or respiratory distress before bronchoscopy. In addition, the exposed group had a higher proportion of males and patients with hepatitis B or C virus coinfection. The incidence of severe prolonged sedation was 9.80% in the exposed group versus 1.58% in the nonexposed group (relative risk [RR] 6.21, 95% confidence interval [CI] 1.53-25.12). Specific protease inhibitors associated with severe prolonged sedation were atazanavir-ritonavir and lopinavir-ritonavir. Length of hospital stay was approximately 3 days longer in the exposed group compared with the nonexposed group. CONCLUSION: Although the interaction between intravenous midazolam and protease inhibitors is well known, this study was the first systematic evaluation, to our knowledge, of the risk of severe prolonged sedation in a cohort of hospitalized HIV-positive patients. Coadministration of protease inhibitors with intravenous midazolam was associated with severe prolonged sedation as well as increased length of hospital stay. Therefore, concomitant use of these drugs should be closely monitored, or alternative sedatives for procedural sedation should be considered. PMID- 22488555 TI - Electrical defibrillation outcome prediction by waveform analysis of ventricular fibrillation in cardiac arrest out of hospital patients. AB - OBJECTIVE: Indexes such as amplitude spectrum area (AMSA) and power spectrum area (PSA) obtained from electrocardiogram waveform analysis are possible predictors of outcome after electrical defibrillation for ventricular fibrillation (VF). In this study, we examined AMSA and PSA to determine whether these parameters can predict defibrillation outcome. MATERIALS AND METHODS: A total of 83 out-of hospital VF victims were classified into four groups according to type of cardiac rhythm after shock: return of spontaneous circulation (ROSC), VF, pulseless electrical activity (PEA), and asystole. AMSA and PSA were calculated from electrocardiograms prior to shock and compared between groups. RESULTS: The mean AMSA (4.0-48 Hz) in the ROSC group was 24.2 +/- 8.5 mV-Hz, which was significantly higher than that in the VF and asystole groups. CONCLUSION: It is possible by analyzing the AMSA of VF to predict cases where electrical defibrillation is more likely to return cardiac rhythm. Furthermore, unnecessary electrical shocks with a low possibility of ROSC can be avoided, and chest compression should be continued to prevent myocardial damage and consequently improve prognosis. PMID- 22488556 TI - A case of chromomycosis treated by surgical therapy combined with preceded oral administration of terbinafine to reduce the size of the lesion. AB - Chromomycosis is a chronic fungal disease of the skin and subcutaneous tissues caused by a group of dematiaceous black fungi. Small lesions can be removed with excision, but other cases are difficult to treat. We report a case of chromomycosis caused by Fonsecaea pedrosoi (F. pedrosoi). The case involved a 74 year-old man, who had noted a lesion on the back of the right thigh, that was gradually enlarging and reaching up to 30 cm in diameter, in 20-years. From microscopic examination, sclerotic cells were seen. We diagnosed this case as chromomycosis caused by F. pedrosoi on mycological examination. The patient was initially treated with oral terbinafine (250 mg/day) as the lesion was very large. After the 18 months treatment, the size of the lesion reduced to 1 cm, then the remaining lesion was excised. PMID- 22488557 TI - The effect of glucagon on FDG uptake in skeletal muscle. AB - Glucagon is used as an anti-motility agent during gastrointestinal tract examinations. We experienced subjects with enhanced 18F-fluorodeoxyglucose (FDG) uptake in whole-body skeletal muscle when conducting positron emission tomography (PET). The subjects had been administered glucagon during gastroscopy just prior to PET. This observation prompted us to perform the present retrospective study to determine whether or not glucagon enhances FDG uptake in skeletal muscle. We randomly selected 30 cases, including subjects who had undergone PET and gastroscopy on the same day as cancer screening procedures, and classified them into three groups. In the NO group (n = 10), no medications were used prior to PET. In the SC group (n = 10), scopolamine butylbromide (10 mg) was intravenously administered during endoscopy. In the GL group (n = 10), glucagon (0.5 mg) was intravenously administered during endoscopy. Both drugs were administered 45-60 min prior to FDG administration. The mean standardized uptake value (SUV) for gluteal muscle was 0.7 +/- 0.14, 0.69 +/- 0.15, and 0.99 +/- 0.7 in the NO, SC, and GL groups, respectively. The SUV in the GL group was highest, but the difference was not statistically significant. In the subject with the highest SUV (3.04; GL group), the quality of the oncologic PET image was impaired, perhaps because of a relative decrease of FDG distribution in the chest and abdomen. Because previous literature showed that via hyperglycemia and hyperinsulinemia glucagon has the effect of increasing FDG uptake in skeletal muscle, the use of glucagon should be avoided just prior to FDG PET, although in our subjects, no statistical proof that glucagon enhances FDG uptake in skeletal muscle was obtained. PMID- 22488558 TI - A case of small bowel ulcer caused by NSAIDs and detected after capsule endoscope retention. AB - We recently detected an annular ulcer thought to have been caused by non steroidal anti-inflammatory drugs (NSAIDs) when we performed small bowel capsule endoscopy on a patient with suspected small-bowel bleeding and a history of frequent use of oral NSAIDs. The patient was a 64-year-old woman who complained of bloody stools and abdominal pain. The annular ulcer showed concentric stenosis, which caused retention of the capsule endoscope. NSAIDs are some of the most frequently used anti-inflammatory analgesics, and even more frequent use can be expected with the aging of society. No reports to date appear to have described retention of a capsule endoscope due to annular ulceration caused by NSAIDs. We report herein our experience with a patient showing small-bowel ulcer caused by NSAIDs. PMID- 22488559 TI - Selective deficit of divided attention following traumatic brain injury: case reports. AB - Divided attention (DA) impairment may be the most salient and commonly reported cognitive dysfunction following traumatic brain injury (TBI). Even so, DA impairment is sometimes overlooked during hospitalization. Our group experienced two TBI patients with selective deficits of DA recognized after their return-to work. Neither patient showed abnormalities in standard tests for higher brain dysfunction. Both, however, performed poorly in a newly developed dual-task test. DA should be assessed more thoroughly and carefully in TBI patients. Dual-task testing may be sensitive in the detection of DA disturbances. PMID- 22488560 TI - A phlebolith in the anterior portion of the masseter muscle. AB - The differential diagnosis of a buccal soft tissue mass containing calcified bodies includes a phlebolith associated with a vascular lesion, such as a hemangioma with a calcified intravascular thrombus, and diseases such as sialolithiasis, traumatic myositis ossificans, calcified acne lesion, neoplasm, and calcified lymph nodes, including tuberculosis. The appearance of the calcified bodies on plain radiographs may help to differentiate these entities. Computed tomography, magnetic resonance imaging, and ultrasonography are also useful for differentiating the soft tissue lesions. We report a 17-year-old girl with a small mass containing a calcified body in the anterior portion of the masseter muscle. The mass was resected surgically and evaluated histologically, confirming the diagnosis of phlebolith. We also discuss the differential diagnosis of a buccal soft tissue mass containing calcifications and suggest that the immunolocalization of CD31 at capillaries in the mass may help to diagnose as a phlebolith. PMID- 22488561 TI - Sentinel lymph node biopsy for thin melanoma-con. PMID- 22488562 TI - Biocompatible zwitterionic sulfobetaine copolymer-coated mesoporous silica nanoparticles for temperature-responsive drug release. AB - A novel nanocontainer, which could regulate the release of payloads, has been successfully fabricated by attaching zwitterionic sulfobetaine copolymer onto the mesoporous silica nanoparticles (MSNs). RAFT polymerization is employed to prepare the hybrid poly(2-(dimethylamino)ethyl methacrylate)-coated MSNs (MSN PDMAEMA). Subsequently, the tertiary amine groups in PDMAEMA are quaternized with 1,3-propanesultone to get poly(DMAEMA-co-3-dimethyl(methacryloyloxyethyl)ammonium propanesulfonate)-coated MSNs [MSN-Poly(DMAEMA-co-DMAPS)]. The zwitterionic PDMAPS component endows the nanocarrier with biocompatibility, and the PDMAEMA component makes the copolymer shell temperature-responsive. Controlled release of loaded rhodamine B has been achieved in the saline solutions. PMID- 22488563 TI - The 100 most-cited articles in Pediatric Surgery International. AB - PURPOSE: Citation analysis within specific journals and subject areas has become a popular method to assess the impact of a journal, article or author. To date, only a few evaluations of citation reports have been published in the field of pediatric surgery. Twenty-six years after its inception, Pediatric Surgery International (PSI) is a firmly established journal in pediatric surgery. The aim of this study was to identify, analyze and categorize the characteristics of the 100 most-cited articles published in PSI since its founding in 1986. METHODS: The Web of Knowledge(SM), hosted by the Institute for Scientific Information, was searched with the all-database function for the 100 most-cited articles in PSI published from 1986 to the present. Each article was reviewed and the following parameters were recorded: number of citations, type of article, topic, year of publication, country of origin, institution and authorship. RESULTS: Between 1986 and 2012, 4,907 articles were published in PSI and 3,608 (73.53 %) of these were cited at least once. The 100 most-cited articles received a total of 3,309 citations with a mean of 33.09 (range 24-81). These articles were published between 1987 and 2007, with 73 articles published after 1997. Leading countries were USA (n = 15), Australia (n = 12), UK (n = 9) and Ireland (n = 9). Articles were categorized as followed: 92 original articles, 5 reviews and 3 case reports. 84 articles derived from clinical research and 16 derived from basic science. The most prolific authors were from 7 different institutions and published 37 articles, which received 1,213 (36.66 %) citations. CONCLUSION: The 100 most cited articles published in PSI were predominately original articles from English speaking countries dealing with clinical topics. This analysis may be of value to the editorial board and authors by providing some insights into what types of manuscripts appear to be of interest to the reading audience of PSI. PMID- 22488564 TI - A novel t(3;8)(p13;q21.1) translocation in a case of lipoblastoma. AB - Lipoblastoma is a rare benign neoplasm of embryonic white fatty tissue primarily found in the extremities of children <3 years old (Batanian et al., Cancer Genet Cytogenet 125(1):10-13, 2001; McVay MR et al., J Pediatr Surg 41(6):1067-1071, 2006; Kamal et al., J Pediatr Surg 46(7):E9-E12, 2011). Translocations affecting the 8q11-13 region are commonly reported with lipoblastoma and proper diagnosis requires cytogenetic analysis to distinguish it from malignant myxoid liposarcoma (Miller et al., J Pediatr Surg 32(12):1771-1772, 1997; Morerio et al., Pediatr Blood Cancer 52(1):132-134, 2009). We describe an additional case of lipoblastoma containing a new translocation t(3;8)(p13;q21.1), which has not previously been reported in a healthy asymptomatic child. PMID- 22488565 TI - Intra-abdominal pressure, LUTS, and tadalafil. Re: Andersson K-E, et al. tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: pathophysiology and mechanism(s) of action. Neurourol urodyn 2011;30:292-301. PMID- 22488566 TI - Healthy food from organic wheat: choice of genotypes for production and breeding. AB - BACKGROUND: In the present study, 40 wheat genotypes were grown in the same soil in organic farming system trials in Alnarp, Sweden. The purpose was to evaluate opportunities for production and breeding of organic wheat of high nutritious value. RESULTS: The results showed a large variation in content of minerals, total tocochromanols and heavy metals in the grain of 40 organically produced wheat genotypes. Principal component and cluster analysis were used as tools for selection of the most suitable genotypes for production and breeding of organic wheat of high nutritious value. No single genotype group was found particularly superior from the studied material to produce this specific type of wheat. However, certain genotypes from different groups were found with promising nutritional characters. The most promising genotypes as related to nutritionally relevant compounds were 6356 spelt, Triticum monococcum, Olands 17 borst spelt, Lv Dal 16 brun borst and Fylgia. CONCLUSION: By choosing these genotypes for organic production and future wheat breeding, nutritionally improved organic wheat products might be developed. However, for future breeding, nutritional components such as protein, fibre, glycaemic index and B-group vitamins should also be considered. PMID- 22488567 TI - Expression of FOXJ1 in hepatocellular carcinoma: correlation with patients' prognosis and tumor cell proliferation. AB - FOXJ1 is a member of the forkhead box (FOX) family of transcription factors. Recent studies suggested that FOXJ1 may function as a tumor suppressor gene in breast cancer. To investigate the potential roles of FOXJ1 in hepatocellular carcinoma (HCC), expression of FOXJ1 was first examined in eight paired frozen HCC and adjacent noncancerous liver tissues by Western blot, and we found that FOXJ1 was upregulated in HCC specimens. In addition, immunohistochemistry was performed to confirm our results in 108 HCC samples. Moreover, we also evaluated its relation with clinicopathological variables and the prognostic significance. The data showed that high expression of FOXJ1 was associated with histological grade (P < 0.001), and FOXJ1 was positively correlated with proliferation marker Ki-67 (P < 0.01). Univariate analysis suggested that FOXJ1 expression was associated with poor prognosis (P < 0.001). Multivariate analysis indicated that tumor grade (P < 0.0001), metastasis (P = 0.0451), tumor size (P = 0.0459), FOXJ1 (P = 0.0011), and Ki-67 (P = 0.0006) were independent prognostic markers for HCC. Furthermore, we noted that there existed the change of the level of FOXJ1 subcellular localization during cell-cycle transition in HepG2 cells by immunofluorescence and cell fractionation. Besides, we employed FOXJ1 overexpression/knockdown approaches to investigate the effects of FOXJ1 on HCC cell proliferation and cell-cycle distribution and found that overexpression of FOXJ1 can promote tumor cell proliferation and cell-cycle transition. Our results suggested that FOXJ1 was overexpressed in HCCs and associated with histological grade and poor prognosis. Overexpression of FOXJ1 was also involved in tumor cell proliferation and cell-cycle progression in HCC cell lines. PMID- 22488568 TI - Pseudo-continuous arterial spin labeling at 7 T for human brain: estimation and correction for off-resonance effects using a Prescan. AB - Pseudo-continuous arterial spin labeling (ASL) can provide best signal-to-noise ratio efficiency with a sufficiently long tag at high fields such as 7 T, but it is very sensitive to off-resonance fields at the tagging location. Here, a robust Prescan procedure is demonstrated to estimate the pseudo-continuous ASL radiofrequency phase and gradients parameters required to compensate the off resonance effects at each vessel location. The Prescan is completed in 1-2 min and is based on acquisition of label/control pair-wise ASL data as a function of the radiofrequency phase increment applied to the pseudo-continuous ASL train. It is shown that this approach can be used to acquire high quality whole-brain pseudo-continuous ASL perfusion data of the human brain at 7 T. PMID- 22488569 TI - Accumulation kinetics of arsenic in Daphnia magna under different phosphorus and food density regimes. AB - In the present study, the dissolved uptake, dietary assimilation, and elimination of arsenic (initially added as arsenate) in the freshwater cladoceran Daphnia magna were examined. A biphasic correlation between the arsenic uptake rate and its ambient concentration, as well as a two-saturation-site arsenic uptake competition with phosphate was observed. The calculated uptake rate constant, as influenced by the ambient phosphorus concentration, ranged from 0.035 to 0.35 L/g/d. Food concentration substantially decreased (by 23.2-64.4%) the arsenic assimilation efficiency with the incipient limiting algal food concentration of 3.86 mg/L dry weight. Arsenic assimilation by the daphnids was independent of their own phosphorus status, but was lower when their algal diet was phosphorus limited and thus contained a higher proportion of arsenite due to the enhanced biotransformation. Arsenic efflux rate constant ranged from 0.34 to 0.44 d(-1) with increased food concentration slightly facilitating its loss. Excretion, accounting for 51.3 to 60.6% of total loss, was the dominant pathway for arsenic elimination with a remarkable contribution from offspring production (24.7 29.8%), whereas molting (3.64-4.05%) and egestion (7.9-11.9%) had minor roles only. According to the well-established biokinetic model, dietary assimilation was predicted to be the main pathway for arsenic bioaccumulation in the daphnids, and arsenic has a great potential to be biodiminished along the food chain. PMID- 22488570 TI - CuBr2--a new multiferroic material with high critical temperature. AB - A new multiferroic material, CuBr(2) , is reported for the first time. CuBr(2) has not only a high transition temperature (close to liquid nitrogen temperature) but also low dielectric loss and strong magnetoelectric coupling. These findings reveal the importance of anion effects, in the search for the high temperature multiferroics materials among these low-dimensional spin systems. PMID- 22488571 TI - Differential expression of particulate methane monooxygenase genes in the verrucomicrobial methanotroph 'Methylacidiphilum kamchatkense' Kam1. AB - Methane monooxygenases (MMOs) are oxygen-dependent enzymes that catalyze the oxidation of methane to methanol in the methanotrophic bacteria. The thermoacidophilic verrucomicrobial methanotroph 'Methylacidiphilum kamchatkense' Kam1 contains three complete and phylogenetically distinct copies of the pmoCAB gene cluster apparently organized as operons, each encoding all three subunits of particulate MMO (pMMO), and a truncated pmoCA cluster encoding only two of the subunits. Two of the clusters are present as a tandem array, but the other clusters occur in isolation. Here, the expression of these clusters has been assessed using the four pmoA genes as targets in reverse transcriptase quantitative PCR analysis. One of the pmoA genes, designated pmoA2, is at least 35-fold more strongly transcribed than the other pmoA copies. Growth at suboptimal temperature and pH conditions did not significantly change the transcription pattern, indicating that the pmoCAB2 cluster encodes the functional pMMO under methane-fuelled growth conditions. During growth on methanol, expression of pmoA2 was reduced approximately tenfold as compared to growth on methane, suggesting a role for the alternative carbon substrates in gene regulation. PMID- 22488572 TI - Desulfonatronovibrio halophilus sp. nov., a novel moderately halophilic sulfate reducing bacterium from hypersaline chloride-sulfate lakes in Central Asia. AB - Four strains of lithotrophic sulfate-reducing bacteria (SRB) have been enriched and isolated from anoxic sediments of hypersaline chloride-sulfate lakes in the Kulunda Steppe (Altai, Russia) at 2 M NaCl and pH 7.5. According to the 16S rRNA gene sequence analysis, the isolates were closely related to each other and belonged to the genus Desulfonatronovibrio, which, so far, included only obligately alkaliphilic members found exclusively in soda lakes. The isolates utilized formate, H(2) and pyruvate as electron donors and sulfate, sulfite and thiosulfate as electron acceptors. In contrast to the described species of the genus Desulfonatronovibrio, the salt lake isolates could only tolerate high pH (up to pH 9.4), while they grow optimally at a neutral pH. They belonged to the moderate halophiles growing between 0.2 and 2 M NaCl with an optimum at 0.5 M. On the basis of their distinct phenotype and phylogeny, the described halophilic SRB are proposed to form a novel species within the genus Desulfonatronovibrio, D. halophilus (type strain HTR1(T) = DSM24312(T) = UNIQEM U802(T)). PMID- 22488573 TI - Nmag_2608, an extracellular ubiquitin-like domain-containing protein from the haloalkaliphilic archaeon Natrialba magadii. AB - Ubiquitin-like proteins (Ubls) and ubiquitin-like domain-containing proteins (Ulds) found in both eukaryotes and prokaryotes display an ubiquitin fold. We previously characterized a 124-amino acid polypeptide (P400) from the haloalkaliphilic archaeon Natrialba magadii having structural homology with ubiquitin family proteins. The reported N. magadii's genome allowed the identification of the Nmag_2608 gene for the protein containing P400, which belongs to specific orthologs of halophilic organisms. It was found that Nmag_2608 has an N-terminal signal peptide with a lipobox motif characteristic of bacterial lipoproteins. Also, it presents partial identity with the ubiquitin like domain-containing proteins, soluble ligand binding beta-grasp proteins. Western blots and heterologous expression tests in E. coli evidenced that Nmag_2608 is processed and secreted outside the cell, where it could perform its function. The analysis of Nmag_2608 expression in N. magadii's cells suggests a co-transcription with the adjoining Nmag_2609 gene encoding a protein of the cyclase family. Also, the transcript level decreased in cells grown in low salinity and starved. To conclude, this work reports for the first time an extracellular archaeal protein with an ubiquitin-like domain. PMID- 22488575 TI - Shifting concepts in rectal cancer management: a review of contemporary primary rectal cancer treatment strategies. AB - The management of rectal cancer has transformed over the last 3 decades and continues to evolve. Some of these changes parallel progress made with other cancers: refinement of surgical technique to improve organ preservation, selective use of neoadjuvant (and adjuvant) therapy, and emergence of criteria suggesting a role for individually tailored therapy. Other changes are driven by fairly unique issues including functional considerations, rectal anatomic features, and surgical technical issues. Further complexity is due to the variety of staging modalities (each with its own limitations), neoadjuvant treatment alternatives, and competing strategies for sequencing multimodal treatment even for nonmetastatic disease. Importantly, observations of tumor response made in the era of neoadjuvant therapy are reshaping some traditionally held concepts about tumor behavior. Frameworks for prioritizing and integrating complex data can help to formulate treatment plans for patients. PMID- 22488574 TI - Evidence-based assessment of compulsive skin picking, chronic tic disorders and trichotillomania in children. AB - Body-focused repetitive behavior (BFRB) is an umbrella term for debilitating, repetitive behaviors that target one or more body regions. Despite regularly occurring in youth, there has been limited investigation of BFRBs in pediatric populations. One reason for this may be that there are few reliable and valid assessments available to evaluate the presence, severity and impairment of BFRBs in youth. Given the shift toward evidence-based assessment in mental health, the development and utilization of evidence-based measures of BFRBs warrants increasing attention. This paper examines the available evidence-base for assessments in youth across three BFRB-related disorders: compulsive skin picking, chronic tic disorders and trichotillomania. Based upon present empirical support in samples of youth, recommendations are made for an evidence-based assessment of each condition. PMID- 22488577 TI - SNP array analysis of acute promyelocytic leukemia may be of prognostic relevance and identifies a potential high risk group with recurrent deletions on chromosomal subband 1q31.3. AB - To search for new copy number alterations (CNAs) in acute promyelocytic leukemia (APL), we analyzed DNA from leukemic blasts of 93 acute promyelocytic leukemia (APL) patients with Genome-Wide SNP 6.0 arrays (SNP-A). We identified 259 CNAs consisting of 170 heterozygous deletions, 82 amplifications, and 7 regions of copy number neutral loss of heterozygosity. One of the most common CNAs was a deletion on chromosomal subband 1q31.3 in 13 of 93 (14%) patients encompassing the coding regions for the microRNAs mir181a1/b1. In multivariable analysis with the covariates age, white blood cell count, platelet count, and FLT3-ITD/FLT3 D835 mutations we found that after adjustment for patients' age (P<0.0001), patients with 2 or more CNAs detected by SNP-A had a higher risk of death (hazard ratio=5.942, P=0.0015) than patients with 0 or 1 CNA. Deletions of 1q31.3 were associated with a higher number of CNAs (median 2 vs. 8, P<0.0001) and were a strong independent prognostic factor for an increased risk of relapse (hazard ratio=28.9, P=0.0031). This study presents a comprehensive assessment of new CNAs as pathomechanistically relevant targets and possible prognostic factors which could refine risk stratification of APL. PMID- 22488576 TI - Intraoperative fluorescence imaging of peripheral and central nerves through a myelin-selective contrast agent. AB - PURPOSE: Patients suffer from complications as a result of unintentional nerve damage during surgery. We focus on improving intraoperative visualization of nerves through the use of a targeted fluorophore and optical imaging instrumentation. PROCEDURE: A myelin-targeting fluorophore, GE3111, was synthesized, characterized for its optical and myelin-binding properties using purified myelin basic protein, and evaluated in mice. Additionally, a compact instrument was adapted to visualize nerves. RESULTS: GE3111 was synthesized using a versatile methodology. Its optical properties were sensitive to the local environment both in vitro and in vivo. Following intravenous injection, central and peripheral nerves were visualized, with the kinetics of nerve uptake modifiable depending on the formulation. Fluorescence polarization showed specific and strong binding to purified myelin basic protein. Nerves were visualized in vivo using a dedicated compact imaging device requiring less than 2.5 mW/cm(2) of illumination at 405 nm. CONCLUSIONS: Fluorescence imaging of nerves through myelin showed a potential for use in image-guided surgery. Intraoperative nerve imaging is an example where contrast agent and instrument development come together as a result of clinical need. PMID- 22488578 TI - Indocyanine green-augmented diode laser therapy of telangiectatic leg veins: a randomized controlled proof-of-concept trial. AB - BACKGROUND: Telangiectatic leg veins, which affect about 40-50% of adults, represent a frequent cosmetic rather than a medical problem. Besides sclerotherapy, various laser devices are common treatment options. However, complete clearance rates can only be achieved in a small number of patients. OBJECTIVE: In this proof-of-concept study, the safety and efficacy of indocyanine green (ICG)-augmented diode laser therapy (808 nm) was evaluated for the treatment of telangiectatic leg veins. METHODS: ICG (2 mg/kg body weight) was intravenously administered in 15 female patients (skin type II to III) with telangiectatic leg veins (measuring between 0.25 and 3 mm in diameter). Immediately after ICG injection, diode laser pulses with different radiant exposures (50-110 J/cm(2)) were applied as one single treatment. Safety and efficacy were assessed 1 and 3 months after treatment by a blinded investigator and the patient. Treatments with the pulsed dye laser (PDL) and the diode laser without ICG served as reference therapies. RESULTS: The safety of ICG application and diode laser treatment was excellent in all patients with no persisting side effects. Vessel clearance was dose-dependent. Diode laser treatment at radiant exposures between 100 and 110 J/cm(2) resulted in good vessel clearance, which even improved to excellent after the application of double pulses. Diode laser therapy without ICG and PDL treatment induced poor to moderate clearance of telangiectatic leg veins. CONCLUSION: ICG-augmented diode laser therapy has proved to be a safe and effective treatment option for telangiectatic leg veins. PMID- 22488579 TI - The toxin-antitoxin proteins relBE2Spn of Streptococcus pneumoniae: characterization and association to their DNA target. AB - The chromosome of the pathogenic Gram-positive bacterium Streptococcus pneumoniae contains between six to 10 operons encoding toxin-antitoxin systems (TAS). TAS are widespread and redundant in bacteria and archaea and their role, albeit still obscure, may be related to important aspects of bacteria lifestyle like response to stress. One of the most abundant TAS is the relBE family, being present in the chromosome of many bacteria and archaea. Because of the high rates of morbility and mortality caused by S. pneumoniae, it has been interesting to gain knowledge on the pneumococcal TAS, among them the RelBE2Spn proteins. Here, we have analyzed the DNA binding capacity of the RelB2Spn antitoxin and the RelB2Spn RelE2Spn proteins by band-shift assays. Thus, a DNA region encompassing the operator region of the proteins was identified. In addition, we have used analytical ultracentrifugation and native mass spectrometry to measure the oligomerization state of the antitoxin alone and the RelBE2Spn complex in solution bound or unbound to its DNA substrate. Using native mass spectrometry allowed us to unambiguously determine the stoichiometry of the RelB2Spn and of the RelBE2Spn complex alone or associated to its DNA target. PMID- 22488580 TI - Brief report: candidate gene study in systemic sclerosis identifies a rare and functional variant of the TNFAIP3 locus as a risk factor for polyautoimmunity. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) share some pathophysiologic bases as evidenced by individual and familial polyautoimmunity and common susceptibility genetic factors. With regard to the latter, there has been a recent shift from the "common variant" to the "rare variant" paradigm, since rare variants of TNFAIP3 and TREX1 with large effect sizes have recently been discovered in SLE. The present study was undertaken to investigate whether rare variants of TNFAIP3 and TREX1 are also associated with SSc. METHODS: TREX1 single-nucleotide polymorphisms (SNPs) rs3135946, rs7626978, rs3135943, and rs11797 and TNFAIP3 SNPs rs9494883, rs72063345, rs5029939, rs2230926, rs117480515, and rs7749323 were genotyped in a discovery set (985 SSc patients and 1,011 controls), and replication analysis of the most relevant results was performed in a second set (622 SSc patients and 493 controls). RESULTS: No association between TREX1 variants and SSc was observed. For TNFAIP3, we first demonstrated that a low-frequency variant, rs117480515, tagged the recently identified TT>A SLE dinucleotide. In the discovery sample, we observed that all tested TNFAIP3 variants were in linkage disequilibrium and were associated with SSc and various SSc subsets, including the polyautoimmune phenotype. We subsequently genotyped rs117480515 in the replication sample and found it to be associated solely with the SSc polyautoimmune subset (odds ratio 3.51 [95% confidence interval 2.28-5.41], P = 8.58 * 10(-9) ) in the combined populations. Genotype-messenger RNA (mRNA) expression correlation analysis revealed that the TNFAIP3 rs117480515 risk allele was associated with decreased mRNA expression. CONCLUSION: The present findings establish the TNFAIP3 locus as a susceptibility factor for the subset of SSc with a polyautoimmune phenotype. Our results support the implication of rare/low-frequency functional variants and the critical role of A20 in autoimmunity. PMID- 22488581 TI - Rational design and synthesis of optimized glycoclusters for multivalent lectin carbohydrate interactions: influence of the linker arm. AB - The design of multivalent glycoclusters requires the conjugation of biologically relevant carbohydrate epitopes functionalized with linker arms to multivalent core scaffolds. The multigram-scale syntheses of three structurally modified triethyleneglycol analogues that incorporate amide moiety(ies) and/or a phenyl ring offer convenient access to a series of carbohydrate probes with different water solubilities and rigidities. Evaluation of flexibility and determination of preferred conformations were performed by conformational analysis. Conjugation of the azido-functionalized carbohydrates with tetra-propargylated core scaffolds afforded a library of 18 tetravalent glycoclusters, in high yields, by Cu(I) catalyzed azide-alkyne cycloaddition (CuAAC). The compounds were evaluated for their ability to bind to PA-IL (the LecA lectin from the opportunistic pathogen Pseudomonas aeruginosa). Biochemical evaluation through inhibition of hemagglutination assays (HIA), enzyme-linked lectin assays (ELLA), surface plasmon resonance (SPR), and isothermal titration microcalorimetry (ITC) revealed improved and unprecedented affinities for one of the monovalent probes (K(d)=5.8 MUM) and also for a number of the tetravalent compounds that provide several new nanomolar ligands for this tetrameric lectin. PMID- 22488584 TI - Solution-processed metallic conducting polymer films as transparent electrode of optoelectronic devices. AB - The conductivity of PEDOT:PSS films was significantly enhanced from 0.3 S cm(-1) to 3065 S cm(-1) through a treatment with dilute sulfuric acids. PEDOT:PSS films with a sheet resistance of 39 Omega sq(-1) and transparency of around 80% at 550 nm are obtained. These PEDOT:PSS films with conductivity and transparency comparable to ITO can replace ITO as the transparent electrode of optoelectronic devices. PMID- 22488585 TI - Alterations of negative regulators of cytokine signalling in immunodeficiency related non-Hodgkin lymphoma. AB - We investigated immunodeficiency-related non-Hodgkin lymphoma for the presence of molecular alterations affecting negative regulators of the Janus family protein tyrosine kinase/signal transducer and activator of transcription pathway. Protein tyrosine phosphatase, non-receptor type 6/Src homology 2-containing tyrosine phosphatase-1 epigenetic silencing was recurrent in primary effusion lymphoma (100%), and diffuse large B-cell lymphoma (63%), with a higher prevalence in the non-germinal centre subtype, and was associated with the activation of the Janus family protein tyrosine kinase/signal transducer and activator of transcription 3 pathway. Suppressor of cytokine signalling (SOCS)1 and SOCS3 epigenetic silencing were occasionally detected, whereas SOCS1 was frequently mutated in diffuse large B-cell lymphoma and polymorphic post-transplant lymphoproliferative disorders, possibly as a cause of aberrant somatic hypermutation. However, the mutation profile of the coding region of the gene was different from that expected from the aberrant somatic hypermutation process, suggesting that, at least in some cases, SOCS1 mutations may have been selected for their functional activity. PMID- 22488586 TI - Dosage and tumour suppression. PMID- 22488587 TI - Stimuli-responsive peptide-based ABA-triblock copolymers: unique morphology transitions with pH. AB - We report the synthesis and solution characterization of poly(L-lysine)-b poly(propylene oxide)-b-poly(L-lysine) (KPK) triblock copolymers with high lysine weight fractions (>75 wt%). In contrast to PK diblock copolymers in this composition range, KPK triblock copolymers exhibit morphology transitions as a function of pH. Using a combination of light-scattering and microscopy techniques, we demonstrate spherical micelle-vesicle and spherical micelle-disk micelle transitions for different K fractions. We interpret these morphology changes in terms of the energy penalty associated with folding the core P block to form a spherical micelle in relation to the interfacial curvature associated with different charged states of the K block. PMID- 22488588 TI - Impact of organic and conventional carrots on intestinal and peripheral immunity. AB - BACKGROUND: Studies on health effects of organic (ORG) products are still limited and often contradictory. We have investigated the impact of ORG and conventional (CV) carrots from two consecutive harvest years on mouse peripheral and intestinal immunity. RESULTS: Danish carrots (Bolero variety) were grown in three ORG (O1, O2 and O3) and one CV cropping system (D-CV). Italian carrots (Maestro and Excelso varieties) were grown in one ORG and one CV field for each variety. Immune phenotypes of blood, spleen and intestinal lymphocytes, and cytokine serum levels were analyzed in mice fed the different carrots for 30 days. Principal component analysis (PCA) was performed in mice fed the Danish carrots. The consumption of the 'more organic' O2 and O3 carrots induced some changes in lymphocyte populations, including an increase in regulatory T cells. In Italian carrots more differences between ORG and CV were observed in the first as compared to the second year. No relevant differences were observed in cytokine secretion. PCA showed a clear separation among mice fed the O1, O2, O3 and D-CV carrots. CONCLUSIONS: Although a great variability was observed between the two years, an immune stimulation was found after the ORG carrot consumption. PMID- 22488589 TI - Coil compression for accelerated imaging with Cartesian sampling. AB - MRI using receiver arrays with many coil elements can provide high signal-to noise ratio and increase parallel imaging acceleration. At the same time, the growing number of elements results in larger datasets and more computation in the reconstruction. This is of particular concern in 3D acquisitions and in iterative reconstructions. Coil compression algorithms are effective in mitigating this problem by compressing data from many channels into fewer virtual coils. In Cartesian sampling there often are fully sampled k-space dimensions. In this work, a new coil compression technique for Cartesian sampling is presented that exploits the spatially varying coil sensitivities in these nonsubsampled dimensions for better compression and computation reduction. Instead of directly compressing in k-space, coil compression is performed separately for each spatial location along the fully sampled directions, followed by an additional alignment process that guarantees the smoothness of the virtual coil sensitivities. This important step provides compatibility with autocalibrating parallel imaging techniques. Its performance is not susceptible to artifacts caused by a tight imaging field-of-view. High quality compression of in vivo 3D data from a 32 channel pediatric coil into six virtual coils is demonstrated. PMID- 22488591 TI - Reliability and validity of the Overactive Bladder Symptom Score in Spanish (OABSS-S). AB - PURPOSE: To validate the Spanish translation of the Overactive Bladder Symptom Score (OABSS) questionnaire. MATERIALS AND METHODS: The OABSS was translated into Spanish (OABSS-S) and back translated. The OABSS-S was self-administered to subjects, following internal IRB and ISPOR Good Practices guidelines. Spanish speaking patients >18 years of age were recruited from primary care clinics. Content validity was achieved by having the first 25 subjects complete the questionnaire in privacy; afterwards they were interviewed and the clarity of each question was discussed with the patient. All subjects recruited, including the first 25, were divided into two groups by the presence of OAB as determined by a previously validated intake question. Subjects completed the OABSS-S in privacy on two occasions within 10 days. Patients were excluded if their symptoms changed between the first and second administration of the questionnaire. Internal consistency was determined with Cronbach's alpha. Test-retest was determined by Spearman's rho. Discriminant validity was assessed between each group using one-way ANOVA and the Tukey post hoc test. RESULTS: One hundred and seventeen of 128 enrolled subjects completed this study (mean age 55; SD 18). Of 117, 74 (63%) were women 29 with OAB and 45 without OAB. There were 43 men (37%), 18 with OAB and 25 without OAB. A high level of consistency was observed among the seven items answered at visit 1 and 2, with a Cronbach's raw alpha statistic of 0.92. No differences in OABSS-S with age or gender were noted. However, subgroup analysis showed patients in the OAB group were significantly older and post-test analysis showed they had higher scores both for each individual question as well as overall symptom severity scores. Spearman's rank order correlation coefficients showed that there was significant difference between the seven items of the OABSS-S; a strong association (Spearman's rho) was also observed between the total seven-item score at visits 1 and 2 for the total score of all subjects r = 0.84, with OAB: r = 0.81, and without OAB: r = 0.83. Comparison of average total scores obtained for all patients at visits 1 and 2 was not significant (10.47 +/- 6.53 vs. 11.02 +/- 0.66). Discriminant validity testing revealed that there were significant differences in the responses between all diagnostic groups at visits 1 and 2: with OAB versus without OAB; total versus with OAB; total versus without OAB. CONCLUSION: The Spanish version of the OABSS is valid and reliable and will allow health care providers to easily and quickly assess a Spanish-speaking patient's symptoms. PMID- 22488590 TI - Inhibition of constitutively activated phosphoinositide 3-kinase/AKT pathway enhances antitumor activity of chemotherapeutic agents in breast cancer susceptibility gene 1-defective breast cancer cells. AB - Loss or decrease of wild type BRCA1 function, by either mutation or reduced expression, has a role in hereditary and sporadic human breast and ovarian cancers. We report here that the PI3K/AKT pathway is constitutively active in BRCA1-defective human breast cancer cells. Levels of phospho-AKT are sustained even after serum starvation in breast cancer cells carrying deleterious BRCA1 mutations. Knockdown of BRCA1 in MCF7 cells increases the amount of phospho-AKT and sensitizes cells to small molecule protein kinase inhibitors (PKIs) targeting the PI3K/AKT pathway. Restoration of wild type BRCA1 inhibits the activated PI3K/AKT pathway and de-sensitizes cells to PKIs targeting this pathway in BRCA1 mutant breast cancer cells, regardless of PTEN mutations. In addition, clinical PI3K/mTOR inhibitors, PI-103, and BEZ235, showed anti-proliferative effects on BRCA1 mutant breast cancer cell lines and synergism in combination with chemotherapeutic drugs, cisplatin, doxorubicin, topotecan, and gemcitabine. BEZ235 synergizes with the anti-proliferative effects of gemcitabine by enhancing caspase-3/7 activity. Our results suggest that the PI3K/AKT pathway can be an important signaling pathway for the survival of BRCA1-defective breast cancer cells and pharmacological inhibition of this pathway is a plausible treatment for a subset of breast cancers. PMID- 22488592 TI - Cadmium-induced changes in trace element bioaccumulation and proteomics perspective in four marine bivalves. AB - Bivalves are employed widely as biomonitors of metal pollution and proteomics has increasingly been applied to solve ecotoxicological issues. This study aimed to investigate the effects of Cd exposure on the bioaccumulation of other trace elements and reveal the molecular mechanisms using proteomics technologies. The results showed that Cd exposure resulted in remarkable changes in body concentrations of Zn, Cu, Ag, Co, Ni, Pb, and Se in four marine bivalves (scallop Chlamys nobilis, clam Ruditapes philippinarum, mussel Perna viridis, and oyster Saccostrea cucullata). Generally, the bivalves exposed to higher Cd concentration accumulated higher concentrations of Zn, Cu, and Se, but a lower concentration of Co. The accumulation of Ag, Ni, and Pb was specific for different species. The data strongly suggest that the influences of one metal exposure on the bioaccumulation of other metals/metalloids need to be considered in interpreting body concentrations of the elements in the biomonitors. Cd exposure had little effect on bivalve proteomes, and the identified proteins were insufficient to explain the observed disruption of trace element metabolism. However, protein expression signatures composed of the altered proteins could distinguish the clams and the mussels with different body Cd levels. The strong up-regulation of galectin in Cd-exposed oysters indicated the protein as a novel biomarker in environmental monitoring. PMID- 22488593 TI - Real-time tissue elastography for evaluation of hepatic fibrosis and portal hypertension in nonalcoholic fatty liver diseases. AB - The aim of this study was to prospectively measure liver stiffness with real-time tissue elastography in patients with nonalcoholic fatty liver diseases (NAFLD) and to compare the result with the clinical assessment of fibrosis using histological stage. One hundred and eighty-one prospectively enrolled patients underwent real-time tissue elastography, with the first 106 being analyzed as the training set and the remaining 75 being evaluated as the validation set. Hepatic and splenic elastic ratios were calculated and compared with stage of histological fibrosis. Portal hypertension (PH) was assessed. Real-time tissue elastography cut-off values by stage in the training set were 2.47 for F1, 2.67 for F2, 3.02 for F3, and 3.36 for F4. Using these cut-off values, the diagnostic accuracy of hepatic fibrosis in the validation set was 82.6%-96.0% in all stages. Only portal fibrosis correlated with the hepatic elastic ratio by multivariate analysis. The area under the receiver operating characteristic curve of elastic ratio better correlated than serum fibrosis markers in both early and advanced fibrosis stages. Patients with PH, defined by splenic elasticity, had early fibrosis. Patients with severe PH were found only in the group with cirrhosis. CONCLUSION: Real-time tissue elastography is useful in evaluating hepatic fibrosis and PH in patients with NAFLD. PMID- 22488594 TI - Xenotransplanted embryonic kidney provides a niche for endogenous mesenchymal stem cell differentiation into erythropoietin-producing tissue. AB - Recent findings have demonstrated that stem cells can differentiate into mature tissue when supplied with a niche containing factors identical to those in the normal developmental program. A niche for the development of an organ can be provided by xenotransplantation of a similar developing organ. However, this process has many technical, safety, and ethical concerns. Here, we established xenotransplantation models that control endogenous mesenchymal stem cell (MSC) differentiation into mature erythropoietin (EPO)-producing tissue in a niche provided by a developing xenometanephros. Transplantation of rat metanephroi into mouse omentum, and similarly pig metanephroi into cat omentum, led to the recruitment of host cells and EPO production. EPO-expressing cells were not differentiated from integrating vessels because they did not coexpress endothelial markers (Tie-2 and VE-cadherin). Instead, EPO-expressing cells were shown to be derived from circulating host cells, as shown by enhanced green fluorescent protein (EGFP) expression in the grown transplants of chimeric mice bearing bone marrow from a transgenic mouse expressing EGFP under the control of the EPO promoter. These results suggest that donor cell recruitment and differentiation in a xenotransplanted developing organ may be consistent between species. The cells responsible for EPO expression were identified as MSCs by injecting human bone marrow-derived MSCs and endothelial progenitor cells into NOD/SCID mice. Furthermore, using metanephroi from transgenic ER-E2F1 suicide inducible mice, the xenotissue component could be eliminated, leaving autologous EPO-producing tissue. Our findings may alleviate adverse effects due to long lasting immunosuppression and help mitigate ethical concerns. PMID- 22488595 TI - Managing obesity in pasture-based horses. AB - Obesity - a common problem in pasture-based horses - warrants intervention because it is associated with an increased risk for development of laminitis. Treating obesity in pasture-based horses is relatively simple and generally involves reducing caloric intake by using grazing muzzles and/or increasing caloric expenditure through exercise. To prevent recurrence of obesity after weight loss, clients should be educated on how to monitor body condition and to adjust feeding and management programs to maintain proper body condition. PMID- 22488596 TI - An update on the therapy of canine demodicosis. AB - Canine demodicosis, a disease caused by a proliferation of Demodex mites, typically leads to alopecia, comedones, follicular papules and pustules, scaling, and crusting. It may be treated with either amitraz rinses or macrocyclic lactones. Amitraz rinse is approved for application every 2 weeks at a concentration of 0.025%. Higher concentrations and more frequent applications increase the success rate but also increase the risk for adverse effects. Ivermectin is used at 0.3 to 0.6 mg/kg/d PO and moxidectin at 0.2 to 0.5 mg/kg/d PO. Both drugs may cause adverse neurologic effects in sensitive dogs. Milbemycin oxime at 1 to 2 mg/kg/d PO is a safer treatment option. A weekly spot-on combination of 2.5% moxidectin and 10% imidacloprid is recommended for milder forms of the disease. PMID- 22488597 TI - Crop burn in an umbrella cockatoo. AB - An 18-week-old umbrella cockatoo presented for continuous vocalization and one episode of regurgitation. The bird had been purchased 3 weeks before presentation and was the first large pet bird owned by this family. The cockatoo was fed a commercial baby bird formula that the owners were heating in the microwave before feeding. The owner had been instructed on formula feeding by the pet store personnel when the bird was purchased. PMID- 22488598 TI - Grooming in pet birds. AB - Grooming a bird refers to clipping wing feathers, trimming claws (nails), and on occasion, smoothing and trimming the beak. A veterinarian or experienced technician can perform this service on an otherwise healthy bird. Some disease states can result in nail and beak problems; consequently, all birds should be properly examined at regular intervals every 6 to 12 months. PMID- 22488599 TI - Nosocomial infections. AB - Nosocomial infections (NIs) are infections acquired during hospitalization. They are characterized by a high incidence of antimicrobial resistance. The most common NIs are pneumonia and urinary tract, surgical site, and bloodstream infections. Hand hygiene has demonstrated efficacy in reducing NIs. PMID- 22488600 TI - Hypercoagulability in dogs: pathophysiology. AB - The risk of hypercoagulability is increased when the hemostatic balance between procoagulant and anticoagulant mechanisms is shifted in favor of coagulation. Hypercoagulability is an increasingly recognized contributor to the deleterious manifestations of veterinary disease. The basis for thrombus formation in many acquired diseases is being investigated and more clearly defined. A thorough understanding of the hemostatic system and knowledge of disorders that lead to hypercoagulable states are critical to a logical therapeutic approach. PMID- 22488601 TI - Comprehensive review of the diagnosis and treatment of biliary tract cancer 2012. Part II: multidisciplinary management. AB - Biliary tract cancers (gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma and selected periampullary cancers) accounted for 12,760 new cases of cancer in the USA in 2010. These tumors have a dismal prognosis with most patients presenting with advanced disease. Early, accurate diagnosis is essential, both for potential cure where possible and for optimal palliative therapy in all others. This review examines the currently available and emerging technologies for diagnosis and treatment of this group of diseases. PMID- 22488602 TI - Porous, fluorescent, covalent triazine-based frameworks via room-temperature and microwave-assisted synthesis. AB - Porous, fluorescent, covalent triazine-based frameworks (CTFs) are obtained in an unprecedentedly mild reaction, opening up a scalable pathway for molecular building blocks previously thought incompatible with this chemistry. Choice of monomers and synthetic conditions determines the optical properties and nano scale ordering of these highly microporous materials with BET surface areas exceeding 1100 m(2) g(-1) and exceptional CO(2) capacities (up to 4.17 mmol g( 1)). PMID- 22488603 TI - Urticaria induced by laser epilation: a clinical and histopathological study with extended follow-up in 36 patients. AB - BACKGROUND: Laser epilation is the most common dermatologic light-based procedure in the world. We describe a unique side effect of the procedure: a delayed persistent urticarial rash. PATIENTS AND METHODS: We conducted a retrospective study involving 13,284 patients who received laser epilation at our clinics from January 2006 through March 2010 with 755 nm alexandrite laser (MiniGentleLase, Gentlelase, and GentleMax, Candela). Using patient clinical data and photos that were recorded on a standard side-effect report chart, we identified patients with suspected urticaria. Those patients were then followed for a period that ranged from 12 to 63 months. Only patients who could be diagnosed, treated, and followed by the dermatologist at our clinics were included in the study. Patients diagnosed or treated by other physicians or nurses and those without clinical photos or insufficient follow-up data were not included. RESULTS: We identified 36 patients who developed a severe, itchy, persistent hive rash on the treated area 6-72 hours after treatment. Eruption occurred most often on the legs (31 cases), followed by the groin (11 cases), axillae (eight cases), forearms (one case), and upper lip (one case). The eruption consisted of a hive rash with multiple pruritic perifollicular papules and confluent plaques on the treated area. Most patients required oral corticosteroids to control the symptoms. Lesions resolved in 7-30 days. The urticaria occurred mostly after the first treatment (26 cases), and was recurrent in subsequent treatments. Pretreating with oral corticosteroids prevented or limited the eruption. Thirty-three of the 36 patients reported a history of allergic rhinitis or some other allergy. Skin biopsies on four patients showed edema and a deep, dense dermal infiltrate consistent with lymphocytes mixed with eosinophils in a perivascular and occasionally perifollicular pattern in the mid and lower dermis. CONCLUSIONS: Persistent urticaria is a rare side effect of laser epilation. Rupture of the hair follicle by laser heat may trigger a delayed hypersensitivity reaction in a subset of predisposed allergic patients. An antigen from the disrupted hair follicle may be the triggering factor. To prevent this side effect, we recommend that laser epilation in allergic patients be preceded by an extended laser patch test, which should be evaluated 24-48 hours later. Preventive prednisone should be prescribed to patients who develop an urticarial rash on the test area. PMID- 22488604 TI - Human pharmaceuticals in the aquatic environment: a review of recent toxicological studies and considerations for toxicity testing. AB - Although an increasingly large amount of data exists on the acute and chronic aquatic toxicity of pharmaceuticals, numerous questions still remain. There remains a dearth of information pertaining to the chronic toxicity of bivalves, benthic invertebrates, fish, and endangered species, as well as study designs that examine mechanism-of-action (MOA)-based toxicity, in vitro and computational toxicity, and pharmaceutical mixtures. Studies examining acute toxicity are prolific in the published literature; therefore, we address many of the shortcomings in the literature by proposing "intelligent" well-designed aquatic toxicology studies that consider comparative pharmacokinetics and pharmacodynamics. For example, few studies on the chronic responses of aquatic species to residues of pharmaceuticals have been performed, and very few on variables that are plausibly linked to any therapeutic MOA. Unfortunately, even less is understood about the metabolism of pharmaceuticals in aquatic organisms. Therefore, it is clear that toxicity testing at each tier of an ecological risk assessment scheme would be strengthened for some pharmaceuticals by selecting model organisms and endpoints to address ecologically problematic MOAs. We specifically recommend that future studies employ AOP approaches (Ankley et al. 2010) that leverage mammalian pharmacology information, including data on side effects and contraindications. Use of conceptual AOP models for pharmaceuticals can enhance future studies in ways that assist in the development of more definitive ecological risk assessments, identify chemical classes of concern, and help protect ecosystems that are affected by WWTP effluent discharge. PMID- 22488605 TI - Fish metalloproteins as biomarkers of environmental contamination. AB - Fish are well-recognized bioindicators of environmental contamination. Several recent proteomic studies have demonstrated the validity and value of using fish in the search and discovery of new biomarkers. Certain analytical tools, such as comparative protein expression analyses, both in field and lab exposure studies, have been used to improve the understanding of the potential for chemical pollutants to cause harmful effects. The metallomic approach is in its early stages of development, but has already shown great potential for use in ecological and environmental monitoring contexts. Besides discovering new metalloproteins that may be used as biomarkers for environmental contamination, metallomics can be used to more comprehensively elucidate existing biomarkers, which may enhance their effectiveness. Unfortunately, metallomic profiling for fish has not been explored, because only a few fish metalloproteins have thus far been discovered and studied. Of those that have, some have shown ecological importance, and are now successfully used as biomarkers of environmental contamination. These biomarkers have been shown to respond to several types of environmental contamination, such as cyanotoxins, metals, and sewage effluents, although many do not yet possess any known function. Examples of successes include MMPs, superoxide dismutases, selenoproteins, and iron-bound proteins. Unfortunately, none of these have, as yet, been extensively studied. As data are developed for them, valuable new information on their roles in fish physiology and in inducing environmental effects should become available. PMID- 22488606 TI - Spatial distribution of arsenic in groundwater of southern Nepal. AB - Groundwater is an important source of both drinking water and of irrigation in the Terai region of Nepal. Although thousands of tubewells have been drilled in this region, the distribution of those that have been sampled and analyzed for As contamination is not consistent across the region. Based on a recent blanket tubewell testing program conducted in Nepal in 2007, preliminary data are available that allows us to provide a perspective on the As-contamination situation in drinking water of the six southern the Terai districts of Nepal. Arsenic concentrations detected in drinking water of tubewells and dug wells in these districts ranged from 0 to 770 jg L-'. It was found that the majority of the tested wells contained water that had As level below 10 jg L-', which is the WHO guideline value for exposure to As. The mean As levels detected varied from 2 jtg L-' in the Sunsari, Dhanusha, and Rupandehi districts, to 6.27 pg L-' in the Kailali district. The distribution of As levels detected, based on the NIS guideline, and expressed as a percentage thereof, was highest in the tubewells of the Bara district (3.8%), followed by the Kailali district (3.4%). Wells that were between 0- and 20-m deep contained water that had the highest percentage of As residues that exceeded both the WHO and NIS guideline values. In shallow tubewells of all six tested districts, the highest As contamination levels were found at depths of <50-m. The proportion of the population that was most often exposed to As levels >50 jig L-' occurred in the Kailali district (4%), followed by the Bara district (3.6%). Using a system developed to classify the relative vulnerability of inhabitants to As through drinking water only the Kailali and Bara districts were classified as "highly vulnerable" to As exposure. The Kota Tulsipur VDC of the Kailali district was found to be the most prominent As hotspot, wherein the majority of tubewells contained more than 50 jtg L-1 of As. PMID- 22488607 TI - Propoxur: a novel mechanism for insecticidal action and toxicity. AB - Propoxur is a carbamate insecticide that has recently attracted considerable attention as a possible treatment option for addressing the bedbug epidemic. The generally accepted mechanism of toxicity for propoxur involves the inhibition of ChE, as is the case for many agents in the category. Considerable research supports the concept that most physiologically active substances induce their effects through multi-faceted action. In this review, we provide evidence that ET -ROS--OS participate mechanistically in both the action and in human toxicity of pesticides, including propoxur. Propoxur is a catechol derivative that contains carbamate and isopropyl groups on the oxygens in its moiety. Metabolic studies with propoxur reveal hydrolysis of the carbamate and dealkylation of the isopropyl group to yield the parent catechol. In addition, nuclear hydroxylation produces a hydroquinone derivative. Both the catechol and this hydroquinone derivative are potentially able to undergo redox cycling with the corresponding quinone to produce ROS. It is primarily for these reasons that we believe propoxur may be similar to other classes of physiologically active compounds in producing effects through ET-ROS-OS. Generally, reactive ROS are generated by metabolic processes that yield ET entities, and this occurs with propoxur as well. Although ROS are commonly associated with toxicity, there is little recognition in the literature that they can also play a role in therapeutic action. PMID- 22488608 TI - Taurolidine: Mode of administration in mouse tumor models. PMID- 22488611 TI - Preventive strategies in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. PMID- 22488610 TI - Challenges in ductal carcinoma in situ risk communication and decision-making: report from an American Cancer Society and National Cancer Institute workshop. AB - In September 2010, the American Cancer Society and National Cancer Institute convened a conference to review current issues in ductal carcinoma in situ (DCIS) risk communication and decision-making and to identify directions for future research. Specific topics included patient and health care provider knowledge and attitudes about DCIS and its treatment, how to explain DCIS to patients given the heterogeneity of the disease, consideration of nomenclature changes, and the usefulness of decision tools/aids. This report describes the proceedings of the workshop in the context of the current literature and discusses future directions. Evidence suggests that there is a lack of clarity about the implications and risks of a diagnosis of DCIS among patients, providers, and researchers. Research is needed to understand better the biology and mechanisms of the progression of DCIS to invasive breast cancer and the factors that predict those subtypes of DCIS that do not progress, as well as efforts to improve the communication and informed decision-making surrounding DCIS. PMID- 22488612 TI - Xanthogranulomatous cholecystitis: sonographic and CT features and differentiation from gallbladder carcinoma: a pictorial essay. AB - The imaging features of xanthogranulomatous cholecystitis closely resemble those of gallbladder carcinoma, especially those of the wall-thickening variety. There is an overlap between these two conditions with respect to the clinical features and certain imaging findings. However, certain finer details like the presence of intramural hypoattenuating nodules and the type of mucosal enhancement may help to differentiate these two conditions. In this article, we have highlighted some of these imaging features. The importance of making an accurate diagnosis lies in the significant difference between the prognosis and the surgical management of the two disease entities. PMID- 22488613 TI - Hemiarthroplasty of the hip with and without cement: a randomized clinical trial. AB - BACKGROUND: Controversy exists regarding the use of cement for hemiarthroplasty to treat a displaced subcapital femoral neck fracture in elderly patients. The primary hypothesis of this study was that use of cement would provide better visual analog pain scores following this procedure in an elderly patient population. METHODS: Elderly patients (at least seventy years of age) without severe cardiopulmonary compromise who presented to one institution with a displaced subcapital femoral neck fracture were offered inclusion in the study. One hundred and sixty patients (mean age, eighty-five years) with an acute displaced femoral neck fracture were randomly allocated to hemiarthroplasty with either a cemented Exeter or an uncemented Zweymuller Alloclassic component. Clinical and radiographic follow-up was performed for two years and the outcomes were recorded by a blinded assessor. The main clinical outcome measures were pain, mortality, mobility, complications, reoperations, and quality of life measured with use of validated instruments. RESULTS: The mean visual analog pain score at rest did not differ significantly between the groups. The total number of complications was greater in the uncemented group (sixty-three compared with twenty-eight in the cemented group). Subsidence was significantly more common in the uncemented group (eighteen compared with one in the cemented group). Intraoperative or postoperative fracture was also significantly more common in the uncemented group (eighteen compared with one in the cemented group). The mortality rate did not differ significantly between the groups at any time point (thirty-five deaths in the uncemented group compared with thirty-two in the cemented group at two years). The Oxford hip score was significantly poorer in the uncemented group at six weeks (38.8 compared with 35.7 in the cemented group), and it was also poorer or similar at later follow-up time points although the differences were not significant. There was also a trend toward poorer mobility and greater dependence on walking aids in the cemented group. The postoperative Short Musculoskeletal Function Assessment and Mini-Mental State Examination scores did not differ significantly between the groups. CONCLUSIONS: In elderly patients (seventy years or older) without severe cardiopulmonary compromise who were treated with hemiarthroplasty for a displaced femoral neck fracture, use of a cemented Exeter implant and use of an uncemented Alloclassic implant provided a comparable outcome with regard to pain. However, implant related complication rates were significantly lower in the group treated with a cemented implant. Trends toward better function and better mobility in the cemented group were observed. These trends reached significance in particular functional scores at some postoperative time points. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 22488614 TI - A prospective multicenter study of Legg-Calve-Perthes disease: functional and radiographic outcomes of nonoperative treatment at a mean follow-up of twenty years. AB - BACKGROUND: Long-term studies have indicated good outcomes for most patients with Legg-Calve-Perthes disease. However, clinical experience suggests that less favorable outcomes are common. We sought to prospectively document pain and function in a cohort of adults who had previously been treated nonoperatively for Legg-Calve-Perthes disease. METHODS: Patients in our region with Legg-Calve Perthes disease were enrolled between 1984 and 1991 as part of a multicenter prospective trial and were treated with hip range-of-motion exercises or bracing. Patients returned for physical examination, radiographs, and completion of outcome measures including the Nonarthritic Hip Score (NAHS) and the Iowa Hip Score (IHS). RESULTS: Fifty-six patients (fifty-eight hips) were examined at a mean of 20.4 years (range, 16.3 to 24.5 years) after enrollment. The mean NAHS was 79 (range, 35 to 100), and the mean IHS was 74 (range, 43 to 100). Three patients had required hip arthroplasty and one patient had required a pelvic osteotomy. Fourteen (26%) of the remaining hips had no hip osteoarthritis, sixteen (30%) had mild osteoarthritis (Tonnis grade 1), and twenty-four (44%) had moderate or severe osteoarthritic changes on radiographs (grade 2 or 3). Femoroacetabular impingement indicated by physical examination was associated with pain and with poorer outcomes on the IHS and the NAHS (p = 0.0004, 0.0014, and 0.0007, respectively). The Stulberg classification was significantly associated with impingement on physical examination (p = 0.0495), the NAHS (p = 0.003), and the Tonnis grade (p = 0.012). Multivariate logistic regression showed that only the Stulberg classification was significantly associated with the NAHS (p = 0.0032); the odds ratio for a Stulberg type of I or II compared with IV or V in patients with a fair or poor NAHS was 0.101 (95% confidence interval, 0.018 to 0.573). CONCLUSIONS: Pain, arthritis, and ongoing hip dysfunction are common in patients with Legg-Calve-Perthes disease that was treated nonoperatively. Hips rated as Stulberg type III or IV more frequently had poor or fair outcomes on the IHS and NAHS (61% and 72% for type III and 77% and 60% for type IV). Patients with a lateral pillar type of B, B/C, or C frequently had pain and radiographic evidence of osteoarthritis. Clinical signs of femoroacetabular impingement were associated with pain and with lower functional scores. This prospective study establishes a modern benchmark for outcomes following nonoperative, weight bearing treatment of Legg-Calve-Perthes disease. PMID- 22488615 TI - Serum and synovial fluid analysis for diagnosing chronic periprosthetic infection in patients with inflammatory arthritis. AB - BACKGROUND: The serum erythrocyte sedimentation rate and C-reactive protein level, as well as the synovial fluid white blood-cell count with differential, are commonly used tests for the diagnosis of periprosthetic joint infection; however, their utility for the diagnosis of periprosthetic joint infection in patients with inflammatory arthritis is unknown. METHODS: Eight hundred and three patients undergoing 871 consecutive hip and knee arthroplasties (including sixty one in patients with inflammatory arthritis and 810 in patients with noninflammatory arthritis) were prospectively evaluated for periprosthetic joint infection. The erythrocyte sedimentation rate, C-reactive protein level, and synovial fluid white blood-cell count with differential were obtained routinely. Receiver operating characteristic curves were used to establish optimal thresholds for the diagnosis of periprosthetic joint infection, and the area under the curve was calculated to determine the overall accuracy of these tests for patients with inflammatory compared with noninflammatory arthritis. RESULTS: The utility of all serum and synovial tests for predicting chronic periprosthetic joint infection was similar for patients with noninflammatory and inflammatory arthritis. The optimal cutoffs in patients with noninflammatory and inflammatory arthritis were 32 and 30 mm/hr, respectively, for the erythrocyte sedimentation rate; 15 and 17 mg/L, respectively, for the C-reactive protein level; 3450/MUL and 3444/MUL, respectively, for the synovial fluid white blood-cell count; and 78% and 75%, respectively, for the differential. The areas under the curves were similar for the two groups (84.9% and 85.0%, respectively, for the erythrocyte sedimentation rate; 88.5% and 85.1%, respectively, for the C-reactive protein level; 94.5% and 93.8%, respectively, for the synovial fluid white blood-cell count, and 95.0% and 93.6%, respectively, for the differential). Finally, the sensitivities, specificities, negative predictive values, and positive predictive values for all tests were also comparable in both groups. The rate of periprosthetic joint infection was significantly higher following procedures in patients with inflammatory arthritis than following procedures in patients with noninflammatory arthritis (31% compared with 18%; p = 0.013). CONCLUSIONS: The erythrocyte sedimentation rate, C-reactive protein level, and synovial fluid white blood-cell count with differential are useful for diagnosing periprosthetic joint infection in patients with inflammatory as well as noninflammatory arthritis, with similar optimal cutoff values and overall testing performance. The synovial fluid white blood-cell count and differential performed the best for the diagnosis of periprosthetic joint infection. Physicians evaluating patients with a failed or painful total hip or knee arthroplasty should not assume that elevation of the erythrocyte sedimentation rate, C-reactive protein level, and synovial fluid white blood-cell count with differential is secondary to inflammatory arthropathy; rather, elevation of these markers may indicate periprosthetic joint infection, and further evaluation for infection is warranted. PMID- 22488616 TI - Gritti-stokes amputations in the trauma patient: clinical comparisons and subjective outcomes. AB - BACKGROUND: The Gritti-Stokes amputation procedure is a modification of the traditional transfemoral amputation, with resection of the bone at a supracondylar femoral level and fixation of the patella to the distal part of the femur as an end-cap. Although well-established in patients with vascular compromise, no evidence exists on its use in the trauma setting. METHODS: Fourteen consecutive patients who underwent Gritti-Stokes amputation and fifteen consecutive patients who underwent traditional transfemoral amputation by fellowship-trained orthopaedic traumatologists at a level-I trauma center were evaluated at more than fourteen months postoperatively. The Sickness Impact Profile (SIP) questionnaire was also administered to both patient groups at more than thirty-six months postoperatively to assess patient-reported functional outcomes. RESULTS: Despite the two groups not having significant differences in preoperative variables or demographics, the Gritti-Stokes group had significantly improved SIP questionnaire overall and domain scores. This procedure also left the patients with a significantly longer residual limb (an average of 46.1 cm of residual femoral length versus 34.6 cm for the transfemoral group). The Gritti Stokes group also had a significantly increased rate of walking without assistive devices (five patients versus none in the transfemoral amputation group). CONCLUSIONS: The Gritti-Stokes amputation appears to be safe and beneficial when utilized in the trauma population. PMID- 22488617 TI - Adipose-derived stem-cell treatment of skeletal muscle injury. AB - BACKGROUND: The aim of the present study was to investigate whether adipose derived stem cells could contribute to skeletal muscle-healing. METHODS: Adipose derived stem cells of male rats were cultured and injected into the soleus muscles of female rats. Two and four weeks after injections, muscles were tested for tetanic force (50 Hz). Histological analysis was performed to evaluate muscle collagen deposition and the number of centronucleated muscle fibers. In order to track donor cells, chimerism was detected with use of real-time polymerase chain reaction targeting the male sex-determining region Y (SRY) gene. RESULTS: Two weeks after cell injection, tetanus strength and the number of centronucleated regenerating myofibers, as well as the number of centronucleated regenerating myofibers, were higher in the treated group than they were in the control group (mean and standard error of the mean, 79.2 +/- 5.0% versus 58.3 +/- 8.1%, respectively [p < 0.05]; and 145 +/- 36 versus 273 +/- 18 per 103 myofibers, respectively [p < 0.05]). However, there were no significant differences at four weeks. Treatment did not decrease collagen deposition. Male gene was not detected in female host tissue at two and four weeks after engraftment by polymerase chain reaction analysis. CONCLUSIONS: Adipose-derived stem-cell therapy increased muscle repair and force at two weeks, but not four weeks, after injection, suggesting that adipose-derived stem-cell administration may accelerate muscle repair; however, the rapid disappearance of injected cells suggests a paracrine mechanism of action. PMID- 22488618 TI - Anatomical and functional results after arthroscopic Hill-Sachs remplissage. AB - BACKGROUND: Large osseous defects of the posterosuperior aspect of the humeral head can engage the glenoid rim and cause recurrent instability after arthroscopic Bankart repair for glenohumeral dislocation. Filling of the humeral head defect with the posterior aspect of the capsule and the infraspinatus tendon (i.e., Hill-Sachs remplissage) has recently been proposed as an additional arthroscopic procedure. Our hypothesis is that the capsulotenodesis heals in the humeral bone defect without a severe adverse effect on shoulder mobility, allowing return to preinjury sports activity. METHODS: Of 459 patients operated on for recurrent traumatic anterior shoulder instability, forty-seven (10.2%) underwent arthroscopic Bankart repair combined with Hill-Sachs remplissage with use of suture anchors. All had a large Hill-Sachs lesion (Calandra grade III), engaging over the glenoid rim, without substantial glenoid bone loss. Nine patients had had prior unsuccessful surgery to address glenohumeral instability (three Bankart and six Bristow-Latarjet procedures). The average age at the time of surgery (and standard deviation) was 29 +/- 5.4 years. Postoperatively, comparative shoulder motion was precisely measured with use of digital photographic images. Capsulotenodesis healing was assessed on a computed tomography (CT) arthrogram (n = 38) or magnetic resonance image (MRI) (n = 4). The mean duration of follow-up was twenty-four months. RESULTS: Healing of the posterior aspect of the capsule and the infraspinatus tendon into the humeral defect was observed in all forty-two patients who underwent postoperative imaging, and thirty-one (74%) had a remplissage of >=75%. Compared with the normal (contralateral) side, the mean deficit in external rotation was 8 degrees +/- 7 degrees with the arm at the side of the trunk and 9 degrees +/- 7 degrees in abduction at the time of the last follow-up. Of forty-one patients involved in sports, thirty-seven (90%) were able to return postoperatively and twenty eight (68%) returned to the same level of sports, including those involving overhead activities. Ninety-eight percent (forty-six) of the forty-seven patients had a stable shoulder at the time of the last follow-up. CONCLUSIONS: Arthroscopic Hill-Sachs remplissage, performed in combination with a Bankart repair, is a potential solution for patients with a large engaging humeral head bone defect but no substantial glenoid bone loss. The posterior capsulotenodesis heals predictably in the humeral defect. The slight restriction in external rotation (approximately 10 degrees ) does not significantly affect return to sports, including those involving overhead activities. The procedure, which may also be useful for revision of previous failed glenohumeral instability surgery, is not indicated for patients with glenoid bone deficiency. PMID- 22488619 TI - Long-term results after gastrocnemius-soleus intramuscular aponeurotic recession as a part of multilevel surgery in spastic diplegic cerebral palsy. AB - BACKGROUND: Equinus of the foot at the ankle is one of the most common deformities in patients with spastic diplegic cerebral palsy, leading to gait disturbances and secondary deformities. During single-event multilevel surgery, equinus is commonly corrected by calf muscle lengthening, such as gastrocnemius soleus intramuscular aponeurotic recession. Various studies have described satisfactory short-term results after gastrocnemius-soleus intramuscular aponeurotic recession. However, there is no evidence for maintenance of equinus correction because of the small and heterogeneous case series and short follow-up time previously reported. METHODS: The present study provides long-term results after gastrocnemius-soleus intramuscular aponeurotic recession as a part of multilevel surgery for the treatment of equinus in forty-four patients with spastic diplegia who were able to walk (forty-eight legs had lengthening of the gastrocnemius and thirty-four legs had lengthening of the gastrocnemius and soleus). Standardized three-dimensional gait analysis and clinical examination were done preoperatively and at one year, a mean (and standard deviation) of 3 +/ 1 years, and a mean of 9 +/- 2 years after surgery. RESULTS: Significant improvements in kinematic and kinetic ankle parameters on gait analysis as well as passive dorsiflexion in clinical examination were found one year after surgery. While there was a significant loss of passive dorsiflexion at the time of long-term follow-up, the improvements in gait analysis parameters were maintained. The endurance of gait improvements was accompanied by a persistent increase of dorsiflexor muscle strength without relevant loss of plantar flexor strength. Although it was not significant, there was a tendency for deterioration of gait analysis parameters over the nine years. The analysis of individual patterns showed recurrence of equinus at the ankle in 24% of the legs. Early onset calcaneal gait was found one year after surgery in seven legs (9%), but without secondary crouch gait, and there was recovery at the time of the long term follow-up. Late-onset calcaneal gait was seen at the time of long-term follow-up in eight legs (10%), of which four had an accompanying crouch gait. CONCLUSIONS: Gastrocnemius-soleus intramuscular aponeurotic recession as a part of multilevel surgery leads to satisfactory correction of mild and moderate equinus deformity in children and adolescents with spastic diplegia without relevant risk for overcorrection and should be preferred over Achilles tendon lengthening to avoid overlengthening. The long-term results in the present study demonstrate that the improvements are long-lasting on average, but individual patients tend to develop recurrence and may need secondary gastrocnemius-soleus intramuscular aponeurotic recession. PMID- 22488620 TI - The outcome of rotating-platform total knee arthroplasty with cement at a minimum of ten years of follow-up. AB - BACKGROUND: Durable, long-term results have been reported for patients managed with first-generation mobile-bearing total knee arthroplasty. Second-generation mobile-bearing total knee arthroplasty has been introduced to enhance instrumentation, to increase flexion, and to improve functional outcome, but, to our knowledge, no long-term results are available. METHODS: From May 1999 to June 2000, 116 consecutive rotating-platform total knee arthroplasties were performed by the two senior authors in 112 patients with use of the LPS-Flex Mobile cemented prosthesis, which was implanted with a measured resection technique. The patella was resurfaced in every knee. The average age of the patients at the time of surgery was sixty-nine years (range, thirty-seven to eighty-five years), and seventy-seven patients (eighty knees) were women. The predominant diagnosis was osteoarthritis. The clinical and radiographic evaluation was performed with use of the Knee Society rating system. The level of activity and patient-reported functional outcome were evaluated with use of the University of California at Los Angeles (UCLA) score and the Knee injury and Osteoarthritis Outcome Score (KOOS), respectively. RESULTS: The average duration of follow-up was 10.6 years (range, ten to 11.8 years). Three patients were lost to follow-up, and five patients died of causes unrelated to knee arthroplasty. Two knees were revised, one because of infection and one because of failure of the medial collateral ligament. Kaplan Meier survivorship analysis showed an implant survival rate of 98.3% at ten years. For the 104 patients (108 knees) who were evaluated at a minimum of ten years, the average Knee Society knee and function scores improved from 34 to 94 points and from 55 to 88 points, respectively, at the time of the latest follow up. There was no periprosthetic osteolysis and no evidence of implant loosening on follow-up radiographs. The average knee flexion was 117 degrees preoperatively and 128 degrees at the time of the latest follow-up evaluation. At the time of the latest follow-up, the KOOS quality-of-life score was significantly better for patients with >125 degrees of flexion (p = 0.00034). CONCLUSIONS: This study demonstrated durable clinical and radiographic results at a minimum of ten years after total knee replacement with a second-generation, cemented, rotating-platform, posterior-stabilized total knee prosthesis. According to the functional outcome results obtained in this study, we believe that this design is a valuable option for active patients undergoing total knee arthroplasty. PMID- 22488621 TI - Surgical and functional outcomes after operative management of complex and displaced intra-articular glenoid fractures. AB - BACKGROUND: Operative treatment is indicated for displaced fractures of the glenoid fossa. However, little is known regarding functional outcomes in these patients. This study assesses surgical and functional results after treatment of displaced, high-energy, complex, intra-articular glenoid fractures. METHODS: Thirty-three patients with displaced intra-articular fractures of the glenoid were treated surgically between 2002 and 2009. The indications for operative treatment included articular fracture gap or step-off of >= 4 mm. Twenty-five patients also had extra-articular scapular involvement. A posterior approach was utilized in twenty-one patients, an anterior approach in seven, and a combined approach in five. Functional outcomes, including Disabilities of the Arm, Shoulder and Hand (DASH) and Short Form-36 (SF-36) scores, shoulder motion and strength, and return to work and/or activities, were obtained for thirty patients (91%). RESULTS: At a mean follow-up of twenty-seven months (range, twelve to seventy-three months), all patients had radiographic union of the fracture. The mean DASH score was 10.8 (range, 0 to 42). All mean SF-36 subscores were comparable with those of the normal population. Twenty-six patients (87%) were pain-free at the time of follow-up, and four had mild pain with prolonged activity. Twenty-seven (90%) of thirty patients returned to their preinjury level of work and/or activities. CONCLUSIONS: Our data suggest that surgical treatment for complex, displaced intra-articular glenoid fractures with or without involvement of the scapular neck and body can be associated with good functional outcomes and a low complication rate. PMID- 22488622 TI - Plantar approach for excision of a Morton neuroma: a long-term follow-up study. AB - BACKGROUND: When nonsurgical treatment of a Morton neuroma is unsuccessful, neurectomy is indicated. The purpose of the present retrospective study was to evaluate the long-term outcomes, complications, and adverse events following a distal plantar transverse incision for the excision of an intermetatarsal neuroma. METHODS: We conducted a retrospective review of 168 consecutive patients who underwent surgical excision of a Morton neuroma that had been unresponsive to nonsurgical treatment. The clinical diagnosis was confirmed by means of magnetic resonance imaging and histological analysis. All patients underwent excision of the neuroma through a distal transverse plantar approach; concomitant foot and ankle disorders were also treated. Postoperatively, a three-grade patient satisfaction scale was administered to assess the results of the procedure and a clinical examination was performed for all patients. RESULTS: One hundred and sixty patients (204 feet, 227 neuromas) were assessed at a median of 7.1 +/- 3.9 years (range, one to twenty-one years) postoperatively. A good result was reported for 143 patients (89.4%); a fair result, for eleven (6.9%); and a poor result, for six (3.8%). The eleven patients with a fair result reported scar related symptoms such as skin hardening, loss of sensation at the incision site, discomfort wearing shoes with high heels, and local paresthesias with no recurrence of the neuroma. The six patients with a poor result reported pain and paresthesias, and the recurrence of a neuroma was confirmed at the time of reoperation. CONCLUSIONS: Producing a marked reduction in pain and high overall patient satisfaction, a distal transverse plantar incision is comparable with other surgical approaches for the surgical treatment of a Morton neuroma. PMID- 22488623 TI - Pathophysiology and new strategies for the treatment of Legg-Calve-Perthes disease. AB - Legg-Calve-Perthes disease is a juvenile form of idiopathic osteonecrosis of the femoral head that can lead to permanent femoral head deformity and premature osteoarthritis. According to two recent multicenter, prospective cohort studies, current nonoperative and operative treatments have modest success rates of producing a good outcome with a spherical femoral head in older children with Legg-Calve-Perthes disease. Experimental studies have revealed that the immature femoral head is mechanically weakened following ischemic necrosis. Increased bone resorption and delayed new bone formation, in combination with continued mechanical loading of the hip, contribute to the pathogenesis of the femoral head deformity. Biological treatment strategies to improve the healing process by decreasing bone resorption and stimulating bone formation appear promising in nonhuman preclinical studies. PMID- 22488624 TI - Anterior shoulder instability associated with coracoid nonunion in patients with a seizure disorder. AB - BACKGROUND: An association between coracoid fracture and glenohumeral instability with both a seizure disorder and the subsequent development of coracoid nonunion has not previously been recognized. This is clinically important as patients with a seizure disorder and glenohumeral instability frequently require a primary osseous reconstructive procedure, such as coracoid osteotomy and transfer to the anterior glenoid rim (the Bristow-Latarjet procedure), to address glenoid osseous deficiency. We report on coracoid fracture nonunion in five patients with a seizure disorder and anterior glenohumeral instability and discuss the implications for surgical treatment. METHODS: Coracoid fracture was specifically sought on three-dimensional reconstructions of computed tomography scans in a consecutive series of 234 patients presenting to our unit with recurrent anterior instability. In addition to demographic data, we specifically sought information on any history of shoulder injury, the mechanism of injury, or previous seizure activity in these patients. In patients with a coracoid fracture or nonunion viewed to be at high risk of failure with a soft-tissue procedure, an open osseous reconstructive procedure was performed. The type of operative procedure was determined by the location of the nonunion. RESULTS: We identified six coracoid fracture nonunions in association with anterior glenohumeral instability in five patients (mean age, 26.8 years; range, twenty-four to thirty years). All patients had instability occurring in association with seizures. In the four shoulders with the anatomic location of the coracoid nonunion at its so-called elbow, a standard Bristow-Latarjet procedure was performed. In the two shoulders in which the nonunion was more distal, an Eden-Hybbinette procedure was performed. CONCLUSIONS: We recommend having a high index of suspicion of coracoid fracture when treating patients with a seizure disorder who have anterior glenohumeral instability. In these patients, preoperative computed tomographic images allow the diagnosis of a coracoid nonunion to be made prior to surgery and help to determine whether there is sufficient intact coracoid bone to allow a Bristow-Latarjet procedure to be performed. PMID- 22488625 TI - A mouse model of massive rotator cuff tears. AB - BACKGROUND: Rotator cuff tears are the most common tendon injury seen in orthopaedic patients. Muscle atrophy and fatty infiltration in rotator cuff muscles are considered among the key factors responsible for the failure of attempted repair of a massive rotator cuff tear. However, the pathophysiology of rotator cuff muscle atrophy and fatty infiltration remains largely unknown, partly because of the lack of appropriate small animal models. The goal of this study was to develop a mouse model of muscle atrophy and fatty infiltration after a rotator cuff tear. We also sought to study the role of denervation on muscle atrophy and fatty infiltration after a rotator cuff tear. METHODS: Adult wild type FVB/N mice were randomly divided into three groups. Mice in different groups received unilateral complete supraspinatus and infraspinatus tendon transection, suprascapular nerve transection, or both procedures. Sham surgery was performed on the contralateral shoulder to serve as a control. Mice were killed twelve weeks after surgery. Histological analysis and high-resolution magnetic resonance imaging were used to evaluate muscle atrophy and fat infiltration after a rotator cuff tear. RESULTS: Significant and consistent muscle atrophy and fatty infiltration were observed in the rotator cuff muscles after rotator cuff tendon transection. We further found that denervation significantly increases the amount of muscle atrophy and fatty infiltration after a rotator cuff tear. CONCLUSIONS: We successfully developed a novel mouse model of a massive rotator cuff tear, which simulates major pathological changes, including muscle atrophy and fatty infiltration after massive rotator cuff tears seen in patients. PMID- 22488626 TI - Sarcoidosis of the spine: a report of five cases and a review of the literature. PMID- 22488627 TI - Isolated dislocation of the peroneus longus tendon over the calcaneal tubercle in an ice skater: a case report. PMID- 22488628 TI - Detection of total hip prostheses at airport security checkpoints: how has heightened security affected patients? AB - BACKGROUND: The sensitivity of airport security screening measures has increased substantially during the past decade, but few reports have examined how this affects patients who have undergone hip arthroplasty. The purpose of this study was to determine the experiences of patients who had hip prostheses and who passed through airport security screenings. METHODS: A consecutive series of 250 patients who presented to the office of a high-volume surgeon were asked whether they had had a hip prosthesis for at least one year and, if so, whether they had flown on a commercial airline within the past year. Patients who responded affirmatively to both questions were asked to complete a written survey that included questions about which joint(s) had been replaced, the number of encounters with airport security, the frequency and location of metal detector activation, any additional screening procedures that were utilized, whether security officials requested documentation regarding the prosthesis, the degree of inconvenience, and other relevant information. RESULTS: Of the 143 patients with hip replacements who traveled by air, 120 (84%) reported triggering the alarm and required wanding with a handheld detector. Twenty-five of these patients reported subsequently having to undergo further inspection, including additional wanding, being patted down, and in two cases having to undress in a private room to show the incision. Ninety-nine (69%) of the 143 patients reported that the prosthetic joint caused an inconvenience while traveling. CONCLUSIONS: This study provides interesting and critical information that allows physicians to understand the real-world implications of implanted orthopaedic devices for patients who are traveling where there has been heightened security since September 11, 2001. Patients should be counseled that they should expect delays and be prepared for such inconveniences, but that these are often only momentary. This information could relieve some anxiety and concerns that patients may have prior to traveling. PMID- 22488629 TI - Cement emerges as the most predictable option for hip hemiarthroplasty: commentary on an article by Fraser Taylor, BSc, MBChB, FRACS, et al.: "Hemiarthroplasty of the hip with and without cement: a randomized clinical trial". PMID- 22488630 TI - Legg-Calve-Perthes disease: Functional prognosis in an era of high expectations: commentary on an article by A. Noelle Larson, MD, et al.: "A prospective multicenter study of Legg-Calve-Perthes disease. Functional and radiographic outcomes of nonoperative treatment at a mean follow-up of twenty years". PMID- 22488631 TI - Inflammatory markers in patients with inflammatory arthritis: perhaps they can be helpful in diagnosing chronic periprosthetic infection: commentary on an article by Cara A. Cipriano, MD, et al.: "Serum and synovial fluid analysis for diagnosing chronic periprosthetic infection in patients with inflammatory arthritis". PMID- 22488632 TI - Serum metabolic profiling in inflammatory bowel disease. AB - BACKGROUND: The inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC), are chronic inflammatory conditions of the gastrointestinal tract whose pathogenesis is not completely understood. (1)H nuclear magnetic resonance (NMR) spectroscopy of serum generates comprehensive metabolic profiles, reflecting systemic metabolism, which may be altered in disease states. AIM: The aim of this study was to use (1)H NMR-based serum metabolic profiling in the investigation of CD patients, UC patients, and controls, potentially to provide insights into disordered metabolism in IBD, and into underlying mechanisms of disease. METHODS: Serum metabolic profiles were acquired from 67 individuals (24 CD patients, 20 UC patients, and 23 healthy controls). The multivariate pattern-recognition techniques of principal components analysis (PCA) and partial least squares discriminant analysis with orthogonal signal correction (OSC-PLS-DA) were used to investigate differences between cohorts. RESULTS: OSC-PLS-DA distinguished CD and UC cohorts with significant predictive accuracy, highlighting differences in lipid and choline metabolism. Metabolic profiles of both CD and UC cohorts, and the combined IBD cohort, differed significantly from controls: metabolites of importance in the OSC-PLS-DA models included lipoproteins (especially HDL cholesterol), choline, N acetylglycoprotein, and amino acids. CONCLUSIONS: (1)H NMR-based metabolic profiling has identified distinct differences in serum metabolic phenotype between CD and UC patients, as well as between IBD patients and controls. PMID- 22488634 TI - Doppler ultrasound of hepatic blood flow for noninvasive evaluation of liver fibrosis compared with liver biopsy and transient elastography. AB - BACKGROUND: Accurate quantification of liver fibrosis is essential for therapeutic decision-making and follow-up of chronic liver diseases. AIMS: To optimize the quality of non-invasive assessment of liver fibrosis in patients with chronic hepatopathy we compared Doppler ultrasound with liver histology and transient elastography (TE). METHODS: In this prospective observational study, we performed Doppler ultrasound of hepatic blood vessels as well as TE in 125 patients who underwent liver biopsy for diagnostic work-up of hepatopathy. Hepatic venous flow was evaluated by determining resistance index (HVRI) of the right hepatic vein. Doppler and TE results were compared with histological staging, grading and degree of steatosis obtained by liver biopsy. RESULTS: HVRI showed a high reliability in predicting fibrosis stage FII or higher (AUROC 93.7 %, HVRI < 1.185; sensitivity 89.66 % and specificity 86.32 %) and was superior to TE. Neither steatosis nor inflammation had significant influence on HVRI-based estimation of fibrosis (1.45 +/- 0.2; 1.26 +/- 0.05; 1.06 +/- 0.06; 0.87 +/- 0.08; 0.46 +/- 0.11 for F0-FIV, respectively). HVRI differed significantly in different stages of fibrosis. In contrast, portal vein and hepatic artery only showed significant changes in higher stages of fibrosis. Hepatic artery resistance index was elevated (0.67-0.74; p < 0.05); portal vein flow maximum and undulation were significantly reduced in higher fibrosis (p < 0.05 and p < 0.01, respectively). CONCLUSIONS: Hepatic blood flow analysis, especially HVRI, provides useful information during assessment of hepatopathy and is a reliable predictor of liver fibrosis stage FII or higher as part of the non-invasive diagnostic work-up and follow-up in chronic liver disease. PMID- 22488633 TI - Tangible resources for preparing patients for antiviral therapy for chronic hepatitis C. AB - BACKGROUND: Chronic hepatitis C (HCV) infected patients with coexisting mental health and/or substance abuse issues face significant barriers to treatment and are often deferred. This paper sought to highlight critical pre-treatment strategies and provide tangible resources for HCV clinicians to facilitate preparation and successful treatment of these patients. METHODS: Guided by the clinical experience of our liver center, a large, tertiary academic medical center, and informed by the extant literature, we summarize pre-treatment strategies and specific resources and recommendations for HCV providers. RESULTS: Four key pre-treatment strategies include: 1) screening for mental health/substance abuse issues using brief, reliable and validated instruments; 2) locating and establishing collaborative care with mental health and substance abuse specialists; 3) using a motivational interviewing communication style; and 4) addressing adherence-related issues. CONCLUSIONS: HCV clinicians are in a unique position to prepare patients with coexisting mental health and/or substance abuse issues for antiviral therapy. PMID- 22488636 TI - Incidence of propofol injection pain and effect of lidocaine pretreatment during upper gastrointestinal endoscopy. PMID- 22488635 TI - Effect of the expression of matrix metalloproteases and their tissue inhibitors on survival of patients with resectable colorectal cancer. AB - BACKGROUND: Matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs) are of crucial importance in the degradation of the stromal connective tissue and basement membrane components. Study of the behavior of these components might help to predict the aggressiveness of tumors. AIMS: To evaluate the expression and clinical relevance of MMPs and TIMPs for patients with resectable colorectal carcinoma. METHODS: An immunohistochemical study was performed using tissue arrays and specific antibodies against MMPs-1, 2, 7, 9, 11, 13, and 14, and TIMPs 1, 2 and 3. Determinations were performed in cancer specimens from 104 patients with resectable colorectal cancer. The minimum period of follow-up was 12.5 years for patients without recurrence. To identify specific groups of tumors with distinct expression profiles, the data were analyzed by unsupervised hierarchical cluster analysis. RESULTS: Expression of MMP-11 by fibroblasts and MMP-13 by tumor cells were associated with poor prognosis. The dendrogram revealed first order division of tumors into two distinct MMP/TIMP molecular profiles, designated group 1 (n = 50) and group 2 (n = 54). Group 2 was characterized by significantly higher expression of MMP-1, 11, and 13, and TIMP-3. CONCLUSION: Our results emphasize the prognostic value of MMP-11 and 13 expression in colorectal cancer. PMID- 22488637 TI - Autobiographical memory in mild cognitive impairment and Alzheimer's disease: a comparison between the Levine and Kopelman interview methodologies. AB - Previous studies have produced inconsistent results concerning the two components of autobiographical memory--personal semantic memory and episodic memory. Results in subjects with mild cognitive impairment (MCI) and dementia of Alzheimer's type (DAT) have varied concerning the existence of a temporal gradient in retrograde amnesia. These results have important theoretical implications regarding multiple trace theory versus standard consolidation models of long-term memory (LTM). We investigated whether this variability arises from differences in the methods used in assessing autobiographical memory. We examined patterns of memory impairment in 20 healthy elderly controls, 20 MCI subjects, and 10 DAT subjects using the Autobiographical Memory Interview (AMI) of Kopelman and the Autobiographical Interview (AI) of Levine. Both the AMI and AI were modified to allow for the test scores to be derived from a single interview without fatiguing the subjects. On the AMI, DAT subjects were significantly impaired on both components of autobiographical memory--episodic memory and personal semantics--with episodic memory showing a significant though gentle temporal gradient sparing childhood memories. Using the AI test, subjects with DAT showed impaired recall of episodic details (but not personal semantics), again with a gentle temporal gradient. Differences between the two interview methods (fewer epochs in the AMI; fewer memories per epoch in the AI) were found to have a significant impact on the pattern of findings; fewer epochs in the AMI brought out the temporal gradient, and fewer memories per epoch (in the AI) diminished it. These data show the importance of technical details of the different tests in favouring one versus another LTM theory. The data are not purely compatible with either theory. PMID- 22488638 TI - The elusive tetrasulfate anion [S4O13](2-). AB - Sulfates united: the unique tetrasulfate S(4)O(13)(2-) anion was observed in the structure of (NO(2))(2)[S(4)O(13)] that forms in the reaction of N(2)O(5) with SO(3). Theoretical investigations show that the anion is a stable member of the polysulfate series [S(n)O(3n+1)](2-), which was investigated up to n=11. PMID- 22488639 TI - Enhanced lithographic imaging layer meets semiconductor manufacturing specification a decade early. PMID- 22488640 TI - Exploring the essential collective dynamics of interacting proteins: application to prion protein dimers. AB - Essential collective dynamics is a promising and robust approach for analysing the slow motions of macromolecules from short molecular dynamics trajectories. In this study, an extension of the method to treat a collection of interacting protein molecules is presented. The extension is applied to investigate the effects of dimerization on the collective dynamics of ovine prion protein molecules in two different arrangements. Examination of the structural plasticity shows that aggregation has a restricting effect on the local mobility of the prion protein molecules in the interfacial regions. Domain motions of the two dimeric ovine prion protein conformations are distinctly different and can be related to interatomic correlations at the interface. Correlated motions are among the slow collective modes extensively analysed by considering both main chain and side-chain atoms. Correlation maps reveal the existence of a vast network of dynamically correlated side groups, which extends beyond individual subunits via interfacial interconnections. The network is formed by a core of hydrophobic side chains surrounded by hydrophilic groups at the periphery. The relevance of these findings are discussed in the context of mutations associated with prion diseases. The binding free energy of the dimeric conformations is evaluated to probe their thermodynamic stability. The descriptions afforded by the analysis of the essential collective dynamics of the prion dimers are consistent with their binding free energies. The agreement validates the extension of the methodology and provides a means of interpreting the collective dynamics in terms of the thermodynamic stability of ovine prion proteins. PMID- 22488641 TI - Association between congenital defects in papillary outgrowth and functional obstruction in Crim1 mutant mice. AB - Crim1 hypomorphic (Crim1(KST264/KST264)) mice display progressive renal disease characterized by glomerular defects, leaky peritubular vasculature, and progressive interstitial fibrosis. Here we show that 27% of these mice also present with hydronephrosis, suggesting obstructive nephropathy. Dynamic magnetic resonance imaging using Magnevist showed fast development of hypo-intense signal in the kidneys of Crim1(KST264/KST264) mice, suggesting pooling of filtrate within the renal parenchyma. Rhodamine dextran (10 kDa) clearance was also delayed in Crim1(KST264/KST264) mice. Pyeloureteric peristalsis, while present, was less co-ordinated in Crim1(KST264/KST264) mice. However, isolated renal pelvis preparations suggest normal pelvic smooth muscle contractile responses. An analysis of maturation during the immediate postnatal period [postnatal day (P) 0 15] revealed defects in papillary extension in Crim1({KST264/KST264) mice. While Crim1 expression is weak in pelvic smooth muscle, strong expression is seen in the interstitium and loops of Henle of the extending papilla, commencing at the tip of the P1 papilla and disseminating throughout the papilla by P15. These results, as well as implicating Crim1 in papillary extension and pelvic smooth muscle contractility, highlight the previously unrecognized association between defects in papillary development and progression to chronic kidney disease later in life. PMID- 22488642 TI - Preparation of CO2/N2-triggered reversibly coagulatable and redispersible polyacrylate latexes by emulsion polymerization using a polymeric surfactant. AB - We report here a novel approach for making reversibly coagulatable and redispersible polyacrylate latexes by emulsion (co)polymerization of methyl methacrylate (MMA) using a polymeric surfactant, poly(2-(dimethylamino)ethyl methacrylate)(10) -block-poly(methyl methacrylate)(14) . The surfactant was protonated with HCl prior to use. The resulted PMMA latexes were readily coagulated with trace amount of caustic soda. The coagulated latex particles, after washing with deionized water, could be redispersed into fresh water to form stable latexes again by CO(2) bubbling with ultrasonication. The recovered latexes could then be coagulated by N(2) bubbling with gentle heating. These coagulation and redispersion processes were repeatable by the CO(2) /N(2) bubbling. PMID- 22488643 TI - Diabetes: On trial--bariatric surgery for treatment of type 2 diabetes mellitus. PMID- 22488645 TI - Paediatrics: Kidney disease in youth-onset type 2 diabetes mellitus. PMID- 22488644 TI - Cardiovascular risk in double diabetes mellitus--when two worlds collide. AB - Historically, clinical management of patients with type 1 diabetes mellitus (T1DM) has been focused on glycaemic control, which is sometimes achieved at the expense of weight gain on intensive insulin regimes. Although HbA(1c) level is an important contributor to increased macrovascular risk, several prospective studies have concluded that factors related to obesity, metabolic syndrome and insulin resistance are more important than HbA(1c) for the prediction of cardiovascular risk, especially for coronary heart disease events. 'Double diabetes mellitus' describes a combination of T1DM with characteristics associated with type 2 diabetes mellitus, including central adiposity and exacerbation of insulin resistance. In lean patients with T1DM, portal insulinopaenia might actually confer cardioprotective effects via changes in hepatic lipid profiles (mainly increased HDL cholesterol levels) and a reduction in hepatic steatosis. In patients with double diabetes mellitus, this situation is reversed and atherothrombotic pathophysiology is potentially accelerated by the combination of chronic hyperglycaemia and abnormal lipid partitioning. The prevalence of double diabetes mellitus is increasing in parallel with the societal trend of increased adiposity. This Review discusses how to identify patients susceptible to double diabetes mellitus and suggests alterations to their clinical management that might reduce their risk of future premature coronary disease. PMID- 22488646 TI - Preventing diabetes mellitus in developing countries. AB - By the year 2030, >70% of people living with T2DM will reside in developing countries, and primary prevention of T2DM should be an urgent priority for such regions. The disease predominantly affects working-age persons and has a devastating economic impact, compounded by the frequent occurrence and interaction of T2DM with infectious diseases (such as AIDS and tuberculosis). Evidence from landmark T2DM prevention trials indicates that lifestyle modification is more effective, cheaper and safer than medication and provides sustained benefits. Lifestyle modification is, therefore, the most promising approach to T2DM prevention in developing countries; however, programmes adapted to their specific needs are lacking. Low-cost strategies to identify at-risk individuals, followed by the implementation of group-based, inexpensive lifestyle interventions, seem to be the best options for resource-poor countries. However, widespread implementation of T2DM prevention in developing countries will require coordinated efforts throughout society, along with comprehensive government policies and novel funding sources. PMID- 22488647 TI - Diabetes: Extended genetic testing improves MODY diagnosis. PMID- 22488649 TI - Ruthenium-catalyzed functionalization of pyrroles and indoles with propargyl alcohols. AB - Several ruthenium-catalyzed atom-economic transformations of propargyl alcohols with pyrroles or indoles leading to alkylated, propargylated, or annulated heteroaromatics are reported. The mechanistically distinct reactions are catalyzed by a single ruthenium(0) complex containing a redox-coupled dienone ligand. The mode of activation regarding the propargyl alcohols determines the reaction pathway and depends on the alcohols' substitution pattern. Secondary substrates form alkenyl complexes by a 1,2-hydrogen shift, whereas the transformation of tertiary substrates involves allenylidene intermediates. 1 Vinyl propargyl alcohols are converted by a cascade allylation/cyclization sequence. The environmentally benign processes are of broad scope and allow the selective synthesis of highly functionalized pyrroles and indoles generating water as the only waste product. PMID- 22488648 TI - Ras-induced melanoma transformation is associated with the proteasomal degradation of the transcriptional repressor ICER. AB - Activation of the mitogen-activated protein kinase (MAPK) pathway targets the putative tumor suppressor protein inducible cAMP early repressor (ICER) to ubiquitin-mediated proteasomal degradation [Yehia et al. JBC 2001; 276: 35272 35279]. We demonstrate that ICER proteasomal degradation is implicated in Ras/MAPK-mediated melanoma tumorigenesis. In a system using Tyr/Tet-Ras INK4a-/- transgenic mice and melanoma cells in culture termed R545 cells isolated from Tyr/Tet-Ras INK4a-/- mice [Chin et al. Nature 1999; 400: 468-472], melanoma genesis and melanoma maintenance is strictly dependent upon expression of H RasV12G. We found that ICER protein was not expressed during melanoma genesis but was strongly expressed in regressing melanomas. Similarly in R545 cells, ICER protein expression was negatively regulated by H-RasV12G. The expression of ICER mRNA was not affected by H-RasV12G expression, suggesting that ICER regulation was post-translational. Indeed, pharmacological inhibition of Ras activity or the proteasome abolished the degradation of ICER caused by H-RasV12G expression indicating that RAS oncogene regulates the expression of ICER protein by targeting ICER to proteasomal degradation. By engineering clones of R545 melanoma cells stably transfected with ICER we were able to determine the prerequisite for Ras-induced tumorigenesis. The reconstitution of physiological levels of ICER showed a significant decrease in cell growth, as well as inhibition of anchorage independent cell growth and tumorigenicity in nude mice. ICER was found to efficiently repress the expression of cyclin D1 in R545 cells due to the binding of ICER to the CRE in the cyclin D1 promoter. Taken together, we postulate that ICER protein might be targeted to degradation in human tumors where Ras is mutated. PMID- 22488650 TI - Intensified therapy followed by autologous stem-cell transplantation (ASCT) versus conventional therapy as first-line treatment of follicular lymphoma: a meta-analysis. AB - There are two different international standards for the treatment of follicular lymphoma (FL): intensified therapy followed by autologous stem-cell transplantation (ASCT) and conventional therapy in the first-line setting. However, their role remains unclear. Our aim was to define the treatment effect of intensified therapy followed by ASCT compared with conventional therapy as first-line treatment of patients with FL in terms of overall survival (OS) and event-free survival (EFS). We searched for randomised controlled trials in Medline, Embase, the Cochrane controlled trials register and the Science Citation Index (1985 to June 2011). Effect measures used were hazard ratios (HR) for OS, EFS and secondary tumour rate. Two independent review authors extracted data and assessed quality of trials. Four trials were identified, covering a total of 941 subjects. The random-effects summary HR by comparing the treatment effect on OS between intensified and conventional therapy was 0.95 [0.70, 1.30] (p = 0.75), indicating that no additional survival benefit was derived from the intensified therapy followed by ASCT. A significant benefit of intensified therapy followed by ASCT as first-line treatment was detected in terms of EFS: the random-effects summary HR (intensified versus conventional therapy) was 0.59 [0.44, 0.79] (p < 0.001). This meta-analysis showed that despite its superior EFS, intensified therapy followed by ASCT does not improve the OS compared with conventional therapy. PMID- 22488651 TI - A three-prong strategy to develop functional food using protein isolates recovered from chicken processing by-products with isoelectric solubilization/precipitation. AB - BACKGROUND: Skin-on bone-in chicken drumsticks were processed with isoelectric solubilization/precipitation to recover muscle proteins. The drumsticks were used as a model for dark chicken meat processing by-products. The main objective of this study was conversion of dark chicken meat processing by-products to restructured functional food product. An attempt was made to develop functional food product that would resemble respective product made from boneless skinless chicken breast meat. A three-prong strategy to address diet-driven cardiovascular disease (CVD)with a functional food was used in this study. The strategy included addition of three ingredients with well-documented cardiovascular benefits: (i) omega-3 polyunsaturated fatty acid-rich oil (flaxseed-algae, 9:1); (ii) soluble fiber; and (iii) salt substitute. Titanium dioxide, potato starch, polyphosphate, and transglutaminase were also added. The batters were formulated and cooked resulting in heat-set gels. RESULTS: Color (L*a*b*), texture (torsion test, Kramer shear test, and texture profile analysis), thermal denaturation (differential scanning calorimetry), and gelation (dynamic rheology) of chicken drumstick gels and chicken breast gels were determined and compared. Chicken drumstick gels generally had comparable color and texture properties to the gels made from chicken breast meat. The endothermic transition (thermal denaturation) of myosin was more pronounced and gelation properties were better for the drumstick gels. CONCLUSION: This study demonstrated a feasibility to develop functional food made of muscle proteins recovered with isoelectric solubilization/precipitation from low-value dark chicken meat processing by products. The functional food developed in this study was enriched with CVD beneficial nutrients and had comparable instrumental quality attributes to respective products made of chicken breast meat. Although the results of this study point towards the potential for a novel, marketable functional food product, sensory tests and storage stability study are recommended. PMID- 22488652 TI - Comprehensive review of the diagnosis and treatment of biliary tract cancer 2012. Part I: diagnosis-clinical staging and pathology. AB - Biliary tract cancers (gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma, and selected periampullary cancers) accounted for 12,760 new cases of cancer in the USA in 2010. These tumors have a dismal prognosis with most patients presenting with advanced disease. Early, accurate diagnosis is essential, both for potential cure where possible and for optimal palliative therapy in all others. This review examines the currently available and emerging technologies for diagnosis and treatment of this group of diseases. PMID- 22488655 TI - Endocrine disruption due to estrogens derived from humans predicted to be low in the majority of U.S. surface waters. AB - In an effort to assess the combined risk estrone (E1), 17beta-estradiol (E2), 17alpha-ethinyl estradiol (EE2), and estriol (E3) pose to aquatic wildlife across United States watersheds, two sets of predicted-no-effect concentrations (PNECs) for significant reproductive effects in fish were compared to predicted environmental concentrations (PECs). One set of PNECs was developed for evaluation of effects following long-term exposures. A second set was derived for short-term exposures. Both sets of PNECs are expressed as a 17beta-estradiol equivalent (E2-eq), with 2 and 5 ng/L being considered the most likely levels above which fish reproduction may be harmed following long-term and short-term exposures, respectively. A geographic information system-based water quality model, Pharmaceutical Assessment and Transport Evaluation (PhATETM), was used to compare these PNECs to mean and low flow concentrations of the steroid estrogens across 12 U.S. watersheds. These watersheds represent approximately 19% of the surface area of the 48 North American states, contain 40 million people, and include over 44,000 kilometers of rivers. This analysis determined that only 0.8% of the segments (less than 1.1% of kilometers) of these watersheds would have a mean flow E2-eq concentration exceeding the long-term PNEC of 2.0 ng/L; only 0.5% of the segments (less than 0.8% of kilometers) would have a critical low flow E2 eq exceeding the short-term PNEC of 5 ng/L. Those few river segments where the PNECs were exceeded were effluent dominated, being either headwater streams with a publicly owned treatment works (POTW), or flowing through a highly urbanized environment with one or several POTWs. These results suggest that aquatic species in most U.S. surface waters are not at risk from steroid estrogens that may be present as a result of human releases. PMID- 22488653 TI - The basic helix-loop-helix transcription factor, heart and neural crest derivatives expressed transcript 2, marks hepatic stellate cells in zebrafish: analysis of stellate cell entry into the developing liver. AB - Hepatic stellate cells (HSCs) are liver-specific mesenchymal cells that play vital roles in liver development and injury. Our knowledge of HSC biology is limited by the paucity of in vivo data. HSCs and sinusoidal endothelial cells (SECs) reside in close proximity, and interactions between these two cell types are potentially critical for their development and function. Here, we introduce a transgenic zebrafish line, Tg(hand2:EGFP), that labels HSCs. We find that zebrafish HSCs share many similarities with their mammalian counterparts, including morphology, location, lipid storage, gene-expression profile, and increased proliferation and matrix production, in response to an acute hepatic insult. Using the Tg(hand2:EGFP) line, we conducted time-course analyses during development to reveal that HSCs invade the liver after SECs do. However, HSCs still enter the liver in mutants that lack most endothelial cells, including SECs, indicating that SECs are not required for HSC differentiation or their entry into the liver. In the absence of SECs, HSCs become abnormally associated with hepatic biliary cells, suggesting that SECs influence HSC localization during liver development. We analyzed factors that regulate HSC development and show that inhibition of vascular endothelial growth factor signaling significantly reduces the number of HSCs that enter the liver. We also performed a pilot chemical screen and identified two compounds that affect HSC numbers during development. CONCLUSION: Our work provides the first comprehensive description of HSC development in zebrafish and reveals the requirement of SECs in HSC localization. The Tg(hand2:EGFP) line represents a unique tool for in vivo analysis and molecular dissection of HSC behavior. PMID- 22488656 TI - The growing array of innate inflammatory ignition switches in osteoarthritis. PMID- 22488657 TI - Prognostic factors in patients with node-negative gastric cancer: a single center experience from China. AB - BACKGROUND AND OBJECTIVES: Lymph node metastasis was the most important prognostic factor in gastric cancer. Patients with node-negative gastric cancer presented better survival. However, some of them would die of the disease. The aim of this study was to evaluate the prognostic factors of patients with node negative gastric cancer. METHODS: From 1996 to 2007, 4,426 patients had undergone curative D2 gastrectomy for gastric cancer at the Fudan University Shanghai Cancer Center. Patients with node-negative gastric cancer who underwent curative D2 gastrectomy with more than 15 lymph nodes dissected were selected into this study. The prognostic value of pathological features was investigated. RESULTS: This study included 234 patients with node-negative gastric cancer. The 5-year overall survival in these patients was 85 %. The factors correlating significantly with overall survival on univariate analysis included age (P = 0.016), depth of invasion (P = 0.000), tumor size (P = 0.013), tumor site (P = 0.000), histological grade (P = 0.009), lymphatic tumor emboli (P = 0.014), vascular tumor emboli (P = 0.005), and nervous invasion (P = 0.033). Multivariate analysis showed that lymphatic tumor emboli (hazard ratio (HR) = 7.270), vascular tumor emboli (HR = 3.010), and depth of invasion (HR = 2.735) were defined as independent prognostic factors. CONCLUSION: Among patients with node-negative gastric cancer and higher risk for recurrence, the use of adjuvant therapies should be considered. PMID- 22488658 TI - MR-guided laser-induced thermal therapy (LITT) for recurrent glioblastomas. AB - BACKGROUND AND OBJECTIVE: Laser-induced thermal therapy (LITT), coupled with magnetic resonance thermal imaging (MRTI) guidance, provides a minimally invasive and safe approach to treat brain tumors, especially metastases. We report here our experience using this treatment for recurrent glioblastomas. MATERIALS AND METHODS: Four patients, from 40 to 58 years old, were diagnosed with glioblastoma. After total resection, chemotherapy and radiation therapy, recurrence occurred. As each was ineligible for a second surgery, LITT was proposed as salvage therapy. Under stereotactic guidance, a fiberoptic applicator was inserted within the tumor LITT was performed under continuous MRTI. Real-time feedback control based on MRTI was employed to assess the quality of local tissue destruction and to prevent unwanted damage to nearby structures. RESULTS: The procedure was well tolerated with no peroperative neurological deterioration. In the short-term follow-up, one transient supplementary motor area syndrome, one epileptic seizure, and one cerebrospinal fluid leakage occurred. All were successfully managed. Post-procedure MRI showed no complication, satisfying treatment volume, and a decrease in size of the treated tumor. For all patients, recurrence was observed with a mean/median progression free survival of 37/30 days. Mean/median overall survival after LITT was 10.5/10 months. CONCLUSION: Focal tumor control was performed safely using minimally invasive LITT with real time MRTI control. LITT could be considered as salvage therapy for high-grade recurrent gliomas if a 1-day treatment is considered useful for a few weeks gain in survival. Larger experience will be required to define indications for such infiltrative disease and accurately determine a potentially significant survival gain in good neurological condition associated with this 1-day procedure. PMID- 22488659 TI - Identifying the origin of atmospheric inputs of trace elements in the Prades Mountains (Catalonia) with bryophytes, lichens, and soil monitoring. AB - The biomonitors Hypnum cupressiforme and Xanthoria parietina were used to assess the deposition of trace elements and their possible origin in the Prades Mountains, a protected Mediterranean forest area of NE Spain with several pollution sources nearby. Al, As, Cd, Co, Cu, Cr, Ni, Pb, Sb, Ti, V, and Zn were determined in 16 locations within this protected area. Soil trace element concentrations were also ascertained to calculate enrichment factors (EF) and use them to distinguish airborne from soilborne trace element inputs. In addition, lichen richness was measured to further assess atmospheric pollution. EF demonstrated to be useful not only for the moss but also for the lichen. Cd, Cr, Cu, Ni, and Zn presented values higher than three in both biomonitors. These trace elements were also the main ones emitted by the potential sources of pollutants. The distance between sampling locations and potential pollution sources was correlated with the concentrations of Cu, Sb, and Zn in the moss and with Cr, Ni, and Sb in the lichen. Lichen richness was negatively correlated with lichen Cu, Pb, and V concentrations on dry weight basis. The study reflected the remarkable influence that the pollution sources have on the presence of trace elements and on lichen species community composition in this natural area. The study highlights the value of combining the use of biomonitors, enrichment factors, and lichen diversity for pollution assessment to reach a better overview of both trace elements' impact and the localization of their sources. PMID- 22488660 TI - Spatiotemporal distribution of airborne elements monitored with the moss bags technique in the Greater Thriasion Plain, Attica, Greece. AB - The well-known moss bags technique was applied in the heavily polluted Thriasion Plain region, Attica, Greece, in order to study the spatiotemporal distribution, in the atmosphere, of the following 32 elements: Na, Al, Cl, Ca, Sc, Ti, V, Cr, Mn, Fe, Ni, Co, Zn, As, Se, Br, Sr, Mo, Sb, I, Ba, La, Ce, Sm, Tb, Dy, Yb, Hf, Ta, Hg, Th, and U. The moss bags were constituted of Sphagnum girgensohnii materials. The bags were exposed to ambient air in a network of 12 monitoring stations scattered throughout the monitoring area. In order to explore the temporal variation of the pollutants, four sets of moss bags were exposed for 3, 6, 9, and 12 months. Instrumental neutral activation analysis was used for the determinations of the elements. The data were analyzed using the Pearson correlations, the partial redundancy analysis, and the biplot statistical methods. Some pairs of elements were highly correlated indicating a probable common source of origin. The levels of the measured pollutants were unevenly distributed throughout the area and different pollutants exhibited different spatial patterns. In general, higher loads were observed in the stations close to and within the industrial zone. Most of the measured elements (e.g., Al, Ca, Ni, I, Zn, Cr, and As) exhibited a monotonic accumulation trend over time. Some elements exhibited different dynamics. The elements Mn, Mo, and Hg showed a decreasing trend, probably due to leaching and/or volatilization processes over time. Na and Br initially showed an increasing trend during the winter and early spring periods but decreased drastically during the late warm period. The results further suggest that the moss bags technique would be considered valuable for the majority of elements but should be used with caution in the cases of elements vulnerable to leaching and/or volatilization. It also suggests that the timing and the duration of the exposure of moss materials should be considered in the interpretation of the results. PMID- 22488661 TI - Impacts of seawater intrusion on soil salinity and alkalinity in Bafra Plain, Turkey. AB - This study was carried out to investigate possible seawater intrusion into groundwater along the coastal lines of the Bafra Plain and salinity-alkalinity problems over land areas irrigated with water exposed to seawater intrusion were evaluated. For this purpose, 32 groundwater wells were selected over the plain, water samples were taken from these wells between October 2007 and September 2008, and chemical analyses were performed over these samples. Soil samples were taken from the fields irrigated with this water at 32 different locations at the end of the irrigation season in September 2008 from 0-30, 30-60, 60-90, and 90 120 cm soil depths and textures. EC, pH, Na, Ca, Mg, and K analyses were performed over these samples. Excessive seawater intrusion was observed in some parts of the plain and impacts of seawater intrusion decreased with the distance from the coastal line. It was determined that groundwater quality was significantly affected from seawater intrusion. Salinity and especially alkalinity problems were observed in land areas irrigated with this water and alkalinity increased with the rate of intrusion. PMID- 22488663 TI - Megaesophagus. AB - Megaesophagus is a disorder of the esophagus characterized by diffuse dilation and decreased peristalsis. It is classified into congenital and acquired forms. Gastrointestinal, endocrine, immune-mediated, neuromuscular, paraneoplastic, and toxic disorders have been associated with acquired megaesophagus. Common clinical signs of megaesophagus are regurgitation, weight loss, coughing, and halitosis. Most cases of megaesophagus can be diagnosed using thoracic radiography; however, diagnosing the underlying cause requires a thorough history and additional diagnostics. The treatment, management, and prognosis of megaesophagus vary greatly depending on the underlying cause. PMID- 22488662 TI - Modifications to induction therapy decrease risk of early death in infants with acute lymphoblastic leukemia treated on Children's Oncology Group P9407. AB - BACKGROUND: Infants (<366 days of age) with acute lymphoblastic leukemia (ALL) have a poor prognosis. Most treatment failures occur within 6-9 months of diagnosis, primarily from relapse. PROCEDURE: The Children's Oncology Group P9407 study was designed to test if early intensified treatment would improve outcome for infants with ALL. Due to a significant number of early deaths (< 90 days from enrollment), Induction therapy was amended three times. Cohorts 1 + 2 (n = 68), received identical Induction therapy except for reduced daunorubicin dose in Cohort 2. Cohort 3 (n = 141) received prednisone (40 mg/m(2)/day) instead of dexamethasone (10 mg/m(2)/day) and short infusion daunorubicin (30 minutes) instead of continuous infusion (48 hours), as well as additional supportive care measures throughout therapy. RESULTS: Early deaths occurred in 17/68 (25%) infants in Cohorts 1 + 2 and 8/141 (5.7%) infants in Cohort 3 (P < 0.0001). Among infants <=90 days of age at diagnosis, early death occurred in 10/17 (58.8%) in Cohorts 1 + 2 and 4/27 (14.8%) in Cohort 3 (P = 0.006). Among infants >90 days of age at diagnosis, early death occurred in 7/51 (13.7%) in Cohorts 1 + 2 and 4/114 (3.5%) in Cohort 3 (P = 0.036). Bacterial, viral, and fungal infections were more common in Cohorts 1 + 2 versus Cohort 3. CONCLUSIONS: Early morbidity and mortality for infants with ALL were reduced by substitution of prednisone (40 mg/m(2)/day) for dexamethasone (10 mg/m(2)/day), the delivery of daunorubicin over 30 minutes instead of a continuous infusion for 48 hours, and the provision of more specific supportive care measures. PMID- 22488664 TI - Azoospermia in stallions: determining the cause. AB - Determining the cause of failure to ejaculate sperm can be a diagnostic dilemma. The first diagnostic step is to ascertain whether the stallion is ejaculating. If the stallion appears to ejaculate, but there is azoospermia (absence of sperm in the seminal fluid), testing alkaline phosphatase (ALP) activity in seminal plasma can determine whether testicular and epididymal fluids are present. If ALP activity is low, the possibility of either blockage to sperm outflow in the excurrent duct system or retrograde ejaculation should be pursued diagnostically. If ALP activity is high, the possibility of a testicular defect should be pursued diagnostically. In some cases (notably plugged ampullae or transient, thermally induced testicular degeneration), treatment or the passage of time may restore a stallion's fertility. PMID- 22488665 TI - Case report: Left dorsal displacement of the large colon manifested as increased y-glutamyl transferase activity in a horse. PMID- 22488666 TI - To screen or not to screen: US Preventive Services Task Force's draft guidelines add to prostate cancer screening debate. PMID- 22488667 TI - Two large trials show prostate screening has limited reduction in mortality. PMID- 22488669 TI - A protein-RNA docking benchmark (I): nonredundant cases. AB - We have developed a nonredundant protein-RNA docking benchmark dataset, which is derived from the available bound and unbound structures in the Protein Data Bank involving polypeptide and nucleic acid chains. It consists of nine unbound unbound cases where both the protein and the RNA are available in the free form. The other 36 cases are of unbound-bound type where only the protein is available in the free form. The conformational change upon complex formation is calculated by a distance matrix alignment method, and based on that, complexes are classified into rigid, semi-flexible, and full flexible. Although in the rigid body category, no significant conformational change accompanies complex formation, the fully flexible test cases show large domain movements, RNA base flips, etc. The benchmark covers four major groups of RNA, namely, t-RNA, ribosomal RNA, duplex RNA, and single-stranded RNA. We find that RNA is generally more flexible than the protein in the complexes, and the interface region is as flexible as the molecule as a whole. The structural diversity of the complexes in the benchmark set should provide a common ground for the development and comparison of the protein-RNA docking methods. The benchmark can be freely downloaded from the internet. PMID- 22488668 TI - Optical fiber-based in vivo quantification of growth factor receptors. AB - BACKGROUND: Growth factor receptors such as epidermal growth factor receptor 1 and human epidermal growth receptor 2 (HER2) are overexpressed in certain cancer cells. Antibodies against these receptors (eg. cetuximab and transtuzumab [Herceptin]) have shown therapeutic value in cancer treatment. The existing methods for the quantification of these receptors in tumors involve immunohistochemistry or DNA quantification, both in extracted tissue samples. The goal of the study was to evaluate whether an optical fiber-based technique can be used to quantify the expression of multiple growth factor receptors simultaneously. METHODS: The authors examined HER2 expression using the monoclonal antibody trastuzumab as a targeting ligand to test their system. They conjugated trastuzumab to 2 different Alexa Fluor dyes with different excitation and emission wavelengths. Two of the dye conjugates were subsequently injected intravenously into mice bearing HER2-expressing subcutaneous tumors. An optical fiber was then inserted into the tumor through a 30-gauge needle, and using a single laser beam as the excitation source, the fluorescence emitted by the 2 conjugates was identified and quantified by 2-photon optical fiber fluorescence. RESULTS: The 2 conjugates bound to the HER2-expressing tumor competitively in a receptor-specific fashion, but they failed to bind to a similar cell tumor that did not express HER2. The concentration of the conjugate present in the tumor as determined by 2-photon optical fiber fluorescence was shown to serve as an index of the HER2 expression levels. CONCLUSIONS: These studies offer a minimally invasive technique for the quantification of tumor receptors simultaneously. PMID- 22488670 TI - Enhanced selectivity for the hydrolysis of block copoly(2-oxazoline)s in ethanol water resulting in linear poly(ethylene imine) copolymers. AB - The ability of merging the properties of poly(2-oxazoline)s and poly(ethylene imine) is of high interest for various biomedical applications, including gene delivery, biosensors, and switchable surfaces and nanoparticles. In the present research, a methodology for the controlled and selective hydrolysis of (co)poly(2 oxazoline)s is developed in an ethanol-water solvent mixture, opening the path toward a wide range of block poly(2-oxazoline-co-ethylene imine) (POx-PEI) copolymers with tunable properties. The unexpected influence of the selected ethanol-water binary solvent mixture on the hydrolysis kinetics and selectivity is highlighted in the pursue of well-defined POx-PEI block copolymers. PMID- 22488672 TI - The roles of microRNAs in sarcomas. AB - MicroRNAs are a class of small regulatory RNAs that influence the stabilities and translational efficiencies of target mRNAs. They have been implicated in an increasing number of biological processes, including carcinogenesis. A huge body of literature exists documenting up- or down-regulation of specific microRNAs during carcinogenesis and identifying molecular pathways by which these microRNAs influence every aspect of cancer development, including proliferation, angiogenesis, and metastasis. These studies have provided many insights into basic cancer biology as well as allowing identification of novel biomarkers and potential drug targets. However, the vast bulk of this literature concerns solid epithelial tumours, while sarcomas remain relatively under-studied. The purpose of this article is to review the roles of microRNAs in sarcomas and to highlight microRNAs or related molecular pathways that demonstrate consistent roles within individual or across sarcoma subtypes, with a view to identifying the key regulatory molecules. Further insights into sarcoma biology may be particularly valuable since sarcomas represent a tumour group with a particularly poor prognosis and rather limited treatment options. PMID- 22488671 TI - Ensembles of human MTL neurons "jump back in time" in response to a repeated stimulus. AB - Episodic memory, which depends critically on the integrity of the medial temporal lobe (MTL), has been described as "mental time travel" in which the rememberer "jumps back in time." The neural mechanism underlying this ability remains elusive. Mathematical and computational models of performance in episodic memory tasks provide a specific hypothesis regarding the computation that supports such a jump back in time. The models suggest that a representation of temporal context, a representation that changes gradually over macroscopic periods of time, is the cue for episodic recall. According to these models, a jump back in time corresponds to a stimulus recovering a prior state of temporal context. In vivo single-neuron recordings were taken from the human MTL while epilepsy patients distinguished novel from repeated images in a continuous recognition memory task. The firing pattern of the ensemble of MTL neurons showed robust temporal autocorrelation over macroscopic periods of time during performance of the memory task. The gradually-changing part of the ensemble state was causally affected by the visual stimulus being presented. Critically, repetition of a stimulus caused the ensemble to elicit a pattern of activity that resembled the pattern of activity present before the initial presentation of the stimulus. These findings confirm a direct prediction of this class of temporal context models and may be a signature of the mechanism that underlies the experience of episodic memory as mental time travel. PMID- 22488675 TI - Electronic effects of linker substitution on Lewis acid catalysis with metal organic frameworks. AB - Functionalized linkers can greatly increase the activity of metal-organic framework (MOF) catalysts with coordinatively unsaturated sites. A clear linear free-energy relationship (LFER) was found between Hammett sigma(m) values of the linker substituents X and the rate k(X) of a carbonyl-ene reaction. This is the first LFER ever observed for MOF catalysts. A 56-fold increase in rate was found when the substituent is a nitro group. PMID- 22488674 TI - Two by-products of the olive oil extraction industry as oleic acid supplement source for Iberian pigs: effect on the meat's chemical composition and induced lipoperoxidation. AB - BACKGROUND: The objective of the present study was to evaluate the effect of two by-products of the olive oil extraction industry-olive soapstocks and olive pomace oil-as added fat sources into feed concentrates, in two different rearing systems (free-range complemented with concentrates and intensive rearing with concentrates) on the chemical composition and oxidative stability of Iberian pig meat. RESULTS: No differences in the chemical composition, colour and fatty acid composition of gluteobiceps m. were found due to added fat source. However, the feeding system had a significant effect on protein (P < 0.05), gamma-tocopherol (P < 0.05), colour (P < 0.01) and fatty acid composition of gluteobiceps m. Neither added fat source nor the feeding system had an effect on the malondialdehyde content. CONCLUSION: The addition of olive soapstock or olive pomace oil as fat sources into concentrates did not influence meat composition or fatty acid profile. However, there are differences in the fatty acid composition of meat from Iberian pigs as a result of the production system used. PMID- 22488673 TI - Splice site, frameshift, and chimeric GFAP mutations in Alexander disease. AB - Alexander disease (AxD) is a usually fatal astrogliopathy primarily caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP), an intermediate filament protein expressed in astrocytes. We describe three patients with unique characteristics, and whose mutations have implications for AxD diagnosis and studies of intermediate filaments. Patient 1 is the first reported case with a noncoding mutation. The patient has a splice site change producing an in-frame deletion of exon 4 in about 10% of the transcripts. Patient 2 has an insertion and deletion at the extreme end of the coding region, resulting in a short frameshift. In addition, the mutation was found in buccal DNA but not in blood DNA, making this patient the first reported chimera. Patient 3 has a single base deletion near the C-terminal end of the protein, producing a short frameshift. These findings recommend inclusion of intronic splice site regions in genetic testing for AxD, indicate that alteration of only a small fraction of GFAP can produce disease, and provide caution against tagging intermediate filaments at their C-terminal end for cell biological investigations. PMID- 22488676 TI - Controllable drug release of electrospun thermoresponsive poly(N isopropylacrylamide)/poly(2-acrylamido-2- methylpropanesulfonic acid) nanofibers. AB - Electrospinning micro- and nanofibers are being increasingly investigated for drug delivery. The components and their stimuli-responsive properties of fibers are important factors influencing the drug release behavior. The aim of this study is to fabricate thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm)/poly(2-acrylamido-2-methylpropanesulfonic acid) (PAMPS) nanofibers by single-spinneret electrospinning technique. The electrospun nanofibers are used as a drug carrier by cospinning with nifedipine (NIF), and the release behaviors of NIF from the thermoresponsive nanofibers can be controlled by the response of nanofibers with temperature. The morphology of the nanofibers and its composites with NIF was determined by scanning electron microscopy (SEM). The hydrogen bond interactions between PNIPAAm/PAMPS and the water-insoluble drug of NIF were introduced and confirmed by Fourier-transform infrared spectroscopy and energy dispersive spectrometer. The thermoresponsive properties of nanofibers were investigated by contact angle (CA) measurements. The release behaviors of NIF from the PNIPAAm/PAMPS nanofibers were observed by SEM and demonstrated by UV-vis spectroscopy. It was found that uniform fibers of NIF and PNIPAAm/PAMPS could be fabricated without particles on the surface. The release of NIF from nanofibers could be controlled effectively by the changes of hydrogen bonds between PNIPAAm/PAMPS and NIF, and by adjusting temperatures of the thermoresponsive nanofibers. PMID- 22488677 TI - Congenital and childhood myeloproliferative disorders with eosinophilia responsive to imatinib. AB - Eosinophilia is seen in several myeloproliferative disorders (MPD). A subset of MPD involves the platelet-derived growth factor receptor beta (PDGFRB) gene. Imatinib mesylate has been efficacious in treating some of these MPDs. Here we describe two patients with MPD with eosinophilia and PDGFRB rearrangements, one of which was congenital. Both patients were treated with single agent imatinib and continue to be in clinical, hematologic, and cytogenetic remission despite weaning doses. No definite guidelines currently exist regarding the exact dosing and duration of imatinib therapy for these patients. PMID- 22488678 TI - The prognostic significance of lymphopenia in peripheral T-cell and natural killer/T-cell lymphomas: a study of 826 cases from the International Peripheral T cell Lymphoma Project. AB - Lymphopenia is a marker of inferior survival in patients with various malignancies. However, the prognostic significance of lymphopenia in peripheral T cell lymphoma (PTCL) is unclear. We analyzed the prognostic significance of lymphopenia in 826 patients with different types of PTCL and natural killer/T cell lymphoma (NKTCL) from the International Peripheral T-cell Lymphoma Project. Lymphopenia was defined as an absolute lymphocyte count of less than 1,000 cells per microliter. The overall frequency of lymphopenia was 35.3%, ranging from 21.1% in ALK(+) anaplastic large cell lymphoma (ALCL) to 47.5% in angioimmunoblastic T-cell lymphoma (AITL). Lymphopenia was independently associated with an inferior overall survival (OS) in patients with the lymphoma type of adult T-cell leukemia/lymphoma (ATLL), with a 2-year OS of 15% versus 40% for those without lymphopenia (P < 0.001). Lymphopenia was also an adverse predictor of survival in PTCL, not otherwise specified, but was associated with other unfavorable prognostic factors. A trend toward inferior survival for lymphopenic patients was also observed in AITL, ALK(-) ALCL and extranasal NKTCL lymphoma, whereas no difference in survival was found in nasal NKTCL, ALK(+) ALCL, or enteropathy-associated T-cell lymphoma. In this study, lymphopenia was identified as a new adverse prognostic factor in the lymphoma type of ATLL. PMID- 22488679 TI - Luminescent blooming of dendronic carbon nanotubes through ion-pairing interactions with an Eu(III) complex. AB - A multiwalled carbon nanotube (MWCNT) scaffold was covalently functionalized with a second-generation polyamidoamine (PAMAM) dendron, presenting four terminal amino groups per grafted aryl moiety. These reactive functions were alkylated to obtain a positively charged polycationic dendron/carbon nanotube system (d MWCNTs?Cl), which eventually underwent anion exchange reaction with a negatively charged and highly luminescent Eu(III) complex ([EuL(4)]?NEt(4), in which L = (2 naphtoyltrifluoroacetonate)). This process afforded the target material d MWCNTs?[EuL(4)], in which MWCNTs are combined with red-emitting Eu(III) centers through electrostatic interactions with the dendronic branches. Characterization of the novel MWCNT materials was accomplished by means of TGA and TEM, whereas d MWCNTs?Cl and d-MWCNTs? [EuL(4)] further underwent XPS, SEM and Raman analyses. These studies demonstrate the integrity of the luminescent [EuL(4)](-) center in the luminescent hybrid, the massive load of the cationic binding sites, and the virtually complete anion-exchange into the final hybrid material. The occurrence of the ion-pairing interaction with MWCNTs was unambiguously demonstrated through DOSY NMR diffusion studies. Photophysical investigations show that MWCNTs?[EuL(4)] is a highly soluble and brightly luminescent red hybrid material in which MWCNTs act as photochemically inert scaffolds with negligible UV/Vis absorption, compared with the grafted Eu complex, and with no quenching activity. The high dispersibility of MWCNTs?[EuL(4)] in a polymer matrix makes it a promising luminophore for applications in material science. PMID- 22488680 TI - Predicted-no-effect concentrations for the steroid estrogens estrone, 17beta estradiol, estriol, and 17alpha-ethinylestradiol. AB - The authors derive predicted-no-effect concentrations (PNECs) for the steroid estrogens (estrone [E1], 17beta-estradiol [E2], estriol [E3], and 17alpha ethinylestradiol [EE2]) appropriate for use in risk assessment of aquatic organisms. In a previous study, they developed a PNEC of 0.35 ng/L for EE2 from a species sensitivity distribution (SSD) based on all available chronic aquatic toxicity data. The present study updates that PNEC using recently published data to derive a PNEC of 0.1 ng/L for EE2. For E2, fish were the most sensitive taxa, and chronic reproductive effects were the most sensitive endpoint. Using the SSD methodology, we derived a PNEC of 2 ng/L for E2. Insufficient data were available to construct an SSD for E1 or E3. Therefore, the authors used in vivo vitellogenin (VTG) induction studies to determine the relative potency of the steroid estrogens to induce VTG. Based on the relative differences between in vivo VTG induction, they derive PNECs of 6 and 60 ng/L for E1 and E3, respectively. Thus, for long-term exposures to steroid estrogens in surface water (i.e., >60 d), the PNECs are 6, 2, 60, and 0.1 ng/L for E1, E2, E3, and EE2, respectively. Higher PNECs are recommended for short-term (i.e., a few days or weeks) exposures. PMID- 22488681 TI - Laparoscopic adjustable gastric banding: a 10-year single-centre experience of 575 cases with weight loss following surgery. AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is one of the commonest bariatric procedures in the UK. This study reports our experience with this procedure over the last 10 years. METHODS: A prospectively maintained database of all the patients undergoing LAGB at our centre between March 2000 and August 2010 was analysed. RESULTS: Five hundred seventy-five patients underwent LAGB at our centre. There was no mortality in this series. Early (30-day) morbidity rate was 2.2 %. Late complications (20 %) comprised: 78 repositioning of the inflation port in 65 patients, repositioning of band in 24 patients (4 %), removal of band in 20 patients (3.4 %), conversion to bypass in 41 patients (7 %), diagnostic laparoscopy in 1 patient and subtotal gastrectomy in 1 patient. Median follow-up was 29 months. The median of percentage of weight loss (%WL) and excess body weight loss (EBWL) was 18.3 and 40 %, respectively, at >= 5 years post-LAGB. Patients with body mass index (BMI) over 50 kg/m(2) were compared to those with BMI <= 50 kg/m(2). No significant difference was noted in the weight loss between both of these groups. No significant difference was noted with regards to weight loss between patients <60 and >60 years of age. CONCLUSIONS: In this cohort of patients, %WL and EBWL were 18.3 and 40 % >= 5 years after LAGB, respectively, and early and late complication rates were 2.2 and 20 %, respectively. Majority of late complications were in the first 100 patients. Multifactorial causes included the surgical learning curve and patient selection process. PMID- 22488682 TI - Psoriasis following bariatric surgery: clinical evolution and impact on quality of life on 10 patients. AB - Psoriasis is a chronic systemic disease with important skin manifestations, affecting 2 % of the population. It is more frequent and severe in obese patients, and both have been associated with a higher cardiovascular risk. Recent studies suggest that weight loss may improve psoriasis and metabolic comorbidities in obese patients. We reviewed our prospective electronic database for all patients with psoriasis who underwent bariatric surgery between 2008 and 2011. We assessed surgical complications, weight progression, and psoriasis related outcomes. The Dermatology Life Quality Index was used retrospectively to assess quality of life (QoL) before and after the operation. Ten patients were included; body mass index was 38.8 +/- 5.2 kg/m(2). Pre-surgical treatment for psoriasis was topical (50 %) and systemic (40 %). Eight patients underwent laparoscopic Roux-en-Y gastric bypass and two underwent laparoscopic sleeve gastrectomy. At follow-up, the mean percent excess weight loss 1, 6, and 12 months after surgery was 45 %, 80 %, and 88 %, respectively. Comorbidity resolution was 75 % for diabetes mellitus, 100 % for insulin resistance, and 57 % for hypertension. Related to psoriasis, 70 % of the patients stayed in remission 6 months after surgery and three of the four patients who were previously medicated with systemic drugs discontinued medication. The impact of psoriasis on QoL improved from 14.9 +/- 6.8 before surgery to 5 +/- 6.3 after surgery (p = 0.005). Bariatric surgery for positive metabolic, skin, and quality of life results should be considered as a useful adjuvant therapy for obese patients with psoriasis. PMID- 22488683 TI - Optimizing perioperative care in bariatric surgery patients. AB - Enhanced recovery after surgery (ERAS) programs have been shown to minimise morbidity in other types of surgery, but comparatively less data exist investigating ERAS in bariatric surgery. This article reviews the existing literature to identify interventions which may be included in an ERAS program for bariatric surgery. A narrative literature review was conducted. Search terms included 'bariatric surgery', 'weight loss surgery', 'gastric bypass', 'ERAS', 'enhanced recovery', 'enhanced recovery after surgery', 'fast-track surgery', 'perioperative care', 'postoperative care', 'intraoperative care' and 'preoperative care'. Interventions recovered by the database search, as well as interventions garnered from clinical experience in ERAS, were used as individual search terms. A large volume of evidence exists detailing the role of multiple interventions in perioperative care. However, efficacy and safety for a proportion of these interventions for ERAS in bariatric surgery remain unclear. This review concludes that there is potential to implement ERAS programs in bariatric surgery. PMID- 22488685 TI - Percutaneous retrieval of fractured Bird's Nest IVC filter penetrating into aorta. AB - Inferior vena cava filters can provide lifesaving protections in patients with recurrent venous thromboembolic disease that are not candidates for anticoagulation. They are, however, associated with short- and long-term complications necessitating frequent follow-up. The authors report, in this article, a case of migration of Bird's Nest filter strut into the descending aorta and its percutaneous retrieval by snaring and capture. This case also underscores the trend to use retrievable filters to avoid longer-term complications. PMID- 22488684 TI - Bariatric surgery and the central nervous system. AB - Bariatric procedures are now known to have an effect on hunger as well as on metabolism. The role of central nervous pathways in causing these effects after bariatric surgery is now being elucidated. A brief overview of these pathways has been presented for the sake of bariatric surgeons. A PubMed search was made using various search phrases to retrieve all original articles concerning the effect of bariatric surgery on the neural pathways. The mechanisms regulating the food intake and energy expenditure can be broadly divided into homeostatic and hedonic systems. The effect of bariatric surgery on the homeostatic system in animal models is not clear. A decrease in preference for sweet taste and high calorie foods has been demonstrated in animal models. The effect of bariatric surgery on the hedonic system in humans has been consistent with decreased activation of the hedonic system being demonstrated by functional MRI and decreased preference for intake of high energy foods also being observed post-surgery. The effect of bariatric surgery on dopamine signaling, which is involved in the hedonic system, is however not clear. Functional MRI studies have also demonstrated increased activation of the hypothalamus after surgery. Various studies utilizing questionnaires have demonstrated increased satiety and decreased hunger after bariatric surgery. PMID- 22488686 TI - 12p13 rearrangements: 6 Mb deletion responsible for ID/MCA and reciprocal duplication without clinical responsibility. AB - Congenital balanced reciprocal translocations are one of the most frequent structural chromosomal aberrations in the population. We report a familial translocation t(12;22)(p13.3;pter) responsible for intellectual disabilities and congenital anomalies characterized by FISH and array CGH. Two patients carried a der(12)t(12;22)(p13.3;pter), resulting in a 6 Mb 12pter deletion. Patients presented with intellectual disabilities, pre- and post-natal growth retardation, ponderal development delay, global hypotonia, feeding problems and dysmorphic features. Two relatives presented with the reciprocal 12pter duplication, which had no clinical manifestations associated. For this translocation, we propose a mechanism based on a non-allelic recombination model, in which recombination of direct oriented segmental duplications between non-homologous chromatids leads to the reciprocal translocation. The characterization of this translocation has been critical for the family. Translocation carriers have a risk of 40% of having offspring carrying unbalanced products. 12p13.3 deletion carriers present with a recognizable syndrome and on the contrary, 12p13.3 duplication carriers present without clinical manifestations. Other published cases of 12p13.3 duplication show that this syndrome has a variable phenotype. It is advisable to delineate the duplication size and to discard other genetic aberrations, in order to give an accurate genetic counseling in patients carrying 12pter duplications. PMID- 22488687 TI - Crystal structure of a supercharged variant of the human enteropeptidase light chain. AB - The highly specific serine protease human enteropeptidase light chain cleaves the Asp4Lys recognition sequence and represents an interesting enzyme for biotechnological applications. The human enzyme shows 10 times faster kinetics compared to other animal sources but low solubility under low salt conditions, which hampers protein production and crystallization. Therefore, a supercharged variant (N6D/G21D/G22D/N142D/K210E/C112S) with increased solubility was used for crystallization. The structure (resolution, 1.9 A) displays a typical alpha/beta trypsin-like serine protease-fold. The mutations introduced for protein supercharging generate larger clusters of negative potential on both sites of the active cleft but do not affect the structural integrity of the protein. PMID- 22488690 TI - Low-intensity laser irradiation at 660 nm stimulates cytochrome c oxidase in stressed fibroblast cells. AB - BACKGROUND AND OBJECTIVE: Low-intensity laser irradiation (LILI) has been used to modulate a variety of biological processes, including diabetic wound healing. The mechanism of action is thought to exist primarily with the mitochondria. This study aimed to determine the effect of irradiation on normal, diabetic, and ischemic mitochondrial electron transport chain (ETC) complexes. MATERIALS AND METHODS: Normal, diabetic and ischemic human skin fibroblast mitochondria were irradiated in vitro at a wavelength of 660 nm and a fluence of either 5 or 15 J/cm(2). Non-irradiated mitochondria served as controls. Enzyme activities of mitochondrial complexes I, II, III, and IV were determined immediately post irradiation. Normal, diabetic, and ischemic cells were irradiated and adenosine triphosphate (ATP) and active mitochondria were determined by luminescence and fluorescent microscopy, respectively. RESULTS: Irradiated diabetic mitochondria at a fluence of 15 J/cm(2) showed a significant decrease in complex III activity (P < 0.05). Normal (P < 0.01) and diabetic (P < 0.05) mitochondria irradiated at either 5 or 15 J/cm(2) showed a significant increase in complex IV activity. ATP results showed a significant increase in irradiated normal cells (5 J/cm(2); P < 0.05) and diabetic cells (15 J/cm(2); P < 0.01). There was a higher accumulation of active mitochondria in irradiated cells than non-irradiated cells. CONCLUSION: Irradiation at 660 nm has the ability to influence mitochondrial enzyme activity, in particular cytochrome c oxidase. This leads to increased mitochondrial activity and ATP synthesis. PMID- 22488688 TI - Osteopontin is a novel downstream target of SOX9 with diagnostic implications for progression of liver fibrosis in humans. AB - Osteopontin (OPN) is an important component of the extracellular matrix (ECM), which promotes liver fibrosis and has been described as a biomarker for its severity. Previously, we have demonstrated that Sex-determining region Y-box 9 (SOX9) is ectopically expressed during activation of hepatic stellate cells (HSC) when it is responsible for the production of type 1 collagen, which causes scar formation in liver fibrosis. Here, we demonstrate that SOX9 regulates OPN. During normal development and in the mature liver, SOX9 and OPN are coexpressed in the biliary duct. In rodent and human models of fibrosis, both proteins were increased and colocalized to fibrotic regions in vivo and in culture-activated HSCs. SOX9 bound a conserved upstream region of the OPN gene, and abrogation of Sox9 in HSCs significantly decreased OPN production. Hedgehog (Hh) signaling has previously been shown to regulate OPN expression directly by glioblastoma (GLI) 1. Our data indicate that in models of liver fibrosis, Hh signaling more likely acts through SOX9 to modulate OPN. In contrast to Gli2 and Gli3, Gli1 is sparse in HSCs and is not increased upon activation. Furthermore, reduction of GLI2, but not GLI3, decreased the expression of both SOX9 and OPN, whereas overexpressing SOX9 or constitutively active GLI2 could rescue the antagonistic effects of cyclopamine on OPN expression. CONCLUSION: These data reinforce SOX9, downstream of Hh signaling, as a core factor mediating the expression of ECM components involved in liver fibrosis. Understanding the role and regulation of SOX9 during liver fibrosis will provide insight into its potential modulation as an antifibrotic therapy or as a means of identifying potential ECM targets, similar to OPN, as biomarkers of fibrosis. PMID- 22488691 TI - Miniaturized Lab-on-a-Disc (miniLOAD). AB - A miniaturized centrifugal microfluidic platform for lab-on-a-chip applications is presented. Unlike its macroscopic Lab-on-a-CD counterpart, the miniature Lab on-a-Disc (miniLOAD) device does not require moving parts to drive rotation of the disc, is inexpensive, disposable, and significantly smaller, comprising a 10 mm-diameter SU-8 disc fabricated through two-step photolithography. The disc is driven to rotate using surface acoustic wave irradiation incident upon a fluid coupling layer from a pair of offset, opposing single-phase unidirectional transducers patterned on a lithium niobate substrate. The irradiation causes azimuthally oriented acoustic streaming with sufficient intensity to rotate the disc at several thousand revolutions per minute. In this first proof-of-concept, the capability of the miniLOAD platform to drive capillary-based valving and mixing in microfluidic structures on a disc similar to much larger Lab-on-a-CD devices is shown. In addition, the ability to concentrate aqueous particle suspensions at radial positions in a channel in the disc dependent on the particles' size is demonstrated. To the best of our knowledge, the miniLOAD concept is the first centrifugal microfluidic platform small enough to be self contained in a handheld device. PMID- 22488692 TI - Prospective evaluation of physical rehabilitation needs in breast cancer survivors: a call to action. PMID- 22488693 TI - A prospective surveillance model for rehabilitation for women with breast cancer. AB - BACKGROUND: The current model of care for individuals with breast cancer focuses on treatment of the disease, followed by ongoing surveillance to detect recurrence. This approach lacks attention to patients' physical and functional well-being. Breast cancer treatment sequelae can lead to physical impairments and functional limitations. Common impairments include pain, fatigue, upper-extremity dysfunction, lymphedema, weakness, joint arthralgia, neuropathy, weight gain, cardiovascular effects, and osteoporosis. Evidence supports prospective surveillance for early identification and treatment as a means to prevent or mitigate many of these concerns. This article proposes a prospective surveillance model for physical rehabilitation and exercise that can be integrated with disease treatment to create a more comprehensive approach to survivorship health care. The goals of the model are to promote surveillance for common physical impairments and functional limitations associated with breast cancer treatment; to provide education to facilitate early identification of impairments; to introduce rehabilitation and exercise intervention when physical impairments are identified; and to promote and support physical activity and exercise behaviors through the trajectory of disease treatment and survivorship. METHODS: The model is the result of a multidisciplinary meeting of research and clinical experts in breast cancer survivorship and representatives of relevant professional and advocacy organizations. RESULTS/CONCLUSIONS: The proposed model identifies time points during breast cancer care for assessment of and education about physical impairments. Ultimately, implementation of the model may influence incidence and severity of breast cancer treatment-related physical impairments. As such, the model seeks to optimize function during and after treatment and positively influence a growing survivorship community. PMID- 22488694 TI - Integrating a prospective surveillance model for rehabilitation into breast cancer survivorship care. AB - At some point during or after treatment, breast cancer may be considered a chronic illness, presenting many choices for managing the disease, its adverse treatment-related effects, other medical comorbidities as well as the biobehavioral burden of having a life-threatening disease, even for individuals with potentially curable breast cancer. Health care models, such as the chronic care model, the medical home, and the shared care model, provide a context for building survivorship health care models. Goals and characteristics of recently proposed shared care models for cancer survivorship health care delivery closely align with the goals and concepts of the prospective surveillance model (PSM) proposed elsewhere in this supplement to the journal Cancer. Given these similarities, along with the growth and expansion of survivorship care models and impending mandates for delivery, there is merit to considering how implementation of the PSM can be integrated with models of survivorship care delivery. The PSM model will likely face many similar challenges and barriers that have impeded widespread dissemination of other survivorship models of care. There exist opportunities to integrate lessons learned as well as to align efforts to achieve greater impact on the shared goal of improving health outcomes for breast cancer survivors. PMID- 22488695 TI - Patient perspectives on breast cancer treatment side effects and the prospective surveillance model for physical rehabilitation for women with breast cancer. AB - Women's experience of breast cancer is complex, affecting all aspects of life during and after treatment. Patients' perspectives about common impairments and functional limitations secondary to breast cancer treatment, including upper extremity motion restriction, lymphedema, fatigue, weight gain, pain, and chemotherapy-induced peripheral neuropathy, are addressed. Women often report being uninformed regarding these side effects and surprised that they do not always disappear after treatment, but remain part of their lives. Breast cancer patients express strong, unmet needs for education, information, and intervention for these side effects. Evidence suggests that rehabilitation and exercise are effective in preventing and managing many physical side effects of breast cancer treatment. Nevertheless, few women are referred to rehabilitation during or after treatment, and fewer receive baseline assessments of impairment and function to facilitate early detection of impairment and functional limitations. The prospective surveillance model of rehabilitation will serve the needs of women with breast cancer by providing education and information about treatment side effects, reducing the incidence and burden of side effects through early identification and treatment, and enhancing access to timely rehabilitation. Integration of exercise as a component of the model benefits patients at every phase of survivorship, by addressing individual concerns about exercise during and after treatment and highlighting the important contribution of exercise to overall health and survival. The prospective surveillance model of rehabilitation can meet the evident and often expressed needs of survivors for information, guidance, and intervention--thus addressing, and potentially improving, overall quality of life for individuals diagnosed with and treated for breast cancer. PMID- 22488696 TI - Prevalence of breast cancer treatment sequelae over 6 years of follow-up: the Pulling Through Study. AB - BACKGROUND: There is a need to better describe and understand the prevalence of breast cancer treatment-related adverse effects amenable to physical therapy and rehabilitative exercise. Prior studies have been limited to single issues and lacked long-term follow-up. The Pulling Through Study provides data on prevalence of adverse effects in breast cancer survivors followed over 6 years. METHODS: A population-based sample of Australian women (n = 287) diagnosed with invasive, unilateral breast cancer was followed for a median of 6.6 years and prospectively assessed for treatment-related complications at 6, 12, and 18 months and 6 years after diagnosis. Assessments included postsurgical complications, skin or tissue reaction to radiation therapy, upper-body symptoms, lymphedema, 10% weight gain, fatigue, and upper-quadrant function. The proportion of women with positive indication for each complication and 1 or more complication was estimated using all available data at each time point. Women were only considered to have a specific complication if they reported the highest 2 levels of the Likert scale for self-reported issues. RESULTS: At 6 years after diagnosis, more than 60% of women experienced 1 or more side effects amenable to rehabilitative intervention. The proportion of women experiencing 3 or more side effects decreased throughout follow-up, whereas the proportion experiencing no side effects remained stable around 40% from 12 months to 6 years. Weight gain was the only complication to increase in prevalence over time. CONCLUSIONS: These data support the development of a multidisciplinary prospective surveillance approach for the purposes of managing and treating adverse effects in breast cancer survivors. PMID- 22488697 TI - A prospective model of care for breast cancer rehabilitation: postoperative and postreconstructive issues. AB - Appropriate and timely rehabilitation is vital in the recovery from breast cancer surgeries, including breast conserving surgery, mastectomy, axillary lymph node dissection (ALND), and breast reconstruction. This article describes the incidence, prevalence, risk factors and time course for early postoperative effects and the role of prospective surveillance as a rehabilitation strategy to prevent and mitigate them. The most common early postoperative effects include wound issues such as cellulitis, flap necrosis, abscess, dehiscence, hematoma, and seroma. Appropriate treatment is necessary to avoid delay in wound healing that may increase the risk of long-term morbidity, unduly postpone systemic and radiation therapy, and delay rehabilitation. The presence of upper quarter dysfunction (UQD), defined as restricted upper quarter mobility, pain, lymphedema, and impaired sensation and strength, has been reported in over half of survivors after treatment for breast cancer. Moreover, evidence suggests that survivors who undergo breast reconstruction may be at higher risk of UQD. Ensuring the survivor's optimum functioning in the early postoperative time period is critical in the overall recovery from breast cancer. The formal collection of objective measures along with patient-reported outcome measures is recommended for the early detection of postoperative morbidity. Prospective surveillance, including preoperative assessment and structured surveillance, allows for early identification and timely rehabilitation. Early evidence supports a prospective approach to address and minimize postoperative effects. PMID- 22488698 TI - Upper-body morbidity after breast cancer: incidence and evidence for evaluation, prevention, and management within a prospective surveillance model of care. AB - The purpose of this paper is to review the incidence of upper-body morbidity (arm and breast symptoms, impairments, and lymphedema), methods for diagnosis, and prevention and treatment strategies. It was also the purpose to highlight the evidence base for integration of prospective surveillance for upper-body morbidity within standard clinical care of women with breast cancer. Between 10% and 64% of women report upper-body symptoms between 6 months and 3 years after breast cancer, and approximately 20% develop lymphedema. Symptoms remain common into longer-term survivorship, and although lymphedema may be transient for some, those who present with mild lymphedema are at increased risk of developing moderate to severe lymphedema. The etiology of morbidity seems to be multifactorial, with the most consistent risk factors being those associated with extent of treatment. However, known risk factors cannot reliably distinguish between those who will and will not develop upper-body morbidity. Upper-body morbidity may be treatable with physical therapy. There is also evidence in support of integrating regular surveillance for upper-body morbidity into the routine care provided to women with breast cancer, with early diagnosis potentially contributing to more effective management and prevention of progression of these conditions. PMID- 22488699 TI - A prospective surveillance model for physical rehabilitation of women with breast cancer: chemotherapy-induced peripheral neuropathy. AB - Chemotherapy-induced peripheral neuropathy (CIPN) results from damage to or dysfunction of the peripheral nerves. The development of CIPN is anticipated for the majority of breast cancer patients who receive neurotoxic chemotherapy, depending on the agent used, dose, and schedule. Sensory symptoms often predominate and include numbness, tingling, and distal extremity pain. Weakness, gait impairment, loss of functional abilities, and other deficits may develop with more severe CIPN. This article outlines a prospective surveillance model for physical rehabilitation of women with breast cancer who develop CIPN. Rehabilitative efforts for CIPN start at the time of breast cancer diagnosis and treatment planning. The prechemotherapy evaluation identifies patients with preexisting peripheral nervous system disorders that may place them at higher risk for the development of CIPN. This clinical evaluation should include a history focusing on symptoms and functional activities as well as a physical examination that objectively assesses the patient's strength, sensation, reflexes, and gait. Ongoing surveillance following the initiation of a neurotoxic agent is important to monitor for the development and progression of symptoms associated with CIPN, and to ensure its resolution over the long term. CIPN is managed best by a multidisciplinary team approach. Early identification of symptoms will ensure appropriate referral and timely symptom management. The prospective surveillance model promotes a patient-centered approach to care, from pretreatment through survivorship and palliative care. In this way, the model offers promise in addressing and minimizing both the acute and long-term morbidity associated with CIPN. PMID- 22488700 TI - Cancer-related fatigue: implications for breast cancer survivors. AB - Cancer-related fatigue (CRF) has been documented as 1 of the most distressing symptoms reported by breast cancer survivors. CRF affects functioning and impacts quality of life. Possible causal factors include physical conditions, affective and cognitive states, proinflammatory cytokines, and metabolic factors. Several common problems are associated with CRF in women with breast cancer, including treatment side effects, obesity, arm/upper quadrant symptoms, sleep disturbances, psychological effects, and comorbid conditions. In this article, the authors review the state of the knowledge regarding these issues and nonpharmacologic and pharmacologic interventions for CRF. Physical activity and psychosocial interventions are recommended for practice. Numerous limitations of past studies need to be considered in the design of future studies. CRF is prevalent in preoperative, postoperative, and ongoing surveillance phases. Throughout the continuum of care for women with breast cancer, clinicians must screen, further assess as indicated, and treat CRF, because it is associated with emotional distress and limits function and willingness to exercise. PMID- 22488701 TI - Prospective surveillance and management of cardiac toxicity and health in breast cancer survivors. AB - Breast cancer is commonly diagnosed in postmenopausal women, the majority of whom express 1 or more cardiovascular disease risk factors. Cardiovascular disease poses a significant competing risk for morbidity and mortality among nonmetastatic breast cancer survivors. Adjuvant systemic therapies may result in late-cardiac toxicity decades after treatment completion. The cumulative incidence of treatment-related cardiotoxic outcomes may be as high as 33% after some adjuvant breast cancer therapies. Breast cancer treatment-induced cardiotoxicity may manifest as cardiomyopathy, coronary ischemia, thromboembolism, arrhythmias and conduction abnormalities, and valvular and pericardial disease. Evidence indicates that preexisting cardiovascular conditions such as hypertension or left ventricular dysfunction may compound the adverse effects of cardiotoxic treatments. There are currently no published clinical practice guidelines that address ongoing cardiac surveillance for cardiotoxicity after breast cancer, and existing guidelines for monitoring and promoting cardiovascular health in older women are often not followed. The multidisciplinary prospective surveillance system proposed elsewhere in this supplement would allow for earlier detection of cardiotoxicity from treatment and may improve monitoring of cardiovascular health in the growing population of breast cancer survivors. PMID- 22488703 TI - A prospective model of care for breast cancer rehabilitation: bone health and arthralgias. AB - Musculoskeletal health can be compromised by breast cancer treatment. In particular, bone loss and arthralgias are prevalent side effects experienced by women treated with chemotherapy and/or adjuvant endocrine therapy. Bone loss leads to osteoporosis and related fractures, while arthralgias threaten quality of life and compliance to treatment. Because the processes that lead to these musculoskeletal problems are initiated when treatment begins, early identification of women who may be at higher risk of developing problems, routine monitoring of bone density and pain at certain stages of treatment, and prudent application of therapeutic interventions are key to preventing and/or minimizing musculoskeletal sequelae. Exercise may be a particularly suitable intervention strategy because of its potential to address a number of impairments; it may slow bone loss, appears to reduce joint pain in noncancer conditions, and improves other breast cancer outcomes. Research efforts continue in the areas of etiology, measurement, and treatment of bone loss and arthralgias. The purpose of this review is to provide an overview of the current knowledge on the management and treatment of bone loss and arthralgias in breast cancer survivors and to present a framework for rehabilitation care to preserve musculoskeletal health in women treated for breast cancer. PMID- 22488704 TI - A prospective model of care for breast cancer rehabilitation: function. AB - A significant proportion of adult breast cancer survivors experience deficits in function and restriction in participation in life roles that may remain many years after diagnosis. Function is a complex construct that takes into account the interactions between an individual, their health condition, and the social and personal context in which they live. Research to date on limitations in activities of daily living, upper extremity function, and functional capacity in breast cancer survivors illustrates the need for prospective measurement of function using measures that are sensitive to the unique issues of breast cancer survivors and the need for the development of effective rehabilitation interventions to improve function. Limitations in function have a significant impact on quality of life, but less is known about the implications on return to work and survival, as well as the impact of other comorbidities and aging on the function limitations in breast cancer survivors. This review provides a rationale for the integration of measures of function into breast cancer care to more fully appreciate the functional limitations associated with breast cancer diagnosis and treatment and to aid in the development of better rehabilitation care for breast cancer survivors. PMID- 22488702 TI - Weight management and its role in breast cancer rehabilitation. AB - Overweight and obesity are risk factors for postmenopausal breast cancer, and many women diagnosed with breast cancer, irrespective of menopausal status, gain weight after diagnosis. Weight management plays an important role in rehabilitation and recovery because obesity and/or weight gain may lead to poorer breast cancer prognosis, as well as prevalent comorbid conditions (eg, cardiovascular disease and diabetes), poorer surgical outcomes (eg, increased operating and recovery times, higher infection rates, and poorer healing), lymphedema, fatigue, functional decline, and poorer health and overall quality of life. Health care professionals should encourage weight management at all phases of the cancer care continuum as a means to potentially avoid adverse sequelae and late effects, as well as to improve overall health and possibly survival. Comprehensive approaches that involve dietary and behavior modification, and increased aerobic and strength training exercise have shown promise in either preventing weight gain or promoting weight loss, reducing biomarkers associated with inflammation and comorbidity, and improving lifestyle behaviors, functional status, and quality of life in this high-risk patient population. PMID- 22488705 TI - Clinical practice guidelines for breast cancer rehabilitation: syntheses of guideline recommendations and qualitative appraisals. AB - BACKGROUND: Despite strides in early detection and management of breast cancer, the primary treatments for this disease continue to result in physical impairments for some of the nearly 3 million people diagnosed annually. Over the past decade, evidence-based clinical practice guidelines (CPGs) have been developed with goals of preventing and ameliorating these impairments. However, translation of these guidelines into clinical practice needs to be accelerated. METHODS: Relevant health science databases (2001-2011) were searched to identify CPGs on breast cancer rehabilitation for the following impairments: upper extremity restrictions, lymphedema, pain, fatigue, chemotherapy-induced peripheral neuropathy, treatment-related cardiotoxicity, bone health, and weight management. RESULTS: Recommendations from 19 relevant CPGs were first summarized by impairment within tables; commonalities across guidelines, within each impairment, were then synthesized within the article. The CPGs were rated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II); wide variability was noted in rigor of development, clarity of presentation, and stakeholder involvement. The most rigorous and comprehensive of those rated was the adult cancer pain guideline from the Scottish Intercollegiate Guidelines Network. CONCLUSIONS: Based on a large body of evidence published in recent years, including randomized trials and systematic reviews, there is an urgent need for updating the guidelines on upper extremity musculoskeletal impairments and lymphedema. Furthermore, additional research is needed to provide an evidence base for developing rehabilitation guidelines on management of other impairments identified in the prospective surveillance model, eg, arthralgia. PMID- 22488706 TI - Cost considerations regarding the prospective surveillance model for breast cancer survivors. AB - For this article, the authors examined the cost implications of the prospective surveillance model (PSM) for breast cancer (BC) survivors, a comprehensive framework designed to preemptively reduce the incidence and virulence of common impairments. The model clearly has the potential of providing significant benefits. However, its accompanying costs and resource requirements remain unclear and may be substantial. Thus, it is critical to examine which BC survivors may benefit from the PSM, how much they will benefit, and the costs of this benefit before its implementation. Because the PSM is not rigidly prescriptive, its examination must allow for different scenarios with emphasis on 4 critical determinants of cost--whether all or only high-risk BC survivors participate, assessment frequencies and locations, the credentials of the assessors, and requirements for supportive equipment. Another issue is the distribution of its cost: hypothetical implementation strategies vary widely in their distribution of fiscal burden across key stakeholders--survivors, providers, and payers--whose financial responsibilities will be an important factor in whether and how rapidly they adopt the PSM. Accurate valuation of the PSM will require capture of direct and indirect cost savings and benefits. Currently, a lack of data regarding these parameters, as well as outcomes that can be reliably attributed to the PSM, impedes cost-effectiveness analyses. Because the PSM may enhance many health state characteristics, assessments that integrate overall composite measures with evaluations of common, discrete impairments may be required to comprehensively assess its benefits. PMID- 22488707 TI - Stakeholder perspectives on dissemination and implementation of a prospective surveillance model of rehabilitation for breast cancer treatment. AB - The prospective surveillance model proposes a paradigm shift in the delivery of care for patients with breast cancer. The model is based on clinical research and clinical practice experience that was reviewed and discussed at a multidisciplinary meeting. The model identifies critical physical sequelae of treatment as well as timeframes for identification of and surveillance for these issues. Although the model of ongoing assessment for physical impairment and early rehabilitative intervention creates a framework for care, broad support and active dissemination among a variety of stakeholders will be required to transform patient care. Translating research findings to transform practice often occurs on a protracted timeline. The authors sought participation from a variety of stakeholder representatives throughout the process of creating this model in an effort to ensure that it reflects the realities of the patient experience and care delivery, to incorporate their input regarding the construct and viability of the model, and to potentiate effective and efficient strategies for implementation. This article summarizes comments from stakeholder representatives concerning the prospective surveillance model for rehabilitation for women treated for breast cancer. Concerns addressed include the scope of impairments included in the model, the potential creation of barriers to exercise and participation in community exercise programs, and cost and feasibility issues. Stakeholder disseminations strategies are also presented. Overall, there is recognition by the stakeholder group that this model calls attention to important unmet needs and defines a crucial opportunity to improve care for breast cancer survivors. PMID- 22488708 TI - Ion-pair recognition by a heteroditopic triazole-containing receptor. AB - A new heteroditopic calix[4]diquinone triazole containing receptor capable of recognising both cations and anions through Lewis base and C-H hydrogen-bonding modes, respectively, of the triazole motif has been prepared. This ion-pair receptor cooperatively binds halide/monovalent-cation combinations in an aqueous mixture, with selectivity trends being established by (1)H NMR and UV/Vis spectroscopy. Cation binding by the calix[4]diquinone oxygen and triazole nitrogen donors enhances the strength of the halide complexation at the isophthalamide recognition site of the receptor. Conversely, anions bound in the receptor's isophthalamide cavity enhance cation recognition. (1)H NMR investigations in solution suggest that the receptor's triazole motifs are capable of coordinating simultaneously to both cation and anion guest species. Solid-state X-ray crystallographic structural analysis of a variety of receptor ion-pair adducts further demonstrates the dual cation-anion binding role of the triazole group. PMID- 22488709 TI - Single chain folding of synthetic polymers by covalent and non-covalent interactions: current status and future perspectives. AB - The present feature article highlights the preparation of polymeric nanoparticles and initial attempts towards mimicking the structure of natural biomacromolecules by single chain folding of well-defined linear polymers through covalent and non covalent interactions. Initially, the discussion focuses on the synthesis and characterization of single chain self-folded structures by non-covalent interactions. The second part of the article summarizes the folding of single chain polymers by means of covalent interactions into nanoparticle systems. The current state of the art in the field of single chain folding indicates that covalent-bond-driven nanoparticle preparation is well advanced, while the first encouraging steps towards building reversible single chain folding systems by the use of mutually orthogonal hydrogen-bonding motifs have been made. PMID- 22488710 TI - Pre-existing Fas ligand (FasL) in cancer cells elicits tumor-specific protective immunity, but delayed induction of FasL expression after inoculation facilitates tumor formation. AB - Overexpression of Fas ligand (FasL) in cancer cells elicits potential antitumor effects via recruitment of neutrophils. Conversely, FasL-expressing tumors may counterattack tumor-infiltrating lymphocytes by delivering apoptotic death signals via Fas/FasL interactions, which may lead to tumor escape. In order to distinguish the role of FasL in antitumor activity and tumor progression, Lewis lung carcinoma cells (LLC-1) were used to establish the cell line LLC-FasL, in which FasL expression was repressed by doxycycline (Dox) treatment and induced in the absence of Dox. LLC-FasL cells promote tumor regression when expressing FasL, whereas tumor outgrowth is observed by depletion of FasL expression. To investigate whether initial expression of FasL during tumor formation is critical for FasL-mediated tumor regression, Dox-treated LLC-FasL cells were inoculated into Dox-treated mice, but Dox treatment was stopped 5 days after inoculation. When low cell numbers were inoculated, we observed 80% survival and no tumor formation, whereas no mice survived inoculation with high cell numbers, despite the delayed induction of FasL by Dox withdrawal. The inoculation of a high density of cells may establish a favorable tumor microenvironment before the expression of FasL. Our findings demonstrate that FasL may elicit antitumor activity when it is initially present on injected cancer cells and thus can act prior to tumor microenvironment formation. Furthermore, a well-established tumor microenvironment abrogates FasL-mediated antitumor activity. PMID- 22488711 TI - Photochemically reversible liquefaction and solidification of single compounds based on a sugar alcohol scaffold with multi azo-arms. AB - Sugar alcohol derivatives with multi azobenzene arms are photochemically and isothermally liquefied from a powdered solid upon irradiation with ultraviolet light at room temperature, and then solidified on irradiation with visible light, where the transition between solid and liquid are reversible. These compounds possess similar chemical structures to comb-like liquid crystalline oligomers. PMID- 22488712 TI - Taurolidine: mode of administration in mouse tumor models. PMID- 22488713 TI - Tailoring substrates for long-term organotypic culture of adult neuronal tissue. AB - Organotypic tissue cultures are highly promising for performing in vivo type studies in vitro. Currently, however, very limited survival times of only a few days for adult tissue often severely limit their application. Here, superhydrophilic nanostructured substrates with ideal material properties ensure tissue adhesion, essential for organotypic culture, while migration of single cells out of the tissue is hampered. Tuning substrate properties, for the first time, adult neuronal tissue could be cultured for 14 days with no indications of degeneration. PMID- 22488714 TI - Introduction to the special section on proteins and proteomics. PMID- 22488715 TI - SURF1-associated Leigh syndrome: a case series and novel mutations. AB - Leigh syndrome (LS) is a mitochondrial disease that typically presents in infancy with subacute neurodegenerative encephalopathy. It is genetically heterogeneous, but mutations in the complex IV assembly genes, particularly SURF1, are an important cause. In this study, SURF1 gene was sequenced in 590 patients with clinical suspicion of LS, complex IV deficiency, or clinical features of mitochondrial disorders. We identified 21 patients with clinical features of LS who are either homozygous or compound heterozygous for SURF1 mutations. Twenty two different mutations were identified, including 13 novel mutations. Of the 42 mutant alleles, 36 (86%) are null mutations (frameshift, splicing, or nonsense) and 6 (14%) are missense. We have also reviewed the previously reported SURF1 mutations and observed a clustering of mutation in exon 8 of SURF1, suggesting a vital function for this region. Although mutations in SURF1 have been mainly associated with typical LS, five of the patients in this report had an atypical course of LS. There is no definite genotype-phenotype correlation; however, frameshift mutations resulting in protein truncation closer to the C-terminus may carry a better prognosis. PMID- 22488716 TI - Microwave ablation versus partial nephrectomy for small renal tumors: intermediate-term results. AB - BACKGROUND AND OBJECTIVES: Prospective randomized comparison of intermediate-term outcomes of patients with small renal tumors who were treated with partial nephrectomy (PN) or microwave ablation. METHODS: Of 102 selected patients with solitary small renal tumors who had prospectively completed at least 2 years of follow-up since December 2004, randomizedly, 54 had either open (19) or laparoscopic (35) PN and 48 had laparoscopic (28) or open (20) microwave ablation. Patient and tumor characteristics, surgical data, complications, histologic and oncologic data, and functional data of the two approaches were compared. RESULTS: Patients in microwave ablation group and PN group matched for age, sex, American Society of Anesthesiologists score, body mass index, and tumor size and were respectively followed for median 32 and 36 months. Surgical and hospitalization times were comparable in both groups. Estimated blood loss, complication rates, and decline of postoperative renal function were significantly less in the microwave ablation group (P = 0.0002, P = 0.0187, and P = 0.0092, respectively). The decrease in estimated glomerular filtration rate at the last available follow-up was similar in both groups (P = 1.0000). There were no disease-specific deaths. Kaplan-Meier estimates of overall local recurrence free survival at 3 years were 91.3% for microwave ablation and 96.0% for PN (P = 0.5414); the respective numbers for renal cell carcinomas were 90.4 and 96.6% (P = 0.4650). CONCLUSIONS: Microwave ablation can be also safely and efficiently done for patients with small renal tumors. This intermediate analysis showed that microwave ablation provides favorable results compared to PN. However, longer term data are still needed. PMID- 22488717 TI - Direct catalytic conversion of methane to methanol in an aqueous medium by using copper-promoted Fe-ZSM-5. PMID- 22488718 TI - Outcome of newly diagnosed children and adolescents with localized lymphoblastic lymphoma treated on Children's Oncology Group trial A5971: a report from the Children's Oncology Group. AB - BACKGROUND: Localized lymphoblastic lymphoma (LL) is rare in pediatric patients. We report the 5-year event-free survival (EFS) and overall survival (OS) for children and adolescents with localized LL treated on a uniform regimen based on Children's Cancer Group (CCG) leukemia therapy (COG A5971). PROCEDURE: From June 2000 to October 2005, the study enrolled 60 patients >12 months old with Murphy stages I or II LL. Central review confirmed 56 eligible patients. Treatment consisted of 24 months of CCG BFM without day 28 intrathecal methotrexate in maintenance therapy or prophylactic cranial radiation. RESULTS: Most patients had pre-B immunophenotype (75%). At a median follow-up of 5.9 years (range 1.4-9.3 years), the 5-year EFS was 90% [95% confidence interval (CI), 78-96%] and the 5 year OS was 96% (95% CI, 84-99%). Stage (I vs. II), immunophenotype, elevated LDH > institutional normal, or primary site did not impact outcome. Five relapses occurred-none in the CNS and none in patients with pre-T lymphoblastic disease. Patients tolerated treatment well with no toxic deaths. CONCLUSION: Outcomes of pediatric patients with localized LL treated with 2 years of intensive acute lymphoblastic leukemia (ALL)-type therapy was excellent and is similar to the outcome for standard risk ALL treated less intensively. CNS prophylaxis was adequate with limited intrathecal methotrexate and no radiation. Future studies should identify biologic prognostic factors or biomarkers for pediatric patients with LL, explore less intensive treatment for patients with localized disease, and explore novel immunophenotype directed therapies. PMID- 22488719 TI - Monoclonal antibody capture and viral clearance by cation exchange chromatography. AB - Traditionally, post-production culture harvest capture of therapeutic monoclonal antibodies (mAbs) is performed using Protein A chromatography. We investigated the efficiency and robustness of cation exchange chromatography (CEX) in an effort to evaluate alternative capture methodologies. Up to five commercially available CEX resins were systematically evaluated using an experimentally optimized buffer platform and a design-of-experiment (DoE) approach for their ability to (a) capture a model mAb with a neutral isoelectric point, (b) clear three model viruses (porcine parvovirus, CHO type-C particles, and a bacteriophage). This approach identified a narrow operating space where yield, purity, and viral clearance were optimal under a CEX capture platform, and revealed trends between viral clearance of PPV and product purity (but not yield). Our results suggest that after unit operation optimization, CEX can serve as a suitable capture step. PMID- 22488721 TI - High-nitrogen-based pyrotechnics: development of perchlorate-free green-light illuminants for military and civilian applications. AB - The development of perchlorate-free hand-held signal illuminants for the US Army's M195 green star parachute is described. Compared with the perchlorate containing control, the optimized perchlorate-free illuminants were less sensitive toward various ignition stimuli while offering comparable burn times and visible-light outputs. The results were also important from the perspective of civilian fireworks because the development of perchlorate-free illuminants remains an important objective of the commercial fireworks industry. PMID- 22488722 TI - Composition and health effects of phenolic compounds in hawthorn (Crataegus spp.) of different origins. AB - Epicatechin, aglycons and glycosides of B-type oligomeric procyanidins and flavonols, phenolic acids and C-glycosyl flavones are the major groups of phenolic compounds in hawthorn (Crataegus spp). The total content of phenolic compounds is higher in the leaves and flowers than in the fruits. Procyanidins dominate in the fruits, whereas flavonol glycosides and C-glycosyl flavones are most abundant in the leaves. Genotype and developmental/ripening stage have strong impacts. Procyanidin glycosides and C-glycosyl flavones may be chemotaxonomic markers differentiating species and varieties of hawthorn. Future research shall improve the separation, identification and quantification of procyanidins with degree of polymerisation (DP) >= 6, procyanidin glycosides, C glycosyl flavones and some flavonol glycosides. In vitro and animal studies have shown cardioprotective, hypolipidaemic, hypotensive, antioxidant, radical scavenging and anti-inflammatory potentials of hawthorn extracts, suggesting different phenolic compounds as the major bioactive components. However, the varying and insufficiently defined composition of the extracts investigated, as a result of different raw materials and extraction methods, makes comparison of the studies very difficult. Clinical evidence indicates that some hawthorn extracts may increase the exercise tolerance of patients with congestive heart failure. More clinical studies are needed to establish the effects of hawthorn, especially in healthy humans. PMID- 22488723 TI - Effect of pore architecture and stacking direction on mechanical properties of solid freeform fabrication-based scaffold for bone tissue engineering. AB - Fabrication of a three-dimensional (3D) scaffold with increased mechanical strength may be an essential requirement for more advanced bone tissue engineering scaffolds. Various material- and chemical-based approaches have been explored to enhance the mechanical properties of engineered bone tissue scaffolds. In this study, the effects of pore architecture and stacking direction on the mechanical and cell proliferation properties of a scaffold were investigated. The 3D scaffold was prepared using solid freeform fabrication technology with a multihead deposition system. Various types of scaffolds with different pore architectures (lattice, stagger, and triangle types) and stacking directions (horizontal and vertical directions) were fabricated with a blend of polycaprolactone and poly lactic-co-glycolic acid. In compression tests, the triangle-type scaffold was the strongest among the experimental groups. Stacking direction affected the mechanical properties of scaffolds. An in vitro cell counting kit-8 assay showed no significant differences in optical density depending on the different pore architectures and stacking directions. In conclusion, mechanical properties of scaffolds can be enhanced by controlling pore architecture and stacking direction. PMID- 22488725 TI - Methylmalonate impairs mitochondrial respiration supported by NADH-linked substrates: involvement of mitochondrial glutamate metabolism. AB - The neurodegeneration that occurs in methylmalonic acidemia is proposed to be associated with impairment of mitochondrial oxidative metabolism resulting from methylmalonate (MMA) accumulation. The present study evaluated the effects of MMA on oxygen consumption by isolated rat brain mitochondria in the presence of NADH linked substrates (alpha-ketoglutarate, citrate, isocitrate, glutamate, malate, and pyruvate). Respiration supported either by glutamate or glutamate plus malate was significantly inhibited by MMA (1-10 mM), whereas no inhibition was observed when a cocktail of NADH-linked substrates was used. Measurements of glutamate transport revealed that the inhibitory effect of MMA on respiration maintained by this substrate is not due to inhibition of its mitochondrial uptake. In light of this result, the effect of MMA on the activity of relevant enzymes involved in mitochondrial glutamate metabolism was investigated. MMA had minor inhibitory effects on glutamate dehydrogenase and aspartate aminotransferase, whereas alpha ketoglutarate dehydrogenase was significantly inhibited by this metabolite (K(i) = 3.65 mM). Moreover, measurements of alpha-ketoglutarate transport and mitochondrial MMA accumulation indicated that MMA/alpha-ketoglutarate exchange depletes mitochondria from this substrate, which may further contribute to the inhibition of glutamate-sustained respiration. To study the effect of chronic in vivo MMA treatment on mitochondrial function, young rats were intraperitoneally injected with MMA. No significant difference was observed in respiration between isolated brain mitochondria from control and MMA-treated rats, indicating that in vivo MMA treatment did not lead to permanent mitochondrial respiratory defects. Taken together, these findings indicate that the inhibitory effect of MMA on mitochondrial oxidative metabolism can be ascribed to concurrent inhibition of specific enzymes and lower availability of respiratory substrates. PMID- 22488726 TI - Dimethylarginine dimethylaminohydrolase 1 regulates nerve growth factor-promoted differentiation of PC12 cells in a nitric oxide-dependent but asymmetric dimethylargenine-independent manner. AB - There are significant morphological and biochemical alterations during nerve growth factor (NGF)-promoted neuronal differentiation, and the process is regulated by molecules, including nitric oxide (NO). Dimethylarginine dimethylaminohydrolase (DDAH) is thought to play a critical role in regulating NO production via hydrolyzing the endogenous NO synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). Thus, we tested the role of DDAH in NGF-promoted differentiation of PC12 (pheochromocytoma) cells. The present results show that both mRNA and protein levels of DDAH1 were increased, whereas those of DDAH2 were decreased, during NGF-promoted cell differentiation. Both the DDAH activity and the ADMA level in cultured medium were unchanged in this process. NGF promoted neurite formation and induced the expression of microtubule-associated protein 2 (MAP2), a neuronal marker, which were both significantly repressed by DDAH1 silence with small interfering RNA but not by DDAH2 silence. The expressions of three isoforms of NOS were markedly upregulated after NGF stimulation with a time course similar to that of DDAH1, which were attenuated by DDAH1 silence. Conversely, overexpression of DDAH1 accelerated neurite formation in PC12 cells, concomitantly with upregulating the expression of three NOS isoforms. In summary, our data reveal the critical regulatory effect of DDAH1 on NGF-promoted differentiation of PC12 cells in an NOS/NO-dependent but ADMA-independent manner. PMID- 22488727 TI - Proteomic study of amyloid beta (25-35) peptide exposure to neuronal cells: Impact on APE1/Ref-1's protein-protein interaction. AB - The genotoxic, extracellular accumulation of amyloid beta (Abeta) protein and subsequent neuronal cell death are associated with Alzheimer's disease (AD). APE1/Ref-1, the predominant apurinic/apyrimidinic (AP) endonuclease and essential in eukaryotic cells, plays a central role in the base excision repair (BER) pathway for repairing oxidized and alkylated bases and single-strand breaks (SSBs) in DNA. APE1/Ref-1 is also involved in the redox activation of several trans-acting factors (TFs) in various cell types, but little is known about its role in neuronal functions. There is emerging evidence for APE1/Ref-1's role in neuronal cells vulnerable in AD and other neurodegenerative disorders, as reflected in its nuclear accumulation in AD brains. An increase in APE1/Ref-1 has been shown to enhance neuronal survival after oxidative stress. To address whether APE1/Ref-1 level or its association with other proteins is responsible for this protective effect, we used 2-D proteomic analyses and identified cytoskeleton elements (i.e., tropomodulin 3, tropomyosin alpha-3 chain), enzymes involved in energy metabolism (i.e., pyruvate kinase M2, N-acetyl transferase, sulfotransferase 1c), proteins involved in stress response (i.e., leucine-rich and death domain, anti-NGF30), and heterogeneous nuclear ribonucleoprotien-H (hnRNP-H) as being associated with APE1/Ref-1 in Abeta(25-35)-treated rat pheochromocytoma PC12 and human neuroblastoma SH-SY5Y cell lines, two common neuronal precursor lines used in Abeta neurotoxicity studies. Because the levels of some of these proteins are affected in the brains of AD patients, our study suggests a neuroprotective role for APE1/Ref-1 via its association with those proteins and modulating their cellular functions during Abeta-mediated neurotoxicity. PMID- 22488728 TI - Extracellular heat shock protein 72 protects schwann cells from hydrogen peroxide induced apoptosis. AB - The cytoprotective role of extracellular heat shock protein (Hsp) 72 has been demonstrated in various cell types, including neuronal cells; however, few studies have investigated the actual role of Hsp72 in the survival of Schwann cells (SCs). In the present study, we investigated the effect of exogenous Hsp72 on Schwann cell apoptotic cell death induced by H2O2. We determined that extracellular exposure to Hsp72 reduced cell death in rat SCs in a dose-dependent manner, with the protection resulting from downregulation of apoptosis induced by H2O2 (as shown by TUNEL and annexin V flow cytometry analyses). Moreover, we observed that Hsp72 suppressed caspase-3 and -9 activation induced by H2O2. This was accompanied by upregulation of the antiapoptotic protein Bcl-2. These findings indicate that extracellular Hsp72 can afford neuroprotection to peripheral nerves via its ability to inhibit Schwann cell apoptosis and diminish oxidative stress-mediated injuries. PMID- 22488729 TI - Behavioral and histological analysis of a partial double-lesion model of parkinson-variant multiple system atrophy. AB - Multiple system atrophy (MSA) is a neurodegenerative disease with progressive autonomic failure, cerebellar ataxia (MSA-C), and parkinsonism (MSA-P) resulting from neuronal loss in multiple brain areas associated with oligodendroglial cytoplasmic alpha-synuclein inclusion bodies. No effective treatments exists, and MSA-P patients often fail to respond to L-DOPA because of the loss of striatal dopaminergic receptors. Rendering MSA-P patients sensitive to L-DOPA administration following striatal tissue transplantation has been proposed as a possible novel therapeutic strategy to improve the clinical condition. Here we describes simple, skilled, and sensorimotor behavior deficits in a unilateral partial double-lesion (DL) rat model of MSA-P. The sequential striatal double lesion model mimicks early MSA-P pathology by combining partial 6-hydroxydopamine (6-OHDA) followed by striatal quinolinic acid (QA) lesion. Animals were tested on spontaneous, learned, or drug-induced behavioral tasks on multiple occasions pre- and postsurgery. The data show robust, lateralized deficits, and the partial 6 OHDA and the double-lesioned animals were most impaired. Importantly, this study identified a behavioral deficit profile unique to the double-lesion animals and distinctive from the single 6-OHDA- or the QA-lesioned animals. Histology confirmed an approximately 40% dopamine loss in the striatum in the 6-OHDA and double-lesion animals as well as a similar loss of striatal projection neurons in the QA and double-lesion animals. In summary, we have established the behavioral deficit profile of a partial double-lesion rat model mimicking the early stage of MSA-P. PMID- 22488730 TI - Optical coherence tomography evaluation of drug-eluting stents: a systematic review. AB - AIMS: We performed a systematic review of studies reporting stent strut coverage and malapposition post implantation of different drug-eluting stent (DES), as assessed by optical coherence tomography (OCT). METHODS: A review of publications and online databases in May 2011 retrieved 33 published studies reporting stent strut coverage and malapposition post-DES implantation using OCT: 24 for sirolimus-eluting stents (SES), 13 for paclitaxel-eluting stents (PES), 10 for zotarolimus-eluting stents (ZES), and two for everolimus-eluting stents (EES). The follow-up duration ranged from 3 months to 4 years. Stent strut coverage and malapposition were compared between DES at various time intervals post implantation. RESULTS: Significant differences in stent strut coverage and malapposition exist between various DES. The SES had the highest frequency of uncovered struts at 3, 6, 9, and 12 months (13.1%, 10.9%, 8.1%, and 7.5%, respectively), followed by PES (5.5%, 4.4%, and 5.7% at 6, 9, and 12 months, respectively) and ZES (0.7%, 0%, and 0.5% at 3, 6, and 9 months, respectively) (P < 0.001 for all comparisons between stents). Only two studies reported 3.1% uncovered struts at 9 months with the EES. Stent strut malapposition at 6, 9, and 12 months was highest with SES (3.2%, 2.2%, and 1.2%, respectively) followed by PES (1.6%, 1.3%, and 0.9%, respectively), EES (0.46% at 9 months), and ZES (0.7% and 0.1% at 6 and 9 months, respectively). CONCLUSIONS: SES had the highest rates of uncovered struts and malapposition, followed by PES and ZES. Such differences may explain the different clinical outcomes between various DES. (c) 2012 Wiley Periodicals, Inc. PMID- 22488731 TI - Large loop conformation sampling using the activation relaxation technique, ART nouveau method. AB - We present an adaptation of the ART-nouveau energy surface sampling method to the problem of loop structure prediction. This method, previously used to study protein folding pathways and peptide aggregation, is well suited to the problem of sampling the conformation space of large loops by targeting probable folding pathways instead of sampling exhaustively that space. The number of sampled conformations needed by ART nouveau to find the global energy minimum for a loop was found to scale linearly with the sequence length of the loop for loops between 8 and about 20 amino acids. Considering the linear scaling dependence of the computation cost on the loop sequence length for sampling new conformations, we estimate the total computational cost of sampling larger loops to scale quadratically compared to the exponential scaling of exhaustive search methods. PMID- 22488732 TI - Hexabromocyclododecane in consumer fish from South China: implications for human exposure via dietary intake. AB - Levels of hexabromocyclododecane (HBCD) were determined in 12 consumer fish species from South China. The concentrations of the sum of HBCD diastereoisomers (SigmaHBCD) ranged from nondetectable to 194 pg/g wet weight, with a detectable frequency of 70%. This was at the low end of the concentration range globally observed. Carnivorous fish species contained higher HBCD concentrations than herbivorous and detritivorous ones, suggesting the potential for biomagnification of HBCDs via the trophic chain. Moreover, SigmaHBCD concentrations were higher in both freshwater and seawater farmed fish than in wild marine fish, indicating that human activities were probably an important input source of HBCD in aquaculture. Among the three diastereoisomers, alpha-HBCD dominated in most samples, with a mean relative abundance of 70%. In agreement with previous studies, a difference in the diastereomer patterns was observed from commercial products and several environmental media to biota samples. For farm-raised snubnose pompano, the concentrations of SigmaHBCD were moderately linearly correlated with lipid contents but were not significantly correlated with fish body lengths and weights. In the worst-case exposure, the mean estimated daily intake of SigmaHBCD via fish consumption for residents of South China ranged from 13 to 16 pg/kg body weight/d for various age groups, much lower than its lowest observed adverse effect level derived from a two-generation reproductive toxicity study on rats. PMID- 22488734 TI - Octahedral rotation-induced ferroelectricity in cation ordered perovskites. AB - Electronic structure calculations based on density functional theory have uncovered a novel mechanism for inducing ferroelectric polarizations in cation ordered perovskites. We outline a materials selection strategy for designing this behavior. The guidelines are based on the octahedral rotations found in the two constituent oxides and the way the perovskite building blocks are interwoven to form the superlattice. PMID- 22488735 TI - Chain-growth polymerization of aryl Grignards initiated by a stabilized NHC-Pd precatalyst. AB - An N-heterocyclic carbene-ligated palladium catalyst was discovered to mediate living, chain-growth polymerizations of both phenylene- and thiophene-based monomers. Polymerization of a fluorene-based monomer, on the other hand, did not proceed through a living, chain-growth pathway. Excitingly, block copolymerizations of phenylene and thiophene proceeded via a chain-growth pathway, regardless of the order of monomer addition. Although some chain termination was observed during these copolymerizations, this pathway could be minimized when the second monomer was added shortly after consumption of the first monomer. These results suggest that the catalyst resting-state at the end of polymerization is unstable. As a result, modifications to the NHC-scaffold or the 3-chloropyridine ligand will be necessary to generate an improved catalyst. PMID- 22488736 TI - A child with an inherited 0.31 Mb microdeletion of chromosome 14q32.33: further delineation of a critical region for the 14q32 deletion syndrome. AB - Chromosome 14q32.3 deletions are uncommon, with most described patients harboring a ring chromosome 14. Only 15 deletions have been described not associated with ring formation or other complex chromosomal rearrangements. Here, we describe a child with the smallest deletion of chromosome 14q32.3 reported in the literature. This child's deletion encompasses at most 0.305 Mb and six genes including NUDT14, BRF1, BTBD6, PACS2, MTA1, and TEX22. He has similar clinical findings, including mild facial dysmorphisms and intellectual disability, as other individuals with much larger deletions of the terminus of the long arm of chromosome 14. This suggests that the genes deleted in our patient contribute to the 14q32 deletion syndrome. PMID- 22488738 TI - How is methane formed and oxidized reversibly when catalyzed by Ni-containing methyl-coenzyme M reductase? AB - Ni-containing methyl-coenzyme M reductase (MCR) is capable of catalyzing methane formation and has recently been observed to also be able to catalyze the reverse reaction, the anaerobic oxidation of methane. The forward reaction has been extensively studied theoretically before and was found to consist of two steps. The first step is rate-limiting and the second step was therefore treated at a lower level. For an accurate treatment of the reverse reaction, both steps have to be studied at the same level. In the present paper, the mechanisms for the reversible formation and oxidation of methane catalyzed by MCR have been investigated using hybrid density functional theory with recent developments, in particular including dispersion effects. An active-site model was constructed based on the X-ray crystal structure. The calculations indicate that the MCR reaction is indeed reversible and proceeds via a methyl radical and a Ni-S(CoM) intermediate with reasonable reaction barriers in both directions. In a competing mechanism, the formation of the crucial Ni-methyl intermediate, was found to be strongly endergonic by over 20 kcal mol(-1) (including a barrier) with dispersion and entropy effects considered, and thus would not be reachable in a reasonable time under natural conditions. PMID- 22488739 TI - Neural stem cells, adult neurogenesis, and galectin-1: from bench to bedside. AB - Neural stem cells (NSCs) in the adult brain have been a consistent focus of biomedical research largely because of their potential clinical application. To fully exploit this potential, the molecular mechanisms that regulate NSCs must be clarified. Several lines of evidence show that a multifunctional protein, Galectin-1, is expressed and has a functional role in a subset of adult NSCs. Researchers, including our group, have explored the physiological role of Galectin-1 in NSCs and its application in the treatment of animal models of neurological disorders such as brain ischemia and spinal cord injury. Here, we summarize what is currently known regarding the role of Galectin-1 in adult NSCs. Furthermore, we discuss current issues in researching the role of Galectin-1 in adult NSCs under both physiological and pathological conditions. PMID- 22488740 TI - Asymmetrical distribution of antennal sensilla in the female Anastatus japonicus Ashmead (Hymenoptera: Eupelmidae). AB - Anastatus japonicus Ashmead (Hymenoptera: Eupelmidae) is an important egg parasitoid of several major insect pests. To better understand its host finding mechanisms, the antennal sensilla of female wasp were investigated by scanning electron microscopy. Sensilla chaetica were found mainly on radicle and pedicel segments of the antennae. i-Type sensilla, s. campaniformia, and corneous sensilla were detected on the leeward side, while s. coeloconica and lance sensilla were presented on the windward side of the antennae. S. trichodea and s. basiconica were more abundant on the leeward side than on the windward side of the antennae. More s. placodea were found on the windward side than on the leeward side of the right antenna, while the opposite results were observed on the left antenna. Overall, more s. placodea were found on the right antenna than that on the left antenna. The numbers of s. trichodea and s. basiconica on the clava or the third flagellum antennomere of the right antenna were more than those of the left antenna, whereas their distribution patterns on the other corresponding antennomeres were reverse. Our results showed that there is a strong asymmetrical antennal sensilla distribution quantitatively and spatially between the left and right antennae. Placoid sensilla are present more on the right antenna than on the left antenna. S. campaniformia, corneous sensilla, and i-type sensilla were found only on the leeward side of the antennal clava, while their external morphology and potential functions were described and discussed in detail for the first time. PMID- 22488741 TI - Clinical significance of azathioprine metabolites for the maintenance of remission in autoimmune hepatitis. AB - Azathioprine (AZA) is used to maintain remission in autoimmune hepatitis (AIH), but up to 18% of patients are unresponsive. AZA is a prodrug, and the formation of active thioguanine nucleotide (TGN) metabolites varies widely. We aimed to assess the relationship between AZA metabolite concentrations (i.e., TGNs and methylmercaptopurine nucleotides [MeMPNs]), thiopurine methyltransferase (TPMT) activity, therapeutic response, and toxicity in adult patients with AIH prescribed a stable dose of AZA for the maintenance of remission. Red blood cell (RBC) TGNs and MeMPNs were measured in serial blood samples over a 2-year period. The average TGNs (avTGNs) and MeMPNs (avMeMPNs) concentrations for each patient were used for analysis. Therapeutic response was defined as the ability to maintain remission, defined as a normal serum alanine aminotransferase (ALT) level (ALT <33 IU/mL). Patients who maintained remission (n = 53), compared to those who did not (n = 17), tended to be on lower doses of AZA (1.7 versus 2.0 mg/kg/day; P = 0.08), but had significantly higher concentrations of avTGN (237 versus 177 pmol/8 * 10(8) RBCs; P = 0.025). There was no difference in MeMPN concentrations or TPMT activities between the two groups. There was a negative correlation between ALT and avTGN (r(s) = -0.32; P = 0.007). An avTGN concentration of >220 pmol/8 * 10(8) RBCs best predicted remission, with an odds ratio of 7.7 (P = 0.003). There was no association between TGN, MeMPN, or TPMT activity and the development of leucopenia. Two patients developed AZA-induced cholestasis and the avMeMPN concentration was higher in those patients, compared to those who did not (14,277 versus 1,416 pmol/8 * 10(8) RBCs). CONCLUSION: TGN concentrations of >220 pmol/8 * 10(8) RBCs are associated with remission. TGN measurement may help identify inadequate immunosupression. AZA-induced cholestasis was associated with increased MeMPN concentrations. PMID- 22488742 TI - Systemic therapy for advanced adrenal cancer. AB - The systemic management of advanced adrenal cancer remains a major therapeutic dilemma as it is both highly resistant to systemic agents and very rare epithelial neoplasm making clinical investigation a significant challenge. The role of mitotane, systemic chemotherapy and novel targeted agents are reviewed. PMID- 22488743 TI - Prevalence of human papillomavirus and cervical intraepithelial neoplasia in China: a pooled analysis of 17 population-based studies. AB - High-risk (HR) human papillomavirus (HPV) prevalence has been shown to correlate well with cervical cancer incidence rates. Our study aimed to estimate the prevalence of HR-HPV and cervical intraepithelial neoplasia (CIN) in China and indirectly informs on the cervical cancer burden in the country. A total of 30,207 women from 17 population-based studies throughout China were included. All women received HPV DNA testing (HC2, Qiagen, Gaithersburg, MD), visual inspection with acetic acid and liquid-based cytology. Women positive for any test received colposcopy-directed or four-quadrant biopsies. A total of 29,579 women had HR-HPV testing results, of whom 28,761 had biopsy confirmed (9,019, 31.4%) or assumed (19,742, 68.6%) final diagnosis. Overall crude HR-HPV prevalence was 17.7%. HR HPV prevalence was similar in rural and urban areas but showed dips in different age groups: at age 25-29 (11.3%) in rural and at age 35-39 (11.3%) in urban women. In rural and urban women, age-standardized CIN2 prevalence was 1.5% [95% confidence interval (CI): 1.4-1.6%] and 0.7% (95% CI: 0.7-0.8%) and CIN3+ prevalence was 1.2% (95% CI: 1.2-1.3%) and 0.6% (95% CI: 0.5-0.7%), respectively. Prevalence of CIN3+ as a percentage of either all women or HR-HPV-positive women steadily increased with age, peaking in 45- to 49-year-old women. High prevalence of HR-HPV and CIN3+ was detected in both rural and urban China. The steady rise of CIN3+ up to the age group of 45-49 is attributable to lack of lesion removal through screening. Our findings document the inadequacy of current screening in China while indirectly raising the possibility that the cervical cancer burden in China is underreported. PMID- 22488744 TI - Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer. AB - BACKGROUND: The objective of this study was to document the differences in testosterone (T) levels between crizotinib-treated and noncrizotinib-treated patients with metastatic nonsmall cell lung cancer (NSCLC). METHODS: Testosterone levels were measured in 19 men with metastatic NSCLC who received crizotinib and in 19 men with metastatic NSCLC who did not receive crizotinib. Clinical characteristics of the patients were compared, and additional hormone assays were performed as appropriate. Two patients who began crizotinib and 4 patients who had dose interruptions or who stopped crizotinib therapy had serial hormone measurements, permitting the documentation of dynamic hormone changes on and off crizotinib treatment. RESULTS: Total T levels were low (<241 ng/dL) in 19 of 19 (100%) crizotinib-treated men and in 6 of 19 men (32%) with metastatic NSCLC who did not receive crizotinib (mean T levels, 131 ng/dL and 311 ng/dL, respectively; P = .0002). Only 1 in 5 patients who had anaplastic lymphoma kinase (ALK) gene rearrangements and had not yet received crizotinib had low T. The initiation of crizotinib in 2 patients who had previously normal T levels was associated with a rapid decreases in T and in luteinizing hormone and follicle stimulating hormone levels within 14 to 21 days. Discontinuation of crizotinib led to increases back to normal T levels. CONCLUSIONS: Crizotinib therapy caused rapid suppression of T levels in men. The current results indicated that the site of action must include a central (hypothalamic or pituitary) effect, but additional direct testicular effects could not be excluded. Further work is required to assess the correlation between low T levels and crizotinib side effects as well as the exact molecular mechanism and site of drug toxicity. PMID- 22488745 TI - Gadofosveset trisodium in the investigation of focal liver lesions in noncirrhotic liver: Early experience. AB - PURPOSE: To investigate enhancement of hepatic lesions with gadofosveset trisodium (Gdfos) (Ablavar) (blood pool agent) compared with the extracellular gadolinium contrast agent (EcGd) gadobutrol (Gadovist). MATERIALS AND METHODS: The prospective study was approved by the Institutional Research Ethics Board with informed consent. Twelve patients underwent magnetic resonance imaging (MRI) with EcGd followed by MRI with Gdfos. For each agent qualitative analysis described the pattern of enhancement and quantitative analysis was performed using lesion-to-liver contrast-to-noise (CNR) ratio. Paired and unpaired Student's t-test used. RESULTS: Twelve hemangiomas, four metastases, one cyst, two focal nodular hyperplasia (FNH), and three adenomas were found. Cyst, FNH, adenomas, and hemangiomas demonstrated the classic pattern of enhancement with both agents. Hemangiomas demonstrated retention of contrast with both agents and their CNR was not statistically different (P > 0.05). Metastases demonstrated retention of contrast on delayed phase with EcGd. Retention of contrast was not seen in metastases with Gdfos. CNR of metastases with Gdfos was statistically lower than CNR of metastases with EcGd (P = 0.005). CNR of hemangiomata and metastases on delayed phase were significantly different (P = 0.0008) with Gdfos, but similar with EcGd (P = 0.4). CONCLUSION: Hemangiomas accumulate Gdfos on delayed phase and metastases do not, a key additional differentiating feature. Liver imaging with Gdfos may improve characterization of liver lesions. PMID- 22488746 TI - Carbon-carbon contacts for robust nanoelectromechanical switches. AB - Nanoelectromechanical devices exhibiting dramatically improved robustness through novel material selection are demonstrated. A unique combination of carbon nanotube active elements and conductive diamond-like carbon contact electrodes results in reliable switching performance not found in devices with ubiquitously used metal thin film electrodes. This in turn represents a viable means to improve the reliability of a diverse, and widely-pursued class of nanoscale devices ranging from single-nanostructure switches to massively parallel arrays. PMID- 22488747 TI - Well-defined nanoclusters as fluorescent nanosensors: a case study on Au(25) (SG)(18). AB - The fluorescence of nanoparticles has attracted much attention in recent research, but in many cases the underlying mechanisms are difficult to evaluate due to the polydispersity of nanoparticles and their unknown structures, in particular the surface structures. Recent breakthroughs in the syntheses and structure determinations of well-defined gold nanoclusters provide opportunities to conduct in-depth investigations. Devising well-defined nanocluster sensors based on fluorescence change is of particular interest not only for scientific studies but also for practical applications. Herein, the potential of the glutathionate (SG)-capped Au(25) nanocluster as a silver ion sensor is evaluated. The Ag(+) detection limit of approximately 200 nM, based on the fluorescence enhancement and good linear fluorescence response in the silver ion concentration range from 20 nM to 11 MUM, in combination with the good selectivity among 20 types of metal cations, makes Au(25) (SG)(18) a good candidate for fluorescent sensors for silver ions. Further experiments reveal three important factors responsible for the unique fluorescence enhancement caused by silver ions: 1) the oxidation state change of Au(25) (SG)(18) ; 2) the interaction of neutral silver species (Ag(0) , reduced by Au(25) (SG)(18) (-) ) with Au(25) (SG)(18) ; and 3) the interaction of Ag(+) with Au(25) (SG)(18.) Experiments demonstrate the very different chemistry of hydrophobic Au(25) (SC(2) H(4) Ph)(18) and hydrophilic Au(25) (SG)(18) in the reaction with silver ions. This work indicates another potential application of gold nanoclusters, offers new strategies for nanocluster-based chemical sensing, and reveals a new way to influence nanocluster chemistry for potential applications. PMID- 22488748 TI - A unified mechanism for abiotic adenine and purine synthesis in formamide. PMID- 22488749 TI - Supramolecular tetrahedra of phosphines and coinage metals. PMID- 22488750 TI - Parallel and partial Fourier imaging with prospective motion correction. AB - Subject motion during scan is a major source of artifacts in MR examinations. Prospective motion correction is a promising technique that tracks subject motion and adjusts the imaging volume in real time; however, additional retrospective correction may be necessary to achieve robust image quality and compatibility with other imaging options. Real-time realignment of the imaging volume by prospective motion correction changes the coil sensitivity weighting and the field inhomogeneity relative to the imaging volume. This can pose image reconstruction problems with parallel imaging and partial Fourier imaging, which rely on coil sensitivity and image phase information, respectively. This work presents a practical method for reconstructing images acquired using prospective motion correction with parallel imaging and/or partial Fourier imaging. Our proposed approach is data driven and noniterative; data are binned into several position bins based on motion measurements made during the prospective motion correction acquisition and the data in each bin are processed through intrabin operations such as parallel imaging reconstruction (in case of undersampling), phase correction, and coil combination before combination of the position bins. We demonstrate the effectiveness of our technique through simulation studies and in vivo experiments using a prospectively motion-corrected three-dimensional fast spin echo sequence. PMID- 22488751 TI - Predictors of a favorable outcome of physiotherapy in fecal incontinence: secondary analysis of a randomized trial. AB - AIMS: It is unclear which patients with fecal incontinence (FI) are likely to benefit from physiotherapy treatment, which is relevant for medical decision making and patient counseling. This study aimed to identify patient characteristics predicting a favorable outcome of physiotherapy. METHODS: Eighty patients with FI, with a mean age of 59.3 (SD +/- 11.9), were recruited at the Maastricht University Medical Centre and enrolled in a randomized controlled trial, which assessed the effect of adding rectal balloon training to pelvic floor muscle training. Treatment groups were combined for prediction modeling. Candidate predictors were obtained from demographics, medical history, physical examination, baseline tests, questionnaires, and physiotherapy diagnostics. Favorable outcome was defined as a combination of: (i) Vaizey score reduction >= 5 points, and (ii) "slightly" to "very much improved" on the nine-point global perceived effect score. Predictors were identified by univariable and multivariable logistic regression analysis. RESULTS: Thirty-seven patients (46.3%) had a favorable outcome. Multivariable analysis showed that longer time since FI onset appeared to be associated with an unfavorable outcome (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.47-1.00; P = 0.05), whereas the use of constipating medication (OR, 3.79; CI, 0.99-14.51; P = 0.05), any obstetric factor (OR, 2.15; CI, 0.94-4.89; P = 0.07), and experiencing minor embarrassment (OR, 2.12; CI, 1.10-4.09; P = 0.03) predicted a favorable outcome. CONCLUSIONS: The small subset of identified predictors for a favorable outcome may be relevant in patient counseling and targeting physiotherapy treatment more efficiently, especially as they are available early in the diagnostic process. PMID- 22488753 TI - The impact of self-reported pubertal status and pubertal timing on disordered eating in Irish adolescents. AB - This paper considers the impact of pubertal status and pubertal timing on disordered eating in Irish adolescents. 1190 boys and 1841 girls completed the Eating Attitudes Test-26, the Eating Disorder Inventory-III and self-report measures of pubertal status and pubertal timing. Regarding pubertal status, greater maturity in girls was associated with increased overall eating concerns, higher drive for thinness and higher levels of body dissatisfaction. In boys, greater maturity was associated with lower drive for thinness and lower body dissatisfaction. Regarding pubertal timing, early-maturing girls showed the most eating concerns, the highest drive for thinness, scored highest on bulimic symptoms and were the most dissatisfied with their bodies. In contrast, late maturing boys had more bulimic symptoms and more dissatisfaction with their bodies than on-time peers. The findings suggest that puberty itself is a risk factor for disordered eating for girls rather than boys; however, pubertal timing is a risk factor for both. PMID- 22488754 TI - Bioactive anti-inflammatory coating for chronic neural electrodes. AB - Chronic electrodes are widely used for brain degenerative and psychiatric diseases such as Parkinson's disease,major depression, and obsessive-compulsive disorder, and for neuronal prosthesis. Brain immune reaction to electrodes in the form of glial scar encapsulates the electrode and reduces the efficacy of deep brain stimulation and neuronal prosthesis.State-of-the-art strategies for improving brain-electrode interface use passive protein coating to "camouflage" the electrode from the immune system. In this study, we actively reduced the brain immune reaction to the chronic electrodes using immune suppressing protein, that is, interleukin (IL)-1 receptor antagonist. IL-1 receptor antagonist-coated electrodes and non coated electrodes were chronically implanted in rats. An additional group of rats was chronically implanted with IL-1 receptor antagonist- and laminin-coated electrodes (as passive protein). Examination of glial scaring 1 and 4 weeks after implantation indicated a significant reduction in the amount of glial scar in the vicinity of the IL-1 receptor antagonist-coated electrode in comparison to both non coated electrode and laminin-coated electrodes. The results strongly suggest that active immune suppressing protein reduces the level of immune reaction to chronic electrodes already after 1 week after implantation and generates less immune reaction than passive protein coating [corrected]. PMID- 22488756 TI - Safety and efficacy of everolimus-eluting stents versus paclitaxel-eluting stents in a diabetic population. AB - OBJECTIVES: This study aimed to analyze the use of everolimus-eluting stents (EES) and paclitaxel-eluting stents (PES) in an unrestricted diabetic population and to compare the performance of these two drug-eluting stents. BACKGROUND: EES have demonstrated superiority in efficacy when compared to PES in a general population. However, it is controversial whether this superiority holds true in a diabetic population. METHODS: From March 2004 to May 2010, 968 patients with consecutive diabetes who underwent percutaneous coronary intervention and implantation of an EES (n = 388) or PES (n = 580) at our institution. In hospital, 1-month, 6-month, and 1-year clinical outcomes were analyzed and compared. Correlates of major adverse cardiac events (MACE) were identified. RESULTS: Baseline clinical characteristics were similar between stent types except for more family history of coronary artery disease in the PES group and more insulin-dependent diabetes and unstable angina at initial diagnosis in the EES group. The PES group had higher number of lesions treated, longer stents used, and a higher proportion of intravascular ultrasound and glycoprotein IIb/IIIa inhibitor use. The EES group had more type C and distal lesions. There was higher target lesion revascularization (TLR)-MACE in the PES group (3.3% vs. 1.0%, P = 0.03) as well as a higher rate of stent thrombosis (ST) (8 patients vs. 0 in the EES group, P = 0.03). ST continued to be higher in the PES group at 6 and 12 months and mortality was higher at 12 months in the PES group (9.4% vs. 5.2%, P = 0.02). After adjustment, no significant differences were found between stent types on Cox regression analysis for hazard ratios at 1-year follow-up of TLR-MACE. CONCLUSIONS: In a diabetic population undergoing PCI, the use of an EES compared to PES was associated with lower rates of stent thrombosis; but after adjustment the composite TLR-MACE at 1 year was similar between both stents. PMID- 22488757 TI - Theoretical analysis of insulin-dependent glucose uptake heterogeneity in 3D bioreactor cell culture. AB - Three-dimensional (3D) cell cultures in bioreactors are becoming relevant as models for biological and physiological in vitro studies. In such systems, mathematical models can assist the experiment design that links the macroscopic properties to single-cell responses. We investigated the relationship between biochemical stimuli and cell response within a 3D cell culture in scaffold with heterogeneous porosity. Specifically, we studied the effect of insulin on the local glucose metabolism as a function of 3D pore size distribution. The multiscale mathematical model combines the mass transport within a 3D scaffold and a signaling pathways model. It considers the scaffold heterogeneity, and it describes spatiotemporal concentration of metabolites, biochemical stimuli, and cell density. The signaling model was integrated into this model, linking the local insulin concentration at cell membrane to the glucose uptake rate through glucose transporter type 4 (GLUT4) translocation from the cytosol to the cell membrane. The integrated model determines the cell response heterogeneities in a single channel, hence the biological response distribution in a 3D system. It also provides macroscopic outcomes to evaluate the feasibility of an experimental measurement of the system response. From our analysis, it became apparent that the flow rate is the most important operative variable, and that an optimum value ensures a fast and detectable cell response. This model on insulin-dependent glucose consumption rate offers insight into the cell metabolism physiology, which is a fundamental requirement for the study metabolic disorder such as Type 2 diabetes mellitus, in which the physiological insulin-dependent glucose metabolism is impaired. PMID- 22488758 TI - Conjugated polyelectrolyte-antibody hybrid materials for highly fluorescent live cell-imaging. AB - Conjugated polyelectrolyte-antibody hybrid materials promise to enhance the utility of conjugated polymers in bioimaging field. Polymer-antibody conjugates that are biologically safe and highly sensitive and selective to cells are designed to image human T or B lymphocytes. In the clear state, the observed efficiency of luminescence is superior to that of commercially available FITC antibody probe. PMID- 22488759 TI - Autoimmune disease and multiple autoantibodies in 42 patients with RASopathies. AB - The association of RASopathies [Noonan syndrome (NS) and Noonan-related syndromes] and autoimmune disorders has been reported sporadically. However, a concomitant evaluation of autoimmune diseases and an assessment of multiple autoantibodies in a large population of patients with molecularly confirmed RASopathy have not been performed. The clinical and laboratory features were analyzed in 42 RASopathy patients, the majority of whom had NS and five individuals had Noonan-related disorders. The following autoantibodies were measured: Anti-nuclear antibodies, anti-double stranded DNA, anti-SS-A/Ro, anti SS-B/La, anti-Sm, anti-RNP, anti-Scl-70, anti-Jo-1, anti-ribosomal P, IgG and IgM anticardiolipin (aCL), thyroid, anti-smooth muscle, anti-endomysial (AE), anti liver cytosolic protein type 1 (LC1), anti-parietal cell (APC), anti mitochondrial (AM) antibodies, anti-liver-kidney microsome type 1 antibodies (LKM 1), and lupus anticoagulant. Six patients (14%) fulfilled the clinical criteria for autoimmune diseases [systemic lupus erythematous, polyendocrinopathy (autoimmune thyroiditis and celiac disease), primary antiphospholipid syndrome (PAPS), autoimmune hepatitis, vitiligo, and autoimmune thyroiditis]. Autoimmune antibodies were observed in 52% of the patients. Remarkably, three (7%) of the patients had specific gastrointestinal and liver autoantibodies without clinical findings. Autoimmune diseases and autoantibodies were frequently present in patients with RASopathies. Until a final conclusion of the real incidence of autoimmunity in Rasopathy is drawn, the physicians should be alerted to the possibility of this association and the need for a fast diagnosis, proper referral to a specialist and ultimately, adequate treatment. PMID- 22488760 TI - Refinement of unreliable local regions in template-based protein models. AB - Contemporary template-based modeling techniques allow applications of modeling methods to vast biological problems. However, they tend to fail to provide accurate structures for less-conserved local regions in sequence even when the overall structure can be modeled reliably. We call these regions unreliable local regions (ULRs). Accurate modeling of ULRs is of enormous value because they are frequently involved in functional specificity. In this article, we introduce a new method for modeling ULRs in template-based models by employing a sophisticated loop modeling technique. Combined with our previous study on protein termini, the method is applicable to refinement of both loop and terminus ULRs. A large-scale test carried out in a blind fashion in CASP9 (the 9th Critical Assessment of techniques for protein structure prediction) shows that ULR structures are improved over initial template-based models by refinement in more than 70% of the successfully detected ULRs. It is also notable that successful modeling of several long ULRs over 12 residues is achieved. Overall, the current results show that a careful application of loop and terminus modeling can be a promising tool for model refinement in template-based modeling. PMID- 22488761 TI - Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism. AB - In this review, we provide a synopsis of work on the epidemiologic evidence for prenatal infection in the etiology of schizophrenia and autism. In birth cohort studies conducted by our group and others, in utero exposure to infectious agents, prospectively obtained after biomarker assays of archived maternal sera and by obstetric records was related to an increased risk of schizophrenia. Thus far, it has been demonstrated that prenatal exposure to influenza, increased toxoplasma antibody, genital-reproductive infections, rubella, and other pathogens are associated with schizophrenia. Anomalies of the immune system, including enhanced maternal cytokine levels, are also related to schizophrenia. Some evidence also suggests that maternal infection and immune dysfunction may be associated with autism. Although replication is required, these findings suggest that public health interventions targeting infectious exposures have the potential for preventing cases of schizophrenia and autism. Moreover, this work has stimulated translational research on the neurobiological and genetic determinants of these conditions. PMID- 22488762 TI - Microscopic comparative study of the exposure effects of testosterone cypionate and ethinylestradiol during prenatal life on the prostatic tissue of adult gerbils. AB - There is an increasing variety of endocrine disrupting chemicals (EDCs) either with (anti)estrogenic or (anti)androgenic potential widely present in the environment. These xenosteroids may mimic endogenous steroid hormones disrupting the homeostasis of physiological pathways and leading to several disturbances, especially in tissues highly dependent on steroid hormones such as the prostate. Taking this into account, this comparative study aimed to verify the potential of ethinylestradiol (EE) and testosterone acting as ECDs on the prostate of both male and female adult gerbils exposed to these agents during the embryonic phase. Consequently, pregnant gerbils were treated either with 10 MUg/kg/day of EE or with a single dose of 1 mg of testosterone cypionate. The pups that were born 6-8 days after testosterone exposure and the pups that were born after 3 days of EE exposure were allowed to grow but were sacrificed within 4 months. Serological, morphological, stereological, and immunohistochemical analyses were used. Overall, the results showed that both sexes exposed to testosterone and EE during gestation had a prostatic gland with an increased stromal and epithelial and a reduced luminal compartment. Moreover, we observed that glands affected with prostatic intraepithelial neoplasia showed intense stromal reshuffling. In conclusion, although these alterations were observed in both sexes, more relevant to this study was the differential responsiveness of males and females exposed to these different drugs. Whereas the EE affected males more, the testosterone was more harmful to the females. PMID- 22488763 TI - Mixture toxicity of wood preservative products in the fish embryo toxicity test. AB - Wood preservative products are used globally to protect wood from fungal decay and insects. We investigated the aquatic toxicity of five commercial wood preservative products, the biocidal active substances and some formulation additives contained therein, as well as six generic binary mixtures of the active substances in the fish embryo toxicity test (FET). Median lethal concentrations (LC50) of the single substances, the mixtures, and the products were estimated from concentration-response curves and corrected for concentrations measured in the test medium. The comparison of the experimentally observed mixture toxicity with the toxicity predicted by the concept of concentration addition (CA) showed less than twofold deviation for all binary mixtures of the active substances and for three of the biocidal products. A more than 60-fold underestimation of the toxicity of the fourth product by the CA prediction was detected and could be explained fully by the toxicity of one formulation additive, which had been labeled as a hazardous substance. The reason for the 4.6-fold underestimation of toxicity of the fifth product could not be explained unambiguously. Overall, the FET was found to be a suitable screening tool to verify whether the toxicity of formulated wood preservatives can reliably be predicted by CA. Applied as a quick and simple nonanimal screening test, the FET may support approaches of applying component-based mixture toxicity predictions within the environmental risk assessment of biocidal products, which is required according to European regulations. PMID- 22488764 TI - The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. PMID- 22488765 TI - Size-dependent nonlinear weak-field magnetic behavior of maghemite nanoparticles. AB - The magnetic behavior at room temperature of maghemite nanoparticles of variable sizes (from 7 to 20 nm) is compared using a conventional super quantum interference device (SQUID) and a recently patented technology, called MIAplex. The SQUID usually measures the magnetic response versus an applied magnetic field in a quasi-static mode until high field values (from -4000 to 4000 kA m(-1)) to determine the field-dependence and saturation magnetization of the sample. The MIAplex is a handheld portable device that measures a signal corresponding to the second derivative of the magnetization around zero field (between -15 and 15 kA m(-1)). In this paper, the magnetic response of the size series is correlated, both in diluted and powder form, between the SQUID and MIAplex. The SQUID curves are measured at room temperature in two magnetic field ranges from -4000 to 4000 kA m(-1) (-5T to 5T) and from -15 to 15 kA m(-1). Nonlinear behavior at weak fields is highlighted and the magnetic curves for diluted solutions evolve from quasi-paramagnetic to superparamagnetic behavior when the size of the nanoparticles increases. For the 7-nm sample, the fit of the magnetization with the Langevin model weighted with log-normal distribution corresponds closely to the magnetic size. This confirms the accuracy of the model of non-interacting superparamagnetic particles with a magnetically frustrated surface layer of about 0.5 nm thickness. For the other samples (10-nm to 21-nm), the experimental weak field magnetization curves are modeled by more than one population of magnetically responding species. This behavior is consistent with a chemically uniform but magnetically distinct structure composed of a core and a magnetically active nanoparticle canted shell. Accordingly the weak-field signature corresponds to the total assembly of the nanoparticles. The impact of size polydispersity is also discussed. PMID- 22488766 TI - Randomized trials and quality assurance in gastric cancer surgery. AB - A D2 lymphadenectomy can be considered standard of surgical care for advanced resectable gastric cancer. Currently, several multimodality strategies are used, including postoperative monochemotherapy in Asia, postoperative chemoradiotherapy in the United States, and perioperative chemotherapy in Europe. As the majority of gastric cancer patients are treated outside the framework of clinical trials, quality assurance programs, including referral to high-volume centers and clinical auditing are needed to improve gastric cancer care on a nationwide level. PMID- 22488767 TI - Artificial electron carriers for photoenzymatic synthesis under visible light. AB - NAD analogues can be employed as artificial electron carriers for photoenzymatic synthesis under visible light. Four different NAD analogues that have a 3 substituted pyridine ring have been investigated. 3-Acetylpyridine adenine dinucleotide and 3-pyridinealdehyde adenine dinucleotide were photochemically reduced much more efficiently than NAD, while their reduced products showed coenzyme activity comparable to natural NAD. PMID- 22488768 TI - Efficient, large area ITO-and-PEDOT-free organic solar cell sub-modules. PMID- 22488769 TI - Replication of N2,3-ethenoguanine by DNA polymerases. PMID- 22488771 TI - Botulinum toxin in "refractory" detrusor overactivity. Re: Makovey I, et al. botulinum toxin outcomes for idiopathic overactive bladder stratified by indication: lack of anticholinergic efficacy versus intolerability. Neurourol Urodyn 2011;30:1538-1540. PMID- 22488770 TI - Partition coefficients for gadolinium chelates in the normal myocardium: comparison of gadopentetate dimeglumine and gadobenate dimeglumine. AB - PURPOSE: To evaluate the influence of contrast agents with different relaxivity on the partition coefficient (lambda) and timing of equilibration using a modified Look-Locker inversion recovery (MOLLI) sequence in cardiac magnetic resonance imaging (MRI). MATERIALS AND METHODS: MOLLI was acquired in 20 healthy subjects (1.5T) at the mid-ventricular short axis precontrast and 5, 10, 20, 25, and 30 minutes after administration of a bolus of 0.15 mmol/kg gadobenate dimeglumine (Gd-BOPTA) (n = 10) or gadopentetate dimeglumine (Gd-DTPA) (n = 10). T1 times were measured in myocardium and blood pool. lambda was approximated by DeltaR1(myocardium) /DeltaR1(blood) . Values for Gd-BOPTA and Gd-DTPA were compared. Interobserver agreement was evaluated (intraclass correlation coefficient [ICC]). RESULTS: T1 times of myocardium and blood pool (P < 0.001) and lambda (0.42 +/- 0.03 and 0.47 +/- 0.04, respectively, P < 0.001; excluding 5 minutes for Gd-BOPTA) were significantly lower for Gd-BOPTA than Gd-DTPA. The lambda((Gd-DTPA)) showed no significant variation between 5 and 30 minutes. The lambda((Gd-BOPTA)) values were significantly lower at 5 minutes compared to other times (0.38 vs. 0.42; P < 0.05). Interobserver agreement for lambda values was excellent with Gd-BOPTA (ICC = 0.818) and good for Gd-DTPA (ICC = 0.631). CONCLUSION: The lambda((Gd-BOPTA)) values were significantly lower compared to lambda((Gd-DTPA)) at the same administered dose. Using Gd-BOPTA, the equilibrium between myocardium and blood pool was not achieved at 5 minutes postcontrast. PMID- 22488774 TI - Nonlinear formulation of the magnetic field to source relationship for robust quantitative susceptibility mapping. AB - Quantitative susceptibility mapping (QSM) opens the door for measuring tissue magnetic susceptibility properties that may be important biomarkers, and QSM is becoming an increasingly active area of scientific and clinical investigations. In practical applications, there are sources of errors for QSM including noise, phase unwrapping failures, and signal model inaccuracy. To improve the robustness of QSM quality, we propose a nonlinear data fidelity term for frequency map estimation and dipole inversion to reduce noise and effects of phase unwrapping failures, and a method for model error reduction through iterative tuning. Compared with the previous phase based linear QSM method, this nonlinear QSM method reduced salt and pepper noise or checkerboard pattern in high susceptibility regions in healthy subjects and markedly reduced artifacts in patients with intracerebral hemorrhages. PMID- 22488776 TI - Control of size dispersity of chitosan biopolymer microparticles and nanoparticles to influence vaccine trafficking and cell uptake. AB - Structurally related surfactant molecules were exploited to generate chitosan emulsions to provide systematic variation in micelle radii of curvature and size. These compositions provide precise control of chitosan particle dispersity, that is, size distribution according to three quantitative distribution parameters as well as shape distribution. This resulted in a suite of particle size distributions spanning 71 nm to 3.7 MUm and a very high degree of particle sphericity, allowing the influence of particle size to be isolated in two in vivo studies relating biopolymer particle size to cellular uptake and trafficking to lymph nodes. Flow cytometry and fluorescence microscopy indicated that the three cell lines examined preferentially internalized chitosan microparticles to a greater extent than nanoparticles over a 24 h period. In an in vivo mouse model, nanoparticles initially trafficked rapidly to lymph nodes draining the site of inoculation followed by further slower uptake. Microparticles trafficked to the lymph nodes with a similar pattern except that the initial discharge was ~50-fold less than that observed with nanoparticles indicating a profound difference in the physiological transport properties of the two particle types. PMID- 22488775 TI - Valproic acid synergistically enhances the cytotoxicity of clofarabine in pediatric acute myeloid leukemia cells. AB - BACKGROUND: Acute myeloid leukemia (AML) remains a major therapeutic challenge in pediatric oncology even with intensified cytarabine (ara-C)-based chemotherapy. Therefore, new therapies are urgently needed to improve treatment outcome of this deadly disease. In this study, we evaluated antileukemic interactions between clofarabine (a second-generation purine nucleoside analog) and valproic acid (VPA, a FDA-approved agent for treating epilepsy in both children and adult and a histone deacetylase inhibitor), in pediatric AML. METHODOLOGY: In vitro clofarabine and VPA cytotoxicities of the pediatric AML cell lines and diagnostic blasts were measured by using MTT assays. The effects of clofarabine and VPA on apoptosis and DNA double strand breaks (DSBs) were determined by flow cytometry analysis and Western blotting, respectively. Active form of Bax was measured by Western blotting post-immunoprecipitation. RESULTS: We demonstrated synergistic antileukemic activities between clofarabine and VPA in both pediatric AML cell lines and diagnostic blasts sensitive to VPA. In contrast, antagonism between the two agents could be detected in AML cells resistant to VPA. Clofarabine and VPA cooperate in inducing DNA DSBs, accompanied by Bax activation and apoptosis in pediatric AML cells. CONCLUSION: Our results document synergistic antileukemic activities of combined VPA and clofarabine in pediatric AML and suggest that this combination could be an alternative treatment option for the disease. PMID- 22488777 TI - A chiral, self-catenating and porous metal-organic framework and its post synthetic metal uptake. PMID- 22488778 TI - A molecular dynamics study of C1r and C1s dimers: implications for the structure of the C1 complex. AB - Complement is an important part of the immune system. It is initiated through three different pathways known as the classical, lectin, and alternative pathway. The multimolecular C1 complex of the classical pathway consists of a subcomponent, C1q, which binds to a tetramer comprising two C1r and two C1s proteases. A detailed description of the structure of the C1 complex is essential to fully understand how the complex acts on pathogens. A variety of different models have been proposed, which differ mainly in the way the proteases interact with C1q. In this study, we have used a combination of homology-based structure prediction and molecular dynamics to predict a partial structure of the C1s/C1r/C1r/C1s tetramer. For computational expediency the study was restricted to the CUB(1) -EGF-CUB(2) domains which are directly involved in the formation of the tetramer and its interaction with C1q; the catalytic fragments (CCP(1) CCP(2) -SP), which mediate C1 activation and subsequent cleavage of substrates, were omitted. A systematic molecular dynamics (MD) study of several possible dimeric combinations suggest that the tetramer is formed when a pair of C1r/C1s dimers form a "doughnut" via a C1s/C1s head-to-tail interaction, which is stabilized by several putative salt bridges at the dimer interface. This result is consistent with biochemical data which have shown that self assembly requires the formation of C1r-C1s contacts and that electrostatic interactions play a key role. Furthermore, it identifies a number of putative binding residues that can be tested using site-directed mutagenesis. PMID- 22488779 TI - Microdeletion 19p13.2 in an almost 5-year-old boy. AB - Deletions of the short arm of chromosome 19 are rarely found by conventional cytogenetic techniques. This region has a high gene density and this is likely the reason why deletions in this region are associated with a severe phenotype. Since the implementation of modern high-resolution SNP- and CGH-array techniques more cases have been reported. Here, we present an almost 5-year-old boy with intellectual disability, minor dysmorphisms, febrile seizures, and a de novo deletion of 834.2 kb on 19p13.2 encompassing 32 genes. The deletion was found by the Illumina Infinium HD Human1M-Duo v1 BeadChip SNP-array and confirmed by the NimbleGen Human CGH 2.1M Whole Genome Tiling v2.0D oligonucleotide array. PCR amplification of the junction fragment and subsequent sequencing defined the breakpoints and indicated that formation was mediated by non-allelic homologous recombination (NAHR). The phenotype of our patient shows that microrearrangements even at gene-dense chromosomes may result in mild clinical consequences. PMID- 22488781 TI - Magnetic-plasmonic dual modulated FePt-Au ternary heterostructured nanorods as a promising nano-bioprobe. AB - Ternary FePt-Au nanorods are synthesized as magnetic-plasmonic 1D nanostructures. Besides their widely tunable magnetic properties, their unique plasmonic response to the illumination polarization provides a powerful tool to optically image these sub-wavelength single nanorods. These nanoparticles also show the potential as a novel nano-bioprobe based on the demonstration of simultaneous magnetic manipulation and optical imaging of single particles inside live cells. PMID- 22488782 TI - Toxicity of crude oil chemically dispersed in a wave tank to embryos of Atlantic herring (Clupea harengus). AB - Tests of crude oil toxicity to fish are often chronic, exposing embryos from fertilization to hatch to oil solutions prepared using standard mixing procedures. However, during oil spills, fish are not often exposed for long periods and the dynamic nature of the ocean is not easily replicated in the lab. Our objective was to determine if brief exposures of Atlantic herring (Clupea harengus) embryos to dispersed oil prepared by standard mixing procedures was as toxic as oil dispersed in a more realistic model system. Embryos were first exposed to chemically dispersed Alaska North Slope crude and Arabian light crude oil for 2.4 h to 14 d from fertilization to determine if exposure time affected toxicity. Toxicity increased with exposure time, but 2.4-h exposures at realistic concentrations of oil induced blue-sac disease and reduced the percentage of normal embryos at hatch; there was little difference in toxicity between the two oils. Secondly, oil was chemically dispersed in a wave tank to determine if the resultant oil solutions were as toxic to herring embryos as laboratory-derived dispersed oil using a single exposure period of 24 h. Samples taken 15 min postdispersion were more toxic than laboratory-prepared solutions, but samples taken at 5, 30, and 60 min postdispersion were less toxic. Overall, the laboratory- and wave tank-derived solutions of dispersed oil provided similar estimates of toxicity despite differences in the methods for preparing test solutions, suggesting that laboratory and wave tank data are a reliable basis for ecological risk assessments of spilled oil. PMID- 22488783 TI - Early versus delayed percutaneous coronary intervention for patients with non-ST segment elevation acute coronary syndrome: a meta-analysis of randomized controlled clinical trials. AB - BACKGROUND: Studies assessing the timing of percutaneous coronary interventions (PCI) in patients with Non-ST segment elevation Acute Coronary Syndromes (NSTE ACS) have failed to generate a consensus on how early PCI should be performed in such patients. PURPOSE: This meta-analysis compares clinical outcomes at 30 days in NSTE-ACS patients undergoing PCI within 24 hours of presentation (early PCI) with those receiving PCI more than 24 hours after presentation (delayed PCI). DATA SOURCES: Data were extracted from searches of MEDLINE (1990-2010) and Google scholar and from scrutiny of abstract booklets from major cardiology meetings (1990-2010). STUDY SELECTION: Randomized clinical trials (RCTs) that included the composite endpoint of death and non-fatal myocardial infarction (MI) at 30 days after PCI were considered. DATA EXTRACTION: Two independent reviewers extracted data using standard forms. The effects of early and delayed PCI were analyzed by calculating pooled estimates for death, non-fatal MI, bleeding, repeat revascularization and the composite endpoint of death or non-fatal MI at 30 days. Univariate analysis of each of these variables was used to create odds ratios. DATA SYNTHESIS: Seven studies with a total of 13,762 patients met the inclusion criteria. There was no significant difference in the odds of the composite endpoint of death or non-fatal MI at 30 days between patients undergoing early PCI and those receiving delayed PCI (OR-0.83, 95%CI 0.62-1.10). Patients receiving delayed PCI experienced a 33% reduction in the odds of repeat revascularization at 30 days compared to those undergoing early PCI (OR-1.33, 95%CI 1.14-1.56, P=0.0004).Conversely, patients undergoing early PCI experienced lower odds of bleeding than those receiving delayed PCI (OR-0.76, 95%CI 0.63 0.91, P = 0.0003). CONCLUSIONS: In NSTE-ACS patients early PCI doesn't reduce the odds of the composite endpoint of death or non-fatal MI at 30 day. This strategy is associated with lower odds of bleeding and higher odds of repeat revascularization at 30 days than a strategy of delayed PCI. PMID- 22488784 TI - A novel technique to assess chromatin texture using pixel optical densitometry in oral squamous cell carcinoma. AB - BACKGROUND: The early detection of neoplasia is the prime aim of a diagnostician. Altered chromatin distribution is the earliest microscopic change observed in malignant transformation making it a valuable morphometric parameter. This study was aimed to assess and correlate the progressive changes in chromatin texture from normal to varying grades of premalignancies to malignancy of the oral cavity. METHODS: Thirty-four archival tissue specimens categorized as normal buccal mucosa (5), low-grade epithelial dysplasia (11), high-grade epithelial dysplasia (7), and squamous cell carcinoma (11) were stained with Feulgen reaction. Pixel optical densitometry histograms were obtained from analysis of an average of 300 cells/case using ImageJ software. Nine histogram curve characteristics (including area under the curve, area integer percentage, center, centroid) were then analyzed statistically for differences between the four groups. RESULTS: Area integer percentage (P = 0.002), center (P = 0.038), and centroid (P = 0.021) were statistically significant within the four groups The parameters showed a dip in their value from normal to low-grade dysplasia but showed a steady increase in high-grade dysplasia and carcinoma. CONCLUSION: The optical density characteristics had the ability to differentiate the progression of neoplastic changes by extracting information of the chromatin distribution not quantifiable by routine microscopy. The early clumping of chromatin in the periphery in low-grade dysplasia followed by progressively increasing chromatin aggregates in high-grade dysplasia and carcinoma correlated well with the shift observed in the histogram center and centroid. The novel pixel optical densitometry technique efficiently predicted malignant transformation. PMID- 22488785 TI - Complete resolution of laryngeal amyloidosis with radiation treatment. AB - BACKGROUND: Localized amyloidosis of the larynx is a rare entity of unclear etiology. Surgical debulking is the primary treatment modality but often is not curative. METHODS AND RESULTS: A 41-year-old woman presenting with increasing hoarseness, dysphagia, dyspnea, and weight loss was found to have a submucosal mass in the left false vocal fold. Biopsy of the specimen revealed amyloid. After negative work-up for systemic disease, the patient underwent surgical debulking. Specimens revealed a population of clonal plasma cells demonstrating lambda restriction. The patient was treated with adjuvant external beam radiation to a dose of 45 Gy. At 11 months, the patient's voice, breathing, and swallowing have all improved substantially. CONCLUSIONS: Recent pathologic studies suggest that localized amyloidosis of the larynx is caused by a localized, nonmalignant plasma cell disorder. Because full resection is difficult, we recommend a combination of surgery and radiation therapy to cure this disease. PMID- 22488786 TI - Definitive treatment of metastatic nasopharyngeal carcinoma: Report of 5 cases with review of literature. AB - BACKGROUND: To review the treatment outcomes of patients presenting to Memorial Sloan-Kettering Cancer Center with metastatic nasopharyngeal carcinoma. METHODS: From April 1999 to April 2008, 5 patients with histologically confirmed nasopharyngeal carcinoma initially presenting with distant metastasis underwent chemotherapy and definitive radiation therapy at our institution. Each patient received platinum-based chemotherapy concurrently with definitive radiotherapy to the primary region and subsequent consolidation radiotherapy to distant metastases. In addition, 2 patients received induction chemotherapy (cisplatin, fluorouracil), and 3 others received adjuvant chemotherapy (cisplatin or carboplatin, fluorouracil). RESULTS: Of 5 patients initially presenting to our institution with M1 disease, 2 have no evidence of disease as of their last follow-up (29 and 91 months). The remaining 3 patients had progression of disease within 12 months of the start of treatment. CONCLUSIONS: Long-term disease-free survival is possible in a select group of patients with M1 disease at presentation treated with platinum-based chemotherapy and definitive radiotherapy. PMID- 22488787 TI - A fight for survival: the challenges faced by a newborn neuron integrating in the adult hippocampus. AB - The hippocampus is one of the only two regions in the adult mammalian brain endowed with life-long neurogenesis. Yet this adult neurogenesis is a challenging process as newborn neurons face several times life-and-death decisions while in the process of stably integrating into a pre-existing network. Here we describe the morphological and physiological changes a young neuron experiences during its first few weeks of life of stepwise integration into the circuit. This process is competitive in nature, with only few of the newly generated neurons being awarded with a grant of survival. Although the underlying mechanisms are far from being understood, evidence suggests that this competition for stable integration and survival amongst cohorts of newborn neurons occurs to large degree on a synaptic level and may involve specific patterns of neural activity. PMID- 22488788 TI - Tridentate thiolate ligands: application to the synthesis of the site differentiated [4Fe-4S] cluster having a hydrosulfide ligand at the unique iron center. AB - We have designed new trithiols Temp(SH)(3) and Tefp(SH)(3) that can be synthesized conveniently in short steps and are useful for preparation of crystalline [3:1] site-differentiated [4Fe-4S] clusters suitable for X-ray structural analysis. The ethanethiolate clusters (PPh(4))(2)[Fe(4)S(4)(SEt)(TempS(3))] (4a) and (PPh(4))(2)[Fe(4)S(4)(SEt)(TefpS(3))] (4b) were prepared as precursors, and the unique iron sites were then selectively substituted. Upon reaction with H(2)S, (PPh(4))(2)[Fe(4)S(4)(SH)(TempS(3))] (6a) and (PPh(4))(2)[Fe(4)S(4)(SH)(TefpS(3))] (6b), which model the [4Fe-4S] cluster in the beta subunit of (R)-2-hydroxyisocaproyl-CoA dehydratase, were synthesized. Clusters 6a and 6b were further converted to the sulfido-bridged double cubanes (PPh(4))(4)[{Fe(4)S(4)(TempS(3))}(2)(MU(2)-S)] (7a) and (PPh(4))(4)[{Fe(4)S(4)(TefpS(3))}(2)(MU(2)-S)] (7b), respectively, via intermolecular condensation with the release of H(2)S. Conversely, addition of H(2)S to 7a,b afforded the hydrosulfide clusters 6a,b. The molecular structures of the clusters reported herein were elucidated by X-ray crystallographic analysis. Their redox properties were investigated by cyclic voltammetry. PMID- 22488789 TI - Towards a structural basis for the relationship between blood group and the severity of El Tor cholera. PMID- 22488791 TI - Polymer pen lithography (PPL)-induced site-specific click chemistry for the formation of functional glycan arrays. AB - Polymer pen lithography (PPL) can be combined with the Cu(I) -catalyzed azide alkyne click reaction to create molecular arrays with control over orientation and sub-1 MUm feature sizes over cm(2) areas. The process has been applied to the deposition of carbohydrates to form functional glycochips. PMID- 22488792 TI - Evaluation of a cognitive remediation therapy group for adolescents with anorexia nervosa: pilot study. AB - OBJECTIVE: Cognitive remediation therapy (CRT) has been used with adults with anorexia nervosa (AN) in individual and group formats; however, evaluation of CRT with adolescents in this population is very limited. METHOD: Seven CRT groups were carried out with a total of 30 adolescents with AN. Adolescents' cognitive flexibility and motivation was assessed before and after the group, and they completed qualitative questionnaires after the group to determine their perceptions. RESULTS: There was a small effect size in self-reported cognitive flexibility post group. Adolescents found the group interesting and useful; however, some wanted more support with application to real life. DISCUSSION: Cognitive remediation therapy has the potential to be used with adolescents with AN. More research is needed to determine if CRT is beneficial for young people with AN. PMID- 22488793 TI - MRI acoustic noise can harm experimental and companion animals. AB - PURPOSE: To assess possible damage to the hearing of experimental and companion animal subjects of magnetic resonance imaging (MRI) scans. MATERIALS AND METHODS: Using animal hearing threshold data and sound level measurements from typical MRI pulse sequences, we estimated "equivalent loudness" experienced by several experimental and companion animals commonly subjects of MRI scans. We compared the equivalent loudness and exam duration to safe noise standards set by the National Institute for Occupational Safety and Health (NIOSH). RESULTS: Monkeys, dogs, cats, pigs, and rabbits are frequently exposed to equivalent loudness levels during MRI scans beyond what is considered safe for human exposure. The sensitive frequency ranges for rats and mice are shifted substantially upward and their equivalent loudness levels fall within the NIOSH safe zone. CONCLUSION: MRI exposes many animals to levels of noise and duration that would exceed NIOSH human exposure limits. Researchers and veterinarians should use hearing protection for animals during MRI scans. Experimental research animals used in MRI studies are frequently kept and reimaged, and hearing loss could result in changed behavior. Damage to companion animals' hearing could make them less sensitive to commands and generally worsen interactions with family members. Much quieter MRI scanners would help decrease stress and potential harm to scanned animals, normalize physiology during MRI, and enable MRI of awake animals. PMID- 22488794 TI - Intravoxel incoherent motion MR imaging for prostate cancer: an evaluation of perfusion fraction and diffusion coefficient derived from different b-value combinations. AB - There has been a resurgent interest in intravoxel incoherent motion (IVIM) MR imaging to obtain perfusion as well as diffusion information on lesions, in which the diffusion was modeled as Gaussian diffusion. However, it was observed that this diffusion deviated from expected monoexponential decay at high b-values and the reported perfusion in prostate is contrary to the findings in dynamic contrast-enhanced (DCE) MRI studies and angiogenesis. Thus, this work is to evaluate the effect of different b-values on IVIM perfusion fractions (f) and diffusion coefficients (D) for prostate cancer detection. The results show that both parameters depended heavily on the b-values, and those derived without the highest b-value correlated best with the results from DCE-MRI studies; specifically, f was significantly elevated (7.2% vs. 3.7%) in tumors when compared with normal tissues, in accordance with the volume transfer constant (K(trans); 0.39 vs. 0.18 min(-1)) and plasma fractional volume (v(p) ; 8.4% vs. 3.4%). In conclusion, it is critical to choose an appropriate range of b-values in studies or include the non-Gaussian diffusion contribution to obtain unbiased IVIM measurements. These measurements could eliminate the need for DCE-MRI, which is especially relevant in patients who cannot receive intravenous gadolinium based contrast media. PMID- 22488795 TI - Ex vivo effects of an Oenothera paradoxa extract on the reactive oxygen species generation and neutral endopeptidase activity in neutrophils from patients after acute myocardial infarction. AB - Oxidative stress induced by reactive oxygen species (ROS) is considered to play an important part in the aetiology of coronary heart disease. Apart from ROS, neutrophils are a source of neutral endopeptidase (NEP) that inactivates protective natriuretic peptides. The aim of the present study was to evaluate the in vitro ROS generation and inhibition of NEP activity in neutrophils obtained from healthy volunteers and from patients after acute myocardial infarction (AMI) by an aqueous extract of Oenothera paradoxa. Neutrophils isolated from AMI patients showed two-fold higher ROS generation compared with cells from healthy donors, especially in the lucigenin-enhanced luminescence model, which suggests intensive O2- generation. The addition of O. paradoxa extract at concentrations of 0.2, 2 and 20 ug/mL resulted in a significant reduction in ROS generation. The extracellular NEP activity was higher in patients after AMI compared with healthy individuals (15.0 +/- 0.9 versus 10.3 +/- 0.5 nmol AMC/10(6) cells/60 min; p = 0.001). The addition of O. paradoxa extract at concentrations of 20, 50 and 100 ug/mL resulted in a significant reduction in NEP activity in both groups. O. paradoxa extract appears to be an interesting candidate for supplementation in the prevention of cardiovascular diseases. PMID- 22488796 TI - Vaccinium myrtillus ameliorates unpredictable chronic mild stress induced depression: possible involvement of nitric oxide pathway. AB - Chronic unpredictable stressors can produce a situation similar to clinical depression and such animal models can be used for the preclinical evaluation of antidepressants. Nitric oxide, a secondary messenger molecule, has been implicated in neurotransmission, synaptic plasticity, learning, aggression and depression. Vaccinium myrtillus (bilberry) extract is a potent inhibitor of reactive oxygen/nitrogen species and cytokine production. The present study investigated the role of nitric oxide in the antidepressant action of Vaccinium myrtillus in unpredictable chronic mild stress-induced depression in mice. Animals were subjected to different stress paradigms daily for a period of 21 days to induce depressive-like behavior. Pretreatment with L-arginine significantly reversed the protective effect of bilberry (500 mg/kg) on chronic stress-induced behavioral (immobility period, sucrose preference) and biochemical (lipid peroxidation and nitrite levels; endogenous antioxidant activities) in stressed mice. Furthermore, L-NAME (10 mg/kg) pretreatment with a sub-effective dose of bilberry (250 mg/kg) significantly potentiated the protective effect of bilberry extract. The study revealed that modulation of the nitric oxide pathway might be involved in antidepressant-like effects of Vaccinium myrtillus in stressed mice. PMID- 22488798 TI - Recent developments in the synthesis of five- and six-membered heterocycles using molecular iodine. AB - Heterocyclic scaffolds represent the key structural subunits of many biologically active compounds. Over the last few years iodine-mediated reactions have been extensively studied due to their low cost and eco-friendliness. This Review covers advances in the field of iodine-mediated synthesis of heterocyclic compounds since 2006, especially with an emphasis on mechanisms of ring formation. In this article, syntheses of different heterocycles are classified based on the manipulation of functional groups. PMID- 22488799 TI - High-rate capability silicon decorated vertically aligned carbon nanotubes for Li ion batteries. PMID- 22488797 TI - ALK+ anaplastic large cell lymphoma exhibits phosphatidylinositol-3 kinase/Akt activity with retained but inactivated PTEN--a report from the Children's Oncology Group. AB - BACKGROUND: ALK+ anaplastic large cell lymphoma (ALCL) is usually a disease of young patients. We investigated phosphatidylinositol-3 kinase (PI3K)/Akt pathway associated factors in pediatric cases and cell lines. PROCEDURE: Patient materials consisted of tissue slides of ALK+/CD30+ ALCL from 33 patients treated on Pediatric Oncology Group protocols (9219, n = 8 and 9315, n = 25). Slides were examined by immunohistochemistry for phospho(p)-Akt and PTEN, the primary feedback regulator of the pathway, as well as for p27kip1 and stathmin-1. ALCL cell lines SUDHL-1 and Karpas-299 were examined for ALK, pALK, pAkt, p27/Kip1, PTEN, pPTEN, CD30, pSTAT3, and pSTAT5; ALK inhibition was performed using compound PF-2341066 and PTEN genes were sequenced. RESULTS: A majority of patients expressed pAkt, PTEN, and stathmin, with p27kip1 levels less than controls. Cell lines showed expression of ALK, pALK, pSTAT3, pSTAT5, CD30, pAkt, PTEN, and pPTEN, with p27 slightly less than positive controls, and germline PTEN DNA. There was evidence of phosphorylated PTEN (pPTEN) associated with inhibited function. Pharmacologic inhibition of activated ALK diminished pSTAT3, pSTAT5, and CD30 expression but not pAkt or pPTEN in cultured cell lines. CONCLUSION: We conclude that the PI3K/Akt pathway is activated in many, though not all, pediatric ALK+ ALCL. Our data suggest that activation of this pathway involves post-translational regulation of PTEN. Pharmacologic inhibition of activated ALK does not reduce modest levels of activated Akt as it does with the more abundant levels of activated STAT3 or STAT5. Future therapy of ALCL might, in selected patients, best combine agents inhibiting PI3K/Akt with those targeting ALK. PMID- 22488800 TI - Urodynamic quantification of decrease in sphincter function after radical prostatectomy: relation to postoperative continence status and the effect of intensive pelvic floor muscle exercises. AB - AIMS: We analyzed the impact of radical retropubic prostatectomy (RRP) on the urethral sphincter function as assessed by urethral pressure profilometry (UPP) and its relation to post-radical prostatectomy continence status. Furthermore, we analyzed the effect of intensive pelvic floor muscle exercises (PFME) on the urethral sphincter function. METHODS: Sixty-six patients were included in the study. UPP was performed before RRP and 26 weeks after catheter removal. All patients were instructed in PFME, however, the intensity of PFME varied between instructions based on an information folder only (F-PFME) and intensive guidance by a physiotherapist, in addition to the folder (PG-PFME). RESULTS: In 66 patients, pre- as well as postoperative UPP was evaluable. After surgery, the functional profile length and the maximum urethral closure pressure (MUCP) showed a median decrease of 64% and 41%, respectively. For men who had regained continence after 6 months the median MUCP was significantly higher both before and after operation as compared to men who were still incontinent. In multivariate analysis, non-nerve sparing approach was a prognostic factors for a higher relative decrease of the MUCP after RRP. Comparing the PG-PFME group with the F-PFME group there were no significant differences in changes in UPP parameters. CONCLUSIONS: A poor preoperative MUCP seems to be an important prognostic factor for persistent incontinence after RRP. Non-nerve sparing approach seems to be an important prognostic factor for impairment of the urethral sphincter function as measured by UPP. More intensive physiotherapy seems to have no additional effect on the postoperative urethral sphincter function as measured by UPP. PMID- 22488802 TI - Accurate measurement of oxygen consumption in children undergoing cardiac catheterization. AB - Oxygen consumption (VO(2) ) is an important part of hemodynamics using the direct Fick principle in children undergoing cardiac catheterization. Accurate measurement of VO(2) is vital. Obviously, any error in the measurement of VO(2) will translate directly into an equivalent percentage under- or overestimation of blood flows and vascular resistances. It remains common practice to estimate VO(2) values from published predictive equations. Among these, the LaFarge equation is the most commonly used equation and gives the closest estimation with the least bias and limits of agreement. However, considerable errors are introduced by the LaFarge equation, particularly in children younger than 3 years of age. Respiratory mass spectrometry remains the "state-of-the-art" method, allowing highly sensitive, rapid and simultaneous measurement of multiple gas fractions. The AMIS 2000 quadrupole respiratory mass spectrometer system has been adapted to measure VO(2) in children under mechanical ventilation with pediatric ventilators during cardiac catheterization. The small sampling rate, fast response time and long tubes make the equipment a unique and powerful tool for bedside continuous measurement of VO(2) in cardiac catheterization for both clinical and research purposes. PMID- 22488801 TI - Structure-property investigations with dielectric study on phosphorylcholine based polyurethane. AB - Polyurethane with zwitterionic phosphorylcholine on the main chain was synthesized and the structures were defined with FTIR and (1)HNMR. The mechanical (tensile strength, elastic modulus) and biological (platelet adhesion) evaluations of its blend films with polyurethane were of satisfactory results, which were in accordance with the requirements of the medical devices, showing their potential applications as anticoagulant biomaterials. The dielectric spectroscopy was recorded with solid films and with films in water. The dielectric dispersion of the solid films demonstrated the existence of condensed ionic structures, which lead to the rigidity enhancement of the soft segment of the phosphorylcholine-based polyurethane, so that its elastic modulus increased. The dielectric measurement with films in water, providing a measurement for the surface properties in the aqueous environment, offered a semiquantitative description of the interface dynamics of the material with a double-layer model, based on which a new hypothesis on the mechanism of blood or bio-compatibility was proposed that the hydrated surface of the satisfactory biomaterials can response to the outside electromagnetic stimuli with slight strength and prompt relaxation. PMID- 22488804 TI - Microtomographic evaluation of the bone-cell interactions with a silorane-based composite. AB - The low-shrink Silorane-based composite could bond effectively to bone and showed the potential be used as a bone cement. Bone organ culture maintains the anatomical order, natural cell-to-cell and cell-to-matrix relationship. The purpose of this study was to evaluate the responses of bone cells to a Silorane based composite which was compared with a representative polymethyl methacrylate (PMMA) bone cement. The critical size defects were created through the parietal bones from one litter of mice. The paired bones were divided into two groups: Silorane-based composite group and PMMA group. The prepared two groups of disks were put into the defects. The cultures were grown in vitro for 38 days and analyzed with microcomputed-tomography, dissecting-microscope, phase- contrast microscope, scanning-electron-microscopy, and energy- dispersive-X-ray. At the 10th day, the Silorane disk was almost fully covered by a sheet of cells but the cells hardly attached to the disk surface. The edge of the PMMA disk was covered by a sheet of cells and the migrated individual cells attached to the whole surface of the disk. At the 38th day, some cells attached to the exposed disk area of the Silorane disk while the formed tissues covered the whole surface of the PMMA disk. The collagen fibers, globular deposits and bone formation were visible in both groups. The Silorane-based composite showed promise as a potential bone cement when compared with PMMA which is used in clinical orthopedics. However, the cell attachment to PMMA was evidently better than to Silorane-based composite. PMID- 22488805 TI - Effects of leachate from tree leaves and grass litter on tadpoles. AB - Tree species composition can change as a result of succession, climate change, fire suppression, and invasive species. These changes clearly affect forests, but they can also affect aquatic ecosystems based on differences in the input quality of leaf litter, such as plant secondary compounds. These compounds vary in type and concentration depending on species and can be toxic to aquatic organisms. To examine toxic effects on Pseudacris maculata and Pseudacris crucifer tadpoles, we conducted 60-d laboratory experiments to compare leaf litter leachate from a dominant canopy species (red oak) and nonnative species (white pine) with an aquatic grass (prairie cordgrass) and plain water control. An additional experiment examined the effects of white pine on Bufo americanus, Hyla versicolor, and tannin concentrations in natural ponds. Compared with the control and grass, tree leaf extracts resulted in reduced tadpole survival. Leached compounds from pine reduced tadpole survival to 3 d or less. Tadpoles were able to metamorphose in significant numbers only from the two controls. The lowered survival with the red oak treatment might have been caused by lowered dissolved oxygen or high tannin concentrations. However, pine is known to have high concentrations of toxic monoterpenes, which should be investigated further. We found that tannin concentrations in natural ponds were much lower than the test concentrations, indicating that these results may represent worst-case scenarios or unrealistic concentrations. PMID- 22488806 TI - Inhibition of interdomain motion in g-actin by the natural product latrunculin: a molecular dynamics study. AB - As part of the cytoskeleton, actin is essential for the morphology, motility, and division of eukaryotic cells. Recent X-ray fiber diffraction studies have shown that the conformation of monomeric actin is flattened upon incorporation into the filament by a relative rotation of its two major domains. The antiproliferative activity of latrunculin, a macrolide toxin produced by sponges, seems to be related to its binding to monomeric actin and inhibition of polymerization. Yet, the mechanism of inhibition is not known in detail. Here, multiple explicit water molecular dynamics simulations show that latrunculin binding hinders the conformational transition related to actin polymerization. In particular, the presence of latrunculin at the interface of the two major domains of monomeric actin reduces the correlated displacement of Domain 2 with respect to Domain 1. Moreover, higher rotational flexibility between the two major domains is observed in the absence of ATP as compared to ATP-bound actin, offering a possible explanation as to why actin polymerizes more favorably in the absence of nucleotides. PMID- 22488807 TI - A fragile X sibship from a consanguineous family with a compound heterozygous female and partially methylated full mutation male. PMID- 22488809 TI - Stem cell maintenance in the adult mammalian hippocampus: a matter of signal integration? AB - The continuous generation of new neurons from stem cells in the hippocampal dentate gyrus is considered an important contributor to hippocampal plasticity. A prerequisite for the life-long generation of new dentate granule neurons is the maintenance of the neural stem cell pool. A number of essential molecular regulators and signals for hippocampal neural stem cell maintenance have been identified, but how these pathways interact to prevent precocious differentiation or exhaustion of the stem cell pool is currently unknown. Here, we summarize the current knowledge on the molecular regulation of the hippocampal stem cell pool and discuss the possibility that signal integration through Notch signaling controls stem cell maintenance in the adult hippocampus. PMID- 22488808 TI - Synthesis of optically pure norcantharidin analogue NCA-01, a highly selective protein phosphatase 2B inhibitor, and its derivatives. AB - An efficient synthetic route to optically pure norcantharidin analogue NCA-01, a highly selective inhibitor of protein phosphatase 2B (PP2B; calcineurin), has been developed. The absolute stereochemistry of the enantiomers was determined by X-ray crystallographic analysis. Optically pure NCA derivatives that had various substituents at the C1 position were synthesized in a similar manner. The PP2B inhibitory activities of NCA-01 and its derivatives were independent of the enantiomeric form. NCA-01 dimethyl ester potently inhibited IL-2 production in Jurkat cells. PMID- 22488810 TI - Hierarchical electrohydrodynamic structures for surface-enhanced Raman scattering. AB - Surface enhanced Raman scattering (SERS) is a well-established spectroscopic technique that requires nanoscale metal structures to achieve high signal sensitivity. While most SERS substrates are manufactured by conventional lithographic methods, the development of a cost-effective approach to create nanostructured surfaces is a much sought-after goal in the SERS community. Here, a method is established to create controlled, self-organized, hierarchical nanostructures using electrohydrodynamic (HEHD) instabilities. The created structures are readily fine-tuned, which is an important requirement for optimizing SERS to obtain the highest enhancements. HEHD pattern formation enables the fabrication of multiscale 3D structured arrays as SERS-active platforms. Importantly, each of the HEHD-patterned individual structural units yield a considerable SERS enhancement. This enables each single unit to function as an isolated sensor. Each of the formed structures can be effectively tuned and tailored to provide high SERS enhancement, while arising from different HEHD morphologies. The HEHD fabrication of sub-micrometer architectures is straightforward and robust, providing an elegant route for high-throughput biological and chemical sensing. PMID- 22488811 TI - A small molecule that walks non-directionally along a track without external intervention. PMID- 22488812 TI - Preliminary results of (125)I interstitial brachytherapy for locally recurrent parotid gland cancer in previously irradiated patients. AB - BACKGROUND: The purpose of this study was to analyze the treatment of recurrent parotid gland cancers with radioactive iodine ((125)I) seed implantation. METHODS: Fifteen patients with recurrent previously irradiated parotid gland cancers were treated with postoperative (125)I seed implantation between April 2004 and June 2009. Local control, survival rates, and side effects were retrospectively reviewed. RESULTS: The 3-year and 5-year local control rates were 67% and 53.6%, and the overall survival rates were 76.2% and 66.7%, respectively. Four patients with House-Brackman (H-B) grade IV cancer recovered to grade II during follow-up. Four patients (26.7%) developed grade IV skin ulceration. Two patients (13.3%) developed moderate fibrosis of the subcutaneous tissues, and 2 patients (13.3%) had hearing loss for 1 year after brachytherapy. CONCLUSION: This study showed excellent local control and a good survival rate in patients who received (125)I brachytherapy. These findings should be interpreted cautiously due to the small number of patients and the relatively short follow up. PMID- 22488814 TI - Scalable total synthesis of (-)-berkelic acid by using a protecting-group-free strategy. AB - Supply chain: the polycyclic core of (-)-berkelic acid (1) was constructed in just one step from very simple starting materials. The total synthesis of 1 involves a seven-step linear sequence. Protection/deprotection steps were avoided and all but the last step were performed on a gram scale. This synthesis could solve the supply problem associated with the exhaustion of the natural source. PMID- 22488815 TI - Regional effects of magnetization dispersion on quantitative perfusion imaging for pulsed and continuous arterial spin labeling. AB - Most experiments assume a global transit delay time with blood flowing from the tagging region to the imaging slice in plug flow without any dispersion of the magnetization. However, because of cardiac pulsation, nonuniform cross-sectional flow profile, and complex vessel networks, the transit delay time is not a single value but follows a distribution. In this study, we explored the regional effects of magnetization dispersion on quantitative perfusion imaging for varying transit times within a very large interval from the direct comparison of pulsed, pseudo continuous, and dual-coil continuous arterial spin labeling encoding schemes. Longer distances between tagging and imaging region typically used for continuous tagging schemes enhance the regional bias on the quantitative cerebral blood flow measurement causing an underestimation up to 37% when plug flow is assumed as in the standard model. PMID- 22488816 TI - Surgical complications in pediatric surgical oncology. AB - Rates of surgical complications in pediatric oncological patients increase with the extension of tumor surgery. Especially in advanced tumors this can mean a relevant challenge to surgeons: The balance between risk of complications and success of surgical treatment is often difficult to accomplish. As a consequence, surgeons not only need profound knowledge about resection techniques and surgical standard procedures but they also have to be able to control and manage surgical complications during and after surgery. This article highlights background and spectrum as well as management of selected surgical complications during or after surgery for abdominal pediatric solid tumors. PMID- 22488818 TI - Editorial for May, 2012. PMID- 22488820 TI - Hole and electron extraction layers based on graphene oxide derivatives for high performance bulk heterojunction solar cells. AB - By charge neutralization of carboxylic acid groups in graphene oxide (GO) with Cs(2)CO(3) to afford Cesium-neutralized GO (GO-Cs), GO derivatives with appropriate modification are used as both hole- and electron-extraction layers for bulk heterojunction (BHJ) solar cells. The normal and inverted devices based on GO hole- and GO-Cs electron-extraction layers both outperform the corresponding standard BHJ solar cells. PMID- 22488817 TI - Can preoperative urodynamic investigation be omitted in women with stress urinary incontinence? A non-inferiority randomized controlled trial. AB - AIMS: To assess in women with stress urinary incontinence (SUI) the value of urodynamics prior to treatment. METHODS: We performed a multicenter non inferiority randomized controlled trial. Women with SUI were randomly allocated to management based on a workup with or without urodynamics. The primary outcome was clinical reduction of complaints as measured with the Urogenital Distress Inventory urinary incontinence subscale (UDI-UI) at 12 months after the onset of treatment. A mean difference in improvement of less than 8 was considered non inferior. The study was analyzed according to intention-to-treat. RESULTS: The trial was stopped prematurely because of slow recruitment. We randomly allocated 59 women to a strategy with (N = 31) or without (N = 28) urodynamics. The mean difference in improvement on the UDI-UI was 14 in favor of the group without urodynamics (48 SD +/- 22 vs. 34 SD +/- 22, 95% CI: -28 to -0.26), confirming non inferiority. Addition of urodynamics did not result in a lower occurrence of de novo overactive bladder complaints compared to a workup without urodynamics (6/31 vs. 1/28; RR 5.4, 95% CI: 0.70-42). In the group allocated to urodynamics, initial surgical management was more often abandoned compared to the group not allocated to urodynamics (5/31 vs. 1/28; RR 4.5, 95% CI: 0.56-36). CONCLUSIONS: In this relatively small study, the omission of urodynamics was not inferior to the use of urodynamics in the preoperative workup of women with SUI. Women with SUI undergoing urodynamics had the risk of a choice for more prudent treatment, which seemed to result in a delay until effective treatment. PMID- 22488821 TI - Sulfangolids, macrolide sulfate esters from Sorangium cellulosum. AB - Sulfangolids are the first sulfate ester containing secondary metabolites from myxobacteria. The metabolites 1-4 and the structurally related kulkenon (5) were isolated from different strains of the species Sorangium cellulosum. In the course of isolation all metabolites proved to be rather sensitive due to their conjugated double bond systems and the strong acidic nature of the sulfate ester in sulfangolids. The relative configuration of sulfangolid C (3) was assigned by extensive 1D and 2D NMR analysis and molecular modelling. In addition, the biosynthesis of 3 was studied by feeding experiments. PMID- 22488822 TI - Evaluating the relevance of seasonal differentiation of human health intake fractions in life cycle assessment. AB - The intake fraction (iF) is the fraction of an emitted mass of chemical that is ultimately taken in by an entire population, and it is used as an indicator of human health potential impacts related to environmental chemical persistence and bioaccumulation in the food chain. In chemical screening applications, the iF can be predicted using multimedia and multipathway fate and exposure models. One of the sources of iF uncertainty is the natural seasonal variability of the input parameters used in the models, i.e., the physicochemical properties of the pollutant and the landscape and exposure parameters. The objective of this article is to determine the relevance of including seasonal differentiation when assessing iFs in life cycle assessment. This was done by calculating and comparing seasonal iFs with each other and with iFs at 25 degrees C, for both Canadian and global contexts. Two Canadian seasonal models based on the IMPACT 2002 predictive tool, and 2 models for the global context based on the USEtox consensus model were developed to calculate summer and winter iFs. Emissions into air and water and a set of 35 representative organic chemicals were considered. Partition coefficients for seasonal conditions were calculated using an integration of the van't Hoff equation. First-order degradation rate constants were calculated assuming that the rate constant doubles with each 10 degrees C increase in temperature. For Canadian air emissions, results indicated that iFs for winter emissions could be up to 1 to 2 orders of magnitude higher than summer iFs or iFs calculated at 25 degrees C. For Canadian water emissions, results showed that iFs for both summer and winter conditions were, in general, closer to each other with outliers within 1 order of magnitude to iFs calculated at 25 degrees C. Results also indicated that seasonal variability was of lesser importance when assessing iFs within a global context. Because the ranking between chemicals was maintained, it can be concluded that seasonal variability is not relevant within a comparative context. However, this difference might be significant when comparing the magnitude of human toxicity impacts versus other impact categories contributing to human health damages. PMID- 22488823 TI - The triterpene cyclase protein family: a systematic analysis. AB - Triterpene cyclases catalyze a broad range of cyclization reactions to form polycyclic triterpenes. Triterpene cyclases that convert squalene to hopene are named squalene-hopene cyclases (SHC) and triterpene cyclases that convert oxidosqualene are named oxidosqualene cyclases (OSC). Many sequences have been published, but there is only one structure available for each of SHCs and OSCs. Although they catalyze a similar reaction, the sequence similarity between SHCs and OSCs is low. A family classification based on phylogenetic analysis revealed 20 homologous families which are grouped into two superfamilies, SHCs and OSCs. Based on this family assignment, the Triterpene Cyclase Engineering Database (TTCED) was established. It integrates available information on sequence and structure of 639 triterpene cyclases as well as on structurally and functionally relevant amino acids. Family specific multiple sequence alignments were generated to identify the functionally relevant residues. Based on sequence alignments, conserved residues in SHCs and OSCs were analyzed and compared to experimentally confirmed mutational data. Functional schematic models of the central cavities of OSCs and SHCs were derived from structure comparison and sequence conservation analysis. These models demonstrate the high similarity of the substrate binding cavity of SHCs and OSCs and the equivalences of the respective residues. The TTCED is a novel source for comprehensive information on the triterpene cyclase family, including a compilation of previously described mutational data. The schematic models present the conservation analysis in a readily available fashion and facilitate the correlation of residues to a specific function or substrate interaction. PMID- 22488824 TI - Iron enhances generation of fibrin fibers in human blood: implications for pathogenesis of stroke. AB - Stroke is associated with the intracerebral formation of fibrin clots which may lead to irreversible brain damage. Thrombolytic therapies employ a variety of natural and/or recombinant plasminogen activators to initiate fibrinolytic degradation of cerebral thrombi. However, such therapies when installed beyond 4- to 6-h window, may fail to achieve the expected outcome. This is due to the hydroxyl radical-induced modification of fibrin(ogen) molecules rendering them refractory to fibrinolytic degradation, but no cause of the increased free radical generation in stroke was offered. Here, we show by means of electron microscopy that iron ions added to human blood dramatically enhances fibrin fibers formation with thrombin, and significantly delays fibrinolysis during spontaneous clotting of native blood. Iron ions caused the appearance dense matted fibrin deposits, similar, if not identical, to those observed in plasma of patients with stroke. These results may explain a known relationship between thrombotic diseases and the increased body concentrations of free iron and/or hemoglobin derivatives. We conclude that any action resulting in the inhibition of hemostatic abnormalities, as well as in the reduction of body free iron and scavenging of hydroxyl radicals (e.g., by polyphenols) can potentially prevent pathological reactions associated with consequences of stroke. PMID- 22488825 TI - Using video-tracking to assess sublethal effects of pesticides on honey bees (Apis mellifera L.). AB - Concern about the role of pesticides in honey bee decline has highlighted the need to examine the effects of sublethal exposure on bee behaviors. The video tracking system EthoVisionXT (Noldus Information Technologies) was used to measure the effects of sublethal exposure to tau-fluvalinate and imidacloprid on honey bee locomotion, interactions, and time spent near a food source over a 24-h observation period. Bees were either treated topically with 0.3, 1.5, and 3 ug tau-fluvalinate or exposed to 0.05, 0.5, 5.0, 50, and 500 ppb imidacloprid in a sugar agar cube. Tau-fluvalinate caused a significant reduction in distance moved at all dose levels (p < 0.05), as did 50 and 500 ppb imidacloprid (p < 0.001). Bees exposed to 50 and 500 ppb spent significantly more time near the food source than control bees (p < 0.05). Interaction time decreased as time in the food zone increased for both chemicals. This study documents that video-tracking of bee behavior can enhance current protocols for measuring the effects of pesticides on honey bees at sublethal levels. It may provide a means of identifying problematic compounds for further testing. PMID- 22488826 TI - Lewis acid-catalyzed intramolecular [3+2] cycloaddition of cyclopropane 1,1 diesters with alkynes for the synthesis of cyclopenta[c]chromene skeletons. AB - An efficient method to construct cyclopenta[c]chromene skeletons by Lewis acid catalyzed intramolecular [3+2] cycloaddition of cyclopropane 1,1-diesters with alkynes is presented. Two new fused cycles can be formed in one step in moderate to excellent yields (up to 94 %), and the products can be converted into bioactive barbituric acid derivatives (1) under simple reaction conditions. PMID- 22488827 TI - Kinetic limitations of intracranial joints in Brachylophosaurus canadensis and Edmontosaurus regalis (Dinosauria: Hadrosauridae), and their implications for the chewing mechanics of hadrosaurids. AB - The highly specialized tooth morphology and arrangement of the dental battery of hadrosaurids has led to much speculation surrounding the chewing mechanics of this successful group of herbivorous dinosaurs. Pleurokinesis, a long established hypothesis explaining the ornithopod chewing mechanism, proposes a transverse power stroke in hadrosaurids that was accommodated by vertical adduction of the mandible, lateral rotation of the maxilla at the maxilla-premaxilla joint, lateral rotation of the jugal-maxilla complex at its contact with the lacrimal, and posterolateral rotation of the quadrate at its contact with the squamosal. A secondary series of movements were also thought to have occurred as a consequence of these primary movements. In this article, the intracranial joint morphology is described for both Brachylophosaurus canadensis and Edmontosaurus regalis and their permissive kinematics are established. Based on this evidence, the movements associated with pleurokinesis are not accommodated in these hadrosaurine dinosaurs. Rather, the movements that seem most likely to have produced the observed dental wear patterns are those associated with the mandible about the jaw joint. The structure of this joint appears well-suited to have accommodated some translation as well as rotation of the mandible about the quadrate condyle. Three-dimensional modeling of the alternate mandibular movements reveals that not all the combined labiolingual width of the lingual and buccal facets of the tooth row was involved in the power stroke. Rather, limits on the degree of mandibular long axis rotation suggest that only the lingual facet and the more medial portion of the buccal facet were utilized. PMID- 22488828 TI - Scanning probe study on the piezotronic effect in ZnO nanomaterials and nanodevices. AB - ZnO nanomaterials with their unique semiconducting and piezoelectric coupled properties have become promising materials for applications in piezotronic devices including nanogenerators, piezoelectric field effect transistors, and diodes. This article will mainly introduce the research progress on piezotronic properties of ZnO nanomaterials investigated by scanning probe microscopy (SPM) and ZnO-based prototype piezotronic nanodevices built in virtue of SPM, including piezoelectric field effect transistors, piezoelectric diodes, and strain sensors. Additionally, nanodamage and nanofailure of ZnO materials and their relevant piezotronic nanodevices will be critically discussed in their safe service in future nanoelectromechanical system (NEMS) engineering. PMID- 22488829 TI - Rationale and methods for quantifying ascending aortic flow eccentricity: back to the underlying mechanism? PMID- 22488830 TI - Micronutrient deficiencies in inflammatory bowel disease: from A to zinc. AB - Inflammatory bowel disease (IBD) has classically been associated with malnutrition and weight loss, although this has become less common with advances in treatment and greater proportions of patients attaining clinical remission. However, micronutrient deficiencies are still relatively common, particularly in CD patients with active small bowel disease and/or multiple resections. This is an updated literature review of the prevalence of major micronutrient deficiencies in IBD patients, focusing on those associated with important extraintestinal complications, including anemia (iron, folate, vitamin B12) bone disease (calcium, vitamin D, and possibly vitamin K), hypercoagulability (folate, vitamins B6, and B12), wound healing (zinc, vitamins A and C), and colorectal cancer risk (folate and possibly vitamin D and calcium). PMID- 22488831 TI - Triple-color super-resolution imaging of live cells: resolving submicroscopic receptor organization in the plasma membrane. AB - In living color: efficient intracellular covalent labeling of proteins with a photoswitchable dye using the HaloTag for dSTORM super-resolution imaging in live cells is described. The dynamics of cellular nanostructures at the plasma membrane were monitored with a time resolution of a few seconds. In combination with dual-color FPALM imaging, submicroscopic receptor organization within the context of the membrane skeleton was resolved. PMID- 22488833 TI - Prototropic tautomerism of 5-aryloxy-1(2)H-tetrazoles. AB - The structure of 5-(2,6-dimethylphenoxy)-1H- and 2H-tetrazoles together with those of 5-(2,6-diisopropyl-phenoxy)-1H and 2H-tetrazoles have been theoretically studied including absolute shieldings and energies. The conclusion of these studies is that a slow tautomerism between 1H- and 2H-tetrazoles cannot explain the experimental observations reported recently in the literature. PMID- 22488832 TI - Transmission of the rare HRAS mutation (c. 173C > T; p.T58I) further illustrates its attenuated phenotype. AB - Costello syndrome was delineated based on its distinctive phenotype including severe failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. Heterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome, and its inheritance pattern would thus be autosomal dominant. With exception of two instances of parental mosaicism, one presumed gonadal and the other proven somatic mosaicism for the p.G12S change, all published cases resulted from de novo mutations, typically arising in the paternal germline. More than 90% of these mutations affect the glycine residues in position 12 or 13, and result in a gain-of-function of the altered protein. A rare heterozygous HRAS alteration (c.173C > T; p.T58I) associated with an attenuated phenotype was previously reported in one patient. We identified two additional individuals with this mutation, father and son. Further studies supported origin of the alteration in the grand-paternal germline. Transmission of the mutation underscores its attenuated phenotype compatible with reproduction. We reviewed the phenotype in the newly identified individuals (Patient 1, 2) and include updated information on the first previously reported individual with HRAS p.T58I (Patient 3). Macrocephaly was present in all three. Cardiac findings included hypertrophic cardiomyopathy with double-chambered right ventricle; or mitral valve prolapse in one patient each. While subtle neurologic abnormalities or developmental delay were present in all, only one showed significant cognitive and functional impairment. None developed papillomata or a malignant tumor. Genetic counseling for Costello syndrome needs to take into consideration the particular HRAS mutation. PMID- 22488834 TI - Prevalence of bladder dysfunction, urodynamic findings, and their correlation with outcome in Guillain-Barre syndrome. AB - AIMS: The micturitional disturbances and related urodynamic studies are infrequently reported in Guillain Barre syndrome (GBS). In the present study, we evaluated patients of GBS for bladder dysfunction and urodynamic abnormalities. We also tried to assess relation between urodynamic findings with disability in patients diagnosed as GBS. METHODS: In this study, 38 patients of GBS were assessed for micturitional disturbances and disability using Hughes motor grade, Overall Disability Sum Score (ODSS), Medical Research Council (MRC) sum score. Urodynamic studies were carried out at baseline and at 2 months. RESULTS: Out of 38 patients, 10 patients had urinary symptoms, 23 patients had urodynamic abnormalities and most common being detrusor underactivity in 15 patients. Other findings were detrusor sphincter dyssynergia in six patients, acontractile bladder in five patients, and detrusor overactivity in three patients. Decreased uroflow rates were seen in 14 patients. Severe disability in the form of Hughes motor grades 4-5, ODSS leg scores 4-7, low MRC scores were significantly more common in patients with urodynamic abnormalities. The axonal variant of GBS patients demonstrated more frequent abnormal urodynamic findings. CONCLUSIONS: Our study revealed fair incidence of micturitional disturbances and urodynamic dysfuctions in GBS. The subclinical bladder involvement was frequently observed, substantiated by urodynamic assessment. The disability, particularly of lower limbs had positive correlation with urodynamic abnormality. PMID- 22488835 TI - Graphene enhances the specificity of the polymerase chain reaction. AB - Graphene can inhibit non-specific DNA fragments, and the specificity of the polymerase chain reaction (PCR) can be retained even after eight rounds of repeated amplification in the presence of graphene in the form of reduced graphene oxide (RGO). In the figure, the numbers at the top give the number of rounds of PCR; lanes marked with C correspond to controls (no RGO), and the concentration of RGO in the other samples is 12 MUg mL(-1) . PMID- 22488836 TI - Chemotherapy compliance in patients with osteosarcoma. AB - PURPOSE: Histological response (HR) to neoadjuvant-chemotherapy (NACT) is considered as a robust prognostic marker in treated osteosarcomas. Chemotherapy compliance can affect both, dose intensity and density and may affect the final outcome in these cases. This vital aspect has been inadequately addressed and therefore merits further investigation. METHOD: A retrospective study of NACT treated osteosarcoma patients, during the year 2010 was conducted. Compliance was defined as receipt of planned cycles of chemotherapy in the planned doses, within the planned duration or up to 25% additional time. HR was assessed by grading for histological necrosis (HN). Good responders (GR) included those with tumors showing >=90% HN. RESULTS: Of 124 patients, 115 were analyzed for post-NACT HR. Of the 73 (64%) compliant patients, 47 were GR and of the 42 (36%) non-compliant patients, 18 were GR. There was significant association between GR and compliance (P = 0.031). However, at a median follow-up of 7.9 months, there was no significant difference in survival between the noncompliant versus compliant group. Non-compliance was justifiable in 26 patients and not justifiable in 16 patients. Using univariate analysis, T-size, pain, performance status, albumin, LDH, and education were identified as significant factors, while in multivariate analysis, only poor performance status was identified as an independent variable for non-compliance. CONCLUSIONS: Two-thirds patients were found to be compliant with NACT. There was a significant association between GR and compliant patients. Significant correlation between compliance and survival may be established with a longer follow-up particularly since "good necrosis" is generally predictive of good survival. PMID- 22488838 TI - Revision of sediment quality triad indicators in Puget Sound (Washington, USA): I. a Sediment Chemistry Index and targets for mixtures of toxicants. AB - The Washington State Department of Ecology annually conducts sediment quality monitoring in Puget Sound as a component of the Puget Sound Ecosystem Monitoring Program. Sediment samples are analyzed to determine the concentrations of about 170 chemical and physical variables. A Sediment Chemistry Index (SCI) was derived using the State of Washington Sediment Management Standards to account for the presence and concentrations of mixtures of toxicants. Mean Sediment Quality Standard quotients (mSQSq) were calculated as the basis for the SCI and compared to the incidence and degree of toxicity in laboratory tests and to metrics of the diversity and abundance of resident benthic assemblages in a database consisting of as many as 664 samples. These data were evaluated with co-occurrence analyses to identify "cut points" (i.e., thresholds) in the index below which the frequency and magnitude of biological effects were relatively low and above which they occurred with increasing frequency or magnitude. Iterative trials of different sets of cut points established the final cut points in mSQSq of 0.1, 0.3, and 0.5. They defined 4 ranges in chemical exposure: Minimum (<0.1), Low (0.1- < 0.3), Moderate (0.3- < 0.5), and Maximum (>=0.5). Across these 4 exposure ranges both the incidence and magnitude of toxicity in some laboratory tests increased, the abundance of most stress-sensitive benthic taxa decreased, and the abundance of most stress-tolerant taxa increased. The mSQSq cut point of 0.1 appears to be the target value for protection of benthic resources, the value below which the probability and magnitude of adverse effects either in the laboratory or the field are the lowest. The mSQSq values are rescaled from 0 to 100 to form the SCI, used by the Puget Sound Partnership and environmental managers as a Dashboard Indicator, with biologically relevant targets selected to monitor ecosystem recovery. PMID- 22488837 TI - A dynamic model for processive transcription elongation and backtracking long pauses by multisubunit RNA polymerases. AB - RNA polymerases are enzymes that transcribe genes from DNA onto strands of RNA. The transcription elongation by multisubunit RNA polymerases is processive but nonuniform: one enzyme can translocate along the DNA template for thousands of nucleotide addition steps but, sometimes, it can enter backtracking long pauses. Here, we present a Brownian ratchet model for the processive transcription elongation and the backtracking long pauses, which is developed based on the available structural and biochemical studies. Using the model, we analytically study the dynamics of the transcription elongation, such as the effects of external force and NTP concentration on the transcription velocity free of pauses, and the dynamics of backtracking long pauses, such as the probabilities of entering and returning from the backtracking pauses, with the analytical results in good agreement with the available single molecule experimental data. Values of several parameters for both Escherichia coli and Saccharomyces cerevisiae RNA polymerases such as their affinities for the DNA/RNA substrate during transcription elongation are determined. Moreover, some testable predictions are presented. PMID- 22488839 TI - Ranking ecological risks of multiple chemical stressors on amphibians. AB - Populations of amphibians have been declining worldwide since the late 1960s. Despite global concern, no studies have quantitatively assessed the major causes of this decline. In the present study, species sensitivity distributions (SSDs) were developed to analyze the sensitivity of anurans for ammonium, nitrate, heavy metals (cadmium, copper), pesticides (18 compounds), and acidification (pH) based on laboratory toxicity data. Ecological risk (ER) was calculated as the probability that a measured environmental concentration of a particular stressor in habitats where anurans were observed would exceed the toxic effect concentrations derived from the species sensitivity distributions. The assessment of ER was used to rank the stressors according to their potential risk to anurans based on a case study of Dutch freshwater bodies. The derived ERs revealed that threats to populations of anurans decreased in the sequence of pH, copper, diazinon, ammonium, and endosulfan. Other stressors studied were of minor importance. The method of deriving ER by combining field observation data and laboratory data provides insight into potential threats to species in their habitats and can be used to prioritize stressors, which is necessary to achieve effective management in amphibian conservation. PMID- 22488840 TI - Synthesis of tin dioxide nanooctahedra with exposed high-index {332} facets and enhanced selective gas sensing properties. AB - High and mighty: Octahedral SnO(2) particles bound by high-index {332} facets were synthesized by a simple hydrothermal route using SnCl(2)?5 H(2)O as the tin salt with the assistance of hydrochloric acid and poly(vinylpyrrolidone). These particles show excellent selective gas sensing performance because they have large numbers of dangling bonds on their surfaces. PMID- 22488841 TI - Genetic analysis and molecular characterisation of laboratory and field mutants of Botryotinia fuckeliana (Botrytis cinerea) resistant to QoI fungicides. AB - BACKGROUND: QoI fungicides, inhibitors of mitochondrial respiration, are considered to be at high risk of resistance development. In several phytopathogenic fungi, resistance is caused by mutations (most frequently G143A) in the mitochondrial cytochrome b (cytb) gene. The genetic and molecular basis of QoI resistance were investigated in laboratory and field mutants of Botryotinia fuckeliana (de Bary) Whetz. exhibiting in vitro reduced sensitivity to trifloxystrobin. RESULTS: B. fuckeliana mutants highly resistant to trifloxystrobin were obtained in the laboratory by spontaneous mutations in wild type strains, or from naturally infected plants on a medium amended with 1-3 mg L(-1) trifloxystrobin and 2 mM salicylhydroxamic acid, an inhibitor of alternative oxidase. No point mutations were detected, either in the complete nucleotide sequences of the cytb gene or in those of the aox and Rieske protein genes of laboratory mutants, whereas all field mutants carried the G143A mutation in the mitochondrial cytb gene. QoI resistance was always maternally inherited in ascospore progeny of sexual crosses of field mutants with sensitive reference strains. CONCLUSIONS: The G143A mutation in cytb gene is confirmed to be responsible for field resistance to QoIs in B. fuckeliana. Maternal inheritance of resistance to QoIs in progeny of sexual crosses confirmed that it is caused by extranuclear genetic determinants. In laboratory mutants the heteroplasmic state of mutated mitochondria could likely hamper the G143A detection, otherwise other gene(s) underlying different mechanisms of resistance could be involved. PMID- 22488843 TI - Pharmacoepidemiology: defining the field and its core content. AB - PURPOSE: Emerging interests in pharmacoepidemiology make it important to define the profession's core content. The International Society for Pharmacoepidemiology (ISPE)'s Education Committee sought to develop a consensus on its core disciplines. This report recapitulates their efforts and conclusions. METHODS: The survey for skill inventories conducted characterized the field of pharmacoepidemiology by five categories of core competency/knowledge (pharmacovigilance, exposure data, epidemiology, clinical pharmacology, and medical product regulation) plus communication and leadership in these areas. It was sent to pharmacoepidemiology units within the industry, academia, and government representing the membership worldwide. RESULTS: After three waves, 125 members responded (~10% of the membership). Respondents were from North America (61%), European Union (23%), and the remainder from Asian Pacific and South American regions, representing the full spectrum of ISPE membership. Pharmacovigilance, analysis of exposure data, epidemiologic methods, and communication skills were the competencies identified as essential. Fourteen competencies were judged to be "essential" by >80% of the respondents; a further 26 had "essential" as the most frequently rated category but represented <80% of the respondents. Six items had "desirable but not a core competency" as the most commonly selected. None of the proposed competencies scored as "not a core competency" by >25% of the respondents. Only five of the competencies were suggested as "not core" by 10% or more. CONCLUSIONS: This survey identified a wide range of content relevant to the field of pharmacoepidemiology. This list will likely evolve over time. A curriculum around these areas will help prepare the next generation of pharmacoepidemiologists. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 22488842 TI - Rapid, sensitive, and quantitative detection of pathogenic DNA at the point of care through microfluidic electrochemical quantitative loop-mediated isothermal amplification. AB - Single-step DNA detection: a microfluidic electrochemical loop mediated isothermal amplification platform is reported for rapid, sensitive, and quantitative detection of pathogen genomic DNA at the point of care. DNA amplification was electrochemically monitored in real time within a monolithic microfluidic device, thus enabling the detection of as few as 16 copies of Salmonella genomic DNA through a single-step process in less than an hour. PMID- 22488845 TI - Resistive switching WOx-Au core-shell nanowires with unexpected nonwetting stability even when submerged under water. AB - The resistive switching (RS) characteristics of a tungsten oxide (WO(x) )-Au core shell nanowire device array is demonstrated for the first time. In addition to the stable bipolar RS characteristics, the nanowire structure of our RS devices provides superhydrophobic properties. The superhydrophobic RS nanowires repelled water that was poured over, such that the device was protected from failure by water contact-driven leakage currents. Moreover, surprisingly, the devices still work even with when the device is submerged underwater. PMID- 22488846 TI - Dietary zinc status reversibly alters both the feeding behaviors of the rats and gene expression patterns in diencephalon. AB - Nutritional status influences feeding behaviors, food preferences, and taste sensations. For example, zinc-deficient rats have been reported to show reduced and cyclic food intake patterns with increased preferences for NaCl. Although some impairments of the central nervous and endocrine systems have been speculated to be involved in these phenomena, the effects of short-term zinc deficiency on the brain have not been well examined to date. In this study, we performed a comprehensive analysis of the gene expression patterns in the rat diencephalon, which is a portion of the brain that includes the hypothalamus and thalamus, after short-term zinc deficiency and also during zinc recovery. The rats showed reduced and cyclic food intake patterns with increased salt preferences after a 10-day dietary zinc deficiency. A comparative analysis of their diencephalons using cDNA microarrays revealed that approximately 1% of the genes expressed in the diencephalons showed significantly altered expression levels. On the other hand, a 6-day zinc supplementation following the deprivation allowed for the recovery to initial food intake behaviors and salt preferences. The expression levels of most of the genes that had been altered by exposure to zinc deficient conditions were also recovered. These results show that feeding behaviors, taste preferences and gene expression patterns in the diencephalon respond quickly to changing zinc levels. PMID- 22488847 TI - The auditory anatomy of the minke whale (Balaenoptera acutorostrata): a potential fatty sound reception pathway in a baleen whale. AB - Cetaceans possess highly derived auditory systems adapted for underwater hearing. Odontoceti (toothed whales) are thought to receive sound through specialized fat bodies that contact the tympanoperiotic complex, the bones housing the middle and inner ears. However, sound reception pathways remain unknown in Mysticeti (baleen whales), which have very different cranial anatomies compared to odontocetes. Here, we report a potential fatty sound reception pathway in the minke whale (Balaenoptera acutorostrata), a mysticete of the balaenopterid family. The cephalic anatomy of seven minke whales was investigated using computerized tomography and magnetic resonance imaging, verified through dissections. Findings include a large, well-formed fat body lateral, dorsal, and posterior to the mandibular ramus and lateral to the tympanoperiotic complex. This fat body inserts into the tympanoperiotic complex at the lateral aperture between the tympanic and periotic bones and is in contact with the ossicles. There is also a second, smaller body of fat found within the tympanic bone, which contacts the ossicles as well. This is the first analysis of these fatty tissues' association with the auditory structures in a mysticete, providing anatomical evidence that fatty sound reception pathways may not be a unique feature of odontocete cetaceans. PMID- 22488848 TI - From composites to solid solutions: modeling of ionic conductivity in the CaF2 BaF2 system. AB - By using calcium fluorite and barium fluorite as test materials, we demonstrated that homovalent "dopants" can greatly affect ionic conductivity through locally changing the defect density. Whilst this doping is a state-of-the-art effect in the case of dopants that replace native ions of different charge (heterovalent dopants), it is a rather surprising effect at a first glance for substitutional dopants of the same charge; here, the phenomenon is not electrostatic, but elastic in nature. As a consequence of size mismatch, the smaller Ca atoms in the BaF(2) lattice favored the formation of interstitial sites that were located close to the Ca atoms, whilst doping larger Ba species into the CaF(2) phase favored vacancy formation. In terms of conductivity, and in agreement with the different mobilities, the first doping effect was favorable, whilst the other decreased conductivity. The concentration effects were formalized by a heterogeneous Frenkel reaction that was distinguished from the mean Frenkel reaction by additional (elastic) trapping that became more pronounced the lower the temperature. It was very revealing to relate this phenomenon to CaF(2)-BaF(2) multilayers and composites. In very general terms, these effects in the solid solutions were understood as being the atomistic limit of the interfacial charge transfer that occurred at the hetero-interface of the crystallites or films, and reflected the transition from heterogeneous doping (higher-dimensional doping) to homogeneous doping (zero-dimensional doping). PMID- 22488849 TI - Alagille syndrome in a Vietnamese cohort: mutation analysis and assessment of facial features. AB - Alagille syndrome (ALGS, OMIM #118450) is an autosomal dominant disorder that affects multiple organ systems including the liver, heart, eyes, vertebrae, and face. ALGS is caused by mutations in one of two genes in the Notch Signaling Pathway, Jagged1 (JAG1) or NOTCH2. In this study, analysis of 21 Vietnamese ALGS individuals led to the identification of 19 different mutations (18 JAG1 and 1 NOTCH2), 17 of which are novel, including the third reported NOTCH2 mutation in Alagille Syndrome. The spectrum of JAG1 mutations in the Vietnamese patients is similar to that previously reported, including nine frameshift, three missense, two splice site, one nonsense, two whole gene, and one partial gene deletion. The missense mutations are all likely to be disease causing, as two are loss of cysteines (C22R and C78G) and the third creates a cryptic splice site in exon 9 (G386R). No correlation between genotype and phenotype was observed. Assessment of clinical phenotype revealed that skeletal manifestations occur with a higher frequency than in previously reported Alagille cohorts. Facial features were difficult to assess and a Vietnamese pediatric gastroenterologist was only able to identify the facial phenotype in 61% of the cohort. To assess the agreement among North American dysmorphologists at detecting the presence of ALGS facial features in the Vietnamese patients, 37 clinical dysmorphologists evaluated a photographic panel of 20 Vietnamese children with and without ALGS. The dysmorphologists were unable to identify the individuals with ALGS in the majority of cases, suggesting that evaluation of facial features should not be used in the diagnosis of ALGS in this population. This is the first report of mutations and phenotypic spectrum of ALGS in a Vietnamese population. PMID- 22488850 TI - Genome-wide search for replicable risk gene regions in alcohol and nicotine co dependence. AB - The present study searched for replicable risk genomic regions for alcohol and nicotine co-dependence using a genome-wide association strategy. The data contained a total of 3,143 subjects including 818 European-American (EA) cases with alcohol and nicotine co-dependence, 1,396 EA controls, 449 African-American (AA) cases, and 480 AA controls. We performed separate genome-wide association analyses in EAs and AAs and a meta-analysis to derive combined P-values, and calculated the genome-wide false discovery rate (FDR) for each SNP. Regions with P < 5 * 10(-7) together with FDR < 0.05 in the meta-analysis were examined to detect all replicable risk SNPs across EAs, AAs, and meta-analysis. These SNPs were followed with a series of functional expression quantitative trait locus (eQTL) analyses. We found a unique genome-wide significant gene region--SH3BP5 NR2C2--that was enriched with 11 replicable risk SNPs for alcohol and nicotine co dependence. The distributions of -log(P) values for all SNP-disease associations within this region were consistent across EAs, AAs, and meta-analysis (0.315 <= r <= 0.868; 8.1 * 10(-52) <= P <= 3.6 * 10(-5)). In the meta-analysis, this region was the only association peak throughout chromosome 3 at P < 0.0001. All replicable risk markers available for eQTL analysis had nominal cis- and trans acting regulatory effects on gene expression. The transcript expression of the genes in this region was regulated partly by several nicotine dependence (ND) related genes and significantly correlated with transcript expression of many alcohol dependence- and ND-related genes. We concluded that the SH3BP5-NR2C2 region on Chromosome 3 might harbor causal loci for alcohol and nicotine co dependence. PMID- 22488851 TI - Bladder dysfunction in advanced Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) patients often have lower urinary tract symptoms. Seventy-four percent of patients with early-to-moderate disease report more than one bladder disturbance symptom. Severe bladder symptoms are reported in 27-39% of PD patients. The aim of this study was to evaluate the severity of bladder dysfunction in patients with advanced PD. METHODS: Patients were enrolled from a cohort with advanced PD. We compared patients receiving oral medications only, with patients treated using either deep-brain stimulation (DBS) in the subthalamic nucleus, or with an apomorphine pump. One hundred seven patients were evaluated using two sets of validated questionnaires [Danish Prostate Symptom Score (DanPSS) and the International Prostate Symptom Score (IPSS)] about bladder symptoms. Postmicturitional residual urine was recorded. RESULTS: There were no statistically significant differences between the treatment groups on the total DanPSS or IPSS scores. Bladder symptom severity correlated to the stage of disease (conventional treatment: r = 0.364, P = 0.004, apomorphine: r = 0.73, P = 0.02), except for patients treated with DBS, whereby symptom severity correlated to DBS duration (r = 0.34, P = 0.038). Patients treated with DBS had significant less nocturia compared to the other groups (P = 0.007). CONCLUSION: Lower urinary tract symptoms are highly prevalent in patients with advanced PD. More than 50% of patients have severe bladder symptoms, most frequently symptoms of overactive bladder. Patients treated with DBS in the STN had the same amount of LUTS symptoms as patients treated with either conventional oral medication therapy or an apomorphine pump, but exhibited significantly less nocturia. PMID- 22488852 TI - The effect of surface treatments on the microroughness of laser-sintered and vacuum-cast base metal alloys for dental prosthetic frameworks. AB - This study aimed to evaluate the effect of four chemomechanical surface treatments on the surface average microroughness and profile of laser-sintered and vacuum-cast dental prosthetic structures. Square-shaped blocks (10 mm * 10 mm * 1.5 mm) were prepared as follows: (1) laser-sintered Co?Cr (L) (ST2724G); (2) cast Co-Cr (C) (Gemium-cn); and (3) cast Ni-Cr-Ti (T) (Tilite). Specimens of each alloy group were randomly divided into five subgroups (n = 10 each), depending on the conditioning method used: (1) no treatment (control); (2) sandblasting (125 MUm Al2O3-particles); (3) silica coating (50 MUm silica-modified Al2O3 particles); (4) oxidation; and (5) oxidation plus opacification. Subgroups 2 and 3 represent "inner" pretreatments proposed for ceramometal restorations to improve the metal surface area available for luting cements. Subgroups 4 and 5 are the "outer" pretreatments required for bonding the aesthetic veneering ceramics to the underlying metal frameworks. Average surface roughness (Ra/MUm) was determined using a surface profilometer. Data were analyzed by two-way ANOVA and Student-Newman-Keuls tests (alpha = 0.05). Metal surface topography was SEM analyzed. Despite the inner pretreatment applied, L samples resulted in the highest microroughness (P < 0.001), whereas sandblasting produced a surface smoothing effect in cast specimens. After oxidation, a significant increase in surface roughness occurred in all groups compared with controls, L specimens being the roughest (P < 0.001). Opacification caused a flattening effect of all oxidized structures; all opacified groups resulting in similar microroughness. Laser sintering of Co-Cr enhances the roughness of metal structures, which may improve the frameworks' microretention of the cements, and of the opaquer before the copings are veneered with the aesthetic ceramics. PMID- 22488853 TI - Detection of the primary lesion in patients with cervical metastases from unknown primary tumors with narrow band imaging endoscopy: preliminary report. AB - BACKGROUND: We investigated whether the addition of narrow band imaging (NBI) to standard diagnostic workups could enhance the detection of primary lesions in patients with carcinoma of unknown primary (CUP). METHODS: Thirty patients with CUP underwent NBI endoscopy and fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) after thorough conventional diagnostic workups between 2009 and 2011. Sites suspected of harboring primary tumors, as determined by NBI and/or FDG-PET/CT, were biopsied for histologic confirmation. RESULTS: Occult primary tumors were identified in 33.3% (10/30), including 13.3% (4/30) by NBI and 20.0% (6/30) by FDG-PET/CT. All of diagnosed lesions by NBI were confirmed histologically as squamous cell carcinomas with T1 classification and identified at 2 supraglottis, 1 hypopharynx, and 1 esophagus, respectively. CONCLUSIONS: NBI endoscopy may be a useful method for detecting primary tumors, especially for small and superficial squamous cell carcinomas of the upper aerodigestive tract, after conventional workup in patients with CUP. PMID- 22488854 TI - Diastereoselective synthesis of C3-quaternary indolenines using alpha,beta unsaturated N-aryl ketonitrones and activated alkynes. PMID- 22488855 TI - Nanotoxicity: how the body develops a way to reduce the toxicity of carbon nanotubes. AB - The interaction of nanoparticles with cells and organisms are often the focus of biomedical, material, and environmental research. This article highlights a paper by Yuliang Zhao, Chunying Chen, Ruhong Zhou, and co-workers (Proc. Natl. Acad. Sci. USA 2011, 108, 16968), which brings a new aspect to the discussion about purpose and mechanisms underlying the reaction of an organism with nanoparticles. The interactions of carbon nanotubes with cells were investigated with regard to the defense mechanisms of the body against foreign materials developed during evolution. Such mechanisms are not only important for nanotoxicity research, but also for targeting nanoparticles in medical applications. The cited article thus gives a new focus to an important aspect of nanotechnology, which will determine the application aspects of this technology in future: the approach of biological systems to nanosized particles. PMID- 22488856 TI - Impact of an insecticide changes with amount of leaf litter input: implications for amphibian populations. AB - Changes in percentage of forest cover can influence nutrient levels in aquatic systems and change abiotic conditions that may influence species. The authors examined how increasing amounts of leaf litter influenced toxicity of the insecticide carbaryl using larval green frogs (Rana clamitans) in outdoor mesocosm ponds. Insecticides can have direct negative effects on individual physiology and behavior and indirect effects on the food web, which can result in trophic cascades. They predicted that direct effects of the insecticide would dominate when nutrients were low (resulting in negative impacts on amphibian development and survival), whereas indirect effects could offset direct effects when nutrients were more abundant through a trophic cascade that leads to more food for tadpoles (resulting in positive effects on amphibian development and survival). The authors found support for this hypothesis: first, total green frog survival was greatest with increased leaf litter input in the presence of carbaryl. Additionally, most green frogs that reached metamorphosis were from ponds with high leaf litter input and carbaryl. Second, the impact of carbaryl on developmental stage and tadpole mass varied depending on the amount of leaf litter present. With high amounts of leaf litter, carbaryl had a positive impact on development and growth; in contrast, with low amounts of leaf litter, carbaryl had negative or no effects on tadpole development and mass. The present study suggests that differences in nutrient levels between ponds exposed to pesticides could play a role in amphibian population dynamics. PMID- 22488857 TI - Solution structure of SWI1 AT-rich interaction domain from Saccharomyces cerevisiae and its nonspecific binding to DNA. AB - SWI1 is a subunit of the SWI/SNF complex involved in chromatin remodeling. It contains an AT-rich interaction domain (ARID) which has the potential DNA binding activity. In this study, we determined the solution structure of the SWI1 ARID domain from Saccharomyces cerevisiae by nuclear magnetic resonance spectroscopy. Yeast SWI1 ARID domain is composed of seven alpha helices, six of which are conserved among the ARID family. In addition, the DNA-binding activity of the SWI1 ARID domain was confirmed by chemical shift perturbation assay. Similar to its human homolog, the yeast SWI1 ARID domain binds DNA nonspecifically. PMID- 22488858 TI - Rapid genetic diagnosis in single-gene movement disorders. PMID- 22488859 TI - Peering through the FoG: visual manipulations shed light on freezing of gait. PMID- 22488861 TI - Investigating visual misperceptions in Parkinson's disease: a novel behavioral paradigm. AB - Visual misperception and hallucinations represent a major problem in advanced PD. The pathophysiological mechanisms underlying these symptoms remain poorly understood, with limited tests for their assessment. A recent hypothesis has suggested that visual misperception and hallucinations may arise from disrupted processing in the attentional networks. To assess and quantify visual misperceptions, we developed the novel bistable percept paradigm (BPP), which consists of a battery of "single" and "hidden" monochromatic images that subjects are required to study until they are satisfied that they have recognized everything that the image may represent. In this experiment, 45 patients and 18 age-matched controls performed the BPP. Using an error score value derived from the control group, 23 patients were identified as having significant deficits on the task. Compared to patients who were unimpaired on the task, this group of patients had significantly higher levels of self-reported hallucinations on the SCales for Outcomes in PArkinson's Disease-Psychiatric Complications and also symptoms of rapid eye movement sleep behavior disorder (RBD). Furthermore, impairment on the BPP was associated with significantly reduced performance on an attentional set-shifting task. Patients with impaired performance on the BPP had higher rates of hallucinations, increased symptoms of RBD, and poorer performance on set shifting, suggesting disrupted processing within the attentional control networks. We propose that the BPP may offer a novel approach for exploring the neural correlates underlying visual hallucinations and misperceptions in PD. PMID- 22488860 TI - Genetic Creutzfeldt-Jakob disease with R208H mutation presenting as progressive supranuclear palsy. PMID- 22488862 TI - Diagnostic agreement in patients with psychogenic movement disorders. AB - BACKGROUND: The reliability and applicability of published diagnostic criteria for psychogenic movement disorders (PMDs) have never been examined. METHODS: Eight movement disorder and six general neurologists rated 14 patients diagnosed with PMD and 14 patients diagnosed with organic movement disorders. Raters provided a dichotomous judgment (i.e., psychogenic or organic) upon review of video-based movement phenomenology and a category of diagnostic certainty based on the Fahn-Williams and Shill-Gerber criteria after accessing standardized clinical information. We measured interobserver agreement on the diagnosis and clinical certainty judgment of PMD. RESULTS: In both groups of raters, agreements were "fair" on the video-based dichotomous judgment, but improved to "substantial" after access to standardized clinical information. "Slight" to "poor" agreement was reached for the "probable" and "possible" categories of diagnostic certainty corresponding to both diagnostic criteria. CONCLUSIONS: Diagnosis according to clinical available criteria for PMD yields poor diagnostic agreement. PMID- 22488865 TI - An unusal case of facile non-degenerate P-C bond making and breaking. AB - Oxidation of Li/X phosphinidenoid complex 2, obtained via selective deprotonation from the P-H precursor 1, with [Ph(3)C]BF(4) led to the formation of two P-F substituted diorganophosphane complexes 6,7; the latter tautomer 7 formed via H shift from 6. In contrast, oxidation of 2 with [(p-Tol)(3)C]BF(4) led to three major and one minor intermediates at low temperature, which we tentatively assign to two pairs of P-C atropisomers 10 a,a' and 10 c,c' and which differ by the relative orientations of their CH(SiMe(3))(2) and W(CO)(5) groups. Conversion of all isomers led finally to complex 11 having a ligand with a long P-C bond to the central trityl* carbon atom, firmly established by single-crystal X-ray analysis. DFT calculations at the B3LYP/def2-TZVPP//BP86/def2-TZVP level of theory on real molecular entities revealed the structures of the in situ formed combined singlet diradicals (4+5 and 5+9) and the nature of intermediates on the way to the final product, complex 11. Remarkable is that all isomers of 11 possess relative energies in the narrow energy regime of about 20 kcal mol(-1). A preliminary study revealed that complex 11 undergoes selective P-C bond cleavage at 75 degrees C in toluene solution. PMID- 22488864 TI - Correlates of continued smoking versus cessation among survivors of smoking related cancers. AB - OBJECTIVE: We examined correlates of continued smoking versus cessation among a sample of survivors of smoking-related cancers who were actively smoking at the time of cancer diagnosis. METHODS: Participants with a history of smoking and a smoking-related cancer diagnosis (lung, oral, pharynx, larynx, esophagus, bladder, stomach, cervix, kidney, pancreas, acute myeloid leukemia) within the past 4 years were identified in the electronic medical record. We recruited 613 individuals to complete a mail-based survey and received 139 completed surveys (22.7% response rate). We focused on 105 participants who smoked at the time of diagnosis and dichotomized them to having either quit since diagnosis (48.6%; n = 51) or continued smoking (51.4%; n = 54). We assessed sociodemographics, type of cancer and treatment(s), and psychosocial factors (depressive symptoms, social support, hope, quality of life). We then conducted structured interviews with a subset of 21 survey respondents. RESULTS: Binary logistic regression indicated that, controlling for age, gender, ethnicity, marital status, and income, factors associated with continued smoking versus cessation included being diagnosed with other smoking-related cancers versus lung or head and neck cancer (OR = 11.21, CI 2.85, 44.02) and having significant depressive symptoms (OR = 1.25, CI 1.08, 1.45). Qualitative findings highlighted motivators for cessation (impact of being diagnosed with cancer, doctor advice to quit, social influences) and barriers to cessation (hopelessness, stress, addiction). CONCLUSIONS: These findings highlight the need to address depressive symptoms among cancer survivors, particularly those continuing to smoke and the importance of exploring messages cancer survivors are given regarding the need for cessation post cancer diagnosis. PMID- 22488866 TI - Case of prednisolone-induced hepatitis in a patient with ulcerative colitis. PMID- 22488867 TI - Graduate medical education changes: yes we can or enough already? AB - The Accreditation Council for Graduate Medical Education (ACGME) established new duty hour recommendations for pediatric subspecialty trainees in July 2011. Short term and long-term implications to Pediatric Hematology/Oncology (PHO) are reviewed. Other modifications have been introduced by the ACGME and the American Board of Pediatrics (ABP) in the last decade, including the introduction of the six core competencies and an expansion in the definition of scholarship for fellows. The effect of these on fellows are discussed with suggested strategies for PHO to prepare for further change likely to result from a new ABP initiative to evaluate subspecialty training and certification over the next 3 years. Pediatr Blood Cancer 2012; 59: 1168-1172. (c) 2012 Wiley Periodicals, Inc. PMID- 22488868 TI - 2-Aminobenzimidazole derivatives strongly inhibit and disperse Pseudomonas aeruginosa biofilms. PMID- 22488869 TI - Metal-filled carbon nanotubes as a novel class of photothermal nanomaterials. AB - Metal-filled carbon nanotubes represent a novel class of photothermal nanomaterials: when illuminated by visible light they exhibit a strong enhancement of the temperature at the metal sites, due to the enhanced plasmonic light absorption at the metal surface, which behaves as a heat radiator. Potential applications include nanomedicine, heat-assisted magnetic recording, and light-activated thermal gradient-driven devices. PMID- 22488870 TI - Halogenated benzene cation radicals. AB - The halogenated benzenes C(6)HF(5), 2,4,6-C(6)H(3)F(3), 2,3,5,6-C(6)H(2)F(4), C(6)F(6), C(6)Cl(6), C(6)Br(6), and C(6)I(6) were converted into their corresponding cation radicals by using various strong oxidants. The cation radical salts were isolated and characterized by electron paramagnetic resonance (EPR) spectroscopy and by single-crystal X-ray diffraction. The thermal stability of the cation radicals increased with decreasing hydrogen content. As expected, the cation radicals [C(6)HF(5)](+) and 2,3,5,6-[C(6)H(2)F(4)](+) had structures with the same geometry as C(6)HF(5) and 2,3,5,6-[C(6)H(2)F(4)]. In contrast, the cation radicals [C(6)F(6)](+), [C(6)Cl(6)](+), and possibly also [C(6)Br(6)](+) exhibited Jahn-Teller-distorted geometries in the crystalline state. In the case of C(6)F(6)(+)Sb(2)F(11)(-), two low-symmetry geometries were observed in the same crystal. Interestingly, the structures of the cation radicals 2,4,6 [C(6)H(3)F(3)](+) and C(6)I(6)(+) did not exhibit Jahn-Teller distortions. DFT calculations showed that the explanation for the lack of distortion of these cations from the D(3h) or D(6h) symmetry of the neutral benzene precursor was different for 2,4,6-[C(6)H(3)F(3)](+) than for [C(6)I(6)](+). PMID- 22488872 TI - Beneficial effect of (-)schisandrin B against 3-nitropropionic acid-induced cell death in PC12 cells. AB - Huntington's disease (HD) is characterized by the dysfunction of mitochondrial energy metabolism, which is associated with the functional impairment of succinate dehydrogenase (mitochondrial complex II), and pyruvate dehydrogenase (PDH). Treatment with 3-nitropropionic acid (3-NP), a potent irreversible inhibitor of succinate dehydrogenase, replicates most of the pathophysiological features of HD. In the present study, we investigated the effect of ( )schisandrin B [(-)Sch B, a potent enantiomer of schisandrin B] on 3-NP-induced cell injury in rat differentiated neuronal PC12 cells. The 3-NP caused cell necrosis, as assessed by lactate dehydrogenase (LDH) leakage, and mitochondrion dependent cell apoptosis, as assessed by caspase-3 and caspase-9 activation, in differentiated PC12 cells. The cytotoxicity induced by 3-NP was associated with a depletion of cellular reduced glutathione (GSH) as well as the activation of redox-sensitive c-Jun N-terminal kinase (JNK) pathway and the inhibition of PDH. (-)Sch B pretreatment (5 and 15 MUM) significantly reduced the extent of necrotic and apoptotic cell death in 3-NP-challenged cells. The cytoprotection afforded by (-)Sch B pretreatment was associated with the attenuation of 3-NP-induced GSH depletion as well as JNK activation and PDH inhibition. (-)Sch B pretreatment enhanced cellular glutathione redox status and ameliorated the 3-NP-induced cellular energy crisis, presumably by suppressing the activated JNK-mediated PDH inhibition, thereby protecting against necrotic and apoptotic cell death in differentiated PC12 cells. PMID- 22488873 TI - Characterization of volatile organic compounds in human leukocyte antigen heterologous expression systems: a cell's "chemical odor fingerprint". AB - The major histocompatibility complex (MHC), or human leukocyte antigen (HLA) gene coding region in humans, plays a significant role in infectious disease response, autoimmunity, and cellular recognition. This super locus is essential in mate selection and kin recognition because of the organism-specific odor which can be perceived by other individuals. However, how the unique MHC genetic combination of an organism correlates with generation of the organism-specific odor is not well understood. In the present work, we have shown that human B-cells produce a set of volatile organic compounds (VOCs) that can be measured by GC-MS. More importantly, our results show that specific HLA alleles are related to production of selected VOCs, and that this leads to a cell-specific odor "fingerprint". We used a C1R HLA class I A and B locus negative cell line, along with C1R cell lines that were stably transfected with specific A and B alleles. Our work demonstrates for the first time that HLA alleles can directly influence production of specific odor compounds at the cellular level. Given that the resulting odor fingerprint depends on expression of specific HLA sequences, it may yield information on unique human scent profiles, composition of exhaled breath, as well as immune response states in future studies. PMID- 22488871 TI - ASTN1 and alcohol dependence: family-based association analysis in multiplex alcohol dependence families. AB - A previous genome-wide linkage study of alcohol dependence (AD) in multiplex families found a suggestive linkage result for a region on Chromosome 1 near microsatellite markers D1S196 and D1S2878. The ASTN1 gene is in this region, a gene previously reported to be associated with substance abuse, bipolar disorder and schizophrenia. Using the same family data consisting of 330 individuals with phenotypic data and DNA, finer mapping of a 26 cM region centered on D1S196 was undertaken using SNPs with minor allele frequency (MAF) >= 0.15 and pair-wise linkage disequilibrium (LD) of r(2) < 0.8 using the HapMap CEU population. Significant FBAT P-values for SNPs within the ASTN1 gene were observed for four SNPs (rs465066, rs228008, rs6668092, and rs172917), the most significant, rs228008, within intron 8 had a P-value of 0.001. Using MQLS, which allows for inclusion of all families, we find three of these SNPs with MQLS P-values < 0.003. In addition, two additional neighboring SNPs (rs10798496 and rs6667588) showed significance at P = 0.002 and 0.03, respectively. Haplotype analysis was performed using the haplotype-based test function of FBAT for a block that included rs228008, rs6668092, and rs172917. This analysis found one block (GCG) over-transmitted and another (ATA) under-transmitted to affected offspring. Linkage analysis identified a region consistent with the association results. Family-based association analysis shows the ASTN1 gene significantly associated with alcohol dependence. The potential importance of the ASTN1 gene for AD risk may be related its role in glial-guided neuronal migration. PMID- 22488874 TI - Solution-processed small molecule-polymer blend organic thin-film transistors with hole mobility greater than 5 cm2/Vs. AB - Using phase-separated organic semiconducting blends containing a small molecule, as the hole transporting material, and a conjugated amorphous polymer, as the binder material, we demonstrate solution-processed organic thin-film transistors with superior performance characteristics that include; hole mobility >5 cm(2) /Vs, current on/off ratio >=10(6) and narrow transistor parameter spread. These exceptional characteristics are attributed to the electronic properties of the binder polymer and the advantageous nanomorphology of the blend film. PMID- 22488875 TI - Target-site mutation associated with glufosinate resistance in Italian ryegrass (Lolium perenne L. ssp. multiflorum). AB - BACKGROUND: Studies were conducted to elucidate the mechanism of glufosinate resistance in an Italian ryegrass population. RESULTS: Glufosinate rates required to reduce growth by 50% (GR(50)) were 0.15 and 0.18 kg AI ha(-1) for two susceptible populations C1 and C2 respectively, and 0.45 kg AI ha(-1) for the resistant population MG, resulting in a resistance index of 2.8. Ammonia accumulation after glufosinate treatment was on average 1.5 times less for the resistant population than for the susceptible populations. The glufosinate concentrations (uM) required to reduce the glutamine synthetase (GS) enzyme activity by 50% (I(50)) were 31 and 137 for C1 and C2 respectively, and 2432 for the resistant population MG. One amino acid substitution in the plastidic GS2 gene, aspartic acid for asparagine at position 171, was identified in the resistant population. CONCLUSIONS: This is the first report of glufosinate resistance in a weed species that involves an altered target site. PMID- 22488876 TI - Predicting the early invasiveness of nasopharyngeal mucosal neoplasia after radiotherapy by narrow-band imaging: a pilot study. AB - BACKGROUND: This study evaluated the correlation between the histologic findings of nasopharyngeal mucosal neoplasias after radiotherapy and narrow-band imaging (NBI) endoscopic findings. METHODS: One hundred six patients were enrolled. All patients underwent conventional white-light endoscopic examinations of the nasopharynx, which were followed by NBI endoscopy. Biopsy specimens were obtained if scattered brown-spotted lesions were identified. RESULTS: We identified 22 patients with brown-spotted lesions by NBI endoscopy. Histopathologic study confirmed that 4 lesions were neoplastic, including 2 dysplastic lesions and 2 carcinomatous lesions. According to pathologic examinations, the thickness of the epithelium in carcinomatous, dysplastic, and nonneoplastic lesions were (mean +/- SD) 0.85 +/- 0.21 mm, 0.45 +/- 0.21 mm, and 0.35 +/- 0.07 mm, respectively. The epithelial thickness of carcinomatous and dysplastic lesions was significantly thicker than that of nonneoplastic lesions (p < .001 and p = .026, respectively). According to the NBI endoscopic examinations, the epithelial thickness of the brown-spotted lesions with irregular borders was significantly thicker than those lesions with tailed/round borders (0.48 +/- 0.24 mm vs 0.26 +/- 0.07 mm, p = .009). Visualization by NBI corresponded to the histopathologic findings; the prevalence of neoplastic lesions with tailed/round borders and irregular borders was 0% (0/13) and 44.4% (4/9), respectively (p = .017). CONCLUSIONS: This study demonstrates that lesions with an irregular pattern tend to be neoplastic lesions. Irregularities observed under NBI are important pathologic indicators of the early invasiveness of nasopharyngeal mucosal neoplasia after radiotherapy. This result warrants further inquiry to confirm its accuracy. PMID- 22488877 TI - Adult presentation of arterial tortuosity syndrome in a 51-year-old woman with a novel homozygous c.1411+1G>A mutation in the SLC2A10 gene. AB - Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disorder, mainly characterized by tortuosity and elongation of the large- and medium-sized arteries with predisposition to stenoses and aneurysms. ATS is caused by mutations in the SLC2A10 gene, encoding for the facilitative glucose transporter 10 (GLUT10) and is described typically in pediatric patients. We report on a 51-year-old woman, originally ascertained because of unexplained widespread chronic pain and positive family history of aortic malformation. The main findings included aged appearance, congenital joint hypermobility, joint instability complications, chronic fatigue syndrome, progressive painful joint stiffness, abdominal hernias, pelvic prolapses, multiple cardiac valve prolapses, varicose veins, easy bruising, and gingival recession. Vascular imaging revealed kinking and anomalous origin of the aortic arch branches, marked tortuosity of the aorta, pulmonary and most middle arteries, and a small aneurysm of the splenic artery. SLC2A10 analysis disclosed homozygosity for the novel c.1411+1G>A splice mutation, leading to a 41 amino acids GLUT10 internal deletion. Expression study by immunofluorescence using healthy control cells showed lack of membrane internalization of GLUT10 in patient's skin fibroblasts. This report describes the first splice-site SLC2A10 mutation and increases to 19 the repertoire of known mutations in this gene. Comparison with the few previously published adult patients with ATS contributes to the natural history of this condition, which is probably under diagnosed within the expanding family of inherited connective tissue disorders. PMID- 22488878 TI - Morphological observations of ampullae of lorenzini in Squatina guggenheim and S. occulta (Chondrichthyes, Elasmobranchii, Squatinidae). AB - We have conducted a morphological study of the ampullae of Lorenzini on two shark species from Squatina Genus. In both species, S. guggenheim and S. occulta, the ampullae were observed like small pores scattered in the head region similar to other species of the Chondrichthyes Class. However, differently of the other species a greatest density of ampullae of Lorenzini was observed along of the body surface. After fixation using 10% formaldehyde, the ampullae were removed and processed for light and scanning electron microscopy. Macroscopically, the two shark species differed by the presence of dorsal spines that appeared from the head to the first dorsal fin in S. guggenheim and were absent in S. occulta. Microscopically, there were no differences between the ampullae of Lorenzini channels in these two species. The wall of the ampulla was formed by a simple squamous epithelium. Bands of connective tissue, hyaline cartilage and collagen fibers were found between the ampulla and the skeletal striated muscle layer. Nerve branches responsible for conducting signal pulses to the central nervous system were visible between the muscle and connective tissue layers. Using scanning electron microscopy and histological analysis, we found that the channels were twisted and positioned parallel to the skin. The inside of the channels contained a large amount of a gelatinous secretion composed by polysaccharides. Therefore, we conclude that the morphological combination of extended distribution of the ampullae of Lorenzini and the body shape may represent an adaptation of these species to their way of life. PMID- 22488879 TI - Principles and emerging applications of nanomagnetic materials in medicine. AB - The development of nanometer-scale magnetic materials for biomedical applications spans the interface between the physical sciences and biology. Applications of these materials are rapidly becoming important in medicine and enable targeted therapies and diagnostics. At the same time, specific applications add focus to the development of novel magnetic materials and facilitate a deeper understanding of the physical mechanisms behind their function. This review presents a broad, nontechnical overview of the basis of magnetism in materials at the nanometer scale and describes how these materials are created, characterized, and used. Specific emerging applications in medical diagnostics and therapies are discussed, including cancer cell targeting for thermal ablation, tissue engineering, and three-dimensional noninvasive molecular imaging. Challenges in these fields are discussed, including the toxicity and delivery of magnetic nanomaterials and the sensitivity of imaging and therapeutic techniques. The development of novel nanomagnetic nanomaterials should continue to accelerate as new applications are identified and researchers uncover new mechanisms to increase and modulate magnetism at the nanometer scale. PMID- 22488880 TI - Efficacy of platelet-rich plasma combined with allograft bone in the management of displaced intra-articular calcaneal fractures: a prospective cohort study. AB - To investigate whether platelet-rich plasma (PRP) when used with allograft bone improves the management outcome of displaced intra-articular calcaneal fractures. Over a 7-year period, all displaced type III calcaneal fractures admitted in our department (276 fractures in 254 patients) were randomly divided into three groups according to the plan of management: autograft alone (n = 101), allograft combined with PRP (n = 85), or allograft alone (n = 90). Radiographic imaging and three-dimensional computed tomography were used to assess the thalamic portion, Bohler's angle, the crucial angle of Gissane, and the height, width and length of the calcaneum. The American Orthopedic Foot and Ankle Society (AOFAS) ankle-hind foot scoring system was used to evaluate the hind foot function at 12, 24, and 72 months postsurgery. At 12 months no significant difference existed in outcome amongst the treatment groups (p > 0.05). However, at 24 and 72 months the results of the autograft, and the allograft combined with PRP, were similar and both were significantly better than that of the allograft alone (p < 0.05). PRP augmented the favorable outcome of allografts in the management of displaced calcaneal fractures, and matched that of autograft used alone. The findings of this study thus support the clinical use of PRP in conjunction with allograft in the treatment of displaced intra-articular calcaneal fractures. PMID- 22488881 TI - Absolute asymmetric synthesis of tertiary alpha-amino acids. AB - Frozen: the spontaneous crystallization of an achiral compound in a chiral conformation is used as the unique source of chirality in an absolute asymmetric synthesis of tertiary amino acids. The dynamic axial chirality of tertiary aromatic amides is frozen in a crystal and is responsible for the stereoselectivity of the deprotonation/alkylation. alpha-Amino acid derivatives are synthesized in up to 96 % ee. PMID- 22488883 TI - Hox-mediated regulation of doublesex sculpts sex-specific abdomen morphology in Drosophila. AB - BACKGROUND: Hox transcription factors are deeply conserved proteins that guide development through regulation of diverse target genes. Furthermore, alteration in Hox target cis-regulation has been proposed as a major mechanism of animal morphological evolution. Crucial to understanding how homeotic genes sculpt the developing body and contribute to the evolution of form is identification and characterization of regulatory targets. Because target specificity is achieved through physical or genetic interactions with cofactors or co-regulators, characterizing interactions between homeotic genes and regulatory partners is also critical. In Drosophila melanogaster, sexually dimorphic abdominal morphology results from sex-specific gene regulation mediated by the Hox protein Abdominal-B (Abd-B) and products of the sex-determination gene doublesex (dsx). Together these transcription factors regulate numerous sex-specific characters, including pigmentation, cuticle morphology, and abdominal segment number. RESULTS: We show Dsx expression in the developing D. melanogaster pupal abdomen is spatiotemporally dynamic, correlating with segments that undergo sexually dimorphic morphogenesis. Furthermore, our genetic analyses show Dsx expression is Abd-B dependent. CONCLUSIONS: Doublesex and Abd-B are not only requisite co regulators of sexually dimorphic abdominal morphology. We propose that dsx is itself a transcriptional target of Abd-B. These data present a testable hypothesis about the evolution of sexually dimorphic segment number in Diptera. PMID- 22488882 TI - Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy. AB - 'Tomacula' and myelin outfoldings are striking neuropathological features of a diverse group of inherited demyelinating neuropathies. Whereas the underlying genetic defects are well known, the molecular mechanisms of tomacula formation have remained obscure. We hypothesized that they are caused by uncontrolled, excessive myelin membrane growth, a process, which is regulated in normal development by neuregulin-1/ErbB2, PI3 Kinase signalling and ERK/MAPK signalling. Here, we demonstrate by targeted disruption of Pten in Schwann cells that hyperactivation of the endogenous PI3 Kinase pathway causes focal hypermyelination, myelin outfoldings and tomacula, even when induced in adult animals by tamoxifen, and is associated with progressive peripheral neuropathy. Activated AKT kinase is associated with PtdIns(3,4,5)P(3) at paranodal loops and Schmidt-Lanterman incisures. This striking myelin pathology, with features of human CMT type 4B1 and HNPP, is dependent on AKT/mTOR signalling, as evidenced by a significant amelioration of the pathology in mice treated with rapamycin. We suggest that regions of non-compact myelin are under lifelong protection by PTEN against abnormal membrane outgrowth, and that dysregulated phosphoinositide levels play a critical role in the pathology of tomaculous neuropathies. PMID- 22488884 TI - Dendritic spine density in multisensory versus primary sensory cortex. AB - In sensory areas, neuronal dendritic spines receive sensory-specific inputs whose net activity drives neuronal spiking responses to effective external stimuli. Previous studies indicate that neurons in primary sensory cortical areas, which largely receive inputs from a single sensory modality, exhibit an average of 0.5 1.4 dendritic spines/MUm, depending on species. In higher-order, associational cortices, inputs converge from multiple sensory sources onto individual, multisensory neurons. This raises the question: when inputs from two different modalities converge onto individual neurons, how are the dendritic spines apportioned to subserve the generation of robust spiking responses to each modality? As inputs arrive from two different sensory sources, it might be expected that neurons in multisensory areas exhibit approximately double the spine density of neurons in areas that receive just one sensory input. The present study examined this possibility in Golgi-stained neurons from ferret primary auditory (A1) and somatosensory (S1) cortices, as well as from regions in which inputs from two different sensory modalities converge: the lateral rostral suprasylvian sulcus (LRSS) and the rostral posterior parietal (PPr) areas. Dendritic spine density (spines/MUm) was measured for pyramidal neurons in layers 2-3 and layers 5-6 for each cortical area from three animals using light microscopy. Primary sensory regions A1 and S1 showed remarkably similar average spine densities (A1 = 1.27 spines/MUm +/- 0.3 s.d.; S1 = 1.14 spines/MUm +/- 0.3), but average spine densities from the multisensory areas were lower (LRSS = 0.98 +/- 0.3; PPr = 1.04 +/- 0.3). Thus, for a given cortical area, dendritic spine density appears to be determined by factors other than the levels of sensory modality convergence. PMID- 22488885 TI - Use of capillary blood to diagnose hereditary spherocytosis. AB - We studied 31 children with hemolytic anemia, or with positive family history for hereditary spherocytosis (HS), to assess the reliability of capillary blood samples for the diagnosis. HS was diagnosed in 20 patients. Cryohemolysis (CH) was positive in 94% and eosin-5'-maleimide flow cytometry in 90% of them, whereas flow cytometric osmotic fragility was positive in 94%. Capillary blood sampling showed to be useful for the diagnosis. Simultaneous use of these three tests allows confirming diagnosis in 100% of patients. The use of very small blood volumes (300 ul) allows an earlier diagnosis in neonates and small infants. PMID- 22488886 TI - Tris(spiroborate)-type anionic nanocycles. AB - Full circle: New cyclic tris(spiroborate)s were prepared as molecular recognition modules for nanometer-sized cationic guests. These cyclophanes were simply prepared by treating corresponding bis(2,3-dihydroxynaphthalene)s with an equimolar amount of boric acid. The molecular recognition ability of these cyclic spiroborates was estimated in solution and crystal phases by the use of [Ir(tpy(2))](3+) as a typical example of a cationic guest. PMID- 22488887 TI - Identical twins with Leucine rich repeat kinase type 2 mutations discordant for Parkinson's disease. PMID- 22488888 TI - Design, synthesis and biological evaluation of potent azadipeptide nitrile inhibitors and activity-based probes as promising anti-Trypanosoma brucei agents. AB - Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas disease and African sleeping sickness, respectively. There is an urgent need for the development of new drugs against both diseases due to the lack of adequate cures and emerging drug resistance. One promising strategy for the discovery of small molecule therapeutics against parasitic diseases has been to target the major cysteine proteases such as cruzain for T. cruzi, and rhodesain/TbCatB for T. brucei. Azadipeptide nitriles belong to a novel class of extremely potent cysteine protease inhibitors against papain-like proteases. We herein report the design, synthesis, and evaluation of a series of azanitrile-containing compounds, most of which were shown to potently inhibit both recombinant cruzain and rhodesain at low nanomolar/picomolar ranges. A strong correlation between the potency of rhodesain inhibition (i.e., target-based screening) and trypanocidal activity (i.e., whole-organism-based screening) of the compounds was observed. To facilitate detailed studies of this important class of inhibitors, selected hit compounds from our screenings were chemically converted into activity-based probes (ABPs), which were subsequently used for in situ proteome profiling and cellular localization studies to further elucidate potential cellular targets (on and off) in both the disease-relevant bloodstream form (BSF) and the insect residing procyclic form (PCF) of Trypanosoma brucei. Overall, the inhibitors presented herein show great promise as a new class of anti-trypanosome agents, which possess better activities than existing drugs. The activity-based probes generated from this study could also serve as valuable tools for parasite-based proteome profiling studies, as well as bioimaging agents for studies of cellular uptake and distribution of these drug candidates. Our studies therefore provide a good starting point for further development of these azanitrile-containing compounds as potential anti-parasitic agents. PMID- 22488889 TI - Reactivity toward oxygen radicals and antioxidant action of thiol compounds. AB - Thiol compounds exert diverse functions in the defense network against oxidative stress in vivo. Above all, the role of glutathione in the enzymatic removal of hydrogen peroxide and lipid hydroperoxides has been well established. The scavenging of reactive free radicals is one of the many functions. In this study, the reactivities of several thiol compounds toward oxygen- and nitrogen-centered radicals were measured from their reaction with galvinoxyl and 1,1-diphenyl-2 picrylhydrazyl (DPPH) radicals and also from their sparing effects on the decay of fluorescein, pyrogallol red, and BODIPY induced by peroxyl radicals. Furthermore, the antioxidant capacity against lipid peroxidation was assessed in the oxidation of methyl linoleate induced by free radicals in micelle systems. Cysteine, homocysteine, and glutathione exhibited considerable reactivity toward galvinoxyl, DPPH, and peroxyl radicals in this order but methionine did not. Bovine serum albumin (BSA) was less reactive toward these radicals than cysteine on molar base. Cysteine, homocysteine, and glutathione suppressed the oxidation of methyl linoleate in micelle systems, but methionine did not. The reactivity toward free radicals and antioxidant capacity of these thiol compounds were less than that of ascorbic acid, but higher than that of uric acid. PMID- 22488890 TI - Dietary traces of neonicotinoid pesticides as a cause of population declines in honey bees: an evaluation by Hill's epidemiological criteria. AB - BACKGROUND: Honey bees are important pollinators of both crops and wild plants. Pesticide regimes that threaten their sustainability should therefore be assessed. As an example, evidence that the agricultural use of neonicotinoid pesticides is a cause of the recently observed declines in honey bees is examined. The aim is to define exacting demographic conditions for a detrimental factor to precipitate a population decline, and Hill's epidemiological 'causality criteria' are employed as a structured process for making an expert judgement about the proposition that trace dietary neonicotinoids in nectar and pollen cause population declines in honey bees. RESULTS: In spite of the absence of decisive experimental results, the analysis shows that, while the proposition is a substantially justified conjecture in the context of current knowledge, it is also substantially contraindicated by a wide variety of circumstantial epidemiological evidence. CONCLUSION: It is concluded that dietary neonicotinoids cannot be implicated in honey bee declines, but this position is provisional because important gaps remain in current knowledge. Avenues for further investigations to resolve this longstanding uncertainty are therefore identified. PMID- 22488892 TI - Dissecting the maturation steps of the lasso peptide microcin J25 in vitro. AB - Microcin J25 is the archetype of a growing class of bacterial ribosomal peptides possessing a knotted topology (lasso peptides). It consists of an eight-residue macrolactam ring through which the C-terminal tail is threaded. It is biosynthesized as a precursor that is processed by two maturation enzymes (McjB/McjC). Insights into the mechanism of microcin J25 biosynthesis have been provided previously by mutagenesis of the precursor peptide in vivo. In this study we have demonstrated distinct functions of McjB and McjC in vitro for the first time, based on the detection of reaction intermediates. McjB was characterized as a new ATP-dependent cysteine protease, whereas McjC was confirmed to be a lactam synthetase. The two enzymes were functionally interdependent, likely forming a structural complex. Their substrate preference was directly investigated with the aid of mutated precursor peptides. Depending on the substitutions, microcin J25 variants with either a lasso or branched cyclic topology could be generated in vitro. PMID- 22488891 TI - Role of LFA-1 in the activation and trafficking of T cells: implications in the induction of chronic colitis. AB - INTRODUCTION: We have previously demonstrated that adoptive transfer of naive CD4(+) T cells devoid of lymphocyte function-associated antigen-1-deficient (LFA 1; CD11a/CD18) into recombination activating gene-1 (RAG-1) deficient (RAG(-/-) ) mice fails to induce chronic colitis whereas transfer of wild type (WT) T-cells induces unrelenting and chronic disease. METHODS: The objectives of this study were to assess the role of lymphocyte function-associated antigen-1 (LFA-1) in enteric antigen (EAg)-induced activation of T cells in vitro and in vivo and to define the importance of this integrin in promoting trafficking of T cells to the mesenteric lymph nodes (MLNs) and colon. RESULTS: We found that EAg-pulsed dendritic cells (DCs) induced proliferation of LFA-1-deficient (CD11a(-/-) ) CD4(+) T cells that was very similar to that induced using WT T cells, suggesting that LFA-1 is not required for activation/proliferation of T cells in vitro. Coculture of WT or CD11a(-/-) T cells with EAg-pulsed DCs induced the generation of similar amounts of interferon-gamma, interleukin (IL)-4, and IL-10, whereas IL 17A production was reduced ~ 2-fold in cocultures with CD11a(-/-) T cells. Short term (20-22 hours) trafficking studies demonstrated that while both WT and CD11a( /-) T cells migrated equally well into the spleen, liver, lungs, small intestine, cecum, and colon, trafficking of CD11a(-/-) T cells to the MLNs was reduced by 50% when compared to WT T cells. When the observation period was extended to 3-7 days posttransfer, we observed ~ 2-3-fold more WT T cells within the MLNs and colon than CD11a(-/-) T cells, whereas T-cell proliferation (as measured by CFSE dilution) was comparable in both populations. CONCLUSIONS: Taken together, our data suggest that LFA-1 is not required for EAg-induced activation of CD4(+) T cells in vitro or in vivo but is required for trafficking of T cells to the MLNs and homing of colitogenic effector cells to the colon where they initiate chronic gut inflammation. PMID- 22488893 TI - Convergent synthesis of deoxypropionates. PMID- 22488894 TI - Icephobic/anti-icing properties of micro/nanostructured surfaces. PMID- 22488895 TI - No associations found between the genes situated at 6p22.1, HIST1H2BJ, PRSS16, and PGBD1 in Japanese patients diagnosed with schizophrenia. AB - Recent GWAS demonstrated an association between candidate genes located at region 6p22.1 and schizophrenia. This region has been reported to house certain candidate SNPs, which may be associated with schizophrenia at HIST1H2BJ, PRSS16, and PGBD1. These genes may presumably be associated with pathophysiology in schizophrenia, namely epigenetics and psychoneuroimmunology. A three-step study was undertaken to focus on these genes with the following aims: (1) whether these genes may be associated in Japanese patients with schizophrenia by performing a 1st stage case-control study (514 cases and 706 controls) using Japanese tagging SNPs; (2) if the genetic regions of interest for the disease from the 1st stage of analyses were found, re-sequencing was performed to search for new mutations; (3) finally, a replication study was undertaken to confirm positive findings from the 1st stage were reconfirmed using a larger number of subjects (2,583 cases and 2,903 controls) during a 2nd stage multicenter replication study in Japan. Genotyping was performed using TaqMan PCR method for the selected nine tagging SNPs. Although three SNPs situated at the 3' side of PGBD1; rs3800324, rs3800327, and rs2142730, and two-window haplotypes between rs3800327 and rs2142730 showed positive associations with schizophrenia, these associations did not have enough power to sustain significance during the 2nd stage replication study. In addition, re-sequencing for exons 5 and 6 situated at this region did not express any new mutations for schizophrenia. Taken together these results indicate that the genes HIST1H2BJ, PRSS16, and PGBD1 were not associated with Japanese patients with schizophrenia. PMID- 22488896 TI - Complex autism spectrum disorder in a patient with a 17q12 microduplication. AB - Autism spectrum disorders (ASDs) are phenotypically complex developmental neuropsychiatric disorders affecting approximately 0.6% of the population. About 30-70% of affected children are also considered to have intellectual disability (ID). The underlying genetic causes of ASDs are diverse with a defined etiology in 16-20%. Array comparative genomic hybridization (aCGH) has proven useful in identifying sub-microscopic chromosome aberrations in a subset of patients, some of which have been shown to be recurrent. One such aberration is the 1.4 Mb microdeletion at chromosome 17q12, which has been reported to be associated with renal disease, growth restriction, diabetes, cognitive impairment, seizures, and in some cases an ASD. Patients with the reciprocal chromosome 17q12 microduplication typically have also been identified with ID and in some cases seizures and behavioral abnormalities. Here we report a patient with a de novo, 1.4 Mb microduplication diagnosed with significant ID involving complex deficits and autism. To our knowledge, this is the first report of a patient with the 17q12 microduplication and a complex ASD phenotype. PMID- 22488897 TI - Reverse-flow scapular osteocutaneous flap for head and neck reconstruction. AB - BACKGROUND: The scapular osteocutaneous flap can be used for the reconstruction of a variety of head and neck defects. In this study, we describe use of the reverse-flow scapular osteocutaneous flap in the setting of a vessel-depleted neck. METHODS AND RESULTS: A retrospective review of patients who underwent scapular osteocutaneous free flap reconstruction over a 5-year period revealed 3 patients who underwent reverse-flow osteocutaneous scapular flaps. Indications for surgery included a large recurrent desmoid tumor of the mandible, recurrent alveolar ridge carcinoma, and osteoradionecrosis. All patients had a history of neck dissection and radiotherapy. Exploration of the contralateral neck was required to identify recipient vessels in all cases. Arterial and venous anastomoses were performed to the distal end of the thoracodorsal artery and subscapular vein, respectively, and no vein grafts were required. There were no cases of flap failures or donor site complications. CONCLUSION: This series demonstrates the safety and efficacy of the reverse flow osteocutaneous flap for complex mandibular reconstruction in cases where recipient vessels are limited. PMID- 22488898 TI - Fluoroalkyl silane modified silicone rubber/nanoparticle composite: a super durable, robust superhydrophobic fabric coating. AB - A superhydrophobic fabric coating made of a crosslinked polydimethylsiloxane elastomer, containing well-dispersed hydrophobic silica nanoparticles and fluorinated alkyl silane, shows remarkable durability against repeated machine washes, severe abrasion, strong acid or base, boiling water or beverages and excellent stain resistance. PMID- 22488899 TI - Relationship between limb length discrepancy and load distribution across the sacroiliac joint--a finite element study. AB - We assessed the relationship between leg length discrepancy (LLD) and the load distribution across the sacro-iliac joint (SIJ). A finite element model of the spine-pelvis was developed with different amounts of LLD by increasing the length of the right femur in the model. Peak stresses and contact loads across the SIJ were computed for different amounts of LLD (1, 2, and 3 cm). The load and the peak stresses across the SIJ articular surfaces progressively increased with the increase in the LLD. Trying to offset the LLD surgically by lengthening of the short side, shortening or stunting the growth (epiphysiodesis) of the long side, or by shoe lifts should decrease the load across the SIJ and should theoretically decrease SIJ pain. PMID- 22488902 TI - Tamed arene and heteroarene trifluoromethylation. PMID- 22488900 TI - Modification of gamma-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease. AB - Inherited familial Alzheimer's disease (AD) is characterized by small increases in the ratio of Abeta42 versus Abeta40 peptide which is thought to drive the amyloid plaque formation in the brain of these patients. Little is known however whether ageing, the major risk factor for sporadic AD, affects amyloid beta peptide (Abeta) generation as well. Here we demonstrate that the secretion of Abeta is enhanced in an in vitro model of neuronal ageing, correlating with an increase in gamma-secretase complex formation. Moreover we found that peroxynitrite (ONOO(-)), produced by the reaction of superoxide anion with nitric oxide, promoted the nitrotyrosination of presenilin 1 (PS1), the catalytic subunit of gamma-secretase. This was associated with an increased association of the two PS1 fragments, PS1-CTF and PS1-NTF, which constitute the active catalytic centre. Furthermore, we found that peroxynitrite shifted the production of Abeta towards Abeta(42) and increased the Abeta(42) /Abeta(40) ratio. Our work identifies nitrosative stress as a potential mechanistic link between ageing and AD. PMID- 22488901 TI - Nanoformulations for molecular MRI. AB - Nanoscale contrast agents have shown the ability to increase the detection sensitivity of magnetic resonance imaging (MRI) by several orders of magnitude, endowing this traditionally macroscopic modality with the ability to observe unique molecular signatures. Herein, we describe three types of nanoparticulate contrast agents: iron oxide nanoparticles, gadolinium-based nanoparticles, and bio-essential manganese, cobalt, nickel, and copper ion-containing nanoformulations. Some of these agents have been approved for clinical use, but more are still under development for medical imaging. The advantages and disadvantages of each nanoformulation, in terms of intrinsic magnetism, ease of synthesis, biodistribution, etc. are discussed. PMID- 22488903 TI - N-acetyl-5-N,4-O-oxazolidinone-protected sialyl sulfoxide: an alpha-selective sialyl donor with Tf2O/(Tol)2SO in dichloromethane. AB - Sweet as sugar: Sialyl sulfoxide protected by N-acetyl-5-N,4-O-oxazolidinone was readily prepared, and its coupling to various sugar acceptors was investigated. When the reaction was promoted by Tf(2)O/(Tol)(2)SO, efficient and highly alpha selective sialylation yielded alpha(2,6), alpha(2,3), and alpha(2,4) glycosidic linkages between sialic acid and glucose/glacotose. PMID- 22488904 TI - To sleep, perchance to dement: RBD and cognitive decline in Parkinson's disease. PMID- 22488905 TI - Formation of columnar liquid crystals on the basis of unconventional triazine based dendrimers by the C3-symmetric approach. AB - Two series of unconventional triazine-based dendrimers with C(2) symmetry and C(3) symmetry were prepared. The newly prepared C(3)-symmetrical dendrimers were characterized by (1)H and (13)C NMR spectroscopy, mass spectrometry, and elemental analysis. Differential scanning calorimetry, polarizing microscopy, and powder XRD showed that the C(3)-symmetrical dendrimers display columnar liquid crystalline phases during thermal treatment, but the C(2)-symmetrical dendrimers were not observed to behave correspondingly. The molecular conformations of C(3)- and C(2)-symmetrical dendrimers were obtained by computer simulation with the MM2 model of the CaChe program in the gas phase. The simulation results reasonably explain the different mesogenicities of C(3)- and C(2)-symmetric dendrimers. This new strategy should be applicable to other types of unconventional dendrimers with rigid frameworks for displaying columnar liquid-crystalline behavior. PMID- 22488906 TI - Antifeedant activity of Jatropha gossypifolia and Melia azedarach senescent leaf extracts on Spodoptera frugiperda (Lepidoptera: Noctuidae) and their potential use as synergists. AB - BACKGROUND: To reduce rates of synthetic insecticide applications, natural product alternatives and synergists are needed. A study has been made of the toxicity of ethanolic senescent leaf extracts (SLEs) of Jatropha gossypifolia and Melia azedarach on larvae of the noctuid pest Spodoptera frugiperda. Their effects as syngergists and inhibitors of several enzyme activities are also reported. RESULTS: When added to the diet, M. azedarach SLE showed lower toxicity than J. gossypifolia SLE. However, after 2 weeks on the diet, the M. azedarach SLE proved to be lethal to 100% of the larval population. Artificial diets with both SLEs have an antifeedant effect on armyworm larvae. Acute toxicity after topical application in a dipping assay was relatively low for both J. gossypifolia and M. azedarach SLEs (LC(50) of 2.6 and 1.4 g L(-1), respectively, after 24 h). However, mixtures of the SLEs of M. azedarach and J. gossypifolia had a strong synergistic effect with cypermethrin. Synergism was higher with the J. gossypifolia SLE, perhaps because it contains several natural products with a methylenedioxyphenyl moiety. Both extracts inhibited P450, general esterase and acetylcholinesterase activities in vitro and in vivo. CONCLUSION: Both J. gossypifolia and M. azedarach SLEs are antifeedants to armyworm larvae when present in the food, and also have a synergistic effect with cypermethrin in topical assays. Although the synergistic effect is less than with piperonyl butoxide, both SLEs have some inhibitor activity against detoxification enzymes and acetylcholinesterase. Thus J. gossypifolia and M. azedarach SLEs may be considered as ecofriendly approaches for the control of S. frugiperda in order to reduce cypermethrin usage. PMID- 22488907 TI - Congenital thrombotic thrombocytopenic purpura (cTTP) with two novel mutations. AB - Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare disorder of childhood that has clinical and laboratory similarities to other, more common conditions. Prompt recognition is required as delays in therapy are associated with significant morbidity and failure to treat may lead to death. While the principles of treatment have not changed, enormous progress in the genetic and molecular understanding has taken place. Emerging treatment options may offer some hope of improved quality of life in future. We describe a Chinese patient with cTTP which resulted from two previously undescribed mutations in the ADAMTS13 gene. PMID- 22488908 TI - Roll-to-roll compatible sintering of inkjet printed features by photonic and microwave exposure: from non-conductive ink to 40% bulk silver conductivity in less than 15 seconds. PMID- 22488909 TI - A re-review of the association between the NOTCH4 locus and schizophrenia. AB - NOTCH4 has long been identified as a candidate susceptibility gene for schizophrenia, but the collective body of genetic association studies of this gene has been less than conclusive. Recently a variant in NOTCH4 was implicated as one of the most reliably associated polymorphisms observed in a genome-wide association scan of the disorder, and the collective evidence for this polymorphism now surpasses criteria for genome-wide significance. To place these developments in context, we now summarize the initial work identifying NOTCH4 as a candidate gene for schizophrenia. The results of the genome-wide association studies that have confirmed this as a risk gene, and novel bioinformatics analyses that reveal potential functional profiles of the most likely risk conferring polymorphisms. These analyses suggest that the NOTCH4 polymorphisms most strongly associated with schizophrenia exert their effects on susceptibility by altering the efficiency and/or alternative splicing of Notch4 transcripts. Further experimental evidence should be pursued to clarify the NOTCH4-regulated molecular and cellular phenotypes of relevance to the disorder, and the functional consequences of the implicated polymorphisms in the gene. PMID- 22488910 TI - Olive oil supplemented with Coenzyme Q(10): effect on plasma and lipoprotein oxidative status. AB - Olive oil consumption is associated with protective cardiovascular properties, including some beneficial modifications in lipoprotein profile and composition. Coenzyme Q(10) (CoQ(10)) exerts a protective effect on plasma lipoproteins. Aim of the study was to investigate whether extra virgin (EV) olive oil enriched with CoQ(10) affects CoQ(10) levels and oxidative status in plasma and in isolated lipoproteins. Twelve subjects were administered 20 mL olive oil per day for 2 weeks, followed by 2 weeks of olive oil enriched with 20 mg and 2 more weeks with 40 mg of CoQ(10). Plasma and isolated lipoproteins were collected in each phase of the study and subsequently analyzed to assess lipid profile, CoQ10 levels, ORAC assay, resistance of lipoproteins to peroxidation and paroxonase 1 activity. Plasma CoQ(10) levels significantly increased with the 20 mg (+73%) and 40 mg dose (+170%), while the percentage of oxidized CoQ(10) decreased. A significant inverse correlation was found in plasma between percentage of oxidized CoQ(10) and total antioxidant capacity. A lower susceptibility of LDL to peroxidation was also found. Finally, a positive correlation was observed between concentration of CoQ(10) in HDL and paraoxonase-1 activity. EV olive oil enriched with both doses of CoQ(10) significantly affects its bioavailability and plasma redox status. These changes are associated with a decreased susceptibility of plasma lipoproteins to peroxidation associated with a chain-breaking antioxidant activity of the formulation. PMID- 22488911 TI - Pellasoren: structure elucidation, biosynthesis, and total synthesis of a cytotoxic secondary metabolite from Sorangium cellulosum. PMID- 22488912 TI - Bioinformatics analysis reveals transcriptome and microRNA signatures and drug repositioning targets for IBD and other autoimmune diseases. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a complex disorder involving pathogen infection, host immune response, and altered enterocyte physiology. Incidences of IBD are increasing at an alarming rate in developed countries, warranting a detailed molecular portrait of IBD. METHODS: We used large-scale data, bioinformatics tools, and high-throughput computations to obtain gene and microRNA signatures for Crohn's disease (CD) and ulcerative colitis (UC). These signatures were then integrated with systemic literature review to draw a comprehensive portrait of IBD in relation to autoimmune diseases. RESULTS: The top upregulated genes in IBD are associated with diabetogenesis (REG1A, REG1B), bacterial signals (TLRs, NLRs), innate immunity (DEFA6, IDO1, EXOSC1), inflammation (CXCLs), and matrix degradation (MMPs). The downregulated genes coded tight junction proteins (CLDN8), solute transporters (SLCs), and adhesion proteins. Genes highly expressed in UC compared to CD included antiinflammatory ANXA1, transporter ABCA12, T-cell activator HSH2D, and immunoglobulin IGHV4-34. Compromised metabolisms for processing of drugs, nitrogen, androgen and estrogen, and lipids in IBD correlated with an increase in specific microRNA. Highly expressed IBD genes constituted targets of drugs used in gastrointestinal cancers, viral infections, and autoimmunity disorders such as rheumatoid arthritis and asthma. CONCLUSIONS: This study presents a clinically relevant gene level portrait of IBD subtypes and their connectivity to autoimmune diseases. The study identified candidates for repositioning of existing drugs to manage IBD. Integration of mice and human data point to an altered B-cell response as a cause for upregulation of genes in IBD involved in other aspects of immune defense such as interferon-inducible responses. PMID- 22488913 TI - Chemical-biological exploration of the limits of the Ras de- and repalmitoylating machinery. AB - A dynamic de-/repalmitoylation cycle determines localization and activity of H- and N-Ras. This combined cellular de- and repalmitoylation machinery has been shown to be substrate tolerant--it accepts variation of amino acid sequence, structure and configuration. Here, semisynthetic Ras-proteins in which the C terminal amino acids are replaced by peptoid residues are used to reveal the first limitations of substrate recognition by the de- and repalmitoylating machinery. PMID- 22488914 TI - Beta oscillations relate to the N400m during language comprehension. AB - The relationship between the evoked responses (ERPs/ERFs) and the event-related changes in EEG/MEG power that can be observed during sentence-level language comprehension is as yet unclear. This study addresses a possible relationship between MEG power changes and the N400m component of the event-related field. Whole-head MEG was recorded while subjects listened to spoken sentences with incongruent (IC) or congruent (C) sentence endings. A clear N400m was observed over the left hemisphere, and was larger for the IC sentences than for the C sentences. A time-frequency analysis of power revealed a decrease in alpha and beta power over the left hemisphere in roughly the same time range as the N400m for the IC relative to the C condition. A linear regression analysis revealed a positive linear relationship between N400m and beta power for the IC condition, not for the C condition. No such linear relation was found between N400m and alpha power for either condition. The sources of the beta decrease were estimated in the LIFG, a region known to be involved in semantic unification operations. One source of the N400m was estimated in the left superior temporal region, which has been related to lexical retrieval. We interpret our data within a framework in which beta oscillations are inversely related to the engagement of task relevant brain networks. The source reconstructions of the beta power suppression and the N400m effect support the notion of a dynamic communication between the LIFG and the left superior temporal region during language comprehension. PMID- 22488915 TI - Autism and epistemology III: Child development, behavioral stability, and reliability of measurement. AB - Early diagnosis and treatment of autism increases the likelihood that symptoms associated with the disorder can be alleviated. However, the behaviors of both typically and atypically developing young infants and toddlers are quite variable and often change as these children age. Studies have shown that this is the case for same-aged children who are diagnosed with autistic disorder (AD) or other Pervasive Developmental Disabilities (PDDs). Therefore, an early accurate assessment of AD or PDD may be problematic. Moreover, instruments used to make the diagnosis may not be as reliable as desired. Statistics employed to evaluate diagnostic accuracy and behavioral stability of instruments' or clinicians' assessments suggest that their diagnoses have been only moderately successful. In addition, the statistics themselves have limitations that would suggest that the measures of diagnostic accuracy and behavioral stability implemented may not be as effective as they would seem. A resolution to these problems is proposed. PMID- 22488916 TI - A self-healing conductive ink. PMID- 22488917 TI - G-quadruplexes in RNA biology. AB - G-quadruplexes are noncanonical structures formed by G-rich DNA and RNA sequences that fold into a four-stranded conformation. Experimental studies and computational predictions show that RNA G-quadruplexes are present in transcripts associated with telomeres, in noncoding sequences of primary transcripts and within mature transcripts. RNA G-quadruplexes at these specific locations play important roles in key cellular functions, including telomere homeostasis and gene expression. Indeed, RNA G-quadruplexes appear as important regulators of pre mRNA processing (splicing and polyadenylation), RNA turnover, mRNA targeting and translation. The regulatory mechanisms controlled by RNA G-quadruplexes involve the binding of protein factors that modulate G-quadruplex conformation and/or serve as a bridge to recruit additional protein regulators. In this review, we summarize the current knowledge on the role of G-quadruplexes in RNA biology with particular emphasis on the molecular mechanisms underlying their specific function in RNA metabolism occurring in physiological or pathological conditions. PMID- 22488919 TI - Is double inactivation of the Nf1 gene responsible for the development of congenital pseudarthrosis of the tibia associated with NF1? AB - The pathogenic mechanism responsible for congenital pseudarthrosis of the tibia (CPT) is not well understood although the possibility of double inactivation of the neurofibromatosis type 1 (Nf1) gene has been suggested. In the present study, loss of heterozygosity was investigated in fibrous hamartoma tissues harvested from 16 patients with CPT associated with NF1 using four genetic markers that span the Nf1 gene. Based on the assumption that a single cell with double inactivation of Nf1 would undergo clonal growth and cause fibrous hamartoma, we investigated clonality in fibrous hamartoma tissues by analyzing X-chromosome inactivation patterns in 11 female patients. Loss of Nf1 heterozygosity in fibrous hamartoma tissues was observed at one or two genetic markers in 4 out of the 16 patients tested. In clonality assays, 3 of 11 patients showed a clonal growth pattern, 5 a non-clonal pattern, and 3 were non-informative. These findings support that double inactivation of the Nf1 gene and subsequent clonal growth could be a pathogenic feature of the fibrous hamartoma tissue at least in some of the CPT but might not be essential requirements of CPT development. PMID- 22488918 TI - Suppression of natural killer-cell and dendritic-cell apoptotic tumoricidal activity in patients with head and neck cancer. AB - BACKGROUND: Natural killer (NK) cells and dendritic cells (DCs) mediate tumor cell apoptosis using tumor necrosis factor superfamily ligands (TNFSFLs). This cytotoxicity is an important anticancer immune defense mechanism. METHODS: We examined TNFSFL expression and apoptotic tumoricidal activity (ATA) of purified NK cells and DCs, and peripheral blood mononuclear leukocytes (PBMLs) of healthy individuals and patients with head and neck cancer (HNC) before and after cancer ablation. RESULTS: PBMLs, NK cells and DCs, but not NK-cell/DC-depleted PBMLs, expressed multiple TNFSFLs and mediated ATA. Both TNFSFL expression and ATA were suppressed in tumor-bearing, and restored in tumor-ablated patients with (HNC) Soluble TNF superfamily receptors (solTNFSFRs) were increasingly bound by PBNLs of tumor-bearing HNC patients. Dissociation of solTNFSFR led to more pronounced increases in TNFSFL expression and ATA of PBMLs of patients with HNC than healthy individuals. CONCLUSION: NK-cell and DC TNFSFL expression and ATA are suppressed in patients with HNC. This suppression is tumor-dependent and possibly mediated by solTNFSFRs. PMID- 22488920 TI - Palladium-catalyzed oxidative double C-H functionalization/carbonylation for the synthesis of xanthones. PMID- 22488921 TI - Stepwise construction of a Ag(I)9-Cu(II)4 heterometallic cluster incorporating two unusual vertex-shared trigonal-bipyramidal silver polyhedra. AB - One step at a time: A novel tridecanuclear Ag(I)(9)-Cu(II)(4) heterometallic cluster comprising four [Cu(phen)(2)](2+) units on the periphery and one interior [Ag(9)(mna)(8)](7-) cluster was synthesized in a stepwise manner and characterized. The interior [Ag(9)(mna)(8)](7-) cluster contains two unusual vertex-shared trigonal-bipyramidal silver polyhedra. PMID- 22488922 TI - Conventional magnetic resonance imaging in confirmed progressive supranuclear palsy and multiple system atrophy. AB - Conventional magnetic resonance imaging (cMRI) is often used to aid the diagnosis of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), but its ability to predict the histopathological diagnosis has not been systematically studied. cMRI from 48 neuropathologically confirmed cases, including PSP (n = 22), MSA (n = 13), Parkinson's disease (PD) (n = 7), and corticobasal degeneration (n = 6), and controls (n = 9) were assessed blinded to clinical details and systematically rated for reported abnormalities. Clinical diagnosis and macroscopic postmortem findings were retrospectively assessed. Radiological assessment of MRI was correct in 16 of 22 (72.7%) PSP cases and 10 of 13 (76.9%) MSA cases with substantial interrater agreement (Cohen's kappa 0.708; P < .001); no PSP case was misclassified as MSA or vice versa. MRI was less sensitive but more specific than clinical diagnosis in PSP and both more sensitive and specific than clinical diagnosis in MSA. The "hummingbird" and "morning glory" signs were highly specific for PSP, and "the middle cerebellar peduncle sign" and "hot cross bun" for MSA, but sensitivity was lower (up to 68.4%) and characteristic findings may not be present even at autopsy. cMRI, clinical diagnosis, and macroscopic examination at postmortem have similar sensitivity and specificity in predicting a neuropathological diagnosis. We have validated specific radiological signs in pathologically confirmed PSP and MSA. However, the low sensitivity of these and macroscopic findings at autopsy suggest a need for imaging techniques sensitive to microstructural abnormalities without regional atrophy. PMID- 22488923 TI - Gold-catalyzed 1,2-/1,2-bis-acetoxy migration of 1,4-bis-propargyl acetates: a mechanistic study. AB - The late transition metal catalyzed rearrangement of propargyl acetates offers an interesting platform for the development of synthetically useful transformations. We have recently shown that gold complexes can catalyze a highly selective tandem 1,2-/1,2-bis-acetoxy migration in 1,4-bis-propargyl acetates to form 2,3-bis acetoxy-1,3-dienes. In this way, (1Z,3Z)- or (1Z,3E)- and (1E,3Z)-1,3-dienes could be obtained in a stereocontrolled manner depending on the electronic and steric features of the ancillary ligand bound to gold and the substituents at the propargylic positions. In this work, we report an experimental study on the scope of this transformation, plus a detailed theoretical examination of the reaction mechanism, which has revealed the key features responsible for the reaction stereoselectivity. Synthetic applications towards the one-pot synthesis of quinoxaline heterocycles and tandem Diels-Alder processes have also been devised. PMID- 22488925 TI - The piezotronic effect of zinc oxide nanowires studied by in situ TEM. AB - Piezotronics is a new field integrating piezoelectric effect into nanoelectronics, which has attracted much attention for the fundamental research and potential applications. In this paper, the piezotronic effect of zinc oxide (ZnO) nanowires, including the response of the electrical transport and photoconducting behaviors on the nanowire bending, has been investigated by in situ transmission electron microscopy (TEM), where the crystal structure of ZnO nanowires were simultaneously imaged. Serials of consecutively recorded current voltage (I-V) curves along with an increase of nanowire bending show the striking effect of bending on their electrical behavior. With increasing the nanowire bending, the photocurrent of ZnO nanowire under ultraviolet illumination (UV) drops dramatically and the photo response time becomes much shorter. In addition, the dynamic nanomechanics of ZnO nanowires were studied inside TEM. These phenomena could be attributed to the piezoelectric effect of ZnO nanowires, and they suggest the potential applications of ZnO nanowires on piezotronic devices. PMID- 22488926 TI - Can rodent outbreaks be driven by major climatic events? Evidence from cyclone Nargis in the Ayeyawady Delta, Myanmar. AB - BACKGROUND: Massive rodent population outbreaks occurred in the Ayeyarwady Delta, Myanmar, in July 2009, 15 months after cyclone Nargis. Satellite imagery with high temporal frequency was used to identify the area and planting time of rice at a landscape scale of > 80 000 ha, and household surveys of farmers were conducted to validate the mapping and to quantify losses. RESULTS: Farmers did not have problems with rodents in 2007-2008; rodents were the principal problem in the 2009 summer and monsoon rice crops. The landscape scale modeling indicated that high rodent densities in 2009 were associated with extended or delayed cropping and harvesting time because of asynchronous planting, and with an increase in the amount of abandoned agricultural land after cyclone Nargis. CONCLUSION: Asynchronous planting following cyclone Nargis provided abundant high quality food for an extended period, which in turn led to a lengthened breeding season of rodents. The outbreak of populations 15 months after cyclone Nargis is consistent with the time it would take rodent populations to build from a low base after a major flooding event. To prevent rodent outbreaks effectively, synchronous planting, use of rice varieties with a similar maturation date and good field sanitation are important actions for subsequent rice crops after a major weather event. PMID- 22488924 TI - Transforming growth factor-alpha mediates estrogen-induced upregulation of glutamate transporter GLT-1 in rat primary astrocytes. AB - Glutamate transporter-1 (GLT-1) plays a central role in preventing excitotoxicity by removing excess glutamate from the synaptic clefts. 17beta-Estradiol (E2) and tamoxifen (TX), a selective estrogen receptor (ER) modulator, afford neuroprotection in a range of experimental models. However, the mechanisms that mediate E2 and TX neuroprotection have yet to be elucidated. We tested the hypothesis that E2 and TX enhance GLT-1 function by increasing transforming growth factor (TGF)-alpha expression and, thus, attenuate manganese (Mn)-induced impairment in astrocytic GLT-1 expression and glutamate uptake in rat neonatal primary astrocytes. The results showed that E2 (10 nM) and TX (1 MUM) increased GLT-1 expression and reversed the Mn-induced reduction in GLT-1, both at the mRNA and protein levels. E2/TX also concomitantly reversed the Mn-induced inhibition of astrocytic glutamate uptake. E2/TX activated the GLT-1 promoter and attenuated the Mn-induced repression of the GLT-1 promoter in astrocytes. TGF-alpha knockdown (siRNA) abolished the E2/TX effect on GLT-1 expression, and inhibition of epidermal growth factor receptor (TGF-alpha receptor) suppressed the effect of E2/TX on GLT-1 expression and GLT-1 promoter activity. E2/TX also increased TGF alpha mRNA and protein levels with a concomitant increase in astrocytic glutamate uptake. All ERs (ER-alpha, ER-beta, and G protein-coupled receptor 30) were involved in mediating E2 effects on the regulation of TGF-alpha, GLT-1, and glutamate uptake. These results indicate that E2/TX increases GLT-1 expression in astrocytes via TGF-alpha signaling, thus offering an important putative target for the development of novel therapeutics for neurological disorders. PMID- 22488927 TI - Plasmablast frequency and trafficking receptor expression are altered in pediatric ulcerative colitis. AB - BACKGROUND: The incidence of pediatric ulcerative colitis (UC), a chronic autoinflammatory disease of the colon, is on the rise. Although an increased infiltration of B cells from the peripheral blood into the colon occurs in UC, B cell trafficking is understudied. We hypothesized that the frequency of circulating plasmablasts (PBs) and their trafficking receptor (TR) expression may be indicative of the location and degree of pathology in pediatric UC. METHODS: We conducted multicolor flow cytometry analyses of circulating IgA(+/-) PBs and IgA(+) memory B cells (MBCs) in pediatric UC patients with remission, mild, moderate, and severe state of disease (n = 12), and healthy pediatric (n = 2) and adult donors (n = 11). RESULTS: Compared to healthy donors the average frequency of PBs among total peripheral blood lymphocytes is increased 30-fold during severe UC activity, and positively correlates with Pediatric Ulcerative Colitis Activity Index score, C-reactive protein level, and erythrocyte sedimentation rate. A greater percent of PBs in severe patients express the gut-homing receptors alpha4beta7 and CCR10, and the inflammatory homing molecule P-selectin ligand (P-sel lig). The percent of IgA(+) MBCs expressing alpha4beta7, however, is reduced. Furthermore, expression of the small intestine TR CCR9 is decreased on alpha4beta7(high) PBs, and on alpha4beta7(high) /CCR10(high) PBs and MBCs in these patients, consistent with preferential cell targeting to the colon. CONCLUSIONS: Peripheral blood PBs with a colon-homing phenotype (alpha4beta7/CCR10/P-sel lig) are elevated in children with severe UC. Screening this B-cell subset may provide a complementary approach in monitoring disease activity or therapeutic efficacy in pediatric UC. PMID- 22488928 TI - Biocompatible polyurea dendrimers with pH-dependent fluorescence. PMID- 22488929 TI - Overexpression of synoviolin facilitates the formation of a functional synovial biomembrane. AB - Digital flexor tendon repair poses a significant challenge for hand surgeons. Currently, extrasynovial tendon grafts are frequently used in clinical settings to bridge flexor tendon defects. However, the healing process is always accompanied by postoperative adhesion. This is mostly due to the fact that no synovial membrane covers the extrasynovial tendon surface, in contrast to the intrasynovial tendon. In this study, we present an efficient method of developing a functional synovial biomembrane on the surface of the extrasynovial tendon. Synoviocytes were isolated from the knee joint of a Japanese white rabbit. After being infected with lentivirus, the over-expression of synoviolin in these synoviocytes was confirmed by semi-quantitative RT-PCR and western blotting. Cellular proliferation and increased hyaluronic acid secretion were confirmed in the synoviolin over-expressing synoviocytes by MTT-based method, cell cycle assays and ELISA. Furthermore, the synoviolin over-expressing synoviocytes were co-cultured with extrasynovial tendons that were harvested from the hind leg of rabbits. After being co-cultured in vitro for 3 and 7 days, these infected synoviocytes were found to accelerate the formation of a biomembrane on the tendon surface compared to the control group. More importantly, Alcian blue staining confirmed the ability of this cultured biomembrane to produce specific matrices containing acidic carboxyl mucopolysaccharides (mainly hyaluronic acid). All these results demonstrate that the over-expression of synoviolin stimulates the proliferation and HA secretion of synoviocytes and facilitates the formation of a functional synovial biomembrane. PMID- 22488931 TI - The role of the pulvinar in distractor processing and visual search. AB - The pulvinar nuclei of the thalamus are hypothesized to coordinate attentional selection in the visual cortex. Different models have, however, been proposed for the precise role of the pulvinar in attention. One proposal is that the pulvinar mediates shifts of spatial attention; a different proposal is that it serves the filtering of distractor information. At present, the relation between these possible operations and their relative importance in the pulvinar remains unresolved. We address this issue by contrasting these proposals in two fMRI experiments. We used a visual search paradigm that permitted us to dissociate neural activity reflecting shifts of attention from activity underlying distractor filtering. We find that distractor filtering, but not the operation of shifting attention, is associated with strong activity enhancements in dorsal and ventral regions of the pulvinar as well as in early visual cortex areas including the primary visual cortex. Our observations indicate that distractor filtering is the preponderant attentional operation subserved by the pulvinar, presumably mediated by a modulation of processing in visual areas where spatial resolution is sufficiently high to separate target from distractor input. PMID- 22488930 TI - The 5-HTTLPR polymorphism moderates the effect of stressful life events on drinking behavior in college students of African descent. AB - Covault et al. [Covault et al. (2007); Biol Psychiatry 61(5): 609-616] reported that the common functional polymorphism, 5-HTTLPR, in the serotonin transporter gene moderated the association between past-year stressful events and daily reports of drinking in a sample of European-American (EA) college students. We examined this effect in college students of African descent. Students recruited at a Historically Black University (n = 564) completed web-based measures of past year stressful life experiences and daily reports of drinking and heavy drinking over a 30-day period. Participants were genotyped for the tri-allelic 5-HTTLPR polymorphism and dichotomized as low-activity S' allele carriers or high-activity L' homozygotes. Generalized linear models were used to examine the effects of life stress, genotype, and their interaction on the two drinking measures. In students who completed 15 or more daily surveys (n = 393), there was a significant interaction of past-year stressful events, 5-HTTLPR genotype, and gender on the number of drinking days (P = 0.002). Similar findings were obtained in relation to heavy drinking days (P = 0.007). Men showed a main effect of past year stressful events on both drinking outcomes (P's < 0.001), but no main or moderator effects of genotype. In women, the S' allele moderated the impact of past-year life stressors on the frequency of drinking and heavy drinking days (P's < 0.001). In college students of African descent, past-year stressful events were associated with more frequent drinking and heavy drinking, an effect that was moderated by the 5-HTTLPR polymorphism. However, in contrast to the findings in EA students, in the current sample, 5-HTTLPR moderated the association only among women. PMID- 22488932 TI - KRAS gene mutations in Noonan syndrome familial cases cluster in the vicinity of the switch II region of the G-domain: report of another family with metopic craniosynostosis. AB - Noonan syndrome (NS) and Noonan-related disorders [cardio-facio-cutaneous (CFC), Costello, Noonan syndrome with multiple lentigines (NS-ML), and neurofibromatosis Noonan syndromes (NFNS)] are a group of developmental disorders caused by mutations in genes of the RAS/MAPK pathway. Mutations in the KRAS gene account for only a small proportion of affected Noonan and CFC syndrome patients that present an intermediate phenotype between these two syndromes, with more frequent and severe intellectual disability in NS and less ectodermal involvement in CFC syndrome, as well as atypical clinical findings such as craniosynostosis. Recently, the first familial case with a novel KRAS mutation was described. We report on a second vertical transmission (a mother and two siblings) with a novel mutation (p.M72L), in which the proband has trigonocephaly and the affected mother and sister, prominent ectodermal involvement. Metopic suture involvement has not been described before, expanding the main different cranial sutures which can be affected in NS and KRAS gene mutations. The gene alteration found in the studied family is in close proximity to the one reported in the other familial case (close to the switch II region of the G-domain), suggesting that this specific region of the gene could have less severe effects on intellectual ability than the other KRAS gene mutations found in NS patients and be less likely to hamper reproductive fitness. PMID- 22488933 TI - Endothelial progenitor cells in diabetes mellitus. AB - Diabetes mellitus is associated with an increased risk of cardiovascular disease due to its negative impact on the vascular endothelium. The damaged endothelium is repaired by resident cells also through the contribution of a population of circulating cells derived from bone marrow. These cells, termed endothelial progenitor cells (EPCs) are involved in maintaining endothelial homeostasis and contributes to the formation of new blood vessels with a process called postnatal vasculogenesis. The mechanisms whereby these cells allow for protection of the cardiovascular system are still unclear; nevertheless, consistent evidences have shown that impairment and reduction of EPCs are hallmark features of type 1 and type 2 diabetes. Therefore, EPC alterations might have a pathogenic role in diabetic complications, thus becoming a potential therapeutic target. In this review, EPC alterations will be examined in the context of macrovascular and microvascular complications of diabetes, highlighting their roles and functions in the progression of the disease. PMID- 22488934 TI - Structural studies on ionic liquid/water/peptide systems by HR-MAS NMR spectroscopy. AB - The present work reports on an assessment of high-resolution magic angle spinning (HR-MAS) NMR spectroscopy for structural investigations of peptides dissolved in aqueous ionic liquids. Highly resolved one- and two-dimensional NMR spectra are obtained that allow for complete proton resonance assignments of both the peptides as solutes and the ionic liquids as solvents. Successful application of the HR-MAS method facilitates for the first time high-resolution NMR analysis of complex ionic liquid/peptide systems at the molecular level, mainly on the basis of chemical-shift changes. PMID- 22488935 TI - Large scale monodisperse hexagonal arrays of superparamagnetic iron oxides nanodots: a facile block copolymer inclusion method. AB - Highly dense hexagonal ordered arrays of superparamagnetic iron oxides nanodots are fabricated by a simple and cost-effective route. Spectroscopic, microscopic and magnetic measurements show that the nanodots have uniform size, shape and their placement mimics the original self-assembled block copolymer pattern. The nanodots show good thermal stability and strong adherence to the substrate surface, making them useful for practical device applications. PMID- 22488936 TI - Involvement of surface-bound radicals in the oxidation of toluene using supported Au-Pd nanoparticles. PMID- 22488937 TI - Shaping the niche: lessons from the Drosophila testis and other model systems. AB - Stem cells are fascinating, as they supply the cells that construct our adult bodies and replenish, as we age, worn out, damaged, and diseased tissues. Stem cell regulation relies on intrinsic signals but also on inputs emanating from the neighbouring niche. The Drosophila testis provides an excellent system for studying such processes. Although recent advances have uncovered several signalling, cytoskeletal and other factors affecting niche homeostasis and testis differentiation, many aspects of niche regulation and maintenance remain unsolved. In this review, we discuss aspects of niche establishment and integrity not yet fully understood and we compare it to the current knowledge in other model systems such as vertebrates and plants. We also address specific questions on stem cell maintenance and niche regulation in the Drosophila testis under the control of Hox genes. Finally, we provide insights on the striking functional conservation of homologous genes in plants and animals and their respective stem cell niches. Elucidating conserved mechanisms of stem cell control in both lineages could reveal the importance underlying this conservation and justify the evolutionary pressure to adapt homologous molecules for performing the same task. PMID- 22488939 TI - Rare-Earth nanoparticles with enhanced upconversion emission and suppressed rare Earth-ion leakage. AB - Upconversion emissions from rare-earth nanoparticles have attracted much interest as potential biolabels, for which small particle size and high emission intensity are both desired. Herein we report a facile way to achieve NaYF(4):Yb,Er@CaF(2) nanoparticles (NPs) with a small size (10-13 nm) and highly enhanced (ca. 300 times) upconversion emission compared with the pristine NPs. The CaF(2) shell protects the rare-earth ions from leaking, when the nanoparticles are exposed to buffer solution, and ensures biological safety for the potential bioprobe applications. With the upconversion emission from NaYF(4):Yb,Er@CaF(2) NPs, HeLa cells were imaged with low background interference. PMID- 22488940 TI - Glial glutamate transport modulates dendritic spine head protrusions in the hippocampus. AB - Accumulating evidence supports the idea that synapses are tripartite, whereby perisynaptic astrocytes modulate both pre- and postsynaptic function. Although some of these features have been uncovered by using electrophysiological methods, less is known about the structural interplay between synapses and glial processes. Here, we investigated how astrocytes govern the plasticity of individual hippocampal dendritic spines. Recently, we uncovered that a subgroup of innervated dendritic spines is able to undergo remodeling by extending spine head protrusions (SHPs) toward neighboring functional presynaptic boutons, resulting in new synapses. Although glutamate serves as a trigger, how this behavior is regulated is unknown. As astrocytes control extracellular glutamate levels through their high-affinity uptake transporters, together with their privileged access to synapses, we investigated a role for astrocytes in SHP formation. Using time-lapse confocal microscopy, we found that the volume overlap between spines and astrocytic processes decreased during the formation of SHPs. Focal application of glutamate also reduced spine-astrocyte overlap and induced SHPs. Importantly, SHP formation was prevented by blocking glial glutamate transporters, suggesting that glial control of extracellular glutamate is important for SHP-mediated plasticity of spines. Hence, the dynamic changes of both spines and astrocytes can rapidly modify synaptic connectivity. PMID- 22488941 TI - Laryngeal tumor volume as a predictor for thyroid cartilage penetration. AB - BACKGROUND: Review of laryngectomy specimens demonstrated that preoperative CT scanning is suboptimal in predicting both thyroid cartilage penetration and extralaryngeal spread. We investigated the association between the CT-based gross tumor volume (GTV) with pathologic evidence of thyroid cartilage penetration among patients undergoing laryngectomy for squamous cell carcinoma (SCC) of the larynx. METHODS: Ninety-four patients were identified who underwent total laryngectomy for SCC of the larynx. GTV, as defined by preoperative diagnostic CT scan, was contoured and analyzed using treatment-planning software. RESULTS: Among the 49 nonirradiated patients, the mean GTVs of patients with (n = 15) and without (n = 34) thyroid cartilage penetration was 60.1 and 28.0 cm(3) (p = .004). When the nonirradiated patients were divided into 3 GTV groups (<=25 cm(3), 25-50 cm(3), >50 cm(3)), the rates of thyroid cartilage penetration were 23%, 17%, and 78%, respectively (p = .003). CONCLUSIONS: Laryngeal tumor volume is associated with pathologic evidence of thyroid cartilage penetration in nonirradiated patients. PMID- 22488943 TI - Genome-wide arrays in routine diagnostics of hematological malignancies. AB - Over the last three decades, cytogenetic analysis of malignancies has become an integral part of disease evaluation and prediction of prognosis or responsiveness to therapy. In most diagnostic laboratories, conventional karyotyping, in conjunction with targeted fluorescence in situ hybridization analysis, is routinely performed to detect recurrent aberrations with prognostic implications. However, the genetic complexity of cancer cells requires a sensitive genome-wide analysis, enabling the detection of small genomic changes in a mixed cell population, as well as of regions of homozygosity. The advent of comprehensive high-resolution genomic tools, such as molecular karyotyping using comparative genomic hybridization or single-nucleotide polymorphism microarrays, has overcome many of the limitations of traditional cytogenetic techniques and has been used to study complex genomic lesions in, for example, leukemia. The clinical impact of the genomic copy-number and copy-neutral alterations identified by microarray technologies is growing rapidly and genome-wide array analysis is evolving into a diagnostic tool, to better identify high-risk patients and predict patients' outcomes from their genomic profiles. Here, we review the added clinical value of an array-based genome-wide screen in leukemia, and discuss the technical challenges and an interpretation workflow in applying arrays in the acquired cytogenetic diagnostic setting. PMID- 22488944 TI - Synthesis, characterization, and CO(2) adsorptive behavior of mesoporous AlOOH supported layered hydroxides. AB - A novel CO(2) solid sorbent was prepared by synthesizing and modifying AlOOH supported CaAl layered double hydroxides (CaAl LDHs), which were prepared by using mesoporous alumina (gamma-Al(2)O(3)) and calcium chloride (CaCl(2)) in a hydrothermal urea reaction. The nanostructured CaAl LDHs with nanosized platelets (3-30 nm) formed and dispersed inside the crystalline framework of mesoporous AlOOH (boehmite). By calcination of AlOOH-supported LDHs at 700 degrees C, the mesoporous CaAl metal oxides exhibited ordered hexagonal mesoporous arrays or uniform nanotubes with a large surface area of 273 m(2) g(-1) , a narrow pore size distribution of 6.2 nm, and highly crystalline frameworks. The crystal structure of the calcined mesoporous CaAl metal oxides was multiphasic, consisting of CaO/Ca(OH)(2), Al(2)O(3), and CaAlO mixed oxides. The mesoporous metal oxides were used as a solid sorbent for CO(2) adsorption at high temperatures and displayed a maximum CO(2) capture capacity (~45 wt %) of the sorbent at 650 degrees C. Furthermore, it was demonstrated that the mesoporous CaAl oxides showed a more rapid adsorption rate (for 1-2 min) and longer cycle life (weight change retention: 80 % for 30 cycles) of the sorbent because of the greater surface area and increased number of activated sites in the mesostructures. A simple model for the formation mechanism of mesoporous metal oxides is tentatively proposed to account for the synergetic effect of CaAl LDHs on the adsorption of CO(2) at high temperature. PMID- 22488946 TI - Association between serotonin transporter gene polymorphism and eating disorders outcome: a 6-year follow-up study. AB - Eating disorder patients show different long-term outcomes, and trait-related alterations of serotonergic function, which might be related with the serotonin transporter (5-HTT) gene. We studied the relationships between 5-HTTLPR polymorphism, eating specific and general psychopathology and the long-term outcome of anorexia nervosa (AN) and bulimia nervosa (BN) patients. We evaluated the distribution of the functional 5-HTTLPR polymorphism in a series of 201 Italian, Caucasian, eating disorder patients (113 with AN and 88 with BN binge/purging (BP subtype) and in 150 Caucasian unrelated controls. Prior to starting an individual cognitive behavior therapy, a clinical assessment was performed by means of the structured clinical interview for DSM-IV axis I disorders and several self-report questionnaires. This assessment was repeated at the end of treatment, 3 years after the end of treatment and 3 years after the first follow-up. Diagnostic changes between AN and BN were frequent (28.3%), and the presence of depressive disorders was associated with a higher rate of diagnostic crossover during the follow-up period. The S-allele of the 5-HTTLPR genotype increases the risk susceptibility for both depressive comorbidity (OR = 4.23; 95% CI, 1.45-12.37) and diagnostic crossover during the follow-up period in AN patients (OR = 5.04; 95% CI, 1.69-14.98). Logistic regression analyses confirmed these findings, when the interaction between genotype and psychiatric comorbidity as predictors of diagnostic instability in AN patients were taken into account. No significant association was found between 5-HTTLPR genotype and recovery. The S-allele of the 5-HTTLPR genotype increases the risk for depressive disorders comorbidity, and moderates the long-term outcome of anorectic patients. PMID- 22488947 TI - Rituximab-associated colitis. PMID- 22488942 TI - Tropomodulins: pointed-end capping proteins that regulate actin filament architecture in diverse cell types. AB - Tropomodulins are a family of four proteins (Tmods 1-4) that cap the pointed ends of actin filaments in actin cytoskeletal structures in a developmentally regulated and tissue-specific manner. Unique among capping proteins, Tmods also bind tropomyosins (TMs), which greatly enhance the actin filament pointed-end capping activity of Tmods. Tmods are defined by a TM-regulated/Pointed-End Actin Capping (TM-Cap) domain in their unstructured N-terminal portion, followed by a compact, folded Leucine-Rich Repeat/Pointed-End Actin Capping (LRR-Cap) domain. By inhibiting actin monomer association and dissociation from pointed ends, Tmods regulate actin dynamics and turnover, stabilizing actin filament lengths and cytoskeletal architecture. In this review, we summarize the genes, structural features, molecular and biochemical properties, actin regulatory mechanisms, expression patterns, and cell and tissue functions of Tmods. By understanding Tmods' functions in the context of their molecular structure, actin regulation, binding partners, and related variants (leiomodins 1-3), we can draw broad conclusions that can explain the diverse morphological and functional phenotypes that arise from Tmod perturbation experiments in vitro and in vivo. Tmod-based stabilization and organization of intracellular actin filament networks provide key insights into how the emergent properties of the actin cytoskeleton drive tissue morphogenesis and physiology. PMID- 22488948 TI - Status dystonicus: predictors of outcome and progression patterns of underlying disease. AB - BACKGROUND: Status dystonicus (SD) is a rare, life-threatening disorder characterized by acute worsening of generalized dystonia. METHODS: This study was conducted to characterize the pathogenesis, clinical course, and prognosis of SD. We reviewed the records of six centers and analyzed them together with all the cases previously reported in the literature. RESULTS: Eighty-nine episodes occurring in 68 patients were studied. The majority of patients were males (64.7%), were <15 years of age (58.8%), and had secondary dystonia as the underlying condition (37.8%). The episodes were mainly characterized by tonic muscle spasms (68.5%), with phasic forms more common in secondary forms and among females. Almost all cases needed a multistaged approach, with surgery being the most successful strategy. Neurological conditions preceding the episode worsened in 16.2% of cases (ending in death in 10.3%). CONCLUSIONS: The course and outcome of SD is highly variable; male gender and prevalent tonic phenotype predict a poor outcome. PMID- 22488949 TI - Calcium upregulated survivin expression and associated osteogenesis of normal human osteoblasts. AB - Survivin is an antiapoptotic protein expressed in all phases of the normal cell cycle but is at its highest level during the G2/M interphase. This protein has been recently identified in normal human osteoblasts and has raised questions about the regulation of its expression. This study intends to verify if survivin expression could be manipulated by external factors such as calcium ions. Normal human alveolar bone explants recovered from six healthy donors were cultured to 2nd passage. Cells were cultured with essential medium as a control and with medium containing supplemental calcium ions at a concentration of 30 parts per million as a study group. Vitamin D(3) was added to all culture groups at the 5th and 18th days to promote differentiation. Differentiation markers were confirmed by performing mineralization, alkaline phosphatase (ALP), and osteocalcin assays at 7 and 21 days. Cell attachment was measured at 16 h and used as a reference for cell proliferation at 7 days and 21 days. Survivin levels were measured at 16 h, 7 and 21 days. Compared with the control group, the study group presented a significant increase of survivin expression at 16 h (p < 0.01), at 7 days (p < 0.01), and at 21 days (p < 0.05), a significant increase of cell proliferation, ALP activity and mineralization at 7 days (p < 0.05) and 21 days (p < 0.05), and a significant increase in osteocalcin expression only at 21 days (p < 0.01). This study demonstrated that survivin expression could be significantly upregulated by calcium-enhanced normal human osteoblast cultures, which might correlate to subsequent upregulation of cell proliferation and differentiation. PMID- 22488950 TI - Liquid-phase deposition of freestanding copper foils and supported copper thin films and their structuring into conducting line patterns. PMID- 22488951 TI - Microwave-assisted synthesis of fluorescent Ag nanoclusters in aqueous solution. AB - Fluorescent Ag nanoclusters are of significant interest because they provide the bridge between atomic and nanoparticle behavior in noble metals. Herein, microwave irradiation was originally used for the synthesis of water-soluble fluorescent Ag nanoclusters. As-prepared Ag nanoclusters present red fluorescence emission around 608 nm and a characteristic absorption peak at about 508 nm. Transmission electron microscopy (TEM) shows an average size of 1.6 nm for Ag nanoclusters. The effect of solution pH on the synthesis process and optical properties of Ag nanoclusters was investigated. The pH-dependent present form and adsorption capacity of poly(methacrylic acid, sodium salt) (PMAA) ligands are believed to be the reason for the pH effect. PMID- 22488953 TI - Human alpha2-macroglobulin--another variation on the venus flytrap. PMID- 22488954 TI - A light-controlled resistive switching memory. AB - Sketch of the configuration of a light-controlled resistive switching memory. Light enters through the Al(2) O(3) uncovered surface and reaches the optically active p-Si substrate, where carriers are photogenerated and subsequently injected in the Al(2) O(3) layer when a suitable voltage pulse is applied. The resistance of the Al(2) O(3) can be switched between different non-volatile states, depending on the applied voltage pulse and on the illumination conditions. PMID- 22488952 TI - Effects of age on prefrontal subregions and hippocampal volumes in young and middle-aged healthy humans. AB - There are limited data available regarding the effects of age and sex on discrete prefrontal gray and white matter volumes or posterior and anterior hippocampal volumes in healthy humans. Volumes of the superior frontal gyrus, anterior cingulate gyrus, and orbital frontal lobe were computed manually from contiguous magnetic resonance (MR) images in 83 (39M/44F) healthy humans (age range = 16-40) and segmented into gray and white matter. Volumes of the posterior and anterior hippocampal formation were also computed with reliable separation of the anterior hippocampal formation from the amygdala. There were significant age-by-tissue type interactions for the superior frontal gyrus and orbital frontal lobe such that gray matter within these regions correlated significantly and inversely with age. In contrast, no significant age effects were evident within regional white matter volumes. Analysis of hippocampal volumes indicated that men had larger volumes of the anterior, but not posterior hippocampal formation compared to women even following correction for total brain size. These data highlight age effects within discrete prefrontal cortical gray matter regions in young and middle aged healthy humans and suggest that the white matter comprising these regions may be more resistant to age effects. Furthermore, understanding the potential role of sex and age in mediating prefrontal cortical and hippocampal volumes may have strong relevance for psychiatric disorders such as schizophrenia that have implicated neurodevelopmental abnormalities within frontotemporal circuits in their pathogenesis. PMID- 22488955 TI - Membrane microdomains in immunity: glycosphingolipid-enriched domain-mediated innate immune responses. AB - Over the last 30 years, many studies have indicated that glycosphingolipids (GSLs) expressed on the cell surface may act as binding sites for microorganisms. Based on their physicochemical characteristics, GSLs form membrane microdomains with cholesterol, sphingomyelin, glycosylphosphatidylinositol (GPI)-anchored proteins, and various signaling molecules, and GSL-enriched domains have been shown to be involved in these defense responses. Among the GSLs, lactosylceramide (LacCer, CDw17) can bind to various microorganisms. LacCer is expressed at high levels on the plasma membrane of human neutrophils, and forms membrane microdomains associated with the Src family tyrosine kinase Lyn. LacCer-enriched membrane microdomains mediate superoxide generation, chemotaxis, and non-opsonic phagocytosis. Therefore, LacCer-enriched membrane microdomains are thought to function as pattern recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs) expressed on microorganisms. In contrast, several pathogens have developed infection mechanisms using membrane microdomains. In addition, some pathogens have the ability to avoid degradation by escaping from the vacuolar compartment or preventing phagosome maturation, utilizing membrane microdomains, such as LacCer-enriched domains, of host cells. The detailed molecular mechanisms of these membrane microdomain-associated host-pathogen interactions remain to be elucidated. PMID- 22488956 TI - Consanguinity and the risk of congenital heart disease. AB - Consanguineous unions have been associated with an increased susceptibility to various forms of inherited disease. Although consanguinity is known to contribute to recessive diseases, the potential role of consanguinity in certain common birth defects is less clear, particularly since the disease pathophysiology may involve genetic and environmental/epigenetic factors. In this study, we ask whether consanguinity affects one of the most common birth defects, congenital heart disease, and identify areas for further research into these birth defects, since consanguinity may now impact health on a near-global basis. A systematic review of consanguinity in congenital heart disease was performed, focusing on non-syndromic disease, with the methodologies and results from studies of different ethnic populations compared. The risks for congenital heart disease have been assessed and summarized collectively and by individual lesion. The majority of studies support the view that consanguinity increases the prevalence of congenital heart disease, however, the study designs differed dramatically. Only a few (n = 3) population-based studies that controlled for potential sociodemographic confounding were identified, and data on individual cardiac lesions were limited by case numbers. Overall the results suggest that the risk for congenital heart disease is increased in consanguineous unions in the studied populations, principally at first-cousin level and closer, a factor that should be considered in empiric risk estimates in genetic counseling. However, for more precise risk estimates a better understanding of the underlying disease factors is needed. PMID- 22488957 TI - Visible-light photooxidation of water to oxygen at hybrid TiO2 -polyheptazine photoanodes with photodeposited Co-Pi (CoO(x)) cocatalyst. AB - A cobalt oxide-based oxygen-evolving cocatalyst (Co-Pi) is photodeposited by visible-light irradiation onto nanocrystalline TiO(2)-polyheptazine (TiO(2)-PH) hybrid photoelectrodes in a phosphate buffer. The Co-Pi cocatalyst couples effectively to photoholes generated in the surface polyheptazine layer of the TiO(2)-PH photoanode, as evidenced by complete photooxidation of water to oxygen under visible-light (lambda>420 nm) irradiation at moderate bias potentials. In addition, the presence of the cocatalyst also reduces significantly the recombination of photogenerated charges, particularly at low bias potentials, which is ascribed to better photooxidation kinetics resulting in lower accumulation of holes. This suggests that further improvements of photoconversion efficiency can be achieved if more effective catalytic sites for water oxidation are introduced to the surface structure of the hybrid photoanodes. PMID- 22488958 TI - Involvement of protein kinase D in uridine diphosphate-induced microglial macropinocytosis and phagocytosis. AB - The clearance of tissue debris by microglia is a crucial component of maintaining brain homeostasis. Microglia continuously survey the brain parenchyma and utilize extracellular nucleotides to trigger the initiation of their dynamic responses. Extracellular uridine diphosphate (UDP), which leaks or is released from damaged neurons, has been reported to stimulate the phagocytotic activity of microglia through P2Y(6) receptor activation. However, the intracellular mechanisms underlying microglial P2Y(6) receptor signals have not been identified. In this study, we demonstrated that UDP stimulation induced immediate and long-lasting dynamic movements in the cell membrane. After 60 min of UDP stimulation, there was an upregulation in the number of large vacuoles formed in the cell that incorporate extracellular fluorescent-labeled dextran, which indicates microglial macropinocytosis. In addition, UDP-induced vacuole formation and continuous membrane motility were suppressed by the protein kinase D (PKD) inhibitors, Go6976 and CID755673, unlike Go6983, which is far less sensitive to PKD. The inhibition of PKD also reduced UDP-induced incorporation of fluorescent-labeled dextran and soluble beta-amyloid and phagocytosis of microspheres. UDP induced rapid phosphorylation and membrane translocation of PKD, which was abrogated by the inhibition of protein kinase C (PKC) with Go6983. However, Go6983 failed to suppress UDP-induced incorporation of microspheres. Finally, we found that inhibition of PKD by CID755673 significantly suppressed UDP-induced engulfment of IgG-opsonized microspheres. These data suggest that a PKC-independent function of PKD regulates UDP-induced membrane movement and contributes to the increased uptake of extracellular fluid and microspheres in microglia. PMID- 22488959 TI - DFT studies on cobalt-catalyzed cyclotrimerization reactions: the mechanism and origin of reaction improvement under microwave irradiation. AB - A DFT computational mechanistic study of the [2+2+2] cyclotrimerization of a diyne with benzonitrile, catalyzed by a cobalt complex, has been carried out. Three alternative catalytic cycles have been examined together with the precatalytic step (responsible for the induction period). The favored mechanism takes place by means of an intramolecular metal-assisted [4+2] cycloaddition. The beneficial role of microwave activation has been studied. It is concluded that microwave irradiation can decrease the catalytic induction period through thermal effects and can also increase the triplet lifetime and promote the reaction, thus improving the final yield. PMID- 22488960 TI - Archipelago architecture of the focal adhesion: membrane molecules freely enter and exit from the focal adhesion zone. AB - The focal adhesion (FA) is an integrin-based structure built in/on the plasma membrane, mechanically linking the extracellular matrix with the termini of actin stress fibers, providing key scaffolds for the cells to migrate in tissues. The FA was considered as a micron-scale, massive assembly of various proteins, although its formation and decomposition occur quickly in several to several 10 s of minutes. The mechanism of rapid FA regulation has been a major mystery in cell biology. Here, using fast single fluorescent-molecule imaging, we found that transferrin receptor and Thy1, non-FA membrane proteins, readily enter the FA zone, diffuse rapidly there, and exit into the bulk plasma membrane. Integrin beta3 also readily enters the FA zone, and repeatedly undergoes temporary immobilization and diffusion in the FA zone, whereas approximately one-third of integrin beta3 is immobilized there. These results are consistent with the archipelago architecture of the FA, which consists of many integrin islands: the membrane molecules enter the inter-island channels rather freely, and the integrins in the integrin islands can be rapidly exchanged with those in the bulk membrane. Such an archipelago architecture would allow rapid FA formation and disintegration, and might be applicable to other large protein domains in the plasma membrane. PMID- 22488961 TI - BRAFV600E mutation in fine-needle aspiration aspirates: Association with poorer prognostic factors in larger papillary thyroid carcinomas. AB - BACKGROUND: Recent studies have shown that BRAF(V600E) mutation is associated with poor prognostic factors in papillary thyroid carcinoma (PTC). However, there are no studies about the association of the BRAF(V600E) mutation with poor prognostic factors according to tumor size in PTC. METHODS: We investigated the prevalence of the BRAF(V600E) mutation and its association with prognostic factors according to tumor size of PTC. BRAF(V600E) mutation status was assessed in thyroid fine-needle aspiration (FNA) specimens from 605 patients before thyroidectomy for PTC, and its association with postoperative clinicopathologic factors was evaluated. RESULTS: The overall prevalence of the BRAF(V600E) mutation was 67%, and larger tumors more often had the BRAF(V600E) mutation (p for trend < .05). The BRAF(V600E) mutation was significantly associated with male sex, tumor size, extrathyroidal invasion, nodal metastasis, and advanced tumor stage (p < .05). There was a significant size-dependent relationship between the presence of the BRAF(V600E) mutation and extrathyroidal invasion, nodal metastasis, and advanced tumor stage (p for trend < .05). CONCLUSION: The prevalence of the BRAF(V600E) mutation increased with increased tumor size. Preoperative FNA-detected BRAF(V600E) mutation was associated with poor prognostic factors, and the association was stronger in larger tumors. PMID- 22488962 TI - Lipid rafts generate digital-like signal transduction in cell plasma membranes. AB - Lipid rafts are meso-scale (5-200 nm) cell membrane domains where signaling molecules assemble and function. However, due to their dynamic nature, it has been difficult to unravel the mechanism of signal transduction in lipid rafts. Recent advanced imaging techniques have revealed that signaling molecules are frequently, but transiently, recruited to rafts with the aid of protein-protein, protein-lipid, and/or lipid-lipid interactions. Individual signaling molecules within the raft are activated only for a short period of time. Immobilization of signaling molecules by cytoskeletal actin filaments and scaffold proteins may facilitate more efficient signal transmission from rafts. In this review, current opinions of how the transient nature of molecular interactions in rafts generates digital-like signal transduction in cell membranes, and the benefits this phenomenon provides, are discussed. PMID- 22488963 TI - Benzylium versus tropylium ion dichotomy: vibrational spectroscopy of gaseous C8H9+ ions. AB - Definitely different: the path towards sorting out a long-standing dichotomy in carbocation chemistry is disclosed by infrared multiple photon dissociation spectroscopy of tropylium and benzylium isomers of C(8)H(9)(+) ions. PMID- 22488964 TI - Light and pH cooperative nanofluidic diode using a spiropyran-functionalized single nanochannel. AB - An artificial nanofluidic diode system is prepared, mimicking the light-gated and pH-tunable ion channels that play an important role in life sciences. When UV light is off, the nanochannel is in the closed state, analogous to a resistance. Under UV light irradiation and at pH 7, the current flows from the tip to the base, analogous to a diode; at pH 3, the situation (and the diode) is reversed. PMID- 22488965 TI - Generation and characterization of a Notch1 signaling-specific reporter mouse line. AB - Signaling through the Notch1 receptor is essential for the control of numerous developmental processes during embryonic life as well as in adult tissue homeostasis and disease. Since the outcome of Notch1 signaling is highly context dependent, and its precise physiological and pathological role in many organs is unclear, it is of great interest to localize and identify the cells that receive active Notch1 signals in vivo. Here, we report the generation and characterization of a BAC-transgenic mouse line, N1-Gal4VP16, that when crossed to a Gal4-responsive reporter mouse line allowed the identification of cells undergoing active Notch1 signaling in vivo. Analysis of embryonic and adult N1 Gal4VP16 mice demonstrated that the activation pattern of the transgene coincides with previously observed activation patterns of the endogenous Notch1 receptor. Thus, this novel reporter mouse line provides a unique tool to specifically investigate the spatial and temporal aspects of Notch1 signaling in vivo. PMID- 22488966 TI - Multiple 3D inversion recovery imaging for volume T1 mapping of the heart. AB - In this article, a three-dimensional inversion recovery sequence was optimized with the aim of generating in vivo volume T(1) maps of the heart using a 1.5-T MR system. Acquisitions were performed before and after gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA) administration in one patient with hypertrophic cardiomyopathy and in two healthy volunteers. Data were acquired with a multishot fast field echo readout using both ECG and respiratory triggers. A dedicated phantom, composed of four solutions with different T(1) values, was positioned on the subjects' thoracic region to perform patient-specific calibration. Pixel based T(1) maps were calculated with a custom Matlab((r)) code. Phantom measurements showed a good accuracy of the technique and in vivo T(1) estimation of liver, skeletal muscle, myocardium, and blood resulted in good agreement with values reported in the literature. Multiple three-dimensional inversion recovery technique is a feasible and accurate method to perform T(1) volume mapping. PMID- 22488967 TI - Identification of a CACNA2D4 deletion in late onset bipolar disorder patients and implications for the involvement of voltage-dependent calcium channels in psychiatric disorders. AB - The GWAS-based association of CACNA1C with bipolar disorder (BPD) is one of the strongest genetic findings to date. CACNA1C belongs to the family of CACN genes encoding voltage-dependent calcium channels (VDCCs). VDCCs are involved in brain circuits and cognitive processes implicated in BPD and schizophrenia (SZ). Recently, it was shown that rare copy number variations (CNVs) are found at an increased frequency in SZ and to a lesser extent also in BPD, suggesting the involvement of CNVs in the causation of these diseases. We hypothesize that CNVs in CACN genes can influence the susceptibility to BPD, SZ, and/or schizoaffective disorder (SZA). A search for CNVs in eight CACN genes in a patient-control sample of European decent was performed. A total of 709 BP patients, 645 SZ patients, 189 SZA patients, and 1,470 control individuals were screened using the Multiplex Amplicon Quantification (MAQ) method. We found a rare, partial deletion of 35.7 kb in CACNA2D4 in two unrelated late onset bipolar I patients and in one control individual. All three deletions shared the same breakpoints removing exons 17-26 of CACNA2D4, comprising part of the CACHE domain. Based on the data we cannot claim causality to BPD of the identified CACNA2D4 deletion but nevertheless this deletion can be important in unraveling the underlying processes leading to psychiatric diseases in general and BPD in particular. PMID- 22488968 TI - An update on advanced glycation endproducts and atherosclerosis. AB - Advanced glycation endproducts (AGEs) are a group of modified molecular species formed by nonenzymatic reactions between the aldehydic group of reducing sugars with proteins, lipids, or nucleic acids. Formation and accumulation of AGEs are related to the aging process and are accelerated in diabetes. AGEs are generated in hyperglycemia, but their production also occurs in settings characterized by oxidative stress and inflammation. These species promote vascular damage and acceleration of atherosclerotic plaque progression mainly through two mechanisms: directly, altering the functional properties of vessel wall extracellular matrix molecules, or indirectly, through activation of cell receptor-dependent signaling. Interaction between AGEs and the key receptor for AGEs (RAGE), a transmembrane signaling receptor which is present in all cells relevant to atherosclerosis, alters cellular function, promotes gene expression, and enhances the release of proinflammatory molecules. The importance of the AGE-RAGE interaction and downstream pathways, leading to vessel wall injury and plaque development, has been amply established in animal studies. Moreover, the deleterious link of AGEs with diabetic vascular complications has been suggested in many human studies. Blocking the vicious cycle of AGE-RAGE axis signaling may be essential in controlling and preventing cardiovascular complications. In this article, we review the pathogenetic role of AGEs in the development, progression and instability of atherosclerosis, and the potential targets of this biological system for the prevention and treatment of cardiovascular disease. PMID- 22488970 TI - Adhesion formation to hemostatic agents and its reduction with a sodium hyaluronate/carboxymethylcellulose adhesion barrier. AB - The impact of hemostatic agents on postoperative adhesion formation has not been well studied. We hypothesized that hemostatic agents would be a significant nidus for adhesion formation and that a resorbable barrier would effectively reduce adhesions to hemostatic agents. Four commercial hemostatic agents, each composed of a different biomaterial matrix, were implanted in female Sprague-Dawley rats, and adhesion formation was examined 7 days after surgery. In separate studies, the effects of serosal trauma (via cecal abrasion), added blood, and the presence of chemically modified sodium hyaluronate/carboxymethylcellulose (HA/CMC) barrier on adhesion formation to hemostatic agents were studied. Significant adhesions formed to hemostatic agents even in the absence of traumatized tissue. When applied after cecal abrasion, the incidence of adhesions to the hemostatic agents increased. Addition of blood to this model increased adhesion formation even further, causing adhesions in every animal in the study. An HA/CMC adhesion barrier reduced adhesions to hemostatic agents in the presence of serosal trauma and maintained effectiveness even in the presence of blood. In conclusion, hemostatic agents potentiated adhesion formation at the site of application in a model without trauma. In more challenging models, their adhesiogenic contribution was overwhelmed by trauma and blood. HA/CMC adhesion barrier applied over hemostatic agents at the time of surgery provided significant protection against postoperative adhesions in these preclinical models. PMID- 22488969 TI - Changes in vitamin D and parathyroid hormone metabolism in incident pediatric Crohn's disease. AB - BACKGROUND: Prior studies of vitamin D metabolism in Crohn's disease (CD) did not include controls or examine changes following diagnosis. This study examined associations among 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and parathyroid hormone (PTH) levels in incident pediatric CD, compared with controls, and following diagnosis. METHODS: Serum vitamin D and PTH were measured at diagnosis (n = 78), 6, 12, and a median of 43 months (n = 52) later in CD participants, and once in 221 controls. Multivariate regression was used to examine baseline associations and quasi-least squares regression to assess subsequent changes. RESULTS: At diagnosis, 42% of CD participants were 25(OH)D-deficient (<20 ng/mL). The odds ratio for deficiency was 2.1 (95% confidence interval [CI]: 1.1, 3.9; P < 0.05) vs. controls, adjusted for age, race, and season. 1,25(OH)(2)D was lower in CD vs. controls (P < 0.05), adjusted for 25(OH)D, tumor necrosis factor alpha (TNF-alpha), and PTH. TNF-alpha was associated with lower 1,25(OH)(2)D (P < 0.05), and the positive association between PTH and 1,25(OH)(2)D in controls was absent in CD (interaction P = 0.02). Among participants with 25(OH)D <30 ng/mL, CD was associated with lower PTH (P < 0.05) vs. controls. Following diagnosis, 25(OH)D and 1,25(OH)(2)D improved (P < 0.001). At the final visit, 3% were 25(OH)D-deficient, PTH was no longer low relative to 25(OH)D, and 1,25(OH)(2)D was significantly elevated (P < 0.001) compared with controls. CONCLUSIONS: Incident CD was associated with 25(OH)D and 1,25(OH)2D deficiency and a relative hypoparathyroidism that resolved following diagnosis. Inflammatory cytokine suppression of PTH and renal 1-alpha-hyroxylase may contribute to these alterations. PMID- 22488971 TI - Laser-induced artificial defects (LIADs): towards the control of the spatiotemporal dynamics in spin transition materials. AB - Micrometer-sized defects, induced by laser ablation, radically change the spatiotemporal dynamics of a first-order structural phase transition, in this case of a spin crossover material. This type of "domain engineering" is thus based on artificial defects, such as that in the image, which can serve either as nucleation sites or as pinning sites. The subsequent growth of the nucleated domains can also be guided to some extent. PMID- 22488972 TI - Solvent-free catalytic depolymerization of cellulose to water-soluble oligosaccharides. AB - The use of cellulose is hampered by difficulties with breaking up the biopolymer into soluble products. Herein, we show that the impregnation of cellulosic substrates with catalytic amounts of a strong acid (e.g., H(2)SO(4), HCl) is a highly effective strategy for minimizing the contact problem commonly experienced in mechanically assisted, solid-state reactions. Milling the acid-impregnated cellulose fully converts the substrate into water-soluble oligosaccharides within 2 h. In aqueous solution, soluble products are easily hydrolyzed at 130 degrees C in 1 h, leading to 91 % conversion of the glucan fraction of alpha-cellulose into glucose, and 96 % of the xylans into xylose. Minor products are glucose dimers (8 %), 5-hydroxymethylfurfural (1 %) and furfural (4 %). Milling practical feedstocks (e.g., wood, sugarcane bagasse, and switchgrass) also results to water soluble products (oligosaccharides and lignin fragments). The integrated approach (solid-state depolymerization in combination with liquid-phase hydrolysis) could well hold the key to a highly efficient "entry process" in biorefinery schemes. PMID- 22488973 TI - Can spherical deconvolution provide more information than fiber orientations? Hindrance modulated orientational anisotropy, a true-tract specific index to characterize white matter diffusion. AB - Diffusion tensor imaging (DTI) methods are widely used to reconstruct white matter trajectories and to quantify tissue changes using the average diffusion properties of each brain voxel. Spherical deconvolution (SD) methods have been developed to overcome the limitations of the diffusion tensor model in resolving crossing fibers and to improve tractography reconstructions. However, the use of SD methods to obtain quantitative indices of white matter integrity has not been extensively explored. In this study, we show that the hindrance modulated orientational anisotropy (HMOA) index, defined as the absolute amplitude of each lobe of the fiber orientation distribution, can be used as a compact measure to characterize the diffusion properties along each fiber orientation in white matter regions with complex organization. We demonstrate that the HMOA is highly sensitive to changes in fiber diffusivity (e.g., myelination processes or axonal loss) and to differences in the microstructural organization of white matter like axonal diameter and fiber dispersion. Using simulations to describe diffusivity changes observed in normal brain development and disorders, we observed that the HMOA is able to identify white matter changes that are not detectable with conventional DTI indices. We also show that the HMOA index can be used as an effective threshold for in vivo data to improve tractography reconstructions and to better map white matter complexity inside the brain. In conclusion, the HMOA represents a true tract-specific and sensitive index and provides a compact characterization of white matter diffusion properties with potential for widespread application in normal and clinical populations. PMID- 22488974 TI - EEC syndrome-like phenotype in a patient with an IRF6 mutation. PMID- 22488975 TI - Multiquantum vibrational excitation of NO scattered from Au(111): quantitative comparison of benchmark data to ab initio theories of nonadiabatic molecule surface interactions. AB - Surface phenomena: measurements of absolute probabilities are reported for the vibrational excitation of NO(v=0->1,2) molecules scattered from a Au(111) surface. These measurements were quantitatively compared to calculations based on ab initio theoretical approaches to electronically nonadiabatic molecule-surface interactions. Good agreement was found between theory and experiment (see picture; T(s) =surface temperature, P=excitation probability, and E=incidence energy of translation). PMID- 22488976 TI - Responding to secondary traumatic stress: a pilot study of torture treatment programs in the United States. AB - Providers who care for torture survivors may be at risk for secondary traumatic stress, yet there has been little documentation of the effects of repeated exposure to traumatic issues on their emotional health or exploration of the support systems and resources available to address their emotional needs. This study assessed the secondary stress experiences of service providers (N = 43) within the National Consortium of Torture Treatment Programs in the United States and examined the supports offered by their organizations. The study found a significant correlation between rates of anxiety and depression among providers, r(34) = .49, p = .003. Although these participants reported that their work with survivors of torture was stressful, 91% indicated that their organizations offered a variety of stress-reduction activities. Overall, participants reported that their own personal activities were the most-effective stress reducers. The results are discussed in light of challenges that professionals who work with this population face and the effectiveness of support systems available to support their work. PMID- 22488977 TI - Cytotoxicity and genotoxicity of chlorhexidine on macrophages in vitro. AB - Chlorhexidine (CHX) is the most widely used antiseptic for wound, skin disinfection, and dental hygiene. The aim of this study is to investigate the possible correlation between CHX-induced cytogenotoxicity and alterations in normal cell cycle on RAW264.7 macrophages. The cytotoxicity, mechanism of cell death, mitotic activity, and reactive oxygen species (ROS) generation were determined by tetrazolium bromide reduction assay, flow cytometry, cytokinesis block proliferation index, and superoxide dismutase-inhibitable reduction of ferricytochrome c, respectively. The genotoxicity was measured using comet assay and cytokinesis-block micronucleus assay. The cytotoxicity of CHX in RAW264.7 cells presented a dose- and time-dependent manner (p < 0.05). The mode of cell death shifted from apoptosis to necrosis when the dosage of CHX increased. The genotoxicity of CHX in RAW264.7 cells had shown DNA damage in a dose-dependent manner (p < 0.05). Prolongation of cell cycle and the increase of ROS generation also expressed in a dose-dependent manner (p < 0.05). Taken together, the data suggested that CHX-induced cytotoxicity and genotoxicity on macrophages may be via ROS generation. PMID- 22488978 TI - Characteristics of premaxillary supernumerary teeth in primary and mixed dentitions: a retrospective analysis of 212 cases. AB - AIM: To investigate the characteristics and distribution of premaxillary supernumerary teeth affecting primary and mixed dentitions in Indian children. METHODS: This retrospective analysis included 11 200 children, aged 3-12 years, who attended a pediatric dental clinic for dental care during the period 2007 2010. The children were divided into group I (aged 3-6 years) and group II (aged 7-12 years), and data regarding maxillary anterior supernumerary teeth, diagnosed both as isolated and/or as unexpected findings during routine clinical and radiological examinations, were gathered. Pearson's chi(2) -test, with a 0.05 level of significance, was used for the analysis. RESULTS: The overall prevalence of premaxillary supernumerary teeth in primary and mixed dentitions was 1.9%. Single supernumerary teeth (84.9%) and conical morphology (68.7%) were commonly seen in both groups. The most common sagittal position was palatal (92.3%) among both erupted and impacted maxillary anterior supernumerary teeth. CONCLUSION: The prevalence of premaxillary supernumerary teeth in Indian children found in this study was 1.9%, with an overall male to female ratio of 1.7:1. Single supernumerary teeth, conical morphology, and erupted supernumerary teeth were the most commonly seen. Supernumerary teeth associated with clinical complications were relatively low (48%), and axial rotation or displacement of maxillary incisors was the most common sequelae. PMID- 22488979 TI - Palladium(II)-catalyzed oxidative C-H/C-H cross-coupling between two structurally similar azoles. AB - Power of two: A widely functional-group tolerant, selective and rapid oxidative cross-coupling between two structurally similar azoles has been carried out by using a palladium/copper co-catalytic twofold C-H activation method (see scheme). PMID- 22488980 TI - Graphene/metal contacts: bistable states and novel memory devices. AB - Graphene field-effect transistors (GFETs) with different metal electrodes are fabricated to explore the contact characteristics. The contact resistance and the spatial potential distribution along the graphene/metal interface are investigated. The low-doped graphene/metal contact can be reversibly switched between "ohmic" and "space-charge region limited" states. The observed switching attributes are highly reproducible and stable, which provides a new avenue to produce high-performance graphene memory devices. PMID- 22488981 TI - Definitive evidence for fast electron transfer at pristine basal plane graphite from high-resolution electrochemical imaging. PMID- 22488982 TI - Absence of changes in GABA concentrations with age and gender in the human anterior cingulate cortex: a MEGA-PRESS study with symmetric editing pulse frequencies for macromolecule suppression. AB - Despite MEGA-PRESS being a robust method for editing the GABA resonance, there are macromolecule resonances at the same chemical shift that are coedited with this sequence. Although this is a known problem, it is still often overlooked. We aimed to evaluate the amount of macromolecule signal coedited, as well as the gender and age dependencies for the GABA resonance at 3.01 ppm using MEGA-PRESS with two different editing pulse frequencies. Forty-five healthy subjects (21-52 years) were included in an in vivo single voxel MEGA-PRESS study at 3.0 T. Phantom measurements were conducted to measure the signal loss when switching the editing pulse between 1.5 and 1.9 ppm instead of the mostly used switching between 1.9 and 7.5 ppm. The in vivo GABA signal detected by switching the editing pulse frequencies between 1.5 and 1.9 ppm was only 50% of the mean GABA detected by switching the editing pulse frequencies between 1.9 and 7.5 ppm. No gender differences were detected. A small age dependency was observed for GABA plus macromolecules, but not for GABA, suggesting an age-dependent macromolecule increase. PMID- 22488983 TI - Label-free ultrasensitive detection of human telomerase activity using porphyrin functionalized graphene and electrochemiluminescence technique. AB - Using porphyrin-functionalized graphene, we construct a PCR-free, low-cost, rapid, and electrochemiluminenscence (ECL) assay for detection of telomerase activity that has been demonstrated in six different cell lines and can be used as initial screening of G-quadruplex DNA binding agents and telomerase inhibitors. This ECL sensor shows highly sensitive for detection of telomerase with the detection limit as low as 10 HeLa cells mL(-1) . PMID- 22488984 TI - A brilliant new addition to the fluorescent probe toolbox. PMID- 22488985 TI - Neural correlates of the perception of contrastive prosodic focus in French: a functional magnetic resonance imaging study. AB - This functional magnetic resonance imaging (fMRI) study aimed at examining the cerebral regions involved in the auditory perception of prosodic focus using a natural focus detection task. Two conditions testing the processing of simple utterances in French were explored, narrow-focused versus broad-focused. Participants performed a correction detection task. The utterances in both conditions had exactly the same segmental, lexical, and syntactic contents, and only differed in their prosodic realization. The comparison between the two conditions therefore allowed us to examine processes strictly associated with prosodic focus processing. To assess the specific effect of pitch on hemispheric specialization, a parametric analysis was conducted using a parameter reflecting pitch variations specifically related to focus. The comparison between the two conditions reveals that brain regions recruited during the detection of contrastive prosodic focus can be described as a right-hemisphere dominant dual network consisting of (a) ventral regions which include the right posterosuperior temporal and bilateral middle temporal gyri and (b) dorsal regions including the bilateral inferior frontal, inferior parietal and left superior parietal gyri. Our results argue for a dual stream model of focus perception compatible with the asymmetric sampling in time hypothesis. They suggest that the detection of prosodic focus involves an interplay between the right and left hemispheres, in which the computation of slowly changing prosodic cues in the right hemisphere dynamically feeds an internal model concurrently used by the left hemisphere, which carries out computations over shorter temporal windows. PMID- 22488986 TI - In situ X-ray structural studies of a flexible host responding to incremental gas loading. AB - Crystallographic pressure-lapse snapshots of a porous material responding to gas loading were used to investigate the stepwise uptake of carbon dioxide and acetylene molecules into discrete confined spaces. Based on the data, a qualitative statistical mechanical model was devised that reproduces even subtle features in the experimental gas sorption isotherms. PMID- 22488987 TI - Confined iron nanowires enhance the catalytic activity of carbon nanotubes in the aerobic oxidation of cyclohexane. AB - Inside job: New applications of carbon materials pave the way towards greener chemical syntheses. The encapsulation of metallic Fe within CNTs improves electron transfer between the metal and the CNTs. The resulting material offers a high catalytic activity and easy magnetic separation of catalyst in the heterogeneous selective oxidation of cyclohexane. PMID- 22488989 TI - Double protein-coated poly-epsilon-caprolactone scaffolds: successful 2D to 3D transfer. AB - In the past decade, tissue engineering has evolved from a promising technology to an established scientific field. Large attention has focussed on developing scaffolds from both biodegradable and nondegradable polymers to be cultivated with cells, to replace human body defects. The major drawback of most polymers is however their limited cell-interactive properties. An additional complication when developing a surface modification protocol for those materials is the transferability of protocols from 2D substrates to 3D scaffolds. In the present work, we therefore report on possible biological effects originating from the transfer of a double protein coating protocol, involving gelatin type B and fibronectin, from 2D poly-epsilon-caprolactone (PCL) films to 3D PCL scaffolds produced by rapid prototyping. A variety of techniques including scanning electron microscopy, X-ray photoelectron spectroscopy and confocal fluorescence microscopy confirmed a successful and homogeneous protein-coating on both 2D and 3D substrates. Interestingly, the biological performance of the double protein coated PCL substrates, reflected by the initial cell adhesion, proliferation, and colonization was superior compared to the other surface modification steps, independent of the material dimension. PMID- 22488990 TI - A protein-RNA docking benchmark (II): extended set from experimental and homology modeling data. AB - We present here an extended protein-RNA docking benchmark composed of 71 test cases in which the coordinates of the interacting protein and RNA molecules are available from experimental structures, plus an additional set of 35 cases in which at least one of the interacting subunits is modeled by homology. All cases in the experimental set have available unbound protein structure, and include five cases with available unbound RNA structure, four cases with a pseudo-unbound RNA structure, and 62 cases with the bound RNA form. The additional set of modeling cases comprises five unbound-model, eight model-unbound, 19 model-bound, and three model-model protein-RNA cases. The benchmark covers all major functional categories and contains cases with different degrees of difficulty for docking, as far as protein and RNA flexibility is concerned. The main objective of this benchmark is to foster the development of protein-RNA docking algorithms and to contribute to the better understanding and prediction of protein-RNA interactions. The benchmark is freely available at http://life.bsc.es/pid/protein rna-benchmark. PMID- 22488991 TI - The validity of vertebral translation and rotation in differentiating patients with lumbar segmental instability. AB - BACKGROUND AND PURPOSE: Lumbar segmental instability (LSI) is a sub-group of non specific low back pain (NSLBP), without any accepted diagnostic tool as a golden standard. Some authors emphasize on clinical findings, and others focus on vertebral translation and rotation, but construct validity of these measures had not been approved. Therefore, the purpose of the study was to evaluate convergent and known group validity of vertebral translation and rotation in differentiating LSI from NSLBP and control subjects. METHODS: Study variables included full-range and mid-range vertebral translation and rotation in sagittal plane. Five x-rays were taken in neutral, full flexion and extension and mid-flexion and mid extension positions of lumbar spine. The variables were calculated using Computer Aided Radiographic Analysis of Spine (CARA) software after scanning. Sixty-six volunteered males participated in three groups. Twenty-two subjects were in the control group, and 44 NSLBP were divided into LSI and not LSI groups according to the criteria adopted by Hicks et al. The ANOVA and Tukey test were used in statistic analysis. RESULTS: ANOVA results demonstrated differences in three groups; for full-range translation and rotation, were not significant. However, the results of ANOVA demonstrated significant difference in L4-5 mid-range translation and rotation (p < 0/05). Tukey test showed significant difference for L4-5 mid-range translation between control (2.14 mm) and LSI (1.33 mm) groups (p < 0/05). Tukey test demonstrated difference between the control (14.18 degrees ) and LSI (11.65 degrees ) groups (p < 0/05); the control and not LSI (10.80) groups (p < 0/05) were significant for L4-5 mid-range rotation. CONCLUSIONS: On the basis of the study results, the full-range translation and rotation cannot differentiate LSI from not LSI and control groups. Moreover, the mid-range translation only differentiates control from LSI, whereas mid-range rotation differentiates control from both LSI and not LSI. PMID- 22488992 TI - Loeys-Dietz syndrome presenting as respiratory distress due to pulmonary artery dilation. AB - Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue condition with clinical features that may include ocular hypertelorism, cleft palate, craniosynostosis, and vascular dilation and tortuosity. Here we describe a patient with LDS confirmed by genetic analysis (R528H mutation of TGFBR2) who presented at 3 months of age in respiratory distress of unknown origin. In addition to expressing several of the classic findings of LDS, including a novel finding of squamosal suture craniosynostosis, CT angiography revealed aortic dilation at the sinus of valsalva, pulmonary artery dilation that extrinsically compressed the right mainstem bronchus causing bronchomalacia, and an apical herniation of the right lung. This is the first documentation of concomitant airway and pulmonary findings in a patient with LDS. We suggest that (1) vascular abnormalities be considered as a cause of unexplained respiratory distress in a patient with LDS, and (2) pediatric patients exhibiting any of the physical findings listed above be evaluated for LDS with particular attention paid to vascular, airway, and/or pulmonary malformations. PMID- 22488993 TI - Connection between the spinal dura mater and suboccipital musculature: evidence for the myodural bridge and a route for its dissection--a review. AB - A connective tissue link between the spinal dura mater and the rectus capitis posterior minor muscle was first described in 1995 and has since been readily demonstrated via dissection, magnetic resonance imaging, and plastinated cross sections of the upper cervical region (Hack et al. [1995] Spine 20:2484-2486). This structure, the so-called "myodural bridge," has yet to be included in any of the American anatomy textbooks or dissection guides commonly used in medical education. This direct anatomic link between the musculoskeletal system and the dura mater has important ramifications for the treatment of chronic cervicogenic headache. This article summarizes the anatomic and clinical research literature related to this structure and provides a simple approach to dissect the myodural bridge and its attachment to the posterior atlanto-occipital membrane/spinal dura mater complex and summarizes the case for its possible inclusion in medical anatomy curricula. PMID- 22488994 TI - Anatomic relationship between the anterior sylvian point and the pars triangularis. AB - The aim of this study was to show morphological sulcal variations of the pars triangularis of the inferior frontal gyrus and to provide a clearer description of the anterior sylvian point. Thirty-six hemispheres of 18 adult cadavers were studied. The hemispheres were harvested by the classical autopsy method and fixed in 10% formalin solution for three weeks. In six hemispheres, the arteries and veins were filled with colored silicone. The proximal and distal segments of the sylvian fissure, the perpendicular distance of both the anterior sylvian point and inferior rolandic point to the insular cortex and the distances between the anterior ascending ramus and the precentral, central, and postcentral sulcus were measured. The anterior horizontal and ascending rami were exposed. The sulcus located on the pars triangularis was appraised. The relationship between the anterior sylvian point and the vascular structure around the sylvian fissure was examined. The rising of the anterior horizontal and ascending ramus from the sylvian fissure defines the shape of the pars triangularis. The pars triangularis has three shapes: V, U, and Y. In V- and Y-shaped pars triangularis both rami merge but in U-shaped pars triangularis the rami do not merge. The pars triangularis was Y-shaped in 30.76% (4/13) of the right hemispheres and in 50% (7/14) of the left hemispheres; U-shaped in 20.3% (3/13) of the right hemispheres and in 35.71% (5/14) of the left hemispheres; V-shaped in 40.61% (6/13) of the right hemispheres and in 14.29% (2/14) of the left hemispheres. Minimally invasive procedures use basic anatomic landmarks intracranially to reach the targeted area; therefore, exact and detailed knowledge of the anatomy of the sylvian fissure and pars triangularis is of great importance. PMID- 22488995 TI - An anatomical investigation of the cervicothoracic ganglion. AB - Anatomical variability within the autonomic nervous system has long been accepted. This study evaluated the anatomical variability of the cervicothoracic ganglion (CTG) according to its form and, in addition, provided precise measurements between the CTG and the anterior tubercle of the transverse process of the sixth cervical vertebra (C6TP), the first costovertebral articulation, and the vertebral artery. Forty-two adult cadavers were dissected, 22 male and 20 females. Five main forms of CTG were documented; spindle (31.9%), dumbbell (23.2%), truncated (21.7%), perforated (14.5%), and inverted-L (8.7%). The means for length, width, and thickness of the CTG were 18.5 mm, 8.2 mm, and 4.5 mm, respectively. The dimensions were found to be slightly larger in the males than females and on the left sides as compared to the right. The mean shortest distance between the CTGs and the vertebral artery was found to be 2.8 mm, whilst the mean shortest distances to C6TP was 25.7 mm and to the first costovertebral articulation was 1.7 mm. There is great variability in the morphology of the CTG with five common forms consistently seen. The relation to the vertebral artery may influence the form of the ganglion. Two previously undocumented forms are recorded; the truncated which describes the important juxtaposition of the CTG and the vertebral artery and the perforated which describes the piercing of the ganglion itself by the artery. The findings are considered to be of clinical importance to anesthetists, surgeons, neurosurgeons, and anatomists. PMID- 22488996 TI - Evaluation of thoracic pedicle morphometry in a Chinese population using 3D reformatted CT. AB - The aim of this study was to investigate the detailed three-dimensional morphology of the pedicles from T1 to T12 in 120 Chinese patients using a light speed Vct CT (General Electric). After reformatting the original images, the following parameters were studied: outer pedicle width (OPW), outer pedicle height (OPH), pedicle chord length (PCL), pedicle cortical thickness (PCT) of the isthmus, and transverse pedicle angle (TPA). The mean outer pedicle width, outer pedicle height, and pedicle chord length were significantly smaller in females than in males at all levels (P < 0.01). The percentage of outer pedicle width <= 5.0 mm and <= 4.5 mm was high at mid-thoracic pedicles. No significant differences were found in transverse pedicle angle and pedicle cortical thickness in males and females. Pedicle cortical thickness was significantly thinner in patients over 50 years old compared with patients below 50 years old at most levels. The results showed that a screw of larger than 4.5 mm would be too large for mid-thoracic segments in Chinese population, especially for female patients. Considering the amount of variation between individuals and the complicated structure of the thoracic pedicles, the use of the transpedicular screw fixation must be individualized for each patient and based on detailed preoperative assessment. Reformatted CT assessment is essential before this procedure is performed. PMID- 22488997 TI - Fiber orientation of the transverse carpal ligament. AB - The transverse carpal ligament is the volar roof of the carpal tunnel. Gross observation shows that the ligament appears to have fibers that roughly orient in the transverse direction. A closer anatomical examination shows that the ligament also has oblique fibers. Knowledge of the fiber orientation of the transverse carpal ligament is valuable for further understanding the ligament's role in regulating the structural function of the carpal tunnel. The purpose of this study is to quantify collagen fiber orientation within the transverse carpal ligament using the small angle light scattering technique. Eight transverse carpal ligament samples from cadaver hands were used in this study. Individual 20 MUm sections were cut evenly along the thickness of the transverse carpal ligament. Sections of three thickness levels (25%, 50%, and 75% from the volar surface) were collected for each transverse carpal ligament. Fibers were grouped in the following orientation ranges: transverse, longitudinal, oblique in the pisiform-trapezium (PT), and oblique in the scaphoid-hamate (SH) directions. In analyzing the fiber percentages, the orientation types for the different thickness levels of the ligament showed that the transverse fibers were the most prominent (>60.7%) followed by the PT oblique (18.6%), SH oblique (13.0%), and longitudinal (8.6%) fibers. PMID- 22488998 TI - Low attenuation areas in normal costal cartilages on CT: clinical implication and correlation with histology. AB - While normal costal cartilages are known to be homogenous in attenuation on computed tomography (CT), they frequently show internal low attenuation. This study was performed to assess CT features of the low attenuation and to correlate them with histological features. Chest CT scans of 80 patients without chest wall abnormalities in the first eight decades of age with ten consecutive patients in each decade were reviewed. Histological examinations and CT of three costal cartilage specimens, one each from three cadavers, were done. Of the 80 patients, low attenuation areas were noted in 32% of the upper seven costal cartilages and in 64 patients (80%) without significant sexual difference (P = 0.503 and 0.786, respectively). The areas appeared more frequently in the lower costal cartilages than the upper ones, and were mostly symmetrical in distribution (82%). They were usually ill defined (74%) and similar in attenuation to the chest wall muscle (94%), located centrally (100%), and at most a half of the cartilage diameter. In all three cartilage specimens, central areas were grossly distinct from surrounding areas, and were corresponded to low attenuation areas on CT. At histological exam, the central areas showed multiple foci of vascularized loose connective tissue and fat on myxoid background, generally agreeing with the previous description of cartilage canals, a kind of nutrient channel. In conclusion, normal costal cartilages can show central low attenuation areas, which are typically symmetrical in distribution and at most a half of the cartilage diameter. PMID- 22488999 TI - Jejunal diverticulum with ectopic pancreatic mucosa: was it really a Meckel's diverticulum? AB - We report the case of a 72-year-old man who underwent surgery for a jejunal intussusception caused by an infarcted mass on the antimesenteric surface of the small bowel approximately 90 cm from the duodenojejunal flexure. The specimen was reported as an infarcted diverticulum containing heterotopic pancreatic mucosa in keeping with infarcted Meckel's diverticulum. We initially wished to establish when the term "Meckel's diverticulum" should be used. The anatomical site in the present case argues against this being a Meckel's diverticulum, a remnant from the mid-gut loop. Non-Meckelian diverticula are usually acquired and often multiple and generally occur on the mesenteric border of the bowel. It is rare for them to contain ectopic mucosa. The diverticulum in our patient thus has features which suggest it may have been congenital. We believe our patient had a rare occurrence of a congenital, but non-Meckelian, diverticulum with associated ectopic epithelium. PMID- 22489000 TI - Soft sensors in bioprocessing: a status report and recommendations. AB - The following report with recommendations is the result of an expert panel meeting on soft sensor applications in bioprocess engineering that was organized by the Measurement, Monitoring, Modelling and Control (M3C) Working Group of the European Federation of Biotechnology - Section of Biochemical Engineering Science (ESBES). The aim of the panel was to provide an update on the present status of the subject and to identify critical needs and issues for the furthering of the successful development of soft sensor methods in bioprocess engineering research and for industrial applications, in particular with focus on biopharmaceutical applications. It concludes with a set of recommendations, which highlight current prospects for the extended use of soft sensors and those areas requiring development. PMID- 22489001 TI - Markers of potential malignancy in chronic hyperplastic candidiasis. AB - AIM: To examine the presence of markers associated with malignancy, including p53, p21 cyclin-dependent kinase inhibitor 1A, murine double minutes-2, and others, in chronic hyperplastic candidiasis. METHODS: Immunohistochemical methods were used to examine the expression of p53, murine double minutes-2, p21 cyclin dependent kinase inhibitor 1A, metallothionein, and proliferating cell nuclear antigen in 42 chronic hyperplastic candidiasis lesions and 11 non-infected control tissues. Terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling was used to examine apoptosis, which was correlated with p53 expression. These markers were measured in lesions of chronic hyperplastic candidiasis that did not show any epithelial dysplasia or histological signs of malignancy. RESULTS: p53 scores were higher in chronic hyperplastic candidiasis than in controls (P = 0.0046). Murine double-minutes 2 levels were not elevated. p21 cyclin-dependent kinase inhibitor 1A was increased in parabasal (P < 0.0001) and basal epithelial cells. Chronic hyperplastic candidiasis lesions showed a similar basal/parabasal metallothionein staining pattern to that seen in normal squamous epithelium. Proliferating cell nuclear antigen was increased (P = 0.0007), as was apoptosis (P = 0.0033). CONCLUSION: Increased p53 in oral chronic hyperplastic candidiasis suggests an increased potential for malignant change in the epithelium, above that of normal tissues. Further functional investigation is required, as well as clinical follow-up studies. PMID- 22489003 TI - Versatile logic devices based on programmable DNA-regulated silver-nanocluster signal transducers. AB - A DNA-encoding strategy is reported for the programmable regulation of the fluorescence properties of silver nanoclusters (AgNCs). By taking advantage of the DNA-encoding strategy, aqueous AgNCs were used as signal transducers to convert DNA inputs into fluorescence outputs for the construction of various DNA based logic gates (AND, OR, INHIBIT, XOR, NOR, XNOR, NAND, and a sequential logic gate). Moreover, a biomolecular keypad that was capable of constructing crossword puzzles was also fabricated. These AgNC-based logic systems showed several advantages, including a simple transducer-introduction strategy, universal design, and biocompatible operation. In addition, this proof of concept opens the door to a new generation of signal transducer materials and provides a general route to versatile biomolecular logic devices for practical applications. PMID- 22489002 TI - Inhibition of polyisoprenylated methylated protein methyl esterase by synthetic musks induces cell degeneration. AB - Synthetic fragrances are persistent environmental pollutants that tend to bioaccumulate in animal tissues. They are widely used in personal care products and cleaning agents. Worldwide production of Galaxolide and Tonalide are in excess of 4500 tons annually. Because of their widespread production and use, they have been detected in surface waters and fish in the US and Europe. Consumption of contaminated water and fish from such sources leads to bioaccumulation and eventual toxicity. Since fragrances and flavors bear structural similarities to polyisoprenes, it was of interest to determine whether toxicity by Galaxolide and Tonalide may be linked with polyisoprenylated methylated protein methyl esterase (PMPMEase) inhibition. A concentration dependent study of PMPMEase inhibition by Galaxolide and Tonalide as well as their effects on the degeneration of cultured cells were conducted. Galaxolide and Tonalide inhibited purified porcine liver PMPMEase with Ki values of 11 and 14 MUM, respectively. Galaxolide and Tonalide also induced human cancer cell degeneration with EC50 values of 26 and 98 MUM (neuroblastoma SH-SY5Y cells) and 58 and 14 MUM (lung cancer A549 cells), respectively. The effects on cell viability correlate well with the inhibition of PMPMEase activity in the cultured cells. Molecular docking analysis revealed that the binding interactions are most likely between the fragrance molecules and hydrophobic amino acids in the active site of the enzyme. These results appear to suggest that the reported neurotoxicity of these compounds may be associated with their inhibition of PMPMEase. Exposure to fragrances may pose a significant risk to individuals predisposed to developing degenerative disorders. PMID- 22489005 TI - The surface science approach for understanding reactions on oxide powders: the importance of IR spectroscopy. PMID- 22489004 TI - Establishment of a versatile seminoma model indicates cellular plasticity of germ cell tumor cells. AB - In western countries, 60% of all malignancies diagnosed in men between 17-45 years of age are germ cell tumors (GCT). GCT arise from the common precursor lesion carcinoma in situ, which transforms within an average of 9 years into invasive Type-II GCTs. Seminomas are considered to be the default developmental pathway of carcinoma in situ cells and the seminoma-like cell line TCam-2 has been used to study seminoma biology in vitro. However, the generation of an animal model, which would allow for the in vivo analysis of seminoma formation, remained elusive. We applied transplantation approaches using TCam-2 cell transfer into ectopic (skin, brain) and orthopic (testis) sites of immunodeficient mice. We demonstrate that a transplantation into the seminiferous tubules results in formation of a carcinoma in situ/seminoma. In contrast, TCam-2 cells adopt an embryonal carcinoma-like fate when grafted to the flank or corpus striatum and display downregulation of the seminoma marker SOX17 and upregulation of the embryonal carcinoma markers SOX2 and CD30. Grafted TCam-2 cells reduce AKT , ERK-, EphA3-, and Tie2/TEK-signaling to levels comparable to embryonal carcinoma cells. Hence, TCam-2 cell transplantation into the testis generated a carcinoma in situ/seminoma mouse model, which enables addressing the biology of these tumors in vivo. The fact that TCam-2 cells give rise to a carcinoma in situ/seminoma or embryonal carcinoma in a transplantation site specific manner implies that conversion of carcinoma in situ/seminoma to an embryonal carcinoma does not require additional genetic aberrations but relies on signals from the tumor-microenvironment. PMID- 22489006 TI - Coaxial organic p-n heterojunction nanowire arrays: one-step synthesis and photoelectric properties. AB - Organic/organic single-crystal coaxial p-n heterojunction nanowire arrays consisting of p-type copper phthalocyanine (CuPc) and n-type 5,10,15,20-tetra(4 pyridyl)-porphyrin (H(2)TPyP) are fabricated through a one-step physical vapor transport (PVT) process. Each single junction wire revealed high photodependent rectifying and sensitive photoresponsive characteristics in devices of light controlled diodes and photoswitches. The typical photovoltaic device based on a single p-n junction exhibited a high open-circuit voltage (Voc) of 0.64 V. PMID- 22489007 TI - Quantification of venous vessel size in human brain in response to hypercapnia and hyperoxia using magnetic resonance imaging. AB - Hypercapnia and hyperoxia give rise to vasodilation and vasoconstriction, respectively. This study investigates the influence of hypercapnia and hyperoxia on venous vessel size in the human brain. Venous vessel radii were measured in response to hypercapnia and hyperoxia. The venous vessel radii were determined by calculation of the changes in R2 * and R2 that are induced by breathing 6% CO2 or pure oxygen. The experimental paradigm consisted of two 3-min intervals of inhaling 6% CO2 or 100% O2 interleaved with three 2-min intervals of breathing air. Hypercapnic and hyperoxic experiments were performed on eight subjects on a 3T scanner. Parametric maps of mean venous vessel radius were calculated from the changes in R2 * and R2 , which were measured by simultaneous acquisition of gradient-echo and spin-echo signals. The mean venous vessel radii in hypercapnia were 7.3+/-0.3 MUm in gray matter and 6.6+/-0.5 MUm in white matter. The corresponding vessel radii in hyperoxia were 5.6+/-0.2 MUm in gray matter and 5.4+/-0.2 MUm in white matter. These results show that the venous vessel radius was larger in hypercapnia than that in hyperoxia in both gray matter and white matter (P<0.005), which agrees with the hypothesis that hypercapnia causes vasodilation and hyperoxia induces vasoconstriction. PMID- 22489008 TI - Flavins secreted by bacterial cells of Shewanella catalyze cathodic oxygen reduction. AB - On Her Majesty's Secrete Service: Oxygen reduction is an important process for microbial fuel cells (MFCs) and microbiologically-influenced corrosion (MIC). We demonstrate that flavins secreted by anode-respiring Shewanella cells can catalyze cathodic oxygen reduction via adsorption on the cathode. The findings will provide new insight for developing methods to improve MFC performance and to prevent MIC. PMID- 22489009 TI - Brilliant violet fluorophores: a new class of ultrabright fluorescent compounds for immunofluorescence experiments. AB - The Nobel Prize in Chemistry was awarded in 2000 for the discovery of conductive organic polymers, which have subsequently been adapted for applications in ultrasensitive biological detection. Here, we report the first use of this new class of fluorescent probes in a diverse range of cytometric and imaging applications. We demonstrate that these "Brilliant Violet" reporters are dramatically brighter than other UV-violet excitable dyes, and are of similar utility to phycoerythrin (PE) and allophycocyanin (APC). They are thus ideally suited for cytometric assays requiring high sensitivity, such as MHC-multimer staining or detection of intracellular antigens. Furthermore, these reporters are sensitive and spectrally distinct options for fluorescence imaging, two-photon microscopy and imaging cytometry. These ultra-bright materials provide the first new high-sensitivity fluorescence probes in over 25 years and will have a dramatic impact on the design and implementation of multicolor panels for high sensitivity immunofluorescence assays. PMID- 22489010 TI - Study of normal and pathological blood vessel morphogenesis in Flt1-tdsRed BAC Tg mice. AB - Blood vessel development and network patterning are controlled by several signaling molecules, including VEGF, FGF, TGF-beta, and Ang-1,2. Among these, the role of VEGF-A signaling in vessel morphogenesis is best understood. The biological activity of VEGF-A depends on its reaction with specific receptors Flt1 and Flk1. Roles of VEGF-A signaling in endothelial cell proliferation, migration, survival, vascular permeability, and induction of tip cell filopodia have been reported. In this study, we have generated Flt1-tdsRed BAC transgenic (Tg) mice to monitor Flt1 gene expression during vascular development. We show that tdsRed fluorescence is observed within blood vessels of adult mice and embryos, indicative of retinal angiogenesis and tumor angiogenesis. Flt1 expression recapitulated by Flt1-tdsRed BAC Tg mice overlapped well with Flk1, while Flt1 was expressed more abundantly in endothelial cells of large blood vessels such as dorsal aorta and presumptive stalk cells in retina, providing a unique model to study blood vessel development. PMID- 22489011 TI - Electrical control of protein conformation. AB - Conducting polymer devices that enable precise control of fibronectin conformation over macroscopic areas are reported. Single conformations as well as conformation gradients are achieved by applying an appropriate potential. These surfaces remain biologically relevant and support cell culture; hence, they may serve as a model to understand and control cell-surface interactions, with applications in basic research, medical diagnostics, and tissue engineering. PMID- 22489012 TI - Poly(propylene fumarate) reinforced dicalcium phosphate dihydrate cement composites for bone tissue engineering. AB - Calcium phosphate cements have many desirable properties for bone tissue engineering, including osteoconductivity, resorbability, and amenability to rapid prototyping-based methods for scaffold fabrication. In this study, we show that dicalcium phosphate dihydrate (DCPD) cements, which are highly resorbable but also inherently weak and brittle, can be reinforced with poly(propylene fumarate) (PPF) to produce strong composites with mechanical properties suitable for bone tissue engineering. Characterization of DCPD-PPF composites revealed significant improvements in mechanical properties for cements with a 1.0 powder to liquid ratio. Compared with nonreinforced controls, flexural strength improved from 1.80 +/- 0.19 MPa to 16.14 +/- 1.70 MPa, flexural modulus increased from 1073.01 +/- 158.40 MPa to 1303.91 +/- 110.41 MPa, maximum displacement during testing increased from 0.11 +/- 0.04 mm to 0.51 +/- 0.09 mm, and work of fracture improved from 2.74 +/- 0.78 J/m(2) to 249.21 +/- 81.64 J/m(2) . To demonstrate the utility of our approach for scaffold fabrication, 3D macroporous scaffolds were prepared with rapid prototyping technology. Compressive testing revealed that PPF reinforcement increased scaffold strength from 0.31 +/- 0.06 MPa to 7.48 +/- 0.77 MPa. Finally, 3D PPF-DCPD scaffolds were implanted into calvarial defects in rabbits for 6 weeks. Although the addition of mesenchymal stem cells to the scaffolds did not significantly improve the extent of regeneration, numerous bone nodules with active osteoblasts were observed within the scaffold pores, especially in the peripheral regions. Overall, the results of this study suggest that PPF-DCPD composites may be promising scaffold materials for bone tissue engineering. PMID- 22489013 TI - Reversible grafting of alpha-naphthylmethyl radicals to epitaxial graphene. AB - The Kolbe electrochemical oxidation strategy has been utilized to achieve an efficient quasireversible electrochemical grafting of the alpha-naphthylmethyl functional group to graphene. The method facilitates reversible bandgap engineering in graphene and preparation of electrochemically erasable organic dielectric films. The picture shows Raman D-band maps of both systems. PMID- 22489014 TI - The Caenorhabditis elegans DAF-12 nuclear receptor: structure, dynamics, and interaction with ligands. AB - A structure for the ligand binding domain (LBD) of the DAF-12 receptor from Caenorhabditis elegans was obtained from the X-ray crystal structure of the receptor LBD from Strongyloides stercoralis bound to (25R)-Delta(7)-dafachronic acid (DA) (pdb:3GYU). The model was constructed in the presence of the ligand using a combination of Modeller, Autodock, and molecular dynamics (MD) programs, and then its dynamical behavior was studied by MD. A strong ligand binding mode (LBM) was found, with the three arginines in the ligand binding pocket (LBP) contacting the C-26 carboxylate group of the DA. The quality of the ceDAF-12 model was then evaluated by constructing several ligand systems for which the experimental activity is known. Thus, the dynamical behavior of the ceDAF-12 complex with the more active (25S)-Delta(7)-DA showed two distinct binding modes, one of them being energetically more favorable compared with the 25R isomer. Then the effect of the Arg564Cys and Arg598Met mutations on the (25R)-Delta(7)-DA binding was analyzed. The MD simulations showed that in the first case the complex was unstable, consistent with the lack of transactivation activity of (25R)-Delta(7)-DA in this mutant. Instead, in the case of the Arg598Met mutant, known to produce a partial loss of activity, our model predicted smaller effects on the LBM with a more stable MD trajectory. The model also showed that removal of the C-25 methyl does not impede the simultaneous strong interaction of the carboxylate with the three arginines, predicting that 27-nor-DAs are putative ceDAF-12 ligands. PMID- 22489015 TI - Radiation-induced reprogramming of breast cancer cells. AB - Breast cancers are thought to be organized hierarchically with a small number of breast cancer stem cells (BCSCs) able to regrow a tumor while their progeny lack this ability. Recently, several groups reported enrichment for BCSCs when breast cancers were subjected to classic anticancer treatment. However, the underlying mechanisms leading to this enrichment are incompletely understood. Using non BCSCs sorted from patient samples, we found that ionizing radiation reprogrammed differentiated breast cancer cells into induced BCSCs (iBCSCs). iBCSCs showed increased mammosphere formation, increased tumorigenicity, and expressed the same stemness-related genes as BCSCs from nonirradiated samples. Reprogramming occurred in a polyploid subpopulation of cells, coincided with re-expression of the transcription factors Oct4, sex determining region Y-box 2, Nanog, and Klf4, and could be partially prevented by Notch inhibition. We conclude that radiation may induce a BCSC phenotype in differentiated breast cancer cells and that this mechanism contributes to increased BCSC numbers seen after classic anticancer treatment. PMID- 22489016 TI - Feasibility and effectiveness of pre-operative inspiratory muscle training in patients undergoing oesophagectomy: a pilot study. AB - BACKGROUND: Patients undergoing oesophageal surgery have a high risk for post operative complications including pulmonary infections. Recently, physical therapy has shifted from the post-operative to the pre-operative phase to diminish post-operative complications and to shorten hospital stay. The purpose of this pilot study was to investigate the feasibility and initial effectiveness of pre-operative inspiratory muscle training (IMT) on the incidence of pneumonia in patients undergoing oesophagectomy. METHODS: A pragmatic non-randomized controlled trial was conducted among all patients who underwent an oesophagectomy between January 2009 and February 2010. Patients in the intervention group received IMT prior to surgery. Feasibility was assessed on the basis of the occurrence of adverse effects during testing or training and patient satisfaction. Initial effectiveness on respiratory function was evaluated by maximal inspiratory pressure (MIP) and endurance, the incidence of post-operative pneumonia and length of hospital stay. RESULTS: Eighty-three patients were included, of which 44 received pre-operative IMT. No adverse effects were observed. IMT was well tolerated and appreciated. In the intervention group, the median MIP and endurance improved significantly after IMT by 32% and 41%, respectively (p < 0.001). The incidence of post-operative pneumonia and the length of hospital stay were comparable for the intervention and the conventional care groups (pneumonia, 25% vs. 23% [p = 0.84]; hospitalization, 13.5 vs. 12 days [p = 0.08]). CONCLUSIONS: Pre-operative IMT is feasible in patients with oesophageal carcinoma and significantly improves respiratory muscle function. This, however, did not result in a reduction of post-operative pneumonia in patients undergoing oesophagectomy. PMID- 22489017 TI - Reduced telomere length in individuals with FMR1 premutations and full mutations. AB - We reported previously that 10 older men (66.4 +/- 4.6 years) with premutation alleles (55-200 CGG repeats) of the FMR1 gene, with or without FXTAS, had decreased telomere length when compared to sex- and age-matched controls. Extending our use of light intensity measurements from a telomere probe hybridized to interphase preparations, we have now found shortened telomeres in 9 younger male premutation carriers (31.7 +/- 17.6 years). We have also shown decreased telomere length in T lymphocytes from 6 male individuals (12.0 +/- 1.8 years) with full mutation FMR1 alleles (>200 CGG repeats). These findings support our hypothesis that reduced telomere length is a component of the sub-cellular pathology of FMR1-associated disorders. The experimental approach involved pair wise comparisons of light intensity values of 20 cells from an individual with either premutation or full mutation CGG-repeat expansions relative to an equivalent number of cells from a sex- and age-matched control. In addition, we demonstrated reduced telomere size in T-lymphocyte cultures from eight individuals with the FMR1 premutation using six different measures. Four relied on detection of light intensity differences, and two involved measuring the whole chromosome, including the telomere, in microns. This new approach confirmed our findings with light intensity measurements and demonstrated the feasibility of direct linear measurements for detecting reductions in telomere size. We have thus confirmed our hypothesis that reduced telomere length is associated with both premutation and full mutation-FMR1 alleles and have demonstrated that direct measurements of telomere length can reliably detect such reductions. PMID- 22489018 TI - Oral conditions in hepatitis C virus-infected Iranian patients: a case-control study. AB - AIM: Hepatitis C virus is now found worldwide, giving rise to concern that general populations might become infected. Extrahepatic manifestations might indicate latent disease. The aim of this study was to evaluate the association between oral lichen planus and xerostomia with hepatitis C virus infection in an Iranian population. METHODS: The study (case) group consisted of 73 individuals with hepatitis C virus infection. The control group consisted of 139 age- and sex matched individuals. All patients were examined for oral conditions, and their hepatitis C virus infection was confirmed by an antihepatitis C virus antibody and hepatitis C virus-RNA polymerase chain reaction. RESULTS: The prevalence of oral lichen planus was 1.4% and 4.1% of individuals complained of a dry mouth. There were no statistically-significant differences between the case and control groups. CONCLUSION: Our findings reinforce other regional studies that there is no association between hepatitis C virus infection and oral conditions in the north of Iran, an area with a low prevalence of this infection. PMID- 22489019 TI - Molecular recognition of T:G mismatched base pairs in DNA as studied by electrospray ionization mass spectrometry. AB - Postreplicative mismatch repair (MMR) is a cellular system involved in the recognition and correction of DNA polymerase errors that escape detection in proofreading. Of the various mismatched bases, T:G pairing in DNA is one of the more common mutations leading to the formation of tumors in humans. In addition, the absence of the MMR system can generate resistance to several chemotherapeutic agents, particularly DNA-damaging substances. The main purpose of this study was the setup and validation of an electrospray ionization (ESI) mass spectrometry method for the identification of small molecules that are able to recognize T:G mismatches in DNA targets. These findings could be useful for the discovery of new antitumor drugs. The analytical method is based on the ability of electrospray to preserve the noncovalent adducts present in solution and transfer them to the gas phase. Lexitropsin derivatives (polyimidazole compounds) have been previously described as selective for T:G mismatch binding by NMR and ITC studies. We synthesized and tested various polyimidazole derivatives, one of which in particular (NMS-057) showed a higher affinity for an oligonucleotide DNA sequence containing a T:G mismatched base pair. To rationalize these findings, molecular docking studies were performed using available NMR structures. Moreover, ESI-MS experiments, performed on an orbitrap mass spectrometer, highlighted the formation of heterodimeric complexes between DNA sequences, distamycin A, and polyimidazole compounds. Our results confirm that this ESI method could be a valuable tool for the identification of new molecules able to specifically recognize T:G mismatched base pairs. PMID- 22489021 TI - Enantiomerically pure phosphaalkene-oxazolines (PhAk-Ox): synthesis, scope and copolymerization with styrene. AB - The design of a synthetic route to a class of enantiomerically pure phosphaalkene oxazolines (PhAk-Ox) is presented. The condensation of a lithium silylphosphide and a ketone (the phospha-Peterson reaction) was used as the P=C bond-forming step. Attempted condensation of PhC(=O)Ox (Ox = CNOCH(iPr)CH(2)) and MesP(SiMe(3))Li gave the unusual heterocycle (MesP)(2)C(Ph)=CN-(S)-CH(iPr)CH(2)O (3). However, PhAk-Ox (S,E)-MesP=C(Ph)CMe(2)Ox (1 a) was successfully prepared by treating MesP(SiMe(3))Li with PhC(=O)CMe(2)Ox (52 %). To demonstrate the modularity and tunability of the phospha-Peterson synthesis several other phosphaalkene-oxazolines were prepared in an analogous manner to 1 a: TripP=C(Ph)CMe(2)Ox (1 b; Trip = 2,4,6-triisopropylphenyl), 2 iPrC(6)H(4)P=C(Ph)CMe(2)Ox (1 c), 2-tBuC(6)H(4)P=C(Ph)CMe(2)Ox (1 d), MesP=C(4 MeOC(6)H(4))CMe(2)Ox (1 e), MesP=C(Ph)C(CH(2))(4)Ox (1 f), and MesP=C(3,5 (CF(3))(2)C(6)H(3))C(CH(2))(4)Ox (1 g). To evaluate the PhAk-Ox compounds as prospective precursors to chiral phosphine polymers, monomer 1 a and styrene were subjected to radical-initiated copolymerization conditions to afford [{MesPC(Ph)(CMe(2)Ox)}(x){CH(2)CHPh}(y)](n) (9 a: x = 0.13n, y = 0.87n; GPC: M(w) = 7400 g mol(-1) , PDI = 1.15). PMID- 22489020 TI - Toxicity thresholds for juvenile freshwater mussels Echyridella menziesii and crayfish Paranephrops planifrons, after acute or chronic exposure to Microcystis sp. AB - Survival of juvenile freshwater mussels (Echyridella menziesii (Gray, 1843) formerly known as Hyridella menziesi) and crayfish (Paranephrops planifrons, White, 1842) decreased after four days exposure to microcystin-containing cell free extracts (MCFE) of Microcystis sp. at concentrations typical of severe cyanobacterial blooms. Crayfish survival was 100, 80, and 50% in microcystin concentrations of 1339, 2426, and 11146 MUg L(-1) respectively, and shade- and shelter-seeking behavior was negatively affected when concentrations were >=2426 MUg L(-1) . Mussel survival decreased to 92% and reburial rates decreased to 16% after exposure for 96 h to MCFE containing microcystins at concentrations of 5300 MUg L(-1) . Crayfish survival was 100% when fed freeze-dried Microcystis sp. incorporated into an artificial diet (6-100 MUg microcystin kg(-1) ww) at dietary doses from 0.03 to 0.55 MUg g(-1) body weight d(-1) for 27 days. Specific growth rate was significantly lower in crayfish fed >=0.15 MUg g(-1) body weight day(-1) compared with controls, but not compared with a diet incorporating nontoxic cyanobacteria. Microcystins accumulated preferentially in crayfish hepatopancreas and mussel digesta as MCFE or dietary concentrations increased. These laboratory data indicate that, assuming dissolved oxygen concentrations remain adequate, and no simultaneous exposure to live Microcystis sp. cells, cell-free microcystins will only be a significant stressor to juvenile crayfish and mussels in severe Microcystis sp. blooms. In contrast, crayfish were negatively affected by relatively low concentrations of microcystins in artificial diets compared with those measured locally in benthic cyanobacterial mats. PMID- 22489022 TI - Reduced field-of-view excitation using second-order gradients and spatial spectral radiofrequency pulses. AB - The performance of multidimensional spatially selective radiofrequency (RF) pulses is often limited by their long duration. In this article, high-order, nonlinear gradients are exploited to reduce multidimensional RF pulse length. Specifically, by leveraging the multidimensional spatial dependence of second order gradients, a two-dimensional spatial-spectral RF pulse is designed to achieve three-dimensional spatial selectivity, i.e., to excite a circular region of-interest in a thin slice for reduced field-of-view imaging. Compared to conventional methods that use three-dimensional RF pulses and linear gradients, the proposed method requires only two-dimensional RF pulses, and thus can significantly shorten the RF pulses and/or improve excitation accuracy. The proposed method has been validated through Bloch equation simulations and phantom experiments on a commercial 3.0T MRI scanner. PMID- 22489023 TI - Differential positioning and close spatial proximity of translocation-prone genes in nonmalignant B-cells from multiple myeloma patients. AB - Accumulating evidence suggests that spatial proximity of potential chromosomal translocation partners influences translocation probability. It is not known, however, whether genome organization differs in nonmalignant cells from patients as compared to their cellular counterparts from healthy donors. This could contribute to translocation potential causing cancer. Multiple myeloma is a hematopoietic cancer of the B-lineage, characterized by karyotypic instability, including chromosomal translocations involving the IGH locus and several translocation partners. Utilizing 3-D FISH and confocal imaging, we investigate whether nuclear spatial positioning of the translocation-prone gene loci, IGH, FGFR3, and CCND1 differs in nonmalignant cell subsets from multiple myeloma patients as compared to positioning in their corresponding healthy donor cell subsets. 3-D analysis software was used to determine the spatial proximity of potential translocation pairs and the radial distribution of each gene. We observed that in all cell subsets, the translocation-prone gene loci are intermediately located in the nucleus, while a control locus occupies a more peripheral position. In nonmalignant B-cells from multiple myeloma patients, however, the translocation-prone gene loci display a more central nuclear position and close spatial proximity. Our results demonstrate that gene positioning in nonmalignant B-cells from multiple myeloma patients differs from that in healthy donors, potentially contributing to translocation probability in patient cells. We speculate that genome reorganization in patient B-cells may closely reflect gene positioning at the time the multiple myeloma-specific translocation initially formed, thus influencing translocation probability between proximal loci in the B-cell population from which the malignancy emerged. PMID- 22489024 TI - Palladium-catalyzed alkylation of 1,4-dienes by C-H activation. AB - Activated: the title reaction proceeds with a broad range of nucleophiles and variously substituted 1,4-dienes under mild conditions, and provides direct access to the corresponding 1,3-diene-containing products with high regio- and stereocontrol (see scheme; 2,6-DMBQ=2,6-dimethylbenzoquinone, EWG=electron withdrawing group). This is the first catalytic allylic C-H alkylation that proceeds in the absence of sulfoxide ligands. PMID- 22489025 TI - The osteoarthritic niche and modulation of skeletal stem cell function for regenerative medicine. AB - Osteoarthritis (OA) is the most common cause of arthritis worldwide and represents a significant healthcare burden, particularly in the context of an ageing population. Traditionally, painkillers, injections and physiotherapy have been the mainstay of treatment, with patients being referred for joint replacement surgery (arthroplasty) when these options fail. Whilst effective in reducing pain and improving joint function, these approaches are not without potential complications. With the development of tissue-engineering techniques over recent years there has been considerable interest in applying these strategies to provide new, innovative, alternative effective means of treating OA. This review explores the unique microenvironment present within an osteoarthritic joint, highlighting the features that comprise the osteoarthritic niche and could be modulated in the development of novel treatments for OA. Existing tissue-engineering strategies for repairing bone and cartilage defects are discussed, with particular reference to how these might be modified, both to improve existing treatments, such as impaction bone grafting, as well as in the development of future treatments for OA. PMID- 22489026 TI - Facile synthesis of a large quantity of graphene by chemical vapor deposition: an advanced catalyst carrier. AB - A large quantity of highly conductive graphene was prepared by a novel CVD method with nickel powder as a template and PMMA as carbon source. With Pt as a model, PtNP-modified graphene showed much better electrocatalytic ability for O(2) and methanol than PtNP-reduced graphene oxide (RGO) and commercial Pt/C, showing that this graphene is a better catalyst carrier than RGO and commercial carbon. PMID- 22489027 TI - Development and laboratory-scale testing of a fully automated online flow cytometer for drinking water analysis. AB - Accurate and sensitive online detection tools would benefit both fundamental research and practical applications in aquatic microbiology. Here, we describe the development and testing of an online flow cytometer (FCM), with a specific use foreseen in the field of drinking water microbiology. The system incorporated fully automated sampling and fluorescent labeling of bacterial nucleic acids with analysis at 5-min intervals for periods in excess of 24 h. The laboratory scale testing showed sensitive detection (< 5% error) of bacteria over a broad concentration range (1 * 10(3) -1 * 10(6) cells mL(-1) ) and particularly the ability to track both gradual changes and dramatic events in water samples. The system was tested with bacterial pure cultures as well as indigenous microbial communities from natural water samples. Moreover, we demonstrated the possibility of using either a single fluorescent dye (e.g., SYBR Green I) or a combination of two dyes (SYBR Green I and Propidium Iodide), thus broadening the application possibilities of the system. The online FCM approach described herein has considerable potential for routine and continuous monitoring of drinking water, optimization of specific drinking water processes such as biofiltration or disinfection, as well as aquatic microbiology research in general. PMID- 22489028 TI - Antimicrobial peptide incorporated poly(2-hydroxyethyl methacrylate) hydrogels for the prevention of Staphylococcus epidermidis-associated biomaterial infections. AB - The effectiveness of the antimicrobial peptide maximin-4, the ultrashort peptide H-Orn-Orn-Trp-Trp-NH(2), and the lipopeptide C(12)-Orn-Orn-Trp-Trp-NH(2) in preventing adherence of pathogens to a candidate biomaterial were tested utilizing both matrix- and immersion-loaded poly(2-hydroxyethyl methacrylate) (poly(HEMA)) hydrogels. Antiadherent properties correlated to both the concentration released and the relative antimicrobial concentrations of each compound against Staphylococcus epidermidis ATCC 35984, at each time point. Immersion-loaded samples containing C(12)-Orn-Orn-Trp-Trp-NH(2) exhibited the lowest adherence profile for all peptides studied over 1, 4, and 24 h. The results outlined in this article show that antimicrobial peptides have the potential to serve as an important weapon against biomaterial associated infections. PMID- 22489029 TI - Use of creative activities in occupational therapy practice in Sweden. AB - The aim of this study was to describe the prevalence of creative activities in occupational therapy in Sweden and how often Swedish occupational therapists use creative activities as a means of intervention. A web-mail survey was sent to 2975 Swedish occupational therapists working in health care at regional, county council or primary health care level, and those working in vocational rehabilitation. A total of 1867 (63%) answered the questionnaire and showed that 44% did use creative activities as a means of intervention and most often by practitioners working in psychiatric health care. The most commonly used form of creative activity was arts and crafts followed by gardening. This web-mail survey was based on a limited amount of items regarding creative activities. Further research should focus on in-depth inquiries about how occupational therapists and their patients perceive the use of creative activities as a means of treatment in occupational therapy. PMID- 22489030 TI - Grafted neuronal precursor cells differentiate and integrate in injured hippocampus in experimental pneumococcal meningitis. AB - Bacterial meningitis (BM) frequently causes persisting neurofunctional sequelae. Autopsy studies in patients dying from BM show characteristic apoptotic brain injury to the stem cell niche in the subgranular zone of the hippocampal dentate gyrus (DG), and this form of brain damage is associated with learning and memory deficits in experimental BM. With an eye to potential regenerative therapies, the survival, migration, and differentiation of neuronal precursor cells (NPCs) were evaluated after engraftment into the injured hippocampus in vitro and in vivo in an infant rat model of pneumococcal meningitis. Green fluorescent protein (GFP) expressing NPCs were grafted into the DG of organotypic hippocampal slice cultures injured by challenge with live Streptococcus pneumoniae. Seven days after engraftment, NPCs had migrated from the site of injection into the injured granular layer of the DG and electro-functionally integrated into the hippocampal network. In vivo, GFP-expressing NPCs migrated within 1 week from the injection site in the hilus region to the injured granular layer of the hippocampal DG and showed neuronal differentiation at 2 and 4 weeks after transplantation. Hippocampal injury induced by BM guides grafted NPCs to the area of brain damage and provides a microenvironment for neuronal differentiation and functional integration. PMID- 22489031 TI - Thinking on your feet: understanding the immediate responses of staff to adults who challenge intellectual disability services. AB - BACKGROUND: A gap prevails between the conceptualization of good practice in challenging behaviour management and its implementation in intellectual disability services. This study aimed to investigate staff members' perspectives of managing clients with challenging behaviours in residential services. MATERIALS AND METHODS: Semi-structured interviews were conducted with eleven staff in two services. Additionally, service documents on challenging behaviour management were examined in these services. A qualitative methodology was used to investigate staff members' immediate responses to clients' difficult behaviours and their decision-making processes. RESULTS: The immediate responses of staff were conceptualized as the result of complex appraisals shaped by their service context involving the core processes of making the right choice and prioritizing the best interests of all involved. CONCLUSIONS: Staff members' responses were understood as a dynamic and retroactive process, where their past and current challenging behaviour management experiences in the service influenced their responses to clients in the future. PMID- 22489032 TI - Changes in attributions as a consequence of training for challenging and complex behaviour for carers of people with learning disabilities: a systematic review. AB - AIM: This paper reviews the evidence for changes in carers' attributions regarding the behaviour of people with intellectual disabilities as a consequence of carer training in challenging and complex behaviour. METHOD: Papers were included in the review if they reported outcomes for carer training on the behaviour of people with intellectual disabilities and used a measure of carer attribution of the behaviour of people with intellectual disabilities. The characteristics of the scales used and the content and length of training are considered as possible factors affecting changes in attribution. RESULTS: Eleven papers were reviewed, most studies using behavioural curricula for their training, and none explicitly set out to change attributions. Eight of the 11 papers reviewed reported changes in attribution although core characteristics of training did not distinguish those papers that reported such changes and those that did not. CONCLUSIONS: Changes in beliefs and attributions occur even though these are not identified as a focus within the training provided. The present authors suggest that the formulation processes involved in behavioural training may play a key part in changing attributions as a consequence of this training. The present authors discuss the potential for more focussed intervention designed to change attributions and for better alignment of measures to specific attribution change expected as a result of specific training approaches. PMID- 22489033 TI - Enabling integration in sports for adolescents with intellectual disabilities. AB - BACKGROUND: Promoting the health and social participation of adolescents with intellectual disability is important as they are particularly vulnerable to encountering difficulties in those areas. Integration of these individuals in integrated sports is one strategy to address this issue. METHODS: The main objective of this study was to gain a better understanding of the factors associated with the integration of adolescents with intellectual disability in sports alongside their non-disabled peers. Individual interviews were completed with 40 adolescents with intellectual disability and their parents, while 39 rehabilitation staff participated via either a discussion group or self administered questionnaires. The Disability Creation Process (DCP) theoretical model was used to frame the analysis and the presentation of the findings (The Quebec Classification: Disability Creation Process. International Network on the Disability Creation Process/CSICIDH, Quebec, QC, 1998). RESULTS: Various personal and environmental factors that have an impact on integration in sports were identified by participants. For example, attitudes, practical support, individuals' experiences in sports and in integrated settings as well as behaviour control emerged as important elements to consider. CONCLUSIONS: Integration in integrated sports can engender a lot of benefits for individuals with intellectual disability, their parents and non-disabled athletes. However, many barriers need to be removed before such benefits can be more widely realized. PMID- 22489034 TI - Physical fitness and fatness in adolescents with intellectual disabilities. AB - BACKGROUND: This study investigated health-related fitness in adolescents with intellectual disabilities and analysed the various performances in physical fitness tests according to degrees of obesity. MATERIALS AND METHODS: Eighty seven French intellectual disabilities adolescents (14.24 +/- 1.48 years) performed the EUROFIT physical fitness test battery. Height, weight and waist circumference were assessed, and BMI and waist-to-height ratio were calculated. 'Bio-impedancemetry' evaluated body fat (BF) percentage. RESULTS: Ninety-four per cent of the adolescents completed the aerobic running test, 52% of which had low VO(2max). Thirty-seven per cent were obese (%BF), and 32% had excess visceral adipose tissue. Adolescents with the lowest cardiorespiratory fitness had the highest BF percentages (P < 0.001). CONCLUSIONS: Intellectual disabilities adolescents showed low physical fitness and high prevalence of obesity. Both could further worsen social participation and health status. PMID- 22489035 TI - The process of perceiving stigmatization: perspectives from Taiwanese young people with intellectual disability. AB - BACKGROUND: There is a dearth of studies about the causes of stigmatization in people with intellectual disability. This study is aimed at gaining an understanding of how feelings of stigmatization are formed and perceived among young people with intellectual disability in Taiwanese cultural and social contexts. MATERIALS AND METHODS: Fourteen young people with intellectual disability, ranging in age from 17 to 22 years, participated in this study. Data were collected and analysed using grounded theory. RESULTS: Three persistent themes were noted in regard to the formation of feelings of stigmatization among these young people with intellectual disability. (i) Being labelled: the sources of their stigma often resulted from the educational and social welfare systems. (ii) Perceiving oneself: they viewed themselves as 'not good' students, as troublemakers, as sick people and as odd people. (iii) Living with the labelling: they attempted to manage the impression that their intellectual disability had on others by using avoidance, isolation and self-promotion. CONCLUSIONS: Stigmatization among this intellectual disability group is invisibly formed while attending school and receiving social services. The value of the intellectual performance is not yet waived for young people with intellectual disability in Taiwan. Changing the social opinions of intellectual disability can help to avoid stigmatizing these people with intellectual disability. PMID- 22489036 TI - Mental health needs in adolescents with intellectual disabilities: cross sectional survey of a service sample. AB - BACKGROUND: Little research has been conducted on the mental health needs of adolescents with intellectual disability, despite the severity and rates of such needs being high throughout childhood and in adulthood. We have investigated the prevalence and predictors of mental health needs and service use in adolescents with intellectual disabilities. MATERIALS AND METHODS: Service-based sample (n = 75) in one catchment area. Individual assessments were carried out. The main outcome was the presence of mental health needs measured by the Developmental Behaviour Checklist. RESULTS: Prevalence of mental health needs increased from 51% as reported by parents to 67% as judged by clinical interviews. Caseness was associated with low adaptive functioning, diagnosis of autism and family history of mental illness. High scores on parent reports of participant mental ill-health showed negative correlations with adaptive functioning scores. Most individuals were in receipt of social and health care. Half of the participants had sought help for mental health needs. Almost half of those receiving medication were on psychiatric medication. CONCLUSIONS: Adolescents with intellectual disabilities may have considerable mental health problems which are functionally impairing yet frequently unidentified and hence untreated. Identification of those at risk and undertaking of a comprehensive needs assessment are essential to maximize potential and quality of life and to reduce further deficits and social exclusion. PMID- 22489037 TI - Context influences the motivation for stereotypic and repetitive behaviour in children diagnosed with intellectual disability with and without autism. AB - BACKGROUND: Children are motivated to engage in stereotypic and repetitive behaviours for a number of reasons. Their motivation seems to change according to context, but little empirical evidence supports that observation. Interventions designed to reduce the behaviours may be improved by an increased understanding of the interaction between motivation and context. METHOD: Using Rasch analysis, we analysed data describing stereotypic behaviours from 279 Revised Motivation Assessment Scales (MAS:R). Data were gathered from two groups of children: Group 1 with intellectual disability (n = 37) and Group 2 with both intellectual disability and autism (n = 37). We examined behaviours in three contexts: free time, transition and while engaged in tasks. MAS:R distinguishes two intrinsic motivators: enhanced sensation and decreased anxiety and three extrinsic motivators: seeking attention or objects or escape. RESULTS: Significant differences in motivators were observed during free time and transition. No one motivator predominated while children were engaged in tasks. For both groups, sensory enhancement was a more likely motivator in free time and anxiety reduction was a more likely motivator during transition. Transition was the context most likely to influence extrinsic motivators, but there were significant differences between the groups. CONCLUSIONS: Context influences the motivation for stereotyped and repetitive behaviours. Transition has a particularly powerful effect. PMID- 22489038 TI - Analogical matrices in young children and students with intellectual disability: reasoning by analogy or reasoning by association? AB - BACKGROUND: Analogical reasoning (AR) is renowned for being a complex activity. Young children tend to reason by association, rather by analogy, and people with intellectual disability present problems of memorization. Both these populations usually show low performances in AR. The present author investigated whether familiar material and external memories could enable them to obtain better performances. MATERIAL: Our computerized AR test uses a touch screen. The 2 * 2 matrices are composed of familiar pictures and relations, and declined in two versions. The classic version requires memorizing all the relations involved in order to discover the solution, whereas the construction version requires constructing the answer part by part by using external memories, which potentially unload the memory. RESULTS: Our results showed that people with intellectual disability reached lower performances than typically developing children in the classic version, but similar performances in the construction version. In addition, both these populations reasoned mostly by analogy and not by association. PMID- 22489039 TI - Choosing staff members reduces time in mechanical restraint due to self-injurious behaviour and requesting restraint. AB - BACKGROUND: Using mechanical restraints to protect a person who engaged in dangerous self-injury was decreased by manipulation of an establishing operation involving the client choosing the staff person who would work with her. MATERIALS AND METHODS: The client was a 28-year-old woman diagnosed with autism, bipolar disorder, static cerebral encephalopathy, moderate intellectual disabilities, hypotonia and musculoskeletal deformities. She had a history of biting herself and further bites could produce irreversible nerve damage. Mechanical restraints were applied when she bit, tried to bite herself or asked for them. RESULTS: When she was allowed to choose staff members, the use of mechanical restraint decreased. CONCLUSION: Reducing the time spent in mechanical restraint by giving the client a choice of staff members who would work with her demonstrates that such a choice may be an establishing operation. The usefulness of cumulative records and scatterplots to evaluate changes in the occurrence of self-injurious behaviour (SIB) and associated mechanical restraint is shown as are the advantages of using alternating treatment designs to assess the effectiveness of treatment conditions for someone who exhibits long-term cyclic behaviour. PMID- 22489040 TI - COL1A1 association and otosclerosis: a meta-analysis. AB - Otosclerosis is a disease of abnormal bone remodeling in the human otic capsule that can lead to progressive hearing loss. Little of the underlying disease etiology has been elucidated thus far, although several studies have suggested that COL1A1 may play a role based on its importance in bone metabolism and other diseases like osteoporosis and osteogenesis imperfecta. Genetic association studies between COL1A1 and otosclerosis, however, have been contradictory. To resolve this issue, we studied a large Belgian-Dutch and a Swiss population for a genetic association between COL1A1 and otosclerosis and additionally performed a meta-analysis to investigate the overall genetic effect of COL1A1 on all otosclerosis populations studied to date. We found a significant association both in the Belgian-Dutch population and in the meta-analysis. In aggregate, our analysis supports evidence for an association between COL1A1 and otosclerosis although effect sizes of the variants reported in the initial studies are likely to be an overestimate of true effect sizes. PMID- 22489041 TI - Hydrogen peroxide induces adaptive response and differential gene expression in human embryo lung fibroblast cells. AB - Hydrogen peroxide (H2 O2 ), a substance involved in cellular oxidative stress, has been observed to induce an adaptive response, which is characterized by a protection against the toxic effect of H2 O2 at higher concentrations. However, the molecular mechanism for the adaptive response remains unclear. In particular, the existing reports on H2 O2 -induced adaptive response are limited to animal cells and human tumor cells, and relatively normal human cells have never been observed for an adaptive response to H2 O2 . In this study, a human embryo lung fibroblast (MRC-5) cell line was used to model an adaptive response to H2 O2 , and the relevant differential gene expressions by using fluoro mRNA differential display RT-PCR. The results showed significant suppression of cytotoxicity of H2 O2 (1100 MUM, 1 h) after pretreatment of the cells with H2 O2 at lower concentrations (0.088-8.8 MUM, 24 h), as indicated by cell survival, lactate dehydrogenase release, and the rate of apoptotic cells. Totally 60 mRNA components were differentially expressed compared to untreated cells, and five of them (sizing 400-600 bp) which demonstrated the greatest increase in expression were cloned and sequenced. They showed identity with known genes, such as BCL-2, eIF3S5, NDUFS4, and RPS10. Real time RT-PCR analysis of the five genes displayed a pattern of differential expression consistent with that by the last method. These five genes may be involved in the induction of adaptive response by H2 O2 in human cells, at least in this particular cell type. PMID- 22489042 TI - Comparative molecular profiling of the PPARalpha/gamma activator aleglitazar: PPAR selectivity, activity and interaction with cofactors. AB - Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that control the expression of genes involved in a variety of physiologic processes, through heterodimerization with retinoid X receptor and complex formation with various cofactors. Drugs or treatment regimens that combine the beneficial effects of PPARalpha and gamma agonism present an attractive therapeutic strategy to reduce cardiovascular risk factors. Aleglitazar is a dual PPARalpha/gamma agonist currently in phase III clinical development for the treatment of patients with type 2 diabetes mellitus who recently experienced an acute coronary event. The potency and efficacy of aleglitazar was evaluated in a head-to-head comparison with other PPARalpha, gamma and delta ligands. A comprehensive, 12-concentration dose-response analysis using a cell-based assay showed aleglitazar to be highly potent, with EC(50) values of 5 nM and 9 nM for PPARalpha and PPARgamma, respectively. Cofactor recruitment profiles confirmed that aleglitazar is a potent and balanced activator of PPARalpha and gamma. The efficacy and potency of aleglitazar are discussed in relation to other dual PPARalpha/gamma agonists, in context with the published X-ray crystal structures of both PPARalpha and gamma. PMID- 22489043 TI - Mutation analysis of ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 in myeloproliferative neoplasms. AB - Since the discovery of the JAK2V617F tyrosine kinase-activating mutation several genes have been found mutated in nonchronic myeloid leukemia (CML) myeloproliferative neoplasms (MPNs), which mainly comprise three subtypes of "classic" MPNs; polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). We searched for mutations in ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 genes in 149 non-CML MPNs, including 127 "classic" MPNs cases. JAK2 was mutated in 100% PV, 66% ET and 68% MF. We found a high incidence of ASXL1 mutation in MF patients (20%) and a low incidence in PV (7%) and ET (4%) patients. Mutations in the other genes were rare (CBL, DNMT3A, IDH2, MPL, SF3B1, SUZ12, NF1) or absent (IDH1). PMID- 22489044 TI - As the inflammatory nature of chronic rhinosinusitis (CRS) has become increasingly recognized, the use of steroids, both systemic and topical, as part of the disease management has significantly increased. PMID- 22489045 TI - Room temperature aerobic oxidation of amines by a nanocrystalline ruthenium oxide pyrochlore nafion composite catalyst. AB - The aerobic oxidation of primary amines to their respective nitriles has been carried out at room temperature using a highly reusable nanocrystalline ruthenium oxide pyrochlore Nafion composite catalyst (see figure). PMID- 22489046 TI - Modeling dispersion in arterial spin labeling: validation using dynamic angiographic measurements. AB - A major assumption in arterial spin labeling (ASL) MRI perfusion quantification is the time course of the signal on arrival in the capillary network. The normally assumed square label profile is not preserved during transit of the label through the vasculature. This change in profile can be attributed to a number of effects collectively denoted as dispersion. A number of models for this effect have been proposed, but they have been difficult to validate. In this study ASL data acquired whilst the label was still within larger arteries was used to compare models of label dispersion. Models were fit using a probabilistic algorithm and evaluated according to their ability to fit the data. Data from an elderly population were considered including both healthy controls and patients with a variety of vascular disease. The authors conclude that modeling ASL dispersion using a convolution of the ideal ASL label profile with a dispersion kernel is most appropriate, where the kernel itself takes the form of a gamma distribution. This model provided a best fit to the data considered, was consistent with the measured flow profile in arteries and was sufficiently mathematically simple to make it practical for ASL tissue perfusion quantification. PMID- 22489048 TI - Extensive Ace2 duplication and multiple mutations on Ace1 and Ace2 are related with high level of organophosphates resistance in Aphis gossypii. AB - Aphis gossypii (Glover) has been found to possess multiple mutations in the acetylcholinesterase (AChE) gene (Ace) that might involve target site insensitivity. In vitro functional expression of AChEs reveals that the resistant Ace1 (Ace1R) and Ace2 (Ace2R) were significantly less inhibited by eserine, omethoate, and malaoxon than the susceptible Ace1 (Ace1S) and Ace2 (Ace2S). Furthermore, in both the mutant and susceptible AChEs, Ace2 was significantly less sensitive to eserine, omethoate, and malaoxon than Ace1. These results suggested that both the mutant Ace1 and Ace2 were responsible for omethoate resistance, while the mutant Ace2 played a major role in insecticide resistance. The DNA copy number and transcription level of Ace2 were 1.52- and 1.88-fold higher in the ORR strain than in the OSS strain. Furthermore, the DNA copy number and transcription level of Ace2 were significantly higher than that of Ace1 in either OSS or ORR strains, demonstrating the involvement of Ace2 gene duplication in resistance. Thus, the authors conclude that omethoate resistance in cotton aphids appears to have evolved through a combination of multiple mutations and extensive Ace2R gene duplication. PMID- 22489047 TI - Homology modeling and molecular dynamics simulations of the active state of the nociceptin receptor reveal new insights into agonist binding and activation. AB - The opioid receptor-like receptor, also known as the nociceptin receptor (NOP), is a class A G protein-coupled receptor (GPCR) in the opioid receptor family. Although NOP shares a significant homology with the other opioid receptors, it does not bind known opioid ligands and has been shown to have a distinct mechanism of activation compared to the closely related opioid receptors mu, delta, and kappa. Previously reported homology models of the NOP receptor, based on the inactive-state GPCR crystal structures, give limited information on the activation and selectivity features of this fourth member of the opioid receptor family. We report here the first active-state homology model of the NOP receptor based on the opsin GPCR crystal structure. An inactive-state homology model of NOP was also built using a multiple template approach. Molecular dynamics simulation of the active-state NOP model and comparison to the inactive-state model suggest that NOP activation involves movements of transmembrane (TM)3 and TM6 and several activation microswitches, consistent with GPCR activation. Docking of the selective nonpeptidic NOP agonist ligand Ro 64-6198 into the active-state model reveals active-site residues in NOP that play a role in the high selectivity of this ligand for NOP over the other opioid receptors. Docking the shortest active fragment of endogenous agonist nociceptin/orphaninFQ (residues 1-13) shows that the NOP extracellular loop 2 (EL2) loop interacts with the positively charged residues (8-13) of N/OFQ. Both agonists show extensive polar interactions with residues at the extracellular end of the TM domain and EL2 loop, suggesting agonist-induced reorganization of polar networks, during receptor activation. PMID- 22489049 TI - Plasma expanders stabilize human microvessels in microfluidic scaffolds. AB - Plasma expanders such as dextran and hydroxyethyl starch (HES) are important components of solutions designed to maintain vascular volume in the clinical setting and to preserve organs ex vivo before transplantation. Here, we show that these polymers also exert stabilizing effects on engineered microvessels in microfluidic type I collagen and fibrin scaffolds. Standard growth media, which did not contain dextran or HES, led to severe leakage, vascular collapse, and catastrophic failure of perfusion. Remarkably, vessels that were provided with 3% dextran or 5% HES had few focal leaks, maintained adhesion to the scaffold, and were typically viable and patent for at least 2 weeks. We found that the junctional marker VE-cadherin localized to a wide band in the presence of plasma expanders, but only at concentrations that also stabilized vessels. In conjunction with a previous computational model (Wong et al., Biomaterials 2010;31:4706-4714), our results suggest that plasma expanders stabilize microvessels via physical mechanisms that enhance VE-cadherin localization at junctions and thereby limit vascular leakiness. PMID- 22489051 TI - Adipose tissue engineering using adipose-derived stem cells enclosed within an injectable carboxymethylcellulose-based hydrogel. AB - In situ gelation of an aqueous solution of carboxymethylcellulose derivative bearing phenolic hydroxyl groups (CMC-Ph) that contained suspended adipose derived stem cells (ASCs) was studied in vitro and in vivo for evaluating feasibility in adipose tissue-engineering strategies. The rat ASCs that were enclosed in the CMC-Ph gels through a horseradish peroxidase-catalysed reaction showed 92.8% viability, good proliferation and adipogenic differentiation in vitro. Ten weeks after the subcutaneous injection of ASCs-suspending CMC-Ph for in situ gelation, clearly visible new vascularized adipose tissue formed at the injection site. The number of blood vessels and the area occupied by adipose tissues were five and eight times larger, respectively, than those found in the implanted acellular gel. The adipogenesis and neovascularization were further enhanced by incorporation of fibroblast growth factor into the CMC-Ph gel containing ASCs. PMID- 22489052 TI - Macromolecules containing metal ions. PMID- 22489053 TI - Flexible, angle-independent, structural color reflectors inspired by morpho butterfly wings. AB - Thin-film color reflectors inspired by Morpho butterflies are fabricated. Using a combination of directional deposition, silica microspheres with a wide size distribution, and a PDMS (polydimethylsiloxane) encasing, a large, flexible reflector is created that actually provides better angle-independent color characteristics than Morpho butterflies and which can even be bent and folded freely without losing its Morpho-mimetic photonic properties. PMID- 22489056 TI - Discovery and target identification of an antiproliferative agent in live cells using fluorescence difference in two-dimensional gel electrophoresis. PMID- 22489058 TI - Spontaneous coronary artery dissection in a young woman with Loeys-Dietz syndrome. PMID- 22489057 TI - Concise review: Stem cells in the corneal stroma. AB - The cornea is a tough transparent tissue admitting and focusing light in the eye. More than 90% of the cornea is stroma, a highly organized, transparent connective tissue maintained by keratocytes, quiescent mesenchymal cells of neural crest origin. A small population of cells in the mammalian stroma displays properties of mesenchymal stem cells, including clonal growth, multipotent differentiation, and expression of an array of stem cell-specific markers. Unlike keratocytes, the corneal stromal stem cells (CSSCs) undergo extensive expansion in vitro without loss of the ability to adopt a keratocyte phenotype. Several lines of evidence suggest CSSCs to be of neural crest lineage and not from bone marrow. CSSCs are localized in the anterior peripheral (limbal) stroma near to stem cells of the corneal epithelium. CSSCs may function to support potency of the epithelial stem cells in their unique limbal niche. On the other hand, little information is available documenting a role for CSSCs in vivo in stromal wound healing or regeneration. In vitro CSSCs reproduce the highly organized connective tissue of the stroma, demonstrating a potential use of these cells in tissue bioengineering. Direct introduction of CSSCs into the corneal stroma generated transparent tissue in a mouse model of corneal opacity. Human CSSCs injected into mice corneas did not elicit immune rejection over an extended period of time. The CSSCs therefore appear offer an opportunity to develop cell- and tissue-based therapies for irreversible corneal blindness, conditions affecting more than 10 million individuals worldwide. PMID- 22489059 TI - Synthesis of Gd and (68)Ga complexes in conjugation with a conformationally optimized RGD sequence as potential MRI and PET tumor-imaging probes. AB - We report the synthesis of novel chelates of Gd and (68)Ga with DPTA, DOTA, HP DOA3, as well as with AAZTA, a novel chelating agent developed by our research group. These chelating agents were appropriately conjugated, prior to metal complexation, with DB58, an RGD peptidomimetic, conformationally constrained on an azabicycloalkane scaffold and endowed with high affinity for integrin alpha(nu)beta(3) . Because alpha(nu)beta(3) is involved in neo-angiogenesis in solid tumors and is also directly expressed in cancer cells (e.g. glioblastomas, melanomas) and ovarian, breast, and prostate cancers, these constructs could prove useful as molecular imaging probes in cancer diagnosis by MRI or PET techniques. Molecular modeling, integrin binding assays, and relaxivity assessments allowed the selection of compounds suitable for multiple expression on dendrimeric or nanoparticulate structures. These results also led us to an exploratory investigation of (68)Ga complexation for the promising (68)Ga-PET technique; the AAZTA complex 15((68)Ga) exhibited uptake in a xenograft model of glioblastoma, suggesting potentially useful developments with new probes with improved affinity. PMID- 22489060 TI - Endoscopic neural blockade for rhinogenic headache and facial pain: 2011 update. AB - BACKGROUND: Over 45 million Americans suffer from recurrent headaches, and an estimated $11.9 million was spent on doctor's visits for rhinogenic pain last year. Sphenopalatine blocks have been described for various facial pain syndromes, but their use and the type of blockade agents remain controversial. The objective of this study was to demonstrate that endoscopic nerve blocks, using a mixture of bupivicaine and triamcinolone-40, injected into the anterior ethmoid or sphenopalatine regions, can be a relative safe and effective option for refractory pain. METHODS: The charts of all patients undergoing endoscopic neural blockade, in a private practice setting from 1998 to 2008 were retrospectively reviewed. A 1:1 mixture of 0.5% bupivicaine and triamcinolone acetonide injectable suspension was injected into the patients' anterior ethmoid or sphenopalatine neural distribution, or both, depending on the pain distribution. Charts were reviewed to assess outcomes and any adverse events from nerve blocks. RESULTS: A total of 882 nerve blocks were administered to 147 patients, over the course of 431 office visits. Four mild complications, 2 moderate complications, and no severe or permanent complications were noted. No permanent visual complications were observed. Of all the charts, 85% had documented effects of the nerve block at follow-up. Of those, 81.3% claimed improvement, 17.9% reported feeling the same, and 0.79% stated they had worse pain. CONCLUSION: Endoscopic neural blockade appears to be a relatively safe and viable option in the treatment of refractory headache and facial pain with a rhinogenic component. PMID- 22489061 TI - Prenatal di-n-butyl phthalate exposure alters reproductive functions at adulthood in male rats. AB - This study was aimed to investigate the reproductive health in adult male rats exposed to di-n-butyl phthalate (DBP) during embryonic development. Pregnant rats were injected with DBP and F1 male rats were weaned and on postnatal day 100, used for mating with normal cycling females to assess reproductive performance. After completion of cohabitation period, rats were analyzed for other reproductive end points. Transplacental exposure to DBP significantly decreased fertility in adult male rats. Prenatal exposure to DBP significantly decreased sperm density, number of motile sperms, viable sperms, and hypoosmotic swelling tail coiled sperms with an increase in morphological abnormalities in sperms. Testicular steroidogenic enzyme activity levels and serum testosterone levels were significantly decreased in rats exposed to DBP during embryonic development. In conclusion, transplacental exposure to DBP impairs male reproductive performance by decreasing steroidogenesis and spermatogenesis. PMID- 22489062 TI - Clustering biomolecular complexes by residue contacts similarity. AB - Inaccuracies in computational molecular modeling methods are often counterweighed by brute-force generation of a plethora of putative solutions. These are then typically sieved via structural clustering based on similarity measures such as the root mean square deviation (RMSD) of atomic positions. Albeit widely used, these measures suffer from several theoretical and technical limitations (e.g., choice of regions for fitting) that impair their application in multicomponent systems (N > 2), large-scale studies (e.g., interactomes), and other time critical scenarios. We present here a simple similarity measure for structural clustering based on atomic contacts--the fraction of common contacts--and compare it with the most used similarity measure of the protein docking community- interface backbone RMSD. We show that this method produces very compact clusters in remarkably short time when applied to a collection of binary and multicomponent protein-protein and protein-DNA complexes. Furthermore, it allows easy clustering of similar conformations of multicomponent symmetrical assemblies in which chain permutations can occur. Simple contact-based metrics should be applicable to other structural biology clustering problems, in particular for time-critical or large-scale endeavors. PMID- 22489063 TI - Adhesion of Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa onto nanohydroxyapatite as a bone regeneration material. AB - In orthopedics due to the enormous number of surgical procedures involving invasive implant biomaterials, infections have a huge impact in terms of morbidity, mortality, and medical costs. In this study the initial adhesion of several strains namely Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa, to nanohydroxyapatite, previously heat-treated at 725 degrees C and 1000 degrees C was assessed. Adherent cells were evaluated by scanning electron microscopy and quantified by confocal laser scanning microscopy and as colony forming units after being released by sonication. The wettability and roughness of samples surfaces were assessed by contact angle measurements and atomic force microscopy, respectively. Nanohydroxyapatite heat-treated at 1000 degrees C appeared to be more resistant to bacterial adhesion, over time, in five of the six tested strains while the clinical strains isolated from orthopedic infections presented superior ability to adhere, as well as better capacity to produce slime. The increase in materials sintering temperature resulted in increased hydrophobicity and roughness; however, other surface features such as the decrease in surface area and on porosity as well as the decrease on zeta potential may be the aspects that contributed to a lower bacterial adhesion on the materials sintered at 1000 degrees C. PMID- 22489064 TI - Advanced core decompression, a new treatment option of avascular necrosis of the femoral head--a first follow-up. AB - Aseptic necrosis of the femoral head (AVN) leads to destruction of the affected hip joint, predominantly in younger patients. Advanced core decompression (ACD) is a new technique that may allow better removal of the necrotic tissue by using a new percutaneous expandable reamer. A further modification is the refilling of the drill hole and the defect with an injectable, hard-setting, composite calcium sulphate (CaSO4)-calcium phosphate (CaPO4) bone graft substitute. Compression tests were performed on seven pairs of femoral cadaver bones. One femur of each pair was treated with ACD, while the opposite side remained untreated. Clinically, the postoperative outcome of 27 hips in 23 patients was performed by physical examination 6 weeks after ACD and at average follow-up of 9.69 months, and compared with the preoperative results. MRI was used to assess the removal of the necrotic tissue, any possible progression of AVN and evaluation of collapse. In the biomechanical analysis, the applied maximum compression force that caused the fracture did not significantly differ from the untreated opposite side. The overall results of postoperative physical examinations were significantly better than preoperatively. Five hips (18.5%) were converted to a total hip replacement. The follow-up MRIs of the other patients showed no progression of the necrotic area. The first follow-up results of ACD have been encouraging for the early stages of aseptic necrosis of the femoral head. In our opinion, an assured advantage is the high stability of the femoral neck after ACD, which allows quick rehabilitation. PMID- 22489065 TI - Validation of a grading system for the attachment of the superior turbinate to the sphenoid face. AB - BACKGROUND: The attachment of the superior turbinate to the sphenoid face may be an important factor in determining the approach for sphenoidotomy. We sought to validate a previously described 4-type grading system for superior turbinate attachment (Type: A, within its medial one-third; B, in its middle one-third; C, to its lateral one-third; and D, directly to the orbit) to the face of the sphenoid sinus and to make recommendations for its use in determining the method of sphenoidotomy (transethmoidal vs transsphenoethmoidal). METHODS: Single-slice images through both sphenoid sinus ostia were obtained from axial series of computed tomography (CT) scans. Eighteen (36 ostia) sets of scans were used. Attachment type (A-D) in each image was classified by 10 experienced sinus surgeons and compared against a "gold standard" grading performed by the senior author (A.J.), who was the developer of the grading system. RESULTS: Mean accuracy was 63% (95% confidence interval [CI], 54%-72%) for the 4-type grading system. When Types A+B and Types C+D were grouped together, mean accuracy was 91% (95% CI, 84%-97%). For the 2-group classification system, bootstrap analysis suggested that 97% of physicians attain an accuracy of at least 80%. CONCLUSION: Accuracy using the 4-type classification is too low to be practically useful. Accuracy using the 2-group system may be sufficiently high to be a useful aid in selecting a surgical approach. We recommend a transethmoid sphenoidotomy for Types A and B and a transsphenoethmoidal approach to the sphenoid for Types C and D. PMID- 22489066 TI - Generation of a porous luminescent structure through ultrasonically induced pathways of silicon modification. PMID- 22489067 TI - DNA origami gatekeepers for solid-state nanopores. AB - DNA has it covered: DNA origami gatekeeper nanoplates convert nanopores in solid state membranes into versatile devices for label-free macromolecular sensing applications. The custom apertures in the nanoplates can be chemically addressed for sequence-specific detection of DNA. PMID- 22489068 TI - Marfanoid habitus, inguinal hernia, advanced bone age, and distinctive facial features: a new collagenopathy? AB - We report on two sibs, a girl, and a boy, with tall stature, long, and triangular faces, prominent foreheads with high frontal hairlines, telecanthus, downward slanting of the palpebral fissures, ptosis of the eyelids, everted lower eyelids, large ears, long noses, full, and everted vermilions, highly arched and narrow palates, tooth crowding, thin and long uvulae, coloboma of the alae, hyperextensible joints, long digits, positive thumb signs, flat feet, slightly diminished muscle strength, myopia, astigmatia, inguinal hernia, and vesical diverticula. Total body X-rays showed the presence of advanced bone age in both sibs and bilateral hallux valgus in the girl. Array-CGH did not reveal any pathological CNV. Molecular analysis of FBN1, FBN2, TGFBR1, TGFBR2, and CHST14 gene was normal, and SNP linkage analysis excluded more candidate genes. Differential diagnoses and the possibility that we might be reporting on a hitherto unreported syndrome are discussed. PMID- 22489069 TI - Hydroxamic acids as potent inhibitors of Fe(II) and Mn(II) E. coli methionine aminopeptidase: biological activities and X-ray structures of oxazole hydroxamate EcMetAP-Mn complexes. AB - New series of acids and hydroxamic acids linked to five-membered heterocycles including furan, oxazole, 1,2,4- or 1,3,4-oxadiazole, and imidazole were synthesized and tested as inhibitors against the Fe(II) , Co(II) , and Mn(II) forms of E. coli methionine aminopeptidase (MetAP) and as antibacterial agents against wild-type and acrAB E. coli strains. 2-Aryloxazol-4-ylcarboxylic acids appeared as potent and selective inhibitors of the Co(II) MetAP form, with IC(50) values in the micromolar range, whereas 5-aryloxazol-2-ylcarboxylic acid regioisomers and 5-aryl-1,2,4-oxadiazol-3-ylcarboxylic acids were shown to be inefficient against all forms of EcMetAP. Regardless of the heterocycle, all the hydroxamic acids are highly potent inhibitors and are selective for the Mn(II) and Fe(II) forms, with IC(50) values between 1 and 2 MUM. One indole hydroxamic acid that we previously reported as a potent inhibitor of E. coli peptide deformylase also demonstrated efficiency against EcMetAP. To gain insight into the positioning of the oxazole heterocycle with reversed substitutions at positions 2 and 5, X-ray crystal structures of EcMetAP-Mn complexed with two such oxazole hydroxamic acids were solved. Irrespective of the [metal]/[apo-MetAP] ratio, the active site consistently contains a dinuclear manganese center, with the hydroxamate as bridging ligand. Asp 97, which adopts a bidentate binding mode to the Mn2 site in the holoenzyme, is twisted in both structures toward the hydroxamate bridging ligand to favor the formation of a strong hydrogen bond. Most of the compounds show weak antibacterial activity against a wild-type E. coli strain. However, increased antibacterial activity was observed mainly for compounds with a 2-substituted phenyl group in the presence of the nonapeptide polymyxin B and phenylalanine-arginine-beta-naphthylamide as permeabilizer and efflux pump blocker, respectively, which boost the intracellular uptake of the inhibitors. PMID- 22489070 TI - Synthesis, structure, and biocompatibility of pulsed laser-deposited TiN nanowires for implant applications. AB - A bottom-up based pulsed laser deposition technique has been used to grow titanium nitride (TiN) nanowires on single crystalline substrates. The first step of this method is the dissolution of laser ablated gaseous TiN material in the nanodimensional catalytic gold (Au) liquid islands located on the substrate surfaces. The continuous dissolution of TiN results in the supersaturation of liquid Au with TiN followed by extrusion of solid TiN material in the nanowire form at the liquid/solid interface. The growth of TiN nanowires continues as long as its dissolution rate into the catalyst Au matches the extrusion rate of solid TiN. This bottom-up approach gives rise to a one-dimensional TiN nanowire structures (length: 200-300 nm and diameter: 20-30 nm) capped with Au. The ascent of Au nanodots to the top of TiN nanowires can be explained based on breaking of weaker bonds and building of stronger bonds. The TiN nanowires are provided vertical alignment by selecting a plane of the substrate that provides the least lattice mismatching to the (111) plane of TiN which has lower surface energy than its other planes: (100) or (110). After the successful formation and structural characterization, a lactate dehydrogenase (LDH) release assay has been used to confirm the biocompatibility and cytotoxicity of these nanowires. PMID- 22489071 TI - Optical mechanical refinement of human amniotic membrane by dehydration and cross linking. AB - The aim of this study was to develop a method for refining the optical and mechanical properties of human amniotic membrane (AM) to provide ophthalmic transparent implants for use during severe donor cornea shortages. AM was allowed to gradually dehydrate at 4-8 degrees C with and without chemical cross-linking. To improve the transparency of AM, a simple dehydration process using a refrigerator at 4-8 degrees C overnight was examined. For further improvements, dehydrated AM was then cross-linked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxy-succimide before rehydration. Light transmittance and tensile strength of individual specimens were evaluated. Light transmittance of AM improved from 50.9-77.7% at 550 nm by this simple low temperature dehydration process. Its high light transmittance was partially maintained at 70.1%, even after rehydration with normal saline. Interestingly, chemically cross-linked AM showed a significantly greater light transmittance of 81.5% under wet conditions. In addition, tensile strength was significantly increased after cross-linking from 2.32 N/mm(2) (native tissue) to 11.78 N/mm(2) (cross-linked specimens). Light transmittance and tensile strength were successfully improved by these approaches, including low temperature dehydration with and without chemical cross linking. The use of refined AM could be feasible for use in current and future ophthalmic treatments. PMID- 22489072 TI - Development of a score to predict clinical deterioration in hospitalized children. AB - BACKGROUND: Identification of the characteristics that put hospitalized children at high risk of deterioration may help to target patients whose physiologic status should be intensively monitored for signs of deterioration, and reduce unnecessary monitoring in patients at very low risk. Previous studies have evaluated vital sign-based early warning scores to detect deterioration that has already begun. OBJECTIVE: To develop a predictive score for deterioration using non-vital sign patient characteristics in order to risk-stratify hospitalized children before signs of deterioration are detectable. DESIGN: Case-control study. SETTING: A 460-bed children's hospital. PATIENTS: Cases (n = 141) were children who deteriorated while receiving care on non-intensive care unit (non ICU) inpatient units. Controls (n = 423) were randomly selected. MEASUREMENTS: The exposures were complex chronic conditions, other patient characteristics, and laboratory studies. The outcome was clinical deterioration, defined as cardiopulmonary arrest, acute respiratory compromise, or urgent ICU transfer. RESULTS: The 7-item score included age <1 year, epilepsy, congenital/genetic conditions, history of transplant, enteral tube, hemoglobin <10 g/dL, and blood culture drawn in the preceding 72 hours. We grouped the patients into risk strata based on their scores. The very low-risk group's probability of deterioration was less than half of baseline risk. The high-risk group's probability of deterioration was more than 80-fold higher than the baseline risk. CONCLUSIONS: We identified a set of characteristics associated with clinical deterioration in children. Used in combination as a score, these characteristics may be useful in triaging the intensity of monitoring and surveillance for deterioration that children receive while hospitalized on non-ICU units. PMID- 22489074 TI - Identification of a selective, activity-based probe for glyceraldehyde 3 phosphate dehydrogenases. PMID- 22489073 TI - Correlates and predictors of disability in vulnerable US Hispanics with rheumatoid arthritis. AB - OBJECTIVE: US Hispanics with rheumatoid arthritis experience worse functional outcomes compared to whites. The determinants of disability, however, are not well established in large Hispanic cohorts. In the present report, we identified factors associated with disability in a cross-sectional design, and evaluated their individual contributions to disability over time. METHODS: Two hundred fifty-one Hispanic subjects from a single center were evaluated. Disease activity, serologies, radiographs, treatments, irreversible articular damage (defined as subluxation, arthrodesis, fusion, or prosthesis), and joint replacement surgeries were recorded. Self-reported disability (Health Assessment Questionnaire disability index), patient pain by a visual analog scale, and depression assessments were collected. Cross-sectional factors associated with disability were identified, and their effects on future disability were evaluated in a subgroup of 114 patients assessed 6 months later. RESULTS: Six parameters were independently related to disability cross-sectionally: pain was the strongest (P < 0.0001), followed by irreversible articular damage, disease activity, depression, age, and fibromyalgia (P < 0.03 for all). Baseline parameters predicting disability 6 months later included, in decreasing significance, irreversible articular damage (P = 0.004), depression, disease activity, age, and pain (all P < 0.04). CONCLUSION: In cross-sectional analysis, self-reported pain had the strongest relationship with disability; however, factors such as irreversible articular damage, depression, and disease activity were more important in predicting future disability. Most of these factors are amenable to targeted interventions and should be addressed in an effort to improve functional outcomes. PMID- 22489075 TI - Photoinduced deformation of crosslinked liquid-crystalline polymer film oriented by a highly aligned carbon nanotube sheet. PMID- 22489076 TI - The Society of Craniofacial Genetics and Developmental Biology 34th annual meeting. PMID- 22489078 TI - Suicidal ideation and thought disorder associated with the formoterol component of combined asthma medication. AB - Combination inhaled asthma medications containing corticosteroids and long-acting beta-adrenergic (LABA) agents are generally well tolerated, although a small minority of children receiving them may develop side-effects. Herein is reported a case of a 9-year-old boy who developed insomnia, pressured speech, agitation, and suicidal ideation within the 1st month after initiating formoterol + budesonide. He had not received oral glucocorticoids for >90 days. All symptoms resolved within 48 hr upon discontinuing formoterol while continuing budesonide. To our knowledge, this is the first report of childhood suicidal ideation strongly associated with use of a combination inhaled corticosteroid/LABA. PMID- 22489077 TI - Selective modification of the N-terminal structure of polytheonamide B significantly changes its cytotoxicity and activity as an ion channel. AB - Chemical point mutation: Polytheonamide B is a naturally occurring polypeptide containing 48 amino acids. It both displays potent cytotoxicity and acts as a monovalent cation channel in vitro. Chemoselective methods to modify the 44th, N , and C-terminal residues of the natural product have been developed, and evaluation of the resultant derivatives suggests that the intrinsic activities of the peptide can only be altered by switching its N-terminal substitution. PMID- 22489079 TI - Pathophysiology, impact, and management of hyponatremia. AB - Hyponatremia's effects can be insidious, particularly in patients with heart failure, cirrhosis, and pneumonia. Appreciating its prevalence in hospitalized patients, recognizing its symptoms, characterizing its etiology, and employing appropriate management promptly will help reduce morbidity and mortality among hyponatremic patients. PMID- 22489080 TI - Hyponatremia in pneumonia. AB - Hyponatremia is relatively common in patients admitted with pneumonia, and it is associated with higher disease severity. The precise mechanism is incompletely understood, but the syndrome of inappropriate antidiuretic hormone secretion is felt to play a significant role. Traditional options to manage hyponatremia in such patients are fraught with challenges. The recently approved vasopressin receptor antagonists offer a new option for the management of this challenging condition. PMID- 22489081 TI - Hyponatremia in cirrhosis. AB - Hyponatremia is common in patients with cirrhosis. Portal hypertension, diuretics, large volume paracentesis without albumin, infection, and multiple medications are connected with the development or worsening of hyponatremia. Hyponatremia in cirrhosis, particularly advanced cirrhosis, is a common development.(1) In a population survey of 997 patients with cirrhosis, 486 (49.4%) and 211 (21.6%) had a serum sodium concentration ([Na(+)]) <135 mEq/L and <= 130 mEq/L, respectively.(2) Hyponatremia and its severity correlate with the presence of severe complications of cirrhosis such as hepatorenal syndrome, encephalopathy, and spontaneous bacterial peritonitis. The presence of hyponatremia frequently complicates the management of the cirrhotic patient. PMID- 22489082 TI - Clinical challenge of hyponatremia in heart failure. AB - Hyponatremia is a significant and independent predictor of outcomes including rehospitalization and mortality in patients with both acute decompensated heart failure (HF) and chronic HF. Even modest degrees of hyponatremia are associated with a poorer prognosis. Treatment options include fluid restriction and the vaptan class ("aquaretics") in select patients. PMID- 22489083 TI - Detailed analysis of the energy barriers for amyloid fibril growth. PMID- 22489084 TI - An ultrasensitive fluorescent sensing nanofilm for organic amines based on cholesterol-modified perylene bisimide. AB - A stable, ultrasensitive, and fully reversible fluorescent sensing film for organic amines has been fabricated by assembling cholesterol (Chol)-derived perylene bisimide on a glass plate surface. The compound exhibits excellent film formation properties and forms well-defined nanofibers, as evidenced by SEM and AFM measurements. It has been revealed that besides the molecular structure of the specially designed perylene derivative, the existence of nanofibers in the film is another key factor to endow the film with superior sensing ability for organic amines, including aniline. The detection limit of the amine is ca. 150.0 ppt in the vapor phase and at room temperature. Furthermore, the sensing process is free of interference from common organic solvents, nitroaromatics, and particularly phenols, which makes the film a potential candidate to be used in lung cancer diagnoses and related applications. PMID- 22489085 TI - Intratracheal budesonide supplementation in addition to surfactant improves pulmonary outcome in surfactant-depleted newborn piglets. AB - Severe respiratory distress syndrome (RDS) is still a major cause of mortality and morbidity in premature infants. The combined use of intratracheal corticosteroid and surfactant in severe RDS, which bypasses the systemic circulation, may not only help recruit the lungs but also alleviates pulmonary inflammation without an increase in systemic adverse effects. Twelve newborn piglets received repeated pulmonary saline lavage to create surfactant-depleted lungs that mimic neonatal RDS, and then were randomly grouped into a control group (standard intratracheal instillation of surfactant-Survanta 100 mg/kg); and a budesonide (Bude) group (intratracheal instillation with the mixed suspension of Budesonide 0.25 mg/kg and Survanta 100 mg/kg). Blood samples were examined, and the observation period was 24 hr. The results showed that oxygenation was significantly better in Bude group compared to the control group over time (P = 0.016). The proinflammatory cytokines tumor necrosis factor-alpha and interleukin 1 beta showed a reduced trend in the Bude group, but was not significantly different from the control group (P > 0.05). Comparing the histological lung injury scores, the Bude group had a significantly lower score than the control group at both dependent and non-dependent sites (P < 0.05). In conclusion, in piglets with severe RDS, intratracheal instillation of budesonide in addition to surfactant seems to results in a sustained improvement in pulmonary outcome over 24 hr. PMID- 22489087 TI - Strong metallophilic interactions in the palladium arylation by gold aryls. AB - It's the second step that counts: arylation of Pd by Au takes place through transition states and intermediates featuring strong Au???Pd metallophilic interactions. However, the aryl transfer from [AuArL] to [PdArClL(2)] is thermodynamically disfavored and will not occur unless an irreversible Ar-Ar coupling from [PdAr(2)L(2)] follows. PMID- 22489088 TI - Pregnancy after liver transplantation. PMID- 22489086 TI - The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation. AB - The bone morphogenetic proteins (BMPs) are a group of powerful morphogens that are critical for development of the nervous system. The effects of BMP signaling on neural stem cells are myriad and dynamic, changing with each stage of development. During early development inhibition of BMP signaling differentiates neuroectoderm from ectoderm, and BMP signaling helps to specify neural crest. Thus modulation of BMP signaling underlies formation of both the central and peripheral nervous systems. BMPs secreted from dorsal structures then form a gradient which helps pattern the dorsal-ventral axis of the developing spinal cord and brain. During forebrain development BMPs sequentially induce neurogenesis and then astrogliogenesis and participate in neurite outgrowth from immature neurons. BMP signaling also plays a critical role in maintaining adult neural stem cell niches in the subventricular zone (SVZ) and subgranular zone (SGZ). BMPs are able to exert such diverse effects through closely regulated temporospatial expression and interaction with other signaling pathways. PMID- 22489089 TI - Extending the aminocatalytic HOMO-raising activation strategy: where is the limit? PMID- 22489091 TI - Knolker's iron complex: an efficient in situ generated catalyst for reductive amination of alkyl aldehydes and amines. AB - An aminated series: a well-defined iron-catalyzed reductive amination reaction of aldehydes and ketones with aliphatic amines using molecular hydrogen is presented. Under mild conditions, good yields for a broad range of alkyl ketones as well as aldehydes were achieved. PMID- 22489092 TI - Structural and electronic properties of endohedral metallofullerenes. AB - This account presents an overview of our achievements in structural and chemical understanding of endohedral metallofullerenes (EMFs), a new class of metal-carbon hybrid materials formed by encapsulation of metals inside fullerene cavities. Structural determination of EMFs is of fundamental importance for understanding their intrinsic properties and the formation mechanism, and for broadening their applications. We have developed an effective method for determining the structures of paramagnetic EMFs, and also succeeded in observing the motion of cluster in a di-metal EMF for the first time. Recently, we unambiguously established the structures of some carbide EMFs which had been wrongly assumed as conventional EMFs previously. More importantly, we have obtained some insoluble EMF species which had never been explored or even expected before. Meanwhile, the chemical properties of various EMFs with different cage structures or different metallic cores have been systematically investigated by means of both covalent and supramolecular considerations, yielding many fascinating results relating to the dictating effect of internal metals. It is noteworthy that all these achievements are based on unambiguous X-ray results of pristine or functionalized EMFs. PMID- 22489093 TI - Structure and reactivity of a hafnocene MU-nitrido prepared from dinitrogen cleavage. PMID- 22489094 TI - Total synthesis of (-)-13-oxyingenol and its natural derivative. AB - Ring functionalization: the total synthesis of a natural derivative of (-)-13 oxyingenol, a potent anti-HIV diterpenoid, is reported. The key steps in this synthesis include a ring-closing olefin metathesis and a Mislow-Evans-type [2,3] sigmatropic rearrangement. This synthesis provides access to (-)-13-oxyingenol and its natural derivative in 21 steps from a synthetic intermediate previously prepared by Kigoshi and co-workers. PMID- 22489095 TI - Synthesis of macroheterocycles through intramolecular oxidative coupling of furanoid beta-ketoesters. PMID- 22489097 TI - Biomimetic total synthesis of (+)-gelsemine. AB - Challenging: (+)-gelsemine was synthesized from (R,R)-aziridine 1 in 25 steps with approximately 1 % overall yield. A multistep, one-pot enol-oxonium cyclization cascade was used to construct, simultaneously, the E ring, F ring, C3 stereocenter, and C7 quaternary stereocenter. This synthesis using the enol oxonium cyclization reaction as a key step to make the cage structure has demonstrated the proposed biosynthetic pathway of the gelsemine family. PMID- 22489096 TI - An N-heterocyclic carbene/Lewis acid strategy for the stereoselective synthesis of spirooxindole lactones. AB - A cooperative catalysis approach for the enantioselective formal [3+2] addition of alpha,beta-unsaturated aldehydes to isatins has been developed. Homoenolate annulations of beta-aryl enals catalyzed by an N-heterocyclic carbene (NHC) require the addition of lithium chloride for high levels of enantioselectivity. This NHC-catalyzed annulation has been used for the total synthesis of maremycin B. PMID- 22489098 TI - 6'-Oxa Analogs of S-Adenosylhomocysteine. AB - S-Adenosylmethionine (AdoMet) is a ubiquitous cofactor in biomethylations and, in that role, becomes S-adenosylhomocysteine (AdoHcy), which serves as a biofeedback inhibitor of the methylation process. In seeking to avail unexplored structural variations of AdoHcy for biological studies, its 6'-oxa analog and two corresponding carbocyclic nucleosides (based on aristeromycin and neplanocin) have been prepared via common convergent syntheses. PMID- 22489099 TI - Interaction of protein phosphatase 1delta with nucleophosmin in human osteoblastic cells. AB - Protein phosphorylation and dephosphorylation has been recognized as an essential mechanism in the regulation of cellular metabolism and function in various tissues. Serine and threonine protein phosphatases (PP) are divided into four categories: PP1, PP2A, PP2B, and PP2C. At least four isoforms of PP1 catalytic subunit in rat, PP1alpha, PP1gamma1, PP1gamma2, and PP1delta, were isolated. In the present study, we examined the localization and expression of PP1delta in human osteoblastic Saos-2 cells. Anti-PP1delta antibody recognized a protein present in the nucleolar regions in Saos-2 cells. Cellular fractionation revealed that PP1delta is a 37 kDa protein localized in the nucleolus. Nucleophosmin is a nucleolar phosphoprotein and located mainly in the nucleolus. Staining pattern of nucleophosmin in Saos-2 cells was similar to that of PP1delta. PP1delta and nucleophosmin were specifically stained as dots in the nucleus. Dual fluorescence images revealed that PP1delta and nucleophosmin were localized in the same regions in the nucleolus. Similar distribution patterns of PP1delta and nucleophosmin were observed in osteoblastic MG63 cells. The interaction of PP1delta and nucleophosmin was also shown by immunoprecipitation and Western analysis. These results indicated that PP1delta associate with nucleophosmin directly in the nucleolus and suggested that nucleophosmin is one of the candidate substrate for PP1delta. PMID- 22489100 TI - Immunohistochemical Characterization of S100A6 in the Murine Ovary. AB - S100 proteins comprise a large family of Ca(2+)-binding proteins and exhibit a variety of intra- and extracellular functions. Despite our growing knowledge about the biology of S100 proteins in some tissues such as brain and smooth muscle, little is known about S100 proteins in the normal mammalian reproductive tissue. In the present study, we investigated the distribution pattern of S100A6 (alternatively named calcyclin) in the murine ovary by immunohistochemical study using specific antibody. S100A6 was localized substantially in the cytoplasm of luteal cells, with concomitant expression of S100A11, another S100 protein, but not in the other type of cells such as oocytes, follicle epithelial cells (granulosa cells), and cells of stroma including theca interna cells in the murine ovary. S100A6-immunoreactive corpora lutea (CLs) were divided into two types: homogeneously and heterogeneously stained CLs, and possibly they may represent differentiating and mature CL, respectively. Our regression analysis revealed that expression level of S100A6 positively correlated with that of cytochrome P450 11A, a steroidogenic enzyme in the heterogeously stained CL. These results suggested that S100A6 may contribute to differentiation of steroidogenic activity of luteal cells in a synergistic manner with S100A11 by facilitating some shared functions. PMID- 22489101 TI - Expression and Localization of TRK-Fused Gene Products in the Rat Brain and Retina. AB - The TRK-fused gene (TFG in human, Tfg in rat) was originally identified in human papillary thyroid cancer as a chimeric form of the NTRK1 gene. It has been reported that the gene product (TFG) plays a role in regulating phosphotyrosine specific phosphatase-1 activity. However, no information regarding the localization of Tfg in rat tissues is available. In this study, we investigated the expression of Tfg mRNA in normal rat tissues using reverse transcription polymerase chain reaction (RT-PCR). We also produced an antibody against Tfg gene products and examined the localization of TFG in the rat brain and retina. The RT PCR experiments demonstrated that two types of Tfg mRNA were expressed in rat tissues: the conventional form of Tfg (cTfg) and a novel variant form, retinal Tfg (rTfg). RT-PCR analyses demonstrated that cTfg was ubiquitously expressed in rat tissues, while rTfg was predominantly expressed in the brain and retina. Western blot analysis demonstrated two bands with molecular weights of about 30 kDa and 50 kDa in the rat brain. Immunohistochemistry indicated that TFG proteins were predominantly expressed by neurons in the brain. In the rat retina, intense TFG-immunoreactivity was detected in the layer of rods and cones and the outer plexiform layer. PMID- 22489102 TI - Significant Correlation between Chromosomal Aberration and Nuclear Morphology in Urothelial Carcinoma. AB - We aimed to identify whether there is any correlation between chromosomal/genetic changes, nuclear morphology and the histological grade of urothelial carcinomas of the urinary bladder. Morphometry and multicolour fluorescence in situ hybridisation (FISH) techniques were applied to 250 cells in five low-grade cases and 350 cells in seven high-grade cases of urothelial carcinoma. Compared with low-grade carcinomas, most high-grade cases showed larger and more variable nuclear size, more frequent polysomy of centromere enumeration probes (CEPs) 3, 7 and 17, and the loss of the 9p21 locus. The number of CEP signals in cells was increased as the nuclear area of the cells became larger. Cells with gains in two or more types of CEP had significantly larger nuclei than cells with normal FISH signal patterns. In conclusion, the present study indicates that there was a correlation between nuclear morphology and chromosomal/genetic changes which were related to histological grading. Thus, we show that differences in the chromosomal/genetic aberrations present in low- and high-grade tumours can affect not only nuclear morphology but also the histopathological and clinical behaviour of urothelial carcinomas. PMID- 22489103 TI - Synaptic Pattern of KA1 and KA2 upon the Direction-Selective Ganglion Cells in Developing and Adult Mouse Retina. AB - The detection of image motion is important to vision. Direction-selective retinal ganglion cells (DS-RGCs) respond strongly to stimuli moving in one direction of motion and are strongly inhibited by stimuli moving in the opposite direction. In this article, we investigated the distributions of kainate glutamate receptor subtypes KA1 and KA2 on the dendritic arbors of DS-RGCs in developing (5, 10) days postnatal (PN) and adult mouse retina to search for anisotropies. The distribution of kainate receptor subtypes on the DS-RGCs was determined using antibody immunocytochemistry. To identify their characteristic morphology, DS RGCs were injected with Lucifer yellow. The triple-labeled images of dendrites, kinesin II, and receptors were visualized by confocal microscopy and were reconstructed from high-resolution confocal images. We found no evidence of asymmetry in any of the kainate receptor subunits examined on the dendritic arbors of both the On and Off layers of DS-RGCs in all periods of developing and adult stage that would predict direction selectivity. PMID- 22489104 TI - Compensatory upregulation of myelin protein zero-like 2 expression in spermatogenic cells in cell adhesion molecule-1-deficient mice. AB - The cell adhesion molecule-1 (Cadm1) is a member of the immunoglobulin superfamily. In the mouse testis, Cadm1 is expressed in the earlier spermatogenic cells up to early pachytene spermatocytes and also in elongated spermatids, but not in Sertoli cells. Cadm1-deficient mice have male infertility due to defective spermatogenesis, in which detachment of spermatids is prominent while spermatocytes appear intact. To elucidate the molecular mechanisms of the impaired spermatogenesis caused by Cadm1 deficiency, we performed DNA microarray analysis of global gene expression in the testis compared between Cadm1-deficient and wild-type mice. Out of the 25 genes upregulated in Cadm1-deficient mice, we took a special interest in myelin protein zero-like 2 (Mpzl2), another cell adhesion molecule of the immunoglobulin superfamily. The levels of Mpzl2 mRNA increased by 20-fold and those of Mpzl2 protein increased by 2-fold in the testis of Cadm1-deficient mice, as analyzed with quantitative PCR and western blotting, respectively. In situ hybridization and immunohistochemistry demonstrated that Mpzl2 mRNA and protein are localized in the earlier spermatogenic cells but not in elongated spermatids or Sertoli cells, in both wild-type and Cadm1-deficient mice. These results suggested that Mpzl2 can compensate for the deficiency of Cadm1 in the earlier spermatogenic cells. PMID- 22489105 TI - Immunohistochemical Mapping of TRK-Fused Gene Products in the Rat Brainstem. AB - The TRK-fused gene (TFG in human, Tfg in rat) was originally identified in human papillary thyroid cancer as a chimeric form of the NTRK1 gene. It was since reported that the gene product (TFG) plays a role in regulating phosphotyrosine specific phosphatase-1 activity. As shown in the accompanying paper, we produced an antibody to rat TFG and used it to localize TFG to selected neurons in specific regions. In the present study, we mapped the TFG-positive neurons in the brainstem, cerebellum, and spinal cord of rats. In the brainstem, neurons intensely positive for TFG were distributed in the raphe nuclei, the gigantocellular reticular nucleus, the reticulotegmental nucleus of the pons, and some cranial nerve nuclei such as the trigeminal nuclei, the vestibulocochlear nuclei, and the dorsal motor nucleus of the vagus. Purkinje cells in the cerebellum and motor neurons in the spinal anterior horn were also positive for TFG. These results provide fundamental data for studying the functions of TFG in the brain. PMID- 22489106 TI - Temporal and Spatial Cellular Distribution of Neural Crest Derivatives and Alpha Cells during Islet Development. AB - Recent studies have revealed that signals from neural crest (NC) derivatives regulate the mass, proliferation, and maturation of beta cells in developing fetal pancreas. However, little is known about the cellular distribution of NC derivatives during pancreatic development or the process whereby the developing islets are enclosed. We studied the temporal and spatial distribution of NC derivatives and endocrine cells at each developmental stage. At embryonic day 10.5 (E10.5) of mouse embryo, NC derivatives that migrated to the prospective pancreatic region were distributed in close proximity to pancreatic epithelial cells. As development advanced, most NC derivatives progressively surrounded endocrine rather than exocrine cells, and were distributed in closer proximity to alpha cells rather than to beta cells. At E20, approximately 70% of the NC derivatives enclosing endocrine cells were distributed in close proximity to alpha cells. Moreover, the expression of SynCAM, a Ca(2+)-independent homophilic trans-cell adhesion molecule, was confirmed from E16.5 on and was more remarkable at the cell boundaries of alpha cells and NC derivatives. These findings suggest that NC derivatives might be distributed in close proximity to alpha cells as a result of homophilic binding of SynCAM expressed by alpha cells and NC derivatives during islet development. PMID- 22489107 TI - Gene suppression of mouse testis in vivo using small interfering RNA derived from plasmid vectors. AB - We evaluated whether inhibiting gene expression by small interfering RNA (siRNA) can be used for an in vivo model using a germ cell-specific gene (Tex101) as a model target in mouse testis. We generated plasmid-based expression vectors of siRNA targeting the Tex101 gene and transfected them into postnatal day 10 mouse testes by in vivo electroporation. After optimizing the electroporation conditions using a vector transfected into the mouse testis, a combination of high- and low-voltage pulses showed excellent transfection efficiency for the vectors with minimal tissue damage, but gene suppression was transient. Gene suppression by in vivo electroporation may be helpful as an alternative approach when designing experiments to unravel the basic role of testicular molecules. PMID- 22489108 TI - Fetuin A concentration in the second trimester amniotic fluid of fetuses with trisomy 21 appears to be lower: phenotypic considerations. AB - OBJECTIVE: We investigated whether the concentration of the glycoprotein fetuin A is altered in the second trimester amniotic fluid of trisomy 21 pregnancies compared with euploid pregnancies. METHODS: 25 pregnancies with an extra chromosome 21 were matched for maternal and gestational age with 25 pregnancies with normal karyotype. Levels of fetuin A in amniotic fluid were measured by a commercially available enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: The median concentration of fetuin A in amniotic fluid of trisomy 21 pregnancies (5.3 ng/ml) was statistically significantly lower (P value = 0.008) compared with that in euploid pregnancies (6.8 ng/mL). CONCLUSION: Lower levels of fetuin A in trisomy 21 may indicate an association with altered metabolic pathways in this early stage that could potentially be associated with features of the syndrome, such as growth restriction or impaired osteogenesis. PMID- 22489109 TI - Comparison of culture and molecular identification of bacteria in chronic wounds. AB - Clinical diagnostics of chronic polymicrobial infections, such as those found in chronic wounds, represent a diagnostic challenge for both culture and molecular methods. In the current retrospective study, the results of aerobic bacterial cultures and culture-free bacterial identification using DNA analyses were compared. A total of 168 chronic wounds were studied. The majority of bacteria identified with culture testing were also identified with molecular testing, but the majority of bacteria identified with the molecular testing were not identified with culture testing. Seventeen (17) different bacterial taxa were identified with culture, and 338 different bacterial taxa were identified with molecular testing. This study demonstrates the increased sensitivity that molecular microbial identification can have over culture methodologies, and previous studies suggest that molecular bacterial identification can improve the clinical outcomes of patients with chronic wounds. PMID- 22489110 TI - Primary study for the therapeutic dose and time window of picroside II in treating cerebral ischemic injury in rats. AB - The aim of this study was to explore the optimal therapeutic dose and time window of picroside II for treating cerebral ischemic injury in rats according to the orthogonal test. The middle cerebral artery occlusion (MCAO) models were established by intraluminally inserting a thread into middle cerebral artery (MCA) from left external carotid artery (ECA). The successful rat models were randomly divided into 16 groups according to the orthogonal layout of [L(16)(4(5))] and treated by injecting picroside II intraperitoneally with different doses at various times. The neurological behavioral function was evaluated by Bederson's test and the cerebral infarction volume was measured by tetrazolium chloride (TTC) staining. The expressions of neuron specific enolase (NSE) and neuroglial mark-protein S-100 were determined by immunohistochemisty assay. The results indicated that the optimal compositions of the therapeutic dose and time window of picroside II in treating cerebral ischemic injury were ischemia 1.5 h with 20 mg/kg body weight according to Bederson's test, 1.0 h with 20 mg/kg body weight according to cerebral infarction volume, 1.5 h with 20 mg/kg body weight according to the expressions of NSE and S-100 respectively. Based on the principle of the minimization of medication dose and maximization of therapeutic time window, the optimal composition of the therapeutic dose and time window of picroside II in treating cerebral ischemic injury should be achieved by injecting picroside II intraperitoneally with 20 mg/kg body weight at ischemia 1.5 h. PMID- 22489111 TI - Isolation and identification of cellulolytic bacteria from the gut of Holotrichia parallela larvae (Coleoptera: Scarabaeidae). AB - In this study, 207 strains of aerobic and facultatively anaerobic cellulolytic bacteria were isolated from the gut of Holotrichia parallela larvae. These bacterial isolates were assigned to 21 genotypes by amplified ribosomal DNA restriction analysis (ARDRA). A partial 16S rDNA sequence analysis and standard biochemical and physiological tests were used for the assignment of the 21 representative isolates. Our results show that the cellulolytic bacterial community is dominated by the Proteobacteria (70.05%), followed by the Actinobacteria (24.15%), the Firmicutes (4.35%), and the Bacteroidetes (1.45%). At the genus level, Gram-negative bacteria including Pseudomonas, Ochrobactrum, Rhizobium, Cellulosimicrobium, and Microbacterium were the predominant groups, but members of Bacillus, Dyadobacter, Siphonobacter, Paracoccus, Kaistia, Devosia, Labrys, Ensifer, Variovorax, Shinella, Citrobacter, and Stenotrophomonas were also found. Furthermore, our results suggest that a significant amount of bacterial diversity exists among the cellulolytic bacteria, and that Siphonobacter aquaeclarae, Cellulosimicrobium funkei, Paracoccus sulfuroxidans, Ochrobactrum cytisi, Ochrobactrum haematophilum, Kaistia adipata, Devosia riboflavina, Labrys neptuniae, Ensifer adhaerens, Shinella zoogloeoides, Citrobacter freundii, and Pseudomonas nitroreducens are reported to be cellulolytic for the first time in this study. Our results indicate that the scarab gut is an attractive source for the study of novel cellulolytic microorganisms and enzymes useful for cellulose degradation. PMID- 22489112 TI - Inhibitory action of antidepressants on mouse Betaine/GABA transporter (BGT1) heterologously expressed in cell cultures. AB - Betaine/gamma-aminobutyric acid (GABA) transporter (BGT1, SLC6A12) is a member of the Na(+)- and Cl(-)-dependent neurotransmitter transporter gene family with a homology to the GABA transporters (GATs), GAT1 (SLC6A1), GAT2 (SLC6A13) and GAT3 (SLC6A11) (HUGO nomenclature). Since antidepressants have been reported to inhibit GABA uptake, we examined those effects on mouse BGT1 (mBGT1) in comparison with other mouse GAT (mGAT) subtypes in the heterologously expressed cell cultures. All antidepressants tested here inhibited the [(3)H]GABA uptake through mBGT1 and mGATs in a rank order of potency with mBGT1 > mGAT1-3. Kinetic analyses for maprotilline, mianserine and trimipramine revealed that they inhibited mBGT1 and mGAT1 noncompetitively, except that mianserine competitively inhibited mBGT1. These results provided a clue to investigate the structure function relationship of mBGT1 using antidepressants as a tool, leading to the identification of potential candidates for selective and specific inhibitors of mBGT1. PMID- 22489113 TI - Highly regio- and stereoselective Diels-Alder cycloadditions via two-step and multicomponent reactions promoted by infrared irradiation under solvent-free conditions. AB - Infrared irradiation promoted the Diels-Alder cycloadditions of exo-2 oxazolidinone dienes 1-3 with the Knoevenagel adducts 4-6, as dienophiles, leading to the synthesis of new 3,5-diphenyltetrahydrobenzo[d]oxazol-2-one derivatives (7, 9, 11 and 13-17), under solvent-free conditions. These cycloadditions were performed with good regio- and stereoselectivity, favoring the para-endo cycloadducts. We also evaluated the one-pot three-component reaction of active methylene compounds 20, benzaldehydes 21 and exo-2 oxazolidinone diene 2 under the same reaction conditions. A cascade Knoevenagel condensation/Diels-Alder cycloaddition reaction was observed, resulting in the final adducts 13-16 in similar yields. These procedures are environmentally benign, because no solvent and no catalyst were employed in these processes. The regioselectivity of these reactions was rationalized by Frontier Molecular Orbital (FMO) calculations. PMID- 22489114 TI - Phage display approaches for the isolation of monoclonal antibodies against dengue virus envelope domain III from human and mouse derived libraries. AB - Domain III of the dengue virus envelope protein (EDIII, aa295-395) has an immunoglobulin fold and is the proposed receptor-binding domain of the virus. Previous studies have shown that monoclonal antibodies against EDIII can be neutralizing and have therapeutic potential. Here, cloned Fab-phage libraries of human and mouse origin were screened for DENV specific antibodies. Firstly, bacterially expressed EDIII or whole virus particles were used as bait in biopanning against a large naive human Fab-phage library (>10 billion independent clones). Multiple panning strategies were employed, and in excess of 1000 clones were screened, but all of the antibodies identified bound the envelope in regions outside EDIII suggesting EDIII antibodies are virtually absent from the naive human repertoire. Next, a chimeric Fab-phage library was constructed from a panel of EDIII specific mouse hybridomas by pooling the VH and VL chain sequences from the hybridomas and cloning these into the pComb3X phagemid vector with human CH and CL encoding sequences. Biopanning against EDIII identified a unique antibody (C9) that cross-reacts with EDIII from DENV1-3 and, in the IgG format, binds and neutralizes DENV2 in cell-based assays. Sequence analysis and saturation mutagenesis of complementary determining regions (CDR) in the C9 light chain suggest an antigen recognition model in which the LCDR3 is a key determinant of EDIII specificity, while modifications in LCDR1 and LCDR2 affect DENV serotype cross-reactivity. Overall, this study supports the current prevailing opinion that neutralizing anti-EDIII monoclonal antibodies can be readily generated in murine systems, but in humans the anti-DENV immune response is directed away from domain III. PMID- 22489115 TI - Role of SDF1/CXCR4 interaction in experimental hemiplegic models with neural cell transplantation. AB - Much attention has been focused on neural cell transplantation because of its promising clinical applications. We have reported that embryonic stem (ES) cell derived neural stem/progenitor cell transplantation significantly improved motor functions in a hemiplegic mouse model. It is important to understand the molecular mechanisms governing neural regeneration of the damaged motor cortex after the transplantation. Recent investigations disclosed that chemokines participated in the regulation of migration and maturation of neural cell grafts. In this review, we summarize the involvement of inflammatory chemokines including stromal cell derived factor 1 (SDF1) in neural regeneration after ES cell derived neural stem/progenitor cell transplantation in mouse stroke models. PMID- 22489116 TI - Increased activity of cell surface peptidases in HeLa cells undergoing UV-induced apoptosis is not mediated by caspase 3. AB - We have previously shown that in HeLa cells treated with a variety of agents there is an increase in cell surface peptidase (CSP) activity in those cells undergoing apoptosis. The increase in CSP activity observed in UVB-irradiated cells undergoing apoptosis was unaffected when the cultures were treated with the aminopeptidase inhibitor bestatin, and matrix metalloprotease inhibitor BB3103, but greatly enhanced when treated with the caspase 3 inhibitor-DEVD, and reduced in the presence of the poly(ADP-ribose) polymerase (PARP) inhibitor-3 aminobenzamide (3AB). Neither 3AB nor DEVD had an effect on the gross morphology of the apoptotic cells observed under electron microscopy, nor did they have an effect on phosphatidylserine eversion on the cell membrane, or that of PARP cleavage. All the agents except for DEVD had no effect on the level of caspase 3 activity in the cells. The results suggest that other caspases may cleave PARP in these cells. Both 3AB and DEVD treatment reduced the level of actin cleavage seen in the apoptotic cells. The increase in CSP activity observed in cells undergoing UVB-induced apoptosis appears to involve PARP but not caspase 3. PMID- 22489117 TI - Sequence analysis and potentials of the native RbcS promoter in the development of an alternative eukaryotic expression system using green Microalga Ankistrodesmus convolutus. AB - The availability of highly active homologous promoters is critical in the development of a transformation system and improvement of the transformation efficiency. To facilitate transformation of green microalga Ankistrodesmus convolutus which is considered as a potential candidate for many biotechnological applications, a highly-expressed native promoter sequence of ribulose-1,5 bisphosphate carboxylase/oxygenase small subunit (AcRbcS) has been used to drive the expression of beta-glucuronidase (gusA) gene in this microalga. Besides the determination of the transcription start site by 5'-RACE, sequence analysis revealed that AcRbcS promoter contained consensus TATA-box and several putative cis-acting elements, including some representative light-regulatory elements (e.g., G-box, Sp1 motif and SORLIP2), which confer light responsiveness in plants, and several potential conserved motifs (e.g., CAGAC-motif, YCCYTGG-motifs and CACCACA-motif), which may be involved in light responsiveness of RbcS gene in green microalgae. Using AcRbcS promoter::gusA translational fusion, it was demonstrated that this promoter could function as a light-regulated promoter in transgenic A. convolutus, which suggested that the isolated AcRbcS promoter was a full and active promoter sequence that contained all cis-elements required for developmental and light-mediated control of gene expression, and this promoter can be used to drive the expression of heterologous genes in A. convolutus. This achievement therefore advances the development of A. convolutus as an alternative expression system for the production of recombinant proteins. This is the first report on development of gene manipulation system for unicellular green alga A. convolutus. PMID- 22489119 TI - Major phenolic compounds, antioxidant capacity and antidiabetic potential of rice bean (Vigna umbellata L.) in China. AB - Interest in edible beans as nutraceuticals is increasing. In the present study, the individual phenolic acids, the total phenolic content (TPC), the total flavonoid content (TFC), and the antioxidant and antidiabetic potential of 13 varieties of rice beans from China were investigated. Eight phenolic compounds (catechin, epicatechin, p-coumaric acid, ferulic acid, vitexin, isovitexin, sinapic acid, quercetin) were analyzed on an ultra-performance liquid chromatography (UPLC) mass spectrometry (MS) system. The rice bean varieties had significant differences in total phenolic compounds (ranging from 123.09 +/- 10.35 to 843.75 +/- 30.15 MUg/g), in TPC (ranging from 3.27 +/- 0.04 to 6.43 +/- 0.25 mg gallic acid equivalents (GAE)/g), in TFC (ranging from 55.95 +/- 11.16 to 320.39 +/- 31.77 mg catechin (CE)/g), in antioxidant activity (ranging from 39.87 +/- 1.37 to 46.40 +/- 2.18 MUM.TE/g), in alpha-glucosidase inhibition activity (ranging from 44.32 +/- 2.12 to 68.71 +/- 2.19) and in advanced glycation end products formation inhibition activity (ranging from 34.11 +/- 0.59 to 75.75 +/- 0.33). This study is the first report on phytochemistry and biological activities in rice beans. PMID- 22489120 TI - Molecular mechanisms of (R,R)ZX-5 on NO synthesis and its anti-angiogenic effect. AB - (R,R)ZX-5 is a NO regulatory compound, which could significantly increase choroidal blood flow in New Zealand rabbit. The aim of this paper is to investigate the molecular mechanism of (R,R)ZX-5 promoting NO production. Besides this, we also investigated the antiangiogenic activity of (R,R)ZX-5. Analysis of Western blot showed that (R,R)ZX-5 up-regulated the expression of Akt, p-Akt (Thr473), eNOS and p-eNOS (Ser1177), down-regulated the expression of Cyclin D1 in human retinal endothelial cells and escalated the intracellular free Ca(2+) concentration. Additionally, (R,R)ZX-5 inhibited the growth of blood vessels in the chick chorioallantoic membrane model. It is concluded that (R,R)ZX-5 promotes choroidal blood flow through PI3K/Akt-eNOS and Akt-Ca(2+)-eNOS pathways. Additionally, (R,R)ZX-5 can inhibit angiogenesis. PMID- 22489121 TI - Synthesis and characterization of privileged monodentate phosphoramidite ligands and chiral Bronsted acids derived from d-mannitol. AB - The synthesis of several novel chiral phosphoramidite ligands (L1-L8) with C(2) symmetric, pseudo C(2) symmetric secondary amines and chiral Bronsted acids 1a,b has been achieved. These chiral auxiliaries were obtained from commercially available d-mannitol, and secondary amines in moderate to excellent yields. Excellent diastereoselectivites of ten chiral auxiliaries were obtained. The chiral phosphoramidite ligands and chiral Bronsted acids were fully characterized by spectroscopic methods. PMID- 22489122 TI - Genome-wide analysis of a TaLEA-introduced transgenic Populus simonii * Populus nigra dwarf mutant. AB - A dwarf mutant (dwf1) was obtained among 15 transgenic lines, when TaLEA (Tamarix androssowii late embryogenesis abundant gene) was introduced into Populus simonii * Populus nigra by Agrobacterium tumefaciens-mediated transformation. Under the same growth conditions, dwf1 height was significantly reduced compared with the wild type and the other transgenic lines. Because only one transgenic line (dwf1) displayed the dwarf phenotype, we considered that T-DNA insertion sites may play a role in the mutant formation. The mechanisms underlying this effect were investigated using TAIL-PCR (thermal asymmetric interlaced PCR) and microarrays methods. According to the TAIL-PCR results, two flanking sequences located on chromosome IV and VIII respectively, were cloned. The results indicated the integration of two independent T-DNA copies. We searched for the potential genes near to the T-DNA insertions. The nearest gene was a putative poplar AP2 transcription factor (GI: 224073210). Expression analysis showed that AP2 was up regulated in dwf1 compared with the wild type and the other transgenic lines. According to the microarrays results, a total of 537 genes involved in hydrolase, kinase and transcription factor activities, as well as protein and nucleotide binding, showed significant alterations in gene expression. These genes were expressed in more than 60 metabolic pathways, including starch, sucrose, galactose and glycerolipid metabolism and phenylpropanoids and flavonoid biosyntheses. Our transcriptome and T-DNA insertion sites analyses might provide some useful insights into the dwarf mutant formation. PMID- 22489118 TI - Flavonoid biosynthesis genes putatively identified in the aromatic plant Polygonum minus via Expressed Sequences Tag (EST) analysis. AB - P. minus is an aromatic plant, the leaf of which is widely used as a food additive and in the perfume industry. The leaf also accumulates secondary metabolites that act as active ingredients such as flavonoid. Due to limited genomic and transcriptomic data, the biosynthetic pathway of flavonoids is currently unclear. Identification of candidate genes involved in the flavonoid biosynthetic pathway will significantly contribute to understanding the biosynthesis of active compounds. We have constructed a standard cDNA library from P. minus leaves, and two normalized full-length enriched cDNA libraries were constructed from stem and root organs in order to create a gene resource for the biosynthesis of secondary metabolites, especially flavonoid biosynthesis. Thus, large-scale sequencing of P. minus cDNA libraries identified 4196 expressed sequences tags (ESTs) which were deposited in dbEST in the National Center of Biotechnology Information (NCBI). From the three constructed cDNA libraries, 11 ESTs encoding seven genes were mapped to the flavonoid biosynthetic pathway. Finally, three flavonoid biosynthetic pathway-related ESTs chalcone synthase, CHS (JG745304), flavonol synthase, FLS (JG705819) and leucoanthocyanidin dioxygenase, LDOX (JG745247) were selected for further examination by quantitative RT-PCR (qRT PCR) in different P. minus organs. Expression was detected in leaf, stem and root. Gene expression studies have been initiated in order to better understand the underlying physiological processes. PMID- 22489123 TI - Isolation and characterization of polymorphic microsatellite loci from Metapenaeopsis barbata using PCR-Based Isolation of Microsatellite Arrays (PIMA). AB - The red-spot prawn, Metapenaeopsis barbata, is a commercially important, widely distributed demersal species in the Indo-West Pacific Ocean. Overfishing has made its populations decline in the past decade. To study conservation genetics, eight polymorphic microsatellite loci were isolated. Genetic characteristics of the SSR (simple sequence repeat) fingerprints were estimated in 61 individuals from adjacent seas of Taiwan and China. The number of alleles, ranging from 2 to 4, as well as observed and expected heterozygosities in populations, ranging from 0.048 to 0.538, and 0.048 and 0.654, respectively, were detected. No deviation from Hardy-Weinberg expectations was detected at either locus. No significant linkage disequilibrium was detected in locus pairs. The polymorphic microsatellite loci will be useful for investigations of the genetic variation, population structure, and conservation genetics of this species. PMID- 22489124 TI - All-trans retinoic acid treatment is associated with prohibitin expression in renal interstitial fibrosis rats. AB - This study was performed to investigate the association of prohibitin with renal interstitial fibrosis (RIF) lesion and to explore the association of all-trans retinoic acid (ATRA) treatment with prohibitin expression in RIF rats. Rats were divided into three groups: the sham operation group (SHO), the model group subjected to unilateral ureteral obstruction (UUO), and the model group treated with ATRA (GA). Renal tissues were collected at 14 and 28 days after surgery, and the relevant indicators were detected. In comparison with the SHO group, the RIF index in the UUO group was markedly elevated (p < 0.01), and the RIF index in the GA group was alleviated compared with that in the UUO group (p < 0.01). Compared with the SHO group, the expression of prohibitin (protein or mRNA) in the UUO group was significantly reduced (each p < 0.01). Prohibitin expression in the GA group was markedly increased when compared with that in the UUO (p < 0.01). The expression of TGF-beta1 (protein and mRNA), protein expressions of Col-IV, fibronectin, alpha-SMA and cleaved Caspase-3, ROS generation and cell apoptosis index in the UUO group were markedly higher than those in the SHO group (all p < 0.01), and their expressions in the GA group were markedly down-regulated compared to those in the UUO group (all p < 0.01, respectively). The protein expression of prohibitin was negatively correlated with the RIF index, protein expression of TGF-beta1, Col-IV, fibronectin, alpha-SMA or cleaved Caspase-3, ROS generation and the cell apoptosis index (each p < 0.01). In conclusion, lower expression of prohibitin is associated with the RIF, and ATRA treatment is associated with increased prohibitin, which can prevent the progression of RIF. PMID- 22489126 TI - An electrochemical method to detect gamma glutamyl transpeptidase. AB - Gamma glutamyl transpeptidase (GGT) is a transferase, which is of great importance in sustaining intracellular cysteine and glutathione levels. The abnormal expression of GGT is significantly associated with features of many metabolic syndromes (e.g., hepatocellular carcinoma). Therefore, it is essential to develop methods to detect GGT so as to monitor the physiological or pathological phenomena related to this species. In this work, by making use of a complex formed by Cu(2+) and glutathione, which may exhibit excellent voltammetric response, we have proposed a novel potential electrochemical method for the detection of the enzyme. Results show that in the presence of GGT, the formation of Cu(2+)-glutathione complex on a working electrode will be disrupted, resulting in greatly depressed electrochemical signals. The primary method exhibits some advantages, such as it being fast, cost-efficient, and conveniently operated. It also has the potential to be further developed as an effective method in the quantitative detection of GGT in real samples. PMID- 22489125 TI - Sequence variants and haplotype analysis of cat ERBB2 gene: a survey on spontaneous cat mammary neoplastic and non-neoplastic lesions. AB - The human ERBB2 proto-oncogene is widely considered a key gene involved in human breast cancer onset and progression. Among spontaneous tumors, mammary tumors are the most frequent cause of cancer death in cats and second most frequent in humans. In fact, naturally occurring tumors in domestic animals, more particularly cat mammary tumors, have been proposed as a good model for human breast cancer, but critical genetic and molecular information is still scarce. The aims of this study include the analysis of the cat ERBB2 gene partial sequences (between exon 17 and 20) in order to characterize a normal and a mammary lesion heterogeneous populations. Cat genomic DNA was extracted from normal frozen samples (n = 16) and from frozen and formalin-fixed paraffin embedded mammary lesion samples (n = 41). We amplified and sequenced two cat ERBB2 DNA fragments comprising exons 17 to 20. It was possible to identify five sequence variants and six haplotypes in the total population. Two sequence variants and two haplotypes show to be specific for cat mammary tumor samples. Bioinformatics analysis predicts that four of the sequence variants can produce alternative transcripts or activate cryptic splicing sites. Also, a possible association was identified between clinicopathological traits and the variant haplotypes. As far as we know, this is the first attempt to examine ERBB2 genetic variations in cat mammary genome and its possible association with the onset and progression of cat mammary tumors. The demonstration of a possible association between primary tumor size (one of the two most important prognostic factors) and the number of masses with the cat ERBB2 variant haplotypes reveal the importance of the analysis of this gene in veterinary medicine. PMID- 22489127 TI - Variation in stability of endogenous reference genes in fallopian tubes and endometrium from healthy and ectopic pregnant women. AB - RT-qPCR is commonly employed in gene expression studies in ectopic pregnancy. Most use RN18S1, beta-actin or GAPDH as internal controls without validation of their suitability as reference genes. A systematic study of the suitability of endogenous reference genes for gene expression studies in ectopic pregnancy is lacking. The aims of this study were therefore to evaluate the stability of 12 reference genes and suggest those that are stable for use as internal control genes in fallopian tubes and endometrium from ectopic pregnancy and healthy non pregnant controls. Analysis of the results showed that the genes consistently ranked in the top six by geNorm and NormFinder algorithms, were UBC, GAPDH, CYC1 and EIF4A2 (fallopian tubes) and UBC and ATP5B (endometrium). mRNA expression of NAPE-PLD as a test gene of interest varied between the groups depending on which of the 12 reference genes was used as internal controls. This study demonstrates that arbitrary selection of reference genes for normalisation in RT-qPCR studies in ectopic pregnancy without validation, risk producing inaccurate data and should therefore be discouraged. PMID- 22489128 TI - Gamma radiation induced oxidation and tocopherols decrease in in-shell, peeled and blanched peanuts. AB - In-shell, peeled and blanched peanut samples were characterized in relation to proximate composition and fatty acid profile. No difference was found in relation to its proximate composition. The three major fatty acids were palmitic acid, oleic acid, and linoleic acid. In order to investigate irradiation and storage effects, peanut samples were submitted to doses of 0.0, 5.0, 7.5 or 10.0 kGy, stored for six months at room temperature and monitored every three months. Peanuts responded differently to irradiation, particularly with regards to tocopherol contents, primary and secondary oxidation products and oil stability index. Induction periods and tocopherol contents were negatively correlated with irradiation doses and decreased moderately during storage. alpha-Tocopherol was the most gamma radiation sensitive and peeled samples were the most affected. A positive correlation was found among tocopherol contents and the induction period of the oils extracted from irradiated samples. Gamma radiation and storage time increased oxidation compounds production. If gamma radiation is considered an alternative for industrial scale peanut conservation, in-shell samples are the best feedstock. For the best of our knowledge this is the first article with such results; this way it may be helpful as basis for future studies on gamma radiation of in-shell crops. PMID- 22489129 TI - Astragalin from Cassia alata induces DNA adducts in vitro and repairable DNA damage in the yeast Saccharomyces cerevisiae. AB - Reverse phase-solid phase extraction from Cassia alata leaves (CaRP) was used to obtain a refined extract. Higher than wild-type sensitivity to CaRP was exhibited by 16 haploid Saccharomyces cerevisiae mutants with defects in DNA repair and membrane transport. CaRP had a strong DPPH free radical scavenging activity with an IC(50) value of 2.27 MUg mL(-1) and showed no pro-oxidant activity in yeast. CaRP compounds were separated by HPLC and the three major components were shown to bind to DNA in vitro. The major HPLC peak was identified as kampferol-3-O-beta d-glucoside (astragalin), which showed high affinity to DNA as seen by HPLC-UV measurement after using centrifugal ultrafiltration of astragalin-DNA mixtures. Astragalin-DNA interaction was further studied by spectroscopic methods and its interaction with DNA was evaluated using solid-state FTIR. These and computational (in silico) docking studies revealed that astragalin-DNA binding occurs through interaction with G-C base pairs, possibly by intercalation stabilized by H-bond formation. PMID- 22489130 TI - Development and characterization of 18 novel EST-SSRs from the western flower Thrips, Frankliniella occidentalis (Pergande). AB - The western flower thrips, Frankliniella occidentalis (Pergande), is an invasive species and the most economically important pest within the insect order Thysanoptera. For a better understanding of the genetic makeup and migration patterns of F. occidentalis throughout the world, we characterized 18 novel polymorphic EST-derived microsatellites. The mutational mechanism of these EST SSRs was also investigated to facilitate the selection of appropriate combinations of markers for population genetic studies. Genetic diversity of these novel markers was assessed in 96 individuals from three populations in China (Harbin, Dali, and Guiyang). The results showed that all these 18 loci were highly polymorphic; the number of alleles ranged from 2 to 15, with an average of 5.50 alleles per locus. The observed (H(O)) and expected (H(E)) heterozygosities ranged from 0.072 to 0.707 and 0.089 to 0.851, respectively. Furthermore, only two locus/population combinations (WFT144 in Dali and WFT50 in Guiyang) significantly deviated from Hardy-Weinberg equilibrium (HWE). Pairwise F(ST) analysis showed a low but significant differentiation (0.026 < F(ST) < 0.032) among all three pairwise population comparisons. Sequence analysis of alleles per locus revealed a complex mutational pattern of these EST-SSRs. Thus, these EST SSRs are useful markers but greater attention should be paid to the mutational characteristics of these microsatellites when they are used in population genetic studies. PMID- 22489131 TI - An oligodeoxynucleotide that induces differentiation of bone marrow mesenchymal stem cells to osteoblasts in vitro and reduces alveolar bone loss in rats with periodontitis. AB - To investigate the effect of oligodeoxynucleotides (ODNs) on the differentiation of rat bone marrow mesenchymal stem cells (BMSCs) to osteoblasts, in order to find a candidate ODN with potential for the treatment of periodontitis, a series of ODNs were designed and selected to test their effect on the promotion of the differentiation of BMSCs to osteoblasts in vitro and on the repair of periodontal tissue in rats with periodontitis. It was found that MT01, one of the ODNs with the sequences of human mitochondrial DNA, stimulated the proliferation of BMSCs, the differentiation of BMSCs to osteoblasts and mRNA expression of bone associated factors including Runx2, Osterix, OPG, RANKL and collagen I in vitro. In vivo study showed that MT01 prevented the loss of alveolar bone in the rats with periodontitis and induced the production of proteins of OPG and Osterix in the bone tissue. These results indicated that MT01 could induce differentiation of BMSCs to osteoblasts and inhibit the alveolar bone absorption in rats with periodontitis. PMID- 22489132 TI - Pro-inflammatory S100A8 and S100A9 proteins: self-assembly into multifunctional native and amyloid complexes. AB - S100A8 and S100A9 are EF-hand Ca(2+) binding proteins belonging to the S100 family. They are abundant in cytosol of phagocytes and play critical roles in numerous cellular processes such as motility and danger signaling by interacting and modulating the activity of target proteins. S100A8 and S100A9 expression levels increased in many types of cancer, neurodegenerative disorders, inflammatory and autoimmune diseases and they are implicated in the numerous disease pathologies. The Ca(2+) and Zn(2+)-binding properties of S100A8/A9 have a pivotal influence on their conformation and oligomerization state, including self assembly into homo- and heterodimers, tetramers and larger oligomers. Here we review how the unique chemical and conformational properties of individual proteins and their structural plasticity at the quaternary level account for S100A8/A9 functional diversity. Additional functional diversification occurs via non-covalent assembly into oligomeric and fibrillar amyloid complexes discovered in the aging prostate and reproduced in vitro. This process is also regulated by Ca(2+)and Zn(2+)-binding and effectively competes with the formation of the native complexes. High intrinsic amyloid-forming capacity of S100A8/A9 proteins may lead to their amyloid depositions in numerous ailments characterized by their elevated expression patterns and have additional pathological significance requiring further thorough investigation. PMID- 22489134 TI - Optimization of freeze drying conditions for purified pectinase from mango (Mangifera indica cv. Chokanan) peel. AB - Response surface methodology (RSM) along with central composite design (CCD) was applied to optimize the freeze drying conditions for purified pectinase from mango (Mangifera indica cv. Chokanan) peel. The effect of pectinase content ( 2.66, 62.66 mg/mL), Arabic gum (-1.21, 10.21%, w/v), and maltodextrin (0.73, 7.26%, w/v) as independent variables on activity, yield, and storage stability of freeze-dried enzyme was evaluated. Storage stability of pectinase was investigated after one week at 4 degrees C and yield percentage of the enzyme after encapsulation was also determined. The independent variables had the most significant (p < 0.05) effect on pectinase activity and yield of the enzyme. It was observed that the interaction effect of Arabic gum and maltodextrin improved the enzymatic properties of freeze-dried pectinase. The optimal conditions for freeze-dried pectinase from mango peel were obtained using 30 mg/mL of pectinase content, 4.5 (%, w/v) of Arabic gum, and 4 (%, w/v) of maltodextrin. Under these conditions, the maximum activity (11.12 U/mL), yield (86.4%) and storage stability (84.2%) of encapsulated pectinase were achieved. PMID- 22489133 TI - Computational identification and modeling of crosstalk between phosphorylation, O beta-glycosylation and methylation of FoxO3 and implications for cancer therapeutics. AB - FoxO3 is a member of the forkhead class of transcription factors and plays a major role in the regulation of diverse cellular processes, including cell cycle arrest, DNA repair, and protection from stress stimuli by detoxification of reactive oxygen species. In addition, FoxO3 is a tumor suppressor and has been considered as a novel target for cancer therapeutics. Phosphorylation of FoxO3 via the AKT, IKK, and ERK pathways leads to deregulation, cytoplasmic retention, degradation of FoxO3 and favors tumor progression. Identification of the amino acid residues that are the target of different posttranslational modifications (PTMs) provides a foundation for understanding the molecular mechanisms of FoxO3 modifications and associated outcomes. In addition to phosphorylation, serine and threonine residues of several proteins are regulated by a unique type of PTM known as O-beta-glycosylation, which serves as a functional switch. We sought to investigate the crosstalk of different PTMs on the FoxO3 which leads to the onset/progression of various cancers and that could also potentially be targeted as a therapeutic point of intervention. A computational workflow and set of selection parameters have been defined for the identification of target sites and crosstalk between different PTMs. We identified phosphorylation, O-beta-GlcNAc modification, and Yin Yang sites on Ser/Thr residues, and propose a potential novel mechanism of crosstalk between these PTMs. Furthermore, methylation potential of human FoxO3 at arginine and lysine residues and crosstalk between methylation and phosphorylation have also been described. Our findings may facilitate the study of therapeutic strategies targeting posttranslational events. PMID- 22489135 TI - Characterization of novel di-, tri-, and tetranucleotide microsatellite primers suitable for genotyping various plant pathogenic fungi with special emphasis on Fusaria and Mycospherella graminicola. AB - The goals of this investigation were to identify and evaluate the use of polymorphic microsatellite marker (PMM) analysis for molecular typing of seventeen plant pathogenic fungi. Primers for di-, tri-, and tetranucleotide loci were designed directly from the recently published genomic sequence of Mycospherlla graminicola and Fusarium graminearum. A total of 20 new microsatellite primers as easy-to-score markers were developed. Microsatellite primer PCR (MP-PCR) yielded highly reproducible and complex genomic fingerprints, with several bands ranging in size from 200 to 3000 bp. Of the 20 primers tested, only (TAGG)4, (TCC)5 and (CA)7T produced a high number of polymorphic bands from either F. graminearum or F. culmorum. (ATG)5 led to successful amplifications in M. graminicola isolates collected from Germany. Percentage of polymorphic bands among Fusarium species ranged from 9 to 100%. Cluster analysis of banding patterns of the isolates corresponded well to the established species delineations based on morphology and other methods of phylogenetic analysis. The current research demonstrates that the newly designed microsatellite primers are reliable, sensitive and technically simple tools for assaying genetic variability in plant pathogenic fungi. PMID- 22489136 TI - Management of diabetes mellitus: could simultaneous targeting of hyperglycemia and oxidative stress be a better panacea? AB - The primary aim of the current management of diabetes mellitus is to achieve and/or maintain a glycated hemoglobin level of <=6.5%. However, recent evidence indicates that intensive treatment of hyperglycemia is characterized by increased weight gain, severe hypoglycemia and higher mortality. Besides, evidence suggests that it is difficult to achieve and/or maintain optimal glycemic control in many diabetic patients; and that the benefits of intensively-treated hyperglycemia are restricted to microvascular complications only. In view of these adverse effects and limitations of intensive treatment of hyperglycemia in preventing diabetic complications, which is linked to oxidative stress, this commentary proposes a hypothesis that "simultaneous targeting of hyperglycemia and oxidative stress" could be more effective than "intensive treatment of hyperglycemia" in the management of diabetes mellitus. PMID- 22489137 TI - Identification and characterization of microRNAs from barley (Hordeum vulgare L.) by high-throughput sequencing. AB - MicroRNAs (miRNAs) are a class of endogenous RNAs that regulates the gene expression involved in various biological and metabolic processes. Barley is one of the most important cereal crops worldwide and is a model organism for genetic and genomic studies in Triticeae species. However, the miRNA research in barley has lagged behind other model species in grass family. To obtain more information of miRNA genes in barley, we sequenced a small RNA library created from a pool of equal amounts of RNA from four different tissues using Solexa sequencing. In addition to 126 conserved miRNAs (58 families), 133 novel miRNAs belonging to 50 families were identified from this sequence data set. The miRNA* sequences of 15 novel miRNAs were also discovered, suggesting the additional evidence for existence of these miRNAs. qRT-PCR was used to examine the expression pattern of six randomly selected miRNAs. Some miRNAs involved in drought and salt stress response were also identified. Furthermore, the potential targets of these putative miRNAs were predicted using the psRNATarget tools. Our results significantly increased the number of novel miRNAs in barley, which should be useful for further investigation into the biological functions and evolution of miRNAs in barley and other species. PMID- 22489138 TI - BDMC33, A curcumin derivative suppresses inflammatory responses in macrophage like cellular system: role of inhibition in NF-kappaB and MAPK signaling pathways. AB - Our preliminary screening has shown that curcumin derivative BDMC33 [2,6-bis(2,5 dimethoxybenzylidene)cyclohexanone] exerted promising nitric oxide inhibitory activity in activated macrophages. However, the molecular basis and mechanism for its pharmacological action is yet to be elucidated. The aim of this study was to investigate the anti-inflammatory properties of BDMC33 and elucidate its underlying mechanism action in macrophage cells. Our current study demonstrated that BDMC33 inhibits the secretion of major pro-inflammatory mediators in stimulated macrophages, and includes NO, TNF-alpha and IL-1beta through interference in both nuclear factor kappaB (NF-kappaB) and mitogen activator protein kinase (MAPK) signaling cascade in IFN-gamma/LPS-stimulated macrophages. Moreover, BDMC33 also interrupted LPS signaling through inhibiting the surface expression of CD-14 accessory molecules. In addition, the inhibitory action of BDMC33 not only restricted the macrophages cell (RAW264.7), but also inhibited the secretion of NO and TNF-alpha in IFN-gamma/LPS-challenged microglial cells (BV-2). The experimental data suggests the inflammatory action of BDMC33 on activated macrophage-like cellular systems, which could be used as a future therapeutic agent in the management of chronic inflammatory diseases. PMID- 22489139 TI - Microsatellite development for an endangered bream Megalobrama pellegrini (Teleostei, Cyprinidae) using 454 sequencing. AB - Megalobrama pellegrini is an endemic fish species found in the upper Yangtze River basin in China. This species has become endangered due to the construction of the Three Gorges Dam and overfishing. However, the available genetic data for this species is limited. Here, we developed 26 polymorphic microsatellite markers from the M. pellegrini genome using next-generation sequencing techniques. A total of 257,497 raw reads were obtained from a quarter-plate run on 454 GS-FLX titanium platforms and 49,811 unique sequences were generated with an average length of 404 bp; 24,522 (49.2%) sequences contained microsatellite repeats. Of the 53 loci screened, 33 were amplified successfully and 26 were polymorphic. The genetic diversity in M. pellegrini was moderate, with an average of 3.08 alleles per locus, and the mean observed and expected heterozygosity were 0.47 and 0.51, respectively. In addition, we tested cross-species amplification for all 33 loci in four additional breams: M. amblycephala, M. skolkovii, M. terminalis, and Sinibrama wui. The cross-species amplification showed a significant high level of transferability (79%-97%), which might be due to their dramatically close genetic relationships. The polymorphic microsatellites developed in the current study will not only contribute to further conservation genetic studies and parentage analyses of this endangered species, but also facilitate future work on the other closely related species. PMID- 22489140 TI - Supercritical fluid extraction of bacterial and archaeal lipid biomarkers from anaerobically digested sludge. AB - Supercritical fluid extraction (SFE) was used in the analysis of bacterial respiratory quinone (RQ), bacterial phospholipid fatty acid (PLFA), and archaeal phospholipid ether lipid (PLEL) from anaerobically digested sludge. Bacterial RQ were determined using ultra performance liquid chromatography (UPLC). Determination of bacterial PLFA and archaeal PLEL was simultaneously performed using gas chromatography-mass spectrometry (GC-MS). The effects of pressure, temperature, and modifier concentration on the total amounts of RQ, PLFA, and PLEL were investigated by 23 experiments with five settings chosen for each variable. The optimal extraction conditions that were obtained through a multiple response optimization included a pressure of 23.6 MPa, temperature of 77.6 degrees C, and 10.6% (v/v) of methanol as the modifier. Thirty nine components of microbial lipid biomarkers were identified in the anaerobically digested sludge. Overall, the SFE method proved to be more effective, rapid, and quantitative for simultaneously extracting bacterial and archaeal lipid biomarkers, compared to conventional organic solvent extraction. This work shows the potential application of SFE as a routine method for the comprehensive analysis of microbial community structures in environmental assessments using the lipid biomarkers profile. PMID- 22489142 TI - Gamma radiation effects on peanut skin antioxidants. AB - Peanut skin, which is removed in the peanut blanching process, is rich in bioactive compounds with antioxidant properties. The aims of this study were to measure bioactive compounds in peanut skins and evaluate the effect of gamma radiation on their antioxidant activity. Peanut skin samples were treated with 0.0, 5.0, 7.5, or 10.0 kGy gamma rays. Total phenolics, condensed tannins, total flavonoids, and antioxidant activity were evaluated. Extracts obtained from the peanut skins were added to refined-bleached-deodorized (RBD) soybean oil. The oxidative stability of the oil samples was determined using the Oil Stability Index method and compared to a control and synthetic antioxidants (100 mg/kg BHT and 200 mg/kg TBHQ). Gamma radiation changed total phenolic content, total condensed tannins, total flavonoid content, and the antioxidant activity. All extracts, gamma irradiated or not, presented increasing induction period (h), measured by the Oil Stability Index method, when compared with the control. Antioxidant activity of the peanut skins was higher than BHT. The present study confirmed that gamma radiation did not affect the peanut skin extracts' antioxidative properties when added to soybean oil. PMID- 22489143 TI - Comparative evolution of S7 Intron 1 and ribosomal internal transcribed spacer in Coilia nasus (Clupeiformes: Engraulidae). AB - Coilia nasus is widely distributed in the Yangtze River, the coastal waters of China, Korea and the Ariake Sound of Japan. Several ecotypes exist and this provides a useful model for the study of comparative diversity between molecular markers. Here we analyze and compare the nucleotide sequences between single-copy ribosomal protein S7 gene intron 1 (rpS7) and multiple-copy ribosomal internal transcribed spacer 1 (ITS1) in this species to compare the phylogenetic signal of the two nuclear genes. Nucleotide substitutions among the two gene sequences and partial sequence of mitochondrial cytochrome c oxidase subunit I (COI) gene were also analyzed. A total of 115 clones for rpS7 and 122 clones for ITS1 were obtained from 37 specimens. The nucleotide sequence length is 741 to 743 bp for rpS7 and 334 to 348 bp for ITS1. Intra- and inter-specimen variation in rpS7 results from nucleotide substitution, while such variation in ITS1 is mainly due to different numbers of short base repeats. The content of G + C is lower in rpS7 (43.5%) than in ITS1 (68.2%). Our results indicate that the proportion of the sequence variable sites is higher in rpS7 (61) than in ITS1 (23); the informative parsimony of rpS7 is evidently higher than that of ITS1 (26 vs. 2); the overall ratio between transitions and transversions in ITS1 is slightly lower than in rpS7, but remarkably lower than in COI. These results suggest that rpS7 is more suitable than ITS1 as a marker for genetic divergence of this group. Furthermore, gene flow is observed between the different geographic populations of C. nasus from the phylogeny of this species based on rpS7, showing that rpS7 has more evolutionary characteristics for understanding the processes of genomic evolution at the intraspecific level. PMID- 22489141 TI - Unraveling the early events of amyloid-beta protein (Abeta) aggregation: techniques for the determination of Abeta aggregate size. AB - The aggregation of proteins into insoluble amyloid fibrils coincides with the onset of numerous diseases. An array of techniques is available to study the different stages of the amyloid aggregation process. Recently, emphasis has been placed upon the analysis of oligomeric amyloid species, which have been hypothesized to play a key role in disease progression. This paper reviews techniques utilized to study aggregation of the amyloid-beta protein (Abeta) associated with Alzheimer's disease. In particular, the review focuses on techniques that provide information about the size or quantity of oligomeric Abeta species formed during the early stages of aggregation, including native PAGE, SDS-PAGE, Western blotting, capillary electrophoresis, mass spectrometry, fluorescence correlation spectroscopy, light scattering, size exclusion chromatography, centrifugation, enzyme-linked immunosorbent assay, and dot blotting. PMID- 22489145 TI - Prediction of genomic islands in three bacterial pathogens of pneumonia. AB - Pneumonia is one kind of common infectious disease, which is usually caused by bacteria, viruses, or fungi. In this paper, we predicted genomic islands in three bacterial pathogens of pneumonia. They are Chlamydophila pneumoniae, Mycoplasma pneumoniae and Streptococcus pneumoniae, respectively. For each pathogen, one clinical strain is involved. After implementing the cumulative GC profile combined with h and BCN index, eight genomic islands are found in three pathogens. Among them, six genomic islands are found to have mobility elements, which constitute a kind of conserved character of genomic islands, and this introduces the possibility that they are genuine genomic islands. The present results show that the cumulative GC profile when combined with h and BCN indexes is a good method for predicting genomic islands in bacteria and it has lower false positive rate than the SIGI method. Specially, three genomic islands are found to contain clusters of genes coding for production of virulence factors and this is useful for research into the pathogenicity of these pathogens and helpful for the treatment of diseases caused by them. PMID- 22489144 TI - Development of on-line high performance liquid chromatography (HPLC)-biochemical detection methods as tools in the identification of bioactives. AB - Biochemical detection (BCD) methods are commonly used to screen plant extracts for specific biological activities in batch assays. Traditionally, bioactives in the most active extracts were identified through time-consuming bio-assay guided fractionation until single active compounds could be isolated. Not only are isolation procedures often tedious, but they could also lead to artifact formation. On-line coupling of BCD assays to high performance liquid chromatography (HPLC) is gaining ground as a high resolution screening technique to overcome problems associated with pre-isolation by measuring the effects of compounds post-column directly after separation. To date, several on-line HPLC BCD assays, applied to whole plant extracts and mixtures, have been published. In this review the focus will fall on enzyme-based, receptor-based and antioxidant assays. PMID- 22489147 TI - Arabidopsis serine decarboxylase mutants implicate the roles of ethanolamine in plant growth and development. AB - Ethanolamine is important for synthesis of choline, phosphatidylethanolamine (PE) and phosphatidylcholine (PC) in plants. The latter two phospholipids are the major phospholipids in eukaryotic membranes. In plants, ethanolamine is mainly synthesized directly from serine by serine decarboxylase. Serine decarboxylase is unique to plants and was previously shown to have highly specific activity to l serine. While serine decarboxylase was biochemically characterized, its functions and importance in plants were not biologically elucidated due to the lack of serine decarboxylase mutants. Here we characterized an Arabidopsis mutant defective in serine decarboxylase, named atsdc-1 (Arabidopsis thaliana serine decarboxylase-1). The atsdc-1 mutants showed necrotic lesions in leaves, multiple inflorescences, sterility in flower, and early flowering in short day conditions. These defects were rescued by ethanolamine application to atsdc-1, suggesting the roles of ethanolamine as well as serine decarboxylase in plant development. In addition, molecular analysis of serine decarboxylase suggests that Arabidopsis serine decarboxylase is cytosol-localized and expressed in all tissue. PMID- 22489146 TI - Glutathione is a key player in metal-induced oxidative stress defenses. AB - Since the industrial revolution, the production, and consequently the emission of metals, has increased exponentially, overwhelming the natural cycles of metals in many ecosystems. Metals display a diverse array of physico-chemical properties such as essential versus non-essential and redox-active versus non-redox-active. In general, all metals can lead to toxicity and oxidative stress when taken up in excessive amounts, imposing a serious threat to the environment and human health. In order to cope with different kinds of metals, plants possess defense strategies in which glutathione (GSH; gamma-glu-cys-gly) plays a central role as chelating agent, antioxidant and signaling component. Therefore, this review highlights the role of GSH in: (1) metal homeostasis; (2) antioxidative defense; and (3) signal transduction under metal stress. The diverse functions of GSH originate from the sulfhydryl group in cysteine, enabling GSH to chelate metals and participate in redox cycling. PMID- 22489148 TI - Modulation Role of abscisic acid (ABA) on growth, water relations and glycinebetaine metabolism in two maize (Zea mays L.) cultivars under drought stress. AB - The role of plant hormone abscisic acid (ABA) in plants under drought stress (DS) is crucial in modulating physiological responses that eventually lead to adaptation to an unfavorable environment; however, the role of this hormone in modulation of glycinebetaine (GB) metabolism in maize particularly at the seedling stage is still poorly understood. Some hydroponic experiments were conducted to investigate the modulation role of ABA on plant growth, water relations and GB metabolism in the leaves of two maize cultivars, Zhengdan 958 (ZD958; drought tolerant), and Jundan 20 (JD20; drought sensitive), subjected to integrated root-zone drought stress (IR-DS) simulated by the addition of polyethylene glycol (PEG, 12% w/v, MW 6000). The IR-DS substantially resulted in increased betaine aldehyde dehydrogenase (BADH) activity and choline content which act as the key enzyme and initial substrate, respectively, in GB biosynthesis. Drought stress also induced accumulation of GB, whereas it caused reduction in leaf relative water content (RWC) and dry matter (DM) in both cultivars. The contents of ABA and GB increased in drought-stressed maize seedlings, but ABA accumulated prior to GB accumulation under the drought treatment. These responses were more predominant in ZD958 than those in JD20. Addition of exogenous ABA and fluridone (Flu) (ABA synthesis inhibitor) applied separately increased and decreased BADH activity, respectively. Abscisic acid application enhanced GB accumulation, leaf RWC and shoot DM production in both cultivars. However, of both maize cultivars, the drought sensitive maize cultivar (JD20) performed relatively better than the other maize cultivar ZD958 under both ABA and Flu application in view of all parameters appraised. It is, therefore, concluded that increase in both BADH activity and choline content possibly resulted in enhancement of GB accumulation under DS. The endogenous ABA was probably involved in the regulation of GB metabolism by regulating BADH activity, and resulting in modulation of water relations and plant growth under drought, especially in the drought sensitive maize cultivar JD20. PMID- 22489149 TI - Tannins, peptic ulcers and related mechanisms. AB - This review of the current literature aims to study correlations between the chemical structure and gastric anti-ulcer activity of tannins. Tannins are used in medicine primarily because of their astringent properties. These properties are due to the fact that tannins react with the tissue proteins with which they come into contact. In gastric ulcers, this tannin-protein complex layer protects the stomach by promoting greater resistance to chemical and mechanical injury or irritation. Moreover, in several experimental models of gastric ulcer, tannins have been shown to present antioxidant activity, promote tissue repair, exhibit anti Helicobacter pylori effects, and they are involved in gastrointestinal tract anti-inflammatory processes. The presence of tannins explains the anti-ulcer effects of many natural products. PMID- 22489150 TI - Applications of circular dichroism for structural analysis of gelatin and antimicrobial peptides. AB - Circular dichroism (CD) is a useful technique for monitoring changes in the conformation of antimicrobial peptides or gelatin. In this study, interactions between cationic peptides and gelatin were observed without affecting the triple helical content of the gelatin, which was more strongly affected by anionic surfactant. The peptides did not adopt a secondary structure in the presence of aqueous solution or Tween 80, but a peptide secondary structure formed upon the addition of sodium dodecyl sulfate (SDS). The peptides bound to the phosphate group of lipopolysaccharide (LPS) and displayed an alpha-helical conformation while (KW)(4) adopted a folded conformation. Further, the peptides did not specifically interact with the fungal cell wall components of mannan or laminarin. Tryptophan blue shift assay indicated that these peptides interacted with SDS, LPS, and gelatin but not with Tween 80, mannan, or laminarin. The peptides also displayed antibacterial activity against P. aeruginosa without cytotoxicity against HaCaT cells at MIC, except for HPA3NT3-analog peptide. In this study, we used a CD spectroscopic method to demonstrate the feasibility of peptide characterization in numerous environments. The CD method can thus be used as a screening method of gelatin-peptide interactions for use in wound healing applications. PMID- 22489151 TI - Use of the MLPA assay in the molecular diagnosis of gene copy number alterations in human genetic diseases. AB - Multiplex Ligation-dependent Probe Amplification (MLPA) assay is a recently developed technique able to evidence variations in the copy number of several human genes. Due to this ability, MLPA can be used in the molecular diagnosis of several genetic diseases whose pathogenesis is related to the presence of deletions or duplications of specific genes. Moreover, MLPA assay can also be used in the molecular diagnosis of genetic diseases characterized by the presence of abnormal DNA methylation. Due to the large number of genes that can be analyzed by a single technique, MLPA assay represents the gold standard for molecular analysis of all pathologies derived from the presence of gene copy number variation. In this review, the main applications of the MLPA technique for the molecular diagnosis of human diseases are described. PMID- 22489152 TI - A combined DNA-affinic molecule and N-mustard alkylating agent has an anti-cancer effect and induces autophagy in oral cancer cells. AB - Although surgery or the combination of chemotherapy and radiation are reported to improve the quality of life and reduce symptoms in patients with oral cancer, the prognosis of oral cancer remains generally poor. DNA alkylating agents, such as N mustard, play an important role in cancer drug development. BO-1051 is a new 9 anilinoacridine N-mustard-derivative anti-cancer drug that can effectively target a variety of cancer cell lines and inhibit tumorigenesis in vivo. However, the underlying mechanism of BO-1051-mediated tumor suppression remains undetermined. In the present study, BO-1051 suppressed cell viability with a low IC(50) in oral cancer cells, but not in normal gingival fibroblasts. Cell cycle analysis revealed that the tumor suppression by BO-1051 was accompanied by cell cycle arrest and downregulation of stemness genes. The enhanced conversion of LC3-I to LC3-II and the formation of acidic vesicular organelles indicated that BO-1501 induced autophagy. The expression of checkpoint kinases was upregulated as demonstrated with Western blot analysis, showing that BO-1051 could induce DNA damage and participate in DNA repair mechanisms. Furthermore, BO-1051 treatment alone exhibited a moderate tumor suppressive effect against xenograft tumor growth in immunocompromised mice. Importantly, the combination of BO-1051 and radiation led to a potent inhibition on xenograft tumorigenesis. Collectively, our findings demonstrated that BO-1051 exhibited a cytotoxic effect via cell cycle arrest and the induction of autophagy. Thus, the combination of BO-1051 and radiotherapy may be a feasible therapeutic strategy against oral cancer in the future. PMID- 22489154 TI - Generating aptamers by cell-SELEX for applications in molecular medicine. AB - Aptamers are single-stranded oligonucleotides of DNA or RNA that bind to target molecules with high affinity and specificity. Typically, aptamers are generated by an iterative selection process, called systematic evolution of ligands by exponential enrichment (SELEX). Recent advancements in SELEX technology have extended aptamer selection from comparatively simple mixtures of purified proteins to whole living cells, and now cell-based SELEX (or cell-SELEX) can isolate aptamers that bind to specific target cells. Combined with nanotechnology, microchips, microfluidic devices, RNAi and other advanced technologies, cell-SELEX represents an integrated platform providing ultrasensitive and highly specific tools for clinical medicine. In this review, we describe the recent progress made in the application of cell-SELEX for diagnosis, therapy and biomarker discovery. PMID- 22489153 TI - Valuable nutrients and functional bioactives in different parts of olive (Olea europaea L.)-a review. AB - The Olive tree (Olea europaea L.), a native of the Mediterranean basin and parts of Asia, is now widely cultivated in many other parts of the world for production of olive oil and table olives. Olive is a rich source of valuable nutrients and bioactives of medicinal and therapeutic interest. Olive fruit contains appreciable concentration, 1-3% of fresh pulp weight, of hydrophilic (phenolic acids, phenolic alchohols, flavonoids and secoiridoids) and lipophilic (cresols) phenolic compounds that are known to possess multiple biological activities such as antioxidant, anticarcinogenic, antiinflammatory, antimicrobial, antihypertensive, antidyslipidemic, cardiotonic, laxative, and antiplatelet. Other important compounds present in olive fruit are pectin, organic acids, and pigments. Virgin olive oil (VOO), extracted mechanically from the fruit, is also very popular for its nutritive and health-promoting potential, especially against cardiovascular disorders due to the presence of high levels of monounsaturates and other valuable minor components such as phenolics, phytosterols, tocopherols, carotenoids, chlorophyll and squalene. The cultivar, area of production, harvest time, and the processing techniques employed are some of the factors shown to influence the composition of olive fruit and olive oil. This review focuses comprehensively on the nutrients and high-value bioactives profile as well as medicinal and functional aspects of different parts of olives and its byproducts. Various factors affecting the composition of this food commodity of medicinal value are also discussed. PMID- 22489155 TI - The hypoglycemic effect of the kelp on diabetes mellitus model induced by alloxan in rats. AB - Hypoglycemic effects and the use of kelp in diabetes mellitus (DM) model rats induced by alloxan were investigated. Sixty healthy male rats were used to establish DM models by injecting alloxan intraperitoneally. Kelp powder was added to the general forage for the rats. The levels of fasting blood glucose (FBG) were determined by an automatic blood glucose device. Electrochemiluminescence immunoassay was applied to determine the serum levels of insulin. The serum levels of malondialdehyde (MDA) were measured by thiobarbituric acid assay and nitric oxide (NO) by nitrate reductase assay. The activities of superoxide dismutase (SOD) were determined by xanthinoxidase assay and glutathione peroxidase (GSH-Px) by chemical colorimetry. The shape and structure of islet cells were observed with Hematine-Eosin staining, and the expression of superoxide dismutase (SOD) and inducible nitric oxide synthase (iNOS) in islet cells were detected by immunohistochemical assay. The results showed that the serum levels of insulin after treatment with kelp powder increased significantly compared to those in the DM-model group, while the FBG in the medium-high dose treated groups decreased significantly compared to those in the DM-model group (P < 0.05). The levels of MDA and NO in the kelp powder groups were lower than those in the DM-model group, while the activities of SOD and GSH-Px were higher than those in the DM-model group, of which a significant difference existed between the medium-high dose treated groups and the DM-model group (P < 0.05). The shape and structure of islet cells improved with the up-expressing SOD and down expressing iNOS in the medium-high dose treated groups compared to those in the DM-model group (P < 0.05). There were no significant differences between the medium and high dose treated groups, all above indexes (P > 0.05). It is suggested that kelp might aid recovery of the the islet cell secreting function and reduce the level of FBG by an antioxidant effect. PMID- 22489156 TI - Preparation and characterization of new nano-composite scaffolds loaded with vascular stents. AB - In this study, vascular stents were fabricated from poly (lactide-E caprolactone)/collagen/nano-hydroxyapatite (PLCL/Col/nHA) by electrospinning, and the surface morphology and breaking strength were observed or measured through scanning electron microscopy and tensile tests. The anti-clotting properties of stents were evaluated for anticoagulation surfaces modified by the electrostatic layer-by-layer self-assembly technique. In addition, nano-composite scaffolds of poly (lactic-co-glycolic acid)/polycaprolactone/nano-hydroxyapatite (PLGA/PCL/nHA) loaded with the vascular stents were prepared by thermoforming particle leaching and their basic performance and osteogenesis were tested in vitro and in vivo. The results show that the PLCL/Col/nHA stents and PLGA/PCL/nHA nano-composite scaffolds had good surface structures, mechanical properties, biocompatibility and could guide bone regeneration. These may provide a new way to build vascularized-tissue engineered bone to repair large bone defects in bone tissue engineering. PMID- 22489157 TI - Chemical composition and antimicrobial activity of the essential oil of kumquat (Fortunella crassifolia Swingle) peel. AB - The aim of this study was to determine the main constituents of the essential oil isolated from Fortunella crassifolia Swingle peel by hydro-distillation, and to test the efficacy of the essential oil on antimicrobial activity. Twenty-five components, representing 92.36% of the total oil, were identified by GC-MS analysis. The essential oil showed potent antimicrobial activity against both Gram-negative (E. coli and S. typhimurium) and Gram-positive (S. aureus, B. cereus, B. subtilis, L. bulgaricus, and B. laterosporus) bacteria, together with a remarkable antifungal activity against C. albicans. In a food model of beef extract, the essential oil was observed to possess an effective capacity to control the total counts of viable bacteria. Furthermore, the essential oil showed strongly detrimental effects on the growth and morphological structure of the tested bacteria. It was suggested that the essential oil from Fortunella crassifolia Swingle peel might be used as a natural food preservative against bacteria or fungus in the food industry. PMID- 22489158 TI - Conformational changes in DNA upon ligand binding monitored by circular dichroism. AB - Circular dichroism (CD) spectroscopy is an optical technique that measures the difference in the absorption of left and right circularly polarized light. This technique has been widely employed in the studies of nucleic acids structures and the use of it to monitor conformational polymorphism of DNA has grown tremendously in the past few decades. DNA may undergo conformational changes to B form, A-form, Z-form, quadruplexes, triplexes and other structures as a result of the binding process to different compounds. Here we review the recent CD spectroscopic studies of the induction of DNA conformational changes by different ligands, which includes metal derivative complex of aureolic family drugs, actinomycin D, neomycin, cisplatin, and polyamine. It is clear that CD spectroscopy is extremely sensitive and relatively inexpensive, as compared with other techniques. These studies show that CD spectroscopy is a powerful technique to monitor DNA conformational changes resulting from drug binding and also shows its potential to be a drug-screening platform in the future. PMID- 22489159 TI - Computational analysis of axonal transport: a novel assessment of neurotoxicity, neuronal development and functions. AB - Axonal transport plays a crucial role in neuronal morphogenesis, survival and function. Despite its importance, however, the molecular mechanisms of axonal transport remain mostly unknown because a simple and quantitative assay system for monitoring this cellular process has been lacking. In order to better characterize the mechanisms involved in axonal transport, we formulate a novel computer-assisted monitoring system of axonal transport. Potential uses of this system and implications for future studies will be discussed. PMID- 22489160 TI - Dietary pseudopurpurin effects on bone mineral density and bone geometry architecture in rats. AB - The objective of our study was to evaluate whether feeding pseudopurpurin affects bone mineral density and bone geometry architecture in rats. Pseudopurpurin was extracted, analyzed and purified using an HLPC-ESI-MS. Rats were given 0% and 0.5% pseudopurpurin powder in their diet. Femurs of rats were examined at 0.5, 1 and 2 months after pseudopurpurin feeding. Compared with rats in the group 0%, the bone mineral density, and the calcium, magnesium, zinc and manganese concentrations in the rats femur in the group 0.5% increased significantly at 1 month and 2 months after pseudopurpurin feeding. Analytical results of micro computed tomography showed that the group 0.5% displayed an increase in the trabecular volume fraction, trabecular thickness and trabecular number of the distal femur at 1 and 2 months after pseudopurpurin feeding, and the mean thickness, inner perimeter, outer perimeter, and area of the femur diaphysis were significantly increased at 2 months after pseudopurpurin feeding compared with the group 0%. In parallel, the trabecular separation and structure model index of the distal femur were decreased, compared with the group 0% at 1 and 2 months after pseudopurpurin feeding. In the 0.5% and 0% groups, there was no damage to kidney and liver by histopathology analysis. The long-term feeding of pseudopurpurin is safe for rats. The feeding of 0.5% pseudopurpurin which has specific chemical affinities for calcium for bone improvement and level of bone mineral density, enhances the geometry architecture compared with the 0% group. PMID- 22489161 TI - Extracts of phenolic compounds from seeds of three wild grapevines-comparison of their antioxidant activities and the content of phenolic compounds. AB - Phenolic compounds were extracted from three wild grapevine species: Vitis californica, V. riparia and V. amurensis seeds using 80% methanol or 80% acetone. The total content of phenolic compounds was determined utilizing the Folin Ciocalteu's phenol reagent while the content of tannins was assayed with the vanillin and BSA precipitation methods. Additionally, the DPPH free radical scavenging activity and the reduction power of the extracts were measured. The RP HPLC method was applied to identify the phenolic compounds in the extracts, such as phenolic acids and catechins. The seeds contained large amounts of tannins, catechins and gallic acid and observable quantities of p-coumaric acid. The total content of phenolic compounds and tannins was similar in the extracts from V. californica and V. riparia seeds. However, the total content of total phenolic compounds and tannins in the extracts from V. californica and V. riperia seeds were about two-fold higher than that in the extracts from V. amurensis seeds. Extracts from seeds of the American species (V. californica and V. riparia) contained similarly high concentrations of tannins, whereas extracts from seeds of V. amurensis had approximately half that amount of these compounds. The content of catechin and epicatechin was similar in all extracts. The highest DPPH(*) anti-radical scavenging activity was observed in the acetonic and methanolic extracts of V. californica and V. riparia seeds- while the acetonic extract from the V. californica seeds was the strongest reducing agent. PMID- 22489162 TI - Homologous NF-YC2 subunit from Arabidopsis and tobacco is activated by photooxidative stress and induces flowering. AB - The transcription factor NF-Y consists of the three subunits A, B and C, which are encoded in Arabidopsis in large gene families. The multiplicity of the genes implies that NF-Y may act in diverse combinations of each subunit for the transcriptional control. We aimed to assign a function in stress response and plant development to NF-YC subunits by analyzing the expression of NF-Y genes and exploitation of nf-y mutants. Among the subunit family, NF-YC2 showed the strongest inducibility towards oxidative stress, e.g. photodynamic, light, oxidative, heat and drought stress. A tobacco NF-YC homologous gene was found to be inducible by photooxidative stress generated by an accumulation of the tetrapyrrole metabolite, coproporphyrin. Despite the stress induction, an Arabidopsis nf-yc2 mutant and NF-YC2 overexpressors did not show phenotypical differences compared to wild-type seedlings in response to photooxidative stress. This can be explained by the compensatory potential of other members of the NF-YC family. However, NF-YC2 overexpression leads to an early flowering phenotype that is correlated with increased FLOWERING LOCUS T-transcript levels. It is proposed that NF-YC2 functions in floral induction and is a candidate gene among the NF-Y family for the transcriptional activation upon oxidative stress. PMID- 22489163 TI - Expression analysis of an R3-Type MYB transcription factor CPC-LIKE MYB4 (TRICHOMELESS2) and CPL4-Related transcripts in Arabidopsis. AB - The CAPRICE (CPC)-like MYB gene family encodes R3-type MYB transcription factors in Arabidopsis. There are six additional CPC-like MYB sequences in the Arabidopsis genome, including TRYPTICHON (TRY), ENHANCER OF TRY AND CPC1 and 2 (ETC1 and ETC2), ENHANCER OF TRY AND CPC3/CPC-LIKE MYB3 (ETC3/CPL3), and TRICHOMELESS1 and 2 (TCL1 and TCL2). We independently identified CPC-LIKE MYB4 (CPL4), which was found to be identical to TCL2. RT-PCR analysis showed that CPL4 is strongly expressed in shoots, including true leaves, but not in roots. Promoter-GUS analyses indicated that CPL4 is specifically expressed in leaf blades. Although CPC expression was repressed in 35S::ETC1, 35S::ETC2 and 35S::CPL3 backgrounds, CPL4 expression was not affected by ETC1, ETC2 or CPL3 over-expression. Notably, several chimeric transcripts may result from inter genic alternative splicing of CPL4 and ETC2, two tandemly repeated genes on chromosome II. At least two chimeric transcripts named CPL4-alpha and CPL4-beta are expected to encode complete CPC-like MYB proteins. PMID- 22489164 TI - Phenolic contents and compositions in skins of red wine grape cultivars among various genetic backgrounds and originations. AB - In order to analyze and compare the phenolic characteristics of red wine grapes with diverse genetic backgrounds, skin phenolics among 21 different cultivars belonging to Vitis vinifera L., East Asian and North American Vitis species and hybrids, as well as 2 varieties of muscadine grapes were estimated by HPLC-MS/MS. There were 45 anthocyanins, 28 flavonols, 8 flavan-3-ols, 9 cinnamic acids, 5 benzoic acids, 5 ellagic acids and 2 stilbenes detected in all the samples. Total contents of each phenolic type varied significantly among the different grape cultivars investigated. There was also a large variability in the phenolic compositions of different grape groups. The differences in anthocyanin composition were obvious between V. vinifera and non-V. vinifera grapes and also between the grapes originating from Eurasia and North America. Quercetin-3 glucuronide and quercetin-3-glucoside were marker flavonol compounds for Euvitis grape skins. Flavan-3-ol monomers were dominant in the skins of muscadine and non V. amurensis East Asian grapes, whereas polymers were more common in V. vinifera and North American grapes. The muscadine grapes were very rich in flavonols, flavan-3-ols and ellagic acids. Via principal component analysis, these grape cultivars were clustered into three groups according to their characteristic phenolic content and composition. PMID- 22489165 TI - A high molar extinction coefficient bisterpyridyl homoleptic ru(II) complex with trans-2-methyl-2-butenoic acid functionality: potential dye for dye-sensitized solar cells. AB - In our continued efforts in the synthesis of ruthenium(II) polypyridine complexes as potential dyes for use in varied applications, such as the dye-sensitized solar cells (DSSCs), this work particularly describes the synthesis, absorption spectrum, redox behavior and luminescence properties of a new homoleptic ruthenium(II) complex bearing a simple trans-2-methyl-2-butenoic acid functionality as the anchoring ligand on terpyridine moiety. The functionalized terpyridine ligand: 4'-(trans-2-methyl-2-butenoic acid)-terpyridyl (L1) was synthesized by aryl bromide substitution on terpyridine in a basic reaction condition under palladium carbide catalysis. In particular, the photophysical and redox properties of the complex formulated as: bis-4'-(trans-2-methyl-2-butenoic acid)-terpyridyl ruthenium(II) bis-hexafluorophosphate [Ru(L1)(2)(PF(6))(2)] are significantly better compared to those of [Ru(tpy)(2)](2+) and compare well with those of the best emitters of Ru(II) polypyridine family containing tridentate ligands. Reasons for the improved photophysical and redox properties of the complex may be attributed partly to the presence of a substituted alpha,beta unsaturated carboxylic acid moiety leading to increase in the length of pi conjugation bond thereby enhancing the MLCT-MC (Metal-to-ligand-charge transfer metal centred) energy gap, and to the reduced difference between the minima of the excited and ground states potential energy surfaces. PMID- 22489166 TI - Arsenic and antimony transporters in eukaryotes. AB - Arsenic and antimony are toxic metalloids, naturally present in the environment and all organisms have developed pathways for their detoxification. The most effective metalloid tolerance systems in eukaryotes include downregulation of metalloid uptake, efflux out of the cell, and complexation with phytochelatin or glutathione followed by sequestration into the vacuole. Understanding of arsenic and antimony transport system is of high importance due to the increasing usage of arsenic-based drugs in the treatment of certain types of cancer and diseases caused by protozoan parasites as well as for the development of bio- and phytoremediation strategies for metalloid polluted areas. However, in contrast to prokaryotes, the knowledge about specific transporters of arsenic and antimony and the mechanisms of metalloid transport in eukaryotes has been very limited for a long time. Here, we review the recent advances in understanding of arsenic and antimony transport pathways in eukaryotes, including a dual role of aquaglyceroporins in uptake and efflux of metalloids, elucidation of arsenic transport mechanism by the yeast Acr3 transporter and its role in arsenic hyperaccumulation in ferns, identification of vacuolar transporters of arsenic phytochelatin complexes in plants and forms of arsenic substrates recognized by mammalian ABC transporters. PMID- 22489168 TI - Autophagy in premature senescent cells is activated via AMPK pathway. AB - Autophagy is a highly regulated intracellular process involved in the turnover of most cellular constituents and in the maintenance of cellular homeostasis. In this study, we show that the activity of autophagy increases in H(2)O(2) or RasV12-induced senescent fibroblasts. Inhibiting autophagy promotes cell apoptosis in senescent cells, suggesting that autophagy activation plays a cytoprotective role. Furthermore, our data indicate that the increase of autophagy in senescent cells is linked to the activation of transcription factor FoxO3A, which blocks ATP generation by transcriptionally up-regulating the expression of PDK4, an inhibitor of pyruvate dehydrogenase complex, thus leading to AMPK activation and mTOR inhibition. These findings suggest a novel mechanism by which FoxO3A factors can activate autophagy via metabolic alteration. PMID- 22489167 TI - A comparative study on the expression, purification and functional characterization of human adiponectin in Pichia pastoris and Escherichia coli. AB - Adiponectin is one of the most bioactive substances secreted by adipose tissue and is involved in the protection against metabolic syndrome, artherosclerosis and type II diabetes. Research into the use of adiponectin as a promising drug for metabolic syndromes requires production of this hormone in high quantities considering its molecular isoforms. The objective of this study is to produce recombinant human adiponectin by Pichia pastoris (P-ADP) as a cheap and convenient eukaryotic expression system for potential application in pharmaceutical therapy. For comparison, adiponectin was also expressed using the Escherichia coli (E-ADP) expression system. Adiponectin was constructed by overlap-extension PCR, and cloned in standard cloning vector and hosts. Recombinant expression vectors were cloned in the P. pastoris and E. coli host strains, respectively. SDS-PAGE and western blotting were used to detect and analyse expressed recombinant protein in both systems. Adiponectin was purified by affinity chromatography and quantified using the Bradford Assay. The results of this study indicated that P-ADP quantity (0.111 mg/mL) was higher than that of E-ADP (0.04 mg/mL) and both were produced in soluble form. However, P-ADP was able to form high molecular weights of adiponectin molecules, whilst E-ADP was not able to form isoforms higher than trimer. In addition, P-ADP was more active in lowering blood glucose compared with E-ADP. The two types of proteins were equally efficient and significantly decreased blood triglyceride and increased high density lipoprotein. We conclude that P. pastoris is able to produce high quantity of bioactive adiponectin for potential use in treatment of metabolic syndromes. PMID- 22489169 TI - Pharmacokinetic comparison of ferulic acid in normal and blood deficiency rats after oral administration of Angelica sinensis, Ligusticum chuanxiong and their combination. AB - Radix Angelica Sinensis (RAS) and Rhizome Ligusticum (RLC) combination is a popular herb pair commonly used in clinics for treatment of blood deficiency syndrome in China. The aim of this study is to compare the pharmacokinetic properties of ferulic acid (FA), a main bioactive constituent in both RAS and RLC, between normal and blood deficiency syndrome animals, and to investigate the influence of compatibility of RAS and RLC on the pharmacokinetic of FA. The blood deficiency rats were induced by injecting 2% Acetyl phenylhydrazine (APH) on the first day, every other day, to a total of five times, at the dosage of 100, 50, 50, 30, 30 mg/kg body mass, respectively. Quantification of FA in rat plasma was achieved by using a simple and rapid HPLC method. Plasma samples were collected at different time points to construct pharmacokinetic profiles by plotting drug concentration versus time, and estimate pharmacokinetic parameters. Between normal and blood deficiency model groups, both AUC((0-) (t) ()) and C(max) of FA in blood deficiency rats after RAS-RLC extract administration increased significantly (P < 0.05), while clearance (CL) decreased significantly. Among three blood deficiency model groups, t(1/2alpha), V(d), AUC((0-) (t) ()) and AUC((0-infinity)) all increased significantly in the RAS-RLC extract group compared with the RAS group. The results indicated that FA was absorbed better and eliminated slower in blood deficiency rats; RLC could significantly prolong the half-life of distribution, increase the volume of distribution and the absorption amount of FA of RAS in blood deficiency rats, which may be due to the synergic action when RAS and RLC were used together to treat blood deficiency syndrome. PMID- 22489170 TI - Improvement of carbon tetrachloride-induced acute hepatic failure by transplantation of induced pluripotent stem cells without reprogramming factor c Myc. AB - The only curative treatment for hepatic failure is liver transplantation. Unfortunately, this treatment has several major limitations, as for example donor organ shortage. A previous report demonstrated that transplantation of induced pluripotent stem cells without reprogramming factor c-Myc (3-genes iPSCs) attenuates thioacetamide-induced hepatic failure with minimal incidence of tumorigenicity. In this study, we investigated whether 3-genes iPSC transplantation is capable of rescuing carbon tetrachloride (CCl(4))-induced fulminant hepatic failure and hepatic encephalopathy in mice. Firstly, we demonstrated that 3-genes iPSCs possess the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) that exhibit biological functions and express various hepatic specific markers. 3-genes iPSCs also exhibited several antioxidant enzymes that prevented CCl(4)-induced reactive oxygen species production and cell death. Intraperitoneal transplantation of either 3-genes iPSCs or 3-genes iPSC-Heps significantly reduced hepatic necrotic areas, improved hepatic functions, and survival rate in CCl(4)-treated mice. CCl(4)-induced hepatic encephalopathy was also improved by 3-genes iPSC transplantation. Hoechst staining confirmed the successful engraftment of both 3-genes iPSCs and 3-genes iPSC-Heps, indicating the homing properties of these cells. The most pronounced hepatoprotective effect of iPSCs appeared to originate from the highest antioxidant activity of 3-gene iPSCs among all transplanted cells. In summary, our findings demonstrated that 3-genes iPSCs serve as an available cell source for the treatment of an experimental model of acute liver diseases. PMID- 22489172 TI - Optimization of serine protease purification from mango (Mangifera indica cv. Chokanan) peel in polyethylene glycol/dextran aqueous two phase system. AB - Mango peel is a good source of protease but remains an industrial waste. This study focuses on the optimization of polyethylene glycol (PEG)/dextran-based aqueous two-phase system (ATPS) to purify serine protease from mango peel. The activity of serine protease in different phase systems was studied and then the possible relationship between the purification variables, namely polyethylene glycol molecular weight (PEG, 4000-12,000 g.mol(-1)), tie line length (-3.42 35.27%), NaCl (-2.5-11.5%) and pH (4.5-10.5) on the enzymatic properties of purified enzyme was investigated. The most significant effect of PEG was on the efficiency of serine protease purification. Also, there was a significant increase in the partition coefficient with the addition of 4.5% of NaCl to the system. This could be due to the high hydrophobicity of serine protease compared to protein contaminates. The optimum conditions to achieve high partition coefficient (84.2) purification factor (14.37) and yield (97.3%) of serine protease were obtained in the presence of 8000 g.mol(-1) of PEG, 17.2% of tie line length and 4.5% of NaCl at pH 7.5. The enzymatic properties of purified serine protease using PEG/dextran ATPS showed that the enzyme could be purified at a high purification factor and yield with easy scale-up and fast processing. PMID- 22489173 TI - Prediction of bioluminescent proteins using auto covariance transformation of evolutional profiles. AB - Bioluminescent proteins are important for various cellular processes, such as gene expression analysis, drug discovery, bioluminescent imaging, toxicity determination, and DNA sequencing studies. Hence, the correct identification of bioluminescent proteins is of great importance both for helping genome annotation and providing a supplementary role to experimental research to obtain insight into bioluminescent proteins' functions. However, few computational methods are available for identifying bioluminescent proteins. Therefore, in this paper we develop a new method to predict bioluminescent proteins using a model based on position specific scoring matrix and auto covariance. Tested by 10-fold cross validation and independent test, the accuracy of the proposed model reaches 85.17% for the training dataset and 90.71% for the testing dataset respectively. These results indicate that our predictor is a useful tool to predict bioluminescent proteins. This is the first study in which evolutionary information and local sequence environment information have been successfully integrated for predicting bioluminescent proteins. A web server (BLPre) that implements the proposed predictor is freely available. PMID- 22489171 TI - The intriguing life of autophagosomes. AB - Autophagosomes are double-membrane vesicles characteristic of macroautophagy, a degradative pathway for cytoplasmic material and organelles terminating in the lysosomal or vacuole compartment for mammals and yeast, respectively. This highly dynamic, multi-step process requires significant membrane reorganization events at different stages of the macroautophagic process. Such events include exchange and flow of lipids and proteins between membranes and vesicles (e.g., during initiation and growth of the phagophore), vesicular positioning and trafficking within the cell (e.g., autophagosome location and movement) and fusion of autophagosomes with the boundary membranes of the degradative compartment. Here, we review current knowledge on the contribution of different organelles to the formation of autophagosomes, their trafficking and fate within the cell. We will consider some of the unresolved questions related to the molecular mechanisms that regulate the "life and death" of the autophagosome. PMID- 22489174 TI - Synthesis and antimicrobial studies of some novel bis-[1,3,4]thiadiazole and bis thiazole pendant to thieno[2,3-b]thiophene moiety. AB - The synthetic utility of 3,3'-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)bis (3 oxopropanenitrile) (1) in the synthesis of some novel bis-[1,3,4-thiadiazole] 6a g and bis-thiazole 10 and 13 derivatives with thieno[2,3-b]thiophene moiety is reported. Antimicrobial evaluation of some selected examples from the synthesized products was carried out and showed promising results. PMID- 22489175 TI - Synthesis and biological activities of a 3'-azido analogue of Doxorubicin against drug-resistant cancer cells. AB - Doxorubicin (DOX), an anthracycline antibiotic, is one of the most active anticancer chemotherapeutic agents. The clinical use of DOX, however, is limited by the dose-dependant P-glycoprotein (P-gp)-mediated resistance. Herein, a 3' azido analogue of DOX (ADOX) was prepared from daunorubicin (DNR). ADOX exhibited potent antitumor activities in drug-sensitive (MCF-7 and K562) and drug-resistant cell lines (MCF-7/DNR, K562/DOX), respectively. The drug resistance index (DRI) values of ADOX were much lower than that of DOX. The cytotoxicity experiments of ADOX or DOX against K562/DOX, with or without P-gp inhibitor, indicated that ADOX circumvents resistance by abolishing the P-gp recognition. This conclusion was further supported by drug influx/efflux flow cytometry experiments, as well as by molecular docking of ADOX to P-gp. In vivo animal tests, ADOX exhibited higher activity and less toxicity than DOX. The current data warranted ADOX for additional pre-clinical evaluations for new drug development. PMID- 22489176 TI - Cellulose biosynthesis inhibitors: comparative effect on bean cell cultures. AB - The variety of bioassays developed to evaluate different inhibition responses for cellulose biosynthesis inhibitors makes it difficult to compare the results obtained. This work aims (i) to test a single inhibitory assay for comparing active concentrations of a set of putative cellulose biosynthesis inhibitors and (ii) to characterize their effect on cell wall polysaccharides biosynthesis following a short-term exposure. For the first aim, dose-response curves for inhibition of dry-weight increase following a 30 days exposure of bean callus cultured cells to these inhibitors were obtained. The compound concentration capable of inhibiting dry weight increase by 50% compared to control (I(50)) ranged from subnanomolar (CGA 325'615) to nanomolar (AE F150944, flupoxam, triazofenamide and oxaziclomefone) and micromolar (dichlobenil, quinclorac and compound 1) concentrations. In order to gain a better understanding of the effect of the putative inhibitors on cell wall polysaccharides biosynthesis, the [(14)C]glucose incorporation into cell wall fractions was determined after a 20 h exposure of cell suspensions to each inhibitor at their I(50) value. All the inhibitors tested decreased glucose incorporation into cellulose with the exception of quinclorac, which increased it. In some herbicide treatments, reduction in the incorporation into cellulose was accompanied by an increase in the incorporation into other fractions. In order to appreciate the effect of the inhibitors on cell wall partitioning, a cluster and Principal Component Analysis (PCA) based on the relative contribution of [(14)C]glucose incorporation into the different cell wall fractions were performed, and three groups of compounds were identified. The first group included quinclorac, which increased glucose incorporation into cellulose; the second group consisted of compound 1, CGA 325'615, oxaziclomefone and AE F150944, which decreased the relative glucose incorporation into cellulose but increased it into tightly-bound cellulose fractions; and the third group, comprising flupoxam, triazofenamide and dichlobenil, decreased the relative glucose incorporation into cellulose and increased it into a pectin rich fraction. PMID- 22489177 TI - Effect of polyethylene glycol modification of TiO2nanoparticles on cytotoxicity and gene expressions in human cell lines. AB - Nanoparticles (NPs) are tiny materials used in a wide range of industrial and medical applications. Titanium dioxide (TiO(2)) is a type of nanoparticle that is widely used in paints, pigments, and cosmetics; however, little is known about the impact of TiO(2) on human health and the environment. Therefore, considerable research has focused on characterizing the potential toxicity of nanoparticles such as TiO(2) and on understanding the mechanism of TiO(2) NP-induced nanotoxicity through the evaluation of biomarkers. Uncoated TiO(2) NPs tend to aggregate in aqueous media, and these aggregates decrease cell viability and induce expression of stress-related genes, such as those encoding interleukin-6 (IL-6) and heat shock protein 70B' (HSP70B'), indicating that TiO(2) NPs induce inflammatory and heat shock responses. In order to reduce their toxicity, we conjugated TiO(2) NPs with polyethylene glycol (PEG) to eliminate aggregation. Our findings indicate that modifying TiO(2) NPs with PEG reduces their cytotoxicity and reduces the induction of stress-related genes. Our results also suggest that TiO(2) NP-induced effects on cytotoxicity and gene expression vary depending upon the cell type and surface modification. PMID- 22489178 TI - Photosensized controlling benzyl methacrylate-based matrix enhanced Eu(3+) narrow band emission for fluorescence applications. AB - This study synthesized a europium (Eu(3+)) complex Eu(DBM)(3)Cl-MIP (DBM = dibenzoyl methane; Cl-MIP = 2-(2-chlorophenyl)-1-methyl-1H-imidazo[4,5 f][1,10]phenanthroline) dispersed in a benzyl methacrylate (BMA) monomer and treated with ultraviolet (UV) light for polymerization. Spectral results showed that the europium complex containing an antenna, Cl-MIP, which had higher triplet energy into the Eu(3+) energy level, was an energetically enhanced europium emission. Typical stacking behaviors of pi-pi interactions between the ligands and the Eu(3+)-ion were analyzed using single crystal X-ray diffraction. Regarding the luminescence performance of this europium composite, the ligand/defect emission was suppressed by dispersion in a poly-BMA (PBMA) matrix. The underlying mechanism of the effective enhancement of the pure Eu(3+) emission was attributed to the combined effects of structural modifications, defect emissions, and carrier charge transfer. Fluorescence spectra were compared to the composite of optimized Eu3+ emission where they were subsequently chelated to four metal ions via carboxylate groups on the BMA unit. The optical enhanced europium composite clearly demonstrated highly efficient optical responses and is, therefore a promising application as an optical detection material. PMID- 22489179 TI - Antihyperglycemic and antioxidative effects of Hydroxyethyl Methylcellulose (HEMC) and Hydroxypropyl Methylcellulose (HPMC) in mice fed with a high fat diet. AB - The effect of dietary feeding of hydroxyethyl methylcellulose (HEMC) and hydroxypropyl methylcellulose (HPMC) on the glucose metabolism and antioxidative status in mice under high fat diet conditions was investigated. The mice were randomly divided and given experimental diets for six weeks: normal control (NC group), high fat (HF group), and high fat supplemented with either HEMC (HF+HEMC group) or HPMC (HF+HPMC group). At the end of the experimental period, the HF group exhibited markedly higher blood glucose and insulin levels as well as a higher erythrocyte lipid peroxidation rate relative to the control group. However, diet supplementation of HEMC and HPMC was found to counteract the high fat-induced hyperglycemia and oxidative stress via regulation of antioxidant and hepatic glucose-regulating enzyme activities. These findings illustrate that HEMC and HPMC were similarly effective in improving the glucose metabolism and antioxidant defense system in high fat-fed mice and they may be beneficial as functional biomaterials in the development of therapeutic agents against high fat dietinduced hyperglycemia and oxidative stress. PMID- 22489180 TI - Expression analysis of four peroxiredoxin genes from Tamarix hispida in response to different abiotic stresses and Exogenous Abscisic Acid (ABA). AB - Peroxiredoxins (Prxs) are a recently discovered family of antioxidant enzymes that catalyze the reduction of peroxides and alkyl peroxides. In this study, four Prx genes (named as ThPrxII, ThPrxIIE, ThPrxIIF, and Th2CysPrx) were cloned from Tamarix hispida. Their expression profiles in response to stimulus of NaCl, NaHCO(3), PEG, CdCl(2) and abscisic acid (ABA) in roots, stems and leaves of T. hispida were investigated using real-time RT-PCR. The results showed that the four ThPrxs were all expressed in roots, stems and leaves. Furthermore, the transcript levels of ThPrxIIE and ThPrxII were the lowest and the highest, respectively, in all tissue types. All the ThPrx genes were induced by both NaCl and NaHCO(3) and reached their highest expression levels at the onset of stress in roots. Under PEG and CdCl(2) stress, the expression patterns of these ThPrxs showed temporal and spatial specificity. The expressions of the ThPrxs were all differentially regulated by ABA, indicating that they are all involved in the ABA signaling pathway. These findings reveal a complex regulation of Prxs that is dependent on the type of Prx, tissue, and the signaling molecule. The divergence of the stress-dependent transcriptional regulation of the ThPrx gene family in T. hispida may provide an essential basis for the elucidation of Prx function in future work. PMID- 22489181 TI - Production of protocatechuic acid in Bacillus Thuringiensis ATCC33679. AB - Protocatechuic acid, or 3,4-dihydroxybenzoic acid, is produced by both soil and marine bacteria in the free form and as the iron binding component of the siderophore petrobactin. The soil bacterium, Bacillus thuringiensis kurstaki ATCC 33679, contains the asb operon, but does not produce petrobactin. Iron restriction resulted in diminished B. thuringiensis kurstaki ATCC 33679 growth and the production of catechol(s). The gene product responsible for protocatechuic acid (asbF) and its receptor (fatB) were expressed during stationary phase growth. Gene expression varied with growth temperature, with optimum levels occurring well below the Bacillus anthracis virulence temperature of 37 degrees C. Regulation of protocatechuic acid suggests a possible role for this compound during soil growth cycles. PMID- 22489182 TI - Recent advances of flowering locus T gene in higher plants. AB - Flowering Locus T (FT) can promote flowering in the plant photoperiod pathway and also facilitates vernalization flowering pathways and other ways to promote flowering. The expression of products of the FT gene is recognized as important parts of the flowering hormone and can induce flowering by long-distance transportation. In the present study, many FT-like genes were isolated, and the transgenic results show that FT gene can promote flowering in plants. This paper reviews the progress of the FT gene and its expression products to provide meaningful information for further studies of the functions of FT genes. PMID- 22489183 TI - Increasing the X-ray diffraction power of protein crystals by dehydration: the case of bovine serum albumin and a survey of literature data. AB - Serum albumin is one of the most widely studied proteins. It is the most abundant protein in plasma with a typical concentration of 5 g/100 mL and the principal transporter of fatty acids in plasma. While the crystal structures of human serum albumin (HSA) free and in complex with fatty acids, hemin, and local anesthetics have been characterized, no crystallographic models are available on bovine serum albumin (BSA), presumably because of the poor diffraction power of existing hexagonal BSA crystals. Here, the crystallization and diffraction data of a new BSA crystal form, obtained by the hanging drop method using MPEG 5K as precipitating agent, are presented. The crystals belong to space group C2, with unit-cell parameters a = 216.45 A, b = 44.72 A, c = 140.18 A, beta = 114.5 degrees . Dehydration was found to increase the diffraction limit of BSA crystals from ~8 A to 3.2 A, probably by improving the packing of protein molecules in the crystal lattice. These results, together with a survey of more than 60 successful cases of protein crystal dehydration, confirm that it can be a useful procedure to be used in initial screening as a method of improving the diffraction limits of existing crystals. PMID- 22489185 TI - Inroads to predict in vivo toxicology-an introduction to the eTOX Project. AB - There is a widespread awareness that the wealth of preclinical toxicity data that the pharmaceutical industry has generated in recent decades is not exploited as efficiently as it could be. Enhanced data availability for compound comparison ("read-across"), or for data mining to build predictive tools, should lead to a more efficient drug development process and contribute to the reduction of animal use (3Rs principle). In order to achieve these goals, a consortium approach, grouping numbers of relevant partners, is required. The eTOX ("electronic toxicity") consortium represents such a project and is a public-private partnership within the framework of the European Innovative Medicines Initiative (IMI). The project aims at the development of in silico prediction systems for organ and in vivo toxicity. The backbone of the project will be a database consisting of preclinical toxicity data for drug compounds or candidates extracted from previously unpublished, legacy reports from thirteen European and European operation-based pharmaceutical companies. The database will be enhanced by incorporation of publically available, high quality toxicology data. Seven academic institutes and five small-to-medium size enterprises (SMEs) contribute with their expertise in data gathering, database curation, data mining, chemoinformatics and predictive systems development. The outcome of the project will be a predictive system contributing to early potential hazard identification and risk assessment during the drug development process. The concept and strategy of the eTOX project is described here, together with current achievements and future deliverables. PMID- 22489184 TI - The effect of osmolytes on protein fibrillation. AB - Osmolytes are small molecules that are exploited by cells as a protective system against stress conditions. They favour compact protein states which makes them stabilize globular proteins in vitro and promote folding. Conversely, this preference for compact states promotes aggregation of unstructured proteins. Here we combine a brief review of the effect of osmolytes on protein fibrillation with a report of the effect of osmolytes on the unstructured peptide hormone glucagon. Our results show that osmolytes either accelerate the fibrillation kinetics or leave them unaffected, with the exception of the osmolyte taurine. Furthermore, the osmolytes that affected the shape of the fibrillation time profile led to fibrils with different structure as revealed by CD. The structural changes induced by Pro, Ser and choline-O-sulfate could be due to specific osmolytes binding to the peptides, stabilizing an otherwise labile fibrillation intermediate. PMID- 22489187 TI - Antinociceptive and anti-inflammatory effects of ethanol extract from Vernonia polyanthes leaves in Rodents. AB - The ethanol extract from Vernonia polyanthes leaves (EEVP) was investigated for antinociceptive and anti-inflammatory effects at the doses (p.o.) of 100, 200 and 400 mg/kg in animal models. The extract reduced the number of abdominal contortions by 16.75% and 31.44% at a dose of 200 and 400 mg/kg, respectively. The results obtained showed that EEVP exerted a significant antinociceptive effect in the two phases of formalin. The EEVP increased the reaction time on a hot plate at the doses of 100, 200 and 400 mg/kg after 90 min of treatment. The paw edema was reduced by EEVP at the doses of 100, 200 and 400 mg/kg after 4 h of application of carrageenan. Doses of 200 and 400 mg/kg, administered 4 h before the carrageenan injection, significantly reduced the exudate volume (29.25 and 45.74%, respectively) and leukocyte migration (18.19 and 27.95%, respectively). These results suggest that V. polyanthes can be an active source of substances with antinociceptive and anti-inflammatory activities. PMID- 22489188 TI - Genetic diversity of the endemic and medicinally important plant Rheum officinale as revealed by Inter-Simpe Sequence Repeat (ISSR) Markers. AB - Rheum officinale Baill., an important but endangered medicinal herb, is endemic to China. Inter-simple sequence repeat (ISSR) markers were employed to investigate the genetic diversity and differentiation of 12 populations of R. officinale. Thirteen selected primers yielded 189 bright and discernible bands, with an average of 14.54 per primer. The genetic diversity was low at the population level, but pretty high at the species level (H = 0.1008, I = 0.1505, PPB = 28.95% vs. H = 0.3341, I = 0.5000, PPB = 95.24%, respectively) by POPGENE analysis. Analysis of molecular variance (AMOVA) showed that the genetic variation was found mainly among populations (74.38%), in line with the limited gene flow (N(m) = 0.2766) among populations. Mantel test revealed a significant correlation between genetic and geographic distances (r = 0.5381, P = 0.002), indicating the role of geographic isolation in shaping the present population genetic structure. Both Bayesian analysis and UPGMA cluster analysis demonstrated the similar results. Our results imply that the conservation efforts should aim to preserve all the extant populations of this endangered species, and cultivation is proposed in this study. PMID- 22489186 TI - Functionalized nanostructures with application in regenerative medicine. AB - In the last decade, both regenerative medicine and nanotechnology have been broadly developed leading important advances in biomedical research as well as in clinical practice. The manipulation on the molecular level and the use of several functionalized nanoscaled materials has application in various fields of regenerative medicine including tissue engineering, cell therapy, diagnosis and drug and gene delivery. The themes covered in this review include nanoparticle systems for tracking transplanted stem cells, self-assembling peptides, nanoparticles for gene delivery into stem cells and biomimetic scaffolds useful for 2D and 3D tissue cell cultures, transplantation and clinical application. PMID- 22489189 TI - Enhancement of biocontrol efficacy of Pichia carribbica to postharvest diseases of strawberries by addition of trehalose to the growth medium. AB - The effects of trehalose on the antagonistic activity of Pichia caribbica against Rhizopus decay and gray mold decay of strawberries and the possible mechanisms involved were investigated. The proteomic analysis and comparison of P. carribbica in response to trehalose was analyzed based on two-dimensional gel electrophoresis. The antagonistic activity of P. carribbica harvested from the culture media of NYDB amended with trehalose at 0.5% was improved greatly compared with that without trehalose. The PPO (Polyphenoloxidase) and POD (Peroxidase) activity of strawberries treated with P. carribbica cultured in the NYDB media amended with trehalose at 0.5% was higher than that of the strawberries treated with P. carribbica harvested from NYDB. The beta-1, 3 glucanase activity of strawberries treated with P. carribbica cultured in the NYDB media amended with trehalose at 0.5% was also higher than that of the strawberries treated with P. carribbica harvested from NYDB and the control. Several differentially expressed proteins of P. carribbica in response to trehalose were identified in the cellular proteome, most of them were related to basic metabolism. PMID- 22489190 TI - A single-chamber microbial fuel cell without an air cathode. AB - Microbial fuel cells (MFCs) represent a novel technology for wastewater treatment with electricity production. Electricity generation with simultaneous nitrate reduction in a single-chamber MFC without air cathode was studied, using glucose (1 mM) as the carbon source and nitrate (1 mM) as the final electron acceptor employed by Bacillus subtilis under anaerobic conditions. Increasing current as a function of decreased nitrate concentration and an increase in biomass were observed with a maximum current of 0.4 mA obtained at an external resistance (R(ext)) of 1 KOmega without a platinum catalyst of air cathode. A decreased current with complete nitrate reduction, with further recovery of the current immediately after nitrate addition, indicated the dependence of B. subtilis on nitrate as an electron acceptor to efficiently produce electricity. A power density of 0.0019 mW/cm(2) was achieved at an R(ext) of 220 Omega. Cyclic voltammograms (CV) showed direct electron transfer with the involvement of mediators in the MFC. The low coulombic efficiency (CE) of 11% was mainly attributed to glucose fermentation. These results demonstrated that electricity generation is possible from wastewater containing nitrate, and this represents an alternative technology for the cost-effective and environmentally benign treatment of wastewater. PMID- 22489191 TI - Cooperative modulation of mineral growth by prismatic-associated Asprich Sequences and Mg(II). AB - Cooperative effects of magnesium ions and acidic polypeptides originating from a family of proteins known as Asprich (mollusk Atrina rigida) were studied. In our previous studies, these two acidic polypeptides were found to be effective in controlling the morphology of the calcium carbonate mineral, the main inorganic constituent of prismatic layer of the mollusk shell. Since these Asprich sequences are believed to contain a putative magnesium binding domain, the morphology-controlling effects were further investigated with the addition of magnesium ions. The mineral morphology was dramatically changed by the combined influence of each polypeptides and the magnesium ions, substantiating the recognized importance of magnesium in the formation of calcium carbonate-based biominerals. PMID- 22489193 TI - Therapeutic effect of Arsenicum album on leukocytes. AB - The therapeutic effects of homoeopathic Arsenicum album potencies were investigated in-vitro, using a continuous cell line (MT4), pre-intoxicated with arsenic trioxide (As(2)O(3)), and then treated with succussed and unsuccussed homoeopathic potencies, 6CH, 30CH and 200CH. This study aimed to verify the homoeopathic law of similars and to determine whether potencies diluted beyond Avogadro's constant had physiological effects on cells; whether various potencies would cause different effects as suggested by the concept of hormesis; whether succussed and unsuccussed homoeopathic potencies had different effects on the cells; and to establish whether a biotechnological method could be used to evaluate the above. As(2)O(3) was used to pre-intoxicate and the MTT assay was used to measure the percentage cytotoxicity and half maximal inhibitory concentration (IC(50)) of the cells. The homoeopathic potencies of Arsenicum album (6CH, 30CH and 200CH) were prepared by either succussing or allowing to diffuse for 30 s. After pre-intoxication of the MT4 cells with the IC(50) As(2)O(3) and treatment with succussed and unsuccussed Arsenicum album (6CH 200CH), the cell viability increased with increasing potency from 81% to 194% (over 72 h). The treatments and the times of exposure were found to be statistically significant determinants of cell viability, whereas succussion did not cause any significant variation in the results. The study provided evidence that a biotechnological method (namely cell viability) may be used to scientifically evaluate the physiological effects of homoeopathic potencies on human cells; it confirmed that the homoeopathic potencies did have therapeutic effects; and that succussion was not required in the potentization method in order to produce a curative remedy. PMID- 22489192 TI - Curcumin: updated molecular mechanisms and intervention targets in human lung cancer. AB - Curcumin, a yellow pigment derived from Curcuma longa Linn, has attracted great interest in the research of cancer during the past decades. Extensive studies documented that curcumin attenuates cancer cell proliferation and promotes apoptosis in vivo and in vitro. Curcumin has been demonstrated to interact with multiple molecules and signal pathways, which makes it a potential adjuvant anti cancer agent to chemotherapy. Previous investigations focus on the mechanisms of action for curcumin, which is shown to manipulate transcription factors and induce apoptosis in various kinds of human cancer. Apart from transcription factors and apoptosis, emerging studies shed light on latent targets of curcumin against epidermal growth factor receptor (EGFR), microRNAs (miRNA), autophagy and cancer stem cell. The present review predominantly discusses significance of EGFR, miRNA, autophagy and cancer stem cell in lung cancer therapy. Curcumin as a natural phytochemicals could communicate with these novel targets and show synergism to chemotherapy. Additionally, curcumin is well tolerated in humans. Therefore, EGFR-, miRNA-, autophagy- and cancer stem cell-based therapy in the presence of curcumin might be promising mechanisms and targets in the therapeutic strategy of lung cancer. PMID- 22489194 TI - Dihydrolipoic acid induces cytotoxicity in mouse blastocysts through apoptosis processes. AB - alpha-Lipoic acid (LA) is a thiol with antioxidant properties that protects against oxidative stress-induced apoptosis. LA is absorbed from the diet, taken up by cells and tissues, and subsequently reduced to dihydrolipoic acid (DHLA). In view of the recent application of DHLA as a hydrophilic nanomaterial preparation, determination of its biosafety profile is essential. In the current study, we examined the cytotoxic effects of DHLA on mouse embryos at the blastocyst stage, subsequent embryonic attachment and outgrowth in vitro, in vivo implantation by embryo transfer, and early embryonic development in an animal model. Blastocysts treated with 50 MUM DHLA exhibited significantly increased apoptosis and a corresponding decrease in total cell number. Notably, the implantation success rates of blastocysts pretreated with DHLA were lower than that of their control counterparts. Moreover, in vitro treatment with 50 MUM DHLA was associated with increased resorption of post-implantation embryos and decreased fetal weight. Data obtained using an in vivo mouse model further disclosed that consumption of drinking water containing 100 MUM DHLA led to decreased early embryo development, specifically, inhibition of development to the blastocyst stage. However, it appears that concentrations of DHLA lower than 50 MUM do not exert a hazardous effect on embryonic development. Our results collectively indicate that in vitro and in vivo exposure to concentrations of DHLA higher than 50 MUM DHLA induces apoptosis and retards early pre- and post implantation development, and support the potential of DHLA to induce embryonic cytotoxicity. PMID- 22489195 TI - Complications of extracorporeal shock wave lithotripsy for urinary stones: to know and to manage them-a review. AB - To identify the possible complications after extracorporeal shock wave lithotripsy (SWL) and to suggest how to manage them, the significant literature concerning SWL treatment and complications was analyzed and reviewed. Complications after SWL are mainly connected to the formation and passage of fragments, infections, the effects on renal and nonrenal tissues, and the effects on kidney function. Each of these complications can be prevented adopting appropriate measures, such as the respect of the contraindications and the recognition and the correction of concomitant diseases or infection, and using the SWL in the most efficient and safe way, tailoring the treatment to the single case. In conclusion, SWL is an efficient and relatively noninvasive treatment for urinary stones. However, as with any other type of therapy, some contraindications and potential complications do exist. The strictness in following the first could really limit the onset and danger of the appearance of others, which however must be fully known so that every possible preventive measure be implemented. PMID- 22489196 TI - Lymphocytes mitochondrial physiology as biomarker of energy metabolism during fasted and fed conditions. AB - Mitochondria are central coordinators of energy metabolism, and changes of their physiology have long been associated with metabolic disorders. Thus, observations of energy dynamics in different cell types are of utmost importance. Therefore, tools with quick and easy handling are needed for consistent evaluations of such interventions. In this paper, our main hypothesis is that during different nutritional situations lymphocytes mitochondrial physiology could be associated with the metabolism of other cell types, such as cardiomyocytes, and consequently be used as metabolic biomarker. Blood lymphocytes and heart muscle fibers were obtained from both fed and 24 h-fasted mice, and mitochondrial analysis was assessed by high-resolution respirometry and western blotting. Carbohydrate linked oxidation and fatty acid oxidation were significantly higher after fasting. Carnitine palmitoil transferase 1 and uncouple protein 2 contents were increased in the fasted group, while the glucose transporters 1 and 4 and the ratio phosphorylated AMP-activated protein kinase/AMPK did not change between groups. In summary, under a nutritional status modification, mitochondria demonstrated earlier adaptive capacity than other metabolic sensors such as glucose transporters and AMPK, suggesting the accuracy of mitochondria physiology of lymphocytes as biomarker for metabolic changes. PMID- 22489197 TI - Assessment of physical-chemical characteristics of water and sediments from a Brazilian tropical estuary: status and environmental implications. AB - The environmental quality of the Jacuipe River's estuary (very important in northeastern Brazil) was assessed during 2007 and 2008. In water, concentrations (mg L-1) of NO2- (<0.004 to 0.016), NO3- (0.01 to 0.33), soluble PO43- (<0.02 to 0.22), dissolved oxygen (3.9 to 9.6), total contents (mg L-1) of Cd (<0.001), Cu (<0.01), Pb (<0.01), and Zn (<0.1), pH (5.60 to 8.00), and electrical conductivity (0.12 to 48.60 mS cm-1) agreed with environmental standards. In sediments, clay and total organic matter (%, m/m) varied, respectively, from 8.8 to 12.0 and from 1.1 to 8.8, while infrared, thermogravimetric profile, electronic micrograph, as well as X-Ray analyses showed desirable adsorptive characteristics. However, maximum exchangeable levels (mg kg-1) of Cd (1.3), Cu (44.6), Pb (35.7), and Zn (43.7) and their respective maximum pseudototal concentrations (mg kg-1): 19.4, 95.1, 68.2, and 30.3 were below the recommended limits. In this sense, it was possible to demonstrate good environmental preservation even with the growing number of industries and touristic activities in the evaluated estuarine area. PMID- 22489198 TI - Immobilization of peroxidase onto magnetite modified polyaniline. AB - The present study describes the immobilization of horseradish peroxidase (HRP) on magnetite-modified polyaniline (PANImG) activated with glutaraldehyde. After the optimization of the methodology, the immobilization of HRP on PANImG produced the same yield (25%) obtained for PANIG with an efficiency of 100% (active protein). The optimum pH for immobilization was displaced by the effect of the partition of protons produced in the microenvironment by the magnetite. The tests of repeated use have shown that PANImG-HRP can be used for 13 cycles with maintenance of 50% of the initial activity. PMID- 22489199 TI - Levels of heavy metals in popular cigarette brands and exposure to these metals via smoking. AB - The levels of selected heavy metals in popular cigarette brands sold and/or produced in Saudi Arabia were determined by graphite furnace-atomic absorption spectrometry (GFAAS). Average concentrations of Cadmium and Lead in different cigarette brands were 1.81 and 2.46 MUg g-1 (dry weight), respectively. The results obtained in this study estimate the average quantity of Cd inhaled from smoking one packet of 20 cigarettes to be in the range of 0.22-0.78 MUg. Results suggest that the quantity of Pb inhaled of smoking one packet of 20 cigarettes is estimated to be 0.97-2.64 MUg. The concentrations of Cd and Pb in cigarettes were significantly different between cigarette brands tested. The results of the present study were compared with those of other regional and international studies. PMID- 22489200 TI - Diagnostic value of dynamic contrast-enhanced magnetic resonance imaging in the evaluation of the biliary obstruction. AB - PURPOSE: In this study, our purpose was to investigate the diagnostic efficacy of the dynamic contrast-enhanced magnetic resonance imaging (MRI) method in the patients with bile duct obstruction. MATERIALS AND METHODS: 108 consecutive patients (53 men, 55 women, mean age; 55.77 +/- 14.62, range 18-86 years) were included in this study. All the patients underwent conventional upper abdomen MRI using intravenous contrast material (Gd-DTPA) and MRCP in 1.5 Tesla MRI scanner. MRCP images were evaluated together with the T1 and T2w images, and both biliary ducts and surrounding tissues were examined for possible pathologies that may cause obstruction. RESULTS: MRI/MRCP findings compared with final diagnoses, MRI/MRCP in the demonstration of bile duct obstruction sensitivity 96%, the specificity 100%, and accuracy 96.3%, in the detection of presence and level of obstruction, the sensitivity 96.7%, specificity 100%, and accuracy 97.2%, in the diagnosis of choledocholithiasis, the sensitivity 82.3%, specificity 96%, and accuracy 91.7%, and in the determination of the character of the stenosis, sensitivity 95.6%, specificity 91.3%, and accuracy 94.5% were found. CONCLUSION: The combination of dynamic contrast-enhanced MRI and MRCP techniques in patients with suspected biliary obstruction gives the detailed information about the presence of obstruction, location, and causes and is a highly specific and sensitive method. PMID- 22489201 TI - New synthetic pyridine derivate as potential elicitor in production of isoflavonoids and flavonoids in Trifolium pratense L. suspension culture. AB - The production of secondary metabolites in Trifolium pratense L. suspension culture of the family of legume plants (Fabaceae) is low, and therefore there was an attempt to increase it by elicitation. New synthetic substance, 2-(2-fluoro-6 nitrobenzylsulfanyl)pyridine-4-carbothioamide, was tested as elicitor--a substance that showed the best elicitation effect after 48-hour application of 1 MUmol L-1 concentration. Maximum contents of genistin (11.60 mg g-1 DW), daidzein (8.31 mg g-1 DW), and genistein (1.50 mg g-1 DW) were recorded, and the production of these isoflavonoids thus significantly increased, when compared with the control, by 152%, 151%, and 400%. The maximum content of flavonoids (5.78 mg g-1 DW) and the increase in the production by 142%, when compared with the control, were induced by 6-hour application of 100 MUmol L-1 concentration. The tested substance showed to be an effective elicitor of phenylpropane metabolism. PMID- 22489202 TI - Ecology of indigenous lactic acid bacteria along different winemaking processes of Tempranillo red wine from La Rioja (Spain). AB - Ecology of the lactic acid bacteria (LAB) during alcoholic fermentation (AF) and spontaneous malolactic fermentation (MLF) of Tempranillo wines from four wineries of La Rioja has been studied analyzing the influence of the winemaking method, processing conditions, and geographical origin. Five different LAB species were isolated during AF, while, during MLF, only Oenococcus oeni was detected. Although the clonal diversity of O. oeni strains was moderate, mixed populations were observed, becoming at least one strain with distinct PFGE profile the main responsible for MLF. Neither the winemaking method nor the cellar situation was correlated with the LAB diversity. However, processing conditions influenced the total number of isolates and the percentage of each isolated species and strains. The winemaking method could cause that genotypes found in semicarbonic maceration did not appear in other wineries. Four genotypes of O. oeni were isolated in more than one of the rest wineries. These four together with other dominant strains might be included in a future selection process. PMID- 22489203 TI - Intra-arterial prostaglandin e(1) infusion in patients with rest pain: short-term results. AB - PURPOSE: To present our results after short-term (1 month) intra-arterial infusion therapy of PGE1-alprostadil via a port system implanted in the ipsilateral external iliac artery (EIA) in patients with severe rest pain. METHODS: Ten patients with severe rest pain were included. All patients showed extensive peripheral vascular disease below the knee. The tip of the catheter was introduced via a retrograde puncture in the ipsilateral external iliac artery (EIA). The patients received intraarterial infusion of PGE1, 20 mgr alprostadil daily, via the port catheter for 1 month. RESULTS: Clinical success was evaluated according to subjective grading of pain (group A significant decrease, group B moderate decrease and group C no response). A significant decrease of rest pain was observed in 8 (group A, 80%) patients, a moderate decrease in 2 (Group B, 20%), whereas no patients demonstrated any significant response. Both patients of group B had Buergers' disease and continue to smoke during therapy. No peripheral thrombosis or clinical deterioration was noticed. CONCLUSION: Intraarterial infusion of PGE1 alprostadil on a daily basis, using a port catheter into the ipsilateral EIA, in selected patients with severe rest pain, seems to be very effective, without any serious complications. PMID- 22489204 TI - Sociodemographic determinants of nonattendance in a population-based mammography screening program in the city of Manisa, Turkey. AB - OBJECTIVES: Community based breast cancer screening has decreased breast cancer mortality in women. This study examined the predictors of nonattendence for invitational breast cancer screening in relation to socioeconomic status in the city of Manisa, in western Turkey. STUDY DESIGN: For the evaluation of the reasons for refusing to participate in the study, two districts were selected. 446 women aged between 50 and 69 years were selected from the program database by systematic random sampling. METHODS: The questionnaire consisted of sociodemographic variables and the adapted version of Champion's Health Belief Model Scale. Univariete and multivariete logistic regression analysis were performed throughout the data analysis. RESULTS: Being from an urban district and being from the western region were the risk factors for not participating in the screening program (P = 0.014, P = 0.023). A statistical significance was found between mammography-benefit, mammography-barrier and program participation (P = 0.044, P = 0.006). Although there were many more barriers for not participating in the screening program for the women of the slum district, the attendence rate of the slum district was higher than that of the urban district. CONCLUSIONS: Increased attendance may be achieved through enhancement of breast cancer awareness and by reducing some of the modifiable barriers. PMID- 22489205 TI - Dietary (n-6 : n-3) fatty acids alter plasma and tissue fatty acid composition in pregnant Sprague Dawley rats. AB - The objective of this paper is to study the effects of varying dietary levels of n-6 : n-3 fatty acid ratio on plasma and tissue fatty acid composition in rat. The treatment groups included control rats fed chow diet only, rats fed 50% soybean oil (SBO): 50% cod liver oil (CLO) (1 : 1), 84% SBO: 16% CLO (6 : 1), 96% SBO: 4% CLO (30 : 1). Blood samples were taken at day 15 of pregnancy, and the plasma and tissue were analyzed for fatty acid profile. The n-3 PUFA in plasma of Diet 1 : 1 group was significantly higher than the other diet groups, while the total n-6 PUFA in plasma was significantly higher in Diet 30 : 1 group as compared to the control and Diet 1 : 1 groups. The Diet 1 : 1 group showed significantly greater percentages of total n-3 PUFA and docosahexaenoic acid in adipose and liver tissue, and this clearly reflected the contribution of n-3 fatty acids from CLO. The total n-6 PUFA, linoleic acid, and arachidonic acid were significantly difference in Diet 30 : 1 as compared to Diet 1 : 1 and control group. These results demonstrated that the dietary ratio of n-6 : n-3 fatty acid ratio significantly affected plasma and tissue fatty acids profile in pregnant rat. PMID- 22489206 TI - Social network characteristics and salivary cortisol in healthy older people. AB - Psychobiological research on aging in humans has been confounded by individual differences that have not been adequately characterized in the literature. This paper is an attempt to shed light on this issue by examining the impact of social network characteristics predictive of successful aging on salivary cortisol among 78 older Chinese people in Hong Kong. Eight salivary cortisol samples were collected each day for two consecutive days from immediately after awakening to 12 hours later. Two components of the cortisol diurnal cycle, response to awakening and diurnal decline, were examined in relation to social network characteristics including size, emotional support, and cultivation. ANOVAs with repeated measured were run to examine influences of the three social network characteristics on the cortisol awakening response and diurnal decline, with the effects of gender, age, socioeconomic status, and waking time controlled. Results indicated that those who spent more time and effort in developing and strengthening their social ties (i.e., those high in "cultivation") exhibited a significantly greater rise in cortisol in the morning and a significantly steeper decline over the day, thus attesting to more effective activation and deactivation of the HPA axis. Network cultivation reflected a positive motivation to nurture social relationships more than the other two network characteristics. Its effect on cortisol might stem from the positivity underlying the motivation. PMID- 22489207 TI - Separation of poly(styrene-block-t-butyl methacrylate) copolymers by various liquid chromatography techniques. AB - The separation of a mixture of three poly(styrene-block-t-butyl methacrylate) copolymers (PS-b-PtBMA), consisting of polystyrene (PS) blocks of similar length and t-butyl methacrylate (PtBMA) blocks of different lengths, was performed using various chromatographic techniques, that is, a gradient liquid chromatography on reversed-phase (C18 and C8) and normal-phase columns, a liquid chromatography under critical conditions for polystyrene as well as a fully automated two dimensional liquid chromatography that separates block copolymers by chemical composition in the first dimension and by molar mass in the second dimension. The results show that a partial separation of the mixture of PS-b-PtBMA copolymers can be achieved only by gradient liquid chromatography on reversed-phase columns. The coelution of the two block copolymers is ascribed to a much shorter PtBMA block length, compared to the PS block, as well as a small difference in the length of the PtBMA block in two of these copolymers, which was confirmed by SEC MALS and NMR spectroscopy. PMID- 22489208 TI - Comparison of epirubicin-iodized oil suspension and emulsion for transcatheter arterial chemoembolization in VX2 tumor. AB - To compare the antitumor efficacy and safety of transcatheter arterial chemoembolization (TACE) by epirubicin suspension (epirubicin suspension: epirubicin-iodized oil mixture without solution) to that by epirubicin emulsion (epirubicin emulsion: epirubicin-iodized oil mixture with solution), the efficacy of treatment by administration of either an epirubicin suspension or emulsion was examined in an animal model. Changes in plasma epirubicin concentration were compared over 24 h immediately after treatment, and enhanced ultrasonographic and histopathological analysis subsequently conducted 7 days after treatment to determine the growth ratio and proportion of viable tumor cells. The growth ratio and proportion of viable tumor cells were found to be significantly lower in the suspension group than in the emulsion group while the plasma epirubicin concentration was found to be significantly higher in the suspension group than in the emulsion group. These results indicate that administration of an epirubicin suspension is a superior form of TACE compared to that of administration of an epirubicin emulsion. PMID- 22489209 TI - Magnetic resonance image-guided biopsies with a high detection rate of prostate cancer. AB - AIM: To explore the potential of transrectal magnetic resonance image- (MRI-) guided biopsies of the prostate in a patient cohort with prior negative ultrasound guided biopsies. PATIENTS AND METHODS: Ninety-six men with suspected prostate cancer underwent MRI-guided prostate biopsies under real-time imaging control in supine position. RESULTS: Adenocarcinoma of the prostate was detected in 39 of 96 patients. For individual core biopsies, MRI yielded a sensitivity of 93.0% and a specificity of 94.4%. When stratifying patients according to the free to-total prostate-specific antigen (PSA) ratio, the prostate cancer discovery rate was significantly higher in the group with ratios less than 0.15 (57.1%). CONCLUSION: MRI-guided biopsy of the prostate is a diagnostic option for patients with suspected prostate cancer and a history of repeatedly negative transrectal ultrasound-guided biopsies. Combined with the free-to-total PSA ratio, it is a highly effective method for detecting prostate cancer. PMID- 22489210 TI - Developmental principles: fact or fiction. AB - While still at school, most of us are deeply impressed by the underlying principles that so beautifully explain why the chemical elements are ordered as they are in the periodic table, and may wonder, with the theoretician Brian Goodwin, "whether there might be equally powerful principles that account for the awe-inspiring diversity of body forms in the living realm". We have considered the arguments for developmental principles, conclude that they do exist and have specifically identified features that may generate principles associated with Hox patterning of the main body axis in bilaterian metazoa in general and in the vertebrates in particular. We wonder whether this exercise serves any purpose. The features we discuss were already known to us as parts of developmental mechanisms and defining developmental principles (how, and at which level?) adds no insight. We also see little profit in the proposal by Goodwin that there are principles outside the emerging genetic mechanisms that need to be taken into account. The emerging developmental genetic hierarchies already reveal a wealth of interesting phenomena, whatever we choose to call them. PMID- 22489211 TI - Fusion pore diameter regulation by cations modulating local membrane anisotropy. AB - The fusion pore is an aqueous channel that is formed upon the fusion of the vesicle membrane with the plasma membrane. Once the pore is open, it may close again (transient fusion) or widen completely (full fusion) to permit vesicle cargo discharge. While repetitive transient fusion pore openings of the vesicle with the plasma membrane have been observed in the absence of stimulation, their frequency can be further increased using a cAMP-increasing agent that drives the opening of nonspecific cation channels. Our model hypothesis is that the openings and closings of the fusion pore are driven by changes in the local concentration of cations in the connected vesicle. The proposed mechanism of fusion pore dynamics is considered as follows: when the fusion pore is closed or is extremely narrow, the accumulation of cations in the vesicle (increased cation concentration) likely leads to lipid demixing at the fusion pore. This process may affect local membrane anisotropy, which reduces the spontaneous curvature and thus leads to the opening of the fusion pore. Based on the theory of membrane elasticity, we used a continuum model to explain the rhythmic opening and closing of the fusion pore. PMID- 22489212 TI - Vitamins and minerals: issues associated with too low and too high population intakes. AB - There is an ongoing increase in the availability of foods fortified with micronutrients and dietary supplements. This may result in differing intakes of micronutrients within the population and perhaps larger differences in intakes. Insight into population micronutrient intakes and evaluation of too low or too high intakes is required to see whether there are potential problems regarding inadequacy or excessive intakes. Too low population intakes are evaluated against an estimated average requirement; potential too high population intakes are evaluated against a tolerable upper intake level (UL). Additional health effects, seriousness, and incidence of these health effects are not considered but these can be taken into account in a benefit-risk assessment. Furthermore, authorities would like to regulate food fortification and supplementation in such a way that most of the population is not at risk of potentially high intakes. Several models are available for estimating maximum levels of micronutrients for food fortification and dietary supplements. Policy makers and risk managers need to decide how to divide the 'free space' between food fortification and/or dietary supplements, while protecting populations from adverse health effects. PMID- 22489213 TI - Assessing and improving the quality of vitamin data in food composition databases. PMID- 22489214 TI - Vitamin composition of ethnic foods commonly consumed in Europe. AB - BACKGROUND: Vitamin analyses are particularly important for estimating dietary intakes, determining nutritional status and regulating food labelling. Due to the increased popularity of ethnic foods, the vitamin composition of these foods is required to ensure that national food databases are up-to-date. OBJECTIVES: The key objective of this study was to generate new and reliable data on the contents of fat-soluble vitamins, including vitamins A (all trans-retinol), D(3) & E (alpha-tocopherol) and those that are water-soluble (vitamins B(6), B(12), C, biotin, folate, niacin, pantothenic acid, riboflavin, and thiamin) in ethnic foods commonly consumed in Europe. DESIGN: Thirty commonly-consumed ethnic foods in Europe (from Belgium, France, Israel, Italy, The Netherlands, and the UK) were analysed using harmonised methodologies for identification of representative foods, sampling, data scrutiny and documentation to generate reliable data. Analyses were carried out using International standard methods. RESULTS: CERTAIN VITAMINS WERE PRESENT IN APPRECIABLE AMOUNTS: beta-carotene in tayer leaves (7919ug/100g), thiamin in frik dry (0.24mg/100g), riboflavin in mbinzo worms (0.79mg/100g,) and niacin in commercial soy patty (17.5mg/100g). However, retinol, pantothenic acid, vitamins D and B(12) were below detectable levels in the majority of the foods analysed. CONCLUSIONS: The majority of the foods contained most of the water-soluble vitamins but lacked fat-soluble vitamins. However, these preliminary data represent only a small number of foods per country and so no conclusions about vitamin imbalances can be drawn. Additional data are required on a much wider range of commonly-consumed ethnic foods to make firm conclusions about adequacy of diets. PMID- 22489215 TI - Micronutrient intake in relation to all-cause mortality in a prospective Danish cohort. AB - BACKGROUND: Few studies have considered source-specific micronutrient intake in relation to mortality under the consideration that dietary and supplemental intake could exhibit different effects. OBJECTIVE: To evaluate the association between intake of vitamin C, E, folate, beta-carotene from diet and supplements, and overall mortality. Furthermore, to examine effect modification by smoking, alcohol intake, and BMI and to investigate if the effect of supplement use differs with dietary micronutrient intake. METHODS AND MATERIAL: In a prospective cohort study of 55,453 middle-aged Danes, information regarding diet, supplement use, and lifestyle was collected through questionnaires. During follow-up, 6,767 deaths were identified and incidence rate ratios (IRRs) of mortality related to micronutrient intake were calculated using Cox proportional hazards models. RESULTS: The present study found no effect of dietary vitamin C, E, folate, or beta-carotene in relation to mortality. In contrast, supplemental folic acid was associated with a significantly increased mortality, whereas no other micronutrient supplement was associated with mortality. Effect modification by smoking and alcohol intake, but not BMI, was suggested in relation to some dietary micronutrients. The effect of supplements did not differ in groups defined by dietary micronutrient intake. CONCLUSION: This study suggests no effect of dietary micronutrients in relation to overall mortality. Supplemental folic acid was found to be associated with increased mortality, but further studies are required. No other supplemental micronutrient was associated with mortality. PMID- 22489216 TI - Serum unmetabolized folic acid in a nationally representative sample of adults >=60 years in the United States, 2001-2002. PMID- 22489217 TI - Vitamin K: food composition and dietary intakes. AB - Vitamin K is present in the diet in the forms of phylloquinone and menaquinones. Phylloquinone, which is the major dietary source, is concentrated in leafy plants and is the vitamin K form best characterized in terms of food composition and dietary intakes. In contrast, menaquinones are the product of bacterial production or conversion from dietary phylloquinone. Food composition databases are limited for menaquinones and their presence in foods varies by region. Dietary intakes of all forms of vitamin K vary widely among age groups and population subgroups. Similarly, the utilization of vitamin K from different forms and food sources appear to vary, although our understanding of vitamin K is still rudimentary in light of new developments regarding the menaquinones. PMID- 22489219 TI - Assessing vitamin status in large population surveys by measuring biomarkers and dietary intake - two case studies: folate and vitamin D. AB - The National Health and Nutrition Examination Survey (NHANES) provides the most comprehensive assessment of the health and nutrition status of the US population. Up-to-date reference intervals on biomarkers and dietary intake inform the scientific and public health policy communities on current status and trends over time.The main purpose of dietary assessment methods such as the food-frequency questionnaire, food record (or diary), and 24-hr dietary recall is to estimate intake of nutrients and, together with supplement usage information, describe total intake of various foods or nutrients. As with all self-reporting methods, these tools are challenging to use and interpret. Yet, they are needed to establish dietary reference intake recommendations and to evaluate what proportion of the population meets these recommendations. While biomarkers are generally expensive and, to some degree, invasive, there is no question as to their ability to assess nutrition status. In some cases biomarkers can also be used to assess intake or function, although rarely can one biomarker fulfill all these purposes. For example, serum folate is a good indicator of folate intake, red blood cell (RBC) folate is a good status indicator, and plasma total homocysteine is a good functional indicator of one-carbon metabolism.Using folate and vitamin D - two vitamins that are currently hotly debated in the public health arena - as two case studies, we discuss the complexities of using biomarkers and total intake information to assess nutrition status. These two examples also show how biomarkers and intake provide different information and how both are needed to evaluate and set public health policy. We also provide guidance on general requirements for using nutrition biomarkers and food and supplement intake information in longitudinal, population-based surveys. PMID- 22489218 TI - The role of vitamers and dietary-based metabolites of vitamin D in prevention of vitamin D deficiency. AB - There is little doubt that vitamin D deficiency across all age groups in Europe is a problem. Low vitamin D status arises due to limited, if any, dermal synthesis during the winter months at latitudes above 40 degrees N, putting increased importance on dietary supply of the vitamin. However, dietary intakes by most populations are low due to the limited supply of vitamin D-rich foods in the food chain. Thus strategies that effectively address this public health issue are urgently required. It has been emphasized and re-emphasized that there are only a limited number of public health strategies available to correct low dietary vitamin D intake: (1) improving intake of naturally occurring vitamin D rich foods, (2) vitamin D fortification (mandatory or voluntarily) of food, and (3) vitamin D supplementation. Recent evidence suggests that the levels of vitamin D added to food would need to be high so as to ensure dietary requirements are met and health outcomes optimized. In addition, knowledge of the most effective forms of vitamin D to use in some of these preventative approaches is important. There is still uncertainty in relation to the relative efficacy of vitamin D(2) versus D(3), the two main food derived forms and those used in vitamin D supplements. The major metabolite of vitamin D with biological activity is 1,25(OH)(2)D; however, this is usually used for pharmacological purposes and is not typically used in normal, healthy people. The other major metabolite, 25(OH)D, which has also been used for pharmacological purposes is present in certain foods such as meat and meat products (particularly offal) as well as eggs. This metabolite may have the potential to boost vitamin D status up to five times more effectively that native vitamin D(3) in foods. However, the exact bioactivity of this compound needs to be established. PMID- 22489220 TI - Enhancement of the folate content in Egyptian pita bread. AB - INTRODUCTION: Egypt has a high incidence of neural tube defects related to folate deficiency. One major food source for folate is pita (baladi) bread, which is consumed daily. Bioprocessing (e.g. germination) has been reported to increase the folate content in cereals. The aim was to produce pita bread with increased folate content using germinated wheat flour (GWF). METHODS: Prior to milling the effects of germination and drying conditions on folate content in wheat grains were studied. Pita bread was baked from wheat flour substituted with different levels of GWF. The folate content in dough and bread and rheological properties of dough were determined. RESULTS: Germination of wheat grains resulted in, depending on temperature, 3- to 4-fold higher folate content with a maximum of 61 ug/100 g DM (dry matter). The folate content in both flour and bread increased 1.5 to 4-fold depending on the level of flour replacement with GWF. Pita bread baked with 50% sieved GWF was acceptable with respect to colour and layer separation, and had a folate content of 50 ug/100 g DM compared with 30 ug/100 g DM in conventional pita bread (0% GWF). CONCLUSION: Using 50% GWF, pita bread with increased folate content, acceptable for the Egyptian consumer, was produced. Consumption of this bread would increase the average daily folate intake by 75 ug. PMID- 22489221 TI - [Not Available]. PMID- 22489222 TI - Increase of vitamin D(2) by UV-B exposure during the growth phase of white button mushroom (Agaricus bisporus). AB - BACKGROUND: Mushrooms are the only non-animal food source of vitamin D. Wild mushrooms have naturally high vitamin D(2) content, and cultivated mushrooms produce vitamin D(2) from ergosterol when exposed to supplementary UV-B during the post-harvest phase. OBJECTIVES: This study investigated the effects of providing supplementary UV-B during the growth phase on vitamin D(2) formation and the interactions with growth of mushrooms, as compared to supplementary UV-B during the post-harvest phase or exposure to sunlight for both cultivated and wild mushrooms. METHODS: Experiments were carried out with exposure to supplementary UV-B just prior to harvest in the range of 0-2,400 mJ cm(-2). Mushrooms grew for 2 days with or without repeated UV-B exposure each day. Vitamin D(2) and growth rate were determined. In addition, some mushrooms were post-harvest treated by exposure at 200 mJ cm(-2) supplementary UV-B or natural sunlight, prior to vitamin D(2) determination. RESULTS: The content of vitamin D(2) was 0.2-164 ug 100 g(-1) fresh weight, and there was a linear relationship between UV-dose up to 1,000 mJ cm(-2) and vitamin D(2) content. The fast growth rate of the mushrooms diluted the vitamin D(2) from 24 to 3 ug 100 g(-1) within 2 days of exposure at 200 mJ cm(-2). Following repeated UV-B exposure, vitamin D(2) increased to 33 ug vitamin D(2) 100 g(-1). Growth was unaffected by UV-B. Post harvest exposure to supplementary UV-B resulted in a higher vitamin D(2) content of 32 ug 100 g(-1) compared to the 24 ug 100 g(-1) obtained from exposure to UV-B during the growth phase. In contrast, wild and cultivated mushrooms with and without exposure to sunlight had vitamin D(2) content in the range of 0.2-1.5 ug vitamin D(2) 100 g(-1). CONCLUSIONS: This study showed that mushrooms with a well defined content of vitamin D(2) can be obtained by exposure to supplementary UV-B just prior to harvest. PMID- 22489223 TI - Accounting for differences in the bioactivity and bioavailability of vitamers. AB - Essentially all vitamins exist with multiple nutritionally active chemical species often called vitamers. Our quantitative understanding of the bioactivity and bioavailability of the various members of each vitamin family has increased markedly, but many issues remain to be resolved concerning the reporting and use of analytical data. Modern methods of vitamin analysis rely heavily on chromatographic techniques that generally allow the measurement of the individual chemical forms of vitamins. Typical applications of food analysis include the evaluation of shelf life and storage stability, monitoring of nutrient retention during food processing, developing food composition databases and data needed for food labeling, assessing dietary adequacy and evaluating epidemiological relationships between diet and disease. Although the usage of analytical data varies depending on the situation, important issues regarding how best to present and interpret the data in light of the presence of multiple vitamers are common to all aspects of food analysis. In this review, we will evaluate the existence of vitamers that exhibit differences in bioactivity or bioavailability, consider when there is a need to address differences in bioactivity or bioavailability of vitamers, and then consider alternative approaches and possible ways to improve the reporting of data. Major examples are taken from literature and experience with vitamin B(6) and folate. PMID- 22489224 TI - Vitamin K: the effect on health beyond coagulation - an overview. AB - Vitamin K is essential for the synthesis of proteins belonging to the Gla-protein family. To the members of this family belong four blood coagulation factors, which all are exclusively formed in the liver. The importance of vitamin K for hemostasis is demonstrated from the fact that vitamin K-deficiency is an acute, life-threatening condition due to excessive bleeding. Other members of the Gla protein family are osteocalcin, matrix Gla-protein (MGP), and Gas6 that play key functions in maintaining bone strength, arterial calcification inhibition, and cell growth regulation, respectively. In total 17 Gla-proteins have been discovered at this time. Recently, it was observed that the dietary vitamin K requirement for the synthesis of the coagulation factors is much lower than for that of the extra-hepatic Gla-proteins. This forms the basis of the triage theory stating that during poor dietary supply, vitamins are preferentially utilized for functions that are important for immediate survival. This explains why in the healthy population all clotting factors are synthesized in their active form, whereas the synthesis of other Gla-proteins is sub-optimal in non-supplemented subjects. Prolonged sub-clinical vitamin K deficiency is a risk factor for osteoporosis, atherosclerosis, and cancer. Present recommendations for dietary intake are based on the daily dose required to prevent bleeding. Accumulating scientific data suggests that new, higher recommendations for vitamin K intake should be formulated. PMID- 22489225 TI - Young Public's Awareness to Refractive Error Deficiency. AB - BACKGROUND: Visual impairment due to uncorrected refractive error affects 200 - 250 million people in the world. Uncorrected vision represents the 2(nd) or the 3(rd) blinding condition in many developing countries. The importance of awareness in dealing with this problem has been shown to reduce the risks of blindness and improve the quality of vision. METHODS: Survey questionnaires have been distributed to 2500 randomly selected people from 6 different locations in Riyadh area between late 2003 and early 2004. Only 2039 data sheets (58% female and 42% male) have been analyzed; the remaining 461 data sheets were cancelled whether for biased responses or for ages those were outside the limited range (15 45 years). The questionnaire was designed to show responses according to three levels of education: basic, intermediate and high. RESULTS: 8% of the sample individuals wear spectacle. Of these, 2/3 acknowledges the importance of wearing spectacles. For those who don't, intellect is a determining factor in how people consider optical correction (21% of basic intellectual backgrounds only think it is important to wear glasses against some 40% of higher intellect). Most of the other results showed the effect of education in increasing the level of awareness in vision related questions. People with higher education are more aware than those with basic intellect in acknowledging: visual symptoms that need care (37% against only 26%), presbyopia condition (23% against 11%), urgency to seek eye care (85% against 29%), factors aggravating refractive errors in children (45% against 29%). Knowledge about the different forms of optical correction showed higher preference for spectacles against both contact lenses and refractive surgery. CONCLUSION: There is an overall tendency to show that the general public is not aware about most of the problems that concern their visual health. This is even more so in those with basic intellectual levels. In order to reduce the impact of visual problems related to ignorance in society, certain steps directed towards the general public should be undertaken, such as information through media and publicity, public education, screenings for ametropia in schools and at work, government subsidies of optical equipments etc. PMID- 22489226 TI - Association of Blood Lead level with Elevated Blood Pressure in Hypertensive Patients. AB - BACKGROUND: Lead is a metal with many important industrial uses. The relationship between lead exposure and the rise of blood pressure has received a great deal of attention as it was implicated that the mortality from cardiovascular diseases might be reduced by lowering lead levels in the environment. OBJECTIVES: The study was to investigate the correlation between the blood lead (B-Pb) levels and the values of blood pressure in hypertensive patients. Moreover, the plasma activities of angiotensin converting enzyme (ACE), plasma levels of nitric oxide (NO), total antioxidants (TAOX) and malondialdehyde (MDA) were estimated to investigate the correlations between the measured parameters and B-Pb levels in hypertensive patients. METHODS: Fifty-five hypertensive patients were compared with fifty-three age and sex matched control group. The B-Pb levels were detected by flame atomic absorption spectrometry. The plasma levels of ACE activities, NO, TAOX and MDA were measured by colorimetric methods. RESULTS: In the hypertensive patients, B-Pb levels were significantly higher than controls. Concomitantly, the plasma levels of ACE activities and MDA were significantly increased while the plasma levels of NO and TAOX were significantly reduced in the hypertensive patients in comparison with controls. There were significant positive correlations between B-Pb and each of MDA, and systolic as well as diastolic blood pressure. Conversely, a significant negative correlation was found between B-Pb and NO. CONCLUSIONS: Our study indicated that a positive relationship exists between blood pressure and B-Pb levels. The increased B-Pb levels were associated with oxidative stress. Moreover, The B-Pb level was negatively correlated with NO and this may clarify the implication of Pb as leading risk factor for the cardiovascular diseases and hypertension. These findings provide support for continued efforts to reduce lead concentration in the population at Qassim region. PMID- 22489227 TI - Health-related quality of life among persons living with buruli ulcer in amasaman community, ga west district accra, ghana. AB - OBJECTIVES: This cross-sectional study compared the health-related quality of life (HRQoL) of individuals with Buruli ulcer (Focus group) and age-matched apparently healthy peers without the ulcer (Control group) living in Amasaman in the Ga West District, Ghana. Gender pattern in the Health-Related Quality of Life of the Focus group was also investigated. METHODOLOGY: Participants comprised of consecutively recruited 84 Focus and 100 Control group subjects. Socio demographics of all participants and the clinical profile of Focus group subjects were obtained. The Nottingham Health Profile Questionnaire was used to measure the quality of life. Data was analysed using Mann-Whitney U statistic at 0.05 alpha. RESULTS: Focus group had significantly higher scores than Control in all the six (6) domains of the Nottingham Health Profile (p<0.05); no significant difference was observed in the total health score of females compared to males in both the Focus and Control groups (p>0.05). CONCLUSION: The findings suggest that, Buruli Ulcer impact negatively on the Health-Related Quality of Life of the victims. Aside medical interventions, the quality of life as well as the socio cultural and economic impacts of Buruli ulcer should be taken in cognizance while planning community-based rehabilitation programmes for those affected. PMID- 22489228 TI - Evaluation of Modified Essay Questions (MEQ) and Multiple Choice Questions (MCQ) as a tool for Assessing the Cognitive Skills of Undergraduate Medical Students. AB - OBJECTIVES: Developing and testing the cognitive skills and abstract thinking of undergraduate medical students are the main objectives of problem based learning. Modified Essay Questions (MEQ) and Multiple Choice Questions (MCQ) may both be designed to test these skills. The objectives of this study were to assess the effectiveness of both forms of questions in testing the different levels of the cognitive skills of undergraduate medical students and to detect any item writing flaws in the questions. METHODS: A total of 50 MEQs and 50 MCQs were evaluated. These questions were chosen randomly from various examinations given to different batches of undergraduate medical students taking course MED 411-412 at the Department of Medicine, Qassim University from the years 2005 to 2009. The effectiveness of the questions was determined by two assessors and was defined by the question's ability to measure higher cognitive skills, as determined by modified Bloom's taxonomy, and its quality as determined by the presence of item writing flaws. 'SPSS15' and 'Medcalc' programs were used to tabulate and analyze the data. RESULTS: The percentage of questions testing the level III (problem solving) cognitive skills of the students was 40% for MEQs and 60% for the MCQs; the remaining questions merely assessed the recall and comprehension. No significant difference was found between MEQ and MCQ in relation to the type of questions (recall; comprehension or problem solving x(2) = 5.3, p = 0.07).The agreement between the two assessors was quite high in case of MCQ (kappa=0.609; SE 0.093; 95%CI 0.426 - 0.792) but lower in case of MEQ (kappa=0.195; SE 0.073; 95%CI 0.052 - 0.338). 16% of the MEQs and 12% of the MCQs had item writing flaws. CONCLUSION: A well constructed MCQ is superior to MEQ in testing the higher cognitive skills of undergraduate medical students in a problem based learning setup. Constructing an MEQ for assessing the cognitive skills of a student is not a simple task and is more frequently associated with item writing flaws. PMID- 22489229 TI - Perceptions of placebo therapy among health practitioners in jazan region of saudi arabia. AB - BACKGROUND: Placebo therapy has always been a subject of controversy in the field of medicine. Some choose to admit it as "fake, irresponsible medicine" while others advocate its effectiveness in various clinical settings. With the advent of the recent concept of mind-body medicine, placebo has entered from fringe to mainstream therapeutics. Some clinicians use it for its actual positive outcomes while others use it merely to buy time until definitive diagnosis or even as a pacifier for patients. OBJECTIVE: The present study was carried out to observe the perceptions about placebo therapy among health practitioners in Jazan region of Saudi Arabia METHODOLOGY: Data was analyzed through statistical analysis of retrospective questionnaires addressing various issues on placebo therapy, including types of placebo used in various clinical settings, mechanism of placebo action, ethics of use and openness with patients etc. RESULTS: The study elucidated that the perceptions regarding placebo therapy are subjective and variable within and between institutions ranging from firm belief in its positive effects and efficacy; to neutral attitudes among some, to strong opposition for it among still others. CONCLUSION: More research is needed to ethically define the boundary between explicit fraudulence and marginalized evidence based therapeutic deception to effectively achieve the goal of positive health outcomes in patients. PMID- 22489230 TI - Prevalence of smoking and its related behaviors and beliefs among secondary school students in riyadh, saudi arabia. AB - OBJECTIVE: To estimate the prevalence of smoking among secondary school students in National Guard area of Riyadh, and explore the reasons for the smoking and the attitude of non-smoker toward smoking habit. DESIGN: A cross-sectional study was conducted in June 2009. By random sampling technique 255 students were enrolled from secondary school of National Guard area, Riyadh, Saudi Arabia. A self administered questionnaire was used for data collection. RESULTS: Current smokers represented 28.6% of the students. The most common reasons for smoking were: having free time (81.6%), for the relief of stress (63.2%) and seeing some of their teachers smoking (61.8%). Most of the smokers started the habit before the age of 15 years old (89%). 84% of non-smokers suggested to ban smoking in public places. 42.2% of students were planning to start smoking in future. Religion was the most important reason for not smoking among non smokers. CONCLUSION: The prevalence of smoking is big enough a problem to be considered as a warning for an impending epidemic Health education provision should have a greater role in schools Governmental commitment and social support are vital if health education and awareness and especially quit smoking programs are to be implemented and sustained. PMID- 22489231 TI - Knowledge and attitude towards patient safety among a group of undergraduate medical students in saudi arabia. AB - OBJECTIVES: This study aimed to measure knowledge and attitude of undergraduate medical students towards patient safety concepts, and to detect variation by the mode of learning. METHODOLOGY: A cross sectional study administrated an anonymous questionnaire to a random sample of 150 medical students graduated from two national medical schools, one follow the traditional lecture based learning (LBL) and the other applies innovative learning strategy (ILS). Students' self-ratings of knowledge level and attitude towards patient safety in relation to the mode of learning were measured. The study was conducted in April 2010. RESULTS: More than half of the participants (52.7%) self-rated their general knowledge on patient safety on good level compared to 27.3% for the specific knowledge issues score. Most participants (60.7%) agreed the importance of patient safety. The majority agreed to support peers who make unintentional errors and not to blame them for their own mistake (76.0 and 80.7% respectively). Less than half (44.7%) of the participants agreed the patients' role in error prevention and 47.3% agreed error disclosure to the patient. ILS participants were significantly more recognizable of the patient safety issues: problem solving (P< 0.01 OR: 3.0) and error management (P< 0.001 OR: 2.4) than the ILS colleagues. CONCLUSION: The study revealed unsatisfied percentages of the participants who self-rated 'good' for their general and specific knowledge on patient safety. The unsatisfied rate was reported for the participants' 'agree' score towards patient safety issues. Basic relevant educational interventions with focus on deficient issues are recommended. PMID- 22489232 TI - Laparoscopic reduction of intussusception in children: role in primary and revisional reduction after failed non-surgical therapies. AB - BACKGROUND AND OBJECTIVE: With the advent of laparoscopy into pediatric surgical filed and with experience gaining, as well as, improvement in instrumentation, it has been used in management of different conditions, including intussusception. However, there is no universal acceptance regarding its role in reduction of intussusception. This is due to the early reports of high conversion rate and the concern of missing a lead point. The aim of this article is to review the literatures about safety and efficacy of laparoscopy in intussusception management and the limitations as well as formulating a working algorithm for management of intussusceptions in pediatric age group up to 18 years. Up to my knowledge this is the first review article in this subject. METHOD: A comprehensive review of the English literature in Pub Med searching engine was conducted with key words laparoscopy, intussusception, management of intussusception, minimal invasive surgery and intussusception, laparoscopic reduction of intussusception, between 1996 and2009 .The results yielded were further explored for citation regarding the role of laparoscopy in reduction of intussusception. RESULTS: The success rate increased from 57% in 1997 to 91% in 2009 while the conversion rate decreased from 43% in 1997 to 9% in 2009.The presence of a lead point and/or ischemic bowel were the main reasons for conversion in the initial reports. CONCLUSION: Laparoscopy is a safe and efficient method for reduction of intussusception. The presence of a lead point or necrotic bowel is no more indication for conversion to open surgery. Laparoscopy should be an integral tool in the management algorithm of intussusception. PMID- 22489233 TI - Neurobrucellosis in children, a report of 2 cases. AB - OBJECTIVE: To report on two cases of neurobrucellosis with different presentations. METHOD: Retrospective report of the data on 2 cases of neurobrucellosis: the first case presented with acute meningo-encephalitis and the second case presented with acute meningitis. RESULT: Both cases had indolent fever for more than a month. The first case presented acutely with a diffuse maculopapular rash all over the body for 1 day prior to admission and a sudden deterioration of the level of consciousness, weakness, and generalized tonic clonic convulsions lasting for 2 minutes. The history of the presenting illness indicated a strong history of contact with animals and animal products. The second case was presented to our hospital with history of fever on and off for 2 months and 1-day history of headache and neck pain, but no history of vomiting, convulsion, or loss of consciousness. Both cases were diagnosed by the serum agglutination test and cerebrospinal fluid Brucella culture. Both cases were treated for 6 months with combination therapy of anti-Brucella drugs with excellent outcome. CONCLUSION: These are rare and serious presentations of this common public health problem, unless the physician has a high index of suspicion, morbidity and mortality will not be prevented. So, the description of both cases and a brief review of the current pediatric literature are provided to familiarize pediatricians with the relatively rare presentations of this common worldwide disease. PMID- 22489234 TI - The international journal of health sciences guidelines for authors. PMID- 22489235 TI - IJHS Guidelines for Peer Review. PMID- 22489236 TI - Are we Prepared? PMID- 22489237 TI - Application of Multiprotocol Medical Imaging Communications and an Extended DICOM WADO Service in a Teleradiology Architecture. AB - Multiprotocol medical imaging communication through the Internet is more flexible than the tight DICOM transfers. This paper introduces a modular multiprotocol teleradiology architecture that integrates DICOM and common Internet services (based on web, FTP, and E-mail) into a unique operational domain. The extended WADO service (a web extension of DICOM) and the other proposed services allow access to all levels of the DICOM information hierarchy as opposed to solely Object level. A lightweight client site is considered adequate, because the server site of the architecture provides clients with service interfaces through the web as well as invulnerable space for temporary storage, called as User Domains, so that users fulfill their applications' tasks. The proposed teleradiology architecture is pilot implemented using mainly Java-based technologies and is evaluated by engineers in collaboration with doctors. The new architecture ensures flexibility in access, user mobility, and enhanced data security. PMID- 22489238 TI - A high-performance lossless compression scheme for EEG signals using wavelet transform and neural network predictors. AB - Developments of new classes of efficient compression algorithms, software systems, and hardware for data intensive applications in today's digital health care systems provide timely and meaningful solutions in response to exponentially growing patient information data complexity and associated analysis requirements. Of the different 1D medical signals, electroencephalography (EEG) data is of great importance to the neurologist for detecting brain-related disorders. The volume of digitized EEG data generated and preserved for future reference exceeds the capacity of recent developments in digital storage and communication media and hence there is a need for an efficient compression system. This paper presents a new and efficient high performance lossless EEG compression using wavelet transform and neural network predictors. The coefficients generated from the EEG signal by integer wavelet transform are used to train the neural network predictors. The error residues are further encoded using a combinational entropy encoder, Lempel-Ziv-arithmetic encoder. Also a new context-based error modeling is also investigated to improve the compression efficiency. A compression ratio of 2.99 (with compression efficiency of 67%) is achieved with the proposed scheme with less encoding time thereby providing diagnostic reliability for lossless transmission as well as recovery of EEG signals for telemedicine applications. PMID- 22489239 TI - Challenges in blood pressure self-measurement. AB - Blood pressure self-measurement (BPSM) requires patients to follow a range of recommendations in order to be considered reliable for diagnostic use. We investigated currently used BPSM interventions at four medical clinics combined with an online questionnaire targeting BPSM users. We found that the participating healthcare personnel perceived BPSM as a relevant and useful intervention method providing that the recommendations are followed. A total of six challenges were identified: (1) existing devices do not guarantee that the recommendations are followed, (2) healthcare providers cannot verify whether self monitoring patients follow the recommendations, (3) patients are not aware of all recommendations and the need to follow them, (4) risk of patient induced reporting bias, (5) risk of healthcare provider induced data-transfer bias, and (6) risk of data being registered as belonging to the wrong patient. We conclude that existing BPSM interventions could be significantly affected by user-induced bias resulting in an indeterminable quality of the measurement data. Therefore, we suggest applying context-aware technological support tools to better detect and quantify user errors. This may allow us to develop solutions that could overcome or compensate for such errors in the future. PMID- 22489240 TI - Thigh Abscess Caused by Yersinia enterocolitica in an Immunocompetent Host. AB - Yersinia enterocolitica is primarily a gastrointestinal tract pathogen known to cause gastroenteritis, although it may produce extra-intestinal infections like sepsis and its sequelae. However, primary cutaneous infections are extremely rare. We present a case of Y. enterocolitica thigh abscess in an immunocompetent adult. The portal of entry is unclear in this case. He did many outdoor activities that involved skin injuries and exposure to soil and contaminated water. Hence, direct inoculation as a result of exposure to contaminated water is postulated in the absence of evidence for a gastrointestinal route of infection. PMID- 22489241 TI - Liposarcoma of the nasopharynx: diagnosis and management of a rare diagnostic entity. AB - Liposarcoma is one of the most frequently occurring soft tissue sarcomas in adulthood. The majority of liposarcomas arise in the lower extremities and retroperitoneum, while the incidence of this tumor in the head and neck region is reported to be extremely low, comprising 1.8%-6.2% of all cases. Nasopharyngeal liposarcoma is exceptionally rare, with only three cases having been reported in the English literature. This paper presents a case of a nasopharyngeal liposarcoma, treated with endoscopic tumor debulking, followed by adjuvant chemotherapy and radiotherapy, and reviews the current literature with regard to diagnosis and management of such lesions. Most authors agree that the imaging modality of choice is magnetic resonance imaging. Although radiographic findings usually support diagnosis, the imaging characteristics of such lesions may considerably vary, depending on the histological subtype and the macroscopic appearance of the tumor. The treatment of choice is complete surgical excision when possible. Although the role of postoperative radiotherapy is not clearly defined, some authors support that radiotherapy might delay or prevent local recurrence. However, there is no adequate evidence that the combination of surgery and radiotherapy lowers the possibility of distant metastasis of the head and neck liposarcomas. The role of adjuvant or neoadjuvant chemotherapy still remains controversial. PMID- 22489242 TI - Ischemic toes after venous thromboembolism: a difficult differential diagnosis with good response to combination therapy-a case report. AB - The obliteration of the arterial vascular system of toes is considered as a potentially catastrophic event in clinical practices. In most instances, the cessation of arterial blood flow heralds a serious underlying pathology. A definite classification of some cases is somehow difficult and subject to diagnostic challenges. The aim of the present case study is to share and discuss potentially complex and multifactorial mechanisms of some acute vascular events. In this report, we deal with a 46-year-old man with a rather gradual-onset ischemia of his toe who responded favorably to a combination of pulsed glucocorticoid and anticoagulation within a week. PMID- 22489243 TI - Penile degloving injury in an adolescent with congenital hypothyroid. AB - This case follows a 17-year-old boy with congenital hypothyroidism who sustained penile skin avulsion secondary to a dog bite. Initially, an attempt was made to repair the wound using the avulsed skin flap itself as coverage. The repair was done immediately upon presentation to enhance the chances of adequate flap viability; however, the dorsal portion of the reconstruction necrosed within the following week. Ultimately a full thickness surgical graft (FTSG) repair was performed to ensure the most desirable outcome. PMID- 22489244 TI - Fatal disruption of a left atrial myxoma associated with trauma. AB - Cardiac myxomas are benign tumors composed of sparse stellate cells in an extensive mucoid stroma. The surface of these tumors is often friable and gelatinous. Their intracardiac location makes embolization a constant threat. We report a patient who had diffuse systemic embolization of a left atrial myxoma coincident with a low-velocity frontal motor vehicle crash. PMID- 22489245 TI - Disorders of sex development: management of gender assignment in a preterm infant with intrauterine growth restriction. AB - We describe how a gender specialist team managed the case of a disorder of sex development in a preterm infant where definitive diagnosis and gender assignment were delayed due to complications of prematurity, anemia, and severe intrauterine growth restriction. PMID- 22489246 TI - Femoral nerve injury as a complication of percutaneous simple renal cyst sclerotherapy with ethanol: a case report. AB - Simple renal cysts are benign, common, and often asymptomatic disease in old age, sometimes treated with ethanol sclerotherapy. We report a case of iatrogenic femoral nerve injury following percutaneous injection of ethanol into a renal cyst under sedation. The percutaneous injection was guided by sonography. At the end of the procedure, the cyst ruptured so the patient progressed to loss of consciousness due to alcohol intoxication. Ethanol was damaged to the femoral nerve, so patient was developed with limping, numbness, and weakness in anteromedial aspect of the right thigh. To the best of our knowledge, this is the first report of femoral nerve injury caused by percutaneous simple renal cyst sclerotherapy with ethanol. This rare event has not been previously described, Physicians should be aware of the possibility of this complication. PMID- 22489247 TI - Clarithromycin-Induced Long QT Syndrome: A Case Report. AB - Long QT syndrome develops for a number of reasons. The number of non antiarrhythmic drugs reported to induce QT interval prolongation with or without torsade de pointes continues to increase. Clarithromycin is a macrolide antibiotic being increasingly used for the treatment of atypical pneumonia. In this paper, we describe a patient who developed long QT prolongation syndrome after receiving clarithromycin for the treatment of atypical pneumonia. PMID- 22489248 TI - The role of regulatory T cells and TH17 cells in multiple myeloma. AB - The development of multiple myeloma (MM) involves a series of genetic alterations and changes in the bone marrow microenvironment, favoring the growth of the tumor and failure of local immune control. Quantitative and functional alterations in CD4(+) and CD8(+) T cells have been described in MM. The balance between T regulatory cells (Treg) and T helper (Th) 17 cells represents one essential prerequisite for maintaining anti-tumor immunity in MM. Tregs play an important role in the preservation of self-tolerance and modulation of overall immune responses against infections and tumor cells. In MM patients, Tregs seem to contribute to myeloma-related immune dysfunction and targeting them could, therefore, help to restore and enhance vital immune responses. Th17 cells protect against fungal and parasitic infections and participate in inflammatory reactions and autoimmunity. The interplay of TGF-beta and IL-6, expressed at high levels in the bone marrow of myeloma patients, may affect generation of Th17 cells both directly or via other pro-inflammatory cytokines and thereby modulate antitumor immune responses. A detailed analysis of the balance between Tregs and Th17 cells seems necessary in order to design more effective and less toxic modes of immunotherapy myeloma which still is an uncurable malignancy. PMID- 22489249 TI - Neurocognitive impairment in HIV-infected naive patients with advanced disease: the role of virus and intrathecal immune activation. AB - OBJECTIVE: To investigate intrathecal immune activation parameters and HIV-RNA in HIV-associated neurocognitive disorders (HAND) of advanced naive HIV-infected patients and to evaluate their dynamics before and after initiation of antiretroviral therapy (ART). METHODS: Cross-sectional and longitudinal analysis of HIV RNA, proinflammatory cytokines (IL-6, IL-10, INF-gamma, TNF-alpha, TGF beta1, and TGF-beta2) and chemokines (MIP-1alpha, MIP-1beta, and MCP-1) in plasma and cerebrospinal fluid (CSF) of HIV-infected patients with CD4 <200/MUL. RESULTS: HAND was diagnosed at baseline in 6/12 patients. Baseline CSF HIV-RNA was comparable in patients with or without HAND, whereas CSF concentration of IL 6 and MIP-1beta, proinflammatory cytokines, was increased in HAND patients. CSF evaluation at 12 weeks was available in 10/12 cases. ART greatly reduced HIV-RNA in all patients. Nevertheless, IL-6 and MIP-1beta remained elevated after 12 weeks of therapy in HAND patients, in whom CSF HIV RNA decay was slower than the plasmatic one as well. CONCLUSION: Immune activation, as indicated by inflammatory cytokines, but not higher levels of HIV-RNA is observed in advanced naive HIV-infected patients with HAND. In HAND patients, ART introduction resulted in a less rapid clearance of CSF viremia compared to plasma and no modifications of intratechal immune activation. PMID- 22489250 TI - HIV RNA suppression and immune restoration: can we do better? AB - HAART has significantly changed the natural history of HIV infection: patients receiving antiretrovirals are usually able to control viremia, even though not all virological responders adequately recover their CD4+ count. The reasons for poor immune restoration are only partially known and they include genetic, demographic and immunologic factors. A crucial element affecting immune recovery is immune activation, related to residual viremia; indeed, a suboptimal virological control (i.e., low levels of plasma HIV RNA) has been related with higher levels of chronic inflammation and all-cause mortality. The sources of residual viremia are not yet completely known, even though the most important one is represented by latently infected cells. Several methods, including 2-LTR HIV DNA and unspliced HIV RNA measurement, have been developed to estimate residual viremia and predict the outcome of antiretroviral therapy. Considering that poor immunologic responders are exposed to a higher risk of both AIDS-related and non AIDS-related diseases, there is a need of new therapeutic strategies, including immunomodulators and drugs targeting the latent viral reservoirs, in order to face residual viremia but also to "drive" the host immunologic responses. PMID- 22489251 TI - Review on the relationship between human polyomaviruses-associated tumors and host immune system. AB - The polyomaviruses are small DNA viruses that can establish latency in the human host. The name polyomavirus is derived from the Greek roots poly-, which means "many," and -oma, which means "tumours." These viruses were originally isolated in mouse (mPyV) and in monkey (SV40). In 1971, the first human polyomaviruses BK and JC were isolated and subsequently demonstrated to be ubiquitous in the human population. To date, at least nine members of the Polyomaviridae family have been identified, some of them playing an etiological role in malignancies in immunosuppressed patients. Here, we describe the biology of human polyomaviruses, their nonmalignant and malignant potentials ability, and their relationship with the host immune response. PMID- 22489253 TI - Impact of previous ART and of ART initiation on outcome of HIV-associated tuberculosis. AB - BACKGROUND: Combination antiretroviral therapy (cART) has progressively decreased mortality of HIV-associated tuberculosis .To date, however, limited data on tuberculosis treatment outcomes among coinfected patients who are not ART-naive at the time of tuberculosis diagnosis are available. METHODS: A multicenter, observational study enrolled 246 HIV-infected patients diagnosed with tuberculosis, in 96 Italian infectious diseases hospital units, who started tuberculosis treatment. A polytomous logistic regression model was used to identify baseline factors associated with the outcome. A Poisson regression model was used to explain the effect of ART during tuberculosis treatment on mortality, as a time-varying covariate, adjusting for baseline characteristics. RESULTS: Outcomes of tuberculosis treatment were as follows: 130 (52.8%) were successfully treated, 36 (14.6%) patients died in a median time of 2 months (range: 0-16), and 80 (32.6%) had an unsuccessful outcome. Being foreign born or injecting drug users was associated with unsuccessful outcomes. In multivariable Poisson regression, cART during tuberculosis treatment decreased the risk of death, while this risk increased for those who were not ART-naive at tuberculosis diagnosis. CONCLUSIONS: ART during tuberculosis treatment is associated with a substantial reduction of death rate among HIV-infected patients. However, patients who are not ART-naive when they develop tuberculosis remain at elevated risk of death. PMID- 22489252 TI - Pulmonary arterial hypertension in systemic lupus erythematosus: current status and future direction. AB - Pulmonary arterial hypertension (PAH) is commonly associated with connective tissue diseases (CTDs) including systemic sclerosis and systemic lupus erythematosus (SLE). The prevalence of PAH in SLE is estimated to be 0.5% to 17.5%. The pathophysiology of PAH involves multiple mechanisms from vasculitis and in-situ thrombosis to interstitial pulmonary fibrosis which increases pulmonary vascular resistance, potentially leading to right heart failure. Immune and inflammatory mechanisms may play a significant role in the pathogenesis or progression of PAH in patients with CTDs, establishing a role for anti inflammatory and immunosuppressive therapies. The leading predictors of PAH in SLE are Raynaud phenomenon, anti-U1RNP antibody, and anticardiolipin antibody positivity. The first-line of diagnostic testing for patients with suspected SLE associated PAH (SLE-aPAH) involves obtaining a Doppler echocardiogram. Once the diagnosis is confirmed by right heart catheterization, SLE-aPAH patients are generally treated with oxygen, anticoagulants, and vasodilators. Although the prognosis and therapeutic responsiveness of these patients have improved with the addition of intensive immunosuppressive therapies, these treatments are still largely unproven. Recent data put the one-year survival rate for SLE-aPAH patients at 94%. Pregnant women are most at risk of dying due to undiagnosed SLE aPAH, and screening should be considered essential in this population. PMID- 22489254 TI - Seizures in primary antiphospholipid syndrome: the relevance of smoking to stroke. AB - OBJECTIVES: To evaluate the frequency of seizures in primary antiphospholipid syndrome (PAPS) and their possible clinical and laboratory associations. METHODS: Eighty-eight PAPS patients (Sydney's criteria) were analyzed by a standard interview, physical examination and review of medical charts. Risk factors for seizures, clinical manifestations, associated comorbidities, and antiphospholipid antibodies were evaluated. RESULTS: Nine (10.2%) patients with seizures were identified, 77.8% had convulsions onset after PAPS diagnosis. Mean age, gender, and race were comparable in groups with or without seizures. Interestingly, a higher frequency of current smoking (44.4 versus 10.1%, P = 0.019) was observed in the first group. Stroke, Sneddon's syndrome, and livedo reticularis were more frequent in PAPS patients with seizures than those without seizures, although not statistically significant (P > 0.05). Comparison between patients with seizures onset after PAPS diagnosis (n = 7) and those without convulsions (n = 79) demonstrated a higher frequency of current smoking (42.9 versus 10%, P = 0.042) and stroke in the first group (71.4 versus 30.4%, P = 0.041). Regression analysis confirmed that smoking (P = 0.030) and stroke (P = 0.042) were independently associated to seizures. CONCLUSION: About 10.2% of PAPS patients had convulsions, predominantly after PAPS diagnosis, and seizures were associated to current smoking and stroke. PMID- 22489255 TI - Are neurocognitive, clinical and social dysfunctions in schizotaxia reversible pharmacologically?: Results from the Changsha study. AB - The Changsha study identifies adult, non-psychotic relatives of patients with schizophrenia who show deficits in neurocognitive, social, clinical and other dimensions, and who meet provisional criteria for a liability syndrome for schizophrenia ('schizotaxia'). In this study, we investigated whether negative symptoms, neurocognitive deficits, or other measures of clinical and social function in subjects who met our research criteria for schizotaxia were amenable to pharmacological remediation with a low dose (2.0 mg) of risperidone, a second generation antipsychotic medication. One hundred eighty nine relatives were assessed at the Mental Health Institute, Second Xiangya Hospital of Central South University, Changsha (Hunan Province, China), between 12/06 - 12/08. Eighty six of these individuals met modified criteria for schizotaxia, and 36 agreed to enter a 6-week, double-blind, placebo-controlled protocol. ANCOVAs using age and gender as covariates showed significant improvement in the risperidone group (n=20) on neurocognitive function (Wisconsin Card Sorting Test Total Errors and Perseverative Errors) and on a self-report measure of social function (Social Adjustment Scale), compared to the placebo-control group (n=16). Effect sizes were small to medium. Notably, risperidone effect sizes were larger (medium to large) in a subset of subjects (risperidone=15; placebo=10) whose membership in the schizotaxic group was supported empirically by cluster analysis. Negative symptoms did not change significantly in either analysis. The results are generally consistent with previous open-label investigations of risperidone administration in subjects with schizotaxia, and provide evidence that some neurocognitive and clinical problems are amenable to remediation in non-psychotic relatives of people with schizophrenia. PMID- 22489257 TI - Liver diseases in developing countries. AB - Liver diseases are an important and largely neglected health issue in low and middle income countries, which carry the highest burden. In this Topic Highlight, experts review hepatitis B and E, alcoholic liver disease, hepatic diseases in human immunodeficiency virus -infected individuals, hepatocellular carcinoma. Numerous gaps in our knowledge that need to be filled are outlined and feasible solutions to the several problems related to diagnosis and management of liver diseases in developing countries are suggested. PMID- 22489258 TI - Hepatitis A: Epidemiology and prevention in developing countries. AB - Hepatitis A is the most common form of acute viral hepatitis in the world. Major geographical differences in endemicity of hepatitis A are closely related to hygienic and sanitary conditions and other indicators of the level of socioeconomic development. The anti-hepatitis A virus (HAV) seroprevalence rate is presently decreasing in many parts of the world, but in less developed regions and in several developing countries, HAV infection is still very common in the first years of life and seroprevalence rates approach 100%. In areas of intermediate endemicity, the delay in the exposure to the virus has generated a huge number of susceptible adolescents and adults and significantly increased the average age at infection. As the severity of disease increases with age, this has led to outbreaks of hepatitis A. Several factors contribute to the decline of the infection rate, including rising socioeconomic levels, increased access to clean water and the availability of a hepatitis A vaccine that was developed in the 1990s. For populations with a high proportion of susceptible adults, implementing vaccination programs may be considered. In this report, we review available epidemiological data and implementation of vaccination strategies, particularly focusing on developing countries. PMID- 22489256 TI - Hepatic encephalopathy: An approach to its multiple pathophysiological features. AB - Hepatic encephalopathy (HE) is a neuropsychiatric complex syndrome, ranging from subtle behavioral abnormalities to deep coma and death. Hepatic encephalopathy emerges as the major complication of acute or chronic liver failure. Multiplicity of factors are involved in its pathophysiology, such as central and neuromuscular neurotransmission disorder, alterations in sleep patterns and cognition, changes in energy metabolism leading to cell injury, an oxidative/nitrosative state and a neuroinflammatory condition. Moreover, in acute HE, a condition of imminent threat of death is present due to a deleterious astrocyte swelling. In chronic HE, changes in calcium signaling, mitochondrial membrane potential and long term potential expression, N-methyl-D-aspartate-cGMP and peripheral benzodiazepine receptors alterations, and changes in the mRNA and protein expression and redistribution in the cerebral blood flow can be observed. The main molecule indicated as responsible for all these changes in HE is ammonia. There is no doubt that ammonia, a neurotoxic molecule, triggers or at least facilitates most of these changes. Ammonia plasma levels are increased two- to three-fold in patients with mild to moderate cirrhotic HE and up to ten-fold in patients with acute liver failure. Hepatic and inter-organ trafficking of ammonia and its metabolite, glutamine (GLN), lead to hyperammonemic conditions. Removal of hepatic ammonia is a differentiated work that includes the hepatocyte, through the urea cycle, converting ammonia into GLN via glutamine synthetase. Under pathological conditions, such as liver damage or liver blood by-pass, the ammonia plasma level starts to rise and the risk of HE developing is high. Knowledge of the pathophysiology of HE is rapidly expanding and identification of focally localized triggers has led the development of new possibilities for HE to be considered. This editorial will focus on issues where, to the best of our knowledge, more research is needed in order to clarify, at least partially, controversial topics. PMID- 22489259 TI - Hepatitis B: Epidemiology and prevention in developing countries. AB - Hepatitis B virus (HBV) infection is a serious global public health problem. The infection may be transmitted through sexual intercourse, parenteral contact or from an infected mother to the baby at birth and, if contracted early in life, may lead to chronic liver disease, including cirrhosis and hepatocellular carcinoma. On the basis of the HBV carrier rate, the world can be divided in 3 regions of high, medium and low endemicity. The major concern is about high endemicity countries, where the most common route of infection remains vertical transmission from mother to child. Screening of all pregnant women and passive immunization with human hepatitis B immunoglobulin are not affordable for many developing countries. The infection rate can be reduced by modifying behavior, improving individual education, testing all blood donations, assuring asepsis in clinical practice and screening all pregnant women. However, availability of a safe and efficacious vaccine and adoption of appropriate immunization strategies are the most effective means to prevent HBV infection and its consequences. The unsolved problem for poorest countries, where the number of people currently infected is high, is the cost of the vaccine. A future challenge is to overcome the social and economic hurdles of maintaining and improving a prevention policy worldwide to reduce the global burden of the disease. PMID- 22489260 TI - Alcoholic liver disease. AB - Alcohol use disorders affect millions of individuals worldwide. Alcohol consumption is directly associated with liver disease mortality and accounts for elevated social and economic costs. Alcoholic liver disease (ALD) may take the form of acute involvement (alcoholic hepatitis) or chronic liver disease (steatosis, steatohepatitis, fibrosis and cirrhosis). The severity and prognosis of alcohol-induced liver disease depends on the amount, pattern and duration of alcohol consumption, as well as on the presence of liver inflammation, diet, nutritional status and genetic predisposition of an individual. While steatosis is an almost completely benign disease, liver cirrhosis is associated with marked morbidity, mortality and life expectancy shortening. The median survival of patients with advanced cirrhosis is 1-2 years. Severe acute alcoholic hepatitis (AH) is associated with mortality as high as 50%. It has been managed with corticoids, pentoxifylline and enteral nutrition, although evidence based data are still conflicting. Some author suggest that pentoxifylline could be a better first-line treatment in patients with severe AH. Absolute abstinence is a basic condition for any treatment of acute or chronic ALD, the other therapeutical procedure being of a supportive nature and questionable significance. Acamprosate appears to be an effective treatment strategy for supporting continuous abstinence in alcohol dependent patients. Patients with advanced liver cirrhosis who demonstrably abstain can be considered for liver transplantation, which leads to a markedly prolonged life expectancy. The crucial step in ALD prevention is in the prevention of alcohol abuse, whereas the prevention of liver injury in active alcohol abusers is not clinically applicable. PMID- 22489261 TI - Human immunodeficiency virus infection and the liver. AB - Liver disease in human immunodeficiency virus (HIV)-infected individuals encompasses the spectrum from abnormal liver function tests, liver decompensation, with and without evidence of cirrhosis on biopsy, to non alcoholic liver disease and its more severe form, non-alcoholic steatohepatitis and hepatocellular cancer. HIV can infect multiple cells in the liver, leading to enhanced intrahepatic apoptosis, activation and fibrosis. HIV can also alter gastro-intestinal tract permeability, leading to increased levels of circulating lipopolysaccharide that may have an impact on liver function. This review focuses on recent changes in the epidemiology, pathogenesis and clinical presentation of liver disease in HIV-infected patients, in the absence of co-infection with hepatitis B virus or hepatitis C virus, with a specific focus on issues relevant to low and middle income countries. PMID- 22489262 TI - Hepatocellular carcinoma in developing countries: Prevention, diagnosis and treatment. AB - Hepatocellular carcinoma (HCC) occurs commonly and with increasing frequency in developing countries, where it also carries an especially grave prognosis. The major risk factor for HCC in these regions is chronic hepatitis B virus (HBV) infection, although dietary exposure to aflatoxin B1 also plays an important etiological role. Prevention of HCC in developing regions is unlikely in the foreseeable future. Although an effective vaccine against HBV is available, the percentage of babies born in developing countries that receive the full course of immunization remains low. Moreover, the usually long interval between infection with HBV and the development of HCC means that 30 to 50 years will elapse before the full effect of the vaccine will be realized. Practical measures to prevent aflatoxin B1 exposure are not in place. Serum alpha-fetoprotein levels are a useful pointer to the diagnosis of HCC in low-income countries, but definitive diagnosis is hampered both by the lack of the sophisticated imaging equipment now available in developed countries and by obstacles to obtaining histological proof. In the majority of patients in low-income regions, the tumor is inoperable by the time the patient presents. Hepatic resection is seldom possible in sub Saharan Africa, although the tumor is successfully resected in a larger number of patients in China. Liver transplantation for HCC is rarely performed in either region. Sophisticated new radiotherapy techniques are not available in developing countries. The beneficial effects of the multikinase inhibitor, sorafenib, are encouraging, although financial considerations may restrict its use in low-income countries. PMID- 22489263 TI - Relationship between interleukin 18 polymorphisms and susceptibility to chronic hepatitis B virus infection. AB - AIM: To identify the relationship between the tagging single nucleotide polymorphism sites (tagSNPs) of the Interleukin-18 (IL-18) gene and genetic susceptibility to chronic hepatitis B virus infection in Chinese patients. METHODS: Five hundred and one cases of chronic hepatitis B virus (HBV) infection and 301 HBV natural clearance controls were studied. Two tagSNPs in the IL-18 gene (rs1946518A/C and rs574424C/G) were genotyped by the Multiplex Snapshot technique. The genotype and allele frequencies were calculated and analyzed. RESULTS: In the genotypes of rs1946518, the AA type was present at a higher frequency in the patients compared to those in the controls. Odds ratio (OR) of the AA genotype for the comparison with that of the AC and the CC genotype was 1.537 (95% confidence intervals (CI): 1.116-2.218, P = 0.009 < 0.025). In phenotypes, the allele C at rs1946518 was of a significantly lower frequency in the patients with chronic hepatitis B than that in the controls (P = 0.017 < 0.025). OR of the allele A for the comparison with that of the allele C was 1.279 (95% CI: 1.045-1.567). As for the rs574424 genotypes, no significant difference in this genotype distribution or in this allele frequency between the patients and the control subjects was observed. No significant difference in the haplotype frequencies between the patients with chronic hepatitis B and HBV natural clearance individuals was displayed. CONCLUSION: The data suggest that genotype AA and the allele A of the IL-18 at position rs1946518 are closely associated with the resistance to chronic hepatitis B and may be the dangerous gene. However, no statistical association was found between polymorphisms of rs574424 for IL-18 and hepatitis B. PMID- 22489264 TI - The anatomic course of the first jejunal branch of the superior mesenteric vein in relation to the superior mesenteric artery. AB - Introduction. The purpose of this study is to determine the anatomic course of the first jejunal branch of the superior mesenteric vein (SMV) in relation to the superior mesenteric artery (SMA). Methods. Three hundred consecutive contrast enhanced computed tomography (CT) scans were reviewed by a surgical oncologist with confirmation of findings by a radiologist. Results. The overall incidence of a first jejunal branch coursing anterior to the SMA was 41%. There was no correlation between patient gender and position of the jejunal branch. In addition, there was no correlation between size of the first jejunal branch and its location in relation to the SMA. The IMV drained into the SMV in 27% of the patients. The IMV drained into the SMV-portal vein confluence in 17% of patients and inserted into the splenic vein in 54%. An anterior coursing first jejunal branch statistically correlated with an IMV that drained into the SMV-portal vein confluence (P = 0.009). Conclusion. The first jejunal branch of the SMV has a highly variable course in relation to the SMA and has a higher incidence of an anterior location in this population than previously reported. PMID- 22489265 TI - Pancreaticojejuno anastomosis after pancreaticoduodenectomy: brief pathophysiological considerations for a rational surgical choice. AB - Introduction. The best pancreatic anastomosis technique after pancreaticoduodenectomy (PD) is still debated. Pancreatic fistula (PF) is the most important complication but is also related to postoperative bleedings and pancreatic remnant involution. We support pancreaticojejuno anastomosis (PJ) advantages describing our technique with brief technical considerations. Materials and Methods. 89 consecutive patients underwent PD with suprapyloric gastric resection and double loop reconstruction. Pancreaticojejunal end-to-end anastomosis was done by simple invagination with a single layer of interrupted pledget-supported Ticron stitches. Results. Pancreatic fistula occurred in seven patients (7.8%): six cases of grade A fistula resolved spontaneously, and in only one case of grade B fistula percutaneous drainage was necessary. Postoperative hemorrhage occurred in only two (2.2%) of 89 patients. Conclusion. Pancreaticojejunostomy with minor changes in anastomotic techniques can contribute to improvement of the outcome of Roux-en-Y reconstruction regarding PF and other related complications. The particular reconstruction reported seems also to preserve the pancreatic exocrine function. PMID- 22489266 TI - Neck dissection for thoracic esophageal squamous cell carcinoma. AB - Subtotal esophagectomy with extended lymph node dissection is a standard procedure for thoracic esophageal squamous cell carcinoma. Three-field lymphadenectomy, including neck dissection, is a standard type of lymph node dissection for complete clearance of tumor cells. Based on various series of analyses for lymph node metastases, the appropriate indication for neck dissection has been clarified. Herein, we describe the established techniques of neck dissection and review recent topics of three-field lymph node dissection for thoracic esophageal squamous cell carcinoma. PMID- 22489267 TI - Proximal gastrojejunal reconstruction after pancreaticoduodenal resection. AB - Introduction. Reconstruction by proximal gastrojejunostomy, and distal biliary and pancreatic anastomoses is infrequently used after resection of the head of the pancreas because of fear of fistulas and cholangitis. Pancreaticoduodenectomy is being performed more frequently for cystic malignant and premalignant lesions. Because of this there is a need for endoscopic visualization and biopsy of the residual pancreatic duct, since multi-centricity is characteristic of some of these malignancies. Since endoscopic access of the bile duct and pancreatic duct is difficult and unsuccessful in 50-70% after B II or Roux Y reconstruction, we prospectively studied the merit and complications (early and late) of proximal gastrojejunal (PGJ) reconstruction after pancreaticoduodenal resection. Material and Methods. Thirty nine consecutive, non-radomized patients underwent pancreaticoduodenectomy and PGJ reconstruction over 14 mos. There were 21 males and 18 females. Results. 7 patients with IPMN have undergone repeat CT scanning for surveillance, with 3 requiring repeat EUS and ERCP. There were no technical difficulties accessing the pancreas or the pancreatic duct, supporting the PGJ reconstruction. Conclusion. Proximal gastrojejunal reconstruction following pancreaticoduodenal resection may be safely done with similar morbidity to traditional pancreaticojejunal reconstructions. PGJ reconstruction may be of greater value when direct visual access to the bile duct or pancreatic duct is necessary, and should be considered when doing resection for mucinous cysts or IPMN of the head of the pancreas. PMID- 22489268 TI - Mammary ductal carcinoma in situ: a fresh look at architectural patterns. AB - Mammary ductal carcinoma in-situ (DCIS), a malignant appearing lesion on cytological and histological grounds, is in fact a non-obligate precancer. DCIS is difficult to manage and is sometimes treated more aggressively than invasive carcinoma. Although most DCIS classifications take into account the architectural growth pattern, when it comes to architecture, the literature is full of contradictory information. We examined 289 breast cancers and found DCIS in 265 of the cases. The majority of the DCIS cases were seen in the setting of invasive cancer and only 9% of the cases represented pure DCIS with no invasive cancer. The DCIS commonly displayed a mixed pattern with micropapillary, cribriform and solid components with the micropapillary type being the rarest, occurring seldom on its own. A continuum of growth with a micropapillary pattern evolving into a cribriform type could be seen in some of the cases. This may explain some of the conflicting information, in the literature, regarding the different architectural types of DCIS. The comedo-pattern of necrosis could be seen in all types of DCIS. We therefore conclude that the study of the determinants of growth pattern in DCIS would be the key to unravelling the diverse, often non-concordant evidence one encounters in the literature. PMID- 22489269 TI - The current role of carotid duplex ultrasonography in the management of carotid atherosclerosis: foundations and advances. AB - The management of atherosclerotic carotid occlusive disease for stroke prevention has entered a time of dramatic change. Improvements in medical management have begun to challenge traditional interventional approaches to asymptomatic carotid stenosis. Simultaneously, carotid artery stenting (CAS) has emerged as an alternative to carotid endarterectomy (CE). Finally, multiple factors beyond degree of stenosis and symptom status now mitigate clinical decision making. These factors include brain perfusion, plaque morphology, and patency of intracranial collaterals (circle of Willis). With all of these changes, it seems prudent to review the role of carotid duplex ultrasonography in the management of atherosclerotic carotid occlusive disease for stroke prevention. Carotid duplex ultrasonography (CDU) for initial and serial imaging of the carotid bifurcation remains an essential component in the management of carotid bifurcation disease. However, correlative axial imaging modalities (computer tomographic angiography (CTA) and contrast-enhanced magnetic resonance angiography (CE-MRA)) increasingly aid in the assessment of individual stroke risk and are important in treatment decisions. The purpose of this paper is twofold: (1) to discuss foundations and advances in CDU and (2) to evaluate the current role of CDU, in light of other imaging modalities, in the clinical management of carotid atherosclerosis. PMID- 22489270 TI - Restenosis and therapy. AB - The vascular disease involves imbalanced function of the blood vessels. Risk factors playing a role in development of impaired vessel functions will be briefly discussed. In ischemia/reperfusion (I/R), ischemic hypoxia is one of the cardinal risk factors of restenosis. Various insults are shown to initiate the phenotype switch of VSMCs. The pathological process, leading to activated inflammatory process, complement activation, and release of growth factors, initiate the proliferation of VSMCs in the media and cause luminal narrowing and impaired vascular function. The review summarizes the alteration process and demonstrates some of the clinical genetic background showing the role of complement and the genotypes of mannose-binding lectin (MBL2). Those could be useful markers of carotid restenosis after stent implantation. Gene therapy and therapeutic angiogenesis is proposed for therapy in restenosis. We suggest a drug candidate (iroxanadine), which ensures a noninvasive treatment by reverse regulation of the highly proliferating VSMCs and the disturbed function of ECs. PMID- 22489271 TI - Low resolution limits and inaccurate algorithms decrease significantly the value of late loss in current drug-eluting stent trials. AB - Quantitative coronary and vascular angiography (QCA resp., QVA) remains the current gold standard for evaluation of restenosis. Late loss as one of the most commonly accepted parameters to highlight efficacy of the various devices has shown high correlation to clinical parameters but, surprisingly, has no impact on the evaluation of the remaining amount of restenostic tissue. The current clinical practice leads to unrealistic late loss calculations. Smaller late loss differences are usually not greater than the inherited resolution limits of QCA, which is especially the case in small differences between the various stents in the drug-eluting stent era. Late loss include additional systematic and random errors, due to the fact that measurements were taken at two different time points including the inherited resolution and calibration limits of QCA on two occasions. Due to the limited value of late loss in discriminating the small differences between the one and other DES, late lumen area loss and clearly defined calculation algorithms (e.g., MLD-relocation) should be used in future DES studies also to fulfill the more stringent regulatory requirements. PMID- 22489272 TI - The effect of antihypertensive drugs on endothelial function as assessed by flow mediated vasodilation in hypertensive patients. AB - Endothelial dysfunction is found in hypertensive patients and may serve as a prognostic marker of future cardiovascular events. Endothelial function can be assessed noninvasively by flow-mediated vasodilation (FMD). The goal of this paper is to summarize comprehensively the clinical trials that investigated the effects of antihypertensive drugs on endothelial function assessed by FMD in hypertensive patients. A PubMed-based search found 38 clinical trial papers published from January 1999 to June 2011. Significant improvement of FMD after antihypertensive treatment was shown in 43 of 71 interventions (among 38 clinical trial papers). Angiotensin II receptor blockers and angiotensin converting enzyme inhibitors appeared to improve FMD more than other drug types. Antihypertensive treatment can improve endothelial dysfunction when assessed by FMD, although there are conflicting data that require further research. PMID- 22489273 TI - Varicose veins: role of mechanotransduction of venous hypertension. AB - Varicose veins affect approximately one-third of the adult population and result in significant psychological, physical, and financial burden. Nevertheless, the molecular pathogenesis of varicose vein formation remains unidentified. Venous hypertension exerted on veins of the lower extremity is considered the principal factor in varicose vein formation. The role of mechanotransduction of the high venous pressure in the pathogenesis of varicose vein formation has not been adequately investigated despite a good progress in understanding the mechanomolecular mechanisms involved in transduction of high blood pressure in the arterial wall. Understanding the nature of the mechanical forces, the mechanosensors and mechanotransducers in the vein wall, and the downstream signaling pathways will provide new molecular targets for the prevention and treatment of varicose veins. This paper summarized the current understanding of mechano-molecular pathways involved in transduction of hemodynamic forces induced by blood pressure and tries to relate this information to setting of venous hypertension in varicose veins. PMID- 22489275 TI - Diversity of dynamics and morphologies of invasive solid tumors. AB - Complex tumor-host interactions can significantly affect the growth dynamics and morphologies of progressing neoplasms. The growth of a confined solid tumor induces mechanical pressure and deformation of the surrounding microenvironment, which in turn influences tumor growth. In this paper, we generalize a recently developed cellular automaton model for invasive tumor growth in heterogeneous microenvironments [Y. Jiao and S. Torquato, PLoS Comput. Biol.7, e1002314 (2011)] by incorporating the effects of pressure. Specifically, we explicitly model the pressure exerted on the growing tumor due to the deformation of the microenvironment and its effect on the local tumor-host interface instability. Both noninvasive-proliferative growth and invasive growth with individual cells that detach themselves from the primary tumor and migrate into the surrounding microenvironment are investigated. We find that while noninvasive tumors growing in "soft" homogeneous microenvironments develop almost isotropic shapes, both high pressure and host heterogeneity can strongly enhance malignant behavior, leading to finger-like protrusions of the tumor surface. Moreover, we show that individual invasive cells of an invasive tumor degrade the local extracellular matrix at the tumor-host interface, which diminishes the fingering growth of the primary tumor. The implications of our results for cancer diagnosis, prognosis and therapy are discussed. PMID- 22489276 TI - Implications of quantum metabolism and natural selection for the origin of cancer cells and tumor progression. AB - Empirical studies give increased support for the hypothesis that the sporadic form of cancer is an age-related metabolic disease characterized by: (a) metabolic dysregulation with random abnormalities in mitochondrial DNA, and (b) metabolic alteration - the compensatory upregulation of glycolysis to offset mitochondrial impairments. This paper appeals to the theory of Quantum Metabolism and the principles of natural selection to formulate a conceptual framework for a quantitative analysis of the origin and proliferation of the disease. Quantum Metabolism, an analytical theory of energy transduction in cells inspired by the methodology of the quantum theory of solids, elucidates the molecular basis for differences in metabolic rate between normal cells, utilizing predominantly oxidative phosphorylation, and cancer cells utilizing predominantly glycolysis. The principles of natural selection account for the outcome of competition between the two classes of cells. Quantum Metabolism and the principles of natural selection give an ontogenic and evolutionary rationale for cancer proliferation and furnish a framework for effective therapeutic strategies to impede the spread of the disease. PMID- 22489277 TI - Physics of cancer propagation: A game theory perspective. AB - This is a theoretical paper which examines at a game theoretical perspective the dynamics of cooperators and cheater cells under metabolic stress conditions and high spatial heterogeneity. Although the ultimate aim of this work is to understand the dynamics of cancer tumor evolution under stress, we use a simple bacterial model to gain fundamental insights into the progression of resistance to drugs under high competition and stress conditions. PMID- 22489278 TI - Integrated intravital microscopy and mathematical modeling to optimize nanotherapeutics delivery to tumors. AB - Inefficient vascularization hinders the optimal transport of cell nutrients, oxygen, and drugs to cancer cells in solid tumors. Gradients of these substances maintain a heterogeneous cell-scale microenvironment through which drugs and their carriers must travel, significantly limiting optimal drug exposure. In this study, we integrate intravital microscopy with a mathematical model of cancer to evaluate the behavior of nanoparticle-based drug delivery systems designed to circumvent biophysical barriers. We simulate the effect of doxorubicin delivered via porous 1000 x 400 nm plateloid silicon particles to a solid tumor characterized by a realistic vasculature, and vary the parameters to determine how much drug per particle and how many particles need to be released within the vasculature in order to achieve remission of the tumor. We envision that this work will contribute to the development of quantitative measures of nanoparticle design and drug loading in order to optimize cancer treatment via nanotherapeutics. PMID- 22489274 TI - Hyperglycemia and endothelial dysfunction in atherosclerosis: lessons from type 1 diabetes. AB - A clear relationship between diabetes and cardiovascular disease has been established for decades. Despite this, the mechanisms by which diabetes contributes to plaque formation remain in question. Some of this confusion derives from studies in type 2 diabetics where multiple components of metabolic syndrome show proatherosclerotic effects independent of underlying diabetes. However, the hyperglycemia that defines the diabetic condition independently affects atherogenesis in cell culture systems, animal models, and human patients. Endothelial cell biology plays a central role in atherosclerotic plaque formation regulating vessel permeability, inflammation, and thrombosis. The current paper highlights the mechanisms by which hyperglycemia affects endothelial cell biology to promote plaque formation. PMID- 22489279 TI - Dynamic density functional theory of solid tumor growth: Preliminary models. AB - Cancer is a disease that can be seen as a complex system whose dynamics and growth result from nonlinear processes coupled across wide ranges of spatio temporal scales. The current mathematical modeling literature addresses issues at various scales but the development of theoretical methodologies capable of bridging gaps across scales needs further study. We present a new theoretical framework based on Dynamic Density Functional Theory (DDFT) extended, for the first time, to the dynamics of living tissues by accounting for cell density correlations, different cell types, phenotypes and cell birth/death processes, in order to provide a biophysically consistent description of processes across the scales. We present an application of this approach to tumor growth. PMID- 22489280 TI - Fabrication of a new multi-walled carbon nanotube paste electrode for stripping voltammetric determination of Ag(I). AB - A new modified carbon paste electrode based on multi-walled carbon nanotubes and a synthesized Schiff base of N,N'-bis(2-hydroxybenzylidene)-2,2'(aminophenylthio) ethane, acting as a chelating agent for Ag(I) ions, is described. The electroanalytical procedure for the determination of Ag(I) was comprised of two steps: the chemical accumulation of the analyte under open-circuit conditions followed by replacing the medium with a 0.1 M HCl solution where the accumulated Ag(I) was reduced for 20 s in -0.7 V. The potential was then scanned from -0.2 to +0.2 V to obtain the voltammetric peak. The effective parameters in the sensor response were examined. Under optimized operational conditions, a linear response range from 0.5-200 ng mL(-1) was obtained. The detection limit for silver determination was 0.092 ng mL(-1). For 7 successive determinations of 15.0 and 60.0 ng mL(-1) of Ag(I), relative standard deviations of 2.2% and 1.2% were obtained, respectively. The procedure was applied in determining Ag(I) in X-ray photographic films and water samples. PMID- 22489282 TI - Fluorescent silver nanoclusters for user-friendly detection of Cu2+ on a paper platform. AB - The development of a user-friendly sensing platform for the detection of Cu(2+) in water is necessary as there are wide concerns due to the substantial impact of Cu(2+) on human health, environmental monitoring, and so on. Motivated by this, we report a fluorescent silver nanoclusters (AgNCs)-based sensor for the detection of Cu(2+). These water-soluble AgNCs, as a new class of fluorescent probes, were synthesized by using azobenzene modified poly(acrylic acid) (MPAA) as templates. Their fluorescence can be quenched in the presence of Cu(2+), which enables the label-free detection of Cu(2+) in real water samples. Furthermore, such AgNCs can be integrated onto cellulose filter paper and used as fluorescent indicators for Cu(2+). The fluorescence quenching can be observed by the naked eye under UV light. It should be noted that this AgNCs-based paper assay performs successfully in barrelled drinking water and river water samples. Therefore, it opens up new avenues to the development of robust clusters-based sensing platforms. PMID- 22489281 TI - Construction of ribosome display library based on lipocalin scaffold and screening anticalins with specificity for estradiol. AB - A new anticalin against estradiol (E(2)), a kind of endocrine disruptor, was obtained in the present study to detect E(2) levels. A member of the lipocalin family from Pieris brassicae called bilin-binding protein (BBP) was employed for the preparation of a random library to specifically complex E(2). Sixteen amino acid residues at the center of the binding site, which were formed by four loops on top of an eight-stranded beta-barrel, were subjected to targeted random mutagenesis. Estradiol-binding BBP variants so-called 'anticalins', which exhibit binding activity for compounds, such as E(2), were selected from the resulting library by combining both ribosome display and screening techniques. Four variants of complex E(2) with high affinity were identified. These variants exhibited dissociation constants (KDs) as low as 54.265 nM. ELISA showed that ribosome displayed anticalin (E(2)-A) specifically bound E(2). The 50% inhibition concentration (IC(50)) for E(2) was 50 ng mL(-1) and the limit of detection (LOD:IC(10)) was 0.071 ng mL(-1). The experimental results suggest that E(2)-A can be used as a potential anticalin to detect E(2) in animals. PMID- 22489283 TI - Recyclable fluorescent gold nanocluster membrane for visual sensing of copper(II) ion in aqueous solution. AB - Recently, metal-selective fluorescent chemosensors have attracted intense attention for their simple and real-time tracking of metal ions in environmental samples. However, most of the existing fluorescent sensors are one-off sensors and thus suffer from large amount of reagent consumption, significant experimental cost and raising the risk of environmental pollution. In this paper, we developed a green (low reagent consumption, low-toxicity reagent use), recyclable, and visual sensor for Cu(2+) in aqueous solution by using a fluorescent gold nanoclusters membrane (FGM) as the sensing unit, basing on our findings on gold nanoclusters (Au NCs) that the bovine serum albumin (BSA)-coated Au NCs exhibit excellent membrane-forming ability under the isoelectric point of BSA, and thus enable us to obtain a new type of sensing membrane (i.e. FGM) by denaturing Au NCs; the fluorescence of FGM can be significantly quenched by Cu(2+) ion, and the quenched fluorescence can be totally recovered by histidine; the as-prepared FGM is very stable and recyclable, which makes it an ideal sensing material. PMID- 22489284 TI - Aptamer-based highly sensitive electrochemical detection of thrombin via the amplification of graphene. AB - Herein, we successfully fabricated a highly sensitive label-free electrochemical aptasensor for thrombin based on the amplification of graphene (Gra). The excellent electrochemical probe of nickel hexacyanoferrate nanoparticles (NiHCFNPs) was introduced to form Nafion-Graphene-NiHCFNPs (Nf-Gra-NiHCFNPs) nanocomposites membrane on the gold electrode. The employment of graphene not only enhanced the surface area of the electrode with increased NiHCFNPs immobilization, but also improved the conductivity of the electrode, which further effectively improved the sensitivity of this proposed aptasensor. Subsequently, AuNPs layer was formed to immobilize the thrombin aptamer (TBA) and enhance the stability of the composite monolayer mentioned above. Then, thiol modified TBA was assembled onto the AuNPs layer. Thereafter, hexanethiol (HT) was employed to block the possible remaining active sites. With the dual amplification of Gra and AuNPs, the resulting aptasensor exhibited good current response to target thrombin with a wide linear range extended from 1 pM to 80 nM (the detection limit was 0.3 pM). Additionally, the morphologies of bare Au substrate, nickel hexacyanoferrate nanoparticles (NiHCFNPs) and nanocomposites were successfully characterized by atomic force microscopy (AFM). PMID- 22489285 TI - Preparation of magnetic molecularly imprinted polymers for separating rutin from Chinese medicinal plants. AB - The preparation of magnetic molecularly imprinted polymers (MMIPs) which can be used for the separation and purification of rutin from Chinese medicinal plants has been proposed. By applying the improved co-precipitation method, magnetic Fe(3)O(4) particles were easily prepared, followed by the modification of TEOS and functionalization with -CH=CH(2). Using functionalized Fe(3)O(4) particles as the magnetic cores, rutin as the template, and acrylamide as the functional monomer, MMIPs were synthesized by surface-imprinted polymerization under the protection of nitrogen gas and successive mechanical stirring at 60 degrees C for 24 h. Magnetic non-molecularly imprinted polymers (MNIPs) were also prepared with the same synthesis procedure as with MMIPs only without the presence of rutin. Magnetic particles were characterized by FT-IR, XRD, and TG analysis. And the selectivity of MMIPs was also investigated in detail. In addition, the performance of the MMIPs for the adsorption of rutin in the analysis of Chinese medicinal plants was assessed. The mean recoveries were 84.33% (RSD: 3.22%, n = 3) for Saururus chinensis (Lour.) Bail and 85.20% (RSD: 3.58%, n = 3) for Flos Sophorae, respectively, which showed that the prepared MMIPs with many advantages possess the value of practical application. PMID- 22489287 TI - US FDA monitored whistleblowers' computers and emails. PMID- 22489286 TI - Automated solid-phase extraction hyphenated to voltammetry for the determination of quercetin using magnetic nanoparticles and sequential injection lab-on-valve approach. AB - In this study, an automated sequential injection lab-on-valve (SI-LOV) system was designed for the on-line matrix removal and preconcentration of quercetin. Octadecyl functionalized magnetic silica nanoparticles were prepared and packed into the microcolumn of the LOV as adsorbents. After being adsorbed through hydrophobic interaction, the analyte was eluted and subsequently introduced into the electrochemical flow cell by voltammetric quantification. The main parameters affecting the performance of solid-phase extraction, such as sample pH and flow rate, eluent solution and volume, accumulation potential and accumulation time were investigated in detail. Under the optimum experimental conditions, a linear calibration curve was obtained in the range of 1.0 * 10(-8) to 1 * 10(-5) mol L( 1) with R(2) = 0.9979. The limit of detection (LOD) and limit of quantitation (LOQ) were 1.3 * 10(-9) and 4.3 * 10(-9) mol L(-1), respectively. The relative standard deviation (RSD) for the determination of 1.0 * 10(-6) mol L(-1) quercetin was found to be 2.9% (n = 11) along with a sampling frequency of 40 h( 1). The applicability and reliability of the automated method described here had been applied to the determination of quercetin in human urine and red wine samples through recovery experiments, and the obtained results were in good agreement with those obtained by the HPLC method. PMID- 22489288 TI - NICE guidance on cetuximab, bevacizumab, and panitumumab for treatment of metastatic colorectal cancer after first-line chemotherapy. PMID- 22489289 TI - Phase i trialist. PMID- 22489290 TI - Tobacco content in video games: 1994-2011. PMID- 22489291 TI - [Strive for innovation and excellence]. PMID- 22489292 TI - [Liver transplantation: challenge today]. PMID- 22489293 TI - [Recurrence and reinfection of viral hepatitis after liver transplantation]. PMID- 22489294 TI - [Immunosuppression strategies for liver transplantation]. PMID- 22489295 TI - Phthalates in medicinal products, with Katherine Kelley. Interview by Ashley Ahearn. PMID- 22489296 TI - [Ethanol-inhibited rat bone marrow mesenchymal stem cell differentiated hepatocytes play a role in liver regeneration]. PMID- 22489297 TI - [Evaluation of the safety of pregnancy initiated by chronic hepatitis B fathers while taking adefovir]. PMID- 22489298 TI - [Causes and diagnosis of non-portal hypertension ascites: a study of 216 cases]. PMID- 22489299 TI - [Association study of Fas gene polymorphisms with susceptibility to autoimmune liver disease]. PMID- 22489300 TI - [Clinical prognosis of drug-susceptible chronic hepatitis B virus patients at year 5 of lamivudine monotherapy]. PMID- 22489301 TI - [A case report of undifferentiated embryonal sarcoma of the liver]. PMID- 22489302 TI - [Dysacusia associated with pegylated-interferon and ribavirin combination therapy during chronic hepatitis C treatment: a report of two cases]. PMID- 22489303 TI - [A case report of superior mesenteric venous thrombosis in hepatitis B-related cirrhosis]. PMID- 22489304 TI - [Understanding immunopathogenic progresses of the hepatitis B virus provides insights into potential novel targets for antiviral therapy]. PMID- 22489305 TI - [The relation between T lymphocyte subsets and chronic hepatitis B]. PMID- 22489306 TI - [The role of cell death in hepatic fibrosis]. PMID- 22489307 TI - Proceedings of the 2010 Second International Meeting on the Effects of Noise on Aquatic Life, August 2010, Cork, Ireland. PMID- 22489308 TI - Retraction notice to "Detection and genotyping of GB virus-C in dromedary camels in the United Arab Emirates" [Vet. Microbiol. 147 (2011) 226-230]. PMID- 22489309 TI - The marketing of responsible drinking: competing voices and interests. AB - INTRODUCTION AND AIMS: This paper contrasts health-oriented low-risk drinking guidelines (LRDGs) with social drinking marketing and popular advice on the amount of alcohol to be provided for social occasions. The questions addressed include:What is the underlying evidence base and rationale for health-oriented versus socially oriented drinking guidelines?What are the recommended amounts of alcohol per person from the LRDGs and from popular advice? DESIGN AND METHODS: This paper draws on existing research, archival data, websites, print media and key informant interviews. The focus is on recent information on LRDGs and social drinking indicators in Canada, the USA, Australia and the UK. RESULTS: There is extensive epidemiological research indicating the associations between drinking pattern and risk for chronic disease and trauma as well as certain potential health benefits from drinking small amounts regularly. This body of evidence is one resource for government or medically sanctioned LRDGs in many jurisdictions. In contrast, for those planning social events where liquor is served, information is available from the hospitality industry, retailers and liquor control boards.While some overlap exists between these two sources of information, in some contexts normative recommendations support drinking at potentially dangerous levels. DISCUSSION AND CONCLUSIONS: The inconsistency among the different guidelines highlights one of the challenges of conveying health information on a drug that is integrated into social life and used extensively. It also reflects a siloed approach to alcohol policy-where retailing and harm reduction practices are managed by different sectors of government that seldom reflect a coordinated response. PMID- 22489310 TI - Proceedings of the Second Latin American Meeting on Biological Inorganic Chemistry, August 15-18, 2010, Angra dos Reis, Brazil. PMID- 22489311 TI - Proceedings of the 4th Panhellenic Congress of the Hellenic Association of Coloproctology, 19-22 May 2011, Thessaloniki, Greece. PMID- 22489312 TI - Proceedings of the Texas Tuberculosis Research Symposium, April 11, 2011, Galveston, TX. PMID- 22489313 TI - Special issue in memory of Tony Ellis. PMID- 22489314 TI - Re: 'Decisions about life-sustaining measures in children: in whose best interests?'. PMID- 22489315 TI - A fitness model for melanoma-initiating cells. PMID- 22489316 TI - Melanocytes and melanoma: hooked on elongation. PMID- 22489317 TI - Evolution in action: highlighting a role for the Agouti gene in development? PMID- 22489318 TI - Erratum for Fernandez et al. "Comparison of adverse cardiovascular events and bleeding complications of loading dose of clopidogrel 300 mg versus 600 mg in stable patients undergoing elective percutaneous intervention (from the CADICE Study)" Am J Cardiol 2011;107: 6 -9. PMID- 22489319 TI - Potential neuroprotective effects of oxyresveratrol against traumatic injury. AB - Oxyresveratrol is a potent antioxidant and free-radical scavenger found in mulberry wood (Morus alba L.) with demonstrated protective effects against cerebral ischemia. We analyzed the neuroprotective ability of oxyresveratrol using an in vitro model of stretch-induced trauma in co-cultures of neurons and glia, or by exposing cultures to high levels of glutamate. Cultures were treated with 25 MUM, 50 MUM or 100 MUM oxyresveratrol at the time of injury. Trauma produced marked neuronal death when measured 24 h post-injury, and oxyresveratrol significantly inhibited this death. Microscopic examination of glia suggested signs of toxicity in cultures treated with 100 MUM oxyresveratrol, as demonstrated by elevated S-100B protein release and a high proportion of cells with condensed nuclei. Cultures exposed to glutamate (100 MUM) for 24 h exhibited ~ 37% neuronal loss, which was not inhibited by oxyresveratrol. These results show that the two pathologies of high glutamate exposure and trauma are differentially affected by oxyresveratrol treatment in vitro. Further studies using oxyresveratrol in trauma models are warranted, as toxicity to glia could be beneficial by inhibiting reactive gliosis, which often occurs after trauma. PMID- 22489320 TI - An interview with P. Jeffrey Conn. PMID- 22489321 TI - Tumor microenvironmental genomic alterations in juvenile nasopharyngeal angiofibroma. AB - BACKGROUND: To better characterize the pathophysiology of juvenile nasopharyngeal angiofibroma (JNA), endothelial and stromal cells were evaluated by genomic imbalances in association with transcript expression levels of genes mapped on these altered regions. METHODS: High-resolution comparative genomic hybridization (HR-CGH) was used in laser-captured endothelial and stromal cells from 9 JNAs. Ten genes were evaluated by quantitative real-timereverse transcription polymerase chain reaction (qRT-PCR) in 15 cases. RESULTS: Although gains were more frequently detected in endothelial cells, 57% of chromosomal alterations were common by both components. Gene expression analyses revealed a positive correlation between endothelial and stromal components for ASPM, CDH1, CTNNB1, FGF18, and SUPT16H. A significant difference was found for FGF18 and AURKB overexpression in stromal cells and AR down-expression in endothelial cells. CONCLUSIONS: A similar pattern of gene expression and chromosomal imbalances in both exponents would suggest a common mechanism of functional regulation. AURKB, FGF18, and SUPT16H were identified as potential molecular markers in JNA. PMID- 22489322 TI - First hand: unexploded mortar shell in an upper extremity. PMID- 22489323 TI - Incidence of hypoglycemia following insulin-based acute stabilization of hyperkalemia treatment. AB - PURPOSE: The aim of this study was to assess the incidence of hypoglycemia in hospitalized patients following acute treatment of hyperkalemia with insulin. A characterization of the affected patients and the administered insulin/dextrose regimens was also performed. METHODS: A retrospective search of the electronic records of a large university-based tertiary care hospital was conducted, from June 1, 2009 to December 1, 2009, to identify patients who developed hypoglycemia following acute stabilization of hyperkalemia treatment with regular insulin. RESULTS: Of 219 hyperkalemic patients who met the criteria of the study, 19 patients (8.7%) were identified ashypoglycemic (blood glucose <70 mg/dl), and 5 of these patients (2.3% of study patients) were classified as severely hypoglycemic (blood glucose <40 mg/dl). Fifteen (79%) of the hypoglycemic patients had acute kidney injury or were end-stage renal disease patients on hemodialysis at the time of treatment. Fifty-eight percent of the hypoglycemic events occurred following the commonly employed 10 units of regular insulin and 25 gm of dextrose 50% treatment regimen. CONCLUSION: Iatrogenic hypoglycemia, as a result of treatment for hyperkalemia, is a common occurrence. Hyperkalemia occurs disproportionately in patients with acute kidney injury or end-stage renal disease, and these patients are predisposed to an increased risk of hypoglycemia. The risk of severe hypoglycemia escalates inpatients with lower body weight and creatinine clearance.Hypoglycemia risk can be minimized by providing sufficient dextrose in the treatment regimen, however, patient variability in treatment response dictates careful blood glucose monitoring before and after treatment. PMID- 22489324 TI - If you can't beat me, join me: collaborating oncogenes circumventing senescence and causing cancer. PMID- 22489326 TI - Grey matter: ageing in developing countries. PMID- 22489325 TI - Perspectives on personalized cancer care. PMID- 22489327 TI - Letter from America. PMID- 22489328 TI - The fall of the schizophrenogenic mother. PMID- 22489329 TI - Effect of population-based screening on breast cancer mortality. PMID- 22489330 TI - Targeting leucine addiction and autophagy in melanoma. PMID- 22489331 TI - Niche work when you can get it: collagen XVII and the melanocyte stem cell. PMID- 22489332 TI - Separating melanins into their primary colors: quantifying contributions from eumelanin and pheomelanin. PMID- 22489333 TI - Fabrication of a definitive cast to facilitate the delivery of an implant-tissue supported overdenture. PMID- 22489334 TI - Direct custom implant impression copings for the preservation of the pontic receptor site architecture. AB - The direct custom implant impression coping technique is designed to record the periimplant gingiva and pontic receptor site after the tissues have been shaped with a provisional restoration. The technique prevents inaccurate recording of the gingival architecture by using a dual polymerizing composite resin placed into the sulcus and pontic receptor sites and adapted to the open tray implant impression copings. This technique may improve soft tissue accuracy between the clinical condition and the laboratory cast. PMID- 22489335 TI - Pressure ulcer rates: 'publish, or be damned'. PMID- 22489336 TI - Pressure ulcer prevention: the role of the multidisciplinary team. AB - Pressure ulcer prevention has long been a priority for health professionals; however, poor pressure-ulcer-related practices like poor documentation continue to be identified. Research has shown that the attitude and behaviour of some nurses towards pressure ulcer prevention are not conducive to the best possible patient outcomes.This article reviews the findings of a Straussian grounded theory study, which sought to ascertain the value that is placed on pressure ulcer prevention by nurses, but also revealed the role that other health professionals in the multidisciplinary team play in the maintenance of skin integrity. The findings of this study which are presented in this paper highlight a number of important issues. Firstly, nurses are expected to know how to prevent and manage pressure ulcers, but in reality they are very reliant on the advice and support of other health professionals to maintain their patients' skin integrity. In addition,the level of support that nurses get from other health professionals in the multidisciplinary varies tremendously. Therefore, nurses in clinical practice need to be proactive in seeking input from other health professionals, as there are many members of the multidisciplinary team who are able to give them the advice and support that they need in prevention and management. PMID- 22489337 TI - Managing overgranulation tissue around gastrostomy sites. AB - The development of overgranulation tissue around gastrostomy sites isa common problem. While there is little evidence to suggest that one treatment is more effective than another, a review of current practice suggests that there is an opportunity to improve clinical practice and patient outcomes in this area of care. The authors performed a simple practice-based audit to identify the extent of the problem within one geographical location. A care pathway approach was introduced,which reinforced the basic principles of care and encouraged the use of a 'double-foam' dressing on overgranulation tissue. A foam dressing impregnated with polyhexamethylene biguanide was used at the wound interface, providing a safe and effective alternative to managing overgranulation. Findings showed that a strategic approach to managing overgranulation tissue around gastrostomy devices can improve patient outcomes and clinical practice. PMID- 22489338 TI - Superabsorbent dressings: clinical and psychosocial benefits. PMID- 22489339 TI - Obstetric perineal wound infection: is there underreporting? AB - Obstetric perineal wound infection is a complication of perineal trauma during vaginal delivery; however, it is difficult to establish its true incidence as women present for treatment to their GP or the hospital. AIM: To establish the incidence and risk factors of wound infection in postpartum women with sutured tears. METHOD: A 3-month prospective audit was carried out on all women who sustained sutured tears. Wound infection was defined as the presence of any two of the following markers: perineal pain, wound dehiscence, or purulent vaginal discharge. A total of 341 women were contacted by telephone 21 days post-delivery and asked about markers for perineal wound infection and antibiotic use. RESULTS: In total, 409 women sustained sutured perineal tears, including episiotomies, and first, second, third and fourth degree tears. Of the 341 (83%) women contacted, 39 (11%) had a perineal wound infection based on the criteria of any two infection markers. Sixteen(5%) women had all three markers of wound infection. Prolonged rupture of membranes and instrumental delivery was a significant risk factor for women with two and three markers of wound infection,respectively. CONCLUSION: One in ten women who sustained a perineal tear at vaginal delivery that required suturing developed perineal wound infection. Instrumental deliveries and prolonged rupture of membranes predispose women to perineal wound infection. PMID- 22489340 TI - Safeguarding quality in health care: what does it mean? PMID- 22489341 TI - Maggot therapy: a literature review of methods and patient experience. AB - Used in wound-bed preparation, larval therapy can be effective both clinically and financially, if used appropriately. In this article,the author reviews contemporary literature and key research on the benefits and challenges of using this therapy for wound care. The article focuses on debridement, as well as associated antimicrobial effects and psychological issues. Considerations and cautions that may affect clinical practice, such as pain management, peri-wound skin care, different methods of application and preparing the patient both physically and psychologically are also explored. PMID- 22489342 TI - Clarifying nurse roles: who exactly is the ward sister? PMID- 22489343 TI - [Asymptomatic pneumatosis intestinalis in immune-competent adult]. PMID- 22489345 TI - PARP inhibition in epithelial ovarian cancer: high hopes undergo a reality check. AB - The treatment strategy of poly(ADP-ribose) polymerase (PARP) inhibition capitalizes on the inherent defect in homologous recombination that occurs in BRCA-deficient tumors by inhibiting the alternative DNA repair pathway involving base excision repair. Although PARP inhibitors were initially considered a potential treatment specifically for tumors with germline BRCA mutations, evidence of frequent somatic deficiency in the BRCA pathway has caused reconsideration of that approach. PARP inhibitors have been shown to have activity in epithelial ovarian, fallopian tube, and primary peritoneal cancer in phase I and II clinical trials. Responses have been seen in both BRCA-deficient and sporadic tumors, and they do not appear to require platinum sensitivity. Although PARP inhibitors are well tolerated as monotherapy, additional study is required to determine their efficacy and toxicity in combination with chemotherapy and other targeted agents. Many hurdles remain along the pathway to drug registration, but the motivation of the community of ovarian cancer patients, researchers, and clinicians to find new treatments may speed the process. PMID- 22489346 TI - The maze of PARP inhibitors in ovarian cancer. PMID- 22489347 TI - The circuitous path of PARP inhibitor development in epithelial ovarian cancer. PMID- 22489348 TI - Immunoglobulin light-chain amyloidosis: growing recognition, new approaches to therapy, active clinical trials. AB - Immunoglobulin light-chain amyloidosis needs to be considered in any patient presenting with cardiomyopathy with preserved systolic function, heavy albuminuria, an unexplained sensorimotor peripheral neuropathy, hepatomegaly, or atypical MGUS (monoclonal gammopathy of undetermined significance) or myeloma.The prognosis of the disease is determined by the levels of cardiac biomarkers and the pretreatment levels of immunoglobulin free light chains. All patients with systemic light-chain amyloid require therapy. There is no presymptomatic phase that warrants observation. Stem-cell transplantation produces a high response rate but is a viable option in only 20% of patients. Corticosteroids, alkylating agents, immunomodulatory drugs, and proteasome inhibitors all have shown activity in this disorder, and combinations are currently being explored in clinical trials. Despite advances in the past decade, 30% of patients still die within a year of diagnosis, suggesting that failure to recognize this disorder prior to advanced organ dysfunction remains a major impediment to improving outcomes. PMID- 22489349 TI - AL amyloidosis: new drugs and tests, but old challenges. PMID- 22489350 TI - AL amyloidosis: who, what, when, why, and where. PMID- 22489351 TI - A step forward toward better characterization of ovarian cancer. PMID- 22489352 TI - Vismodegib granted FDA approval for treatment of basal cell carcinoma. PMID- 22489353 TI - New testing for lung cancer screening. AB - Lung cancer is the leading cause of cancer-related death worldwide. At the time of initial presentation, most patients are at an advanced stage of disease with an associated poor prognosis.Those diagnosed and treated at earlier stages have a significantly better outcome, with 5-year survival for stage I disease approaching 75%. Ideally, a screening strategy for lung cancer would detect disease at an earlier stage and allow for potential surgical cure in those with cancer and avoid unnecessary morbidity in those without. Until recently, there had not been a screening test that demonstrated a mortality reduction in lung cancer. The National Lung Cancer Screening Trial showed that screening high-risk persons with low-dose CT scanning could significantly reduce lung cancer mortality; however, there are difficulties in generalizing these results to the community. Several new testing techniques, including measurement of volatile organic compounds in exhaled breath, an airway epithelial gene expression biomarker, and serum sampling for antibodies to tumor-associated antigens, are currently being evaluated and may prove useful as part of a screening algorithm for lung cancer. PMID- 22489354 TI - Formidable challenges ahead for lung cancer screening. PMID- 22489355 TI - Lung cancer screening: a new era. PMID- 22489356 TI - Splenic marginal zone lymphoma: current knowledge and future directions. AB - Splenic marginal zone lymphoma (SMZL), along with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and nodal marginal zone lymphoma (NMZL), share a common origin from the "marginal zone." However, these three entities display different clinical characteristics, reflecting probable biological variations according to the organ and cellular origin. Within the past decade, new data have been reported regarding pathogenic mechanisms as well as therapeutic advances. Clinically, SMZL presents as an indolent and disseminated disease at diagnosis, with a specific clinical presentation that includes predominantly splenomegaly, and in half of patients, autoimmune manifestations. Establishing the diagnosis may be difficult, especially distinguishing SMZL from other low-grade lymphomas, such as small B-cell lymphomas; however, recent findings have contributed to a better characterization of the disease, and the criteria for diagnosis have been improved. Therapeutic approaches consist of splenectomy or immunochemotherapy, but there is no consensus regarding the best treatment, except when SMZL is associated with hepatitis C virus infection. In this article, we review the current knowledge on the biological findings, clinical features, and therapeutic approaches for SMZL. PMID- 22489357 TI - Splenic lymphomas: is there still a role for splenectomy? PMID- 22489358 TI - Splenic marginal zone lymphoma: villous, not necessarily villainous. PMID- 22489359 TI - Three challenges for care staff. PMID- 22489360 TI - Emergency nurses prepare to take the Care Challenge. PMID- 22489361 TI - Nurse killing prompts launch of organ donation scheme. PMID- 22489362 TI - Specialist care for frail older people. AB - At Leicester Royal Infirmary, the care of frail older people occupies a disproportionate amount of emergency department (ED) staff's time and resources. Too few ED staff are trained to deal with the complex comorbidities associated with older patients, 90 per cent of whom are therefore admitted to hospital. To take the pressure off the ED and reduce the number of avoidable admissions, the hospital has set up an emergency frailty unit to treat patients over the age of 70 who need not be admitted to hospital and to ensure they can receive community care as soon as possible. This article describes how the unit operates. PMID- 22489363 TI - Treatment options for ankle ligament sprain. AB - There is a wealth of literature on the management of ankle sprains, but the quality of evidence is variable and conclusions diverge. Practice in emergency departments (EDs) also varies and in some cases does not reflect the evidence base. This article reviews some of the most recent research on the subject and suggests air-stirrup ankle braces can be used in EDs for management of moderate and severe ankle sprains. PMID- 22489364 TI - Managing 'pulled elbow' in the paediatric emergency department. AB - Nurses are bound by the Nursing and Midwifery Council code of conduct (2008) to deliver care based on the best available evidence, which involves a combination of clinical expertise and incorporating research into practice (Thompson et al 2004). This article critically evaluates the evidence base of methods available to reduce radial head subluxation in children. The author is a senior staff nurse at an inner-city paediatric emergency department in which about 30,000 children are treated each year. PMID- 22489365 TI - Are emergency care staff prepared for disaster? AB - When disasters occur, nurses of all specialties require the appropriate knowledge and skills to respond effectively and efficiently. To assess the extent to which nurses in the US are prepared for emergencies, researchers have developed the Emergency Preparedness Information Questionnaire (EPIQ), in which participants are invited to assess their familiarity with aspects of emergency preparedness. This article discusses a pilot study of the use of the EPIQ among minor injury unit nurses and healthcare assistants in the UK. The results suggest that the principle of the EPIQ is sound but that it should be adapted to cater for different disaster situations and the needs of individual nurses. Terms that describe disasters and large-scale emergency situations are often used interchangeably so, to avoid confusion, this article uses 'disaster' to refer to all such events. PMID- 22489366 TI - Will every child still matter? PMID- 22489367 TI - Formal networks needed to improve surgical care. PMID- 22489368 TI - The drive for wellbeing at home. PMID- 22489369 TI - Care planning for children with lower limb amputation. AB - This article explores the pathways of care for children who undergo lower limb amputation, from pre-surgery to rehabilitation. The consequences of surgery are manifold, including that children and their families must cope with life with a disability, effects on mobility, greater demands on metabolic reserve, disfigurement, pain and discomfort. Care can be divided into multidisciplinary pre-operative, post-operative, mid-term rehabilitation, including prosthetic limb casting and fitting, and long-term rehabilitation over many weeks and years. The involvement of the multidisciplinary team as the child progresses is described. It is recommended that care should be co-ordinated by a nominated lead professional. Effective discharge planning is crucial to a successful transition home and continuing rehabilitation. PMID- 22489370 TI - Securing ethical permissions to conduct research with children. AB - The process of obtaining ethical permission for medical research is particularly complex in multicentre studies. This article explores the experience of seeking approval for a mixed-method study of children's palliative care in the UK. The study recruited participants through the NHS (nurses and consultants) and third sector (hospice staff and families). The stringent checks and balances that are discussed here apply to any medical research, and can reassure all interested parties of consistently high ethical standards. PMID- 22489371 TI - Origins, purpose and future of Sure Start children's centres. AB - Sure Start began in England under the UK's former Labour government as an intervention for families with young children, particularly targeting the most deprived in society. More than a decade later the service is under threat in many parts of the country as local councils face financial difficulties. This article considers the origins, purpose and future of the service. PMID- 22489372 TI - Technology dependence and children: a review of the evidence. AB - Much has been written about the needs of children who are technology dependent and their care. This literature review aims to highlight some of this work--with a particular focus on children who are ventilator dependent--a group that has been extensively researched in the UK. The views of children and their parents were also sought to identify the emotional, financial and practical burdens of living with technology dependence. The most frequently found consequences for children and their families were: a striving for normalisation, social isolation, the emotional burden of caring, financial and practical difficulties, and the tension between parenting and caring. PMID- 22489373 TI - Trait empathy as a predictor of individual differences in perceived loneliness. AB - Loneliness has been shown to be inversely correlated with empathy in younger adults. The present study extends previous research by investigating the association between empathy and loneliness across the adult lifespan and examining the role of relevant demographic and personality factors. 110 community dwelling adults (18 to 81 years old) completed the UCLA Loneliness Scale and the Empathy Quotient. Empathy scores were inversely associated with rated loneliness and predicted 8.7% of variance in loneliness scores after accounting for sex, age, relationship status, education, and neuroticism. The Social Skills factor of the Empathy Quotient was the strongest predictor of the association between perceived empathy and loneliness. Previous research is extended by the finding that rated loneliness was inversely associated with empathy scores across the adult lifespan. Underlying this relationship may be negative perceptions of personal social proclivity as a function of difficulty in understanding the mental states of others and high trait neuroticism. PMID- 22489374 TI - Convergent validity of the Arabic scale of mental health. AB - To estimate the convergent validity of the Arabic Scale of Mental Health, three convenience separate samples (ns = 162, 168, 138) of volunteer Kuwaiti college students, ages 19 to 32 years, responded anonymously to several scales measuring psychopathology. Analyses showed total ratings for the scale correlated negatively with those of the Kuwait University Anxiety Scale, Factorial Arabic Neuroticism Scale, Somatic Symptoms Inventory, Arabic Scale of Insomnia, the nine subscales of the Symptom Checklist-90-R, the Beck Depression Inventory, and the seven subscales of the General Health Questionnaire. Three separate correlation matrices were subjected to principal components analyses for which a single bipolar factor, Mental health versus psychopathology, was retained in all three matrices. Loadings for the Arabic Scale of Mental Health were -.76, -.64, and .76. It was concluded that this scale has suitable convergent validity. PMID- 22489375 TI - Gelotophobia and thinking styles in Sternberg's theory'. AB - A hypothesis was examined, that gelotophobia (the fear of being laughed at) was negatively related to Type I thinking styles and positively related to Type II thinking styles as defined in Sternberg's theory of mental self-government. 431 university students (250 women, 181 men; M age = 20.4 yr., SD = 1.2) completed self-report measures of gelotophobia (GELOPH <15>) and thinking styles (Thinking Styles Inventory-Revised). Correlation and regression analyses were conducted. The results indicated that gelotophobia was negatively and significantly related to four Type I thinking styles (legislative, judicial, liberal, and hierarchical thinking styles) and a Type III thinking style (external), while it was positively and significantly related to a Type II thinking style (conservative). Thinking styles uniquely explained 18% of the total variance in gelotophobia scores. Possible interventions from the perspective of thinking styles in the treatment of gelotophobia were discussed. PMID- 22489376 TI - Associations between television viewing and love styles: an interpretation using cultivation theory. AB - This study evaluated the associations between television viewing and love styles. The Love Attitudes Scale (LAS), based on Lee's love style taxonomy, was administered to a sample of 338 unmarried Israeli students along with questions about TV viewing habits, current involvement in a serious romantic relationship, and marital intentions. A confirmatory factor analysis of the LAS indicated that the expected six-factor solution adequately fit the data. Correlations between individual love styles and TV viewing were small to moderate, ranging from .12 to .29. Scores for Ludus love style correlated positively with viewing of news and general programming. Those for Pragma love style correlated positively with news viewing and negatively with viewing genres frequently including love themes such as soap operas and family drama, while scores for Eros love style positively correlated with watching these love abundant genres. No significant association was found for TV viewing with Storge, Mania, and Agape love styles. Hierarchical regression using demographic variables, love status, and viewing habits mirrored these results, with the unique R2 for Ludus, Pragma, and Eros ranging from 1.8% to 8%, while the total variance accounted for by the models ranged from 12% to 21%. The findings can be interpreted as support for a weak cultivation effect, in which habits in long-term TV viewing among young adults correspond to small to moderate tendencies for particular love styles that thematically relate them. However, because they are correlational, the findings could equally be interpreted in terms of tendencies that exist due to modeling within families and socialization during development. PMID- 22489377 TI - Decreased aggressive and locomotor behaviors in Betta splendens after exposure to fluoxetine. AB - The failure of sewage treatment plants to remove pharmaceuticals such as fluoxetine from waste water has become a concern given that these products are being detected in the surface waters of many countries of the world. The effects of fluoxetine in sub-lethal doses on the neural systems and behaviors of aquatic life are worthy of investigation. This study investigated the effects of sub lethal amounts fluoxetine dissolved in water on the aggressive and locomotor behaviors of 44 male Betta splendens. Fish treated with 705 microg/l of fluoxetine and 350 microg/l of fluoxetine generally demonstrated significant decreases in locomotion and number of aggressive attacks compared to 0 microg/l of fluoxetine (controls) on Days 11 and 19 of drug exposure and persisted for at least 13 days after removal of fluoxetine. Consistent with decreases in the number of aggressive attacks, there was a significant increase in aggression response time to a perceived intruder for treated males on Days 11 and 19 and persisted for 6 days following removal of fluoxetine. However, the differences in aggressive and locomotor behaviors seen in the fluoxetine-treated groups were indistinguishable from controls three weeks following drug removal. PMID- 22489378 TI - Nocturnal polysomnographic correlates of daytime sleepiness. AB - The relations of nighttime polysomnographic sleep variables with daytime sleepiness scores on the Epworth Sleepiness Scale were assessed in a retrospective chart review of 38 patients referred to a sleep clinic. Of the variables assessed, only slow wave sleep was statistically significantly correlated with daytime sleepiness, regardless of whether the analysis was based on absolute minutes of slow wave sleep or percentage of total sleep time spent in slow wave sleep. Stepwise linear regression suggested that other polysomnographic variables did not provide additional predictive value beyond the two indices of slow wave sleep. Apparently, reduced quantity of slow wave sleep was weakly but significantly related to increased daytime sleepiness among these sleep-clinic patients. PMID- 22489379 TI - A phenomenological study of spontaneous spiritual and paranormal experiences in a 21st-century sample of normal people. AB - Summary.-This paper presents a phenomenological study using the methodology of Woodard's phenomenological and perceptual research. This method examines individuals' internal meanings during spontaneous spiritual and paranormal experiences, as described from their point of view. A group of 40 adults was phenomenologically interviewed after they responded to a newspaper announcement in New Hampshire asking for volunteers who had had spiritual and paranormal experiences. Using the method, Six Individual Situated Structures and a General Structure were identified and examined. Nine major themes were explicated during the participants' spontaneous experiencing: unexpectedness, contrariness to belief, certainty, contradictory experiencing, language as a barrier to expression, external influences, internal dialogue, evil as separateness, and some social psychological influences. Several themes observed in hypnotic experiencing, such as the characteristics of the Adequate Personality in Perceptual Psychology, are interpreted and discussed. This research illustrates how subjective experience can be adequately researched in a qualitative manner outside the confines of the laboratory setting. Limitations of the study and suggestions for further research are given. PMID- 22489380 TI - Influence of motion on face recognition. AB - The influence of motion information and temporal associations on recognition of non-familiar faces was investigated using two groups which performed a face recognition task. One group was presented with regular temporal sequences of face views designed to produce the impression of motion of the face rotating in depth, the other group with random sequences of the same views. In one condition, participants viewed the sequences of the views in rapid succession with a negligible interstimulus interval (ISI). This condition was characterized by three different presentation times. In another condition, participants were presented a sequence with a 1-sec. ISI among the views. That regular sequences of views with a negligible ISI and a shorter presentation time were hypothesized to give rise to better recognition, related to a stronger impression of face rotation. Analysis of data from 45 participants showed a shorter presentation time was associated with significantly better accuracy on the recognition task; however, differences between performances associated with regular and random sequences were not significant. PMID- 22489381 TI - Student ethics in an era of personal entitlement. AB - 397 students arriving to take an exam in a junior level Principles of Management course were clearly warned on several occasions to keep cell phones outside the testing area or receive a failing test grade if the policy was violated. Just before the examination was administered, with all students sitting in their assigned seats, the professor made a final announcement that anyone still in possession of a cell phone would have one last opportunity to come forward and place it in a box at the front of the testing room. After eight students accepted this final "opportunity," the professor produced a hand-held metal detector, demonstrated how it could detect cell phones placed inside clothing, and informed the class that random screening of students would be conducted as they handed in their examinations. He then added that, as a special favor, he would allow a two minute amnesty period during which any student could bring a cell phone to the front of the room for storage during the test. 38 students responded by turning in cell phones they had retained in direct violation of course policy. Implications of this cell phone dishonesty for creating viable business ethics and the role of perceived entitlement in shaping the behavior of these future business leaders were discussed. PMID- 22489382 TI - Negative pragmatic transfer in Chinese students' complimentary speech acts. AB - Summary.-This study was designed to examine negative pragmatic transfer of the speech act of English compliments by Chinese who learn English as a foreign language and to estimate the correlation between the amount of negative pragmatic transfer and English proficiency of the Chinese learners. Frequencies of students' performance showed that both in the favored compliments and the response strategies, differences were evident between Chinese English learners and native English speakers. This indicated that Chinese learners had trouble with the "slang" or "idioms" of the target language and tended to transfer negatively their L1 pragmatic norms to their L2 communication. Moreover, the favored compliment response strategies used by two groups of Chinese learners- who had different levels of English proficiency--differed, and negative pragmatic transfer decreased as proficiency in English increased. PMID- 22489383 TI - Forming impressions from English and French first names: is there an in-group effect in Quebec? AB - Using the Name Connotation Profile, English Canadian and French Canadian university students rated their impressions of people with English or French first names. Both the English and French students formed a more favorable impression of people who had names from their own linguistic group. These results are consistent with social identity theory, according to which people define themselves in part by groups to which they belong, with the contact hypothesis, according to which people feel more positively towards those with whom they have interacted more, and perhaps with the mere exposure effect, according to which liking for an object increases with the frequency with which it is presented. PMID- 22489384 TI - Conditioned withdrawal in goldfish: a simple and inexpensive preparation for the study of classical fear conditioning in vertebrates. AB - Summary.-A preparation for the study of classical fear conditioning in vertebrates is described. Its unique features are that it is inexpensive and easy to construct and operate. The following classical conditioning phenomena are demonstrated using this preparation: excitatory conditioning, extinction, contextual conditioning, blocking, a conditioned inhibition discrimination, and latent inhibition. PMID- 22489385 TI - Self-handicapping and burnout. AB - Self-handicapping is a process containing strategies of externalization in which an individual can excuse failure and internalize success. This study investigated the relationship of self-handicapping with measures of burnout. The Self handicapping Scale and the Maslach Burnout Inventory were administered to 309 university students. Self-handicapping was positively correlated to emotional exhaustion, lowered personal accomplishment, and depersonalization. A structural equation model fit the data well and accounted for 20% of the variance in emotional exhaustion, 14% in lowered personal accomplishment, and 10% in depersonalization. PMID- 22489386 TI - The Children's Behavior Questionnaire very short scale: psychometric properties and development of a one-item temperament scale. AB - Little research has been conducted on the psychometrics of the very short scale (36 items) of the Children's Behavior Questionnaire, and no one-item temperament scale has been tested for use in applied work. In this study, 237 United States caregivers completed a survey to define their child's behavioral patterns (i.e., Surgency, Negative Affectivity Effortful Control) using both scales. Psychometrics of the 36-item Children's Behavior Questionnaire were examined using classical test theory, principal factor analysis, and item response modeling. Classical test theory analysis demonstrated adequate internal consistency and factor analysis confirmed a three-factor structure. Potential improvements to the measure were identified using item response modeling. A one item (three response categories) temperament scale was validated against the three temperament factors of the 36-item scale. The temperament response categories correlated with the temperament factors of the 36-item scale, as expected. The one-item temperament scale may be applicable for clinical use. PMID- 22489387 TI - Initial development of a brief measure of psychological distress. AB - This paper addresses the preliminary development, construct validity, and psychometric properties of a brief self-report measure of psychological distress. 40 items were originally generated by doctoral level psychologists for use in the preliminary clinical sample. Inpatients from a psychiatric unit (N = 125) completed the items, and a principal-components analysis with a direct oblimin rotation was used to evaluate construct validity. The study indicated a four factor solution, using the constructs of Depression, Hopelessness, Anxiety, and Anger, with good estimates of reliability. After evaluation of factor structure, item analyses, and reliability estimates, a redacted 19-item scale was identified. PMID- 22489388 TI - Gender role conflict scale: validation for a sample of gay men and lesbian women. AB - This study tested the oblique four-factor model of the Gender Role Conflict Scale for a sample of gay men and lesbian women residing in the United States. 400 gay men and 292 lesbian women recruited from university and college gay, lesbian, bisexual, and transgender LISTSERVs participated. The internal consistency reliability of the Gender Role Conflict Scale scores was high, but low means on the expressive dimension of gender role conflict were noted. The results of two separate sets of confirmatory factor analyses indicated that the four-factor model's fit to the data could be enhanced for both groups by applying item parceling to lower the number of indicators per factor, suggesting that the actual structural validity of the Gender Role Conflict Scale may be better than suggested by the reported fit indices. PMID- 22489389 TI - Psychometric properties of a Chinese translation of the political skill inventory. AB - Ferris and colleagues defined political skill in organizations as "the ability to effectively understand others at work and to use such knowledge to influence others to act in ways that enhance one's personal and/or organizational objectives." In this study, the psychometric properties of a Chinese translation of the Political Skill Inventory were investigated, supporting construct, convergent, discriminant, and criterion validities. The results suggested that the Chinese translation retained a four-factor structure. Political skill was positively correlated with self-monitoring, conscientiousness, political savvy, emotional intelligence, extraversion, agreeableness, and proactive personality, and was negatively correlated with trait anxiety and external locus of control. After controlling for age, sex, and job tenure, political skill was predictive of task performance, work contribution, and interpersonal help. PMID- 22489390 TI - Spirituality and religiosity as predictors of depression and suicidal ideation: an exploratory study. AB - In a sample of 149 undergraduate students, measures of religiosity and spirituality were positively associated with measures of depression, mania, and past suicidal ideation. PMID- 22489391 TI - Acquisition of a same-different discrimination task by pigeons (Columba livia). AB - Four homing pigeons were trained to discriminate two figures simultaneously presented on an LCD screen. The figure was either a rectangle (A) or a square (B), and four combinations of the two figures, AA, AB, BA, BB, appeared in a pseudo-randomized order. The pigeons' task was to peck one of these figures based upon whether the two figures were identical or not. One pigeon successfully learned this discrimination, with proportions of correct responses above 90% in two consecutive sessions. Of the other birds, two performed above chance level but had difficulty meeting a learning criterion of above 80% in two consecutive sessions. All birds achieved this criterion when the combinations of figures presented were reduced to two. Results suggested that learning the present same different discrimination is within the capacity of pigeons to a certain extent, although there exists considerable individual variation in the pigeons' skills to acquire complex discrimination. PMID- 22489392 TI - Exploratory and confirmatory factor analysis of a short-form of the EMBU among Chinese adolescents. AB - The present study used a sample of Chinese adolescents and validated a short-form of the Egna Minnen Betraffande Uppfostran: One's Memories of Upbringing (s-EMBU) assessing perceived parental rearing styles. A Chinese revision of the s-EMBU by the authors was administered to a total of 779 high school students, ages 11 to 19 years. Exploratory factor analysis with half of the sample yielded a three factor solution of Rejection, Emotional Warmth, and Overprotection, accounting for 47.1% of the total variance onthe father form and 48.8% of the total variance on the mother form. Then, confirmatory factor analysis indicated a good fit of the three-factor model to the data in the other half of the sample. The three subscales consisted of 6, 6, and 7 items, respectively. Scores on these subscales had Cronbach alphas ranging from .71 to .81, indicating adequate internal consistency. These psychometric properties suggest its applicability for research with Chinese adolescents. PMID- 22489393 TI - Frequently cited journals in forensic psychology. AB - Works cited in six forensic psychology journals published 2008-2010 were counted to identify the most frequently cited journals. The sample of works cited (N = 21,776) was not a definitive ranked list of important journals in forensic psychology, but was large enough to indicate high-impact journals. The list of frequently cited publications included more general psychiatry and psychology journals than titles specific to forensic psychology. The implications of the proportion of general versus specific titles for collections supporting research in forensic psychology were discussed. PMID- 22489394 TI - Quality of college students' same-sex friendships as a function of personality and interpersonal competence. AB - The aim of the current study was to investigate personality traits and interpersonal competencies as predictors of the quality of same-sex friendships in young adulthood. Undergraduate students (N = 176), who attended a mid-Atlantic U.S., medium-sized university, completed self-report surveys on their personality, interpersonal competence, and friendship quality. Sex, class status, extraversion, agreeableness, and interpersonal competencies were associated with higher friendship quality, but only the interpersonal competence of self disclosure significantly predicted friendship quality after controlling for sex, class status, and the five personality factors. PMID- 22489395 TI - Self-esteem among college students from four Arab countries. AB - This study had three objectives: (a) to compare undergraduates from four Arab countries on self-esteem, (b) to explore the sex-related differences in self esteem in these four Arab countries, and (c) to examine the association of self esteem with both per-capita income and unemployment rate. Four samples of 2,643 students were recruited from Egypt (n = 576), Kuwait (n = 674), Lebanon (n = 826), and Oman (n = 567). They responded to the Arabic version of the Rosenberg Self-Esteem Scale. Kuwaiti and Omani men had a significantly higher mean score on self-esteem than did Egyptian and Lebanese men. Egyptian women scored significantly lower than the Omani women, but the effect size was small. Regarding the sex-related differences in self-esteem, Kuwaiti men had a significantly higher mean score than did their female peers, but the effect size was small, whereas there were no significant sex differences in the other samples. The sex-related difference in self-esteem is a controversial result and it may not be replicable in different countries. It was suggested that self esteem is associated with high per-capita income and low unemployment rate. PMID- 22489396 TI - Empathy with fictional stories: reconsideration of the fantasy scale of the interpersonal reactivity index. AB - The present research compared empathy for real people with empathy for fictional characters. 95 university students (53 men, 42 women) ages 18-22 years (M = 19.5, SD = 1.9) completed the Interpersonal Reactivity Index (IRI) and the Fictional IRI. The IRI is a widely used measure of human empathy, and the Fictional IRI contains items from the original IRI that have been modified to investigate empathy for fictional characters. Empathy for characters in fictional stories was found to correlate statistically significantly with empathy for real people on all but a few factors. The results of the present study indicate that empathy for real people and empathy for fictional characters are similar, suggesting that the Fantasy subscale of the IRI, which is limited to fictional stories, should be reconsidered. PMID- 22489397 TI - Studies of transformational leadership in consumer service: leadership trust and the mediating-moderating role of cooperative conflict management. AB - This is the third in a series of studies evaluating how transformational leadership is associated with related variables such as job satisfaction, change commitment, leadership trust, cooperative conflict management, and market orientation. The present paper evaluates the effects of transformational leadership and cooperative conflict management along with their mediating and moderating of leadership trust in the life insurance industry for two sample groups, sales managers and sales employees. The main effect of leadership trust was mediated and moderated by cooperative conflict management. Cooperative conflict management made a more important contribution than transformational leadership or the moderating effect (interaction), but these three together were the most important variables predicting highest leadership trust. Transformational leadership has an indirect influence on leadership trust. This work summarizes the specific contribution and importance of building successful leadership trust associations with employees in relation to leadership and satisfaction with change commitment. PMID- 22489398 TI - Recognition of emotional facial expressions: the role of facial and contextual information in the accuracy of recognition. AB - Recognition of emotional facial expressions is a central area in the psychology of emotion. This study presents two experiments. The first experiment analyzed recognition accuracy for basic emotions including happiness, anger, fear, sadness, surprise, and disgust. 30 pictures (5 for each emotion) were displayed to 96 participants to assess recognition accuracy. The results showed that recognition accuracy varied significantly across emotions. The second experiment analyzed the effects of contextual information on recognition accuracy. Information congruent and not congruent with a facial expression was displayed before presenting pictures of facial expressions. The results of the second experiment showed that congruent information improved facial expression recognition, whereas incongruent information impaired such recognition. PMID- 22489399 TI - The role of diffusion-weighted MR imaging and ADC values in the diagnosis of gastric tumors. AB - BACKGROUND: The aim of this study was to investigate the role of diffusion weighted MR imaging (DWI) in the diagnosis of gastric tumors by means of measuring the apparent diffusion coefficient (ADC) values of these lesions, and making a comparison with the endoscopic biopsy results. SUBJECTS AND METHODS: Seventy patients having gastric tumor constituted the case group. For the control group 30 healthy individuals were included. Abdominal MRI examinations were performed with a 1,5 Tesla unit. DWI examinations were obtained by single shot spin echoplanar imaging. The ADC was measured based on the tissue of the gastric tumoral entities and normal gastric mucosa in the control group. RESULTS: Mean ADC values were 0,84 +/- 0,17 x 10(-3) mm2/s and 1,79 +/- 0,08 x 10 mm2/s in gastric tumor group and in control group, respectively, being statistically significant (p<0.05).There was no significance among ADC values of adenocarcinoma subgroups. The comparison of the ADC values in the adenocarcinoma and lymphoma cases were also found to be statistically significant. CONCLUSIONS: DWI is beneficial in the diagnosis of malignant gastric lesions by the aid of ADC measurements. Although ADC quantification seems to be invaluable in the evaluation of histopathologic subgroups of adenocarcinoma, it can help in the diagnosis of gastric lymphoma. PMID- 22489400 TI - Sternocleidomastoid pseudotumor of infancy: a report of thirteen cases. AB - Stemocleidomastoid tumor of infancy (SCMTI) is a rare cause of benign neck masses in neonates and infants. It has to be differentiated from other congenital space occupying lesions in the cervical region. PATIENTS AND METHODS: The files of 13 infants with a mean age of 6 weeks, presenting with a lateral neck mass at Sahloul University Hospital in Sousse (Tunisia) between 2007 and 2009 were retrospectively studied. All of them underwent physical and ultrasonographic examination. MRI was performed in only one case. RESULTS: Ultrasonography (US) showed a soft tissue mass of sternocleidomastoid muscle (SCMM), or a homogenously enlarged muscle without any focal mass. MRI revealed a fusiform enlarged muscle. Diagnosis of SCMTI was established in all cases. Conservative treatment was recommended in all cases with physiotherapy in 2 cases. CONCLUSION: US is the best imaging modality for the diagnosis of SCMTI and the first one to be performed. Additional diagnostic imaging modalities are unnecessary in most of the cases. PMID- 22489401 TI - 'Trampoline fracture' of the proximal tibia in children: report of 3 cases and review of literature. AB - We present three cases of fracture of the proximal tibia in young children who were jumping on a trampoline. The typical radiological findings and the underlying mechanism of trauma are discussed. The key radiological features are: a transverse hairline fracture of the upper tibia often accompanied by a buckle fracture of the lateral or medial tibial cortex, buckling of the anterior upper tibial cortex and anterior tilting of the epiphyseal plate. New types of injuries related to specific recreational activities are recognized. It is often helpful to associate a typical injury with a particular activity. Trampoline related injuries have increased dramatically over the last years. The most common lesions are fractures and ligamentous injuries, in particular a transverse fracture of the proximal tibia. However the radiological findings can be very subtle and easily overlooked. It is therefore important to be aware of the typical history and radiological findings. PMID- 22489402 TI - Pylephlebitis complicating peridiverticulitis without hepatic abscess: early detection with contrast-enhanced CT of the abdomen. AB - Pylephlebitis is a very rare and dangerous complication of inflammatory abdominal processes, mainly appendicitis (1) and diverticulitis (2).We describe a case of peridiverticular inflammation leading to a extensive phlebitis of the adjacent sigmoid vein, extending to the inferior mesenteric vein up to the proximal portal vein, with distal embolus into the left portal vein. Contrast CT and multiplanar reconstructions allowed early diagnosis, and with antibiotic and anticoagulation therapy, no liver abscess developed. PMID- 22489403 TI - Soft tissue chondroma of Hoffa's fat pad. AB - We report mutimodal imaging findings of an extraskeletal chondroma of the Hoffa's fat pad. Plain radiographic or CT scan studies demonstrate a large soft tissue mass with calcifications and central ossification, characteristic features of these tumors. Magnetic resonance (MR) imaging shows heterogeneous signal due to polymorphic histopathological appearance. Correlation between MR imaging and plain film or CT findings is essential to restrict differential diagnosis. The knowledge of this particular pathology is the key to the diagnosis. PMID- 22489404 TI - Sphenoid mucocoele as a complication of fibrous dysplasia of the facial bones. AB - We report on a 28-year-old man with severe headache. Imaging studies included CT and MR. A large sphenoid mucocoele was demonstrated as well as findings compatible with fibrous dysplasia of the facial bones. Both disorders had been previously unknown. Imaging findings suggested that the sphenoid mucocoele was related to an obstruction caused by the expansile bone of fibrous dysplasia. These findings were confirmed surgically. Fibrous dysplasia with subsequent outflow obstruction is an extremely rare cause of sphenoid mucocoele development. PMID- 22489405 TI - Two foreign body reactions caused by suture materials: mammograms mimic cancer as a spiculated lesion. AB - A spiculated breast lesion on mammogram is highly suggestive of malignancy. However, it can be seen on rare occasions in benign conditions including foreign body associated granuloma. We describe two foreign body reactions in the breast caused by suture materials and describe the clinical, radiological and pathological features. PMID- 22489406 TI - A bare area of the glenoid misdiagnosed as a cartilage ulceration. AB - We report on a 17-year-old girl who developed shoulder pain after a fall on an outstretched arm. CT arthrography and MR imaging demonstrated a cartilage defect centrally located in the glenoid. This was accompanied by an eroded appearance of the underlying bone. Since symptoms persisted over several months it was initially thought this represented a cartilage injury. Subsequently arthroscopy was performed and the abnormality was identified as a bare area of the glenoid. A tear of the superior glenohumeral ligament was depicted and was repaired. The bare area is an oval area denuded of cartilage that is probably developmental and that should be differentiated from true cartilage injuries to avoid unnecessary interventions. An eroded appearance of the underlying bone may occur on imaging, a finding that has not been previously reported. PMID- 22489407 TI - Radiation-induced aortic occlusion. AB - Arterial occlusion is a late complication of radiotherapy usually seen in extracranial vessels following treatment for head and neck malignancy. Determining the etiology behind vessel occlusion can be difficult and involves consideration of several factors. We present a case of radiotherapy induced aortic occlusion and discuss the relevant clinical and imaging factors that allow the diagnosis to be made. PMID- 22489408 TI - Radiological findings in a rare case of eyelid swelling: Pott's puffy tumor. AB - Pott's puffy tumor (PPT), or osteomyelitis of the frontal bone, is a rare entity especially in adults. PPT is believed to occur as a complication of fronto ethmoidal sinusitis or trauma to the frontal bone. We present the computed tomography and magnetic resonance imaging findings in such a rare case of Pott's puffy tumor. PMID- 22489409 TI - Single right coronary artery with a "malignant course" of the left main coronary artery. PMID- 22489410 TI - Hypermobile coccyx syndrome. PMID- 22489411 TI - Uterine lipoleiomyoma. PMID- 22489412 TI - Left ventricular non-compaction cardiomyopathy. PMID- 22489413 TI - Spontaneous regression of pulmonary sequestration: prenatal and postnatal imaging findings. PMID- 22489414 TI - Breast augmentation by injection of free silicone: MRI findings. PMID- 22489415 TI - High resolution CT diagnosis of isolated fracture of the malleus handle. PMID- 22489416 TI - Popliteal venous aneurysm. PMID- 22489417 TI - Aberrant retropharyngeal internal carotid artery associated with retropharyngeal abscess: determination of a safe drainage zone with computed tomography. PMID- 22489418 TI - The giant seminal vesicle cyst: magnetic resonance imaging findings. PMID- 22489419 TI - [The patient in the center of the multidisciplinary team]. PMID- 22489421 TI - [A new process for research]. PMID- 22489420 TI - [A new plan for financing health professionals]. PMID- 22489422 TI - [Improving patient safety]. PMID- 22489423 TI - [Health promotion actions in a prison environment]. AB - Prisoners must be able to benefit from the same level of healthcare as the general population. With this objective in mind, nurses from the consultations and outpatient care unit (UCSA) of La Sante prison in Paris take part in the development of health promotion actions. Active participation methods are favoured in order to encourage prisoners to become involved in protecting their health. PMID- 22489424 TI - [Sexuality between couples in palliative care, from the taboo to the possible]. AB - Nurses are frequently confronted with issues around the theme of sexuality often poorly formulated by the patients or those close to them and rarely taken into account by the teams. The teams are often isolated by the confidential nature of their exchanges with the patient, weakened by their own reactions or representations of sexuality, helpless due to the absence of training or reflections on this subject. In the framework of a palliative approach sensitive to the patient as a whole person, a reflection on this theme has enabled some areas of care on which to focus to be envisaged. PMID- 22489425 TI - [Venous and venous/arterial leg ulcers. Complex and multidisciplinary management]. PMID- 22489426 TI - [Diagnosing venous and venous/arterial ulcers]. AB - A venous ulcer can be diagnosed on the basis of elements arising from the questioning and the clinical examination of the patient. A venous Doppler ultrasound can specify the type of reverse flow (superficial and/or deep). Measuring the ankle brachial pressure index helps to eliminate or confirm any arterial involvement. Depending on the systolic pressure index, the ulcer will be considered as purely venous, mixed (arterial-venous) or predominantly arterial. PMID- 22489427 TI - [Compression treatment of venous and venous/arterial leg ulcers]. AB - The French National Authority for Health has recalled recommendations for the use of compression in the treatment of venous or venous/arterial leg ulcers. Different types of bandages and compression stockings must be used. The pressure to be achieved is between 30 and 40 mm Hg at the ankle (and below 30 mm Hg in case of mixed ulcers). In daily practice, beyond these recommendations, the choice of type of compression must also take into account the size of the ulcer, the appearance of the wound, the existence of leg dysmorphia, the volume of the oedema and also the general condition of the patient. PMID- 22489428 TI - [Compression material]. AB - The compression of a venous ulcer is carried out with the use of bandages, and for less exudative ulcers, with socks, stockings or tights. The system of bandages is complex. Different forms of extension and therefore different types of models exist. PMID- 22489429 TI - [The role of the nurse in the treatment of leg ulcers]. AB - A university diploma in wounds and healing is now open to state-qualified nurses. They must manage the pain when removing the dressing and adapt the dressing, treat the infection, encourage the progression of the granulation and take charge of the compression. New information transfer tools such as remote assistance are increasingly being used to avoid patients having to travel to a clinic and to reinforce the complementary skills offered by nurses and experts. PMID- 22489430 TI - [Recognizing and treating complications of venous and venous/arterial leg ulcers]. AB - Several signs can point to an infection of a leg ulcer and lead to the setting up of suitable treatment (new generation antiseptics and silver impregnated dressings). The observation of an increase in the number of bacteria characterises a pre-infectious phase. A biopsy can identify the germ responsible for the infection. A risk of cancerous degeneration is a possibility. Treatment is then generally surgical. PMID- 22489431 TI - [The surgeon and venous and mixed venous/arterial ulcers]. AB - The treatment of leg ulcers encompasses several techniques: mechanical and surgical debridement under local anaesthetic, the excision of the ulcerous base followed by pinch skin or mesh grafting. Varicose vein surgery is based on stripping methods or ligation of the perforators with the aim of relieving the venous overload. These methods are evolving with the use of endoscopic techniques (endovenous laser, radio frequency technique). PMID- 22489432 TI - [Home care of the patient with a leg ulcer]. PMID- 22489433 TI - [Biofilm and leg ulcers]. PMID- 22489434 TI - [Bibliography. Venous and venous/arterial leg ulcers]. PMID- 22489435 TI - [Phenomenology]. AB - The epistemological diversity which characterises research in nursing science offers the researcher several possible methodologies. Among the qualitative methodologies, phenomenology is frequently selected in order to explore a number of research objects. Its philosophical basis seems particularly appropriate for the nursing approach. PMID- 22489436 TI - [Understanding the context and the framework for patient education]. PMID- 22489437 TI - Courage and character, leaders and legends: an interview with Paul I. Terasaki, PhD. Interview by Linda Ohler. PMID- 22489438 TI - History of deceased organ donation, transplantation, and organ procurement organizations. AB - The historical development of deceased organ donation, transplantation, and organ procurement organizations is reviewed. The concept of transplantation, taking parts from one animal or person and putting them into another animal or person, is ancient. The development of organ transplantation brought on the need for a source of organs. Although many early kidney transplants used kidneys from living donors, these donors could not satisfy the ever-growing need for organs, and extrarenal organs were recovered only from deceased donors. This need for organs to satisfy the great demand led to specialized organizations to identify deceased donors, manage them until recovery occurred, and to notify transplant centers that organs were available for their patients. The functions of these organ procurement organizations expanded to include other required functions such as education, accounting, and compliance with state and federal requirements. Because of the shortage of organs relative to the demand, lack of a unified organ allocation system, the perception that organs are a national resource and should be governed by national regulations, and to improve results of organ procurement organizations and transplant centers, the federal government has regulated virtually all phases of organ procurement and transplantation. PMID- 22489439 TI - A Department of Motor Vehicles intervention yields moderate increases in donor designation rates. AB - CONTEXT: Nearly all persons (37% of public) who have a joined an organ donor registry in the United States have done so through their Department of Motor Vehicles (DMV) office, which is an underused venue for organ donation campaigns. OBJECTIVE: To evaluate the effectiveness of a statewide DMV-based intervention to increase donor designation rates. DESIGN AND SETTING: Thirty DMV offices in Florida were randomly assigned to receive usual care (n = 15) or an organ donation intervention (n = 15). MEASUREMENT AND PRIMARY OUTCOME: Donor designation rates were assessed at baseline (before the intervention), during the intervention, and at follow-up. RESULTS: When baseline donor designation rate and region were controlled for, the intervention group showed a significantly higher aggregate monthly donor designation rate than the usual care group during the intervention phase of the study (P = .02). Donor designation rates did not differ significantly (P = .13) during the follow-up phase. Lower donor designations rates were significantly associated with DMV service regions with more minorities, less education, and lower income. CONCLUSION: We conclude that a comprehensive DMV-based intervention focused on staff education and direct interactions with the public could yield modest increases in donor designation rates. PMID- 22489440 TI - Addressing the unintended adverse consequences of first-person consent and donor registries. AB - One of the most common reasons given for the refusal to donate in both the United States and the United Kingdom is that the potential donor, in his lifetime, said he did not want to be a donor. This objection has not always been given by families refusing to donate and appears to be an unintended consequence of donation strategies based on public education, donor registries, and first-person consents. A history of the objection is given, possible meanings are explored, and strategies for dealing with it are suggested. PMID- 22489441 TI - Asian American adolescents' willingness to donate organs and engage in family discussion about organ donation and transplantation. AB - CONTEXT: Despite the growing need for organ donation among Asian Americans, studies suggest that they are reluctant to donate. OBJECTIVE: To examine the association of attitudes and knowledge about organ donation and transplantation with willingness to donate and willingness to engage in family discussion about organ donation among Asian American adolescents. DESIGN: A cross-sectional study. SETTING: The Big Island of Hawaii. PARTICIPANTS: Self-identified Asian American adolescents (Japanese, Chinese, Filipino, Korean), ages 16 to 17 years old, and each adolescent's parent or guardian. MAIN OUTCOME MEASURES: Asian American adolescents provided demographic information and completed the Modified Organ Donation Attitude Survey, the Organ Donation and Transplantation Knowledge Survey, and the Suinn-Lew Asian Self-Identity Acculturation Scale. A parent or guardian also provided demographic information. Linear regression analyses were used to examine the associations with willingness to donate and to engage in family discussion about organ discussion. RESULTS: Willingness to donate was associated with positive knowledge related to general aspects about organ donation and cultural limitations in receiving an organ transplant, a high level of acculturation, and a low level of negative attitudes (R2 = 0.402, F = 18.86, P = .005). Asian American adolescents with approving or positive attitudes were likely to engage in family discussion about organ donation (R2 = 0.195, F = 27.93, P = .005). To reinforce and maintain high levels of knowledge and positive attitudes, organ donation education is most likely needed in high schools. PMID- 22489443 TI - Seligman's theory of attributional style: optimism, pessimism, and quality of life after heart transplant. AB - CONTEXT: Posttransplant quality of life can be significantly affected by personality characteristics identified before transplant. OBJECTIVE: Although overall quality of life in heart transplant patients improves after transplant, many studies reveal poorer mental health outcomes after transplant. We aimed to determine whether transplant recipients with an optimistic explanatory style had improved quality of life, fewer depressive symptoms, and increased survival. DESIGN: We reviewed 68 patients who had completed a Minnesota Multiphasic Personality Inventory a mean of 2 years before transplant and examined associations between scores on the Optimism-Pessimism scale, survival rates, and results from the Health Status Questionnaire nearly 4 years after transplant. RESULTS: Optimism was significantly associated with higher quality of life even after age (at the time of transplant), sex, depression score before transplant, time from the personality inventory to transplant, and time from transplant to the Health Status Questionnaire were controlled for. Furthermore, a pessimistic explanatory style was significantly associated with self-reported depressive symptoms, even after depression before transplant was adjusted for. Neither optimism nor pessimism was associated with length of survival. CONCLUSIONS: Pretransplant patients with a pessimistic explanatory style reported depressive symptoms nearly 5 years later. Furthermore, over the same time span, patients with an optimistic explanatory style described a significantly higher quality of life than the pessimists described. PMID- 22489442 TI - Daily burdens of recipients and family caregivers after lung transplant. AB - CONTEXT: Lung transplant recipients are prescribed a complex medical regimen that is thought to be burdensome and to interfere with daily activities of recipients and family caregivers. Yet empirical studies describing the activities that lung transplant recipients and their family caregivers perform on a typical day and the emotions associated with performing these activities are lacking. OBJECTIVE: To identify the daily activities and burdens after lung transplant. DESIGN: The Day Reconstruction Method and content analysis were used to reconstruct a typical day for lung transplant recipients and their family caregivers. SETTING: The adult cardiothoracic transplant program of The University of Pittsburgh Medical Center. PARTICIPANTS: Twenty-one dyads of lung transplant recipients and their family caregivers. MAIN OUTCOME MEASURES: Variables of interest included lung transplant recipients' and family caregivers' daily activities and associated emotions, sociodemographics, clinical characteristics, and patient-reported outcomes of quality of life, symptoms of depression and anxiety, and functional performance. RESULTS: Participants reported 286 daily activities and 138 associated positive and negative emotions. No activities or emotions were uniquely reported by lung transplant recipients or caregivers, providing evidence of the shared responsibility for caregiving and health maintenance. Most activities reported by caregivers and lung transplant recipients were health related. Compared with lung transplant recipients, caregivers reported positive emotions more often, yet reported lower overall daily mood. This finding is consistent with results of previous studies indicating that specific caregiving tasks were typically rewarding for caregivers, but overall, care giving takes its toll. CONCLUSION: Findings enhance our understanding of the burdens lung transplant recipients and caregivers face and point to the need for further support for dyads after lung transplant. PMID- 22489444 TI - Effect of a study map intended to support informed consent in transplant research. AB - CONTEXT: Research participants' informed consent is integral to the protection of human subjects; studies exploring the enhancement of standard informed consent processes have had mixed success in increasing patients' understanding of complex research protocols. OBJECTIVE: To determine the effect of a "study map," a flow diagram of a research protocol, on research participants' understanding of research purpose and procedures. DESIGN: This study was an experimental posttest only design using 30 research participants enrolling in a study of decision making and recovery among living kidney donors. Participants were randomly assigned to the standard care group (verbal description with consent documents) or the experimental group (standard of care plus study map). An instrument measured perceived and objective understanding, and the differences between groups were determined by an independent t test. DISCUSSION: The high level of comprehension in the control group made detecting improvements in understanding difficult. Objective knowledge and perceived understanding were positively related, suggesting the importance of periodically confirming comprehension with research participants during the informed consent process. Future research should examine the effect of study maps in patients with lower educational levels. RESULTS: Knowledge levels were high in all participants (mean objective = 3.7 on a 5-point scale, SD = 1.02; mean subjective = 9.3 on a 10-point scale, SD = 1.29). There was a significant relationship between objective knowledge and perceived understanding (r = 0.56, P = .001); however, the study map itself had no significant effect on objective or perceived understanding. PMID- 22489445 TI - Characterizing dietary intake and physical activity affecting weight gain in kidney transplant recipients. AB - CONTEXT: Weight gain after kidney transplantation affects 50% to 90% of kidney transplant recipients. Factors leading to weight gain in recipients are thought to include a change in lifestyle (eg, dietary intake and physical activity), age, race, sex, and immunosuppressant medications. OBJECTIVE: To examine dietary intake and physical activity of kidney transplant recipients at baseline and 3 and 6 months after transplantation to identify contributing factors to weight gain. DESIGN: Descriptive, correlational study using secondary data from a larger parent study examining genetic and environmental contributors to weight gain after kidney transplantation. PARTICIPANTS AND SETTING: Forty-four kidney transplant recipients at a mid-South university hospital-based transplant institute who had dietary intake, physical activity, and clinical data at baseline and 3 and 6 months were included. MAIN OUTCOME MEASURES: Dietary intake, physical activity, weight, and body mass index. RESULTS: Mean weight gain increased by 6% from baseline to 6 months. Interestingly, dietary intake did not change significantly from baseline to 6 months. Hours of sleep per day decreased during the same period (P = .02). Dietary intake, physical activity, age, race, sex, and immunosuppression showed no significant relationship to weight gain at 6 months. CONCLUSION: Little consideration has been given to dietary intake and physical activity of kidney transplant recipients and the effects of these variables on weight gain. Further studies with a larger sample are needed, as weight gain after transplantation is a significant risk factor for diminished long-term outcomes. PMID- 22489446 TI - Lessons learned: experiences of gaining weight by kidney transplant recipients. AB - CONTEXT: Weight gain after kidney transplantation is a widespread phenomenon, but the question of effective strategies to intervene in patterns that lead to weight gain has not been well studied. OBJECTIVE: To obtain (1) insight into recipients' perceptions of weight gain and (2) information on intervention strategies that recipients think could prevent weight gain. DESIGN: Qualitative focus groups and a 13-question, multiple-choice survey were used. SETTING: A regional mid-South transplant center. PARTICIPANTS: Seven kidney transplant recipients (86% African American, 57% female, mean age 55.0 years) who had gained at least 12% of their total body weight during a 12-month larger observational study. MAIN OUTCOME MEASURES: Content from the focus group sessions was analyzed for major and minor themes. The survey results were analyzed with descriptive statistics. RESULTS: Identified themes included barriers to healthy eating caused by medications and removal of dietary restrictions. Barriers to physical activity included fear of injuring the new organ and health problems both related and unrelated to transplant. Perceived effects of weight gain included hypertension, diabetes, and embarrassment and concern at the rapid weight gain. Recipients would like an early start to implementation of lifestyle changes. Useful ideas included written materials regarding appropriate physical activities and dietary information, healthy cooking classes, and support groups. PMID- 22489447 TI - Impact of preclinical exposure to organ donation on knowledge and attitudes of medical students. AB - CONTEXT: Medical students receive little exposure to organ donation and procurement programs. OBJECTIVE: To describe a student-run elective and its effect on participants' knowledge about and attitudes toward organ donation. INTERVENTION: Preclinical students interacted directly with donor families, organ recipients, and donation representatives; many participated in an organ procurement with the surgical team. DESIGN: Between 2005 and 2007, 13 students who participated in the elective and a procurement were compared with 72 students who took the elective but did not participate in a procurement and with 22 control students. Students who participated in a procurement wrote reflections about their experience. In 2010, 15 first-year students who participated in the elective and a procurement and 59 randomly selected control students completed a previously validated measure. OUTCOME: Themes included awe, surgical procedures, learning opportunities, and brain death. Regardless of procurement participation, the elective participants from 2005 to 2007 reported higher 4-item knowledge scores (P<.001) than control students reported, but their 4-item attitude scores did not differ (P = .21). The 2010 students did not differ from control students in their number of correct responses to the 20 knowledge questions (P = .48) or their individual responses to each of the 14 attitude questions (all P>.05). RESULTS: Although elective participants reflected positively on their experiences and professed greater knowledge than control students via a researcher-made tool, these results were not sustained with a previously validated measure. These results point to the need for careful elective design and the need for more accurate measures to study the effectiveness of such interventions. PMID- 22489448 TI - Use of standardized patients to teach medical students about living organ donation. AB - Educators routinely use standardized patients to teach medical students a variety of clinical concepts. Standardized patients have also been used to teach students about medical ethics and deceased organ donation. Not reported before, however, is the use of standardized patients to educate medical students about the ethical issues in living organ donation. It seems important to fill this gap because in the United States, roughly 45% of organ donors are living donors, and these patients will visit physicians throughout their lifespan, not just with the occurrence of donation. This article reports an experience teaching concepts in living donation and transplant ethics to second-year osteopathic medicine students using a standardized patient and supplementary instructional materials (eg, film, panel discussion, reading list). Specifically, a transplant ethics module was created that included an actor portraying a living donor candidate who had a number of case variables pertaining to medical and psychosocial matters. Instructional themes included informed consent, altruism, patient selection criteria, organ vending, and post-donation support systems. PMID- 22489449 TI - Psychosocial predictors of adherence after liver transplant in a single transplant center in Portugal. AB - CONTEXT: Nonadherence has important implications for morbidity and mortality, reduced quality of life, and increased medical costs after transplant. OBJECTIVE; To investigate which psychiatric and psychosocial factors determine adherence after liver transplant. DESIGN: A group of 150 consecutive transplant candidates attending the outpatient clinics of the transplant unit of Hospital de Curry Cabral were studied between January 1,2006, and December 1, 2007. Among these, 84 received a transplant and of those 84, 11 recipients died, 3 received another transplant, and 8 refused to finish the study (62 patients remained). MEASURES: Before transplant, prospective recipients were assessed via the Hospital Anxiety and Depression Scale, the NEO Five-Factor Inventory, and the revised Illness Perception Questionnaire. Both before and after transplant, patients were assessed with the Multidimensional Adherence Questionnaire. RESULTS AND CONCLUSIONS: Adherence to medication improved significantly from before to after transplant. This kind of adherence after transplant was associated with adherence to medication before transplant and high scores on the personal control dimension of the Illness Perception Questionnaire before transplant. Therefore it might be useful to focus on patients with poor adherence to medication and low scores on the personal control dimension of the Illness Perception Questionnaire before transplant in order to design interventions for them. PMID- 22489450 TI - Factors influencing living kidney donation in Singapore. AB - CONTEXT: Kidney transplantation is the best treatment option for kidney failure, but the supply of donor kidneys remains small. OBJECTIVE: To understand the public's attitude toward living donor kidney donation in Singapore. DESIGN, SETTING AND PARTICIPANTS, INTERVENTION, OUTCOME MEASURES: A crosssectional study of a convenience sample of 1520 members of the general public seeking care at local medical centers. A self-administered questionnaire included questions on demographics and subjects' willingness and unwillingness to donate a kidney. Respondents were aged at least 18 years and did not have underlying chronic kidney disease, end-stage renal disease requiring dialysis, or history of kidney transplant. RESULTS: Overall mean age of respondents was 49 (SD, 15) years and 50% were male. Response rate to the question on "willingness to donate kidney while alive" was 96% (1460); 707 (48.4%) were willing to donate a kidney while alive. Respondents who were willing to donate were younger (<40 years; P<.001); had above a secondary level education (P<.001); had monthly household income 2000 SGD (or US$1660; exchange rate at 1 SGD = US$0.83) or higher (P<.001); were not married, single, or divorced (P<.001); and were professionals (P<.001). Fear of surgical risks (86.5% strongly agree or agree) and poorer health consequent to donation (87.5% strongly agree or agree) were the main reasons for not considering being a living kidney donor. Demographic factors and concerns of surgical risks and ill health after transplant influenced willingness to donate a kidney while alive. Addressing these concerns may alleviate anxiety with regard to living kidney donation. PMID- 22489451 TI - Kidney transplant with multiple renal artery grafts from deceased donors: are long-term graft and patient survival compromised? AB - BACKGROUND: Kidneys with multiple arteries are often transplanted. However, the long-term outcome of such kidneys recovered exclusively from deceased donors is not clear. OBJECTIVE: To determine whether use of renal grafts with multiple arteries affects long-term graft survival and function. METHODS: The outcomes of 259 consecutive kidney transplants between 1996 and 2000 were retrospectively reviewed. Patients were divided into 2 groups, multiple renal artery graft recipients (n = 70) and single renal artery graft recipients (n = 189). Short term complications and long-term outcomes (survival rates, blood pressure after transplant, creatinine clearance, and proteinuria levels at 1, 3, 5, and 7 years after transplant) were compared between the 2 groups. RESULTS: Early vascular complications were more common (P = .02) in multiple artery graft recipients (18.6%) than in single artery graft recipients (7.9%), mainly because of occlusion of a polar artery in grafts with multiple renal arteries (7.1%). Urologic complications were no more frequent in one group than in the other (5.7% vs 5.3%; P = .89). The 2 groups did not differ significantly (P = .33) in long term graft survival, with a median follow-up of 9.05 years (range, 0.1-12.7 years). Mean (SD) for creatinine clearance (59.4 [22.6] vs 55.9 [20.3] mL/min; P = .47), proteinuria (0.77 [2.1] vs 0.4 [0.8] g/24 h; P = .19), and systolic blood pressure (133.6 [14.5] vs 133.7 [17.5] mm Hg; P = .85) did not differ significantly between the 2 groups 7 years after transplant. CONCLUSIONS: Kidney transplant with grafts containing multiple renal arteries rather than grafts with a single renal artery does not significantly influence patient and graft outcomes. PMID- 22489452 TI - Disseminated candidiasis developing during prophylaxis with fluconazole in a small-intestine transplant recipient. AB - A 31-year-old man underwent immunosuppressive treatment and was treated with 150 mg per day of prophylactic oral fluconazole after receiving a small-intestine transplant. The patient had acute rejection by the end of the first week after the transplant. Endoscopic examination showed white plaques. In blood and urine cultures, growth of Candida albicans was detected. Biopsy specimens showed high levels of conidia and hyphae in all regions. Intravenous treatment with caspofungin was started for the patient. Candidal findings had regressed on follow-up endoscopy. However, the patient died 3 months after transplant because of the effects of immunosuppression on his bone marrow and the development of disseminated intravascular coagulation. Candida species are the most common cause of invasive fungal infections that develop after solid-organ transplant. Following transplant, candidemia may develop during systemic antifungal treatment with a high level of mortality. PMID- 22489453 TI - [The characteristics analysis of projects received and funded in Division of Microbiology, NSFC in 2011]. PMID- 22489454 TI - [Advances in the molecular mechanism of natural bacterial transformation--a review]. AB - Naturally transformable bacteria are able to take up DNA to acquire new genetic traits in the environment. To be naturally transformed, bacteria need to establish a physiological state, called natural competence, in which DNA uptake and processing genes are expressed. DNA uptake proteins assemble a complex to pull exogenous DNA into the cytoplasm where it can recombine with the genome DNA or establish as a plasmid. In general, DNA uptake of bacteria could be divided into two stages: DNA is transported from the milieu to the periplasm at the first stage (for Gram-negative bacteria) and is translocated across the inner membrane at the second stage. Our work and other studies revealed new plasmid DNA transformation modes in Escherichia coli. Here, we first reviewed recent advances in the molecular mechanism of natural transformation and then described the distinctive plasmid transformation mode in E. coli. PMID- 22489455 TI - [Gene transfer agent--a novel and widespread occurrence mechanism of gene exchange in ocean-a review]. AB - Gene Transfer Agent (GTA) particles are released by bacteria and resemble small, tailed bacteriophages. GTA particles contain small, random pieces of host DNA rather than GTA structural genes or a phage genome. Gene transfer mediated by GTA is efficient and species specific based on knowledge of currently best studied GTAs produced by 4 anaerobes. Genome sequencing projects have revealed a remarkable distribution of GTA gene clusters in the genomes of marine bacterioplankton, implying GTA may be an important mechanism for horizontal gene transfer in ocean. On basis of characterization of the 4 best studied GTAs, this review described GTAs released by numerically dominant marine bacteria, discussed their properties that were important for horizontal gene transfer in ocean, and gave future perspectives to advance GTA research. PMID- 22489456 TI - [Systematic analysis and metabolic regulation of physiological functions for lactic acid bacteria--a review]. AB - As cell factories, lactic acid bacteria are widely used in food, agriculture, medicine and other industries, and play a great role in industrial processes. However, lactic acid bacteria encounter various environmental stresses both in industrial processes and in the gastrointestinal tract, which impair their physiological functions and food manufacture efficiency. Recently, the development of metabolic engineering and system biology brings unprecedented opportunity for the physiological modification of lactic acid bacteria. In this review, we addresses the progress of lactic acid bacterium system biology, and based on this, the metabolic engineering strategies for manipulating and optimizing lactic acid bacteria physiological function were summarized. PMID- 22489457 TI - [Construction of a new bacterial artificial chromosome (BAC) vector for cloning of large DNA fragments and heterologous expression in Streptomyces]. AB - OBJECTIVE: Many natural product biosynthetic gene clusters are too large to be entirely cloned into one cosmid for heterologous expression. Because bacterial artificial chromosome (BAC) vectors are well known for their capacity of cloning large DNA fragments, we constructed a new BAC vector for cloning and heterologous expression of natural product biosynthesis gene clusters in Streptomyces. METHODS: The chloramphenicol resistance gene on the original BAC vector pCUGIBAC1 was substituted with a streptomycin resistance gene via lambda RED-mediated PCR targeting technique. The streptomycin resistance gene was then excised by digestion with NheI and the left gap was filled with the origin of transfer (oriT), the phiC31 integrase gene, the integrating attP site, and an apramycin resistance gene. RESULTS: We achieved the final BAC vector pMSBBACs. To test the newly established vector, pMSBBACs was used to build up a genomic BAC library of Streptomyces U27. The average size of inserts in the library is about 100kb. A 140 kb BAC plasmid as a representative was successfully introduced into heterologous hosts, S. lividans and S. albus, by either conjugation or protoplast transformation. It demonstrated that the BAC plasmids constructed by pMSBBACs could be integrated into chromosomes via site-specific recombination for heterologous expression. CONCLUSION: The newly constructed pMSBBACs was verified to be a good BAC vector for cloning of large DNA fragments and heterologous expression in Streptomyces. PMID- 22489458 TI - [Cloning and expression of the redox-sensing transcriptional repressor Rex and in vitro DNA-binding assay of the Rex and rex operator in Streptomyces rimosus M4018]. AB - OBJECTIVE: The aim is to explore the self-regulation mechanism of the rex in Streptomyces rimosus M4018. METHODS: We cloned the rex of S. rimosus M4018 (Sr rex) based on its homologoussequence in Streptomyces coelicolor A3(2) and its upstream rex operator (ROP) fragment using PCR and genome walking. An electrophoretic mobility shift assay (EMSA) was applied to analyze the regulation of rex to ROP in vitro. RESULTS: Sr-rex is 846 bp in length and has a 84% identity with the one in S. coelicolor A3(2) in amino acid sequence. It was deposited in Genbank under the accession number GQ849479. The expressed Sr-Rex by E. coli was mainly composed of alpha-helixes and beta-sheets, which was in compliance with the prediction. An Electrophoretic Mobility Shift Assay (EMSA) confirmed the specific binding activity of Sr-Rex with ROP. Meanwhile, we synthesized a 22 bp DNA fragment (ROP1) based on the minimal binding site of ROP. The maximal binding ratio of this fragment to Sr-Rex was 5:1 (molar). NADH negatively affected the binding activity, however, NAD+ had no impact on it. CONCLUSION: In S. rimosus M4018, the Rex regulated the gene expression of ROP via sensing the intracellular level of NAD (H). PMID- 22489459 TI - [Agrobacterium tumefaciens-mediated transformation (ATMT) for the screening for genes involved in laccase glucose repression in the pathogenic yeast Cryptococcus neoformans]. AB - OBJECTIVE: To identify genes in glucose repression of laccase in the human pathogen Cryptococcus neoformans. METHODS: We created a random insertional mutagenesis library containing over 200000 transformants by Agrobacterium tumefaciens-mediated transformation (ATMT). We screened the glucose derepression mutants under high-glucose condition and obtained the genes for glucose repression of laccase via inverse polymerase chains reaction (PCR). RESULTS: Totally, we isolted 30 glucose derepression mutants from the library. We found that that 83% of the mutants contain a single T-DNA via Southern blot. We preliminarily identified 10 genes, which fall into a broad range of biological processes including: carbohydrate metabolism, sterol biosynthesis, chitin biosynthesis and glycosylphatidylinositol (GPI) anchor biosynthesis. Additionally, we found that three glucose derepression mutants have a single T DNA insertion in the promoter region of LAC1, which encodes cryptococcal laccase. CONCLUSION: As an effective way, ATMT can be utilized for identifying genes in glucose repression of laccase, which sheds lights on the roles of laccase in virulence and provides information for laccase production in industry. PMID- 22489460 TI - [Hepatitis C virus core protein upregulates the transcription of PCK1 through FOXO1/PGC-1alpha pathway]. AB - OBJECTIVE: We analyzed the effect of the stable expressed Hepatitis C virus core protein on PCK1 mRNA expression level and the molecular mechanisms involved in Huh7-lunet cells. METHODS: A retroviral vector mediated mammalian cell expression cell line of the HCV core protein was constructed. The mRNA and protein levels of PCK1, FOXO1 and PGC-1alpha were analyzed by Real-time PCR and luciferase assay in Huh7-lunet-core cells. RESULTS: HCV CORE upregulated the mRNA levels of PCK1 significantly. Both the mRNA and protein levels of FOXO1 were not affected in Huh7-lunet-core cells, whereas a decreased phosphorylation status of FOXO1 was exhibited. Moreover, activation of FOXO1 by HCV CORE was detected. Further, the mRNA level of PGC-1alpha was found to be significantly elevated in Huh7-lunet core cells. CONCLUSION: Our results revealed for the first time that HCV core protein expression-mediated FOXO1 activation and the increased PGC-1alpha leaded to the elevation of PCK1 at the mRNA level, which suggesting the immoderate gluconeogenesis in HCV-infected hepatocytes. Our findings contributed to the understanding of the molecular mechanisms of HCV-related insulin resistance and provided potential new clues for the prevention and therapy of diabetes. PMID- 22489461 TI - [Expression detection of med-ORF12 encoding a stereochemical ketoreductase possibly involved in medermycin biosynthesis]. AB - Medermycin, an aromatic polyketide antibiotic produced by streptomyces, possesses a stereochemical-pyran-ring lactone critical for its strong anticancer activity. The med-ORF12 located in the biosynthetic gene cluster of medermycin encodes a stereochemical ketoreductase. Based on many indirect data, we proposed it to be involved in the enantioselective reduction at C-3 in the formation of the pyran ring of medermycin. The direct genetic evidence about the function of med-ORF12 in the medermycin-producing strain has yet to be obtained. Enzymatic features, expression and regulation pattern of Med-ORF12 in the medermycin-producer still remain obscure. OBJECTIVE AND METHODS: The present study aimed to investigate the expression profiles of med-ORF12 and relationship between Med-ORF12 and medermycin accumulation in medermycin-producers using prokaryotic expression, protein purification, polyclonal antiserum preparation, western blot. RESULTS: First, we established a prokaryotic expression system of med-ORF12 using a pET vector and optimized the induction conditions to accumulate the soluble Med ORF12. Subsequently, we acquired the polyclonal antiserum against Med-ORF12 by immunizing the New Zealand rabbit with the purified protein. Finally, we detected the expression pattern of med-ORF12 in the medermycin producers with the obtained polyclonal antiserum, and found that med-ORF12 could express with a fairly high amount during the late stationary phase of the medermycin-producers, consistent with the accumulation of medermycin as a secondary metabolite. CONCLUSION: These data indicated that Med-ORF12 expressing efficiently in the secondary metabolism could be involved in the biosynthesis of medermycin in the medermycin-producers. PMID- 22489462 TI - [Regulation of tandem repeats on the function of flocculation protein in Saccharomyces cerevisiae]. AB - OBJECTIVE: There are a large numbers of tandem repeats in FLO1, which are highly dynamic components in genome leading to the unstable flocculation profiles in Saccharomyces cerevisiae. The effects of repeated unite B or D deletion on the function of flocculation protein was studied to provide theory basis for constructing genetically stable flocculation gene with minimal size. METHODS: We cloned the intact flocculation gene FLO1 from S. cerevisiae YS59 by PCR, and constructed the derived genes FLO1b and FLO1d with repeated unite B or D deletion respectively by fusion PCR. We analyzed the physiological characteristics of flocculation in yeast strains YSF1, YSF1b and YSF1d containing FLO1, FLO1b and FLO1d respectively. RESULTS: YSF1b and YSF1d displayed almost the same level of Flo1-type flocculation as YSF1. However, flocculation of YSF1b and YSF1d, especially YSF1d was more tolerant to pH change and mannose concentration than strain YSF1. CONCLUSION: Tandem repeats regulate the function of flocculation protein. Deletion of repeated unite B or D, especially D increases the stability of flocculation protein. PMID- 22489463 TI - [Cloning and expression of Micrococcus luteus IAM 14879 Rpf and its role in the recovery of the VBNC state in Rhodococcus sp. DS471]. AB - OBJECTIVE: The purpose of the present study was to produce the Rpf (resuscitation promoting factor) protein by cloning and expressing the rpf gene, secreted by Micrococcus luteus IAM 14879, in Escherichia coli and to evaluate its role in the recovery of the VBNC (viable but non-culturable) state in high-GC Gram-positive bacteria. METHODS: Genomic DNA was extracted from Micrococcus luteus IAM 14879 and the rpf gene was amplified by PCR using specific primers. The PCR products was purified, cloned into a pET15b expression vector, and transformed into Escherichia coli BL21 (DE3). Then the pET15b plasmid expression vector was used to confirm the purification of the recombinant proteins via SDS-PAGE. The VBNC state cells from the high-GC Gram-positive bacteria, Rhodococcus sp. DS471, were used to confirm the promotion and recovery of growth capacity. Rhodococcus sp. DS471 were isolated from soil and closely related to Micrococcus luteus IAM 14879. RESULTS: The gene sequences confirmed that the rpf gene from Micrococcus luteus IAM 14879 that was expressed in Escherichia coli, was 672 bp. SDS-PAGE analysis showed that the recombinant Rpf protein was obtained successfully, and further studies showed it capable of promoting the recovery of the VBNC state by about 100-fold relative to the control. CONCLUSION: Rpf of Micrococus luteus IAM 14879 can be successfully cloned and expressed in Escherichia coli and shows a strong ability to promote the recovery of the VBNC state of cells of Rhodococcus sp. DS471. PMID- 22489464 TI - [Cloning, expression and characterization of chiral alcohol dehydrogenase from Rhodococcus erythropolis ATCC 4277]. AB - OBJECTIVE: We characterized alcohol dehydrogenase from Rhodococcus erytropolis to catalyze ketoesters or ketones. METHODS: We cloned alcohol dehydrogenase gene (adh) of 1047 bp from Rhodococcus erythropolis ATCC 4277, inserted the open reading frame of adh into vector pET-22b(+) and expressed in auto-inducing media for 24 h at 15 degrees C. The enzyme activity was determined at 30 degrees C using acetophenone as substrate. RESULTS: Under the above conditions, the specific enzyme activity of crude extract was 2.6 U/mg. The optimal pH was between 6.0 and 6.5 and the enzyme can survived up to 60 degrees C. After incubation at 60 degrees C for 5 h, 80% enzyme activity remained. The optimal substrate among beta-ketoesters examined was ethyl acetoaetate. Ethyl 4 chloroacetoacetate was catalyzed by whole cell in aqueous phase. After chiral liquid chromatography, the product showed (R)-enantioselective. CONCLUSION: The study shows that the enzyme might have potential in beta-ketoesters transformation on industrial scale. PMID- 22489465 TI - [Construction of an expression vector with elastin-like polypeptide tag to purify xylanase]. AB - OBJECTIVE: This paper reports the purification of xylanase using the shortest, sensitive ELP [KV8F-20]. METHODS: We designed a thermophilic xylanase gene, and recombined it with the ELP via a random coil sequence to generate the vector pET 22b-SoxB-M2-S-ELP. The expressed xylanase was purified by inverse transition cycling through high-speed centrifugation, and then we characterized the purified xylanase. RESULTS: The phase transition temperature of the ELPs dropped to 22 degrees C with 0.5 mol/L sodium carbonate (pH = 7). Under this condition, SoxB-M2 S-ELP was purified by 3.16 folds after centrifugation. The recovery rate was 21.2%, and purity of the xylanase was 64.3%. CONCLUSION: Elastin-like polypeptide as a purification tag to purify recombinant proteins is simple, fast, gentle and cheaper. The expression vector we constructed here might be a very useful and reliable tool to purify many other target proteins. PMID- 22489466 TI - [Screening and identification of a microcystin-degrading bacterium strain and its enzymatic degradation of microcystin-LR by intracellular extract of Bacillus cereus]. AB - OBJECTIVE: To provide effective microorganisms for the treatment of water polluted by microcystins (MCs), the strains capable of biodegrading microcystin LR (MC-LR) were isolated from the sediment of Chaohu Lake. The degradation of microcystin-LR by the intracellular extracts of the strains were studied. METHODS: The enrichment culture using MC-LR as the sole carbon source was utilized to isolate the microcystin-degrading strains. The isolated strain was identified according to the observation of morphology, the physiological and chemical tests and the analysis of 16S rRNA gene sequences. The degradation of MC LR by the intracellular extracts was studied. RESULTS: Strain M6 effectively degrading MC-LR was isolated and the strain M6 could grow utilizing MC-LR as the sole carbon source. Phylogenetic analysis based on 16S rRNA gene showed the similarity of 99% between strain M6 and Bacillus cereus. The experimental results suggest that the active substances for degrading MC-LR were the intracellular extracts which were the tissue enzymes of cells rather than induced enzymes. The degradation of MC-LR may be due to the catalytic effects of three enzymes. The degradation rate of 98.7% could be reached under the following conditions: pH 8.0, 404.9 mg/L of intracellular extracts, and 10 mg/L of the initial concentration of MC-LR. CONCLUSION: Strain M6 which could biodegrade MC-LR efficiently was identified as Bacillus cereus. The influences of pH, the concentration of intracellular extracts and the initial concentration of MC-LR on the enzymatic reaction were obvious. PMID- 22489467 TI - [Community structure of ammonia-oxidizing prokaryotes at the dry-up lake in Huitengxile grassland]. AB - OBJECTIVE: To investigate the structure of ammonia-oxidation microbial communities in the wetlands to dry-up process at 99 degraded lakes of the Huitengxile grassland in the Inner Mongolia Plateau. METHODS: The microbial quantity of ammonia-oxidizing archaea (AOA) and ammonia oxidizing bacteria (AOB) were examined by most probable number-polymerase chain reaction (MPN-PCR). The clone libraries of amoA were constructed and phylogenetics were analyzed. With analysis of the soil properties, we evaluated the effects of wetlands degradation on ammonia-oxidation microbes communities. RESULTS: In 75% of the samples, the quantity of AOB communities was higher than that of AOA; moreover, quantity of bacterial were up to 18.1-fold more abundant than Archaea's. The AOB microbial quantity was strongly correlated with NH4+-N content in the soil. Phylogenetic analyses of the amoA gene fragments showed that most AOB sequences from degraded wetlands were affiliated with Nitrosomonas-like species and a few close to Nitrosospira. All AOA sequences belonged to the kingdom Crenarchaeote. CONCLUSION: Experimental results showed that quantity of ammonia-oxidation microbes increased but community diversity declined during wetlands degradation , and oxidation conditions and ammonium concentration in the soil might play important roles in the community structure of both the AOA and AOB. PMID- 22489468 TI - [Construction of a full-length infectious cDNA clone of inter-genotypic chimeric foot-and-mouth disease virus]. AB - OBJECTIVE: A series of type O foot-and-mouth disease (FMD) outbreaks occurred in China seriously affect development of Chinese husbandry. Its causative agent-type O foot-and-mouth disease virus (FMDV) has been evolved three topotypes: Cathay, Middle East-South Asia and Southeast Asia, specifically, the viruses of Cathay topotype are highly adapted to pig, representing the biggest threat on Chinese pig industry. The available FMD vaccine in China provides insufficient protection against some arising viruses of Chathay topotype, which exert important obstacle to control porcinophilic FMD epidemics in China. To develop vaccine candidate with characteristics of good immunogenicity and broad spectrotype, a full-length infectious cDNA clone of inter-genotypic chimeric FMDV was constructed, which replaced part VP3 and VP1 gene of O/HN/93 strain with the corresponding to the variants of Cathay topotype (mainly replaced the B-C and G-H loop of structure protein VP1). METHODS: Linearized recombinant plasmid and plasmid expressing T7 RNA polymerase were cotransfected into BHK-21 cells to rescue the chimeric virus in vivo. RESULT: The transfected cells showed apparent cytopathic effects (CPE) after 36 h post-transfection. The rescued virus was checked by RT-PCR, indirect immunofluorescence, electron microscope. Results show that chimeric FMDV was successfully rescued in vivo. The study of sulk mice pathogenicity show chimeric FMDV has attenuated pathogenicity for suckling mice compared with its parental virus. CONCLUSION: The construction of inter-genotypic chimeric FMDV will lay the basis for developing novel vaccine against FMD. PMID- 22489469 TI - [Two new sequence type isolates of Bacillus anthracis by multilocus sequence typing]. AB - OBJECTIVE: To define the sequence type (ST) isolates of Bacillus anthracis by multilocus sequence typing (MLST). METHODS: Fragments of seven housekeeping genes (glpF, gmk, ilvD, pta, pur, pycA, and tpi) were amplified by PCR using the standard primers as described on the website for MLST of Bacillus and the sequences were compared with existing allele sequences on the MLST website. RESULTS: Two novel allele combinations of the seven loci were found in two isolates 17003-14 and 17003-32. CONCLUSION: Two novel ST isolates of B. anthracis were identified by this study and confirmed by the MLST website, and the pubMLST ids were id-1053 and id-1054. PMID- 22489470 TI - [Cholesterol-degrading in mice by Lactobacillus plantarum LpT1 and LpT2 in vivo]. AB - OBJECTIVE: To explore the cholesterol-degrading in mice by Lactobacillus plantarum LpT1 and LpT2 in vivo. METHODS: The hypercholesterolemia mice were randomly classified into 4 groups: A, B, C and D and fed with strain LpT1, LpT2, lovastatin and distilled water, respectively, and then TC, TG, HDL-C, LDL-C and AI were determined. The tissue slice of liver was made and observed by transmission electron microscope. RESULTS: The hypercholesterolemia mice model was successfully constructed after feeding the hypercholesterol forage for 7 days. Lactobacillus plantarum LpT1 and the positive control lovastatin could significantly degrade the total cholesterol content (p<0.01) after 28 days, higher than Lactobacillus plantarum LpT2 (p<0.05). However, the negative control water could not degrade it. The transmission electron microscope result showed that the strains could effectively regulate the lipid metabolism to develop towards the regular trend after they were absorbed into the intestines. CONCLUSION: The results further laid foundation for studying the cholesterol degrading mechanism by Lactobacillus plantarum in vivo. PMID- 22489471 TI - [Characterization of metalloprotease of Slr0643 and Sll0862, the S2P homologs from Synechocystis sp. PCC6803]. AB - OBJECTIVE: It is a conserved mechanism in bacteria that metalloprotease site-2 protease (S2P) cleaves transmembrane anti-sigma factor to release sequestered sigma factor in response to extracytoplasmic stress. However, the function of site-2 protease homologs in cyanobacteria remains elusive, so we investigated the metalloprotease activity of Slr0643 and Sll0862, the site-2 protease homologs from Synechocystis sp. PCC6803. METHODS: Recombinant Slr0643 and Sll0862 were constructed and overexpressed in Escherichia coli BL21 (CE3). Their protease activities were tested against beta-casein and then resolved on SDS-PAGE. RESULTS: Results from caseinolytic assay indicated that Slr0643 and Sll0862 have proteolytic activity which is blocked by o-phenanthroline, a metalloprotease inhibitor. These metalloprotease activity of Slr0643 and Sll0862 in vitro provide the foundation for futher analysis of their substrates in vivo. CONCLUSION: The site-2 protease homologs in Synechocystis sp. PCC6803 have metalloprotease activity. PMID- 22489472 TI - [Effects of Eucalyptus grandis leaf litter decomposition on the growth and photosynthetic characteristics of Cichorium intybus]. AB - A pot experiment was conducted to study the effects of Eucalyptus grandis leaf litter during its early stage decomposition on the growth and the photosynthesis of Cichorium intybus. Each pot contained 12 kg soil mixed with different amounts of E. grandis leaf litter (30 g x pot(-1), A1; 60 g x pot(-1), A2; 90 g x pot( 1), A3; and 0 g x pot(-1), CK), and sowed with C. intybus. The growth indicators and the photosynthetic characteristics of C. intybus were measured after the third leaf of C. intybus seedlings fully expanded in treatment A3. At the early stage of leaf litter decomposition, the C. intybus biomass accumulation, leaf area growth, and synthesis of photosynthetic pigments were inhibited significantly, and the inhibition effect was getting stronger with the increasing amount of the leaf litter addition. The intercellular CO2 concentration of C. intybus was increased by litter addition, while the net photosynthetic rate, stomatal conductance, and transpiration rate were significantly lower than those of the control. With the increase of leaf litter addition, all the parameters of C. intybus light response and CO2 response except CO2 compensation point showed an obvious downward trend, and there existed significant differences between the treatments of litter additions and the control. It was suggested that during the decomposition of E. grandis leaf litter, its allelopathic substances released gradually and acted on receptor plants, inhibited the synthesis of photosynthetic pigments and the photosynthesis of the receptors, decreased the receptors environmental adaptation ability, and accordingly, inhibited the growth of C. intybus. PMID- 22489473 TI - [Litter decomposition of dominant plantations in Guangxi and its effects on leachate quality]. AB - To understand the decomposition characteristics of the litters in different forest plantations and the effects of released substances during litter decomposition on the leachate quality, litter samples (leaf, shoot, and cortices) were collected from five forest plantations (1 year-old Eucalyptus urophylla x E. grandis, EU1; 4 year-old Eucalyptus urophylla x E. grandis, EU4; 7 year-old Acacia mangium x A. auriculaef, AM; 13 year-old Pinus massoniana Lamb, PL; and mixed broad-leaved softwood, BL), and incubated at 28 degrees C, using water leached for 255 days. In the first 105 days, the litter leachates of EU1 and EU4 had significantly higher coloration and N and P contents and lower pH than those of AM, PL, and BL. On the 255th day, the cumulative chemical oxygen demand (COD) in the leaf litters leachates of EU1 and EU4 was 193.9 and 212.8 g x kg(-1), being 4.2, 4.0, and 4.3 times and 5.3, 4.4, and 4.7 times higher than that of AM, PL, and BL, respectively. The mass loss rate and the N and P leaching rate of the leaf litter of EU1 were significantly higher than those of AM, PL, and BL. The mass loss rate of cortices of EU1 was significantly higher than that of PL. No significant difference was observed for the leaching rate of the shoot litters between AM, PL, and BL. Among the litter samples, leaf litter was easiest to be decomposed, while shoot litter was most difficult to be decomposed. The pH value of the litter leachates of Eucalyptus plantations was significantly negatively correlated with leachate chroma and COD, and the COD had significant positive correlations with the concentrations of total N and P in the leachates. PMID- 22489474 TI - [Seasonal variations of soil CH4 uptake rate in Castanopsis carlesii forest in mid-subtropical China]. AB - A monthly measurement of soil CH4 uptake rate (V(CH4)) in a natural Castanopsis carlesii forest in Wanmulin Natural Reserve of Fujian Province, East China was conducted from March 2010 to February 2011. The VCH4 showed a pronounced seasonal fluctuation, being higher in summer-autumn than in winter-spring, with the maximum value (95.13 microg x m(-2) x h(-1)) in September and the minimum value (9.13 microg x m(-2) x h(-1)) in March. With the increase of soil temperature and moisture, the V(CH4) showed an increasing and a decreasing trend, respectively, but the correlations of the V(CH4) with soil temperature and moisture were not significant. The annual soil CH4 flux of the forest (3.93 kg x hm(-2) x a(-1)) was higher than the average value of global natural forests (2.4 kg x hm(-2) x a( 1)) and of Asian tropical natural forests (2.07 kg x hm(-2) x a(-1)), but lower than that of Asian temperate natural forests (8.12 kg x hm(-2) x a(-1)). PMID- 22489475 TI - [Effects of different disturbance modes on the morphological characteristics and aboveground biomass of Alhagi sparsifolia in oasis-desert ecotone]. AB - Taking Cele oasis at the southern fringe of Taklimakan Desert as a case, this paper studied the effects of different disturbances (burning in spring, cutting in spring, and cutting in fall) on the morphological characteristics and aboveground biomass of natural vegetation Alhagi sparsifolia in the ecotone of oasis-desert. Burning in spring decreased the A. sparsifolia plant height, crown width, and biomass significantly, being harmful to the regeneration and growth of the vegetation. Cutting in spring decreased the A. sparsifolia plant height, crown width, and biomass but increased the leaf biomass, thorn length, and thorn diameter, whereas cutting in fall decreased the plant height and crown width but increased the ramification amount and biomass of A. sparsifolia. Moderate cutting in fall could benefit the protection of A. sparsifolia at the southern fringe of Taklimakan Desert. PMID- 22489476 TI - [Estimation of soil carbon sequestration potential in typical steppe of Inner Mongolia and associated uncertainty]. AB - Based on the measurements in the enclosure and uncontrolled grazing plots in the typical steppe of Xilinguole, Inner Mongolia, this paper studied the soil carbon storage and carbon sequestration in the grasslands dominated by Leymus chinensis, Stipa grandis, and Stipa krylovii, respectively, and estimated the regional scale soil carbon sequestration potential in the heavily degraded grassland after restoration. At local scale, the annual soil carbon sequestration in the three grasslands all decreased with increasing year of enclosure. The soil organic carbon storage was significantly higher in the grasslands dominated by L. chinensis and Stipa grandis than in that dominated by Stipa krylovii, but the latter had much higher soil carbon sequestration potential, because of the greater loss of soil organic carbon during the degradation process due to overgrazing. At regional scale, the soil carbon sequestration potential at the depth of 0-20 cm varied from -0.03 x 10(4) to 3.71 x 10(4) kg C x a(-1), and the total carbon sequestration potential was 12.1 x 10(8) kg C x a(-1). Uncertainty analysis indicated that soil gravel content had less effect on the estimated carbon sequestration potential, but the estimation errors resulted from the spatial interpolation of climate data could be about +/- 4.7 x 10(9) kg C x a( 1). In the future, if the growth season precipitation in this region had an average variation of -3.2 mm x (10 a)(-1), the soil carbon sequestration potential would be de- creased by 1.07 x 10(8) kg C x (10 a)(-1). PMID- 22489477 TI - [Effects of different irrigation minima on green period and cold-resistance physiological indices of Festuca arundinacea]. AB - A pot experiment was conducted to study the effects of different irrigation minima [80% field capacity (FC), 70% FC, 60% FC and 50% FC] from late autumn to early winter on the green period and cold-resistance of Festuca arundinacea. Under the low temperature in winter, treatments 80% FC and 70% FC made the leaf relative water content, POD, CAT, and SOD activities, and chlorophyll, soluble sugar, and free proline contents of F. arundinacea maintained at a higher level, but made the MDA content and electrolyte leakage decreased, resulting in an increased cold-resistance of F. arundinacea. Treatment 80% FC made the green period of F. arundinacea prolonged by 4, 22 and 28 days, as compared with treatments 70% FC, 60% FC, and 50% FC, respectively, and made F. arundinacea have the shortest time to wither in winter and to turn green in spring, with the longest green period. Taking water-saving and water use efficiency into consideration, 70% FC would be the optimum irrigation low limit from late autumn to early winter for F. arundinacea. PMID- 22489478 TI - [Effects of aluminum stress on ecophysiological characteristics of male and female Populus cathayana seedlings]. AB - This paper studied the sex-specific differences of male and female Populus cathayana seedlings in their ecophysiological characteristics and photosynthesis under the stress of aluminum (216 mg Al(3+) x kg(-1)). Under the effects of aluminum, the malonaldehyde (MDA) and soluble protein (Pr) contents of the male and female seedlings increased significantly (P < 0.001), and the males had a significantly lower MDA content and a significantly higher Pr content than the females. The peroxidase (POD) activity of the males increased but the superoxide dismutase (SOD) activity decreased significantly, while the POD and SOD activities of the females had no significant variation. The net photosynthetic rate (Pn) of both male and female seedlings decreased significantly (P = 0.001), and the transpiration rate (Tr) of the female seedlings decreased (P = 0.007) and the instant water use efficiency (WUEi) increased significantly, while no significant variations were observed in the Tr and WUEi of the male seedlings. The total chlorophyll and chlorophyll a contents and chlorophyll a/b ratio of the females decreased significantly, resulting in a significantly higher chlorophyll a/b ratio of the males. The specific leaf area (SLA) of the females decreased but that of the males increased significantly. No significant variation was observed on the leaf- and stem dry mass. Comparing with the females, the males had higher Pr and chlorophyll contents and higher active antioxidant enzymes activity to maintain higher Pn, and thus, had greater resistance against aluminum stress. PMID- 22489479 TI - [Fire behavior of Mongolian oak leaves fuel-bed under no-wind and zero-slope conditions. I. Factors affecting fire spread rate and modeling]. AB - Aimed to understand the fire behavior of Mongolian oak leaves fuel-bed under field condition, the leaves of a secondary Mongolian oak forest in Northeast Forestry University experimental forest farm were collected and brought into laboratory to construct fuel-beds with varied loading, height, and moisture content, and a total of 100 experimental fires were burned under no-wind and zero slope conditions. It was observed that the fire spread rate of the fuel-beds was less than 0.5 m x min(-1). Fuel-bed loading, height, and moisture contents all had significant effects on the fire spread rate. The effect of fuel-bed moisture content on the fire spread had no significant correlations with fuel-bed loading and height, but the effect of fuel-bed height was related to the fuel-bed loading. The packing ratio of fuel-beds had less effect on the fire spread rate. Taking the fuel-bed loading, height, and moisture content as predictive variables, a prediction model for the fire spread rate of Mongolian oak leaves fuel-bed was established, which could explain 83% of the variance of the fire spread rate, with a mean absolute error 0.04 m x min(-1) and a mean relative error less than 17%. PMID- 22489480 TI - [Differences in phosphorus utilization efficiency among wheat cultivars]. AB - A pot experiment was conducted to study the differences in the biomass, phosphorus concentration, phosphorus use efficiency for dry matter, and phosphorus use efficiency for grain yield among different wheat cultivars under low phosphorus supply, aimed to screen the wheat varieties with high phosphorus use efficiency. For the test cultivars, their biomass per plant at tillering, jointing, flowering, and maturing stages was 0.46-1.09, 0.85-2.10, 3.00-7.00, and 3.85-12.88 g, and their phosphorus concentration was 2.21-4.26, 2.38-4.42, 2.44 4.96, and 1.30-5.09 mg x g(-1), respectively. From tillering to maturing stages, the phosphorus accumulation in plant and the phosphorus use efficiency for dry matter displayed a decreasing effect on the biomass formation. Significant differences were observed in the phosphorus use efficiency for dry matter (tillering stage CV = 16.3%, jointing stage CV = 15.0%, and flowering stage CV = 13.3%) and in the phosphorus use efficiency for grain yield (maturing stage CV = 20.5%) among the cultivars. The cultivars CD1158-7 and Sheng A3 Yi 034 had higher phosphorus use efficiency for dry matter and phosphorus use efficiency for grain yield, while the Yu 02321 was in adverse. The phosphorus concentration in the cultivars with high phosphorus use efficiency was significantly lower than that in the cultivars with low phosphorus use efficiency, and the grain yield of CD1158-7 and Sheng A3 Yi 03-4 was 0.98 times and 0.78 times higher than that of Yu 02321. PMID- 22489481 TI - [Effects of sulfur- and polymer-coated controlled release urea fertilizers on wheat yield and quality and fertilizer nitrogen use efficiency]. AB - A field experiment was conducted to study the effects of sulfur- and polymer coated controlled release urea fertilizers on wheat yield and its quality, plow layer soil inorganic nitrogen (N) contents, and fertilizer N use efficiency. Compared with traditional urea fertilizer, both sulfur- and polymer-coated controlled release urea fertilizers increased the grain yield by 10.4%-16.5%, and the grain protein and starch contents by 5.8%-18.9% and 0.3%-1.4%, respectively. The controlled release urea fertilizers could maintain the topsoil inorganic N contents to meet the N requirement for the wheat, especially during its late growth stage. In the meantime, the fertilizer N use efficiency was improved by 58.2%-101.2%. Polymer-coated urea produced better wheat yield and higher fertilizer N use efficiency, compared with sulfur-coated controlled release urea. PMID- 22489482 TI - [Estimation of winter wheat leaf nitrogen accumulation based on coupling ground- and space-remotely sensed information]. AB - By coupling the SPOT-5 multi-spectral RS images, ground-spectrum, and field measured data of different winter wheat ecological zones, a pure pixel spectrum extraction method was developed based on spectral response function and pixel unmixed, and the quantitative relationships between leaf nitrogen accumulation (LNA) and simulated, measured, and pure pixel spectra were analyzed. The estimation accuracy for LNA was in the sequence of simulated pixel spectra > pure pixel spectra > measured pixel spectra. However, the LNA monitoring model based on simulated pixel spectra couldn't be extrapolated directly to spatial level. The results of model verification also indicated that the monitoring model based on pure pixel spectra performed well in two different wheat ecological zones. Therefore, the pure pixel spectrum extraction method could be applied to other varied and remotely sensed data with different spatial and spectral resolutions by making use of the merits of ground- and space- remote sensing simultaneously, which provided a technological basis for estimating winter wheat nitrogen status in regional scale. PMID- 22489483 TI - [Mechanisms for the increased fertilizer nitrogen use efficiency of rice in wheat rice rotation system under combined application of inorganic and organic fertilizers]. AB - A pot experiment was conducted to study the effects of combined application of organic and inorganic fertilizers on the nitrogen uptake by rice and the nitrogen supply by soil in a wheat-rice rotation system, and approach the mechanisms for the increased fertilizer nitrogen use efficiency of rice under the combined fertilization from the viewpoint of microbiology. Comparing with applying inorganic fertilizers, combined application of organic and inorganic fertilizers decreased the soil microbial biomass carbon and nitrogen and soil mineral nitrogen contents before tillering stage, but increased them significantly from heading to filling stage. Under the combined fertilization, the dynamics of soil nitrogen supply matched best the dynamics of rice nitrogen uptake and utilization, which promoted the nitrogen accumulation in rice plant and the increase of rice yield and biomass, and increased the fertilizer nitrogen use efficiency of rice significantly. Combined application of inorganic and organic fertilizers also promoted the propagation of soil microbes, and consequently, more mineral nitrogen in soil was immobilized by the microbes at rice early growth stage, and the immobilized nitrogen was gradually released at the mid and late growth stages of rice, being able to better satisfy the nitrogen demand of rice in its various growth and development stages. PMID- 22489484 TI - [Effects of different fertilization modes on paddy field topsoil organic carbon content and carbon sequestration duration in South China]. AB - Based on the organic carbon data of 222 topsoil samples taken from 38 paddy field experiment sites in South China, calculations were made on the relative annual change of topsoil organic carbon content (RAC) and carbon sequestration duration in the paddy fields in South China under five fertilization modes (inorganic nitrogen fertilization, N; inorganic nitrogen and phosphorus fertilization, NP; inorganic nitrogen, phosphorus, and potassium fertilization, NPK; organic fertilization, O; and inorganic plus organic fertilization, OF). The RAC under the fertilizations was 0-0.4 g x kg(-1) x a(-1), with an increment of 0.20 and 0.26 g x kg(-1) x a(-1) in double and triple cropping systems, respectively. The RAC was higher in treatments O and OF than in treatments N, NP, and NPK, being the highest (0.32 g x kg(-1) x a(-1)) in treatment OF. The topsoil organic carbon accumulation rate decreased with increasing time, and the carbon sequestration duration in treatments N, NP, NPK, O, and OF was about 22, 28, 38, 57, and 54 years, respectively. Inorganic plus organic fertilization was the most effective practice for soil carbon sequestration in the paddy fields in South China. PMID- 22489485 TI - [Effects of transgenic Bt rice on soil dissolved organic carbon and nitrogen contents and microbiological properties]. AB - A two-year field experiment (2009 and 2010) was conducted to evaluate the effects of three transgenic Bt rice lines (KMD, HH1, and BtSY63) and their non-Bt lines (XSD, MH63, and SY63) on soil dissolved organic carbon (DOC) and nitrogen (DON) and microbiological properties. All the measured indices changed significantly with sampling time. Comparing with their corresponding non-Bt lines, the test transgenic Bt lines had little effects on the soil DOC, DON, and microbial biomass nitrogen (MBN). The transgenic Bt lines had significant effects on the soil microbial biomass carbon (MBC), basal respiration (BR), and microbial metabolic quotient (qCO2) in certain periods of time in the first year, but no effects in the second year. Among the soils planted with the three non-Bt rice lines, no difference was observed in the DOC, DON, and microbiological properties, whereas in the soil planted with BtSY63, the MBC and BR were significantly higher, but the qCO2 was significantly lower, as compared with those in the soils planted with KMD and HH1. In sum, two years' planting transgenic Bt rice had little effects on the soil DOC, DON, and microbiological properties, but the differences of soil microbiological properties induced by the planting of different transgenic Bt rice lines were larger than those induced by the planting of different non-Bt lines, implying that long term monitoring would help to reveal the effects of transgenic Bt rice on the structure and function of soil ecosystem. PMID- 22489486 TI - [Effects of combined application of maize- and horsebean straws on the straws decomposition and soil nutrient contents]. AB - A laboratory incubation experiment was conducted to study the straw decomposition and soil nutrient contents after single and combined applications of maize- and horsebean straws. With the single application of maize straw, the mineralization rates of the straw and soil organic C were lower, and the immobilization of soil mineral N sustained longest. Combined application of maize- and horsebean straws promoted the mineralization of the straws organic C and soil immobilized N. Both single and combined application of the straws increased the contents of soil microbial biomass C and N significantly. It was suggested that a combined application of gramineous and leguminous straws could promote the straws decomposition and harmonize the soil nutrient supply. PMID- 22489487 TI - [Effects of organic material amendment on vegetable soil nitrate content and nitrogenous gases emission under flooding condition]. AB - Applying large amount of nitrogen fertilizer into vegetable field can induce soil NO(3-)-N accumulation, while rapidly removing the accumulated NO(3-)-N can improve vegetable soil quality and extend its service duration. In this study, a vegetable soil containing 360 mg N x kg(-1) was amended with 0, 2500, 5000, and 7500 kg C x hm(-2) of ryegrass (noted as CK, C2500, C5000, and C7500), respectively, and incubated in a thermostat at 30 degrees C for 240 h under flooding condition, aimed to investigate the effects of organic material amendment on vegetable soil nitrate concentration and nitrogenous gases emission. By the end of the incubation, the soil NO(3-)-N concentration in CK was still up to 310 mg N x kg(-1). Ryegrass amendment could remove the accumulated NO(3-)-N effectively. In treatments C2500, C5000, and C7500, the duration for the soil NO(3-)-N concentration dropped below 10 mg N x kg(-1) was 240 h, 48 h, and 24 h, respectively. After the amendment of ryegrass, soil pH increased significantly, and soil EC decreased, with the increment and decrement increased with increasing amendment amount of ryegrass. The cumulative emissions of soil N2O and N2 in ryegrass amendment treatments amounted to 270-378 mg N x kg(-1), and the N2O/N2 ratio ranged from 0.6 to 1.5. Incorporating with ryegrass under flooding condition could rapidly remove the accumulated NO(3-)-N in vegetable soil, but the high N2O emission during this process should be attached importance to. PMID- 22489488 TI - [Distribution and accumulation characteristics of nutrients in solar greenhouse soil in Ji'nan, Shandong Province of East China]. AB - Taking the solar greenhouses with different cultivating years and vegetables in Ji'nan as test objects, this paper studied the amounts and frequency distribution of soil nutrients and the relationships between cultivating years and soil nutrients accumulation characteristics, and analyzed the factors causing soil salinization and acidification by fitting soil nutrients contents with cultivating years and vegetables. In the greenhouses, the contents of soil alkali hydrolysable nitrogen, available phosphorus, available potassium, organic matter, and electrical conductivity were significantly higher than those in the open field, with an increment of 135.3%, 475.2%, 290.1%, 97.7%, and 188.7%, respectively, but the soil pH value was 0.31 lower than that of open field. The frequency distribution of soil nutrients presented a normal curve. Differences were observed in the soil nutrients contents in the greenhouses with different cultivating vegetables. The soil alkali-hydrolysable nitrogen content and electrical conductivity were in the order of tomato > cucumber > sweet pepper, soil organic matter content and pH value were cucumber > sweet pepper > tomato, soil available phosphorus content was cucumber > tomato > sweet pepper, and soil available potassium content was tomato > cucumber > sweet pepper. There was a mild tendency of soil acidification in soil alkali-hydrolysable nitrogen and available potassium. The decrease of soil pH was closely related to the accumulation of alkali-hydrolysable nitrogen. The soil nutrients accumulation in the greenhouses had the similar patterns, i. e. , rapid accumulation in the first two cultivating years, slowed down in the third and fourth year, and kept stable later, demonstrating a dynamic balance on the whole. All the nutrients contents were positively accumulated, while soil pH presented negatively. In the greenhouses with different cultivating vegetables, there was a significant correlation between soil nutrients and cultivating years, which could be fitted by conic curve or cubic curve. PMID- 22489489 TI - [Effects of different cropping modes on crop root growth, yield, and rhizosphere soil microbes' number]. AB - A multi-year field experiment was conducted to study the variation features of rhizosphere environment and crop root growth under the cropping modes of wheat soybean (A1), wheat-sweet potato (A2), maize (A3), wheat/maize/soybean (A4), and wheat/maize/sweet potato (A). Among the five modes, A4 increased the plant biomass, root activity, and root dry mass of wheat, maize, and soybean at their flowering and maturing stages, and the quantity of rhizosphere soil bacteria, fungi, and actinomycetes. The biomass and quantity of rhizosphere soil microbes were relay strip intercropping > single cropping, soybean > sweet potato, and fringe row > center row. It was suggested that wheat/maize/soybean relay trip intercropping could improve rhizosphere environment, promote the crops root growth and increase their aboveground biomass, and accordingly, realize yield increasing. PMID- 22489490 TI - [Effects of high- and low temperature stress on the leaf PSII functions and physiological characteristics of tree peony (Paeonia suffruticosa cv. 'Roufurong')]. AB - Taking the detached leaves of tree peony (Paeonia suffruticosa cv. 'Roufurong') as test materials, this paper studied the effects of high temperature (40 degrees C) and low temperature (15 degrees C) stresses on the PS II functions and physiological characteristics of peony leaves under strong light intensity (1400 micromol x m(-2) x s(-1)), with 25 degrees C as the control. With the increasing time of high- and low temperature stress, the maximal photochemical efficiency (Fv/Fm), actual quantum yield of photosystem II (Phi(PS II)) , and efficiency of excitation capture of open PS II center (Fv'/Fm') all decreased continuously. After recovered in the dark for 4 hours, the Fv/Fm in treatments 15 degrees C and 25 degrees C quickly recovered, but that in treatment 40 degrees C only recovered to 75.5% of non-treatment, even if the leaves were treated in the dark for 15 hours. At 40 degrees C, the balance of excited energy between PS I and PS II under strong light intensity was perturbed seriously. Treatment 40 degrees C inhibited the superoxide dismutase (SOD) activity, enhanced the production of O2 , H2O2, and MDA, and reduced the contents of chlorophyll and soluble protein. This study revealed that strong light combined with high temperature impaired the photosynthetic apparatus of the tree peony irreversibly, whereas strong light plus low temperature had weaker impact. PMID- 22489491 TI - [Effects of exogenous 24-epibrassinolide on the leaf photosynthetic characteristics and polyamines content of cucumber seedlings under hypoxia stress]. AB - A water culture experiment with 1/2 Hoagland solution was carried out to study the effects of exogenous 24-epibrassinolide (EBR) on the leaf photosynthetic characteristics and polyamines (PAs) content of cucumber seedlings under hypoxia stress. Under the stress, the leaf net photosynthetic rate (Pn), stomatal conductance (g(s)), transpiration rate (Tr), and intercellular CO2 concentration (Ci) decreased significantly while the chlorophyll content was in adverse, and the seedling growth was inhibited. Hypoxia stress increased the leaf Put, Spd, and Spm contents and Put/PAs ratio significantly, but decreased the (Spd+Spm)/Put. Under the stress, exogenous EBR not only increased the Pn, g(s), Tr, and chlorophyll content significantly, but also increased the contents of free Spm, conjugated Spd and Spm, and bound Put, Spd, and Spm significantly. Meanwhile, the PAs content and (Spd + Spm)/Put ratio were further increased, and the Put/PAs ratio decreased. The results suggested that exogenous EBR could regulate the formation and form transformation of PAs in cucumber seedling leaf, made the leaf keep a higher photosynthetic performance, promote the increase of leaf area and dry mass, and alleviate the damage of hypoxia stress. PMID- 22489492 TI - [Physiological responses of cucumber seedlings grafted on different salt-tolerant rootstocks to NaCI stress]. AB - Based on the salt-tolerance identification of a series of cucumber rootstock varieties, the cucumber cultivar 'Xintaimici' grafted on different salt-tolerant rootstock varieties 'Sherpa', 'Shintosa' , 'Tielizhen' , and 'Figleaf gourd' was selected to study its seedlings physiological responses to NaCl stress, taking the self-rooted ones as the control. Under the stress of 100 mmol NaCl x L(-1), the leaf electrolyte leakage rate and malondialdehyde (MDA) content of the grafted seedlings were significantly lower than those of self-rooted seedlings, and the seedlings grafted on 'Figleaf gourd' showed the lowest electrolyte leakage rate and malondialdehyde (MDA) content, followed by the seedlings grafted on 'Tielizhen', 'Shintosa' , and 'Sherpa'. The leaf proline and soluble sugar contents and peroxidase (POD), superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase (APX) activities of the grafted seedlings were significantly higher than those of the self-rooted seedlings, and the POD, SOD, CAT, and APX activities were the highest for the seedlings grafted on 'Figleaf gourd' and the lowest for the seedlings grafted on 'Sherpa', but had no significant differences for the seedlings grafted on 'Tielizhen' and 'Shintosa'. The leaf Na+ content of the seedlings grafted on different rootstock varieties ranked as 'Figleaf gourd' < 'Tielizhen' < 'Shintosa' < 'Sherpa', while the leaf K+ content had little difference for the seedlings grafted on 'Figleaf gourd', 'Tielizhen', and 'Shintosa' but was significantly higher than that for the seedlings grafted on 'Sherpa'. The self-rooted seedlings had the highest leaf Na+ content but the lowest leaf K+ content. The leaf Na+/K+ ratio of grafted seedlings was significantly lower than that of self-rooted ones, and the seedlings grafted on 'Figleaf gourd' had the lowest leaf Na+/K+ ratio. PMID- 22489493 TI - [Effects of arbuscular mycorrhiza fungi (AMF) on the plant growth, fruit yield, and fruit quality of cucumber under salt stress]. AB - By adopting organic substrate culture, and salt-sensitive cucumber variety 'Jinchun No. 2' was used as test material, this paper studied the effects of inoculating arbuscular mycorrhiza fungi (AMF) on the plant growth, fruit yield, and fruit quality of cucumber under salt stress. AMF-inoculation could effectively promote the plant growth and nutrient uptake, and improve the fruit yield and fruit nutrient quality, compared with ordinary cultivation. Under salt stress, the plant growth was inhibited, and the plant N, P, K, Cu, and Zn contents and K+/Na+ ratio, fruit yield, and fruit soluble protein, total sugar, vitamin C, and nitrate contents decreased, while inoculation with AMF could mitigate the inhibitory effect of salt stress on the plant growth, made the plant N, P, K, Cu, and Zn contents increased by 7.3%, 11.7%, 28.2%, 13.5%, and 9.9%, respectively, and made the plant K+/Na+ ratio, fruit yield, and fruit soluble protein, total sugar, and vitamin C contents have an obvious increase and the fruit nitrate content have a significant decrease. It was suggested that AMF could promote the plant growth and nutrient uptake of cucumber under salt stress, increase the plant salt-tolerance, and improve the fruit yield and its nutrient quality. PMID- 22489494 TI - [Effects of organic manure application on dry land soil organic matter and water stable aggregates]. AB - A four-year (2007-2010) field experiment was conducted to study the effects of applying different amounts (7500, 15000, and 22500 kg x hm(-2)) of organic manure on the organic matter content, aggregate particle size distribution, and aggregate stability in different soil layers in a continuously cropped maize field on the Weibei Dry Land, Shaanxi Province of Northwest China. In 0-20 cm soil layer, the organic matter content in treatment 22500 kg x hm(-2) of organic manure was 4.1%-4.6% higher than that in treatment 7500 kg x hm(-2) of organic manure (P < 0.05), and the organic matter content in treatments 15000 and 22500 kg x hm(-2) of organic manure was 4.6%-11.2% higher than that in CK (chemical fertilization) (P < 0.05). In the fourth year (2010) of applying 7500 kg x hm(-2) of organic manure, the organic matter content in 0-20 cm soil layer was 4.7%-6.3% higher than that of CK (P < 0.05). In 0-30 cm soil layer, all treatments with organic manure application had an increased amount of soil water stable aggregates (> 5 mm), and the amount of the aggregates increased significantly with the increasing application rate of organic manure. Applying organic manure increased the amount of soil water stable aggregates (> 0.25 mm), aggregate mean mass diameter, and aggregate stability in 0-30 cm soil layer, as compared with CK, and these three indices increased significantly with increasing organic manure application rate. PMID- 22489495 TI - [Effects of nitrification inhibitors DCD and DMPP on cinnamon soil' s gross nitrogen mineralization and nitrification rates]. AB - By using 15N pool dilution technique in combining with in situ soil cultivation, this paper studied the effects of nitrification inhibitors dicyandiamide (DCD) and 3,4-dimethylpyrazole phosphate (DMPP) on the gross nitrogen (N) mineralization and nitrification rates in a saline-alkali cinnamon soil in North China. The experiment was carried out in a maize-wheat rotation field in Yuncheng City of Shanxi Province, and three treatments were installed, i.e., urea, urea + DCD, and urea + DMPP. In the first two weeks after fertilization, DCD and DMPP made the gross N mineralization rate and gross N nitrification rate decreased by 25.5% and 7.3%, and by 60.3% and 59.1%, respectively, with a significant difference in the gross N mineralization rate but less difference in the gross N nitrification rate between the effects of DCD and DMPP. However, significant difference was observed in the gross N nitrification rate between the effects of DCD and DMPP after seven weeks of fertilization. The gross N mineralization and nitrification rates and the NH4+ and NO3-consumption rates after two weeks of fertilization were 7.2-10.0, 5.5-21.5, 9.1-12.2, and 5.1-8.4 times of those before fertilization, respectively, possibly due to the stimulating effect of N fertilization. DCD and DMPP made the fertilizer urea N more maintained in NH(4+) N form and less accumulated in NO(3-)-N form in soil. The decreases of the gross N mineralization and nitrifications rate in the test soil due to the effects of the inhibitors would benefit the reduction of N2O emission from the soil. PMID- 22489496 TI - [Water stability of biological soil crusts in hilly regions of Loess Plateau, Northwest China]. AB - By using an improved wet sieving method, this paper studied the water stability of biological soil crusts with different biological components and biomass in the hilly regions of Loess Plateau. The water stability of the biological soil crusts was related to the crusts' biological components. Moss-dominated crust had significantly higher water stability than cyanobacteria-dominated crust. After 390 shakings, the thickness- and mass losses of moss-dominated crust were only 47.3% and 40.1% of those of cyanobacteria-dominated crust, respectively. Moss dominated crust had the highest water stability when the moss coverage was up to 60%, and the thickness- and mass losses were 22.7% and 28.6% of those of cyanobacteria-dominated crust (no moss coverage), respectively. The horizontal stability of the biological soil crusts was significantly higher than the vertical stability. After 390 shakings, the area loss of moss-dominated crust was only 6.4% of thickness loss. The biological soil crusts had a layer structure with strong stability in horizontal direction, which increased the crusts' resistance against wind- and water erosion. PMID- 22489497 TI - [Nitrogen cycling in rice-duck mutual ecosystem during double cropping rice growth season]. AB - Raising duck in paddy rice field is an evolution of Chinese traditional agriculture. In May-October 2010, a field experiment was conducted in a double cropping rice region of Hunan Province, South-central China to study the nitrogen (N) cycling in rice-duck mutual ecosystem during early rice and late rice growth periods, taking a conventional paddy rice field as the control. Input-output analysis method was adopted. The N output in the early rice-duck mutual ecosystem was 239.5 kg x hm(-2), in which, 12.77 kg x hm(-2) were from ducks, and the N output in the late rice-duck mutual ecosystem was 338.7 kg x hm(-2), in which, 23.35 kg x hm(-2) were from ducks. At the present N input level, there existed soil N deficit during the growth seasons of both early rice and late rice. The N input from duck sub-system was mainly from the feed N, and the cycling rate of the duck feces N recycled within the system was 2.5% during early rice growth season and 3.5% during late rice growth season. After late rice harvested, the soil N sequestration was 178.6 kg x hm(-2). PMID- 22489498 TI - [Effects of spatial heterogeneity on spatial extrapolation of sampling plot data]. AB - By using model combination method, this paper simulated the changes of response variable (tree species distribution area at landscape level under climate change) under three scenarios of environmental spatial heterogeneous level, analyzed the differentiation of simulated results under different scenarios, and discussed the effects of environmental spatial heterogeneity on the larger spatial extrapolation of the tree species responses to climate change observed in sampling plots. For most tree species, spatial heterogeneity had little effects on the extrapolation from plot scale to class scale; for the tree species insensitive to climate warming and the azonal species, spatial heterogeneity also had little effects on the extrapolation from plot-scale to zonal scale. By contrast, for the tree species sensitive to climate warming, spatial heterogeneity had effects on the extrapolation from plot scale to zonal scale, and the effects could be varied under different scenarios. PMID- 22489499 TI - [Dynamics of regional ecological frangibility under natural hazard stress: a case study in Qingping Town of Sichuan Province, Southwest China]. AB - By using the aerial remote sensing images after May 12, 2008 (the date of catastrophic Wenchuan Earthquake) and the unmanned aircraft vehicle remote sensing images after August 13, 2010 (the date of extraordinary debris flow), and in combining with the land use map (1:10000), topographic map (1:50000), and collected field investigation data of Qingping Town, Mianzhu City of Sichuan Province in 2006, this paper analyzed and evaluated the ecological frangibility of the Town. In the Town, the slightly, lightly, moderately, heavily, and extremely fragile ecological zones after the extraordinary debris flow occupied 1.9%, 7.9%, 18.7%, 23.0%, and 48.5%, respectively, with the area of heavily and extremely fragile ecological zones accounting for 71.5% of the total, being 238.45 km2, i. e., the ecological environment was overall very fragile. Under the impact of the two natural hazards, the ecological frangibility degree of the Town increased obviously. As compared with that before the Earthquake, the area of heavily and extremely fragile ecological zones after the Earthquake increased by 12.4%, and the area of extremely fragile ecological zone was 1.67 times larger. The dynamic evolution of the ecological frangibility of the Town was mainly manifested in the conversion of heavily fragile ecological zone into extremely fragile ecological zone. Complex terrain was the key factor of the ecological frangibility of the Town. PMID- 22489500 TI - [Influence of land use change on vegetation cover dynamics in Dapeng Peninsula of Shenzhen, Guangdong Province of South China]. AB - To study the vegetation cover dynamics under urbanization is of significance to direct regional ecological conservation. Based on the 1995-2007 remote sensing data and the investigation data of 1996 and 2007 land use change in Shenzhen, and by using NDVI index tracking and algebraic overlay calculation, this paper analyzed the vegetation types and their spatial differentiation, land use change pattern, and the relationships between land use change and vegetation cover dynamics in Dapeng Peninsula of Shenzhen. In 1995-2007, the vegetation cover in 65% of the study area changed significantly, with an overall increasing trend. Land use change was mainly caused by the development of urbanization and commercial agriculture, with 31% of the land surface changed in land use function. The land use change was one of the main causes of vegetation cover dynamics, and about 35% of the region where vegetation cover significantly degraded was related to land use change. 55% of the region where land use function changed due to mechanical disturbance caused the degradation of vegetation cover, but by the end of the study period, the vegetation cover in most of the degraded region had being improved significantly. PMID- 22489501 TI - [Habitat assessment of giant panda in Qingmuchuan Nature Reserve, Shaanxi Province of Northwest China]. AB - Based on field survey and data collection, this paper studied the characteristics of habitat selection of giant panda (Ailuropoda melanoleuca) in Qingmuchuan National Nature Reserve, and assessed the core and buffer zones of habitats from the aspects of topography, vegetation, food, and human disturbance, with the assistance of hierarchy analysis and Geographic Information System software (ArcMap and ArcView). In the study area, the suitable and secondary suitable habitats for Ailuropoda melanoleuca covered 62.1% and 31.0%, respectively, and the unsuitable habitats covered 6.9%. The suitable habitats were mainly distributed in the west and north parts with high altitudes, while the unsuitable habitats were mainly affected by vegetation coverage, bamboo distribution, and human disturbance. To reduce the unsuitable habitats, management mechanism should be further improved, e. g., controlling human disturbances, especially the grazing, bamboo-cutting, and firewood collection in the regions with altitude 900 1600 m. PMID- 22489502 TI - [An approach for integrated assessment of eco-risk in coastal waters based on catastrophe theory: taking Luoyuan Bay as a case]. AB - Based on catastrophe theory, this paper established an index system and catastrophe progression model for the integrated assessment of eco-risk in coastal waters, including three risk types of "eutrophication-heavy metal pollution-organic pollution" and three dimensions of "water-sediment-organism". According to the related quality standards, a four-level evaluation standard of eco-risk (zero, low, medium, and high) was proposed, and by using the monitoring data of 2007 and 2009, an integrated assessment of the eco-risk in Luoyuan Bay was conducted. In 2007-2009, the spatial variation of the eco-risk in Luoyuan Bay had a downward trend from bayhead to baymouth, and the risk level in 2009 was overall lower than that in 2007. The key factor of the eco-risk in the Bay was eutrophication. The approach established in this paper could identify the spatiotemporal variation characteristics of eco-risk in coastal waters, and better reflect the key eco-risk factor, providing a basic approach for effective forecasting and early warning of eco-risk in coastal waters. PMID- 22489503 TI - [An evaluation of potential occurrence of grasshopper plague in Xianghuangqi grasslands of Inner Mongolia, North China]. AB - In this study, the key climatic factors in spawning, overwintering, and hatching periods of grasshopper were taken as the main factors to establish the climatic suitability index of potential occurrence of grasshopper (POG) in Inner Mongolia, and an evaluation was conducted on the climatic suitability of POG in Xianghuangqi County of Inner Mongolia in 2010. Based on the field investigation data collected in early and mid July 2010, seven relatively stable habitat factors including elevation, aspect, soil type, soil sand content, vegetation type, vegetation coverage, and land cover type were selected, and the habitat suitability for POG throughout the County was estimated by using fuzzy evaluation combining with 3S (GIS, RS, and GPS) technology. The POG ranks in 2010 were estimated by integrating the climatic and habitat suitability for POG. The simulated locations where grasshopper occurred were verified by the field investigation data in 2010, and the simulated areas infected by grasshopper were verified by historical data from 2001 to 2010. The results confirmed that the estimated POG ranks were reliable. The climatic suitability for POG was very homogeneous over the study area, and the vast majority of the study area was in the rank of "suitable". The spatial heterogeneity of the potential locations where the grasshopper might occur was mainly related to habitat factors. The highest POG rank was found at the locations with elevation 1300-1400 m, flat or aspect of east or south, typical chestnut soil, soil sand content 60%-80%, and vegetation coverage 30%-50% in temperate bunchgrass steppe. PMID- 22489504 TI - [Screening, identification, and phosphate-solubilizing capability of phosphate solubilizing bacterial strain B25]. AB - Various phosphate-solubilizing bacterial strains were isolated from the Hippochaete ramosissimum rhizosphere in Tongguanshan copper tailings in Tongling of Anhui Province, East China. After many times of screening and purification, a strain B25 with stronger phosphate-solubilizing capability was obtained, which belonged to Bacillus genus, as identified by transmission electron microscope and DNA molecular approaches. A culture experiment was conducted to study the phosphate-solubilizing capability of the B25 within 168 h and the variations of the medium pH and B25 growth as well as the phosphate-solubilizing capability of B25 under different culture conditions. A weak correlation was observed between the phosphate-solubilizing capability of B25 and the medium pH. The B25 displayed a better phosphate-solubilizing capability when the carbon source was glucose, medium initial pH was 7.0, and culture temperature was 30 degrees C. PMID- 22489505 TI - [Analysis of conserved flanking elements associated with antibiotic resistance genes dissemination]. AB - The overuse of antibiotics in medicine, animal husbandry, and aquiculture industry increases the emergence of antibiotic resistant bacteria and antibiotic resistance genes (ARGs), and also, accelerates the dissemination of ARGs within environmental bacteria. In this study, the total DNA was directly extracted from environmental samples, and the upstream and downstream of antibiotic resistance genes were directly amplified by thermal asymmetric interlaced PCR (Tail-PCR) technique. By optimizing the Tail-PCR program, the multiple flanking sequences of tetW, including 6 upstream sequences and 9 downstream sequences, were simultaneously acquired. Through the bioinformatics analysis, the upstream of tetW presented a perfect inverted repeat (IR), a known tetW regulator peptide, and an insertional sequence (IS), whereas the downstream of tetW presented a most conservative fragment and a common open reading frame (ORF) coding methyltransferase. This study not only revealed several conserved flanking tetW gene modules, but also supplied a highly-efficient and convenient methodology for the research of tetW's dissemination within bacteria, i. e., several flanking sequences could be concisely obtained from one sample by using Tail-PCR program. PMID- 22489506 TI - [Macrobenthos community structure of macrobenthos and bioassessment of water quality in main stream of Songhua River]. AB - An investigation was conducted on the community structure of macrozoobenthos in the main stream of Songhua River in spring (April and May), summer (July and August), and autumn (from September to November), and the water quality of the main stream was assessed with biotic indices. A total of 116 species of macrobenthos were collected, belonging to 36 families and 16 orders, among which, aquatic insects had the largest number, with 74 species (63.8% of the total) belonging to 21 families and 6 orders. The annual average density and biomass of the macrobenthos were 66.80 ind x m(-2) and 24.30 g x m(-2), respectively. The average density was the highest (90.52 ind x m(-2)) in spring, followed by in autumn (61.26 ind x m(-2)), and in summer (48.63 ind x m(-2)), while the average biomass was the highest (35.35 g x m(-2)) in autumn, followed by in summer (23.12 g x m(-2)), and in spring (14.41 g x m(-2)). The Shannon index, Pielou index, and Simpson index were the highest in spring, and were nearly the same in summer and autumn. Few species inhabited in the same types of microhabitats in all river sections. The species similarity in all sections was lower, with the largest similarity being only 60%. The species quantity of each functional feeding group was near, with 26 shredders, 32 collectors, 28 scrapers, and 30 predators. The water quality assessed with biotic index (BI) and family biotic index (FBI) was basically coincident with each other, and was accordant with chemical monitoring. The water quality above the Harbin Section of Songhua River was fair, and that below the Harbin Section was contaminated or seriously contaminated. It was presumed that the macrobenthos species composition and community structure had been affected due to the building of ship-electricity hinge in Dadingzi Mountain. PMID- 22489507 TI - [Synergistic effects of water temperature and salinity on the growth and liver antioxidant enzyme activities of juvenile GIFT Oreochromis niloticus]. AB - By adopting two-factor central composite design (CCD) and response surface methodology (RSM), this paper studied the synergistic effects of water temperature (16-37 degrees C) and salinity (0-18) on the specific growth rate (SGR) and liver superoxide dismutase (SOD) and catalase (CAT) activities of juvenile GIFT Oreochromis niloticus. Water temperature and salinity had significant linear and quadratic effects on the SGR (P < 0.05), respectively. With increasing water temperature or salinity, the SGR decreased after an initial increase. There existed significant synergistic effects between water temperature and salinity (P < 0.05). The SGR was higher at 16-20 degrees C and salinity 9-10, at 27-32 degrees C and salinity 3-5, and at 35-37 degrees C and in freshwater. The SOD and CAT activities were higher at 28-30 degrees C and salinity 6-8. The linear of temperature and quadratic of salinity had significant effects on the two enzymes (P < 0.05), and there was a significant synergistic effect on CAT activity. High temperature and high salinity were not favorable to the expression of SOD and CAT activities. The coefficients of determination of quadratic regression equations for SGR, SOD and CAT activities reached to 0. 954, 0. 831, and 0. 942 (P < 0. 05), respectively, and could be used for prediction. The growth and antioxidant enzyme activities were more affected by water temperature than by water salinity. In the culture practice of 0. niloticus, it would be necessary to optimize culture environment and reduce oxidative stress to promote the growth and disease-resistance of the tilapia. PMID- 22489508 TI - [Phosphorus threshold for the shift between grass- and algae-stable states in Dahong Harbor of Gehu Lake]. AB - Taking the macrophytes remaining area in Dahong Harbor of Gehu Lake as test object, this paper studied the phosphorus threshold for the shift between grass- and algae-stable states under natural conditions. The correlation analysis on the environmental factors showed that the total phosphorous in water body had better liner relationships with phytoplankton chlorophyll a and Secchi depth, and principal component analysis indicated that total phosphorous and nitrogen in the water body were the two main components affecting the water quality, among which, total phosphorous was the maximum weight source and played a determinant role in the shift between grass- and algae-stable states. The Harbor was in grass-stable state in winter, shifted to grass-algae intermediate state in spring, and kept the intermediate state in summer and autumn. The total phosphorous threshold for grass-stable state shifting to grass-algae intermediate state was 61 microg x L( 1), and that for grass-algae intermediate state shifting to algae-stable state was 115 microg x L(-1). In order to make the ecosystem shift from algae-stable state to grass-stable state, some measures such as cutting and controlling the Lake's nutrient sources, removing the sediment rich in organic matter, and constructing submerged macrophytes areas should be adopted to make the total phosphorous threshold in the water body dropped to below 61 microg x L(-1). PMID- 22489509 TI - [Development of insecticide resistance and its effect factors in field population of Bemisia tabaci in Fujian Province, East China]. AB - Abstract: The development of insecticide resistance in field populations of Bemisia tabaci from different regions of Fujian Province, China were monitored with adult leaf-dipping bioassay. Compared with bioassay data of 2005, all field populations tested in 2009 still had high levels of resistance to the lambda cyhalothrin, fenpropathrin and chlorpyrifos, low levels of resistance to methomyl, and no resistance to abamectin. However, resistance to the neonicotinoids imidacloprid and thiamethoxam had increased from moderate levels (23 folds and 25 folds, respectively) in 2005 to high levels (103 folds and 228 folds, respectively) in 2009 in Zhangzhou population, and low levels (1.5-3.3 folds and 1.7-5.5 folds, respectively) in 2005 to moderate levels (23-33 folds and 29-49 folds, respectively) in 2009 for other populations. The biotype of eight B. tabaci populations collected from different regions and hosts were determined according to the mitochondria cytochrome oxidase I (mtCO I ) sequence, and two different biotypes (B-biotype and indigenous whitefly) were detected. The samples collected from geographical regions and hosts showed a prevalence of the B-biotype, and indigenous whitefly (unknown biotype) existed only in croton of Zhangzhou. Host plants and temperature had limited effects on insecticide development in B. tabaci, while extensive and high frequent use of neonicotinoids could be the most important factors responsible for rapid development of insecticide resistance in field populations of B-biotype B. tabaci. PMID- 22489510 TI - [Impact of fish aggregation devices on tropical tuna's behavioral pattern: a review]. AB - Tuna prefers to aggregate around floating objects. Based on this behavioral characteristic, people developed fish aggregation devices (FADs) to trap tuna, and made the catch and fishing efficiency of tuna purse seine fisheries improved greatly. However, there still exist uncertainties whether the FADs can attract tuna and what's the potential impact of widely applying FADs in tuna purse seine fishery on tuna resources and oceanic pelagic ecosystem. Aiming at these uncertainties, scientists conducted a great deal experiments to study the behavioral biology of tuna around FADs. This paper reviewed the related classic and more credible experiments in the past 30 years, and summed up five behavioral patterns of the tunas around drifting and anchored FADs, i. e., tropism behavior, schooling behavior, association behavior, feeding behavior, and vertical movement pattern. The related main research methods currently in use were introduced, and the issues on this subject needed to be paid great attention to were discussed. PMID- 22489511 TI - [Eco-physiological functions of mycorrhizal fungi]. AB - Abstract: Mycorrhizal fungi are an important member of soil microorganisms, not only rich in genetic diversity and species diversity, but also in functional diversity, which mainly manifest in: 1) affecting the origin, evolution, and distribution of terrestrial plants, 2) promoting plant growth and development, 3) enhancing plant tolerance against environmental stress, 4) remedying polluted and degraded soils, 5) promoting agricultural, forestry, and animal husbandry production, and 6) maintaining ecological equilibrium and stabilizing ecosystem and its sustainable productivity. With the development of technique and research, more functions contributed by mycorrhizal fungi would be discovered. PMID- 22489512 TI - [Thoughts of surgical therapeutic principle and operative indicatio in atlanto axial dislocation]. PMID- 22489513 TI - [Clinical application of titanium miniplate in cervical expansive open-door laminoplasty]. AB - OBJECTIVE: To evaluate the clinical effects of titanium miniplate in cervical expansive open-door laminoplasty in treating cervical spondylosis. METHODS: From February 2009 to April 2011, 16 patients underwent expansive open-door laminoplasty by titanium miniplate fixation were classified as group A; 18 patients with conventional unilaterally open-door laminoplasty from March 2007 to January 2009 were served as control (group B). The operative time, blood loss during the operations, JOA score of the 6 months after operation, the incidence of axial symptom, curvature of cervical vertebrae were compared respectively between the two groups. RESULTS: Operative time, blood loss, improvement rate of JOA in group A were respectively (122.0 +/- 26.8) min, (153.0 +/- 46.7) ml, (59.4 +/- 11.6)%; and in group B were (119.0 +/- 28.6) min, (151.0 +/- 50.4) ml, (58.7 +/- 12.7)%. Those showed no significant difference between two groups (P > 0.05). Three cases (18.75%) occurred obviously axial symptom in group A and six cases (33.33%) occurred in group B, there was significant difference in the incidence of axial symptom between two groups (P < 0.01). Preoperative and postoperative curvature of cervical vertebrae in group A was (17.9 +/- 5.2) degrees and (18.2 +/- 4.8) degrees, without significant difference; in group B, postoperative curvature of cervical vertebrae decreased obviously than the preoperative [(16.3 +/- 5.9) degrees vs (18.1 +/- 6.3) degrees] (P < 0.05). CONCLUSION: Both surgical protocols are effective on preventing reclose of opened laminae, moreover the modified laminoplasty is advanced on reducing the occurrence of axial symptoms and loss of cervical curvature. PMID- 22489514 TI - [Systematic review of clinical randomized controlled trials on manipulation treatment for vertebral artery type of cervical spondylosis]. AB - OBJECTIVE: To evaluate the safety and efficacy of the manipulation treatment for vertebral artery type of cervical spondylosis and analyze the current status of clinical study. METHODS: To retrievie the PubMed, OVID, Cochrane library, CBM disc database, CNKI database, VIP database, 265 literatures of the manipulation treatment of vertebral artery type of cervical spondylosis were collected, including 251 literatures Chinese and 14 literatures English. Among the literatures, 5 studies of Chinese literatures accorded with inclusion criteria. Cochrane systematic review was used to quality evaluation; and 5 studies were used RevMan 4.2 for Meta analysis of literature. RESULTS: Five documents included a total of 736 patients. Summary of the literature combined OR for the cure rate was 2.93, 95% CI was [2.10,4.08]. Summary OR for the combined efficiency was 3.99, 95% CI was [2.47,6.44]. Manipulation group's cure rate of vertebral artery type of cervical spondylosis was efficient and clearly superior to the other therapies. Expect of the manipulation, the traction and the drugs, hereinafter referred to as "other therapies" (P < 0.01). CONCLUSION: At present, documents included in this study have shown that manipulation treatment on vertebral artery type of cervical spondylosis is safe, both cure rate and the effective rate are much better than other therapies; but the incorporation of a limited number of documents and the quality is not very high, the conclusion is still uncertain, high-quality evidence should be needed to be further validated. PMID- 22489515 TI - [Clinical study on curing the cervical spondylotic radiculopathy with the methods of Blade needle closed loosing and reduction with traction at the same time]. AB - OBJECTIVE: To observe the effects of curing the cervical spondylotic radiculopathy with the methods of Blade needle closed loosing and reduction with traction at the same time. METHODS: From May 2006 to May 2009, 65 patients with cervical spondylotic radiculopathy were divided into treatment group and control group according the random number table produced by SAS Software. There were 18 males and 17 females in the treatment group,age in range from 42 to 73 years old with an average of (61.3 +/- 6.4) years, course of disease was from 8 to 42 months with an average of (23.8 +/- 13.8) months, preoperatively cervical functional score was from 4 to 17 scores with the mean of (11.45 +/- 3.31) scores. And in the control group, including 14 males and 16 females, aged from 44 to 76 years old with an average of (62.4 +/- 8.8) years, course of disease was from 7 to 43 months with an average of (24.4 +/- 16.8) months, preoperatively cervical functional score was from 4 to 18 scores with the mean of (11.40 +/- 3.24) scores. The patients of treatment group were treated with Blade needle closed loosing the specific pain point on the neck and shoulder, then immediately underwent traction and reduction after operation. And the patients of control group were treated with traditional traction. The cervical functional score were compared between the two groups at 10, 20, 180 d after treatment, including pain of neck and shoulder, limitation of motion of neck, tenderness of neck, numbness and muscle weakness of upper limb. RESULTS: (1) At the 10th day after treatment, the total score of treatment group was (15.43 +/- 3.46) scores, which was obviously higher than that of control group's (13.17 +/- 3.18) scores (P < 0.01). In different symptoms, treatment group also was better than that of control group (P < 0.05), so as in the tenderness of neck, and especially in the limitation of motion of neck and muscle weakness of upper limb decreased obviously (P < 0.01). (2) At the 20th day after treatment, the total score of treatment group was (18.00 +/- 2.94) scores, which was obviously better than that of control group's (15.90 +/- 2.89) scores (P < 0.01). In different symptoms, treatment group also was better than that of control group (P < 0.05), so as in the pain of neck and shoulder, numbness and muscle weakness of upper limb (P < 0.05), and especially in the limitation of motion of neck, tenderness of neck decreased obviously (P < 0.01). (3) At the 180th day after treatment, the total score of treatment group was (16.63 +/- 3.32) scores, which was obviously better than that of control group's (12.67 +/- 3.42) scores (P < 0.01); In different symptoms, treatment group also was better than that of control group (P < 0.05), so as in the numbness of upper limb (P < 0.05), and especially in the pain of neck and shoulder, muscle weakness of upper limb, limitation of motion of neck, tenderness of neck decreased obviously (P < 0.01). CONCLUSION: Compared with method of traditional traction, Blade needle closed loosing and traction in treating cervical spondylotic radiculopathy can significantly obtain clinical effects,which can quickly improve symptoms, relieve pain of neck and shoulder, limitation of motion of neck, tenderness of neck, numbness and muscle weakness of upper limb. PMID- 22489516 TI - [Effects of manipulation on mechanical properties of cervical and degree of fatigue in patients with cervical spondylosis]. AB - OBJECTIVE: To explore the mechanism of manipulation in treating cervical spondylosis. METHODS: From August 2008 to December 2009, 65 patients with cervical spondylosis were randomly divided into manipulation group and traction group. There were 32 patients in manipulation group, of which 30 cases obtained followed-up, including 10 males and 20 females, ranging in age from 30 to 65 years,with an average of (42.31 +/- 13.23) years; the mean course of diseases was (12.40 +/- 6.23) months, and the average weight was (61.21 +/- 10.23) kg. In traction group, there were 33 patients, 30 cases obtained follow-up, including 11 males and 19 males, ranging in age from 30 to 65 years, with an average of (45.54 +/- 14.35) years; the mean course of diseases was (13.25 +/- 6.06) months and average weight was (62.31 +/- 10.45) kg. Biodex III Isokinetic Testing System and TeleMyo 2400 T Surface EMG was applied to test the mechanical properties and fatigue of neck muscles before and after treatment. RESULTS: The mechanical properties of neck muscles: measuring in the 60 degrees/s and 120 degrees/s angular velocity, there were no significant difference (P > 0.05) in peak torque (PT), average power (AP), peak torque of flexor/extensor peak torque ratio (F/E) before treatment, while manipulation group was improved more than traction group in PT, AP, F/E after treatment (P < 0.05), and there was significant difference (P < 0.05). For the degree of fatigue: there was no significant difference (P > 0.05) in IEMG, MPF compared by two groups before treatment, but the manipulation group was improved more than the traction group in IEMG, MPF after treatment (P < 0.05), and there was significant difference (P < 0.05) on the right side. CONCLUSION: Manipulation can improve contraction forces and work efficiency of neck muscle, coordination ability of flexors and extensors muscles, efficiency of neck muscle, and recover mechanical properties and can alleviate fatigue of neck muscles in patients with cervical spondylosis. PMID- 22489517 TI - [Clinical study on acupotomy of occipitalia on the treatment of cervicogenic headache]. AB - OBJECTIVE: To observe the effects of acupotomy on cervicogenic headache and explore the function of cutaneous nerve entrapment in the mechanism of cervicogenic headache. METHODS: From October 2008 to June 2009, 82 patients with cervicogenic headache were treated with acupotomy. There were 23 males and 59 females, ranging in age from 17 to 73 years (averaged 41.57 years). The course of disease ranged from 0.5 to 50 years,with an average of 10.4 years. The location of treatment was occipitalia, both of left and right side: altogether were 8 points, including tenderness point of postmastoid; the mid-point between mastoid and C2 spinous process; the internal 1/3 attachment between occipital protuberance and mastoid process; the posterior midline of C2 spinous process open to 1.5-2 cm. The chief complaint of all patients was headache. PPI assessment rating was observed. RESULTS: The total effective rate at 1 month after treatment was 81.70% (67/82). Recurrence of headache within 3 months after treatment was obvious. However, 17.07% (14/82) patients did not reoccur at 6 months after treatment. CONCLUSION: 17.07% patients with cervicogenic headache recovered by acupotomy, so it shows cutaneous nerve entrapment plays an important role in the mechanism of cervicogenic headache. For the patients whose headache recurred at 3 months after treatment, increasing the treatment time and therapeutic range is suggested. PMID- 22489518 TI - [Study on the efficacy of orthopedic footwear in treating lumbar intervertebral disc herniation with spinal manipulation]. AB - OBJECTIVE: To observe the efficacy and mechanism of orthopedic footwear in treating lumbar intervertebral disc herniation with spinal manipulation. METHODS: From September 2009 to September 2010, 44 patients with the lumbar intervertebral disc herniation with posture change were selected in the study. There were 28 males (aged from 24 to 58 years) and 16 females (aged from 21 to 60 years). Firstly, the average EMG (AEMG) and spectrum area (SPA) of bilateral lumbar erector spinae of the patients were tested by surface electromyogram (sEMG), and then absolute value of the difference between AEMG and SPA (larAEMG and larSPA) were compared. After that, they were randomly divided into two groups (experiment group and control group), each group had 22 cases. The patients of experiment group received the spinal manipulation treatment assisted with orthopedic footwear and the other group received the spinal manipulation treatment only. Orthopedic footwear was put on by leg with lower iliac crest line, sole thickness of which depended on the degree of pelvic tilt. According to mitigation degree of symptom and sign, sole thickness was modified till removal of orthopedic footwear. Manipulative therapeutic method which was manipulative by doctors set spinal process to normal anatomical position. Manipulative treatment was 2 - 3 times every week. The clinical healing time were observed in the two groups. RESULTS: The larSPA was 0.12 +/- 0.73, 0.65 +/- 0.61 and the larAEMG was 3.43 +/- 25.56, 21.74 +/- 20.34 in standing 1 minute of two positions of patients with orthopedic footwear and without orthopedic footwear, respectively; the larSPA was 0.15 +/- 0.36, 0.57 +/- 0.24 and the larAEMG was 4.65 +/- 12.87, 25.18 +/- 16.58 in walking 1 minute of two positions of patients with orthopedic footwear and without orthopedic footwear. There were significant difference between the two groups (P < 0.01). The time of healing well in experiment group and control group were respectively (20.36 +/- 4.92) d and (28.14 +/- 7.13) d, experiment group was shorter than that of control group (P < 0.01). CONCLUSION: Orthopedic footwear can obviously improve the unsymmetrical shrink of bilateral lumbar erector spinae and balance lumbar muscle. Therefore,orthopedic footwear can create favourable conditions for the spinal manipulation in treatment of lumbar intervertebral disc herniation, which can shorten the healing well. PMID- 22489519 TI - [Case-control study on ultra-early application with intermittent pneumatic compression to prevent postoperative deep venous thrombosis of intertrochanteric femoral fracture in elderly patients]. AB - OBJECTIVE: To evaluate the clinical effects of ultra-early application with intermittent pneumatic compression (IPC) in preventing postoperative lower limbs deep venous thrombosis (DVT) of intertrochanteric fractures in elder patients. METHODS: From May 2008 to May 2010, 80 patients with intertrochanteric fractures were randomly divided into ultra-early group and postoperative group. In ultra early group, there were 21 males and 19 females, ranging in age from 67 to 86 years with an average of (76.4 +/- 13.27) years; in postoperative group, there were 26 males and 14 females, ranging in age from 68 to 89 years with an average age (75.8 +/- 12.71) years. IPC was respectively used at the 3rd day before operation (ultra-early group) and postoperative that day (postoperative group). Serum D-dimer of all the patients were measured at the 3rd day before operation and at the 3rd, 7th,14th days after operation. Lower limbs DVT were observed by ultrasound at the 3rd, 14th days postoperatively. Perioperative bleeding volume of patients were compared between two groups. RESULTS: There was no statistical difference in the serum D-dimer concentration and lower limbs DVT between two groups at the 3rd day before operation (P > 0.05). There was no statistical difference in perioperative bleeding volume between two groups (P > 0.05). In ultra-early group, Serum D-dimer concentration at the 3rd, 7th days after operation was respectively (351.00 +/- 104.34), (412.31 +/- 106.95) microg/ml; and in postoperative group, the item was respective (419.34 +/- 145.38), (509.16 +/- 146.05) microg/ml; serum D-dimer concentration in ultra-early group was lower than postoperative group (P < 0.05). There was no significant differences in serum D-dimer concentration at the 14th day after operation between two groups (P > 0.05). Incidence of DVT in postoperative group was 22.5%, which was higher than that of ultra-early group at the 14th day after operation (P < 0.05). There was no significant differences at the 3rd day after operation between two groups (P > 0.05). CONCLUSION: Compared with postoperative application with IPC, ultra-early application with IPC could reduce the level of serum-dimer and the incidence of DVT without increase perioperative blood of intertrochanteric fracture in elder patients. PMID- 22489521 TI - [Case-control study on treatment of ankle fractures of supination-extorsion with different fixed position]. AB - OBJECTIVE: To explore the best external fixation posture of ankle fracture of Lauge-Hanson III degree and IV degree supintion-eversion after manipulation. METHODS: From January 2007 to June 2010, 46 patients with ankle fracture of Lauge Hanson III degree and IV degree supintion-eversion were selected for this study and were randomly divided into two groups (group A and group B). There were 14 males and 9 females in group A; and the Lauge-Hanson III degree was in 13 cases and IV degree was in 10 cases; fractures were reduced and fixed with plaster splint of U-shape to the posture with inversion, internal rotation and plantar flexion. There was 15 males and 8 females in group B, and the Lauge-Hanson III degree was in 14 case and IV degree was in 9 cases; fractures were reduced and fixed with plaster splint of U-shape to the posture with inversion, internal rotation and dorsiflexion. The clinical effects were evaluated according to AOFAS scoring system. RESULTS: All the patient were followed up from 6 to 18 months with an average of 12 months. In group A, AOFAS scoring was from 73 to 100 scores with an average of (92.58 +/- 5.73) scores, 16 cases obtained excellent results, 6 good, 1 fair; in group B, AOFAS scoring was from 66 to 100 scores with an average of (85.74 +/- 7.56) scores, 9 cases obtained excellent results, 7 good, 6 fair and 1 poor. The result of group A was better than that of group B. In group A, 1 case occurred with ankle joint ache after long walk and swelling in night. In group B, 6 cases also occurred with ankle joint ache after long walk and swelling in night and 1 case with stiffness of joint. So there was obvious difference (P < 0.05). CONCLUSION: For treatment of ankle fracture of Lauge Hanson III degree and IV degree supintion-eversion, the posture with inversion, internal rotation and plantar flexion exceeds another one with inversion, internal rotation and dorsiflexion with plaster after manipulative reduction. PMID- 22489520 TI - [Therapic choice of intertrochanteric fracture of femur in aged patient]. AB - OBJECTIVE: To investigate the therapic choice of intertrochanteric fractures of femur in aged patient. METHODS: From June 2006 to June 2010,58 patients with intertrochanteric fracture were treated with surgical methods. There were 25 males and 33 females, aged from 65 to 93 years old (averaged 79 years old). According to the Evans type, type I was in 30 cases, type II was in 28 cases. Of them, 25 patients were treated with hip replacement (group A) and 33 patients were treated with internal fixation (group B). The operative time, blood loss volume, the time of get out of bed, drainage volume, complications and function of joint motion were compared between two groups. According to Harris scoring to evaluate function of joint motion at the 3rd, 6th, 12th months after operation. RESULTS: All patients were followed up more than 12 months (averaged 16.4 months). One patient in group A died of pneumonia one month later after operation and other patients live safely through peri-operation. The group B was better than that of group A at operative time, blood loss volume, drainage volume. In group A, 1 case died and 1 case got DVT, 2 cases got urinary tract infection and 1 case got pneumonia. While in group B, 1 case got bedsore, 1 case got coxa vara and 2 cases got urinary tract infection. The incidence rate of complication in group B was lower than that of group A (P < 0.05). According to Harris scoring system, at the 3rd, 6th,12th months after operation, Harris scoring in group A was respectively (78.43 +/- 5.32), (81.67 +/- 4.87), (87.66 +/- 4.01) scores and in group B was respectively (75.45 +/- 3.22), (76.33 +/- 4.12), (88.65 +/- 3.77) scores. There was statistical significance in Harris scoring at the 3rd, 6th months after operation between two groups (P < 0.05) and there was no statistical significance at the 12th months after operation (P > 0.05). At three months after operation, in group A,14 cases obtained excellent results, 5 good, 5 fair and 1 poor; and in group B, 8 cases obtained excellent results, 13 good, 9 fair and 3 poor. Six months later, in group A,18 excellent, 5 good, 2 fair and 0 poor, and in group B,10 excellent, 15 good, 6 fair and 2 poor. Twelve months later,in group A,18 excellent, 5 good, 1 fair and 1 poor; and in group B, 21 excellent, 9 good, 3 fair and 0 poor. Three and six months later after operation, the clinical effect in group A was better than that of group B (P < 0.05); but twelve months later, there was no significant differences between two groups (P > 0.05). CONCLUSION: The internal fixation is especially the preferred method for the aged patient with intertrochanteric fractures. Hip replacement refer to pathologicalfracture caused by cancer, unheeded fracture abnormity, osteoprosis too serious to be treated by internal fixation or patients with ipsilateral symptomatic degenerative joint or revisions caused by failed internal fixation and severely intertrochanteric comminuted fractures and merged severely osteoporosis. PMID- 22489522 TI - [Single-segment pedicle screw fixation for the treatment of thoracolumbar fractures through the gap of paravertebral muscles]. AB - OBJECTIVE: To compare the clinical effect of thoracolumbar fractures between single-segment pedicle screw fixation approach for the gap of paravertebral muscles and double-segment pedicle screw fixation approach for the stripping of paravertebral muscles. METHODS: From September 2008 to January 2010, 65 patients with incomplete compressed thoracolumbar fractures or burst thoracolumbar fractures with unilateral endplate injury were randomly divided into two groups. Thirty patients were treated with single-segment pedicle screw fixation through the gap of paravertebral muscles (treatment group). Thirty-five patients were treated with double-segment pedicle screw fixation through the stripping of the paravertebral muscles (control group). All the internal fixations were taken out during 10-12 months after operation. Operative time, perioperative blood loss volume and postoperative drainage volume were compared between two groups. At final follow-up, the change of neurological ASIA grade were recorded; and postoperative 5 days and final follow-up, compared Denis classification of lumbar and back pain between two groups; and analyzed the sagittal index and compressibility of anterior border of vertebral body by X -ray lateral projection. RESULTS: All patients were follow-up from 14 to 22 months with an average of 18.3 months. No postoperative infection, secondary spinal cord injury was found. One case of control group occurred internal fixation breakage at the 11th month after operation and other internal fixation no loosening. There was no significant difference in operative time, the recovery of neurological function between the two groups (P > 0.05). Perioperative blood loss volume and postoperative drainage volume of treatment group was less than that of control group (P < 0.01). And in Denis classification of lumbar and back pain, the treatment group recovered more quickly, and the residual pain of lumbar and back was less than that of control group (P < 0.01). Postoperative posterior salient and compression of anterior border of vertebral body improved in two groups (P < 0.01), there was no significant difference in degree of improvement between two groups (P > 0.05); but both loss existed at final follow-up (P < 0.01), there was no significant difference in loss of posterior salient between two groups (P > 0.05). In the treatment group, the loss of rectify of anterior border of vertebral body existed, but it was less than that of the control group. CONCLUSION: In the premise of strict controlling surgery indications, the treatment of thoracolumbar fractures with single-segment pedicle screw fixation through the gap of paraspinal muscles, can effectively recover the height of vertebral body and rectify posterior salient, and reduce the fixed segment. Compared with the traditional operative method of double-segment pedicle screw fixation through the stripping of paraspinal muscle, it can obviously reduce the operation wound and the bleeding, lessen the pain of lumbar and back. And the recent clinical effect is satisfied. PMID- 22489523 TI - [Transfection of exogenous gene: Lac Z into spinal cord of SD rats and its protein expression:an in vivo study]. AB - OBJECTIVE: To explore a way of the gene therapy for acute spinal cord injury (ASCI) by vivo transfection of exogenous gene into spinal cord tissue. METHODS: Twenty-four rats of SD were divided into experiment group and control group (each group had 12 rats). After anaesthesia by abdominal cavity, lamina of thoracic vertebra of all rats were cut-open in prone position. Complex of plasmid and report gene-Lac Z, and plasmid without report gene-Lac Z were respectively injected into cavum subdural of SD rats of experiment group and control group by cation liposome (DOTAP) encapsulation. The rats were killed at the 2nd week after operation, spinal cord tissue of injected segments were detected by reverse transcription-polymerase chain raction (RT-PCR) and immunohistochemistry. RESULTS: In experiment group, positive staining of beta-galactosidase can be clearly observed in neuron and glia cell of rat's spinal cord by immunohistochemistry detection. Lac Z mRNA in same area was also detected by RT PCR. But, in control group, no above-mentioned positive results were found. CONCLUSION: Effective transfection of exogenous gene in vivo into spinal cord is a new hot spot for treatment of SCI. Thus certain nerve growth factor imput partly area of spinal cord injury can promote central nerve regrowth and avoid early secondary injury. PMID- 22489524 TI - [Reliability research of spine stiffness test system]. AB - OBJECTIVE: To investigate the reliability of the spine stiffness test system (SSTS) by animal experiments. METHODS: A hundred SD male rats with weight body of 350-450 g were divided randomly into 5 groups according to feeding time of 1, 2, 4, 8,12 weeks. The externally linked fixation systems were implanted into all rats in L4, L5, and L6. At the end of every feeding time, the stiffness of the fixed segment was measured by SSTS, and the relationship between linking time and the stiffness were observed. The parameters of pressure sensor of SSTS were demarcated before measuring the stiffness in order to ensure the accuracy of SSTS. RESULTS: The actual error of the spine stiffness test system was less than 0.04%. Its reliability was good, ICC = 0.948 (P < 0.01). And the stiffness of the fixed segment increased with linking times. CONCLUSION: The accuracy and reliability of SSTS were good. Its operating system was very simple to manipulate. And SSTS may accurately collect pressure load and infinitesimal displacement of the spinal motion segment. In order to fit more spinal injuries models, SSTS needs improvements in fixed accessories, measurement range, disturbance variable, and so on. PMID- 22489525 TI - [Opinious of lumbar intervertebral disc herniation]. PMID- 22489526 TI - [Treatment of carpal tunnel syndrome with mini-incision decompression]. AB - OBJECTIVE: To introduce the method of the transverse carpal ligament (TCL) transection through palmar mini-incision for carpal tunnel syndrome (CTS) and evaluate its efficacy and safety. METHODS: From January 2006 to September 2007, 15 patients (18 hands) with CTS were treated with palmar longitudinal mini incision decompression. There were 2 males and 13 females, with an average age of 48 years (ranged 34 to 69) and an average course of 18 months (ranged 8 to 26). The main clinical symptom including the radial numbness or pain of the 3 and a half fingers, wrist pain and radiation to the forearm, the night awake history of numbness, thenar muscle atrophy, positive Tinel sign and Phalen sign. Median nerve electrophysiology showed that sensory nerve conduction velocity (SCV) slowed down and sensory nerve action potential (SNAP) decreased or missed, short abductor muscle of thumb had spontaneous potential in severe cases. Clinical effect were evaluated according to the Global symptom score (GSS) scoring in aspect of pain, numbness, paraesthesia, weakness and nocturnal awakening. RESULTS: Postoperative wound smoothly healed in all patients and no complications occurred. All patients were followed up from 20 to 28 months with an average of 24 months. Symptoms of 1 patient had not incomplete relief, other patient's symptoms disappeared and muscle force of abductor pollicis brevis reinforced. Postoperative GSS scoring obviously improved than preoperative (P < 0.05). CONCLUSION: Treatment of carpal tunnel syndrome through palmar mini-incision decompression has advantages such as higher safe, shorter operative time, less invasive, smaller scar, which can cut off carpi transversum ligament and thoroughly decompress median nerve under direct sight, it is a safe and effective operative approach. PMID- 22489527 TI - [Non-surgical treatment for fracture-disloction of ankle]. AB - OBJECTIVE: To summarize the clinical effects of the manipulative reduction and splint fixation for the treatment of fracture-dislocation of ankle. METHODS: From April 1990 to June 2010, 53 patients with fracture dislocation of ankle were treated with non-operative treatment including manipulative reduction, splint fixation, oral herbal soup and early functional exercises. There were 32 males and 21 females with an average age of 42.5 years (ranged, 25 to 60). There were 30 cases in left and 23 cases in right. Ankle joint function was evaluated according to standard of Mazur. RESULTS: Follow up time was from 6 to 60 months with an average of 33 months; all the fractures healed with an average of 4 months (ranged, 3 to 5). The mean of Mazur scoring was 90.11+/- 8.40, 36 cases got excellent results, 11 good, 3 fair and 3 poor. CONCLUSION: With non-operative treatment such as manipulative reduction and splint external fixation for fracture-dislocation of ankle can obtain satisfactory effects, which has advantage of simple operation, less trauma. PMID- 22489528 TI - [Extra-articular pigmented villonodular synovitis of the shoulder joint: a case report]. PMID- 22489529 TI - [Diagnosis and treatment for rupture of epidural cavernous angioma within cervical spinal canal: a case report]. PMID- 22489530 TI - [Percutaneous screw fixation for pelvic fractures with fluoroscopy-based navigation]. AB - OBJECTIVE: To investigate the applications of fluoroscopy-based navigation in pelvic fractures and related surgical considerations. METHODS: From May 2010 to December, 16 patients with pelvic fractures were treated with computerized navigation. There were 12 males and 4 females with an average age of 37 years (ranged from 20 to 54 years). Fractures were caused by traffic accident in 5 cases, crush injury in 5 cases and falling from height in 6 cases. Based on the Tile classification, there were 15 cases of Tile C type and 1 case of Tile B type. In these patients, 4 patients were treated with sacroiliac screw fixation; 2 patients were treated with sacroiliac screw fixation, screw fixation for pubic symphysis diastasis and pubic fractures; 8 patients were treated with sacroiliac screw fixation and screw fixation for pubic fractures; 2 patients were treated with screw fixation for pubic fractures. The index such as screw inserting time, accurance of inserting screws, intra-operative blood losing, injuries of nerve, vascular and other organs, reduction conditions were observed. RESULTS: A total of 36 screws were inserted. The average time was 20 min for each screw placement. The blood loss ranged from 10 to 20 ml. There were no wound infections, neurovascualr injuries and other organ injuries. The postoperative pelvic X-ray and three-dimensional CT showed that the fractures had good reduction and all the screws had good position. CONCLUSION: Percutaneous screw fixation of pelvic fractures with fluoroscopy-based navigation have advantages such as little trauma, less blood loss, little complication, reliable fixation and no blood transfusion, which can reconstruct the stability of the pelvic ring, but need adequate preoperative reperation and high requirements for the surgeon. PMID- 22489531 TI - [Analysis of perioperation complications of total hip arthroplasty in treating Crowe type IV developmental dysplasia of the hip]. AB - OBJECTIVE: To evaluate the clinical effects of total hip arthroplasty (THA) for Crowe type IV developmental dysplasia of the hip (DDH) and analyze perioperative complications. METHODS: From March 2000 to March 2010, 19 patients (23 hips, of them, 4 patients with bilateral hips) with Crowe type IV DDH underwent THA. There were 5 males and 14 females, with average age of 61.3 years (ranged, 41 to 72 years). All hips were treated with small acetabular components combined with medial protrusion technique in acetabular reconstruction, as well as subtrochanteric shortening osteotomy in femur. Joint function of hips were evaluated according to Harris scoring. RESULTS: All patients were followed up with an average of 4.2 years (ranged, 1 to 8 years). Postoperative X-ray films showed all acetabular prosthesis were in true acetabulum. No loosening and nonunion were found in all patients. Harris scoring improved from preoperative 34.0 +/- 6.9 to postoperative 85.0 +/- 7.5. Complications occurred in 11 cases in the patients, including femoral split fracture in 3 cases, nerve injury in 3 cases, delayed union in 2 cases, dislocation in 3 cases. CONCLUSION: Total hip arthroplasty using small acetabular component, medial protrusion, femoral subtrochanteric shortening osteotomy technique for the Crowe type IV DDH can effectively restore hip function and leg length. But incidence of complications is high. The long-term follow-up is necessary for further study. PMID- 22489532 TI - [Treatment of contracture of achilles tendon with minimally invasive achilles tendon lengthening and system rehabilitation]. AB - OBJECTIVE: To investigate the safety and efficacy of minimally invasive achilles tendon lengthening and system rehabilitation for the treatment of contracture of achilles tendon. METHODS: From January 2002 to December 2010, 27 patients (31 feet) with contracture of achilles tendon were treated with minimally invasive achilles tendon lengthening and system rehabilitation. There were 11 males and 16 females with an average age of 35.5 years (ranged 3 to 65 years). Right foot was in 13 cases, left foot was in 10 cases, both feet were in 4 cases. Course of disease was from 1 to 5 years with an average of 2.3 years. The cause of contracture included postoperative complication of tibia fractures treated with intramedullary nailing in 7 feet, sequelae of lower leg compartment syndrome in 11 feet, congenital talipes equinovarus in 13 feet (both feet in 4). Before operation, all the patients walked with limping, plantar flexion anomaly was from 15 degrees to 50 degrees with an average of 35.5 degrees. The strength of quadriceps muscle of thigh was grade V in 27 feet, grade IV in 4 feet, the strength of musculus triceps surae was grade V in 24 feet, grade IV in 7 feet. RESULTS: All the patients were followed-up for 6-24 months with an average of 11.3 months. According to standard of Arner-Lindholm to evaluate function of ankle joint, 29 feet obtained excellent results and 2 feet good. No infection, re rupture or re-contracture was found. CONCLUSION: Minimally invasive achilles tendon lengthening and system rehabilitation in treating contracture of achilles tendon has advantage such as simple operation, less complication, lower recurrence rate, which is favourable for thoroughly rehabilitation of patients. But, the case in which the strength of quadriceps muscle of thigh or musculus triceps surae still less than grade III after preoperative rehabilitation care should not choose the method. PMID- 22489533 TI - [Early diagnosis and treatment of compartment syndrome caused by landslides:a report of 20 cases]. AB - OBJECTIVE: To summarize early diagnosis and treatment methods of 20 patients with compartment syndrome caused by landslides during coal mine accidents in order to improve the level of diagnosis and treatment of compartment syndrome and reduce disability. METHODS: From September 2006 to April 2010,20 patients with compartment syndrome were treated with the methods of early decompression, systemic support. All the patients were male with an average age of 42 years (ranged, 23 to 54). All the patients with high tension limb swelling, pain, referred pain passive positive; 5 extremities feeling diminish or disappear and the distal blood vessel beat were normal or weakened or disappeared; myoglobinuria, hyperkalemia, serum urea nitrogen and creatinine increased in 5 cases and oliguria in occurred 1 case. The function of affected limbs was observed according to disability ratings. RESULTS: Three cases complicated with infection of affected limb and 6 cases occurred with renal function insufficiency. Total recovery was in 16 cases, basically recovery in 3, amputation in 1 case. All patients were followed up for 6-15 months with an average of 12 months. The ability to work according to national standard identification--Employee work-related injuries and occupational disability rating classification (GB/T16180-2006) to assess, grade 5 was in 1 case, grade 8 in 2 cases, grade 10 in 1 case, no grade in 16 cases. CONCLUSION: Arteriopalmus of dorsalis pedis weaken and vanished can not be regard as an evidence in early diagnosis of compartment syndrome. Early diagnosis and decompression, systemic support and treatment is the key in reducing disability. PMID- 22489534 TI - [Basic research progress of knee osteoarthritis]. AB - The exact etiology and pathogenesis of knee osteoarthritis (KOA) are still unknown and it is hard to treat the disease fundamentally. With new therapeutic methods and techniques appearing, the present situation of treating the disease will be changed in the near future. Basic research of knee osteoarthritis will contribute to clarifying the pathogenesis and exploring the therapeutic methods. This article makes a brief review on the up-to-date basic researches of knee osteoarthritis by reviewing literature concerned in recent years. PMID- 22489535 TI - [Treatment of small joint disorder of thoracic vertebrae with press reduction on supine position]. PMID- 22489536 TI - Developing an intervention to promote young people's participation in asthma review consultations with practice nurses. AB - AIM: The article is a report of a study to develop an evidence-based pre consultation guide for young people to use prior to an asthma review with a practice nurse. BACKGROUND: The participation of young people aged 13-19 in consultations with health professionals can be limited by the lack of opportunity to learn the appropriate skills in triadic consultations. Evidence-based interventions to promote participation of adults in consultations have been developed but young people's needs have not been specifically addressed. DESIGN: Multiple methods design informed by guidelines for the development of complex interventions. METHODS: A pre-consultation guide for young people was developed in 2007 by application of a model of health behaviour change, development of criteria by an expert panel and in consultation with young people using a nominal group technique. RESULTS: The concepts of the Health Action Process Approach model were applied to the development of criteria underpinning the pre consultation guide. In the nominal groups young people agreed that they had different needs to other children and adults. The consensus was that the preconsultation guide should include disease-specific information, realistic photographs rather than Clip Art, consistent styles of fonts, bullet points and colours, short words and mature language. Statements and example questions written by young people were included in the evidence-based guide. CONCLUSION: Young people's views can contribute to the development of interventions designed to promote communication in consultations with nurses. There is potential for this approach to be used to develop interventions in primary and secondary care of a range of long-term conditions. PMID- 22489537 TI - Search for an aetiological virus candidate in chronic lymphocytic leukaemia by extensive transcriptome analysis. AB - As an approach to determining the aetiology of chronic lymphocytic leukaemia (CLL), we searched for a virus expressed in human CLL B-cells by combining high throughput sequencing and digital subtraction. Pooled B-cell mRNA transcriptomes from five CLL patients and five healthy donors were sequenced with 454 Life Sciences technology. Human reads were excluded by BLAST (Basic Local Alignment Search Tool) and BLAT (BLAST-like alignment tool) searches. Remaining reads were screened with BLAST against viral databases. Purified B-cells from two CLL patients, with and without stimulation by phorbol-esters, were sequenced using Illumina technology to achieve depth of sequencing. Burrows-Wheeler Aligner mapping and BLAST searches were used for the Illumina data. Pyrosequencing resulted in about 400 000 reads per sample. No viral candidate could be found. Illumina single-end sequencing for 115 cycles yielded an average of 26 +/- 2.5 million filtered reads per sample, of which 2.2 +/- 0.6 million remained unmapped to human references. BLAST searches of these reads against viral and human databases assigned nine reads to an Epstein-Barr virus origin, in one sample following phorbol-ester stimulation. Other reads showing a putative viral origin were dismissed after further analysis. Despite an in-depth analysis of the CLL transcriptome reaching more than 100 million sequences, we have not found evidence for a putative viral candidate in CLL. PMID- 22489538 TI - Evaluation of anxiolytic effect of Medicago sativa in mice. AB - CONTEXT: Medicago sativa Linn. (Leguminosae) has a long tradition of use as an Ayurvedic and Homoeopathic medicine in a variety of central nervous system (CNS) disorders. Traditionally, M. sativa is used to improve the memory, as a rejuvenator, antidiabetic, antioxidant, anti-inflammatory, and in CNS disorders. Despite a long tradition of use, no systematic phytochemical and pharmacological work has been carried out on this potential plant. M. sativa was subjected to preliminary anti-anxiety screening studies, with a view to ascertain the verity of its traditional use as an anxiolytic. OBJECTIVE: Various extracts, viz., petroleum ether, chloroform, methanol and aqueous extract from the aerial parts of M. sativa was subjected to preliminary anti-anxiety screening studies, with a view to ascertain the truth on evidence of its traditional use as an anxiolytic. MATERIALS AND METHODS: The aerial parts of the plant were extracted using solvents in order of increasing polarity, viz., petroleum ether (60-80 degrees C), chloroform, methanol and distilled water. All the crude extracts were evaluated for anti-anxiety activity in mice using elevated plus-maze apparatus. Diazepam was used as the standard drug. RESULTS: Among all extracts, only the methanol extract exhibited significant (p < 0.05) anti-anxiety activity by increasing the average time spent, and number of entries in open arms at a dose of 100 mg/kg in mice with respect to the vehicle treated control as well as the standard (2 mg/kg). CONCLUSION: These results suggest that administration of M. sativa exerts anxiolytic effect on mice, and it could serve as a new approach for the treatment of anxiety. PMID- 22489539 TI - Structural investigation of Titan tholins by solution-state 1H, 13C, and 15N NMR: one-dimensional and decoupling experiments. AB - Titan, the largest moon of Saturn, is enveloped in a reddish brown organic haze. Titan haze is presumed to be formed from methane and nitrogen (CH(4) and N(2)) in Titan's upper atmosphere through energetic photochemistry and particle bombardment. Though Titan haze has been directly investigated using methods including the Cassini mission, its formation mechanism and the contributing chemical structures and prebiotic potential are still not well developed. We report here the structural investigation of the (13)C and (15)N labeled, simulated Titan haze aerosol (tholin) by solution-state NMR. The one-dimensional (1)H, (13)C, and (15)N NMR spectra and decoupling experiments indicate that the tholin sample contains amine, nitrile, imine, and N-heteroaromatic compounds of tremendous import in understanding complex organic chemistry in anaerobic, extraterrestrial environments. PMID- 22489540 TI - People supersede illness. PMID- 22489541 TI - Confronting deep uncertainties in risk analysis. AB - How can risk analysts help to improve policy and decision making when the correct probabilistic relation between alternative acts and their probable consequences is unknown? This practical challenge of risk management with model uncertainty arises in problems from preparing for climate change to managing emerging diseases to operating complex and hazardous facilities safely. We review constructive methods for robust and adaptive risk analysis under deep uncertainty. These methods are not yet as familiar to many risk analysts as older statistical and model-based methods, such as the paradigm of identifying a single "best-fitting" model and performing sensitivity analyses for its conclusions. They provide genuine breakthroughs for improving predictions and decisions when the correct model is highly uncertain. We demonstrate their potential by summarizing a variety of practical risk management applications. PMID- 22489542 TI - Characterization of the key aroma compounds in rape honey by means of the molecular sensory science concept. AB - By application of aroma extract dilution analysis (AEDA) on the volatile fraction isolated by solvent extraction and solvent-assisted flavor evaporation (SAFE) from unifloral rape honey harvested in July 2009, 28 odor-active areas could be detected within a flavor dilution factor (FD) range of 4-2048. The highest FD factors were found for (E)-beta-damascenone (cooked apple-like), phenylacetic acid (honey-like), 4-methoxybenzaldehyde (aniseed-like), 3-phenylpropanoic acid (flowery, waxy), and 2-methoxy-4-vinylphenol (clove-like). Twenty-three odorants were then quantitated by application of stable isotope dilution assays, and their odor activity values (OAV, ratio of concentration to odor threshold) were calculated on the basis of newly determined odor thresholds in an aqueous fructose-glucose solution. The highest OAVs were calculated for (E)-beta damascenone, 3-phenylpropanoic acid, phenylacetic acid, dimethyl trisulfide, and phenylacetaldehyde. Quantitative measurements on a rape honey produced in 2011 confirmed the results. A model mixture containing the 12 odorants showing an OAV >= 1 at the same concentrations as they occurred in the rape honey was able to mimick the aroma impression of the original honey. The characterization of the key odorants in rape flowers from the same field suggested 3-phenylpropanoic acid, phenylacetic acid, and three further odorants to be transferred via the bees into the honey. PMID- 22489543 TI - Prenatal hazardous substance use and adverse birth outcomes. AB - OBJECTIVE: Assess the relative effects of a variety of illicit and licit drugs on risk for adverse birth outcomes. METHODS: We used data from two large prospective investigations, and a novel analytic method, recursive partitioning class analysis to identify risk factors associated with preterm birth and delivering a small for gestational age infant. RESULTS: Compared to cocaine and opiate non users, cocaine users were 3.53 times as likely (95% CI: 1.65-7.56; p = 0.001) and opiate users 2.86 times as likely (95% CI: 1.11-7.36; p = 0.03) to deliver preterm. The odds of delivering a small for gestational age infant for women who smoked more than two cigarettes daily was 3.74, (95% CI: 2.47-5.65; p<0.0001) compared to women who smoked two or less cigarettes daily and had one previous child. Similarly, less educated, nulliparous women who smoked two or fewer cigarettes daily were 4.12 times as likely (95% CI: 2.04-8.34; p < 0.0001) to have a small for gestational age infant. CONCLUSIONS: Among our covariates, prenatal cocaine and opiate use are the predominant risk factors for preterm birth; while tobacco use was the primary risk factor predicting small for gestational age at delivery. Multi-substance use did not substantially increase risk of adverse birth outcomes over these risk factors. PMID- 22489544 TI - Effect of playing violent video games cooperatively or competitively on subsequent cooperative behavior. AB - Research on video games has yielded consistent findings that violent video games increase aggression and decrease prosocial behavior. However, these studies typically examined single-player games. Of interest is the effect of cooperative play in a violent video game on subsequent cooperative or competitive behavior. Participants played Halo II (a first-person shooter game) cooperatively or competitively and then completed a modified prisoner's dilemma task to assess competitive and cooperative behavior. Compared with the competitive play conditions, players in the cooperative condition engaged in more tit-for-tat behaviors-a pattern of behavior that typically precedes cooperative behavior. The social context of game play influenced subsequent behavior more than the content of the game that was played. PMID- 22489545 TI - Association between problematic Internet use and impulse control disorders among Iranian university students. AB - Previous studies have examined the relationship between problematic Internet use (PIU) with pathological gambling and impulsivity. However, few studies have investigated the association between PIU and other impulse control disorders. This study aimed to assess whether PIU is related to compulsive buying, kleptomania, trichotillomania, intermittent explosive disorder, and pyromania, among a sample of Iranian university students. A cross-sectional study design was used among a random sample of (n=950) university students. Self-reported questionnaires, including demographic, Problematic Internet Use Questionnaire (PIUQ) and Minnesota Impulse Disorders Interview were utilized. The prevalence of PIU was 21.2 percent. Students with diagnosis of either compulsive buying, or intermittent explosive disorder, or pyromania had significantly higher scores on PIUQ compared to the students without the diagnosis. Multivariate regression analyses indicated that in the male gender, the diagnosis of either compulsive buying or intermittent explosive disorder were significant predictors of the risk of the PIU. The results support the proposal that PIU should be considered as a spectrum of impulse control disorder. PMID- 22489546 TI - Self-disclosure among bloggers: re-examination of social penetration theory. AB - Based on Social Penetration theory, this study explores the topics that bloggers disclose on their blogs, and in the real world. A total of 1,027 Taiwanese bloggers participated in this online survey, which revealed that bloggers self disclosed nine topics (attitude, body, money, work, feelings, personal, interests, experiences, and unclassified). Further, we examined the depth and width of what bloggers self-disclosed to three target audiences (online audience, best friend, and parents), confirming that their disclosure is significantly different for each of these target audiences. Bloggers seemingly express themselves to their best friends the most, followed by parents and online audiences, both in depth and in width. The "wedge model," proposed by Altman and Taylor (1973), has been extended to online relationships in this study. In comparison to male bloggers, female bloggers seemed to disclose more to their best friends and parents in their daily lives; however, no significant difference was observed in their disclosure to online audiences. Younger bloggers (<20 years old) seemed to disclose a wider range of topics; however, there was no significant difference in the depth of their disclosure on their blogs. Discussions of these results are also presented. PMID- 22489547 TI - Total sleep time in Muslim football players is reduced during Ramadan: a pilot study on the standardized assessment of subjective sleep-wake patterns in athletes. AB - Ramadan is a period in which Muslims fast during daylight hours and is associated with disturbances in sleep-wake behaviour and adverse effects on physical and mental health in normal volunteers. Studies using athletes are rare and remain equivocal as to whether Ramadan influences sleep-wake patterns. Notably, the standardized assessment of subjective sleep quality and daytime sleepiness in athletes has not been established. This study employed the Arabic version of the Pittsburgh Sleep Quality Index, Insomnia Severity Index, and Epworth Sleepiness Scale in nine football players aged 20-35 years (mean +/- s: 26 +/- 4) one week before and during the last week of Ramadan. Compliance rates with self administration were high (71%) and the results demonstrated a robust decline in total sleep time (before Ramadan: 6.6 +/- 2 h; at the end of Ramadan: 5.3 +/- 1 h; P < 0.05, effect size 0.81). Compared with previous research, the study questionnaires offer improved methodology, including less time constraints plus standardization in scoring. Thus, this study demonstrates a framework for greater reproducibility and reliability in the assessment of subjective sleep-wake patterns in athletes before and during Ramadan. PMID- 22489548 TI - Isoleucine-catalyzed direct asymmetric aldol addition of enolizable aldehydes. AB - Isoleucine-catalyzed direct enantioselective aldol additions between enolizable aldehydes are reported. Intermediate acetal structures dictate the configurative outcome and were supported by a hydrogen bond. This direct isoleucine-catalyzed aldol addition represents a welcome complement to both proline- and histidine catalyzed aldol additions of enolizable aldehydes. PMID- 22489549 TI - Determination of tricyclazole content in paddy rice by surface enhanced Raman spectroscopy. AB - An ultrasensitive method based on Surface enhanced Raman scattering (SERS) has been developed to determine content of a pesticide which is tricyclazole in paddy rice using sliver colloid as a substrate and pyridine as an internal standard. The peaks at 424 and 1035 cm(-1) in a SERS spectrum were selected as analytic and internal peaks, respectively, and their intensity ratio I(t)/I(p) was used to calculate the regression concentration of tricyclazole. The correlation between I(t)/I(p) and concentration showed significant linear relationship with a correlation coefficient of R(2)= 0.995 in a concentration range of 0.05 to 0.70 mg/L and the tricyclazole solution can be detected to be low as 0.002 mg/L by SERS. The method was applied to determine tricyclazole contents of 3 real rice samples with a standard addition method in order to eliminate interference of matrix. The errors of SERS measurements for the 3 samples were 0.0008 to 0.0246, 0.0013 to 0.0028, and 0.0129 to 0.0304 mg/kg, respectively, compared with the results obtained by high performance liquid chromatography method. This also showed a good reproducibility with low values of relative standard deviation (n= 3) for the 3 samples ranged from 3.63% to 4.64%. PMID- 22489550 TI - Evanescent wave cavity ring-down spectroscopy (EW-CRDS) as a probe of macromolecule adsorption kinetics at functionalized interfaces. AB - Evanescent wave cavity ring-down spectroscopy (EW-CRDS) has been employed to study the interfacial adsorption kinetics of coumarin-tagged macromolecules onto a range of functionalized planar surfaces. Such studies are valuable in designing polymers for complex systems where the degree of interaction between the polymer and surface needs to be tailored. Three tagged synthetic polymers with different functionalities are examined: poly(acrylic acid) (PAA), poly(3-sulfopropyl methacrylate, potassium salt) (PSPMA), and a mannose-modified glycopolymer. Adsorption transients at the silica/water interface are found to be characteristic for each polymer, and kinetics are deduced from the initial rates. The chemistry of the adsorption interfaces has been varied by, first, manipulation of silica surface chemistry via the bulk pH, followed by surfaces modified by poly(L-glutamic acid) (PGA) and cellulose, giving five chemically different surfaces. Complementary atomic force microscopy (AFM) imaging has been used for additional surface characterization of adsorbed layers and functionalized interfaces to allow adsorption rates to be interpreted more fully. Adsorption rates for PSPMA and the glycopolymer are seen to be highly surface sensitive, with significantly higher rates on cellulose-modified surfaces, whereas PAA shows a much smaller rate dependence on the nature of the adsorption surface. PMID- 22489551 TI - Mammary mucinous cystadenocarcinoma. PMID- 22489552 TI - Eighteen-year follow-up study of a Scottish birth cohort with epiphora. PMID- 22489553 TI - Counterion exchange as a decisive factor in the formation of host:guest complexes by p-sulfonatocalix[4]arene. AB - Calorimetric and NMR titration experiments have been done to measure the binding constant between p-sulfonatocalix[4]arene and a quaternary ammonium ion. Our results show that the binding constants depend both on the calixarene concentration and on the presence of added Na(+). These results have been interpreted by considering the ion-exchange equilibrium between sulfonatocalixarene counterions and the added organic cation. Our results show that it is necessary to extrapolate the binding constants to zero calixarene concentration and zero added salts in order to get the true equilibrium constant. PMID- 22489554 TI - Social workers as transition brokers: facilitating the transition from pediatric to adult medical care. AB - Transition from pediatric to adult medical care and the significant psychosocial considerations impacting this developmental process are a primary focus in health care today. Social workers are often the informal brokers of this complex and nuanced process and are uniquely trained to complete biopsychosocial assessments to understand the needs of patients and families and address psychosocial factors. Their extensive knowledge of resources and systems, along with their sophisticated understanding of the relationship issues, family dynamics, cultural implications, and basic person-in-context approach allow for unique collaboration with the health care team, family, and community supports to develop successful transition plans and programs. PMID- 22489555 TI - Is work beneficial to good health? AB - Unemployment and insecurity at work are a source of stress and may create a threat to individual physical and psychological health. The purpose of this study was to examine the connection between personal, functional, and professional variables and reports of how the health of hospital patients is impacted by financial status in Israel. One hundred and forty three hospitalized patients completed demographic, health-functional, and financial status questionnaires. Of the respondents, 32.9% reported a correlation between financial status and health. Significant connections were found between family status, lack of work, a change in partner's employment status, job insecurity, and financial commitments and reports of a correlation between financial status and health. The multivariate model predicting reports of a correlation between financial status and health was statistically significant. Discussion and implications focus on the need to create special preparation among health care professionals, in the community and in hospitals, to identify and treat people suffering from financial stress. PMID- 22489556 TI - Men at risk: considering masculinity during hospital-based social work intervention. AB - The needs of hospitalized male patients are often unrecognized and unmet. Men occupy greater than half of all inpatient hospital beds and incur a broad array of illnesses and injuries at higher rates than women--yet often receive health care that pays surprisingly little attention to the concept of patient masculinity, or to masculinity's influence on the male patient's perspectives, behaviors, goals, interests, needs, and challenges. Little emphasis is placed on considering hospitalized male patients as men , understanding their need for patient-centered care within this context, and intervening in ways that regularly allow strengths to be adequately recognized and utilized. In this article, we explore how hospital social workers can reconsider masculinity as a vibrant and formative component of male patients' lives and actively view its characteristics as comprising more than just potential challenges to medical treatment--but also as untapped sources of resilience and strength. PMID- 22489557 TI - In search of healing between two worlds: the use of traditional and modern health services by older women in rural Bangladesh. AB - The objective of this study is to gain a deeper understanding of the use of traditional and modern medicine among older adult women living in rural Bangladesh. Factors are identified that guide the women's decisions about who to seek help from when they are ill. The findings provide evidence that, in spite of the availability of modern health care, traditional healers--faith-based and herbalists--are widely utilized. Reasons given for their choice of health care providers fall into two categories: belief in the effectiveness of the intervention and service delivery considerations. These data suggest that use of traditional healers persists among women in rural areas of Bangladesh and that health policy should be developed with an acknowledgment of these health practices. PMID- 22489558 TI - The efficacy of a senior outreach program in the reduction of hospital readmissions and emergency department visits among chronically ill seniors. AB - This study reports on the effectiveness of a community-based senior outreach program in decreasing rehospitalizations and emergency department visits among chronically ill seniors. Participants had been repeatedly hospitalized with chronic illnesses and were subsequently served in an in-home program designed to address their psychosocial and medical needs. Participation in the program was found to be related to lower hospital readmission rates and emergency department usage. Clients also reported decreased financial concerns and depression and anxiety and increased social support. The study adds to the growing body of work supporting community-based programs as effective strategies for decreasing health care usage and improving quality of life for chronically ill seniors. PMID- 22489559 TI - Social work student attitudes toward contraception and the HPV vaccine. AB - The purpose of the current study was to examine social work student attitudes toward the social work profession's perspective on certain aspects of reproductive health in the United States: contraception, emergency contraception, and the Human Papillomavirus (HPV) vaccine. Students at a large, public, land grant university were surveyed to determine whether their personal attitudes were in line with the National Association of Social Workers (NASW) stance on reproductive health outlined in the NASW policy statement on family planning and reproductive health. The relationship between levels of religious activity and attitudes toward these aspects of reproductive health was also examined. Results suggest that almost all of the respondents support public funding for family planning. Furthermore, almost all students indicate willingness to refer clients for general contraception. However, results related to emergency contraception indicate that 72% of students disagree that it should be available for adolescents over the counter, even with parental consent, which is inconsistent with the NASW perspective. Sixty-four percent of students report believing that the HPV vaccine is unsafe. Further, as levels of religious activity increased, acceptance of some of these aspects of reproductive health decreased. Implications for social work practice, education, and directions for future research are discussed. PMID- 22489560 TI - Increasing trends in childlessness in recent birth cohorts - a registry-based study of the total Danish male population born from 1945 to 1980. AB - The fertility rate has recently declined in many parts of the World, including Europe. To a large extent, this change can be explained by the socio-economic development. However, increasing fertility problems and widespread occurrence of poor semen quality could in part explain the few births. The objective of this registry based study was to investigate birth cohort related trends in fertility and childlessness among Danish men. The study population comprised all 1 616 677 men in Denmark born from 1945 to 1980 of whom 1 359 975 (84.1%) were native Danes. Data were obtained from Statistics Denmark and contained information from The National Danish Birth Registry and The Danish In Vitro Fertilization (IVF) Registry. For consecutive birth cohorts of native Danish men cumulative fertility rates at age 45 declined from 1.91 children per man in the 1945 birth cohort to 1.71 for men born in 1960. The proportion of childless men at age 45 increased from 14.8% to 21.9% in the same birth cohorts. Assisted reproductive technology (ART) seemed to compensate partly for the lower fertility and to reduce the proportion of childless men. In contrast, recent reports on corresponding birth cohorts of Danish women showed that the proportion remaining childless throughout life has been lower than in men and has not shown a similar increase. In conclusion, using unique Danish registries the study showed a birth cohort related decline in fertility rates and an increase in childlessness among men. In the more recent cohorts more than one in five men remained childless. The causes behind the findings are likely multi-factorial. Hitherto, most attention has been given to socio-economic factors which undoubtedly play a major role. Our findings lend support to the hypothesis that the high prevalence of low sperm counts among young Danish men may be a contributing factor. PMID- 22489561 TI - WNT2 locus is involved in genetic susceptibility of Peyronie's disease. AB - INTRODUCTION: Peyronie's disease (PD) is a fibromatosis of the penis, with a pathology very similar to what is seen in the hand (palmar fascia) in Dupuytren's disease (DD). Recently, we performed a genome-wide association study and identified nine genetic loci containing common variants associated with DD. Seven of these loci mapped within or near genes of the canonical WNT pathway and each locus yielded relatively large odds ratios (ORs) for DD disease status. AIM: Given the clinical overlap between PD and DD, we examined whether the nine DD susceptibility loci are also involved in PD. METHODS: An association study was performed using a case/control design. From 2007 to 2010, we prospectively included 111 men who had been clinically diagnosed with PD. Control subjects (N = 490 males) were randomly drawn from a population-based cohort from the same region of the Netherlands. Allele frequencies in the 111 PD cases and 490 controls were compared using a 1-degree-of-freedom basic chi-square test. A P value < 0.05 after Bonferroni correction for the nine tested single nucleotide polymorphisms (SNPs) was considered statistically significant (i.e., P < 0.0056). MAIN OUTCOME MEASURE: Association of genetic markers (SNPs) with PD. RESULTS: We observed significant association with SNP rs4730775 at the wingless-type MMTV integration site family member 2 (WNT2) locus on chromosome 7 (P = 0.0015, OR 0.61), but found no evidence for the other eight loci being involved with PD despite the large effect size seen for some of these variants in DD. The WNT2 association was even more significant after we removed 15 patients with comorbid DD. CONCLUSIONS: WNT2 is a susceptibility locus for PD and our finding provides evidence for a partly shared genetic susceptibility between PD and DD. PMID- 22489562 TI - Relationship between nutrition status and dental occlusion in community-dwelling frail elderly people. AB - AIM: This study aimed to determine the risk of malnutrition in some communities where the frail elderly receive public long-term care insurance. We also clarified the dental problems in those at risk of malnutrition. METHODS: A total of 716 frail elderly who lived in eight cities in Japan (240 males and 476 females with a mean age of 83.2+/-8.6 years) were divided into three groups according to Mini Nutritional Assessment short form results: well nourished, at risk of malnutrition and malnourished. They were also divided into three groups in terms of remaining teeth occlusion and denture occlusion: group A, natural dentition with adequate function; group B, partially or fully edentulous, but maintaining functional occlusion with dentures in either or both jaws; and group C, functionally inadequate occlusion with no dentures. The relationship between nutrition status and dental occlusion was evaluated using logistic regression analysis with sex, age, activities of daily living and cognitive function as covariates. RESULTS: The number of participants in each of the groups was as follows: 251 well nourished, 370 at risk of malnutrition and 95 malnourished. When they were divided into just two groups, (i) well nourished and (ii) at risk of malnutrition plus malnourished, in order to study malnutrition risk factors, there were significant relationships between their nutritious status and sex, Barthel index, and occlusion. CONCLUSION: This large-scale cross-sectional survey showed that loss of natural teeth occlusion was a risk factor for malnutrition among community-dwelling frail elderly. PMID- 22489563 TI - Probing surface and bulk electrochemical processes on the LaAlO3-SrTiO3 interface. AB - Local electrochemical phenomena on the surfaces of the LaAlO(3)-SrTiO(3) heterostructure are explored using unipolar and bipolar dynamic electrochemical strain microscopy (D-ESM). The D-ESM suggests the presence of at least two distinct electrochemical processes, including fast reversible low-voltage process and slow high-voltage process. The latter process is associated with static surface deformations in the sub-nanometer regime. These behaviors are compared with Kelvin probe force microscopy hysteresis data. The possible origins of observed phenomena are discussed, and these studies suggest that charge-writing behavior in LAO-STO includes a strong surface/bulk electrochemical component and is more complicated than simple screening by surface adsorbates. PMID- 22489564 TI - Proline kink angle distributions for GWALP23 in lipid bilayers of different thicknesses. AB - By using selected (2)H and (15)N labels, we have examined the influence of a central proline residue on the properties of a defined peptide that spans lipid bilayer membranes by solid-state nuclear magnetic resonance (NMR) spectroscopy. For this purpose, GWALP23 (acetyl-GGALW(5)LALALALALALALW(19)LAGA-ethanolamide) is a suitable model peptide that employs, for the purpose of interfacial anchoring, only one tryptophan residue on either end of a central alpha-helical core sequence. Because of its systematic behavior in lipid bilayer membranes of differing thicknesses [Vostrikov, V. V., et al. (2010) J. Biol. Chem. 285, 31723 31730], we utilize GWALP23 as a well-characterized framework for introducing guest residues within a transmembrane sequence; for example, a central proline yields acetyl-GGALW(5)LALALAP(12)ALALALW(19)LAGA-ethanolamide. We synthesized GWALP23-P12 with specifically placed (2)H and (15)N labels for solid-state NMR spectroscopy and examined the peptide orientation and segmental tilt in oriented DMPC lipid bilayer membranes using combined (2)H GALA and (15)N-(1)H high resolution separated local field methods. In DMPC bilayer membranes, the peptide segments N-terminal and C-terminal to the proline are both tilted substantially with respect to the bilayer normal, by ~34 +/- 5 degrees and 29 +/- 5 degrees , respectively. While the tilt increases for both segments when proline is present, the range and extent of the individual segment motions are comparable to or smaller than those of the entire GWALP23 peptide in bilayer membranes. In DMPC, the proline induces a kink of ~30 +/- 5 degrees , with an apparent helix unwinding or "swivel" angle of ~70 degrees . In DLPC and DOPC, on the basis of (2)H NMR data only, the kink angle and swivel angle probability distributions overlap those of DMPC, yet the most probable kink angle appears to be somewhat smaller than in DMPC. As has been described for GWALP23 itself, the C-terminal helix ends before Ala(21) in the phospholipids DMPC and DLPC yet remains intact through Ala(21) in DOPC. The dynamics of bilayer-incorporated, membrane-spanning GWALP23 and GWALP23-P12 are less extensive than those observed for WALP family peptides that have more than two interfacial Trp residues. PMID- 22489565 TI - An experimental model of neonatal normocapnic hypoxia and resuscitation in Landrace/Large White piglets. AB - OBJECTIVE: The aim of this study is to describe and evaluate an experimental model of neonatal normocapnic hypoxia and resuscitation. METHODS: Ten male Landrace/Large White neonatal piglets were studied. Following anaesthesia and intubation, the animals were mechanically ventilated. Surgical procedures included catheterization of the right internal jugular vein and the carotid artery. After stabilization with 21% O(2), normocapnic hypoxia was induced by decreasing the inspired O(2) to 6-8%. When piglets developed bradycardia (heart rate < 60 beats/min), reoxygenation was initiated by administering 21% O(2). Arterial blood samples were taken during baseline, hypoxia and reoxygenation in order to measure interleukine-6 and interleukine-8. RESULTS: Nine out of ten animals were successfully resuscitated (one of these required chest compressions and a dose of adrenaline) and one died despite resuscitation efforts. After returning to baseline haemodynamic values, euthanasia was performed using thiopental overdose. CONCLUSIONS: Haemodynamic fluctuations at baseline, during normocapnic hypoxia and reoxygenation in Landrace/Large White piglets are comparable to that in human neonates, making the breed a favorable model of human neonatal hypoxia investigation. PMID- 22489566 TI - Driving mechanisms of ionic polymer actuators having electric double layer capacitor structures. AB - Two solid polymer electrolytes, composed of a polyether-segmented polyurethaneurea (PEUU) and either a lithium salt (lithium bis(trifluoromethanesulfonyl)amide: Li[NTf2]) or a nonvolatile ionic liquid (1 ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)amide: [C2mim][NTf2]), were prepared in order to utilize them as ionic polymer actuators. These salts were preferentially dissolved in the polyether phases. The ionic transport mechanism of the polyethers was discussed in terms of the diffusion coefficients and ionic transference numbers of the incorporated ions, which were estimated by means of pulsed-field gradient spin-echo (PGSE) NMR. There was a distinct difference in the ionic transport properties of each polymer electrolyte owing to the difference in the magnitude of interactions between the cations and the polyether. The anionic diffusion coefficient was much faster than that of the cation in the polyether/Li[NTf2] electrolyte, whereas the cation diffused faster than the anion in the polyether/[C2mim][NTf2] electrolyte. Ionic polymer actuators, which have a solid-state electric-double-layer-capacitor (EDLC) structure, were prepared using these polymer electrolyte membranes and ubiquitous carbon materials such as activated carbon and acetylene black. On the basis of the difference in the motional direction of each actuator against applied voltages, a simple model of the actuation mechanisms was proposed by taking the difference in ionic transport properties into consideration. This model discriminated the behavior of the actuators in terms of the products of transference numbers and ionic volumes. The experimentally observed behavior of the actuators was successfully explained by this model. PMID- 22489567 TI - Validity and reliability of tests determining performance-related components of wheelchair basketball. AB - The purpose of this study was to investigate the reliability and validity of wheelchair basketball field tests. Nineteen wheelchair basketball players performed 10 test items twice to determine the reliability. The validity of the tests was assessed by relating the scores to the players' classification and competition standard, and rating of coach and player. Six field tests' test retest showed good reliability (Intraclass correlation coefficient (ICC) = 0.80 0.97), while the pass-for-accuracy, free throws, lay-up and spot shot showed weak to moderate reliability (ICC = 0.26-0.67). Most tests showed moderate to good validity (r > 0.60). The results suggest that wheelchair basketball field tests are reliable and valid with the exception of the shooting and passing items, which should be interpreted carefully. PMID- 22489568 TI - Evaluation of visual field parameters in patients with chronic obstructive pulmonary disease. AB - PURPOSE: To evaluate the effects of chronic obstructive pulmonary disease (COPD) on retina and optic nerve. METHODS: Thirty-eight patients with COPD and 29 healthy controls, totally 67 subjects, were included in the study. Visual evoked potentials (VEP) and visual field assessment (both standard achromatic perimetry (SAP) and short-wavelength automated perimetry (SWAP)) were performed on each subject after ophthalmological, neurological and pulmonary examinations. RESULTS: Mean deviation (MD), pattern standard deviation (PSD) and corrected pattern standard deviation (CPSD) were significantly different between patient and control groups as for both SAP and SWAP measurements (p = 0.001, 0.019, 0.009 and p = 0.004,0.019, 0.031, respectively). Short-term fluctuation (SF) was not statistically different between the study and the control groups (p = 0.874 and 0.694, respectively). VEP P100 latencies were significantly different between patients with COPD and the controls (p = 0.019). CONCLUSION: Chronic obstructive pulmonary disease is a systemic disease, and hypoxia in COPD seems to affect the retina and the optic nerve. PMID- 22489569 TI - Oil-in-alcohol highly concentrated emulsions as templates for the preparation of macroporous materials. AB - New oil-in-alcohol highly concentrated emulsions were formulated and were used as a templates to obtain macroporous poly(furfuryl alcohol) monoliths by a one-step method. The oil-in-alcohol highly concentrated emulsions were prepared by stepwise addition of the oil phase to the surfactant-alcohol solution and were characterized by optical microscopy and by laser diffraction. The typical structure of highly concentrated emulsions, with close-packed polyhedral droplets, has been observed. Poly(furfuryl alcohol) monoliths were obtained by polymerizing in the external phase of these emulsions. These materials are mainly macroporous and retain the size distribution and morphology from the highly concentrated emulsions. The internal structure of the monoliths was observed by scanning electron microscopy. The images showed an interconnected network with pore size similar to the droplet size of the highly concentrated emulsions used as templates. PMID- 22489570 TI - Aggregation and interaction of cationic nanoparticles on bacterial surfaces. AB - Cationic monolayer-protected gold nanoparticles (AuNPs) with sizes of 6 or 2 nm interact with the cell membranes of Escherichia coli (Gram-) and Bacillus subtilis (Gram+), resulting in the formation of strikingly distinct AuNP surface aggregation patterns or lysis depending upon the size of the AuNPs. The aggregation phenomena were investigated by transmission electron microscopy and UV-vis spectroscopy. Upon proteolytic treatment of the bacteria, the distinct aggregation patterns disappeared. PMID- 22489571 TI - Comparing midwife-led and doctor-led maternity care: a systematic review of reviews. AB - AIMS: A report of a systematic review of reviews which examines the impact of having midwives-led maternity care for low-risk women, rather than physicians. BACKGROUND: A rising birth rate, increasing complexity of births, and economic constraints pose difficulties for maternity services in the UK. Evidence about the most effective, cost-effective, and efficient ways to give maternity services is needed. DATA SOURCES: Searches were carried out in August-September 2009 of ten electronic databases, 16 key nursing and research websites, and reference lists of 56 relevant reviews. We also contacted 38 experts for information. No date restrictions were employed. REVIEW METHODS: A narrative review of systematic reviews or 'meta review' was conducted using transparent and systematic procedures to limit bias at all stages. Systematic reviews that compared midwife-led care during pregnancy and birth with physician-led care were eligible for inclusion. RESULTS: Three meta-analytic reviews were included. Midwife-led care for low-risk women was found to be better for a range of maternal outcomes, reduced the number of procedures in labour, and increased satisfaction with care. For some maternal, foetal, and neonatal outcomes reviews found no evidence that care led by midwives is different to that led by physicians. No adverse outcomes associated with midwife-led care were identified. CONCLUSIONS: For low-risk women, health and other benefits can result from having their maternity care led by midwives rather than physicians. Moreover, there appear to be no negative impacts on mothers and infants receiving midwife led care. PMID- 22489572 TI - Anti-Streptococcus mutans efficacy of Thai herbal formula used as a remedy for dental caries. AB - CONTEXT: Traditional knowledge of herbal remedies plays an important role in the search for more effective alternative treatment of a variety of disorders. The ethnobotanical surveys in southern Thailand have revealed that 35 Thai herbal formulas have been used by Thai traditional healers against dental caries. However, the scientific evaluation to confirm their rational uses is scarce. OBJECTIVE: To test in vitro anti-Streptococcus mutans activity of Thai herbal formulas used against dental caries (THF-DC). MATERIALS AND METHODS: Ethanol extracts of Thai herbal formulas were evaluated for antibacterial activity against S. mutans. Agar disc diffusion was employed as a preliminary screening assay, followed by broth microdilution assay to assess minimum inhibitory concentration (MIC). Furthermore, medicinal plants contained in the most active THF-DC were investigated for their phytochemicals. RESULTS: Eleven THF-DC extracts exhibited clear inhibition zones of 7.0-22.5 mm against S. mutans. Subsequent determination of their MIC revealed that the formula containing Albizia myriophylla Benth. (Leguminosae), Alpinia galanga (L.) Willd. (Zingiberaceae), Avicennia marina (Forssk.) Vierh. (Acanthaceae), and Ocimum sanctum L. (Lamiaceae) was the most active, with MIC at 250 ug/mL. Among these medicinal plants, A. myriophylla gave the strongest activity with MIC at 3.9 ug/mL, followed by A. marina with MIC at 62.5 ug/mL. Various classes of bioactive phytochemicals including tannins, flavonoids, alkaloids, and terpenoids were found in these extracts. CONCLUSION: Anti-S. mutans activity of THF-DC extracts was established. Further investigations may be required for the isolation and chemical characterization of the active ingredients in A. myriophylla. PMID- 22489573 TI - Manufacture and properties of bifidogenic saccharides derived from wood mannan. AB - Pinus pinaster wood samples were subjected to double hydrothermal processing. The liquors coming from the second stage, containing soluble saccharides of polymeric or oligomeric nature from hemicelluloses (POHs), were subjected to membrane processing (operating in discontinuous diafiltration) for refining and fractionation. Refined POH fractions were characterized by matrix-assisted laser desorption/ionization time of flight mass spectrometry and chromatographic techniques. The most complex POH component was made up of 14 hexoses and contained 4 acetyl groups. The fermentability of purified POHs by human fecal inocula was assessed by measuring both carbon source consumption and formation of short-chain fatty acids. The bifidogenic ability of POHs was confirmed by fluorescence in situ hybridization. The stimulatory effects on the bifidobacterial population reached by POHs were of the same order as those obtained with commercial fructooligosaccharides. PMID- 22489574 TI - Association of c-Jun gene polymorphism with susceptibility to systemic lupus erythematosus in a Chinese population. AB - C-Jun has been proved as playing an important role in the pathogenesis of tumors, as a main component of Activator protein 1 and c-Jun gene polymorphisms are associated with colorectal cancer. However, the relationship between the c-Jun gene polymorphism and the susceptibility to systemic lupus erythematosus (SLE) has not been known. Our purpose is to evaluate whether the c-Jun gene polymorphism (SNP rs3748814) is associated with susceptibility to SLE in a Chinese population. In this study, we enrolled 502 SLE patients and 652 healthy controls. The c-Jun polymorphism (rs3748814) was specified from genomic DNA using the TaqMan genotyping assay on a 7300 real-time reverse transcription polymerase chain reaction system. We found that the frequency of the A/G genotype in SLE patients was lower than in healthy controls, whereas the frequency of the G/G genotype was significantly higher in SLE patients than in healthy controls (A/G vs. G/G p = 8.670e-08, odds ratio [OR] = 0.290, 95% confidence interval [CI] = 0.184-0.456). In addition, the frequency of allele A in the patients group was significantly lower than in the control group (A vs. G p=5.221e-09, OR = 0.308, 95% CI = 0.212-0.466). The distribution of genotype and allele frequency in SLE patients with lupus nephritis (LN) compared with SLE patients without LN was not statistically significant (A/G vs. G/G p = 0.744, OR = 1.157, 95% CI=0.481-2.785; A vs. G p = 0.748, OR = 1.152, 95% CI = 0.486-2.734; A/A+A/G vs. G/G p = 0.744, OR = 1.157, 95% CI = 0.481-2.785). Furthermore, we did not find any significant association between other clinical features and genotypes. Our findings suggest that the c-Jun polymorphism (rs3748814) may be significantly associated with the susceptibility to SLE in a Chinese population. PMID- 22489575 TI - Adjusting the attB site in donor plasmid improves the efficiency of PhiC31 integrase system. AB - PhiC31 integrase, a site-specific recombinase, can catalyze integration of circular DNA bearing attB site into pseudo attP sites in mammalian genomes. However, the integration efficiency mediated by integrase is relatively low. Our study centered on the investigation of the impact of the position, orientation, and number of attBs in the donor plasmid on the efficiency of PhiC31 integrase system. Donor plasmids bearing various types of attBs (including forward and reverse directions, tandem, and intersperse) and reporter enhanced green fluorescent protein (EGFP) were constructed. The plasmids plus helper plasmid encoding integrase were co-transfected into HeLa cells. After G418 selection, the resistant cell colonies were counted for calculating chromosomal integration frequency. EGFP expression was detected by fluorescence-activated cell sorter and enzyme-linked immunosorbent assay analysis. The results showed that efficiency of integration mediated by integrase accounted for 70% +/- 7.1% of total integration events in the transfected HeLa cells. Compared with a forward orientation of attB in donor plasmid, a reverse direction of attB or interspersed attBs showed 1.5- or 2.8-fold increase in integration efficiency, respectively, while tandem attBs in donor plasmids caused a decreased efficiency of integration. We conclude that the adjustment of attB sites in donor plasmids may be of value for gene therapy and routine genetic engineering by using PhiC31 integrase system. PMID- 22489576 TI - Aberrant expression of MIR9 indicates poor prognosis in acute myeloid leukaemia. PMID- 22489577 TI - H-bonded clusters in the trimethylamine/water system: a matrix isolation and computational study. AB - The environmentally important interaction products of trimethylamine (TMA) and water molecules have been observed by Matrix Isolation Fourier Transform Infrared Spectroscopy (MIS-FTIR). Infrared spectra of solid argon matrix layers, in which both TMA and H(2)O molecules were entrapped as impurities, were analyzed for bands in the nu(O-H) region, not seen in matrix layers containing either of the parent molecules alone. Results were interpreted on the basis of the emergence of several spectral band pairs and their red shifts from the position of the matrix isolated H(2)O monomers as compared to semiempirically scaled frequencies from the B3LYP/aug-cc-pVTZ calculations and empirical correlations with a large body of data on H-bonded complexes. Bands were assigned to a complex cluster of two TMA molecules flanking a closed ring of four H-bonded H(2)O molecules. The formation of this cluster is argued to be formed in the vapor phase (as opposed to being a result of diffusion of the trapped species) and is related to its large stabilization energy (enthalpy) because of strong cooperative effects in its H-bond system. PMID- 22489578 TI - High-intensity erotic visual stimuli de-activate the primary visual cortex in women. AB - INTRODUCTION: The primary visual cortex, Brodmann's area (BA 17), plays a vital role in basic survival mechanisms in humans. In most neuro-imaging studies in which the volunteers have to watch pictures or movies, the primary visual cortex is similarly activated independent of the content of the pictures or movies. However, in case the volunteers perform demanding non-visual tasks, the primary visual cortex becomes de-activated, although the amount of incoming visual sensory information is the same. AIM: Do low- and high-intensity erotic movies, compared to neutral movies, produce similar de-activation of the primary visual cortex? METHODS: Brain activation/de-activation was studied by Positron Emission Tomography scanning of the brains of 12 healthy heterosexual premenopausal women, aged 18-47, who watched neutral, low- and high-intensity erotic film segments. MAIN OUTCOME MEASURES: We measured differences in regional cerebral blood flow (rCBF) in the primary visual cortex during watching neutral, low-intensity erotic, and high-intensity erotic film segments. RESULTS: Watching high-intensity erotic, but not low-intensity erotic movies, compared to neutral movies resulted in strong de-activation of the primary (BA 17) and adjoining parts of the secondary visual cortex. CONCLUSIONS: The strong de-activation during watching high-intensity erotic film might represent compensation for the increased blood supply in the brain regions involved in sexual arousal, also because high intensity erotic movies do not require precise scanning of the visual field, because the impact is clear to the observer. PMID- 22489579 TI - Empirical awakening: the new science on mutual help and implications for cost containment under health care reform. AB - Over the past 75 years, Alcoholics Anonymous (AA) has grown from 2 members to over 2 million members. AA and similar organizations (e.g., Narcotics Anonymous [NA]) are among the most commonly sought sources of help for substance-related problems in the United States. It is only relatively recently, however, that the scientific community has conducted rigorous studies on the clinical utility and health care cost-offset potential of mutual-help groups and developed and tested professional treatments to facilitate their use. As a result of this research, AA as an organization has experienced an "empirical awakening," evolving from its peripheral status as a "nuisance variable" and perceived obstacle to progress to playing a more central role in a scientifically informed recovery oriented system of care. Also, professionally delivered interventions designed to facilitate the use of AA and NA ("Twelve-Step Facilitation" [TSF]) are now "empirically supported treatments" as defined by US federal agencies and the American Psychological Association. Under the auspices of health care reform, a rational societal response to the prodigious health and social burden posed by alcohol and other drug misuse should encompass the implementation of empirically based strategies (e.g., TSF) in order to maximize the use of ubiquitous mutual-help recovery resources. PMID- 22489580 TI - The relationship between substance abuse treatment completion, sociodemographics, substance use characteristics, and criminal history. AB - The purpose of this study is to determine if a significant relationship exists between the sociodemographics, substance use characteristics, criminal history, and completion of substance abuse treatment. In this study, 115 individuals being monitored for substance abuse treatment on probation at the Probation and Help Center under the Republic of Turkey's Ministry of Justice's Chief Public Prosecutor's Office of Istanbul were included successively between the dates of April 2008 and April 2009. During a 24-week follow-up, individuals whose urine analyses were clean 6 times consecutively were considered to have completed the treatment successfully. To determine the effect of sociodemographic factors and substance use characteristics on treatment completion, a semistructured sociodemographic data survey was used. Also, the participants' criminal records were examined. A total of 115 people participated in the study. One hundred ten (95.7%) of them were male. Sixty-eight (59.1%) of the participants had completed treatment. Age group, education level, age of onset for substance use, number of substances used, employment status, and criminal records showed a significant difference between treatment completers and noncompleters. When a logistic regression analysis was done, only number of substances used and criminal record (other than drug possession) were significantly different for the 2 groups. The current treatment program for polysubstance users and individuals with a criminal record is insufficient. It is necessary that treatment systems be developed so they can be beneficial for these types of patients. PMID- 22489581 TI - Concordance between urinary cotinine levels and self-reported tobacco use among drug-dependent persons: a pilot study. AB - Self-reported drug use is a principle measure in the evaluation of treatment outcome. As there have been concerns about the accuracy of self-reporting, it is necessary to establish its validity by an objective method. The aim of the study was to examine the concordance between urinary cotinine concentrations and self reported tobacco use among drug dependents seeking treatment at National Drug Dependence Treatment Centre, AIIMS, New Delhi, India. Eighty consecutive male drug addicts attending the OPD at National Drug Dependence Treatment Centre were interviewed by the clinician. Their tobacco as well as drug use history was recorded, and thereafter their urine sample was analyzed for drug testing. Mean age of the subjects was found to be 33 years (SD: 10). Urinalysis showed high concentration of cotinine (mean +/- SD: 586.40 +/- 222.15 ng/ml) in 95% of the subjects. High concordance was observed between self-report of tobacco use and urinary cotinine. The quantity of tobacco consumption and FTND scores were also correlated with the urinary cotinine levels. Urinalysis also showed misuse of opioids, benzodiazepines and antihistaminics. The treatment for tobacco use has been given low priority in the de-addiction centers. Tobacco is highly prevalent among the drug abusers. The effectiveness of the treatment program may be increased by using the combination of urine analysis along with self-report. PMID- 22489582 TI - Practices, perceptions, and concerns of primary care physicians about opioid dependence associated with the treatment of chronic pain. AB - When prescribing opioids to treat chronic pain, physicians face the dilemma of balancing effective pain management while avoiding iatrogenic opioid addiction. Through mailed surveys, the current study assessed concerns, perceptions, and practices of primary care physicians related to this dilemma. Of the 35 (43%) physicians that replied, 32 (91.4%) reported to prescribe opioids for pain. Twenty-six (81.3%) physicians mentioned that "legitimate pain" was the main reason why most patients who are opioid dependent begin using opioids. Most physicians (71.5%) rated their knowledge/comfort of treatment/management of opioid dependence as being low. Although these physicians believed training is essential to learning about the risks involved with chronic pain and opioid dependence, many of these physicians evaluated their own medical training in these areas as unsatisfactory. Training programs may better equip primary care physicians when addressing the treatment of chronic pain and addiction to opioids. PMID- 22489583 TI - Implementing a statewide Screening, Brief Intervention, and Referral to Treatment (SBIRT) service in rural health settings: New Mexico SBIRT. AB - This is a report on the New Mexico Screening, Brief Intervention, and Referral to Treatment (SBIRT) project conducted over 5 years as part of a national initiative launched by the Substance Abuse and Mental Health Services Administration with the aim of increasing integration of substance use services and medical care. Throughout the state, 53,238 adults were screened for alcohol and/or drug use problems in ambulatory settings, with 12.2% screening positive. Baseline substance use behaviors among 6,360 participants eligible for brief intervention, brief treatment, or referral for treatment are examined and the process of implementation and challenges for sustainability are discussed. PMID- 22489584 TI - Client attitudes toward alcohol use self-report. AB - Because psychiatric illnesses and problematic alcohol use frequently co-occur and heavy alcohol use can exacerbate depression and anxiety, mental health clinicians should perform alcohol-use screenings. The aim of this study was to determine if psychiatric patients would be accepting of their mental health clinician screening them for heavy alcohol use. Using a written survey, patients rated their levels of agreement with 9 statements regarding opinions about alcohol screening by their mental-health providers. They also completed the Alcohol Use Disorders Identification Test-C (AUDIT-C), a screening instrument for heavy alcohol use. One hundred fifty-four patients were surveyed in 2 psychiatric outpatient clinics. Nearly 40% screened positively for heavy alcohol use on the AUDIT-C. Nearly 8 out of 10 psychiatric patients were in favor of being screened for alcohol use by either self-report or biomarkers, independent of AUDIT-C status and gender. Thus, mental health clinicians should not be deterred from alcohol screening by perceived negative attitudes from patients. PMID- 22489585 TI - Characteristics of psychopathology and the relationship between routes of drug administration and psychiatric symptoms in heroin addicts. AB - The objective of this study was to explore the characteristics of comorbid psychiatric symptoms and the relationship between different routes of drug administration and psychiatric symptoms. Five hundred and nine heroin addicts were studied in Drug Detoxification and Rehabilitation Centers in Yunnan and Heilongjiang provinces of China. The measure instrument, including demographic characteristics, history of drug abuse, and the Symptom Checklist-90 (SCL-90) scale (Chinese version), was administered to eligible heroin addicts. Among the subjects, comorbid psychopathology conditions were more severe on all dimensions of SCL-90 comparing with normal adults and the average score of Depression was highest among the 9 dimensions in heroin addicts; psychiatric symptoms were more severe in heroin injecting group than in "chasing the dragon" group and only the difference in Obsessive-Compulsive was significant, but more significant differences were found between snorting heroin addicts and chasing or injecting heroin addicts, and the average score of each dimension of SCL-90 was higher in the snorting group than in the other 2 groups. The reasons of the results and meaning for the present study are discussed. In summary, comorbid psychiatric symptoms in the heroin addicts were very common and severe and their severity varied with different routes of drug administration, suggesting that routes of drug administration should be considered as an important risk factor to mental health of heroin addicts. PMID- 22489586 TI - Exploration of the comorbidity of alcohol use disorders and mental health disorders among inpatients presenting to all hospitals in New South Wales, Australia. AB - Alcohol is one of the most commonly used legal psychoactive substances, and its use often coexists with mental health disorders. This study explores the relationships between alcohol use and some common mental health disorders. Admissions to all New South Wales (NSW) hospitals were analyzed. The data were extracted from the NSW Department of Health Inpatient Statistics Data Collection for the period 1 July 2006 to 30 June 2007. Readmissions within 28 days were excluded. Data extraction and analyses were performed by using the SAS program. Chi-square tests and odds ratio were used to measure the association. Of the 1.8 million admissions, associations between alcohol use disorders and mental health disorders were strong (odds ratio 7.8 to 10.7, P < .001). A 33.8% of patients who used alcohol had at least 1 identifiable mental disorder. Higher comorbidity rates were observed for females (39.6%) and for those aged between 30 and 49 years. The most common mental disorders were anxiety disorders, bipolar affective disorders, major depressive disorders, personality disorders, schizophrenia, and severe stress disorders. Comorbidity with one of these mental disorders ranged from 1% to 17.6%, with significant associations (odds ratio 5.6 to 14.1). The average length of stay (ALOS) for alcohol use disorders were 6.4 days and the ALOS for the most common mental health admissions was 11.2 days. This study provides detailed information about the association between alcohol use and mental health disorders and extends our understanding of comorbidity presentations in inpatient admissions. PMID- 22489587 TI - Social modeling influences and alcohol consumption during the first semester of college: a natural history study. AB - The authors examine both the alcohol consumption pattern of freshmen students during their first semester and the degree to which social modeling of peer behavior impacts consumption. A total of 534 students, residing on campus, were prospectively examined at four 30-day intervals. Data were evaluated on the basis of age, gender, and the effects of time using generalized estimating equations (GEEs). Results reflected nonsignificant increases in the amount of alcohol consumed; however, affiliations with alcohol-consuming peer groups was significantly associated with increased alcohol consumption. The mean number of drinks consumed in the past 30 days remained the same for whites (chi(2) = 3.35, 3 df, P = .3411) but increased slightly for blacks (chi(2) = 7.99, 3 df, P = .0462). Prevention programs should include screening for growth in alcohol consumption among first-year university students, and such screenings should include the extent and nature of affiliation with peers who consume alcohol. PMID- 22489588 TI - Comorbid trajectories of tobacco and marijuana use as related to psychological outcomes. AB - Heterogeneous classes of comorbid trajectories of tobacco and marijuana use were examined in order to determine how they are related to subsequent antisocial behavior, poor self-control, and internalizing behavior. Data are from a 4-wave longitudinal study of African American (n = 243) and Puerto Rican (n = 232) adolescents and adults in the community. Logistic regression analyses were employed to measure the association between the comorbid trajectories of tobacco and marijuana use and the psychological difficulty variables. The authors found 6 joint trajectory groups. The authors compared the non-or-experimental tobacco/marijuana use group with the other user groups in each of the psychological difficulty domains. The infrequent tobacco/late-onset marijuana use and chronic tobacco/marijuana use groups differed most strongly from the non-or experimental tobacco/marijuana use group across the antisocial behavior, poor self-control, and internalizing problems domains. The chronic tobacco/maturing out marijuana use group also had significant associations in each of these domains. The infrequent tobacco/marijuana use and late-onset tobacco/infrequent marijuana use groups had no or weak associations with the psychological outcomes. Tobacco and marijuana cessation programs should identify and address comorbid use of tobacco and marijuana, and antisocial behavior, poor self-control, and internalizing problems, which are associated with histories of comorbid use of the 2 substances. PMID- 22489589 TI - Developing and implementing a multispecialty graduate medical education curriculum on Screening, Brief Intervention, and Referral to Treatment (SBIRT). AB - The authors sought to evaluate the feasibility and acceptability of initiating a Screening, Brief Intervention, and Referral to Treatment (SBIRT) for alcohol and other drug use curriculum across multiple residency programs. SBIRT project faculty in the internal medicine (traditional, primary care internal medicine, medicine/pediatrics), psychiatry, obstetrics and gynecology, emergency medicine, and pediatrics programs were trained in performing and teaching SBIRT. The SBIRT project faculty trained the residents in their respective disciplines, accommodating discipline-specific implementation issues and developed a SBIRT training Web site. Post-training, residents were observed performing SBIRT with a standardized patient. Measurements included number of residents trained, performance of SBIRT in clinical practice, and training satisfaction. One hundred and ninety-nine residents were trained in SBIRT: 98 internal medicine, 35 psychiatry, 18 obstetrics and gynecology, 21 emergency medicine, and 27 pediatrics residents. To date, 338 self-reported SBIRT clinical encounters have occurred. Of the 196 satisfaction surveys completed, the mean satisfaction score for the training was 1.60 (1 = very satisfied to 5 = very dissatisfied). Standardized patient sessions with SBIRT project faculty supervision were the most positive aspect of the training and length of training was a noted weakness. Implementation of a graduate medical education SBIRT curriculum in a multispecialty format is feasible and acceptable. Future efforts focusing on evaluation of resident SBIRT performance and sustainability of SBIRT are needed. PMID- 22489590 TI - Using standardized patients in continuing medical education courses on proper prescribing of controlled substances. AB - Controlled prescription drug (CPD) abuse is an increasing threat to patient safety and health care providers (HCPs) are not adequately prepared nor do they routinely employ proper screening techniques. Using standardized patients (SPs) as an instructional strategy, the trained physicians on proper prescribing practices and SBIRT (Screening, Brief Intervention, and Referral to Treatment) in a continuing medical education (CME) course. The authors compared two physician cohorts receiving standard CME course (control) versus CME plus SP practice. They measured knowledge and attitudes in all participants and skills and perceived competence in the SP group only. Knowledge and attitudes improved significantly for both groups. Screening behaviors for CPD use also improved. Participants overestimated their performance but increased their use of SBIRT with practice. The SP comfort levels with physician's competence improved after 2 practice sessions. Standardized patients can be an effective teaching tool in CME courses. Impact on knowledge or attitudes did not increase significantly over controls. PMID- 22489591 TI - Psychosis induced by the interaction between disulfiram and methylphenidate may be dose dependent. AB - There are few studies describing psychiatric symptoms occurring when methylphenidate and disulfiram are used together. The authors report a case of disulfiram and methylphenidate interaction in which psychotic symptoms could be dose dependent. The patient, diagnosed of alcohol and cocaine dependence and attention deficit hyperactivity disorder (ADHD), started treatment with methylphenidate increasing doses and disulfiram 250 mg/day over 4 weeks. During the first 2 weeks at doses of 36 mg/day of methylphenidate and maintaining disulfiram, side effects were not observed. However, by increasing to 54 mg/day, psychotic symptoms were detected. The authors reported that the effects are dose dependent. This is the first report about dose-dependent side effects in substance use disorder with ADHD. PMID- 22489592 TI - Naphthalene addiction. AB - Inhalant abuse such as kerosene, petrol, gasoline, and typewriter correction fluid has been reported from India. Naphthalene or mothballs, a commonly used substance in households and freely available in the market is an uncommon form of inhalant abuse which may lead to severe medical complications. We report an adolescent with addiction to naphthalene balls who developed severe anemia. PMID- 22489593 TI - Spice: a new "legal" herbal mixture abused by young active duty military personnel. AB - Spice is an herbal mixture smoked for euphoria and mixed with synthetic cannabinoids that are undetected on urine drug screens. Spice use has increased in the military because it is considered legal and is not detected on urine drug screen. The authors describe 3 cases of Spice use in military members. Case 1: 19 year-old male presented with paranoia, agitation, and visual hallucinations after smoking the "Space" brand of Spice. Urine thin-layer chromatography (TLC) and gas chromatography-mass spectrometry (GC-MS) were negative. Case 2: 19-year-old female presented with sedation, amnesia, and agitation. She smoked the "Space" brand. She was alert within 3 hours of arrival. Urine GC-MS detected levorphanol. Case 3: 23-year-old male presented with delusions and paranoia. He complained of "monsters on his back." His symptoms improved in the emergency department (ED). His urine TLC and GC-MS were negative. All cases were admitted and evaluated by a toxicologist; all 3 had their history corroborated by family or friends, or with drug paraphernalia. Spice is a new herbal mixture that is increasingly used in the military. Expected effects are similar to cannabis, but may include more paranoia and hallucinations, and may differ for each brand. PMID- 22489594 TI - Megadose bromazepam and zolpidem dependence: two case reports of treatment with flumazenil and valproate. PMID- 22489596 TI - Effect of inert atmosphere on the postharvest browning of manzanilla olives and optimization by response surface methodology of the aqueous treatments. AB - Subjecting bruised olives to a nitrogen atmosphere during the postharvest period prevented the oxidation of phenols and subsequent browning. However, a rapid phenol oxidation and browning occurred when fruits were re-exposed to air. Based on models deduced from the effects of aqueous antioxidant solutions on changes in different color parameters in the fermented product, the treatments to prevent browning were optimized. The recommended procedure consists of placing the harvested olives in a cold (4 to 8 degrees C) solution of 3% sodium metabisulfite with the pH adjusted to 3.0 (by adding food grade HCl) and applying the lye treatment before 8 h from picking. The use of these conditions led to mechanically harvested Spanish style olives with hardly any visible browning. PMID- 22489597 TI - Effectiveness of acute geriatric units in the real world: the case of short-term mortality among seniors hospitalized for pneumonia. AB - AIM: We sought to compare the effectiveness of acute geriatric units with usual medical care in reducing short-term mortality among seniors hospitalized for pneumonia in the real world. METHODS: In a retrospective cohort study, we merged chart and administrative data of seniors aged 65 years and older admitted to acute geriatric units and other medical units for pneumonia at three hospitals over 1 year. The outcome was 30-day mortality. Hierarchical logistic regression modeling was carried out to estimate the treatment effect of acute geriatric units for all seniors, those aged 80 years and older, and those with premorbid ambulation impairment, after adjusting for demographic and clinical characteristics, and accounting for clustering around hospitals. RESULTS: Among 2721 seniors, 30-day mortality was 25.5%. For those admitted to acute geriatric and other medical units, this was 24.2% and 25.8%, respectively. Using hierarchical logistic regression modeling, treatment in acute geriatric units was not associated with significant mortality reduction among all seniors (OR 0.72, 95% CI 0.52-1.00). However, significant mortality reduction was observed in the subgroups of those aged 80 years and older (OR 0.73, 95% CI 0.54-0.99), and with premorbid ambulation impairment (OR 0.65, 95% CI 0.46-0.93). CONCLUSIONS: Acute geriatric units reduced short-term mortality among seniors hospitalized for pneumonia who were aged 80 years and older or had premorbid ambulation impairment. Further research is required to determine if this beneficial effect extends to seniors hospitalized for other acute medical disorders. PMID- 22489598 TI - Prospective prediction of college adjustment using self- and informant-rated personality traits. AB - Studies that relate normal personality traits to students' adjustment to college have relied heavily on self-rating methods, concurrent designs, and academic performance indicators as criteria. We conducted a prospective study of high school seniors with a follow-up assessment made near the end of their freshman year of college. Self-ratings of personality traits and college adjustment were obtained from 90 students using the revised NEO personality inventory (NEO PI-R; Costa & McCrae, 1992) and the student adaptation to college questionnaire (SACQ; Baker & Siryk, 1989 ). Ratings of personality were also obtained from parents (n = 66) and same-sex peers from the college setting (n = 78) using the NEO five factor inventory (NEO-FFI; Costa & McCrae, 1992 ). SACQ academic adjustment was correlated with conscientiousness ratings by all three sources and with openness ratings by parents and peers. SACQ Social Adjustment was correlated with self ratings of neuroticism and peer ratings of extraversion. SACQ personal-emotional adjustment was correlated with self-ratings and parent ratings of neuroticism. Ratings by parents and peers showed significant incremental validity over self ratings in the prediction of certain trait-adjustment relationships. PMID- 22489599 TI - Reduced artery diameters in Klinefelter syndrome. AB - Various epidemiological studies in relatively large cohorts of patients with Klinefelter syndrome (KS) described the increased morbidity and mortality in these subjects. Our aim was to study the structure and function of arteries in different districts to investigate in these subjects possible alterations. A total of 92 patients having non-mosaic KS, diagnosed in Centre for Human Reproduction Pathology at the University of Padova, and 50 age-matched healthy male controls were studied. Klinefelter syndrome subjects and controls evaluation included complete medical history, physical examination, measurement of concentrations of the reproductive hormones, lipidic and glycidic metabolism, AR function and sensitivity, ultrasound examinations (diameters, carotid intima media thickness and brachial flow-mediated dilation) of brachial, common carotid and common femoral artery and abdominal aorta. Klinefelter syndrome patients showed significantly reduced artery diameters in all districts evaluated. On the contrary no statistically significant difference was found in cIMT and brachial FMD values between KS patients and controls. Furthermore, we found no statistically significant correlation of artery diameters with reproductive hormones, metabolic parameters, anthropometric measures and weighted CAG repeats. To our knowledge, this is the first study finding a reduced artery diameter in several districts in KS patients compared with that of normal male subjects and overlapping to that of female subjects. We have not an explanation for this phenomenon, even if a possible involvement of genes controlling the development of vascular system might be hypothesized, and further research is required to verify this hypothesis. PMID- 22489601 TI - Effect of microstructure of nitrogen-doped graphene on oxygen reduction activity in fuel cells. AB - The development of fuel cells as clean-energy technologies is largely limited by the prohibitive cost of the noble-metal catalysts needed for catalyzing the oxygen reduction reaction (ORR) in fuel cells. A fundamental understanding of catalyst design principle that links material structures to the catalytic activity can accelerate the search for highly active and abundant nonmetal catalysts to replace platinum. Here, we present a first-principles study of ORR on nitrogen-doped graphene in acidic environment. We demonstrate that the ORR activity primarily correlates to charge and spin densities of the graphene. The nitrogen doping and defects introduce high positive spin and/or charge densities that facilitate the ORR on graphene surface. The identified active sites are closely related to doping cluster size and dopant-defect interactions. Generally speaking, a large doping cluster size (number of N atoms >2) reduces the number of catalytic active sites per N atom. In combination with N clustering, Stone Wales defects can strongly promote ORR. For four-electron transfer, the effective reversible potential ranges from 1.04 to 1.15 V/SHE, depending on the defects and cluster size. The catalytic properties of graphene could be optimized by introducing small N clusters in combination with material defects. PMID- 22489600 TI - Effects of membrane lipids on the activity and processivity of purified gamma secretase. AB - The 19-transmembrane multisubunit gamma-secretase complex generates the amyloid beta-peptide (Abeta) of Alzheimer's disease (AD) by intramembrane proteolysis of the beta-amyloid precursor protein (APP). Despite substantial advances in elucidating how this protein complex functions, the effect of the local membrane lipid microenvironment on gamma-secretase cleavage of substrates is still poorly understood. Using detergent-free proteoliposomes to reconstitute purified human gamma-secretase, we examined the effects of fatty acyl (FA) chain length, saturation and double-bond isomerization, and membrane lipid polar headgroups on gamma-secretase function. We analyzed gamma-secretase activity and processivity [i.e., sequential cleavages in the APP transmembrane domain that convert longer Abeta species (e.g., Abeta(46)) into shorter ones (e.g., Abeta(40))] by quantifying the APP intracellular domain (AICD) and various Abeta peptides, including via a bicine/urea gel system that detects multiple Abeta lengths. These assays revealed several trends. (1) Switching from a cis to a trans isomer of a monounsaturated FA chain in phosphatidylcholine (PC) increased gamma-activity, did not affect Abeta(42):Abeta(40) ratios, but decreased the ratio of long (>=42) versus short (<=41) Abeta peptides. (2) Increasing the FA carbon chain length (14, 16, 18, and 20) increased gamma-activity, reduced longer Abeta species, and reduced the Abeta(42):Abeta(40) ratio. (3) Shifting the position of the double bond in 18:1(Delta9-cis) PC to the Delta6 position substantially reduced activity. (4) Gangliosides increased gamma-activity but decreased processivity, thus elevating the Abeta(42):Abeta(40) ratio. (5) Phosphatidylserine decreased gamma-activity but increased processivity. (6) Phosphatidylinositol strongly inhibited gamma-activity. Overall, our results show that subtle changes in membrane lipid composition can greatly influence gamma-secretase activity and processivity, suggesting that relatively small changes in lipid membrane composition may affect the risk of AD at least as much as presenilin or APP mutations do. PMID- 22489602 TI - Congenital cytomegalovirus infection following antenatal negative diagnostic amniotic fluid analysis - a single center experience. AB - OBJECTIVE: To determine the perinatal outcome of confirmed congenital cytomegalovirus (CMV) infection despite a negative prenatal amniotic-fluid analysis. METHODS: A retrospective cohort study of all neonates diagnosed with congenital CMV infection from January 2006 to December 2011 despite negative results on polymerase chain reaction and shell's vial assays of amniotic fluid. Data were collected on all neonates by physical examination, blood work-up (complete blood count, bilirubin, liver enzymes), fundoscopy, brainstem evoked response (BSER), and brain ultrasound, at birth and during follow-up in the neonatal period. RESULTS: The study group included 10 patients with primary congenital CMV infection during pregnancy. Follow-up time ranged from 1 to 62 months (median, 17 months). Four patients had consistently normal findings throughout follow-up, and three developed mild hepatosplenomegaly (1-32 months). In the remaining four offspring, brain ultrasound preformed after birth revealed lenticular striated vasculopathy (LSV) and in three of them the BSER test showed decreased hearing ability. Treatment with ganciclovir/valganciclovir was administered at age of 2 weeks, 2, 18, and 32 months. The BSER normalized after 9 and 12 months of treatment in two patients for whom follow-up data were available. CONCLUSION: Negative findings on amniotic-fluid tests for CMV do not rule out neonatal infection with clinical morbidity. PMID- 22489603 TI - Positive affect predicts avoidance goals in social interaction anxiety: testing a hierarchical model of social goals. AB - Models of self-regulation suggest that social goals may contribute to interpersonal and affective difficulties, yet little research has addressed this issue in the context of social anxiety. The present studies evaluated a hierarchical model of approach and avoidance in the context of social interaction anxiety, with affect as a mediating factor in the relationship between motivational tendencies and social goals. This model was refined in one undergraduate sample (N = 186) and cross-validated in a second sample (N = 195). The findings support hierarchical relationships between motivational tendencies, social interaction anxiety, affect, and social goals, with higher positive affect predicting fewer avoidance goals in both samples. Implications for the treatment of social interaction anxiety are discussed. PMID- 22489604 TI - pH-responsive layer-by-layer nanoshells for direct regulation of cell activity. AB - Saccharomyces cerevisiae yeast cells encapsulated with pH-responsive synthetic nanoshells from lightly cross-linked polymethacrylic acid showed a high viability rate of around 90%, an indication of high biocompatibility of synthetic pH responsive shells. We demonstrated that increasing pH above the isoelectric point of the polymer shell leads to a delay in growth rate; however, it does not affect the expression of enhanced green fluorescent protein. We suggest that progressive ionization and charge accumulation within the synthetic shells evoke a structural change in the outer shells which affect the membrane transport. This change facilitates the ability to manipulate growth kinetics and functionality of the cells with the surrounding environment. We observed that hollow layer-by layer nanoshells showed a remarkable degree of reversible swelling/deswelling over a narrow pH range (pH 5.0-6.0), but their assembly directly on the cell surface resulted in the suppression of large dimensional changes. We suggest that the variation in surface charges caused by deprotonation/protonation of carboxylic groups in the nanoshells controlled cell growth and cell function, which can be utilized for external chemical control of cell-based biosensors. PMID- 22489606 TI - Seasonal and lunar variation in the emergence time of a population of Uca lactea annulipes (Milne-Edwards, 1837) at a shore in Kuwait. AB - This study monitored the endogenous emergence time of the fiddler crab Uca lactea annulipes (Milne-Edwards, 1837) in the field, for the first time, at an intertidal shore in Kuwait, from 1997 to 2001. The results revealed a significant cyclic change in the median emergence time as the season progressed from winter, through spring and summer, to autumn (.44, 1.29, 3.12, and 1.1 h prior to the dead-low tide, respectively). The data also revealed a significant shift in the median emergence time according to moon phase (2.27 h at new moon versus 2.56 h at full moon prior to the dead-low tide). PMID- 22489605 TI - Site-selective glycosylation of hemoglobin with variable molecular weight oligosaccharides: potential alternative to PEGylation. AB - Poly(ethylene glycol) (PEG) conjugation (i.e., PEGylation) is a commonly used strategy to increase the circulatory half-life of therapeutic proteins and colloids; however, few viable alternatives exist to replicate its functions. Herein, we report a method for the rapid site-selective glycosylation of proteins with variously sized carbohydrates, up to a molecular weight (MW) of 10,000, thus serving as a potential alternative for PEGylation. More importantly, the method developed has two unique features. First, traditional protecting group strategies that typically accompany the modification of the carbohydrate fragments are circumvented, allowing for the facile site-selective glycosylation of a desired protein with variously sized glycans. Second, the methodology employed is not limited by oligosaccharide size; consequently, glycans of MW similar to that of PEG, used in the PEGylation of therapeutic proteins, can be employed. To demonstrate the usefulness of this technology, hemoglobin (Hb) was site selectively glycosylated with a series of carbohydrates of increasing MW (from 504 to ~10,000). Hb was selected on the basis of the vast wealth of biochemical and biophysical knowledge present in the literature and because of its use as a precursor in the synthesis/formulation of artificial red blood cell substitutes. Following the successful site-selective glycosylation of Hb, the impact of increasing the glycan MW on Hb's biophysical properties was investigated in vitro. PMID- 22489607 TI - The endogenous melatonin (MT) signal facilitates reentrainment of the circadian system to light-induced phase advances by acting upon MT2 receptors. AB - The indolamine melatonin is an important rhythmic endocrine signal in the circadian system. Exogenous melatonin can entrain circadian rhythms in physiology and behavior, but the role of endogenous melatonin and the two membrane-bound melatonin receptor types, MT1 and MT2, in reentrainment of daily rhythms to light induced phase shifts is not understood. The present study analyzed locomotor activity rhythms and clock protein levels in the suprachiasmatic nuclei (SCN) of melatonin-deficient (C57BL/6J) and melatonin-proficient (C3H/HeN) mice, as well as in melatonin-proficient (C3H/HeN) mice with targeted deletion of the MT1, MT2, or both receptors, to determine effects associated with phase delays or phase advances of the light/dark (LD) cycle. In all mouse strains and genotypes, reentrainment of locomotor activity rhythms was significantly faster after a 6-h phase delay than a 6-h phase advance. Reentrainment after the phase advance was, however, significantly slower than in melatonin-deficient animals and in mice lacking functional MT2 receptors than melatonin-proficient animals with intact MT2 receptors. To investigate whether these behavioral differences coincide with differences in reentrainment of clock protein levels in the SCN, mPER1, mCRY1 immunoreactions were compared between control mice kept under the original LD cycle and killed at zeitgeber time 04 (ZT04) or at ZT10, respectively, and experimental mice subjected to a 6-h phase advance of the LD cycle and sacrificed at ZT10 on the third day after phase advance. This ZT corresponds to ZT04 of the original LD cycle. Under the original LD cycle, the numbers of mPER1- and mCRY1 immunoreactive cell nuclei were low at ZT04 and high at ZT10 in the SCN of all mouse strains and genotypes investigated. Notably, mouse strains with intact melatonin signaling and functional MT2 receptors showed a significant increase in the number of mPER1- and mCRY1-immunoreactive cell nuclei at the new ZT10 as compared to the former ZT04. These data suggest the endogenous melatonin signal facilitates reentrainment of the circadian system to phase advances on the level of the SCN molecular clockwork by acting upon MT2 receptors. PMID- 22489608 TI - Sex differences in estimating multiple intelligences in self and others: a replication in Russia. AB - This was a crosscultural study that focused on sex differences in self- and other estimates of multiple intelligences (including 10 that were specified by Gardner, 1999 and three by Sternberg, 1988) as well as in an overall general intelligence estimate. It was one of a programmatic series of studies done in over 30 countries that has demonstrated the female "humility" and male "hubris" effect in self-estimated and other-estimated intelligence. Two hundred and thirty Russian university students estimated their own and their parents' overall intelligence and "multiple intelligences." Results revealed no sex difference in estimates of overall intelligence for both self and parents, but men rated themselves higher on spatial intelligence. This contradicted many previous findings in the area which have shown that men rate their own overall intelligence and mathematical intelligence significantly higher than do women. Regressions indicated that estimates of verbal, logical, and spatial intelligences were the best predictors of estimates of overall intelligence, which is a consistent finding over many studies. Regressions also showed that participants' openness to experience and self-respect were good predictors of intelligence estimates. A comparison with a British sample showed that Russians gave higher mother estimates, and were less likely to believe that IQ tests measure intelligence. Results were discussed in relation to the influence of gender role stereotypes on lay conception of intelligence across cultures. PMID- 22489609 TI - Dignity therapy for older people in care homes: a qualitative study of the views of residents and recipients of 'generativity' documents. AB - AIM: To report the findings of a study exploring the views and experiences of care home resident's family on Dignity Therapy. BACKGROUND: As the proportion of older people dying in care homes increases, it is important to enhance their dignity, reduce distress at the end-of-life, and provide bereavement support to their families. Pilot studies show that hospice patients and care home residents feel Dignity Therapy had or would help their families; however, there are no qualitative studies of their views. DESIGN: Qualitative exploration. METHODS: Qualitative interviews were conducted between January 2009-March 2010 with 14 family members of care home residents who had received Dignity Therapy. The Framework approach to qualitative analysis was used. FINDINGS: Four categories are reported: views on the document: impact on residents; impact on family; and potential impact on care homes. While contact with the therapist provided much needed company for residents, Dignity Therapy helped residents reappraise aspects of their lives positively, while enjoying the opportunity to reminisce. Concerns focused on resident's anxiety over document content. Memory problems and perceived lack of distress in some residents were viewed as factors affecting delivery and impact of Dignity Therapy. Family discovered new information and were prompted to discuss the content with them. For bereaved family members, documents provided comfort during their grief. If made available to carers, documents could enhance care delivery in homes. CONCLUSION: Family members felt Dignity Therapy had helped them and the residents. Findings suggest that Dignity Therapy may be useful for enhancing the end-of-life experience for residents and their families. PMID- 22489611 TI - The maximum height of grasses is determined by roots. AB - Grasses such as bamboos can produce upright stems more than 30 m tall, yet the processes that constrain plant height in this important group have never been investigated. Air embolisms form commonly in the water transport system of grasses and we hypothesised that root pressure-dependent refilling these embolisms should limit the maximum height of grass species to the magnitude of their root pressure. Confirming this hypothesis, we show that in 59 species of bamboo grown in two common gardens, the maximum heights of culms of 67 clones are closely predicted by the maximum measured root pressure overnight. Furthermore, we demonstrate that water transport in these bamboo species is dependent on root pressure to repair hydraulic dysfunction sustained during normal diurnal gas exchange. Our results established the critical importance of root pressure in the tallest grass species and provide a new basis for understanding the limits for plant growth. PMID- 22489610 TI - Pharmacokinetic, pharmacodynamic and pharmacogenetic profile of the oral antiplatelet agent ticagrelor. AB - Acute coronary syndromes (ACS) remain life-threatening disorders associated with high morbidity and mortality, despite advances in treatment over the last decade. Adenosine diphosphate-induced platelet activation via P2Y(12) receptors plays a pivotal role in the pathophysiology of ACS. The current standard of treatment involves dual antiplatelet therapy with aspirin (acetylsalicylic acid) and the thienopyridine clopidogrel. Numerous studies and wide use in clinical practice have established the value of this approach in the treatment of ACS. However, clopidogrel treatment has a number of limitations, including a delayed onset of action due to the need for metabolic activation, variable and reduced antiplatelet effects in patients with certain genotypes, and prolonged recovery of platelet function due to irreversible P2Y(12) receptor binding. Prasugrel, a new thienopyridine, has demonstrated more consistent inhibition of platelet aggregation (IPA) than clopidogrel, although this thienopyridine also requires metabolic activation and treatment is associated with a significantly increased risk of life-threatening and fatal bleeding. The recently approved oral antiplatelet agent ticagrelor has the potential to overcome some of the limitations of current therapy due to its unique pharmacokinetic and pharmacodynamic profiles. It is a member of a new chemical class, the cyclopentyltriazolopyrimidines, and is a potent P2Y(12) receptor antagonist. Ticagrelor is rapidly absorbed, with a median time to maximum concentration of 1.3-2.0 hours. Ticagrelor does not require metabolic activation to an active form and binds rapidly and reversibly to the P2Y(12) receptor. As well as exerting effects via platelet P2Y(12) receptors, ticagrelor may confer additional benefits via inhibition of non-platelet P2Y(12) receptors. The pharmacokinetic profile of ticagrelor is not significantly affected by age, gender or administration with food, nor by prior treatment with, or responsiveness to, clopidogrel. Ticagrelor is primarily metabolized via the cytochrome P450 (CYP) 3A4 enzyme, rapidly produces plasma concentration-dependent IPA that is greater and more consistent than that observed with clopidogrel, and can also enhance platelet inhibition and overcome non-responsiveness in patients previously treated with clopidogrel. Importantly, the pharmacodynamic characteristics of ticagrelor are not influenced by CYP2C19 and ABCB1 genotypes. This article summarizes our current knowledge regarding the pharmacokinetic, pharmacodynamic and pharmacogenetic profile of ticagrelor. PMID- 22489612 TI - Negotiating the coresearcher mandate - service users' experiences of doing collaborative research on mental health. AB - PURPOSE: Traditionally, the voices of service users have been silent in research into mental health issues. A Norwegian research network, however, recognizes the importance of involving service users as coresearchers and initiated a training program in research methodology and design intended to empower them as active participants in research projects. In this article, we explore how these coresearchers with a mental health service user background experience their participation in projects as well as in attending the training: What is it like being a service user coresearcher in collaborative studies on issues in mental health? How do coresearchers negotiate their roles and mandate? METHOD: We used focus groups as our data collection method, transcribed the group discussions verbatim, and analyzed the transcriptions using qualitative methodology. We then took the preliminary analyses back to the participants for discussion, auditing, and reanalysis. RESULTS: We identified themes that represent important social processes around which the participants developed a consensual understanding: self-definition, constructive differentiation and negotiations. CONCLUSION: Our findings generate hypotheses on how participatory research into mental health issues can be fruitfully organized, in a way that empowers service users to active and constructive participation. PMID- 22489613 TI - Pharmacokinetics of stanozolol in Thoroughbred horses following intramuscular administration. PMID- 22489614 TI - Validating an inventory for the assessment of egoistic bias and moralistic bias as two separable components of social desirability. AB - The psychometric properties of the German adaptation of the balanced inventory of desirable responding were investigated. This 2-factor inventory taps the egoistic bias and the moralistic bias as the 2 distinguishable components of social desirability. In 2 validation studies, both subscales showed satisfactory internal consistency and temporal stability. To examine convergent and discriminant validity, the scales were correlated with those of a measure of unrealistic optimism, various measures of self-enhancement, 1-dimensional scales of social desirability, and the tendency to overclaim in a test of general knowledge. PMID- 22489615 TI - A risk assessment of campylobacteriosis and salmonellosis linked to chicken meals prepared in households in Dakar, Senegal. AB - We used a quantitative microbiological risk assessment model to describe the risk of Campylobacter and Salmonella infection linked to chicken meals prepared in households in Dakar, Senegal. The model uses data collected specifically for this study, such as the prevalence and level of bacteria on the neck skin of chickens bought in Dakar markets, time-temperature profiles recorded from purchase to consumption, an observational survey of meal preparation in private kitchens, and detection and enumeration of pathogens on kitchenware and cooks' hands. Thorough heating kills all bacteria present on chicken during cooking, but cross contamination of cooked chicken or ready-to-eat food prepared for the meal via kitchenware and cooks' hands leads to a high expected frequency of pathogen ingestion. Additionally, significant growth of Salmonella is predicted during food storage at ambient temperature before and after meal preparation. These high exposures lead to a high estimated risk of campylobacteriosis and/or salmonellosis in Dakar households. The public health consequences could be amplified by the high level of antimicrobial resistance of Salmonella and Campylobacter observed in this setting. A significant decrease in the number of ingested bacteria and in the risk could be achieved through a reduction of the prevalence of chicken contamination at slaughter, and by the use of simple hygienic measures in the kitchen. There is an urgent need to reinforce the hygiene education of food handlers in Senegal. PMID- 22489616 TI - Zebrafish (Danio rerio) larvae as a system to test the efficacy of polysaccharides as immunostimulants. AB - The present study was carried out to examine the use of zebrafish (Danio rerio) as a preliminary screening model for testing the effect of potential immunostimulant substances on the innate immune system. beta-Glucan, a polysaccharide used widely as an immunostimulant, was used as a representative molecule and tested on zebrafish embryos and larvae. The efficacy of the molecule was evaluated by determining the differential expression of some selected genes related to the immune system by RT-qPCR. Larvae from 72 hours post fertilization were found at the optimal developmental stage for assessing the expression of the selected genes. To verify if the beta-glucan entered the larvae and therefore was responsible for the effects produced, the molecule was labeled fluorescently to check its localization by using microscopy. For estimating the effects of beta glucan on gene expression, zebrafish embryos and larvae were immersed in three different concentrations of beta-glucan (50, 100, and 150 MUg/mL) using five different exposure times. A stronger gene induction was observed when longer times of exposure and older larvae were used. The most evident effects of beta glucan were the overexpression of the genes TNFalpha, MPO, TRF, and LYZ. Moreover, slight changes in MPO expression were detected using a transgenic line of zebrafish (MPO::GFP), and a temporal increase in resistance against Vibrio anguillarum was found after beta-glucan immersion. The assay used in this study permits the testing potential of immunostimulants in a simple and cost-effective way. PMID- 22489617 TI - Food and conspecific chemical cues modify visual behavior of zebrafish, Danio rerio. AB - Animals use the different qualities of olfactory and visual sensory information to make decisions. Ethological and electrophysiological evidence suggests that there is cross-modal priming between these sensory systems in fish. We present the first experimental study showing that ecologically relevant chemical mixtures alter visual behavior, using adult male and female zebrafish, Danio rerio. Neutral-density filters were used to attenuate the light reaching the tank to an initial light intensity of 2.3*10(16) photons/s/m2. Fish were exposed to food cue and to alarm cue. The light intensity was then increased by the removal of one layer of filter (nominal absorbance 0.3) every minute until, after 10 minutes, the light level was 15.5*10(16) photons/s/m2. Adult male and female zebrafish responded to a moving visual stimulus at lower light levels if they had been first exposed to food cue, or to conspecific alarm cue. These results suggest the need for more integrative studies of sensory biology. PMID- 22489618 TI - The somatic and autonomic innervation of the clitoris; preliminary evidence of sexual dysfunction after minimally invasive slings. AB - INTRODUCTION: Vaginal sling procedures may have a negative effect on sexual function due to damage to vascular and/or neural genital structures. Even though autonomic innervation of the clitoris plays an important role in female sexual function, most studies on the neuroanatomy of the clitoris focus on the sensory function of the dorsal nerve of the clitoris (DNC). The autonomic and somatic pathways in relationship to sling surgery have up to the present not been described in detail. AIM: The aim of this study is to reinvestigate and describe the neuroanatomy of the clitoris, both somatic and autonomic, in relation to vaginal sling procedures for stress urinary incontinence. METHOD: Serially sectioned and histochemically stained pelves from 11 female fetuses (10-27 weeks of gestation) were studied, and three-dimensional reconstructions of the neuroanatomy of the clitoris were prepared. Fourteen adult female hemipelves were dissected, after a tension-free vaginal tape (TVT) (7) or tension-free vaginal tape-obturator (TVT-O) (7) procedure had been performed. MAIN OUTCOME MEASURES: Three-dimensional (3-D) reconstruction and measured distance between the clitoral nerve systems and TVT/TVT-O. RESULTS: The DNC originates from the pudendal nerve in the Alcock's canal and ascends to the clitoral bodies. In the dissected adult pelves, the distance of the TVT-O to the DNC had a mean of 9 mm. The cavernous nerves originate from the vaginal nervous plexus and travel the 5 and 7 o'clock positions along the urethra. There, the autonomic nerves were found to be pierced by the TVT needle. At the hilum of the clitoral bodies, the branches of the cavernous nerves medially pass/cross the DNC and travel further alongside it. Just before hooking over the glans of the clitoris, they merge with DNC. CONCLUSION: The DNC is located inferior of the pubic ramus and was not disturbed during the placement of the TVT-O. However, the autonomic innervation of the vaginal wall was disrupted by the TVT procedure, which could lead to altered lubrication-swelling response. PMID- 22489619 TI - The empirical correlation between hydrogen bonding strength and excited-state intramolecular proton transfer in 2-pyridyl pyrazoles. AB - A series of 2-pyridyl pyrazoles 1a and 1-5 with various functional groups attached to either pyrazole or pyridyl moieties have been strategically designed and synthesized in an aim to probe the hydrogen bonding strength in the ground state versus dynamics of excited-state intramolecular proton transfer (ESIPT) reaction. The title compounds all possess a five-membered-ring (pyrazole)N H...N(pyridine) intramolecular hydrogen bond, in which both the N-H bond and the electron density distribution of the pyridyl nitrogen lone-pair electrons are rather directional, so that the hydrogen bonding strength is relatively weak, which is sensitive to the perturbation of subtle chemical substitution and consequently reflected from the associated ESIPT dynamics. Various approaches such as (1)H NMR (N-H proton) to probe the hydrogen bonding strength and absorption titration to assess the acidity-basicity property were made for all the title analogues. The results, together with supplementary support provided by a computational approach, affirm that the increase of acidity (basicity) on the hydrogen bonding donor (acceptor) sites leads to an increase of hydrogen-bonding strength among the title 2-pyridyl pyrazoles. Luminescence results and the associated ESIPT dynamics further reveal an empirical correlation in that the increase of the hydrogen bonding strength leads to an increase of the rate of ESIPT for the title 2-pyridyl pyrazoles, demonstrating an interesting relationship among N-H acidity, hydrogen bonding strength, and the associated ESIPT rate. PMID- 22489620 TI - New highly stable dimeric 3-deoxyanthocyanidin pigments from sorghum bicolor leaf sheath. AB - The growing interest in natural alternatives to synthetic petroleum-based dyes for food applications necessitates looking at nontraditional sources of natural colors. Certain sorghum varieties accumulate large amounts of poorly characterized pigments in their nongrain tissue. We used High Performance Liquid Chromatography-Tandem Mass Spectroscopy to characterize sorghum leaf sheath pigments and measured the stability of isolated pigments in the presence of bisulfite at pH 1.0 to 7.0 over a 4-wk period. Two new 3-deoxyanthocyanidin compounds were identified: apigeninidin-flavene dimer and apigenin-7-O methylflavene dimer. The dimeric molecules had near identical UV-Vis absorbance profiles at pH 1.0 to 7.0, with no obvious sign of chalcone or quinoidal base formation even at the neutral pH, indicating unusually strong resistance to hydrophilic attack. The dimeric 3-deoxyanthocyanidins were also highly resistant to nucleophilic attack by SO(2); for example, apigeninidin-flavene dimer lost less than 20% of absorbance, compared to apigeninidin monomer, which lost more than 80% of absorbance at lambda(max) within 1 h in the presence of SO(2). The increased molecular complexity of the dimeric 3-deoxyanthocyanidins compared to their monomers may be responsible for their unusual stability in the presence of bisulfite; these compounds present new interesting opportunities for food applications. PMID- 22489621 TI - Secretin family (Class B) G protein-coupled receptors - from molecular to clinical perspectives. AB - Family B G protein-coupled receptors represent an important but under-researched group of receptors. This edition of the British Journal of Pharmacology considers the roles and pharmacology of a number of these receptors. Whilst common themes emerge, it is clear that more work is needed to understand the details of each receptor in order to properly exploit them therapeutically. PMID- 22489622 TI - The effect of adjuvant drugs on the quality of tracheal intubation without muscle relaxants in children: a systematic review of randomized trials. AB - Intubation without prior administration of muscle relaxants is a common practice in children. However, succinylcholine may be considered as the golden standard for optimizing intubating conditions. We conducted a systematic review of the literature to identify drug combinations that included induction of anesthesia with sevoflurane or propofol. Our aim was to select drug combinations that yield excellent intubating conditions >=80%; we identified six combinations in children aged 1-9 years. Sevoflurane with remifentanil (1 or 2 MUg.kg(-1) ), lidocaine (2 mg.kg(-1) ), or propofol (2 mg.kg(-1) ) as the adjuvant shared the following characteristics: premedication with midazolam and/or ketamine, long sevoflurane exposure time, high inspired and endtidal sevoflurane concentration, and assisted ventilation. One combination using sevoflurane with propofol (3 mg.kg(-1) ) without premedication, with shorter sevoflurane exposure time, and spontaneous breathing indicated that propofol may be the adjuvant of choice for a rapid sevoflurane induction. The only adjuvant identified in propofol induction was remifentanil (4 MUg.kg(-1) ). No serious adverse events were reported with these combinations. PMID- 22489624 TI - Maternal serum placental growth hormone at 11-13 weeks' gestation in pregnancies delivering small for gestational age neonates. AB - OBJECTIVE: To investigate whether the maternal serum concentration of human placental growth hormone (PGH) at 11-13 weeks' gestation is altered in pregnancies that deliver small for gestational age (SGA) neonates. METHODS: Maternal serum concentration of PGH was measured in 60 cases that subsequently delivered SGA neonates in the absence of preeclampsia and compared to 120 non-SGA controls. RESULTS: In the SGA group, compared to the non-SGA group, there was no significant difference in the median PGH MoM (0.95 MoM, IQR 0.60-1.30 vs. 1.00 MoM, IQR 0.70-1.30, p = 0.97). There was no significant association between PGH MoM and birth weight percentile in either the SGA (p = 0.72) or in the non-SGA group (p = 0.63). CONCLUSION: Maternal serum PGH at 11-13 weeks' gestation is unlikely to be a useful biochemical marker for early prediction of SGA. PMID- 22489623 TI - Effect of hypertrophic cardiomyopathy-linked troponin C mutations on the response of reconstituted thin filaments to calcium upon troponin I phosphorylation. AB - The objective of this work was to investigate the effect of hypertrophic cardiomyopathy-linked A8V and E134D mutations in cardiac troponin C (cTnC) on the response of reconstituted thin filaments to calcium upon phosphorylation of cardiac troponin I (cTnI) by protein kinase A. The phosphorylation of cTnI at protein kinase A sites was mimicked by the S22D/S23D double mutation in cTnI. Our results demonstrate that the A8V and E134D mutations had no effect on the extent of calcium desensitization of reconstituted thin filaments induced by cTnI pseudophosphorylation. However, the A8V mutation enhanced the effect of cTnI pseudophosphorylation on the rate of dissociation of calcium from reconstituted thin filaments and on the calcium dependence of actomyosin ATPase. Consequently, while the A8V mutation still led to a slower rate of dissociation of calcium from reconstituted thin filaments upon pseudophosphorylation of cTnI, the ability of the A8V mutation to decrease the rate of calcium dissociation was weakened. In addition, the ability of the A8V mutation to sensitize actomyosin ATPase to calcium was weakened after cTnI was replaced by the phosphorylation mimetic of cTnI. Consistent with the hypothesis that the E134D mutation is benign, it exerted a minor to no effect on the rate of dissociation of calcium from reconstituted thin filaments or on the calcium sensitivity of actomyosin ATPase, regardless of the cTnI phosphorylation status. In conclusion, our study enhances our understanding of how cardiomyopathy-linked cTnC mutations affect the response of reconstituted thin filaments to calcium upon cTnI phosphorylation. PMID- 22489625 TI - Biased attentional processing of positive stimuli in social anxiety disorder: an eye movement study. AB - Despite the established relationship between social anxiety and attentional bias towards threat, a growing base of evidence suggests that social anxiety is additionally maintained by a deficit in the attentional processing of positive information. However, it remains unclear which component of attention is implicated in this deficit. Using eye movement-based measures and a novel attentional cuing methodology, the present study sought to investigate the presence of anxiety-linked bias in attentional engagement with, attentional disengagement from, and total fixation time to, socially relevant emotional stimuli in individuals diagnosed with social anxiety disorder, relative to non socially anxious controls. Socially anxious individuals were found to exhibit faster attentional disengagement from positive stimuli, and reduced total fixation time to all emotional stimuli, relative to controls. Additionally for socially anxious individuals, lower total fixation times to positive stimuli were associated with higher levels of state anxiety. No differential pattern of engagement was evident between groups. We conclude that social anxiety is maintained in part by the aberrant processing of positive social stimuli. PMID- 22489626 TI - pH-Dependent solubility and permeability criteria for provisional biopharmaceutics classification (BCS and BDDCS) in early drug discovery. AB - The Biopharmaceutics Classification System (BCS) is a scientific framework that provides a basis for predicting the oral absorption of drugs. These concepts have been extended in the Biopharmaceutics Drug Disposition Classification System (BDDCS) to explain the potential mechanism of drug clearance and understand the effects of uptake and efflux transporters on absorption, distribution, metabolism, and elimination. The objective of present work is to establish criteria for provisional biopharmaceutics classification using pH-dependent passive permeability and aqueous solubility data generated from high throughput screening methodologies in drug discovery settings. The apparent permeability across monolayers of clonal cell line of Madin-Darby canine kidney cells, selected for low endogenous efflux transporter expression, was measured for a set of 105 drugs, with known BCS and BDDCS class. The permeability at apical pH 6.5 for acidic drugs and at pH 7.4 for nonacidic drugs showed a good correlation with the fraction absorbed in human (Fa). Receiver operating characteristic (ROC) curve analysis was utilized to define the permeability class boundary. At permeability >= 5 * 10(-6) cm/s, the accuracy of predicting Fa of >= 0.90 was 87%. Also, this cutoff showed more than 80% sensitivity and specificity in predicting the literature permeability classes (BCS), and the metabolism classes (BDDCS). The equilibrium solubility of a subset of 49 drugs was measured in pH 1.2 medium, pH 6.5 phosphate buffer, and in FaSSIF medium (pH 6.5). Although dose was not considered, good concordance of the measured solubility with BCS and BDDCS solubility class was achieved, when solubility at pH 1.2 was used for acidic compounds and FaSSIF solubility was used for basic, neutral, and zwitterionic compounds. Using a cutoff of 200 MUg/mL, the data set suggested a 93% sensitivity and 86% specificity in predicting both the BCS and BDDCS solubility classes. In conclusion, this study identified pH-dependent permeability and solubility criteria that can be used to assign provisional biopharmaceutics class at early stage of the drug discovery process. Additionally, such a classification system will enable discovery scientists to assess the potential limiting factors to oral absorption, as well as help predict the drug disposition mechanisms and potential drug-drug interactions. PMID- 22489627 TI - Predictors of anxiety and resilience in adolescents undergoing cancer treatment. AB - AIMS: To report a study examining the relationships among coping, anxiety and resilience and to identify predictors of anxiety and resilience in adolescents undergoing cancer treatment. BACKGROUND: Anxiety is the main psychological disturbance in adolescents with cancer, but predictors in the context of anxiety related cancer treatments have not been investigated. DESIGN: Cross-sectional study. METHODS: Adolescents (n = 131) recruited from three medical centres between 2010-2011. The eligible participants were diagnosed with cancer, without mental disease and receiving chemotherapy. Participants were assessed with the paediatric cancer coping scale, revised children's manifest anxiety scale, second edition, and the Haase adolescent resilience in illness scale. RESULTS: Over 20% of participants scored high on worry. The most commonly used coping strategy was cognitive coping, followed by problem-oriented coping and finally by defensive coping. There was a statistically significant correlation between defensive coping and level of worry. Resilience was positively correlated with cognitive coping and problem-oriented coping. The cognitive coping and defensive coping were found to predict anxiety and resilience significantly by a step-wise multiple regression analysis and accounted for 40.9% and 46.5% of total variance, respectively. CONCLUSIONS: Cognitive coping and defensive coping are predictors for the level of anxiety and resilience in adolescents undergoing cancer treatment. Health providers should evaluate coping behaviour in patients and work towards a cognitive and problem-oriented coping style that will benefit the patient's mental health during treatment. PMID- 22489628 TI - Hemisphere specialisation and inter-hemispheric cooperation during a phonological task: effect of lexicality as assessed by the divided visual field approach. AB - In the presented experiment we explored the effect of lexicality on hemisphere specialisation and cooperation during a phonological task. The divided visual field (DVF) method with bilateral presentation (BVF) of redundant (identical) stimuli is considered an appropriate approach to assess inter-hemispheric cooperation (IHC). IHC is supposed to increase the efficiency of cognitive processes. Specifically, it has been shown that, compared to unilateral hemifield presentation, word processing is significantly more efficient if stimuli were presented under bilateral redundancy conditions. The performance enhancement during bilateral vs. unilateral presentation is called bilateral redundant gain (BRG). In the present experiment a DVF was used and participants were required to perform a rhyme detection task in two blocks, one in words and another one in pseudowords. Each item was presented in two different modes, one unilateral (right or left hemi-visual field) and another one bilateral (simultaneous redundant presentation). Unilateral trials allow one to study hemispheric specialisation, while bilateral redundant trials allow one to study inter hemispheric cooperation. We obtained left hemisphere specialisation for both types of items (word, pseudoword). Moreover, words were more efficiently processed than pseudowords. Additionally, words were processed more efficiently in BVF than in unilateral presentation, inducing BRG. No similar effect was obtained for pseudowords. These results are discussed in respect to findings reported by other studies suggesting that hemispheric specialisation depends on lexicality. Moreover, compared to lexical decision tasks used in previous studies, the phonological task used in the present study seems to modulate the inter-hemispheric cooperation less. PMID- 22489629 TI - Highly stable water splitting on oxynitride TaON photoanode system under visible light irradiation. AB - Highly stable photoelectrochemical water splitting is demonstrated for the first time on a tantalum oxynitride (TaON) photoanode under visible light irradiation. Highly dispersed CoO(x) nanoparticles on the TaON photoanode efficiently scavenge photogenerated holes and effectively suppress self-oxidative deactivation of the TaON surface, resulting in a stable photocurrent. The use of highly dispersed CoO(x) cocatalyst on TaON together with phosphate solutions significantly increased the photocurrent due to the formation of a cobalt/phosphate phase. This enabled us to stably split water into H(2) and O(2) under visible light irradiation at a relatively low applied bias (0.6 V vs Pt counter electrode). PMID- 22489630 TI - Detection of multiple genotypes of calicivirus infection in asymptomatic swine in Taiwan. AB - Noroviruses (NoVs) and sapoviruses (SaVs) of the family Caliciviridae are emerging enteric pathogens in humans and animals. Recent detection of genogroup II norovirus (GII NoV) RNA from swine raises public health concerns about zoonotic transmission of porcine NoVs to humans. However, few papers reported genotype distributions and epidemiological features in swine farms and their genetic relationship to human strains, which was the objective of our study. This study investigated the epidemiological features and genotypes of caliciviruses in swine farms using 533 pig faecal samples from six farms in central and southern Taiwan, tested for viral RNA using RT-PCR targeting the conserved polymerase gene. NoVs and SaVs were detected with a positive rate of 7.1% and 0.6%, respectively. To confirm the positive rate of NoVs, 255 pig faecal samples from two farms in central Taiwan were tested with primer pairs targeting the partial capsid gene of GII, and 32.3% of the positive rate was found. Furthermore, the results from the capsid region suggested a higher positive rate of 41.7% in winter than 26.4% in summer with statistical significance (P < 0.05). Sequence analysis showed 29 strains belonging to GII.4 (human) and nine strains belonging to GII.11 (swine) identified based on the partial polymerase gene. Additional genotypes clustered with GII.2 (human) and GII.18 (swine) were also characterized based on the partial capsid gene. SaVs detected in porcine faecal samples belonged to genogroup III (GIII), which clustered with the PEC-Cowden strain. Our study demonstrated the presence of multiple genotypes of both human and porcine NoVs infecting swine of various ages asymptomatically. Although the zoonotic potential of detected human NoVs in swine was not conclusive owing to the lack of local human faecal samples, our study revealed the importance of monitoring emerging strains in swine to mitigate the potential impact of recombinant NoVs infecting the human population. PMID- 22489631 TI - Encouraging family engagement in the rehabilitation process: a rehabilitation provider's development of support strategies for family members of people with traumatic brain injury. AB - PURPOSE: After a moderate to severe traumatic brain injury, it is widely recommended that family members be actively engaged in the client's rehabilitation journey because evidence suggests that this is associated with better outcomes. The ability of family members to fully engage in rehabilitation may be hindered by the barriers (logistical and psychological) they encounter. However, rehabilitation services can facilitate family engagement through a person-centred approach that provides support to remove barriers. Limited published guidance exists regarding practical and effective methods for delivering such support. This paper describes how one rehabilitation service has developed an eight-tiered approach. KEY MESSAGES AND IMPLICATIONS: Family support is provided by explicit structuring of services to include (i) early engagement, (ii) meeting cultural needs, (iii) keeping families together, (iv) actively listening, (v) active involvement, (vi) education, (vii) skills training, and (viii) support for community re-integration. Implementation of these support strategies are individualised based on the expressed needs of each family. Families report a high level of satisfaction with the service. CONCLUSION: A practice-based quality improvement model identified challenges, implemented changes, and observed/evaluated the results to successfully develop a multifaceted strategy for supporting families, thereby encouraging their engagement in rehabilitation. Ongoing refinements and evaluation are planned. PMID- 22489633 TI - Improved correlation energy extrapolation schemes based on local pair natural orbital methods. AB - It is well-known that the basis set limit is difficult to reach in correlated post Hartree-Fock ab initio calculations. One possible route forward is to employ basis set extrapolation schemes. In order to avoid prohibitively expensive calculations, the highest level calculation (typically based on the "gold standard" coupled cluster theory with single, double, and perturbative triple excitations, CCSD(T)) is only performed with the smallest basis set, and the remaining basis set incompleteness is estimated at a lower level of theory, typically second-order Moller-Plesset perturbation theory (MP2). In this work, we provide a comprehensive investigation of alternative schemes where the MP2 extrapolation is replaced by the coupled-electron pair approximation, version 1 (CEPA/1) or the local pair natural orbital version of this method (LPNO-CEPA/1). It is shown that the MP2 method achieves apparent accuracy only due to error cancellation. Systematically more accurate results at small additional computational cost are obtained if the MP2 step is replaced by LPNO-CEPA/1. The errors of LPNO-CEPA/1 relative to canonical CEPA/1 are negligible. Owing to the highly systematic nature of the deviations between canonical and LPNO methods, basis set extrapolation reduces the LPNO errors in the total energies by 1 order of magnitude (~0.2 kcal/mol) and errors in energy differences to essentially zero. Using the CCSD(T)/LPNO-CEPA/1-based extrapolation scheme, new reference values are proposed for the recently published S66 set of interaction energies. The deviations between the new values and the original interactions energies are mostly very small but reach values up to 0.3 kcal/mol. PMID- 22489634 TI - Five-factor measure of borderline personality traits. AB - This study provides psychometric data for a new self-report measure of borderline personality traits from the perspective of the Five-factor model (FFM) of general personality. Subscales were constructed in an undergraduate sample (n = 109) to assess maladaptive variants of 12 FFM traits (e.g., Affective Dysregulation as a maladaptive variant of FFM Vulnerability). On the basis of data from a second undergraduate sample (n = 111), the Five Factor Borderline Inventory (FFBI) subscales were shown to have good internal consistency, convergent, discriminant, and incremental validity. These psychometric results were replicated in a clinical sample of female residents at a substance abuse treatment facility (n = 94). PMID- 22489635 TI - Comparison of continuous infusion with intermittent bolus administration of cefotaxime on blood and cavity fluid drug concentrations in neonatal foals. AB - Healthy neonatal foals were treated with cefotaxime by bolus (40 mg/kg i.v. q6h for 12 doses; n=10) or by infusion (loading dose of 40 mg/kg i.v. followed by continuous infusion of a total daily dose of 160 mg/kg per 24 h for 3 days; n=5). Population pharmacokinetics was determined, and concentrations in cavity fluids were measured at steady state (72 h). Highest measured serum drug concentration in the bolus group was 88.09 MUg/mL and minimum drug concentration (C(min)) was 0.78 MUg/mL at 6-h postadministration (immediately before each next dose), whereas infusion resulted in a steady-state concentration of 16.10 MUg/mL in the infusion group. Mean cefotaxime concentration in joint fluid at 72 h was higher (P=0.051) in the infusion group (5.02 MUg/mL) compared to the bolus group (0.78 MUg/mL). Drug concentration in CSF at 72 h was not different between groups (P=0.243) and was substantially lower than serum concentrations in either group. Insufficient data on pulmonary epithelial lining fluid were available to compare the methods of administration for cefotaxime in this cavity fluid. Results support continuous drug infusion over bolus dosing in the treatment for neonatal foal septicemia to optimize time that cefotaxime concentration exceeds the minimum inhibitory concentration of common equine pathogens. PMID- 22489636 TI - Sexuality and risk behavior among men who have sex with men in Leon, Nicaragua: a mixed methods approach. AB - INTRODUCTION: HIV prevalence among men who have sex with men (MSM) is 38 times higher than among the general population in Nicaragua. There are little data about the sexuality and sexual behaviors of MSM. It is essential to gain a better understanding of this understudied population. AIMS: The nature of sexual relationships among MSM, their reasons for engaging in risky sexual behaviors, and the sociocultural context in Leon, Nicaragua, were investigated through in depth interviews. Our findings resulted in a structured overview of sociodemographic characteristics and HIV-related knowledge, attitudes, and risk behaviors. METHODS: Fifteen participants recruited by purposive sampling completed an in-depth interview that was then thematically analyzed. An additional 104 participants were surveyed by means of an interviewer-administered questionnaire. MAIN OUTCOME MEASURES: The in-depth interview guide and the survey covered topics related to sociodemographics, childhood, social and sexual relationships, knowledge and attitudes toward HIV and AIDS, identity, and networks. RESULTS: The resulting ecological model explored sexuality and behaviors in four categories. It showed that despite a homophobic and heterosexist society, there is an increasing gay community and greater social acceptance of homosexuality. Nevertheless, interpersonal and intrapersonal factors continue to negatively influence MSM behavior. Quantitative findings demonstrate a satisfactory understanding of HIV transmission among this population, 75% of whom reported concerns of becoming infected with HIV in the future. Approximately one-half claimed that they always used condoms when having sex with men, but only one-third of the time with women, indicating inconsistent condom use. Negative attitudes toward HIV/AIDS were seldom heard. CONCLUSIONS: This study is the first mixed methods approach in a Nicaraguan context that shows the interrelations among sex, sexuality, and identity at various levels of MSM life, and how they influence the sexual risk behaviors of individuals. Engaging in unprotected sex and postponing HIV testing are seen as cognitive dissonances. PMID- 22489637 TI - The dual-oscillator system of Drosophila melanogaster under natural-like temperature cycles. AB - Dual-oscillator systems that control morning and evening activities can be found in a wide range of animals. The two coupled oscillators track dawn and dusk and flexibly adapt their phase relationship to seasonal changes. This is also true for the fruit fly Drosophila melanogaster that serves as model organism to understand the molecular and anatomical bases of the dual-oscillator system. In the present study, the authors investigated which temperature parameters are crucial for timing morning and evening activity peaks by applying natural-like temperature cycles with different daylengths. The authors found that the morning peak synchronizes to the temperature increase in the morning and the evening peak to the temperature decrease in the afternoon. The two peaks did not occur at fixed absolute temperatures, but responded flexibly to daylength and overall temperature level. Especially, the phase of the evening peak clearly depended on the absolute temperature level: it was delayed at high temperatures, whereas the phase of the M peak was less influenced. This suggests that the two oscillators have different temperature sensitivities. The bimodal activity rhythm was absent in the circadian clock mutants Clk(Jrk) and cyc(01) and reduced in per(01) and tim(01) mutants. Whereas the activity of Clk(Jrk) mutants just followed the temperature cycles, that of per(01) and tim(01) mutants did not, suggesting that these mutants are not completely clockless. This study revealed new characteristics of the dual-oscillator system in Drosophila that were not detected under different photoperiods. PMID- 22489638 TI - Circadian variations in exsorptive transport: in situ intestinal perfusion data and in vivo relevance. AB - The circadian timing system (CTS) governs the 24-h rhythm of the organism and, hence, also main pathways responsible for drug pharmacokinetics. P-glycoprotein (P-gp) is a drug transporter that plays a pivotal role in drug absorption, distribution, and elimination, and temporal changes in its activity may affect input, output, activity, and toxicity profile of drugs. In the current study, the influence of different circadian stages on the overall intestinal permeability (P(eff)) of the P-gp substrates talinolol and losartan was evaluated in in situ intestinal perfusion studies in rats. Additionally, in vivo studies in rats were performed by employing the P-gp probe talinolol during the day (nonactive) and night (active) period in rats. Effective intestinal permeabilities of talinolol and losartan were smaller in studies performed during the night (p < .05), indicating that P-gp-dependent intestinal secretion is greater during the nighttime activity span than daytime rest span of the animals. P-gp modulators vinblastine and PSC833 led to a significant decrease of talinolol and losartan exsorption in the intestinal segments as compared with control groups. Strikingly, the permeability-enhancing effect of vinblastine and PSC833 was higher with night perfusions, for both talinolol and losartan. In vivo studies performed with talinolol revealed-consistent with the in situ studies (P(eff) day > night)-a day vs. night difference in the oral availability of talinolol in the group of male rats in terms of the area under the curve (AUC) data (AUC(day) > AUC(night)). The P-gp modulator vinblastine significantly increased talinolol AUC(day) (p < .05), whereas only a weak vinblastine effect was seen in night. According to the in situ data, the functional activity of P-gp was regulated by the CTS in jejunum and ileum, which are major intestinal segments for energy dependent efflux. In conclusion, circadian rhythms may affect carrier-mediated active efflux and play a role in the absorption process. In addition to daily rhythms in P-gp activity in rat intestine, the in vivo studies indicate that absorption-, distribution-, metabolism-, and elimination-relevant rhythms may be involved in the circadian kinetics of the drug, besides transporter-dependent efflux, such well-known aspects as metabolic or renal clearance or motility. Since this also holds true for a potentially interacting second compound (modulator), modulator effects should be evaluated carefully in transporter related drug-drug interactions. PMID- 22489632 TI - Taxa-area relationship and neutral dynamics influence the diversity of fungal communities on senesced tree leaves. AB - This study utilized individual senesced sugar maple and beech leaves as natural sampling units within which to quantify saprotrophic fungal diversity. Quantifying communities in individual leaves allowed us to determine if fungi display a classic taxa-area relationship (species richness increasing with area). We found a significant taxa-area relationship for sugar maple leaves, but not beech leaves, consistent with Wright's species-energy theory. This suggests that energy availability as affected plant biochemistry is a key factor regulating the scaling relationships of fungal diversity. We also compared taxa rank abundance distributions to models associated with niche or neutral theories of community assembly, and tested the influence of leaf type as an environmental niche factor controlling fungal community composition. Among rank abundance distribution models, the zero-sum model derived from neutral theory showed the best fit to our data. Leaf type explained only 5% of the variability in community composition. Habitat (vernal pool, upland or riparian forest floor) and site of collection explained > 40%, but could be attributed to either niche or neutral processes. Hence, although niche dynamics may regulate fungal communities at the habitat scale, our evidence points towards neutral assembly of saprotrophic fungi on individual leaves, with energy availability constraining the taxa-area relationship. PMID- 22489639 TI - Ductal ligation in the very low-birth weight infant: simple anesthesia or extreme art? AB - Management of the very low-birth weight infant in the neonatal intensive care unit (NICU) is geared to provide optimal outcome not only in term of survival but increasingly with a goal of limitation of long-term neurological and pulmonary morbidities. Careful follow-up studies have demonstrated that relatively small variations in oxygenation and gas exchange, ventilator management, and other management modalities can have long-term consequences. Within this context, there are good data that closure of a clinically significant patent ductus arteriosus has outcome benefit, but little data on the idealized anesthetic to manage such fragile patients. Does the anesthetic management matter? Given the attention to detail within the NICU, it would seem prudent to try to choose techniques that limit changes in hemodynamics, gas exchange, and ventilation within the context of the surgery. Anesthesia for ductal ligation in the very low-birth weight infant may need to be judged by more than simple survival and brings into question the current techniques and monitoring used. PMID- 22489641 TI - Poly(vinyl alcohol) nanocomposites filled with poly(vinyl alcohol)-grafted graphene oxide. AB - We present a novel approach to the fabrication of advanced polymeric nanocomposites from poly(vinyl alcohol) (PVA) by incorporation of PVA-grafted graphene oxide. In this work, we have synthesized PVA-grafted graphene oxide (PVA g-GO) for the strong interfacial adhesion of graphene oxide (GO) to the PVA matrix. It was found that the mechanical properties of PVA were greatly improved by incorporating PVA-g-GO. For example, the tensile strength and Young's modulus of the PVA nanocomposite films containing 1 wt % net GO in the PVA-g-GO significantly increased by 88 and 150%, respectively, as compared to unfilled PVA. The elongation at break was also increased by 22%, whereas the GO/PVA nanocomposite containing 1 wt % pristine GO was decreased by 15%. Therefore, the presence of the PVA-g-GO in the PVA matrix could make the PVA not only stronger but also tougher. The strong interfacial adhesion between PVA-g-GO and the PVA matrix was attributed to the good compatibility between PVA-g-GO and the matrix PVA as well as the hydrogen-bonding between them. PMID- 22489640 TI - Early steps in the development of a claims-based targeted healthcare safety monitoring system and application to three empirical examples. AB - BACKGROUND: Several efforts are under way to develop and test methods for prospective drug safety monitoring using large, electronic claims databases. Prospective monitoring systems must incorporate signalling algorithms and techniques to mitigate confounding in order to minimize false positive and false negative signals due to chance and bias. OBJECTIVE: The aim of the study was to describe a prototypical targeted active safety monitoring system and apply the framework to three empirical examples. METHODS: We performed sequential, targeted safety monitoring in three known drug/adverse event (AE) pairs: (i) paroxetine/upper gastrointestinal (UGI) bleed; (ii) lisinopril/angioedema; (iii) ciprofloxacin/Achilles tendon rupture (ATR). Data on new users of the drugs of interest were extracted from the HealthCore Integrated Research Database. New users were matched by propensity score to new users of comparator drugs in each example. Analyses were conducted sequentially to emulate prospective monitoring. Two signalling rules--a maximum sequential probability ratio test and an effect estimate-based approach--were applied to sequential, matched cohorts to identify signals within the system. RESULTS: Signals were identified for all three examples: paroxetine/UGI bleed in the seventh monitoring cycle, within 2 calendar years of sequential data; lisinopril/angioedema in the second cycle, within the first monitoring year; ciprofloxacin/ATR in the tenth cycle, within the fifth year. CONCLUSION: In this proof of concept, our targeted, active monitoring system provides an alternative to systems currently in the literature. Our system employs a sequential, propensity score-matched framework and signalling rules for prospective drug safety monitoring and identified signals for all three adverse drug reactions evaluated. PMID- 22489642 TI - The interplay between knowledge, perceived efficacy, and concern about global warming and climate change: a one-year longitudinal study. AB - If the long-term goal of limiting warming to less than 2 degrees C is to be achieved, rapid and sustained reductions of greenhouse gas emissions are required. These reductions will demand political leadership and widespread public support for action on global warming and climate change. Public knowledge, level of concern, and perceived personal efficacy, in positively affecting these issues are key variables in understanding public support for mitigation action. Previous research has documented some contradictory associations between knowledge, personal efficacy, and concern about global warming and climate change, but these cross-sectional findings limit inferences about temporal stability and direction of influence. This study examines the relationships between these three variables over a one-year period and three waves with national data from New Zealand. Results showed a positive association between the variables, and the pattern of findings was stable and consistent across the three data points. More importantly, results indicate that concern mediates the influence of knowledge on personal efficacy. Knowing more about global warming and climate change increases overall concern about the risks of these issues, and this increased concern leads to greater perceived efficacy and responsibility to help solving them. Implications for risk communication are discussed. PMID- 22489643 TI - Single enzyme studies reveal the existence of discrete functional states for monomeric enzymes and how they are "selected" upon allosteric regulation. AB - Allosteric regulation of enzymatic activity forms the basis for controlling a plethora of vital cellular processes. While the mechanism underlying regulation of multimeric enzymes is generally well understood and proposed to primarily operate via conformational selection, the mechanism underlying allosteric regulation of monomeric enzymes is poorly understood. Here we monitored for the first time allosteric regulation of enzymatic activity at the single molecule level. We measured single stochastic catalytic turnovers of a monomeric metabolic enzyme (Thermomyces lanuginosus Lipase) while titrating its proximity to a lipid membrane that acts as an allosteric effector. The single molecule measurements revealed the existence of discrete binary functional states that could not be identified in macroscopic measurements due to ensemble averaging. The discrete functional states correlate with the enzyme's major conformational states and are redistributed in the presence of the regulatory effector. Thus, our data support allosteric regulation of monomeric enzymes to operate via selection of preexisting functional states and not via induction of new ones. PMID- 22489644 TI - Nicotine does not influence NF-kappaB activity in neonatal mice reoxygenated with room-air or 100% oxygen. AB - BACKGROUND: Nuclear factor kappa B (NF-kappaB) is considered an important mediator of inflammation, but is also important for developing organs and is constitutive active in neurons in the newborn brain. OBJECTIVES: We wanted to test the effects of preconditioning with nicotine on neonatal mice subjected to hypoxia and reoxygenated with either room-air or 100% oxygen. We hypothesized that nicotine would be neuroprotective and possibly reduce detrimental effects of 100% oxygen on body organs. METHODS: In this randomized study, we used neonatal transgenic NF-kappaB reporter mice that were preconditioned with nicotine or vector only prior to hypoxia, and then subjected to resuscitation with room-air or 100% oxygen. RESULTS: We did not find any differences in NF-kappaB activity in whole body or in the brain of animals resuscitated with room-air or 100% oxygen. Resuscitation with 100% oxygen attenuated NF-kB activity when compared with resuscitation with room-air. However, when bioluminescence was properly corrected for body weight, the difference between room-air and 100% reoxygenation was no longer evident. CONCLUSIONS: Preconditioning with nicotine does not have any effect on NF-kappaB activity in body organs or in the brain of neonatal mice after hypoxia and resuscitation with either room-air or 100% oxygen. 100% oxygen did not alter NF-kappaB activity when compared to room-air resuscitation alone. PMID- 22489645 TI - Bartonella henselae seroprevalence in cattle breeders and veterinarians in the rural areas of Aydin and Denizli, Turkey. AB - Bartonella henselae infections are usually detected among people who have close contact with animals. Veterinarians and cattle breeders, in particular, are considered as the risk groups for B. henselae infections. In this study, the seroprevalence of antibodies to B. henselae was investigated in these two groups of subjects in the two cities of Aydin and Denizli, which are located in the same region in the southwest of Turkey. Total antibodies to B. henselae were evaluated by indirect immunofluorescence assay in serum samples taken from 63 cattle breeders and 27 veterinarians. Twenty samples (22.2%) were found to react on 1/64 titre with B. henselae antigens. Bartonella henselae seroprevalence was found to be significantly related to age (P = 0.033) and higher in those living in Aydin (P = 0.047). Age was the only independent factor in multivariate analysis (P = 0.008). Seroprevalence was found to be 2-fold higher in those people who had had tick contact (P = 0.093). In conclusion, the physicians in the region should consider B. henselae infection among veterinarians and breeders in their differential diagnosis list of fever of unknown origin. PMID- 22489646 TI - Self-directed speech affects visual search performance. AB - People often talk to themselves, yet very little is known about the functions of this self-directed speech. We explore effects of self-directed speech on visual processing by using a visual search task. According to the label feedback hypothesis (Lupyan, 2007a), verbal labels can change ongoing perceptual processing-for example, actually hearing "chair" compared to simply thinking about a chair can temporarily make the visual system a better "chair detector". Participants searched for common objects, while being sometimes asked to speak the target's name aloud. Speaking facilitated search, particularly when there was a strong association between the name and the visual target. As the discrepancy between the name and the target increased, speaking began to impair performance. Together, these results speak to the power of words to modulate ongoing visual processing. PMID- 22489647 TI - The bivalent fear of evaluation model of social anxiety: further integrating findings on fears of positive and negative evaluation. AB - Accumulating evidence supports the premise that fear of evaluation in general is important in social anxiety, including fear of positive evaluation (FPE) as well as fear of negative evaluation (FNE). This study tested various hypotheses pertaining to a novel, expanded conceptualization of social anxiety involving these two distinct fears: the bivalent fear of evaluation (BFOE) model. Responses from a large undergraduate sample (N = 585) were examined. In addition, responses from a subsample of participants qualifying for a probable diagnosis of social anxiety disorder (SAD; n = 133) were examined, via mediational analyses, for potential mechanisms underlying FPE within highly socially anxious individuals. FPE exhibited a unique and significantly stronger relationship with concerns of social reprisal due to making positive impressions than did FNE. FPE related uniquely and negatively to trait positive affect/automatic thoughts, whereas FNE, FPE, and social anxiety all related uniquely and positively to trait negative affect/automatic thoughts. FPE, FNE, and social anxiety all related uniquely and positively to disqualification of positive social outcomes (DPSO). However, FPE related most strongly to DPSO attributions at the level of the self, and these attributions mediated the relationship between FPE and negative automatic thoughts in an analog clinical sample. Concerns of social reprisal due to making positive impressions on others mediated the relationship between FPE and DPSO attributions to others in an analog clinical sample. The obtained findings replicate and extend support for the BFOE model of social anxiety. Implications for the theoretical conceptualization and treatment of SAD are discussed. PMID- 22489649 TI - A complex standard for protein identification, designed by evolution. AB - Shotgun proteomic investigations rely on the algorithmic assignment of mass spectra to peptides. The quality of these matches is therefore a cornerstone in the analysis and has been the subject of numerous recent developments. In order to establish the benefits of novel algorithms, they are applied to reference samples of known content. However, these were recently shown to be either too simple to resemble typical real-life samples or as leading to results of lower accuracy as the method itself. Here, we describe how to use the proteome of Pyrococcus furiosus , a hyperthermophile, as a standard to evaluate proteomics identification workflows. Indeed, we prove that the Pyrococcus furiosus proteome provides a valid method for detecting random hits, comparable to the decoy databases currently in popular use, but we also prove that the Pyrococcus furiosus proteome goes squarely beyond the decoy approach by also providing many hundreds of highly reliable true positive hits. Searching the Pyrococcus furiosus proteome can thus be used as a unique test that provides the ability to reliably detect both false positives as well as proteome-scale true positives, allowing the rigorous testing of identification algorithms at the peptide and protein level. PMID- 22489650 TI - Using the epigenetic code to promote the unpackaging and transcriptional activation of DNA polyplexes for gene delivery. AB - Nonviral gene delivery has seen limited clinical application due in part to the inefficiency with which most nonviral vehicles navigate the intracellular gene delivery pathway. One key problem is the inability of most DNA-packaging materials to release DNA and enable its efficient transcription. Thus, our aim was to develop gene delivery polyplexes capable of initiating their own transcription upon arrival in the nucleus. We created nuclease-resistant polyplexes with plasmid DNA (pDNA) and post-translationally modified histone 3 (H3K4Me3) tail peptides known to signal transcriptional activation on chromosomal DNA. When the H3K4Me3-pDNA polyplexes were directly microinjected into the nuclei of NIH/3T3 mouse fibroblasts, protein expression occurred earlier and in a greater fraction of cells than when polyethylenimine-pDNA polyplexes were microinjected. The rate of protein expression initiated by the H3K4Me3-pDNA polyplexes was also significantly accelerated in comparison with the rate initiated by non-trimethylated H3-pDNA polyplexes. These differences in protein expression rates were quantified by the development of a noncompartmentalized cellular kinetics model. These results highlight the importance of polyplex unpackaging as a gene delivery barrier, and demonstrate for the first time that the epigenetic code can be utilized in nonviral gene delivery. PMID- 22489648 TI - 1-Dehydro-[10]-gingerdione from ginger inhibits IKKbeta activity for NF-kappaB activation and suppresses NF-kappaB-regulated expression of inflammatory genes. AB - BACKGROUND AND PURPOSE: Pungent constituents of ginger (Zingiber officinale) have beneficial effects on inflammatory pain and arthritic swelling. However, the molecular basis for these pharmacological properties is only partially understood. Here, we investigated the molecular target of 1-dehydro-[10] gingerdione (D10G), one of the pungent constituents of ginger, that mediates its suppression of NF-kappaB-regulated expression of inflammatory genes linked to toll-like receptor (TLR)-mediated innate immunity. EXPERIMENTAL APPROACH: RAW 264.7 macrophages or primary macrophages-derived from bone marrows of C57BL/6 or C3H/HeJ mice were stimulated with the TLR4 agonist LPS in the presence of D10G. Catalytic activity of inhibitory kappaB (IkappaB) kinase beta (IKKbeta) was determined by a kinase assay and immunoblot analysis, and the expression of inflammatory genes by RT-PCR analysis and a promoter-dependent reporter assay. KEY RESULTS: D10G directly inhibited the catalytic activity of cell-free IKKbeta. Moreover, D10G irreversibly inhibited cytoplasmic IKKbeta-catalysed IkappaBalpha phosphorylation in macrophages activated by TLR agonists or TNF-alpha, and also IKKbeta vector-elicited NF-kappaB transcriptional activity in these cells. These effects of D10G were abolished by substitution of the Cys(179) with Ala in the activation loop of IKKbeta, indicating a direct interacting site of D10G. This mechanism was shown to mediate D10G-induced disruption of NF-kappaB activation in LPS-stimulated macrophages and the suppression of NF-kappaB-regulated gene expression of inducible NOS, COX-2 and IL-6. CONCLUSION AND IMPLICATIONS: This study demonstrates that IKKbeta is a molecular target of D10G involved in the suppression of NF-kappaB-regulated gene expression in LPS-activated macrophages; this suggests D10G has therapeutic potential in NF-kappaB-associated inflammation and autoimmune disorders. PMID- 22489651 TI - The effects of pentoxifylline on lung inflammation in a rat model of meconium aspiration syndrome. AB - To examine the effects of pentoxifylline (PTX) on regional pulmonary and systemic inflammation after meconium aspiration, we studied 26 anesthetized and ventilated adult rats for 3 hours. Seventeen rats were instilled with human meconium (1.5 mL/kg, 65 mg/mL) intratracheally. After instillation of meconium, PTX (20 mg/kg, i.a.; n = 9) or saline (n = 8) was given to the subjects. Nine rats that were ventilated and not instilled with meconium served as sham group. Meconium instillation resulted in increased bronchoalveolar lavage (BAL) fluid tumor necrosis factor-alpha (TNF-alpha; P = 0.004 and P = 0.002, respectively), protein (P = 0.005 and P = 0.001, respectively) levels, and arterial oxygenation index (OI) in PTX and saline groups. PTX treatment prevented the increase of BAL fluid TNF-alpha, protein concentrations, and OI in the meconium-instilled lungs but had no statistically significant effect. These results indicate that meconium aspiration induces severe inflammation in the lung. PTX treatment affects the TNF alpha production in the lungs and it may attenuate meconium-induced derangements. PMID- 22489652 TI - Variation in 17 obstetric care pathways: potential danger for health professionals and patient safety? AB - AIM: To report a study to determine whether or not variations exist in evidence based key interventions in pathway documents for normal delivery across hospitals. BACKGROUND: Care pathways are used worldwide to standardize and follow up patient-focused care. Minimal variations in pathway documents increase standardization and patient safety. DESIGN: A descriptive study design using qualitative methods was used, to examine the various key interventions present in care pathway documents for normal delivery. METHODS: Between January-March 2009, we evaluated the content of the care pathway document for normal delivery from 17 different hospitals. The key interventions in these pathways were compared with the 40 evidence-based key interventions of Map of Medicine(r). RESULTS: There was much variation in the characteristics and the presence of key interventions in the pathway documents. Only 6 of the 40 evidence-based key interventions (15%) were found in all 17 pathway documents and 20 of the 40 interventions (50%) were found in only 10 pathway documents. CONCLUSION: If variation already exists among the care pathway documents, this may lead to a high probability of variation in the actual performance of daily care. In this study is shown that, even for highly predictable medical conditions, there are huge differences in the evidence based content and structure of pathways. Lack of evidence base could potentially endanger both patient safety and the health professional. PMID- 22489653 TI - An attempt to identify the likely sources of Escherichia coli harboring toxin genes in rainwater tanks. AB - In this study, 200 Escherichia coli isolates from 22 rainwater tank samples in Southeast Queensland, Australia were tested for the presence of 10 toxin genes (i.e., stx(1), stx(2), hlyA, ehxA, LT1, ST1, cdtB, east1, cnf1, and cvaC) associated with intestinal and extraintestinal pathotypes. Among the 22 rainwater tanks tested, 5 (28%), 7 (32%), 7 (32%), and 1 (5%) tanks contained E. coli harboring ST1, east1, cdtB, and cvaC genes, respectively. Of the 200 E. coli isolates from the 22 tanks, 43 (22%) strains from 13 (59%) tanks were harboring toxin gene. An attempt was made to establish a link between bird and possum fecal contamination and the presence of these potential clinically significant E. coli strains harboring toxin genes in rainwater tanks. Among the 214 E. coli isolates tested from birds, 30 (14%), 11 (5%) and 18 (8%) strains contained east1, cdtB, and cvaC toxin genes, respectively. Similarly, among the 214 possum E. coli isolates, 74 (35%) contained only the east1 toxin gene. All E. coli strains from rainwater tanks, bird and possum fecal samples harboring toxin genes were biochemically fingerprinted. Biochemical phenotypes (BPTs) of 14 (33%) E. coli strains from 7 rainwater tanks and 9 (21%) E. coli strains from 6 rainwater tanks were identical to a number of BPTs of E. coli strains isolated from bird and possum feces suggesting that these animals may be the sources of these E. coli in rainwater tanks. as a precautionary measure, it is recommended that rainwater should be treated prior to drinking. In addition, proper maintenance of roof and gutter hygiene and elimination of overhanging tree branches and other structures where possible to prevent the movement of possums are highly recommended. PMID- 22489654 TI - Techniques in laparoscopic donor nephrectomy. AB - What's known on the subject? and What does the study add? Innovations in laparoscopic surgery have provided transplant surgeons with a range of techniques as well as a vast array of minimally invasive instruments. Whilst randomized control trials have compared open and laparoscopic donor nephrectomy, there is a paucity of high quality data comparing different laparoscopic approaches. This article summarizes the main techniques of laparoscopic donor nephrectomy currently in use and reviews the evidence available for each. In addition, controversial aspects of donor nephrectomy are examined, including the technological advances applicable to this operation. Increasing numbers of living donor kidney transplants are being performed worldwide, and the majority of donor operations are now laparoscopic. Transperitoneal 'pure' and hand-assisted laparoscopic donor nephrectomy are the two most commonly performed procedures, although retroperitoneal approaches are advocated by some centres. Controversy persists with respect to the technical aspects of donor nephrectomy, including both the approach and the method of ligation of the hilar vessels. More recently, robot-assisted, laparo-endoscopic single site surgery (LESS) and natural orifice transluminal endoscopic surgery (NOTES) -assisted donor nephrectomy have also been performed, further increasing the number of options available, but creating uncertainty as to the ideal approach. PMID- 22489655 TI - Band propagation, scaling laws and phase transition in a precipitate system. I: Experimental study. AB - In the first part of this work, we present an experimental study of the precipitation/redissolution reaction-diffusion system of initially separated components in two distinct organic gels: agar and gelatin. The system is prepared by diffusing a concentrated ammonia solution into a gel matrix that contains nickel sulfate. In agar, the system exhibits a pulse propagation due to the concomitant precipitation reaction between Ni(II) and hydroxide ions and redissolution due to ammonia. At a later stage of propagation, a transition to Liesegang banding is shown to take place. The dynamics of the distance traveled by the precipitation pulse, its width, and mass are shown to exhibit power laws. Moreover, the mass of the bands is shown to oscillate in time, indicating the emergence of a complex mass enrichment mechanism of the formed Liesegang bands. At the microscopic level, we show evidence that the system undergoes a continuous polymorphic transition concomitant with a morphological change whereby the solid in the pulse, which consists of nanospheres of alpha-nickel hydroxide transforms to form the bands, which consists of larger platelets of beta-nickel hydroxide. This clearly indicates the existence of a dynamic Ostwald ripening mechanism that underlies the dynamics on both scales. On the other hand, in gelatin, although we can still obtain similar power laws as in the case of agar, no transition to bands was observed. It is shown that in this case, the propagating pulse is made of nanoparticles of alpha-nickel hydroxide with an average diameter ~50 nm. PMID- 22489656 TI - The influence of esomeprazole and cisapride on gastroesophageal reflux during anesthesia in dogs. AB - BACKGROUND: Gastroesophageal reflux (GER) is common in anesthetized dogs and can cause esophagitis, esophageal stricture, and aspiration pneumonia. OBJECTIVE: To determine whether preanesthetic IV administration of esomeprazole alone or esomeprazole and cisapride increases esophageal pH and decreases the frequency of GER in anesthetized dogs using combined multichannel impedance and pH monitoring. ANIMALS: Sixty-one healthy dogs undergoing elective orthopedic surgery procedures. METHODS: Prospective, randomized, placebo-controlled study. Dogs were randomized to receive IV saline (0.9% NaCl), esomeprazole (1 mg/kg) alone, or a combination of esomeprazole (1 mg/kg) and cisapride (1 mg/kg) 12-18 hours and 1 1.5 hours before anesthetic induction. An esophageal pH/impedance probe was utilized to measure esophageal pH and detect GER. RESULTS: Eight of 21 dogs in the placebo group (38.1%), 8 of 22 dogs in the esomeprazole group (36%), and 2 of 18 dogs in the combined esomeprazole and cisapride group (11%) had >= 1 episode of GER on impedance testing during anesthesia (P < .05). Esomeprazole was associated with a significant increase in gastric and esophageal pH (P = .001), but the drug did not significantly decrease the frequency of GER (P = .955). Concurrent administration of cisapride was associated with a significant decrease in the number of reflux events (RE) compared to the placebo and esomeprazole groups (P < .05). CONCLUSIONS AND CLINICAL RELEVANCE: Preanesthetic administration of cisapride and esomeprazole decreases the number of RE in anesthetized dogs, but administration of esomeprazole alone was associated with nonacid and weakly acidic reflux in all but 1 dog. PMID- 22489657 TI - Translation, cross-cultural adaptation, and psychometric validation of the 5-item International Index of Erectile Function (IIEF-5) into Urdu. AB - INTRODUCTION: Patients suffering from erectile dysfunction (ED) feel shy to discuss this issue with their physician. Self-report questionnaires are a key instrument to break this barrier. Most of these questionnaires are in English, and their validated translations in Urdu, the official language of Pakistan, are not available. AIM: The aim of our study is to translate, cross-culturally adapt, and perform psychometric validation of an Urdu translation of the 5-item international index of erectile function (IIEF-5). METHODS: The translation of IIEF-5 was done in Urdu and was refined through reverse translation and expert committee reviews. It was then pretested on 20 bilingual men and reviewed again to develop a final Urdu version of the questionnaire. We selected 47 patients who had been in a stable sexual relationship over the past 6 months and asked them to fill out the IIEF-5 questionnaire in both languages (Urdu and English), followed by evaluation of ED by a clinician, who was blinded to the responses of the patient to the questionnaire. MAIN OUTCOME MEASURES: The self-report to questionnaire and independent clinical assessment were compared. Patients refilled out the questionnaire again at the end of the interview to assess test retest consistency. These data were now analyzed statistically using descriptive statistics, Cohen's kappa, and Cronbach's alpha analysis. RESULTS: The Cohen's kappa showed a very high degree of agreement between the two versions (P < 0.0001), and a high degree of internal consistency was demonstrated on Cronbach's alpha analysis ([0.882] with 95% confidence interval [0.839-0.916]). The clinical assessment of the presence and severity of ED also matched with the self-report questionnaire. CONCLUSION: We can safely conclude that this Urdu version of IIEF 5 is a valid instrument for use in the literate population of Pakistan. PMID- 22489658 TI - The interplay between online and offline explorations of identity, relationships, and sex: a mixed-methods study with LGBT youth. AB - Although the Internet is commonly used by lesbian, gay, bisexual, and transgender (LGBT) youth to explore aspects of sexual health, little is known about how this usage relates to offline explorations and experiences. This study used a mixed methods approach to investigate the interplay between online and offline explorations of multiple dimensions of sexual health, which include sexually transmitted infections, sexual identities, romantic relationships, and sexual behaviors. A diverse community sample of 32 LGBT youth (ages 16-24) completed semi-structured interviews, which were transcribed and then qualitatively coded to identify themes. Results indicated that, although many participants evaluated online sexual health resources with caution, they frequently used the Internet to compensate for perceived limitations in offline resources and relationships. Some participants turned to the Internet to find friends and romantic partners, citing the relative difficulty of establishing offline contact with LGBT peers. Further, participants perceived the Internet as an efficient way to discover offline LGBT events and services relevant to sexual health. These results suggest that LGBT youth are motivated to fill gaps in their offline sexual health resources (e.g., books and personal communications) with online information. The Internet is a setting that can be harnessed to provide support for the successful development of sexual health. PMID- 22489659 TI - Targeting free prostate-specific antigen for in vivo imaging of prostate cancer using a monoclonal antibody specific for unique epitopes accessible on free prostate-specific antigen alone. AB - This study investigated the feasibility of targeting the free, unbound forms of prostate-specific antigen (fPSA) for in vivo imaging of prostate adenocarcinomas (PCa), as PSA is produced and secreted at abundance during every clinical stage and grade of PCa, including castration-resistant disease. We injected (125)I labeled monoclonal antibody PSA30 (specific for an epitope uniquely accessible on fPSA alone) intravenously in male nude mice carrying subcutaneous xenografts of LNCaP tumors (n=36). Mice were sacrificed over a time course from 4 hours to 13 days after injecting (125)I-labeled PSA30. Tissue uptake of (125)I-PSA30 at 48 and 168 hours after intravenous injection was compared with two clinically used positron emission tomography radiopharmaceuticals, (18)F-fluoro-deoxy-glucose ((18)F-FDG) or (18)F-choline, in cryosections using Digital AutoRadiography (DAR) and also compared with immunohistochemical staining of PSA and histopathology. On DAR, the areas with high (125)I-PSA30 uptake corresponded mainly to morphologically intact and PSA-producing LNCaP cells, but did not associate with the areas of high uptake of either (18)F-FDG or (18)F-choline. Biodistribution of (125)I-PSA30 measured in dissected organs ex vivo during 4 to 312 hours after intravenous injection demonstrated maximum selective tumor uptake 24-48 hours after antibody injection. Our data showed selective uptake in vivo of a monoclonal antibody highly specific for fPSA in LNCaP cells. Hence, in vivo imaging of fPSA may be feasible with putative usefulness in disseminated PCa. PMID- 22489660 TI - Noxa enhances the cytotoxic effect of gemcitabine in human ovarian cancer cells. AB - Noxa is an important proapoptotic protein in the intrinsic pathway of cell apoptosis. Experiments were carried out to investigate whether Noxa could, therefore, enhance the cytotoxic effect of gemcitabine in human ovarian cancer cell lines (A2780 and COC1). In this study, the combined treatment of Noxa and gemcitabine, in vitro, significantly inhibited the proliferation of A2780 and COC1 cells, as verified by MTT assay, Hoechst staining, and flow cytometric analysis. Moreover, the combination of Noxa and gemcitabine inhibited tumor growth and prolonged the survival of nude mice in vivo. The combined treatment also inhibited the growth of tumor xenografts through the inhibition of proliferation and the induction of apoptosis, as observed in immunohistochemical anti-PCNA staining and TdT-mediated dUTP-biotin nick-end labeling (TUNEL) assay. Our data suggest that Noxa exhibited potent proapoptotic activity against human ovarian cancer cells, and the combination of Noxa and gemcitabine showed a more significant cytotoxic effect against ovarian cancer cells in comparison with either of these agents alone. To our knowledge, we have provided the first evidence that Noxa can enhance therapeutic responses of ovarian cancer cells to gemcitabine, and that it could be potentially useful as a chemosensitizer in ovarian cancer therapy. PMID- 22489662 TI - In vivo distribution of (131)I and (125)I dual-labeled gelatin microspheres after implantation into rabbit liver. AB - OBJECTIVE: The purpose of this study was to explore the radionuclide distribution and metabolism of (131)I and (125)I dual-labeled gelatin microspheres ((131)I (125)I-GMSs) implanted in rabbit liver. METHODS: The simultaneous radiolabeling of (131)I and (125)I into GMSs was performed by a chloramine-T method to prepare biodegradable dual-labeled radionuclide microspheres. The microspheres were injected into rabbit liver. Radionuclide distribution and metabolism in vivo were examined using single photon emission computed tomography (SPECT) and by blood and urine radioactivity counting. RESULTS: (131)I and (125)I were labeled into the biodegradable GMSs in accordance with the mixture ratio of batch feeding. After (131)I-(125)I-GMSs had been implanted in rabbit liver, small amounts of (131)I and (125)I were released into the blood along with the degradation of microspheres and excreted via the urine within 24 days. The radionuclides in the rabbit liver injection site could be detected by SPECT until day 48. The microspheres could be observed by histological methods on day 32. No signs of thyroid damage were observed throughout the entire experimental period. CONCLUSION: (131)I-(125)I-GMS can be retained long term in the injection site. Due to the advantages of combining two radionuclides, (131)I-(125)I-GMS may be a safe and effective choice for cancer brachytherapy. PMID- 22489661 TI - Radiation/paclitaxel treatment of p53-abnormal non-small cell lung cancer xenograft tumor and associated mechanism. AB - BACKGROUND: Mutations in key tumor suppressor genes such as tumor protein 53 (TP53) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) are the main genetic alterations in cancers. TP53 mutations have been found in most patients with non-small cell lung cancer (NSCLC), whereas PTEN mutations are rarely found in lung cancer, though most NSCLCs lack PTEN protein synthesis. However, the signaling involved in radio- and chemotherapy of NSCLC with wild type PTEN and nonfunctional p53 is not clearly understood. METHODS: In this study, we established a xenograft tumor model with H358 NSCLC cells expressing wild-type PTEN, but nonfunctional p53. Protein expression and phosphorylation of PTEN and its downstream signal molecules in NSCLC tissues were detected by Western blot. RESULTS: We demonstrated that radiation and paclitaxel alone inhibited tumor growth, but a combined therapy of radiation and paclitaxel was more effective in inhibiting NSCLC tumor growth. Interestingly, both radiation and paclitaxel significantly increased PTEN protein expression and phosphorylation. Further identification of the affected PTEN downstream molecules showed that Akt phosphorylation at Ser(473) and Thr(308) residues was significantly decreased, whereas Bax and cleaved caspase-3 levels were significantly increased in tumor tissues treated with both radiation and paclitaxel. The combined treatment was more effective than either treatment alone in regulating the studied molecules. We also found that paclitaxel, but not radiation, inhibited phosphoinositide 3-kinase (PI3K) activity. CONCLUSIONS: Our study suggested that a PTEN-PI3K-Akt-Bax signaling cascade is involved in the therapeutic effect of combined radiation/paclitaxel treatment in NSCLC without p53 expression. Our study also suggested that PTEN is an ideal target in tumors with wild-type PTEN and a lack of functional p53. PMID- 22489663 TI - Analysis of mutations in the BCR-ABL1 kinase domain, using direct sequencing: detection of the T315I mutation in bone marrow CD34+ cells of a patient with chronic myelogenous leukemia 6 months prior to its emergence in peripheral blood. AB - BACKGROUND AND OBJECTIVE: It has been shown that the occurrence of the BCR-ABL1 T315I mutation leads to a very poor therapeutic outcome in chronic myelogenous leukemia (CML) patients treated with tyrosine kinase inhibitors. Therefore, early detection of this mutation could potentially lead to early therapeutic intervention and a better prognosis with the ongoing treatment regimen. METHODS: The detection of BCR-ABL1 kinase domain (KD) mutations was performed by direct sequencing of peripheral blood (PB), total bone marrow (BM), and BM CD34+ cells from a reported CML patient. RESULTS: In this patient, the T315I mutation was detected in BM CD34+ cells 6 months prior to its emergence in PB, suggesting evolution and expansion of the T315I mutation clone, which most likely originated from more primitive CML cells. CONCLUSION: Our finding reflects the natural development of a T315I mutation within the hematopoietic system of the reported patient and indicates the importance of BCR-ABL1 mutation monitoring in more primitive cell populations. Considering the natural history of T315I development in this reported CML case, we hypothesize that BCR-ABL1 KD mutations may be pre concentrated in more primitive CML cells, which subsequently expand into the PB. These findings may have future implications for the strategy used for detecting BCR-ABL1 mutations. PMID- 22489664 TI - The clinico-pathologic role of microRNAs miR-9 and miR-151-5p in breast cancer metastasis. AB - BACKGROUND: MicroRNAs (miRNAs) may function as suppressors or promoters of tumor metastasis according to their messenger RNA targets. Previous studies have suggested that miR-9 and miR-151-5p are associated with metastasis in breast cancer and hepatocellular carcinoma, respectively. We aimed to further establish the potential roles of miR-9 and miR-151-5p in tumor invasion and metastasis and investigate their use as biomarkers. METHODS: We used quantitative real-time PCR (qRT-PCR) to measure differences in miR-9 and miR-151-5p expression between primary breast tumors and their lymph-node metastases in 194 paired tumor samples from 97 patients. We also correlated expression levels with histologic data to investigate their utility as biomarkers. RESULTS: There were no significant differences in miR-9 expression between the primary tumors and lymph nodes; however, miR-151-5p expression was significantly lower in the lymph-node metastases than in their corresponding tumors (p < 0.05). miR-9 levels were elevated in primary breast tumors from patients diagnosed with higher-grade tumors (p < 0.05); however, no differences were observed in miR-151-5p levels between different grades of tumor. Interestingly, miR-9 levels were elevated in invasive lobular carcinomas (ILC) compared with invasive ductal carcinomas (IDC; p < 0.01). CONCLUSIONS: In aggregate, these data suggest that miR-151-5p upregulation may suppress metastasis in primary breast tumors. Both miRNAs may serve as useful biomarkers in future clinical trials in breast cancer. PMID- 22489665 TI - MMP-Cliffs: systematic identification of activity cliffs on the basis of matched molecular pairs. AB - Activity cliffs are generally defined as pairs of structurally similar compounds having large differences in potency. The analysis of activity cliffs is of general interest because structure-activity relationship (SAR) determinants can often be deduced from them. Critical questions for the study of activity cliffs include how similar compounds should be to qualify as cliff partners, how similarity should be assessed, and how large potency differences between participating compounds should be. Thus far, activity cliffs have mostly been defined on the basis of calculated Tanimoto similarity values using structural descriptors, especially 2D fingerprints. As any theoretical assessment of molecular similarity, this approach has its limitations. For example, calculated Tanimoto similarities might often be difficult to reconcile and interpret from a chemical perspective, a point of critique frequently raised in medicinal chemistry. Herein, we have explored activity cliffs by considering well-defined substructure replacements instead of calculated similarity values. For this purpose, the matched molecular pair (MMP) formalism has been applied. MMPs were systematically derived from public domain compounds, and activity cliffs were extracted from them, termed MMP-cliffs. The frequency of cliff formation was determined for compounds active against different targets, MMP-cliffs were analyzed in detail, and re-evaluated on the basis of Tanimoto similarity. In many instances, chemically intuitive activity cliffs were only detected on the basis of MMPs, but not Tanimoto similarity. PMID- 22489666 TI - Salt-induced chloroplast protrusion is the process of exclusion of ribulose-1,5 bisphosphate carboxylase/oxygenase from chloroplasts into cytoplasm in leaves of rice. AB - Chloroplast protrusions (CPs) are often observed under environmental stresses, but their role has not been elucidated. The formation of CPs was observed in the leaf of rice plants treated with 75 mm NaCl for 14 d. Some CPs were almost separated from the main chloroplast body. In some CPs, inner membrane structures and crystalline inclusions were included. Similar structures surrounded by double membranes were observed in the cytoplasm and vacuole. Ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) was detected in CPs and the similar structures in the cytoplasm and vacuole. These results suggest that CP is one of the pathways of Rubisco exclusion from chloroplasts into the cytoplasm under salinity, and the exclusions could be transported to vacuole for their degradation. PMID- 22489667 TI - Silica nanoparticles treated by cold atmospheric-pressure plasmas improve the dielectric performance of organic-inorganic nanocomposites. AB - We report on the application of cold atmospheric-pressure plasmas to modify silica nanoparticles to enhance their compatibility with polymer matrices. Thermally nonequilibrium atmospheric-pressure plasma is generated by a high voltage radio frequency power source operated in the capacitively coupled mode with helium as the working gas. Compared to the pure polymer and the polymer nanocomposites with untreated SiO(2), the plasma-treated SiO(2)-polymer nanocomposites show higher dielectric breakdown strength and extended endurance under a constant electrical stress. These improvements are attributed to the stronger interactions between the SiO(2) nanoparticles and the surrounding polymer matrix after the plasma treatment. Our method is generic and can be used in the production of high-performance organic-inorganic functional nanocomposites. PMID- 22489668 TI - Oxidative stress and liver disease. AB - In humans, oxidative stress and antioxidant defenses are the sum of a complicated network of enzymatic and non-enzymatic processes. Depending on the stage and severity of diseases, a patient's antioxidant armamentarium may increase as an appropriate response to an oxidant challenge, whereas others may decrease as an indication of unbalanced consumption. In some cases, the formation of reactive oxygen species is a requisite and healthy event. In fact, free radicals can affect intracellular signal transduction and gene regulation, resulting in cytokine production essential to the inflammatory process. In many other cases, especially liver diseases, excessive oxidative stress undoubtedly contributes to the progression and pathological findings of disease and serves as a prognostic indicator. Reactive oxygen species are highly reactive molecules that are naturally generated in small amounts through metabolism and could damage cellular molecules such as lipids, proteins or DNA. Oxidative stress plays a major role in many liver diseases. In this review, we summarize the biological character of free radicals and some antioxidants, and the related methods of analysis. Then, we discusses the association of oxidative stress to many types of liver diseases. PMID- 22489669 TI - Lexical decision in children: sublexical processing or lexical search? AB - Length effects in the lexical decision latencies of children might indicate that children rely on sublexical processing and essentially approach the task as a naming task. We examined this possibility by means of the effects of neighbourhood size and articulatory suppression on lexical decision performance. Sixty-six beginning and 62 advanced readers performed a lexical decision task in a standard, articulatory suppression, or tapping condition. We found length effects on words and nonwords in the children's lexical decisions. However, the effects of neighbourhood size were similar to those reported for adult lexical decisions, rather than the effects previously found in children's naming. In addition, no effect was found of articulatory suppression. Both findings suggest that, despite clear length effects, children do not adopt a naming task approach but, like adults, base lexical decisions mainly on a lexical search. These results pose a challenge for several computational models of reading. PMID- 22489670 TI - Fibroblastic potential of CD41+ cells in the mouse aorta-gonad-mesonephros region and yolk sac. AB - CD41 (alphaIIb integrin), a specific marker for megakaryocytes and platelets, was recently shown to mark the initiation of definitive hematopoiesis in mouse embryos. However, whether embryonic CD41(+) populations have a nonhematopoietic potential remains elusive. Here, we report that the CD41(+) cells from the mouse E11.0 aorta-gonad-mesonephros (AGM) region and yolk sac (YS) expressed a set of mesenchymal markers (as revealed by reverse transcriptase-polymerase chain reaction), displayed myofibroblastic/fibroblastic potential in vitro under mesenchymal culture conditions, and differentiated into alpha SMA(+)/epimorphin(+)/vimentin(+) cells in the lungs of adult recipients after systemic transplantation. This unique cell population with fibroblastic potential expressed intermediate rather than high levels of CD41 and was negative for CD34 in the AGM region. In contrast, circulating CD41(+) cells in the embryonic blood stream harbored no similar fibroblastic potential. Compared with the YS, the AGM derived CD41(+) cells had a more robust fibroblastic potential, as revealed by higher in vitro growth rates. Interestingly, the AGM-derived CD41(+) cells demonstrated a stronger response to the chemotaxin of circulating blood plasma than the YS-derived CD41(+) cells. We are the first group that illustrates the fibroblastic potential of an embryonic CD41(+) population in vitro and in vivo, reflecting the close association between blood and mesenchyme development during mouse mid-gestation. The precise origin of these mesenchymal populations needs further clarification. PMID- 22489672 TI - Cord blood interleukin-6 and neonatal morbidities among preterm infants with PCR positive Ureaplasma urealyticum. AB - OBJECTIVES: To evaluate the clinical significance of Ureaplasma urealyticum recovery from umbilical cord blood, using Polymerase Chain Reaction (PCR), and its association with umbilical cord interleukin-6 (IL-6) levels and neonatal morbidity in preterm infants. METHODS: Cord blood PCR for Ureaplasma urealyticum, and IL-6 were assessed in relation to neonatal outcomes of 30 preterm deliveries of less than 35 weeks' gestation. RESULTS: Ureaplasma urealyticum was present in 43.3% of the examined cord blood samples. Positive neonatal Ureaplasma urealyticum was more common in association with premature rupture of membranes, chorioamnionitis, antenatal maternal use of antibiotics, and earlier gestation. Ureaplasma urealyticum was also associated with an early pro-inflammatory immune response (i.e. elevated IL-6 and positive C-reactive protein). Cutoff level of interleukin-6 of 240 pg% predicts the occurrence of respiratory distress syndrome (RDS), in neonates with positive PCR for Ureaplasma urealyticum. CONCLUSIONS: Preterm patients with positive cord blood PCR for Ureaplasma urealyticum were more likely to have premature rupture of membrane, antenatal antibiotics, chorioamnionitis, earlier gestation, pro-inflammatory response, and RDS than those with a negative PCR. High IL-6 is more likely associated with RDS in Ureaplasma urealyticum positive neonates. PMID- 22489673 TI - Macrolides vs. quinolones for community-acquired pneumonia: meta-analysis of randomized controlled trials. AB - The relative efficacy, safety and ecological implications of macrolides vs. quinolones in the treatment of community-acquired pneumonia (CAP) are debatable. We performed a systematic review and meta-analysis of randomized controlled trials comparing any macrolide vs. any quinolone for the treatment of CAP among adult inpatients or outpatients, as monotherapy or both in combination with a beta-lactam. We did not limit inclusion by pneumonia severity, publication status, language or date of publication. The primary outcomes assessed were 30 day all-cause mortality and treatment failure. Two authors independently extracted the data. Fixed effect meta-analysis of risk ratios (RRs) with 95% confidence intervals was performed. Sixteen trials (4989 patients) fulfilling inclusion criteria were identified, mostly assessing outpatients with mild to moderate CAP. All-cause mortality was not significantly different for macrolides vs. quinolones, RR 1.03 (0.63-1.68, seven trials), with a low event rate (2%). Treatment failure was significantly lower with quinolones, RR 0.78 (0.67-0.91, 16 trials). The definition of failure used in the primary studies was not clearly representative of patients' benefit. Microbiological failure was lower with quinolones, RR 0.63 (0.49-0.81, 13 trials). All adverse events, adverse events requiring discontinuation and any premature antibiotic discontinuation were significantly more frequent with macrolides, mainly on account of gastrointestinal adverse events. Resistance development was not assessed in the trials. Randomized controlled trials show an advantage of quinolones in the treatment of CAP with regard to clinical cure without need for antibiotic modification at end of treatment and gastrointestinal adverse events. The clinical significance of this advantage is unclear. PMID- 22489671 TI - Endoplasmic reticulum stress modulates nicotine-induced extracellular matrix degradation in human periodontal ligament cells. AB - BACKGROUND AND OBJECTIVE: Tobacco smoking is considered to be one of the major risk factors for periodontitis. For example, about half the risk of periodontitis can be attributable to smoking in the USA. It is evident that smokers have greater bone loss, greater attachment loss and deeper periodontal pockets than nonsmoking patients. It has recently been reported that endoplasmic reticulum (ER) stress markers are upregulated in periodontitis patients; however, the direct effects of nicotine on ER stress in regard to extracellular matrix (ECM) degradation are unclear. The purpose of this study was to examine the effects of nicotine on cytotoxicity and expression of ER stress markers, selected ECM molecules and MMPs, and to identify the underlying mechanisms in human periodontal ligament cells. We also examined whether ER stress was responsible for the nicotine-induced cytotoxicity and ECM degradation. MATERIAL AND METHODS: Cytotoxicity and cell death were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide assay and flow cytometric annexin V and propidium iodide staining. The mRNA and protein expressions of MMPs and ER markers were examined by RT-PCR and western blot analysis. RESULTS: Treatment with nicotine reduced cell viability and increased the proportion of annexin V-negative, propidium iodide-positive cells, an indication of cell death. Nicotine induced ER stress, as evidenced by survival molecules, such as phosphorylated protein kinase like ER-resident kinase, phosphorylated eukaryotic initiation factor-2alpha and glucose-regulated protein-78, and apoptotic molecules, such as CAAT/enhancer binding protein homologous protein (CHOP). Nicotine treatment led to the downregulation of ECM molecules, including collagen type I, elastin and fibronectin, and upregulation of MMPs (MMP-1, MMP-2, MMP-8 and MMP-9). Inhibition of ER stress by salubrinal and transfection of CHOP small interfering RNA attenuated the nicotine-induced cell death, ECM degradation and production of MMPs. Salubrinal and CHOP small interfering RNA inhibited the effects of nicotine on the activation of Akt, JNK and nuclear factor-kappaB. CONCLUSION: These results indicate that nicotine-induced cell death is mediated by the ER stress pathway, involving ECM degradation by MMPs, in human periodontal ligament cells. PMID- 22489674 TI - Investigation of cavitation as a possible damage mechanism in blast-induced traumatic brain injury. AB - Cavitation was investigated as a possible damage mechanism for war-related traumatic brain injury (TBI) due to an improvised explosive device (IED) blast. When a frontal blast wave encounters the head, a shock wave is transmitted through the skull, cerebrospinal fluid (CSF), and tissue, causing negative pressure at the contrecoup that may result in cavitation. Numerical simulations and shock tube experiments were conducted to determine the possibility of cranial cavitation from realistic IED non-impact blast loading. Simplified surrogate models of the head consisted of a transparent polycarbonate ellipsoid. The first series of tests in the 18-inch-diameter shock tube were conducted on an ellipsoid filled with degassed water to simulate CSF and tissue. In the second series, Sylgard gel, surrounded by a layer of degassed water, was used to represent the tissue and CSF, respectively. Simulated blast overpressure in the shock tube tests ranged from a nominal 10-25 pounds per square inch gauge (psig; 69-170 kPa). Pressure in the simulated CSF was determined by Kulite thin line pressure sensors at the coup, center, and contrecoup positions. Using video taken at 10,000 frames/sec, we verified the presence of cavitation bubbles at the contrecoup in both ellipsoid models. In all tests, cavitation at the contrecoup was observed to coincide temporally with periods of negative pressure. Collapse of the cavitation bubbles caused by the surrounding pressure and elastic rebound of the skull resulted in significant pressure spikes in the simulated CSF. Numerical simulations using the DYSMAS hydrocode to predict onset of cavitation and pressure spikes during cavity collapse were in good agreement with the tests. The numerical simulations and experiments indicate that skull deformation is a significant factor causing cavitation. These results suggest that cavitation may be a damage mechanism contributing to TBI that requires future study. PMID- 22489676 TI - Oxygen-evolving Mn cluster in photosystem II: the protonation pattern and oxidation state in the high-resolution crystal structure. AB - Extensive quantum chemical DFT calculations were performed on the high-resolution (1.9 A) crystal structure of photosystem II in order to determine the protonation pattern and the oxidation states of the oxygen-evolving Mn cluster. First, our data suggest that the experimental structure is not in the S(1)-state. Second, a rather complete set of possible protonation patterns is studied, resulting in very few alternative protonation patterns whose relevance is discussed. Finally, we show that the experimental structure is a mixture of states containing highly reduced forms, with the largest contribution (almost 60%) from the S(-3)-state, Mn(II,II,III,III). PMID- 22489675 TI - Distribution patterns of influenza virus receptors and viral attachment patterns in the respiratory and intestinal tracts of seven avian species. AB - This study assessed the presence of sialic acid alpha-2,3 and alpha-2,6 linked glycan receptors in seven avian species. The respiratory and intestinal tracts of the chicken, common quail, red-legged partridge, turkey, golden pheasant, ostrich, and mallard were tested by means of lectin histochemistry, using the lectins Maackia amurensis agglutinin II and Sambucus nigra agglutinin, which show affinity for alpha-2,3 and alpha-2,6 receptors, respectively. Additionally, the pattern of virus attachment (PVA) was evaluated with virus histochemistry, using an avian-origin H4N5 virus and a human-origin seasonal H1N1 virus. There was a great variation of receptor distribution among the tissues and avian species studied. Both alpha-2,3 and alpha-2,6 receptors were present in the respiratory and intestinal tracts of the chicken, common quail, red-legged partridge, turkey, and golden pheasant. In ostriches, the expression of the receptor was basically restricted to alpha-2,3 in both the respiratory and intestinal tracts and in mallards the alpha-2,6 receptors were absent from the intestinal tract. The results obtained with the lectin histochemistry were, in general, in agreement with the PVA. The differential expression and distribution of alpha-2,3 and alpha 2,6 receptors among various avian species might reflect a potentially decisive factor in the emergence of new viral strains. PMID- 22489677 TI - S-protected thiolated chitosan for oral delivery of hydrophilic macromolecules: evaluation of permeation enhancing and efflux pump inhibitory properties. AB - The objective of this study was the investigation of permeation enhancing and P glycoprotein (P-gp) inhibition effects of a novel thiolated chitosan, the so named S-protected thiolated chitosan. Mediated by a carbodiimide, increasing amounts of thioglycolic acid (TGA) were covalently bound to chitosan (CS) in the first step of modification. In the second step, these thiol groups of thiolated chitosan were protected by disulfide bond formation with the thiolated aromatic residue 6-mercaptonicotinamide (6-MNA). Mucoadhesive properties of all conjugates were evaluated in vitro on porcine intestinal mucosa based on tensile strength investigations. Permeation enhancing effects were evaluated ex vivo using rat intestinal mucosa and in vitro via Caco-2 cells using the hydrophilic macromolecule FD(4) as the model drug. Caco-2 cells were further used to show P gp inhibition effects by using Rho-123 as P-gp substrate. Apparent permeability coefficients (P(app)) were calculated and compared to values obtained from each buffer control. Three different thiolated chitosans were generated in the first step of modification, which displayed increasing amounts of covalently attached free thiol groups on the polymer backbone. In the second modification step, more than 50% of these free thiol groups were covalently linked with 6-MNA. Within 3 h of permeation studies on excised rat intestine, P(app) values of all S-protected chitosans were at least 1.3-fold higher compared to those of corresponding thiomers and more than twice as high as that of unmodified chitosan. Additional permeation studies on Caco-2 cells confirmed these results. Because of the chemical modification and higher amount of reactive thiol groups, all S-protected thiolated chitosans exhibit at least 1.4-fold pronounced P-gp inhibition effects in contrast to their corresponding thiomers. These features approve S-protected thiolated chitosan as a promising excipient for various drug delivery systems providing improved permeation enhancing and efflux inhibition effects. PMID- 22489678 TI - A tailed PCR procedure for cost-effective, two-order multiplex sequencing of candidate genes in polyploid plants. AB - Complex polyploid crop genomes can be recalcitrant towards conventional DNA sequencing approaches for allele mining in candidate genes for valuable traits. In the past, this has greatly complicated the transfer of knowledge on promising candidate genes from model plants to even closely related polyploid crops. Next generation sequencing offers diverse solutions to overcome such difficulties. Here, we present a method for multiplexed 454 sequencing in gene-specific PCR amplicons that can simultaneously address multiple homologues of given target genes. We devised a simple two-step PCR procedure employing a set of barcoded M13/T7 universal fusion primers that enable a cost-effective and efficient amplification of large numbers of target gene amplicons. Sequencing-ready amplicons are generated that can be simultaneously sequenced in pools comprising multiple amplicons from multiple genotypes. High-depth sequencing allows resolution of the resulting sequence reads into contigs representing multiple homologous loci, with only insignificant off-target capture of paralogues or PCR artefacts. In a case study, the procedure was tested in the complex polyploid genome of Brassica napus for a set of nine genes identified in Arabidopsis as candidates for regulation of seed development and oil content. Up to six copies of these genes were expected in B. napus. SNP discovery was performed by pooled multiplex sequencing of 30 amplicons in 20 diverse B. napus accessions with interesting trait variation for oil content, providing a basis for comparative mapping to relevant quantitative trait loci and for subsequent marker-assisted breeding. PMID- 22489679 TI - Solvent-free and catalyst-free Biginelli reaction to synthesize ferrocenoyl dihydropyrimidine and kinetic method to express radical-scavenging ability. AB - Benzoyl and ferrocenoyl 3,4-dihydropyrimidin-2(1H)-ones (-thiones) (DHPMs) were synthesized in modest yields via catalyst-free and solvent-free Biginelli condensation of 1-phenylbutane-1,3-dione or 1-ferrocenylbutane-1,3-dione, hydroxyl benzaldehyde, and urea or thiourea. This synthetic protocol revealed that catalysts may not be necessary for the self-assembling Biginelli reaction. The radical-scavenging abilities of the obtained 11 DHPMs were carried out by reacting with 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+*)), galvinoxyl radical, and 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH), respectively. The variation of the concentration of these radicals with the reaction time (t) followed exponential function, [radical] = Ae(-t/a) + Be( t/b) + C. Then, the differential style of this equation led to the relationship between the reaction rate (r) and the reaction time (t), -d[radical]/dt = (A/a)e( t/a) + (B/b)e(-t/b), which can be used to calculate the reaction rate at any time point. On the basis of the concept of the reaction rate, r = k[radical][antioxidant], the rate constant (k) can be calculated with the time point being t = 0. By the comparison of k of DHPMs, it can be concluded that phenolic ortho-dihydroxyl groups markedly enhanced the abilities of DHPMs to quench ABTS(+*), but the introduction of ferrocenoyl group made DHPMs efficient ABTS(+*) scavengers even in the absence of phenolic hydroxyl group. This phenomenon was also found in DHPM-scavenging galvinoxyl radical. In contrast, the ferrocenoyl group cannot enhance the abilities of DHPMs to scavenge DPPH, and phenolic ortho-dihydroxyl groups still played the key role in this case. PMID- 22489680 TI - No difference in 5-HTTLPR and Stin2 polymorphisms frequency between premature ejaculation patients and controls. AB - INTRODUCTION: Premature ejaculation (PE) is defined as the inability of men to control ejaculation and it is the most prevalent male sexual dysfunction. The neurobiogenesis of ejaculation is very complex and involves the serotoninergic (5 hydroxytryptamine [5-HT]) system. A genetic etiology of PE in humans was stated accounting for around 30%. Recently, genetic polymorphisms located on SLC6A4 gene codifying for 5-HT transporter (5-HTT or serotonin transporter [SERT]), the major regulator of serotonergic neurotransmission, have been linked with the pathogenesis of PE and associated with the clinical response to therapy with contrasting results. AIM: In order to establish a possible pathogenetic link between PE and SLC6A4 polymorphisms, we analyzed the 5-HTT-linked polymorphic region (5-HTTLPR), rs25531, and STin2 polymorphisms in 121 patients affected by lifelong and acquired PE. METHODS: Polymerase chain reaction (PCR)-based technology followed by restriction fragment length polymorphism (RFLP) analysis. MAIN OUTCOME MEASURES: Intravaginal ejaculatory latency time was measured by stopwatch in order to diagnose PE, and the results of the SLC6A4 polymorphisms analysis in PE patients was compared with the control group. RESULTS: Genotype frequencies for 5-HTTLPR, rs25531, and STin2 for both patients and controls showed no significant deviation from Hardy-Weinberg equilibrium. No statistically significant differences were found in the frequency of SLC6A4 gene polymorphisms in PE patients vs. controls, or in lifelong PE patients vs. controls, or acquired PE patients vs. controls, or lifelong PE vs. acquired PE patients. The obtained data were contrasting with three out of four previously published reports. CONCLUSIONS: The present results indicate that no difference exists in SLC6A4 polymorphisms frequency between PE patients and controls. A comparison with the previously published reports on this field is reported. PMID- 22489681 TI - Comparative co-expression analysis in plant biology. AB - The analysis of gene expression data generated by high-throughput microarray transcript profiling experiments has shown that transcriptionally coordinated genes are often functionally related. Based on large-scale expression compendia grouping multiple experiments, this guilt-by-association principle has been applied to study modular gene programmes, identify cis-regulatory elements or predict functions for unknown genes in different model plants. Recently, several studies have demonstrated how, through the integration of gene homology and expression information, correlated gene expression patterns can be compared between species. The incorporation of detailed functional annotations as well as experimental data describing protein-protein interactions, phenotypes or tissue specific expression, provides an invaluable source of information to identify conserved gene modules and translate biological knowledge from model organisms to crops. In this review, we describe the different steps required to systematically compare expression data across species. Apart from the technical challenges to compute and display expression networks from multiple species, some future applications of plant comparative transcriptomics are highlighted. PMID- 22489682 TI - Giardia and Cryptosporidium on dairy farms and the role these farms may play in contaminating water sources in Prince Edward Island, Canada. AB - BACKGROUND: Cattle represent a reservoir for Giardia and Cryptosporidium and may contaminate water sources. OBJECTIVES: To determine the distribution of Cryptosporidium and Giardia on dairy farms and in water bodies near the farms. FARMS AND WATER SOURCES: Twenty dairy farms and 20 wells and 13 surface water samples associated with dairy farms. METHODS: Proportions of samples positive for Cryptosporidium or Giardia were determined by a direct immunofluorescence assay. Fecal and water samples were taken at different times. RESULTS: Thirty-two (95% CI: 29-35%) and 14% (95% CI: 12-17%) of fecal samples, and 100 (95% CI: 96-100) and 55% (95% CI: 32-77%) of herds, were positive for Giardia and Cryptosporidium, respectively. Giardia duodenalis assemblage E was detected in high proportions (90%) of fecal samples. Cryptosporidium bovis predominated (51%) in all cattle. C. andersoni predominated in adult cattle (53%), whereas the predominant species in animals < 2 months and 2-6 months was C. bovis, respectively. Only calves < 2 months of age were positive for C. parvum. In 46% (95% CI: 19-75%) and 85% (95% CI: 55-98%) of surface water, concentrations of Giardia cysts and Cryptosporidium oocysts were higher in downstream, than in upstream, locations of farms, whereas only 1 groundwater sample was positive for Cryptosporidium. CONCLUSIONS: This sample of dairy cattle was predominantly infected with nonzoonotic species and genotypes of Cryptosporidium, Giardia, or both. More studies are needed to determine if the presence of Giardia or Cryptosporidium in surface water was associated with shedding in animals from nearby farms. PMID- 22489683 TI - Sexual scripts among young heterosexually active men and women: continuity and change. AB - Whereas gendered sexual scripts are hegemonic at the cultural level, research suggests they may be less so at dyadic and individual levels. Understanding "disjunctures" between sexual scripts at different levels holds promise for illuminating mechanisms through which sexual scripts can change. Through interviews with 44 heterosexually active men and women aged 18 to 25, the ways young people grappled with culture-level scripts for sexuality and relationships were delineated. Findings suggest that, although most participants' culture-level gender scripts for behavior in sexual relationships were congruent with descriptions of traditional masculine and feminine sexuality, there was heterogeneity in how or whether these scripts were incorporated into individual relationships. Specifically, three styles of working with sexual scripts were found: conforming, in which personal gender scripts for sexual behavior overlapped with traditional scripts; exception-finding, in which interviewees accepted culture-level gender scripts as a reality, but created exceptions to gender rules for themselves; and transforming, in which participants either attempted to remake culture-level gender scripts or interpreted their own nontraditional styles as equally normative. Changing sexual scripts can potentially contribute to decreased gender inequity in the sexual realm and to increased opportunities for sexual satisfaction, safety, and well-being, particularly for women, but for men as well. PMID- 22489684 TI - Functional health literacy, medication-taking self-efficacy and adherence to antiretroviral therapy. AB - AIMS: To report a study of the relationship between functional health literacy and medication adherence, as mediated by medication-taking self-efficacy, while controlling for the effect of key demographic variables (such as race, income and level of education). BACKGROUND: Medication adherence is critical to successful HIV/AIDS self-management. Despite simplified regimens and the availability of tools to assist with medication-taking, adherence remains a challenge for many people living with HIV/AIDS. DESIGN: Cross-sectional, secondary analysis. METHODS: Data for this study of 302 adults living with HIV/AIDS who were taking antiretroviral medications were collected from January 2004-December 2007. Medication adherence was measured using electronic event monitors. Bivariate analyses and stepwise regression were conducted to examine the associations among functional health literacy, medication-taking self-efficacy and HIV medication adherence. RESULTS: Overall, functional health literacy was much higher than expected; however, adherence in this sample was sub-optimal. Higher medication taking self-efficacy was associated with higher medication adherence; however, functional health literacy was not significantly related to either medication adherence or self-efficacy beliefs. Hence, medication-taking self-efficacy did not mediate the relationship between functional health literacy and medication adherence. CONCLUSIONS: Medication adherence continues to be an issue for people living with HIV/AIDS. Additional research is needed to understand the disparate findings related to functional health literacy and medication adherence in this and other studies examining this association. PMID- 22489685 TI - Chronic Aspergillus fumigatus exposure upregulates the expression of mucin 5AC in the airways of asthmatic rats. AB - BACKGROUND: Airway mucus hypersecretion is associated with increased morbidity and mortality in patients with asthma. Chronic Aspergillus fumigatus (A. fumigatus) exposure leads to aggravation of airway inflammation and remodeling, including goblet cell hyperplasia (GCH) and mucus hypersecretion in a rat model of asthma. The effects of chronic A. fumigatus exposure on the expression of airway mucin 5AC (MUC5AC) are unknown. METHODS: The rat model of chronic asthma was set up by systemic sensitization and repeated challenge to ovalbumin (OVA). The asthmatic rats were exposed to chronic intranasal inhalation of A. fumigatus spores. The changes of MUC5AC expression, the extent of GCH, and airway hyperreactivity (AHR) were measured after exposure to the fungus. RESULTS AND CONCLUSIONS: Chronic exposure to A. fumigatus upregulates the expression of MUC5AC, and induces GCH in the airways of asthma rats, and the remodeling changes of the airway epithelium was positively correlated with AHR. Upregulation of MUC5AC and induction of GCH may be mechanisms by which chronic A. fumigatus exposure promotes the progression of asthma. PMID- 22489686 TI - Significant vertical phase separation in solvent-vapor-annealed poly(3,4 ethylenedioxythiophene):poly(styrene sulfonate) composite films leading to better conductivity and work function for high-performance indium tin oxide-free optoelectronics. AB - In the present study, a novel polar-solvent vapor annealing (PSVA) was used to induce a significant structural rearrangement in poly(3,4 ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) films in order to improve their electrical conductivity and work function. The effects of polar solvent vapor annealing on PEDOT:PSS were systematically compared with those of a conventional solvent additive method (SAM) and investigated in detail by analyzing the changes in conductivity, morphology, top and bottom surface composition, conformational PEDOT chains, and work function. The results confirmed that PSVA induces significant phase separation between excess PSS and PEDOT chains and a spontaneous formation of a highly enriched PSS layer on the top surface of the PEDOT:PSS polymer blend, which in turn leads to better 3 dimensional connections between the conducting PEDOT chains and higher work function. The resultant PSVA-treated PEDOT:PSS anode films exhibited a significantly enhanced conductivity of up to 1057 S cm(-1) and a tunable high work function of up to 5.35 eV. The PSVA-treated PEDOT:PSS films were employed as transparent anodes in polymer light-emitting diodes (PLEDs) and polymer solar cells (PSCs). The cell performances of organic optoelectronic devices with the PSVA-treated PEDOT:PSS anodes were further improved due to the significant vertical phase separation and the self-organized PSS top surface in PSVA-treated PEDOT:PSS films, which can increase the anode conductivity and work function and allow the direct formation of a functional buffer layer between the active layer and the polymeric electrode. The results of the present study will allow better use and understanding of polymeric-blend materials and will further advance the realization of high-performance indium tin oxide (ITO)-free organic electronics. PMID- 22489687 TI - Development of Ecom50 and retention index models for nontargeted metabolomics: identification of 1,3-dicyclohexylurea in human serum by HPLC/mass spectrometry. AB - The goal of many metabolomic studies is to identify the molecular structure of endogenous molecules that are differentially expressed among sampled or treatment groups. The identified compounds can then be used to gain an understanding of disease mechanisms. Unfortunately, despite recent advances in a variety of analytical techniques, small molecule (<1000 Da) identification remains difficult. Rarely can a chemical structure be determined from experimental "features" such as retention time, exact mass, and collision induced dissociation spectra. Thus, without knowing structure, biological significance remains obscure. In this study, we explore an identification method in which the measured exact mass of an unknown is used to query available chemical databases to compile a list of candidate compounds. Predictions are made for the candidates using models of experimental features that have been measured for the unknown. The predicted values are used to filter the candidate list by eliminating compounds with predicted values substantially different from the unknown. The intent is to reduce the list of candidates to a reasonable number that can be obtained and measured for confirmation. To facilitate this exploration, we measured data and created models for two experimental features; MS Ecom50 (the energy in electronvolts required to fragment 50% of a selected precursor ion) and HPLC retention index. Using a data set of 52 compounds, Ecom50 models were developed based on both Molconn and CODESSA structural descriptors. These models gave r2 values of 0.89 to 0.94 depending on the number of inputs, the modeling algorithm chosen, and whether neutral or protonated structures were used. The retention index model was developed with 400 compounds using a back-propagation artificial neural network and 33 Molconn structure descriptors. External validation gave a v2 = 0.87 and standard error of 38 retention index units. As a test of the validity of the filtering approach, the Ecom50 and retention index models, along with exact mass and collision induced dissociation spectra matching, were used to identify 1,3-dicyclohexylurea in human plasma. This compound was not previously known to exist in human biofluids and its elemental formula was identical to 315 other candidate compounds downloaded from PubChem. These results suggest that the use of Ecom50 and retention index predictive models can improve nontargeted metabolite structure identification using HPLC/MS derived structural features. PMID- 22489688 TI - Determination of free and conjugated forms of bisphenol A in human urine and serum by liquid chromatography-tandem mass spectrometry. AB - Exposure of humans to bisphenol A (BPA), a widely used industrial chemical, is well-known. In humans and animals, conjugation of BPA molecule with glucuronide or sulfate is considered as a mechanism for detoxification. Nevertheless, very few studies have directly measured free, conjugated (e.g., glucuronidated), and substituted (e.g., chlorinated) forms of BPA in human specimens. In this study, free, conjugated (BPA glucuronide or BPAG and BPA disulfate or BPADS), and substituted (chlorinated BPA; mono- [BPAMC], di-[BPADC], and trichloride [BPATrC]) forms of BPA were determined in human urine and serum samples, using solid-phase extraction (SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques. The instrumental calibration for each of the target compounds ranged from 0.01 to 100 ng/mL and showed excellent linearity (r > 0.99). The limits of quantification (LOQs) were 0.01 ng/mL for free BPA and 0.05 ng/mL for the conjugated and substituted BPA. Respective recoveries of the six target compounds spiked into water blanks and sample matrices (urine and serum), and passed through the entire analytical procedure, were 96 +/- 14% and 105 +/- 18% (mean +/- SD) for urine samples and 87 +/- 8% and 80 +/- 13% for serum samples. The optimal recoveries of BPAG and BPADS in the analytical procedure indicted that no deconjugation occurred during the SPE procedure. The method was applied to measure six target chemicals in urine and serum samples collected from volunteers in Albany, New York. BPA and its derivatives were found in urine samples at concentrations ranging from < LOQ to a few tens of ng/mL. In serum, free and conjugated BPA were detected at sub ng/mL concentrations, whereas BPA chlorides were not detected. The urine and serum samples were also analyzed by enzymatic deconjugation and liquid-liquid extraction (LLE) for the determination of total BPA, and the results were compared with those measured by the SPE method. To our knowledge, this is the first report on the occurrence of BPAG and BPADS in human serum. PMID- 22489689 TI - Fluorescence in situ hybridization assay detects upper urinary tract transitional cell carcinoma in patients with asymptomatic hematuria and negative urine cytology. AB - We evaluated the performance of a multiprobe FISH (fluorescence in situ hybridization) assay for noninvasive detection of upper urinary tract transitional cell carcinoma (UUT-TCC) in patients with asymptomatic hematuria and negative urine cytology. Voided urine samples from 285 patients with asymptomatic hematuria and negative urine cytology were prospectively analyzed by FISH technique. FISH assays were performed to detect chromosomal changes frequently associated with TCC, including aneuploidy of chromosomes 3, 7 and 17, and loss of the 9p21 locus. Eleven (3.9%) had a positive FISH result. Of the 11 patients, nine (81.8%) were found to have a TCC of the upper urinary tract, while no patients with negative FISH findings were found to have UUT-TCC. In this selected cohort, the sensitivity and specificity of FISH for the detection of UUT-TCC was 100% and 99.3%, respectively. Our preliminary data suggest that the clinical utility of FISH assay of chromosomes 3, 7, 9, and 17 as a noninvasive ancillary test for the diagnosis of UUT-TCC in a selected patient population with asymptomatic hematuria and negative urine cytology and by significant high sensitivity and specificity may be a reliable diagnostic approach for early detection of UUT-TCC patients. Further larger prospective and multicenter trials are needed to confirm our results. PMID- 22489690 TI - Cellular stress response in Eca-109 cells inhibits apoptosis during early exposure to isorhamnetin. AB - The flavonol aglycone isorhamnetin shows anti-proliferative activity in a variety of cancer cells. Previous work, from our laboratory showed that isorhamnetin inhibits the proliferation of human esophageal squamous carcinoma Eca-109 cells in vitro, but only after 72 h of exposure. This led us to propose that isorhamnetin exposure induces a cellular stress response that inhibits the antiproliferative and apoptotic effects of the compound during early exposure. To test this hypothesis, the present study examined the effects of isorhamnetin on Eca-109 cells during the first 72 h of exposure. Cell growth was assessed using the trypan blue exclusion assay, and expression of IkappaBalpha, NF-kappaB/p65, NF-kappaB/p50, phospho-Akt, Bcl-2, COX-2, Mcl-1, Bax, p53 and Id-1 were analyzed by Western blot. During the first 72 h of exposure, NF-kappaB/p65 and NF kappaB/p50 accumulated in nuclei and expression of COX-2, Bcl-2 and Mcl-1 increased. In contrast, expression of IkappaBalpha and Bax fell initially but later increased. Expression of phospho-Akt and p53 showed no detectable change during the first 48 h. Pretreatment with the NF-kappaB inhibitor MG132 before exposure to isorhamnetin blocked the nuclear accumulation of p50 and p65, thereby inhibiting cell proliferation. These results show that during early exposure of Eca-109 cells to isorhamnetin, the NF-kappaB signaling pathway is activated and COX-2 expression increases, and this increase in expression partially inhibits isorhamnetin-induced apoptosis. Beyond 72 h of exposure, however, the apoptotic effect of isorhamnetin dominates, leading to inhibition of the NF-kappaB pathway and of cellular proliferation. These results will need to be taken into account when exploring the use of isorhamnetin against cancer in vivo. PMID- 22489691 TI - Phase I study of docetaxel, cisplatin and concurrent radiotherapy for locally advanced gastric adenocarcinoma. AB - This phase I study is designed to determine the maximal tolerated dose and the dose-limiting toxicity of docetaxel with cisplatin and concurrent radiotherapy in patients with unresectable locally advanced gastric adenocarcinoma. Docetaxel was given once a week with the dosage escalated from 5 mg/m(2) to 15 mg/m(2) in increments of 2.5 mg/m(2). Cisplatin were administered at 20 mg/m(2) once a week. Radiotherapy was delivered to 50.4Gy at 1.8Gy/day. At least three patients were enrolled at each level. The maximal tolerated dose (MTD) and dose-limiting toxicity (DLTs) was determined. The DLTs were defined as grade 3 or 4 hematologic and nonhematologic toxicity. Twenty-one patients with locally advanced gastric adenocarcinoma were enrolled. Grade 1-2 neutropenia and nausea/vomiting were the most common side effects. The first DLT (grade-3 neutropenia) was observed in one of three patients at 12.5 mg/m(2) docetaxel. Three more patients were enrolled, but DLT was not observed and 6 patients were enrolled into 15 mg/m(2) group, DLT occurred in 3 patients (1 Grade 3 neutropenia, 1 Grade 4 neutropenia and 1 Grade 3 nausea/vomiting). Overall tumor response rate was 66.7% with 28.6% complete and 38.1% partial response. In conclusion, the MTD of docetaxel was 15 mg/m(2), and the recommended dose of docetaxel for Phase II study was 12.5 mg/m(2) weekly. The docetaxel and cisplatin with concurrent radiotherapy were tolerable and feasible in treating locally advanced gastric adenocarcinoma. PMID- 22489692 TI - Mutation pattern of KRAS and BRAF oncogenes in colorectal cancer patients. AB - The aim of this study was to identify KRAS and BRAF gene mutations in colorectal cancer patients and to assess whether they are linked with clinicopathological features. The results of KRAS and BRAF mutation analysis could be used in the selection of patients for anti-EGFR therapy. All specimens were obtained during routine surgery of patients with colorectal carcinoma. The diagnoses were established by standard procedures and confirmed histopathologically. After DNA extraction, KRAS mutations were analyzed using quantitative real-time PCR and BRAF mutations were analyzed using real-time PCR by fluorescence melting curve analysis. Our results show that KRAS gene mutations were detected in 35.6% samples and the most frequent mutation was Gly12Val. BRAF gene mutation Val600Glu was detected in 8.5% samples. Statistical analysis revealed a significant association between the KRAS mutation and Dukes' stage (p=0.034), with the lowest frequency in Dukes'A, and between the KRAS mutation and histological grade (p=0.044), with no KRAS mutation found in poor differentiated tumors. The first data about KRAS and BRAF mutational status in the sample of Croatian population with colorectal cancer shows that the incidence of KRAS and BRAF mutations is within generally valid limits. Prospective studies are to be continued in order to determine whether these mutations contribute to progression of colorectal cancer. PMID- 22489693 TI - Altered angiogenesis gene expression in gastrointestinal stromal tumors: potential use in diagnosis, outcome prediction, and treatment. AB - Gastrointestinal stromal tumors (GISTs) occur in diverse locations of the gastrointestinal system. We studied the pathogenesis of GIST by measurement of microvascular density (MVD) and expression of nine signal transduction molecules that have known roles in diverse types of cancers (PI3K, Akt, pTEN, uPA, MMP2, MMP9, HIF1, NOS2, and VEGF) in the tumorous tissues and adjacent normal tissues of 124 GIST patients. We also compared the MVD (a measure of angiogenesis) in tumorous and adjacent normal tissues. Our results indicated significant differences in the expression of the assayed mRNAs and proteins in GIST cells and in adjacent normal cells. In addition, tumorous tissues had significantly higher MVD than adjacent normal tissues. These nine genes have potential for use for diagnosis, outcome prediction, and as new targeted treatments for GISTs. PMID- 22489694 TI - Increased ischemia-modified albumin levels in patients with gastric cancer. AB - Reactive oxygen species (ROS) are found in the development stages of carcinogenesis. Fifty two patients with gastric cancer and 35 controls were enrolled in this trial. IMA, MDA, Total Oxidant Status (TOS), Total Antioxidant Status (TAS) and Oxidative Stress Index (OSI) were evaluated. There was a significant increase in IMA and MDA levels in the patient group (0.405+/-0.111, 0.271+/-0.066; p= 0.0001 and 0.207+/-0.251, 0.077+/-0.103; p= 0.004 respectively). TOS was also higher in the patient group but it was not statistically different. TAS was statistically lower and there was significant difference in OSI (0.621+/-0.394, 0.996+/-0.37; p=0.0001 and 9.68+/-18.2, 2.9+/ 3.85; p=0.001 respectively). The areas under receiver operating characteristics curves for the determination of gastric cancer were 0.842 for IMA and 0.708 for MDA. Increased levels of IMA, MDA and oxidative stress index were detected and this condition is associated with the impairment of oxidant-antioxidant balance. PMID- 22489695 TI - Biologic importance and prognostic significance of selected clinicopathological parameters in patients with oral and oropharyngeal squamous cell carcinoma, with emphasis on smoking, protein p16(INK4a) expression, and HPV status. AB - The aim of this study is to evaluate the biologic importance and prognostic significance of selected clinicopathological parameters in patients with oral (OSCC) and oropharyngeal (OPSCC) squamous cell carcinoma, with emphasis on smoking, protein p16(INK4a) (p16) expression, and human papillomavirus (HPV) status.The study sample consisted of 48 patients with OSCC and 44 patients with OPSCC. Half of the patients were nonsmokers and the other half were gender-, age- and tumor localization-matched smokers. p16 expression was detected in 17/48 (35 %) OSCCs and in 36/44 (82 %) OPSCCs and HPV DNA was present in 7/48 (15 %) OSCCs and in 35/44 (80 %) OPSCCs. The sensitivity and specificity of p16 expression for HPV DNA presence were 0.74 and 0.88, respectively. The OPSCCs were more frequently basaloid (p < 0.001) while the OSCCs were more frequently conventional (p < 0.000001). The OSCCs were more likely to recur locally and to be the cause of death (p = 0.009 in both parameters).The HPV-positive tumors were more frequently localized in oropharynx, were basaloid SCCs and were p16- and HPV positive (p < 0.000001 in all 4 parameters). The HPV-negative tumors were more frequently localized in oral cavity (p < 0.000001), more frequently asociated with local, regional and locoregional recurence (p = 0.011, p = 0.019 and p = 0.030, respectively) and with tumor-related death (p = 0.003). There was no significant difference with regard to smoking history (p > 0.05). The survival of patients with HPV-positive tumors was significantly longer (median 112 months; 95% CI 54 - 112 months) than that of patients with HPV-negative tumors (median 17 months; 95% CI 12 - 39 months) (p < 0.001). The HPV status of OSCC/OPSCC is an important biological and prognostic parameter and should be examined in all cases, using PCR or immunohistochemical detection of surrogate marker p16. Smoking itself does not seem to be an important prognostic factor. PMID- 22489696 TI - Overexpression of ECM1 contributes to migration and invasion in cholangiocarcinoma cell. AB - Although the expression of extracellular matrix protein-1 (ECM1) has been documented in several tumor models, the function of ECM1 has remained unclear. In this study, expression of ECM1 was detected by real time PCR and immunohistochemistry. The role and mechanism of ECM1 overexpression in cholangiocarcinoma (CCA) cells were assessed by wound-healing, matrigel invasion assay and Western blotting. Expression of ECM1 was significantly elevated in CCA tissues than that in adjacent noncancerous, cholangitis and normal bile duct tissues. Its overexpression was associated with poor differentiation, lymph node metastasis, poor prognosis, and the level of CA199, MMP-9, estrogen receptor. Knockdown of ECM1 suppressed migration and invasion of CCA cells. Using PI3K or IKK inhibitor reduced the level of phospho-Akt or phospho-IkappaBalpha as well as ECM1. Taken together, overexpression of ECM1 may contribute to CCA initiation and progression through promoting migration and invasion of CCA cells, its overexpression was associated with Akt/NF-kappaB signaling axis. PMID- 22489698 TI - Apoptosis-, proliferation, immune function-, and drug resistance- related genes in ER positive, HER2 positive and triple negative breast cancer. AB - The aim of our study was to examine an association between gene expression assessed using a 23-gene microarray and receptor status of breast cancer samples categorized as ER positive, HER2 positive and triple negative subtypes. The ER positive cohort was subsequently divided into Luminal A, Luminal B HER2 negative and Luminal B HER2 positive subtypes. Core- needle biopsies were collected from 78 female patients with inoperable locally advanced breast cancer or resectable tumors suitable for downstaging, before any treatment. Expressions of 23 genes were determined by means of TagMan Low Density Arrays. Analysis of variance was used to select genes with discriminatory potential between receptor subtypes. We introduced a correction for false discovery rates (presented as q values) due to testing multiple hypothesis. Pairwise post-hoc comparisons of receptor subtypes were performed using Tukey 's HSD test. Five genes out of a 23-gene microarray differed significantly in relation to breast cancer receptor-based subtypes. Among these five genes, we identified: BCL2 (p=0.0002, q=0.0009), MKI67 (p=0.0037, q=0.0064), IGF1R (p=0.0040, q=0.0064), FOXC1 (p=0.0113, q=0.0135) and IRF1 (p=0.0435, q=0.0416) as ones showing ER positive, HER2 positive and triple negative -subtype specific expression profiles. When incorporating Luminal A, Luminal B HER2 negative, Luminal B HER2 positive subtypes into analysis, four genes: BCL2 (p=0.0006, q=0.0034), MKI67 (p=0.0078, q=0.0198), FOXC1 (p=0.0102, q=0.0198) and IGF1R (p=0.0174, q=0.0254) were selected. Elevated levels of IGF1R and BCL2 were significantly linked with Luminal A subtype. Triple negative breast cancer subtype was associated with higher expression of IRF1, FOXC1 and MKI67. In HER2 positive cohort lower expression of all five analyzed genes was noted. PMID- 22489697 TI - DeltaNp63alpha mediates proliferation and apoptosis in human gastric cancer cells by the regulation of GATA-6. AB - The oncogenic isoform of the p63 protein, DeltaNp63alpha, has been found to be overexpressed in numerous human squamous cell carcinomas. However, the role of DeltaNp63alpha in human gastric cancer remains unknown. To evaluate this role, we screened a panel of gastric cancer cell lines for DeltaNp63alpha expression and found that they are correlated with the differentiation status of the cell lines. Using the MKN28 gastric cancer cell line for loss-of-function or gain-of-function of DeltaNp63alpha in our experiments, we observed that forced expression of DeltaNp63alpha promoted cell proliferation as assessed by the MTT and colony formation assays, and increased the GATA-6 expression. In contrast, down regulation of DeltaNp63alpha via small interfering RNA suppressed cell proliferation, induced cell apoptosis, and reduced the expression of GATA-6. In conclusion, our data suggest that DeltaNp63alpha plays an important role in cell growth and proliferation of gastric cancer cells, which may be associated with the regulation of GATA-6 expression. This is the first study exploring the biological functions and the underlying mechanism of DeltaNp63alpha during gastric cancer development. It also identifies potential targets for anti-tumor treatment. PMID- 22489699 TI - Vascular endothelial growth factor and soluble intercellular adhesion molecule-1 in lung adenocarcinoma with malignant pleural effusion: correlations with patient survival and pleural effusion control. AB - The mechanisms by which vascular endothelial growth factor (VEGF) and soluble intercellular adhesion molecule-1 (sICAM-1) contribute to lung cancer growth have not been fully elucidated. This study aimed to assess the role of VEGF and sICAM 1 in control of pleural effusions (PE) and survival in patients with primary human lung adenocarcinoma. Using enzyme-linked immunoadsorbent assay, the concentrations of VEGF and sICAM-1 were measured in pleural effusions and serum from a total of 79 lung adenocarcinoma patients with malignant pleural effusions (MPE) and 24 patients with tuberculosis. Data were correlated with the efficacy of MPE control and survival. Compared to patients with tuberculosis, the levels of VEGF and sICAM-1 in both PE and serum were significantly higher in patients with lung adenocarcinoma. Statistically significant correlation was observed between PE VEGF levels and MPE control. PE VEGF>=2760 pg/ml was used as a cut-off point for failure to MPE control (odds ratio=7.06; 95% confidence interval (CI), 2.40-20.78; P<0.001). The median progression-free survival (PFS) from response assessment was 3 months. In a multivariate analysis, PE VEGF (hazard ratio [HR], 1.16; 95% CI, 1.02-1.32), serum sICAM-1 (HR, 1.90; 95% CI, 1.17-3.07) were confirmed as independent prognostic factors for PFS. The levels of VEGF in PE can be used to predict the therapeutic efficacy in the control of MPE and this, together with serum level of sICAM-1 is potential survival factors in lung adenocarcinoma patients with MPE. PMID- 22489700 TI - Efficacy and safety of Id-protein-loaded dendritic cell vaccine in patients with multiple myeloma--phase II study results. AB - In a phase II clinical study, pretreated multiple myeloma patients with relapsing or stable disease received autologous anticancer vaccine containing dendritic cells loaded with Id-protein. Patients received a total of 6 vaccine doses intradermally in monthly intervals. No clinical responses were observed. During the follow-up with a median of 33.1 months (range: 11-43 months), the disease remained stable in 7/11 (64%) of patients. Immune responses measured by ELISpot were noted in 3/11 (27%) and DTH skin test for Id-protein was positive in 8/11 (73%) of patients; out of those, 1/11 (9%) and 5/11 (46%), respectively, had preexisting immune response to Id-protein before the vaccination began. Outcomes were compared to those of a control group of 13 patients. A trend to lower cumulative incidence of progression in the vaccinated group was observed at 12 months from the first vaccination (p= 0.099). More patients from the control group compared to vaccinated patients required active anticancer therapy [4/11 (36%) vs. 8/13 (62%)]. Vaccines based on dendritic cells loaded with Id-protein are safe and induce specific immune response in multiple myeloma patients. Our results suggest that the vaccination could stabilize the disease in approximately two-thirds of patients. KEYWORDS: dendritic cells, immunotherapy, anticancer vaccines, Id-protein, multiple myeloma. PMID- 22489701 TI - Tumor-specific histone signature and DNA methylation in multiple myeloma and leukemia cells. AB - Understanding the epigenetics of tumor cells is of clinical significance for the treatment of cancer, and thus, chemists have focused their efforts on the synthesis of new generation of inhibitors of histone deacetylases (HDACs) or methylation-specific enzymes as novel important anti-cancer drugs. Here, we tested whether the histone signature and DNA methylation in multiple myeloma (MM) and leukemia cells is tumor-specific as compared with that in non-malignant lymphoblastoid cells. We observed a distinct histone signature in c-myc, Mcl-1, and ribosomal gene loci in MOLP8 MM and K562 leukemia cells, when compared with lymphoblastoid cells. Histone and DNA methylation patterns in MOLP8 cells were partially modified by the clinically promising HDAC inhibitor, vorinostat. In comparison with lymphoblastoid WIL2NS cells, MOLP8 cells and K562 cells were characterized by an absence of the gene silencing marker H3K9me2 in the c-myc and ribosomal genes. However, high levels of H3K27me3 were detected in the promoters and coding regions of selected genomic regions in these cells. Treatment by vorinostat increased the level of DNA methylation at the c-myc promoter, and this alteration was accompanied by a decrease in c-MYC protein. In MOLP8 cells, vorinostat significantly increased the H3K9 acetylation in the Mcl-1 coding regions and promoter. Both MOLP8 and K562 leukemia cells were characterized by decreased levels of H3K9me2 in the Mcl-1 gene as compared with lymphoblastoid WIL2NS cells. Lower levels of H3K9me1 in the Mcl-1 promoter, however, were specific for MM cells as compared with the other cell types studied. In other MM and leukemia cell lines, COLO677, OPM2, and U937, the ribosomal genes were less prone to epigenetic heterogeneity as compared to the c-myc and Mcl-1 proto oncogenes. Taken together, these data describe both tumor-specific and loci specific histone signature and DNA methylation profiles. PMID- 22489702 TI - Chromosomal rearrangements in lymphocytes of head and neck squamous cell carcinoma treated with chemotherapeutic agents. AB - Squamous cell carcinoma especially of oral cavity is one of the most prevalent diseases in the world. Chromosomal rearrangements are known to play important role in the pathogenesis of many diseases including cancer. In case of Head and Neck Squamous Cell Carcinoma, chromosomal changes are detectable at all stages of tumor development providing excellent opportunity for chromosomal prognosis and therapy. The present work aimed to study the frequency and pattern of chromosomal aberrations in human peripheral blood lymphocyte culture of freshly diagnosed Head and Neck squamous cell carcinoma patients. Further In vitro anticancer drugs (5-Fluorouracil {5-FU } and Cisplatin) effects were studied for clastogenicity. Results indicated significant impact of chemotherapeutic agents on the frequency of different types of chromosomal rearrangements. PMID- 22489703 TI - Melatonin enhanced bexarotene efficacy in experimental mammary carcinogenesis. AB - The aim of this paper was to test lower, safe bexarotene dose administered alone and in combination with melatonin to improve its efficacy. Mammary carcinogenesis was induced by N-methyl-N-nitrosourea in female Sprague-Dawley rats, administered in two doses intraperitoneally between 42.-54. postnatal days and chemoprevention was initiated 7 days prior to first N-methyl-N-nitrosourea injection and lasted 15 weeks. Bexarotene, particularly in combination with melatonin decreased mammary tumor incidence and frequency with a shift from poorly to well differentiated carcinomas. Bexarotene alleviated glycaemia and liver/heart muscle glycogen concentration decreased as well as liver/thymus malondialdehyde increased in comparison with control group. The combination of bexarotene and melatonin is therefore beneficial in preventive-curative model of experimental mammary carcinogenesis and may be applied in oncological practice as such. PMID- 22489704 TI - Low molecular-weight chitosan as a pH-sensitive stealth coating for tumor specific drug delivery. AB - When a nanoparticle is developed for systemic application, its surface is typically protected by poly(ethylene glycol) (PEG) to help prolonged circulation and evasion of immune clearance. On the other hand, PEG can interfere with interactions between nanocarriers and target cells and negatively influence the therapeutic outcomes. To overcome this challenge, we propose low molecular-weight chitosan (LMWC) as an alternative surface coating, which can protect the nanomedicine in neutral pH but allow cellular interactions in the weakly acidic pH of tumors. LMWCs with a molecular weight of 2-4 kDa, 4-6.5 kDa, and 11-22 kDa were produced by hydrogen peroxide digestion and covalently conjugated with poly(lactic-co-glycolic acid) (PLGA). Nanoparticles created with PLGA-LMWC conjugates showed pH-sensitive cell interactions, which enabled specific drug delivery to cells in a weakly acidic environment. The hydrophilic LMWC layer reduced opsonization and phagocytic uptake. These properties qualify LMWCs as a promising biomaterial for pH-sensitive stealth coating. PMID- 22489705 TI - Media, risk, and absence of blame for "acts of God": attenuation of the European volcanic ash cloud of 2010. AB - This article analyzes the character, extent, and patterns of media coverage of the 2010 volcanic ash cloud, comparing it with coverage of other major natural hazards, such as Deepwater Horizon. It does so drawing upon sociological themes and concludes that the ash cloud was reported largely in its own terms rather than being amplified as a wider, uncertain threat. As well as the absence of major incident and casualties two interrelated factors are highlighted to explain this result. Emphasizing the importance of hazard duration, the unexpected arrival and short-lived character of the ash cloud was one important factor that limited the potential for sustained media amplification. More broadly, this was an "act of God" with no clear responsible agents. This preliminary study suggests that contemporary media risk narrative requires a focus for institutional blame attribution, and without a plausible candidate amplification may not acquire momentum. PMID- 22489707 TI - Prospective memory reminders: a laboratory investigation of initiation source and age effects. AB - Prior research indicates that, in some circumstances, reminders may facilitate prospective remembering. However, it remains unclear whether this effect is dependent on the initiation source (self vs. external), whether it is moderated by task type (event vs. time based), or whether the provision of standardized reminders particularly benefits older adults. In the current study, young (n = 48) and older adults (n = 47) were tested on a laboratory-based prospective memory task in which they encountered three counterbalanced reminder conditions: no reminders, self-initiated reminders, and experimenter-initiated reminders. The results indicated that while the provision of reminders enhanced prospective memory performance, no difference was seen between self-initiated and experimenter-initiated reminder conditions, nor was there any interaction with age or prospective memory type (event vs. time based). These data support the role of both self- and externally generated external reminders as an aid to prospective remembering. However, the absence of any interaction with age is not consistent with theoretical models of ageing that consider the provision of such reminders to reduce strategic demands (or increase automatic processing). PMID- 22489708 TI - Hydration of the bisulfate ion: atmospheric implications. AB - Using molecular dynamics configurational sampling combined with ab initio energy calculations, we determined the low energy isomers of the bisulfate hydrates. We calculated the CCSD(T) complete basis set (CBS) binding electronic and Gibbs free energies for 53 low energy isomers of HSO(4)(-)(H(2)O)(n=1-6) and derived the thermodynamics of adding waters sequentially to the bisulfate ion and its hydrates. Comparing the HSO(4)(-)/H(2)O system to the neutral H(2)SO(4)/H(2)O cluster, water binds more strongly to the anion than it does to the neutral molecules. The difference in the binding thermodynamics of HSO(4)(-)/H(2)O and H(2)SO(4)/H(2)O systems decreases with increasing number of waters. The thermodynamics for the formation of HSO(4)(-)(H(2)O)(n=1-5) is favorable at 298.15 K, and that of HSO(4)(-)(H(2)O)(n=1-6) is favorable for T < 273.15 K. The HSO(4)(-) ion is almost always hydrated at temperatures and relative humidity values encountered in the troposphere. Because the bisulfate ion binds more strongly to sulfuric acid than it does to water, it is expected to play a role in ion-induced nucleation by forming a strong complex with sulfuric acid and water, thus facilitating the formation of a critical nucleus. PMID- 22489706 TI - MT5-MMP, ADAM-10, and N-cadherin act in concert to facilitate synapse reorganization after traumatic brain injury. AB - Matrix metalloproteinases (MMPs) influence synaptic recovery following traumatic brain injury (TBI). Membrane type 5-matrix metalloproteinase (MT5-MMP) and a distintegrin and metalloproteinase-10 (ADAM-10) are membrane-bound MMPs that cleave N-cadherin, a protein critical to synapse stabilization. This study examined protein and mRNA expression of MT5-MMP, ADAM-10, and N-cadherin after TBI, contrasting adaptive and maladaptive synaptogenesis. The effect of MMP inhibition on MT5-MMP, ADAM-10, and N-cadherin was assessed during maladaptive plasticity and correlated with synaptic function. Rats were subjected to adaptive unilateral entorhinal cortical lesion (UEC) or maladaptive fluid percussion TBI+bilateral entorhinal cortical lesion (TBI+BEC). Hippocampal MT5-MMP and ADAM 10 protein was significantly elevated 2 and 7 days post-injury. At 15 days after UEC, each MMP returned to control level, while TBI+BEC ADAM-10 remained elevated. At 2 and 7 days, N-cadherin protein was below control. By the 15-day synapse stabilization phase, UEC N-cadherin rose above control, a shift not seen for TBI+BEC. At 7 days, increased TBI+BEC ADAM-10 transcript correlated with protein elevation. UEC ADAM-10 mRNA did not change, and no differences in MT5-MMP or N cadherin mRNA were detected. Confocal imaging showed MT5-MMP, ADAM-10, and N cadherin localization within reactive astrocytes. MMP inhibition attenuated ADAM 10 protein 15 days after TBI+BEC and increased N-cadherin. This inhibition partially restored long-term potentiation induction, but did not affect paired pulse facilitation. Our results confirm time- and injury-dependent expression of MT5-MMP, ADAM-10, and N-cadherin during reactive synaptogenesis. Persistent ADAM 10 expression was correlated with attenuated N-cadherin level and reduced functional recovery. MMP inhibition shifted ADAM-10 and N-cadherin toward adaptive expression and improved synaptic function. PMID- 22489709 TI - Obstetrical outcome in women with self-prepared birth plan. AB - OBJECTIVE: To determine whether introducing a pre-prepared birth plan upon labor admission has an impact on obstetrical outcome. METHODS: A retrospective study of all women who prepared an ante-partum birth plan, from 2007-2010. Outcome was compared with a control group consisting of women without a birth plan matched by age, parity and gestational week in a 3:1 ratio. RESULTS: 154 women were compared to a matched control group of 462 women. Women preparing a birth plan, were less likely to undergo an intra partum cesarean section (11.7% vs. 20.3%, p = 0.016). First and second degree perineal tears occurred more frequently in women preparing a birth plan (72.1% vs. 25.5%, p < 0.001). The utilization of birth plan was also associated with a higher rate of epidural administration (81.2% vs. 68.8%, p = 0.004) and a lower rate of intravenous analgesics use (1.3% vs. 10.2%, p < 0.001). CONCLUSION: Women presenting with a birth plan, compared to an age-, parity- and gestational week- matched control group are less likely to undergo a cesarean section, more likely to have first and second degree perineal tears and more likely to use an epidural. The paucity of data and the mis-concepts of medical staff suggest that larger prospective studies are needed. PMID- 22489710 TI - An unusual morphology of patent ductus arteriosus in a dog. AB - A 12-week old, entire female Border terrier weighing 3.5 kg was presented for investigation of a continuous left heart base murmur. The clinical presentation and preoperative echocardiogram were consistent with a standard morphology of patent ductus arteriosus (PDA) but a discrete ductal vessel was not identified during surgical dissection. Surgery had to be abandoned due to deterioration of the patient's condition under general anaesthesia which led to cardiorespiratory arrest and death despite attempts at resuscitation. Necropsy identified a recess within the wall of the aorta communicating with the pulmonary artery via an ostium at the heart base which determined this structure as an intramural PDA. This morphology of PDA is previously unreported. This report demonstrates that an intramural PDA is not readily identifiable surgically because of the absence of a discrete ductal vessel and it is important to appreciate that unusual morphologies of PDA may occur. PMID- 22489712 TI - Clinical utility of biomarkers in premature atherosclerosis. AB - Atherosclerosis is a very complex procedure responsible for the development of coronary artery disease which is the leading cause of death in the civilized world. The obvious pandemic character of atherosclerosis augments the need to discover an ideal biomarker, which will be able to facilitate the clinical diagnosis of the atherosclerosis from the physicians especially in the early stages of the atherosclerotic process. Among the biomarkers that are already used there are classical ones, such as c-reactive protein, interleukins, tumour necrosis factor, apolipoproteins, fibrinogen, homocysteine, and novel promising ones such as lipoprotein-associated phospholipase, asymmetric dimethylarginine, myeloperoxidase, cathepsins and cystatin C. The possibility of combining circulating biomarkers with other methods such as non-invasive and invasive imaging is clinically attractive because this could contribute to the improved diagnosis and understanding of premature atherosclerosis pathogenesis. PMID- 22489711 TI - Pregabalin- and topiramate-mediated regulation of cognitive and motor impulsivity in DBA/2 mice. AB - BACKGROUND AND PURPOSE: Impulsivity is a core symptom in many neuropsychiatric disorders. The main objective of this study was to evaluate the effects of topiramate and pregabalin on the modulation of different impulsivity dimensions in DBA/2 mice. EXPERIMENTAL APPROACH: The effects of acute and chronic administration of pregabalin (10, 20 and 40 mg.kg(-1) ) and topiramate (12.5, 25 and 50 mg.kg(-1) ) were evaluated in the light-dark box (LDB), hole board test (HBT) and delayed reinforcement task (DRT). alpha(2A) -Adrenoceptor, D(2) receptor and TH gene expression were evaluated by real-time PCR in the prefrontal cortex (PFC), accumbens (ACC) and ventral tegmental area (VTA), respectively. KEY RESULTS: Acute pregabalin administration showed a clear anxiolytic-like effect (LDB) but did not modify novelty-seeking behaviour (HBT). In contrast, topiramate produced an anxiolytic effect only at the highest dose, whereas it reduced novelty seeking at all doses tested. In the DRT, acute pregabalin had no effect, whereas topiramate only reduced motor impulsivity. Chronically, pregabalin significantly increased motor impulsivity and topiramate diminished cognitive impulsivity. Pregabalin decreased alpha(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively, and increased TH in the VTA. In contrast, chronic administration of topiramate increased alpha(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively, and also increased TH in the VTA. CONCLUSIONS AND IMPLICATIONS: These results suggest that the usefulness of pregabalin in impulsivity-related disorders is related to its anxiolytic properties, whereas topiramate modulates impulsivity. These differences could be linked to their opposite effects on alpha(2A) -adrenoceptor and D(2) -receptor gene expression in the PFC and ACC, respectively. PMID- 22489714 TI - Assessment of acute coronary syndromes: focus on novel biomarkers. AB - Coronary artery disease (CAD) is the leading cause of mortality in Western Societies and several developing countries. Recent evidence suggests that most detrimental clinical manifestations of CAD, such as acute coronary syndromes (ACS), are the outcome of inflammatory processes that lead to plaque formation and rupture and eventually to ischemia and potentially myocardial necrosis. Neither of the traditionally used biomarkers is thought to be the gold standard in detection of myocardial ischemia or necrosis. A biomarker that could detect quite early the ischemic myocardium as well as define the risk of a future event with high sensitivity and specificity is still lacking. Several biomarkers, implicated in the pathogenesis and clinical evolution of atherosclerosis, have emerged as potent biomarkers for early detection of myocardial ischemia. In the current review, we summarize recent evidence of the most promising biomarkers and discuss their potential role in clinical practice in patients suffering from ACSs. PMID- 22489715 TI - Predictive value of biomarkers in patients with heart failure. AB - Heart failure (HF) is a complex syndrome with high morbidity and mortality while, myocardial injury, hemodynamic overload, genetic, neurohormonal, inflammatory and biochemical factors are implicated in the development and progression of the disease. Interestingly, despite the development of several diagnostic tests, HF diagnosis remains clinical, based on symptoms and signs, while there is a poor relationship between symptoms and the prognosis of HF. Several biomarkers have recently been examined for their efficacy to predict outcome and assess prognosis of HF patients. The best studied for its prognostic ability sub-group of biomarkers is the neurohormones including the natriuretic peptides, the components of the renin-angiotensin-aldosterone system and the catecholamines. Others sub-groups of biomarkers include inflammatory and oxidative stress markers, extracellular matrix remodeling markers and myocardial injury markers (such as troponins I and T). Nevertheless, it is difficult to access a single biomarker fulfilling our need to evaluate prognosis and guiding treatment in acute or chronic HF patients, thus the predictive ability of combined biomarkers is recently under research. Therefore, further studies are needed to elucidate the clinical significance of these biomarkers. In the present review, we will discuss the usefulness and significance of potentials or established biomarkers in HF patients focusing on their ability to predict adverse events, morbidity and mortality. PMID- 22489716 TI - Monitoring calcific aortic valve disease: the role of biomarkers. AB - Calcific aortic valve disease is a common disease in the elderly associated with significant morbidity and mortality. It was once described as a passive degenerative process during which serum calcium attaches to the valve surface and binds to the leaflet. However, during the last decade mounting evidence demonstrated that this disease has an active biologic process with numerous signaling pathways. The histological hallmarks seem to be inflammation, oxidized lipids-also detectable in aortic valve lesions-and a remodeling of the extracellular matrix leading to bone formation. Over the years, growing evidence has indicated the risk factors for calcific aortic stenosis including lipids, hypertension, male gender, renal failure, and diabetes. Additional monitoring tools, such as molecular imaging, could improve risk stratification, while assessment of severity and prognosis of patients with chronic aortic regurgitation, is desirable. Also, several studies have investigated the role of biomarkers regarding their utility in the screening of calcific aortic valve disease and their putative clinical value, though their role still remains undetermined. PMID- 22489713 TI - Evaluating oxidative stress in human cardiovascular disease: methodological aspects and considerations. AB - Oxidative stress is a key feature in atherogenesis, since reactive oxygen species (ROS) are involved in all stages of the disease, from endothelial dysfunction to atheromatic plaque formation and rupture. It is therefore important to identify reliable biomarkers allowing us to monitor vascular oxidative stress status. These may lead to improved understanding of disease pathogenesis and development of new therapeutic strategies. Measurement of circulating biomarkers of oxidative stress is challenging, since circulation usually behaves as a separate compartment to the individual structures of the vascular wall. However, measurement of stable products released by the reaction of ROS and vascular/circulating molecular structures is a particularly popular approach. Serum lipid hydroperoxides, plasma malondialdehyde or urine F2-isoprostanes are widely used and have a prognostic value in cardiovascular disease. Quantification of oxidative stress at a tissue level is much more accurate. Various chemiluminescence and high performance liquid chromatography assays have been developed over the last few years, and some of them are extremely accurate and specific. Electron spin resonance spectroscopy and micro-electrode assays able to detect ROS directly are also widely used. In conclusion, measurement of circulating biomarkers of oxidative stress is valuable, and some of them appear to have predictive value in cardiovascular disease. However, these biomarkers do not necessarily reflect intravascular oxidative stress and therefore cannot be used as therapeutic targets or markers to monitor pharmacological treatments in clinical settings. Measurement of vascular oxidative stress status is still the only reliable way to evaluate the involvement of oxidative stress in atherogenesis. PMID- 22489717 TI - Biomarkers determining cardiovascular risk in patients with kidney disease. AB - Cardiovascular disease (CVD) remains the leading cause of premature death in patients with chronic kidney disease (CKD). Recent evidence suggests that the interaction of "classic" and "non-classic" cardiovascular risk factors is an important contributor in excessive and accelerated CVD in patients with CKD. Indeed, the imposing cardiovascular morbidity and mortality of CKD patients corresponds to a significant extent in endothelial dysfunction, inflammation, oxidative stress, vascular calcification and volume overload. In addition, the kidney's function decline is independently associated with CVD in patients with chronic kidney disease. Currently, there is a growing interest in the role of new biomarkers that are closely correlated with CVD in CKD population. In current review, we summarize the so far acquired knowledge of the most promising biomarkers and we discuss the major clinical correlations of novel risk factors and new biomarkers of CVD in CKD patients, their predictive value for future cardiovascular events and their use in the treatment monitoring of this population. PMID- 22489718 TI - Circulating endothelial progenitor cells as biomarkers for prediction of cardiovascular outcomes. AB - Experimental studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial integrity and hemostasis. The number of circulating EPC has been shown to be inversely correlated with cardiovascular risk factors and vascular function and to predict cardiovascular events independent of both traditional and non-traditional risk factors. Thus, EPCs provide a clinical advantage over the use of other biomarkers as their measurement is directly associated with endothelial function, and available evidence suggests that they are consistently and significantly associated with a spectrum of cardiovascular complications, such as acute coronary syndromes and coronary artery disease. However, many issues in the field of EPC isolation and identification, particularly in regards to the effective and unequivocal molecular characterization of these cells still remain unresolved. In addition, simple EPC counts do not adequately describe cardiovascular disease risk. This limitation is attributable to variation in the definition of EPCs, the number of existing cardiovascular risk factors in different patients as well as a difference in the interaction between EPCs and other hematopoietic progenitor, inflammatory cells or platelets. PMID- 22489719 TI - Biomarkers as a guide of medical treatment in cardiovascular diseases. AB - There is increasing interest in utilizing novel markers of cardiovascular disease risk and consequently, there is a need to assess the value of their use. In this paper, we will review the role of biomarkers in acute coronary syndromes, heart failure and risk stratification for cardiovascular events as guide for treatment scribing. In particular, high sensitivity assays for troponin evaluation detect with greater precision patients with elevated troponin. Therefore, direct and appropriate management is succeeded in these patients with reduction of complications due to earlier treatment, as well. Regarding heart failure, randomized trials that have evaluated biomarker guided treatment approach have not succeeded in establishing specific results for natriuretic peptides (BNP, NT proBNP) use in terms of therapy guidance. Apart from them, a variety of novel or already used biomarkers, have been tested by small trials for heart failure management, without however, managing to dominate in every day care. Finally, as far as risk stratification for cardiovascular events is concerned, hsCRP has proved to be a strong but doubted biomarker. Therefore, lifestyle and behavioral modification remain the cornerstone of primary prevention. PMID- 22489720 TI - Functional, genetic and biochemical biomarkers of peripheral arterial disease. AB - Patients with peripheral arterial disease (PAD) suffer from increased cardiovascular morbidity and mortality. The ankle brachial index has been widely used as an easy tool to identify and stratify patients with PAD, however its predictive value remains limited. Higher levels of inflammatory and prothrombotic biomarkers have been associated with the development and progression of PAD and recent data suggest that may provide additional information for cardiovascular risk stratification of these patients. The current review will present available information on functional, genetic and biochemical biomarkers which have been associated with PAD in cross sectional and large prospective studies and highlight their additive value for risk stratification of these patients. PMID- 22489721 TI - The role of microRNAs in cardiovascular disease. AB - Cardiovascular disease, which is multifactorial and can be influenced by a multitude of environmental and heritable risk factors, remains a major health problem, even though its pathophysiology is far from been elucidated. Discovered just over a decade ago, microRNAs comprise short, non-coding RNAs, which have evoked a great deal of interest, due to their importance for many aspects of homeostasis and disease. Hundreds of different microRNAs are constantly being reported in various organisms. According to a growing body of literature, they have been implicated in the regulation of human physiological processes. More specifically, miRNAs are expressed in the cardiovascular system and could have crucial roles in normal development and physiology, as well as in disease development. Furthermore, they have been shown to participate in cardiovascular disease pathogenesis including atherosclerosis, coronary artery disease, myocardial infarction, heart failure and cardiac arrhythmias. In contrast to our original thought, miRNAs exist in circulating blood and are relatively stable, thus, they could be proved useful as biomarkers in that state. Understanding the underlying mechanisms, in which these major regulatory gene families are implicated, will provide novel opportunities for diagnosis and therapy of cardiovascular diseases. PMID- 22489722 TI - Biomarkers associated with vulnerable atheromatous plaque. AB - Atherogenesis progresses through lipid core expansion and macrophage accumulation at the plaque, leading to fibrous cap rupture. Plaque rupture occurs in the plaque fissuring at one point, which ultimately brings the platelets into contact with the content of the lipid core, and the blood coagulation factors together with tissue factor. The transition from stable atherosclerotic plaques to vulnerable plaques finally resulting in the plaque rupture is the consequence of an inflammatory reaction. This process involves complex cellular interactions engaging many mediators, chemokines, and cytokines which can be measured in serum and plasma and thus serve as biomarkers that differentiate the pathophysiologic phases of disease progression. Pathological studies support the risk of inflammation in high-risk patients to a greater extent than the degree of vessel stenosis. It is therefore important to identify reliable biomarkers allowing us to monitor vascular inflammatory state. In clinical investigations, several new biomarkers have been identified that provide increasing diagnostic and prognostic significance. However, more confirmatory studies are required to clinical use. Furthermore, assays for automated use need to be developed, and cut-off levels need to be defined. Further technological advances will likely facilitate the use of multimarker profiling to identify with coronary vulnerable plaque. PMID- 22489723 TI - Biomarkers in cardiovascular disease. PMID- 22489724 TI - Chelating agents for neurodegenerative diseases. AB - It has become apparent in the last years that metal ion homeostasis and its dysfunction which results in increased accumulation in brain, notably of copper, iron and zinc, may be associated with a number of neurodegenerative diseases, such that chelation therapy may be one therapeutic option. We briefly outline chelators currently available together with strategies to develop new chelators capable of crossing the blood-brain-barrier. The homeostasis of iron in brain together with changes in brain iron with ageing are reviewed as well as the role of iron in Parkinson's disease, and the potential of chelation therapy in PD. Copper and zinc homeostasis in brain and age associated changes are then outlined, along with a discussion of the possible involvement of Zn, Cu and Fe in Alzheimer's disease. We conclude with a brief summary of chelation therapy in AD. PMID- 22489725 TI - Compounds derived from endophytes: a review of phytochemistry and pharmacology. AB - OBJECTIVE: Endophytes, microorganisms that reside in the tissues of living plants, are a promising source of novel compounds with biological activity, or an alternative source of compounds originally isolated from higher plants. The intent of this review is to provide insights into their occurrence in nature, the products that they make, and how some of these organisms are beginning to show some potential for human use. METHODS: Information for analysis of endophytic microorganisms was obtained from libraries and Internet scientific databases such as Scirus, Google Scholar, CAB-Abstracts, MedlinePlus, PubMed, SciFinder, Scopus and Web of Science. RESULTS: Many of the compounds reported here were isolated exclusively from endophytes in culture, while other compounds had been previously reported as chemical constituents of higher plants. A survey of the literature shows endophytic microorganisms are mainly known for their alkaloids with cytotoxic, chemopreventive, anti-metastatic and antitumor properties used in the treatment of several types of cancer. The studies of these alkaloids highlight the existence of various potential leads for the development of novel anti-cancer agents. Modern pharmacology studies demonstrated that their crude extracts and active compounds possess wide pharmacological actions, especially for anti microbial drug discovery, with neuroprotective, antioxidant, nematicidal, antiplasmodium, anti-inflammatory activities. AIM OF THE REVIEW: This review summarizes the up-to-date and comprehensive information on compounds from endophytes fungi from 1995 to 2011 that relates to 313 compounds isolated from endophytic microorganisms, together with the botany, phytochemistry, pharmacology and toxicology, and discusses possible trends and the scope for future research of endophytes. PMID- 22489726 TI - New therapeutic approaches by using microorganism-derived compounds. AB - The role of natural products as a source for remedies has been recognized since ancient times. Despite major scientific and technological progress in combinatorial chemistry, drugs derived from natural product still make an enormous contribution to drug discovery today. Nature is an attractive source of new therapeutic candidate compounds since a tremendous chemical diversity is found in millions of species of plants, animals, marine organisms and microorganisms. Microorganisms such as bacteria and fungi have been invaluable to discover drugs and lead compounds. These microorganisms produce a large variety of antimicrobial agents which have evolved to give their hosts an advantage over their competitors in the microbiological world. The screening of microorganisms became highly popular after the discovery of penicillin but in recent years the list of antibacterial agents (bacteria- or fungi-derived) has increased considerably with the arrival of cephalosporins, tetracyclines, aminoglycosides, rifamycins, and chloramphenicol. Although most of the drugs derived from microorganisms are used in antibacterial therapy, some microbial metabolites have provided lead compounds in other fields of medicine. For example: the fungal metabolite lovastatin, which was the lead compound for a series of drugs that lower cholesterol levels, the ciclosporin (fungal metabolite) currently used to suppress the immune response after transplantation operations and sirolimus- a bacterium-derived macrolide- used in the treatment of some cancers. The aim of this review is to analyze the current uses and the future applications in therapeutic treatments of microorganism-derived products (MdPs) and discuss the results obtained in the some clinical trials. PMID- 22489727 TI - My fortuitous encounter with dialysis therapy. PMID- 22489728 TI - Bariatric surgery at the time of ventricular assist device implantation for morbidly obese patients prior to heart transplantation. PMID- 22489730 TI - Cortisol reactions to a social evaluative paradigm in 5- and 6-year-old children. AB - The goal of the present study was to develop a stress paradigm to elicit cortisol secretory responses in a group of 5- and 6-year-old children as a whole. To this end, we tested a paradigm containing elements of social evaluative threat, unpredictability and uncontrollability, and with a duration of 20 min. The Children's Reactions to Evaluation Stress Test is composed of three short tasks that children have to perform in front of a judge. The tasks are rigged so as to provoke (partial) failure in the child's performance. Participants were 42 children (M = 68.0 months, SD = 4.3). Six saliva samples were taken during the testing session to obtain cortisol measurements of baseline concentrations, stress reactivity, and recovery. Our findings showed that this paradigm was effective in provoking a significant increase in salivary cortisol concentration in the group as a whole, with no effects of possible confounders (child's sex, age or school, parental educational level, time of testing, sex of experimenter, and sex of judge). The mean cortisol concentration increase for the group was 127.5% (SD = 190.9); 61% of the children could be classified as reactors (mean increase of 214%, SD = 201.5), and 39% as non-reactors (mean decrease of 7.8%, SD = 16.8). To our knowledge, this is the first study in this age group that shows a significant cortisol response for the group as a whole to a standardized laboratory paradigm. As such, this paradigm is a promising tool to be used in future research on early life interactions between physiology and psychology. PMID- 22489731 TI - Role of oxidative stress in a rat model of radiation-induced erectile dysfunction. AB - INTRODUCTION: Chronic oxidative stress is one of the major factors playing an important role in radiation-induced normal tissue injury. However, the role of oxidative stress in radiation-induced erectile dysfunction (ED) has not been fully investigated. Aims. To investigate role of oxidative stress after prostate confined irradiation in a rat model of radiation-induced ED. METHODS: Fifty-four young adult male rats (10-12 weeks of age) were divided into age-matched sham radiotherapy (RT) and RT groups. Irradiated animals received prostate-confined radiation in a single 20 Gy fraction. MAIN OUTCOME MEASURES: Intracavernous pressure (ICP) measurements with cavernous nerve electrical stimulation were conducted at 2, 4, and 9 weeks following RT. The protein expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits (Nox4 and gp91(phox)), markers of oxidative DNA damage (8-hydroxy-2'-deoxyguanosine [8 OHdG]), lipid peroxidation (4-hydroxynonenal [4HNE]), and inflammatory response including inducible nitric oxide synthase, macrophage activation (ED-1), and nitrotyrosine, and endogenous antioxidant defense by nuclear factor erythroid 2 related factor (Nrf2) were evaluated in irradiated prostate tissue and corpora cavernosa (CC). In addition, we investigated the relationships between results of ICP/mean arterial pressure (MAP) ratios and expression level of oxidative stress markers. RESULTS: In the RT group, hemodynamic functional studies demonstrated a significant time-dependent decrease in ICP. Increased expression of Nox4, gp91(phox), 8-OHdG, and 4HNE were observed in the prostate and CC after RT. Similarly, expressions of inflammatory markers were significantly increased. There was a trend for increased Nrf2 after 4 weeks. ICP/MAP ratio negatively correlated with higher expression level of oxidative markers. CONCLUSION: NADPH oxidase activation and chronic oxidative stress were observed in irradiated prostate tissue and CC, which correlated with lower ICP/MAP ratio. Persistent inflammatory responses were also found in both tissues after RT. These findings suggest that oxidative stress plays a crucial role in the development of radiation-induced ED. PMID- 22489732 TI - Perceived prevalence and definitions of sexual dysfunction as predictors of sexual function and satisfaction. AB - Evidence for the influence of sexual beliefs on sexual functioning and satisfaction has mainly emanated from clinical lore. Empirical investigations on this topic remain sparse. This study investigated whether beliefs regarding prevalence and definitions of male and female sexual dysfunctions predicted sexual function and satisfaction in a sample of 131 undergraduate students. Results indicated that higher perceived prevalence of male and female sexual dysfunctions was predictive of lower sexual functioning and poorer sexual satisfaction in women. For the male participants, none of the examined sexual beliefs emerged as significant predictors of their sexual functioning or satisfaction. Surprisingly, it was also found that participants estimated the prevalence of female sexual dysfunctions to be higher than male sexual dysfunctions, while defining male sexual dysfunctions more broadly than female sexual dysfunctions. Possible mechanisms for the findings are provided. PMID- 22489733 TI - Bidirectional perception-production relations in phonological development: evidence from positional neutralization. AB - Many children who neutralize phonemic contrasts in production exhibit diminished perception of the same contrasts. It is usually difficult to determine whether the perception deficit caused the production error, or vice versa; however, the direction of causation has implications for treatment planning. This study examines perception-production relationships in the phenomenon of neutralization in strong position, where children neutralize only in perceptually salient contexts. To test a hypothesis that this phenomenon arises from a child-specific pattern of perceptual sensitivity, a non-word discrimination task was administered to a 4-year-old boy with neutralization in strong position in production. Contrary to the perceptual hypothesis, his discrimination accuracy was greatest for contrasts in initial/strong position, where his production errors occurred. Independent of position, however, his perception of a phonemic contrast he neutralized was decreased relative to other contrasts. This case is argued to constitute evidence that a primary production deficit can cause decreased perceptual ability. PMID- 22489734 TI - Development and predictive value of early vocalizations in very-low-birth-weight children: a longitudinal study. AB - The aim of the present study was to analyze early vocalization development, the predictive value of this development in terms of later language skills, and possible gender difference in early vocalization development in a selected cohort of 32 very-low-birth-weight (VLBW) children and 35 full-term controls. The data on early vocalization development were gathered using a structured maternal report method. Language skills were assessed at 2.0. No significant difference was found between the groups in the rate of early vocalization development when corrected age was used for the VLBW children. The rate of early vocalization development correlated significantly with later language performance in VLBW children. Only weak correlations were detected in the control group. We found no gender difference in early vocalization development in either of the groups. The findings suggest that the rate of early vocalization development can be used as a clinical predictor of later linguistic performance in VLBW children. PMID- 22489735 TI - Phonological mean length of utterance in specific language impairment: a multi case study of children acquiring Finnish. AB - This study assesses the phonological development of four Finnish-speaking children (ages 4;8, 4;9, 4;9 and 5;5) with specific language impairment (SLI) and dyspractic features in speech. The analysis is performed using the phonological mean length of utterance (pMLU) method. Moreover, the children's phonological abilities are evaluated qualitatively in relation to segments, phonotactics and word structure. The results are compared with those obtained from four age matched typically developing peers and with the data from an earlier study using the pMLU method on younger, typically developing Finnish children. In the pMLU analysis, the children with SLI performed roughly at the level of typically developing 2-year-old children. The qualitative analyses revealed that children with SLI had difficulties in producing word-medial clusters and word-initial consonants and that they exhibited frequent consonant assimilations, infrequent errors and vowel errors. The pMLU method did differentiate between children with SLI and typically developing children. However, qualitative analyses revealed some weaknesses of the pMLU method when assessing Finnish children with SLI. PMID- 22489736 TI - Encoding, memory, and transcoding deficits in Childhood Apraxia of Speech. AB - A central question in Childhood Apraxia of Speech (CAS) is whether the core phenotype is limited to transcoding (planning/programming) deficits or if speakers with CAS also have deficits in auditory-perceptual encoding (representational) and/or memory (storage and retrieval of representations) processes. We addressed this and other questions using responses to the Syllable Repetition Task (SRT) [Shriberg, L. D., Lohmeier, H. L., Campbell, T. F., Dollaghan, C. A., Green, J. R., & Moore, C. A. (2009). A nonword repetition task for speakers with misarticulations: The syllable repetition task (SRT). Journal of Speech, Language, and Hearing Research, 52, 1189-1212]. The SRT was administered to 369 individuals in four groups: (a) typical speech-language (119), (b) speech delay-typical language (140), (c) speech delay-language impairment (70), and (d) idiopathic or neurogenetic CAS (40). CAS participants had significantly lower SRT competence, encoding, memory, and transcoding scores than controls. They were 8.3 times more likely than controls to have SRT transcoding scores below 80%. We conclude that speakers with CAS have speech processing deficits in encoding, memory, and transcoding. The SRT currently has moderate diagnostic accuracy to identify transcoding deficits, the signature feature of CAS. PMID- 22489738 TI - Human papillomavirus (HPV) infection and genotype frequency in the oral mucosa of newborns in Milan, Italy. AB - Human papillomavirus (HPV) causes cutaneous and mucosal infections in both adults and children. In order to evaluate HPV prevalence and the spectrum of genotypes in the oral cavity of paediatric subjects, a retrospective study was carried out on oral-pharyngeal swabs collected from 177 newborns aged 0-6 months. HPV-DNA was detected by a nested-PCR; the viral typing was made through DNA sequencing. HPV infection was identified in 25 subjects (14.1%) and the sequence analysis showed eight distinct genotypes. These data confirm HPV detection in newborn oral mucosa. Further investigations are needed to clarify the methods of HPV acquisition. PMID- 22489739 TI - Functionality of proteins bound to plasma polymer surfaces. AB - The deposition of a thin film layer by plasma polymerization enables the surface functionalization of a wide range of substrate materials for biointerfacial interactions. Plasma polymers can surface-bind proteins specifically via covalent linkages or nonspecifically through other irreversible adsorption mechanisms; key questions are whether covalent chemisorption has indeed occurred, and whether the protein retains functionality. Here the mode of surface binding of streptavidin and the biotin binding functionality of the bound streptavidin layer are studied on plasma polymer (pp) surfaces deposited using propionaldehyde and ethanol that were plasma polymerized at different powers (P) to investigate possible mechanisms for protein binding to a range of different surface chemistries. As expected, with pp surfaces composed principally of aldehyde groups, protein conjugation appears to be specific (chemisorption) allowing the immobilization of streptavidin (SAV) molecules retaining the ability to bind biotinylated probes. To contrast with this, we present the first study of protein adsorption to ethanol pp surfaces prepared at different P. This provides an investigation into retention of the hydroxyl functionality in the pp at low P and its effect on protein adsorption. Adsorption of human serum albumin (HSA) to ethanol pp was similar to that on propionaldehyde pp except at low P (5 W) where hydroxyl group retention and hydration presumably has a role in reducing protein adsorption. Although we observed SAV adsorption to ethanol pp surfaces at all P, interestingly, the protein lost its ability to bind biotinylated probes. Thus we suggest that irreversible, nonspecific adsorption of protein on ethanol pp surfaces results in apparent protein denaturation despite the hydrophilic nature of the ethanol pp surface. We conclude by making inferences between the pp structure as measured by X-ray photoelectron spectroscopy (XPS) and the related protein adsorption mechanisms. PMID- 22489740 TI - Stereocontrolled 1,3-phosphatyloxy and 1,3-halogen migration relay toward highly functionalized 1,3-dienes. AB - A double migratory cascade reaction of alpha-halogen-substituted propargylic phosphates to produce highly functionalized 1,3-dienes has been developed. This transformation features 1,3-phosphatyloxy group migration followed by 1,3-shifts of bromine and chlorine as well as the unprecedented 1,3-migration of iodine. The reaction is stereodivergent: (Z)-1,3-dienes are formed in the presence of a copper catalyst, whereas gold-catalyzed reactions exhibit inverted stereoselectivity, producing the corresponding E products. PMID- 22489742 TI - Identification of novel liver X receptor activators by structure-based modeling. AB - Liver X receptors (LXRs) are members of the nuclear receptor family. Activators of LXRs are of high pharmacological interest as LXRs regulate cholesterol, fatty acid, and carbohydrate metabolism as well as inflammatory processes. On the basis of different X-ray crystal structures, we established a virtual screening workflow for the identification of novel LXR modulators. A two-step screening concept to identify active compounds included 3D-pharmacophore filters and rescoring by shape alignment. Eighteen virtual hits were tested in vitro applying a reporter gene assay, where concentration-dependent activity was proven for four novel lead structures. The most active compound 10, a 1,4-naphthochinone, has an estimated EC50 of around 5 MUM. PMID- 22489743 TI - Low-back pain, leg pain, and chronic idiopathic testicular pain treated with chiropractic care. AB - OBJECTIVES: The purpose of this article is to report the case of a patient who had low-back pain, leg pain, and idiopathic chronic testicular pain and who sought chiropractic care for his low-back and leg pain and received pain relief including his testicular pain. SUBJECT: A 36-year-old male patient had low-back pain, right leg pain, and testicular pain that was worsening. All had been present for 5 years. He had been seen by several medical physicians and had lumbar magnetic resonance imaging and x-rays performed. All were read as normal. Examination revealed tenderness of the testicles bilaterally with no masses or other abnormality of the testicles or scrotum. Orthopedic and neurological testing was unremarkable. Tenderness rated 8 out of 10 was noted at the L4 spinous process. INTERVENTION: The patient was treated with Cox Technic (flexion distraction) of the lumbar spine, receiving a total of 19 treatments over an 8 week time period. RESULTS: After 4 weeks, the patient's low-back pain was decreased and his leg pain was gone. The testicular pain was improved after the first treatment and gone after 3 weeks of care. The patient was followed up by telephone at 3 and 6 months after discharge to find out if the testicle pain had returned, which it had not. CONCLUSIONS: This case was one of chronic idiopathic testicular pain. The patient was treated with the Cox Technic, and his low-back pain improved with complete remission of his leg and testicular pain. The testicular pain had not returned 6 months following his discharge from care. PMID- 22489744 TI - Aqueous phototransformation of diazepam and related human metabolites under simulated sunlight. AB - Phototransformation of the widely used benzodiazepine pharmaceuticals diazepam and human metabolites nordiazepam, temazepam and oxazepam under simulated sunlight in water was investigated. Photolysis experiments were conducted in the presence and absence of humic acids. Half-lives for each of the benzodiazepine pharmaceuticals were <200 h (under all conditions) suggesting that phototransformation is an important process for such chemicals in the photic zone of receiving waters. Due to the observed phototransformation of the benzodiazepines, significant emphasis was placed on identification of the photoproducts. A total of fourteen photoproducts, including benzophenones, acridinones and quinazolinones or quinazolines was identified and measured by liquid chromatography-multistage mass spectrometry (LC-MS(n)). Phototransformation studies were also undertaken on authentic samples of two of the identified photoproducts, 5-chloro-methylaminobenzophenone and 2-amino-5 chlorobenzophenone, in order to establish the phototransformation pathways. Interestingly, these two photoproducts showed relatively higher persistence than some of the benzodiazepines, suggesting that the fate and effects of photoproducts should also be incorporated into future risk assessments and environmental models of the fate of benzodiazepines. PMID- 22489745 TI - Solubilization mechanism and characterization of the structural change of bacterial cellulose in regenerated states through ionic liquid treatment. AB - A statistical approach was used to characterize the heterogeneous structures of bacterial cellulose samples pretreated with four kinds of ionic liquids (ILs). The structural heterogeneity of these samples was measured by Fourier transform infrared spectroscopy as well as solid-state NMR methods such as cross polarization magic-angle spinning and dipolar-assisted rotational resonance. The obtained data matrices were then evaluated by principal components analysis. The measured 1-D data clearly revealed the modification of crystalline cellulose; in addition, the statistical approach revealed subtle structural changes that occurred upon pretreatment with different kinds of ILs. To investigate whether such regenerated structural changes occurred because of solubilization, we examined the intermolecular nuclear Overhauser effect between cellulose and an IL. Our results clarify how the nucleophilic imidazole is attacked and suggest that the cation of the IL is associated with the collapse of hydrogen bonds in cellulose. PMID- 22489746 TI - Motor interference and facilitation arising from observed movement kinematics. AB - Previous studies demonstrate that observing the movements of others can interfere with concurrent movement execution. This interference effect is attributed to incongruence between the observed and executed movements. The study presented here examined different aspects of observed and executed movement congruency. Participants attempted to trace straight lines in the air using one of two movement tasks while observing an experimenter perform movements varied by their task and spatial congruency. The data revealed that kinematic aspects of the observed movements were incorporated into the observer's own movements. Observing the same kinematics led to interference or facilitation effects depending on whether the direction of the observed movement was congruent or incongruent with the movement the participant performed. These data suggest that low-level properties of observed movements can modulate participant performance. PMID- 22489747 TI - Synthesis of beta-fluoroamines by Lewis base catalyzed hydrofluorination of aziridines. AB - Lewis base catalysis promotes the in situ generation of amine-HF reagents from benzoyl fluoride and a non-nucleophilic alcohol. The hydrofluorination of aziridines to provide beta-fluoroamines using this latent HF source is described. This protocol displays a broad scope with respect to aziridine substitution and N protecting groups. Examples of regio- and diastereoselective ring opening to access medicinally relevant beta-fluoroamine building blocks are presented. PMID- 22489748 TI - Less invasive biomarkers of acute rejection: reaching the elusive clinic. PMID- 22489749 TI - Initial evaluation of canine urinary cystatin C as a marker of renal tubular function. AB - OBJECTIVES: To evaluate the performance of a particle-enhanced turbidimetric assay for measuring canine urinary cystatin C and to investigate if the urinary cystatin C to creatinine ratio is higher in dogs with renal disease than in non renal disease dogs. METHODS: Urinary cystatin C was measured by particle-enhanced turbidimetric assay using an avian antihuman cystatin C antibody and the performance of this assay was evaluated. Clinical relevance was tested in 46 dogs that were divided into three groups: healthy dogs (n=14), non-renal disease dogs (n=17) and dogs with renal disease (n=15). RESULTS: The assay was linear (R(2)=0.99) and precise (mean intra- and inter-assay coefficients of variation were 2.3 and 2.9%, respectively). The recovery was 111.5% and the limit of blank was 0.02 mg/L. Urinary cystatin C and urinary cystatin C to creatinine ratio differed significantly (P<0.001) between the three cohorts of dogs. CLINICAL SIGNIFICANCE: Measurement of cystatin C by particle-enhanced turbidimetric assay performed with high precision and linearity. This assay can be processed on automated clinical chemistry analysers making it widely available to commercial laboratories. Urinary cystatin C to creatinine ratio can differentiate dogs with renal disease from dogs without renal disease. These preliminary results suggest that urinary cystatin C to creatinine ratio is a promising marker for evaluating renal tubular function. PMID- 22489750 TI - Mycophenolate mofetil in the therapy of uveitic macular edema--long-term results. AB - PURPOSE: To assess the long-term efficacy of mycophenolate mofetil (MMF) in uveitic cystoid macular edema (CMO). METHODS: Thirty-eight uveitis patients with CMO treated with MMF with a follow-up of at least 5 years were analyzed. The patients were divided into two groups: group A, 24 patients with CMO that had occurred before initiation of MMF; group B, 14 patients who developed CMO for the first time during MMF. RESULTS: In group A, a complete remission of CMO without recurrences was observed in 12 of 24 patients (50%, rate: 0.12/patient-year). In group B, CMO occurred in 7 patients (50%) despite standard dosage of MMF, and in 7 patients (50%) during MMF dose reduction. CONCLUSIONS: The results show that MMF is not always sufficiently effective as a long-term treatment for uveitic macular edema. Moreover, in some uveitis patients MMF cannot prevent new development of CMO. PMID- 22489751 TI - Contribution of human growth hormone-releasing hormone receptor (GHRHR) gene sequence variation to isolated severe growth hormone deficiency (ISGHD) and normal adult height. AB - OBJECTIVE: Molecular causes of isolated severe growth hormone deficiency (ISGHD) in several genes have been established. The aim of this study was to analyse the contribution of growth hormone-releasing hormone receptor (GHRHR) gene sequence variation to GH deficiency in a series of prepubertal ISGHD patients and to normal adult height. DESIGN, SUBJECTS AND MEASUREMENTS: A systematic GHRHR gene sequence analysis was performed in 69 ISGHD patients and 60 normal adult height controls (NAHC). Four GHRHR single-nucleotide polymorphisms (SNPs) were genotyped in 248 additional NAHC. An analysis was performed on individual SNPs and combined genotype associations with diagnosis in ISGHD patients and with height-SDS in NAHC. RESULTS: Twenty-one SNPs were found. P3, P13, P15 and P20 had not been previously described. Patients and controls shared 12 SNPs (P1, P2, P4-P11, P16 and P21). Significantly different frequencies of the heterozygous genotype and alternate allele were detected in P9 (exon 4, rs4988498) and P12 (intron 6, rs35609199); P9 heterozygous genotype frequencies were similar in patients and the shortest control group (heights between -2 and -1 SDS) and significantly different in controls (heights between -1 and +2 SDS). GHRHR P9 together with 4 GH1 SNP genotypes contributed to 6.2% of height-SDS variation in the entire 308 NAHC. CONCLUSIONS: This study established the GHRHR gene sequence variation map in ISGHD patients and NAHC. No evidence of GHRHR mutation contribution to ISGHD was found in this population, although P9 and P12 SNP frequencies were significantly different between ISGHD and NAHC. Thus, the gene sequence may contribute to normal adult height, as demonstrated in NAHC. PMID- 22489752 TI - Vaginal fetal fibronectin as a predictor of spontaneous preterm delivery in triplet gestations. AB - OBJECTIVE: To assess the diagnostic accuracy of vaginal fetal fibronectin (fFN) sampling for predicting preterm birth in asymptomatic women carrying triplet gestations. METHODS: An historical cohort of patients carrying triplet gestations between 1998 and 2010 was identified from a single practice by chart review. All patients were screened with fFN testing at 2-3 week intervals from 22 weeks to 32 weeks of gestation. Outcomes evaluated were spontaneous preterm birth prior to 28, 30, and 32 weeks' gestation and delivery within 2 and 3 weeks of testing. RESULTS: There were 56 pregnancies that met criteria for inclusion. For delivery prior to 30 weeks' gestation, the test had a sensitivity of 75%, a specificity of 85.4%, a positive predictive value of 46.2%, a negative predictive value of 95.3%, positive likelihood ratio of 5.13, and a negative likelihood ratio of 0.29 (p < 0.0001). For delivery within 3 weeks of a single fFN assessment, the test had a sensitivity of 53.3%, a specificity of 95.8%, a positive predictive value of 53.3%, a negative predictive value of 95.8%, positive likelihood ratio of 12.7 and negative likelihood ratio of 0.48 (p < 0.0001). CONCLUSION: Fetal fibronectin testing provides moderate to high prediction of spontaneous preterm birth in triplet gestations. PMID- 22489753 TI - HIV testing among heterosexual young adults: the influence of partners' risk behaviors and relationship dynamics. AB - Using relational theory and survey data from the Toledo Adolescent Relationships Study (n = 665), this article examined whether individuals were tested for HIV while intimately involved in a current or recent heterosexual relationship. The analyses included the respondent's and partner's sexual risk factors (non exclusivity and lifetime number of partners), relational variables, prior testing, and demographic characteristics. It was found that 39% of respondents had an HIV test while involved in their current or most recent sexual relationship, and women (47%), compared with men (29%), were significantly more likely to have been tested. Whereas some predictors operated similarly (number of sex partners and pressured to have sex), others displayed significant gender differences (partner's sexual exclusivity, sexual communication difficulties, and pregnancy), particularly related to women's testing behaviors. Excerpts from qualitative interviews with male respondents suggested that some relational dynamics, not well reflected in relational theory, played a role in their testing. Results highlight the need to consider gendered dynamics when targeting young adults for routine HIV testing. PMID- 22489755 TI - Nationwide survey of adolescents and young adults with end-stage kidney disease. AB - AIM: To better understand the health-care needs of adolescents and young adults (AYA) with end-stage kidney disease (ESKD), we sought to describe the demographic characteristics of a national cohort. METHODS: Data were retrieved from the Australia and New Zealand Dialysis and Transplant Registry. We included all patients aged 15-25 years, living in Australia and receiving renal replacement therapy (RRT) on 31 December 2009. Data included race, aetiology of kidney disease, postal code, transition and migration history. RESULTS: A total of 495 AYA were receiving RRT in Australia giving a prevalence of 143 per million age related population. Sixty-three per cent had a functioning transplant, 24% were receiving haemodialysis and 13% peritoneal dialysis. Median current age was 22 years (interquartile range (IQR) 19-24). The most prevalent cause of ESKD was glomerulonephritis (33%). The majority of patients lived in capital cities. Indigenous patients were more likely to live in more remote areas. Eighty-five per cent of patients were currently receiving care at an adult unit and 35% of these patients had transitioned from a paediatric unit since starting RRT. The median number of patients per adult unit was 5 (IQR 3-10). CONCLUSIONS: The majority of Australian AYA with ESKD are managed in adult units; however, the number at any one unit is low. As most live in the capital cities there may be an opportunity to establish centralized services designed to cater for the needs of AYA patients. However, the needs of patients living in more remote areas, including a significant proportion of Indigenous patients, may not be met by such a model. PMID- 22489754 TI - Clues to gamma-secretase, huntingtin and Hirano body normal function using the model organism Dictyostelium discoideum. AB - Many neurodegenerative disorders, although related by their destruction of brain function, display remarkable cellular and/or regional pathogenic specificity likely due to a deregulated functionality of the mutant protein. However, neurodegenerative disease genes, for example huntingtin (HTT), the ataxins, the presenilins (PSEN1/PSEN2) are not simply localized to neurons but are ubiquitously expressed throughout peripheral tissues; it is therefore paramount to properly understand the earliest precipitating events leading to neuronal pathogenesis to develop effective long-term therapies. This means, in no unequivocal terms, it is crucial to understand the gene's normal function. Unfortunately, many genes are often essential for embryogenesis which precludes their study in whole organisms. This is true for HTT, the beta-amyloid precursor protein (APP) and presenilins, responsible for early onset Alzheimer's disease (AD). To better understand neurological disease in humans, many lower and higher eukaryotic models have been established. So the question arises: how reasonable is the use of organisms to study neurological disorders when the model of choice does not contain neurons? Here we will review the surprising, and novel emerging use of the model organism Dictyostelium discoideum, a species of soil-living amoeba, as a valuable biomedical tool to study the normal function of neurodegenerative genes. Historically, the evidence on the usefulness of simple organisms to understand the etiology of cellular pathology cannot be denied. But using an organism without a central nervous system to understand diseases of the brain? We will first introduce the life cycle of Dictyostelium, the presence of many disease genes in the genome and how it has provided unique opportunities to identify mechanisms of disease involving actin pathologies, mitochondrial disease, human lysosomal and trafficking disorders and host-pathogen interactions. Secondly, I will highlight recent studies on the function of HTT, presenilin gamma-secretase and Hirano bodies conducted in Dictyostelium. I will then outline the limitations and future directions in using Dictyostelium to study disease, and finally conclude that given the evolutionary conservation of genes between Dictyostelium and humans and the organisms' genetic tractability, that this system provides a fertile environment for discovering normal gene function related to neurodegeneration and will permit translational studies in higher systems. PMID- 22489756 TI - Hormonal association and sexual dysfunction in patients with impaired fasting glucose: a cross-sectional and longitudinal study. AB - INTRODUCTION: The category of impaired fasting glucose (IFG) denotes a state of nondiabetic hyperglycemia, considered a risk factor for the further development of diabetes mellitus (DM) and cardiovascular (CV) diseases. AIM: The aim of the present study is to evaluate the impact of IFG on sexual health in men. In addition, its effect on CV morbidity and mortality will also be addressed. METHODS: A consecutive series of 3,451 men (mean age 57.3 +/- 10.1 years) attending our outpatient clinic for sexual dysfunction was retrospectively studied. A subset of this sample (N = 1,687) was enrolled in a longitudinal study. MAIN OUTCOME MEASURES: Several clinical, biochemical (including testosterone), and instrumental (penile color Doppler ultrasound) factors were evaluated. IFG was defined by fasting glucose concentrations between 5.6 and 6.9 mmol/L (100-125 mg/dL). A higher threshold (6.1-6.9 mmol/L, 110-125 mg/dL) was also considered. RESULTS: Among the patients studied, 747 (21.7%) had DM. In addition, 659 (19.1%) subjects were classified as IFG. Patients with IFG, however defined, more often had severe ED, reduced penile blood flow, and overt hypogonadism when compared with patients with normal glucose levels. In addition, men with ED and IFG show poorer blood pressure and lipid profile with an overall increase in CV risk. Unadjusted incidence of major adverse CV events was significantly associated with baseline DM, whereas there was a trend toward higher risk also for IFG, but this did not reach statistical significance. Conversely, both IFG and DM were significantly associated with a higher risk of fatal and nonfatal cerebral events. CONCLUSIONS: Checking glucose and testosterone levels is mandatory in subjects with ED because testosterone substitution in impotent IFG subjects might ameliorate not only their sexual life but also their overall health. PMID- 22489757 TI - A high-valent iron-oxo corrolazine activates C-H bonds via hydrogen-atom transfer. AB - Oxidation of the Fe(III) complex (TBP(8)Cz)Fe(III) [TBP(8)Cz = octakis(4-tert butylphenyl)corrolazinate] with O-atom transfer oxidants under a variety of conditions gives the reactive high-valent Fe(O) complex (TBP(8)Cz(+*))Fe(IV)(O) (2). The solution state structure of 2 was characterized by XAS [d(Fe-O) = 1.64 A]. This complex is competent to oxidize a range of C-H substrates. Product analyses and kinetic data show that these reactions occur via rate-determining hydrogen-atom transfer (HAT), with a linear correlation for log k versus BDE(C H), and the following activation parameters for xanthene (Xn) substrate: DeltaH(++) = 12.7 +/- 0.8 kcal mol(-1), DeltaS(++) = -9 +/- 3 cal K(-1) mol(-1), and KIE = 5.7. Rebound hydroxylation versus radical dimerization for Xn is favored by lowering the reaction temperature. These findings provide insights into the factors that control the intrinsic reactivity of Compound I heme analogues. PMID- 22489758 TI - Treatments for precursors of cervical cancer and preterm labour. PMID- 22489759 TI - Cervical screening: primary human papillomavirus testing. PMID- 22489760 TI - The prevalence of maternal near miss: a systematic review. AB - BACKGROUND: Severe maternal morbidity or 'near miss' is a promising indicator to improve quality of obstetric care. OBJECTIVES: To systematically review all available studies on 'near miss'. SEARCH STRATEGY: Following a pre-defined protocol, our review covered articles between January 2004 and December 2010. We used a combination of the following terms: near miss morbidity, severe maternal morbidity, severe acute maternal morbidity, obstetric near-miss, maternal near miss, obstetric near miss, emergency hysterectomy, emergency obstetric hysterectomy, maternal complications, pregnancy complications, intensive care unit. SELECTION CRITERIA: Nearly 4000 articles were screened by title and abstract, and 153 articles were retrieved for full text evaluation. There were no language restrictions. DATA COLLECTION AND ANALYSIS: Data extraction was performed using an instrument that included sections on study characteristics, quality of reporting, prevalence/incidence and the definition and identification criteria. Univariate analysis and meta-analysis for sub-groups were performed. MAIN RESULTS: A total of 82 studies from 46 countries were included. Criteria for identification of cases varied widely. Prevalence rates varied between 0.6 and 14.98% for disease-specific criteria, between 0.04 and 4.54% for management-based criteria and between 0.14 and 0.92% for organ-based dysfunction based on Mantel criteria. The rates are higher in low-income and middle-income countries of Asia and Africa. Based on meta-analysis, the estimate of near miss was 0.42% (95% CI 0.40-0.44%) for the Mantel (organ dysfunction) criteria and 0.039% (95% CI 0.037 0.042%) for emergency hysterectomy. Our meta-regression results indicate that emergency hysterectomy rates have been increasing by about 8% per year. AUTHORS' CONCLUSIONS: There is growing interest in the application of the maternal near miss concept as an adjunct to maternal mortality. However, in the literature published before 2011 there was still important variation in the criteria used to identify maternal near-miss cases. The World Health Organization recently published criteria based on markers of management and of clinical and organ dysfunction which would enable systematic data collection on near miss and development of summary estimates. Comparing the rates over time and across regions, it is clear that different approaches are needed to lower the rates of near miss and that interventions must be developed with the local context in mind. PMID- 22489761 TI - Depot medroxyprogesterone acetate and epithelial ovarian cancer: a multicentre case-control study. AB - OBJECTIVE: To evaluate the effect of depot medroxyprogesterone acetate (DMPA) in protecting against epithelial ovarian cancer (EOC) and to evaluate factors associated with the risk of EOC. DESIGN: A multicentre, case-control study. SETTING: Twelve hospitals located across Thailand. POPULATION: Three hundred and thirty patients with EOC ('cases') and 982 matched controls were recruited from the 12 hospitals. Cases were newly diagnosed patients with EOC, demonstrated pathologically. Controls were age-matched patients admitted to different wards in the same hospital. METHODS: Cases and controls were interviewed by trained interviewers using a standardised pre-tested questionnaire. The factors associated with EOC were evaluated using univariate and multivariate analyses. MAIN OUTCOME MEASURES: The odds ratio (OR) and 95% confidence interval (95% CI) were calculated to assess the relationship between DMPA and EOC. RESULTS: The use of DMPA was found to be associated with a 39% reduction in the risk of EOC with an OR of 0.61 and a 95% CI of 0.44-0.85 (P = 0.002). A significant risk reduction (83%) was observed when the duration of DMPA use was >3 years (OR 0.17; 95% CI 0.07-0.39; P < 0.001). Other factors associated with a reduced risk of EOC were the use of combined oral contraceptive pills and breastfeeding. A factor associated with an increased risk of EOC was a family history of gynaecological cancer. CONCLUSIONS: The results suggest that DMPA may have a protective effect against EOC. If this effect is real, then it represents an important non contraceptive benefit of DMPA. PMID- 22489762 TI - Maternal weight gain during the first half of pregnancy and offspring obesity at 16 years: a prospective cohort study. AB - OBJECTIVE: To assess the association between maternal gestational weight gain (GWG) during the first 20 weeks of gestation and overweight/obesity and abdominal obesity of offspring at the age of 16 years. DESIGN: A prospective cohort study. SETTING: The two northernmost provinces of Finland. POPULATION: Mothers and their adolescent offspring born from singleton pregnancies (3265 boys; 3372 girls) in the Northern Finland Birth Cohort 1986. METHODS: Maternal weight at 20 weeks of gestation was measured in municipal maternity clinics. Maternal GWG was based on the difference between the measured weight and self-reported pre-pregnancy weight, and was classified into quartiles. Offspring weight, height and waist circumference were measured by study nurses during a clinical examination. Logistic regression analyses [with and without adjustment for maternal pre pregnancy body mass index (BMI), glucose metabolism, education level, haemoglobin, smoking status, parity, and gender of offspring] were performed. MAIN OUTCOME MEASURE: Offspring overweight/obesity, based on BMI and abdominal obesity at 16 years. RESULTS: The highest quartile of maternal weight gain (>7.0 kg during the first 20 weeks of gestation) was independently associated with BMI based overweight/obesity and abdominal obesity in the 16-year-old offspring (OR 1.46, 95% CI 1.16-1.83, and OR 1.37, 95% CI 1.10-1.72, respectively). Among all covariates, maternal pregravid obesity showed the highest odds for both overweight/obesity and abdominal obesity (OR 4.57, 95% CI 3.18-6.57, and OR 4.43, 95% CI 3.10-6.34, respectively). CONCLUSIONS: Maternal overnutrition during the first half of gestation predicts offspring overweight/obesity and abdominal obesity in adolescence, yet a high pregravid BMI appears to be a more important determinant of both outcomes. PMID- 22489763 TI - Homocysteine and folate concentrations in early pregnancy and the risk of adverse pregnancy outcomes: the Generation R Study. AB - OBJECTIVE: To investigate associations between early pregnancy homocysteine, folate and vitamin B12 concentrations and placental weight, birthweight and adverse pregnancy outcomes. DESIGN: Population-based birth cohort study. SETTING: Rotterdam, the Netherlands. POPULATION: Cohort of 5805 pregnant women. METHODS: To analyse homocysteine, folate and vitamin B12 concentrations, blood was drawn in early pregnancy. These concentrations were divided into quintiles. Information on birth outcomes was retrieved from medical records. Multivariate regression analyses were used. MAIN OUTCOME MEASURES: Placental weight, birthweight, small for gestational age at birth (SGA) (<5th centile), prematurity and pre-eclampsia. RESULTS: High homocysteine concentrations (highest quintile) were associated with lower placental weight (difference 30 g; P < 0.001) and birthweight (difference 110 g; P < 0.001), and increased risk of SGA [odds ratio (OR) 1.7; P = 0.006] compared with lowest quintile (reference). Low folate concentrations (lowest quintile) were associated with lower placental weight (difference 26 g; P = 0.001) and birthweight (difference 125 g; P < 0.001), and increased risks of SGA (OR 1.9; P = 0.002), prematurity (OR 2.2; P = 0.002) and pre-eclampsia (OR 2.1; P = 0.04) compared with highest quintile (reference). The risk of developing SGA and pre-eclampsia was substantially higher in women who had higher homocysteine and lower folate concentrations. No associations were found with vitamin B12. CONCLUSIONS: Higher homocysteine and lower folate concentrations in early pregnancy are associated with lower placental weight and birthweight, and higher risk of adverse pregnancy outcomes. These findings suggest that high homocysteine and low folate concentrations in early pregnancy may adversely influence placentation and subsequently affect the success of pregnancy and birth outcomes. PMID- 22489764 TI - Improvements in survival of gynaecological cancer in the Anglia region of England: are these all real? PMID- 22489770 TI - Flexible and microporous chitosan hydrogel/nano ZnO composite bandages for wound dressing: in vitro and in vivo evaluation. AB - Current wound dressings have disadvantages such as less flexibility, poor mechanical strength, lack of porosity, and a tendency for dressings to adhere onto the wound surface; in addition, a majority of the dressings did not possess antibacterial activity. Hydrogel-based wound dressings would be helpful to provide a cooling sensation and a moisture environment, as well as act as a barrier to microbes. To overcome these hassles, we have developed flexible and microporous chitosan hydrogel/nano zinc oxide composite bandages (CZBs) via the incorporation of zinc oxide nanoparticles (nZnO) into chitosan hydrogel. The prepared nanocomposite bandages were characterized using Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry (XRD), and scanning electron microscopy (SEM). In addition, swelling, degradation, blood clotting, antibacterial, cytocompatibility, cell attachment on the material, and cell infiltration into the composite bandages were evaluated. The nanocomposite bandage showed enhanced swelling, blood clotting, and antibacterial activity. Cytocompatibility of the composite bandage has been analyzed in normal human dermal fibroblast cells. Cell attachment and infiltration studies showed that the cells were found attached to the nanocomposite bandages and penetrated into the interior. Furthermore, the in vivo evaluations in Sprague-Dawley rats revealed that these nanocomposite bandages enhanced the wound healing and helped for faster re-epithelialization and collagen deposition. The obtained data strongly encourage the use of these composite bandages for burn wounds, chronic wounds, and diabetic foot ulcers. PMID- 22489771 TI - Effect of parameter variations on the hemodynamic response under rotary blood pump assistance. AB - Numerical models, able to simulate the response of the human cardiovascular system (CVS) in the presence of an implantable rotary blood pump (IRBP), have been widely used as a predictive tool to investigate the interaction between the CVS and the IRBP under various operating conditions. The present study investigates the effect of alterations in the model parameter values, that is, cardiac contractility, systemic vascular resistance, and total blood volume on the efficiency of rotary pump assistance, using an optimized dynamic heart-pump interaction model previously developed in our laboratory based on animal experimental measurements obtained from five canines. The effect of mean pump speed and the circulatory perturbations on left and right ventricular pressure volume loops, mean aortic pressure, mean cardiac output, pump assistance ratio, and pump flow pulsatility from both the greyhound experiments and model simulations are demonstrated. Furthermore, the applicability of some of the previously proposed control parameters, that is, pulsatility index (PI), gradient of PI with respect to pump speed, pump differential pressure, and aortic pressure are discussed based on our observations from experimental and simulation results. It was found that previously proposed control strategies were not able to perform well under highly varying circulatory conditions. Among these, control algorithms which rely on the left ventricular filling pressure appear to be the most robust as they emulate the Frank-Starling mechanism of the heart. PMID- 22489772 TI - The relationship between structural aspects of self-concept and psychosocial adjustment in adolescents from alcoholic families. AB - Sixty adolescents from alcoholic families living in two large cities in Poland were examined in 2008 and 2009. Richness, stability, and certainty of their self concepts, as well as levels of school adjustment, anxiety, and depression, were evaluated using a set of questionnaires. In a series of bivariate analyses, the strongest associations found were between richness of the self-concept and the social withdrawal syndrome, and between stability of the self-concept and depression. Both relationships remained significant, using multiple regression models, after controlling for possible confounding factors. Possible explanations and implications for the findings, as well as the study's limitations, are noted and discussed. PMID- 22489774 TI - How do plants in hospital waiting rooms reduce patient stress? PMID- 22489773 TI - Attenuated Streptococcus equi ssp. zooepidemicus as a bacterial vector for expression of porcine circovirus type 2 capsid protein. AB - Porcine circovirus type 2 (PCV2) infection and other concurrent factors is associated with post-weaning multisystemic wasting syndrome, which is becoming a major problem for the swine industry worldwide. Coinfection of Streptococcus equi ssp. zooepidemicus (SEZ) and PCV2 in swine has necessitated demand for a recombinant vaccine against these two pathogens. A recombinant SEZ-Cap strain expressing the major immunogenic capsid protein of PCV2 in place of the szp gene of acapsular SEZ C55138 DeltahasB was constructed. Fluorescence-activated cell sorting and immunofluorescence microscopy analyses indicated that the capsid protein is expressed on the surface of the recombinant strain. Experiments in mice demonstrated that strain SEZ-Cap was less virulent than the parental strain and that it induced significant anti-PCV2 antibodies when administered intraperitoneally, which is worthy of further investigation in swine. PMID- 22489776 TI - Editorial: From genes to the 3D structure of proteins: crystallizing difficult targets. PMID- 22489775 TI - Biosynthetically intriguing chlorinated lipophilic metabolites from geographically distant tropical marine cyanobacteria. AB - Five new vinylchlorine-containing metabolites, the lipoamides janthielamide A and kimbeamides A-C and the ketide-extended pyranone kimbelactone A, have been isolated from collections of marine cyanobacteria made in Curacao and Papua New Guinea. Both janthielamide A and kimbeamide A exhibited moderate sodium channel blocking activity in murine Neuro-2a cells. Consistent with this activity, janthielamide A was also found to antagonize veratridine-induced sodium influx in murine cerebrocortical neurons. These lipoamides represent the newest additions to a relatively rare family of marine cyanobacterial-derived lipoamides and a new structural class of compounds exhibiting neuromodulatory activities from marine cyanobacteria. PMID- 22489777 TI - A dialogue about protein crystallization and phase diagrams. AB - A lighthearted researcher and a disheartened student discuss the challenges of protein crystallization and how phase diagrams can be used to address these challenges. The student feels a little better afterwards, but many proteins remain uncrystallized. PMID- 22489778 TI - Randomness in crystallization of proteins from Staphylococcus aureus. AB - Of many factors affecting protein crystallization, randomness in proteins has been given less attention although highly structured proteins would be at low entropy state. The factors, which impact on protein crystallization, are almost exclusively related to non-random amino acid properties such as physiochemical properties of amino acids. In this study, we used logistic regression and neural network to model the success rate of crystallization of 420 proteins from Staphylococcus aureus with each of non-random and random amino acid properties in order to determine whether randomness in a protein plays a role in the crystallization process. The results show that randomness is indeed involved in the crystallization process, and this rationale would enrich our knowledge on crystallization process and enhance our ability to crystallize more important proteins. PMID- 22489779 TI - Difficult macromolecular structures determined using X-ray diffraction techniques. AB - Macromolecular crystallography has been, for the last few decades, the main source of structural information of biological macromolecular systems and it is one of the most powerful techniques for the analysis of enzyme mechanisms and macromolecular interactions at the atomic level. In addition, it is also an extremely powerful tool for drug design. Recent technological and methodological developments in macromolecular X-ray crystallography have allowed solving structures that until recently were considered difficult or even impossible, such as structures at atomic or subatomic resolution or large macromolecular complexes and assemblies at low resolution. These developments have also helped to solve the 3D-structure of macromolecules from twin crystals. Recently, this technique complemented with cryo-electron microscopy and neutron crystallography has provided the structure of large macromolecular machines with great precision allowing understanding of the mechanisms of their function. PMID- 22489780 TI - Predicting protein crystallizability and nucleation. AB - The outcome of protein crystallization attempts is often uncertain due to inherent features of the protein or to the crystallization process that are not fully under control of the experimentalist. The aim of this contribution is to propose user-friendly tools that can increase the success rate of a protein crytallization project. Different bioinformatic approaches to predict the crystallization feasibility (before any crystallization attempts are undertaken) are discussed and a novel approach to assess the nucleation process of a given protein is proposed. Practical examples illustrate these two points. PMID- 22489781 TI - Bioactive peptides from marine organisms: a short overview. AB - Marine organisms are an immense source of new biologically active compounds. These compounds are unique because the aqueous environment requires a high demand of specific and potent bioactive molecules. Diverse peptides with a wide range of biological activities have been discovered, including antimicrobial, antitumoral, and antiviral activities and toxins amongst others. These proteins have been isolated from different phyla such as Porifera, Cnidaria, Nemertina, Crustacea, Mollusca, Echinodermata and Craniata. Purification techniques used to isolate these peptides include classical chromatographic methods such as gel filtration, ionic exchange and reverse-phase HPLC. Multiple in vivo and in vitro bioassays are coupled to the purification process to search for the biological activity of interest. The growing interest to study marine natural products results from the discovery of novel pharmacological tools including potent anticancer drugs now in clinical trials. This review presents examples of interesting peptides obtained from different marine organisms that have medical relevance. It also presents some of the common methods used to isolate and characterize them. PMID- 22489782 TI - Enhanced crystallizability by protein engineering approaches: a general overview. AB - The limiting step in macromolecular crystallography is the preparation protein crystals suitable for X-ray diffraction studies. A strong prerequisite for the success of crystallization experiments is the ability to produce monodisperse and properly folded protein samples. Since the production of most protein is usually achieved using recombinant methods, it has become possible to engineer target proteins with increased propensities to form well diffracting crystals. Recent advances in bioinformatics, which takes advantage from an enhanced information in the protein databases, are of enormous help for the design of modified proteins. Based on bioinformatics analyses, the reduction of the structural complexity of proteins or their site-specific mutagenesis has proven to have a dramatic impact on both the yield of heterologous protein expression and its crystallizability. Therefore, protein engineering represents a valid tool which supports the classical crystallization screenings with a more rational approach. This review describes key methods of protein-engineering and provides a number of examples of their successful use in crystallization. Scope of proposed topic: This Topic is focused on state-of-art protein engineering techniques to increase the propensity of proteins to form crystals with suitable X-ray diffraction properties. Protein engineering methods have proven to be of great help for the crystallization of difficult targets. We herein review molecular biology and chemical methods to help protein crystallization. PMID- 22489783 TI - Perspectives on high-throughput technologies applied to protein crystallization. AB - High-throughput crystallisation requires the rapid and accurate dispensing of protein and precipitating agent solutions at nanovolumes, but does not end there. The choice of the initial screens is very important, especially with respect to the availability of protein material. Data from previous crystallisation experiments that are scattered in the literature and only partially available in databases have to be analysed in efficient ways that will maximise their utility for designing new screens. A larger portion of crystallisation parameter space should be made accessible to screening, through the use of nucleants and seeding. Observation, assessment and scaling up of the crystallisation trials should be efficiently performed and, finally yet importantly, optimisation of conditions must also be adapted to the high-throughput environment. The above requirements are briefly addressed in the following paper. PMID- 22489784 TI - In situ observation of elementary growth processes of protein crystals by advanced optical microscopy. AB - To start systematically investigating the quality improvement of protein crystals, the elementary growth processes of protein crystals must be first clarified comprehensively. Atomic force microscopy (AFM) has made a tremendous contribution toward elucidating the elementary growth processes of protein crystals and has confirmed that protein crystals grow layer by layer utilizing kinks on steps, as in the case of inorganic and low-molecular-weight compound crystals. However, the scanning of the AFM cantilever greatly disturbs the concentration distribution and solution flow in the vicinity of growing protein crystals. AFM also cannot visualize the dynamic behavior of mobile solute and impurity molecules on protein crystal surfaces. To compensate for these disadvantages of AFM, in situ observation by two types of advanced optical microscopy has been recently performed. To observe the elementary steps of protein crystals noninvasively, laser confocal microscopy combined with differential interference contrast microscopy (LCM-DIM) was developed. To visualize individual mobile protein molecules, total internal reflection fluorescent (TIRF) microscopy, which is widely used in the field of biological physics, was applied to the visualization of protein crystal surfaces. In this review, recent progress in the noninvasive in situ observation of elementary steps and individual mobile protein molecules on protein crystal surfaces is outlined. PMID- 22489785 TI - Synchrotron radiation in life sciences. AB - Synchrotron Radiation (SR) presents itself as a "play-ground" with a large range of methods and techniques suitable to unveil the mysteries of life. Here we attempt to present a few of these methods that complement those employed in the home laboratory. SR diffraction, spectroscopy and imaging methods relevant to the atomic structure determination and characterization of the properties and function of chemical compounds and macromolecules of biological relevance, are introduced. PMID- 22489786 TI - Practical physics behind growing crystals of biological macromolecules. AB - The aim of this review is to provide biocrystallographers who intend to tackle protein-crystallization with theory and practical examples. Crystallization involves two separate processes, nucleation and growth, which are rarely completely unconnected. Here we give theoretical background and concrete examples illustrating protein crystallization. We describe the nucleation of a new phase, solid or liquid, and the growth and transformation of existing crystals obtained by primary or secondary nucleation or by seeding. Above all, we believe that a thorough knowledge of the phase diagram is vital to the selection of starting position and path for any crystallization experiment. PMID- 22489787 TI - Formation of Protein Condensed Phases: Nucleation Mechanisms. AB - Proteins in solution form a number of condensed phases. Even omitting the amyloid structures formed after partial protein unfolding, these phases include crystals, polymers, and other solid aggregates, as well as dense liquids and gels. Some of these condensed phases underlie pathological conditions, others play a crucial role in the biological function of the respective protein or are an essential part of its laboratory or industrial processing. In this review, we summarize the fundamentals and recent findings on the kinetics of nucleation of dense liquid droplets and crystals. We define the transition from nucleation to spinodal decomposition for these two phase transitions. We review the two-step mechanism of protein crystal nucleation, in which mesoscopic metastable protein clusters serve as precursors to the ordered crystal nuclei. The concepts and mechanisms reviewed here provide powerful tools for control of the nucleation process by varying the solution thermodynamic parameters. PMID- 22489788 TI - Determination of neo- and D-chiro-inositol hexakisphosphate in soils by solution 31P NMR spectroscopy. AB - The inositol phosphates are an abundant but poorly understood group of organic phosphorus compounds found widely in the environment. Four stereoisomers of inositol hexakisphosphate (IP(6)) occur, although for three of these (scyllo, neo, and D-chiro) the origins, dynamics, and biological function remain unknown, due in large part to analytical limitations in their measurement in environmental samples. We synthesized authentic neo- and D-chiro-IP(6) and used them to identify signals from these compounds in three soils from the Falkland Islands. Both compounds resisted hypobromite oxidation and gave quantifiable (31)P NMR signals at delta = 6.67 ppm (equatorial phosphate groups of the 4-equatorial/2 axial conformer of neo-IP(6)) and delta = 6.48 ppm (equatorial phosphate groups of the 2-equatorial/4-axial conformer of D-chiro-IP(6)) in soil extracts. Inositol hexakisphosphate accounted for 46-54% of the soil organic phosphorus, of which the four stereoisomers constituted, on average, 55.9% (myo), 32.8% (scyllo), 6.1% (neo), and 5.2% (D-chiro). Reappraisal of the literature based on the new signal assignments revealed that neo- and D-chiro-IP(6) occur widely in both terrestrial and aquatic ecosystems. These results confirm that the inositol phosphates can constitute a considerable fraction of the organic phosphorus in soils and reveal the prevalence of neo- and D-chiro-IP(6) in the environment. The hypobromite oxidation and solution (31)P NMR spectroscopy procedure allows the simultaneous quantification of all four IP(6) stereoisomers in environmental samples and provides a platform for research into the origins and ecological significance of these enigmatic compounds. PMID- 22489790 TI - Coherent control of ultracold photoassociation. PMID- 22489789 TI - Regioselective oxidation of phospho-NSAIDs by human cytochrome P450 and flavin monooxygenase isoforms: implications for their pharmacokinetic properties and safety. AB - BACKGROUND AND PURPOSE: Phospho-ibuprofen (MDC-917) and phospho-sulindac (OXT 328) are highly effective in cancer and arthritis treatment in preclinical models. Here, we investigated their metabolism by major human cytochrome P450s (CYPs) and flavin monooxygenases (FMOs). EXPERIMENTAL APPROACH: The CYP/FMO catalysed metabolism of phospho-ibuprofen and phospho-sulindac was studied by using in silico prediction modelling and a direct experimental approach. KEY RESULTS: The CYP isoforms catalyse the oxidation of non-steroidal anti inflammatory drugs (NSAIDs) and phospho-NSAIDs, with distinct activity and regioselectivity. CYP1A2, 2C19, 2D6 and 3A4 oxidize phospho-ibuprofen, but not ibuprofen; whereas CYP2C9 oxidizes ibuprofen, but not phospho-ibuprofen. All CYPs tested oxidize phospho-sulindac, but not sulindac. Among the five CYPs evaluated, CYP3A4 and 2D6 are the most active in the oxidation of phospho-ibuprofen and phospho-sulindac respectively. FMOs oxidized phospho-sulindac and sulindac, but not phospho-ibuprofen or ibuprofen. FMOs were more active towards phospho sulindac than sulindac, indicating that phospho-sulindac is a preferred substrate of FMOs. The susceptibility of phospho-NSAIDs to CYP/FMO-mediated metabolism was also reflected in their rapid oxidation by human and mouse liver microsomes, which contain a full complement of CYPs and FMOs. Compared with conventional NSAIDs, the higher activity of CYPs towards phospho-ibuprofen and phospho sulindac may be due to their greater lipophilicity, a key parameter for CYP binding. CONCLUSIONS AND IMPLICATIONS: CYPs and FMOs play an important role in the metabolism of phospho-NSAIDs, resulting in differential pharmacokinetic profiles between phospho-NSAIDs and NSAIDs in vivo. The consequently more rapid detoxification of phospho-NSAIDs is likely to contribute to their greater safety. PMID- 22489791 TI - Enumeration of small and large numerosities: the effect of element visibility. AB - Precise enumeration is associated with small numerosities within the subitizing range (<4 items), while approximate enumeration is associated with large numerosities (>4 items). To date, there is still debate on whether a single continuous process or dual mutually exclusive processes mediate enumeration of small and large numerosities. Here, we evaluated a compromise between these two notions: that the precise representation of number is limited to small numerosities, but that the approximate representation of numerosity spans across both small and large numerosities. We assessed the independence of precise and approximate enumeration by looking at how luminance contrast affected enumeration of elements that differ by ones (1-8) or by tens (10-80). We found that enumeration functions of ones and tens have different characteristics, which is consistent with the presence of two number systems. Subitizing was preserved for small numerosities. However, simply decreasing element visibility changed the variability signatures of small numerosities to match those of large numerosities. Together, our results suggest that small numerosities are mediated by both precise and approximate representations of numerosity. PMID- 22489792 TI - Vanishing bronchus intermedius syndrome in a pediatric patient with cystic fibrosis after lung transplantation. AB - Airway complications occur frequently after lung transplantation. Bronchial stenosis is the most frequently encountered complication with the most severe form of that being the vanishing bronchus intermedius syndrome (VBIS). This rare disorder has never been reported in the pediatric population. This is the first report of VBIS in a pediatric patient, specifically a 16-yr-old male patient with cystic fibrosis whose course was complicated by a lower airway infection with Aspergillus fumigatus. The VBIS responded to bronchoscopic balloon dilation and placement of an airway stent. PMID- 22489793 TI - T cells activation and interferon-gamma/nitric oxide production during Behcet disease: a study in Algerian patients. AB - The aim of the current study is to situate CDs expression (CD3+, CD4+, CD8+) and their relationship with IFNgamma and NO production in Algerian patients with Behcet disease (n = 34 ). Our results revealed an elevated expression of T cells markers tested in patients in active stage of the disease in relation to IFNgamma and NO increase levels. Most interestingly, we noted that CD4+/CD8+ expression correlated with IFNgamma and NO production in active stage. In contrast, we observed a decrease of these mediators in inactive stage. Collectively, our results indicate a dependent relation between these parameters and inflammatory response associated with the evolutionary stage of the disease. PMID- 22489794 TI - Association of nutrition parameters including bioelectrical impedance and systemic inflammatory response with quality of life and prognosis in patients with advanced non-small-cell lung cancer: a prospective study. AB - Early identification and treatment of nutritional deficiencies can lead to improved outcomes in the quality of life (QoL) and survival of patients with nonsmall cell lung cancer (NSCLC). Noninvasive techniques are needed to evaluate changes in body composition as part of determining nutritional status. The aim of the study was to evaluate the association of nutritional parameters in health related quality of life (HRQL) and survival in patients with advanced NSCLC. Chemotherapy-naive patients with advanced NSCLC with good performance status Eastern Cooperative Oncology Group (ECOG) 0-2 were included prospectively in the study. We evaluated inflammatory parameters such as C-reactive protein, platelet/lymphocyte index, neutrophil/lymphocyte index, serum interleukin (IL)-6, and tumor necrosis factor-alpha, and nutritional variables such as body mass index (BMI) and serum albumin levels. Bioelectrical impedance analysis including phase angle was obtained before cisplatin-based chemotherapy was started. HRQL was assessed by application of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ)-C30 and QLQ-LC13 instruments at baseline. Overall survival (OS) was calculated with the Kaplan Meier method and analyzed with log-rank and Cox proportional hazard models. One hundred nineteen patients were included. Mean BMI was 24.8 +/- 4.5 kg/m(2), average weight loss of patients was 8.4%, and median phase angle was 5.8 degrees . Malnutrition measured by subjective global assessment (SGA), weight loss >10%, BMI >20 was associated with lower HRQL scales. Patients with ECOG 2, high content serum IL-6, lower phase angle, and malnutrition parameters showed lower OS; however, after multivariate analysis, only ECOG 2 [Hazard ratio (HR), 2.7; 95% confidence interval (95% CI), 1.5-4.7; P = 0.001], phase angle <=5.8 degrees (HR = 3.02; 95% CI: 1.2-7.11; P = 0.011), and SGA (HR = 2.7; 95% CI, 1.31-5.5; P = 0.005) were associated with poor survival. Patients were divided into low-, intermediate-, and high-risk groups according to regression coefficients; OS at 1 yr was 78.4, 53, and 13.8%, respectively. Malnutrition is associated with low HRQL and is an independent prognostic factor in advanced NSCLC. The results warrant prospective trials to evaluate the impact of different nutritional interventions on HRQL and survival. PMID- 22489796 TI - Toggle rod stabilisation of coxofemoral luxation in 14 cats. AB - OBJECTIVES: To describe the surgical technique and to report outcomes in cats with coxofemoral luxation treated with open reduction and toggle rod stabilisation. METHODS: Retrospective study of cats with coxofemoral luxation stabilised via the toggle rod method. Short-term follow-up included clinical examination and radiographs. Long-term follow-up was via owner questionnaire. RESULTS: Fourteen cats were included. All of the cats had reported unilateral craniodorsal hip luxation. Nine cats (64.3%) had additional orthopaedic injuries. Luxations were stabilised with a 3.2-mm toggle rod (2.7-mm toggle rod in one cat) and two loops of four-metric polydioxanone (five-metric polydioxanone in one cat and three loops of four-metric polydioxanone in two cats). Success rate, in terms of maintenance of reduction, was 86%. Reluxation occurred in two cats (14%), both of which had multiple limb injuries. Eleven owner questionnaires (mean follow-up time 15.5 months) reported a functional outcome of "very good" to "excellent". Although the diameter of the pelvic canal was reduced by the presence of the toggle rod (mean narrowing 16.2%), none of the cats had defaecatory issues. CLINICAL SIGNIFICANCE: Toggle rod stabilisation is an effective method for the treatment of coxofemoral luxation in cats. Injuries to multiple limbs may be a risk factor for reluxation. PMID- 22489795 TI - Effect of testosterone and frequent low-dose sildenafil/tadalafil on cavernous tissue oxidative stress of aged diabetic rats. AB - This study aimed to assess the effect of testosterone (T) administration and chronic low-dose sildenafil/tadalafil on cavernous tissue oxidative stress (OS) of aged diabetic rats. In all, 140 Sprague-Dawley aged rats were subdivided into the following: controls; streptozotocin (STZ)-induced diabetic rats; diabetic rats injected with T every 4 weeks; diabetic rats on sildenafil orally daily; diabetic rats on T and daily sildenafil; diabetic rats on tadalafil orally every other day; diabetic rats on T and tadalafil; diabetic rats on alternate sildenafil/tadalafil; and diabetic rats on alternate sildenafil/tadalafil with T. After 12 weeks, the rats were euthanised where in dissected cavernous tissues malondialdehyde (MAD), glutathione peroxidase (GPx) and cGMP (cyclic guanosine monophosphate) were estimated. Compared with controls, aged diabetic rats demonstrated significant increase in cavernous tissue MDA and significant decrease in GPx and cGMP where diabetic rats injected with T had marked improvement of these parameters. Diabetic rats on sildenafil, tadalafil or alternate sildenafil/tadalafil demonstrated significant increased cavernous tissue GPx, cGMP and decreased cavernous MDA that was further improved when supplemented with T. It is concluded that frequent low-dose use of sildenafil and/or tadalafil supplemented with T has a marked impact on ameliorating cavernous OS in aged diabetic rats. PMID- 22489797 TI - Population dynamics with a mixed type of sexual and asexual reproduction in a fluctuating environment. AB - BACKGROUND: Carassius gibelio, a cyprinid fish from Eurasia, has the ability to reproduce both sexually and asexually. This fish is also known as an invasive species which colonized almost all continental Europe, most likely originating from Asia and Eastern Europe. Populations of both sexually and asexually reproducing individuals exist in sympatry. In this study we try to elucidate the advantages of such a mixed type of reproduction. We investigate the dynamics of two sympatric populations with sexual and asexual reproduction in a periodically fluctuating environment. We define an individual-based computational model in which genotypes are represented by L loci, and the environment is composed of L resources for which the two populations compete. RESULTS: Our model demonstrates advantageous population dynamics where the optimal percentage of asexual reproduction depends on selection strength, on the number of selected loci and on the timescale of environmental fluctuations. We show that the sexual reproduction is necessary for "generating" fit genotypes, while the asexual reproduction is suitable for "amplifying" them. The simulations show that the optimal percentage of asexual reproduction increases with the length of the environment stability period and decrease with the strength of the selection and the number of loci. CONCLUSIONS: In this paper we addressed the advantages of a mixed type of sexual and asexual reproduction in a changing environment and explored the idea that a species that is able to adapt itself to environmental fluctuation can easily colonize a new habitat. Our results could provide a possible explanation for the rapid and efficient invasion of species with a variable ratio of sexual and asexual reproduction such as Carassius gibelio. PMID- 22489798 TI - VEGF and MMP-9: biomarkers for canine lymphoma. AB - Vascular endothelial growth factor (VEGF) and metalloproteinase (MMP) 2 and 9 are useful biomarkers in human lymphoma. During cancerogenesis, transforming growth factor beta (TGF-beta) stimulates VEGF and MMPs production. VEGF and TGF-beta plasma levels were tested by ELISA, MMP-2 and MMP-9 by gelatine zymography in 37 dogs with lymphoma, 13 of which were also monitored during chemotherapy. Ten healthy dogs served as control. Lymphoma dogs showed higher act-MMP-9 (P < 0.01) and VEGF (P < 0.05), and lower TGF-beta than controls, and a positive correlation between act-MMP-9 and VEGF (P < 0.001). Act-MMP-9 and VEGF were significantly higher in T-cell lymphomas, and in stage V compared with stages III-IV disease, regardless of immunophenotype. VEGF was higher in high-grade compared with low grade T-cell lymphomas. No correlation was found between cytokines levels at presentation and outcome. During chemotherapy, act-MMP-9 and VEGF decreased in B cell lymphomas (P < 0.01), suggesting a possible predictive role in this group of dogs. PMID- 22489799 TI - Numerical optimization studies of cardiovascular-rotary blood pump interaction. AB - A heart-pump interaction model has been developed based on animal experimental measurements obtained with a rotary blood pump in situ. Five canine experiments were performed to investigate the interaction between the cardiovascular system and the implantable rotary blood pump over a wide range of operating conditions, including variations in cardiac contractility and heart rate, systemic vascular resistance (SVR), and total blood volume (V(total) ). It was observed in our experiments that SVR decreased with increasing mean pump speed under the healthy condition, but was relatively constant during the speed ramp study under reduced cardiac contractility conditions. Furthermore, we also found a significant increase in pulmonary vascular resistance with increasing mean pump speed and decreasing total blood volume, despite a relatively constant SVR. Least squares parameter estimation methods were utilized to fit a subset of model parameters in order to achieve better agreement with the experimental data and to evaluate the robustness and validity of the model under various operating conditions. The fitted model produced reasonable agreement with the experimental measurements, both in terms of mean values and steady-state waveforms. In addition, all the optimized parameters were within physiological limits. PMID- 22489800 TI - Reversible changes in solution pH resulting from changes in thermoresponsive polymer solubility. AB - Pendant groups on polymers that have lower-critical solution temperature (LCST) properties experience a water-like environment below the LCST where the polymer is soluble but are less hydrated above the LCST when the polymer phase separates from solution. When these pendant groups are amphoteric groups like carboxylate salts or ammonium salts, the change in solvation that accompanies the polymer precipitation event significantly changes these groups' acidity or basicity. These changes in acidity or basicity can lead to carboxylate salts forming carboxylic acid groups by capturing protons from the bulk solvent or ammonium salts reverting to the neutral amine by release of protons to the bulk solvent, respectively. When polymers like poly(N-isopropylacrylamide) that contain a sufficient loading of such comonomers are dissolved in solutions whose pH is near the pK(a) of the pendant acid or basic group and undergo an LCST event, the LCST event can change the bulk solution pH. These changes are reversible. These effects were visually followed using common indicators with soluble polymers and or by monitoring solution pH as a function of temperature. LCST events triggered by the addition of a kosmotropic salt lead to similar reversible solution pH changes. PMID- 22489801 TI - Differential expression of Axl and correlation with invasion and multidrug resistance in cancer cells. AB - Dysregulation of Axl receptor tyrosine kinases is implicated in the pathogenesis of several sensitive and refractory cancers. In this study we showed that Axl expression was upregulated in drug-resistant cancer cells, as compared to those in parental cells. Downregulation of Axl expression by RNAi led to a decrease of K562/ADR and MCF-7/ADR cells invasion, proliferation in soft agar, and increased cells chemosensitivity in vitro. In nude mice bearing xenografts, downregulation of Axl in MDR cells enhanced the anticancer activity of intraperitoneally applied chemotherapeutic drugs. Our observations suggest that Axl represents a promising gene for overcoming MDR in cancer therapy. PMID- 22489802 TI - Investigation of the effects of the level of glycemic control on erectile function and pathophysiological mechanisms in diabetic rats. AB - INTRODUCTION: Poor glycemic control is associated with erectile dysfunction (ED); however, differences in ED according to the level of glycemic control have been poorly investigated. AIM: The aim of this paper is to investigate the change in erectile function according to the level of glycemic control and to clarify the pathophysiological mechanism of diabetes-associated ED. METHODS: Streptozotocin was injected into 55 male Sprague-Dawley rats classified into four groups: control (group 1), diabetes with multiple insulin injections (group 2), diabetes with a single injection (group 3), and untreated diabetes (group 4). Daily insulin injections in groups 2 and 3 were administered for 4 weeks after 10 weeks of diabetic induction. MAIN OUTCOME MEASURES: The main outcome measures are the anova or Kruskal-Wallis tests to evaluate glycosylated hemoglobin (HbA1c), testosterone levels, the ratios of intracavernosal pressure to mean arterial pressure (ICP/MAP), area under the ICP curve to MAP (AUC/MAP), and changes in cavernous tissue and protein expression related to Rho kinase and nitric oxide pathways. RESULTS: HbA1c levels were different between pairs of groups. Group 4 showed the lowest erectile parameters and group 2 showed near normal level. No differences in erectile parameters were found between groups 1 and 2 or between groups 3 and 4, except the ratio of AUC to MAP for group 1 was significantly higher than that of group 2 (20 Hz stimulation). Decrease in erectile function of group 2 was related to decreased expression of nitrergic nitric oxide synthase or decreased testosterone level compared with group 1. Groups 2 and 3 showed significant differences in erectile parameters, which were associated with difference in apoptotic index. Groups 3 and 4 showed no differences in erectile parameters, although these groups had significant differences in apoptotic index, smooth muscle component, and protein expression ratios of phosphorylated to total myosin phosphatase target subunit 1, endothelial nitric oxide synthase, and Akt. CONCLUSIONS: Improvement in glycemic control assists recovery from diabetes associated ED; however, only tight glycemic control can provide recovery from ED to a near normal status. PMID- 22489803 TI - Cryopreservation of ovarian tissue in pediatrics: what is the child's best interest? AB - In paediatric female patients the only option for restoring fertility after chemotherapy and radiotherapy is ovarian tissue banking. Even if this procedure is considered the most promising available, anyway it is still an experimental option due to the paucity of data. The possibility to offer an experimental preventive technique with potential benefits but with known risks arises a dilemma: what is the best interest for suffering child? Is it most important to minimize risk of the disease or to preserve the future fertility? However, if it is right to propose fertility preservation when physical and psychic risks are acceptable, we think it is not in the child's best interest to retrieve ovarian tissue from very young patients whose ovaries are small and for whom surgery is a high risk procedure. Moreover fertility preservation should not be offered if this could increase the risk of disease worsening. PMID- 22489804 TI - Vitamin D deficiency, CD4+CD28null cells and accelerated atherosclerosis in chronic kidney disease. AB - AIM: Cardiovascular disease (CVD) is the leading cause of death among chronic kidney disease (CKD) patients. The role of vitamin D remains controversial in this process. We evaluated the relationship between 25-hydroxyvitamin D, abnormal T helper cells (CD4+CD28null cells), systemic inflammation and atherosclerosis in CKD patients. METHODS: A total of 101 stage 4-5 non-dialysis CKD patients and 40 healthy controls were studied. Common carotid artery intima media thickness (CCA IMT) was measured with an ultrasound system. 25(OH) vitamin D and highly sensitive C-reactive protein (hsCRP) were measured in serum by enzyme linked immunosorbent assay. The frequency of circulating CD4+CD28null cells was evaluated by flowcytometry. RESULTS: CKD subjects exhibited higher CCA-IMT (0.71 +/- 0.01 vs 0.56 +/- 0.01 mm, P < 0.0001), hsCRP (90.7 +/- 5.8 vs 50.1 +/- 8.6 ug/mL, P < 0.0001), CD4+CD28null cell frequency (9.1 +/- 0.9 vs 3.6 +/- 0.5%, P < 0.0001) and lower 25(OH) vitamin D levels (17.9 +/- 1.9 vs 26.9 +/- 3.5 ng/mL, P < 0.0001). In CKD subjects, serum 25 (OH) vitamin D level showed a strong inverse correlation with CCA-IMT (r = -0.729, P < 0.0001) and correlated with CD4+CD28null cell frequency (r = -0.249, P = 0.01) and hsCRP (r = -0.2, P = 0.047). We also noted correlation of IMT with patient age (r = 0.291, P = 0.004) and CD4+CD28null cells (r = 0.34, P = 0.001). On multiple regression analysis, 25(OH) vitamin D level, diabetic status and CD4+CD28null cell frequency exhibited independent association with IMT in CKD subjects. CONCLUSIONS: Vitamin D deficiency, inflammatory activation and higher frequency of CD4+CD28null T lymphocyte population correlate with preclinical atherosclerotic changes in CKD population. These findings suggest possible linkage between vitamin D metabolism and T cell modulation - abnormalities that may contribute to development of atherosclerosis in CKD. PMID- 22489805 TI - Natural polypill Xuezhikang: its clinical benefit and potential multicomponent synergistic mechanisms of action in cardiovascular disease and other chronic conditions. AB - Polypill has been a hot issue since it was first advanced in 2003. This new concept immediately spurred a worldwide discussion. Xuezhikang is a partially purified extract of fermented red yeast rice (Monascus purpureus). It is composed of 13 kinds of natural statins, unsaturated fatty acids, ergosterol, amino acids, flavonoids, alkaloid, trace element, and other substances, and thus could be regarded as a natural lipid-lowering polypill. Interestingly, Xuezhikang in the China Coronary Secondary Prevention Study trial lowered lipid levels less as compared with provastatin in the Cholesterol and Recurrent Events trial, but seemed to gain more benefit in reducing the cardiovascular events and the risk of death from cancer. In recent years, Xuezhikang has been further demonstrated to have additional health benefits and thus raised great interest. This article reviews the clinical benefits of Xuezhikang and the potential multicomponent synergetic mechanism. The authors hold that polypill is anticipated to be a more effective and feasible way to treat complicated diseases. PMID- 22489806 TI - Stress-reducing effects of real and artificial nature in a hospital waiting room. AB - OBJECTIVES: This field study investigated the potential stress-reducing effects of exposure to real or artificial nature on patients in a hospital waiting room. Additionally, it was investigated whether perceived attractiveness of the room could explain these effects. DESIGN: In this between-patients experimental design, patients were exposed to one of the following: real plants, posters of plants, or no nature (control). These conditions were alternately applied to two waiting rooms. LOCATION: The location of this study was two waiting rooms at the Radiology Department of a Dutch hospital. SUBJECTS: The subjects comprised 457 patients (60% female and 40% male) who were mostly scheduled for echocardiogram, dual-energy x-ray absorptiometry, magnetic resonance imaging, computed tomography scans, or nuclear research. RESULTS: Patients exposed to real plants, as well as patients exposed to posters of plants, report lower levels of experienced stress compared to the control condition. Further analyses show that these small but significant effects of exposure to nature are partially mediated by the perceived attractiveness of the waiting room. CONCLUSIONS: Natural elements in hospital environments have the potential to reduce patients' feelings of stress. By increasing the attractiveness of the waiting room by adding either real plants or posters of plants, hospitals can create a pleasant atmosphere that positively influences patients' well-being. PMID- 22489807 TI - Clinical effects of scalp electrical acupuncture in stroke: a sham-controlled randomized clinical trial. AB - OBJECTIVES: The majority of individuals who survive a stroke are disabled because of persisting neurological impairments. The objective of this study was to evaluate the efficacy of subcutaneous electrical stimulation of the scalp in spontaneous functional recovery of patients with chronic ischemic stroke, by evaluating clinical, neurological, and functional findings. SUBJECTS AND METHODS: Sixty-two (62) subjects who were at least 18 months postdiagnosis of ischemic stroke were randomized to receive 10 sessions of placebo or active low-frequency electrical stimulation (2/100 Hz) using subcutaneous acupuncture needles over the scalp. Functional and neurological evaluations were indexed by the Barthel, Rankin, and National Institutes of Health Stroke Scale (NIHSS). RESULTS: Results show that there was a significant difference in functional improvement between the sham and active group as indexed by NIHSS scale. The active group had a larger functional improvement after 10 sessions of scalp electrical acupuncture. The other two functional scales (Rankin and Barthel) failed to show significant differences between the two treatment groups. CONCLUSIONS: These results support further testing of scalp electrical acupuncture for the treatment of stroke as well further mechanistic studies to understand mechanisms associated with the observed improvement. Further studies need to consider longer follow-up assessments to investigate potential functional changes associated with electrical acupuncture. PMID- 22489808 TI - Ginkgo biloba extract: a novel addition to antipsoriasis ammunition? PMID- 22489810 TI - beta2-Glycoprotein I inhibits endothelial cell migration through the nuclear factor kappaB signalling pathway and endothelial nitric oxide synthase activation. AB - beta2-GPI (beta2-glycoprotein I) is a plasma glycoprotein ascribed with an anti angiogenic function; however, the biological role and molecular basis of its action in cell migration remain unknown. The aim of the present study was to assess the contribution of beta2-GPI to HAEC (human aortic endothelial cell) migration and the details of its underlying mechanism. Using wound healing and Boyden chamber assays, we found that beta2-GPI inhibited endothelial cell migration, which was restored by its neutralizing antibody. NF-kappaB (nuclear factor kappaB) inhibitors and lentiviral siRNA (small interfering RNA) silencing of NF-kappaB significantly attenuated the inhibitory effect of beta2-GPI on cell migration. Moreover, beta2-GPI was found to induce IkappaBalpha (inhibitor of NF kappaB) phosphorylation and translocation of p65 and p50. We further demonstrated that mRNA and protein levels of eNOS [endothelial NO (nitric oxide) synthase] and NO production were all increased by beta2-GPI and these effects were remarkably inhibited by NF-kappaB inhibitors and siRNAs of p65 and p50. Furthermore, beta2 GPI-mediated inhibition of cell migration was reversed by eNOS inhibitors and eNOS siRNAs. The findings of the present study provide novel insight into the ability of beta2-GPI to inhibit endothelial cell migration predominantly through the NF-kappaB/eNOS/NO signalling pathway, which indicates a potential direction for clinical therapy in vascular diseases. PMID- 22489811 TI - A beam of "chimeric" darkness: presence, interconnectedness, and transformation in the psychoanalytic treatment of a patient convicted of sex offenses. AB - The paper puts forward the dimension created by analytic presence and the ensuing patient-analyst interconnectedness in the process of psychoanalytic treatment and change, particularly with more disturbed patients. Working within this dimension, at a fundamental level of contact and impact, opens up new possibilities of extending the reach of psychoanalytic treatment. The analyst's "presencing" and interconnectedness with the patient forge a living therapeutic entity that is not a one-person or two-person psychology, but an emergent two-in-one new entity that goes beyond the confines of the separate subjectivities of patient and analyst and the simple summation of the two. The paper describes the kind of knowledge, experience, and powerful therapeutic potential that comes into being through analytic "presencing" and patient-analyst interconnectedness, and particularly focuses on the chimeric element, or quality, of this interconnectedness. The term "chimera/chimerism"-chosen here for its wealth of mythological, genetic, biological, biomedicinal (chimeric proteins), and psychoanalytical associations is used in this paper to highlight the complex quality of patient-analyst interconnectedness, especially in difficult, psychotic, psychically foreclosed, dissociative and perverse states. The author offers an extensive clinical account of psychoanalytic treatment of a patient convicted of sex offenses in order to illustrate "presencing," interconnectedness, and the extent and intricate emotional meaning of the extreme chimerism that this kind of (difficult) treatment entailed. PMID- 22489809 TI - Cannabinoid CB1 receptors mediate the effects of corticotropin-releasing factor on the reinstatement of cocaine seeking and expression of cocaine-induced behavioural sensitization. AB - BACKGROUND AND PURPOSE: The endocannabinoid and corticotropin-releasing factor (CRF) systems have been implicated in several long-lasting behavioural effects of prior cocaine experience. The present experiments were designed to probe functional interactions between endocannabinoids and CRF by testing the role of cannabinoid CB(1) receptors in cocaine-related behaviours induced or mediated by CRF. EXPERIMENTAL APPROACH: In Experiment 1, rats trained to self-administer cocaine were pretreated with the CB(1) receptor antagonist, AM251 (0, 10, 100 or 200 ug, i.c.v.), before tests for reinstatement in response to CRF (0, 0.5 ug, i.c.v.), intermittent footshock stress (0, 0.9 mA) or cocaine (0, 10 mg.kg(-1) , i.p.). In Experiment 2, rats pre-exposed to cocaine (15-30 mg.kg(-1) , i.p.) or saline for 7 days were pretreated with AM251 (0, 10 or 100 ug, i.c.v.) before tests for locomotion in response to CRF (0.5 ug, i.c.v.), cocaine (15 mg.kg(-1) , i.p.) or saline (i.c.v.). KEY RESULTS: Pretreatment with AM251 selectively interfered with CRF-, but not footshock- or cocaine-induced reinstatement. AM251 blocked the expression of behavioural sensitization induced by challenge injections of both CRF and cocaine. CONCLUSIONS AND IMPLICATIONS: These findings reveal a mediating role for CB(1) receptor transmission in the effects of CRF on cocaine-related behaviours. PMID- 22489812 TI - A spectrum of shadowed mirroring. AB - The central focus of this paper is to explore and extend Kohut's theory of maternal mirroring and to place it within the current context of psychoanalytic thinking. Kohut believed a child must experience "positive" mirroring from his or her mother in infancy and beyond to ensure development of a healthy self. Kohut alludes, however, to a possible situation in which the mother's face, metaphorically a mirror, can appear "faceless" to her child. From this I have inferred the concept of what I shall call "shadowed mirroring." Clinical and literary examples show that distorted, "shadowed" mirroring appears on a spectrum, with passive mirroring at one end and hostile (either verbal or nonverbal) mirroring on the other; some individuals experience both. I then consider how "shadowed mirroring," especially hostile mirroring, can be understood within the twin contexts of the overall mother-child relationship and present-day Intersubjective/Relational thinking that is both bidirectional and co constructed. Shadowed mirroring can lead to severe personality dysfunction along the borderline-narcissistic range, as well as to difficulties in the areas of identity formation, failure of self-cohesiveness, and the blunting of certain humane qualities like empathy. PMID- 22489813 TI - Working with the relational unconscious: an integration of intrapsychic and relational analysis. AB - From its inception, psychoanalysis has tended to idealize the curative value of insight while devaluing the mutative significance of the analytic relationship. This paper argues that applying the construct of the "relational unconscious" in clinical practice offers a possible resolution of this "mind-relationship" rift. From this perspective, transference and countertransference provoke a continual intersubjective/interpersonal enactment of a co-created infantile drama emanating from the internal worlds of analyst and analysand in which a vital form of parental and/or self loving is at stake. Case vignettes demonstrate how to apply the relational unconscious in clinical practice. PMID- 22489814 TI - Pathological organizations and psychic retreats in eating disorders. AB - A set of characteristic symptoms allow for the relatively straightforward diagnosis of eating disorders. Simultaneously and paradoxically, underlying the eating disorders are a wide variety of personality organizations/disorders, stretching from the neurotic to the borderline and narcissistic, and even to conditions approaching psychosis. This paper will argue that the inherent commonalities can be ascribed to pathological organizations of a similar nature and quality, operational across the spectrum of eating disorders and functioning in a particular, sadomasochistic way. The typical forms that eating disorders take are based on the specific ways that food and the body are used, that is, symptom manifestation. These distinctive symptom manifestations appear to be related to Steiner's (1982, 1993) notion of a psychic retreat. Pathological organizations and psychic retreats are latent until called upon either sporadically or continuously. When activated, these defensive structures operate like a complex psychic skeleton around which the unique psychodynamics of each patient become rearranged and thereby transformed. PMID- 22489815 TI - Use and usefulness of psychoanalytic scripture in the treatment of the eating disordered patient: the psychoanalyst's retreat? PMID- 22489816 TI - The demons of phenomenological contextualism: a conversation. PMID- 22489819 TI - Microbiomes of built environments: 2011 symposium highlights and workgroup recommendations. PMID- 22489820 TI - A 1,4-diphenyl-1,2,3-triazole-based beta-turn mimic constructed by click chemistry. AB - A series of 1,4-diphenyl-1,2,3-triazole-incorporated amide derivatives have been designed and prepared. X-ray crystallographic and (1D and 2D) (1)H NMR studies reveal that these compounds fold into stable U-shaped conformations driven by three-center intramolecular C-H...O hydrogen-bonding formed between the triazole C-5 H atom and the two ether O atoms. Such folded structures make this 1,4 diphenyl-1,2,3-triazole skeleton a good candidate to be used as beta-turn mimic. To prove this, the formation of a beta-hairpin structure induced by this beta turn motif has been further demonstrated. PMID- 22489821 TI - NDRG4 is downregulated in glioblastoma and inhibits cell proliferation. AB - NDRG4 is a member of the N-myc downregulated gene family (NDRG) belonging to the alpha/beta hydrolase superfamily. We have previously documented discrepancy between our analysis of the expression and function of NDRG4 in glioblastoma multiforme (GBM) and a recent publication by Schilling et al., who reported that NDRG4 is upregulated in GBM compared to human cortex tissues and knock down of NDRG4 reduced the viability of GBM cells. In the present study, we found that NDRG4 is indeed downregulated, at both RNA and protein levels, by quantitative RT PCR and Western blot analysis, in GBM compared to normal tissues, and that over expression of NDRG4 inhibited proliferation of GBM cells. These new observations can inform the selection of lead molecular compounds for drug discovery as well as novel diagnostics for GBM. They also lend evidence to NDRG4 a role of tumor suppressor. PMID- 22489822 TI - Presentation of atopic disease in a large cohort of pediatric liver transplant recipients. AB - Atopic disease occurs in solid organ transplant recipients with an increasingly recognized frequency. The time course for the development of these atopic diseases in liver transplantation has not been described. The objective was to characterize the atopic manifestations of children receiving chronic immunosuppression after orthotopic liver transplantation (OLT). Chart review and follow-up questionnaire were utilized for 176 OLT pediatric recipients at a single institution for manifestations of allergic disease. Atopic disease was present in 25 (14.2%) patients. Median age at transplant was 16 months with a median follow-up of 63 months. Food allergy and non-food related atopic symptoms presented at a median of 11.5 (IQR, 6-28) and 19 (IQR, 5-41) months post transplantation, respectively. The median age at transplant of the non-atopic children was 72 months, higher than patients with atopy (p < 0.001). Food allergy and atopic skin disease symptoms were present in 40% and 56% of cases, respectively. Asthma, allergic rhinitis, or both were found in 66% of cases. The onset of symptoms of food allergy and eczema (median, 12 months post transplantation) preceded symptoms of allergic rhinitis and asthma. (median of 27 and 30 months post-transplantation, respectively). Atopy occurs in ~14% of pediatric liver transplant recipients, with manifestations including food allergy, eczema, allergic rhinitis, and asthma. PMID- 22489823 TI - Expression profile of genes regulated by curcumin in Y79 retinoblastoma cells. AB - Curcumin, a well-known chemopreventive agent from turmeric, inhibits the expression of several oncogenes and cell proliferation genes in tumor cells. This study aims to understand the precise molecular mechanism by which curcumin exerts its effects on retinoblastoma cells, by performing whole genome microarray analysis to determine the gene expression profiles altered by curcumin treatment. Curcumin suppressed cell viability and altered the cell cycle of retinoblastoma cells. We identified 903 downregulated genes and 1,319 upregulated genes when compared with the control cells after treatment with 20 MUM curcumin concentration for 48 h. These genes were grouped into respective functional categories according to their biological function. We found that curcumin regulated the expression of genes that are involved in the regulation of apoptosis, tumor suppressor, cell-cycle arrest, transcription factor, and angiogenesis. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was used to validate the results of genome array, and the results were consistent with the obtained data. In conclusion, treatment of curcumin affects the expression of genes involved in various cellular functions and plays an important role in tumor metastasis and apoptosis. Thus, curcumin might be an effective chemopreventive agent for retinoblastoma cancer. PMID- 22489824 TI - Signal amplification using colloidal gold in a biolayer interferometry-based immunosensor for the mycotoxin deoxynivalenol. AB - Deoxynivalenol (DON) is a toxin produced by certain species of Fusarium fungi that can infest wheat, barley and corn. The fungi cause diseases in crops worldwide and some of the secondary metabolites, such as DON, can adversely affect animal health and food safety. To monitor DON in wheat rapidly, a biosensor using the principle of biolayer interferometry (BLI) was developed. The signal from the sensor was substantially amplified through the use of a primary antibody-colloidal gold conjugate. The amplification was much greater in the presence of wheat matrix than in buffered solution, suggesting matrix components may have contributed to the enhancement. The improved signal provided by the amplification allowed for the development of rapid qualitative and quantitative assays. The limit of detection of the method was 0.09 mg kg(-1); the limit of quantitation was 0.35 mg kg(-1). Recovery from wheat spiked over the range from 0.2 to 5 mg kg(-1) averaged 103% (RSD = 12%). The quantitative assay compared favourably (r(2) = 0.9698) with a reference chromatographic method for 40 naturally contaminated wheats. The qualitative assay was able to classify accurately the same group of 40 samples as either above or below a 0.5 mg kg(-1) threshold. These results suggest that the BLI technique can be used to measure DON in wheat rapidly. PMID- 22489825 TI - Scanometric microRNA array profiling of prostate cancer markers using spherical nucleic acid-gold nanoparticle conjugates. AB - We report the development of a novel Scanometric MicroRNA (Scano-miR) platform for the detection of relatively low abundance miRNAs with high specificity and reproducibility. The Scano-miR system was able to detect 1 fM concentrations of miRNA in serum with single nucleotide mismatch specificity. Indeed, it provides increased sensitivity for miRNA targets compared to molecular fluorophore-based detection systems, where 88% of the low abundance miRNA targets could not be detected under identical conditions. The application of the Scano-miR platform to high density array formats demonstrates its utility for high throughput and multiplexed miRNA profiling from various biological samples. To assess the accuracy of the Scano-miR system, we analyzed the miRNA profiles of samples from men with prostate cancer (CaP), the most common noncutaneous malignancy and the second leading cause of cancer death among American men. The platform exhibits 98.8% accuracy when detecting deregulated miRNAs involved in CaP, which demonstrates its potential utility in profiling and identifying clinical and research biomarkers. PMID- 22489826 TI - Computational studies of protonated beta-D-galactose and its hydrated complex: structures, interactions, proton transfer dynamics, and spectroscopy. AB - We present an exploration of proton transfer dynamics in a monosaccharide, based upon ab initio molecular dynamic (AIMD) simulations, conducted "on-the-fly", in beta-d-galactose-H(+) (betaGal-H(+)) and its singly hydrated complex, betaGal H(+)-H2O. Prior structural calculations identify O6 as the preferred protonation site for O-methyl alpha-d-galactopyranoside, but the beta-anomeric configuration favors the inversion of the pyranose ring from the (4)C1 chair configuration, to (1)C4, and the formation of proton bridges to the (axial) O1 and O3 sites. In the hydrated complex, however, the proton bonds to the water molecule inserted between the O6 and Ow sites, and the ring retains its original (4)C1 conformation, supported by a circular network of co-operatively linked hydrogen bonds. Two distinct proton transfer processes, operating over a time scale of 10 ps, have been identified in betaGal-H(+) at 500 K. One of them leads to chemical reaction and the formation of an oxacarbenium ion (accompanied by the loss of an H2O molecule). In the hydrated complex, betaGal-H(+)-H2O, this reaction is suppressed, and the proton transfer, which involves multiple jumps between the sugar and the H2O, creates an H3O(+) ion, relevant, perhaps, to the reactivity of protonated sugars both in the gas and condensed phases. Anticipating future spectroscopic investigations, the vibrational spectra of betaGal-H(+) and betaGal H(+)-H2O have also been computed through AIMD simulations conducted at average temperatures of 300 and 40 K and also through vibrational self-consistent field (VSCF) calculations at 0 K. PMID- 22489827 TI - Development of a fetal risk assessment score for the prediction of neonatal outcome in the growth-restricted fetus. AB - OBJECTIVE: To develop and analyze a fetal risk assessment score (FRAS) that incorporates fetal arterial and venous blood flow studies (BFS), amniotic fluid volume, the non-stress test (NST) and an estimated fetal weight to improve the ability of antenatal testing to identify fetuses at risk for poor perinatal outcome and compare it to the Biophysical Profile (BPP). STUDY DESIGN: The Perinatal data base of the author's institution was searched for all patients with singleton gestation with the diagnosis of intrauterine growth restriction, and who had both a biophysical profile (BPP) and fetal BFS (umbilical and middle cerebral artery, ductus venosus) within 4 days of delivery. Fetuses with major congenital abnormalities, chromosomal anomalies, or who delivered less than 25 weeks gestation were excluded. A FRAS score was developed by assigning numerical points for increasing abnormal arterial and venous BFS, and one point each for a non-reactive NST, oligohydramnios or if the fetus was small for gestational age. Recommendations for delivery were based on the clinical situation and the results of the Biophysical Profile (BPP); the FRAS score was not available to the attending physician. The FRAS was then compared to the BPP for the prediction of poor neonatal outcome (significant neonatal complications or prolonged hospital stay) using receiver operating characteristic (ROC) curve analysis and chi(2) analysis. RESULTS: Two hundred twenty-nine patients were included in the study. The results of the ROC analysis showed that the designed FRAS (area: 0.802) was slightly better than the BPP (area: 0.659) at predicting poor perinatal outcome in a group of growth-restricted fetuses. CONCLUSION: The study gives support to the hypothesis that combining biophysical tests with BFS will improve the identification of potential high-risk patients at increased risk for poor neonatal outcome, but prospective, randomized studies are needed to confirm this hypothesis. PMID- 22489828 TI - Intraperitoneal antineoplastic drug delivery: experience with a cyclophosphamide, vincristine and prednisolone protocol in cats with malignant lymphoma. AB - In this retrospective study, the efficacy and safety were examined for an intraperitoneal chemotherapy protocol-cyclophosphamide, vincristine and prednisolone (IP-COP) in 26 cats with malignant lymphoma. Certainly in cats fiercely resisting IV administration the IP route is a more practical method, safer for the administrator and less stressful for the cat. Complete remission (CR) rate was 76.9% (n = 20). Median duration of first remission was 421 days. Estimated 1- and 2-year disease free period were 67.1 and 48.0%, respectively. Median duration of survival was 388 days and estimated overall 1- and 2-year survival periods were 54.7 and 46.9% respectively. Young cats had a more favourable prognosis. Reaching CR was essential for long-term survival. No specific IP-related adverse events (AE) were seen. AE were generally scored as mild and were not excessively abundant. These results indicate that the IP route is a safe and effective alternative for the administration of COP protocol chemotherapeutics. PMID- 22489829 TI - Expression of CD39 on FoxP3+ T regulatory cells correlates with progression of HBV infection. AB - BACKGROUND: Although it is known that regulatory T cells (Tregs) can suppress the function of effector T cells, and may contribute to impaired immune response, the precise role of Tregs during the course of hepatitis B virus (HBV) infection remains to be elucidated. A newly identified subset of the CD4+Foxp3+ Tregs, the CD39+ Tregs, has been associated with viral infections and autoimmune diseases. Therefore, we hypothesized that this discrete Treg subset may contribute to the chronic infection of HBV. RESULTS: Initial characterization studies of healthy peripheral CD39+FoxP3+CD4+ T cells revealed that the majority were CD45RA- Treg cells. Subsequent analysis of HBV-infected patients (38 asymptomatic HBV carriers (AsCs), 37 chronic active hepatitis B (CAH), 29 HBV-associated acute-on-chronic liver failure (ACLF)) and healthy individuals (25 controls) was conducted to assess association with HBV copy number and the liver injury marker alanine aminotransferase (ALT). A higher percentage of CD39+ Tregs was detected within the population of FoxP3+CD4+ T cells in peripheral blood of AsCs patients. Moreover, the percentage of CD39+ Tregs was significantly less in CAH and ACLF patients. The increased proportions of circulating CD39+ Tregs were positively correlated with serum viral load, but inversely correlated with serum ALT level. CONCLUSION: These findings not only suggest that CD39+ Treg cells may be involved in HBV disease progression but also identify CD39+ Tregs as a dynamic immune regulatory cell population that may represent a new target of immunomodulatory therapeutic interventions. PMID- 22489830 TI - Biomimetic synthesis of the antimalarial flindersial alkaloids. AB - A biomimetic strategy for the synthesis of the antimalarial flindersial alkaloids is described. Flinderoles A, B, and C, desmethylflinderole C, isoborreverine, and dimethylisoborreverine were all synthesized in three steps from tryptamine. The key step is an acid-promoted dimerization of the natural product borrerine. This approach is thought to mirror the biosynthesis of these compounds. PMID- 22489831 TI - Clinicopathological study of canine transmissible venereal tumour in leishmaniotic dogs. AB - INTRODUCTION: Canine transmissible venereal tumour is occasionally observed in leishmaniotic dogs, and Leishmania amastigotes can be harboured in canine transmissible venereal tumour cells. OBJECTIVES: The aim of this paper was to investigate the clinicopathological significance of the association of both diseases. METHODS: Nineteen dogs affected by canine transmissible venereal tumour and canine leishmaniasis were studied retrospectively. RESULTS: In these dogs, the tumour manifested a large size and often aggressive behaviour (42%) and no predictive sign of spontaneous regression was observed. Sporadic Leishmania amastigotes were found within the canine transmissible venereal tumour in three cases, probably transported by infected macrophages often infiltrating the tumour. A high Leishmania parasitisation of canine transmissible venereal tumour was observed in two other cases and verified by immunohistochemistry. CLINICAL SIGNIFICANCE: Canine transmissible venereal tumour is a tumour of the dog able to harbour a large number of Leishmania parasites. Alternatively, the systemic disease (canine leishmaniasis) may lower the immune defence against malignancy (canine transmissible venereal tumour). PMID- 22489832 TI - Measurement of LNAPL flux using single-well intermittent mixing tracer dilution tests. AB - The stability of subsurface Light Nonaqueous Phase Liquids (LNAPLs) is a key factor driving expectations for remedial measures at LNAPL sites. The conventional approach to resolving LNAPL stability has been to apply Darcy's Equation. This paper explores an alternative approach wherein single-well tracer dilution tests with intermittent mixing are used to resolve LNAPL stability. As a first step, an implicit solution for single-well intermittent mixing tracer dilution tests is derived. This includes key assumptions and limits on the allowable time between intermittent mixing events. Second, single-well tracer dilution tests with intermittent mixing are conducted under conditions of known LNAPL flux. This includes a laboratory sand tank study and two field tests at active LNAPL recovery wells. Results from the sand tank studies indicate that LNAPL fluxes in wells can be transformed into formation fluxes using corrections for (1) LNAPL thicknesses in the well and formation and (2) convergence of flow to the well. Using the apparent convergence factor from the sand tank experiment, the average error between the known and measured LNAPL fluxes is 4%. Results from the field studies show nearly identical known and measured LNAPL fluxes at one well. At the second well the measured fluxes appear to exceed the known value by a factor of two. Agreement between the known and measured LNAPL fluxes, within a factor of two, indicates that single-well tracer dilution tests with intermittent mixing can be a viable means of resolving LNAPL stability. PMID- 22489833 TI - Contribution of respiratory gating techniques for optimization of breast cancer radiotherapy. AB - A comparative, nonrandomized, multicenter, and prospective analysis were performed between April 2004 and June 2008 in 20 French centers in order to compare clinical aspects of respiratory-gated conformal radiotherapy (RGRT) during breast cancer irradiation versus conventional conformal radiotherapy. The final results based on 233 evaluable patients at 48 months confirm the feasibility and good reproducibility of the RGRT systems. The main results demonstrated a marked reduction of dosimetric parameters predictive of lungs and cardiac toxicities in the RGRT group; especially the dose delivered to the heart during irradiation of the left breast; mostly observed with deep inspiration breath-hold techniques. PMID- 22489834 TI - Imino hydrogen positions in nucleic acids from density functional theory validated by NMR residual dipolar couplings. AB - Hydrogen atom positions of nucleotide bases in RNA structures solved by X-ray crystallography are commonly derived from heavy-atom coordinates by assuming idealized geometries. In particular, N1-H1 vectors in G and N3-H3 vectors in U are commonly positioned to coincide with the bisectors of their respective heavy atom angles. We demonstrate that quantum-mechanical optimization of the hydrogen positions relative to their heavy-atom frames considerably improves the fit of experimental residual dipolar couplings to structural coordinates. The calculations indicate that deviations of the imino N-H vectors in RNA U and G bases result from H-bonding within the base pair and are dominated by the attractive interaction between the H atom and the electron density surrounding the H-bond-acceptor atom. DFT optimization of H atom positions is impractical in structural biology studies. We therefore have developed an empirical relation that predicts imino N-H vector orientations from the heavy-atom coordinates of the base pair. This relation agrees very closely with the DFT results, permitting its routine application in structural studies. PMID- 22489835 TI - Red chlorophyll: the new barium? AB - Imaging of gastrointestinal (GI) motility remotely through the abdominal wall has always been a tradeoff between resolution and invasiveness. Skin reflects and/or absorbs wavelengths of radiation in the ultraviolet and visible ranges, but is largely transparent to both high-energy radiation (Gamma to X-rays; <0.1-10 nm) and low-energy radiation (infrared to radio waves; 700 nm-10 m). Imaging using short wavelength radiation such as X-ray cinematography has excellent spatial and temporal resolution, but ionization can produce acute and long-term deleterious effects to the patient or animal. Other 'slice-based' imaging techniques such as ultrasound/MRI/CT minimize tissue damage, but are limited in the planar area that can be imaged in a timely fashion. This viewpoint article will summarize and explore the implications of recent advances in infrared imaging of the GI tract, in particular, an article published in this issue of NGM entitled 'In vivo dynamic imaging of intestinal motions using diet-related autofluorescence' in which the authors have used infrared imaging in combination with that most elusive ingredient, standard mouse chow, to capture the motions of the mouse GI tract. PMID- 22489836 TI - Esophageal high resolution manometry: a new gold standard for the detection of transient lower esophageal sphincter relaxations? PMID- 22489838 TI - Microwave-induced degradation of atrazine sorbed in mineral micropores. AB - The herbicide atrazine is a common pollutant in reservoirs and other sources of drinking water worldwide. The adsorption of atrazine from water onto zeolites CBV 720 and 4A, mesoporous silica MCM-41, quartz sand, and diatomite, and its microwave-induced degradation when sorbed on these minerals, were studied. Dealuminated HY zeolite CBV-720 exhibited the highest atrazine sorption capacity among the mineral sorbents because of its high micropore volume, suitable pore sizes, and surface hydrophobicity. Atrazine sorbed on the minerals degraded under microwave irradiation due to interfacial selective heating by the microwave, while atrazine in aqueous solution and associated with PTFE powder was not affected. Atrazine degraded rapidly in the micropores of CBV-720 under microwave irradiation and its degradation intermediates also decomposed with further irradiation, suggesting atrazine could be fully mineralized. Two new degradation intermediates of atrazine, 3,5-diamino-1,2,4-triazole and guanidine, were first identified in this study. The evolution of degradation intermediates and changes in infrared spectra of CBV-720 after microwave irradiation consistently indicate the creation of microscale hot spots in the micropores and the degradation of atrazine following a pyrolysis mechanism. These results indicate that microporous mineral sorption coupled with microwave-induced degradation could serve as an efficient treatment technology for removing atrazine from drinking water. PMID- 22489839 TI - Isometric elbow extensors strength in supine- and prone-lying positions. AB - The purpose of this study was to compare isometric strength of elbow extensors measured in supine- and prone-lying positions at elbow flexion angles of 45 and 90 degrees. Twenty-two male subjects under single-blind procedures participated in the study. Each subject participated in both supine-lying and prone-lying measuring protocols. Calibrated cable tensiometer was used to measure isometric strength of the right elbow extensors and a biofeedback electromyography was used to assure no substitution movements from shoulder girdle muscles. The mean values of isometric strength of elbow extensors measured from supine-lying position at elbow flexion angles of 45 and 90 degrees were 11.1 +/- 4.2 kg and 13.1 +/- 4.6 kg, while those measured from prone-lying position were 9.9 +/- 3.6 kg and 12 +/- 4.2 kg, respectively. There is statistical significant difference between the isometric strength of elbow extensors measured from supine-lying position at elbow flexion angles of 45 and 90 degrees compared to that measured from prone-lying position (p < 0.05). The results suggest that in manual muscle testing starting position can affect the isometric strength of elbow extensors since supine-lying starting position is better than prone-lying starting position. PMID- 22489840 TI - Force-induced apoptosis mediated by the Rac/Pak/p38 signalling pathway is regulated by filamin A. AB - Cells in mechanically challenged environments cope with high-amplitude exogenous forces that can lead to cell death, but the mechanisms that mediate force-induced apoptosis and the identity of mechanoprotective cellular factors are not defined. We assessed apoptosis in NIH 3T3 and HEK (human embryonic kidney)-293 cells exposed to tensile forces applied through beta1-integrins. Apoptosis was mediated by Rac-dependent activation of p38alpha. Depletion of Pak1 (p21-activated kinase 1), a downstream effector of Rac, prevented force-induced p38 activation and apoptosis. Rac was recruited to sites of force transfer by filamin A, which inhibited force-induced apoptosis mediated by Rac and p38alpha. We conclude that, in response to tensile force, filamin A regulates Rac-dependent signals, which induce apoptosis through Pak1 and p38. PMID- 22489841 TI - Corneal sensitivity is related to established measures of diabetic peripheral neuropathy. AB - PURPOSE: The objective was to investigate the association between corneal sensitivity and established measures of diabetic peripheral neuropathy (DPN). METHODS: Corneal sensitivity was measured in 93 individuals with diabetes, 146 diabetic individuals without neuropathy and 61 control individuals without diabetes or neuropathy using a non-contact corneal aesthesiometer at the baseline visit of a five-year longitudinal natural history study of DPN. The correlation between corneal sensitivity and established measures of neuropathy was estimated and multi-dimensional scaling was used to represent similarities and dissimilarities between variables. RESULTS: The corneal sensitivity threshold was significantly correlated with a majority of established measures of DPN. Correlation coefficients ranged from -0.32 to 0.26. Using multi-dimensional scaling, non-contact corneal aesthesiometry was closer to the neuropathy disability score, diabetic neuropathy symptom score and Neuropad and most dissimilar to electrophysiological parameters and quantitative sensory testing. CONCLUSION: Corneal sensitivity, although not strongly related, is associated with other functional measures of DPN and might provide a useful adjunct in identifying functional loss of small nerve fibre integrity. PMID- 22489842 TI - Significantly improved trapping lifetime of nanoparticles in an optical trap using feedback control. AB - We demonstrate an increase in trapping lifetime for optically trapped nanoparticles by more than an order of magnitude using feedback control, with no corresponding increase in beam power. Langevin dynamics simulations were used to design the control law, and this technique was then demonstrated experimentally using 100 nm gold particles and 350 nm silica particles. No particle escapes were detected with the controller on, leading to lower limits on the increase in lifetime for 100 nm gold particles of 26 times (at constant average beam power) and 22 times for 350 nm silica particles (with average beam power reduced by one third). The approach described here can be combined with other techniques, such as counter propagating beams or higher-order optical modes, to trap the smallest nanoparticles and can be used to reduce optical heating of particles that are susceptible to photodamage, such as biological systems. PMID- 22489843 TI - Mechanism and rates of exchange of L7/L12 between ribosomes and the effects of binding EF-G. AB - The ribosomal stalk complex binds and recruits translation factors to the ribosome during protein biosynthesis. In Escherichia coli the stalk is composed of protein L10 and four copies of L7/L12. Despite the crucial role of the stalk, mechanistic details of L7/L12 subunit exchange are not established. By incubating isotopically labeled intact ribosomes with their unlabeled counterparts we monitored the exchange of the labile stalk proteins by recording mass spectra as a function of time. On the basis of kinetic analysis, we proposed a mechanism whereby exchange proceeds via L7/L12 monomers and dimers. We also compared exchange of L7/L12 from free ribosomes with exchange from ribosomes in complex with elongation factor G (EF-G), trapped in the posttranslocational state by fusidic acid. Results showed that binding of EF-G reduces the L7/L12 exchange reaction of monomers by ~27% and of dimers by ~47% compared with exchange from free ribosomes. This is consistent with a model in which binding of EF-G does not modify interactions between the L7/L12 monomers but rather one of the four monomers, and as a result one of the two dimers, become anchored to the ribosome EF-G complex preventing their free exchange. Overall therefore our results not only provide mechanistic insight into the exchange of L7/L12 monomers and dimers and the effects of EF-G binding but also have implications for modulating stability in response to environmental and functional stimuli within the cell. PMID- 22489844 TI - Effect of household and industrial processing on the levels of pesticide residues and degradation products in melons. AB - Two varieties of melons (Cucumis melo) were treated with two fungicides (carbendazim and maneb) and four insecticides (acetamiprid, cyromazin, imazalil and thiamethoxam) to quantify the effect of household processing on the pesticide residues. To ensure sufficiently high levels of residues in flesh and peel, the most concentrated formulations were applied observing good agricultural practice. The peeling step decreased the concentration of pesticide residues for maneb, imazalil and acetamiprid by more than 90%. Cyromazin, carbendazim and thiamethoxam were reduced by approximately 50%. The reduction of the pesticides could not be fully explained by the systemic character of the pesticides. However, the agricultural practices (time of application), solubility and mode of action (systemic versus contact pesticide) of the pesticides could be used to explain the difference in processing factors for the studied pesticides. Degradation products (melamine and ethylenethiourea) were also investigated in this study, but were not detected. PMID- 22489845 TI - Development of a swallowing frequency meter using a laryngeal microphone. AB - Disuse atrophy of swallowing-related organs is suspected when decreased swallowing frequency is seen in the elderly. However, swallowing frequency has not been examined in elderly people during daily life. We developed a swallowing frequency meter containing a laryngeal microphone that does not restrict the subject's ability to perform daily activities. In this study, the utility of the meter was assessed. Experiment 1: The ability of the meter to detect swallowing was examined. The subject was instructed to swallow saliva or foods at a voluntarily pace. During these procedures, swallowing events were simultaneously recorded by the meter, self-enumeration and videofluorography. As a result, all of the swallowing events identified by the meter coincided with the swallowing events identified by self-enumeration and videofluorography. Experiment 2: Swallowing sounds display various patterns both between and within individuals. Therefore, we examined the concordance rate between the number of swallowing events counted by the meter and that counted by self-enumeration in 15 subjects over a longer period than in experiment 1. The concordance rates calculated by two examiners between the meter and self-enumeration were 96.8 +/- 4.5% and 98.9 +/- 3.3% at rest and 95.2 +/- 4.5% and 96.1 +/- 4.1% during meals, respectively. Our findings indicate that this meter is useful for measuring the frequency of swallowing during daily situations. PMID- 22489846 TI - Chronic diarrhea, ascites, and protein-losing enteropathy in an infant with hepatic venous outflow obstruction after liver transplantation. AB - An 18-month-old female status post-orthotopic liver transplant for biliary atresia presented nine months after transplant with severe diarrhea and intolerance of feeds. She was found to have a PLE as evidenced by a low serum albumin and a persistent elevation of fecal A1AT. Investigation eventually revealed that the cause of the PLE was a stricture at the anastomosis site between the hepatic vein and inferior cava, supported by resolution of the PLE after venoplasty of the stricture. The patient has subsequently required several repeat venoplasties for recurrence of her symptoms correlating with recurrence of the stricture. This is a very rare presentation of hepatic venous outflow obstruction. Moreover, normal duplex ultrasound imaging of liver vasculature and her unusual presentation led to a delay in her diagnosis highlighting the need for an increased index of suspicion. PMID- 22489847 TI - Molecular beacon lighting up on graphene oxide. AB - A molecular beacon (MB) is comprised of a fluorophore and a quencher linked by a DNA hairpin. MBs have been widely used for homogeneous DNA detection. In addition to molecular quenchers, many nanomaterials such as graphene oxide (GO) also possess excellent quenching efficiency. Most reported fluorescent sensors relied on DNA probes physisorbed by GO, which may suffer from nonspecific probe displacement and false positive signal. In this work, we report the preparation and characterization of a MB using graphene oxide (GO) as quencher, where an amino and FAM (6-carboxyfluorescein) dual labeled DNA was covalently attached to GO via an amide linkage. A major challenge was to remove noncovalently attached probes due to strong DNA adsorption by GO. While DNA desorption was favored at low salt, high pH, high temperature, and by using organic solvents, the cDNA was required to achieve complete desorption of noncovalently linked DNA probes. The DNA adsorption energy was measured using isothermal titration calorimetry, revealing the heterogeneous nature of GO. The covalent probe has a detection limit of 2.2 nM using a sample volume of 0.05 mL. With a 2 mL sample, the detection limit can reach 150 pM. The covalent probe is highly resistant to nonspecific probe displacement and will find applications in serum and cellular samples where high probe stability is demanded. PMID- 22489848 TI - Orbital bruit in Churg-Strauss orbitopathy; a novel sign. PMID- 22489849 TI - A comparison of external and endonasal dacryocystorhinostomy in regard to patient satisfaction and cost. AB - BACKGROUND: Definitive treatment of nasolacrimal duct obstruction is with external or endonasal dacryocystorhinostomy (DCR). Recent trials suggest surgical equivalency between techniques. We sought to compare alternative outcomes of DCR techniques in terms of quality of life and cost. METHODS: This study was a multicentre prospective nonrandomized case series comparing adult patients treated with external or endonasal DCR. Groups were allocated according to DCR technique. Participation did not affect treatment choice. The Glasgow Benefit Inventory (GBI) was utilized to compare postoperative quality of life, and an activity-based costing (ABC) method used to estimate costs of the two techniques. Surgical data were also collected. A minimum of 3 months follow-up was observed. RESULTS: Seventy-seven patients were included--37 external and 40 endonasal. Both techniques resulted in positive health status change, with mean GBI scores of +16.1 for external DCR and +24.1 for endonasal (p = 0.18). Using an ABC method, the operative costs of external DCR were less than endonasal at $715.79 AUD and $932.52 AUD respectively. CONCLUSIONS: This trial suggests that external and endonasal DCR produce comparable outcomes in terms of postoperative quality of life, with external DCR resulting in lower operative costs. PMID- 22489850 TI - Lacrimal scintigraphy: "interpretation more art than science". AB - Lacrimal scintigraphy (LS) or dacryoscintigraphy can demonstrate abnormalities in 80%-95% of patients with symptoms of epiphora and a patent lacrimal system on syringing and up to 40% asymptomatic individuals. Precise localization of the site of delay may not always be possible due to lack of anatomic detail on LS. LS is considered useful in patients with epiphora with delayed tear clearance and patency to syringing and suspected to have either nasolacrimal duct (NLD) stenosis or lacrimal pump failure. It remains unclear, however, as to whether LS can reliably distinguish between the two. The literature reports considerable variation in the technique, normative data, analysis, and interpretation of LS. Qualitative or visual analysis is simpler to perform and to our knowledge used more frequently in comparison to quantitative analysis. There is little extra information to be gained from LS in cases with complete NLD obstruction or severe NLD stenosis on syringing. PMID- 22489851 TI - A review of the complications of lacrimal occlusion with punctal and canalicular plugs. AB - Punctal and canalicular plugs are widely used for both temporary and permanent occlusion of the lacrimal puncta in dry eyes. There are many designs and materials available on the market. While their efficacy in improving dry eye symptoms is widely proven, the gamut of complications associated with these devices have never been subject to a general review, although there are numerous case series in the literature associated with one particular device. This review aims to examine the track record of a variety of plugs currently in use, to review the management of complications, and propose strategies for both the prevention of these complications and their treatment. PMID- 22489852 TI - Direct frontalis flap with and without levator pulley for correction of severe ptosis with poor levator function in the same patient. AB - PURPOSE: To compare two techniques of frontalis muscle flap suspension in different eyelids of the same patient for correction of severe ptosis with minimal levator function. MATERIAL AND METHODS: A prospective study of four patients with severe bilateral ptosis and poor levator function, who underwent direct frontalis muscle flap on the right eyelid and frontalis muscle flap with levator pulley on the left eyelid was conducted. Eyelid studies measurements were taken at baseline, 2 months, one year and 5 years after surgery. The presence of complications, flap function and palpebral contour were evaluated. RESULTS: Despite the surgical technique performed, good results in terms of functionality, contour and aesthetics were observed. In the eyes that underwent frontalis muscle flap (FMF)-direct, there were 2 cases with moderate anteriorization of eyelid margin in extreme upgaze and all patients showed eyelash ptosis that persisted one year after surgery, but improved after 5 years. In the eyes that underwent FMF-pulley, no upgaze anteriorization of eyelid margin was observed and three patients had eyelash ptosis of lesser extent than the fellow eye, improving after 1 year follow-up. FMF-pulley showed more long-term stability in eyelid height, compared with FMF-direct. CONCLUSIONS: Frontalis muscle flap with a pulley in the levator aponeurosis prevents some complications caused by the excessive vertical component of the direct frontalis muscle flap, especially in deep-set eye patients, with better stability of the eyelid height and contour over time. PMID- 22489853 TI - Epidemiology of oculoplastic conditions: the Singapore experience. AB - PURPOSE: To study the prevalence of eyelid, lacrimal, orbital conditions in an outpatient and surgical environment in a tertiary care hospital in Singapore. METHODS: An 8-month study was conducted in the Oculoplastics Department at the National University Health System (NUHS). Demographic data, diagnosis details and surgical records were compared. RESULTS: Of 623 patients seen over 906 visits, prevalence was as follows: eyelid (60.3%), orbital (20.6%), lacrimal (16.3%), dysthyroid exophthalmos (6.0%). Sixty-two (10.0%) patients had more than one condition. The most common conditions encountered included blepharoptosis, lacrimal obstruction, and orbital deformities (including fractures). During the same period, distribution of surgical procedures was as follows: eyelid (77.4%), lacrimal (13.1%) and orbit (9.5%). Interestingly, epiblepharon correction comprised 9.5% of the clinical/surgical cases. CONCLUSIONS: Although eyelid related conditions are most common, lacrimal and orbital pathologies cause significant morbidity. Oculoplastics specialists and ophthalmologists should consider placing more emphasis on surgical training specific to such conditions. We also propose separate classifications for epiblepharon and thyroid eye disease in the International Classification of Diseases (ICD) as they are unique clinical problems in their own right. A postoperative status will also help efficiently classify patients as such patients are at risk for related complications subsequently. An examination of healthcare budget allocation for such conditions is also suggested. PMID- 22489854 TI - The use of a pleated strip of autogenous temporalis fascia graft for frontalis suspension in recurrent poor levator function ptosis in adult patients. AB - PURPOSE: Poor levator function (LF) blepharoptosis can be corrected surgically using frontalis muscle suspension with a variety of materials. Autogenous grafts such as fascia lata are commonly used. The need for a remote surgical site and the risk of an unattractive leg scar makes the use of an autogenous temporalis fascia (ATF) graft appealing as the scar is concealed in the hair. We describe the use of a pleated, lengthened ATF graft that is easy to prepare and insert, and provides a cosmetically acceptable outcome. METHODS: Prospective case series describing six patients with previous multiple failed lid surgeries and recurrent poor (<= 5 mm) LF (mean 2.87 +/- 1.72 mm) ptosis. The pleated graft technique was used to yield a strip of ATF up to 18-cm long from a short 2-cm temporal incision. Eight eyelids then underwent ATF graft frontalis suspension surgery using the modified Fox pentagon technique. Outcomes included eyelid measurements with 4.5-year follow-up. RESULTS: All patients achieved good functional and esthetic outcome. The mean central palpebral aperture 6 weeks postsurgery was 7.14 +/- 1.67 mm, equating to a mean increase of 3.27 mm (p < 0.05 using the paired t-test). The improvement in eyelid height was maintained at the 4.5-year follow-up in all patients, except one who died of unrelated cause. CONCLUSION: A pleated strip of ATF graft provides a simpler alternative to fascia lata grafting for frontalis suspension in poor LF ptosis in adult patients with good long-term results. PMID- 22489855 TI - Bisphosphonate-associated orbital inflammation--a case report and review. AB - Bisphosphonates are becoming more widespread as indications for them broaden. Several ocular side effects due to bisphosphonates have been described, among the most potentially serious of which is orbital inflammation. Thirteen case reports of this side effect exist in the literature, with an additional case reported here. The most common presenting signs are lid edema, conjunctival hyperemia, and chemosis, while common symptomatology includes pain, diplopia, and blurry vision. A concomitant anterior uveitis is present in 30% of cases, and some degree of bilaterality is also seen in 30% of cases. There are two reported instances of profound visual loss, highlighting the importance of prompt recognition and treatment of this entity. Despite a paucity of rechallenge data, available reports suggest that development of orbital inflammation does not necessarily exclude patients from future bisphosphonate use. PMID- 22489856 TI - Mesenchymal chondrosarcoma of the orbit. AB - PURPOSE: To report a case of mesenchymal chondrosarcoma of the orbit and describe its clinical features, radiological findings and management. METHOD: Interventional case report. RESULT: A 50 year old man presented with right sided proptosis of 3 months duration. CT scan showed well circumscribed lobulated extraconal mass lesion in the inferotemporal qaudrant with specked calcification within. Patient underwent excisional biospsy with excision of mass lesion in toto. Histopathological examination was suggestive of mesenchymal chondrosarcoma of orbit. Post operatively patient was advised radiotherapy. CONCLUSION: Orbital mesenchymal chondrosarcoma is a rare tumor characterized by undifferentiated mesenchymal cells with islands of mature hyaline cartilage. Multimodality treatment (surgery, chemotherapy, and radiotherapy) may lead to long-term survival. PMID- 22489857 TI - Orbital gastrointestinal stromal tumor metastasis. AB - PURPOSE: To report an uncommon case of orbital gastrointestinal stromal tumor (GIST) metastasis. MATERIAL AND METHODS: Observational case report. RESULTS: A 65 year-old woman with metastatic GIST involving the left orbit with a history of two separate GIST nodules involving the stomach 6 years earlier. Computed tomography (CT) scan demonstrated a well-circumscribed enhancing lesion confined to the anterior orbit. Histopathology analysis of the tumor showed predominantly spindle cells with focal epithelioid forms. It also stained positive for c-KIT (CD117) on immunochemistry, confirming the diagnosis. Additional medical treatment was not required, and the patient was followed up regularly for disease recurrence. CONCLUSION: GISTs typically occur as sporadic solitary tumors. In malignant cases, it usually metastasizes to the liver or other intraabdominal sites. Orbital involvement is extremely rare. This is the first case of metastatic GIST involving the anterior orbit with histopathological and immunochemical confirmation. PMID- 22489858 TI - Rosai-dorfman with bilateral involvement of lacrimal sac as extranodal disease. AB - A 45 year old female presented with painless swelling over the inner side of both eyes since one year. Magnetic resonance imaging (MRI) scan revealed well defined lesions in the bilateral lacrimal sac area with extension along the naso-lacrimal duct. Systemic work up showed polyclonal hyperglobulinemia, raised erythrocyte sedimentation rate (ESR) and anemia. The patient also had subcutaneous swelling in thoracic area over back. The histopathology of the bilateral excised tumor and fine needle aspiration cytology of thoracic swelling was consistent with features of Rosai-Dorfman syndrome. PMID- 22489859 TI - Bilateral acute ptosis leading to the diagnosis of a presumed metastatic gastric adenocarcinoma. AB - We report the case of a 57 year old diabetic Indian male with no history of malignancy, who presented with severe bilateral upper lid acute aponeurotic ptosis, following intravitreal bevacizumab for diabetic retinopathy. Brain MRI revealed lesions in the vault of the skull, both superior recti and an intraorbital lesion on the lateral aspect of the right optic nerve. PET-CT revealed multiple metabolically active lesions in both the lobes of the liver, cervical vertebrae and in the lesser curvature of the stomach. A biopsy taken from the lesion in the lesser curvature of the stomach showed poorly differentiated adenocarcinoma. The patient was treated with palliative chemotherapy (Epirubicin, Oxaliplatin and Capecitabine), but had progressive disease after two cycles and died 8 weeks after diagnosis. Gastric carcinoma is a quiescent carcinoma wherein metastatic manifestations often lead to the diagnosis of the primary tumor. PMID- 22489860 TI - Orbital myiasis complicating squamous cell carcinoma in xeroderma pigmentosum. AB - Ophthalmomyiasis is a rare infection seen in susceptible individuals. We report a case of orbital myiasis in squamous cell carcinoma (SCC) in a patient of xeroderma pigmentosum. On presentation, reddish brown ulcerated mass with numerous maggots in orbit were seen. Computed tomography scan showed the presence of soft tissue lesion without any bony destruction. Following debridement, emergency exenteration with sacrifice of eyelid skin was performed. The diagnosis of SCC was confirmed on histopathologic evaluation. The maggots belonged to family Calliphoridae and secondary bacterial infection with Klebsiella organism was identified. Management issues included extensive involvement requiring exenteration, non-availability of skin graft, delayed secondary healing and recurrence of pigmented lesions in skin lining of orbit. The skin grafting was avoided as it can harbour the neoplasm. PMID- 22489861 TI - Multiple apocrine hidrocystomas of the eyelids. AB - A 52-year-old man presented with a 5-year history of multiple bilateral apocrine hidrocystomas of the eyelids. For the past 3 years, the patient had developed a mechanical ectropion of the right inferior eyelid secondary to progressive enlargement of the lesions. Different therapeutic options were discussed with the patient. Surgical excision of all lesions was performed under local anesthesia. There was no recurrence after 15 months of follow-up. PMID- 22489862 TI - Umbilical cord blood levels of cortisol and dehydroepiandrosterone sulfate in preterm prelabor rupture of membrane pregnancies complicated by the presence of histological chorioamnionitis. AB - OBJECTIVE: The main aim of this study was to determine the levels of cortisol and dehydroepiandrosterone sulfate (DHEA-S) and the cortisol/DHEA-S ratio in the umbilical cord blood according to the presence of histological chorioamnionitis and fetal inflammatory response in pregnancies complicated by prelabor rupture of membranes at fewer than 34 gestational weeks. METHODS: Seventy-two women with singleton pregnancies complicated by preterm prelabor rupture of membranes between gestational ages 24+0 and 33+6 weeks were included in the study. The sample of blood was obtained from the umbilical cord after delivery of the newborn. The umbilical cord blood cortisol and DHEA-S levels were evaluated using commercial immunoassay kits. A cortisol/DHEA-S ratio was calculated. RESULTS: The presence of histological chorioamnionitis was not associated with higher median levels of cortisol (32.1 nmol/L vs. 33.0 nmol/L; p = 0.53), DHEA-S (2.6 MUmol/L vs. 2.5 MUmol/L; p = 0.83), or cortisol/DHEA-S ratio (19.5 vs. 18.7;p = 0.90). Higher median levels of DHEA-S (3.1 MUmol/L vs. 2.3 MUmol/L; p = 0.03) but not cortisol (91.0 nmol/L vs. 32.0 nmol/L; p = 0.06) or cortisol/DHEA-S ratio (24.5 vs. 18.7; p = 0.46) were observed when fetal inflammatory response was present. CONCLUSIONS: The presence of fetal inflammatory response but not the presence of histological chorioamnionitis per se was associated with increased DHEA-S levels in the umbilical cord blood. PMID- 22489863 TI - Improvements to Emergy evaluations by using Life Cycle Assessment. AB - Life Cycle Assessment (LCA) is a widely recognized, multicriteria and standardized tool for environmental assessment of products and processes. As an independent evaluation method, emergy assessment has shown to be a promising and relatively novel tool. The technique has gained wide recognition in the past decade but still faces methodological difficulties which prevent it from being accepted by a broader stakeholder community. This review aims to elucidate the fundamental requirements to possibly improve the Emergy evaluation by using LCA. Despite its capability to compare the amount of resources embodied in production systems, Emergy suffers from its vague accounting procedures and lacks accuracy, reproducibility, and completeness. An improvement of Emergy evaluations can be achieved via (1) technical implementation of Emergy algebra in the Life Cycle Inventory (LCI); (2) selection of consistent Unit Emergy Values (UEVs) as characterization factors for Life Cycle Impact Assessment (LCIA); and (3) expansion of the LCI system boundaries to include supporting systems usually considered by Emergy but excluded in LCA (e.g., ecosystem services and human labor). Whereas Emergy rules must be adapted to life-cycle structures, LCA should enlarge its inventory to give Emergy a broader computational framework. The matrix inversion principle used for LCAs is also proposed as an alternative to consistently account for a large number of resource UEVs. PMID- 22489864 TI - Use and timeliness of radiation therapy after breast-conserving surgery in low income women with early-stage breast cancer. AB - PURPOSE: To characterize overall receipt and timeliness of radiation therapy (RT) following breast-conserving surgery among Medicaid-insured patients. METHOD: State cancer registry data linked with Medicaid claims from 2003 to 2009 were analyzed. Multivariate logistic and Cox proportional hazards regressions were employed. RESULTS: Overall, 81% of patients received guideline-recommended RT. Significant variation in timing of RT initiation was documented. Having fewer comorbitidies and receiving chemotherapy were correlated with higher odds of RT initiation within 1 year. CONCLUSION: Although RT use in Medicaid-insured women appears to have improved since earlier studies, documented delays in RT are troublesome and warrant further investigation. PMID- 22489866 TI - Shifts in exercise capacity are not reported adequately in patients with congenital heart disease. AB - OBJECTIVE: In cross-sectional studies, self-reported health status and quality of life have only poorly correlated with objective exercise capacity in patients with congenital heart disease (CHD). We tested the hypothesis whether longitudinal changes in exercise ability are related to changes in self-reported quality of life. PATIENTS AND METHODS: One hundred eighty-two patients (79 female, 103 male, age 14-70 years) with various congenital heart defects were investigated twice. Every time, they completed the SF-36 quality of life survey and performed a symptom-limited cardiopulmonary exercise test. Between the two tests, 32 patients had open heart surgery, 10 had a catheter intervention, 48 patients had a medication change, and 92 had no changes in their management for at least 6 months. RESULTS: Patients were classified into three groups. Peak oxygen uptake increased by more than 10% in 43 patients; in 84, patients it did not change substantially (+/-10%); and in 55 patients, it declined by more than 10%. Comparing the three groups, the changes in any of the life quality scales did not differ significantly. Even in self-reported physical functioning, we could not find any differences (Kruskal-Wallis test, P= .563). CONCLUSIONS: In patients with CHD, there was no detectable relation of changes in exercise capacity and changes in self-reported health status or quality of life. PMID- 22489865 TI - Distinctive binding of three antagonistic peptides to the ephrin-binding pocket of the EphA4 receptor. AB - The EphA4 receptor tyrosine kinase interacts with ephrin ligands to regulate many processes, ranging from axon guidance and nerve regeneration to cancer malignancy. Thus antagonists that inhibit ephrin binding to EphA4 could be useful for a variety of research and therapeutic applications. In the present study we characterize the binding features of three antagonistic peptides (KYL, APY and VTM) that selectively target EphA4 among the Eph receptors. Isothermal titration calorimetry analysis demonstrated that all three peptides bind to the ephrin binding domain of EphA4 with low micromolar affinity. Furthermore, the effects of a series of EphA4 mutations suggest that the peptides interact in different ways with the ephrin-binding pocket of EphA4. Chemical-shift changes observed by NMR spectroscopy upon binding of the KYL peptide involve many EphA4 residues, consistent with extensive interactions and possibly receptor conformational changes. Additionally, systematic replacement of each of the 12 amino acids of KYL and VTM identify the residues critical for EphA4, binding. The peptides exhibit a long half-life in cell culture medium which, with their substantial binding affinity and selectivity for EphA4, makes them excellent research tools to modulate EphA4 function. PMID- 22489867 TI - EnzyBase: a novel database for enzybiotic studies. AB - BACKGROUND: Enzybiotics are becoming increasingly recognized as potential alternative therapies for drug-resistant bacteria. Although only a few enzybiotics are currently well characterized, much information is still missing or is unavailable for researchers. The construction of an enzybiotics database would therefore increase efficiency and convenience in investigating these bioactive proteins and thus help reduce or delay the recent increase in antibiotic resistance. DESCRIPTION: In the present manuscript, we describe the development of a novel and original database called EnzyBase, which contains 1144 enzybiotics from 216 natural sources. To ensure data quality, we limited the source of information to authoritative public databases and published scientific literature. The interface of EnzyBase is easy to use and allows users to rapidly retrieve data according to their desired search criteria and blast the database for homologous sequences. We also describe examples of database-aided enzybiotics discovery and design. CONCLUSION: EnzyBase serves as a unique tool for enzybiotic studies. It has several potential applications, e.g. in silico enzybiotic combination as cocktails, and novel enzybiotic design, in response to continuously emerging drug-resistant pathogens. This database is a valuable platform for researchers who are interested in enzybiotic studies. EnzyBase is available online at http://biotechlab.fudan.edu.cn/database/EnzyBase/home.php. PMID- 22489869 TI - Comparison of the clinical outcome and systemic inflammatory marker levels between retroperitoneal and transperitoneal laparoscopic donor nephrectomy. AB - BACKGROUND AND PURPOSE: Whether the retroperitoneal approach (RA) or the transperitoneal approach (TA) for performing laparoscopic donor nephrectomy (LDN) in kidney transplant donors is less invasive is unclear. In this study, we compared the clinical outcome and systemic inflammatory marker levels between RA and TA to assess surgical invasiveness. PATIENTS AND METHODS: We enrolled 105 donors (RA: 41, TA: 64) who underwent LDN in our hospital. Evaluation of both approaches included comparison of conventional clinical parameters and preoperative, immediate postoperative, and 1-day postoperative levels of the following circulating inflammatory cytokines: Tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-10, and IL-12p70. RESULTS: The frequency of right nephrectomy being performed was significantly lower in the TA than in the RA group (3/64 vs 12/41, P<0.001). Other clinical parameters in the TA group, including the frequency of surgical complications and incidence of delayed graft function, were comparable to those in the RA group. Immediate and 1-day postoperative mean serum IL-6 levels were significantly higher in the RA than in the TA group (P=0.023 and 0.044, respectively). The 1-day postoperative mean serum IL-10 level was also significantly higher in the RA than in the TA group (P=0.041). Meanwhile, the mean serum IL-6 and IL-10 levels were not associated with surgical duration or estimated intraoperative blood loss. CONCLUSIONS: Conventional clinical parameters related to surgical invasiveness were comparable in both approaches, thus indicating that both LDN approaches were similar and equally effective as minimally invasive procedures. The clinical significance of the higher postoperative mean serum IL-6 and IL-10 levels in the RA group remains to be clarified in a future study. PMID- 22489868 TI - Role of interleukin-6 in hemopoietic and non-hemopoietic synergy mediating TLR4 triggered late murine ileus and endotoxic shock. AB - BACKGROUND: Early murine endotoxin-induced ileus at 6 h is exclusively mediated by non-hemopoietic TLR4/MyD88 signaling despite molecular activation of hemopoietic cells which included a significant IL-6 mRNA induction. Our objective was to define the role of hemopoietic cells in LPS/TLR4-triggered ileus and inflammation over time, and identify mechanisms of ileus. METHODS: CSF-1(-/-) , TLR4 non-chimera and TLR4 chimera mice were single-shot intraperitoneal injected with ultrapure lipopolysaccharide (UP-LPS) and studied up to 4 days. Subgroups of TLR4(WT) mice were additionally intravenously injected with exogenous recombinant IL-6 (rmIL-6) or murine soluble IL-6 receptor blocking antibody (anti-sIL-6R mAB). KEY RESULTS: Hemopoietic TLR4 signaling independently mediated UP-LPS induced ileus at 24 h, but chemotactic muscularis neutrophil extravasation was not causatively involved and mice lacking CSF-1-dependent macrophages died prematurely. Synergy of hemopoietic and non-hemopoietic cells determined ileus severity and mortality which correlated with synergistic cell lineage specific transcription of inflammatory mediators like IL-6 within the intestinal muscularis. Circulating IL-6 levels were LPS dose dependent, but exogenous rmIL-6 did not spark off a self-perpetuating inflammatory response triggering ileus. Sustained therapeutic inhibition of functional IL-6 signaling efficiently ameliorated late ileus while preemptive antibody-mediated IL-6R blockade was marginally effective in mitigating ileus. However, IL-6R blockade did not prevent endotoxin-associated mortality nor did it alter circulating IL-6 levels. CONCLUSIONS & INFERENCES: A time-delayed bone marrow-driven mechanism of murine endotoxin-induced ileus exists, and hemopoietic cells synergize with non hemopoietic cells thereby prolonging ileus and fueling intestinal inflammation. Importantly, IL-6 signaling via IL-6R/gp130 drives late ileus, yet it did not regulate mortality in endotoxic shock. PMID- 22489872 TI - Radial flow permeability testing of an argillaceous limestone. AB - Argillaceous Lindsay limestone is the geologic storage formation that will be encountered at the site for the construction of a deep ground repository in Ontario, Canada, for the storage of low to intermediate level nuclear waste. The permeability of the Lindsay limestone is a key parameter that will influence the long-term movement of radionuclides from the repository to the geosphere. This paper describes the use of both steady-state and transient radial flow laboratory tests to determine the permeability of this argillaceous limestone. The interpretation of the tests is carried out using both analytical results and computational models of flow problems that exhibit radial symmetry. The results obtained from this research investigation are compared with the data available in the literature for similar argillaceous limestones mainly found in the Lindsay (Cobourg) formation. The experiments give permeabilities in the range of 1.0 * 10(-22) to 1.68 * 10(-19) m(2) for radial flows that are oriented along bedding planes under zero axial stress. The factors influencing transient pulse tests in particular and the interpretation of the results are discussed. PMID- 22489871 TI - Validity of measuring humeral torsion using palpation of bicipital tuberosities. AB - The magnitude of humeral torsion (HT) affects the internal and external rotation range of motion at the shoulder. Currently imaging is required to quantify the HT angle, however, factors such as cost and non-availability of imaging to musculoskeletal clinicians limits its use. The aim of this study was to examine the validity of palpation of the bicipital tuberosities as an alternative to imaging for quantifying HT angles. The bicipital-forearm angle, an indirect measure of HT, was measured using palpation and real-time ultrasound imaging in 25 subjects. The agreement among the two methods was excellent with the Intraclass Correlation Coefficient (3,k) = 0.92, and the mean difference between the two methods was -0.2 degrees (SD 4.1 degrees ) with 95% limits of agreement of -8.3 degrees to 7.9 degrees . Pearson's correlation coefficient (r) among the two methods was 0.85. In a clinical setting, palpation appears to be a practical alternative to US imaging for measuring HT. PMID- 22489873 TI - Effect of signalment on the presentation of canine patients suffering from cranial cruciate ligament disease. AB - OBJECTIVE: To determine the effect of signalment on the incidence and presentation of patients suffering from cranial cruciate ligament disease. METHODS: Data relating to 426 dogs (44 breeds) that met specific selection criteria were obtained from the hospital archive (2002 to 2008). Cases were followed up for 2 years. RESULTS: The breeds most commonly presented with cranial cruciate ligament disease were Labrador retriever (16%), Rottweiler (15%), golden retriever (12%) and boxer (9%). Rottweilers were significantly more likely (69%; P=0.05) to develop and present with (50%; P=0.03) bilateral cranial cruciate ligament disease. Rottweilers presenting with cranial cruciate ligament disease were significantly younger (median 977 days; P<0.0001) than other breeds; golden retrievers being significantly older at presentation (median 1994 days; P=0.004). Neither sex nor neutered status significantly affected the incidence of developing (P=0.77 and P=0.30, respectively) or presenting with (P=0.62 and P=0.35, respectively) bilateral cranial cruciate ligament disease. Entire dogs were significantly younger than neutered dogs at presentation (P=0.0004). Entire female dogs presented significantly younger than neutered females (P=0.0002), entire males (P=0.01) and neutered males (P=0.0001). CLINICAL SIGNIFICANCE: Breed affects the incidence of developing and presenting with bilateral cranial cruciate ligament disease. Breed and sex both affect the age that patients present with cranial cruciate ligament disease. PMID- 22489874 TI - Synthesis of (6-(13)C)pyrimidine nucleotides as spin-labels for RNA dynamics. AB - We present a (13)C-based isotope labeling protocol for RNA. Using (6 (13)C)pyrimidine phosphoramidite building blocks, site-specific labels can be incorporated into a target RNA via chemical oligonucleotide solid-phase synthesis. This labeling scheme is particularly useful for studying milli- to microsecond dynamics via NMR spectroscopy, as an isolated spin system is a crucial prerequisite to apply Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion type experiments. We demonstrate the applicability for the characterization and detection of functional dynamics on various time scales by incorporating the (6-(13)C)uridine and -cytidine labels into biologically relevant RNAs. The refolding kinetics of a bistable terminator antiterminator segment involved in the gene regulation process controlled by the preQ(1) riboswitch class I was investigated. Using (13)C CPMG relaxation dispersion NMR spectroscopy, the milli- to microsecond dynamics of the HIV-1 transactivation response element RNA and the Varkud satellite stem loop V motif was addressed. PMID- 22489875 TI - Prognostic factors and a prognostic index for cats with acute kidney injury. AB - BACKGROUND: The clinical manifestations of acute kidney injury (AKI) range from mild to fatal in cats; however, prognosis factors have been rarely studied. HYPOTHESIS/OBJECTIVES: To find the clinical factors significantly correlated with the outcome among cats with AKI and to develop a simple prognostic index. ANIMALS: Seventy cats with AKI were recruited. METHODS: Demographic and clinicopathological data obtained from 70 cats with AKI were retrospectively collected. Student's t-test or Mann-Whitney U-test and Pearson chi-square test or Fisher's exact were applied to determine the factors associated with survival in cats with AKI. Using logistic regression, the statistically significant factors associated with prognosis were identified and a new prediction model was generated. RESULTS: The overall case fatality rate was 64% (45/70). The results showed that nonsurviving cats had significantly lower levels of PCV, WBC, RBC, LDH and albumin, a lower albumin/globulin ratio, lower blood glucose, and a reduced body temperature, as well as being older. Serum urea and creatinine concentrations were not statistically significant as prognostic factors, but a decrease in these 2 variables in 3 days was significantly related to a reduction in death. A summary prognostic index including body temperature and LDH and albumin concentrations had area under the receiver-operating characteristic curve (AUROC) for predicting death of 0.86 (P < .05) and a cut-off value of 0.82, a sensitivity of 77% and a specificity of 90%. CONCLUSIONS: The prognosis in cats with AKI is quite different from that found for human and dogs. PMID- 22489876 TI - Recent advances in first principles computational research of cathode materials for lithium-ion batteries. AB - To meet the increasing demands of energy storage, particularly for transportation applications such as plug-in hybrid electric vehicles, researchers will need to develop improved lithium-ion battery electrode materials that exhibit high energy density, high power, better safety, and longer cycle life. The acceleration of materials discovery, synthesis, and optimization will benefit from the combination of both experimental and computational methods. First principles (ab Initio) computational methods have been widely used in materials science and can play an important role in accelerating the development and optimization of new energy storage materials. These methods can prescreen previously unknown compounds and can explain complex phenomena observed with these compounds. Intercalation compounds, where Li(+) ions insert into the host structure without causing significant rearrangement of the original structure, have served as the workhorse for lithium ion rechargeable battery electrodes. Intercalation compounds will also facilitate the development of new battery chemistries such as sodium-ion batteries. During the electrochemical discharge reaction process, the intercalating species travel from the negative to the positive electrode, driving the transition metal ion in the positive electrode to a lower oxidation state, which delivers useful current. Many materials properties change as a function of the intercalating species concentrations (at different state of charge). Therefore, researchers will need to understand and control these dynamic changes to optimize the electrochemical performance of the cell. In this Account, we focus on first-principles computational investigations toward understanding, controlling, and improving the intrinsic properties of five well known high energy density Li intercalation electrode materials: layered oxides (LiMO2), spinel oxides (LiM2O4), olivine phosphates (LiMPO4), silicates-Li2MSiO4, and the tavorite-LiM(XO4)F (M = 3d transition metal elements). For these five classes of materials, we describe the crystal structures, the redox potentials, the ion mobilities, the possible phase transformation mechanisms, and structural stability changes, and the relevance of these properties to the development of high-energy, high-power, low-cost electrochemical systems. These results demonstrate the importance of computational tools in real-world materials development, to optimize or minimize experimental synthesis and testing, and to predict a material's performance under diverse conditions. PMID- 22489879 TI - Management of bleeding associated with malignant wounds. AB - Bleeding malignant wounds in palliative care patients can be anxiety-provoking for patients, their caregivers, and healthcare providers, and can be difficult to manage. We present the case of a 60-year-old man with a bleeding neck wound due to squamous cell carcinoma of the hypopharynx admitted to our inpatient palliative care unit. Management of bleeding included local wound care measures and psychosocial support for the patient and his wife. We review therapeutic approaches to managing bleeding malignant wounds with the aim of providing clinically useful information. PMID- 22489878 TI - Aspergillus nidulans CkiA is an essential casein kinase I required for delivery of amino acid transporters to the plasma membrane. AB - Type I casein kinases are highly conserved among Eukaryotes. Of the two Aspergillus nidulans casein kinases I, CkiA is related to the delta/epsilon mammalian kinases and to Saccharomyces cerevisiae Hrr25p. CkiA is essential. Three recessive ckiA mutations leading to single residue substitutions, and downregulation using a repressible promoter, result in partial loss-of-function, which leads to a pleiotropic defect in amino acid utilization and resistance to toxic amino acid analogues. These phenotypes correlate with miss-routing of the YAT plasma membrane transporters AgtA (glutamate) and PrnB (proline) to the vacuole under conditions that, in the wild type, result in their delivery to the plasma membrane. Miss-routing to the vacuole and subsequent transporter degradation results in a major deficiency in the uptake of the corresponding amino acids that underlies the inability of the mutant strains to catabolize them. Our findings may have important implications for understanding how CkiA, Hrr25p and other fungal orthologues regulate the directionality of transport at the ER-Golgi interface. PMID- 22489880 TI - Wearing of complete dentures reduces slow fibre and enhances hybrid fibre fraction in masseter muscle. AB - Edentulous conditions and use of complete dentures alter the function of jaw muscles, which is presumably reflected in the myosin heavy chain (MyHC) isoform composition. This study is the first dealing with MyHC isoforms expression in edentulous persons with the aim to clarify to which extent the decreased functional load following teeth loss contributes to the changed muscle phenotype during ageing. We analysed MyHC expression in old masseter muscle at decreased and full functional load by comparing age-matched edentulous and dentate subjects. Edentulous subjects had upper and lower complete dentures. Dentate subjects had at least 24 natural teeth in continuous dental arches with two molars present in each quadrant and normal intermaxillary relationship. The adaptive response to the reduced masticatory load was lower numerical and area proportion of MyHC-1 expressing fibres and higher numerical proportion of hybrid fibres in edentulous compared with dentate subjects with no significant difference in the proportion of MyHC-neo-expressing fibres between both groups. We conclude that the observed differences in the proportion of fibre types between denture wearers and dentate subjects cannot be ascribed to degenerative changes intrinsic to the ageing muscle, but to functional differences in muscle activity and to morphological alterations of stomatognathic system accompanying the complete teeth loss. PMID- 22489881 TI - Microfluidic paper-based analytical device for particulate metals. AB - A microfluidic paper-based analytical device (MUPAD) fabricated by wax printing was designed to assess occupational exposure to metal-containing aerosols. This method employs rapid digestion of particulate metals using microliters of acid added directly to a punch taken from an air sampling filter. Punches were then placed on a MUPAD, and digested metals were transported to detection reservoirs upon addition of water. These reservoirs contained reagents for colorimetric detection of Fe, Cu, and Ni. Dried buffer components were used to set the optimal pH in each detection reservoir, while precomplexation agents were deposited in the channels between the sample and detection zones to minimize interferences from competing metals. Metal concentrations were quantified from color intensity images using a scanner in conjunction with image processing software. Reproducible, log-linear calibration curves were generated for each metal, with method detection limits ranging from 1.0 to 1.5 MUg for each metal (i.e., total mass present on the MUPAD). Finally, a standard incineration ash sample was aerosolized, collected on filters, and analyzed for the three metals of interest. Analysis of this collected aerosol sample using a MUPAD showed good correlation with known amounts of the metals present in the sample. This technology can provide rapid assessment of particulate metal concentrations at or below current regulatory limits and at dramatically reduced cost. PMID- 22489882 TI - Efficient photocatalytic decomposition of perfluorooctanoic acid by indium oxide and its mechanism. AB - Perfluorooctanoic acid (C(7)F(15)COOH, PFOA) has increasingly attracted worldwide concerns due to its global occurrence and resistance to most conventional treatment processes. Though TiO(2)-based photocatalysis is strong enough to decompose most organics, it is not effective for PFOA decomposition. We first find that indium oxide (In(2)O(3)) possesses significant activity for PFOA decomposition under UV irradiation, with the rate constant about 8.4 times higher than that by TiO(2). The major intermediates of PFOA were C(2)-C(7) shorter-chain perfluorocarboxylic acids, implying that the reaction proceeded in a stepwise manner. By using diffuse reflectance infrared Fourier transform spectroscopy, (19)F magic angle spinning nuclear magnetic resonance, and electron spin resonance, we demonstrate that the terminal carboxylate group of PFOA molecule tightly coordinates to the In(2)O(3) surface in a bidentate or bridging configuration, which is beneficial for PFOA to be directly decomposed by photogenerated holes of In(2)O(3) under UV irradiation, while PFOA coordinates to TiO(2) in a monodentate mode, and photogenerated holes of TiO(2) preferentially transform to hydroxyl radicals, which are inert to react with PFOA. PFOA decomposition in wastewater was inhibited by bicarbonate and other organic matters; however, their adverse impacts can be mostly avoided via pH adjustment and ozone addition. PMID- 22489883 TI - Increased expression of interleukin-18 and its receptor in peripheral blood of patients with chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a complex systemic disorder characterized by both local pulmonary and systemic inflammation. Many studies suggested that activation of circulating inflammatory cells and increased circulating levels of inflammatory cytokines occur in COPD. Interleukin (IL)-18 is a unique proinflammatory cytokine that mediates its effects by binding to the IL-18 receptor (IL-18R). In the present study, the expression of IL-18 in serum and IL-18R on peripheral blood T lymphocytes was analyzed. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum levels of IL-18 and interferon (IFN)-gamma, and high sensitivity C-reactive protein (hsCRP) were measured by chemiluminiscent immunoassay. Expression of IL-18R was examined using a three-color flow cytometry method. In total, 120 subjects were recruited including 32 nonsmokers, 30 current smokers and 58 stable COPD patients. Serum levels of IL-18 and hsCRP were significantly higher in stable COPD patients than those in nonsmokers and current smokers. A significant negative correlation existed between pulmonary function and serum level of IL-18 rather than hsCRP in stable COPD patients. The proportions of IL-18Ralpha-expressing T lymphocytes and CD8(+) T lymphocytes were significantly higher in stable COPD patients than in nonsmokers and current smokers. The current study extended prior analyses by examining IL-18R expression in peripheral blood. The results suggested that IL 18/IL-18R system was active in peripheral blood of COPD patients. PMID- 22489885 TI - Stable fixation of an osseointegated implant system for above-the-knee amputees: titel RSA and radiographic evaluation of migration and bone remodeling in 55 cases. AB - BACKGROUND AND PURPOSE: Rehabilitation of patients with transfemoral amputations is particularly difficult due to problems in using standard socket prostheses. We wanted to assess long-term fixation of the osseointegrated implant system (OPRA) using radiostereometric analysis (RSA) and periprosthetic bone remodeling. METHODS: 51 patients with transfemoral amputations (55 implants) were enrolled in an RSA study. RSA and plain radiographs were scheduled at 6 months and at 1, 2, 5, 7, and 10 years after surgery. RSA films were analyzed using UmRSA software. Plain radiographs were graded for bone resorption, cancellization, cortical thinning, and trabecular streaming or buttressing in specifically defined zones around the implant. RESULTS: At 5 years, the median (SE) migration of the implant was -0.02 (0.06) mm distally. The rotational movement was 0.42 (0.32) degrees around the longitudinal axis. There was no statistically significant difference in median rotation or migration at any follow-up time. Cancellization of the cortex (plain radiographic grading) appeared in at least 1 zone in over half of the patients at 2 years. However, the prevalence of cancellization had decreased by the 5-year follow-up. INTERPRETATION: The RSA analysis for the OPRA system indicated stable fixation of the implant. The periprosthetic bone remodeling showed similarities with changes seen around uncemented hip stems. The OPRA system is a new and promising approach for addressing the challenges faced by patients with transfemoral amputations. PMID- 22489884 TI - Regulation of intracellular membrane trafficking and cell dynamics by syntaxin-6. AB - Intracellular membrane trafficking along endocytic and secretory transport pathways plays a critical role in diverse cellular functions including both developmental and pathological processes. Briefly, proteins and lipids destined for transport to distinct locations are collectively assembled into vesicles and delivered to their target site by vesicular fusion. SNARE (soluble N ethylmaleimide-sensitive factor-attachment protein receptor) proteins are required for these events, during which v-SNAREs (vesicle SNAREs) interact with t SNAREs (target SNAREs) to allow transfer of cargo from donor vesicle to target membrane. Recently, the t-SNARE family member, syntaxin-6, has been shown to play an important role in the transport of proteins that are key to diverse cellular dynamic processes. In this paper, we briefly discuss the specific role of SNAREs in various mammalian cell types and comprehensively review the various roles of the Golgi- and endosome-localized t-SNARE, syntaxin-6, in membrane trafficking during physiological as well as pathological conditions. PMID- 22489886 TI - Low BMD affects initial stability and delays stem osseointegration in cementless total hip arthroplasty in women: a 2-year RSA study of 39 patients. AB - BACKGROUND AND PURPOSE: Immediate implant stability is a key factor for success in cementless total hip arthroplasty (THA). Low bone mineral density (BMD) and age-related geometric changes of the proximal femur may jeopardize initial stability and osseointegration. We compared migration of hydroxyapatite-coated femoral stems in women with or without low systemic BMD. PATIENTS AND METHODS: 61 female patients with hip osteoarthritis were treated with cementless THA with anatomically designed hydroxyapatite-coated femoral stems and ceramic-ceramic bearing surfaces (ABG-II). Of the 39 eligible patients between the ages of 41 and 78 years, 12 had normal systemic BMD and 27 had osteopenia or osteoporosis. According to the Dorr classification, 21 had type A bone and 18 had type B. Translational and rotational migration of the stems was evaluated with radiostereometric analysis (RSA) up to 2 years after surgery. RESULTS: Patients with low systemic BMD showed higher subsidence of the femoral stem during the first 3 months after surgery than did those with normal BMD (difference = 0.6, 95% CI: 0.1-1.1; p = 0.03). Low systemic BMD (odds ratio (OR) = 0.1, CI: 0.006 1.0; p = 0.02), low local hip BMD (OR = 0.3, CI: 0.1-0.7; p = 0.005) and ageing (OR = 1.1, CI: 1.0-1.2; p = 0.02) were risk factors for delayed translational stability. Ageing and low canal flare index were risk factors for delayed rotational stabilization (OR = 3, CI: 1.1-9; p = 0.04 and OR = 1.1, CI: 1.0-1.2; p = 0.02, respectively). Harris hip score and WOMAC score were similar in patients with normal systemic BMD and low systemic BMD. INTERPRETATION: Low BMD, changes in intraosseous dimensions of the proximal femur, and ageing adversely affected initial stability and delayed osseointegration of cementless stems in women. PMID- 22489887 TI - Physeal growth arrest after tibial lengthening in achondroplasia: 23 children followed to skeletal maturity. AB - BACKGROUND AND PURPOSE: Bilateral tibial lengthening has become one of the standard treatments for upper segment-lower segment disproportion and to improve quality of life in achondroplasia. We determined the effect of tibial lengthening on the tibial physis and compared tibial growth that occurred at the physis with that in non-operated patients with achondroplasia. METHODS: We performed a retrospective analysis of serial radiographs until skeletal maturity in 23 achondroplasia patients who underwent bilateral tibial lengthening before skeletal maturity (lengthening group L) and 12 achondroplasia patients of similar height and age who did not undergo tibial lengthening (control group C). The mean amount of lengthening of tibia in group L was 9.2 cm (lengthening percentage: 60%) and the mean age at the time of lengthening was 8.2 years. The mean duration of follow-up was 9.8 years. RESULTS: Skeletal maturity (fusion of physis) occurred at 15.2 years in group L and at 16.0 years in group C. The actual length of tibia (without distraction) at skeletal maturity was 238 mm in group L and 277 mm in group C (p = 0.03). The mean growth rates showed a decrease in group L relative to group C from about 2 years after surgery. Physeal closure was most pronounced on the anterolateral proximal tibial physis, with relative preservation of the distal physis. INTERPRETATION: Our findings indicate that physeal growth rate can be disturbed after tibial lengthening in achondroplasia, and a close watch should be kept for such an occurrence-especially when lengthening of more than 50% is attempted. PMID- 22489888 TI - Low-dose external beam radiotherapy as a postoperative treatment for patients with diffuse pigmented villonodular synovitis of the knee: 4 recurrences in 23 patients followed for mean 9 years. AB - BACKGROUND AND PURPOSE: Pigmented villonodular synovitis (PVNS) is a rare proliferative disorder involving synovial membranes, and patients with PVNS have a variable prognosis. We retrospectively analyzed clinical outcomes after synovectomy plus low-dose external beam radiotherapy for diffuse PVNS of the knee. METHODS: We reviewed the medical records of 23 patients who underwent postoperative radiotherapy between 1998 and 2007. 19 patients had primary disease and 4 had recurrent disease with an average of 2.5 prior surgeries. After synovectomy (17 arthroscopic surgeries; 6 open), all 23 patients received 4-MV or 6-MV external beam radiotherapy with a median dose of 20 (12-34) Gy in 10 fractions. RESULTS: At a median follow-up of 9 (0.8-12) years, 4 patients had recurrent disease, with a median disease-free interval of 5 years. Of these 4 patients, 3 received salvage synovectomy and regained local control. Univariate analysis showed that age, sex, history of trauma, and total dose of radiation were not predictive of local control. 22 patients reported excellent or good joint function, and 1 who refused salvage synovectomy had poor joint function. None of the patients experienced grade 3 or higher radiation-related toxicity or radiation-induced secondary malignancies. INTERPRETATION: Postoperative external beam radiotherapy is an effective and acceptable modality to prevent local recurrence and preserve joint function in patients with diffuse PVNS of the knee. Low-dose (20 Gy) radiotherapy appears to be as effective as moderate-dose treatment (around 35 Gy). PMID- 22489889 TI - Radiostereometry and new prostheses. PMID- 22489890 TI - Registration rate in the Norwegian Cruciate Ligament Register: large-volume hospitals perform better. AB - BACKGROUND AND PURPOSE: The Norwegian Cruciate Ligament Register (NCLR) was founded in 2004. The purpose of the NCLR is to provide representative and reliable data for future research. In this study we evaluated the development of the registration rate in the NCLR. METHODS: The Norwegian Patient Register (NPR) and the electronic patient charts (EPCs) were used as reference data for public and private hospitals, respectively. Data were retrieved for all primary and revision anterior cruciate ligament (ACL) surgery during 2008-2009 in public hospitals and during 2008 in private hospitals. The NOMESCO classification of surgical procedures was used for identification of ACL surgeries. Public hospitals were divided into subgroups according to the annual number of operations in the NPR: small hospitals (< 30 operations) and large hospitals (>= 30 operations). RESULTS: For the 2-year data extracted from public hospitals, 2,781 and 2,393 operations met the inclusion criteria according to the NPR and the NCLR, respectively, giving an average registration rate of 86% (95% CI: 0.85 0.87). The registration rate for small public hospitals was 69% (CI: 0.65-0.73), which was significantly less than for large public hospitals (89%, CI: 0.88-0.90; p < 0.001). In 2008, private hospitals reported 548 operations to the NCLR while 637 were found in the EPCs, giving a registration rate of 86% (CI: 0.83-0.89). In that year, the registration rate for public hospitals was 86%, which was similar to that for private hospitals. INTERPRETATION: The NCLR registration rate for the period 2008-09 was similar in both 2008 and 2009, and is satisfactory for research. There is room for improvement of registration rates, particularly in hospitals with a small volume of ACL operations. PMID- 22489891 TI - Congenital talipes equinovarus: an epidemiological study in Sicily. AB - BACKGROUND AND PURPOSE: Congenital talipes equinovarus (clubfoot) can present in 2 forms: "syndromic", in which other malformations exist, and the more common "idiopathic" form, where there are no other associated malformations. We analyzed the epidemiology of congenital talipes equinovarus in the Sicilian population, looking for potential etiological factors. PATIENTS AND METHODS: Among the 801,324 live births recorded between January 1991 and December 2004, 827 cases were registered (560 males; M/F sex ratio: 2.1). Control infants were randomly selected from a historical cohort of live births without any major congenital malformations. RESULTS: A positive family history of clubfoot, gender, and maternal smoking were found to be risk factors for clubfoot. Patients with clubfoot were born most frequently during the period January-March. No association was found between clubfoot and reproductive history, peri conceptional maternal drug exposure, maternal education, or ethnicity. INTERPRETATION: Our findings emphasize the importance of birth defects surveillance programs and their usefulness in investigating potential risk factors. PMID- 22489892 TI - Early prosthetic joint infections treated with debridement and implant retention: 38 primary hip arthroplasties prospectively recorded and followed for median 4 years. AB - BACKGROUND AND PURPOSE: Debridement and retention of the prosthesis is often attempted to treat early prosthetic joint infection (PJI). However, previous studies have found inconsistent results, with success rates ranging from 21% to 100%, and little has been written in the literature about hip function. We have therefore analyzed the clinical and functional outcome of early PJIs treated with this procedure. PATIENTS AND METHODS: 38 patients with early PJI after primary hip arthroplasty who were treated with debridement and retention of the implant between 1998 and 2005 were studied prospectively, with a median follow-up time of 4 (0.8-10) years. Early infection was defined as that which occurred within 4 weeks of index arthroplasty. The primary outcome measure was infection control. Functional outcome was assessed with the Harris hip score. RESULTS: 27 of 38 patients were successfully treated, with no signs of infection or continued antibiotic treatment at the latest follow-up. Median Harris hip score was 86 (47 100) points. In 9 of the 11 patients for whom treatment failed, infection was successfully treated with 1-stage or 2-stage reimplantation or resection. Intraoperative cultures were positive in 36 hips, and the most frequently isolated organisms were Staphylococcus aureus and coagulase-negative staphylococci (CoNS). 15 infections were polymicrobial, and only 8 of them were successfully treated with debridement and retention of the implant. INTERPRETATION: Our data suggest that debridement and retention of the prosthesis is a reasonable treatment option in early PJI after primary hip arthroplasty, with satisfactory functional results. PMID- 22489893 TI - Microparticles expressing tissue factor are concurrently released with markers of inflammation and coagulation during human endotoxemia. PMID- 22489894 TI - Benzalkonium chloride induces anterior chamber inflammation in previously untreated patients with ocular hypertension as measured by flare meter: a randomized clinical trial. AB - PURPOSE: The deleterious effects of benzalkonium chloride (BAK) on the ocular surface are well known. However, few clinical data are available to prove a toxic effect at the level of the anterior chamber. The laser flare meter is a reliable tool to detect low levels of inflammation in the anterior chamber. We wanted to know whether instillation of BAK-preserved timolol in one eye would result in higher laser flare values than the instillation of preservative-free timolol in the fellow eye. METHODS: Randomized prospective, single-masked clinical trial. Twenty-eight untreated patients with ocular hypertension were recruited. After obtaining baseline flare values, we randomly assigned one eye to BAK-preserved timolol and the fellow eye to preservative-free timolol. After 1 month, flare measurements were repeated. RESULTS: There was a significant increase in the flare values in the two treatment regimens, but the increase in the BAK-treated eyes was higher than in the preservative-free treated eyes, and this difference in increase was statistically significant. CONCLUSION: This is the first study to show that short-term BAK administration produces inflammation in the anterior segment of previously untreated patients whose blood-aqueous barrier was not affected by recent intraocular surgery. PMID- 22489895 TI - Radical prostatectomy after previous transurethral resection of the prostate: robot-assisted laparoscopic versus open radical prostatectomy in a matched-pair analysis. AB - PURPOSE: To determine whether previous transurethral resection of the prostate (TURP) compromises the surgical outcome and pathologic findings in patient who underwent either radical robot-assisted laparoscopic prostatectomy (RALP) or open retropubic radical prostatectomy (RRP) after TURP, because TURP is reported to complicate radical prostatectomy and there are conflicting data. PATIENTS AND METHODS: From July 2008 to July 2010, 357 patients underwent RALP. Of these, 19 (5.3%) patients had undergone previous TURP. Operative and perioperative data of patients were compared with those of matched controls selected from a database of 616 post-RRP patients. Matching criteria were age, clinical stage, the level of preoperative prostate-specific-antigen, the biopsy Gleason score, the American Society of Anesthesiologists classification score, and prostate volume assessed during transrectal ultrasonography. All RRP and RALP procedures were performed by experienced surgeons. RESULTS: Mean time to prostatectomy was 67.4 months in the RALP group and 53.1 months in the RRP group. Mean operative time was 217 +/- 51.9 minutes for RALP and 174 +/- 57.7 minutes for RRP (P<0.05). The overall positive surgical margin rate was 15.8% in both groups (pT(2) tumors: 10.5% for RALP and 5.3% for RRP; P=1.0). Mean estimated blood loss was 333 +/- 144 mL in RALP patients and 1103 +/- 636 mL in RRP patients (P<0.001). The difference between preoperative and postoperative hemoglobin levels was 3.22 +/- 0.98 g/dL for RALP and 5.85 +/- 1.95 g/dL for RRP (P=0.0002). The RALP and RRP groups also differed in terms of hospital stay (8.58 +/- 1.17 vs 11.74 +/- 5.22 days; P=0.0037), duration of catheterization (7.95 +/- 5.69 vs 11.78 +/- 6.97 days; P=0.0016), postoperative complications according to the Clavien classification system (6 vs 15 patients; P=0.0027), and transfusion rate (0% vs 10.5%; P<0.001). CONCLUSION: RALP offers advantages over open radical prostatectomy after previous surgery. Although both techniques are associated with adequate surgical outcomes, RALP appeared to be preferable in our population of patients with previous prostate surgery. PMID- 22489896 TI - Dose estimates for the local inhabitants from 210Po ingestion via dietary sources at a proposed uranium mining site in India. AB - PURPOSE: To study the distribution of (210)Po activity in food in Bagjata in East Singhbhum, India. MATERIALS AND METHODS: (210)Po were analyzed in the food samples of plant origin such as cereals, pulses, fruits, vegetables and food of animal origin such fish, chicken, egg, etc., in and around Bagjata uranium mining area as a part of baseline study after acid digestion. The intake and ingestion dose of the radionuclide was estimated. RESULTS: The general range of (210)Po activity in all the dietary components ranged widely from <0.2-36 Bqkg( 1)(fresh). In the food of plant origin, the minimum activity of (210)Po was estimated in vegetables while maximum in pulses. In food of animal origin, the observed minimum activity of (210)Po was in eggs and the maximum observed was in chicken samples. The intake of (210)Po considering all dietary components was found to be 464 Bq.Y(-1) while the ingestion dose was calculated to be 557 MUSv.Y(-1), respectively. The estimated doses are reflecting the natural background dose via the route of ingestion, which is much below the 1 mSv limit set in the International Commission on Radiological Protection (ICRP) recommendations. CONCLUSION: The study confirms that current levels of (210)Po do not pose a significant radiological risk to the local inhabitants. PMID- 22489897 TI - Discovery of novel potent and highly selective glycogen synthase kinase-3beta (GSK3beta) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines. AB - Glycogen synthase kinase-3beta, also called tau phosphorylating kinase, is a proline-directed serine/threonine kinase which was originally identified due to its role in glycogen metabolism. Active forms of GSK3beta localize to pretangle pathology including dystrophic neuritis and neurofibrillary tangles in Alzheimer's disease (AD) brain. By using a high throughput screening (HTS) approach to search for new chemical series and cocrystallization of key analogues to guide the optimization and synthesis of our pyrazine series, we have developed highly potent and selective inhibitors showing cellular efficacy and blood-brain barrier penetrance. The inhibitors are suitable for in vivo efficacy testing and may serve as a new treatment strategy for Alzheimer's disease. PMID- 22489898 TI - Unravelling stability-complexity relationships. PMID- 22489899 TI - Modeling the molecular and climatic controls on flowering. PMID- 22489900 TI - Beware: alien invasion. Where to next for an understanding of weed ecology? PMID- 22489901 TI - Flammability as a biological concept. PMID- 22489902 TI - The importance of individuals: intraspecific diversity of mycorrhizal plants and fungi in ecosystems. AB - A key component of biodiversity is the number and abundance of individuals (i.e. genotypes), and yet such intraspecific diversity is rarely considered when investigating the effects of biodiversity of mycorrhizal plants and fungi on ecosystem processes. Within a species, individuals vary considerably in important reproductive and functional attributes, including carbon fixation, mycelial growth and nutrient utilization, but this is driven by both genetic and environmental (including climatic) factors. The interactions between individual plants and mycorrhizal fungi can have important consequences for the maintenance of biodiversity and regulation of resource transfers in ecosystems. There is also emerging evidence that assemblages of genotypes may affect ecosystem processes to a similar extent as assemblages of species. The application of whole-genome sequencing and population genomics to mycorrhizal plants and fungi will be crucial to determine the extent to which individual variation in key functional attributes is genetically based. We argue the need to unravel the importance of the diversity (especially assemblages of different evenness and richness) of individuals of both mycorrhizal plants and fungi, and the need to take a 'community genetics' approach to better understand the functional significance of the biodiversity of mycorrhizal symbioses. PMID- 22489903 TI - Moderate-to-high-intensity training and a hypocaloric Mediterranean diet enhance endothelial progenitor cells and fitness in subjects with the metabolic syndrome. AB - A reduction in EPC (endothelial progenitor cell) number could explain the development and progression of atherosclerosis in the MetS (metabolic syndrome). Although much research in recent years has focused on the Mediterranean dietary pattern and the MetS, the effect of this diet with/without moderate-to-high intensity endurance training on EPCs levels and CrF (cardiorespiratory fitness) remains unclear. In the present study, the objective was to assess the effect of a Mediterranean diet hypocaloric model with and without moderate-to-high intensity endurance training on EPC number and CrF of MetS patients. Thus 45 MetS patients (50-66 years) were randomized to a 12-week intervention with the hypocaloric MeD (Mediterranean diet) or the MeDE (MeD plus moderate-to-high intensity endurance training). Training included two weekly supervised sessions [80% MaxHR (maximum heart rate); leg and arm pedalling] and one at-home session (65-75% MaxHR; walking controlled by heart rate monitors). Changes in: (i) EPC number [CD34(+)KDR(+) (kinase insert domain-containing receptor)], (ii) CrF variables and (iii) MetS components and IRH (ischaemic reactive hyperaemia) were determined at the end of the study. A total of 40 subjects completed all 12 weeks of the study, with 20 in each group. The MeDE led to a greater increase in EPC numbers and CrF than did the MeD intervention (P <= 0.001). In addition, a positive correlation was observed between the increase in EPCs and fitness in the MeDE group (r=0.72; r(2)=0.52; P <= 0.001). Body weight loss, insulin sensitivity, TAGs (triacylglycerols) and blood pressure showed a greater decrease in the MeDE than MeD groups. Furthermore, IRH was only improved after the MeDE intervention. In conclusion, compliance with moderate-to-high-intensity endurance training enhances the positive effects of a model of MeD on the regenerative capacity of endothelium and on the fitness of MetS patients. PMID- 22489904 TI - Related bifunctional restriction endonuclease-methyltransferase triplets: TspDTI, Tth111II/TthHB27I and TsoI with distinct specificities. AB - BACKGROUND: We previously defined a family of restriction endonucleases (REases) from Thermus sp., which share common biochemical and biophysical features, such as the fusion of both the nuclease and methyltransferase (MTase) activities in a single polypeptide, cleavage at a distance from the recognition site, large molecular size, modulation of activity by S-adenosylmethionine (SAM), and incomplete cleavage of the substrate DNA. Members include related thermophilic REases with five distinct specificities: TspGWI, TaqII, Tth111II/TthHB27I, TspDTI and TsoI. RESULTS: TspDTI, TsoI and isoschizomers Tth111II/TthHB27I recognize different, but related sequences: 5'-ATGAA-3', 5'-TARCCA-3' and 5'-CAARCA-3' respectively. Their amino acid sequences are similar, which is unusual among REases of different specificity. To gain insight into this group of REases, TspDTI, the prototype member of the Thermus sp. enzyme family, was cloned and characterized using a recently developed method for partially cleaving REases. CONCLUSIONS: TspDTI, TsoI and isoschizomers Tth111II/TthHB27I are closely related bifunctional enzymes. They comprise a tandem arrangement of Type I-like domains, like other Type IIC enzymes (those with a fusion of a REase and MTase domains), e.g. TspGWI, TaqII and MmeI, but their sequences are only remotely similar to these previously characterized enzymes. The characterization of TspDTI, a prototype member of this group, extends our understanding of sequence-function relationships among multifunctional restriction-modification enzymes. PMID- 22489905 TI - British Dietetic Association evidence-based guidelines for the dietary management of irritable bowel syndrome in adults. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a chronic debilitating functional gastrointestinal disorder. Diet and lifestyle changes are important management strategies. The aim of these guidelines is to systematically review key aspects of the dietary management of IBS, with the aim of providing evidence-based guidelines for use by registered dietitians. METHODS: Questions relating to diet and IBS symptom management were developed by a guideline development group. These included the role of milk and lactose, nonstarch polysaccharides (NSP), fermentable carbohydrates in abdominal bloating, probiotics and empirical or elimination diets. A comprehensive literature search was conducted and relevant studies from January 1985 to November 2009 were identified using the electronic database search engines: Cinahl, Cochrane Library, Embase, Medline, Scopus and Web of Science. Evidence statements, recommendations, good practice points and research recommendations were developed. RESULTS: Thirty studies were critically appraised. A dietetic care pathway was produced following a logical sequence of treatment and formed the basis of these guidelines. Three lines of dietary management were identified. first line: Clinical and dietary assessment, healthy eating and lifestyle management with some general advice on lactose and NSP. Second line: Advanced dietary interventions to improve symptoms based on NSP, fermentable carbohydrates and probiotics. Third line: Elimination and empirical diets. Research recommendations were also identified relating to the need for adequately powered and well designed randomised controlled trials. CONCLUSIONS: These guidelines provide evidence-based details of how to achieve the successful dietary management of IBS. PMID- 22489906 TI - Safety and acceptance of non-sedated upper gastrointestinal endoscopy: a prospective observational study. AB - BACKGROUND: The study was conducted to assess the patient acceptability of non sedated upper gastrointestinal (GI) endoscopy and to study cardiorespiratory changes during the procedure. SUBJECTS AND METHODS: This study was conducted in the outpatient endoscopy room of Department of Surgery of a teaching tertiary care hospital in North India. The patients underwent diagnostic GI endoscopy under topical pharyngeal anesthesia using 5% lidocaine. No sedation was used. Pulse rate (PR), respiratory rate (RR), oxygen saturation (SpO(2)), and mean blood pressure (BP) were recorded immediately prior to endoscopy, during endoscopy, and 5, 15, and 30 minutes after endoscopy. Using a 10-point Likert scale, all the patients were asked to record their expected discomfort for the endoscopy as a pre-test score and their actual level of discomfort during endoscopy as a post-test score. Patients were also asked about whether they would opt for non-sedated upper GI endoscopy again in the future if required. RESULTS: Sixty patients underwent diagnostic upper GI endoscopy during the study period. Post hoc tests using Bonferroni's correction revealed that mean PR, RR, and mean BP changed significantly during endoscopy. However, these parameters normalized at 30 minutes following endoscopy. Mean SpO(2) did not differ significantly at the different time points. Pre- and post-endoscopy mean visual analog scale scores to assess the expected level of discomfort during endoscopy were not statistically different. Forty-four patients (73.3%) indicated their willingness to undergo repeat non-sedated endoscopy in the future if required. Binary logistic regression analysis identified young age, male gender, and long duration of procedure as significant factors for unwillingness to undergo repeat non sedated endoscopy. CONCLUSION: Non-sedated endoscopy is a feasible, safe, and fast office procedure and seems well tolerated by most patients. PMID- 22489907 TI - Robotic thyroidectomy: an initial experience with the gasless transaxillary approach. AB - BACKGROUND: Thyroid surgery has recently emerged as one of the most promising fields for the application of robotic surgery. We report the results of the first year of experience with a gasless transaxillary thyroidectomy. SUBJECTS AND METHODS: From January 2009 to December 2009, 10 consecutive patients (8 women) underwent robotic thyroidectomy through a gasless transaxillary approach. The median age was 44 years (range, 27-42 years). Eight total and two partial thyroidectomies (one left and one right) were performed using the da Vinci((r)) Robotic Surgical System (Intuitive Surgical, Sunnyvale, CA). Preoperative diagnosis included solitary nodules with a median size of 16+/-11 mm (range, 3-44 mm) at preoperative imaging. RESULTS: All procedures were successfully completed robotically, except one that was converted because of difficulty in achieving an optimal exposure. The overall mean operative time was 177.4+/-40 minutes (range, 120-240 minutes) with minimal blood loss (<10 mL). Pathological diagnoses included papillary carcinoma (n=6), colloid nodule (n=2), and multinodular goiter (n=2). The mean number of lymph nodes harvested in the cases of malignant disease was 4+/-5 (range, 3-15). The median postoperative length of stay was 1.05 days (range, 1-1.4 days). CONCLUSIONS: Thyroid surgery using a gasless transaxillary approach can be performed safely for selected benign and malignant pathology. This approach offers superior cosmetic results and a short hospital stay over conventional thyroid surgery. For selected patients, this technique offers a promising scarless option for minimally invasive thyroid surgery. PMID- 22489908 TI - Long term persistence of thyrotropin receptor antibodies in wild-type and transgenic mice in a Graves' disease model. AB - Background: Graves'-like disease, reflected by TSHR antibodies and hyperthyroidism in some mouse strains, can be induced by immunization with adenovirus expressing DNA for the human thyrotropin receptor (TSHR) or it's A subunit. The conventional approach involves two or three adenovirus injections at three-weekly intervals and euthanasia 10 weeks after the first injection. In order to investigate TSHR antibody persistence in mice with differing degrees of self-tolerance to the TSHR A-subunit, we studied the effect of delaying euthanasia until 20 weeks after the initial immunization. Methods: Wild-type mice and transgenic mice expressing low intrathyroidal levels of the human TSHR A subunit were immunized with A-subunit-adenovirus on two occasions; a second group of mice was immunized on three occasions. Sera obtained 4, 10 and 20 weeks (euthanasia) after the initial immunization were tested for TSH binding inhibition (TBI), antibody binding to TSHR A-subunit protein-coated ELISA plates and thyroid stimulating antibody activity (TSAb; cAMP generation). Serum thyroxine and thyroid histology were studied at euthanasia. Results: The majority of wild-type mice retained high TSHR antibody levels measured by TBI or ELISA at euthanasia but only about 50% were TSAb positive. Low expressor transgenics exhibited self-tolerance, with fewer mice positive by TBI or ELISA and antibody levels were lower than in wild-type littermates. In wild-type mice, antibody persistence was similar after two or three immunizations; for transgenics, only mice immunized three times had detectable TSAb at 20 weeks. Unlike our previous observations of hyperthyroidism in wild-type mice examined 4 or 10 weeks after immunization, all mice were euthyroid at 20 weeks. Conclusions: Our findings for induced TSHR antibodies in mice, similar to data for human thyroid autoantibodies, indicate that the parameters that contribute to the concentration of the antibody and thereby play a critical role in long term persistence of TSHR antibodies are the degree of self-tolerance to the TSHR and chronic stimulation. PMID- 22489909 TI - Experimental evaluation of new concepts in hip arthroplasty. AB - In this thesis we evaluated two different hip arthroplasty concepts trough in vitro studies and numerical analyses. The cortical strains in the femoral neck area were increased by 10 to 15 % after insertion of a resurfacing femoral component compared to values of the intact femur, shown in an in vitro study on human cadaver femurs. There is an increased risk of femoral neck fracture after hip resurfacing arthroplasty. An increase of 10 to 15 % in femoral neck strains is limited, and cannot alone explain these fractures. Together with patient specific and surgical factors, however, increased strain can contribute to increased risk of fracture. An in vitro study showed that increasing the neck length in combination with retroversion or reduced neck shaft angle on a standard cementless femoral stem does not compromise the stability of the stem. The strain pattern in the proximal femur increased significantly at several measuring sites when the version and length of neck were altered. However, the changes were probably too small to have clinical relevance. In a validation study we have shown that a subject specific finite element analysis is able to perform reasonable predictions of strains and stress shielding after insertion of a femoral stem in human cadaver femurs. The usage of finite element models can be a valuable supplement to in vitro tests of femoral strain pattern around hip arthroplasty. Finally, a patient case shows that bone resorption around an implant caused by stress shielding can in extreme cases lead to periprosthetic fracture. PMID- 22489910 TI - Spirometric thresholds for diagnosing COPD: 0.70 or LLN, pre- or post-dilator values? AB - In absence of a gold standard for chronic obstructive pulmonary disease (COPD) it remains difficult to compare the true diagnostic characteristics of the forced expiratory volume in 1 second to the forced vital capacity (FEV(1)/FVC) <0.70 and < lower limit of normal (LLN). COPD is a clinical diagnosis, based on symptoms signs and lung function results combined, and an expert panel assessment would be an adequate reference standard. We compared the diagnostic properties of FEV(1)/FVC 50, consulting for persistent cough, but without physician-diagnosed COPD, were prospectively enrolled. All underwent extensive history taking, physical examination, spirometry and diffusion testing. An expert panel, including a board certified respiratory physician, assessed all diagnostic information to determine the presence or absence of COPD and served as reference standard. Then, 104 participants were diagnosed with COPD by the panel. The reproducibility of the panel diagnosis was high (kappa of 0.94). Sensitivity estimates of <0.70 were significantly higher than that of 403.0 mg/dL (odds ratio 3.4, 95% confidence interval [CI], 2.1, 5.6) than were people with normal lung function, after adjusting for covariates. An elevated fibrinogen level increased the risk of mortality (hazards ratio [HR] 1.36, 95% CI 1.13, 1.63) in the entire study sample and in subjects with Stage 3 or 4 (HR 2.11, 95% CI 1.27, 3.50) or Stage 2 (HR 1.45, 95% CI 1.08, 1.96) COPD. CONCLUSION: In the nationally representative NHANES III data, impaired lung function is a correlate of fibrinogen levels and the presence of higher fibrinogen levels increases the risk of mortality both in the overall population and among subjects with COPD. PMID- 22489913 TI - Creating a monster: non-adherence underlying late transplant rejection. PMID- 22489916 TI - Anterior visual pathway assessment by magnetic resonance imaging in normal pressure glaucoma. AB - PURPOSE: To analyze the axonal architecture of the optic nerve in patients with normal-pressure glaucoma and determine whether these parameters correlate with the disease severity. METHODS: Using magnetic resonance (MRI) imaging (1.5 Tesla unit) and diffusion tensor (DT) MRI, we measured the optic nerve diameter, optic chiasm height and lateral geniculate nucleus (LGN) volume in patients with normal-pressure glaucoma and an age-matched control group. The retinal nerve fibre layer thickness (RNFL) was determined by optical coherence tomography (OCT). RESULTS: The study included 30 patients with normal-pressure glaucoma and 30 age-matched control subjects. Optic nerve diameter (p < 0.001), optic chiasm height (p < 0.001) and LGN volume (p = 0.02) were significantly smaller in the glaucoma group than in the control group and were significantly correlated with RNFL thickness and perimetric loss. In the control group, the parameters significantly (p < 0.05) decreased with age. The DT-MRI-derived fractional anisotropy for the optic nerve was significantly lower (p < 0.001), and the DT MRI-derived mean diffusivity (p < 0.001), radial diffusivity (lambda(?) ; p < 0.001) and axial diffusivity (lambda(||) ; p = 0.009) for the optic nerve were significantly higher in the glaucoma group and significantly correlated with RNFL thickness and mean perimetric defect. CONCLUSIONS: Patients with normal pressure glaucoma show an age-adjusted reduced optic nerve diameter, optic chiasm height and LGN volume as measured by MRI, correlating with a reduced RNFL thickness and increased perimetric loss. MRI may be applied to examine the optic nerve in patients with glaucoma with opaque optic media. PMID- 22489915 TI - ITAM receptor-mediated generation of reactive oxygen species in human platelets occurs via Syk-dependent and Syk-independent pathways. AB - BACKGROUND: Ligation of the platelet-specific collagen receptor, GPVI/FcRgamma, causes rapid, transient disulfide-dependent homodimerization, and the production of intracellular reactive oxygen species (ROS) generated by the NADPH oxidase, linked to GPVI via TRAF4. OBJECTIVES: The aim of this study was to evaluate the role of early signaling events in ROS generation following engagement of either GPVI/FcRgamma or a second immunoreceptor tyrosine-based activation motif (ITAM) containing receptor on platelets, FcgammaRIIa. METHODS AND RESULTS: Using an H(2) DCF-DA-based flow cytometric assay to measure intracellular ROS, we show that treatment of platelets with either the GPVI agonists, collagen-related peptide (CRP) or convulxin (Cvx), or the FcgammaRIIa agonist 14A2, increased intraplatelet ROS; other platelet agonists such as ADP and TRAP did not. Basal ROS in platelet-rich plasma from 14 healthy donors displayed little inter individual variability. CRP, Cvx or 14A2 induced an initial burst of ROS within 2 min followed by additional ROS reaching a plateau after 15-20 min. The Syk inhibitor BAY61-3606, which blocks ITAM-dependent signaling, had no effect on the initial ROS burst, but completely inhibited the second phase. CONCLUSIONS: Together, these results show for the first time that ROS generation downstream of GPVI or FcgammaRIIa consists of two distinct phases: an initial Syk-independent burst followed by additional Syk-dependent generation. PMID- 22489917 TI - SmI2-mediated coupling of nitrones and tert-butanesulfinyl imines with allenoates: synthesis of beta-methylenyl-gamma-lactams and tetramic acids. AB - Nitrones and tert-butanesulfinyl imines undergo conjugate addition to alkyl allenoates under SmI(2)-mediated reductive coupling conditions to produce novel beta-methylenyl-substituted gamma-amino esters. The latter were readily transformed into the corresponding beta-methylenyl-gamma-lactams by simple zinc reduction (N-hydroxy amines) or by acid hydrolysis (sulfinamides). The diastereoselective preparation of various beta-methylenyl-gamma-lactams offers a route to tetramic acids, the key structural features of an important class of bioactive natural products. PMID- 22489919 TI - The impact of the National Denture Service on oral health-related quality of life among poor elders. AB - The objective of this study was to assess the effects of the Korean National Denture Service (NDS) for poor elderly people requiring dentures on oral health related quality of life (OHRQOL). Data from follow-up studies were collected from 439 subjects at eight public health centres who answered every question of a questionnaire, and the OHRQOL was measured at the baseline and at 3-month follow up after receiving the NDS according to the type of denture provision. The multivariate linear mixed model with a public health centre as a random effect for the score change of Oral Health Impact Profile (OHIP)-14K was carried out to confirm the factors related to the improvement in OHRQOL. The mean OHIP-14K was 28.60 at the baseline time points, and there was a decrease in the OHIP-14 scores to 21.14 +/- 12.52 at the 3-month follow-up of the removable partial denture beneficiaries. The changes in OHIP-14K among complete denture beneficiaries were 21.53 +/- 12.01 for previously dentate subjects and 22.54 +/- 11.12 for edentate subjects. The multivariate linear mixed model of dentate subjects demonstrated that the improvement in the OHRQOL was associated with the number of remaining teeth, satisfaction with denture and self-reported oral health status after 3 months. In the case of the edentate model, satisfaction with denture was the only factor related to the improvement in OHRQOL. This study revealed considerable improvement in OHRQOL among poor elderly people after NDS. Satisfaction with provision of dentures was associated with improvement in the OHRQOL. PMID- 22489918 TI - Mechano-transcription of COX-2 is a common response to lumen dilation of the rat gastrointestinal tract. AB - BACKGROUND: In obstructive bowel disorders (OBDs) such as achalasia, pyloric stenosis, and bowel obstruction, the lumen of the affected segments is markedly dilated and the motility function is significantly impaired. We tested the hypothesis that mechanical stress in lumen dilation leads to induction of cyclooxygenase-2 (COX-2) in smooth muscle throughout the gastrointestinal (GI) tract, contributing to motility dysfunction. METHODS: Lumen dilation was induced in vivo with obstruction bands (12 * 3 mm) applied over the lower esophageal sphincter (LES), the pyloric sphincter, and the ileum in rats for 48 h. Mechanical stretch in vivo was also emulated by balloon distension of the distal colon. Direct stretch of muscle strips from the esophagus, gastric fundus, and ileum was mimicked in an in vitro tissue culture system. KEY RESULTS: Partial obstruction in the LES, pylorus, and ileum significantly increased the expression of COX-2 mRNA and protein in the muscularis externae of the dilated segment oral to the occlusions, but not in the aboral segment. Direct stretch of the lumen in vivo or of muscle strips in vitro markedly induced COX-2 expression. The smooth muscle contractility was significantly suppressed in the balloon-distended segments. However, treatment with COX-2 inhibitor NS-398 restored the contractility. Furthermore, in vivo administration of NS-398 in gastric outlet obstruction significantly improved gastric emptying. CONCLUSIONS & INFERENCES: Mechanical dilation of the gut lumen by occlusion or direct distension induces gene expression of COX-2 throughout the GI tract. Mechanical stress-induced COX-2 contributes to motility dysfunction in conditions with lumen dilation. PMID- 22489920 TI - Role of ultrasound elastography in prediction of malignancy in thyroid nodules. AB - BACKGROUND: Ultrasonography is considered useful to distinguish between solid and cystic thyroid nodules and to stratify a nodule's risk of cancer as low, medium, or high. Ultrasound (US) elastography has been applied to study the hardness/elasticity of nodules to differentiate malignant from benign lesions. Elastography possibly can solve the dilemma in reaching an accurate diagnosis for the cytologically known as indeterminate nodules. AIM: To evaluate the sensitivity and specificity of US elastography in the diagnosis of thyroid cancer. PATIENTS AND METHODS: This prospective study included 40 patients. The total number of nodules was 46, they were all euthyroid. Laboratory investigations were done including FT3, FT4, and TSH to exclude hot nodules. Neck US, US elastography, and fine-needle aspiration were done to all patients, and US elastography scoring system from 1 to 4 was used. RESULTS: Four out of the 46 studied nodules were malignant. The ROC curve for elastography score (E-score) showed high sensitivity, specificity for the diagnosis of malignant thyroid nodules with a cut-off value of E-score 4 and high significance (p<0.001), the area under curve was 0.92. The sensitivity was 75.0% and specificity was 100%. For E-score more than 2, the sensitivity was 100% and specificity was 85.37%. CONCLUSION: US elastography can be used to increase both the sensitivity and the specificity of US for the detection of malignant thyroid nodules, and so it seems to have great potential as a new tool for the diagnosis of thyroid cancer. PMID- 22489921 TI - Plasma kisspeptin levels in pregnancies with diabetes and hypertensive disease as a potential marker of placental dysfunction and adverse perinatal outcome. AB - BACKGROUND: The aim of this study was to prospectively evaluate plasma kisspeptin levels in 129 singleton pregnancies with diabetes [pregestational insulin dependent diabetes mellitus (type 1) and gestational diabetes (GD)] and hypertensive disease [chronic hypertension (CH), gestational hypertension, and preeclampsia (PE)] as a potential marker of placental dysfunction and adverse perinatal outcome. STUDY DESIGN: Kisspeptin levels were evaluated in the first, second, and third trimesters in patients with type 1 diabetes (16 patients), H (22), and healthy control (25) and in the second and third trimesters in patients with GD (20), gestational hypertension (18), and PE (28). Maternal kisspeptin levels were correlated with pregnancy outcome, parameters of fetoplacental circulation, ultrasound-detected abnormalities of placental morphology, and placental weight at delivery. RESULTS: In pregnancies with type 1 diabetes and H, mean kisspeptin levels were significantly lower compared with the control group (p<0.001 in the first and second trimesters and p<0.05 in the third trimester). Decreased plasma kisspeptin levels in the second and third trimesters were found in patients with GD (p<0.001 in the second and third trimesters) and PE (p<0.001 in the second trimester and p<0.05 in the third trimester). In patients with PE and placental dysfunction, low kisspeptin levels in the third trimester were associated with adverse perinatal outcome. CONCLUSIONS: Our study demonstrates reduced kisspeptin levels in pregnancies with diabetes, H, PE, and placental dysfunction. In patients with PE and placental dysfunction, decreased kisspeptin levels were associated with adverse perinatal outcome. Larger studies are needed to investigate the role of kisspeptin as a potential marker of placental dysfunction and adverse perinatal outcome. PMID- 22489923 TI - Implications of mercury speciation in thiosulfate treated plants. AB - Mercury uptake was induced in two cultivars of Brassica juncea under field conditions using thiosulfate. Analysis was conducted to better understand the mechanism of uptake, speciation of mercury in plants, and redistribution of mercury in the soil. Plant mercury and sulfur concentrations were increased after thiosulfate treatment, and a linear correlation between mercury and sulfur was observed. Mercury may be absorbed and transported in plants as the Hg-thiosulfate complex. The majority of mercury in treated plant tissues (two cultivars) was bound to sulfur in a form similar to beta-HgS (66-94%). Remaining mercury was present in forms similar to Hg-cysteine (1-10%) and Hg-dicysteine (8-28%). The formation of beta-HgS may relate to the transport and assimilation of sulfate in plant tissues. Mercury-thiosulfate complex could decompose to mercuric and sulfate ions in the presence of free protons inside the plasma membrane, while sulfide ions would be produced by the assimilation of sulfate. The concomitant presence of mercuric ions and S(2-) would precipitate beta-HgS. The mercury concentration in the rhizosphere decreased in the treated relative to the nontreated soil. The iron/manganese oxide and organic-bound fractions of soil mercury were transformed to more bioavailable forms (soluble and exchangeable and specifically sorbed) and taken up by plants. PMID- 22489922 TI - CD8+CD28-lymphocytes in peripheral blood and serum concentrations of soluble interleukin 6 receptor are increased in patients with Graves' orbitopathy and correlate with disease activity. AB - BACKGROUND: The extrathyroid, orbital manifestation of Graves' disease (GD)- Graves' orbitopathy (GO)--presents a difficult clinical problem. The immunological status of GO patients is still under investigation. The aim of this study was to assess the serum concentration of interleukin 6 (IL-6), soluble interleukin 6 receptor (sIL-6R), and CD8+CD28- lymphocytes in GO patients and to evaluate if these parameters were associated with disease activity. PATIENTS: Thirty-nine patients (29 women and 10 men, aged 24-71, mean 50.18) with newly diagnosed GD were enrolled in the study. Active GO was diagnosed in 20 patients. The control group included 12 healthy individuals. METHODS: Serum concentrations of IL-6 and sIL-6R were estimated by ELISA. Percentages of CD8+CD28- lymphocytes in peripheral blood were assessed by flow cytometry. RESULTS: Mean serum IL-6 and sIL-6R concentrations were significantly higher in all GD patients and in GO and non-GO patients than in normal controls. In all GD patients and the non-GO group, serum IL-6 and sIL-6R concentrations were significantly reduced after efficient treatment. In GO patients, only serum sIL-6R concentration was significantly lower after efficient treatment. In all GD patients, the mean percentage of CD8+CD28- lymphocytes was significantly lower after efficient treatment. In GO patients, the mean percentage of CD8+CD28- lymphocytes was significantly higher than in the non-GO group or in normals. Moreover, in the GO group, the mean percentage of CD8+CD28- lymphocytes was significantly lower after treatment. CONCLUSION: Our results have shown that CD8+CD28- lymphocyte percentage in peripheral blood and serum concentration of sIL-6R are increased in GO patients and correlate with disease activity. PMID- 22489924 TI - Qualitative and quantitative characteristics of the electroencephalogram in normal horses after sedation. AB - BACKGROUND: The administration of certain sedatives has been shown to promote sleep in humans. Related agents induce sleep-like behavior when administered to horses. Interpretation of electroencephalograms (EEGs) obtained from sedated horses should take into account background activity, presence of sleep-related EEG events, and the animal's behavior. HYPOTHESIS: Sedatives induce states of vigilance that are indistinguishable on EEGs from those that occur naturally. ANIMALS: Six healthy horses. METHODS: Digital EEG with video was recorded after administration of 1 of 4 sedatives (acepromazine, butorphanol, xylazine, or detomidine). Serum drug concentrations were measured. Recordings were reviewed, states were identified, and representative EEG samples were analysed. These data were compared with data previously obtained during a study of natural sleep. RESULTS: Butorphanol was associated with brief episodes resembling slow wave sleep in 1 horse. Acepromazine led to SWS in 3 horses, including 1 that also exhibited rapid eye movement sleep. Periods of SWS were observed in all horses afer xylazine or detomidine administration. Normal sleep-related EEG events and heart block, occurred in association with SWS regardless of which sedative was used. Spectral data varied primarily by state, but some differences were observed between sedative and natural data. CONCLUSIONS AND CLINICAL IMPORTANCE: Qualitatively, EEG findings appeared identical whether sedation-induced or naturally occurring. The startle response and heart block associated with some sedatives may be related to sleep. Alpha(2) agonists can be used to obtain high quality EEGs in horses, but acepromazine does not promote a relaxed state in all animals. PMID- 22489925 TI - A new promising application for highly cytotoxic metal compounds: eta6 areneruthenium(II) phosphite complexes for the treatment of alveolar echinococcosis. AB - Two series of eta(6)-areneruthenium(II) phosphite complexes were prepared, characterized, and evaluated in vitro for their toxic potential against Echinococcus multilocularis metacestodes. Neutral complexes of general formula [(eta(6)-p-cymene)RuCl(2){P(OR)(3)}] (R = Et, (i)Pr, Ph) with two easily exchangable chloride ligands showed only minor toxicity, whereas the substitution of these moieties against a beta-diketonate (2,2,6,6-tetramethylheptanedionate) ligand led to hydrolytically stable complex salts of type [(eta(6)-p cymene)Ru(beta-diketonate){P(OR)(3)}][BF(4)] (R = Et, (i)Pr, Ph) with comparable in vitro toxicity (50% PGI release at c = 1.4 - 4.7 MUM) to the reference drug nitazoxanide (50% PGI release at c = 1.2 MUM). In addition, the latter complexes were highly toxic against rat hepatoma cells (IC(50) = 0.40-2.0 MUM) and less toxic against human foreskin fibroblasts (IC(50) = 1.1-2.9 MUM) and Vero cells (IC(50) = 1.2-8.9 MUM). The measured cytotoxicities against mammalian cells are, to the best of our knowledge, among the highest ever observed for ruthenium-based complexes. In conclusion, complex salts of type [(eta(6)-p-cymene)Ru(beta diketonate){P(OR)(3)}][BF(4)] might be interesting candidates for further development toward anthelmintic drugs and/or highly cytotoxic metal compounds. PMID- 22489926 TI - 2.45-Gz wireless devices induce oxidative stress and proliferation through cytosolic Ca2+ influx in human leukemia cancer cells. AB - PURPOSE: Electromagnetic radiation from wireless devices may affect biological systems by increasing free radicals. The present study was designed to determine the effects of 2.45 GHz radiation on the antioxidant redox system, calcium ion signaling, cell count and viability in human leukemia 60 cells. MATERIALS AND METHODS: Twelve cell cultures were equally divided into two main groups as controls (n = 6) and irradiated (n = 6) and then subdivided into four different subgroups depending on the duration of exposure, namely 1, 2, 12 and 24 hours. The samples were analyzed immediately after the experimental period. RESULTS: The extent of lipid peroxidation, cytosolic free Ca2+ and cell numbers were higher in 2.45 GHz groups than in the controls. The increase of cytosolic free Ca2+ concentrations was radiation time-dependent and was highest at 24-h exposure. The reduced glutathione, glutathione peroxidase, vitamin C and cell viability values did not show any changes in any of the experimental groups. 2-aminoethyl diphenylborinate inhibits Ca2+ ions influx by blockage of the transient receptor potential melastatin 2. CONCLUSIONS: 2.45 GHz electromagnetic radiation appears to induce proliferative effects through oxidative stress and Ca2+ influx although blocking of transient receptor potential melastatin 2 channels by 2-aminoethyl diphenylborinate seems to counteract the effects on Ca2+ ions influx. PMID- 22489927 TI - Anthropogenic landscape change promotes asymmetric dispersal and limits regional patch occupancy in a spatially structured bird population. AB - 1. Local extinctions in habitat patches and asymmetric dispersal between patches are key processes structuring animal populations in heterogeneous environments. Effective landscape conservation requires an understanding of how habitat loss and fragmentation influence demographic processes within populations and movement between populations. 2. We used patch occupancy surveys and molecular data for a rainforest bird, the logrunner (Orthonyx temminckii), to determine (i) the effects of landscape change and patch structure on local extinction; (ii) the asymmetry of emigration and immigration rates; (iii) the relative influence of local and between-population landscapes on asymmetric emigration and immigration; and (iv) the relative contributions of habitat loss and habitat fragmentation to asymmetric emigration and immigration. 3. Whether or not a patch was occupied by logrunners was primarily determined by the isolation of that patch. After controlling for patch isolation, patch occupancy declined in landscapes experiencing high levels of rainforest loss over the last 100 years. Habitat loss and fragmentation over the last century was more important than the current pattern of patch isolation alone, which suggested that immigration from neighbouring patches was unable to prevent local extinction in highly modified landscapes. 4. We discovered that dispersal between logrunner populations is highly asymmetric. Emigration rates were 39% lower when local landscapes were fragmented, but emigration was not limited by the structure of the between population landscapes. In contrast, immigration was 37% greater when local landscapes were fragmented and was lower when the between-population landscapes were fragmented. Rainforest fragmentation influenced asymmetric dispersal to a greater extent than did rainforest loss, and a 60% reduction in mean patch area was capable of switching a population from being a net exporter to a net importer of dispersing logrunners. 5. The synergistic effects of landscape change on species occurrence and asymmetric dispersal have important implications for conservation. Conservation measures that maintain large patch sizes in the landscape may promote asymmetric dispersal from intact to fragmented landscapes and allow rainforest bird populations to persist in fragmented and degraded landscapes. These sink populations could form the kernel of source populations given sufficient habitat restoration. However, the success of this rescue effect will depend on the quality of the between-population landscapes. PMID- 22489928 TI - Are bruxism and the bite causally related? AB - In the dental profession, the belief that bruxism and dental (mal-)occlusion ('the bite') are causally related is widespread. The aim of this review was to critically assess the available literature on this topic. A PubMed search of the English-language literature, using the query 'Bruxism [Majr] AND (Dental Occlusion [Majr] OR Malocclusion [Majr])', yielded 93 articles, of which 46 papers were finally included in the present review*. Part of the included publications dealt with the possible associations between bruxism and aspects of occlusion, from which it was concluded that neither for occlusal interferences nor for factors related to the anatomy of the oro-facial skeleton, there is any evidence available that they are involved in the aetiology of bruxism. Instead, there is a growing awareness of other factors (viz. psychosocial and behavioural ones) being important in the aetiology of bruxism. Another part of the included papers assessed the possible mediating role of occlusion between bruxism and its purported consequences (e.g. tooth wear, loss of periodontal tissues, and temporomandibular pain and dysfunction). Even though most dentists agree that bruxism may have several adverse effects on the masticatory system, for none of these purported adverse effects, evidence for a mediating role of occlusion and articulation has been found to date. Hence, based on this review, it should be concluded that to date, there is no evidence whatsoever for a causal relationship between bruxism and the bite. PMID- 22489929 TI - Strain release in organic photonic nanoparticles for protease sensing. AB - Proteases are overexpressed in most cancers and proteolytic activity has been shown to be a viable marker for cancer imaging in vivo. Herein, we describe the synthesis of luminescence-quenched shell cross-linked nanoparticles as photonic nanoprobes for protease sensing. Protease sensing scheme is based on a "turn-on" mechanism where the protease cleaves peptide cross-linkers of the fluorescence quenched shell cross-linked NP (OFF state) leading to a highly emissive non-cross linked NP (ON state). The cross-linked particles can be strained by exposure to a good solvent and proteolysis allows for particle expansion (swelling) and a recovery of the luminescence. PMID- 22489930 TI - Telehealth--a change in a practice model in oncology. AB - BACKGROUND: A clinical study to examine the barriers to using telehealth for oncologic visits was performed by the British Columbia Cancer Agency's Vancouver Island Centre (BCCAVIC) and the Vancouver Island Health Authority in 2006-2007. One of the major barriers encountered was physician engagement. The current observational study was to determine whether patients' enthusiasm and the introduction of telehealth in a study resulted in telehealth becoming integrated within BCCAVIC. METHODS: Telehealth appointment statistics continued to be kept after the original study was completed. Data were kept on the number of visits, the type of visit (follow-up or new patient), the oncologist seeing the patient, the location of the patient, and the type of cancer. RESULTS: During the study, 106 patients were seen via telehealth. In the years following the trial, the number of telehealth follow-up patients seen markedly increased, so that in 2010 2011, close to 1,200 patients were seen. Medical oncology saw 91.4% of these. CONCLUSIONS: The introduction of oncology telehealth in BCCSVIC/Vancouver Island Health Authority was in an ethics-approved study. Following the completion of the trial, there was a 10-fold increase in follow-up patients seen using this modality. Reluctance to see new patients through telehealth probably relates to the necessity to change the patient encounter paradigm. There is a need to develop a model where patients who are a distance from specialists concentrated in larger centers have reasonable access to the same standard of care, without incurring the time and financial burdens. Telehealth would be a part of that model. PMID- 22489932 TI - Association between residence location and likelihood of transplantation among pediatric dialysis patients. AB - Many children with ESRD reside far from a kidney transplant center. It is unknown whether this geographical barrier affects likelihood of transplantation. We used data from a national ESRD database. Patients <= 18 yr old who started renal replacement in nine Canadian provinces during 1992-2007 were followed until death or last contact. Primary outcome was kidney transplantation (living or deceased donor). Distance between nearest pediatric transplant center and each patient's residence was categorized as: <50, 50 to <150, 150 to <300, and >= 300 km. Using survival analysis, we compared likelihood of transplantation between whites and non-whites living in various distance categories. Among 728 patients, 52.2% were males and 62.5% were whites. Compared to white children living < 50 km from a transplant center, white (HR, 0.73; 95% CI, 0.56-0.95) and non-white (HR, 0.66; 95% CI, 0.48-0.92) children living >= 300 km away were less likely to receive a transplant. Non-white children living < 50 km away (HR, 0.59; 95% CI 0, 45-0.78) were also less likely to receive a transplant compared to otherwise similar whites living < 50 km away. Although equitable access to transplantation by residence location is observed among remote-dwelling adults with ESRD, white and non-white children with ESRD living >= 300 km from a transplant center were less likely to receive transplants. PMID- 22489931 TI - Teledermatology patient satisfaction in the Pacific Northwest. AB - BACKGROUND: The aim of this quality improvement project is to assess patient satisfaction with a store-and-forward teledermatology project and to identify factors associated with patient satisfaction and dissatisfaction. SUBJECTS AND METHODS: Veterans receiving care in rural clinics in the Pacific Northwest were surveyed using a 5-point Likert scale about satisfaction with face-to-face care for a skin complaint prior to any teledermatology exposure. One year later, veterans in the same rural clinics were surveyed about satisfaction with teledermatology care using a more comprehensive survey. Ninety-six patients completed the face-to-face satisfaction survey questions, and 501 completed the teledermatology satisfaction survey. RESULTS: Most (78%) of surveyed patients were highly satisfied or satisfied with face-to-face dermatology care. After 1 year of teledermatology, 77% of patients were highly satisfied or satisfied with teledermatology care. The mean patient satisfaction score for teledermatology was equivalent to face-to-face care (4.1+/-1.2 and 4.3+/-1.0, p=0.4). Factors associated with teledermatology patient satisfaction included short wait times for initial consultation, a perception that the initial wait time was not too long, a perception that the skin condition was properly treated, and the belief that adequate follow-up was received. Factors associated with teledermatology patient dissatisfaction included perceptions that the skin condition was not properly treated and that inadequate follow-up was received. CONCLUSIONS: Teledermatology was widely accepted by the majority of patients receiving care at rural clinics. Patient satisfaction with care received through teledermatology was equivalent to that with face-to-face dermatology. PMID- 22489933 TI - Training community practitioners to work more effectively with parents to prevent childhood obesity: the impact of HENRY upon Children's Centres and their staff. AB - BACKGROUND: One in four children in England is overweight/obese upon starting school. HENRY (Health Exercise Nutrition for the Really Young) offers a novel, preventive approach to this problem by training practitioners to work more effectively with the parents of preschool children around obesity and lifestyle issues. The programme is being delivered to all Sure Start Children's Centres (the UK government initiative providing family support and childcare in disadvantaged areas) in Leeds, UK. METHODS: The evaluation covered the first 12 Centres to be trained (these had a reach of approximately 5000 families). A series of semi-structured interviews were conducted with Centre managers, and 'drop boxes' were provided for all staff to leave their comments. Interviews took place up to 11 months post-training, allowing a consideration of any long-term impact. RESULTS: Data from 12 interviews and 106 comment slips indicated that HENRY training was associated with considerable changes to the Centre environment. Immediate effects included changes to Centre policy and practice, including the provision of age-appropriate portion sizes and the introduction of healthy snacks; a strengthening of team working and increased staff confidence around tackling lifestyle change; and enhanced skills when working with families. Training also induced changes within the staff's personal lives (e.g. increased physical activity and family mealtimes). CONCLUSIONS: The findings suggest that positive and lasting lifestyle effects can be achieved by brief training courses involving Children's Centre staff teams. Both staff and attendant families appear to benefit. The effect on levels of preschool obesity across the city once HENRY has extended to the remaining Centres is yet to be seen. PMID- 22489934 TI - Selection and inertia in the evolution of holocentric chromosomes in sedges (Carex, Cyperaceae). AB - * Changes in chromosome number as a result of fission and fusion in holocentrics have direct and immediate effects on the recombination rate. We investigate the support for the classic hypothesis that environmental stability selects for increased recombination rates. * We employed a phylogenetic and cytogenetic data set from one of the most diverse angiosperm genera in the world, which has the largest nonpolyploid chromosome radiation (Carex, Cyperaceae; 2n = 12-124; 2100 spp.). We evaluated alternative Ornstein-Uhlenbeck models of chromosome number adaptation to the environment in an information-theoretic framework. * We found moderate support for a positive influence of lateral inflorescence unit size on chromosome number, which may be selected in a stable environment in which resources for reproductive investment are larger. We found weak support for a positive influence on chromosome number of water-saturated soils and among-month temperature constancy, which would be expected to be negatively select for pioneering species. Chromosome number showed a strong phylogenetic signal. * We argue that our finding of small but significant effects of life history and ecology is compatible with our original hypothesis regarding selection of optima in recombination rates: low recombination rate is optimal when inmediate fitness is required. By contrast, high recombination rate is optimal when stable environments allow for evolutionary innovation. PMID- 22489935 TI - Patient-specific surgical simulator for the pre-operative planning of single incision laparoscopic surgery with bimanual robots. AB - INTRODUCTION: The trend of surgical robotics is to follow the evolution of laparoscopy, which is now moving towards single-incision laparoscopic surgery. The main drawback of this approach is the limited maneuverability of the surgical tools. Promising solutions to improve the surgeon's dexterity are based on bimanual robots. However, since both robot arms are completely inserted into the patient's body, issues related to possible unwanted collisions with structures adjacent to the target organ may arise. MATERIALS AND METHODS: This paper presents a simulator based on patient-specific data for the positioning and workspace evaluation of bimanual surgical robots in the pre-operative planning of single-incision laparoscopic surgery. RESULTS: The simulator, designed for the pre-operative planning of robotic laparoscopic interventions, was tested by five expert surgeons who evaluated its main functionalities and provided an overall rating for the system. DISCUSSION: The proposed system demonstrated good performance and usability, and was designed to integrate both present and future bimanual surgical robots. PMID- 22489936 TI - Computer-assisted surgery simulations and directed practice of total knee arthroplasty: educational benefits to the trainee. AB - Orthopaedic residents typically learn to perform total knee arthroplasty (TKA) through an apprenticeship-type model, which is a necessarily slow process. Surgical skills courses, using artificial bones, have been shown to improve technical and cognitive skills significantly within a couple of days. The addition of computer-assisted surgery (CAS) simulations challenges the participants to consider the same task in a different context, promoting cognitive flexibility. We designed a hands-on educational intervention for junior residents with a conventional tibiofemoral TKA station, two different tibiofemoral CAS stations, and a CAS and conventional patellar resection station, including both qualitative and quantitative analyses. Qualitatively, structured interviews before and after the course were analyzed for recurring themes. Quantitatively, subjects were evaluated on their technical skills before and after the course, and on a multiple-choice knowledge test and error detection test after the course, in comparison to senior residents who performed only the testing. Four themes emerged: confidence, awareness, deepening knowledge and changed perspectives. The residents' attitudes to CAS changed from negative before the course to neutral or positive afterwards. The junior resident group completed 23% of tasks in the pre-course skills test and 75% of tasks on the post test (p<0.01), compared to 45% of tasks completed by the senior resident group. High-impact educational interventions, promoting cognitive flexibility, would benefit trainees, attending surgeons, the healthcare system and patients. PMID- 22489937 TI - Accuracy assessment of an imaging technique to examine ulnohumeral joint congruency during elbow flexion. AB - A CT-based imaging technique to investigate ulnohumeral joint congruency of elbows undergoing physiologic flexion is introduced. This technique, which employed landmark registration and a previously developed inter-bone distance algorithm, was validated experimentally. Results obtained with this imaging technique were validated in a single specimen by comparing the resulting joint congruency maps to results obtained with experimental casting in a static position. Additionally, the accuracy of the registration technique was assessed in four specimens using fiducial and target registration error to evaluate the positional and angular accuracy. Preliminary data from an intact cadaveric elbow was shown to demonstrate the utility of this technique. The overall accuracy of the registration was better than 1 mm, and the congruency maps showed excellent correspondence with the casting, validating the use of a CT-based imaging technique to examine the congruency of joints undergoing quasi-static flexion. PMID- 22489938 TI - High-resolution single-molecule recognition imaging of the molecular details of ricin-aptamer interaction. AB - We studied the molecular details of DNA aptamer-ricin interactions. The toxic protein ricin molecules were immobilized on a Au(111) surface using a N hydroxysuccinimide (NHS) ester to specifically react with lysine residues located on the ricin B chains. A single ricin molecule was visualized in situ using the AFM tip modified with an antiricin aptamer. Computer simulation was used to illustrate the protein and aptamer structures, the single-molecule ricin images on a Au(111) surface, and the binding conformations of ricin-aptamer and ricin antibody complexes. The various ricin conformations on a Au(111) surface were caused by the different lysine residues reacting with the NHS ester. It was also observed that most of the binding sites for aptamer and antibody on the A chains of ricin molecules were not interfered by the immobilization reaction. The different locations of the ricin binding sites to aptamer and antibody were also distinguished by AFM recognition images and interpreted by simulations. PMID- 22489940 TI - Life cycle comparison of environmental emissions from three disposal options for unused pharmaceuticals. AB - We use life cycle assessment methodology to compare three disposal options for unused pharmaceuticals: (i) incineration after take-back to a pharmacy, (ii) wastewater treatment after toilet disposal, and (iii) landfilling or incineration after trash disposal. For each option, emissions of active pharmaceutical ingredients to the environment (API emissions) are estimated along with nine other types of emissions to air and water (non-API emissions). Under a scenario with 50% take-back to a pharmacy and 50% trash disposal, current API emissions are expected to be reduced by 93%. This is within 6% of a 100% trash disposal scenario, which achieves an 88% reduction. The 50% take-back scenario achieves a modest reduction in API emissions over a 100% trash scenario while increasing most non-API emissions by over 300%. If the 50% of unused pharmaceuticals not taken-back are toileted instead of trashed, all emissions increase relative to 100% trash disposal. Evidence suggests that 50% participation in take-back programs could be an upper bound. As a result, we recommend trash disposal for unused pharmaceuticals. A 100% trash disposal program would have similar API emissions to a take-back program with 50% participation, while also having significantly lower non-API emissions, lower financial costs, higher convenience, and higher compliance rates. PMID- 22489939 TI - Scanning laser ophthalmoscopy in the retromode in diabetic macular oedema. AB - PURPOSE: To determine the validity of scanning laser ophthalmoscopy in the retromode (RM-SLO) versus other imaging modalities in the diagnosis of diabetic macular oedema (DME). METHODS: Two hundred and sixty-three eyes were examined. Inclusion criteria were any stage of untreated or treated diabetic retinopathy and four imaging modalities of the macula carried out on the same day: time domain optical coherence tomography (OCT), fundus autofluorescence (FAF), RM-SLO and fluorescein angiography (FA). Two masked retinal specialists independently graded all images. Agreement between RM-SLO and OCT, FA and FAF in evaluating the presence and patterns of DME was evaluated by kappa statistics, sensitivity, specificity, observed proportional agreement, and proportional agreement in positive and negative cases. RESULTS: The agreement in evaluating the presence/absence of DME between RM-SLO and OCT, FA and FAF was good: kappa = 0.73 (confidence interval; CI, 0.64-0.83), kappa = 0.71 (CI, 0.61-0.81) and kappa = 0.73 (CI, 0.63-0.83), respectively. The agreement in evaluating cystoid pattern of DME was almost perfect between RM-SLO and OCT, RM-SLO and FA, kappa > 0.8; and good between RM-SLO and FAF, kappa > 0.7. The agreement in evaluating the presence/absence of subfoveal neuroretinal was almost perfect between RM-SLO and OCT (kappa = 0.83; 95% CI, 0.70-0.96). Subfoveal neuroretinal detachment did not show any specific pattern on FA or FAF. Sensitivity and specificity of RM-SLO in evaluating DME was 97.7% and 71.9% versus OCT, 97.4% and 68.1% versus FA and 96.1% and 73.3% versus FAF. Retinal thickness of 233 MUm represented the cut-off value to define DME by RM-SLO. CONCLUSIONS: The combined use of non-invasive imaging techniques can improve the diagnostic interpretation of different aspects of DME. PMID- 22489941 TI - Detection of anti-HLA antibodies by solid-phase assay in kidney transplantation: friend or foe? AB - Pre-formed and de novo anti-human leukocyte antigen (HLA) antibodies induce antibody-mediated rejection and are also involved in mechanisms leading to chronic graft nephropathy. The detection of anti-HLA antibodies by solid-phase assay (SPA) has revolutionized the management of immunized patients before and after kidney transplantation. Characterized by high sensitivity and specificity, the clinical relevance of anti-HLA antibodies by SPA has to be clarified. The presence of donor-specific antibody at the epitope level, their titer, and the use of different crossmatch technologies could help to determine which of the anti-HLA antibodies are friends and which are foes in kidney transplantation. In this review, we summarize the current state of the art on this debated topic, and give clinical guidelines for the management of antibody detection pre- and post transplantation, based on these evidences and our own clinical expertise. PMID- 22489942 TI - Genotypes and haplotypes in the 3' untranslated region of the HLA-G gene and their association with clinical outcome of hematopoietic stem cell transplantation for beta-thalassemia. AB - Polymorphisms in the 3' untranslated region (3'UTR) of HLA-G, an important player in immunological tolerance, could be involved in post-transcriptional expression control, and their association with different clinical immune-related conditions including autoimmunity and transplantation is of mounting interest. Most studies have focused on a 14 base pair (bp) insertion/deletion (ins/del), while additional single-nucleotide polymorphisms (SNPs) in the HLA-G 3'UTR have been described but not extensively investigated for their clinical relevance. Here we have comparatively studied the association between 3'UTR haplotypes of HLA-G, or the 14 bp ins/del, with clinical outcome of HLA-identical sibling hematopoietic stem cell transplantation (HSCT) in 147 Middle Eastern beta-thalassemia patients. Sequence based typing of 3'UTR HLA-G polymorphisms in the patients and in 102 healthy Italian blood donors showed strong linkage disequilibrium between the 14 bp ins/del and five 3'UTR SNPs, which together could be arranged into eight distinct haplotypes based on expectation-maximization studies, with four predominant haplotypes (UTRs1-4). After HSCT, we found a moderate though not significant association between the presence of UTR-2 in double dose and protection from acute graft versus host disease (hazard ratio (HR) 0.45, 95% confidence intervals (CI): 0.14-1.45; P = 0.18), an effect that was also seen when the corresponding 14 bp ins/ins genotype was considered alone (HR 0.42, 95% CI: 0.16-1.06; P = 0.07). No association was found with rejection or survival. Taken together, our data show that there is no apparent added value of considering entire 3'UTR HLA-G haplotypes for risk prediction after allogeneic HSCT for beta-thalassemia. PMID- 22489943 TI - Closing the gap: discrimination of the expression profile of HLA questionable alleles by a cytokine-induced secretion approach using HLA-A*32:11Q. AB - Matching of human leukocyte antigen (HLA) alleles between donors and recipients plays a major role in hematopoietic stem cell transplantation (HSCT). Null or questionably expressed HLA allelic variants are a major issue in HLA matching, because the aberrant expression of such alleles can have a major impact on the outcome of HSCT and/or its complications such as graft-versus-host disease. The goal of this study was to investigate the potential of a recently developed cytokine-induced secretion assay to differentiate the expression levels of HLA A*32:11Q (questionable) into a null (N) or low (L) expression variant. An amino acid mutation at position 164 of HLA-A*32:11Q disrupts the disulfide bridge in the alpha2 domain. HLA-A*32:11Q is not detectable by standard microlymphocytotoxicity assay. To this end, we cloned soluble HLA-A*32:11Q and a reference allele (HLA-A*32:01) into expression vectors and transfected/transduced HEK293 and K562 cells. Allele-expressing K562 cells were simultaneously transfected/transduced with a beta2-microglobulin (B2M)-encoding vector to ensure the intact HLA structure with B2M. After treatment with proinflammatory cytokines, secreted soluble HLA molecules were determined by enzyme-linked immunosorbent assay in the supernatant and intracellular accumulation of the recombinant proteins by flow cytometry. HLA-A*32:11Q was nearly undetectable in untreated transfectants. Cytokine treatment increased the secretion of HLA A*32:11Q to detectable levels and resulted in intracellular accumulation of the allele. There was no difference in mRNA transcription between the A*32 alleles. On the basis of these results, we recommend reclassification of HLA-A*32:11Q as a low expression (L) variant. PMID- 22489944 TI - Evidence of recombination producing allelic diversity in MHC class I Mafa-B and A alleles in cynomolgus macaques. AB - The MHC class I-A and -B genes of cynomolgus macaques are highly polymorphic. These genes encode proteins presenting peptides to CD8+ T cells to initiate adaptive immune response. Recombination events are one way the diversity of these alleles can be increased. Such events have been well characterized in humans, but have not been as well characterized in macaques. In order to identify and examine recombinations that create new alleles, it is important to analyze intron sequences. Intron sequences have been shown to be important to understand the evolutionary mechanisms involved in the generation of major histocompatibility complex (MHC) alleles and loci. Thus far, there have been relatively few intron sequences reported for MHC class I alleles in macaques, and this has hampered the understanding of MHC organization and evolution in macaques. In this study, we present evidence of a gene conversion event generating the Mafa-B*099 allele lineage by the combination of Mafa-B*054 and Mafa-B*095 allele lineages. A potential recombination between the Mafa-A3*13 and Mafa-A4:14 lineages was also observed, but it is less clear due to lack of intron 2 sequence. This report stresses the role that recombination can play in MHC class I diversity in cynomologus macaques, and the importance of introns in identifying and analyzing such events. PMID- 22489945 TI - Somatic mutations in the HLA genes of patients with hematological malignancy. AB - Somatic mutations and genomic alterations are frequent events in the clonal evolution of hematologic malignancies. Recent studies have reported copy neutral loss of heterozygosity (LOH) for the mismatched human leukocyte antigen (HLA) haplotype in patients relapsed after haploidentical hematopoietic cell transplantation (HCT) for a hematologic malignancy. Herein, we report 15 cases of somatic mutations in the HLA genes of patients with a variety of hematologic diseases, including acute myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma, encountered at our institute over the past decade. While two of the cases were identified in patient relapse specimens collected post-HCT, 13 cases were found in peripheral blood specimens submitted for HLA typing prior to transplantation. Ten patients exhibited acquired LOH for all or part of one HLA haplotype. Five other cases involved somatic mutations in the nucleotide sequences of common HLA-A or HLA-B alleles. Since they are not systematically evaluated prior to HCT, acquired mutations in HLA genes are likely under reported. Beyond the implications for accurate HLA typing and donor selection, alternations that result in the loss of HLA expression may allow escape from immune surveillance and adversely impact transplant outcome. PMID- 22489946 TI - Assessment of fidelity and utility of the whole-genome amplification for the clinical tests offered in a histocompatibility and immunogenetics laboratory. AB - Increasing emphasis on the use of molecular tests in a histocompatibility and immunogenetics laboratory (HIL) poses a potential problem of lack of sufficient DNA to perform multiple genetic analyses. In this study, we report the feasibility, fidelity and utility of multiple displacement amplification (MDA) method to perform whole-genome amplification (WGA) to generate DNA specimens that can be analyzed by multiple molecular techniques and can be used for different clinical tests offered by an HIL. The MDA-generated DNA when compared with the native DNA showed 100% congruency in genotyping of 37 genes/loci using multiple downstream molecular techniques: sequence-based typing and sequence-specific primer-based typing for 5 human leukocyte antigen (HLA) class I and II genes (HLA A, B, C, DRB1 and DQB1), luminex-based sequence-specific oligonucleotide (SSO) genotyping for a panel of 16 killer immunoglobulin-like receptor (KIR) genes and automated fragment size analysis for a panel of 15 short tandem repeat (STR) loci and amelogenin gene. For post-allogeneic hematopoietic cell transplantation (HCT) chimerism analysis, MDA-generated DNA appeared useful for enriching pre transplant DNA but not for enriching post-transplant chimeric DNA. Overall, our results show that MDA-based WGA could generate DNA of high yield and fidelity that can be used for various clinical tests and research purposes. PMID- 22489947 TI - The replication of the association of the rs6832151 within chromosomal band 4p14 with Graves' disease in a Polish Caucasian population. AB - Recently Chu et al. conducted a genome-wide association study in a Chinese Han population and identified two novel Graves' disease (GD) susceptibility loci within 4p14 (rs6832151) and 6q27 (rs9355610). Our purpose was to replicate these associations in a Polish Caucasian population. We analyzed rs6832151 and rs9355610 genotypes in a case-control study based on 560 GD patients and 1475 unrelated controls using TaqMan assays. Our study had the power of 0.8 and 0.6 to detect the effects originally reported for rs6832151 and rs9355610, respectively. We found an association between GD and the rs6832151 G allele (odds ratio OR = 1.27, P = 0.002). Analysis of model of inheritance suggested that the dominant model should be preferred (P(fit) = 0.938, OR = 1.39, P = 0.001). For rs9355610 a formally significant effect was observed assuming a recessive model (OR = 1.24, P = 0.028), whereas analysis of allele distribution showed a trend for association (OR = 1.14,95%, P = 0.082). Our findings are the first to show that rs6832151 and possibly rs9355610 contribute to GD pathogenesis also in Caucasians. PMID- 22489948 TI - A novel HLA-A*31 allele, A*31:57, identified by sequence-based typing. AB - The novel allele A*31:57 allele showed a single nucleotide difference with A*31:01:02 at nt 235 G>C in exon 2. PMID- 22489949 TI - Identification of a novel HLA-A*23 variant allele, A*23:50. AB - HLA-A*23:50 differs from HLA-A*23:01:01 by one nucleotide at position 112 resulting in an amino acid change, Arginine to Tryptophan, at codon 14 of exon 2. PMID- 22489950 TI - Full-length coding sequences of the two novel HLA-C alleles, C*14:36 and C*01:02:15. AB - Full-length coding sequences of C*14:36 and C*01:02:15 differ from C*14:02:01 and C*01:02:01 by one nucleotide in exons 3 and 4, respectively. PMID- 22489951 TI - Nomenclature for factors of the HLA system, update January 2012. PMID- 22489952 TI - Synthesis and biological evaluation of 4-phenylquinazoline-2-carboxamides designed as a novel class of potent ligands of the translocator protein. AB - A series of novel 4-phenylquinazoline-2-carboxamides (1-58) were designed as aza isosters of PK11195, the well-known 18 kDa translocator protein (TSPO) reference ligand, and synthesized by means of a very simple and efficient procedure. A number of these derivatives bind to the TSPO with K(i) values in the nanomolar/subnanomolar range, show selectivity toward the central benzodiazepine receptor (BzR) and exhibit structure-affinity relationships consistent with a previously published pharmacophore/topological model of ligand-TSPO interaction. PMID- 22489953 TI - Multiple imputation of missing covariates with non-linear effects and interactions: an evaluation of statistical methods. AB - BACKGROUND: Multiple imputation is often used for missing data. When a model contains as covariates more than one function of a variable, it is not obvious how best to impute missing values in these covariates. Consider a regression with outcome Y and covariates X and X2. In 'passive imputation' a value X* is imputed for X and then X2 is imputed as (X*)2. A recent proposal is to treat X2 as 'just another variable' (JAV) and impute X and X2 under multivariate normality. METHODS: We use simulation to investigate the performance of three methods that can easily be implemented in standard software: 1) linear regression of X on Y to impute X then passive imputation of X2; 2) the same regression but with predictive mean matching (PMM); and 3) JAV. We also investigate the performance of analogous methods when the analysis involves an interaction, and study the theoretical properties of JAV. The application of the methods when complete or incomplete confounders are also present is illustrated using data from the EPIC Study. RESULTS: JAV gives consistent estimation when the analysis is linear regression with a quadratic or interaction term and X is missing completely at random. When X is missing at random, JAV may be biased, but this bias is generally less than for passive imputation and PMM. Coverage for JAV was usually good when bias was small. However, in some scenarios with a more pronounced quadratic effect, bias was large and coverage poor. When the analysis was logistic regression, JAV's performance was sometimes very poor. PMM generally improved on passive imputation, in terms of bias and coverage, but did not eliminate the bias. CONCLUSIONS: Given the current state of available software, JAV is the best of a set of imperfect imputation methods for linear regression with a quadratic or interaction effect, but should not be used for logistic regression. PMID- 22489954 TI - Antiphospholipid antibodies in dogs with immune mediated hemolytic anemia, spontaneous thrombosis, and hyperadrenocorticism. AB - BACKGROUND: The pathophysiology of thrombus formation in canine IMHA and other diseases remains unclear. Antiphospholipid antibodies (aPL) are an important cause of thrombosis in humans and might cause thrombosis in dogs. HYPOTHESIS: Dogs with IMHA, spontaneous thrombosis, and hyperadrenocorticism will have increased levels of aPL and lupus anticoagulants (LA), compared with healthy and sick dogs. ANIMALS: Thre aPL were measured in healthy controls (n = 40-45); sick dogs without thrombosis (n = 86); IMHA (n = 37); spontaneous thrombosis (ST, n = 11); and hyperadrenocorticism (n = 17). Four groups of dogs were also tested for the presence of LA: healthy controls (n = 40); sick dogs without thrombosis (n = 13); IMHA (n = 13); and ST (n = 5). METHODS: Prospective cohort study. Dogs were tested for aPL by an ELISA and for LA by the dilute Russell's Viper venom time (dRVVT). Median values were compared by Kruskal-Wallis (aPL) or ANOVA (LA), and an odds ratio for development of thrombosis in dogs positive for aPL was calculated. RESULTS: aPL are uncommon in healthy dogs. A total of 13/86 sick dogs without thrombosis, 7/37 dogs with IMHA, 1/11 dogs with ST, and 3/17 dogs with HAC were positive for protein binding-dependent aPL. There was no significant difference in the number of dogs positive for aPL for any of the study groups, and there was no increased risk for thrombosis in dogs positive for aPL. No dogs had LA. CONCLUSIONS: Our preliminary research does not support a strong role for aPL for the development of thrombosis in dogs with IMHA and other thrombotic diseases, although future studies are warranted. PMID- 22489955 TI - Seroprevalence study on Theileria equi and Babesia caballi antibodies in horses from central province of Saudi Arabia. AB - In total, 241 sera from clinically healthy adult horses were collected from 6 locations in Saudi Arabia and examined for Theileria equi and Babesia caballi antibodies by an indirect fluorescent antibody test. Antibodies to Theileria equi were detected in 25 horses (10.4%) while the antibodies to Babesia caballi were observed in 18 horses (7.5%). In addition, 7 serum samples were positive for antibodies to both parasites (3%). The horses sampled in Al-Janadriah had the highest prevalence of infection with T. equi at 16.5% and with B. caballi at 8.8%, while the lowest prevalence of infection with T. equi (4.7%) and B. caballi (3.1%) was observed among horses examined from the Dyrab district. However, significant differences (P < 0.05) in seroprevalence were not observed between these districts. This study represents the first report on the status of T. equi and B. caballi infection in the central province of Saudi Arabia. PMID- 22489956 TI - Universality of categorical perception deficit in developmental dyslexia: an investigation of Mandarin Chinese tones. AB - BACKGROUND: While previous studies have shown that children affected by dyslexia exhibit a deficit in categorical perception of segmental features in alphabetic languages, it remains unclear whether the categorical perception deficit generalizes to nonalphabetic languages at the suprasegmental level. In this study, we investigated the occurrence of categorical perception deficit in Mandarin lexical tones in Chinese children with dyslexia. METHODS: Both behavioral and electrophysiological measures were taken to compare Chinese dyslexic children with age-matched controls. Auditory event-related potentials were collected with a passive listening oddball paradigm. RESULTS: Behavioral data showed that dyslexic children perceived lexical tone contrasts less categorically and less precisely than age-matched controls. Consistent with the behavioral data, the across-category tone contrast elicited larger mismatch negativity than the within-category distinction in the left hemisphere for the age-matched controls but not for the dyslexic children. CONCLUSION: The behavioral and electrophysiological results demonstrate impaired categorical perception of lexical tones in Chinese children with dyslexia. Our findings support the hypothesis that children affected by dyslexia have a general deficit in categorical perception of speech, which generalizes to nonalphabetic languages at the suprasegmental level. PMID- 22489957 TI - Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). AB - BACKGROUND: In patients with unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulation is anchored on estimating the risk of disease recurrence. OBJECTIVES: We aimed to develop a score that could predict the recurrence risk following a first episode of unprovoked VTE, pooling individual patient data from seven prospective studies. METHODS: One thousand eight hundred and eighteen cases with unprovoked VTE treated for at least 3 months with a vitamin K antagonist were available for analysis. Optimism-corrected Cox regression coefficients were used to develop a recurrence score that was subsequently internally validated by bootstrap analysis. RESULTS: Abnormal D dimer after stopping anticoagulation, age <50 years, male sex and VTE not associated with hormonal therapy (in women) were the main predictors of recurrence and were used to derive a prognostic recurrence score (DASH, D-dimer, Age, Sex, Hormonal therapy) showing a satisfactory predictive capability (ROC area =0.71). The annualized recurrence risk was 3.1% (95% confidence interval [CI], 2.3-3.9) for a score <= 1, 6.4% (95% CI, 4.8-7.9) for a score=2 and 12.3% (95% CI, 9.9-14.7) for a score >= 3. By considering at low recurrence risk those patients with a score <= 1, life-long anticoagulation might be avoided in about half of patients with unprovoked VTE. CONCLUSIONS: The DASH prediction rule appears to predict recurrence risk in patients with a first unprovoked VTE and may be useful to decide whether anticoagulant therapy should be continued indefinitely or stopped after an initial treatment period of at least 3 months. PMID- 22489959 TI - Synthesis and electrochemical and spectroscopic characterization of biicosahedral Au25 clusters. AB - The synthesis and electrochemical and spectroscopic characterization of biicosahedral Au(25) clusters with a composition of [Au(25)(PPh(3))(10)(thiolate)(5)Cl(2)](2+) are described. The biicosahedral Au(25) clusters protected with various types of thiol ligands including alkanethiols, 2-phenylethanethiol, 11-mercaptoundecanoic acid, and 11-mercapto-1 undecanol were synthesized in high yields using a one-step, one-phase procedure in which Au(PPh(3))Cl is reduced with tert-butylamine-borane in the presence of the thiol ligand in a 3:1 v/v chloroform/ethanol solution. All biicosahedral Au(25) clusters prepared exhibit characteristic optical absorption and photoluminescence properties. The emission energy is found to be substantially smaller than the optical absorption energy gap of 1.82 eV, indicating a subgap energy luminescence. The electrochemical HOMO-LUMO gap (~1.54 eV) of the clusters is also substantially smaller than the optical absorption energy gap but rather similar to the emission energy. These electrochemical and optical properties of the biicosahedral Au(25) clusters are distinctly different from those of the Au(25)(thiolate)(18) clusters. PMID- 22489958 TI - Induction of lethal bystander effects in human breast cancer cell cultures by DNA incorporated Iodine-125 depends on phenotype. AB - PURPOSE: This study uses a three-dimensional cell culture model to investigate lethal bystander effects in human breast cancer cell cultures (MCF-7, MDA-MB-231) treated with (125)I-labeled 5-iodo-2 -deoxyuridine ((125)IdU). These breast cancer cell lines respectively form metastatic xenografts in nude mice in an estrogen-dependent and independent manner. MATERIALS AND METHODS: In the present study, these cells were cultured in loosely-packed three-dimensional architecture in a CytomatrixTM carbon scaffold. Cultures were pulse-labeled for 3 h with (125)IdU to selectively irradiate a minor fraction of cells, and simultaneously co-pulse-labeled with 0.04 mM 5-ethynyl-2'-deoxyuridine (EdU) to identify the radiolabeled cells using Click-iT((r)) EdU and flow cytometry. The cultures were then washed and incubated for 48 h. The cells were then harvested, serially diluted, and seeded for colony formation. Aliquots of cells were subjected to flow cytometry to determine the percentage of cells labeled with (125)IdU/EdU. Additional aliquots were used to determine the mean (125)I activity per labeled cell. The percentage of labeled cells was about 15% and 10% for MCF-7 and MDA cells, respectively. This created irradiation conditions wherein the cross-dose to unlabeled cells was small relative to the self-dose to labeled cells. The surviving fraction relative to EdU-treated controls was measured. RESULTS: Survival curves indicated significant lethal bystander effect in MCF-7 cells, however, no significant lethal bystander effect was observed in MDA-MB-231 cells. CONCLUSIONS: These studies demonstrate the capacity of (125)IdU to induce lethal bystander effects in human breast cancer cells and suggest that the response depends on phenotype. PMID- 22489960 TI - Screening of ecotoxicological, qualitative and reproductive variables in male European sea bass Dicentrarchus labrax (L.) reared in three different fish farms: Facility location and typology. AB - The aim of this study was to investigate the influence of both facility location and typology of fish farm on some ecotoxicological, qualitative and reproductive variables in European sea bass Dicentrarchus labrax L. Several variables were investigated: gonado-somatic index (GSI), liver-somatic index (LSI); 7 ethoxyresorufin-O-deethylase (EROD), benzo(a)pyrene monooxygenase and acetylcholinesterase activities; glutathione (GSH), testosterone, 17beta estradiol, total lipid, phospholipid (PL) and triglyceride contents. In addition, the histological sections of gonads were examined. Results suggest that LSI, EROD activity, GSI, GSH, PL, hormone levels and gonad morphology were influenced by different facility locations and typologies of fish farm. PMID- 22489961 TI - Benzylic arylation of 2-methyl-5-membered heterocycles using TMP-bases. AB - A new general Pd-catalyzed arylation of various 2-methyl-5-membered heterocycles is reported. This novel method requires Li-, Mg-, or Zn-TMP bases and allows selective metalation of the benzylic position. Subsequent Negishi cross-coupling provides the corresponding arylated heterocycles. PMID- 22489962 TI - Rehabilitation of occlusion - science or art? AB - The primary objective of rehabilitating occlusion is to improve stomatognathic function in patients experiencing dysfunction in mastication, speech, and swallowing as a consequence of tooth loss. The procedure of occlusal treatment involves improving the morphology and the stomatognathic function. Several practical methods and morphological endpoints have been described in occlusal rehabilitation. We made a selection of these (mandibular position, occlusal plane, occlusal guidance, occlusal contact, face-bow transfer, use of an adjustable articulator and occlusal support) and performed a literature review to verify the existence of compelling scientific evidence for each of these. A literature search was conducted using Medline/PubMed in March 2011. Over 400 abstracts were reviewed, and more than 50 manuscripts selected. An additional hand search was also conducted. Of the many studies investigating stomatognathic function in relation to specific occlusal schemes, most studies were poorly designed and of low quality, thus yielding ambiguous results. Overall, there is no scientific evidence that supports any specific occlusal scheme being superior to others in terms of improving stomatognathic function, nor that sophisticated methods are superior to simpler ones in terms of clinical outcomes. However, it is obvious that the art of occlusal rehabilitation requires accurate, reproducible, easy and quick procedures to reduce unnecessary technical failures and/or the requirement for compensatory adjustments. Therefore, despite the lack of scientific evidence for specific treatments, the acquisition of these general skills by dentists and attaining profound knowledge and skills in postgraduate training will be necessary for specialists in charge of complicated cases. PMID- 22489963 TI - Explaining the structure of the OH stretching band in the IR spectra of strongly hydrogen-bonded dimers of phosphinic acid and their deuterated analogs in the gas phase: a computational study. AB - We present a simulation of the OH stretching band in the gas-phase IR spectra of strongly hydrogen-bonded dimers of phosphinic acid and their deuterated analogs [(R(2)POOH(D), with R = CH(2)Cl, CH(3)], which is based on a model for a centrosymmetric hydrogen-bonded dimer that treats the high-frequency OH stretches harmonically and the low-frequency intermonomer (i.e., O...O) stretches anharmonically. This model takes into account the following effects: anharmonic coupling between the OH and O...O stretching modes; Davydov coupling between the two hydrogen bonds in the dimer; promotion of symmetry-forbidden OH stretching transitions; Fermi resonances between the fundamental of the OH stretches and the overtones of the in- and out-of-plane bending modes involving the OH groups; direct relaxation of the OH stretches; and indirect relaxation of the OH stretches via the O...O stretches. Using a set of physically sound parameters as input into this model, we have captured the main features in the experimental OH(D) bands of these dimers. The effects of key parameters on the spectra are also elucidated. By increasing the number and strength of the Fermi resonances and by promoting symmetry-forbidden OH stretching transitions in our simulations, we directly see the emergence of the ABC structure, which is a characteristic feature in the spectra of very strongly hydrogen-bonded dimers. However, in the case of the deuterated dimers, which do not exhibit the ABC structure, the Fermi resonances are found to be much weaker. The results of this model therefore shed light on the origin of the ABC structure in the IR spectra of strongly hydrogen bonded dimers, which has been a subject of debate for decades. PMID- 22489964 TI - Hybridization of Neotyphodium endophytes enhances competitive ability of the host grass. AB - * Associations with microbial symbionts may lead to niche differentiation of their host. Vertically transmitted Neotyphodium endophytes of grasses often hybridize in nature. Infection by these hybrid symbionts may result in different host-plant phenotypes from those caused as a result of infection by nonhybrid symbionts. Observations of wild Arizona fescue (Festuca arizonica) populations show that hybrid Neotyphodium-infected (H+) grasses dominate in resource-poor environments, whereas nonhybrid endophyte-infected (NH+) grasses dominate in environments with more resources. We studied the hypothesis that hybridization of endophytes increases stress tolerance of the host. * To test whether hybridization of Neotyphodium affects performance and competitive abilities of the host depending on resources, we conducted a glasshouse experiment where competition, nutrients and watering were manipulated. * H+ plants had greater wet biomass than NH+ and endophyte-free plants, when grown in competition, but only in low-water and low-nutrient treatments. By contrast, NH+ plants did not perform better than H+ or endophyte-free plants regardless of the treatment combination. * Our results suggest that hybridization of symbiotic Neotyphodium endophytes may increase competitive potential of the host in stressful environments and that this hybridization may be underlying niche expansion of Arizona fescue in the environments with low resources. PMID- 22489965 TI - Fine needle aspiration cytology of a clear cell (lipid-rich) pancreatic neuroendocrine tumour in a patient without von Hippel-Lindau disease. PMID- 22489966 TI - Different patterns of spoken and written word comprehension deficit in aphasic stroke patients. AB - This study presents neuropsychological evidence for differences in the semantic representations underpinning spoken and written word comprehension. Potential modality-based discrepancies in the semantic system were examined by testing whether spoken word (auditory-verbal input) and written word (visual-verbal input) comprehension exhibited the same effect profile on variables typically used to distinguish so-called access and storage disorders (e.g., response consistency, sensitivity to item frequency). The study was based on the premise that damage to a common set of semantic representations should have an equivalent impact upon comprehension performance irrespective of input modality, whereas damage to partially dissociable semantic representations may give rise to different qualities of deficit (access/storage) in the comprehension of stimuli presented in different input modalities (spoken/written). The study involved two patients with global aphasia following left middle cerebral artery stroke (F.B.I. and H.O.P.). The two patients showed matched performance on conventional tests of single word comprehension with clear evidence of semantic impairment for stimuli presented in both the spoken and written input modalities. However, in H.O.P., spoken and written word comprehension was affected in the same way by variations in stimulus category, frequency, and multiple stimulus presentations, whilst in F.B.I., there were clear differences between input modalities with all three variables. More specifically, F.B.I.'s written word comprehension was significantly affected by category (living > nonliving) and frequency (high > low) but not multiple presentations (single = multiple), more consistent with degradation of stored representations (storage deficit). By contrast, his spoken word comprehension was unaffected by category (living = nonliving) and frequency (high = low) but was affected by multiple presentations (single > multiple; serial position effects), more consistent with impaired access to stored representations (access deficit). These spoken/written input modality differences were observed on tasks matched closely for output modality, stimulus identity, and executive control requirements. It is argued that subtle differences in comprehension performance for stimuli presented in different input modalities may reflect damage to multimodal representations, which are intermediate between unimodal and amodal representations on a continuum of convergence within the semantic system. These ideas are discussed in the context of existing "distributed-only", "distributed-plus-convergence", or "distributed-plus-hub" models of conceptual knowledge. PMID- 22489967 TI - Preparation of mesoporous submicrometer silica capsules via an interfacial sol gel process in inverse miniemulsion. AB - Mesoporous silica capsules with submicrometer sizes were successfully prepared via the interfacial hydrolysis and condensation reactions of tetraethoxysilane (TEOS) in inverse miniemulsion by using hydrophilic liquid droplets as template. The inverse miniemulsions containing pH-controlled hydrophilic droplets were first prepared via sonication by using poly(ethylene-co-butylene)-b-poly(ethylene oxide) (P(E/B)-PEO) or SPAN 80 as surfactant. TEOS was directly introduced to the continuous phase of an inverse miniemulsion. The silica shell was formed by the deposition of silica on the surface of droplets. The formation of capsule morphology was confirmed by transmission electron microscopy (TEM) and field emission scanning electron microscopy (FESEM). The mesoporous structure was verified by nitrogen sorption measurements. The specific surface area could be tuned by the variation of the amount of cetyltrimethylammonium bromide (CTAB) and TEOS, and the pore size by the amount of CTAB. The influences of synthetic parameters on the particle size and morphology were investigated in terms of the amount of CTAB, pH value in the droplets, TEOS amount, surfactant amount, and type of solvent with low polarity. A formation mechanism of silica capsules was proposed. PMID- 22489968 TI - Central corneal thickness in full-term Saudi newborns. AB - PURPOSE: To establish a standard of normal central corneal thickness (CCT) in normal full-term Saudi newborn. These values could be used as a reference in the early diagnosis and control of the fairly common primary congenital glaucoma in Saudi newborns. METHODS: The CCT was measured in 100 normal full-term Saudi newborns (200 eyes) during the first 6 days of the postnatal period. All measurements were carried out by one investigator using ultrasonic pachymeter DGH 1000. RESULTS: The mean CCT of 200 eyes (right and left) was 616 +/- 61 MUm. The mean CCT of the right and left eyes was similar (CCTRE was 617 +/- 62 MUm, and mean CCTLE was 616 +/- 60 MUm), with no statistically significant difference (p = 0.417). The mean CCT for males was 631 +/- 66 MUm and for females 600 +/- 50 MUm. This difference was statistically significant (p = 0.01). The mean CCT decreases significantly by age [day-1: 626 +/- 65 MUm, day-2: 601 +/- 48 MUm and day-3: 574 +/- 45 MUm (p = 0.049)]. No correlations were found between CCT and gestational age, birth weight, birth length and head circumference. CONCLUSION: The average CCT in full-term Saudi newborns was found to be 616 +/- 61 MUm. The mean CCT in males was significantly higher than in females. There was no correlation between CCT and gestational age, birth weight, birth length and head circumference. There were borderline significant differences between CCT in 1-day-, 2-day-, and 3-day old babies. PMID- 22489969 TI - Third-year medical students' knowledge of privacy and security issues concerning mobile devices. AB - BACKGROUND: The use of mobile devices are ubiquitous in medical-care professional settings, but information on privacy and security concerns of mobile devices for medical students is scarce. AIMS: To gain baseline information about third-year medical students' mobile device use and knowledge of privacy and security issues concerning mobile devices. METHODS: We surveyed 67 third-year medical students at a Midwestern university on their use of mobile devices and knowledge of how to protect information available through mobile devices. Students were also presented with clinical scenarios to rate their level of concern in regards to privacy and security of information. RESULTS: The most used features of mobile devices were: voice-to-voice (100%), text messaging (SMS) (94%), Internet (76.9%), and email (69.3%). For locking of one's personal mobile phone, 54.1% never physically lock their phone, and 58% never electronically lock their personal PDA. Scenarios considering definitely privacy concerns include emailing patient information intact (66.7%), and posting de-identified information on YouTube (45.2%) or Facebook (42.2%). CONCLUSIONS: As the ease of sharing data increases with the use of mobile devices, students need more education and training on possible privacy and security risks posed with mobile devices. PMID- 22489970 TI - Psychometric properties of DREEM in a sample of Malaysian medical students. PMID- 22489971 TI - Medical education in the United States of America. AB - This article was written to provide a brief history of the medical educational system in the USA, the current educational structure, and the current topics and challenges facing USA medical educators today. The USA is fortunate to have a robust educational system, with over 150 medical schools, thousands of graduate medical education programs, well-accepted standardized examinations throughout training, and many educational research programs. All levels of medical education, from curriculum reform in medical schools and the integration of competencies in graduate medical education, to the maintenance of certification in continuing medical education, have undergone rapid changes since the turn of the millennium. The intent of the changes has been to involve the patient sooner in the educational process, use better educational strategies, link educational processes more closely with educational outcomes, and focus on other skills besides knowledge. However, with the litany of changes have come increased regulation without (as of yet) clear evidence as to which of the changes will result in better physicians. In addition, the USA governmental debt crisis threatens the current educational structure. The next wave of changes in the USA medical system needs to focus on what particular educational strategies result in the best physicians and how to fund the system over the long term. PMID- 22489972 TI - Training more doctors in the developed English speaking world: impact on post graduate training and employment. PMID- 22489973 TI - Living and working with the people of 'the bush': a foundation for rural and remote clinical placements in undergraduate medical education. AB - BACKGROUND: The Australian Government's policies and programmes to redress the medical workforce shortage in rural and remote areas focus on recruitment of rural students and provision of rural clinical placements. The University of Notre Dame's Rural and Remote Health Placement Programme (RRHPP) uses an additional approach to address this issue. AIM: This article describes the RRHPP undertaken by all medical students in the first 2-years of their course and examines the educational worth of this approach. METHOD: Data were obtained from curricular documents, publications about the RRHPP and evaluation questionnaires administered to students and supervisors. RESULTS: The RRHPP provides students with opportunities to develop a patient- and community-centred perspective on the health issues of rural and remote populations by having them live and work with people in these areas prior to clinical placements. It is based on sound educational principles and underpinned by participation of rural/remote communities as experts and equal teaching partners. The RRHPP is valued and perceived by a majority of students and placement hosts as a useful strategy to develop medical students' understanding of the rural/remote community context and its impact on health. CONCLUSION: This community participatory approach benefits medical students and rural/remote communities. PMID- 22489974 TI - Quantitative evaluation of public health teaching in a multi-site medical school. PMID- 22489975 TI - Feasibility of utilization of experts outside the country for education intervention on adolescent health: case study on Macao general practitioners. PMID- 22489976 TI - The AMEE Research Committee: Initiatives to stimulate research and practice. PMID- 22489977 TI - Log-book implementation in anaesthesiology residency training: a retrospective analysis. PMID- 22489978 TI - Facilitators and barriers to a nationwide implementation of competency-based postgraduate medical curricula: a qualitative study. AB - BACKGROUND: Postgraduate medical education (PGME) curricula are being redesigned across the western world. AIM: This study examined the implementation process (what works where and why) of new competency-based PGME curricula and relevant factors influencing this process. METHODS: In a nationwide project (2006-2010) in the Netherlands, competency-based PGME curricula were implemented for residents in Pediatrics and Obstetrics & Gynecology. The authors conducted 25 semi structured interviews and used a multi-level theoretical framework to guide coding. RESULTS: The implementation process proved to be highly dynamic, non linear, and influenced by many factors. These could be divided into attributes of the innovations/adopters, the implementation process, and the organization. The context determined the speed, quality, and direction of the process and how a factor affected the process. CONCLUSIONS: We identified specific features of PGME innovation: the challenge of implementing other competencies than that of the medical expert; the importance of regional implementation strategies and educational support; the balance between training and patient care; and the need for regional inter-organizational networks of hospitals. The authors recommend: design the curriculum with the needs of the users in mind; facilitate knowledge sharing; organize educational support; translate the national curriculum to the local workplace; and promote regional inter-organizational networks between hospitals. PMID- 22489979 TI - The proof is in the pudding: putting Actor-Network-Theory to work in medical education. AB - What constitutes valid evidence from medical education research is typically grounded in the scientific paradigm of proof through experiment. Here, explanation through single meaning is privileged over exploration of multiple presentations of phenomena--short, interpretation eclipses appreciation. This approach is challenged as reductive by naturalistic qualitative methods such as rich ethnographic field reports, presented as narratives. Contemporary ethnographic approaches have entered medical education by a back door--disguised as a stable of 'social learning theories'. Communities of Practice theory, Activity Theory and Actor-Network-Theory (ANT) all serve as research practices forming identifiable contemporary ethnographies. 'Evidence' is conceived as exploratory rather than explanatory, through baroque descriptions of innovations in learning organizations, including medicine. ANT is then both a theory of innovation in organizations and an ethnographic method, where practice and theory coincide. ANT is interested primarily not in epistemologies, but in how a phenomenon such as an 'illness' is conceived across differing practices as multiple ontologies (experienced meanings), each meaning generated and suspended within a particular network of effects. How such networks are initiated and developed has significance for rethinking the nature of 'evidence', restoring faith in the value of a good story. PMID- 22489980 TI - Randomized controlled trials and meta-analysis in medical education: what role do they play? AB - Education researchers seek to understand what works, for whom, in what circumstances. Unfortunately, educational environments are complex and research itself is highly context dependent. Faced with these challenges, some have argued that qualitative methods should supplant quantitative methods such as randomized controlled trials (RCTs) and meta-analysis. I disagree. Good qualitative and mixed-methods research are complementary to, rather than exclusive of, quantitative methods. The complexity and challenges we face should not beguile us into ignoring methods that provide strong evidence. What, then, is the proper role for RCTs and meta-analysis in medical education? First, the choice of study design depends on the research question. RCTs and meta-analysis are appropriate for many, but not all, study goals. They have compelling strengths but also numerous limitations. Second, strong methods will not compensate for a pointless question. RCTs do not advance the science when they make confounded comparisons, or make comparison with no intervention. Third, clinical medicine now faces many of the same challenges we encounter in education. We can learn much from other fields about how to handle complexity in RCTs. Finally, no single study will definitively answer any research question. We need carefully planned, theory building, programmatic research, reflecting a variety of paradigms and approaches, as we accumulate evidence to change the art and science of education. PMID- 22489981 TI - Using interprofessional education strategies to improve collaborative attitudes among infectious diseases and cardiology physician trainees. PMID- 22489982 TI - Using standardized patients to teach cross-cultural communication skills. PMID- 22489983 TI - A proposed program for revising training in diagnostic and interventional cardiac catheterization using a didactic lecture series and virtual reality simulation. PMID- 22489984 TI - The use of assisted performance within an online social network to develop reflective reasoning in undergraduate physiotherapy students. AB - BACKGROUND: The development of practice knowledge is an important component of clinical education and reflective reasoning is known to play a role in its development. Online social networks may have some potential for developing practice knowledge by providing tools for clinical educators to guide students' reasoning practices. AIM: To determine if an online social network could be used to facilitate reflective reasoning in clinical contexts, as it relates to developing practice knowledge. METHOD: The study was conducted within a South African university, physiotherapy department, using an online social network to facilitate engagement. Tharp and Gallimore's theory of assisted performance was used as a framework to conduct qualitative analysis of students' reflective blog posts within the network. RESULTS: The lecturer was able to use strategies within the assisted performance framework to facilitate reflection among students. These included modelling, contingency management, feedback, instruction, questioning and cognitive structuring. The features of the social network enabled enhanced communication between teacher and student, as well as promoted engagement around clinical scenarios. CONCLUSION: Online social networks can be used to facilitate reflective reasoning as part of the development of practice knowledge by exposing students' understanding of clinical practice. However, careful facilitation using sound pedagogy is still necessary to guide students to deeper understanding. PMID- 22489985 TI - Digital photographs in clinical teaching of dermatology: what is their proper place? PMID- 22489986 TI - An innovative approach to inculcate analytical and non-analytical clinical reasoning among medical students. PMID- 22489987 TI - A comprehensive process of content validation of curriculum consensus guidelines for a medical specialty. AB - In this article, we outline an innovative and comprehensive approach to the development by consensus of curriculum content guidelines for a medical specialty. We initially delineated the content domain by triangulation of sources, validated a curriculum blueprint by both quantitative and qualitative methodology, and finally reached consensus on content by Delphi methodology. Development of curricular objectives is an important step in curriculum development. Content definition or "blueprinting" refers to the systematic definition of content from a specified domain for the purpose of creating test items with validity evidence. Content definition can be achieved in a number of ways and we demonstrate how the concepts of content definition or validation can be transferred beyond assessment, to other steps in curriculum development and instructional design. Validity in Education refers to the multiple sources of evidence to support the use or interpretation of different aspects of a curriculum. In this approach, there are multiple sources of content-related validity evidence which, when accumulated, give credibility and strength to curriculum consensus guidelines. PMID- 22489988 TI - Thomas the Tank Engine significantly improves the understanding of oxygen delivery and hypoxaemia. PMID- 22489989 TI - Environmental and dietary factors and lung cancer risk among Chinese women: a case-control study in southeast China. AB - After decades of increase, lung cancer has become the leading cause of cancer death among women. The mortality rate from lung cancer is ascending at a relatively steady rate, which has greatly affected the health of the female population and become a serious issue. A case-control study of 226 female lung cancer cases and 269 controls was conducted from 2006 to 2010 in Fujian Province. A structured questionnaire was used to gather information on demographic characteristics as well as dietary and environmental factors. Odds ratios and 95% confidence intervals were estimated by using univariate logistic regression. Multivariate unconditional logistic regression analysis was applied to evaluate the potential interactions of variables or confounders. The consumption of fruit, eggs, and tea was inversely associated with the risk of lung cancer. As expected, cooking oil fumes and environmental tobacco exposure were positively associated with elevated risk. In addition, frequent physical activity and late age at menarche were identified as protective factors of female lung cancer. The results demonstrate that some environmental and dietary factors are related to the risk of lung cancer among the female population in southeast China. PMID- 22489990 TI - Tracheal intubation conditions - the importance of timing. PMID- 22489991 TI - Transillumination-assisted orotracheal intubation: a comparison of the Bonfils fibrescope and the lightwand (Trachlight). AB - BACKGROUND: Because the Bonfils fibrescope has a semi-rigid optical stylet and is similar in shape to a lightwand, we aimed to evaluate and compare the efficacy of transillumination-assisted orotracheal intubation with the Bonfils fibrescope and the Trachlight(TM) lightwand in patients with normal airways. METHODS: As a preliminary investigation to form a basis for later studies, therefore, we performed a randomized, single-blind study of 300 patients with normal airways to compare the efficiency of Trachlight and transillumination-assisted Bonfils orotracheal intubation in these patients. In both groups, orotracheal intubation was performed using a transillumination technique. The first attempt and overall success rates of tracheal intubation, the times required, and any untoward effects were recorded. RESULTS: Although the overall success rates were similar for Bonfils and Trachlight intubations (97.3% and 98.7%, respectively), tracheal intubation was successful on the first attempt in 87.3% of patients with the Bonfils fibrescope compared with 95.3% of patients with the Trachlight (P < 0.05). The mean intubation time for the first attempt was 15 +/- 5 s with the Bonfils fibrescope and 9 +/- 2 s with the Trachlight (P < 0.001). Patients intubated using the Bonfils fibrescope also experienced significantly more sore throat and hoarseness than those intubated using the Trachlight. CONCLUSIONS: For patients with normal airways, the Trachlight is superior for orotracheal intubation with respect to reliability, rapidity, and safety compared with the Bonfils fibrescope used with the transillumination technique. PMID- 22489992 TI - Recombinant factor VIIa as last-resort treatment of desperate haemorrhage. AB - INTRODUCTION: Studies are inconclusive regarding clinical outcomes after administration of recombinant activated coagulation factor VII (rFVIIa) during severe haemorrhage. The circumstances encountered during desperate haemorrhage make it difficult to include the most critically ill patients that could possibly benefit the most from such treatment into randomized controlled trials. We report our experience with rFVIIa as last-resort treatment of desperate haemorrhage when all standard treatment has failed. MATERIALS AND METHODS: Hospital charts of all consecutive patients treated with rFVIIa for desperate non-haemophilic bleeding over a 10-year period at the single institution administering rFVIIa were surveyed for treatment indications, clinical outcome, transfusion need and coagulation profiles. RESULTS: Fifty-five rFVIIa treatment occasions of desperate bleeding were identified in 54 patients (median age 54 years). A single rFVIIa dose was used in 86%, and haemorrhage was considered effectively contained by immediate clinical response on 81% of occasions. Overall, 38 patients (71%) survived for over 30 days. Two thromboembolic events occurred (3.6%). The 24-h mortality in 45 rFVIIa immediate clinical responders and 10 non-responders was 2% and 50%, respectively (P = 0.0004), and the 30-day mortality was 25% and 60%, respectively (P = 0.05). Blood product use decreased with rFVIIa (P < 0.01) as did the prothrombin time (20.0-13.3 s, P < 0.0001). CONCLUSIONS: The majority of unselected consecutive patients receiving rFVIIa as last-resort treatment for desperate haemorrhage were considered to have immediate clinical response as well as reduced transfusion requirements and correction of coagulation parameters. An immediate clinical response to rFVIIa may possibly be predictive of survival. PMID- 22489994 TI - Retraction. Spinal 2-chloroprocaine: effective dose for ambulatory surgery. PMID- 22489997 TI - Systemic inflammation and endothelial dysfunction in dogs with congestive heart failure. AB - BACKGROUND: Congestive heart failure (CHF) is associated with endothelial dysfunction in people and in dogs with experimentally induced CHF, but this is not well characterized in dogs with naturally occurring CHF. HYPOTHESIS/OBJECTIVES: To evaluate endothelial function via assessment of reactive hyperemia (RH) in healthy dogs and dogs with CHF, and to assess for relationships with plasma biomarkers of vascular function and clinical markers of disease severity. ANIMALS: Twenty client-owned animals with CHF due to myxomatous mitral valve disease (n = 15) or dilated cardiomyopathy (n = 5) and 17 healthy control dogs. METHODS: Prospective case-controlled observational study. Dogs underwent blood sampling, echocardiography, and Doppler assessment of brachial artery velocity (VTI) at baseline and during reactive hyperemia (RH-VTI). RH-VTIs between control dogs and dogs with CHF were compared, and the relationships between RH-VTI, clinical parameters, and plasma biomarkers were assessed. RESULTS: Dogs with CHF (96.5 +/- 51.7%) had an attenuated % increase in VTI during RH compared to healthy controls (134.8 +/- 58.7%; P = .04). Increasing ISACHC class (R(2) = 0.24; P = .004), plasma NT-proBNP (R(2) = 0.15; P = .03) and CRP (R(2) = 0.2; P = .02) were associated with reduced RH-VTI. Increased plasma CRP, NO(x) , and NT-proBNP concentrations were found in dogs with CHF (P < .02 for all). No differences were detected in other plasma markers. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with CHF have an attenuated RH response, and increased plasma CRP and NO(x) concentrations. Doppler assessment of RH velocity could represent a novel noninvasive method of evaluating endothelial function in the dog. PMID- 22489996 TI - The impact of different nursing skill mix models on patient outcomes in a respiratory care center. AB - BACKGROUND: Many hospitals have reformed hospital policies and changed nursing models to cope with shortages in nursing staff and control medical costs. However, the nursing skill mix model that most successfully achieves both cost effectiveness and quality care has yet to be determined. AIM: The aim of this study was to explore the impact of different nurse staffing models on patient outcomes in a respiratory care center (RCC). METHODS: Retrospective data from 2006 to 2008 were obtained from records monitoring nursing care quality, as well as patient records and nursing personnel costs in an RCC as a medical center, in southern Taiwan. A total of 487 patients were categorized into two groups according to the RCC's mix of nursing staff. The "RN/Aide" group comprised 247 patients who received RN and aide care, with a 0.7-0.8 proportion of RNs, from July 2006 to June 2007. The other 240 patients ("All-RN") received 100% RN care from January 2008 to December 2008. RESULTS: The results of this study indicated no significant differences in occurrence of pressure ulcer or respiratory tract infections, days of hospitalization, mortality, or nursing costs. However, significant differences were observed in ventilator weaning and occurrence of urinary tract and bloodstream infections. CONCLUSIONS: A higher proportion of RNs was associated not only with a lower rate of urinary tract infection but also with more patients being weaned successfully from ventilators. The findings of this study have implications for how managers and administrators manage nurse staffing in respiratory care. PMID- 22489998 TI - Gluten-dependent antibodies in horses with inflammatory small bowel disease (ISBD). AB - BACKGROUND: Equine inflammatory small bowel disease (ISBD) is an idiopathic pathologic condition seeming to increase in prevalence. OBJECTIVE: To investigate the potential role of gluten in equine ISBD. ANIMALS & METHODS: Antibodies known to be important in the diagnosis of human coeliac disease (CD): IgA antibodies to human recombinant and guinea pig tissue-transglutaminase (TGA), native gliadin (AGA), deamidated-gliadin-peptides (DGPA), and primate and equine endomysium (EMA) were assessed in blood samples from three different groups of horses: ISBD affected (n = 12) on a gluten-rich diet and controls either on gluten-rich (n = 22) or gluten-poor (n = 25) diets. Significant differences (p < 0.05) between groups were assessed using the Wilcoxon test. RESULTS: Both ISBD-affected horses and gluten-rich controls had significantly (p < 0.0004) higher hrTGA titers than gluten-poor controls. However, ISBD horses did not show significantly increased levels of any of the CD related antibodies when compared to gluten-rich controls. Nevertheless, markedly increased antibody levels (TGA, EMA and DGPA) were found in one of the ISBD horses. The introduction of a gluten-free ration in this 14 year-old warmblood stallion resulted after 6 months in the reduction of antibody levels and clinical recovery associated with improved duodenal histopathology. CONCLUSION: To the best of our knowledge, this is the first study assessing gluten-related antibodies in horses and results suggest a potential pathogenic role of gluten in at least some cases of equine ISBD. Clinical importance and impact for human medicine: Given serology and concurrent clinical findings, this study warrants further investigations into the immunologic basis of possible gluten-sensitive enteropathy in horses and analogy with human disease. PMID- 22489999 TI - International workshop: radiation effects on mutation in somatic and germline stem cells. AB - PURPOSE: New developments in knowledge of radiation effects on tissue stem cells were discussed in a Workshop held at the Radiation Effects Research Foundation (RERF) in Hiroshima, Japan, 18-19 January 2012. RESULTS: Stem cells and their niche in intestinal mucosa, haemopoietic tissue, hair follicles, and spermatogenesis were discussed variously with regard to radiosensitivity, repair, regeneration, age-dependency of effects, genetic effects, and protection aspects. These tissues all possess a common basic template, but there are structural and hierarchical differences between tissues which continue to be elucidated in terms of a stem-cell age structure and niche regulatory signals which together govern radiation responses. CONCLUSIONS: Stem cells and their niche have become much better characterized in recent years, and their radiation response can be elucidated in detail in experimental systems to help underpin both protection and therapeutic recommendations established from human epidemiological evidence. This report summarizes the presentations at the meeting, and concludes with some remaining questions which may be answered with the help of this type of research. PMID- 22490001 TI - Pathways for psychological adjustment in breast cancer: a longitudinal study on coping strategies and posttraumatic growth. AB - This longitudinal study examined the role of coping strategies and posttraumatic growth (PTG) on the psychological adjustment to breast cancer trajectory. The participants were 50 women assessed at the time of surgery (T1), during adjuvant treatment (T2) and six months after the end of treatment (T3). Women completed questionnaires assessing coping strategies, PTG and psychological adjustment (psychological quality of life, anxiety and depression). Results showed that the greatest impact of breast cancer on women's adjustment occurred at T1, when patients were significantly more anxious than in the other phases of the disease. The type of surgery and adjuvant treatment did not account for the course of PTG and adjustment. Coping through seeking social support and using cognitive strategies at T1 were linked to psychological quality of life and depression at T3 via PTG dimension of personal resources and skills at T2. Findings emphasise the value of promoting adaptive coping strategies and PTG in order to improve psychological adjustment in breast cancer patients. PMID- 22490000 TI - A retrospective case-control study of hepatitis C virus infection and oral lichen planus in Japan: association study with mutations in the core and NS5A region of hepatitis C virus. AB - BACKGROUND: The aims of this study were to assess the prevalence of hepatitis C virus (HCV) infection in Japanese patients with oral lichen planus and identify the impact of amino acid (aa) substitutions in the HCV core region and IFN sensitivity-determining region (ISDR) of nonstructural protein 5A (NS5A) associated with lichen planus. METHODS: In this retrospective study, 59 patients (group 1-A) with oral lichen planus among 226 consecutive patients who visited our hospital and 85 individuals (group 1-B, controls) with normal oral mucosa were investigated for the presence of liver disease and HCV infection. Risk factors for the presence of oral lichen planus were assessed by logistic regression analysis. We compared aa substitutions in the HCV core region (70 and/or 91) and ISDR of NS5A of 12 patients with oral lichen planus (group 2-A) and 7 patients who did not have oral lichen planus (group 2-B) among patients (high viral loads, genotype 1b) who received interferon (IFN) therapy in group1 A. RESULTS: The prevalence of anti-HCV and HCV RNA was 67.80% (40/59) and 59.32% (35/59), respectively, in group 1-A and 31.76% (27/85) and 16.47% (14/85), respectively, in group 1-B. The prevalence of anti-HCV (P < 0.0001) and HCV RNA (P < 0.0001) in group 1-A was significantly higher than those in group 1-B. According to multivariate analysis, three factors - positivity for HCV RNA, low albumin level (< 4.0 g/dL), and history of smoking - were associated with the development of oral lichen planus. The adjusted odds ratios for these three factors were 6.58, 3.53 and 2.58, respectively, and each was statistically significant. No significant differences in viral factors, such as aa substitutions in the core region and ISDR of NS5A, were detected between the two groups (groups 2-A and -B). CONCLUSION: We observed a high prevalence of HCV infection in patients with oral lichen planus. Longstanding HCV infection, hypoalbuminemia, and smoking were significant risk factors for the presence of oral lichen planus in patients. It is advisable for Japanese patients with lichen planus to be tested for HCV infection during medical examination. PMID- 22490002 TI - Vibrational spectra of proximal water in a thermo-sensitive polymer undergoing conformational transition across the lower critical solution temperature. AB - The vibrational spectrum of water near a thermo-sensitive polymer poly(N isopropylacrylamide) (PNIPAM) undergoing conformational transition through the lower critical solution temperature (LCST) is calculated using molecular dynamics simulations. The characteristic structural features observed at the atomic scale for these proximal water molecules in a solvated polymer chain while undergoing the conformational transition are strongly correlated to their vibrational densities of states. Comparison of the vibrational spectrum below LCST for the proximal water with the vibrational spectrum obtained for bulk water reveals a significant fraction of the hydrogen bonding between the proximal water molecules and the polymer side groups. Hydrogen-bonded bridges of water molecules are formed between two adjacent and alternate monomers. This network of hydrogen bonding results in formation of locally ordered water molecules at temperatures below the LCST. Analysis of the simulation trajectories confirms the presence of a quasi-stable solvation structure near the PNIPAM. The calculated vibrational spectra for proximal water above the LCST suggest significantly reduced hydrogen bonding with the polymer and indicate a reduction in the structural stability of proximal water around a collapsed polymer chain. Systematic trends in the observed peak intensities and frequency shifts at the low- and high-frequency ends of the spectrum can be correlated with the structural and dynamical changes of water molecules below and above the LCST transition, respectively, for various polymer chain lengths. The simulations reveal that, compared to bulk water, the libration bands are blue shifted and OH stretch bands red shifted for water in proximity to PNIPAM with 30 monomer units below the LCST. The simulations suggest that vibrational spectra can be used as a predictive tool for quantifying atomic scale structural transitions in solvation of thermo-sensitive polymers such as PNIPAM. PMID- 22490003 TI - Preparations, crystal structures, and magnetic properties of N,N dipyridylaminoxyl as a new magnetic coupler and its one-dimensional cobalt(II) chains. AB - N,N-Dipyridilaminoxyl, NOpy(2), having a stable aminoxyl, was prepared as a new magnetic coupler for heterospin systems. Solutions of NOpy(2) were mixed with those of bis{1,1,1,5,5,5, hexafluoro-4-(phenylimino)-2-pentanonate}cobalt derivatives, Co(hfpip-X)(2), at a 1:1 ratio to afford the polymeric cobalt(II) complexes, [Co(hfpip-X)(2)(NOpy(2))](n); X = H (1), F (2), F(3) (3), F(5) (4), Cl (5), Cl(3) (6), Br (7), and I (8) as single crystals. In all complexes, the local structures of the cobalt-complex units were compressed octahedra and the pyridine ligands in NOpy(2) units coordinated to the cobalt ions in trans configuration to form linear chains for 1-4 and in cis configuration to form helical chains for 5 8. In the chains, the aminoxyl in NOpy(2) ferromagnetically interacted with the cobalt ions to produce the ferromagnetic chains with J(intra)/k(B) = 9-14 K. In the magnetic susceptibility experiments of aligned sample of 6, the magnetic easy axis was determined to be the a* axis, which was the direction perpendicular to the b axis of the chain axis. The resulting chains, all except 4, interacted antiferromagnetically among each other, and especially in 1, 5, 7, and 8, the magnetic behaviors characteristic to canted two-dimensional (2D) antiferromagnets with T(c) = 5.6, 4.0, 4.0, and 6.2 K, respectively, were observed. All complexes showed slow magnetic relaxations affected by the interchain antiferromagnetic interaction. The effective activation barriers, Delta(eff)/k(B), for the reorientation of the magnetism for all complexes except 4 were estimated to be 25 39 K in the presence of a direct current (dc) field. PMID- 22490004 TI - The reaction OH + C2H4: an example of rotational channel switching. AB - The low-temperature data for the reaction between OH and C(2)H(4) is treated canonically as either a two-well or one-well problem using the "Multiwell" suite of codes, in which a "well" refers to a minimum in the potential energy surface. The former is analogous to the two transition state model of Greenwald et al. [Greenwald, E. E.; North, S. W.; Georgievskii, Y.; Klippenstein, S. J. J. Phys. Chem. A2005, 109, 6031], while the latter reflects the dominance of the so-called "inner transition state". External rotations are treated adiabatically, causing changes in the magnitude of effective barriers as a function of temperature. Extant data are well-described with either model using only the average energy transferred in a downward direction, upon collision, DeltaE(d)(T), as a fitting parameter. The best value for the parameters describing the rate coefficient as a function of temperature (200 < T/K < 400) (Data at lower temperature is too sparse to yield a recommendation.) and pressure in the form used in the NASA/JPL format [Sander, S. P.; Abbatt, J.; Barker, J. R.; Burkholder, J. B.; Friedl, R. R.; Golden, D. M.; Huie, R. E.; Kolb, C. E.; Kurylo, M. J.; Moortgat, G. K et al., Chemical Kinetics and Photochemical Data for Use in Atmospheric Studies, Evaluation Number 17, Jet Propulsion Laboratory, 2011] are k(0) = 1.0 * 10( 28)(T/300)(-3.5) cm(6) molecule(-2) s(-1) and k(infinity) to 8.0 * 10( 12)(T/300)(-2.3) cm(3) molecule(-1) s(-1). PMID- 22490005 TI - Development of a work addiction scale. AB - Research into excessive work has gained increasing attention over the last 20 years. Terms such as "workaholism,""work addiction" and "excessive work" have been used interchangeably. Given the increase in empirical research, this study presents the development of the Bergen Work Addiction Scale (BWAS), a new psychometrically validated scale for the assessment of work addiction. A pool of 14 items, with two reflecting each of seven core elements of addiction (i.e., salience, mood modification, tolerance, withdrawal, conflict, relapse, and problems) was initially constructed. The items were then administered to two samples, one recruited by a web survey following a television broadcast about workaholism (n = 11,769) and one comprising participants in the second wave of a longitudinal internet-based survey about working life (n = 368). The items with the highest corrected item-total correlation from within each of the seven addiction elements were retained in the final scale. The assumed one-factor solution of the refined seven-item scale was acceptable (root mean square error of approximation = 0.077, Comparative Fit Index = 0.96, Tucker-Lewis Index = 0.95) and the internal reliability of the two samples were 0.84 and 0.80, respectively. The scores of the BWAS converged with scores on other workaholism scales, except for a Work Enjoyment subscale. A suggested cut-off for categorization of workaholics showed good discriminative ability in terms of working hours, leadership position, and subjective health complaints. It is concluded that the BWAS has good psychometric properties. PMID- 22490006 TI - The use of indicators to improve the quality of intensive care: theoretical aspects and experiences from the Dutch intensive care registry. AB - In the concept of total quality management that was originally developed in industry, the use of quality indicators is essential. The implementation of quality indicators in the intensive care unit to improve the quality of care is a complex process. This process can be described in seven subsequent steps of an indicator-based quality improvement (IBQI) cycle. With this IBQI cycle, a continuous quality improvement can be achieved with the use of indicator data in a benchmark setting. After the development of evidence-based indicators, a sense of urgency has to be created, registration should start, raw data must be analysed, feedback must be given, and interpretation and conclusions must be made, followed by a quality improvement plan. The last step is the implementation of changes that needs a sense of urgency, and this completes the IBQI cycle. Barriers and facilitators are found in each step. They should be identified and addressed in a multifaceted quality improvement strategy. PMID- 22490007 TI - Polymorphic phases of sp3-hybridized carbon under cold compression. AB - It is well established that graphite can be transformed into superhard carbons under cold compression (Mao et al. Science 2003, 302, 425). However, structure of the superhard carbon is yet to be determined experimentally. We have performed an extensive structural search for the high-pressure crystalline phases of carbon using the evolutionary algorithm. Nine low-energy polymorphic structures of sp(3) hybridized carbon result from the unbiased search. These new polymorphic carbon structures together with previously reported low-energy sp(3)-hybridized carbon structures (e.g., M-carbon, W-carbon, and Cco-C(8) or Z-carbon) can be classified into three groups on the basis of different ways of stacking two (or more) out of five (A-E) types of buckled graphene layers. Such a classification scheme points out a simple way to construct a variety of sp(3)-hybridized carbon allotropes via stacking buckled graphene layers in different combinations of the A-E types by design. Density-functional theory calculations indicate that, among the nine low energy crystalline structures, seven are energetically more favorable than the previously reported most stable crystalline structure (i.e., Cco-C(8) or Z carbon) in the pressure range 0-25 GPa. Moreover, several newly predicted polymorphic sp(3)-hybridized carbon structures possess elastic moduli and hardness close to those of the cubic diamond. In particular, Z-carbon-4 possesses the highest hardness (93.4) among all the low-energy sp(3)-hybridized carbon structures predicted today. The calculated electronic structures suggest that most polymorphic carbon structures are optically transparent. The simulated X-ray diffraction (XRD) spectra of a few polymorphic structures are in good agreement with the experimental spectrum, suggesting that samples from the cold-compressed graphite experiments may consist of multiple polymorphic phases of sp(3) hybridized carbon. PMID- 22490008 TI - Validation of the Chinese version of the Halitosis Associated Life-quality Test (HALT) questionnaire. AB - OBJECTIVE: This study aimed to evaluate the reliability and validity of the Chinese version of the Halitosis Associated Life-quality Test (HALT) questionnaire. METHODS: A total of 106 patients with oral malodour were recruited to complete the questionnaire after its translation and cross-cultural adaptation. The reliability of the Chinese version of the HALT was evaluated using internal consistency and test-retest methods. Both construct validity and discriminative validity were adopted to evaluate the validity of the HALT. RESULTS: The Cronbach's alpha value (internal reliability) for the total HALT score was 0.95, and the intraclass correlation coefficient (ICC) value (test retest reliability) was 0.89 (95% CI = 0.74-0.98). The construct validity was determined by exploratory factor analysis. Four factors were extracted, which accounted for 85.18% of the variance. All items had factor loadings above 0.40, ranging from 0.53 to 0.94. In addition, the Chinese version of the HALT was found to be valid for distinguishing patients with different degrees of oral malodour. CONCLUSION: The results suggest that the Chinese version of the HALT has satisfactory psychometric properties and is applicable to patients with oral malodour in Chinese-speaking populations. PMID- 22490009 TI - Assessment of the status of prehospital care in 13 low- and middle-income countries. AB - BACKGROUND: Injury and other medical emergencies are becoming increasingly common in low- and middle-income countries (LMICs). Many to most of the deaths from these conditions occur outside of hospitals, necessitating the development of prehospital care. Prehospital capabilities are inadequately developed to meet the growing needs for emergency care in most LMICs. OBJECTIVE: In order to better plan for development of prehospital care globally, this study sought to better understand the current status of prehospital care in a wide range of LMICs. METHODS: A survey was conducted of emergency medical services (EMS) leaders and other key informants in 13 LMICs in Africa, Asia, and Latin America. Questions addressed methods of transport to hospital, training and certification of EMS providers, organization and funding of EMS systems, public access to prehospital care, and barriers to EMS development. RESULTS: Prehospital care capabilities varied significantly, but in general were less developed in low-income countries and in rural areas, where utilization of formal EMS was often very low. Commercial drivers, volunteers, and other bystanders provided a large proportion of prehospital transport and occasionally also provided first aid in many locations. Although taxes and mandatory motor vehicle insurance provided supplemental funds to EMS in 85% of the countries, the most frequently cited barriers to further development of prehospital care was inadequate funding (36% of barriers cited). The next most commonly cited barriers were lack of leadership within the system (18%) and lack of legislation setting standards (18%). CONCLUSIONS: Expansion of prehospital care to currently underserved or unserved areas, especially in low-income countries and in rural areas, could make use of the already-existing networks of first responders, such as commercial drivers and laypersons. Efforts to increase their effectiveness, such as more widespread first-aid training, and better encompassing their efforts within formal EMS, are warranted. In terms of existing formal EMS, there is a need for increased and more regular funding, integration and coordination among existing services, and improved organization and leadership, as could be accomplished by making EMS administration and leadership a more desirable career path. PMID- 22490012 TI - Is there an existing healthy threshold for carbon storage in the ecosystem? PMID- 22490010 TI - A 20S combined with a 22R configuration markedly increases both in vivo and in vitro biological activity of 1alpha,25-dihydroxy-22-methyl-2-methylene-19 norvitamin D3. AB - Six new analogues of 1alpha,25-dihydroxy-19-norvitamin D(3) (3a-4b, 5, and 6) were prepared by a convergent synthesis applying the Wittig-Horner reaction as a key step. The influence of methyl groups at C-22 on their biological activity was examined. It was established that both in vitro and in vivo activity is strongly dependent on the configuration of the stereogenic centers at C-20 and C-22. Introduction of the second methyl group at C-22 (analogues 5 and 6) generates the compounds that are slightly more potent than 1alpha,25-(OH)(2)D(3) in the in vitro tests but much less potent in vivo. The greatest in vitro and in vivo biological activity was achieved when the C-20 is in the S configuration and the C-22 is in the R configuration. The building blocks for the synthesis, the respective (20R,22R)-, (20R,22S)-, (20S,22R)-, and (20S,22S)-diols, were obtained by fractional crystallization of mixtures of the corresponding diastereomers. Structures and absolute configurations of the diols 21a, 21b, and 22a as well as analogues 3a, 5, and 6 were confirmed by the X-ray crystallography. PMID- 22490011 TI - Copper-catalyzed aerobic intramolecular carbo- and amino-oxygenation of alkynes for synthesis of azaheterocycles. AB - A synthetic method of highly substituted quinolines has been developed from N-(2 alkynylaryl)enamine carboxylates under Cu-catalyzed aerobic conditions via intramolecular carbo-oxygenation of alkynes. This strategy was further applied for N-alkynylamidines for amino-oxygenation of alkynes, leading to imidazole and quinazoline derivatives. PMID- 22490013 TI - Arabica and robusta coffees: identification of major polar compounds and quantification of blends by direct-infusion electrospray ionization-mass spectrometry. AB - Considering that illegal admixture of robusta coffee into high-quality arabica coffee is an important task in coffee analysis, we evaluated the use of direct infusion electrospray ionization-mass spectrometry (ESI-MS) data combined with the partial least-squares (PLS) multivariate calibration technique as a fast way to detect and quantify arabica coffee adulterations by robusta coffee. A total of 16 PLS models were built using ESI+/- quadrupole time-of-flight (QTOF) and ESI+/- Fourier transform ion cyclotron resonance (FT-ICR) MS data from hot aqueous extracts of certified coffee samples. The model using the 30 more abundant ions detected by ES+ FT-ICR MS produced the most accurate coffee blend percentage prediction, and thus, it was later successfully employed to predict the blend composition of commercial robusta and arabica coffee. In addition, ESI+/- FT-ICR MS analysis allowed for the identification of 22 compounds in the arabica coffee and 20 compounds in the robusta coffee, mostly phenolics. PMID- 22490014 TI - Characteristics of autism spectrum disorder in Cornelia de Lange syndrome. AB - BACKGROUND: The prevalence of autism spectrum disorder (ASD) symptomatology is comparatively high in Cornelia de Lange syndrome (CdLS). However, the profile and developmental trajectories of these ASD characteristics are potentially different to those observed in individuals with idiopathic ASD. In this study we examine the ASD profile in CdLS in comparison to a matched group of individuals with ASD. METHOD: The Autism Diagnostic Observation Schedule (ADOS) was administered to 20 individuals with CdLS (mean age = 11.34; range = 6-13 years) and 20 individuals with idiopathic ASD (mean age = 10.42; range = 8-11 years). Participants were matched according to adaptive behaviour and receptive language skills. RESULTS: Sixty-five percent (N = 13) of individuals with CdLS met the cut-off score for autism on the total ADOS score. Further analysis at domain and item level indicated that individuals with CdLS showed significantly less repetitive behaviour, (specifically sensory interests); more eye contact, more gestures and less stereotyped speech than the ASD group. The CdLS group also showed higher levels of anxiety. CONCLUSIONS: The comparison between CdLS and idiopathic ASD indicates subtle group differences in the profile of ASD symptomatology that are not accounted for by degree of intellectual disability or receptive language skills. These differences may not be evident when relying solely upon clinical and domain level scores, but may be distinguishing features of the ASD presentations in the two disorders. The findings have implications for the conceptualisation and assessment of ASD in individuals with genetic syndromes. PMID- 22490015 TI - Serial selection for invasiveness increases expression of miR-143/miR-145 in glioblastoma cell lines. AB - BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary central nervous system malignancy and its unique invasiveness renders it difficult to treat. This invasive phenotype, like other cellular processes, may be controlled in part by microRNAs - a class of small non-coding RNAs that act by altering the expression of targeted messenger RNAs. In this report, we demonstrate a straightforward method for creating invasive subpopulations of glioblastoma cells (IM3 cells). To understand the correlation between the expression of miRNAs and the invasion, we fully profiled 1263 miRNAs on six different cell lines and two miRNAs, miR-143 and miR-145, were selected for validation of their biological properties contributing to invasion. Further, we investigated an ensemble effect of both miR-143 and miR-145 in promoting invasion. METHODS: By repeated serial invasion through Matrigel(r)-coated membranes, we isolated highly invasive subpopulations of glioma cell lines. Phenotypic characterization of these cells included in vitro assays for proliferation, attachment, and invasion. Micro-RNA expression was compared using miRCURY arrays (Exiqon). In situ hybridization allowed visualization of the regional expression of miR-143 and miR-145 in tumor samples, and antisense probes were used investigate in vitro phenotypic changes seen with knockdown in their expression. RESULTS: The phenotype we created in these selected cells proved stable over multiple passages, and their microRNA expression profiles were measurably different. We found that two specific microRNAs expressed from the same genetic locus, miR-143 and miR-145, were over expressed in our invasive subpopulations. Further, we also found that combinatorial treatment of these cells with both antisense-miRNAs (antimiR-143 and -145) will abrogated their invasion without decreasing cell attachment or proliferation. CONCLUSIONS: To best of our knowledge, these data demonstrate for the first time that miR-143 and miR-145 regulate the invasion of glioblastoma and that miR-143 and -145 could be potential therapeutic target for anti-invasion therapies of glioblastoma patients. PMID- 22490016 TI - Controlling the role of nanopore morphology in capillary condensation. AB - The effect of pore morphology on capillary condensation and evaporation in nanoporous silicon is studied experimentally. A variety of cooperative and local effects are observed in tailored nanopores with well-defined regions by directly probing gas adsorption in each region using optical interferometry. All observations are ascribed to the ability of the nanopore region to access the gas reservoir directly and the nucleation of liquid bridges at local heterogeneities within the nanopore region. These assumptions, consistent with recent simulations, can be extended to any real nanoporous system. PMID- 22490017 TI - An N-terminal dileucine motif directs two-pore channels to the tonoplast of plant cells. AB - Two-pore channels (TPCs) constitute a family of endolysosomal cation channels with functions in Ca2+ signaling. We used a mutational analysis to investigate the role of channel domains for the trafficking of the Arabidopsis TPC1 to the tonoplast, a process that is generally not well understood in plants. The results show that the soluble C-terminus was not essential for targeting but for channel function, while further C-terminal truncations of two or more transmembrane domains impaired protein trafficking. An N-terminal dileucine motif (EDPLI) proved to be critical for vacuolar targeting of TPC1, which was independent of the adaptor protein AP-3. Deletion or mutation of this sorting motif, which is conserved among TPCs caused redirection of the protein transport to the plasma membrane. An N-terminal region with a predicted alpha-helical structure was shown to support efficient vacuolar trafficking and was essential for TPC1 function. Similar to their localization in mammalian endosomes and lysosomes, MmTPC1 and MmTPC2 were targeted to small organelles and the membrane of the lytic vacuole, respectively, when expressed in plant cells. These results shed new light on the largely uncharacterized sorting signals of plant tonoplast proteins and reveal similarities between the targeting machinery of plants and mammals. PMID- 22490018 TI - Decreased chewing activity during mouth breathing. AB - This study examined the effect of mouth breathing on the strength and duration of vertical effect on the posterior teeth using related functional parameters during 3 min of gum chewing in 39 nasal breathers. A CO(2) sensor was placed over the mouth to detect expiratory airflow. When no airflow was detected from the mouth throughout the recording period, the subject was considered a nasal breather and enrolled in the study. Electromyographic (EMG) activity was recorded during 3 min of gum chewing. The protocol was repeated with the nostrils occluded. The strength of the vertical effect was obtained as integrated masseter muscle EMG activity, and the duration of vertical effect was also obtained as chewing stroke count, chewing cycle variation and EMG activity duration above baseline. Baseline activity was obtained from the isotonic EMG activity during jaw movement at 1.6 Hz without making tooth contact. The duration represented the percentage of the active period above baseline relative to the 3-min chewing period. Paired t-test and repeated analysis of variance were used to compare variables between nasal and mouth breathing. The integrated EMG activity and the duration of EMG activity above baseline, chewing stroke count and chewing cycle significantly decreased during mouth breathing compared with nasal breathing (P<0.05). Chewing cycle variance during mouth breathing was significantly greater than nasal breathing (P<0.05). Mouth breathing reduces the vertical effect on the posterior teeth, which can affect the vertical position of posterior teeth negatively, leading to malocclusion. PMID- 22490019 TI - Computational model of chromosome aberration yield induced by high- and low-LET radiation exposures. AB - We present a computational model for calculating the yield of radiation-induced chromosomal aberrations in human cells based on a stochastic Monte Carlo approach and calibrated using the relative frequencies and distributions of chromosomal aberrations reported in the literature. A previously developed DNA-fragmentation model for high- and low-LET radiation called the NASARadiationTrackImage model was enhanced to simulate a stochastic process of the formation of chromosomal aberrations from DNA fragments. The current version of the model gives predictions of the yields and sizes of translocations, dicentrics, rings, and more complex-type aberrations formed in the G(0)/G(1) cell cycle phase during the first cell division after irradiation. As the model can predict smaller-sized deletions and rings (<3 Mbp) that are below the resolution limits of current cytogenetic analysis techniques, we present predictions of hypothesized small deletions that may be produced as a byproduct of properly repaired DNA double strand breaks (DSB) by nonhomologous end-joining. Additionally, the model was used to scale chromosomal exchanges in two or three chromosomes that were obtained from whole-chromosome FISH painting analysis techniques to whole-genome equivalent values. PMID- 22490020 TI - TGF-beta-activated kinase 1 promotes cell cycle arrest and cell survival of X-ray irradiated HeLa cells dependent on p21 induction but independent of NF-kappaB, p38 MAPK and ERK phosphorylations. AB - Transforming growth factor-beta-activated kinase 1 (TAK1) appears to play a role in inhibiting apoptotic death in response to multiple stresses. To assess the role of TAK1 in X-ray induced apoptosis and cell death, we irradiated parental and siRNA-TAK1-knockdown HeLa cells. Changes in gene expression levels with and without TAK1-knockdown were also examined after irradiation to elucidate the molecular mechanisms involved. After X-ray irradiation, cell death estimated by the colony formation assay increased in the TAK1-knockdown cells. Apoptosis induction, determined by caspase-3 cleavage, suggested that the increased radiosensitivity of the TAK1-knockdown cells could be partially explained by the induction of apoptosis. However, cell cycle analysis revealed that the percentage of irradiated cells in the G(2)/M-phase decreased, and those in the S- and SubG(1)-phases increased due to TAK1 depletion, suggesting that the loss of cell cycle checkpoint regulation may also be involved in the observed increased radiosensitivity. Interestingly, significant differences in the induction of NF kappaB, p38 MAPK and ERK phosphorylation, the major downstream molecules of TAK1, were not observed in TAK1 knockdown cells compared to their parental control cells after irradiation. Instead, global gene expression analysis revealed differentially expressed genes after irradiation that bioinformatics analysis suggested are associated with cell cycle regulatory networks. In particular, CDKN1A (coding p21(WAF1)), which plays a central role in the identified network, was up-regulated in control cells but not in TAK1 knockdown cells after X-ray irradiation. Si-RNA knockdown of p21 decreased the percentage of cells in the G(2)/M phase and increased the percentage of cells in the S- and SubG(1)-phases after X-ray irradiation in a similar manner as TAK-1 knockdown. Taken together, these findings suggest that the role of TAK1 in cell death, cell cycle regulation and apoptosis after X irradiation is independent of NF-kappaB, p38 MAPK, and ERK phosphorylation, and dependent, in part, on p21 induction. PMID- 22490022 TI - Protecting children in agriculture. Commitment and cooperation for a common cause. PMID- 22490021 TI - The future structure of childhood agricultural injury prevention: first the blueprint. PMID- 22490023 TI - Developing the 2012 national action plan for protecting children in agriculture. AB - In 1996 the US launched a National Childhood Agricultural Injury Prevention Initiative, guided by an action plan generated by a 42-member multidisciplinary committee. A major update to the plan was released following the 2001 Summit on Childhood Agricultural Injury Prevention. From the year 2010 through 2011 a comprehensive assessment of progress to date was conducted followed by the drafting, review and finalizing of a new action plan-"The 2012 Blueprint for Protecting Children in Agriculture." This paper briefly describes the purpose and process for generating the new action plan then provides a listing of the 7 goals and 26 strategies within the plan. These goals and strategies account for trends in childhood agricultural injuries, changes in agricultural production and the demographics of its workforce, effectiveness of interventions, and the increasing use of social media, marketing and social networking. Primary funding for this project was provided by the National Institute for Occupational Safety and Health (NIOSH), which continues to serve as the lead federal agency for the national initiative. PMID- 22490024 TI - Enhancing surveillance of injuries and disease among agricultural youth. AB - Public health surveillance is fundamental to monitoring trends and for planning, implementation, and evaluation of health conditions in order to develop appropriate prevention and control programs. Farms and ranches are places where work and home life intersect in a unique way where risks are shared between work, home, and leisure. Public health surveillance systems have not been adapted to include agricultural youth as a subset at high risk of injuries and illnesses. Occupational health surveillance is used to monitor work-related illnesses and injuries but most have not allowed for continuous monitoring of agricultural related illnesses, injuries, and disability. Limited evaluation of data sets available for surveillance or periodic reporting of disease, disability, medical care utilization, and risk factors relevant for youth living and working on farms and ranches other than traumatic injuries has been published. The purpose of this paper is to discuss the current most commonly used databases and their limitations, and to list potentially relevant databases and their limitations, as well as making recommendations to augment their usefulness in monitoring trends among youth living and working on farms and ranches. PMID- 22490025 TI - Characteristics of evaluated childhood agricultural safety interventions. AB - The goal of this paper was to examine interventions focused on childhood agricultural safety since the last general assessment conducted for the 2001 Summit on Childhood Agricultural Injury Prevention. The objectives were to identify the strengths and weaknesses of the knowledge base and identify challenges to and recommendations for improving programs, interventions, and policies. Published literature from 2001 to 2009 was identified and reviewed. We found 26 studies evaluating the effectiveness of interventions aimed at preventing farm-related injuries to children. There were mixed results in a number of studies, weak methods in many, and a lack of randomized controlled trials, in particular. Most interventions focused on the individual level of the socio ecological model and only on education as a strategy, with behavior change and knowledge acquisition as the objectives. Although more studies have been published in recent years, the quality of the research and intervention design has not necessarily improved. Based upon this review, key recommendations for future childhood agricultural safety interventions are proposed. PMID- 22490027 TI - Guidelines for children's work in agriculture: implications for the future. AB - The North American Guidelines for Children's Agricultural Tasks (NAGCAT) were developed to assist parents in assigning developmentally appropriate and safe farm work to their children aged 7-16 years. Since their release in 1999, a growing body of evidence has accumulated regarding the content and application of these guidelines to populations of working children on farms. The purpose of this paper is to review the scientific and programmatic evidence about the content, efficacy, application, and uptake of NAGCAT and propose key recommendations for the future. The methods for this review included a synthesis of the peer-reviewed literature and programmatic evidence gathered from safety professionals. From the review, it is clear that the NAGCAT tractor guidelines and the manual material handling guidelines need to be updated based upon the latest empirical evidence. While NAGCAT do have the potential to prevent serious injuries to working children in the correct age range (7-16 years), the highest incidence of farm related injuries and fatalities occur to children aged 1-6 years and NAGCAT are unlikely to have any direct effect on this leading injury problem. It is also clear that NAGCAT, as a voluntary educational strategy, is not sufficient by itself to protect children working on farms. Uptake of NAGCAT has been sporadic, despite being geographically widespread and has depended, almost solely, on a few interested and committed professionals. Key recommendations for the future are provided based upon this review. PMID- 22490028 TI - Supervision of children in agricultural settings: implications for injury risk and prevention. AB - Farm environments pose unique safety hazards for children. With this in mind, this paper raises several points about how caregiver supervision influences risk of childhood injuries. First, research suggests that it is not the absence of a supervisor per se but the poorer quality of supervision that leads to pediatric injuries on farms, particularly for young children who behave in unpredictable ways at a time when caregivers are likely to be distracted with farm work. Second, research suggests that "adequate" supervision varies with context. In nonfarm contexts, continuous attention and close proximity (i.e., being within arm's reach) constitute an adequate level of supervision to ensure young children's safety. In agricultural contexts, attention and continuity are also relevant. However, close proximity is less beneficial because this often results in exposing children to hazards (animals, dangerous equipment) if the supervisor is working. Third, research suggests that in both agricultural and nonagricultural contexts, the extent to which supervision is associated with injury varies with a child's developmental level. Specifically, supervision seems to play a more primary role in moderating injury risk for young children (preschool), and this influence decreases as children age and increasingly independent are allowed to engage in more activities without a supervisor present. Building on these findings, practical recommendations are provided to enhance the safety of children on farms and future research directions are discussed. PMID- 22490026 TI - Children's environmental health in agricultural settings. AB - Children residing in rural settings may encounter environmental hazards derived from agricultural production activities. Health consequences of organic dusts, farm chemicals including pesticides, machinery noise, excess sun exposure, and zoonotic infectious agents have been clearly described among farm-working adults. The author reviews the related evidence base on child health with a life-stage perspective on their differential exposure and vulnerabilities. Methemoglobinemia among infants consuming nitrate-contaminated well water, neurodevelopmental health impacts associated with early life exposure to organophosphate pesticides, and diarrheal disease due to zoonotic infectious agents are well-described pediatric concerns. There is suggestive but more limited evidence for respiratory health consequences from air contaminants associated with confined animal feeding operations and hearing deficits for children exposed to machinery-related noise. Many contaminants of concern for children in these environments remain largely understudied-diesel exhaust, biomass burning, solvents, veterinary antibiotics, and silica-containing particulate matter. Overall, the state of knowledge and programmatic activities on agriculturally derived environmental contaminants and child health is immature and much less complete than for working adults. This overview provides a context for research, policy, and programmatic needs. PMID- 22490029 TI - Historical background of the child labor regulations: strengths and limitations of the agricultural hazardous occupations orders. AB - The purpose of this paper is to review the background of key legislative and regulatory milestones of the initial laws and federal child labor provisions limiting hazardous work by children in agriculture up to the more recent developments contributing to the proposed updates to the agricultural hazardous occupations orders. A summary of the key changes are described and the significant differences between agricultural and nonagricultural regulations are highlighted. Recommendations for future policy are provided. PMID- 22490030 TI - Unique agricultural safety and health issues of migrant and immigrant children. AB - Immigrant and migrant youth who live and work in agricultural settings experience unique agricultural safety and health issues. Mobility, poverty, cultural differences, immigration status, language, education, housing, food security, regulatory standards and enforcement, and access to childcare and health care influence exposure risk and the well-being of this population. Approximately 10% of the migrant agricultural labor force is composed of unaccompanied minors, whose safety and health is further compounded by lack of social supports and additional stresses associated with economic independence. This paper examines the current demographic and health data, regulatory protections, and programs and practices addressing safety and health in this sector of youth in agriculture. Gaps in knowledge and practice are identified, with emphasis on data collection and regulatory limitations. Best practices in programs addressing the special needs of this population are highlighted. Recommendations identify seven priority areas for impact to promote transformative change in the agricultural health and safety concerns of unaccompanied minors and children of immigrant, migrant and seasonal farmworkers. This framework may be used to examine similar needs in other identified subpopulations of children as they merit attention, whether now or in the future. PMID- 22490031 TI - Child labor in agriculture: some new developments to an ancient problem. AB - Advocates for working children worldwide strive to eradicate the employment that minimizes a child's opportunities for education, good health and future potential. In agriculture, some promising developments in corporate social responsibility may generate partial solutions to child labor problems that have persisted for generations across world regions where food, fiber and fuel are produced. The purpose of this paper is to review these promising developments and propose recommendations in the context of a future of continued agricultural globalization and industrialization. PMID- 22490032 TI - Child care needs of farm families. AB - One crucial strategy for preventing childhood agricultural injuries is to provide feasible, safe alternatives to on-farm parental care of young children. The on- and off-farm work demands of farming parents often compromise their ability to provide adequate supervision of their children on the farm, particularly during periods of intense production activities, creating a demand for alternative child care options. In order for child care options to be of value to farming families, they must be perceived by parents as trustworthy; available when parents need them; and financially feasible. The challenge of creating sufficient child care options for farm families will only be met when communities and business leaders address child care as a matter of community economic well-being as well as child and family well-being. Recommendations are given for engaging community and business leaders, crafting solutions that meet families' preferences and needs, and expanding available data on farm parents' and child care. A description of a model program and a list of recommended resources are also given. PMID- 22490033 TI - The role of child and adolescent development in the occurrence of agricultural injuries: an illustration using tractor-related injuries. AB - Agricultural settings are dangerous, especially for children. This article focuses on child and adolescent development, and how development might influence children's safety in the occurrence of pediatric farm injuries. The authors focus especially on one of the most traumatic causes of pediatric farm injury, those associated with tractor operation. The roles of physical, perceptual, cognitive, and social development are reviewed and discussed, as are relevant sociocultural factors. Following review of developmental risks for child injury in agricultural settings, the authors present a case study of a fatal youth tractor injury and provide illustrations of the child development factors that may have contributed to the death. The authors conclude with a discussion of the implications of developmental aspects of pediatric agricultural injury for behaviorally oriented intervention strategies, including public policy. PMID- 22490034 TI - Partnering strategies for childhood agricultural safety and health. AB - The National Institute for Occupational Safety and Health (NIOSH) has been the lead federal agency of the national Childhood Agricultural Injury Prevention Initiative (CAIPI) since the program's inception in 1996 and in this role, collaborated with numerous partners in childhood agricultural injury prevention activities. This collaboration has likely helped achieve the current reduction in childhood agricultural injury. The paper looks at existing groups with past and current childhood agricultural injury prevention activities for partnering strategies that could contribute to reducing the morbidity and mortality of childhood agricultural injuries. Based upon the review, suggestions are made for future partnering strategies to continue progress in this area. PMID- 22490035 TI - The potential for social media to educate farm families about health and safety for children. AB - Social media has the potential to reach farm families to educate them about health and safety for children. It offers advantages over traditional approaches because of the shorter time between creation and distribution and because of the greater reach and engagement possible. Recommendations are provided for how government agencies and the private sector can learn about and use social media to promote health and safety for children as a supplement to traditional approaches. PMID- 22490036 TI - Using social marketing to address barriers and motivators to agricultural safety and health best practices. AB - Social marketing is an intervention development strategy that pays considerable attention to barriers to and motivators for behavioral change or adoption of recommended behaviors. Barriers are obstacles that prevent individuals from changing or adopting behaviors and are often referred to as the "cons" or "costs" of doing something. Motivators, on the other hand, are factors that encourage individuals to change or adopt behaviors and are often referred to as the "pros," "benefits," or "influencing factors" of doing something. Importantly, social marketing does not target education or knowledge change as an end point; rather, it targets behavior change. Studies across several types of desired behaviors (e.g., smoking cessation, weight control, more exercise, sunscreen use, radon testing) using the Stages of Change model have found systematic relationships between stages of change and pros and cons of changing behavior. A review of literature identifies numerous research and intervention studies that directly reference social marketing in agricultural safety and health, studies that identify reasons why parents allow their children to be exposed to hazardous situations on the farm, and reasons why youth engage in risky behaviors, but only two studies were found that show evidence of systematically researching specific behavioral change motivating factors. The authors offer several suggestions to help address issues relating to social marketing and agricultural safety and health. PMID- 22490037 TI - Culturally competent safety interventions for children in Old Order Anabaptist communities. AB - This commentary describes the challenges of child safety interventions in Old Order Amish and Mennonite communities in North America. It proposes nine culturally sensitive interventions appropriate for these separatist communities. PMID- 22490038 TI - Children's safety on American Indian farms: information and recommendations. AB - It is estimated that 1.2 million youth younger than age 20 live on farms; American Indian children constitute an important but understudied subset of this at-risk group. Despite documented risks of injuries and death among children who live and work on farms and a descending trend in the overall reported fatalities among youth who live and/or work on farms, very little is known about the agriculture-related injury and fatality experience of American Indian youth. Limited data indicate that drowning, motor vehicles, and poisonings are leading causes of unintentional mortality and morbidity for this group, although the attribution to agricultural exposure is not evident. The scant available data indicate a need to look more closely at agricultural work, bystander exposures, and other farm events that put American Indian youth at risk of illness, injury, or death compared to factors more fully reported for majority youth in the agriculture population, in order to guide intervention and prevention programs that are appropriate and acceptable to this vulnerable population. PMID- 22490041 TI - Neuropsychological performance in older insomniacs. AB - The purpose of this study was to examine daytime performance in older adults fulfilling the diagnostic criteria for DSM-IV Insomnia, using a comprehensive battery of neuropsychological tests, and to compare these objective findings with measures of self-reported cognitive functioning. A total of 121 participants (69% women) with a mean age of 64.0 were part of a thorough neuropsychological examination at a University-based neuropsychological clinic in Western Norway. Twenty-five percent of the participants fulfilled the diagnostic criteria for insomnia. In sum, the insomnia patients were not different from the good sleepers on any neuropsychological test measure, and none of the results on the performance measures were associated with the sleep-related daytime complaints. However, the insomniacs did rate their subjective memory performance as significantly worse than the good sleepers, and they also reported more depressive symptoms. We conclude that DSM-IV defined insomnia was not associated with any performance based measure; only with self-reported symptoms. PMID- 22490043 TI - Cytokine concentration in aqueous humour of eyes with exudative age-related macular degeneration. AB - PURPOSE: To measure the concentration of cytokines in the aqueous humour of eyes with exudative age-related macular degeneration (AMD). METHODS: The clinical interventional study included a study group of 18 patients with exudative AMD and a control group of 20 patients undergoing routine cataract surgery. Age did not vary significantly (p = 0.36) between study group (80.8 +/- 6.4 years) and control group (77.0 +/- 9.9 years), nor did gender (p = 0.75). During the interventions, aqueous humour samples were obtained, in which the concentration of cytokines was measured using a solid-phase chemiluminescence immunoassay. Macular thickness was measured by optical coherence tomography (OCT). RESULTS: In the study group as compared to the control group, significantly higher concentrations were measured for epithelial growth factor (EGF) (p = 0.017), human growth factor (HGF) (p= 0.048), intercellular adhesion molecule-1 (ICAM1) (p = 0.028), interleukin 12p40 (IL12p40) (p = 0.009), interleukin 1a2 (IL1a2) (p = 0.01), interleukin 3 (IL3) (p = 0.02), interleukin 6 (IL6) (p = 0.006), interleukin 8 (IL8) (p = 0.02), monocyte chemoattractant protein-1 (MCP-1) (p = 0.048), monokine induced by interferon gamma (MIG) (p = 0.016), matrix metalloproteinase 9 (MMP9) (p = 0.004) and plasminogen activator inhibitor 1 (PAI1) (p = 0.006). Macular thickness was significantly associated with the concentrations of EGF (p = 0.001), HGF (p = 0.02), ICAM1 (p = 0.001), interleukin 12p40 (p = 0.006), IL 1a2 (p = 0.002), MIG (p = 0.001), MMP9 (p < 0.001) and PAI1 (p = 0.01). Interleukin 6 and MCP-1 showed significant associations with the height of retinal pigment epithelium detachment. CONCLUSIONS: Numerous cytokines are associated with the presence and the amount of exudative AMD. PMID- 22490042 TI - Peroxiredoxin III and sulfiredoxin together protect mice from pyrazole-induced oxidative liver injury. AB - AIMS: To define the mechanisms underlying pyrazole-induced oxidative stress and the protective role of peroxiredoxins (Prxs) and sulfiredoxin (Srx) against such stress. RESULTS: Pyrazole increased Srx expression in the liver of mice in a nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent manner and induced Srx translocation from the cytosol to the endoplasmic reticulum (ER) and mitochondria. Pyrazole also induced the expression of CYP2E1, a primary reactive oxygen species (ROS) source for ethanol-induced liver injury, in ER and mitochondria. However, increased CYP2E1 levels only partially accounted for the pyrazole-mediated induction of Srx, prompting the investigation of CYP2E1 independent ROS generation downstream of pyrazole. Indeed, pyrazole increased ER stress, which is known to elevate mitochondrial ROS. In addition, pyrazole up regulated CYP2E1 to a greater extent in mitochondria than in ER. Accordingly, among Prxs I to IV, PrxIII, which is localized to mitochondria, was preferentially hyperoxidized in the liver of pyrazole-treated mice. Pyrazole induced oxidative damage to the liver was greater in PrxIII(-/-) mice than in wild-type mice. Such damage was also increased in Srx(-/-) mice treated with pyrazole, underscoring the role of Srx as the guardian of PrxIII. INNOVATION: The roles of Prxs, Srx, and ER stress have not been previously studied in relation to pyrazole toxicity. CONCLUSION: The concerted action of PrxIII and Srx is important for protection against pyrazole-induced oxidative stress arising from the convergent induction of CYP2E1-derived and ER stress-derived ROS in mitochondria. PMID- 22490044 TI - Interventions for shared decision-making about life support in the intensive care unit: a systematic review. AB - BACKGROUND: Healthcare professionals and families make decisions about the use of life support for patients in the intensive care unit (ICU), including decisions to withhold or withdraw life support at the end-of-life. Best practice guidelines recommend using a shared decision-making (SDM) approach to improve the quality of end-of-life decision-making but do not describe how this should be done in practice. AIMS: To know what elements of SDM had been tested to improve communication between healthcare professionals, patients, and their family about the decision. Trials relevant to our review assessed whether these interventions were more effective than usual care. METHODS: A systematic review of randomized controlled trials of SDM interventions for the decision about using life support, limiting the use of life support, or withdrawing life support for hospitalized patients. We searched databases from inception to January 2011. RESULTS: Of 3,162 publications, four unique trials were conducted between 1992 and 2005. Of four trials, three interventions were evaluated. Two studies of interventions including three of nine elements of SDM did not report improvements in communication. Two studies of the same ethics consultation, which included eight of nine elements of SDM, did not evaluate the benefit to communication. The interventions were not harmful; they decreased family member anxiety and distress, shortened intensive care unit stay, but did not affect patient mortality. IMPLICATIONS FOR RESEARCH AND PRACTICE: Few studies have evaluated interventions to improve communication between healthcare professionals and patients/families when facing the decision about whether or not to use life support in the ICU. Interventions that include essential elements of SDM need to be more thoroughly evaluated in order to determine their effectiveness and health impact and to guide clinical practice. PMID- 22490045 TI - Comparing risk factors of HIV among hijra sex workers in Larkana and other cities of Pakistan: an analytical cross sectional study. AB - BACKGROUND: In 2005, Pakistan was first labeled as a country with concentrated epidemic of Human Immunodeficiency Virus (HIV). This was revealed through second generation surveillance conducted by HIV/AIDS Surveillance Project (HASP). While injection drug users (IDUs) were driving the epidemic, subsequent surveys showed that Hijra (transgender) sex workers (HSWs) were emerging as the second most vulnerable group with an average national prevalence of 6.4%. An exceptionally high prevalence (27.6%) was found in Larkana, which is a small town on the right bank of river Indus near the ruins of Mohenjo-Daro in the province of Sindh. This paper presents the risk factors associated with high prevalence of HIV among HSWs in Larkana as compared to other cities of the country. METHODS: Data were extracted for secondary analysis from 2008 Integrated behavioral and biological survey (IBBS) to compare HSWs living in Larkana with those living in other cities including Karachi and Hyderabad in Sindh; Lahore and Faisalabad in Punjab; and Peshawar in Khyber Pakhtunkhwa provinces. After descriptive analysis, univariate and multivariate analyses were performed to identify risk factors. P value of 0.25 or less was used to include factors in multivariate analysis. RESULTS: We compared 199 HSWs from Larkana with 420 HSWs from other cities. The average age of HSWs in Larkana was 26.42 (+/-5.4) years. Majority were Sindhi speaking (80%), uneducated (68%) and unmarried (97%). In univariate analysis, factors associated with higher prevalence of HIV in Larkana included younger age i.e. 20-24 years (OR: 5.8, CI: 2.809-12.15), being unmarried (OR: 2.4, CI: 1.0-5.7), sex work as the only mode of income (OR: 5.5, CI: 3.70-8.2) and longer duration of being involved in sex work 5-10 years (OR: 3.3, CI: 1.7-6.12). In multivariate logistic regression the HSWs from Larkana were more likely to lack knowledge regarding preventive measures against HIV (OR 11.9, CI: 3.4-41.08) and were more prone to use of alcohol during anal intercourse (OR: 6.3, CI: 2.77-17.797). CONCLUSION: Outreach programs focusing on safer sexual practices and VCT are urgently needed to address the upsurge of HIV among HSWs in Larkana. PMID- 22490046 TI - Plasma ACTH precursors in cats with pituitary-dependent hyperadrenocorticism. AB - BACKGROUND: Diagnosis of pituitary-dependent hyperadrenocorticism (PDH) in cats is challenging because there is no specific diagnostic test. HYPOTHESIS/OBJECTIVE: The determination of plasma ACTH precursor (POMC and pro ACTH) concentration might facilitate the diagnosis of PDH in cats. The aim of the study was to evaluate prospectively the plasma concentrations of ACTH precursors in a small cohort of cats with PDH and to estimate the value of this approach for diagnosis. ANIMALS: Four groups of cats were included: group 1 (cats with PDH), group 2 (cats with diabetes mellitus but not hyperadrenocorticism (HAC)), group 3 (cats with diabetes mellitus and confirmed acromegaly but not HAC), and group 4 (healthy cats). METHODS: PDH diagnosis was based on clinical data, low-dose dexamethasone suppression test (LDDST), and adrenal and pituitary gland computed tomography (CT) scan. For groups 2, 3, and 4, hyperadrenocorticism was excluded by LDDST or urine cortisol:creatinine ratio (UCCR). An immunoluminometric assay was used to determine plasma concentrations of ACTH precursors in the 4 groups of cats. RESULTS: Group 1 contained 9 cats (enlarged pituitary gland in 7/9). Plasma ACTH precursor concentrations ranged from <53 to >1010 pmol/L with 8/9 concentrations >= 229 pmol/L. Groups 2, 3, and 4 included 13, 7, and 13 cats, respectively. Plasma ACTH precursor concentrations ranged from <53 to 96 pmol/L in group 2, <53 to 72 pmol/L in group 3, and <53 to 99 pmol/L in group 4. CONCLUSION AND CLINICAL IMPORTANCE: High plasma concentration of ACTH precursors in cats (>100 pmol/L) is highly suggestive of PDH. PMID- 22490047 TI - Point-of-sale alcohol promotions in the Perth and Sydney metropolitan areas. AB - INTRODUCTION AND AIMS: Point-of-sale (POS) is increasingly being used as a marketing tool for alcohol products, and there is a growing body of evidence suggesting that these materials are positively associated with drinking and contribute to creating a pro-alcohol environment. The purpose of the present study was to document the nature and extent of POS alcohol promotions in bottle shops in two Australian capital cities. DESIGN AND METHODS: A purposive sample of 24 hotel bottle shops and liquor stores was selected across Sydney (New South Wales) and Perth (Western Australia) and audited for the presence and nature of POS marketing. RESULTS: Point-of-sale promotions were found to be ubiquitous, with an average of 33 promotions per outlet. Just over half were classified as 'non-price' promotions (e.g. giveaways and competitions). Spirits were the most commonly promoted type of alcohol. The average number of standard drinks required to participate in the promotions ranged from 12 for ready to drinks to 22 for beer. Alcohol outlets that were part of supermarket chains had a higher number of promotions, more price-based promotions, and required a greater quantity of alcohol to be purchased to participate in the promotion. DISCUSSION AND CONCLUSIONS: The data collected in this study provides a starting point for our understanding of POS promotions in Australia, and poses important questions for future research in this area. PMID- 22490049 TI - Insight into eukaryotic topoisomerase II-inhibiting fused heterocyclic compounds in human cancer cell lines by molecular docking. AB - Etoposide is effective as an anti-tumour drug by inhibiting eukaryotic DNA topoisomerase II via establishing a covalent complex with DNA. Unfortunately, its wide therapeutic application is often hindered by multidrug resistance (MDR), low water solubility and toxicity. In our previous study, new derivatives of benzoxazoles, benzimidazoles and related fused heterocyclic compounds, which exhibited significant eukaryotic DNA topoisomerase II inhibitory activity, were synthesized and exhibited better inhibitory activity compared with the drug etoposide itself. To expose the binding interactions between the eukaryotic topoisomerase II and the active heterocyclic compounds, docking studies were performed, using the software Discovery Studio 2.1, based on the crystal structure of the Topo IIA-bound G-segment DNA (PDB ID: 2RGR). The research was conducted on a selected set of 31 fused heterocyclic compounds with variation in structure and activity. The structural analyses indicate coordinate and hydrogen bonding interactions, van der Waals interactions and hydrophobic interactions between ligands and the protein, as Topo IIA-bound G-segment DNA are responsible for the preference of inhibition and potency. Collectively, the results demonstrate that the compounds 1a, 1c, 3b, 3c, 3e and 4a are significant anti tumour drug candidates that should be further studied. PMID- 22490048 TI - Synthesis, structure-activity relationship, and pharmacological studies of novel melanin-concentrating hormone receptor 1 antagonists 3-aminomethylquinolines: reducing human ether-a-go-go-related gene (hERG) associated liabilities. AB - Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K(+) channel inhibition in a patch-clamp study. To decrease hERG K(+) channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2 (acetylamino)ethyl]amino group as the amine portion eliminated hERG K(+) channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3 [(1R)-1-{[2-(acetylamino)ethyl]amino}ethyl]-8-methylquinolin-7-yl}-4 (cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R) 10h was performed to determine the molecule's absolute configuration. PMID- 22490050 TI - Safety culture and exposure to blood and body fluids among paramedics. PMID- 22490053 TI - Femtomolar Ln(III) affinity in peptide-based ligands containing unnatural chelating amino acids. AB - The incorporation of unnatural chelating amino acids in short peptide sequences leads to lanthanide-binding peptides with a higher stability than sequences built exclusively from natural residues. In particular, the hexadentate peptide P(22), which incorporates two unnatural amino acids Ada(2) with aminodiacetate chelating arms, showed picomolar affinity for Tb(3+). To design peptides with higher denticity, expected to show higher affinity for Ln(3+), we synthesized the novel unnatural amino acid Ed3a(2) which carries an ethylenediamine triacetate side chain and affords a pentadentate coordination site. The synthesis of the derivative Fmoc-Ed3a(2)(tBu)(3)-OH, with appropriate protecting groups for direct use in the solid phase peptide synthesis (Fmoc strategy), is described. The two high denticity peptides P(HD2) (Ac-Trp-Ed3a(2)-Pro-Gly-Ada(2)-Gly-NH(2)) and P(HD5) (Ac-Trp-Ada(2)-Pro-Gly-Ed3a(2)-Gly-NH(2)) led to octadentate Tb(3+) complexes with femtomolar stability in water. The position of the high denticity amino acid Ed3a(2) in the hexapeptide sequence appears to be critical for the control of the metal complex speciation. Whereas P(HD5) promotes the formation of polymetallic species in excess of Ln(3+), P(HD2) forms exclusively the mononuclear complex. The octadentate coordination of Tb(3+) by both P(HD) leads to total dehydration of the metal ion in the mononuclear complexes with long luminescence lifetimes (>2 ms). Hence, we demonstrated that unnatural amino acids carrying polyaminocarboxylate side-chains are interesting building blocks to design high affinity Ln-binding peptides. In particular the novel peptide P(HD2) forms a unique octadentate Tb(3+) complex with femtomolar stability in water and an improvement of the luminescence properties with respect to the trisaquo TbP(22) complex by a factor of 4. PMID- 22490054 TI - Influence of coffee roasting on the incorporation of phenolic compounds into melanoidins and their relationship with antioxidant activity of the brew. AB - In the present study, the influence of coffee roasting on free and melanoidin bound phenolic compounds and their relationship with the brews' antioxidant activity (AA), evaluated by TRAP, TEAC, and TRAP, were investigated. Changes in the relative content of free chlorogenic acids (CGA), free lactones, and melanoidin-bound phenolic acids during roasting indicate that phenolic compounds were incorporated into melanoidins mainly at early stages of the process, being thereafter partly oxidized to dihydrocaffeic acid, and degraded. Although less than 1% of CGA in green coffee was incorporated into melanoidins during roasting, the relative content of melanoidin-bound phenolic acids increased significantly during this process, reaching up to 29% of total phenolic compounds in brews from dark roasted coffees. Regardless of the AA assay used and considering all roasting degrees, the overall contribution of CGA to the AA of the whole brews was higher than that of melanoidin-bound phenolic compounds. It was estimated that the latter compounds contributed to 25-47% of the AA, depending on the assay used. PMID- 22490055 TI - Mitigation of building-related polychlorinated biphenyls in indoor air of a school. AB - BACKGROUND: Sealants and other building materials sold in the U.S. from 1958 - 1971 were commonly manufactured with polychlorinated biphenyls (PCBs) at percent quantities by weight. Volatilization of PCBs from construction materials has been reported to produce PCB levels in indoor air that exceed health protective guideline values. The discovery of PCBs in indoor air of schools can produce numerous complications including disruption of normal operations and potential risks to health. Understanding the dynamics of building-related PCBs in indoor air is needed to identify effective strategies for managing potential exposures and risks. This paper reports on the efficacy of selected engineering controls implemented to mitigate concentrations of PCBs in indoor air. METHODS: Three interventions (ventilation, contact encapsulation, and physical barriers) were evaluated in an elementary school with PCB-containing caulk and elevated PCB concentrations in indoor air. Fluorescent light ballasts did not contain PCBs. Following implementation of the final intervention, measurements obtained over 14 months were used to assess the efficacy of the mitigation methods over time as well as temporal variability of PCBs in indoor air. RESULTS: Controlling for air exchange rates and temperature, the interventions produced statistically significant (p < 0.05) reductions in concentrations of PCBs in indoor air of the school. The mitigation measures remained effective over the course of the entire follow-up period. After all interventions were implemented, PCB levels in indoor air were associated with indoor temperature. In a "broken-stick" regression model with a node at 20 degrees C, temperature explained 79% of the variability of indoor PCB concentrations over time (p < 0.001). CONCLUSIONS: Increasing outdoor air ventilation, encapsulating caulk, and constructing a physical barrier over the encapsulated material were shown to be effective at reducing exposure concentrations of PCBs in indoor air of a school and also preventing direct contact with PCB caulk. In-place management methods such as these avoid the disruption and higher costs of demolition, disposal and reconstruction required when PCB-containing building materials are removed from a school. Because of the influence of temperature on indoor air PCB levels, risk assessment results based on short-term measurements, e.g., a single day or season, may be erroneous and could lead to sub-optimal allocation of resources. PMID- 22490056 TI - Myoelectric manifestations of jaw elevator muscle fatigue and recovery in healthy and TMD subjects. AB - The effects of muscle pain and fatigue on the control of jaw elevator muscles are not well known. Furthermore, the myoelectric manifestations of fatigue and recovery from fatigue in the masticatory muscles are not reported in literature. The main aims of this study were (i) to evaluate the possible use of surface electromyography (sEMG) as an objective measure of fatigue of the jaw elevator muscles, (ii) to compare the myoelectric manifestations of fatigue in the temporalis anterior and masseter muscles bilaterally, (iii) to assess recovery of the investigated muscles after an endurance test and (iv) to compare fatigue and recovery of the jaw elevator muscles in healthy subjects and patients with muscle related temporomandibular disorders (TMD). The study was performed on twenty healthy volunteers and eighteen patients with muscle-related TMD. An intra-oral compressive-force sensor was used to measure the voluntary contraction forces close to the intercuspal position and to provide visual feedback of submaximal forces to the subject. Surface EMG signals were recorded with linear electrode arrays during isometric contractions at 20%, 40%, 60% and 80% of the maximum voluntary contraction force, during an endurance test and during the recovery phase. The results showed that (i) the slope of the mean power spectral frequency (MNF) and the initial average rectified value (ARV) could be used to monitor fatigue of the jaw elevators, (ii) the temporalis anterior and masseter muscle show the same myoelectric manifestations of fatigue and recovery and (iii) the initial values of MNF and ARV were lower in patients with muscle-related TMD. The assessment of myoelectric manifestations of fatigue in the masticatory muscles may assist in the clinical assessment of TMDs. PMID- 22490057 TI - Cirrhosis and mortality risks of biopsy-verified alcoholic pure steatosis and steatohepatitis: a nationwide registry-based study. AB - BACKGROUND: Alcoholic fatty liver disease comprises alcoholic pure steatosis and alcoholic steatohepatitis. These diseases are prevalent, but their prognostic outcome is uncertain, particularly regarding the impact of hepatic inflammation. The paucity of data based on liver biopsy diagnoses contributes to this uncertainty. AIM: To examine the cirrhosis and mortality risks of Danish men and women with biopsy-verified alcoholic pure steatosis or steatohepatitis. METHODS: In this registry-based historical cohort study we combined liver biopsy diagnoses with hospital discharge diagnoses from nationwide healthcare registries to identify all Danish citizens with alcoholic pure steatosis (N = 136) or alcoholic steatohepatitis (N = 58) during 1997-2008. We enrolled a reference cohort of 100 gender- and age-matched persons from the general population for each patient and compared cirrhosis and mortality risks through 2010. RESULTS: The 5-year cirrhosis risks were 6.9% (95% CI: 3.4-12.2%) for patients with alcoholic pure steatosis and 16.0% (95% CI: 7.8-26.8%) for patients with alcoholic steatohepatitis, their 5-year mortality risks were 16.7% (95% CI: 11.3-24.2%) and 25.1% (95% CI: 15.7-38.9%), respectively. Patients with steatohepatitis had a higher liver-related mortality than patients with pure steatosis. In the reference cohort, the 5-year cirrhosis and mortality risks were 0.3% and 4.3%, respectively. CONCLUSIONS: Patients with alcoholic fatty liver disease had markedly increased cirrhosis and mortality risks compared with a matched reference cohort. The cirrhosis risk was more than twice as high for the patients with steatohepatitis than for those with pure steatosis; and was higher for women than for men. PMID- 22490058 TI - Synthesis and characterization of novel fused porphyrinoids based on cyclic carbazole[2]indolones. AB - The carbazole- and indolone-based porphyrinoids 3 and 4 were synthesized by stepwise transition-metal-catalyzed coupling reactions. Palladium metalation of 4 produced 4Pd, which exhibits near-infrared absorption. PMID- 22490059 TI - Urban legends series: Sjogren's syndrome. AB - Sjogren's syndrome (SjS) is one of the most common autoimmune rheumatic diseases, clinically characterized by xerostomia and keratoconjunctivitis sicca. We investigated the following controversial topics: (i) Do we have reliable ways of assessing saliva production? (ii) How important are the quantity and quality of saliva? (iii) Are only anti-SSA/Ro and anti-SSB/La relevant for the diagnosis of SjS? (iv) Are the American-European Consensus criteria (AECC) the best way to diagnose SjS? Results from literature searches suggested the following: (i) Despite the fact that numerous tests are available to assess salivation rates, direct comparisons among them are scarce with little evidence to suggest one best test. (ii) Recent developments highlight the importance of investigating the composition of saliva. However, more research is needed to standardize the methods of analysis and collection and refine the quality of the accumulating data. (iii) In addition to anti-Ro/La autoantibodies, anti alpha-fodrin IgA and anti-MR3 autoantibodies seem to be promising diagnostic markers of SjS, but more studies are warranted to test their sensitivity and specificity. (iv) AECC are classification, not diagnostic criteria. Moreover, recent innovations have not been incorporated into these criteria. Consequently, treatment directed to patients diagnosed using the AECC might exclude a significant proportion of patients with SjS. PMID- 22490060 TI - Bartonella species antibodies and hyperglobulinemia in privately owned cats. AB - BACKGROUND: Bartonella species are zoonotic agents and primary pathogens in cats. Hyperglobulinemia has been associated with bartonellosis in humans and cats. HYPOTHESIS/OBJECTIVES: To evaluate for associations between Bartonella species immunoglobulin G (IgG) antibodies and serum biochemistry panel results in privately owned cats. ANIMALS: 1,477 privately owned cats. METHODS: Residual sera were collected after biochemical evaluation for this prospective, cross-sectional serosurvey. Bartonella species IgG ELISA was performed with a cutoff value of >= 1 : 64. Stepwise logistic regression analysis was performed with the endpoint titer as the outcome variable. The final statistical model included age, albumin, ALP activity, ALT activity, bilirubin, creatinine, glucose, and globulin as covariates. Serum protein electrophoresis was performed with serum from 50 cats with and without antibodies to Bartonella species and hyperglobulinemia. Sera from cats seropositive to Bartonella species and with hyperglobulinemia were assessed for evidence of exposure to other infectious agents associated with hyperglobulinemia. RESULTS: Risk of seropositivity to Bartonella species was positively associated with the natural log of globulin concentration (OR = 11.90, 95% CI 6.15-23.02, P < .0001), and inversely associated with the natural log of glucose concentration (OR = 0.66, 95% CI 0.50-0.87, P = .004). Another explanation for hyperglobulinemia was not identified for most cats with Bartonella species antibodies. Hyperglobulinemia was primarily caused by polyclonal gammopathy in cats that were seronegative and seropositive for Bartonella species. CONCLUSIONS AND CLINICAL IMPORTANCE: Hyperglobulinemia was significantly associated with seropositivity to Bartonella species. Testing for bartonellosis is warranted in cats with unexplained hyperglobulinemia and clinical or laboratory findings suggestive of bartonellosis. PMID- 22490061 TI - European ST80 community-associated methicillin-resistant Staphylococcus aureus orbital cellulitis in a neonate. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus is a serious cause of morbidity and mortality in hospital environment, but also, lately, in the community. This case report is, to our knowledge, the first detailed description of a community-associated methicillin-resistant S. aureus ST80 orbital cellulitis in a previously healthy neonate. Possible predisposing factors of microbial acquisition and treatment selection are also discussed. CASE PRESENTATION: A 28 day-old Caucasian boy was referred to our hospital with the diagnosis of right orbital cellulitis. His symptoms included right eye proptosis, periocular edema and redness. Empirical therapy of intravenous daptomycin, rifampin and ceftriaxone was initiated. The culture of pus yielded a methicillin-resistant S. aureus isolate and the molecular analysis revealed that it was a Panton-Valentine leukocidine-positive ST80 strain. The combination antimicrobial therapy was continued for 42 days and the infection was successfully controlled. CONCLUSIONS: Clinicians should be aware that young infants, even without any predisposing condition, are susceptible to orbital cellulitis caused by community-associated methicillin-resistant S. aureus. Prompt initiation of the appropriate empirical therapy, according to the local epidemiology, should successfully address the infection, preventing ocular and systemic complications. PMID- 22490062 TI - The pattern and predictors of mortality of HIV/AIDS patients with neurologic manifestation in Ethiopia: a retrospective study. AB - BACKGROUND: Even though the prevalence of HIV infection among the adult population in Ethiopia was estimated to be 2.2% in 2008, the studies on the pattern of neurological manifestations are rare. The aim of this retrospective study was to assess the pattern and predictors of mortality of HIV/AIDS patients with neurologic manifestations. METHODS: Medical records of 347 patients (age >=13 years) admitted to Tikur Anbesa Hospital from September 2002 to August 2009 were reviewed and demographic and clinical data were collected. RESULTS: Data from 347 patients were analysed. The mean age was 34.6 years. The diagnosis of HIV was made before current admission in 33.7% and 15.6% were on antiretroviral therapy (ART). Causes of neurological manifestation were: cerebral toxoplasmosis (36.6%), tuberculous meningitis (22.5%), cryptococcal meningitis (22.2%) and bacterial meningitis (6.9%). HIV-encephalopathy, primary central nervous system (CNS) lymphoma and progressive multifocal leukoencephalopathy were rare in our patients. CD4 count was done in 64.6% and 89.7% had count below 200/mm3[mean = 95.8, median = 57] and 95.7% were stage IV. Neuroimaging was done in 38% and 56.8% had mass lesion. The overall mortality was 45% and the case-fatality rates were: tuberculous meningitis (53.8%), cryptococcal meningitis (48.1%), cerebral toxoplasmosiss (44.1%) and bacterial meningitis (33.3%). Change in sensorium and seizure were predictors of mortality. CONCLUSIONS: CNS opportunistic infections were the major causes of neurological manifestations of HIV/AIDS and were associated with high mortality and morbidity. Almost all patients had advanced HIV disease at presentation. Early diagnosis of HIV, prophylaxis and treatment of opportunistic infections, timely ART, and improving laboratory services are recommended. Mortality was related to change in sensorium and seizure. PMID- 22490063 TI - A cross-sectional study of US rural adults' consumption of fruits and vegetables: do they consume at least five servings daily? AB - BACKGROUND: Rural residents are increasingly identified as being at greater risk for health disparities. These inequities may be related to health behaviors such as adequate fruits and vegetable consumption. There is little national-level population-based research about the prevalence of fruit and vegetable consumption by US rural population adults. The objective of this study was to examine the prevalence differences between US rural and non-rural adults in consuming at least five daily servings of combined fruits and vegetables. METHODS: Cross sectional analysis of weighted 2009 Behavioral Risk Factor Surveillance Survey (BRFSS) data using bivariate and multivariate techniques. 52,259,789 US adults were identified as consuming at least five daily servings of fruits and vegetables of which 8,983,840 were identified as living in rural locales. RESULTS: Bivariate analysis revealed that in comparison to non-rural US adults, rural adults were less likely to consume five or more daily servings of fruits and vegetables (OR=1.161, 95% CI 1.160-1.162). Logistic regression analysis revealed that US rural adults consuming at least five daily servings of fruits and vegetables were more likely to be female, non-Caucasian, married or living with a partner, living in a household without children, living in a household whose annual income was > $35,000, and getting at least moderate physical activity. They were also more likely to have a BMI of <30, have a personal physician, have had a routine medical exam in the past 12 months, self-defined their health as good to excellent and to have deferred medical care because of cost. When comparing the prevalence differences between rural and non-rural US adults within a state, 37 States had a lower prevalence of rural adults consuming at least five daily servings of fruits and vegetables and 11 States a higher prevalence of the same. CONCLUSIONS: This enhanced understanding of fruit and vegetable consumption should prove useful to those seeking to lessen the disparity or inequity between rural and non-rural adults. Additionally, those responsible for health-related planning could benefit from the knowledge of how their state ranks in comparison to others vis-a-vis the consumption of fruits and vegetables by rural adults---a population increasingly being identified as one at risk for health disparities. PMID- 22490064 TI - Do harsh and positive parenting predict parent reports of deceitful-callous behavior in early childhood? AB - BACKGROUND: The relationship between parenting and the development of antisocial behavior in children is well established. However, evidence for associations between dimensions of parenting and callous-unemotional (CU) traits is mixed. As CU traits appear critical to understanding a subgroup of youth with antisocial behavior, more research addressing the link between early parenting and CU traits is needed. METHODS: The current study investigated longitudinal predictions between measures of harsh and positive parenting, and early CU behavior. Data from mother-child dyads (N = 731; 49% female) were collected from a multi-ethnic, high-risk sample with young children, and included self-reported and multi-method observed parenting. CU behavior was assessed using a previously validated measure of deceitful-callous behavior (Hyde et al., 2011). RESULTS: Results suggest that dimensions of harsh parenting, but not positive parenting, contribute to the development of child deceitful-callous behavior. Nevertheless, deceitful-callous behavior showed strong stability over time and the effects of harsh parenting, especially observed harshness, were modest. CONCLUSIONS: The current findings have implications for developmental psychopathology and early interventions for antisocial behavior. The results also raise a number of issues about measuring emerging CU behavior in very young children, including the interrelation between parent perceptions and reports of child behavior, parent reactions, and the subsequent development of severe antisocial behavior. PMID- 22490065 TI - Detection technique for artificially illuminated objects in the outer solar system and beyond. AB - Existing and planned optical telescopes and surveys can detect artificially illuminated objects, comparable in total brightness to a major terrestrial city, at the outskirts of the Solar System. Orbital parameters of Kuiper belt objects (KBOs) are routinely measured to exquisite precisions of<10(-3). Here, we propose to measure the variation of the observed flux F from such objects as a function of their changing orbital distances D. Sunlight-illuminated objects will show a logarithmic slope alpha = (d log F/d log D)=-4, whereas artificially illuminated objects should exhibit alpha=-2. The proposed Large Synoptic Survey Telescope (LSST) and other planned surveys will provide superb data and allow measurement of alpha for thousands of KBOs. If objects with alpha=-2 are found, follow-up observations could measure their spectra to determine whether they are illuminated by artificial lighting. The search can be extended beyond the Solar System with future generations of telescopes on the ground and in space that would have the capacity to detect phase modulation due to very strong artificial illumination on the nightside of planets as they orbit their parent stars. PMID- 22490066 TI - Lack of individualized perspective: a qualitative study of diabetes care for immigrants in Sweden. AB - This study describes the care provided by a diabetes nurse specialist, and the care needs expressed by people with type 2 diabetes mellitus and an immigrant background. Clinical encounters between a diabetes nurse specialist and 10 people diagnosed with type 2 diabetes mellitus were observed and analyzed by means of qualitative content analysis. One theme, "the diabetes nurse specialist as the conductor of the visit", and four categories emerged from the findings, illustrating the power imbalance between the patients and the diabetes nurse specialist, as well as the lack of an individual perspective. Shifting from a medical perspective to one of openness towards the people's experiences provides a possibility for caregivers to empower patients suffering from type 2 diabetes mellitus. The medical perspective seemed to steer the visit towards curative activities. Thus, technique-centered care should be developed by including individualized care. PMID- 22490067 TI - Optimization of (2,3-dihydro-1-benzofuran-3-yl)acetic acids: discovery of a non free fatty acid-like, highly bioavailable G protein-coupled receptor 40/free fatty acid receptor 1 agonist as a glucose-dependent insulinotropic agent. AB - G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified glucose-stimulated insulin secretion in pancreatic beta-cells. We previously identified (2,3-dihydro-1 benzofuran-3-yl)acetic acid derivative 2 as a candidate, but it had relatively high lipophilicity. Adding a polar functional group on 2 yielded several compounds with lower lipophilicity and little effect on caspase-3/7 activity at 30 MUM (a marker of toxicity in human HepG2 hepatocytes). Three optimized compounds showed promising pharmacokinetic profiles with good in vivo effects. Of these, compound 16 had the lowest lipophilicity. Metabolic analysis of 16 showed a long-acting PK profile due to high resistance to beta-oxidation. Oral administration of 16 significantly reduced plasma glucose excursion and increased insulin secretion during an OGTT in type 2 diabetic rats. Compound 16 (TAK-875) is being evaluated in human clinical trials for the treatment of type 2 diabetes. PMID- 22490068 TI - Poor compliance with standard precautions against infections during minor gynaecological procedures. AB - BACKGROUND: Splash injuries occurring during minor surgical procedures are associated with a significant infective risk to the operator. It is a common misconception that minor operations carry low risks. AIM: To determine the prevalence of the practice of Standard Precautions by medical staff in the obstetric and gynaecology (O & G) units of two hospitals in New Zealand, and to assess self-observed splash injury rates. METHOD: A cross-sectional survey of all doctors working in the O & G units of two public hospitals servicing a population of 435 000. A self-administered questionnaire was provided to 43 doctors with questions related to the use of Standard Precautions, perceived likelihood of infection from a splash and splash injuries sustained during procedures. RESULTS: The response rate was 76.6% (n = 33/43). Of the respondents, only 30.3% (n = 10) used Standard Precautions during minor procedures. Sixty-four per cent (n = 21) routinely used goggles/visor for eye protection. Forty-five per cent (n = 15) thought they were likely to get an infection from a splash, and 55% (n = 18) of clinicians had experienced a splash injury. Of the minor procedures during which splash injuries had occurred, repair of episiotomy 45.8% (n = 11) was the commonest. CONCLUSIONS: This survey shows poor compliance with guidelines for Standard Precautions to protect from infection despite self-reported rates of splash injury being high at 55%. Effective interventions are needed to increase compliance and prevent infection. PMID- 22490069 TI - AGHE Distinguished Teaching Lecture. Foreword. PMID- 22490070 TI - Engaged teaching for engaged learning: sharing your passion for gerontology and geriatrics. AB - Gerontologists face a unique set of obstacles in attracting newcomers to the field. Despite demographic trends favorable to a wide range of employment opportunities and job security, aging is rarely top of mind for many students when it comes to career choices. For most gerontologists, aging is our passion. How do we share that passion with others who have yet to discover its interdisciplinary opportunities, or who may be held at bay by negative stereotypes of aging and older persons? This article explores various approaches to enhance engaged teaching and engaged learning that can help personalize and contextualize the field so that educators and students at all levels and disciplines can find their passion for gerontology and geriatrics. PMID- 22490071 TI - Health care workforce development in rural america: when geriatrics expertise is 100 miles away. AB - The Geriatric Scholar Program (GSP) is a Department of Veterans Affairs' (VA) workforce development program to infuse geriatrics competencies in primary care. This multimodal educational program is targeted to primary care providers and ancillary staff who work in VA's rural clinics. GSP consists of didactic education and training in geriatrics and gerontology and in quality improvement (QI) and support to implement a local QI project; in addition, elective options include webinars, audio conferences, clinical practica, and mentoring. The program is effective in improving core competencies in geriatrics and in improving clinical care for older Veterans who receive health care in rural clinics. PMID- 22490072 TI - A community-based approach for integrating geriatrics and gerontology into undergraduate medical education. AB - Medical school accreditation requirements require educational opportunities in geriatrics. Twenty-six minimum graduating competencies in geriatrics have recently been identified for medical students. The authors describe how these competencies are being integrated into a new medical curriculum through coursework and community-based experiences. This approach is intended to expose students to older adults from diverse communities and adequately prepare students to address the complex and individual needs of these patients. Initial results indicate proficiency in the minimum geriatric competencies covered. The growth and diversity of the older adult population makes it important to integrate and evaluate geriatrics education in undergraduate medical education. PMID- 22490073 TI - Tomorrow belongs to those who prepare for it today: gerontology doctoral students career aspirations. AB - This research seeks to examine the characteristics and goals of students enrolled in gerontology doctoral education. The authors seek to identify the unique characteristics of scholars enrolled in the interdisciplinary study of aging and elicit discussion on the ways in which these scholars will contribute to the growth and development of the field. This article describes results from an ongoing longitudinal study examining the relationship between gerontology doctoral education and overarching frameworks that define and advance the field. Four cohorts of first-year doctoral students were invited to participate in an online survey. Results reveal three distinct typologies of gerontology doctoral students: traditional academics, applied specialists, and general educators. Traditional academics are seeking postdoc and tenure-track faculty positions upon completion of the doctoral degree whereas the applied specialists intend to pursue careers in allied health fields or within a government setting. Educators plan to seek academic positions within teaching intensive or balanced teaching research institutions. Gerontology doctoral students are being trained to serve as leaders in practice and research by linking and integrating multiple perspectives. Doctoral education will continue to facilitate applications of research to practice, identify the meaning of being a "gerontologist," and to advance the field of gerontology. However, students are entering with diverse academic and professional backgrounds and have varied career goals. PMID- 22490074 TI - How are gerontology doctoral graduates viewed in the academic job market? Findings from an exploratory study. AB - Although doctorally trained gerontologists have unique types of expertise as a result of their interdisciplinary training, research exploring perceptions of their hirability in faculty positions is lacking. This exploratory study examined the perceptions of administrators and faculty at institutions identified as having a doctoral program in gerontology or a doctoral program in another aging related area. A short, semistructured 27 question survey was disseminated online. Twenty-five (N = 25) deans, associate deans, or other faculty participated in this study. Results indicate varying views of the attractiveness of hiring doctorally trained gerontologists, who or what is a gerontologist, and the value of having a doctorally trained gerontologist as a faculty member. PMID- 22490075 TI - Globalization of gerontology education: current practices and perceptions for graduate gerontology education in the United States. AB - The purpose of this study is to document current practices and understandings about globalization of gerontology education in the United States. Better understanding of aging requires international perspectives in global communities. However, little is known about how globalization of gerontology education is practiced in U.S. graduate-level degree programs. The authors conducted qualitative interviews with representatives of the Association for Gerontology in Higher Education, the major national organization supporting higher education in gerontology, graduate program directors, and students. Although all respondents expressed their interest in globalizing gerontology education, actual practices are diverse. The authors discuss suggested conceptualization and strategies for globalizing gerontology education. PMID- 22490076 TI - The current state and developments in higher education in gerontology in the nordic countries. AB - The growing size of the older population challenges not only researchers but also higher education in gerontology. On the basis of an online survey the authors describe the situation of Nordic higher education in gerontology in 2008 and 2009 and also give some good examples of Nordic- and European-level collaboration. The survey results showed that gerontological education was given in every Nordic country, in 31 universities and 60 other higher education institutions. Although separate aging-related courses and modules were relatively numerous, programs for majors were relatively few. Networking in the Nordic region offers a good example on how to further develop higher education in gerontology. Emphasis should be put on strengthening networking on the European and trans-Atlantic levels. PMID- 22490077 TI - Decorin expression, straw-like structure, and differentiation of human costal cartilage. AB - Costal cartilage is much understudied compared with the load-bearing cartilages. Abnormally grown costal cartilages are associated with the inherited chest wall deformities pectus excavatum and pectus carinatum resulting in sunken and pigeon chests, respectively. A lack of understanding of the ultrastructural and molecular biology of costal cartilage is a major confounder in predicting causes and outcomes of these disorders. This study analyzed the structure of marginal human costal cartilage (ribs 6-10) through scanning electron and atomic force microscopes and identified the presence of straw-like structures running longitudinally. We also demonstrated that chondrocytes tend to occur singly or as doublets and that centrally located cells produce high levels of aggrecan compared with more peripherally located cells measured using immunohistochemistry. Gene expression from mRNA extracted from cartilage showed high levels of decorin expression, likely associated with the large, complex tubular structures running through this cartilage type. COL2A1, ACAN, and TIMP1 also showed higher levels of expression compared with ACTB. Analysis of gene expression ratios demonstrate that costal cartilage is under differentiated compared with published ratios for articular cartilage, likely due to the vastly different biomechanical environments of each cartilage type. Further studies need to establish whether findings described here from the costal margins are significantly different than the cartilage of the "true ribs" and how these values change with age. PMID- 22490078 TI - Stereocontrol in a combined allylic azide rearrangement and intramolecular Schmidt reaction. AB - Pre-equilibration of an interconverting set of isomeric allylic azides is coupled with an intramolecular Schmidt reaction to afford substituted lactams stereoselectively. The effect of substitution and a preliminary mechanistic study are reported. The synthetic potential of this method is demonstrated in the context of an enantioselective synthesis of an advanced intermediate leading toward pinnaic acid. PMID- 22490079 TI - Incidence of Charles Bonnet syndrome after intravitreal bevacizumab injection in neovascular age-related macular degeneration. PMID- 22490080 TI - Prevalence of human papillomavirus infection in a Kashmiri ethnic female population. AB - Human papillomavirus (HPV) infection is estimated to be the most common sexually transmitted infection and is one of the causal factors in cervical cancer. Understanding the epidemiology of this infection is an important step toward developing strategies for its prevention. Cervical samples from 210 healthy women with normal and abnormal cytomorphology were studied for the detection of HPV DNA by polymerase chain reaction (PCR), utilizing the two most commonly used consensus primer sets. The primers; MY09/MY11 and GP5+/GP6+ located within the L1 region of HPV genome, amplified a broad spectrum of HPV genotypes in a single reaction. The PCR amplification of HPV genomes is a sensitive method that is used for the detection of cervicovaginal HPV. With the aim of identifying the HPV types, samples were also subjected to PCR using specific primers for HPV types 16 and 18. In addition, basic demographic information, sociodemographic characteristics, and sexual behavior were recorded. HPV was detected in 13.8% of the study population aged 18 to 57 years using PCR. HPV16 (6.6%) was more commonly detected than HPV18 (3.8%). The highest prevalence of HPV infection was seen in women below 27 years old, and then, a new increase was seen higher than the age of 48. In conclusion, our study demonstrated that younger age at marriage, economic status, parity, and dwelling are the major risk factors determining HPV infection. PMID- 22490081 TI - The balancing act: experts' opinions about the relative resourcing of tobacco control efforts for the general population versus disadvantaged populations. AB - INTRODUCTION AND AIMS: Despite the persistent socioeconomic gradient associated with smoking, little is known about how to 'close the gap'. There is a debate regarding the implications of directing resources away from general population efforts towards disadvantaged groups. The study explored views of those with expertise in tobacco control about the appropriate balance of tobacco control resourcing between the general population and disadvantaged groups. DESIGN AND METHODS: A Web-based survey of 192 respondents (response rate 65%) working in tobacco control in Australia and New Zealand was completed. Respondents were sampled from the Australian and New Zealand Tobacco Control Contact List and a literature search. Respondents were asked to allocate a hypothetical budget for: (a) anti-tobacco mass media campaigns; and (b) tobacco control research. RESULTS: The vast majority (93%) of respondents believed that some tobacco control resources should be specifically directed towards disadvantaged groups. Respondents believed up to half of mass media resources should be directed towards disadvantaged groups. In the case of tobacco control research, the median allocation to the general population was approximately one-third of a hypothetical research budget. DISCUSSION AND CONCLUSIONS: It appears there is a desire among the Australian and New Zealand tobacco control community for substantial effort to be directed towards disadvantaged groups. It is important to develop an evidence base to ensure an efficient and equitable approach to balancing the potentially competing demands of general population versus disadvantaged group activities in relation to tobacco control. PMID- 22490083 TI - Effect of online journal club on evidence-based practice knowledge, intent, and utilization in school nurses. AB - BACKGROUND: In the United States, an estimated 73,697 school nurses provide leadership in the provision of health care in the school setting. School nurses face challenges, such as providing quality health care in an educational setting and working in isolation. Journal clubs are one strategy to help incorporate evidence into practice. AIM: An online school nurse journal club for school nurses was conducted as a pilot project to determine feasibility for replication and potential expansion. OBJECTIVES: To determine if an online journal club changed knowledge of, and intent to use evidence. To determine if school nurses used the evidence in practice and felt more connected to colleagues. METHODS: Three synchronous online journal club sessions were conducted for school nurses across three states. Thirty-five registered nurses enrolled and participation varied by session. Self-report surveys were used. RESULTS: Participants increased their knowledge of evidence-based practice and shared evidence with stakeholders. Participants intended to and did use evidence in practice, including prioritizing based on evidence. Collegial connections increased. One of the most successful features was connecting authors of the articles directly to participants. CONCLUSIONS: A school nurse online journal club is one strategy to bring evidence to practitioners. Technology exists for nurses experiencing practice isolation to connect through online avenues. Nursing researchers, educators, and administrators seeking to disseminate research to school nurses or other clinical specialties could replicate or expand this project. Expanding online journal clubs would allow busy clinicians to connect with colleagues and researchers to integrate evidence into practice. PMID- 22490085 TI - Absence of oxysterol-like side effects in human monocytic cells treated with phytosterols and oxyphytosterols. AB - Oxysterols, found in some commonly consumed foods, can induce a wide range of cytotoxic effects, which have been extensively studied. On the other hand, the side effects of phytosterols and oxyphytosterols are less well-known. Over the past few years, different types of foods have been enriched with phytosterols on the basis of the properties of these compounds that reduce circulating cholesterol levels in certain experimental conditions. It is therefore important to gain better knowledge of the risks and benefits of this type of diet. In this study, conducted in human monocytic U937 cells, the ability of phytosterols (sitosterol, campesterol) and oxyphytosterols (7beta-hydroxysitosterol, 7 ketositosterol) to induce cell death, polar lipid accumulation, and pro inflammatory cytokine (MCP-1; IL-8) secretion was determined and compared to that of oxysterols (7-ketocholesterol, 7beta-hydroxycholesterol). Phytosterols and oxyphytosterols had no significant effects on the parameters studied; only 7beta hydroxysitosterol slightly increased cell death, whereas at the concentration used (20 MUg/mL), strong cytotoxic effects were observed with the oxysterols. With sitosterol, campesterol, and 7-ketositosterol, IL-8 secretion was decreased, and with campesterol the intracellular polar lipid level was reduced. The data show that phytosterols and oxyphytosterols have no oxysterol-like side effects, and they rather argue in favor of phytosterols' beneficial effects. PMID- 22490084 TI - Design of high-performance parallelized gene predictors in MATLAB. AB - BACKGROUND: This paper proposes a method of implementing parallel gene prediction algorithms in MATLAB. The proposed designs are based on either Goertzel's algorithm or on FFTs and have been implemented using varying amounts of parallelism on a central processing unit (CPU) and on a graphics processing unit (GPU). FINDINGS: Results show that an implementation using a straightforward approach can require over 4.5 h to process 15 million base pairs (bps) whereas a properly designed one could perform the same task in less than five minutes. In the best case, a GPU implementation can yield these results in 57 s. CONCLUSIONS: The present work shows how parallelism can be used in MATLAB for gene prediction in very large DNA sequences to produce results that are over 270 times faster than a conventional approach. This is significant as MATLAB is typically overlooked due to its apparent slow processing time even though it offers a convenient environment for bioinformatics. From a practical standpoint, this work proposes two strategies for accelerating genome data processing which rely on different parallelization mechanisms. Using a CPU, the work shows that direct access to the MEX function increases execution speed and that the PARFOR construct should be used in order to take full advantage of the parallelizable Goertzel implementation. When the target is a GPU, the work shows that data needs to be segmented into manageable sizes within the GFOR construct before processing in order to minimize execution time. PMID- 22490086 TI - Neuron damage and protection. Introduction. PMID- 22490088 TI - Do preceptors with more rating experience provide more reliable assessments of medical student performance? AB - BACKGROUND: Although the existing psychometric literature provides guidance on the best method for acquiring a reliable clinical evaluation form (CEF)-based score, it also shows that a single CEF rating has very low reliability. PURPOSE: This study examines whether experience with rating students might act as a form of rater training and hence improve the quality of CEF ratings. METHODS: Preceptors were divided into two groups based on rater experience. The univariate and multivariate G study designs used were simple rater (r)-nested-within-person (p) [r : p and r(?) : p(*)] models, and in the univariate analysis was applied separately to CEFs completed by high and low experienced raters. RESULTS: The high experienced rater group yielded a substantially higher observed reliability in both the univariate and multivariate analyses. CONCLUSIONS: These results support the hypothesis that high experienced raters produce more reliable ratings of student performance and suggest methods for improving CEF ratings. PMID- 22490087 TI - Exposures to fine particulate air pollution and respiratory outcomes in adults using two national datasets: a cross-sectional study. AB - BACKGROUND: Relationships between chronic exposures to air pollution and respiratory health outcomes have yet to be clearly articulated for adults. Recent data from nationally representative surveys suggest increasing disparity by race/ethnicity regarding asthma-related morbidity and mortality. The objectives of this study are to evaluate the relationship between annual average ambient fine particulate matter (PM2.5) concentrations and respiratory outcomes for adults using modeled air pollution and health outcome data and to examine PM2.5 sensitivity across race/ethnicity. METHODS: Respondents from the 2002-2005 National Health Interview Survey (NHIS) were linked to annual kriged PM2.5 data from the USEPA AirData system. Logistic regression was employed to investigate increases in ambient PM2.5 concentrations and self-reported prevalence of respiratory outcomes including asthma, sinusitis and chronic bronchitis. Models included health, behavioral, demographic and resource-related covariates. Stratified analyses were conducted by race/ethnicity. RESULTS: Of nearly 110,000 adult respondents, approximately 8,000 and 4,000 reported current asthma and recent attacks, respectively. Overall, odds ratios (OR) for current asthma (0.97 (95% Confidence Interval: 0.87-1.07)) and recent attacks (0.90 (0.78-1.03)) did not suggest an association with a 10 MUg/m3 increase in PM2.5. Stratified analyses revealed significant associations for non-Hispanic blacks [OR = 1.73 (1.17-2.56) for current asthma and OR = 1.76 (1.07-2.91) for recent attacks] but not for Hispanics and non-Hispanic whites. Significant associations were observed overall (1.18 (1.08-1.30)) and in non-Hispanic whites (1.31 (1.18-1.46)) for sinusitis, but not for chronic bronchitis. CONCLUSIONS: Non-Hispanic blacks may be at increased sensitivity of asthma outcomes from PM2.5 exposure. Increased chronic PM2.5 exposures in adults may contribute to population sinusitis burdens. PMID- 22490089 TI - The effects of electronic health record implementation on medical student educators. AB - BACKGROUND: Electronic heath records (EHRs) are being rapidly adopted. Little attention has been paid to the effects of EHR implementation on teaching. PURPOSE: The goal was to determine the effect of EHR implementation on medical student educators and to characterize features that might influence their responses. METHODS: A survey of all clinical faculty at Oregon Health & Science University was taken. The authors inquired about the effect of EHR implementation on enthusiasm for teaching and characterized factors that might contribute to responses. RESULTS: Nearly half of the faculty reported decreased enthusiasm for teaching following EHR implementation (48.2%). Most (65.1%) reported that the EHR distracted from teaching, and few saw its advantages. Most reported that EHR implementation led them to teach less (62.3%); the most enthusiastic teachers were most affected. CONCLUSIONS: EHR implementation in an academic medical center has substantial effects on educators. Further work is needed to determine how to train medical educators and modify the EHR to best support teaching. PMID- 22490090 TI - Trainees' perceptions of practitioner competence during patient transfer. AB - BACKGROUND: Technical and communicative skills are both important features for one's perception of practitioner competence. PURPOSE: This research examines how trainees' perceptions of practitioner competence change as they view health care practitioners who vary in their technical and communicative skill proficiencies. METHODS: Occupational therapy students watched standardized encounters of a practitioner performing a patient transfer in combinations of low and high technical and communicative proficiency and then reported their perceptions of practitioner competence. RESULTS: The reports indicate that technical and communicative skills have independently identifiable impacts on the perceptions of practitioner competency, but technical proficiency has a special impact on the students' perceptions of practitioner communicative competence. CONCLUSIONS: The results are discussed with respect to the way in which students may evaluate their own competence on the basis of either technical or communicative skill. The issue of how this may lead trainees to dedicate their independent learning efforts to an incomplete set of features needed for the development of practitioner competency is raised. PMID- 22490091 TI - Medical student attitudes toward patients in diverse care settings: the impact of a patient evaluation course. AB - BACKGROUND: First-year medical students typically have limited exposure to patients in diverse care settings, such as rehabilitation facilities and nursing homes. PURPOSE: It is unknown whether students bring predetermined attitudes toward these patients, or whether attitudes are influenced by early exposure. We studied this in a new course that provides opportunities for students to interact with patients of various ages and disabilities. METHODS: We conducted surveys of 1st-year medical students at the University of Rochester in the year prior to the new course and during its initial year. We used factor analysis to derive underlying dimensions of students' responses. We also investigated the impact that the course had on their perceptions. RESULTS: In both years, we found that students conceptualize patient care along 2 affective dimensions (comfort and pleasure) and 2 attitudinal dimensions (bias and pessimism), rather than by type of disability. CONCLUSIONS: This 10-week course improved their affect toward these patient groups but had little effect on their general attitudes toward the value of caring for them. PMID- 22490092 TI - Use of mannequin-based simulation to decrease student anxiety prior to interacting with male teaching associates. AB - BACKGROUND: Previous studies have compared the usefulness of teaching associates versus mannequin trainers for learning physical exam skills. Little work has been done to assess the usefulness of mannequin trainers prior to students' interaction with teaching associates. PURPOSE: We studied the effects of mannequin-based simulators on student comfort levels toward learning the male genitourinary examination. METHODS: First-year medical students (N = 346) were surveyed before and after a mannequin-based curriculum to assess their comfort levels toward learning the male genitourinary examination. RESULTS: The mannequin based curriculum significantly increased (p < .001) student comfort levels toward the male genitourinary exam. However, the pre-post improvements were small, and on average students only progressed from being "very uncomfortable" to "somewhat comfortable." The intimate nature of the examination was the top cause of anxiety toward learning the male genitourinary exam. Students were least comfortable with the digital rectal examination at the beginning of class. CONCLUSIONS: We suggest that mannequin-based simulators be used prior to students' experience with male teaching associates when learning the male genitourinary exam. PMID- 22490093 TI - Gifted students' academic performance in medical school: a study of Olympiad winners. AB - BACKGROUND: The present study examines the performance of academically talented students (i.e., those who received awards in Olympiads, the international competitions for gifted students in science or mathematics) in medical school. PURPOSE: The goal is to investigate whether students exceptionally talented in science and mathematics excel in medical school. METHODS: A retrospective analysis of 13 cohorts of medical students (N = 475) was conducted to compare learning outcomes of academically talented students (ATS) with their peers in terms of their grade point averages (GPAs) and national licensing exam (KMLE) scores. RESULTS: ATS outperformed their peers in total GPAs (p < .001); yet there was a statistical trend of gradually diminishing performance gap between the groups as they progressed into the later years of the program. KMLE scores were comparable between the groups (p = .89). In addition, there was no significant difference in GPAs and KLME scores among ATS regardless of their areas of excellence. CONCLUSIONS: Academic merit alone is not a strong predictor of success in medical school, even among those with exceptional talent. Better understanding of nonacademic factors associated with medical school performance is warranted to improve our selection processes and to better help academically talented students succeed in medical school. PMID- 22490094 TI - The cognitive behavior survey: testing for factorial validity and time invariance across two years of medical school. AB - BACKGROUND: The Cognitive Behavior Survey (CBS) assesses learner behavior in healthcare-related fields. PURPOSE: The study aims were to evaluate the factorial validity of the CBS, which purports to measure three dimensions of learner behavior--conceptualization, reflection, and memorization--and propose and test an alternative model including its time invariance. METHODS: The CBS was administered to 3 cohorts of medical students upon matriculation and at the end of their 1st and 2nd year. RESULTS: Confirmatory factor analysis (CFA) did not support the original CBS model. Exploratory factor analysis (EFA) with an independent sample provided a new model. Retesting the EFA model using CFA with the original sample yielded a model with improved fit and time invariance. CONCLUSIONS: This study provides evidence for the original CBS 3-factor structure but requires alternative scoring for a time-invariant model. PMID- 22490095 TI - Teaching on three-dimensional presentation does not improve the understanding of according CT images: a randomized controlled study. AB - BACKGROUND: Randomized studies have already described the advantages of three dimensional (3D) presentations in understanding complex spatial interactions. However, the clinical setting is mainly characterized by presentations of two dimensional (2D) images. PURPOSE: This study evaluates whether training on 3D presentation enhances the understanding of 2D images. METHODS: A teaching module was used consisting of one learning part and two examination parts (EP). Students were randomized to training with either 2D or 3D. RESULTS: This study of 73 students showed that training on 3D presentations did not improve the ability to interpret 2D images. Further, the results revealed no significant differences between the results of Week 1 (2D: M = 6.5, SD = 1.8; 3D: M = 6.6, SD = 1.4; p > .95) and Week 2 (2D: M = 6.1, SD = 1.9; 3D: M = 6.0, SD = 1.4; p > .7). There were no significant gender differences. However, students randomized to 2D who completed only the first EP performed significantly worse if compared to students who completed both EP ( p = .04). CONCLUSIONS: This randomized controlled study shows that correct interpretation of 2D imaging does not differ in students trained with either 3D or 2D. PMID- 22490097 TI - Beyond good and evil: exploring medical trainee use of social media. AB - BACKGROUND: Medicine has struggled to integrate a new generation of social media technologies. Rather than focusing on the promise of these emerging tools, the academic literature is replete with admonishments of how social media pose a danger to medical professionals, and guidelines regarding social media are written with expectations of misuse rather than consideration of positive application. SUMMARY: To better learn how new technology might be integrated into professional lives, it is imperative to seek perspectives from younger trainees who have already begun navigating the unique professional and ethical dilemmas posed by social media and might assist in identifying innovative uses of existing tools. CONCLUSIONS: The views and practices of current trainees can provide important insight into the proactive role social media can play in the delivery of more effective health care during an era in which social media usage is invariably increasing for medical professionals and patients. PMID- 22490096 TI - Accepting diagnostic suggestions by residents: a potential cause of diagnostic error in medicine. AB - BACKGROUND: Psychological research has shown that people tend toward accepting rather than refuting hypotheses. Diagnostic suggestions may evoke such confirmatory tendencies in physicians, which may lead to diagnostic errors. PURPOSE: This study investigated the influence of a suggested diagnosis on physicians' diagnostic decisions on written clinical cases. It was hypothesized that physicians would tend to go along with the suggestions and therefore would have more difficulty rejecting incorrect suggestions than accepting correct suggestions. METHODS: Residents (N = 24) had to accept or reject suggested diagnoses on 6 cases. Three of those suggested diagnoses were correct, and 3 were incorrect. RESULTS: Results showed the mean correct evaluation score on cases with a correct suggested diagnosis (M = 2.21, SD = 0.88) was significantly higher than the score on cases with an incorrect suggested diagnosis (M = 1.42, SD = 0.97), meaning physicians indeed found it easier to accept correct diagnoses than to reject incorrect diagnoses, t(23) = 2.74, p < .05, d = .85, despite equal experience with the diagnoses. CONCLUSION: These findings indicate that suggested diagnoses may evoke confirmatory tendencies and consequently may lead to diagnostic errors. PMID- 22490098 TI - Teaching medical students about cancer impact through a longitudinal surgical experience: a case study. AB - BACKGROUND: We designed and execute a longitudinal curriculum that provides a comprehensive understanding of cancer illness and its impact upon the patient. SUMMARY: The Harvard Medical School-Cambridge Integrated Clerkship is a redesign of the 3rd year where the traditional rotations are replaced by a single integrated year-long experience. Students are required to follow a patient with newly diagnosed gastrointestinal cancer and breast cancer, across all venues and disciplines. Twenty-nine of 34 students responded to a survey. On average patients were followed for 7 months, through 12 encounters across 4 different specialties. Students responded that this experience facilitated their understanding of cancer in a way not feasible in a traditional clerkship model. CONCLUSIONS: Medical students perceive that this longitudinal model of cancer education improves integration of the surgical, medical, scientific, emotional, and social issues. Traditional "block rotation" students and even residents are rarely afforded such an educational opportunity. PMID- 22490099 TI - Morning report: is the time ripe for a change? AB - BACKGROUND: Morning report is a time-honored part of the medical day. However, recent changes in house officer training and staffing raise questions about the educational efficacy of this daily conference. SUMMARY: As it is currently conducted, Morning Report is an exercise in role playing that fails to achieve its main teaching objectives. This article suggests ways to modify Morning Report in an attempt to sustain the valuable purpose for which it was initially conceived. CONCLUSIONS: Refocusing the objectives of Morning Report and shifting the time to noon may restore the educational value of this important conference. PMID- 22490100 TI - A teaching oath: a commitment to medical students' learning and development. AB - BACKGROUND: There are several oaths and affirmations that are integrated into the academic customs of the health sciences, such as the Hippocratic Oath and the Ethical Affirmation for Scientists. What current oaths do not communicate is that teaching and learning are the foundation of the professions. SUMMARY: We articulated an oath to punctuate the important role of teaching and to emphasize that educating students is not a marginal responsibility but an important duty. The goal of this oath is to include all educators who contribute to teaching medical students, including basic science and clinical faculty, residents, nurses, and healthcare providers. This oath is also designed to be concise, allowing for a public declaration during ceremonies that call attention to teaching and learning. CONCLUSIONS: Publically declaring the Teaching Oath is an opportunity to clarify the highest standards of teaching and to energize educators to fulfill the promise of a dynamic learning community. PMID- 22490101 TI - A predictive and construct validity study of a high-stakes objective clinical examination for assessing the clinical competence of international medical graduates. AB - BACKGROUND: The purpose of this study was to investigate the predictive and construct validity of a high-stakes objective structured clinical examination (OSCE) used to select candidates for a 3-month clinical rotation to assess practice-readiness status. SUMMARY: Analyses were undertaken to establish the reliability and validity of the OSCE. The generalizability coefficient (Ep(2)) for the assessment scores (checklist, global, and total) were all high, ranging from 0.73 to 0.84. Two discriminant analyses (promotion to the 3-month rotation and pass/fail status on the rotation) provided evidence of predictive validity with a 100% correct classification rate in the pass/fail rotation results. Factor analysis results provided evidence of construct validity with four factors identified: Clinical Skills, Internal Medicine, General Medical Knowledge, and Counseling. The known group differences between licensing status and residency experience also provided evidence of construct validity. CONCLUSIONS: The results are encouraging for the predictive and construct validity of the OSCE as an assessment of clinical competence. PMID- 22490102 TI - Does the authenticity of preclinical teaching format affect subsequent clinical clerkship outcomes? A prospective randomized crossover trial. AB - BACKGROUND: Educational theories predict conflicting results for the effect of increasing the authenticity of the teaching format of complex information on educational outcomes. We sought to determine the effect of increasingly authentic small-group, preclerkship teaching format on clerkship outcomes to further enlighten this debate. SUMMARY: Students enrolled in a prospective randomized crossover trial that involved three content areas. For each content area, three teaching formats were tested. Participants were randomized to teaching format by content area. Clerkship outcomes were performance on an objective structured clinical exam, a DVD exam, internal medicine clerkship grades, and performance on the subject examination. The data were analyzed using a multivariate analysis of covariance. One hundred and thirty-three (78%) students participated. Teaching format did not have a statistically significant effect on any of the specified clerkship outcomes. However, number of patients seen was significantly associated with higher scores in respective outcomes by topic. CONCLUSIONS: Second-year teaching format did not directly influence subsequent clerkship performance. Our study adds to the literature by demonstrating that the authenticity of preclinical teaching format does not appear to matter for clerkship performance; however, the number of actual patients seen does appear to influence related clerkship outcomes. PMID- 22490106 TI - Detection of West Nile virus-specific antibodies and nucleic acid in horses and mosquitoes, respectively, in Nuevo Leon State, northern Mexico, 2006-2007. AB - In the last 5 years, there has been only one reported human case of West Nile virus (WNV) disease in northern Mexico. To determine if the virus was still circulating in this region, equine and entomological surveillance for WNV was conducted in the state of Nuevo Leon in northern Mexico in 2006 and 2007. A total of 203 horses were serologically assayed for antibodies to WNV using an epitope blocking enzyme-linked immunosorbent assay (bELISA). Seroprevalences for WNV in horses sampled in 2006 and 2007 were 26% and 45%, respectively. Mosquito collections in 2007 produced 7365 specimens representing 15 species. Culex mosquitoes were screened for WNV RNA and other genera (Mansonia, Anopheles, Aedes, Psorophora and Uranotaenia) were screened for flaviviruses using reverse transcription (RT)-PCR. Two pools consisting of Culex spp. mosquitoes contained WNV RNA. Molecular species identification revealed that neither pool included Culex quinquefasciatus (Say) (Diptera:Culicidae) complex mosquitoes. No evidence of flaviviruses was found in the other mosquito genera examined. These data provide evidence that WNV is currently circulating in northern Mexico and that non-Cx. quinquefasciatus spp. mosquitoes may be participating in the WNV transmission cycle in this region. PMID- 22490107 TI - Synthesis of [60]fullerene-fused sultones via sulfonic acid group-directed C-H bond activation. AB - Functionalization with the sulfonic acid group as the directing group in a C-H activation reaction has been revealed for the first time. [60]Fullerene has been employed in the unprecedented palladium-catalyzed C-H activation reaction of arylsulfonic acids to afford [60]fullerene-fused sultones. PMID- 22490108 TI - Heat shock protein 27 expression in areca quid chewing-associated oral squamous cell carcinomas. AB - OBJECTIVES: Heat shock protein (HSP) 27 is a low-molecular-weight protein that functions as a molecular chaperone and plays a cytoprotective role through its antioxidant activity during cell stress. Areca quid chewing is associated with the high incidence of oral squamous cell carcinomas (OSCCs) in Taiwan. The aim of this study was to compare heat shock protein 27 (HSP27) expression in OSCCs and the normal oral tissues. METHODS: Forty-eight OSCCs from areca quid chewers and ten normal oral tissue biopsy samples without areca quid chewing were analyzed by immunohistochemistry for HSP27. The normal human oral keratinocytes (HOKs) were challenged with arecoline, the major alkaloid of areca nut, by Western blot for HSP27. Furthermore, epigallocatechin-3 gallate (EGCG), glutathione precursor N acetyl-L-cysteine (NAC), cyclooxygenase-2 inhibitor NS-398, HSP inhibitor quercetin, extracellular signal-regulated protein kinase (ERK) inhibitor PD98059, and p38 inhibitor SB203580 were added to find the possible regulatory mechanisms. RESULTS: Heat shock protein 27 exhibited higher expression in OSCCs than normal specimens (P < 0.05). Arecoline was found to elevate HSP27 expression in a dose- and time-dependent manner (P < 0.05). The additions of pharmacological agents were found to inhibit arecoline-induced HSP27 expression (P < 0.05). CONCLUSIONS: Heat shock protein 27 expression is significantly elevated in areca quid chewing associated OSCCs. Arecoline-induced HSP27 expression was downregulated by EGCG, NS398, NAC, quercetin, PD98059, and SB203580. PMID- 22490109 TI - Mortality after admission for acute myocardial infarction in Aboriginal and non Aboriginal people in New South Wales, Australia: a multilevel data linkage study. AB - BACKGROUND: Heart disease is a leading cause of the gap in burden of disease between Aboriginal and non-Aboriginal Australians. Our study investigated short- and long-term mortality after admission for Aboriginal and non-Aboriginal people admitted with acute myocardial infarction (AMI) to public hospitals in New South Wales, Australia, and examined the impact of the hospital of admission on outcomes. METHODS: Admission records were linked to mortality records for 60047 patients aged 25-84 years admitted with a diagnosis of AMI between July 2001 and December 2008. Multilevel logistic regression was used to estimate adjusted odds ratios (AOR) for 30- and 365-day all-cause mortality. RESULTS: Aboriginal patients admitted with an AMI were younger than non-Aboriginal patients, and more likely to be admitted to lower volume, remote hospitals without on-site angiography. Adjusting for age, sex, year and hospital, Aboriginal patients had a similar 30-day mortality risk to non-Aboriginal patients (AOR: 1.07; 95% CI 0.83 1.37) but a higher risk of dying within 365 days (AOR: 1.34; 95% CI 1.10-1.63). The latter difference did not persist after adjustment for comorbid conditions (AOR: 1.12; 95% CI 0.91-1.38). Patients admitted to more remote hospitals, those with lower patient volume and those without on-site angiography had increased risk of short and long-term mortality regardless of Aboriginal status. CONCLUSIONS: Improving access to larger hospitals and those with specialist cardiac facilities could improve outcomes following AMI for all patients. However, major efforts to boost primary and secondary prevention of AMI are required to reduce the mortality gap between Aboriginal and non-Aboriginal people. PMID- 22490110 TI - A web-based computer-tailored smoking prevention programme for primary school children: intervention design and study protocol. AB - BACKGROUND: Although the number of smokers has declined in the last decade, smoking is still a major health problem among youngsters and adolescents. For this reason, there is a need for effective smoking prevention programmes targeting primary school children. A web-based computer-tailored feedback programme may be an effective intervention to stimulate youngsters not to start smoking, and increase their knowledge about the adverse effects of smoking and their attitudes and self-efficacy regarding non-smoking. METHODS & DESIGN: This paper describes the development and evaluation protocol of a web-based out-of school smoking prevention programme for primary school children (age 10-13 years) entitled 'Fun without Smokes'. It is a transformation of a postal mailed intervention to a web-based intervention. Besides this transformation the effects of prompts will be examined. This web-based intervention will be evaluated in a 2 year cluster randomised controlled trial (c-RCT) with three study arms. An intervention and intervention + prompt condition will be evaluated for effects on smoking behaviour, compared with a no information control condition. Information about pupils' smoking status and other factors related to smoking will be obtained using a web-based questionnaire. After completing the questionnaire pupils in both intervention conditions will receive three computer-tailored feedback letters in their personal e-mail box. Attitudes, social influences and self-efficacy expectations will be the content of these personalised feedback letters. Pupils in the intervention + prompt condition will - in addition to the personalised feedback letters - receive e-mail and SMS messages prompting them to revisit the 'Fun without Smokes' website. The main outcome measures will be ever smoking and the utilisation of the 'Fun without Smokes' website. Measurements will be carried out at baseline, 12 months and 24 months of follow-up. DISCUSSION: The present study protocol describes the purpose, intervention design and study protocol of 'Fun without Smokes'. Expectations are that pupils receiving tailored advice will be less likely to smoke after 24 months in contrast to pupils in the control condition. Furthermore, tailored feedback letters and prompting is expected to be more effective than providing tailored feedback letters only. TRIAL REGISTRATION: Dutch Trial Register NTR3116. PMID- 22490111 TI - Management of limbal stem cell deficiency in severe ocular chemical burns. PMID- 22490112 TI - Diabetes and dietary fibre: directive or distraction? PMID- 22490114 TI - Enhanced competitive chemiluminescent enzyme immunoassay for the trace detection of insecticide triazophos. AB - A direct competitive chemiluminescent enzyme immunoassay (CLEIA) for triazophos was developed, which was based on the anti-THHe IgG monoclonal antibody and a heterogeneous enzyme tracer (THHu-HRP). Several components of chemiluminescent enhanced solution (CES) were optimized. The results showed that 1 mM of p-iodo phenol, 0.625 mM of luminol, and 4 mM of H(2)O(2) had the best performance. Based on the study of CES, the influence of several factors (assay buffer, blocking substance, and solvent) on the immunoassay was investigated. The sensitivity for detection, IC(50) value was 0.87 ng/mL at a practical working concentration range between 0.04 ng/mL and 5 ng/mL and the limit of detection for triazophos was 0.063 ng/mL. The average recovery of triazophos added to lettuce, carrot, apple, water, and soil were 78.71%, 67.52%, 118.3%, 117.2%, and 122.0%, respectively. Finally, comparison between the methods of CLEIA and high-performance liquid chromatography-tandem mass spectrum (HPLC-MS/MS) was performed. The results obtained from CLEIA were in agreement with those of HPLC-MS/MS. PMID- 22490115 TI - Respiratory viruses in children hospitalized for acute lower respiratory tract infection in Ghana. AB - BACKGROUND: Acute respiratory tract infections are one of the major causes of morbidity and mortality among young children in developing countries. Information on the viral aetiology of acute respiratory infections in developing countries is very limited. The study was done to identify viruses associated with acute lower respiratory tract infection among children less than 5 years. METHOD: Nasopharyngeal samples and blood cultures were collected from children less than 5 years who have been hospitalized for acute lower respiratory tract infection. Viruses and bacteria were identified using Reverse Transcriptase Real-Time Polymerase Chain Reaction and conventional biochemical techniques. RESULTS: Out of 128 patients recruited, 33(25.88%%, 95%CI: 18.5% to 34.2%) were positive for one or more viruses. Respiratory Syncytial Virus (RSV) was detected in 18(14.1%, 95%CI: 8.5% to 21.3%) patients followed by Adenoviruses (AdV) in 13(10.2%, 95%CI: 5.5% to 16.7%), Parainfluenza (PIV type: 1, 2, 3) in 4(3.1%, 95%CI: 0.9% to 7.8%) and influenza B viruses in 1(0.8%, 95%CI: 0.0 to 4.3). Concomitant viral and bacterial co-infection occurred in two patients. There were no detectable significant differences in the clinical signs, symptoms and severity for the various pathogens isolated. A total of 61.1% (22/36) of positive viruses were detected during the rainy season and Respiratory Syncytial Virus was the most predominant. CONCLUSION: The study has demonstrated an important burden of respiratory viruses as major causes of childhood acute respiratory infection in a tertiary health institution in Ghana. The data addresses a need for more studies on viral associated respiratory tract infection. PMID- 22490116 TI - Atrial-based pacing for sinus node dysfunction in dogs: initial results. AB - BACKGROUND: An important consideration for the treatment of sick sinus syndrome (SSS) lies in the function of the atrioventricular (AV) node because most patients with SSS retain the ability to conduct atrial impulses. HYPOTHESIS/OBJECTIVES: This retrospective study examined the feasibility of atrial pacing (AAI) in dogs with sinus node dysfunction (SND). ANIMALS: Sixteen dogs with SND and AAI pacing were identified. METHODS: Retrospective review of medical records. RESULTS: Follow-up time ranged from 45 to 1,227 days (mean: 292 days). Only 1 dog developed AV block 3 days postoperatively. Complete lead dislodgment occurred in 3/16 dogs 1, 19, and 27 days postoperatively. Lead perforation into the pericardial space occurred in 2/16 dogs. Rising thresholds for pacing with possible lead microdislodgment or fibrosis were suspected in another 3/16 dogs 57, 192, and 1,016 days after implantation. None of these dogs had complete loss of capture but all required higher thresholds for pacing. CONCLUSIONS AND CLINICAL IMPORTANCE: Based on this small group of dogs, clinically important AV block does not appear to occur in the long-term for dogs with SND. Risks of lead perforation, complete dislodgment, and rising thresholds for pacing, possibly because of microdislodgment, may be related to the initial skill level of the operator or the leads that were used. Use of leads with reduced torque at the lead tip, higher flexibility, increased lead-tip surface of contact with the endocardium or, more likely, use of alternate locations for pacing in the small right atrium of dogs with SND may decrease the frequency of these complications. PMID- 22490117 TI - Tolerance of anhydrobiotic eggs of the Tardigrade Ramazzottius varieornatus to extreme environments. AB - Tardigrades are tiny (less than 1 mm in length) invertebrate animals that have the potential to survive travel to other planets because of their tolerance to extreme environmental conditions by means of a dry ametabolic state called anhydrobiosis. While the tolerance of adult tardigrades to extreme environments has been reported, there are few reports on the tolerance of their eggs. We examined the ability of hydrated and anhydrobiotic eggs of the tardigrade Ramazzottius varieornatus to hatch after exposure to ionizing irradiation (helium ions), extremely low and high temperatures, and high vacuum. We previously reported that there was a similar pattern of tolerance against ionizing radiation between hydrated and anhydrobiotic adults. In contrast, anhydrobiotic eggs (50% lethal dose; 1690 Gy) were substantially more radioresistant than hydrated ones (50% lethal dose; 509 Gy). Anhydrobiotic eggs also have a broader temperature resistance compared with hydrated ones. Over 70% of the anhydrobiotic eggs treated at either -196 degrees C or +50 degrees C hatched successfully, but all the hydrated eggs failed to hatch. After exposure to high-vacuum conditions (5.3*10(-4) Pa to 6.2*10(-5) Pa), the hatchability of the anhydrobiotic eggs was comparable to that of untreated control eggs. PMID- 22490118 TI - Changes in severity of depressive symptoms and mortality: the Italian Longitudinal Study on Aging. AB - BACKGROUND: Depression is recognized as being associated with increased mortality. However, there has been little previous research on the impact of longitudinal changes in late-life depressive symptoms on mortality, and of their remission in particular. METHOD: As part of a prospective, population-based study on a random sample of 5632 subjects aged 65-84 years, with a 10-year follow-up of vital status, depressive symptoms were assessed by the 30-item Italian version of the Geriatric Depression Scale (GDS). The number of participants in the GDS measurements was 3214 at baseline and 2070 at the second survey, 3 years later. Longitudinal changes in depressive symptoms (stable, remitted, worsened) were examined in participants in both evaluations (n=1941). Mortality hazard ratios (MHRs) according to severity of symptoms and their changes over time were obtained by means of Cox proportional hazards regression models, adjusting for age and other potentially confounding factors. RESULTS: Severity is significantly associated with excess mortality in both genders. Compared to the stability of depressive symptoms, a worsened condition shows a higher 7-year mortality risk [MHR 1.46, 95% confidence interval (CI) 1.15-1.84], whereas remission reduces by about 40% the risk of mortality in both genders (women MHR 0.55, 95% CI 0.32 0.95; men MHR 0.59, 95% CI 0.37-0.93). Neither sociodemographic nor medical confounders significantly modified these associations. CONCLUSIONS: Consistent with previous reports, the severity and persistence of depression are associated with higher mortality risks. Our findings extend the magnitude of the association demonstrating that remission of symptoms is related to a significant reduction in mortality, highlighting the need to enhance case-finding and successful treatment of late-life depression. PMID- 22490119 TI - Safety and efficacy of a long-acting liposomal formulation of plasma-derived factor VIII in haemophilia A patients. PMID- 22490120 TI - Comparison of the triterpenoid content of berries and leaves of lingonberry Vaccinium vitis-idaea from Finland and Poland. AB - Triterpenoid compounds extracted from fruits and leaves of lingonberry ( Vaccinium vitis-idaea L.) collected in Finland and Poland were identified and quantitated by GC-MS/FID. The main lingonberry triterpenoid profile consisted of alpha-amyrin, beta-amyrin, betulin, campesterol, cycloartanol, erythrodiol, fern 7-en-3beta-ol, friedelin, lupeol, sitosterol, stigmasterol, stigmasta-3,5-dien-7 one, swert-9(11)-en-3beta-ol, taraxasterol, urs-12-en-29-al, uvaol, oleanolic acid, and ursolic acid. To our knowledge, this is the first thorough description of triterpenoid compounds in this species. Ursolic acid was identified as a principal triterpene in lingonberry fruit. The influence of geographical origin on the level of individual triterpenoid compounds was examined, and considerable variations in triterpenoid profile between berries and leaves obtained from the two locations were observed. The most striking difference concerned the occurrence of fernenol and taraxasterol, which were found to be the major triterpenol in lingonberry leaves of Finnish and Polish origin, respectively. PMID- 22490123 TI - Optimistic bias about H1N1 flu: testing the links between risk communication, optimistic bias, and self-protection behavior. AB - Using two-wave panel survey data (N = 348) collected in South Korea in the context of H1N1 flu, we explored several important aspects of optimistic bias that have been relatively unexplored in previous research, including: (a) the extent to which risk communication and indirect risk experience affect changes in optimistic bias over time; (b) the utility of the concept of optimistic bias to predict subsequent risk behavior; and (c) how optimistic bias moderates the effect of risk communication and indirect risk experience on self-protection behavior. The findings revealed that optimistic bias is rather enduring and resilient, as it changed only under one condition (high indirect risk experience combined with low interpersonal communication). Optimistic bias had a nonsignificant association with self-protection behavior, but played an important moderating role by reducing the effect of interpersonal communication on self protection behavior. PMID- 22490124 TI - Association of self-reported physical activity patterns and socio-demographic factors among normal-weight and overweight Japanese men. AB - BACKGROUND: It is still not known whether overweight men have different patterns and socio-demographic correlates of self-reported physical activity (PA) compared with normal-weight men. Thus, this study examined the perceived PA patterns and associated socio-demographic factors among normal-weight and overweight Japanese men. METHODS: Data were analyzed for 1,420 men (aged 44.4 +/- 8.3 years) who responded to an Internet-based cross-sectional survey relating to socio demographic variables, BMI status, and a short version of the International Physical Activity Questionnaire. Mann-Whitney, chi-square, and binary logistic regression analyses were employed. RESULTS: Normal-weight men were significantly more likely to attain 150 minutes per week of moderate-to-vigorous PA than overweight men (26.6% vs. 21.3%; p=0.035), whereas there were no significant proportional differences in total PA and walking between the two BMI subgroups. With PA, a significant interaction was observed between BMI status and household income (p=0.004 for total PA; p=0.02 for walking). In the subgroup analyses, having a lower household income (odds ratio, 0.63; 95% confidence interval, 0.41 0.96) was negatively associated with attaining 150 minutes of walking per week among normal-weight men. No significant associations between household income and attaining 150 minutes per week of total PA and walking were found among overweight men. CONCLUSIONS: The results revealed that patterns and socio demographic correlates of self-reported PA in overweight men are different from those in normal-weight men. This finding suggests the necessity of developing specific strategies for PA intervention among overweight men. Socio-demographic correlates of PA may be more important for normal-weight than overweight men. PMID- 22490126 TI - Emission and burnt smell characteristics from combustion experiments with defined materials. AB - Typical burnt smell often results from fire accidents or in general from incomplete combustion. Recently, eleven compounds were identified, which are basically responsible for this odour. When analyzing residual materials from different fire accidents, the pattern that means the relative ratios of these compounds among each other varies strongly, although always causing a burnt smelling. Consequently, lab-scale combustion experiments were performed in order to investigate the influence of defined materials from domestic environment on the burnt-smell fingerprints. Furthermore, the occurrence of other polar and higher molecular combustion products was studied. It was found that under good combustion conditions, the burnt smell patterns resulting from the single materials were astonishingly consistent, mostly dominated by methylphenols or naphthalene. No correlation could be found between these 'fingerprints' and combustion product groups identified by GC/MS-screenings. LC/MS/MS-measurements especially pointed at the existence of higher molecular weight phenolic and acidic functionalized compounds in the combustion residues. PMID- 22490125 TI - Adenocarcinoma arising in a cystic duplication of the small bowel: case report and review of literature. AB - Enteric duplications are rare, but can occur anywhere along the digestive tract. Most of the patients become symptomatic in early childhood and only a few cases of adult patients have been reported in literature. Here we report a unique case of an adenocarcinoma arising in a coincidentally found cystic duplication of the small bowel. PMID- 22490127 TI - Children's physical health complaints after exposure to intimate partner violence. AB - OBJECTIVES: A clear association between exposure to intimate partner violence (IPV) and children's physical health is still not well determined, because adverse effects might be explained by the confounding detrimental effects of other traumatic experiences. This study investigated whether children exposed to IPV have higher risks for physical health complaints compared to children in a general population sample. Second, health complaint differences were explored between IPV witnesses and those who in addition experienced other forms of abuse or neglect. DESIGN: Risk estimates for 21 everyday physical health complaints were made for children exposed to IPV compared to a general population sample using odds ratios. METHODS: Primary caregivers of 275 child witnesses of IPV (6 12 years of age) referred to several specialized mental health or child welfare institutes throughout the Netherlands (2004-2009) reported on children's somatic complaints using 21 items of the Child Behaviour Checklist (CBCL; Achenbach & Rescorla, 2001) reflecting sleeping, eating, pain complaints, and self-harm. RESULTS: Compared to a population sample (n= 903), child witnesses more often experienced health complaints, in particular, more eating, sleeping, and pain problems and more self-harm. Few differences in health complaints were found between child witnesses with and without additional adverse experiences of maltreatment. CONCLUSIONS: The degree of physical health complaints in children exposed to IPV is considerable, whether or not they were also victims of other forms of abuse. Early attention to everyday health complaints in children exposed to IPV might prevent more serious health problems in adolescence and adulthood. PMID- 22490128 TI - Challenges for gene therapy of CNS disorders and implications for Parkinson's disease therapies. PMID- 22490129 TI - Gene therapy for retinal dystrophies: twenty years in the making. PMID- 22490131 TI - [Significance and challenges to the establishment of the China National Center for Food safety Risk Assessment]. PMID- 22490130 TI - Adherence to antihypertensive treatment and associated factors among patients on follow up at University of Gondar Hospital, Northwest Ethiopia. AB - BACKGROUND: Hypertension is an overwhelming global challenge with high morbidity and mortality rates. The prevalence of HTN is estimated to be 6% in Ethiopia and 30% in Addis Ababa. Poor adherence is associated with bad outcome of the disease and wastage of healthcare resources. In Ethiopia, particularly in the study area little is known about treatment adherence and associated factors. Therefore this study aimed to assess adherence to antihypertensive therapy and associated factors among HTN patients on follow up at University of Gondar Referral Hospital. METHOD: Institution based cross sectional study was conducted. Systematic sampling technique was used to select 384 participants. A structured standard questionnaire was used after some modifications. Morisky Medication Adherence Scale was used for labeling patients as adherent or non-adherent. Data were entered and analyzed using SPSS version 16. RESULTS: More than half (64.6 %) of the study participants were found to be adherent to their treatment. Sex (AOR = 0.48, 95%CI = 0.28, 0.82), knowledge about HTN and its treatment (AOR = 6.21, 95%CI = 3.22, 11.97), distance from the hospital (AOR = 2.02, 95% CI =1.19-3.43) and co morbidity (AOR = 2.5, 95%CI = 1.01, 6.21) variables were found significantly associated with treatment adherence. CONCLUSION: Only 64.6% of the study subjects were found to be adherent to their treatment. Factors such as sex, distance from the hospital, number of co morbidities, Knowledge about HTN and its treatment were associated with adherence behavior of patients. Early diagnosis and management of co morbidities, adherence counseling and patient education about the disease and its treatment are important to improve adherence status of patients. PMID- 22490132 TI - [Depth study of child neglect to effectively enhance the capacity for the protection of children]. PMID- 22490133 TI - [Development of national neglect norms for children aged 3 to 6 years in rural areas of China]. AB - OBJECTIVE: To develop the national neglect norms for rural children aged 3 to 6 years, which are suitable for Chinese situations. METHODS: According to the multi stage stratified cluster sampling principle, 84 towns of 10 provinces or municipalities were selected in China. Children aged 3 to 6 years were surveyed in November 2010, the sample of analysis were 3240 (of whom males were 49.6% (1608/3240) and the Han nationality were 93.3% (3023/3240)). Questionnaire was designed by authors and deleted items that did not meet the requirements through several statistical analysis methods, such as item analysis method, factor analysis method, reliability analysis method. The reliability analysis and validity analysis were used to test the stability and reliability of the norm. The evaluation criteria of the scale was determined by the percentile method, then the initial development of the norm completed. RESULTS: After deleting inappropriate items by statistical processing, finally, the scale consisted of 57 items, and included 6 neglected dimensions (physical neglect, emotional neglect, educational neglect, safe neglect, medical neglect and social neglect). Its item loadings ranged from 0.359 to 0.789, which met the statistical requirements. The scale's total Cronbach alpha coefficients 0.904, the total split-half reliability coefficients were 0.820, the 6 neglect dimensions' Cronbach alpha coefficients ranged from 0.620 to 0.815, the 6 neglect dimensions' split-half reliability coefficients ranged from -0.034 to 0.789, the scale's parallel reliability were 0.785 and it's re-test reliability were 0.613. After construct validity, external validity and content validity testing, the result showed that this scale could effectively reflect the real neglected status of children investigated. The total neglect cut-off score of this scale were 121. CONCLUSION: The scale has good stability and reliability. And it adapts Chinese conditions and it's convenient to operate. PMID- 22490134 TI - [The status of child neglect among rural areas children aged 0 - 6 years in China]. AB - OBJECTIVE: To explore the status of child neglect among rural areas children aged 0 - 6 years in China. METHODS: A total of 7411 rural children aged 0 - 6 years old who were composed of two age groups (3315 children aged 0 - 2 years old and 4096 children aged 3 - 6 years old) were multistage stratified randomly sampled from 84 villages which were representative of 10 provinces of China, in accordance with sex and age in November 2010. To identify the child neglect based on the Neglect Norms for Children Aged 0 to 2 and 3 to 6 Years Old in Rural Areas of China, SPSS 13.0 was employed for analyzing neglect frequency and degree for every group of different age, sex and neglect type (including physical, emotional, educational, medical, safety and social neglects). chi(2) test and analysis of variance were also used. RESULTS: The degree of child neglect for the children aged 0 - 2 years old was 45.01 +/- 7.56, the neglect frequency was 54.9% (1819/3315); the degree of child neglect for the children aged 3 - 6 years old was 44.42 +/- 7.57, the neglect frequency was 53.8% (2203/4096). The neglect frequency of children aged 0, 1, 2 years old were 58.5% (654/1117), 52.2% (597/1144), 53.9% (568/1054) (P < 0.05). For children aged 3 - 6 years old, the degrees of emotional and safety neglect for males (44.60 +/- 7.86, 36.82 +/- 9.03) were higher than females (44.03 +/- 7.72, 36.25 +/- 9.05) (P < 0.05); and the frequencies of emotional and social neglect for males (16.8% (349/2072), 28.3% (586/2072)) were also higher than females (14.1% (286/2024), 24.8% (503/2024)) (P < 0.05). All children of two age groups suffered neglect mainly on one of the six neglect types (incidences were 20.6% (683/3315) and 22.7% (931/4096)). For 0-2 age groups, the higher neglect frequencies happened in the single-parent family and the remarried family (62.5% (15/24) and 63.2% (12/19)), but for children aged 3 - 6 years old groups, it happened in the single-parent family (60.0%, 27/45). CONCLUSION: Degree and frequency of child neglect among children aged 0 to 6 years old in the rural areas of China are high, and we should find out risk factors and provide efficient prevention measures. PMID- 22490135 TI - [The status of child neglect for children aged 3 - 17 years in China]. AB - OBJECTIVE: To explore the status of child neglect among urban areas children and adolescents aged 3 - 17 years in China. METHODS: Using multi-stage stratified cluster sampling method, 8001 children and adolescents were recruited from 30 cities of 14 provinces in December 2008. The investigation was carried based on The 3 - 6 years old children Neglect Norms of city in China and The 6 - 17 years old children Neglect Norms of city in China. SPSS 13.0 was employed for analyzing neglect rate and degree for group of areas, age, sex and neglect type (including neglect of physical, emotional, educational, medical, safety and social). RESULTS: The degrees of child neglect for urban children aged 3 - 6 (children aged 6 were not in school), 6 - 8 (children aged 6 were school children), 9 - 11, 12 - 14 and 15 - 17 were 42.2 +/- 6.9, 42.8 +/- 8.4, 42.1 +/- 9.1, 46.4 +/- 9.2 and 49.7 +/- 8.4(P < 0.05), the neglect rates were 28.0% (326/1163), 28.8% (431/1496), 27.2% (543/1962), 22.4% (373/1664) and 32.8% (563/1716) (P < 0.05), respectively. There were differences in six neglect types for each group; the neglect degrees and rates were high in the group aged 12 - 14 and 15 - 17 (46.4 +/- 9.2 and 49.1 +/- 8.4, 22.4% (373/1664) and 32.8% (563/1716), respectively); for each neglect type, the neglect degree of children aged 15 - 17 were highest (52.8 +/- 8.0, 47.3 +/- 11.6, 49.5 +/- 10.8, 42.4 +/- 10.3, 52.2 +/- 16.0, 56.0 +/- 10.1). The degree and rate of neglect in West were highest, Middle was next, the East was lowest (the neglect degrees were 45.4 +/- 9.1, 45.0 +/- 9.3 and 44.0 +/- 8.8, P < 0.05;the rates were 30.7% (1340/4361), 25.0% (756/3024) and 21.2% (131/616), P < 0.05). Degree and rate of child neglect for children without siblings were lower than children with siblings (the neglect degrees were 44.2 +/ 9.0 and 47.6 +/- 9.1, P < 0.01; the rates were 26.1% (1572/6017) and 33.0% (655/1984), P < 0.01). Neglect degree of school children aged 6 years old (43.1 +/- 7.3) was higher than children not in school (40.7 +/- 7.8) (P < 0.01), but neglect rate was lower (the rates were 35.4% (60/169) and 21.3% (84/394), P < 0.01). CONCLUSION: Neglect degree and rate of urban children and adolescents aged 3 - 17 years in China were both high, and neglect deserved more attentions. PMID- 22490136 TI - [The current situation of children neglect and its influencing factors for rural children aged 0 - 6 years in Chongqing]. AB - OBJECTIVE: To learn the current situation of children neglect and its influencing factors among children aged from 0 - 6 years in rural Chongqing. METHODS: Scales and evaluation methods in the "Chinese rural child neglected evaluation model" were used in this study. The investigation was conducted by using multistage stratified cluster sampling method in December 2010, and 822 rural children aged 0 to 6 years of three districts in Chongqing were randomly select for the survey, with neglect rate and the neglect degree to describe their neglect status, using logistic regression analysis to analyze factors affecting children neglect. RESULTS: The total neglect rate and the neglect degree in the rural children were 35.64% (293/822) and 49.69 +/- 6.45, respectively. The neglect degree in boys was higher than that of girls (boys: 50.23 +/- 6.40 vs girls: 49.09 +/- 6.47, P < 0.05). Further, Our data demonstrated both the neglect rate and the neglect degrees in children whose parents away from home were higher than that of the children whose parents stayed with them (neglect rate: 40.48% (202/499) vs 28.17% (91/323), P < 0.05; neglect degree: 50.64 +/- 6.29 vs 48.23 +/- 6.44, P < 0.05). Based on multivariate unconditional logistic regression analysis, the determinants of children neglect were: parents were away from home (OR = 1.61, 95%CI: 1.17 - 2.21), single mother and remarried family (OR = 1.39, 95%CI: 1.10 - 1.76), maternal occupation(OR = 0.81, 95%CI: 0.73 - 0.90), estrangement relationship between children and their mothers (OR = 1.42, 95%CI: 1.02 - 1.97). CONCLUSION: The neglect situation of rural children is serious in Chongqing, and the main factors are parents away from home, single mother and remarried family, maternal occupation, and estrangement relationship between children and their mothers. PMID- 22490137 TI - [The situation of children neglect between left-behind children and living-with parents children in rural areas of two western provinces of China]. AB - OBJECTIVE: To understand the children neglect situation of left-behind children (children who do not grow up with their parents) and non-left-behind children in China's western rural and its influencing factors. METHODS: Scales and evaluation methods in the "Chinese rural child neglected evaluation model" were used in this study. The investigation was conducted by using multistage stratified cluster sampling method; three countries were sampled randomly in Shanxi and Chongqing in November 2010, respectively. And, in every county, children from rural area aged from zero to six were randomly selected, with neglect rate and degree to describe their neglected status, using logistic regression analysis to analyze factors affecting the neglect rate. RESULTS: Among 1568 subjects (859 left-behind and 709 living-with-parents), the total neglect rates were 29.78% (467/1568), and the total neglect degrees were 48.51 +/- 6.49; the neglect rates for left-behind ones and living-with parents ones were 34.34% (295/859) and 24.26% (172/709) (P < 0.05); the neglect degree were 49.59 +/- 6.54 and 47.19 +/- 6.18 (P < 0.05). The neglect degree among left-behind ones and living-with parents ones between 0 to 2 years old were 48.59 +/- 6.33 and 45.78 +/- 5.94 (P < 0.05); in 3 to 6 years old group, which were 50.43 +/- 6.60 and 48.25 +/- 6.16(P < 0.05). The degrees in boy's group of these two kinds of children were 49.83 +/- 6.67, 47.36 +/- 6.28(P < 0.05) and girl's were 49.32 +/- 6.38, 47.01 +/- 6.08 (P < 0.05). On the other side, the neglect rate of left-behind and non-left-behind children between 0 to 2 years old were 39.33% (153/389) and 18.54% (56/302) (P < 0.05). The rates of boy's group were 34.91% (162/464) and 25.13% (94/374) (P < 0.05), and girl's were 33.67% (133/395) and 23.28% (78/335) (P < 0.05). Results showed that if the left behind child's father was with lower education background, and the child and his mother feel stranger to each other, which led to the conclusion there was more chance for them to be neglected (OR values were 1.29 and 1.55, P < 0.05). If the non-neglected child's father was farmer or migrant worker and the relationship between the mother and father was poor, then there was more chance for them to be neglected (OR values were 0.85 and 1.92, P < 0.05). CONCLUSION: The situation of children neglect in the western rural regions in China is serious. Both the neglect rate and degree among left-behind children are higher than those living with-parents children. The influencing factors of neglect rate are different in the two groups. PMID- 22490138 TI - [Exposure assessment on dietary lead and cadmium of residents in three areas of Zhejiang province from 2009 to 2010]. AB - OBJECTIVE: To assess the safety of dietary lead and cadmium intake in 3 areas of Zhejiang province. METHODS: Using the total dietary study method, the study was conducted in 3 regions which represented coastal, city and rural areas in Zhejiang province from 2009 to 2010. The dietary survey was conducted on the residents (512 subjects) and the categories and volume of food consumption were obtained. The analytical food samples were obtained by food consumption survey, food aggregation, food sampling and preparation. The food samples were detected by inductively coupled plasma mass spectrometry (ICP-MS). The safety of dietary lead and cadmium intake was evaluated. RESULTS: The median dietary lead intake (P50) in Zhejiang province was 37.8 ug/d. The 97.5% dietary lead intake (P97.5) was 72.3 ug/d. The P50 dietary lead intakes of different age and gender groups ranged from 23.2 to 44.2 ug/d. The P97.5 dietary lead intakes of different age and gender groups ranged from 34.2 to 88.1 ug/d. The P50 dietary cadmium intake in Zhejiang province was 9.6 ug/d. The P97.5 dietary cadmium intake was 15.7 ug/d. The P50 dietary cadmium intakes of different age and gender groups ranged from 6.4 to 11.4 ug/d, accounting 15.6% - 42.6% of PTMI (provisional tolerable monthly intake, 25 ug/kg). The P97.5 dietary cadmium intakes of different age and gender groups ranged from 10.5 to 21.4 ug/d, accounting 27.5% - 77.6% of PTMI. Vegetable (11.3 ug), cereal (11.0 ug) and meat (9.8 ug) were the first three food sources which accounted for 84.9% of dietary lead (P50: 37.8 ug/d). Cereal (3.6 ug), vegetable (2.1 ug) and legume (0.9 ug) were the first three food sources which accounted for 68.8% of dietary cadmium (P50: 9.6 ug/d). CONCLUSION: Dietary lead and cadmium intakes of most residents in 3 areas of Zhejiang province as well as the average level are safe. PMID- 22490139 TI - [The epidemiological impact of varicella vaccination in kindergartens, primary and secondary schools in Beijing]. AB - OBJECTIVE: To study the epidemiological impact of varicella vaccine vaccination on kindergartens and school children in Beijing. METHODS: According to "China Information System for Diseases Control and Prevention", the reported clinical diagnosis varicella cases were tracked in kindergartens, primary and secondary schools whose onset date were from 2008 to 2010. Epidemiological survey was conducted and epidemiological features were analyzed. RESULTS: A total of 21 474 varicella cases were investigated: 55.3% (11 883 cases) had been vaccinated by varicella vaccine. Of cases with definite immunization history, interval between vaccination date and onset date were from 30 days to 1 year accounted for 3.4% (286/8510), 1 to 3 years accounted for 18.2% (1551/8510), 3 to 5 years accounted for 28.6% (2431/8510), 5 to 10 years accounted for 34.3% (2916/8510) (left-closed right-open interval); The peak age of onset was 4 years old in cases without immunization history, which was 6 years old in cases with immunization history; The proportion of cases with immunization history (>= 30 days) had increased from 42.4% (2862/6754) in 2008 to 56.3% (4327/7679) in 2010. The cases with no fever had a higher proportion (54.9%, 6413/11 679) of immunization history (>= 30 days) than cases with fever (47.7%, 4533/9500) (P < 0.01); The cases with rashes less than 50 had a higher proportion (57.4%, 8045/14 020) of immunization history (>= 30 days) than cases with rashes more than 50 (40.2%, 2902/7216) (P < 0.01). CONCLUSION: Varicella vaccine delays the peak age of onset, alleviates the symptoms. The current immunization strategy can not block varicella spread in kindergartens, primary and secondary schools. PMID- 22490140 TI - [The vascular endothelial function damage as well as early atherosclerosis in hypertensive youth]. AB - OBJECTIVE: To explore young hypertensive people's vascular endothelial dysfunction and the early atherosclerosis changes. METHODS: Rural youth subjects aged 20 to 35 in 6 villages were randomly selected from 20 villages of 3 townships, including Qili, Laojun and Shayan, in Hanzhong, Shanxi, China, from March to April of 2005, to survey their blood pressure and other related factors. 97 subjects with high blood pressure (hypertensive group) were detected while 400 with normal blood pressure (normal group). We measured their brachial artery flow mediated vascular endothelial-dependent diastolic function (FMD) and the carotid intima-media thickness (IMT) by high resolution vascular ultrasound method, and other biochemical indexes. RESULTS: The body mass index (BMI) ((24.7 +/- 4.3) kg/m2), waistline ((84.1 +/- 11.7) cm), hipline ((92.5 +/- 7.4) cm), TC ((4.6 +/- 0.8) mmol/L), LDL-C ((2.8 +/- 0.5) mmol/L), TG ((1.7 +/- 1.1) mmol/L) and the blood insulin (INS) ((8.6 +/- 4.4) mIu/L) were all significantly increased in young hypertensive group than those in normotensive group (respectively were (22.1 +/- 3.0) kg/m(2), (76.7 +/- 8.9) cm, (88.9 +/- 5.6) cm, (4.3 +/- 0.7) mmol/L, (2.6 +/- 0.4) mmol/L, (1.4 +/- 0.8) mmol/L and (6.9 +/- 2.1) mIu/L) (P < 0.05). The FMD of the brachial artery in hypertensive group was markedly lower than normal group ((0.103 +/- 0.04)% and (0.117 +/- 0.05)%, P < 0.05). The IMT of two groups were (0.49 +/- 0.07) mm and (0.48 +/- 0.07) mm, but there was no statistically significant differences (P > 0.05). CONCLUSION: Young hypertensive people with a few cardiovascular risk factors earlier appear dysfunction of the flow-mediated vascular endothelial-dependent dilation, which is prior to the increase in carotid IMT. PMID- 22490141 TI - [Correlation between polymorphism in the promoter of DNA methyltransferase-3B and the risk of colorectal cancer]. AB - OBJECTIVE: To explore the correlation between the polymorphism in the DNA methyltransferase-3B (DNMT3B) gene promoter single nucleotide polymorphism (SNP) 149C->T (rs2424913) and-579G->T(rs1569686) and the genetic susceptibility to colorectal cancer in Jiangsu population. METHODS: Genomic DNA was extracted from the leukocyte cell of blood samples collected from 544 colorectal cancer (CRC) patients (including 280 cases of colon cancer and 264 cases of rectal cancer) since January 2009 and July 2010, in a hospital, Jiangsu Province. The same samples were collected from the other 533 control subjects. Polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing analysis were employed to assess the polymorphism of DNMT3B gene promoter-149C->T and-579G->T. RESULTS: For DNMT3B-149C->T, no significant deviation was observed in the genotype distributions of polymorphisms between CRC cases (TT: 98.90% (538/544); CT: 1.10% (6/544)) and controls (TT: 97.75% (521/533); CT: 2.25% (12/533)) (chi(2) = 2.07, P = 0.15). The CC genotype was not detected in either patients or control subjects. The DNMT3B-149CT genotype was not associated with the risk of CRC (adjusted OR = 0.48, 95%CI: 0.18 - 1.30). For DNMT3B-579G->T, the genotype distributions of polymorphisms in CRC patients (TT: 90.07% (490/544); GT: 9.19% (50/544); GG: 0.74% (4/544)) were significantly different from those in control group (TT: 81.80% (436/533); GT: 17.82% (95/533); GG: 0.38% (2/533)) (chi(2) = 15.49, P < 0.05). The results showed that the-579 G allele could significantly decrease the risk of CRC (adjusted OR = 0.50, 95%CI: 0.35 - 0.72) in comparison with the -579 TT genotype. In addition, stratification analysis showed that for DNMT3B-579G->T, the genotype distributions of polymorphisms in colon cancer (TT: 92.50% (259/280); GT: 7.50% (21/280)) were significantly different from those in the controls (TT: 81.80% (436/533); GT: 17.82% (95/533); GG: 0.38% (2/533)) (chi(2) = 13.53, P < 0.05); and similar result was found in rectal cancer (TT: 87.50% (231/264); GT: 10.98% (29/264); GG: 1.52% (4/264)) and controls (TT: 81.80% (436/533); GT: 17.82% (95/533); GG: 0.38% (2/533)) (chi(2) = 5.64, P = 0.018). G allele carriers could decrease the risk of colon cancer (adjusted OR = 0.38, 95%CI: 0.23 - 0.63), and the risk of rectal cancer (adjusted OR = 0.65, 95%CI: 0.42 - 0.99). However, for DNMT3B-149C->T , there were no significant deviation in the genotype distributions of polymorphisms between colon cancer (TT: 98.57% (276/280); CT: 1.43% (4/280)) and controls (TT: 97.75% (521/533); CT: 2.25% (12/533)) (chi(2) = 0.82, P = 0.366); and there was no significant deviation between rectal cancer (TT: 99.24% (262/264); CT: 0.76% (2/264)) and controls (TT: 97.75% (521/533); CT: 2.25% (12/533)) either (chi(2) = 1.89, P = 0.169). CONCLUSION: Our research demonstrates that the-579 G allele is a potential protective factor for the occurrence of CRC, however, the polymorphism of DNMT3B-149 gene shows no close correlation with the occurrence and development of CRC among Chinese population. PMID- 22490142 TI - [Involvement of intron A into eukaryotic expression vector to improve immunogenicity of mycobacterial heat-shock protein 65 DNA vaccine in mice]. AB - OBJECTIVE: To explore the involvement of intron A into eukaryotic expression vector to improve antigen expression efficiency and enhance immunogenicity of DNA vaccine in mice. METHODS: As model antigen, the coding gene of mycobacterial Hsp65 was cloned into eukaryotic expression vector pCMV4.0 with intron A involved and pVAX1 without intron A involved, respectively. The resulted recombinant expression vectors were transfected into 293T cells and were then injected into BALB/c mice as DNA vaccines. Anti-Hsp65 specific IgG and isotype were detected by ELISA and T cell immune response was analyzed by enzyme-linked immunosorbent spot (ELISPOT) assay and intracellular cytokine staining. RESULTS: Compared with non intron A pVAX1hsp65, the recombinant plasmid pCMV4.0hsp65 involved with intron A pVAX1hsp65 caused higher expression level of Hsp65 in 293T cells, and enhanced Th1 type immune response, which was defined as higher level of anti-Hsp65 specific total IgG level (3.76 +/- 0.23 vs 3.15 +/- 0.22, P < 0.01) and IgG2a/IgG1 ratio (4.08 +/- 0.04 vs 2.23 +/- 0.12, P < 0.01) and more IFN-gamma secreting CD4(+) ((2.0 +/- 0.058)% vs (1.5 +/- 0.087)%, t = 4.804, P < 0.01) and CD8(+) ((0.6 +/- 0.058)% vs (1.0 +/- 0.115)%, t = 3.098, P < 0.05) T lymphocytes. The difference showed statistical significance. CONCLUSION: Intron A can improve the expression efficiency of mycobacterial Hsp65 antigen and enhance immunogenicity of DNA vaccine in mice when involved into eukaryotic expression vector. PMID- 22490143 TI - [The relationship among congenital Toxoplasma gondii infection, pregnancy outcome and T lymphocyte subsets in umbilical cord blood]. AB - OBJECTIVE: To reveal the relationship among congenital Toxoplasma gondii (T. gondii) infection, T lymphocyte cell subsets in umbilical cord blood and pregnancy outcome. METHODS: 784 umbilical cord blood samples were collected and information of pregnancy outcomes was collected in a hospital of Hefei city, Anhui province during March 2009 to May 2010. T. gondii IgM antibodies in the sera were detected by ELISA. For all neonates infected with T. gondii and 10 healthy neonates, T lymphocyte cell subsets were detected by flow cytometry. RESULTS: According to the detection results of T. gondii IgM antibodies, 784 neonates were divided into infection group (21 neonates) and control group (763 neonates). The body weight and 1 min Apgar score of infection group were (3116.4 +/- 352.6) g and (8.21 +/- 1.26) points, respectively, which were statistically lower than control group ((3220.1 +/- 242.3) g and (8.77 +/- 1.61) points, respectively) (P < 0.01). The proportion of adverse pregnancy outcome of infection group was 19.0% (4/21), which was statistically greater than control group (4.8%, 37/763) (P < 0.01). The percentage of CD(3)(+) T lymphocyte cells in umbilical cord blood in infection group with and without adverse pregnancy outcomes were (64.51 +/- 5.27)% and (64.32 +/- 4.56)%, respectively, which were statistically lower than control group ((69.32 +/- 4.32)%) (P < 0.01). The ratio value of CD(4)(+)/CD(8)(+) in infection group with, without adverse pregnancy outcomes and control group are 1.39 +/- 0.24, 1.64 +/- 0.28 and 2.34 +/- 0.46, respectively, which showed statistical difference between any 2 groups (P < 0.01). CONCLUSION: T. gondii infection leads to adverse pregnancy outcomes and disorder of cellular immunity while T lymphocyte cell subsets are closely associated with adverse pregnancy outcome. PMID- 22490144 TI - [Evaluation of the protective performance of a positive pressure bio-protective clothing against viral aerosol]. AB - OBJECTIVE: To evaluate the protective performance of a positive pressure bio protective clothing against viral aerosol. METHODS: The suspension of indicating virus phage Phi-X174 was made for viral aerosol generating in a hermetic cabin. The diameter of viral aerosol particles were measured with a aerodynamics size analyzer. By adjusting the inner humidity of the cabin, the protective efficiency of the positive pressure bio-protective clothing against viral aerosol in high and low windshield conditions was determined with Andersen six-stage air sampler sampling and plage forming unit (PFU) counting, respectively. RESULTS: The mass median diameter of Phage Phi-X174 aerosol particles was about 0.922 um and the background concentration is beyond 2 * 104 particles/m3. The protective efficiency of the clothing against phage Phi-X174 aerosol particles was above 99.9% under different test conditions with the range of viral aerosol concentration between 0 - 23 PFU/m3. Airflow (P = 0.84), environment humidity conditions (P = 0.33) and sampling time (P = 0.07) did not affect the protective efficiency statistically. CONCLUSION: The positive pressure bio-protective clothing provided a relatively high efficiency against phage Phi-X174 aerosol regardless of airflow rate, environment humidity and sampling time. PMID- 22490145 TI - [Diagnosis of cervical intraepithelial neoplasia by visual inspection with acetic acid among Chinese women: a meta-analysis]. AB - OBJECTIVE: To evaluate the performance of visual inspection with acetic acid (VIA) in preliminary screening of cervical cancer and its precancerous lesions among Chinese women by meta-analysis of diagnosis. METHODS: Pubmed, Cochrane, Wanfang, CNKI and Weipu databases were employed to search for citations using the MeSH terms as "acetic acid", "cervical intraepithelial neoplasia", and "cervical cancer" both in Chinese and English. Additional relevant references cited in retrieval articles were also searched.40 pieces of research paper related with screening of cervical cancer and precancerous lesions of cervical cancer in Chinese women by VIA were collected. Bivariate random effects model was adopted using SAS 8.02. RESULTS: Twenty-two studies including 23 330 cases were finally selected in the analysis, among which 19 studies were reported in Chinese and the other 3 in English. These studies were reported from 2004 to 2010 and the age range of subjects was between 15 and 81 years old. Stratified analysis of diagnosis threshold showed that the pooled diagnostic odds ratio (DOR) of VIA for CIN1+ (4.11, 95%CI: 3.20 - 5.04) was similar to that for CIN2+ (4.45, 95%CI: 3.73 - 5.15). Either CIN1+ or CIN2+, the DOR in younger women (<= 40 year) (4.22, 95%CI: 3.29 - 5.16; 4.53, 95%CI: 3.46 - 5.47) was also similar to it in older women (> 40 year) (3.66, 95%CI: 2.27 - 5.37; 4.26, 95%CI: 3.32 - 5.26). There was no difference in the screening performance between county-level doctors (DOR = 4.62, 95%CI: 3.13 - 5.93) and municipal-level doctors (DOR = 4.48, 95%CI: 3.71 - 5.16). CONCLUSION: The screening performances of VIA were relatively consistent among different lesion grades and aging groups of Chinese women. After professional training, there was no difference in performance between county level hospitals and municipal-level hospitals. PMID- 22490146 TI - Impact of three years of large scale Indoor Residual Spraying (IRS) and Insecticide Treated Nets (ITNs) interventions on insecticide resistance in Anopheles gambiae s.l. in Benin. AB - BACKGROUND: In Benin, Indoor Residual Spraying (IRS) and long-lasting insecticidal nets (LLINs) are the cornerstones of malaria prevention. In the context of high resistance of Anopheles gambiae to pyrethroids, The National Malaria Control Program (NMCP) has undertaken a full coverage of IRS in a no flood zone in the Oueme region, coupled with the distribution of LLINs in a flood zone. We assessed the impact of this campaign on phenotypic resistance, kdr (knock-down resistance) and ace-1(R) (insensitive acetylcholinesterase) mutations. METHODS: Insecticides used for malaria vector control interventions were bendiocarb WP (0.4 g/m2) and deltamethrin (55 mg/m2), respectively for IRS and LLINs. Susceptibility status of An. gambiae was assessed using World Health Organization bioassay tests to DDT, permethrin, deltamethrin and bendiocarb in the Oueme region before intervention (2007) and after interventions in 2008 and 2010. An. gambiae specimens were screened for identification of species, molecular M and S forms and for the detection of the West African kdr (L1014F) as well as ace-1(R) mutations using PCR techniques. RESULTS: The univariate logistic regression performed showed that kdr frequency has increased significantly during the three years in the intervention area and in the control area. Several factors (LLINs, IRS, mosquito coils, aerosols, use of pesticides for crop protection) could explain the selection of individual resistant An. gambiae. The Kdr resistance gene could not be the only mechanism of resistance observed in the Oueme region. The high susceptibility to bendiocarb is in agreement with a previous study conducted in Benin. However, the occurrence of ace-1(R) heterozygous individuals even on sites far from IRS areas, suggests other factors may contribute to the selection of resistance other than those exerted by the vector control program. CONCLUSION: The results of this study have confirmed that An.gambiae have maintained and developed the resistance to pyrethroids, but are still susceptible to bendiocarb. Our data clearly shows that selection of resistant individuals was caused by other insecticides than those used by the IRS and LLINs. PMID- 22490148 TI - [Application of Da Vinci surgical system in surgery]. PMID- 22490147 TI - Factoring-in agglomeration of carbon nanotubes and nanofibers for better prediction of their toxicity versus asbestos. AB - BACKGROUND: Carbon nanotubes (CNT) and carbon nanofibers (CNF) are allotropes of carbon featuring fibrous morphology. The dimensions and high aspect ratio of CNT and CNF have prompted the comparison with naturally occurring asbestos fibers which are known to be extremely pathogenic. While the toxicity and hazardous outcomes elicited by airborne exposure to single-walled CNT or asbestos have been widely reported, very limited data are currently available describing adverse effects of respirable CNF. RESULTS: Here, we assessed pulmonary inflammation, fibrosis, oxidative stress markers and systemic immune responses to respirable CNF in comparison to single-walled CNT (SWCNT) and asbestos. Pulmonary inflammatory and fibrogenic responses to CNF, SWCNT and asbestos varied depending upon the agglomeration state of the particles/fibers. Foci of granulomatous lesions and collagen deposition were associated with dense particle-like SWCNT agglomerates, while no granuloma formation was found following exposure to fiber like CNF or asbestos. The average thickness of the alveolar connective tissue--a marker of interstitial fibrosis--was increased 28 days post SWCNT, CNF or asbestos exposure. Exposure to SWCNT, CNF or asbestos resulted in oxidative stress evidenced by accumulations of 4-HNE and carbonylated proteins in the lung tissues. Additionally, local inflammatory and fibrogenic responses were accompanied by modified systemic immunity, as documented by decreased proliferation of splenic T cells ex vivo on day 28 post exposure. The accuracies of assessments of effective surface area for asbestos, SWCNT and CNF (based on geometrical analysis of their agglomeration) versus estimates of mass dose and number of particles were compared as predictors of toxicological outcomes. CONCLUSIONS: We provide evidence that effective surface area along with mass dose rather than specific surface area or particle number are significantly correlated with toxicological responses to carbonaceous fibrous nanoparticles. Therefore, they could be useful dose metrics for risk assessment and management. PMID- 22490150 TI - [Relationship of hyperuricemia and chronic kidney disease]. PMID- 22490149 TI - [Progress of early diagnostic technique for lung cancer]. PMID- 22490151 TI - [Combined usage of diffusion-weighted magnetic resonance imaging and transrectal ultrasound for transrectal prostate biopsy: a preliminary study]. AB - OBJECTIVE: To retrospectively analyze the clinical value of diffusion-weighted magnetic resonance imaging (MRDWI) in the detection of prostate cancer in suspected patients. METHODS: Between January 2009 and December 2010, 141 patients with suspected prostate cancer underwent MRDWI and transrectal ultrasound (TRUS) guided prostate biopsy. They were divided into 4 groups by prostate surface antigen (PSA) < 10 ug/L, 10 ug/L <= PSA < 20 ug/L, 20 ug/L <= PSA < 50 ug/L and PSA >= 50 ug/L. Then the diagnostic accuracy of MRDWI was tested. RESULTS: The diagnostic rate of patients with PSA < 10 ug/L, 10 ug/L <= PSA < 20 ug/L, 20 ug/L <= PSA < 50 ug/L and PSA >= 50 ug/L were 23.7%, 35.5%, 66.7% and 96.3% respectively. The sensitivity of MRDWI was significantly better than TRUS. In patients with PSA < 10 ug/L, 10 ug/L <= PSA < 20 ug/L, 20 ug/L <= PSA < 50 ug/L and PSA >= 50 ug/L, the patient-based sensitivities were 85.7%, 72.7%, 97.8%, 100.0% respectively; when based by segment of specimen, the sensitivities were 85.5%, 71.9%, 91.5% and 94.4% respectively. CONCLUSION: The sensitivity of MDWI is significantly better than TRUS in the diagnosis of prostate cancer. The combined use of MDWI and TRUS has the benefit of guiding the biopsy of cancer foci in patients with suspected prostate cancer. PMID- 22490152 TI - [Phenotypic differences of stroma cells in benign and malignant human prostate tissues]. AB - OBJECTIVE: To analyze the stroma changes of benign and malignant human prostate tissues. METHODS: For the identification of stroma cells phenotype in human prostate cancer and benign prostate hyperplasia tissues, Masson method and immunohistochemical analysis of alpha-smooth muscle actin (alpha-SMA), desmin, and vimentin were performed. The relative volume of intratumor stroma (0%, Grade 0; 1% - 33%, Grade 1; 34% - 66%, Grade 2; 67% - 100%, Grade 3) were quantified and analyzed in local and advanced prostate cancer tissues. RESULTS: Stroma myofibroblasts in prostate cancer were stained green by Masson staining and showed a co-expression of alpha-SMA and vimentin without an expression of desmin. It was significantly different from smooth muscle cells in benign prostate hyperplasia stained red and co-expressing a-SMA and desmin. Statistical analysis showed that high stroma volume (Grade 2/3) in advanced prostate cancer were significantly higher than that in an early stage of prostate cancer (83% vs 55%, P < 0.05). CONCLUSION: Significant phenotypic differences of stroma cells existed in benign and malignant human prostate tissues. A high expression of myofibroblasts in advanced prostate cancer may play an important role in cancer progression. And its clinical significance should raise a high alert. PMID- 22490153 TI - [Efficacy of low dose ketoconazole therapy for Chinese patients with castration resistant prostate cancer]. AB - OBJECTIVE: To assess the efficacy of low dose ketoconazole therapy for Chinese patients with castration resistant prostate cancer (CRPC) and explore possible prognosis factors. METHODS: From August 2006 to August 2011, 71 patients with CRPC were analyzed retrospectively, who received oral ketoconazole 200 mg, three times a day with prednisone 5 mg, twice a day. Prostate specific antigen (PSA) response rate was defined as the percentage of patients with PSA decline >= 50% compared to baseline PSA level during low dose ketoconazole therapy. Multivariate Logistic regression analysis and receiver operating characteristic curve were used to assess the prognostic factors and their accuracy. RESULTS: The mean initial serum PSA level was (205 +/- 38) ng/ml for these patients with mean age (69 +/- 1) years old. After first androgen deprivation therapy failure, the prostate cancer progressed into castration resistant stage. The baseline PSA was (93 +/- 24) ng/ml and the baseline serum testosterone was (0.13 +/- 0.02) ng/ml. During the low dose ketoconazole therapy, 31 patients (43.7%) had PSA decrease and 22 cases (31.0%) were effective with PSA decline more than 50%. PSA doubling time and baseline serum testosterone were positive correlation with PSA response rate by multivariate Logistic regression analysis. Patients with PSA doubling time of >= 3.0 months had a PSA response rate of 64.3% and the PSA response rate in those with < 3.0 months decreased to 22.8%, hazard rate (HR) = 0.149 (95% confidence interval [CI] 0.029 - 0.766), P = 0.023, area under the curve (AUC) = 0.707. The PSA response rate for patients with baseline serum testosterone >= 0.1 and < 0.1 ug/L were 55.6% and 5.7%, respectively, HR = 0.068 (95%CI 0.012 - 0.380), P = 0.002, AUC = 0.749. The common adverse reactions included liver dysfunction (17.9%), renal dysfunction (16.4%), fatigue (11.9%), nausea (6.0%) and anorexia (4.5%) and so on. CONCLUSIONS: Low dose ketoconazole therapy was a moderate, low toxicity hormonal therapy option for patients with CRPC. PSA doubling time >= 3 months and baseline serum testosterone >= 0.1 ug/L were predictors of desired effect for low dose ketoconazole therapy. PMID- 22490154 TI - [Evaluation of gefitinib plus radiotherapy in non-small-cell lung cancer patients with brain metastases]. AB - OBJECTIVE: To evaluate the efficacies of gefitinib plus radiotherapy in the treatment of brain metastases in non-small-cell lung carcinoma (NSCLC) patients. METHODS: A retrospective analysis was conducted for 161 NSCLC patients with brain metastases treated in Xinqiao Hospital from January 2001 to January 2010. And 38 patients aged 38 - 77 years old received the combined regimen of gefitinib plus radiotherapy. It consisted of synchronically practicing general or stereotactic brain radiotherapy and an oral intake of gefitinib (250 mg, QD for at least 8 consecutive weeks). The efficacies and toxicity were evaluated at Week 12 after the initial treatment. A total of 123 patients aged 37 - 76 years old undergoing whole brain or stereotactic radiotherapy were used as control. chi(2) test between two groups was carried out to evaluate the objective response rate (ORR), disease control rate (DCR), brain metastasis related symptoms and III-IV degree of toxicity. Non-parametric rank tests were performed to compare the U.S. Eastern Cooperative Oncology Group (ECOG) performance status score between two groups. RESULTS: In the combination therapy group, the levels of ORR and DCR were significantly higher than those in the conventional treatment group (31.6%, 78.9% vs 15.4%, 60.2%). The differences were statistically significant (chi(2) = 4.859, P = 0.027 and chi(2) = 4.479, P = 0.034); significant difference existed in brain metastasis-related symptoms between two groups (chi(2) = 4.612, P = 0.037); the ECOG scores were evaluated in the combination therapy group. And they were as follows: 0 - 1 (n = 18), 2 (n = 11), 3 - 4 (n = 9) at pre-treatment vs 0 - 1 (n = 27), 2 (n = 6), 3 - 4 (n = 5) at post-treatment. The ECOG score significantly improved after treatment (Z = -2.012, P = 0.044). Regarding the III-IV degree of toxicity, the combination therapy group had 4 patients with acne-like rash and it was significantly higher than that in the conventional therapy group (n = 0) (P = 0.003). But no difference existed in the occurrence of fatigue, nausea, vomiting, diarrhea and myelosuppression. CONCLUSION: The combined regimen of gefitinib plus radiotherapy can improve the therapeutic efficacies of brain metastases and enhance the quality-of-life in NSCLC patients, side effects are tolerable. PMID- 22490155 TI - [Evaluation of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of hilar and mediastinal masses of unknown etiologies]. AB - OBJECTIVE: To explore the diagnostic values of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the patients with hilar and mediastinal masses. METHODS: A total of 91 patients with mediastinal/hilar masses undergoing EBUS-TBNA in Zhongshan Hospital between September 2009 and March 2011 were retrospectively enrolled. Their unknown etiologies were difficult to be assessed by a traditional biopsy. The association of pathologic examinations and clinical data were analyzed. RESULTS: Among them, 61 patients had malignant lesions while 30 patients were diagnosed with benign diseases. In the cases with malignant lesions, the diagnostic sensitivity, specificity and accordance rate were 91.67%, 100% and 91.80% respectively. The diagnostic accordance rate of benign lesions was 60%. And 36.9% (24/65) of the samples were small-sized so as to improve the diagnostic accuracy. The combination of cytology and histology significantly increased the diagnostic accordance versus cytology alone in all cases (P < 0.01). But there was no statistically significant difference in the malignant lesion subgroup with a better tendency (P > 0.05). No severe complication occurred. CONCLUSION: With a high diagnostic accuracy and a low complication rate for the patients with hilar and mediastinal masses of unknown etiologies, EBUS-TBNA has different values for diagnosing malignant and benign lesions. PMID- 22490156 TI - [Significance of expression of chemokine receptor and matrix metalloproteinase in small cell lung cancer]. AB - OBJECTIVE: To explore the expressions of CXC chemokine receptor 4 (CXCR4) and matrix metalloproteinase-9 (MMP-9) and examine their correlations with metastasis and prognosis in small cell lung cancer (SCLC). METHODS: Immunohistochemistry was employed to detect the expressions of CXCR4 and MMP-9 in the tissue samples from 65 SCLC patients treated in Cancer Institute and Hospital Attached to Tianjin Medical University from January 2003 to October 2009. And their correlations with metastasis and prognosis were analyzed by Chi-square test and Kaplan-Meier method and Cox regression. RESULTS: The positive expression rates of CXCR4 and MMP-9 were 100.0% (65/65) and 87.7% (57/65) in SCLC tissues respectively. Significant difference of the expression rate of CXCR4 was found between patients undergoing bone metastasis or not (P = 0.004). But the differences were not significant between brain metastasis or not (P = 0.068) and lymph node metastasis or not (P = 0.085). A high expression rate of MMP-9 was significantly associated with pathological staging (P = 0.048). But the difference between lymph node metastasis or not was not significant (P = 0.085). Univariate analysis suggested that a high expression rate of CXCR4 was significantly correlated with the disease-free survival (DFS) of SCLC patients (P = 0.005). But a high expression rate of MMP-9 was not associated with DFS (P = 0.341). Multivariate analysis suggested that a high expression rate of CXCR4 was an independent prognostic factor for DFS in SCLC. CONCLUSIONS: The elevated levels of CXCR4 and MMP-9 are found in SCLC tissues. And the expression rate of CXCR4 may be correlated with bone metastasis, but the correlation is not notable for MMP-9. The expression rate of CXCR4 is an independent prognostic factor for DFS in SCLC. PMID- 22490157 TI - [Alterations of immune status in liver transplant patients with sepsis]. AB - OBJECTIVE: To explore the alterations of immune status in liver transplant recipients with sepsis so as to provide rationales for the adjustments of immunosuppressive agents. METHODS: A total of 47 cases complicated with sepsis after abdominal operations from January 2009 to December 2010 were divided into 4 groups according to the type of operations and the stage of sepsis: A. sepsis after transplantation (TS, n = 11), B. severe sepsis after transplantation (TSS, n = 10), C. sepsis without transplantation (NTS, n = 15) and D. severe sepsis without transplantation (NTSS, n = 11). Ten healthy volunteers were selected as the control group. Blood samples were collected from these patients to measure the immunological parameters associated with T lymphocyte. RESULTS: The APACHII and SOFA score of TSS group and NTSS group were both higher than TS group and NTS group respectively (all P < 0.01). In addition, SOFA score in TSS group was significantly higher than that in NTSS group (17.0 +/- 4.5 vs 12.1 +/- 2.8, P < 0.01). The percentages of T cell in 4 groups were all significantly lower than healthy volunteers (all P < 0.01). The CD4/CD8 ratio was slightly lower in the TSS group than those in the control group and the other three groups (P = 0.095). As compared with the control group, the IFN-gamma/IL-4 ratios were significant lower in the TSS and NTSS groups (0.039 +/- 0.012, 0.047 +/- 0.018 vs 0.062 +/- 0.006) while the level of IL-10 was higher ((32.6 +/- 7.5), (25.9 +/- 4.3) vs (8.2 +/- 1.4) ng/L, all P < 0.05). And the difference was more significant in the TSS group. As compared with the healther, the percentage of CD4(+)CD25(+)Foxp3(+)Treg was lower in NTS group (2.21% +/- 0.96% vs 4.06% +/- 0.52%, P < 0.01), and significantly higher in NTSS group (8.02% +/- 3.57% vs 4.06% +/- 0.52%, P = 0.003). No significant difference existed in the percentage of Treg between the TS and control groups (P = 0.398). And it was significantly higher that in the TSS group (5.16% +/- 0.99% vs 4.06% +/- 0.52%, P = 0.006). But the magnitude of increase level was not so great as that in the NTSS group. The changes of Foxp3 mRNA demonstrated the similar trend as the percentage of Treg. CONCLUSIONS: The immune states of transplant recipients with sepsis are comparable with healthy persons during sepsis. It may subsequently develop into serious immunosuppression. Immunosuppressant should be withdrawn in severe sepsis stage so as to reconstitute the immune system. PMID- 22490158 TI - [Correlation of serum uric acid and islet beta cell functions in female type 2 diabetics]. AB - OBJECTIVE: To examine the correlation of serum uric acid and islet beta cell functions in female type 2 diabetics. METHODS: A total of 533 female type 2 diabetics were recruited. And their clinicobiochemical parameters were measured. The levels of acute insulin response (AIR) and acute C-peptide response (ACPR) were measured by a stimulation of arginine. Among them, 262 patients received the examinations of OGTT (oral glucose tolerance test), area under the curve of insulin (AUC-insulin) and C peptide (AUC-C peptide). Serum uric acid > 360 umol/L was defined as hyperuricemia. RESULTS: The serum uric acid levels of the hyperuricemia and control groups were (430 +/- 8) and (248 +/- 3) umol/L respectively. The AIR, ACPR, AUC-insulin and AUC-C peptide levels were significantly higher in the hyperuricemia group than those in the control group (P < 0.01). There was a significant positive correlation between serum uric acid and AIR, ACPR, AUC-insulin and AUC-C peptide (r = 0.194, P < 0.01; r = 0.146, P < 0.01; r = 0.307, P < 0.01 and r = 0.420, P < 0.01). The serum levels of uric acid were significantly different between tertile groups of AIR (260 +/- 7), (264 +/- 8), (302 +/- 7) umol/L, ACPR ((263 +/- 8), (271 +/- 7), (296 +/- 7) umol/L), AUC insulin ((241 +/- 10), (279 +/- 10), (301 +/- 8) umol/L) and AUC-C peptide ((229 +/- 8), (265 +/- 9), (326 +/- 10) umol/L, P < 0.01). Multivariate linear regression demonstrated that the serum level of uric acid were associated with AIR (beta = 0.002, 95%CI 0.0010 - 0.0030, P < 0.01), ACPR (beta = 0.001, 95%CI 0.0002 - 0.0020, P = 0.02), AUC-insulin (beta = 0.002, 95%CI 0.0004 - 0.0030, P < 0.01) and AUC-C peptide (beta = 0.003, 95%CI 0.0020 - 0.0030, P < 0.01) after an adjustment of related risk factors. CONCLUSION: The serum level of uric acid is significantly correlated with AIR, ACPR, AUC-insulin and AUC-C peptide in female type 2 diabetics. And it may be an independent risk factor of predicting islet beta cell functions in female type 2 diabetics. PMID- 22490159 TI - [Evaluation on protocol SCMS-ALL-2005 for childhood B lineage acute lymphoblastic leukemia]. AB - OBJECTIVE: To reduce the risk of therapy related complication during the treatment and keeps the long term event free survival, and to evaluate the results and risk factors of SCMC-lymphoblastic leukemia (ALL)-2005 protocol. METHODS: Designed the new protocol SCMC-ALL-2005 based on the previous protocol XH-99 for ALL. Divided the patients into low, median and high risk groups depends on risk factors including day 33 and 55 minimal residual disease (MRD) level. The higher risk group, the more intensive therapy was given. All the cases were registed on pediatric oncology network database (POND). All the abandonment patients were counted as event. From May 1(st) 2005 to April 30(th) 2009, 351 children who were newly diagnosed as B lineage ALL were enrolled in this study. The prognoses relating to risk grouping, age, mutation gene and MRD level were analyzed. RESULTS: Up to June 30, 2011, 273 patients were followed up with median time 49 months (range 26 to 74 months). Three hundred and forty-five patients (98.29%) achieved complete remission on day 35 induction. 12 cases were younger than 1 year old (3.42%), 285 cases between 1 and 9 years old (81.20%), 54 cases 10 to 18 years old (15.38%). Five year event-free survival (EFS) was 34%, 72% and 63%, respectively. One hundred and fifty-six cases belonged to lowered risk (44.44%), 177 to middle risk (50.43%) and 18 to higher risk (5.13%). Five year EFS was 78%, 64% and 30%, respectively. In this study, 18 patients were detected positive for BCR/ABL, 3 for MLL/AF4, 16 for PBX/E2A, and 36 for TEL/AML. The 5 year EFS were 11%, 66%, 75% and 74%, respectively. A total of 300 cases were tested for MRD levels on day 35. Of them, 241 cases were with MRD <= 0.01% (negative), and 59 cases > 0.01% (positive). The 5 year relapse free survival (RFS) was 79% and 58%, respectively. Total 6 patients died of complication (1.71%). 18 patients were abundant treatment with no disease progress. 70 patients relapsed (19.94%), including 52 bone marrow, 8 central nerve system (CNS), 1 both in bone marrow and CNS, 1 second cancer (M(4)) and 8 testis. Five year overall survival (OS) and EFS are 84% and 69%. CONCLUSIONS: The risk of therapy related death is low with the protocol SCMC-ALL-2005. MRD affects the prognosis. The long term prognosis is poor for high risk group, with BCR/ABL and positive MRD. PMID- 22490160 TI - [Risk factors and scoring system in the prediction of contrast induced nephropathy in patients undergoing percutaneous coronary intervention]. AB - OBJECTIVE: To develop a simplified risk scoring system of contrast induced nephropathy (CIN) after percutaneous coronary intervention (PCI). METHODS: A retrospective study was performed on 1500 patients in the development set undergoing PCI from January 2008 to December 2009. And 1000 patients treated from January 2010 to May 2011 were selected for the validation set. Logistic regression analysis was applied to identify the risk factors of CIN. Based on the odds ratio, the sum of integers was a total risk score for each patient. RESULTS: (1) Among them, CIN occurred in 246 patients with an overall incidence of 16.4%. (2) Eleven identified variables were identified as the risk factors of CIN (with weighted integer): diabetes (3 scores), hypotension (3 scores), left ventricular ejection fraction (LVEF <= 45%) (3 scores), eGFR < 60 [ml*min(-1).(1.73 m(2))( 1)] (3 scores), age >70 years (2 scores), myocardial infarction (2 scores), emergency PCI (2 scores), anemia (2 scores), decreased high-density lipoprotein (HDL) concentration (< 1 mmol/L) (2 scores), contrast agent dose > 200 ml (2 scores) and low permeability contrast agent (1 score). (3) The sum of integers was a total risk score for each patient. The incidence of CIN was 5.2% in the low risk group (<= 4), 13.6% in the moderate-risk group (5 - 10), 32.3% in the high risk group (11 - 14) and 59.0% in the very-high-risk group (>= 15). (4) Good discriminative power was found in the validation population. And the risk score was strongly correlated with CIN (c-statistic = 0.82). CONCLUSION: This scoring system provides a good estimate of the risk of CIN after PCI. It may be used for the prevention and treatment of CIN. PMID- 22490161 TI - [Hemodynamic and efficacies of domestic levosimendan versus dobutamine in patients with acute decompensated heart failure]. AB - OBJECTIVE: To compare the hemodynamic effects of domestic levosimendan versus dobutamine on patients with acute decompensated heart failure (ADHF). METHODS: A total of 78 ADHF patients with pulmonary capillary wedge pressure (PCWP) >= 15 mm Hg and cardiac index (CI) <= 2.5 L*min(-1)*m(-2) were enrolled into this blind, positive-controlled, randomized and multicenter study to receive 24 h intravenous levosimendan or dobutamine therapy. They were randomized into 2 groups: levosimendan and dobutamine (n = 39 each). RESULTS: In the levosimendan group, the PCWP 24 h decreased significantly ((14.2 +/- 7.6) vs (23.1 +/- 8.1) mm Hg, P < 0.01)and CI increased significantly versus the baseline levels ((2.8 +/- 0.7) L*min(-1)*m(-2) vs (2.0 +/- 0.4) L*min(-1)*m(-2), P < 0.01). As compared with the dobutamine group, the change percentages versus baseline in PCWP, pulmonary arterial mean pressure (PAMP), systemic vascular resistance (SVR) at 24 h (median) decreased or increased significantly in the levosimendan group 45.5% vs 22.1% (P < 0.05); 20.8% vs 15.0% (P < 0.05); 34.5% vs 12.7% (P < 0.01); CI increased 39.8% vs 13.5% (P < 0.01). As compared with the baseline level, LVEF increased at 24 h in the levosimendan group (27.4% +/- 6.1% vs 32.5% +/- 8.7%, P < 0.05). Both PCWP and CI at 24 h correlated significantly with NT-proBNP at Day 3 (r = 0.31, P < 0.01; r = -0.29, P < 0.05). Dyspnea improved greatly at 24 h in the levosimendan group than that in the dobutamine group. CONCLUSION: As compared with dobutamine, domestic levosimendan may bring about better outcomes of hemodynamics and dyspnea. PMID- 22490162 TI - [Diagnosis and treatment of diverticulums in laryngopharynx and cervical esophagus]. AB - OBJECTIVE: To explore the clinical presentations, diagnosis and treatment of diverticulums in laryngopharynx and cervical esophagus. METHODS: Nineteen cases of diverticulums in laryngopharynx and cervical esophagus with general clinical information available from 1985 to 2010 at Peking Union Medical College Hospital were reviewed retrospectively and analyzed with a literature review. RESULTS: One case of lateral hypopharyngeal pouch presented with fetor oris and pharyngalgia. Three cases of Killian-Jamieson diverticulums had fetor oris and dysphagia. Among 15 cases of Zenker diverticulums, 3 had fetor oris, sour regurgitation and dysphagia while another 12 cases were asymptomatic. Seven patients with subjective complaints underwent diverticulectomy through open surgeries or endoluminal approaches and their symptoms were resolved and no recurrences were found during a follow-up period of 6 months-18 years. In 12 cases of asymptomatic Zenker diverticulums, observation was adopted and there was no complaint during a follow-up period of 1 - 25 years. CONCLUSION: Lateral hypopharyngeal pouch, Killian-Jamieson diverticulum and Zenker's diverticulum are rare entities with different clinical presentations. For symptomatic diverticulum, the most common treatment is surgical resection of diverticulectom and the prognosis is satisfactory. But for asymptomatic diverticulum, observation suffices. PMID- 22490163 TI - [Laparoscopic adrenalectomy in the treatment of adrenal ganglioneuroma]. AB - OBJECTIVE: To evaluate the feasibility of laparoscopic adrenalectomy in the treatment of adrenal ganglioneuromas. METHODS: The clinical data of 12 cases of adrenal ganglioneuromas undergoing laparoscopic adrenalectomy between February 2002 and August 2010 were reviewed retrospectively. RESULTS: None of them had endocrine function. The average long diameter of ganglioneuromas was 6.5 cm (range: 1.5 - 16.8 cm). Ten tumors were resected through retroperitoneal approach with an average long diameter of 6.0 cm and another two through transperitoneal approach with 7.5 and 10.7 cm in size respectively. Three tumors surrounded renal pedicle and one adhered to kidney. The average operative duration was 144 minutes, average blood loss 194 ml and average postoperative hospitalization stay 5.4 days. None had local recurrence and distant metastasis during a mean follow up period of 45 months. CONCLUSION: Laparoscopic adrenalectomy is both safe and feasible for adrenal ganglioneuromas if an appropriate approach is chosen and renal pedicle well-protected. PMID- 22490164 TI - [Effects of matrix metallopeptidase 9 on the proliferation, apoptosis, type I and III procollagen synthesis of rat dermal fibroblasts]. AB - OBJECTIVE: To explore the effects of matrix metallopeptidase 9 (MMP-9) on the proliferation, apoptosis, type I and III procollagen synthesis of rat dermal fibroblasts. METHODS: Lipopolysaccharide (LPS) at 0.1 and 1.0 ug/ml was used to stimulate fibroblasts to up-regulate the expression of MMP-9 for 18 and 48 h. And then RNA interference was employed to inhibit the high expression of MMP-9. Cell proliferation was tested by CCK-8, cell apoptosis by flow cytometry and type I and III procollagen expressions by quantitative reverse transcriptase PCR (qRT PCR). RESULTS: The MMP-9 expression of fibroblasts increased after the stimulation of LPS. And the 1.0 ug/ml LPS stimulation of 48 hours was 14.25 times of mRNA expression and 2.31 times of protein expression versus that of the normal group (both P < 0.05). The RNA interference obviously inhibited the high expression of MMP-9. The mRNA expression was 1/8 and protein expression 1/3 (both P < 0.05) as compared with the control group. Cell proliferation decreased with the rising expression of MMP-9 to some extent [(1.08 +/- 0.08) vs (1.18 +/- 0.09), P < 0.05] and improved after the inhibition of high expression of MMP-9 [(1.78 +/- 0.17) vs (1.53 +/- 0.15), P < 0.01]. There was no change of apoptosis accompanied with high expression of MMP-9 (P > 0.05). Apoptosis decreased after the inhibition of high expression of MMP-9 for 48 hours (3.53% +/- 0.22% vs 4.47% +/- 0.46%, P < 0.05). The synthesis of type I procollagen was the same no matter up-regulation or down-regulation of MMP-9 expression (P > 0.05). As the expression of MMP-9 increased, the synthesis of type III procollagen decreased (P < 0.01), but not increased by 1.02 folds after the inhibited expression of MMP-9 (P > 0.05). CONCLUSION: MMP-9 can affect the biological behaviors of rat dermal fibroblasts. PMID- 22490165 TI - [Enhancing effects of perlecan or vascular endothelial growth factor-165 on angiogenesis in mice]. AB - OBJECTIVE: To explore the angiogenesis-promoting effects of perlecan or vascular endothelial growth factor (VEGF) at different time points through quantitative analysis of microvessel density (MVD). METHODS: Four kinds of scaffolds: open cell polylactic acid (OPLA) (control), OPLA + VEGF-165, OPLA + perlecan and OPLA + VEGF-165 + perlecan were implanted into mice. At Weeks 1, 2, 3, 4, 6 and 8, OPLA was harvested and then HE and immunocytochemistry were employed to detect the angiogenesis-promoting effects of scaffold. MVD of each group was appraised by the Tukey test. RESULTS: The scaffolds exhibited excellent biocompatibility with tissue. Numerous vessels were spotted obviously around the implants, especially at Week 8. And the OPLA scaffold degraded with the elapsing of time and its inner part was divided into many sections along with the ingrowth of vessels. Compared with the other three groups, the MVD of the OPLA + VEGF-165 + perlecan group was the highest at all time points. There were statistical differences between the OPLA + VEGF-165 + perlecan and OPLA groups at Week 1 (3.30 +/- 0.42 vs 1.80 +/- 0.29); MVD of the OPLA + VEGF-165 + perlecan group was thrice as much as the OPLA group at Week 3 (11.70 +/- 0.87 vs 4.50 +/- 0.34); at Week 8, MVD of the OPLA + VEGF-165 + perlecan group was more than thrice as much as the OPLA group (31.40 +/- 1.35 vs 9.90 +/- 0.67). CONCLUSION: Angiogenesis is synergistically enhanced by the combined application of VEGF-165 and perlecan in mice. PMID- 22490166 TI - Comparison of the frying performance of olive oil and palm superolein. AB - Deep-fat frying is an important method of food preparation in which foods are immersed in hot oil. Repeated use of frying oils is a common practice, and in the presence of atmospheric oxygen it produces various undesirable reactions in used oils. Stable frying oils usually require low linolenic acid (LnA < 3%), increased oleic acid (OA > 40%), and decreased linoleic acid (LA < 50%). The aim of this study was to establish the behavior of palm superolein (PSO) (OA 45%; LA 12.5%; LnA 0.2%) and olive oil (OO) during repeated, discontinuous deep frying of French fries. The behavior of the oils under controlled heating conditions was also studied by maintaining all of the process variables the same as those in deep frying, except that there was no food in the oil. The PSO selected to be tested in this study may represent an alternative to OO as a frying medium. Although PSO presented a faster increase in some oxidation indices, such as free fatty acid and total polar compounds, for other indicators, PSO showed better behavior than OO (less formation of C8:0 and lower peroxide value). PMID- 22490167 TI - Testing the nearest neighbor model for canonical RNA base pairs: revision of GU parameters. AB - Thermodynamic parameters for GU pairs are important for predicting the secondary structures of RNA and for finding genomic sequences that code for structured RNA. Optical melting curves were measured for 29 RNA duplexes with GU pairs to improve nearest neighbor parameters for predicting stabilities of helixes. The updated model eliminates a prior penalty assumed for terminal GU pairs. Six additional duplexes with the 5'GG/3'UU motif were added to the single representation in the previous database. This revises the DeltaG degrees (37) for the 5'GG/3'UU motif from an unfavorable 0.5 kcal/mol to a favorable -0.2 kcal/mol. Similarly, the DeltaG degrees (37) for the 5'UG/3'GU motif changes from 0.3 to -0.6 kcal/mol. The correlation coefficients between predicted and experimental DeltaG degrees (37), DeltaH degrees , and DeltaS degrees for the expanded database are 0.95, 0.89, and 0.87, respectively. The results should improve predictions of RNA secondary structure. PMID- 22490168 TI - Ontological labels for automated location of anatomical shape differences. AB - A method for automated location of shape differences in diseased anatomical structures via high resolution biomedical atlases annotated with labels from formal ontologies is described. In particular, a high resolution magnetic resonance image of the myocardium of the human left ventricle was segmented and annotated with structural terms from an extracted subset of the Foundational Model of Anatomy ontology. The atlas was registered to the end systole template of a previous study of left ventricular remodeling in cardiomyopathy using a diffeomorphic registration algorithm. The previous study used thresholding and visual inspection to locate a region of statistical significance which distinguished patients with ischemic cardiomyopathy from those with nonischemic cardiomyopathy. Using semantic technologies and the deformed annotated atlas, this location was more precisely found. Although this study used only a cardiac atlas, it provides a proof-of-concept that ontologically labeled biomedical atlases of any anatomical structure can be used to automate location-based inferences. PMID- 22490169 TI - Trajectories of maternal depressive symptoms predict child problem behaviour: the Generation R study. AB - BACKGROUND: It is unclear how the course of maternal depressive symptoms affects child development. We modelled trajectories of maternal depressive symptoms from mid-pregnancy to 3 years after childbirth to better determine their associations with child problem behaviour. METHOD: Mother-child dyads (n = 4167) participated in a population-based prospective cohort in The Netherlands. Depressive symptoms were assessed with the Brief Symptom Inventory during pregnancy and at 2, 6 and 36 months postnatally. When children were 3 years old, problem behaviour was assessed with the Child Behaviour Checklist completed by each parent. A group based modelling technique was used to model trajectories of maternal depressive symptoms and to examine their association with child problem behaviour. The added value of trajectory modelling was determined with successive linear regressions. RESULTS: We identified four trajectories of maternal depressive symptoms; 'no' (34%), 'low' (54%), 'moderate' (11%) and 'high' (1.5%). Child problem behaviour varied as a function of maternal trajectory membership. Whether rated by mother or father, children of mothers assigned to higher trajectories had significantly more problem behaviours than children of mothers assigned to lower trajectories. The model including trajectories had additive predictive value over a model relying only on a summed repeated measure of severity and a predefined chronicity variable. CONCLUSIONS: Depending on their course, maternal depressive symptoms have different effects on child problem behaviour. More information is gained by studying trajectories of symptoms, than only predefined measures of severity and chronicity. Moreover, trajectories can help identifying clinically depressed mothers who are possible candidates for early interventions. PMID- 22490170 TI - Striving for better health through health research in post-conflict Timor-Leste. AB - The Cabinet of Health Research and Development (CHRD) has recently been established as the first health research institute in one of the world's newest nations, Timor-Leste. We discuss the development of this initiative to build health research capacity within the context of Timor-Leste's health system, history and future goals. PMID- 22490171 TI - Reduced looming sensitivity in primary school children with Developmental Co ordination Disorder. AB - Almost all locomotor animals are sensitive to optical expansion (visual looming) and for most animals this sensitivity is evident very early in their development. In humans there is evidence that responses to looming stimuli begin in the first 6 weeks of life, but here we demonstrate that as children become independent their perceptual acuity needs to be 50 to 100 times better than has been demonstrated in infants in order to be skilful at collision avoidance at a roadside. We have recently established that sensitivity to the detection of visual looming in 6- to 11-year-old children is significantly below that of adults (Wann, Poulter & Purcell, 2011). Here, using comparable methods, we explore looming detection sensitivity in children with Developmental Co ordination Disorder (DCD), who show broad patterns of impairment in visuo-motor control. We presented visual simulations of approaching vehicles, scaled to represent different approach rates, to children with DCD aged between 6 and 11 years (n = 11) and typically developing age and gender matched controls (n = 11). Looming detection thresholds were measured under foveal and perifoveal viewing conditions, for isotropic expansion and isotropic expansion with simulated viewpoint motion. Our results show that there are situations in which children with DCD may fail to detect vehicles approaching at speeds in excess of 22 km/h, suggesting a developmental immaturity in looming sensitivity. This provides one of the first clear demonstrations of low-level motion processing deficits in children with DCD. The decrement observed may give rise to potential errors in the road crossing behaviour of these children, whereby approaching vehicles could be perceived as stationary. These findings further contribute towards understanding the adverse statistic that children under 9 years of age are four times more likely than adults to be involved in a road accident as a pedestrian. PMID- 22490172 TI - Amygdala response to mother. AB - In altricial species, like the human, the caregiver, very often the mother, is one of the most potent stimuli during development. The distinction between mothers and other adults is learned early in life and results in numerous behaviors in the child, most notably mother-approach and stranger wariness. The current study examined the influence of the maternal stimulus on amygdala activity and related circuitry in 25 developing children (n = 13) and adolescents (n = 12), and how this circuitry was associated with attachment-related behaviors. Results indicated that maternal stimuli were especially effective in recruiting activity in the left dorsal amygdala, and activity in this amygdala region showed increased functional connectivity with evaluative and motor regions during viewing of maternal stimuli. Increases in this left dorsal amygdala activity and related amygdala-cortical functional connectivity were associated with increased mother-approach behaviors as measured by in-scanner behavioral responding and out-of-scanner child-report. Moreover, age-related changes in amygdala activity to strangers statistically mediated the developmentally typical decline in stranger wariness seen across this period. These results suggest that mother-induced behaviors are enacted by maternal influence on amygdala-cortical circuitry during childhood and adolescence. PMID- 22490173 TI - The growth of reading skills in children with Down Syndrome. AB - There appears to be a close and probably causal relationship between early variations in phoneme skills and later reading skills in typically developing children, though the pattern in children with Down Syndrome is less clear. We present the results of a 2-year longitudinal study of 49 children with Down Syndrome (DS) and 61 typically developing (TD) control children with similar initial levels of reading skill. Phoneme awareness and vocabulary were strong concurrent predictors of initial levels of reading skill in both groups. However, longitudinally phoneme awareness was a predictor of the growth of reading skills in TD children but not in children with DS. There was a very high degree of longitudinal stability in reading skills in children with DS, and initial levels of reading skills seemed to be highly constrained by general language skills, as indexed by vocabulary knowledge, in this population. We conclude that reading development in children with DS shows similarities and differences to the pattern observed in TD children and that phoneme awareness appears to be a less powerful influence on the development of reading skills in children with DS. PMID- 22490174 TI - Electrophysiological evidence for late maturation of strategic episodic retrieval processes. AB - Improvement in source memory performance throughout development is thought to be mediated by strategic processes that facilitate the retrieval of task-relevant information. Using event-related potentials (ERPs), we examined developmental changes in these processes during adolescence. Adolescents (13-14 years) and adults (19-29 years) completed a memory exclusion task which required the discrimination between words studied in one color ('targets') and words studied in the alternative color ('non-targets') under two conditions that put different demands on strategic control. Memory accuracy improved with age and also increased with decreasing control demands in both age groups. The parietal old/new effect, an ERP correlate of recollection, was reliable for targets across conditions in both age groups. By contrast, ERP correlates of non-target recollection were present in adolescents across conditions but not in adults. This suggests that adults implemented a strategy to prioritize recollection of target information with greater success than adolescents regardless of control demands, presumably reflecting maturational differences in cognitive control. In support of this view, the ERP amplitude difference between targets and non targets was positively correlated with a measure of working memory capacity (WMC) in adults but not in adolescents. A further age-related difference was that ERP correlates of post-retrieval processing, including late right-frontal old/new effects and late posterior negativities, were observed in adults only. Together, our data suggest protracted maturation in the strategic processes that underlie selective recollection and post-retrieval control. PMID- 22490176 TI - Building biases in infancy: the influence of race on face and voice emotion matching. AB - Early in the first year of life infants exhibit equivalent performance distinguishing among people within their own race and within other races. However, with development and experience, their face recognition skills become tuned to groups of people they interact with the most. This developmental tuning is hypothesized to be the origin of adult face processing biases including the other-race bias. In adults the other-race bias has also been associated with impairments in facial emotion processing for other-race faces. The present investigation aimed to show perceptual narrowing for other-race faces during infancy and to determine whether the race of a face influences infants' ability to match emotional sounds with emotional facial expressions. Behavioral (visual paired comparison; VPC) and electrophysiological (event-related potentials; ERPs) measures were recorded in 5-month-old and 9-month-old infants. Behaviorally, 5 month-olds distinguished faces within their own race and within another race, whereas 9-month-olds only distinguish faces within their own race. ERPs were recorded while an emotion sound (laughing or crying) was presented prior to viewing an image of a static African American or Caucasian face expressing either a happy or a sad emotion. Consistent with behavioral findings, ERPs revealed race specific perceptual processing of faces and emotion/sound face congruency at 9 months but not 5 months of age. In addition, from 5 to 9 months, the neural networks activated for sound/face congruency were found to shift from an anterior ERP component (Nc) related to attention to posterior ERP components (N290, P400) related to perception. PMID- 22490175 TI - Electrophysiological evidence of altered memory processing in children experiencing early deprivation. AB - Associations between early deprivation and memory functioning were examined in 9- to 11-year-old children. Children who had experienced prolonged institutional care prior to adoption were compared to children who were adopted early from foster care and children reared in birth families. Measures included the Paired Associates Learning task from the Cambridge Neuropsychological Test and Automated Battery (CANTAB) and a continuous recognition memory task during which ERPs were also recorded. Children who experienced prolonged institutionalization showed deficits in both behavioral memory measures as well as an attenuated P300 parietal memory effect. Results implicate memory function as one of the domains that may be negatively influenced by early deprivation in the form of institutional care. PMID- 22490177 TI - Sex differences in fetal habituation. AB - There is some evidence for sex differences in habituation in the human fetus, but it is unknown whether this is due to differences in central processing (habituation) or in more peripheral processes, sensory or motor, involved in the response. This study examined whether the sex of the fetus influenced auditory habituation at 33 weeks of gestation, and whether this was due to differences in habituation or in the sensory or motor components using a set of four experiments. The first experiment found that female fetuses required significantly fewer stimulus presentations to habituate than males. The second experiment revealed no difference in the spontaneous motor behaviour of male and female fetuses. The third experiment examined auditory intensity thresholds for the stimuli used to habituate the fetus. No differences in thresholds were found between males and females, although there was inter-individual variability in thresholds. A final experiment, using stimuli individualized for that particular fetus' auditory intensity threshold, found that female fetuses habituated faster than males. In combination, the studies reveal that habituation in the human fetus is affected by sex and this is due to a difference in central 'information processing' of the stimuli rather than peripheral aspects of the response. It is argued that male and female fetuses present different neurobehavioural developmental trajectories, with females more advanced at 33 weeks than males. This study suggests that research examining prenatal behaviour should consider the factor of fetal sex. This may be particularly pertinent where there is an intention to use the results diagnostically. PMID- 22490178 TI - Ethnic differences in mother-infant language and gestural communications are associated with specific skills in infants. AB - We examined gestural and verbal interactions in 226 mother-infant pairs from Mexican, Dominican, and African American backgrounds when infants were 14 months and 2 years of age, and related these interactions to infants' emerging skills. At both ages, dyads were video-recorded as they shared a wordless number book, a wordless emotion book, and beads and string. We coded mothers' and infants' gestures and language/vocalizations. Each maternal utterance was coded as referential (e.g. 'That's a bead') or regulatory (e.g. 'Put it there'). Mothers reported on infants' gestural, receptive, and productive vocabularies at 14 months, and infants were assessed on receptive language, expressive language, and action sequencing and imitation at 2 years of age. Mothers of the three ethnicities differed in their gesturing, distributions of the two types of language, and coupling of language and gestures. Mothers' ethnicity, language, and gestures were differentially associated with infants' 2-year skills. Mother infant communicative interactions are foundational to infant learning and development, and ethnic differences in modes of early communication portend divergent pathways in the development of specific skills. PMID- 22490179 TI - Active music classes in infancy enhance musical, communicative and social development. AB - Previous studies suggest that musical training in children can positively affect various aspects of development. However, it remains unknown as to how early in development musical experience can have an effect, the nature of any such effects, and whether different types of music experience affect development differently. We found that random assignment to 6 months of active participatory musical experience beginning at 6 months of age accelerates acquisition of culture-specific knowledge of Western tonality in comparison to a similar amount of passive exposure to music. Furthermore, infants assigned to the active musical experience showed superior development of prelinguistic communicative gestures and social behaviour compared to infants assigned to the passive musical experience. These results indicate that (1) infants can engage in meaningful musical training when appropriate pedagogical approaches are used, (2) active musical participation in infancy enhances culture-specific musical acquisition, and (3) active musical participation in infancy impacts social and communication development. PMID- 22490180 TI - Circadian rhythms in executive function during the transition to adolescence: the effect of synchrony between chronotype and time of day. AB - To explore the influence of circadian rhythms on executive function during early adolescence, we administered a battery of executive function measures (including a Go-Nogo task, the Iowa Gambling Task, a Self-ordered Pointing task, and an Intra/Extradimensional Shift task) to Morning-preference and Evening-preference participants (N = 80) between the ages of 11 and 14 years who were tested in the morning or afternoon. Significant Chronotype * Time of Day interactions (controlling for amount of sleep the previous night) revealed that adolescents tested at their optimal times of day performed better than those tested at their nonoptimal times. Implications for our understanding of physiological arousal, sleep, and executive function during adolescence are discussed. PMID- 22490181 TI - Best friends: children use mutual gaze to identify friendships in others. AB - This study examined children's ability to use mutual eye gaze as a cue to friendships in others. In Experiment 1, following a discussion about friendship, 4-, 5-, and 6-year-olds were shown animations in which three cartoon children looked at one another, and were told that one target character had a best friend. Although all age groups accurately detected the mutual gaze between the target and another character, only 5- and 6-year-olds used this cue to infer friendship. Experiment 2 replicated the effect with 5- and 6-year-olds when the target character was not explicitly identified. Finally, in Experiment 3, where the attribution of friendship could only be based on synchronized mutual gaze, 6-year olds made this attribution, while 4- and 5-year-olds did not. Children occasionally referred to mutual eye gaze when asked to justify their responses in Experiments 2 and 3, but it was only by the age of 6 that reference to these cues correlated with the use of mutual gaze in judgements of affiliation. Although younger children detected mutual gaze, it was not until 6 years of age that children reliably detected and justified mutual gaze as a cue to friendship. PMID- 22490182 TI - Dynamic pointing triggers shifts of visual attention in young infants. AB - Pointing, like eye gaze, is a deictic gesture that can be used to orient the attention of another person towards an object or an event. Previous research suggests that infants first begin to follow a pointing gesture between 10 and 13 months of age. We investigated whether sensitivity to pointing could be seen at younger ages employing a technique recently used to show early sensitivity to perceived eye gaze. Three experiments were conducted with 4.5- and 6.5-month-old infants. Our first goal was to examine whether these infants could show a systematic response to pointing by shifting their visual attention in the direction of a pointing gesture when we eliminated the difficulty of disengaging fixation from a pointing hand. The results from Experiments 1 and 2 suggest that a dynamic, but not a static, pointing gesture triggers shifts of visual attention in infants as young as 4.5 months of age. Our second goal was to clarify whether this response was based on sensitivity to the directional posture of the pointing hand, the motion of the pointing hand, or both. The results from Experiment 3 suggest that the direction of motion is necessary but not sufficient to orient infants' attention toward a distal target. Infants shifted their attention in the direction of the pointing finger, but only when the hand was moving in the same direction. These results suggest that infants are prepared to orient to the distal referent of a pointing gesture which likely contributes to their learning the communicative function of pointing. PMID- 22490183 TI - Epistemic trust: modeling children's reasoning about others' knowledge and intent. AB - A core assumption of many theories of development is that children can learn indirectly from other people. However, indirect experience (or testimony) is not constrained to provide veridical information. As a result, if children are to capitalize on this source of knowledge, they must be able to infer who is trustworthy and who is not. How might a learner make such inferences while at the same time learning about the world? What biases, if any, might children bring to this problem? We address these questions with a computational model of epistemic trust in which learners reason about the helpfulness and knowledgeability of an informant. We show that the model captures the competencies shown by young children in four areas: (1) using informants' accuracy to infer how much to trust them; (2) using informants' recent accuracy to overcome effects of familiarity; (3) inferring trust based on consensus among informants; and (4) using information about mal-intent to decide not to trust. The model also explains developmental changes in performance between 3 and 4 years of age as a result of changing default assumptions about the helpfulness of other people. PMID- 22490184 TI - Word learning in deaf children with cochlear implants: effects of early auditory experience. AB - Word-learning skills were tested in normal-hearing 12- to 40-month-olds and in deaf 22- to 40-month-olds 12 to 18 months after cochlear implantation. Using the Intermodal Preferential Looking Paradigm (IPLP), children were tested for their ability to learn two novel-word/novel-object pairings. Normal-hearing children demonstrated learning on this task at approximately 18 months of age and older. For deaf children, performance on this task was significantly correlated with early auditory experience: Children whose cochlear implants were switched on by 14 months of age or who had relatively more hearing before implantation demonstrated learning in this task, but later implanted profoundly deaf children did not. Performance on this task also correlated with later measures of vocabulary size. Taken together, these findings suggest that early auditory experience facilitates word learning and that the IPLP may be useful for identifying children who may be at high risk for poor vocabulary development. PMID- 22490185 TI - Knowledge of heart attack and stroke symptomology: a cross-sectional comparison of rural and non-rural US adults. AB - BACKGROUND: Understanding the signs and symptoms of heart attacks and strokes are important not only in saving lives, but also in preserving quality of life. Findings from recent research have yielded that the prevalence of cardiovascular disease risk factors are higher in rural populations, suggesting that adults living in rural locales may be at higher risk for heart attack and/or stroke. Knowledge of heart attack and stroke symptomology as well as calling 911 for a suspected heart attack or stroke are essential first steps in seeking care. This study sought to examine the knowledge of heart attack and stroke symptoms among rural adults in comparison to non-rural adults living in the U.S. METHODS: Using multivariate techniques, a cross-sectional analysis of an amalgamated multi-year Behavioral Risk Factor Surveillance Survey (BRFSS) database was performed. The dependent variable for this analysis was low heart attack and stroke knowledge score. The covariates for the analysis were: age, sex, race/ethnicity, annual household income, attained education, health insurance status, having a health care provider (HCP), timing of last routine medical check-up, medical care deferment because of cost, self-defined health status and geographic locale. RESULTS: The weighted n for this study overall was 103,262,115 U.S. adults > =18 years of age. Approximately 22.0% of these respondents were U.S. adults living in rural locales. Logistic regression analysis revealed that those U.S. adults who had low composite heart attack and stroke knowledge scores were more likely to be rural (OR=1.218 95%CI 1.216-1.219) rather than non-rural residents. Furthermore, those with low scores were more likely to be: male (OR=1.353 95%CI 1.352-1.354), >65 years of age (OR=1.369 95%CI 1.368-1.371), African American (OR=1.892 95%CI 1.889-1.894), not educated beyond high school (OR=1.400 955CI 1.399-1.402), uninsured (OR=1.308 95%CI 1.3-6-1.310), without a HCP (OR=1.216 95%CI 1.215 1.218), and living in a household with an annual income of < $50,000 (OR=1.429 95%CI 1.428-1.431). CONCLUSIONS: Analysis identified clear disparities between the knowledge levels U.S. adults have regarding heart attack and stroke symptoms. These disparities should guide educational endeavors focusing on improving knowledge of heart attack and stroke symptoms. PMID- 22490186 TI - High levels of soluble VEGF receptor 1 early after trauma are associated with shock, sympathoadrenal activation, glycocalyx degradation and inflammation in severely injured patients: a prospective study. AB - BACKGROUND: The level of soluble vascular endothelial growth factor receptor 1 (sVEGFR1) is increased in sepsis and strongly associated with disease severity and mortality. Endothelial activation and damage contribute to both sepsis and trauma pathology. Therefore, this study measured sVEGFR1 levels in trauma patients upon hospital admission hypothesizing that sVEGFR1 would increase with higher injury severity and predict a poor outcome. METHODS: Prospective observational study of 80 trauma patients admitted to a Level I Trauma Centre. Data on demography, biochemistry, Injury Severity Score (ISS), transfusions and 30-day mortality were recorded and plasma/serum (sampled a median of 68 min (IQR 48-88) post-injury) was analyzed for sVEGFR1 and biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), tissue injury (histone complexed DNA fragments, hcDNA), endothelial activation and damage (von Willebrand Factor Antigen, Angiopoietin-2, soluble endothelial protein C receptor, syndecan-1, soluble thrombomodulin (sTM)), coagulation activation/inhibition and fibrinolysis (prothrombinfragment 1 + 2, protein C, activated Protein C, tissue-type plasminogen activator, plasminogen activator inhibitor-1, D-dimer) and inflammation (interleukin-6). Spearman correlations and regression analyses to identify variables associated with sVEGFR1 and its predictive value. RESULTS: Circulating sVEGFR1 correlated with injury severity (ISS, rho = 0.46), shock (SBE, rho = -0.38; adrenaline, rho = 0.47), tissue injury (hcDNA, rho = 0.44) and inflammation (IL-6, rho = 0.54) (all p < 0.01) but by multivariate linear regression analysis only lower SBE and higher adrenaline and IL-6 were independent predictors of higher sVEGFR1. sVEGFR1 also correlated with biomarkers indicative of endothelial glycocalyx degradation (syndecan-1, rho = 0.67), endothelial cell damage (sTM, rho = 0.66) and activation (Ang-2, rho = 0.31) and hyperfibrinolysis (tPA, rho = 0.39; D-dimer, rho = 0.58) and with activated protein C (rho = 0.31) (all p < 0.01). High circulating sVEGFR1 correlated with high early and late transfusion requirements (number of packed red blood cells (RBC) at 1 h (rho = 0.27, p = 0.016), 6 h (rho = 0.27, p = 0.017) and 24 h (rho = 0.31, p = 0.004) but was not associated with mortality. CONCLUSIONS: sVEGFR1 increased with increasing injury severity, shock and inflammation early after trauma but only sympathoadrenal activation, hypoperfusion, and inflammation were independent predictors of sVEGFR1 levels. sVEGFR1 correlated strongly with other biomarkers of endothelial activation and damage and with RBC transfusion requirements. Sympathoadrenal activation, shock and inflammation may be critical drivers of endothelial activation and damage early after trauma. PMID- 22490188 TI - [The discovery, understanding and implication of fever, thrombocytopenia and leukopenia syndrome (FTLS) caused by new bunyavirus]. PMID- 22490187 TI - The role of cytokines and hot flashes in perimenopausal depression. AB - BACKGROUND: An imbalance in the production of proinflammatory and anti inflammatory cytokines may play a role in the pathophysiology of perimenopausal depression. The aim of this study was to examine serum levels of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFalpha), and the anti-inflammatory cytokine IL-10, in perimenopausal women suffering from depression. Furthermore, to assess whether serum cytokine levels are associated with the presence of hot flashes or the use of selective serotonin reuptake inhibitors (SSRIs). We also evaluated the possible association of hot flashes and perimenopausal depression. METHODS: Serum samples from 65 perimenopausal women, 41 with depression and 24 without depression, were assessed for serum IL-6, TNFalpha and IL-10 by conventional enzyme-linked immunosorbent assays. Depression was evaluated by the 17-item Hamilton Depression Rating Scale (HAM-D 17) and a psychiatric interview. The presence and severity of hot flashes were examined using the Menopause Rating Scale (MRS). RESULTS: Serum levels cytokines did not differ between depressed women and normal controls. Serum levels of cytokines did not change significantly in depressed women with hot flashes or in depressed women treated with SSRIs. Hot flashes were strongly associated (P < 0.0001) with perimenopausal depression. CONCLUSION: The study supports the hypothesis that perimenopausal depression is not characterized by increased proinflammatory cytokines and decreased anti-inflammatory cytokines. Women with perimenopausal depression suffer from more severe and more frequent hot flashes than women without perimenopausal depression. PMID- 22490189 TI - [Analysis of the epidemic characteristics of fever and thrombocytopenia syndrome in Henan province, 2007 - 2011]. AB - OBJECTIVE: To analyze the epidemiological characteristics of fever thrombocytopenia and leukopenia syndrome (FTLS) in Henan province, China in 2007 2011. METHODS: Data from specific surveillance system for FTLS in Henan and Information Management System of Chinese Center for Disease Control and Prevention were used to collect the information of the cases.Descriptive epidemiological methods were used to analyze the surveillance data during 2007 - 2011. Patients' sera were collected to detect new bunyavirus using fluorescent RT PCR and virus isolation. RESULTS: During 2007 - 2011, 1021 FTLS cases were reported in Henan province. The fatality rate was 2.25%with 23 deaths. The cases reported in Xinyang city were 1007, accounting for 98.75%.Cases were mainly occurred between April and October, accounting for 96.47% (985/1021). Epidemic peak was May to July, accounting for 59.16% (604/1021). The second peak occurred in September, accounting for 12.05% (123/1021). The age of the cases ranged from 1 to 88 years old with the median age of 59. Sex ratio (male:female) was 1:1.50 (408:613). In all cases, 93.73% (957/1021) were farmers. In 465 patients' sera, the positive rate of new bunyavirus was 69.25% (322/465) using fluorescent RT PCR. In 164 patients' sera, 67 strains of new bunyavirus were isolated with isolation rate of 40.85% (67/164). CONCLUSION: FTLS in Henan province is caused mainly by the new bunyavirus and has certain regional and seasonal characteristics. Most cases are female older farmers. PMID- 22490190 TI - [Analysis on the diagnosis and treatment of a cluster of cases infected by new bunyavirus]. AB - OBJECTIVE: To analyze and summarize the clinical characteristics, experience of diagnosis and treatment of cases infected by new bunyavirus, which occurred in Henan province in 2010. METHODS: The clinical characteristics and effect of diagnosis and treatment of 5 cases were analyzed using descriptive epidemiological method. Blood specimens were detected by RT-PCR and pathogen separation. RESULTS: PCR testing was positive for all 5 cases. New bunyavirus were isolated from 2 cases. In 5 cases, fever (5/5), the whole body aches (5/5), fatigue (5/5), anorexia (5/5), nausea (5/5), the chills (4/5), cough (4/5), expectoration (4/5), vomiting (3/5), conjunctival hyperemia (3/5); Leukocyte reduction (5/5), thrombocytopenia (5/5), elevated alanine aminotransferase (4/5), elevated aspartate aminotransferase (4/5), elevated lactate dehydrogenase (5/5), creatine kinase elevations (4/5), urinary protein (3/5). By symptomatic and supportive treatment and prophylactic antibiotics, the first case died and the other 4 cases were cured. The average course of disease was 15.4 days. CONCLUSION: Cases infected by new bunyavirus have complicated clinical feature and multiple organ damage. If symptomatic treatment is in time, prognosis will be good. PMID- 22490191 TI - [Evaluation on the effect of comprehensive control strategy of schistosomiasis with emphasis on infection source control in Anhui province]. AB - OBJECTIVE: To evaluate the effect of comprehensive control strategy of schistosomiasis with emphasis on infection source control in Anhui province. METHODS: Forty endemic villages in Guichi district, Chizhou city, Anhui province were selected as national pilot villages in the years from 2006 to 2008, and another 10 provincial pilot villages were respectively selected from 10 highly endemic villages in 7 cities in 2007. The comprehensive infection source control measures, including "replace cattle with machines", "raise livestock in pens", "improve the sanitary toilets", "supply safe water " and so on were carried out among the above pilot villages. At the end of 2008, 13 national pilot villages and 6 provincial pilot villages were selected to investigate the popularity of schistosomiasis, and the effect of the comprehensive control strategy in those villages were compared. RESULTS: After implementing the comprehensive control strategy, the infectious rate of schistosomiasis in national pilot villages decreased from 4.57% (487/10 659) to 1.76% (147/8370), with the reduction rate at 61.49%, whose difference showed statistical significance (chi(2) = 115.16, P < 0.01); and the density of infected snails decreased from 0.0067/0.1 m(2) to 0.0008/0.1 m(2), the infectious rate of snails decreased from 0.28% to 0.04%, whose reduction rates were 88.06% and 85.71% respectively. While as to the provincial pilot villages, the infectious rate of schistosomiasis decreased from 1.27% (54/4254) to 0.21% (14/6592), with the reduction rate at 83.46%, whose difference showed statistical significance (chi(2) = 94.57, P < 0.01); and the density of infected snails decreased from 0.0025/0.1 m(2) to 0.0003/0.1 m(2), the infection rate of snails decreased from 0.13% to 0.05%, whose reduction rates were 88.00% and 61.54% respectively. CONCLUSION: The comprehensive control strategy with emphasis on infection source control implemented in marshland and lake regions can effectively control the transmission of schistosomiasis. PMID- 22490192 TI - [The occurrence and survival condition of primary liver cancer among residents in Yangpu district of Shanghai between year 2002 and 2010]. AB - OBJECTIVE: To analyze the incidence and survival rates of primary liver cancer (PLC) among residents in Yangpu district of Shanghai. METHODS: A total of 9 730 736 permanent residents (male 4 996 390 and female 4 734 346) of Yangpu district in Shanghai were recruited in the study between year 2002 and 2010; among whom 2726 PLC cases were diagnosed and 2427 death cases were certified. The incidence and mortality of PLC were calculated under the analysis of the new PLC cases and death cases between year 2002 and 2010. The rates were standardized by the demographic composition developed in the Fifth Nationwide Census in year 2000, in order to analyze the survival condition of PLC patients and explore the prognosis of surgical excision treatment. RESULTS: Among the new PLC cases between year 2002 and 2010, 1966 cases were male, whose average age of onset was 59.81; while 760 cases were female, whose average age of onset was 68.93. The crude incidence rate was 39.35/100 000 in male, which was higher than it in female, as 16.05/100 000. The difference showed statistical significance (U = 7.32, P < 0.01). The standardized incidence rates were 21.98/100 000 and 6.96/100 000 in male and female, respectively. The difference showed statistical significance (U = 221.76, P < 0.01). There were 2427 PLC death cases in total, including 1734 male death cases and 693 female death cases. The crude mortality rate was 34.71/100 000 in male and 14.64/100 000 in female, whose difference were statistically significant (U = 6.68, P < 0.01). The standardized mortality rate was 19.16/100 000 in male and 6.06/100 000 in female, whose difference were statistically significant (U = 207.18, P < 0.01). The incidence and mortality rates both increased apparently since males aging over 35 and females over 45. The 1 - 5 year survival rates of PLC patients were 33.95%, 23.11%, 17.04%, 14.42% and 12.29%, respectively. In the surgical excision treatment group (321 cases), the 1 - 5 year survival rates were separately 66.78%, 52.87%, 41.88%, 33.57% and 32.64%; while in the non-surgical treatment group (2405 cases), the 1 - 5 year survival rates were separately 29.04%, 18.58%, 13.30%, 11.16% and 9.01%. The differences in 1 - 5 year survival rates between surgical and non-surgical groups all showed statistical significance (U = 12.78, 10.52, 8.28, 5.56 and 5.12, respectively, P < 0.01). CONCLUSION: The incidence of PLC was close to its mortality in Yangpu district of Shanghai. The male incidence and mortality rates were significantly higher than female corresponding rates. The surgical excision treatment could improve the prognosis of PLC. PMID- 22490193 TI - [Comparison of incidence of nasopharyngeal carcinoma in populations with different fluctuation modes of immunoglobulin A antibody levels against Epstein Barr virus capsid antigen]. AB - OBJECTIVE: To explore the incidence regularity in populations with different fluctuation modes of Epstein-Barr virus (EBV) antibody levels. METHODS: Based on the data of a NPC mass screening for nasopharyngeal carcinoma (NPC) in Jianggu town and Didou town of Sihui city, Guangdong province from 1992 to 1998, 586 subjects who were positive and retested for twice or above were divided into ascending group (114 subjects), stable or fluctuating group (313 subjects), and descending group (159 subjects) according to the fluctuation of immunoglobulin A antibody against EBV capsid antigen (VCA-IgA) level; 9889 subjects who were negative in the first test of VCA-IgA were set as control group. All the participants were followed-up till December 31, 2007. The incidence, onset time and clinical characteristics of NPC were compared among groups. RESULTS: The 5 year cumulative detection rates of ascending, stable or fluctuating, and descending group were 3.51% (4/114), 0.64% (2/313) and 0.00% (0/159), respectively; the 5-year cumulative detection proportions were 4/4, 2/6 and 0/2, respectively. Comparing to the control group, the hazard ratio (HR) for the incidence of NPC in ascending group was highest (HR = 10.96, 95%CI: 3.91 - 30.74), followed by stable or fluctuating group (HR = 5.79, 95%CI: 2.45 - 13.69), and descending group (HR = 3.84, 95%CI: 0.92 - 16.01) which had the lowest HR. CONCLUSION: Individuals with stable, fluctuating or ascending VCA-IgA level showed higher risk and earlier onset of NPC was found in ascending group. PMID- 22490194 TI - [Detection of the viable but nonculturable Escherichia coli O157:H7 in aquatic microcosm]. AB - OBJECTIVES: This study is to monitor the survival of E. coli O157:H7 in the aquatic microcosm from Han River and explore the feasibility of fluorescence staining, heterotrophic plate count and ELISA in detection of viable but nonculturable E. coli O157:H7. METHODS: E. coli O157:H7 were added into aquatic microcosm from Han River and cultured with low temperature and oligo-nutrition. Then the survival of E. coli O157:H7 were real-time monitored by acridine orange direct count (AODC), direct viable count (DVC)-CTC staining, DVC-nalidixic acid (NA) staining, heterotrophic plate count (HPC) and ELISA. RESULTS: E. coli O157:H7 can be converted to a viable but nonculturable state in the aquatic microcosm from Han River 58 days after cultured at 4 degrees C with oligo nutrition. The amount of viable E. coli O157:H7 was measured as 1.2 * 10(5) CFU/ml by DVC-CTC and 9.0 * 10(4) CFU/ml by DVC-NA, whereas the amount of culturable bacterial determined by HPC is 0. The amounts of bacteria determined by ELISA are basically stable within 58 days around 10(6) CFU/ml. CONCLUSION: E. coli O157:H7 can be converted into a viable but nonculturable state in Han River water at 4 degrees C with oligo-nutrition, and ELISA combined with fluorescence staining and heterotrophic plate count can be used in quantitative detection of the viable but nonculturable E. coli O157:H7. PMID- 22490195 TI - [Investigation on the levels of carbon-, nitrogen-, iodine-containing disinfection by-products in a water plant in Jiangsu province, China]. AB - OBJECTIVE: This work aimed to investigate the carbon-, nitrogen-, iodine containing disinfection by-products (DBPs) formation and pollution situation in different treatment processes and pipe water of a water plant in Jiangsu province China. METHODS: 12 water samples were collected from raw water, different time points after the addition of chlorine, finished water and pipe water in July, 2011. Trihalomethanes (THM(4)), haloacetic acids (HAA(6)), haloacetonitriles (HAN(s)), chloropicrin (CPs), haloketones (HK(s)), iodoform (IF) and iodoacetic acid (IAA) were detected by gas chromatography with electron capture detector (GC ECD) after liquid-liquid extraction. Nitrosamines (NAms) were detected by gas chromatography with mass spectrometer (GC-MS) after solid-phase extraction. The concentration of DBPs was represented as the mean of duplicate samples. RESULTS: Most DBPs were found in water treatment processes except dibromochloromethane (0.61 ug/L), chloroform (1.64 ug/L) and N-nitrosodimethylamine (3.06 ng/L), which were detected in raw water. Pre-chlorination formed HAA(6) (5.01 ug/L), HKs (0.66 ug/L), HANs (0.57 ug/L) and NAms (98.09 ng/L). Chlorination and post-chlorination led to a dramatic increase in the levels of THM(4), HAA(6) (70.31 and 43.71 ug/L, respectively), while Nams didn't increase. In finished water, bromodichloromethane (34.12 ug/L) had the highest concentration among THM(4) (70.31 ug/L), and so was trichloroacetic acid (13.45 ug/L) among HAA(6) (43.71 ug/L). Levels of HANs, HKs, and CPs were 14.96, 2.32, 0.96 ug/L, respectively. Levels of N-nitrosodimethylamine and N-nitrosodipropylamine were 21.22, 69.43 ng/L, respectively. IAA, IF and other six NAms including N nitrosomethylethylamine, N-nitrosodiethylamine, N-nitrosopyrrolidine, N nitrosomorpholine, N-nitrosopiperidine and N-nitrosodibutylamine were not detected in all water samples. CONCLUSION: Levels of DBPs in this water plant are relative high.and measures should be taken to control DBPs. PMID- 22490196 TI - [Time-series analysis on relationship between air pollution and mortality from circulatory system diseases among registered residents in Chaoyang district of Beijing]. AB - OBJECTIVE: This study aims to investigate relationship between daily concentration of PM(10), SO(2), NO(2) and daily mortality due to circulatory system diseases in Chaoyang district, Beijing. METHODS: The time-series data of daily mortality from circulatory system diseases of registered residents in Chaoyang were obtained from Chaoyang District Center for Disease Control and Prevention. The daily concentration of sulfur dioxide (SO(2)), nitrogen dioxide (NO(2)), and particulate matter (PM(10)) were collected from Beijing Municipal Environmental Monitoring Center. And the routine monitoring meteorological data were collected from Beijing Meteorological Bureau, including daily mean temperature and daily mean relative humidity. The time-series analysis was then conducted to determine the relationship of mortality from circulatory system diseases with daily concentrations of SO(2), NO(2) and PM(10) by using Poisson regression with generalized additive model (GAM). RESULTS: During January 2004 to September 2008, the cumulative death number from circulatory system diseases of registered residents in Chaoyang district of Beijing was 19 241, the daily average concentration of SO(2), NO(2), PM(10) was 48.7, 63.9, 146.1 ug/m(3), respectively. The single pollutant model showed an increase of daily concentration of PM(10), SO(2) and NO(2) by 10 ug/m(3) will augment the mortality from circulatory system diseases by 0.20% (95%CI: 0.01% - 0.39%), 0.36% (95%CI: 0.13% - 0.85%) and 0.30% (95%CI: -0.34% - 0.94%), respectively. In the multiple air pollutants models, combinatorial effects of PM(10) and SO(2) still positively correlated with increased mortality from circulatory system diseases (P < 0.05), whereas changes of the concentration of NO(2) had no significant effect on mortality from circulatory system diseases (P > 0.05). CONCLUSION: Our findings in this study elucidated that changes of the concentration of PM(10) and SO(2) had a positive correlation with daily mortality from circulatory system diseases among the local residents in Chaoyang District, whereas the daily concentration of NO(2) was irrelevant with that. PMID- 22490197 TI - [Influences of compound whole grain on oxidative stress to hyperlipidemia population]. AB - OBJECTIVE: To explore the influence of compound whole grain complex antioxidant chain on oxidative stress to the hyperlipidemia population. METHODS: From March 2008 to March 2009, 418 hyperlipemia residents (45 to 75 years of age) of Han group were screened from 3 main districts in Nanjing, according to the community, blood lipids and oxidative indicators, stratified into intervention and control group by quasi-experimental design. The intervention group (212 individuals) were provided with compound whole grain and health education while only health education was provided for the control group (206 individuals). Body mass index (BMI), waist-to-hip ratio (WHR), total cholesterol (TC), triglyceride (TG) and high density lipoprotein cholesterol (HDL-C) and oxidative indicators (including T-AOC, MDA, SOD, GSH-Px) were measured before and after the one-year intervention period. Analyses of the correlation between posture, biochemical markers and oxidative stress indicators before and after intervention were carried out. RESULTS: After intervention, BMI ((25.53 +/- 2.77) kg/m(2)), WHR (0.82 +/- 0.03), TC ((4.60 +/- 0.98) mmol/L), TG ((1.26 +/- 0.88) mmol/L) in the intervention group were decreased significantly compared to the levels of BMI ((26.60 +/- 3.18) kg/m(2)), WHR (0.93 +/- 0.05), TC ((4.97 +/- 1.02) mmol/L), TG ((1.98 +/- 1.11) mmol/L) in the control group (all P values < 0.05); while HDL-C ((1.34 +/- 0.26) mmol/L) in the intervention group was increased significantly compared to the level of HDL-C ((1.18 +/- 0.17) mmol/L) in the control group (P < 0.05); After intervention, levels of T-AOC (19.52 +/- 0.81), SOD ((85.42 +/- 21.65) U/ml) and GSH-Px ((128.26 +/- 33.65) umol/L) were increased significantly compared to the levels of T-AOC (11.11 +/- 1.30), SOD ((78.68 +/- 30.48) U/ml) and GSH-Px ((118.48 +/- 24.19) umol/L) in the control group (all P values < 0.05); while MDA ((1.78 +/- 1.16) nmol/ml) decreased significantly compared to the level of MDA ((2.12 +/- 1.37) nmol/ml in the control group (P < 0.05); Pearson product moment correlation analysis showed that: T-AOC with TC, TG, BMI showed a negative correlation (r values were -0.258, -0.266, -0.230, respectively, all P values < 0.05), while with HDL-C was a positive correlation (r values was 0.194, P < 0.05); SOD with TC, TG, BMI showed a negative correlation (r values were -0.282, -0.311, -0.217, respectively, all P values < 0.05), while with HDL-C was a positive correlation (r values was 0.169, P < 0.05). CONCLUSION: Compound whole grain could improve lipid metabolism to the hyperlipidemia population. There was a correlation between common human metabolism and the levels of oxidative stress. PMID- 22490198 TI - [Investigation of thyroid function abnormalities in children in high water iodine areas of Hebei province]. AB - OBJECTIVE: To understand the level of thyroid function and the prevalence of the thyroid diseases of children in high water iodine areas. METHOD: Two primary schools were selected by purposive sampling from Haixing county, Hebei province in April 2010. A total of 371 children were selected from six classes by cluster sampling in the schools. Morning-urine and venous blood (5 ml) were collected to measure the levels of urinary iodine, free triiodothyronine (FT(3)), free thyroxine (FT(4)) and sensitive thyroid-stimulating hormone (sTSH) in serum and to evaluate the iodine status and thyroid function of children. RESULTS: The median urinary iodine of the children was 1032.08 ug/L. Overall, 96.2% (357/371) of the children's urinary iodine were >= 300 ug/L and 68.5% (254/371) were >= 800 ug/L. The level of FT(3) and FT(4) were (6.28 +/- 0.81) pmol/L and (16.37 +/- 2.72) pmol/L, respectively. The median of sTSH was 4.01 mU/L. The FT(4) among boys ((16.63 +/- 2.60) pmol/L) was significantly higher than that among girls ((15.99 +/- 2.85) pmol/L) (P < 0.05). Overall, 44 subjects were diagnosed as thyroid disease (11.9%), 25 were subclinical hypothyroidism (57% of the total patients), 4 were hypothyroidism (9%), 10 were hyperthyroidism (23%) and 5 were subclinical hyperthyroidism (11%). In the urinary iodine of 200 - 799 ug/L, the prevalence of thyroid disease and hypothyroidism were 6.3% (7/111) and 14.6% (27/254), respectively. When urinary iodine >= 800 ug/L, the prevalence of thyroid diseases and hypothyroidism were 3.6% (4/111) and 8.3% (21/254), respectively. CONCLUSION: Most of the children in high water iodine areas had excessive iodine intake. Levels of the children's thyroid hormone were within the normal range. The prevalence of thyroid disease were high, in these areas and the thyroid disease were mainly the subclinical hypothyroidism. PMID- 22490199 TI - [Effect of trichloroethylene intake via drinking water on Th17 cells in BALB/c mice]. AB - OBJECTIVE: This study aimed to investigate the effect of trichloroethylene (TCE) intake via drinking water on Th17 cells in mice. METHODS: Forty eight six weeks old female BALB/c mice were divided into blank control, vehicle control, 2.5 mg/ml TCE and 5.0 mg/ml TCE groups by random number table (12 mice each group), and exposed to TCE by drinking water. On the 14(th), 28(th), 56(th), 84(th) days, blood were collected and assayed for IL-17, IL-6, and TGF-beta concentration in serum through ELISA. Animals were killed and spleen biopsies were taken sterility. The proportion of Th17 cells among CD4(+) T cells and RORgammat mRNA expression level in spleen were measured by FCM and real-time PCR. RESULTS: In 2.5 mg/ml TCE and 5.0 mg/ml TCE group mice, Th17 cells/CD4(+) T cells in spleen were (3.46 +/- 0.32)% and (5.45 +/- 0.45)% on day 14, (3.47 +/- 0.33)% and (4.10 +/- 0.39)% on day 84, which were significantly higher than those for solvent control group at the same time point ((2.15 +/- 0.20)%, (2.16 +/- 0.35)%, respectively) (P < 0.01). RORgammat mRNA expression levels were (1.870 +/- 0.084) and (1.965 +/- 0.060) on 14 day, (1.998 +/- 0.079) and (2.028 +/- 0.073) on day 56, which were also significantly higher than those for solvent control group at the same time point (1.77 +/- 0.04 and 1.75 +/- 0.09, respectively) (P < 0.05). IL-17 concentrations in serum were (32.28 +/- 5.38) and (34.47 +/- 5.02) pg/ml on day 14, and (34.87 +/- 5.48) and (41.94 +/- 6.19) pg/ml on day 28, which were significantly higher than those for solvent control group at the same time point((21.57 +/- 5.23), (22.11 +/- 5.11) pg/ml). IL-6 concentration in serum were (43.07 +/- 6.71) and (47.86 +/- 8.52) pg/ml on day14, (41.32 +/- 7.04) and (46.74 +/- 9.33) pg/ml on day 56, which were significantly higher than solvent control group at the same time point ((7.56 +/- 7.71) and (28.26 +/- 7.22) pg/ml). TGF beta concentration were (17.48 +/- 3.06) and (18.93 +/- 3.12) pg/ml on day 14, which did not show significant difference from solvent control group ((15.25 +/- 2.95) pg/ml). Correlation analysis showed that IL-6 in serum were significantly positively correlated with the proportion of Th17 cells among CD4(+) T cells and RORgammat expression level in spleen (r = 0.741, 0.765, P < 0.01). CONCLUSION: TCE might promote the differentiation of Th17 cells and increase IL-17 secretion by inducing IL-6 and up-regulating RORgammat expression together with TGF-beta. PMID- 22490200 TI - [Meta analysis on the correlation between Mycobacterium tuberculosis Beijing family strains and drug resistance]. AB - OBJECTIVE: To explore the correlation between Beijing genotype (Beijing family) strains of Mycobacterium tuberculosis (MTB) and drug resistance. METHODS: A computer retrieval of Medline, Embase, SCI, EBSCO, CNKI, Weipu and Wanfang databases from 1990 to 2010 was conducted. A total of 525 articles exploring the relationship of Beijing genotype of MTB and drug resistance were found through literature search. Following the inclusion and exclusion criteria, a Meta subgroup analysis was conducted in Beijing genotype of MTB and drug resistance. RESULTS: A total of 38 articles were selected, including 22 articles on isoniazid resistance, 24 articles on rifampin resistance, 19 articles on ethambutol resistance, 18 articles on ethambutol resistance, 26 articles on multi-drug resistance (MDR). Meta-subgroup analysis showed that in China, there was an association between Beijing genotype and resistance to rifampin, ethambutol and MDR: rifampin (OR = 1.62, 95%CI: 1.13 - 2.31), ethambutol (OR = 1.67, 95%CI: 1.16 - 2.40), MDR (OR = 1.79, 95%CI: 1.20 - 2.68); in Russia, there was an association between Beijing genotype and resistance to isoniazid, rifampin, ethambutol and MDR: isoniazid (OR = 4.82, 95%CI: 3.19 - 7.29), rifampin (OR = 4.84, 95%CI: 3.84 6.10), ethambutol (OR = 3.32, 95%CI: 2.51 - 4.40), MDR (OR = 5.42, 95%CI: 3.36 - 8.74); in Vietnam, there was an association between Beijing genotype and resistance to isoniazid, rifampin, ethambutol and MDR: isoniazid (OR = 2.12, 95%CI: 1.55 - 2.91), rifampin (OR = 4.71, 95%CI: 3.01 - 7.36), ethambutol (OR = 3.78, 95%CI: 1.63 - 8.77), MDR (OR = 4.21, 95%CI: 1.58 - 11.18); in other countries, there was an association between Beijing genotype and resistance to isoniazid, rifampin, ethambutol and MDR: isoniazid (OR = 1.69, 95%CI: 1.19 - 2.42), rifampin (OR = 2.48, 95%CI: 1.92 - 3.19), ethambutol (OR = 3.04, 95%CI: 2.13 - 4.33), MDR (OR = 2.36, 95%CI: 1.52 - 3.68). CONCLUSION: Beijing genotype of MTB was positively associated with three kinds of first-line anti-tuberculosis drugs (isoniazid, rifampin, ethambutol) and MDR, and the relationship intensity was different in different countries. PMID- 22490201 TI - [Establishment of indirect immunofluorescence assay (IFA) for detection of IgG antibody against new bunyavirus]. AB - OBJECTIVE: To develop an indirect immunofluorescence assay (IFA) for detection of IgG antibodies against new bunyavirus. METHODS: The antigen slides were prepared with 5 new bunyavirus strains isolated using Africa green monkey kidney (Vero) cells. Specificity and sensitivity evaluation of IFA were carried out by optimizing working conditions of IFA. Using established IFA, serum samples from both acute and recovery phases were tested for 126 cases with fever thrombocytopenia and leukopenia syndrome in Xinyang, Henan province in 2007 - 2011. The results were compared with detections by RT-PCR. RESULTS: The new bunyavirus stable immunofluorescence specific WZ69 strain was selected to prepare antigen slides of IFA. The optimum conditions of IFA were: optimum dilution for primary antibody (serum) and secondary antibody (isosulfocyanic acid fluorescence marked goat anti-human IgG antibody) was 1:40 and 1:150 respectively. The optimum dilution for Evans blue in secondary antibody was 1:20 000. Among the 126 patients, 96 paired serum specimens were tested positive to the new bunyavirus and 30 patients were tested negative to the virus. The positive rate of antibodies was 76.19%. There was no significant difference in results between IFA and RT-PCR (72.22% (91/126)) (P > 0.05). CONCLUSION: The IFA has high sensitivity and specificity with easy operation. It can be used in detecting the new bunyavirus infection in patients with fever, thrombocytopenia and leukopenia syndrome. PMID- 22490202 TI - [Culture, isolation and identification of new bunyavirus in African green monkey kidney(Vero) cells]. AB - OBJECTIVE: To culture, isolate and identify new bunyavirus in Vero cell line. METHODS: Samples of 164 new bunyavirus positive by real time RT-PCR detection and well preserved serum specimens were selected from cases of fever, thrombocytopenia and leukopenia syndrome (FTLS) in Xinyang, Henan province in 2009 - 2011. These sera were cultured in Vero cell line and new bunyavirus were detected by observing cytopathic effect (CPE), Real-time RT-PCR, indirect immunofluorescence assay (IFA) and thin-section electron microscopy observation. A total of 10 positive PCR products were selected randomly for sequencing and the results were compared with sequence in Genbank. RESULTS: Among 164 FTLS serum specimens cultured in Vero cell line, no special CPE were observed and 67 strains (40.85%) were positive detected by Real-time RT-PCR. Nucleic acid similarity of 10 specimens were 97.8% - 100% and there's also a high similarity (> 99%) between specimens and new bunyavirus isolates (Accession No. HQ141600.1). Among 67 positive strains, 58 of them showed specific fluorescence particles by IFA. The viral particles were observed to be spheres with a diameter of 80 - 100 nm by electron microscopy. CONCLUSION: Vero cell line is suitable for culture, isolation and identification of new bunyavirus. PMID- 22490203 TI - Effect of radio frequency postdrying of partially baked cookies on acrylamide content, texture, and color of the final product. AB - Effect of radio frequency (RF) postdrying of partially baked cookies on acrylamide content, texture, and color of the final product was investigated in this study. Control cookies were prepared by baking in a conventional oven at 205 degrees C for 11 min. Cookies partially baked for 8 and 9 min were postdried in a 27.12 MHz RF tunnel oven until attainment of the moisture content of control cookies. Internal temperature of cookies was monitored during the experiments to better explain the results. Cookies were analyzed for acrylamide content using a liquid chromatography-mass spectrometry (LC-MS) method. Texture measurements were performed using a Texture Analyzer, while digital image analysis was used for color measurement. The results showed that RF postdrying of partially baked cookies resulted in lower acrylamide levels (107.3 ng/g for control cookies, 74.6 ng/g upon RF postdrying of cookies partially baked for 9 min, 51.1 ng/g upon RF postdrying of cookies partially baked for 8 min). Instrumental texture analysis showed no significant difference among the texture of cookies, whereas RF postdried samples had a lower degree of browning. According to sensory evaluation results, control had a more crumbly texture, and RF postdried sample that was conventionally baked for 8 min had a slightly uncooked flavor. PMID- 22490204 TI - A personal perspective on the early, early history of in vivo (DNA-based) gene therapy. AB - Our first efforts in the laboratory to explore the concept of in vivo gene therapy began in late 1984. Our first peer-reviewed paper demonstrating success in vitro was published in January 1988, and our first demonstration of proof-of principle in vivo in an experimental animal was published in August 1989. At this stage, as a strong supporter of the future of gene and cell therapy, I felt I could make a more important contribution as a scientific leader than as a bench scientist. Accordingly, in late 1989, I moved to the University of Pennsylvania in a senior leadership position where I was able, among other accomplishments, to establish the Institute for Human Gene Therapy in 1992 and the Department of Molecular and Cellular Engineering in 1993. Dr. Jim Wilson was recruited in 1993 to head these two academic units as Director and Chairman, respectively. The burgeoning growth and accelerating successes in the field of gene and cell therapy worldwide, the important contributions to the field by a large number of faculty at the University of Pennsylvania, and my role early in this history have been richly rewarding. A brief summary of this early, early history is provided below. PMID- 22490205 TI - The clinical effectiveness and cost-effectiveness of home-based, nurse-led health promotion for older people: a systematic review. AB - BACKGROUND: In older age, reduction in physical function can lead to loss of independence, the need for hospital and long-term nursing or residential home care, and premature death. Home-visiting programmes for older people, carried out by nurses and other health-care professionals (e.g. occupational therapists and physiotherapists), aim to positively affect health and functional status, and may promote independent functioning of older people. OBJECTIVE: The main research question addressed by this assessment is 'What is the clinical effectiveness and cost-effectiveness of home-based, nurse-led health promotion intervention for older people in the UK?' DATA SOURCES: A comprehensive literature search was undertaken across 12 different databases and research registries from the year 2001 onwards (including MEDLINE, MEDLINE in Process & Other Non-Indexed Citations, EMBASE, Science Citation Index Expanded, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, NHS Health Economic Evaluation Database, Health Technology Assessment Database, Database of Abstracts of Reviews of Effects, Cumulative Index to Nursing and Allied Health Literature). Published systematic reviews were also hand searched to identify other trials previously published. REVIEW METHODS: Potentially relevant studies were sifted by one reviewer, and inclusion decisions were agreed among the broader research team. The methodological quality of included studies was assessed using the Cochrane Risk of Bias tool. The results of included studies were synthesised using narrative and statistical methods. A separate systematic search was undertaken to identify existing health economic analyses of home based, nurse-led health promotion programmes. Included studies were critically appraised using a published checklist. Owing to resource constraints, a de novo health economic model was not developed. RESULTS: Eleven studies were included in the systematic review of clinical effectiveness. There was considerable heterogeneity among the studies with respect to the nature of the intervention, the nurses delivering the programmes and the populations in which the interventions were assessed. Overall, the quality of the included studies was good: all but one of the included studies were judged to be at medium or low risk of bias. Meta-analysis of eight studies suggested a statistically significant mortality benefit for the home-based health promotion groups, whereas a meta analysis of four studies suggested non-significant benefits in terms of fewer falls in the intervention groups than in the control groups. Positive outcomes for home-based, nurse-led health promotion interventions were also reported within individual studies across several other outcomes. Only three economic studies met the criteria for inclusion in the review of cost-effectiveness. This evidence base consists of one non-randomised cost minimisation analysis and two economic evaluations undertaken alongside randomised controlled trials. Two of these studies involved an intervention targeted specifically at patients with a known underlying incurable disease, whereas the third study examined the clinical effectiveness and cost-effectiveness of early discharge in patients with a range of conditions, including fractures, neurological conditions and cardiorespiratory conditions. Each study indicated some likelihood that home-based, nurse-led health promotion may offer cost savings to the NHS and associated sectors, such as social services. However, one study did not report any comparison of health outcomes and instead simply assumed equivalence between the intervention and comparator groups, whereas the other two studies suggested at best a negligible incremental benefit in terms of preference-based health-related quality-of-life measures. LIMITATIONS: The evidence base for clinical effectiveness is subject to considerable heterogeneity. The UK economic evidence base is limited to three studies. CONCLUSIONS: On the basis of the evidence included in this systematic review, home-based, nurse-led health promotion may offer clinical benefits across a number of important health dimensions. However, it is generally unclear from the available studies which components of this type of complex intervention contribute towards individual aspects of benefit for older people. Given the limitations of the current evidence base, it remains unclear whether or not home based health promotion interventions offer good value for money for the NHS and associated sectors. Given the considerable uncertainties in the available evidence base, it is difficult to isolate the key areas in which future research would be valuable or the exact study design required. Although this report does not identify specific studies that should be undertaken, it does set out a number of key considerations for the design of future research in this area. STUDY REGISTRATION: PROSPERO number: CRD42012002133. PMID- 22490207 TI - Global health funding and economic development. AB - The impact of increased national wealth, as measured by Gross Domestic Product (GDP), on public health is widely understood, however an equally important but less well-acclaimed relationship exists between improvements in health and the growth of an economy. Communicable diseases such as HIV, TB, Malaria and the Neglected Tropical Diseases (NTDs) are impacting many of the world's poorest and most vulnerable populations, and depressing economic development. Sickness and disease has decreased the size and capabilities of the workforce through impeding access to education and suppressing foreign direct investment (FDI). There is clear evidence that by investing in health improvements a significant increase in GDP per capita can be attained in four ways: Firstly, healthier populations are more economically productive; secondly, proactive healthcare leads to decrease in many of the additive healthcare costs associated with lack of care (treating opportunistic infections in the case of HIV for example); thirdly, improved health represents a real economic and developmental outcome in-and-of itself and finally, healthcare spending capitalises on the Keynesian 'economic multiplier' effect. Continued under-investment in health and health systems represent an important threat to our future global prosperity. This editorial calls for a recognition of health as a major engine of economic growth and for commensurate investment in public health, particularly in poor countries. PMID- 22490206 TI - Rheological and biological properties of a hydrogel support for cells intended for intervertebral disc repair. AB - BACKGROUND: Cell-based approaches towards restoration of prolapsed or degenerated intervertebral discs are hampered by a lack of measures for safe administration and placement of cell suspensions within a treated disc. In order to overcome these risks, a serum albumin-based hydrogel has been developed that polymerizes after injection and anchors the administered cell suspension within the tissue. METHODS: A hydrogel composed of chemically activated albumin crosslinked by polyethylene glycol spacers was produced. The visco-elastic gel properties were determined by rheological measurement. Human intervertebral disc cells were cultured in vitro and in vivo in the hydrogel and their phenotype was tested by reverse-transcriptase polymerase chain reaction. Matrix production and deposition was monitored by immuno-histology and by biochemical analysis of collagen and glycosaminoglycan deposition. Species specific in situ hybridization was performed to discriminate between cells of human and murine origin in xenotransplants. RESULTS: The reproducibility of the gel formation process could be demonstrated. The visco-elastic properties were not influenced by storage of gel components. In vitro and in vivo (subcutaneous implants in mice) evidence is presented for cellular differentiation and matrix deposition within the hydrogel for human intervertebral disc cells even for donor cells that have been expanded in primary monolayer culture, stored in liquid nitrogen and re-activated in secondary monolayer culture. Upon injection into the animals, gels formed spheres that lasted for the duration of the experiments (14 days). The expression of cartilage- and disc-specific mRNAs was maintained in hydrogels in vitro and in vivo, demonstrating the maintenance of a stable specific cellular phenotype, compared to monolayer cells. Significantly higher levels of hyaluronan synthase isozymes-2 and -3 mRNA suggest cell functionalities towards those needed for the support of the regeneration of the intervertebral disc. Moreover, mouse implanted hydrogels accumulated 5 times more glycosaminoglycans and 50 times more collagen than the in vitro cultured gels, the latter instead releasing equivalent quantities of glycosaminoglycans and collagen into the culture medium. Matrix deposition could be specified by immunohistology for collagen types I and II, and aggrecan and was found only in areas where predominantly cells of human origin were detected by species specific in situ hybridization. CONCLUSIONS: The data demonstrate that the hydrogels form stable implants capable to contain a specifically functional cell population within a physiological environment. PMID- 22490209 TI - [Say "goodbye" to 2011 and face the new challenges]. PMID- 22490208 TI - Abnormal vital signs are strong predictors for intensive care unit admission and in-hospital mortality in adults triaged in the emergency department - a prospective cohort study. AB - BACKGROUND: Assessment and treatment of the acutely ill patient have improved by introducing systematic assessment and accelerated protocols for specific patient groups. Triage systems are widely used, but few studies have investigated the ability of the triage systems in predicting outcome in the unselected acute population. The aim of this study was to quantify the association between the main component of the Hillerod Acute Process Triage (HAPT) system and the outcome measures; Admission to Intensive Care Unit (ICU) and in-hospital mortality, and to identify the vital signs, scored and categorized at admission, that are most strongly associated with the outcome measures. METHODS: The HAPT system is a minor modification of the Swedish Adaptive Process Triage (ADAPT) and ranks patients into five level colour-coded triage categories. Each patient is assigned a triage category for the two main descriptors; vital signs, T(vitals), and presenting complaint, T(complaint). The more urgent of the two determines the final triage category, T(final). We retrieved 6279 unique adult patients admitted through the Emergency Department (ED) from the Acute Admission Database. We performed regression analysis to evaluate the association between the covariates and the outcome measures. RESULTS: The covariates, T(vitals), T(complaint) and T(final) were all significantly associated with ICU admission and in-hospital mortality, the odds increasing with the urgency of the triage category. The vital signs best predicting in-hospital mortality were saturation of peripheral oxygen (SpO(2)), respiratory rate (RR), systolic blood pressure (BP) and Glasgow Coma Score (GCS). Not only the type, but also the number of abnormal vital signs, were predictive for adverse outcome. The presenting complaints associated with the highest in-hospital mortality were 'dyspnoea' (11.5%) and 'altered level of consciousness' (10.6%). More than half of the patients had a T(complaint) more urgent than T(vitals), the opposite was true in just 6% of the patients. CONCLUSION: The HAPT system is valid in terms of predicting in-hospital mortality and ICU admission in the adult acute population. Abnormal vital signs are strongly associated with adverse outcome, while including the presenting complaint in the triage model may result in over-triage. PMID- 22490210 TI - [Advancement of treatment philosophy and consideration of standardized management principles for temporomandibular disorders]. PMID- 22490211 TI - [Magnetic resonance imaging assessment of the lateral pterygoid muscle in Class III malocclusion subjects]. AB - OBJECTIVE: To analyze the relationship between Class III malocclusion and pathological changes in temporomandibular joint (TMJ) structures using magnetic resenonce imaging (MRI). METHODS: Twenty-four Class III malocclusion adult patients and 10 normal control cases were included in the study. The characteristics of lateral pertygoid muscle (LPM) in the sample group and the control group were assessed. RESULTS: More pathological changes of LPM were found in Class III malocclusion adult patients (36 TMJ). The changes included hypertrophy, atrophy and contracture. And there was no relation between the pathological changes of LPM and the symptom of temporomandibular disorders (TMD). CONCLUSIONS: The frequency of pathological changes of LPM was greater in patients with Class III malocclusion than in the control group. PMID- 22490212 TI - [New bone and cartilage tissues formed from human bone marrow mesenchymal stem cells derived from human condyle in vivo]. AB - OBJECTIVE: To investigate the ability to form new bone and cartilage tissues of bone marrow mesenchymal stem cells (BMSC) derived from human condyle in vivo, to search the new source of seed cells in constructing tissue engineering condyle. METHODS: Bone marrow was collected from the irrigation solution from resected human condyle, and was isolated by density gradient centrifugation and then purified by adherent separation and cultured in vitro. P3 or P4 BMSC populations were induced into osteoblasts and chondroblast under inductive medium in vitro and then seeded on porous coral scaffolds. The appearance and affinity of cells were investigated via scanning electron microscope. And then osteoblast or chondroblast/coral scaffolds composites were implanted into the dorsum of nude mice. The mice were sacrificed by anaesthesia overdose at six and nine weeks after surgery and the scaffolds were removed for analysis. RESULTS: Scanning electron microscope showed that BMSC were adhering to the surface of coral and having an overlapped growth or to contact each other as net and stride over the pores. The in vivo scaffold specimens maintained the initial shape of the coral scaffold. The new formed bone tissues were clearly evident and islands of cartilage tissues were also found at nine weeks after implantation. CONCLUSIONS: These BMSC derived from human condyle possess the ability of forming bone and cartilage tissues when being implanted in vivo, and can be used as a kind of seed cells in constructing tissue engineering condyle. PMID- 22490213 TI - [Effect of orofacial inflammatory pain on p38 mitogen-activated protein kinase activation in trigeminal caudal nucleus of rats]. AB - OBJECTIVE: To evaluate the potential role of p38 mitogen-activated protein kinase (MAPK) in the orofacial inflammatory pain. METHODS: SD rats received subcutaneous injection of 2.5% formalin 50 ul in the left vibrissa pad to establish the inflammatory pain model. The rats were grouped into the control group, the formalin group (FOR group), the formalin + saline group (FOR + NS group) and the formalin + SB203580 group (FOR + SB group). SB203580 or saline was inserted into the rat's cisterna magna 20 minutes prior to the formalin injection, then the behavioral changes were tested. The immunofluorescence staining and Western blotting analysis were performed to examine c-fos, p38MAPK and phosphorylated p38 (p-p38) activity in Vc at 20, 60, 120, 180 minutes after formalin injection. RESULTS: p38MAPK was constitutively expressed in Vc (P > 0.05) and p38MAPK was activated following formalin injection.Compared with the control group at 20 min (0.12 +/- 0.01), the level of p-p38 in FOR group (0.66 +/- 0.04) and FOR + NS group (0.64 +/- 0.04) increased significantly (P < 0.001). The expression of p p38 peaked at 20 minutes, and then declined in each group. Intracisterna magna pretreatment of p38MAPK inhibitor SB203580 resulted in potent attenuation of phase II of pain behavior (P < 0.05), while the expression of c-fos was also inhibited, especially at the point of 120 min (P < 0.01). CONCLUSIONS: Activation of p38 mitogen-activated protein kinase played a major role in the development of orofacial inflammatory pain and it was verified by the experimental result that p38MAPK inhibitor SB203580 inhibited the formalin-induced orofacial pain. PMID- 22490214 TI - [Investigation of the prevalence of temporomandibular disorders in 352 aged edentulous individuals]. AB - OBJECTIVE: To study the prevalence of temporomandibular disorders (TMD) in 352 aged edentulous individuals in Beijing area and to analyze the correlative risk factors. METHODS: Three hundred and fifty-two aged edentulous subjects were included in the study (198 males and 154 females). The adopted questionnaire was designed according to Helkimo index, and the subjects were examined by the same examiner who would record every result as well. RESULTS: The prevalence of TMD's clinical positive signs in the edentulous subjects was 43.2% (152/352), among which temporomandibular joint (TMJ) noise [34.1% (120/352)] was the highest prevalent sign while TMJ pain on movemert was the lowest. The prevalence of mandibular movement deviation [18.2% (64/352)] fitted in between. The prevalence of TMD's clinical positive signs of male individuals was 36.9% (73/198), and the female was 51.3% (79/154). There was a significant difference in prevalence of TMD's clinical positive signs between males and females (P = 0.0067 < 0.01). The prevalence of TMD's clinical positive signs in denture wearing group was 38.6% (91/236) and that in no denture group was 52.6% (61/116). There was a significant correlation between the prevalence of TMD's clinical positive signs and wearing denture [P = 0.0125 < 0.05, OR = 1.767 (1.130 ~ 2.763)]. CONCLUSIONS: Gender and malocclusion may be the risk factors of TMD in edentulous individuals. PMID- 22490215 TI - [Strategies of manipulating temporomandibular joint problems in orthodontic treatment]. PMID- 22490216 TI - [Genes involved in temporomandibular osteoarthritis and the relationship between estrogen and joint inflammatory pain: proceedings from Chinese researchers]. PMID- 22490217 TI - [Summary of the 8th Chinese Conference On Temporomandibular Disorders]. PMID- 22490218 TI - [Summary of the 6th Chinese Annual Meeting Of Geriatric Dentistry]. PMID- 22490219 TI - [Effect of the bone resorption supernatant from RAW264.7 osteoclast on the osteogenic activity of mouse MC3T3-E1 cell]. AB - OBJECTIVE: To investigate the effect of osteoclast bone resorption supernatants on the osteogenic activity of mouse MC3T3-E1 cell line. METHODS: Mouse RAW264.7 cell line was induced to osteoclast which was identified with tartrate resistant acid phosphatase (TRAP) staining and osteoclast specific gene detection. The differentiated RAW264.7 osteoclast was co-cultured with bovine milling bone specimen followed by toluidine blue staining. Then mouse MC3T3-E1 cell was cultured with supernatant from the osteoclast bone absorbent model. Methyl thiazolyl tetrazolium (MTT) method, alizarin red S staining, enzyme-linked immunosorbent assay detection of osteocalcin, and reverse transcriptase polymerase chain reaction detection were adopted to investigate the proliferation, calcification and osteogenic activity of MC3T3-E1 cells. RESULTS: TRAP staining, osteoclast specific gene detection and toluidine blue staining all indicated that RAW264.7 cell could be differentiated into functioning osteoclast. The supernatant from the osteoclast bone absorbent model could inhibit the proliferation of MC3T3-E1 cells, with the A value between 0.062 +/- 0.004 and 0.405 +/- 0.033 (P < 0.05). It could also increase the formation of calcification nods, promote the osteocalcin level which peaked with the tenth day's supernatant at a level of (2.965 +/- 0.047) ug/L, as well as enhance the transcription of the alkaline phosphatase and Runt related transcription factor 2 gene. CONCLUSIONS: RAW264.7 osteoclast bone absorbent supernatant might influence the osteogenic activity of osteoblast-like cell by inhibiting proliferation, promoting differentiation and calcification. PMID- 22490220 TI - [Effect of cyclosporin A and tumor necrosis factor-alpha on cell proliferation of cultured human gingival fibroblasts]. AB - OBJECTIVE: To investigate the effect of cyclosporin A (CsA) and tumor necrosis factor-alpha (TNF-alpha) on cell proliferation of cultured human gingival fibroblasts (GF), and the relationship between gingival inflammation and drug induced gingival overgrowth. METHODS: Human GF were cultured in vitro using tissue culture method. then cells from the 4 - 8 th passage were used in the experiment. The cells were cultured and incubated with various concentrations of CsA and TNF-alpha (A: blank group, B1: 10 ug/L CsA, B2: 50 ug/L CsA, B3: 250 ug/L CsA, B4: 1250 ug/L CsA, C: 5 ug/L TNF-alpha, D1: 10 ug/L CsA + 5 ug/L TNF-alpha, D2: 50 ug/L CsA + 5 ug/L TNF-alpha, D3: 250 ug/L CsA + 5 ug/L TNF-alpha, D4: 1250 ug/L CsA + 5 ug/L TNF-alpha) solution for 3, 5 and 7 days. Methyl thiazolyl tetrazolium assay was used to evaluate the cell proliferation in the culture meidiun. RESULTS: The proliferation of fibroblasts was inhibited when exposed to different concentration of CsA and A value decreased. There was no significant difference between group B1, B2, B3 and the control group, while the A value of group B4 was significantly higher than that of control group (P < 0.01). Fibroblast proliferation was significantly increased while cultured with 5 ug/L TNF-alpha. A value increased (P < 0.01). When exposed to CsA + TNF-alpha, A value of group D1, D2, D3 was much higher than that of group A, but was lower than that of group C (P < 0.05). Cell proliferation in group D4 was significantly increased, and significantly different with that in group C (P < 0.01). CONCLUSIONS: CsA did not stimulate the cell proliferation, and high concentration of CsA inhibited cell proliferation. TNF-alpha can stimulate the cell proliferation. High-concentration CsA + TNF-alpha can enhance the fibroblast proliferation, which suggests that CsA in certain concentration have amplification effect on TNF-alpha to stimulate fibroblast proliferation. PMID- 22490221 TI - [Influence of glucose concentration on the inhibition of Streptococcus oligofermentans on Streptococcus mutans]. AB - OBJECTIVE: To investigate the inhibition of Streptococcus oligofermentans (So) on Streptococcus mutans (Sm) and the producibility of hydrogen peroxide by So under the influence of glucose concentration environment. METHODS: The inhibition between So and Sm was observed by plating method under the different glucose concentration environment. The initial synthesis rates and production of hydrogen peroxide by So were determined under the different glucose concentration environment by 4-aminoantipyine-horseradish peroxidase method at A(510). RESULTS: Under 0, 10 and 50 mmol/L glucose environment, the inhibition of So on Sm was evident. When both Sm and So were inoculated at the same time, the ratio of inhibition area by bacterial membrane area was 0.202 +/- 0.005, 0.467 +/- 0.025, 0.468 +/- 0.028 under 0, 10, 50 mmol/L glucose environment. When So was cultivated first and then Sm applied, the ratio was 0.394 +/- 0.004, 0.811 +/- 0.075 and 0.816 +/- 0.007 under 0, 10 and 50 mmol/L glucose environment respectively. The inhibition under 10 and 50 mmol/L glucose environment were more significant than that under non-glucose environment. There was no significant difference between these two glucose concentrations (P > 0.05). The initial synthesis rates of H2O2 by So under the 10 mmol/L [(23.573 +/- 0.263) umo*L( 1)*min(-1)] and 50 mmol/L [(23.337 +/- 0.473) umol*L(-1)*min(-1)] glucose were higher than without glucose[(10.513 +/- 0.516) umol*L(-1)*min(-1)], P < 0.05. H2O2 was not detected in 1000 mmol/L glucose. However, the production of H2O2 by So under 0 mmol/L glucose was higher than other glucose concentrations (P < 0.05). CONCLUSIONS: The capability of the inhibition of So on Sm was affected by glucose environment and was much stronger under certain glucose concentrations (10, 50 mmol/L). PMID- 22490222 TI - [Experimental study on co-culture of salivary adenoid cystic carcinoma cells and ganglia]. AB - OBJECTIVE: To construct the co-culture models of salivarya denoid cystic carcinoma (SACC) cells and dorsal root ganglia (DRG) of chickens and investigate the promotive effects of SACC on neural tissue. METHODS: Glass-base culture dish was adopted to construct co-culture model of SACC-83 cells and DRG. SACC-83 cells were seeded in the medium pore with DRG around them. Outgrowth of neuronal processes was observed. Then DRG was cultured in the conditioned medium of SACC 83, with the groups of conditioned medium of MC3T3-E1 and HGF, the group of cell lysis buffer, the groups of serum-free medium and serum-plus medium as the controls. Outgrowth of neuronal processes was also recorded and compared with control groups. RESULTS: In the co-culture model of tumor and neuronal tissue, SACC-83 cells produced a suitable microenvironment in which neuronal processes remarkably grow. Neuronal processes of most DRG displayed growth tendency toward SACC. The group of conditioned medium from SACC-83 manifested obvious promotive effects on DRG. CONCLUSIONS: Co-culture model of tumor and neuronal tissue was successfully constructed, with which the promotive effects of tumor on outgrowth of neuronal processes could be observed. So hypothesized that SACC could secrete some neurotrophic factors to guide peripheral nerves gemmating and to trigger the cascade of the neural invasion in succession. PMID- 22490223 TI - [The role of the flexors hallucis longus muscle in the mandibula or maxillary reconstruction with free fibula flap]. PMID- 22490224 TI - [Right maintenance and self-discipline of practicing dentist on the liability in medical damage of the tortuous liability (VI): impetigo on palm and toe induced by silver mercury filling treatment of caries in a case]. PMID- 22490225 TI - [Problem solving in endodontic diseases: XII. Crucial factors in preparation of root canal system (II): irrigation and disinfection in endodontics]. PMID- 22490226 TI - Determining the best population-level alcohol consumption model and its impact on estimates of alcohol-attributable harms. AB - BACKGROUND: The goals of our study are to determine the most appropriate model for alcohol consumption as an exposure for burden of disease, to analyze the effect of the chosen alcohol consumption distribution on the estimation of the alcohol Population- Attributable Fractions (PAFs), and to characterize the chosen alcohol consumption distribution by exploring if there is a global relationship within the distribution. METHODS: To identify the best model, the Log-Normal, Gamma, and Weibull prevalence distributions were examined using data from 41 surveys from Gender, Alcohol and Culture: An International Study (GENACIS) and from the European Comparative Alcohol Study. To assess the effect of these distributions on the estimated alcohol PAFs, we calculated the alcohol PAF for diabetes, breast cancer, and pancreatitis using the three above-named distributions and using the more traditional approach based on categories. The relationship between the mean and the standard deviation from the Gamma distribution was estimated using data from 851 datasets for 66 countries from GENACIS and from the STEPwise approach to Surveillance from the World Health Organization. RESULTS: The Log-Normal distribution provided a poor fit for the survey data, with Gamma and Weibull distributions providing better fits. Additionally, our analyses showed that there were no marked differences for the alcohol PAF estimates based on the Gamma or Weibull distributions compared to PAFs based on categorical alcohol consumption estimates. The standard deviation of the alcohol distribution was highly dependent on the mean, with a unit increase in alcohol consumption associated with a unit increase in the mean of 1.258 (95% CI: 1.223 to 1.293) (R2 = 0.9207) for women and 1.171 (95% CI: 1.144 to 1.197) (R2 = 0. 9474) for men. CONCLUSIONS: Although the Gamma distribution and the Weibull distribution provided similar results, the Gamma distribution is recommended to model alcohol consumption from population surveys due to its fit, flexibility, and the ease with which it can be modified. The results showed that a large degree of variance of the standard deviation of the alcohol consumption Gamma distribution was explained by the mean alcohol consumption, allowing for alcohol consumption to be modeled through a Gamma distribution using only average consumption. PMID- 22490227 TI - Lyn kinase mediates cell motility and tumor growth in EGFRvIII-expressing head and neck cancer. AB - PURPOSE: EGF receptor variant III (EGFRvIII) has been detected in several cancers in which tumors expressing this truncated growth factor receptor show more aggressive behavior. The molecular mechanisms that contribute to EGFRvIII mediated tumor progression that are amenable to targeted therapy are incompletely understood. The present study aimed to better define the role of Src family kinases (SFKs) in EGFRvIII-mediated cell motility and tumor growth of head and neck squamous cell carcinomas (HNSCC). EXPERIMENTAL DESIGN: HNSCC models expressing EGFRvIII were treated with dasatinib, a pharmacologic inhibitor of SFKs. RESULTS: SFK inhibition significantly decreased cell proliferation, migration, and invasion of EGFRvIII-expressing HNSCC cells. Administration of dasatinib to mice bearing EGFRvIII-expressing HNSCC xenografts resulted in a significant reduction of tumor volume compared with controls. Immunoprecipitation with anti-c-Src, Lyn, Fyn, and Yes antibodies followed by immunoblotting for phosphorylation of the SFK activation site (Y416) showed specific activation of Lyn kinase in EGFRvIII-expressing HNSCC cell lines and human HNSCC tumor specimens. Selective inhibition of Lyn using siRNA decreased cell migration and invasion of EGFRvIII-expressing HNSCCs compared with vector control cells. CONCLUSIONS: These findings show that Lyn mediates tumor progression of EGFRvIII expressing HNSCCs in which strategies to inhibit SFK may represent an effective therapeutic strategy. PMID- 22490228 TI - Derivation and validation of clinical prediction rules for reduced vancomycin susceptibility in Staphylococcus aureus bacteraemia. AB - Reduced vancomycin susceptibility (RVS) may lead to poor clinical outcomes in Staphylococcus aureus bacteraemia. We conducted a cohort study of 392 patients with S. aureus bacteraemia within a university health system. The association between RVS, as defined by both Etest [vancomycin minimum inhibitory concentration (MIC) >1.0 MUg/ml] and broth microdilution (vancomycin MIC >=1.0 MUg/ml), and patient and clinical variables were evaluated to create separate predictive models for RVS. In total, 134 (34.2%) and 73 (18.6%) patients had S. aureus isolates with RVS by Etest and broth microdilution, respectively. The final model for RVS by Etest included methicillin resistance [odds ratio (OR) 1.51, 95% confidence interval (CI) 0.97-2.34], non-white race (OR 0.67, 95% CI 0.42-1.07), healthcare-associated infection (OR 0.56, 95% CI 0.32-0.96), and receipt of any antimicrobial therapy <=30 days prior to the culture date (OR 3.06, 95% CI 1.72-5.44). The final model for RVS by broth microdilution included methicillin resistance (OR 2.45, 95% CI 1.42-4.24), admission through the emergency department (OR 0.54, 95% CI 0.32-0.92), presence of an intravascular device (OR 2.24, 95% CI 1.30-3.86), and malignancy (OR 0.51, 95% CI 0.26-1.00). The availability of an easy and rapid clinical prediction rule for early identification of RVS can be used to help guide the timely and individualized management of these serious infections. PMID- 22490229 TI - Species-dependent uptake of glycylsarcosine but not oseltamivir in Pichia pastoris expressing the rat, mouse, and human intestinal peptide transporter PEPT1. AB - The purpose of this study was to determine whether glycylsarcosine (a model dipeptide) and oseltamivir (an antiviral prodrug) exhibited a species-dependent uptake in yeast Pichia pastoris expressing the rat, mouse, and human homologs of PEPT1. Experiments were performed with [(3)H]glycylsarcosine (GlySar) in yeast P. pastoris expressing human, mouse, and rat peptide transporter 1 (PEPT1), in which uptake was examined as a function of time, concentration, potential inhibitors, and the dose-response inhibition of GlySar by oseltamivir. Studies with [(14)C]oseltamivir were also performed under identical experimental conditions. We found that GlySar exhibited saturable uptake in all three species, with K(m) values for human (0.86 mM) > mouse (0.30 mM) > rat (0.16 mM). GlySar uptake in the yeast transformants was specific for peptides (glycylproline) and peptide like drugs (cefadroxil, cephradine, and valacyclovir), but was unaffected by glycine, l-histidine, cefazolin, cephalothin, cephapirin, acyclovir, 4-acetamido 4'-isothiocyanostilbene-2,2'-disulfonic acid, tetraethylammonium, and elacridar. Although oseltamivir caused a dose-dependent inhibition of GlySar uptake [IC(50) values for human (27.4 mM) > rat (18.3 mM) > mouse (10.7 mM)], the clinical relevance of this interaction would be very low in humans. Of importance, oseltamivir was not a substrate for the intestinal PEPT1 transporter in yeast expressing the three mammalian species tested. Instead, the prodrug exhibited nonspecific binding to the yeast vector and PEPT1 transformants. Finally, the mouse appeared to be a better animal model than the rat for exploring the intestinal absorption and pharmacokinetics of peptides and peptide-like drugs in human. PMID- 22490230 TI - Time-dependent inhibition and estimation of CYP3A clinical pharmacokinetic drug drug interactions using plated human cell systems. AB - The current studies assessed the utility of freshly plated hepatocytes, cryopreserved plated hepatocytes, and cryopreserved plated HepaRG cells for the estimation of inactivation parameters k(inact) and K(I) for CYP3A. This was achieved using a subset of CYP3A time-dependent inhibitors (fluoxetine, verapamil, clarithromycin, troleandomycin, and mibefradil) representing a range of potencies. The estimated k(inact) and K(I) values for each time-dependent inhibitor were compared with those obtained using human liver microsomes and used to estimate the magnitude of clinical pharmacokinetic drug-drug interaction (DDI). The inactivation kinetic parameter, k(inact), was most consistent across systems tested for clarithromycin, verapamil, and troleandomycin, with a high k(inact) of 0.91 min(-1) observed for mibefradil in HepaRG cells. The apparent K(I) estimates derived from the various systems displayed a range of variability from 3-fold for clarithromycin (5.4-17.7 MUM) to 6-fold for verapamil (1.9-12.6 MUM). In general, the inactivation kinetic parameters derived from the cell systems tested fairly replicated what was observed in time-dependent inhibition studies using human liver microsomes. Despite some of the observed differences in inactivation kinetic parameters, the estimated DDIs derived from each of the tested systems generally agreed with the clinically reported DDI within approximately 2-fold. In addition, a plated cell approach offered the ability to conduct longer primary incubations (greater than 30 min), which afforded improved ability to identify the weak time-dependent inhibitor fluoxetine. Overall, results from these studies suggest that in vitro inactivation parameters generated from plated cell systems may be a practical approach for identifying time-dependent inhibitors and for estimating the magnitude of clinical DDIs. PMID- 22490232 TI - Comparative population genetic analysis of bocaccio rockfish Sebastes paucispinis using anonymous and gene-associated simple sequence repeat loci. AB - Comparative population genetic analyses of traditional and emergent molecular markers aid in determining appropriate use of new technologies. The bocaccio rockfish Sebastes paucispinis is a high gene-flow marine species off the west coast of North America that experienced strong population decline over the past 3 decades. We used 18 anonymous and 13 gene-associated simple sequence repeat (SSR) loci (expressed sequence tag [EST]-SSRs) to characterize range-wide population structure with temporal replicates. No F(ST)-outliers were detected using the LOSITAN program, suggesting that neither balancing nor divergent selection affected the loci surveyed. Consistent hierarchical structuring of populations by geography or year class was not detected regardless of marker class. The EST-SSRs were less variable than the anonymous SSRs, but no correlation between F(ST) and variation or marker class was observed. General linear model analysis showed that low EST-SSR variation was attributable to low mean repeat number. Comparative genomic analysis with Gasterosteus aculeatus, Takifugu rubripes, and Oryzias latipes showed consistently lower repeat number in EST-SSRs than SSR loci that were not in ESTs. Purifying selection likely imposed functional constraints on EST-SSRs resulting in low repeat numbers that affected diversity estimates but did not affect the observed pattern of population structure. PMID- 22490233 TI - The formation and design of the 'Acute Admission Database'- a database including a prospective, observational cohort of 6279 patients triaged in the emergency department in a larger Danish hospital. AB - BACKGROUND: Management and care of the acutely ill patient has improved over the last years due to introduction of systematic assessment and accelerated treatment protocols. We have, however, sparse knowledge of the association between patient status at admission to hospital and patient outcome. A likely explanation is the difficulty in retrieving all relevant information from one database. The objective of this article was 1) to describe the formation and design of the 'Acute Admission Database', and 2) to characterize the cohort included. METHODS: All adult patients triaged at the Emergency Department at Hillerod Hospital and admitted either to the observationary unit or to a general ward in-hospital were prospectively included during a period of 22 weeks. The triage system used was a Danish adaptation of the Swedish triage system, ADAPT. Data from 3 different data sources was merged using a unique identifier, the Central Personal Registry number; 1) Data from patient admission; time and date, vital signs, presenting complaint and triage category, 2) Blood sample results taken at admission, including a venous acid-base status, and 3) Outcome measures, e.g. length of stay, admission to Intensive Care Unit, and mortality within 7 and 28 days after admission. RESULTS: In primary triage, patients were categorized as red (4.4%), orange (25.2%), yellow (38.7%) and green (31.7%). Abnormal vital signs were present at admission in 25% of the patients, most often temperature (10.5%), saturation of peripheral oxygen (9.2%), Glasgow Coma Score (6.6%) and respiratory rate (4.8%). A venous acid-base status was obtained in 43% of all patients. The majority (78%) had a pH within the normal range (7.35-7.45), 15% had acidosis (pH < 7.35) and 7% had alkalosis (pH > 7.45). Median length of stay was 2 days (range 1-123). The proportion of patients admitted to Intensive Care Unit was 1.6% (95% CI 1.2-2.0), 1.8% (95% CI 1.5-2.2) died within 7 days, and 4.2% (95% CI 3.7-4.7) died within 28 days after admission. CONCLUSIONS: Despite challenges of data registration, we succeeded in creating a database of adequate size and data quality. Future studies will focus on the association between patient status at admission and patient outcome, e.g. admission to Intensive Care Unit or in hospital mortality. PMID- 22490234 TI - Left main bronchus resection and reconstruction. A single institution experience. AB - BACKGROUND: Left main bronchus resection and reconstruction (LMBRR) is a complex surgical procedure indicated for management of inflammatory, benign and low grade malignant lesions. Its application provides maximal parenchymal sparing. METHODS: Out of 98 bronchoplastic procedures performed at the Authors' Institution in the 1995-2011 period, 4 were LMBRR. Indications were bronchial carcinoid in 2 cases, inflammatory pseudotumor in 1 case, TBC stricture in 1 case. All patients underwent preoperatively a rigid bronchoscopy to restore the airway lumen patency. At surgery a negative resection margin was confirmed by frozen section in the neoplastic patients. In all patients an end-to-end bronchial anastomosis was constructed according to Grillo. RESULTS: There were neither mortality nor major complications. Airway lumen was optimal in 3 patients, good in 1. CONCLUSION: LMBRR is a valuable option for the thoracic surgeon. It maximizes the parenchyma-sparing philosophy, broadening the spectrum of potential candidates for cure. It remains a technically demanding procedure, to be carried out by an experienced surgical team. Correct surgical planning affords excellent results, both in the short and long term. PMID- 22490235 TI - Human dendritic cells engineered to secrete interleukin-18 activate MAGE-A3 specific cytotoxic T lymphocytes in vitro. AB - Adoptive cell transfer (ACT) involves the administration of tumor specific cytotoxic T lymphocytes (CTLs) into a patient to kill cancer cells. Although a promising cancer therapy, limitations on the generation of activated CTLs have restricted ATC's clinical application. Interleukin-18 (IL-18) is an interferon gamma (IFN-gamma) inducing factor that plays an important functional role in regulating CTLs. Here, we attempt to use dendritic cells (DCs) modified with a recombinant adenovirus encoding IL-18 (rAd/IL-18) to improve the generation of activated tumor-specific CTLs. These engineered DCs secrete IL-18, increase the expression of co-stimulatory molecules, and enhance the cytotoxic efficacy of melanoma antigen 3 (MAGE-A3)-specific CTLs in vitro. We show that stimulation of CTLs with rAd/IL-18-loaded DCs increases the specific lysis of MAGE-A3-expressing human breast cancer MCF-7 cells, and at the same time increases the production of activated MAGE-A3-specific CTLs. Our results indicate that transducing DCs with rAd/IL-18 increases both the maturation of DCs and the activation level of MAGE A3-specific CTLs, greatly enhancing the cytotoxic efficacy of CTLs towards tumor cells. PMID- 22490236 TI - Designing the ideal model for assessment of wound contamination after gunshot injuries: a comparative experimental study. AB - BACKGROUND: Modern high-velocity projectiles produce temporary cavities and can thus cause extensive tissue destruction along the bullet path. It is still unclear whether gelatin blocks, which are used as a well-accepted tissue simulant, allow the effects of projectiles to be adequately investigated and how these effects are influenced by caliber size. METHOD: Barium titanate particles were distributed throughout a test chamber for an assessment of wound contamination. We fired .22-caliber Magnum bullets first into gelatin blocks and then into porcine hind limbs placed behind the chamber. Two other types of bullets (.222-caliber bullets and 6.5 * 57 mm cartridges) were then shot into porcine hind limbs. Permanent and temporary wound cavities as well as the spatial distribution of barium titanate particles in relation to the bullet path were evaluated radiologically. RESULTS: A comparison of the gelatin blocks and hind limbs showed significant differences (p < 0.05) in the mean results for all parameters. There were significant differences between the bullets of different calibers in the depth to which barium titanate particles penetrated the porcine hind limbs. Almost no particles, however, were found at a penetration depth of 10 cm or more. By contrast, gas cavities were detected along the entire bullet path. CONCLUSION: Gelatin is only of limited value for evaluating the path of high velocity projectiles and the contamination of wounds by exogenous particles. There is a direct relationship between the presence of gas cavities in the tissue along the bullet path and caliber size. These cavities, however, are only mildly contaminated by exogenous particles. PMID- 22490231 TI - Whole transcriptome analysis of the coral Acropora millepora reveals complex responses to CO2-driven acidification during the initiation of calcification. AB - The impact of ocean acidification (OA) on coral calcification, a subject of intense current interest, is poorly understood in part because of the presence of symbionts in adult corals. Early life history stages of Acropora spp. provide an opportunity to study the effects of elevated CO(2) on coral calcification without the complication of symbiont metabolism. Therefore, we used the Illumina RNAseq approach to study the effects of acute exposure to elevated CO(2) on gene expression in primary polyps of Acropora millepora, using as reference a novel comprehensive transcriptome assembly developed for this study. Gene ontology analysis of this whole transcriptome data set indicated that CO(2) -driven acidification strongly suppressed metabolism but enhanced extracellular organic matrix synthesis, whereas targeted analyses revealed complex effects on genes implicated in calcification. Unexpectedly, expression of most ion transport proteins was unaffected, while many membrane-associated or secreted carbonic anhydrases were expressed at lower levels. The most dramatic effect of CO(2) driven acidification, however, was on genes encoding candidate and known components of the skeletal organic matrix that controls CaCO(3) deposition. The skeletal organic matrix effects included elevated expression of adult-type galaxins and some secreted acidic proteins, but down-regulation of other galaxins, secreted acidic proteins, SCRiPs and other coral-specific genes, suggesting specialized roles for the members of these protein families and complex impacts of OA on mineral deposition. This study is the first exhaustive exploration of the transcriptomic response of a scleractinian coral to acidification and provides an unbiased perspective on its effects during the early stages of calcification. PMID- 22490237 TI - Do residents of food deserts express different food buying preferences compared to residents of food oases? A mixed-methods analysis. AB - BACKGROUND: Many people lack access to food stores that provide healthful food. Neighborhoods with poor supermarket access have been characterized as "food deserts" (as contrast with "food oases"). This study explored factors influencing food buying practices among residents of food deserts versus food oases in the city of Boston, USA. METHODS: We used the mixed-methods approach of concept mapping, which allows participants to identify, list, and organize their perceptions according to importance. Resulting maps visually illustrate priority areas. RESULTS: Sixty-seven low-income adults completed the concept mapping process that identified 163 unique statements (e.g. relating to affordability, taste, and convenience) that influence food buying practices. Multivariate statistical techniques grouped the 163 statements into 8 clusters or concepts. Results showed that average cluster ratings and rankings were similar between residents of food deserts and food oases. CONCLUSIONS: The implication of this study pertains to the importance of community resources and emergency food assistance programs that have served to minimize the burden associated with hunger and poor food access among low-income, urban populations. PMID- 22490238 TI - Liars, medicine, and compassion. AB - This paper defends an account of compassion and argues for the centrality of compassion to the proper practice of medicine. The argument proceeds by showing that failures of compassion can lead to poor medical treatment and disastrous outcomes. Several case studies are discussed, exemplifying the difference between compassionate and noncompassionate responses to patients seeking help. Arguments are offered in support of approaching reports of persistent pain with a trusting attitude, rather than distrust or skepticism. The article concludes by suggesting educational improvements to encourage compassion. PMID- 22490240 TI - [Recent advances of periodontology in China]. PMID- 22490241 TI - [A preliminary study on the genetic mode of aggressive periodontitis in Chinese Han nationality]. AB - OBJECTIVE: To investigate the potential genetic mode of aggressive periodontitis (AgP) in Chinese Han nationality. METHODS: A total of 233 subjects from 73 nuclear families were recruited. All probands were diagnosed according to the criteria of AgP in 1999 classification of periodontal diseases. Ninety parents, 35 siblings and three grandparents and two offspring were examined based on full mouth periodontal chartings (including parameter of probing depths, attachment loss, bleeding on probing at six sites per tooth) and full-mouth periapical radiographs. The genetic ratio was calculated and analyzed by the methods of Edwards and simple segregation. RESULTS: The prevalence of AgP in probands' siblings was close to the square root of the prevalence of general population. The segregation ratio was 0.2419, which was close to the theoretical ratio for autosomal recessive inheritance. However, autosomal dominant inheritance could not be rejected in families whose parent(s) suffered from severe chronic periodontitis. CONCLUSIONS: The genetic heterogeneity of AgP existed in Chinese Han nationality. The genetic mode was autosomal recessive inheritance in general, and autosomal dominant inheritance could not be excluded in families whose parent(s) suffered from severe chronical periodontitis. The results imply the genetic heterogeneity of AgP, and further demonstrate that AgP was a multifactorial disease with major genetic component in the disease etiology. PMID- 22490239 TI - Opioid receptor heteromers in analgesia. AB - Opiates such as morphine and fentanyl, a major class of analgesics used in the clinical management of pain, exert their effects through the activation of opioid receptors. Opioids are among the most commonly prescribed and frequently abused drugs in the USA; however, the prolonged use of opiates often leads to the development of tolerance and addiction. Although blockade of opioid receptors with antagonists such as naltrexone and naloxone can lessen addictive impulses and facilitate recovery from overdose, systemic disruption of endogenous opioid receptor signalling through the use of these antagonistic drugs can have severe side effects. In the light of these challenges, current efforts have focused on identifying new therapeutic targets that selectively and specifically modulate opioid receptor signalling and function so as to achieve analgesia without the adverse effects associated with chronic opiate use. We have previously reported that opioid receptors interact with each other to form heteromeric complexes and that these interactions affect morphine signalling. Since chronic morphine administration leads to an enhanced level of these heteromers, these opioid receptor heteromeric complexes represent novel therapeutic targets for the treatment of pain and opiate addiction. In this review, we discuss the role of heteromeric opioid receptor complexes with a focus on mu opioid receptor (MOR) and delta opioid receptor (DOR) heteromers. We also highlight the evidence for altered pharmacological properties of opioid ligands and changes in ligand function resulting from the heteromer formation. PMID- 22490242 TI - [Preliminary study on gingival biotype by periodontal probing]. AB - OBJECTIVE: To establish a convenient, objective and applicable method to assess gingival biotype using periodontal probing. METHODS: A total of 66 maxillary anterior teeth from 14 volunteers (6 males, 8 females) with healthy gingiva, aged from 20 to 30 years, were recruited in this study. The gingival biotypes were evaluated by whether or not the outline of the periodontal probe was clear inside the gingiva. Gingival thickness of the cemento-enamel junction (CEJ) in upper anterior teeth was measured by cone-beam CT (CBCT). RESULTS: The method of periodontal probing-assessed gingival biotype had good consistency and repeatability. The result of probing-assessed gingival biotype was consistent with that obtained by CBCT. The mean thickness of gingiva in thin, compromised and thick gingival biotype was (1.02 +/- 0.20), (1.28 +/- 0.25) and (1.46 +/- 0.25) mm. These differences were significant for all three comparisons (P = 0.001, respectively). CONCLUSIONS: Periodontal probing-assessed gingival biotype is a simple, relatively objective and suitable method for clinical examination. PMID- 22490243 TI - [Long term follow-up of a patient with chronic periodontitis received comprehensive treatment]. PMID- 22490244 TI - [Case report: combined treatment of aggressive periodontitis]. PMID- 22490245 TI - [Systemic treatment of generalized severe chronic periodontitis: a case report]. PMID- 22490246 TI - [Comprehensive periodontal treatment of severe chronic periodontitis: a case report with four years follow-up]. PMID- 22490247 TI - [Maintenance after a complex treatment in a case of generalized aggressive periodontitis: 5-year result]. PMID- 22490248 TI - [Periodontal endogenous regeneration: strategies and perspectives]. PMID- 22490249 TI - [Summary of the 9th Periodontal Academic Congress and Chinese Society of Periodontal Council Meeting]. PMID- 22490250 TI - [Influence of timing of coronal preparation on microleakage of fiber post and core systems]. AB - OBJECTIVE: To evaluate the microleakage of fiber post and core systems after high speed handpiece preparation at different time points. METHODS: The crowns of forty-five extracted human premolar were removed and the roots were endodontically treated. The samples were devided into five groups. Root canal preparation was performed on each premolar followed by fiber post cementation and core build up. Tooth preparation was applied at 5 min in group 1, at 15 min in group 2 and at 30 min in group 3 after post cementation. Five teeth with only 5 mm apical sealing were served as a positive control group, and ten with fiber post and core build-up but no coronal preparation were taken as a negative control group. Microleakage was evaluated using a fluid filtration system. The bonding interface was observed by scanning electronic microscope (SEM). RESULTS: The microleakage was significantly increased after coronal preparation with high speed handpiece. The negative control group has less leakage [(1.50 * 10(-6) +/- 0.37 * 10(-6)) ul*min(-1)*Pa(-1)] than the groups with coronal preparation (P < 0.05); Group 1 leaked significantly more [(6.02 * 10(-5) +/- 1.02 * 10(-5)) ul*min(-1)*Pa(-1)] than group 2 [(1.50 * 10(-5) +/- 0.26 * 10(-5)) ul.min(-1)*Pa( 1)] and group 3 [(1.50 * 10(-5) +/- 0.39 * 10(-5)) ul*min(-1)*Pa(-1)] did (P < 0.05). Corresponding to microleakage, the micro gaps between the resin cement and dentine in group 1 were wider than those in the other groups. The coronal section was wider than the apical part. CONCLUSIONS: High-speed handpiece had negative effects on microleakage of fiber post and core systems. Coronal preparation should be performed 15 min or more after post cementation. PMID- 22490251 TI - [Maxillary sinus floor augmentation using gene-enhanced tissue engineered bone]. AB - OBJECTIVE: To evaluate the effect of maxillary sinus elevation with gene-enhanced tissue engineering bone in dogs. METHODS: bone marrow stromal cells (BMSC) derived from dog marrow were cultured, and transduced with the adenovirus carrying bone morphogenetic protein-2 (BMP-2) gene (AdBMP-2), the adenovirus carrying green fluorescent protein (GFP) gene (AdGFP) in vitro. The bone formation ability of gene modified BMSC with scaffold was examined in nude mice and in elevated maxillary sinus of dog. Student's t-test was used for statistical analysis with SPSS 11.0 software package. RESULTS: Gene transfection efficiency reached up to (83.95 +/- 2.43)% as demonstrated by GFP expression. Ectopic bone formation was detected in nude mice. As for maxillary sinus floor elevation in a dog model, new bone formation area in the AdBMP-2 gene transduced BMSC with Bio Oss group was significantly higher than in BMSC with Bio-Oss group at 120 d (P < 0.05). CONCLUSIONS: AdBMP-2 gene transduced BMSC can stimulate ectopic bone formation in nude mice, and promote bone formation and maturation in the dog maxillary sinus. PMID- 22490252 TI - [The situation of stomatological basic research supported by National Natural Science Foundation of China in the past decade]. AB - OBJECTIVE: To review the situation of stomatological research projects supported by National Natural Science Foundation of China (NSFC) and to analyze the status of stomatological research and obtained achievements in the past decade. METHODS: The internet-based science information system of NSFC together with Yearbook of Chinese Stomatology was served as the basis of data collection. All of the data were arranged and analyzed by Excel. RESULTS: A total of 866 projects and 234.4054 billion Yuan were supported by NSFC during the past decade, and they were increasing continuously. The average supportive strength of each single project was also enhanced. The percentage of projects supported by the NSFC for young scientists accounted for the biggest proportion. The approved projects of stomatology were covering an increasingly wide area of the subjects. The projects number of different areas kept growing, and further investigations were done in these projects. The areas number were from 10 increasing to 26. CONCLUSIONS: With the support of NSFC, great progress has been made in stomatology, and the interdisciplinary research between stomatology and other disciplines is more active. PMID- 22490253 TI - [Effect of diameter-controlled Ti-TiO2 nanotubes on the adhesion of osteoblast and fibroblast]. AB - OBJECTIVE: To study the effect of Ti-TiO2 nanotubes with different diameters on the adhesion of fibroblast and osteoblast, and to find which diameter was more favorable for cells' respective adhesion. METHODS: Pure titanium sheets were polished and then anodized at different potentials for 1 h with Ti as anode and Pt as cathode. TiO2 nanotubes formed at 1, 5, 10 and 20 V potentials served as experimental groups and polished pure titanium served as control group. Field emission scanning electron microscopy (Fe-SEM) was used to analyze the surface topography. Stained nucleus with Hoechst33342 were used to measure the cell adhesion. The cell shape on the sample surface were analyzed with Fe-SEM. RESULTS: TiO2 nanotube array of different inner diameters from 15 nm to 100 nm were grown on titanium sheets by anodization at potentials from 1 to 20 V. At 30, 60 and 120 min, fibroblast adhesion at nanotubes anodized at 5 V was (141 +/- 9), (388 +/- 14) and (489 +/- 15) respectively, significantly less than any other nanotube surface at the same time (P < 0.01). Nanotubes anodized at 20 V had the least inhibitory effect for fibroblast adhesion with a number of (579 +/- 14) at 120 min, and the cell shape was also inhibited. At 30, 60 and 120 min, osteoblast had a significant better adhesion on nanotubes formed at 5 V than it did on any other surface at the same time (P < 0.01), except the control group at 30 min, with the adhesion number of (198 +/- 10), (431 +/- 10) and (501 +/- 10) respectively, and osteoblast had a abundant spread on nanotubes formed at 5 V; while osteoblast adhesion on nanotubes anodized at 20 V was (152 +/- 11), (403 +/ 9) and (465 +/- 12) respectively, less than on any other nanotube surface within the same time (P < 0.05), and the cell shape on the surface changed to be more elongate. CONCLUSIONS: Fibroblast adhesion is inhabited more or less on Ti-TiO2 nanotubes of different diameters. Nanotubes formed at 5 V have the most osteoblast adhesion, and inhibit fibroblast adhesion. PMID- 22490254 TI - [Correction of vermilion border malformation with a sliding subcutaneous pedicle flap]. PMID- 22490255 TI - Disentangling the genetic origins of a plant pathogen during disease spread using an original molecular epidemiology approach. AB - The advent of molecular epidemiology has greatly improved our ability to identify the population sources and track the pathogen movement. Yet the wide spatial and temporal scales usually considered are useful only to infer historical migration pathways. In this study, Bayesian genetic assignments and a landscape epidemiology approach were combined to unravel genetic origin and annual spread during a single epidemic of a plant pathogen: the poplar rust fungus Melampsora larici-populina. The study focused on a particular area-the Durance River valley which enabled inoculum sources to be identified and channelled spread of the epidemic along a one-dimensional corridor. Spatio-temporal monitoring of disease showed that the epidemic began in the upstream part of the valley and spread out downstream. Using genetic assignment tests, individuals collected at the end of the epidemic were sorted into two genetic groups; very few hybrids were detected, although individuals from both groups coexisted locally downstream in the valley. The epidemic originated from two genetically distinct inoculum sources. Individuals of each group then dispersed southwards along the Durance River and became mixed in poplar riparian stands. These two genetic groups were found previously at a wider spatial scale and proved to result from distinct evolutionary histories on either wild or cultivated poplars. This study showed that the two groups can mix during an epidemic but do not hybridize because they then reproduce asexually. In general, the methods employed here could be useful for elucidating the genetic origin and retracing the colonization history and migration pathways of recent epidemics. PMID- 22490256 TI - Prescribing trends in veterans with posttraumatic stress disorder. AB - OBJECTIVE: The revised Department of Veterans Affairs (VA) and Department of Defense Clinical Practice Guideline for Management of Post-Traumatic Stress recommends against long-term use of benzodiazepines to manage posttraumatic stress disorder (PTSD). An analysis of recent trends among veterans receiving care for PTSD in the VA noted a decreasing proportion receiving benzodiazepines. The authors examined prescribing patterns for other medications to better understand the general context in which the changes in benzodiazepine prescribing have occurred in the VA. METHOD: Administrative VA data from fiscal years 1999 through 2009 were used to identify veterans with PTSD using ICD-9 codes extracted from inpatient discharges and outpatient encounters. Prescribing of antidepressants, antipsychotics, and hypnotics was determined for each fiscal year using prescription drug files. RESULTS: The proportion of veterans receiving either of the 2 Clinical Practice Guideline-recommended first-line pharmacotherapy treatments for PTSD, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, increased from 49.7% in 1999 to 58.9% in 2009. In addition to reduced benzodiazepine prescriptions, the overall frequency of antipsychotic use declined 6.1%, from 20.0% in 1999 to 13.9% in 2009. Nonbenzodiazepine hypnotic prescribing tripled when zolpidem was added to the VA national formulary in 2008. Buspirone prescribing decreased steadily, while prazosin prescribing expanded nearly 7-fold. CONCLUSIONS: This work highlights several clinically important trends in prescribing over the past decade among veterans with PTSD that are generally consistent with the revised VA/Department of Defense Clinical Practice Guideline recommendations. However, the findings illustrate the limitations of administrative data and point to a need to supplement this work with a qualitative examination of PTSD prescribing from interviews with providers to better understand the strategies used to make medication management decisions. PMID- 22490257 TI - Emerging bias in the treatment of posttraumatic stress disorder. PMID- 22490258 TI - Benzodiazepines, posttraumatic stress disorder, and veterans: good news and why we're not done yet. PMID- 22490259 TI - How successful are physicians in eliciting the truth from their patients? A large scale Internet survey from patients' perspectives. AB - OBJECTIVE: How honestly patients report their symptoms and medication adherence to their physicians has not been adequately addressed in patients with depression. We therefore conducted a large-scale Internet survey in an effort to discover how successful physicians are in eliciting the truth from their patients and also to examine reasons for patients' truth-concealing behaviors. METHOD: 2,354 participants who had received treatment for depression within the past year and had been diagnosed with depression by Patient Health Questionaire were identified from 323,226 registrants at the Macromill database through screening procedures. Participants were asked to complete a questionnaire regarding their treatment for depression with a special focus on patient-physician relationship. This study was conducted from December 7 to 13, 2010, in Japan. RESULTS: 2,020 participants successfully completed the questionnaire. Overall, 70.2% of responders reported that they had withheld the truth from their physicians. A logistic regression model found significant associations of such a behavior with female sex (95% CI, 1.15-1.74; P = .001), younger age (95% CI, 0.49-0.97; P = .030), and a lower degree of satisfaction in mutual communication (95% CI, 3.17 6.58; P < .001). 69.2% and 52.6% of the participants refrained from telling about their "daily activities" and "symptoms," respectively. Female participants were more likely to hide the facts concerning "adherence to prescribed medication" and "figures such as body temperature and weight." 31.9% of participants had discontinued the treatment without consulting their physician, which was again more frequent in females, younger persons, and those who were not satisfied with communication with their physician. CONCLUSIONS: While the findings obtained herein need to be replicated in other patient populations, a majority of patients with depression were reluctant to uncover the truth, which emphasizes the need for more fine-tuned suspicion among physicians about symptoms and medication adherence. PMID- 22490260 TI - Successful monitoring of fluoxetine-induced nocturnal bruxism: a case report. PMID- 22490262 TI - Shift work disorder: overview and diagnosis. AB - Shift work disorder is a type of sleep disorder that occurs when an individual is unable to successfully synchronize his or her internal clock with a work schedule that requires staying awake and working when it is dark and sleeping when it is light. Approximately 10% of shift workers suffer from this disorder, which seriously impairs their ability to function. Shift work disorder is associated with increased risk of gastrointestinal problems, cancer, depression, heart disease, excessive sleepiness and accidents, and decreased productivity. This report describes the prevalence, diagnostic criteria, differential diagnosis, and clinical consequences of shift work disorder to help clinicians recognize this impairing condition. PMID- 22490263 TI - Management of fibromyalgia in primary care. AB - Most treatments for patients with fibromyalgia can be provided in primary care practices. When clinicians, therapists, and community resources work together, a range of pharmacologic and nonpharmacologic treatments can be tailored to provide effective long-term care. Treatments found to be effective for various fibromyalgia symptoms, such as pain and problems with sleep or mood, include antidepressants and anticonvulsants. Additionally, other effective strategies include patient education, light exercise, and cognitive-behavioral therapy. PMID- 22490264 TI - Understanding antidepressant mechanism of action and its effect on efficacy and safety. AB - Common side effects of antidepressants, such as weight gain, sexual dysfunction, and fatigue and sleepiness, may be attributable to their mechanisms of action. Antidepressants are neurotransmitter uptake blockers, enzyme inhibitors, and neurotransmitter receptor blockers. Various mechanisms of action can determine how quickly therapeutic benefit becomes apparent and whether certain acute and persistent side effects occur. Understanding mechanism of action can help clinicians select appropriate antidepressants for individual patients and manage adherence problems due to intolerability. Although more research is needed to further elucidate specific antidepressant mechanisms of action, clinicians can use current knowledge to tailor treatment decisions, such as switching patients to a medication with a different mechanism of action when intolerable adverse events are experienced. PMID- 22490265 TI - A review of current bipolar disorder treatment guidelines. AB - With the help of the Texas Implementation of Medication Algorithms (TIMA) and the American Psychiatric Association (APA) practice guidelines, primary care physicians can devise a treatment plan for their patients with bipolar disorder. Clinicians should keep in mind the goals of treatment, engage the patient in the treatment plan, and encourage the patient to keep a mood log and undertake psychoeducation or cognitive therapy. Patients who are unable to participate in treatment, who are suicidal, who have psychotic symptoms, or who require advanced treatments should be referred to a psychiatrist or hospital. PMID- 22490267 TI - 1-Germavinylidene (Ge?CH2), germyne (HGeCH), and 2-germavinylidene (H2Ge?C) molecules and isomerization reactions among them: anharmonic rovibrational analyses. AB - Theoretical investigations of three equilibrium structures and two associated isomerization reactions of the GeCH(2) - HGeCH - H(2)GeC system have been systematically carried out. This research employed ab initio self-consistent field (SCF), coupled cluster (CC) with single and double excitations (CCSD), and CCSD with perturbative triple excitations [CCSD(T)] wave functions and a wide variety of correlation-consistent polarized valence cc-pVXZ and cc-pVXZ-DK (where X = D, T, Q) basis sets. For each structure, the total energy, geometry, dipole moment, harmonic vibrational frequencies, and infrared intensities are predicted. Complete active space SCF (CASSCF) wave functions are used to analyze the effects of correlation on physical properties and energetics. For each of the equilibrium structures, vibrational second-order perturbation theory (VPT2) has been utilized to obtain the zero-point vibration corrected rotational constants, centrifugal distortion constants, and fundamental vibrational frequencies. The predicted rotational constants and anharmonic vibrational frequencies for 1-germavinylidene are in good agreement with available experimental observations. Extensive focal point analyses, including CCSDT and CCSDT(Q) energies and basis sets up to quintuple zeta, are used to obtain complete basis set (CBS) limit energies. At all levels of theory employed in this study, the global minimum of the GeCH(2) potential energy surface (PES) is confirmed to be 1-germavinylidene (GeCH(2), 1). The second isomer, germyne (HGeCH, 2) is predicted to lie 40.4(41.1) +/- 0.3 kcal mol(-1) above the global minimum, while the third isomer, 2-germavinylidene (H(2)GeC, 3) is located 92.3(92.7) +/- 0.3 kcal mol(-1) above the global minimum; the values in parentheses indicate core-valence and zero-point vibration energy (ZPVE) corrected energy differences. The barriers for the forward (1->2) and reverse (2->1) isomerization reactions between isomers 1 and 2 are 48.3(47.7) +/- 0.3 kcal mol(-1) and 7.9(6.6) +/- 0.3 kcal mol(-1), respectively. On the other hand, the barriers of the forward (2->3) and reverse (3->2) isomerization reactions between isomers 2 and 3 are predicted to be 55.2(53.2) +/- 0.3 kcal mol(-1) and 3.3(1.6) +/- 0.3 kcal mol(-1), respectively. PMID- 22490266 TI - Cost-effectiveness of 12-month therapeutic assertive community treatment as part of integrated care versus standard care in patients with schizophrenia treated with quetiapine immediate release (ACCESS trial). AB - OBJECTIVE: To compare the 1-year cost-effectiveness of therapeutic assertive community treatment (ACT) with standard care in schizophrenia. ACT was specifically developed for patients with schizophrenia, delivered by psychosis experts highly trained in respective psychotherapies, and embedded into an integrated care system. METHOD: Two catchment areas in Hamburg, Germany, with similar population size and health care structures were assigned to offer 12 month ACT (n = 64) or standard care (n = 56) to 120 first- and multiple-episode patients with schizophrenia spectrum disorders (DSM-IV), the latter with a history of relapse due to medication nonadherence. Primary outcome was the incremental cost-effectiveness ratio (ICER) based on mental health care costs from a payer perspective and quality-adjusted life-years (QALYs) as a measure of health effects during the 12-month follow-up period (2006-2007). RESULTS: ACT was associated with significantly lower inpatient but higher outpatient costs than standard care, resulting in nonsignificantly lower total costs (P = .27). Incremental QALYs in the ACT group were 0.1 (P < .001). Thus, the point estimate for the ICER showed dominance of ACT. The probability of an ICER below ?50,000 per QALY gained was 99.5%. CONCLUSIONS: The implementation of a psychotherapeutically oriented schizophrenia-specific and -experienced ACT team led to an improved patient outcome with reduced need of inpatient care. Despite the introduction of such a rather "costly" ACT team, treatment in ACT was cost effective with regard to improved quality of life at comparable yearly costs. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01081418. PMID- 22490268 TI - Polymorphism in 4'-hydroxyacetophenone: a molecular dynamics simulation study. AB - A molecular dynamics simulation study of the two known polymorphs of 4' hydroxyacetophenone (HAP; form I, monoclinic; form II, orthorhombic) is described. The modeling of the lattice energetics was found to be particularly sensitive to the atomic point charge (APC) selection method, to the number of molecules in the asymmetric unit (Z'), and to the flexibility allowed for the molecules. In order to improve the quality of the APCs, a new strategy that attempts to simulate the polarizability effects of the molecules in the crystal lattice was developed. This method relies in the application of the CHelpG methodology to a molecular aggregate with the same spatial arrangement present in the crystal lattice of the compound. This approach led to Delta(trs)H(m)o(II->I) = +2.4 +/- 0.3 kJ.mol(-1) and Delta(trs)H(m)o(II->I) = +2.0 +/- 0.9 kJ.mol(-1) when rigid and flexible models were used, respectively, in good agreement with the corresponding experimental value Delta(trs)H(m)o(II->I) = +0.49 +/- 0.13 kJ.mol(-1). Concerning the volumetric properties (density and unit cell parameters), it was concluded that the use of a flexible molecular model was largely insensitive to the chosen methodology for the selection of the APC. Overall, it was concluded that the best performance in the prediction of the energetic and volumetric properties of the two HAP polymorphs was achieved by combining a flexible molecular framework with atomic charges obtained for a molecular aggregate mimicking the crystal packing. PMID- 22490271 TI - Anemia, iron depletion, and the blood donor: it's time to work on the donor's behalf. PMID- 22490269 TI - Surgical treatment of tricuspid regurgitation after mitral valve surgery: a retrospective study in China. AB - BACKGROUND: Functional tricuspid regurgitation (TR) occurs in patients with rheumatic mitral valve disease even after mitral valve surgery. The aim of this study was to analyze surgical results of TR after previous successful mitral valve surgery. METHODS: From September 1996 to September 2008, 45 patients with TR after previous mitral valve replacement underwent second operation for TR. In those, 43 patients (95.6%) had right heart failure symptoms (edema of lower extremities, ascites, hepatic congestion, etc.) and 40 patients (88.9%) had atrial fibrillation. Twenty-six patients (57.8%) were in New York Heart Association (NYHA) functional class III, and 19 (42.2%) in class IV. Previous operations included: 41 for mechanical mitral valve replacement (91.1%), 4 for bioprosthetic mitral valve replacement (8.9%), and 7 for tricuspid annuloplasty (15.6%). RESULTS: The tricuspid valves were repaired with Kay's (7 cases, 15.6%) or De Vega technique (4 cases, 8.9%). Tricuspid valve replacement was performed in 34 cases (75.6%). One patient (2.2%) died. Postoperative low cardiac output (LCO) occurred in 5 patients and treated successfully. Postoperative echocardiography showed obvious reduction of right atrium and ventricle. The anterioposterior diameter of the right ventricle decreased to 25.5 +/- 7.1 mm from 33.7 +/- 6.2 mm preoperatively (P < 0. 05). CONCLUSION: TR after mitral valve replacement in rheumatic heart disease is a serious clinical problem. If it occurs or progresses late after mitral valve surgery, tricuspid valve annuloplasty or replacement may be performed with satisfactory results. Due to the serious consequence of untreated TR, aggressive treatment of existing TR during mitral valve surgery is recommended. PMID- 22490273 TI - The human platelet antigen-21bw is relatively common among Asians and is a potential trigger for neonatal alloimmune thrombocytopenia. PMID- 22490274 TI - Strict anaerobic Staphylococcus saccharolyticus isolates recovered from contaminated platelet concentrates fail to multiply during platelet storage. PMID- 22490275 TI - Is the SCID mouse model applicable to human acute lung injury? PMID- 22490277 TI - A macroepigenetic approach to identify factors responsible for the autism epidemic in the United States. AB - The number of children ages 6 to 21 in the United States receiving special education services under the autism disability category increased 91% between 2005 to 2010 while the number of children receiving special education services overall declined by 5%. The demand for special education services continues to rise in disability categories associated with pervasive developmental disorders. Neurodevelopment can be adversely impacted when gene expression is altered by dietary transcription factors, such as zinc insufficiency or deficiency, or by exposure to toxic substances found in our environment, such as mercury or organophosphate pesticides. Gene expression patterns differ geographically between populations and within populations. Gene variants of paraoxonase-1 are associated with autism in North America, but not in Italy, indicating regional specificity in gene-environment interactions. In the current review, we utilize a novel macroepigenetic approach to compare variations in diet and toxic substance exposure between these two geographical populations to determine the likely factors responsible for the autism epidemic in the United States. PMID- 22490278 TI - Polar extracts from (Tunisian) Acacia salicina Lindl. Study of the antimicrobial and antigenotoxic activities. AB - BACKGROUND: Methanolic, aqueous and Total Oligomer Flavonoids (TOF)-enriched extracts obtained from the leaves of Acacia salicina 'Lindl.' were investigated for antibacterial, antimutagenic and antioxidant activities. METHODS: The antimicrobial activity was tested on the Gram positive and Gram negative reference bacterial strains. The Mutagenic and antimutagenic activities against direct acting mutagens, methylmethane sulfonate (MMS) and 4-nitro-o phenylenediamine (NOPD), and indirect acting mutagens, 2-aminoanthracene (2-AA) and benzo[a]pyrene (B(a)P) were performed with S. typhimurium TA102 and TA98 assay systems. In addition, the enzymatic and nonenzymatic methods were employed to evaluate the anti-oxidative effects of the tested extracts. RESULTS: A significant effect against the Gram positive and Gram negative reference bacterial strains was observed with all the extracts. The mutagenic and antimutagenic studies revealed that all the extracts decreased the mutagenicity induced by B(a)P (7.5 MUg/plate), 2-AA (5 MUg/plate), MMS (1.3 mg/plate) and NOPD (10 MUg/plate). Likewise, all the extracts showed an important free radical scavenging activity towards the superoxide anion generated by the xanthine/xanthine oxidase assay system, as well as high Trolox Equivalent Antioxidant Capacity (TEAC), against the 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulfonic acid) diammonium salt (ABTS)+* radical. TOF-enriched extract exhibited the highest protective effect against free radicals, direct acting-mutagen and metabolically activated S9-dependent mutagens. CONCLUSIONS: The present study indicates that the extracts from A. salicina leaves are a significant source of compounds with the antimutagenic and antioxidant activities, and this may be useful for developing potential chemopreventive substances. PMID- 22490280 TI - [Molecular prediction of metastatic recurrence of hepatocellular carcinoma: from omics to clinical application]. PMID- 22490279 TI - Postglacial colonization of Europe by the barbastelle bat: agreement between molecular data and past predictive modelling. AB - The barbastelle (Barbastella barbastellus) is a rare forest bat with a wide distribution in Europe. Here, we combine results from the analysis of two mtDNA fragments with species distribution modelling to determine glacial refugia and postglacial colonization routes. We also investigated whether niche conservatism occurs in this species. Glacial refugia were identified in the three southern European peninsulas: Iberia, Italy and the Balkans. These latter two refugia played a major role in the postglacial colonization process, with their populations expanding to England and central Europe, respectively. Palaeo distribution models predicted that suitable climatic conditions existed in the inferred refugia during the last glacial maximum (LGM). Nevertheless, the overlap between the current and the LGM distributions was almost inexistent in Italy and in the Balkans, meaning that B. barbastellus populations were forced to shift range between glacial and interglacial periods, a process that probably caused some local extinctions. In contrast, Iberian populations showed a 'refugia within refugium' pattern, with two unconnected areas containing stable populations (populations that subsisted during both glacial and interglacial phases). Moreover, the match between LGM models and the refugial areas determined by molecular analysis supported the hypothesis of niche conservatism in B. barbastellus. We argue that geographic patterns of genetic structuring, altogether with the modelling results, indicate the existence of four management units for conservation: Morocco, Iberia, Italy and UK, and Balkans and central Europe. In addition, all countries sampled possessed unique gene pools, thus stressing the need for the conservation of local populations. PMID- 22490281 TI - [Progress of endovascular techniques for below-knee arterial ischemic lesions]. PMID- 22490282 TI - [Clinicopathologic features, diagnosis and treatment with solid-pseudopapillary tumor of the pancreas: a report of 33 cases]. AB - OBJECTIVE: To study the clinicopathologic and immunohistochemical features, biological behavior, diagnosis and treatment of solid pseudopapillary tumor of the pancreas (SPTP). METHODS: A retrospective clinical and clinicopathologic analysis was made on 33 cases of SPTP admitted from May 2001 to 2010 July. There were 7 male and 26 female patients, aging from 13 to 66 years with a mean of 34.3 years. RESULTS: The tumor was located in pancreatic head of 10 patients, in pancreatic neck of 5 patients, in pancreatic body and tail of 18 patients. Of the 33 patients treated with surgery, 8 underwent simple resection of pancreatic tumor, 6 underwent pancreaticoduodenectomy, 3 underwent tumor resection plus pancreaticojejunostomy, 1 underwent tumor resection plus pancreaticogastrostomy, 11 underwent distal pancreatectomy, 4 underwent distal pancreatectomy plus spleen resection (1 underwent mesohepatectomy for hepatic metastasis). Sixteen of the 33 operations were completed by laparoscopy. Histologically, tumors were composed of papillary and microcystic solid structures, with uniformed population of cells. The pancreas and blood vessels invasion were identified in 3 cases, one of them was combined with liver metastasis, and they are male. Immunohistologically, the tumors were positive for alpha1-antitrypsin, alpha1-antichymotrypsin, beta catenin, CD10, CD56 and vimentin (all cases), neuron-specific enolase (3 cases), synaptophysin (6 cases), chromogranin A (4 cases), progesterone receptor (28 cases), estrogen receptor (3 cases), S-100 (6 cases). Totally 33 cases were followed up with a median period of 49 months without tumor recurrence. CONCLUSIONS: SPTP is of low graded malignancy. It primarily affects young women. It may be located in any part of pancreas. Immunohistochemistry is very important for the diagnosis and differential diagnosis of SPTP. Surgical resection is recommended as the treatment of choice. Laparoscopic distal pancreatectomy or tumor resection is feasible and safe for some selected patients, and the prognosis is good. PMID- 22490283 TI - [Catheter directed thrombolysis for early left lower extremity deep venous thrombosis without vena cava filters protection]. AB - OBJECTIVE: To investigate the indications, safety and efficacy of catheter directed thrombolysis for early left lower extremity deep venous thrombosis (DVT) without vena cava filters protection. METHODS: Clinical data of 54 cases of early left lower extremity DVT received catheter directed thrombolysis without vena cava filters from July 2008 to June 2010 were retrospectively analyzed. The thrombosis was entire without free floating clots and no thrombosis in vena cava detected with ultrasound scan. Twenty-five patients were male and 29 were female with the average age of 52.8 years. Fifty-one of which were iliofemoral and popliteal, the other 3 were iliofemoral. The course were <= 7 d in 45 cases and these were 8 to 30 d in 9 cases. Urokinase of 300 000 U was infused through catheters per 2 h twice a day. Meanwhile 4000 U of low weight heparin was administered subcutaneously per 12 h, or heparin infusion at dosage of 18 U*kg( 1)*h(-1). RESULTS: The procedure technically succeeded in all patients. In total cases venous score decreased to 4.6 +/- 2.1 post 6 to 10 d of thrombolysis from 10.8 +/- 1.0 with thrombolysis rate of 58% +/- 18% which was not significantly different between groups of <= 7 d and 8 to 30 d (t = 1.02, P = 0.34). On 14(th) day, 11 patients (20.4%) completely recovered, 35 cases (64.8%) experienced large improvement, 8 patients (14.8%) had mild improvement and nobody was failed, resulting in total efficacy of 100%. No patient developed clinical symptomatic pulmonary embolism. SpO2 did not alter markedly post thrombolysis [(91.0 +/- 2.6)% vs. (90.8 +/- 2.4)%, t = 2.03, P = 0.05]. No patients suffered from cerebral hemorrhage and haemoturia, and catheter induced inflammation occurred in 4 cases (7.41%). There was mild bleeding in puncture sites in 11 patients (20.4%) during the course. There were 36 patients (66.7%) had been followed up with the time of 6 to 21 months. In which 31 cases had no lower extremity edema or had mild edema after activities. Two patients developed serious edema after activities for deep venous insufficiency. Three cases combined with malignant tumor or renal failure recurred. CONCLUSIONS: For early left extremity DVT which is entire without free floating clots and no thrombosis in vena cava, catheter directed thrombolysis without filter protection maybe administered with safety, efficiency and lower expense. PMID- 22490284 TI - [Successful short-segment fixation for thoracolumbar burst fractures using CYL pedicle screw]. AB - OBJECTIVE: To access the efficacy of posterior short-segment fixation for single level thoracolumbar burst fractures without spinal injury using CYL-pedicle screw. METHODS: From September 2007 to December 2009, 74 cases who underwent posterior short-segment fixation for single level thoracolumbar burst fractures (Denis burst fracture type A, B, C) without spinal injury were analyzed retrospectively. There were 53 male and 21 female, mean age was (39 +/- 15) years. Neither of them treated with direct decompression, grafting or fusion. Changes in the anterior vertebral height ratio, vertebral wedge angle, Cobb angle, regional angle were measured preoperatively, postoperatively, before implant removal, and at final follow-up to find the statistic difference. Pain status and work status were evaluated using Denis criterion. The incidence of incision infection, screw breakage, iatrogenic spinal injury were recorded as well. RESULTS: The time of follow-up was (20 +/- 11) months, no significant change was noted in anterior vertebral height ratio and vertebral wedge angle (P > 0.05). A significant loss was noted in Cobb angle and regional angle, which were 9.8 degrees +/- 5.1 degrees and 9.1 degrees +/- 4.8 degrees respectively (t = 2.48 and 3.41, P < 0.05). Comparing with the patients with Cobb angle > 20 degrees , the patients with Cobb angle <= 20 degrees had better pain scale rate (chi(2) = 4.16, P = 0.04) and work scale rate (chi(2) = 24.34, P < 0.01). There were incision infection in 1 case, screw breakage in 1, screw loose in 1, and no iatrogenic spinal injury. CONCLUSIONS: CYL-pedicle screw could be successfully used in posterior short-segment fixation for single level thoracolumbar burst fractures without spinal injury based on radiographic and clinic outcomes. PMID- 22490285 TI - [The posterior surgical treatment of old tuberculous kyphosis]. AB - OBJECTIVE: To observe the results of posterior osteotomy and correction in the surgical treatment of old tuberculous kyphosis. METHODS: From June 2004 to December 2008, 31 cases of old tuberculous kyphosis with posterior osteotomy and correction technique were treated. There were 12 cases of male and 19 cases of female. The average age was 33.4 years. Pedicle subtraction osteotomy or vertebral column resection were applied in surgery. The kyphosis angle, lumbar lordosis angle and sagittal balance condition of the spine were measured before and after surgery, as well as follow-up. The Frankel grading system for neurological function of lower extremities, the Oswestry disability index (ODI) for life quality, and patient satisfactory index (PSI) for satisfaction of surgery were applied before surgery and at follow-up. RESULTS: The average kyphosis angle was 94 degrees +/- 27 degrees , the average lumbar lordosis angle was 71 degrees +/- 20 degrees , and the average sagittal C(7) plumb line was ( 15 +/- 44) mm away from the balance region before surgery. The average kyphosis angle decreased to 26 degrees +/- 11 degrees in one week after surgery, with an improvement rate of 71.4%. The average follow-up time was 22.5 months. The average kyphosis angle was 28 degrees +/- 12 degrees at the final follow-up, with an improvement rate of 70.0%. The average lumbar lordosis angle was 46 degrees +/- 11 degrees , with an improvement rate of 35.1%. The postoperative kyphosis angle and lumbar lordosis angle were significantly different with that of pre-operation (for kyphosis angle: t = 16.3, P < 0.05; for lumbar lordosis angle: t = 8.1, P < 0.05). The average sagittal C(7) plumb line was (-4 +/- 22) mm away from the balance region at the final follow-up, with an improvement rate of 73.4%. The Frankel grading were E in 13 cases, D in 13 cases, and C in 5 cases before surgery, and were E in 20 cases, D in 8 cases, and C in 3 cases at the final follow-up. The average ODI was 13 +/- 12 before surgery, and was 7 +/- 8 at the final follow-up, with an improvement rate of 45.2%. The PSI results showed a satisfied rate of 90.3%. CONCLUSION: Good results can be achieved by applying proper posterior osteotomy and correction technique according to the severity of old tuberculous kyphosis. PMID- 22490286 TI - [Using titanium cerclage band to teat intra- and post-operative femoral fracture in total hip arthroplasty]. AB - OBJECTIVE: To discuss the treatment and clinical result of using titanium cerclage band to teat intra- and post-operative femoral fracture in total hip arthroplasty. METHODS: From August 1999 to September 2007, twenty-two patients who suffered from intra-and post-operative femoral oblique fracture in total hip arthroplasty were reviewed among 2186 consecutive total hip arthroplasty patients performed by one surgeon. There were 12 fractures occurred intraoperative and 10 fractures postoperative. There are 9 primary and 13 revision total hip arthroplasty patients including 10 men and 12 women. All fractures are classified as Vancouver B1 type in 15 cases and B2 type in 7 cases. Two to five titanium cerclage bands had been used to fix the fracture followed by open reduction with 13 cases using 2 cerclage bands and 7 cases using 3 bands and 1 case using 4 bands and 1 case using 5 bands. Whether change the original stem or not depended on the classification of fractures and stability of stems. There were 15 cases of type B1 and 1 case of type B2 without changing stems and 6 cases of type B2 changing to revision stems of the same series of original stems. RESULTS: All fractures showed successfully union for 12 - 20 weeks (average 18 weeks) after operation. The average Harris score of the hip improved to 90 points (80 to 95 points) at an average 6.5 years follow-up (4 to 11 years) and the average range of motion of the hip got to 120 degrees (105 degrees - 135 degrees ). Femoral prostheses were well-fixed without any subsidence or lucent lines or loosening. All patients were satisfied with the results with well-fixed and good alignment of femoral stem. CONCLUSIONS: Strong fixation of the fractures and good initial stability of femoral stem can be obtained using titanium cerclage bands to fix the intra- and post-operative femoral oblique fracture. Original stems should be changed to revision stems in case of type B2 and be retained in case of type B1. PMID- 22490287 TI - [Clinical analysis of the edge-to-edge technique for mitral regurgitation due to myxomatous degeneration]. AB - OBJECTIVES: To explore the feature of the edge-to-edge technique and its effect for mitral regurgitation due to myxomatous degeneration. METHODS: The in-patient data and follow-up outcomes of 58 patients after the edge-to-edge technique for mitral regurgitation due to myxomatous degeneration from January 2000 to January 2009 were analyzed retrospectively. Of the 58 patients, 32 patients were male and 26 patients were female, and the age range was from 43 years to 65 years with a mean of (56 +/- 6) years, and moderate mitral regurgitation was observed in 18 patients and severe regurgitation in 40 patients, and the prolapse of the anterior leaflet was observed in 50 patients and the prolapse of the bileaflet in 8 patients. The edge-to-edge technique was performed in all patients and the annuloplasty was performed in 44 patients. RESULTS: There was no perioperative death and serious complication. Postoperative transthoracic echocardiography of all the survivors indicated that the dimensions of left atrial and left ventricular were obviously decreased (P < 0.05) and mitral insufficiency was obviously improved (no regurgitation was observed in 9 patients and trace regurgitation in 30 patients and mild regurgitation in 19 patients) and there was no mitral stenosis. Totally 58 patients were followed up from 24 months to 95 months with a mean of (58 +/- 20) months. During the follow-up, there were 2 deaths for noncardiac factors. Freedom from recurrent moderate or severe mitral regurgitation at 5 years after operations was 91.9%. According to undergoing combined annuloplasty or not, 58 patients were divided into the edge-to-edge technique group (14 cases) and the edge-to-edge technique + annuloplasty group (44 cases), and the survival analysis shows there was significant difference on freedom from long-term recurrent moderate or severe mitral regurgitation after operations between two groups (chi(2) = 4.034, P = 0.045) and long-term effect of the latter group was better. CONCLUSIONS: The edge-to-edge technique can be conveniently used and bring about satisfactory perioperative and long-term effects for mitral regurgitation due to myxomatous degeneration. The combination of the edge-to-edge technique and the annuloplasty can improve the long-term effect significantly. PMID- 22490288 TI - [The value of diffusion-weighted MR imaging combined with transrectal ultrasound for transrectal prostate biopsy]. AB - OBJECTIVE: To retrospectively analyze the clinical value of diffusion-weighted MR imaging in the detection of prostate cancer in suspected patients. METHODS: Between January 2009 and December 2010, the 551 patients suspected as prostate cancer underwent prostate biopsy. Patients in group A were accepted to a transrectal ultrasound (TRUS) guided transrectal prostate biopsy (n = 410), while patients in group B were accepted to a diffusion weighted imaging (DWI) and TRUS jointly guided transrectal prostate biopsy (n = 141). The two groups were divided into 4 subgroups by prostate specific antigen (PSA) < 10 ug/L, 10 ug/L <= PSA < 20 ug/L, 20 ug/L <= PSA < 50 ug/L and PSA >= 50 ug/L. Then, the diagnostic rates of prostate biopsy guided by combination of DWI and TRUS with only TRUS were compared. RESULTS: The diagnostic rate of patients with PSA < 10 ug/L, 10 ug/L <= PSA < 20 ug/L, 20 ug/L <= PSA < 50 ug/L and PSA >= 50 ug/L were 12.1%, 31.1%, 48.0%, 91.2% in group A, and 23.7%, 35.5%, 66.7%, 96.3% in group B, respectively. In the patients with PSA less than 10 ug/L, there were significant differences in diagnostic rate between the two biopsy techniques (chi(2) = 4.405, P < 0.05). CONCLUSION: The combination of DWI and TRUS showed the potential to guide biopsy to cancer foci in patients suspected as prostate cancer. For patients with PSA < 10 ug/L, a DWI and TRUS jointly guided transrectal prostate biopsy was recommended. PMID- 22490289 TI - [Treatment of large circular soft tissue defect in lower extremities with a combination of bridge flaps and free skin graft covered by vacuum sealing drainage]. AB - OBJECTIVE: To explore the surgical technique and clinical value of treatment for posttraumatic large circular soft tissue defect in the lower extremities using a combination of posterior tibial vascular bridge flap in the unaffected leg and skin graft covered by vacuum sealing drainage (VSD). METHODS: From January 2008 to June 2010, 11 cases with posttraumatic large circular soft tissue defects with deep tissue exposed or partial necrosis in the lower extremities were treated by bridge flaps and combined with free skin graft covered by VSD. There are 7 males and 4 females, with an average age of 32.5 years (range from 15 to 52 years). The size of wound varied from 24 cm * 13 cm to 45 cm * 24 cm. After the wound were completely debrided, the external fixation or internal fixation was conducted for the patients with unstable fracture. Then VSD were used to covered the wound for 1-2 times with a period of 5 to 7 days according to the wound condition. After granulation tissue grew, bridge flap transplantation was performed to repair tissue defect and cover the exposed bone, which combined with skin graft covered by VSD was used to cover the residual wound. Survival rate and quality healing of the flaps were followed up postoperatively. RESULTS: The granulation growth of 11 cases with large circular soft tissue defect in the lower extremities associated tissue exposure was good after the application of VSD. All the cases were covered by free flap transplantation and skin grafting except for 6 cases due to large defect. The wound was covered by skin re-grafting in 4 cases and frequently dressing change in 2 cases. All the flaps were successful with good infection control and no sinus. The average period of follow-up was 10.6 months (5 - 24 months). All the patients were satisfied with the good outline and good function of the affected limb. CONCLUSION: Patients with posttraumatic large circular soft tissue defect in the lower extremities can be effectively treated with a combination of bridge flaps and free skin graft covered by VSD, which can shorten the course of treatment, and restore the function of affected extremities as much as possible. PMID- 22490290 TI - [An experiment study and clinical observation of the influence of free-skin grafted scrotal avulsion injuries on spermatogenesis]. AB - OBJECTIVE: To explore the influence of Free-skin-grafted penoscrotal avulsion injuries on spermatogenesis. METHODS: Forty-two male New Zealand albino rabbits during child-bearing period were divided into the experimental group (n = 24) and the control group (n = 18) using random digits table, and 24 female rabbits with reproductive history were used for mating experiment. The experimental group animal's scrotum skin were excised, and the split skin from abdominal region was used to repair the skin defect of scrotum. The control group did not any processing. Six rabbits were randomly chosen respectively in control group and on the 3rd and 8th weekend after the model was successfully established in experimental group. The testicular surface temperature was measured in the eighteen rabbits using the method of burying thermometer, then the testicular biopsy were performed for hematoxylin-eosin (HE) staining. On the 8(th) weekend after the model was successfully established in experimental group, matched-pair feed was performed in the other 12 rabbits respectively in experimental group and in control group. Observation of corresponding mother rabbit fertility. Three patients of penoscrotal avulsion injuries were treated using split skin grafts, and the information of sex life and the quality of sperm were obtained by follow up. RESULTS: The testicular surface temperature was similar on the 3rd and 8th weekend after the model was successfully established in experimental group [(36.15 +/- 0.24) degrees C, (36.77 +/- 0.42) degrees C] with that of the control group. Testis tissue (HE) staining showed the tier of spermatogenic cells was rule arrangement and lot of mature sperms were found in the convoluted seminiferous tubules in control group. The tier of spermatogenic cells was diminished and disposed derangement, the spermatozoa were not seen on the 3(th) weekend of the experiment group. The tier of spermatogenic cells was increased and some spermatozoa were seen on the 8th weekend of the experiment group. Male and female matched-pair feed showed the experimental group conception rate 8/12, and 4.1 +/- 3.2 rabbit babies were born averagely, while that of was 12/12 and 6.0 +/- 1.3 in control group (P > 0.05). The skin grafts there were some contracture in early stage (1 - 2 months) when the skin grafts applied to repair the avulsing scrotum in three patients. But the skin grafts became loose with downward sagging and there were the good cosmetic result in one year, and without any contracture. The sperm quality was normal after the skin grafts applied to repair the avulsing scrotum in the late stage. CONCLUSIONS: The skin grafting is little arrest the testicle spermatogenesis in the three methods (skin flap reconstruction scrotum, testicle buried, split skin grafting) that have usually been used to repair scrotum skin lose. For a young male, the best treatment for penoscrotal avulsion injuries is free skin grafting, while skin flaps are not recommended for reconstructing the scrotum. PMID- 22490291 TI - [The prognostic significance of Omi/HtrA2 expression, and correlation between Omi/HtrA2 and hypoxia-inducible factor-1alpha in primary hepatocellular carcinoma cells]. AB - OBJECTIVES: To investigate the prognostic significance of Omi/HtrA2 expression, and the correlation between Omi/HtrA2 and Hypoxia-inducible factor (HIF)-1alpha in primary hepatocellular carcinoma cells. METHODS: The expression of HIF-1alpha and Omi/HtrA2 in 43 cases of hepatic carcinoma tissues were detected immunohistochemically. Follow-up data were obtained to perform the Kaplan-Meier survival analysis. The change of Omi/HtrA2 expression in HepG2 cell was measured after HIF-1alpha expression of HepG2 in vitro was regulated by Tet-on expression system. RESULTS: Omi/HtrA2 expression was correlated with lymph node metastasis and recurring within liver during 2 years. Statistical analysis estimation showed the cumulative survival rate of post-hepatectomy for the patients with the positive expression of Omi/HtrA2 was higher than that for other patients with the negative expression of Omi/HtrA2 (chi(2) = 6.13, P = 0.013). In the common paraffin-embedded specimen of hepatocellular carcinoma, most of the samples showing negative or weak positive HIF-1alpha immunopositivity showed moderate positive or strong positive Omi/HtrA2 immunopositivity, while most of the samples showing moderate positive or strong positive HIF-1alpha immunopositivity showed negative or weak positive Omi/HtrA2 immunopositivity. The mRNA expression intensity of Omi/HtrA2 was decreasing with the HIF-1alpha expression increasing, and the difference was statistically significant(F = 106.766, P < 0.01). CONCLUSIONS: Omi/HtrA2 may be an important prognostic marker for primary hepatocellular carcinoma. Omi/HtrA2 expression is reversely correlated with HIF 1alpha expression in hepatocellular carcinoma. During the apoptotic process Omi/HtrA2 participating in hepatocellular carcinoma cells, HIF-1alpha is involved in the controlling and regulating of Omi/HtrA2 expression. PMID- 22490292 TI - [Correlation of polymorphism rs1563828 in MDM4 gene with breast cancer risk and onset age]. AB - OBJECTIVE: To explore effect of polymorphism rs1563828 (C > T) in human murine double minute 4 gene (MDM4) on genetic susceptibility for early-onset breast cancer and potential association with age of onset of breast cancer. METHODS: One hundred and twenty-four early-onset breast cancer patients (age <= 35 years at time of diagnosis) from independent families admitted from January 2006 to June 2010 and 101 age-matched healthy control subjects were analyzed. Genotype analysis was conducted by polymerase chain reaction and then MALDI-TOF-MS assay. Association of genotype distribution and breast cancer risk was evaluated by chi(2) test. The odd-ratios (OR) and 95% confidence intervals (CI) were calculated by unconditional Logistic regression model. The t test was used to compare the age and demographic differences among groups. RESULTS: The frequency of rs1563828 polymorphism genotypes in control group were CC 43.6% (44/101), CT 42.6% (43/101), TT 13.9% (14/101), and in case group were 42.7% (53/124), 46.0% (57/124), 11.3% (14/124), respectively. No significant difference (chi(2) = 0.449, P = 0.799) was reached by chi(2) test. rs1563828CT or TT genotype does not confer a significantly increased risk for breast cancer compared with CC genotype after adjusting for age, menarche in Logistic regression analysis (OR = 1.024, 95%CI: 0.581 - 1.806, P = 0.934). TT carriers were observed to develop breast cancer earlier than CC/CT carriers [(30 +/- 4) years vs. (32 +/- 3) years, P = 0.028]. CONCLUSIONS: The rs1563828(C > T) polymorphism in MDM4 gene may not confer risk to breast cancer, especially for early-onset breast cancer patients. Homozygous TT of rs1563828 is associated with younger age to develop breast cancer. PMID- 22490293 TI - [Clinical significance of CC3/TIP30 expression in breast carcinoma and its correlation with HER-2/neu]. AB - OBJECTIVE: To explore the clinical significance of CC3/TIP30 protein's expression in breast carcinoma and its correlation with HER-2/neu. METHODS: The expression of CC3/TIP30 and HER-2/neu protein was detected in 112 breast cancer tissues which was collected from January 2004 to January 2005 by immunohistochemistry and the relationship with clinic pathological parameters and prognosis was analyzed. Small interfering RNA (siRNA) which target to knock out CC3/TIP30 were transfected into SK-BR-3 cells. Real-time PCR were used to detect the level of CC3/TIP30 and HER-2/neu mRNA. RESULTS: The results of immunohistochemistry showed CC3/TIP30 protein was correlated with TNM stage, lymph node status, HER-2 status and molecule classification (P = 0.048, 0.019, 0.027, 0.011), but there was no association with age, tumor size, estrogen receptor and progesterone receptor. Real-time PCR results revealed that CC3/TIP30 siRNA down-regulation the level of its mRNA, accompanied by a decline in the expression of HER-2/neu gene mRNA, the difference was statistically significant (F = 56.797, P = 0.000; F = 165.101, P = 0.000). In addition, Kaplan-Meier curves of disease-specific survival analysis showed a marked difference in the subtype of HER-2 protein positive between CC3/TIP30 positive group and negative group (chi(2) = 10.732, P = 0.001). CONCLUSIONS: The loss of CC3/TIP30 is related to occurrence and development in breast cancer, suggesting early onset of metastasis and recurrence. Perhaps CC3/TIP30 can be considered as a sub-typing indicator in HER-2 positive breast cancer. PMID- 22490294 TI - [Bio-mechanical evaluation of extreme lateral transforaminal lumbar interbody fusion]. AB - OBJECTIVE: To evaluate the feasibility and post-operation stability of extreme lateral transforaminal lumbar interbody fusion (E-TLIF) and other traditional surgical approach via bio-mechanical test. METHODS: There were 24 normal lumbar spine segment of swine were divided into the following four groups: control group, standard group (internal fixed with pedicle screws only), transforaminal lumbar interbody fusion (TLIF) group and E-TLIF group. The specimen in anteflect, hypsokinesis, lateral flexion and rotate movements were tested respectively with bio-mechanical devices to study on the load-straining changes and biomechanics index. RESULTS: After TLIF or E-TLIF, specimen turned out more steady than normal control group (t = 4.17 - 4.53, P < 0.01). Compared with TLIF group [linear displacement (3.98 +/- 0.22) mm, angular displacement 3.03 degrees +/- 0.18 degrees ], specimen after E-TLIF [linear displacement (3.40 +/- 0.09) mm, angular displacement 2.57 degrees +/- 0.12 degrees ] were more stable in biomechanics index on lateral flection movement (t = 2.61, P < 0.05), but no difference on axial or rotational movements (P > 0.05). CONCLUSION: E-TLIF is a safe and more efficient operation approach. PMID- 22490295 TI - [Association between tartrate-resistant acid phosphatase 5 gene polymorphism and adolescent idiopathic scoliosis]. AB - OBJECTIVE: To investigate whether the titrate-resistant acid phosphatase 5 (ACP5) gene polymorphisms were associated with the occurrence or curve severity of adolescent idiopathic scoliosis (AIS). METHODS: There were 372 AIS patients from January 2006 to December 2008 and 239 normal controls from March 2005 to August 2006 were recruited. The Cobb angles were >= 10 degrees in all AIS patients. Using the haplotype data of Han population from the Hapmap Project, two tag SNPs (rs2229531, rs2071484) were defined for ACP5 gene. PCR-restriction fragment length polymorphism was used for the genotyping. RESULTS: No polymorphism in rs2229531 was found in this study. The genotype and allele frequency distribution in rs2071484 were similar between AIS patients and normal controls (chi(2) = 3.336 and 1.438, P > 0.05). The mean maximum Cobb angles of different genotypes of rs2071484 in ACP5 gene were 38 degrees +/- 19 degrees in AA, 34 degrees +/- 14 degrees in AG and 38 degrees +/- 21 degrees in GG, which were similar with each other among AIS patients who reached skeletal maturity or received surgery treatment (P = 0.157). CONCLUSION: The ACP5 gene is neither associated with the occurrence nor the curve severity of AIS. PMID- 22490296 TI - [Research on the relationship between levels of soluble cluster of differentiation 40 ligand, matrix metalloproteinase 9 and pregnancy-associated plasma protein A in serum and stability of carotid plaques]. AB - OBJECTIVES: To study the relationship between serum levels of some inflammatory markers and stability of carotid plaques in the patients with carotid plaques and evaluate the ability of each serum marker in identifying vulnerable carotid plaques. METHODS: The study included 65 consecutive patients with carotid plaques confirmed by imaging examinations from March 2008 to March 2010. All the patients were classified as stable plaques group (n = 21) and unstable plaques group (n = 44) according to the characteristic findings of the plaques in MRI such as the thickness of fibrous cap, the existence of large lipid core and the intra-plaque hemorrhage. The patients of unstable plaques group were further classified as unruptured plaques group (n = 29) and rupture plaques group (n = 15) according to the integrity of fibrous cap. Serum levels of soluble cluster of differentiation 40 ligand (sCD40L), matrix metalloproteinase 9 (MMP-9) and pregnancy-associated plasma protein A (PAPP-A) were determined by ELISA. RESULTS: Serum levels of sCD40L and MMP-9 in patients of unstable plaques group, unruptured plaques group and rupture plaques group were all significantly enhanced compared to individuals of stable plaques group (SCD40L: chi(2) = 6.45, 12.04 and 16.23, P < 0.01; MMP-9; F = 2.55, 5.10 and 4.69, P < 0.05). Serum levels of PAPP-A in patients of unstable plaques group and rupture plaques group were all significantly enhanced compared to individuals of stable plaques group (chi(2) = 11.71 and 13.55, P < 0.05). Serum levels of PAPP-A in patients of rupture plaques group were significantly enhanced compared to individuals of unruptured plaques group (chi(2) = 13.19, P = 0.000). sCD40L >= 673.22 ng/L (OR = 22.47, 95%CI: 2.11 - 239.81, P = 0.010), MMP-9 >= 84.09 ug/L (OR = 10.01, 95%CI: 1.74 - 57.78, P = 0.010) and PAPP-A >= 0.101 ug/L (OR = 14.29, 95%CI: 2.69 - 75.90, P = 0.002) were all significantly correlated with the vulnerability of carotid plaques. CONCLUSIONS: There appear to be a relationship between the serum levels of sCD40L, MMP-9 and PAPP-A and the stability of carotid plaques in patients with carotid plaques. High serum levels of the above-mentioned markers may indicate that the plaques were vulnerable or ruptured. PMID- 22490297 TI - [Clinical safety about repairing the peripheral nerve defects with chemically extracted acellular nerve allograft]. AB - OBJECTIVE: To discuss the clinical safety about repairing the peripheral nerve defects with the acellular allogeneic nerve. METHODS: The 41 patients (male 38, female 3, age 10 - 55 years old, average 28.9 years old) who were performed chemically extracted acellular nerve allograft transplanting to repair nerve defects from 2002 to 2011. The average interval from injury to nerve repairing was 4.1 months (range, 10 hours to 9 months). There were 41 cases nerve defects including 10 brachial plexus nerves, 3 radial nerves of upper arm, 4 ulnar nerves of forearm, 12 digital and toe nerves, 2 sciatic nerves, 2 femoral nerves, 3 tibial nerves and 5 common peroneal nerves. There were 12 cases combined fractures and 20 soft tissue injury or defects. The average length of the nerve allograft to bridge the nerve defects was 6.1 cm (range, 2 - 10 cm). No immunosuppressive drugs were used in all cases. The clinical safety was evaluated through physical examination, blood biochemistry and immunity detection. RESULTS: All cases were followed up post-operation. They got primary wound healing except 2 superficial infection who got delay healing through dressings changing. No any adverse effects happened including immunological rejection, hypersensitivity reaction, deep infection, hepatotoxicity and nephrotoxicity. CONCLUSIONS: It is safe and feasible to repairing human peripheral nerve defects with chemically extracted acellular nerve allograft. PMID- 22490298 TI - Using client experiences for quality improvement in long-term care organizations. AB - OBJECTIVE: To examine whether client experiences measured with the Consumer Quality Index (CQ-index or CQI) questionnaires are used in Dutch nursing homes and homes for the elderly for quality improvement. DESIGN: Information was gathered through face-to-face interviews with day-to-day workers, quality managers and middle and senior management representatives on the subjects of quality policy and CQI. SETTING: Twelve long-term care organizations in the Netherlands. STUDY PARTICIPANTS: A total of 47 employees were interviewed. RESULTS: Long-term care organizations that systematically incorporate client experiences into their quality system are more active in using the CQI for quality improvement: information was disseminated throughout the organization, project groups pointed out quality improvement initiatives and every worker was involved in this process. These organizations had often held a certificate for their quality policy for some length of time. In other organizations, CQI information was used less systematically. For instance, only the quality manager was involved, or improvement initiatives were left to employees working in the primary process. The actual improvement initiatives varied. For example, employees created more individual time for clients to avoid the feeling of being rushed; other organizations changed the food delivery to enhance food enjoyment. CONCLUSIONS: Although measuring client experiences obligatory, it is not sufficient guarantee that client feedback is used for quality improvement. Although measuring client experiences has led to various improvement initiatives, their effectiveness remains unclear. There is need for guidance on effective improvement of client experiences. PMID- 22490299 TI - Patient safety and medical errors: knowledge, attitudes and behavior among Italian hospital physicians. AB - OBJECTIVE: To investigate physicians' knowledge about evidence-based patient safety practices, their attitudes on preventing and managing medical errors and to explore physicians' behavior when facing medical errors. DESIGN: A nationwide cross-sectional survey. SETTING: We first stratified our population by the 20 Italian regions. Then, within each stratum, we selected by simple random sampling, for each region, one regional general hospital and one district general hospital to yield a sample of 40 hospitals overall. PARTICIPANTS: Twelve hundred physicians involved in direct patient care (30 per hospital) were sent a survey by mail and 696 responded. MAIN OUTCOME MEASURES: Knowledge on patient safety practices, attitudes and practices toward the prevention of medical errors. RESULTS: Physicians' knowledge of evidence-based safety practices was inconsistent. More than 90% of physicians reported that counting surgical items during an invasive surgical procedure represented a patient safety practice. Positive attitudes about patient safety were revealed by responses, but 44.5 and 44.1%, respectively, agreed or were uncertain about the disclosure of errors to the patients. The pattern of behavior showed that 7.6% of physicians reported to have never been involved in medical errors, and among system failures, 'overwork, stress or fatigue of health professionals' was the most highly rated item. CONCLUSIONS: The results from our study highlight that greater efforts are needed to facilitate the translation of positive attitudes towards patient safety into appropriate practices that have proven to be effective in the reduction of medical errors. PMID- 22490300 TI - Measuring chronic care delivery: patient experiences and clinical performance. AB - OBJECTIVE: To assess the relationship between clinical care metrics and patient experiences of care among patients with chronic disease. DESIGN: Cross-sectional survey and clinical performance data. SETTING: Eighty-nine medical groups across California caring for patients with chronic disease. PARTICIPANTS: Using patient surveys, we identified 51 129 patients with a chronic disease. MAIN OUTCOME MEASURES: Using patient surveys, we produced five composite measures of patient experiences of care and self-management support (scale 0-100). Using Health Plan Employer Data and Information Set data, we analyzed care for asthma, diabetes and cardiovascular disease, producing one composite summarizing clinical processes of care and one composite summarizing outcomes of care. We calculated adjusted Spearman's correlation coefficients to assess the relationship between patient experiences of care, clinical processes and clinical outcomes. RESULTS: Clinical performance was higher for process measures compared with outcomes measures, ranging from 91% for appropriate asthma medication use to 59% for controlling low density lipoprotein cholesterol in the presence of diabetes. Performance on patient experiences of care measures was the highest for the quality of clinical interactions (88.5) and the lowest for delivery of self-management support (68.8). Three of the 10 patient experience-clinical performance composite correlations were statistically significant. These three correlations involved composites summarizing integration of care and quality of clinical interactions, and ranged from a low of 0.30 to a high of 0.39. CONCLUSIONS: Chronic care delivery is variable across diseases and domains of care. Improving care integration processes and communication between health-care providers and their patients may lead to improved clinical outcomes. PMID- 22490301 TI - New paradigms for measuring clinical performance using electronic health records. AB - Measures of provider success are the centerpiece of quality improvement and pay for-performance programs around the globe. In most nations, these measures are derived from administrative records, paper charts and consumer surveys; increasingly, electronic patient record systems are also being used. We use the term 'e-QMs' to describe quality measures that are based on data found within electronic health records and other related health information technology (HIT). We offer a framework or typology for e-QMs and describe opportunities and impediments associated with the transition from old to new DATA SOURCES: If public and private systems of care are to effectively use HIT to support and evaluate health-care system quality and safety, the quality measurement field must embrace new paradigms and strategically address a series of technical, conceptual and practical challenges. PMID- 22490302 TI - Toward integrative cancer immunotherapy: targeting the tumor microenvironment. AB - The development of cancer has historically been attributed to genomic alterations of normal host cells. Accordingly, the aim of most traditional cancer therapies has been to destroy the transformed cells themselves. There is now widespread appreciation that the progressive growth and metastatic spread of cancer cells requires the cooperation of normal host cells (endothelial cells, fibroblasts, other mesenchymal cells, and immune cells), both local to, and at sites distant from, the site at which malignant transformation occurs. It is the balance of these cellular interactions that both determines the natural history of the cancer, and influences its response to therapy. This active tumor-host dynamic has stimulated interest in the tumor microenvironment as a key target for both cancer diagnosis and therapy. Recent data has demonstrated both that the presence of CD8+ T cells within a tumor is associated with a good prognosis, and that the eradication of all malignantly transformed cells within a tumor requires that the intra-tumoral concentration of cytolytically active CD8+ effector T cells remain above a critical concentration until every tumor cell has been killed. These findings have stimulated two initiatives in the field of cancer immunotherapy that focus on the tumor microenvironment. The first is the development of the immune score as part of the routine diagnostic and prognostic evaluation of human cancers, and the second is the development of combinatorial immune-based therapies that reduce tumor-associated immune suppression to unleash pre-existing or therapeutically-induced tumor immunity. In support of these efforts, the Society for the Immunotherapy of Cancer (SITC) is sponsoring a workshop entitled "Focus on the Target: The Tumor Microenvironment" to be held October 24-25, 2012 in Bethesda, Maryland. This meeting should support development of the immune score, and result in a position paper highlighting opportunities for the development of integrative cancer immunotherapies that sculpt the tumor microenvironment to promote definitive tumor rejection. PMID- 22490303 TI - Interferon-alpha as antiviral and antitumor vaccine adjuvants: mechanisms of action and response signature. AB - Interferon-alpha (IFN-alpha) are cytokines endowed with multiple biologic effects, including activities on cells of the immune system, which are important for inducing protective antiviral and antitumor responses. Studies in mouse models have been instrumental for understanding the immune adjuvant activity of these cytokines and some of their mechanisms of action. In particular, recent studies conducted on both mouse and human models suggest that IFN-alpha act as effective immune adjuvants for inducing antiviral and antitumor immunity and that the effects of IFN on the differentiation and activation of dendritic cells (DC) play an important role in the induction of protective responses. In spite of the long record of IFN-alpha clinical use, a few clinical trials have attempted to evaluate the efficacy of these cytokines used as vaccine adjuvants. Recently, studies on the IFN-alpha signature in cells from patients treated with IFN-alpha under different modalities and various clinical settings have provided important insights for understanding the in vivo mechanisms of the IFN immune adjuvant activity in humans and may contribute to the identification of molecular markers with a clinical response. These studies further support the interest of evaluating the clinical efficacy of IFN-alpha when used as a vaccine adjuvant and also suggest that the DC generated in vitro from monocytes in the presence of this cytokine can exhibit a special advantage for the development of effective therapeutic vaccination strategies in cancer patients. PMID- 22490304 TI - Scientific expertise and the Athlete Biological Passport: 3 years of experience. AB - Expert evaluation of biological data is a key component of the Athlete Biological Passport approach in the fight against doping. The evaluation consists of a longitudinal assessment of biological variables to determine the probability of the data being physiological on the basis of the athlete's on own previous values (performed by an automated software system using a Bayesian model) and a subjective evaluation of the results in view of possible causes (performed by experts). The role of the expert is therefore a key component in the process. Experts should be qualified to evaluate the data regarding possible explanations related to the influence of doping products and methods, analytical issues, and the influence of exercise or pathological conditions. The evaluation provides a scientific basis for the decision taken by a disciplinary panel. This evaluation should therefore encompass and balance all possible causes for a given blood profile and provide a likelihood for potential scenarios (pathology, normal variation, doping) that might have caused the pattern. It should comply with the standards for the evaluation of scientific evidence in forensics. On the basis of their evaluation of profiles, experts might provide assistance in planning appropriate target testing schemes. PMID- 22490305 TI - 'It's coming at things from a very different standpoint': evaluating the 'Supporting Self-Care in General Practice Programme' in NHS East of England. AB - AIM: To undertake a service evaluation of the NHS East of England Supporting Self Care in General Practice programme. BACKGROUND: The number of people purported to live with long-term conditions continues to rise generating increasing policy emphasis on the importance of self-care. Previous work has highlighted barriers to implementing self-care interventions in general practice, including a lack of organisational approaches to providing self-care and limited engagement and training of healthcare professionals. In response to these barriers and policy drivers, NHS East of England Strategic Health Authority developed and commenced the Supporting Self-care in General Practice (SSCiGP) programme, which seeks to transform the relationships between people with long-term conditions and primary care practitioners. METHODS: This was a mixed methods study, carried out over two phases, which included interviews, survey work and practice-based case studies. RESULTS: This paper focuses on findings related to clinician and practice level change. Clinicians reported changes in their perceptions and in consultation practices following attendance on the SSCiGP programme. These changes were linked to empathy and patient-centredness that mirrored what patients valued in interactions with clinicians. There were qualitative and descriptive differences, but no statistically significant differences between clinicians who had and had not attended the SSCiGP programme. Time was recognised as a significant barrier to implementing, and sustaining skills learnt from the SSCiGP programme. Greater impact at practice level could be achieved when there was whole practice commitment to values that underpinned the SSCiGP programme. There was evidence that such approaches are being incorporated to change practice systems and structures to better facilitate self-care, particularly in practices who were early programme adopters. CONCLUSION: This evaluation demonstrates that training around clinician change can be effective in shifting service delivery when sat within a cultural framework that genuinely situates patients at the centre of consultations and practice activity. PMID- 22490306 TI - Can the economic crisis have an impact on tuberculosis in the EU/EEA? PMID- 22490307 TI - Epidemiology of tuberculosis in the EU/EEA in 2010: monitoring the progress towards tuberculosis elimination. AB - The 2012 combined tuberculosis (TB) surveillance and monitoring report for the European Union and European Economic Area identifies a mean annual decline in TB notification rate by 4.4% from 2006 to 2010. Culture confirmation for new pulmonary cases and drug susceptibility testing have increased to 65.6% and 70.8%, but remain under their targets of 80% and 100%, respectively. Reporting of treatment outcome and coinfection with human immunodeficiency virus also remain suboptimal. Strengthened control practices are needed to allow progress towards TB elimination. PMID- 22490308 TI - Early estimates of the effectiveness of the 2011/12 influenza vaccine in the population targeted for vaccination in Spain, 25 December 2011 to 19 February 2012. AB - We present early estimates of influenza vaccine effectiveness (VE) in the population targeted for vaccination, during 25 December 2011 to 19 February 2012. The adjusted VE was 55% (95% CI: 3 to 79) against any type of influenza virus and 54% (95% CI: 1 to 79) against influenza A(H3N2) virus. This suggests a moderate protective effect of the vaccine in the targeted population in a late influenza epidemic with limited match between vaccine and circulating strains. PMID- 22490309 TI - Fatal case of imported human rabies in Amadora, Portugal, August 2011. AB - We report on a case of imported human rabies in Portugal, in July 2011 in a woman who presented initially complaining of back pain, without relating exposure to animal bites. She had travelled from Portugal to Bissau, Guinea-Bissau, in April where she had been bitten by a dog on 1 May. She was diagnosed with rabies on 26 July and died two weeks later in spite of being treated following the Milwaukee protocol. PMID- 22490310 TI - Tick-borne encephalitis transmitted by unpasteurised cow milk in western Hungary, September to October 2011. AB - In October 2011, a cluster of four tick-borne encephalitis (TBE) cases was identified in Hungary. Initial investigations revealed a possible link with consumption of unpasteurised cow milk sold by a farmer without authorisation. We performed a cohort study including all regular customers of the farmer. Overall, eleven cases (seven confirmed and four suspected) were identified. Customers who had consumed the farmer's unpasteurised cow milk had more than a two-fold increased risk for being a TBE case, although not at statistically significant level. PMID- 22490311 TI - Letter to the editor: Rabid puppy-dog imported into the Netherlands from Morocco via Spain, February 2012. PMID- 22490315 TI - Evaluation of the effect of intravenous lidocaine on propofol requirements during total intravenous anaesthesia as measured by bispectral index. AB - BACKGROUND: I.V. lidocaine is increasingly used as an adjuvant during general anaesthesia. The aim of this study was to evaluate the effect of i.v. lidocaine in reducing propofol anaesthetic requirements during total i.v. anaesthesia (TIVA) maintenance and to evaluate its effect on early recovery from anaesthesia. METHODS: Forty adult patients undergoing elective laparoscopic cholecystectomy under TIVA were randomly allocated into the lidocaine group (administered 1.5 mg kg(-1) i.v. lidocaine over 5 min followed by 2 mg kg(-1) h(-1)) and the control group (administered an equal volume of saline). Propofol was administered using a target-controlled infusion to maintain the bispectral index values between 40 and 60. After surgery, all infusions were discontinued and the time to extubation was recorded. Serial arterial blood samples were drawn to assess drug plasma levels. RESULTS: The maintenance dose of propofol was significantly lower in the lidocaine group [6.00 (0.97) mg kg(-1) h(-1)] vs the control group [7.25 (1.13) mg kg(-1) h(-1); P=0.01]. Propofol plasma levels measured at the end of the infusion were 3.71 (0.89) MUg ml(-1) in the lidocaine group and 3.67 (1.28) MUg ml(-1) in the control group (P=0.91). The median time to extubation was longer (11.0 min; range: 10.0-21.0) in the lidocaine group vs the control group (8.3 min; range: 5.5-12.5; P=0.02). CONCLUSIONS: I.V. lidocaine reduces propofol requirements during the maintenance phase of TIVA, particularly during surgical stimulation. This sparing effect is associated with an increased time to extubation. Owing to its effect on early recovery from anaesthesia, i.v. lidocaine should be taken into account when used as a component of i.v. anaesthesia. PMID- 22490316 TI - Association between fibrinogen level and severity of postpartum haemorrhage: secondary analysis of a prospective trial. AB - BACKGROUND: The aim of the study was to determine whether the fibrinogen level at diagnosis of postpartum haemorrhage (PPH) is associated with the severity of bleeding. METHODS: This is a secondary analysis of a population-based study in 106 French maternity units identifying cases of PPH prospectively. PPH was defined by a blood loss exceeding 500 ml during the 24 h after delivery or a peripartum haemoglobin decrease of more than 20 g litre(-1). This analysis includes 738 women with PPH after vaginal delivery. Fibrinogen levels were compared in patients whose PPH worsened and became severe and those whose PPH remained non-severe. Severe PPH was defined as haemorrhage by occurrence of one of the following events: peripartum haemoglobin decrease >= 40 g litre(-1), transfusion of concentrated red cells, arterial embolization or emergency surgery, admission to intensive care, or death. RESULTS: The mean fibrinogen concentration at diagnosis was 4.2 g litre(-1) [standard deviation (sd)=1.2 g litre(-1)] among the patients without worsening and 3.4 g litre(-1) (sd=0.9 g litre(-1)) (P<0.001) in the group whose PPH became severe. The fibrinogen level was associated with PPH severity independently of other factors [adjusted odds ratio=1.90 (1.16-3.09) for fibrinogen between 2 and 3 g litre(-1) and 11.99 (2.56 56.06) for fibrinogen <2 g litre(-1)]. CONCLUSIONS: The fibrinogen level at PPH diagnosis is a marker of the risk of aggravation and should serve as an alert to clinicians. PMID- 22490317 TI - Exposure to nicotine and carcinogens among Southwestern Alaskan Native cigarette smokers and smokeless tobacco users. AB - BACKGROUND: The prevalence of tobacco use, both cigarette smoking and smokeless, including iqmik (homemade smokeless tobacco prepared with dried tobacco leaves mixed with alkaline ash), and of tobacco-related cancer is high in Alaskan Native people (AN). To investigate possible mechanisms of increased cancer risk we studied levels of nicotine and tobacco-specific nitrosamines (TSNA) in tobacco products and biomarkers of tobacco toxicant exposure in Southwestern AN people. METHODS: Participants included 163 cigarette smokers, 76 commercial smokeless tobacco, 20 iqmik, 31 dual cigarette smokers and smokeless tobacco, and 110 nontobacco users. Tobacco use history, samples of tobacco products used, and blood and urine samples were collected. RESULTS: Nicotine concentrations were highest in cigarette tobacco and TSNAs highest in commercial smokeless tobacco products. The AN participants smoked on average 7.8 cigarettes per day. Nicotine exposure, assessed by several biomarker measures, was highest in iqmik users, and similar in smokeless tobacco and cigarette smokers. TSNA exposure was highest in smokeless tobacco users, and polycyclic aromatic hydrocarbon exposure was highest in cigarette smokers. CONCLUSIONS: Despite smoking fewer cigarettes per day, AN cigarette smokers had similar daily intake of nicotine compared to the general U.S. population. Nicotine exposure was greatest from iqmik, likely related to its high pH due to preparation with ash, suggesting high addiction potential compared to other smokeless tobacco products. TSNA exposure was much higher with smokeless tobacco than other product use, possibly contributing to the high rates of oral cancer. IMPACT: Our data contribute to an understanding of the high addiction risk of iqmik use and of the cancer-causing potential of various forms of tobacco use among AN people. PMID- 22490319 TI - Selection bias in population-based cancer case-control studies due to incomplete sampling frame coverage. AB - BACKGROUND: Increasing numbers of individuals are choosing to opt out of population-based sampling frames due to privacy concerns. This is especially a problem in the selection of controls for case-control studies, as the cases often arise from relatively complete population-based registries, whereas control selection requires a sampling frame. If opt out is also related to risk factors, bias can arise. METHODS: We linked breast cancer cases who reported having a valid driver's license from the 2004-2008 Wisconsin women's health study (N = 2,988) with a master list of licensed drivers from the Wisconsin Department of Transportation (WDOT). This master list excludes Wisconsin drivers that requested their information not be sold by the state. Multivariate-adjusted selection probability ratios (SPR) were calculated to estimate potential bias when using this driver's license sampling frame to select controls. RESULTS: A total of 962 cases (32%) had opted out of the WDOT sampling frame. Cases age <40 (SPR = 0.90), income either unreported (SPR = 0.89) or greater than $50,000 (SPR = 0.94), lower parity (SPR = 0.96 per one-child decrease), and hormone use (SPR = 0.93) were significantly less likely to be covered by the WDOT sampling frame (alpha = 0.05 level). CONCLUSIONS: Our results indicate the potential for selection bias due to differential opt out between various demographic and behavioral subgroups of controls. As selection bias may differ by exposure and study base, the assessment of potential bias needs to be ongoing. IMPACT: SPRs can be used to predict the direction of bias when cases and controls stem from different sampling frames in population-based case-control studies. PMID- 22490318 TI - Increased levels of tetra-antennary N-linked glycan but not core fucosylation are associated with hepatocellular carcinoma tissue. AB - BACKGROUND: Alterations in glycosylation have long been associated with the development of cancer. In the case of primary hepatocellular carcinoma (HCC), one alteration that has often been associated is increased amounts of fucose attached to the N-glycans of serum proteins secreted by the liver. METHODS: In an effort to determine the origin of this increased fucosylation, we have conducted N linked glycan analysis of HCC tissue, the surrounding nontumor tissue, and compared this to tissue from a nondiseased adult liver. RESULTS: Surprisingly, no difference in the level of fucosylation was observed from the three donor groups, suggesting that the increased levels of fucosylation observed in serum of those with HCC is not the result of increased synthesis of fucosylated proteins in the cancer tissue. On the other hand, increased levels of a tetra-antennary glycan were observed in the HCC tissue as compared with the surrounding tissue or to the nondiseased livers. CONCLUSIONS: This represents, to our knowledge, one of the first reports associating increased levels of branching with the development of HCC. IMPACT: The identification of increased levels of tetra-antennary glycan on liver tumor tissue, as opposed to adjacent or nondiseased tissue may lead to improved detection of HCC. PMID- 22490320 TI - Patterns of colorectal cancer test use, including CT colonography, in the 2010 National Health Interview Survey. AB - BACKGROUND: Recommended colorectal cancer (CRC) screening tests for adults ages 50 to 75 years include home fecal occult blood tests (FOBT), sigmoidoscopy with FOBT, and colonoscopy. A newer test, computed tomographic (CT) colonography, has been recommended by some, but not all, national organizations. METHODS: We analyzed 2010 National Health Interview Survey data, including new CT colonography questions, from respondents ages 50 to 75 years (N = 8,952). We (i) assessed prevalence of CRC test use overall, by test type, and by sociodemographic and health care access factors and (ii) assessed reported reasons for not having a CRC test. RESULTS: The age-standardized percentage of respondents reporting FOBT, sigmoidoscopy, or colonoscopy within recommended time intervals was 58.3% [95% confidence interval (CI), 57.0-59.6]. Colonoscopy was the most commonly reported test [within past 10 years: 54.6% (95% CI, 53.2 55.9)]. Home FOBT and sigmoidoscopy with FOBT were less frequently used [FOBT within past year: 8.8% (95% CI, 8.1-9.6); sigmoidoscopy within past 5 years with FOBT within past 3 years: 1.3% (95% CI, 1.0-1.6)]. CT colonography was rare: 1.3% (95% CI, 1.0-1.7). Increasing age, education, income, having health care insurance, and having a usual source of health care were associated with higher CRC test use. Test use within recommended time intervals was particularly low among individuals ages 50 to 64 years without health care insurance [21.2% (95% CI, 18.3-24.4)]. The most common reason for nonuse was "no reason or never thought about it." CONCLUSIONS: About 40% of Americans ages 50 to 75 years do not meet the recommendations for having CRC screening tests. IMPACT: Expanded health care coverage and greater awareness of CRC screening are needed to further decrease CRC mortality. PMID- 22490321 TI - Oral bisphosphonates and risk of esophageal cancer: a dose-intensity analysis in a nationwide population. AB - BACKGROUND: Esophageal cancer has been associated with oral bisphosphonate use, but current data are conflicting and devoid of Asian studies where esophageal squamous carcinoma prevails. METHODS: We assessed the association between dose intensity, stratified by use duration (observation period) and exposure frequency, of oral bisphosphonates and the risk of esophageal cancer using 16,204 esophageal cancer cases and 64,816 malignancy-free controls identified from the population-based National Health Insurance Research Database of Taiwan from 1997 to 2008. RESULTS: Neither duration nor frequency of bisphosphonate exposures was positively correlated to esophageal cancer risk. The ORs for rare users of 1-, 3 , 5-year observation periods were 3.86, 2.58, and 2.27, respectively (P < 0.001). Similar trend of descending ORs was also observed for rare-, frequent-, and regular users of 1-year observation period (ORs = 3.86, 1.93, and 0.95, respectively). CONCLUSION: Our data suggest that bisphosphonates are not likely risk factors for esophageal cancer in Taiwan. IMPACT: The study shows no evidence of an association between bisphosphonate use and esophageal cancer risk from Asian perspective. PMID- 22490323 TI - Pervasive ocular tremor in patients with Parkinson disease. AB - OBJECTIVE: To further assess oculomotor control of patients with Parkinson disease (PD) during fixation and with movement. DESIGN: Case-control study. SETTING: A Parkinson disease research, education, and clinical center. PATIENTS One hundred twelve patients with PD, including 18 de novo untreated patients, and 60 age-matched controls. INTERVENTION: Modern, precise eye tracking technology was used to assess oculomotor parameters. Oculomotor function was compared between groups during fixation and while tracking a randomly displaced target on a PC monitor. MAIN OUTCOME MEASURES: Fixation stability and saccadic parameters. RESULTS: All patients with PD and 2 of 60 control subjects showed oscillatory fixation instability (ocular tremor), with an average fundamental frequency of 5.7 Hz and average magnitude of 0.27 degrees . Saccadic parameters and occurrences of square wave jerks did not differ between subjects with PD and controls. The amplitude and frequency of fixation instability did not correlate with disease duration, clinical Unified Parkinson's Disease Rating Scale scores, or dopa-equivalent dosing. No differences in oculomotor parameters were found between medicated and unmedicated patients with PD. CONCLUSIONS: All patients with PD exhibited persistent ocular tremor that prevented stability during fixation. The pervasiveness and specificity of this feature suggest that modern, precise oculomotor testing could provide a valuable early physiological biomarker for diagnosing PD. PMID- 22490322 TI - Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. AB - Coenzyme Q(10) (CoQ(10)) deficiency has been associated with 5 major clinical phenotypes: encephalomyopathy, severe infantile multisystemic disease, nephropathy, cerebellar ataxia, and isolated myopathy. Primary CoQ(10) deficiency is due to defects in CoQ(10) biosynthesis, while secondary forms are due to other causes. A review of 149 cases, including our cohort of 76 patients, confirms that CoQ(10) deficiency is a clinically and genetically heterogeneous syndrome that mainly begins in childhood and predominantly manifests as cerebellar ataxia. Coenzyme Q(10) measurement in muscle is the gold standard for diagnosis. Identification of CoQ(10) deficiency is important because the condition frequently responds to treatment. Causative mutations have been identified in a small proportion of patients. PMID- 22490324 TI - Painful legs and moving toes syndrome: a 76-patient case series. AB - OBJECTIVE: To better characterize the clinical features, electrophysiologic features, and treatment outcomes of painful legs and moving toes (PLMT) syndrome. DESIGN: Large case series. SETTING: Neurology outpatient clinic at a tertiary referral center, 1983-2011. PATIENTS: All cases of PLMT seen at our institution during an 18-year period were identified using our medical record linkage system. MAIN OUTCOME MEASURES: Key demographic, clinical, imaging, and electrophysiologic features of PLMT. Treatment outcomes and long-term follow-up are also reported. RESULTS: Of 76 cases identified (including 50 women [66%]), the mean age at onset was 58 years (range, 24-86 years) and at neurologic evaluation was 63 years (range, 26-88 years). Pure lower limb involvement was most common (69 patients [91%]), and 44 cases (58%) were bilateral. The most frequently diagnosed causes were peripheral neuropathy (21 cases [28%]), previous trauma (8 [11%]), and radiculopathy (7 [9%]); 32 cases (42%) were cryptogenic. Electromyography consistently showed irregular 50-millisecond to 1-second bursts of normal motor unit potential firing at 2 to 200 Hz accompanying the movements. Pain occurred first in nearly all cases and was more distressing to patients than the movements. Both components were difficult to treat, with no consistent benefit from a variety of drugs and therapeutic modalities. The syndrome persisted in most patients (83%) during the mean follow-up of 4.6 years, suggesting low likelihood of spontaneous resolution. CONCLUSIONS: Painful legs and moving toes syndrome is a debilitating clinical syndrome, not because of the movements but rather because of the pain, which often is refractory to treatment. Segmental lower limb involvement is most common, and neurophysiologic findings support a pathophysiologic process localizing to a central generator at the spinal cord or brainstem level. PMID- 22490325 TI - Minocycline-induced fulminant intracranial hypertension. AB - OBJECTIVE: To describe the clinical course of an unusually severe case of minocycline-induced intracranial hypertension. DESIGN: Case study. SETTING: Academic medical center. PATIENT: Twelve-year-old girl with a fulminant course of intracranial hypertension. INTERVENTIONS: Magnetic resonance imaging and venography of the brain, lumbar puncture, and optic nerve sheath fenestration. RESULTS: Although the patient ceased minocycline treatment, there was ongoing and rapid worsening of symptoms and vision loss. Lumbar puncture, which normally acts as a temporizing measure to preserve vision, failed to prevent, and may even have precipitated, further deterioration in vision, necessitating surgical intervention with optic nerve sheath fenestration. CONCLUSION: Minocycline can cause a fulminant syndrome of elevated intracranial pressure, with severe vision loss, even after the medication has been discontinued. PMID- 22490327 TI - Charybdotoxin and margatoxin acting on the human voltage-gated potassium channel hKv1.3 and its H399N mutant: an experimental and computational comparison. AB - The effect of the pore-blocking peptides charybdotoxin and margatoxin, both scorpion toxins, on currents through human voltage-gated hK(v)1.3 wild-type and hK(v)1.3_H399N mutant potassium channels was characterized by the whole-cell patch clamp technique. In the mutant channels, both toxins hardly blocked current through the channels, although they did prevent C-type inactivation by slowing down the current decay during depolarization. Molecular dynamics simulations suggested that the fast current decay in the mutant channel was a consequence of amino acid reorientations behind the selectivity filter and indicated that the rigidity-flexibility in that region played a key role in its interactions with scorpion toxins. A channel with a slightly more flexible selectivity filter region exhibits distinct interactions with scorpion toxins. Our studies suggest that the toxin-channel interactions might partially restore rigidity in the selectivity filter and thereby prevent the structural rearrangements associated with C-type inactivation. PMID- 22490326 TI - Comparison of cerebrospinal fluid levels of tau and Abeta 1-42 in Alzheimer disease and frontotemporal degeneration using 2 analytical platforms. AB - OBJECTIVE: To use values of cerebrospinal fluid tau and beta-amyloid obtained from 2 different analytical immunoassays to differentiate Alzheimer disease (AD) from frontotemporal lobar degeneration (FTLD). DESIGN: Cerebrospinal fluid values of total tau (T-tau) and beta-amyloid 1-42 (Abeta 1-42) obtained using the Innotest enzyme-linked immunosorbent assay were transformed using a linear regression model to equivalent values obtained using the INNO-BIA AlzBio3 (xMAP; Luminex) assay. Cutoff values obtained from the xMAP assay were developed in a series of autopsy-confirmed cases and cross validated in another series of autopsy-confirmed samples using transformed enzyme-linked immunosorbent assay values to assess sensitivity and specificity for differentiating AD from FTLD. SETTING: Tertiary memory disorder clinics and neuropathologic and biomarker core centers. PARTICIPANTS: Seventy-five samples from patients with cerebrospinal fluid data obtained from both assays were used for transformation of enzyme linked immunosorbent assay values. Forty autopsy-confirmed cases (30 with AD and 10 with FTLD) were used to establish diagnostic cutoff values and then cross validated in a second sample set of 21 autopsy-confirmed cases (11 with AD and 10 with FTLD) with transformed enzyme-linked immunosorbent assay values. MAIN OUTCOME MEASURE: Diagnostic accuracy using transformed biomarker values. RESULTS: Data obtained from both assays were highly correlated. The T-tau to Abeta 1-42 ratio had the highest correlation between measures (r = 0.928, P < .001) and high reliability of transformation (intraclass correlation coefficient= 0.89). A cutoff of 0.34 for the T-tau to Abeta 1-42 ratio had 90% and 100% sensitivity and 96.7% and 91% specificity to differentiate FTLD cases in the validation and cross validation samples, respectively. CONCLUSIONS: Values from 2 analytical platforms can be transformed into equivalent units, which can distinguish AD from FTLD more accurately than the clinical diagnosis. PMID- 22490328 TI - A gallotannin-rich fraction from Caesalpinia spinosa (Molina) Kuntze displays cytotoxic activity and raises sensitivity to doxorubicin in a leukemia cell line. AB - BACKGROUND: Enhancement of tumor cell sensitivity may help facilitate a reduction in drug dosage using conventional chemotherapies. Consequently, it is worthwhile to search for adjuvants with the potential of increasing chemotherapeutic drug effectiveness and improving patient quality of life. Natural products are a very good source of such adjuvants. METHODS: The biological activity of a fraction enriched in hydrolysable polyphenols (P2Et) obtained from Caesalpinia spinosa was evaluated using the hematopoietic cell line K562. This fraction was tested alone or in combination with the conventional chemotherapeutic drugs doxorubicin, vincristine, etoposide, camptothecin and taxol. The parameters evaluated were mitochondrial depolarization, caspase 3 activation, chromatin condensation and clonogenic activity. RESULTS: We found that the P2Et fraction induced mitochondrial depolarization, activated caspase 3, induced chromatin condensation and decreased the clonogenic capacity of the K562 cell line. When the P2Et fraction was used in combination with chemotherapeutic drugs at sub-lethal concentrations, a fourfold reduction in doxorubicin inhibitory concentration 50 (IC50) was seen in the K562 cell line. This finding suggested that P2Et fraction activity is specific for the molecular target of doxorubicin. CONCLUSIONS: Our results suggest that a natural fraction extracted from Caesalpinia spinosa in combination with conventional chemotherapy in combination with natural products on leukemia cells may increase therapeutic effectiveness in relation to leukemia. PMID- 22490329 TI - Brazilian solar saltworks - ancient uses and future possibilities. AB - Coastal solar saltworks of Brazil are exploited for sea salt, which becomes progressively concentrated by evaporation. This study aimed to review the current and new potential uses of these systems, in order to provide more dynamic for this activity. The first evaporation ponds are also used for artisanal fisheries, ensuring the livelihood of many families. All the brine rich in secondary salts (bittern) can be widely used by the chemical industry, while the Brazil shows an incipient production of "flower of salt", a salt with distinct characteristics with higher market value than sodium chloride. On the other hand, the saltponds have a high potential for management and obtaining of large populations of Artemia spp., purifying the brine through the action as biological filter. This microcrustacean occurs naturally in intermediate salinity ponds, being commonly used in aquaculture. Species of microalgae and halobacteria found in the saltworks are employed for extraction of beta-carotene and glycerol, used in an extensive list of products with high commercial value. These ecosystems represent refuge zones for many species of migratory birds, becoming imperative to promote the conservation of these hypersaline wetlands. PMID- 22490330 TI - Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia. AB - The prevalence, the prognostic effect, and interaction with other molecular markers of DNMT3A mutations was studied in 415 patients with acute myeloid leukemia (AML) younger than 60 years. We show mutations in DNMT3A in 96 of 415 patients with newly diagnosed AML (23.1%). Univariate Cox regression analysis showed that patients with DNMT3A(mutant) AML show significantly worse overall survival (OS; P = .022; hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.04-1.81), and relapse-free survival (RFS; P = .005; HR, 1.52; 95% CI, 1.13 2.05) than DNMT3A(wild-type) AMLs. In a multivariable analysis, DNMT3A mutations express independent unfavorable prognostic value for OS (P = .003; HR, 1.82; 95% CI, 1.2-2.7) and RFS (P < .001; HR, 2.2; 95% CI, 1.4-3.3). In a composite genotypic subset of cytogenetic intermediate-risk AML without FLT3-ITD and NPM1 mutations, this association is particularly evident (OS: P = .013; HR, 2.09; 95% CI, 1.16-3.77; RFS: P = .001; HR, 2.65; 95% CI, 1.48-4.89). The effect of DNMT3A mutations in human AML remains elusive, because DNMT3A(mutant) AMLs did not express a methylation or gene expression signature that discriminates them from patients with DNMT3A(wild-type) AML. We conclude that DNMT3A mutation status is an important factor to consider for risk stratification of patients with AML. PMID- 22490331 TI - Early autologous stem cell transplantation for chronic lymphocytic leukemia: long term follow-up of the German CLL Study Group CLL3 trial. AB - The CLL3 trial was designed to study intensive treatment including autologous stem cell transplantation (autoSCT) as part of first-line therapy in patients with chronic lymphocytic leukemia (CLL). Here, we present the long-term outcome of the trial with particular focus on the impact of genomic risk factors, and we provide a retrospective comparison with patients from the fludarabine cyclophosphamide-rituximab (FCR) arm of the German CLL Study Group (GCLLSG) CLL8 trial. After a median observation time of 8.7 years (0.3-12.3 years), median progression-free survival (PFS), time to retreatment, and overall survival (OS) of 169 evaluable patients, including 38 patients who did not proceed to autoSCT, was 5.7, 7.3, and 11.3 years, respectively. PFS and OS were significantly reduced in the presence of 17p- and of an unfavorable immunoglobulin heavy variable chain mutational status, but not of 11q-. Five-year nonrelapse mortality was 6.5%. When 110 CLL3 patients were compared with 126 matched patients from the FCR arm of the CLL8 trial, 4-year time to retreatment (75% vs 77%) and OS (86% vs 90%) was similar despite a significant benefit for autoSCT in terms of PFS. In summary, early treatment intensification including autoSCT can provide very effective disease control in poor-risk CLL, although its clinical benefit in the FCR era remains uncertain. The trial has been registered with www.clinicaltrials.gov as NCT00275015. PMID- 22490332 TI - Comprehensive analysis of unique cases with extraordinary control over HIV replication. AB - True long-term nonprogressors (LTNPs)/elite controllers (ECs) maintain durable control over HIV replication without antiretroviral therapy. Herein we describe 4 unique persons who were distinct from conventional LTNPs/ECs in that they had extraordinarily low HIV burdens and comparatively weak immune responses. As a group, typical LTNPs/ECs have unequivocally reactive HIV-1 Western blots, viral loads below the lower threshold of clinical assays, low levels of persistent viral reservoirs, an over-representation of protective HLA alleles, and robust HIV-specific CD8(+) T-cell responses. The 4 unique cases were distinguished from typical LTNPs/ECs based on weakly reactive Western blots, undetectable plasma viremia by a single copy assay, extremely low to undetectable HIV DNA levels, and difficult to isolate replication-competent virus. All 4 had at least one protective HLA allele and CD8(+) T-cell responses that were disproportionately high for the low antigen levels but comparatively lower than those of typical LTNPs/ECs. These unique persons exhibit extraordinary suppression over HIV replication, therefore, higher-level control than has been demonstrated in previous studies of LTNPs/ECs. Additional insight into the full spectrum of immune-mediated suppression over HIV replication may enhance our understanding of the associated mechanisms, which should inform the design of efficacious HIV vaccines and immunotherapies. PMID- 22490333 TI - Identification, immunomodulatory activity, and immunogenicity of the major helper T-cell epitope on the K blood group antigen. AB - The K blood group remains an important target in hemolytic disease of the newborn (HDN), with no immune prophylaxis available. The aim was to characterize the Th response to K as a key step in designing specific immunotherapy and understanding the immunogenicity of the Ag. PBMCs from K-negative women who had anti-K Abs after incompatible pregnancy, and PBMCs from unimmunized controls, were screened for proliferative responses to peptide panels spanning the K or k single amino acid polymorphism. A dominant K peptide with the polymorphism at the C terminus elicited proliferation in 90% of alloimmunized women, and it was confirmed that responding cells expressed helper CD3(+)CD4(+) and "memory" CD45RO(+) phenotypes, and were MHC class II restricted. A relatively high prevalence of background peptide responses independent of alloimmunization may contribute to K immunogenicity. First, cross-reactive environmental Ag(s) pre-prime Kell-reactive Th cells, and, second, the K substitution disrupts an N-glycosylation motif, allowing the exposed amino acid chain to stimulate a Th repertoire that is unconstrained by self-tolerance in K-negative individuals. The dominant K peptide was effective in inducing linked suppression in HLA-transgenic mice and can now be taken forward for immunotherapy to prevent HDN because of anti-K responses. PMID- 22490334 TI - Human extramedullary bone marrow in mice: a novel in vivo model of genetically controlled hematopoietic microenvironment. AB - The interactions between hematopoietic cells and the bone marrow (BM) microenvironment play a critical role in normal and malignant hematopoiesis and drug resistance. These interactions within the BM niche are unique and could be important for developing new therapies. Here, we describe the development of extramedullary bone and bone marrow using human mesenchymal stromal cells and endothelial colony-forming cells implanted subcutaneously into immunodeficient mice. We demonstrate the engraftment of human normal and leukemic cells engraft into the human extramedullary bone marrow. When normal hematopoietic cells are engrafted into the model, only discrete areas of the BM are hypoxic, whereas leukemia engraftment results in widespread severe hypoxia, just as recently reported by us in human leukemias. Importantly, the hematopoietic cell engraftment could be altered by genetical manipulation of the bone marrow microenvironment: Extramedullary bone marrow in which hypoxia-inducible factor 1alpha was knocked down in mesenchymal stromal cells by lentiviral transfer of short hairpin RNA showed significant reduction (50% +/- 6%; P = .0006) in human leukemic cell engraftment. These results highlight the potential of a novel in vivo model of human BM microenvironment that can be genetically modified. The model could be useful for the study of leukemia biology and for the development of novel therapeutic modalities aimed at modifying the hematopoietic microenvironment. PMID- 22490336 TI - Characterization of the 1st and 2nd EF-hands of NADPH oxidase 5 by fluorescence, isothermal titration calorimetry, and circular dichroism. AB - BACKGROUND: Superoxide generated by non-phagocytic NADPH oxidases (NOXs) is of growing importance for physiology and pathobiology. The calcium binding domain (CaBD) of NOX5 contains four EF-hands, each binding one calcium ion. To better understand the metal binding properties of the 1st and 2nd EF-hands, we characterized the N-terminal half of CaBD (NCaBD) and its calcium-binding knockout mutants. RESULTS: The isothermal titration calorimetry measurement for NCaBD reveals that the calcium binding of two EF-hands are loosely associated with each other and can be treated as independent binding events. However, the Ca2+ binding studies on NCaBD(E31Q) and NCaBD(E63Q) showed their binding constants to be 6.5 * 105 and 5.0 * 102 M-1 with DeltaHs of -14 and -4 kJ/mol, respectively, suggesting that intrinsic calcium binding for the 1st non-canonical EF-hand is largely enhanced by the binding of Ca2+ to the 2nd canonical EF-hand. The fluorescence quenching and CD spectra support a conformational change upon Ca2+ binding, which changes Trp residues toward a more non-polar and exposed environment and also increases its alpha-helix secondary structure content. All measurements exclude Mg2+-binding in NCaBD. CONCLUSIONS: We demonstrated that the 1st non-canonical EF-hand of NOX5 has very weak Ca2+ binding affinity compared with the 2nd canonical EF-hand. Both EF-hands interact with each other in a cooperative manner to enhance their Ca2+ binding affinity. Our characterization reveals that the two EF-hands in the N-terminal NOX5 are Ca2+ specific. GRAPHICAL PMID- 22490335 TI - Genome-wide miRNA profiling of mantle cell lymphoma reveals a distinct subgroup with poor prognosis. AB - miRNA deregulation has been implicated in the pathogenesis of mantle cell lymphoma (MCL). Using a high-throughput quantitative real-time PCR platform, we performed miRNA profiling on cyclin D1-positive MCL (n = 30) and cyclin D1 negative MCL (n = 7) and compared them with small lymphocytic leukemia/lymphoma (n = 12), aggressive B-cell lymphomas (n = 138), normal B-cell subsets, and stromal cells. We identified a 19-miRNA classifier that included 6 up-regulated miRNAs and 13 down regulated miRNA that was able to distinguish MCL from other aggressive lymphomas. Some of the up-regulated miRNAs are highly expressed in naive B cells. This miRNA classifier showed consistent results in formalin-fixed paraffin-embedded tissues and was able to distinguish cyclin D1-negative MCL from other lymphomas. A 26-miRNA classifier could distinguish MCL from small lymphocytic leukemia/lymphoma, dominated by 23 up-regulated miRNAs in MCL. Unsupervised hierarchical clustering of MCL patients demonstrated a cluster characterized by high expression of miRNAs from the polycistronic miR17-92 cluster and its paralogs, miR-106a-363 and miR-106b-25, and associated with high proliferation gene signature. The other clusters showed enrichment of stroma associated miRNAs, and also had higher expression of stroma-associated genes. Our clinical outcome analysis in the present study suggested that miRNAs can serve as prognosticators. PMID- 22490337 TI - Experience from experimental cell transplantation therapy of myocardial infarction: what have we learned? AB - During the past 15 years, our research group has transplanted fetal/neonatal cardiomyocytes, mesenchymal stem cells, and embryonic stem cell-derived cardiomyocytes into infarcted myocardium in a rat myocardial infarction model. Our experimental data demonstrated that cell transplantation therapy provides a potential approach for the treatment of injured myocardium after myocardial infarction based on the reported positive effects upon histological appearance and left ventricular function. However, the underlying mechanisms of the benefits from cell transplantation therapy remain unclear and may involve replacement of scar tissue by transplanted cells, induced neoangiogenesis and paracrine effects of factors released by the transplanted cells. In this review, we summarize our experiences from experimental cell transplantation therapy in a rat myocardial infarction model and discuss the controversies and questions that need to be addressed in future studies. PMID- 22490338 TI - Evaluation of intracellular labeling with micron-sized particles of iron oxide (MPIOs) as a general tool for in vitro and in vivo tracking of human stem and progenitor cells. AB - Magnetic resonance imaging (MRI)-based tracking is increasingly attracting attention as a means of better understanding stem cell dynamics in vivo. Intracellular labeling with micrometer-sized particles of iron oxide (MPIOs) provides a practical MRI-based approach due to superior detectability relative to smaller iron oxide particles. However, insufficient information is available about the general utility across cell types and the effects on cell vitality of MPIO labeling of human stem cells. We labeled six human cell types from different sources: mesenchymal stem cells derived from bone marrow (MSCs), mesenchymal stem cells derived from adipose tissue (ASCs), presumptive adult neural stem cells (ad-NSCs), fetal neural progenitor cells (f-NPCs), a glioma cell line (U87), and glioblastoma tumor stem cells (GSCs), with two different sizes of MPIOs (0.9 and 2.84 um). Labeling and uptake efficiencies were highly variable among cell types. Several parameters of general cell function were tested in vitro. Only minor differences were found between labeled and unlabeled cells with respect to proliferation rate, mitotic duration, random motility, and capacity for differentiation to specific phenotypes. In vivo behavior was tested in chicken embryos and severe combined immunodeficient (SCID) mice. Postmortem histology showed that labeled cells survived and could integrate into various tissues. MRI-based tracking over several weeks in the SCID mice showed that labeled GSCs and f-NPCs injected into the brain exhibited translocations similar to those seen for unlabeled cells and as expected from migratory behavior described in previous studies. The results support MPIO-based cell tracking as a generally useful tool for studies of human stem cell dynamics in vivo. PMID- 22490339 TI - Putative population of adipose-derived stem cells isolated from mediastinal tissue during cardiac surgery. AB - Mesenchymal stem cells have been isolated from various adult human tissues and are valuable for not only therapeutic applications but for the study of tissue homeostasis and disease progression. Subcutaneous adipose depots have been shown to contain large amounts of stem cells. There is little information that has been reported to date describing the isolation and characterization of mesenchymal stem cells from visceral adipose tissue. In this study, we describe a mesenchymal stem cell population isolated from mediastinal adipose depots. The cells express CD44, CD105, CD166, and CD90 and are negative for hematopoietic markers CD34, CD45, and HLA-DR. In addition, the cells have a multilineage potential, with the ability to differentiate into adipogenic, osteogenic, and chondrogenic cell types. The biological function of visceral adipose tissue remains largely unknown and uncharacterized. However, the proximity of adipose tissue to the heart suggests a potential role in the pathogenesis of cardiovascular disease in obesity. In addition, with the ability of fat to regulate metabolic activity in humans, this novel stem cell source may be useful to further study the mechanisms involved in metabolic disorders. PMID- 22490340 TI - Safety and efficacy of autologous cell therapy in critical limb ischemia: a systematic review. AB - Researchers have accumulated a decade of experience with autologous cell therapy in the treatment of critical limb ischemia (CLI). We conducted a systematic review of clinical trials in the literature to determine the safety and efficacy of cell therapy in CLI. We searched the literature for clinical trials of autologous cell therapy in CLI, including observational series of five or more patients to accrue a large pool of patients for safety analysis. Safety analysis included evaluation of death, cancer, unregulated angiogenesis, and procedural adverse events such as bleeding. Efficacy analysis included the clinical endpoints amputation and death as well as functional and surrogate endpoints. We identified 45 clinical trials, including seven RCTs, and 1,272 patients who received cell therapy. The overall adverse event rate was low (4.2%). Cell therapy patients did not have a higher mortality rate than control patients and demonstrated no increase in cancer incidence when analyzed against population rates. With regard to efficacy, cell therapy patients had a significantly lower amputation rate than control patients (OR 0.36, p = 0.0004). Cell therapy also demonstrated efficacy in a variety of functional and surrogate outcomes. Clinical trials differed in the proportion of patients with risk factors for clinical outcomes, and these influenced rates of amputation and death. Cell therapy presents a favorable safety profile with a low adverse event rate and no increase in severe events such as mortality and cancer and treatment with cell therapy decreases the risk of amputation. Cell therapy has a positive benefit-to-risk ratio in CLI and may be a valuable treatment option, particularly for those challenging patients who cannot undergo arterial reconstruction. PMID- 22490341 TI - Human insulin secreted from insulinogenic xenograft restores normoglycemia in type 1 diabetic mice without immunosuppression. AB - In the present study, we examined the therapeutic potential of human amnion derived insulin-secreting cells for type 1 diabetes. Human amniotic mesenchymal stem cells (hAMs) were isolated from amnion and cultivated to differentiate into insulin-secreting cells in vitro. After culture in vitro, the differentiated cells (hAM-ISCs) were intensively stained with dithizone and secreted insulin and c-peptide in a high-glucose-dependent manner. They expressed mRNAs of pancreatic cell-related genes, including INS, PDX1, Nkx6-1, NEUROG3, ISL1, NEUROD1, GLUT1, GLUT2, PC1/3, PC2, GCK, PPY, SST, and GC, and were positive for human insulin and c-peptide. Transplantation of hAM-ISCs into the kidneys of mice with streptozotocin-induced diabetes restored body weight and normalized the blood glucose levels, which lasted for 210 days. Only human insulin and c-peptide were detected in the blood of normalized mice after 2 months of transplantation, but little mouse insulin and c-peptide. Removal of graft-bearing kidneys from these mice resulted in causing hyperglycemia again. Human cell-specific gene, hAlu, and human pancreatic cell-specific genes, insulin, PDX1, GLUT1, GLP1R, Nkx6-1, NEUROD1, and NEUROG3, were detected in the graft-bearing kidneys. Colocalization of human insulin and human nuclei antigen was also observed. These results demonstrate that hAMs could differentiate into functional insulin-secreting cells in vitro, and human insulin secreted from hAM-ISCs following transplantation into type 1 diabetic mice could normalize hyperglycemia, overcoming immune rejection for a long period. PMID- 22490342 TI - Dermal papilla cells serially cultured with Wnt-10b sustain their hair follicle induction activity after transplantation into nude mice. AB - Dermal papilla (DP) cells are associated with the development of hair follicles (HFs) and regulation of the hair cycle. However, primary DP cells prepared from cultured HFs are known to lose their ability to induce HF after culturing in standard media, for example, fibroblast growth conditions. We explored a new culture condition by which DP cells maintained their HF induction ability. The addition of Wnt-10b to the first culture of primary DP cells promoted their proliferation and maintained their Wnt responsiveness and HF induction ability. Furthermore, DP cells in Wnt-10b-containing medium sustained those characteristics after 10 passages (100 days), which encompassed the entire experimental period. These results suggest that Wnt-10b plays a pivotal role in proliferation and maintenance of DP cells in vitro. PMID- 22490343 TI - [Surgical management of nodular hyperplasia tumor-like hepatic lesions: a study of 72 cases]. AB - OBJECTIVE: To explore and improve the diagnosis and treatment of benign hyperplasia tumor-like hepatic lesion. METHODS: The clinical data of 72 patients who had undergone hepatic resection for benign non-cystic hepatic lesions between January 1987 and December 2010 were analyzed retrospectively. There were 46 male and 26 female patients. The median age was 49 years (ranging 15 to 72 years), and diagnosis were confirmed by postoperative pathological examination. Thirty-four cases had symptoms, such as abdominal discomfort in right upper quadrant, fever, fatigue. All the cases had undergone hepatic resection; totally 78 lesions were removed. The surgical procedure including hepatic lobectomy for 13 cases, hepatic segmentectomy for 19 cases and non-anatomy resection for 39 cases. RESULTS: The finally diagnosis included focal nodular hyperplasia in 47 cases, adenomatous hyperplasia in 3 cases, hepatic dysplastic nodule in 3 cases, inflammatory pseudotumor in 3 cases, hepatic granuloma in 4 cases, nodular cirrhosis in 3 cases, hepatitis nodule in 6 cases, nodular regenerative hyperplasia in 1 case, lymphoid hyperplasia in 1 case. The postoperative complication rate was low (19.4%, 14/72). The follow-up period was 6 to 96 months. There was no mortality caused by lesion. One patient developed recurrence after 3 years. CONCLUSIONS: It is suggested that symptomatic lesions, lesions when malignancy cannot be excluded, and lesions which have canceration tendency, just like adenomatous hyperplasia, dysplastic nodule, and nodular cirrhosis regenerative hyperplasia need surgical resection. Operation is not necessary for other nodular hyperplasia lesions if the diagnoses are identified. PMID- 22490344 TI - [The value of gastric bare area, left adrenal gland and perirenal space involvement in predicting complications of acute pancreatitis]. AB - OBJECTIVE: To investigate CT findings and incidence rate of gastric bare area involvement (GBAI), left adrenal gland involvement (LAGI) and perirenal space involvement (PSI) in acute pancreatitis, and to also explore the value of these appearances in predicting complications and mortality of patients. METHODS: CT imaging data of 575 patients with AP diagnosed by clinic from October 2009 to April 2011 were analyzed retrospectively. There were 339 male and 236 female patients, aging from 16 to 93 years with a mean of (51 +/- 16) years. Involvement with or without gastric bare area, left adrenal gland, perirenal space were focused, and the relationship were analyzed between these CT findings and complications and mortality of patients. RESULTS: Among 167 patients (29.0%) with GBAI, 132 had complications and 16 died. The sensitivity and specificity of GBAI for predicting complications were 45.4% and 87.7%, respectively, and 84.2%and 72.8% for predicting mortality. In all 107 patients (18.6%) with LAGI, 81 had complications and 18 died. The sensitivity and specificity of LAGI for predicting complications were 27.8% and 90.8%, respectively, and 94.7% and 84.0% for predicting mortality. Among 335 patients (58.3%) with PSI, 201 had complications and 19 died. The sensitivity and specificity of PSI for predicting complications were 69.1% and 52.8%, respectively, and 100% and 43.2% for predicting mortality. Of all patients, 210 (36.5%) owned two or more positive CT findings among GBAI, LAGI, and PSI. One hundred ninety-eight of these patients had complications and 19 died, that predicted the sensitivity and specificity for complications were 68.0% and 95.8%, respectively, and 100% and 65.6% for mortality. The risk of complications in the patients with GBAI or LAGI was increased than normal gastric bare area or left adrenal gland 5.9 or 3.8 times respectively, and the risk of death was improved 14.3 or 94.5 times respectively. The risk of complications in those patients with two or more positive findings increased by 48.3 times. By analyzing receiver operating characteristic (ROC) curve, the combination of GBAI, LAGI, and PSI was the best way to predict the complications of AP. The area under the ROC was 0.819. CONCLUSIONS: The CT imaging could effectively indicate the signs of GBAI, LAGI and PSI of AP. The GBAI. LAGI and PSI were related with the severity and prognosis of AP, and these findings could be clinical indicators for evaluating prognosis of AP. PMID- 22490345 TI - [A retrospective analysis of clinic-pathological characteristics and prognostic factors for 204 cases of primary gastric lymphoma]. AB - OBJECTIVE: To explore the clinicopathological characteristics and prognostic factors of primary gastric lymphoma (PGL). METHODS: The clinical data of 204 patients with PGL was reviewed and analyzed. There were 106 males and 98 females, their age were 19 to 85 years (average age was 53.7 years). The Focal areas included gastric fundus lesions 41 cases (20.1%), stomach body lesions 127 cases (62.3%), distal gastric lesions 105 cases (51.5%), cardia lesions 13 cases (6.4%), duodenal bulb lesion 1 cases (0.5%). The clinical characteristics and the outcomes in patients with influence were analysed. RESULTS: In 204 PGL patients, the most common complaints were abdominal pain (62.3%) and weight loss (52.9%). Most of the PGL patients appeared ulcerative (76.0%) and results showed that 62.7% patients involved single location. As to the factors of cellulate grading and pathological characteristics, most patients (87.7%) show low-grade or intermediate-grade lymphoma, Musshoff stages I and II (74.0%). In 186 patients with complete follow-up data, survival rates of 1-, 3- and 5-year were 75.8%, 63.4% and 60.2% respectively. The median overall survival time was 50.0 months. In univariate survival analysis, age (chi(2) = 5.030), level of LDH (chi(2) = 40.084), cellulate grading (chi(2) = 35.238), Musshoff stage (chi(2) = 71.601), tumor diameter (chi(2) = 12.018) and option of managements (chi(2) = 14.140) were obviously correlated with the prognosis (all P < 0.05). Musshoff stage (RR = 2.230, 95%CI: 1.372 - 3.625) and cellulate grading (RR = 1.892, 95%CI: 1.010 - 3.543) were independent prognostic factors in multivariable analysis (both P < 0.05). There was no prognostic difference between surgery and chemotherapy in stage I and II (chi(2) = 1.223, P = 0.542). CONCLUSIONS: Musshoff stage and grade malignancy are independent prognostic factors. For patients with stage I and II, surgical resection is not the first-choice for clinical therapy. PMID- 22490346 TI - [Clinical manifestation and surgical treatment of spinal osteoblastoma]. AB - OBJECTIVE: To investigate the clinical manifestation and surgical outcome of spinal osteoblastoma. METHODS: From June 2006 to July 2010, 11 patients with spinal osteoblastoma treated surgically were analyzed retrospectively. There were 7 males and 4 females with an average age of 23.5 years (range, 16 - 34 years). The tumors were located at C(5) in 3, C(6) in 4, C(7) in 2, C(6) ~ T(1) in 1 and T(11) in 1. Based on WBB classification, 9 were 1 - 3 or 10 - 12 and 2 were 4 - 9 and 1 - 3. All the operations had been performed with en-bloc resection. The posterior approach was used for 9 patients, and combined posterior and anterior approach was used for 2 patients. Reconstruction using instrumentation and fusion was performed using spinal instrumentation in 8 patients. To evaluate the change of pain before and after the operation by visual analogue scales (VAS), and to assess functional status of the spine by McCormick scale. Imaging test was used to review the stability and recurrence rate of spine cord, and the confluence of graft bones. RESULTS: All cases were followed up for 12 - 64 months (average, 28.4 months). The average surgical time was 130.5 minutes (range, 90 - 210 minutes), with the average intraoperative blood loss of 560 ml (range, 300 - 1000 ml). During the follow-up period, the VAS grade reduced from 6.3 +/- 1.1 to 2.5 +/- 1.0 (t = 8.48, P < 0.05). There were 8 patients had neurological function improved and 3 remained no change which was evaluated by McCormick scale for spinal function status at final follow-up. CONCLUSIONS: Spinal osteoblastoma has its own specific radiographic feature. There are some recurrence in simple curettage of tumor lesion. The thoroughly en-bloc resection of tumor or spondylectomy, bone fusion and strong in ter fixation are the key points for successful surgical treatment. PMID- 22490347 TI - [The effect of Topping-off surgery on preventing adjacent segment degeneration, a retrospective study]. AB - OBJECTIVE: To investigate the early-middle stage clinical results of Topping-off surgery in preventing adjacent segment degeneration when mild or moderate adjacent segment degeneration exists before surgery. METHODS: All the cases that received L(5)-S(1) posterior lumbar interbody fusion (PLIF)+L(4)-L(5) interspinous process (ISP) surgeries between April 2008 and March 2010 (Topping off group) were analyzed retrospectively. The cases received L(5)-S(1) PLIF surgery and whose intervertebral disc degeneration using modified Pfirrmann's grading system were grade 4 - 6 were analyzed retrospectively at the same time (PLIF group). Both groups matched in gender, age, body mass index and Pfirrmann's grading of disc. All the patients were evaluated with visual analogue scale (VAS) and Japanese orthopaedic association (JOA) scores before the surgery and in the last follow-up. The X-ray films before and after surgery were measured. RESULTS: There were 25 patients in Topping-off group and 42 patients in PLIF group were included in the final analysis. The follow-up averaged 24.8 and 23.7 months. No symptomatic or radiological adjacent segment degeneration was observed. The average surgery time was (120 +/- 24) min and (106 +/- 21) min. There was no significant difference in the blood loss during surgery or post-operation drainage (P > 0.05). VAS and lumbar JOA score improved in both groups (P < 0.01). In the lateral view of lumbar spine, neither of anterior or posterior disk height was significantly changed (P > 0.05), segmental lordosis of L(4)-L(5), total lordosis were all increased (Topping-off group: t = -2.30 and -2.24, P < 0.05; PLIF group: t = -2.76 and -1.83, P < 0.05). In the hyperextension and hyperflexion view, Topping-off group's range of motion (ROM) and olisthesis in the L(4-5) segment did not significantly change in flexion (P > 0.05), but decreased in extension (t = 5.83 and 4.92, P < 0.01). In PLIF group, the ROM (t = -7.82 and -4.90, P < 0.01) and olisthesis (t = -15.67 and -18.58, P < 0.01) both significantly increased in extension and flection. CONCLUSIONS: Compared with single segmental PLIF surgery, Topping-off surgery can achieve similar symptomatic improvement in cases with pre-existing mild or moderate adjacent segment degeneration, restrict the adjacent segment's range of motion in extension and prevent excessive olisthesis of adjacent segment in both extension and flexion. Topping-off surgery has a potential effect of preventing adjacent segmental degeneration. PMID- 22490348 TI - [Surgery treatment for pulmonary sclerosing hemangioma]. AB - OBJECTIVE: To investigate the clinicopathological features and surgical treatment of pulmonary sclerosing hemangioma (PSH). METHODS: Clinic data of PSH patients admitted by surgical resection from January 1985 to December 2010 was analyzed retrospectively. One hundred and sixty-five patients were enrolled in the study. There were 27 male and 138 female patients with a mean age of (48 +/- 13) years. Seventy-nine patients were asymptomatic at the time of diagnosis. Eighty-nine tumors arose in the right lung (27 in right upper lobe, 24 in right middle lobe, 34 in right lower lobe, 2 in right upper lobe with invasion of right middle lobe, 1 in right middle lobe with invasion of right lower lobe, and 1 case with multiple lobe lesions), 75 in the left (33 in left upper lobe, 42 in left lower lobe), and 1 in the bilateral. There were huge mass lesions in 2 cases, endobronchial lesions in 2 cases, and multiple lesions in 6 cases. The mean size of the lesion was (2.6 +/- 0.9) cm (ranging from 0.9 to 10.0 cm). Forty-eight cases (29.1%) were misdiagnosed as malignancies preoperatively, and 41 cases (24.8%) were misdiagnosed intraoperatively. RESULTS: Resections were performed by means of video-assisted thoracoscopy (n = 53) and thoracotomy (n = 112). Surgical resection included pulmonary wedge excision in 61 patients, lobectomy in 89 patients, right bilobectomy in 5 patients, anatomic segmentectomy in 2 patient, enucleation in 6 patients, and synchronous bilateral pulmonary wedge resection in 1 patient. Operative mortality and morbidity occurred in 0 and 2 (4.3%) patients, respectively. Mean follow-up was 34.7 months (ranging from 6 to 62 months). There was no local recurrence or death from PSH. CONCLUSIONS: PSH is a rare benign lung tumor. It is difficult to make accurate diagnosis preoperatively, and sometimes even intraoperative frozen sections can't differentiate it from malignant tumors. Surgical resection is usually indicated for definite diagnosis and treatment. Partial resection is a sufficient treatment in view of uncommon tumor recurrence. Thoracoscopic surgery is recommended for PSH. PMID- 22490349 TI - [Extra-anatomic bypass for complex aortic coarctation in adults]. AB - OBJECTIVE: To demonstrate an effective operation of extra-anatomic bypass for complex aortic coarctation in adults. METHODS: Between July 1997 and October 2010, 51 patients underwent extra-anatomic aortic bypass. There were 39 male and 12 female patients. Mean age was (40 +/- 14) years (ranging from 18 to 63 years). Operative technique of extra-anatomic bypass consisted of performing an ascending to-descending or abdominal or femoral aorta bypass (8, 39 and 4 patients). Concomitant procedures were performed in 38 patients: 10 isolated aortic valve replacements (AVR), 11 aortic root replacements (Bentall), 4 ascending aorta replacements including 3 concomitant AVR, 5 mitral valve replacements including 3 concomitant AVR, 4 ventricular septal defect correcting with AVR, and 4 coronary artery bypass graft. RESULTS: Mean follow-up time was (30 +/- 9) months (ranging from 5 to 60 months). Two patients were reoperated for hemorrhage in descending aorta anastomosis, one of whom was dead of multiple organ failure in perioperative period. Upper-extremity blood pressure after coarctation correction with extra-anatomic aortic bypass was significantly improved (< 10 mmHg, 1 mmHg = 0.133 kPa). Arterial hypertension was well improved, except 10 patients controlled with less drug therapy. All grafts were patent without obstruction or pseudoaneurysm formation in the follow-up period evaluated by vascular ultrasound and computed tomographic angiogram. CONCLUSION: Extra-anatomic aortic bypass is a safe and effective option for complex aortic coarctation in adults. PMID- 22490350 TI - [Early and midterm outcomes of coronary artery bypass grafting in octogenarians]. AB - OBJECTIVE: To investigate the early and midterm postoperative outcomes and analyze risk factors of coronary artery bypass grafting (CABG) in octogenarians. METHODS: Clinical data of 38 patients aged 80 years or greater receiving isolated coronary artery bypass grafting from September 2001 to November 2010 were reviewed. There were 33 male and 5 female patients, aging from 80 to 87 years with a mean of (82.6 +/- 1.2) years. Twelve patients underwent conventional (on pump) CABG and 26 patients underwent off-pump CABG. The number of bypass grafts was 1 to 5 (mean 2.5 +/- 1.1). Left internal mammary artery was used in 37 (97.3%) patients. RESULTS: The perioperative mortality was 2.6% (1/38). Postoperative complications included stroke (4 cases), respiratory infection (1 case). The atrial arrhythmias occurred in 25 patients. Intensive care unit and hospital length of stay lasted (3.8 +/- 1.4) days and (15 +/- 6) days, respectively. Totally 38 patients were followed up for 4 to 70 months. Six patients died during the follow-up period. The 92.6% patients recovered without any cardiac events. CONCLUSIONS: Isolated CABG can be performed safely with acceptable postoperative morbidity and mortality in octogenarians. Appropriate surgical strategy and intensive perioperative treatment must be enhanced in octogenarians who underwent CABG. PMID- 22490351 TI - [Comparison of 2 um continuous-wave laser enucleation of the prostate and transurethral resection of the prostate for benign prostatic hyperplasia]. AB - OBJECTIVE: To compare the safety and efficacy of RevoLix 120 W 2 um continuous wave (cw) laser enucleation of the prostate with transurethral resection of prostate (TURP) in patients with symptomatic benign prostatic hyperplasia (BPH). And to evaluate clinical value of 120 W 2 um cw laser enucleation. METHODS: All 168 patients with BPH underwent 2 um cw laser enucleation (n = 88) or TURP (n = 80) between January 2010 and January 2011. The operative time, drop in hemoglobin, drop in serum sodium, indwelling catheterization time and operative complications were recorded. International prostate symptom score (IPSS), quality of life (QOL), urinary peak flow rate (Qmax) and post-voiding residual urine (PVR) were also compared. RESULTS: The mean operative time was slightly longer in the 2 um laser group ((63.2 +/- 21.6) min) than the TURP group ((59.4 +/- 18.6) min) (P > 0.05). Transfusions were not necessary in 2 um laser group. Catheter indwelling time were (1.8 +/- 0.6) days vs. (3.5 +/- 2.6) days in 2 um laser group than in TURP group (t = 3.912, P < 0.05). All cases were followed up for 3 12 months, the IPSS, QOL, Qmax and PVR were 6.1 +/- 2.0, 4.4 +/- 1.6, (18.8 +/- 4.8) ml/s and (21.6 +/- 16.5) ml in the 2 um laser group, and were 6.3 +/- 2.4, 1.9 +/- 1.1, (18.4 +/- 4.2) ml/s, (23.2 +/- 14.6) ml in TURP group respectively. All the markers were improved significantly compared with that of preoperative in both groups (t = 12.453 - 26.213, P < 0.01), but no statistical differences could be found between the two groups. Perioperative complications were less in the 2 um laser group. CONCLUSIONS: The 120 W 2 um cw laser enucleation is an novel excellent treatment for BPH as well as TURP, and has the advantage of significantly less blood loss, shorter hospitalization, shorter catheter indwelling time and rapid recovery after surgery. PMID- 22490352 TI - [Effect of modified Badenoch operation on the treatment of posterior urethral stricture]. AB - OBJECTIVE: To determine the effects of modified pull-through operation (Badenoch operation) on the treatment of posterior urethral stricture. METHODS: From September 2001 to December 2010 traditional pull-through operation was Modified for two times in our center. A total of 129 patients with posttraumatic posterior urethral stricture resulting from pelvic fracture injury underwent the modified urethral pull-through operation. Stricture length was 1.5 to 5.3 cm (mean 2.9 cm). Of the patients 43 had undergone at least 1 previous failed management for stricture. In phase 1 (from September 2001 to January 2008), the improving items include: (1) The distal urethral end was stitched and tied to the catheter. (2) As catheter was inserted into bladder and 20 ml water was injected into catheter balloon, the distal urethral end was fixed in the proximal urethra and an overlaying of 1.5 cm was formed between the two ends. (3) Three weeks later, it was tried to insert the catheter to bladder. After the urethral stump necrosis and the catheter separating from the urethra, the catheter was removed. In phase 2 (from February 2008 to December 2010), based on the above, irrigating catheter was used. After the surgery, urethra was irrigated with 0.02% furacillin solution through the catheter 3 times a day. All patients were followed up for at least 6 months. If patients had no conscious dysuria and maximum urinary flow rate (Qmax) > 15 ml/s, the treatment was considered successful. All complications were recorded. RESULTS: In phase 1, the 96 patients (101 times) underwent the procedure. The treatment was successful in 88 patients (success rate 92%). Within 1 to 13 days after removal of the catheter, urethral stricture was recurred in 8 patients. They had to undergo cystostomy once more for 3 to 11 months before reoperation (the 3 patients' reoperation was in phase 2). The 8 cases were treated successfully. In phase 2, 33 patients (total 36 times) underwent the procedure. One patient was failed (success rate 97%). The actual follow-up time is 7 to 93 months (An average of 37.6 months). Qmax is (22 +/- 5) ml/s. No complications such as urinary incontinence, erectile pain, urinary shortening happened. CONCLUSIONS: The modified urethral pull-through operation is effective for the surgical treatment of posttraumatic posterior urethral stricture. It has a high success rate with durable long-term results. Complications are few. The procedure is simple, less demanding and especially suitable in patients who had previously undergone failed surgical treatments. PMID- 22490353 TI - [Experiences of transcallosal-interforniceal approach for resection of the third ventricle and the pineal region tumors: report of 24 cases]. AB - OBJECTIVE: To discuss the advantages and disadvantages of transcallosal interforniceal approach for resection of the third ventricle and the pineal region tumors. METHODS: The clinical data of 24 cases from July 2008 to March 2011 were retrospectively analyzed. All 24 patients operated by transcallosal interforniceal approach, among them, there were 14 males and 10 females, with a average age of 32 years ranged from 17 to 65 years and with medical history from 1 month to 10 years. Issues of managements were analyzed and discussed, including reasonable incision design, the managements of draining vein, the site and the length of the incision of the corpus callosum, tumor exposure in increased intracranial pressure, prevention of complications, skills of surgery, treatments of obstructive hydrocephalus, and postoperative managements. RESULTS: In the 24 cases, there were 5 cases of pineal parenchymal tumors, 4 cases of germinoma, 3 cases of astrocytoma, 2 cases of hypothalamus hamartomas, 2 cases of ependymoma, 2 cases of mixed germ cell tumour, 2 cases of malignant lymphomas, 1 case of pineoblastoma, 1 case of dermoid cyst, 1 case of chordoid glioma and 1 case of craniopharyngioma. After surgeries, total removal achieved in 9 cases, and subtotal removal in 10 cases and partial removal in 5 cases. Operative mortality was 0. Combined third ventriculostomy were performed in 13 cases. Postoperative complications occurred in 5 cases, including frontoparietal epidural hematoma in 1 case; postoperative short-term memory loss in 3 cases, postoperative memory loss within 1 month in 2 cases and within 3 months in 1 case; frontoparietal subdural effusion in 1 case and the effusion disappeared without any treatment. Ventriculoperitoneal shunt was performed in 1 case. CONCLUSIONS: The transcallosal-interforniceal approach is ideal for the removal of tumors in third ventricle as well as majority tumor in posterior of third ventricle in a skillful hand. Tumor resection combined with third ventriculostomy is the significant advantages in the approach. PMID- 22490354 TI - [Analysis of prognostic factors on posterior communicating artery aneurysm caused oculomotor nerve palsy]. AB - OBJECTIVE: To study and analyze the factors affecting the recovery of posterior communicating artery aneurysm-induced oculomotor nerve palsy (ONP). METHODS: The clinical and follow-up data of posterior communicating artery aneurysm-induced ONP in 23 patients from May 2005 to May 2009 were retrospectively compared. There were 7 male and 16 female with a mean age of 50.4 years. Among the 23 patients, 13 patients underwent endovascular coiling (endovascular group) and 10 patients underwent surgical clipping (surgical group). RESULTS: Of the patients with 2 year of follow-up, 6 patients recovered completely and 7 patients recovered partially in the endovascular group, compared with 6 patients recovered completely and 4 patients recovered partially in the surgical group (P = 0.407). Compared to the patients with preoperative complete ONP, the rate of complete recovery was higher in the patients with preoperative partial ONP, while the results did not reach the significance (P = 0.095). Patients accepted treatment in 14 days since the onset of symptoms recovered significantly than who accepted treatment after 14 days since the onset of symptoms (P = 0.045). CONCLUSIONS: There is no significant difference in recovery from ONP between endovascular coiling and surgical clipping as treatment for posterior communicating artery aneurysm patients with ONP. Timing of treatment after onset of symptoms is a factor affects the recovery of ONP. PMID- 22490355 TI - [The development of a type II endoleak domesticated pig model with continuous pressure monitor]. AB - OBJECTIVE: To develop a type II endoleak porcine model with continuous pressure monitor by the strain-gauge pressure transducer and the patch. METHODS: Nine tamed porcine was randomized as the experiment group of 6 domesticated pigs and the control group of 3 domesticated pigs. When the abdominal aortic aneurysm (AAA) was created, the 2(nd) and 3(rd) pair of infrarenal lumber arteries were preserved in the experiment group, while ligated in the control group. The stent graft was implanted in the endovascular repair. CT angiography was performed to seek endoleak, and the angiography was performed to excluded the type I and type III endoleak. The pressure in the excluded AAA monitored by the strain-gauge pressure transducer was recorded and compared in both groups to evaluated the effect of type II endoleak in the experiment group. RESULTS: The AAA porcine model with pressure monitor were successfully developed in all 9 porcine. The endoleak and the retrograde flow of the lumber arteries were confirmed by CT angiography in the experiment group. The ratio of the average pressure after the procedure to before the procedure was higher in the experiment group than the control group (U = 0.000, P = 0.020). The ratio of the pulse pressure after the procedure to the average pressure before the procedure was higher in the experiment group than the control group (U = 0.000, P = 0.020). CONCLUSION: It is feasible to develop type II endoleak domesticated pig model by preserving the lumber arteries for the retrograde flow, and the AAA model with pressure monitor by the strain-gauge pressure transducer and the patch. PMID- 22490356 TI - [Proteomics analysis of distinct proteins in human atherosclerosis obliterans: identification and verification]. AB - OBJECTIVE: To identify distinct proteins involved in human atherosclerosis obliterans (ASO) by a differential proteomic approach. METHODS: Eight atherosclerotic femoral arteries with a mean age of 68.6 years (6 male and 2 female) and 5 normal femoral arteries with a mean age of 44.2 years (3 male and 2 female) were obtained from high amputation patients. Then the first 2-dimensional maps of the proteome of human femoral arteries was plotted to compare ASO and control specimens. Proteomic profiling was to differentiate and identify histological proteins that were associated with ASO. The differentially expressed proteins were sequenced by matrix assisted laser desorption/ionization mass spectrometry (MALDI-TOF-MS). The result was verified by immunohistochemistry (IHC) and Western blot. RESULTS: ASO was associated with distinct patterns of protein expression in the femoral arteries. A total of 25 distinct spots corresponding to 13 different proteins were identified by MALDI-TOF-MS using the NCBI and IPI databases. These proteins were mainly involved in the pathogenetic mechanisms such as inflammation, oxidative stress, proliferation and transformation of SMCs. The low level of heat shock protein 27 (HSP27) in ASO was verified by IHC and western-blot in accord with the result of MS. CONCLUSION: Proteomic analysis can be used to investigate differentially expressed proteins, which may provide new insights into ASO pathogenesis, such as HSP27. PMID- 22490357 TI - [Face and content validation of the virtual reality transurethral prostatic resection simulator]. AB - OBJECTIVE: To evaluate the face and content validation of the virtual reality transurethral resection of the prostate simulator (TURPSim(TM)). METHODS: The 60 urology doctor aged 26 - 50 years old all over the country were enrolled for virtual reality training of TURP from September 2010 to June 2011. Participants classified as experts (more than 50 procedures performed) and novices (50 or fewer procedures performed) performed TURPs on TURPSim(TM) involving resection of 25 - 80 g prostate. They completed questionnaires regarding utility for residency training, realism and overall score of the TURPSim(TM). Performances of two groups were evaluated after 2-day training. RESULTS: were recorded and analyzed. RESULTS: Mean utility for residency training, realism and overall score were (8.8 +/- 1.1) and (8.5 +/- 1.4), (8.0 +/- 1.2) and (8.4 +/- 1.1), (8.7 +/- 0.9) and (8.6 +/- 0.8) in experts and novices respectively. There was no significant difference between two groups (P > 0.05). Spearman's correlation coefficients analysis showed an significant positive correlation between utility for residency training and realism (r = 0.625, P = 0.000), utility for residency training and overall score (r = 0.691, P = 0.000) in experts, utility for residency training and realism (r = 0.702, P = 0.000), utility for residency training and overall score (r = 0.664, P = 0.001) in novices. Prostate resection rate (87.3% +/- 7.7%), bleeding control rate (94.4% +/- 6.6%) and safety (95.2% +/- 5.5%) in novices increased after training (t = -3.689, -2.274, -2.507, all P < 0.05). CONCLUSIONS: The face and content validation of transurethral resection of the prostate simulator is good, virtual reality training of TURP may improve the skills necessary to perform TURP. Transurethral resection of the prostate simulator can be used to train urology residents. PMID- 22490358 TI - [The effect of cell killing by ABT-737 synergized with docetaxel in human prostate cancer PC-3 cells]. AB - OBJECTIVE: To investigate the synergistical killing effect of docetaxel combined with ABT-737 on human prostate cancer cell line PC-3 by inducing apoptosis and further to determine the mechanism underlying such effect. METHODS: PC-3 cells were treated with various concentrations of docetaxel or (and) ABT-737. Cell viability was determined using MTT assay. Apoptosis was assessed by fluorescence microscopy analysis of cells with condensed and segmented nuclei following staining with 4',6-diamidino-2-phenylindole (DAPI). Cellular DNA was stained with propidium iodide and flow cytometric analysis was performed to analyze the cell cycle distribution. Bcl-2, Bax, Bcl-xL and Mcl-1 protein changes were detected by Western blot. The activity of caspase-3 was measured using a colorimetric assay. RESULTS: Docetaxel (20 nmol/L) combination with ABT-737 (400 nmol/L) for 48 hours, the cell viability was decreased to 19.7% +/- 3.2% to compare with 44.2% +/- 4.4% (t = 4.45) of docetaxel and 93.2% +/- 1.8% of ABT-737 separately and there was a synergistic effect between the two drugs (CI = 0.8). Apoptosis rate of the combination group was higher than other two drugs. Docetaxel increased the cell number arrested in G(2)/M phase compared with control group (P < 0.05), but the combination treatment resulted in a significant arrest in the G(0)/G(1) phase. The combination treatment could significantly reduced the Bcl-2, Bcl-xL and Mcl-1 expression (F = 369.53, 57.89 and 32.77, all P < 0.05) and enhanced the activity of caspase-3 (419.7% +/- 15.6%) (F = 207.33, P < 0.05). CONCLUSIONS: The combination of ABT-737 with docetaxel can synergistically inhibit the proliferation of PC-3 cells through inducing apoptosis, which may be associated with cell cycle arrest, down-regulation of Bcl-2, Bcl-xL and Mcl-1 expression and activation of caspase-3. PMID- 22490359 TI - [Effect of expression of c-jun N-terminal kinase on neuron autophagy following diffuse brain injury in rats]. AB - OBJECTIVE: To study the effect and potential mechanism of expression of c-jun N terminal kinase (JNK) signal pathway on neuron autophagy after diffuse brain injury (DBI). METHODS: Male Sprague Dawley rats (n = 216) were randomly divided into four groups: DBI group (n = 54), SP600125 intervene group (n = 54), DMSO group (n = 54) and sham operation group (n = 54). DBI rat model was established according to the description of Marmarou DBI. At different time points (1, 6, 12, 24, 48 and 72 h) after operation, the histopathologic changes of neurons in cortex were observed by HE staining method; The expression of p-JNK, p-P53, DRAM and Beclin-1 were detected by Western blot and immunohistochemistry. RESULTS: The results showed that under light microscope degenerated and necrotic neurons were observed to be scattered in cortex at 6 h after operation in DBI group, but these changes were low in SP600125 intervene group. Compared with SP600125 intervene group, the expression of p-JNK in DBI group were enhanced obviously at 6, 12 and 24 h (F = 17.902, P < 0.05); the expression of p-P53 in DBI group were enhanced obviously at 12, 24, 48 and 72 h (F = 7.107, P < 0.05); the expression of DRAM in DBI group were enhanced obviously at 6, 12, 24, 48 and 72 h (F = 15.455, P < 0.05); the expression of Beclin-1 in DBI group were enhanced obviously at 6, 12, 24, 48 and 72 h (F = 11.517, P < 0.05). Compared with DBI group, the expression of p-JNK, p-P53, DRAM and Beclin-1 in DMSO group were similar at 1, 6, 12, 24, 48 and 72 h (F = 1.509, P > 0.05). CONCLUSIONS: The present results indicate that SP600125 can dramatically improve trauma brain injury from autophagy after DBI and the molecular mechanism is related to the modulation of JNK signal pathway following DBI, while it measures the neuron autophagy by means of intervening JNK signal pathway. PMID- 22490360 TI - [A analysis on the effect of with or without patellar replacement in total knee arthroplasty]. AB - OBJECTIVE: To evaluate the outcome of total knee arthroplasty with or without resurfacing of the patella with particular attention to knee score, knee function score and incidence of postoperative anterior knee pain, providing the basis for the choice of surgical procedure. METHODS: CNKI, PubMed, ScienceDirect, Highwire and other databases were searched for the randomized controlled trials relevant to the patellar with or without replacement in total knee replacement arthroplasty between 1998 and 2010, evaluating of the methodological quality of included studies and extracting valid data. RESULTS: The 80 citations were identified as related to patellar resurfacing during total knee arthroplasty, 13 articles meet all inclusion criteria for this study. The incidence of postoperative anterior knee pain is greater in knees without replaced patellas (RR = 0.78, 95%CI: 0.61 - 0.99, P = 0.04). No differences are observed between the 2 groups for knee score and knee function score. Knee score (WMD = -0.49, 95%CI: -1.79 - 0.81, P = 0.46), knee function score (WMD = 1.10, 95%CI: -1.77 - 3.98, P = 0.45). CONCLUSIONS: The patella replacement can significantly reduce the incidence of postoperative anterior knee pain. There is no difference in the knee score and knee function score between two groups. PMID- 22490361 TI - Phosphorylated AKT and MAPK expression in primary tumours and in corresponding metastases and clinical outcome in colorectal cancer patients receiving irinotecan-cetuximab. AB - BACKGROUND: Clinical observations suggested that a non negligible proportion of patients, ranging from 40% to 70%, does not seem to benefit from the use of anti EGFR targeted antibodies even in the absence of a mutation of the K- RAS gene. The EGFR pathway activation via the Ras-Raf-MAP-kinase and the protein serine/threonine kinase AKT could determine resistance to anti-EGFR treatment. METHODS: We tested the interaction between phosphorylated AKT and MAPK expression in colorectal tumours and corresponding metastases and global outcome in K-RAS wild type patients receiving irinotecan-cetuximab. RESULTS: Seventy-two patients with histologically proven metastatic colorectal cancer, treated with Irinotecan and Cetuximab based chemotherapy, were eligible for our analysis.In metastases pAKT correlated with RR (9% vs. 58%, p = 0.004), PFS (2.3 months vs. 9.2 months p < 0.0001) and OS (6.1 months vs. 26.7 months p < 0.0001) and pMAPK correlated with RR (10% vs. 47%, p = 0.002), PFS (2.3 months vs. 8.6 months p < 0.0001) and OS (7.8 months vs. 26 months p = 0.0004). At multivariate analysis pAKT and pMAPK in metastases were able to independently predict PFS. pAKT in metastases independently correlated with RR as well DISCUSSION: pAKT and pMAPK expression in metastases may modulate the activity of EGFR-targeted antibodies. We could speculate that in patients with pAKT and pMAPK metastases expression targeting these factors may be crucial. PMID- 22490362 TI - Inhibitory effects of hyperoxia and methemoglobinemia on H(2)S induced ventilatory stimulation in the rat. AB - The aim of this study was to clarify, using in vitro and in vivo approaches in the rat, the site of mediation of the inhibition of H(2)S induced arterial chemoreceptor stimulation, by hyperoxia and methemoglobinemia. We first determined the ventilatory dose-response curves during intravenous injections of H(2)S. A very high dose of NaHS, i.e. 0.4 MUmol (concentration: 800 MUM), was needed to stimulate breathing within 1s following i.v. injection. Above this level (and up to 2.4 MUmol, with a concentration of 4800 MUM), a dose-dependent effect of H(2)S injection was observed. NaHS injection into the thoracic aorta produced the same effect, suggesting that within one circulatory time, H(2)S pulmonary exchange does not dramatically reduce H(2)S concentrations in the arterial blood. The ventilatory response to H(2)S was abolished in the presence of MetHb (12.8%) and was significantly depressed in hyperoxia and, surprisingly, in 10% hypoxia. MetHb per se did not affect the ventilatory response to hypoxia or hyperoxia, but dramatically enhanced the oxidation of H(2)S in vitro, with very fast kinetics. These findings suggest that, the decrease/oxidation of exogenous H(2)S in the blood is the primary effect of MetHb in vivo. In contrast, the in vitro oxidative properties of blood for H(2)S were not affected by the level of [Formula: see text] between 23 and >760 mmHg. This suggests that the inhibition of the ventilatory response to H(2)S by hyperoxia during aortic or venous injection originates within the CB and not in the blood. The implications of these results on the role of endogenous H(2)S in the arterial chemoreflex are discussed. PMID- 22490363 TI - The impact of compaction, moisture content, particle size and type of bulking agent on initial physical properties of sludge-bulking agent mixtures before composting. AB - This study aimed to experimentally acquire evolution profiles between depth, bulk density, Free Air Space (FAS), air permeability and thermal conductivity in initial composting materials. The impact of two different moisture content, two particle size and two types of bulking agent on these four parameters was also evaluated. Bulk density and thermal conductivity both increased with depth while FAS and air permeability both decreased with it. Moreover, depth and moisture content had a significant impact on almost all the four physical parameters contrary to particle size and the type of bulking agent. PMID- 22490364 TI - Object recognition testing: methodological considerations on exploration and discrimination measures. AB - The object recognition task (ORT) is a popular one-trial learning test for animals. In the current study, we investigated several methodological issues concerning the task. Data was pooled from 28 ORT studies, containing 731 male Wistar rats. We investigated the relationship between 3 common absolute- and relative discrimination measures, as well as their relation to exploratory activity. In this context, the effects of pre-experimental habituation, object familiarity, trial duration, retention interval and the amnesic drugs MK-801 and scopolamine were investigated. Our analyses showed that the ORT is very sensitive, capable of detecting subtle differences in memory (discrimination) and exploratory performance. As a consequence, it is susceptible to potential biases due to (injection) stress and side effects of drugs. Our data indicated that a minimum amount of exploration is required in the sample and test trial for stable significant discrimination performance. However, there was no relationship between the level of exploration in the sample trial and discrimination performance. In addition, the level of exploration in the test trial was positively related to the absolute discrimination measure, whereas this was not the case for relative discrimination measures, which correct for exploratory differences, making them more resistant to exploration biases. Animals appeared to remember object information over multiple test sessions. Therefore, when animals have encountered both objects in prior test sessions, the object preference observed in the test trial of 1h retention intervals is probably due to a relative difference in familiarity between the objects in the test trial, rather than true novelty per se. Taken together, our findings suggest to take into consideration pre-experimental exposure (familiarization) to objects, habituation to treatment procedures, and the use of relative discrimination measures when using the ORT. PMID- 22490365 TI - Massive sublingual hematoma secondary to anticoagulant therapy complicated by a traumatic denture: a case report. AB - INTRODUCTION: Sublingual hematoma secondary to excessive anticoagulation is a rare but potentially fatal condition, and few cases have been documented in the literature. CASE PRESENTATION: We report the case of a 73-year-old Caucasian woman who attended our Accident and Emergency department with massive sublingual hematoma causing superior displacement of the tongue. The condition was found to be the result of an elevated international normalized ratio, further complicated by a traumatic mandibular denture. CONCLUSIONS: In summary, we recommend the immediate reversal of anticoagulation therapy on admission of patients with severe sublingual hematoma. We further advise surgical decompression/drainage if required and to continue meticulous monitoring. In all cases of early recognition of sublingual hematoma, prompt medical treatment and continuous clinical monitoring is essential, and may prevent the need for a surgical airway procedure. PMID- 22490366 TI - Combining statistical potentials with dynamics-based entropies improves selection from protein decoys and docking poses. AB - Protein structure prediction and protein-protein docking are important and widely used tools, but methods to confidently evaluate the quality of a predicted structure or binding pose have had limited success. Typically, either knowledge based or physics-based energy functions are employed to evaluate a set of predicted structures (termed "decoys" in structure prediction and "poses" in docking), with the lowest energy structure being assumed to be the one closest to the native state. While successful for many cases, failures are still common. Thus, improvements to structure evaluation methods are essential for future improvements. In this work, we combine multibody statistical potentials with dynamics models, evaluating fluctuation-based entropies that include contributions from the entire structure. This leads to enhanced selection of native-like structures for CASP9 decoys, refined ClusPro docking poses, as well as large sets of docking poses from the Benchmark 3.0 and Dockground data sets. The data used include both bound and unbound docking, and positive results are found for each type. Not only does this method yield improved average results, but for high quality docking poses, we often pick the best pose. PMID- 22490367 TI - Consumers' experiences and values in conventional and alternative medicine paradigms: a problem detection study (PDS). AB - BACKGROUND: This study explored consumer perceptions of complementary and alternative medicine (CAM) and relationships with CAM and conventional medicine practitioners.A problem detection study (PDS) was used. The qualitative component to develop the questionnaire used a CAM consumer focus group to explore conventional and CAM paradigms in healthcare. 32 key issues, seven main themes, informed the questionnaire (the quantitative PDS component - 36 statements explored using five-point Likert scales.) RESULTS: Of 300 questionnaires distributed (Brisbane, Australia), 83 consumers responded. Results indicated that consumers felt empowered by using CAM and they reported positive relationships with CAM practitioners. The perception was that CAM were used most effectively as long-term therapy (63% agreement), but that conventional medicines would be the best choice for emergency treatment (81% agreement). A majority (65%) reported that doctors appeared uncomfortable about consumers' visits to CAM practitioners. Most consumers (72%) believed that relationships with and between health practitioners could be enhanced by improved communication. It was agreed that information sharing between consumers and healthcare practitioners is important, and reported that "enough" information is shared between CAM practitioners and consumers. Consumers felt comfortable discussing their medicines with pharmacists, general practitioners and CAM practitioners, but felt most comfortable with their CAM practitioners. CONCLUSIONS: This PDS has emphasized the perceived importance of open communication between consumers, CAM and conventional providers, and has exposed areas where CAM consumers perceive that issues exist across the CAM and conventional medicine paradigms. There is a lot of information which is perceived as not being shared at present and there are issues of discomfort and distrust which require resolution to develop concordant relationships in healthcare. Further research should be based on optimisation of information sharing, spanning both conventional and CAM fields of healthcare, due to both the relevance of concordance principles within CAM modalities and the widespread use of CAM by consumers. PMID- 22490368 TI - Elevated production of radical oxygen species by polymorphonuclear neutrophils in cerebrospinal fluid infection. AB - BACKGROUND: Central nervous system infection is a daily concern in neurointensive care; however, diagnosis remains difficult because classical criteria based on cerebrospinal fluid (CSF) analysis are difficult to interpret in post-trauma or neurosurgery patients after recent bleeding. A rapid, specific, sensitive test to diagnose CSF infection would help streamline therapeutic decisions in clinical practice and limit the risk of multiresistant bacteria. We hypothesized that polymorphonuclear neutrophil (PMN) phenotype and radical oxygen species (ROS) production in CSF may be specific to the presence of infection. METHODS: This study included 30 patients with suspected CSF infection with ventricular hemorrhage requiring external ventricular drainage, and 13 patients after trauma or surgery. Criteria for evaluating CSF infection included positive culture and > 100 leukocytes/mm3. Analysis of PMN phenotype was performed using flow cytometry (CD16, CD11b, and CD62L). ROS production was analyzed through luminometry (luminol). RESULTS: Infected CSF exhibited higher production of ROS compared with noninfected CSF. PMNs in CSF exhibited low CD16 and high annexin V expression, suggesting apoptosis. CONCLUSIONS: Measurement of ROS production may discriminate infected from noninfected CSF. This simple test would be easy to employ in clinical practice to improve CSF infection management. PMID- 22490369 TI - Surgical ablation for atrial fibrillation. AB - This paper reviews the history of surgical procedures developed for eradication of atrial fibrillation (AF) during cardiac surgery for structural heart disease, and in patients with AF without other indication for cardiac surgery. Current evidence indicates that, despite their proven efficacy, the Cox-Maze procedure and its modifications require cardiopulmonary bypass and cannot be easily justified in the case of AF without other indication for cardiac surgery. In patients undergoing cardiac surgery for mitral valve disease, concomitant ablation techniques using modifications of the Maze and alternative energy sources appear to be safe and effective in treating AF, especially in non rheumatic disease. Minimally invasive epicardial ablation has been recently developed and can be performed on a beating heart through small access incision ports. Various techniques combining pulmonary vein isolation, ganglionated plexi ablation, and left atrial lines have been tried. Initial results are promising but further clinical experience is required to establish ideal lesion sets, appropriate energy sources, and the benefit-risk ratio of such an approach in patients without other indication for cardiac surgery. The role of surgical ablation in the current management of AF is under investigation. PMID- 22490370 TI - Managing fatigue in the syncope unit. AB - The symptom of fatigue is frequently described by patients attending the syncope unit with a wide range of conditions including vasovagal syncope and postural orthostatic tachycardia syndrome. It is possible that the presence of autonomic dysfunction provides the common pathogenetic mechanism linking neurally mediated hypotension and fatigue. Managing this debilitating symptom can often be challenging but, with a structured approach, immensely rewarding, and as a result improve how patients cope with their disease. PMID- 22490371 TI - Prevalence of atrial fibrillation in the general population and in high-risk groups: the ECHOES study. AB - AIMS: To establish the prevalence of atrial fibrillation (AF) in the general population in the UK, and in those with risk factors. METHODS AND RESULTS: The prevalence of AF on electrocardiography was established in prospectively selected groups: 3960 randomly selected from the population, aged 45+; 782 with a previous diagnosis of heart failure; and 1062 with a record of myocardial infarction, hypertension, angina, or diabetes. Patients were also assessed clinically and with echocardiography. Mortality was tracked for 8 years. Atrial fibrillation was found in 78 of the random population sample (2.0%). Prevalence was 1.6% in women and 2.4% in men, rising with age from 0.2% in those aged 45-54 to 8.0% in those aged 75 and older. Half of all cases were in patients aged 75 and older. Only 23 of the 78 (29.5%) of those in AF took warfarin. Of the 782 patients, 175 (22.4%) with a diagnosis of heart failure were in AF, with normal left ventricular function in 95 (54.3%) of these. Atrial fibrillation was found in 14 of the 244 (5.7%) of those with a history of myocardial infarction, 15 of the 388 (3.9%) of those with hypertension, 15 of the 321 (4.7%) of those with angina, and 11 of the 208 (5.3%) of diabetics. Adjusting for age and sex, mortality was 1.57 times higher for those in AF. CONCLUSION: Atrial fibrillation is common in the elderly and those with clinical risk factors. Screening these groups would identify many with AF. Use of anticoagulation was low at the time of the initial assessments in the late 1990s; practice may have changed recently. PMID- 22490372 TI - Comparison of quick optimization of interventricular delay between simple methods: intracardiac electrogram and surface electrocardiogram after cardiac resynchronization therapy. AB - AIMS: It is time consuming to obtain optimal interventricular (VV) delay by conventional methods. This study is designed to compare quick optimization between intracardiac electrogram (IEGM) with surface electrocardiogram (ECG) guided VV delay optimization for cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Fifty-one heart failure patients (M/F = 34/17, age = 71 +/- 10-year old) scheduled for CRT implantation were included. After atrioventricular optimization, VV delay optimization was performed by either the IEGM or surface ECG method. Aortic velocity time integral (AVTI) was used as a reference in comparing these two methods. Real-time three-dimensional echocardiography was studied under three varying parameters-CRT switched off or CRT switched on, and VV delay optimized by IEGM guided or surface ECG. The AVTI could be improved equally by either IEGM-guided or surface ECG-guided VV optimization. All the other parameters [QRS width, systolic dyssynchrony index (SDI), left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV)] could be improved by either the IEGM or ECG method in these patients. In the multivariate logistic regression analysis, the immediate improvement of acute LVEF was independently related to favourable outcomes (odds ratio 1.23, 95% CI = 1.03-1.47, P = 0.02). CONCLUSIONS: The AVTI, QRS width, SDI, LVEF, LVEDV, and LVESV could be improved equally by either IEGM guided or surface ECG-guided method after CRT. PMID- 22490373 TI - Ventricular fibrillation hampers the restoration of creatine-phosphate levels during simulated cardiopulmonary resuscitations. AB - AIMS: Recurrences of ventricular fibrillation (VF) during cardiopulmonary resuscitation (CPR) are associated with a reduced chance of survival. The effect of VF during CPR on the myocardium is unknown. We tested the hypothesis that VF during simulated CPR reduces the restoration of the myocardial energy state and contractile function. METHODS AND RESULTS: Twelve porcine hearts were isolated and perfused with the pig's own blood. First, cardiac oxygen consumption was measured by blood gas analysis. Secondly, we simulated sudden cardiac arrest by VF (7 min VF, zero flow) followed by simulated CPR (7 min, 0.3 mL/g/min perfusion rate) in the absence and presence of VF [six hearts were maintained in VF (VF group), six were defibrillated (defib-group)]. The VF increased the cardiac oxygen consumption by 71% (0.87 +/- 0.12 vs. 1.49 +/- 0.14 MUmol O2/g/min; mean +/- SEM, P< 0.001) compared with a ventricular rhythm of 62 beats/min. The presence of VF during simulated CPR after 7 min of cardiac arrest hampered restoration of myocardial creatine-phosphate levels compared with defibrillated hearts (61 +/- 9 vs. 87 +/- 7% of baseline values, respectively; P< 0.05). The cardiac contractile function was significantly higher in the defib- than in the VF-group (area under the pressure curve 2.29 +/- 0.22 vs. 1.72 +/- 0.14 s*mm Hg respectively; P< 0.05). CONCLUSIONS: These data demonstrate that the cardiac oxygen consumption is increased by VF and that the presence of VF during CPR hampers the restoration of the myocardial energy state and contractility. Strategies that reduce VF duration without disrupting chest compressions will benefit the restoration of the cardiac energy state during resuscitations. PMID- 22490374 TI - Small left atrium and mild mitral regurgitation predict super-response to cardiac resynchronization therapy. AB - AIMS: Cardiac resynchronization therapy (CRT) can result in profound reverse remodelling. The goal of this study was to identify factors predictive of such beneficial response. METHODS AND RESULTS: Super-response to CRT was defined as normalization or near normalization of left ventricular systolic function without recognized reversible causes of heart failure. In a retrospective study, we compared baseline demographic, electrocardiogram, and echocardiographic characteristics of super-responders (n = 21) with a population of unselected consecutive cardiac CRT patients (Control 1, n = 330) and another sex-, age-, and aetiology-matched control group (Control 2, n = 43). Compared with Control 1, super-responders had significantly smaller left ventricular end-diastolic diameter (65.4 +/- 6.4 vs. 73.4 +/- 9.3 mm, P = 0.0001), higher ejection fraction (0.25 +/- 0.05 vs. 0.22 +/- 0.04, P = 0.004), smaller degree of mitral regurgitation (MR; mean value 1.9 +/- 0.9 vs. 2.6 +/- 0.8, P = <0.0001), and smaller left atrium (LA; 42.8 +/- 4.6 vs. 50.0 +/- 6.5 mm, P < 0.0001). Septal flash and inter-ventricular mechanical dyssynchrony were both more frequent among super-responders than in Control 2 subjects (93.8 vs. 69.8%; P = 0.01, and 93.8 vs. 62.8%; P = 0.01, respectively). In a multivariate analysis, smaller LA diameter and milder MR remained independent predictors of super-response. CONCLUSION: Super-response to cardiac CRT was associated with less advanced left sided structural involvement as described by echocardiography. In particular, smaller LA and milder MR were independent predictors of pronounced reverse remodelling. PMID- 22490375 TI - Ventricular oversensing of an implantable cardioverter-defibrillator during electroconvulsive therapy. PMID- 22490376 TI - Are apolipoprotein E alleles correlated with semen quality? AB - Apolipoproteins have a unique role in lipoprotein metabolism regulation, aiding lipid transport and acting as a cofactor of the enzymes involved in metabolism. There are three co-dominant alleles, APOE*2, APOE*3 and APOE*4, which encode three protein isoforms, apoE2, apoE3 and apoE4. APOE*3 is the most frequent in all populations thus far investigated, ranging from 50 to 90%. Some studies have tried to resolve a genetic 'dilemma' by evaluating the cause of the frequency and survival of the three alleles. Genetic drift, migration or natural selection could explain the current distribution of APOE gene frequencies worldwide. If APOE*4 is the ancestral allele, APOE*3 must have offered a considerable selective advantage, perhaps consisting of a positive effect during the reproductive period. Given this, there is a need to understand if APOE gene polymorphism might affect reproductive capacity. Few studies have been conducted in this area, and they generally correlate APOE polymorphism with reproductive efficiency in terms of number of children. The aim of our study was to look for correlations between APOE polymorphism in humans and semen quality, to establish if APOE genotypes have any demonstrable effect on spermatogenesis. In conclusion, our data show that APOE polymorphism is not associated with semen quality, as it is present to a similar extent in both normal and impaired or absent spermatogenesis. This demonstrates once again that the use of number of children as an index of fertility is not indicative of real male reproductive capacity. PMID- 22490377 TI - Reversal of EDTA Interference in the Measurement of Visinin-Like Protein 1. PMID- 22490378 TI - The beta2-adrenoceptor agonist formoterol stimulates mitochondrial biogenesis. AB - Mitochondrial dysfunction is a common mediator of disease and organ injury. Although recent studies show that inducing mitochondrial biogenesis (MB) stimulates cell repair and regeneration, only a limited number of chemicals are known to induce MB. To examine the impact of the beta-adrenoceptor (beta-AR) signaling pathway on MB, primary renal proximal tubule cells (RPTC) and adult feline cardiomyocytes were exposed for 24 h to multiple beta-AR agonists: isoproterenol (nonselective beta-AR agonist), (+/-)-(R*,R*)-[4-[2-[[2-(3 chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL 37344) (selective beta(3)-AR agonist), and formoterol (selective beta(2)-AR agonist). The Seahorse Biosciences (North Billerica, MA) extracellular flux analyzer was used to quantify carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled oxygen consumption rate (OCR), a marker of maximal electron transport chain activity. Isoproterenol and BRL 37244 did not alter mitochondrial respiration at any of the concentrations examined. Formoterol exposure resulted in increases in both FCCP-uncoupled OCR and mitochondrial DNA (mtDNA) copy number. The effect of formoterol on OCR in RPTC was inhibited by the beta-AR antagonist propranolol and the beta(2)-AR inverse agonist 3-(isopropylamino)-1 [(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride (ICI-118,551). Mice exposed to formoterol for 24 or 72 h exhibited increases in kidney and heart mtDNA copy number, peroxisome proliferator-activated receptor gamma coactivator 1alpha, and multiple genes involved in the mitochondrial electron transport chain (F0 subunit 6 of transmembrane F-type ATP synthase, NADH dehydrogenase subunit 1, NADH dehydrogenase subunit 6, and NADH dehydrogenase [ubiquinone] 1beta subcomplex subunit 8). Cheminformatic modeling, virtual chemical library screening, and experimental validation identified nisoxetine from the Sigma Library of Pharmacologically Active Compounds and two compounds from the ChemBridge DIVERSet that increased mitochondrial respiratory capacity. These data provide compelling evidence for the use and development of beta(2)-AR ligands for therapeutic MB. PMID- 22490379 TI - Combining doublecortin-like kinase silencing and vinca alkaloids results in a synergistic apoptotic effect in neuroblastoma cells. AB - Microtubule-destabilizing agents, such as vinca alkaloids (VAs), are part of the treatment currently applied in patients with high-risk neuroblastoma (NB). However, the development of drug resistance and toxicity make NB difficult to treat with these drugs. In this study we explore the combination of VAs (vincristine or vinblastine) with knockdown of the microtubule-associated proteins encoded by the doublecortin-like kinase (DCLK) gene by using short interference RNA (siRNA). We examined the effect of VAs and DCLK knockdown on the microtubule network by immunohistochemistry. We performed dose-response studies on cell viability and proliferation. By combining VA with DCLK knockdown we observed a strong reduction in the EC(50) to induce cell death: up to 7.3-fold reduction of vincristine and 21.1-fold reduction of vinblastine. Using time-lapse imaging of phosphatidylserine translocation and a terminal deoxynucleotidyl transferase dUTP nick-end labeling-based assay, we found a significant increase of apoptosis by the combined treatment. Induction of caspase-3 activity, as detected via cleavage of N-acetyl-Asp-Glu-Val-Asp-7-amido-4-methylcoumarin, showed a 3.3- to 12.0-fold increase in the combined treatment. We detected significant increases in caspase-8 activity as well. Moreover, the multidrug dose effect calculated by using the median effect method showed a strong synergistic inhibition of proliferation and induction of apoptosis at most of the combined concentrations of siRNAs and VAs. Together, our data demonstrate that the silencing of DCLK sensitizes NB cells to VAs, resulting in a synergetic apoptotic effect. PMID- 22490380 TI - Pharmacology of JNJ-37822681, a specific and fast-dissociating D2 antagonist for the treatment of schizophrenia. AB - All marketed antipsychotics act by blocking dopamine D(2) receptors. Fast dissociation from D(2) receptors may be one of the elements contributing to the lower incidence of extrapyramidal symptoms (EPS) exhibited by newer antipsychotics. Therefore, we screened for specific D(2) receptor blockers with a fast rate of dissociation. Radioligand binding experiments identified N-[1-(3,4 difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (JNJ 37822681) as a fast-dissociating D(2) ligand. Its D(2) receptor specificity was high compared with atypical antipsychotics, with little activity at receptors associated with unwanted effects [alpha(1), alpha(2), H(1), muscarinic, and 5 hydroxytryptamine (5-HT) type 2C] and for receptors that may interfere with the effects of D(2) antagonism (D(1), D(3), and 5-HT(2A)). JNJ-37822681 occupied D(2) receptors in rat brain at relatively low doses (ED(50) 0.39 mg/kg) and was effective in animal models of psychosis (e.g., inhibition of apomorphine-induced stereotypy or D-amphetamine/phencyclidine-induced hyperlocomotion). Prolactin levels increased from an ED(50) (0.17 mg/kg, peripheral D(2) receptors) close to the ED(50) required for apomorphine antagonism (0.19 mg/kg, central D(2) receptors), suggesting excellent brain disposition and minimal prolactin release at therapeutic doses. JNJ-37822681 induced catalepsy and inhibited avoidance behavior, but with a specificity margin relative to apomorphine antagonism that was larger than that obtained for haloperidol and similar to that obtained for olanzapine. This larger specificity margin (compared with haloperidol) may reflect lower EPS liability and less behavioral suppression after JNJ-37822681. JNJ-37822681 is a novel, potent, specific, centrally active, fast-dissociating D(2) antagonist with optimal brain disposition, and it is the first compound that allows the evaluation of the potential value of fast D(2) antagonism for the treatment of schizophrenia and bipolar disorder. PMID- 22490381 TI - Ongoing outbreak of Shigella flexneri serotype 3a in men who have sex with men in England and Wales, data from 2009-2011. AB - Diagnoses of Shigella flexneri in the United Kingdom (UK) are usually travel related. However, since 2009, there has been an overall increase in UK-acquired cases. The Health Protection Agency has been investigating a national outbreak of S. flexneri detected in 2011 and which is still ongoing. Cases occurred mostly in men who have sex with men and were of serotype 3a. The investigation aimed at obtaining epidemiological data to inform targeted outbreak management and control. PMID- 22490382 TI - Severe leptospirosis in a Dutch traveller returning from the Dominican Republic, October 2011. AB - In October 2011, a case of leptospirosis was identified in a Dutch traveller returning from the Dominican Republic to the Netherlands. The 51-year-old man had aspired muddy water in the Chavon river on 29 September. Twenty days later he presented with fever, nausea, vomiting, diarrhoea, arthralgia, headache, conjunctival suffusion and icterus. Leptospira serovar Icterohaemorrhagiae or Australis infection was confirmed ten days later by laboratory testing. PMID- 22490383 TI - Risk perception and information-seeking behaviour during the 2009/10 influenza A(H1N1)pdm09 pandemic in Germany. AB - During the influenza A(H1N1)pdm09 pandemic in 2009/10, a total of 13 consecutive surveys were carried out of the general population in Germany to monitor knowledge, attitude and behaviour concerning the disease and vaccination against pandemic influenza in real time. In total, 13,010 persons aged 14 years or older were interviewed by computer-assisted telephone techniques between November 2009 and April 2010. During the peak of the pandemic, only 18% of participants stated that they perceived the risk of pandemic influenza as high; this proportion fell to 10% in January 2010. There was a significant difference in information-seeking behaviour among population subgroups concerning the disease and vaccine uptake. However, in all subgroups, conventional media sources such as television, radio and newspapers were more frequently used than the Internet. While the majority of participants (78%) felt sufficiently informed to make a decision for or against vaccination, overall vaccination coverage remained low. Among those who decided against vaccination, fear of adverse events and perception that the available vaccines were not sufficiently evaluated were the most frequently stated reasons. Such mistrust in the vaccines and the perceived low risk of the disease were the main barriers that contributed to the low vaccination coverage in Germany during the pandemic. PMID- 22490384 TI - An outbreak of severe respiratory tract infection caused by human metapneumovirus in a residential care facility for elderly in Utrecht, the Netherlands, January to March 2010. AB - Recognition of infections with human metapneumovirus (HMPV) among institutionalised elderly is rising. When HMPV was found to be the causative agent of an outbreak of pneumonia in a residential care facility for elderly in the Netherlands, an elaborate outbreak investigation was set up, including active surveillance for new cases. From clinical cases, defined by fever (> 38 degrees C) and symptoms of respiratory tract infections, respiratory samples for analyses of viral pathogens by real-time Reverse Transcriptase Polymerase Chain Reaction (rRT-PCR) and blood samples for determination of HMPV-specific IgM and IgG antibody titres were taken. Five staff members and 18 residents fulfilled the clinical case definition. Of those, five residents tested positive for HMPV by rRT-PCR. The combination of rRTPCR and serology identified nine confirmed cases, six probable cases, six possible cases and ruled out two persons as cases. Among residents, the outbreak of HMPV had an attack rate, ranging from 5% for laboratory- confirmed cases, to 13% for clinical cases. This outbreak investigation shows that HMPV is a potential serious pathogen for institutionalised elderly. PMID- 22490388 TI - A reinvestigation of somatic hypermethylation at the PTEN CpG island in cancer cell lines. AB - BACKGROUND: PTEN is an important tumour suppressor gene that is mutated in Cowden syndrome as well as various sporadic cancers. CpG island hypermethylation is another route to tumour suppressor gene inactivation, however, the literature regarding PTEN hypermethylation in cancer is controversial. Furthermore, investigation of the methylation status of the PTEN CpG island is challenging due to sequence homology with the PTEN pseudogene, PTENP1. PTEN shares a CpG island promoter with another gene known as KLLN. Here we present a thorough reinvestigation of the methylation status of the PTEN CpG island in DNA from colorectal, breast, ovarian, glioma, lung and haematological cancer cell lines. RESULTS: Using a range of bisulphite-based PCR assays we investigated 6 regions across the PTEN CpG island. We found that regions 1-4 were not methylated in cancer cell lines (0/36). By allelic bisulphite sequencing and pyrosequencing methylation was detected in regions 5 and 6 in colorectal, breast and haematological cancer cell lines. However, methylation detected in this region was associated with the PTENP1 promoter and not the PTEN CpG island. CONCLUSIONS: We show that methylation of the PTEN CpG island is a rare event in cancer cell lines and that apparent methylation most likely originates from homologous regions of the PTENP1 pseudogene promoter. Future studies should utilize assays that reliably discriminate between PTEN and PTENP1 to avoid data misinterpretation. PMID- 22490389 TI - Clinical software development for the Web: lessons learned from the BOADICEA project. AB - BACKGROUND: In the past 20 years, society has witnessed the following landmark scientific advances: (i) the sequencing of the human genome, (ii) the distribution of software by the open source movement, and (iii) the invention of the World Wide Web. Together, these advances have provided a new impetus for clinical software development: developers now translate the products of human genomic research into clinical software tools; they use open-source programs to build them; and they use the Web to deliver them. Whilst this open-source component-based approach has undoubtedly made clinical software development easier, clinical software projects are still hampered by problems that traditionally accompany the software process. This study describes the development of the BOADICEA Web Application, a computer program used by clinical geneticists to assess risks to patients with a family history of breast and ovarian cancer. The key challenge of the BOADICEA Web Application project was to deliver a program that was safe, secure and easy for healthcare professionals to use. We focus on the software process, problems faced, and lessons learned. Our key objectives are: (i) to highlight key clinical software development issues; (ii) to demonstrate how software engineering tools and techniques can facilitate clinical software development for the benefit of individuals who lack software engineering expertise; and (iii) to provide a clinical software development case report that can be used as a basis for discussion at the start of future projects. RESULTS: We developed the BOADICEA Web Application using an evolutionary software process. Our approach to Web implementation was conservative and we used conventional software engineering tools and techniques. The principal software development activities were: requirements, design, implementation, testing, documentation and maintenance. The BOADICEA Web Application has now been widely adopted by clinical geneticists and researchers. BOADICEA Web Application version 1 was released for general use in November 2007. By May 2010, we had > 1200 registered users based in the UK, USA, Canada, South America, Europe, Africa, Middle East, SE Asia, Australia and New Zealand. CONCLUSIONS: We found that an evolutionary software process was effective when we developed the BOADICEA Web Application. The key clinical software development issues identified during the BOADICEA Web Application project were: software reliability, Web security, clinical data protection and user feedback. PMID- 22490390 TI - Vancomycin-induced Henoch-Schonlein purpura: a case report. AB - INTRODUCTION: Henoch-Schonlein purpura is a small-vessel systemic vasculitis. Although its exact pathophysiology remains unknown, Henoch-Schonlein purpura has been reported in association with various medical conditions including hypersensitivity. We report the case of a patient with vancomycin-induced Henoch Schonlein purpura. CASE PRESENTATION: A 42-year-old Caucasian man who had previously undergone a heart transplant was diagnosed as having an intra abdominal abscess after he underwent a Hartmann procedure. At 15 days after initiation of antibiotic therapy including vancomycin, he developed a purpuric rash of the lower limbs, arthralgia, and macroscopic hematuria. At that time, our patient was already on hemodialysis for end-stage renal disease. Henoch-Schonlein purpura was diagnosed. After a second 15-day course of vancomycin, a second flare of Henoch-Schonlein purpura occurred. Skin biopsies showed leucocytoclastic vasculitis with IgA deposits and eosinophils in the peri-capillary inflammatory infiltrate, suggesting an allergic mechanism. After vancomycin was stopped, we did not observe any further flares. Only five cases of isolated cutaneous vasculitis, one case of lupus-like syndrome and one case of Henoch-Schonlein purpura after vancomycin treatment have been described to date in the literature. CONCLUSIONS: Clinicians should be aware that systemic vasculitis can be induced by some treatments. Vancomycin is a widely prescribed antibiotic. Occurrence of rare but serious Henoch-Schonlein purpura associated with vancomycin requires its prompt discontinuation. PMID- 22490391 TI - Comparison of two leukocyte reduction filters for whole blood derived platelets. AB - BACKGROUND: Leukocyte reduction filters are widely used for platelet transfusion therapy, and effective leukocyte removal is mandatory for transfusion safety. We evaluated both the performance of leukocyte reduction filters for platelets and the effect of filtration on platelet function. METHODS: A total of 100 pooled products (eight platelet concentrates were randomly pooled for each product) were used in this study: 50 were filtered by BioP-plus (Fresenius Kabi AG, Homburg, Germany) and 50 by PXL-8 (Pall Corporation, East Hills, NY, USA). Leukocyte reduction, platelet recovery, and filtration time were evaluated in each leukocyte reduction filter. Platelet aggregation responses to thrombin receptor activation peptide stimulation were compared in pre- and post-filtration products using impedance aggregometry (Multiplate Analyzer, Dynabyte Medical, Munich, Germany). RESULTS: Leukocyte counts were uniformly less than 8.3*10(5) in all the post-filtration products, except one filtered by the PXL-8. Leukocyte reduction was 99.1% for BioP-plus and 99.7% for PXL-8, and platelet recovery was 84.2% for the BioP-plus and 86.7% for PXL-8. Filtration time of the BioP-plus was significantly shorter than that of PXL-8. Post-filtration platelet aggregation tended to decrease in both filters, showing no difference between them. CONCLUSIONS: Both BioP-plus and PXL-8 leukocyte reduction filters for platelets performed well with effective leukocyte reduction and satisfactory platelet recovery. Although platelet function was decreased after filtration procedures, its clinical relevance is uncertain. PMID- 22490393 TI - Pregnancy outcomes and risk factors for low birth weight and preterm delivery among HIV-infected pregnant women in Guangxi, China. AB - BACKGROUND: Six provinces in China accounted for 70% - 80% of all reported HIV/AIDS cases in the country in 2009 and five provinces accounted for 78% of all reported mother-to-child transmission (MTCT) of HIV cases. Because Guangxi belonged to both groups, the Prevention of Mother-to-Child Transmission (PMTCT) Plus program was established there to understand better low birth weight (LBW) and preterm delivery (PD) birth outcomes and their associated risk factors better. METHODS: Pregnancy outcomes were examined among HIV-infected pregnant women who enrolled in the PMTCT Plus program from June 2006 to February 2009 in Guangxi, China. Multivariate Logistic regression analysis was used to explore the risk factors associated with LBW (< 2500 g) and PD (gestational age < 37 weeks). RESULTS: The prevalence of LBW and PD among 194 HIV-positive mothers was 19.6% (38/194) and 9.8% (19/194), respectively. Multivariate Logistic regression analysis showed that CD4 cell count < 100 cell/ul (multivariate-adjusted odds ratio (AOR) 5.52; 95%CI 1.11 - 25.55) and CD4 cell count 100 - 199 cells/ul (AOR 3.40; 95%CI 1.03 - 11.25, compared to CD4 cell count >= 350 cells/ul), gestational age < 37 weeks (AOR 4.38; 95%CI 1.29 - 14.82, compared to >= 37 weeks), maternal weight < 45 kg (AOR 5.64; 95%CI 1.09 - 29.07) and maternal weight 45 - 54 kg (AOR 3.55; 95%CI 1.31 - 9.60, compared to >= 55 kg) at enrollment, and HIV RNA >= 100 000 copies/ml at enrollment (AOR 4.22; 95%CI 1.24 14.32) and 20 000 - 99 999 (AOR 2.77; 95%CI 1.01 - 7.77, compared to < 20 000 copies/ml) were associated with a higher risk of LBW. For PD, only maternal injection drug use as the route of HIV transmission (AOR 5.30; 95%CI 1.33 - 21.14, compared to those infected with HIV through sexual transmission) was significantly associated with a higher risk of PD. CONCLUSIONS: Lower CD4 cell count and higher HIV RNA viral load at enrollment were associated with LBW. Optimal antenatal care, including earlier antenatal screening and HIV diagnosis, is critical to earlier PMTCT prophylaxis and/or HIV treatment to prevent transmission of HIV to the infant and also to prevent LBW pregnancy outcomes. PMID- 22490392 TI - Induction of superficial zone protein (SZP)/lubricin/PRG 4 in muscle-derived mesenchymal stem/progenitor cells by transforming growth factor-beta1 and bone morphogenetic protein-7. AB - INTRODUCTION: Articular cartilage (AC) is an avascular tissue with precise polarity and organization. The three distinct zones are: surface, middle and deep. The production and accumulation of the superficial zone protein (SZP), also known as lubricin, by the surface zone is a characteristic feature of AC. To date, there is a wealth of evidence showing differentiation of AC from mesenchymal stem cells. Most studies that described chondrogenic differentiation did not focus on AC with characteristic surface marker SZP/lubricin. The present investigation was initiated to determine the induction of SZP/lubricin in skeletal muscle-derived mesenchymal stem/progenitor cells (MDMSCs) by transforming growth factor-beta1 (TGF-beta1) and bone morphogenetic protein-7 (BMP-7). METHODS: MDMSCs were cultured as a monolayer at a density of 1 * 105 cells/well in 12-well tissue culture plates. Cell cultures were treated for 3, 7 and 10 days with TGF-beta1 and BMP-7. The medium was analyzed for SZP. The cells were used to isolate RNA for RT-PCR assays for SZP expression. RESULTS: The SZP/lubricin increased in a time-dependent manner on Days 3, 7 and 10 in the medium. As early as Day 3, there was a three-fold increase in response to 3 ng/ml of TGF-beta1 and 300 ng/ml of BMP-7. This was confirmed by immunochemical localization of SZP as early as Day 3 after treatment with TGF-beta1. The expression of SZP mRNA was enhanced by TGF-beta1. CONCLUSIONS: The present investigation demonstrated the efficient and reproducible induction of SZP/lubricin accumulation by TGF-beta1 and BMP-7 in skeletal MDMSCs. Optimization of the experimental conditions may permit the utility of MDMSCs in generating surface zone-like cells with phenotypic markers of AC and, therefore, constitute a promising cell source for tissue engineering approaches of superficial zone cartilage. PMID- 22490394 TI - Evaluation of whether serum tumor markers in patients with epithelial ovarian carcinoma change following chemotherapy. AB - BACKGROUND: Phenotypic and genotypic heterogeneity is a known feature of many cancers. Whether serum tumor marker kinds vary and change following chemotherapy is still unclear. The aim of this study was to investigate whether there is a change in the expression of serum tumor markers following chemotherapy, and the potential clinical significance in patients with epithelial ovarian carcinoma (EOC) or primary serous peritoneal carcinoma (PSPC). METHODS: Samples were collected before surgery, during chemotherapy and during follow-up for enzyme linked immunosorbent assay (ELISA)-based evaluation of serum CA-125, CA19-9 and CP2 levels in patients with EOC or PSPC who had received primary debulking surgery followed by adjuvant chemotherapy. In total, 72 patients were examined, including 37 patients with recurrent lesions and 35 patients receiving first-line chemotherapy. RESULTS: In 35 de novo patients, 20% (7/35) demonstrated a significant changed serum tumor marker kinds among whom the patients with mucinous carcinoma (57.1%, 4/7) showed resistance to chemotherapy. In the 37 recurrent patients, 51.4% (19/37) had changed serum tumor markers, of whom 57.9% (11/19) presented with serous carcinoma. There was no significant difference in median progression-free survival or overall survival in patients with drug sensitive or drug-resistant recurrence in patients with changed tumor marker kinds relative to those with unchanged markers. However, for patients with changed serum tumor markers there was a trend towards prolonged survival compared with the unchanged serum tumor marker group. In the 17 patients with secondary recurrence, 37.5% (6/17) had changed tumor marker levels. The ratios of CA 125/CP2 and CA-125/CA19-9 were significantly different after either chemotherapy or recurrence. CONCLUSIONS: Serum tumor marker expression in patients with EOC or PSPC may change after chemotherapy or recurrence, indicating that in addition to the markers that are abnormal before surgery, those markers that are normal should also be monitored during chemotherapy and follow-up. PMID- 22490395 TI - Role of transvaginal contrast-enhanced ultrasound in the early diagnosis of endometrial carcinoma. AB - BACKGROUND: Endometrial carcinoma is one of the most common gynecological malignancies among women. Early diagnosis and correct preoperative evaluation of myometrial invasion are necessary to improve the prognosis. This study aimed to determine whether features and time-intensity curves (TIC) of transvaginal contrast-enhanced ultrasound (CEUS) differ from those of conventional ultrasound for endometrial carcinoma, and to further explore the clinical role of transvaginal CEUS in the early diagnosis of endometrial carcinoma. METHODS: Forty women with a normal uterus and seventy-nine patients with endometrial carcinoma were examinedby the transvaginal CEUS with SonoVue (Bracco, Imaging B.V, Switzerland). The enhancement patterns and TIC of lesions were analyzed. The results of CEUS were compared with those of conventional ultrasound and pathology. RESULTS: In the early and late enhanced stages, the intensity of enhancement of the normal endometrium was always lower than that in the myometrium, and the boundary between normal endometrium and myometrium was clear. A total of 65.8% (52/79) of lesions presented with inhomogeneous enhancement, 34.2% (27/79) presented with homogeneous enhancement; 60.8% (48/79) presented with hyperechoic enhancement, 27.8% (22/79) presented with isoechoic enhancement, and 11.4% (9/79) presented with hypoechoic enhancement. The average arrival time, time to peak, rise time, half-wash out time of lesions were shorter than of normal endometrium (P < 0.05). The average peak intensity, relative rise in intensity, half-wash out intensity of lesions were higher than of normal endometrium (P < 0.05). There were 49 (must be and may be present) cases of endometrial carcinoma by ultrasound (US); 24 cases were consistent with pathology results, 16 cases were underestimated and 9 cases were overestimated. There were 72 (must be and may be present) cases of endometrial carcinoma by CEUS; 53 cases were consistent with pathology results, 12 cases were underestimated and 7 cases were overestimated. The qualitative diagnosis of endometrial carcinoma by CEUS was more accurate and definite than that by US (P < 0.01). CONCLUSIONS: By evaluating contrast-enhanced patterns and analyzing TIC, we found that CEUS can increase the accuracy of ultrasound qualitative diagnosis of endometrial carcinoma. CEUS shows lesions more clearly than conventional ultrasound, which is an advantage in evaluating the encroachment of endometrial carcinoma. PMID- 22490396 TI - Awareness and knowledge of hepatitis B infection and prevention and the use of hepatitis B vaccination in the Hong Kong adult Chinese population. AB - BACKGROUND: Hepatitis B virus (HBV) infection remains a global public health problem and it is an important cause of acute, chronic and fulminant hepatitis, liver cirrhosis and hepatocellular carcinoma. The prevalence of HBV infection in Hong Kong over the past decade remained unchanged at 10%, despite the implementation of universal neonatal and availability of adult vaccination. We suspect that the current state of affairs is attributable to inadequate awareness and knowledge of HBV transmission and prevention in the general population, resulting in a low rate of uptake of HBV vaccination by the lay public. Therefore, we have embarked in this study to evaluate the awareness and knowledge on HBV infection in our local Chinese population, their attitude on the prevention of horizontal transmission of HBV, and the use of HBV vaccination, especially in those who were born before the era of universal neonatal vaccination. METHODS: The factors associated with HBV screening, vaccination uptake, and knowledge were examined in a face-to-face questionnaire survey on a group of adult Chinese in Hong Kong. RESULTS: Within this group, 14% was considered to have good knowledge for HBV infection, and 26% had HBV vaccination. Age, occupation, having children, and family monthly income, are independent factors associated with vaccination. CONCLUSION: This study suggests insufficient public awareness of HBV infection in the Hong Kong Adult Chinese population. PMID- 22490398 TI - Completely video-assisted thoracoscopic lobectomy versus open lobectomy for non small cell lung cancer greater than 5 cm: a retrospective study. AB - BACKGROUND: Completely video-assisted thoracoscopic lobectomy is a reasonable treatment for early-stage non-small-cell lung cancer (NSCLC). At present, the indication for this procedure is stage Ia and Ib peripheral lung cancer (<= 5 cm); however, for larger tumors, it remains controversial whether this surgical technique is comparable to open lobectomy. This study aimed to evaluate the safety, completeness, and efficacy of thoracoscopic lobectomy, and to compare this technique with open lobectomy for the treatment of non-small-cell lung cancer when the tumor's diameter was greater than 5 cm. METHODS: From May 2001 to April 2011, 802 patients underwent a lobectomy for treatment of non-small-cell lung cancer at our center. In 133 patients, the tumor was > 5 cm. There were 98 men and 35 women, median age 63 years (range: 29 - 81 years). We divided the patients into two groups, group V (completely video-assisted thoracoscopic surgery), and group T (open lobectomy), and evaluated the two groups for age, gender, tumor size, pathological type, location, duration of surgery, blood loss, lymph node dissection, pathological stage, time of drainage, hospitalization, complications, overall survival and recurrence. RESULTS: There were 46 cases in group V and 87 cases in group T. Age, gender, tumor size, location, pathological type and stage were similar between the two groups. Group V had shorter operative duration ((186.5 +/- 62.8) minutes vs. (256.7 +/- 67.5) minutes, P < 0.001) and reduced bleeding ((218.5 +/- 174.6) ml vs. (556.9 +/- 187.2) ml, P < 0.001). There were no significant differences between the two groups in complications, lymph node dissection, time of drainage and hospitalization. The recurrence between the two groups was equivalent (2.4% vs. 3.8%, P = 0.670). The overall survival at 1, 2 and 3 years was 95.1%, 81.6% and 69.6% for group V and 88.3%, 78.8% and 64.0% for group T. Kaplan-Meier survival curves showed that there was no significant differences between the two groups (P = 0.129). CONCLUSIONS: Completely video-assisted thoracoscopic lobectomy was similar to open lobectomy in safety, completeness, and efficacy, but had a shorter operative duration, and reduced bleeding. This is a minimally invasive procedure that is feasible for a subset of non-small-cell lung cancer patients with tumor size > 5 cm. PMID- 22490397 TI - A prospective study to evaluate the efficacy of an intracardiac electrogram-based atrioventricular and interventricular intervals optimization method in cardiac resynchronization therapy. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) with biventricular pacing improves cardiac function, functional capacity and quality of life in selected patients with heart failure. The current study aimed to evaluate the efficacy of the intracardiac electrogram (IEGM)-based optimization method, QuickOpt(TM), in Chinese patients treated with CRT. METHODS: Aortic time velocity integrals (AVTI) achieved at the sensed atrioventricular (AV), paced AV and interventricular (VV) interval settings recommended by both QuickOpt(TM) and standard echocardiographic optimization were measured in 101 patients. Consistency and the strength of the relationship between the two timing cycle optimization methods were assessed by intra-class correlation coefficient (ICC). RESULTS: The ICC showed good agreement and correlation with what the AVTI achieved at the optimal sensed AV (ICC = 0.9683 (0.9535 - 0.9785)), paced AV (ICC = 0.9642 (0.9475 - 0.9757)) and VV (ICC = 0.9730 (0.9602 - 0.9817)) interval settings determined by the two optimization methods. The average time required by echocardiographic optimization and by QuickOpt(TM) were (78.32 +/- 32.40) minutes and (1.98 +/- 1.64) minutes respectively (P < 0.0001). CONCLUSION: The QuickOpt(TM) algorithm provides a quicker, simpler and reliable alternative to the standard method for timing cycle optimization. PMID- 22490399 TI - Three methods assess nutritional status of leukemia patients before hematopoietic stem cell transplantation. AB - BACKGROUND: Some leukemia patients before hematopoietic stem cell transplantation (HSCT) have nutritional risk or undernutrition, which was one of the main reasons that caused series of complications during transplantation. The aim of this study was to find out some appropriate methods to learn about the nutritional status of leukemia patients before HSCT. METHODS: Nutritional status of patients with leukemia was assessed with three common methods of nutritional assessment (nutritional risk screening 2002 (NRS2002), mini nutritional assessment (MNA) and subjective global assessment (SGA)) before HSCT. The assessment results of NRS2002 and MNA were compared by paired chi(2) test. The consistency was analyzed by Kappa test. RESULTS: In this study, 13 of 50 patients (26.0%) with leukemia had nutritional risk before HSCT assessed by NRS2002, including 7 patients (14.0%) with undernutrition. Of 50 patients assessed by SGA, only 1 case (2.0%) was mild or moderate undernutrition, and the remaining 49 patients (98.0%) were well-nutrition. Assessed by MNA, 1 case (2.0%) was undernutrition, 11 cases (22.0%) were potential undernutrition, and 38 cases (76.0%) were well-nutrition. Paired chi(2) test results showed that the difference between NRS2002 and MNA was statistically significant (chi(2) = 13.64, P < 0.05); Kappa test results showed that they were consistent between NRS2002 and MNA (Kappa = 0.62, P < 0.05). CONCLUSIONS: It is important to know the nutritional status of patients with leukemia before HSCT, and NRS2002 should be the first choice of nutritional assessment for patients with leukemia. If NRS2002 and MNA used at the same time, the accuracy and comprehensiveness of the assessment can be improved. PMID- 22490400 TI - Association of common polymorphisms in the LRP6 gene with sporadic coronary artery disease in a Chinese population. AB - BACKGROUND: Genetic factors contribute to the development of coronary artery disease (CAD). Recently, a missense mutation in the low density lipoprotein receptor related protein 6 (LRP6) gene, encoding low density lipoprotein receptor related protein 6, has been implicated in an autosomal dominant form of early onset CAD. The aim of this study was to determine whether the common variants in LRP6 are associated with sporadic CAD in Chinese. METHODS: A total of 766 CAD patients and 806 healthy controls were included in this study. The presence of angiographic CAD was determined by coronary angiographic analysis. Six signal nucleotide polymorphisms (SNPs) were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: A significant association was detected between rs11054731 in LRP6 intron 2 and CAD in our cohort (P = 0.001). The CC genotype and C allele frequency in the case group were 52% and 72%. Using a dominant model of inheritance, the C allele of rs11054731 was shown to be an independent risk factor for CAD with an OR of 1.45 (95%CI: 1.19 - 1.77, P = 0.0002). With the stratification according to the number of affected coronary arteries, an association was observed between rs11054731 and CAD (P = 0.0002). No significant association was observed between any other SNPs and the risk of CAD. CONCLUSION: The C allele of the rs11054731 within the LRP6 gene was associated with increased risk and extent of CAD in Chinese. PMID- 22490401 TI - Correlation of epidermal growth factor receptor overexpression with increased epidermal growth factor receptor gene copy number in esophageal squamous cell carcinomas. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignancies in China and epidermal growth factor receptor (EGFR) is widely distributed in human epithelial cell membrane. The aim of this study was to investigate the protein overexpression and gene copy number of EGFR in ESCC, and help to identify patients who may benefit from EGFR targeted therapies. METHODS: Immunohistochemistry (IHC) was performed to analyze the expression of EGFR in 105 cases of ESCC, 16 cases of squamous epithelial atypical hyperplasia, and 11 cases of normal esophageal tissue. Fluorescence in situ hybridization (FISH) was performed to analyze the gene copy number in 80 cases of ESCC, eight cases of squamous epithelial atypical hyperplasia, and eight samples of normal esophageal tissue. RESULTS: The IHC-positive rates of EGFR in 105 cases of ESCC, 16 cases of squamous epithelial atypical hyperplasia, and 11 normal esophageal tissues were 97% (102/105), 44% (7/16), and 18% (2/11) respectively. The difference in the expression of EGFR among different esophageal tissue groups had statistically significance (P < 0.05). Among the 105 cases of ESCC, overexpression of EGFR was found in 90 cases (86%), of which 55 cases scored 3+ for EGFR staining and 35 cases scored 2+. In ESCC, the expression of EGFR was significantly correlated with depth of invasion and TNM stage (P < 0.05), but not with other parameters. The FISH-positive rates of EGFR in 80 cases of ESCC, the eight cases of squamous epithelial atypical hyperplasia, and eight samples of normal esophageal tissue were 31.3% (25/80), 0 (0/8) and 0 (0/8) respectively. In ESCC, EGFR gene amplification was found in 17 (21%) cases, high polysomy in 8 (10%) cases, disomy in 34 cases, low trisomy in 17 cases, and high trisomy in four cases. EGFR FISH positive was significantly correlated with depth of invasion and lymph node metastasis (P < 0.05). EGFR FISH-positive was significantly associated with overexpression of EGFR. CONCLUSION: Protein overexpression and/or increased gene copy number of EGFR is common in ESCC, and EGFR targeted therapy may be appropriate for ESCC patients. PMID- 22490402 TI - Association between the incidence of typhoid and paratyphoid fever and meteorological variables in Guizhou, China. AB - BACKGROUND: Typhoid/paratyphoid fever (TPF) is endemic in Guizhou. We conducted wavelet analysis and Spearman's rank correlation analysis to explore the impact of meteorological variations on TPF infection in Guizhou, in an attempt to assess the risk factors associated with TPF epidemics. METHODS: We examined the association between TPF incidence in Guizhou and temperature, precipitation and relative humidity using 24 years of data from 1984 to 2007. Periodicities of TPF incidence and the impact of climate factors on the TPF were detected by Spearman's rank correlation and wavelet analysis, RESULTS: Temperature and precipitation with a 1-month lag were positively correlated with the monthly incidence of TPF. The multiyear incidence pattern of TPF in Guizhou was explicitly periodic. Moreover, the association and driving effect of precipitation on TPF were observed, and the results showed that the incidence of TPF in Guizhou had a closer correlation with precipitation than with temperature. CONCLUSIONS: Safe water supply is the key issue for TPF control in Guizhou. Moreover, climate variation might impact the enteric infections, which may inform policy assessment for TPF control in Guizhou. PMID- 22490403 TI - Evaluation and treatment of marginal grafts with surgical diseases in kidney transplantation. AB - BACKGROUND: Marginal renal grafts may alleviate the shortage of suitable organs to meet an increasing demand of kidney transplantation, especially when live donors are currently limited to relatives of patients in China. The aim of this study was to investigate how to increase the available donors pool, evaluation, and treatment of marginal donors. METHODS: We had performed 121 kidney transplantation cases with living relative donors. Five out of these cases applied marginal grafts with surgical diseases, including one renal stone, one duplex kidney, one renal leiomyoma and two cases of simple renal cysts. In each case, particular surgical interventions were exerted on the graft prior to standard engrafting procedures. RESULTS: All recipients recovered with functioning transplants given that their serum creatinine levels declined to a normal range within one week after operation. These recipients were subsequently followed up for 10 months on average and their kidney functions remained stable. CONCLUSIONS: Marginal renal grafts with surgical diseases, which can be treated surgically before engrafting, may provide satisfying transplantation outcomes. Positive and cautious consideration of these grafts may increase renal donor pool. PMID- 22490404 TI - Quantitative evaluation of cardiopulmonary functional reserve in treated patients with pulmonary embolism. AB - BACKGROUND: There is no research, either at home or abroad, focusing on assessing the cardiopulmonary functional reserve and exercise tolerance in patients with pulmonary embolism (PE), but the benefits of early exercise are well recognized. The goals of this study were to assess cardiopulmonary functional reserve in treated PE patients using the inert gas rebreathing method of the cardiopulmonary exercise test (CPET), and to compare it with traditional methods. METHODS: CPET on the bicycle ergometer were performed in 40 patients with age, gender, body mass index, systolic blood pressure, and pulmonary function matched. The first group was the PE group composed of 16 PE patients (5 male, 11 female) who were given the standard antithrombotic therapy for two weeks. The second group was composed of 24 normal individuals (10 male, 14 female). Both groups were evaluated by cardiac ultrasound examination, 6-minute walking test (6MWT), and CPET. RESULTS: (1) Right ventricular systolic pressure (RVSP) in the PE group increased significantly compared to the control group, (34.81 +/- 8.15) mmHg to (19.75 +/- 3.47) mmHg (P < 0.01). But neither right atrial end-systolic diameter (RASD) nor right ventricular end-diastolic diameter (RVDD) in the PE patients had changed when compared with the controls. The 6-minute walk distance was significantly reduced in the PE patients compared with normal subjects, (447.81 +/- 79.20) m vs. (513.75 +/- 31.45) m (P < 0.01). Both anaerobic threshold oxygen consumption (VO(2)AT) and peak oxygen consumption (VO(2)peak) were significantly lower in patients with PE, while CO(2) equivalent ventilation (VE/VCO(2) slope) was higher; VO(2)AT (9.44 +/- 3.82) ml*kg(-1)*min(-1) vs. (14.62 +/- 2.93) ml*kg( 1)*min(-1) (P < 0.01) and VO2peak (12.26 +/- 4.06) ml*kg(-1)*min(-1) vs. (23.46 +/- 6.15) ml*kg(-1)*min(-1) (P < 0.01) and VE/VCO(2) slope 35.47 +/- 6.66 vs. 26.94 +/- 3.16 (P < 0.01). There was no significant difference in resting cardiac output (CO) between the PE and normal groups, whereas peak cardiac output (peak CO) and the difference between exercise and resting cardiac output (DeltaCO) were both significantly reduced in the PE group; peak CO (5.97 +/- 2.25) L/min to (8.50 +/- 3.13) L/min (P < 0.01), DeltaCO (1.29 +/- 1.59) L/min to (3.97 +/- 2.02) L/min (P < 0.01). (2) The 6-minute walk distance did not correlated with CPET except for the VO2 peak in patients with PE, r = 0.675 (P < 0.01). CONCLUSIONS: The cardiopulmonary functional reserve was reduced in patients with PE. CPET is an accurate, quantitative evaluation of cardiopulmonary functional reserve for PE patients. PMID- 22490405 TI - Hypopyon in patients with fungal keratitis. AB - BACKGROUND: Hypopyon is common in eyes with fungal keratitis. The evaluation of the clinical features, culture results and the risk factors for hypopyon and of the possible correlation between hypopyon and the treatment outcome could be helpful for making treatment decisions. METHODS: The medical records of 1066 inpatients (1069 eyes) with fungal keratitis seen at the Shandong Eye Institute from January 2000 to December 2009 were reviewed retrospectively for demographic features, risk factors, clinical characteristics, laboratory findings and treatment outcomes. The incidence of hypopyon, the fungal culture positivity for hypopyon, risk factors for hypopyon and the effect of hypopyon on the treatment and prognosis were determined. RESULTS: We identified 1069 eyes with fungal keratitis. Of the 850 fungal culture-positive eyes, the Fusarium species was the most frequent (73.6%), followed by Alternaria (10.0%) and Aspergillus (9.0%). Upon admission, 562 (52.6%) eyes with hypopyon were identified. The hypopyon of 66 eyes was evaluated via fungal culturing, and 31 eyes (47.0%) were positive. A total of 194 eyes had ocular hypertension, and 172 (88.7%) of these eyes had hypopyon (P < 0.001). Risk factors for incident hypopyon included long duration of symptoms (P < 0.001), large lesion size (P < 0.001) and infection caused by the Fusarium and Aspergillus species (P < 0.001). The positivity of fungal culture for hypopyon was associated with duration of symptoms and lesion size. Surgical intervention was more common in cases with hypopyon (P < 0.001). Hypopyon was a risk factor for the recurrence of fungal keratitis after corneal transplantation (P = 0.002). CONCLUSIONS: Hypopyon is common in patients with severe fungal keratitis and can cause ocular hypertension. About half of the hypopyon cases were positive based on fungal culture. Long duration of symptoms, large lesion size and infection with the Fusarium and Aspergillus species were risk factors for hypopyon. The presence of hypopyon increases the likelihood of surgical intervention. PMID- 22490406 TI - ROR2 gene is associated with risk of non-syndromic cleft palate in an Asian population. AB - BACKGROUND: The receptor tyrosine kinase-like orphan receptor 2 (ROR2) gene has been recently shown to play important roles in palatal development in animal models and resides in the chromosomal region linked to non syndromic cleft lip with or without cleft palate in humans. The aim of this study was to investigate the possible association between ROR2 gene and non-syndromic oral clefts. METHODS: Here we tested 38 eligible single-nucleotide polymorphisms (SNPs) in ROR2 gene in 297 non-syndromic cleft lip with or without cleft palate and in 82 non-syndromic cleft palate case parent trios recruited from Asia and Maryland. Family Based Association Test was used to test for deviation from Mendelian inheritance. Plink software was used to test potential parent of origin effect. Possible maternally mediated in utero effects were assessed using the TRIad Multi Marker approach under an assumption of mating symmetry in the population. RESULTS: Significant evidence of linkage and association was shown for 3 SNPs (rs7858435, rs10820914 and rs3905385) among 57 Asian non-syndromic cleft palate trios in Family Based Association Tests. P values for these 3 SNPs equaled to 0.000068, 0.000115 and 0.000464 respectively which were all less than the significance level (0.05/38 = 0.0013) adjusted by strict Bonferroni correction. Relevant odds ratios for the risk allele were 3.42 (1.80 - 6.50), 3.45 (1.75 - 6.67) and 2.94 (1.56 - 5.56), respectively. Statistical evidence of linkage and association was not shown for study groups other than non-syndromic cleft palate. Neither evidence for parent-of-origin nor maternal genotypic effect was shown for any of the ROR2 markers in our analysis for all study groups. CONCLUSION: Our results provided evidence of linkage and association between the ROR2 gene and a gene controlling risk to non-syndromic cleft palate. PMID- 22490407 TI - Cancer risk and key components of metabolic syndrome: a population-based prospective cohort study in Chinese. AB - BACKGROUND: The key components of metabolic syndrome (MS) are waist circumference, blood pressure, fast blood glucose, high density lipoprotein cholesterol (HDL-c) and triglycerides (TG). These components have, separately and jointly, been associated with an increased risk of cardiovascular diseases. In this study, we aimed to explore the association between MS components and cancer risk in a population-based cohort in China. METHODS: We established a population based cohort with 17 779 individuals aged 35 and above at baseline in 2004 and 2005 in Changzhou, Jiangsu Province, China. All participants were face-to-face interviewed to complete a questionnaire and were accepted physical examinations including blood tests for glucose and lipids and physical measurements for obesity and blood pressure. In 2009, a total of 16 284 subjects (6886 men and 9398 women, 91.6%) attended the flow-up interviews and the participants or their family members reported all the hospitalizations and diseases including cancer occurred during the follow-up period. Multivariate Cox regression was used to estimate the hazard ratios (HRs) of metabolic syndrome components and cancer incidence. RESULTS: There was a dose-response association between cancer risk and the number of MS components presented at baseline (P for trend = 0.012) and the HR (95% confidence interval (CI)) was 2.63 (1.27 - 5.45) for subjects carrying 3 or more metabolic syndrome components after adjustment for possible confounding factors. Specifically, the multivariate-adjusted HRs (95%CIs) for cancer risk in subjects with central obesity, high fasting glucose, low HDL-c were 1.94 (1.01 - 3.74), 2.04 (1.10 - 3.77) and 2.05 (1.09 - 3.88), respectively. CONCLUSIONS: In this population-based, prospective cohort study in China, we found MS components, e.g., central obesity, high fasting glucose, low HDL-c were risk factors for cancer development. Early intervention of MS components may be also beneficial to reduce cancer burden. PMID- 22490408 TI - Investigation of attention via the counting Stroop task in patients with functional constipation. AB - BACKGROUND: The etiology and pathology of functional constipation (FC) is unclear. Some researches suggest that psychological factors may be related to this common problem. This study aimed to investigate the relationship between attention processing and emotional status in FC patients compared with healthy controls. METHODS: We investigated selective attention and emotional status in patients with FC using the counting Stroop task. Thirty-five FC patients (FCP group) and 24 healthy controls (HCs) underwent an event-related potential (ERP) study while performing the task. Response time, latency and amplitude of P300 were collected and compared between the two groups. The Hamilton Depression Rating Scale (HAMD-17), Hamilton Anxiety Scale (HAMA), Symptom Checklist-90 (SCL 90) and Eysenck Personality Questionnaire (EPQ) were administered prior to the counting Stroop task. RESULTS: Scores for the FCP group differed significantly from those for the HCs on the HAMD-17, HAMA, SCL-90 (Global Severity Index, Positive Symptoms Total, dimensions of somatization, obsessive-compulsive, depression, anxiety, and psychosis), as well as extraversion and neurosis dimensions of the EPQ (P < 0.05). There was no significant difference in response time or accuracy rate between the two groups (P > 0.05). ERP results showed prolonged latency at F4, additionally found enhanced activation at F3, FC1 and T8, and decreased activation at sites FC6 and P7 in the patients with FC. Statistically, significant differences of P300 latency at site F4 (P < 0.05) and P300 amplitude at F3, F4, T8, P7, FC1 and FC6 (P < 0.05) between the patients with FC and the HC were revealed. CONCLUSIONS: The findings suggest that patients with FC are more susceptible to depression and anxiety, as well as somatization, obsessive-compulsive tendencies and other neurotic personality characteristics. Patients may employ psychological defense mechanisms to avoid the pain of depression and anxiety. ERP results imply there may be some brain dysfunction and attention deficits in patients with FC. PMID- 22490410 TI - Endothelial progenitor cell down-regulation in a mouse model of Kawasaki disease. AB - BACKGROUND: Cardiovascular complications of Kawasaki disease (KD) are a common cause of heart disease in pediatric populations. Previous studies have suggested a role for endothelial progenitor cells (EPCs) in coronary artery lesions associated with KD. However, long-term observations of EPCs during the natural progression of this disorder are lacking. Using an experimental model of KD, we aimed to determine whether the coronary artery lesions are associated with down regulation of EPCs. METHODS: To induce KD, C57BL/6 mice were administered an intraperitoneal injection of Lactobacillus casei cell wall extract (LCWE; phosphate buffered saline used as control vehicle). Study groups included: group A (14 days following LCWE injection), group B (56 days following LCWE injection) and group C (controls). Numbers of circulating EPCs (positively staining for both CD34 and Flk-1 while staining negative for CD45) were evaluated using flow cytometry. Bone marrow mononuclear cells were cultured in vitro to expand EPCs for functional analysis. In vitro EPC proliferation, adhesion and migration were assessed. RESULTS: The model was shown to exhibit similar coronary artery lesions to KD patients with coronary aneurysms. Numbers of circulating EPCs decreased significantly in the KD models (groups A and B) compared to controls ((0.017 +/- 0.008)% vs. (0.028 +/- 0.007)%, P < 0.05 and (0.016 +/- 0.007)% vs. (0.028 +/- 0.007)%, P < 0.05). Proliferative, adhesive and migratory properties of EPCs were markedly impaired in groups A and B. CONCLUSION: Coronary artery lesions in KD occur as a consequence of impaired vascular injury repair, resulting from excess consumption of EPCs together with a functional impairment of bone marrow EPCs and their precursors. PMID- 22490409 TI - Azithromycin inhibits neutrophil accumulation in airways by affecting interleukin 17 downstream signals. AB - BACKGROUND: Azithromycin can reduce neutrophil accumulation in neutrophilic pulmonary diseases. However, the precise mechanism behind this action remains unknown. Our experiment assessed whether azithromycin inhibits neutrophil accumulation in the airways by affecting interleukin-17 (IL-17) downstream signals. METHODS: Mice were pretreated with azithromycin before murine IL-17A (mIL-17) stimulation. After the mIL-17 stimulation, the levels of six neutrophil mobilizing cytokines were determined by enzyme-linked immunosorbent assay (ELISA) tests in bronchoalveolar lavage (BAL) fluid; IL-6, CXC chemokine ligand-1 (CXCL 1), CXCL-5, macrophage inflammatory protein-2 (MIP-2), granulocyte colony stimulating factor (G-CSF), and granulocyte macrophage colony-stimulating factor (GM-CSF). The number of neutrophils in BAL fluid were evaluated by cytospin preparations. RESULTS: (1) Azithromycin pretreatment significantly inhibited both the release of three neutrophil-mobilizing cytokines (MIP-2, CXCL-5 and GM-CSF) and the accumulation of neutrophils in airways caused by mIL-17 stimulation. (2) The levels of three neutrophil-mobilizing cytokines (IL-6, MIP-2 and GM-CSF) were positively correlated with the numbers of neutrophil in BAL fluid. CONCLUSIONS: Azithromycin can inhibit neutrophil accumulation in the airways by affecting IL 17 downstream signals. This finding suggests that macrolide antibiotic application might be useful in prevention of neutrophilic pulmonary diseases characterized by high levels of IL-17. PMID- 22490411 TI - Abnormal mitochondrial function impairs calcium influx in diabetic mouse pancreatic beta cells. AB - BACKGROUND: Abnormal insulin secretion of pancreatic beta cells is now regarded as the more primary defect than the insulin function in the etiology of type 2 diabetes. Previous studies found impaired mitochondrial function and impaired Ca(2+) influx in beta cells in diabetic patients and animal models, suggesting a role for these processes in proper insulin secretion. The aim of this study was to investigate the detailed relationship of mitochondrial function, Ca(2+) influx, and defective insulin secretion. METHODS: We investigated mitochondrial function and morphology in pancreatic beta cell of diabetic KK-Ay mice and C57BL/6J mice. Two types of Ca(2+) channel activities, L-type and store-operated Ca(2+) (SOC), were evaluated using whole-cell patch-clamp recording. The glucose induced Ca(2+) influx was measured by a non-invasive micro-test technique (NMT). RESULTS: Mitochondria in KK-Ay mice pancreatic beta cells were swollen with disordered cristae, and mitochondrial function decreased compared with C57BL/6J mice. Ca(2+) channel activity was increased and glucose induced Ca(2+) influx was impaired, but could be recovered by genipin. CONCLUSION: Defective mitochondrial function in diabetic mice pancreatic beta cells is a key cause of abnormal insulin secretion by altering Ca(2+) influx, but not via Ca(2+) channel activity. PMID- 22490412 TI - Ecological surveys of the Cryptococcus species complex in China. AB - BACKGROUND: Despite recent reports on the molecular epidemiology of cryptococcal infections in China, clinical isolates have been mostly reported from human immunodeficiency virus (HIV)-negative patients, and environmental isolates from China have rarely been included. The aim of this study was to investigate the ecological profile of Cryptococcus (C.) neoformans and C. gattii in China. METHODS: A survey was performed in 10 cities from 20 degrees N (North latitude) to 50 degrees N and in a Eucalyptus (E.) camaldulensis forestry farm at the Guixi forestry center, China. RESULTS: Six hundred and twenty samples of pigeon droppings from 10 cities and 819 E. camaldulensis tree samples were collected and inoculated on caffeic acid cornmeal agar (CACA). The brown-colored colonies were recultured to observe their morphology, growth on canavanine-glycine-bromothymol blue (CGB) medium, phenol oxidase and urease activities, serotype and mating type. There were obvious differences in the positive sample rates of C. neoformans in pigeon droppings collected from the different cities, ranging from 50% in the cities located at latitudes from 30 degrees N - 40 degrees N, 29% at 20 degrees N - 30 degrees N and 13% at 40 degrees N - 50 degrees N. CONCLUSIONS: There were no differences in positive bevy rates (approximately 80%) among the three grouped cities. Mycological tests of 101 isolates purified from pigeon droppings revealed that they were C. neoformans var. grubii. We also observed variable capsular size around the C. neoformans cells in colonies with variable melanin production and the bio-adhesion of the natural C. neoformans cells with other microorganisms. One urease-negative C. neoformans isolate was isolated from pigeon droppings in Jinan city. No C. gattii was isolated in this study. PMID- 22490413 TI - Influences of the interferon induced transmembrane protein 1 on the proliferation, invasion, and metastasis of the colorectal cancer SW480 cell lines. AB - BACKGROUND: Interferon-induced transmembrane protein 1 (IFITM1) has been identified as a molecular marker of the colorectal tumors; however its influences on the biological behaviors of the colorectal cancer cells are currently unknown. We aimed to study the influences of IFITM1 on the proliferation, invasion, and metastasis of the colorectal cancer SW480 cell lines. METHODS: We constructed IFITM1/pEGFP-C3 recombinant plasmids and transfected them into the colorectal cancer SW480 cell lines. IFITM1/pEGFP-C3 recombinant plasmids were identified by means of immunofluorescence, laser confocal scanning microscopy, and reverse transcription polymerase chain reaction. IFITM1/SW480 cells with stable over expression of IFITM1 were confirmed by G418 screening. The influences of IFITM1 on the proliferation of the SW480 cell lines were investigated by MTT assay and tumor transplantation experiments in nude mice. Cell invasion experiments were performed to determine the invasion capacity of the IFITM1/SW480 cells. Matrix metalloproteinase 2 (MMP-2) and MMP-9 activities were detected by the gelatin zymographic analysis, and MMP-9 expression by the Western blotting analysis. RESULTS: IFITM1/pEGFP-C3 recombinant plasmids were successfully constructed in this study, and the IFITM1/SW480 cells with stable IFITM1 gene over-expression were confirmed by G418 screening. MTT results showed that the proliferation of the IFITM1/SW480 cells was significantly enhanced (P < 0.01). Tumors were harvested from four weeks old mice. Tumor volumes were (1347.00 +/- 60.94) mm(3), (1032.40 +/- 111.38) mm(3) and (1018.78 +/- 28.83) mm(3); and tumor weights were (1522.34 +/- 62.76) mg, (1137.78 +/- 97.22) mg and (1155.76 +/- 133.31) mg for mice inoculated with the IFITM1/SW480 cells, pEGFP-C3/SW480 cells and SW480 cells, respectively. Tumor volumes and weights from mice inoculated with the IFITM1/SW480 cells were significantly increased (P < 0.01). In addition, the numbers of the SW480 cells and IFITM1/SW480 cells that migrated through Matrigel were 448.64 +/- 38.09 and 540.45 +/- 44.61, respectively; so the invasive ability of the SW480 cells transfected with IFITM1 gene was significantly greater than that of the SW480 cells (P < 0.01). Gelatin zymographic analysis showed that MMP 9 and MMP-2 protein activities in the IFITM1/SW480 cells were significantly enhanced, and Western blotting analysis showed that MMP-9 expression in the IFITM1/SW480 cells was also increased. CONCLUSION: IFITM1 can enhance the proliferation, invasion, and metastasis of the colorectal cancer SW480 cell lines. PMID- 22490414 TI - Role of microRNA-181a in the apoptosis of tubular epithelial cell induced by cisplatin. AB - BACKGROUND: Cisplatin (DDP) is one of most effective and most commonly used therapeutic agent in treating tumors, it can accumulate in the kidney and lead to acute renal failure. MicroRNA-181a can induce cell apoptosis by suppressing the expression of Bcl-2 family. In the present study, we investigated the role of microRNA-181a in the apoptosis of tubular epithelial cell induced by DDP. METHODS: HK-2 cells were cultured, transfected with microRNA-181a inhibitor for 48 hours, and stimulated with 50 umol/L cisplatin for 24 hours. MicroRNA-181a expression was analyzed by real time PCR, and cell apoptosis was detected by flow cytometry. Moreover, Bcl-2 and Bcl-2-associated X protein (Bax) expression were measured by Western blotting. RESULTS: MicroRNA-181a expression significantly down-regulated in cells transfected with microRNA-181a inhibitor, compared with that in untransfectd cells (21.19 +/- 2.01 vs. 38.87 +/- 1.97, P < 0.05). Cell apoptosis induced by DDP significantly decreased in cells transfected with MicroRNA-181a inhibitor. Compared with DDP treated cells alone, Bcl-2 expression strikingly was up-regulated and Bax expression was down-regulated in cells transfected with microRNA-181a inhibitor. CONCLUSION: One pathway of DDP induces apoptosis of tubular epithelial cell by suppressing Bcl-2 expression is achieved by regulating the target gene of MicroRNA-181a. PMID- 22490415 TI - Integrase interactor 1 regulates proliferation, apoptosis and invasion in gastric cancer cells. AB - BACKGROUND: Integrase interactor 1 (INI1), which encodes a component of the ATP dependent chromatin remodeling hSWI-SNF complex, has been identified as a tumor suppressor in many tumors. Nonetheless, the role of INI1 in gastric tumor progression is not known exactly. The aim of this research was to investigate the effect of INI1 in the carcinogenesis and progression of gastric cancer. METHODS: Gastric tumor tissues with different differentiation levels from clinical gastric carcinoma samples and adjacent control normal tissues were taken. Expression levels of INI1 were detected by quantitative reverse transcriptation-polymerase chain reaction (RT-PCR) and Western blotting. Gastric cancer cell line SGC7901 was transfected with INI1 eukaryotic expressing vector INI1-GFP. Cell proliferation activities were assessed by MTT; cell count and cell cycle were detected by flow cytometry (FCM); cell apoptosis were measured by TUNEL and FCM; cell migration and invasiveness were evaluated by wound healing and transwell assays. Expression levels of INI1 and proliferation-related genes including p16, p21, cyclin D1 and cyclin A, apoptosis genes p53, B-cell non-Hodgkin lymphoma-2 (Bcl-2), Bcl-2-associated x protein (Bax) and caspase-3, and invasion-related genes including intercellular adhesion molecule 1 (ICAM1), matrix metalloproteinase 2 (MMP2), MMP9 and tissue inhibitor of matrix metalloproteinase 1 (TIMP1), were detected by quantitative RT-PCR and Western blotting. RESULTS: INI1 expression levels were lower in gastric carcinoma compared with adjacent control normal tissues. Overexpression of INI1 in SGC7901 cells inhibited its proliferation and invasiveness, but increased anoikis and G(0)/G(1) cell number. INI1-GFP transfection upregulated expression of INI1 and proliferation related genes p16 and p21, apoptosis genes p53 and Bax, and invasion-related genes TIMP1; cyclin D1, cyclin A, Bcl2, ICAM1, MMP2 and MMP9 were downregulated, and there was no significant change in caspase 3 levels. CONCLUSION: INI1 plays a key role in gastric carcinogenesis by affecting proliferation, apoptosis and invasion. PMID- 22490416 TI - An improved risk of malignancy index in diagnosis of adnexal mass. AB - BACKGROUND: With the advent of color Doppler flow imaging (CDFI) and technological development of detection of serum tumor markers, new opportunities are presented to the improved risk of malignancy index (RMI) based on Jacobs' research for predicting ovarian malignancy in patients with adnexal masses. METHODS: One hundred and eighty women with an adnexal mass admitted for primary laparotomy were studied. Tumor specific growth factor (TSGF) adjusted ultrasound scores and the results of Doppler blood flow analysis were obtained before the operation. Based on the parameters which had been studied in Jacobs' research, TSGF levels and the findings of color Doppler flow imaging, the risk of malignancy model was redesigned using a binary Logistic regression model. The diagnostic efficacy of the improved risk of malignancy index (improved RMI) was compared with the Jacobs' model RMI by receiver operator characteristic (ROC) curve. RESULTS: The ROC curve showed a higher sensitivity (Mcnamer's test, P < 0.05) in the discrimination between benign and malignant adnexal masses for the improved RMI than the RMI. Compared with the RMI, the improved RMI had an advantage in prediction of ovarian germ cell tumors and granular cell tumor (28.57% vs.71.43%, P < 0.05) and the early stage tumors and borderline tumors (33.33% vs. 66.67%, P < 0.05). CONCLUSION: The predictability of the improved RMI is better than the classic Jacobs' model, especially in diagnosis of the ovarian germ cell tumors and granular cell tumor and other early stage adnexal tumors. PMID- 22490417 TI - Stercoral colonic diverticulum perforation with jejunal diverticulitis mimicking upper gastrointestinal perforation. AB - Stercoral perforation of the colon is an unusual pathological condition with fewer than 150 cases reported in the literature to date. We present a case of stercoral colonic perforation mimicking upper gastrointestinal perforation, which was diagnosed by computed tomography preoperatively. However, at laparotomy, stercoral colonic diverticulum perforation with jejunal diverticulitis became the most appropriate diagnosis. PMID- 22490418 TI - Endovascular treatment of a giant internal carotid artery bifurcation aneurysm with drainage into cavernous sinus. AB - This report documents the treatment of a giant aneurysm of the internal carotid artery bifurcation with a fistula to the cavernous sinus, which appeared following closed head trauma. A 39-year-old man suffered from a blunt head trauma in an automobile accident. Two weeks after the trauma, progressive chemosis of left eye was presented. Four months after the trauma, digital subtraction angiography showed an internal carotid artery bifurcation aneurysm, with drainage into the cavernous sinus. The lesion was successfully obliterated with preservation of the parent artery by using coils in conjunction with Onyx. Follow up angiography obtained 3 months postoperatively revealed persistent obliteration of the aneurysm and fistula as well as patency of the parent artery. Endovascular treatment involving the use of coils combined with Onyx appears to be a feasible and effective option for treatment of this hard-to-treat lesion. PMID- 22490419 TI - Horseshoe kidney with retrocaval ureter: one case report. AB - Horseshoe kidney and retrocaval ureter are uncommon congenital anomalies of the genitourinary system that are easily diagnosed by typical imaging features. Both anomalies presenting in one patient is a rare disease characterized by isthmus of horseshoe kidney between the abdominal aorta and inferior vena cava. The clinical diagnosis and treatment of horseshoe kidney with retrocaval ureter remain a challenge. Here, we reported a case of a 44-year-old man with the two anomalies who was preoperatively diagnosed by unenhanced computed tomography scanning immediately after retrograde pyelography. The literatures on such combined anomalies are reviewed and the diagnostic evaluation and surgical management of this rare entity are discussed. PMID- 22490420 TI - A live birth of activated one-day-old unfertilized oocyte for a patient who experienced repeatedly near-total fertilization failure after intracytoplasmic sperm injection. AB - Total or near-total fertilization failure after intracytoplasmic sperm injection (ICSI) is a rare event, but it occurs repeatedly because of sperm defects in activating oocyte. The case presents a successful pregnancy and live birth after calcium ionophore A23187 (A23187) activation on one-day-old unfertilized oocytes in a patient whose husband suffered oligoasthenoteratozoospermia, and who had experienced repeated near-total fertilization failure after ICSI. In the second ICSI cycle, only one oocyte was fertilized while nine were unfertilized. Oocyte activation with A23187 were performed on the one-day-old unfertilized oocytes after ICSI and resulted in fertilization and embryo transfer. A clinical pregnancy was achieved and a healthy baby was born. To our knowledge, this is the first reported case of a healthy birth after oocyte activation on the one-day-old unfertilized oocyte. This indicates that "rescue oocyte activation" on one-day old unfertilized oocytes after ICSI may be helpful for preventing total or near total fertilization failure after ICSI. PMID- 22490421 TI - Unilateral pulmonary artery stenosis and late-onset cataract in an adult: a case of suspected congenital rubella syndrome. AB - Congenital rubella syndrome is characterized by the triad of deafness, cataract and cardiovascular malformations. The great majority of the cases in the literature have been usually diagnosed in infancy and childhood because of various defects at birth. However, we report a rare case of suspected congenital rubella syndrome in an adult with unilateral pulmonary artery stenosis and late onset cataract. PMID- 22490422 TI - An unusual case of Welder's siderosis with local massive fibrosis: a case report. AB - Welder's siderosis was traditionally described as "benign pneumoconiosis" because of the absence of associated symptoms, functional impairment or pulmonary fibrosis. Although several authors have reported evidence of fibrosis in the lungs of welders, siderosis with local massive fibrosis has been rarely described. In this paper, we present a case of Welder's siderosis with local massive fibrosis mimicking lung cancer. PMID- 22490423 TI - A case of systemic amyloidosis beginning with purpura. AB - Primary systemic amyloidosis is a relatively rare disease, caused when abnormal extracellular deposition of fibrillary protein builds up in a variety of target organs, such as heart, kidneys, lungs liver, and so forth. The symptoms of the disease are usually vague, while many kinds of auxiliary or laboratory examinations especially pathologic biopsy can provide a clue for the diagnosis. Here we described a case who had purpura-like lesions in the initial stage, followed by progressive malfunctions in the kidneys, the heart, the lungs, as well as the liver. The final diagnosis was primary systemic amyloidosis determined by skin pathologic biopsy. And the disease led to a fatal outcome within three months after the diagnosis. PMID- 22490424 TI - Multibacillary leprosy: erythema as the only clinical presentation. AB - Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae, which primarily affects the skin and peripheral nerves. In this article, we present a 45-year-old man and a 39-year-old women who suffered from asymptomatic irregular erythemas on their trunk and extremities. Since both patients denied the history of exposure to leprosy patients and were absent clinical signs of superficial sensation dysfunction and enlarged peripheral nerves, they were diagnosed of mycosis fungoides and livedo reticularis clinically. Nevertheless the biopsies of erythemas showed perineural and periadnexal foamy-cell granulomas in the dermis and Fite staining revealed a large number of acid-fast bacilli. A diagnosis of multibacillary leprosy was made finally. These cases revealed that since leprosy is still epidemic in some remote area in China and in other developing countries and its clinical manifestations may be very weird sometimes, the dermatologists should be alert of it and skin biopsy could confirm the diagnosis. PMID- 22490425 TI - Stimulus-induced drop episodes in Coffin-Lowry syndrome. AB - The Coffin-Lowry syndrome (CLS) is a rare but well-defined X-linked semidominant syndrome characterized by psychomotor and growth retardation, and progressive skeletal changes. CLS is caused by loss of function mutations in the Rps6ka3 gene encoding the ribosomal S6 kinase 2 (RSK2) protein. A distinctive paroxysmal disorder has been described in some CLS patients, characterized by episodes of sudden falling, without apparent alteration of consciousness, usually induced by unexpected tactile or auditory stimuli. Duration of episodes is very short, usually lasting a few seconds. The appellation "Stimulus-induced drop episodes" (SIDEs) was proposed for these non-epileptic events in CLS patients. SIDEs are clinically heterogeneous; with some patients exhibiting cataplexy-like events characterized by sudden hypotonia and collapse, and others hyperekplexia-like episodes with a startle response. The pathophysiology of SIDEs is not well understood. PMID- 22490426 TI - Pelizaeus-Merzbacher disease caused by a duplication-inverted triplication duplication in chromosomal segments including the PLP1 region. AB - Pelizaeus-Merzbacher disease (PMD; MIM#312080) is a rare X-linked leukodystrophy presenting with motor developmental delay associated with spasticity and nystagmus. PMD is mainly caused by abnormalities in the proteolipid protein 1 gene (PLP1), most frequently due to duplications of chromosomal segments including PLP1. In this study, a 9-year-old male patient manifesting severe developmental delay and spasticity was analyzed for PLP1 alteration, and triplication of PLP1 was identified. Further examination revealed an underlying genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV DUP), in which a triplicated segment was nested between 2 junctions. One of the 2 junctions was caused by inverted homologous regions, and the other was caused by non-homologous end-joining. PMD patients with PLP1 duplications usually show milder-classical forms of the disease compared with patients with PLP1 missense mutations manifesting severe connatal forms. The present patient showed severe phenotypic features that represent an intermediate form of PMD between classical and connatal forms. This is the first report of a patient with PLP1 triplication caused by a DUP-TRP/INV-DUP structure. This study adds additional evidence about the consequences of PLP1 triplication. PMID- 22490427 TI - Developing a standardized approach to the assessment of pain in children and youth presenting to pediatric rheumatology providers: a Delphi survey and consensus conference process followed by feasibility testing. AB - BACKGROUND: Pain in children with rheumatic conditions such as arthritis is common. However, there is currently no standardized method for the assessment of this pain in children presenting to pediatric rheumatologists. A more consistent and comprehensive approach is needed to effectively assess, treat and monitor pain outcomes in the pediatric rheumatology population. The objectives of this study were to: (a) develop consensus regarding a standardized pain assessment tool for use in pediatric rheumatology practice and (b) test the feasibility of three mediums (paper, laptop, and handheld-based applications) for administration. METHODS: In Phase 1, a 2-stage Delphi technique (pediatric rheumatologists and allied professionals) and consensus meeting (pediatric pain and rheumatology experts) were used to develop the self- and proxy-report pain measures. In Phase 2, 24 children aged 4-7 years (and their parents), and 77 youth, aged 8-18 years, with pain, were recruited during routine rheumatology clinic appointments and completed the pain measure using each medium (order randomly assigned). The participant's rheumatologist received a summary report prior to clinical assessment. Satisfaction surveys were completed by all participants. Descriptive statistics were used to describe the participant characteristics using means and standard deviations (for continuous variables) and frequencies and proportions (for categorical variables) RESULTS: Completing the measure using the handheld device took significantly longer for youth (M = 5.90 minutes) and parents (M = 7.00 minutes) compared to paper (M = 3.08 and 2.28 minutes respectively p = 0.001) and computer (M = 3.40 and 4.00 minutes respectively; p < 0.001). There was no difference in the number of missed responses between mediums for children or parents. For youth, the number of missed responses varied across mediums (p = 0.047) with the greatest number of missed responses occurring with the handheld device. Most children preferred the computer (65%, p = 0.008) and youth reported no preference between mediums (p = 0.307). Most physicians (60%) would recommend the computer summary over the paper questionnaire to a colleague. CONCLUSIONS: It is clinically feasible to implement a newly developed consensus-driven pain measure in pediatric rheumatology clinics using electronic or paper administration. Computer-based administration was most efficient for most users, but the medium employed in practice may depend on child age and economic and administrative factors. PMID- 22490428 TI - Being wrong. PMID- 22490429 TI - Survival of patients after ST-elevation myocardial infarction: external validation of a predictive biomarker model. PMID- 22490430 TI - Cerebrovascular geometry in the anterior circulation: an analysis of diameter, length and the vessel taper. AB - BACKGROUND: A study was undertaken to determine the typical length, diameter and taper of vessels in the anterior cerebral circulation. METHODS: The sample size was calculated at 100 patients based on similar measurements in the literature and divided into cohorts based on gender and side. These patients were consecutively collected from a population that had undergone CT angiography and did not have any vascular abnormality. The arterial diameter was measured at the proximal cavernous internal carotid artery (ICA), the ICA terminus, the middle cerebral artery (MCA) origin and an M2 origin. The length between these endpoints was calculated along the center line. The vessel taper was calculated for the ICA as the change in caliber per unit length. RESULTS: The mean length of the ICA from the proximal cavernous segment to the ICA terminus was 33.1 +/- 6.1 mm. The mean diameter at the cavernous ICA and the ICA terminus was 5 +/- 0.6 mm and 3.6 +/- 0.4 mm, respectively. The mean ICA taper was 0.04 +/- 0.02 mm/1 mm. For the MCA, the diameter at the MCA and M2 origins measured 3.1 +/- 0.4 mm and 2.4 +/- 0.4 mm, respectively. The mean MCA length was 22.5 +/- 8.1 mm. There was no significant difference based on gender or between right and left sides. Patients aged >60 years had longer ICAs (p=0.02), larger cavernous ICA (p=0.003), ICA terminus (p<0.0001) and MCA origin (p=0.01) diameters than those aged 40-60 years. The ICA vessel taper did not change with age. CONCLUSION: ICA and MCA vessel size did not change based on gender or side. Older patients had more redundant vessels based on diameter and length. The ICA has a gentle taper from its proximal cavernous segment to the ICA terminus. This information can be important in planning interventions or designing endovascular devices. PMID- 22490431 TI - Endovascular intervention for delayed stenosis of extracranial-intracranial bypass saphenous vein grafts. AB - PURPOSE: Bypass graft stenosis is an uncommon but significant issue which can be encountered following extracranial-intracranial (EC-IC) bypass surgery and carries significant potential for morbidity and mortality. Angioplasty for graft stenosis (with or without stenting) has been extensively discussed in the cardiothoracic literature but its application for neurosurgical purposes has not been well documented. METHODS: Cases of EC-IC bypass undergoing endovascular intervention for graft stenosis were retrospectively reviewed; a literature search was performed. Diagnosis, pathology and indications for intervention were reviewed. RESULTS: Three patients underwent 13 endovascular interventions for EC IC saphenous vein graft stenosis. The indication for the initial bypass was an unsecured intracranial aneurysm in all cases, using an interposition saphenous vein graft. The initial endovascular procedure was needed 9-23 weeks after the bypass surgery, a timeframe suggestive of intimal hyperplasia as the underlying etiology of stenosis. There were nine cases of angioplasty alone, three with stent placement and one case in which vasodilators were infused. Non-invasive phase contrast quantitative MR angiography was effective in predicting graft stenosis. Despite intervention, two grafts ultimately occluded and a third has remained patent only after multiple angioplasties and placement of a drug eluting coronary stent. CONCLUSION: Although rare, bypass graft stenosis can occur in the subacute period, and likely represents a flow related venopathy. Given the challenges of re-do bypass surgery, endovascular intervention is an attractive treatment option. However, although repeated interventions with diligent follow up may allow graft salvage, failure of endovascular intervention can also ultimately result in graft occlusion. PMID- 22490432 TI - School toilets: facilitating hand hygiene? A review of primary school hygiene facilities in a developed country. AB - BACKGROUND: Clean hands play an important role in preventing infectious disease transmission. The physical quality of any toilet and handwashing facilities is an important determinant of whether and how it is used, especially for school children. METHODS: This study assessed the physical quality of toilet and handwashing facilities used by 9 year olds at 68 primary schools in three cities in the South Island of New Zealand. The facilities were assessed for availability, functionality and provision of hand basins, hygiene products and drying facilities. RESULTS: Nineteen schools (28%) followed the New Zealand Ministry of Education Code of Practice for toilet and bathroom facilities in schools, by providing warm water, liquid soap at every basin and functioning hand drying facilities. A further 25 schools (37%) would have met the standards except they provided only cold water (21 schools) or the cloth roller towels were unusable (4 schools). The other 24 schools' toilet facilities were deficient in some way, including one with no soap and six that provided no drying facilities. School socioeconomic position and toilet facility quality were not related. CONCLUSIONS: These results suggest that a significant number of New Zealand children do not currently have access to high quality hygiene facilities at school. PMID- 22490433 TI - Cost-utility analysis of different treatments for post-traumatic stress disorder in sexually abused children. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is diagnosed in 20% to 53% of sexually abused children and adolescents. Living with PTSD is associated with a loss of health-related quality of life. Based on the best available evidence, the NICE Guideline for PTSD in children and adolescents recommends cognitive behavioural therapy (TF-CBT) over non-directive counselling as a more efficacious treatment. METHODS: A modelled economic evaluation conducted from the Australian mental health care system perspective estimates incremental costs and Quality Adjusted Life Years (QALYs) of TF-CBT, TF-CBT combined with selective serotonin reuptake inhibitor (SSRI), and non-directive counselling. The "no treatment" alternative is included as a comparator. The first part of the model consists of a decision tree corresponding to 12 month follow-up outcomes observed in clinical trials. The second part consists of a 30 year Markov model representing the slow process of recovery in non-respondents and the untreated population yielding estimates of long-term quality-adjusted survival and costs. Data from the 2007 Australian Mental Health Survey was used to populate the decision analytic model. RESULTS: In the base-case and sensitivity analyses, incremental cost effectiveness ratios (ICERs) for all three active treatment alternatives remained less than A$7,000 per QALY gained. The base-case results indicated that non directive counselling is dominated by TF-CBT and TF-CBT + SSRI, and that efficiency gain can be achieved by allocating more resources toward these therapies. However, this result was sensitive to variation in the clinical effectiveness parameters with non-directive counselling dominating TF-CBT and TF CBT + SSRI under certain assumptions. The base-case results also suggest that TF CBT + SSRI is more cost-effective than TF-CBT. CONCLUSION: Even after accounting for uncertainty in parameter estimates, the results of the modelled economic evaluation demonstrated that all psychotherapy treatments for PTSD in sexually abused children have a favourable ICER relative to no treatment. The results also highlighted the loss of quality of life in children who do not receive any psychotherapy. Results of the base-case analysis suggest that TF-CBT + SSRI is more cost-effective than TF-CBT alone, however, considering the uncertainty associated with prescribing SSRIs to children and adolescents, clinicians and parents may exercise some caution in choosing this treatment alternative. PMID- 22490435 TI - Dietary omega-6 and omega-3 fatty acids and prostate cancer - letter. PMID- 22490436 TI - Cryptotanshinone activates p38/JNK and inhibits Erk1/2 leading to caspase independent cell death in tumor cells. AB - Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism is not well understood. Here, we show that CPT induced caspase independent cell death in human tumor cells (Rh30, DU145, and MCF-7). Besides downregulating antiapoptotic protein expression of survivin and Mcl-1, CPT increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c jun N-terminal kinase (JNK), and inhibited phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2). Inhibition of p38 with SB202190 or JNK with SP600125 attenuated CPT-induced cell death. Similarly, silencing p38 or c Jun also in part prevented CPT-induced cell death. In contrast, expression of constitutively active mitogen-activated protein kinase kinase 1 (MKK1) conferred resistance to CPT inhibition of Erk1/2 phosphorylation and induction of cell death. Furthermore, we found that all of these were attributed to CPT induction of reactive oxygen species (ROS). This is evidenced by the findings that CPT induced ROS in a concentration- and time-dependent manner; CPT induction of ROS was inhibited by N-acetyl-L-cysteine (NAC), a ROS scavenger; and NAC attenuated CPT activation of p38/JNK, inhibition of Erk1/2, and induction of cell death. The results suggested that CPT induction of ROS activates p38/JNK and inhibits Erk1/2, leading to caspase-independent cell death in tumor cells. PMID- 22490437 TI - Does vitamin E prevent or promote cancer? AB - The cancer preventive activity of vitamin E has been suggested by many epidemiologic studies. However, several recent large-scale human trials with alpha-tocopherol, the most commonly recognized and used form of vitamin E, failed to show a cancer preventive effect. The recently finished follow-up of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) even showed higher prostate cancer incidence in subjects who took alpha-tocopherol supplementation. The scientific community and the general public are faced with a question: "Does vitamin E prevent or promote cancer?" Our recent results in animal models have shown the cancer preventive activity of gamma- and delta-tocopherols as well as a naturally occurring mixture of tocopherols, and the lack of cancer preventive activity by alpha-tocopherol. On the basis of these results as well as information from the literature, we suggest that vitamin E, as ingested in the diet or in supplements that are rich in gamma- and delta-tocopherols, is cancer preventive; whereas supplementation with high doses of alpha-tocopherol is not. PMID- 22490438 TI - Constitutive nuclear localization of NFAT in Foxp3+ regulatory T cells independent of calcineurin activity. AB - Foxp3 plays an essential role in conferring suppressive functionality to CD4(+)/Foxp3(+) regulatory T cells (Tregs). Although studies showed that Foxp3 has to form cooperative complexes with NFAT to bind to target genes, it remains unclear whether NFAT is available in the nucleus of primary Tregs for Foxp3 access. It is generally believed that NFAT in resting cells resides in the cytoplasm, and its nuclear translocation depends on calcineurin (CN) activation. We report that a fraction of NFAT protein constitutively localizes in the nucleus of primary Tregs, where it selectively binds to Foxp3 target genes. Treating Tregs with CN inhibitor does not induce export of NFAT from the nucleus, indicating that its nuclear translocation is independent of CN activity. Consistently, Tregs are resistant to CN inhibitors in the presence of IL-2 and continue to proliferate in response to anti-CD3 stimulation, whereas proliferation of non-Tregs is abrogated by CN inhibitors. In addition, PMA, which activates other transcription factors required for T cell activation but not NFAT, selectively induces Treg proliferation in the absence of ionomycin. TCR interaction with self-MHC class II is not required for PMA-induced Treg proliferation. Tregs expanded by PMA or in the presence of CN inhibitors maintain Treg phenotype and functionality. These findings shed light on Treg biology, paving the way for strategies to selectively activate Tregs. PMID- 22490439 TI - Host genetic factors in susceptibility to herpes simplex type 1 virus infection: contribution of polymorphic genes at the interface of innate and adaptive immunity. AB - HSV-1 establishes life-long latency that can result in clinical relapses or in asymptomatic virus shedding. Although virtually all adults have been exposed to HSV-1, the clinical course varies remarkably. Genetic host variability could be related to this clinical diversity. In this study, we analyzed the contribution of gene families in chromosomes 1, 6, 12, and 19, which encode key regulators of the innate and adaptive immunity, in a cohort of 302 individuals. Class I and class II alleles of the HLA system, the copy-number variation of NK cell receptor genes (KIR and NKG2C), the combinations of killer cell Ig-like receptor and their HLA ligands, and CD16A and CD32A allotypes of variable affinity for IgG subclasses were all studied. Although no major susceptibility locus for HSV-1 was identified, our results show that the risk of suffering clinical HSV-1 infection is modified by MHC class I allotypes (B*18, C*15, and the group of alleles encoding A19), the high-affinity receptor/ligand pair KIR2DL2/HLA-C1, and the CD16A-158V/F dimorphism. Conversely, HLA class II and CD32A polymorphisms and NKG2C deletion did not seem to influence the clinical course of herpetic infection. Collectively, these findings support an important role in host defense against herpetic infection for several polymorphic genes implicated in adaptive immunity and in surveillance of its subversion. They confirm the crucial role of cytotoxic cells (CTL and NK) and the contribution of genetic diversity to the clinical course of HSV-1 infection. PMID- 22490441 TI - Infant B cell memory differentiation and early gut bacterial colonization. AB - Germ-free animal models have demonstrated that commensal bacterial colonization of the intestine induces B cell differentiation and activation. Whether colonization with particular bacterial species or groups is associated with B cell development during early childhood is not known. In a prospective newborn/infant cohort including 65 Swedish children, we examined the numbers and proportions of CD20(+), CD5(+), and CD27(+) B cells in blood samples obtained at several time points during the first 3 y of life using flow cytometry. Fecal samples were collected and cultured quantitatively for major facultative and anaerobic bacteria at 1, 2, 4, and 8 wk of life. We found that the numbers of CD20(+) B cells and CD5(+)CD20(+) B cells reached their highest levels at 4 mo, whereas CD20(+) B cells expressing the memory marker CD27 were most numerous at 18 and 36 mo of age. Using multivariate analysis, we show that early colonization with Escherichia coli and bifidobacteria were associated with higher numbers of CD20(+) B cells that expressed the memory marker CD27 at 4 and 18 mo of age. In contrast, we were unable to demonstrate any relation between bacterial colonization pattern and numbers of CD20(+) or CD5(+)CD20(+) B cells. These results suggest that the intestinal bacterial colonization pattern may affect the B cell maturation also in humans, and that an early gut microbiota including E. coli and bifidobacteria might promote this maturation. PMID- 22490440 TI - SIRPalpha/CD172a and FHOD1 are unique markers of littoral cells, a recently evolved major cell population of red pulp of human spleen. AB - Asplenic individuals are compromised not only in their ability to destroy infectious agents, but are at increased risk for death from autoimmune disease, certain tumors, and ischemic heart disease. Enhanced mortality is attributed to lack of phagocytes sequestered in spleen that efficiently engulf and destroy appropriate targets, although related cells are found elsewhere. To determine whether a unique population regulates RBC-pathogen clearance and filtration of altered self, we reviewed the anatomic literature and analyzed in situ by immunohistochemistry and immunofluorescence the expression patterns of a little characterized cell that dominates the splenic red pulp of humans and closely related primates: the venous sinus-lining or littoral cell (LC). High expression of the formin homology domain protein 1 outlines the LC population. Although LCs are endothelial-like in distribution, they express several macrophage-directed proteins, the RBC Duffy Ag receptor for chemokines and T cell coreceptor CD8alpha/alpha, yet they lack lineage-associated markers CD34 and CD45. Strikingly, SIRPalpha (CD172a) expression in human spleen concentrates on LCs, consistent with recent demonstration of a key role in RBC turnover and elimination versus release of infected or altered self. Our results indicate human LCs (SIRPalpha(+), formin homology domain protein 1(+), CD8alpha/alpha(+), CD34(-), CD45(-)) comprise a highly plastic barrier cell population that emerged late in primate evolution coordinate with CD8 expression. Unique to Hominidae, LCs may be the ultimate determinant of which cells recirculate after passage through human spleen. PMID- 22490442 TI - The dual effects of B cell depletion on antigen-specific T cells in BDC2.5NOD mice. AB - B cells play a critical role in the pathogenesis of autoimmune diabetes. To investigate the mechanisms by which B cell depletion therapy attenuates islet beta cell loss and particularly to examine the effect of B cells on both diabetogenic and regulatory Ag-specific T cells, we generated a transgenic BDC2.5NOD mouse expressing human CD20 on B cells. This allowed us to deplete B cells for defined time periods and investigate the effect of B cell depletion on Ag-specific BDC2.5 T cells. We depleted B cells with anti-human CD20 Ab using a multiple injection protocol. We studied two time points, before and after B cell regeneration, to examine the effect on BDC2.5 T cell phenotype and functions that included antigenic response, cytokine profile, diabetogenicity, and suppressive function of regulatory T (T(reg)) cells. We found unexpectedly that B cell depletion induced transient aggressive behavior in BDC2.5 diabetogenic T cells and reduction in T(reg) cell number and function during the depletion period. However, after B cell reconstitution, we found that more regenerated B cells, particularly in the CD1d(-) fraction, expressed immune regulatory function. Our results suggest that the regenerated B cells are likely to be responsible for the therapeutic effect after B cell depletion. Our preclinical study also provides direct evidence that B cells regulate both pathogenic and T(reg) cell function, and this knowledge could explain the increased T cell responses to islet Ag after rituximab therapy in diabetic patients in a recent report and will be useful in design of future clinical protocols. PMID- 22490444 TI - Changes to the law on consent in South Africa: implications for school-based adolescent sexual and reproductive health research. AB - BACKGROUND: The National Health Act, No 61, 2003 in South Africa is the first effort made by the government to protect health-related research participants under law. Implemented on March 1, 2012, the law mandates active consent from a parent or legal guardian for all research conducted with research participants under the age of 18 years. This paper focuses on the Act's implications for school-based adolescent sexual and reproductive health research. DISCUSSION: Although well intentioned, the added legal protections in the National Health Act may have the unintended consequence of reducing participation rates in school based adolescent sexual and reproductive health research, thereby excluding the most at-risk students. The Act may also compromise adolescents' right to dignity and privacy, especially considering the personal nature of research on sex and sexuality. Devolved, discretionary decision-making, which empowers local human research ethics committees to permit a wider range of protective measures, including passive consent, independent adolescent consent or community consultation ought to be considered. The continued and direct involvement of young people in their sexual and reproductive health and well-being is an important principle to uphold. SUMMARY: This paper calls for a re-examination of section 71's ethical guidelines relating to informed consent in the National Health Act, No 61, 2003 in South Africa in order to better serve the interests of South African adolescents in sexual and reproductive health research. PMID- 22490443 TI - IL-22 is expressed by the invasive trophoblast of the equine (Equus caballus) chorionic girdle. AB - The invasive trophoblast cells of the equine placenta migrate into the endometrium to form endometrial cups, dense accumulations of trophoblast cells that produce equine chorionic gonadotropin between days 40 and 120 of normal pregnancy. The mechanisms by which the trophoblast cells invade the endometrium while evading maternal immune destruction are poorly defined. A gene expression microarray analysis performed on placental tissues obtained at day 34 of gestation revealed a >900-fold upregulation of mRNA encoding the cytokine IL-22 in chorionic girdle relative to noninvasive chorion. Quantitative RT-PCR assays were used to verify high expression of IL-22 in chorionic girdle. Additional quantitative RT-PCR analysis showed a striking increase in IL-22 mRNA expression in chorionic girdle from days 32 to 35 and an absence of IL-22 expression in other conceptus tissues. Bioinformatic analysis and cDNA sequencing confirmed the predicted length of horse IL-22, which carries a 3' extension absent in IL-22 genes of humans and mice, but present in the cow and pig. Our discovery of IL-22 in the chorionic girdle is a novel finding, as this cytokine has been previously reported in immune cells only. IL-22 has immunoregulatory functions, with primary action on epithelial cells. mRNA of IL-22R1 was detected in pregnant endometrium at levels similar to other equine epithelia. Based upon these findings, we hypothesize that IL-22 cytokine produced by the chorionic girdle binds IL-22R1 on endometrium, serving as a mechanism of fetal-maternal communication by modulating endometrial responses to trophoblast invasion. PMID- 22490445 TI - Genes with bimodal expression are robust diagnostic targets that define distinct subtypes of epithelial ovarian cancer with different overall survival. AB - In some cancer types, certain genes behave as molecular switches, with on and off expression states. These genes tend to define tumor subtypes associated with different treatments and different patient survival. We hypothesized that clinically relevant molecular switch genes exist in epithelial ovarian cancer. To test this hypothesis, we applied a bimodal discovery algorithm to a publicly available ovarian cancer expression microarray data set, GSE9891 [285 tumors: 246 malignant serous (MS), 20 endometrioid (EM), and 18 low malignant potential (LMP) ovarian carcinomas]. Genes with robust bimodal expression patterns were identified across all ovarian tumor types and also within selected subtypes: 73 bimodal genes demonstrated differential expression between LMP versus MS and EM; 22 bimodal genes distinguished MS from EM; and 14 genes had significant association with survival among MS tumors. When these genes were combined into a single survival score, the median survival for patients with a favorable versus unfavorable score was 65 versus 29 months (P < 0.0001, hazard ratio = 0.4221). Two independent data sets [high-grade, advanced-stage serous (n = 53) and advanced-stage (n = 119) ovarian tumors] validated the survival score performance. We conclude that genes with bimodal expression patterns not only define clinically relevant molecular subtypes of ovarian carcinoma but also provide ideal targets for translation into the clinical laboratory. PMID- 22490446 TI - Divergent pathways for the angiotensin-(1-12) metabolism in the rat circulation and kidney. AB - Evidence of endogenous angiotensin-(1-12) [Ang-(1-12)] may necessitate revision of the accepted view that Ang I is the immediate peptide product derived from the precursor protein angiotensinogen. As the processing of this peptide has not been fully elucidated, we characterized Ang-(1-12) metabolism in the serum and kidney of the mRen2.Lewis rat, a model of high circulating renin and ACE expression. A sensitive HPLC-based method to detect the metabolism ex vivo of low concentrations of (125)I-labeled Ang-(1-12) was utilized. Ang-(1-12) processing to serum did not reveal the participation of renin; however, serum ACE readily converted Ang-(1-12) to Ang I with subsequent metabolism to Ang II. Ang I and Ang II forming activities for serum ACE were 102+/-4 and 104+/-3 fmol/ml/min serum (n=3), respectively, and both products were abolished by the potent ACE inhibitor lisinopril. The metabolism of Ang-(1-12) in renal cortical membranes also revealed the formation of Ang I; however, the main products were Ang-(1-7) and Ang-(1-4) at 129+/-9 and 310+/-12 fmol/mg/min protein (n=4), respectively. Neprilysin inhibition abolished these products and substantially reduced the overall metabolism of Ang-(1-12). Incubation of Ang-(1-12) with either human or mouse neprilysin revealed identical products. We conclude that endogenous Ang-(1 12) may contribute to the expression of biologically active angiotensins through a renin-independent pathway. The preferred route for Ang-(1-12) metabolism likely reflects the relative tissue content of ACE and neprilysin. PMID- 22490447 TI - Inhibitory role of kinins on microglial nitric oxide and tumor necrosis factor alpha production. AB - Brain inflammation is sustained by chronic activation of microglia and the over production of pro-inflammatory cytokines and nitric oxide (NO), which in turn can be highly neurotoxic. Microglial activation can be regulated by neuropeptides such as bradykinin (BK) and other members of the kinin family. Kinins are well known inflammatory regulators outside the CNS. Although the kinin system is well distributed throughout the brain, the precise role of BK in the CNS is not yet clear. The aim of this study was to examine and characterize the effects of BK and related kinins on the production of NO and TNF-alpha in microglia. We found that BK and selective agonists for both B1 and B2 receptors, attenuated both NO and TNF-alpha levels in the media of BV2 microglial cells that had been stimulated with LPS. The effects of BK that were observed in BV2 cells were confirmed in primary neonatal rat microglial cells as well. In addition, all kinin agonists reduced the expression of iNOS and TNF-alpha protein and mRNA levels in LPS-stimulated BV2 cells. Also, while LPS activated the nuclear factor kappaB (NF-kappaB) pathway, BK inhibited NF-kappaB activation by preventing degradation of the kappaB protein (IkappaB) inhibitor, abolishing translocation of p65 and p50 subunits to the nucleus and inhibiting NF-kappaB transcription activity. These results suggest a role for bradykinin in modulation of glial inflammation, as evidenced by attenuation of NO and TNF-alpha synthesis pathways in activated microglial cells. PMID- 22490448 TI - Effects of the antimicrobial peptide cecropin AD on performance and intestinal health in weaned piglets challenged with Escherichia coli. AB - This study was conducted to determine the effects of the antimicrobial peptide cecropin on performance and intestinal health in piglets. Newly weaned barrows were randomly assigned to one of three treatments (n=8), including a corn-soybean basal diet or similar diets supplemented with antibiotics (100 mg/kg kitasamycin plus 800 mg/kg colistin sulfate) or 400 mg/kg cecropin AD. On day 13, all piglets were orally challenged with 10(9)CFU/mL of Escherichia coli K88. On day 19, all piglets were euthanized and sampled. Before challenge, piglets fed antibiotics had greater weight gain, feed efficiency, nitrogen and energy retention than the control (P<0.05). E. coli challenge decreased weight gain, feed intake and feed efficiency for the control piglets (P<0.05) but not for the antibiotic or cecropin AD treated piglets. The incidence of diarrhea post-challenge in the antibiotic and cecropin AD treatments decreased compared with the control piglets. The total viable counts of cecal E. coli were lower while the Lactobacilli counts were higher in the antibiotic and cecropin AD treatments compared with the control (P<0.05). Cecropin AD treatment decreased total aerobes while increasing total anaerobes in the ileum (P<0.05). A higher villus height to crypt depth ratio in the jejunum and ileum as well as a deeper crypt depth in the jejunum and higher villus height in the ileum were observed in piglets fed antibiotics or cecropin AD compared with control piglets (P<0.05). Piglets fed the control diet had lower levels of secretory IgA in their jejunum and lower serum IgA, IgG, interleukin-1beta and interleukin-6 compared with the other treatments (P<0.05). Overall, these data suggest that cecropin AD enhances pig performance through increasing immune status and nitrogen and energy retention as well as reducing intestinal pathogens in weaned piglets. PMID- 22490449 TI - Bilateral temporomandibular joint pain as the first and only symptom of ischemic cardiac disease: a case report. AB - Pain of ischemic and non-ischemic cardiac disease can be referred to the craniofacial region. Also, in 6% of patients, craniofacial pain can be the first and only and symptom of cardiac ischemia. Missed diagnoses of these cases may lead to unnecessary dental treatment and a significant number of deaths in patients with atypical symptoms of coronary disease. Therefore the aim of this report, was to present a 48-year-old man with a chief compliant of severe bilateral pain in the temporomandibular joint who was referred to us for evaluation of a suspected temporomandibular disorder. Clinical and radiological examinations we did not find any origin for his pain. The patient was referred for cardiological evaluation (exercise test, electrocardiography, laboratory tests and coronary angiography) and was diagnosed with angina pectoris. The patient had no previous history of heart disease or chest pain. In conclusion, awareness of this symptomatology can be useful for diagnosis of coronary insufficiency and timely treatment. Therefore, cardiac disease should be considered in the differential diagnosis of orofacial pain. PMID- 22490450 TI - Health-related physical fitness management for a child with Tourette syndrome. AB - Tourette syndrome (TS) is a neurobiological disorder characterized by tics, which are repetitive, stereotypical, involuntary movements and vocalizations. Although the causes of TS are not completely understood, previous studies indicated that many children with TS not only experience comorbid conditions such as a lack of concentration, hyperactivity, impulsive behavior, and obsessive-compulsive symptoms, but also demonstrate poorer motor skills than their peers with typical development. There is limited information on health-related fitness exercises and/or physical therapy for children with TS. A 12-year-old boy with TS demonstrated below-age appropriate motor function with a less optimal musculoskeletal condition, including pain in the posterior portion of both lower extremities. After performing individualized health-related physical fitness exercises, he demonstrated a better musculoskeletal condition and motor function. Unexpectedly, he reported he was able to suppress motor tics occasionally by doing stretching exercises. The results suggest that evaluation and management of health-related fitness may be helpful for children with TS. These promising results warrant further investigation of the impact of health-related physical exercises on children with TS. PMID- 22490451 TI - Unilateral ectopic kidney in the pelvis--a case report. AB - Abnormalities of the kidney and/or urinary tract are common, and are more common in males than females. We present a case of unilateral pelvic kidney on the left side in a 26-year-old man. A pelvic kidney is a rare entity with a low clinical incidence. An ectopic kidney is often associated with an increased incidence of stone formation as a result of stasis caused by the altered geometry of urinary drainage. PMID- 22490452 TI - Slipped upper femoral epiphysis: a case of missed diagnosis. AB - A slipped upper femoral epiphysis (SUFE) is a known hip disorder in adolescents in which the proximal femoral epiphysis slips and displaces relative to the metaphysis. We report an obese 12-year-old boy who presented with acute pain in the left hip after a fall. He was otherwise healthy with no prior joint pain. Pelvic radiography was misread twice before a second fall led to a severe SUFE. PMID- 22490453 TI - Acute pulmonary embolism in a patient with hypereosinophilia and psoriasis. AB - Peripheral blood hypereosinophilia reflects various underlying disorders. However, its thromboembolic consequences are not often highlighted. We report a case of acute pulmonary embolism in a 42 year-old male prisoner hospitalized for erythrodermic psoriasis who presented with generalized edema and shortness of breath. Severe eosinophilia (absolute eosinophil count 6232/MUL) was also noted. Although severe psoriasis can be associated with eosinophilia and metabolic syndrome, acute pulmonary embolism is very rare in these patients. Immobilization secondary to severe psoriatic arthritis and prolonged use of leg cuffs can exacerbate the formation of thromboembolism. Although investigating the underlying causes of eosinophilia is important, we would like to highlight the importance of being aware of thromboembolic events, especially in patients with other thrombotic risk factors. PMID- 22490454 TI - Unusual branching pattern of the external carotid artery in a cadaver. AB - With the increasing use of invasive diagnostic and interventional procedures in cardiovascular disease, it is important to document and understand the types and frequencies of vascular variations. A sound knowledge of neurovascular variations is important for surgeons who remove cervical lymph nodes, for anesthesiologists, and for vascular surgeons. The external carotid arterial system is a complex vascular system which nourishes the terminal areas of the head, face and neck. The branches of the external carotid artery are the key landmarks for adequate exposure and appropriate placement of cross-clamps on the carotid arteries during carotid endarterectomy, and understanding their anatomy is necessary to successfully remove plaque and minimize postoperative complications in a bloodless surgical field. Variations in the course, branching, and distribution of the carotid arteries are commonly encountered. We report an extremely rare variation in the branching of the external carotid artery noted during routine cadaver dissection. All branches in the carotid triangle arose close together from a common point just above the origin of the external carotid artery from the common carotid artery. The clinical importance of this variation is discussed. PMID- 22490455 TI - Anesthetic management of a repeat cesarean section in a parturient with severe peripartum cardiomyopathy requiring ECMO in a previous pregnancy: a case report. AB - The number of pregnant women with cardiac disease is increasing with improvements in technology. In addition, more people are part of the national health insurance plan. However, there are few reports concerning the best method for anesthesia and mode of delivery in these high-risk patients. We report a 29-year-old woman scheduled for a planned caesarean section, who had a history of severe peripartum cardiomyopathy requiring extracorporeal membrane oxygenation in a previous pregnancy. The patient had regular prenatal care in our obstetric clinic. At 29 weeks' gestation, she developed severe dyspnea. A chest radiograph revealed bilateral pulmonary edema and 2-dimensional echocardiography showed a global hypokinesis and severe valve regurgitation with left ventricular ejection fraction of 41.2%. She had an emergency caesarean section and a cardiovascular surgeon was consulted to stand-by. Anesthesia was induced by ketamine 25 mg, midazolam 2.5 mg and rocuronium 50 mg for rapid intubation. The patient tolerated the procedure well and was extubated on postoperative day 1. She was discharged one week after surgery. Postoperatively, the patient was followed in the obstetric and cardiovascular surgery outpatient departments and at 5 months after surgery she was in good condition without any complaints. PMID- 22490456 TI - Unusually high alanine aminotransferase to aspartate aminotransferase ratio in a patient with cyproterone-induced icteric hepatitis. AB - A 70-year-old man with prostatic adenocarcinoma received cyproterone acetate 200 mg per day. Three months later, mild fatigue and anorexia with elevation of the alanine aminotransferase (ALT) level to 1311 U/L, total bilirubin level to 14 mg/dL and prothrombin time of 15/11.9 seconds developed. At that time the aspartate aminotransferase (AST) level was only 82 U/L. Viral hepatitis and autoimmune markers were all negative. This hepatitis resolved quickly after cyproterone therapy was discontinued. One and a half years later, the patient was prescribed cyproterone 100 mg daily at another hospital where staff were unaware of his previous history. General malaise, upper abdominal pain and jaundice developed two months later. Laboratory studies at emergency room revealed an AST of 245 U/L, ALT of 255 U/L, total bilirubin of 8.2 mg/dL, amylase of 6055 U/L, prothrombin time of 15.2/11.1 seconds and platelet count of 68000 cells/mL. Although cyproterone was discontinued, the patient died of multiple organ failure 20 days after admission. This case report presents a rare situation with marked elevation of the ALT level without AST level elevation. This finding suggests that cyproterone may induce specific damage to the plasma membrane, and the mitochondria are not involved in the initial stage. PMID- 22490457 TI - High origin of an ulnar artery--development and surgical significance. AB - Variations in the main arteries of the upper limb are common and these anomalies can be of substantial interest to orthopedic surgeons, plastic surgeons, radiologists and anatomists. We present here a case of a high origin of the ulnar artery from the brachial artery found during anatomical dissection of a right upper limb of a 50-year-old man. This superficial ulnar artery, after running over the bicipital aponeurosis in the cubital fossa superficial to the flexor muscles in the forearm terminated as the superficial palmar arch in the hand. The embryological and clinical importance of the anomalous ulnar artery is discussed. PMID- 22490458 TI - Y-shaped colonic duplication: report of a case and literature review. AB - Colonic duplication is a very rare congenital anomaly that is usually detected in infancy and early childhood. In the English literature, 6 cases of Y-shaped colonic duplication have been reported since 1953. We conducted a review of the reported cases, and we present a new case of a Y-shaped duplication of the sigmoid colon manifesting as long-term abdominal pain and constipation. PMID- 22490459 TI - Cisplatin-induced acute hyponatremia leading to a seizure and coma: a case report. AB - We report a rare case of cisplatin-induced acute hyponatremia leading to a seizure and coma. A 66-year-old woman with breast cancer received adjuvant chemotherapy with docetaxel and cisplatin. She had no nausea, vomiting, or diarrhea during or after chemotherapy administration. She had an acute onset of a generalized seizure and coma on the fourth day after chemotherapy. On arrival in the emergency department, she was unconscious with a Glasgow Coma Score of 6 (eyes 1, verbal 1, motor 4). Computed tomography of the brain did not show any lesions. She had no underlying diseases except breast cancer. The laboratory studies showed severe hyponatremia (Na 113 mmol/L) with low plasma osmolality, and elevation of both urinary sodium and urinary osmolality. In addition, polyuria (about 4 L/day) was also noted. Her consciousness level gradually improved the next day with a rise in serum sodium after 3% NaCl infusion. She recovered fully with no sequelae. Assessment using the Naranjo probability scale suggested that cisplatin was the probable cause for the adverse event. The mechanism of hyponatremia induced by cisplatin in our case was thought to be renal salt wasting syndrome (RSWS). In conclusion, cisplatin-induced acute hyponatremia leading to seizures and coma is seen rarely. When RSWS is suspected, hypertonic saline should be administered. PMID- 22490460 TI - Spontaneous splenic rupture with hematoma in a patient with brucellosis. AB - Brucellosis is one of the most common zoonotic diseases worldwide with a variable frequency in European countries. Brucellosis is usually transmitted after direct contact with or consumption of dairy products from an infected animal. Initially, our patient, a 65 year-old man, had nonspecific manifestations of fever, malaise, headache, anorexia and arthralgia which are the classic symptoms of this disease. After the diagnosis of brucellosis had been confirmed by blood culture and serology, progressive thrombocytopenia developed in spite of appropriate antibiotic administration. Radiological investigation revealed imaging findings consistent with splenic rupture. The complete recovery was observed after administration of antibiotic therapy and platelet transfusion. Spontaneous rupture of the spleen with subcapsular hematoma is an extremely rare condition in brucellosis. We want to remind clinicians of this rare complication. PMID- 22490461 TI - A clinically-occult gastrointestinal stromal tumor in a Meckel's diverticulum presenting as hollow organ perforation. AB - Meckel's diverticulum is the most common congenital anomaly of the gastrointestinal tract. However, a neoplasm is a rare complication of Meckel's diverticulum. We report a case of a ruptured gastrointestinal stromal tumor (GIST) in a Meckel's diverticulum, presenting as hollow organ perforation, in a 76 year-old woman. To our knowledge, the case we presented here is the 6th report describing a perforated GIST within a Meckel's diverticulum. In addition, the diverticular neoplasm in our case was clinically occult because of an unusual tumor configuration. Since the treatment of asymptomatic Meckel's diverticula remains controversial, our case raises suspicion that managing asymptomatic Meckel's diverticula by pure observation may leave some clinically occult diverticular neoplasms untreated. The role of prophylactic diverticulectomy requires further evaluation. PMID- 22490462 TI - Supernumerary peronei in the leg musculature- utility for reconstruction. AB - Muscular variations in the lower extremity are frequently encountered when performing cadaveric dissections. The utility of supernumerary muscles assumes importance in reparative foot surgery. The purpose of the current case study is to report the unilateral presence of double peroneal muscles in the evertors of the foot. The peroneal compartment of an adult Indian male cadaver was dissected during a demonstration class for medical undergraduates. Two bellies of the peroneal longus and brevis muscles were observed. The peroneus longus split into two bellies, superficial and deep, while the brevis displayed superficial/lateral and deep/medial bellies. These additional bellies gained attachment to the lateral calcaneal surface. Disorders of the peroneal tendons provide a basis for lateral ankle pain and instability. Anatomical variants have been associated with lateral ankle diseases. Magnetic resonance imaging can demonstrate these soft tissue variants, and detailed information on the anatomy of the crural region enables a surgeon to plan an operation. This study shows duplication of the peroneal muscle, which may have an impact on reconstructive surgery. PMID- 22490463 TI - Bilateral metachronous osteosarcoma of the mandibular body: a case report. AB - Osteosarcoma of the jaw (JOS) is a rare phenomenon constituting 5% to 13% of all cases of osteosarcoma (OS). JOS has histological features similar to OS, but the biological behavior is different. The chief complaint of patients with long bone OS is pain, whereas patients with JOS usually have painless swelling as the first sign. OS may affect multiple sites. Multifocal or multicentric osteosarcoma is usually defined as metachronous (new tumors developing after initial treatment) or synchronous (multiple lesions at presentation) without pulmonary metastases. The incidence of this entity has been reported to be between 1% and 10% of all cases of OS. A 27-year-old man presented with bilateral metachronous osteosarcoma as painful swellings in the mandibular body. He was treated with a mandibulectomy and chemotherapy. Therefore, the physician should be aware that osteosarcomas can occur in different sites as true multicentric or metastatic lesions. PMID- 22490464 TI - Tumor lysis syndrome in patients with light chain multiple myeloma: report of two cases. AB - Tumor lysis syndrome (TLS) is a severe life-threatening complication which typically occurs in highly proliferative malignancies, such as Burkitt's lymphoma, acute leukemia or germ cell tumors. Although TLS is unusual in multiple myeloma, it should not be overlooked as it is associated with significant morbidity. In recent years, emerging new agents such as thalidomide and bortezomib have been found to be highly effective in the treatment of multiple myeloma. In this milieu, there is greater concern that the rate of TLS in multiple myeloma will increase. We herein report 2 patients with light chain multiple myeloma who developed TLS during treatment. One patient improved after hydration, allopurinol and forced diuresis. The other underwent hemodialysis because of oliguria. These 2 patients did not have heavy tumor burdens. They also lacked risk factors of TLS that were described in previous reports. Our experience suggests light chain myeloma with underlying myeloma kidney is associated with a risk of TLS. Clinical awareness, close monitoring and early intervention are the keystones in the management of these patients. PMID- 22490465 TI - Resolution-enhanced native acidic gel electrophoresis: a method for resolving, sizing, and quantifying prion protein oligomers. AB - The formation of beta-sheet-rich prion protein (PrP(beta)) oligomers from native or cellular PrP(c) is thought to be a key step in the development of prion diseases. To assist in this characterization process we have developed a rapid and remarkably high resolution gel electrophoresis technique called RENAGE (resolution-enhanced native acidic gel electrophoresis) for separating, sizing, and quantifying oligomeric PrP(beta) complexes. PrP(beta) oligomers formed via either urea/salt or acid conversion can be resolved by RENAGE into a clear set of oligomeric bands differing by just one subunit. Calibration of the size of the PrP(beta) oligomer bands was made possible with a cross-linked mouse PrP(90-232) ladder (1- to 11-mer) generated using ruthenium bipyridyl-based photoinduced cross-linking of unmodified proteins (PICUP). This PrP PICUP ladder allowed the size and abundance of PrP(beta) oligomers formed from urea/salt and acid conversion to be determined. This distribution consists of 7-, 8-, 9-, 10-, and 11-mers, with the most abundant species being the 8-mer. The high-resolution separation afforded by RENAGE has allowed us to investigate distinctive size and population changes in PrP(beta) oligomers formed under various conversion conditions, with various construct lengths, from various species or in the presence of anti-prion compounds. PMID- 22490466 TI - Development of a near-infrared fluorescence ELISA method using tyramide signal amplification. AB - In this study, we applied tyramide signal amplification (TSA) to fluorescence enzyme-linked immunosorbent assay (ELISA) employing horseradish peroxidase (HRP) as the detection enzyme. When used with a human epidermal growth factor ELISA kit, the TSA method led to a >100-fold increase in fluorescence signal intensity in comparison to an unamplified method. It also showed wider dynamic range and better sensitivity compared to a conventional method using tetramethylbenzidine as the HRP substrate. PMID- 22490467 TI - Active inclusion body formation using Paenibacillus polymyxa PoxB as a fusion partner in Escherichia coli. AB - Overexpression of Paenibacillus polymyxa PoxB in Escherichia coli induced the formation of inclusion bodies. An enzyme assay showed that the inclusion bodies exhibited PoxB activity, indicating that they were biologically active. Fusion of GFP and Bacillus subtilis AmyE to the C-terminus of the PoxB also induced the formation of biologically active aggregates when they were overexpressed in E. coli. Therefore, P. polymyxa PoxB can be used as a fusion partner to promote the formation of active inclusion bodies in E. coli. PMID- 22490468 TI - The use of underloaded C(18) solid-phase extraction plates increases reproducibility of analysis of tryptic peptides from unfractionated human plasma. AB - Bottom-up proteomics requires the digestion of proteins into peptides by processes that use salts for denaturing and buffering purposes. These salts need to be removed prior to mass spectrometry analysis to reduce ion suppression; solid-phase extraction (SPE) is a commonly used strategy. There are many commercially available SPE sorbent types and sizes, which are generally provided with manufacturer recommendations for use, including protein loading capacity. We found that these general suggestions were often not ideal, and our data suggest that context-specific evaluation of sorbent type and amount can improve reproducibility. Specifically, the universal Oasis HLB sorbent provided better retention of the more hydrophilic peptides than the traditional C(18) reversed phase SPE, but it did so at the expense of an increased loss of the more hydrophobic peptides. We found that increasing the amount of the C(18) sorbent beyond the manufacturer's guidelines decreased breakthrough (i.e., increased retention) of 12 hydrophilic, identifiable peptides without loss of hydrophobic peptides. This procedure was robust in a 96-well plate format. PMID- 22490469 TI - Expression of functional full-length hSRC-1 in eukaryotic cells using modified vaccinia virus Ankara and baculovirus. AB - Purified protein expression level and quality are contingent upon specific host expression systems. This differential production is particularly observed for proteins of high molecular weight, hampering further structural studies. We developed an expression method aimed at producing proteins in Escherichia coli, insect, and mammalian systems. Our novel protocol was used to produce in large scale the full-length 160-kDa steroid receptor coactivator 1 (SRC-1), a coregulator of nuclear receptors. The results indicate that we can produce biologically active human SRC-1 in mammalian and insect cells in large scale. PMID- 22490470 TI - Fatal myocarditis in a child with systemic onset juvenile idiopathic arthritis during treatment with an interleukin 1 receptor antagonist. AB - BACKGROUND: The pathologic diagnosis of isolated myocarditis without pericardial involvement is uncommonly encountered in systemic onset Juvenile Idiopathic Arthritis (soJIA). CASE: An eleven year-old boy with soJIA died suddenly while being treated with the interleukin 1 (IL-1) receptor inhibitor, anakinra. His autopsy revealed an enlarged heart and microscopic findings were consistent with myocarditis, but not pericarditis. Viral PCR testing performed on his myocardial tissue was negative. CONCLUSION: This case illustrates myocarditis as a fatal complication of soJIA, potentially enabled by anakinra. PMID- 22490471 TI - Integrating a quantitative risk appraisal in a health impact assessment: analysis of the novel smoke-free policy in Hungary. AB - BACKGROUND: Although the quantification of health outcomes in a health impact assessment (HIA) is scarce in practice, it is preferred by policymakers, as it assists various aspects of the decision-making process. This article provides an example of integrating a quantitative risk appraisal in an HIA performed for the recently adopted Hungarian anti-smoking policy which introduced a smoking ban in closed public places, workplaces and public transport vehicles, and is one of the most effective measures to decrease smoking-related ill health. METHODS: A comprehensive, prospective HIA was conducted to map the full impact chain of the proposal. Causal pathways were prioritized in a transparent process with special attention given to those pathways for which measures of disease burden could be calculated for the baseline and predicted future scenarios. RESULTS: The proposal was found to decrease the prevalence of active and passive smoking and result in a considerably positive effect on several diseases, among which lung cancer, chronic pulmonary diseases, coronary heart diseases and stroke have the greatest importance. The health gain calculated for the quantifiable health outcomes is close to 1700 deaths postponed and 16,000 life years saved annually in Hungary. CONCLUSION: The provision of smoke-free public places has an unambiguously positive impact on the health of the public, especially in a country with a high burden of smoking-related diseases. The study described offers a practical example of applying quantification in an HIA, thereby promoting its incorporation into political decision making. PMID- 22490472 TI - Seventeen-year time trend in poor self-rated health in older adults: changing contributions of chronic diseases and disability. AB - BACKGROUND: Studies on trends in the self-rated health (SRH) of older people have shown conflicting results, which might partly be explained by changing associations between SRH and indicators of other health dimensions over time. Therefore, this study investigates 17-year time trends in older adults' poor SRH, in the context of trends in chronic diseases and disability, between 1992 and 2009. METHODS: Data originate from six measurement waves of the Longitudinal Aging Study Amsterdam (N = 4009, ages 60-85 years). SRH was assessed with the question 'How is your health in general?' The presence of lung disease, cardiac disease, peripheral arterial disease, diabetes mellitus, stroke, arthritis and cancer was assessed by self-report. Two severity levels of disability were assessed with six questions on physical functioning. Generalized Estimating Equations (GEE) analysis was applied to assess statistical significance in each time trend. RESULTS: There was a stable trend in the prevalence of poor SRH and severe disability, while the mean number of chronic diseases (1.3-1.8) and the prevalence of mild disability (20.5-32.1%) increased between 1992 and 2009. The association between poor SRH and chronic diseases became weaker, whereas the association between poor SRH and severe disability became stronger over time. Most unfavourable trends were observed in the older old and the lower educated. CONCLUSION: Our results suggest that the seeming stability of poor SRH hides underlying increases in chronic diseases and disability: over time, people may attach importance to different aspects of health when rating their overall health. PMID- 22490473 TI - Naturalization of immigrants and perinatal mortality. AB - BACKGROUND: Differences in neonatal mortality among immigrants have been documented in Belgium and elsewhere, and these disparities are poorly understood. Our objective was to compare perinatal mortality rates in immigrant mothers according to citizenship status. METHODS: This was a population-based study using 2008 data from the Belgian birth register data pertaining to regions of Brussels and Wallonia. Odds ratio (OR) and 95% confidence intervals (95% CIs) for perinatal mortality according to naturalization status were calculated by logistic regression analyses adjusting for parents' medical and social characteristics. RESULTS: Four hundred and thirty-seven perinatal deaths were registered among 60,881 births (7.20/00). Perinatal mortality rate varied according to the origin of the mother and her naturalization status: among immigrants, non-naturalized immigrants had a higher incidence of perinatal mortality (10.30/00) than their naturalized counterparts (6.10/00) with an adjusted OR of 2.2, 95% CI (1.1-4.5). CONCLUSION: In a country with a high frequency of naturalization, and universal access to health care, naturalized immigrant mothers experience less perinatal mortality than their not naturalized counterparts. PMID- 22490474 TI - Impact of potentially lethal ventricular arrhythmias on long-term outcome in patients with chronic heart failure. AB - BACKGROUND: Potentially lethal ventricular arrhythmias (PLVAs) occur frequently in survivors after acute myocardial infarction and are increasingly recognized in other forms of structural heart diseases. This study investigated the prevalence and prognostic significance of PLVAs in patients with chronic heart failure (CHF). METHODS: Data concerning demographics, etiology of heart failure, NYHA functional class, biochemical variables, electrocardiographic and echocardiographic findings, and medical treatments were collected by reviewing hospital medical records from 1080 patients with NYHA II-IV and a left ventricular (LV) ejection fraction <= 45%. PLVAs were defined as multi-focal ventricular ectopy (> 30 beats/h on Holter monitoring), bursts of ventricular premature beats, and nonsustained ventricular tachycardia. All-cause mortality, sudden death, and rehospitalization due to worsening heart failure, or cardiac transplantation during 5-year follow-up after discharge were recorded. RESULTS: The occurrence rate of PLVAs in CHF was 30.2%, and increased with age; 23.4% in patients < 45 years old, 27.8% in those between 45 - 65 years old, and 33.5% in patients > 65 years old (P = 0.033). Patients with PLVAs had larger LV size and lower ejection fraction (both P < 0.01) and higher all-cause mortality (P = 0.014) during 5-year follow-up than those without PLVAs. Age (OR 1.041, 95%CI 1.004 - 1.079, P = 0.03) and LV end-diastolic dimension (OR 1.068, 95%CI 1.013 - 1.126, P = 0.015) independently predicted the occurrence of PLVAs. And PLVA was an independent factor for all-cause mortality (RR 1.702, 95%CI 1.017 - 2.848, P = 0.031) and sudden death (RR 1.937, 95%CI 1.068 - 3.516, P = 0.030) in patients with CHF. CONCLUSION: PLVAs are common and exert a negative impact on long-term clinical outcome in patients with CHF. PMID- 22490475 TI - Combination of high-sensitivity C-reactive protein and homocysteine may predict an increased risk of coronary artery disease in Korean population. AB - BACKGROUND: The association of emerging biomarkers such as high-sensitivity C reactive protein (hs-CRP), homocysteine and fibrinogen with the risk of coronary artery disease (CAD) is still uncertain in Asian population including Koreans and little is known about the combined effect of biomarkers on the risk of CAD. METHODS: A total of 10 650 subjects (6538 men and 4112 women) were enrolled in this study. A 10-year CAD risk was calculated using Framingham risk score modified by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) and levels of circulating hs-CRP, homocysteine and fibrinogen were measured using validated assays. RESULTS: The 10-year CAD risk gradually augmented with increase in the circulating levels of hs-CRP, homocysteine and fibrinogen. For the highest quartile of hs-CRP, odds ratio (OR) of high-risk for CAD (10-year risk >= 20%) compared with the lowest quartile was 3.97 (95%CI: 2.51 - 6.29). For homocysteine and fibrinogen, ORs in the highest quartile compared to the lowest quartile were 5.10 (95%CI: 3.05 - 8.53, P < 0.001) and 1.46 (95%CI: 0.69 - 3.11, P = 0.325), respectively. OR of high-risk for CAD in both the highest quartile of hs-CRP and homocysteine was 9.05 (95%CI: 5.30 - 15.45) compared with the below median of hs-CRP and homocysteine. CONCLUSIONS: The present study demonstrated that hs-CRP and homocysteine are well associated with the 10-year CAD risk estimated using NCEP ATP III in Koreans and combination of hs-CRP and homocysteine can have strong synergy in predicting the development of CAD. PMID- 22490476 TI - Multicenter follow-up study of ankle fracture surgery. AB - BACKGROUND: Few data on ankle fractures in China from large multicenter epidemiological and clinical studies are available. The aim of this research was to evaluate the epidemiological features and surgical outcomes of ankle fractures by reviewing 235 patients who underwent ankle fracture surgery at five hospitals in China. METHODS: This study included patients who underwent ankle fracture surgery at five Chinese hospitals from January 2000 to July 2009. Age, gender, mechanism of injury, Arbeitsgemeinschaft fur Osteosynthesefragen (AO) fracture type, fracture pattern, length of hospital stay and treatment outcome were recorded. Statistical analyses were conducted using SPSS software. The American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale, visual analogue scale (VAS), and arthritis scale were used to evaluate outcome. RESULTS: Of 235 patients with ankle fractures, 105 were male with an average age of 37.8 years and 130 were female with an average age of 47.3 years. The average follow-up period was 55.7 months. There were significant differences in the ratios of patients in different age groups between males and females, and in mechanisms of injury among different age groups. There were also significant differences in the length of hospital stay among different fracture types and mechanisms of injury. In healed fractures, the average AOFAS ankle-hindfoot score was 95.5, with an excellence rate of 99.6%, the average VAS score was 0.17, and the average arthritis score was 0.18. Movement of the injured ankle was significantly different to that of the uninjured ankle. There were no significant differences between AO fracture types, fracture patterns or follow-up periods and AOFAS score, but there were some significant differences between these parameters and ankle joint movements, pain VAS score and arthritis score. CONCLUSIONS: Ankle fractures occur most commonly in middle-aged and young males aged 20 - 39 years and in elderly females aged 50 - 69 years. The most common mechanisms of injury are twisting injuries and falls from a standing height or less. The results of surgical treatment are satisfactory. PMID- 22490477 TI - Preemptive analgesic effects of flurbiprofen axetil in patients undergoing radical resection of esophageal carcinoma via the left thoracic approach. AB - BACKGROUND: Systemic non-steroidal anti-inflammatory drugs have been evaluated for their possible preemptive analgesic effects. The efficacy of flurbiprofen axetil for preemptive analgesia in patients undergoing radical resection of esophageal carcinoma via the left thoracic approach needs further investigation. The aim of this study was to research the preemptive analgesic effects of flurbiprofen axetil in thoracic surgery, and the influence of preoperative administration on postoperative respiratory function. METHODS: This randomized, double-blind, controlled trial enrolled 60 patients undergoing radical resection of esophageal carcinoma via the left thoracic approach. Anesthesia management was standardized. Each patient was randomly assigned to receive either 100 mg flurbiprofen axetil intravenously 15 minutes before incision (PA group) or intravenous normal saline as a control (C group). Postoperative analgesia was with sufentanil delivered by patient-controlled analgesia pump. Postoperative sufentanil consumption, visual analog scale pain scores, plasma levels of interleukin-8, and oxygenation index were measured. RESULTS: Compared with the preoperative baseline, postoperative patients in the PA group had no obvious increase in pain scores (P > 0.05), but patients in the C group had significantly increased pain scores (P < 0.05). Pain scores in the C group were significantly higher at 24 hours postoperatively than preoperatively. Intergroup comparisons showed lower visual analog scale scores at 2 - 24 hours postoperatively in the PA group than the C group (P < 0.05). Sufentanil consumption and plasma interleukin 8 levels at 2 and 12 hours postoperatively were significantly lower in the PA group than the C group (P < 0.05). The oxygenation index at 2 and 12 hours postoperatively was significantly higher in the PA group than the C group (P < 0.05). CONCLUSIONS: Intravenous flurbiprofen axetil appears to have a preemptive analgesic effect in patients undergoing radical resection of esophageal carcinoma via the left thoracic approach, and appears to contribute to recovery of respiratory function and to reduction of the postoperative inflammatory reaction. PMID- 22490478 TI - Association of serum uric acid levels with the progression of Parkinson's disease in Chinese patients. AB - BACKGROUND: Uric acid (UA) is suspected to play a neuro-protective role in Parkinson's disease (PD). This study aimed to evaluate whether the serum UA level was associated with the disease progression of PD in a relatively large population of Chinese patients. METHODS: Serum UA levels were measured from 411 Chinese PD patients and 396 age-matched controls; following the uric acid colorimetric method, the serum creatinine (Scr) levels were also measured to reduce the bias caused by possible differences in renal excretion function. The disease progression was scored by Hoehn and Yahr (H&Y) scales and disease durations; PD group was divided into 3 subgroups according to H&Y scales. Independent-samples t test was performed to analyze the differences between PD group and control group. Multiple analysis of covariance was performed to analyze the differences between PD subgroups. Spearman rank-correlation was performed to evaluate the associations between serum UA or Scr level and disease progression. RESULTS: PD patients were found to have significantly lower levels of serum UA than controls ((243.38 +/- 78.91) vs. (282.97 +/- 90.80) umol/L, P < 0.01). As the disease progression, the serum UA levels were gradually reduced. There was a significantly inverse correlation of UA levels with H&Y scales (Rs = -0.429, P < 0.01) and disease duration (Rs = -0.284, P < 0.01) in PD patients of both females and males. No significant difference of the Scr level between PD patients and controls was found ((70.01 +/- 14.70) vs. (69.84 +/- 16.46) umol/L), and the Scr level was not involved in disease progression. CONCLUSION: Lower serum UA levels may possess a higher risk of PD, which may be a potential useful biomarker to indicate the progression of PD. PMID- 22490479 TI - Lack of association between three single nucleotide polymorphisms in the PARK9, PARK15, and BST1 genes and Parkinson's disease in the northern Han Chinese population. AB - BACKGROUND: Parkinson's disease (PD) is an autosomally inherited neurodegenerative disease in elderly people. The etiology of PD has long been thought to be associated with both genetic and environmental factors. To explore potential genetic risk factors for PD in the northern Han Chinese population, we investigated three single nucleotide polymorphisms (SNPs) (rs4538475, rs11107 and rs12564040) in the BST1, PARK15 and PARK9 genes. METHODS: Genomic DNA from 215 PD patients and 212 matched controls was amplified in two independent PCR systems and subsequently genotyped by digestion with the endonuclease PstI. Genetic parameter and association studies were carried out with SPSS 13.0 and PLINK 1.07 software. RESULTS: We could accurately detect all genotypes in the three loci with the PCR-RFLP or mismatched PCR-RFLP techniques. The observed heterozygosities of the rs4538475 and rs11107 loci in PD and control groups ranged from 0.460 - 0.481 and 0.410 - 0.441, in BST1, PARK15 respectively, while we detected no heterozygosity at the rs12564040 locus in PARK9. The similar distributions of genotypic frequency between both groups suggest that the three SNPs investigated in this study are unlikely to play roles as common risk factors or pathogenic mutations for PD in northern Han Chinese. CONCLUSION: The SNPs investigated in the BST1, PARK15 and PARK9 genes associated with PD susceptibility are not associated with PD in the northern Han Chinese population. PMID- 22490480 TI - The more, the less: age and chemotherapy load are predictive of poor stem cell mobilization in patients with hematologic malignancies. AB - BACKGROUND: Intensive treatment such as autologous peripheral blood stem cell (PBSC) transplantation is an important therapeutic strategy in many hematologic malignancies. A number of factors have been reported to impact PBSC mobilization, but the predictive factors varied from one study to another. This retrospective study assessed our current mobilization and collection protocols, and explored the factors predictive of PBSC mobilization in patients with hematologic malignancies. METHODS: Data of 64 consecutive patients with hematologic malignancies (multiple myeloma, n = 22; acute leukemia, n = 27; lymphoma, n = 15) who underwent PBSC mobilization for over 1 year were analyzed. Four patients with response to treatment of near complete remission or better were administered granulocyte colony-stimulating factor (G-CSF) to mobilize PBSCs. Sixty patients received G-CSF followed by chemotherapy mobilizing regimens. Poor mobilization (PM) was defined as when <= 2.0'10(6) CD34(+) cells/kg body weight were collected within three leukapheresis procedures. RESULTS: The incidence of PM at the first mobilization attempt was 19% (12/64). The PM group was older than the non-PM group (median age, 51 vs. 40 years; P = 0.013). In univariate analysis, there were no significant differences in gender, diagnosis, and body weight between the PM and non-PM groups. A combination of chemotherapy and G-CSF was more effective than G-CSF alone as a mobilizing regimen (P = 0.019). Grade III or IV hematopoietic toxicity of chemotherapy had no significant effect on the mobilization efficacy. Supportive care and the incidence of febrile neutropenia were not significantly different between the two groups. In multivariate analysis, age (odds ratio (OR), 9.536; P = 0.002) and number of previous chemotherapy courses (OR 3.132; P = 0.024) were two independent negative predictive factors for CD34(+) cell yield. PM patients could be managed well by remobilization. CONCLUSION: Older age and a heavy load of previous chemotherapy are the negative risk factors for PBSC mobilization. PMID- 22490481 TI - Relative performance of two equations for estimation of glomerular filtration rate in a Chinese population having chronic kidney disease. AB - BACKGROUND: The new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was developed to address the systematic underestimation of glomerular filtration rate (GFR) by the Modification of Diet in Renal Disease (MDRD) Study equation in patients with relatively well-preserved kidney function. Performance of the new equation in the Chinese population is unknown. The goal of the present study was to compare performance of these two equations in Chinese patients with chronic kidney disease (CKD). METHODS: We enrolled 450 Chinese patients (239 women and 211 men) with CKD in the present study. The renal dynamic imaging method was used to measure the referenced standard GFR (rGFR) for comparison with estimations using the two equations. Their overall performance was assessed with the Bland-Altman method and receiver-operating characteristics (ROC) analysis. Performance of the two equations in lower and higher estimated GFR (eGFR) subgroups was further investigated. RESULTS: Both eGFRs correlated well with rGFR (r = 0.88, 0.81, P < 0.05). In overall performance, the CKD-EPI equation showed less bias, higher precision and improved accuracy, and was better for detecting CKD. In the higher-eGFR subgroup, the CKD-EPI equation corrected the underestimation of GFR by the abbreviated MDRD equation. CONCLUSIONS: The CKD-EPI equation outperformed the abbreviated MDRD equation not only in overall performance but also in the subgroups studied. For the present, the CKD-EPI equation appears to be the first-choice prediction equation for estimating GFR. PMID- 22490482 TI - The heterogeneity of aging brain: altered functional connectivity in default mode network in older adults during verbal fluency tests. AB - BACKGROUND: Successful aging (SA) and mild cognitive impairment (MCI) are heterogeneous groups of aging. To explore the heterogeneity, the functional connectivity was studied in these populations. METHODS: The present study utilized functional connectivity magnetic resonance imaging (fcMRI) to investigate default mode network (DMN) in 8 healthy subjects of SA, 8 subjects of usual aging (UA), and 8 MCI patients during verbal fluency tests (VFTs). Functional connectivity (based seeds) of different groups was analyzed by using statistical test. RESULTS: Compared with SA and UA groups, MCI subjects exhibited decreased functional connectivity in the DMN regions, including the inferior parietal lobule and left angular gyrus (t = 3.53, P < 0.001). Compared with UA and MCI groups, the SA elderly exhibited increased functional connectivity in the precuneus (t = 3.53, P < 0.001). CONCLUSIONS: These findings suggested that abnormalities of functional connectivity in DMN might be related with semantic memory impairment in aging. Left angular gyrus and precuneus might be the potential imaging-based biomarker for distinguishing heterogeneous process of elderly. PMID- 22490483 TI - Effect of basic fibroblast growth factor and transforming growth factor beta1 on the healing of reconstructed dura by carbon dioxide laser soldering in minipigs. AB - BACKGROUND: Carbon dioxide (CO2) laser soldering is an alternative technique for tissue bonding. Basic fibroblast growth factor (bFGF) and transforming growth factor beta(1) (TGFbeta(1)) are two key factors for wound healing. This study was performed to demonstrate the efficacy of CO2 laser soldering for dural reconstruction and the effect of bFGF and TGFbeta(1) on healing. METHODS: In Part I, 10 minipigs were randomized into two equal groups. Dural defects were reconstructed by conventional fibrin glue bonding (group I(a)) or CO2 laser soldering (group I(b)). The reconstructed dura was subjected to burst pressure (BP) measurement and immunohistochemical staining after 1 week. In Part II, 36 minipigs were randomized into three equal groups. Dural reconstruction was achieved by CO2 laser soldering. Exogenous bFGF (group II(b)) or TGFbeta(1) (group II(c)) was administered while group II(a) served as a control group. The specimens were subjected to BP measurement after 1, 2, 3, and 4 weeks, respectively. RESULTS: In Part I, the dura specimens displayed positive staining of only bFGF in group I(a) and of both bFGF and TGFbeta(1) in group I(b). Group I(b) showed higher BP than group I(a) ((98.00 +/- 21.41) mmHg vs. (70.80 +/- 15.09) mmHg, respectively; P < 0.05). In Part II, BP of group II(c) was significantly higher than that of group II(a) (P < 0.01). The BP of group II(a) trended toward stabilization after 3 weeks of growth, while that of groups II(b) and II(c) trended toward stabilization after 2 weeks of growth. CONCLUSIONS: CO2 laser soldering is a reliable technique for dural reconstruction. The superior healing of dural reconstruction by CO2 laser soldering may be related to higher expression of bFGF and TGFbeta(1), and CO2 lasers may stimulate their secretion. Exogenous bFGF or TGFbeta(1) may improve healing by shortening the wound healing time, and exogenous TGFbeta(1) may improve the tensile strength. PMID- 22490484 TI - E-cadherin mediates adhesion and endocytosis of Aspergillus fumigatus blastospores in human epithelial cells. AB - BACKGROUND: Aspergillus fumigatus (A. fumigatus) is a ubiquitous saprophytic fungus responsible for the majority of invasive mold infections in patients undergoing chemotherapy, organ transplantation or with persistent neutropenia. This study aimed to determine the role of E-cadherin for adhesion and endocytosis of A. fumigatus blastospores in the human epithelial cell line A549. METHODS: A. fumigatus blastospores were incubated with the total protein of A549 to investigate the binding of E-cadherin and blastospores followed by an affinity purification procedure. After establishing the adhesion model, the adhesion and endocytosis of A. fumigatus blastospores by A549 cells were evaluated by down regulating E-cadherin of A549 cells using blocking antibody or small interfering RNA (siRNA). RESULTS: E-cadherin was adhered to the surface of A. fumigatus blastospore. Adhesion and endocytosis of the blastospores were reduced by blocking or down-regulating E-cadherin in A549 cells. CONCLUSIONS: E-cadherin is a receptor for adhesion and endocytosis of A. fumigatus blastospores in epithelial cells. This may open a new approach to treat this fungal infection. PMID- 22490485 TI - Association of polymorphisms in the DCDC2 gene with developmental dyslexia in the Han Chinese. AB - BACKGROUND: Genetic association studies on populations of European origin have identified the DCDC2 gene as a susceptibility locus for developmental dyslexia. Here, we sought to investigate the association of DCDC2 polymorphisms with developmental dyslexia in children of Han Chinese origin. METHODS: We undertook a case-control genetic association study on 76 dyslexic children and 79 non dyslexic matched controls. We isolated DNA from oral mucosal cell samples and genotyped two DCDC2 coding-sequence single nucleotide polymorphisms, rs2274305 and rs6456593, in each sample using SNaPshot single nucleotide extension. We compared the allele and genotype frequencies between the groups using the chi(2) test and analyzed the relationship between dyslexia and the polymorphism at both loci using unconditional logistic regression. We also predicted haplotypes and compared their frequencies between the two groups. RESULTS: The differences in the genotype distribution and the allelic genes of the two single nucleotide luci of the DCDC2 gene, rs2274305 and rs6456593, between the two dyslexic and non dyslexic groups were statistically meaningless (P > 0.05). The differences in the haplotype distributions of the DCDC2 gene between the dyslexic and normal group were statistically meaningless (P > 0.05). CONCLUSION: The DCDC2 gene may not be a susceptibility factor for developmental dyslexia among the Han Chinese. However, methodological issues may have prevented the detection of positive associations. PMID- 22490486 TI - A single institution, retrospective study of treatment experience in primary mediastinal germ cell tumors: elucidating the significance of systemic chemotherapy. AB - BACKGROUND: Primary malignant germ cell tumors (GCTs) of mediastinum are rare neoplasms. We introduce our institutional experience in managing patients with primary malignant GCTs of the mediastinum, focusing on the analysis of therapeutic modalities. METHODS: A retrospective review was done in 39 consecutive patients with mediastinal malignant GCTs treated in our institution between 1991 and 2007. RESULTS: A total of 39 patients were enrolled in this study with a median age of 27 years. The 5-year overall survival (OS) and progression-free survival (PFS) rates of the whole population were 60.2% and 57.7%, respectively. Stratified by the histology, 18 patients (46.2%) had seminoma and 21 patients (53.8%) had nonseminomatous germ cell tumors (NSGCTs). The 5-year OS rate of patients with seminoma was 87.4% as compared with 36.7% in patients with NSGCTs (P = 0.0004). The 5-year PFS rate was also significantly higher in seminoma patients (87.4% vs. 31.6%, P = 0.003). For 19 patients with NSGCTs managed with multi-modality treatment, chemotherapy exposure appeared to impact the prognosis. The 5-year OS rate was 44.9% in patients with chemotherapy exposure as compared with 20.0% in patients without it (P = 0.43). CONCLUSION: Our study confirmed the significance of systemic chemotherapy in the treatment of primary mediastinal GCTs. PMID- 22490487 TI - Earlier application of loading doses of aspirin and clopidogrel decreases rate of recurrent cardiovascular ischemic events for patients undergoing percutaneous coronary intervention. AB - BACKGROUND: Aspirin and clopidogrel resistance plays a significant role in the development of cardiovascular ischemic events for ninety patients undergoing percutaneous coronary intervention. Recent studies have indicated that increasing the dose of antiplatelet drugs maybe a potent method to improve the inhibition of platelet aggregation. METHODS: Thrombelastograph (TEG) determinations were used to evaluate the effect of antiplatelet therapy. According to the results, 90 patients were divided into three groups and given different doses of aspirin and clopidogrel. Thirty patients with both an inhibition rate of aspirin > 50% and an inhibition rate of clopidogrel > 50% were defined as the control group. Sixty patients with an inhibition rate for aspirin < 50% and an inhibition rate for clopidogrel < 50% were defined as the resistance group. Patients in resistance group were randomly assigned to be given a routine dose (100 mg aspirin plus 75 mg clopidogrel per day, which we called a resistance plus routine dose group, R + R) and a loading dose (200 mg aspirin and 150 mg clopidogrel per day, which we called resistance plus loading dose group, R + L) of antiplatelet therapy. A 12 month follow-up was observed to examine the change of inhibition rate of antiplatelet therapy and to estimate the relationship between inhibition rate and the occurrence of cardiovascular ischemic events. RESULTS: After 6 months of antiplatelet therapy, the inhibition rate of aspirin in the R + L group increased from (31.4 +/- 3.7)% to (68.6 +/- 7.1)%, which was significantly higher than that in R + R group, (51.9 +/- 8.2)% (P < 0.01). The inhibition rate of clopidogrel in the R + L group increased from (22.1 +/- 3.8)% to (60.2 +/- 7.4)%, which was significantly higher than in the R + R group, (45.9 +/- 4.3)% (P < 0.01). The occurrence rates of cardiovascular ischemic events, stent thrombosis, recurrent unstable angina and myocardial infarction in the R + R group were 20%, 36% and 17%, respectively. Occurrence was significantly increased compared with that in the control group, 3%, 10% and 1%, respectively (P < 0.01). In contrast, the occurrence rates in the R + L group (10%, 23% and 6%, respectively) were attenuated compared with those in the R + R group (P < 0.01), although still higher than in the control group (P < 0.01). CONCLUSIONS: Almost all of the cardiovascular ischemic events occurred in the first six months after percutaneous coronary intervention. According to the result of TEG determinations, earlier application of a loading dose of aspirin and clopidogrel can decrease the rate of recurrent cardiovascular ischemic events. PMID- 22490488 TI - Efficacy and significance of various scores for pneumonia severity in the management of patients with community-acquired pneumonia in China. AB - BACKGROUND: Community-acquired pneumonia (CAP) remains one of the leading causes of death from infectious diseases around the world. Most severe CAP patients are admitted to the intensive care unit (ICU), and receive intense treatment. The present study aimed to evaluate the role of the pneumonia severity index (PSI), CURB-65, and sepsis score in the management of hospitalized CAP patients and explore the effect of ICU treatment on prognosis of severe cases. METHODS: A total of 675 CAP patients hospitalized in the Second Affiliated Hospital of Zhejiang University School of Medicine were retrospectively investigated. The ability of different pneumonia severity scores to predict mortality was compared for effectiveness, while the risk factors associated with 30-day mortality rates and hospital length of stay (LOS) were evaluated. The effect of ICU treatment on the outcomes of severe CAP patients was also investigated. RESULTS: All three scoring systems revealed that the mortality associated with the low-risk or intermediate-risk group was significantly lower than with the high-risk group. As the risk level increased, the frequency of ICU admission rose in tandem and LOS in the hospital was prolonged. The areas under the receiver operating characteristic curve in the prediction of mortality were 0.94, 0.91 and 0.89 for the PSI, CURB-65 and sepsis score, respectively. Compared with the corresponding control groups, the mortality was markedly increased in patients with a history of smoking, prior admission to ICU, respiratory failure, or co-morbidity of heart disease. The differences were also identified in LOS between control groups and patients with ICU treatment, heart, or cerebrovascular disease. Logistic regression analysis showed that age over 65 years, a history of smoking, and respiratory failure were closely related to mortality in the overall CAP cohort, whereas age, ICU admission, respiratory failure, and LOS at home between disease attack and hospital admission were identified as independent risk factors for mortality in the high-risk CAP sub-group. The 30-day mortality of patients who underwent ICU treatment on admission was also higher than for non-ICU treatment, but much lower than for those patients who took ICU treatment subsequent to the failure of non-ICU treatment. CONCLUSIONS: Each severity score system, CURB-65, sepsis severity score and especially PSI, was capable of effectively predicting CAP mortality. Delayed ICU admission was related to higher mortality rates in severe CAP patients. PMID- 22490489 TI - A follow-up study on newer anti-epileptic drugs as add-on and monotherapy for partial epilepsy in China. AB - BACKGROUND: Recently, new anti-epileptic drugs (AEDs) have been more frequently selected to treat epilepsy. In the present study, we evaluated the dynamic changes of efficacy and safety of three newer AEDs for treating partial epilepsy in China. METHODS: Patients were collected sequentially and were divided into three groups which accepted oxcarbazepine (OXC), lamotrigine (LTG) or topiramate (TPM) therapy. Each group included monotherapy and add-on therapy subgroups. We followed all patients for one year and recorded the indexes of efficacy and safety in detail. RESULTS: A total of 909 patients finished the follow-up observation. No significant difference was found in proportion of patients with > or = 50% reduction, > or = 75% reduction and 100% seizure reduction in the LTG and OXC groups between the first and the second six months. In the TPM group there was a statistical difference between the first and the second six months in proportion of patients with > or = 50% reduction (P = 0.002), > or = 75% reduction (P < 0.0001) and 100% seizure reduction (P = 0.009) in the monotherapy subgroup, and about > or = 75% reduction and 100% seizure reduction in the add-on therapy subgroup (P < 0.0001). The efficacy between the add-on and monotherapy subgroups showed a statistical difference. The safety of the three newer AEDs was good. CONCLUSIONS: The three newer AEDs all showed good efficacy and tolerability for partial epilepsy. And the efficacy can be maintained for at least one year. PMID- 22490490 TI - Quantitative evaluation of acute renal failure in rabbits with contrast-enhanced ultrasound. AB - BACKGROUND: Assessment of perfusion in the early period of acute renal failure (ARF) is important, and can not be made by conventional ultrasound. The aim of this study was to prospectively test in a rabbit ARF model whether real-time contrast-enhanced ultrasound (CEUS) can quantitatively evaluate the hemodynamic changes of renal cortex in the early period. METHODS: The model of ARF was induced in 30 healthy New Zealand white rabbits (2.5 - 3.0 kg), by intramuscular injection of 50% glycerin solution (12 ml/kg). CEUS were performed on right kidneys before, 6 and 24 hours after glycerin injection. CEUS quantitative indexes were measured in renal cortex using QLAB software. Comparisons between different stages were performed using paired t test. The sensitivity of CEUS in diagnosing ARF was compared with blood serum urea nitrogen (BUN), serum creatinine (SCr) level and color Doppler flow imaging (CDFI). RESULTS: Among quantitative indexes, time to peak (TTP) and area under curve (AUC) increased significantly from (5.86 +/- 2.57) seconds and (124.4 +/- 46.7) dB.s before glycerin injection to (7.66 +/- 2.05) seconds and (288.1 +/- 64.9) dB.s 6 hours after injection (P < 0.05). Slope rate of ascending curve (A) and descending curve (a) decreased slightly from (3.00 +/- 1.22) dB/s and (0.19 +/- 0.15) 1/s to (2.80 +/- 1.45) dB.s and (0.09 +/- 0.02) 1/s (P < 0.05). Twenty-four hours later, only AUC increased significantly from (124.4 +/- 46.7) dB.s to (466.2 +/- 52.2) dB.s (P < 0.05). CONCLUSION: Quantitative indexes of CEUS might be useful in predicting the hemodynamic changes of renal cortex in the early six hours of ARF model. PMID- 22490491 TI - Early evaluation for treatment efficacy of 5-fluorouracil and hyperthermia on HCT 116 colon cancer cells by fluorine-18-fluorodeoxyglucose uptake. AB - BACKGROUND: Fluorine-18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography imaging can be used to assess the treatment efficacy of chemotherapy and prognosis. The aim of this study was to determine the uptake rate of (18)F FDG in colon cancer HCT-116 cells, and to evaluate the treatment efficacy of chemotherapy, hyperthermia and thermo-chemotherapy through the uptake inhibition rate of (18)F-FDG. METHODS: The uptake rate of (18)F-FDG in HCT-116 cells was determined at various experimental conditions. The inhibition rate of cell growth, uptake rate of (18)F-FDG and uptake inhibition rate of (18)F-FDG in HCT 116 cells treated with 5-fluorouracil (5-FU) at various concentrations were determined. In HCT-116 cells subjected to chemotherapy (5-FU, 100 ug/ml), hyperthermia (43 degrees C, 40 minutes) and thermo-chemotherapy for 24 hours, the inhibition rate of cell growth and uptake inhibition rate of (18)F-FDG were determined; early apoptosis, the morphology and ultrastructure of HCT-116 cells were examined; and the contents of glucose and lactate dehydrogenase (LDH) in the cell culture medium of HCT-116 cells were determined. One-way analysis of variance (ANOVA) and correlation analyses were conducted by using SPSS 16.0 software. RESULTS: The uptake rate of (18)F-FDG in HCT-116 cells was (44.25 +/- 2.19)%. Under the condition of adding 5-FU at various concentrations for 24 hours, the uptake rate of (18)F-FDG was negatively correlated with 5-FU dosage (r = -0.879, P < 0.01); the inhibition rate of cell growth revealed a positive correlation with the uptake inhibition rate of (18)F-FDG (r = 0.831, P < 0.01). In HCT-116 cells subjected to hyperthermia, chemotherapy, and thermo-chemotherapy for 24 hours, the uptake inhibition rates of (18)F-FDG were (12.94 +/- 2.80)%, (28.25 +/- 4.59)%, and (21.60 +/- 3.68)%, respectively. The early apoptotic rates of HCT-116 cells were (9.80 +/- 0.16)%, (19.80 +/- 2.40)%, and (15.70 +/- 1.80)%, respectively. Moreover, the contents of glucose and LDH in cell culture medium of HCT-116 cells after treatments were higher than those before treatment. CONCLUSION: The uptake inhibition rate of (18)F-FDG can be used for early evaluation of hyperthermia and 5-FU treatment efficacy on cancer cells although hyperthermia (43 degrees C, 40 minutes) does not reveal the synergistic effect on 5-FU at the low dosage. PMID- 22490492 TI - Nicotine inhibits histone deacetylase 6 activity and chaperone-dependent activation of the glucocorticoid receptor in A549 cells. AB - BACKGROUND: Nicotine, a major component of tobacco, is the main cause of smoking addiction. It was found that asthmatic patients who smoke were insensitive to glucocorticoid treatment. In this paper, we investigated whether nicotine could inhibit histone deacetylase 6 activity (HDAC6) and chaperone-dependent activation of the glucocorticoid receptor (GR) in A549 cells. Furthermore, the expression level of heat shock protein 90 (HSP90) was determined. METHODS: Quantitative real time polymerase chain reaction was used to detect the levels of RNA transcription, and Western blotting was applied to analyze the levels of protein expression of HDAC6, GR, and HSP90 in A549 cells. Moreover, the effects of dexamethasone and trichostatin A were observed in A549 cells. RESULTS: A549 cell proliferation was inhibited in the presence of nicotine, and the level of RNA and protein expression of HDAC6 and GR were down-regulated. CONCLUSIONS: Nicotine could inhibit HDAC6 activity and chaperone-dependent activation of GR. This might be the main reason why asthmatic patients who smoke show insensitivity to the glucocorticoid treatment. PMID- 22490493 TI - Use of preoperative ultrasound in designing the true pectoralis major myocutaneous island flap. AB - BACKGROUND: Traditional techniques used for harvesting the pectoralis major myocutaneous (PMMC) flap have accompanying disadvantages, such as the necessity for an upper chest skin incision, the bulkiness of myocutaneous tissue at the pedicle of the flap, and the risk of total or partial necrosis of flap tissue. The aim of this study was to develop a safe and fast method for preparing PMMC island flaps using preoperative ultrasonography for vessel detection. METHODS: Forty-one PMMC island flaps were used for one-stage reconstruction of head and neck defects, including 21 cases in the treatment group and 20 cases in the control group. In the treatment group, ultrasonography was used to mark out the course of the thoracic branches of the thoracoacromial artery and the lower end of this artery perforating from the fascia into the muscles, as well as the largest perforating branch of the fourth or fifth internal mammary artery entering the PMMC flap. A line, from the lower end of the thoracic branch to the largest perforating branch of the fourth or fifth internal mammary artery, was drawn to determine the axis of the PMMC flap. In the control group, PMMC island flaps were designed according to conventional methods without using ultrasonography. RESULTS: According to the ultrasonic marks, the distance from lower end of thoracic branch to the midpoint of the margin of the inferior clavicular was (5.1 +/- 1.2) cm. The time from designing to transferring the island flap was significantly shorter in the treatment group ((51.0 +/- 10.5) minutes) compared with the control group ((78.0 +/- 13.9) minutes, P < 0.01). The rate of partial necrosis was 4.7% (1/21) in the treatment group and 35.0% (7/20) in the control group. There was one case of flap failure in the control group due to vascular injury during vascular pedicle dissection. CONCLUSION: Preoperative vessel detection by ultrasonography facilitates easy and safe harvesting of the true PMMC island flap. PMID- 22490494 TI - Construction and identification of the recombinant adenovirus vector carrying a small interfering RNA targeting the peroxisome proliferator-activated receptor gamma. AB - BACKGROUND: Steroid-induced osteonecrosis of the femoral head (ONFH) is a common clinical disease, with a high disability rate. At present, efficient prevention and treatment of steroid-induced ONFH is still lacking. The peroxisome proliferator-activated receptor-gamma (PPARgamma) is recognized as an important pathogenic gene for the development of steroid-induced ONFH. RNA interference (RNAi) is a tool for functional gene analysis, which has been successfully used to down-regulate the levels of specific target proteins. Therefore, down regulation of PPARgamma expression by RNAi may prevent the incidence of steroid induced ONFH. METHODS: According to the principles of siRNA design, three duplex siRNA sequences (971 - 989, 1253 - 1271 and 1367 - 1385) derived from the PPARgamma gene (NM_001082148) were synthesized. These duplexes were annealed, purified and ligated into 1.0-cytomegalovirus (CMV) shuttle vector. The shuttle vector was transfected into HEK293 cells. The HEK293 generated recombinant adenovirus vector carrying PPARgamma siRNA sequences was purified and the titer of recombinant adenovirus was determined. RESULTS: After the annealing of single strand DNA oligo encoding short hairpin RNA (shRNA) sequences, products were identified by gel electrophoresis. These products were ligated into the 1.0-CMV shuttle vector and the recombinant shuttle vectors 1.0-CMV-971, 1.0-CMV-1253 and 1.0-CMV-1367 were constructed. These sequences of these recombinant vectors were confirmed. We then successfully constructed the recombinant adenovirus vector carrying siRNA targeting PPARgamma. After purification, the virus titer was higher than 10(10) plaque forming unit (PFU)/ml. CONCLUSION: In this study, three recombinant adenovirus shuttle vectors carrying siRNA targeting PPARgamma, including shuttle vectors 1.0-CMV-971, 1.0-CMV-1253 and 1.0-CMV-1367, were successfully constructed and high titers of recombinant adenovirus were obtained. PMID- 22490495 TI - A new experimental model to study healing process of metaphyseal fracture. AB - BACKGROUND: There are few researches for the healing of metaphyseal fractures; moreover, the animal models to study the metaphyseal fractures are usually made by the oscillating saw osteotomy without reliable fixation, which is not in accordance with our current clinical practice. In this study, we established a new model to observe the healing process of metaphyseal fractures. METHODS: Eighteen New Zealand rabbits were used in the study. The fracture model was created by splitting the medial tibial plateau in rabbits, then reset, and fixed with compression screws. At 1, 2, 3, 4, 6, and 8 weeks postoperatively, the tibial specimens were collected; firstly, a general observation and an X-ray examination of the specimens was done, and then they were embedded in methylmethacrylate and cut into sections with hard tissue slicer. The sections were stained with Giemsa reagent and examined under light microscopy. RESULTS: There was no fracture displacement in the tibial specimens of all time points, except for one showing a collapse. No external callus formation could be observed by X-ray and general examination. After 1 week of the operation, the fracture gap was filled by mesenchymal tissue; 2 weeks postoperatively, a large number of woven bones were formed; from the third week onwards, the woven bone began to turn into lamellar bone, and new trabecular structure began to form. In all of the slices, no obvious chondrocytes formed in fracture areas; thus, there was no endochondral ossification. CONCLUSIONS: This model was an ideal fracture animal model and suitable for the study of metaphyseal fracture healing. The X-ray and histological images demonstrated that metaphyseal fracture healing was a process of direct bone healing through intramembranous bone formation under the conditions of minor trauma, good reduction, and firm fixation. PMID- 22490496 TI - Effects of exogenous human leptin on heat shock protein 70 expression in MCF-7 breast cancer cells and breast carcinoma of nude mice xenograft model. AB - BACKGROUND: It is important to identify the multiple sites of leptin activity in obese women with breast cancer. In this study, we examined the effect of exogenous human leptin on heat shock protein 70 (HSP70) expression in MCF-7 human breast cancer cells and in a breast carcinoma xenograft model of nude mice. METHODS: We cultured MCF-7 human breast cancer cells and established nude mice bearing xenografts of these cells, and randomly divided them into experimental and control groups. The experimental group was treated with human leptin, while the control group was treated with the same volume of normal saline. A real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay was developed to quantify the mRNA expression of HSP70 in the MCF-7 human breast cancer cells and in tumor tissues. Western blotting analysis was applied to quantify the protein expression of HSP70 in the MCF-7 cells. Immunohistochemical staining was done to assess the positive rate of HSP70 expression in the tumor tissues. RESULTS: Leptin activated HSP70 in a dose-dependent manner in vitro: leptin upregulated significantly the expression of HSP70 at mRNA and protein levels in MCF-7 human breast cancer cells (P < 0.001). There was no significant difference in expression of HSP70 mRNA in the implanted tumors between the leptin-treated group and the control group (P > 0.05). Immunohistochemical staining revealed no significant difference in tumor HSP70 expression between the leptin-treated group and the control group (P > 0.05). CONCLUSIONS: A nude mouse xenograft model can be safely and efficiently treated with human leptin by subcutaneous injections around the tumor. HSP70 may be target of leptin in breast cancer. Leptin can significantly upregulate the expression of HSP70 in a dose-dependent manner in vitro. PMID- 22490497 TI - Gemifloxacin for the treatment of community-acquired pneumonia and acute exacerbation of chronic bronchitis: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Gemifloxacin is a fluoroquinolone antibiotic with broad spectrum of antibacterial activity. The aim of the study was to evaluate the comparative effectiveness and safety of gemifloxacin for the treatment of patients with community-acquired pneumonia (CAP) or acute exacerbation of chronic bronchitis (AECB). METHODS: We performed a meta-analysis of randomized controlled trials (RCTs) comparing gemifloxacin with other approved antibiotics. The PubMed, EMBASE, Chinese Biomedical Literature Database and the Cochrane Central Register of Controlled Trials were searched, with no language restrictions. RESULTS: Ten RCTs, comparing gemifloxacin with other quinolones (in 5 RCTs) and beta-lactams and/or macrolides (in 5 RCTs), involving 3940 patients, were included in this meta-analysis. Overall, the treatment success was higher for gemifloxacin when compared with other antibiotics (odds ratio 1.39, 95% confidence interval 1.15 - 1.68 in intention-to-treat patients, and 1.33, 1.02 - 1.73 in clinically evaluable patients). There was no significant difference between the compared antibiotics regarding microbiological success (1.19, 0.84 - 1.68) or all-cause mortality (0.82, 0.41 - 1.63). The total drug related adverse events were similar for gemifloxacin when compared with other quinolones (0.89, 0.56 - 1.41), while lower when compared with beta-lactams and/or macrolides (0.71, 0.57 - 0.89). In subgroup analyses, administration of gemifloxacin was associated with fewer cases of diarrhoea and more rashes compared with other antibiotics (0.66, 0.48 - 0.91, and 2.36, 1.18 - 4.74, respectively). CONCLUSIONS: The available evidence suggests that gemifloxacin 320 mg oral daily is equivalent or superior to other approved antibiotics in effectiveness and safety for CAP and AECB. The development of rash represents potential limitation of gemifloxacin. PMID- 22490498 TI - Hippocampal impairments are associated with intermittent hypoxia of obstructive sleep apnea. AB - Obstructive sleep apnea (OSA), which is the most common sleep-related breathing disorder, is characterized as frequent upper airway collapse and obstruction. It is a treatable disorder but if left untreated is associated with complications in several organ systems. The health risk to OSA patients shows a strong association with acute cardiovascular events, and with chronic conditions. To the central nervous system, OSA causes behavioral and neuropsychologic deficits including daytime sleepiness, depression, impaired memory, mood disorders, cognition deficiencies, language comprehension and expression deficiencies, all of which are compatible with impaired hippocampal function. Furthermore, there exists a significant correlation between disease severity and cognitive deficits in OSA. Children with severe OSA have significantly lower intelligence quotient (IQ) and executive control functions compared to normal children matched for age, gender and ethnicity. This corroborates the findings of several pediatric studies of cognition in childhood OSA, where deficits are reported in general intelligence and some measures of executive function. In studies of OSA, it is difficult to differentiate the effects of its two main pathologic traits, intermittent hypoxia (IH) and sleep fragmentation. Many OSA studies, utilize IH as the only exposure factor in OSA studies. These approaches simplify research process and attain most of the academic goals. IH, continuous hypoxia and intermittent continuous hypoxia can all result in decreases in arterial O2. There are striking differences to them in the response of physiological systems. There are multiple studies showing that IH treatment in a rodent model of OSA can impair performance of standard water maze tests associated with deficits in spatial learning and memory which most likely are hippocampal-dependent. Cellular damage to the hippocampal cornuammonis 1 (CA1) region likely contributes to neuropsychological impairment among OSA patients, since neural circuits in the hippocampus are important in learning and memory. In this article, studies of hippocampal impairments from IH are reviewed for elucidating the mechanisms and relationships between hippocampal impairments and IH of OSA. PMID- 22490499 TI - Newborn screening in Zhejiang, China. AB - BACKGROUND: It has been 11 years since newborn screening started in Zhejiang in 1999. The aim of this study was to analyze and summarize the status of newborn screening in Zhejiang from 1999 to 2009. METHODS: Blood samples were collected from the heels of newborns 72 hours after birth. We have conducted laboratory tests that the congenital hypothyroidism (CH) and circulating levels of thyroid stimulating hormone (TSH) was detected. Blood phenylalanine (Phe) was detected for phenylketonuria (PKU). Dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA) was used for detection. RESULTS: From 1999 to 2009, 3 875 228 newborns were screened and 2309 cases were confirmed as CH and 155 cases were confirmed as PKU. The incidence of CH and PKU were 1:1678 and 1:25 001 respectively. CONCLUSION: In 11 years, the Zhejiang newborn screening center screened more than 3.8 million newborns, and helped more than 2000 CH and PKU patients to obtain early treatment in order to prevent physical disability and mental retardation. PMID- 22490500 TI - Altered regional homogeneity in spontaneous cluster headache attacks: a resting state functional magnetic resonance imaging study. AB - BACKGROUND: Functional neuroimaging study has opened an avenue for exploring the pathophysiology of cluster headache (CH). The aim of our study was to assess the changes in brain activity in CH patients by the regional homogeneity method using resting-state functional magnetic resonance imaging technique. METHODS: The functional magnetic resonance imaging scans were obtained for 12 male CH patients with spontaneous right-sided headache attacks during "in attack" and "out of attack" periods and 12 age- and sex-matched normal controls. The data were analyzed to detect the altered brain activity by the regional homogeneity method using statistical parametric mapping software. RESULTS: Altered regional homogeneity was detected in the anterior cingulate cortex, the posterior cingulate cortex, the prefrontal cortex, insular cortex, and other brain regions involved in pain processing and modulation among different groups. CONCLUSION: It is referred that these brain regions with altered regional homogeneity might be related to the pain processing and modulation of CH. PMID- 22490501 TI - Regional prevalence and transmission route of Kaposi's sarcoma-associated herpes virus in Zhejiang, China. AB - BACKGROUND: The infection of Kaposi's sarcoma-associated herpes virus (KSHV) is most likely the cause of clinical Kaposi's sarcoma, primary effusion lymphoma, and multi-center Castleman's disease. KSHV infection has very limited epidemiological survey data in China, and its definite mode of transmission remains controversial. This study aimed to determine the infection status and the main transmission route of KSHV in Chinese population. METHODS: An enzyme-linked immunosorbent assay (ELISA) utilizing KSHV ORF65 recombinant protein was employed to analyze the antibody response to KSHV ORF65 in sera from 122 healthy physical examination people, 107 intravenous drug users, 135 non-intravenous drug users, 211 hepatitis B (HBV) patients infected via blood transmission, 107 kidney transplant recipients, and 72 female sex workers in Zhejiang Province in Southeast China. RESULTS: KSHV infection occurred relatively common (13.1%) in healthy population in Zhejiang, China. Infection rate was 16.7% in female sex workers, but significantly elevated in intravenous drug addicts (58.9%), blood transmitted HBV patients (28.0%) and kidney transplant patients (41.1%). CONCLUSION: Blood borne transmission of KSHV is probably the main route of infection in Zhejiang Province. PMID- 22490502 TI - Decreased expression of beta-nerve growth factor correlated with histological changes in a cryptorchidism rat model. AB - BACKGROUND: Nerve growth factor (NGF) is well-known for its important role in the development and maintenance of the nervous system. Along with its neurotrophic role, NGF has been detected in the testis of mouse, rat and human, suggesting an additional non-neurotrophic effect in the male reproductive system. The expression of beta-NGF in the undescended testes (cryptorchidism) has not been detected at present. The aim of this study was to evaluate the expression of beta nerve growth factor mRNA and protein in experimental cryptorchidism. METHODS: A unilateral mechanical cryptorchidism model in the Sprague-Dawley rat was established and the expression of beta-NGF with histologic changes in experimental cryptorchidism were investigated using one step quantitative real time reverse transcription-polymerase chain reaction, in situ hybridization histochemistry, immunofluorescence and hematoxylin-eosin staining. RESULTS: The expression of beta-NGF mRNA and protein were both significantly decreased in the development of unmarred testis and cryptorchidism-induced testis, and the decrease of beta-NGF in cryptorchidism-induced testis was far greater than that in uninjured testis. CONCLUSION: From this investigation, we confirmed a lower expression of beta-NGF in undescended testes than in the development of testis. PMID- 22490503 TI - A case of laparoscopic cystogastrostomy for pancreatic abscess. PMID- 22490504 TI - A Chinese girl with cystic fibrosis: a case report identified by sweat and genetic tests. PMID- 22490505 TI - Matrix metalloproteinase-9 in patients with acute coronary syndrome. PMID- 22490506 TI - Increased frequency of CCR4+ and CCR6+ memory T-cells including CCR7+CD45RAmed very early memory cells in granulomatosis with polyangiitis (Wegener's). AB - INTRODUCTION: Chemokine receptors play an important role in mediating the recruitment of T cells to inflammatory sites. Previously, small proportions of circulating Th1-type CCR5+ and Th2-type CCR3+ cells have been shown in granulomatosis with polyangiitis (GPA). Wondering to what extent CCR4 and CCR6 expression could also be implicated in T cell recruitment to inflamed sites in GPA, we investigated the expression of CCR4 and CCR6 on T cells and its association with T cell diversity and polarization. METHODS: Multicolor flow cytometry was used to analyze CCR4, CCR6, and intracellular cytokine expression of T cells from whole blood of GPA-patients (n = 26) and healthy controls (n = 20). CCR7 and CD45RA were included for phenotypic characterization. RESULTS: We found a significant increase in the percentages of circulating CCR4+ and CCR6+ cells within the total CD4+ T cell population in GPA. In contrast, there was no difference in the percentages of CD8+CCR4+ and CD8+CCR6+ T cells between GPA and healthy controls. CCR4 and CCR6 expression was largely confined to central (TCM) and effector memory T cells (TEM, TEMRA). A significant increase in the frequency of CCR4+ and CCR6+ TEMRA and CCR6+ TCM was shown in GPA. Of note, we could dissect CCR4 and CCR6 expressing CCR7+CD45RAmed very early memory T cells (TVEM) from genuine CCR7+CD45RAhigh naive T cells lacking CCR4 and CCR6 expression for peripheral tissue-migration within the CCR7+CD45RA+ compartment. The frequencies of CCR4+ and CCR6+ TVEM were also significantly increased in GPA. An increased percentage of IL-17+ and IL-22+ cells was detected in the CCR6+ cell subsets and IL-4+ cells in the CRR4+ cell subset when compared with CD4+ cells lacking CCR4 and CCR6 expression. CONCLUSIONS: Increased frequencies of circulating CCR4+ and CCR6+ memory T cell subsets including hitherto unreported TVEM suggest persistent T cell activation with the accumulation of CCR4+ and CCR6+ cells in GPA. CCR4 and CCR6 could be involved in the recruitment of T cells including cytokine-producing subsets to inflamed sites in GPA. PMID- 22490508 TI - Tracking dynamics of plant biomass composting by changes in substrate structure, microbial community, and enzyme activity. AB - BACKGROUND: Understanding the dynamics of the microbial communities that, along with their secreted enzymes, are involved in the natural process of biomass composting may hold the key to breaking the major bottleneck in biomass-to biofuels conversion technology, which is the still-costly deconstruction of polymeric biomass carbohydrates to fermentable sugars.However, the complexity of both the structure of plant biomass and its counterpart microbial degradation communities makes it difficult to investigate the composting process. RESULTS: In this study, a composter was set up with a mix of yellow poplar (Liriodendron tulipifera) wood-chips and mown lawn grass clippings (85:15 in dry-weight) and used as a model system. The microbial rDNA abundance data obtained from analyzing weekly-withdrawn composted samples suggested population-shifts from bacteria dominated to fungus-dominated communities. Further analyses by an array of optical microscopic, transcriptional and enzyme-activity techniques yielded correlated results, suggesting that such population shifts occurred along with early removal of hemicellulose followed by attack on the consequently uncovered cellulose as the composting progressed. CONCLUSION: The observed shifts in dominance by representative microbial groups, along with the observed different patterns in the gene expression and enzymatic activities between cellulases, hemicellulases, and ligninases during the composting process, provide new perspectives for biomass-derived biotechnology such as consolidated bioprocessing (CBP) and solid-state fermentation for the production of cellulolytic enzymes and biofuels. PMID- 22490509 TI - Improved cycling performance with ingestion of hydrolyzed marine protein depends on performance level. AB - BACKGROUND: The effect on performance of protein ingestion during or after exercise is not clear. This has largely been attributed to the utilization of different scientific protocols and the neglection of accounting for factors such as differences in physical and chemical properties of protein supplements and differences in athletic performance level. METHODS: We hypothesized that ingestion of unprocessed whey protein (15.3 g.h-1) together with carbohydrate (60 g.h-1), would provide no ergogenic effect on 5-min mean-power performance following 120 min cycling at 50% of maximal aerobic power (2.8 +/- 0.2 W.kg-1, corresponding to 60 +/- 4% of VO2max), compared to CHO alone (60 g.h-1). Conversely, we hypothesized that ingestion of the hydrolyzed marine protein supplement NutriPeptinTM (Np, 2.7 g.h-1), a processed protein supplement with potentially beneficial amino acid composition, together with a PROCHO beverage (12.4 g.h-1 and 60 g.h-1, respectively) would provide an ergogenic effect on mean power performance. We also hypothesized that the magnitude of the ergogenic effect of NpPROCHO would be dependent on athletic performance. As for the latter analysis, performance level was defined according to a performance factor, calculated from individual pre values of Wmax, VO2max and 5-min mean-power performance, wherein the performance of each subject was ranked relative to the superior cyclist whos performance was set to one. Twelve trained male cyclists (VO2max = 65 +/- 4 ml.kg-1.min-1) participated in a randomized double-blinded cross-over study. RESULTS AND CONCLUSIONS: Overall, no differences were found in 5-min mean-power performance between either of the beverages (CHO 5.4 +/- 0.5 W.kg-1; PROCHO 5.3 +/- 0.5 W.kg-1; NpPROCHO 5.4 +/- 0.3 W.kg-1) (P = 0.29). A negative correlation was found between NpPROCHO mean-power performance and athletic performance level (using CHO-performance as reference; Pearson R = 0.74, P = 0.006). Moreover, ingestion of NpPROCHO resulted in improved 5-min mean power performance relative to ingestion of CHO in the six lesser performing subjects compared to the six superior performing subjects (P < 0.05). This suggests that with the current protocol, NpPROCHO provided an ergogenic effect on 5-min mean-power performance in athletes with a lower performance level. PMID- 22490507 TI - What is a preferred angiotensin II receptor blocker-based combination therapy for blood pressure control in hypertensive patients with diabetic and non-diabetic renal impairment? AB - Hypertension has a major associated risk for organ damage and mortality, which is further heightened in patients with prior cardiovascular (CV) events, comorbid diabetes mellitus, microalbuminuria and renal impairment. Given that most patients with hypertension require at least two antihypertensives to achieve blood pressure (BP) goals, identifying the most appropriate combination regimen based on individual risk factors and comorbidities is important for risk management. Single-pill combinations (SPCs) containing two or more antihypertensive agents with complementary mechanisms of action offer potential advantages over free-drug combinations, including simplification of treatment regimens, convenience and reduced costs. The improved adherence and convenience resulting from SPC use is recognised in updated hypertension guidelines. Despite a wide choice of SPCs for hypertension treatment, clinical evidence from direct head-to-head comparisons to guide selection for individual patients is lacking. However, in patients with evidence of renal disease or at greater risk of developing renal disease, such as those with diabetes mellitus, microalbuminura and high-normal BP or overt hypertension, guidelines recommend renin-angiotensin system (RAS) blocker-based combination therapy due to superior renoprotective effects compared with other antihypertensive classes. Furthermore, RAS inhibitors attenuate the oedema and renal hyperfiltration associated with calcium channel blocker (CCB) monotherapy, making them a good choice for combination therapy. The occurrence of angiotensin-converting enzyme (ACE) inhibitor-induced cough supports the use of angiotensin II receptor blockers (ARBs) for RAS blockade rather than ACE inhibitors. In this regard, ARB-based SPCs are available in combination with the diuretic, hydrochlorothiazide (HCTZ) or the calcium CCB, amlodipine. Telmisartan, a long-acting ARB with preferential pharmacodynamic profile compared with several other ARBs, and the only ARB with an indication for the prevention of CV disease progression, is available in two SPC formulations, telmisartan/HCTZ and telmisartan/amlodipine. Clinical studies suggest that in CV high-risk patients and those with evidence of renal disease, the use of an ARB/CCB combination may be preferred to ARB/HCTZ combinations due to superior renoprotective and CV benefits and reduced metabolic side effects in patients with concomitant metabolic disorders. However, selection of the most appropriate antihypertensive combination should be dependent on careful review of the individual patient and appropriate consideration of drug pharmacology. PMID- 22490511 TI - Producing striatal phenotypes for transplantation in Huntington's disease. AB - Neural transplantation as a therapeutic strategy in neurodegenerative disorders offers to replace cells lost during the disease process, with the potential to reconstruct dysfunctional circuitry, thus alleviating associated disease symptoms. The focal loss of striatal cells, specifically medium-sized spiny neurons (MSN) in Huntington's disease (HD), makes transplantation a therapeutic option. Here, we review the progress made in generating striatal MSN phenotypes for transplantation in HD. We discuss the use of primary fetal tissue as a donor source in both preclinical and clinical studies and assess the options for renewable cell sources. We evaluate progress in directing the differentiation of renewable cells towards a striatal MSN phenotype for HD. PMID- 22490510 TI - Programmable bio-nano-chip systems for serum CA125 quantification: toward ovarian cancer diagnostics at the point-of-care. AB - Point-of-care (POC) implementation of early detection and screening methodologies for ovarian cancer may enable improved survival rates through early intervention. Current laboratory-confined immunoanalyzers have long turnaround times and are often incompatible with multiplexing and POC implementation. Rapid, sensitive, and multiplexable POC diagnostic platforms compatible with promising early detection approaches for ovarian cancer are needed. To this end, we report the adaptation of the programmable bio-nano-chip (p-BNC), an integrated, microfluidic, and modular (programmable) platform for CA125 serum quantitation, a biomarker prominently implicated in multimodal and multimarker screening approaches. In the p-BNCs, CA125 from diseased sera (Bio) is sequestered and assessed with a fluorescence-based sandwich immunoassay, completed in the nano nets (Nano) of sensitized agarose microbeads localized in individually addressable wells (Chip), housed in a microfluidic module, capable of integrating multiple sample, reagent and biowaste processing, and handling steps. Antibody pairs that bind to distinct epitopes on CA125 were screened. To permit efficient biomarker sequestration in a three-dimensional microfluidic environment, the p BNC operating variables (incubation times, flow rates, and reagent concentrations) were tuned to deliver optimal analytical performance under 45 minutes. With short analysis times, competitive analytical performance (inter- and intra-assay precision of 1.2% and 1.9% and limit of detection of 1.0 U/mL) was achieved on this minisensor ensemble. Furthermore, validation with sera of patients with ovarian cancer (n = 20) showed excellent correlation (R(2) = 0.97) with gold-standard ELISA. Building on the integration capabilities of novel microfluidic systems programmed for ovarian cancer, the rapid, precise, and sensitive miniaturized p-BNC system shows strong promise for ovarian cancer diagnostics. PMID- 22490512 TI - Composition of molecular cardiolipin species correlates with proliferation of lymphocytes. AB - The mitochondrial phospholipid cardiolipin (CL) is required for oxidative phosphorylation. Oxidation of CL results in the disruption of CL-cytochrome c binding and the induction of apoptosis. Large variations in the acyl-chain residues of CL have been reported, but evidence as to whether these variants exert distinct biological effects has been limited. We have studied the acyl chain composition of CL in lymphocytes, and found marked differences between highly and slowly proliferating cells. In fast growing cells, we detected a decreased number of double bonds, and a higher amount of C16 acyl-chain residues in CL, compared with slower growing cells. However, fewer C18 acyl-chain residues were found in CL from fast growing cells compared with slower proliferating cells. Our results suggest a functional link between acyl-chain composition of CL and cell proliferation. PMID- 22490513 TI - Role of the spleen in the development of steatohepatitis in high-fat-diet-induced obese rats. AB - Obesity is considered a systemic low-grade inflammatory state. Although the spleen is the main immune organ with a close anatomical relationship with the liver, its role in the progression of fatty liver disease remains uncertain. Therefore, we sought to clarify the functional role of the spleen in the development of steatohepatitis in high-fat (HF)-diet-induced obese rats. Male Sprague-Dawley rats were fed HF food and divided into two groups, a splenectomy (SPX) group and a sham-operation (Sham) group. The liver and abdominal white adipose tissue (WAT) were removed one and six months after surgery, and we evaluated the effects of SPX on WAT and HF-induced fatty liver. SPX rats exhibited worse dyslipidemia and inflammatory changes in WAT one month after surgery. Hepatic steatosis and inflammation were accelerated by SPX, based on the time after surgery. At one month after surgery, the tissue triglyceride content increased in SPX rats, compared with Sham controls (P < 0.05). The liver histology also showed a worsening of steatosis in those rats. At six months after SPX, dramatic inflammatory and fibrotic changes were observed in liver tissue sections. Hepatic carnitine palmitoyltransferase-1 was suppressed at one and six months after SPX (P < 0.05 for each). WAT and liver tissue levels of inflammatory markers such as tumor necrosis factor-alpha, and the expression of Kupffer cells were all increased at six months in SPX rats, compared with Sham controls (P < 0.05 for each). Our results indicate that the preservation of the spleen contributes to the prevention of the progression of hepatic steatosis to steatohepatitis in obese rats. PMID- 22490514 TI - Expression and function of heme oxygenase-1 in human gastric cancer. AB - Heme oxygenase-1 (HO-1) potently influences tumor growth and metastasis. To date, no study has been performed on HO-1 expression pattern and its clinicopathological significance in human gastric cancer (GC) cases. In this study, the expression of HO-1 in human GC tissues (n = 74) and matched non tumoral adjacent parenchyma (n = 46) was investigated by immunohistochemistry. The correlation of HO-1 with the clinicopathological characteristics was analyzed. Results showed that HO-1 was expressed in 62 GC tissues from 74 cases (83.8%), which is significantly higher than non-tumoral adjacent parenchyma (20/46, 43.8%, P < 0.05). A high HO-1 expression rate showed a close association with well/moderate histological differentiation and negative lymph node metastasis (P < 0.05). The expression of matrix metallopeptidase 9 (MMP9) and vascular endothelial growth factor A (VEGF-A) as well as chemosensitivity to cisplatin of MKN-45 cell lines with genetically altered HO-1 status were then determined by realtime polymerase chain reaction and 3-(4,5 dimethyl thiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT), respectively. Whether the induction or inhibition of HO-1 by cobalt-protoporphyrin-IX (CoPP) or zinc-protoporphyrin-IX (ZnPP) could affect the sensitivity of MKN-45 cells to cisplatin was also studied. Results showed that the expression of MMP9 and VEGF-A were up-regulated in MKN-45 cells overexpressing HO-1, and down-regulated in HO-1 interfered cells. HO-1 overexpression could lead to an increased resistance to cisplatin, whereas down-regulation of HO-1 expression by siRNA or chemical inhibition of HO-1 could lead to increased chemosensitivity to cisplatin in MKN-45 cells. HO-1 may have multiple effects on protection against carcinogenesis and progression in GC. PMID- 22490515 TI - Evaluating cap-assisted colonoscopy: the relevance of study design. PMID- 22490516 TI - Tumour necrosis factor alpha secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice. AB - BACKGROUND: Acute pancreatitis has long been considered a disorder of pancreatic self-digestion, in which intracellular activation of digestive proteases induces tissue injury. Chemokines, released from damaged pancreatic cells then attract inflammatory cells, whose systemic action ultimately determines the disease severity. In the present work the opposite mechanism is investigated; that is, whether and how inflammatory cells can activate intracellular proteases. DESIGN: Using mice either deficient for the CD18-alpha subunit of the membrane attack complex-1 (MAC-1) complex or tumour necrosis factor (TNF)alpha, as well as after depletion of leucocyte subpopulations, pancreatitis was induced by 7-hourly caerulein injections (50 MUg/kg, intraperitoneally). Pancreatic acini were coincubated in vitro from wild-type and cathepsin-B-deficient animals with phorbol-12-myristate-13-acetate (PMA)-activated neutrophils and macrophages, caerulein or TNFalpha, and activities of trypsin, cathepsin-B and caspase-3 were measured, as well as necrosis using fluorogenic substrates. TNFalpha was inhibited with monospecific antibodies. RESULTS: Deletion of CD18 prevented transmigration of leucocytes into the pancreas during pancreatitis, greatly reduced disease severity and abolished digestive protease activation. Depletion of neutrophils and macrophages equally reduced premature trypsinogen activation and disease severity. In vitro activated neutrophils and macrophages directly induced premature protease activation and cell death in pancreatic acini and stimulation of acini with TNFalpha induced caspase-3 activation and necrosis via a cathepsin-B and calcium-dependent mechanism. Neutralising antibodies against TNFalpha and genetic deletion of TNFalpha prevented leucocyte-induced trypsin activity and necrosis in isolated acini. CONCLUSIONS: The soluble inflammatory cell mediator TNFalpha directly induces premature protease activation and necrosis in pancreatic acinar cells. This activation depends on calcium and cathepsin-B activity. The findings from the present work further suggest that targeting TNFalpha, for which pharmaceutical agents are readily available, could be an effective treatment strategy that directly addresses the cellular causes of pancreatitis. PMID- 22490518 TI - Cost-effectiveness of one versus two sample faecal immunochemical testing for colorectal cancer screening. AB - OBJECTIVE: The sensitivity and specificity of a single faecal immunochemical test (FIT) are limited. The performance of FIT screening can be improved by increasing the screening frequency or by providing more than one sample in each screening round. This study aimed to evaluate if two-sample FIT screening is cost-effective compared with one-sample FIT. DESIGN: The MISCAN-colon microsimulation model was used to estimate costs and benefits of strategies with either one or two-sample FIT screening. The FIT cut-off level varied between 50 and 200 ng haemoglobin/ml, and the screening schedule was varied with respect to age range and interval. In addition, different definitions for positivity of the two-sample FIT were considered: at least one positive sample, two positive samples, or the mean of both samples being positive. RESULTS: Within an exemplary screening strategy, biennial FIT from the age of 55-75 years, one-sample FIT provided 76.0-97.0 life years gained (LYG) per 1000 individuals, at a cost of ? 259,000-264,000 (range reflects different FIT cut-off levels). Two-sample FIT screening with at least one sample being positive provided 7.3-12.4 additional LYG compared with one sample FIT at an extra cost of ? 50,000-59,000. However, when all screening intervals and age ranges were considered, intensifying screening with one-sample FIT provided equal or more LYG at lower costs compared with two-sample FIT. CONCLUSION: If attendance to screening does not differ between strategies it is recommended to increase the number of screening rounds with one-sample FIT screening, before considering increasing the number of FIT samples provided per screening round. PMID- 22490517 TI - Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals. AB - OBJECTIVE: Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data. DESIGN: Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39,266) and in combination with gender, age and FH (n=11,324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks. RESULTS: The median number of risk alleles was greater in cases than controls (10 vs 9, p<2.2 * 10(-16)), confirmed in external validation sets (Sweden p=1.2 * 10(-6), Finland p=2 * 10(-5)). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with >5% predicted 10-year absolute risk. CONCLUSION: Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance. PMID- 22490519 TI - miR-574-5p negatively regulates Qki6/7 to impact beta-catenin/Wnt signalling and the development of colorectal cancer. AB - OBJECTIVE: Deficiency or reduced expression of signal transduction and activation of RNA family protein Quaking (Qki) is associated with developmental defects in neural and vascular tissues and the development of debilitating human diseases including colorectal cancer (CRC). However, the mechanisms underlying the aberrant downregulation or deficiency of Qki were uncertain. DESIGN: Expression of miR-574-5p, Qki5/6/7/7b splicing variants, beta-catenin and p27(Kip1) was determined in mouse and human CRC cells and tissues to investigate the post transcriptional regulation of Qki isoforms by miR-574-5p and its impact on beta catenin/p27(Kip1) signalling, cell cycle progression, proliferation, migration, invasion and tumour growth. RESULTS: In the CRC tissues of C57BL/6-Apc(min/+) mice, miR-574-5p was found to be significantly upregulated and negatively correlated with the expression of Qki but positively correlated with the expression of beta-catenin. In mouse and human CRC cells, miR-574-5p was shown to regulate Qki isoforms (Qki6/7 in particular) post-transcriptionally and caused altered expression in beta-catenin and p27(Kip1) , increased proliferation, migration and invasion and decreased differentiation and cell cycle exit. Furthermore, in clinical CRC tissues, miR-574-5p was shown to be greatly upregulated and inversely correlated with the expression of Qkis. Finally, inhibition of miR-574-5p was shown to suppress the growth of tumours in the nude mice. CONCLUSIONS: Together, these novel findings suggest that miR-574-5p is a potent ribo-regulator for Qkis and that aberrant miR-574-5p upregulation can be oncogenic. PMID- 22490520 TI - Colorectal cancer: a tale of two sides or a continuum? PMID- 22490521 TI - Serrated polyposis: rapid and relentless development of colorectal neoplasia. AB - OBJECTIVE: Serrated (hyperplastic) polyposis (SP) is a rare disorder with multiple colorectal hyperplastic polyps and often sessile serrated adenomas/polyps (SSA/P) or adenomas. Although associated with colorectal cancer, the course of SP is not well described. DESIGN: 44 patients with SP were studied. The results of 146 colonoscopies with median follow-up of 2.0 years (range 0-30) and a median of 1.0 years (range 0.5-6) between surveillance colonoscopies were evaluated. Findings from oesophogastroduodenoscopy examinations were analysed. RESULTS: The mean age at diagnosis of SP was 52.5 +/- 11.9 years (range 22-78). In two pedigrees (5%) another family member had SP. None of 22 patients had gastroduodenal polyps. All patients had additional colorectal polyps at surveillance colonoscopy. SSA/P or adenomas were found in 25 patients (61%) at first colonoscopy and 83% at last colonoscopy. Recurrent SSA/P or adenomas occurred in 68% of patients at surveillance colonoscopy. Three patients had colorectal cancer. Eleven patients (25%) underwent surgery (mean time from diagnosis of SP 2.0 +/- 0.9 years). After surgery all seven surveyed patients developed recurrent polyps in the retained colorectum (4/7 had SSA/P or adenomas). No association was found between colorectal neoplasia and sex, age at diagnosis of SP or initial number of colorectal polyps. CONCLUSIONS: In SP, rapid and unrelenting colorectal neoplasia development continues in the intact colorectum and retained segment after surgery. These findings support the possibility of annual colonoscopic surveillance, consideration for colectomy when SSA/P or adenomas are encountered and frequent postoperative endoscopic surveillance of the retained colorectum. PMID- 22490522 TI - HDGF-related protein-3 is required for anchorage-independent survival and chemoresistance in hepatocellular carcinomas. AB - OBJECTIVE: Hepatoma-derived growth factor (HDGF)-related proteins (HRPs) comprise a family of six members and are characterised by a conserved HATH domain. Among the family members, HDGF was the first to be identified as a mitogenic factor and shown to play an important role in hepatocellular carcinoma pathogenesis. The aim of the present study is to examine the relevance of HDGF-related protein-3 (HRP 3), another member of the HRP family in hepatocellular carcinoma (HCC). DESIGN: HRP-3 expression in HCC tissues was measured by quantitative reverse transcriptase PCR, western blot and immunohistochemistry analysis. The biological consequences of overexpression and knockdown of HRP-3 in HCC cell lines were studied in vitro and in vivo. RESULTS: Expression of HRP-3 mRNA and protein was shown to be highly upregulated in HCC tissues. While knockdown of HRP-3 by small interference RNAs failed to affect anchorage-dependent growth of HCC cells, it inhibited anchorage-independent growth of HCC cells in vitro and xenograft tumour growth in vivo. Further, knockdown of HRP-3 was shown to sensitise HCC cells to anoikis. Moreover, HRP-3 specifically activated the extracellular-signal regulated kinase (ERK) pathway without affecting c-Jun N-terminal kinase (JNK), p38, AKT and signal transducer and activator of transcription 3 (STAT3). Importantly, inhibition of the ERK pathway diminished HRP-3-mediated protection of HCC cells from anoikis. Finally, knockdown of HRP-3 was shown to enhance apoptosis of HCC cells induced by multiple chemotherapeutic drugs. CONCLUSION: These findings indicate that HRP-3 plays an essential role in HCC pathogenesis and suggest that it may serve as a novel prognostic marker and molecular target for development of drugs for treatment of HCC. PMID- 22490523 TI - Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis. AB - OBJECTIVE: Entecavir (ETV) is a potent inhibitor of viral replication in chronic hepatitis B and prolonged treatment may result in regression of fibrosis. The aim of this study was to investigate the effect of ETV on disease progression. DESIGN: In a multicentre cohort study, 372 ETV-treated patients were investigated. Clinical events were defined as development of hepatocellular carcinoma (HCC), hepatic decompensation or death. Virological response (VR) was defined as HBV DNA <80 IU/ml. RESULTS: Patients were classified as having chronic hepatitis B without cirrhosis (n=274), compensated cirrhosis (n=89) and decompensated cirrhosis (n=9). The probability of VR was not influenced by severity of liver disease (p=0.62). During a median follow-up of 20 months (IQR 11-32), the probability of developing clinical events was higher for patients with cirrhosis (HR 15.41 (95% CI 3.42 to 69.54), p<0.001). VR was associated with a lower probability of disease progression (HR 0.29 (95% CI 0.08 to 1.00), p=0.05) which remained after correction for established risk factors such as age. The benefit of VR was only significant in patients with cirrhosis (HR 0.22 (95% CI 0.05 to 0.99), p=0.04) and remained after excluding decompensated patients (HR 0.15 (95% CI 0.03 to 0.81), p=0.03). A higher HBV DNA threshold of 2000 IU/ml was not associated with the probability of disease progression (HR 0.20 (95% CI 0.03 to 1.10), p=0.10). CONCLUSION: VR to ETV is associated with a lower probability of disease progression in patients with cirrhosis, even after correction for possible baseline confounders. When using a threshold of 2000 IU/ml, the association between viral replication and disease progression was reduced, suggesting that complete viral suppression is essential for nucleoside/nucleotide analogue treatment, especially in patients with cirrhosis. PMID- 22490524 TI - Selectin binding is essential for peritoneal carcinomatosis in a xenograft model of human pancreatic adenocarcinoma in pfp--/rag2-- mice. AB - BACKGROUND AND OBJECTIVE: E- and P-selectins expressed on the luminal surface of mesodermally derived endothelial cells play a crucial role in the formation of haematogenous metastases in a number of malignancies. As peritoneal mesothelial cells are also derived form the mesoderm, it was hypothesised that selectins are also of importance in peritoneal tumour spread. METHODS: Immunohistochemistry was used to identify selectin expression on normal human peritoneum and isolated mesothelial cells. E- and P-selectin interactions with human pancreatic adenocarcinoma cells were investigated in dynamic flow assays and flow cytometry; the latter was also used to determine the main selectin ligands on pancreatic adenocarcinoma cell lines PaCa 5061, BxPC-3 and PaCa 5072, and selectin expression on human mesothelial cells. All cell lines were xenografted into the peritoneum of E- and P-selectin-deficient pfp/rag2 mice and selectin wild-type controls. Peritoneal carcinomatosis was quantified using MRI or a scoring system. RESULTS: E- and P-selectin were constitutively expressed on human mesothelial and endothelial cells in the peritoneum. PaCa 5061 and BxPC-3 cells interacted with E and P-selectins in dynamic flow assays and flow cytometry, with CA19-9 (Sialyl Lewis a) being the main E-selectin ligand. For xenografted PaCa 5061 and BxPC-3 cells, peritoneal metastasis was significantly reduced in E- and P-selectin double knockout mice compared with wild-type pfp/rag2 animals. In contrast, PaCa 5072 cells were almost devoid of selectin binding sites and no intraperitoneal tumour growth was observed. CONCLUSION: Interactions of tumour cells with peritoneal selectins play an important role in the peritoneal spread of pancreatic adenocarcinoma. PMID- 22490525 TI - Epiphenomenon of telomere lengths: lessons from ulcerative colitis. PMID- 22490526 TI - Dysbiosis modulates capacity for bile acid modification in the gut microbiomes of patients with inflammatory bowel disease: a mechanism and marker of disease? PMID- 22490527 TI - Lymphocytic oesophagitis, a condition in search of a disease? PMID- 22490528 TI - NKT cells and the hedgehog pathway: an unhealthy marriage in non-alcoholic fatty liver disease? PMID- 22490529 TI - Prey orientation and the role of venom availability in the predatory behaviour of the centipede Scolopendra subspinipes mutilans (Arthropoda: Chilopoda). AB - Many animal phyla contain clades in which most or all species are venom-injecting predators. An example, in the arthropods, is the class Chilopoda, containing the approximately 3500 species of centipedes. Very little ecological or behavioural work yielding quantitative data has been conducted on centipede predation. Here, we describe a study of this kind. Our experiments employed one centipede species a large tropical one, Scolopendra subspinipes mutilans - and two species of prey - a cricket, Gryllus assimilis, and a locust, Schistocerca gregaria. We conducted two experiments. The first was aimed at investigating the extent to which the centipedes attacked prey in particular tagmata as opposed to at random over the whole body surface. The results showed that the centipedes were highly selective, preferring to attack the head or thorax rather than the abdomen; indeed, they often reoriented the prey in order to achieve this. A possible explanation of this behaviour is to maximize the speed with which the neurotoxins in the venom reach either the brain or the thoracic ganglia that control limb movement. The second experiment was aimed at investigating the effect of venom-extraction on the attack rate, and specifically at testing if the magnitude of any such effect differed between the two types of prey, which differ considerably in size. The results showed a major effect of venom extraction in relation to both types of prey, but with the time taken to return to a 'normal' attack rate being longer in the case of the larger prey-type, namely the locust. We discuss these results in relation to the 'venom optimization hypothesis' and, more generally, to the principle of minimizing the production/use of venom, which is an energetically expensive resource. PMID- 22490530 TI - [Enhance the connotation of establishment of wound healing department]. AB - Following the development of social economy, the acceleration of aging problem, and the changes in disease spectrum, the incidence of various chronic wound diseases increased significantly, and it has become one of the most frequently encountered diseases that affect the people's health. The contradiction between the increase of medical need of wound diseases and the insufficiency of the medical service in our country is becoming increasingly conspicuous. Wound healing department, as a new cross subject that has emerged as the times require, needs to be perfected in its diagnostic and treatment strategies and methods. At present time, how to explore the new theory and pathologic mechanism of various chronic wounds, in order to establish the clinical guidelines in diagnosis and treatment that conform to national conditions of our country, and to establish efficient clinical pathway and medical-seeking model have become serious challenges to the establishment of wound healing department in our country. Thus, it is imperative for us to enhance the connotation of establishment of wound healing department. For this purpose, this article mainly elaborates on three aspects, including "enriching traditional diagnostic system with new theory and new technology", "improving treatment effect by ameliorating traditional methods and absorbing new technology from relating subspecialty", "establishing a new medical-seeking model by applying digital technology and vertically integrating medical resources". PMID- 22490531 TI - [Facing wound healing-let our mind soar]. AB - When I started my career as a burn doctor, I looked over all those chapters dealing with wound healing wishing desperately to help me understand the healing process and mechanism of wound. Whereas is that the whole picture of wound healing? Decades have passed; we are still following these protocols. Do we really have nothing better to do with wound healing? When I was asked to write this comment, I was thinking that we should think high and wide in facing wound healing. PMID- 22490533 TI - [Repair of finger soft tissue defects using axial pattern flaps]. AB - OBJECTIVE: To investigate the feasibility and effect of different types of axial pattern flaps in repairing soft tissue defects of the fingers. METHODS: Five types of axial pattern flaps were used to repair soft tissue defects of the fingers of 30 patients admitted to the Second Hospital of Shaoxing Municipality from 2005 to 2010, including distally-based dorsal thumb neurocutaneous vascular flaps in 4 cases, free flaps from the fibular side of the great toe in 6 cases, modified retrograde dorsal metacarpal artery flaps in 8 cases, free flaps based on the radial dorsal septum muscular perforator of the posterior interosseous artery in 6 cases, and free posterior interosseous artery flaps carrying a long segment of the posterior interosseous artery in 6 cases. The flap size ranged from 2.5 cm * 2.0 cm to 8.0 cm * 3.0 cm. The donor sites were sutured directly or covered with skin graft. The condition of flaps was observed. The local feeling, function, and appearance of affected hands were followed up. RESULTS: Twenty seven flaps grew well without infection. Partial necrosis at the distal portion in two flaps and venous congestion in 1 flap were observed after surgery, and they were healed with suitable treatment. Eighteen patients were followed up for 1 to 12 months. The flaps were found to have good color, texture, and thickness. Satisfactory appearance and function both in the donor sites and in the recipient areas were found in most patients. The sense of two-point discrimination of repaired fingers ranged from 5 to 9 mm. CONCLUSIONS: Optimizing the repair method for soft tissue defects in the fingers by taking both the characteristics of various axial pattern flaps and the specific conditions of soft tissue defects into account can achieve expected effect. PMID- 22490532 TI - [Exploring the three-dimensional structure of dermal tissues of normal skin and scar in rat with synchrotron radiation X-ray imaging technology]. AB - OBJECTIVE: To compare the morphological difference between dermal tissue of normal skin and that of scar in rat, and to explore its structural pattern. METHODS: The full-thickness skin and the scar tissue formed 3 weeks after wound healing from SD rats were harvested as samples, which were prepared appropriately afterwards. Samples were scanned and imaged with synchrotron radiation technology, micro-CT, and phase-contrast imaging technology. The images were rebuilt with three-dimensional software. RESULTS: The micro-CT was materialized by using X-ray generated by synchrotron radiation light source. The structure of dermal tissues was clearly shown with the assistance of phase-contrast imaging technology in the process. It was demonstrated that the dermal tissues of normal skin of rat were mainly composed of collagenous fibers, which twined together to form an olive-like structure. These olive-like structures as basic units were arranged randomly in a certain way. The collagenous fibers in dermal tissue of the scar were arranged in a parallel manner, while some fibers were crooked and arranged in a disorderly manner. CONCLUSIONS: Dermal tissue of normal skin in rat has stable three-dimensional structure, and its basic structure and manner of composition are obviously different from those of scar dermal tissue. PMID- 22490534 TI - [Effects of different artificial dermal scaffolds on vascularization and scar formation of wounds in pigs with full-thickness burn]. AB - OBJECTIVE: To investigate the effects of three kinds of artificial dermal scaffolds on vascularization and scar formation of wounds in pigs with full thickness burn. METHODS: Eighteen Bama miniature pigs were divided into chitosan scaffold (CS) group, sulfonated carboxymethyl chitosan scaffold (SCCS) group, and acellular dermal matrix (ADM) scaffold group according to the random number table, with 6 pigs in each group. Every pig in all groups was inflicted with 4 or 8 full-thickness scald wounds on the back (totally 96 wounds). Forty-eight hours after injury, eschars of all wounds were excised. Twenty-four wounds in CS group were transplanted with double-layer artificial dermis of collagen-chitosan and silicone rubber, those in SCCS group with double-layer artificial dermis of collagen-sulfonated carboxymethyl chitosan and silicone rubber, and those in ADM scaffold group with ADM. The rest 24 wounds in the three groups were dressed with vaseline gauze as control group. After 2 weeks of treatment, all wounds of every group were covered with skin. In post treatment (scaffold transplantation or gauze covering) week (PTW) 1, 2, 3, and 4, gross condition of wound was observed, and specimens from central parts of wounds were harvested for observation and assessment of vessels or cells with positive expression of CD31, alpha smooth muscle actin (alpha-SMA), TGF-beta(1) and TGF-beta(3) with SP staining. Data were processed with one-way analysis of variance and LSD test. RESULTS: (1) Degree of vascularization in SCCS group was better than that in the other three groups. (2) The number of vessels with positive expression of CD31 in CS, SCCS, ADM scaffold, and control groups increased gradually from PTW 1 to PTW 3, and decreased in PTW 4. There were statistical differences among 4 groups from PTW 1 to PTW 4 (with F value respectively 24.005, 38.822, 25.274, 3.856, P < 0.05 or P < 0.01). The numbers of vessels that expressed CD31 in SCCS group from PTW 1 to PTW 3 were more than those in the other three groups (with P values all below 0.05). (3) The numbers of vessels that expressed alpha-SMA in CS, SCCS, and ADM scaffold groups from PTW 1 to PTW 3 showed the similar trend of change to those of vessels that expressed CD31, which increased gradually in control group from PTW 1 to PTW 4. There were obvious differences among 4 groups from PTW 1 to PTW 4 (with F value respectively 22.637, 28.087, 62.651, 18.055, P values all below 0.01). The number of vessels that expressed alpha-SMA in SCCS group from PTW 1 to PTW 4 was more than that in the other three groups (with P values all below 0.05). (4) From PTW 1 to PTW 4, the number of cells with expression of TGF-beta(1) in CS group was respectively (127 +/- 8), (167 +/- 19), (170 +/- 18), (144 +/- 10) per 400 times visual field, that in SCCS group was respectively (171 +/- 17), (207 +/- 25), (130 +/- 30), (69 +/- 16) per 400 times visual field, that in ADM scaffold group was respectively (106 +/- 8), (159 +/- 17), (171 +/- 11), (145 +/- 11) per 400 times visual field, and that in control group was respectively (100 +/- 20), (150 +/- 18), (200 +/- 14), (172 +/- 20) per 400 times visual field. There were statistical differences among 4 groups from PTW 1 to PTW 4 (with F value respectively 29.675, 9.503, 13.107, 54.515, P values all below 0.01). Compared with those in SCCS group, the number of cells that expressed TGF-beta(1) in the other three groups was decreased in PTW 1, 2 but increased in PTW 3, 4 (with P values all below 0.05). (5) The number of cells that expressed TGF-beta(3) in 4 groups increased gradually from PTW 1 to PTW 3, and decreased or increased continually in PTW 4. There were statistical differences among 4 groups from PTW 1 to PTW 4 (with F value respectively 140.612, 945.850, 714.037, 119.147, P values all below 0.01). The number of cells with positive expression of TGF beta(3) in SCCS group from PTW 1 to PTW 4 was more than that in the other three groups (with P values all below 0.05). CONCLUSIONS: The collagen-sulfonated carboxymethyl chitosan dermal scaffold can rapidly induce growth and maturation of blood vessels during wound healing after burn. It is beneficial for wound repair at early stage with inhibition of scar proliferation. PMID- 22490535 TI - [Role of tumor necrosis factor alpha in endothelial-mesenchymal transition in vitro]. AB - OBJECTIVE: To observe the role of tumor necrosis factor alpha (TNF-alpha) in endothelial-mesenchymal transition (EnMT), and to explore the mechanism of fibrosis disease. METHODS: Human umbilical vein endothelial cells (HUVEC) from umbilical cord of healthy fetus were isolated by enzymatic digestion and identified by immunofluorescence assay. The third to fifth generations of cultured HUVEC in logarithmic phase were harvested and seeded in 12-well plates and 6-well plates, and they were divided into control group (ordinary culture without any stimulation), 5, 10, 25, 50, and 100 ng/mL TNF-alpha groups (5, 10, 25, 50, 100 ng/mL of TNF-alpha was respectively added into the nutrient solution) according to the random number table, with three samples in each group. After being cultured for 72 hours, the cell morphology was observed under inverted phase-contrast microscope; the expression levels of coagulation factor VIII and alpha smooth muscle actin (alpha-SMA) were detected by immunofluorescence assay, and the ratios of numbers (absorbance values) of cells with expression of both factors were calculated. The mRNA expression levels of cadherin, alpha-SMA, and type I collagen were detected by RT-PCR (denoted as gray value ratio). Data were processed with one-way analysis of variance and LSD test. RESULTS: (1) The shape of primary HUVEC was round, short-spindle, or flat, and cells grew vigorously in cobblestone appearance after passages. After being subcultured for 1, 2, 3, 4, 5 passage (s), the positive rate of coagulation factor VIII of HUVEC was respectively (85.5 +/- 1.8)%, (88.1 +/- 5.0)%, (93.6 +/- 3.7)%, (92.9 +/- 4.8)%, (89.5 +/- 1.1)%, and they were significantly higher than that of primary HUVEC [(81.4 +/- 3.8)%, with F values all equal to 7.481, P values all below 0.05]. (2) As compared with that in control group, the appearance of cells in 5, 10, 25, 50, and 100 ng/mL TNF-alpha groups was gradually transformed from round, short spindle, or flat shape to long-spindle shape with reduced intercellular junction and larger intercellular gap along with the increase in the concentration of TNF alpha. (3) The ratios of numbers and the absorbance values of coagulation factor VIII and alpha-SMA double positive cells in control group (0.055 +/- 0.015, 0.078 +/- 0.017) were significantly lower than those in 5, 10, 25, 50, and 100 ng/mL TNF-alpha groups (0.257 +/- 0.106, 0.280 +/- 0.129, 0.505 +/- 0.059, 0.817 +/- 0.035, 0.929 +/- 0.101 and 0.437 +/- 0.040, 0.456 +/- 0.097, 0.496 +/- 0.082, 0.787 +/- 0.131, 0.885 +/- 0.087, with F value respectively 45.009, 50.099, P values all below 0.01). (4) The expression levels of cadherin mRNA in 5, 10, 25, 50, and 100 ng/mL TNF-alpha groups were 0.70 +/- 0.05, 0.63 +/- 0.06, 0.60 +/- 0.10, 0.45 +/- 0.16, and 0.26 +/- 0.14, and it was significantly lower in the latter four groups than in control group (0.83 +/- 0.03, with F values all equal to 11.593, P < 0.05 or P < 0.01). The mRNA expression levels of alpha-SMA and collagen I in 5, 10, 25, 50, and 100 ng/mL TNF-alpha groups were 0.45 +/- 0.10, 0.51 +/- 0.16, 0.49 +/- 0.12, 0.60 +/- 0.09, 0.76 +/- 0.03 and 0.38 +/- 0.18, 0.45 +/- 0.15, 0.52 +/- 0.12, 0.66 +/- 0.17, 0.76 +/- 0.20, and they were significantly higher in the latter three groups than in control group (0.37 +/- 0.14, 0.31 +/- 0.12, with F value respectively 7.839, 2.898, P < 0.05 or P < 0.01). CONCLUSIONS: TNF-alpha can obviously promote EnMT in a dose-dependent manner. EnMT may be another significant source of myofibroblasts that contributes to fibrotic tissue in scar formation. PMID- 22490536 TI - [Effect of substance P combined with epidermal stem cells on wound healing and nerve regeneration in rats with diabetes mellitus]. AB - OBJECTIVE: To observe the effect of sensory neuropeptide substance P combined with epidermal stem cells (ESC) on wound healing and nerve regeneration in diabetic rats. METHODS: ESC that had been isolated from SD rats were identified and cultured in vitro, and they were inoculated onto nourishing layer of amniotic membrane to construct amniotic membrane-ESC. Four full-thickness skin wounds were produced on the back of each of 48 diabetic rats. The resulted 192 wounds were randomly divided into ESC + substance P group, ESC group, substance P group, and control group according to the lottery method, with 48 wounds in each group. Wounds in ESC + substance P group and ESC group were transplanted with amniotic membrane-ESC, and those in substance P group and control group were transplanted with amniotic membrane. After transplantation, 250 uL substance P in the concentration of 1 * 10(-7) mol/L was injected around and into the middle of the wounds in ESC + substance P group and substance P group, 2 times a day, and continued for 4 days, while 250 uL PBS solution was injected in the above mentioned position in ESC group and control group as control, 2 times a day, and continued for 4 days. On post injury day (PID) 4, 7, 10, 14, 17, and 23, the wound healing rate (with 8 wounds at each time point) was observed and determined, and changes in wound tissue structure were observed with HE staining. On PID 4, 7, and 10, collagen distribution in wound tissue was observed with Masson staining, and type I and type III collagen deposition in wound tissue was respectively observed after immunohistochemical staining. The distribution of protein gene product 9.5 (PGP 9.5) and regeneration of substance P positive nerve fibers in wound tissue were observed with immunohistochemical staining on PID 14 and 23. Data were processed with one-way analysis of variance and t test. RESULTS: (1) The wound healing rate in ESC + substance P group reached 100.0% on PID 14, which was obviously earlier than that in ESC group, substance P group, and control group, healing was respectively observed on PID 17, 17, and 23. The wound healing quality in ESC + substance P group was better than that in the other three groups as shown by HE staining. (2) On PID 10, collagen that was darkly stained and widely distributed was observed in wound tissue of ESC + substance P group and substance P group, while collagen in the other two groups was lightly stained and narrowly distributed. Deposition quantity of type I collagen gradually increased, and that of type III collagen gradually decreased in the wounds of each group over time. On PID 4, 7, and 10, distribution amount of type I collagen in wound tissue of ESC + substance P group was significantly higher than that in ESC group (with t value respectively 32.72, 118.21, 26.71, P values all below 0.01) and control group (with t value respectively 44.37, 22.76, 30.32, P values all below 0.01), while there was no significance between ESC + substance P group and substance P group. On PID 4, 7, and 10, distribution amount of type III collagen in wound tissue of ESC + substance P group was significantly higher than that in ESC group (with t value respectively 32.27, 28.68, 14.51, P values all below 0.01) and control group (with t value respectively 35.68, 22.52, 22.24, P values all below 0.01). (3) A large amount of PGP 9.5 and regeneration of substance P positive nerve fibers, and some peripheral nerve fibers in deep wound extending to epidermis were observed in wound tissue of ESC + substance P group and substance P group. A small amount of PGP 9.5 and regeneration of substance P positive nerve fibers without peripheral nerve fibers extending to epidermis were observed in deep wound tissue of ESC group and control group. On PID 14, 23, ratios of area of PGP 9.5 positive nerve fiber in the wounds of ESC + substance P group were (3.86 +/- 0.25)% and (7.03 +/- 0.28)%, and they were significantly higher than those of ESC group [(1.48 +/- 0.30)%, (3.01 +/- 0.43)%, with t value respectively 23.95, 30.27, P values all below 0.01] and control group [(1.46 +/- 0.23)%, (2.84 +/- 0.29)%, with t value respectively 27.35, 40.32, P values all below 0.01]. On PID 14, 23, ratios of substance P positive nerve fiber area in the wounds of ESC + substance P group were (2.01 +/- 0.14)% and (1.19 +/- 0.11)%, which were obviously higher than those of ESC group [(0.85 +/- 0.17)%, (1.34 +/- 0.21)%, with t value respectively 20.50, 2.60, P < 0.05 or P < 0.01] and control group [(0.74 +/- 0.15)%, (1.30 +/- 0.17)%, with t value respectively 23.98, 2.41, P < 0.05 or P < 0.01]. CONCLUSIONS: Joint application of substance P and ESC can effectively promote healing of wound and nerve regeneration in diabetic rats. PMID- 22490537 TI - [Effects of advanced glycation end products and its receptor on oxidative stress in diabetic wounds]. AB - OBJECTIVE: To investigate the accumulation of advanced glycation end products (AGE) and the inflammatory response of skin and wound in diabetic patients, and to analyze their relationship in vitro. METHODS: Histological staining and immunohistochemical staining was respectively performed on skin and wound tissue specimens collected from 10 patients with Type II diabetes mellitus (diabetes group) and 12 non-diabetic patients with skin injury (control group) to observe the arrangement of collagen and the distribution of inflammatory cells, and to determine the expression levels of AGE and its receptor (RAGE). Malondialdehyde (MDA) levels in skin and wound tissue homogenates were assayed by enzyme-linked immunosorbent assay. In vitro, human neutrophils were isolated and treated with RPMI-1640 culture medium or that containing AGE-human serum albumin in the concentration of 0.315, 0.625, 1.250 mg/mL, and they were identified as normal control (NC) group, low concentration (L) group, moderate concentration (M) group, and high concentration (H) group. Cell viability in each group was determined by MTT colorimetric assay, and the reactive oxygen species (ROS) in cell was measured with 2', 7'-dichlorofluorescein-diacetate. Data were processed with t test. RESULTS: Compared with those of skin in control group, collagens of skin tissues in diabetes group atrophied and disorderly arranged. Inflammatory cells in wounds in diabetes group were dispersed, in which collagens arranged loosely and irregularly, as compared with those of wounds in control group. Expression levels of AGE and RAGE of skin in diabetes group were higher than those in control group. In diabetes and control groups, especially in diabetes group, the numbers of RAGE-positive cells in wound tissue were more than those in skin tissue. Large amount of inflammatory cells with positive expression of RAGE were observed in diabetes group. MDA level of skin and wound tissue in diabetes group was respectively (6.3 +/- 1.0), (7.1 +/- 2.4) nmol per milligram protein, which were obviously higher than those in control group [(2.9 +/- 1.0), (3.6 +/- 1.4) nmol per milligram protein, with t value respectively 8.017, 4.349, P < 0.05 or P < 0.01]. Cell viability and ROS levels in neutrophils were increased in L, M, and H groups [(59 +/- 8)%, (77 +/- 5)%, (67 +/- 6)% and 1.67 +/- 0.14, 2.13 +/ 0.17, 3.48 +/- 0.48] as compared with those in NC group [(34 +/- 5)% and 0.58 +/ 0.06, with t value respectively 7.195, 14.890, 11.130 and 20.195, 24.905, 16.864, P < 0.05 or P < 0.01]. CONCLUSIONS: Abnormal oxidative stress in diabetic skin leads to an atypical origin of wound repair. AGE-RAGE effect is a critical mediator for oxidative stress in diabetic wound tissue during wound healing. PMID- 22490538 TI - [Effect of granulocyte-macrophage colony-stimulating factor on the mammalian target of sirolimus signaling pathway in the wound of rat]. AB - OBJECTIVE: To investigate the effects of granulocyte-macrophage colony stimulating factor (GM-CSF) on wound healing and mammalian target of sirolimus (rapamycin) signaling pathway in rats. METHODS: Fifty SD rats were divided into control group (n = 25) and treatment group (n = 25) according to the random number table. All rats were inflicted with 2 cm * 2 cm full-thickness skin wound on the back. Recombinant human GM-CSF gel (10 ug/cm(2)) was applied onto the wounds in treatment group, and the actual quantity was 1 * 10(-4) ug/cm(2). Gel vehicle (10 ug/cm(2)) without any medicine was applied onto the wounds in control group. The treatment was conducted once a day up to the day of wound healing. Five rats from two groups were sacrificed on post injury day (PID) 1, 3, 5, 7, 14 respectively to observe and determine the wound healing rate. Wound tissue samples were collected at the former 4 time points to observe the histopathological changes with HE staining, and to detect the content of GM-CSF with enzyme-linked immunosorbent assay, and the expression levels of GM-CSF, CD31, and the mTOR signal pathway associated molecules P70S6K, phosphorylated (p ) P70S6K, 4E-BP1, p-4E-BP1, mTOR, p-mTOR with Western blotting. Data were processed with t test. RESULTS: (1) Wound healing rates in control group and treatment group were close on PID 1 (t = 0.307, P > 0.05). Wound healing rate in treatment group was obviously higher than that in control group on PID 3, 5, 7, and 14 (with t values from 2.704 to 4.030, P < 0.05 or P < 0.01). (2) Compared with those in control group, more abundant granulation tissue was observed in treatment group, in which an increase in the number of microvessels and obvious proliferation of keratinized epithelial cells in wound margin were observed at each time point. (3) The content and the protein expression level of GM-CSF peaked on PID 3 in two groups, and they were (720.9 +/- 0.9) pg/mL, 2.45 +/- 0.10 in control group and (910.5 +/- 1.3) pg/mL, 2.80 +/- 0.48 in treatment group. The content of GM-CSF in treatment group was significantly higher than that in control group at each time point (with t values from 105.743 to 298.971, P values all equal to 0.000). The protein expression level of GM-CSF in treatment group was significantly higher than that in control group on PID 1, 5, and 7 (with t values from 4.070 to 5.275, P values all below 0.01). (4) The expression level of CD31 in treatment group was obviously higher than that in control group on PID 1, 3, and 7 (with t values from 7.237 to 26.401, P values all below 0.01). (5) The expression levels of mTOR and p-mTOR in treatment group were significantly higher than those in control group at each time point (with t values from 2.921 to 23.143, P < 0.05 or P < 0.01). In treatment group, the expression level of P70S6K was obviously higher than that in control group on PID 3, 5, and 7 (with t values from 2.950 to 5.275, P < 0.05 or P < 0.01), and the expression level of p-P70S6K was significantly higher than that in control group on PID 1, 3, and 7 (with t values from 3.307 to 22.793, P < 0.05 or P < 0.01). In treatment group, the expression level of 4E-BP1 was significantly lower than that in control group on PID 1, 3, and 5 (with t values from 2.449 to 6.431, P < 0.05 or P < 0.01), but the expression level of p-4E-BP1 was significantly higher than that in control group on PID 1, 3, and 7 (with t values from 5.522 to 11.613, P values all below 0.01). CONCLUSIONS: GM-CSF can promote wound healing in rats by activating mTOR signaling pathway through phosphorylating mTOR proteins and its downstream signal molecules P70S6K and 4E-BP1. PMID- 22490539 TI - [Significance and assessments of impaired microcirculation in chronic wounds]. AB - Chronic wounds pose a clinical challenge. Such wounds may present all over the body although the majority appear on the lower extremities. In the main, wounds are caused by hypertension (venous or arterial), diabetes, although infection, trauma, and animal bites can result in non-healing wounds. It is vital to have a reliable diagnosis in order to plan treatment. Despite advances in diagnostics and the development of standard care packages, chronic wounds present a growing burden to all societies. One of the problems faced is the poor understanding of the pathophysiology of wounds; it is commonly accepted that microcirculation is impaired in lower extremity chronic wounds. This paper is focused on the significance and assessment of impaired microcirculation. PMID- 22490540 TI - [System of classification of diabetic foot and its appraisal]. AB - The classification system of diabetic foot not only helps to assess the wound, but it also can be used to predict the outcome of diabetic foot ulcer in the early stage, dynamically monitor the changes in the wound, and rationally direct the therapeutic schedule. At present, there are diverse systems for classifying the diabetic foot, but none has been internationally recognized. The classification systems can be categorized by time sequence, research objective, or structure type. When one of the classification systems is chosen, it is still very important to take the population, facility, and research type into consideration. PMID- 22490541 TI - [Advances in research of the mechanism of "covert disorder" in diabetic skin]. AB - The diabetic ulceration is not uncommon, and becomes refractory, as the skin in a diabetic patient is relatively thin as well as hypoesthetic and less sensitive to temperature. As there are already preexisting histological and cellular derangement in the skin, healing of the skin injury is difficult, thus resulting in an intractable ulceration. When diabetes is not controlled, the skin contents of sugar and advanced glycation end product accumulate, invoking cellular deformation and accumulation of matrix metalloproteinases (MMP), resulting in an imbalance between MMP and its inhibitors, malfunction of growth factors, and inflammatory reaction. These processes lead to obvious skin thinning, denaturation of connective tissues, thickening of vascular basal membrane, and neuropathy, etc. These pathological alterations could be recognized as "covert disorder" of skin in diabetic patients and may be underlying disorders in producing indolent diabetic ulcers. PMID- 22490542 TI - [Repair of pressure sores over ischial tuberosity with long head of biceps femoris muscle flap combined with semi-V posterior thigh fasciocutaneous flap]. AB - OBJECTIVE: To explore the clinical effect of transplantation of the long head of biceps femoris muscle flap in combination with semi-V posterior thigh fasciocutaneous flap for repair of pressure sores over ischial tuberosity. METHODS: Eight patients with 10 deep pressure sores over ischial tuberosity were admitted to the First Affiliated Hospital to the PLA General Hospital and the 98th Hospital of PLA from April 2004 to June 2010. The wounds measured from 2 cm * 2 cm to 6 cm * 4 cm were covered with the long head of biceps femoris muscle flap and semi-V posterior thigh fasciocutaneous flap (ranged from 10 cm * 6 cm to 13 cm * 8 cm). The condition of flaps was observed and followed up for a long time. RESULTS: All flaps survived. Nine wounds healed by first intention. Subcutaneous accumulation of fluids occurred in one wound with formation of a sinus at drainage site, and it healed after dressing change for 25 days. Patients were followed up for 7 to 34 months. Sore recurred in one patient 9 months after surgery, and it was successfully repaired with the same flap for the second time. Flaps in the other 7 patients appeared satisfactory with soft texture and without ulceration. CONCLUSIONS: This combined flap is easy in formation and transfer, and it causes little side injury with good resistance against pressure. It is a new method for repair of pressure sore over sacral region. PMID- 22490543 TI - [Analysis of the binding domain of hydroxypyruvate isomerase homologues in hypertrophic scar fibroblasts]. AB - OBJECTIVE: To explore the binding domain of hydroxypyruvate isomerase homologues (HYI) in the interaction with protein P311 in hypertrophic scar fibroblasts (Fb). METHODS: (1) P 311 was amplified by PCR using plasmid pMD18-T-P 311 as template. The total RNA of hypertrophic scar Fb was extracted by Trizol to amplify HYI with RT-PCR. Recombinant vectors pGADT7-P 311 and pGBKT7-HYI were constructed by double-enzyme digestion, and they were verified by PCR and sequencing. The secondary structure of protein HYI was analyzed with software Prot Seale and HNN. Fragments of HYI-1 (1-447 bp), HYI-2 (247-447 bp), HYI-3 (1-279 bp), and HYI-4 (247-654 bp) were amplified based on the result of software analysis. And then the recombinant vectors pGBKT7-HYI-1, 2, 3, and 4 were constructed by double enzyme digestion and verified by PCR and sequencing. (2) AH109 yeast cells were transformed into competent cells by lithium acetate method and divided into 7 groups roughly in the same amount, including HYI full length, HYI-1, HYI-2, HYI 3, and HYI-4 hybrid groups, positive control group, and negative control group. Cells in the first five groups were respectively transformed with recombinant vector pGBKT7-HYI full length, pGBKT7-HYI-1, pGBKT7-HYI-2, pGBKT7-HYI-3, pGBKT7 HYI-4 and recombinant vector pGADT7-P 311, and that in the rest two groups were transformed with recombinant vectors pGBKT7-53 and pGADT7-RecT, pGADT7-RecT and pGBKT7-Lam by polyethyleneglycol/lithium acetate method. Immediately after transformation, a part of the transformed cells in each group was spread onto the medium lacking leucine, tryptophan, adenine, and histidine (briefly called four factor lacking medium), and another portion of the cells was spread onto the medium lacking leucine and tryptophan (briefly called two-factor lacking medium). After 3 to 6 days' culture, the growth of yeast was observed, and the expression of beta-galactosidase of yeast was detected by color reaction with 5-bromo-4 chloro-indolyl-beta-D-galactopyranoside. RESULTS: (1) Cloned P 311 and the reported P 311 (GenBank ID hsu36189) had the same sequence. The A base at 496 bp in reported HYI (GenBank ID AY775560) was replaced by G base as found in cloned HYI. It was verified that the insert segment of each recombinant vector was correct. (2) Among those 216 amino acids which composed the protein HYI, 101 amino acids might form alpha helices, 90 amino acids might form random coils, 25 amino acids might form extended-chains as revealed in the simulated structure analysis by computer. (3) Cloned segments HYI-1, 2, 3, 4 showed expected lengths. It was verified that the insert segment of each recombinant vector was correct. (4) Except for strains in negative control group which did not show growth on four-factor lacking medium, all strains in other groups grew on both kinds of media, and growth of colonies was less in HYI-2 (with the fewest number of alpha helices) and HYI-3 hybrid groups. (5) Positive expression of beta-galactosidase was observed in strains of all groups growing on four-factor lacking medium except for the HYI-2 hybrid group. No expression of beta-galactosidase was observed in strains of negative control group which grew on two-factor lacking medium. CONCLUSIONS: Protein HYI may closely bind with protein P311 by alpha helix, which plays an important role in fibroblast-to-myofibroblast transdifferentiation in hypertrophic scar. PMID- 22490544 TI - [Advances in research of heat shock factor 1 and its relation with expression of heat shock protein]. AB - This article reviews the advances in the research of the structural characteristics and the activating process of heat shock factor 1 (HSF-1), the factors that influence the expression of HSF-1, and the relationship between HSF 1 and the expression levels of NF-kappaB and heat shock protein (HSP). The expression of HSF-1 could be regulated in several stages in the course of interconversion between its active and inactive status. Unusual expression of HSF 1 mediated by NF-kappaB can lead to the quantitative and functional change of HSP. The quantitative and functional variation of HSP caused by regulation of HSF 1 could influence the normal synthesis and the pathological changes induced by excessive synthesis of protective proteins in cells under stress. We expect that further research would help elucidate novel pathways about the genesis and evolution mechanism of keloid, and it may finally help to find a novel strategy in the treatment of keloid. PMID- 22490545 TI - Characterizing mammographic images by using generic texture features. AB - INTRODUCTION: Although mammographic density is an established risk factor for breast cancer, its use is limited in clinical practice because of a lack of automated and standardized measurement methods. The aims of this study were to evaluate a variety of automated texture features in mammograms as risk factors for breast cancer and to compare them with the percentage mammographic density (PMD) by using a case-control study design. METHODS: A case-control study including 864 cases and 418 controls was analyzed automatically. Four hundred seventy features were explored as possible risk factors for breast cancer. These included statistical features, moment-based features, spectral-energy features, and form-based features. An elaborate variable selection process using logistic regression analyses was performed to identify those features that were associated with case-control status. In addition, PMD was assessed and included in the regression model. RESULTS: Of the 470 image-analysis features explored, 46 remained in the final logistic regression model. An area under the curve of 0.79, with an odds ratio per standard deviation change of 2.88 (95% CI, 2.28 to 3.65), was obtained with validation data. Adding the PMD did not improve the final model. CONCLUSIONS: Using texture features to predict the risk of breast cancer appears feasible. PMD did not show any additional value in this study. With regard to the features assessed, most of the analysis tools appeared to reflect mammographic density, although some features did not correlate with PMD. It remains to be investigated in larger case-control studies whether these features can contribute to increased prediction accuracy. PMID- 22490546 TI - Effects of parietal TMS on visual and auditory processing at the primary cortical level -- a concurrent TMS-fMRI study. AB - Accumulating evidence suggests that multisensory interactions emerge already at the primary cortical level. Specifically, auditory inputs were shown to suppress activations in visual cortices when presented alone but amplify the blood oxygen level-dependent (BOLD) responses to concurrent visual inputs (and vice versa). This concurrent transcranial magnetic stimulation-functional magnetic resonance imaging (TMS-fMRI) study applied repetitive TMS trains at no, low, and high intensity over right intraparietal sulcus (IPS) and vertex to investigate top down influences on visual and auditory cortices under 3 sensory contexts: visual, auditory, and no stimulation. IPS-TMS increased activations in auditory cortices irrespective of sensory context as a result of direct and nonspecific auditory TMS side effects. In contrast, IPS-TMS modulated activations in the visual cortex in a state-dependent fashion: it deactivated the visual cortex under no and auditory stimulation but amplified the BOLD response to visual stimulation. However, only the response amplification to visual stimulation was selective for IPS-TMS, while the deactivations observed for IPS- and Vertex-TMS resulted from crossmodal deactivations induced by auditory activity to TMS sounds. TMS to IPS may increase the responses in visual (or auditory) cortices to visual (or auditory) stimulation via a gain control mechanism or crossmodal interactions. Collectively, our results demonstrate that understanding TMS effects on (uni)sensory processing requires a multisensory perspective. PMID- 22490547 TI - Category learning increases discriminability of relevant object dimensions in visual cortex. AB - Learning to categorize objects can transform how they are perceived, causing relevant perceptual dimensions predictive of object category to become enhanced. For example, an expert mycologist might become attuned to species-specific patterns of spacing between mushroom gills but learn to ignore cap textures attributable to varying environmental conditions. These selective changes in perception can persist beyond the act of categorizing objects and influence our ability to discriminate between them. Using functional magnetic resonance imaging adaptation, we demonstrate that such category-specific perceptual enhancements are associated with changes in the neural discriminability of object representations in visual cortex. Regions within the anterior fusiform gyrus became more sensitive to small variations in shape that were relevant during prior category learning. In addition, extrastriate occipital areas showed heightened sensitivity to small variations in shape that spanned the category boundary. Visual representations in cortex, just like our perception, are sensitive to an object's history of categorization. PMID- 22490548 TI - DICCCOL: dense individualized and common connectivity-based cortical landmarks. AB - Is there a common structural and functional cortical architecture that can be quantitatively encoded and precisely reproduced across individuals and populations? This question is still largely unanswered due to the vast complexity, variability, and nonlinearity of the cerebral cortex. Here, we hypothesize that the common cortical architecture can be effectively represented by group-wise consistent structural fiber connections and take a novel data driven approach to explore the cortical architecture. We report a dense and consistent map of 358 cortical landmarks, named Dense Individualized and Common Connectivity-based Cortical Landmarks (DICCCOLs). Each DICCCOL is defined by group-wise consistent white-matter fiber connection patterns derived from diffusion tensor imaging (DTI) data. Our results have shown that these 358 landmarks are remarkably reproducible over more than one hundred human brains and possess accurate intrinsically established structural and functional cross subject correspondences validated by large-scale functional magnetic resonance imaging data. In particular, these 358 cortical landmarks can be accurately and efficiently predicted in a new single brain with DTI data. Thus, this set of 358 DICCCOL landmarks comprehensively encodes the common structural and functional cortical architectures, providing opportunities for many applications in brain science including mapping human brain connectomes, as demonstrated in this work. PMID- 22490549 TI - EphA signaling impacts development of topographic connectivity in auditory corticofugal systems. AB - Auditory stimulus representations are dynamically maintained by ascending and descending projections linking the auditory cortex (Actx), medial geniculate body (MGB), and inferior colliculus. Although the extent and topographic specificity of descending auditory corticofugal projections can equal or surpass that of ascending corticopetal projections, little is known about the molecular mechanisms that guide their development. Here, we used in utero gene electroporation to examine the role of EphA receptor signaling in the development of corticothalamic (CT) and corticocollicular connections. Early in postnatal development, CT axons were restricted to a deep dorsal zone (DDZ) within the MGB that expressed low levels of the ephrin-A ligand. By hearing onset, CT axons had innervated surrounding regions of MGB in control-electroporated mice but remained fixed within the DDZ in mice overexpressing EphA7. In vivo neurophysiological recordings demonstrated a corresponding reduction in spontaneous firing rate, but no changes in sound-evoked responsiveness within MGB regions deprived of CT innervation. Structural and functional CT disruption occurred without gross alterations in thalamocortical connectivity. These data demonstrate a potential role for EphA/ephrin-A signaling in the initial guidance of corticofugal axons and suggest that "genetic rewiring" may represent a useful functional tool to alter cortical feedback without silencing Actx. PMID- 22490551 TI - Switching off LTP: mGlu and NMDA receptor-dependent novelty exploration-induced depotentiation in the rat hippocampus. AB - Both electrically induced synaptic long-term potentiation (LTP) and long-term depression have been extensively studied as models of the cellular basis of learning and memory mechanisms. Recently, considerable interest has been generated by the possibility that the activity-dependent persistent reversal of previously established synaptic LTP (depotentiation) may play a role in the time- and state-dependent erasure of memory. Here, we examined the requirement for glutamate receptor activation in experience-induced reversal of previously established LTP in the CA1 area of the hippocampus of freely behaving rats. Continuous exploration of non-aversive novelty for ~30 min, which was associated with hippocampal activation as measured by increased theta power in the electroencephalogram, triggered a rapid and persistent reversal of high frequency stimulation-induced LTP both at apical and basal synapses. Blockade of metabotropic glutamate (mGlu) receptors with mGlu5 subtype-selective antagonists, or N-methyl-D-aspartate (NMDA) receptors with GluN2B subunit-selective antagonists, prevented novelty-induced depotentiation. These findings strongly indicate that activation of both mGlu5 receptors and GluN2B-containing NMDA receptors is required for experience-triggered induction of depotentiation at CA3 CA1 synapses. The mechanistic concordance of the present and previous studies of experience-induced and electrically induced synaptic depotentiation helps to integrate our understanding of the neurophysiological underpinnings of learning and memory. PMID- 22490550 TI - Cerebral processing of voice gender studied using a continuous carryover FMRI design. AB - Normal listeners effortlessly determine a person's gender by voice, but the cerebral mechanisms underlying this ability remain unclear. Here, we demonstrate 2 stages of cerebral processing during voice gender categorization. Using voice morphing along with an adaptation-optimized functional magnetic resonance imaging design, we found that secondary auditory cortex including the anterior part of the temporal voice areas in the right hemisphere responded primarily to acoustical distance with the previously heard stimulus. In contrast, a network of bilateral regions involving inferior prefrontal and anterior and posterior cingulate cortex reflected perceived stimulus ambiguity. These findings suggest that voice gender recognition involves neuronal populations along the auditory ventral stream responsible for auditory feature extraction, functioning in pair with the prefrontal cortex in voice gender perception. PMID- 22490552 TI - Applicability of independent component analysis on high-density microelectrode array recordings. AB - Emerging complementary metal oxide semiconductor (CMOS)-based, high-density microelectrode array (HD-MEA) devices provide high spatial resolution at subcellular level and a large number of readout channels. These devices allow for simultaneous recording of extracellular activity of a large number of neurons with every neuron being detected by multiple electrodes. To analyze the recorded signals, spiking events have to be assigned to individual neurons, a process referred to as "spike sorting." For a set of observed signals, which constitute a linear mixture of a set of source signals, independent component (IC) analysis (ICA) can be used to demix blindly the data and extract the individual source signals. This technique offers great potential to alleviate the problem of spike sorting in HD-MEA recordings, as it represents an unsupervised method to separate the neuronal sources. The separated sources or ICs then constitute estimates of single-neuron signals, and threshold detection on the ICs yields the sorted spike times. However, it is unknown to what extent extracellular neuronal recordings meet the requirements of ICA. In this paper, we evaluate the applicability of ICA to spike sorting of HD-MEA recordings. The analysis of extracellular neuronal signals, recorded at high spatiotemporal resolution, reveals that the recorded data cannot be modeled as a purely linear mixture. As a consequence, ICA fails to separate completely the neuronal signals and cannot be used as a stand-alone method for spike sorting in HD-MEA recordings. We assessed the demixing performance of ICA using simulated data sets and found that the performance strongly depends on neuronal density and spike amplitude. Furthermore, we show how postprocessing techniques can be used to overcome the most severe limitations of ICA. In combination with these postprocessing techniques, ICA represents a viable method to facilitate rapid spike sorting of multidimensional neuronal recordings. PMID- 22490553 TI - The role of muscle spindles in the development of the monosynaptic stretch reflex. AB - Muscle sensory axons induce the development of specialized intrafusal muscle fibers in muscle spindles during development, but the role that the intrafusal fibers may play in the development of the central projections of these Ia sensory axons is unclear. In the present study, we assessed the influence of intrafusal fibers in muscle spindles on the formation of monosynaptic connections between Ia (muscle spindle) sensory axons and motoneurons (MNs) using two transgenic strains of mice. Deletion of the ErbB2 receptor from developing myotubes disrupts the formation of intrafusal muscle fibers and causes a nearly complete absence of functional synaptic connections between Ia axons and MNs. Monosynaptic connectivity can be fully restored by postnatal administration of neurotrophin-3 (NT-3), and the synaptic connections in NT-3-treated mice are as specific as in wild-type mice. Deletion of the Egr3 transcription factor also impairs the development of intrafusal muscle fibers and disrupts synaptic connectivity between Ia axons and MNs. Postnatal injections of NT-3 restore the normal strengths and specificity of Ia-motoneuronal connections in these mice as well. Severe deficits in intrafusal fiber development, therefore, do not disrupt the establishment of normal, selective patterns of connections between Ia axons and MNs, although these connections require the presence of NT-3, normally supplied by intrafusal fibers, to be functional. PMID- 22490554 TI - Neurons with inverted tuning during the delay periods of working memory tasks in the dorsal prefrontal and posterior parietal cortex. AB - The dorsolateral prefrontal and posterior parietal cortices are two interconnected brain areas that are coactivated in tasks involving functions such as spatial attention and working memory. The response properties of neurons in the two areas are in many respects indistinguishable, yet only prefrontal neurons are able to resist interference by distracting stimuli when subjects are required to remember an initial stimulus. Several mechanisms have been proposed that could account for this functional difference, including the existence of specialized interneuron types, specific to the prefrontal cortex. Although such neurons with inverted tuning during the delay period of a working memory task have been described in the prefrontal cortex, no comparative data exist from other cortical areas that would establish a unique prefrontal role. To test this hypothesis, we analyzed a large database of recordings obtained in the dorsolateral prefrontal and posterior parietal cortex of the same monkeys as they performed working memory tasks. We found that in the prefrontal cortex, neurons with inverted tuning were more numerous and manifested unique properties. Our results give credence to the idea that a division of labor exists between separate neuron types in the prefrontal cortex and that this represents a functional specialization that is not present in its cortical afferents. PMID- 22490555 TI - Touch responsiveness in zebrafish requires voltage-gated calcium channel 2.1b. AB - The molecular and physiological basis of the touch-unresponsive zebrafish mutant fakir has remained elusive. Here we report that the fakir phenotype is caused by a missense mutation in the gene encoding voltage-gated calcium channel 2.1b (CACNA1Ab). Injection of RNA encoding wild-type CaV2.1 restores touch responsiveness in fakir mutants, whereas knockdown of CACNA1Ab via morpholino oligonucleotides recapitulates the fakir mutant phenotype. Fakir mutants display normal current-evoked synaptic communication at the neuromuscular junction but have attenuated touch-evoked activation of motor neurons. NMDA-evoked fictive swimming is not affected by the loss of CaV2.1b, suggesting that this channel is not required for motor pattern generation. These results, coupled with the expression of CACNA1Ab by sensory neurons, suggest that CaV2.1b channel activity is necessary for touch-evoked activation of the locomotor network in zebrafish. PMID- 22490556 TI - Incomplete spinal cord injury promotes durable functional changes within the spinal locomotor circuitry. AB - While walking in a straight path, changes in speed result mainly from adjustments in the duration of the stance phase while the swing phase remains relatively invariant, a basic feature of the spinal central pattern generator (CPG). To produce a broad range of locomotor behaviors, the CPG has to integrate modulatory inputs from the brain and the periphery and alter these swing/stance characteristics. In the present work we raise the issue as to whether the CPG can adapt or reorganize in response to a chronic change of supraspinal inputs, as is the case after spinal cord injury (SCI). Kinematic data obtained from six adult cats walking at different treadmill speeds were collected to calculate the cycle and subphase duration at different stages after a first spinal hemisection at T(10) and after a subsequent complete SCI at T(13) respectively aimed at disconnecting unilaterally and then totally the spinal cord from its supraspinal inputs. The results show, first, that the neural control of locomotion is flexible and responsive to a partial or total loss of supraspinal inputs. Second, we demonstrate that a hemisection induces durable plastic changes within the spinal locomotor circuitry below the lesion. In addition, this study gives new insights into the organization of the spinal CPG for locomotion such that phases of the step cycle (swing, stance) can be independently regulated for adapting to speed and also that the CPGs controlling the left and right hindlimbs can, up to a point, be regulated independently. PMID- 22490557 TI - Stimulus repetition affects both strength and synchrony of macaque inferior temporal cortical activity. AB - Repetition of a visual stimulus reduces the firing rate of macaque inferior temporal (IT) neurons. The neural mechanisms underlying this adaptation or repetition suppression are still unclear. In particular, we do not know how the IT circuit is affected by stimulus repetition. To address this, we measured local field potentials (LFPs) and multiunit spiking activity (MUA) simultaneously at 16 sites with a laminar electrode in IT while repeating visual images. Stimulus exposures and interstimulus intervals were each 500 ms. The rhesus monkeys were performing a passive fixation task during the recordings. Induced LFP power decreased with repetition for spectral frequencies above 60 Hz but increased with repetition for lower frequencies, the latter because of a delayed decrease in power when repeating a stimulus. LFP-LFP and MUA-LFP coherences decreased with repetition for frequencies above 60 Hz. This repetition suppression of the MUA LFP coherence was not due to differences in firing rate since it was present when spike counts were equated for the adapter and repeated stimuli. For frequencies between 15 and 40 Hz, the effect of repetition on synchronization depended on the electrode depth: For the putative superficial layers synchronization was enhanced with repetition, while the LFPs of the putative deep layers decreased their synchrony across layers. The between-site, trial-to-trial covariations in MUA ("noise correlations") decreased with repetition, but this might have reflected repetition suppression of the firing rate. This work demonstrates that short-term stimulus repetition affects the synchronized activity, in addition to response strength, in IT cortex. PMID- 22490558 TI - Two-stage AMPA receptor trafficking in classical conditioning and selective role for glutamate receptor subunit 4 (tGluA4) flop splice variant. AB - Previously, we proposed a two-stage model for an in vitro neural correlate of eyeblink classical conditioning involving the initial synaptic incorporation of glutamate receptor A1 (GluA1)-containing alpha-amino-3-hydroxy-5-methylisoxazole 4-propionic acid type receptors (AMPARs) followed by delivery of GluA4-containing AMPARs that support acquisition of conditioned responses. To test specific elements of our model for conditioning, selective knockdown of GluA4 AMPAR subunits was used using small-interfering RNAs (siRNAs). Recently, we sequenced and characterized the GluA4 subunit and its splice variants from pond turtles, Trachemys scripta elegans (tGluA4). Analysis of the relative abundance of mRNA expression by real-time RT-PCR showed that the flip/flop variants of tGluA4, tGluA4c, and a novel truncated variant tGluA4trc1 are major isoforms in the turtle brain. Here, transfection of in vitro brain stem preparations with anti tGluA4 siRNA suppressed conditioning, tGluA4 mRNA and protein expression, and synaptic delivery of tGluA4-containing AMPARs but not tGluA1 subunits. Significantly, transfection of abducens motor neurons by nerve injections of tGluA4 flop rescue plasmid prior to anti-tGluA4 siRNA application restored conditioning and synaptic incorporation of tGluA4-containing AMPARs. In contrast, treatment with rescue plasmids for tGluA4 flip or tGluA4trc1 failed to rescue conditioning. Finally, treatment with a siRNA directed against GluA1 subunits inhibited conditioning and synaptic delivery of tGluA1-containing AMPARs and importantly, those containing tGluA4. These data strongly support our two-stage model of conditioning and our hypothesis that synaptic incorporation of tGluA4 containing AMPARs underlies the acquisition of in vitro classical conditioning. Furthermore, they suggest that tGluA4 flop may have a critical role in conditioning mechanisms compared with the other tGluA4 splice variants. PMID- 22490560 TI - Longitudinal changes in muscle activity during infants' treadmill stepping. AB - Previous research has described kinetic characteristics of treadmill steps in very stable steppers, in cross-sectional designs. In this study we examined, longitudinally, muscle activation patterns during treadmill stepping, without practice, in 12 healthy infants at 1, 6, and 12 mo of age. We assessed lateral gastrocnemius, tibialis anterior, rectus femoris, and biceps femoris as infants stepped on a treadmill during twelve 20-s trials. Infants showed clear changes in kinematics, such as increased step frequency, increased heel contact at touch down, and more flat-footed contact at midstance. Electromyographic data showed high variability in muscle states (combinations), with high prevalence of all muscles active initially, reducing with age. Agonist-antagonist muscle coactivation also decreased as age increased. Probability analyses showed that across step cycles, the likelihood a muscle was on at any point tended to be <50%; lateral gastrocnemius was the exception, showing an adultlike pattern of probability across ages. In summary, over time, healthy infants produce a wide variety of muscle activation combinations and timings when generating stepping patterns on a treadmill, even if some levels of muscle control arose with time. However, the kinematic stability improved much more clearly than the underlying kinetic strategies. We conclude that although innate control of limb movement improves as infants grow, explore, and acquire functional movement, stepping on a treadmill is a novel and unpracticed one. Hence, developing stable underlying neural activations will only arise as functional practice ensues, similarly to that observed for other functional movements in infancy. PMID- 22490559 TI - Reversal of quinpirole inhibition of ventral tegmental area neurons is linked to the phosphatidylinositol system and is induced by agonists linked to G(q). AB - Putative dopaminergic (pDAergic) ventral tegmental area neurons play an important role in brain pathways related to addiction. Extended exposure of pDAergic neurons to moderate concentrations of dopamine (DA) results in a time-dependent decrease in sensitivity of pDAergic neurons to DA inhibition, a process called dopamine inhibition reversal (DIR). We have shown that DIR is mediated by phospholipase C and conventional protein kinase C through concurrent stimulation of D2 and D1-like receptors. In the present study, we further characterized this phenomenon by using extracellular recordings in brain slices to examine whether DIR is linked to phosphatidylinositol (PI) or adenylate cyclase (AC) second messenger pathways. A D1-like dopaminergic agonist associated with PI turnover (SKF83959), but not one linked to AC (SKF83822), promoted reversal of inhibition produced by quinpirole, a dopamine D2-selective agonist. Other neurotransmitter receptors linked to PI turnover include serotonin 5-HT(2), alpha(1)-adrenergic, neurotensin, and group I metabotropic glutamate (mGlu) receptors. Both serotonin and neurotensin produced significant reversal of quinpirole inhibition, but agonists of alpha(1)-adrenergic and group I mGlu receptors failed to significantly reverse quinpirole inhibition. These results indicate that some agonists that stimulate PI turnover can facilitate desensitization of D2 receptors but that there may be other factors in addition to PI that control that interaction. PMID- 22490562 TI - Friction on a single MoS2 nanotube. AB - Friction was measured on a single molybdenum disulfide (MoS2) nanotube and on a single MoS2 nano-onion for the first time. We used atomic force microscopy (AFM) operating in ultra-high vacuum at room temperature. The average coefficient of friction between the AFM tip and MoS2 nanotubes was found considerably below the corresponding values obtained from an air-cleaved MoS2 single crystal or graphite. We revealed a nontrivial dependency of friction on interaction strength between the nanotube and the underlying substrate. Friction on detached or weakly supported nanotubes by the substrate was several times smaller (0.023 +/- 0.005) than that on well-supported nanotubes (0.08 +/- 0.02). We propose an explanation of a quarter of a century old phenomena of higher friction found for intracrystalline (0.06) than for intercrystalline slip (0.025) in MoS2. Friction test on a single MoS2 nano-onion revealed a combined gliding-rolling process.PACS, 62.20, 61.46.Fg, 68.37 Ps. PMID- 22490563 TI - Adoptability and limitation of cancer treatment guidelines: a Chinese oncologist's perspective. PMID- 22490561 TI - M2 muscarinic acetylcholine receptors regulate long-term potentiation at hippocampal CA3 pyramidal cell synapses in an input-specific fashion. AB - Muscarinic receptors have long been known as crucial players in hippocampus dependent learning and memory, but our understanding of the cellular underpinnings and the receptor subtypes involved lags well behind. This holds in particular for the hippocampal CA3 region, where the mechanisms of synaptic plasticity depend on the type of afferent input. Williams and Johnston (Williams S, Johnston D. Science 242: 84-87, 1988; Williams S, Johnston D. J Neurophysiol 64: 1089-1097, 1990) demonstrated muscarinic depression of mossy fiber (MF) long term potentiation (LTP) through a presynaptic site of action and Maeda et al. (Maeda T, Kaneko S, Satoh M. Brain Res 619: 324-330, 1993) proposed a bidirectional modulation of MF LTP by muscarinic receptor subtypes. Since then, this issue, as well as muscarinic regulation of plasticity at associational/commissural (A/C) fiber-CA3 synapses has remained largely neglected, not least because of the lack of highly selective ligands for the different muscarinic receptor subtypes. In the present study, we performed field potential and whole cell recordings from the hippocampal CA3 region of M(2) receptor knockout mice to determine the role of M(2) receptors in short-term and long-term plasticity at A/C and MF inputs to CA3 pyramidal cells. At the A/C synapse, M(2) receptors promoted short-term facilitation and LTP. Unexpectedly, M(2) receptors mediated the opposite effect on LTP at the MF synapse, which was significantly reduced, most likely involving a depressant effect of M(2) receptors on adenylyl cyclase activity in MF terminals. Our data demonstrate that cholinergic projections recruit M(2) receptors to redistribute the gain of LTP in CA3 pyramidal cells in an input-specific manner. PMID- 22490564 TI - Magnifying endoscopy with narrow-band imaging may improve diagnostic accuracy of differentiated gastric intraepithelial neoplasia: a feasibility study. AB - BACKGROUND: Magnifying narrow-band imaging has enabled observation of the mucosal and vascular patterns of gastrointestinal lesions. This study investigated the potential value of magnifying endoscopy with narrow-band imaging for the classification of gastric intraepithelial neoplasia. METHODS: Seventy-six patients with gastric intraepithelial neoplasia (82 lesions) at People's Liberation Army General Hospital from December 2009 to November 2010 were analyzed. All patients underwent magnifying endoscopy with narrow-band imaging, and their lesions were differentiated into probable low-grade intraepithelial neoplasia or possible high-grade intraepithelial neoplasia on the basis of the imaging features. Pathologic proof was subsequently obtained by endoscopic submucosal dissection in every case. The validity of magnifying endoscopy with narrow-band imaging was calculated, considering histopathology to be the gold standard. RESULTS: Magnifying endoscopy with narrow-band imaging showed 22 low grade intraepithelial neoplastic lesions and 60 high-grade intraepithelial neoplastic lesions. Of the 22 low-grade intraepithelial neoplastic lesions, 16 showed the same results on both imaging and pathology. Of the 60 high-grade intraepithelial neoplastic lesions, 53 showed the same results on both imaging and pathology. Thus, the sensitivity of magnifying endoscopy with narrow-band imaging for high-grade intraepithelial neoplasia was 89.83%, which was higher than that for low-grade intraepithelial neoplasia (69.57%). However, the specificity for high-grade intraepithelial neoplasia (69.57%) was lower than that for low-grade intraepithelial neoplasia (89.83%). The overall accuracy of magnifying endoscopy with narrow-band imaging was 84.15%. CONCLUSIONS: Magnifying endoscopy with narrow-band imaging can distinguish between gastric low- and high grade intraepithelial neoplasia. It may be a convenient and effective method for the classification of gastric intraepithelial neoplasia. PMID- 22490565 TI - Risk factors related to female breast cancer in regions of Northeast China: a 1:3 matched case-control population-based study. AB - BACKGROUND: There has been an increase in the incidence of breast cancer in China, but no definite risk and protective factors for breast cancer have been identified in Chinese females. This study was designed to identify the risk factors for female breast cancer in North and East China. METHODS: A 1:3 matched, case-control study was conducted. All of the subjects in the case and control groups were selected from a previous epidemiological survey of 122 058 females aged 25 to 70 years. Single and multiple Logistic regression analyses were used to study potential factors in the development of breast cancer. RESULTS: Significant differences at the level of alpha=0.20 between case and control groups were observed for the following factors: economic status, social status, family annual income, bean product consumption, body mass index (BMI), family history of breast cancer in the first or second degree, number of miscarriages, menstrual pattern, benign breast disease history, nipple leakage, inverted nipple, history of diabetes mellitus, history of hypertension, history of ovarian cyst, physical exercise, current and global quality of life satisfaction, healthy behavior and prevention, and scores of breast cancer-related knowledge. After Cox regression model analysis (alpha=0.10), six factors were found to be significantly related to breast cancer, of which the ORs and 95%CIs were: BMI, 1.696 (1.169-2.460, P=0.005); benign breast disease history, 2.672 (0.848-8.416, P=0.093); family history of breast cancer, 7.080 (1.758-28.551, P=0.006); number of miscarriages, 1.738 (1.014-2.978, P=0.044); global quality of life satisfaction, 3.044 (1.804-5.136, P=0.000); healthy behavior and prevention, 3.294 (1.692-6.412, P=0.000). CONCLUSIONS: A comprehensive range of factors related to breast cancer was identified. Women should be educated about a healthy lifestyle, especially those with a family history of breast cancer or a personal history of benign breast disease. PMID- 22490566 TI - Polymorphisms of dihydropyrimidine dehydrogenase gene and clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population. AB - BACKGROUND: Dihydropyrimidine dehydrogenase (DPD), a key enzyme involved in the catabolism of 5-fluorouracil (5-FU), is the attractive candidate for pharmacogenetic research on efficacies and toxicities of 5-FU. The aim of this study is to explore the association between polymorphisms of dihydropyrimidine dehydrogenase gene (DPYD) and clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in the Chinese population. METHODS: Three hundred and sixty-two patients with gastric cancer in the Chinese population were treated with fluorouracil-based adjuvant chemotherapy. The single nucleotide polymorphic genotypes of DPYD were determined by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) using DNA samples isolated from peripheral blood collected before treatment. RESULTS: The average response rate for chemotherapy was 46.7%. A significantly different distribution of the rs1801159 (c2=8.76, P=0.012) genotypes was observed. Homozygous genotype rs1801159A/A was over-represented in responsive patients. Conversely, carriers of the rs1801159A/G genotype were prevalent in non responsive patients. In the haplotype association analysis, there was significant difference in global haplotype distribution between the groups (c2=3.96, P=0.0465). CONCLUSIONS: These results suggest that polymorphisms of rs1801159 in DPYD may be used as valuable predictors of the response to fluorouracil-based chemotherapy for gastric cancer patients in the Chinese population. Well designed, comprehensive, and prospective studies on determining these polymorphisms of DPYD as predictive markers for gastric cancer in response to fluorouracil-based therapies are warranted. PMID- 22490567 TI - Correlation between the survival rate of the patients with synchronous hepatic metastases from gastric carcinoma after surgical resection and patient's index. AB - BACKGROUND: Many studies have reported the benefit of hepatic resection for solitary and metachronous metastases from gastric cancer. However, indications and surgical results for synchronous hepatic metastases from gastric carcinoma have not been clearly defined. This study was performed to assess the benefits and limits of simultaneous combined resection of both primary gastric cancer and synchronous hepatic metastases, as well as to identify prognostic factors affecting the survival. METHODS: Between January 2005 and June 2008, 13 patients with synchronous hepatic metastases underwent simultaneous combined resection. The clinicopathologic features and the surgical results of the 13 patients were retrospectively analyzed. Patient, tumor (primary and metastatic carcinoma), and operative parameters were analyzed for their influence on survival. RESULTS: No patient died and two patients (15.4%) developed complications during peri operative course. The actuarial 6-month, 1-year, and 2-year survival rates after hepatic resection were 76.9%, 38.5%, and 30.8%, respectively, and two patients survived for more than 2 years after surgery without any signs of recurrences until latest follow-up. In univariate analysis, hepatic tumor distribution (P=0.01) and number of hepatic metastases (P=0.003) were significant prognostic factors that influenced survival. Factors associated with the primary lesion were not significant prognostic factors. CONCLUSIONS: Satisfactory survival may be achieved by simultaneous combined resection of both primary gastric cancer and synchronous hepatic metastases in strictly selected patients. The number of hepatic metastases and hepatic tumor distribution are significant prognostic determinants of survival. PMID- 22490568 TI - Role of radical resection in patients with gallbladder carcinoma and jaundice. AB - BACKGROUND: Gallbladder carcinoma (GBC) is a commonly-seen malignancy of the biliary tract characterized by difficult early diagnosis, rapid growth, early metastasis, and poor prognosis. Nearly half of GBC patients also have jaundice, which is a mark of the advanced stage of GBC. The role of radical resection in patients of gallbladder carcinoma with jaundice is still a matter of uncertainty, which we attempted to clarify in this study. METHODS: Totally, 251 GBC patients who received treatment at the Eastern Hepatobiliary Surgery Hospital (EHBH) from December 2002 to January 2010 were recruited into this study. We divided them into group A (jaundice group, n=117) and group B (non-jaundice group, n=134). Clinical records and follow-up data were collected and retrospectively analyzed in both groups. RESULTS: Compared with group A, patients in group B had a longer median survival time ((6.0+/-0.5) months vs. (15.0+/-2.6) months, P<0.01). Even in patients with stage III or stage IV GBC, the median survival time in patients without jaundice (n=111), was still longer than that in patients with jaundice (n=116) (P<0.01). The radical resection rate was lower in group A patients than in group B patients with stage III or stage IV GBC; 31.9% vs. 63.1%. However, the median survival time of patients undergoing radical resection did not show a statistical difference between jaundice patients and non-jaundice patients; (12.0+/-4.3) months vs. (18.0+/-3.0) months (P>0.05). CONCLUSIONS: GBC with jaundice usually implies advanced stage disease and a poor prognosis for the patients. However, our findings indicate that as long as the patient's condition allows, radical resection is still feasible for GBC patients with jaundice, and may achieve a prognosis close to those GBC patients without jaundice. PMID- 22490569 TI - Metabolic disorders of fatty acids and fatty acid amides associated with human gastric cancer morbidity. AB - BACKGROUND: Gastric cancer (GC) is one of the most common types of cancer in the world. A change in the metabolism of lipids in tumor cells could lead to the pathogenesis of cancer. In this study, we investigated fatty acid and fatty acid amide metabolic perturbations associated with GC morbidity. METHODS: Gas chromatography/mass spectrometry (GC/MS) was utilized to analyze fatty acids (FAs) and fatty acid amides (FAAs) of GC tissues and matched normal mucosae from 30 GC patients. Acquired lipid data was analyzed using non parametric Wilcoxon rank sum test to find the differential biomarkers for GC and diagnostic models for GC were established by using orthogonal partial least squares discriminant analysis (OPLS-DA). RESULTS: A total of 13 FAs and 4 FAAs were detected using GC/MS and 5 differential FAs as well as oleamide were identified with significant difference (P<0.05). The OPLS-DA model generated from lipid profile showed adequate discrimination of GC tissues from normal mucosae while the OPLS-DA model failed to separate GC specimens of different TNM stages. A total of 8 variables were obtained for their most contribution in the discriminating model (Variable importance in the projection (VIP) value>1.0), five of which were detected with significant difference (P<0.05). CONCLUSIONS: FA and FAA metabolic profiles have great potential in detecting GC and helping understand perturbations of lipid metabolism associated with GC morbidity. PMID- 22490570 TI - Safety and efficacy of first-line bevacizumab combined with taxane therapy in Chinese patients with HER2-negative locally recurrent or metastatic breast cancer: findings from the ATHENA study. AB - BACKGROUND: Three randomised trials have demonstrated that combining bevacizumab with first-line chemotherapy significantly improves progression-free survival versus chemotherapy alone in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). However, data from Chinese populations are limited and possible differences between ethnic and geographic populations are unknown. This study was conducted to determine whether there are differences in safety and efficacy in patients with HER2-negative LR/mRC between Chinese and Western populations after they receive first-line bevacizumab combined with taxane-based therapy. METHODS: In the single-arm, open-label, Avastin Therapy for Advanced Breast Cancer (ATHENA) study (NCT00448591), patients with HER2-negative LR/mBC received first line bevacizumab (investigator's choice of 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) combined with taxane-based therapy. The primary endpoint was safety profile and the secondary is time to progression (TTP). A subpopulation analysis was conducted to assess safety and efficacy in Chinese patients. RESULTS: Of 2264 patients treated in ATHENA, 202 were enrolled in China. Bevacizumab was combined with docetaxel in 90% of Chinese patients and paclitaxel in 10%. The most common grade 3/4 adverse events were diarrhoea (in 5.0% of patients) and hypertension (in 2.5% of patients). Grade 3/4 proteinuria occurred in 0.5%. After median follow-up of 17.6 months and events in 56% of patients, median TTP was 9.0 months (95%CI, 8.4-11.1). Overall survival data were immature. CONCLUSIONS: We found no evidence of increased bevacizumab-related toxicity or reduced efficacy in Chinese LR/mBC patients receiving first-line bevacizumab taxane therapy compared with predominantly Western populations. The safety profile was generally similar to previously reported LR/mBC trials. Subtle differences may be attributable to different lifestyle and cardiovascular risk factors in Chinese patients compared with the overall population. It appears reasonable to extrapolate findings from bevacizumab-based randomised trials to Chinese populations. PMID- 22490572 TI - Clinicopathological characteristics and prognosis of early gastric cancer after gastrectomy. AB - BACKGROUND: Assessment of lymph node metastasis (LNM) is important in early gastric cancer (EGC) and affects treatment decisions. However, the relationship between clinicopathological characteristics and LNM in EGC remains unclear. This study therefore explored favorable predictors of LNM in EGC. METHODS: A total of 716 specimens from gastric cancer patients who underwent curative gastrectomy between 1996 and 2003 at Zhejiang Provincial People's Hospital were reviewed. Forty-five cases were EGC, and clinicopathological characteristics such as gender, age, tumor size, location, gross type, differentiation, invasion depth, and vessel involvement were assessed to identify predictive factors for LNM and survival time. RESULTS: The overall cumulative 5-year survival rate of EGC patients was 88.92%. Among these, 22.4% developed LNM, which was associated with a poor 5-year survival rate of only 72.7%. Patients with tumors larger than 2 cm in diameters, with depth of tumor invasion to the submucosa, and with positive lymphatic or nerve involvement were also inclined to have poorer survival performances. EGC limited to the mucosa but poorly differentiated also had a high risk for LNM. Multivariate analysis identified lymphatic invasion and tumor size as independent prognosis factors related to survival in EGC patients. CONCLUSIONS: Careful planning is required in EGC patients at high risk of lymph node metastases. Endoscopic mucosal resection or endoscopic submucosal dissection and laparoscopic partial gastrectomy should be cautiously used in EGC, and curative gastrectomy including lymphatic dissection and postoperative adjuvant therapy might be considered to improve the prognosis. PMID- 22490573 TI - Oral etoposide monotherapy is effective for metastatic breast cancer with heavy prior therapy. AB - BACKGROUND: Treatment option for metastatic breast cancer (MBC) patients pre treated with chemotherapy is limited. Oral etoposide has shown some promises in these patients. However, patients who received heavy prior chemotherapy may have poor tolerance to prolonged oral etoposide exposure. This study is a single-arm clinical trial that evaluates the efficacy and safety of short-term oral etoposide in Chinese patients with MBC who had received heavy prior therapy. METHODS: MBC patients receiving at least two chemotherapy regimens prior to the enrollment were treated with repeated cycles of oral etoposide (60 mg*m(-2)*d(-1) on days 1-10, followed by 11 days of rest). The primary end point was the progression free survival (PFS). The secondary end points were objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and toxicity profiles. RESULTS: Thirty-two patients received 230 cycles of oral etoposide with a median of 6 cycles (range, 2-20 cycles) per patient. Eight patients (25%) had partial response (PR) and 14 patients achieved stable disease (SD). The ORR was 25%. Nine patients achieved SD for more than 24 weeks and CBR was 53%. The median PFS and OS were 5 (range, 1.5-17.0 months) and 16 months (range, 3.0-51.0 months), respectively. The patients who achieved clinical benefit had longer survival time than those who did not (25.0 versus 11.0 months, P<0.01). Among the 16 patients who received more than four regimens prior to this study, four patients achieved PR and four achieved SD for more than 24 weeks, with a CBR of 50%. The most common hematologic adverse events were anemia (43.8%) and neutropenia (38.5%). Nausea/vomiting (75.0%) and alopecia (62.5%) were the most frequent non-hematologic toxicities. CONCLUSION: Oral etoposide is effective and well tolerated in Chinese women with heavily pretreated MBC. PMID- 22490574 TI - Retrospective analysis of 56 patients with advanced gastric cancer treated with combination of intravenous and intra-arterial intensified neoadjuvant chemotherapy. AB - BACKGROUND: Pre-operative chemotherapy has gained widespread interest while treating advanced gastric cancer in eastern countries. However, there is currently no established standard regimen for gastric cancer. The aim of this research was to explore the value of preoperative chemotherapy with a combination of intravenous and intra-arterial intensified chemotherapy in advanced gastric cancer. METHODS: A total of 56 histologically proven gastric cancer patients, who were considered to be stage II or higher with metastatic lymph nodes and with or without distant metastasis (T2-4, N1-3, and M0-1), were treated with a neoadjuvant chemotherapy. Patients received a combination of intravenous 5-Fu (370 mg/m2) and leucovorin (200 mg/m2) on days 1-5, and intra-arterial etoposide (80 mg/m2) and cisplatin (80 mg/m2) on days 6 and 20. After two cycles of preoperative chemotherapy, patients with resectable tumors underwent laparotomy. RESULTS: All patients finished two cycles of chemotherapy. The overall response rate was 78.57% (44 cases), of which 7.14% (four cases) clinical complete response. Forty-six patients underwent resection, including 21 initially unresectable diseases. R0 resection rate for prechemotherapy resectable and unresectable diseases was 96.15% (25/26 cases) and 66.67% (20/30 cases), respectively. Pathological complete response was observed in 8.70% of patients. Toxicity was moderate and there were no chemotherapy-related deaths. With a median follow-up of 31 months (range 6-76 months), the 5-year survival rate for the whole group and patients with initially resectable tumors were 21.8% and 42.3%, respectively. The median survival for initially resectable and unresectable patients were 41 months (95%CI, 31.006-50.994) and 18 months (95%CI, 13.399-22.601; P<0.01), respectively. CONCLUSION: Preliminary results proved that the combined intensive chemotherapy was a safe and promising regimen for pre operative treatment of advanced gastric cancer. PMID- 22490575 TI - Propofol-induced myoclonic seizures after endoscopic procedure in an elderly woman. PMID- 22490576 TI - Inhibiting effect of Astragalus polysaccharides on the functions of CD4+CD25 highTreg cells in the tumor microenvironment of human hepatocellular carcinoma. AB - BACKGROUND: Astragalus polysaccharides (APS), the main active extract from Astragalus membranaceus (a traditional Chinese medicinal herb), is associated with a variety of immunomodulatory activities. The purpose of the present study was to examine the effect of APS on the function of Treg cells in the tumor microenvironment of human hepatocellular carcinoma (HCC) and to identify the pharmacologic mechanism of APS responsible for the anti-chemotactic activity in CD4+CD25highTreg cells in tumor site of HCC. METHODS: The prevalence of Treg in fresh tissue samples from 31 patients with HCC after radicalhepatectomy was detected. CD4, CD25 and CD127 were selected as Treg cell makers to phenotype cell populations. The expression of FOXp3 mRNA was also analyzed. The migration and proliferation of Treg cells were observed. Interleukin (IL)-4, IL-10, IFN-gamma and SDF-1 in cell supernatant were detected. For all tests, functions of Treg cells were evaluated after treatment with APS. RESULTS: APS can inhibit the growth and proliferation of CD4+CD25+Treg cells in vitro in a dose- and time dependent manner. APS may inhibit CD4+CD25+Treg cells through restoring the cytokine imbalance and reducing the expression of FOXp3 in local HCC microenvironments. SDF-1 played an important role in there recruitment of Treg cells into the tumor microenvironment of HCC. APS might have inhibiting effects on Treg cell migration by blocking SDF-1 or its receptor through the CXCR4/CXCL12 pathway. CONCLUSIONS: The increase in numbers of tumor associated Treg cells might play a role in modulation of the immune response against HCC. APS can restore the cytokine balance in the tumor micro environment and suppress the expression of FOXp3 mRNA to inhibit the immune suppressive effects of Treg cells. The application of APS in the tumor microenvironment might act to enhance the anti-tumor effects of the immunotherapy-based methods, and consequently to increase the survival rate in HCC. PMID- 22490577 TI - Effective adoptive transfer of haploidentical tumor-specific T cells in B16 melanoma bearing mice. AB - BACKGROUND: Adoptive transfer of allogeneic tumor-specific T cells often results in severe graft-versus-host disease (GVHD). Here, we sought to maximize graft versus-tumor and minimize GVHD by using haploidentical T cells in pre-irradiated B16-melanoma bearing mice. METHODS: C57BL/6 mice bearing B16-melanoma tumors were irradiated with 0, 5, or 7 Gy total body irradiation (TBI), or 7 Gy TBI plus bone marrow transplantation. Tumor areas were measured every 3 days to assess the influence of irradiation treatment on tumor regression. B16-melanoma bearing mice were irradiated with 7 Gy TBI; sera and spleens were harvested at days 1, 3, 5, 7, 9, 11, and 13 after irradiation. White blood cell levels were measured and transforming growth factor beta1 (TGF-b1) and interleukin 10 (IL-10) levels in serum were detected using enzyme-linked immunosorbent assay (ELISA) kits. Real time reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry were performed to test TGF-b1, IL-10 and Foxp3 mRNA levels and the proportion of CD4+CD25+Foxp3+ T-regulatory cells (Tregs) in spleens. B16-melanoma bearing C57BL/6 mice were irradiated with 7 Gy TBI followed by syngeneic (Syn1/Syn2) or haploidentical (Hap1/Hap2), dendritic cell-induced cytotoxic T lymphocytes (DC CTLs) treatment, tumor areas and system GVHD were observed every 3 days. Mice were killed 21 days after the DC-CTLs adoptive transfer; histologic analyses of eyes, skin, liver, lungs, and intestine were then performed. RESULTS: Irradiation with 7 Gy TBI on the B16-melanoma-bearing mice did not influence tumor regression compared to the control group; however, it down-regulated the proportion of Tregs in spleens and the TGF-b1 and IL-10 levels in sera and spleens, suggesting inhibition of autoimmunity and intervention of tumor microenvironment. Adoptive transfer of haploidentical DC-CTLs significantly inhibited B16-melanoma growth. GVHD assessment and histology analysis showed no significant difference among the groups. CONCLUSION: Adoptive transfer of haploidentical tumor-specific T cells in irradiation-pretreated B16-melanoma bearing mice preserved antitumor capacity without causing a GVHD response. PMID- 22490578 TI - Fatty acid desaturase 1 polymorphisms are associated with coronary heart disease in a Chinese population. AB - BACKGROUND: A recent genome-wide association study in Caucasians revealed that three loci (rs174547 in fatty acid desaturase 1 (FADS1), rs2338104 near mevalonate kinase/methylmalonic aciduria, cobalamin deficiency, cblB type (MVK/MMAB) and rs10468017 near hepatic lipase (LIPC)) influence the plasma concentrations of high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG). However, there are few reports on the associations between these polymorphisms and plasma lipid concentrations in Chinese individuals. This study aimed to evaluate the associations between these three polymorphisms with HDL-C and TG concentrations, as well as coronary heart disease (CHD) susceptibility in Chinese individuals. METHODS: We conducted a population-based case-control study in Chinese individuals to evaluate the associations between these three polymorphisms and HDL-C and TG concentrations, and also evaluated their associations with susceptibility to CHD. Genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism assays and TaqMan genotyping assays. RESULTS: We found significant differences in TG and HDL C concentrations among the TT, TC and CC genotypes of FADS1 rs174547 (P=0.017 and 0.003, respectively, multiple linear regression). The CC variant of rs174547 was significantly associated with hyperlipidemia compared with the TT variant (adjusted odds ratio (OR)=1.71, 95% confidence intervals (CI): 1.16-2.54). The FADS1 rs174547 CC variant was also associated with significantly increased CHD risk compared with the TT and TC variant (adjusted OR=1.53, 95%CI: 1.01-2.31), and the effect was more evident among nonsmokers and females. The polymorphisms rs2338104 and rs10468017 did not significantly influence HDL-C or TG concentrations in this Chinese population. CONCLUSION: rs174547 in FADS1 may contribute to the susceptibility of CHD by altering HDL-C and TG levels in Chinese individuals. PMID- 22490579 TI - Neuregulin-1 attenuates mitochondrial dysfunction in a rat model of heart failure. AB - BACKGROUND: Mitochondrial dysfunction plays a pivotal role in the progression of left ventricular (LV) remodeling and heart failure (HF). Recombinant human neuregulin-1 (rhNRG-1) improves cardiac function in models of experimental HF and in clinical trials; however, its impact on mitochondrial function during chronic HF remains largely unknown. The purpose of this study was to investigate whether rhNRG-1 could attenuate the functional and structural changes that occur in cardiac mitochondria in a rat model of HF induced by myocardial infarction. METHODS: Sixty adult rats underwent sham or coronary ligation to induce HF. Four weeks after ligation, 29 animals with LV ejective fraction <= 50% were randomized to receive either vehicle or rhNRG-1 (10 ug*kg(-1)*d(-1), I.V.) for 10 days, another 12 sham-operated animals were given no treatment. Echocardiography was used to determine physiological changes. Mitochondrial membrane potential (MMP), respiratory function and tissue adenosine triphosphate (ATP) production were analyzed. Cytochrome c expression and cardiomyocyte apoptosis were determined. Oxidative stress was evaluated by reactive oxygen species production using fluorescence assays and gene expression of glutathione peroxidase measured by real-time quantitative PCR. RESULTS: Compared with sham-operated animals, vehicle treated HF rats exhibited severe LV remodeling and dysfunction, significant mitochondrial dysfunction, increased mitochondrial cytochrome c release, increased myocyte apoptosis and enhanced oxidative stress. Short-term treatment with rhNRG-1 significantly attenuated LV remodeling and cardiac function. Concomitant with this change, mitochondrial dysfunction was significantly attenuated; with ATP production, MMP and respiratory function restored, cytochrome c release and apoptosis inhibited, and oxidative stress reduced. CONCLUSION: The present study demonstrated that rhNRG-1 can significantly improve LV remodeling and cardiac function in the failing heart, this beneficial effect is related to reducing mitochondrial dysfunction, myocyte apoptosis and oxidative stress. PMID- 22490580 TI - Effect of metoprolol on sarcoplasmic reticulum Ca2+ leak in a rabbit model of heart failure. AB - BACKGROUND: Studies have shown that beta-blockers can improve cardiac performance in heart failure (HF) by reversing protein kinase A (PKA)-mediated sarcoplasmic reticulum (SR) Ca2+ leak. However, it is being strongly questioned as to whether the PKA-mediated ryanodine receptor (RyR2) hyper-phosphorylation is a critical regulator of SR Ca2+ leak. In this study, we used a rabbit HF model to investigate whether beta-blockers affect SR Ca2+ leak by other potential mechanisms. METHODS: New Zealand white rabbits were randomly divided in three groups (n=7 in each group): normal group, metoprolol-untreated group and metoprolol-treated group. Cardiac function was determined by echocardiography and hemodynamic assays. The SR Ca2+ leak was measured by a calcium-imaging device, and the expression and activities of related proteins were evaluated by Western blotting and auto-phosphorylation. RESULTS: In the metoprolol-untreated group, there was significantly increased ventricular cavity size, reduced systolic function, increased SR Ca2+ leak, reduced associated amount of FK506 binding protein 12.6 (FKBP12.6), increased expression and activity of PKA and Ca2+/calmodulin-dependent protein kinase II (CaMKII), and increased phosphorylated RyR2 phosphorylation sites (with unchanged RyR2-P2030). In the treated group, there was partly increased ventricular cavity size with preserved systolic function, but no prominent Ca2+ leak, with unchanged expression and activity of PKA, CaMKII and their RyR2 phosphorylation sites. CONCLUSION: Chronic administration of metoprolol prevented the SR Ca2+ leak by restoring not only PKA dependent but also CaMKII-dependent hyper-phosphorylation of RyR2, which may be one of the potential mechanisms by which beta-blockers improve cardiac function and reduce the incidence of fatal arrhythmia in HF. PMID- 22490581 TI - Genetic diversity analysis of Penicillium marneffei isolated from AIDS patients in Guangdong, China using randomly amplified polymorphic DNA. AB - BACKGROUND: Penicillium marneffei (P. marneffei) is an emerging pathogenic fungus that can cause invasive mycosis in patients with AIDS. The epidemiological features of P. marneffei infection in AIDS patients in Guangdong province remain unclear so far. This study aimed to investigate the genetic diversity within a population of 163 P. marneffei isolates obtained from AIDS patients and search for the dominant clinical strains in Guangdong province. METHODS: One hundred and sixty-three P. marneffei isolates obtained from AIDS patients in Guangdong province during January 2004 and December 2009 were studied by randomly amplified polymorphic DNA (RAPD) using two random primers (H2 and H22). The degree of similarity between samples was calculated through similarity coefficients from RAPD fragment data and the dendrogram was assessed using the unweighted pair group method with arithmetic mean (UPGMA). RESULTS: Two primers showed a high degree of discrimination and good stability. Primer H2 yielded eight different patterns (H2-1 to H2-8) among 163 isolates with the discriminatory power being 0.413. Primer H22 identified seven types (H22-1 to H22-7) among 163 isolates with the discriminatory power being 0.467. Genetic similarity coefficients based on RAPD data among 163 P. marneffei isolates ranged from 0.681 to 0.957, 61.96% of which were no less than 0.83. The discriminatory power of the two primers was 0.524. One hundred and sixty-three P. marneffei isolates were clustered into nine distinct groups (groups I to IX) at the similarity coefficient value of 0.83 and group I was the most common, including 101 strains (61.96%). CONCLUSION: The RAPD analyses could provide important information as to the degree of genetic diversity and the relationship among clinical P. marneffei isolates, revealing genetic polymorphism and dominant strains. PMID- 22490582 TI - Epidemiological features and risk factors of sepsis-associated encephalopathy in intensive care unit patients: 2008-2011. AB - BACKGROUND: Encephalopathy is a common complication of sepsis, and its onset can occur at any stage of sepsis and implies worse prognosis. However, the incidence, epidemiology, and pathogenesis of sepsis-associated encephalopathy remain controversial. The purpose of this study was to investigate the epidemiological features and risk factors for sepsis-associated encephalopathy. METHODS: Our retrospective study included all patients with sepsis admitted to our intensive care unit from 2008 to 2011. After excluding 91 patients, 232 patients were assigned to either a sepsis-associated encephalopathy group or sepsis without encephalopathy group. Between-group differences in baseline patient data including vital signs, disease severity, pathogens, sites of infection, biochemical indicators, and time on a mechanical ventilator, intensive care unit (ICU) stay, and 28-day mortality rate were analyzed. RESULTS: The incidence of sepsis-associated encephalopathy was 17.7%. The sepsis-associated encephalopathy group had significantly higher 28-day mortality (56.1% vs. 35.1%; P=0.013), spent a significantly longer time on a ventilator ((8.2+/-2.2) days vs. (2.9+/-0.4) days; P=0.021), and had a significantly longer ICU stay ((12.4+/-2.4) days vs. (7.1+/-0.6) days; P=0.042). Acute physiology and chronic health evaluation II score, Glasgow coma scale, heart rate, blood lactate, serum sodium, platelets, serum albumin, and pH values were related to the presence of encephalopathy. Patients with biliary tract infections and intestinal infections caused by Staphylococcus aureus, Enterococcus faecium, Acinetobacter spp, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia, were more prone to develop sepsis associated encephalopathy. CONCLUSIONS: Encephalopathy increases mortality rate in septic patients. Clinical intervention to reduce risk factors and thereby morbidity and mortality depends on a correct understanding of the differences between patients with sepsis and patients with both sepsis and encephalopathy. PMID- 22490583 TI - Impaired brachial artery flow-mediated dilation and increased carotid intima media thickness in rheumatoid arthritis patients. AB - BACKGROUND: Carotid artery intima-media thickness (CIMT) and brachial artery flow mediated dilation percentage (FMD%) are common parameters used for detecting subclinical atherosclerosis. This study compared subclinical atherosclerosis of the carotid and brachial arteries in rheumatoid arthritis (RA) patients and healthy controls using high resolution ultrasonography. We also investigated their correlation with clinical factors and the association between FMD% and CIMT. METHODS: One hundred and two RA patients and 46 age-gender matched healthy controls were included in the study. FMD of the brachial artery and CIMT were measured ultrasonographically. Patients with diabetes mellitus, hypertension, renal failure, history of cardiovascular or cerebrovascular disease were excluded. Subjects who were receiving or used high dose steroids were also excluded. RESULTS: The CIMT was significantly higher in patients than that in the control group ((0.697+/-0.053) vs. (0.554+/-0.051) mm, P<0.001), whereas brachial artery FMD% was lower in patients than that in the controls ((5.454+/-2.653)% vs. (8.477+/-2.851)%, P<0.001). CIMT was related to age, disease duration, tender and swollen joint score, C-reactive protein, systolic blood pressure and high-density lipoprotein. However, FMD% was only association with systolic blood pressure. There was no significant correlation between CIMT and FMD%. CONCLUSIONS: Compared with the healthy control subjects, RA patients without clinically evident cardiovascular disease had subclinical atherosclerosis in terms of impaired FMD% and increased CIMT. FMD% and CIMT may measure a different stage of subclinical atherosclerosis in RA patients. PMID- 22490584 TI - Somatosensory disinhibition in patients with paroxysmal kinesigenic dyskinesia. AB - BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is characterized by recurrent brief episodes of chorea and dystonia induced by sudden movement. Whether the central nervous system is hyper- or hypoexcitable in PKD remains undetermined. The aim of our study was to compare the somatosensory evoked potential (SEP) recovery cycle, a marker of somatosensory system excitability, in PKD patients and controls. METHODS: Twenty-four PKD patients (mean age of (20.0+/-5.3) years; 21 males, 3 females) and 18 control age-matched subjects (mean age of (22.0+/ 5.0) years; 17 males, 1 female) were studied. The stimuli were delivered to the median nerve in the affected dominant arm in patients and in the dominant arm in controls. The change in SEP amplitude was measured after paired electrical stimulation at interstimulus intervals (ISIs) of 5, 20, and 40 ms. The SEPs evoked by S2 (test stimulus) were calculated by subtracting the response to S1 (the conditioning stimulus) from the response to a pair of stimuli (S1+S2), and their amplitudes were compared with those of the control response (S1) at each ISI. Analysis of variance (ANOVA) or equivalent was used for non-parametric data. RESULTS: In patients, the P27 amplitude after the single stimulus (S1) was significantly larger than that after the control stimulus. The (S2/S1)*100 ratio for P14 and N30 SEPs did not differ significantly between PKD patients and normal subjects at ISI of 5 ms but were significantly higher in patients at ISIs of 20 and 40 ms (P<0.05). CONCLUSIONS: Somatosensory system disinhibition takes place in PKD. The finding of reduced suppression of different SEPs, each thought to have a different origin, suggests an abnormality of intracortical and subcortical inhibitory circuits. PMID- 22490585 TI - Quantitative T2 mapping evaluation for articular cartilage lesions in a rabbit model of anterior cruciate ligament transection osteoarthritis. AB - BACKGROUND: Quantitative T2 mapping has been a widely used method for the evaluation of pathological cartilage properties, and the histological assessment system of osteoarthritis in the rabbit has been published recently. The aim of the study was to investigate the effectiveness of quantitative T2 mapping evaluation for articular cartilage lesions of a rabbit model of anterior cruciate ligament transection (ACLT) osteoarthritis. METHODS: Twenty New Zealand White (NZW) rabbits were divided into ACLT surgical group and sham operated group equally. The anterior cruciate ligaments of the rabbits in ACLT group were transected, while the joints were closed intactly in sham operated group. Magnetic resonance (MR) examinations were performed on 3.0T MR unit at week 0, week 6, and week 12. T2 values were computed on GE ADW4.3 workstation. All rabbits were killed at week 13, and left knees were stained with Haematoxylin and Eosin. Semiquantitative histological grading was obtained according to the osteoarthritis cartilage histopathology assessment system. Computerized image analysis was performed to quantitate the immunostained collagen type II. RESULTS: The average MR T2 value of whole left knee cartilage in ACLT surgical group ((29.05+/-12.01) ms) was significantly higher than that in sham operated group ((24.52+/-7.97) ms) (P=0.024) at week 6. The average T2 value increased to (32.18+/-12.79) ms in ACLT group at week 12, but remained near the baseline level ((27.66+/-8.08) ms) in the sham operated group (P=0.03). The cartilage lesion level of left knee in ACLT group was significantly increased at week 6 (P=0.005) and week 12 (P<0.001). T2 values had positive correlation with histological grading scores, but inverse correlation with optical densities (OD) of type II collagen. CONCLUSION: This study demonstrated the reliability and practicability of quantitative T2 mapping for the cartilage injury of rabbit ACLT osteoarthritis model. PMID- 22490586 TI - Performance comparison between Logistic regression, decision trees, and multilayer perceptron in predicting peripheral neuropathy in type 2 diabetes mellitus. AB - BACKGROUND: Various methods can be applied to build predictive models for the clinical data with binary outcome variable. This research aims to explore the process of constructing common predictive models, Logistic regression (LR), decision tree (DT) and multilayer perceptron (MLP), as well as focus on specific details when applying the methods mentioned above: what preconditions should be satisfied, how to set parameters of the model, how to screen variables and build accuracy models quickly and efficiently, and how to assess the generalization ability (that is, prediction performance) reliably by Monte Carlo method in the case of small sample size. METHODS: All the 274 patients (include 137 type 2 diabetes mellitus with diabetic peripheral neuropathy and 137 type 2 diabetes mellitus without diabetic peripheral neuropathy) from the Metabolic Disease Hospital in Tianjin participated in the study. There were 30 variables such as sex, age, glycosylated hemoglobin, etc. On account of small sample size, the classification and regression tree (CART) with the chi-squared automatic interaction detector tree (CHAID) were combined by means of the 100 times 5-7 fold stratified cross-validation to build DT. The MLP was constructed by Schwarz Bayes Criterion to choose the number of hidden layers and hidden layer units, alone with levenberg-marquardt (L-M) optimization algorithm, weight decay and preliminary training method. Subsequently, LR was applied by the best subset method with the Akaike Information Criterion (AIC) to make the best used of information and avoid overfitting. Eventually, a 10 to 100 times 3-10 fold stratified cross-validation method was used to compare the generalization ability of DT, MLP and LR in view of the areas under the receiver operating characteristic (ROC) curves (AUC). RESULTS: The AUC of DT, MLP and LR were 0.8863, 0.8536 and 0.8802, respectively. As the larger the AUC of a specific prediction model is, the higher diagnostic ability presents, MLP performed optimally, and then followed by LR and DT in terms of 10-100 times 2-10 fold stratified cross-validation in our study. Neural network model is a preferred option for the data. However, the best subset of multiple LR would be a better choice in view of efficiency and accuracy. CONCLUSION: When dealing with data from small size sample, multiple independent variables and a dichotomous outcome variable, more strategies and statistical techniques (such as AIC criteria, L-M optimization algorithm, the best subset, etc.) should be considered to build a forecast model and some available methods (such as cross-validation, AUC, etc.) could be used for evaluation. PMID- 22490587 TI - Functional MRI study of mild Alzheimer's disease using amplitude of low frequency fluctuation analysis. AB - BACKGROUND: Previous studies have shown that the functional brain activity in the resting state is impaired in Alzheimer's disease (AD) patients. However, most studies focused on the relationship between different brain areas, rather than the amplitude or strength of the regional brain activity. The purpose of this study was to explore the functional brain changes in AD patients by measuring the amplitude of the blood oxygenation level dependent (BOLD) functional MRI (fMRI) signals. METHODS: Twenty mild AD patients and twenty healthy elderly subjects participated in the fMRI scan. The amplitude of low frequency fluctuation (ALFF) was calculated using REST software. RESULTS: Compared with the healthy elderly subjects, the mild AD patients showed decreased ALFF in the right posterior cingulate cortex, right ventral medial prefrontal cortex, and in the bilateral dorsal medial prefrontal cortex. No brain region with increased ALFF was found in the AD group compared with the control group. CONCLUSIONS: The reduced activity in the posterior cingulate cortex and medial prefrontal cortex observed in the present study suggest that the functional abnormalities of those areas are at an early stage of AD. The ALFF analysis may provide a useful tool in fMRI study of AD. PMID- 22490588 TI - Three-dimensional cultures of human endometrial cells on Matrigel mimic in vivo morphology. AB - BACKGROUND: The regulation of endometrial physiology and morphogenesis by the paracrine effectors has been well established using in vivo studies. A more complete understanding of the endometrial function has been delayed due, in part, to a lack of appropriate culture models. In this study, we aimed to simulate the in vivo three-dimensional (3-D) growth pattern of endometrial cells using a 3-D in vitro culture system. METHODS: Isolated endometrial epithelial cells, stromal cells and RL95-2 cells were seeded into culture chambers coated with the extracellular matrix Matrigel and observed using light microscopy. Fluorescence staining and immunohistochemistry were used to assess the morphology. RESULTS: Depending on the culture conditions, epithelial cells and RL95-2 cells formed multicellular structures on Matrigel; stromal cells remained individually distinguishable or grew together to form 3-D lattice-like structures. CONCLUSIONS: Matrigel provided a good microenvironment for culturing endometrial cells. The cells cultured in the Matrigel-coated chambers closely resembled those seen in vivo. PMID- 22490589 TI - Comparison of the effectiveness of dexmedetomidine versus propofol target controlled infusion for sedation during coblation-assisted upper airway procedure. AB - BACKGROUND: Sedation for the coblation-assisted upper airway procedure has lacked easy modulation between appropriate pain control and airway protection. This study aimed to compare the effectiveness of dexmedetomidine versus target controlled propofol infusion in providing sedation during a coblation-assisted upper airway procedure. METHODS: In a prospective, randomized trial, 60 adult patients with obstructive sleep apnea syndrome due to undergoing a coblation assisted upper airway procedure were enrolled and randomly allocated to receive dexmedetomidine, 1.0 ug/kg over 10 minutes and maintain dosage 0.7 ug*kg(-1)*h( 1) (n=30) or propofol target controlled infusion (n=30). Satisfaction with the analgesia and tolerance of the procedure by the patient, as assessed by a visual analogue scale, were evaluated as primary outcomes. Cardiopulmonary parameters and some side effects were monitored and recorded. RESULTS: Both groups of 30 patients had comparable demographics and initial parameters. Patients in the propofol group reported more pain (P<0.05), tolerated the procedure less well (P<0.05), and were less satisfied with the different stages of procedure (P<0.05 or P<0.01). Changes in mean arterial pressure and heart rate were more dramatic in the propofol group (P<0.05). The dexmedetomidine group experienced fewer airway events and less respiratory depression than did the propofol group. CONCLUSION: Dexmedetomidine in conjunction with local anesthesia offered better analgesia and conscious sedation for a coblation-assisted upper airway procedure as well as less airway obstruction, apnea and greater haemodynamic stability. PMID- 22490590 TI - Up-regulation of visfatin expression in subjects with hyperthyroidism and hypothyroidism is partially relevant to a nonlinear regulation mechanism between visfatin and tri-iodothyronine with various concentrations. AB - BACKGROUND: Visfatin, a visceral fat-derived adipocytokine, plays a significant physiological function in lipid metabolism. However, the precise function of visfatin and its regulation by thyroid hormones are still unknown. This study observed the plasma visfatin concentrations in subjects with hyperthyroidism and hypothyroidism in vivo, and investigated the possible regulation mechanism between visfatin and tri-iodothyronine (T3) in vitro as a further interpretation. METHODS: The experiment in vivo included clinical subjects (57 patients with thyroid dysfunction and 29 euthyroid healthy volunteers) and an animal model (24 Wistar rats). All subjects were divided into hyperthyroidism, hypothyroidism and euthyroidism groups, with plasma thyroid hormones, thyrotropin, visfatin and triglyceride concentrations determined. Visfatin mRNA expression in visceral fat and liver of rats was detected by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). The experiment in vitro studied 3T3-L1 cells and visfatin mRNA expression under nine different T3 concentrations (0, 0.1, 0.25, 0.5, 1, 5, 10, 20, 100 nmol/L) using quantitative real-time RT-PCR. RESULTS: Clinical subjects and animal models showed elevated plasma visfatin concentrations in the hyperthyroidism group (20.466 ng/ml (15.263, 26.795 ng/ml) and (1209.164+/-165.292) ng/L) and hypothyroidism group (12.457 ng/ml (11.115, 15.454 ng/ml) and (1205.425+/-109.200) ng/L) compared to euthyroidism group (6.891 ng/ml (5.888, 8.803 ng/ml) and (926.650+/-54.002) ng/L, P<0.001). For animal models, visfatin mRNA expression in visceral fat in the hyperthyroidism and hypothyroidism groups increased about 3.33-fold and 1.98-fold compared to the euthyroidism group (P<0.001), which was positively correlated with plasma visfatin concentrations (r=0.713, P<0.001). However, no significant group difference (P>0.05) and correlation (r=0.121, P=0.572) was found in the liver. T3 induced a remarkable increase of visfatin mRNA expression in 3T3-L1 cells at low concentrations (0-0.5 nmol/L T3) followed by a sharp decrease at higher concentrations (0.5-100 nmol/L T3), with an inflection point at 0.5 nmol/L T3. CONCLUSION: Elevated circulating visfatin levels in subjects with hyperthyroidism and hypothyroidism are possibly due to an increase of visfatin mRNA expression in visceral fat, and a nonlinear regulation mechanism on visfatin mRNA expression under various T3 concentrations might be involved. PMID- 22490591 TI - Prognosis investigation in patients with chronic heart failure and pericardial effusion. AB - BACKGROUND: Researchers still do not reach the consensus on the incidence, characters and the prognostic value of pericardial effusion (PE) in patients with chronic heart failure (CHF). This study is to investigate the incidence, characters and the prognostic value of pericardial effusion (PE) in patients with CHF. METHODS: One thousand one hundred and eighty-nine patients, with a diagnosis of CHF consecutively admitted to three centers, were enrolled. M-mode echocardiography was used to determine the presence or absence of PE and to semi quantify it. The 118 patients with PE and 472 without PE were followed up. The relationship between the PE and other parameters and the prognostic value of PE for CHF were analyzed by univariate and multivariate analyses. RESULTS: After following up, 550 patients were analyzed, of which 226 were dead. The incidence of PE was 9.92%. Moderate PE was the most common which account 90.68% (107/118). The 6.78% of the patients (8/118) had small while only 2.54% (3/118) had large one. The systolic blood pressure (OR=1.04, 95%CI (1.01-1.07), P=0.08), left ventricular ejection fraction (LVEF) (OR=1.09, 95%CI (1.02-1.15), P=0.06), and main pulmonary artery diameter (MPAD) (OR=1.51, 95%CI (1.24-1.85), P<0.001) were the independent predictors of PE. The glomerular filtration rate (GFR) (OR=1.013, 95%CI (1.005-1.026), P=0.02), systolic blood pressure (OR=1.02, 95%CI (1.00 1.03), P=0.015), LVEF (OR=1.08, 95%CI (1.04-1.12), P<0.001) and diabetes mellitus (OR=3.53, 95%CI (1.99-6.44), P<0.001) were determined as the independent predictors of CHF prognosis. CONCLUSIONS: The PE is not uncommon in CHF patients and most PE are small to moderate. PE is not related to the etiology of CHF while is strongly connected with higher systolic blood pressure, low LVEF and large MPAD. PE dose not increase the risk of death in patients with CHF. PMID- 22490592 TI - Inhibition of integrin-linked kinase by angiotensin II receptor antagonist, irbesartan attenuates podocyte injury in diabetic rats. AB - BACKGROUND: Integrin-linked kinase (ILK) dysregulation is involved in the progression of diabetic nephropathy (DN). The aim of this study was to investigate the effects of angiotensin II receptor blocker (ARB), irbesartan, on ILK expression and podocyte injury in DN. METHODS: DN was induced by the combined feeding of high-sucrose, high-fat diet and intra-peritoneal injection of low dose of streptozotocin (35 mg/kg) in spontaneously hypertensive rats. Diabetic rats were treated with irbesartan (50 mg*kg(-1)*d(-1)) by gavage for 8 weeks. The renal morphologic changes and podocyte injury were investigated by light and electron microscopy, and the ILK expression was evaluated by real-time RT-PCR and Western blotting analysis. RESULTS: Diabetic rats exhibited with the similar clinical feature of type 2 DN. Morphologically, they were characterized by expansion of mesangial matrix, loss of podocyte and podocyte injury. Impressively, compared to controls, the ILK expression in diabetic rats were upregulated, which were positively correlated with both podocyte injury and albuminuria. Irbesartan significantly prevented ILK overexpression, along with the amelioration of podocyte injury and albuminuria. CONCLUSIONS: ILK plays an important role in mediating podocyte injury in DN; irbesartan inhibits ILK upregulation and attenuates podocyte injury, which might offer a new insight into the role of ARB in preventing DN progression. PMID- 22490593 TI - Prevalence and characterization of plasmid-mediated blaESBL with their genetic environment in Escherichia coli and Klebsiella pneumoniae in patients with pneumonia. AB - BACKGROUND: The extended spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) are the major pathogens causing pneumonia and have a significant impact on the clinical course. Limited data exist on molecular characterization of ESBL-producing E. coli and K. pneumoniae that cause pneumonia. The aim of this study was to investigate the comprehensive multilevel characteristics of E. coli and K. pneumoniae causing pneumonia in China for the first time. METHODS: E. coli (17) and K. pneumoniae (21) isolates responsible for pneumonia were isolated from 1270 specimens collected in a prospective multi-center study in eight teaching hospitals in China from June to December in 2007. The susceptibilities, ESBL confirmation, sequence typing, blaCTX-M and blaSHV genes, their genetic environment and plasmid Inc/rep types were determined. RESULTS: Sixteen E. coli (94.1%) and eleven K. pneumoniae (52.4%) isolates were ESBL producers. About 77.8% and 66.7% of them were resistance to ciprofloxacin and levofloxacin, and 100% were susceptible to imipenem. The most prevalent ESBL gene was CTX-M-14, followed by SHV-2, CTX-M-15, CTX-M-3, CTX-M-65, SHV-12, SHV-26 and SHV-28. SHV-1 and SHV-11 were also detected and coexisted with blaCTX-Ms in five strains, and three strains contained only SHV-1. All CTX-M-14 were detected ISEcp1 upstream and nine were found IS903 downstream and the majority of them (64.3%) were carried by IncF plasmids. All blaSHV were flanked by recF and deoR, located on IncF, IncN, IncX and IncH plasmids. Two SHV-2, one SHV-1 and the only SHV-28 were further preceded by IS26. Genes lacY and lacZ were detected at further upstream of two blaSHV-1. The K. pneumoniae carrying SHV-28 was susceptible to beta-lactams, and no mutations or deletions in gene or promoter sequences were identified to account for susceptibility. Multilocus sequence typing experiments showed the ESBL-producing strains were genetically diverse. CONCLUSIONS: The rate of occurrence of blaESBL in E. coli and K. pneumoniae causing pneumonia was high, and blaCTX-M-14 was dominant and probably mobilized by ISEcp1 mainly on IncF plasmids. Importantly, unexpressed blaESBL genes may occur in susceptible isolates and hence may have clinical implications. PMID- 22490594 TI - Three-fin acetabular prosthesis for superior acetabular bone defects: a three dimensional finite element analysis. AB - BACKGROUND: Given that three-dimensional finite element models have been successfully used to analyze biomechanics in orthopedics-related research, this study aimed to establish a finite element model of the pelvic bone and three-fin acetabular component and evaluate biomechanical changes in this model after implantation of a three-fin acetabular prosthesis in a superior segmental bone defect of the acetabulum. METHODS: In this study, three-dimensional finite element models of the pelvic bone and three-fin acetabular component were first established. The prosthesis model was characterized by three different conformational fins to facilitate and optimize the prosthetic design. The spongy and cortical bones were evaluated using a different modulus of elasticity in this established model. RESULTS: The maximum and minimum von Mises stresses on the fins of the acetabular component were 15.2 and 0.74, respectively. The maximum and minimum micromotion between the three-fin acetabular component and the acetabulum bone interface were 27 and 13 um, respectively. A high primary stability and implied better clinical outcome were revealed. CONCLUSION: Finite element analysis may be an optimal strategy for biomechanics-related research of prosthetic design for segmental acetabular bone defects. PMID- 22490595 TI - Transfect bone marrow stromal cells with pcDNA3.1-VEGF to construct tissue engineered bone in defect repair. AB - BACKGROUND: We previously showed that nano-hydroxyapatite/carboxymethyl chitosan (n-Ha/CMCS) displayed excellent mechanical properties, good degradation rates and exceptional biocompatibility, with negligible toxicity. The aim of this study was to determine the effect of the same composite with vascular endothelial growth factor (VEGF)- transfected bone marrow stromal cells (BMSCs) in a rabbit radial defect model. METHODS: The nano-hydroxyapatite was produced through co precipitation. The n-HA/CMCS scaffold was produced by particle filtration and lyophilization followed by genipin crosslinking. Total RNA from rabbit bone was reverse-transcribed to synthesize VEGF165-pcDNA3.1 that was transfected into the BMSCs. The composite was implanted into a rabbit radial defect model, and the osteogenic activity examined by gross morphology, X-ray examination and hematoxylin and eosin (HE) staining. RESULTS: The microstructure and mechanical property of the n-HA/CMCS scaffold resembled natural cancellous bone. Compared with glutaric dialdehyde crosslinked scaffolds, the genipin crosslinked scaffold was less toxic, and displayed a higher capacity to promote cell adhesion and proliferation. Spontaneous fluorescence of the composite permitted visualization of the composite-bone interface and the adhesion behavior of cells on the scaffold under laser scanning confocal microscopy. The scaffold with VEGF transfected BMSCs bridged the bony defect and promoted healing, with most of the implanted material being replaced by natural bone over time with little residual implant. Using X-ray, we noted obvious callus formation and recanalization of the bone marrow cavity. Furthermore, HE stained sections showed new cortical bone formation. CONCLUSIONS: The n-HA/CMCS scaffold composite with VEGF-trasnfected BMSCs is biocompatible, nontoxic, promotes the infiltration and formation of the microcirculation, and stimulates bone defect repair. Furthermore, the degradation rate of the composite matched that of growing bone. Overall, this composite material is potentially useful for bone defect repair. PMID- 22490596 TI - A high-fat diet reverses improvement in glucose tolerance induced by duodenal jejunal bypass in type 2 diabetic rats. AB - BACKGROUND: Bariatric surgery offers successful resolution of type 2 diabetes mellitus (T2DM). However, recurrence of T2DM has been observed in a number of patients with initial resolution after bariatric surgery. This study aimed to induce reversal of the improvement of diabetes in T2DM rats after duodenal jejunal bypass (DJB), and identify the effects of weight changes and gut hormones that might be involved. METHODS: DJB surgery was performed in two T2DM rat models (n=20 for each group): non-obese Goto-Kakizaki (GK) rats, and moderately-obese T2DM rats induced by a combination of a high-fat diet (HFD) and low-dose streptozotocin (HS rats). The controls were sham-operated and non-treated rats. All rats were then randomly divided into HFD- and low-fat diet (LFD)-fed groups. Glucose tolerance, insulin tolerance, glucose-stimulated insulin, glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretion, food intake and body weight were measured and compared with controls. RESULTS: DJB surgery resulted in a significant improvement in glucose tolerance in both GK and HS rats fed with either HFD or LFD. In contrast to LFD-fed rats, improved glucose tolerance was impaired in GK and HS rats fed with an HFD, accompanied by re-impairment of insulin tolerance and failure in enhancement of insulin secretion. There was no significant difference in food intake and body weight between DJB-operated and control rats, and between HFD- and LFD-fed rats. Glucose-stimulated GLP-1 and PYY levels were significantly increased after DJB surgery; however, they were not significantly different between HFD- and LFD-fed rats. CONCLUSION: An HFD reverses the improvement in glucose tolerance induced by DJB surgery in T2DM rats, primarily ascribing to the re-impairment of insulin sensitivity, but does not change body weight, GLP-1 and PYY levels. PMID- 22490597 TI - Vitamin D receptor genetic polymorphisms and tuberculosis among Chinese Han ethnic group. AB - BACKGROUND: In epidemiological studies, tuberculosis (TB) appears intimately with vitamin D insufficiency whereas its relationship with vitamin D receptor (VDR) polymorphism caused by radical difference remains unspecified. This study aimed to investigate the relationship between vitamin D genetic polymorphism and tuberculosis in Han ethnic group. METHODS: Meta-analysis was adopted in the synthetic quantitative analysis of documents home and abroad on the relationship between vitamin D genetic polymorphisms and tuberculosis, which were openly published during June 2000 to January 2010. Random effect model and fixed effect model analyses were used to calculate the incorporated odds ratio (OR) based on the heterogeneity test data. RESULTS: A total of 6 eligible studies were included in this analysis. The FokI-ff genotype showed a significant marginal association (Fixed effect model: OR 1.91, 95%CI 1.44-2.52; Random effect model: OR 1.91, 95%CI 0.94-3.88), yet TaqI polymorphisms was not significantly related to TB. CONCLUSION: The interaction between FoKI genotype polymorphism and TB observed demonstrates that vitamin D deficiency might exist as a risk factor during the development of TB in Han ethnic group and more evidences needed to validate the conclusion. PMID- 22490598 TI - Present and future of robot-assisted endoscopic thyroid surgery. AB - OBJECTIVE: Robot-assisted endoscopic surgery has been increasingly accepted because of its unique three-dimensional vision and precise simulation-based technology. However, the utilization of robotic systems in thyroid surgery is limited. We conducted a systematic review to assess the application and development of robot-assisted endoscopic surgical technique in thyroid surgery. DATA SOURCES: Articles published in PubMed before June, 2011 about robot-assisted endoscopic surgery were selected. STUDY SELECTION: Original articles and critical reviews selected were related to robot-assisted (thyroid) surgery or endoscopic thyroid surgery, and a total of 3540 relevant articles were retrieved and 34 were finally cited. RESULTS: Robot-assisted operation of benign thyroid diseases were successfully performed, although the operation time is too long to exhibit its advantages. Nevertheless, the superiority of robot-assisted endoscopic surgical technique compared to conventional endoscopic surgery in the treatment of thyroid carcinoma were obvious, since robotic radical thyroidectomy with central and lateral neck lymph node dissection could be achieved while maintaining operative results and cosmetic outcomes equivalent to or better than conventional endoscopic surgery. Furthermore, the learning curve duration of robot-assisted endoscopic thyroid surgery was shorter than that of conventional endoscopy, especially for the novices without any endoscopic surgical basis. CONCLUSION: Robot-assisted endoscopic thyroid surgery, with its safety, feasibility, thoroughness, cosmetic benefits, and ability to overcome the limitations of conventional endoscopic surgery, will be further improved and applied, and is worthy of attention. PMID- 22490599 TI - Primary Ewing's sarcoma/primitive neuroectodermal tumor of the urogenital tract in children. AB - BACKGROUND: Primary Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) of urogenital tract is a rare condition with non-specific clinical presentations, which can make it difficult to diagnose. In this study, we summarize the clinical presentation, pathological features, therapeutic strategies, and prognosis of ES/PNET. METHODS: Clinical information on two cases of ES/PNET in the penis and ureter was analyzed, and relevant literature was reviewed. RESULTS: ES/PNET was confirmed pathologically, immunohistochemically and via molecular biology techniques in the penis (n=1) and ureter (n=1). In one case, a tumor was found at the base of penis, which had invaded the corpus cavernosum, and resulted in a massive enlargement of the penis. This tumor was initially diagnosed as an endocrine disorder. However, a confirmed diagnosis was made 11 months later when massive metastases in both lungs were noted. A tumor biopsy was performed to confirm the diagnosis, and chemotherapy with a CAV (cyclophosphamide+doxorubicin+vincristine)+IE (ifosfamide+etoposide) regimen for 9 months was prescribed. In the second case, a child was admitted due to abdominal pain and a hydroureter in the right kidney, as determined by ultrasonography. A tumor was found in the right ureter at the level of iliac vessels. Removal of the tumor and ureteral anastomosis were performed, and chemotherapy with CAV+IE for 8 months were prescribed. Both patients are currently being followed-up closely. CONCLUSIONS: ES/PNET is a highly malignant tumor and has poor prognosis. Pre-operative diagnosis of ES/PNET of urogenital tract is difficult and largely depends on pathology, immunohistochemistry, and, if applicable, molecular biology. Comprehensive therapy may include surgery, chemotherapy and radiotherapy. PMID- 22490600 TI - A case of Klinefelter's syndrome with type 1 diabetes mellitus. AB - Klinefelter's syndrome (KS) is the most common sex chromosome disease in men. Classical features of the syndrome include a eunuchoidal body habitus, small testes and hypergonadotrophic hypogonadism. There has been an increased risk of diabetes mellitus and autoimmune disease for KS patients. This paper reports a case of KS in association with type 1 diabetes mellitus. The patient was a 21 year-old man, who has been confirmed by absolute insulin deficiency and positive IA-2 autoantibody. The hyperinsulinemic euglycemic clamp test indicated his insulin sensitivity in normal range, and his blood glucose was controlled well by the insulin therapy. PMID- 22490601 TI - Transient ST-segment elevation after transseptal puncture for atrial fibrillation ablation in two cases. AB - The present report demonstrates two cases of transient inferior ST-segment elevation accompanied by profound hypotension and bradycardia immediately after transseptal puncture for catheter ablation of atrial fibrillation. This rare complication of transseptal puncture was resolved quickly within several minutes. The most likely mechanism of this phenomenon is coronary vasospasm, although coronary embolism can not be ruled out completely. This complication is characterized as follows: (1) The right coronary artery might be the most likely involved vessel and therefore myocardial ischemia usually occurs in the inferior wall of left ventricular; (2) Reflex hypotension and bradycardia by the Bezold Jarisch reflex secondary to inferior ischemia often occur at the same time. Though it appears to be a transient and completely reversible phenomenon, there are still potential life-threatening risks because of myocardial ischemia and profound haemodynamic instability. Clinical cardiologists should be aware of this rare complication and properly deal with it. PMID- 22490602 TI - Chylous pleural effusion caused by mediastinal angiomyolipomas. AB - Classical angiomyolipomas are benign tumors composed of various tissues, including fat, abnormal blood vessels and smooth muscle cells. The present study reports a male patient affected by mediastinal angiomyolipomas with massive chylous pleural effusion. The tumors were characterized with histological and immunohistochemical methods. PMID- 22490603 TI - Allo-hematopoietic stem cell transplantation is a potential treatment for a patient with a combined disorder of hereditary spherocytosis. AB - Both human hereditary spherocytosis (HS) and chronic myelogenous leukemia (CML) are life threatening. Herein we have reported the case of a woman with a combined disorder of HS and CML who underwent the matched sibling allogeneic stem cell transplantation. The complete donor erythroid cells were obtained. The red blood cell counts significantly improved throughout life comparing with pre hematopoietic stem cell transplantation (HSCT). Reticulocyte counts normalized, and BCR-ABL was cleared away. The total bilirubin level was also corrected in this recipient. Our case is a rare example with a combined disorder of HS and CML following allogeneic stem cell transplantation. HS was not a contraindication for patient in the matched sibling transplant setting. PMID- 22490604 TI - Necrotizing fasciitis following varicella in a child. AB - Varicella is a self-limited disease, but sometimes it may be associated with some serious life-threatening complications.Necrotizing fasciitis is a rare complication of varicella. This is a case of a 7-year-old girl with septic shock caused by necrotizing fasciitis as a complication of varicella. Swelling and pain in the left inguinal region and left axillary region were found five days after varicella. Then a high fever occurred followed by hypotension. Fluid infusion, vasopressor and antibiotics were administered. Group A beta-hemolytic Streptococcus was isolated from exudates from the wounds. The clinical symptoms markedly improved after surgical drainage and removal of the necrotic tissue. Both wounds were covered with skin grafts after healthy granulation tissue formed. Although there have been few reports of life-threatening necrotizing fasciitis following varicella in western countries, it is rare in China. Usually patients with varicella were admitted to pediatric or infectious disease department but not surgical departments; so that the clinicians should be aware that varicella may be complicated by life-threatening surgical infections. Necrotizing fasciitis should be suspected in patients of varicella who showed an increasing pain and swelling in any body areas associated with increasing fever and local erythema. Early identification, surgical drainage and debridement are essential for successful treatment of necrotizing fasciitis. PMID- 22490606 TI - Takotsubo cardiomyopathy in a 90-year-old Chinese man. AB - A 90-year-old Chinese man was transferred to the Emergency Department of the Affiliated Shantou Hospital of Sun Yat-sen University for treatment of an acute myocardial infarction. He suffered chest pain with three days of cough, dyspnea and fever. A diagnosis of Takotsubo cardiomyopathy was made in normal coronary arteries from urgent coronary angiography and characteristic apical dyskinesis and basal hyper contractility in left ventriculography. The patient died from severe multi-organ failure on the second day of hospitalization. PMID- 22490605 TI - Pulmonary vein sarcoma: a case report. AB - Recently, we treated a patient with pulmonary vein sarcoma. The patient was a 41 year-old woman, had cough, short of breath and apsychia, with obvious jugular venous distention, rales in both lungs and a diastolic murmur at the apex. CT and Echo revealed a tumor in the left atrium. She received an emergency surgery to remove the mass in the heart. The pathological diagnosis demonstrated it as leiomyosarcoma. Though the patient accepted radiotherapy and chemotherapy, she still died of recurrence and metastasis of the sarcoma 10 months after operation. PMID- 22490607 TI - Possible involvement of mitochondrial uncoupling protein-2 in cytotoxicity mediated by acquired N-methyl-D-aspartate receptor channels. AB - We have previously shown the possible involvement of mitochondrial membrane potential disruption in the mechanisms underlying the neurotoxicity seen after activation of N-methyl-d-aspartate (NMDA) receptors (NMDAR) in primary cultured rat hippocampal neurons. In this study, we attempted to demonstrate a pivotal role of mitochondrial uncoupling protein-2 (UCP2) as a determinant of the NMDA neurotoxicity by using acquired NMDAR channels artificially orchestrated in HEK293 cells. In cells with overexpression of UCP2, immunoreactive UCP2 was exclusively detected at intracellular locations stained with the mitochondrial marker MitoTracker. In cells with acquired NMDAR channels, exposure to either NMDA or the calcium ionophore A23187 similarly led to a significant increase in cytosolic Ca(2+) levels determined by Fluo-3 imaging irrespective of the overexpression of UCP2. By contrast, NMDA, but not A23187, was significantly more effective in increasing mitochondrial Ca(2+) levels determined by Rhod-2 fluorescence imaging in cells transfected with NMDAR subunit and UCP2 expression vectors than in those without UCP2 overexpression. Overexpression of UCP2 significantly increased the number of cells stained with propidium iodide in cultures with acquired NMDAR channels, but failed to significantly affect that in cells exposed to A23187. Immunocytochemical and immunoprecipitation analyses similarly revealed the possible interaction between GluN1 subunit and UCP2 in HEK293 cells with acquired NMDAR channels and UCP2 overexpression. These results suggest that UCP2 could play a role as a determinant of the neurotoxicity mediated by NMDAR through a mechanism related to the unidentified interaction with the essential GluN1 subunit toward modulation of mitochondrial Ca(2+) levels in neurons. PMID- 22490608 TI - Therapeutic potentials of neural stem cells treated with fluoxetine in Alzheimer's disease. AB - Recent studies have proposed that chronic treatment with antidepressants increases neurogenesis in the adult hippocampus. However, the effect of antidepressants on fetal neural stem cells (NSCs) has not been well defined. Our study shows the dose-dependent effects of fluoxetine on the proliferation and neural differentiation of NSCs. Fluoxetine, even at nanomolar concentrations, stimulated proliferation of NSCs and increased the number of betaIII-tubulin (Tuj 1)- and neural nucleus marker (NeuN)-positive cells, but not glial fibrillary acidic protein (GFAP)-positive cells. These results suggest that fluoxetine can enhance neuronal differentiation. In addition, fluoxetine has protective effects against cell death induced by oligomeric amyloid beta (Abeta(42)) peptides. Taken together, these results clearly show that fluoxetine promotes both the proliferation and neuronal differentiation of NSCs and exerts protective effects against Abeta(42)-induced cytotoxicities in NSCs, which suggest that the use of fluoxetine is applicable for cell therapy for various neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases by its actions in NSCs. PMID- 22490609 TI - Ontogenetic changes in the distribution of the vesicular GABA transporter VGAT correlate with the excitation/inhibition shift of GABA action. AB - GABA is the major inhibitory neurotransmitter in the adult CNS and is among others involved in the synchronization of large neuronal networks. During development, GABA acts as a morphogenetic factor and has transient excitatory actions in many brain regions. One distinct protein, the vesicular GABA transporter (VGAT), has been identified accumulating GABA into presynaptic vesicles prior to its exocytotic release. The function of VGAT and its distribution is well defined in the adult, but its contribution to the transient excitatory action at putative GABAergic nerve terminals in the immature brain and its potential roles in putative glutamatergic nerve terminals remain elusive. We have studied VGAT expression in the brain from late embryonic stages through several postnatal stages until adulthood. Quantitative immunoblotting and immunolabeling of tissue sections at the light microscope and the electron microscope levels show an abrupt augmentation in VGAT staining in the cerebral cortex during the first three postnatal weeks, resembling the increase in other proteins involved in GABA synthesis and recycling in the same time frame - such as GAD65, GAD67, GAT1 (Slc6a1) and SN1 (Slc38a3) - and coincides with the synaptogenetic spurt. Dynamic changes in the expression of VGAT are seen in many cellular populations and in several layers in different brain regions. However, mossy fiber terminals (MFT) elude staining for VGAT. We also demonstrate that VGAT(+) nerve terminals undergo a developmental reorganization so that from targeting primarily the dendrites of the principal neurons in several brain regions in the immature brain, they target the soma of the same cells in the adult. This shift in the targeted subcellular compartment coincides with the conversion of the chloride gradient across neuronal membranes and suggests that it may be important for the shift of GABA action from excitation to inhibition and for the establishment of the potent synchronization of neuronal networks. PMID- 22490610 TI - Reduced brain levels of DHEAS in hepatic coma patients: significance for increased GABAergic tone in hepatic encephalopathy. AB - Increased neurosteroids with allosteric modulatory activity on GABA(A) receptors such as 3alpha-5alpha tertrahydroprogesterone; allopregnanolone (ALLO), are candidates to explain the phenomenon of "increased GABAergic tone" in hepatic encephalopathy (HE). However, it is not known how changes of other GABA(A) receptor modulators such as dehydroepiandrosterone sulfate (DHEAS) contribute to altered GABAergic tone in HE. Concentrations of DHEAS were measured by radioimmunoassay in frontal cortex samples obtained at autopsy from 11 cirrhotic patients who died in hepatic coma and from an equal number of controls matched for age, gender, and autopsy delay intervals free from hepatic or neurological diseases. To assess whether reduced brain DHEAS contributes to increased GABAergic tone, in vitro patch clamp recordings in rat prefrontal cortex neurons were performed. A significant reduction of DHEAS (5.81+/-0.88 ng/g tissue) compared to control values (9.70+/-0.79 ng/g, p<0.01) was found. Brain levels of DHEAS in patients with liver disease who died without HE (11.43+/-1.74 ng/g tissue), and in a patient who died in uremic coma (12.56 ng/g tissue) were within the control range. Increasing ALLO enhances GABAergic tonic currents concentration-dependently, but increasing DHEAS reduces these currents. High concentrations of DHEAS (50 MUM) reduce GABAergic tonic currents in the presence of ALLO, whereas reduced concentrations of DHEAS (1 MUM) further stimulate these currents. These findings demonstrate that decreased concentrations of DHEAS together with increased brain concentrations of ALLO increase GABAergic tonic currents synergistically; suggesting that reduced brain DHEAS could further increase GABAergic tone in human HE. PMID- 22490611 TI - Neuroprotection by the soy isoflavone, genistein, via inhibition of mitochondria dependent apoptosis pathways and reactive oxygen induced-NF-kappaB activation in a cerebral ischemia mouse model. AB - Recently, the treatment of stroke has focused on antioxidant therapies, where oxidative stress is implicated. The preventive and therapeutic potential of plant compounds on ischemic stroke has been intensively studied because many of them contain antioxidant properties. Genistein, one of the active ingredients in soybean, possesses many bioactivities. In this study, we investigated the potential neuroprotective effects of genistein and its possible mechanism of action in a cerebral ischemia mouse model. Mice were pretreated with genistein (2.5, 5, and 10mg/kg) or vehicle orally once daily for 14 consecutive days before transient middle cerebral artery occlusion was performed. Genistein at doses of 2.5-10mg/kg significantly reduced the infarct volume, improved the neurological deficit and prevented cell apoptosis after ischemia. In addition, genistein pretreatment was shown to inhibit the ischemia-induced reactive oxygen species (ROS) production, enhance the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), and decrease levels of malondialdehyde (MDA) in stroke mice. Moreover, genistein reversed the mitochondria dysfunction after ischemia, as evidenced by decreasing mitochondria ROS levels, preventing cytochrome C release to the cytoplasm and inhibiting caspase-3 activation. Western blotting showed ischemia activated the ROS dependent nuclear factor-kappaB (NF-kappaB) signaling pathway, and genistein suppressed phosphorylation and activation of the NF-kappaB p65 subunit, as well as the phosphorylation and degradation of the inhibitor protein of kappaBalpha (IkappaBalpha). Our findings suggested that genistein has a neuroprotective effect in transient focal ischemia, which may involve regulation of mitochondria dependent apoptosis pathways and suppression of ROS-induced NF-kappaB activation. PMID- 22490612 TI - Meiotic errors followed by two parallel postzygotic trisomy rescue events are a frequent cause of constitutional segmental mosaicism. AB - Structural copy number variation (CNV) is a frequent cause of human variation and disease. Evidence is mounting that somatic acquired CNVs are prevalent, with mosaicisms of large segmental CNVs in blood found in up to one percent of both the healthy and patient populations. It is generally accepted that such constitutional mosaicisms are derived from postzygotic somatic mutations. However, few studies have tested this assumption. Here we determined the origin of CNVs which coexist with a normal cell line in nine individuals. We show that in 2/9 the CNV originated during meiosis. The existence of two cell lines with 46 chromosomes thus resulted from two parallel trisomy rescue events during postzygotic mitoses. PMID- 22490613 TI - The role of Na+/H+ exchanger in Ca2+ overload and ischemic myocardial damage in hearts from type 2 diabetic db/db mice. AB - BACKGROUND: A higher increase in intracellular Na(+) via Na(+)/H(+) exchanger (NHE) during ischemia has been reported in type 2 diabetic mouse hearts. We investigated the role of NHE in inducing changes in cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) and alterations in ventricular function during ischemia-reperfusion in type 2 diabetic mouse hearts. METHODS: Hearts from male type 2 diabetic db/db (12-15 weeks old) and age-matched control db/+ mice were subjected to Langendorff perfusion and loaded with 4 MUM of the Ca(2+) indicator fura-2. The hearts were exposed to no-flow ischemia for 15 minutes and then reperfused. [Ca(2+)](i) was measured by monitoring fura-2 fluorescence at 500 nm (excitation wavelengths of 340 and 380 nm), while left ventricular (LV) pressure was simultaneously measured. RESULTS: db/db hearts exhibited a lower recovery of LV developed pressure than db/+ hearts during reperfusion following ischemia. Diastolic [Ca(2+)](i) was increased to a greater level in diabetic hearts than in the control hearts during ischemia and reperfusion. Such an increase in cytoplasmic Ca(2+) overload during ischemia-reperfusion in diabetic hearts was markedly reduced in the presence of the NHE inhibitor cariporide. This was accompanied by a significantly improved recovery of ventricular function on reperfusion, as shown by a lower increase in diastolic pressure and increased recovery of developed pressure. CONCLUSION: NHE plays a key role in enhancing cytoplasmic Ca(2+) overload during ischemia-reperfusion and severely impairing post-ischemic cardiac function in hearts from type 2 diabetic db/db mice. PMID- 22490614 TI - Treatment effectiveness of two Chinese herbal medicine formulae in upper respiratory tract infections--a randomized double-blind placebo-controlled trial. AB - AIM AND OBJECTIVES: To study the effect of two Chinese herbal medicines (CHMs) formulae in treating acute upper respiratory tract infections (URTIs), diagnosed by Traditional Chinese medicine (TCM), compared to placebo. DESIGN: Two randomized, double-blind placebo-controlled trials nested in a study of 327 patients who were diagnosed with URTIs in Hong Kong. Subjects were classified into one of two TCM syndrome groups by a Chinese medicine practitioner and randomized to receive the corresponding CHM formulae or placebo up to maximum of 10 days. The proportions of patients who had resolution of illness on Days 4 and 7 were the primary outcomes. The duration of symptom resolution, health-related quality of life scores measured by the SF-36 and ChQOL, and adverse effects were secondary outcomes. RESULTS: There was no statistically significant difference between the treatment and placebo in resolution rates at Day 4 or 7. The mean time of resolution of symptoms was Day 10, for either wind-cold or wind-heat syndrome. Both patients in treatment and placebo had significantly improved in health-related quality of life with time, but patients in wind-cold group had significantly more improvement in the SF-36 general health score (P = 0.01) than placebo. CONCLUSIONS: Two CHM formulae commonly used for URTIs were not found to be more effective than placebo in either cure or reduction of symptoms of URTIs. However, Jing Fan Bai Du san might be able to improve general health more than placebo for patients with wind-cold syndrome. Both formulae were not associated with any more side effects. PMID- 22490615 TI - Multidrug resistant bacteria in wounds of combatants of the Libyan uprising. PMID- 22490616 TI - Staphylococcus aureus infections in pediatric patients with diabetes mellitus. AB - OBJECTIVES: To describe Staphylococcus aureus infections in children with diabetes mellitus (DM). METHODS: Children with DM (cases) and S. aureus infections (2/02-6/10) were identified from a surveillance database. Patient charts were reviewed, and S. aureus isolates were characterized by molecular methods. Cases were compared to age-matched controls without DM but with CA-S. aureus skin and soft tissue infections (SSTI) using conditional logistic regression. RESULTS: Forty-seven cases were identified; 41 were matched with 123 controls. Four cases had osteomyelitis and 43 had SSTI. Mean age was 14.2 years and 63% of cases had hemoglobin (Hb) A1c levels above 10%. Cases and controls differed by gender (85% vs. 45% female, P < 0.001), BMI% (median 87% vs. 72%, P = 0.04), methicillin-resistant S. aureus (MRSA) infection (49% vs. 68%, P = 0.04), and recurrent infections (22% vs. 4%, P = 0.001). Among cases, 88% of recurrences were caused by MRSA. CONCLUSIONS: The majority of cases had poor glycemic control, more recurrences, fewer primary MRSA infections and were more likely to be female compared to a control group. Improved glycemic control may reduce the risk for infection, and decrease hospitalizations due to S. aureus infections. PMID- 22490617 TI - Troponin-specific autoantibody interference in different cardiac troponin I assay configurations. AB - BACKGROUND: Autoantibodies to cardiac troponins (cTnAAb) can interfere with the measurement of cardiac troponin I (cTnI) by immunoassays. The aim of this study was to explore the degree of cTnAAb interference in different cTnI assay configurations. METHODS: Ternary troponin complex was added into samples (serum or plasma, n = 132, 68% cTnAAb positive) from individuals without known cardiac conditions. The recovery of cTnI was then measured with 6 investigational cTnI assays (2, 3, or 4 antibodies per assay). Three of these assays were then selected for further comparison by use of samples (plasma, n = 210, 33% cTnAAb positive) from non-ST-elevation acute coronary syndrome patients in the FRISC-II (FRagmin/Fast Revascularisation during InStability in Coronary artery disease) cohort. Finally, these results were compared to those obtained with 3 commercial cTnI assays. RESULTS: Analytical recoveries varied widely among the 6 investigational assays. Notably the low recoveries (median 9%) of the midfragment targeting reference assay were normalized (median 103%) with the use of the 4 antibody assay construct (3 capture, 1 tracer antibody) with only 1 antibody against a midfragment epitope. Reduced analytical recoveries correlated closely with measured autoantibody amounts. cTnI concentrations from cTnAAb-positive patient samples determined with 3 investigational assays confirmed the reduced concentrations expected from the low analytical recoveries. The results from the commercial cTnI assays with antibody selections representative for contemporary assay constructs revealed a similar underestimation (up to 20-fold) of cTnI in cTnAAb-positive samples. CONCLUSIONS: A novel cTnI assay deviating from the conventional IFCC-recommended midfragment approach substantially improves cTnI detection in samples containing cTnAAbs. PMID- 22490618 TI - Newborn screening for spinal muscular atrophy by calibrated short-amplicon melt profiling. AB - BACKGROUND: The management options for the autosomal recessive neurodegenerative disorder spinal muscular atrophy (SMA) are evolving; however, their efficacy may require presymptom diagnosis and continuous treatment. To identify presymptomatic SMA patients, we created a DNA-based newborn screening assay to identify the homozygous deletions of the SMN1 (survival of motor neuron 1, telomeric) gene observed in 95%-98% of affected patients. METHODS: We developed primers that amplify a 52-bp PCR product from homologous regions in the SMN1 and SMN2 (survival of motor neuron 2, centromeric) genes that flank a divergent site at site c.840. Post-PCR high-resolution melt profiling assessed the amplification product, and we used a unique means of melt calibration to normalize profiles. Samples that we had previously characterized for the numbers of SMN1 and SMN2 copies established genotypes associated with particular profiles. The system was evaluated with approximately 1000 purified DNA samples, 100 self-created dried blood spots, and >1200 dried blood spots from newborn screening tests. RESULTS: Homozygous deletion of SMN1 exon 7 produced a distinctive melt profile that identified SMA patients. Samples with different numbers of SMN1 and SMN2 copies were resolved by their profiles. All samples with homozygous deletions were unambiguously recognized, and no normal sample was misidentified as a positive. CONCLUSIONS: This assay has characteristics suitable for population-based screening. A reliable screening test will facilitate the identification of an SMA affected cohort to receive early intervention to maximize the benefit from treatment. A prospective screening trial will allow the efficacy of treatment options to be assessed, which may justify the inclusion of SMA as a target for population screening. PMID- 22490619 TI - Unraveling the transcriptional heterogeneity in human colon cancer: potential new insights regarding pathobiology and treatment. PMID- 22490620 TI - Assessing the effects of a parent-implemented language intervention for children with language impairments using empirical benchmarks: a pilot study. AB - PURPOSE: The purpose of this study was to investigate the extent to which a parent-implemented language intervention improves language skills in toddlers at risk for persistent language impairment (LI) as compared with a group of typically developing toddlers. METHOD: Thirty-four children with LI between 24 and 42 months of age were randomly assigned to a treatment or nontreatment experimental condition. Participants in the treatment group received 24 biweekly 1-hr sessions for 3 months. An additional sample of 28 age- and gender-matched children with typically developing language (TL) was also included. Norm referenced child assessments and observational measures were used to assess changes in children's language growth. RESULTS: Results from multilevel modeling indicate that children in the treatment group made greater gains than children in the control group on most language measures. Whereas children in the treatment group had lower language scores than children with TL at the end of intervention, the rate of language growth was not significantly different between groups. Child receptive language and parent use of matched turns predicted expressive language growth in both children with and without LI. CONCLUSION: The results of this preliminary study indicate that parent-implemented interventions may be an effective treatment for children with expressive and receptive LI. PMID- 22490621 TI - Influences of sentence length and syntactic complexity on the speech motor control of children who stutter. AB - PURPOSE: To investigate the potential effects of increased sentence length and syntactic complexity on the speech motor control of children who stutter (CWS). METHOD: Participants repeated sentences of varied length and syntactic complexity. Kinematic measures of articulatory coordination variability and movement duration during perceptually fluent speech were analyzed for 16 CWS and 16 typically developing children (CTD) between 4 and 6 years of age. Behavioral data from a larger pool of children were also examined. RESULTS: For both groups, articulatory coordination variability increased with sentence length. For syntactically simple sentences, CWS had higher coordination variability than CTD. There was no group difference in coordination variability for complex sentences. Coordination variability increased significantly with complexity for CTD, whereas that of CWS remained at the high level demonstrated for simple sentences. There was a trend for higher overall coordination variability in CWS compared with CTD. For both groups, movement duration was greater for syntactically complex, as compared with simple, sentences. CONCLUSIONS: Results indicate more variable speech motor coordination during fluent speech production in many CWS as compared with CTD. Disproportionate effects of length and complexity on coordination variability and duration were not found for CWS. Considerable individual differences in performance were observed. PMID- 22490622 TI - Age or experience? The influence of age at implantation and social and linguistic environment on language development in children with cochlear implants. AB - PURPOSE: The authors investigated the influence of social environmental variables and age at implantation on language development in children with cochlear implants. METHOD: Participants were 25 children with cochlear implants and their parents. Age at implantation ranged from 6 months to 42 months ( M (age) = 20.4 months, SD = 22.0 months). Linguistic progress was assessed at 12, 18, 24, and 30 months after implantation. At each data point, language measures were based on parental questionnaire and 45-min spontaneous speech samples. Children's language and parents' child-directed language were analyzed. RESULTS: On all language measures, children displayed considerable vocabulary and grammatical growth over time. Although there was no overall effect of age at implantation, younger and older children had different growth patterns. Children implanted by age 24 months made the most marked progress earlier on, whereas children implanted thereafter did so later on. Higher levels of maternal education were associated with faster linguistic progress; age at implantation was not. Properties of maternal language input, mean length of utterance, and expansions were associated with children's linguistic progress independently of age at implantation. CONCLUSIONS: In children implanted within the sensitive period for language learning, children's home language environment contributes more crucially to their linguistic progress than does age at implantation. PMID- 22490624 TI - [The key to address the non-communicable disease crisis is action: vision, values, responsibility and mission]. PMID- 22490623 TI - Identification of prelinguistic phonological categories. AB - PURPOSE: The prelinguistic infant's babbling repertoire of syllables--the phonological categories that form the basis for early word learning--is noticed by caregivers who interact with infants around them. Prior research on babbling has not explored the caregiver's role in recognition of early vocal categories as foundations for word learning. In the present work, the authors begin to address this gap. METHOD: The authors explored vocalizations produced by 8 infants at 3 ages (8, 10, and 12 months) in studies illustrating identification of phonological categories through caregiver report, laboratory procedures simulating the caregiver's natural mode of listening, and the more traditional laboratory approach (phonetic transcription). RESULTS: Caregivers reported small repertoires of syllables for their infants. Repertoires of similar size and phonetic content were discerned in the laboratory by judges who simulated the caregiver's natural mode of listening. However, phonetic transcription with repeated listening to infant recordings yielded repertoire sizes that vastly exceeded those reported by caregivers and naturalistic listeners. CONCLUSIONS: The results suggest that caregiver report and naturalistic listening by laboratory staff can provide a new way to explore key characteristics of early infant vocal categories, a way that may provide insight into later speech and language development. PMID- 22490625 TI - [Impact of CACNA1C polymorphisms on antihypertensive efficacy of calcium channel blocker]. AB - OBJECTIVE: To explore the relationship between genetic polymorphisms of CACNA1C that encoded the a1c subunit of the L-type calcium channel and the efficacy of calcium channel blocker (CCB, Nifedipine extended release tablet/20 mg/d) in essential hypertension (EH) patients of Han Chinese in Wenzhou. METHODS: For the enrolled 103 EH patients, Multiplex Polymerase Chain Reaction (Multi-PCR) and matrix assisted laser desorption ionization time of flight MS (MLDI-TOF MS) were performed to detect their genotypes (rs216008, rs1051375, rs2299661, rs10848683, rs215976), blood pressure (BP) after CCB monotherapy was compared among patients with different genotypes. RESULTS: (1) Blood pressure was significantly reduced in all patients post CCB (P < 0.05 vs. pre-CCB). (2) Diastolic blood pressure reduction was more significant in subjects with rs2299661 C/C genotype (wild genotype) than in subjects with rs2299661C/G and rs2299661G/G genotype (mutational genotype) [(12.46 +/- 7.91) mm Hg (1 mm Hg = 0.133 kPa) vs. (7.22 +/- 8.01) mm Hg and (5.93 +/- 9.77) mm Hg, P < 0.05]. (3) Systolic blood pressure reduction was more significant in subjects with rs216008 C/C genotype (wild genotype) than in subjects with rs216008 C/T genotype (mutational genotype) [(20.60 +/- 12.35) mm Hg vs. (13.62 +/- 10.21) mm Hg, P < 0.05]. (4) Blood pressure reduction was similar between subjects with genotype of rs1051375, rs10848683 and rs215976. CONCLUSION: EH patients with wild genotype of rs2299661 and rs216008 in CACNA1C are more likely to be responders of CCB monotherapy. PMID- 22490626 TI - [Effects of valsartan combined with amlodipine or hydrochlorothiazide regimen on blood pressure variation in elderly hypertensive patients]. AB - OBJECTIVE: To compare the effects of valsartan combined with amlodipine or hydrochlorothiazide regimen on blood pressure variation and plasma nitric oxide (NO) and endothelin (ET) in elderly hypertensive patients. METHODS: A total of 61 elderly patients with grade 2 or 3 hypertension were randomized into valsartan + amlodipine (the amlodipine group, n = 31) or valsartan + hydrochlorothiazide (the hydrochlorothiazide group, n = 30) group. Blood lipids, fasting plasma glucose and uric acid were determined before the treatment. 24-hour dynamic blood pressure, NO and ET were monitored at baseline, 8 and 16 weeks after treatment. RESULTS: 24 hours blood pressure and daytime blood pressure were similar between two groups at all 3 time points. At 16 weeks, morning systolic blood pressure surge was significantly lower in amlodipine group than in hydrochlorothiazide group [(22.6 +/- 8.8) mm Hg (1 mm Hg = 0.133 kPa) vs. (26.3 +/- 13.7) mm Hg, P < 0.05]. 24 hours systolic blood pressure variability (SBPV) decreased progressively in both groups [the amlodipine group: (12.5 +/- 2.8) mm Hg vs. (10.2 +/- 2.2) mm Hg vs. (8.8 +/- 1.6) mm Hg, P < 0.01; the hydrochlorothiazide group: (12.5 +/- 2.5) mm Hg vs. (10.7 +/- 2.2) mm Hg vs. (9.6 +/- 2.0) mm Hg, P < 0.01]. Daytime SBPV also decreased progressively in both groups [the amlodipine group: (12.2 +/- 3.0) mm Hg vs. (10.1 +/- 2.3) mm Hg vs. (8.4 +/- 1.9) mm Hg, P < 0.01; the hydrochlorothiazide group: (11.8 +/- 2.7) mm Hg vs. (10.4 +/- 1.9) mm Hg vs. (9.6 +/- 2.2) mm Hg, P < 0.01]. 24 hours diastolic blood pressure variability (DBPV) was significantly reduced post therapy in the amlodipine group [(15.5 +/- 3.4) mm Hg vs. (13.0 +/- 3.5) mm Hg vs. (12.3 +/- 2.5), P < 0.01] but not in the hydrochlorothiazide group. NO increased progressively [(27.3 +/- 13.6) umol/L vs. (47.2 +/- 16.3) umol/L vs. (69.5 +/- 18.9) umol/L in the amlodipine group, P < 0.01; (33.5 +/- 13.9) umol/L vs. (49.7 +/- 21.9) umol/L vs. (66.7 +/- 24.7) umol/L in the hydrochlorothiazide group, P < 0.01] and ET decreased progressively [(45.3 +/- 8.0) ng/L vs. (37.4 +/- 3.9) ng/L vs. (34.2 +/- 4.4) ng/L in the amlodipine group, P < 0.01; (46.6 +/- 10.4) ng/L vs. (37.0 +/- 5.4) ng/L vs. (36.1 +/- 8.2) ng/L in the hydrochlorothiazide group, P < 0.01] in both groups. CONCLUSION: Valsartan in combination with amlodipine or hydrochlorothiazide can both effectively lower BPV in elderly hypertensive patients and improve the vascular endothelial function and the former regimen is more suitable for elderly hypertensive patients. PMID- 22490627 TI - [Efficacy of catheter-based renal denervation in mongrel neurogenic hypertensive dogs]. AB - OBJECTIVE: Hypertension is the most common risk factor for cardiovascular diseases and stroke. Renal sympathetic hyperactivity is associated with hypertension. The aim of this study was to explore the efficacy of renal denervation for hypertension. METHODS: Eighteen mongrel neurogenic hypertensive dogs were divided into intervention [mean arterial pressure: (150.6 +/- 18.8) mm Hg (1 mm Hg = 0.133 kPa) plus renal sympathetic denervation by percutaneous catheter-based radiofrequency, n = 10] and control [mean arterial pressure (147.4 +/- 13.2) mm Hg, n = 8] group. Mean arterial pressure before and at 2, 4, 6 and 10 weeks after procedure was invasively measured. Renin activity (PRA), angiotensin II (AngII), aldosterone (Ald), and creatinine (Cr) were detected at 2, 6 and 10 weeks after procedure. RESULTS: Mean arterial pressure remained unchanged in control group. In intervention group, mean arterial pressure (MAP) decreased to (130.4 +/- 14.1) mm Hg, (136.2 +/- 17.1) mm Hg, (128.7 +/- 14.7) mm Hg and (126.1 +/- 12.7) mm Hg respectively at 2, 4, 6, and 10 weeks after procedure. Meanwhile, the level of PRA, AngII, Ald significantly reduced post procedure compared with pre-procedural level (P < 0.05) and the Cr level remained unchanged post procedure (P > 0.05). CONCLUSION: Sympathetic nervous system plays an important role in the progression of hypertension. Catheter-based renal denervation results in substantial and sustained blood-pressure reduction in this model. PMID- 22490628 TI - [Impact of admission heart rate on short-term outcome of ST-elevation myocardial infarction patients]. AB - OBJECTIVE: To evaluate the impact of admission heart rate (HR) on 30-day all cause death and cardiovascular events in Chinese patients with ST-elevation acute myocardial infarction (STEMI). METHODS: A total of 7485 Chinese STEMI patients from a global randomized controlled trial (CREATE) database were divided into six groups by admission HR: < 60, 60 - 69, 70 - 79, 80 - 89, 90 - 99 and >= 100 bpm. The primary outcome was 30-day all-cause death; the secondary outcomes were the composite of 30-day all-cause death, reinfarction, cardiogenic shock or deadly arrhythmia. RESULTS: Admission glucose level, proportion of female gender, incidence of anterior myocardial infarction, previous diabetes mellitus, hypertension and Killip level II-IV were significantly higher in patients with admission HR >= 90 bpm compared to 60 - 69 bpm group (P < 0.05). The 30-day mortality was lowest (6.3%) in the 60 - 69 bpm group and was 9.6% in HR < 60 bpm group (P < 0.05 vs. 60 - 69 bpm group). In patients with admission HR > 60 bpm, the 30-day mortality increased in proportion to higher admission HR: 8.1% in 70 - 79 bpm, 9.2% in 80 - 89 bpm, 12.6% in 90 - 99 bpm and 24.6% in >= 100 bpm groups (all P < 0.05 vs. 60 - 69 bpm group). The incidence of MACE was similar as that of 30-day mortality: 27.0% in < 60 bpm, 12.5% in 60 - 69 bpm, 13.7% in 70 - 79 bpm, 14.3% in 80 - 89 bpm, 17.5% in 90 - 99 bpm and 31.1% in >= 100 bpm groups. Multivariate analysis showed that the incidence of 30-day mortality positively correlated with the admission HR (P < 0.05) except in the patients with admission HR < 60 bpm (OR = 0.832, P = 0.299), the risk of joint endpoint events was higher in the patients with HR < 60 bpm (OR = 1.532, 95%CI: 1.201 - 1.954, P < 0.05), 90 - 99 bpm (OR = 1.436, 95%CI: 1.091 - 1.889, P < 0.05) or >= 100 bpm (OR = 1.893, 95%CI: 1.471 - 2.436, P < 0.001). CONCLUSION: Admission HR is an independent risk factor for short-term outcome in Chinese STEMI patients. PMID- 22490629 TI - [Effects of intensive antiplatelet therapy for patients with high on-treatment platelet reactivity after coronary stent implantation]. AB - OBJECTIVE: To explore the effects of intensive antiplatelet therapy for patients with high on-treatment platelet reactivity (HPR) after coronary stent implantation. METHODS: Between March 2009 and February 2011, a total of 3316 consecutive acute coronary syndrome patients undergoing drug-eluting stent implanting from 3 hospitals were enrolled. Among them, 840 patients (25.3%) were identified as HPR (defined as 20 umol/L adenosine diphosphate induced platelet aggregation of >= 55% at 24 hours after administration of 300 mg clopidogrel loading dose and 300 mg aspirin). The HPR patients were randomly assigned to receive standard (aspirin 300 mg/d and clopidogrel 75 mg/d, n = 280) or intensified (n = 560) antiplatelet therapy by the ratio of 1:2. Patients in the intensive group were initially treated with a double maintenance dose of clopidogrel (150 mg/d) and aspirin (300 mg/d). After 3 days, patients with unsolved HPR received additional cilostazol treatment (50 - 100 mg, bid). The reversion rate of HPR and clinical events were observed. RESULTS: In the intensive group, HPR reversed in 304 out of 560 patients (54.3%) at 3 days post therapy and the remaining 256 patients with HPR were treated with additional cilostazol regimen for another 3 days and the total reversion rate of HPR was 81.1% (454/560). The reversion rate of HPR at 30 days in the intensified group was significantly higher than that of the standard group (69.9% vs. 55.7%, P = 0.000). At 30 days after percutaneous coronary intervention, 1 patient suffered from subacute stent thrombosis (0.2%) in intensified group and no stent thrombosis was observed in standard group (P = 1.000). There were no death, major or minor bleeding in both two groups. Minimal bleeding was also similar in the two groups (intensive: 4.28% vs. standard: 2.14%, P = 0.166). CONCLUSIONS: The intensified antiplatelet therapy regimens could significantly increase the reversion rate of HPR in acute coronary syndrome patients undergoing coronary stenting without increasing the risk of bleeding. The clinic impact of this strategy needs to be elucidated by long term follow-up outcome studies. PMID- 22490630 TI - [Clinical outcome of patients undergoing emergent coronary artery bypass grafting following failed percutaneous coronary intervention in stent era]. AB - OBJECTIVE: To explore clinical outcomes of patients undergoing emergent coronary artery bypass grafting (CABG) following failed percutaneous coronary intervention (PCI) in the stent era. METHODS: Eleven patients who underwent emergent CABG following failed PCI from January, 2002 to December 2010 were enrolled. The in hospital follow-up included cardiac deaths, Q-wave myocardial infarction, kidney failure, and cerebrovascular events. The clinical end-point of out-hospital follow-up was the major adverse cardiac events including death, myocardial infarction, and target lesion revascularization. RESULTS: The patients were (61 +/- 5) years old. Coronary angiography showed 5 patients had triple vessel lesions. There were 9 target lesions on left anterior descending artery. There were 3 (27.3%) severe calcified, 4 (36.4%) chronic total occlusion, and 4 (36.4%) diffused long lesions. Reasons for emergent CABG were dissection (n = 5, 45.5%), perforation (n = 3, 27.3%), failure to sufficient predilation (n = 1, 9.1%), acute closure (n = 1, 9.1%) and stent loss (n = 1, 9.1%). The average duration of follow-up was (47 +/- 33) months. During in-hospital follow-up, there were 1 (9.1%) cardiac death and 2 (18.2%) Q wave myocardial infarction. During follow-up after hospital discharge, 1 patient (9.1%) died of kidney failure, and there was no rehospitalization due to cardiac events. CONCLUSIONS: Emergent CABG after failed PCI often happened in patients with complex coronary lesions. The long term outcome of patients requiring emergent CABG after failed PCI was favorable in this cohort. PMID- 22490631 TI - [Value of plasma NT-proBNP for diagnosing heart failure in patients with previous myocardial infarction]. AB - OBJECTIVE: The study aimed to evaluate the value of plasma NT-proBNP in diagnosing heart failure in patients with previous myocardial infarction. METHODS: Plasma concentration of NT-proBNP was measured in patients with previous myocardial infarction by ELISA method at admission. Patients were divided into non heart failure group (NYHA class I) and heart failure group (NYHA class II IV). The NT-proBNP levels were compared between NYHA class I, II, III and IV, and between heart failure group and non heart failure group. ROC analyses were performed to evaluate the diagnosing value of plasma NT-proBNP for heart failure and to identify the optimal cut-off point for diagnosing heart failure patients. RESULTS: Total 586 patients [aged from 25 - 83 (58 +/- 11) years, 80% male] with previous myocardial infarction were enrolled in his study (n = 374 of NYHA class I, n = 99 of NYHA classes II, n = 82 of NYHA class III, n = 31 of NYHA class IV). Plasma NT-proBNP levels in these four NYHA classes were 484.7 (381.6, 647.8) pmol/L, 907.6 (516.6, 1290.3) pmol/L, 1420.2 (879.5, 2336.2) pmol/L, 2442.6 (1695.4, 3670.7) pmol/L, respectively (P < 0.01). The plasma NT-proBNP level in heart failure group was significantly higher than in non heart failure group [1148.2 (707.9, 2145.3) pmol/L vs. 484.7 (381.6, 647.8) pmol/L, P < 0.01]. Plasma NT-proBNP level in patients with age >= 60 years was significantly higher than patients with age < 60 years [702.3 (472.4, 1208.5) pmol/L vs. 526.6 (392.1, 855.6) pmol/L, P < 0.01]. ROC analysis showed that the area under the curve (AUC) for diagnosing heart failure was 0.844 (95%CI: 0.809 - 0.880, P < 0.01), the optimal plasma NT-proBNP cut-off point for diagnosing heart failure was 700 pmol/L with a sensitivity of 75.9%, a specificity of 79.9%, an accuracy of 78.3%, a positive predictive value of 67.9% and a negative predictive value of 85.3%. The optimal plasma NT-proBNP cut-off point was 600 pmol/L for patients >= 60 years old and 800 pmol/L for patients < 60 years old. CONCLUSION: Plasma NT proBNP level is a valuable parameter for diagnosing heart failure in patients with previous myocardial infarction. PMID- 22490632 TI - [Impact of pre-procedural plasma brain natriuretic peptide level on atrial fibrillation recurrence post radiofrequency catheter ablation]. AB - OBJECTIVE: Brain natriuretic peptide (BNP) levels are elevated in patients with atrial fibrillation (AF). The aim of this study is to investigate the relation between the pre-procedural BNP level and the incidence of recurrence AF after circumferential pulmonary vein ablation (CPVA). METHODS: Plasma BNP level was measured before CPVA in 69 consecutive symptomatic paroxysmal AF (PAF) patients without heart failure symptom. Atrial thrombus was detected by transesophageal echocardiography in 15 patients and CPVA was not performed in these patients. CPVA was successful in the remaining 54 patients and followed up for 3 months. All patients were asked to keep a log of the duration and frequency of their symptoms and underwent 24 h ECG monitoring at least once per month after the ablation. RESULTS: At the end of follow up, 39 patients were free of AF recurrence (successful group) and 15 patients experienced AF recurrence (failure group). BNP concentration was below the heart failure range (< 500 ng/L) in 69.6% patients, but exceeded the normal range (0 - 144 ng/L) in 59.4% patients. Median baseline BNP level was significantly higher in failure group than in successful group (371.6 ng/L vs. 97.4 ng/L, P = 0.001). Left atrial (LA) dimension was also larger in failure group than in successful group [(53.3 +/- 15.1) mm vs. (45.2 +/ 11.2) mm, P = 0.036]. Moreover, BNP level was positively correlated with LA dimension (r = 0.574, P < 0.01). CONCLUSION: The pre-procedural BNP level and LA dimension are predictive of successful CPVA for PAF patients. PMID- 22490633 TI - [Time course of interleukin-21 and related cytokines expression in rats with experimental autoimmune myocarditis]. AB - OBJECTIVE: To observe the time course of interleukin (IL)-21 and related cytokines expression in rats with experimental autoimmune myocarditis (EAM). METHODS: Antigen was prepared with an emulsion of porcine cardiac myosin in complete Freund's adjuvant, plus Mycobacterium tuberculosis H37Ra strain. EAM model was made by hypodermic injection of myosin in hind legs of Lewis rats.mRNA expression of IL-21 and related cytokines (IL-21R, IL-17, TGF-beta, IL-6) in different tissues (heart, liver, spleen, kidney) were determined at 2 weeks after immunization by RT-PCR and quantitative real-time RT-PCR. Furthermore, the time course of IL-21 and related cytokines expression in the acute phase of EAM (2 w, 3 w, 4 w) was determined by quantitative real-time RT-PCR, and IL-21, IL-17 protein expression was determined by Western blot and ELISA. The location of IL 21R was examined by immunohistochemistry at 2 w after immunization. RESULTS: Histopathology examination evidenced abundant mononuclear cells in the myocardium of 2 weeks EAM rats. Fibrosis and multinucleated giant cells were observed in the myocardium of 3 weeks EAM rats. Inflammation was reduced and large amount of fibrosis could be found in 4 weeks EAM rats. The heart weight/body weight ratio in normal, EAM 2 w, 3 w, 4 w group was (3.011 +/- 0.117) mg/g, (4.736 +/- 1.279) mg/g, (7.200 +/- 0.308) mg/g and (4.622 +/- 0.978) mg/g respectively. IL-21 mainly expressed in heart and spleen, IL-21R, IL-17, TGF-beta mainly expressed in spleen, and IL-17, IL-6 mainly expressed in heart of EAM rats. IL-21R mainly distributed in cardiomyocytes of 2 weeks EAM rats. In line with pathological EAM course, the expression of IL-21 and related cytokines peaked at 2 weeks and then returned to normal at 4 weeks after immunization. CONCLUSION: IL-21 and related cytokines were involved in the pathological process of EAM, upregulated IL-21 expression might promote Th17 cell differentiation and enhance Th17 cell secretion. PMID- 22490634 TI - [Ghrelin stimulates in vitro angiogenic capacity of rat cardiac microvascular endothelial cells]. AB - OBJECTIVE: To clarify whether ghrelin could promote in vitro rat cardiac microvascular endothelial cells (CMECs) angiogenesis and related mechanisms. METHODS: CMECs were isolated from myocardial tissue of adult male SD rats and characterized by the immunocytochemistry staining with Factor VIII and the capacity of in vitro capillary tube-like formation. The mRNAs and protein expressions of ghrelin and its receptor (growth hormone secretagogue receptor, GHS-R) of CMECs were determined by RT-PCR, Immunofluorescence, ELISA and Western blot. Proliferation, migration and in vitro angiogenesis as well as ERK2 phosphorylation of CMECs were tested in the presence of ghrelin (10(-9) - 10(-7) mol/L) with or without pretreatment with specific MAPK/ERK2 inhibitor PD98059. RESULTS: Purity of CMECs characterized by immunocytochemistry staining with Factor VIII was about 95%, and the cells showed a high ability to form the capillary tube-like structures on Matrigel. Ghrelin and GHS-R were constitutively expressed in CMECs. Proliferation, migration and in vitro angiogenesis capacities of CMECs (72.20 +/- 5.72 vs. 28.60 +/- 5.13, P < 0.001; 71.00 +/- 7.78 vs. 28.60 +/- 5.13, P < 0.001) as well as ERK2 phosphorylation (0.92 +/- 0.13 vs. 0.29 +/- 0.04, P < 0.001; 1.15 +/- 0.16 vs. 0.29 +/- 0.04, P < 0.001) were significantly enhanced by exogenous ghrelin (10(-8) - 10(-7) mol/L). PD98059 abolished ghrelin induced ERK2 phosphorylation and in vitro angiogenesis. CONCLUSIONS: Ghrelin and its receptor are expressed in CMECs and ghrelin could stimulate CMECs in vitro angiogenesis through activation of MAPK/ERK2 signaling pathway. PMID- 22490635 TI - [Relationship and interactions between elevated fasting glucose and hypertension for cardiocerebral vascular disease]. AB - OBJECTIVE: To explore the relationship and interaction of elevated fasting glucose and hypertension on cardiocerebral vascular disease. METHODS: 10 054 males and females were recruited for our cross-sectional study during May 2007 to August 2007. Unconditional logistic regression was used to analysis the relationship between fasting glucose and hypertension on cardiocerebral vascular disease. A product of fasting glucose and hypertension was added to the logistic regression model to evaluate the multiplicative interaction and relative excess risk of interaction (RERI), attributable proportion (AP) of interaction and synergy index (S) was applied to evaluate the additive interaction of the two factors. Bootstrap was used to calculate 95% confidence intervals (CI) of RERI, AP and S. RESULTS: After adjusting age, gender, smoking, drinking, body mass index (BMI) and region, the product of fasting glucose and hypertension was not statistically significant, which means there was no multiplicative interaction between the two. But the additive indexes RERI, AP and S with 95%CI of diabetes and hypertension were 0.64 (0.03, 1.25), 0.27 (0.01, 0.47) and 1.83 (1.02, 5.13) respectively, which means significant additive interaction was shown between the two on cardiovascular disease but not no stroke. And there were no additive interaction between impaired fasting glucose on cardiovascular disease or stroke. CONCLUSIONS: Hypertension was independently related to cardiovascular disease and stroke in Beijing citizens, and diabetes were independently related to stroke. There was additive interaction between diabetes and hypertension on cardiovascular disease. PMID- 22490636 TI - [The prevalence and distribution of ideal cardiovascular health behavior in employees of Kailuan Group cohort]. AB - OBJECTIVE: To observe the prevalence and distribution of ideal cardiovascular health behavior. METHODS: Health examination data between 2008 to 2009 from the employees of Kailuan Group were analyzed. RESULTS: A total of 101 333 subjects took part in the health examination, subjects with previous myocardial infarction (n = 871), stroke (n = 2255), myocardial infarction and stroke (n = 162) and subjects with incomplete examination data (n = 9311) were excluded and 88 534 subjects were included for final analysis [mean age (50.6 +/- 12.3) years, male 69 916]. (1) Body mass index (BMI), systolic and diastolic pressure, cholesterol (TC) and triglyceride were significantly higher in males than in females (all P < 0.05), women's income and the education lever were significantly higher than men (P < 0.05). (2) The distribution of ideal cardiovascular health behavior (smoking, BMI, physical exercise, salt intake) was 55.8%, 41.4%, 18.9% and 14.0% respectively among the population; the ideal cardiovascular factors (fasting blood glucose, TC, blood pressure) was 80.9%, 61.8% and 18.5%, respectively. (3) The subjects with distribution of seven, six, five, four ideal cardiovascular health behavior and factors was 0.1%, 1.9%, 9.1%, 20.3%, respectively. (4) Multiple logistic regression analysis showed that female, age < 55 and high education level were associated with the ideal cardiovascular health status with a RR value (95%CI) of 4.52 (4.32 - 4.72), 1.46 (1.39 - 1.53) and 2.23 (2.10 - 2.37), respectively. CONCLUSION: The prevalence of ideal cardiovascular health is extremely low in the study population, most persons were not in the ideal cardiovascular health behavior and factors and female, age < 55 and high education level are linked with ideal cardiovascular health status. PMID- 22490637 TI - [Efficacy of rate and rhythm control strategy in patients with atrial fibrillation: meta-analysis]. AB - OBJECTIVE: The efficacy of rate and rhythm control strategies for treating atrial fibrillation (AF) patients was analyzed in this meta-analysis. METHODS: Eligible trials were searched in MEDLINE, the Cochrane Library, the Clinical Trials, the Chinese VIP database up to May 31, 2010. Ten prospective randomized control trials with 7876 patients (rate control n = 3932, rhythm control n = 3944) were included for final analysis. RESULTS: All cause mortality (5.3% vs. 5.0%; OR: 1.03; 95%CI: 0.84 - 1.26; I(2) < 25%) and incidence of worsening heart failure (3.81% vs. 3.61%; OR: 1.04; 95%CI: 0.80 - 1.36; I(2) < 50%) were similar between the two groups. Subgroup analysis showed that all cause mortality (3.6% vs.1.9%; OR: 1.89; 95%CI: 1.01 - 3.53; I(2) < 25%) and rate of worsening heart failure (2.3% vs. 0.3%; OR: 5.6; 95%CI: 1.44 - 21.69; I(2) < 25%) were significantly higher in rate control group than in rhythm control group in patients with age < 65 years. Thromboembolic events (1.49% vs. 1.46%; OR: 1.02, 95%CI: 0.71 - 1.48) and bleeding events (1.78% vs. 1.73%; OR: 1.02, 95%CI: 0.70 - 1.49) were similar between rhythm control and rate control groups while rehospitalization rate was significantly lower in rate control group than in rhythm control group (17.56% vs. 22.98%; OR: 0.37, 95%CI: 0.19 - 0.71). CONCLUSION: This meta-analysis shows that rhythm control strategy is superior to rate control strategy for AF patients with age < 65 years in terms of reducing all cause mortality and incidence of worsening heart failure. PMID- 22490638 TI - [Coronary artery thrombus embolism after mitral valve replacement leading to acute myocardial infarction:a case report]. PMID- 22490639 TI - [Cardiac hydatid disease: a case report]. PMID- 22490640 TI - [One case of instable vulnerable plague rupture complicated with very late drug eluting stent thrombosis]. PMID- 22490641 TI - [Research advance of renal sympathetic denervation: a new treatment for resistant hypertension]. PMID- 22490642 TI - [Cardiovascular disease and osteoporosis]. PMID- 22490644 TI - Multimodal cross-talk of olfactory and gustatory information in the endopiriform nucleus in rats. AB - The endopiriform nucleus (EPN) is a large group of multipolar cells located in the depth of the piriform cortex (PC). Although many studies have suggested that the EPN plays a role in temporal lobe epilepsy, the normal function of the EPN remains to be elucidated. By using optical imaging of coronal brain slice preparations with voltage-sensitive dye, we found signal propagation from the PC or gustatory cortex (GC) to the EPN in normal medium. In our previous research, we failed to elicit a reliable signal reproducibly in the EPN by single stimulation either to the PC or GC. In our current research, we found that a double-pulse stimulation to either the PC or GC (interpulse interval: 20-100 ms) induced robust signal propagation to the EPN through excitation in the agranular division of the insular cortex (AI), with further extension to the claustrum. Finally, double site paired-pulse stimulation to the PC and GC also evoked excitation in the AI, claustrum, and EPN. These results suggest that the EPN has dual roles: 1) further processing of modality-specific olfactory and gustatory information from the PC and GC, respectively and 2) synergistic integration of PC derived olfactory information and GC-derived gustatory information. PMID- 22490643 TI - Oral nystatin prophylaxis in surgical/trauma ICU patients: a randomised clinical trial. AB - INTRODUCTION: Candida prophylaxis in ICU is still a matter of debate. Oral chemoprophylaxis has been advocated to reduce the incidence of Candida colonisation and infection. METHODS: We performed a randomised trial studying a single drug (nystatin) versus control in surgical/trauma ICU patients. Multiple site testing for fungi was performed in each patient on ICU admission (T0) and subsequently every 3 days (T3, T6, T9, and so forth). The primary evaluation criterion was the time course of the corrected colonisation index. RESULTS: Ninety-nine patients were enrolled. At admission, 69 patients exhibited Candida colonisation: the most frequently colonised body sites were the stomach and the pharynx. The most frequent isolated species was Candida albicans. The corrected colonisation index was similar in the two groups at T0 (P = 0.36), while a significant statistical difference was observed between the treatment and control groups at T6 (median 0.14 and 0.33, respectively; P = 0.0016), at T9 (median 0.00 and 0.28, respectively; P = 0.0001), at T12 (median 0.00 and 0.41, respectively; P = 0.0008), and at T15 (median 0.00 and 0.42, respectively; P < 0.0003). The same results were obtained in the subgroup of patients already colonised at ICU admission. CONCLUSION: This trial shows that nystatin prophylaxis significantly reduces fungal colonisation in surgical/trauma ICU patients, even if already colonised. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01495039. PMID- 22490645 TI - [It is time to act to actively fight non-communicable diseases]. PMID- 22490646 TI - [Co-oral contraceptive pills with women protection post abortion]. PMID- 22490647 TI - [Comparison of ultrasound plus radiography versus computed tomography in the diagnosis of ectopic intrauterine devices]. AB - OBJECTIVE: To compare the effectiveness of ultrasound plus radiography versus computed tomography (CT) in the diagnosis of ectopic intrauterine device (IUD) and analyze the ratio of cost and effectiveness (C/E) so as to provide scientific rationales for the selection of appropriate diagnostic methods. METHODS: A total of 70 cases were recruited from two major Chinese hospitals in 2009. They were examined with ultrasound plus radiography and CT respectively. The gold diagnostic criterion was postoperative diagnosis to compare the sensitivity, specificity, diagnostic index (DI), accuracy and C/E for different diagnostic methods. The SPSS 13.0 statistical analysis software was employed for data analysis. RESULTS: The data of 65 subjects were collected and analyzed. For ultrasound plus radiography, the sensitivity, specificity, DI, accuracy and C/E were 82.1%, 88.9%, 171.0%, 83.1% and 137.3 respectively. As for CT, the above indices were 96.4%, 55.6%, 152.0%, 90.8% and 170.7 respectively. CONCLUSION: Considering the higher levels of specificity and DI and a lower C/E, ultrasound plus radiography is superior to CT so that the former modality shall become a first-choice in the diagnosis of ectopic IUD, especially at the grass-root family planning service stations. PMID- 22490648 TI - [Correlations between chemokines CXCL12, CCL2, RANTES and early abortion]. AB - OBJECTIVE: To explore the correlations between chemokines stromal cell-derived factor-1 (CXCL12), monocyte chemotactic protein-1 (CCL2), regulated upon activation normal T cell expressed and secreted (RANTES) and early abortion. METHODS: The villus and decidua tissues of recurrent spontaneous abortion group (n = 26), medical abortion group (n = 30) and normal early pregnancy women (control group, n = 30) were collected at our hospital from 2008 to 2009. And their expressions of CXCL12, CCL2, RANTES mRNA were determined by real-time fluorescence quantitative PCR (polymerase chain reaction). RESULTS: The CXCL12, CCL2 and RANTES mRNA gene expressions were detected in first-trimester placental villus and decidua tissues. And the gene expressions of CXCL12 mRNA in villus and decidua tissues in spontaneous abortion and medical abortion groups were significantly lower than that in the control group (P < 0.01). But the gene expressions of CCL2 and RANTES mRNA in villus and decidua tissues were significantly higher than that in the control group (P < 0.01). CONCLUSION: CXCL12, CCL2 and RANTES are co-expressed in human villus and decidua tissues. The lower CXCL12 mRNA expression and the higher expressions of CCL2 and RANTES mRNA play important roles in the pathogenesis of early abortion. PMID- 22490649 TI - [Clinical study of induced abortion of early-early pregnancy: an analysis of 10, 404 cases]. AB - OBJECTIVE: To evaluate the advantages and disadvantages of early-early pregnancy induced abortion (EPIA). METHODS: A total of 10 404 cases of EPIA performed at our hospital from January 1993 to December 2003 were retrospectively analyzed and compared with 9434 cases of common induced abortion (CIA). The amount of hemorrhage and operative duration, degree of pain, rate of induced-abortion syndrome, rate of incomplete abortion, menstrual changes and post-operative onset of Asherman's syndrome were observed and compared between 2 groups. RESULTS: The average age, ratio of parous cases, ratio of the cases of first-pregnancy induced abortion were not different between 2 groups (P > 0.05). The amount of hemorrhage bleeding ((4.9 +/- 3.2) ml), operative duration ((90.3 +/- 12.4) s), degree of pain, rate of induced-abortion syndrome, menstrual changes and the rate of Asherman's syndrome in the EPIA group were all significantly less than those in the CIA group (P < 0.05). However, the rate of incomplete abortion (0.44%) in the EPIA group was significantly higher than that (0.21%) in the CIA group (P < 0.05). CONCLUSION: EPIA has the advantages of lesser hemorrhage, less pain, shorter operative duration and fewer complications over CIA. Therefore the recovery of EPIA cases is earlier than that of CIA cases. While the risk of incomplete abortion stays high. PMID- 22490650 TI - [Mifepristone inhibits the progesterone-induced expressions of HLA-G, -E, -F genes in trophoblasts during first trimester]. AB - OBJECTIVE: To explore the effects of mifepristone on the expressions of HLA-G, HLA-E and HLA-F in extravillous cytotrophoblasts (EVCT). METHODS: Cultured EVCT during the first trimester were treated in vitro with progesterone and mifepristone. And the transcription levels of HLA-G, HLA-E and HLA-F genes were detected by RT-PCR (reverse transcription-polymerase chain reaction). RESULTS: As compared with the controls, the levels of HLA-G, HLA-E and HLA-F mRNA significantly increased in EVCT after incubating with 0.1 ng/L progesterone (P < 0.05). These effects could be completely blocked by a co-incubation with mifepristone at the same concentrations. CONCLUSION: Mifepristone can inhibit the effects of progesterone by down-regulating the expressions of HLA-G, HLA-E and HLA-F mRNA in trophoblasts during the first trimester. PMID- 22490651 TI - [Clinical efficacy and safety of mifepristone in the treatment of abortive remnants of induced abortion]. AB - OBJECTIVE: To evaluate the efficacy and safety of treating abortive remnants of induced abortion with different doses of mifepristone. METHODS: A total of 101 women undergoing post-abortion treatment at our family planning clinic from October 2009 to February 2011 were recruited and divided randomly into 4 groups. They were diagnosed as abortive remnants by ultrasound and blood level of beta HCG (human chorionic gonadotrophin). Three test groups received different doses of mifepristone and one group as control. The efficacy and safety of four groups were evaluated by clinical observations, ultrasonic examinations and blood level of beta-HCG. RESULTS: The effective rates of mifepristone test and control groups were 61.60% and 21.40% respectively. And there were statistical significances between two groups (P < 0.01). After a 2-week treatment, the changes of blood level of beta-HCG and reduction of residual size tested by ultrasound were better than those of the control group. And there were significant statistical differences (P < 0.01). The group with high dose in short term achieved the best outcomes. After four weeks of treatment, blood level of beta-HCG of test groups had no statistical significance (P > 0.05). There was statistical significance in pairwise comparison on reduction of residual size tested by ultrasound among test groups (P < 0.05). The high-dose group with achieved the largest short-term reduction. Statistical significances existed in the hemostatic time of vaginal hemorrhage and menstrual recovery between three test groups and the control group (P < 0.05). No statistical significance was found in healing time and the occurrence of adverse events among these 3 test groups (both P > 0.05). CONCLUSION: Mifepristone is effective in the treatment of induced incomplete abortion. And a short-term large dose offers a better efficacy. PMID- 22490652 TI - [Survival analysis of short-term prognosis of patients with HBV-related acute-on chronic liver failure]. AB - OBJECTIVE: To investigate the independent risk factors of influencing short-term survival and prognosis of patients with HBV-related acute-on-chronic liver failure (HBV-ACLF). METHODS: The clinical data of 338 HBV-ACLF patients hospitalized from January 2007 to December 2010 were collected and analyzed by a Cox regression model. RESULTS: The Cox regression analysis showed that gastrointestinal hemorrhage, hepatorenal syndrome, electrolyte imbalance and hepatic encephalopathy could significantly increase their recent mortality risks. And the values of relative risk (RR) were 2.526, 2.356, 2.068 and 1.896 respectively. Prothrombin activity (Exp(beta): 0.821) and opportunity of antiviral therapy (Exp(beta) of early stage: 0.526; Exp(beta) of medium stage: 0.601) were protective factors of reduced mortality. CONCLUSION: Gastrointestinal hemorrhage, hepatorenal syndrome, electrolyte imbalance, hepatic encephalopathy, prothrombin activity and opportunity of antiviral therapy are independent risk factors of influencing short-term survival and prognosis of HBV-ACLF patients. The combination of MELD score and multivariate analysis is a more scientific method of determining the prognosis of HBV-related ACLF. PMID- 22490653 TI - [Microsurgery assisted by intraoperative magnetic resonance imaging and neuronavigation for small lesions in deep brain]. AB - OBJECTIVE: To explore the practicability of resecting small lesions in deep brain by intraoperative magnetic resonance imaging (iMRI) and neuronavigator-assisted microsurgery and its clinical efficacies. METHODS: A total of 42 cases with small lesions in deep brain underwent intraoperative MRI and neuronavigator-assisted microsurgery. The drifting of neuronavigation was corrected by images acquired from intraoperative MR rescanning. RESULTS: All lesions were successfully identified and 40 cases totally removed without mortality. Only 3 cases developed new neurological deficits post-operatively while 2 of them returned to normal neurological functions after a follow-up duration of 3 months to 2 years. CONCLUSION: The application of intraoperative MRI can effectively correct the drifting of neuronavigation and enhance the accuracy of microsurgical neuronavigation for small lesions in deep brain. PMID- 22490654 TI - [Study of endocardiac and extracardiac haemodynamics changes in fetus with increased nuchal translucency thickness]. AB - OBJECTIVE: To explore the characteristics of endocardiac and extracardiac haemodynamics parameters in fetus with thickened nuchal translucency (NT) and analyze the relationship between hemodynamic changes and fetal prognosis. METHODS: The fetal appearance was observed during the first trimester. And the thickness of NT or soft tissue of neck was quantified. The endocardiac and extracardiac haemodynamic parameters were measured by ultrasound Doppler. The parameters were compared between fetus with thickened NT and normal fetus. Echocardiography was performed individually in both 2nd trimester and newborn stage. RESULTS: Eight cases with greater NT thickness were found. Four cases terminated pregnancy during the first or second trimester: one was diagnosed as persistent arterial trunk during a 13-week gestation, one with congenital cystic adenomatoid malformation during second trimester. Both were confirmed by autopsy; one with pleural fluid and ascites while another aborted at the expectant mother's will. Four cases were delivered full-term. Among them, one had congenital anal atresia while the other 3 cases were normal. Endocardiac haemodynamic parameters were normal in all cases with thickened NT and no heart malformation. Higher pulsatility index (PI), resistive index (RI) and ratio of velocity of systole and diastole (S/D) in venous duct were observed in 5 cases. The endocardiac and extracardiac haemodynamics parameters of the cases with thickened NT and complicated with heart malformation were different from normal cases. CONCLUSION: Greater NT thickness is closely correlated with chromosomal abnormalities, congenital cardic defects, other structure abnormalities and a poor prognosis. Ultrasound Doppler can evaluate the fetal heart functions accurately. If abnormal endocardiac and extracardiac parameters are found in fetus with thickened NT, the existence of heart malformation should be considered. When abnormal extracardiac Doppler waveshape or greater blood flow resistance is found with normal endocardiac parameters, prognostic follow-ups should be conducted with chromosomal examinations. PMID- 22490655 TI - [Etiological profiles and pathogen detection of infectious endophthalmitis]. AB - OBJECTIVE: To retrospectively analyze the etiological characteristics of infectious endophthalmitis so as to improve the positive detection rate of its pathogens in laboratory test. METHODS: The epidemiological features and laboratory findings of 319 inpatients (319 eyes) diagnosed with infectious endophthalmitis at our institute from January 2000 to December 2010 were retrospectively reviewed and analyzed. RESULTS: Ocular trauma (n = 230, 72.10%) was a major risk factor for infectious endophthalmitis. Bacteria and fungi were isolated from intraocualr specimens with the positive rates of 43.57% (139/319) and 18.22% (49/269) respectively. The positive rates of bacteria culture were 29.00% for nutrient broth medium and 50.23% for blood enrichment medium respectively. And the difference was statistically significant (chi(2) = 12.58, P < 0.01). The sensitivity of isolated bacteria to levofloxacin was 81.82%. The geometric mean of minimal inhibitory concentrations of amphotericin B, fluconazole, ketoconazole and itraconazole against fungi were 1.05, 5.07, 3.00 and 2.42 ug/ml respectively. CONCLUSION: The major cause of infectious endophthalmitis is ocular trauma and the dominant pathogen is bacteria. The use of blood enrichment medium may improve the positive rate of bacteria culture. Levofloxacin and amphotericin B are indicated for the treatment of bacterial and fungal endophthalmitis. PMID- 22490656 TI - [Comparison of efficacies for two surgical methods in the treatment of medial tibial-femoral osteoarthritis]. AB - OBJECTIVE: To compare the clinical efficacies of two surgical methods in the treatment of medial tibial-femoral osteoarthritis. METHODS: Between October 2007 and June 2010, a total of 22 cases (25 knees) with severe osteoarthritis in medial tibial-femoral compartment underwent minimally invasive unicompartmental knee arthroplasty (UKA) with Sled prosthesis after arthroscopic procedure. And its clinical efficacy was compared with that of 22 cases (25 knees) undergoing total knee arthroplasty (TKA) with Gemini MKII prosthesis almost simultaneously. RESULTS: There were no significant difference in general data between 2 groups (P > 0.05). Compared with the TKA group, the UKA group had a smaller blood loss ((148 +/- 26) vs (278 +/- 36) ml), a shorter operative duration ((68 +/- 12) vs (86 +/- 12) min), a faster progress of resuming 90 degrees flexion ((3.18 +/- 1.8) vs (9.1 +/- 2.2) d) and an earlier off-bed time (P < 0.05). All patients were followed up for 6 - 34 months. There was no significant difference in KSS (Knee Society Score), function score or WOMAC (Western Ontario and McMaster Universities) score between 2 groups at the last follow-up (P > 0.05). CONCLUSION: The treatment of medial tibial-femoral osteoarthritis with minimally invasive UKA is superior to that with TKA in that it is less invasive, there is a faster recovery of joint functions and no significant difference exists in the mid-term clinical efficacies between them. PMID- 22490657 TI - [Effects of different stress force stimulations on the expression of vascular endothelial growth factor in Beagle dogs in the repairing process of osteonecrosis of the femoral head]. AB - OBJECTIVE: To explore the changes and its significance of the expression of vascular endothelial growth factor (VEGF) protein and messenger RNA in the Beagle dogs femoral head during the repairing process of the osteonecrosis of femoral head (ONFH) under different stress force stimulations. METHODS: Twenty-four Beagle dogs were selected to establish the model of ONFH through the method of liquid nitrogen cryopreservation. In the mean time, the necrotic femoral heads stimulated by different stress forces were enrolled into 3 groups: group B (low stress force stimulation group), group C (high stress force stimulation group) and group D (average stress force stimulation group). Group A was control group. The beagle dogs were sacrificed at Weeks 4 and 8 post-operation. The changes of femoral head were evaluated by histological observation, immunohistochemical staining and quantitative reverse transcription-polymerase chain reaction (RT PCR). RESULTS: Histological observation showed that articular cartilage, morphology and structure of trabecular bone in group D was better than those of groups B and C. Immunohistochemistry revealed that the VEGF protein positive staining in group D was significantly higher than that in groups A, B and C at Weeks 4 and 8 post-operation. The expression of VEGF mRNA in group D was much more than that in groups A, B and C by RT-PCR. And the expression was higher at Week 8 post-operation. CONCLUSION: Proper stress force stimulation can effectively promote the expression of VEGF protein and messenger RNA in necrotic femoral head of Beagle dogs and boost angiogenesis to improve the blood supply of necrotic femoral head so as to accelerate the repairing process of ONFH. PMID- 22490658 TI - [Molecular mechanism of Aurora kinase inhibitor PHA739358 in inhibited proliferation and induced apoptosis of breast cancer cells]. AB - OBJECTIVE: To explore the molecular mechanisms of Aurora kinase inhibitor PHA739358 in inhibited proliferation and in vitro induced apoptosis of breast cancer cells. METHODS: The in vitro cultured T47D cells in logarithmic growth phase were used. The effects of PHA739358 on cell proliferation were examined by MTT (methyl thiazolyl tetrazolium) assay. The variety of nuclear and spindle morphologies was examined by immunofluorescence. And G2/M arrest was determined by flow cytometry. The morphological changes of apoptotic cells were observed by fluorescent microscope. The levels of Aurora kinase relative protein expression phosphonate-AuroraA (p-AuroraA), AuroraA, phosphonate-histone H3 (p-histone H3), histone H3, cell cycle-specific protein expression CyclinB1, cell cycle regulative protein expression Cdc2, Cdc25c, phosphonate-Cdc2 (p-Cdc2), phosphonate-Cdc25c (p-Cdc25c) and apoptosis relative protein expression PARP, Bcl 2 and Bax were detected by Western blot. The apoptotic rate was examined by flow cytometer. RESULTS: PHA739358 obviously inhibited the proliferation of T47D cells after a 24 h or 48 h treatment in a dose-dependent and time-dependent manner. Their IC50 values were (3.44 +/- 0.54) and (0.21 +/- 0.67) umol/L respectively. Flow cytometry showed that G2/M arrested in a dose-dependent manner. PHA739358 dose-dependently and time-dependently promoted the dissection of PARP (poly (ADP ribose) polymerase); down-regulated the expressions of Bcl-2, p-AuroraA, p histone H3, CyclinB1 and up-regulated the levels of Bax, p-Cdc25c, p-Cdc2, P21 and P53 protein. PHA739358 had no significant effects on the expressions of AuroraA and histone H3. Flow cytometry and fluorescence microscope showed that PHA739358 significantly induced apoptosis. Flow cytometry showed the rate of apoptosis significantly increased from 0.31% +/- 0.03% to 40.6% +/- 0.81%. CONCLUSION: The proliferation-inhibiting and apoptosis-inducing effects of PHA739358 may provide new therapeutic approaches of breast cancer. PMID- 22490659 TI - [Cloning and expression of fusion gene of amyloid beta binding alcohol dehydrogenase decoy peptide aptamer (TRX1-ABAD-DP-TRX2)]. AB - OBJECTIVE: To construct TRX-ABAD-DP-TRX (T-A-T) fusion gene of a novel ABAD-DP aptamer through the insertion of ABAD-DP into the modified human thioredoxin (hTRX) and exploit the possibility of further applications for the gene therapy of Alzheimer's disease. METHODS: According to the designed sequence, the target fragments of TRX1, TRX2 and ABAD-DP were created by PCR (polymerase chain reaction) and then inserted into the multiple clone site of adeno-associated virus shuttle plasmid pSSHG-CMV with gene cloning technique. The corresponding fusion gene TRX1-ABAD-DP-TRX2 was identified by restriction enzymes digestion with EcoRI and BamHI. The recombinant adeno-associated virus (AAV/T-A-T) was produced in HeLa cells with linear polyethylenimine. The expression of T-A-T fusion gene and co-localization between T-A-T and Abeta peptide in NIH 3T3 cells were examined by fluorescent immunohistochemistry. RESULTS: The size of fusogenic fragment TRX1-ABAD-DP-TRX2 was approximately 435 bp. And it was consistent with our design. T-A-T fusion gene was expressed in NIH 3T3 cells. Through co expression, T-A-T aptamer and intracellular Abeta peptide were co-localized. It indicated that T-A-T aptamer could bind Abeta within NIH 3T3 cells. CONCLUSION: The TRX1-ABAD-DP-TRX2 fusion gene is successfully cloned and expressed. And it may provide rationales for further applications in the gene therapy of Alzheimer's disease's. PMID- 22490660 TI - [Adenovirus vector mediated human 14-3-3 gamma gene transfer protects dopaminergic cells against rotenone-induced injury]. AB - OBJECTIVE: To explore the protective effect of human 14-3-3 gamma gene transfer on dopaminergic cells against rotenone-induced injury. METHODS: Adenovirus vector carrying the gene of 14-3-3 gamma (Ad/14-3-3 gamma) was employed to transfect PC12 cells. Then the cells were exposed to rotenone as a model of Parkinson's disease. Methyl thiazolyl tetrazolium (MTT) was used to assay the viability of PC12 cells. The 4',6-diamidino-2-phenylindole (DAPI) staining was used to analyze the apoptotic ratio of PC12 cells among the groups of control, Ad/14-3-3 gamma, Ad-null and Rotenone. And high performance liquid chromatography (HPLC) was performed to detect the secreting functions of PC12 cells. The aggregates of alpha-Synuclein protein were detected under confocal microscopy. RESULTS: MTT showed that the cell absorbance A(570) of Ad/14-3-3 gamma group (0.46 +/- 0.09) was higher than that of Ad-null group (0.19 +/- 0.08) and rotenone group (0.16 +/ 0.07), but lower than that of normal control (0.63 +/- 0.11), (all P < 0.01); HPLC-ECD showed that the levels of dopamine (189 +/- 11) ng/ml and noradrenalin (55 +/- 8) ng/ml in the culture fluid of Ad/14-3-3 gamma group were higher than those of Ad-null group (79 +/- 12, 38 +/- 7) ng/ml and rotenone group (81 +/- 13, 39 +/- 7) ng/ml (all P < 0.01). DAPI staining showed that cell apoptosis ratio of group Ad/14-3-3 gamma (27% +/- 64%) was lower than that of group Ad-null (53% +/- 10%) and rotenone group (56% +/- 12%, P < 0.01), but higher than that of control group (10% +/- 5%, P < 0.01). Under confocal microscopy, the aggregates of alpha synuclein protein in PC12 cells were detected more in Ad-null group and rotenone group than that in Ad/14-3-3 gamma group. CONCLUSION: Gene transfer of Ad/14-3-3 gamma has a protective effect on dopaminergic cells against rotenone-induced injury. PMID- 22490661 TI - Gs cascade regulates canonical transient receptor potential 5 (TRPC5) through cAMP mediated intracellular Ca2+ release and ion channel trafficking. AB - Canonical transient receptor potential (TRPC) channels are Ca(2+)-permeable, non selective cation channels those are widely expressed in mammalian cells. Various molecules have been found to regulate TRPC both in vivo and in vitro, but it is unclear how heterotrimeric G proteins transmit external stimuli to regulate the activity of TRPC5. Here, we demonstrated that TRPC5 was potentiated by the Galpha(s) regulatory pathway. Whole-cell TRPC5 current was significantly increased by beta-adrenergic receptor agonist, isoproterenol (ISO, 246+/-36%, n=6), an activator of the adenylate cyclase, forskolin (FSK, 273+/-6%, n=5), or a membrane permeable cAMP analogue, 8-Br-cAMP (251+/-63%, n=7). In addition, robust Ca(2+) transient induced by isoproterenol was observed utilizing a Ca(2+) imaging technique. When intracellular [Ca(2+)](i) was buffered to 50nM, cAMP-induced potentiation was attenuated. We also found that the Ca(2+) release is mediated by IP(3) since intracellular IP(3) infusion attenuated the potentiation of TRPC5 by Galpha(s) cascade. Finally, we identified that the membrane localization of TRPC5 was significantly increased by ISO (155+/-17%, n=3), FSK (172+/-39%, n=3) or 8-Br cAMP (216+/-59%, n=3). In conclusion, these results suggest that the Galpha(s) cAMP pathway potentiates the activity of TRPC5 via facilitating intracellular Ca(2+) dynamics and increasing channel trafficking to the plasma membrane. PMID- 22490662 TI - Structural insights into selectivity and cofactor binding in snake venom L-amino acid oxidases. AB - L-Amino acid oxidases (LAAOs) are flavoenzymes that catalytically deaminate L amino acids to corresponding alpha-keto acids with the concomitant production of ammonia (NH(3)) and hydrogen peroxide (H(2)O(2)). Particularly, snake venom LAAOs have been attracted much attention due to their diverse clinical and biological effects, interfering on human coagulation factors and being cytotoxic against some pathogenic bacteria and Leishmania ssp. In this work, a new LAAO from Bothrops jararacussu venom (BjsuLAAO) was purified, functionally characterized and its structure determined by X-ray crystallography at 3.1 A resolution. BjsuLAAO showed high catalytic specificity for aromatic and aliphatic large side chain amino acids. Comparative structural analysis with prokaryotic LAAOs, which exhibit low specificity, indicates the importance of the active-site volume in modulating enzyme selectivity. Surprisingly, the flavin adenine dinucleotide (FAD) cofactor was found in a different orientation canonically described for both prokaryotic and eukaryotic LAAOs. In this new conformational state, the adenosyl group is flipped towards the 62-71 loop, being stabilized by several hydrogen-bond interactions, which is equally stable to the classical binding mode. PMID- 22490663 TI - DCK is frequently inactivated in acquired gemcitabine-resistant human cancer cells. AB - Although gemcitabine is the most effective chemotherapeutic agent against pancreatic cancer, a growing concern is that a substantial number of patients acquire gemcitabine chemoresistance. To elucidate the mechanisms of acquisition of gemcitabine resistance, we developed gemcitabine-resistant cell lines from six human cancer cell lines; three pancreatic, one gastric, one colon, and one bile duct cancer. We first analyzed gemcitabine uptake using three paired parental and gemcitabine resistant pancreatic cancer cell lines (PK-1 and RPK-1, PK-9 and RPK 9, PK-59 and RPK-59) and found that uptake of gemcitabine was rapid. However, no DNA damage was induced in resistant cells. We further examined the microarray based expression profiles of the cells to identify genes associated with gemcitabine resistance and found a remarkable reduction in the expression of deoxycytidine kinase (DCK). DCK is a key enzyme that activates gemcitabine by phosphorylation. Genetic alterations and expression of DCK were studied in these paired parental and derived gemcitabine-resistant cell lines, and inactivating mutations were found only in gemcitabine-resistant cell lines. Furthermore, siRNA mediated knockdown of DCK in the parental cell lines yielded gemcitabine resistance, and introduction of DCK into gemcitabine-resistant cell lines invariably restored gemcitabine sensitivities. Mutation analyses were expanded to three other different paired cell lines, DLD-1 and RDLD-1 (colon cancer cell line), MKN-28 and RMKN-28 (gastric cancer cell line), and TFK-1 and RTFK -1 (cholangiocarcinoma cell line). We found inactivating mutations in RDLD-1 and RTFK-1 and decreased expression of DCK in RMKN-28. These results indicate that the inactivation of DCK is one of the crucial mechanisms in acquisition of gemcitabine resistance. PMID- 22490664 TI - Chimeric hexon HVRs protein reflects partial function of adenovirus. AB - Adenovirus is widely used in gene therapy and vaccination as a viral vector, and its hypervariable regions (HVRs) on hexon are the main antigen recognition sites of adenovirus. The modification of this area by genetic engineering will change the antigenic specificity of the virus. In addition, recent studies have demonstrated the importance of coagulation factor X (FX) in adenovirus serotype 5 mediated liver transduction in vivo. The binding site of adenovirus to FX is the HVRs on hexon. By constructing five proteins containing chimeric HVRs from different adenovirus serotypes, we focused on the antigenic specificity and the affinity for FX of these proteins compared with the corresponding viruses. Our data showed that HVR5 and HVR7 had only a part of hexon activity to neutralizing antibodies (NAbs) compared with the complete activity of HVR1-7. Results also demonstrated a differential high-affinity interaction of the HVRs proteins with FX and indicated that HVRs protein had a similar binding ability with corresponding adenovirus serotype. These results highlighted some properties of chimeric HVRs proteins and revealed the influence on the structure and function of hexon proteins and adenovirus resulting from the HVRs. PMID- 22490665 TI - Lipid rafts and functional caveolae regulate HIV-induced amyloid beta accumulation in brain endothelial cells. AB - Amyloid beta (Abeta) levels are increased in HIV-1 infected brains due to not yet fully understood mechanisms. In the present study, we investigate the role of lipid rafts, functional caveolae, and caveolae-associated signaling in HIV-1 induced Abeta accumulation in HBMEC. Both silencing of caveolin-1 (cav-1) and disruption of lipid rafts by pretreatment with beta-methyl-cyclodextrin (MCD) protected against Abeta accumulation in HBMEC. Exposure to HIV-1 and Abeta activated caveolae-associated Ras and p38. While inhibition of Ras by farnesylthiosalicylic acid (FTS) effectively protected against HIV-1-induced accumulation of Abeta, blocking of p38 did not have such an effect. We also evaluated the role of caveolae in HIV-1-induced upregulation of the receptor for advanced glycation end products (RAGE), which regulates Abeta transfer from the blood stream into the central nervous system. HIV-1-induced RAGE expression was prevented by infecting HBMEC with cav-1 specific shRNA lentiviral particles or by pretreatment of cells with FTS. Overall, the present results indicate that Abeta accumulation in HBMEC is lipid raft and caveolae dependent and involves the caveolae-associated Ras signaling. PMID- 22490666 TI - Destabilization of PDK1 by Hsp90 inactivation suppresses hepatitis C virus replication through inhibition of PRK2-mediated viral RNA polymerase phosphorylation. AB - Heat shock protein 90 (Hsp90), which chaperones multiple client proteins, has been shown to be implicated in HCV replication. Pharmacological inhibitors of Hsp90 display an anti-HCV activity. However, little is known about the mechanisms of regulation of HCV replication by Hsp90. Here, we show that Hsp90 inhibition by 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) destabilizes phosphoinositide-dependent kinase-1 (PDK1), an upstream kinase of the protein kinase C-related kinase 2 (PRK2) responsible for phosphorylation of HCV RNA polymerase, through the proteosome pathway. Destabilization of PDK1 led to inhibition of phosphorylation of the viral RNA polymerase through a decrease in the abundance of active form PRK2 level. Consequently, Hsp90 inhibition resulted in suppression of HCV replication both in human hepatoma Huh7 cells harboring an HCV subgenomic replicon and in HCV-infected cells. 17-DMAG treatment did not interfere with HCV internal ribosome entry site-mediated translation and the cell cycle in Huh7 cells. Co-treatment of 17-DMAG with interferon-alpha or HA1077, an inhibitor of PRK2, enhanced the anti-HCV activity of 17-DMAG. Taken together, these findings suggest that Hsp90 plays a critical role in the regulation of HCV RNA polymerase phosphorylation via the PDK1-PRK2 signaling pathway. PMID- 22490667 TI - Di (2-ethylhexyl) phthalate modulates cholinergic mini-presynaptic transmission of projection neurons in Drosophila antennal lobe. AB - Di (2-ethylhexyl) phthalate (DEHP) is one of the Phthalic acid esters which are added in polyvinyl chloride (PVC) products. Previous animal studies have showed that exposure to DEHP has a negative effect on the liver, kidneys, lungs, and reproductive system, particularly the developing testes of prenatal and neonatal males, but few can match the dramatic impact on the nervous system. Drosophila melanogaster as a model organism has been widely used in research of the nervous system. In order to examine the modulation of DEHP in excitatory cholinergic transmission, electrophysiological properties of spontaneous activities, spontaneous action potential (sAP), mini excitatory postsynaptic currents (mEPSCs), and calcium currents were measured in projection neurons (PNs) of Drosophila antennal lobe. In this study, DEHP (100MUM) was showed to influence the spontaneous activities of the PNs and DEHP (300 MUM) significantly decrease the frequency of sAP. Meanwhile, DEHP (100 and 300 MUM) also reduced the frequency and amplitude of mEPSCs. Furthermore, ion channel studies showed DEHP (100 and 300 MUM) inhibited the peak current amplitude of calcium channel. These results indicated that the DEHP modulated the cholinergic mini-synaptic transmission of projection neurons in Drosophila antennal lobe, and this modulation might be mediated by inhibiting the calcium channel activities. PMID- 22490668 TI - Modulation of oxidative stress by gamma-glutamylcysteine (GGC) and conjugated linoleic acid (CLA) isomer mixture in human umbilical vein endothelial cells. AB - Individually, gamma-glutamylcysteine (GGC), a dipeptide and precursor of glutathione (GSH), and conjugated linoleic acid (CLA), a trans-fatty acid, exhibit antioxidant properties. The objective of this study was to compare effects of co-administration of GGC and CLA to treatment with GGC alone on oxidative stress and GSH synthesis in human endothelial cells. Changes in levels of 8-epi-PGF2alpha, thiobarbituric acid reactive substances (TBARS), GSH, total antioxidants, GSH synthetase (GSS) expression, and transcription factor DNA binding were assessed in human umbilical vein endothelial cells (HUVEC) treated with GGC alone (100 MUmol/L) or combined with CLA isomer mixture (10, 50, 100 MUmol/L) for 24h. Significantly higher levels of TBARS, 8-epi-PGF2alpha, GSH, and GSS protein were found in cells treated with GGC and 10 MUmol/L CLA, compared to cells treated with GGC alone, indicative of prooxidant effects of CLA. Approximately 40% cell death was microscopically observed in cells incubated with GGC and 100 MUmol/L CLA. Despite lower levels of GSH, treatment with GGC and 50 MUmol/L CLA appeared to be protective from oxidative stress similar to treatment with GGC alone, as indicated by lower levels of TBARS, compared to control cells not treated with GGC and CLA. PMID- 22490669 TI - Effects of flavored mineral waters on AhR-CYP1A1 signaling pathway in primary human hepatocytes and in human hepatic and intestinal cancer cells. AB - Food-drug interaction is an emerging phenomenon, comprising pharmacokinetic or toxicokinetic interactions between food constituents and drugs. The mechanisms include inhibition of enzymes and transporters, and induction of drug metabolizing enzymes. A prominent regulator of drug-metabolizing enzymes is an aryl hydrocarbon receptor (AhR) that transcriptionally regulates CYP1 enzymes, phase II enzymes and many other genes. In the current paper, we have examined the effects of 28 different flavored mineral waters on AhR-CYP1A1 signaling pathway in primary cultures of human hepatocytes and in human cancer cell lines HepG2 (hepatic) and LS174T (intestinal). The techniques of Western blot, RT-PCR and gene reporter assays were employed to determine the expression of CYP1A1 mRNA, protein and activation of AhR, respectively. We have identified four flavored mineral waters which activated AhR and/or induced CYP1A1. These data imply a potential of some flavored mineral waters to cause food-drug interactions. In addition, activation of AhR-CYP1A1 signaling may result in chemically-induced carcinogenesis and alteration of intermediary metabolism. PMID- 22490670 TI - Lysolipid containing liposomes for transendothelial drug delivery. AB - BACKGROUND: Designing efficient 'vectors', to deliver therapeutics across endothelial barriers, in a controlled manner, remains one of the key goals of drug development. Recently, transcytosis of liposome encapsulated fluorescence marker calcein across a tight cell barrier was studied. The most efficient liposomes were found to be liposomes containing sufficient amount of alkyl phospholipid (APL) perifosine. APLs have similar structure as lysophosphatidyl choline (LPC), since APLs were synthesized as metabolically stable analogues of LPC, which increases endothelial permeability directly by inducing endothelial cell contraction, resulting in formation of gaps between endothelial cells. Since one of the unique properties of lysolipid, containing liposomal formulations is dynamic equilibrium of lysolipids, which are distributed among liposomes, micelles, and free form, such liposomes represent a reservoir of free lysolipids. On the other hand lysolipid containing liposomes also represent a reservoir of an encapsulated hydrophilic drug. PRESENTATION OF THE HYPOTHESIS: We hypothesize that free lysolipids, with highest concentration in vicinity of drug carrying liposomes, compromise endothelial integrity, primarily where concentrations of liposomes is the highest, in a similar manner as LPC, by formation of gaps between endothelial cells. Liposome encapsulated drug, which leaks from liposomes, due to liposome destabilization, caused by lysolipid depletion, can therefore be efficiently transported across the locally compromised endothelial barrier. TESTING THE HYPOTHESIS: This hypothesis could be verified: by measuring binding of perifosine and other lysolipids to albumin and to lysophospholipid receptor (LPL-R) group; formation of stress fibers and subsequent cell contraction; activation of RhoA, and endothelial barrier dysfunction; by a synthesis of other LPC analogues with high critical micellar concentration and measuring their effect on transendothelial permeability in presence and absence of albumin. IMPLICATIONS OF THE HYPOTHESIS: We propose that lysolipid containing liposomal formulations might be used as nonspecific transendothelial transport vector, since leakage of liposome encapsulated active drug occurs simultaneously with the release of the lysolipids. The concentration of the active drug is therefore expected to be the highest at the site of compromised endothelial barrier. By appropriate choice of the lysolipids an endothelial barrier would stay open only for a short time. Use of such liposomes would potentially maximize the delivery of the drug while limiting the passage of toxic substances and pathogens across the endothelial barrier. Combining lysolipid containing liposomes with superparamagnetic iron oxide nanoparticles or a targeting ligand might be required to efficiently localize drug delivery to a disease affected tissue and to avoid endothelial disruption over the entire body. PMID- 22490673 TI - Circulating cell-free mitochondrial DNA: a better early prognostic marker in patients with out-of-hospital cardiac arrest. PMID- 22490672 TI - Gut-central nervous system axis is a target for nutritional therapies. AB - Historically, in the 1950s, the chemist Linus Pauling established a relationship between decreased longevity and obesity. At this time, with the advent of studies involving the mechanisms that modulate appetite control, some researchers observed that the hypothalamus is the "appetite centre" and that peripheral tissues have important roles in the modulation of gut inflammatory processes and levels of hormones that control food intake. Likewise, the advances of physiological and molecular mechanisms for patients with obesity, type 2 diabetes mellitus, inflammatory bowel diseases, bariatric surgery and anorexia-associated diseases has been greatly appreciated by nutritionists. Therefore, this review highlights the relationship between the gut-central nervous system axis and targets for nutritional therapies. PMID- 22490674 TI - Out-of-hospital cardiac arrest outcomes stratified by rhythm analysis. AB - BACKGROUND: Survival data for out-of-hospital cardiac arrest (OHCA) victims initially in PEA or asystole who convert to a shockable rhythm during attempted resuscitation, relative to an initial shockable rhythm, have never been previously reported. This study was done to assess OHCA outcomes among a large cohort of adults in the CARES dataset stratified by three rhythm categories: initial shockable (IS), converted shockable (CS), and never shockable (NS). METHODS: The study was IRB approved. All adult index events at participating sites (2005-2010) were study eligible. All patient data elements were provided. Odds ratios of CS and NS status for survival to hospital discharge were calculated via multivariate logistic regression that adjusted for demographics, site, resuscitation initiators, AED use, and other covariates. RESULTS: There were 40,274 OHCA records submitted to the CARES registry during the study period. After exclusions, our final sample size was 30,939 (7404 IS [23.9%], 3225 CS [10.4%], 20,310 NS [65.7%]). Raw survival rates of CS and NS patients were similar (4.7% vs. 4.1%, respectively; p=0.08) but significantly lower than IS patients (26.9%; p<0.001). The adjusted OR of survival to hospital discharge for CS was 0.17 (95% CI: 0.14, 0.20) and for NS it was 0.17 (95% CI: 0.15, 0.18) with IS as the referent. CONCLUSION: After OHCA, the survival rate for CS victims is significantly lower than for IS patients. These findings suggest that CS and IS are different entities and that alternatives to existing resuscitation algorithm tailored to patients with CS should be investigated. PMID- 22490675 TI - Hybrid magnetite nanoparticles/Rosmarinus officinalis essential oil nanobiosystem with antibiofilm activity. AB - Biofilms formed by fungal organisms are associated with drastically enhanced resistance against most antimicrobial agents, contributing to the persistence of the fungi despite antifungal therapy. The purpose of this study is to combine the unique properties of nanoparticles with the antimicrobial activity of the Rosmarinus officinalis essential oil in order to obtain a nanobiosystem that could be pelliculised on the surface of catheter pieces, in order to obtain an improved resistance to microbial colonization and biofilm development by Candida albicans and C. tropicalis clinical strains. The R. officinalis essential oils were extracted in a Neo-Clevenger type apparatus, and its chemical composition was settled by GC-MS analysis. Functionalized magnetite nanoparticles of up to 20 nm size had been synthesized by precipitation method adapted for microwave conditions, with oleic acid as surfactant. The catheter pieces were coated with suspended core/shell nanoparticles (Fe3O4/oleic acid:CHCl3), by applying a magnetic field on nanofluid, while the CHCl3 diluted essential oil was applied by adsorption in a secondary covering treatment. The fungal adherence ability was investigated in six multiwell plates, in which there have been placed catheters pieces with and without hybrid nanoparticles/essential oil nanobiosystem pellicle, by using culture-based methods and confocal laser scanning microscopy (CLSM). The R. officinalis essential oil coated nanoparticles strongly inhibited the adherence ability and biofilm development of the C. albicans and C. tropicalis tested strains to the catheter surface, as shown by viable cell counts and CLSM examination. Due to the important implications of Candida spp. in human pathogenesis, especially in prosthetic devices related infections and the emergence of antifungal tolerance/resistance, using the new core/shell/coated shell based on essential oil of R. officinalis to inhibit the fungal adherence could be of a great interest for the biomedical field, opening new directions for the design of film-coated surfaces with antibiofilm properties. PMID- 22490676 TI - Antibodies causing thrombocytopenia in patients treated with RGD-mimetic platelet inhibitors recognize ligand-specific conformers of alphaIIb/beta3 integrin. AB - Arginine-glycine-aspartic acid (RGD)-mimetic platelet inhibitors act by occupying the RGD recognition site of alpha(IIb)/beta(3) integrin (GPIIb/IIIa), thereby preventing the activated integrin from reacting with fibrinogen. Thrombocytopenia is a well-known side effect of treatment with this class of drugs and is caused by Abs, often naturally occurring, that recognize alpha(IIb)/beta(3) in a complex with the drug being administered. RGD peptide and RGD-mimetic drugs are known to induce epitopes (ligand-induced binding sites [LIBS]) in alpha(IIb)/beta(3) that are recognized by certain mAbs. It has been speculated, but not shown experimentally, that Abs from patients who develop thrombocytopenia when treated with an RGD-mimetic inhibitor similarly recognize LIBS determinants. We addressed this question by comparing the reactions of patient Abs and LIBS-specific mAbs against alpha(IIb)/beta(3) in a complex with RGD and RGD-mimetic drugs, and by examining the ability of selected non-LIBS mAbs to block binding of patient Abs to the liganded integrin. Findings made provide evidence that the patient Abs recognize subtle, drug-induced structural changes in the integrin head region that are clustered about the RGD recognition site. The target epitopes differ from classic LIBS determinants, however, both in their location and by virtue of being largely drug-specific. PMID- 22490677 TI - Sequence and structure relationships within von Willebrand factor. AB - In the present study, we re-annotated von Willebrand factor (VWF), assigned its entire sequence to specific modules, and related these modules to structure using electron microscopy (EM). The D domains are assemblies of smaller modules visible as lobes in EM. Modules in the D-domain assemblies include von Willebrand D, 8 cysteine, trypsin inhibitor-like, E or fibronectin type 1-like domains, and a unique D4N module in D4. The D1-D2 prodomain shows 2 large connected assemblies, each containing smaller lobes. The previous B and C regions of VWF are re annotated as 6 tandem von Willebrand C (VWC) and VWC-like domains. These 6 VWC domains correspond to 6 elongated domains that associate in pairs at acidic pH in the stem region of VWF dimeric bouquets. This correspondence is demonstrated by binding of integrin alpha(IIb)beta(3) to the fourth module seen in EM, VWC4, which bears the VWF Arg-Gly-Asp motif. The C-terminal cystine knot domain dimerizes end-to-end in a manner predicted by homology to TGF-beta and orients approximately perpendicular to the VWC domains in dimeric bouquets. Homologies of domains in VWF to domains in other proteins allow many disulfide bonds to be tentatively assigned, which may have functional implications. PMID- 22490679 TI - Matrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase. AB - Lymphatic dysfunctions are associated with several human diseases, including lymphedema and metastatic spread of cancer. Although it is well recognized that lymphatic capillaries attach directly to interstitial matrix mainly composed of fibrillar type I collagen, the interactions occurring between lymphatics and their surrounding matrix have been overlooked. In this study, we demonstrate how matrix metalloproteinase (MMP)-2 drives lymphatic morphogenesis through Mmp2-gene ablation in mice, mmp2 knockdown in zebrafish and in 3D-culture systems, and through MMP2 inhibition. In all models used in vivo (3 murine models and thoracic duct development in zebrafish) and in vitro (lymphatic ring and spheroid assays), MMP2 blockage or down-regulation leads to reduced lymphangiogenesis or altered vessel branching. Our data show that lymphatic endothelial cell (LEC) migration through collagen fibers is affected by physical matrix constraints (matrix composition, density, and cross-linking). Transmission electron microscopy and confocal reflection microscopy using DQ-collagen highlight the contribution of MMP2 to mesenchymal-like migration of LECs associated with collagen fiber remodeling. Our findings provide new mechanistic insight into how LECs negotiate an interstitial type I collagen barrier and reveal an unexpected MMP2-driven collagenolytic pathway for lymphatic vessel formation and morphogenesis. PMID- 22490678 TI - Hematopoietic stem cells lacking Ott1 display aspects associated with aging and are unable to maintain quiescence during proliferative stress. AB - Aging degrades hematopoietic stem cell (HSC) functions, including stress response; however, the involved molecular pathways are incompletely defined. Murine BM conditionally deleted for One-Twenty-Two-1 (Ott1), is able to maintain lifelong hematopoiesis and has preserved numbers of long-term HSCs, yet cannot repopulate nor sustain itself after transplantation against a competitor even when Ott1 is excised after engraftment. We show, specifically under replicative stress, that Ott1-deleted HSCs have a significant reduction of the G(0) cell cycle fraction associated with self-renewal and undergo early failure. Therefore, Ott1 is required to preserve HSC quiescence during stress but not steady-state hematopoiesis. Reduced tolerance of replicative stress, increased myeloid potential, and greater absolute numbers are mutual characteristics of both Ott1 deleted and aged HSCs, and comparison of their gene expression profiles reveals a shared signature. Ott1-deleted HSCs share multiple aging-associated physiologic changes, including increases in NF-kappaB activation and DNA damage. Loss of Ott1 causes increased reactive oxygen species; however, antioxidant treatment does not rescue the competitive defect, indicating the existence of additional essential Ott1-dependent HSC pathways. In conclusion, our data establish a requirement for Ott1 in stress hematopoiesis and suggest that Ott1-dependent processes may converge with those affected by aging. PMID- 22490680 TI - Immunostimulatory conventional dendritic cells evolve into regulatory macrophage like cells. AB - Dendritic cell (DC) homeostasis in peripheral tissues reflect a balance between DC generation, migration, and death. The current model of DC ontogeny indicates that pre-cDCs are committed to become terminal conventional DCs (cDCs). Here, we report the unexpected finding that proliferating immunostimulatory CD11c(+) MHC class II(+) cDCs derived from pre-cDCs can lose their DC identity and generate progeny that exhibit morphologic, phenotypic, and functional characteristics of regulatory macrophages. DC-derived-macrophages (DC-d-Ms) potently suppress T-cell responses through the production of immunosuppressive molecules including nitric oxide, arginase, and IL-10. Relative deficiency of granulocyte-macrophage colony stimulating factor (GM-CSF) provided a permissive signal for DC-d-M generation. Using a transgenic mouse model that allows tracking of CD11c(+) cells in vivo, we found that DC-d-M development occurs commonly in cancer, but not in lymphoid or nonlymphoid tissues under steady-state conditions. We propose that this developmental pathway serves as an alternative mechanism of regulating DC homeostasis during inflammatory processes. PMID- 22490681 TI - Maturing reticulocytes internalize plasma membrane in glycophorin A-containing vesicles that fuse with autophagosomes before exocytosis. AB - The erythrocyte is one of the best characterized human cells. However, studies of the process whereby human reticulocytes mature to erythrocytes have been hampered by the difficulty of obtaining sufficient numbers of cells for analysis. In the present study, we describe an in vitro culture system producing milliliter quantities of functional mature human adult reticulocytes from peripheral blood CD34(+) cells. We show that the final stage of reticulocyte maturation occurs by a previously undescribed mechanism in which large glycophorin A-containing vesicles forming at the cytosolic face of the plasma membrane are internalized and fuse with autophagosomes before expulsion of the autophagosomal contents by exocytosis. Early reticulocyte maturation is characterized by the selective elimination of unwanted plasma membrane proteins (CD71, CD98, and beta1 integrin) through the endosome-exosome pathway. In contrast, late maturation is characterized by the generation of large glycophorin A-decorated vesicles of autophagic origin. PMID- 22490682 TI - Chronic HIV infection affects the expression of the 2 transcription factors required for CD8 T-cell differentiation into cytolytic effectors. AB - CD8 T cells lose the capacity to control HIV infection, but the extent of the impairment of CD8 T-cell functions and the mechanisms that underlie it remain controversial. Here we report an extensive ex vivo analysis of HIV-specific CD8 T cells, covering the expression of 16 different molecules involved in CD8 function or differentiation. This approach gave remarkably homogeneous readouts in different donors and showed that CD8 dysfunction in chronic HIV infection was much more severe than described previously: some Ifng transcription was observed, but most cells lost the expression of all cytolytic molecules and Eomesodermin and T-bet by chronic infection. These results reveal a cellular mechanism explaining the dysfunction of CD8 T cells during chronic HIV infection, as CD8 T cells are known to maintain some functionality when either of these transcription factors is present, but to lose all cytotoxic activity when both are not expressed. Surprisingly, they also show that chronic HIV and lymphocytic choriomeningitis virus infections have a very different impact on fundamental T cell functions, "exhausted" lymphocytic choriomeningitis virus-specific cells losing the capacity to secrete IFN-gamma but maintaining some cytotoxic activity as granzyme B and FasL are overexpressed and, while down-regulating T-bet, up regulating Eomesodermin expression. PMID- 22490683 TI - Abnormalities in IgA and IgM are associated with treatment-resistant ITP. AB - We hypothesized that immune dysregulation, as represented by abnormal immunoglobulin (Ig) levels, may increase immune thrombocytopenia (ITP) severity. A cross-sectional analysis was performed encompassing patients with ITP seen at the New York Presbyterian Platelet Disorder Center in the past 10 years. The subjects' Ig levels were measured, and subjects were analyzed for differences in treatment response. Subjects with an IgA level greater than median had a significantly increased chance of failing to respond to standard treatment (steroids, intravenous Ig, and intravenous anti-D) than did subjects with an IgA level lower than median (37 of 271, 14%; vs 22 of 281, 8%; P = .03) and an increased risk for bleeding (36 of 378, 10%; vs 19 of 386, 5%; P = .02). Subjects with an IgM less than 56 (lower limit of normal) failed to respond to standard treatment more often than patients with a normal IgM (12 of 67, 18%; vs 44 of 467, 9%; P = .05) with a trend toward worsened response to splenectomy (3 of 18, 17%; vs 36 of 86, 42%; P = .06). These observations suggest that immune dysregulation, as represented by elevations in IgA or decreased levels of IgM, are associated with ITP that is more resistant to treatment. PMID- 22490685 TI - [The origin and evolution of academic medicine as well as its revelation to China]. PMID- 22490686 TI - [Consensus of the Chinese Specialists for Diagnosis, treatment & control of Acinetobacter baumannii infection]. PMID- 22490684 TI - Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta thalassemia. AB - Inappropriately low expression of the key iron regulator hepcidin (HAMP) causes iron overload in untransfused patients affected by beta-thalassemia intermedia and Hamp modulation provides improvement of the thalassemic phenotype of the Hbb(th3/+) mouse. HAMP expression is activated by iron through the bone morphogenetic protein (BMP)-son of mothers against decapentaplegic signaling pathway and inhibited by ineffective erythropoiesis through an unknown "erythroid regulator." The BMP pathway is inactivated by the serine protease TMPRSS6 that cleaves the BMP coreceptor hemojuvelin. Here, we show that homozygous loss of Tmprss6 in Hbb(th3/+) mice improves anemia and reduces ineffective erythropoiesis, splenomegaly, and iron loading. All these effects are mediated by Hamp up-regulation, which inhibits iron absorption and recycling. Because Hbb(th3/+) mice lacking Tmprss6 show residual ineffective erythropoiesis, our results indicate that Tmprss6 is essential for Hamp inhibition by the erythroid regulator. We also obtained partial correction of the phenotype in Tmprss6 haploinsufficient Hbb(th3/+) male but not female mice and showed that the observed sex difference reflects an unequal balance between iron and erythropoiesis-mediated Hamp regulation. Our study indicates that preventing iron overload improves beta-thalassemia and strengthens the essential role of Tmprss6 for Hamp suppression, providing a proof of concept that Tmprss6 manipulation can offer a novel therapeutic option in this condition. PMID- 22490687 TI - [Effects of soluble epoxide hydrolase inhibitors on the expression of fatty acid synthase in peripheral blood mononuclear cell of patients and inflammatory response with acute coronary syndrome]. AB - OBJECTIVE: To explore the effects of soluble epoxide hydrolase inhibitor (sEHi) on the expressions of fatty acid synthase (FASN) mRNA and protein in peripheral blood mononuclear cell (PBMCs) of patients with acute coronary syndrome (ACS) and to discuss the influences of sEHi in the regulated expression of FASN and inflammatory reaction. METHODS: The hospitalized ACS patients were selected as the ACS group (n = 35) while the healthy normal subjects as the control group (n = 30). The levels of lipoproteins, fasting blood glucose, myocardial enzyme and hs-CRP (high-sensitive C-reactive protein) were measured within 24 hours after admission. Meanwhile the PBMCs were separated and cultured and then t-AUCB was added in various concentrations (0, 1, 10, 50, 100 umol/L). The cellular expressions of FASN, IL-6 mRNA and protein were detected by real-time PCR (polymerase chain reaction) and Western blot respectively. RESULTS: (1) The serum concentration of hs-CRP reached (5.6 +/- 4.1) mg/L in the ACS group. And it was obviously higher than (1.3 +/- 0.9) mg/L in the control group (P < 0.05). Compared with the control group, the expression levels of FASN, IL-6 mRNA and protein significantly increased in the ACS group (the relative expression amount of FASN mRNA: 1 vs 1.709 +/- 0.272, FASN protein: 0.407 +/- 0.065 vs 1.298 +/- 0.087; relative expression amount of IL-6 mRNA: 1 vs 2.302 +/- 0.200, IL-6 protein: 0.715 +/- 0.058 vs 1.146 +/- 0.083, P < 0.05). Moreover, the levels of FASN and IL-6 mRNA had positive correlations with the serum concentration of hs CRP (r = 0.714, P < 0.01; r = 0.685, P < 0.01). (2) Compared with the control group (t-AUCB 0 umol/L), 10, 50, 100 umol/L t-AUCB had inhibited the expressions quantity of FASN, IL-6 mRNA and protein in PBMCs from the ACS group (P < 0.05). The relative expressions of FASN mRNA in t-AUCB 0, 10, 50, 100 umol/L group were 1, 0.813 +/- 0.038, 0.564 +/- 0.100, 0.293 +/- 0.043 respectively. The relative expressions of FASN protein in t-AUCB 0, 10, 50 and 100 umol/L group were 0.957 +/- 0.280, 0.935 +/- 0.275, 0.855 +/- 0.253, 0.685 +/- 0.206 respectively. CONCLUSION: The inflammatory level increases obviously in the ACS group. And the expression level of FASN in PBMCs is closely correlated with the inflammatory level in the ACS patients; t-AUCB may prevent the ruptures of atherosclerotic lesions by regulating FASN and inhibiting inflammatory reactions in ACS patients. PMID- 22490688 TI - [Outcomes of chronic radiation intestinal injury treated with surgical interventions]. AB - OBJECTIVE: To explore the surgical approaches and clinical outcomes of chronic radiation intestinal injury (CRII). METHODS: From January 1, 2001 to December 31, 2010, at Department of Surgery, Nanjing General Hospital of Nanjing Command a consecutive series of 206 CRII patients undergoing surgical interventions was reviewed retrospectively. There were 64 males and 142 females with an age range of (50 +/- 11) years old. The indications, surgical approaches, surgical complications and mortality were analyzed. RESULTS: 206 CRII patients received 229 surgical treatment, 31 patients underwent two or more operations. The course of surgical interventions included intestinal obstruction (n = 142), intestinal fistula (n = 56), proctitis (n = 12), bleeding (n = 6) and others (n = 13). They underwent 229 laparotomies including intestinal resection and primary anastomosis (n = 142), intestinal resection and enterostomy (n = 57), exclusion of radiation related gastrointestinal diseases (n = 14) and other procedures (n = 16). The occurrence rate of postoperative intestinal complications was 25.7% (53/206). Five patients (2.4%) died within the postoperative 28 days. CONCLUSION: Surgery is often required for patients with chronic radiation-induced intestinal obstruction, fistula, hemorrhage and perforation, etc. Resection and primary anastomosis with undamaged segments may be performed safely in selected patients. And a judicious use of stoma can reduce the rates of major surgical mortality and morbidity. PMID- 22490689 TI - [Association between serum adipocyte fatty acid binding protein level and dyslipidemia in patients with obstructive sleep apnea syndrome]. AB - OBJECTIVE: To explore the association between serum adipocyte fatty acid binding protein (A-FABP) levels and dyslipidemia in patients with obstructive sleep apnea syndromes (OSAS). METHODS: Eighty snoring patients were monitored by overnight polysomnography (PSG) in Second Affiliated Hospital of Soochow University from November 2010 to May 2011. There were 63 males and 17 females with a mean age of (48 +/- 14) years (range: 22 - 77 years). Based on the results of apnea-hypopnea index (AHI), they were divided into 3 groups: primary snoring group (AHI < 5/h, n = 19), mild-moderate OSAS group (5/h <= AHI <= 40/h, n = 22) and severe OSAS group (AHI > 40/h, n = 39). The levels of A-FABP, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured and compared between the primary snoring group and OSAS patients of different severities. And the correlations between serum A-FABP and plasma lipid as well as PSG parameters were further evaluated by partial correlation analysis. RESULTS: Compared with the primary snoring group ((15.7 +/- 3.3) ug/L) and mild-moderate group ((17.3 +/- 4.3) ug/L), there was a significant elevation of serum A-FABP level in the severe OSAS group ((20.4 +/- 4.6) ug/L) (P = 0.001, P = 0.026). Additionally, after adjustment for body mass index and age, the serum A-FABP level showed significant positive correlations with TC, TG and LDL-C (r = 0.469, P = 0.000; r = 0.239, P = 0.035 and r = 0.366, P = 0.001). Serum A-FABP level was positively correlated with AHI and the time of oxygen saturation (SaO2) < 90% (r = 0.231, P = 0.042 and r = 0.226, P = 0.047). Nevertheless, the serum A-FABP level showed significant negative correlations with the lowest SaO2 and the mean SaO2 (r = -0.234, P = 0.039 and r = -0.270, P = 0.017). CONCLUSION: Dyslipidemia and elevated level of serum A-FABP are common in OSAS patients. PMID- 22490690 TI - [Evaluation of short-term efficacy and safety after laparoscopic resection for mid-low rectal cancer]. AB - OBJECTIVE: To investigate the safety, feasibility and short-term efficacy of laparoscopic surgery in patients with middle-low rectal cancer. METHODS: From January 2008 to January 2010, a total of 108 patients with middle-low rectal cancer at Department of Gastrointestinal Surgery, Affiliated Tumor Hospital, Xinjiang Medical University were divided into 2 groups by different treatments: laparoscopic resection group (LR, n = 63) and conventional open resection group (OR, n = 45). The choice of two surgical options was based on patient's desire. The outcomes of two patient groups with radical surgery were prospectively evaluated. RESULTS: Seven cases were converted into open surgery from the laparoscopic group. The operative durations in the LR and OR groups were (246 +/- 57) min and (229 +/- 53) min respectively (P > 0.05). The laparoscopic group had a lesser amount of blood loss during surgery ((51 +/- 20) ml vs (110 +/- 41) ml, P < 0.05). The time needed for the recovery of gastrointestinal functions in the laparoscopic group was significantly shorter than that in the open surgery group ((3.0 +/- 0.8) d vs (3.7 +/- 1.3) d, P < 0.05). In terms of the length of specimen, the range of radical surgery and the rate of complication, no significant difference were found between two groups (all P > 0.05). The numbers of dissected lymph nodes were 13 and 12 cases respectively (P > 0.05). No instance of incision implantation, local recurrence or short-term death was found in neither group. There was 2 cases with lung metastasis in the LR group and 2 cases with the metastasis of liver and lung in the OR group. CONCLUSION: As a safe, feasible, effective and mini-invasive with similar radical resection and satisfactory short-term outcomes, laparoscopic surgery for low-middle rectal cancer has better prospects in the future. PMID- 22490691 TI - [Risks of type 2 diabetes mellitus and impaired glucose regulation among elderly patients with essential hypertension: a 10-years cohort study]. AB - OBJECTIVE: To explore the incidence of type 2 diabetes mellitus (T2DM) and impaired glucose regulation (IGR) among elderly patients with and without hypertension during a follow-up period of 10 years. METHODS: The subjects were elderly patients (> 60 years old) undergoing annual health examinations at our hospital. And the previously diagnosed T2DM and IGR patients were excluded. And the incidence and risk factors were analyzed by Kaplan-Meier method and COX's proportional hazard. RESULTS: Among a total of 1136 subjects, 582 were enrolled. They were divided into essential hypertension group (HT, n = 384) and non essential hypertension group (NHT, n = 198) (including new-onset 67 subjects). During a 10-year follow-up, the incidence of new-onset diabetes was 27.6% in HT group and 18.7% in NHT group (HR = 1.48; 95%CI: (1.07 - 2.04), P < 0.05). And the incidence density of T2DM were 33.80/00 and 20.60/00 respectively in two groups. There was no difference in the prevalence of IGR among HT and NHT groups and no difference was found in the prevalence of T2DM or IGR among new-onset HT and NHT groups. The independent risk factors of T2DM was dyslipidemia (HR = 1.459; 95%CI: 1.027 - 2.072, P < 0.05) and hypertension (HR = 1.516; 95%CI: 1.039 - 2.212, P < 0.05) based upon the COX's proportional hazard analysis. Dyslipidemia (HR = 1.545; 95%CI: 1.087 - 2.195, P < 0.05) and hypertension (HR = 1.524; 95%CI: 1.044 - 2.224, P < 0.05) were also independent risk factors of abnormal glycometabolism (T2DM and IGR). Kaplan-Meier analysis indicated that the accumulative incidence of DM and abnormal glycometabolism was different between the HT and NHT groups. CONCLUSION: The DM risk is 1.516 folds higher in elderly patients with HT than in those without. According to multivariate analysis, hypertension and dyslipidemia are independent risk factors of T2DM and abnormal glycometabolism (T2DM and IGR). PMID- 22490692 TI - [Expression and significance of E-cadherin in adenoid cystic carcinoma of salivary glands]. AB - OBJECTIVE: To examine the expression of E-cadherin and the methylation status of CDH1 and explore their clinical significance in salivary adenoid cystic carcinoma (SACC). METHODS: The expression of E-cadherin was detected by the immunohistochemical method. And the methylation of CDH1 gene promoter 5'-CpG island was analyzed by real-time methylation-specific polymerase chain reaction (real-time MSP) in salivary adenoid cystic carcinoma and normal salivary gland tissue respectively. RESULTS: The expression rate of E-cadherin was lower in SACC than that in normal salivary gland tissue (100.0% vs 55.6%, P < 0.05). And the expression of E-cadherin was associated with different histopathological types, T stage, nerve invasion, lymphatic and distant metastasis (P < 0.05). However, there was no correlation between the expression of E-cadherin and gender, age and tumor location. Partial methylation of CDH1 was detected in 3 of 30 cases with a positive expression of E-cadherin and full methylation of CDH1 in 23 of 24 cases with a negative expression of E-cadherin. There was a negative correlation between the expression of E-cadherin and the methylation of CDH1 in salivary adenoid cystic carcinoma (r = -0.483, P < 0.001). CONCLUSION: The down-regulation of E-cadherin, as modulated by the methylation of CDH1, may contribute to nerve invasion, lymphatic and distant metastasis in SACC. Thus it may be used as a biological indicator of malignancy and prognosis. PMID- 22490693 TI - [Clinical trial of sexual dysfunctions in male patients with pituitary adenomas]. AB - OBJECTIVE: To explore the clinical features and related factors of sexual dysfunctions in male patients with pituitary adenomas. METHODS: The questionnaires of sexual functions were collected from 86 male patients with pituitary adenomas. We examined the clinical features of sexual dysfunctions and analyzed the correlations between sexual behaviors and age, tumor type, invasiveness, tumor size, serum levels of prolactin (PRL) and testosterone. RESULTS: The incidence of sexual dysfunctions was 80.2% (69/86). Sexual dysfunctions were found in 84.6% (66/78) of the patients with functioning pituitary adenomas and 37.5% (3/8) of those with non-functioning pituitary adenoma respectively. In the PRL group, the incidence of erectile dysfunctions was 92.1% (35/38) and it was higher than those in the FSH (follicle-stimulating hormone) and GH (growth hormone) groups (P < 0.05). In the FSH group, the incidence of reduced sexual desire was 78.3% (18/23). In the GH group, the incidence of erectile dysfunctions was 70.6% (12/17) and the incidence of reduced sexual desire or ejaculation dysfunction was lower than that of the PRL/FSH group (P < 0.05). CONCLUSION: The incidence of sexual dysfunctions is quite high in males with pituitary adenomas, especially for those with functioning pituitary adenomas. The clinical features of sexual dysfunctions vary in different types of functioning pituitary adenoma. The incidence of erectile dysfunctions is the highest in the PRL group. Pathological type of pituitary tumors is a major risk factor of sexual dysfunctions. PMID- 22490694 TI - [A novel technique of ureterointestinal anastomosis for urinary diversion]. AB - OBJECTIVE: To introduce a novel technique of ureterointestinal anastomosis for urinary diversion and report the preliminary clinical data. METHODS: Between June 2007 and June 2011, a total of 50 patients underwent radical cystectomy and ileal neobladder for invasive bladder carcinoma or carcinoma in situ. A novel, separate and direct end-to-end technique for ureteral reimplantation to the entrance of a segment of ileum was applied. in all patients. Details are as follow. The entrance of afferent loop was divided equally in to two lumens. Then each ureter was directly, end-to-end anastomosed to the above lumens respectively after lengthwise incisions for 1.5 cm. The mean follow-up period was 22 months (range, 3 - 48 months). RESULTS: Ureterointestinal anastomosis was performed successfully in 100 units. The operative durations were (18.4 +/- 4.2) minutes. Ureteral stricture developed in 4 of 100 (4%) units and refluxing in 6 of 100 (6%) units. One patient with stricture was successful repaired by balloon dilation. CONCLUSION: With low stricture and reflux rates, this novel procedure of ureterointestinal anastomosis is simple to handle and worthy of further promotion. PMID- 22490695 TI - [Diagnostic value of soluble B7-H4 in malignant pleural effusion]. AB - OBJECTIVE: To explore the diagnostic value of soluble B7-H4 (sB7-H4) in tuberculous pleural effusion and malignant pleural effusion. METHODS: A total of 98 patients of pleural effusion treated in Nanjing Chest Hospital from January 2007 to December 2009 were enrolled. The etiologies were tuberculous (n = 48) and malignant (n = 50). The levels of sB7-H4 in pleural effusion were detected by sandwich enzyme linked immunosorbent assay. The rational clinical diagnostic value was established by receiver operating characteristic (ROC) curves. RESULTS: The level of sB7-H4 in malignant pleural effusion was significant higher than that in tuberculous effusion ((65.7 +/- 5.8) vs (28.6 +/- 8.7) ug/L, P < 0.05). The cut-off value of sB7-H4 was 36.5 ug/L for malignant pleural effusion. And the rates of sensitivity, specificity and accuracy were 92.0%, 83.3% and 87.8% respectively. CONCLUSION: The level of sB7-H4 may be used as a valuable parameter in the differentiation of tuberculous from malignant effusion. PMID- 22490696 TI - [Ocular features of multiple endocrine neoplasia type 2b]. AB - OBJECTIVE: To analyze the ocular features of multiple endocrine neoplasia type 2b (MEN 2b). METHODS: Three cases with MEN 2b were reviewed and their ocular features analyzed. RESULTS: All patients had medullary thyroid carcinoma and thickened corneal nerve fibers. Adrenal pheochromocytoma, oral mucosal neuroma, marfanoid body habitus, eyelid nodule and conjunctival nodule were found in two patients. And iris nodule was found in one patient. CONCLUSIONS: The most common ocular manifestations of MEN 2b is thickened corneal nerve fibers. PMID- 22490697 TI - [Percutaneous nephroscopic 2 um laser incision and drainage treatment of peripelvic renal cysts]. AB - OBJECTIVE: To explore the surgical approaches, efficacy and safety of percutaneous nephroscopic 2 um laser incision and drainage in the treatment of peripelvic renal cysts. METHODS: The peripelvic renal cysts were punctured percutaneously. A 1.5 - 4.0 cm incision was made at thin avascular area between cyst and pelvis by the 2 um laser to connect the cyst with the renal collecting system with the help of injecting methylene blue solution into renal pelvis through ureteral catheter. The double-J tube was placed for drainage. RESULTS: The operations were successful in all cases. There were 16 males and 15 females with a mean age of 49 years old. The operative durations ranged from 25 to 120 minutes. And no severe complications occurred. The patients were followed up for an average of 12 months (range: 3 - 36). Among them, cysts disappeared in 18 cases and diminished over 1/3 in 13 cases. There was no recurrence of peripelvic renal cyst. CONCLUSION: Percutaneous nephroscopic 2 um laser incision and drainage for peripelvic renal cyst is safe, effective and mini-invasive. PMID- 22490698 TI - [Role of auto-secreted interferon alpha in all-trans retinoic acid-induced expression of RIG-G gene]. AB - OBJECTIVE: To explore the relationship between interferon (IFN) alpha and all trans retinoic acid (ATRA)-induced signaling pathways in the expression of retinoic acid-induced gene G (RIG-G). METHODS: Acute promyelocytic leukemia cell line NB4 and signal transducer and activator of transcription (STAT)1-deficient U3A cells were used. The protein levels of tyrosine-phosphorylated STAT2 in ATRA treated NB4 cells were detected by Western blot. The culture supernatants of NB4 cells treated with ATRA for different time or U3A cells transfected with interferon regulatory factor (IRF)-1 were respectively collected. And the concentration of IFN-alpha was determined by enzyme-linked immunosorbent assay (ELISA). The effects of NB4 cell culture supernatants on the phosphorylation of STAT2 and the expression of RIG-G were detected by Western blot. RESULTS: The level of phosphorylated-STAT2 was obviously up-regulated in NB4 cells treated with ATRA for 72 hours, as well as the concentration of IFN-alpha in culture supernatants. The concentration of IFN-alpha increased from (1.5 +/- 0.5) pg/ml in the untreated group to (7.6 +/- 0.3) pg/ml (P < 0.05). After a 96-hour treatment, the concentration of IFN-alpha was up to (63.8 +/- 5.8) pg/ml. And these culture supernatants could induce the tyrosine phosphorylation of STAT2 and up-regulate the protein level of RIG-G. As for U3A cells transfected with IRF-1, the concentration of IFN-alpha from the culture supernatant also increased 3-fold versus the control group transfected with empty vectors [(8.8 +/- 1.4) pg/ml vs (3.4 +/- 0.4) pg/ml, P < 0.05]. CONCLUSIONS: RIG-G gene expression is closely correlated with the cross-talk between ATRA and IFN-alpha-induced signaling pathways. ATRA increases the secretion of IFN-alpha by up-regulating the protein level of IRF-1. Then the secreted IFN-alpha may induce the phosphorylation of STAT2 and reinforce the expression of RIG-G. PMID- 22490699 TI - [Insulin-like growth factor-1 gene therapy improves the levels of mRNA and protein of endothelial nitric oxide synthase in aging related erectile dysfunction in rats]. AB - OBJECTIVE: To explore the effects of gene transfer of insulin like growth factor 1 (IGF-1) on the penis of senile rats and the altered levels of mRNA and protein of endothelial nitric oxide synthase (eNOS). METHODS: Ten young (4 months) and 20 senile (24 months) Sprague-Dawley male rats were selected. The senile rats were divided into 2 groups: phosphate buffer solution (PBS)-only (n = 10) and 100 ug IGF-1 plasmid treatment group (n = 10). After a 4-week injection of IGF-1, the responses of intracavernous pressure (ICP) with electrical stimulation to the cavernous nerve and systemic mean arterial pressure (MAP) were evaluated. In the control and transfected senile rats, the levels of eNOS mRNA and protein were examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot respectively. RESULTS: The ICP/MAP and total ICP were significantly higher in the young control group versus the PBS-only group at Week 4 (P < 0.05). The ICP/MAP and total ICP were significantly higher in the young control group and the 100 ug IGF-1 treatment group versus the PBS-only group at Week 4 (P < 0.05). The levels of mRNA and protein of eNOS were higher in the 100 ug IGF-1 treatment group versus the PBS-only group at Week 4 (0.62 +/- 0.16 vs 0.25 +/- 0.08, 0.71 +/- 0.19 vs 0.27 +/- 0.09, both P < 0.05, respectively). CONCLUSION: The gene therapy of IGF-1 can ameliorate erectile functions and improve the levels of mRNA and protein of eNOS in senile rats. PMID- 22490700 TI - Phosphorylation of deoxycytidine kinase on Ser-74: impact on kinetic properties and nucleoside analog activation in cancer cells. AB - Deoxycytidine kinase (dCK) (EC 2.7.1.74) is a key enzyme in the activation of several therapeutic nucleoside analogs (NA). Its activity can be increased in vivo by Ser-74 phosphorylation, a property that could be used for enhancing NA activation and clinical efficacy. In line with this, studies with recombinant dCK showed that mimicking Ser-74 phosphorylation by a S74E mutation increases its activity toward pyrimidine analogs. However, purine analogs had not been investigated. Here, we show that the S74E mutation increased the k(cat) for cladribine (CdA) by 8- or 3-fold, depending on whether the phosphoryl donor was ATP or UTP, for clofarabine (CAFdA) by about 2-fold with both ATP and UTP, and for fludarabine (F-Ara-A) by 2-fold, but only with UTP. However, the catalytic efficiencies (k(cat)/Km) were not, or slightly, increased. The S74E mutation also sensitized dCK to feed-back inhibition by dCTP, regardless of the phosphoryl donor. Importantly, we did not observe an increase of endogenous dCK activity toward purine analogs after in vivo-induced increase of Ser-74 phosphorylation. Accordingly, treatment of CLL cells with aphidicolin, which enhances dCK activity through Ser-74 phosphorylation, did not modify the conversion of CdA or F-Ara-A into their active triphosphate form. Nevertheless, the same treatment enhanced activation of gemcitabine (dFdC) into dFdCTP in CLL as well as in HCT-116 cells and produced synergistic cytotoxicity. We conclude that increasing phosphorylation of dCK on Ser-74 might constitute a valuable strategy to enhance the clinical efficacy of some NA, like dFdC, but not of CdA or F-Ara-A. PMID- 22490701 TI - Rottlerin potentiates camptothecin-induced cytotoxicity in human hormone refractory prostate cancers through increased formation and stabilization of topoisomerase I-DNA cleavage complexes in a PKCdelta-independent pathway. AB - Combination therapy, which can optimize killing activity to cancers and minimize drug resistance, is a mainstream therapy against hormone-refractory prostate cancers (HRPCs). Rottlerin, a natural polyphenolic component, synergistically increased PC-3 (a HRPC cell line) apoptosis induced by camptothecin (a topoisomerase I inhibitor). Using siRNA technique to knockdown protein kinase C delta (PKCdelta), the data showed that rottlerin-mediated synergistic effect was PKCdelta-independent, although rottlerin has been used as a PKCdelta inhibitor. Rottlerin potentiated camptothecin-induced DNA fragmentation at S phase and ATM phosphorylation at Ser1981. The effect was correlated to apoptosis (r2 = 0.9). To detect upstream signals, the data showed that camptothecin acted on and stabilized topoisomerase I-DNA complex, leading to the formation of camptothecin trapped cleavage complexes (TOP1cc). The effect was potentiated by rottlerin. To determine DNA repair capability, the time-related gammaH2A.X formation was examined after camptothecin removal. Consequently, rottlerin significantly inhibited camptothecin removal-mediated decline of gammaH2A.X formation at S phase, indicating the impairment of DNA repair activity in the presence of rottlerin. The combinatory treatment of camptothecin and rottlerin induced conformational change and activation of Bax and formation of truncated Bad, suggesting the contribution of mitochondria stress to apoptosis. In summary, the data suggest that rottlerin-mediated camptothecin sensitization is through the augmented stabilization of TOP1cc, leading to an increase of DNA damage stress and, possibly, an impairment of DNA repair capability. Subsequently, mitochondria involved apoptosis is triggered through Bax activation and truncated Bad formation. The novel discovery may provide an anticancer approach of combinatory use between rottlerin and camptothecin for the treatment of HRPCs. PMID- 22490703 TI - [Recommendations on concerning about the psychological health of cardiovascular disease]. PMID- 22490702 TI - Tissue-specific effects of allergic rhinitis in mouse nasal epithelia. AB - Allergic rhinitis (AR) can cause significant olfactory loss, but few studies have specifically investigated AR effects on olfactory and nasal respiratory tissues per se. To address this, we used a murine AR protocol employing nasal allergen infusion for both sensitization and challenges. Seven- to 11-week BALB/c mice were bilaterally infused with 1% ovalbumin (OVA) in phosphate-buffered saline (PBS) or PBS alone for 6 or 11 weeks, given single bilateral PBS or OVA infusions 24 h before sacrifice, or left untreated. High OVA-specific IgE serum levels and eosinophil infiltration confirmed AR induction. Olfactory (OE) and respiratory (RE) epithelia showed distinctly different responses, most conspicuously, massive eosinophil infiltration of immediately RE-subjacent lamina propria. In OE, such infiltration was minimal. Significant RE hypertrophy and hyperplasia also occurred, although OE organization was generally maintained and extensive disruption localized despite a 20% reduction in sensory neurons and globose basal cells after 11 weeks OVA. Pronounced Bowman's gland hypertrophy crowded both OE and olfactory nerve bundles. Cellular proliferation was widely distributed in RE but in OE was localized to normally thinner OE and RE-proximal OE, suggesting possible indirect RE influences. Terminal deoxynucleotide transferase (TdT) nick end labeling was greater in OE than RE and, in contrast to other effects, occurred with acute infusions and chronic PBS alone, often unilaterally. Following chronic OVA, AR-related bilateral increases appeared superimposed on those. These findings indicate AR effects on olfactory function may be complex, reflecting various levels of RE/OE responses and interactions. PMID- 22490704 TI - [Pay attention to the psychological rehabilitation of patients with coronary artery disease after percutaneous coronary intervention]. PMID- 22490705 TI - [Analysis of quality of life in elderly patients with coronary artery disease after drug-eluting stent implantation]. AB - OBJECTIVE: To compare the change of quality of life (QOL) between elderly (>= 65 years) and non-elderly (< 65 years) coronary artery disease (CAD) patients after drug-eluting stents (DES) implantation. METHODS: Patients with CAD treated with DES between March 2009 and January 2010 were enrolled. All patients were prospectively interviewed at baseline and 6-month after DES implantation. Changes of overall health perception between the elderly and non-elderly patients were compared by using validated questionnaire (SF-36 health survey). RESULTS: Scores for physical component summary (PCS) and mental component summary (MCS) were significantly worse in elderly patients than in non-elderly patients both at baseline and 6 months after DES implantation (baseline: 45.3 +/- 16.2 vs. 55.6 +/ 22.2, 61.7 +/- 21.5 vs. 65.6 +/- 17.9; 6-month: 55.4 +/- 19.9 vs. 66.7 +/- 18.1, 65.9 +/- 19.8 vs. 73.6 +/- 16.8, all P < 0.05). QOL improved significantly after DES implantation for all eight scales and PCS as well as MCS in both age groups (all P < 0.01). The change of PCS score was similar between the two age groups (10.92 +/- 7.62 vs. 10.53 +/- 6.81, P = 0.43). Physiological function [22.11 (10.28 to 41.49) vs. 11.13 (-0.23 to 19.65), P < 0.01] improvement was better but the change of physical function, body pain and general health [6.65 +/- 2.45 vs. 7.65 +/- 2.16, 10.61 (4.38 - 14.47) vs. 21.20 (11.81 to 31.14), 2.10 (-2.30 to 5.70) vs. 4.72 (2.28 to 6.74), all P < 0.01] were worse in elderly patients than in non-elderly group. The improvement of MCS in non-elderly group was superior to elderly group [6.43 (3.11 to 8.70) vs. 5.52 (-1.01 to 9.33), P < 0.01] exampled by social function [8.14 (3.53 to 14.03) vs. 1.74 (-1.73 to 6.79)] and mental health score [1.26 (0.61 to 7.15) vs. 0.81 (0.59 to 7.18), all P < 0.01]. CONCLUSION: QOL is significantly improved in both elderly and non-elderly CAD patients after DES implantation. Improvement in physical health is similar between the two age groups, but the improvement of mental health is more significant in non-elderly patients than in elderly CAD patients. PMID- 22490706 TI - [Heparin induced fulminant thrombocytopenia:one case report]. PMID- 22490707 TI - [Impact of depression on prognosis of patients with coronary heart disease undergoing revascularization]. AB - OBJECTIVE: To investigate the impact of depression on clinical outcome of patients undergoing revascularization. METHODS: Self-rating depression scale (SDS) assessment was made before and after coronary artery bypass grafting (CABG, n = 345) and percutaneous coronary intervention (PCI, n = 308) procedure. Patients were divided into depression and non-depression group. All patients were followed up for 12 months after procedure for the occurrence of rehospitalization and major adverse cardiovascular events (MACE) including all-cause mortality, nonfatal myocardial infarction or target lesion revascularization. RESULTS: Depression was present in 40.9% (n = 141) of patients after CABG, which was significantly higher than before procedure (24.3%, P < 0.01). The MACE rate was significantly higher in patients with post-procedure depression [8.5% (12/141)] than in patients without depression [2.9% (6/204), P < 0.05] and the incidences of target lesion revascularization and rehospitalization were also significantly higher in depression patients than in non-depression patients during the 12 months follow-up (all P < 0.05). Depression was present in 36.4% (n = 112) of patients after PCI, which was significantly higher than that before procedure (28.6%, P < 0.05). The MACE rate [8.0% (9/112) vs. 2.0% (4/196)] and rehospitalization rate [12.5% (14/112) vs. 4.6% (9/196)] were significantly higher in depression patients than in patients without depression during the 12 months follow-up (P < 0.05). There was no significant difference on SDS score between the PCI and CABG before the procedure. However, after the procedure, the SDS score for patients undergoing CABG was significantly higher than in patients undergoing PCI (48.9 +/- 9.8 vs. 45.7 +/- 10.5 P = 0.01). The level of serum IL-6 was significantly higher in depression patients than in patients without depression (P < 0.05). CONCLUSION: Prevalence of depression is high in patients treated with revascularization procedures and is linked with poor post-procedure prognosis. PMID- 22490708 TI - [Risk factors of cognitive impairment after off-pump coronary artery bypass grafting]. AB - OBJECTIVE: To analyze the risk factors of cognitive impairment after off-pump coronary artery bypass grafting (OPCABG). METHODS: A total of 102 patients [male: 82, age: (65.7 +/- 7.1) years] undergoing OPCABG in our hospital between January 2009 and December 2010 were divided into postoperative cognitive dysfunction (POCD) group and non-POCD group by the MMSE questionnaire survey conducted at 7 days pre- and post-operation respectively. RESULTS: The incidence of POCD was 48.0% (49/102). Multivariate logistic stepwise regression analysis showed: advanced age (OR = 1.32, 95%CI: 1.10 - 1.46, P = 0.002), smoking (OR = 1.26, 95%CI: 1.18 - 1.32, P = 0.001), hypertension (OR = 1.66, 95%CI: 1.36 - 1.78, P = 0.023), diabetes (OR = 1.62, 95%CI: 1.02 - 2.84, P = 0.032), stroke (OR = 3.32, 95%CI: 1.68 - 6.49, P < 0.001), mitral regurgitation (OR = 1.48, 95%CI: 1.26 - 1.89, P < 0.001), and time of wall clamp (OR = 4.84, 95%CI: 1.08 - 7.28, P < 0.001) were independent risk factors of POCD. CONCLUSION: Advanced age, smoking, hypertension, diabetes, stroke, mitral regurgitation, and prolonged time of wall clamp are major risk factors for POCD in patients undergoing OPCABG. PMID- 22490709 TI - [Comparison on therapeutic approach and short-term outcomes between male and female patients with ST-segment elevation myocardial infarction]. AB - OBJECTIVE: To compare the differences on therapeutic approach and short-term outcomes between male and female patients with ST-elevation myocardial infarction (STEMI). METHODS: Data of Chinese STEMI patients were retrospectively analyzed from a global multicenter clinical trial of reviparin and metabolic modulation in acute myocardial infarction treatment evaluation (CREATE). The patients were divided into two groups according to gender and difference on demographic, baseline clinical characteristics at admission, reperfusion and drug therapy and 30-day all-cause mortality, re-infarction, stroke, hemorrhage, heart failure and combined end points were compared. RESULTS: Of the 7431 patients, 29.1% were female. Female patients were older than male patients [(68.2 +/- 9.1) years vs. (60.3 +/- 12.1) years]. On admission, heart rate, diastolic blood pressure and Killip class were higher and the delay between onset of chest pain and arrival at hospital was longer in female patients than in male patients (all P < 0.01). Male patients often presented MI in anterior leads while female patients often presented MI in inferior and lateral leads. History of diabetes mellitus, hypertension and heart failure was significantly higher in female than in male patients (all P < 0.01). Incidence of high blood glucose was higher in female while high blood potassium was higher in male patients (P < 0.01). Rate of reperfusion therapy was lower and the use aspirin and diuretic was more frequent in female patients than in male patients, while frequency of clopidogrel, Glycoprotein IIb/IIIa receptor inhibitor, beta-blockers, angiotensin converting enzyme inhibitor, lipid-lowering drug use was significantly higher in male than in female patients (all P < 0.01). Multivariate logistic regression analysis showed that female gender was a predictor for less PCI therapy (P < 0.01). Thirty day all cause mortality (OR = 1.425, 95%CI: 1.163 - 1.747, P < 0.01) and combined end points (OR = 1.193, 95%CI: 1.010 - 1.410, P = 0.04) were significantly higher in female patients than in male patients. CONCLUSIONS: There are gender-related differences on therapeutic approach and short-term outcome in Chinese STEMI patients. The unfavorable demographic and baseline clinical profile could partially explain the less reperfusion therapy rate and worse prognosis in female patients. PMID- 22490710 TI - [Serum 25-hydroxyvitamin D concentration is negatively related to carotid artery intima-media thickness in type 2 diabetic patients]. AB - OBJECTIVE: To evaluate the relationship between 25-hydroxy vitamin D [25(OH)D] and carotid artery intimal medial thickness (IMT) in type 2 diabetic (T2DM) patients. METHODS: Serum 25(OH)D and carotid IMT were measured in 300 T2DM patients. Patients were divided into four quartile groups according to the serum 25(OH)D levels (Q1: < 26.17 nmol/L, 74 cases; Q2: 26.17 - 32.75 nmol/L, 76 cases; Q3: 32.75 - 42.93 nmol/L, 78 cases; Q4 > 42.93 nmol/L, 72 cases). RESULTS: Carotid IMT, carotid artery plaque prevalence, duration of diabetes, HbA1c, CRP and PTH were significantly higher in subjects with low 25(OH)D compared subjects with high 25(OH)D (P < 0.05). Carotid artery IMT in Q1 and Q2 groups were significantly higher than that in Q4 group (1.03 +/- 0.21 vs. 0.90 +/- 0.20, 1.01 +/- 0.26 vs. 0.90 +/- 0.20, P < 0.05), was similar among Q1 and Q2 and Q3 groups. Prevalence of carotid atherosclerotic plaque in Q1 group (50.0%) was also significantly higher than in Q3 (29.5%, P < 0.05) and Q4 (16.7%, P < 0.05). Similarly, 25(OH)D concentration was significantly lower in patients with carotid plaque compared patients without carotid plaque [(28.31 +/- 4.91) nmol/L vs. (36.31 +/- 4.31) nmol/L, P < 0.01]. Pearson correlation analysis showed that carotid IMT was positively correlated with age, smoking, BMI, HbA1c, CRP, LDL-C, PTH/25(OH)D ratio (P < 0.05), and was negatively correlated with 25 (OH) D (r = 0.51, P < 0.01). Multivariate regression analysis showed that 25(OH)D concentration was an independent predictor of carotid IMT in this cohort (beta = 0.39, P < 0.01). CONCLUSION: Serum 25(OH)D concentration is negatively correlated with carotid IMT and low 25 (OH) D level is a risk factor for preclinical atherosclerosis in T2DM patients. PMID- 22490711 TI - [Impact of body mass index on incidence of obstructive sleep apnea-hypopnea syndrome in hospitalized hypertensive patients]. AB - OBJECTIVE: To investigate the impact of obesity on incidence of obstructive sleep apnea-hypopnea syndrome (OSAHS) in hospitalized hypertensive patients. METHODS: A total of 825 hospitalized hypertensive patients from April 1 to June 30 in 2009 in our hospital were included. Patients were asked to answer the questions concerning snoring, daytime sleepiness. Patients with loud snoring and daytime sleepiness, tubbiness neck, retrognathia, enlarged tongue, orolingual cyanosis were selected to undergo polysomnography monitoring for a whole night. OSAHS is defined by clinical symptoms and apnea-hypopnea index (AHI) not less than 5 per hour. RESULTS: (1) The detection rate of OSAHS in this cohort was 23.52% (178/825), 34.34% (148/431) in males and 11.68% (46/394) in females respectively. (2) The detection rate was 6.6% (12/183) in normal weight subjects, 22.22% (78/351) in overweight subjects and 36.75% (104/283) in obesity subjects (chi(2) = 56.736, P < 0.01). The severe OSAHS rate in obesity group (16.61%) was significantly higher than that in normal weight group (2.19%) and overweight group (7.69%, chi(2) = 29.219, P < 0.01). (3) The OSAHS rate was 7.83% (9/115) in normal waist circumference group and 26.29% (184/700) in centricity obesity group (chi(2) = 18.623, P < 0.01). The severe OSAHS rate was 2.61% (3/115) in normal waist circumference group and 10.57% (74/700) in centricity obesity (chi(2) = 7.32, P < 0.01). (4) The moderate to severe OSAHS rate increased in proportion with BMI increase in female patients (chi(2) = 5.846, P < 0.05) and increased in proportion with BMI and waist circumference increase in male patients (P < 0.01). CONCLUSIONS: The incidence of OSAHS in hypertensive patients is high. Obesity further increases the morbidity of OSAHS in hypertensive patients. PMID- 22490712 TI - [Relations between fasting serum lipids and high-sensitivity C-reactive protein level in Chengdu residents]. AB - OBJECTIVE: To explore the associations between fasting serum lipids and high sensitivity C-reactive protein (hsCRP). METHODS: Serum triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and hsCRP were measured in residents of Chengdu, China. Subjects with potential factors which might influence lipids and hsCRP were excluded, 580 subjects [mean age (62.3 +/- 6.6) years; male: 58.7%] were finally recruited by random sampling methods. RESULTS: There was a weak positive relationship between TG and hsCRP (r = 0.108, P = 0.01) and a weak negative relationship between HDL-C and hsCRP (r = -0.197, P < 0.001), this was also true in the sub-group with BMI < 24 kg/m(2) (r = 0.236, -0.140 respectively, all P < 0.001). In subjects with BMI < 24 kg/m(2), the hsCRP concentration was significantly higher in subjects with higher TG or lower HDL-C (all P < 0.05). hsCRP increased in proportion with the degree of dyslipidemia. After adjusting for gender, age, TC, LDL-C, fasting blood glucose, systolic blood pressure, diastolic blood pressure, history of hypertension and diabetes, smoking and alcohol drinking, logistic regression analysis showed that the odds ratio for increased hsCRP was 1.970 in subjects with either increased TG or lower HDL-C (P = 0.105) and 9.098 in subjects with both higher TG or lower HDL-C levels (P = 0.031). However, the observed relationship between TG, HDL-C and hsCRP in subjects with BMI < 24 kg/m(2) could not be observed in subjects with subjects with BMI > 24 kg/m(2) despite significant more cardiovascular risk factors in these subjects. CONCLUSIONS: A weak positive correlation between TG and hsCRP as well as a weak negative correlation between HDL-C and hsCRP was evidenced in the whole cohort suggesting dyslipidemia might be related to enhanced inflammatory status. However, this relationship is not observed in subjects with BMI > 24 kg/m(2) despite existence of more cardiovascular risk factors in these subjects. PMID- 22490713 TI - [Effect of early high-loading-dose tirofiban on platelet activity in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention]. AB - OBJECTIVE: To investigate the effect of early high-loading-dose tirofiban on platelet activity for patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. METHODS: A total of 120 acute STEMI patients were treated with 300 mg aspirin and 600 mg loading dose clopidogrel and randomized to high-dose tirofiban (25 ug/kg bolus followed by 0.15 ug*kg(-1)*min(-1) infusion for 36 hours, n = 40), standard dose tirofiban (10 ug/kg bolus followed by 0.15 ug*kg(-1)*min(-1) infusion for 36 hours, n = 40) or control (no tirofiban, n = 40) before angiography. Inhibition of platelet aggregation (IPA) was assessed before angiography, at 10 min and 24 hours after tirofiban infusion, and at 12 and 24 hours after stopping tirofiban infusion by the thrombelastography assay. RESULTS: There was no significant difference in baseline of IPA between the 3 groups (P > 0.05). IPA was significantly higher in high-dose tirofiban group compared with standard-dose tirofiban and no tirofiban group at 10 minutes after tirofiban infusion [(84.2 +/ 12.0)% vs. (67.8 +/- 26.8)% and (31.5 +/- 21.9)%, all P < 0.01]. At 24 hours after tirofiban infusion, the IPA of high-dose and standard-dose tirofiban was similar [(93.0 +/- 9.8)% vs. (88.5 +/- 18.1)%, P > 0.05] and was significantly higher than no tirofiban group [(40.4 +/- 22.8)%, all P < 0.01]. IPA was similar at 12 and 24 hours after stopping tirofiban use among the 3 groups (all P > 0.05). The maximum amplitude of high-dose tirofiban and standard-dose tirofiban groups at different time points was similar (all P > 0.05), and maximum amplitude in both tirofiban groups was significantly lower than in no tirofiban group at 10 min [(47.2 +/- 7.6) mm and (50.0 +/- 9.8) mm vs. (57.7 +/- 6.5) mm, all P < 0.01] and at 24 hours after stopping tirofiban infusion [(54.6 +/- 5.6) mm and (54.3 +/ 9.0) mm vs. (59.6 +/- 4.0) mm, all P < 0.01]. CONCLUSION: Early use of high loading-dose of tirofiban on top of 600 mg loading dose clopidogrel is more efficient on inhibiting platelet activity than standard dose of tirofiban in patients with acute STEMI undergoing primary primary percutaneous coronary intervention. PMID- 22490714 TI - [Sirolimus use in heart transplantation recipients with chronic renal dysfunction]. AB - OBJECTIVE: To observe the effect of sirolimus-based immunosuppression administered on heart transplant recipients with chronic renal dysfunction. METHODS: From June 2004 to December 2008, standard calcineurin inhibitors (CNI) based immunosuppressive regimen was changed to reduced-dose CNI plus sirolimus due to CNI-related chronic renal dysfunction in 20 out of 138 cardiac transplant recipients at Fuwai Hospital. The standard immunosuppressive regimen included steroid, CNI (cyclosporine or tacrolimus), and mycophenolate mofetil or azathioprine. Sirolimus was started at 0.75 - 1.50 mg/d with titration to achieve levels of 5 - 15 ug/L, and CNI dose was reduced gradually to 1/2-2/3 of the baseline level. Patients were followed for changes in renal function, lipid level and clinical side effects related to immunosuppressive therapy. Endomyocardial biopsy (EMB) was performed routinely at 3 weeks, 3, 6 and 12 months after transplantation. EMB was also performed at 3 months after regimen change within 1 year post-transplantation or when rejections were suspected in patients beyond 1 year post-transplantation. Echocardiography was performed for monitoring purpose. RESULTS: The mean follow-up after regimen change was (7.9 +/- 6.3) months. Final sirolimus dose was (0.89 +/- 0.22) mg/d and blood drug level was (7.6 +/- 3.8)ug/L. Cyclosporine dose was reduced from (191.7 +/- 60.0) mg/d to (123.6 +/- 34.8) mg/d, with blood drug concentration reduced from (175.5 +/- 58.0) ug/L to (111.9 +/- 56.0) ug/L in 18 patients (P < 0.01). Tacrolimus average dose was reduced from 4.25 mg/d to 3.00 mg/d, with blood drug concentration reduced from 13.5 ug/L to 10.5 ug/L in 2 patients. Serum creatinine level fell from (160.4 +/- 25.5) umol/L to (134.4 +/- 26.8) umol/L (P < 0.01) and urea nitrogen fell from (13.8 +/- 4.7) umol/L to (10.4 +/- 3.0) umol/L (P < 0.01) at one month after regimen change. Twenty two EMBs were performed in 11 patients within 1 year post transplant, there were 4 episodes of acute rejected (ISHLT grade 2). Twenty patients are all alive and cardiac function was normal. The most common side effect was hyperlipidemia, and triglycerides, total cholesterol and low density lipoprotein levels were significantly increased at 1 month post regimen change (P < 0.05 or P < 0.01). Leukocyte, hemoglobin and platelet as well as liver function remained unchanged at 1 month post regimen change (all P > 0.05). CONCLUSION: Our results show that change from CNI-based immunosuppressive regimen to reduced-dose CNI plus sirolimus is an effective and safe approach for the management of patients with CNI-related chronic renal dysfunction, leading to an improvement in renal function without compromise in anti-rejection efficacy and with tolerable side effects. PMID- 22490715 TI - [Effects of extracorporeal cardiac shock wave therapy in patients with ischemic heart failure]. AB - OBJECTIVE: To evaluate the feasibility, safety and efficiency of extracorporeal cardiac shock wave therapy (CSWT) in patients with ischemic heart failure. METHODS: Fifty patients with ischemic heart failure and left ventricular ejection fraction (LVEF) < 50% were randomized to CSWT (shots/spot at 0.09 mJ/mm(2) for 9 spots, 9 times within 3 month) or control group. Dual isotope simultaneous acquisition single-photon emission computed tomography with (99)Tc(m) sestamibi/(18)F-fluorodeoxyglucose ((99)Tc(m)-MIBI/(18)F-FDG) was performed before randomization and at 1 month after CSWT/control to locate and evaluate viable myocardium region. Canadian cardiovascular society (CCS) class sores, NYHA, Seattle Angina Questionnaire (SAQ), 6-min walk test (6 MWT), left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD) and the dosage of nitroglycerin use were compared between two groups at each time point. RESULTS: All patients completed the study protocol without procedural complications. At 1 month, patients in CSWT group experienced improvement in NYHA (P < 0.01), CCS (P < 0.01), SAQ (P = 0.021), 6 MWT (P = 0.012) and dosage of nitroglycerin use (P < 0.01) compared to baseline. LVEF [45.0 (39.0, 48.0) vs. 47.0 (42.0, 50.0) P = 0.001], LVEDD [58.0 (56.0, 59.0) vs. 56.0 (55.0, 58.0) P = 0.002], summed perfused score [23.0 (20.5, 24.5) vs. 20.0 (18.0, 22.0) P < 0.01] and metabolic score [25.0 (23.0, 26.0) vs. 24.0 (21.5, 25.0) P = 0.028] were also improved in CSWT group. All these parameters remained unchanged in control group between baseline and at 1 month. CSWT was independent factor for improved cardiac function, quality of life and echocardiography parameters after adjusting for known factors which might affect outcome. CONCLUSION: CSWT could improve symptom, cardiac function, quality of life and exercise tolerance in patients with ischemic heart failure, CSWT might serve as a new, non-invasive, safe and efficient therapy for these patients. PMID- 22490716 TI - [Evaluation of left ventricular function and twist in patients with diabetic cardiovascular autonomic neuropathy by speckle tracking imaging]. AB - OBJECTIVE: To evaluate left ventricular (LV) function and twist in patients with diabetic cardiovascular autonomic neuropathy (CAN) by two-dimensional speckle tracking imaging (STI). METHODS: STI was performed in 56 subjects with type 2 diabetes mellitus (DM) (35 with DM only: group A, 21 with CAN: group B) and 34 normal subjects (Control) from LV short-axis view. LV peak systolic, peak early (E') and peak late (A') diastolic circumferential strain in 18 myocardial segments were measured at the levels of mitral annulus, papillary muscle and apex and the rotation at mitral annulus and apex levels were also measured. LV peak systolic and the ratio of E' and A' of global and three levels, twist, untwisting rate and untwisting half-time were calculated. RESULTS: In group A, compared with control group, LV peak systolic radial circumferential strain has no significant difference (P > 0.05), E'/A' was reduced (P < 0.05), twist at aortic valve closure and twist at mitral valve opening were significantly increased (P < 0.05), untwisting rate reduced, and untwisting half time delayed. In group B, compared with control group and group A, circumferential strain parameters [( 12.64 +/- 6.49)% vs. (-19.11 +/- 9.98)% and (-21.14 +/- 10.13)%, P < 0.05] and E'/A' [(0.90 +/- 0.35) vs. (1.24 +/- 0.47) and (1.98 +/- 0.63), P < 0.05] were significantly decreased, twist at aortic valve closure [(19.08 +/- 5.62) degrees vs. (16.57 +/- 2.84) degrees and (14.36 +/- 4.06) degrees , P < 0.05] and twist at mitral valve opening [(13.99 +/- 2.31) degrees vs. (11.36 +/- 2.63) degrees and (9.04 +/- 5.63) degrees , P < 0.05] were significantly increased, untwisting rate [(0.40 +/- 0.28)%/ms vs. (0.46 +/- 0.14)%/ms and (0.53 +/- 0.21)%/ms, P < 0.05] reduced, and untwisting half time [(489.61 +/- 97.14) ms vs. (445.21 +/- 54.53) ms and (410.60 +/- 50.23) ms, P < 0.05] delayed. CONCLUSION: Speckle tracking imaging could be used to evaluate early changes on LV twist deformation and LV systolic function in patients with type 2 diabetes mellitus. PMID- 22490717 TI - [Comparison on efficacy and safety between domestic levosimendan versus dobutamine for patients with acute decompensated heart failure]. AB - OBJECTIVE: To compare the efficacy and safety of domestic levosimendan versus dobutamine for patients with acute decompensated heart failure (ADHF). METHODS: ADHF patients from 8 medical centers were recruited in this multicenter, blind, positive-controlled, randomized study and received 24 h intravenous levosimendan (n = 114) or dobutamine (n = 114) therapy. SWAN-GANZ catheter was performed in patients with pulmonary capillary wedge pressure (PCWP) >= 15 mm Hg (1 mm Hg = 0.133 kPa) and cardiac index (CI) <= 2.5 L.min(-1)*m(-2) (n = 39 each). RESULTS: Compared with baseline level, LVEF increased [(31.56 +/- 9.69)% vs. (28.44 +/- 7.08)%, P < 0.01] at 24 h in both groups. LVEF increase at 24 h was similar between two groups [(3.11 +/- 6.90)% vs. (3.00 +/- 6.63)%, P > 0.05]. The PCWP decrease at 24 h was significantly greater in levosimendan group than in dobutamine group [(-8.90 +/- 7.14) mm Hg vs. (-5.64 +/- 6.83) mm Hg, P = 0.04]. Decrease in NT-proBNP at 3 days was also more significant in levosimendan group than in dobutamine group [the percentage change compared to baseline: (-22.36 +/- 38.98)% vs. (-8.56 +/- 42.42)%, P < 0.01]. Dyspnea improvement at 24 h was more significant in levosimendan group than in dobutamine group. The incidences of adverse reactions and events were similar between two groups. CONCLUSION: LVEF improvement is similar between dobutamine and domestic levosimendan while greater decreases in PCWP and NT-proBNP are achieved with domestic levosimendan in patients with ADHF. PMID- 22490718 TI - [Role of C-type natriuretic peptide receptor and large-conductance calcium activated potassium channels in brain natriuretic peptide-induced porcine coronary artery dilation]. AB - OBJECTIVE: To investigate the role of C-type natriuretic peptide receptor (NPR-C) and large-conductance calcium-activated potassium channels (BK(Ca)) in brain natriuretic peptide (BNP) induced porcine coronary artery dilation. METHODS: Porcine coronary artery rings were obtained and treated with BNP (10(-6) mol/L), BNP + NPR-C antagonist cANF4-28 (10(-6) mol/L) and BNP + BK(Ca) blocker tetraethylammonium (TEA, 1 mmol/L). The vascular tone experiments were observed on 10 vessel segments. BK(Ca) current density was measured by the whole-cell patch clamp technique. RESULTS: The maximum diastolic rate was similar between BNP group (68.51% +/- 11.50%) and cANF4-28 + BNP group (65.67% +/- 11.90%, P > 0.05) while significantly reduced in TEA + BNP group (28.87% +/- 4.55%, all P < 0.05). When the holding potential was set at +60 mV, the BK(Ca) current density of BNP group was (78.48 +/- 5.86) pA/pF, which was significantly higher than control group [(53.84 +/- 4.55) pA/pF, P < 0.05], which was equally reduced in the TEA group and TEA + BNP group [(28.80 +/- 2.76) pA/pF and (30.60 +/- 3.88) pA/pF respectively, all P < 0.05 vs. control group]. CONCLUSION: BNP could relax the porcine coronary arterial smooth muscles by increasing BK(Ca) current, and this effect is not mediated by NPR-C. PMID- 22490719 TI - [Effect of liver X receptor agonist T0901317 on endothelin-1 induced murine HL-1 cardiomyocytes hypertrophy]. AB - OBJECTIVE: To investigate the role of liver X receptors (LXRs) on endothelin-1 (ET-1) induced murine HL-1 cardiomyocytes hypertrophy. METHODS: Cultured murine HL-1 cardiomyocytes were divided into four experiment groups: (1) CONTROL GROUP:treated with DMSO; (2) T0901317 group:treated with LXRs agonist T0901317 (1 umol/L); (3) ET-1 group:treated with ET-1 (1 nmol/L); (4) T0901317 + ET-1 group:treated with T0901317 (1 umol/L) for 8 hours, then treated with ET-1 (1 nmol/L). Twenty-four hours later, immunofluorescent staining was performed on HL 1 cells, the surface area of HL-1 cells was analyzed with NIH Image J software, and the synthetic rate of protein in HL-1 cells was detected by (3)H-leucine incorporation. The mRNA level of atrial natriuretic peptide (ANP) and beta-myosin heavy chain (beta-MyHC) was measured by quantitative realtime PCR. The effect of T0901317 on mRNA expression of ANP was also detected after LXRs gene silencing. RESULTS: The surface area of HL-1 cells, mRNA expression of ANP and beta-MyHC, and (3)H-leucine incorporation in ET-1 group were 2.00 +/- 0.29, 1.98 +/- 0.47, 2.13 +/- 0.39 and 1.79 +/- 0.17, respectively, which were significantly higher than those of control group (1.00 +/- 0.26, 1.00 +/- 0.21, 1.00 +/- 0.31 and 1.00 +/- 0.03, respectively, all P < 0.05). Compared with ET-1 group, the surface area of HL-1 cells, mRNA expression of ANP and beta-MyHC, and (3)H-leucine incorporation were significantly decreased in T0901317 + ET-1 group (1.24 +/- 0.25, 1.19 +/- 0.21, 1.48 +/- 0.27 and 1.15 +/- 0.11, respectively, all P < 0.05). After inhibition of LXRalpha/beta expression in HL-1 cardiomyocytes using the specific siRNAs, the mRNA expression of ANP in T0901317 + ET-1 group was 1.78 +/- 0.05, which was similar as that in ET-1 group (1.94 +/- 0.17, P > 0.05). CONCLUSION: T0901317, an agonist of LXRs, could inhibit ET-1 induced cardiac hypertrophy in vitro, and LXR ligand-mediated inhibition on ANP mRNA expression by T0901317 is receptor dependent. PMID- 22490720 TI - [Basic and clinical research advance in calcific aortic valve disease]. PMID- 22490721 TI - [Proteomics application for the screening of atherosclerosis biomarkers]. PMID- 22490722 TI - Bilateral sudden sensorineural hearing loss and chronic venous cerebrospinal insufficiency: a case report. AB - OBJECTIVES: We report a case of bilateral sudden sensorineural hearing loss (SSHL) in a patient suffering from chronic venous cerebrospinal insufficiency (CCSVI). METHODS: Audiometric testing confirmed bilateral sensorineural hearing loss with hypoexcitability to caloric stimulation on the left side and echo colour Doppler examination showed abnormal cerebral venous deficiency. RESULTS: The patient's condition improved after 15 days following medical treatment. CONCLUSIONS: CCSVI may explain the anatomical background which provides a predisposing factor for SSHL although further studies are needed to verify whether this observation is casual or coincidental. PMID- 22490723 TI - Simple external manual manoeuvres to pass the radiofrequency catheter through a bending segment of a saphenous vein. AB - Smooth passage of a catheter through a varicose saphenous vein during radiofrequency ablation may prove a challenging task. Various types of venous bending in the transverse and sagittal planes and their combinations within the saphenous compartment may be pretty well appreciated by ultrasound examination. Several simple manual manoeuvres like stretching, pushing or lifting along with limb re-positioning may often help the surgeon to advance the catheter through the segments by temporarily changing their special configuration. In this way the number of patients otherwise considered unsuitable for endovascular catheter procedures like radiofrequency or laser ablation may be considerably reduced. PMID- 22490724 TI - Endovenous laser ablation for major varicose tributaries. AB - OBJECTIVE: The purpose was to determine whether endovenous laser ablation (EVLA) could be used to treat major varicose tributaries as well as saphenous veins. METHODS: From 173 major venous systems in 95 patients treated by EVLA over a 12 month period, 108 had major varicose tributaries, of which 78 (70%) were treated by attempted EVLA of the saphenous veins and associated tributaries. RESULTS: Treatment was successful in 71 venous segments (83%). The lengths of saphenous veins treated were 3-46 (median 18) cm. and the lengths of tributaries treated were 3-38 (median 14) cm. The diameters of treated saphenous veins were 4-10 (median 6) mm, and the estimated mean diameters of treated tributaries were 3-8 (median 5) mm, as measured prior to operation with the patient in 45 degrees reverse Trendelenburg on a tilt table. There were no early or delayed complications. CONCLUSIONS: Major varicose tributaries as well as the saphenous veins can be treated by EVLA in approximately two-thirds of cases, with success in the majority selected and with no significant complications. PMID- 22490725 TI - Stream-based Hebbian eigenfilter for real-time neuronal spike discrimination. AB - BACKGROUND: Principal component analysis (PCA) has been widely employed for automatic neuronal spike sorting. Calculating principal components (PCs) is computationally expensive, and requires complex numerical operations and large memory resources. Substantial hardware resources are therefore needed for hardware implementations of PCA. General Hebbian algorithm (GHA) has been proposed for calculating PCs of neuronal spikes in our previous work, which eliminates the needs of computationally expensive covariance analysis and eigenvalue decomposition in conventional PCA algorithms. However, large memory resources are still inherently required for storing a large volume of aligned spikes for training PCs. The large size memory will consume large hardware resources and contribute significant power dissipation, which make GHA difficult to be implemented in portable or implantable multi-channel recording micro systems. METHOD: In this paper, we present a new algorithm for PCA-based spike sorting based on GHA, namely stream-based Hebbian eigenfilter, which eliminates the inherent memory requirements of GHA while keeping the accuracy of spike sorting by utilizing the pseudo-stationarity of neuronal spikes. Because of the reduction of large hardware storage requirements, the proposed algorithm can lead to ultra-low hardware resources and power consumption of hardware implementations, which is critical for the future multi-channel micro-systems. Both clinical and synthetic neural recording data sets were employed for evaluating the accuracy of the stream-based Hebbian eigenfilter. The performance of spike sorting using stream-based eigenfilter and the computational complexity of the eigenfilter were rigorously evaluated and compared with conventional PCA algorithms. Field programmable logic arrays (FPGAs) were employed to implement the proposed algorithm, evaluate the hardware implementations and demonstrate the reduction in both power consumption and hardware memories achieved by the streaming computing RESULTS AND DISCUSSION: Results demonstrate that the stream based eigenfilter can achieve the same accuracy and is 10 times more computationally efficient when compared with conventional PCA algorithms. Hardware evaluations show that 90.3% logic resources, 95.1% power consumption and 86.8% computing latency can be reduced by the stream-based eigenfilter when compared with PCA hardware. By utilizing the streaming method, 92% memory resources and 67% power consumption can be saved when compared with the direct implementation of GHA. CONCLUSION: Stream-based Hebbian eigenfilter presents a novel approach to enable real-time spike sorting with reduced computational complexity and hardware costs. This new design can be further utilized for multi channel neuro-physiological experiments or chronic implants. PMID- 22490726 TI - The bactericidal effect of human secreted group IID phospholipase A2 results from both hydrolytic and non-hydrolytic activities. AB - The Human Secreted Group IID Phospholipase A(2) (hsPLA2GIID) may be involved in the human acute immune response. Here we have demonstrated that the hsPLA2GIID presents bactericidal and Ca(2+)-independent liposome membrane-damaging activities and we have compared these effects with the catalytic activity of active-site mutants of the protein. All mutants showed reduced hydrolytic activity against DOPC:DOPG liposome membranes, however bactericidal effects against Escherichia coli and Micrococcus luteus were less affected, with the D49K mutant retaining 30% killing of the Gram-negative bacteria at a concentration of 10MUg/mL despite the absence of catalytic activity. The H48Q mutant maintained Ca(2+)-independent membrane-damaging activity whereas the G30S and D49K mutants were approximately 50% of the wild-type protein, demonstrating that phospholipid bilayer permeabilization by the hsPLA2GIID is independent of catalytic activity. We suggest that this Ca(2+)-independent damaging activity may play a role in the bactericidal function of the protein. PMID- 22490727 TI - Modulation of the cardiovascular system by leptin. AB - It is well established that individuals with the metabolic syndrome have a significantly increased risk of cardiovascular disease and much effort has been expended to elicit the underlying mechanisms. Various studies have proposed that excessive or deficient physiological effects mediated by leptin make an important contribution, yet many paradoxical observations often preclude a clear definition of the role of leptin. This review article will briefly discuss principal and most recent evidence on direct and indirect regulation of the cardiovascular system by leptin, focusing on cardiac structural and functional as well as vascular effects. PMID- 22490730 TI - Morphological changes in the lateral meniscus in end stage lateral compartment osteoarthritis: translating to clinical practice. PMID- 22490728 TI - Hepatic steatosis in HIV-HCV coinfected patients receiving antiretroviral therapy is associated with HCV-related factors but not antiretrovirals. AB - BACKGROUND: In HIV and hepatitis C virus (HCV) coinfected patients, the role of antiretroviral therapy (ART) on hepatic steatosis (HS) remains controversial. METHODS: HIV/HCV coinfected patients receiving ART and previously untreated for HCV who underwent a liver biopsy were included. Cumulative duration of exposure to each antiretroviral was recorded up to liver biopsy date. Logistic regression analyses evaluated factors associated with steatosis and its severity. RESULTS: 184 patients were included: median age 41 years, 84% male, 89% Caucasian, 61% with a past history of intravenous drug use. HCV genotypes were 1 (55%), 2 (6%), 3 (26%), and 4 (13%). Median HCV-RNA was 6.18 log10 IU/ml. HIV-RNA was undetectable (<400 copies/ml) in 67% of patients. Median CD4 count was 321/mm3. All patients had been exposed to nucleoside reverse transcriptase inhibitors (median cumulative exposure 56 months); 126 received protease inhibitors (23 months), and 79 non-nucleoside reverse transcriptase inhibitors (16 months). HS was observed in 102 patients (55%): 41% grade 1; 5% grade 2, and 9% grade 3. In multivariate analysis, HCV genotype 3 and HCV viral load were moderately associated with mild steatosis but strongly with grade 2-3 steatosis. After adjustment for the period of biopsy, no association was detected between HS and exposure to any antiretroviral class or drug, or duration of ART globally or comparing genotype 3 to others. CONCLUSIONS: Among our ART-treated HIV-HCV cohort predominantly infected with genotype 1, 55% of patients had HS which was associated with HCV-related factors, but not ART class or duration of exposure. PMID- 22490732 TI - [Pay attention to the prevention and treatment of mild cognitive impairment]. PMID- 22490731 TI - Preparation of hollow magnetite microspheres and their applications as drugs carriers. AB - Hollow magnetite microspheres have been synthesized by a simple process through a template-free hydrothermal approach. Hollow microspheres were surface modified by coating with a silica nanolayer. Pristine and modified hollow microparticles were characterized by field-emission electron microscopy, transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, FT-IR and Raman spectroscopy, and VSM magnetometry. The potential application of the modified hollow magnetite microspheres as a drug carrier was evaluated by using Rhodamine B and methotrexate as model drugs. The loading and release kinetics of both molecules showed a clear pH and temperature dependent profile. GRAPHICAL Hollow magnetite microspheres have been synthesized. Load-release experiments with Rhodamine-B as a model drug and with Methotrexate (chemotherapy drug used in treating certain types of cancer) demonstrated the potential applications of these nanostructures in biomedical applications. PMID- 22490733 TI - [Characteristics of cognitive impairment in patients with leukoaraiosis]. AB - OBJECTIVE: To explore the characteristics of cognitive impairment in patients with leukoaraiosis (LA). METHODS: Forty-six LA patients and 38 age and gender matched healthy subjects were recruited from the Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University between September 2010 and March 2011. All participants underwent the neuropsychological tests recommended by the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards (NINDS/CSN). The were divided into 3 different groups (mild, moderate and severe) according to the Fazekas scale. The differences of neuropsychological performances were compared among 3 groups. RESULTS: The LA patients were associated with comprehensive cognitive function deficits, including MMSE (24.4 +/- 3.2 vs 28.3 +/- 1.2), MoCA (20.4 +/- 3.0 vs 26.2 +/- 0.8), digital span forward (5.7 +/- 0.9 vs 6.8 +/- 1.0), digital span backward (3.5 +/- 0.7 vs 4.1 +/- 0.7), Stroop-B (69 +/- 13 vs 43 +/- 5), Stroop-C (141 +/- 42 vs 65 +/- 10), trail making test-A (73 +/- 15 vs 31 +/- 7), trail making test-B (126 +/- 18 vs 82 +/- 6) and digit symbol test (25 +/- 6 vs 37 +/- 5, P < 0.05). However, there was no difference in the performance of verbal fluency (12.7 +/- 2.5 vs 13.4 +/- 2.5, P > 0.05). Correlation analysis showed that the severity of LA had a negative correlation with the performance of MoCA (r = -0.601, P = 0.002). CONCLUSIONS: The LA patients are closely correlated with cognitive impairments of attention, memory, executive function and information processing speed. It may be attributed to the frontal-subcortical circuitry dysfunction. PMID- 22490734 TI - [Neuropsychological features of elderly patients with mild cognitive impairment susceptible to Alzheimer's disease]. AB - OBJECTIVE: To explore the neuropsychological features of elderly patients with mild cognitive impairment (MCI) susceptible to Alzheimer's disease (AD). METHODS: A total of 47 patients with MCI diagnosed from June to October 2008 and 21 controls with normal cognition at the same convalescent camp were selected and followed up for two years. Montreal cognitive assessment (MoCA), mini mental state examination (MMSE) and clock drawing test (CDT) were performed for all subjects at the onset of study and repeated annually. RESULTS: At Month 12, the visuospatial skill scores of MCI patients decreased significantly versus those of the control (0.6 +/- 0.7 vs 0.1 +/- 0.6, P = 0.008). No one progressed to AD in neither groups. And at Month 24, both visuospatial skill scores (0.9 +/- 0.9 vs 0.4 +/- 0.9) and attention scores (1.0 +/- 1.0 vs 0.2 +/- 0.8) of MCI patients declined significantly versus the control (P = 0.021, 0.001). Among 47 MCI patients, 7 progressed to AD. No obvious difference existed in the score of all items between the AD converters and non-converters at baseline. However, the scores of MMSE (27.6 +/- 0.8 vs 28.9 +/- 1.0), MoCA (24.3 +/- 3.1 vs 27.9 +/- 1.6) and such MoCA subitems as visuospatial skill (3.9 +/- 0.7 vs 4.5 +/- 0.6), language (1.86 +/- 0.38 vs 2.65 +/- 0.53) and delayed recall (2.1 +/- 1.5 vs 3.9 +/- 1.0) of the converters were obviously lower than those of the non-converters at Month 12 (P < 0.05). Furthermore, all other scores of the AD converters, except for designation and abstract, were significantly lower than those of the non-converters at Month 24 (P < 0.05). CONCLUSION: The visuospatial skill, executive function, delayed recall and language function of MCI patients progressing to AD tend to have early impairment and significant changes. It may be useful to predict AD among the MCI patients. PMID- 22490735 TI - [Survey of comorbidities for hospitalized patients with cognitive disorders]. AB - OBJECTIVE: To provide rationales for the prevention and treatment of elderly patients with cognitive disorders through comparing the comorbidities according to different etiologies and severities. METHODS: Six groups of different cognitive status were selected. There were 438 normal cognitive subjects (NC) from Jing'an community of Shanghai. Five other groups were from the Memory Clinic at our hospital from June 2006 to June 2010. There were subjective memory complaints (n = 443, SMC), mild cognitive impairment (n = 540, MCI), vascular cognitive impairment-non dementia (n = 119, VCI-ND), Alzheimer's disease (n = 337, AD) and vascular dementia (n = 54, VaD). All participants finished a battery of neuropsychological tests and completed the survey of such comorbidities as stroke, conscious disturbance, hypertension, diabetes, head injuries and excessive drinking. RESULTS: The comorbidity rates of diabetes were 11.4%, 9.9%, 16.1%, 14.2%, 12.4% and 18.5% in 6 groups (NC, SMC, MCI, VCI-ND, AD, VaD) respectively. There were no differences for overall or pairwise chi square tests. The rates of stroke, hypertension and excessive drinking in patients of VCI-ND and VaD were higher than those of SMC, MCI and AD. The comorbidity rates in the VCI-ND and VaD group were 54.6% vs 62.9% for stroke; 61.3% vs 79.6% for hypertension; 22.6% vs 37.0% for excessive drinking. Whereas in the SMC, MCI and AD groups, the rates were 9.4%, 10.9% and 3.0% for stroke; 44.9%, 47.2% and 42.1% for hypertension; 18.0%, 18.3% and 15.1% for excessive drinking. No distinct differences existed for the comorbidity rates among SMC, MCI and AD groups or among different degrees of AD. CONCLUSION: Etiologies rather than severities determine the different rates of comorbidities in the elders with cognitive impairment. PMID- 22490736 TI - [Difference in sundowning of wandering behavior in patients with Alzheimer disease and frontotemporal dementia]. AB - OBJECTIVES: To delineate the difference in sundowning of wandering behavior between patient with Alzheimer Disease (AD) and frontotemporal dementia (FTD). METHODS: The study was conducted in a dementia care unit at A hospital in Osaka, Japan from September 2008 to September 2009. Twenty-four-hour movements of 27 ambulatory inpatients with AD and 7 with FTD were coded consecutively by the IC tag monitoring system. RESULTS: Repeated measures ANOVA after the adjustment of Huynh-Feldt Epsilon (H-F) showed no significant difference in 24 h standardized activity level between two groups (F = 3.74, P = 0.06), and there was no interaction between diagnosis and time (F = 1.42, P > 0.05). The standardized activity levels gradually increased from late afternoon to evening and then reached the highest point at 18:00 in AD group and 19:00 in FTD group. Test of within-subjects contrasts for order 17 was significant (F = 5.24, P < 0.05) and for order 9 was a tendency of significant (F = 4.26; P = 0.05) between two groups. AD group was significant greater active at 5:00, 6:00 and 7:00 (0.75 +/- 0.08 vs 0.35 +/- 0.16, F = 4.91; 1.13 +/- 0.13 vs 0.49 +/- 0.26, F = 5.06; 1.24 +/- 0.15 vs 0.56 +/- 0.28, F = 4.47 respectively, P < 0.05), and less active at 16:00 (1.65 +/- 0.11 vs 2.22 +/- 0.22, P < 0.05) comparing to FTD group by Bonferroni's multiple comparison test. Meanwhile, the time of peak value of hourly distance moved per day (PV-time) was delayed in FTD group comparing to AD by circular chi2 test (14:12 +/- 5:12 vs 15:47 +/- 4:19, chi2 = 87.31, P < 0.01). CONCLUSIONS: The study suggests great possibility of sundowning of wandering behavior in both two subtypes with different temporal pattern of wandering behavior. Comparing to FTD patients, AD patients showed an advanced PV-time and prolonged active phase. PMID- 22490737 TI - [Effects of total intravenous anesthesia on evoked potentials during aneurysm clip placement surgery]. AB - OBJECTIVE: To explore the influences of total intravenous anesthesia (TIVA) on the feasibility and success rate of monitoring the evoked potentials (EP) and examine the correlations between EP changes and clinical outcomes in intracranial aneurysm surgery. METHODS: Thirty-one patients undergoing intracranial aneurysm surgery received TIVA. TIVA was maintained with a target controlled infusion (TCI) of propofol and a continuous infusion of remifentanyl. The bilateral SEP (somatosensory evoked potential) and MEP (motor evoked potentials) were monitored intra-operatively. And the changes of evoked potential and success rate were recorded. The preoperative and postoperative neurological outcomes and radiological manifestations were compared. RESULTS: Bilateral SEP was detected in all cases. And the control side MEP was unsuccessfully monitored. Three patients had postoperative neurological deficits. The amplitudes of MEP and SEP declined simultaneously and failed to revert back to the baseline levels in 1 case. There was postoperative hemiplegia. And computed tomography showed multiple sites of ischemic brain infarction. CONCLUSION: The administration of TIVA with propofol and remifentanyl enables successful SEP and MEP monitoring during intracranial aneurysm surgery. This protocol may detect early cerebral ischemia and reduce the incidence of ischemic stroke. PMID- 22490738 TI - [Solid-pseudopapillary tumor of pancreas: different types of imaging features and their correlation with pathological findings]. AB - OBJECTIVE: To explore the correlation between imaging features of solid pseudopapillary tumor of pancreas (SPTP) and their pathological findings. METHODS: Analyze the imaging of 19 patients (female 15, male 4, median age 25 years) who underwent surgery for SPTP, and divide their into solid-predominance type, solid-cyst type and cyst-predominance type to compare with their pathological specimens. All patients plain and enhanced CT examination and plain and enhanced MR examination. RESULTS: (1) 2 cases of solid-predominance type (11%), 13 cases solid-cyst type (68%), 4 cases of cyst-predominance type (21%). Cyst are located in the surrounding area of solid-predominance type; Solid and cyst are mixed in cyst-solid type; cyst-predominance type are thick-walled cystic tumors with nodules. (2) 12 cases (63%) show obvious signs of haemorrhage and 4 cases (21%) had calcification on CT; All cases (100%) which on MR can be seen signs of haemorrhage. (3) Pathological findings demonstrate SPTP have two ingredients: solid and cystic. However, the two ingredients occupy different ratio in different types. Haemorrhage are seen in all of tumors. CONCLUSION: As a sort of neoplasm which preferentially arising in SPTP occur in pancreas of young women, its different types of imaging features related to their pathological findings. PMID- 22490739 TI - [Morphological and quantitative evaluation of myocardial bridge and mural coronary artery with 256-slice CT angiography: initial clinical experience]. AB - OBJECTIVE: To determine the morphological characteristics of myocardial bridge and mural coronary artery (MB-MCA) and initially quantify the changes of MB-MCA in diastole and systole phase with multiple-phase reconstruction technique using 256-slice CT angiography (256-slice CTA). METHODS: We retrospectively collected the coronary artery imaging data of 861 patients undergoing 256-slice CTA with suspected or documented coronary artery disease. The images were reviewed by two independent radiologists, the diagnosis of MB-MCA was confirmed when consistency was obtained. The length, diameter and thickness of MB-MCA in the middle segment of LAD (LAD2) in diastole and systole phase were recorded, and changes of MB-MCA were calculated. RESULTS: Among the 861 patients, 150 MB-MCA were found in 131 patients (15.2%). 99 MB-MCA (66.0%) were located in LAD2, the remaining 51 (34.0%) in the other segments of coronary arteries. The average length and thickness of MB was (17.6 +/- 5.7) mm and (2.6 +/- 0.7) mm, respectively. The average diameter change of MCA in LAD2 from systole phase to diastole phase was (1.2 +/- 0.5) mm, and 41% of MCA have diameter stenosis more than 50% in systole phase. CONCLUSION: The changes of MB-MCA from diastole to systole phase could be determined to some extent by 256-slice CTA multiple-phase reconstruction technique. PMID- 22490740 TI - [Application of prospective ECG-triggering dual-source CT angiography in infants and children with congenital heart disease]. AB - OBJECTIVE: To explore the application of prospective ECG-triggering dual-source CT (DSCT) angiography in infants and children with complex congenital heart disease (CHD) compared with transthoracic echocardiography (TTE). METHODS: Eighty seven patients (mean age: 28 months, range 3 months to 6 years; male 46; mean weight: 15 kg) underwent prospective ECG-triggering DSCT angiography and TTE. Surgery was performed in 54 patients. The overall imaging quality was evaluated on a four-point scale. Inter-observer agreement in subjective image quality grading was assessed by kappa statistics. The accuracy of DSCT angiography and TTE was calculated based on the surgery findings in the 54 patients who were performed with surgery. RESULTS: A total of 267 cardiovascular deformities were diagnosed by DSCT angiography, and 231 deformities were diagnosed by TTE. There was a good agreement on overall image quality (kappa = 0.78). A total of 173 cardiovascular deformities were confirmed by surgery findings in 54 patients. The accuracy of DSCT angiography and TTE was 97.69% (169/173) and 82.08% (142/173). The mean effective dose was (0.40 +/- 0.08) mSv. CONCLUSIONS: Prospective ECG triggering DSCT angiography with a very low effective radiation dose allows the accurate diagnosis of anomalies in infants and children with complex CHD compared with TTE. It has great value for preoperative assessment of CHD. PMID- 22490741 TI - [Endoscopic treatment for fourth ventricular outlet obstruction]. AB - OBJECTIVE: To explore the therapeutic efficacies of endoscope for fourth ventricular outlet obstruction (FVOO). METHODS: Endoscopic third ventriculostomy (ETV) was performed for 30 cases. The circumstances of third ventricular floor and basal cistern were observed and recorded intra-operatively. Meanwhile the fourth ventricular exploration and fistulation were performed across enlarged aqueduct. And the velocity and flow rate of aqueduct, fourth ventricular outlet and stoma were evaluated post-operatively with Cine-MR (magnetic resonance). RESULTS: Standard ETV was performed successfully in 28 patients. Fourth ventricular exploration (n = 6) and outlet membrane fistulation (n = 2) were carried out. The mean follow-up period was 2.3 years (range: 0.5 - 4.0). The overall success rate was 78.6%. CONCLUSION: ETV is a viable therapeutic option for FVOO patients. The therapeutic effects of outlet membrane fistulation require further observations. PMID- 22490742 TI - [Application of AO miniplate and screw in the treatment of metacarpophalangeal joint periarticular fractures]. AB - OBJECTIVE: To evaluate the clinical efficacies for open reduction and internal fixation of unstable periarticular fractures of metacarpophalangeal joint (MCP) with the AO miniature plate system. METHODS: A total of 265 patients (172 males and 93 females) with 302 MCP periarticular fractures were retrospectively reviewed. Their mean age was 32.5 years old (range: 17 - 59). The standard internal fixation treatment method was established on the basis of the AO/ASIF Comprehensive Classification of Fractures. A "T" shape plate, double-row-plate or a condylar plate was used for A2, A3, C1, C2 type fractures. Screws alone were used for B type fractures. Active and passive flexion and extension exercises at Day 3 post-operation within the limits of patient pain tolerance. All patients were evaluated regarding the total active motion (TAM) score, average PROM, quick DASH score, the power of gripping, pinching and Kapandji score. RESULTS: The patients were followed up for an average of 4.6 months (range: 4 - 24). Radiological examinations showed that the fracture line disappeared in an average of 8.2 weeks (average: 8.2). According to TAM rating criteria, the functions of hands were as follows: excellent (n = 113), good (n = 136) and poor (n = 53). The fair rate was 82.8%. The average PROM of MP joint was 82.3 degrees +/- 4.7 degrees and the average quick-DASH score 17.4. Contrast to the health side, the power of gripping recovered for 94.5% and pinching for 88.6%. The Kapandji score was 90%. A total of 103 MCP (34.1%) completely recovered. Contrasting between the head of metacarpal fracture combined the base of proximal phalangeal fracture and alone the head of metacarpal fracture or the base of proximal phalangeal fracture, the post-operative rates of complications and tendon adhesion were higher. As compared with traditional methods, each of the above parameters had statistic significances (P < 0.01). CONCLUSION: Because of complex anatomic structures, the MCP periarticular fractures have such complications as tendon adhesion, joint stiffness and post-traumatic arthritis, etc. The traditional treatment method is less effective. The AO miniplate and screw system provides rigid and stable fixation so that it is a preferred technique in the treatment of MCP periarticular fractures. PMID- 22490743 TI - [Application of an integrated omics analysis for the discovery of biomarkers for osteosarcoma]. AB - OBJECTIVE: To apply an integrated omics analysis so as to discover potential biomarkers for an early diagnosis of osteosarcoma. METHODS: Gene chip and surface enhanced laser desorption/ionization-time of flight-mass spectra (SELDI-TOF-MS) were employed to screen the marker genes and serum markers of osteosarcoma respectively. The associations of potential biomarkers from the SELDI data and microarray analysis were further inferred by Link-test to identify stable and specific diagnostic biomarkers. RESULTS: A total of 653 pre-biomarkers were found in osteosarcoma cells. And six differentially expressed protein peaks with strong statistical significances were detected by SELDI-TOF-MS in the patient's serum samples. Thirteen potential biomarkers for an early diagnosis of osteosarcoma were screened by Link-test. CONCLUSION: As an effective method of identifying osteosarcoma biomarkers, the integrated omics analysis may serve as a monitoring platform for an early diagnosis of osteosarcoma. PMID- 22490744 TI - [Therapeutic efficacies of bone grafing for calcaneal intra-calcaneal fractures]. AB - OBJECTIVE: To evaluate the efficacies of treating intra-calcaneal fractures with bone grafting. METHODS: From January 2005 to October 2011, a total of 182 calcaneal patients underwent operations for closed fractures. There were 159 males and 23 females with an average age of 41.2 years old. The fractures were of the following types: left calcaneal (n = 68), right calcaneal (n = 86) and bilateral (n = 28). According to the Sander's classification, there were type II (n = 27), type III (n = 109) and type IV (n = 46). And they were divided into bone graft (n = 94) and non-bone graft (n = 88) groups. All of them underwent a profiled plate fixation via a lateral approach. No external fixation was necessary and early ankle functional exercises started postoperatively. They handled partial weight-bearing at Week 6 and full weight-bearing at Week 12. Their outcomes were assessed by the American Orthopedic Foot and Ankle Society ankle-hindfoot scale (AOFAS) while classification comparison affected the prognosis (P < 0.05). RESULTS: The follow-ups of 10 patients were lost at Month 3. And 172 cases were followed up for an average period of 14.2 months (range: 9 16). The average healing duration was 12 weeks (range: 6 - 15). None of follow up cases had any complication, such as vascular and nerve injury and osteomyelitis. Twenty-nine cases in the non-bone graft group had articular cave in after weight bearing. And 21 cases were associated with subtalar arthritis. And in the bone graft group, there was no articular cave-in and only 1 case was associated with subtalar arthritis. The outcomes of bone graft and non-graft groups were as follows: excellent (n = 68), good (n = 20), fair (n = 5) and poor (n = 1) vs. excellent (n = 44), good (n = 26), fair (n = 7) and poor (n = 9). The rate of excellent and good was 87.9%. And the post-operative AOFAS scores had statistical differences between 2 groups (P < 0.05). CONCLUSION: Bone grafting is important for improving the therapeutic efficacies for intra-calcaneal fractures. PMID- 22490745 TI - [Effects of levonorgestrel intrauterine system on endometrial tissue after endometrial polyps resection by hysteroscopy]. AB - OBJECTIVE: To explore the changes of endometrial tissues after the insertion of levonorgestrel intrauterine system (LNG-IUS). METHODS: The endometrial tissues were harvested from 21 cases after endometrial polyps resection by hysteroscopy. And the patients received a 1-year follow-up. The immunohistochemical stains for estrogen receptor (ER), progesterone receptor (PR), Ki-67, bcl-2 and bax were used for semi-quantitative analyses. The changes of endometrial thickness were monitored and uterine weight was observed with a 3-year follow-up. RESULTS: The endometrial thickness and uterine weight declined continuously after the insertion of LNG-IUS. The endometrial thickness decreased from the preoperative level of (9.8 +/- 1.2) mm to (3.5 +/- 1.0) mm while the uterine weight dropped from the preoperative level of (98.8 +/- 8.6) g to (66.6 +/- 9.8) g. The expressions of ER, PR and Ki-67 were significantly lower than those of the para polyps endometrial tissue (P < 0.05). The expressions of bcl-2 and bax were significantly higher than those of the para-polyps endometrial tissue (P < 0.05). CONCLUSION: LNG-IUS may prevent the recurrence of uterine endometrial polyps through its inhibited expressions of ER, PR and Ki-67 and induced endometrial apoptosis. PMID- 22490746 TI - [Treatment of chronic subdural hematoma by minimally invasive drilling and drainage]. AB - OBJECTIVE: To discuss the treatment of chronic subdural hematoma by minimally invasive drilling and drainage. METHODS: The clinical data were collected and analyzed for 118 cases with chronic subdural hematoma at our hospital from May 2003 to August 2011. They underwent minimally invasive drilling and drainage. RESULTS: A total of 101 cases (85.6%) were cured and 17 cases (14.4%) improved. Hematoma recurred in 6 cases (5.08%). Among them, 5 cases recurred at Months 1-2 and 1 case at Month 77 post-operation. Three cases died. The causes included heart failure (n = 1), cirrhosis and renal failure (n = 1) and sudden cardiac death (n = 1). Six recurrent cases were cured by minimally invasive drilling and drainage. And 85 cases received a follow-up period of 1 - 80 months. No further recurrence was found for 6 recurrent cases. CONCLUSION: The treatment of chronic subdural hematoma by minimally invasive drilling and drainage is safe, simple and efficacious. PMID- 22490747 TI - [Clinical analysis of 20 cases of muscular tuberculosis]. AB - OBJECTIVE: To explore the clinical manifestations of muscular tuberculosis (MT) and analyze its risk factors. METHODS: Twenty MT patients were recruited from our department during 2000 - 2010. There were 9 males and 11 females with an average age of 43.5 years old. And their clinical manifestations were recorded and analyzed. RESULTS: All patients had local masses. And 19 patients had the involvement of single muscle and multiple muscles were involved in 1 patient. Gastrocnemius was affected in 9 patients. Nine patients had a previous history of tuberculosis or suffered concurrent tuberculosis of other body parts. Three patients with immune system disease received glucocorticoid therapy. And 11 patients underwent PPD (purified protein derivative) test and only 1 was strongly positive while 10 others were negative. MT was confirmed by pathological examinations in 20 cases. All patients underwent muscle biopsy and received effective chemotherapy. CONCLUSION: As a kind of systemic disease, MT is mainly characterized by painful or painless muscle mass. The patients with a history of tuberculosis, tuberculosis of other body parts and immune system disease are susceptible to MT. Diagnosis is mainly made through biopsy. And chemotherapy is effective. PMID- 22490748 TI - [Systematic reviews of mini-invasive surgery versus standard approaches for total knee arthroplasty]. AB - OBJECTIVE: To conduct a systematic review to compare the early efficacies of minimally invasive surgery (MIS) versus conventional approaches in TKA (total knee arthroplasty). METHODS: Randomized controlled trials (RCTs) and clinical controlled trials (CCTs) were retrieved from the databases of MEDLINE (1996.6 - 2010.12), EMBASE (1996.6 - 2010.12), PubMed (1996 - 2010.12) and Cochrane Library (Issue 2, 2012). Journal of Orthopedics (from establishment to December 2010) and Orthopedic Journal of China (from establishment to December 2010) were manually searched. Both RCTs and CCTs were included. The data were extracted by two reviewers with designed extraction form RevMan 4.2.8 software for data analysis. The criteria were as follows: (1) operative duration and reduced blood loss; (2) VAS (visual analog scale) score; (3) faster recovery of ROM (range of movement); (4) quadriceps muscle strength; (5) component positioning malalignment; (6) tibiofemoral angle; (7) rate of complications. RESULTS: A total of 18 RCTs were included. Compared with the standard TKA procedure, the MIS group had a longer operative duration (WMD (weighted mean difference) 14.16, 95%CI (confidence interval) (12.61, 15.71)); reduced blood loss (WMD 8.31, 95%CI (6.16, 10.46)); lower VAS score at Days 3-5 post-operation (WMD 4.99, 95%CI (4.19, 5.78)); better Mean Knee Society scores at Week 6 post-operation (WMD 4.99, 95%CI (4.19, 5.78)), improvement in ROM occurred more rapidly at Month 3 post-TKA (WMD 14.59, 95%CI (8.39, 20.80)). Although the differences were not statistically significant, tibiofemoral angle was more precise in the standard group and the rate of component malalignment occurred more frequently in the MIS group (WMD 0.20, 95%CI (-0.12, 0.52)) (RR 1.57, 95%CI (0.88, 2.83)). CONCLUSION: MIS leads to a faster recovery than conventional surgery with a shorter operative duration, a reduced blood loss, a lower VAS score and a faster recovery of ROM and quadriceps muscle strength. However, the rates of component malalignment and complications occur more frequently in the MIS group. Potential benefits in long-term survival rate and functional improvement require further investigations. PMID- 22490749 TI - [Confusion and thought of the diagnosis and treatment for thyroid diseases in pregnancy]. PMID- 22490750 TI - [Pancreatic beta-cell damages in obesity]. PMID- 22490751 TI - [The application of a high resolution melting-based genotyping method in studying the association between FTO rs9930506 polymorphism and metabolic syndrome in Beijing population]. AB - OBJECTIVE: To set up a new method, which is sensitive, low cost, rapid and suitable for clinical application for FTO gene rs9930506 variant genotyping basing on high resolution melting (HRM) platform, and to preliminarily put into practice in susceptibility analysis for metabolic syndrome (MS) in Beijing. METHODS: Unlabelled probe with C3-spacer block specific for rs9930506 variant has been designed according to the Refseq from GenBank. With LC-Green plus dye pre mixed, we scanned the signal for the genotype analysis after PCR amplification and HRM reaction. Restriction fragment length polymorphism (RFLP) and PCR sequencing methods were designed as 2 control genotyping methods for the evaluation of accuracy and convenience. Afterwards, the HRM-based method was put into practice in metabolic syndrome patients (n = 500) and control groups (n = 500) for rs9930506 genotyping, and primarily study the association between rs9930506 and MS. RESULTS: All the 3 methods could genotype rs9930506 appropriately, although the 2 control methods seemed to be a little time inefficient. The call rate of HRM-method was 100% and sampling accuracy reached 99.3% according to sequencing results. In the MS group, AA, AG and GG genotypes were found in 290, 185 and 25 cases, respectively. And in the control group, those were found in 344, 138 and 18 cases. No genotype distribution difference was detected between control group and HapMap-CHB data (P = 0.520). The genotype distributions were all in Hardy-Weinberg equilibrium in each group. AA genotype of rs9930506 seemed to reduce the risk for MS (OR = 0.626, 95%CI = 0.483 - 0.812). CONCLUSIONS: The AA genotype of rs9930506 variant in FTO might be a protective factor for MS in Beijing population. The susceptibility related genotyping in clinical samples could be more rapid, precise and inexpensive with the development of HRM in genotyping. PMID- 22490752 TI - [A comparison of clinical effectiveness of different neuropathy scoring systems in screening asymptomatic diabetic peripheral neuropathy]. AB - OBJECTIVE: To evaluate the clinical effectiveness in screening asymptomatic diabetic peripheral neuropathy (ADPN) by the Michigan neuropathy screening instrument (MNSI) and the Toronto clinical scoring system (TCSS). METHODS: MNSI, TCSS and neural electrophysiological test (NET) were conducted in 232 neurologically asymptomatic type 2 diabetes patients. By using the results of NET as the golden criteria for diagnosis of ADPN, we evaluated the effectiveness of the two different scoring system by the receiver operator characteristic curve. The sensitivity, specificity, positive and negative predictive values, accuracy, Youden indexes and kappa values on different diagnostic cut-off points of MNSI and TCSS were analyzed. The correlation between the two different scoring system and the risk factors of diabetic peripheral neuropathy (DPN) were also analyzed. RESULTS: The area under the ROC curve of MNSI and TCSS were 0.792, 0.704, respectively. The sensitivity, specificity, accuracy, Youden indexes and kappa values of MNSI over 2 and TCSS over 2 were 66.2%vs 73.3%, 90.4% vs 63.7%, 78.3% vs 68.5%, 0.566 vs 0.370, and 0.588 vs 0.345, respectively. MNSI was better than TCSS in the effectiveness of diagnosing ADPN and consistence with the result of NET. Moreover, MNSI was associated with the most related risk factors of DPN including age, glycosylated hemoglobin (HbA1c), HbA1c * disease duration, islet function and HDL-C. CONCLUSIONS: MNSI could be used as a relatively simple and reliable method for clinical and epidemiological screening and assessment of ADPN. PMID- 22490753 TI - [The prevalence and risk factors of kidney disease in type 2 diabetic patients in rural Shanghai]. AB - OBJECTIVE: To identify the prevalence and etiology of kidney disease and the related risk factors in type 2 diabetic patients in rural Shanghai. METHODS: A cross-sectional study in type 2 diabetic patients was conducted in a community of Shanghai. Questionnaire, clinical examination and laboratory tests were completed to collect the information about sociodemographic and healthcare characteristics. RESULTS: A total of 1421 eligible patients with complete information were screened from 1487 type 2 diabetic patients between November 2008 and March 2009. Of them, 40.75% were men, 59.25% were women, aged 37 - 86 (61.33 +/- 9.65) years old, with diabetic duration of 0.25 - 43.92 (7.85 +/- 6.34) years. Among them, 43.42% had diabetic retinopathy, 21.18% had neuropathy; 69.95% met the screening definition for hypertension, 76.07% for hyperlipidemia, 15.55% for hyperuricemia and 23.65% for cardiovascular disease. The control rates of fasting blood glucose, glycosylated hemoglobin, blood pressure and serum cholesterol were 57.71%, 33.99%, 14.22% and 2.46%, respectively. The prevalence of kidney disease, diabetic nephropathy and non-diabetic renal disease was 41.31%, 18.51% and 13.44%, respectively; and 9.36% were diagnosed as renal insufficiency of unknown reasons. Age, diabetic duration, hyperuricemia, diabetic retinopathy and poor control of blood pressure were independently associated with kidney disease; age and poor control of blood pressure were independently associated with diabetic nephropathy; age and hyperuricemia were independent risk factors of renal insufficiency in patients with diabetic nephropathy. CONCLUSIONS: Although the diabetic duration of these subjects is relatively short, the prevalence of complications including diabetic nephropathy is high. The high prevalence of non diabetic renal disease shows the importance of further screening and diagnoses for prevention. Strict control of blood glucose, blood pressure, serum cholesterol and serum uric acid are key points of cutting down the prevalence of diabetic nephropathy and chronic kidney disease. PMID- 22490754 TI - [A clinical analysis of reninoma-induced hypertensive crisis associated with reversible posterior encephalopathy syndrome]. AB - OBJECTIVE: Reninoma is a rare benign tumor of the renal juxtaglomerular cell apparatus that causes hypertension and hypokalemia via hypersecretion of renin, while it is extremely rare that reninoma induced hypertensive crisis with reversible posterior encephalopathy syndrome (RPES). To improve the clinical understanding for this disease, we conducted a case-analysis. METHODS: To analyze the clinical and pathological data of a case of reninoma-induced hypertensive crisis with reversible posterior encephalopathy syndrome, who was admitted to Peking University First Hospital in November, 2007 and follow-up. RESULTS: This was a 16-year old female patient, onset with suddenly spasm with loss of consciousness, while blood pressure stepped up to 210/140 mm Hg (1 mm Hg = 0.133 kPa), and the head magnetic resonance imaging (MRI) revealed "multiple long-T(2) signal", and hypokalemia (2.8 - 3.2 mmol/L), urine protein positive, ultrasound cardiogram revealed left ventricular hypertrophy, laboratory study revealed hyperreninism (38.23 ng.ml(-1)*h(-1), normal range 0.07 - 1.15 ng.ml(-1)*h(-1)) and hyperaldosteronism (660.9 ng/L, normal range 60 - 174 ng/L), abdominal CT Scan revealed a mass at right kidney, blood pressure achieved safety range and the head MRI was rechecked and revealed "the abnormal long-T(2) signal disappeared". The clinical diagnosis was reninoma induced hypertensive crisis with RPES. The tumor was resected and the pathologic diagnosis was reninoma. The patient remained normotensive in the postoperative period without any medication. CONCLUSIONS: Reninoma represents a rare but surgically curable cause of hypertension, thus the clinical suspicion of it is very important in young patients. If the diagnosis is confirmed, positive treatment must be done immediately to improve the prognosis. The most common cause of RPES is hypertension, and the diagnosis depends on the distinctive head MRI. There is always a good prognosis with the decline of blood pressure rapidly. PMID- 22490755 TI - [The cardiac function changes before and after pituitary tumor resection in patients with pituitary adenoma complicated with dilated cardiomyopathy]. AB - OBJECTIVE: To evaluate the cardiac function changing before and after resection of pituitary tumor in patients with pituitary adenoma complicated with dilated cardiomyopathy with retrospective analysis method. METHODS: The clinical data of 14 cases of patients with pituitary adenoma complicated with dilated cardiomyopathy, treated with resection of pituitary tumor, in PLA General Hospital, from 2005 to 2011, were collected and analyzed. Comparative analysis of cardiac function were made in these patients before and after the surgery, also with the postoperative recovery status, using echocardiography and other noninvasive detection means to detect the growth hormone (GH), left ventricular end-diastolic diameter (LVEDD), septal thickness (ST), left ventricular posterior wall thickness (LVPWT), left ventricular ejection fraction (LVEF) values. RESULTS: After the resection of pituitary tumor, the LVEDD, ST, LVPWT, LVEF levels were all significantly better than that before the surgery. Before the surgery the GH, ST, LVPWT, LVEF levels were 93.89 ug/L, 11.13 mm, 43.92% and 10.53 mm, while those after the surgery were 5.16 ug/L, 10.64 mm, 49.28% and 8.87 mm. The difference of the GH level before and after the surgery was correlated with the difference of ST, LVEDD and LVEF in a linear manner. CONCLUSIONS: Resection of pituitary tumor can significantly improve the cardiac function in patients with pituitary adenoma complicated with dilated cardiomyopathy, and the cardiac function improving level is correlated with the difference of GH levels before and after the surgery. PMID- 22490756 TI - [The value of SYNTAX score in predicting outcome patients undergoing percutaneous coronary intervention]. AB - OBJECTIVE: To assess the value of SYNTAX score to predict major adverse cardiac and cerebrovascular events (MACCE) among patients with three-vessel or left-main coronary artery disease undergoing percutaneous coronary intervention. METHODS: 190 patients with three-vessel or left-main coronary artery disease undergoing percutaneous coronary intervention (PCI) with Cypher select drug-eluting stent were enrolled. SYNTAX score and clinical SYNTAX score were retrospectively calculated. Our clinical Endpoint focused on MACCE, a composite of death, nonfatal myocardial infarction (MI), stroke and repeat revascularization. The value of SYNTAX score and clinical SYNTAX score to predict MACCE were studied respectively. RESULTS: 29 patients were observed to suffer from MACCE, accounting 18.5% of the overall 190 patients. MACCE rates of low (<= 20.5), intermediate (21.0 - 31.0), and high (>= 31.5) tertiles according to SYNTAX score were 9.1%, 16.2% and 30.9% respectively. Both univariate and multivariate analysis showed that SYNTAX score was the independent predictor of MACCE. MACCE rates of low (<= 19.5), intermediate (19.6 - 29.1), and high (>= 29.2) tertiles according to clinical SYNTAX score were 14.9%, 9.8% and 30.6% respectively. Both univariate and multivariate analysis showed that clinical SYNTAX score was the independent predictor of MACCE. ROC analysis showed both SYNTAX score (AUC = 0.667, P = 0.004) and clinical SYNTAX score (AUC = 0.636, P = 0.020) had predictive value of MACCE. Clinical SYNTAX score failed to show better predictive ability than the SYNTAX score. CONCLUSIONS: Both SYNTAX score and clinical SYNTAX score could be independent risk predictors for MACCE among patients with three-vessel or left main coronary artery disease undergoing percutaneous coronary intervention. Clinical SYNTAX score failed to show better predictive ability than the SYNTAX score in this group of patients. PMID- 22490757 TI - [A study of motor unit number estimation by multiple point stimulation in patients with Hirayama disease]. AB - OBJECTIVE: To explore the significance of motor unit number estimation (MUNE) by using multiple point stimulating technique to evaluate patients with Hirayama disease (HD). METHODS: Multiple point stimulating technique was used to estimate the motor unit number of abductor pollicis brevis and abductor digiti minimi in 35 normal subjects [14 - 33 years old, mean (20.9 +/- 4.0) years old, 33 men and 2 women] without nerve and muscle disease and 69 patients definitely diagnosed as HD [16 - 35 years old, mean (21.46 +/- 6.61) years old, 67 men and 2 women]. The differences between the two groups were examined by Fisher's exact test and t test. RESULTS: There were 42 patients with atrophy and 27 patients with normal clinical manifestation of left hand. For right hand there were 54 patients with atrophy and 15 normal. For controls, the MUNE value of left abductor pollicis brevis was 226.97 +/- 30.59, while that of right side was 228.31 +/- 25.35. The MUNE value of left abductor digiti minimi was 237.43 +/- 30.78, while that of right side was 240.20 +/- 37.73. For HD patients, the MUNE of left abductor pollicis brevis and abductor digiti minimi was 145.66 +/- 126.10 (t = 5.07, P < 0.01) and 102.20 +/- 112.67 (t = 9.31, P < 0.01) respectively, while those of right hand was 149.72 +/- 117.80 (t = 5.31, P < 0.01) and 64.23 +/- 69.27 (t = 16.76, P < 0.01) respectively. MUNE of left abductor digiti minimi in 17 patients that was below 200 among 27 patients with normal clinical manifestation (chi(2) = 9.57, P = 0.002). MUNE of right abductor digiti minimi in 12 patients that was below 200 among 15 patients with normal clinical manifestation (chi(2) = 4.64, P = 0.03). CONCLUSIONS: The differences of MUNE values by multiple point stimulating technique between the normal subjects and the HD patients is significant, which suggests this method is very useful to evaluate HD in the early state. PMID- 22490758 TI - [The efficacy and safety of low-dose rituximab in treatment of primary Sjogren's syndrome with thrombocytopenia]. AB - OBJECTIVE: To investigate the clinical efficacy and safety of low-dose rituximab (RTX) for patients in primary Sjogren's syndrome (pSS) with thrombocytopenia. METHODS: Four pSS patients, 2 with refractory thrombocytopenia and 2 with glucocorticoid-dependent thrombocytopenia, were treated with rituximab at 100 mg, intravenous, weekly for a total of two cycles, together with prednisone 1 - 2 mg*kg(-1)*d(-1), and the counts of platelets and B-cells were evaluated. RESULTS: Efficacy of treatment was observed in all patients. The counts of platelets, at (3 - 39) * 10(9)/L baseline, increased in 1 - 2 weeks, and went up to (107 - 241) * 10(9)/L in 3 - 8 weeks. Sustained remission had been achieved for 27 - 52 weeks. The doses of prednisone were tappered to 3.75 - 7.50 mg/day in 12 weeks. One patient who relapsed at the 27th week (platelet count 47 * 10(9)/L), was retreated with 100 mg of RTX and still had good efficacy. The counts of B-cells reduced to (0.007 - 0.010) * 10(9)/L, but they did not achieved the depletion. There were no severe adverse events during RTX therapy. CONCLUSIONS: Our study has shown good efficacy and tolerability of low-dose RTX for pSS with thrombocytopenia. Low-dose RTX allows for reduction in corticosteroid doses and B cells, while large-scale randomized double-blind controlled trials are needed to confirm the results. PMID- 22490759 TI - [An analysis of the clinicopathological features and misdiagnosis of 16 adults pulmonary sequestration]. AB - OBJECTIVE: To explore the clinicopathological features of adult pulmonary sequestration and summarize the misdiagnosis experiences. METHODS: Data of 16 cases of adult pulmonary sequestration (18 years), who were confirmed by surgery and biopsy in our hospital were collected and reviewed. RESULTS: The median age of all the patients was 38.5 years. The female seemed to be more likely to suffer from adult pulmonary sequestration (n = 12) with cough to be the most frequent symptom (n = 9). CT scans revealed most of the lesions were located in the left lower lobes of the lungs (n = 9). Half of the lesions were characterized by pulmonary cyst-like changes and/or multiple cystic bronchiectasis (n = 8), followed by soft tissue mass in or out of the lung fields (n = 7). Enhanced CT scans showed abnormal arteries from the systemic circulation. Only two cases were diagnosed as pulmonary sequestration correctly in the primary diagnosis. The remaining were mostly misdiagnosed as pulmonary cyst-like changes with bronchiectasis (n = 6) or tumors (n = 6). According to the findings during surgery, 13 cases were intralobar pulmonary sequestrations; 3 cases were extralobars, whose tissues were all detected dysplasia and chronic inflammatory by histopathological examinations. CONCLUSIONS: The misdiagnosis rate of pulmonary sequestration is high because of its non-specific clinical symptoms. Since it is characterized by abnormal arteries and pulmonary dysplasia, enhanced CT scans should be used as a preferred screening method for suspected cases, especially for those middleaged patients with cystic or mass-like lesions in the left lower lobes of the lungs. PMID- 22490760 TI - [A study of the relationship between neutropenia and clinical infection risk during treatment with peginterferon alfa-2a and ribavirin for chronic hepatitis C]. AB - OBJECTIVE: To investigate the correlation between neutropenia (ANC) incidence and infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C. METHODS: A retrospective cohort study of 399 patients treated with peginterferon and ribavirin derived from database of Department of Infectious Diseases, the Second Affiliated Hospital, Harbin Medical University was conducted. The incidence of infections and their relation with ANC were investigated. Potential risk factors for infection were identified by multivariate analysis. RESULTS: During treatment, neutropenia (ANC < 1.50 * 10(9)/L) occurred in 251 patients. Among which, mild neutropenia [ANC: (> 0.75 - < 1.50) * 10(9)/L], moderate neutropenia [ANC: (0.50 - 0.75) * 10(9)/L] and severe neutropenia (ANC < 0.50 * 10(9)/L) occurred in 132 patients, 103 patients and 16 patients, respectively. A total of 80 infections (20.1%) occurred, among which, 14 infections were defined as severe. There was no significant difference in infection rate between patients with and without neutropenia (19.9%, 50/251 vs 20.3%, 50/251; chi(2) = 0.007, P = 0.933). There was no significant difference in infection rate between patients with and without peginterferon dose reduction (21.5%, 31/144 vs 19.2%, 49/255; chi(2) = 0.307, P = 0.580). In multivariate logistic regression analysis, the independent factors associated with infection were age (P = 0.021), diabetes (P = 0.004) and cirrhosis (P = 0.012). CONCLUSIONS: Infections during treatment with peginterferon alfa and ribavirin for chronic hepatitis C are irrelevant to neutropenia. The independent factors associated with infection are age, diabetes and cirrhosis. PMID- 22490761 TI - No significant improvement of cardiovascular disease risk indicators by a lifestyle intervention in people with familial hypercholesterolemia compared to usual care: results of a randomised controlled trial. AB - BACKGROUND: People with Familial Hypercholesterolemia (FH) may benefit from lifestyle changes supporting their primary treatment of dyslipidaemia. This project evaluated the efficacy of an individualised tailored lifestyle intervention on lipids (low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), total cholesterol (TC) and triglycerides), systolic blood pressure, glucose, body mass index (BMI) and waist circumference in people with FH. METHODS: Adults with FH (n = 340), recruited from a Dutch cascade screening program, were randomly assigned to either a control group or an intervention group. The personalised intervention consisted of web-based tailored lifestyle advice and personal counselling. The control group received care as usual. Lipids, systolic blood pressure, glucose, BMI, and waist circumference were measured at baseline and after 12 months. Regression analyses were conducted to examine differences between both groups. RESULTS: After 12 months, no significant between-group differences of cardiovascular disease (CVD) risk indicators were observed. LDL-C levels had decreased in both the intervention and control group. This difference between intervention and control group was not statistically significant. CONCLUSIONS: This project suggests that an individually tailored lifestyle intervention did not have an additional effect in improving CVD risk indicators among people with FH. The cumulative effect of many small improvements in all indicators on long term CVD risk remains to be assessed in future studies. TRIAL REGISTRATION: NTR1899 at ww.trialregister.nl. PMID- 22490762 TI - Airway constriction in asthma during sustained emotional stimulation with films. AB - BACKGROUND: Individuals with asthma have been shown to respond to unpleasant stimuli with bronchoconstriction, but little is known about the time course of responding during sustained emotional stimulation and whether it varies with patients' experience. OBJECTIVE: To examine the time course of oscillatory resistance (R(os)) during emotionally evocative films in 15 asthma patients and 14 healthy controls. METHODS: Participants viewed unpleasant, surgery, and neutral films, each ranging 3-5min in duration. R(os) and the respiratory pattern (respiration rate, tidal volume, minute ventilation) were monitored continuously. Following each film, participants rated their affective response and symptoms. The time course of R(os) during films was explored using multilevel modeling. RESULTS: Compared to neutral film sequences, unpleasant films (including those with surgery scenes) elicited a uniform pattern of initial increases in R(os) with peaks within the first 1-2min, followed by a gradual decline. Increases were more pronounced in asthma and during surgery films. Including additional respiratory parameters as time-varying covariates did not affect the temporal course of R(os) change. The rate of decline in R(os) (after the initial increase) was less in participants who experienced greater arousal and in patients who reported more shortness of breath. Patients more susceptible to psychological triggers in daily life showed slower rates of decline in R(os). CONCLUSION: The temporal course of bronchoconstriction to unpleasant stimulation is highly uniform in asthma, with strong constriction in early stages of stimulation. More sustained constriction in emotion-induced asthma could be a risk factor for developing asthma exacerbation in daily life. PMID- 22490763 TI - Somatic aphasia: mismatch of body sensations with autonomic stress reactivity in psychopathy. AB - BACKGROUND: Although one of the main characteristics of psychopaths is a deficit in emotion, it is unknown whether they show a fundamental impairment in appropriately recognizing their own body sensations during an emotion-inducing task. METHOD: Skin conductance and heart rate were recorded in 138 males during a social stressor together with subjective reports of body sensations. Psychopathic traits were assessed using the Psychopathy Checklist-Revised (PCL-R) 2nd edition (Hare, 2003). RESULTS: Nonpsychopathic controls who reported higher body sensations showed higher heart rate reactivity, but this verbal-autonomic consistency was not found in psychopathic individuals. This mind-body disconnection is particularly associated with the interpersonal-affective factor of psychopathy. CONCLUSIONS: Findings are the first to document this body sensation-autonomic mismatch in psychopaths, and suggest that somatic aphasia - the inaccurate identification and recognition of one's own somatic states - may partly underlie the interpersonal-affective features of psychopathy. PMID- 22490764 TI - Biologically targeted therapeutics in pediatric brain tumors. AB - Pediatric brain tumors are often difficult to cure and involve significant morbidity when treated with traditional treatment modalities, including neurosurgery, conventional chemotherapy, and radiotherapy. During the past two decades, a clearer understanding of tumorigenesis, molecular growth pathways, and immune mechanisms in the pathogenesis of cancer has opened up promising avenues for therapy. Pediatric clinical trials with novel biologic agents are underway to treat various pediatric brain tumors, including high and low grade gliomas and embryonal tumors. As the therapeutic potential of these agents undergoes evaluation, their toxicity profiles are also becoming better understood. These agents have potentially better central nervous system penetration and lower toxicity profiles compared with conventional chemotherapy. In infants and younger children, biologic agents may prove to be of equal or greater efficacy compared with traditional chemotherapy and radiation therapy, and may reduce the deleterious side effects of traditional therapeutics on the developing brain. Molecular pathways implicated in pediatric brain tumors, agents that target these pathways, and current clinical trials are reviewed. Associated neurologic toxicities will be discussed subsequently. Considerable work is needed to establish the efficacy of these agents alone and in combination, but pediatric neurologists should be aware of these agents and their rationale. PMID- 22490766 TI - Identification of TSC1 and TSC2 mutations in Korean patients with tuberous sclerosis complex. AB - Tuberous sclerosis complex is a genetic disorder caused by mutations in the genes TSC1 or TSC2. Studies of these mutations are very rare in Korean populations. A previous study identified mutations in only 30% of patients by denaturing high performance liquid chromatography with sequencing. Here, we sought to determine the mutational frequency in Koreans. Eleven patients who fulfilled the diagnostic criteria for tuberous sclerosis complex were included. All patients underwent sequencing of both TSC genes, and if no mutations were evident, multiplex ligation-dependent probe amplification was performed. Mutations were detected by sequencing in 82% (9/11) of patients: 36.4% (4/11) in TSC1 and 45.5% (5/11) in TSC2. Two patients with no mutations carried large deletions that included exon 1 of TSC1 in one patient and exons 1-15 of TSC2 in the other patient. Mutations were completely identified in the present study. Therefore, mutation rates in Korean patients may not be lower than those in other ethnic groups. Direct sequencing followed by multiplex ligation-dependent probe amplification analysis may constitute a rational approach to identify disease-causing mutations in Korean patients. PMID- 22490765 TI - Neurotoxicity of biologically targeted agents in pediatric cancer trials. AB - Biologically targeted agents offer the promise of delivering specific anticancer effects while limiting damage to healthy tissue, including the central and peripheral nervous systems. During the past 5-10 years, these agents were examined in preclinical and adult clinical trials, and are used with increasing frequency in children with cancer. This review evaluates current knowledge about neurotoxicity from biologically targeted anticancer agents, particularly those in pediatric clinical trials. For each drug, neurotoxicity data are reviewed in adult (particularly studies of brain tumors) and pediatric studies when available. Overall, these agents are well tolerated, with few serious neurotoxic effects. Data from younger patients are limited, and more neurotoxicity may occur in the pediatric population because these agents target pathways that control not only tumorigenesis but also neural maturation. Further investigation is needed into long-term neurologic effects, particularly in children. PMID- 22490767 TI - Extracorporeal life support for critical enterovirus 71 rhombencephalomyelitis: long-term neurologic follow-up. AB - Enterovirus 71 rhombencephalomyelitis with cardiopulmonary dysfunction has become an endemic problem in Taiwan since an epidemic outbreak in 1998. Such cases frequently involve significant morbidity and mortality. From October 2000-June 2008, we collected 10 consecutive patients diagnosed with enterovirus 71 rhombencephalomyelitis complicated by left heart failure, with or without pulmonary edema, and surviving more than 3 months after receiving extracorporeal life support. Follow-up neurologic outcomes were analyzed prospectively. The median duration of neurologic follow-up was 7 years and 2 months. Significant morbidities included bulbar dysfunction, respiratory failure, and flaccid quadriparesis. Eight patients exhibited bulbar dysfunction, and feeding tubes could be removed from four patients (median, 15.5 months). Respiratory failure was observed in seven patients. Three patients were gradually withdrawn from their tracheostomy tube (median period, 30 months). Intelligence tests revealed four patients with normal cognitive function, one with borderline cognitive function, and one with mild mental retardation. Four were bedridden survivors. Extracorporeal life support for critical enterovirus 71 rhombencephalomyelitis demonstrated decreased neurologic sequelae during long-term follow-up, allowing for decannulation of feeding and tracheostomy tubes, and resulting in improved cognitive function. PMID- 22490768 TI - Cognitive profiles of neurofibromatosis type 1 patients with minor brain malformations. AB - Neurofibromatosis type 1 is a genetic condition associated with increased risk of abnormal brain development. The relationship between a specific type of brain malformation and a distinct cognitive sign/deficiency remains unknown. This study investigated the frequency of brain malformations in children with neurofibromatosis type 1, and the impact of those brain malformations on cognitive performance. A retrospective examination was performed of cranial magnetic resonance imaging and clinical records in 604 neurofibromatosis type 1 patients. Eighteen patients with brain malformations and intellectual evaluations were available and compared to a subset of neurofibromatosis type 1 patients (n = 20) without brain malformations. The most common brain malformations included hypothalamic hamartomas and Chiari I malformation. More complex migration disorders were also observed. Comparisons of cognitive profiles between groups revealed differences in patients with hamartomas compared with those manifesting Chiari I malformations or control subjects. As a group, those with hamartomas demonstrated below-average global intellect, whereas patients with Chiari I or no malformations performed in the average range. Disorders in cell organization, expressed as brain malformations (hamartomas or more complex defects), may comprise part of the expression of organizational and developmental defects in patients with neurofibromatosis type 1 and possibly other rat sarcoma gene mitogen activated protein kinase pathway disorders. PMID- 22490769 TI - Inheritance of febrile seizures in sudden unexplained death in toddlers. AB - Sudden unexplained death in toddlers has been associated with febrile seizures, family history of febrile seizures, and hippocampal anomalies. We investigated the mode of inheritance for febrile seizures in these families. A three generation pedigree was obtained from families enrolled in the San Diego Sudden Unexplained Death in Childhood Research Project, involving toddlers with sudden unexplained death, febrile seizures, and family history of febrile seizures. In our six cases, death was unwitnessed and related to sleep. The interval from last witnessed febrile seizure to death ranged from 3 weeks to 6 months. Hippocampal abnormalities were identified in one of three cases with available autopsy sections. Autosomal dominant inheritance of febrile seizures was observed in three families. A fourth demonstrated autosomal dominant inheritance with incomplete penetrance or variable expressivity. In two families, the maternal and paternal sides manifested febrile seizures. In this series, the major pattern of inheritance in toddlers with sudden unexplained death and febrile seizures was autosomal dominant. Future studies should develop markers (including genetic) to identify which patients with febrile seizures are at risk for sudden unexplained death in childhood, and to provide guidance for families and physicians. PMID- 22490770 TI - Social preferences in Rett syndrome. AB - Children with Rett syndrome manifest profound impairments in their ability to speak and use their hands, and exhibit a very limited repertoire of abilities to express themselves, to be neuropsychologically tested, and consequently to be understood. This study examined nonverbal cognitive abilities and visual preferences by analyzing the pattern of visual fixation in 49 girls with Rett syndrome, compared with a group of typical control subjects. The girls with Rett syndrome demonstrated a tendency toward socially weighted stimuli/social preferences. They looked at people, and into people's eyes. Eye tracking represents a feasible method to assess cognition, and provide insights into the burden of isolation of these children and the mismatch between their social preferences and incompetence, caused by movement disorder and apraxia. PMID- 22490771 TI - Amantadine for the treatment of refractory absence seizures in children. AB - Amantadine has demonstrated efficacy in small series for absence and myoclonic type seizures. We examined the efficacy of amantadine for treating refractory absence seizures in a cohort of pediatric patients. We retrospectively reviewed medical records for patients with absence seizures treated with amantadine at Cook Children's Medical Center after January 2007. Abstracted data included sex, age at initiation, concomitant antiepileptic drugs, amantadine dosing, and seizure frequency. Outcomes at 3, 6, and 12 months after initiation were categorized as >90%, >=50%, or <50% reduction in seizure frequency. Of 13 patients included in the study, many were exposed to multiple antiepileptic drugs (median, 3; range, 1-6). Three were implanted with a vagus nerve stimulator. A response of at least 50% seizure reduction was reported in more than 50% of patients reviewed at 3, 6, and 12 months after initiating treatment. Among responders, a majority had >90% reduction in seizure frequency. Amantadine may constitute an efficacious alternative treatment for refractory absence seizures. PMID- 22490772 TI - Nonparaneoplastic anti-N-methyl-D-aspartate receptor encephalitis: a case series of four children. AB - A rare, severe form of immune-mediated encephalitis recently has been described, associated with antibodies against N-methyl-D-aspartate receptors. It is reported mostly in women with ovarian tumors. Nonparaneoplastic presentations are less common. We describe four children with a neuropsychiatric and extrapyramidal syndrome associated with the presence of anti-N-methyl-D-aspartate receptor antibodies in cerebrospinal fluid and serum, without evidence of neoplasia. Three children recovered completely after immunomodulatory therapy, i.e., intravenous immunoglobulin and/or steroids, methylprednisolone, and/or adrenocorticotrophic hormone. PMID- 22490773 TI - Charles Bonnet syndrome after herpes simplex encephalitis. AB - Visual impairment associated with Charles Bonnet syndrome is rarely reported in childhood. We describe a child who presented with visual hallucinations and postinfectious bilateral retrobulbar optic neuritis. The patient had undergone acyclovir therapy for 3 weeks because of herpes encephalitis. Four days after therapy was completed, he experienced visual impairment in both eyes. He manifested a bilateral decrease in visual acuity, with normal funduscopic findings. The patient experienced visual hallucinations for about 1 week, and then experienced total loss of vision. During his hallucinations, the patient did not exhibit behavioral changes or cognitive impairment. The visual hallucinations included unfamiliar children hiding under his bed, and he spoke to someone whom he did not know. Magnetic resonance imaging indicated bilateral optic nerve hyperintensity on T(2)-weighted and contrast-enhanced images. The patient received corticosteroid therapy for his retrobulbar optic neuritis, and his vision returned to normal after 1 month. Although rare, visual impairment can be associated with complex visual hallucinations indicative of Charles Bonnet syndrome. PMID- 22490774 TI - Recurrent COLQ mutation in congenital myasthenic syndrome. AB - Congenital myasthenic syndromes comprise clinically and genetically heterogeneous disorders resulting from presynaptic, synaptic, or postsynaptic defects. Mutations in the COLQ gene result in acetylcholinesterase deficiency and cause a rare, autosomal recessive synaptic form of congenital myasthenic syndrome, with variable age of onset and clinical severity. We present four unrelated patients with a homozygous W148X mutation in the COLQ gene. Signs began at birth in all, but subsequent severity ranged from independent ambulation to wheelchair use during childhood. Treatment was partly effective; one patient was asymptomatic with 3,4-diaminopyridine treatment. These cases illustrate the clinical features and treatment results associated with this particular genotype, which appears to be relatively frequent among Turkish patients with congenital myasthenic syndrome. PMID- 22490775 TI - Central hypoventilation and brainstem dysgenesis. AB - We report on a newborn with congenital hypotonia, unilateral facial palsy, sucking and swallowing difficulties, velopalatine incoordination, and unilateral impairment of the auditory brainstem responses, attributable to brainstem dysgenesis. On follow-up, the child manifested developmental delay and central hypoventilation syndrome during sleep. The ventilation abnormality during sleep with insensitivity to hypercapnia, associated with unilateral facial paralysis, indicates a pontine lesion, including the parafacial respiratory group. PMID- 22490776 TI - Chronic inflammatory demyelinating polyneuropathy in common variable immunodeficiency. AB - Common variable immunodeficiency comprises a heterogeneous group of primary antibody deficiencies with complex clinical and immunologic phenotypes. Immune dysregulation leads to the generation of multiple autoantibodies against various antigenic targets in patients with common variable immunodeficiency. Chronic inflammatory demyelinating polyneuropathy is a heterogeneous disorder that indicates an autoimmune response against peripheral nerve myelin. We describe a 7 year-old girl with common variable immunodeficiency who developed chronic inflammatory polyneuropathy. A 5-day course of intravenous immunoglobulin (500 mg/kg/day) improved her neurologic disorder. Chronic inflammatory demyelinating polyneuropathy should be added to the broadening spectrum of neurologic complications in common variable immunodeficiency. Early detection and consequent treatment may reverse the neurologic sequelae. PMID- 22490777 TI - Locked-in syndrome in three children with Guillain-Barre syndrome. PMID- 22490779 TI - On the estimation of heat-intensity and heat-duration effects in time series models of temperature-related mortality in Stockholm, Sweden. AB - BACKGROUND: We examine the effect of heat waves on mortality, over and above what would be predicted on the basis of temperature alone. METHODS: Present modeling approaches may not fully capture extra effects relating to heat wave duration, possibly because the mechanisms of action and the population at risk are different under more extreme conditions. Modeling such extra effects can be achieved using the commonly left-out effect-modification between the lags of temperature in distributed lag models. RESULTS: Using data from Stockholm, Sweden, and a variety of modeling approaches, we found that heat wave effects amount to a stable and statistically significant 8.1-11.6% increase in excess deaths per heat wave day. The effects explicitly relating to heat wave duration (2.0-3.9% excess deaths per day) were more sensitive to the degrees of freedom allowed for in the overall temperature-mortality relationship. However, allowing for a very large number of degrees of freedom indicated over-fitting the overall temperature-mortality relationship. CONCLUSIONS: Modeling additional heat wave effects, e.g. between lag effect-modification, can give a better description of the effects from extreme temperatures, particularly in the non-elderly population. We speculate that it is biologically plausible to differentiate effects from heat and heat wave duration. PMID- 22490780 TI - P2X7 receptor-stimulation causes fever via PGE2 and IL-1beta release. AB - Prostaglandins (PGs) are important lipid mediators involved in the development of inflammatory associated pain and fever. PGE2 is a well-established endogenous pyrogen activated by proinflammatory cytokine interleukin (IL)-1beta. P2X7 receptors (P2X7Rs) expressed by inflammatory cells are stimulated by the danger signal extracellular ATP to activate the inflammasome and release IL-1beta. Here we show that P2X7R activation is required for the release of PGE2 and other autacoids independent of inflammasome activation, with an ATP EC(50) for PGE2 and IL-1beta release of 1.58 and 1.23 mM, respectively. Furthermore, lack of P2X7R or specific antagonism of P2X7R decreased the febrile response in mice triggered after intraperitoneal LPS or IL-1beta inoculation. Accordingly, LPS inoculation caused intraperitoneal ATP accumulation. Therefore, P2X7R antagonists emerge as novel therapeutics for the treatment for acute inflammation, pain and fever, with wider anti-inflammatory activity than currently used cyclooxygenase inhibitors. Barbera-Cremades, M., Baroja-Mazo, A., Gomez, A. I., Machado, F., Di Virgilio, F., Pelegrin, P. P2X7 receptor-stimulation causes fever via PGE2 and IL-1beta release. PMID- 22490781 TI - Identification of a novel amyloid precursor protein processing pathway that generates secreted N-terminal fragments. AB - Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system. The proteolytic processing of the amyloid precursor protein (APP) into the beta-amyloid (Abeta) peptide is a central event in AD. While the pathway that generates Abeta is well described, many questions remain concerning general APP metabolism and its metabolites. It is becoming clear that the amino-terminal region of APP can be processed to release small N-terminal fragments (NTFs). The purpose of this study was to investigate the occurrence and generation of APP NTFs in vivo and in cell culture (SH-SY5Y) in order to delineate the cellular pathways implicated in their generation. We were able to detect 17- to 28-kDa APP NTFs in human and mouse brain tissue that are distinct from N-APP fragments previously reported. We show that the 17- to 28-kDa APP NTFs were highly expressed in mice from the age of 2 wk to adulthood. SH-SY5Y studies indicate the generation of APP NTFs involves a novel APP processing pathway, regulated by protein kinase C, but independent of alpha-secretase or beta-secretase 1 (BACE) activity. These results identify a novel, developmentally regulated APP processing pathway that may play an important role in the physiological function of APP. PMID- 22490784 TI - The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of pediatric acute lymphoblastic leukemia: update of the 2005 evidence based review. ASBMT Position Statement. PMID- 22490782 TI - Heme oxygenase-1 regulates the immune response to influenza virus infection and vaccination in aged mice. AB - Underlying mechanisms of individual variation in severity of influenza infection and response to vaccination are poorly understood. We investigated the effect of reduced heme oxygenase-1 (HO-1) expression on vaccine response and outcome of influenza infection. HO-1-deficient and wild-type (WT) mice (kingdom, Animalia; phylum, Chordata; genus/species, Mus musculus) were infected with influenza virus A/PR/8/34 with or without prior vaccination with an adenoviral-based influenza vaccine. A genome-wide association study evaluated the expression of single nucleotide polymorphisms (SNPs) in the HO-1 gene and the response to influenza vaccination in healthy humans. HO-1-deficient mice had decreased survival after influenza infection compared to WT mice (median survival 5.5 vs. 6.5 d, P=0.016). HO-1-deficient mice had impaired production of antibody following influenza vaccination compared to WT mice (mean antibody titer 869 vs. 1698, P=0.02). One SNP in HO-1 and one SNP in the constitutively expressed isoform HO-2 were independently associated with decreased antibody production after influenza vaccination in healthy human volunteers (P=0.017 and 0.014, respectively). HO-1 deficient mice were paired with sex- and age-matched WT controls. HO-1 affects the immune response to both influenza infection and vaccination, suggesting that therapeutic induction of HO-1 expression may represent a novel adjuvant to enhance influenza vaccine effectiveness. PMID- 22490785 TI - A retrospective study on endovascular management of iatrogenic vascular injuries. AB - The purpose of this study was to evaluate the outcome of endovascular management of iatrogenic vascular injuries (IVIs). We retrospectively reviewed the clinical records of 19 consecutive patients who underwent endovascular therapy of IVIs. Endograft implantation was conducted in 13 patients, intravascular embolization using coil was performed in four patients, combined treatment involving endovascular balloon intervention and percutaneous thrombin injection was done in one patient and the remaining one patient received balloon compression for hemostasis. There were no deaths after the operation. In the patients with vessel rupture (n = 9) or perforation (n = 4), cessation of bleeding and restoration of blood flow were achieved following the endovascular treatments. Four cases of pseudoaneurysm and one case of arteriovenous fistula were successfully eliminated. At a median follow-up of 23.8 months (range 4-84), one patient suffered a mild cerebral infarction secondary to covered stent placement and one patient developed a partial renal infarction secondary to coil embolization. Additionally, stent collapse was found in one patient with stenosis of the iliofemoral vein, accounting for the failure to resolve the lower limb edema. In conclusion, endovascular therapy is an effective technique in the management of different types of IVIs, but is associated with minor ischemic complications. PMID- 22490787 TI - [Diabetic peripheral arterial disease: a overlooked problem by the clinician]. PMID- 22490788 TI - [Pharmacotherapy in diabetics with arterial occlusion of lower extremity]. PMID- 22490786 TI - The NAMPT inhibitor FK866 reverts the damage in spinal cord injury. AB - BACKGROUND: Emerging data implicate nicotinamide phosphoribosyl transferase (NAMPT) in the pathogenesis of cancer and inflammation. NAMPT inhibitors have proven beneficial in inflammatory animal models of arthritis and endotoxic shock as well as in autoimmune encephalitis. Given the role of inflammatory responses in spinal cord injury (SCI), the effect of NAMPT inhibitors was examined in this setting. METHODS: We investigated the effects of the NAMPT inhibitor FK866 in an experimental compression model of SCI. RESULTS: Twenty-four hr following induction of SCI, a significant functional deficit accompanied widespread edema, demyelination, neuron loss and a substantial increase in TNF-alpha, IL-1beta, PAR, NAMPT, Bax, MPO activity, NF-kappaB activation, astrogliosis and microglial activation was observed. Meanwhile, the expression of neurotrophins BDNF, GDNF, NT3 and anti-apoptotic Bcl-2 decreased significantly. Treatment with FK866 (10 mg/kg), the best known and characterized NAMPT inhibitor, at 1 h and 6 h after SCI rescued motor function, preserved perilesional gray and white matter, restored anti-apoptotic and neurotrophic factors, prevented the activation of neutrophils, microglia and astrocytes and inhibited the elevation of NAMPT, PAR, TNF-alpha, IL-1beta, Bax expression and NF-kappaB activity.We show for the first time that FK866, a specific inhibitor of NAMPT, administered after SCI, is capable of reducing the secondary inflammatory injury and partly reduce permanent damage. We also show that NAMPT protein levels are increased upon SCI in the perilesional area which can be corrected by administration of FK866. CONCLUSIONS: Our findings suggest that the inflammatory component associated to SCI is the primary target of these inhibitors. PMID- 22490789 TI - [Reflections on the treatment of burn patients in disaster medicine rescue]. PMID- 22490790 TI - [Clinical characteristics and medical costs of diabetics with amputation at central urban hospitals in China]. AB - OBJECTIVE: To explore the clinical characteristics, medical costs and its influencing factors in diabetics with amputation. METHODS: The data of diabetic amputation for the whole year of 2010 at 39 central municipal Class 3A hospitals all across China were retrospectively analyzed according to a unified protocol, including demographic characteristics, diabetic complications, classification of diabetic foot disease, level and prognosis of amputation and medical costs at hospitals. RESULTS: Among them, 28.2% of all amputated patients or 39.5% of non traumatic patients were diabetics. There were 313 males and 162 females. The average age and duration of diabetes were (66 +/- 12) years and (130 +/- 94) months. The level of HbA1c was 8.9% +/- 2.4%. Among all amputated diabetics, the concurrent conditions included neuropathy (50.1%), peripheral artery disease (74.8%), nephropathy (28.4%) and retinopathy (25.9%). The patients with foot ulcer at Wagner 4 (50.3%) were more common. Among them, 67.5% had minor amputation with a median hospitalization stay of 33.0 (24.0 - 45.0) days and a medical cost of 26 138 (16 155 - 46 021) yuan RMB. The duration of diabetes, diabetic complications, severity and location of ulcers and amputation level influenced their hospitalization durations and medical costs. CONCLUSION: The patients with diabetes and amputation are elder with more chronic diabetic complications and uncontrolled hyperglycemia. Most of them have complications of local gangrene and require minor amputation at admission. Their hospital stays are longer and medical costs higher significantly correlated with diabetic complications, severity and location of foot ulcers and level of amputations. PMID- 22490791 TI - [Risk factors for infections of methicillin-resistant Staphylococci in diabetic foot patients]. AB - OBJECTIVE: To examine the distribution patterns of pathogens isolated from the patients with diabetic foot ulcers and explore the risk factors for infections of methicillin-resistant S. aureus (MRSA) or methicillin-resistant S. epidermidis (MRSE). METHODS: A total of 388 diabetic-foot patients hospitalized at Tianjin Metabolic Diseases Hospital between January 2008 and June 2010 were recruited. The distribution profiles of pathogens isolated from diabetic foot ulcers were summarized. The patients with S. aureus infections were divided into MRSA and MSSA groups while those with S. epidermidis infections into MRSE and MSSE groups. The clinical features of these patients were compared between all groups. Logistic regression was employed to identify the risk factors for the MRSA/MRSE infections. RESULTS: A total of 362 pathogens were isolated from them. And the Gram-positive bacteria were the most predominant (57.2%, 207/362), followed by Gram-negative bacilli (39.2%, 142/362) and true fungi (3.6%, 13/362). The three most frequently isolated pathogens were S. aureus (27.1%), S. epidermidis (18.8%) and Pseudomonas aeruginosa (15.5%). Statistically significant differences existed in antibiotic usage in 6 months prior to hospitalization, course of ulcer, ulcer size, deep ulcer, osteomyelitis, hypertension, anemia, hypoproteinemia and erythrocyte sedimentation rate between the patients infected with MRSA and MSSA (P < 0.05). The MRSE infection was correlated with recurrent ulcer, osteomyelitis, hypoproteinemia, HbA1c and lower total serum protein (P < 0.05). Multiple Logistic regression analysis revealed that antibiotic usage in 6 months prior to hospitalization, long course of ulcer, osteomyelitis, hypertension and hypoproteinemia were risk factors for the MRSA infection. And HbA1c was a risk factor for the MRSE infection. CONCLUSION: In the present study, the Gram positive cocci are the main pathogens isolated from diabetic foot ulcers. And S. aureus and S. epidermidis are the most frequently isolated pathogens. Antibiotic usage in 6 months prior to hospitalization, long course of ulcer, osteomyelitis, hypertension and hypoproteinemia are risk factors for the MRSA infection. And HbA1c is a risk factor for the MRSE infection. PMID- 22490792 TI - [Variance of mean platelet volume in subjects with normal glucose tolerance, impaired glucose regulation and type 2 diabetic mellitus and its relationship with diabetic peripheral artery disease]. AB - OBJECTIVE: To explore the variance of mean platelet volume (MPV) in subjects with normal glucose tolerance (NGT), impaired glucose regulation (IGR) and type 2 diabetes mellitus (T2DM) and risk factors of MPV changes and analyze the relationship between MPV and diabetic peripheral artery disease (PAD). METHODS: A total of 173 subjects were enrolled into this observational cross-sectional study. They were divided into 3 groups: NGT (n = 41), IGR (n = 41) and T2DM (n = 91). Blood pressure (BP), platelet count (PLT), mean platelet volume (MPV) and such fasting serum lipids as triglycerides (TG), total cholesterol (TC), high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), fast plasma glucose (FPG) and serum uric acid (UA) were determined. HbA1c and ankle/brachial index (ABI) were also measured. RESULTS: (1) The MPV level was highest in the T2DM group (12.3 +/- 1.5) fl. And it was significantly higher in the IGR group than in the NGT group (9.7 +/- 0.9 vs 8.0 +/- 0.9) fl (P < 0.01). It was significantly higher in diabetics with HbA1c >= 7% (13.2 +/- 1.9) fl than in patients those with HbA1c 7% (11.8 +/- 1.7) fl (P < 0.01); (2) Stepwise multiple regression analysis showed that age, serum creatinine, LDL-C and fasting plasma glucose (FPG) were important influencing factors of MPV (adjusted R(2) = 0.891); (3) Multiple Logistic regression analysis indicated that MPV was an important risk factor of PAD. CONCLUSION: The MPV level in T2DM is significantly higher than that in NGT and IGR subjects. FPG, LDL-C, age and serum creatinine are important contributors to MPV. And MPV is an important risk factor of PAD. PMID- 22490793 TI - [Association of a high ankle brachial index with microvascular diseases of diabetes]. AB - OBJECTIVE: To evaluate the association of a high ankle brachial index (ABI) with microvascular diseases of diabetes and to compare its strength with that of a low ABI. METHODS: ABI was obtained in 3293 patients undergoing the screening of chronic complications at the Diabetic Center, No. 306 Hospital of PLA during the period of September 2003 to June 2010. The patient profiles and laboratory data were reviewed. The associations of ABI with microvascular diseases of diabetes were determined by univariate and stepwise Logistic regression analysis. RESULTS: ABI was normal in 3060 patients. 44 had ABI measurements < 0.7, 139 had ABI measurements between 0.7 - 0.9, and 50 had ABI measurements > 1.3. Multivariate analysis indicated that the factors significantly associated with a high ABI were smoking (OR: 2.605; 95%CI: 1.458 - 4.656, P = 0.001) and systolic blood pressure (OR: 1.019; 95%CI: 1.005 - 1.033, P = 0.006). The conditions of nephropathy, neuropathy and retinopathy were not associated with a high ABI. CONCLUSION: Diabetics with a high ABI carry not more adverse atherosclerotic risk factors and suffer no more severe microvascular diabetic complications than those with a normal ABI. PMID- 22490794 TI - [Managements of open wounds from an earthquake]. AB - OBJECTIVE: To explore the surgical managements of open wounds from 5.12 Wenchuan Earthquake. METHODS: In this report, fifty one patients with open wounds were treated after transported into West China Hospital from May 12 to 26 in 2008 after 5.12 Wenchuan Earthquake. Among 51 cases, open wounds were due to open fractures (n = 8), fasciotomy (n = 6), exposed bone (n = 8) and defects of skin and soft tissue (n = 29). All cases had wound infections. Sixty operations were performed, including muscle and myocutaneous flap (n = 4), skin grafting (n = 30), NPWT (negative pressure wound therapy) (n = 2) and debridement (n = 24). RESULTS: Four cases of muscle and myocutaneous flaps survived with an excellent blood circulation. And 30 cases of skin grafting had a survival rate of over 90%, 2 cases of NPWT and 24 cases of debridement required further treatment. CONCLUSION: With adequate surgical managements, open wound healing from an earthquake may be accelerated and the functions maximally preserved. PMID- 22490795 TI - [Characteristics and treatment of skin and soft-tissue defects caused by 5.12 Wenchuan earthquake]. AB - OBJECTIVE: To investigate the features and the treatment of skin and soft-tissue defects caused by 5.12 Wenchuan Earthquake. METHODS: From May 12 to June 7 in 2008, 37 injured persons (43 wounds) were treated in West China Hospital, including 20 males and 17 females with a mean age of 40 years old (range: 2 - 85). The wound locations included head (n = 2), trunk (n = 3), upper arm (n = 5), forearm (n = 5), thigh (n = 13) and lower extremity (n = 15). Their sizes ranged from 5 cm * 4 cm - 27 cm * 20 cm. In 19 cases (51.3%), the bacterial culture results of wound secretion were positive. After thorough debridement and supportive treatment, the wounds were covered by hydropathic dressings. When the infections were under control and granulation tissues grew well, the method of either skin grafting (41 wounds) or flap transposition (2 wounds) was employed to repair the wounds. The survival rate of skin flaps or free skin was used to evaluate the therapeutic efficacy. RESULTS: From Days 6-15 post-admission, the wounds were repaired by skin grafting or flap transposition. All free skin grafts and flaps achieved an excellent survival. Two flaps survived completely, 33 grafts survived > 95% and other 8 grafts > 90%. The stay of hospitalization lasted for 12 - 23 days. None of the patients had any symptom of severe systemic infections and all survived. CONCLUSIONS: Skin and soft-tissue defect wounds caused by earthquake are usually present in extremities and head. And there is a high incidence of local infections and severe contaminations. Early debridement, symptomatic supports and suturing by skin or flap transposition may repair the wounds as early as possible and contribute to a rapid recovery of patients. PMID- 22490796 TI - [Clinical study of oral alendronate in the treatment of pediatric osteogenesis imperfecta]. AB - OBJECTIVE: To explore the clinical efficacy and safety of oral alendronate in children with osteogenesis imperfecta (OI). METHODS: Eleven OI children were recruited from August 2008 to April 2011 at Shanghai Institute of Pediatric Research to receive alendronate for a duration of (1.7 +/- 0.3) years. The growth, fracture incidence, physical activity, the quality of daily life and safety parameters were evaluated. RESULTS: All patients obtained marked improvement. The rates of bone fractures decreased more remarkably than that at pre-treatment (0 - 1.2 fractures per year vs 0.5 - 5.0 fractures per year, medium 0 vs 1.40 fractures per year) (P = 0.003). Their levels of physical activities improved significantly (median level from 4 to 3, P = 0.004). There was significant post-treatment improvement in the self-care activity scores (median score from 43 to 73, P = 0.003). The bone density of lumbar vertebrae, long bones and metaphysis improved at post-treatment. The radiographic examinations revealed the thickness of bone cortex. The change in height did not show any significant difference. No change was found in the serum levels of calcium, phosphorus, parathyroid hormone, alkaline phosphate or other biochemical markers. No adverse reaction occurred throughout treatment. CONCLUSION: Oral alendronate treatment reduces the incidence of bone fracture and improves physical activity and life quality in OI children, and as a well-tolerated regimen, it is both safe and effective in clinical practice. PMID- 22490797 TI - [Prevalence status and mutation pattern of H221Y in subtype B' of HIV-1]. AB - OBJECTIVE: To explore the prevalence and mutation pattern of H221Y at reverse transcriptase (RT) among the subtype B' of human immunodeficiency virus1 (HIV-1) in antiviral therapy-failure patients. METHODS: A total of 1363 sequences, comprising of 1205 therapy-failure individuals and 158 therapy-naive individuals, were submitted to the Stanford HIV drug resistance database (SHDB) to analyze the frequency and mutation pattern of H221Y. RESULTS: The prevalence of mutation H221Y in the therapy-failure population was significantly higher than that of the therapy-naive (6.59% vs 0.60%) (chi(2) = 6.59, P = 0.027). The emergence of H221Y usually accompanied the position mutations of T215, M184, K103 and Y181 of RT, and the pattern of TAMs/H221Y/Y181C/I was common. Frequency of H221Y in the regimen of AZT/ddI/NVP was more popular than the other 4 regimens (14.6% vs 3.5%, 4.9%, 2.3%, 2.6%, all P < 0.01). CONCLUSION: With a unique mutation pattern, H221Y has a low prevalence in the individuals of first-line therapy-failure patients. PMID- 22490798 TI - [Identification of a novel pathogenic mutation in MATP gene with oculocutaneous albinism type IV from a consanguineous marriage family]. AB - OBJECTIVE: To clarify the pathogenicity-related genes and its mutations in an oculocutaneous albinism (OCA) patient from a consanguineous marriage family. METHODS: Polymerase chain reaction (PCR) and automatic DNA sequencing methods, chromosome walking by PCR amplification techniques (PCR-Walking), multiplex PCR in a single PCR tube with 3 primers bridging the breakpoint (Gap-PCR) and bioinformatic analysis were employed for screening the mutations and identifying the novel mutation in the patient and his family. RESULTS: A pathogenic deletion of 6365 bp was found in MATP gene with a range of c.562-1118 (+/- 2) to c.885 + 4923 (+/- 2). The patient was homozygous for deletion mutation. CONCLUSION: A large deletion mutation was first detected and identified in OCA4. PMID- 22490799 TI - [Applicability of anatomical vascular occlusion in hepatectomy for grand hepatocarcinoma]. AB - OBJECTIVE: To retrospectively explore the clinical efficacies and applicability of anatomical vascular occlusion (AVO) in hepatectomy for grand primary hepatocarcinoma at different locations. METHODS: A total of 212 grand primary hepatocarcinoma cases undergoing hepatectomy were divided into 2 groups by vascular occlusion in the process of resection: AVO group (n = 97) and Pringle group (Pringle maneuver, n = 115). According to whether or not tumor was adjacent to main vessels, the cases were divided into 2 types: centrally (n = 98) and peripherally (n = 114) located lesions. And the perioperative outcomes were compared between 2 groups totally and by types respectively. RESULTS: No significance existed between the AVO and Pringle groups in the demographic characteristics and tumor background (P > 0.05). For total cases, there were no significant differences between 2 groups regarding the intraoperative blood loss volume ((632 +/- 437) ml vs (546 +/- 549) ml, P = 0.217) and the blood transfusion requirement (44.3% vs 33.0%, P = 0.092). The AVO group showed significantly better postoperative liver functions in terms of serum levels of total bilirubin and aminotransferase (P > 0.05). But no significant difference was found between 2 groups in the postoperative complication rate (18.6% vs 22.6%, P = 0.469) and hospital stay duration ((10.5 +/- 4.8) vs (11.8 +/- 5.6) days, P = 0.087). In centrally located lesions: the AVO group showed a significantly smaller intraoperative blood loss volume ((722 +/- 492) ml vs (1032 +/- 618) ml, P = 0.007) and blood transfusion requirement (45.6% vs 68.3%, P = 0.026). Also the AVO group showed significantly better postoperative liver functions in terms of serum levels of total bilirubin and aminotransferase (P < 0.01). As a consequence, the AVO group had a significantly lower postoperative complication rate (19.3% vs 39.0%, P = 0.031) and a shorter hospital stay duration ((10.7 +/- 5.0) days vs (13.0 +/- 6.2) days, P = 0.042). In peripheral located lesions: there were significantly larger intraoperative blood loss volume (504 +/- 307 vs 278 +/- 237 ml, P = 0.000) and blood transfusion requirement (42.5% vs 13.5%, P = 0.001) in the AVO group. The postoperative liver functions (total bilirubin and aminotransferase levels, P > 0.05), postoperative complication rate (17.5% vs 13.5%, P = 0.808) and hospital stay duration ((10.3 +/- 4.6) days vs (11.1 +/- 5.1) days, P = 0.429) showed no significant differences between 2 groups. CONCLUSION: The technique of AVO is unsuitable for all types of grand hepatocarcinoma. Whether or not the tumor is adjacent to main vessels is an important consideration of choosing the vascular control technique. Considering the risk of vascular damage in the process of hepatectomy, the AVO technique is indicated for the resection of central lesions but not for peripheral lesions. PMID- 22490800 TI - [Expression and significance of Slug, E-cadherin and N-cadherin in gastrointestinal stromal tumors]. AB - OBJECTIVE: To explore the expression and clinical significance of Slug, E cadherin and N-cadherin in gastrointestinal stromal tumors (GIST). METHODS: Seventy eight GIST specimens removed surgically from 2004 to 2007 were collected from the Department of Gastrointestinal Surgery at Guizhou Provincial People's Hospital. There were 48 males and 30 females with an age range of 28 - 87 years old. The expressions of Slug, E-cadherin and N-cadherin in GIST were determined by immunohistochemistry. And the correlations with their clinicopathologic characteristics were analyzed. RESULTS: The positive rates of Slug, E-cadherin and N-cadherin in GIST were 53.8% (42/78), 35.9% (28/78) and 75.6% (59/78) respectively. And the differences were statistically significant (chi(2) = 24.98, P < 0.05). Slug was expressed markedly higher in the cases of GIST with distant metastasis or distant metastasis and local invasion: 75% (18/24) vs 44.4% (24/54), 63.6% (28/44) vs 41.2% (14/34), both P < 0.05. And E-cadherin was expressed markedly lower in the cases of GIST with distant metastasis: 16.7% (4/24) vs 44.4% (24/54), P < 0.05. The expression of N-cadherin was not significantly different between its clinicopathological characteristics (allP > 0.05). The expression of Slug correlated negatively with that of E-cadherin (r(s) = -0.267, P = 0.018). But it had no correlation with that of N-cadherin (r(s) = 0.056, P = 0.625). CONCLUSION: Slug is expressed markedly higher while E-cadherin markedly lower in metastatic GIST, and both are closely correlated with the metastasis of GIST. PMID- 22490801 TI - [Survey of quality of life scale for patients with congenital ear malformation]. AB - OBJECTIVE: To explore the congenital ear malformation (CEM)-specific quality of life (QOL) and examine the effects of total ear reconstruction surgery for QOL of CEM patients. METHODS: A self-composed QOL scale was used for 129 patients with congenital external and middle ear malformation. All patients were requested to fill in the QOL scale before and 1 month after ear reconstruction surgery. RESULTS: The level of QOL varied according to the degree of ear malformation. The total QOL score of patients with unilateral and bilateral CEM was 28.5 +/- 18.4 and 51.6 +/- 23.6, respectively. The total QOL score of patients pre- and post operation was 21.0 +/- 14.0 and 14.2 +/- 9.7 respectively. Physiological functions, psychological status and social interactions of the patients were of statistical significance after ear reconstruction surgery compared to that of at pre-operation. CONCLUSION: Congenital ear malformation-specific QOL scale can show sensitively the changes of QOL of CEM patients. And ear reconstruction surgery is beneficial for the patients. PMID- 22490802 TI - [Predictors and reasons for readmission into cardiac intensive care unit]. AB - OBJECTIVE: To evaluate the predictors and reasons for readmission into cardiac intensive care unit (ICU). METHODS: A total of 4978 patients underwent cardiac surgery between January 2008 and August 2010. The perioperative risk factors for readmission were analyzed by multivariate regression. And the reasons, outcomes and therapy were analyzed. RESULTS: Among them, 139 patients required ICU readmission. There were 80 males and 59 females with a mean age of 50.3 years (range: 9 - 78). Their median length of first and second stays were 2.00 (1.00 - 4.00) and 3.00 (1.00 - 5.00) days respectively. The median interval from ICU discharge to ICU readmission was 3 (2.00 - 6.75) days and the median hospital stay 24.00 (16.00 - 41.25) days. Readmitted patients had a higher mortality rate than those requiring no readmission (9.4% vs 0.4%, P < 0.01). The major reasons for readmission were respiratory (n = 69, 49.6%) and circulatory complications (n = 33, 23.7%). Multivariate analysis showed that NYHA (New York Heart Association) classification (95%CI: 1.091 - 3.176, P = 0.023) and the length of initial ICU stay (95%CI: 1.105 - 1.251, P < 0.01) were independent risk factors of readmission. CONCLUSION: NYHA classification and the length of first ICU stay are independent risk factors of readmission. Respiratory complications are the most common reasons for readmission. PMID- 22490803 TI - [Comparison of natural orifice transumbilical endoscopic surgery versus conventional laparoscopic surgery in renal cyst deroofing]. AB - OBJECTIVE: To compare the safety and feasibility of natural orifice transumbilical endoscopic surgery (NOTES) versus conventional laparoscopic surgery in renal cyst deroofing. METHODS: From May 2010 to August 2011, 8 cases of renal cysts underwent cyst deroofing by the technique of NOTES (Triport) (group A) and 14 cases by conventional laparoscopic surgery (Group B) respectively. The data of patient age, cyst size, operative duration, estimated blood loss, intra-operative complications, drainage duration, post-operative pain score (VAPS) and post-operative hospital stay were recorded and analyzed. RESULTS: The average cyst sizes of groups A and B were 6.6 +/- 2.4 and 7.0 +/- 2.5 cm. There was no conversion to open surgery in neither groups and no conversion to standard laparoscopic surgery in group A. The operative duration, estimated blood volume, VAPS and post-operative hospital stay of both groups were 49 vs 35 min, 12 vs 10 ml, 0 vs 1 and 4 vs 5 days respectively. The drainage duration was 1 day for both groups. No severe complication, secondary hemorrhage or wound infection occurred in neither groups. As judged by both surgeons and patients, the post-operative cosmetic appearances of group A were better than those of group B. CONCLUSION: The cyst deroofing by NOTES is a safe and feasible option for the treatment of renal cysts. As compared with conventional laparoscopic surgery, NOTES may achieve better cosmetic effects with smaller wounds. PMID- 22490805 TI - HHV-8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice. AB - Human herpes virus 8 (HHV-8) or Kaposi sarcoma-associated herpes virus is the etiologic agent of Kaposi sarcoma, primary effusion lymphoma, and plasma cell type multicentric Castleman disease (MCD). HHV-8 encodes a viral homolog of human IL-6, called viral IL-6 (vIL-6), which does not require the cellular IL-6 receptor for binding to the ubiquitously expressed gp130 receptor subunit and subsequent JAK-STAT signaling. Thus, in contrast to IL-6, vIL-6 can stimulate virtually all cells in the body. To elucidate the mechanism by which vIL-6 drives human diseases, we generated transgenic mice that constitutively express vIL-6 under control of the MHC class I promoter. The mice were found to exhibit vIL-6 serum levels comparable with those observed in HHV-8-infected patients, to contain elevated amounts of phosphorylated STAT3 in spleen and lymph nodes, where vIL-6 was produced, and to spontaneously develop key features of human plasma cell-type MCD, including splenomegaly, multifocal lymphadenopathy, hypergammaglobulinemia, and plasmacytosis. Transfer of the vIL-6 transgene onto an IL-6-deficient genetic background abrogated MCD-like phenotypes, indicating that endogenous mouse IL-6 is a crucial cofactor in the natural history of the disease. Our results in mice suggest that human IL-6 plays an important role in the pathogenesis of HHV-8-associated MCD. PMID- 22490804 TI - Zebrafish screen identifies novel compound with selective toxicity against leukemia. AB - To detect targeted antileukemia agents we have designed a novel, high-content in vivo screen using genetically engineered, T-cell reporting zebrafish. We exploited the developmental similarities between normal and malignant T lymphoblasts to screen a small molecule library for activity against immature T cells with a simple visual readout in zebrafish larvae. After screening 26 400 molecules, we identified Lenaldekar (LDK), a compound that eliminates immature T cells in developing zebrafish without affecting the cell cycle in other cell types. LDK is well tolerated in vertebrates and induces long-term remission in adult zebrafish with cMYC-induced T-cell acute lymphoblastic leukemia (T-ALL). LDK causes dephosphorylation of members of the PI3 kinase/AKT/mTOR pathway and delays sensitive cells in late mitosis. Among human cancers, LDK selectively affects survival of hematopoietic malignancy lines and primary leukemias, including therapy-refractory B-ALL and chronic myelogenous leukemia samples, and inhibits growth of human T-ALL xenografts. This work demonstrates the utility of our method using zebrafish for antineoplastic candidate drug identification and suggests a new approach for targeted leukemia therapy. Although our efforts focused on leukemia therapy, this screening approach has broad implications as it can be translated to other cancer types involving malignant degeneration of developmentally arrested cells. PMID- 22490807 TI - [Advances on the diagnosis and treatment of gastrointestinal bleeding]. PMID- 22490806 TI - Enhanced generation of retinal progenitor cells from human retinal pigment epithelial cells induced by amniotic fluid. AB - BACKGROUND: Retinal progenitor cells are a convenient source of cell replacement therapy in retinal degenerative disorders. The purpose of this study was to evaluate the expression patterns of the homeobox genes PAX6 and CHX10 (retinal progenitor markers) during treatment of human retinal pigment epithelium (RPE) cells with amniotic fluid (AF), RPE cells harvested from neonatal cadaver globes were cultured in a mixture of DMEM and Ham's F12 supplemented with 10% FBS. At different passages, cells were trypsinized and co-cultured with 30% AF obtained from normal fetuses of 1416 weeks gestational age. RESULTS: Compared to FBS treated controls, AF-treated cultures exhibited special morphological changes in culture, including appearance of spheroid colonies, improved initial cell adhesion and ordered cell alignment. Cell proliferation assays indicated a remarkable increase in the proliferation rate of RPE cells cultivated in 30% AF supplemented medium, compared with those grown in the absence of AF. Immunocytochemical analyses exhibited nuclear localization of retinal progenitor markers at a ratio of 33% and 27% for CHX10 and PAX6, respectively. This indicated a 3-fold increase in retinal progenitor markers in AF-treated cultures compared to FBS-treated controls. Real-time PCR data of retinal progenitor genes (PAX6, CHX10 and VSX-1) confirmed these results and demonstrated AF's capacity for promoting retinal progenitor cell generation. CONCLUSION: Taken together, the results suggest that AF significantly promotes the rate of retinal progenitor cell generation, indicating that AF can be used as an enriched supplement for serum-free media used for the in vitro propagation of human progenitor cells. PMID- 22490808 TI - [The clinical and endoscopic efficacy of step-up and top-down infliximab therapy in Crohn's disease]. AB - OBJECTIVE: To compare the efficacy of step-up and top-down infliximab therapy on patients with Crohn's disease (CD). METHODS: A prospective and open-label study was performed by the First Affiliated Hospital of SUN Yat-sen University during September 2007 to December 2010. Active CD patients who were refractory to steroid/immunomodulator or who were steroid-dependent were enrolled into step-up group. Active CD patients who had no steroid or immunomodulator therapy before were enrolled into top-down group. All patients were intravenously infused with infliximab of 5 mg/kg body weight in an induction regimen of 3 doses at week 0, 2 and 6, followed by maintenance dosing every 8 weeks beginning at week 14. The clinical and endoscopic follow up lasted 30 weeks. Clinical symptoms and mucosal healing status under endoscopy were evaluated by follow-up at week 10 and 30. RESULTS: Forty-one CD patients were enrolled, with 24 in step-up group and 17 in top-down group. There were significant differences in disease duration (P = 0.006), combination therapy (P < 0.001) and severity of disease (P = 0.011) in baseline between step-up and top-down groups. At week 10 and 30 during treatment, the clinical remission rates in step-up group were 45.8% (11/24) and 58.3% (14/24) respectively; the mucosal healing rates in step-up group were 33.3% (8/24) and 54.2% (13/24) respectively; the clinical remission rates in top-down group were 70.6% (12/17) and 82.4% (14/17) respectively; and the mucosal healing rates in top-down group were 35.3% (6/17) and 52.9% (9/17) respectively. No significant differences in clinical remission and mucosal healing rates at both week 10 and 30 were observed between the two groups. The prevalences of adverse events in step-up and top-down group were 41.7% (10/24) and 29.4% (5/17) respectively (P = 0.422). CONCLUSION: Both step-up and top-down infliximab therapy can induce remission in more than half of CD patients, while top-down therapy might be more beneficiary to symptom and endoscopic remission. PMID- 22490809 TI - [The role of a workflow in diagnosing biliary causes for acute pancreatitis]. AB - OBJECTIVE: To establish a practical and effective clinical pathway (CP) for the etiological diagnosis of acute biliary pancreatitis. METHODS: A total of 2216 patients enrolled were randomly divided into control group (n = 1120) and CP group (n = 1096) according to different etiological diagnosis methods including following doctor's established experiences and habits and the designed CP in our study. RESULTS: There was no significant difference in baseline data between the two groups. The etiology of acute pancreatitis was determined in 91.1% (999/1096) of cases in the CP group which was significantly higher than the control group (65.5%, 734/1120), P < 0.05. The enhanced etiological determination of CP group was mainly consisted of the increased detection of biliary stones, duodenal diseases as well as pancreas divisum, P < 0.05. The positive etiological determination of magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography in the CP group were 59.1% (273/462) and 86.0% (98/114), respectively. CONCLUSIONS: The CP established in this study significantly enhances the biliary etiological determination of acute pancreatitis. It is easy to be conducted and may be of importance to improve the quality of etiological diagnosis of acute pancreatitis. PMID- 22490810 TI - [The classification and prognostic implication of islet beta cell function before and in remission period in newly diagnosed diabetic patients with ketosis]. AB - OBJECTIVE: To observe beta cell function in newly diagnosed diabetic patients with ketosis before and in remission period and evaluate its classification and predictive value. METHODS: A total of 206 patients newly diagnosed as diabetic ketosis who had been treated with intensive insulin therapy in our hospital and entered in the "honeymoon" after the withdraw of insulin therapy were followed for 36 months from onset of diabetes. They were divided into two groups of type 1 and type 2 diabetes (group A and B), according to the dependence or independence on insulin treatment. The beta cell function of the two groups before and in remission period was compared by oral glucose tolerance test (OGTT). beta cell function was measured with the AUC of insulin and C-peptide and homeostatic model assessment beta-cell function (HOMA-beta), while homeostatic model assessment insulin resistant (HOMA-IR) for insulin resistant. The duration of the "honeymoon" and the change of insulin and C-peptide curve before and in "honeymoon" were also observed. RESULTS: The AUC of insulin and C-peptide, the HOMA-beta and the HOMA-IR before and after the intensive insulin treatment were lower in group A than that in group B [before the insulin treatment: (10.18 +/- 2.36) mIU*h*L(-1) vs (20.28 +/- 6.89) mIU*h*L(-1), (1.56 +/- 0.53) ug*h*L(-1) vs (3.75 +/- 0.67) ug*h*L(-1), 3.68 +/- 1.08 vs 18.20 +/- 6.59, 1.22 +/- 0.49 vs 3.06 +/- 1.54, respectively; after the insulin treatment: (29.86 +/- 8.65) mIU*h*L(-1) vs (93.35 +/- 19.42) mIU*h*L(-1), (3.99 +/- 0.79) ug*h*L(-1) vs (12.54 +/- 3.83) ug*h*L(-1), 8.50 +/- 2.46 vs 56.17 +/- 19.42, 0.63 +/- 0.56 vs 1.42 +/- 0.78, respectively]. The duration of the "honeymoon" in group A was significantly shorter than in group B [(7.9 +/- 5.2) months vs (20.9 +/- 9.9) months]. In oral glucose insulin and C-peptide release test, the peak of insulin and C-peptide releasing curve in group A was brought forward by a half to 1 hour after intensive treatment while delayed in group B by 1 or 2 hours. The releasing peak of insulin and C-peptide in group A was less than two folds of the basic value, while four to ten fold of the basic value in group B. The positive ratio of glutamic acid decarboxylase antibody, insulin autoantibody and insular cellular antibody in group A and group B were 21.2% vs 4.8%, 18.1% vs 3.3%, 9.2% vs 10.6%, respectively. CONCLUSIONS: Of all the patients newly diagnosed as diabetes ketosis who had entered into the honeymoon after intensive insulin therapy, 91% were type 2 diabetes. Inferior beta cell function before insulin therapy, weaker remission after insulin therapy and shorter duration of remission period suggest the classification of type 1 diabetes. PMID- 22490811 TI - [A comparative analysis of three diagnostic criteria for multiple myeloma]. AB - OBJECTIVE: To compare the sensitivity among three diagnostic criteria for multiple myeloma. METHODS: A total of 220 patients with multiple myeloma were studied retrospectively to compare the sensitivity, as well as their clinical manifestations, cell morphology in bone marrow and immunophenotype. RESULTS: (1) The sensitivity of domestic diagnostic criterion in 1975 was 79.1% (174/220) and there were some drawbacks in type identify. The sensitivity of WHO diagnostic criterion in 2001 was 97.3% (214/220) and the sensitivity of domestic diagnostic criteria in 2011 was 100%. (2) Immunoglobulin level in 12.7% (28/220) patients was < 30 g/L, plasma cells count in bone marrow in 13.6% (30/220) was < 10%; 2.7% (6/220) patients had not met the standard in immunity globulin and bone marrow plasma cells count. (3) The immunophenotype was CD(38) positive (100%), restricted light chain (kappa/lambda) and CD(19)100%, CD(138) (98.2%, 216/220) negative. CONCLUSIONS: Among the three diagnostic criteria, the highest was 2011 domestic diagnostic criteria. Comprehensive analysis include clinical manifestations, cell morphology, immunophenotype will contribute to the diagnosis for multiple myeloma. PMID- 22490812 TI - [Triptolide combined with irbesartan synergistically blocks podocyte injury in a type 2 diabetes rat model]. AB - OBJECTIVE: To investigate the protective effect of combination of triptolide and irbesartan on the podocytes in a type 2 diabetic(T2DM) rat model, and evaluate its mechanism. METHODS: T2DM rats were induced by fed with high-sucrose-high-fat diet combined with a low dose of streptozocin. The rats were randomly divided into 5 groups: normal control group (NC, n = 10), diabetes group (DM, n = 11), triptolide treatment group (DT, n = 12), irbesartan treatment group (DI, n = 12) and triptolide combined with irbesartan treatment group (DTI, n = 13). Ultrastructure of podocytes was observed by electronic microscopy and urinary albumin (UAL) excretion by ELISA was determined after 8 weeks. The expression of nephrin and bone morphogenetic protein-7 (BMP-7), connective tissue growth factor (CTGF), transforming growth factor (TGF)beta(1) mRNA and proteins were detected by immunohistochemistry, real-time PCR and Western blot. RESULTS: Increased UAL was significantly attenuated in all treatment groups. Compared to NC group, UAL in DM group was increased significantly (0.45 +/- 0.09 vs 6.36 +/- 0.87, P < 0.01), while decreased in triptolide or irbesartan alone treatment group (2.48 +/ 0.37 and 2.68 +/- 0.42, both P < 0.01). Compared with those in control groups, kidney expression of nephrin, BMP-7 mRNA and proteins were downregulated while CTGF, TGFbeta(1) mRNA and proteins were significantly upregulated in T2DM rats. Triptolide or irbesartan each alone moderately ameliorated albuminuria and podocyte damage. However, their combined usage showed a dramatic therapeutic synergism, manifested by prevention of progressive albuminuria, restoration of the glomerular filtration barrier, reversal of the decline in slit diaphragm proteins, reduction expression of CTGF, TGFbeta(1), and upregulation of BMP-7. CONCLUSION: Our findings show that triptolide can increase the efficacy of irbesartan, leading to a more effective prevention of kidney disease in T2DM rat model, which may through upregulation of BMP-7 and inhibition the over-expression of CTGF and TGFbeta(1). PMID- 22490813 TI - [The prevalence and risk factors of coronary heart disease combined with chronic kidney disease]. AB - OBJECTIVE: To investigate the prevalence rate and risk factors of inpatients with coronary atherosclerotic heart disease (CHD) combined chronic kidney disease (CKD). METHODS: All people who underwent CHD combined CKD in CHD department of the First Affiliated Hospital of Xinjiang Medical University during January to December 2009 were enrolled in the retrospective study. RESULTS: A total of 960 hospitalized patients with CHD were enrolled during the observation period. The prevalence of proteinuria and reduced eGFR were 11.04% and 10.52%, respectively. The total CKD prevalence rate was 16.77%, with male of 16.67% and female of 17.11%. There was no significant difference in prevalence rate between male and female (P > 0.05). The multi-factors logistic regression analysis showed that diabetes mellitus (OR 2.60, 95%CI 1.17 - 3.29) was risk factor for CHD combined proteinuria. Ten-years older in age (OR 1.55, 95%CI 1.31 - 1.83), diabetes mellitus (OR 1.69, 95%CI 1.15 - 2.47), hypercholesterolemia (OR 2.89, 95%CI 1.49 5.61), and hyperuricemia (OR 1.49, 95%CI 0.96 - 2.33) were risk factors for CHD combined CKD. CONCLUSION: More attention should be paid to the high prevalence of CHD combined CKD. PMID- 22490814 TI - [The association of target organ damage with abnormal ankle brachial index in hypertensive patients]. AB - OBJECTIVE: To investigate the association of hypertensive target organ damage with abnormal ankle brachial index (ABI) in high-risk hypertensive patients. METHODS: During December 2008 to May 2009, a cross-sectional study was conducted to investigated the prevalence of abnormal ABI (ABI < 0.90) in 2674 community dwelling, hypertensive patients, who aged > 40 years, without coronary heart disease, stroke/transient ischemic attack or known arteriosclerosis, from 18 centers in China. Data were acquired through history, physical examination, laboratory and other diagnostic tests. RESULTS: There were 2615 subjects eligible for the full analysis set. The high-risk hypertensive patients with arterial wall thickening, arterial wall thickening and slightly elevated serum creatinine had a higher prevalence of abnormal ABI than their counterparts respectively (P < 0.05). Compared with the normal group, the abnormal ABI group had a higher serum creatinine level on average (P < 0.01). After adjustment for certain factors including investigation center, demographic factors, cardiovascular disease (CVD) risk and CVD risk factors using an unconditional logistic regression model, arterial wall thickening (OR 2.416, 95%CI 1.395 - 4.183, P = 0.0016) and slightly elevated serum creatinine (OR 3.377, 95%CI 1.267 - 8.997, P = 0.0149) were positively associated with abnormal ABI. However, arterial wall thickening (OR 0.988, 95%CI 0.576 - 1.695, P = 0.9664) and microalbuminuria (OR 1.389, 95%CI 0.685 - 2.817, P = 0.3621) were irrelevant to abnormal ABI. CONCLUSIONS: So far as a high-risk hypertensive patient is concerned, there are significant statistical correlations between arterial wall thickening and/or slightly elevated serum creatinine and an abnormal ABI, but no significant statistical correlations between arterial wall thickening or microalbuminuria and an abnormal ABI is observed. PMID- 22490815 TI - [The association of vitamin D receptor gene ApaI and BsmI polymorphism with systemic lupus erythematosus]. AB - OBJECTIVE: To determine the distribution of vitamin D receptor (VDR) gene ApaI and BsmI polymorphism in systemic lupus erythematosus (SLE) and the association with SLE in Chinese Han patients. METHODS: Genomic DNA from 244 Chinese SLE patients and 162 sex and ethnically matched controls were typed for VDR ApaI and BsmI polymorphism combination by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Clinical characteristics were analyzed between different ApaI and BsmI genotypes. RESULTS: There was no significant difference between the distribution frequencies of allelic gene A and a in SLE patients and the controls, but the distribution frequency of genotypes heterozygote Aa in SLE patients was higher than that in the controls (38.9% vs 22.2%, chi(2) = 12.442, P = 0.000). There was no significant difference between the distribution frequency of allelic gene and genotypes of BsmI in SLE patients and the controls (P > 0.05). However, there was significant difference between the distribution frequencies of ApaI and BsmI genotypes combination in SLE patients and the controls (chi(2) = 18.226, P = 0.006). The distribution frequency of genotypes Aa bb in SLE patients was higher than that in the controls (32.4% vs 17.9%, chi(2) = 10.449 P = 0.001), while the distribution frequency of genotypes Aa-bb in SLE patients was lower than that in the controls (30.3% vs 42.0%, chi(2) = 5.808, P = 0.016). Furthermore, analyzing the effect of VDR ApaI and BsmI polymorphism combination to the symptoms of SLE, significant difference was observed in SLE patients carrying Aa-bb genotypes involved in serositis (P = 0.003), hematological system disorder (P = 0.021), and anti-Sm antibodies (P = 0.01) compared with other genotypes. CONCLUSION: There is significant association between ApaI and BsmI gene polymorphism Aa-bb genotypes and the incidence of SLE in the Han population of China, and genotype Aa-bb is more involved in serositis, hematological system disorder and has a positive effect on production of antibodies. PMID- 22490816 TI - [The effects and mechanisms of BTBD10 on the proliferation of islet beta cell]. AB - OBJECTIVE: To explore the role of BTBD10 overexpression in the proliferation of insulinoma cell line INS-1 and its mechanism. METHODS: The recombined expression plasmid of pcDNA4.0-BTBD10 was constructed by gene cloning technique and was transfected into INS-1 cell by lipofectamine 2000. The stable overexpression BTBD10 of INS-1 cell was selected at 48(th) hour after transfection. INS-1 cell proliferation activity was measured by MTT method. The expression of BTBD10, protein kinase B (Akt), phospho-Akt (p-Akt), mammal target of rapamycin (mTOR) and phospho-mTOR (p-mTOR) were determined by Western blot. RESULTS: The stable overexpression BTBD10 of INS-1 cell was successfully constructed. Overproduction of BTBD10 promoted beta cell proliferation. The phosphorylation of Akt and mTOR was increased and the ratio of p-Akt/Akt and p-mTOR/mTOR was enhanced in the INS 1 overexpressed by BTBD10. But the expression of total Akt and mTOR presented no obvious changes. CONCLUSION: The overexpression BTBD10 of INS-1 cell could activate of Akt/mTOR signalling pathway via stimulating phospho-mTOR and Akt, and enhance overall cell protein translation, so as to promote proliferation of INS-1 cell. PMID- 22490817 TI - Effect of dietary supplementation with Suaeda maritima on blood physiology, innate immune response, and disease resistance in olive flounder against Miamiensis avidus. AB - The effect of Suaeda maritima enriched diet on blood physiology, innate immune response, and disease resistance in olive flounder Paralichythys olivaceus against Miamiensis avidus on weeks 1, 2, and 4 was investigated. Feeding with any enriched diet and then challenging with M. avidus significantly increased white blood cells (WBC) on weeks 2 and 4; the red blood cells (RBC) significantly increased with 0.1% and 1.0% enriched diets on week 4. The hemoglobin (Hb) and hematocrit (Ht) levels significantly increased when fed with 0.1% and 1.0% supplementation diets on weeks 2 and 4. The mean corpuscular volume (MCV) did not significantly vary with any diet and time; however the mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) significantly increased with 0.1% and 1.0% supplementation diets on weeks 2 and 4. The leukocytes such as lymphocytes (Lym), monocytes (Mon), neutrophils (Neu) and biochemical parameters such as total protein (TP), glucose (GLU), and calcium (CAL) levels significantly increased in 0.1% and 1.0% supplementation diet fed groups on weeks 2 and 4. The serum lysozyme activity was significantly enhanced in 0.1% and 1.0% supplementation diet fed groups from weeks 1 to 4 when compared to the control (0% herbal extract enriched diet). The scuticocidal activity and respiratory burst activity were significantly enhanced when fish were fed with 0.1% and 1.0% supplementation diets from weeks 2 and 4. The protective effect in terms of cumulative mortality (50% and 40%) was low in groups on being fed with 0.1% and 1.0% supplemented diet. Therefore the present study suggested that 0.1% and 1.0% S. maritime-supplemented diets protect the hematological and biochemical parameters, improving the innate immunity, affording protection disease from M. avidus infection in olive flounder. PMID- 22490818 TI - Trichinella spiralis: infection changes serum paraoxonase-1 levels, lipid profile, and oxidative status in rats. AB - Paraoxonase-1 (PON1) is an HDL-associated enzyme with anti-atherogenic properties. Reduced PON1 activity has previously been observed in Nippostrongylus brasiliensis-infected rats. However, the effect of chronic zoonotic nematode infections on serum PON1 activity has not yet been studied. Therefore, we evaluated the effect of Trichinella spiralis infection on serum PON1 activity, the lipid profile, and oxidative stress in rats. There were significant reductions in serum PON1 activities (Day 2-Week 7 post-infection) in rats infected with T. spiralis, and these reductions were associated with significant increases in the serum levels of triglyceride and LDL/VLDL, as well as a significant reduction in the level of HDL. Moreover, T. spiralis infection was associated with a status of oxidative stress indicated by increased concentrations of superoxide dismutase and malondialdehyde. Given the zoonotic prevalence of T. spiralis and the cardioprotective role of PON1, further mechanistic research in this area is warranted. PMID- 22490819 TI - Selection on synonymous sites for increased accessibility around miRNA binding sites in plants. AB - Synonymous codons are widely selected for various biological mechanisms in both prokaryotes and eukaryotes. Recent evidence suggests that microRNA (miRNA) function may affect synonymous codon choices near miRNA target sites. To better understand this, we perform genome-wide analysis on synonymous codon usage around miRNA target sites in four plant genomes. We observed a general trend of increased site accessibility around miRNA target sites in plants. Guanine cytosine (GC)-poor codons are preferred in the flank region of miRNA target sites. Within-genome analyses show significant variation among miRNA targets in species. GC content of the target gene can partly explain the variation of site accessibility among miRNA targets. miRNA targets in GC-rich genes show stronger selection signals than those in GC-poor genes. Gene's codon usage bias and the conservation level of miRNA and its target also have some effects on site accessibility, but the expression level of miRNA or its target and the mechanism of miRNA activity do not contribute to site accessibility differences among miRNA targets. We suggest that synonymous codons near miRNA targets are selected for efficient miRNA binding and proper miRNA function. Our results present a new dimension of natural selection on synonymous codons near miRNA target sites in plants, which will have important implications of coding sequence evolution. PMID- 22490820 TI - Pervasive indels and their evolutionary dynamics after the fish-specific genome duplication. AB - Insertions and deletions (indels) in protein-coding genes are important sources of genetic variation. Their role in creating new proteins may be especially important after gene duplication. However, little is known about how indels affect the divergence of duplicate genes. We here study thousands of duplicate genes in five fish (teleost) species with completely sequenced genomes. The ancestor of these species has been subject to a fish-specific genome duplication (FSGD) event that occurred approximately 350 Ma. We find that duplicate genes contain at least 25% more indels than single-copy genes. These indels accumulated preferentially in the first 40 my after the FSGD. A lack of widespread asymmetric indel accumulation indicates that both members of a duplicate gene pair typically experience relaxed selection. Strikingly, we observe a 30-80% excess of deletions over insertions that is consistent for indels of various lengths and across the five genomes. We also find that indels preferentially accumulate inside loop regions of protein secondary structure and in regions where amino acids are exposed to solvent. We show that duplicate genes with high indel density also show high DNA sequence divergence. Indel density, but not amino acid divergence, can explain a large proportion of the tertiary structure divergence between proteins encoded by duplicate genes. Our observations are consistent across all five fish species. Taken together, they suggest a general pattern of duplicate gene evolution in which indels are important driving forces of evolutionary change. PMID- 22490821 TI - Expression of the nucleus-encoded chloroplast division genes and proteins regulated by the algal cell cycle. AB - Chloroplasts have evolved from a cyanobacterial endosymbiont and their continuity has been maintained by chloroplast division, which is performed by the constriction of a ring-like division complex at the division site. It is believed that the synchronization of the endosymbiotic and host cell division events was a critical step in establishing a permanent endosymbiotic relationship, such as is commonly seen in existing algae. In the majority of algal species, chloroplasts divide once per specific period of the host cell division cycle. In order to understand both the regulation of the timing of chloroplast division in algal cells and how the system evolved, we examined the expression of chloroplast division genes and proteins in the cell cycle of algae containing chloroplasts of cyanobacterial primary endosymbiotic origin (glaucophyte, red, green, and streptophyte algae). The results show that the nucleus-encoded chloroplast division genes and proteins of both cyanobacterial and eukaryotic host origin are expressed specifically during the S phase, except for FtsZ in one graucophyte alga. In this glaucophyte alga, FtsZ is persistently expressed throughout the cell cycle, whereas the expression of the nucleus-encoded MinD and MinE as well as FtsZ ring formation are regulated by the phases of the cell cycle. In contrast to the nucleus-encoded division genes, it has been shown that the expression of chloroplast-encoded division genes is not regulated by the host cell cycle. The endosymbiotic gene transfer of minE and minD from the chloroplast to the nuclear genome occurred independently on multiple occasions in distinct lineages, whereas the expression of nucleus-encoded MIND and MINE is regulated by the cell cycle in all lineages examined in this study. These results suggest that the timing of chloroplast division in algal cell cycle is restricted by the cell cycle regulated expression of some but not all of the chloroplast division genes. In addition, it is suggested that the regulation of each division-related gene was established shortly after the endosymbiotic gene transfer, and this event occurred multiple times independently in distinct genes and in distinct lineages. PMID- 22490822 TI - Adaptive evolution and effective population size in wild house mice. AB - Estimates of the proportion of amino acid substitutions that have been fixed by selection (alpha) vary widely among taxa, ranging from zero in humans to over 50% in Drosophila. This wide range may reflect differences in the efficacy of selection due to differences in the effective population size (N(e)). However, most comparisons have been made among distantly related organisms that differ not only in N(e) but also in many other aspects of their biology. Here, we estimate alpha in three closely related lineages of house mice that have a similar ecology but differ widely in N(e): Mus musculus musculus (N(e) ~ 25,000-120,000), M. m. domesticus (N(e) ~ 58,000-200,000), and M. m. castaneus (N(e) ~ 200,000-733,000). Mice were genotyped using a high-density single nucleotide polymorphism array, and the proportions of replacement and silent mutations within subspecies were compared with those fixed between each subspecies and an outgroup, Mus spretus. There was significant evidence of positive selection in M. m. castaneus, the lineage with the largest N(e), with alpha estimated to be approximately 40%. In contrast, estimates of alpha for M. m. domesticus (alpha = 13%) and for M. m. musculus (alpha = 12 %) were much smaller. Interestingly, the higher estimate of alpha for M. m. castaneus appears to reflect not only more adaptive fixations but also more effective purifying selection. These results support the hypothesis that differences in N(e) contribute to differences among species in the efficacy of selection. PMID- 22490823 TI - Molecular and functional evolution of class I chitinases for plant carnivory in the caryophyllales. AB - Proteins produced by the large and diverse chitinase gene family are involved in the hydrolyzation of glycosidic bonds in chitin, a polymer of N acetylglucosamines. In flowering plants, class I chitinases are important pathogenesis-related proteins, functioning in the determent of herbivory and pathogen attack by acting on insect exoskeletons and fungal cell walls. Within the carnivorous plants, two subclasses of class I chitinases have been identified to play a role in the digestion of prey. Members of these two subclasses, depending on the presence or absence of a C-terminal extension, can be secreted from specialized digestive glands found within the morphologically diverse traps that develop from carnivorous plant leaves. The degree of homology among carnivorous plant class I chitinases and the method by which these enzymes have been adapted for the carnivorous habit has yet to be elucidated. This study focuses on understanding the evolution of carnivory and chitinase genes in one of the major groups of plants that has evolved the carnivorous habit: the Caryophyllales. We recover novel class I chitinase homologs from species of genera Ancistrocladus, Dionaea, Drosera, Nepenthes, and Triphyophyllum, while also confirming the presence of two subclasses of class I chitinases based upon sequence homology and phylogenetic affinity to class I chitinases available from sequenced angiosperm genomes. We further detect residues under positive selection and reveal substitutions specific to carnivorous plant class I chitinases. These substitutions may confer functional differences as indicated by protein structure homology modeling. PMID- 22490824 TI - The cytonuclear dimension of allopolyploid evolution: an example from cotton using rubisco. AB - During allopolyploid speciation, two divergent nuclear genomes merge, yet only one (usually the maternal) of the two sets of progenitor organellar genomes is maintained. Rubisco (1,5-bisphosphate carboxylase/oxygenase) is composed of nuclear-encoded small subunits (SSUs) and plastome-encoded large subunits (LSUs), providing an ideal system to explore the evolutionary process of cytonuclear accommodation. Here, we take initial steps in this direction, using Gossypium allopolyploids as our model. SSU copies from divergent (5-10 My) progenitor diploids ("A" and "D" genomes) were combined at the time of polyploid formation 1 2 Ma, with the LSU encoded by the maternal A-genome parent. LSU genes from A- and D-genome diploids and AD-genome allopolyploids were sequenced, revealing several nonsynonymous substitutions and suggesting the possibility of differential selection on the nuclear-encoded rbcS partner following allopolyploid formation. Sequence data for the rbcS gene family revealed nonreciprocal homoeologous recombination between A- and D-rbcS homoeologs in all polyploid species but not in a synthetic intergenomic F1 hybrid, demonstrating "gene conversion" during allopolyploid evolution. All progenitor rbcS genes are retained and expressed in the five extant allopolyploid species, but analysis of the leaf transcriptome showed that A-homoeologs are preferentially expressed in both the allopolyploid and hybrid, consistent with the maternal origin of rbcL. Although rbcS genes from both progenitor genomes are expressed, some appear to have experienced mutations that may represent cytonuclear coevolution. PMID- 22490825 TI - Looking for Darwin in genomic sequences--validity and success of statistical methods. AB - The use of codon substitution models to compare synonymous and nonsynonymous substitution rates is a widely used approach to detecting positive Darwinian selection affecting protein evolution. However, in several recent papers, Hughes and colleagues claim that codon-based likelihood-ratio tests (LRTs) are logically flawed as they lack prior hypotheses and fail to accommodate random fluctuations in synonymous and nonsynonymous substitutions Friedman and Hughes (2007) also used site-based LRTs to analyze 605 gene families consisting of human and mouse paralogues. They found that the outcome of the tests was largely determined by irrelevant factors such as the GC content at the third codon positions and the synonymous rate d(S), but not by the nonsynonymous rate d(N) or the d(N)/d(S) ratio, factors that should be related to selection. Here, we reanalyze those data. Contra Friedman and Hughes, we found that the test results are related to sequence length and the average d(N)/d(S) ratio. We examine the criticisms of Hughes and suggest that they are based on misunderstandings of the codon models and on statistical errors. Our analyses suggest that codon-based tests are useful tools for comparative analysis of genomic data sets. PMID- 22490827 TI - [A correct understanding of degenerative cervical canal stenosis]. PMID- 22490826 TI - Associations between household and neighbourhood socioeconomic status and systolic blood pressure among urban South African adolescents. AB - Factors resulting in high risk for cardiovascular disease have been well studied in high income countries, but have been less well researched in low/middle income countries. This is despite robust theoretical evidence of environmental transitions in such countries which could result in biological adaptations that lead to increased hypertension and cardiovascular disease risk. Data from the South African Birth to Twenty cohort, Bone Health sub-sample (n = 358, 47% female), were used to model associations between household socioeconomic status (SES) in infancy, household/neighbourhood SES at age 16 years, and systolic blood pressure (multivariate linear regression) and risk for systolic pre-hypertension (binary logistic regression). Bivariate analyses revealed household/neighbourhood SES measures that were significantly associated with increased systolic blood pressure. These significant associations included improved household sanitation in infancy/16 years, caregiver owning the house in infancy and being in a higher tertile (higher SES) of indices measuring school problems/environment or neighbourhood services/problems/crime at 16 years of age. Multivariate analyses adjusted for sex, maternal age, birth weight, parity, smoking, term birth, height/body mass index at 16 years. In adjusted analyses, only one SES variable remained significant for females: those in the middle tertile of the crime prevention index had higher systolic blood pressure (beta = 3.52, SE = 1.61) compared with the highest tertile (i.e. those with the highest crime prevention). In adjusted analyses, no SES variables were significantly associated with the systolic blood pressure of boys, or with the risk of systolic pre-hypertension in either sex. The lack of association between SES and systolic blood pressure/systolic pre-hypertension at age 16 years is consistent with other studies showing an equalization of adolescent health inequalities. Further testing of the association between SES and systolic blood pressure would be recommended in adulthood to see whether the lack of association persists. PMID- 22490828 TI - [Longitudinal spinous splitting laminoplasty with coral bone for cervical stenosis]. AB - OBJECTIVE: To explore the outcomes of longitudinal spinous splitting laminoplasty with coral bone (abbreviated as SLAC) for cervical stenosis. METHODS: A total of 142 patients underwent conventional SLAC while 147 other patients modified SLAC. Assessments were made at pre-operation, post-operation and 3-month follow-up to examine the effects of two surgical approaches on the recovery rate of JOA (Japanese Orthopedic Association) score. The change of cervical alignment, change of cervical motions, axial syndrome, operative duration and intra-operative blood loss were recorded and analyzed with SPSS 13.0. RESULTS: No significant difference existed between two groups in the recovery rate of JOA score and intra operative blood loss. The smaller change of cervical alignment and change of cervical motions were found in the modified SLAC group. The modified SLAC group had fewer patients with axial syndrome during the follow-up period. The operative duration was shorter in the modified SLAC group. CONCLUSION: Preventing muscle injuries in cervical laminoplasty can reduce the incidence of complications. The modified SLAC approach may protect cervical posterior extensor musculature, maintain the cervical lordotic alignment and reduce the incidence of post operative axial syndrome. PMID- 22490829 TI - [Efficacies of anterior approach for cervical spinal canal stenosis]. AB - OBJECTIVE: To evaluate the therapeutic efficacies and surgical procedures of anterior approach for cervical spinal canal stenosis. METHODS: A total of 162 cases of cervical spinal canal stenosis underwent anterior surgical procedure from March 2007 to March 2010. The operative duration, the volume of blood loss and the days of postoperative hospital stay were recorded and analyzed. The Cobb angle and canal sagittal diameter were measured. The bone graft fusion and nerve functions were evaluated postoperatively. RESULTS: The average operative duration was 86.4 minutes with an intraoperative blood loss of 80.2 ml and a postoperative hospital stay of 5.3 days. A follow-up visit of 9-18 months (average: 12.8) showed that bone graft fusion was achieved in all cases and Cobb angle increased by an average of 7.2 degree. The spinal canal sagittal diameter increased by 4.23 mm. And the JOA (Japanese Orthopedic Association) score increased by an average of 6.1 points at 3 Month post-operation. CONCLUSION: For cervical spinal canal stenosis, the pressure comes mostly from the front part. The anterior surgical procedure can decompress directly with a shorter operative duration, a smaller volume of blood loss, a shorter hospitalization stay and an effective recovery of cervical curvature and canal volume. PMID- 22490830 TI - [Cement leakages in percutaneous vertebroplasty:analysis of postoperative computed tomography]. AB - OBJECTIVE: To evaluate the influencing factors of cement leakage in vertebroplasty for the treatment of osteoporosis vertebral compression fracture (OVCF) and vertebral metastases (VM). METHODS: Retrospective analysis was conducted for 653 vertebrae in 356 patients undergoing vertebroplasty at our hospital from May 2007 to January 2011. 251 cases had 438 vertebrae with painful OVCF while 105 cases had 215 vertebrae with VM. Pre-operative computed tomography (CT) was performed to determine the presence of cortical defects or osteolysis and within 3 days after PVP to observe the distribution of polymethylmethacrylate (PMMA) in vertebrae and whether leakage occurred. Volume of PMMA injected into each vertebral body and types of cement leakage were compared between the OVCF and VM groups by Z test or chi2. The correlation between cortical defects and cement leakages around vertebrae was assessed with Pearson correlation coefficient. RESULTS: The successful rate of PVP was 100%. The mean volume of PMMA injected into each vertebra was (5.0 +/- 2.0) ml and (4.0 +/- 1.7) ml in the OVCF and VM groups respectively (P < 0.05). Asymptomatic PMMA leakage was demonstrated by CT in 93 vertebrae (21.2%) in the OVCF group and in 53 vertebrae (28.8%) in the VM group respectively (P < 0.05). Cement leakages into disk were found in 58 vertebrae in the OVCF group and 16 vertebrae in the VM group respectively (P = 0.025). Cement leakages into paravertebral vein were found in 12 vertebrae in the OVCF group and 26 vertebrae in the VM group respectively (P < 0.0001). Correlation was found between cortical defects and cement leakage into paravertebral soft tissues in the OVCF group (r = 0.14) or in the VM group (r = 0.27), between end-plate defects and cement leakage into disk in the OVCF group (r = 0.29) or in the VM group (r = 0.31). CONCLUSION: As a common occurrence in vertebroplasty, cement extravasation is well-tolerated in most patients. It occurs more frequently in the patients with VM than those with OVCF, especially in cases of leakage into paravertebral vein. Cement leakage into disc or paravertebral soft tissue is predisposed in vertebrae with end plate, cortical defects or osteolysis. PMID- 22490831 TI - [Correlates of cognitive impairment in patients with leukoaraiosis by magnetic resonance spectroscopy]. AB - OBJECTIVE: To explore the pathological changes in patients with leukoaraiosis (LA) by magnetic resonance spectroscopy (MRS) and examine its relationship with cognitive function. METHODS: Twenty-three LA patients and 23 age and gender matched healthy subjects were recruited from the Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University between August 2010 and November 2010. All participants underwent the neuropsychological tests. Multi-voxel chemical shift imaging was performed and the regions of interest were positioned in bilateral frontal white matter. The relative metabolite ratios, involving N acetyl aspartate/choline ratio (NAA/Cho), N-acetyl aspartate/creatine (NAA/Cr) and choline/creatine (Cho/Cr), were estimated. The correlation of the MRS data and the performance of cognitive function was analyzed. RESULTS: The LA patients were associated with a worse performance of mini mental state examination (MMSE) versus the healthy controls (24 +/- 3 vs 28 +/- 1, P < 0.05). Univariate analysis of the MRS data revealed the ratios of NAA/Cho and NAA/Cr significantly decreased in bilateral frontal white matter lesions in the LA group versus the control group (1.72 +/- 0.20 vs 1.96 +/- 0.36, 1.67 +/- 0.17 vs 1.85 +/- 0.21, P < 0.05). The values of NAA/Cr and NAA/Cho in normal appearing white matter increased versus the LA group (1.83 +/- 0.24 vs 1.72 +/- 0.20, 1.78 +/- 0.28 vs 1.67 +/- 0.17) and decreased versus the control group (1.83 +/- 0.24 vs 1.96 +/- 0.36, 1.78 +/- 0.28 vs 1.85 +/- 0.21). But no significant differences were found (P > 0.05). The ratio of Cho/Cr did not differ among 3 groups (P > 0.05). The pathological change of NAA/Cr in white matter lesion in LA patients was markedly correlated with the performance of MMSE (r = 0.47, P < 0.05). CONCLUSION: NAA may be a marker of axonal loss/dysfunction in LA patients. And the changes of NAA/Cr have a positive correlation with cognitive impairment. PMID- 22490832 TI - [Vascular risk factors and cognitive impairment of patients with magnetic resonance imaging-defined subcortical ischemic depression]. AB - OBJECTIVE: To explore the vascular risk factors and neuropsychological profiles of patients with magnetic resonance imaging (MRI)-defined subcortical ischemic depression (SID). METHODS: Thirty-five SID patients, 37 patients with subcortical ischemic vascular disease without depression (SIVD) and 40 normal controls (NC) participated in this case-control study. The SID and SIVD groups were recruited from the Department of Neurology, First Affiliated Hospital, Anhui Medical University between October 2010 and September 2011. And the NC group came from Medical Center, First Affiliated Hospital of Anhui Medical University over the same period. The vascular risk factors of all participants were assessed by the Framingham scale. Depression symptoms were assessed by the geriatric depression scale (GDS) and Hamilton depression scale (HAMD) while cognitive functions by the mini-mental state examination (MMSE) and Montreal cognitive clock drawing task (CDT). RESULTS: Both the SID (12.3 +/- 4.7) and SIVD (13.5 +/- 3.4) groups showed significantly higher Framingham scores than the NC group (8.6 +/- 1.8) (F = 20.850, P = 0.000). Compared with the NC group (28.3 +/- 1.8; 23.1 +/- 3.4; 8.0 +/- 1.8), the MMSE, MoCA and CDT scores were significantly lower in the SID (26.7 +/- 2.5; 20.0 +/- 4.0; 2.0 +/- 2.7) and SIVD (26.8 +/- 1.9; 20.7 +/- 3.0; 6.1 +/- 2.1) groups (P < 0.05). There were significantly lower CAMCOG-C scores in the SID (82.7 +/- 9.0) and SIVD (86.2 +/- 6.9) groups versus the NC group (92.3 +/- 6.2) (P < 0.05) and similarly in the SID group versus the SIVD group (P < 0.05). Among the subtests of CAMCOG-C, the orientation, language and memory scores in both SID (9.0 +/- 1.4; 24.7 +/- 4.0; 19.5 +/- 3.4) and SIVD (9.4 +/- 0.9; 25.5 +/- 2.1; 20.3 +/- 2.3) groups were significantly lower than those in the NC group (9.9 +/- 0.4; 27.4 +/- 1.9; 22.1 +/- 2.4) (P < 0.05); the praxis scores in the SID group (9.4 +/- 1.9) were significantly lower than those in the NC group (10.4 +/- 1.5) (P < 0.05). And the thinking and perception scores in the SID group (5.4 +/- 1.7; 6.3 +/- 1.4) were significantly lower than those in the SIVD (6.2 +/- 1.3; 7.0 +/ 1.4) and NC (6.6 +/- 1.3; 7.2 +/- 1.4) groups. In the SID group, no significant correlation was found between the Framingham scores and neuropsychological assessments. There were a negative correlation between the GDS, HAMD scores and MMSE, MoCA, CAMCOG-C and CDT scores (P < 0.05). CONCLUSION: The SID patients demonstrate multiple neuropsychological deficits, especially in thinking, perception and praxis. No significant correlation between vascular risk factors and depression symptoms is found in SID patients. PMID- 22490833 TI - [Endovascular management of iatrogenic vascular injuries: a retrospective study of 21 cases]. AB - OBJECTIVE: To evaluate the early outcome of endovascular management of iatrogenic vascular injury (IVI). METHODS: From July 2002 to July 2010, 21 cases of IVI undergoing endovascular therapy were studied retrospectively. There were aorta injury (n = 2), peripheral artery injury (n = 11), visceral artery injury (n = 5), arteriovenous injury (n = 1) and venous injury (n = 2). And the procedures included endograft implantation (n = 15), intravascular embolization with coil (n = 4), combination of endovascular balloon intervention and percutaneous thrombin injection (n = 1) and balloon compression for hemostasis (n = 1). RESULTS: Technical success was achieved in all patients. And clinical success, defined as arrested hemorrhage and hemodynamic stabilization, was obtained in 20 (95.2%) patients. There was one case of intra-operative mortality. After the procedure, there were cerebral infarction (n = 2) and partial renal infarction (n = 1). Among them, 19 patients received a median follow-up period of 23.9 months (range: 4 - 84 months). Only 1 patient with iliofemoral vein stent implantation developed stent collapse and thrombosis at Week 3. There were no other complications. CONCLUSION: Endovascular therapy is an effective procedure in the management of different types of IVI. Despite its encouraging early results, the long-term outcomes require further follow-ups and observations. PMID- 22490834 TI - [Risk factors for excessive bleeding in patients undergoing open heart surgery with cardiopulmonary bypass]. AB - OBJECTIVE: To evaluate the pre- and intraoperative risk factors associated with excessive bleeding during the perioperative period in adult patients undergoing open heart surgery with cardiopulmonary bypass (CPB). METHODS: A total of 1079 consecutive patients undergoing open heart surgery with CPB from January 2001 to May 2010 were included (except for emergency operation). The possible risk factors associated with excessive bleeding were retrospectively analyzed. Patients who received >= 7 units of RBC or had a re-operation during which no active bleeding point was found within one day of operation were classified as excessive bleeding. According to the occurrence of excessive bleeding, they were divided into 2 groups: excessive and non-excessive bleeding groups. The possible risk factors associated with excessive bleeding were retrospectively analyzed. Univariate analysis and multivariate Logistic regression analysis were used to examine the relationship between these factors and excessive bleeding. RESULTS: Among them, 120 (11.1%) developed excessive bleeding. Multivariate Logistic analysis indicated that the risk factors for excessive bleeding were age (OR = 4.533, 95%CI 2.624 - 7.831), previous sternotomy (OR = 2.781, 95%CI 1.410 - 5.486), preoperative hematocrit concentration (OR = 0.896, 95%CI 0.861 - 0.932), CPB duration (OR = 2.782, 95%CI 1.791 - 4.322) and type of procedure (OR = 2.292, 95%CI 1.376 - 3.817). CONCLUSION: Age >= 65 years, previous sternotomy, preoperative low hematocrit concentration, CPB duration >= 120 min and complex operation were the significant predictors for excessive bleeding in patient undergoing open heart surgery with CPB. PMID- 22490835 TI - [Differential expression analysis of prolactinoma-related microRNAs]. AB - OBJECTIVE: To explore the relationship between the prolactinoma-related microRNAs (miRNA) and the development, growth and hormone secretion of prolactinoma. METHODS: The technique of Solexa sequencing was employed to analyze the differential expressions of prolactinoma and normal anterior pituitary gland samples. And the stem-loop real-time polymerase chain reaction (PCR) was utilized for confirmation. RESULTS: According to the differentially expressed profiles of miRNAs, 4 miRNAs were down-regulated (miR-130a, miR-199b-3p, miR-200b, miR-125b, P < 0.05) and 6 miRNAs up-regulated (miR-342-3p, miR-432, miR-23b, miR-493, miR 493(*), miR-664(*), P < 0.05). The expression levels of miR-493(*) and miR-432 had a significant positive correlation with the serum level of prolactin (r = 0.47, P < 0.05; r = 0.528, P < 0.01) while miR-342-3p a significantly positive correlation with the invasiveness (r = 0.402, P < 0.05). CONCLUSION: miRNAs are differentially expressed between normal anterior pituitary gland and prolactinomas, between invasive and localized prolactinomas and among different hormone secretion levels. It suggests that miRNAs may be involved in the physiological process of development, growth and hormone secretion of prolactinoma. PMID- 22490836 TI - [The related study of first pregnancy women with Cu-IUD on copper content of blood serum and decidua, chorion tissues]. AB - OBJECTIVE: Through determine the copper content of decidua, chorion and blood serum of first pregnancy women with Cu-IUD, we offer date for security of offspring. METHODS: March 2010 to December 2010, in family planning clinics of the general hospital of Tianjin medical university, we selected twenty-five first pregnancy women with Cu-IUD who intended to terminate pregnancy to be experimental group and twenty-five normal first pregnancy women who intended to terminate pregnancy to be control group, and determined the copper content of decidua, chorion and blood serum in experimental group and control group. RESULTS: The copper content of decidua, chorion and blood serum in experimental group is (0.91 +/- 0.51) mg/kg, (0.72 +/- 0.50) mg/kg, (0.79 +/- 0.15) mg/L; the copper content of decidua, chorion and blood serum in control group is (0.57 +/- 0.21) mg/kg, (0.46 +/- 0.21) mg/kg, (0.71 +/- 0.15) mg/L. The copper content of blood serum has no significant difference between experimental group and control group (P > 0.05). The copper content of decidua, chorion of experimental group is higher than control group (P < 0.05). CONCLUSION: Copper ion released from Cu-IUD only has an influence on the uterus tissues, but having no influence on the copper metabolism all over the body. The effects of high copper content of chorion in first pregnancy women with Cu-IUD on the offspring security will be researched further. PMID- 22490837 TI - [Clinical curative effects of preoperative neoadjuvant chemotherapy on cervical cancer: analysis of 62 patients]. AB - OBJECTIVE: To explore the clinical curative effects of preoperative neoadjuvant chemotherapy (NACT) on locally advanced cervical cancer. METHODS: A total of 62 patients of stage Ib2-IIb cervical cancer received neoadjuvant chemotherapy of paclitaxel plus cisplatin for 2 - 3 courses. The clinical curative effects were evaluated according to the changes of lesion size, intraoperative conditions and postoperative pathological reactions. RESULTS: The overall response rate was 90.32% (56/62) and the complete response rate 30.65% (19/62). The tumor volumes decreased after NACT. The differences were significant (P < 0.05). After NACT, 56 patients undergoing radical hysterectomy recovered smoothly. The surgical resection rate was 90.32%. Chemotherapeutic reactions of cancerous tissue and a large number of infiltrated lymphocytes were seen in 50 cases. Lymph nodes were positive in 3 cases. There were parametrial invasion (n = 2) and vascular tumor emboli (n = 2). CONCLUSION: Preoperative neoadjuvant chemotherapy is efficacious in cervical cancer. The parametrium becomes softer and the tumor staging decreases. PMID- 22490838 TI - [Mechanism of ginsenoside Rg1 regulating the activity of beta secretase in N2a/APP695 cells]. AB - OBJECTIVE: To explore whether or not ginsenoside Rg1 can modify the metabolism of amyloid precursor protein (APP) and the generation of amyloid beta (Abeta) by nuclear factor-kappa B (NF-kappaB). METHODS: N2a/APP695 cells, a mutated APP overexpressing neuronal cell line, was used to mimic the APP metabolism and Abeta generation in vitro. The BACE1 mRNA and protein levels were detected by RT-PCR (reverse transcription-polymerase chain reaction) and Western blot respectively. Then the expression levels and subcellular localization of NF-kappaB were detected by Western blot and confocal laser scanning microscope respectively. RESULTS: The treatment of ginsenoside Rg1 at a dose of 2.5 umol/L decreased the levels of Abeta1-40 and Abeta1-42 (13.3 +/- 4.3) ng/ml vs (12.0 +/- 5.4) ng/ml in N2a/APP695 cells, decreased the protein level of BACE1 (BACE1/beta-actin 0.26 +/- 0.05), increased the protein level of NF-kappaB p65 (p-p65/p65 0.93 +/- 0.02) and resulted in the translocation of NF-kappaB from cytoplasm to nucleus. Quinazoline inhibited the activation of NF-kappaB with a reduction of p-p65 and p-p65/p65 in N2a/APP695 cells and increased the BACE1 protein level. And the treatment of ginsenoside Rg1 showed similar changes in N2a/APP695 cells when compared with the treatment of quinazoline alone. CONCLUSION: Ginsenoside Rg1 may modify the metabolism of APP by enhancing the nuclear binding of NF-kappaB to BACE1 promoter and inhibiting the transcription and translation of BACE1. PMID- 22490839 TI - [Effects of low-dose X-ray on morphology of neuron and expression of microtubule associated protein-2 in hippocampus of young rats]. AB - OBJECTIVE: To explore the effects of a continuous low-dose of X-ray upon neuronal morphology and expression of microtubule associated protein-2 (MAP-2) in hippocampus of young rats. METHODS: A total of 18 Sprague-Dawley rats aged 35 days were randomly divided into two irradiated groups and one control group (n = 6 each). The irradiated groups received different doses of 0.2 mGy/d, 1.0 mGy/d for 7 consecutive days while the control group sham radiation. The hippocampal pyramidal cell was observed by HE staining, the expression of MAP-2 by immunohistochemistry and Western blot, and the morphologies of microtubule and synapse in CA1 by electron microscopy. RESULTS: (1) The phenomenon of neurodegeneration was observed in the 1.0 mGy group while the control and 0.2 mGy groups were normal; (2) the average optical density of positive MAP-2 protein significantly decreased in the 1.0 mGy group (0.242 +/- 0.017) in the region of CA1 versus the control group (0.282 +/- 0.016) (F = 14.419, P = 0.005). And the average optical density of positive MAP-2 significantly increased in the 0.2 mGy group (0.331 +/- 0.017) compared with the control group (F = 21.700, P = 0.002). The expression of total MAP-2 significantly decreased in the 1.0 mGy group (0.332 +/- 0.001) versus the control group (0.370 +/- 0.012) (F = 28.055, P = 0.000). And the expression of total MAP-2 significantly increased in the 0.2 mGy group (0.455 +/- 0.018) versus the control group (F = 61.974, P = 0.002); (3) there were the reduction of microtubule and the damage of postsynaptic density (PSD) in the 1.0 mGy group in hippocampal CA1. Increased microtubule and normal synapses were found in the 0.2 mGy group in hippocampal CA1. CONCLUSION: The expression of MAP-2 is strongly associated with the integrity of hippocampal neurons in young rats. The 0.2 mGy group may promote the proliferation of hippocampal microtubule in hippocampus and further promote the expression of MAP-2. And the damage of microtubule and PSD on neuron could reduce the expression of MAP-2 in the 1.0 mGy group. PMID- 22490840 TI - [Magnetic liposome mediated shRNA specifically suppresses the growth of non-small cell lung cancer in vitro and in vivo]. AB - OBJECTIVE: To evaluate the inhibition of shRNA mediated by magnetic liposome in the growth of non-small cell lung cancer (NSCLC) under the interference of magnetic field in vitro and in vivo and explore the effects of magnetic field on the efficiency of magnetofection. METHODS: The plasmid of pGFPshIGF-1R was constructed for expressing GFP and shRNA against IGF-1R. CombiMAG as superparamagnetic iron oxide nanoparticles (SPIONs) and Lipofectamine2000 as cationic liposome comprised the magnetic liposome. pGFPshIGF-1R was transferred into A549 cells by magnetofection under a series of interaction durations and intensity of external magnetic fields. pGFPshIGF-1R was delivered into A549 cells in vitro and injected intravenously into the tumor-bearing mice every 48 h for four doses in vivo by way of lipofection or magnetofection. The magnetofection efficiency was analyzed by cytometry and the potency of IGF-1R knockdown by Western blot. At Week 3 after the 4th injection, the mice were sacrificed and the tumors removed and weighed. The tumor inhibition rate was calculated. RESULTS: The interaction durations and intensity of magnetic field could influence the magnetofection efficiency. In vitro, IGF-1R specific-shRNA transfected by lipofection inhibited IGF-1R protein by 56.1% +/- 6.0% and by liposomal magnetofection by 85.1% +/- 3.0%. In vivo, pGFPshIGF-1R delivered by both lipofection and magnetofection significantly inhibited the tumor growth by 41.3% (P < 0.01) and 65.2% (P < 0.01). CONCLUSIONS: Based on magnetic liposome as gene vectors, magnetofection may become a promising targeted therapy for lung cancer. And the transfection efficiency is influenced by magnetic field. PMID- 22490841 TI - [Feasibility of a novel material for the reconstruction of skull base in a canine]. AB - OBJECTIVE: To explore the therapeutic efficacy of a novel complex material of shape-memory alloy brace and artificial dura (nitinol brace and NormalGEN) for the reconstruction of skull base in a canine model with lateral media skull base defect. METHODS: The complex of nitinol brace and NormalGEN was developed with corresponding apparatus. A common adult dog model with lateral media skull base defect was established and then reconstructed with the complex. At Month 3 post operation, cranial lateral radiographic projection, three-dimensional reconstruction of computer tomography, 1.5T magnetic resonance imaging and histopathological examination were detected. RESULTS: Five animal models and cranial reconstructions were made. All survived without any complication, such as leakage of cerebrospinal fluid, local tissue eminence and neurological function defect. The imaging detection showed that nitinol brace was distinct and satisfactorily positioned without shift and artifact. And histopathological examination showed that granulation tissue substituted NormalGEN and grew around the brace with numerous fibroblasts. CONCLUSION: The complex of shape-memory alloy brace and artificial is suitable for the reconstruction of skull base on dog model with lateral media skull base defect. PMID- 22490842 TI - [Combined effects of interferon gamma and gamma ray irradiation on A549 cells in vitro]. AB - OBJECTIVE: To define the role of interferon-gamma on radiotherapy of lung cancer and explore a new way to clinical treatment. METHODS: A549 cells were exposed to gamma ray with or without IFN-gamma co-treatment. MTT assay was performed to evaluate cell viability. Western blot was used to observe the expression of P53 protein. RESULTS: The results showed that co-treatment of IFN-gamma decreased the cell viability significantly compared with the gamma ray irradiation group (71.4% +/- 2.1% vs 44.1% +/- 3.1%, n = 7, P < 0.01). In addition, the expression of P53 protein also increased significantly after co-treatment (P < 0.01); Furthermore, the cell cycle was changed obviously in co-treatment group compared with gamma ray irradiation group, S phase increased (12.9% vs 20.9%, n = 5, P < 0.05) and also blocked the G2/M phase (28.8% vs 38.9%, n = 5, P < 0.05). CONCLUSIONS: The results suggested that gamma ray irradiation combined with IFN-gamma can increase the efficiency of radiotherapy on A549 cells and there is much broad prospect in the clinical treatment of lung cancer. PMID- 22490843 TI - [Expressions and significance of cyclinD1 in epithelial ovarian cancer cell 3AO]. AB - OBJECTIVE: To explore the expression of cyclinD1 in ovarian carcinoma cell 3AO and analyze its relationship with the proliferation of ovarian cancer cell. METHODS: Human ovarian epithelium and ovarian cancer cells 3AO were cultured in vitro. CyclinD1 genes and proteins were detected by reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry before and after the activation of cell 3AO by cis-platinum. Also the cell activity and cell cycle were observed. RESULTS: Abnormal gene amplification and over-expressions of cyclinD1 were found in ovarian cancer cell while the expression of cyclinD1 was negative in normal ovarian epithelium. Under cis-platinum, different expressions of cyclinD1 genes were found in 3AO by RT-PCR. The higher the concentrations of cisplatin, the lower expressions of cyclinD1 genes. By flow cytometry, it was also found that there were lower expressions of cyclinD1 protein in 3AO under cisplatin than without it. With the rising concentrations of cisplatin, the low expressions of cyclinD1 protein in 3AO were detected. The mean numbers were 105.9, 15.42 and 8.59, the cell apoptotic rates 0.63%, 9.08% and 27.41% and the proliferation index (PI) numbers 38.83%, 44.54%, 37.31%. The differences were statistically significant (P < 0.01). CONCLUSION: The up-regulation of cyclinD1 is detected in ovarian cancer cell. A positive correlation is found between the lower expressions of cyclinD1 and the concentration of cisplatin. There is a close relationship between the expressions of cyclinD1 and ovarian cancer cell activity. PMID- 22490845 TI - The moralization of healthy living: Burke's rhetoric of rebirth and older adults' accounts of healthy eating. AB - This article develops a rhetorical analysis of how older adults in Canada and the UK engage with civic-moral imperatives of healthy living. The analysis draws on Burke's concepts of 'symbolic hierarchies' and the 'rhetoric of rebirth' to explore how participants discursively negotiate the moralizing framework of self regulation and self-improvement central to healthy eating discourse, in particular. Working from the premise that healthy eating is a 'principle of perfection' that citizens are encouraged to strive to achieve, the article traces the vocabularies and logical distinctions of 'guilt', 'purification' and 'redemption' in participants' accounts of what healthy eating means to them. This analysis reveals some of the complex, situated and often strategic ways in which they rearticulate and reconfigure the normative imperatives of healthy eating in ways suited to their lived experience and their priorities for health and well being in older age. PMID- 22490846 TI - [Advances in combined modality therapy for patients with operable non-small cell lung cancer]. PMID- 22490844 TI - Neovascularization of coronary tunica intima (DIT) is the cause of coronary atherosclerosis. Lipoproteins invade coronary intima via neovascularization from adventitial vasa vasorum, but not from the arterial lumen: a hypothesis. AB - BACKGROUND: An accepted hypothesis states that coronary atherosclerosis (CA) is initiated by endothelial dysfunction due to inflammation and high levels of LDL C, followed by deposition of lipids and macrophages from the luminal blood into the arterial intima, resulting in plaque formation. The success of statins in preventing CA promised much for extended protection and effective therapeutics. However, stalled progress in pharmaceutical treatment gives a good reason to review logical properties of the hypothesis underlining our efforts, and to reconsider whether our perception of CA is consistent with facts about the normal and diseased coronary artery. ANALYSIS: To begin with, it must be noted that the normal coronary intima is not a single-layer endothelium covering a thin acellular compartment, as claimed in most publications, but always appears as a multi-layer cellular compartment, or diffuse intimal thickening (DIT), in which cells are arranged in many layers. If low density lipoprotein cholesterol (LDL-C) invades the DIT from the coronary lumen, the initial depositions ought to be most proximal to blood, i.e. in the inner DIT. The facts show that the opposite is true, and lipids are initially deposited in the outer DIT. This contradiction is resolved by observing that the normal DIT is always avascular, receiving nutrients by diffusion from the lumen, whereas in CA the outer DIT is always neovascularized from adventitial vasa vasorum. The proteoglycan biglycan, confined to the outer DIT in both normal and diseased coronary arteries, has high binding capacity for LDL-C. However, the normal DIT is avascular and biglycan-LDL C interactions are prevented by diffusion distance and LDL-C size (20 nm), whereas in CA, biglycan in the outer DIT can extract lipoproteins by direct contact with the blood. These facts lead to the single simplest explanation of all observations: (1) lipid deposition is initially localized in the outer DIT; (2) CA often develops at high blood LDL-C levels; (3) apparent CA can develop at lowered blood LDL-C levels. This mechanism is not unique to the coronary artery: for instance, the normally avascular cornea accumulates lipoproteins after neovascularization, resulting in lipid keratopathy. HYPOTHESIS: Neovascularization of the normally avascular coronary DIT by permeable vasculature from the adventitial vasa vasorum is the cause of LDL deposition and CA. DIT enlargement, seen in early CA and aging, causes hypoxia of the outer DIT and induces neovascularization. According to this alternative proposal, coronary atherosclerosis is not related to inflammation and can occur in individuals with normal circulating levels of LDL, consistent with research findings. PMID- 22490847 TI - [5-aza-2'-deoxycytidine-induced inhibition of CDH13 expression and its inhibitory effect on methylation status in human colon cancer cells in vitro and on growth of xenograft in nude mice]. AB - OBJECTIVE: To determine the inhibitory effect of 5-aza-2'-deoxycytidine (5-Aza CdR) on the growth of human colon carcinoma cells and xenografts in nude mice, to observe its effect on CDH13 gene expression and methylation in the xenografts, and to explore the possible mechanisms. METHODS: Human colon carcinoma cell line HCT116 cells were treated with 5-Aza-CdR, and the cell morphology was observe by phase contrast microscopy. The cell growth was assessed by MTT assay. A tumor bearing mouse model was generated by subcutaneous inoculation of human colon carcinoma HCT116 cells into nude mice. The tumor growth in the nude mice was observed, the CDH13 gene expression and its methylation status in the tumors were detected using methylation specific PCR (MSP), RT-PCR, Western blotting and immunohistochemistry. RESULTS: After treatment with 5-Aza-CdR, the inhibition rate of the growth of cultured HCT116 cells was increased as the concentration was increasing. The growth of the xenografts in nude mice was significantly inhibited, and the methylated CDH13 gene was reactivated. After 4 weeks of 5-Aza CdR treatment, no significant difference was found between the body weights of nude mice in the 5-Aza-CdR group [(18.06 +/- 1.29) g] and control group [(17.07 +/- 0.84) g], (P > 0.10), and the average volume of xenografts of the 5-Aza-CdR group was (907.00 +/- 87.29) mm(3), significantly smaller than the (1370.93 +/- 130.20) mm(3) in the control group (P < 0.005). No expression of CDH13 gene was found in the control group. The expression of CDH13 gene in the 5-Aza-CdR group was increased along with the increasing concentration of 5-Aza-CdR. CONCLUSIONS: 5-Aza-CdR inhibits the growth of human colon cancer cells in culture and in nude mice, and induces the cancer cells to re-express CDH13 in nude mice. Its mechanism may be that demethylation of the methylated CDH13 promoter induced by 5 Aza-CdR restores CDH13 expression and thus inhibits the tumor growth in nude mice. PMID- 22490848 TI - [Cytotoxic activity of spleen lymphocytes in BALB/c mice immunized by HSP110 HER2/neu ICD]. AB - OBJECTIVE: To explore the cytotoxic responses of spleen T lymphocytes (CTL) in BALB/c mice induced by recombinant HSP110-HER2/neu ICD complex. METHODS: Tumor bearing mouse model was immunized by HSP110-HER2/neu ICD complex. The IFN-gamma level secreted by activated spleen T lymphocytes was detected by enzyme linked immunospot assay (ELISPOT). The corresponding CTL activity was measured by granzyme release assay. RESULTS: The BALB/c mouse model of human mammary tumor highly expressing HER2/neu was established. HSP110-HER2/neu ICD complex immunization led to a significantly higher level of INF-gamma than that in HSP110 P(789-797) immunized and HER2/neu ICD immunized mice. HSP110-HER2/neu ICD complex immunized animals also show significant CTL activity. The results of immunohistochemical staining showed that the number of blue spots in the PBS group was 4.57 +/- 1.33, HSP110 group 6.83 +/- 2.08, HER2/neu ICD group 16.17 +/- 2.86, HSP110-P(789-797) group 43.67 +/- 4.78, and SP110-HER2/neu ICD group 76.51 +/- 8.17. The number of IFN-gamma-secreting spleen lymphocytes in the HSP110 HER2/neu ICD group was significantly higher than that in the HSP110-P(789-797) group, and that of HSP110-P(789-797) group was significantly higher than that of HER2/neu ICD group (P < 0.01). The target cell-killing rate of the PBS group was (8.15 +/- 1.27)%, HSP110 group (9.51 +/- 1.51)%, HER2/neu ICD group (14.03 +/- 2.45)%, HSP110-P(789-797) group (25.99 +/- 3.04)% and HSP110-HER2/neu ICD group (38.15 +/- 3.95)% (all P < 0.01). CONCLUSIONS: HSP110-HER2/neu ICD complex can promote the proliferation and maturation of T lymphocytes into CTLs, and might be used as anti-tumor vaccine to induce potent cytotoxic T lymophocyte immunoresponse against specific tumor cells. PMID- 22490849 TI - [Association between H-ras and L-myc gene polymorphisms and susceptibility to colorectal cancer]. AB - OBJECTIVE: To explore the association between the polymorphisms of oncogenes H ras and L-myc and colorectal cancer risk, and the interaction of those genes. METHODS: The genotypes of H-ras and L-myc genes were determined by polymerase chain reaction-based restriction fragment length polymorphism analysis. Stratified analysis and logistic model were used to detect the gene-gene interaction. The gene-gene interaction was validated by multifactor dimensionality reduction (MDR) analysis. RESULTS: The single SNP model showed that the polymorphisms of H-ras and L-myc genes were not significantly related with colorectal cancer risk (P > 0.05). Stratified analysis revealed that among the L-myc LS + SS genotype carriers, those with H-ras TC + CC genotype showed significantly increased risk of rectal cancer than those with TT genotype (OR = 1.81, P = 0.005). The positive interaction between L-myc and H-ras was detected by logistic regression model. The OR of the interaction effect was 2.74 (P = 0.024). This result was confirmed in the MDR model, with 54.83% testing balanced accuracy and 10/10 cross-validation consistency, and the model was still significant after the 1000 times permutation test (P = 0.001). CONCLUSION: Our findings suggest that the polymorphism of H-ras and L-myc genes is not related to colorectal cancer risk, but there is a synergy between H-ras and L-myc polymorphisms in the development of rectal cancer. PMID- 22490850 TI - [Expression of multiple tumor suppressor gene p16 and its relationship with prognosis of gastric cancer patients]. AB - OBJECTIVE: To investigate the relationship between p16 expression and cell proliferation and prognosis in gastric cancer patients. METHODS: Gastric cancer cell lines SGC-7901, MKN45, MKN28, human embryonic kidney cell line HEK293, human fibroblast cell line MRC-5, and surgical specimens of gastric carcinoma and adjacent normal gastric mucosa from 65 patients were included in this study. RT PCR, MTT and FCM assays were used to detect p16 expression in gastric cancer cell lines and surgical specimens of gastric cancer. MTT assay was used to determine cancer cell viability and FCM to detect cell cycle. Kaplan-Meier survival curve and Log-Rank statistics were used to analyze the relationship between p16 expression and survival of petients with gastric cancer. RESULTS: Gastric cancer cell lines were mostly negative for p16 expression, and p16 was re-expressed after the cells transfected with p16 gene by adenovirus AdCMV-p16. p16 re expression resulted in the decrease of cancer cell viability and cancer cell cycle arrest with increased G(1) phase and decreased S phase. p16 expression in cancer specimens was 32.3% (21/65), significantly lower than the 81.5% (53/65) in normal mucosa (chi(2) = 32.124, P < 0.001). The disease-free survival was significantly shorter in p16-negative patients than that in p16-positive patients (P < 0.01), but not the overall survival (P > 0.05). p16 expression was significantly correlated with differentiation and lymph node metastasis, but not significantly correlated with sex, age, tumor size or invasion depth of the gastric cancer. CONCLUSIONS: p16 gene is important for cancer cell proliferation. The inactivation gives cancer cells a high activity for proliferation and metastasis, and then influences the disease-free survival of gastric cancer patients. PMID- 22490851 TI - [Expression of Notch1, MMP-2 and MMP-9 and their significance in glioma patients]. AB - OBJECTIVE: To study the expression of Notch1, MMP-2 and MMP-9 in glioma patients and their relationship with progression and prognosis of gliomas. METHODS: Sixty four cases of glioma were included in this study. There were four cases of grade 1 tumor, twenty-five cases of grade 2, nine cases of grade 3, and twenty-six cases of grade 4. Immunohistochemistry (SP staining method) was used to detect the expression of Notch1, MMP-2 and MMP-9 in glioma tissues and adjacent non tumor tissues, and the patients were followed up. RESULTS: Notch1, MMP-2 and MMP 9 were detected in glioma tissues but not in adjacent non-tumor tissues. The expression of Notch1 was increased with the pathological grade of the gliomas (r = 0.262, P < 0.05). The survival time of patients with strong expression of Notch1 was 31.0 months, significantly shorter than that of patients with non strong positive (negative, weak and moderately) Notch1 expression (53.0 months, P < 0.05). Significant difference in survival time was observed between patients with negative and positive expression of MMP-9 (P < 0.05). CONCLUSIONS: Notch1, MMP-2 and MMP-9 are closely correlated with the progression and prognosis of malignant gliomas. Notch1 may participate in the expression regulation of MMP-2 and MMP-9. Compared with MMP-2, MMP-9 may play a more important role in determining the prognosis of malignant glioma. Notch1 and MMP-9 may become new biological markers for prognosis of patients with malignant glioma. PMID- 22490852 TI - [Death-associated protein kinase promoter (DAPK) hypermethylation in uterine cervical cancer and intraepithelial neoplasia in Uyghur nationality women]. AB - OBJECTIVE: To investigate the methylation levels of death-associated protein kinase (DAPK) in Uyghur female patients with different cervical lesions in Xinjiang, and to discuss the relationship of the expression and significance of DAPK in normal cervix, chronic cervicitis, cervical intraepithelial neoplasia (CINI, CIN II/III) and invasive cervical squamous cell carcinoma. METHODS: 30 cases of normal cervix and chronic cervicitis, 30 cases of CINI, 30 cases of CINII/III and 30 cases of cervical squamous cell carcinoma were tested by methylation specific PCR (MSP). Expressions of DAPK in 30 cases of normal cervix and chronic cervicitis, 30 cases of CINI, 30 cases of CINII/III and 30 cases of cervical squamous cell carcinoma were assayed using immunohistochemical SP staining. RESULTS: The methylation rate of DAPK gene in normal cervix and chronic cervicitis was 3.33%, 10% in cervical intraepithelial neoplasia CINI, 36.7% in CINII/III, and 63.3% in invasive cervical squamous cell carcinoma. The methylation rate of DAPK in the SCC group was significantly higher than that in the other groups (P < 0.05). Aberrant promoter methylation of the DAPK gene was positively correlated with the degree of cervical lesions. The positive rate of DAPK protein in normal cervix and chronic cervicitis was 93.3%, 83.3% in cervical intraepithelial neoplasia CINI, 60.0% in CINII/III, and 33.3% in invasive cervical squamous cell carcinoma. The expression of DAPK in the SCC group was significantly lower than that in the other groups (P < 0.05). The positive rate of DAPK protein was negatively correlated with the degree of cervical lesions (r(s) = -0.603, P < 0.001). CONCLUSIONS: Methylation of DAPK is involved in the cervical carcinogenesis and DAPK gene promoter methylation occurs in the early development of cervical cancer in Uyghur women in Xinjiang. Detection of DAPK gene methylation may provide a basis for use in early detection of cervical cancer. DAPK protein expression is decreasing even disappears along with the progression of cervical lesions. PMID- 22490853 TI - [Significance of urodynamic analysis in the patients with recent voiding dysfunction after radical hysterectomy]. AB - OBJECTIVE: To study the urodynamic changes in patients with recent non-infective voiding dysfunction following radical hysterectomy and assess its significance. METHODS: Ninety-six patients with cervical cancer, who were not found any abnormal representation of urodynamics before the operation, were selected into this study group. Eighty-three patients in the study group without urinary infection were detected by urodynamic examination following radical hysterectomy, in order to analyze the urodynamic reasons for the non-infective voiding dysfunction following the surgery. RESULTS: Forty-two patients were found with non-infective voiding dysfunction after the operation. Low compliance bladder, bladder destrusor dysfunction and destrusor overactivity were the three leading types of postoperative bladder dysfunction. Moreover, the incidences of low compliance bladder (50.0% vs. 17.1%), bladder destrusor dysfunction (58.4% vs. 14.6%) and destrusor overactivity (31.0% vs. 4.9%) in the group with voiding dysfunction were significantly higher than the corresponding values in the group without voiding dysfunction (P < 0.01). Secondarily, forty-two patients with recent non-infective voiding dysfunction were divided into simple irritation sign group, simple obstruction sign group and mixed sign group according to their main symptoms. The incidence of bladder destrusor dysfunction in the simple obstruction sign group was significant higher than that in the simple irritation sign group, and the incidence of detrusor overactivity in the simple irritation sign group was significant higher than that in the other two groups (P < 0.05). CONCLUSIONS: There were many different types of urodynamic disorder in the patients with recent non-infective voiding dysfunction after radical hysterectomy. Low compliance bladder, bladder destrusor dysfunction and detrusor overactivity caused by the damage of the pelvic autonomic nerve during the operation may be the main reasons for the recent non-infective voiding dusfunction after radical hysterectomy. Moreover, bladder destrusor dysfunction and detrusor overactivity may be the key points for the symptoms of bladder irritation and bladder obstruction. Urodynamic study is important for the etiology analysis and clinical treatment of recent non-infective voiding dysfunction postoperation. PMID- 22490854 TI - [Role of pharmacokinetic monitoring of serum fluorouracil concentration in patients with local advanced and metastatic colorectal cancer and further improving efficacy of fluorouracil-based chemotherapy]. AB - OBJECTIVE: To investigate the relationship between serum concentration of fluorouracil and therapeutic efficacy as well as adverse reactions in patients with unresectable locally advanced or measurable metastatic colorectal cancer, and to analyze its role in further improving therapeutic efficacy and reducing adverse reactions of fluorouracil-based chemotherapy. METHODS: Eighty-six patients were randomly assigned into three groups according to the average plasma concentration of fluorouracil after three cycles of chemotherapy with the initial regimen of two weeks FOLFOX-4 (oxaliplatin + leucovorin + fluorouracil) or FOLFIRI (irinotecan + leucovorin + fluorouracil): group 1 (plasma concentration of fluorouracil < 25 ng/ml), group 2 (25 - 35 ng/ml) and group 3 (> 35 ng/ml). The blood samples were taken at 12 h after continuous infusion of fluorouracil in each cycle and the plasma concentration of fluorouracil was detected by high performance liquid chromatography (HPLC) (about 5 am +/- 1 h). The relationship between the drug plasma concentration, therapeutic efficacy and adverse reactions in different fluorouracil plasma concentration arms was analyzed retrospectively. RESULTS: The average plasma concentrations of fluorouracil of the three groups were (23.48 +/- 1.95) ng/ml, (31.47 +/- 2.33) ng/ml and (39.89 +/- 3.87) ng/ml, respectively (P < 0.01). As for therapeutic efficacy, the median OS of the groups 2 and 3 were 18.0 and 17.5 months, significantly higher than that in the group 1 (13.0 months, P < 0.01). The PFS were 4.5, 7.5 and 8.0 months, respectively (P < 0.01). In terms of adverse reactions, the incidences of bone marrow suppression, mucositis and diarrhea in the group 3 were significantly higher than that in the first two groups (P = 0.02, P = 0.04 and P = 0.02). CONCLUSIONS: The patients with local advanced and metastatic colorectal cancer, receiving fluorouracil based chemotherapy, and with an average plasma concentration of fluorouracil between 25 - 35 mg/L have a better prognosis, and lower incidence of adverse reactions such as bone marrow suppression, mucositis and diarrhea. PMID- 22490855 TI - [Expression and clinical significance of DAPK1 and CD147 in esophageal squamous cell carcinoma]. AB - OBJECTIVE: To explore the amplification and expression status of DAPK1 and CD147 in esophageal squamous cell carcinoma (ESCC) and their relationship with the prognosis of ESCC. METHODS: Immunohistochemical staining and RT-PCR were used to detect the expression and amplification of DAPK1 and CD147 in esophageal squamous carcinoma tissue and normal esophageal mucosa. Statistical analysis of the clinocopathological data was performed with SPSS 11.5 software package. RESULTS: The positive rates of expression of DAPK1 protein and CD147 protein in the specimens of esophageal carcinoma were 31.3% and 58.5%, and in normal esophageal mucosa 57.5% and 25.0%, respectively, with a statistically significant difference (P < 0.001). The expressions of DAPK1 and CD147 were significant correlated with invasion depth, lymph node metastasis, TNM stage and the degree of cancer differentiation. (P < 0.05). The negative expression of DAPK1 and positive expression of CD147 indicated a poor prognosis. In 52 ESCC cases, the expression of DAPK1 in cancer tissues was 0.236 +/- 0.049, and 0.395 +/- 0.058 in normal esophageal mucosa, while that of CD147 mRNA expression was 0.942 +/- 0.204 and 0.821 +/- 171, respectively, statistically both with a very significant difference (P < 0.01). There was a higher expression level of DAPK1 mRNA in the cancer tissue in patients with no lymph node metastasis, well differentiation, and earlier pathological stage, and a higher expression level of CD147 mRNA in the cancer tissues in patients with lymph node metastasis, poor differentiation, and later pathological stage. CONCLUSIONS: The expression of DAPK1 and CD147 proteins is closely correlated with the clinicopathological characteristics of ESCC. The genes DAPK1 and CD147 may participate in the metastasis and apoptosis of ESCC. The expression of DAPK1 and CD147 may be used as important prognostic predictors in ESCC. PMID- 22490856 TI - [Infiltration of M2 macrophages and its relationship with lymph node metastasis and prognosis in esophageal cancer patients]. PMID- 22490857 TI - [Role of conventional pulmonary function tests and cardiopulmonary exercise test in the prediction of postoperative cardiopulmonary complications in high risk thoracic cancer patients]. AB - OBJECTIVE: To evaluate and compare the value of cardiopulmonary exercise test and conventional pulmonary function tests in the prediction of postoperative cardiopulmonary complications in high risk patients with chest malignant tumors. METHODS: From January 2006 to January 2009, 216 consecutive patients with thoracic malignant tumors underwent conventional pulmonary function tests (PFT, spirometry + DLCOsb for diffusion capacity) and cardiopulmonary exercise test (CPET) preoperatively. The correlation of postoperative cardiopulmonary complications with the parameters of PFT and CPET were retrospectively analyzed using Chi-square test, independent sample t-test and logistic regression analysis. The P value < 0.05 was considered as statistically significant. RESULTS: Of the 216 patients, 57 did not receive operation due to advanced stage diseases or poor cardiopulmonary function in most of them. The remaining 159 underwent different modes of operations. Thirty-six patients (22.6%) in this operated group had postoperative cardiopulmonary complications and 10 patients (6.3%) developed operation-related complications. Three patients (1.9%) died of the complications within 30 days postoperatively. The patients were stratified into groups based on V(O(2)) max/pred (>= 65.0%, < 65.0%); V(O(2)) max*kg( 1)*min(-1) (>= 20 ml, 15 - 19.9 ml, < 15 ml) and FEV1 (>= 2.0 L, 1.2 - 1.99 L, < 1.2 L) according to the criteria in reported papers. There was statistically significant difference among these groups in the parameters (P < 0.05), the rates of postoperative cardiopulmonary complications were much higher in the groups with poor cardiopulmonary function (V(O(2)) max/pred < 65.0%; V(O(2)) max*kg( 1)*min(-1) < 15 ml or FEV1 < 1.2 L). It was shown by logistic regression analysis that postoperative cardiopulmonary complications were significantly correlated with age, associated diseases, poor results of PFT or CPET, operation modes and operation-related complications. CONCLUSIONS: FEV1 in spirometry, V(O(2)) max*kg( 1)*min(-1) and V(O(2)) max/pred in cardiopulmonary exercise test can be used to stratify the patients' cardiopulmonary function status and is correlated well with FEV1. V(O(2)) max*kg(-1)*min(-1) is the best parameter among these three parameters to predict the risk of postoperative cardiopulmonary complications in patients with chest malignant tumors and borderline cardiopulmonary function. PMID- 22490858 TI - [Comparison of the diagnosis and treatment of mechanical bowel obstruction due to tumor or other causes]. AB - OBJECTIVE: The aim of this study was to review the etiology and pathogenesis of patients who underwent surgery for mechanical bowel obstruction. The treatment and prognosis of bowel obstructions caused by intra-abdominal tumors were compared with those due to other causes. METHODS: The clinical data of 203 patients with mechanical bowel obstruction undergoing operation were analyzed retrospectively. The tumor cases were classified as group I, and all other cases as group II. A range of factors were investigated to estimate the postoperative outcome: gender, age, comorbidities, symptoms and findings of physical and radiological examinations, sites of the obstruction, etiology, therapeutic approach, postoperative complications and mortality. RESULTS: Group I included 73 patients and Group II 130. Large bowel carcinoma and peritoneal adhesions were the most common causes of Group I and II, contributing 58 and 86 of all cases, respectively. There was no significant difference in terms of gender between the two groups, but the rate of elderly (>= 70 years) patients was significantly higher (53.4%) than that of the < 70 years old patients (35.4%) (P = 0.012). There was a significant difference between the patients with previous surgical operation history in the tumor group (23.3%) and non-tumor group (58.5%) (P < 0.001). In the 73 cases of the tumor group, the obstruction was located in the large bowel in 58 cases (79.5%), small bowel in 12 cases (16.4%), both small and large bowels in 2 cases (2.7%) and gastric cancer invading the splenic flexure of colon in 1 case, while in the non-tumor group, 111 cases (85.4%) of the obstruction was located in the small bowel and 19 cases (14.6%) and in the large bowel (P < 0.001). Sixty-six cases (90.4%) of the tumor-group underwent intestinal segment excision and 21 cases (28.8%) underwent intestinal fistulation in the tumor group, but in the non-tumor group 61 cases (46.9%) underwent intestinal segment excision and 5 cases (3.8%) underwent intestinal fistulation (all P < 0.001). The hospital stay was (18 +/- 6) days in the tumor group and (11 +/- 3) days in the non-tumor group (P < 0.01). The complication rate (P = 0.104) and mortality rate (P = 0.187) were not significantly different between the two groups. CONCLUSIONS: Tumor mechanical bowel obstruction is more frequently seen in patients in elder age, with colorectal location and without previous operation history. CT scan may provide effective diagnosis and ascertain the presence of the malignant obstruction. Intestinal fistulation is more often needed in patients with tumor intestinal obstruction and endoscopic stenting is a safe option in selected patients with tumor intestinal obstruction. PMID- 22490859 TI - [Clinical characteristics and surgical treatment for localized Castleman's disease]. AB - OBJECTIVE: To investigate the clinical characteristics and treatment of localized Castleman's disease (CD), and review the literatures to improve the diagnosis and management of this disease. METHODS: The clinical symptoms, histopathology, CT, MRI findings and results of surgery in 20 patients with localized CD were evaluated retrospectively. RESULTS: The average age of the patients was 37.7 years. The lesions were located in the retroperitoneal space (9 cases), mediastinum (7 cases), pelvic cavity (1 case), neck (1 case), upper arm (1 case), and axillary (1 case). All patients underwent surgical resection, including 9 cases for retroperitoneal resection (6 cases had open operation and 3 cases laparoscopic resection) and 7 cases for mediastinal resection (open operation in 5 cases and thoracoscopic resection in 2 cases). The Castleman's disease was confirmed by histopathology. There were hyaline vascular type of CD in 17 cases, plasma cell type of CD in 1 case, and mixed cellularity type of CD in 2 cases. The duration of follow-up ranged from 12 to 165 months for 16 cases. Among them 15 patients were alive without recurrence, and 1 case had recurrence in the primary site at 47 months after the operation. CONCLUSIONS: Patients with Castleman's disease have no typical clinical symptoms and have normal laboratory results. The majority of patients are of hyaline vascular type of the disease. Imaging examination is helpful to diagnosis, and the final diagnosis depends on pathologic examination. Complete surgical resection of the tumor is the best treatment for localized Castleman's disease. PMID- 22490860 TI - [Application of an arc-shaped transperineal incision in front of the apex of coccyx during the resection of pelvic retroperitoneal tumors]. AB - OBJECTIVE: To explore a better operative approach to resect complicated pelvic retroperitoneal tumors. METHODS: A total of 28 patients with complicated pelvic retroperitoneal tumors who received surgical resection in our hospital from 2006 to 2010 were included in this study. The surgical operation was assisted with an arc-shaped transperineal incision in front of the apex of coccyx. The operation time, intraoperative blood loss, death toll and length of hospital stay of the patients were retrospectively analyzed. RESULTS: The median operation time was 122.5 minutes. The median blood loss was 420 ml, and the median length of hospital stay of the patients was 17.5 days. There was no postoperative death in this group of patients. CONCLUSION: With the assistance of this arc-shaped transperineal incision in front of the apex of coccyx, the resection of pelvic retroperitoneal tumors can be effectively improved and the surgery risk is reduced. PMID- 22490861 TI - [Efficacy evaluation of high intensity focused ultrasound combined with intra arterial infusion of gemcitabine in the treatment of pancreatic cancer]. AB - OBJECTIVE: The aim of this study was to discuss the clinical effectiveness of high intensity focused ultrasound (HIFU) combined with gemcitabine administered by intra-arterial infusion on intermediate and advanced pancreatic cancer. METHODS: Forty-eight patients with intermediate and advanced pancreatic cancer were divided into two groups. Twenty-four patients of the experimental group were treated by HIFU combined with gemcitabine, and 24 patients of the the HIFU group were treated by HIFU alone. Then the curative effect, extent of pain relief, and survival time were compared in the course of the treatment between the two groups. RESULTS: As compared with those in the control group, the overall response rate, level of pain relief, and 12-month survival rate after therapy were higher and the median survival time was longer in the joint group (P < 0.05). CONCLUSIONS: Ultrasound imaging, CT and associated tumor marker detection can make effective measurement to evaluate curative effect on pancreatic carcinoma. HIFU plus gemcitabine administered by intra-arterial infusion can improve the clinical therapeutic efficacy, pain relief, quality of life and long term survival rate of patients with pancreatic cancer. PMID- 22490862 TI - [Controversy and consensus on the delineation of clinical target volume in radiotherapy for esophageal cancer]. PMID- 22490863 TI - Selective blockade of herpesvirus entry mediator-B and T lymphocyte attenuator pathway ameliorates acute graft-versus-host reaction. AB - The cosignaling network mediated by the herpesvirus entry mediator (HVEM; TNFRSF14) functions as a dual directional system that involves proinflammatory ligand, lymphotoxin that exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT; TNFSF14), and the inhibitory Ig family member B and T lymphocyte attenuator (BTLA). To dissect the differential contributions of HVEM/BTLA and HVEM/LIGHT interactions, topographically-specific, competitive, and nonblocking anti-HVEM Abs that inhibit BTLA binding, but not LIGHT, were developed. We demonstrate that a BTLA-specific competitor attenuated the course of acute graft-versus-host reaction in a murine F(1) transfer semiallogeneic model. Selective HVEM/BTLA blockade did not inhibit donor T cell infiltration into graft-versus-host reaction target organs, but decreased the functional activity of the alloreactive T cells. These results highlight the critical role of HVEM/BTLA pathway in the control of the allogeneic immune response and identify a new therapeutic target for transplantation and autoimmune diseases. PMID- 22490864 TI - Myeloid cell-derived hypoxia-inducible factor attenuates inflammation in unilateral ureteral obstruction-induced kidney injury. AB - Renal fibrosis and inflammation are associated with hypoxia, and tissue pO(2) plays a central role in modulating the progression of chronic kidney disease. Key mediators of cellular adaptation to hypoxia are hypoxia-inducible factor (HIF)-1 and -2. In the kidney, they are expressed in a cell type-specific manner; to what degree activation of each homolog modulates renal fibrogenesis and inflammation has not been established. To address this issue, we used Cre-loxP recombination to activate or to delete both Hif-1 and Hif-2 either globally or cell type specifically in myeloid cells. Global activation of Hif suppressed inflammation and fibrogenesis in mice subjected to unilateral ureteral obstruction, whereas activation of Hif in myeloid cells suppressed inflammation only. Suppression of inflammatory cell infiltration was associated with downregulation of CC chemokine receptors in renal macrophages. Conversely, global deletion or myeloid-specific inactivation of Hif promoted inflammation. Furthermore, prolonged hypoxia suppressed the expression of multiple inflammatory molecules in noninjured kidneys. Collectively, we provide experimental evidence that hypoxia and/or myeloid cell-specific HIF activation attenuates renal inflammation associated with chronic kidney injury. PMID- 22490866 TI - U1-small nuclear ribonucleoprotein activates the NLRP3 inflammasome in human monocytes. AB - The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is a caspase-1-containing cytosolic protein complex that is essential for processing and secretion of IL-1beta. The U1-small nuclear ribonucleoprotein (U1-snRNP) that includes U1-small nuclear RNA is a highly conserved intranuclear molecular complex involved in splicing pre-mRNA. Abs against this self nuclear molecule are characteristically found in autoimmune diseases like systemic lupus erythematosus, suggesting a potential role of U1-snRNP in autoimmunity. Although endogenous DNA and microbial nucleic acids are known to activate the inflammasomes, it is unknown whether endogenous RNA-containing U1-snRNP could activate this molecular complex. In this study, we show that U1-snRNP activates the NLRP3 inflammasome in CD14(+) human monocytes dependently of anti-U1-snRNP Abs, leading to IL-1beta production. Reactive oxygen species and K(+) efflux were responsible for this activation. Knocking down the NLRP3 or inhibiting caspase-1 or TLR7/8 pathway decreased IL-1beta production from monocytes treated with U1 snRNP in the presence of anti-U1-snRNP Abs. Our findings indicate that endogenous RNA-containing U1-snRNP could be a signal that activates the NLRP3 inflammasome in autoimmune diseases like systemic lupus erythematosus where anti-U1-snRNP Abs are present. PMID- 22490865 TI - Sphingosine analogue AAL-R increases TLR7-mediated dendritic cell responses via p38 and type I IFN signaling pathways. AB - Sphingosine analogues display immunosuppressive activities and thus have therapeutic potential in the treatment of autoimmune diseases. In this study, we investigated the effects of the sphingosine analogue AAL-R (FTY720 derivative) on dendritic cell (DC) response upon TLR stimulation. Unlike its known immunosuppressive activity, AAL-R increased TLR7-mediated DC responses by elevating the levels of MHC class I and costimulatory molecules and type I IFN expression and by enhancing the capacity of DCs to induce CD8(+) T cell proliferation. Importantly, the stimulatory activity of AAL-R was dependent on type I IFN signaling, as type I IFN receptor-deficient DCs failed to respond to AAL-R. Also, AAL-R activated p38 MAPK to increase type I IFN synthesis and TLR7 mediated DC maturation. These findings enhance our understanding of sphingosine regulation of the host immune system, in particular upon pathogenic infections. PMID- 22490867 TI - NLRC5 controls basal MHC class I gene expression in an MHC enhanceosome-dependent manner. AB - Nucleotide-binding domain and leucine-rich repeat (NLR) proteins play important roles in innate immune responses as pattern-recognition receptors. Although most NLR proteins act in cell autonomous immune pathways, some do not function as classical pattern-recognition receptors. One such NLR protein is the MHC class II transactivator, the master regulator of MHC class II gene transcription. In this article, we report that human NLRC5, which we recently showed to be involved in viral-mediated type I IFN responses, shuttles to the nucleus and activates MHC class I gene expression. Knockdown of NLRC5 in different human cell lines and primary dermal fibroblasts leads to reduced MHC class I expression, whereas introduction of NLRC5 into cell types with very low expression of MHC class I augments MHC class I expression to levels comparable to those found in lymphocytes. Expression of NLRC5 positively correlates with MHC class I expression in human tissues. Functionally, we show that both the N-terminal effector domain of NLRC5 and its C-terminal leucine-rich repeat domain are needed for activation of MHC class I expression. Moreover, nuclear shuttling and function depend on a functional Walker A motif. Finally, we identified a promoter sequence in the MHC class I promoter, the X1 box, to be involved in NLRC5 mediated MHC class I gene activation. Taken together, this suggested that NLRC5 acts in a manner similar to class II transactivator to drive MHC expression and revealed NLRC5 as an important regulator of basal MHC class I expression. PMID- 22490868 TI - Defective autoimmune regulator-dependent central tolerance to myelin protein zero is linked to autoimmune peripheral neuropathy. AB - Chronic inflammatory demyelinating polyneuropathy is a debilitating autoimmune disease characterized by peripheral nerve demyelination and dysfunction. How the autoimmune response is initiated, identity of provoking Ags, and pathogenic effector mechanisms are not well defined. The autoimmune regulator (Aire) plays a critical role in central tolerance by promoting thymic expression of self-Ags and deletion of self-reactive T cells. In this study, we used mice with hypomorphic Aire function and two patients with Aire mutations to define how Aire deficiency results in spontaneous autoimmune peripheral neuropathy. Autoimmunity against peripheral nerves in both mice and humans targets myelin protein zero, an Ag for which expression is Aire-regulated in the thymus. Consistent with a defect in thymic tolerance, CD4(+) T cells are sufficient to transfer disease in mice and produce IFN-gamma in infiltrated peripheral nerves. Our findings suggest that defective Aire-mediated central tolerance to myelin protein zero initiates an autoimmune Th1 effector response toward peripheral nerves. PMID- 22490869 TI - NLRC5 cooperates with the RFX transcription factor complex to induce MHC class I gene expression. AB - Tight regulation of MHC class I gene expression is critical for CD8 T cell activation and host adaptive-immune responses. The promoters of MHC class I genes contain a well-conserved core module, the W/S-X-Y motif, which assembles a nucleoprotein complex termed MHC enhanceosome. A member of the nucleotide-binding domain, leucine-rich repeat (NLR) protein family, NLRC5, is a newly identified transcriptional regulator of MHC class I genes. NLRC5 associates with and transactivates the proximal promoters of MHC class I genes, although the molecular mechanism of transactivation has not been understood. In this article, we show that NLRC5-mediated MHC class I gene induction requires the W/S and X1, X2 cis-regulatory elements. The transcription factors RFX5, RFXAP, and RFXANK/B, which compose the RFX protein complex and associate with the X1 box, cooperate with NLRC5 for MHC class I expression. Coimmunoprecipitation experiments revealed that NLRC5 specifically interacts with the RFX subunit RFXANK/B via its ankyrin repeats. In addition, we show that NLRC5 can cooperate with ATF1 and the transcriptional coactivators CBP/p300 and general control nonderepressible 5, which display histone acetyltransferase activity. Taken together, our data suggest that NLRC5 participates in an MHC class I-specific enhanceosome, which assembles on the conserved W/S-X-Y core module of the MHC class I proximal promoters, including the RFX factor components and CREB/ATF1 family transcription factors, to promote MHC class I gene expression. PMID- 22490872 TI - Predictive value of interferon-gamma release assays and tuberculin skin testing for progression from latent TB infection to disease state: a meta-analysis. AB - BACKGROUND: Given the current lack of effective vaccines against TB, the accuracy of screening tests for determining or excluding latent TB infection (LTBI) is decisive in effective TB control. This meta-analysis critically appraises studies investigating the positive and the negative predictive value (PPV and NPV, respectively) from a test-determined LTBI state for progression to active TB of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST). METHODS: We searched MEDLINE, EMBASE, and Cochrane bibliographies for relevant articles. After qualitative evaluation, the PPV and NPV for progression of commercial and "in-house" IGRAs and the TST for persons not receiving preventive treatment in the context of the respective IGRA studies were pooled using both a fixed and a random-effect model. Weighted rates were calculated for all study populations and for groups solely at high risk of TB development. RESULTS: The pooled PPV for progression for all studies using commercial IGRAs was 2.7% (95% CI, 2.3%-3.2%) compared with 1.5% (95% CI, 1.2%-1.7%) for the TST (P < .0001). PPV increased to 6.8% (95% CI, 5.6%-8.3%) and 2.4% (95% CI, 1.9%-2.9%) for the IGRAs and the TST, respectively, when only high-risk groups were considered (P < .0001). Pooled values of NPV for progression for both IGRAs and the TST were very high, at 99.7% (95% CI, 99.5%-99.8%) and 99.4% (95% CI, 99.2%-99.5%), respectively, although they were significantly higher for IGRAs (P < .01). CONCLUSIONS: Commercial IGRAs have a higher PPV and NPV for progression to active TB compared with those of the TST, especially when performed in high-risk persons. PMID- 22490871 TI - Effects of commercial air travel on patients with pulmonary hypertension air travel and pulmonary hypertension. AB - BACKGROUND: Limited data are available on the effects of air travel in patients with pulmonary hypertension (PH), despite their risk of physiologic compromise. We sought to quantify the incidence and severity of hypoxemia experienced by people with PH during commercial air travel. METHODS: We recruited 34 participants for a prospective observational study during which cabin pressure, oxygen saturation (Sp O 2 ), heart rate, and symptoms were documented serially at multiple predefined time points throughout commercial flights. Oxygen desaturation was defined as SpO2, <85%. RESULTS: Median flight duration was 3.6 h (range, 1.0-7.3 h). Mean +/- SD cabin pressure at cruising altitude was equivalent to the pressure 1,968 +/- 371 m (6,456 +/- 1,218 ft) above sea level (ASL)(maximum altitude 5 2,621 m [8,600 ft] ASL). Median change in Sp O 2 from sea level to cruising altitude was 2 4.9% (range, 2.0% to 2 15.8%). Nine subjects (26% [95% CI, 12%-38%]) experienced oxygen desaturation during flight (minimum Sp O 2 5 74%). Thirteen subjects (38%) reported symptoms during flight, of whom five also experienced desaturations. Oxygen desaturation was associated with cabin pressures equivalent to . 1,829 m (6,000 ft) ASL, ambulation, and flight duration(all P values , .05). CONCLUSIONS: Hypoxemia is common among people with PH traveling by air, occurring in one in four people studied. Hypoxemia was associated with lower cabin pressures, ambulation during flight, and longer flight duration. Patients with PH who will be traveling on flights of longer duration or who have a history of oxygen use, including nocturnal use only, should be evaluated for supplemental in-flight oxygen. PMID- 22490873 TI - The association of mental health over time with cardiac outcomes in HEMO study patients. AB - BACKGROUND AND OBJECTIVES: Poor mental health over time is significantly associated with cardiovascular morbidity and mortality in the general population, which is the leading cause of death in dialysis patients. Most studies of dialysis patients, however, have investigated the relationship between baseline mental health measurements and all-cause mortality and not mental health measured longitudinally throughout a study and cause-specific mortality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study examined the association of changes in mental health over time with all-cause and cause-specific deaths and cardiac hospitalizations in the Hemodialysis study patients. Mental health was assessed at baseline and annually during the study with short form 36 mental health index scores. Poorer mental health was defined by a mental health index score<=60. RESULTS: Patients with poorer mental health at baseline were more likely to have less than a high school education and be unmarried, have significantly higher index of coexistent disease scores, and report taking beta-blockers and sleep medications. Low mental health scores over time were independently associated with a decrease in survival time from all-cause mortality by -0.06 (-0.10, -0.03; P<0.001), and they also significantly hastened time to first cardiac hospitalization by -0.08 (-0.13, -0.02; P=0.01) and composite of first cardiac hospitalization or cardiac death by -0.04 (-0.07, -0.02; P<0.001). CONCLUSIONS: This study found an independent association between poor mental health over time and all-cause mortality, cardiac hospitalization, and the composite of cardiac death or cardiac hospitalization in hemodialysis patients. The results underscore the importance of attention to mental health related to cardiac complications and even death in dialysis patients. PMID- 22490874 TI - Osteoprotegerin/RANKL axis and progression of coronary artery calcification in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Vascular calcification is associated with increased cardiovascular mortality in chronic hemodialysis patients. This prospective study investigated the relationship between serum osteoprotegerin, receptor activator of NF-kappaB ligand, inflammatory markers, and progression of coronary artery calcification score. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Seventy-eight hemodialysis patients were enrolled. Serum IL-1beta, IL-6, TNF-alpha, osteoprotegerin, receptor activator of NF-kappaB, fetuin A, and bone alkaline phosphatase were measured by ELISA. Coronary artery calcification score was measured two times with 1-year intervals, and patients were classified as progressive or nonprogressive. RESULTS: Baseline and first-year serum osteoprotegerin levels were significantly higher in the progressive than nonprogressive group (17.39+/-9.67 versus 12.90+/-6.59 pmol/L, P=0.02; 35.17+/ 18.35 versus 24+/-11.65 pmol/L, P=0.002, respectively). The ratio of serum osteoprotegerin to receptor activator of NF-kappaB ligand at 1 year was significantly higher in the progressive group (0.26 [0.15-0.46] versus 0.18 [0.12 0.28], P=0.004). Serum osteoprotegerin levels were significantly correlated with coronary artery calcification score at both baseline (r=0.36, P=0.001) and 1 year (r=0.36, P=0.001). Importantly, progression in coronary artery calcification score significantly correlated with change in serum osteoprotegerin levels (r=0.39, P=0.001). In addition, serum receptor activator of NF-kappaB ligand levels were significantly inversely correlated with coronary artery calcification scores at both baseline (r=-0.29, P=0.01) and 1 year (r=-0.29, P=0.001). In linear regression analysis for predicting coronary artery calcification score progression, only baseline coronary artery calcification score and change in osteoprotegerin were retained as significant factors in the model. CONCLUSIONS: Baseline coronary artery calcification score and serum osteoprotegerin levels were significantly associated with progression of coronary artery calcification score in hemodialysis patients. PMID- 22490875 TI - Immunosuppressive regimen and interstitial fibrosis and tubules atrophy at 12 months postrenal transplant. AB - BACKGROUND AND OBJECTIVES: Chronic renal transplant dysfunction is histopathologically characterized by interstitial fibrosis and tubular atrophy. This study investigated the relative contribution of baseline donor, recipient, and transplant characteristics to interstitial fibrosis and tubular atrophy score at month 12 after renal transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective study includes all 109 consecutive recipients with adequate implantation and month 12 biopsies transplanted between April of 2003 and February of 2007. Immunosuppression regimen was tacrolimus and steroids (10 days) plus either sirolimus or mycophenolate mofetil. RESULTS: Average interstitial fibrosis and tubular atrophy score increased from 0.70 to 1.65 (P<0.001). In an adjusted multiple linear regression analysis, interstitial fibrosis and tubular atrophy score at month 12 was significantly related to donor type (donors after cardiac death versus living donor had interstitial fibrosis and tubular atrophy score+0.41, 95% confidence interval=0.05-0.76, P=0.02), baseline interstitial fibrosis and tubular atrophy, and immunosuppression regimen. Because of interaction between the latter two variables (P=0.002), results are given separately: recipients with a baseline interstitial fibrosis and tubular atrophy score of zero had a 0.60 higher score at month 12 (95% confidence interval=0.09-1.10, P=0.02) when mycophenolate mofetil-treated, whereas recipients with a baseline interstitial fibrosis and tubular atrophy score more than zero had a 0.38 higher score at month 12 (95% confidence interval=0.01-0.74, P=0.04) when sirolimus-treated. A higher score at month 12 correlated with a lower estimated GFR (rho=-0.45, P<0.001). CONCLUSIONS: These findings suggest that histologic assessment of a preimplantation biopsy may guide choice of immunosuppresion to maximize transplant survival and its interaction with type of immunosuppression. PMID- 22490877 TI - The production of p-cresol sulfate and indoxyl sulfate in vegetarians versus omnivores. AB - BACKGROUND AND OBJECTIVES: The uremic solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) are generated by colon bacteria acting on food components that escape absorption in the small bowel. The production of these potentially toxic compounds may thus be influenced by diet. This study examined whether production of PCS and IS is different in vegetarians and omnivores. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The production of PCS and IS was assessed by measuring their urinary excretion rates in participants with normal kidney function. Studies were carried out in 15 vegetarians and 11 individuals consuming an unrestricted diet. Participants recorded food intake over 4 days and collected urine over the final 2 days of each of two study periods, which were 1 month apart. RESULTS: Average PCS excretion was 62% lower (95% confidence interval [95% CI], 15-83) and average IS excretion was 58% lower (95% CI, 39-71) in vegetarians than in participants consuming an unrestricted diet. Food records revealed that lower excretion of PCS and IS in vegetarians was associated with a 69% higher (95% CI, 20-139) fiber intake and a 25% lower (95% CI, 3-42) protein intake. PCS and IS excretion rates varied widely among individual participants and were not closely correlated with each other but tended to remain stable in individual participants over 1 month. CONCLUSIONS: PCS and IS production rates are markedly lower in vegetarians than in individuals consuming an unrestricted diet. PMID- 22490879 TI - Natural occurrence of Zoophthora radicans (Entomophthorales: Entomophthoraceae) on Thaumastocoris peregrinus (Heteroptera: Thaumastocoridae), an invasive pest recently found in Brazil. AB - Occurrence of Zoophthora radicans infecting nymphs and adults of Thaumastocoris peregrinus Carpintero and Dellape, 2006 is reported in Brazil. This is a new record of host for this fungal species and the first fungal pathogen associated with this pest worldwide. Infection of Z. radicans on T. peregrinus populations on commercial Eucalyptus plantation (Eucalyptus spp.) reached up to 100%, and low insect densities were associated with high levels of fungal infection in three out of seven plots. This pathogen seems to be virulent against T. peregrinus and may play an important role in population regulations of this invasive pest through naturally induced epizootics. PMID- 22490876 TI - Sexual dysfunction in women with ESRD requiring hemodialysis. AB - BACKGROUND AND OBJECTIVES: The few existing studies of sexual dysfunction in women on hemodialysis are limited by small sample size. This large, cross sectional study evaluated the prevalence and correlates of female sexual dysfunction in advanced kidney disease. DESIGN, SETTING, PARTICIPANTS, METHODS: A total of 1472 women with ESRD undergoing hemodialysis were recruited to a multinational, cross-sectional study conducted within a collaborative dialysis network in Europe and South America. Sexual dysfunction was identified by the Female Sexual Function Index. Correlates of self-reported sexual dysfunction were identified by regression analyses. RESULTS: Of the 1472 women, 659 completed questionnaires (45%). More than half (362 of 659 [55%]) lived with a partner, and 232 of 659 (35%) reported being sexually active. Of these 659 respondents, 555 (84%) reported sexual dysfunction. Women with a partner (282 of 362 [78%]) were less likely to report sexual dysfunction than those without a partner (273 of 297 [92%]) (P<0.001). Sexual dysfunction was independently associated with age, depressive symptoms, less education, menopause, diabetes, and diuretic therapy. Nearly all women who were not wait-listed for a kidney transplant and were living without a partner (249 of 260 [96%]) reported sexual dysfunction. More than half (128 of 232 [55%]) of sexually active women reported sexual dysfunction, associated with age, depressive symptoms, menopause, low serum albumin, and diuretic therapy. CONCLUSIONS: This descriptive study suggests most women on hemodialysis experience sexual problems. Additional research on the relevance of sexual dysfunction to symptom burden and quality of life in these women is needed. PMID- 22490878 TI - Long-term renal and cardiovascular outcomes in Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants by baseline estimated GFR. AB - BACKGROUND AND OBJECTIVES: CKD is common among older patients. This article assesses long-term renal and cardiovascular outcomes in older high-risk hypertensive patients, stratified by baseline estimated GFR (eGFR), and long-term outcome efficacy of 5-year first-step treatment with amlodipine or lisinopril, each compared with chlorthalidone. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a long-term post-trial follow-up of hypertensive participants (n=31,350), aged >=55 years, randomized to receive chlorthalidone, amlodipine, or lisinopril for 4-8 years at 593 centers. Participants were stratified by baseline eGFR (ml/min per 1.73 m(2)) as follows: normal/increased (>=90; n=8027), mild reduction (60-89; n=17,778), and moderate/severe reduction (<60; n=5545). Outcomes were cardiovascular mortality (primary outcome), total mortality, coronary heart disease, cardiovascular disease, stroke, heart failure, and ESRD. RESULTS: After an average 8.8-year follow-up, total mortality was significantly higher in participants with moderate/severe eGFR reduction compared with those with normal and mildly reduced eGFR (P<0.001). In participants with an eGFR <60, there was no significant difference in cardiovascular mortality between chlorthalidone and amlodipine (P=0.64), or chlorthalidone and lisinopril (P=0.56). Likewise, no significant differences were observed for total mortality, coronary heart disease, cardiovascular disease, stroke, or ESRD. CONCLUSIONS: CKD is associated with significantly higher long-term risk of cardiovascular events and mortality in older hypertensive patients. By eGFR stratum, 5-year treatment with amlodipine or lisinopril was not superior to chlorthalidone in preventing cardiovascular events, mortality, or ESRD during 9-year follow-up. Because data on proteinuria were not available, these findings may not be extrapolated to proteinuric CKD. PMID- 22490880 TI - Brain oscillatory 4-35 Hz EEG responses during an n-back task with complex visual stimuli. AB - Brain oscillatory responses of 4-35 Hz EEG frequencies elicited during performance of a visual n-back task with complex visual stimuli were assessed in 20 adult volunteers. Spectral power changes were assessed separately for target and non-target stimuli in four different memory load conditions (0, 1, 2, and 3 back). The presentation of both target and non-target stimuli elicited long lasting ~4-8 Hz power increases, which were more prominent at the beginning of stimulus onset during presentation of target stimuli, as compared to non-target stimuli, in the 0-back memory load condition. ~8-25 Hz power decreases appeared at stimulus onset. These power decreases were more prominent during the presentation of target stimuli, as compared to non-target stimuli, and their duration increased as a function of memory load between the 0-, 1-, and 2-back, but not the 3-back, memory load conditions. The current results provide further evidence in support of the notion of a complex interplay between both ~4-8 Hz power increases and ~8-25 Hz power decreases during cognitive memory task performance. PMID- 22490881 TI - Lysosomal degradation of retinal glial AQP4 following its internalization induced by acute ocular hypertension. AB - The membrane-bound water channel aquaporin-4 plays a significant role in the regulation of water movement within the retina. In retinal ischemia-reperfusion injury, changes in the expression and localization of aquaporin-4 have been reported. Previous studies also suggest that the internalization of several membrane-bound proteins, including aquaporin-4, may occur with or without lysosomal degradation. In this study, the internalization of aquaporin-4 was detected in the ischemic rat retina via double immunofluorescence labeling. Specifically, both aquaporin-4 and the mannose-6-phosphate receptor co-localized post-ischemic injury (10, 30 and 60 min). The same results were found during a 12 h reperfusion window (2, 4 and 8 h, respectively) following 60 min of ischemia. Moreover, the co-expression of aquaporin-4 and lysosomal-associated membrane protein-1 was observed at 1-12 h of reperfusion, with co-expression increasing followed by a gradual decrease. These combined findings suggest that AQP4 is internalized in the ischemic-reperfused retina, and the lysosome is involved in degrading the internalized aquaporin-4 during the reperfusion phase. Both the internalization of aquaporin-4 and its lysosomal degradation may serve as valuable therapeutic targets for managing ischemic-reperfused retinal injury. PMID- 22490882 TI - Dipyrone attenuates acute sickness response to lipopolysaccharide in mice. AB - Sickness behavior appears to be the expression of a central motivational state that reorganizes the organism's priorities to cope with infectious pathogens. To evaluate the effect of dipyrone in lipopolysaccharide (LPS)-induced sickness behavior, mice were subjected to the forced swim test (FST), tail suspension test (TST), dark-light box test, open field test, sucrose preference intake test and food intake test. LPS administration increased the immobility time in the TST, increased the time spent floating in the FST, and depressed locomotor activity in the open field test. Treatment with LPS decreased the total number of transitions made between the dark and light compartments of the apparatus and induced anhedonia and anorexia. Pre-treatment with dipyrone (10, 50, or 200 mg/kg) attenuated behavioral changes induced by LPS in the FST, TST, open field and light-dark box tests. In addition, dipyrone prevented anhedonia and anorexia in mice challenged with LPS. Considering that dipyrone attenuates LPS-induced behavioral changes, it is proposed that LPS-induced sickness behavior is dependent on the COX pathway. PMID- 22490884 TI - Doubts about actions and flanker incongruity-related potentials and performance. AB - The brain networks that are involved in flanker incongruity and error processing are also consistently implicated in mental disorders such as obsessive compulsive disorder (OCD) that feature increased "Doubts about Actions" (DaA) scores. In the present study we investigated whether DaA scores, similar to what has been found for its positive correlate, OCD symptom severity scores, predict less interference from incompatible flankers during an Eriksen flanker task. Sixteen healthy right-handed female participants performed the flanker task and event related potentials to the stimuli were recorded. DaA, but not other trait measures such as concern over mistakes and punishment sensitivity, related to less interference from incompatible flankers on performance and a smaller increase in N2 amplitude on incongruent compared to congruent flanker trials. This seems to point to a strategy or focused attention capacity to minimize flanker interference effects. The present results suggest that specific attentional capacities or strategies that appear to characterize disorders such as OCD, are related to disorder-associated traits in healthy populations as well. PMID- 22490883 TI - AMPA receptor subunit expression in the cuneate nucleus of adult squirrel monkeys after peripheral nerve injury. AB - The primate somatosensory system provides an excellent model system with which to investigate adult neural plasticity. Here, we report immunohistochemical staining data for the GluR1 and GluR2/3 AMPA receptor subunits in the cuneate nucleus of adult squirrel monkeys one week after median nerve compression. These data are compared to subunit changes in the area 3b cortex of the same animals. We report differences between control and deprived brainstem implying that deprivation induced changes in subunit expression mirror those reported in the cortex. There are significant increases in GluR1 receptor subunit staining intensity and significant decreases in GluR2/3 receptor subunit staining intensity. This pattern of expression resembles receptor configurations reported in developing sensory systems. Taken together, these results suggest that the brainstem and the cortex initially progress through a phase of developmental recapitulation prior to the onset of NMDA mediated adult somatosensory reorganization. PMID- 22490885 TI - Relationships between hippocampal shape and cognitive performances in drug-naive patients with Alzheimer's disease. AB - Previous studies provided hippocampal shape analysis of Alzheimer's disease (AD) patients using automated segmentation techniques. However, the relationships between the hippocampal deformations and various cognitive impairments were not clear. The aim of this study was to investigate hippocampal shape changes and their relationship to cognitive impairments. Fifty-one drug-naive patients with AD and 50 group-matched healthy control subjects underwent 3T MRI scanning, and the hippocampal volumes and deformations were compared between the groups. Additionally, we explored the correlation pattern between the hippocampal deformations and the cognitive dysfunctions in AD using the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-K). AD subjects exhibited significant hippocampal deformations in the cornu ammnonis (CA1) and subiculum areas compared to those in healthy subjects (p<0.05, false discovery rate (FDR) corrected). Significant correlations were observed between hippocampal deformations in CA1 and subiculum areas and verbal immediate recall, verbal delayed recall, verbal recognition memory, and constructional recall scores (p<0.05, FDR corrected). This study was the first to explore the relationships between hippocampal deformations and various cognitive impairments of drug-naive patients with AD. These structural changes in hippocampal CA1 and subiculum areas might be the core of the underlying neurobiological mechanisms of hippocampal dysfunction and their relevance to the various cognitive dysfunctions in AD. PMID- 22490886 TI - Insulin-like growth factor-1 induces the phosphorylation of PRAS40 via the PI3K/Akt signaling pathway in PC12 cells. AB - Insulin-like growth factor-1 (IGF-1) is a polypeptide tropic factor that plays an important role in the survival and differentiation of both neuronal and non neuronal cells. Numerous studies have demonstrated that IGF-1 promotes neuronal cell survival via the PI3K/Akt signaling pathway. Proline-rich Akt substrate of 40kDa (PRAS40) is a recently discovered downstream target of Akt. However, the relationship between IGF-1 and PRAS40 is not known. In this study, we characterized the phosphorylation of PRAS40 induced by IGF-1 in PC12 cells and explored the signaling pathway responsible for the effect of IGF-1. IGF-1 induced the phosphorylation of Akt at Thr473 and PRAS40 at Thr246 in PC12 cells. The phosphorylation of Akt and PRAS40 induced by IGF-1 (100ng/ml) was inhibited by the phosphatidylinositide 3-kinase (PI3K) specific inhibitor LY294002 (50MUM), while no inhibitory effect was observed for a MAPK kinase pathway specific inhibitor PD98059 nor a p38 MAPK inhibitor PD169316, suggesting that the phosphorylation of PRAS40 induced by IGF-1 is mediated by the PI3K pathway in PC12 cells and primary cultured neurons. In further support this hypothesis, an Akt kinase specific inhibitor, Akt inhibitor VIII, attenuated IGF-1-induced phosphorylation of PRAS40 at the concentration that blocked the phosphorylation of Akt induced by IGF-1. Taken together, these data demonstrate that IGF-1 stimulates the phosphorylation of PRAS40 at Thr246 in neuronal cells and the effect of IGF-1 is mediated, at least in part, by the PI3K/Akt signaling pathway. PMID- 22490887 TI - Upper limb kinesthetic asymmetries: gender and handedness effects. AB - Proprioceptive and motor information contribute to movement representation; however, the equivalence of homologous contralateral sensorimotor processes as a function of gender and handedness has received little attention. The present work investigated asymmetry in contralateral reproductions of movements elicited by tendon vibration in right and left handed young adults of both genders. With eyes closed, illusions of elbow flexion movement elicited by a 100 Hz vibration applied to the distal tendon of the right or left triceps muscle were matched concurrently with the opposite limb. Overall, movement velocity was larger for females than males, asymmetric and handedness dependent in males. Conversely, consistent symmetry was found between left and right-handed females. These findings lead us to suggest that hand preference and gender contribute to differences in movement representation that may result from the combination of cortical structural differences and information processing specific to each hemisphere and gender. PMID- 22490888 TI - Ferulic acid attenuates the focal cerebral ischemic injury-induced decrease in parvalbumin expression. AB - Ferulic acid exerts a neuroprotective effect through its anti-oxidant and anti inflammation properties. Parvalbumin has calcium buffering capacity and protects neuronal cells from cytotoxic Ca(2+) overload. This study investigated whether ferulic acid regulates parvalbumin expression in cerebral ischemia and glutamate toxicity-induced neuronal cell death. Male Sprague-Dawley rats were immediately treated with vehicle or ferulic acid (100 mg/kg, i.v.) after middle cerebral artery occlusion (MCAO), and cerebral cortex tissues were collected 24 h after MCAO. A proteomics approach elucidated the decrease of parvalbumin in MCAO operated animals, and ferulic acid treatment attenuated the injury-induced decrease in parvalbumin expression. Moreover, RT-PCR and Western blot analyses clearly showed that ferulic acid treatment prevents the injury-induced decrease in parvalbumin levels. The number of parvalbumin-positive cells also decreased in MCAO-operated animals, and ferulic acid attenuated this injury-induced decrease in parvalbumin-positive cells. In cultured hippocampal cells, glutamate toxicity significantly increased the intracellular Ca(2+) concentration, whereas this increase in Ca(2+) levels was inhibited by ferulic acid treatment. In addition, ferulic acid treatment attenuated the glutamate exposure-induced decrease in parvalbumin levels. These results suggest that ferulic acid exerts a neuroprotective effect by attenuating the injury-induced decrease of parvalbumin and modulating intracellular Ca(2+) levels. PMID- 22490889 TI - GRP78 counteracts cell death and protein aggregation caused by mutant huntingtin proteins. AB - The ER-localized chaperone glucose-regulated protein (GRP78) protects neurons against excitotoxicity and apoptosis. Here we show that overexpressing GRP78 protects N2a cells against mutant huntingtin proteins, reduces formation of mutant huntingtin aggregates, inhibits caspase-12 activation and blocks cell death. Our data suggest that GRP78 may be a promising therapeutic target for the treatment of Huntington's disease. PMID- 22490890 TI - Protective effects of vitamins E, B and C and L-carnitine in the prevention of cisplatin-induced ototoxicity in rats. AB - OBJECTIVE: This experimental study aimed to investigate the effects of vitamins E, B and C and L-carnitine in preventing cisplatin-induced ototoxicity. METHODS: Twenty-five adult, male, Wistar albino rats were randomly allocated to receive intraperitoneal cisplatin either alone or preceded by vitamins B, E or C or L carnitine. Auditory brainstem response (i.e. hearing thresholds and wave I-IV intervals) and distortion product otoacoustic emissions (i.e. signal-to-noise ratios) were recorded before and 72 hours after cisplatin administration. RESULTS: The following statistically significant differences were seen: control group pre- vs post-treatment wave I-IV interval values (p < 0.05); control vs vitamin E and B groups' I-IV interval values (p < 0.05); control vs other groups' hearing thresholds; vitamin E vs vitamin B and C and L-carnitine groups' hearing thresholds (p < 0.05); and vitamin B vs vitamin C and L-carnitine groups' hearing thresholds (p < 0.05). Statistically significant decreases were seen when comparing the initial and final signal-to-noise ratios in the control, vitamin B and L-carnitine groups (2000 and 3000 Hz; p < 0.01), and the initial and final signal-to-noise ratios in the control group (at 4000 Hz; p < 0.01). CONCLUSION: Vitamins B, E and C and L-carnitine appear to reduce cisplatin-induced ototoxicity in rats. The use of such additional treatments to decrease cisplatin induced ototoxicity in humans is still under discussion. PMID- 22490891 TI - [How to determine biomarkers of lymph node metastasis in gastric cancer]. PMID- 22490892 TI - [Attach importance to the chemotherapy of muscle invasive bladder cancer]. PMID- 22490893 TI - [Association between the expression and methylation of energy-related genes with Helicobacter pylori infection in gastric cancer]. AB - OBJECTIVE: To explore the association between the Helicobacter pylori (H. pylori) infection and the expression and methylation of energy-related genes in gastric cancer. METHODS: Real-time fluorescence quantitative reverse transcription (RT) PCR was performed to quantify the expressions level of lactate dehydrogenase (LDH), dihydrolipoamide dehydrogenase (DLD) and Ran-specific GTPase-activating protein (RanGAP) genes in the samples of human gastric cancer (n = 30), metastatic lymph node (n = 30) and peri-cancerous tissues (n = 30) as confirmed by pathological examinations. Those patients were chosen of Affiliated Hospital of Guiyang Medical University, from January 2005 to December 2009. The relationship between the gene expression and H. pylori infection was analyzed. The methylation of LDH, DLD and RanGAP genes at promoter CpG island was measured by bisulfite sequencing (BSP). RESULTS: The relative gene expressions of LDH, DLD and RanGAP in peri-cancerous tissues, gastric cancer and metastatic lymph nodes were 1.0, 3.1, 3.0 and 1.0, 3.1, 2.8, and 1.0, 0.4, 0.5 respectively (all P < 0.05). The expression levels of LDH and DLD genes in H. pylori-positive gastric cancer was high than those in the negative group (2.3 vs 1.0, 3.0 vs 1.0, 2.6 vs 1.0, all P < 0.05). The demethylation of LDH and DLD genes at promoter -2325 and 1885 site as well as the over methylation of RanGAP gene at the promoter -570 and -170 sites respectively were detected in H. pylori infection and cagA overexpressed cells. CONCLUSION: H. pylori infection may promote the development and progression of gastric cancer by inducing the aberrant methylation of LDH, DLD and RanGAP genes to up-regulate the gene expressions of LDH and DLD and down regulate the gene expression of RanGAP. PMID- 22490894 TI - [Expression of GC-C mRNA in peripheral blood mononuclear cells and its clinical roles in determining state of gastric cancer]. AB - OBJECTIVE: To detect the expression of GC-C mRNA in peripheral blood of gastric carcinoma patients and determine its potential candidacy as a molecular biological marker for predicting the micrometastasis and determining the status of gastric cancer. METHODS: GC-C mRNA from peripheral blood samples of gastric carcinoma (n = 60), dysplastic (n = 21), intestinal metaplasia (n = 15) and healthy cases (n = 20) from November 2009 to August 2010 at Affiliated Hospital of Nantong University were assessed by real-time fluorescent quantitative PCR (RFQ-PCR). RESULTS: The expressions of GC-C mRNA in peripheral blood from patients with dysplasia, intestinal metaplasia and healthy controls were absent or very low. And a high level of GC-C mRNA was detected in the patients with gastric carcinoma than those with dysplastic and intestinal metaplasia, and the positive rate were 48.3% (29/60), 9.5% (2/21), 20.0% (3/15), respectively (all P < 0.05). The levels of GC-C mRNA were significantly correlated with Lauren typing, clinical stage, tumor differentiation degree, depth of invasion and lymph node metastasis (all P < 0.05). The GC-C mRNA expressions were positively correlated in peripheral blood and gastric carcinomas tissues (r = 0.4009, P = 0.0015). CONCLUSIONS: The over-expression of GC-C mRNA is found in peripheral blood from gastric carcinoma patients. Due to its close correlation with clinical stage and lymph node metastasis, it may become a potential prognostic marker of gastric carcinoma. PMID- 22490895 TI - [Predicative value of expression of TrkB and TRIM29 in biopsy tissues from preoperative gastroscopy in lymph node metastasis of gastric cancer]. AB - OBJECTIVE: To analyze the expressions of TrkB and TRIM29 in biopsy tissues from preoperative gastroscopy in patients with gastric cancer and investigate the relationship between their expression and rate of lymph node metastasis. METHODS: Through immunohistochemistry, the authors analyzed the expression status of TRIM29 and TrkB in biopsy tissues from preoperative gastroscopy in 67 patients with a diagnosis of gastric cancer undergoing radical operations during 2005 - 2009 at Peking University Third Hospital. There were 39 males and 28 females. Then the relationship was explored between the expression of both proteins and lymph node metastasis and other clinical pathological factors. Image pro Plus 6.0 software was used for image analysis. The data underwent a logarithmic process and were analyzed through SPSS 17.0 statistical software. RESULTS: The expression of TrkB in lymph node metastasis (n = 42) was higher than that in without lymph node metastasis (n = 25) (lgA 4.79 +/- 0.42 vs 3.98 +/- 0.71, t = -5.873, P = 0.003), while the expression of TRIM29 with lymph node metastasis (n = 36) was also higher than that in without lymph node metastasis (n = 24) (5.21 +/- 0.27 vs 5.02 +/- 0.37, t = -2.257, P = 0.040). Logistic regression analysis showed that the TrkB expression was an independent predictor for lymph node metastasis. A discriminant was set based on the result (discriminant value = 1.705 * TrkB lgA+ 1.803 * TRIM29 lgA-16.880, cutoff value = 0). This discriminant achieved a prediction accuracy of 80.0% (48/60), a positive likelihood ratio 3.332 and a negative likelihood ratio 0.223. Patients with a high expression of TrkB showed a worse survival rate than those with a low TrkB expression [36.0% (9/25) vs 66.7% (16/24), P = 0.047). Patients with a high TRIM 29 expression showed a worse survival rate than those with a low TRIM29 expression [38.1% (8/21) vs 66.7% (14/21), P = 0.044]. CONCLUSION: The expressions of TrkB and TRIM29 are correlated with lymph node metastasis in gastric cancer, and discriminant based on the expressions of TrkB and TRIM29 had important values for preoperative prediction of lymph node metastasis in gastric cancer. PMID- 22490896 TI - [Analysis of N-E cadherin switch as an independent predictive parameter of bladder cancer survival outcomes]. AB - OBJECTIVE: To explore the expression patterns of cadherins (N-cadherin and E cadherin) in urothelial carcinomas and understand the values of N-E cadherin switch in the predictions of postoperative recurrence and prognosis. METHODS: The expressions of N-cadherin and E-cadherin were measured by immunohistochemistry in 64 transurethral bladder tumor resection (TURBT) or partial cystectomy samples (48 cases) in 2005 by the method of streptavidin-biotin peroxidase. RESULTS: A positive expression of N-cadherin and a negative expression of E-cadherin were noted in 27 (42.2%) and 16 (25.0%) specimens respectively. Patients with more poorly differentiated bladder cancer were accompanied with a higher expression of N-cadherin and a lower expression of E-cadherin (both P < 0.05). A positive expression of N-cadherin decreased the recurrence-free and cancer-related survival rates while a negative expression of E-cadherin was correlated with a lower cancer-related survival rate (all P < 0.05). No significant association was found between the expression of E-cadherin and the recurrence-free survival rate. Furthermore, the N-E cadherin switch (a negative expression of E-cadherin and a positive expression of N-cadherin) showed a higher predictive power in both recurrence-free and cancer-related survival according to multivariate analysis (HR = 0.428, 95%CI: 0.217 - 0.845, HR = 0.098, 95%CI: 0.013 - 0.767). No significant association was found between the expressions of two cadherins and postoperative progression. CONCLUSION: Although the expressions of E-cadherin and N-cadherin appear to be correlated with survival outcomes in bladder cancer, N-E cadherin switch may be a better predicator for postoperative recurrence and cancer-related survival. PMID- 22490897 TI - [Evaluation of novel gene UCA1 as a tumor biomarker for the detection of bladder cancer]. AB - OBJECTIVE: To evaluate the clinical utility of novel gene urothelial carcinoma antigen 1 (UCA1) as a urinary tumor marker for the diagnosis of bladder urothelial carcinoma. METHODS: A cohort of 180 cases of bladder cancer (including 94 cases in previous study), 144 cases of non-bladder-cancer individuals as control group (including 85 cases in previous study) from 2005 to 2009 were recruited. Reverse transcription PCR (RT-PCR) of urinary sediments was performed to detect the expression of UCA1. RNasin was added to the urinary sediments collected after 2007 from 86 cases of bladder cancer and 59 cases in control group to improve the quantity and quality of RNA isolation. The parameters of sensitivity, specificity, area under curve (AUC) of ROC and its 95%CI were calculated.chi(2) test was used to compare the sensitivity of UCA1 with NMP22 and cytology in 116 cases of bladder cancer with the parallel data of UCA1 and NMP22 and in 108 cases with the parallel data of UCA1 and cytology. RESULTS: 95.4% of RNA was isolated successfully from urinary sediments after the addition of RNasin UCA1 was highly specific (92.4%, 133/144) and quite sensitive (84.4%, 152/180) in the diagnosis of bladder cancer with a favorable AUC-ROC of 0.898 (95%CI: 0.851 - 0.945). It was especially valuable for superficial G(2)-G(3) patients (sensitivity: 86.4%, 92.3%) at a high risk for muscular invasion. CONCLUSION: With a high level of sensitivity and specificity, UCA1 is a promising urinary marker for the diagnosis of bladder cancer. PMID- 22490898 TI - [Proliferation effects of sirolimus, cyclosporine A and mycophenolate mofetil on human transitional cell carcinoma cells]. AB - OBJECTIVE: To compared the effects of three immunosuppressive agents, i.e. sirolimus (SRL), cyclosporine A (CsA) and mycophenolate mofetil (MMF), with different mechanisms of action on the in vitro growth of various tumor cell lines of human transitional cell carcinoma of bladder cell lines EJ and T24 and in vivo growth of cell line of EJ in nude mice model. METHODS: The effects of SRL, CsA and MMF on the proliferation of transitional cell carcinoma of bladder cell lines were examined with the method of methyl thiazolyl tetrazolium (MTT). The effects of these immunosuppressants on tumor growth and metastasis were explored in a nude mice model with human transitional cell carcinoma of bladder cell line EJ. Forty-two nude mice were divided into 7 groups to receive normal saline (control), SRL, CsA, MMF, SRL + CsA, SRL + MMF and CsA + MMF respectively (n = 6 each). RESULTS: The in vitro cell proliferation was inhibited by SRL and MMF versus the control groups. But no obvious inhibition of proliferation was observed at < 1000 ng/ml in the CsA-treated group. In the in vivo nude mice mode, the tumor volume of SRL, CsA group were lower than that in control group ((441 +/ 231), (463 +/- 110) vs (1032 +/- 382) mm(3), both P < 0.05). In the in vivo nude mice mode of EJ treated by SRL, CsA, SRL + CsA, SRL + MMF and CsA + MMF, tumor volume at Day 23 was the lowest in the SRL + CsA group ((191 +/- 92) vs (1032 +/- 382) mm(3), P < 0.05). There was an inhibition of 75.26% in SRL + CsA group versus the control groups. CONCLUSIONS: SRL and MMF demonstrate dose-dependent antiproliferative effects in human transitional cell carcinoma of bladder cell both in vitro and in vivo. CsA can inhibit the growth of human transitional cell carcinoma of bladder cell lines EJ cells in vivo. PMID- 22490899 TI - [Role of NF-kappaB in the anti-tumor effect of thymoquinone on bladder cancer]. AB - OBJECTIVE: To explore the effects and mechanism of thymoquinone in the growth inhibition of bladder cancer both in vitro and in vivo. METHODS: After the treatment of thymoquinone, the cellular proliferation of human bladder cancer cell line BIU-87 was detected by the method of methyl thiazolyl tetrazolium (MTT). Flow cytometry (FCM) was used to determine the cellular apoptosis. And the location of nuclear factor (NF)-kappaB was identified by the method of immunofluorescent histochemistry. Western blotting was employed to detect the cellular expressions of NF-kappaB, survivin and XIAP. BIU-87 cells were injected subcutaneously into nude mice to establish a xenograft model. After 2 weeks of implantation, the mice were randomized into 2 groups (n = 8): (a) vehicle alone (control), (b) thymoquinone (5 mg/kg daily by intragastric intubation). All treatments lasted for 2 weeks. At Week 7 post-implantation, the mice were sacrificed and their tumor weights and inhibition rates evaluated. Immunohistochemistry was used to detect the positive expressions of Ki-67, NF kappaB and XIAP in tumors. RESULTS: The proliferation of bladder cancer cells was inhibited significantly by thymoquinone at 20, 40, 80 umol/L (81.2% +/- 4.6%, 72.5% +/- 6.5%, 58.4% +/- 8.9% vs 100%, all P < 0.05). Apoptosis rate induced by thymoquinone was more significant than that of the control (7.6% +/- 1.6%, 11.2% +/- 2.1%, 14.3% +/- 2.8%vs 1.6% +/- 0.5%, all P < 0.05). Immunofluorescent histochemistry showed that thymoquinone could significantly lower the nuclear expression of NF-kappaB. The expressions of NF-kappaB and XIAP were down regulated in BIU-87 cells after the treatment of thymoquinone. But thymoquinone had no effect on the expression of survivin. The final tumor weight showed significant decrease in the test group versus the control group ((0.41 +/- 0.12) vs (0.89 +/- 0.23) g, P < 0.05). Furthermore, the positive expressions of Ki-67, NF-kappaB and XIAP decreased in tumors after the administration of thymoquinone. CONCLUSION: Thymoquinone exerts anti-tumor effects on bladder cancer both in vitro and in vivo through the down-regulations of NF-kappaB and its regulated molecules such as XIAP. PMID- 22490900 TI - [Survey of vitamin D status in 700 healthy adult males in Guiyang, China]. AB - OBJECTIVE: To evaluate the vitamin D status of healthy adult males living in Guiyang. METHODS: A total of 700 healthy volunteers aged 20 - 79 years were selected randomly from a community in Guiyang by stratified sampling method. Questionnaires for living habits and fasting blood samples were collected in the morning from November 2009 to January 2010. The serum concentrations of 25 hydroxyvitamin D were measured by the DiaSorin radioimmunoassay kit. RESULTS: The mean levels of serum 25(OH)D was (21 +/- 10) ug/L. And the percentages of vitamin D deficiency (25(OH)D < 20 ug/L), insufficiency (20 ug/L <= 25(OH)D < 30 ug/L) and sufficiency (25(OH)D >= 30.0 ug/L) were 315(50.2%), 202 (32.2%) and 110(17.6%)respectively. The concentrations of serum 25(OH)D in young, middle-aged and old adults were (18 +/- 10) ug/L, (24 +/- 10) ug/L and (22 +/- 8)ug/L respectively. The serum level of 25(OH)D was lower in the smokers than that in the non-smokers (20 ug/L vs 22 ug/L, P = 0.003). The serum concentrations of 25(OH)D were (24 +/- 10) ug/L, (23 +/- 10) ug/L, (22 +/- 9) ug/L and (18 +/- 9) ug/L in education level (<= 6, 7 - 9, 10 - 12 and >= 10 years in school) respectively. Significant inverse correlations existed between the concentrations of serum 25(OH)D and the education levels (r = -0.138, P = 0.000). CONCLUSION: The prevalence of hypovitaminosis D is common in healthy adult males in Guiyang, especially among the youth, smokers and higher educated groups. PMID- 22490901 TI - [Clinical observation of home noninvasive positive pressure ventilation in hypercapnic patient with stable severe chronic obstructive pulmonary disease]. AB - OBJECTIVE: To evaluate the efficacy and safety of home noninvasive positive pressure ventilation (HNIPPV) in hypercapnic patients with stable severe chronic obstructive pulmonary disease (COPD). METHODS: Forty four patients (30 males and 14 females, mean age 68.5 years (range: 60 - 80)) were recruited from a total of 106 patients with arterial PaCO2 >= 55 mm Hg in Second Hospital Affiliated to Harbin Medical University from January 2009 to December 2010. Their clinical data were collected and analyzed. The patients in the HNIPPV group (n = 20) accepted tiotropium bromide, doxofylline tablets and HNIPPV treatment while those in the control group (n = 24) tiotropium bromide, doxofylline tablets and a low-flow inhalation of oxygen. The entire observation period was 6 months. The parameters before and after 6-month follow-up were compared, including lung function test, 6 min walking distance (6MWD), arterial blood gases (PaO2 and PaCO2), dyspnea grade, scores of emotional disorders and mean pulmonary artery pressure (mPAP). RESULTS: No significant difference existed in the baseline data between the HNIPPV and control groups. The forced expiratory volume in one second (FEV(1)), forced vital capacity (FVC), inspiratory capacity (IC), 6MWD, PaO2, PaCO2, dyspnea grade, hospitalization rate, anxiety scores, depression scores and mPAP showed no significant difference between the HNIPPV and control groups before treatment. However, at Month 6, the differences of IC, 6MWD, PaO2, PaCO2, dyspnea grade, anxiety scores, depression scores and mPAP in HNIPPV group ((1.80 +/- 0.14) L, (266 +/- 24) m, (62.6 +/- 4.6) mm Hg, (46.8 +/- 2.2) mm Hg, (2.2 +/- 0.5), (6.5 +/- 2.4), (6.0 +/- 1.6), (33.8 +/- 2.4) mm Hg) were statistically significant compared with the control group ((1.62 +/- 0.14) L, (194 +/- 23) m, (56.2 +/- 3.8) mm Hg, (55.6 +/- 3.0) mm Hg, (3.2 +/- 0.6), (10.6 +/- 2.8), (10.2 +/- 2.4), (36.6 +/- 2.4) mm Hg) (P values: 0.031, 0.018, 0.025, 0.026, 0.001, 0.013, 0.002, 0.014 respectively). FEV(1) and FVC in the HNIPPV group improved slightly but with no statistically significant difference (all P > 0.05). Two patients in the control group were taken to hospital because of acute exacerbation. And hospitalization rates increased in the control group. But no statistically significant difference existed between the HNIPPV and control groups (P > 0.05). The tolerance and compliance of HNIPPV in the HNIPPV group were better and the patients in the HNIPPV group had no pulmonary barotraumas. CONCLUSION: HNIPPV plus tiotropium bromide and doxofylline tablets is both effective and safe in the treatment of hypercapnic patient with stable severe COPD. PMID- 22490902 TI - [Mechanism of impaired attention network in patients with stable chronic obstructive pulmonary disease]. AB - OBJECTIVE: To explore the influences of stable chronic obstructive pulmonary disease (COPD) on attention functions. METHODS: The research objects came from the Hospital Affiliated to Anhui Medical University from February to September in 2011. Attention network test (ANT) was employed to compare stable COPD patients (n = 38) with healthy controls (n = 36) in the efficiencies of anatomically defined attentional networks: alertness, orientation and executive attention. RESULTS: Significant group differences were found in orientation ((27 +/- 8) ms vs (57 +/- 4) ms, P = 0.001), but not in alertness ((19 +/- 7) ms vs (32 +/- 4) ms, P = 0.115) or executive attention network ((94 +/- 15) ms vs (119 +/- 11) ms, P = 0.196). The accuracy of attention network test was significantly slower in the COPD group than in the healthy controls (90.2% +/- 1.6% vs 96.3% +/- 1.7%, P = 0.011). The score of verbal fluency test was significantly lower in COPD patients than in healthy controls (18.2 +/- 0.5 vs 21.4 +/- 0.6, P = 0.000). CONCLUSIONS: The attention functions of COPD patients are impaired, especially oriental network efficiency. It is probably due to chronic hypoxia, hypoxia related low blood flow of temporal or parietal lobe or long-term anticholinergic drug use. PMID- 22490903 TI - [High maintenance dose of clopidogrel improves long-term clinical outcomes in patients with elective percutaneous coronary intervention]. AB - OBJECTIVE: To evaluate the efficacy of a 300 mg loading dose of clopidogrel followed by 150 mg as maintenance dose in patients with percutaneous coronary intervention (PCI). METHODS: A total of 108 consecutive patients undergoing elective PCI were recruited from our hospital from July 2007 to July 2008. A 300 mg loading dose was administered prior to PCI. Then they were randomized to receive clopidogrel 75 mg (n = 55) or 150 mg (n = 46) daily for 30 days. From Day 30 to Month 6 post-operation, all of them received 75 mg/d clopidogrel and were followed up for a mean period of 6 months. RESULTS: Thirty days after PCI, the platelet inhibition of the 150 mg group was significantly higher than the 75 mg group (64.2% +/- 13.3% vs 52.6% +/- 14.3%, P = 0.00). The ratios of fatal or non fatal myocardial infarction (MI) (1(1.8%) vs 3 (6.5%), P = 0.405) and target vessel revascularization (TVR) (4(7.2%) vs 6 (13.0%), P = 0.714) were significantly lower in the 150 mg group than those in the 75 mg group. So the overall incidence of MACE including death, MI and TVR was obviously lower in the 150 mg group than that in the 75 mg group (13.0% vs 20.2%, absolute risk reduction 7.3%). CONCLUSION: A high clopidogrel maintenance dose of 150 mg daily for the first month after PCI reduces the risk of long-term adverse events in patients with elective percutaneous coronary intervention. PMID- 22490904 TI - [Transjugular intrahepatic portosystemic shunt plus embolotherapy in the treatment of gastroesophageal varices: a report of 38 patients]. AB - OBJECTIVE: To evaluate the efficacy of transjugular intrahepatic portosystemic shunt (TIPS) plus embolotherapy in the treatment of patients with gastroesophageal varices. METHODS: A total of 36 patients with gastroesophageal varices underwent the therapies of TIPS plus embolotherapy from July 2005 to March 2011 at Provincial Hospital Affiliated to Shandong University. The rechecked items included abdominal ultrasound examination, liver function test and blood routine examination at Day 7 post-operation. All received endoscopic examinations at Month 1. RESULTS: The technical success rate of TIPS plus embolotherapy was 100%. The portal vein pressures declined from (28 +/- 8) mm Hg (1 mm Hg = 0.133 kPa) to (14 +/- 7) mm Hg at post-operation. Angiography showed gastroesophageal varices disappeared in all patients. Both liver function and gastroesophageal varices markedly improved. During the follow-up period of 3 - 6 months, 4 cases had hepatic encephalopathy and 1 case stent restenosis at post operation. And most cases were resolved after treatment. No rebleeding occurred during the follow-up period. CONCLUSIONS: The combined modality of TIPS plus embolotherapy can effectively lower portal vein pressure and cure esophageal and gastric varice bleeding. As a safe and excellent interventional procedure with fewer complications and a lower recurrence rate of portal hypertension, it has great clinical values in the treatment of portal hypertension and gastroesophageal varices. PMID- 22490905 TI - [Clinical diagnosis and treatment of spontaneous urinary extravasation caused by primary lower ureteral tumor]. AB - OBJECTIVE: To explore the clinical characteristics of spontaneous urinary extravasation caused by primary lower ureteral cancer. METHODS: Eight cases of spontaneous urinary extravasation caused by the obstruction of primary ureteral cancer from January 2005 to June 2010 from Department of Urology, Peking Union Medical College Hospital, were reported. There were 5 males and 3 females with an age range of 56-81 years old. Six cases presented with an onset of acute flank pains and 2 cases complained of flank discomforts with a lower fever. All cases had peripelvic fluid collection of varying levels on computed tomography (CT) scan and extravasation of contrast medium was found in delayed enhanced CT. The tumors of ureter were detected in 6 cases through preoperative imaging examinations while another 2 cases had no evidence of tumor. RESULTS: Unilateral nephroureterectomy was performed in 6 cases, including 5 cases undergoing retroperitoneal laproscopic surgery and 1 case with open surgery. In 5 laproscopic operations, the mean operative duration was 152 (120 - 235) minutes and the mean estimated intraoperative blood loss 130 (100 - 430) ml. The patient of open nephroureterectomy had an operative duration of 175 minutes and an intraoperative blood loss of 200 ml respectively. One patient underwent a local resection of ureteral carcinoma. A 81-year-old patient was diagnosed of tumor by ureteroscopic biopsy and accepted neither surgery or adjunctive therapy. All patients had a pathological diagnosis of urothelial carcinoma. One patient received local radiotherapy and chemotherapy with gemcitabine after nephroureterectomy while another one had local radiotherapy only. During a follow up period of 6-36 months, CT showed that five cases undergoing nephroureterectomy were free of recurrence. One patient with local lymphatic metastasis had a local recurrence, developed multiple metastases at Month 3 and died of exhaustion at Month 8 post-operation. The patient with a local resection had a local bladder recurrence at Month 6 and underwent unilateral nephroureterectomy and radical cystectomy after local radiotherapy and neoadjuvant chemotherapy. Tumor progression was found in the patient without surgery. No implantation metastasis was found. CONCLUSIONS: Spontaneous urinary extravasation caused by the obstruction of primary lower ureteral cancer is rare and mostly peripelvic. Biopsy may exclude tumors for those patients with no obvious cause of ureteral obstruction. And radical operation is a preferred option. PMID- 22490906 TI - [Effects of erythropoietin on mesenchymal stem cells' function of differentiation and secretion cultured under acute kidney injury microenvironment]. AB - OBJECTIVE: To explore the effects of erythropoietin (EPO) on the differentiation and secretion of cultured bone marrow-derived mesenchymal stem cells (BM-MSC) in the microenvironment of acute kidney injury (AKI). METHODS: C57BL/6 murine BM-MSC (mBM-MSC) were successfully isolated by the methods of Percoll density gradient centrifugation and adherence cultivation. The AKI murine model was induced by ischemia/reperfusion (I/R). The homogenate supernatants were prepared for normal and I/R murine kidney. P3-mBM-MSC were treated differently: Group A: low glucose DMEM medium with 10% fetal bovine serum, Group B: normal murine kidney homogenate supernatant intervention, Group C: I/R kidney homogenate supernatant intervention, Group D: I/R kidney homogenate supernatant plus different concentrations of EPO (1, 5, 10, 50 U/ml). Each group was incubated for 1, 3, 5 and 7 days. Inverted microscope was used to observe the morphological changes of these cells and their ultrastructural changes were observed by transmission electron microscope. Cytokeratin-18 was detected by flow cytometry. The levels of bone morphogenetic protein-7 (BMP-7), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) were detected by ELISA in culture medium. RESULTS: The cells yielded a high expression of CD29 and CD44 and a low expression of CD34 and CD45. Compared with Groups A and B, the cells of Group C presented oval and short fusiform shapes. After the intervention of EPO, Group D showed a cobble appearance. More organelles were also found. A trace expression of CK18 was found in Groups A and B. A positive expression of CK18 was significantly higher in Groups C and D than Groups A and B (P < 0.01). The expression of EPO 50 U/ml at Day 5 and 7 was higher than Group C of the same time (5 d: 35.22 +/- 4.04 vs 8.72 +/- 0.38, 7 d: 42.00 +/- 5.39 vs 13.20 +/- 1.14, both P < 0.01). The results of ELISA showed that the levels of BMP-7, HGF and VEGF in Group C decreased significantly (P < 0.01 or P < 0.05). CONCLUSION: The intervention of EPO may boost the differentiation of mBM-MSC but reverse its low secretion. PMID- 22490907 TI - [Innovative development in Ophthalmology, raise the level of running a journal]. PMID- 22490908 TI - [Emphasis treatment on eyelid during perioperation]. AB - The eyelid and conjunctival sac of healthy individuals inherently supports a small population of bacteria. Alterations in the concentration and type of bacteria present in blepharitis and meibomian gland dysfunction have been reported. The most common sources of the bacteria causing endophthalmitis of postcataract surgery and corneal infections following laser in situ keratomileusis attribute to the eyelids and conjunctiva of the patients, It has become a routine admitting antibiotic eye drops during perioperation and irrigating conjunctival sac before operation, but it is not paid enough attention for dealing with eyelid. So, this article will discuss the impact of eyelid on surgical outcome, and it is helpful for reducing postoperative infection. PMID- 22490909 TI - [Focus on graft dislocation of endothelial keratoplasty]. AB - Descemet's stripping with automated endothelial keratoplasty (DSAEK) has the advantage of minor surgical injury and fast visual recovery, which has become the optimal surgical choice for endothelial disorders. It has unique complications closely related to surgical maneuver, skill of operation, and proper intervention. The most common complication is graft dislocation. The clinical finding appears corneal edema and whitish. A space is detected between the donor graft and recipient. The risk factors are lens-iris diaphragm defect and vitrectomy eyes. The common situation, rebubbling is a effective method. But viscoelastic maybe needed for abnormal anterior segment structure to reattach the dislocated graft. So DSAEK is a new type of surgery and it is necessary to acknowledge and understand its surgical features and complication. PMID- 22490910 TI - [In vivo confocal microscopy study of corneal endotheliitis]. AB - OBJECTIVE: To study the cellular morphological characteristics and changes of corneal endotheliitis by corneal microstructure in vivo. METHODS: Forty-eight clinical diagnosed patients of corneal endotheliitis were examined by in vivo confocal microscopy. Confocal images of different layers were collected and observed. Of all the patients, 39 were disciform and 9 were diffuse. The history of the 48 patients was from 7 days to 23 years and the duration was from 4 to 180 days. RESULTS: Epithelium revealed cellular edema, enlarged intercellular gaps, and bubble between the cells. The density of sub-basal nerve plexus was significantly lower than that of normal, even disappeared in 24 patients. A numerous dendritic cells (Langerhans cells, LCs) presented in the basal epithelium layer and gradually abated with disease regression, but the density of LCs was significantly higher than that of the contralateral eye. The keratocyte revealed edema and to be activated. Inflammatory cell was found in stroma of the patients with long history and duration disease. Endothelium cells were observed edema, with enlarged intercellular gaps. Inflammatory cells was found to infiltrate into the endothelial layer, most them gathered to be keratic precipitates (KP), which were rounded or elliptic and inserted between the endothelium by pushing the endothelium away, and induced decayed area between the endothelium. CONCLUSION: Corneal endotheliitis was not only the inflammation of endothelium, but also varied pathological changes of all layer of the cornea. Corneal endotheliitis patients with long history and duration presented the mixed type with stromal keratitis. The lower density of sub-basal nerve plexus and the higher density of dendritic LCs were the characteristics of endotheliitis. Impairment of intercellular junction by KP might be another important role of cornea edema. Sufficient and accurate treatment of endotheliitis was important. PMID- 22490911 TI - [Non-Descemet stripping automated endothelial keratoplasty for graft failure after penetrating keratoplasty]. AB - OBJECTIVE: To report clinical results of non-Descemet stripping automated endothelial keratoplasty (nDSAEK) to treat graft failure after penetrating keratoplasty. METHODS: It was a retrospective case series study. Five cases of grafts failure after penetrating keratoplasty (PKP) were enrolled in this study. All patients had a cloudy and swollen grafts, which thicker than 620 um, and had foreign body sensation, vision decrease. Of this 5 cases, 4 of them are pseudophakic eye, 1 is aphakic eye. One patient had previous vitrectomy, and 3 of them had one time history of PKP, 2 of them had twice PKP treatment. All cases were treated by nDSAEK, the nDSAEK grafts were prepared as a 200 um thickness and 8.00 to 8.75 mm in diameter by using hand or femtosecond laser assisted methods. The graft was inserted by forceps or suture pulling method through a 5.00 mm scleral tunel incision. RESULTS: One graft dislocated at 1day postoperation, and was reattached by rebuble. All grafts keep clear during 8 - 28 months follow up period, and no immune rejection episodes were noted. The endothelial density were 865 to 2410/mm(2). Postoperative best corrected vision (pBCVA) are better or equal to previous BCVA after pkp. CONCLUSION: nDSAEK appears a good alternative surgical method for patients of grafts failure after pkp, especially for high risk patients of immune rejection. PMID- 22490912 TI - [Expression of matrix metalloproteinases and inhibitor on the cornea tissue in rabbit after implantation of modified titanium skirt for keratoprosthesis]. AB - OBJECTIVES: To investigate the expression of matrix metalloproteinase-2 (MMP-2) and Tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) in rabbit corneas implanted with modified titanium skirt of keratoprosthesis in order to explore the potential roles. METHODS: A total of 20 New Zealand white rabbits with corneal alkali burn in right eye rabbit corneas were divided into three groups. There were 6 animals in each group. Skirt of hydroxyapatite/Sandblast-Titanium and Sandblast-Titanium were inserted into the corneal stroma of rabbits in group A and group B. The group C did not insert skirt as surgical control.2 rabbits were as normal control D group. A total of 20 New Zealand white rabbits were divided into four groups with the same way. The expression of MMP-2 and TIMP-2 was determined by immunohistochemistry at 1 month, 3 months. The expression of MMP-2 and TIMP-2 mRNA level was determined by real time-polymerase chain reaction, and its protein level was determined by western blot. The optical cylinder was implanted to rabbit corneas, which were implanted with modified titanium skirt after 3 months. RESULTS: There was one case of corneal dissolution being found in group F. MMP-2 and TIMP-2 immunoreactivities were expressed in the normal corneas, predominantly in the corneal epithelium. After injury, immunoreactivities of both MMP-2 and TIMP-2 were increased notably in the healing corneal epithelium, infiltrating inflammatory cells, stromal fibroblasts and in growing vascular endothelial cells. The expression of MMP-2 was lower in group A and E than that in group B and F after 1 month and 3 months (t = 12.05, 2.93, 12.006, 3.781, P < 0.05). The Western blot revealed no significant differences of MMP-2 mRNA between group 3 months and 2 weeks (t = 2.104, P > 0.05); MMP-2 immunoreactivities were absent or lowly expressed predominantly in the corneal epithelium of normal corneas. The expression of MMP-2, TIMP-2 mRNA level was parallel that of protein level. CONCLUSIONS: The expression of MMP-2 was lower in the corneal tissue sections of HA/SB-Ti skirt inserted eyes than that in the tissue sections of SB-Ti skirt inserted eyes. The studies of MMP-2, TIMP-2 can provide a new way to prevent the incidence of corneal dissolving after surgery for keratoprosthesis. PMID- 22490913 TI - [An experimental study on the fate of the amniotic membrane after amniotic membrane transplantation for acute alkaline burn of rat cornea]. AB - OBJECTIVE: Use three different methods of amniotic membrane transplantation for acute alkaline burn of rat cornea, to investigate the difference on operation time, reabsorption time of amniotic membrane, integration patterns of amniotic membrane into the cornea among the three amniotic membrane transplantation methods. METHODS: SD rats were randomly assigned into five groups. Group A: simply alkaline burn of cornea; Group B: inlay method; Group C: overlay method; Group D: sutureless method; Group E: normal. Prepared the model of corneal alkaline burn of the right eyes of group A-D rats, performed three different methods of amniotic membrane transplantation on Group B-D rats respectively within 24 hours after alkaline burn. The operation time was recorded. Observed the eyes with slit-lamp microscopy after transplantation, recorded the reabsorption time of amniotic membrane. HE staining and immunohistochemical staining against human collagen IV were performed for pathological study. The results were analysed with Image-Pro Plus 6.0 software. The integration patterns of amniotic membrane into the cornea after amniotic membrane reabsorbed were observed. RESULTS: (1) Operation time: Group B was (35.500 +/- 2.878) minutes; Group C was (33.375 +/- 2.973) minutes; Group D was (9.875 +/- 1.246) minutes. There was statistical significance between group B and group D (P < 0.001), group C and group D (P < 0.001). There was no statistical significance between group B and group C (P = 0.102). (2) Reabsorption time of amniotic membrane: Group B was (16.625 +/- 3.662) days; Group C was (9.250 +/- 2.188) days; Group D was (12.833 +/- 2.483) days. There was statistical significance among group B, C, D (P < 0.001). (3) There was significant inflammatory reaction around the suture in Group B and Group C, and there was inconspicuous inflammatory reaction in Group D. (4) There were three integration patterns of amniotic membrane into the cornea after amniotic membrane reabsorption: superficial localization, intraepithelial and intrastromal. We could find one or more integration patterns in same method of amniotic membrane transplantation, there was no statistical significance among group B, C, D (P = 0.86). CONCLUSIONS: Amniotic membrane can integrate into the cornea after amniotic membrane reabsorption. Sutureless amniotic membrane transplantation which has short operation time and inconspicuous inflammatory reaction is better than traditional amniotic membrane transplantation, and it will be used extensively in the ophthalmology field in future. PMID- 22490914 TI - [Therapeutic effects of Pyranoprofen on the mouse dry eye induced by topical medication of Benzalkonium Chloride]. AB - OBJECTIVE: Randomized controlled experimental study to investigate the therapeutic effect and the possible mechanism of Pranoprofen on the recovery of dry eye induced by topical medication of Benzalkonium Chloride (BAC) in mouse. METHODS: It was an experimental study. Seventy BALB/c mice were treated with topical administration of 0.25% BAC to establish the dry eye condition. Based on the consistency of break-up time of tear-film (BUT), corneal fluorescein staining scores and inflammation index, the eyes were re-selected and randomly divided into four groups on day (D) 21 after the BAC treatment. Group A was set up as blank control, while group B, C and D were treated respectively with 0.1% sodium hyaluronate eye drops, 0.1% fluorometholone eye drops plus 0.1% sodium hyaluronate eye drops, 0.1% pyranoprofen eye drops plus 0.1% sodium hyaluronate eye drops. BUTs, tear volumes, corneal fluorescein staining scores and inflammation index were evaluated in each group on D0, 1, 3 and 5 after the therapeutic treatment. Global specimens were collected on D6. Sections were stained with hematoxylin and eosin (HE) or by periodic acid-schiff (PAS) assay, and labeled with cytokeratin 10 (K10) antibody. The expression of tumor necrosis factor-alpha (TNF-alpha) in the cornea and conjunctiva was quantified by western blot. RESULTS: 72 eyes were included in the sequential experiment, 18 eyes for each group. On D0, 1 and 3, no clinical differences were observed among the groups. On D5, the BUT was (2.933 +/- 0.320), (2.900 +/- 0.280), (3.464 +/- 0.498) and (3.643 +/- 0.413) s in group A, B, C and D respectively; the BUTs in group C and D were significant longer than those of group A and B (F = 13.774, P = 0.000). The corneal fluorescein staining score was (11.640 +/- 1.008), (11.790 +/- 1.188), (10.330 +/- 1.371) and (10.270 +/- 1.104)s in group A, B, C and D respectively; the scores in group C and D were significant lower than those of group A and B (F = 6.145, P = 0.001). The corneal inflammatory index was (0.232 +/- 0.059), (0.229 +/- 0.078), (0.151 +/- 0.055) and (0.154 +/- 0.056) in group A, B, C and D respectively; the index in group C and D were significant lower than those of group A and B (F = 6.703, P = 0.001). No significant difference was found in tear volume among groups. No significant difference was found between Pyranoprofen and Fluorometholone treatment in BUT, corneal fluorescein score or inflammatory index. Corneal morphology showed the feature of thicker corneal epithelial layer in group A and uniformity in group C and D. PAS assay revealed similar goblet cell numbers in group C and D, but less goblet cells in group A and B. Cytokeratin 10 was almost negatively expressed in Pranoprofen or Fluorometholone treated groups, and remained positive in the corneal epithelium with other treatments. The level of TNF-alpha in the cornea was down-regulated in Pranoprofen or Fluorometholone treated groups. CONCLUSIONS: Pranoprofen or Fluorometholone combined with sodium hyaluronate treatment presented similar therapeutic effects on BAC-induced mouse dry eye, with the more stable tear film, the better regularity of epithelium recovery, the down-regulation of inflammatory TNF-alpha, the increased number of goblet cells, and the elimination of squamous metaplasia, when compared with the treatment of sodium hyaluronate eye drops only. Our results showed the great potentialities of Pranoprofen in the clinical treatment of ocular surface inflammation in the mild and severity dry eye. PMID- 22490915 TI - [Characters of contrast sensitivity in diabetic patients without diabetic retinopathy]. AB - OBJECTIVE: To explore the change of contrast sensitivity (CS) in diabetic patients without diabetic retinopathy. METHODS: It was a case-control study. We screened and tested 52 type 2 diabetic patients (89 eyes) and 47 healthy persons (68 eyes). OPTEC 6500 contrast sensitivity tester was used to examine near and distance CS values on 1.5, 3.0, 6.0, 12.0, 18.0 cycles/degree (c/d) respectively. We kept strict inclusion criteria on subjects, no retinopathy was found and best corrected vision acuity was above 1.0. The difference of CS values between these two groups was investigated, and the influence of gender, age, duration of diabetic mellitus and application time of insulin on CS values, respectively. T test or u-test was used to compare the means of CS values between these two groups, near and distance CS values in each group. Simple linear correlation and multiple regression analysis were used to analyze the single factor and multiple factors correlation between CS values and age, duration, gender, and application time of insulin, respectively. RESULTS: The maximum CS values in both distance and near were 112.67 +/- 43.97, 85.85 +/- 41.83 and 83.68 +/- 35.91, 55.20 +/- 24.14, both appeared in 6.0 c/d. The minimum CS values in both distance and near were 26.19 +/- 17.69, 12.69 +/- 7.09 and 18.68 +/- 11.81, 8.22 +/- 5.68, respectively, both appeared in 18.0 c/d. Distance and near CS values in diabetic group and control group had very significant differences at these five spatial frequencies (From 1.5 to 18.0 c/d, the test values on distance, t = 3.11, 3.38, 2.77, 3.48, 3.86; P < 0.05; the test values on near, u = 3.70, 3.22; t' = 3.69, 3.88, 4.25; P < 0.05). Abnormal rate in diabetic group on high, medium, low and all frequencies were higher than control group, regardless of distance or near CS values (in near chi(2) = 11.86, 8.17, 9.14, 5.81; P < 0.05; on 4 combinations in distance chi(2) = 13.27, 6.70, 4.01, 4.50; P < 0.05). In diabetic group, gender related with 3.0 and 6.0 c/d CS values on near-distance (r = 0.26, 0.28; P < 0.05); age related with high-frequencies on near (r = -0.45, -0.28; P < 0.05); duration of diabetic mellitus related with high-frequencies on near (r = -0.25, 0.39; P < 0.05), and related with medium, high frequencies on distance (r = 0.26, -0.28, -0.30, -0.34; P < 0.05); application time of insulin related with high-frequencies on distance (r = -0.30, -0.31; P < 0.05). CONCLUSIONS: There exists important sense of CS value on showing visual function changes accurately in early-stage of diabetes mellitus. The high frequencies on distance is the sensitive index in vision impairment. Duration of diabetes closely relates with changes of retinal function ultimately, can be classified as the most important risk factor of CS values decline in early-stage diabetic patients. PMID- 22490916 TI - [Clinical diagnosis and curative effect observation of seventeen patients hemangiopericytoma in orbit]. AB - OBJECTIVE: To conclusion the clinical features and image features, the diagnosis and management of orbital hemangiopericytoma, in order to direct clinical diagnosis and differential diagnosis. METHODS: Seventeen patients with pathologically confirmed orbital hemangiopericytoma were analyzed retrospectively. RESULTS: Patients usually complained of exophthalmos. Fourteen patients can be touched the tumor in the orbit. In B-scan ultrasound, a well outlined lesion was revealed. The type of it was often similarly circular or anomaly. The extent of internal echo was associated with histological structure of lesion. Color doppler flow imaging show that the tumor has rich feeding vessels. Some of them is arterial feeding vessels. On CT scan, hemangiopericytoma generally appears to be a uniform high-density mass with obvious enhancement upon injection of contrast material. All cases underwent surgical resection and are proved by pathological examination. CONCLUSIONS: Orbital hemangiopericytoma is a potentially malignant tumor. The prognosis and clinical behavior can't be predicted on the basis of their histopathologic classification. Medical imaging can help to demonstrate the site, configuration, and characteristics of the tumors and contribute to the treatment. But, there has not characteristic medical features. The final diagnosis must be depend on the pathology. The best management of hemangiopericytoma is complete local excision. All the patients must be observed nearly. PMID- 22490917 TI - [Critical role and involvement of vascular endothelial growth factor and transforming growth factor-beta2 in collagen gel contraction induced by retinal pigment epithelial cells]. AB - OBJECTIVE: To investigate the influence of vascular endothelial growth factor(VEGF) and transforming growth factor (TGF)-beta(2) to human retinal pigment epithelium(RPE) cell differentiation, and the mechanism of collagen gel contraction mediated by RPE cells. METHODS: Experiment study. An in vitro collagen gel contraction assay was performed to evaluate the effect of cultured human RPE in addition of VEGF and TGF-beta(2) at indicated time points (24 h, 48 h and 72 h). Three groups were established in the experiment:control group, 50 ug/L VEGF group and 5 ug/L TGF-beta(2) group. The effects of both cytokines on the collagen gel contraction were analyzed by the reduced diameter of the collagen gel. And the changes of cell morphology and their transdifferentiation were assessed to estimate the possible connection between RPE transdifferentiation and collagen gel contraction. One-way ANOVA was used in conjunction with SNK-q test to assess statistical significance at different time periods within groups. RESULTS: There were differences on collagen gel contraction rates among VEGF group [(34.7 +/- 3.1)%, (44.3 +/- 6.0)%, (44.0 +/- 7.2)%], TGF-beta(2) group [(29.3 +/- 3.1)%, (31.7 +/- 3.5)%, (29.0 +/- 3.6)%] and control group [(20.0 +/- 0.5)%, (17.3 +/- 3.6)%, (19.1 +/- 0.8)%] at 24 h, 48 h and 72 h after cultured (24 h: F = 26.220, P = 0.001; 48 h: F = 26.796, P = 0.001; 72 h: F = 21.522, P = 0.002), and on each time point two two comparison in the three groups (SNK-q test, P < 0.05). There were differences on protein expression level of alpha-smooth muscle actin (alpha-SMA) in 50 ug/L VEGF group and 5 ug/L TGF-beta(2) group at difference time points, respectively (TGF-beta(2) group: F = 1.134, P = 0.000; each time point: SNK-q test, P < 0.05; VEGF group: F = 279.179, P = 0.000; each time point: SNK-q test, P < 0.05). Moreover, TGF beta(2) (5 ug/L) demonstrated stronger and more permanent gel contraction than VEGF (50 ug/L) (6 h: F = 3.646, P = 0.000; 24 h: F = 18.706, P = 0.003; 48 h: F = 124.195, P = 0.000; 72 h: F = 76.811, P = 0.000). RPE cells' form happened fibroblasts sample transformation in both VEGF group and TGF-beta(2) group. CONCLUSIONS: Both VEGF and TGF-beta(2) can induce the collagen gel contraction, partly by means of inducing the expression of alpha-SMA and RPE contraction, which may thus contribute to the explanations of vitro-retinal diseases. PMID- 22490918 TI - [Zebrafish-a new animal models of anterior segment embryonic development and diseases basic research]. AB - In recent years, zebrafish has become ideal animal models of human disease with its unique characteristics, such as small body, fecundity, fast development and growth, embryo transparency, and so on. Furthermore, the structure and gene of zebrafish eye are highly conservative with human eye, which make ophthalmologists to pay close attention to zebrafish. This review focus on the studies and applications on zebrafish embryonic development of anterior segment, including the morphogenesis of cornea, lens and anterior chamber, and diseases of anterior segment (corneal diseases, cataract, glaucoma). PMID- 22490919 TI - [Signal transduction pathways mediated by Toll-like receptors and their relations with fungal keratitis]. AB - Toll-like receptors (TLRs) were identified as transmembrane signal transduction proteins in recent years. As a group of pattern recognition receptors (PRRs), TLRs play important roles in the innate immunity by recognizing pathogen associated molecular patterns (PAMPs). Activated innate immunity subsequently leads to effective adaptive immunity. It, thereby, activities not only innate but ultimately also adaptive immunity. It has been reported that some kinds of TLRs expressed in corneal epithelial cells, stroma cells and endothelial cells. In addition to their recognition function, TLR activation triggers a complex signal transduction cascade that induces the production of inflammatory cytokines and co stimulatory molecules, thus initiating innate and adaptive immunity. And TLRs play an important role in innate and adaptive immunity of fungal keratitis. In summary, further studies on the regulation of intracellular signaling transduction will contribute significantly to our understanding of immunoregulation of fungal keratitis, eventually provide some way to cure the fungal infection. PMID- 22490920 TI - [Glial cell and glaucomatous optic neuropathy]. AB - Glaucomatous optic neuropathy is a chronic disease accompanied by visual field loss, cupping of optic nerve head, and apoptosis of retinal ganglion cells (RGCs). The mechanism of glaucomatous optic neuropathy is unknown but glial cells play an important role in glaucomatous optic nerve damage and the repair process. We review the role of glial cells in the remodeling of optic nerve head, apoptosis of RGCs and immune reactions in glaucoma. PMID- 22490921 TI - [Risk factors of primary angle closure glaucoma]. AB - Primary angle closure glaucoma is one of the common diseases causing blindness. The pathogenesis inducing primary angle closure glaucoma has not been entirely clear. Traditionally identified risk factors include shallow anterior chamber, short axial length and thicker lens. Recent studies begin to pay attention to other new risk factors, not only including static anatomical factors, such as anterior chamber volume, iris curvature and lens vault, but also including dynamic changing factors, such as dynamic dilation of iris volume and choroidal effusion. Comprehensive assessment of these risk factors is of great significance for early diagnosis and treatment of angle closure glaucoma. This article briefly reviews research advances in risk factors of primary angle closure glaucoma. PMID- 22490922 TI - Toward routine use of 3D histopathology as a research tool. AB - Three-dimensional (3D) reconstruction and examination of tissue at microscopic resolution have significant potential to enhance the study of both normal and disease processes, particularly those involving structural changes or those in which the spatial relationship of disease features is important. Although other methods exist for studying tissue in 3D, using conventional histopathological features has significant advantages because it allows for conventional histopathological staining and interpretation techniques. Until now, its use has not been routine in research because of the technical difficulty in constructing 3D tissue models. We describe a novel system for 3D histological reconstruction, integrating whole-slide imaging (virtual slides), image serving, registration, and visualization into one user-friendly package. It produces high-resolution 3D reconstructions with minimal user interaction and can be used in a histopathological laboratory without input from computing specialists. It uses a novel method for slice-to-slice image registration using automatic registration algorithms custom designed for both virtual slides and histopathological images. This system has been applied to >300 separate 3D volumes from eight different tissue types, using a total of 5500 virtual slides comprising 1.45 TB of primary image data. Qualitative and quantitative metrics for the accuracy of 3D reconstruction are provided, with measured registration accuracy approaching 120 MUm for a 1-cm piece of tissue. Both 3D tissue volumes and generated 3D models are presented for four demonstrator cases. PMID- 22490923 TI - The neural dynamics of updating person impressions. AB - Person perception is a dynamic, evolving process. Because other people are an endless source of social information, people need to update their impressions of others based upon new information. We devised an fMRI study to identify brain regions involved in updating impressions. Participants saw faces paired with valenced behavioral information and were asked to form impressions of these individuals. Each face was seen five times in a row, each time with a different behavioral description. Critically, for half of the faces the behaviors were evaluatively consistent, while for the other half they were inconsistent. In line with prior work, dorsomedial prefrontal cortex (dmPFC) was associated with forming impressions of individuals based on behavioral information. More importantly, a whole-brain analysis revealed a network of other regions associated with updating impressions of individuals who exhibited evaluatively inconsistent behaviors, including rostrolateral PFC, superior temporal sulcus, right inferior parietal lobule and posterior cingulate cortex. PMID- 22490925 TI - When emulation becomes reciprocity. AB - It is well known that perceiving another's body movements activates corresponding motor representations in an observer's brain. It is nevertheless true that in many situations simply imitating another's actions would not be an effective or appropriate response, as successful interaction often requires complementary rather than emulative movements. At what point does the automatic tendency to mirror another's actions become the inclination to carry out appropriate, complementary movements? In the present study, single-pulse transcranial magnetic stimulation (TMS) was used to explore corticospinal excitability in participants observing action sequences evoking imitative or complementary movements. TMS was delivered at five time points corresponding to different moments in time when key kinematic landmarks characterizing an observed action occurred. A variation in motor evoked potentials (MEPs) confirmed that the motor system flexibly shifts from imitative to complementary action tendencies. That shift appears to take place very precociously in time. Observers are attuned to advance movement information and can use it to anticipate a future course of action and to prepare for an appropriate, complementary action. Altogether, these findings represent a step forward in research concerning social action-perception coupling mechanisms providing important data to better understand the role of predictive simulation in social contexts. PMID- 22490924 TI - No fear, no panic: probing negation as a means for emotion regulation. AB - This electroencephalographic study investigated if negating one's emotion results in paradoxical effects or leads to effective emotional downregulation. Healthy participants were asked to downregulate their emotions to happy and fearful faces by using negated emotional cue words (e.g., no fun, no fear). Cue words were congruent with the emotion depicted in the face and presented prior to each face. Stimuli were presented in blocks of happy and fearful faces. Blocks of passive stimulus viewing served as control condition. Active regulation reduced amplitudes of early event-related brain potentials (early posterior negativity, but not N170) and the late positive potential for fearful faces. A fronto-central negativity peaking at about 250 ms after target face onset showed larger amplitude modulations during downregulation of fearful and happy faces. Behaviorally, negating was more associated with reappraisal than with suppression. Our results suggest that in an emotional context, negation processing could be quite effective for emotional downregulation but that its effects depend on the type of the negated emotion (pleasant vs unpleasant). Results are discussed in the context of dual process models of cognition and emotion regulation. PMID- 22490926 TI - Stroke-induced activation of the alpha7 nicotinic receptor increases Pseudomonas aeruginosa lung injury. AB - Infectious complications, predominantly pneumonia, are the most common cause of death in the postacute phase of stroke, although the mechanisms underlying the corresponding immunosuppression are not fully understood. We tested the hypothesis that activation of the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) pathway is important in the stroke-induced increase in lung injury caused by Pseudomonas aeruginosa pneumonia in mice. Prior stroke increased lung vascular permeability caused by P. aeruginosa pneumonia and was associated with decreased lung neutrophil recruitment and bacterial clearance in mice. Pharmacologic inhibition (methyllycaconitine IC(50): 0.2-0.6 nM) or genetic deletion of the alpha7nAChR significantly (P<0.05) attenuates the effect of prior stroke on lung injury and mortality caused by P. aeruginosa pneumonia in mice. Finally, pretreatment with PNU-282987, a pharmacologic activator of the alpha7nAChR (EC(50): 0.2 MUM), significantly (P<0.05) increased lung injury caused by P. aeruginosa pneumonia, significantly (P<0.05) decreased the release of KC, a major neutrophil chemokine, and significantly (P<0.05) decreased intracellular bacterial killing by a mouse alveolar macrophage cell line and primary mouse neutrophils. In summary, the alpha7 nicotinic cholinergic pathway plays an important role in mediating the systemic immunosuppression observed after stroke and directly contributes to more severe lung damage induced by P. aeruginosa. PMID- 22490927 TI - Endogenous erythropoietin signaling facilitates skeletal muscle repair and recovery following pharmacologically induced damage. AB - Erythropoietin acts by binding to its cell surface receptor on erythroid progenitor cells to stimulate erythrocyte production. Erythropoietin receptor expression in nonhematopoietic tissue, including skeletal muscle progenitor cells, raises the possibility of a role for erythropoietin beyond erythropoiesis. Mice with erythropoietin receptor restricted to hematopoietic tissue were used to assess contributions of endogenous erythropoietin to promote skeletal myoblast proliferation and survival and wound healing in a mouse model of cardiotoxin induced muscle injury. Compared with wild-type controls, these mice had fewer skeletal muscle Pax-7(+) satellite cells and myoblasts that do not proliferate in culture, were more susceptible to skeletal muscle injury and reduced maximum load tolerated by isolated muscle. In contrast, mice with chronic elevated circulating erythropoietin had more Pax-7(+) satellite cells and myoblasts with increased proliferation and survival in culture, decreased muscle injury, and accelerated recovery of maximum load tolerated by isolated muscle. Skeletal muscle myoblasts also produced endogenous erythropoietin that increased at low O(2). Erythropoietin promoted proliferation, survival, and wound recovery in myoblasts via the phosphoinositide 3-kinase/AKT pathway. Therefore, endogenous and exogenous erythropoietin contribute to increasing satellite cell number following muscle injury, improve myoblast proliferation and survival, and promote repair and regeneration in this mouse induced muscle injury model independent of its effect on erythrocyte production. PMID- 22490929 TI - The great East Japan disaster. PMID- 22490928 TI - Structure of the beta2-alpha2 loop and interspecies prion transmission. AB - Prions are misfolded, aggregated conformers of the prion protein that can be transmitted between species. The precise determinants of interspecies transmission remain unclear, although structural similarity between the infectious prion and host prion protein is required for efficient conversion to the misfolded conformer. The beta2-alpha2 loop region of endogenous prion protein, PrP(C), has been implicated in barriers to prion transmission. We recently discovered that conversion was efficient when incoming and host prion proteins had similar beta2-alpha2 loop structures; however, the roles of primary vs. secondary structural homology could not be distinguished. Here we uncouple the effect of primary and secondary structural homology of the beta2-alpha2 loop on prion conversion. We inoculated prions from animals having a disordered or an ordered beta2-alpha2 loop into mice having a disordered loop or an ordered loop due to a single residue substitution (D167S). We found that prion conversion was driven by a homologous primary structure and occurred independently of a homologous secondary structure. Similarly, cell-free conversion using PrP(C) from mice with disordered or ordered loops and prions from 5 species correlated with primary but not secondary structural homology of the loop. Thus, our findings support a model in which efficient interspecies prion conversion is determined by small stretches of the primary sequence rather than the secondary structure of PrP. PMID- 22490930 TI - An evolving opportunity. PMID- 22490931 TI - The development of multidisciplinary core competencies: the first step in the professionalization of disaster medicine and public health preparedness on a global scale. PMID- 22490932 TI - Disaster preparedness and medical response: it's a global responsibility. PMID- 22490933 TI - Children and terror casualties receive preference in ICU admissions. AB - OBJECTIVE: Trauma casualties caused by terror-related events and children injured as a result of trauma may be given preference in hospital emergency departments (EDs) due to their perceived importance. We investigated whether there are differences in the treatment and hospitalization of terror-related casualties compared to other types of injury events and between children and adults injured in terror-related events. METHODS: Retrospective study of 121 608 trauma patients from the Israel Trauma Registry during the period of October 2000-December 2005. Of the 10 hospitals included in the registry, 6 were level I trauma centers and 4 were regional trauma centers. Patients who were hospitalized or died in the ED or were transferred between hospitals were included in the registry. RESULTS: All analyses were controlled for Injury Severity Score (ISS). All patients with ISS 1 24 terror casualties had the highest frequency of intensive care unit (ICU) admissions when compared with patients after road traffic accidents (RTA) and other trauma. Among patients with terror-related casualties, children were admitted to ICU disproportionally to the severity of their injury. Logistic regression adjusted for injury severity and trauma type showed that both terror casualties and children have a higher probability of being admitted to the ICU. CONCLUSIONS: Injured children are admitted to ICU more often than other age groups. Also, terror-related casualties are more frequently admitted to the ICU compared to those from other types of injury events. These differences were not directly related to a higher proportion of severe injuries among the preferred groups. PMID- 22490934 TI - Mental health outcomes among adults in Galveston and Chambers counties after Hurricane Ike. AB - OBJECTIVE: To examine the mental health effects of Hurricane Ike, the third costliest hurricane in US history, which devastated the upper Texas coast in September 2008. METHOD: Structured telephone interviews assessing immediate effects of Hurricane Ike (damage, loss, displacement) and mental health diagnoses were administered via random digit-dial methods to a household probability sample of 255 Hurricane Ike-affected adults in Galveston and Chambers counties. RESULTS: Three-fourths of respondents evacuated the area because of Hurricane Ike and nearly 40% were displaced for at least one week. Postdisaster mental health prevalence estimates were 5.9% for posttraumatic stress disorder, 4.5% for major depressive episode, and 9.3% for generalized anxiety disorder. Bivariate analyses suggested that peritraumatic indicators of hurricane exposure severity-such as lack of adequate clean clothing, electricity, food, money, transportation, or water for at least one week-were most consistently associated with mental health problems. CONCLUSIONS: The significant contribution of factors such as loss of housing, financial means, clothing, food, and water to the development and/or maintenance of negative mental health consequences highlights the importance of systemic postdisaster intervention resources targeted to meet basic needs in the postdisaster period. PMID- 22490935 TI - The new normal: twelve months of resiliency and recovery in Christchurch. AB - The series of earthquakes and aftershocks that have hit Christchurch, New Zealand, for more than one year has been severe and sustained, resulting in major damage to homes, buildings, essential services, and resources in water, sewerage, food, access to health care, energy for heating and cooling, and unprecedented challenges to resiliency. Large swathes of destroyed buildings, land damage, and liquefaction have made rebuilding impossible for many. Populations have moved or report that they either wish to or plan to do so. For those who remain, a "new normal" mindset has taken hold and serves as an objective measure for the process that defines daily life and future decisions. The new normal serves as an uncomfortable but realistic guideline by which further resiliency can be measured. A number of factors have led to the development of the new normal state for the Christchurch earthquake survivors. PMID- 22490937 TI - Integrating the disaster cycle model into traditional disaster diplomacy concepts. AB - Disaster diplomacy is an evolving contemporary model that examines how disaster response strategies can facilitate cooperation between parties in conflict. The concept of disaster diplomacy has emerged during the past decade to address how disaster response can be leveraged to promote peace, facilitate communication, promote human rights, and strengthen intercommunity ties in the increasingly multipolar modern world. Historically, the concept has evolved through two camps, one that focuses on the interactions between national governments in conflict and another that emphasizes the grassroots movements that can promote change. The two divergent approaches can be reconciled and disaster diplomacy further matured by contextualizing the concept within the disaster cycle, a model well established within the disaster risk management community. In particular, access to available health care, especially for the most vulnerable populations, may need to be negotiated. As such, disaster response professionals, including emergency medicine specialists, can play an important role in the development and implementation of disaster diplomacy concepts. PMID- 22490936 TI - Core competencies for disaster medicine and public health. AB - Effective preparedness, response, and recovery from disasters require a well planned, integrated effort with experienced professionals who can apply specialized knowledge and skills in critical situations. While some professionals are trained for this, others may lack the critical knowledge and experience needed to effectively perform under stressful disaster conditions. A set of clear, concise, and precise training standards that may be used to ensure workforce competency in such situations has been developed. The competency set has been defined by a broad and diverse set of leaders in the field and like minded professionals through a series of Web-based surveys and expert working group meetings. The results may provide a useful starting point for delineating expected competency levels of health professionals in disaster medicine and public health. PMID- 22490938 TI - The integration of mental and behavioral health into disaster preparedness, response, and recovery. AB - The close interplay between mental health and physical health makes it critical to integrate mental and behavioral health considerations into all aspects of public health and medical disaster management. Therefore, the National Biodefense Science Board (NBSB) convened the Disaster Mental Health Subcommittee to assess the progress of the US Department of Health and Human Services (HHS) in integrating mental and behavioral health into disaster and emergency preparedness and response activities. One vital opportunity to improve integration is the development of clear and directive national policy to firmly establish the role of mental and behavioral health as part of a unified public health and medical response to disasters. Integration of mental and behavioral health into disaster preparedness, response, and recovery requires it to be incorporated in assessments and services, addressed in education and training, and founded on and advanced through research. Integration must be supported in underlying policies and administration with clear lines of responsibility for formulating and implementing policy and practice. PMID- 22490939 TI - The H1N1 crisis: a case study of the integration of mental and behavioral health in public health crises. AB - In substantial numbers of affected populations, disasters adversely affect well being and influence the development of emotional problems and dysfunctional behaviors. Nowhere is the integration of mental and behavioral health into broader public health and medical preparedness and response activities more crucial than in disasters such as the 2009-2010 H1N1 influenza pandemic. The National Biodefense Science Board, recognizing that the mental and behavioral health responses to H1N1 were vital to preserving safety and health for the country, requested that the Disaster Mental Health Subcommittee recommend actions for public health officials to prevent and mitigate adverse behavioral health outcomes during the H1N1 pandemic. The subcommittee's recommendations emphasized vulnerable populations and concentrated on interventions, education and training, and communication and messaging. The subcommittee's H1N1 activities and recommendations provide an approach and template for identifying and addressing future efforts related to newly emerging public health and medical emergencies. The many emotional and behavioral health implications of the crisis and the importance of psychological factors in determining the behavior of members of the public argue for a programmatic integration of behavioral health and science expertise in a comprehensive public health response. PMID- 22490941 TI - [Focus on clinical application of optical coherence tomography and image analysis]. AB - Optical coherence tomography (OCT) is a non-invasive, high-resolution imaging modality to acquire cross-sections and three-dimensional images of the microstructure in biological specimens. Because of rapid improvement of acquisition speed and axial resolution of OCT over recent years, OCT is becoming increasingly used in clinic for diagnosing or analyzing diseases of the eye, especially in the fundus. However, OCT has been used regardless of the location of lesions and the clarity of optical media. This misuse wastes resources and delays diagnosis and treatment of certain ocular diseases. Furthermore, the image of SD-OCT cannot be analyzed completely at present. Therefore, how to apply OCT in clinic appropriately and to analyze its image professionally is crucial, which should attract the attention of ophthalmologists. In addition, comprehensively analyzing ocular diseases combined with other examinations is extremely important to improve the level of diagnosis. PMID- 22490940 TI - Validation of the Long-term Difficulties Inventory (LDI) and the List of Threatening Experiences (LTE) as measures of stress in epidemiological population based cohort studies. AB - BACKGROUND: Stress questionnaires are included in many epidemiological cohort studies but the psychometric characteristics of these questionnaires are largely unknown. The aim of this study was to describe these characteristics for two short questionnaires measuring the lifetime and past year occurrence of stress: the List of Threatening Events (LTE) as a measure of acute stress and the Long term Difficulties Inventory (LDI) as a measure of chronic stress. METHOD: This study was performed in a general population cohort consisting of 588 females (53.7%) and 506 males (46.3%), with a mean age of 53.5 years (s.d.=11.3 years). Respondents completed the LTE and the LDI for the past year, and for the age categories of 0-12, 13-18, 19-39, 40-60, and >60 years. They also completed questionnaires on perceived stress, psychological distress (the General Health Questionnaire, GHQ-12), anxiety and depression (the Symptom Checklist, SCL-8) and neuroticism (the Eysenck Personality Questionnaire - Revised Short Scale, EPQ-RSS N). Approximately 2 years later, 976 respondents (89%) completed these questionnaires for a second time. RESULTS: The stability of the retrospective reporting of long-term difficulties and life events was satisfactory: 0.7 for the lifetime LDI and 0.6 for the lifetime LTE scores. The construct validity of these lists is indicated by their positive associations with psychological distress, mental health problems and neuroticism. CONCLUSIONS: This study in a large population-based sample shows that the LDI and LTE have sufficient validity and stability to include them in major epidemiological cohort studies. PMID- 22490942 TI - [Standardization the process of intravitreal injection to prevent the risk of endophthalmitis]. AB - Millions of intravitreal injections were performed for the patients with neovascular eye diseases each year. The intravitreal injection has become a routine medical procedure in daily practice of ophthalmologist. Although the risk of post-injection endophthalmitis is low, the prevalence is increasing as more patients received injections. Once occurred, endophthalmitis can lead to irreversible vision loss. To reduce the potential rising risk of post-injection endophthalmitis, establishing guidelines for intravitreal injection is urgent. We reviewed the clinical research evidences on the causes and characters of post injection endophthalmitis as well as the preventive actions. A standard operation pattern on intravitreal injection is also introduced. PMID- 22490943 TI - [Correctly evaluate the role of visual acuity in age-related macular degeneration treatment]. AB - Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in aged population. As the aging of population, the prevalence of AMD increases gradually. Anti-VEGF medication intravitreal injection, which can obtain good therapeutic efficiency and is relatively safe, becomes the main therapy for neovascular AMD. However, high-frequency repeated treatment increases the intravitreal injections risk, as well as the costs. In clinical practice, to pursue the best-corrected visual acuity, high-frequency repeated injections are implemented and inflict psychological pressure and economic burden on patients. The author believes that to pursue the best corrected visual acuity is the ultimate aim but not the only one for every ophthalmologist and patient. The activity of lesions should be overall evaluated with fundus imaging technologies. Being people-oriented is the principle in clinical medicine. A treatment plan is made according to the patients' sickness and economy and to coordinate the relation between the best corrected visual acuity and the numbers of treatment. Based on the stabilized lesion, patient should be benefited at the lowest risk and cost with the best effect. PMID- 22490944 TI - [Photodynamic therapy for treatment of chronic or recurrent central serous chorioretinopathy]. AB - OBJECTIVE: To evaluate the effect of Spectral HRA + OCT-guided photodynamic therapy with half-dose verteporfin in the treatment of chronic or recurrent central serous chorioretinopathy. METHODS: It was a retrospective case series. Twenty eyes of 18 patients with chronic or recurrent central serous chorioretinopathy were included. PDT was applied with half-dose verteporfin (3 mg/m(2)) on the site of active area shown on Spectral HRA + OCT (defined as focal or diffuse retinal pigment epithelial leakage, choroidal hyperpermeability, or pigment epithelial detachment located within the neurosensory detachment), and patients were observed to determine the anatomic and functional outcomes. Statistical analysis was performed using SAS (version 9.2). A P value of 0.05 was considered statistically significant. Comparisons of pre- and post-treatment best corrected visual acuity (BCVA) and central foveal thickness (CFT) were performed using a paired t test. The relationship between BCVA and CFT post-treatment was analyzed by linear correlation analysis. Comparisons of the BCVA of eyes with and without the integrity of photoreceptor IS-OS and/or external limiting membrane at the last follow-up visit were performed using two sample t test. RESULTS: The median CSC duration was 4.5 months (ranged 1 month to 2 years). The median follow up period after PDT was 8 months (ranged 6 to 20 months). The mean BCVA before PDT was 0.35 +/- 0.16 (ranged 0.05 to 0.6), at 3 months after PDT was 0.72 +/- 0.32 (ranged 0.1 to 1.5) and at the last follow-up visit was 0.78 +/- 0.29 (ranged 0.3 to 1.5) (t = 6.444, 6.883, P < 0.05). Fifteen eyes (75.0%) had improved vision, and 5 eyes (25.0%) had stable vision. The mean CFT was reduced from (369.0 +/- 120.9) um before PDT to (193.3 +/- 30.6) um 1 month after PDT, (194.9 +/- 28.3) um 3 month after PDT and (190.6 +/- 33.7) um at the last follow up visit (t = -6.836, -6.826, -7.316; P < 0.05). At the last follow-up visit BCVA was not correlated with CFT (r = 0.166, P > 0.05), but BCVA of the eyes with the integrity of photoreceptor IS-OS and/or external limiting membrane was better than that of without (t = -3.53, P < 0.05). Subretinal fluid disappeared in all eyes 1 month after PDT and there was no recurrence during the follow-up. CONCLUSIONS: Spectral HRA + OCT-guided photodynamic therapy with half-dose of verteporfin seems effective and safe for the treatment of chronic or recurrent central serous chorioretinopathy. PMID- 22490945 TI - [Use of buccal swab as a source of genomic DNA for genetic screening in patients with age-related macular degeneration]. AB - OBJECTIVE: The collection of buccal cells with swabs provides a noninvasive method for obtaining genomic DNA for genetic screening. We aimed to study the feasibility of using buccal swabs for genetic screening in patients with exudative age-related macular degeneration (AMD). METHODS: Blood and buccal swabs were collected for genetic analysis from 65 patients with exudative AMD. Genomic DNA was isolated from either blood or buccal swabs. The yield of genomic DNA from both sources was determined by spectrophotometer. Genotyping for CFH, LOC387715, and HTRA1 Polymorphisms was performed using a method of polymerase chain reaction (PCR) followed by restriction enzyme digestion. Results using genomic DNA from blood or buccal swabs were compared. RESULTS: Three swabs were obtained from each patient, 2 from each side of buccal mucosa, and 1 from both upper and inferior gingival mucosa. From swabs with genomic DNA extracted within a week after sample collection, an average of (3.17 +/- 1.46) ug genomic DNA was obtained from swab collected from the left or right side buccal mucosa, and (3.94 +/- 1.04) ug from swab collected from the upper and inferior gingival mucosa, with relatively higher yield of genomic DNA from the upper and inferior gingival mucosa (t = 6.79, P < 0.05). From swabs of the left or right side buccal mucosa after being stored at -20 degrees C for 12 months, an average of (3.10 +/- 1.17) ug genomic DNA was obtained, which showed no statistically significant difference as compared to the yield of genomic DNA extracted from newly collected swabs (t = 0.59, P > 0.05). In all 65 patients, genomic DNA isolated from either buccal swabs or blood samples showed exactly the same results regarding the genotypes of CFH, LOC387715, and HTRA1 Polymorphisms. CONCLUSIONS: Buccal swab is a simple, noninvasive, and reliable source for obtaining genomic DNA. Swabs stored for 12 months at -20 degrees C provide similar amount of genomic DNA as the freshly collected swabs. PMID- 22490946 TI - [A comparative study of macular thickness and function before and after idiopathic macular epiretinal membrane surgery]. AB - OBJECTIVE: To compare the thickness and functional changes of the macula after idiopathic macular epiretinal membrane (IEM) surgery. METHODS: A retrospective study. Thirty-seven patients (37 eyes) received surgical treatment of IEM. All patients received standard three-port vitrectomy as well as epiretinal membrane peeling. The best corrected visual acuity (BCVA, LogMAR) were recorded and optical coherence tomography (OCT) were used to evaluate central foveal thickness (CFT). Microperimetry (MP)-1 was used for the mean sensitivity (MS) of central 10 degrees macula area. SPSS13.0 was used for statistical analysis. Rank and testing methods were used to compare the preoperative and postoperative BCVA, paired t testing method was used to compare the preoperative and postoperative CFT and MS values. Correlation analysis was used to study the BCVA, CFT, and MS. Pearson correlation analysis was applied to analyze measurement data and Spearman rank correlation analysis was used to analyze rating data. RESULTS: Postoperatively, the BCVA (0.1 - 0.7, median 0.4) was significantly better (Z = 4.97, P < 0.05) than the preoperative one (0.3 - 1.3, median 0.7). The CFT (246.2 +/- 60.4) um was significantly thinner (t = 15.86, P < 0.05) than the preoperative one (482.2 +/- 101.8)um. The MS of central 10 degrees macula area (18.6 +/- 1.8) dB was significantly higher (t = -9.20, P < 0.05) than the preoperative one (14.1 +/- 3.4) dB. Thicker preoperative CFT was associated with a lower preoperative BCVA (r(s) = 0.91, P < 0.05), a lower MS of central 10 degrees macula area (r = -0.82, P < 0.05) and a lower postoperative BCVA level (r(s) = 0.63, P < 0.05). But with a significant postoperative CFT reduce (r = 0.81, P < 0.05) and a significant postoperative BCVA increase (r(s) = 0.71, P < 0.05). CONCLUSIONS: Vitrectomy combined with macular epiretinal membrane removal can effectively promote the recovery of macular thickness and function in patients with IEM. Examination and analysis of preoperative CFT, BCVA and MS of macula area may help to predict the recovery of CFT and function objectively in patients of IEM. PMID- 22490947 TI - [Fundus manifestation and treatment of Takayasu's arteritis]. AB - OBJECTIVE: To evaluate the fundus manifestation and treatment of Takayasu's arteritis. METHODS: Retrospective case series was taken to study the clinical data of 15 patients (30 eyes) diagnosed with Takayasu's arteritis at Peking Union Medical College Hospital from 1992 to 2010. Examinations included visual acuity, slit-lamp, fundus, fundus fluorescein angiography (FFA), large vascular ultrasound, digital subtraction angiography (DSA), erythrocyte sedimentation rate (ESR) and reactive protein C (CRP). All patients were given systemic corticosteroids, immunosuppressive agents and anticoagulants. Three patients (4 eyes) received retinal photocoagulation, and 1 patient (1 eye) received vitrectomy combined with silicone oil tamponade. RESULTS: Fifteen cases aged 13 - 49 years [mean (33.6 +/- 11.1) years] were enrolled, including 2 male and 13 female patients. Two patients recognized by initial presentation of impaired vision prior to the diagnosis of Takayasu's arteritis. Visual acuity: light perception -0.05, 6 eyes; 0.1 - 0.5, 4 eyes; 0.6 - 1.0, 5 eyes; and above 1.0, 15 eyes. The fundus examination revealed chronic ischemic retinopathy in 16 eyes characterized by microaneurysms, cotton-wool spots and peripapillary arteriovenous anastomosis, and complicated by vitreous hemorrhage, retinal detachment and proliferative retinopathy at the late stage. There was hypertensive retinopathy in 14 eyes with features of narrow retinal artery, arteriovenous crossing signs and retinal hemorrhage. FFA showed prolonged arm-to retina circulation time and retinal circulation time, microaneurysms and neovasculature. Six cases were classified as brachiocephalic arteritis, and 9 patients belonged to extensive arteritis. ESR increased in 9 patients and CRP elevated in 5 patients. Capillary non-perfusion areas in 4 eyes subsided after retinal photocoagulation, and retina reattached in 1 eye after vitrectomy with visual acuity improved from light perception to count finger. CONCLUSIONS: Fundus manifestation of Takayasu's arteritis is usually characterized by chronic ischemic retinopathy and hypertensive retinopathy, and complications such as vitreous hemorrhage, retinal detachment and proliferative retinopathy occur at advanced stage. The first symptom in some patients can be impaired vision. The prognosis could be improved if ophthalmologists know fundus characteristics of Takayasu's arteritis and give timely and correct diagnosis and treatment. PMID- 22490948 TI - [Clinical characteristics and pathogenesis of intracapillary hemorrhage with adjacent peripapillary subretinal hemorrhage]. AB - OBJECTIVE: To study the clinical characteristics and pathogenesis of intracapillary hemorrhage with adjacent peripapillary subretinal hemorrhage (IHAPSH). METHODS: A retrospective review of 8 patients with IHAPSH. The demographical data of the patients, the symptoms, initial and final visual acuities, biomicroscopic findings, fundus photographs, and the results of various special examinations, including fluoresce in angiography, B-scan ultrasonography, optical coherence tomography (OCT) and CT were analyzed. RESULTS: Fundus examination of 8 patients showed various changes of optic disc, including: a small and tilted optic disc with elevation and blurring of the nasal or superonasal edge. Hemorrhage of the optic disc was present in the cup and/or on the nasal edge, extended to the surface of the optic disc, the superficial layer of the retina and the subretinal space. Subretinal hemorrhage was located on the nasal, superior and inferior side of the optic disc. OCT examination showed an elevated optic nerve head with an enlarged nasal peripapillary subretinal space. CONCLUSIONS: In the IHAPSH patient, bleeding may originate from the posterior ciliary artery that traverse the sclera window of the disc, passes through the space between the optic nerve and the scleral canal, reaches the edge of the optic disc and the subretinal space, penetrates into the optic nerve tissues anterior to the lamina cribrosa, reaches the optic cup and extends to the surface of the optic disc, the retina or the vitreous. PMID- 22490949 TI - [Depth of focus in spherical and aspheric intraocular lenses]. AB - OBJECTIVE: To investigate depth of focus (DOF) in spherical and aspheric IOL eye models. METHODS: Computer numerical simulation experiment was used. IOL eye model based on Liou-Brennan eye model was constructed by using ZEMAX optical design software. Different IOL were implanted in this eye model. Monochromatic through focus modulation transfer function (MTF) curves were computed. Pupil and aspheric designs' effect on DOF were analyzed. RESULTS: DOF of eye model increased with pupil shrinkage in 550 nm monochromatic light (FY60AD 1.20 D at 6 mm pupil, 1.35 D at 5 mm pupil, 1.70 D at 4 mm pupil, 2.46 D at 3 mm pupil; YA60BBR 1.24 D at 6 mm pupil, 1.48 D at 5 mm pupil, 1.80 D at 4 mm pupil, 2.50 D at 3 mm pupil). MTF in spherical IOL eye model was higher with minus defocus, this trend was obvious at larger pupil. MTF of aspheric IOL eyes were higher than spherical IOL eyes when well focused at 5 mm pupil, while the DOF was lower in aspheric IOL with negative spherical aberration (Tecnis Z9000 1.31 D, FY60AD 1.35 D, CeeOn911 1.55 D, YA60BBR 1.48 D). DOF decreased less in aspheric IOL with zero spherical aberration (LI61AO 1.42 D). CONCLUSIONS: DOF in IOL eye model was higher at smaller pupil. When the pupil was large, well focused aspheric IOL improved optical quality compared with spherical IOL, while DOF and the tolerance to defocus in aspheric IOL were partially lost; this phenomenon was obvious with minus defocus. PMID- 22490950 TI - [Study on the treatment of dry eye with Loteprednol Etabonate]. AB - OBJECTIVE: To observe the efficacy and safety of 0.5% Loteprednol Etabonate ophthalmic suspension in the treatment of moderate dry eye. METHODS: Totally 34 dry eye patients (68 eyes) in grade 2 or grade 3 (DEWS standard) enrolled in our hospital from March 2009 to September 2010 were randomly divided into two groups: the experimental group (Loteprednol Etabonate Group) and the control group (Cyclosporine A, CsA group). 0.5% Loteprednol Etabonate ophthalmic suspension or 1% CsA eye drops was applied 2 times a day respectively together with 0.2% Liposic eye drops (4 - 6 times/day). Questionnaire was used in these patients before the treatment and repeated every 2 weeks during the treatment till 8 weeks. Slit lamp microscope examination, fluorescent staining, tear break-up time (BUT), Schirmer I test (SIt) and intraocular pressure measurement were carried out at the same time point. The conjunctival impression cytology (IC) was performed before the treatment and 8 weeks after the treatment. The mean of the results were compared by t-tests and chi(2) test. RESULTS: After 2 weeks of the treatment, the mean score of the questionnaire was significantly lower than that before the treatment in each group (t = 5.36, 3.63, P < 0.01). After 4 weeks of the treatment, the inflammation of the ocular surface was relieved obviously in both group and the mean score of the corneal fluorescein staining (FL) was lower than that before the treatment in each group. The average density of the goblet cells before the treatment was (181.2 +/- 16.1)/mm(2) and (179.4 +/- 17.5)/mm(2) in each group respectively. After 8 weeks of the treatment, this increased to (348.6 +/- 22.5)/mm(2) and (360.4 +/- 27.8)/mm(2) significantly (t = 16.9, 16.3, P < 0.05). BUT was significantly prolonged in each group after the treatment (P < 0.01). There was no significant change in ST I or NCT in each group (P > 0.05). CONCLUSIONS: Topical 0.5% Loteprednol Etabonate ophthalmic suspension is safe and effective for the treatment of moderate dry eye. PMID- 22490951 TI - [Changes of opsin expression in experimental form-deprivation and defocus myopia in guinea pig]. AB - OBJECTIVE: To investigate the opsin expression in form-deprived and defocus myopia in guinea pig and to study the relationship between the opsin expression and the experimental myopia. METHODS: Fifty guinea pigs were randomized into form deprived group, defocus group (n = 20 in each group) and normal group (n = 10). Guinea pigs in form-deprived group wore a diffuser RGP on one eye since one week after birth. Those in defocus group wore -4.00 D RGP on one eye. The contralateral eyes wore 0 D RGP were used as the control. Refraction, axial length and depth of vitreous cavity were measured after 1 and 2 weeks. Animals were sacrificed and the retina were dissected at 10:00 - 12:00 AM. The level of opsin and its mRNA were measured by Western-blot and real-time PCR, respectively. RESULTS: Two weeks after the experiment, the refraction in form-deprived group and defocus group were (-4.00 +/- 0.87) and (-2.00 +/- 1.17) D respectively, which were significant different compared with contralateral eyes or normal control group (F = 203.98, 88.66, P < 0.05). These also accompany with increase of axial length and depth of vitreous cavity in form-deprived group and defocus group. Expression of S-opsin mRNA were increased both in form-deprived and defocus groups and the ratios of S-opsin mRNA/beta-actin expression were 0.752 +/ 0.05 and 1.117 +/- 0.13 in two weeks treatment, which were significant different from contralateral eyes (the ratios of S-opsin mRNA/beta-actin expression were 0.536 +/- 0.04 and 0.772 +/- 0.10.t = 6.10, 6.28, P < 0.05). Similar findings were also demonstrated in the expression of L-opsin mRNA, which were increased in form-deprived group and defocus group (the ratios of L-opsin mRNA/beta-actin expression were 0.42 +/- 0.01) compared with contralateral eyes (the ratios were 0.24 +/- 0.0 and 0.34 +/- 0.04. t = 6.30, 4.93, P < 0.05) after two weeks experiment. The western-blot results also indicated the high expression of S opsin and L-opsin level compared to contralateral eyes in form-deprived and defocus groups. CONCLUSIONS: Cone might be the detector receiving the signal of form-deprivation and defocus. Changes of opsin expression might play a role in the occurrence of experimental myopia in guinea pig. PMID- 22490952 TI - [The electrophysiological properties of voltage-gated potassium channels on cultivated porcine retinal ganglion cells irradiated with continuous near infrared laser]. AB - OBJECTIVE: To investigate the influence of continuous near-infrared (CNI) laser to potassium ion channels on retinal ganglion cell (RGC). METHODS: Experiment study. Porcine RGC was cultured with enzymatic digestion method in vitro by taking off the retina from the piglets. Whole-cell patch clamp mode recordings were obtained from primary cultured porcine RGC. Whole-cell currents of porcine RGC irradiated with a single-mode CNI laser of 845 nm wavelength and 30 mW power were also recorded. The primary cultured porcine RGC were divided into laser irradiation group and control group according to whether they accepted CNI laser of 845 nm wavelength. t test was used to analyze the average peak amplitude between the two groups. RESULTS: The cells had the morphological characteristics of typical neurons after one week cultured observed by inverted phase contrast microscope. The body and bumps with yellow-green fluorescence was positive cell which observed by immune cell fluorescence chemical testing. CNI laser had a regulation on outward potassium current of porcine RGC in a voltage-dependent manner. There was significant difference on the average peak amplitude of potassium current between the laser irradiation group [(634.4 +/- 86.8) Pa] and the control group [(580.5 +/- 116.4) Pa], respectively (n = 30, t = 7.923, P = 0.000). CONCLUSIONS: CNI laser can change the properties of outward K(+) channel. Therefore, formation and releasing of action potential is affected. Further, physiological functions of RGC are regulated, which might contribute to the protection and restoration of injured RGC. It can be provided a new scholar direction for the protection of the RGC, which are injured by glaucoma. PMID- 22490953 TI - [siRNA-mediated downregulation of the integrin-linked kinase alters the proliferation and apoptosis in retinoblastoma cells]. AB - OBJECTIVE: To explore the effects of siRNA-mediated downregulation of integrin linked kinase (ILK) gene expression on the proliferation and apoptosis in retinoblastoma cells. METHODS: Experiment study. Human retinoblastoma cells, HXO Rb(44) cells, were divided into four groups: ILK siRNA intervention group, control siRNA intervention group, empty liposome group and blank control group. ILK siRNA was transfected into HXO-Rb(44) cells by lipofection. The expression of ILK mRNA and protein was detected at 48 hours after transfection by RT-PCR and Western blot, respectively. Cell proliferation inhibition was measured by Cell Counting Kit-8 assay. The apoptosis was detected by Annexin/PI double immunofluorescence and flow cytometry. Statistical method adopted one-way ANOVA between each group overall comparison. RESULTS: The HXO-Rb(44) cells were transfected by ILK siRNA successfully with lipofection. RT-PCR analysis showed that the expression of ILK mRNA in the ILK siRNA intervention group was significantly decreased as compared to the control siRNA intervention group, empty liposome group and blank control group (0.12 +/- 0.02 vs. 0.45 +/- 0.04, 0.42 +/- 0.05 and 0.40 +/- 0.04, F = 12.781, P = 0.000). Similar results were obtained for protein expression as revealed by Western blot analysis (0.10 +/- 0.03 vs. 0.38 +/- 0.07, 0.40 +/- 0.05 and 0.43 +/- 0.03, F = 18.647, P = 0.000). The proliferation inhibition rate in the ILK siRNA intervention group (35.0%) was higher than that in the blank control group (0%), control siRNA intervention group (2.1%) and empty liposome group (1.8%) (F = 23.573, P = 0.000). The results of immunofluorescence and flow cytometry showed that ratio of Annexin positive cells was highest in the ILK siRNA intervention group (26.5%), which was 5.0%, 4.6%, 5.3% in the empty liposome group, blank control group, control siRNA intervention group, respectively (F = 65.217, P = 0.000). CONCLUSION: ILK siRNA can downregulate the expression of ILK gene in HXO-Rb(44) cells inhibited the cell proliferation and induced their apoptosis. PMID- 22490954 TI - [Continuous funding of National Natural Science Foundation of China has boosted the development of the discipline of ophthalmology over the past 25 years]. AB - OBJECTIVE: To analyze the role of National Natural Science Foundation of China (NSFC) on the development of the discipline of Ophthalmology from 1986 to 2010. METHODS: Data on the total number of projects and funding of NSFC allocated to Ophthalmology, as well as papers published, awards, personnel training, subject construction were collected, and the role of NSFC on other sources of funding was evaluated. RESULTS: From 1986 to 2010, NSFC supported a total of 593 scientific research projects of Ophthalmology, funding a total amount of 152.44 million Yuan, among which were 371 free application projects, 156 Young Scientist Funds, 9 Key Programs, 5 National Science Fund for Distinguished Young Scholars, 3 Major international (regional) joint research programs, 1 Science Fund for Creative Research Group and 48 other projects. Over the past 25 years, the number of NSFC projects received by Ophthalmology has been an overall upward trend in the share in the Department of Life (Health) Sciences. Take the projects (186 of 292, 63.7%) as examples completed between 2002 and 2010, a total 262 papers were published in Science Citation Index (SCI) included journals and 442 papers were published in Chinese journals. Meanwhile, 8 Second prizes of National Science and Technology Progress Award and 1 State Technological Invention Award were received. As of 2010, the training of a total of more than 40 postdoctoral, more than 400 doctoral students and more than 600 graduate students have been completed. 5 national key disciplines and 1 national key laboratory have been built. Moreover, 2 "973" programs from Ministry of Science and Technology and 1 project of special fund in the public interest from Ministry of Public Health were obtained. 2 scholars were among the list of Yangtze Fund Scholars granted by Ministry of Education. CONCLUSIONS: Over the past 25 years, a full range of continuous funding from NSFC has led to fruitful results and a strong impetus to the progress of discipline of Ophthalmology. PMID- 22490955 TI - [Progress in genetic studies of age-related macular degeneration]. AB - Age related macular degeneration (AMD) is the most common cause of irreversible blindness in the aged population in the western world. AMD is considered to be a multifactorial disease with involvement of both genetic and environmental factors. With the development of molecular biology and molecular genetics, numerous susceptibility genes have been identified. Here we review the recent advances in the genetic studies regarding the AMD susceptibility genes. PMID- 22490956 TI - Landscape phages and their fusion proteins targeted to breast cancer cells. AB - Breast cancer is a leading cause of death among women in the USA. The efficacy of existing anticancer therapeutics can be improved by targeting them through conjugation with ligands binding to cellular receptors. Recently, we developed a novel drug targeting strategy based on the use of pre-selected cancer-specific 'fusion pVIII proteins' (fpVIII), as targeting ligands. To study the efficiency of this approach in animal models, we developed a panel of breast cancer cell binding phages as a source of targeted fpVIIIs. Two landscape phage peptide libraries (8-mer f8/8 and 9-mer f8/9) were screened to isolate 132 phage variants that recognize breast carcinoma cells MCF-7 and ZR-75-1 and internalize into the cells. When tested for their interaction with the breast cancer cells in comparison with liver cancer cells HepG2, human mammary cells MCF-10A cells and serum, 16 of the phage probes selectively interacted with the breast cancer cells whereas 32 bound both breast and liver cancer cells. The most prominent cancer specific phage DMPGTVLP, demonstrating sub-nanomolar Kd in interaction with target cells, was used for affinity chromatography of cellular membrane molecules to reveal its potential binding receptor. The isolated protein was identified by direct sequencing as cellular surface nucleolin. This conclusion was confirmed by inhibition of the phage-cell interaction with nucleolin antibodies. Other prominent phage binders VPTDTDYS, VEEGGYIAA, and DWRGDSMDS demonstrate consensus motifs common to previously identified cancer-specific peptides. Isolated phage proteins exhibit inherent binding specificity towards cancer cells, demonstrating the functional activity of the selected fused peptides. The selected phages, their peptide inserts and intact fusion proteins can serve as promising ligands for the development of targeted nanomedicines and their study in model mice with xenograft of human cells MCF-7 and ZR-75-1. PMID- 22490957 TI - A V(L) single-domain antibody library shows a high-propensity to yield non aggregating binders. AB - A synthetic human V(L) phage display library, created by the randomization of all complementarity-determining regions (CDRs) in a V(L) scaffold, was panned against three test antigens to determine the propensity of the library to yield non aggregating binders. A total of 22 binders were isolated against the test antigens and the majority (20) were monomeric. Thus, human V(L) repertoires provide an efficient source of non-aggregating binders and represent an attractive alternative to human V(H) repertoires, which are notorious for containing high proportions of aggregating species. Moreover, the solubility of V(L)s, in contrast to V(H)s, appears much less CDR dependent. PMID- 22490958 TI - Directed evolution of (betaalpha)(8)-barrel enzymes: establishing phosphoribosylanthranilate isomerisation activity on the scaffold of the tryptophan synthase alpha-subunit. AB - Phosphoribosylanthranilate (PRA) isomerase (TrpF) and tryptophan synthase alpha subunit (TrpA) are (betaalpha)(8)-barrel enzymes that are involved in the biosynthesis of tryptophan. They contain a conserved phosphate binding site, which indicates a common evolutionary origin. In order to experimentally back this hypothesis, we have established TrpF activity on the scaffold of TrpA from Salmonella typhimurium using protein engineering. Based on the superposition of crystal structures with bound ligands, two residues in the active site of TrpA were replaced with catalytic residues from TrpF using site-directed mutagenesis. This TrpA variant as well as wild-type TrpA were each subjected to random mutagenesis using error-prone PCR. The two resulting trpA gene libraries were used to transform an auxotrophic Escherichia coli trpF deletion strain, and TrpA variants with PRA isomerisation activity were isolated by in vivo complementation. The amino acid substitutions of the selected TrpA variants were recombined by DNA shuffling, again followed by complementation in vivo. Several TrpA variants were produced in E. coli and purified, and their catalytic TrpF activities were determined in vitro by steady-state enzyme kinetics. Our results support that TrpA and TrpF have evolved by gene duplication and diversification from each other or a common predecessor, and provide insights into the minimum requirements for the catalysis of PRA isomerisation. PMID- 22490959 TI - [We should pay attention to the clinical application of neuromodulation techniques in neuropathic pain]. PMID- 22490960 TI - [Changes of glycogen synthase kinase-3beta and its phosphorylation in spinal cord neurons in rats with incisional pain-remifentanil-induced hyperalgesia]. AB - OBJECTIVE: To investigate the change in glycogen synthase kinase-3beta (GSK 3beta) in spinal cord neurons in rats with incisional pain (IP)-remifentanil induced hyperalgesia. METHODS: 32 SD male rats (240 - 260 g) were randomly divided into 4 groups (n = 8 each): group R, group I, group R + I and group C. IP was established as Brennan's description. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were measured 24h before anesthesia and 2, 6, 24, 48 h after anesthesia. The rats were sacrificed after the last threshold measurement. The expressions of GSK-3beta mRNA in rats' spinal cord neurons were determined by real-time PCR. The expressions of GSK-3beta and pGSK-3beta in rats' spinal cord neurons were determined by Western blot. RESULTS: Remifentanil-induced hyperalgesia developed in group R, I and R + I. The expression of GSK-3beta mRNA and the expression of GSK-3beta in rats' spinal cord neurons were highest in group R + I. In addition, the ratio of pGSK-3beta/GSK-3beta was smallest in group R + I. CONCLUSION: These data indicate that the increased GSK-3beta activity in rats spinal cord neurons is involved in remifentanil-induced hyperalgesia. PMID- 22490961 TI - [Role of cannabinoid 2 receptor in the development of bone cancer pain]. AB - OBJECTIVE: To explore the effects of cannabinoid 2 receptor (CB2) in the development of bone cancer pain in mice. METHODS: A total of 84 mice (C3H/HeJ) were randomly divided into 4 groups:tumor group (Group T, n = 30), medication administration group (Group J, n = 12), vehicle group (Group D, n = 12) and sham group (Group S, n = 30). And 2 * 10(5) osteolytic NCTC2472 cells in alpha-MEM were injected into medullary cavity of right distal femur to induce bone cancer pain in a murine model while sham mice received an injection of only alpha-MEM. All mice were tested for pain-related behaviors at pre-inoculation and at Days 5, 7, 10 and 14 post-inoculation. The tests included paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). Group J and Group D were injected intrathecally with 2 ug JWH015 dissolved in 4% DMSO and only 4% DMSO respectively in a 5 ul. volume. Pain behavior tests were performed before and at 1, 6, 24, 48 and 72 h after an intrathecal injection. Lumbar intumescentia of mice in each group were harvested to examine the expression level of CB2 by Western blot after pain behavior tests at Days 5, 7, 10 and 14 post-inoculation and 12 h after an intrathecal injection. RESULTS: (1) Pain behavior tests:Mechanical allodynia appeared at Day 7 post-inoculation. The value of PWMT was (1.27 +/- 0.28) g (P < 0.05) and it declined gradually to (0.53 +/- 0.20) g at Day 14. The threshold of mechanical hyperalgesia increased to (1.00 +/- 0.20) g at 6 h after an intrathecal injection of JWH015, peaked at (1.40 +/- 0.39) g at 12 h, became alleviated after 48 h and recovered to the pre-dosing levels at 72 h. Thermal hyperalgesia appeared at Day 10 post-inoculation. The value of PWTL was (16.9 +/- 0.4) s (P < 0.05) at Day 10 and declined to (11.5 +/- 0.7) s at Day 14 post-inoculation. The threshold of thermal hyperalgesia increased to (15.7 +/- 1.9) g at 6 h after an intrathecal injection of JWH015, peaked at (18.6 +/- 2.3) g at 12 h, became alleviated after 48 h and recovered to the pre-dosing levels at 72 h. (2) Western blot: From Day 5 post-inoculation, the ratio of CB2/beta-actin increased gradually. Compared with the ratio of 0.190 +/- 0.010 at Day 5 post inoculation, the ratio of CB2/beta-actin increased to 0.660 +/- 0.010 at Day 14 post-inoculation (P < 0.05); compared with the ratio of 0.903 +/- 0.006 in group D at 12 h after an intrathecal injection of JWH015, the ratio of CB2/beta-actin 0.510 +/- 0.010 significantly decreased (P < 0.05). CONCLUSION: The cannabinoid 2 receptor plays an important role in the formation of bone cancer pain. PMID- 22490963 TI - [A survey of normal reference ranges of tenderness threshold in healthy undergraduates]. AB - OBJECTIVE: To analyze the profiles of pressure pain threshold (PPT) and pressure pain tolerance (PTO) of healthy undergraduates so as to establish the normal reference ranges of PPT and PTO. METHODS: The levels of PPT and PTO were measured at lateral brachioradialis of lateral elbow joint with a pressure algometer in 113 healthy undergraduates. Then the influencing factors of tenderness thresholds were analyzed and the normal reference ranges of PPT and PTO established. RESULTS: The females exhibited a lower PPT than the males (P < 0.01). And the gender differences of PTO were statistically insignificant (P > 0.05). Meanwhile, there was no significant difference in either PPT or PTO between the right and left sides (P > 0.05). The normal reference ranges (kg/cm(2)) of PPT and PTO were obtained at the measuring spot of all subjects. As a result, the ranges of PPT were 1.19 - 4.63 in the males and 0.37 - 3.63 in the females. And the range of PTO was 1.80 - 8.50 in all subjects. CONCLUSION: This survey establishes the normal reference ranges of tenderness thresholds at the specific measuring spot for some specific population. These ranges may serve as a reference for the sensitivity of individual tenderness safely, accurately and simply. PMID- 22490962 TI - [Clonidine and dexmedetomidine's effect on the altered expressions of growth associated protein-43 mRNA in rat dorsal root ganglion during the development of chronic neuropathic pain]. AB - OBJECTIVE: To explore the effects of alpha(2) adrenergic receptor (alpha(2)AR) agonists clonidine and dexmedetomidine on the injury model of peripheral nerve chronic constriction in rats. METHODS: A total of 72 male SD rats weighing 180 - 250 g were randomly divided into 4 groups (n = 18 each). In sham operation group (S), the right sciatic nerves were exposed but not ligated. But, in other groups, four ligatures were placed around the right sciatic nerve according to the Bennett's method. From the instant after operation, 0.4 mg * kg(-1)* d(-1) clonidine and 50.0 ug * kg(-1)* d(-1) were injected intraperitoneally into the clonidine group (CL) and dexmedetomidine group (Dex) daily. And the same volume of normal saline was injected into the S and CCI groups (C) respectively. Mechanical and thermal pain thresholds were measured by paw withdrawal latencies at Day 1 pre-operation and Day 3, 7 and 14 post-operation. After that, the L(4-6) dorsal root ganglions to chronic constriction injured sciatic nerves were harvested. Reverse transcription-polymerase chain reaction (RT-PCR) and agarose gel electrophoresis were used to examine the expression of GAP-43 mRNA. RESULTS: Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of groups C, CL and Dex markedly decreased and the expression of GAP-43 mRNA in dorsal root ganglions significantly increased at Days 3, 7 and 14 post-operation versus those at pre-operation and group S (P < 0.05). TWL and MWT of groups CL and Dex at Days 7 and 14 post-operation significantly increased while the expression of GAP-43 mRNA in dorsal root ganglions markedly decreased versus those of group C (P < 0.05). TWL and MWT of group Dex were significantly higher while the expression of GAP-43 mRNA in dorsal root ganglions was lower than those of group CL (P < 0.05). Compared with Day 3, TWL and MWT of groups C, CL and Dex markedly decreased while the expression of GAP-43 mRNA significantly increased in dorsal root ganglions at Day 7 (P < 0.05). Compared with Day 7, TWL and MWT of groups CL and Dex markedly increased while the expression of GAP-43 mRNA in dorsal root ganglions significantly decreased at Day 14 (P < 0.05). CONCLUSION: Clonidine and dexmedetomidine both show evident analgesic effects on chronic neuropathic pain in rats probably through a reduction of nerve regeneration. But dexmedetomidine has a better efficacy due to of its high selectivity of alpha(2)AR. PMID- 22490964 TI - [Preliminary clinical evaluations of panipenem-betamipron in the treatment of hematological malignancy infections]. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of intravenous panipenem betamipron in the treatment of hematological malignancies infections. METHODS: From October 2009 to December 2010, a total of 286 hematological malignancy infection patients were recruited into this open-label, perspective and multicenter clinical trial to receive an intravenous daily dose panipenem betamipron of 0.5 g every 6 or 8 hours for 7 - 14 days. All clinical change and adverse reactions were recorded. RESULTS: The total effective rate of panipenem betamipron in the treatment of hematological malignancy infections was 86.6% (206/238). The effective rates of septicemia, pulmonary infections, urinary tract infections, digestive canal infections, oral infections and other infections were 68.2% (15/22), 89.3% (100/112), 77.8% (14/18), 100% (22/22), 83.3% (10/12) and 86.5% (45/52) respectively. The overall bacterial eradication rate was 85.07% (57/67) and the rate of adverse reactions 5.9% (17/286). CONCLUSION: Panipenem betamipron is both safe and effective in the treatment of hematological malignancy infections. PMID- 22490965 TI - [Diagnostic role of triple stimulation technique in patients with multifocal motor neuropathy]. AB - OBJECTIVE: To detect the conduction block (CB) between nerve root and Erb's point by triple stimulation technique (TST) in patients with multifocal motor neuropathy (MMN). METHODS: The subjects were recruited from Peking University Third Hospital during the period of April 2010 to April 2011. Twelve MMN patients, 30 healthy subjects, 30 patients with cubital tunnel syndrome and 30 patients with amyotrophic lateral sclerosis (ALS) underwent TST along with clinical assessments and nerve conduction studies. TST combined transcranial magnetic stimulation (TMS) of motor cortex with peripheral collision studies. The results were expressed by the TST amplitude ratio. And the conduction block was judged by TST amplitude ratio or the amplitude ratio of compound muscle action potential (CMAP). RESULTS: The TST amplitude ratio of healthy volunteers was 93.0% +/- 2.7%. And it was 42.3% +/- 7.1% in patients with MMN indicating a proximal CB. There were 47 CBs in distal segments by routine nerve conduction study. Compared with the baseline levels, the patients with definite MMN increased (chi(2) = 6.31, P < 0.05). The TST amplitude ratio (30.5% +/- 4.8%) of those with ALS indicated the lesion of pyramid tract (t = 2.43, P < 0.05). And the TST amplitude ratio (92.2% +/- 2.6%) of those with cubital tunnel syndrome was normal (t = 0.68, P > 0.05) while the nerve conduction velocity of cubital tunnel syndrome patients (below elbow-above elbow) was slower ((23.6 +/- 3.5) m/s) (t = 2.00, P < 0.05). CONCLUSION: TST may be used to detect proximal CB and facilitate the diagnosis of MMN. PMID- 22490966 TI - [Expression and significance of Th17 and Treg cells in peripheral blood of patients with systemic lupus erythematosus]. AB - OBJECTIVE: To explore the expression and significance of Th17 and Treg cells in peripheral blood of patients with systemic lupus erythematosus (SLE). METHODS: Thirty active SLE patients (including 17 SLE patients with lupus nephritis), 20 inactive SLE patients and 20 healthy controls were enrolled. The expressions of Th17 cells and CD4+CD25+Foxp3+Treg cells in peripheral blood mononuclear cells (PBMC) were evaluated by flow cytometry. The correlations between the expression of Th17 cells, CD4+CD25+Foxp3+Treg cells and disease activity (SLEDAI), as well as the ratios of Th17 cells and Treg cells (Th17/Treg) in SLE patients and healthy controls were analyzed respectively. RESULTS: The expression of Th17 cells in PBMC of SLE patients was higher than that in healthy controls [(1.39 +/- 0.60)% vs (0.80 +/- 0.33)%, P < 0.01] while the expression of CD4+CD25+Foxp3+Treg cells decreased in SLE patients [(3.09 +/- 1.54)% vs (6.04 +/- 1.49)%, P < 0.01]. The increased expression of Th17 cells and reduced CD4+CD25+Foxp3+Treg cells in PBMC were positively correlated with SLEDAI and negatively correlated with complements C3 and C4. There were increased expression of Th17 cells and reduced CD4+CD25+Foxp3+Treg cells in PBMC of lupus nephritis versus SLE patients without nephritis. CONCLUSION: There is an abnormal elevation of Th17 cells and decrease of CD4+CD25+Foxp3+Treg cells in PBMC of SLE patients. The imbalance between Th17 and Treg cells may play a critical role in the pathogenesis of SLE. PMID- 22490967 TI - [Effects of methadone maintenance treatment on working memory in male heroin dependent patients]. AB - OBJECTIVE: To explore the differences of working memory task performance between male patients with heroin dependence in methadone maintenance treatment (MMT) and healthy controls (HC). METHODS: A total of 42 heroin-dependent patients at Huainan City Psychiatric Hospital from May 2011 to October 2011 were compared with 31 gender- and age-matched HCs on such working memory tests as visual-space, visual-verbal and visual-face. Then the accurate rate and reaction time of the above tasks were between two groups. RESULTS: The participants with anxiety or depression were excluded. All MMT subjects were required to have negative urine toxicology screening tests. The accurate rate of verbal working memory of the patients was worse than that of HCs (83% +/- 9% vs 89% +/- 10%). And the difference was significant between two groups (t(71) = -2.631, P = 0.010). The accurate rate of visual-object and visual-spatial working memory showed no significant differences between two groups (P > 0.05). The differences in reaction time on these tasks showed no statistical significance between two groups (P > 0.05). In addition, the dose of methadone and the duration of MMT revealed no significant effects on the performance of working memory and executive functions. CONCLUSION: The disproportion impairment of patients on space, verbal and face working memory is probably due to the differential heroin mediated injuries of encephalic regions. Methadone has no effect on working memory and executive functions in the patients with a history of heroin use during maintenance treatment intervention. PMID- 22490968 TI - [Surgical treatment of scoliosis associated with syringomyelia]. AB - OBJECTIVE: To explore the clinical manifestations and surgical strategies of scoliosis associated with syringomyelia. METHODS: A total of 50 cases diagnosed as scoliosis with syringomyelia between January 2003 and November 2010 were recruited. They were divided into 2 groups: Group A, neurosurgery before scoliosis correction, including suboccipital decompression and syrinx shunting; Group B, one-staged posterior correction and instrumentation without previous neurosurgery. The preoperative, postoperative and last follow-ups of Cobb angle of coronal main curve and thoracic kyphosis were measured. Also the preoperative and postoperative apical vertebra translation, apical vertebra rotation and trunk shift were measured by the same person. The surgical efficacies and complications of correction were compared between 2 groups. RESULTS: All patients underwent posterior pedicle screw instrumentation and had a mean follow-up period of 32.1 months. Among them, 42 patients had clinical symptoms or signs preoperatively and 3 patients improved postoperatively. The mean correction of coronal curve was 65.7% and a mean loss of correction 6.4% during the follow-up. The mean correction of apical vertebra translation and apical vertebra rotation were 63.0% and 60.0% respectively. However, the trunk shift increased 0.4 cm. There were no statistically significant differences for the correction efficacies and complications between 2 groups (P > 0.05). CONCLUSION: Scoliosis associated with syringomyelia may be effectively managed if a surgeon manipulates carefully intraoperatively and perioperative spinal monitoring is practiced. Furthermore syrinx will not increase the incidence of postoperative complications without prophylactic neurosurgery. PMID- 22490969 TI - [Treatment of unstable chronic anterior cruciate ligament-deficient knee with osteoarthritis]. AB - OBJECTIVE: Untreated ruptures of anterior cruciate ligament (ACL) lead to progressive meniscus tear and development of knee osteoarthritis over decades. The present study was designed to explore the early results of ACL reconstruction for the patients with unstable ACL-deficient knee with osteoarthritis. METHODS: Twelve patients with a mean age of 46 years (range: 35 - 54) underwent ACL reconstruction for ACL-deficient knee with osteoarthritis. All had chronic anterior instability and one or more episodes of knee instability. There was no previous diagnosis of ACL ruptures and no prior ligament surgery on involved knee. The preoperative duration of symptoms was 1 to 5 years. ACL reconstruction with arthroscopic single-bundle four-strand hamstring tendon autograft was performed for all patients. The laxity of knee was determined with Lachman and pivot tests. The patient subjective evaluation of function was examined with the modified Lysholm scoring scale pre- and post-operatively. RESULTS: Obvious articular cartilage degeneration and cartilage space stenosis in medial compartment were found in 9 patients and complex medial meniscus tear in 10. During the follow-up period of 9 - 36 months, there was no graft failure or loss of ROM (range of motion) for any of these knees. The symptoms of instability were relieved in all patients. The post-operative knee stability improved markedly. The modified Lysholm scores improved from a median pre-operative score of 62.0 points to an average of 89.5 at the last follow-up. CONCLUSION: ACL reconstruction with hamstring tendon may significantly relieve symptoms and improve knee functions in the patients of chronic anterior cruciate ligament deficient knee with osteoarthritis, especially in those with primary symptoms of instability. PMID- 22490970 TI - [Treatment strategies for complicated craniocervical junction malformations]. AB - OBJECTIVE: To explore the treatment strategies for complicated craniocervical junction malformations with diverse clinical and imaging features. METHODS: The clinical data of 67 cases of complicated craniocervical junction malformation treated between January 2000 to December 2010 were retrospectively analyzed. Based on their clinical manifestations and imaging findings, different operative procedures were adopted, including odontoidectomy via transoral transpharyngeal approach (n = 3), occipito-cervical fusion and(or) suboccipital decompression (n = 19) and odontoidectomy via transoral transpharyngeal approach followed by occipito-cervical fusion in two-stage operation (n = 25). Four cases underwent merely odontoidectomy via transoral transpharyngeal approach and died postoperatively. Sixteen cases had occipito-cervical fusion and(or) transorally surgical release for reduction in one stage. RESULTS: Clinical symptoms significantly improved in 19 cases, partially improved in 21 cases and remained unchanged in 12 cases. Nine cases deteriorated postoperatively and 6 cases died. The effective rate was 59.7%. CONCLUSION: The complexity of craniocervical junction malformations may be fully assessed based on different clinical manifestations and thorough imaging studies. Then personalized operative plans are to be designed. PMID- 22490971 TI - [Clinical experiences of normal saline pressed injection via lumbar puncture in the treatment of apnea due to acute tonsillar hernia]. AB - OBJECTIVE: To summarize the clinical experiences of normal saline pressed injection via lumbar puncture in the treatment of acute tonsillar hernia induced apnea. This procedure was routinely carried out after external ventricular drainage and/or lesion removal via open craniotomy. METHODS: During the period of 1969 to 2005, a total of 43 patients failed to regain respiratory after external ventricular drainage using rapid small hole cranio-puncture apparatus or lesion removal via open craniotomy. They underwent lumbar puncture and normal saline was pressed injected via a lumbar puncture needle. The patient data were retrospectively analyzed. RESULTS: Eleven of 43 patients had spontaneous respiration and fully recovered (25.6%), 16 patients regained respiration but died eventually (37.2%) and 16 patients failed to regain respiration (37.2%). The effective rate was 62.8%. CONCLUSION: For the patients failing to regain respiration after external ventricular drainage or supratentorial lesion removal via open craniotomy, the conservative treatment should not be the first choice. The pressed injection of normal saline via lumbar puncture may rescue some patients. PMID- 22490972 TI - [Magnetic resonance imaging features of pancreatic neuroendocrine carcinoma: a literature review]. AB - OBJECTIVE: To explore the magnetic resonance imaging (MRI) manifestations of pancreatic neuroendocrine carcinoma (PNC). METHODS: The clinical data of 7 PNC patients as confirmed by pathological examination were analyzed retrospectively and the relevant literatures discussed. RESULTS: Among them, 2 patients were misdiagnosed for benign tumor lesion, one for SPT and another for pancreatic cancer with liver metastasis. And 3 were diagnosed correctly. The lesions showed irregular or lobulated shapes: 5 in body and tail of pancreas and 2 in head of pancreas. All lesions were hypointense on T(1)WI. They were iso- to slightly hyperintense (n = 5) and heterogeneously hyperintense (n = 2) on T(2)WI. Dynamic contrast-enhanced MRI was performed in all. There were slight enhancement (n = 2) and moderate enhancement (n = 5) during arterial phase. During interstitial and delayed phases, there were gradual enhancement (n = 2) and less enhancement (n = 5) than pancreatic parenchyma. There were metastasis of lymph nodes (n = 1), splenic metastasis (n = 2), liver metastasis (n = 1) and invasion of pancreatic capsule (n = 3). CONCLUSION: Due to the lack of MRI specificities, a definite diagnosis of pancreatic neuroendocrine carcinoma must be made by pathological examination and immunohistochemistry. PMID- 22490973 TI - [Destruction of Walker-256 tumor vasculature by a novel ultrasound cavitation technique]. AB - OBJECTIVE: To explore the feasibility of disrupting tumor microcirculation by the cavitation of microbubbles enhanced ultrasound (US) and analyze its pathological mechanism. METHODS: Twenty-four SD male rats with subcutaneously transplanted Walker-256 tumor were divided into 3 groups, i.e. ultrasound plus microbubbles group (US + MB), US group and sham group. Pulsed US was delivered to tumor for 3 minutes during an intravenous infusion of microbubbles at 0.2 ml/kg in the US + MB group. The control groups received only the US exposure or the MB injection. Tumor perfusion was visualized with contrast enhanced ultrasound before and 0 min after treatment. Finally the pathological examination was performed. RESULTS: The contrast perfusion of Walker-256 tumors vanished immediately after treatment in the US + MB group and the gray scale value (GSV) decreased from 121 +/- 12 (pre treatment) to 81 +/- 9 (post-treatment, P < 0.01). There was no significant difference of GSV before and after treatment in two control groups (P > 0.05). The GSV values were 112 +/- 14 and 111 +/- 12 pre-treatment and 113 +/- 14 and 103 +/- 13 post-treatment in the sham and US groups. The pathological examination showed remarkable hemorrhage, endothelial injuries, increased intercellular edema and in situ thrombosis. CONCLUSION: Microbubble-enhanced ultrasound can significantly disrupt tumor vasculature and block its circulation. And it may become a novel physical anti-angiogenetic therapy for tumor. PMID- 22490974 TI - [Effects of vascular endothelial growth factor vector on vascular buds of vertebral cartilaginous endplate in rabbits]. AB - OBJECTIVE: To directly inject recombinant pcDNA3.1-VEGF165 plasmid into degeneration intervertebral disc and explore its effects on vascular buds of vertebral cartilage endplate and intervertebral disc in rabbits. METHODS: Rabbits were randomly assigned into the experimental and control groups (n = 10 each). For the experimental group, the animals were anesthetized and the front vertebral body exposed. With the longitudinal ossature of front vertebral body of lumbar vertebrae as a mark, a needle was inserted at the central point of the front fourth and fifth lumbar intervertebral disc and 20 ul pcDNA3.1-VEGF165 injected. For the control group, 20 ul pcDNA3.1 was injected. At Weeks 4 and 8 post injection, the changes of vertebral cartilage endplate were monitored by radiograph, histology and scanning electron microscopy. RESULTS: The vertebral cartilage endplate calcification and degeneration in the experimental group were less pronounced than that in the control group at Week 8 post-operation. The average number and diameter of vascular buds obviously increased in the experimental group at Weeks 4 and 8 post-operation. The number and diameter of vascular buds in the region of inner annulus increased compared with those in the area near nucleus pulposus. CONCLUSION: The pcDNA3.1-VEGF165 plasmid may promote the vascular buds of vertebral cartilage endplate by increasing their average number and diameter and arresting the intervertebral disc degeneration. PMID- 22490975 TI - [Roles of axonal transport affected by K141N mutant HSP22 in the pathogenesis of CMT2L]. AB - OBJECTIVE: To compare the axonal transport of wild-type (WT) and K141N mutant HSP22 in transfected primary cultured cortical neurons. METHODS: The plasmid (pCAGGS-HA-wtHSP22 or pCAGGS-HA-K141NHSP22) with WT or K141N mutant HSP22 gene and a GFP-expressing plasmid (pEGFP-N1) were co-transfected respectively into primary cultured cortical neurons. The axonal transport of WT and K141N mutant HSP22 was observed. And the distance traveled by WT and K141N mutant HSP22 was analyzed. RESULTS: The WT HSP22 was transported within axons and uniformly present throughout the entire length of axons. K141N mutant HSP22 failed to be transported to the same extent and was present only in cell body and proximal portion of axons. Analysis of distance traveled revealed that WT HSP22 traveled significantly further than the K141N mutant HSP22. CONCLUSION: The axonal transport of K141N mutant HSP22 may play an important role in the pathogenesis of CMT2L. PMID- 22490976 TI - Sequential priming measures of implicit social cognition: a meta-analysis of associations with behavior and explicit attitudes. AB - In a comprehensive meta-analysis of 167 studies, the authors found that sequential priming tasks were significantly associated with behavioral measures (r = .28) and with explicit attitude measures (r = .20). Priming tasks continued to predict behavior after controlling for the effects of explicit attitudes. These results generalized across a variety of study domains and methodological variations. Within-study moderator analyses revealed that priming tasks have good specificity, only predicting behavior and explicit measures under theoretically expected conditions. Together, these results indicate that sequential priming-one of the earliest methods of investigating implicit social cognition--continues to be a valid tool for the psychological scientist. PMID- 22490977 TI - When death is good for life: considering the positive trajectories of terror management. AB - Research derived from terror management theory (TMT) has shown that people's efforts to manage the awareness of death often have deleterious consequences for the individual and society. The present article takes a closer look at the conceptual foundations of TMT and considers some of the more beneficial trajectories of the terror management process. The awareness of mortality can motivate people to enhance their physical health and prioritize growth-oriented goals; live up to positive standards and beliefs; build supportive relationships and encourage the development of peaceful, charitable communities; and foster open-minded and growth-oriented behaviors. The article also tentatively explores the potential enriching impact of direct encounters with death. Overall, the present analysis suggests that although death awareness can, at times, generate negative outcomes, it can also function to move people along more positive trajectories and contribute to the good life. PMID- 22490979 TI - Risk of cancer in first seven years after metal-on-metal hip replacement compared with other bearings and general population: linkage study between the National Joint Registry of England and Wales and hospital episode statistics. AB - OBJECTIVE: To determine whether use of metal-on-metal bearing surfaces is associated with an increased risk of a diagnosis of cancer in the early years after total hip replacement and specifically with an increase in malignant melanoma and haematological, prostate, and renal tract cancers. DESIGN: Linkage study with multivariable competing risks flexible parametric survival model to examine the incidence of new diagnoses of cancer in patients with metal-on-metal hip replacement compared with those with alternative bearings and to compare the observed incidence of diagnoses in patients undergoing hip replacement with that predicted by national incidence rates in the general population. SETTING: National Joint Registry of England and Wales (NJR) linked to NHS hospital episode statistics data. PARTICIPANTS: 40,576 patients with hip replacement with metal-on metal bearing surfaces and 248,995 with alternative bearings. MAIN OUTCOME MEASURES: Incidence of all cancers and incidence of malignant melanoma and prostate, renal tract, and haematological cancers. RESULTS: The incidence of new diagnoses of cancer was low after hip replacement (1.25% at one year, 95% confidence interval 1.21% to 1.30%) and lower than that predicted from the age and sex matched normal population (1.65%, 1.60% to 1.70%). Compared with alternative bearings, there was no evidence that metal-on-metal bearing surfaces were associated with an increased risk of any cancer diagnosis in the seven years after surgery (mean follow-up of three years, 23% (n=67,361) of patients observed for five years or more). Similarly, there was no increase in the risk of malignant melanoma or haematological, prostate, and renal tract cancers. The adjusted five year incidence of all cancers for men aged 60 was 4.8% (4.4% to 5.3%) with resurfacing, 6.2% (5.7% to 6.7%) with stemmed metal-on-metal, and 6.7% (6.5% to 7.0%) for other bearing surfaces. Equivalent rates for women aged 60 were lower: 3.1% (2.8% to 3.4%) with resurfacing, 4.0% (3.7% to 4.3%) with stemmed metal-on-metal, and 4.4% (4.2% to 4.5%) with other bearings. CONCLUSIONS: These data are reassuring, but the findings are observational with short follow up. The use of hospital episode statistics data might underestimate cancer diagnoses, and there is the possibility of confounding by indication. Furthermore, as some cancers have a long latency period it is important that we study the longer term outcomes and continue to investigate the effects of exposure to orthopaedic metals. PMID- 22490980 TI - Managed clinical networks in neonatal care. PMID- 22490978 TI - Impact of managed clinical networks on NHS specialist neonatal services in England: population based study. AB - OBJECTIVE: To assess the impact of reorganisation of neonatal specialist care services in England after a UK Department of Health report in 2003. DESIGN: A population-wide observational comparison of outcomes over two epochs, before and after the establishment of managed clinical neonatal networks. SETTING: Epoch one: 294 maternity and neonatal units in England, Wales, and Northern Ireland, 1 September 1998 to 31 August 2000, as reported by the Confidential Enquiry into Stillbirths and Sudden Deaths in Infancy Project 27/28. Epoch two: 146 neonatal units in England contributing data to the National Neonatal Research Database at the Neonatal Data Analysis Unit, 1 January 2009 to 31 December 2010. PARTICIPANTS: Babies born at a gestational age of 27(+0)-28(+6) (weeks+days): 3522 live births in epoch one; 2919 babies admitted to a neonatal unit within 28 days of birth in epoch two. INTERVENTION: The national reorganisation of neonatal services into managed clinical networks. MAIN OUTCOME MEASURES: The proportion of babies born at hospitals providing the highest volume of neonatal specialist care (>= 2000 neonatal intensive care days annually), having an acute transfer (within the first 24 hours after birth) and/or a late transfer (between 24 hours and 28 days after birth) to another hospital, assessed by change in distribution of transfer category ("none," "acute," "late"), and babies from multiple births separated by transfer. For acute transfers in epoch two, the level of specialist neonatal care provided at the destination hospital (British Association of Perinatal Medicine criteria). RESULTS: After reorganisation, there were increases in the proportions of babies born at 27-28 weeks' gestation in hospitals providing the highest volume of neonatal specialist care (18% (631/3495) v 49% (1325/2724); odds ratio 4.30, 95% confidence interval 3.83 to 4.82; P<0.001) and in acute and late postnatal transfers (7% (235) v 12% (360) and 18% (579) v 22% (640), respectively; P<0.001). There was no significant change in the proportion of babies from multiple births separated by transfer (33% (39) v 29% (38); 0.86, 0.50 to 1.46; P=0.57). In epoch two, 32% of acute transfers were to a neonatal unit providing either an equivalent (n=87) or lower (n=26) level of specialist care. CONCLUSIONS: There is evidence of some improvement in the delivery of neonatal specialist care after reorganisation. The increase in acute transfers in epoch two, in conjunction with the high proportion transferred to a neonatal unit providing an equivalent or lower level of specialist care, and the continued separation of babies from multiple births, are indicative of poor coordination between maternity and neonatal services to facilitate in utero transfer before delivery, and continuing inadequacies in capacity of intensive care cots. Historical data representing epoch one are available only in aggregate form, preventing examination of temporal trends or confounding factors. This limits the extent to which differences between epochs can be attributed to reorganisation and highlights the importance of routine, prospective data collection for evaluation of future health service reorganisations. PMID- 22490981 TI - Transfollicular enhancement of gel containing cationic niosomes loaded with unsaturated fatty acids in rice (Oryza sativa) bran semi-purified fraction. AB - The 20mM cationic niosomes composed of Tween61/cholesterol/CTAB at 1:1:0.5M ratio which gave the best physical appearance, particle size, zeta potential and in vitro cytotoxicity were selected from six cationic niosomes prepared from various cationic lipids. The selected cationic niosomes were loaded with the semi purified fraction 3 of Oryza sativa (OSF3) which gave the highest in vitro 5alpha reductase inhibition activity. The physicochemical characteristics as well as transfollicular penetration through porcine skin by Franz diffusion cells of gel OSF3 niosomes, OSF3 niosomes, gel OSF3 and OSF3 solution were investigated. Gel containing niosomes loaded with OSF3 exhibited physical stability with 77.68% of gamma-linolenic acid, 85.34% of linoleic acid and 89.47% of oleic acid remaining for 3 months at 25 degrees C. In the skin, the OSF3 niosomes (120.27 ng/cm(2)) and gel OSF3 niosomes (118.17 ng/cm(2)) showed the highest cumulative amounts of the total unsaturated fatty acids (gamma-linolenic acid, linoleic acid and oleic acid) in comparing to those from the gel OSF3 (15.34 ng/cm(2)) and OSF3 solution (20.31 ng/cm(2)) of about 8 and 6 times, respectively. In the receiver compartment, the gel OSF3 niosomes (6.27 ng/cm(2)) exhibited lower cumulative amount of the total unsaturated fatty acids than that of the OSF3 niosomes (11.20 ng/cm(2)) of about 2 times. This study has suggested that gel containing OSF3 loaded in niosomes appeared to be the suitable system for topical anti-androgenic alopecia application because of the convenient use and high transfollicular penetration in the skin, but not in the receiving compartment with the advantage of low systemic effect. PMID- 22490982 TI - Modelling and inference for epidemic models featuring non-linear infection pressure. AB - We consider a Susceptible-Infective-Removed (SIR) stochastic epidemic model in which the infection rate is of the form betaN-1X(t)Y(t)(alpha). It is demonstrated that both the threshold behaviour of this model and the behaviour of the corresponding deterministic model differ markedly from the standard SIR model (i.e. alpha=1). Methods of statistical inference for this model are described, given outbreak data, and the extent to which all three model parameters can be estimated is considered. PMID- 22490983 TI - Image reconstruction and system modeling techniques for virtual-pinhole PET insert systems. AB - Virtual-pinhole PET (VP-PET) imaging is a new technology in which one or more high-resolution detector modules are integrated into a conventional PET scanner with lower resolution detectors. It can locally enhance the spatial resolution and contrast recovery near the add-on detectors, and depending on the configuration, may also increase the sensitivity of the system. This novel scanner geometry makes the reconstruction problem more challenging compared to the reconstruction of data from a stand-alone PET scanner, as new techniques are needed to model and account for the non-standard acquisition. In this paper, we present a general framework for fully 3D modeling of an arbitrary VP-PET insert system. The model components are incorporated into a statistical reconstruction algorithm to estimate an image from the multi-resolution data. For validation, we apply the proposed model and reconstruction approach to one of our custom-built VP-PET systems-a half-ring insert device integrated into a clinical PET/CT scanner. Details regarding the most important implementation issues are provided. We show that the proposed data model is consistent with the measured data, and that our approach can lead to reconstructions with improved spatial resolution and lesion detectability. PMID- 22490984 TI - Isolation and biophysical study of fruit cuticles. AB - The cuticle, a hydrophobic protective layer on the aerial parts of terrestrial plants, functions as a versatile defensive barrier to various biotic and abiotic stresses and also regulates water flow from the external environment. A biopolyester (cutin) and long-chain fatty acids (waxes) form the principal structural framework of the cuticle; the functional integrity of the cuticular layer depends on the outer 'epicuticular' layer as well as the blend consisting of the cutin biopolymer and 'intracuticular' waxes. Herein, we describe a comprehensive protocol to extract waxes exhaustively from commercial tomato (Solanum lycopersicum) fruit cuticles or to remove epicuticular and intracuticular waxes sequentially and selectively from the cuticle composite. The method of Jetter and Schaffer (2001) was adapted for the stepwise extraction of epicuticular and intracuticular waxes from the fruit cuticle. To monitor the process of sequential wax removal, solid-state cross-polarization magic-angle spinning (CPMAS) (13)C NMR spectroscopy was used in parallel with atomic force microscopy (AFM), providing molecular-level structural profiles of the bulk materials complemented by information on the microscale topography and roughness of the cuticular surfaces. To evaluate the cross-linking capabilities of dewaxed cuticles from cultivated wild-type and single-gene mutant tomato fruits, MAS (13)C NMR was used to compare the relative proportions of oxygenated aliphatic (CHO and CH(2)O) chemical moieties. Exhaustive dewaxing by stepwise Soxhlet extraction with a panel of solvents of varying polarity provides an effective means to isolate wax moieties based on the hydrophobic characteristics of their aliphatic and aromatic constituents, while preserving the chemical structure of the cutin biopolyester. The mechanical extraction of epicuticular waxes and selective removal of intracuticular waxes, when monitored by complementary physical methodologies, provides an unprecedented means to investigate the cuticle assembly: this approach reveals the supramolecular organization and structural integration of various types of waxes, the architecture of the cutin wax matrix, and the chemical composition of each constituent. In addition, solid state (13)C NMR reveals differences in the relative numbers of CHO and CH(2)O chemical moieties for wild-type and mutant red ripe tomato fruits. The NMR techniques offer exceptional tools to fingerprint the molecular structure of cuticular materials that are insoluble, amorphous, and chemically heterogeneous. As a noninvasive surface-selective imaging technique, AFM furnishes an effective and direct means to probe the structural organization of the cuticular assembly on the nm-MUm length scale. PMID- 22490985 TI - Concomitant Brugada-like and short QT electrocardiogram linked to SCN5A mutation. AB - Mutations in the alpha-subunit of cardiac sodium channel gene SCN5A can lead to the overlapping phenotypes of both the Brugada and type 3 long QT syndromes. However, the combination of Brugada and a short QT phenotype resulting from mutation in SCN5A has not previously been described. A man with concomitant Brugada-like and short QT electrocardiogram (ECG) was identified and the SCN5A gene was sequenced. Whole-cell patch clamp analysis of human embryo kidney (HEK) 293 cells expressing a SCN5A channel with the patient's sequence was used to investigate the biophysical properties of the channel. The patient with the family history of sudden death showed Brugada-like and short QT interval ECG. Sequence analysis of the coding region of the SCN5A gene, identified a G to A heterozygous missense mutation at nucleotide site 2066 that resulted in a amino acid substitution of arginine to histidine at amino-acid site 689 (R689H). Patch clamp analysis showed that the R689H failed to generate current when heterologously expressed in HEK293 cells, indicating it was a loss-of-function mutation. Our finding firstly shows that a heterozygous missense mutation R689H in SCN5A gene results in the loss of protein function and the coexistents of the Brugada-like and short QT interval ECG phenotypes. PMID- 22490986 TI - Is there a Mendelian transmission ratio distortion of the c.429_452dup(24bp) polyalanine tract ARX mutation? AB - Intellectual disability is common. Aristaless-related homeobox (ARX) gene is one of the most frequently mutated and pleiotropic genes, implicated in 10 different phenotypes. More than half of ~100 reported cases with ARX mutations are due to a recurrent duplication of 24 bp, c.429_452dup, which leads to polyalanine tract expansion. The excess of affected males among the offspring of the obligate carrier females raised the possibility of transmission ratio distortion for the c.429_452dup mutation. We found a significant deviation from the expected Mendelian 1:1 ratio of transmission in favour of the c.429_452dup ARX mutation. We hypothesise that the preferential transmission of the c.429_452dup mutation may be due to asymmetry of meiosis in the oocyte. Our findings may have implications for genetic counselling of families segregating the c.429_452dup mutation and allude to putative role of ARX in oocyte biology. PMID- 22490987 TI - Novel homozygous, heterozygous and hemizygous FRMD7 gene mutations segregated in the same consanguineous family with congenital X-linked nystagmus. AB - Congenital nystagmus (NYS) is characterized by bilateral, spontaneous, and involuntary movements of the eyeballs that most commonly presents between 2 and 6 months of life. To date, 44 different FRMD7 gene mutations have been found to be etiological factors for the NYS1 locus at Xq26-q27. The aim of this study was to find the FRMD7 gene mutations in a large eleven-generation Indian pedigree with 71 members who are affected by NYS. Mutation analysis of the entire coding region and splice junctions of the FRMD7 gene revealed a novel missense mutation, c.A917G, predicts a substitution of Arg for Gln at codon 305 (Q305R) within exon 10 of FRMD7. The mutation was detected in hemizygous males, and in homozygous and heterozygous states in affected female members of the family. This mutation was not detected in unaffected members of the family or in 100 unrelated control subjects. This mutation was found to be at a highly conserved residue within the FERM-adjacent domain in affected members of the family. Structure prediction and energetic analysis of wild-type FRMD7 compared with mutant (Q305R) revealed that this change in amino acid led to a change in secondary structure predicted to be an energetically unstable protein. The present study represents the first confirmation of FRMD7 gene mutations in a multigenerational Indian family and expands the mutation spectrum for this locus. PMID- 22490988 TI - De novo and inherited CNVs in MZ twin pairs selected for discordance and concordance on Attention Problems. AB - Copy number variations (CNVs) have been reported to be causal suspects in a variety of psychopathologic traits. We investigate whether de novo and/or inherited CNVs contribute to the risk for Attention Problems (APs) in children. Based on longitudinal phenotyping, 50 concordant and discordant monozygotic (MZ) twin pairs were selected from a sample of ~3200 MZ pairs. Two types of de novo CNVs were investigated: (1) CNVs shared by both MZ twins, but not inherited (pre twinning de novo CNVs), which were detected by comparing copy number (CN) calls between parents and twins and (2) CNVs not shared by co-twins (post-twinning de novo CNVs), which were investigated by comparing the CN calls within MZ pairs. The association between the overall CNV burden and AP was also investigated for CNVs genome-wide, CNVs within genes and CNVs outside of genes. Two de novo CNVs were identified and validated using quantitative PCR: a pre-twinning de novo duplication in a concordant-unaffected twin pair and a post-twinning deletion in the higher scoring twin from a concordant-affected pair. For the overall CNV burden analyses, affected individuals had significantly larger CNVs that overlapped with genes than unaffected individuals (P=0.008). This study suggests that the presence of larger CNVs may increase the risk for AP, because they are more likely to affect genes, and confirms that MZ twins are not always genetically identical. PMID- 22490989 TI - A novel menin gene deletional mutation in a little series of Italian patients affected by apparently sporadic multiple endocrine neoplasia type 1 syndrome. AB - AIM: To perform a genetic screening for the multiple endocrine neoplasia type 1 (MEN1) gene mutations in patients affected by an apparently sporadic form of the disease, referred to an internal medicine unit of a large general hospital. SUBJECTS AND METHODS: In a group of 12 consecutive patients presenting clinical features of MEN type 1 syndrome, we performed a genetic screening for germline MEN1 gene mutations, including complete sequencing of the coding region (exons 2 to 10) and multiplex ligation-dependent probe amplification analysis for large deletion detection. RESULTS: Among these patients affected by apparently sporadic MEN type 1 syndrome, a targeted clinical history could detect indirect support for a diagnosis of familial condition only in 2 cases. The genetic screening identified pathogenic germline MEN1 gene mutations in 3 patients (25%). A previously unknown 18 base-pair deletion within exon 3, c.564_581delCAATGGGGAGCAGACAGC, resulting in loss of 6 amino acids (pAsp189_Ala194del), was found in heterozygosis in a woman affected by primary hyperparathyroidism and multifocal pancreatic neoplasia. CONCLUSIONS: Our results underscore the importance of performing genetic testing also in apparently sporadic MEN1 patients and extend the list of molecular variants leading to inactivation of the MEN1 gene. PMID- 22490990 TI - A mathematical model in the analysis of the response to growth hormone treatment in pediatric patients with diagnosis of growth hormone deficiency. AB - In the literature, few studies analyze the effect of GH therapy on height, preferring a more indirect approach, where factors influencing the total pubertal and pre-pubertal growth in GH-deficient patients are evaluated and subsequently used to estimate the overall effect at the end of the therapy; unfortunately, this approach does not quantify the real growth gain in treated patients. Using a non-parametric Empirical Bayes approach, our study analyzes the growth response to GH treatment in a homogeneous cohort of 317 patients with pituitary GH deficiency who were enrolled during their pre-pubertal stage in the GH Piedmont Registry (Italy), between January 2000-October 2008, and have at least 2 yr of follow-up. To estimate the growth curve for males and females, a non-parametric regression model was fitted, applying Empirical Bayes techniques. A validation of the model was also performed. Improvement was evident in both genders, since both males and females mean growth curve, which started below the 3rd percentile at the beginning of the therapy, reached the 10th percentile of the Tanner curve at the end of observation (17 yr old for males and 14 yr old for females); the estimation procedure achieved a good precision. The methodological approach allows for fitting a model able to evaluate longitudinally the response to GH treatment, by means of estimating the overall growth curve, even in presence of sparse information about children heights. PMID- 22490991 TI - Non-alcoholic fatty liver disease is independently associated with left ventricular hypertrophy in hypertensive Type 2 diabetic individuals. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and left ventricular hypertrophy (LVH) are highly prevalent in Type 2 diabetes and both conditions are associated with an increased risk of incident cardiovascular disease. The aim of this study is to evaluate whether there is an association between NAFLD and echocardiographically detected LVH in Type 2 diabetes. METHODS: We studied 116 consecutive patients with hypertension and Type 2 diabetes after excluding those with pre-existing history of cardiovascular disease, advanced kidney disease, excessive alcohol consumption and other known causes of chronic liver disease (e.g., virus, medications, autoimmunity, iron overload). NAFLD was diagnosed by means of ultrasonography, whereas LVH was diagnosed by means of conventional trans-thoracic echocardiography in all patients. RESULTS: The prevalence of LVH was markedly higher among diabetic patients with NAFLD than among those without this disease (82% vs 18%; p=0.01). Multivariate logistic regression analysis revealed that NAFLD was associated with LVH independently of age, sex, body mass index, systolic blood pressure, glycated hemoglobin, duration of diabetes, and parameters of kidney function. CONCLUSIONS: Our findings suggest that hypertensive Type 2 diabetic patients with NAFLD have a remarkably higher frequency of LVH than do hypertensive diabetic patients without steatosis, and that NAFLD is associated with LVH independently of classical cardiovascular risk factors and other potential confounders. PMID- 22490992 TI - The use of local reference growth charts for clinical use or a universal standard: a balanced appraisal. PMID- 22490994 TI - Endocrinology and Art. Madonna del Rosario (Lady of the rosary) - Michelangelo Merisi called Caravaggio (1571-1610). PMID- 22490993 TI - Does use of metformin protect against cancer in Type 2 diabetes mellitus? AB - BACKGROUND: Type 2 diabetes mellitus has been associated with an increased cancer risk, which can be modified by specific hypoglycemic drugs. In particular, metformin, the most frequently prescribed biguanide, is now considered a protective agent against cancer incidence and mortality in Type 2 diabetic patients. AIMS: To review the potential associations between metformin use and cancer incidence and mortality and the possible biological links implicated in these associations. MATERIALS AND METHODS: We searched English-language original investigations published through September 2011. RESULTS: Metformin could block the mitogenic effects of insulin, but this effect does not entirely explain the reduction in cancer incidence. Metformin also plays a direct inhibition of cancer cell growth via the inhibitory effects of AMP-activated protein kinase on the mTOR pathway, which regulates cell growth and proliferation. Accordingly, many epidemiological studies have shown that metformin use is associated with a lower cancer incidence and mortality through a dose-response relationship, with greater exposure being associated with stronger risk reduction. Randomized clinical trials testing the effects of metformin on both recurrence and survival in early stage breast cancer are on-going; these trials are based on pilot studies demonstrating an adjuvant effect of this drug in breast cancer. CONCLUSIONS: Metformin is an inexpensive and safe drug, that may modify the increased cancer risk of Type 2 diabetic patients. On-going clinical trials will show whether this drug can enhance the effect of chemotherapy in the treatment of cancer. PMID- 22490995 TI - Exposure to herpes simplex virus type 1 and cognitive impairments in individuals with schizophrenia. AB - Latent infection with neurotropic herpes viruses, such as herpes simplex virus, type 1 (HSV1), has been generally considered benign in most immunocompetent individuals except for rare cases of encephalitis. However, several recent studies have shown impaired cognitive functions among individuals with schizophrenia exposed to HSV1 compared with schizophrenia patients not exposed to HSV1. Such impairments are robust and are prominently observed in working memory, verbal memory, and executive functions. Brain regions that play a key role in the regulation of these domains have shown smaller volumes, along with correlation between these morphometric changes and cognitive impairments in schizophrenia. One study noted temporal decline in executive function and gray matter loss among HSV1-exposed first-episode antipsychotic-naive schizophrenia patients. Furthermore, a proof-of-concept double-blind placebo-controlled trial indicated improvement in cognitive performance following supplemental anti-herpes-specific medication among HSV1 seropositive schizophrenia patients. Cross-sectional studies have also identified an association between HSV1 exposure and lesser degrees of cognitive impairment among healthy control individuals and patients with bipolar disorder. These studies fulfill several Bradford-Hill criteria, suggesting etiological links between HSV1 exposure and cognitive impairment. Exposure to other human herpes viruses such as cytomegalovirus and herpes simplex virus type 2 (HSV2) may also be associated with cognitive impairment, but the data are less consistent. These studies are reviewed critically and further lines of enquiry recommended. The results are important from a public health perspective, as HSV1 exposure is highly prevalent in many populations. PMID- 22490996 TI - Evolution of vertebrate tissues driven by differential modes of gene duplication. AB - In this study, we investigated the evolution of vertebrate tissues by examining the potential association among gene expression, duplication, and base substitution patterns. In particular, we compared whole-genome duplication (WGD) with small-scale duplication (SSD), as well as tissue restricted with ubiquitously expressed genes. All patterns were also analysed in the light of gene evolutionary rates. Among those genes characterized by rapid evolution and expressed in a restricted range of tissues, SSD was represented in a larger proportion than WGD. Conversely, genes with ubiquitous expression were associated with slower evolutionary rates and a larger proportion of WGD. The results also show that evolutionary rates were faster in genes expressed in endodermal tissues and slower in ectodermal genes. Accordingly, the proportion of the SSD and WGD genes was highest in the endoderm and ectoderm, respectively. Therefore, quickly evolving SSD genes might have contributed to the faster evolution of endodermal tissues, whereas the comparatively slowly evolving WGD genes might have functioned to maintain the basic characteristics of ectodermal tissues. Mesenchymal tissues occupied an intermediate position in this regard, whereas the patterns observed for haemocytes were unique. Rapid tissue evolution could be related to a specific gene duplication mode (SSD) and faster molecular evolution in response to exposure to the external environment. These findings reveal general patterns underlying the evolution of tissues and their corresponding genes. PMID- 22490998 TI - Risk factors in lateral epicondylitis (tennis elbow): a case-control study. AB - Lateral epicondylitis is a common condition, but relatively little is known about its aetiology and associated risk factors. We have undertaken a large case control study using The Health Improvement Network database to assess and quantify the relative contributions of some constitutional and environmental risk factors for lateral epicondylitis in the community. Our dataset included 4998 patients with lateral epicondylitis who were individually matched with a single control by age, sex, and general practice. The median age at diagnosis was 49 (interquartile range 42-56) years . Multivariate analysis showed that the risk factors associated with lateral epicondylitis were rotator cuff pathology (OR 4.95), De Quervain's disease (OR 2.48), carpal tunnel syndrome (OR 1.50), oral corticosteroid therapy (OR 1.68), and previous smoking history (OR 1.20). Diabetes mellitus, current smoking, trigger finger, rheumatoid arthritis, alcohol intake, and obesity were not found to be associated with lateral epicondylitis. PMID- 22490997 TI - Comparison of step-cut and Pulvertaft attachment for flexor tendon graft: a biomechanics evaluation in an in vitro canine model. AB - The purpose of this study was to compare two different methods of joining tendons of similar and dissimilar sizes between recipient and donor tendons for flexor tendon grafts. Flexor digitorum profundus (FDP) and peroneus longus (PL) canine tendons were harvested and divided into four groups. The repair technique we compared was a step-cut (SC) suture and a Pulvertaft weave (PW). FDP tendons were significantly larger in diameter than PL tendons (p < 0.05). The volume of the SC repairs using either FDP or PL tendon as a graft was significantly smaller than PW repairs (p < 0.05). The ultimate load to failure and repair stiffness in FDP graft tendons significantly increased compared with the PL graft tendons (p < 0.05). The SC suture can be used as an alternative to the PW, with similar strength and less bulk for repairs using graft tendons of similar diameter. Surgeons should be aware of the effect of graft tendon size and repair method on strength and bulk when performing flexor tendon grafts. PMID- 22490999 TI - Computed tomography improves intra-observer reliability, but not the inter observer reliability of the Eaton-Glickel classification. AB - This study aimed to evaluate whether computed tomography improves the intra- and inter-observer reliability of the Eaton-Glickel classification of trapeziometacarpal joint osteoarthritis. The osteoarthritis of the trapeziometacarpal joint was evaluated with conventional radiographs and computed tomography by two hand surgeons, two registrars and one radiologist in 50 hands of 43 patients (12 male and 31 female) who had a median age of 60 years (46-80). Using plain radiographs, we found a mean intra-observer reliability of 0.54 (0.51 0.74), and the intra-observer reliability was improved to 0.76 (0.64-0.86) using computed tomography. Using plain radiographs, the mean inter-observer reliability was poor at 0.17 (0.04-0.51) and did not improve using computed tomography with a mean inter-observer reliability of 0.22 (0.02-0.38). In particular, the agreement in the distinction between Eaton-Glickel stage III and IV and the evaluation of the degenerative changes in the scaphotrapezio joint was low using computed tomography-scans. The detection of bone cysts on computed tomography was more precise than on plain radiographs. PMID- 22491000 TI - Elektra prosthesis for trapeziometacarpal osteoarthritis: a follow-up of 39 consecutive cases. AB - We present a prospective follow-up of 39 Elektra prostheses in 37 patients (32 women and five men), with a mean age of 56.5 (range 46-71) years; 34 patients had osteoarthritis and three had rheumatoid arthritis. Patients were followed using clinical examination, including measurement of pain on a visual analogue scale, mobility, and strength, after 6, 12, 26, and 52 weeks, and annually thereafter. Radiological examination was done preoperatively and after 6, 26, and 52 weeks, and annually thereafter. The mean follow-up time was 48 (range 3-91) months. Although we observed a fast recovery, including maintenance of mobility and a gradual increase in grip strength, there was a revision rate of 7/38 (24%) after 36 months, increasing to 17/38 (44%) after 72 months. The main reason for revision was loosening of the trapezial component, and biomechanical properties of the trapezial fixation may be the key problem in treating trapeziometacarpal osteoarthritis using a total prosthesis. PMID- 22491001 TI - The seed cone Eathiestrobus gen. nov.: fossil evidence for a Jurassic origin of Pinaceae. AB - PREMISE OF THE STUDY: Pinaceae and nonpinoid species are sister groups within the conifer clade as inferred from molecular systematic comparisons of living species and therefore should have comparable geological ages. However, the fossil record for the nonpinoid lineage of extant conifer families is Triassic, nearly 100 million years older than the oldest widely accepted Lower Cretaceous record for Pinaceae. An anatomically preserved fossil conifer seed cone described here extends the stratigraphic range of Pinaceae nearly 30 million years, thus reducing the apparent discrepancy between evidence from the fossil record and inferences from systematic studies of living species. METHODS: Material was prepared as serial thin sections by the cellulose acetate peel technique, mounted on microscope slides, and viewed and photographed using transmitted light. KEY RESULTS: A large cylindrical cone consisting of bract-scale complexes that diverge from the cone axis in a helical phyllotaxis has bracts and scales that separate from each other in the midregion and are of equal length and of nearly equal width. The cone has two inverted and winged seeds that are attached to the adaxial surface of each cone scale and, thus, represents an early member of the Pinaceae. CONCLUSIONS: Eathiestrobus mackenziei gen. et sp. nov. extends the fossil record for well-documented members of the family Pinaceae from the Lower Cretaceous to the Kimmeridgian Stage of the Upper Jurassic. This species also clarifies the set of characters that are diagnostic for seed cones of Pinaceae and reveals possible plesiomorphic characters for seed cones of the family. PMID- 22491002 TI - Flowering asynchrony and mating system effects on reproductive assurance and mutualism persistence in fragmented fig-fig wasp populations. AB - PREMISE OF THE STUDY: Plants and animals may experience reproductive Allee effects in fragmented populations, and obligate pollination mutualisms may be especially sensitive to extinction risk via this density-dependent process. In this study we examine how a shift from within-crown reproductive synchrony to asynchrony influences reproductive assurance through contributions to selfing and outcrossing in small, spatially isolated populations of Ficus. METHODS: The research focuses on the monoecious fig F. petiolaris and consists of phenological analyses and genetic assessments of selfing and outcrossing for populations located in Baja California's Sonoran Desert. KEY RESULTS: Phenological censuses of eight populations revealed within-crown asynchrony in 44% of reproducing trees, with 16% having sufficient overlap of male and female flowering phases to permit selfing via the cycling of pollinating fig wasps within natal trees. In mating system analyses of two of these populations, however, multilocus outcrossing rates (t(m)) were indistinguishable from 1. This result, combined with low levels of inbreeding, indicates selfing to be absent or at best a minor contributor to reproductive assurance. CONCLUSIONS: The results indicate that the fitness benefits of within-crown asynchrony lie not with selfing, as commonly asserted, but with increased opportunities for outcross pollen transmission and receipt, changing our understanding of the mechanisms by which reproduction is facilitated and extinction risk minimized in naturally fragmented Ficus populations. Given the role of fig fruit as a keystone food resource in many tropical environments, trait variation leading to reproductive assurance in figs, such as within-crown asynchrony, has broader ecosystem-level implications. PMID- 22491003 TI - Communicating about phase I trials: objective disclosures are only a first step. PMID- 22491004 TI - Trastuzumab for small HER-2+ breast cancer: small tumor, big decision. AB - A 53-year-old postmenopausal woman was found to have a new area of microcalcification at the 10 o'clock position of her right breast during a routine screening mammogram. Ultrasound-guided core biopsy revealed a grade 2 invasive ductal carcinoma, estrogen receptor (ER)+ (90%), progesterone receptor positive (20%), and human epidermal growth factor receptor (HER)-2+ (3+ by immunohistochemistry). A right breast lumpectomy and sentinel node biopsy were performed. The invasive tumor measured 0.7 cm, no lymphovascular space invasion was identified, surgical margins were uninvolved, and the sentinel lymph nodes were negative for tumor. She was evaluated postoperatively in the medical oncology clinic to discuss an adjuvant treatment strategy. The question for our colleagues is: should she be offered adjuvant chemotherapy and trastuzumab prior to adjuvant radiation and 5 years of hormonal therapy? PMID- 22491005 TI - Tamoxifen alters the plasma concentration of molecules associated with cardiovascular risk in women with breast cancer undergoing chemotherapy. AB - OBJECTIVES: The objective of this study was to evaluate the effect of tamoxifen on blood markers that are associated with cardiovascular risk, such as C-reactive protein (CRP), apolipoprotein A-1 (Apo-A), and apolipoprotein B-100 (Apo-B), in women undergoing chemotherapy for breast cancer. METHODS: Over a period of 12 months, we followed 60 women with breast cancer. The women were divided into the following groups: a group that received only chemotherapy (n = 23), a group that received chemotherapy plus tamoxifen (n = 21), and a group that received only tamoxifen (n = 16). Plasma CRP levels were assessed at 0, 3, 6, and 12 months, and Apo-A and Apo B levels as well as the Apo-B/Apo-A ratio were assessed at 0 and 12 months. RESULTS: We found increases in the plasma concentration of CRP in the chemotherapy alone and chemotherapy plus tamoxifen groups after 3 and 6 months of treatment (before the introduction of tamoxifen). However, after 12 months of treatment, women who used tamoxifen (the chemotherapy plus tamoxifen and tamoxifen alone groups) showed a significant reduction in CRP and Apo-B levels and a decrease in the Apo-B/Apo-A ratio. A significant increase in serum Apo-A levels was observed in the group receiving chemotherapy alone as a treatment for breast cancer. CONCLUSION: The use of tamoxifen after chemotherapy for the treatment of breast cancer significantly reduces the levels of cardiovascular disease risk markers (CRP, Apo-B, and the Apo-B/Apo-A ratio). PMID- 22491006 TI - Religious congregations' collaborations: with whom do they work and what resources do they share in addressing HIV and other health issues? AB - This study explores how religious congregations interact with other community organizations to address health and, in particular, HIV-related needs within their membership and/or local communities. Case study data from a diverse sample of 14 urban congregations (6 Black, 4 Latino, 2 White, and 2 mixed race ethnicity) indicate that they engaged in three types of relationships to conduct HIV and other health-related activities: (a) resources flowed to congregations from external entities, (b) resources flowed from congregations to external entities, and (c) congregations interacted with external entities. These types of relationships were present in roughly equal proportions; thus, congregations were not primarily the recipients of resources from other organizations in these interactions. Financial, material, and human capital resources were shared across these three relationship types, and the most common organization types that congregations were involved with for health efforts were prevention and social service organizations, health care providers, and other congregations. In addition, congregations tended to have more collaborative relationships with other faith-based organizations (FBOs) and tended to engage with non-FBOs more to either receive or provide resources. Results suggest that congregations contribute to community health by not only sponsoring health activities for their own members but also by providing specific support or resources to enhance the programming of other community organizations and collaborating with external organizations to sponsor congregation-based and community-based health activities. PMID- 22491007 TI - Limited evidence that competitive food and beverage practices affect adolescent consumption behaviors. AB - Childhood obesity is emerging as a considerable public health problem with no clear antidote. The school food environment is a potential intervention point for policy makers, with competitive food and beverage regulation as a possible policy lever. This research examines the link between competitive food and beverage availability in school and adolescent consumption patterns using data from the Early Childhood Longitudinal Study, Kindergarten Class of 1998-1999. Results from value-added multivariate regression models reveal limited evidence that competitive food policy affects fruit and vegetable consumption. Findings suggest a stronger link between competitive beverage policy and consumption of sweetened beverages for population subgroups. PMID- 22491008 TI - The South Australia health chronic disease self-management Internet trial. AB - OBJECTIVES: To evaluate the effectiveness of an online chronic disease self management program for South Australia residents. METHOD: Data were collected online at baseline, 6 months, and 12 months. The intervention was an asynchronous 6-week chronic disease self-management program offered online. The authors measured eight health status measures, seven behaviors, and four utilization measures; self-efficacy; and health care satisfaction. RESULTS: Two hundred fifty four South Australian adults with one or more chronic conditions completed baseline data. One hundred forty-four completed 6 months and 194 completed 1 year. Significant improvements (p < .05) were found at 6 months for four health status measures, six health behaviors, self-efficacy, and visits to emergency departments. At 12 months, five health status indicators, six health behaviors, self-efficacy, and visits to emergency departments remained significant. Satisfaction with health care trended toward significance. DISCUSSION: The peer led online program was both acceptable and useful for this population. It appeared to decrease symptoms, improve health behaviors, self-efficacy, and reduce health care utilization up to 1 year. This intervention also has large potential implications for the use of a public health education model for reaching large numbers of people. It demonstrates that an Internet self management program, which includes social media, can reach rural and underserved people as well as be effective and reduce health care costs. If this intervention can be brought to scale, it has the potential for improving the lives of large numbers of people with chronic illness. It represents a way the medical care and public health sectors can interact. PMID- 22491009 TI - Location, timing, and social structure patterns related to physical activity participation in weight loss programs. AB - Less than half of the adults in the United States meet national guidelines for physical activity. Physical activity programs can induce short-term improvements in physical activity. To develop effective interventions, researchers and practitioners should consider the timing, location, and social structure patterns of participants. Using a pretest, posttest study design, 329 adults in a weight loss program completed surveys on their patterns and physical activity participation. Men preferred weight lifting, cycling, and jogging, whereas women preferred walking and aerobics. Black participants preferred being active in the home. Additionally, participating in a mix of group and individual activities compared with individual-only activities was predictive of posttest moderate-to vigorous intensity and total physical activity. Providing a variety of activities for adults in both location and social structure may lead to sustained physical activity participation. PMID- 22491010 TI - Evaluation of deformable image registration and a motion model in CT images with limited features. AB - Deformable image registration (DIR) is increasingly used in radiotherapy applications and provides the basis for a previously described model of patient specific respiratory motion. We examine the accuracy of a DIR algorithm and a motion model with respiration-correlated CT (RCCT) images of software phantom with known displacement fields, physical deformable abdominal phantom with implanted fiducials in the liver and small liver structures in patient images. The motion model is derived from a principal component analysis that relates volumetric deformations with the motion of the diaphragm or fiducials in the RCCT. Patient data analysis compares DIR with rigid registration as ground truth: the mean +/- standard deviation 3D discrepancy of liver structure centroid positions is 2.0 +/- 2.2 mm. DIR discrepancy in the software phantom is 3.8 +/- 2.0 mm in lung and 3.7 +/- 1.8 mm in abdomen; discrepancies near the chest wall are larger than indicated by image feature matching. Marker's 3D discrepancy in the physical phantom is 3.6 +/- 2.8 mm. The results indicate that visible features in the images are important for guiding the DIR algorithm. Motion model accuracy is comparable to DIR, indicating that two principal components are sufficient to describe DIR-derived deformation in these datasets. PMID- 22491011 TI - The many functions of cohesin--different rings to rule them all? PMID- 22491012 TI - Phosphoproteomic analysis reveals that PP4 dephosphorylates KAP-1 impacting the DNA damage response. AB - Protein phosphatase PP4C has been implicated in the DNA damage response (DDR), but its substrates in DDR remain largely unknown. We devised a novel proteomic strategy for systematic identification of proteins dephosphorylated by PP4C and identified KRAB-domain-associated protein 1 (KAP-1) as a substrate. Ionizing radiation leads to phosphorylation of KAP-1 at S824 (via ATM) and at S473 (via CHK2). A PP4C/R3beta complex interacts with KAP-1 and silencing this complex leads to persistence of phospho-S824 and phospho-S473. We identify a new role for KAP-1 in DDR by showing that phosphorylation of S473 impacts the G2/M checkpoint. Depletion of PP4R3beta or expression of the phosphomimetic KAP-1 S473 mutant (S473D) leads to a prolonged G2/M checkpoint. Phosphorylation of S824 is necessary for repair of heterochromatic DNA lesions and similar to cells expressing phosphomimetic KAP-1 S824 mutant (S824D), or PP4R3beta-silenced cells, display prolonged relaxation of chromatin with release of chromatin remodelling protein CHD3. Our results define a new role for PP4-mediated dephosphorylation in the DDR, including the regulation of a previously undescribed function of KAP-1 in checkpoint response. PMID- 22491014 TI - The effect of a multifaceted educational intervention on medication preparation and administration errors in neonatal intensive care. AB - OBJECTIVE: To examine the effect of a multifaceted educational intervention on the incidence of medication preparation and administration errors in a neonatal intensive care unit (NICU). DESIGN: Prospective study with a preintervention and postintervention measurement using direct observation. SETTING: NICU in a tertiary hospital in the Netherlands. INTERVENTION: A multifaceted educational intervention including teaching and self-study. MAIN OUTCOME MEASURES: The incidence of medication preparation and administration errors. Clinical importance was assessed by three experts. RESULTS: The incidence of errors decreased from 49% (43-54%) (151 medications with one or more errors of 311 observations) to 31% (87 of 284) (25-36%). Preintervention, 0.3% (0-2%) medications contained severe errors, 26% (21-31%) moderate and 23% (18-28%) minor errors; postintervention, none 0% (0-2%) was severe, 23% (18-28%) moderate and 8% (5-12%) minor. A generalised estimating equations analysis provided an OR of 0.49 (0.29-0.84) for period (p=0.032), (route of administration (p=0.001), observer within period (p=0.036)). CONCLUSIONS: The multifaceted educational intervention seemed to have contributed to a significant reduction of the preparation and administration error rate, but other measures are needed to improve medication safety further. PMID- 22491013 TI - Disabled-2 (Dab2) inhibits Wnt/beta-catenin signalling by binding LRP6 and promoting its internalization through clathrin. AB - Canonical Wnt signalling requires caveolin-dependent internalization of low density lipoprotein receptor-related protein 6 (LRP6). Here we report that the tumour suppressor and endocytic adaptor disabled-2 (Dab2), previously described as an inhibitor of Wnt/beta-catenin signalling, selectively recruits LRP6 to the clathrin-dependent endocytic route, thereby sequestering it from caveolin mediated endocytosis. Wnt stimulation induces the casein kinase 2 (CK2)-dependent phosphorylation of LRP6 at S1579, promoting its binding to Dab2 and internalization with clathrin. LRP6 receptor mutant (S1579A), deficient in CK2 mediated phosphorylation and Dab2 binding, fails to associate with clathrin, and thus escapes the inhibitory effects of Dab2 on Wnt/beta-catenin signalling. Our data suggest that the S1579 site of LRP6 is a negative regulatory point during LRP6-mediated dorsoventral patterning in zebrafish and in allograft mouse tumour models. We conclude that the tumour suppressor functions of Dab2 involve modulation of canonical Wnt signalling by regulating the endocytic fate of the LRP6 receptor. PMID- 22491015 TI - The 3:1 is superior to a 15:2 ratio in a newborn manikin model in terms of quality of chest compressions and number of ventilations. AB - BACKGROUND: Most cases of delivery room cardiopulmonary arrest result from an asphyxial process. Experimental evidence supports an important role for ventilation during asphyxial arrest. The optimal compression: ventilation (CV) ratio remains unclear and recommendations for newborns have varied from 3:1, 5:1 and 15:2. OBJECTIVE: Compare 3:1, 5:1 and 15: 2 CV ratios using the two-thumb technique in relationship to depth of compressions, decay of compression depth over time, compression rates and breaths delivered. METHODS: Thirty-two subjects, physicians and neonatal nurses, participated with compressions performed on a manikin. Evaluations included 2 min of compressions using 3:1, 5:1 and 15:2 CV ratios. RESULTS: Compression depth was comparable between groups. By paired analysis per subject, the depth was only greater for 3:1 versus 15:2 (ie, 0.91+/ 2.2 mm) (p=0.01) and greater for women than men. Comparing the initial and second minute of compressions, no decay in compression depth for 3:1 ratio was noted, however significant decay was observed for 5:1 and 15:2 ratios (p<0.05). The compression rates were least and ventilations breaths were highest for 3:1 as opposed to the other ratios (p<0.05). CONCLUSIONS: Providers using a 3:1 versus 15:2 achieve a greater depth of compressions over 2 min with a greater difference noted in women. More consistent compression depth over time was achieved with 3:1 as opposed to the other ratios. Thus, the 3:1 ratio is appropriate for newly born infants requiring resuscitation. PMID- 22491016 TI - In vivo electroporation of morpholinos into the regenerating adult zebrafish tail fin. AB - Certain species of urodeles and teleost fish can regenerate their tissues. Zebrafish have become a widely used model to study the spontaneous regeneration of adult tissues, such as the heart, retina, spinal cord, optic nerve, sensory hair cells, and fins. The zebrafish fin is a relatively simple appendage that is easily manipulated to study multiple stages in epimorphic regeneration. Classically, fin regeneration was characterized by three distinct stages: wound healing, blastema formation, and fin outgrowth. After amputating part of the fin, the surrounding epithelium proliferates and migrates over the wound. At 33 degrees C, this process occurs within six hours post-amputation (hpa, Figure 1B). Next, underlying cells from different lineages (ex. bone, blood, glia, fibroblast) re-enter the cell cycle to form a proliferative blastema, while the overlying epidermis continues to proliferate (Figure 1D). Outgrowth occurs as cells proximal to the blastema re-differentiate into their respective lineages to form new tissue (Figure 1E). Depending on the level of the amputation, full regeneration is completed in a week to a month. The expression of a large number of gene families, including wnt, hox, fgf, msx, retinoic acid, shh, notch, bmp, and activin-betaA genes, is up-regulated during specific stages of fin regeneration. However, the roles of these genes and their encoded proteins during regeneration have been difficult to assess, unless a specific inhibitor for the protein exists, a temperature-sensitive mutant exists or a transgenic animal (either overexpressing the wild-type protein or a dominant-negative protein) was generated. We developed a reverse genetic technique to quickly and easily test the function of any gene during fin regeneration. Morpholino oligonucleotides are widely used to study loss of specific proteins during zebrafish, Xenopus, chick, and mouse development. Morpholinos basepair with a complementary RNA sequence to either block pre-mRNA splicing or mRNA translation. We describe a method to efficiently introduce fluorescein-tagged antisense morpholinos into regenerating zebrafish fins to knockdown expression of the target protein. The morpholino is micro-injected into each blastema of the regenerating zebrafish tail fin and electroporated into the surrounding cells. Fluorescein provides the charge to electroporate the morpholino and to visualize the morpholino in the fin tissue. This protocol permits conditional protein knockdown to examine the role of specific proteins during regenerative fin outgrowth. In the Discussion, we describe how this approach can be adapted to study the role of specific proteins during wound healing or blastema formation, as well as a potential marker of cell migration during blastema formation. PMID- 22491017 TI - An individual coding polymorphism and the haplotype of the SPARC gene predict gastric cancer recurrence. AB - The 5-year survival rate for gastric adenocarcinoma (GA) remains only 40% and biomarkers to identify patients at high risk of tumor recurrence are urgently needed. Secreted protein acidic and rich in cysteine (SPARC) is an extracellular matrix glycoprotein that mediates cell matrix interactions, and upregulation of SPARC can promote tumor progression and metastasis. This study investigated whether single-nucleotide polymorphisms (SNPs) in SPARC impact the prognosis of GA. Blood or formalin-fixed, paraffin-embedded tissues were obtained from 137 GA patients at the University of Southern California and Memorial Sloan-Kettering Cancer Center medical facilities. DNA was isolated and five SNPs in the SPARC 3' untranslated region (UTR) were evaluated by DNA sequencing or PCR-restriction fragment length polymorphism. Associations between SNPs and time to tumor recurrence (TTR) were analyzed using Kaplan-Meier curves, log-rank tests, and likelihood-ratio test within logistic or Cox regression model as appropriate. Patients carrying at least one G allele of the SPARC rs1059829 polymorphism (GG, AG) showed a median TTR of 3.7 years compared with 2.1 years TTR for patients with AA (hazard ratio (HR) 0.57; P=0.033). In a multivariate analysis adjusted for T and N category as covariates and stratified by race, hospital and chemotherapy, patients with at least one SPARC rs1059829 G allele (GG, AG) remained significantly associated with superior TTR than patients with AA genotype (adjusted P=0.026). In addition, patients harboring the G-A-A haplotype had the highest risk of tumor recurrence (HR 1.892; adjusted P=0.016). Our findings suggest that SPARC 3'-UTR SNPs may be useful in predicting GA patients at increased risk of recurrence. PMID- 22491018 TI - Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease affecting the joints. A heterogeneous response to available therapies demonstrates the need to identify those patients likely to benefit from a particular therapy. Our objective was to identify genetic factors associated with response to tocilizumab, a humanized monoclonal antibody targeting the interleukin (IL)-6 receptor, recently approved for treating RA. We report the first genome-wide association study on the response to tocilizumab in 1683 subjects with RA from six clinical studies. Putative associations were identified with eight loci, previously unrecognized as linked to the IL-6 pathway or associated with RA risk. This study suggests that it is unlikely that a major genetic determinant of response exists, and it illustrates the complexity of performing genome-wide association scans in clinical trials. PMID- 22491020 TI - Testing, testing, testing. PMID- 22491019 TI - Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes. AB - To determine CYP2C19 and CYP2C8 allele frequencies, 28 coding and/or functional variants were genotyped in 1250 African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish (AJ) individuals. The combined CYP2C19 variant allele frequencies ranged from ~0.30 to 0.41; however, the CYP2C8 frequencies were much lower (~0.04-0.13). After incorporating previously reported CYP2C9 genotyping results from these populations (36 total CYP2C variants), 16 multi-ethnic CYP2C haplotypes were inferred with frequencies >0.5%. Notably, the 2C19*17-2C9*1-2C8*2 haplotype was identified among African-Americans (8%) and Hispanics (2%), indicating that CYP2C19*17 does not always tag a CYP2C haplotype that encodes efficient CYP2C-substrate metabolism. The 2C19*1-2C9*2-2C8*3 haplotype was identified in all populations except African-Americans and additional novel haplotypes were identified in selected populations (for example, 2C19*2-2C9*1 2C8*4 and 2C19*4B-2C9*1-2C8*1), together indicating that both CYP2C19*17 and *2 can be linked with other CYP2C loss-of-function alleles. These results have important implications for pharmacogenomic association studies involving the CYP2C locus and are clinically relevant when administering CYP2C-substrate medications. PMID- 22491021 TI - Brainstem sensing of meal-related signals in energy homeostasis. AB - The dorsovagal complex comprises: (1) a chemosensory structure, the area postrema (AP), (2) a center for integrating distension, mechanosensory and other inputs from the viscera, the nucleus of the tractus solitarius (NTS), and (3) a center to integrate motor and secretory drive to the viscera, the dorsal motor nucleus of the vagus (DMX). There is recent evidence for considerable autonomy of dorsovagal reflexes traversing this loop in ingestive control, especially in meal termination/anorexic responses, and in other controls on nutrient flux. The characteristics of this system, including (1) activation of several parallel effector pathways, and (2) glucose-sensitivity (hypoglycemic override) have profound therapeutic implications for anti-diabetic and anti-obesity drug development. Agents acting via the brain structures similar to those activated by amylin promise efficacy via multiple effectors, but, via glucose-dependence of effects, without increased risk of hypoglycemia. Several peptides, including those secreted in response to meals, are sensed at area postrema, and because they degrade to innocuous metabolites (amino acids) are thereby candidates as safe and effective drugs. Recently developed GLP-1 agonists and amylin agonists are examples of the therapeutic potential of such agents for metabolic diseases. Others in development include PYY agonists and MC4 agonists. Especially promising may be combinations of peptides and/or their analogs. Certain pairs of peptides, including those acting via the dorsovagal complex, exhibit surprising synergies (eg amylin + CCK (Bhavsar et al., 1998), amylin + leptin (Roth et al., 2008), CCK + glucagon + bombesin (Hinton et al., 1986), PYY and GLP-1 (Paulik et al., 2011)). Peptide combinations may thus attain transformational efficacy without invoking burdensome toxic risk. This article is part of a Special Issue entitled 'Central Control of Food Intake'. PMID- 22491023 TI - Actions of Xanthurenic acid, a putative endogenous Group II metabotropic glutamate receptor agonist, on sensory transmission in the thalamus. AB - Xanthurenic acid (XA), a molecule arising from tryptophan metabolism by transamination of 3-hydroxykynurenine, has recently been identified as an endogenous Group II (mGlu2 and mGlu3) metabotropic glutamate (mGlu) receptor ligand in vitro. Impairments in Group II mGlu receptor expression and function have been implicated in the pathophysiology of schizophrenia, as have multiple steps in the kynurenine metabolism pathway. Therefore, we examined XA in vivo to further investigate its potential as a Group II mGlu receptor ligand using a preparation that has been previously demonstrated to efficiently reveal the action of other Group II mGlu receptor ligands in vivo. Extracellular single neurone recordings were made in the rat ventrobasal thalamus (VB) in conjunction with iontophoresis of agonists, an antagonist and a positive allosteric modulator and/or intravenous (i.v.) injection of XA. We found the XA effect on sensory inhibition, when applied iontophoretically and i.v., was similar to that of other Group II mGlu receptor agonists in reducing inhibition evoked in the VB from the thalamic reticular nucleus upon physiological sensory stimulation. Furthermore, we postulate that XA may be the first potential endogenous allosteric agonist (termed 'endocoid') for the mGlu receptors. As the Group II receptors and kynurenine metabolism pathway have both been heavily implicated in the pathophysiology of schizophrenia, XA could play a pivotal role in antipsychotic research as this potential endocoid represents both a convergence within these two biological parameters and a novel class of Group II mGlu receptor ligand. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID- 22491022 TI - Inhibition of T-type calcium current in rat thalamocortical neurons by isoflurane. AB - Thalamocortical (TC) neurons provide the major sensory input to the mammalian somatosensory cortex. Decreased activity of these cells may be pivotal in the ability of general anesthetics to induce loss of consciousness and promote sleep (hypnosis). T-type voltage-gated calcium currents (T-currents) have a key function regulating the cellular excitability of TC neurons and previous studies have indicated that volatile general anesthetics may alter the excitability of these neurons. Using a patch-clamp technique, we investigated the mechanisms whereby isoflurane, a common volatile anesthetic, modulates isolated T-currents and T-current-dependent excitability of native TC neurons in acute brain slices of the rat. In voltage-clamp experiments, we found that isoflurane strongly inhibited peak amplitude of T-current, yielding an IC(50) of 1.1 vol-% at physiological membrane potentials. Ensuing biophysical studies demonstrated that inhibition was more prominent at depolarized membrane potentials as evidenced by hyperpolarizing shifts in channel availability curves. In current-clamp experiments we found that isoflurane decreased the rate of depolarization of low threshold-calcium spikes (LTCSs) and consequently increased the latency of rebound spike firing at the same concentrations that inhibited isolated T currents. This effect was mimicked by a novel selective T-channel blocker 3,5 dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4 ylmethyl]-benzamide (TTA-P2). In contrast, isoflurane and TTA-P2 had minimal effect on resting membrane potential and cell input resistance. We propose that the clinical properties of isoflurane may at least partly be provided by depression of thalamic T-currents. PMID- 22491024 TI - Synergy between L-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: implications for Parkinson's disease treatment and dyskinesia. AB - Group III metabotropic glutamate (mGlu) receptors are localized in presynaptic terminals within basal ganglia (BG) circuitry that become hyperactive due to dopamine depletion in Parkinson's disease (PD). For this reason, group III mGlu receptors, in particular mGlu4, have been considered as key strategic targets for non-dopaminergic pharmacological treatments aimed at modulating these synapses, without producing the well known side-effects of l-DOPA, in particular the highly disabling l-DOPA-induced dyskinesia (LID). Herein we add physiological and functional support to this hypothesis using Lu AF21934, a novel selective and brain-penetrant mGlu4 receptor positive allosteric modulator (PAM) tool compound. By in vitro electrophysiological recordings we demonstrate that Lu AF21934 inhibits corticostriatal synaptic transmission and enhances the effect of the orthosteric mGlu4 receptor-preferred agonist LSP1-2111. In naive rats, Lu AF21934 dose-dependently (10 and 30 mg/kg) alleviated haloperidol-induced catalepsy. In hemiparkinsonian rats (unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta), Lu AF21934 alone did not affect akinesia at the doses tested (10 and 30 mg/kg). However, when Lu AF21934 was combined with sub threshold doses of l-DOPA (1 and 5 mg/kg), it acted synergistically in alleviating akinesia in a dose-dependent manner and, notably, also reduced the incidence of LID but not its severity. Interestingly, these effects occurred at Lu AF21934 brain free concentrations that showed functional activity in in vitro screens (calcium flux and electrophysiology assays). These results support the potential for antiparkinsonian clinical use of a combined treatment consisting in l-DOPA and a mGlu4 receptor PAM to reduce efficacious l-DOPA doses (generally known as l-DOPA sparing), while maintaining the same benefit on PD motor troubles, and at the same time minimizing the development of LID. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID- 22491025 TI - The duration of acute health problems in people involved with the cleanup operation of the Hebei Spirit oil spill. AB - The authors investigated the duration of health problems of people involved with cleanup efforts for the Hebei Spirit oil spill, which occurred in December 2007 in Taean County, South Korea. The study identified risk factors correlated with the continuation of symptoms. Approximately one year after the accident, 442 people who had participated in the cleanup operation were examined. Data regarding demographic information, risk factors, and the continuation and duration of any symptoms were obtained. Eye symptoms (9.7 months), headaches (8.4 months), skin symptoms (8.3 months), and neurovestibular symptoms (6.9 months) had a relatively longer duration than did back pain (1.8 months) or respiratory symptoms (2.1 months). In particular, the remission of headaches had a negative correlation with female gender (HR 0.57, 0.34-0.95, 95% CI), and remission of eye symptoms had a negative correlation with the total hours of daily participation in the cleanup operation (HR 0.24, 0.06-0.95, 95% CI). PMID- 22491026 TI - In vitro selection of proteins via emulsion compartments. AB - In vitro compartmentalization (IVC) is a method to generate numerous, small, aqueous compartments (up to 10(10) compartments per ml) by mixing water, surfactants, and oil. The water phase is surrounded by surfactants and an oil phase, and to a first approximation each water-in-oil compartment is like an artificial cell. By introducing single genes into compartments that are competent for transcription and translation, these cell-like compartments can synthesize RNA protein variants in libraries. Screening or selecting for function has in turn led to schemes for the directed evolution of biomolecules. However, IVC selections can cover larger library sizes, and provide greater control over selection conditions and stringencies. The key issue in designing and executing IVC selections is how to couple genotype and phenotype, and in this review we have organized and presented a variety of mechanisms by which proteins and RNA can attach to or amplify their own templates following emulsification and selection. PMID- 22491027 TI - Stemness as a cell default state. PMID- 22491028 TI - Back down to Earth. Even if it has not yet lived up to its promises, systems biology has now matured and is about to deliver its first results. PMID- 22491030 TI - The new geography of scientific collaborations. Changing patterns in the geography of science pose ethical challenges for collaborations between established and emerging scientific powers. PMID- 22491029 TI - Mitotic spindle orientation can direct cell fate and bias Notch activity in chick neural tube. AB - Inheritance of apical membrane is proposed to maintain vertebrate neural stem cell proliferation. However, evidence for this is contradictory. Using direct clonal analysis and live imaging in chick neural tube, we show that divisions that separate apical and basal components generate an apical daughter, which becomes a neuron, and a basal daughter, which rapidly re-establishes apico-basal polarity and divides again. Using a recently described real-time reporter of Notch activity, we confirm progenitor status and demonstrate that division orientation can influence Notch signalling. In addition, we reveal loss of apical complex proteins on neuronal differentiation onset, suggesting that removal of this inherited complex is part of the neuronal differentiation mechanism. These findings reconcile contradictory data, link asymmetric division to Notch signalling dynamics and identify apical complex loss as a new step towards neuronal differentiation. PMID- 22491033 TI - Sperm counts and fertility in men: a rocky road ahead. Science & Society Series on Sex and Science. PMID- 22491032 TI - Enhancers: emerging roles in cell fate specification. AB - Enhancers are regulatory DNA elements that dictate the spatial and temporal patterns of gene expression during development. Recent evidence suggests that the distinct chromatin features of enhancer regions provide the permissive landscape required for the differential access of diverse signalling molecules that drive cell-specific gene expression programmes. The epigenetic patterning of enhancers occurs before cell fate decisions, suggesting that the epigenetic information required for subsequent differentiation processes is embedded within the enhancer element. Lineage studies indicate that the patterning of enhancers might be regulated by the intricate interplay between DNA methylation status, the binding of specific transcription factors to enhancers and existing histone modifications. In this review, we present insights into the mechanisms of enhancer function, which might ultimately facilitate cell reprogramming strategies for use in regenerative medicine. PMID- 22491034 TI - Toward automatic detection of vessel stenoses in cerebral 3D DSA volumes. AB - Vessel diseases are a very common reason for permanent organ damage, disability and death. This fact necessitates further research for extracting meaningful and reliable medical information from the 3D DSA volumes. Murray's law states that at each branch point of a lumen-based system, the sum of the minor branch diameters each raised to the power x, is equal to the main branch diameter raised to the power x. The principle of minimum work and other factors like the vessel type, impose typical values for the junction exponent x. Therefore, deviations from these typical values may signal pathological cases. In this paper, we state the necessary and the sufficient conditions for the existence and the uniqueness of the solution for x. The second contribution is a scale- and orientation- independent set of features for stenosis classification. A support vector machine classifier was trained in the space of these features. Only one branch was misclassified in a cross validation on 23 branches. The two contributions fit into a pipeline for the automatic detection of the cerebral vessel stenoses. PMID- 22491035 TI - Functional determinants of temperature adaptation in enzymes of cold- versus warm adapted mussels (Genus Mytilus). AB - Temperature is a strong selective force on the evolution of proteins due to its effects on higher orders of protein structure and, thereby, on critical protein functions like ligand binding and catalysis. Comparisons among orthologous proteins from differently thermally adapted species show consistent patterns of adaptive variation in function, but few studies have examined functional adaptation among multiple structural families of proteins. Thus, with our present state of knowledge, it is difficult to predict what fraction of the proteome will exhibit adaptive variation in the face of temperature increases of a few to several degrees Celsius, that is, temperature increases of the magnitude predicted by models of global warming. Here, we compared orthologous enzymes of the warm-adapted Mediterranean mussel Mytilus galloprovincialis and the cold adapted Mytilus trossulus, a native of the North Pacific Ocean, species whose physiologies exhibit significantly different responses to temperature. We measured the effects of temperature on the kinetics (Michaelis-Menten constant K(m)) of five enzymes that are important for ATP generation and that represent distinct protein structural families. Among phosphoglucomutase (PGM), phosphoglucose isomerase (PGI), pyruvate kinase (PK), phosphoenolpyruvate carboxykinase (GTP) (PEPCK), and isocitrate dehydrogenase (NADP) (IDH), only IDH orthologs showed significantly different thermal responses of K(m) between the two species. The K(m) of isocitrate of M. galloprovincialis-IDH was intrinsically lower and more thermally stable than that of M. trossulus-IDH and thus had higher substrate affinity at high temperatures. Two amino acid substitutions account for the functional differences between IDH orthologs, one of which allows for more hydrogen bonds to form near the mobile region of the active site in M. galloprovincialis-IDH. Taken together, our findings cast light on the targets of adaptive evolution in the context of climate change; only a minority of proteins might adapt to small changes in temperature, and these adaptations may involve only small changes in sequence. PMID- 22491036 TI - Modeling protein evolution with several amino acid replacement matrices depending on site rates. AB - Most protein substitution models use a single amino acid replacement matrix summarizing the biochemical properties of amino acids. However, site evolution is highly heterogeneous and depends on many factors that influence the substitution patterns. In this paper, we investigate the use of different substitution matrices for different site evolutionary rates. Indeed, the variability of evolutionary rates corresponds to one of the most apparent heterogeneity factors among sites, and there is no reason to assume that the substitution patterns remain identical regardless of the evolutionary rate. We first introduce LG4M, which is composed of four matrices, each corresponding to one discrete gamma rate category (of four). These matrices differ in their amino acid equilibrium distributions and in their exchangeabilities, contrary to the standard gamma model where only the global rate differs from one category to another. Next, we present LG4X, which also uses four different matrices, but leaves aside the gamma distribution and follows a distribution-free scheme for the site rates. All these matrices are estimated from a very large alignment database, and our two models are tested using a large sample of independent alignments. Detailed analysis of resulting matrices and models shows the complexity of amino acid substitutions and the advantage of flexible models such as LG4M and LG4X. Both significantly outperform single-matrix models, providing gains of dozens to hundreds of log likelihood units for most data sets. LG4X obtains substantial gains compared with LG4M, thanks to its distribution-free scheme for site rates. Since LG4M and LG4X display such advantages but require the same memory space and have comparable running times to standard models, we believe that LG4M and LG4X are relevant alternatives to single replacement matrices. Our models, data, and software are available from http://www.atgc-montpellier.fr/models/lg4x. PMID- 22491037 TI - Long-lived dichotomous lineages of the proteasome subunit beta type 8 (PSMB8) gene surviving more than 500 million years as alleles or paralogs. AB - On an evolutionary time scale, polymorphic alleles are believed to have a short life, persisting at most tens of millions of years even under long-term balancing selection. Here, we report highly diverged trans-species dimorphism of the proteasome subunit beta type 8 (PSMB8) gene, which encodes a catalytic subunit of the immunoproteasome responsible for the generation of peptides presented by major histocompatibility complex (MHC) class I molecules, in lower teleosts including Cypriniformes (zebrafish and loach) and Salmoniformes (trout and salmon), whose last common ancestor dates to 300 Ma. Moreover, phylogenetic analyses indicated that these dimorphic alleles share lineages with two shark paralogous genes, suggesting that these two lineages have been maintained for more than 500 My either as alleles or as paralogs, and that conversion between alleles and paralogs has occurred at least once during vertebrate evolution. Two lineages termed PSMB8A and PSMB8F show an A(31)F substitution that would probably affect their cleaving specificity, and whereas the PSMB8A lineage has been retained by all analyzed jawed vertebrates, the PSMB8F lineage has been lost by most jawed vertebrates except for cartilaginous fish and basal teleosts. However, a possible functional equivalent of the PSMB8F lineage has been revived as alleles within the PSMB8A lineage at least twice during vertebrate evolution in the amphibian Xenopus and teleostean Oryzias species. Dynamic evolution of the PSMB8 polymorphism through long-term persistence, loss, and regaining of dimorphism and conversion between alleles and paralogs implies the presence of strong selective pressure for functional polymorphism of this gene. PMID- 22491040 TI - Measuring health literacy in individuals with diabetes: a systematic review and evaluation of available measures. AB - OBJECTIVE: To identify instruments used to measure health literacy and numeracy in people with diabetes; evaluate their use, measurement scope, and properties; discuss their strengths and weaknesses; and propose the most useful, reliable, and applicable measure for use in research and practice settings. METHODS: A systematic literature review was conducted to identify the instruments. Nutbeam's domains of health literacy and a diabetes health literacy skill set were used to evaluate the measurement scope of the identified instruments and to evaluate their applicability in people with diabetes. RESULTS: Fifty-six studies were included, from which one diabetes-specific (LAD) and eight generic measures of health literacy (REALM, REALM-R, TOFHLA, s-TOFHLA, NVS, 3-brief SQ, 3-level HL Scale, SILS) and one diabetes-specific (DNT) and two generic measures of numeracy (SNS, WRAT) were identified. These instruments were categorized into direct measures, that is, instruments that assess the performance of individuals on health literacy skills and indirect measures that rely on self-report of these skills. The most commonly used instruments measure selective domains of health literacy, focus mainly on reading and writing skills, and do not address other important skills such as verbal communication, health care system navigation, health-related decision making, and numeracy. The structure, mode, and length of administration and measurement properties were found to affect the applicability of these instruments in clinical and research settings. Indirect self- or clinician-administered measures are the most useful in both clinical and research settings. CONCLUSION: This review provides an evaluation of available health literacy measures and guidance to practitioners and researchers for selecting the appropriate measures for use in clinical settings and research applications. PMID- 22491039 TI - Eye tracking young children with autism. AB - The rise of accessible commercial eye-tracking systems has fueled a rapid increase in their use in psychological and psychiatric research. By providing a direct, detailed and objective measure of gaze behavior, eye-tracking has become a valuable tool for examining abnormal perceptual strategies in clinical populations and has been used to identify disorder-specific characteristics, promote early identification, and inform treatment. In particular, investigators of autism spectrum disorders (ASD) have benefited from integrating eye-tracking into their research paradigms. Eye-tracking has largely been used in these studies to reveal mechanisms underlying impaired task performance and abnormal brain functioning, particularly during the processing of social information. While older children and adults with ASD comprise the preponderance of research in this area, eye-tracking may be especially useful for studying young children with the disorder as it offers a non-invasive tool for assessing and quantifying early-emerging developmental abnormalities. Implementing eye-tracking with young children with ASD, however, is associated with a number of unique challenges, including issues with compliant behavior resulting from specific task demands and disorder-related psychosocial considerations. In this protocol, we detail methodological considerations for optimizing research design, data acquisition and psychometric analysis while eye-tracking young children with ASD. The provided recommendations are also designed to be more broadly applicable for eye tracking children with other developmental disabilities. By offering guidelines for best practices in these areas based upon lessons derived from our own work, we hope to help other investigators make sound research design and analysis choices while avoiding common pitfalls that can compromise data acquisition while eye-tracking young children with ASD or other developmental difficulties. PMID- 22491038 TI - Predictors of tobacco outlet density nationwide: a geographic analysis. AB - OBJECTIVE: To elucidate how demographics of US Census tracts are related to tobacco outlet density (TOD). METHOD: The authors conducted a nationwide assessment of the association between socio-demographic US Census indicators and the density of tobacco outlets across all 64,909 census tracts in the continental USA. Retail tobacco outlet addresses were determined through North American Industry Classification System codes, and density per 1000 population was estimated for each census tract. Independent variables included urban/rural; proportion of the population that was black, Hispanic and women with low levels of education; proportion of families living in poverty and median household size. RESULTS: In a multivariate analysis, there was a higher TOD per 1000 population in urban than in rural locations. Furthermore, higher TOD was associated with larger proportions of blacks, Hispanics, women with low levels of education and with smaller household size. Urban-rural differences in the relation between demographics and TOD were found in all socio-demographic categories, with the exception of poverty, but were particularly striking for Hispanics, for whom the relation with TOD was 10 times larger in urban compared with rural census tracts. CONCLUSIONS: The findings suggest that tobacco outlets are more concentrated in areas where people with higher risk for negative health outcomes reside. Future studies should examine the relation between TOD and smoking, smoking cessation, as well as disease rates. PMID- 22491041 TI - If the choices are all the same, why not prefer the less-expensive option? PMID- 22491042 TI - Evidence and insights in the NCCN guidelines. PMID- 22491043 TI - A perspective on the evolution of management of cancer- and chemotherapy-induced anemia. PMID- 22491044 TI - Locally recurrent endometrial cancer: a case report. AB - Endometrial cancer is the most common malignancy of the female genital tract. It is typically a disease of postmenopausal women and often presents with postmenopausal vaginal bleeding. In 75% of cases, it is diagnosed at an early stage and is associated with better overall survival rates than many malignancies. The appropriate staging surgery for patients diagnosed with endometrial cancer is a total hysterectomy and bilateral salpingo-oophorectomy with pelvic and para-aortic lymphadenectomy. Adjuvant radiation therapy in early stage disease is associated with decreased rates of locoregional recurrences but does not improve overall survival. The role of chemotherapy is not well established for early-stage disease. Treatment recommendations for locoregional recurrence of endometrial cancer after hysterectomy are poorly defined and include tumor-directed radiation therapy, and/or chemotherapy, and/or surgical resection. Because the current guidelines are not specific, they are confusing to clinicians. To illustrate this, this report presents a patient who was diagnosed with stage IA endometrial cancer and developed vaginal cuff recurrence 3 months after surgery. PMID- 22491045 TI - Anal Carcinoma, Version 2.2012: featured updates to the NCCN guidelines. AB - The workup and management of squamous cell anal carcinoma, which represents the most common histologic form of the disease, are addressed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Anal Carcinoma. These NCCN Guidelines Insights provide a summary of major discussion points of the 2012 NCCN Anal Carcinoma Panel meeting. In summary, the panel made 4 significant changes to the 2012 NCCN Guidelines for Anal Carcinoma: 1) local radiation therapy was added as an option for the treatment of patients with metastatic disease; 2) multifield technique is now preferred over anteroposterior-posteroanterior (AP-PA) technique for radiation delivery and the AP-PA technique is no longer recommended as the standard of care; 3) PET/CT should now be considered for radiation therapy planning; and 4) a section on risk reduction was added to the discussion section. In addition, the panel discussed the use of PET/CT for the workup of anal canal cancer and decided to maintain the recommendation that it can be considered in this setting. They also discussed the use of PET/CT for the workup of anal margin cancer and for the assessment of treatment response. They reaffirmed their recommendation that PET/CT is not appropriate in these settings. PMID- 22491046 TI - Antiemesis. PMID- 22491047 TI - Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting. AB - Before the introduction of the serotonin receptor antagonists (5-HT3 receptor antagonists) in the early 1990s, limited effective options were available to prevent and treat chemotherapy-induced nausea and vomiting (CINV). In 1985, the FDA approved 2 cannabinoid derivatives, dronabinol and nabilone, for the treatment of CINV not effectively treated by other agents. Today, the standard of care for prevention of CINV for highly and moderately emetogenic chemotherapy is a 5-HT3 receptor antagonist, dexamethasone, with or without aprepitant or fosaprepitant. With the approval of safer and more effective agents, cannabinoids are not recommended as first-line treatment for the prevention of CINV and are reserved for patients with breakthrough nausea and vomiting. Because of medical and legal concerns, the use of marijuana is not recommended for management of CINV and is not part of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis. Although patients may like to pursue this treatment option in states that have approved the use of marijuana for medical purposes, its use remains legally and therapeutically controversial. PMID- 22491048 TI - Corticosteroids in the treatment of chemotherapy-induced nausea and vomiting. AB - Chemotherapy-induced nausea and vomiting (CINV) is one of the most feared side effects of cancer treatment, despite the advances over the past decades. Corticosteroids have been shown to be effective in the management of CINV. These agents are usually used in combination with serotonin antagonists and neurokinin 1 antagonists for highly or moderately emetogenic chemotherapy or as monotherapy for low-emetogenic chemotherapy. Consensus guidelines provide guidance regarding the scenarios in which corticosteroids are recommended. This article reviews the mechanism of action, role, and safety of corticosteroids in the management of CINV. PMID- 22491049 TI - Testicular cancer. PMID- 22491050 TI - Late cardiovascular toxicity following chemotherapy for germ cell tumors. AB - The introduction of cisplatin-based chemotherapy has transformed germ cell tumors (GCTs), the most common malignancy to affect young adult men, into a highly curable cancer, even in the setting of advanced disease. However, over the past decade, the success of these chemotherapy regimens in curing GCTs has been temporized by an increasing recognition of their important late toxicities, such as cardiovascular disease. The relative risk of coronary artery disease in this population is particularly elevated within the first 10 years of follow-up, when patients are still in their 30s and 40s, which are age groups often considered too young to experience cardiovascular events. Two hypotheses have been proposed to explain the association between chemotherapy and cardiovascular disease in this population. The direct hypothesis asserts that chemotherapy causes diffuse endothelial damage, including in the coronary arteries, gradually leading to cardiovascular disease. In contrast, the indirect hypothesis proposes that chemotherapy leads to an increased incidence of cardiovascular disease risk factors, such as hypertension, hyperlipidemia, and the metabolic syndrome, which in turn enhance the risk of cardiovascular disease. This article summarizes the data on the association between chemotherapy (predominantly cisplatin-based) and the development of cardiovascular disease among GCT survivors, and reviews the evidence supporting both mechanistic hypotheses. In addition, recommendations are provided for the management of GCT survivors who received cisplatin-based chemotherapy and are therefore at risk for cardiovascular toxicity. PMID- 22491051 TI - Second malignant neoplasms in testicular cancer survivors. AB - Second malignant neoplasms (SMNs) are a potentially life-threatening late effect of testicular cancer (TC) and its therapy. Although the increased risk for developing solid tumors among TC survivors is largely attributed to radiotherapy, chemotherapy may also be associated with excess risks. However, the baseline risks of developing site-specific SMNs in TC survivors have not yet been quantified, nor have interactions between treatments and other risk factors been elucidated. Studies to date report overall relative risks ranging from 1.4- to 2.8-fold for SMN in TC survivors, with significantly elevated risks apparent for more than 35 years. Analytic investigations show relationships between increasing radiation dose and/or field size and solid tumor risk. Small excess risks of leukemia follow treatment with either chemotherapy or radiotherapy. Recently, concern has been expressed about the increased risk of SMN from radiation exposure during imaging surveillance for recurrence. A small number of studies have examined this issue, generating inconclusive results. Given the current changes in TC treatment that result in lower radiation doses, in the future solid tumors will likely have a considerably lower impact on the lives of TC survivors, although diligent follow-up will be required to accurately quantify long-term risks and to ascertain risks associated with chemotherapy. PMID- 22491052 TI - Hypogonadism and infertility in testicular cancer survivors. AB - Testicular cancer is the most common cancer in men in their 20s and 30s, and has been considered a model of a curable neoplasm. The longer life expectancy of testicular cancer survivors makes minimizing the long-term health issues related to hypogonadism particularly important, and because testicular cancer affects men mostly in their reproductive years, infertility can also be a major concern. Hypogonadism, infertility, and testicular cancer have been associated with one another. These associations suggest the existence of common etiologic factors, including improper testicular development during fetal life. The effect of cancer treatment on testosterone, luteinizing hormone, and follicle-stimulating hormone levels, and on fertility and overall paternity rates among testicular cancer survivors, are potentially significant issues. As the biologic mechanisms underlying hypogonadism, infertility, and testicular cancer become clearer, more research is needed to provide clinicians with evidence-based guidelines for the management of testicular cancer survivors. PMID- 22491056 TI - Sensitivity to nonaccidental properties across various shape dimensions. AB - Nonaccidental properties (NAPs) are image properties that are invariant over orientation in depth and are distinguished from metric properties (MPs) that can change continuously with variations over depth orientation. To a large extent NAPs allow facile recognition of objects at novel viewpoints. Two match-to-sample experiments with 2D or 3D appearing geons assessed sensitivity to NAP vs. MP differences. A matching geon was always identical to the sample and the distractor differed from the matching geon in either a NAP or an MP on a single generalized cone dimension. For example, if the sample was a cylinder with a slightly curved axis, the NAP distractor would have a straight axis and the MP distractor would have an axis of greater curvature than the sample. Critically, the NAP and MP differences were scaled so that the MP differences were slightly greater according to pixel energy and Gabor wavelet measures of dissimilarity. Exp. 1 used a staircase procedure to determine the threshold presentation time required to achieve 75% accuracy. Exp. 2 used a constant, brief display presentation time with reaction times and error rates as dependent measures. Both experiments revealed markedly greater sensitivity to NAP over MP differences, and this was generally true for the individual dimensions. The NAP advantage was not reflected in the similarity computations of the C2 stage of HMAX, a widely cited model of later stage cortical ventral stream processing. PMID- 22491058 TI - Novel structural and functional insights into the MoxR family of AAA+ ATPases. AB - The MoxR family of AAA+ ATPases is widespread among bacteria and archaea, although their cellular functions are not well characterized. Based on recent studies, MoxR ATPases are proposed to have chaperone-like function for the maturation of specific protein complexes or for the insertion of cofactors into proteins. MoxR proteins have been found to be important modulators of multiple stress response pathways in different organisms. For example, the respective MoxR proteins have been found to play important roles in the cell envelope stress response in Rhizobium leguminosarum, in the oxidative stress, acid stress, and heat stress responses in Francisella tularensis, in the acid stress and stringent responses in Escherichia coli, in viral tail formation in the crenarchaeal Acidianus two-tailed virus, and in the utilization of carbon monoxide as the sole carbon source by the Gram-negative chemolithoautotrophe Oligotropha carboxidovorans. Recent structural studies on the MoxR proteins from E. coli and Cytophaga hutchinsonii show the unique spatial arrangement of the alphabetaalpha and all-alpha subdomains of the AAA+ domain in these proteins compared to the typical arrangement found in canonical AAA+ proteins such as HslU. The spatial organization of the subdomains in the AAA+ domain of MoxR proteins is similar to that found in the ATPase component of the magnesium chelatase complexes, possibly suggesting a similar mechanism of function. In this review, we provide an overview of the newly identified functions and the newly obtained structures of MoxR AAA+ ATPases. PMID- 22491057 TI - Survey sequencing reveals elevated DNA transposon activity, novel elements, and variation in repetitive landscapes among vesper bats. AB - The repetitive landscapes of mammalian genomes typically display high Class I (retrotransposon) transposable element (TE) content, which usually comprises around half of the genome. In contrast, the Class II (DNA transposon) contribution is typically small (<3% in model mammals). Most mammalian genomes exhibit a precipitous decline in Class II activity beginning roughly 40 Ma. The first signs of more recently active mammalian Class II TEs were obtained from the little brown bat, Myotis lucifugus, and are reflected by higher genome content (~5%). To aid in determining taxonomic limits and potential impacts of this elevated Class II activity, we performed 454 survey sequencing of a second Myotis species as well as four additional taxa within the family Vespertilionidae and an outgroup species from Phyllostomidae. Graph-based clustering methods were used to reconstruct the major repeat families present in each species and novel elements were identified in several taxa. Retrotransposons remained the dominant group with regard to overall genome mass. Elevated Class II TE composition (3-4%) was observed in all five vesper bats, while less than 0.5% of the phyllostomid reads were identified as Class II derived. Differences in satellite DNA and Class I TE content are also described among vespertilionid taxa. These analyses present the first cohesive description of TE evolution across closely related mammalian species, revealing genome-scale differences in TE content within a single family. PMID- 22491059 TI - Exploring structural and thermodynamic stabilities of human prion protein pathogenic mutants D202N, E211Q and Q217R. AB - The central event in the pathogenesis of prion protein (PrP) is a profound conformational change from its alpha-helical (PrP(C)) to its beta-sheet-rich isoform (PrP(Sc)). Many single amino acid mutations of PrP are associated with familial prion diseases, such as D202N, E211Q, and Q217R mutations located at the third native alpha-helix of human PrP. In order to explore the underlying structural and dynamic effects of these mutations, we performed all-atom molecular dynamics (MD) simulations for the wild-type (WT) PrP and its mutants. The obtained results indicate that these amino acid substitutions have subtle effects on the protein structures, but show large changes of the overall electrostatic potential distributions. We can infer that the changes of PrP electrostatic surface due to the studied mutations may influence the intermolecular interactions during the aggregation process. In addition, the mutations also affect the thermodynamic stabilities of PrP. PMID- 22491060 TI - Genetic and epigenetic analysis of non-small cell lung cancer with NotI microarrays. AB - This study aimed to clarify genetic and epigenetic alterations that occur during lung carcinogenesis and to design perspective sets of newly identified biomarkers. The original method includes chromosome 3 specific NotI-microarrays containing 180 NotI clones associated with genes for hybridization with 40 paired normal/tumor DNA samples of primary lung tumors: 28 squamous cell carcinomas (SCC) and 12 adenocarcinomas (ADC). The NotI-microarray data were confirmed by qPCR and bisulfite sequencing analyses. Forty-four genes showed methylation and/or deletions in more than 15% of non-small cell lung cancer (NSCLC) samples. In general, SCC samples were more frequently methylated/deleted than ADC. Moreover, the SCC alterations were observed already at stage I of tumor development, whereas in ADC many genes showed tumor progression specific methylation/deletions. Among genes frequently methylated/deleted in NSCLC, only a few were already known tumor suppressor genes: RBSP3 (CTDSPL), VHL and THRB. The RPL32, LOC285205, FGD5 and other genes were previously not shown to be involved in lung carcinogenesis. Ten methylated genes, i.e., IQSEC1, RBSP3, ITGA 9, FOXP1, LRRN1, GNAI2, VHL, FGD5, ALDH1L1 and BCL6 were tested for expression by qPCR and were found downregulated in the majority of cases. Three genes (RBSP3, FBLN2 and ITGA9) demonstrated strong cell growth inhibition activity. A comprehensive statistical analysis suggested the set of 19 gene markers, ANKRD28, BHLHE40, CGGBP1, RBSP3, EPHB1, FGD5, FOXP1, GORASP1/TTC21, IQSEC1, ITGA9, LOC285375, LRRC3B, LRRN1, MITF, NKIRAS1/RPL15, TRH, UBE2E2, VHL, WNT7A, to allow early detection, tumor progression, metastases and to discriminate between SCC and ADC with sensitivity and specificity of 80-100%. PMID- 22491061 TI - A multipurpose quality assurance phantom for the small animal radiation research platform (SARRP). AB - In this work, the suitability and performance of a mouse-size MOSFET (Mousefet) phantom is investigated for routine quality assurance (QA) of the small animal radiation research platform (SARRP). This Mousefet phantom is a simple construction consisting of five micro-MOSFETS custom integrated in a quincunx pattern within a tissue-equivalent phantom, allowing repeat/multiple QA tasks to be quickly performed in one experimental set-up. The Mousefet phantom is particularly evaluated for facilitating SARRP QA tasks which may warrant daily evaluation, including output constancy, isocenter congruency test and cone beam computed tomography (CBCT) image geometric accuracy. Results for the output constancy measurements showed a maximum daily variation of less than 2.6% for all MOSFETS, in consonance with observations from concurrent ion chamber measurements. It is also shown that the design of the Mousefet phantom allows the output check data to be used for prompt verification of beam energy and cone profile constancy. For the isocenter congruency test, it is demonstrated that the Mousefet phantom can detect 0.3 mm deviations of the CBCT isocenter from the radiation isocenter. Meanwhile, results for CBCT image geometric accuracy were consistently found to be within 2% of the expected value. Other CBCT image quality parameters could also be assessed in terms of image intensity constancy, noise and image uniformity. Overall, the results establish the Mousefet phantom as a simple and time-efficient multipurpose tool that could be employed effectively for routine QA of the SARRP. PMID- 22491063 TI - Male offspring production by asexual Potamopyrgus antipodarum, a New Zealand snail. AB - As only females contribute directly to population growth, sexual females investing equally in sons and daughters experience a two-fold cost relative to asexuals producing only daughters. Typically, researchers have focused on benefits of sex that can counter this 'cost of males' and thus explain its predominance. Here, we instead ask whether asexuals might also pay a cost of males by quantifying the rate of son production in 45 experimental populations ('lineages') founded by obligately asexual female Potamopyrgus antipodarum. This New Zealand snail is a powerful model for studying sex because phenotypically similar sexual and asexual forms often coexist, allowing direct comparisons between sexuals and asexuals. After 2 years of culture, 23 of the 45 lineages had produced males, demonstrating that asexual P. antipodarum can make sons. We used maximum-likelihood analysis of a model of male production in which only some lineages can produce males to estimate that ~50% of lineages have the ability to produce males and that ~5% of the offspring of male-producing lineages are male. Lineages producing males in the first year of the experiment were more likely to make males in the second, suggesting that some asexual lineages might pay a cost of males relative to other asexual lineages. Finally, we used a simple deterministic model of population dynamics to evaluate how male production affects the rate of invasion of an asexual lineage into a sexual population, and found that the estimated rate of male production by asexual P. antipodarum is too low to influence invasion dynamics. PMID- 22491062 TI - Magnitude and sign epistasis among deleterious mutations in a positive-sense plant RNA virus. AB - How epistatic interactions between mutations determine the genetic architecture of fitness is of central importance in evolution. The study of epistasis is particularly interesting for RNA viruses because of their genomic compactness, lack of genetic redundancy, and apparent low complexity. Moreover, interactions between mutations in viral genomes determine traits such as resistance to antiviral drugs, virulence and host range. In this study we generated 53 Tobacco etch potyvirus genotypes carrying pairs of single-nucleotide substitutions and measured their separated and combined deleterious fitness effects. We found that up to 38% of pairs had significant epistasis for fitness, including both positive and negative deviations from the null hypothesis of multiplicative effects. Interestingly, the sign of epistasis was correlated with viral protein-protein interactions in a model network, being predominantly positive between linked pairs of proteins and negative between unlinked ones. Furthermore, 55% of significant interactions were cases of reciprocal sign epistasis (RSE), indicating that adaptive landscapes for RNA viruses maybe highly rugged. Finally, we found that the magnitude of epistasis correlated negatively with the average effect of mutations. Overall, our results are in good agreement to those previously reported for other viruses and further consolidate the view that positive epistasis is the norm for small and compact genomes that lack genetic robustness. PMID- 22491064 TI - Epigenetic regulation of glucocorticoid receptor expression in aorta from mice with hyperhomocysteinemia. AB - Hyperhomocysteinemia (HHcy) is a risk factor for vascular disease but its underlying molecular pathology is not understood. Homocysteine is metabolically linked to the epigenetic process of DNA methylation. Tissue-specific changes in DNA methylation have been observed in HHcy but little is known about vascular tissue. The objective of this study was to determine if changes in the epigenetic regulation of glucocorticoid receptor (GR) expression (encoded by Nr3c1) in aorta are associated with HHcy. C57BL/6 mice heterozygous for disruption of the cystathionine-beta-synthase gene (Cbs+/-) and controls (Cbs+/+) were fed a control or high methionine/low folate (HH) diet to induce HHcy. Cbs+/- and Cbs+/+ fed the HH diet had higher plasma total homocysteine levels (19.9 +/- 3.2 and 7.0 +/- 0.9 MUM, respectively) than Cbs+/+ mice fed the control diet (2.7 +/- 0.2 MUM), and this was accompanied by lower Nr3c1 mRNA and lower GR protein in aorta. The Nr3c1 gene contains multiple first exons producing heterogeneous RNA transcripts expressed in a tissue-specific manner. We identified expression of two transcripts in aorta. Bisulfite pyrosequencing found increased methylation of the promoter regions for these transcripts at sites corresponding to Sp1 and Nrf1 binding sites. Chromatin immunoprecipitation found lower binding of Nrf1 to the Nr3c1 promoter but higher expression of Nrf1 protein in aorta from mice with HHcy. These findings show methylation and silencing of vascular Nr3c1 expression and suggest a role for epigenetic regulation of gene expression in HHcy. PMID- 22491066 TI - Interferon signatures in immune disorders and disease. AB - The interferon (IFN) family and the type-I IFNs specifically have an important and well-characterized role in antiviral defence, immune modulation and cell cycle control and are regularly applied in the clinical context. Advances in high content technologies have facilitated an enhanced understanding of the global IFN response capable of being induced. Recent application of these technologies is improving our understanding of the specificity and subtleties associated with this response. This review considers our current understanding of the temporal gene profile induced through IFN stimulation across a diversity of disease conditions including autoimmune diseases, bacterial and viral infections. Understanding these signatures, the disease-specific differences and the biological effects induced has the potential to facilitate IFN-driven therapeutic development. PMID- 22491067 TI - Keystone Symposia on Epigenomics and Chromatin Dynamics: Keystone resort, CO, January 17-22, 2012. AB - Keystone Symposia kicked off the start of 2012 with two joint meetings on Epigenomics and Chromatin Dynamics and a star-studded list of speakers. Held in Keystone, CO, January 17-22, and organized by Steven Jacobsen and Steven Henikoff and by Bradley Cairns and Genevieve Almouzni, respectively, there was plenty happening in these sessions that it did not seem to matter that the ski-slope conditions were not ideal. PMID- 22491068 TI - Multiple rearrangements in mitochondrial genomes of Isopoda and phylogenetic implications. AB - In this study, we analyse the evolutionary dynamics and phylogenetic implications of gene order rearrangements in five newly sequenced mitochondrial (mt) genomes and four published mt genomes of isopod crustaceans. The sequence coverage is nearly complete for four of the five newly sequenced species, with only the control region and some tRNA genes missing, while in Janira maculosa only two thirds of the genome could be determined. Mitochondrial gene order in isopods seems to be more plastic than that in other crustacean lineages, making all nine known mt gene orders different. Especially the asellote Janira is characterized by many autapomorphies. The following inferred ancestral isopod mt gene order exists slightly modified in modern isopods: nad1, tnrL1, rrnS, control region, trnS1, cob, trnT, nad5, trnF. We consider the inferred gene translocation events leading to gene rearrangements as valuable characters in phylogenetic analyses. In this first study covering major isopod lineages, potential apomorphies were identified, e.g., a shared relative position of trnR in Valvifera. We also report one of the first findings of homoplasy in mitochondrial gene order, namely a shared relative position of trnV in unrelated isopod lineages. In addition to increased taxon sampling secondary structure, modification in tRNAs and GC-skew inversion may be potentially fruitful subjects for future mt genome studies in a phylogenetic context. PMID- 22491065 TI - IL-6 triggers IL-21 production by human CD4+ T cells to drive STAT3-dependent plasma cell differentiation in B cells. AB - Interleukin (IL)-21-producing CD4(+)T cells are central to humoral immunity. Deciphering the signals that induce IL-21 production in CD4(+) T cells and those triggered by IL-21 in B cells are, therefore, of importance for understanding the generation of antibody (Ab) responses. Here, we show that IL-6 increased IL-21 production by human CD4(+) T cells, particularly in those that express the transcriptional regulator B cell lymphoma (BCL)6, which is required in mice for the development of C-X-C chemokine receptor type 5 (CXCR5(+)) IL-21-producing T follicular helper (T(FH)) cells. However, retroviral overexpression of BCL6 in total human CD4(+) T cells only transiently increased CXCR5, the canonical T(FH) defining surface marker. We show here that IL-21 was required for the induction of Ab production by IL-6. In IL-21-treated B cells, signal transducer and activator of transcription (STAT)3 was required for optimal immunoglobulin production and upregulation of PR domain containing 1 (PRDM1(+)), the master plasma cell factor. These results, therefore, demonstrate the critical importance of STAT3 activation in B cells during IL-21-driven humoral immunity and suggest that BCL6 expression, although not sufficient, may serve as a platform for the acquisition of a T(FH)-like phenotype by human CD4(+) T cells. PMID- 22491069 TI - Using directed phylogenetic networks to retrace species dispersal history. AB - Methods designed for inferring phylogenetic trees have been widely applied to reconstruct biogeographic history. Because traditional phylogenetic methods used in biogeographic reconstruction are based on trees rather than networks, they follow the strict assumption in which dispersal among geographical units have occurred on the basis of single dispersal routes across regions and are, therefore, incapable of modelling multiple alternative dispersal scenarios. The goal of this study is to describe a new method that allows for retracing species dispersal by means of directed phylogenetic networks obtained using a horizontal gene transfer (HGT) detection method as well as to draw parallels between the processes of HGT and biogeographic reconstruction. In our case study, we reconstructed the biogeographic history of the postglacial dispersal of freshwater fishes in the Ontario province of Canada. This case study demonstrated the utility and robustness of the new method, indicating that the most important events were south-to-north dispersal patterns, as one would expect, with secondary faunal interchange among regions. Finally, we showed how our method can be used to explore additional questions regarding the commonalities in dispersal history patterns and phylogenetic similarities among species. PMID- 22491070 TI - Molecular phylogenetics of the Brazilian giant bromeliads (Alcantarea, Bromeliaceae): implications for morphological evolution and biogeography. AB - The genus Alcantarea comprises near 30 species endemic to rocky outcrops from eastern Brazil. Most species are ornamental and several are threatened due to habitat loss and over collection. In this paper we examine the phylogenetics of Alcantarea and its relationship with the Brazilian members of Vriesea, a genus of which Alcantarea has been treated as a subgenus. We discuss the morphological evolution of the stamen position and its implication for pollination and the occurrence of Alcantarea in the Espinhaco mountain range rocky savanna-like habitat vegetation. DNA sequence data derived from two plastid markers (trnK rps16, trnC-petN) and from a low copy nuclear gene (Floricaula/Leafy) together with 20 nuclear microsatellite loci were the data source to perform analyses and construct phylogenetic and Neighbor Joining trees for the genus. Alcantarea is well supported as monophyletic in both Bayesian and parsimony analyses, but sections of Vriesea, represented by the eastern Brazilian species, appear paraphyletic. Microsatellites delimit geographically isolated species groups. Nevertheless individuals belonging to a single species may appear related to distinct clusters of species, suggesting that hybridization and/or homoplasy and/or incomplete lineage sorting are also influencing the analysis based on such markers and may be the reasons for some unexpected results. Alcantarea brasiliana is hypothesized as putative hybrid between A. imperialis and A. geniculata. Spreading stamens, a morphological floral characteristic assumed to be related to Chiropterophily, apparently evolved multiple times within the genus, and invasion of rocky savanna-like habitat vegetation by Atlantic rainforest ancestors seems to have occurred multiple times as well. PMID- 22491071 TI - Multiple gene sequences resolve phylogenetic relationships in the shorebird suborder Scolopaci (Aves: Charadriiformes). AB - Shorebirds (Charadriiformes) are a diverse assemblage of species renowned for their variation in behavior, morphology, and life-history traits, but comparative studies of trait variation remain limited by the lack of a well-supported phylogeny based on DNA sequences. In this study we build upon previous shorebird phylogenies to construct the first sequence-based species-level phylogeny for the Scolopaci, one of three shorebird suborders. We sampled 84 species in the Scolopaci, and collected data for five genes (one nuclear and four mitochondrial) via PCR and sequencing or from GenBank. The phylogeny was estimated using Bayesian inference on a partitioned dataset of 6365 aligned base pairs, and was well-supported except for the radiations within Tringa and Calidris. The shanks and phalaropes are sister to the snipes, woodcocks and dowitchers, which in turn are sister to the sandpipers. The godwits and curlews are successive sister groups to these clades, and the morphologically disparate taxa (jacanas, painted snipes, seedsnipes, and the Plains-wanderer) are the basal sister-group in the Scolopaci. We show that Tringa, Gallinago, and Calidris are paraphyletic assemblages, and thus are in need of taxonomic revision. The clade of Calidridine sandpipers has very short internal branches indicative of a relatively recent rapid radiation, and will require a gene tree/species tree approach to resolve relationships among species. PMID- 22491072 TI - Interior tomography in x-ray differential phase contrast CT imaging. AB - Differential phase contrast computed tomography (DPC-CT) is an x-ray imaging method that uses the wave properties of imaging photons as the contrast mechanism. It has been demonstrated that DPC images can be obtained using a conventional x-ray tube and a Talbot-Lau-type interferometer. Due to the limited size of the gratings, current data acquisition systems only offer a limited field of view, and thus are prone to data truncation. As a result, the reconstructed DPC-CT image may suffer from image artifacts and increased inaccuracy in the reconstructed image values. In this paper, we demonstrate that a small region of interest (ROI) within a large object can be accurately and stably reconstructed using fully truncated projection datasets provided that a priori information on electron density is known for a small region inside the ROI. The method reconstructs an image iteratively to satisfy a group of physical conditions by using a projection onto convex set (POCS) approach. In this work, this POCS algorithm is validated using both numerical simulations and physical phantom experimental data. In both cases, the root mean square error is reduced by an order of magnitude with respect to the truncated analytic reconstructions. Truncation artifacts observed in the latter reconstructions are eliminated using the POCS algorithm. PMID- 22491073 TI - Dissection of adult mouse utricle and adenovirus-mediated supporting-cell infection. AB - Hearing loss and balance disturbances are often caused by death of mechanosensory hair cells, which are the receptor cells of the inner ear. Since there is no cell line that satisfactorily represents mammalian hair cells, research on hair cells relies on primary organ cultures. The best-characterized in vitro model system of mature mammalian hair cells utilizes organ cultures of utricles from adult mice (Figure 1). The utricle is a vestibular organ, and the hair cells of the utricle are similar in both structure and function to the hair cells in the auditory organ, the organ of Corti. The adult mouse utricle preparation represents a mature sensory epithelium for studies of the molecular signals that regulate the survival, homeostasis, and death of these cells. Mammalian cochlear hair cells are terminally differentiated and are not regenerated when they are lost. In non mammalian vertebrates, auditory or vestibular hair cell death is followed by robust regeneration which restores hearing and balance functions. Hair cell regeneration is mediated by glia-like supporting cells, which contact the basolateral surfaces of hair cells in the sensory epithelium. Supporting cells are also important mediators of hair cell survival and death. We have recently developed a technique for infection of supporting cells in cultured utricles using adenovirus. Using adenovirus type 5 (dE1/E3) to deliver a transgene containing GFP under the control of the CMV promoter, we find that adenovirus specifically and efficiently infects supporting cells. Supporting cell infection efficiency is approximately 25-50%, and hair cells are not infected (Figure 2). Importantly, we find that adenoviral infection of supporting cells does not result in toxicity to hair cells or supporting cells, as cell counts in Ad-GFP infected utricles are equivalent to those in non-infected utricles (Figure 3). Thus adenovirus-mediated gene expression in supporting cells of cultured utricles provides a powerful tool to study the roles of supporting cells as mediators of hair cell survival, death, and regeneration. PMID- 22491074 TI - A comparative study of graph-based, eikonal, and monodomain simulations for the estimation of cardiac activation times. AB - The bidomain and monodomain equations are well established as the standard set of equations for the simulation of cardiac electrophysiological behavior. However, the computational cost of detailed bidomain/monodomain simulations limits their applicability in scenarios where a large number of simulations needs to be performed (e.g., parameter estimation). In this study, we present a graph-based method, which relies on point-to-point path finding to estimate activation times for single points in cardiac tissue with minimal computational costs. To validate our approach, activation times are compared to monodomain simulation results for an anatomically based rabbit ventricular model, incorporating realistic fiber orientation and conduction heterogeneities. Differences in activation times between the graph-based method and monodomain results are less than 10% of the total activation time, and computational performance is orders of magnitude faster with the proposed method when calculating activation times at single points. These results suggest that the graph-based method is well suited for estimating activation times when the need for fast performance justifies a limited loss of accuracy. PMID- 22491075 TI - Challenges of drug resistance in the developing world. PMID- 22491076 TI - 3Rs for innovating novel antibiotics: sharing resources, risks, and rewards. PMID- 22491077 TI - New communications technologies can improve responses to disasters, says report. PMID- 22491078 TI - Aspirin and cancer prevention. PMID- 22491079 TI - NHS still needs major changes to achieve required efficiency gains, says chief executive. PMID- 22491080 TI - US board gives green light to publication of bird flu studies it previously blocked. PMID- 22491081 TI - Transferring visual prior for online object tracking. AB - Visual prior from generic real-world images can be learned and transferred for representing objects in a scene. Motivated by this, we propose an algorithm that transfers visual prior learned offline for online object tracking. From a collection of real-world images, we learn an overcomplete dictionary to represent visual prior. The prior knowledge of objects is generic, and the training image set does not necessarily contain any observation of the target object. During the tracking process, the learned visual prior is transferred to construct an object representation by sparse coding and multiscale max pooling. With this representation, a linear classifier is learned online to distinguish the target from the background and to account for the target and background appearance variations over time. Tracking is then carried out within a Bayesian inference framework, in which the learned classifier is used to construct the observation model and a particle filter is used to estimate the tracking result sequentially. Experiments on a variety of challenging sequences with comparisons to several state-of-the-art methods demonstrate that more robust object tracking can be achieved by transferring visual prior. PMID- 22491082 TI - A CURE for noisy magnetic resonance images: chi-square unbiased risk estimation. AB - n this article we derive an unbiased expression for the expected mean-squared error associated with continuously differentiable estimators of the noncentrality parameter of a chisquare random variable. We then consider the task of denoising squared-magnitude magnetic resonance image data, which are well modeled as independent noncentral chi-square random variables on two degrees of freedom. We consider two broad classes of linearly parameterized shrinkage estimators that can be optimized using our risk estimate, one in the general context of undecimated filterbank transforms, and another in the specific case of the unnormalized Haar wavelet transform. The resultant algorithms are computationally tractable and improve upon most state-of-the-art methods for both simulated and actual magnetic resonance image data. PMID- 22491083 TI - Distribution and risk factors of 2009 pandemic influenza A (H1N1) in mainland China. AB - Data from all reported cases of 2009 pandemic influenza A (H1N1) were obtained from the China Information System for Disease Control and Prevention. The spatiotemporal distribution patterns of cases were characterized through spatial analysis. The impact of travel-related risk factors on invasion of the disease was analyzed using survival analysis, and climatic factors related to local transmission were identified using multilevel Poisson regression, both at the county level. The results showed that the epidemic spanned a large geographic area, with the most affected areas being in western China. Significant differences in incidence were found among age groups, with incidences peaking in school-age children. Overall, the epidemic spread from southeast to northwest. Proximity to airports and being intersected by national highways or freeways but not railways were variables associated with the presence of the disease in a county. Lower temperature and lower relative humidity were the climatic factors facilitating local transmission after correction for the effects of school summer vacation and public holidays, as well as population density and the density of medical facilities. These findings indicate that interventions focused on domestic travel, population density, and climatic factors could play a role in mitigating the public health impact of future influenza pandemics. PMID- 22491084 TI - Association of long-term exposure to community noise and traffic-related air pollution with coronary heart disease mortality. AB - In metropolitan areas, road traffic is a major contributor to ambient air pollution and the dominant source of community noise. The authors investigated the independent and joint influences of community noise and traffic-related air pollution on risk of coronary heart disease (CHD) mortality in a population-based cohort study with a 5-year exposure period (January 1994-December 1998) and a 4 year follow-up period (January 1999-December 2002). Individuals who were 45-85 years of age and resided in metropolitan Vancouver, Canada, during the exposure period and did not have known CHD at baseline were included (n = 445,868). Individual exposures to community noise and traffic-related air pollutants, including black carbon, particulate matter less than or equal to 2.5 MUm in aerodynamic diameter, nitrogen dioxide, and nitric oxide, were estimated at each person's residence using a noise prediction model and land-use regression models, respectively. CHD deaths were identified from the provincial death registration database. After adjustment for potential confounders, including traffic-related air pollutants or noise, elevations in noise and black carbon equal to the interquartile ranges were associated with 6% (95% confidence interval: 1, 11) and 4% (95% confidence interval: 1, 8) increases, respectively, in CHD mortality. Subjects in the highest noise decile had a 22% (95% confidence interval: 4, 43) increase in CHD mortality compared with persons in the lowest decile. These findings suggest that there are independent effects of traffic-related noise and air pollution on CHD mortality. PMID- 22491085 TI - Research guidelines in the era of large-scale collaborations: an analysis of Genome-wide Association Study Consortia. AB - Scientific research has shifted from studies conducted by single investigators to the creation of large consortia. Genetic epidemiologists, for example, now collaborate extensively for genome-wide association studies (GWAS). The effect has been a stream of confirmed disease-gene associations. However, effects on human subjects oversight, data-sharing, publication and authorship practices, research organization and productivity, and intellectual property remain to be examined. The aim of this analysis was to identify all research consortia that had published the results of a GWAS analysis since 2005, characterize them, determine which have publicly accessible guidelines for research practices, and summarize the policies in these guidelines. A review of the National Human Genome Research Institute's Catalog of Published Genome-Wide Association Studies identified 55 GWAS consortia as of April 1, 2011. These consortia were comprised of individual investigators, research centers, studies, or other consortia and studied 48 different diseases or traits. Only 14 (25%) were found to have publicly accessible research guidelines on consortia websites. The available guidelines provide information on organization, governance, and research protocols; half address institutional review board approval. Details of publication, authorship, data-sharing, and intellectual property vary considerably. Wider access to consortia guidelines is needed to establish appropriate research standards with broad applicability to emerging forms of large-scale collaboration. PMID- 22491087 TI - A comparison of organic and inorganic nitrates/nitrites. AB - Although both organic and inorganic nitrates/nitrites mediate their principal effects via nitric oxide, there are many important differences. Inorganic nitrate and nitrite have simple ionic structures and are produced endogenously and are present in the diet, whereas their organic counterparts are far more complex, and, with the exception of ethyl nitrite, are all medicinally synthesised products. These chemical differences underlie the differences in pharmacokinetic properties allowing for different modalities of administration, particularly of organic nitrates, due to the differences in their bioavailability and metabolic profiles. Whilst the enterosalivary circulation is a key pathway for orally ingested inorganic nitrate, preventing an abrupt effect or toxic levels of nitrite and prolonging the effects, this is not used by organic nitrates. The pharmacodynamic differences are even greater; while organic nitrates have potent acute effects causing vasodilation, inorganic nitrite's effects are more subtle and dependent on certain conditions. However, in chronic use, organic nitrates are considerably limited by the development of tolerance and endothelial dysfunction, whereas inorganic nitrate/nitrite may compensate for diminished endothelial function, and tolerance has not been reported. Also, while inorganic nitrate/nitrite has important cytoprotective effects against ischaemia reperfusion injury, continuous use of organic nitrates may increase injury. While there are concerns that inorganic nitrate/nitrite may induce carcinogenesis, direct evidence of this in humans is lacking. While organic nitrates may continue to dominate the therapeutic arena, this may well change with the increasing recognition of their limitations, and ongoing discovery of beneficial effects and specific advantages of inorganic nitrate/nitrite. PMID- 22491088 TI - A novel class of nonlinear optical materials based on host-guest composites: zeolites as inorganic crystalline hosts. AB - The demand for nonlinear optical (NLO) materials with exceptional NLO properties is very large, and hence the search for such materials should be continued not only to enhance their functions in current applications but also to help expedite the materialization of photonics in which photons instead of electrons are used for signal processing, transmission, and storage. This article summarizes the preparation, characteristics, and the future perspectives of novel second order nonlinear optical (2NLO) materials prepared by orientation-controlled incorporation of 2NLO molecules into zeolite channels and third order nonlinear optical (3NLO) materials prepared by compartmentalization of very small (<1.3 nm) PbS QDs within zeolite nanopores under different environments, and the novel chemistry newly unveiled during the preparation of novel zeolite based NLO materials. PMID- 22491089 TI - Online Signature Verification Based on Generative Models. AB - The success of generative models for online signature verification has motivated many research works on this topic. These systems may use hidden Markov models (HMMs) in two different modes: user-specific HMM (US-HMM) and user-adapted universal background models (UBMs) (UA-UBMs). Verification scores can be obtained from likelihood ratios and a distance measure on the Viterbi decoded state sequences. This paper analyzes several factors that can modify the behavior of these systems and which have not been deeply studied yet. First, we study the influence of the feature set choice, paying special attention to the role of dynamic information order, suitability of feature sets on each kind of generative model-based system, and the importance of inclination angles and pressure. Moreover, this analysis is also extended to the influence of the HMM complexity in the performance of the different approaches. For this study, a set of experiments is performed on the publicly available MCYT-100 database using only skilled forgeries. These experiments provide interesting outcomes. First, the Viterbi path evidences a notable stability for most of the feature sets and systems. Second, in the case of US-HMM systems, likelihood evidence obtains better results when lowest order dynamics are included in the feature set, while likelihood ratio obtains better results in UA-UBM systems when lowest dynamics are not included in the feature set. Finally, US-HMM and UA-UBM systems can be used together for improved verification performance by fusing at the score level the Viterbi path information from the US-HMM system and the likelihood ratio evidence from the UA-UBM system. Additional comparisons to other state-of-the-art systems, from the ESRA 2011 signature evaluation contest, are also reported, reinforcing the high performance of the systems and the generality of the experimental results described in this paper. PMID- 22491086 TI - A trigger-based design for evaluating the safety of in utero antiretroviral exposure in uninfected children of human immunodeficiency virus-infected mothers. AB - The Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring of ART Toxicities Study is a prospective cohort study conducted at 22 US sites between 2007 and 2011 that was designed to evaluate the safety of in utero antiretroviral drug exposure in children not infected with human immunodeficiency virus who were born to mothers who were infected. This ongoing study uses a "trigger-based" design; that is, initial assessments are conducted on all children, and only those meeting certain thresholds or "triggers" undergo more intensive evaluations to determine whether they have had an adverse event (AE). The authors present the estimated rates of AEs for each domain of interest in the Surveillance Monitoring of ART Toxicities Study. They also evaluated the efficiency of this trigger-based design for estimating AE rates and for testing associations between in utero exposures to antiretroviral drugs and AEs. The authors demonstrate that estimated AE rates from the trigger-based design are unbiased after correction for the sensitivity of the trigger for identifying AEs. Even without correcting for bias based on trigger sensitivity, the trigger approach is generally more efficient for estimating AE rates than is evaluating a random sample of the same size. Minor losses in efficiency when comparing AE rates between persons exposed and unexposed in utero to particular antiretroviral drugs or drug classes were observed under most scenarios. PMID- 22491090 TI - On prioritized multiple-criteria aggregation. AB - We describe multicriteria aggregation and discuss its central role in many modern applications. The concept of aggregation imperative is introduced to indicate the description of how the individual criteria satisfactions should be combined to obtain the overall score. We focus on a particular type of aggregation imperative called prioritized aggregation that is characteristic of situations where lack of satisfaction to criteria denoted as higher priority cannot be compensated by increased satisfaction by those denoted as lower priority. We discuss two approaches to the formulation of this type of aggregation process. One of these uses the prioritized aggregation operator, and the second is based on an integral type aggregation using a monotonic set measure to convey the prioritized imperative. PMID- 22491091 TI - Weight change following US military service. AB - BACKGROUND: Although overweight and obesity are less prevalent among active-duty military personnel compared with similar persons not serving in the military, no such differences have been observed between veterans and non-veterans. OBJECTIVES: To assess the magnitude of weight changes before, concurrent with and following discharge from the military, relative to weight during service, and to determine the demographic, service-related and psychological characteristics associated with clinically important weight gain among those who were discharged from military service during follow-up. METHODS: Eligible Millennium Cohort Study participants (n=38 686) completed the questionnaires approximately every 3 years (2001, 2004 and 2007) that were used to estimate annual weight changes, as well as the percentage experiencing clinically important weight gain, defined as ?10%. Analyses were stratified by sex. RESULTS: Weight gain was greatest around the time of discharge from service and in the 3 years before discharge (1.0-1.3 kg per year), while it was nearly half as much during service (0.6-0.7 kg per year) and ?3 years after service ended (0.7 kg per year). Consequently, 6-year weight gain was over 2 kg greater in those who were discharged compared with those who remained in the military during follow-up (5.7 vs 3.5 kg in men; 6.3 vs 4.0 kg in women). In those who were discharged, younger age, less education, being overweight at baseline, being in the active-duty component (vs Reserve/National Guard) and having experienced deployment with combat exposures (vs non deployment) were associated with increased risks of clinically important weight gain. CONCLUSIONS: This study provides the first prospectively collected evidence for an increased rate of weight gain around the time of military discharge that may explain previously reported higher rates of obesity in veterans, and identifies characteristics of higher-risk groups. Discharge from military service presents a window of risk and opportunity to prevent unhealthy weight gain in military personnel and veterans. PMID- 22491092 TI - Transcription-independent function of Polycomb group protein PSC in cell cycle control. AB - Polycomb group (PcG) proteins control development and cell proliferation through chromatin-mediated transcriptional repression. We describe a transcription independent function for PcG protein Posterior sex combs (PSC) in regulating the destruction of cyclin B (CYC-B). A substantial portion of PSC was found outside canonical PcG complexes, instead associated with CYC-B and the anaphase-promoting complex (APC). Cell-based experiments and reconstituted reactions established that PSC and Lemming (LMG, also called APC11) associate and ubiquitylate CYC-B cooperatively, marking it for proteosomal degradation. Thus, PSC appears to mediate both developmental gene silencing and posttranslational control of mitosis. Direct regulation of cell cycle progression might be a crucial part of the PcG system's function in development and cancer. PMID- 22491094 TI - Magnetic reconnection in the near Venusian magnetotail. AB - Observations with the Venus Express magnetometer and low-energy particle detector revealed magnetic field and plasma behavior in the near-Venus wake that is symptomatic of magnetic reconnection, a process that occurs in Earth's magnetotail but is not expected in the magnetotail of a nonmagnetized planet such as Venus. On 15 May 2006, the plasma flow in this region was toward the planet, and the magnetic field component transverse to the flow was reversed. Magnetic reconnection is a plasma process that changes the topology of the magnetic field and results in energy exchange between the magnetic field and the plasma. Thus, the energetics of the Venus magnetotail resembles that of the terrestrial tail, where energy is stored and later released from the magnetic field to the plasma. PMID- 22491093 TI - A stem cell-based approach to cartilage repair. AB - Osteoarthritis (OA) is a degenerative joint disease that involves the destruction of articular cartilage and eventually leads to disability. Molecules that promote the selective differentiation of multipotent mesenchymal stem cells (MSCs) into chondrocytes may stimulate the repair of damaged cartilage. Using an image-based high-throughput screen, we identified the small molecule kartogenin, which promotes chondrocyte differentiation (median effective concentration = 100 nM), shows chondroprotective effects in vitro, and is efficacious in two OA animal models. Kartogenin binds filamin A, disrupts its interaction with the transcription factor core-binding factor beta subunit (CBFbeta), and induces chondrogenesis by regulating the CBFbeta-RUNX1 transcriptional program. This work provides new insights into the control of chondrogenesis that may ultimately lead to a stem cell-based therapy for osteoarthritis. PMID- 22491095 TI - Coupling quantum tunneling with cavity photons. AB - Tunneling of electrons through a potential barrier is fundamental to chemical reactions, electronic transport in semiconductors and superconductors, magnetism, and devices such as terahertz oscillators. Whereas tunneling is typically controlled by electric fields, a completely different approach is to bind electrons into bosonic quasiparticles with a photonic component. Quasiparticles made of such light-matter microcavity polaritons have recently been demonstrated to Bose-condense into superfluids, whereas spatially separated Coulomb-bound electrons and holes possess strong dipole interactions. We use tunneling polaritons to connect these two realms, producing bosonic quasiparticles with static dipole moments. Our resulting three-state system yields dark polaritons analogous to those in atomic systems or optical waveguides, thereby offering new possibilities for electromagnetically induced transparency, room-temperature condensation, and adiabatic photon-to-electron transfer. PMID- 22491096 TI - An SNMP-based solution to enable remote ISO/IEEE 11073 technical management. AB - This paper presents the design and implementation of an architecture based on the integration of simple network management protocol version 3 (SNMPv3) and the standard ISO/IEEE 11073 (X73) to manage technical information in home-based telemonitoring scenarios. This architecture includes the development of an SNMPv3 proxyX73 agent which comprises a management information base (MIB) module adapted to X73. In the proposed scenario, medical devices (MDs) send information to a concentrator device [designated as compute engine (CE)] using the X73 standard. This information together with extra information collected in the CE is stored in the developed MIB. Finally, the information collected is available for remote access via SNMP connection. Moreover, alarms and events can be configured by an external manager in order to provide warnings of irregularities in the MDs' technical performance evaluation. This proposed SNMPv3 agent provides a solution to integrate and unify technical device management in home-based telemonitoring scenarios fully adapted to X73. PMID- 22491097 TI - An Examination of the Motor Unit Number Index (MUNIX) in muscles paralyzed by spinal cord injury. AB - The objective of this study was to assess whether there is evidence of motor unit loss in muscles paralyzed by spinal cord injury (SCI), using a measurement called motor unit number index (MUNIX). The MUNIX technique was applied in SCI (n=12) and neurologically intact (n=12) subjects. The maximum M waves and voluntary surface electromyography (EMG) signals at different muscle contraction levels were recorded from the first dorsal interosseous (FDI) muscle in each subject. The MUNIX values were estimated using a mathematical model describing the relation between the surface EMG signal and the ideal motor unit number count derived from the M wave and surface EMG measurements. We recorded a significant decrease in both maximum M wave amplitude and in estimated MUNIX values in paralyzed FDI muscles, as compared with neurologically intact muscles. Across all subjects, the maximum M wave amplitude was 8.3 +/- 4.4 mV for the paralyzed muscles and 14.4 +/- 2.0 mV for the neurologically intact muscles (p<0.0001). These measurements, when combined with voluntary EMG recordings, resulted in a mean MUNIX value of 112 +/- 71 for the paralyzed muscles, much lower than the mean MUNIX value of 228 +/- 49 for the neurologically intact muscles (p<0.00001). A motor unit size index was also calculated, using the maximum M wave recording and the MUNIX values. We found that paralyzed muscles showed a mean motor unit size index value of 80.7 +/- 17.7 iV, significantly higher than the mean value of 64.9 +/- 10.1 iV obtained from neurologically intact muscles (p<0.001). The MUNIX method used in this study offers several practical benefits compared with the traditional motor unit number estimation technique because it is noninvasive, induces minimal discomfort due to electrical nerve stimulation, and can be performed quickly. The findings from this study help understand the complicated determinants of SCI induced muscle weakness and provide further evidence of motoneuron degeneration after a spinal injury. PMID- 22491098 TI - Comparison of block matching and differential methods for motion analysis of the carotid artery wall from ultrasound images. AB - Motion of the carotid artery wall is important for the quantification of arterial elasticity and contractility and can be estimated with a number of techniques. In this paper, a framework for quantitative evaluation of motion analysis techniques from B-mode ultrasound images is introduced. Six synthetic sequences were produced using 1) a real image corrupted by Gaussian and speckle noise of 25 and 15 dB, and 2) the ultrasound simulation package Field II. In both cases, a mathematical model was used, which simulated the motion of the arterial wall layers and the surrounding tissue, in the radial and longitudinal directions. The performance of four techniques, namely optical flow (OF (HS)), weighted least squares optical flow (OF (LK(WLS))), block matching (BM), and affine block motion model (ABMM), was investigated in the context of this framework. The average warping indices were lowest for OF (LK(WLS)) (1.75 pixels), slightly higher for ABMM (2.01 pixels), and highest for BM (6.57 pixels) and OF (HS) (11.57 pixels). Due to its superior performance, OF (LK(WLS)) was used to quantify motion of selected regions of the arterial wall in real ultrasound image sequences of the carotid artery. Preliminary results indicate that OF (LK(WLS)) is promising, because it efficiently quantified radial, longitudinal, and shear strains in healthy adults and diseased subjects. PMID- 22491099 TI - Photodissociation dynamics of tert-butylnitrite following excitation to the S1 and S2 states. A study by velocity-map ion-imaging and 3D-REMPI spectroscopy. AB - Excitation of tert-butylnitrite into the first and second UV absorption bands leads to efficient dissociation into the fragment radicals NO and tert-butoxy in their electronic ground states (2)Pi and (2)E, respectively. Velocity distributions and angular anisotropies for the NO fragment in several hundred rotational and vibrational quantum states were obtained by velocity-map imaging and the recently developed 3D-REMPI method. Excitation into the well resolved vibronic progression bands (k = 0, 1, 2) of the NO stretch mode in the S1<- S0 transition produces NO fragments mostly in the vibrational state with v = k, with smaller fractions in v = k- 1 and v = k- 2. It is concluded that dissociation occurs on the purely repulsive PES of S1 without barrier. All velocity distributions from photolysis via the S1(npi*) state are monomodal and show high negative anisotropy (beta~-1). The rotational distributions peak near j = 30.5 irrespective of the vibronic state S1(k) excited and the vibrational state v of the NO fragment. On average 46% of the excess energy is converted to kinetic energy, 23% and 31% remain as internal energy in the NO fragment and the t-BuO radical, respectively. Photolysis via excitation into the S2<- S0 transition at 227 nm yields NO fragments with about equal populations in v = 0 and v = 1. The rotational distributions have a single maximum near j = 59.5. The velocity distributions are monomodal with positive anisotropy beta~ 0.8. The average fractions of the excess energy distributed into translation, internal energy of NO, and internal energy of t-BuO are 39%, 23%, and 38%, respectively. In all cases ~8500 cm(-1) of energy remain in the internal degrees of freedom of the t BuO fragment. This is mostly assigned to rotational energy. An ab initio calculation of the dynamic reaction path shows that not only the NO fragment but also the t-BuO fragment gain large angular momentum during dissociation on the purely repulsive potential energy surface of S2. PMID- 22491101 TI - EFMI initiatives for inter-regional cooperation: the TrEHRT project. AB - The paper refers to EFMI's initiatives to develop an international cooperation with different regional groups of IMIA. More details are presented about the successful project "TrEHRT - Traveler's Electronic Health Record Template". Its potential applicability, compact structure and functional simplicity turned this product into a template capable to become an international standard, using mobile phones. PMID- 22491102 TI - The Swedish strategy and method for development of a national healthcare information architecture. AB - "We need a precise framework of regulations in order to maintain appropriate and structured health care documentation that ensures that the information maintains a sufficient level of quality to be used in treatment, in research and by the actual patient. The users shall be aided by clearly and uniformly defined terms and concepts, and there should be an information structure that clarifies what to document and how to make the information more useful. Most of all, we need to standardize the information, not just the technical systems." (eHalsa - nytta och naring, Riksdag report 2011/12:RFR5, p. 37). In 2010, the Swedish Government adopted the National e-Health - the national strategy for accessible and secure information in healthcare. The strategy is a revision and extension of the previous strategy from 2006, which was used as input for the most recent efforts to develop a national information structure utilizing business-oriented generic models. A national decision on healthcare informatics standards was made by the Swedish County Councils, which decided to follow and use EN/ISO 13606 as a standard for the development of a universally applicable information structure, including archetypes and templates. The overall aim of the Swedish strategy for development of National Healthcare Information Architecture is to achieve high level semantic interoperability for clinical content and clinical contexts. High level semantic interoperability requires consistently structured clinical data and other types of data with coherent traceability to be mapped to reference clinical models. Archetypes that are formal definitions of the clinical and demographic concepts and some administrative data were developed. Each archetype describes the information structure and content of overarching core clinical concepts. Information that is defined in archetypes should be used for different purposes. Generic clinical process model was made concrete and analyzed. For each decision-making step in the process where information is processed, the amount and type of information and its structure were defined in terms of reference templates. Reference templates manage clinical, administrative and demographic types of information in a specific clinical context. Based on a survey of clinical processes at the reference level, the identification of specific clinical processes such as diabetes and congestive heart failure in adults were made. Process-specific templates were defined by using reference templates and populated with information that was relevant to each health problem in a specific clinical context. Throughout this process, medical data for knowledge management were collected for each health problem. Parallel with the efforts to define archetypes and templates, terminology binding work is on-going. Different strategies are used depending on the terminology binding level. PMID- 22491103 TI - Lessons from the English National Programme for IT about structure, process and utility. AB - Sharing of health data though the effective deployment of information systems should allow safer and more efficient health systems. However, to date many large IT system deployments in health care have had major short comings. This paper critically appraises the UK National Programme for IT and suggests where there are important lessons of for other large scale eHealth projects. Our method combined the classic evaluation methods of Donnabedian with Pawson's realistic review to analyze the impact of the program at health service, locality or major provider, and client-service impact levels. Financial incentives promoted uptake and use of IT systems at all levels. Health service level interventions that were capable of incorporation into clinical workflow were used. These included: a national unique identifier, creation of national registries and electronic transfer of data, records, and results. At the regional and major provider level we identified how vendors offer very different electronic patient record (EPR) systems which influence what is recorded and health care delivery. Using the EPR at the point of care takes longer, but this investment of time creates a more usable record and facilitates quality. National IT systems need to be clinically orientated, patient accessible, and underpinned by a secure, standardized back office system that enables messaging and information sharing between authenticated users. Learning the lessons from the UK and other large system deployments might enable other countries to leap to the forefront of health care computing. PMID- 22491104 TI - Nation-wide primary healthcare research network: a privacy protection assessment. AB - Efficiency and privacy protection are essential when setting up nationwide research networks. This paper investigates the extent to which basic services developed to support the provision of care can be re-used, whilst preserving an acceptable privacy protection level, within a large Belgian primary care research network. The generic sustainable confidentiality management model used to assess the privacy protection level of the selected network architecture is described. A short analysis of the current architecture is provided. Our generic model could also be used in other countries. PMID- 22491105 TI - MedCom: laboratory test ordering--fully implemented nationwide in less than 3 years. AB - Lab test result reporting has been fully implemented in Denmark since early 2000. Labtest ordering is much more complicated due to different handling and labeling procedures in more than 70 Danish labs. Until 2004 all orders were based on preprinted paper forms. A new electronic national lab test order solution based on national MedCom standards and codes was introduced in 2005 and it was fully implemented in all 2100 GP clinics and 1000 private specialist clinics in 3 years. It also included 42 biochemistry labs, 14 Microbiology labs and 16 histopathology and cytology labs. Implementation was organized by MedCom and planned in rough details. During the implementation period a set of planed and ad hoc activities to reach 100 % implementation was successfully launched. Today more than 6.000.000 lab test orders (100%) are now handled electronically each year. The implementation process, the challenges: organizational and technically as well as outcome is described in the paper. PMID- 22491106 TI - National registries in the Russian healthcare system. AB - A number of registries of various levels (national, regional, etc.) were created in the Russian Federation during last two decades. Main principles of registries formation, as well as some limitations of the use of registries for assessment of treatment effectiveness and drug safety are discussed. PMID- 22491107 TI - HL7 CDA in the national ePrescription efforts of Finland & Greece: a comparison. AB - This paper presents an overview and comparison of national efforts on ePrescribing in Finland and Greece focusing on aspects of interoperability and standards. Building on experience of HL7 affiliates in Finland and Greece, the role of HL7 Clinical Document Architecture (CDA) in assuring interoperability within the national and cross-border framework for ePrescription is addressed underlining current use of standards and interoperability challenges for large scale adoption. PMID- 22491109 TI - IMIA accreditation of health informatics programs. AB - Health informatics programs usually are evaluated by national accreditation committees. Not always are the members of these committees well informed about the international level of (education in) health informatics. Therefore, when a program is accredited by a national accreditation committee, this does not always mean that the program is of an international level. Institutions may invite international experts to assess their educational programs. IMIA can serve as an intermediary for organizing the peer review. IMIA can play the role of accreditation committee and together with the institution assign an independent site visit committee to carry out the peer review. This contribution describes the IMIA accreditation procedure. PMID- 22491110 TI - EuroMISE Center: research and education in biomedical and healthcare informatics. AB - EuroMISE Center was established in the year 1994bas the joint workplace of Charles University in Prague and Academy of Sciences of the Czech Republic with the support of the European project focused on higher education in methodology field of healthcare. Nowadays, the EuroMISE Center is working as the joint workplace of five organizations. We describe in more details history and nowadays activities of the EuroMISE Center in the field of research, higher education and e3 Health applications. PMID- 22491111 TI - Implementation of the recommendations in master's courses in health informatics. AB - The publication of the International Medical Informatics Association revised version of the existing international recommendations in health informatics / medical informatics education was welcome positively by the educational community. The recommendations help to establish courses and complete programs in the field of Biomedical and Health Informatics (BMHI), to further develop existing educational activities in the various nations and to support international initiatives. The paper focuses on the Master's courses, which are the most widely established programs following the recommendations. The number of citations of the recommendations shows the worldwide acceptance. However, an in depth review is recommended. PMID- 22491112 TI - Teaching medical informatics at SSMU Tomsk for modernization health care. AB - Education is the basis for running a health care system effectively and efficiently. It is integrated into the curriculum for medical students and supported by training. International participation in concept and practice will be necessary for success and further development. Institutional cooperation will transfer experience and recommendations. It may lead to a partnership for modernization on European level. PMID- 22491113 TI - Online education in a large scale rehabilitation institution. AB - Large scale multiple venue institutions face problems when delivering educations to their healthcare staff. The present study is aimed at evaluating the feasibility of relying on e-learning for at least part of the training of the Salvatore Maugeri Foundation healthcare staff. The paper reports the results of the delivery of e-learning courses to the personnel during a span of time of 7 months in order to assess the attitude to online courses attendance, the proportion between administered online education and administered traditional education, the economic sustainability of the online education delivery process. 37% of the total healthcare staff have attended online courses and 46% of nurses have proved to be the very active. The ratio between total number of credits and total number of courses for online and traditional education are respectively 18268/5 and 20354/96. These results point out that eLearning is not at all a niche tool used (or usable) by a limited number of people. Economic sustainability, assessed via personnel work hour saving, has been demonstrated. When distance learning is appropriate, online education is an effective, sustainable, well accepted mean to support and promote healthcare staff's education in a large scale institution. PMID- 22491114 TI - Blended-learning strategy in the Altay State medical university. AB - New educational technologies prove to be capable of solving many problems in the medical training. Students do not see e-Learning as replacing traditional instructor-led training but as a complement to it, forming part of a blended learning strategy. Innovations in e-Learning technologies point toward a revolution in education, allowing learning to be individualized (adaptive learning), enhancing learners' interactions with others (collaborative learning), and transforming the role of the teacher. The integration of e-Learning into medical education can catalyze the shift towards applying adult learning theory, where educators will no longer serve mainly as the distributors of content, but will become more involved as facilitators of learning and assessors of competency. This survey analyzes possibilities to effectively use e-Learning in medical education, and what steps are to be made in that direction. PMID- 22491116 TI - Information system for the implementation of individual rehabilitation programs for persons with disabilities in Nizhny Novgorod region. AB - In December 2011, the first phase of the project aimed at developing an information system for the implementation of individual rehabilitation programs for persons with disabilities was finished in Nizhny Novgorod region of Russia. It included the installation of 40 workstations in the Ministry for Social Policy and 8 institutions of Nizhny Novgorod region. Accumulated data were moved to a new information system based on a distributed database. In 2012, the rest of the regional rehabilitation institutions are to join this information system. A transition to a centralized database is planned. PMID- 22491117 TI - Consistent data recording across a health system and web-enablement allow service quality comparisons: online data for commissioning dermatology services. AB - A new distributed model of health care management is being introduced in England. Family practitioners have new responsibilities for the management of health care budgets and commissioning of services. There are national datasets available about health care providers and the geographical areas they serve. These data could be better used to assist the family practitioner turned health service commissioners. Unfortunately these data are not in a form that is readily usable by these fledgling family commissioning groups. We therefore Web enabled all the national hospital dermatology treatment data in England combining it with locality data to provide a smart commissioning tool for local communities. We used open-source software including the Ruby on Rails Web framework and MySQL. The system has a Web front-end, which uses hypertext markup language cascading style sheets (HTML/CSS) and JavaScript to deliver and present data provided by the database. A combination of advanced caching and schema structures allows for faster data retrieval on every execution. The system provides an intuitive environment for data analysis and processing across a large health system dataset. Web-enablement has enabled data about in patients, day cases and outpatients to be readily grouped, viewed, and linked to other data. The combination of web-enablement, consistent data collection from all providers; readily available locality data; and a registration based primary system enables the creation of data, which can be used to commission dermatology services in small areas. Standardized datasets collected across large health enterprises when web enabled can readily benchmark local services and inform commissioning decisions. PMID- 22491118 TI - Pathogens and gene product normalization in the biomedical literature. AB - We present a new approach for pathogens and gene product normalization in the biomedical literature. The idea of this approach was motivated by needs such as literature curation, in particular applied to the field of infectious diseases thus, variants of bacterial species (S. aureus, Staphyloccocus aureus, ...) and their gene products (protein ArsC, Arsenical pump modifier, Arsenate reductase, ...). Our approach is based on the use of an Ontology Look-up Service, a Gene Ontology Categorizer (GOCat) and Gene Normalization methods. In the pathogen detection task the use of OLS disambiguates found pathogen names. GOCat results are incorporated into overall score system to support and to confirm the decisionmaking in normalization process of pathogens and their genomes. The evaluation was done on two test sets of BioCreativeIII benchmark: gold standard of manual curation (50 articles) and silver standard (507 articles) curated by collective results of BCIII participants. For the cross-species GN we achieved the precision of 46% for silver and 27% for gold sets. Pathogen normalization results showed 95% of precision and 93% of recall. The impact of GOCat explicitly improves results of pathogen and gene normalization, basically confirming identified pathogens and boosting correct gene identifiers on the top of the results' list ranked by confidence. A correct identification of the pathogen is able to improve significantly normalization effectiveness and to solve the disambiguation problem of genes. PMID- 22491119 TI - Cloud computing technology applied in healthcare for developing large scale flexible solutions. AB - An extremely important area in which there is also vital information needed in different locations is the healthcare domain. In the areas of healthcare there is an important exchange of information since there are many departments where a patient can be sent for investigation. In this regard cloud computing is a technology that could really help supporting flexibility, seamless care and financial cuts. PMID- 22491120 TI - Can social web help to detect influenza related illnesses in Turkey? AB - In this study, a content analysis of Twitter is carried out to determine the frequency of tweets mentioning influenza like illnesses (swine flu, cold etc.) and results have been compared with news articles, Google search trends and national health statistics in Turkey. Between 1st January 2009 and 31st December 2010, over 4,165 influenza-related Turkish posts on Twitter and 10,000 news articles in three leading Turkish newspaper websites containing influenza related keywords have been analyzed. No strong correlation has been found between influenza related online data and the real world records. Although there is no significant relationship, this study shows that there is a huge amount of data can be harvested from the social web applications such as Twitter. PMID- 22491121 TI - Computational biomedicine: a challenge for the twenty-first century. AB - With the relentless increase of computer power and the widespread availability of digital patient-specific medical data, we are now entering an era when it is becoming possible to develop predictive models of human disease and pathology, which can be used to support and enhance clinical decision-making. The approach amounts to a grand challenge to computational science insofar as we need to be able to provide seamless yet secure access to large scale heterogeneous personal healthcare data in a facile way, typically integrated into complex workflows-some parts of which may need to be run on high performance computers-in a facile way that is integrated into clinical decision support software. In this paper, we review the state of the art in terms of case studies drawn from neurovascular pathologies and HIV/AIDS. These studies are representative of a large number of projects currently being performed within the Virtual Physiological Human initiative. They make demands of information technology at many scales, from the desktop to national and international infrastructures for data storage and processing, linked by high performance networks. PMID- 22491122 TI - Merging genomic and phenomic data for research and clinical impact. AB - Driven primarily by advances in genomics, pharmacogenomics and systems biology technologies, large amounts of genomic and phenomic data are today being collected on individuals worldwide. Integrative analysis, mining, and computer modeling of these data, facilitated by information technology, have led to the development of predictive, preventive, and personalized medicine. This transformative approach holds the potential inter alia to enable future general practitioners and physicians to prescribe the right drug to the right patient at the right dosage. For such patient-specific medicine to be adopted as standard clinical practice, publicly accumulated knowledge of genes, proteins, molecular functional annotations, and interactions need to be unified and with electronic health records including phenotypic information, most of which still reside as paper-based records in hospitals. We review the state-of-the-art in terms of electronic data capture and medical data standards. Some of these activities are drawn from research projects currently being performed within the European Virtual Physiological Human (VPH) initiative; all are being monitored by the VPH INBIOMEDvision Consortium. Various ethical, legal and societal issues linked with privacy will increasingly arise in the post-genomic era. This will require a closer interaction between the bioinformatics/systems biology and medical informatics/healthcare communities. Planning for how individuals will own their personal health records is urgently needed, as the cost of sequencing a whole human genome will soon be less than U.S. $100. We discuss some of the issues that will need to be addressed by society as a result of this revolution in healthcare. PMID- 22491123 TI - Distributed and grid computing projects with research focus in human health. AB - Distributed systems and grid computing systems are used to connect several computers to obtain a higher level of performance, in order to solve a problem. During the last decade, projects use the World Wide Web to aggregate individuals' CPU power for research purposes. This paper presents the existing active large scale distributed and grid computing projects with research focus in human health. There have been found and presented 11 active projects with more than 2000 Processing Units (PUs) each. The research focus for most of them is molecular biology and, specifically on understanding or predicting protein structure through simulation, comparing proteins, genomic analysis for disease provoking genes and drug design. Though not in all cases explicitly stated, common target diseases include research to find cure against HIV, dengue, Duchene dystrophy, Parkinson's disease, various types of cancer and influenza. Other diseases include malaria, anthrax, Alzheimer's disease. The need for national initiatives and European Collaboration for larger scale projects is stressed, to raise the awareness of citizens to participate in order to create a culture of internet volunteering altruism. PMID- 22491124 TI - A user-friendly tool for medical-related patent retrieval. AB - Health-related information retrieval is complicated by the variety of nomenclatures available to name entities, since different communities of users will use different ways to name a same entity. We present in this report the development and evaluation of a user-friendly interactive Web application aiming at facilitating health-related patent search. Our tool, called TWINC, relies on a search engine tuned during several patent retrieval competitions, enhanced with intelligent interaction modules, such as chemical query, normalization and expansion. While the functionality of related article search showed promising performances, the ad hoc search results in fairly contrasted results. Nonetheless, TWINC performed well during the PatOlympics competition and was appreciated by intellectual property experts. This result should be balanced by the limited evaluation sample. We can also assume that it can be customized to be applied in corporate search environments to process domain and company-specific vocabularies, including non-English literature and patents reports. PMID- 22491126 TI - Analysis of metrics for the usability evaluation of electronic health record systems. AB - Electronic health records are gradually replacing conventional paper-based health records. For a doctor, it is a working instrument, which can significantly reduce the time spent on paper work. At the same time, patients can benefit from accessing the electronic health records even though they usually do not have a medical background. Therefore, when specifying a graphical user interface (GUI) it is necessary to take into account the requirements of the different users: e.g. the functionality for the doctors and the presentation of data in an understandable manner for the patients. The study aims to review and analyze metrics used to evaluate the usability of user interfaces in health information systems. A literature review was performed to identify existing metrics. The scope of the search included the analysis of existing usability evaluation metrics that are applied both in healthcare and other domains, where standards for storage and presentation of information are applied. The analysis focused on metrics that are applicable for evaluating GUIs of health information systems. Several approaches and standards have been studied. Finally, a set of metrics and evaluation methods that provide holistic evaluation facilities for graphical user interfaces has been identified. PMID- 22491127 TI - Applying GEP-HI for the planning of an evaluation study: a case study walkthrough (workshop). AB - A Good evaluation practice in Health Informatics (GEP-HI) Evaluation Practice guideline has been developed through a consensus making process. The guideline lists a set of 60 issues that are relevant for planning, implementation and execution of an evaluation study in the health informatics domain. These issues cover the phases of an evaluation study: Study exploration, first study design, operationalization of methods, detailed study design, execution and finalization of an evaluation study. In this seminar we walk through a case study to present how to plan a health information system evaluation study applying the good evaluation practice guideline. PMID- 22491131 TI - An implantable closedloop asynchronous drug delivery system for the treatment of refractory epilepsy. AB - In this paper, we present an implantable device for intra-cerebral electroencephalography (icEEG) data acquisition and real-time epileptic seizure detection with simultaneous focal antiepileptic drug injection feedback. This implantable device includes a neural signal amplifier, an asynchronous seizure detector, a drug delivery system (DDS) including a micropump, and a hybrid subdural electrode (HSE). The asynchronous detection algorithm is based on data dependent analysis and validated with Matlab tools. The detector and DDS have a power saving mode. The HSE contacts are made of Platinum (Pt) encapsulated with polydimethylsiloxane (PDMS). Given the heterogeneity of electrographic seizure signals and seizure suppression threshold, the implantable device provides tunable parameters facility through an external transmitter to adapt to each individual's neurophysiology prior to clinical deployment. The proposed detector and DDS were assembled in O 50 mm and O 30 mm circular printed circuit boards, respectively. The detector was validated using icEEG recordings of seven patients who had previously undergone an intracranial investigation for epilepsy surgery. The triggering of the DDS was tested and a predefined seizure suppression dose was delivered ~16 s after electrographical seizure onsets. The device's power consumption was reduced by 12% in active mode and 49% in power saving mode compared to similar seizure detection algorithms implemented with synchronous architecture. PMID- 22491132 TI - Endothelial cell co-culture mediates maturation of human embryonic stem cell to pancreatic insulin producing cells in a directed differentiation approach. AB - Embryonic stem cells (ESC) have two main characteristics: they can be indefinitely propagated in vitro in an undifferentiated state and they are pluripotent, thus having the potential to differentiate into multiple lineages. Such properties make ESCs extremely attractive for cell based therapy and regenerative treatment applications. However for its full potential to be realized the cells have to be differentiated into mature and functional phenotypes, which is a daunting task. A promising approach in inducing cellular differentiation is to closely mimic the path of organogenesis in the in vitro setting. Pancreatic development is known to occur in specific stages, starting with endoderm, which can develop into several organs, including liver and pancreas. Endoderm induction can be achieved by modulation of the nodal pathway through addition of Activin A in combination with several growth factors. Definitive endoderm cells then undergo pancreatic commitment by inhibition of sonic hedgehog inhibition, which can be achieved in vitro by addition of cyclopamine. Pancreatic maturation is mediated by several parallel events including inhibition of notch signaling; aggregation of pancreatic progenitors into 3-dimentional clusters; induction of vascularization; to name a few. By far the most successful in vitro maturation of ESC derived pancreatic progenitor cells have been achieved through inhibition of notch signaling by DAPT supplementation. Although successful, this results in low yield of the mature phenotype with reduced functionality. A less studied area is the effect of endothelial cell signaling in pancreatic maturation, which is increasingly being appreciated as an important contributing factor in in-vivo pancreatic islet maturation. The current study explores such effect of endothelial cell signaling in maturation of human ESC derived pancreatic progenitor cells into insulin producing islet-like cells. We report a multi-stage directed differentiation protocol where the human ESCs are first induced towards endoderm by Activin A along with inhibition of PI3K pathway. Pancreatic specification of endoderm cells is achieved by inhibition of sonic hedgehog signaling by Cyclopamine along with retinoid induction by addition of Retinoic Acid. The final stage of maturation is induced by endothelial cell signaling achieved by a co-culture configuration. While several endothelial cells have been tested in the co-culture, herein we present our data with rat heart microvascular endothelial Cells (RHMVEC), primarily for the ease of analysis. PMID- 22491133 TI - Health promotion in megachurches: an untapped resource with megareach? AB - INTRODUCTION. In the United States, megachurches (churches with 2,000+ attendance) represent a community institution with extensive reach within the population. Despite this potential for reach, the current health promotion practices of megachurches are unknown. This study aimed to document current health promotion activities and resources for health promotion in megachurches. METHOD: Staff at megachurches were recruited to take an online survey of health promotion programs, health promotion-related beliefs, barriers, and existing resources. RESULTS: Respondents (n = 110 churches) indicated that churches were primarily Baptist (23.6%) or nondenominational (21.1%), had 2,500 to 4,999 congregation members (44.5%), primarily White congregation members (83.5%), and 31 to 60 employees (45.4%). Churches reported 4.73 +/- 2.54 activities/year, most commonly reporting clubs or teams related to physical activity (74.5%), hands-on classes (65.5%), and educational activities (59.1%). Most churches (39.1%) reported their primary faith leader was minimally involved in health-related activities. The most common barrier was competition for time/space with other church activities (46.2%). Churches reported several employee health-related policies. Respondents reported a budget of $0 to $499/year for health-related programs (44.4%). CONCLUSION: These findings provide insight regarding the current status of health promotion in megachurches. These large churches are a potential health promotion partner for researchers and practitioners for developing culturally tailored interventions. PMID- 22491134 TI - Vancomycin MICs of the resistant mutants of S. aureus ATCC43300 vary based on the susceptibility test methods used. AB - Clinical failures with vancomycin against meticillin-resistant Staphylococcus aureus (MRSA) infections have challenged vancomycin's standing as a first-line antimicrobial for these infections. Conventional MIC tests were not predictive of the in vivo therapeutic effect of vancomycin. Thus, we tested the susceptibility for the resistant mutants in the mutant selection window of S. aureus ATCC43300 (a MRSA strain) by three different MIC-testing methods in this paper. The MIC of vancomycin was estimated at 2 MUg ml-1 on the Mueller-Hinton agar (MHA) plate only for the resistant mutant that was selected from the plate of vancomycin concentration 12 MUg ml-1. The obvious changes of susceptibility testing were found between the resistant mutants and S. aureus ATCC43300 on the Brain-Heart Infusion Agar (BHIA) plates. There were subtle changes in the MIC trend within the susceptible range with the result of Etest for the resistant mutants. The susceptibility for the subcultures of resistant mutants would fall back when the external drug environment disappeared. In comparison with the S. aureus ATCC43300, sequence analysis revealed that there were no mutations in the staphylococcal protein A (spa) sequencing of the resistant mutants. The spa tape is t421 for all isolates. PMID- 22491135 TI - Isolation and structural determination of a new macrolide, makinolide, from the newly isolated Streptomyces sp. MK-30. PMID- 22491137 TI - Development of the ability to produce secondary metabolites in Streptomyces through the acquisition of erythromycin resistance. PMID- 22491136 TI - Selection and identification of non-pathogenic bacteria isolated from fermented pickles with antagonistic properties against two shrimp pathogens. AB - In this study, potential probiotic strains were isolated from fermented pickles based on antagonistic activity against two shrimp pathogens (Vibrio harveyi and Vibrio parahaemolyticus). Two strains L10 and G1 were identified by biochemical tests, followed by16S ribosomal RNA gene sequence analysis as Bacillus subtilis, and characterized by PCR amplification of repetitive bacterial DNA elements (Rep PCR). Subsequently, B. subtilis L10 and G1 strains were tested for antibacterial activity under different physical conditions, including culture medium, salinity, pH and temperature using the agar well diffusion assay. Among the different culture media, LB broth was the most suitable medium for antibacterial production. Both strains showed the highest level of antibacterial activity against two pathogens at 30 degrees C and 1.0% NaCl. Under the pH conditions, strain G1 showed the greatest activity against V. harveyi at pH 7.3-8.0 and against V. parahaemolyticus at pH 6.0-8.0, whereas strain L10 showed the greatest activity against two pathogens at pH 7.3. The cell-free supernatants of both strains were treated with four different enzymes in order to characterize the antibacterial substances against V. harveyi. The result showed considerable reduction of antibacterial activity for both strains, indicating the proteinaceous nature of the antibacterial substances. A wide range of tolerance to NaCl, pH and temperature was also recorded for both strains. In addition, both strains showed no virulence effect in juvenile shrimp Litopenaeus vannamei. On the basis of these results and safety of strains to L. vannamei, they may be considered for future challenge experiments in shrimp as a very promising alternative to the use of antibiotics. PMID- 22491138 TI - Isolation and characterization of a new iturinic lipopeptide, mojavensin A produced by a marine-derived bacterium Bacillus mojavensis B0621A. AB - Three lipopeptides were isolated by bioactivity-guided fractionation from the fermentation broth of Bacillus mojavensis B0621A. A new iturinic lipopeptide, named mojavensin A, was tentatively characterized by 1D, 2D NMR and MS spectroscopy, Marfey's method containing a novel peptide backbone of L-Asn1, D Tyr2, D-Asn3, L-Gln4, L-Pro5, D-Asn6, L-Asn7 and an anteiso-type of the saturated beta-fatty acid side chain. Compound 2 and 3 were tentatively identified as iso C16 fengycin B and anteiso-C17 fengycin B, respectively. These lipopeptides displayed dose-dependent antifungal activity against a broad spectra of phytopathogens and were weakly antagonistic to Staphylococcus aureus. Moreover, they all revealed cytotoxic activities against the human leukemia (HL-60) cell line. Mojavensin A, iso-C16 fengycin B, and anteiso-C17 fengycin B inhibited the growth of HL-60 with IC50 of 100, 100 and 1.6 MUM, respectively. PMID- 22491139 TI - Abstracts of the 8th International Congress of Update in Cardiology and Cardiovascular Surgery. March 1-4, 2012. Antalya, Turkey. PMID- 22491140 TI - Luminescent ultrathin film of anionic styrylbiphenyl derivative-layered double hydroxide and its reversible sensing for heavy metal ions. AB - Ordered ultrathin films (UTFs) with blue luminescence based on a styrylbiphenyl derivative (BTBS) and Mg-Al-layered double hydroxide (LDH) nanosheets have been constructed employing the layer-by-layer assembly technique. UV-visible absorption and fluorescence spectroscopy showed a stepwise and regular growth of the films upon increasing the number of deposition cycles. XRD, AFM and SEM indicated that the films possess a periodic layered structure with a period of ca. 1.5 nm, and uniform surface morphology. The film thickness can be precisely controlled in the range ca. 15-53 nm. The BTBS-LDH UTFs exhibit improved UV-light resistance capability compared with the pristine BTBS and show well-defined polarized photoemission, with anisotropy of ca. 0.24. The UTFs show a fast, selective and reversible luminescent response to aqueous solutions containing different heavy metal ions, with the most significant luminescent quenching occurring for the Hg(2+) solution, shedding light on the fact that these films can serve as a new type of selective solid luminescent metal-ion sensor. PMID- 22491141 TI - A vapoluminescent Eu-based metallo-supramolecular polymer. AB - An Eu-based metallo-supramolecular polymer (polyEu) was prepared by self-assembly coordination polymerization. Unique vapoluminescence property of polyEu triggered by acid-base vapor was found and a photoluminescence display in switchable imaging by acid-base vapor was fabricated. PMID- 22491142 TI - How to be proactive about interference: lessons from animal memory. AB - Processes of proactive interference were explored using the pigeon as a model system of memory. This study shows that proactive interference extends back in time at least 16 trials (and as many minutes), revealing a continuum of interference and providing a framework for studying memory. Pigeons were tested in a delayed same/different task containing trial-unique pictures. On interference trials, sample pictures from previous trials reappeared as test pictures on different trials. Proactive-interference functions showed greatest interference from the most recent trial and with the longer of two delays (10 s vs. 1 s). These interference functions are accounted for by a time-estimation model based on signal detection theory. The model predicts that accuracy at test is determined solely by the ratio of the elapsed time since the offset of the current-trial sample to the elapsed time since the offset of the interfering sample. Implications for comparing memory of different species and different types of memory (e.g., familiarity vs. recollection) are discussed. PMID- 22491143 TI - Warm thoughts: attachment anxiety and sensitivity to temperature cues. PMID- 22491144 TI - Current understanding of the immune response to tuberculosis in children. AB - PURPOSE OF REVIEW: Even in the era of promising molecular diagnostics for tuberculosis, understanding of the immune response remains urgent and fundamental to combating paediatric tuberculosis, given its paucibacillary nature. RECENT FINDINGS: Significant advances have been made in unravelling the contributions of previously underappreciated components of the immune response to Mycobacterium tuberculosis. Research into the role of the 'innate' immune system such as neutrophils alongside 'adaptive' cells such as CD4(+), CD8(+), polyfunctional and regulatory T cells has highlighted the complexity of their interactions. Lessons from children with congenital or acquired susceptibility to mycobacterial disease, including HIV, continue to illuminate a broader understanding of the host immune response. The role of vitamin D is becoming apparent and highlights the importance of the environmental and clinical context of patients, especially in high prevalence areas. Several approaches show promise as diagnostic tests and in monitoring treatment response, although distinguishing latent from active disease remains a challenge. SUMMARY: Research into novel immunological biomarkers, and greater understanding of the complex network of interactions between the innate and adaptive immune systems, is key to understanding why following exposure some children are unaffected, others latently infected and yet another group succumb to disease. PMID- 22491145 TI - The direct PAK1 inhibitor, TAT-PAK18, blocks preferentially the growth of human ovarian cancer cell lines in which PAK1 is abnormally activated by autophosphorylation at Thr 423. AB - So far no effective therapeutic has been developed for the FDA-approved treatment of ovarian cancer patients. Recently we provided the first evidence indicating that an old antibiotic (antiparasitic drug) called Ivermectin suppresses the growth of a variety of human ovarian cancer cell lines in vitro by inactivating the oncogenic kinase PAK1 somehow (Hashimoto H, et al. Drug Discov Ther. 2009;3:243-246). This kinase is now known to be essential for the growth of more than 70% of all human cancers including breast, prostate, pancreatic, colon, gastric, lung, cervical, thyroid cancers as well as hepatoma, glioma, melanoma, MM (multiple myeloma) and NF (neurofibromatosis) tumors. In this study, using the cell-permeable PAK1-inactivating peptide TAT-PAK18 which blocks the essential PAK1-PIX interaction, we examined the relationship between the sensitivity of ovarian cancer cell lines to this anti-PAK1 peptide and the protein expression/autophosphorylation levels of PAK1 in these cell lines, and found that the more PAK1 is abnormally activated (autophosporylated at Thr 423), the more their growth is sensitive to this peptide, regardless of their PAK1 expression levels. This observation provides the first direct evidence that ovarian cancers also belong to the PAK1-dependent cancers which represent more than 70% of all human cancers, suggesting that anti-PAK1 drugs would be effective therapeutics for ovarian cancers. PMID- 22491146 TI - Design, synthesis, and primary activity evaluation of pyrrolidine derivatives as matrix metalloproteinase inhibitors. AB - A series of novel pyrrolidine derivatives was designed, synthesized, and assayed to determine the derivatives' activity against matrix metalloproteinase-2 (MMP-2) and aminopeptidase N (APN)/CD13. Preliminary biological tests showed that most compounds inhibit MMP-2 in a highly selective manner compared to APN. Compounds 9d, 9e, and 9g had better inhibitory activity than LY52 and could be used as lead compounds in the future. PMID- 22491147 TI - Hypotensive response in rats and toxicological mechanisms induced by shuanghuanglian, an herbal extract mixture. AB - Shuanghuanglian (SHL), an extract mixture isolated from three medicinal herbs, has been used in China as an injection in traditional Chinese medicine to treat viral or bacterial infection. This study examined the hypotensive response in rats induced by SHL and its possible mechanisms. Mean arterial pressure (MAP) and electrocardiograms (ECGs) were studied after intravenous injection of histamine and SHL. Diphenhydramine, an H1 receptor antagonist, the compound 48/80, a promoter of histamine release, and cromolyn, a histamine release inhibitor, were also used to investigate the potential mechanisms of that response. In addition, the histamine level in plasma was measured after administration of SHL and compound 48/80. Both SHL and histamine led to a MAP reduction immediately but did not affect ECGs when initially administered in a similar manner, though this reduction was partially attenuated by diphenhydramine. Pretreatment blocked the rats' reaction to compound 48/80 but not to SHL. The plasma histamine level in rats was also elevated by SHL. SHL can induce severe hypotension through histamine release upon initial administration. In combination with the direct effects of its histaminelike substances on target tissue, SHL likely has the potential to cause an anaphylactoid reaction. PMID- 22491148 TI - In vitro modulating effects of glutathione on vascular tension and involvement of extracellular calcium. AB - This study investigated the involvement of endothelium and extracellular calcium on the vasorelaxant activity of glutathione (GSH) using in vitro model of isolated rat aorta.The aortic tensions upon treatment with GSH in the presence and absence of endothelium were compared in various conditions. In phenylephrine precontracted aortic rings, GSH (2-8 mM) significantly induced vasorelaxation in concentration-dependent manner. The influence of endothelium was demonstrated in determining the responses of aortic muscle toward GSH treatment. GSH (up to 5 mM) caused a higher loss of vascular tensions in the endothelium-intact aortic rings than those in the endothelium-denude preparations. The vasorelaxant effect of GSH in endotheliumintact rings was inhibited by glibenclamide (3 MUM), methylene blue (10 MUM) and N-nitro-L-arginine methyl ester (10 MUM), indicating the involvement of membrane K+ channels and NO-cGMP pathway. In the endothelium-denude preparations, only glibenclamide inhibited the modulating effect of GSH on aortic tension. Furthermore, the endothelium-dependent vasorelaxation of GSH was abolished in Ca2+-free medium containing EGTA, but not in the medium containing BAPTA-AM (10 MUM). Taken together, our findings suggested that vasorelaxant activity of GSH depended on influx of extracellular Ca2+ to activate NO production in endothelium cells. In addition, other possible mechanisms included its hyperpolarizing actions in vascular muscle cells. PMID- 22491149 TI - Evaluation of in vitro dissolution profile comparison methods of sustained release tramadol hydrochloride liquisolid compact formulations with marketed sustained release tablets. AB - The aim of the present work was to prepare and evaluate sustained release liquisolid compact formulations of tramadol hydrochloride. The dissolution profile of the prepared compacts was also compared to that of a marketed preparation. Liquisolid sustained release formulations were prepared by using HPMC K4M as a sustained release agent. Precompression studies of characteristics such as flow properties were also carried out. Liquisolid compacts were evaluated by hardness, friability, and in vitro dissolution studies. Comparison of dissolution profiles was carried out by using a modelindependent, model dependent, and statistical approach. The prepared liquisolid compacts are new dosage forms with better sustained release behavior compared to a marketed sustained formulation. The dissolution profile followed the Peppas model as "best fit" model. Two-way ANOVA results revealed a significant difference in dissolution profiles. This systematic approach to producing a formulation was found to help with analyzing the sustained release of tramadol hydrochloride. The use and evaluation of model-dependent methods is more complicated. These methods provide an acceptable model approach that indicates the true relationship between percent drug release and time variables, including statistical assumptions. PMID- 22491150 TI - Formulation and evaluation of clotrimazole from pluronic F127 gels. AB - Thermally re v e r s i b l e g e l s of poly(oxyethylene)-poly(oxypropylene)- poly(oxyethylene)-triblock copolymer, pluronic F127 (PF127), were evaluated as a vehicle for topical administration of clotrimazole as a model of a broad spectrum antifungal agent against superficial fungal infections. The solubility of clotrimazole was significantly increased as a linear function of pluronic F127 concentration at four temperatures. Clotrimazole was highly trapped by the micelles as indicated by a large partition coefficient. The micellar solubilization was a spontaneous (DeltaG < 0) and exothermic (DeltaH < 0) process which resulted in a less orderly state (DeltaS > 0). Different additives were used to enhance drug release from preparations including propylene glycol, polyethylene glycol 400, glycerin, and dimethyl sulfoxide at concentrations of 5 and 10% and polysorbate 80 at concentrations of 1 and 2%. Different formulae were characterized in terms of drug content, pH and particle size measurement, spreadability, rheological properties, drug release, diffusion, and permeation. The formulae showing the best drug release were selected to study the effect of storage on various parameters over a period of 6 months and for microbiological evaluation. The best release enhancers were propylene glycol and polyethylene glycol 400 at a concentration of 10% and polysorbate 80 at a concentration of 2% and the formulae containing it were stable and proved to be effective in inhibition. Furthermore they were tested microbiologically against three fungi as well as yeast. The antimicrobial activities of the tested preparations were compared with the pure drug at the same concentrations and also tested for their antifungal activity. It was found to be effective against Aspergillus niger, A. flaves, Candida albicans, and Sacharomyces cerevisiae with inhibition zones of 39, 39, 35, and 32 mm, respectively. PMID- 22491151 TI - Exposure-response modeling and clinical trial simulation of the effect of tolterodine on QT intervals in healthy volunteers. AB - The objective of this analysis was to explore exposure-response modeling of data from a thorough QT (TQT) study of tolterodine in CYP2D6 extensive (EMs) and poor metabolizers (PMs). Crossover treatments of the TQT study included the recommended (2 mg twice daily) and supratherapeutic (4 mg twice daily) doses of tolterodine, moxifloxacin (400 mg once daily), and placebo. The concentration response relationships for the QTc effects of moxifloxacin and tolterodine were described using a linear model with baseline effect, placebo effect, and a drug effect. The mixed effects modeling approach, using the first order conditional estimation method, was implemented in NONMEM. Simulated data from 250 trial replicates were used for limited predictive check and to describe the expected extreme responders in this study, under the derived model and point estimates. Modeling results for tolterodine showed linear concentrationdependent increases in QTc interval, with no difference in slopes between EMs and PMs. Modelpredicted QTc prolongations for tolterodine and moxifloxacin were consistent with their respective observed mean results. No subjects were predicted to have increases of > 60 milliseconds (ms); the predicted incidence of borderline QTc increases (> 30 and <= 60 ms) remained low at the supratherapeutic tolterodine dose in both PMs (9.1%) and EMs (3.9%). In conclusions, this analysis supports our clinical experience that tolterodine does not have a clinically significant effect on QT interval. PMID- 22491152 TI - Preparation of parasagittal slices for the investigation of dorsal-ventral organization of the rodent medial entorhinal cortex. AB - Computation in the brain relies on neurons responding appropriately to their synaptic inputs. Neurons differ in their complement and distribution of membrane ion channels that determine how they respond to synaptic inputs. However, the relationship between these cellular properties and neuronal function in behaving animals is not well understood. One approach to this problem is to investigate topographically organized neural circuits in which the position of individual neurons maps onto information they encode or computations they carry out. Experiments using this approach suggest principles for tuning of synaptic responses underlying information encoding in sensory and cognitive circuits. The topographical organization of spatial representations along the dorsal-ventral axis of the medial entorhinal cortex (MEC) provides an opportunity to establish relationships between cellular mechanisms and computations important for spatial cognition. Neurons in layer II of the rodent MEC encode location using grid-like firing fields. For neurons found at dorsal positions in the MEC the distance between the individual firing fields that form a grid is on the order of 30 cm, whereas for neurons at progressively more ventral positions this distance increases to greater than 1 m. Several studies have revealed cellular properties of neurons in layer II of the MEC that, like the spacing between grid firing fields, also differ according to their dorsal-ventral position, suggesting that these cellular properties are important for spatial computation. Here we describe procedures for preparation and electrophysiological recording from brain slices that maintain the dorsal-ventral extent of the MEC enabling investigation of the topographical organization of biophysical and anatomical properties of MEC neurons. The dorsal-ventral position of identified neurons relative to anatomical landmarks is difficult to establish accurately with protocols that use horizontal slices of MEC, as it is difficult to establish reference points for the exact dorsal-ventral location of the slice. The procedures we describe enable accurate and consistent measurement of location of recorded cells along the dorsal-ventral axis of the MEC as well as visualization of molecular gradients. The procedures have been developed for use with adult mice (> 28 days) and have been successfully employed with mice up to 1.5 years old. With adjustments they could be used with younger mice or other rodent species. A standardized system of preparation and measurement will aid systematic investigation of the cellular and microcircuit properties of this area. PMID- 22491153 TI - In people with hand osteoarthritis, chondroitin sulphate therapy for 6 months improves pain and function compared with placebo. PMID- 22491154 TI - Systematic reviews to evaluate causation: an overview of methods and application. AB - Currently systematic reviews focus on diagnosis or effectiveness of treatment. It is the understanding of disease aetiology that underpins medical education, practice and research. Whether an association meets causal criteria is usually assessed qualitatively. However, this can also be examined through evidence synthesis and systematic reviews to evaluate disease causation and mechanisms are much needed. It is important in such a review to specify the questions to be addressed regarding causal criteria such as strength, consistency, temporality, specificity, biological gradient, plausibility and experimental evidence. The next step is to conduct a thorough literature search to identify the relevant studies and to assess them for their quality, particularly in relation to the risk of bias, ascertainment of exposures and ascertainment of outcomes. Data synthesis can then examine if the observed associations in collated studies are consistent, strong and temporal using techniques such as meta-analysis, testing for heterogeneity and meta-regression. Biological plausibility and coherence with existing theories can also be examined systematically through an assessment of the basic scientific literature. Experimental evidence might also be collated and synthesised to determine if removal of a causal agent alters the outcome. Through these steps a systematic review can help to establish whether an association is causal or not. PMID- 22491155 TI - Delivering minocycline into brain endothelial cells with liposome-based technology. AB - Minocycline has been proposed as a way to blunt neurovascular injury from matrix metalloproteinases (MMPs) during stroke. However, recent clinical trials suggest that high levels of minocycline may have deleterious side-effects. Here, we showed that very high minocycline concentrations damage endothelial cells via calpain/caspase pathways. To alleviate this potential cytotoxicity, we encapsulated minocycline in liposomes. Low concentrations of minocycline could not reduce tumor necrosis factor alpha (TNFalpha)-induced MMP-9 release from endothelial cells. But low concentrations of minocycline-loaded liposomes significantly reduced TNFalpha-induced MMP-9 release. This study provides proof of-concept that liposomes may be used to deliver lower levels of minocycline for targeting MMPs in cerebral endothelium. PMID- 22491156 TI - Imaging of perfusion, angiogenesis, and tissue elasticity after stroke. AB - Blood flow interruption in a cerebral artery causes brain ischemia and induces dramatic changes of perfusion and metabolism in the corresponding territory. We performed in parallel positron emission tomography (PET) with [(15)O]H(2)O, single photon emission computed tomography (SPECT) with [(99m)Tc]hexamethylpropylene-amino-oxime ([(99m)Tc]HMPAO) and ultrasonic ultrafast shear wave imaging (SWI) during, immediately after, and 1, 2, 4, and 7 days after middle cerebral artery occlusion (MCAO) in rats. Positron emission tomography and SPECT showed initial hypoperfusion followed by recovery at immediate reperfusion, hypoperfusion at day 1, and hyperperfusion at days 4 to 7. Hyperperfusion interested the whole brain, including nonischemic areas. Immunohistochemical analysis indicated active angiogenesis at days 2 to 7, strongly suggestive that hyperperfusion was supported by an increase in microvessel density in both brain hemispheres after ischemia. The SWI detected elastic changes of cerebral tissue in the ischemic area as early as day 1 after MCAO appearing as a softening of cerebral tissue whose local internal elasticity decreased continuously from day 1 to 7. Taken together, these results suggest that hyperperfusion after cerebral ischemia is due to formation of neovessels, and indicate that brain softening is an early and continuous process. The SWI is a promising novel imaging method for monitoring the evolution of cerebral ischemia over time in animals. PMID- 22491157 TI - Probing hydrogen positions in hydrous compounds: information from parametric neutron powder diffraction studies. AB - We demonstrate the extent to which modern detector technology, coupled with a high flux constant wavelength neutron source, can be used to obtain high quality diffraction data from short data collections, allowing the refinement of the full structures (including hydrogen positions) of hydrous compounds from in situ neutron powder diffraction measurements. The in situ thermodiffractometry and controlled humidity studies reported here reveal that important information on the reorientations of structural water molecules with changing conditions can be easily extracted, providing insight into the effects of hydrogen bonding on bulk physical properties. Using crystalline BaCl2.2H2O as an example system, we analyse the structural changes in the compound and its dehydration intermediates with changing temperature and humidity levels to demonstrate the quality of the dynamic structural information on the hydrogen atoms and associated hydrogen bonding that can be obtained without resorting to sample deuteration. PMID- 22491158 TI - Kulinkovich-type reactions of thioamides: similar to those of carboxylic amides? AB - The behaviour of thioamides under Kulinkovich-type conditions is compared with the known reactivity of carboxylic amides. Dramatic differences are disclosed. PMID- 22491159 TI - Comparison of the novel Angio-Seal Evolution with Angio-Seal STS closure device. AB - BACKGROUND: Angio-Seal Evolution (ASE) is a novel vascular closure device (VCD) engineered to reduce deployment skills. It is unknown if these changes translated into better clinical results. METHODS AND RESULTS: Early VCD failure and major and minor vascular complications were prospectively assessed in 584 consecutive patients treated by ASE (ASE group) and in 633 consecutive patients treated by the older Angio-Seal STS (AS-STS group). Early VCD failure was rare (ASE 1.7% vs AS-STS 1.3%, P = .52). Major vascular complication risk was similar (odds ratio [OR] = 1.76, 95% confidence interval [CI] = 0.79-3.90, P = .17), but minor vascular complication rate was significantly higher in the ASE group (OR = 3.36, 95% CI = 1.57-7.21, P = .002). At logistic regression ASE was an independent predictor of vascular complications. Early VCD failure was associated with the highest risk for vascular complications. CONCLUSIONS: In a large unselected population, ASE-treated patients showed increased risk for minor vascular complications. Early VCD failure negatively affected short-term vascular prognosis. PMID- 22491160 TI - Fruit volatile analysis using an electronic nose. AB - Numerous and diverse physiological changes occur during fruit ripening, including the development of a specific volatile blend that characterizes fruit aroma. Maturity at harvest is one of the key factors influencing the flavor quality of fruits and vegetables. The validation of robust methods that rapidly assess fruit maturity and aroma quality would allow improved management of advanced breeding programs, production practices and postharvest handling. Over the last three decades, much research has been conducted to develop so-called electronic noses, which are devices able to rapidly detect odors and flavors. Currently there are several commercially available electronic noses able to perform volatile analysis, based on different technologies. The electronic nose used in our work (zNose, EST, Newbury Park, CA, USA), consists of ultra-fast gas chromatography coupled with a surface acoustic wave sensor (UFGC-SAW). This technology has already been tested for its ability to monitor quality of various commodities, including detection of deterioration in apple; ripeness and rot evaluation in mango; aroma profiling of thymus species; C(6) volatile compounds in grape berries; characterization of vegetable oil and detection of adulterants in virgin coconut oil. This system can perform the three major steps of aroma analysis: headspace sampling, separation of volatile compounds, and detection. In about one minute, the output, a chromatogram, is produced and, after a purging cycle, the instrument is ready for further analysis. The results obtained with the zNose can be compared to those of other gas-chromatographic systems by calculation of Kovats Indices (KI). Once the instrument has been tuned with an alkane standard solution, the retention times are automatically converted into KIs. However, slight changes in temperature and flow rate are expected to occur over time, causing retention times to drift. Also, depending on the polarity of the column stationary phase, the reproducibility of KI calculations can vary by several index units. A series of programs and graphical interfaces were therefore developed to compare calculated KIs among samples in a semi-automated fashion. These programs reduce the time required for chromatogram analysis of large data sets and minimize the potential for misinterpretation of the data when chromatograms are not perfectly aligned. We present a method for rapid volatile compound analysis in fruit. Sample preparation, data acquisition and handling procedures are also discussed. PMID- 22491161 TI - Development of mitochondrial permeability transition inhibitory agents: a novel drug target. AB - Apoptosis is a genetically conserved mechanism that eliminates unnecessary or surplus cells and is also involved in the pathomechanism of a wide variety of diseases. The intrinsic pathway of apoptosis includes the mitochondria where numerous pro-apoptotic proteins are sequestered and their release marks the point of-no-return, indicating the ultimate commitment to cell death. The mitochondrial permeability transition (mPT) is a mechanism enabling the release of Cytochrome-c (Cyt-c), AIF and other pro-apoptotic proteins, and is characterized by an alteration in the permeability of the organelle's membrane. This is due to reactive oxygen species or Ca(2+) triggered dynamic assemble of a trans bi membrane channel from various protein components including the voltage dependent anion channel, the adenine nucleotide translocase, the cyclophyllin D that enables solutes up to 1.5 kDa to pass through. The resultant influx of water into the mitochondrial matrix leads to mitochondrial swelling and the rupture of the membranes. Numerous agents can inhibit mPT including amiodarone, a widely used antiarrhythmic agent. Modification of this benzofuran derivate with nitroxides or their secondary amine derivates that exhibits antioxidant properties leads to the enhancement of mPT inhibitory effect of the original compound. Furthermore this hybrid compound is also capable of influencing the necrotic cell death pathway. This strategy may prove to be beneficial to increase the effectiveness of other mPT inhibitory agents. However, further studies are necessary to identify the components and structure of the permeability transition pore in order to design more effective mPT inhibitory compounds to fully exploit the therapeutic potential of this novel drug target. PMID- 22491162 TI - Uses of single-particle tracking in living cells. AB - Single-particle tracking (SPT) techniques have been developing rapidly in the field of cellular biology as a means of unraveling the diffusion dynamics of bio molecules and the function of proteins in the regulation of cellular activity at single molecule sensitivity and nanometer spatial resolution. Suitable probes and technological improvements have made SPT more accessible than it used to be and paved the way for broad applications in cellular biology. This review summarizes the principles of SPT and discusses the main findings yielded by the technique and its contribution to the understanding of proteins in living cells. PMID- 22491163 TI - Proton magnetic resonance ((1)HNMR) spectroscopy and physicochemical studies of zaleplon-hydroxypropyl-beta-cyclodextrin inclusion compounds. AB - Proton magnetic resonance spectroscopy ((1)HNMR) studies on inclusion compounds of zaleplon with hydroxypropyl-beta- cyclodextrin (HPbetaCD) were carried out in order to elucidate the strength and binding mode of association. Chemical shift measurements revealed that inclusion complexes of zaleplon and HPbetaCD were formed by penetration of aromatic rings into the HPbetaCD cavity from the wider rim side with deep penetration of the amide-substituted ring while inclusion of the cyano-substituted pyrazole ring was shallow. A higher magnitude of DeltadeltaH-3' and DeltadeltaH-5' protons of HPbetaCD indicated higher stability of the lyophilized product than the kneaded one. Even from the values of DeltadeltaH-5'/DeltadeltaH-3', it could be concluded that zaleplon deeply penetrated inside the HPbetaCD cavity in the lyophilized product as compared to the kneaded product. The stoichiometry of the inclusion complexes was assessed to be a 1:1 molar ratio with an AL-type of phase solubility curve and a stability constant of 57.89 +/- 1.82 M-1, according to Higuchi and Connors. In the case of dissolution experiments, a lyophilized product displayed a higher release rate of zaleplon (DE30: 77.64 +/- 5.74) than the kneaded complex and physical mixture. PMID- 22491164 TI - Enhancement of the dissolution profile of allopurinol by a solid dispersion technique. AB - The aim of the present study was to improve the solubility, and therefore the dissolution of poorly water-soluble allopurinol. Solid dispersions of allopurinol were prepared with different polymers or carriers such as polyvinylpyrrolidone (PVP K30 and PVP K90), polyethylene glycol (PEG 4000 and PEG 6000), urea and mannitol at two drug : carrier ratios (1:1) and (1:2). Different methods such as melting and solvent evaporation methods were used to improve dissolution characteristics and solubility of allopurinol. The solid dispersions were characterized using a differential scanning calorimeter (DSC) and X-ray diffraction (XRD) while the interactions which took place were identified with fourier transform infrared (FTIR) spectroscopy. Due to formation of hydrogen bonds between allopurinol and urea and mannitol, a transition of allopurinol from the crystalline to amorphous state was achieved. The DSC thermograms of the solid dispersions indicated the potential of heat induced interactions between allopurinol and the carriers used could influence dissolution rate of the drug. The dissolution amount (%) of pure allopurinol was 80% at 45 min. F5, F3, F6, F7, and F1 showed better dissolution percentages of 100, 93, 92.4, 90.6, and 89%, respectively, at 45 min. PMID- 22491165 TI - Formulation and bioavailability of controlled release salbutamol sulphate tablets using natural additives. AB - Salbutamol sulphate granules and physical mixtures were prepared using mastic with various natural additives. The prepared granules and physical mixtures were examined using IR and DSC. The obtained results indicate that there is no interaction between salbutamol sulphate and the formulation ingredients used. The physical properties and release behavior of the formulated tablets prepared from granules and physical mixtures were evaluated and showed good physical properties. The rate of drug release from tablets prepared from granules was found to be lower than that prepared from physical mixtures at fixed mastic concentration and the same additive. The rate of drug release decreased with increased mastic concentration in formulated tablets. Pectin and sodium alginate allowed the best controlled release rate of the drug. On the basis of the results obtained from the controlled release studies, selected sulbutamol formulations were subjected to an in vivo comparison with commercial sulbutamol tablets. The pharmacokinetic parameters AUC(0-24), C(max), and T(max) of sulbutamol from the selected formulation were determined after administration of a single oral dose of 8 mg and compared statistically using an ANOVA test. There was no significant difference in the AUC(0-24). On the other hand, there was a significant difference in the C(max) and T(max) between the commercial and the formulated tablets. These results demonstrate that the formulated tablets extended the time of the drug effect. PMID- 22491166 TI - Stability, bioavailability, and ulcerative activity of diclofenac sodium-mastic controlled release tablets. AB - Controlled release tablets containing 50 mg diclofenac sodium (DS) and 40% mastic with other natural additives were prepared. Drug release was examined and stability was studied using non-isothermal and isothermal thermogravimetric analysis (TGA). The bioavailability of two controlled release tablet formulations was studied and compared to that of commercial tablets, and rabbit stomachs were also histologically examined 24 h after administration of the various tablets. Additives of pectin and sodium alginate indicated the controlled release profile of the drug. Non-isothermal TG revealed two stages of thermal decomposition for all formulations. Isothermal TG revealed that degradation of the drug in the tablet formulations follows first-order kinetics. The obtained degradation rate constants at various temperatures were plotted according to the Arrhenius equation. The degradation rate constant at 25 degrees C was determined and used in estimation of shelf life. The obtained shelf lives of all formulations ranged from 3.38-4.92 years. In comparative studies with commercial tablets, the bioavailability of the drug from the two formulated tablets had no statistically significant difference in terms of the AUC and produced prolonged blood levels of DS with a delayed peak. The two controlled release tablet formulations resulted in no histological alterations in the stomach in terms of mucous surface cells and glands; in comparison, commercial tablets resulted in a disrupted mucous layer, necrotic ulcerations, hemorrhaging, and inflammatory cell infiltration along the base of the gastric glands. PMID- 22491167 TI - Biopharmaceutical evaluation of formulated metformin/rosiglitazone tablets. AB - The study aimed to combine two antidiabetic agents with different mechanisms of action, namely, metformin HCl and rosiglitazone maleate, in a tablet to improve glycemic control in patients with type II diabetes. The preformulation study started with development and validation of an HPLC method for the determination of both drugs in the mixture. The results of visual inspection, TLC, DSC, and FT IR verified the absence of any physical or chemical interaction between both compounds. Four compatible excipients were selected for the formulation of the tablets by wet granulation according to a 2(2) factorial design. The prepared tablet blends were acceptable in terms of the modal size of particle distribution, bulk density, Hausner's ratio, Carr's index, and flowability. All formulations fulfilled the pharmacopoeial specifications for weight variation, content uniformity, friability, and hardness. They released 100% of the drug during the first 45 min, displaying higher dissolution efficiency than commercially available Rosiplus tablets. The tablet formulation that passed the physical and chemical stability study for 24 months at ambient conditions was tested in vivo on healthy volunteers in a cross-over design. Statistical analysis proved that the prepared tablets were bioequivalent to the commercial ones in terms of both the rate and the extent of absorption. PMID- 22491168 TI - Calcium alginate cross-linked polymeric microbeads for oral sustained drug delivery in arthritis. AB - After the successful optimization and development of a drug entity, design of dosage form then plays an important role. Hence, research continuously keeps on searching for ways to deliver drugs over an extended period of time. With aceclofenac, a novel NSAID used in the treatment of rheumatoid arthritis, frequency of administration may cause certain GI-adverse effects. The objective of the present research work was to develop a microparticulate oral sustained release dosage form, to reduce dosing frequency, to eliminate the dose related adverse effects and to ultimately improve compliance in the pharmacotherapy of arthritis. The microbeads were prepared by an ionotropic external gelation technique, by using sodium alginate as the hydrophilic carrier and calcium chloride as the cross-linking agent. The shape and surface characteristics were determined by scanning electron microscopy (SEM). Particle size distribution was determined by an optical microscope. The physical state of the drug in the formulation was determined by differential scanning calorimetry (DSC). While increasing the concentration of sodium alginate dispersion increased flow properties, mean particle size, swelling ratio and drug entrapment efficiency. The mean particle sizes of drug-loaded microbeads were found to be in the range 596.45 +/- 1.04 to 880.10 +/- 0.13 MUm. The drug entrapment efficiency was obtained in the range of 63.24-98.90% (w/v). The release of drug from the microbeads at pH 1.2 is negligible. Under neutral conditions, the beads will swell and the drug release depends on swelling and the erosion process resulting in an optimum level of drug released in a sustained manner which exhibits zero order kinetics. PMID- 22491169 TI - Effects of lubricants on binary direct compression mixtures. AB - The objective of this study was to investigate the effects of conventional lubricants including a new candidate lubricant on binary direct compression mixtures. Magnesium stearate (MGST), stearic acid (STAC), glyceryl behenate (COMP) and hexagonal boron nitride (HBN) were tested. The binary mixtures were 1:1 combinations of spray dried lactose (FlowLac 100), dicalcium phosphate dihydrate (Emcompress), and modified starch (Starch 1500) with microcrystalline cellulose (Avicel PH 102). Tablets were manufactured on a single-station instrumented tablet press with and without lubricants. In the case of unlubricated granules, the modified starch-microcrystalline cellulose mixture provided the highest percent compressibility value at 8.25%, spray dried lactose microcrystalline cellulose mixture was 7.33%, and the dialcium phosphate dihydrate-microcrystalline cellulose mixture was 5.79%. Their corresponding tablet crushing strength values were: 104 N, 117 N, and 61 N, respectively. The lubricant concentrations studied were 0.5, 1, 2, and 4%. Effects of lubricant type and lubricant concentration on crushing strength were analyzed using a factorial ANOVA model. It was found that the Avicel PH 102-Starch 1500 mixture showed the highest lubricant sensitivity (110 N vs. 9 N), the least affected formulation was FlowLac-Avicel PH 102 mixture (118 N vs. 62 N). The crushing strength vs. concentration curve for MGST showed a typical biphasic profile, a fast drop up to 1% and a slower decline between 1 and 4%. The STAC, COMP, and HBN for all formulations showed a shallow linear decline of tablet crushing strength with increasing lubricant concentration. The HBN was as effective as MGST as a lubricant, and did not show a significant negative effect on the crushing strength of the tablets. The COMP and STAC also did not interfere with the crushing strength, however, they were not as effective lubricants as MGST or HBN. PMID- 22491170 TI - Effects of the herbal medicine Hachimi-jio-gan (Ba-Wei-Di-Huang-Wan) on insulin secretion and glucose tolerance in type 2 diabetic Goto-Kakizaki rats. AB - Hachimi-jio-gan (HJ) is a Chinese medicine that has been widely used for the treatment of nephrotic syndromes, hypertension, and diabetes mellitus. We reported that HJ lowers plasma glucose in type 1 diabetic rats. We investigated the effects of HJ on diabetic hyperglycemia and insulin secretion in type 2 diabetic Goto-Kakizaki (GK) rats. Eight-week-old diabetic GK rats were given free access to pellets containing 1% HJ extract powder for 14 weeks. HJ consumption increased the food intake and body weight of these rats in comparison to control rats. HJ may control the body weight loss observed in GK rats. HJ also reduced hyperglycemia in diabetic GK rats, and it significantly increased insulin secretion in non-fasting GK rats over the experimental period. In oral glucose tolerance tests, HJ significantly improved the insulin response at 30 min and reduced the plasma glucose level at 60 min after glucose administration (p < 0.05). Ten weeks after administration, the plasma leptin levels significantly increased in the HJ group rats. These results demonstrate that in diabetic GK rats, HJ decreased the level of postprandial glucose via enhanced insulin secretion coupled with the regulation of food intake by leptin. PMID- 22491171 TI - Phagocytosis plays a dual role in activating dendritic cells; digestive production of active Toll-like receptor ligands and cooperation with Toll-like receptor signaling. AB - Phagocytosis is an initial step in innate immunity, which is also stimulated by signals via Toll-like receptors (TLRs); however, the cooperation of phagocytosis with signals through TLRs to establish acquired immunity is unknown. We found that phagocytosis is an essential process to induce an immune reaction against an insoluble TLR ligand. Cell-wall skeleton prepared from Mycobacterium bovis BCG (BCG-CWS), an insoluble TLR2 ligand, activated and matured murine splenic dendritic cell (DC) line BC-1 as well as a soluble TLR2 ligand, Pam3CSK4. Surprisingly, BC-1 maturation with BCG-CWS was completely suppressed by inhibiting phagocytosis, while that with Pam3CSK4 was not affected. Moreover, BCGCWS induced intense delayed-type hypersensitivity (DTH) reactions against mitomycin C-inactivated Lewis lung carcinoma cells but Pam3CSK4 did not. These results suggested that the phagocytosis process enables the insoluble TLR2 ligand to activate DCs via TLR2 comparable to a soluble TLR2 ligand in vitro, and stimulating TLR2 alone is not sufficient to establish T cell-mediated immunity in vivo. It is therefore conceivable that the process of phagocytosis induces additional effects on TLR2-stimulated DCs to activate cellmediated immunity in vivo. PMID- 22491172 TI - Two-dimensional (14)N HYSCORE spectroscopy of the coordination geometry of ligands in dimanganese di-MU-oxo mimics of the oxygen evolving complex of photosystem II. AB - We use two-dimensional hyperfine sublevel correlation (HYSCORE) spectroscopy to investigate the coordination geometry of the nitrogen ligands of biomimetic models of the oxygen-evolving complex of photosystem II. In the 2D HYSCORE spectroscopy study, [(bpy)2Mn(III)(MU-O)2Mn(IV)(bpy)2](ClO4)3 (bpy, 2,2' bipyridine) (1) and [H2O(terpy)Mn(III)(MU-O)2Mn(IV)(terpy)OH2](NO3)3 (terpy = 2,2':6',2"-terpyridine) (2) exhibit electron-nuclear hyperfine interactions that depend on both the oxidation state of the manganese ion and the geometry of the nitrogen ligand. We observe four types of (14)N hyperfine interactions corresponding to the Mn(iii) and Mn(iv) ion of each mixed-valence complex and the equatorial and axial geometry of the ligand, respectively. The strongest and the weakest hyperfine interactions arise from the axial and equatorial ligands of the Mn(iii) ion, respectively. The hyperfine interactions of intermediate strength are due to the axial and equatorial ligands of the Mn(iv) ion. Based on the results of this study, we assign the location and ligand geometry of the Mn(iii) ion of the tetranuclear manganese-calcium-oxo cluster in the S2 state of photosystem II. PMID- 22491173 TI - A 3D star-shaped non-fullerene acceptor for solution-processed organic solar cells with a high open-circuit voltage of 1.18 V. AB - A novel 3D star-shaped acceptor based on triphenylamine as a core and diketopyrrolopyrrole as arms (S(TPA-DPP)) was synthesized. S(TPA-DPP) exhibited excellent thermal stability, strong absorption, and very high open-circuit voltage (1.18 V) in solution-processed organic solar cells based on P3HT:S(TPA DPP). PMID- 22491174 TI - Sample size and power calculations for medical studies by simulation when closed form expressions are not available. AB - This paper shows how Monte Carlo simulation can be used for sample size, power or precision calculations when planning medical research studies. Standard study designs can lead to the use of analysis methods for which power formulae do not exist. This may be because complex modelling techniques with optimal statistical properties are used but power formulae have not yet been derived or because analysis models are employed that divert from the population model due to lack of availability of more appropriate analysis tools. Our presentation concentrates on the conceptual steps involved in carrying out power or precision calculations by simulation. We demonstrate these steps in three examples concerned with (i) drop out in longitudinal studies, (ii) measurement error in observational studies and (iii) causal effect estimation in randomised controlled trials with non compliance. We conclude that the Monte Carlo simulation approach is an important general tool in the methodological arsenal for assessing power and precision. PMID- 22491175 TI - Sexual development and ascospore discharge in Fusarium graminearum. AB - Fusarium graminearum has become a model system for studies in development and pathogenicity of filamentous fungi. F. graminearum most easily produces fruiting bodies, called perithecia, on carrot agar. Perithecia contain numerous tissue types, produced at specific stages of perithecium development. These include (in order of appearance) formation of the perithecium initials (which give rise to the ascogenous hyphae), the outer wall, paraphyses (sterile mycelia which occupy the center of the perithecium until the asci develop), the asci, and the ascospores within the asci. The development of each of these tissues is separated by approximately 24 hours and has been the basis of transcriptomic studies during sexual development. Refer to Hallen et al. (2007) for a more thorough description of development, including photographs of each stage. Here, we present the methods for generating and harvesting synchronously developing lawns of perithecia for temporal studies of gene regulation, development, and physiological processes. Although these methods are written specifically to be used with F. graminearum, the techniques can be used for a variety of other fungi, provided that fruiting can be induced in culture and there is some synchrony to development. We have recently adapted this protocol to study the sexual development of F. verticillioides. Although individual perithecia must be hand picked in this species, because a lawn of developing perithecia could not be induced, the process worked well for studying development (Sikhakolli and Trail, unpublished). The most important function of fungal fruiting bodies is the dispersal of spores. In many of the species of Ascomycota (ascus producing fungi), spores are shot from the ascus, due to the generation of turgor pressure within the ascus, driving ejection of spores (and epiplasmic fluid) through the pore in the ascus tip. Our studies of forcible ascospore discharge have resulted in development of a "spore discharge assay", which we use to screen for mutations in the process. Here we present the details of this assay. F. graminearum is homothallic, and thus can form fruiting bodies in the absence of a compatible partner. The advantage of homothallism is that crossing is not necessary to generate offspring homozygous for a particular trait, a facet that has facilitated the study of sexual development in this species. However, heterothallic strains have been generated that can be used for crossing. It is also possible to cross homothallic strains to obtain mutants for several genes in one strain. This is done by coinoculating one Petri dish with 2 strains. Along the meeting point, the majority of perithecia will be recombinant (provided a mutation in one of the parent strains does not inhibit outcrossing). As perithecia age, they exude ascospores en masse instead of forcibly discharging them. The resulting spore exudate (called a cirrhus) sits at the tip of the perithecium and can easily be removed for recovery of individual spores. Here we present a protocol to facilitate the identification of recombinant perithecia and the recovery of recombinant progeny. PMID- 22491176 TI - The role of neutrophils during intestinal inflammation. AB - Polymorphonuclear leukocytes or neutrophils play a critical role in the maintenance of intestinal homeostasis. They have elegant defense mechanisms to eliminate microbes that have translocated across a single layer of mucosal epithelial cells that form a critical barrier between the gut lumen and the underlying tissue. During the inflammatory response, neutrophils also contribute to the recruitment of other immune cells and facilitate mucosal healing by releasing mediators necessary for the resolution of inflammation. Although the above responses are clearly beneficial, excessive recruitment and accumulation of activated neutrophils in the intestine under pathological conditions such as inflammatory bowel disease is associated with mucosal injury and debilitating disease symptoms. Thus, depending on the circumstances, neutrophils can be viewed as either good or bad. In this article, we summarize the beneficial and deleterious roles of neutrophils in the intestine during health and disease and provide an overview of what is known about neutrophil function in the gut. PMID- 22491178 TI - Free radicals in the regulation of damage and cell death - basic mechanisms and prevention. AB - Reactive oxygen (ROS) and nitrogen (RNS) species are known to accumulate intracellularly due to both exogenous and/or endogenous factors. In normal physiological conditions, these reactive species are maintained in an equilibrium state by the cells' antioxidant defence systems. In addition, they are recognised to play important roles in several physiological functions. However, when an imbalance in the equilibrium between oxidants and antioxidants occurs in favour of the former, we come to a situation defined as oxidative stress. ROS/RNS can cause damage to all biomolecules (namely proteins, lipids and DNA) and ultimately participate in the regulation of mechanisms leading to cell death, being implicated in the etiology of several pathologies (like neurodegenerative and cardiovascular diseases). To cope with oxidative stress, cells possess effective enzymatic (e.g. superoxide dismutase, catalase, glutathione peroxidase) and non enzymatic (e.g. glutathione, thioredoxin, coenzyme Q) antioxidant systems. In addition, several compounds present in plants and vegetables (e.g. vitamins C and E, polyphenols) have been described to react with free radicals. However, some drawbacks associated to these natural compounds are in part responsible for the undergoing development of novel synthetic compounds capable of acting as antioxidants and protect cells against oxidative stress-induced cell death. Here, we review the basic mechanisms of ROS/RNS formation, as well as their interaction with biomolecules and regulation of cell death, in order to identify possible drug targets. We also report the importance of natural antioxidant systems and the ongoing research leading to the development of more powerful and effective antioxidant drugs. PMID- 22491179 TI - 3D QSAR investigations on locomotor activity of 5-cyano-N1,6-disubstituted 2 thiouracil derivatives. AB - Three dimensional quantitative structure activity relationship (3D QSAR) investigations were carried out on a series of 5-cyano-N1,6-disubstituted 2 thiouracil derivatives for their locomotor activity. The structures of all compounds were built on a workspace of VlifeMDS3.5 molecular modeling software and 3D QSAR models were generated by applying a partial least square (PLS) linear regression analysis coupled with a stepwise variable selection method. Both derived models were found to be statistically significant in terms of regression and internal and external predictive ability (r(2) = 0.9414 and 0.8511, q(2) = 0.8582 and 0.6222, pred_r(2) = 0.5142 and 0.7917). The QSAR models indicated that both electrostatic and steric interaction energies were contributing significantly to locomotor activity of thiouracil derivatives. PMID- 22491177 TI - Targeted deletion of MyD88 in intestinal epithelial cells results in compromised antibacterial immunity associated with downregulation of polymeric immunoglobulin receptor, mucin-2, and antibacterial peptides. AB - Intestinal epithelial cells (IECs) form a physical and immunological barrier that separates the vast gut microbiota from host tissues. MyD88-dependent Toll-like receptor signaling is a key mediator of microbial-host cross-talk. We examined the role of epithelial MyD88 expression by generating mice with an IEC-targeted deletion of the Myd88 gene (MyD88(DeltaIEC)). Loss of epithelial MyD88 signaling resulted in increased numbers of mucus-associated bacteria; translocation of bacteria, including the opportunistic pathogen Klebsiella pneumoniae, to mesenteric lymph nodes; reduced transmucosal electrical resistance; impaired mucus-associated antimicrobial activity; and downregulated expression of polymeric immunoglobulin receptor (the epithelial IgA transporter), mucin-2 (the major protein of intestinal mucus), and the antimicrobial peptides RegIIIgamma and Defa-rs1. We further observed significant differences in the composition of the gut microbiota between MyD88(DeltaIEC) mice and wild-type littermates. These physical, immunological, and microbial defects resulted in increased susceptibility of MyD88(DeltaIEC) mice to experimental colitis. We conclude that MyD88 signaling in IECs is crucial for maintenance of gut homeostasis. PMID- 22491181 TI - Rehmanniae Radix provides most of the free fructose and glucose in Si-Wu-Tang decoction. AB - Our previous study showed that free fructose is an important active constituent responsible for Si-Wu-Tang's (SWT) effect promoting hematopoiesis and immunity. However, the contribution from SWT's four ingredient drugs to the free fructose content in the SWT decoction was not clear. To answer this question, in this study, the fructose, glucose and sucrose content in the SWT decoction, in the decoctions of each single ingredient drug, and in the decoctions of the four formulae lacking each single ingredient drug were determined by HPLC-ELSD. The results showed that the fructose and glucose content in the decoction of single Rehmanniae Radix were almost the same as those in the SWT decoction. In the single Rehmanniae Radix decoction concentrations were: 4.25 +/- 0.53 mg/mL for fructose, and 3.43 +/- 0.60 mg/mL for glucose; in the SWT decoction concentrations were: 4.10 +/- 0.43 mg/mL for fructose, and 3.42 +/- 0.32 mg/mL for glucose, while the content of fructose and glucose in the decoctions of single Angelica Radix, single Paeoniae Radix, single Chuanxiong Rhizoma and the formula lacking Rehmanniae Radix were either very small or undetectable. On the other hand, the fructose and glucose content in the decoctions of the formulae lacking Angelica Radix, lacking Paeoniae Radix and lacking Chuanxiong Rhizoma also were approximately the same as those in the SWT decoction. This indicated that Rehmanniae Radix provides most of the free fructose and glucose in the SWT decoction, and therefore plays an important role in SWT's effect promoting hematopoiesis and immunity. As for sucrose in the SWT decoction, Angelica Radix was shown to be a major donor. PMID- 22491180 TI - Serum fructose concentration in rats after single dose oral administration of Si Wu-Tang. AB - Our previous study showed that fructose is an important active constituent that is responsible for Si-Wu-Tang's (SWT) effects promoting hematopoiesis and immunity. In order to provide primary data for analysis of the mechanism of fructose's bioactivity, the concentration of serum fructose in rats after a single oral administration dose of Si-Wu-Tang was determined. The concentration of serum fructose in fasting rats was 0.34 +/- 0.24 mg/dL. After oral administration of 7.2 mL per kg body weight of SWT extract (1 mL extract corresponds to 1 g SWT dried herbs), serum fructose levels reached a peak concentration of 1.03 +/- 0.25 mg/dL within 60 min, and then declined to the baseline level within 180 min, a pattern which is similar to the one reported for oral administration of pure fructose. The peak concentration was only 2-3 times higher than the baseline serum fructose concentration. These results showed that the increase of blood fructose concentration after oral administration of SWT is small and transient, which is very probably due to the quick metabolism of fructose by the liver. We suggest, for future research, it is necessary to consider the probability that fructose's bioactivity on hematopoiesis and immunity is not exerted by fructose in its original form, but after it is metabolized by the liver. PMID- 22491182 TI - Effects of components present in flaxseed on human colon adenocarcinoma Caco-2 cells: Possible mechanisms of flaxseed on colon cancer development in animals. AB - Previous studies from our laboratory have shown chemopreventive effects of dietary flaxseed on azoxymethane-induced colon tumor development in male Fischer rats and Apc(Min) mice. Tumorigenesis is associated with uncontrolled cell growth and loss of apoptosis. Accordingly, the objective of this investigation was to study the effects of mammalian lignans (enterodiol and enterolactone) and omega-3 polyunsaturated fatty acid alpha-linolenic acid, principal active components in flaxseed on cell proliferation and apoptosis in human colon adenocarcinoma Caco-2 cells, thus elucidating possible mechanism of action. BrdU incorporation assay was used for cell proliferation and fluorescence-activated cell sorting (FACS) analysis of annexin V/propidium iodide staining was used for determining apoptotic cells. Results showed that enterodiol, enterolactone and alpha linolenic acid at different concentrations caused a significant (p < 0.05) increase in apoptotic cells and decrease in cell proliferation. Therefore, dietary flaxseed containing alpha-linolenic acid and lignans causes a decrease in cell proliferation and an increase in apoptosis resulting in the effective chemoprevention for intestinal and colon tumor development. PMID- 22491184 TI - Isolation and structure elucidation of antioxidant compounds from leaves of Laurus nobilis and Emex spinosus. AB - In recent years, there has been increasing interest in finding naturally occurring antioxidants from plants for use in food and medicinal materials to replace synthetic antioxidants since such antioxidants are being restricted due to their side effects like carcinogenicity. The aim of this work was to examine the in vitro antioxidant activity of Laurus nobilis and Emex spinosus leaves and to isolate and structurally elucidate the active compounds in those leaves. The aqueous ethanolic extracts (70%) of Laurus nobilis and Emex spinosus leaves exhibited free radical scavenging action against 1,1-diphenyl-2-picrylhydrazyl (DPPH). Their concentrations of 50% inhibition (IC(50)) were 25.3 and 20.73 MUg/mL, respectively. Activity-guided separation of these extracts using a combination of different chromatographic methods (TLC and column chromatography) resulted in the isolation of five chromatographically pure compounds (three from Laurus nobilis and two from Emex spinosus leaves). Spectroscopic methods ((1)H, (13)C-NMR, UV and MS) and chemical methods (detection tests and acidic hydrolysis) revealed the isolated antioxidant compounds to be flavonoid substances that were identified as kaempferol, kaempferol-3-rhamnopyranoside, and kaempferol-3,7-dirhamnopyranoside from Laurus nobilis extract and luteolin and rutin from Emex spinosus extract. The five flavonoids had varying ability to inhibit DPPH radicals (IC(50) from 4 to 35.8 MUg/mL). Luteolin and rutin had strong scavenging action with an IC(50) of 4 and 4.6 MUg/mL, respectively, and this action was stronger than that of synthetic antioxidant BHA, i.e., butylated hydroxyanisole (IC50 = 5.6 MUg/mL). PMID- 22491185 TI - Optimization and characterization of diclofenac sodium microspheres prepared by a modified coacervation method. AB - A modified coacervation method for preparing diclofenac sodium loaded chitosan (DFS-C) microspheres, using sodium citrate as cross-linking agent was optimized. A full 2(3) factorial design was used to evaluate the effect of chitosan (CS) concentration, cross-linking agent concentration, and cross-linking time on the properties of the prepared microspheres. The modified coacervation method resulted in higher yield of spherical microspheres even with a lower concentration of CS (0.3%, w/v). The morphology of the microspheres was found to be dependent on the formulation and process parameters. The cross-linking agent concentration had the largest impact on swelling, mucoadhesion, and drug release. Kinetic analysis of the release data revealed a quasi-Fickian diffusion mechanism. PMID- 22491183 TI - Characterization, thermodynamic parameters and in vivo antimalarial activity of inclusion complexes of artemether. AB - The present study aimed to improve solubility, dissolution and ultimate bioavailability of poorly soluble artemether, an antimalarial drug, by encapsulating it in beta-cyclodextrin (beta-CD) and its methyl and hydroxylpropyl derivatives. The effect of these complexes was confirmed by in vivo studies. Phase solubility studies indicated 1:1 stoichiometry and were supported by mass spectrometry and proton nuclear magnetic resonance ((1)H-NMR) spectroscopy. True inclusion of artemether into the cyclodextrin cavity was observed in lyophilized complexes by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR) studies. The mode of inclusion was supported by two-dimensional (2D) NMR. Solution calorimetry was used to confirm 1:1 stiochiometry by determining the enthalpy of interaction between the drug and cyclodextrins. The stability constant (K) of inclusion and other thermodynamic parameters such as enthalpy (DeltaH) as well as entropy (DeltaS) of binding accompanying the encapsulation were determined. The calculated value of K indicated that M-beta-CD has maximum complexing efficiency. Dissolution studies indicated that the highest release rate was observed for lyophilized complexes. In vivo studies of lyophilized complexes of M-beta-CD showed a 3-fold increase in antimalarial activity compared to artemether and resulted in 100% eradication of parasite. However, 83% and 50% survival rates were achieved in 40 days using HP-beta-CD and beta-CD complexes respectively. The study concludes that encapsulation of artemether by cyclodextrins is a good alternative to enhance the bioavailability of the drug. PMID- 22491186 TI - Membrane electrodes for determination of two antihypertensive drugs in pharmaceutical formulations of either single or binary mixtures and in biological fluids. AB - Membrane-selective electrodes were used to determine benazepril hydrochloride (BZ) and trandolapril (TR) in their binary mixtures with hydrochlorothiazide (HZ) and verapamil (VR), respectively. This method involves construction of four water insoluble ion-association complexes: benazepril-tetraphenyl borate (BZ-TPB), benazepril-reineckate (BZ-R), trandolapril-tetraphenyl borate (TR-TPB), and trandolapril-reineckate (TR-R). These complexes were used as electroactive materials in polyvinyl chloride (PVC) matrix membrane sensors in order to determine the two aforementioned drugs in their pharmaceutical formulations and in plasma. The performance characteristics of these sensors, evaluated according to IUPAC recommendations, revealed a fast, stable, and linear response for BZ and TR. The suggested procedures were checked using laboratory-prepared mixtures and were successfully used to analyze their pharmaceutical preparations. The results obtained using the proposed method were statistically analyzed and compared with those obtained using previously reported methods. PMID- 22491188 TI - Interview with Amar Flood. PMID- 22491187 TI - A qualitative failure of B3LYP for textbook organic reactions. AB - Depending on the selected DFT functional, two different mechanisms are found for two organic reactions (an intramolecular nucleophilic aromatic substitution and a nucleophilic addition on a carbonyl moiety). Indeed, B3LYP predicts a concerted mechanism whereas M06-2X foresees a multistep one. Calculations at the MP4(SDQ) level proved the mechanisms to be stepwise. We studied these reactions with a large panel of exchange-correlation functionals and demonstrated that the amount of exact exchange is of first importance. For some borderline cases, the form of the functional has also an impact, e.g. the Meisenheimer sigma-adduct of the intramolecular nucleophilic aromatic substitution can be located with B3PW91 but not with B3LYP. These results stress the need to use recently proposed functionals to investigate chemical reactivity. PMID- 22491189 TI - Population genetics models of local ancestry. AB - Migrations have played an important role in shaping the genetic diversity of human populations. Understanding genomic data thus requires careful modeling of historical gene flow. Here we consider the effect of relatively recent population structure and gene flow and interpret genomes of individuals that have ancestry from multiple source populations as mosaics of segments originating from each population. This article describes general and tractable models for local ancestry patterns with a focus on the length distribution of continuous ancestry tracts and the variance in total ancestry proportions among individuals. The models offer improved agreement with Wright-Fisher simulation data when compared to the state-of-the art and can be used to infer time-dependent migration rates from multiple populations. Considering HapMap African-American (ASW) data, we find that a model with two distinct phases of "European" gene flow significantly improves the modeling of both tract lengths and ancestry variances. PMID- 22491190 TI - Estimating the strength of selective sweeps from deep population diversity data. AB - Selective sweeps are typically associated with a local reduction of genetic diversity around the adaptive site. However, selective sweeps can also quickly carry neutral mutations to observable population frequencies if they arise early in a sweep and hitchhike with the adaptive allele. We show that the interplay between mutation and exponential amplification through hitchhiking results in a characteristic frequency spectrum of the resulting novel haplotype variation that depends only on the ratio of the mutation rate and the selection coefficient of the sweep. On the basis of this result, we develop an estimator for the selection coefficient driving a sweep. Since this estimator utilizes the novel variation arising from mutations during a sweep, it does not rely on preexisting variation and can also be applied to loci that lack recombination. Compared with standard approaches that infer selection coefficients from the size of dips in genetic diversity around the adaptive site, our estimator requires much shorter sequences but sampled at high population depth to capture low-frequency variants; given such data, it consistently outperforms standard approaches. We investigate analytically and numerically how the accuracy of our estimator is affected by the decay of the sweep pattern over time as a consequence of random genetic drift and discuss potential effects of recombination, soft sweeps, and demography. As an example for its use, we apply our estimator to deep sequencing data from human immunodeficiency virus populations. PMID- 22491191 TI - Corticomotoneuronal integrity and adaptation in spinal muscular atrophy. AB - OBJECTIVE: To gain further insight into disease pathophysiologic process and potential adaptations through investigating whether cortical dysfunction or plasticity is a feature of spinal muscle atrophy (SMA). DESIGN: Prospective, double-center study. SETTING: Outpatient clinics and research institute. PARTICIPANTS: Clinical assessments, combined with threshold-tracking transcranial magnetic stimulation techniques, were completed in 11 genetically characterized patients with SMA. MAIN OUTCOME MEASURES: Clinical, functional, and neurophysiologic variables were compared between the 11 patients with SMA types 2 and 3, 24 healthy control participants, and 81 patients with amyotrophic lateral sclerosis (ALS) serving as disease controls. RESULTS: Maximal motor-evoked potential amplitude as a percentage of the compound muscle action potential was significantly increased in patients with SMA compared with the healthy controls but was similar to that in ALS (SMA, mean [SE], 39.7% [4.0%]; ALS, 38.8% [2.8%]; controls, 20.3% [2.5%]; F = 10.1; P < .001). In contrast, short-interval intracortical inhibition (SMA, 14.4% [1.6%]; ALS, 4.3% [1.8%]; controls, 17.0% [2.3%]; F = 11.4; P < .001) and cortical silent-period duration (SMA, 204.4 [9.8] milliseconds; ALS, 182.7 [5.2] milliseconds; controls, 208.8 [3.7] milliseconds; F = 4.8; P = .01), similar between SMA patients and healthy controls, were significantly larger when compared with the findings in ALS. Of relevance, peripheral disease burden as measured by the compound muscle action potential amplitude (SMA, 6.3 [0.8] mV; ALS, 5.9 [0.4] mV; controls, 11.8 [0.5] mV; F = 35.5; P < .001) and Neurophysiological Index (SMA, 0.7 [0.2]; ALS, 0.7 [0.1]; controls, 3.1 [0.2]; F = 108.2; P < .001), were significantly reduced in both SMA and ALS patients when compared with healthy controls. CONCLUSIONS: Taken together, findings from the present study suggest that despite spinal motoneuron degeneration there remains preservation of corticomotoneuronal function in SMA. The greater corticomotoneuronal projections to surviving spinal motoneurons likely represent an adaptive response to spinal motoneuron degeneration in SMA. PMID- 22491192 TI - Familial adult myoclonic epilepsy: recognition of mild phenotypes and refinement of the 2q locus. AB - BACKGROUND: Familial adult myoclonic epilepsy (FAME) is an autosomal dominant syndrome characterized by a core triad of cortical tremor, multifocal myoclonus, and generalized tonic-clonic seizures. OBJECTIVES: To expand the phenotypic spectrum of FAME, to highlight diagnostic pointers to this underrecognized disorder, and to refine the FAME2 genetic locus. DESIGN: Observational family study. SETTING: The study was coordinated in a tertiary academic hospital, with data acquired in diverse primary, secondary, and tertiary care settings. PARTICIPANTS: Consenting members of a single large family. RESULTS: A 6 generation FAME kindred of European descent was ascertained in New Zealand and Australia. Affected family members (N = 55) had fine hand tremor, with onset typically in adolescence (median age, 15 years; age range, 4-60 years). Proximal myoclonus was present in 44 of 55 (80%), arising later than hand tremor (median age, 17 years; age range, 5-60 years). Generalized tonic-clonic seizures occurred in 8 of 55 (15%), with a median age at onset of 43.5 years (age range, 18-76 years). Neurophysiological testing confirmed features of cortical reflex myoclonus. Genetic mapping narrows the FAME2 (OMIM 607876) locus on chromosome 2 to a 13.3-megabase interval, harboring 99 known protein-coding genes. CONCLUSIONS: The most common FAME phenotype in this large family is mild postural hand tremor resembling essential tremor, combined with subtle proximal myoclonus. Generalized tonic-clonic seizures are uncommon and occur around sleep onset following severe generalized myoclonus. PMID- 22491193 TI - Age-dependent structural connectivity effects in fragile x premutation. AB - OBJECTIVE: To examine the effects of premutation alleles on major brain fiber tracts in males. DESIGN: Cross-sectional study performed in 2007-2009. SETTING: Institutional practice. PATIENTS: Fifteen younger (18-45 years old) carriers, 11 older (>45 years old) unaffected carriers, and 15 older carriers with fragile X associated tremor/ataxia syndrome, together with 19 younger and 15 older controls matched by age and educational level. MAIN OUTCOME MEASURES: Diffusion tensor imaging was performed on all study participants. Eleven fiber tracts important for motor, social, emotional, and cognitive functions were reconstructed and quantified. Complementary tract-based spatial statistical analyses were performed in core white matter. RESULTS: In the younger carriers, premutation status was associated with a greater age-related connectivity decline in the extreme capsule. Among older carriers, unaffected individuals did not display structural alterations, whereas the affected carriers showed connectivity loss in 5 fiber tracts and exhibited greater age-related connectivity decline in all 11 tracts compared with the controls. In addition, 9 fiber tracts showed significantly higher variability relative to the controls, and symptom severity explained the variability in 6 measurements from the superior cerebellar peduncle, corpus callosum, and cingulum. CONCLUSIONS: The findings revealed widespread alterations in structural connectivity associated with fragile X-associated tremor/ataxia syndrome and preserved or subtle changes in structural connectivity in unaffected carriers. Diffusion tensor imaging is sensitive to pathologic changes in the white matter associated with this neurodegenerative disorder. Wang et al examine the effects of premutation alleles on major brain fiber tracts in males, who are at risk of developing fragile X-associated tremor/ataxia syndrome and may manifest subtle cognitive, social, and emotional disturbances before clinical involvement. PMID- 22491194 TI - Loss of myelin-associated glycoprotein in kearns-sayre syndrome. AB - OBJECTIVE: To explore myelin components and mitochondrial changes within the central nervous system in patients with well-characterized mitochondrial disorders due to nuclear DNA or mitochondrial DNA (mtDNA) mutations. DESIGN: Immunohistochemical analysis, histochemical analysis, mtDNA sequencing, and real time and long-range polymerase chain reaction were used to determine the pathogenicity of mtDNA deletions. SETTING: Department of Clinical Pathology, Columbia University Medical Center, and Newcastle Brain Tissue Resource. PATIENTS: Seventeen patients with mitochondrial disorders and 7 controls were studied from August 1, 2009, to August 1, 2010. MAIN OUTCOME MEASURE: Regions of myelin-associated glycoprotein (MAG) loss. RESULTS: Myelin-associated glycoprotein loss in Kearns-Sayre syndrome was associated with oligodendrocyte loss and nuclear translocation of apoptosis-inducing factor, whereas inflammation, neuronal loss, and axonal injury were minimal. In a Kearns-Sayre syndrome MAG loss region, high levels of mtDNA deletions together with cytochrome c oxidase-deficient cells and loss of mitochondrial respiratory chain subunits (more prominent in the white than gray matter and glia than axons) confirmed the pathogenicity of mtDNA deletions. CONCLUSION: Primary mitochondrial respiratory chain defects affecting the white matter, and unrelated to inflammation, are associated with MAG loss and central nervous system demyelination. PMID- 22491195 TI - Factors influencing disease progression in autosomal dominant cerebellar ataxia and spastic paraplegia. AB - OBJECTIVES: To evaluate disease progression and determine validity of clinical tools for therapeutic trials. DESIGN: Prospective cohort study (36 months). SETTING: Referral center. PATIENTS: One hundred sixty-two patients with autosomal dominant cerebellar ataxia and 64 with hereditary spastic paraplegia. MAIN OUTCOME MEASURES: The quantitative Composite Cerebellar Functional Severity Score with the writing test (CCFSw) and Scale for the Assessment and Rating of Ataxia (SARA) score. RESULTS: Disease worsened in patients with SCA1, SCA2, and SCA3 mutations (mean [SE] increase in CCFSw, +0.014 [0.005] to +0.025 [0.004] per year), improved in patients with SPG4 mutations (mean [SE] increase in CCFSw, 0.012 [0.003] per year; P = .02), and remained stable in patients with SCA6, SCA7, or other SCA mutations (mean [SE] increase in CCFSw, -0.015 [0.011] to +0.009 [0.013] per year) or hereditary spastic paraplegia with other SPG mutations (mean [SE] increase in CCFSw, -0.005 [0.005] per year). Progression was faster in patients with SCA2 mutations and normal alleles with 22 or fewer repeats (P = .02) and in patients with SCA3 mutations with parkinsonism and/or dystonia at baseline (P = .003). Whereas CCFSw distinguished between patients with ataxia and spasticity, SARA scores increased in both groups. A 2-arm trial with SARA score as the outcome measure would require 57 patients with SCA2 mutations, 70 with SCA1 mutations, and 75 with SCA3 mutations per group to detect a 50% reduction in disease progression (power, 80%; alpha = .05). CONCLUSIONS: Disease progressed faster in SCA s with polyglutamine expansions in SCA1, 2, and 3 than the other groups. Both outcome measures are suitable for therapeutic trials; SARA requires fewer patients to attain the same power, but CCFSw needs less stratification. We demonstrate that the choice of clinical outcome measure is critical for reliable evaluation of progression in neurodegenerative diseases. PMID- 22491197 TI - Bypassing trouble. PMID- 22491198 TI - Treatment of arteriovenous malformations: a meta-analysis. PMID- 22491196 TI - Saccade abnormalities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer disease. AB - BACKGROUND: Deficits in the generation and control of saccades have been described in clinically defined frontotemporal dementia (FTD) and Alzheimer disease (AD). OBJECTIVE: To determine the saccade abnormalities associated with autopsy-defined cases of frontotemporal lobar degeneration (FTLD) and of AD, because clinical FTD syndromes can correspond to a number of different underlying neuropathologic FTD and non-FTD diagnoses. DESIGN: An infrared eye tracker was used to record visually guided saccades to 10 degrees targets and antisaccades in subjects with autopsy-confirmed FTD and subjects with autopsy-confirmed AD, a mean (SE) of 35.6 (10.0) months prior to death, and age-matched normal controls. Twelve subjects with FTD had an FTLD-TAR DNA-binding protein 43 pathology, 15 had an FTLD-tau pathology, and 1 subject showed an FTLD-fused in sarcoma protein pathology. Receiver operating curve statistics were used to determine the diagnostic value of the oculomotor variables. Neuroanatomical correlates of oculomotor abnormalities were investigated using voxel-based morphometry. SETTING: Memory and Aging Center, Department of Neurology, University of California, San Francisco. PARTICIPANTS: A total of 28 subjects with autopsy confirmed FTD, 10 subjects with autopsy-confirmed AD, and 27 age-matched normal controls. RESULTS: All subjects with FTD or AD were impaired relative to normal controls on the antisaccade task. However, only FTLD-tau and AD cases displayed reflexive visually guided saccade abnormalities. The AD cases displayed prominent increases in horizontal saccade latency that differentiated them from the FTD cases. Impairments in velocity and gain were most severe in individuals with progressive supranuclear palsy but were also present in other tauopathies. By using vertical and horizontal saccade velocity and gain as our measures, we were able to differentiate patients with progressive supranuclear palsy from other patients. Vertical saccade velocity was strongly correlated with dorsal midbrain volume. CONCLUSION: Decreased visually guided saccade velocity and gain are suggestive of underlying tau pathology in FTD, with vertical saccade abnormalities most diagnostic of progressive supranuclear palsy. PMID- 22491199 TI - Blocked muscle fat oxidation during exercise in neutral lipid storage disease. AB - OBJECTIVE: To determine whether impaired exercise capacity in neutral lipid storage disease with myopathy is solely caused by muscle weakness or whether a defect in energy metabolism (blocked fat oxidation) may also play a role. DESIGN: We studied a 37-year-old woman with neutral lipid storage disease with myopathy, who cycled while lipid oxidation was assessed using U-(13)C palmitate tracer dilution technique. The effect of a glucose infusion during exercise was also studied. SETTING: Neuromuscular research unit. RESULTS: The exercise-induced increase in fat oxidation was virtually abolished in the patient. Treatment with intravenous glucose infusion improved maximal oxygen uptake from 23 to 27 mL * kg(-1) * min(-1), and maximal workload from 75 to 100 W. CONCLUSIONS: These results demonstrate that in addition to fixed weakness, neutral lipid storage disease with myopathy is also characterized by a profound block in fat oxidation, which limits exercise tolerance. PMID- 22491200 TI - Progressive weakness with respiratory failure in a patient with sarcoidosis. AB - A 29-year-old African American woman with an 8-year history of biopsy-proven renal sarcoidosis and end-stage renal disease requiring hemodialysis was admitted to the hospital with progressive weakness and shortness of breath for 2 months. Eight months prior to admission, she was prescribed 15 mg of prednisone twice a day and 200 mg of hydroxychloroquine sulfate twice a day for hypercalcemia and elevated angiotensin-converting enzyme level. As her laboratory abnormalities improved, the prednisone dose was gradually decreased, and hydroxychloroquine was continued. Six months earlier, she noticed numbness in her feet and progressive loss of muscle bulk in her feet and hands. She also noticed difficulty reaching overhead, getting out of a chair, and climbing stairs. She denied any pain or muscle cramps. Results of electrophysiological tests at that time, which included nerve conduction studies and needle electromyography, revealed moderately severe axonal sensorimotor polyneuropathy. Her weakness worsened and so she was admitted to the hospital and subsequently transferred to our facility for further management. PMID- 22491201 TI - What lies beyond plain sight. PMID- 22491202 TI - Cranial neuropathies in multiple sclerosis defined by magnetic resonance imaging and fludeoxyglucose F 18 positron emission tomography. PMID- 22491203 TI - Cerebral and spinal cord subdural hematomas. PMID- 22491204 TI - Affinity precipitation of active Rho-GEFs using a GST-tagged mutant Rho protein (GST-RhoA(G17A)) from epithelial cell lysates. AB - Proteins of the Rho family of small GTPases are central regulators of the cytoskeleton, and control a large variety of cellular processes, including cell migration, gene expression, cell cycle progression and cell adhesion. Rho proteins are molecular switches that are active in GTP-bound and inactive in GDP bound state. Their activation is mediated by a family of Guanine-nucleotide Exchange Factor (GEF) proteins. Rho-GEFs constitute a large family, with overlapping specificities. Although a lot of progress has been made in identifying the GEFs activated by specific signals, there are still many questions remaining regarding the pathway-specific regulation of these proteins. The number of Rho-GEFs exceeds 70, and each cell expresses more than one GEF protein. In addition, many of these proteins activate not only Rho, but other members of the family, contributing further to the complexity of the regulatory networks. Importantly, exploring how GEFs are regulated requires a method to follow the active pool of individual GEFs in cells activated by different stimuli. Here we provide a step-by-step protocol for a method used to assess and quantify the available active Rho-specific GEFs using an affinity precipitation assay. This assay was developed a few years ago in the Burridge lab and we have used it in kidney tubular cell lines. The assay takes advantage of a "nucleotide free" mutant RhoA, with a high affinity for active GEFs. The mutation (G17A) renders the protein unable to bind GDP or GTP and this state mimics the intermediate state that is bound to the GEF. A GST-tagged version of this mutant protein is expressed and purified from E. coli, bound to glutathione sepharose beads and used to precipitate active GEFs from lysates of untreated and stimulated cells. As most GEFs are activated via posttranslational modifications or release from inhibitory bindings, their active state is preserved in cell lysates, and they can be detected by this assay. Captured proteins can be probed for known GEFs by detection with specific antibodies using Western blotting, or analyzed by Mass Spectrometry to identify unknown GEFs activated by certain stimuli. PMID- 22491205 TI - Bioactive constituents of Corni Fructus: The therapeutic use of morroniside, loganin, and 7-O-galloyl-D-sedoheptulose as renoprotective agents in type 2 diabetes. AB - Corni Fructus, the fruit of Cornus officinalis Sieb. et Zucc. (Cornaceae), is an important crude herb used in Chinese medicine to exhibit several biological activities, including hypoglycemic, antineoplastic, and antimicrobial effects, and to improve liver and kidney functions. We have been investigating the mechanism and bioactive constituents of Corni Fructus using diabetic animal models. Morroniside, loganin, and 7-O-galloyl-D-sedoheptulose, the main active compounds of Corni Fructus, exhibit the same lowering effects of elevated triglyceride, oxidative stress and advanced glycation endproduct (AGE) formation in the kidney of db/db mice. The effects of morroniside and 7-O-galloyl-D sedoheptulose were mediated through modulation by renal sterol regulatory element binding proteins and nuclear factor-kappa B expression, but the effect of loganin was presumably mediated by hypoglycemic and antioxidant effects in the kidney, and also indirectly by the amelioration of metabolic disorders in other organs such as the liver. These findings led us to conclude that morroniside, loganin, and 7-O-galloyl-D-sedoheptulose would synergistically contribute to the inhibition of metabolic disorders (hyperglycemia and dyslipidemia), oxidative stress, inflammation, as well as AGE formation in the diabetic kidney. PMID- 22491206 TI - Stability of MALAT-1, a nuclear long non-coding RNA in mammalian cells, varies in various cancer cells. AB - Recent large-scale transcriptome analyses have revealed a large number of transcripts with low protein-coding potential, known as non-coding RNAs (ncRNAs). Many studies revealed that several long ncRNAs are involved in the regulation of genome organization and gene expression, or in the structural components of functional domains in the nucleus. As regulation of mRNA decay in the cytoplasm is crucial for controlling the abundance of cellular transcripts and the levels of protein expression, so regulation of long non-coding RNA decay in the nucleus is considered to be important for biological function. Although enzymatic pathways involved in cytoplasmic mRNA decay have been studied extensively, far less is known about those in nuclear long ncRNA decay. Here, we have investigated decay of metastasis associated lung adenocarcinoma transcript 1 (MALAT-1), which is a long (~ 8 kb) ncRNA that is misregulated in many human cancers and was shown to be retained specifically in the nucleus in nuclear speckles, as a model of nuclear long ncRNA in mammalian cells. We have found that the half-life of MALAT 1 ranges from ~ 9 h to > 12 h in various cancer cells. Moreover, Xrn2, PM/Scl-75, PARN, and Mtr4, known nuclear RNases or RNA helicases, did not affect MALAT-1 degradation or single knockdown of these components did not change the MALAT-1 decay rate. PMID- 22491207 TI - Di(hetero)arylamines in the benzo[b]thiophene series as novel potent antioxidants. AB - The damaging consequences of oxidative stress are known to be involved in several pathologies. So, the development of new drugs that can aid cells to cope with excessive levels of free radicals still assumes great relevance. Here, we investigated the antioxidant properties of four novel di(hetero)arylamines (named MJQ1, MJQ3, MJQ4 and MJQ5), sharing a common benzo[b]thiophene nucleus (an indole analogue), against oxidative damage induced to H9c2 myoblasts. Cell proliferation, evaluated by the sulforhodamine B assay, was not compromised by the presence of any of these compounds for concentrations below 50 MUM (at 24 h) and 1 MUM (72 h). Moreover, all of them showed a dose-dependent protective effect against tert-butylhydroperoxide (t-BHP)-induced cell death for concentrations in the nanomolar range. Their ability to scavenge free radicals seems to account for their protective effects, as they were able to prevent almost completely, at 25 nM, t-BHP-induced intracellular ROS formation, assessed by DCF fluorescence. Furthermore, their relatively high partition coefficient values are indicative of their ability to easily permeate lipid membranes and act intracellularly. Additionally, these novel diarylamines led to a reduction, between 60-70%, of the amount of DNA strand breaks induced by t-BHP, evaluated by the Comet assay, and lipid peroxidation (TBARS assay) induced by the oxidant pair ascorbate/iron. In all these parameters, which show their ability to prevent the oxidation of the main biomolecules, their protective role was superior to the traditional antioxidant Trolox. Although the mechanisms underlying the action of these diarylamines are currently under investigation, the data obtained so far reveals their high pharmacological potential as antioxidant molecules. PMID- 22491208 TI - Development of a microemulsion-based formulation to improve the availability of poorly water-soluble drug. AB - The objective of our investigation was to design a thermo-dynamically stable microemulsion formulation of the model drug piroxicam with minimum surfactant concentration in order to improve its solubility. The solubility of piroxicam in different oils was examined. Effects of the co-surfactant:surfactant ratio and water content on microemulsion formulation were evaluated. Phase studies were performed for systems composed of oleic acid as the oil phase, Tween-80 as surfactant, and propylene glycol as co-surfactant at a constant percentage of water to elucidate the effect of microemulsion components on the area of microemulsion formulation. The viscosity and conductivity of certain microemulsion formulations were examined as a function of water dilution. The results showed that oleic acid, Tween-80, and propylene glycol resulted in the highest solubilization of piroxicam. The amount of water that was successfully incorporated into a microemulsion system was directly proportional to the co surfactant:surfactant ratio and inversely proportional to the percentage amount of the oil phase present in the system. Microemulsion systems displayed changes in their viscosity and conductivity upon water dilution. The pre-microemulsion systems could be used as solvents to provide enhanced solubilizing capacity and stabilization for the solubilized drug. These systems could be loaded with the drug and stored in their original form in order to produce a microemulsion containing the drug in situ upon aqueous dilution. The incorporation of piroxicam in microemulsion formulations led to enhancement of the piroxicam release profile by allowing constant and regular in vitro release as well as reducing piroxicam's particle size to that suited to a microemulsion. Thus, the usage of a microemulsion technique led to improvement in piroxicam availability, suggesting the potential for technique's use as a topical vehicle for piroxicam delivery. PMID- 22491209 TI - Preparation, characterization, and stability studies of piroxicam-loaded microemulsions in topical formulations. AB - The main purpose of this work was to determine the in vitro release of piroxicam in microemulsion formulations from different pharmaceutical topical preparations including different gel bases, such as, methyl cellulose (MC), carboxy methyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), Carbopol 934, Carbopol 940, and Pluronic F-127 bases. The effect of the employed gel bases on the in vitro release profiles of piroxicam was examined to choose the base which gave the highest in vitro release. The kinetic treatments and parameters derived from in vitro release of piroxicam formulations were calculated according to different kinetic orders or systems. These gel formulations were selected for rheological and stability studies. Stability studies were conducted to investigate the change in drug content, viscosity, and pH of the semisolid formulations. The results showed that, the incorporation of piroxicam in microemulsion formulas could lead to enhancement of piroxicam release profiles by allowing constant and regular in vitro release. Three percent MC gel base showed the highest release of piroxicam microemulsion after 180 min (97.70%) followed by 3% HPMC (94.0%) when compared to bases containing piroxicam alone. All the medicated gel bases containing piroxicam exhibit pseudoplastic flow with thixotropic behavior. The degradation of piroxicam from its topical formulations was found to be a zero-order reaction based on the mean value of correlation coefficients. All formulations were quite stable. The shelf life of the gel containing HPMC base was about 2.85 years. Considering the in vitro release, rheological properties and shelf life, HPMC gel base containing 0.5% piroxicam in a microemulsion formula was the best among the studied formulations. PMID- 22491210 TI - The potential therapeutic effect of nitric oxide modulators in experimentally induced gastric ulcers. AB - Nitric oxide (NO) appears to play a critical role in modulating gastric mucosal defense. Administration of NO donors has been reported to protect the gastrointestinal mucosa against damage induced by several irritants. However, the possible role of NO in healing existing ulcers must be clarified further. Therefore, the present study was designed to assess the effect of modulation of NO on the healing of an indomethacin-induced peptic ulcer using a NO precursor, L arginine, and a competitive inhibitor of NO synthase, L-NAME. Results of administering L-arginine were compared to those using nitroglycerin (NTG), an NO donor. Rats were injected with a single oral dose of indomethacin (30 mg/kg) and then treated with L-arginine (200 mg/kg, i.p.), NTG (1 mg/kg, i.p.) or L-NAME (15 mg/kg, i.p.) once daily for 7 d starting 4 h after the indomethacin injection. Gross lesion examination and histological assessment were done. NO, prostaglandin (PGE2), and mucin content in gastric tissue were detected. In addition, oxidative stress markers including glutathione (GSH) and lipid peroxides were measured. L arginine and NTG almost completely healed indomethacin-induced ulceration as indicated by macroscopic and histological examination, restoration of normal levels of NO and GSH, and a significant attenuation of the increase in PGE2 and lipid peroxides induced by indomethacin. In contrast, L-NAME was found to exacerbate mucosal damage. In conclusion, the present study provides further evidence for the role of NO in gastric ulcer healing and it suggests an alternative path to treating the universal problem of non-steroidal anti inflammatory-drug-induced gastropathy. PMID- 22491211 TI - Effect of trazodone and nefazodone on hepatic injury induced by carbon tetrachloride. AB - The present study aimed to evaluate the effect of the serotonin antagonists and reuptake inhibitors trazodone and nefazodone on liver injury induced by treatment with carbon tetrachloride (CCl(4)) in rats. Liver damage was induced in rats by oral administration of CCl(4) (2.8 mL/kg in olive oil). Nefazodone (5, 10, or 20 mg/kg), trazodone (5, 10, or 20 mg/kg), silymarin (25 mg/kg), or saline (control) was orally administered once daily in association with CCl(4) and for one week thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. In CCl(4)-treated rats, treatment with trazodone (5, 10, 20 mg/ kg), reduced serum alanine aminotransferase (ALT) levels by 24, 38.6, and 49.3%. Serum aspartate aminotransferase (AST) levels were decreased by 18.1, 37.9, and 42.2%, and alkaline phosphatase (ALP) levels decreased by 25.7, 32.6, and 39.7%, respectively. Nefazodone (5, 10, 20 mg/kg) in a dose-dependent manner reduced the elevation of ALT levels by 15.6, 36.5, and 45.9%, AST levels by 16.7, 17.3, and 43%, and ALP by 30.5, 37.5, and 42.9%, respectively. Silymarin treatment reduced the levels of ALT, AST, and ALP by 56.1-62.8, 56.0-64.0, and 50.1-58.2%, respectively. The administration of CCl(4) decreased levels of reduced glutathione in blood compared to the vehicle-treated group. In CCl(4) treated rats, reduced glutathione levels increased after trazodone in a dose dependent manner. Reduced glutathione was increased by nefazodone at concentrations of 5 and 10 mg/kg, but not after 20 mg/kg nefazodone. Reduced glutathione levels were increased by the administration of silymarin to near normal values. The administration of CCl(4) resulted in a marked increase in nitric oxide levels in serum (the concentrations of nitrite/nitrate) as compared to the control group. Treatment with trazodone or nefazodone caused a dose dependent decrease in serum nitric oxide levels compared with the CCl(4) control group. Histopathological and histomorphometric examinations also indicated that CCl(4)-induced liver injury was less severe in trazodone and nefazodone-treated groups than in the CCl(4) control groups. Metabolic perturbations caused by CCl(4) in the form of decreased intracellular protein and mucopolysaccharide content in hepatocytes were improved by treatment with trazodone and nefazodone. It is concluded that administration of serotonin antagonists and reuptake inhibitors trazodone and nefazodone is associated with a reduction in experimental liver injury induced by CCl(4). PMID- 22491212 TI - Specific counter-ion and co-ion effects revealed in mixing of aqueous solutions of 3,3 and 6,6-ionenes with solutions of low molecular weight salts. AB - Enthalpies of mixing of aliphatic 3,3 and 6,6-ionene fluorides with low molecular weight salts (sodium formate, acetate, nitrate, chlorate(v), and thiocyanate), all dissolved in water, were determined. In addition, to complement our previous study (Luksicet al., Phys. Chem. Chem. Phys., 2012, 14, 2024), new measurements were performed where aqueous solutions of 3,3 and 6,6-ionene bromides were mixed with solutions of sodium fluoride, chloride, bromide, and iodide. Electrostatic theory, based on Manning's limiting law or the Poisson-Boltzmann equation, predicted the enthalpy of mixing to be endothermic in all the cases, while experiments showed that this is not always true. When an aqueous solution of 3,3 ionene fluoride was mixed with a solution of sodium fluoride (or formate and acetate) in water, the effect was indeed endothermic. For all other salts, i.e. sodium chlorate, nitrate, and thiocyanate, heat was released upon mixing. The situation was similar for 6,6-ionene fluoride solutions with an exception of mixing with sodium chlorate, where the effect was endothermic. The enthalpy of mixing was strongly correlated with the enthalpy of hydration of the counterion of the low molecular weight salt. A lyotropic series, similar to that of Hofmeister, was obtained. To examine also the effect of co-ions, ionene bromides were titrated with tetramethyl-, tetraethyl-, or tetrapropylammonium bromides. The enthalpy was exothermic for all mixtures while, somewhat unexpectedly, the co ion specific effect was quite strong. PMID- 22491213 TI - SCL/TAL1 regulates hematopoietic specification from human embryonic stem cells. AB - Determining the molecular regulators/pathways responsible for the specification of human embryonic stem cells (hESCs) into hematopoietic precursors has far reaching implications for potential cell therapies and disease modeling. Mouse models lacking SCL/TAL1 (stem cell leukemia/T-cell acute lymphocytic leukemia 1) do not survive beyond early embryogenesis because of complete absence of hematopoiesis, indicating that SCL is a master early hematopoietic regulator. SCL is commonly found rearranged in human leukemias. However, there is barely information on the role of SCL on human embryonic hematopoietic development. Differentiation and sorting assays show that endogenous SCL expression parallels hematopoietic specification of hESCs and that SCL is specifically expressed in hematoendothelial progenitors (CD45(-)CD31(+)CD34(+)) and, to a lesser extent, on CD45(+) hematopoietic cells. Enforced expression of SCL in hESCs accelerates the emergence of hematoendothelial progenitors and robustly promotes subsequent differentiation into primitive (CD34(+)CD45(+)) and total (CD45(+)) blood cells with higher clonogenic potential. Short-hairpin RNA-based silencing of endogenous SCL abrogates hematopoietic specification of hESCs, confirming the early hematopoiesis-promoting effect of SCL. Unfortunately, SCL expression on its own is not sufficient to confer in vivo engraftment to hESC-derived hematopoietic cells, suggesting that additional yet undefined master regulators are required to orchestrate the stepwise hematopoietic developmental process leading to the generation of definitive in vivo functional hematopoiesis from hESCs. PMID- 22491214 TI - A tubulin binding peptide targets glioma cells disrupting their microtubules, blocking migration, and inducing apoptosis. AB - Despite aggressive treatment regimes, glioma remains a largely fatal disease. Current treatment limitations are attributed to the precarious locations within the brain where such tumors grow, their highly infiltrative nature precluding complete resection and lack of specificity among agents capable of attenuating their growth. Here, we show that in vitro, glioma cells of diverse origins internalize a peptide encompassing a tubulin-binding site (TBS) on the neurofilament light protein. The internalized peptide disrupts the microtubule network, inhibits migration and proliferation, and leads to apoptosis. Using an intracerebral transplant model, we show that most, if not all, of these responses to peptide exposure also occur in vivo. Notably, a single intratumor injection significantly attenuates tumor growth, while neither peptide uptake nor downstream consequences are observed elsewhere in the host nervous system. Such preferential uptake suggests that the peptide may have potential as a primary or supplementary glioblastoma treatment modality by exploiting its autonomous microtubule-disrupting activity or engaging its capacity to selectively target glioma cells with other cell-disrupting cargos. PMID- 22491215 TI - In vivo tracking of mesechymal stem cells using fluorescent nanoparticles in an osteochondral repair model. AB - We devised and tested an in vivo system to monitor the migration of mesenchymal stem cells (MSCs) within the marrow cavity. In vitro studies confirmed that platelet-derived growth factor (PDGF)-AA had the most potent chemotactic effect of the tested factors, and possessed the greatest number of receptors in MSCs. MSCs were labeled with fluorescent nanoparticles and injected into the marrow cavity of nude rats through osteochondral defects created in the distal femur. The defects were sealed with HCF (heparin-conjugated fibrin) or PDGF-AA-loaded HCF. In the HCF-only group, the nanoparticle-labeled MSCs dispersed outside the marrow cavity within 3 days after injection. In the PDGF-AA-loaded HCF group, the labeled cells moved time-dependently for 14 days toward the osteochondral defect. HCF-PDGF in low dose (LD; 8.5 ng/ul) was more effective than HCF-PDGF in high dose (HD; 17 ng/ul) in recruiting the MSCs to the osteochondral defect. After 21 days, the defects treated with PDGF and transforming growth factor (TGF)-beta1 loaded HCF showed excellent cartilage repair compared with other groups. Further studies confirmed that this in vivo osteochondral MSCs tracking system (IOMTS) worked for other chemoattractants (chemokine (C-C motif) ligand 2 (CCL2) and PDGF BB). IOMTS can provide a useful tool to examine the effect of growth factors or chemokines on endogenous cartilage repair. PMID- 22491216 TI - Lipid-based nanoparticle delivery of Pre-miR-107 inhibits the tumorigenicity of head and neck squamous cell carcinoma. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with about 600,000 new cases diagnosed in the last year. Our laboratory showed that miR-107 expression is reduced and functions as a tumor suppressor gene in HNSCC suggesting the potential application of miR-107 as a novel anticancer therapeutic. In this study, we determined the efficiency and efficacy of cationic lipid nanoparticles to deliver pre-miR-107 (NP/pre-miR-107) in HNSCC cells in vitro and in vivo. NP/pre-miR-107 increased delivery of miR-107 into HNSCC cells by greater than 80,000-fold compared to free pre-miR-107. Levels of known miR-107 targets, protein kinase Cepsilon (PKCepsilon), cyclin-dependent kinase 6 (CDK6), and hypoxia-inducible factor 1-beta (HIF1-beta), decreased following NP/pre-miR-107 treatment. Clonogenic survival, cell invasion, and cell migration of HNSCC cells was inhibited with NP/pre-miR-107. Moreover, NP/pre-miR 107 reduced the cancer-initiating cell (CIC) population and dampened the expression of the core embryonic stem cell transcription factors, Nanog, Oct3/4, and Sox2. In a preclinical mouse model of HNSCC, systemic administration of NP/pre-miR-107 significantly retarded tumor growth by 45.2% compared to NP/pre miR-control (P < 0.005, n = 7). Kaplan-Meier analysis showed a survival advantage for the NP/pre-miR-107 treatment group (P = 0.017). Our results demonstrate that cationic lipid nanoparticles are an effective carrier approach to deliver therapeutic miRs to HNSCC. PMID- 22491218 TI - Sexual predators and prey: a comparative study of the hunting behavior of rapists and child molesters. AB - Although there has been an increase in research on sex offenders' modus operandi, geographic decision making, and hunting behavior, most studies still tend to emphasize criminal motivation while overlooking the role of situational and environmental factors. Studies of mixed samples of rapists and child molesters typically neglect to conduct comparative analyses. Consequently, the full nature of their distinction is not clear. This is particularly problematic for the understanding of crossover or polymorphous sex offenders, who target victims from various age groups. Using a sample of 216 incarcerated sexual offenders, hunting behavior patterns were identified and tested to establish which hunting behavior patterns were associated with each type of offender. Relationships between modus operandi, geographic decision making, and hunting behavior were also examined. Three types of offender were identified: (a) manipulative; (b) opportunist; and (c) coercive. The manipulative offender is typically a child molester. The coercive offender is typically a rapist. The opportunist offender includes both rapists and child molesters. These findings emphasize the relevance of polymorphous, crossover, or versatile sex offenders and suggest new ways of conceptualizing sex offenders and their study. PMID- 22491217 TI - Female versus male perpetrated femicide: an exploratory analysis of whether offender gender matters. AB - Femicide, the murder of females (most often at the hands of males), is an understudied area in homicide research. Furthermore, femicide perpetrated by females has been all but ignored. One reason this may be is because of the rarity of homicide victimization perpetrated by females. Rather, most homicide incidents consist of a male offender and a male victim. When a homicide does involve a female, either as a victim or as an offender, the other party implicated is generally a male. The primary goal of the proposed study is to provide an in depth, albeit exploratory, examination of female-perpetrated femicide. Using homicide data taken from the Dallas Homicide Unit, 403 cases of femicide will be analyzed, with special attention devoted to comparing female-perpetrated femicide incidents (n = 39) against male-perpetrated femicide incidents (n = 364). Specifically, the current study will explore the similarities and differences in sociodemographic characteristics of victims and suspects, offense characteristics, and offense circumstances. Contrary to what was expected, results, at first glance, seem to suggest an overwhelming similarity between femicide suspects and victims, irrespective of gender. However, when the relationship between victim and suspect is considered, distinct differences appear. Implications from these findings as well as limitations and suggestions for further research are discussed. PMID- 22491219 TI - Parental warmth amplifies the negative effect of parental hostility on dating violence. AB - Past research has documented the positive association between parental hostility and offspring involvement in intimate partner violence. Researchers, practitioners, and parents typically adopt the standpoint that parental warmth may counter these negative lessons. However, Straus and colleagues argue that parents foster IPV to the extent that they teach their child that verbal and physical aggression are a normal and legitimate component of loving relationships. A strict interpretation of social learning theory would suggest that these lessons are more, not less, likely to occur when parental hostility is interspersed with displays of affection. The present study tests this idea using data from 2,088 undergraduate students from a large university in the Southeast. Consistent with Straus' arguments, findings suggest that, rather than attenuating the negative effects of hostility, supportive interactions seem to amplify the probability that offspring will emulate aggressive behaviors in their own romantic relationships. The same is true for the effects of harsh parenting for women. It seems that the best way parents can avoid contributing to their child's chances of being in a violent dating relationship is to eschew family interaction involving verbal and physical aggression. PMID- 22491220 TI - Revisiting the role of communication in adolescent intimate partner violence. AB - A growing literature suggests that communication strategies can promote or inhibit intimate partner violence (IPV). Research on communication is still needed on a group ripe for early IPV intervention: high school-aged adolescents. This article revisits our previous analyses of young female reproductive clinic patients (Messinger, Davidson, & Rickert, 2011) by examining how the adolescent and young adult respondents differ. To explore replicability of the adolescent results across populations, they are compared to 487 adolescent female students sampled from four urban high schools. Across samples, all communication strategies were used more frequently within violent relationships. Multivariate analysis identified escalating strategies used and received as being positively associated with physical violence used and received in all three samples. Regarding verbal reasoning and temporary conflict avoidance, substantial differences appeared between the young adult and adolescent clinic samples, and results from the adolescent clinic sample were largely replicated with the adolescent school sample, suggesting that young adult samples in this literature are not adequate proxies for adolescents. PMID- 22491221 TI - Variations in wounding by relationship intimacy in homicide cases. AB - There are numerous examples in the homicide literature of a presumed connection between the victim-offender relationship and the manner, extent, and body location of wounds inflicted in homicides. The current study examined variations in wounding patterns according to the intimacy of the victim-offender relationship in a sample of urban homicides to explore the investigative utility of this information in an average homicide event. The findings demonstrated that victims who had a current or former intimate relationship with their offender were more likely to receive wounds to the face and be injured with a weapon from the scene compared with all other relationship groups, whereas injury to the head and use of manual violence were more likely among intimates and family/friends compared with acquaintances or strangers. However, the groups did not significantly differ in terms of the overall amount of wounds inflicted. Implications of the findings and suggested areas of future research are discussed. PMID- 22491222 TI - Men's alcohol intoxication and condom use during sexual assault perpetration. AB - We assessed the association between alcohol consumption and condom use during penetrative sexual assault acts perpetrated by young adult men. Men aged 21 to 35 who reported inconsistent condom use and heavy episodic drinking (N = 225) completed a questionnaire assessing their perpetration of sexual assault since the age of 15, their consumption of alcohol prior to these acts, and their use of condoms during acts involving penetration. Descriptive statistics and Pearson's chi-square tests were used to examine the simultaneous use of alcohol and condom nonuse during penetrative sexual assault acts. More than one third of respondents reported perpetrating at least one penetrative sexual assault 35.6% (n = 79). Condoms were not used in 70.0% of penetrative sexual assaults. When they had consumed alcohol, perpetrators were significantly less likely to use condoms. The sexual assaults reported by this sample typically consisted of perpetrator alcohol consumption and the nonuse of condoms. Programs targeting sexual health and assault risk reduction would be enhanced by addressing this interplay of alcohol, violence, and risk. PMID- 22491223 TI - What puts women at risk of violence from their husbands? Findings from a large, nationally representative survey in Turkey. AB - A large, nationally representative, cross-sectional survey was conducted in Turkey in 2008. In this survey, which used the WHO (World Health Organization) study module on violence, information about lifetime and current violence (past 12 months) was obtained using weighted, stratified, and multistage cluster sampling. This article describes factors associated with physical or sexual violence experienced by ever-married women, aged 15 to 49, from their current or most recent husbands in the 12 months before the survey. Logistic regression analysis is used to describe the risk and protective factors from a considerable range of explanatory variables. The findings confirm that many factors are similar to the experiences of other countries. The physical or sexual violence experienced by ever-married women from their husbands was 15.1%. The violence experienced by women is significantly positively associated with early childhood abuse experiences of both women and their husbands; marriages decided by families or others; husband's behaviors such as drunkenness, adultery, controlling women's behavior, and preventing contact with women's family and friends. The age of the women, their contribution to the household income, support from women's families, women's acceptance of male authority, and nonpartner violence experience as well as regional differentials also affect the risk of violence. No significant associations were found with the employment status of women and men or education difference. This study, as one of the largest surveys ever conducted on the issue of domestic violence using face-to-face interviews, demonstrated how the patriarchal family structure still affects women's lives in Turkey. This is particularly significant, given Turkey's setting between traditional and modern values. PMID- 22491225 TI - Interview with Robert Mulvey. PMID- 22491224 TI - Protection orders protect against assault and injury: a longitudinal study of police-involved women victims of intimate partner violence. AB - The objective of this study was to measure the efficacy of protection orders (POs) in reducing assault and injury-related outcomes using a matched comparison group and tracking outcomes over time. This study was a retrospective review of police, emergency department, family court, and prosecutor administrative records for a cohort of police-involved female IPV victims; all events over a 4-year study period were abstracted. Victims who obtained POs were compared with a propensity-score-based match group without POs over three time periods: Before, During, and After the issuance of a PO. Having a PO in place was associated with significantly more calls to police for nonassaultive incidents and more police charging requests that were of multiple-count and felony-level. Comparing outcomes, PO victims had police incident rates that were more than double the matched group prior to the PO but dropped to the level of the matched group during and after the order. ED visits dropped over time for both groups. This study confirmed the protective effect of POs, which are associated with reduced police incidents and emergency department visits both during and after the order and reduced police incidents compared with a matched comparison group. PMID- 22491226 TI - Reprogramming human somatic cells into induced pluripotent stem cells (iPSCs) using retroviral vector with GFP. AB - Human embryonic stem cells (hESCs) are pluripotent and an invaluable cellular sources for in vitro disease modeling and regenerative medicine(1). It has been previously shown that human somatic cells can be reprogrammed to pluripotency by ectopic expression of four transcription factors (Oct4, Sox2, Klf4 and Myc) and become induced pluripotent stem cells (iPSCs)(2-4) . Like hESCs, human iPSCs are pluripotent and a potential source for autologous cells. Here we describe the protocol to reprogram human fibroblast cells with the four reprogramming factors cloned into GFP-containing retroviral backbone(4). Using the following protocol, we generate human iPSCs in 3-4 weeks under human ESC culture condition. Human iPSC colonies closely resemble hESCs in morphology and display the loss of GFP fluorescence as a result of retroviral transgene silencing. iPSC colonies isolated mechanically under a fluorescence microscope behave in a similar fashion as hESCs. In these cells, we detect the expression of multiple pluripotency genes and surface markers. PMID- 22491227 TI - Ductal carcinoma in situ (DCIS): raising signposts on an ill-marked treatment path. PMID- 22491228 TI - Risk of breast cancer after false-positive test results in screening mammography. AB - BACKGROUND: Screening for disease in healthy people inevitably leads to some false-positive tests in disease-free individuals. Normally, women with false positive screening tests for breast cancer are referred back to routine screening. However, the long-term outcome for women with false-positive tests is unknown. METHODS: We used data from a long-standing population-based screening mammography program in Copenhagen, Denmark, to determine the long-term risk of breast cancer in women with false-positive tests. The age-adjusted relative risk (RR) of breast cancer for women with a false-positive test compared with women with only negative tests was estimated with Poisson regression, adjusted for age, and stratified by screening round and technology period. All statistical tests were two-sided. RESULTS: A total of 58 003 women, aged 50-69 years, were included in the analysis. Women with negative tests had an absolute cancer rate of 339/100 000 person-years at risk, whereas women with a false-positive test had an absolute rate of 583/100 000 person-years at risk. The adjusted relative risk of breast cancer after a false-positive test was 1.67 (95% confidence interval [CI] 1.45 to 1.88). The relative risk remained statistically significantly increased 6 or more years after the false-positive test, with point estimates varying between 1.58 and 2.30. When stratified by assessment technology phase and using equal follow-up time, the false-positive group from the mid 1990s had a statistically significantly higher risk of breast cancer (RR = 1.65, 95% CI = 1.22 to 2.24) than the group with negative tests, whereas the false-positive group from the early 2000s was not statistically significantly different from the group testing negative. CONCLUSIONS: The implementation of new assessment technology coincided with a decrease in the size of excess risk of breast cancer for women with false positive screening results. However, it may be beneficial to actively encourage women with false-positive tests to continue to attend regular screening. PMID- 22491229 TI - Re: prostate cancer screening in the randomized prostate, lung, colorectal, and ovarian cancer screening trial: mortality results after 13 years of follow-up. PMID- 22491231 TI - Re: Mobile phone use and brain tumors in children and adolescents: a multicenter case-control study. PMID- 22491230 TI - Ten-year risk of diagnostic mammograms and invasive breast procedures after breast-conserving surgery for DCIS. AB - BACKGROUND: Breast-conserving surgery (BCS) is the most common treatment for ductal carcinoma in situ (DCIS); however, how often women experience subsequent diagnostic evaluations over time is not known. METHODS: We identified 2948 women with DCIS who were treated with BCS from 1990 to 2001 and followed for up to 10 years at three integrated health-care delivery systems. We calculated the percentages of diagnostic mammograms and ipsilateral invasive procedures following the initial breast excision to treat DCIS, estimated the 10-year cumulative incidence of these procedures, and determined hazard ratios for both types of procedures with Cox regression modeling. All statistical tests were two sided. RESULTS: Over 10 years, 907 women (30.8%) had 1422 diagnostic mammograms and 1813 (61.5%) had 2305 ipsilateral invasive procedures. Diagnostic mammograms occurred in 7.3% of women in the first 6 months and continued at a median annual rate of 4.3%. Ipsilateral invasive procedures occurred in 51.5% of women in the first 6 months and continued at a median annual rate of 3.1%. The estimated 10 year cumulative risk of having at least one diagnostic mammogram after initial DCIS excision was 41.0% (95% confidence interval [CI] = 38.5% to 43.5%); at least one invasive procedure, 65.7% (95% CI = 63.7% to 67.8%); and either event, 76.1% (95% CI = 74.1% to 78.1%). Excluding events in the first 6 months following initial DCIS excision, corresponding risks were 36.4% (95% CI = 33.8% to 39.0%) for diagnostic mammograms, 30.4% (95% CI = 26.9% to 33.8%) for invasive procedures, and 49.5% (95% CI = 45.6% to 53.5%) for either event. CONCLUSIONS: Women with DCIS treated with BCS continue to have diagnostic and invasive breast procedures in the conserved breast over an extended period. The frequency of ongoing diagnostic breast evaluations should be included in discussions about treatment. PMID- 22491232 TI - Re: Mobile phone use and brain tumors in children and adolescents. PMID- 22491233 TI - Development in malarial vaccine: A review. AB - Malaria, a vector-borne infectious disease, is currently a grave and universal concern with a significant social, economic, and human cost, mainly in developing countries. In addition, the emergence and spread of resistance to antimalarial therapies have further aggravated the global situation. Currently most of the research is focused on development of antimalarial drugs, drug resistance, and novel formulations to maximize the therapeutic effect. A number of novel molecules potentially active against malarial parasites are being developed. A vaccine is still viewed as a critical part of a long-term malaria control strategy. In the last several years various studies have shown significant progress in the development of vaccines against malaria. Advancement in vaccine technology and immunology is being used to develop malaria subunit vaccines that would open up new vistas for effective treatment and control of malaria. The development of an effective malaria vaccine represents one of the most important approaches that would provide a cost-effective intervention in addition to currently available malaria control strategies. An overview on progress in antimalarial vaccines is presented. PMID- 22491234 TI - Fruit and vegetable peels: Paving the way towards the development of new generation therapeutics. AB - Cardiovascular diseases (CVDs), diabetes mellitus (DM), cancer, and thyroid abnormalities are major health problems prevalent around the world and are responsible for a large portion of morbidity and mortality out of health problems overall. Advances in genomics and proteomics in recent years have led to an explosion in the number of possible therapeutic targets and drug candidates through use of molecular approaches, chemical synthesis, traditional medicinal chemistry, and phyto-chemistry and through the exploration of novel herbal preparations. However, virtually none of these candidates are devoid of potential adverse drug reaction(s) or undesirable side effects. Therefore, the clear need is to look to alternative ways to develop novel drug candidates with fewer side effects and less cost. Interestingly, the last few years have seen an increase in the number of available reports on fruits and vegetable peels, and particularly on their biological activity, their content of different bioactive compounds, their chemical characterization, understanding of their structure-activity relationships, isolation and purification of commercially important chemicals without using high throughput techniques, etc. Therefore, research in the field of fruit and vegetable peels should present immense possibilities for drug discovery and development of cost-effective therapies that have fewer or practically no side effects. This virtual explosion of interest in fruit and vegetable peels as a source of medicinal and nutritional value has led to the present review. PMID- 22491235 TI - Potential application of arginine in interaction analysis. AB - Aqueous solution of 0.1-2 M arginine at mildly acidic to neutral pH is widely used in biotechnology and protein research, including protein refolding, purification, and formulation. This is largely because of its ability to suppress non-specific protein-protein and protein-surface interactions. Here we propose potential applications of arginine in interaction analysis for proteins. One of the important goals of such analysis is discovery of small molecule antagonistic or agonistic ligands that bind to target proteins and thereby modulate their function. Such research is often hampered by the low solubility of the small molecules, the instability of target proteins and the non-specific protein-ligand interactions. Aqueous arginine solution increases the solubility of small molecules, which should give an alternative to conventional dissolution method of small molecules by organic solvents. Arginine may also directly impact on the analysis of protein-protein or protein-ligand interactions by suppressing weak non-specific interactions. PMID- 22491236 TI - Anti-hyperlipidemic activity of Withania coagulans in streptozotocin-induced diabetes: A potent anti-atherosclerotic agent. AB - Dyslipidemia is one of the most common complications in diabetes mellitus, which increases risk of premature atherosclerosis. Drugs having antihyperlipidemic activity in addition to their hypoglycemic effect in diabetes may be suitable anti-atherosclerotic agents in diabetic patients. The present study was aimed to investigate the anti-atherosclerotic activity of an aqueous extract of Withania coagulans (AWC) in terms of atherogenic index (AI) in normal and streptozotocin (STZ)-induced diabetes. AWC (1,000 mg/kg body weight, BW) was orally administrated in normal and STZ (70 mg/kg)-induced diabetic rats and levels of glucose, total cholesterol (CHL), high density lipoprotein (HDL)-cholesterol and triglyceride (TG) levels in the plasma were analyzed spectrophotometrically. BW was measured and AI was calculated in each group. Results show that after sub chronic dosing, AWC reduced plasma glucose levels both in normal and diabetic rats, while significantly decreasing plasma levels of CHL, HDL and TG only in STZ induced diabetic rats. Repeated administration of AWC also significantly decreased AI and prevented weight loss in STZ-induced diabetic animals. Hence, AWC showed anti-hyperlipidemic activity in diabetic rats and was suggested to be a suitable candidate for the treatment of atherosclerosis associated with diabetes. PMID- 22491237 TI - Investigation of phenolic leaf extract of Heimia myrtifolia (Lythraceae): Pharmacological properties (stimulation of mineralization of SaOS-2 osteosarcoma cells) and identification of polyphenols. AB - Evaluation of the activity of an aqueous alcoholic extract obtained from the leaves of Heimia myrtifolia (Lythraceae) by determining its stimulating effect on two human osteoblastic cell lines HOS58 and SaOS-2 indicated its potential for use in the prevention and treatment of osteoporosis. In addition, the extract was found to significantly increase the mineralization of cultivated human bone cell SaOS-2, in which a strong dose-dependent increase was observed. A phytochemical investigation of the extract also confirmed that H. myrtifolia is capable of synthesizing and accumulating appreciable amounts of several phenolics, thus leading to the isolation and characterization of sixteen of these constituents. Identified among these isolates were a new natural product, 1,6-di-O dehydrotrigalloyl-beta-D-(4)C(1)-glucopyranose, and a rare natural product (this marks its second report), 5,7,4'-trihydroxy-3-methoxyflavanone (dihydrokaempferol 3-O-methyl ether). Structures of these isolates were fully elucidated on the basis of conventional methods of analysis and confirmed by ESI/MS and (1)H and (13)C-NMR analysis. PMID- 22491238 TI - Evaluation of therapeutic effects and pharmacokinetics of antibacterial chromogenic agents in a silkworm model of Staphylococcus aureus infection. AB - The therapeutic effect of dye compounds with antibacterial activity was evaluated in a silkworm model of Staphylococcus aureus infection. Among 13 chromogenic agents that show antibacterial activity against S. aureus (MIC = 0.02 to 19 MUg/mL), rifampicin had a therapeutic effect. The ED(50) value in the silkworm model was consistent with that in a murine model. Other 12 dyes did not increase survival of the infected silkworms. We examined the reason for the lack of therapeutic efficacy. Amidol, pyronin G, and safranin were toxic to silkworms, which explained the lack of therapeutic effects. Fuchsin basic and methyl green disappeared quickly from the hemolymph after injection, suggesting that they are not stable in the hemolymph. Although coomassie brilliant blue R250/G250, cresyl blue, and nigrosin showed no toxic effects or instability in the hemolymph, they also did not have a therapeutic effect. The in vitro antibacterial actions of these dyes were inhibited by silkworm plasma or bovine serum albumin and filtration experiments demonstrated that cresyl blue bound to plasma proteins in the silkworm, suggesting that plasma protein binding inhibited the therapeutic efficacy of these four dyes. These findings indicate that drug screening using the silkworm infection model is useful for evaluating toxicity and pharmacokinetics of potential antibiotics. PMID- 22491239 TI - Effect of heparin-superoxide dismutase on gamma-radiation induced DNA damage in vitro and in vivo. AB - The effects of heparin-superoxide dismutase (SOD) conjugate (heparin-SOD) on gamma-radiation induced DNA damage in vivo and in vitro were evaluated. Plasmid pcDNA3.0 solution was mixed with heparin-SOD, SOD, and a mixture of heparin and SOD (heparin + SOD), respectively, and irradiated with (60)Co at a dosage of 120 Gy. DNA injury was analyzed using agarose gel electrophoresis. The results showed that the degree of injury of pcDNA3.0 mixed with heparin-SOD, SOD, or heparin + SOD was less than that of untreated pcDNA3.0, and among them the degree of injury of pcDNA3.0 mixed with heparin-SOD was the least. It also showed that the protective effect increased with an increase of heparin-SOD concentration. The effects of SOD and heparin-SOD on the DNA damage and tumor inhibition rate of (60)Co gamma-radiation exposure on tumor-bearing mice were also studied. Agarose gel electrophoresis showed that, when different SOD samples were administered before irradiation, the thymus DNA injuries of heparin-SOD, SOD, or heparin + SOD groups were more serious than that of the control group, and the DNA injuries of heparin-SOD or heparin + SOD groups were the most serious, which contradicted the above in vitro experiments. However, when heparin-SOD was administered post irradiation, it showed a repairing effect on the injured DNA. PMID- 22491240 TI - In vivo evaluation of black and green tea dermal products against UV radiation. AB - Aqueous extracts of black and green tea (Camellia sinensis) were obtained by freeze-drying for this study. The extracts were evaluated based on tea quality control tests, UV, IR scans, and in vitro antioxidant capacity tests. Dermal products from the tea extracts were designed and manufactured. Black and green tea gels were tested in vivo in the forearms of six subjects using an artifical UV (200-400 nm) source. The tested formulations were green tea gel, black tea gel, 0.3% caffeine gel, carbomer gel base, and a control. Depending on tea quality, the samples resulted in water soluble fractions of 24.5-39.5%. UV and IR scans specifically showed peaks for alkaloids like caffeine, catechins such as epigallocatechin gallate, and polyphenols with dimeric and polymeric structures such as theaflavins (TFs) and thearubigins (TRs). Antioxidant and free radical scavenging activities of black and green tea samples were found to be high and comparable; activity levels for black tea, green tea, high quality black tea, and L-ascorbic acid were 0.48, 0.50, 0.82, and 1.32 mM TR/mg, respectively. No UV induced erythema was observed at the black and green tea gel sites in any of the subjects. UV-induced erythema was consistently present in various grades at caffeine gel, carbomer gel, and control sites. Results led to the conclusion that freeze-dried black and green tea extracts had strong UV absorbance. Formulating those extracts into dermal gels protected the skin against UV-induced erythema. Therefore, tea extracts were found to be promising candidates for their ability to protect against the harmful effects of UV radiation, such as erythema and premature aging of the skin. PMID- 22491241 TI - Reduced expression of Sytl 1 and Ccdc21 and impaired induction of Mt I by oxidative stress in SII-K1 knockout mice. AB - SII-K1 is a member of the transcription elongation factor S-II family. In the mouse, SII-K1 is expressed exclusively in the liver, kidney, heart, and skeletal muscle. Here, we report that deletion of the SII-K1 gene in mice resulted in the downregulation of the synaptotagmin-like 1 (Sytl 1) gene in liver and of the coiled-coil domain-containing 21 (Ccdc21) gene in liver and kidney. Moreover, the induction of the metallothionein I (Mt I) gene in SII-K1-deficient mice liver was impaired in diethyl maleate-induced oxidative stress conditions. Our results suggest that SII-K1 regulates these genes in vivo. PMID- 22491242 TI - Preparation and in vitro evaluation of self-nanoemulsifying drug delivery systems (SNEDDS) containing clotrimazole. AB - This study sought to formulate and evaluate a self-nanoemulsified drug delivery system (SNEDDS) for clotrimazole (CT), a poorly water-soluble antimycotic drug, used in vaginal delivery. SNEDDS was developed to increase the CT dissolution rate, solubility, and ultimately bioavailability. The solubility of CT in various oils, surfactants, and co-surfactants was determined. Based on solubility studies, oil phase (oleic acid without or with coconut oil), surfactant (Tween 20), and co-surfactants (PEG 200 and n-butanol) were selected and grouped in two combinations for phase studies. Pseudo-ternary phase diagrams were used to evaluate the area of self-nanoemulsification. Essential properties of the prepared systems with regard to emulsion droplet size and turbidity value were determined. In order to investigate the potential for interaction between any of the SNEDDS ingredients used, FTIR spectroscopy was performed. In vitro release studies were performed with SNEDDS formulations in capsules, and the plain drug served as a control. The droplet size of the nanoemulsion was greatly affected by the ratio of the surfactant and co-surfactant. Based on the results with regard to droplet size, turbidity values, and complete drug release after 3 h, three optimized formulations were selected; each contained oleic acid/coconut oil/Tween 20/PEG 200/n-butanol in ratios of 10:0:60:15:15 (%, w/w), 7.5:2.5:53.5:13.3:13.3 (%, w/w), and 6.7:3.3:60:10:10 (%, w/w), respectively. Results suggested that the prepared SNEDDS formulations produced acceptable properties in terms of immediate drug release and could increase the bioavailability of CT. PMID- 22491244 TI - Interview with David Parker. PMID- 22491243 TI - Comparative evaluation of ketoconazole-beta-cyclodextrin systems prepared by coprecipitation and kneading. AB - Ketoconazole (KZ), an imidazole antifungal, was formulated into inclusion complexes via coprecipitation and kneading with beta-cyclodextrin (beta-CD) as a carrier in 1:1 and 1:2 drug to carrier ratios. The KZ-beta-CD solid complexes were characterized by X-ray diffraction and differential scanning calorimetry (DSC). The diffraction pattern of the pure drug revealed the drug to be highly crystalline in nature, as indicated by numerous distinctive peaks. The lack of numerous distinctive peaks of the drug in KZ-beta-CD complexes prepared by the two methods revealed that a large number of the drug molecules were dissolved in a solid-state carrier matrix with an amorphous structure. The thermograms of the KZ-beta-CD complexes showed a strong reduction in the intensity and broadening of drug peaks somewhat in both kneading and coprecipitation systems, suggesting that the drug is monomolecularly dispersed in the beta-CD cavity. The prepared tablets of KZ-beta-CD solid complexes prepared by the two methods were evaluated for their quality control testing, and an in vitro release study and the results of quality control complied with pharmacopeial requirements and the release profiles indicated complete drug release after 30 min. The kinetic parameters obtained from release data were analyzed in order to explain the mechanism of drug release and revealed non-Fickian transport. Accelerated stability testing at 35 degrees C, 45 degrees C, and 55 degrees C and at 75% relative humidity was carried out for six months and revealed somewhat stable systems as indicated by a t(90) of about 2 years for both KZ-beta-CD systems. A microbiological in vitro assay of KZ from the prepared tablets was performed using Candida albicans as a model fungus, and KZ had improved microbiological activity when administered as an inclusion complex with beta-CD. The results confirmed the benefit of using CDs as a useful tool to enhance the dissolution and hence bioavailability of poorly water-soluble drugs by forming solubilizing systems when exposed to gastrointestinal fluid. PMID- 22491245 TI - Reactive oxygen species produced by the NADPH oxidase 2 complex in monocytes protect mice from bacterial infections. AB - Chronic granulomatous disease (CGD) is an inherited disorder characterized by recurrent life-threatening bacterial and fungal infections. CGD results from defective production of reactive oxygen species by phagocytes caused by mutations in genes encoding the NADPH oxidase 2 (NOX2) complex subunits. Mice with a spontaneous mutation in Ncf1, which encodes the NCF1 (p47(phox)) subunit of NOX2, have defective phagocyte NOX2 activity. These mice occasionally develop local spontaneous infections by Staphylococcus xylosus or by the common CGD pathogen Staphylococcus aureus. Ncf1 mutant mice were more susceptible to systemic challenge with these bacteria than were wild-type mice. Transgenic Ncf1 mutant mice harboring the wild-type Ncf1 gene under the human CD68 promoter (MN(+) mice) gained the expression of NCF1 and functional NOX2 activity specifically in monocytes/macrophages, although minimal NOX2 activity was also detected in some CD11b(+)Ly6G(+) cells defined as neutrophils. MN(+) mice did not develop spontaneous infection and were more resistant to administered staphylococcal infections compared with MN(-) mice. Most strikingly, MN(+) mice survived after being administered Burkholderia cepacia, an opportunistic pathogen in CGD patients, whereas MN(-) mice died. Thus, monocyte/macrophage expression of functional NCF1 protected against spontaneous and administered bacterial infections. PMID- 22491246 TI - TLR3 but not TLR7/8 ligand induces allergic sensitization to inhaled allergen. AB - Epidemiological studies suggest that viral infections during childhood are a risk factor for the development of asthma. However, the role of virus-specific pattern recognition receptors in this process is not well defined. In the current study, we compare the effects of the inhaled viral TLR ligands polyinosinic polycytidylic acid (TLR3) and resiquimod (TLR7/8) on sensitization to a model allergen (OVA) in a murine model. Both compounds enhance the migration, activation, and Ag-processing of myeloid dendritic cells from the lung to the draining lymph nodes comparable to the effects of LPS. Application of polyinosinic-polycytidylic acid [poly(I:C)] or LPS induces production of allergen specific IgE and IgG1, whereas resiquimod (R848) had no effect. In addition, rechallenge of mice with OVA resulted in airway inflammation and mucus production in animals that received either poly(I:C) or LPS but not after application of R848. In summary, these results show that activation of TLR3 in combination with inhaled allergen results in induction of dendritic cell activation and migration similar to the effects of LPS. This leads to the development of allergic airway disease after allergen rechallenge, whereas mice treated with R848 did not develop allergic airway disease. These findings give further insight into the effects of stimulation of different TLRs on the development of asthma. PMID- 22491247 TI - Poxvirus infection-associated downregulation of C-type lectin-related-b prevents NK cell inhibition by NK receptor protein-1B. AB - Innate immune recognition of virus-infected cells includes NK cell detection of changes to endogenous cell-surface proteins through inhibitory receptors. One such receptor system is the NK cell receptor protein-1B (NKR-P1B) and its ligand C-type lectin-related-b (Clr-b). NKR-P1B and Clr-b are encoded within the NK cell gene complex, a locus that has been linked to strain-dependent differences in susceptibility to infection by poxviruses. In this study, we report the impact of vaccinia virus (VV) and ectromelia virus infection on expression of Clr-b and Clr b-mediated protection from NK cells. We observed a loss of Clr-b cell-surface protein upon VV and ectromelia virus infection of murine cell lines and bone marrow-derived macrophages. The reduction of Clr-b is more rapid than MHC class I, the prototypic ligand of NK cell inhibitory receptors. Reduction of Clr-b requires active viral infection but not expression of late viral genes, and loss of mRNA appears to lag behind loss of Clr-b surface protein. Clr-b-mediated protection from NK cells is lost following VV infection. Together, these results provide the second example of Clr-b modulation during viral infection and suggest reductions of Clr-b may be involved in sensitizing poxvirus-infected cells to NK cells. PMID- 22491248 TI - Lyn-dependent signaling regulates the innate immune response by controlling dendritic cell activation of NK cells. AB - The innate immune response is a first line of defense against invading pathogens; however, the magnitude of this response must be tightly regulated, as hyper- or suboptimal responses can be detrimental to the host. Systemic inflammation resulting from bacterial infection can lead to sepsis, which remains a serious problem with high mortality rates. Lyn tyrosine kinase plays a key role in adaptive immunity, although its role in innate immunity remains unclear. In this study, we show that Lyn gain-of-function (Lyn(up/up)) mice display enhanced sensitivity to endotoxin and succumb to upregulated proinflammatory cytokine production at a dose well tolerated by control animals. Endotoxin sensitivity in Lyn(up/up) mice depends on dendritic cells (DCs) and NK cells and occurs though a mechanism involving increased maturation and activation of the DC compartment, leading to elevated production of IFN-gamma by NK cells. We further show that modulation of endotoxin-induced signal transduction in DCs by Lyn involves the phosphatases Src homology 2 domain-containing phosphatase-1 and SHIP-1. Collectively, we demonstrate that Lyn regulates DC physiology such that alterations in Lyn-dependent signaling have profound effects on the nature and magnitude of inflammatory responses. Our studies highlight how perturbations in signaling pathways controlling DC/NK cell-regulated responses to microbial products can profoundly affect the magnitude of innate immune responses. PMID- 22491249 TI - Joint NOD2/RIPK2 signaling regulates IL-17 axis and contributes to the development of experimental arthritis. AB - Intracellular pattern recognition receptors such as the nucleotide-binding oligomerization domain (NOD)-like receptors family members are key for innate immune recognition of microbial infection and may play important roles in the development of inflammatory diseases, including rheumatic diseases. In this study, we evaluated the role of NOD1 and NOD2 on development of experimental arthritis. Ag-induced arthritis was generated in wild-type, NOD1(-/-), NOD2(-/-), or receptor-interacting serine-threonine kinase 2(-/-) (RIPK2(-/-)) immunized mice challenged intra-articularly with methylated BSA. Nociception was determined by electronic Von Frey test. Neutrophil recruitment and histopathological analysis of proteoglycan lost was evaluated in inflamed joints. Joint levels of inflammatory cytokine/chemokine were measured by ELISA. Cytokine (IL-6 and IL-23) and NOD2 expressions were determined in mice synovial tissue by RT-PCR. The NOD2( /-) and RIPK2(-/-), but not NOD1(-/-), mice are protected from Ag-induced arthritis, which was characterized by a reduction in neutrophil recruitment, nociception, and cartilage degradation. NOD2/RIPK2 signaling impairment was associated with a reduction in proinflammatory cytokines and chemokines (TNF, IL 1beta, and CXCL1/KC). IL-17 and IL-17 triggering cytokines (IL-6 and IL-23) were also reduced in the joint, but there is no difference in the percentage of CD4(+) IL-17(+) cells in the lymph node between arthritic wild-type and NOD2(-/-) mice. Altogether, these findings point to a pivotal role of the NOD2/RIPK2 signaling in the onset of experimental arthritis by triggering an IL-17-dependent joint immune response. Therefore, we could propose that NOD2 signaling is a target for the development of new therapies for the control of rheumatoid arthritis. PMID- 22491250 TI - Improvement of psoriasis after tonsillectomy is associated with a decrease in the frequency of circulating T cells that recognize streptococcal determinants and homologous skin determinants. AB - Exacerbation of chronic psoriasis can be associated with streptococcal throat infections, and T cells that respond to peptide sequences common to streptococcal M proteins and skin keratins have been detected in patients' blood. To our knowledge, we have conducted the first blinded, prospective study to assess the impact of tonsillectomy on psoriasis. Twenty-nine patients with chronic psoriasis and history of exacerbation after sore throat were randomly assigned to tonsillectomy (n = 15) or control (n = 14) groups and monitored for 2 y clinically and by enumeration of circulating skin homing T cells that respond to short homologous M protein or keratin peptides. Thirteen patients (86%) showed sustained improvement after tonsillectomy ranging from 30 to 90% reduction in disease severity. Furthermore, there was a close correlation between the degree of clinical improvement in individual patients and reduction in the frequency of peptide-reactive skin-homing T cells in their circulation. No corresponding clinical or immunologic changes were observed among the controls. These findings indicate that tonsillectomy may have a beneficial effect on chronic psoriasis because the palatine tonsils generate effector T cells that recognize keratin determinants in the skin. PMID- 22491251 TI - PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis. AB - PD-1, a member of the CD28 family of immune regulatory molecules, is expressed on activated T cells, interacts with its ligands, PD-L1/B7-H1 and PD-L2/B7-DC, on other cells, and delivers inhibitory signals to the T cell. We studied the role of this pathway in modulating autoreactive T cell responses in two models of myocarditis. In a CD8(+) T cell-mediated adoptive transfer model, we found that compared with Pd1(+/+) CD8(+) T cells, Pd1(-/-) CD8(+) T cells cause enhanced disease, with increased inflammatory infiltrate, particularly rich in neutrophils. Additionally, we show enhanced proliferation in vivo and enhanced cytotoxic activity of PD-1-deficient T lymphocytes against myocardial endothelial cells in vitro. In experimental autoimmune myocarditis, a disease model dependent on CD4(+) T cells, we show that mice lacking PD-1 develop enhanced disease compared with wild-type mice. PD-1-deficient mice displayed increased inflammation, enhanced serum markers of myocardial damage, and an increased infiltration of inflammatory cells, including CD8(+) T cells. Together, these studies show that PD-1 plays an important role in limiting T cell responses in the heart. PMID- 22491252 TI - Usp18 promotes conventional CD11b+ dendritic cell development. AB - Dendritic cells (DCs) represent the key cells linking innate and adaptive immune responses. It is critical to understand the molecular factors regulating DC differentiation. Usp18 is an IFN-inducible member of the ubiquitin-specific protease family, which deconjugates ubiquitin-like modifier ISG15 from target proteins and competitively inhibits IFN-alpha/beta-induced JAK/STAT activation. This study demonstrates that the frequency of conventional CD11b(+) DCs in the spleen of Usp18(-/-) mice was significantly reduced, whereas the frequencies of conventional CD8(+) DCs and plasmacytoid DCs remained normal. In addition, Usp18( /-) bone marrow (BM) cells generate DCs less efficiently in GM-CSF-supplemented culture, demonstrating a fundamental defect throughout the DC differentiation pathway. Usp18(-/-) BM cells were rescued by exogenous expression of either wild type or deconjugation-inactive Usp18, and superimposition of an IFN-alpha/beta receptor knockout returned in vivo DC populations to normal, clearly showing that the defect seen is due solely to Usp18's effect on IFN signaling. Finally, Usp18( /-) BM-derived DCs expressed high levels of SOCS1/SOCS3, known inhibitors of GM CSF signaling, providing a mechanistic explanation for the phenotype. In conclusion, we have identified a novel role of Usp18 in modulating conventional CD11b(+) DC development via its inhibitory effect on type I IFN signaling. PMID- 22491253 TI - Elevation of Sema4A implicates Th cell skewing and the efficacy of IFN-beta therapy in multiple sclerosis. AB - Multiple sclerosis (MS) is a demyelinating autoimmune disease of the CNS and a leading cause of lasting neurologic disabilities in young adults. Although the precise mechanism remains incompletely understood, Ag presentation and subsequent myelin-reactive CD4(+) T cell activation/differentiation are essential for the pathogenesis of MS. Although semaphorins were initially identified as axon guidance cues during neural development, several semaphorins are crucially involved in various phases of immune responses. Sema4A is one of the membrane type class IV semaphorins, which we originally identified from the cDNA library of dendritic cell (DC). Sema4A plays critical roles in T cell activation and Th1 differentiation during the course of experimental autoimmune encephalomyelitis, an animal model of MS; however, its pathological involvement in human MS has not been determined. In this study, we report that Sema4A is increased in the sera of patients with MS. The expression of Sema4A is increased on DCs in MS patients and shed from these cells in a metalloproteinase-dependent manner. DC-derived Sema4A is not only critical for Th1 but also for Th17 cell differentiation, and MS patients with high Sema4A levels exhibit Th17 skewing. Furthermore, patients with high Sema4A levels have more severe disabilities and are unresponsive to IFN-beta treatment. Taken together, our results suggest that Sema4A is involved in the pathogenesis of MS by promoting Th17 skewing. PMID- 22491254 TI - Cutting edge: human FcRL4 and FcRL5 are receptors for IgA and IgG. AB - Fc receptor-like (FcRL) proteins are a family of cellular receptors homologous to FcgammaRI and are predominantly expressed by B cells. They function to costimulate or inhibit BCR signaling through consensus ITAMs and ITIMs; however, the extracellular ligands of these receptors remain unknown or controversial. In this study, we tested the ability of human FcRL proteins to bind Igs and found FcRL4 and FcRL5 to be bona fide Fc receptors. In cellular binding assays, FcRL4 bound efficiently to IgA and FcRL5 binds all IgG isotypes with varied efficiency. Additionally, we generated mAbs capable of specifically blocking these interactions. Given their expression on activated B cells and potential for inhibitory signaling, FcRL4 and FcRL5 are likely to be important for immune complex-dependent human B cell regulation, and they represent novel therapeutic targets for receptor blockade therapies. PMID- 22491256 TI - Arsenic trioxide prevents murine sclerodermatous graft-versus-host disease. AB - Chronic graft-versus-host disease (GVHD) follows allogeneic hematopoietic stem cell transplantation. It results from alloreactive processes induced by minor MHC incompatibilities triggered by activated APCs, such as plasmacytoid dendritic cells (pDCs), and leading to the activation of CD4 T cells. Therefore, we tested whether CD4(+) and pDCs, activated cells that produce high levels of reactive oxygen species, could be killed by arsenic trioxide (As(2)O(3)), a chemotherapeutic drug used in the treatment of acute promyelocytic leukemia. Indeed, As(2)O(3) exerts its cytotoxic effects by inducing a powerful oxidative stress that exceeds the lethal threshold. Sclerodermatous GVHD was induced in BALB/c mice by body irradiation, followed by B10.D2 bone marrow and spleen cell transplantation. Mice were simultaneously treated with daily i.p. injections of As(2)O(3). Transplanted mice displayed severe clinical symptoms, including diarrhea, alopecia, vasculitis, and fibrosis of the skin and visceral organs. The symptoms were dramatically abrogated in mice treated with As(2)O(3). These beneficial effects were mediated through the depletion of glutathione and the overproduction of H(2)O(2) that killed activated CD4(+) T cells and pDCs. The dramatic improvement provided by As(2)O(3) in the model of sclerodermatous GVHD that associates fibrosis with immune activation provides a rationale for the evaluation of As(2)O(3) in the management of patients affected by chronic GVHD. PMID- 22491255 TI - Structural analysis of a dengue cross-reactive antibody complexed with envelope domain III reveals the molecular basis of cross-reactivity. AB - Dengue virus infections are still increasing at an alarming rate in tropical and subtropical countries, underlying the need for a dengue vaccine. Although it is relatively easy to generate Ab responses to dengue virus, low avidity or low concentrations of Ab may enhance infection of FcR-bearing cells with clinical impact, posing a challenge to vaccine production. In this article, we report the characterization of a mAb, 2H12, which is cross-reactive to all four serotypes in the dengue virus group. Crystal structures of 2H12-Fab in complex with domain III of the envelope protein from three dengue serotypes have been determined. 2H12 binds to the highly conserved AB loop of domain III of the envelope protein that is poorly accessible in the mature virion. 2H12 neutralization varied between dengue serotypes and strains; in particular, dengue serotype 2 was not neutralized. Because the 2H12-binding epitope was conserved, this variation in neutralization highlights differences between dengue serotypes and suggests that significant conformational changes in the virus must take place for Ab binding. Surprisingly, 2H12 facilitated little or no enhancement of infection. These data provide a structural basis for understanding Ab neutralization and enhancement of infection, which is crucial for the development of future dengue vaccines. PMID- 22491258 TI - Myeloid-specific tristetraprolin deficiency in mice results in extreme lipopolysaccharide sensitivity in an otherwise minimal phenotype. AB - Tristetraprolin (TTP) is a mRNA-destabilizing protein that binds to AU-rich elements in labile transcripts, such as the mRNA encoding TNF, and promotes their deadenylation and degradation. TTP-deficient (knockout [KO]) mice exhibit an early-onset, severe inflammatory phenotype, with cachexia, erosive arthritis, left-sided cardiac valvulitis, myeloid hyperplasia, and autoimmunity, which can be prevented by injections of anti-TNF Abs, or interbreeding with TNF receptor deficient mice. To determine whether the excess TNF that causes the TTP KO phenotype is produced by myeloid cells, we performed myeloid-specific disruption of Zfp36, the gene encoding TTP. We documented the lack of TTP expression in LPS stimulated bone marrow-derived macrophages from the mice, whereas fibroblasts expressed TTP mRNA and protein normally in response to serum. The mice exhibited a minimal phenotype, characterized by slight slowing of weight gain late in the first year of life, compared with the early-onset, severe weight loss and inflammation seen in the TTP KO mice. Instead, the myeloid-specific TTP KO mice were highly and abnormally susceptible to a low-dose LPS challenge, with rapid development of typical endotoxemia signs and extensive organ damage, and elevations of serum TNF levels to 110-fold greater than control. We conclude that myeloid-specific TTP deficiency does not phenocopy complete TTP deficiency in C57BL/6 mice under normal laboratory conditions, implying contributions from other cell types to the complete phenotype. However, myeloid cell TTP plays a critical role in protecting mice against LPS-induced septic shock, primarily through its posttranscriptional regulation of TNF mRNA stability. PMID- 22491259 TI - Reforming accelerated approval. PMID- 22491257 TI - Complement activation product C5a is a selective suppressor of TLR4-induced, but not TLR3-induced, production of IL-27(p28) from macrophages. AB - There is accumulating evidence that the complement activation product, C5a, can orchestrate cellular immune functions. IL-27(p28/EBI3) is an emerging key player essential for regulating inflammatory responses and T cells. In this article, we report that C5a robustly suppressed IL-27(p28) gene expression and release in peritoneal macrophages. These cells from C57BL/6J mice abundantly produced IL 27(p28) after engagement of either the TLR3 (polyinosinic-polycytidylic acid) or TLR4 (LPS) receptor. Genetic deficiency of either TLR4 or LBP completely incapacitated the ability of macrophages to secrete IL-27(p28) in response to LPS. IL-27(p28)-producing macrophages also expressed the C5aR receptor, thus displaying an IL-27(p28)(+)F4/80(+)C5aR(+) phenotype. C5a suppressed IL-27(p28) in LPS-stimulated macrophages via interactions with the C5aR receptor rather than the C5L2 receptor. After endotoxemia, C5aR(-/-) mice displayed higher plasma levels of IL-27(p28) compared with C57BL/6J mice. C5a did not affect the release of IL-27(p28) or the frequency of IL-27(p28)(+)F4/80(+) macrophages after engagement of TLR3. Mechanistically, LPS activated both the NF-kappaB and the PI3K/Akt pathways, whereas C5a activated only the PI3K/Akt pathway. Engagement of PI3K/Akt was inhibitory for IL-27(p28) production, because PI3K/Akt pharmacologic blockade resulted in increased amounts of IL-27(p28) and reversed the suppressive effects of C5a. Blockade of PI3K/Akt in endotoxemic C57BL/6J mice resulted in higher generation of IL-27(p28). In contrast, the PI3K/Akt pathway was not involved in TLR3-mediated release of IL-27(p28). These data provide new evidence about how complement activation may selectively interfere with production of T cell regulatory cytokines by APCs in the varying contexts of either bacterial (TLR4 pathway) or viral (TLR3 pathway) infection. PMID- 22491260 TI - Oxford Nanopore announcement sets sequencing sector abuzz. PMID- 22491261 TI - Biotech innovators jump on biosimilars bandwagon. PMID- 22491268 TI - Amgen swallows Micromet to BiTE into ALL market. PMID- 22491269 TI - Biologics inch toward cholesterol-lowering market. PMID- 22491271 TI - Hemacord approval may foreshadow regulatory creep for HSC therapies. PMID- 22491272 TI - Tensha therapeutics. PMID- 22491273 TI - Positive signals from Washington. PMID- 22491274 TI - National prescription for drug development. PMID- 22491275 TI - The art of the alliance. PMID- 22491276 TI - Addgene provides an open forum for plasmid sharing. PMID- 22491278 TI - Bias in high-tier medical journals concerning physician-academic relationships with industry. PMID- 22491277 TI - Use of genome-wide association studies for drug repositioning. PMID- 22491279 TI - Gene patents in Australia: where do we stand? PMID- 22491282 TI - Selecting antigens for cancer vaccines. PMID- 22491281 TI - DNA sequencing with nanopores. PMID- 22491283 TI - Test driving genome assemblers. PMID- 22491284 TI - Omics gets personal. PMID- 22491290 TI - Finding correlations in big data. PMID- 22491294 TI - The rise of the professional master's degree: the answer to the postdoc/PhD bubble. PMID- 22491297 TI - Engineering and evolution of synthetic adeno-associated virus (AAV) gene therapy vectors via DNA family shuffling. AB - Adeno-associated viral (AAV) vectors represent some of the most potent and promising vehicles for therapeutic human gene transfer due to a unique combination of beneficial properties(1). These include the apathogenicity of the underlying wildtype viruses and the highly advanced methodologies for production of high-titer, high-purity and clinical-grade recombinant vectors(2). A further particular advantage of the AAV system over other viruses is the availability of a wealth of naturally occurring serotypes which differ in essential properties yet can all be easily engineered as vectors using a common protocol(1,2). Moreover, a number of groups including our own have recently devised strategies to use these natural viruses as templates for the creation of synthetic vectors which either combine the assets of multiple input serotypes, or which enhance the properties of a single isolate. The respective technologies to achieve these goals are either DNA family shuffling(3), i.e. fragmentation of various AAV capsid genes followed by their re-assembly based on partial homologies (typically >80% for most AAV serotypes), or peptide display(4,5), i.e. insertion of usually seven amino acids into an exposed loop of the viral capsid where the peptide ideally mediates re-targeting to a desired cell type. For maximum success, both methods are applied in a high-throughput fashion whereby the protocols are up scaled to yield libraries of around one million distinct capsid variants. Each clone is then comprised of a unique combination of numerous parental viruses (DNA shuffling approach) or contains a distinctive peptide within the same viral backbone (peptide display approach). The subsequent final step is iterative selection of such a library on target cells in order to enrich for individual capsids fulfilling most or ideally all requirements of the selection process. The latter preferably combines positive pressure, such as growth on a certain cell type of interest, with negative selection, for instance elimination of all capsids reacting with anti-AAV antibodies. This combination increases chances that synthetic capsids surviving the selection match the needs of the given application in a manner that would probably not have been found in any naturally occurring AAV isolate. Here, we focus on the DNA family shuffling method as the theoretically and experimentally more challenging of the two technologies. We describe and demonstrate all essential steps for the generation and selection of shuffled AAV libraries (Fig. 1), and then discuss the pitfalls and critical aspects of the protocols that one needs to be aware of in order to succeed with molecular AAV evolution. PMID- 22491298 TI - Structure-properties correlations in Fe chalcogenide superconductors. AB - The focus of this review article is on the PbO-type Fe chalcogenides that recently emerged as a new class of superconductors. The fundamental correlations between structural details and chemical compositions are discussed together with their influence on the electronic properties. PMID- 22491299 TI - Beginning again: West African women's experiences of being migrants in Australia. AB - Settling in a new country exposes immigrants to various health risk factors, and the existing literature alludes to immigrant women being more vulnerable than men. This article highlights some of the difficulties faced by West African women while settling into life in Australia. A qualitative DESIGN: beginning again and experiencing loneliness and isolation. Participants encountered difficulties in developing social networks and obtaining employment, and as a result, they felt lonely and isolated. Therefore, nurses and health care professionals need to incorporate screening for precursors of emotional and social well-being issues when caring for this population. PMID- 22491300 TI - Using culturally competent community-based participatory research with older diabetic Chinese Americans: lessons learned. AB - The purpose of this article is to share culturally competent strategies and lessons learned from a study that used a community-based participatory research (CBPR) approach with older adult diabetic Chinese Americans. This approach was essential to gain insight into the health beliefs, attitudes, and practices of selected communities. The vulnerable population conceptual model (VPCM) provided a framework for the study. The CBPR, a collaborative research approach, and the VPCM provided the basis for the development of culturally competent research strategies. Strategies and lessons learned to be particularly effective for this CBPR study included (a) developing an in-depth understanding of the community ethnic culture; (b) developing mutual respect and trust with community members and study participants; (c) appreciating and praising community partners' knowledge, expertise, and experiences; (d) developing a sense of ownership by incorporating their needs, ideas, suggestions, and opinions and empowering study participants to make decisions concerning the study approach and wording; (e) soliciting participant feedback and clarification of study results and involving them in disseminating the study findings to their community; and (f) having fun with them and encouraging them to have fun. PMID- 22491301 TI - Social support, acculturation, and optimism: understanding positive health practices in Asian American college students. AB - PURPOSE: This study developed and tested a theory to better understand positive health practices (PHP) among Asian Americans aged 18 to 21 years. It tested theoretical relationships postulated between PHP and (a) social support (SS), (b) optimism, and (c) acculturation, and between SS and optimism and acculturation. Optimism and acculturation were also tested as possible mediators in the relationship between SS and PHP. DESIGN: A correlational study design was used. A convenience sample of 163 Asian college students in an urban setting completed four questionnaires assessing SS, PHP, optimism, and acculturation and one demographic questionnaire. FINDINGS: There were statistically significant positive relationships between SS and optimism with PHP, between acculturation and PHP, and between optimism and SS. Optimism mediated the relationship between SS and PHP, whereas acculturation did not. DISCUSSION: Findings extend knowledge regarding these relationships to a defined population of Asian Americans aged 18 to 21 years. IMPLICATIONS FOR FURTHER RESEARCH: Findings contribute to a more comprehensive knowledge base regarding health practices among Asian Americans. The theoretical and empirical findings of this study provide the direction for future research as well. Further studies need to be conducted to identify and test other mediators in order to better understand the relationship between these two variables. PMID- 22491302 TI - Clinical development of histone deacetylase inhibitor romidepsin. AB - Histone deactylase inhibitors have emerged as a promising epigenetic therapy for neoplasic indications. The US Food and Drug Administration granted approval to romidepsin for treatment of cutaneous T cell lymphoma (CTCL) in 2009. Phase I/II trials of romidepsin as monotherapy or hybird therapy have demonstrated substantial efficacy profoundly in CTCL and peripheral T-cell lymphoma and marginally in other hematogological malignancies and solid tumors, with a tolerable safety and toxicity profile. The current status of the clinical evaluation of romidepsin is detailed in the present contribution. PMID- 22491303 TI - Synthesis, characterization, and anthelmintic activity of novel 6,7,8,9 tetrahydro-5H-5-phenyl-2-benzylidine-3-substituted hydrazino thiazolo (2,3-b) quinazoline derivatives and analogues. AB - Several novel 6,7,8,9-tetrahydro-5H-5-phenyl-2-benzylidine-3-substituted hydrazine thiazolo (2,3-b) quinazoline derivatives were synthesized and evaluated for their anthelmintic activity in a passive avoidance test. Chemical structures of all of the newly synthesized compounds were confirmed by infrared spectroscopy, (1)H-nuclear magnetic resonance, mass spectroscopy, and elemental analyses. Out of 15 compounds, only 6e and 6o had good anthelmintic activity. Experimental data led to the conclusion that the synthesized compounds have anthelmintic activity. PMID- 22491304 TI - A new furoquinoline alkaloid with antifungal activity from the leaves of Ruta chalepensis L. AB - Bioassay-guided separation with an eye toward antifungal activity led to the isolation of the new alkaloid 5-(1,1-dimethylallyl)-8-hydroxyfuro[2-3-b] quinoline (1) and the known biscoumarin daphnoretin (2) as the active constituents of the chloroform extract obtained from the leaves of Ruta chalepensis. The structures of the metabolites were elucidated on the basis of their spectral characteristics (NMR, UV, and MS) and were compared with the literature. The antifungal activity of the isolated compounds was evaluated against the phytopathogenic fungi Rhizoctonia solani, Sclerotium rolfsii, and Fusarium solani, which cause root-rot and wilt diseases in several economically important food crops such as potato, sugar beet, and tomato. PMID- 22491305 TI - Taxonomic identification of a novel strain of Streptomyces cavourensis subsp. washingtonensis, ACMA006, exhibiting antitumor and antibacteria activity. AB - Taxonomically diverse and genetically specialized, marine microorganisms have great potential in generating bioactive substances. A previous study isolated a novel actinomycete strain designated ACMA006 and revealed that the fermentation broth of ACMA006 (FBA6) significantly inhibited the growth of a series of tumor cell lines. The present study examined various characteristics of the ACMA006 strain, including its morphological, physiological, and biochemical nature, and the 16S rDNA gene sequence of ACMA006 and biological activity of FBA6. The ACMA006 strain grew at an optimal temperature of 28 degrees C on nearly all media tested, except for Czapek's agar, producing an exuberant substrate and aerial hyphae. Phylogenetic analysis showed that the 16S rDNA gene sequence of ACMA006 was closely related to that of Streptomyces cavourensis subsp. washingtonensis, with a sequence similarity of nearly 100%. However, ACMA006 differed somewhat from Streptomyces cavourensis subsp. washingtonensis in terms of its morphological, physiological, and biochemical characteristics. According to a bioactivity assay, FBA6 strongly inhibited the growth of hepatocellular carcinoma cell line HepG2, while it was weakly cytotoxic to human normal hepatocytes LO2 according to an MTT assay. In addition, the growth of bacterial strains Bacillus subtilis and Staphylococcus aureus but not Escherichia coli, B. aerogenes, Pseudomonas fluorescence, and B. proteus was significantly suppressed by FBA6 as indicated by the filter paper disc method. Results of this study indicated that the strain ACMA006 represents a new strain of the Streptomyces cavourensis subsp. washingtonensis and that the active metabolites of this strain are candidates for utilization as anticancer or antibacterial agents. PMID- 22491306 TI - Novel CYP2C19 629c>a mutant gene detection in Japanese subjects and estimation of its effect on conformation. AB - Gene polymorphism is considered to be one of the causes of poor metabolism (PM), and approximately 20 mutants have been reported for CYP2C19 thus far. In our analysis of the CYP2C19*3 mutant gene, we detected new CYP2C19 SNPs by cross checking with different procedures. We confirmed a new c>a mutation at the 629 position. Among the 587 healthy Japanese volunteers studied, two subjects carrying a mutant CYP2C19 allele were found to be heterozygotes (0.17%). Accordingly, we predicted the effect of this novel mutation on CYP2C19 conformation. The 629c>a mutation was located on exon 4 and was an amino acid substitution, in which Thr210 was changed to Asn. The modeled structure of CYP2C19 showed that the hydrogen bond between the main chain oxygen of Ile207 and the side chain Ogamma of Thr210 would be lost when Thr210 was substituted by Asn; however, no steric constraint was observed, although Asn is larger than Thr in size. Although the CYP2C19 629c>a mutation induces an amino acid substitution, it is predicted to scarcely change its conformation. On the basis of these findings, we speculate that the mutant is not a causative gene for PM in CYP2C19 carriers. PMID- 22491307 TI - Quantification of nebivolol hydrochloride in human plasma by liquid chromatography using fluorescence detection: Use in pharmacokinetic study. AB - A simple, rapid, and sensitive method of reversed-phase high-performance liquid chromatography with fluorescence detection has been developed and validated for use in determining levels of nebivolol*HCl in human plasma. Sample preparation involves a simple single-step protein precipitation procedure and extraction of nebivolol in acetonitrile. The separation was performed on a Kromasil(r) RP-C18 column (F 4.6 mm * 250 mm, 5 MUm) with a mobile phase consisting of 0.05 M potassium dihydrogen phosphate buffer/acetonitrile (40:60, v/v) adjusted to pH 3 using orthophosphoric acid. Analysis was carried out under isocratic conditions at a flow rate of 1.5 mL/min and at room temperature using a fluorescence detector with excitation at 288 nm and emission at 310 nm. The chromatographic run was 4 min. The calibration curve was linear over the concentration range 0.2 20 ng/mL. The method was validated in terms of its accuracy, precision, and specificity. The assay enabled the measurement of nebivolol with a minimum quantification limit of 0.16 ng/mL. The average recovery of nebivolol from spiked human plasma was 98.4 +/- 3.3%. This method was successfully used in a pharmacokinetic study of oral administration of 5-mg tablets to healthy human volunteers. PMID- 22491308 TI - Use of factorial design in formulation and evaluation of ophthalmic gels of gatifloxacin: Comparison of different mucoadhesive polymers. AB - The aim of this research was to develop different ophthalmic gels of gatifloxacin using mucoadhesive polymers. To improve intraocular delivery of topically applied drugs such as gatifloxacin, gel formulations were prepared since solutions have a shorter ocular residence time because of tear turnover. A 3(2) factorial design was used to investigate the combined effect of two independent formulation variables in the preparation of the gels. Nine batches were prepared as per experimental design and evaluated for gelation temperature, gel strength, bioadhesion, viscosity, permeation, and antimicrobial efficacy. A surface plot was also created to graphically represent the effect of the independent variables on the evaluation parameters. Drug polymer compatibility was evaluated by differential scanning calorimetry and Fourier transform infrared spectroscopy. The prepared gels were observed to have a satisfactory gelation temperature, gel strength, and bioadhesion. Rheological study of the formulations indicated that gels exhibited pseudoplastic rheology. A modified device was used to evaluate drug permeation through a sheep's corneal membrane. In vitro permeation studies showed that a Peppas model was the best-fit model. Antimicrobial studies also indicated efficacy comparable to that of a marketed formulation. This systematic approach to formulation design should help in investigating the effect of variables in formulation processing. PMID- 22491309 TI - Improvement in the dissolution profile of diacerein using a surfactant-based solid dispersion technique. AB - In an attempt to improve the dissolution rate of poorly aqueous soluble diacerein (DCN), solid dispersions (SDs) were prepared with a surfactant Pluronic(r) F 127 (PXMR) at drug to polymer ratios of 1:0.5, 1:1.5, and 1:2.5 (w/w) by an ordinary melting technique. The interaction of DCN with PXMR in all solid binary systems was evaluated by thin layer chromatography (TLC), Fourier transform infrared spectrometry (FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM) studies. TLC indicated an absence of chemical interaction of DCN with PXMR whereas FTIR studies demonstrated an existence of strong hydrogen bonding between them. A uniform molecular dispersion of DCN was observed in DSC thermograms, and this finding was further supported by loss of the crystalline and irregular shape of DCN detected in SEM photomicrographs. Dissolution studies were promptly conducted to examine the release rate performance of DCN from all binary systems. The drug dissolution properties of binary systems improved significantly in comparison to crystalline DCN. The rate and extent of DCN release were observed to be strongly dependent on the proportion of PXMR present within the formulations. PMID- 22491310 TI - Solid-state characterization and in vitro dissolution behavior of lorazepam: Hydroxypropyl-beta-cyclodextrin inclusion complex. AB - The objectives of this research were to prepare and characterize inclusion complexes of lorazepam with hydroxypropyl-beta-cyclodextrin and to study the effect of complexation on the dissolution rate of lorazepam, a water-insoluble drug. The phase solubility profile of lorazepam with hydroxypropyl-beta cyclodextrin was an AP-type, indicating the formation of 2:1 stoichiometric inclusion complexes. Gibbs free energy values were all negative, indicating the spontaneous nature of lorazepam solubilization, and they decreased with an increase in the cyclodextrin concentration, demonstrating that the reaction conditions became more favorable as the concentration of cyclodextrins increased. Complexes of lorazepam were prepared with cyclodextrin using various methods such as physical mixing, kneading, spray-drying, and lyophilization. The complexes were characterized by differential scanning calorimetry, Fourier-transform infrared, scanning electron microscopy, and powder X-ray diffraction studies. These studies indicated that a complex prepared by lyophilization had successful inclusion of the lorazepam molecule into the cyclodextrin cavity. Complexation resulted in a marked improvement in the solubility and wettability of lorazepam. Among all the samples, a complex prepared with hydroxypropyl-beta-cyclodextrin by lyophilization had the greatest improvement in the in vitro rate of lorazepam dissolution. The mean dissolution time for lorazepam decreased significantly after preparing complexes and physical mixtures of lorazepam with cyclodextrin. The similarity factor indicated a significant difference between the release profiles of lorazepam from complexes and physical mixtures and from plain lorazepam. Tablets containing complexes prepared with cyclodextrins had significant improvement in the release profile of lorazepam as compared to tablets containing lorazepam without cyclodextrin. PMID- 22491311 TI - Formulation, development, and optimization of immediate release nateglinide tablets by factorial design. AB - In the present study, selection of superdisintegrants among sodium starch glycolate, cross povidone, Starch-1500 and cross carmellose sodium (CCS) was carried out for development of immediate release nateglinide tablets (NTG). A 3(2) full factorial design was used to investigate the influence of two independent variables, i.e., amount of selected superdisintegrants and hardness of the tablets, on two dependent variables, i.e., disintegration time and percentage of drug release at 30 min (DR(0.5h)). The results revealed that CCS was the best superdisintegrant for the development of immediate release tablets of NTG. The sign of the coefficient of the polynomial equation signified that the disintegration time was decreased and DR(0.5h) was increased by decreasing the hardness of the tablets as well as by increasing the concentration of CCS in the tablets. A checkpoint batch of the tablets was prepared by changing the value of independent variables within the range used in the preparation of factorial batches of tablets to check the validity of the evolved optimized mathematical model. Stability studies of optimized formulations indicated that there was no significant change in the physical parameters, disintegration time, and percentage of drug release of tablets. The systematic formulation approach helped to understand the effect of formulation processing variables. PMID- 22491312 TI - Formulation of microemulsion gel systems for transdermal delivery of celecoxib: In vitro permeation, anti-inflammatory activity and skin irritation tests. AB - The aim of this study was to develop suitable microemulsion gel systems for transdermal delivery that could assist dissolution enhancement of poorly water soluble celecoxib and thus improve its skin permeability. Long term oral administration of celecoxib causes serious gastrointestinal adverse effects, which makes it a good candidate for transdermal formulations, yet its low water solubility (4 mg/L) makes this challenging. Ternary phase diagrams were constructed using isopropyl myristate and oleic acid as oils, Tween 80 as surfactant, and Cremophor RH40 as cosurfactant. Microemulsion areas were identified and two systems each of 36 formulas were prepared and assessed for visual inspection, spreadability, pH measurements, and droplet size analysis. Drug release and in vitro permeation of celecoxib from microemulsion formulas through semi-permeable membranes and excised abdominal rabbit skin, respectively, were carried out and compared to celecoxib cream. In all tested formulas, celecoxib was released and permeation was at a higher rate than that from the corresponding cream. The optimized formula (F12) was found to be superior to all other formulas. This formula increased the permeation rate of celecoxib up to 11 times compared to that of the cream. Its stability was retained after one year of storage under ambient conditions and its anti-inflammatory effect was significantly higher than that of celecoxib cream and the oral commercial formula. Skin irritancy and histopathological investigation of rat skin revealed its safety. The results revealed that the developed microemulsion gel has great potential for transdermal delivery of celecoxib. PMID- 22491313 TI - Preparation and characterization of oxybenzone-loaded solid lipid nanoparticles (SLNs) with enhanced safety and sunscreening efficacy: SPF and UVA-PF. AB - The objective of the current study was to formulate solid lipid nanoparticles of oxybenzone to enhance its sunscreening efficacy while reducing its side effects. Solid lipid nanoparticles (SLNs) of oxybenzone were prepared by the solvent diffusion method. A complete 2(4) factorial design was used to optimize preparations. The study design involves the investigation of four independent variables, namely lipid type (Glyceryl monostearate, GMS; and Witepsol E85, WE85), lipid concentration (5 and 10%), polyvinyl alcohol (PVA) concentration (1 and 2%), and ethanol/acetone ratios (1:1 and 3:1, v/v), in terms of their effect on the particle size and entrapment efficiency. GMS was found to significantly increase the p.s. and EE%. SLNs prepared using 10% lipid had slower drug release compared to those prepared using 5%. The candidate oxybenzone-loaded SLN formula (SLN2) consisting of 0.5% oxybenzone, 10% GMS, 1% PVA, and ethanol/acetone (1:1, v/v) was then formulated into a gel and compared to the corresponding free oxybenzone nanosuspension and placebo SLN. The formulations were evaluated for skin irritation, in vitro sun protection factor, and ultraviolet A protection factors. The incorporation of oxybenzone into solid lipid nanoparticles greatly increased the SPF and UVA protection factor of oxybenzone more than five-fold while providing the advantage of overcoming skin irritancy problems. PMID- 22491314 TI - Comparative study on the different techniques for the preparation of sustained release hydrophobic matrices of a highly water-soluble drug. AB - The objective of the present study was to control the release of freely water soluble salbutamol sulphate (SS) over a prolonged period of time by embedding the drug into slowly eroding waxy matrix materials such as Precirol(r) ATO5, Compritol(r) 888 ATO, beeswax, paraffin wax, carnauba wax, and stearyl alcohol. The matrices were prepared by either direct compression or hot fusion techniques. The compatibility of the drug with the various excipients was examined using differential scanning calorimetry (DSC). A factorial design was employed to study the effect of polymer type, polymer concentration (15% and 35%), and filler type (Avicel(r) PH101 and dibasic calcium phosphate dehydrate (DCP) on the in vitro drug release at 6 h. Results of DSC confirmed drugexcipient compatibility. Increasing the polymer ratio resulted in a significant retardation of drug release. The use of DCP resulted in significant retardation and incomplete drug release while the use of Avicel did not. The hot fusion method was found to be more effective than the direct compression method in retarding SS release. A Precirol formulation, prepared using the hot fusion technique, had the slowest drug release, releasing about 31.3% of SS over 6 h. In contrast, Compritol, prepared using the direct compression technique, had the greatest retardation, providing sustained release of 59.3% within 6 h. A hydrophobic matrix system is thus a useful technique for prolonging the release of freely water-soluble drugs such as salbutamol sulphate. PMID- 22491315 TI - Effect of Ceolus KG-802 on the dissolution rate of fenofibrate liquisolid tablets: Preformulation and formulation development studies. AB - The purpose of the present research was to study the effects of Ceolus KG-802 on the dissolution behavior of fenofibrate liquisolid tablets. The fenofibrate liquisolid tablets were formulated using the mathematical model described by Spireas et al. In the present research, Ceolus KG-802, a different form of microcrystalline cellulose (PH 102 grade), was used as a carrier material. The developed formulations were subjected to preformulation studies such as differential scanning calorimetry, X-ray powder diffraction, and determination of flow properties. The liquisolid tablets prepared were studied for their in vitro dissolution and compared to liquisolid tablets prepared using Avicel PH 102. The in vitro dissolution profiles of liquisolid tablets prepared using Ceolus KG-802 indicated slower dissolution than those of liquisolid tablets prepared using Avicel PH 102, which was a subject of earlier studies. This might be due to the particle size, shape, and characteristic properties of Ceolus KG-802. PMID- 22491316 TI - The treatment effect of the atopic dermatitis by electrolytic-reduction ion water lotion. AB - A female in her late 20s was diagnosed with systemic atopic dermatitis in another hospital 5 years earlier and treated by steroid ointment application to the affected areas and oral steroid administration. She visited our hospital due to the aggravation of dermatitis symptoms over the entire face from 1 week earlier. Lesions were present on the face, chest, neck, and bilateral upper limbs, and, in particular, facial dermatitis was extensive. A diagnosis of systemic atopic dermatitis complicated by infection was made. As oral drugs, a herbal medicine and steroid/antihistamine combination tablet were used. As topical drugs, an steroid/antibiotic combination ointment and vitamin E/A ointment were applied. In addition, injections for the treatment of allergic disease were used, and acidic electrolyzed water and an electrolyticreduction ion water (ERI) lotion were topically applied. While receiving the two types of oral drug, she received a subcutaneous injection once a week and the application of acidic electrolyzed water, ERI lotion, steroid/antibiotic combination ointment, and vitamin E/A ointment to the lesions twice a day. One week after the initiation of treatment, redness and swelling decreased. After 1 month, the swelling further decreased, but the redness remained. After 1.5 months, the redness further decreased, showing a favorable course. Three months after the initiation of treatment, slight redness remained, but the skin color was almost normal. This patient showed the improvement of skin redness and swelling and an almost normal skin state without pigmented scars. These results suggest the effectiveness of complex therapy consisting of a herbal medicine and steroid/antihistamine combination drug as oral drugs and an steroid/antibiotic combination ointment and vitamin E/A ointment as topical drugs, injections for allergic disease, and acidic electrolyzed water and ERI lotion for disinfection and skin care. PMID- 22491317 TI - Structural analysis of water and carbon tetrachloride adsorbed in activated carbon fibres. AB - We report X-ray diffraction studies of water and carbon tetrachloride adsorbed in nanoporous activated carbon fibres. The fibres are built of turbostratic nanoparticles separated by quasi two-dimensional voids, forming narrow slit shaped pores. In order to determine the structure of water within the pores and its influence on the fibres' structure, mean interatomic and intermolecular distances have been estimated from the positions of the maxima of the normalized angular distribution functions obtained by X-ray diffraction. We observe a cluster arrangement of the water molecules, as well as significant changes in the interlayer distance of the carbon nanoparticles upon adsorption of both water and carbon tetrachloride. The results suggest that very high pressures arise within the pores, as has been observed in molecular simulations, and this may give rise to the large change in electronic properties of the fibres after adsorption of guest molecules. The in-pore pressure normal to the pore walls is estimated from the experimental data, and is found to be positive and of the order 4000 bar. Molecular simulation results for the normal pressure component are presented for both water and carbon tetrachloride in carbon slit pores, and are in general agreement with the experiments. For both fluids the normal pressure is an oscillating function of pore width. PMID- 22491318 TI - A primary neuron culture system for the study of herpes simplex virus latency and reactivation. AB - Herpes simplex virus type-1 (HSV-1) establishes a life-long latent infection in peripheral neurons. This latent reservoir is the source of recurrent reactivation events that ensure transmission and contribute to clinical disease. Current antivirals do not impact the latent reservoir and there are no vaccines. While the molecular details of lytic replication are well-characterized, mechanisms controlling latency in neurons remain elusive. Our present understanding of latency is derived from in vivo studies using small animal models, which have been indispensable for defining viral gene requirements and the role of immune responses. However, it is impossible to distinguish specific effects on the virus neuron relationship from more general consequences of infection mediated by immune or non-neuronal support cells in live animals. In addition, animal experimentation is costly, time-consuming, and limited in terms of available options for manipulating host processes. To overcome these limitations, a neuron only system is desperately needed that reproduces the in vivo characteristics of latency and reactivation but offers the benefits of tissue culture in terms of homogeneity and accessibility. Here we present an in vitro model utilizing cultured primary sympathetic neurons from rat superior cervical ganglia (SCG) (Figure 1) to study HSV-1 latency and reactivation that fits most if not all of the desired criteria. After eliminating non-neuronal cells, near-homogeneous TrkA(+) neuron cultures are infected with HSV-1 in the presence of acyclovir (ACV) to suppress lytic replication. Following ACV removal, non-productive HSV-1 infections that faithfully exhibit accepted hallmarks of latency are efficiently established. Notably, lytic mRNAs, proteins, and infectious virus become undetectable, even in the absence of selection, but latency-associated transcript (LAT) expression persists in neuronal nuclei. Viral genomes are maintained at an average copy number of 25 per neuron and can be induced to productively replicate by interfering with PI3-Kinase / Akt signaling or the simple withdrawal of nerve growth factor(1). A recombinant HSV-1 encoding EGFP fused to the viral lytic protein Us11 provides a functional, real-time marker for replication resulting from reactivation that is readily quantified. In addition to chemical treatments, genetic methodologies such as RNA-interference or gene delivery via lentiviral vectors can be successfully applied to the system permitting mechanistic studies that are very difficult, if not impossible, in animals. In summary, the SCG-based HSV-1 latency / reactivation system provides a powerful, necessary tool to unravel the molecular mechanisms controlling HSV1 latency and reactivation in neurons, a long standing puzzle in virology whose solution may offer fresh insights into developing new therapies that target the latent herpesvirus reservoir. PMID- 22491320 TI - Earliest known coelacanth skull extends the range of anatomically modern coelacanths to the Early Devonian. AB - Coelacanths are known for their evolutionary conservatism, and the body plan seen in Latimeria can be traced to late Middle Devonian Diplocercides, Holopterygius and presumably Euporosteus. However, the group's early history is unclear because of an incomplete fossil record. Until now, the only Early Devonian coelacanth is an isolated dentary (Eoactinistia) from Australia, whose position within the coelacanths is unknown. Here we report the earliest known coelacanth skull (Euporosteus yunnanensis sp. nov.) from the Early Devonian (late Pragian) of Yunnan, China. Resolved by maximum parsimony, maximum likelihood and Bayesian analyses as crownward of Diplocercides or as its sister taxon, the new form extends the chronological range of anatomically modern coelacanths by about 17 Myr. The finding lends support to the possibility that Eoactinistia is also an anatomically modern coelacanth, and provides a more refined reference point for studying the rapid early diversification and subsequent evolutionary conservatism of the coelacanths. PMID- 22491319 TI - CYLD negatively regulates transforming growth factor-beta-signalling via deubiquitinating Akt. AB - Lung injury, whether induced by infection or caustic chemicals, initiates a series of complex wound-healing responses. If uncontrolled, these responses may lead to fibrotic lung diseases and loss of function. Thus, resolution of lung injury must be tightly regulated. The key regulatory proteins required for tightly controlling the resolution of lung injury have yet to be identified. Here we show that loss of deubiquitinase CYLD led to the development of lung fibrosis in mice after infection with Streptococcus pneumoniae. CYLD inhibited transforming growth factor-beta-signalling and prevented lung fibrosis by decreasing the stability of Smad3 in an E3 ligase carboxy terminus of Hsc70 interacting protein-dependent manner. Moreover, CYLD decreases Smad3 stability by deubiquitinating K63-polyubiquitinated Akt. Together, our results unveil a role for CYLD in tightly regulating the resolution of lung injury and preventing fibrosis by deubiquitinating Akt. These studies may help develop new therapeutic strategies for preventing lung fibrosis. PMID- 22491321 TI - Auditory cortex of newborn bats is prewired for echolocation. AB - Neuronal computation of object distance from echo delay is an essential task that echolocating bats must master for spatial orientation and the capture of prey. In the dorsal auditory cortex of bats, neurons specifically respond to combinations of short frequency-modulated components of emitted call and delayed echo. These delay-tuned neurons are thought to serve in target range calculation. It is unknown whether neuronal correlates of active space perception are established by experience-dependent plasticity or by innate mechanisms. Here we demonstrate that in the first postnatal week, before onset of echolocation and flight, dorsal auditory cortex already contains functional circuits that calculate distance from the temporal separation of a simulated pulse and echo. This innate cortical implementation of a purely computational processing mechanism for sonar ranging should enhance survival of juvenile bats when they first engage in active echolocation behaviour and flight. PMID- 22491322 TI - Staged decline of neuronal function in vivo in an animal model of Alzheimer's disease. AB - The accumulation of amyloid-beta in the brain is an essential feature of Alzheimer's disease. However, the impact of amyloid-beta-accumulation on neuronal dysfunction on the single cell level in vivo is poorly understood. Here we investigate the progression of amyloid-beta load in relation to neuronal dysfunction in the visual system of the APP23*PS45 mouse model of Alzheimer's disease. Using in vivo two-photon calcium imaging in the visual cortex, we demonstrate that a progressive deterioration of neuronal tuning for the orientation of visual stimuli occurs in parallel with the age-dependent increase of the amyloid-beta load. Importantly, we find this deterioration only in neurons that are hyperactive during spontaneous activity. This impairment of visual cortical circuit function also correlates with pronounced deficits in visual pattern discrimination. Together, our results identify distinct stages of decline in sensory cortical performance in vivo as a function of the increased amyloid beta-load. PMID- 22491323 TI - Atomic-scale evolution of modulated phases at the ferroelectric-antiferroelectric morphotropic phase boundary controlled by flexoelectric interaction. AB - Physical and structural origins of morphotropic phase boundaries (MPBs) in ferroics remain elusive despite decades of study. The leading competing theories employ either low-symmetry bridging phases or adaptive phases with nanoscale textures to describe different subsets of the macroscopic data, while the decisive atomic-scale information has so far been missing. Here we report direct atomically resolved mapping of polarization and structure order parameter fields in a Sm-doped BiFeO(3) system and their evolution as the system approaches a MPB. We further show that both the experimental phase diagram and the observed phase evolution can be explained by taking into account the flexoelectric interaction, which renders the effective domain wall energy negative, thus stabilizing modulated phases in the vicinity of the MPB. Our study highlights the importance of local order-parameter mapping at the atomic scale and establishes a hitherto unobserved physical origin of spatially modulated phases existing in the vicinity of the MPB. PMID- 22491324 TI - Dissecting a central flip-flop circuit that integrates contradictory sensory cues in C. elegans feeding regulation. AB - Feeding behaviour is modulated by both environmental cues and internal physiological states. Appetite is commonly boosted by the pleasant smell (or appearance) of food and destroyed by a bad taste. In reality, animals sense multiple environmental cues at the same time and it is not clear how these sensory inputs are integrated and a decision is made to regulate feeding behaviour accordingly. Here we show that feeding behaviour in Caenorhabditis elegans can be either facilitated by attractive odours or suppressed by repellents. By identifying mutants that are defective for sensory-mediated feeding regulation, we dissected a central flip-flop circuit that integrates two contradictory sensory inputs and generates bistable hormone output to regulate feeding behaviour. As feeding regulation is fundamental to animal survival, we speculate that the basic organizational logic identified here in C. elegans is likely convergent throughout different phyla. PMID- 22491325 TI - Soluble amyloid precursor protein-alpha modulates beta-secretase activity and amyloid-beta generation. AB - In sporadic age-related forms of Alzheimer's disease (AD), it is unclear why amyloid-beta (Abeta) peptides accumulate. Here we show that soluble amyloid precursor protein-alpha (sAPP-alpha) decreases Abeta generation by directly associating with beta-site APP-converting enzyme (BACE)1, thereby modulating APP processing. Whereas specifically targeting sAPP-alpha using antibodies enhances Abeta production; in transgenic mice with AD-like pathology, sAPP-alpha overexpression decreases beta-amyloid plaques and soluble Abeta. In support, immunoneutralization of sAPP-alpha increases APP amyloidogenic processing in these mice. Given our current findings, and because a number of risk factors for sporadic AD serve to lower levels of sAPP-alpha in brains of AD patients, inadequate sAPP-alpha levels may be sufficient to polarize APP processing towards the amyloidogenic, Abeta-producing route. Therefore, restoration of sAPP-alpha or enhancement of its association with BACE may be viable strategies to ameliorate imbalances in APP processing that can lead to AD pathogenesis. PMID- 22491327 TI - Discreteness-induced concentration inversion in mesoscopic chemical systems. AB - Molecular discreteness is apparent in small-volume chemical systems, such as biological cells, leading to stochastic kinetics. Here we present a theoretical framework to understand the effects of discreteness on the steady state of a monostable chemical reaction network. We consider independent realizations of the same chemical system in compartments of different volumes. Rate equations ignore molecular discreteness and predict the same average steady-state concentrations in all compartments. However, our theory predicts that the average steady state of the system varies with volume: if a species is more abundant than another for large volumes, then the reverse occurs for volumes below a critical value, leading to a concentration inversion effect. The addition of extrinsic noise increases the size of the critical volume. We theoretically predict the critical volumes and verify, by exact stochastic simulations, that rate equations are qualitatively incorrect in sub-critical volumes. PMID- 22491326 TI - Nanodomain Ca2+ of Ca2+ channels detected by a tethered genetically encoded Ca2+ sensor. AB - Coupling of excitation to secretion, contraction and transcription often relies on Ca(2+) computations within the nanodomain-a conceptual region extending tens of nanometers from the cytoplasmic mouth of Ca(2+) channels. Theory predicts that nanodomain Ca(2+) signals differ vastly from the slow submicromolar signals routinely observed in bulk cytoplasm. However, direct visualization of nanodomain Ca(2+) far exceeds optical resolution of spatially distributed Ca(2+) indicators. Here we couple an optical, genetically encoded Ca(2+) indicator (TN-XL) to the carboxy tail of Ca(V)2.2 Ca(2+) channels, enabling near-field imaging of the nanodomain. Under total internal reflection fluorescence microscopy, we detect Ca(2+) responses indicative of large-amplitude pulses. Single-channel electrophysiology reveals a corresponding Ca(2+) influx of only 0.085 pA, and fluorescence resonance energy transfer measurements estimate TN-XL distance to the cytoplasmic mouth at ~55 A. Altogether, these findings raise the possibility that Ca(2+) exits the channel through the analogue of molecular portals, mirroring the crystallographic images of side windows in voltage-gated K channels. PMID- 22491328 TI - Diversity-oriented synthesis: producing chemical tools for dissecting biology. AB - Small molecule modulators of biological function can be discovered by the screening of compound libraries. However, it became apparent that some human disease related targets could not be addressed by the libraries commonly used which typically are comprised of large numbers of structurally similar compounds. The last decade has seen a paradigm shift in library construction, with particular emphasis now being placed on increasing a library's structural, and thus functional diversity, rather than only its size. Diversity-oriented synthesis (DOS) aims to generate such structural diversity efficiently. This tutorial review has been written to introduce the subject to a broad audience and recent achievements in both the preparation and the screening of structurally diverse compound collections against so-called 'undruggable' targets are highlighted. PMID- 22491329 TI - Deconstructing the Veterans Affairs MRSA prevention bundle. PMID- 22491330 TI - Successful Veterans Affairs initiative to prevent methicillin-resistant Staphylococcus aureus infections revisited. AB - In 2011 Jain et al reported a 62% reduction of healthcare-associated methicillin resistant Staphylococcus aureus infections that resulted from an intervention bundle. Here we present a mathematical model and prove, using parameters from the study by Jain et al, that the universal screen and isolate strategy can have contributed only marginally to the reduction in infections. PMID- 22491332 TI - CD31+ cell percentage correlation with speed of CD4+ T-cell count recovery in HIV infected adults is reversed in children: higher thymic output may be responsible. PMID- 22491333 TI - HIV-1 drug resistance resulting from antiretroviral therapy far exceeds that from pre-exposure prophylaxis. PMID- 22491335 TI - Severe outcomes are associated with genogroup 2 genotype 4 norovirus outbreaks: a systematic literature review. AB - BACKGROUND: Noroviruses (NoVs) are the most common cause of epidemic gastroenteritis; however, the relative impacts of individual factors underlying severe illness are poorly understood. This report reviews published NoV outbreak reports to quantify hospitalization and mortality rates and assess their relationship with outbreak setting, transmission route, and strain. METHODS: Using a string of terms related to "norovirus" and "outbreak," we 2435 nonduplicate articles identified in PubMed, EMBASE, and Web of Knowledge published between January 1993 and June 2011. Inclusion criteria included outbreaks with a minimum of 2 ill persons with a common exposure and at least 1 reverse-transcription polymerase chain reaction-confirmed case of NoV disease. Univariate analyses were performed, and multivariable models were fitted to estimate the independent effect of each factor. RESULTS: We analyzed 843 NoV outbreaks reported in 233 published articles from 45 countries. Based upon 71724 illnesses, 501 hospitalizations, and 45 deaths, overall hospitalization and mortality rates were 0.54% and 0.06%, respectively. In multivariate analysis, genogroup 2 genotype 4 (GII.4) NoV strains were associated with higher hospitalization (incidence rate ratio [IRR], 9.4; 95% confidence interval [CI], 6.1-14.4; P< .001) and mortality rates (IRR, 3.1; 95% CI, 1.3-7.6; P = .01). Deaths were much more likely to occur in outbreaks occurring in healthcare facilities (IRR, 60; 95% CI, 6-109; P = .01). CONCLUSIONS: Our review suggests that hospitalizations and deaths were more likely in outbreaks associated with GII.4 viruses, independent of other factors, and underscores the importance of developing vaccines against GII.4 viruses to prevent severe disease outcomes. PMID- 22491336 TI - Kaposi sarcoma-associated immune reconstitution inflammatory syndrome: in need of a specific case definition. PMID- 22491337 TI - A simple scoring algorithm predicting vascular infections in adults with nontyphoid Salmonella bacteremia. AB - BACKGROUND: Nontyphoid Salmonella (NTS) can cause fatal vascular infections. This study aims to establish a predictive scoring algorithm to identify adults aged >= 50 years with NTS bacteremia who are at risk for vascular infections. METHODS: There were 358 adults aged >= 50 years with NTS bacteremia at 2 medical centers in southern Taiwan included in this study. Multiple logistic regression was used to identify risk factors for imaging-documented vascular infections. The prediction capability of the proposed scoring algorithm was indicated by a receiver operating characteristic curve and measures of sensitivity and specificity. RESULTS: Sixty patients (16.8%) with vascular infections were noted. The 4 risk factors significantly associated with vascular infections-male sex, hypertension, coronary arterial disease, and serogroup C1 infections-were each assigned +1 point to form the NTS vascular infection (NTSVI) score. In contrast, malignancy and immunosuppressive therapy were each assigned -1 point, owing to their negative associations with vascular infections. Based on the proposed NTSVI scoring, the prevalence of vascular infections in patients with <= 0, 1, 2, 3, or 4 points was 2.2% (3 of 138 patients), 10.6% (13 of 123 patients), 39.4% (26 of 66 patients), 55.2% (16 of 29 patients), and 100% (2 of 2 patients), respectively (P< .0001). The scoring algorithm shows an area under the curve of 0.83 (95% confidence interval, .78-.89; P < .0001). A cutoff value of +1 represents a high sensitivity (95.0%) and an acceptable specificity (45.3%). CONCLUSIONS: This simple scoring algorithm can be used to identify patients with NTS bacteremia with a high risk of vascular infections. The cost-effectiveness of this algorithm should be further studied. PMID- 22491338 TI - The roles of Clostridium difficile and norovirus among gastroenteritis-associated deaths in the United States, 1999-2007. AB - BACKGROUND: Globally, gastroenteritis is recognized as an important contributor to mortality among children, but population-based data on gastroenteritis deaths among adults and the contributions of specific pathogens are limited. We aimed to describe trends in gastroenteritis deaths across all ages in the United States and specifically estimate the contributions of Clostridium difficile and norovirus. METHODS: Gastroenteritis-associated deaths in the United States during 1999-2007 were identified from the National Center for Health Statistics multiple cause-of-death mortality data. All deaths in which the underlying cause or any of the contributing causes listed gastroenteritis were included. Time-series regression models were used to identify cause-unspecified gastroenteritis deaths that were probably due to specific causes; seasonality of model residuals was analyzed to estimate norovirus-associated deaths. RESULTS: Gastroenteritis mortality averaged 39/1000000 person-years (11 255 deaths per year) during the study period, increasing from 25/1 000 000 person-years in 1999-2000 to 57/1 000 000 person-years in 2006-2007 (P < .001). Adults aged >= 65 years accounted for 83% of gastroenteritis deaths (258/1 000 000 person-years). C. difficile mortality increased 5-fold from 10/1 000 000 person-years in 1999-2000 to 48/1 000 000 person-years in 2006-2007 (P < .001). Norovirus contributed to an estimated 797 deaths annually (3/1 000 000 person-years), with surges by up to 50% during epidemic seasons associated with emergent viral strains. CONCLUSIONS: Gastroenteritis-associated mortality has more than doubled during the past decade, primarily affecting the elderly. C. difficile is the main contributor to gastroenteritis-associated deaths, largely accounting for the increasing trend, and norovirus is probably the second leading infectious cause. These findings can help guide appropriate clinical management strategies and vaccine development. PMID- 22491339 TI - Cost-effective screening for acute hepatitis C virus infection in HIV-infected men who have sex with men. AB - BACKGROUND: We used a Monte Carlo computer simulation to estimate the effectiveness and cost-effectiveness of screening for acute hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected men who have sex with men. METHODS: One-time screening for prevalent HCV infection was performed at the time of enrollment in care, followed by either symptom-based screening, screening with liver function tests (LFTs), HCV antibody (Ab) screening, or HCV RNA screening in various combinations and intervals. We considered both treatment with pegylated interferon and ribavirin (PEG/RBV) alone and with an HCV protease inhibitor. Outcome measures were life expectancy, quality-adjusted life expectancy, direct medical costs, and cost-effectiveness, assuming a societal willingness to pay $100000 per quality-adjusted life-year (QALY) gained. RESULTS: All strategies increased life expectancy (from 0.49 to 0.94 life-months), quality adjusted life expectancy (from 0.47 to 1.00 quality-adjusted life-months), and costs (from $1900 to $7600), compared with symptom-based screening. The incremental cost-effectiveness ratio of screening with 6-month LFTs and a 12 month HCV Ab test, compared with symptom-based screening, was $43 700/QALY (for PEG/RBV alone) and $57 800/QALY (for PEG/RBV plus HCV protease inhibitor). The incremental cost-effectiveness ratio of screening with 3-month LFTs, compared with 6-month LFTs plus a 12-month HCV Ab test, was $129 700/QALY (for PEG/RBV alone) and $229 900/QALY (for PEG/RBV plus HCV protease inhibitor). With HCV protease inhibitor-based therapy, screening with 6-month LFTs and a 12-month HCV Ab test was the optimal strategy when the HCV infection incidence was <=1.25 cases/100 person-years. The 3-month LFT strategy was optimal when the incidence was >1.25 cases/100 person-years. CONCLUSIONS: Screening for acute HCV infection in HIV-infected MSM prolongs life expectancy and is cost-effective. Depending on incidence, regular screening with LFTs, with or without an HCV Ab test, is the optimal strategy. PMID- 22491341 TI - Editorial commentary: Hepatitis C virus and the infectious disease physician: a perfect match. PMID- 22491340 TI - Features of infections due to Klebsiella pneumoniae carbapenemase-producing Escherichia coli: emergence of sequence type 131. AB - BACKGROUND: Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae has become endemic in many US hospitals. On the other hand, KPC-producing Escherichia coli remains rare. METHODS: We studied infection or colonization due to KPC producing E. coli identified at our hospital between September 2008 and February 2011. A case-control study was conducted to document clinical features associated with this organism. Susceptibility testing, sequencing of beta-lactamase genes, pulsed-field gel electrophoresis, multilocus sequence typing, and plasmid analysis were performed for characterization of the isolates. RESULTS: Thirteen patients with KPC-producing E. coli were identified. The patients had multiple comorbid conditions and were in hospital for variable periods of time before KPC producing E. coli was identified. The presence of liver diseases was independently associated with recovery of KPC-producing E. coli when compared with extended-spectrum beta-lactamase-producing E. coli. The isolates showed variable susceptibility to carbapenems. Seven isolates belonged to sequence type (ST) 131, which is the international epidemic, multidrug-resistant clone, but their plasmid profiles were diverse. KPC-producing organisms other than E. coli were isolated within 1 month from 5 of the patients. The KPC-encoding plasmids were highly related in 3 of them, suggesting the occurrence of their interspecies transfer. CONCLUSIONS: KPC-producing E. coli infections occur in severely ill patients who are admitted to the hospital. Acquisition of the KPC-encoding plasmids by the ST 131 clone, reported here for the first time to our knowledge in the United States, seems to represent multiple independent events. These plasmids are often shared between E. coli and other species. PMID- 22491342 TI - Hepatitis C treatment highlights from the 2011 American Association for the Study of Liver Disease meeting. AB - Development of more effective hepatitis C (HCV) antivirals has been rapid. The addition of orally administered medications that target the virus (direct acting antivirals [DAA]) to pegylated interferon and ribavirin have dramatically increased sustained virologic response rates in genotype 1-infected patients. However, the side effect profile remains challenging and the dosing schedule complicated. The DAAs currently in development possess the promise of once- or twice-daily dosing schedules, improved tolerance profiles, higher resistance barriers, and pan-genotypic antiviral activity. Emerging interferon-sparing, combination DAA data demonstrates that an interferon is not essential to achieve sustained virological response. This will expand the proportion of HCV-infected patients who can be considered for therapy and will allow for better-tolerated regimens. Expertise in HCV antiviral resistance, drug metabolism, and drug-drug interactions and optimization of drug adherence are now key requirements in the DAA era. PMID- 22491344 TI - Fragment occupations in partition Density Functional Theory. AB - The exact ground-state energy and density of a molecule can in principle be obtained via Partition Density Functional Theory (PDFT), a method for calculating molecular properties from Kohn-Sham calculations on isolated fragments. For a given choice of fragmentation, unique fragment densities are found by requiring that the sum of fragment energies be minimized subject to the constraint that the fragment densities sum to the correct molecular ground-state density. We investigate two interrelated aspects of PDFT: the connections between fragment densities obtained via different choices of fragmentation, for which we find "near-additivity", and the nature of their corresponding fragment occupations. Whereas near-integer occupations arise for very large inter-fragment separations, strictly integer occupations appear for small inter-fragment separations. Cases where the fragment chemical potentials cannot be equalized lead to fragment occupations that lock into integers. PMID- 22491345 TI - Assumptions of expected benefits in randomized phase III trials evaluating systemic treatments for cancer. AB - BACKGROUND: In designing phase III randomized clinical trials (RCTs), the expected magnitude of the benefit of the experimental therapy (delta) determines the number of patients required and the number of person-years of follow-up. We conducted a systematic review to evaluate how reliably delta approximates the observed benefit (B) in RCTs that evaluated cancer treatment. METHODS: RCTs evaluating systemic therapy in adult cancer patients published in 10 journals from January 1, 2005, through December 31, 2009, were identified. Data were extracted from each publication independently by two investigators. The related samples Sign test was used to determine whether the median difference between delta and B was statistically significant in different study subsets and was two sided. RESULTS: A total of 253 RCTs met the eligibility criteria and were included in the analysis. Regardless of whether benefit was defined as proportional change (median difference between delta and B = -13.0%, 95% confidence interval [CI] = -21.0% to -8.0%), absolute change (median difference between delta and B = -8.0%, 95% CI = -9.9% to -5.1%), or median increase in a time-to-event endpoint (median difference between delta and B = -1.4 months, 95% CI = -2.1 to -0.8 months), delta was consistently and statistically significantly larger than B (P < .001, for each, respectively). This relationship between delta and B was independent of year of publication, industry funding, management by cooperative trial groups, type of control arm, type of experimental arm, disease site, adjuvant treatment, or treatment for advanced disease, and likely contributed to the high proportion of negative RCTs (158 [62.5%] of 253 studies). CONCLUSIONS: Investigators consistently make overly optimistic assumptions regarding treatment benefits when designing RCTs. Attempts to reduce the number of negative RCTs should focus on more realistic estimations of delta. Increased use of interim analyses, certain adaptive trial designs, and better biological characterization of patients are potential ways of mitigating this problem. PMID- 22491346 TI - Why do phase III clinical trials in oncology fail so often? PMID- 22491348 TI - Applications of dewetting in micro and nanotechnology. AB - Dewetting is a spontaneous phenomenon where a thin film on a surface ruptures into an ensemble of separated objects, like droplets, stripes, and pillars. Spatial correlations with characteristic distance and object size emerge spontaneously across the whole dewetted area, leading to regular motifs with long range order. Characteristic length scales depend on film thickness, which is a convenient and robust technological parameter. Dewetting is therefore an attractive paradigm for organizing a material into structures of well-defined micro- or nanometre-size, precisely positioned on a surface, thus avoiding lithographical processes. This tutorial review introduces the reader to the physical-chemical basis of dewetting, shows how the dewetting process can be applied to different functional materials with relevance in technological applications, and highlights the possible strategies to control the length scales of the dewetting process. PMID- 22491349 TI - Measurement of cellular chemotaxis with ECIS/Taxis. AB - Cellular movement in response to external stimuli is fundamental to many cellular processes including wound healing, inflammation and the response to infection. A common method to measure chemotaxis is the Boyden chamber assay, in which cells and chemoattractant are separated by a porous membrane. As cells migrate through the membrane toward the chemoattractant, they adhere to the underside of the membrane, or fall into the underlying media, and are subsequently stained and visually counted (1). In this method, cells are exposed to a steep and transient chemoattractant gradient, which is thought to be a poor representation of gradients found in tissues (2). Another assay system, the under-agarose chemotaxis assay, (3, 4) measures cell movement across a solid substrate in a thin aqueous film that forms under the agarose layer. The gradient that develops in the agarose is shallow and is thought to be an appropriate representation of naturally occurring gradients. Chemotaxis can be evaluated by microscopic imaging of the distance traveled. Both the Boyden chamber assay and the under-agarose assay are usually configured as endpoint assays. The automated ECIS/Taxis system combines the under-agarose approach with Electric Cell-substrate Impedance Sensing (ECIS) (5, 6). In this assay, target electrodes are located in each of 8 chambers. A large counter-electrode runs through each of the 8 chambers (Figure 2). Each chamber is filled with agarose and two small wells are the cut in the agarose on either side of the target electrode. One well is filled with the test cell population, while the other holds the sources of diffusing chemoattractant (Figure 3). Current passed through the system can be used to determine the change in resistance that occurs as cells pass over the target electrode. Cells on the target electrode increase the resistance of the system (6). In addition, rapid fluctuations in the resistance represent changes in the interactions of cells with the electrode surface and are indicative of ongoing cellular shape changes. The ECIS/Taxis system can measure movement of the cell population in real-time over extended periods of time, but is also sensitive enough to detect the arrival of a single cell at the target electrode. Dictyostelium discoidium is known to migrate in the presence of a folate gradient (7, 8) and its chemotactic response can be accurately measured by ECIS/Taxis (9). Leukocyte chemotaxis, in response to SDF1alpha and to chemotaxis antagonists has also been measured with ECIS/Taxis (10, 11). An example of the leukocyte response to SDF1alpha is shown in Figure 1. PMID- 22491350 TI - Reduced subjective response to acute ethanol administration among young men with a broad bipolar phenotype. AB - Elevated lifetime prevalence rates of alcohol use disorders (AUDs) are a feature of bipolar disorder (BD). Individuals at-risk for AUDs exhibit blunted subjective responses to alcohol (low levels of response), which may represent a biomarker for AUDs. Thus, individuals at-risk for BD may exhibit low responses to alcohol. Participants were 20 unmedicated adult males who reported high rates of hypomanic experiences (bipolar phenotype participants; BPPs), aged 18 to 21 years, and 20 healthy controls matched on age, gender, IQ, BMI, and weekly alcohol intake. Subjective and pharmacokinetic responses to acute alcohol (0.8 g/kg) vs placebo administration were collected in a randomized, double-blind, cross-over, placebo controlled, within-subjects design. BPP participants reported significantly lower subjective intoxication effects ('feel high': F=14.2, p=0.001; 'feel effects': F=8.1, p=0.008) across time, but did not differ in their pharmacokinetic, stimulant, or sedative responses. Paradoxically, however, the BPP participants reported significantly higher expectations of the positive effects of alcohol than controls. Our results suggest that unmedicated young males with previous hypomanic experiences exhibit diminished subjective responses to alcohol. These blunted alcohol responses are not attributable to differences in weekly alcohol intake, pharmacokinetic effects (eg, absorption rates), or familial risk of AUDs. These observations suggest that the dampened intoxication may contribute to the increased rates of alcohol misuse in young people at-risk for BD, and suggest possible shared etiological factors in the development of AUDs and BD. PMID- 22491351 TI - Evidence that behavioral phenotypes of morphine in beta-arr2-/- mice are due to the unmasking of JNK signaling. AB - The altered behavioral effects of morphine, but not most other mu agonists, in mice lacking beta-arrestin 2, suggest that this scaffolding protein regulates the signaling cascade of this commonly used analgesic. One of the cascades that could be regulated by beta-arrestin 2 is cJun-N-terminal kinase (JNK), which binds with beta-arrestin 2 and modulates the analgesic effects of morphine. Using neurons lacking beta-arrestin 2 (beta-arr2-/-) to examine this interaction, we found that beta-arr2-/- neurons show altered intracellular distribution of JNK and cJun, and that morphine, but not fentanyl, increased the nuclear localization of the phosphorylated, therefore activated, form of cJun, a JNK target in dorsal root ganglia neurons. This suggests that deleting beta-arrestin 2 affects the JNK cascade. We therefore examined whether some of the behavioral phenotypes of mice lacking beta-arrestin 2 could be a result of altered JNK signaling. Indeed, two different JNK inhibitors reversed the enhanced analgesic effect of morphine, a known phenotype of beta-arr2-/- mice, to +/+ levels. Both the reduced locomotor effect of morphine and the psychomotor sensitization to repeated morphine administration in beta-arr2-/- mice were also returned to +/+ levels by inhibiting JNK. In contrast, the behavioral effects of fentanyl were neither genotype-dependent nor affected by JNK inhibition. Furthermore, a PKC inhibitor had a similar effect as inhibiting JNK in reducing the enhanced analgesic effect of morphine in beta-arr2-/- mice to +/+ levels. In summary, removing beta arrestin 2 reveals mu receptor activation of the JNK cascade in a ligand-specific manner explaining several behavioral phenotypes of beta-arr2-/- mice. PMID- 22491352 TI - Reduced tissue levels of noradrenaline are associated with behavioral phenotypes of the TgCRND8 mouse model of Alzheimer's disease. AB - Noradrenergic cell loss is well documented in Alzheimer's disease (AD). We have measured the tissue levels of catecholamines in an amyloid precursor protein transgenic 'TgCRND8' mouse model of AD and found reductions in noradrenaline (NA) within hippocampus, temporoparietal and frontal cortices, and cerebellum. An age related increase in cortical NA levels was observed in non-Tg controls, but not in TgCRND8 mice. In contrast, NA levels declined with aging in the TgCRND8 hippocampus. Dopamine levels were unaffected. Reductions in the tissue content of NA were found to coincide with altered expression of brain-derived neurotrophic factor (BDNF) mRNA and to precede the onset of object memory impairment and behavioral despair. To test whether these phenotypes might be associated with diminished NA, we treated mice with dexefaroxan, an antagonist of presynaptic inhibitory alpha(2)-adrenoceptors on noradrenergic and cholinergic terminals. Mice 12 weeks of age were infused systemically for 28 days with dexefaroxan or rivastigmine, a cholinesterase inhibitor. Both dexefaroxan and rivastigmine improved TgCRND8 behavioral phenotypes and increased BDNF mRNA expression without affecting amyloid-beta peptide levels. Our results highlight the importance of noradrenergic depletion in AD-like phenotypes of TgCRND8 mice. PMID- 22491353 TI - Dopamine-related deficit in reward learning after catecholamine depletion in unmedicated, remitted subjects with bulimia nervosa. AB - Disturbances in reward processing have been implicated in bulimia nervosa (BN). Abnormalities in processing reward-related stimuli might be linked to dysfunctions of the catecholaminergic neurotransmitter system, but findings have been inconclusive. A powerful way to investigate the relationship between catecholaminergic function and behavior is to examine behavioral changes in response to experimental catecholamine depletion (CD). The purpose of this study was to uncover putative catecholaminergic dysfunction in remitted subjects with BN who performed a reinforcement-learning task after CD. CD was achieved by oral alpha-methyl-para-tyrosine (AMPT) in 19 unmedicated female subjects with remitted BN (rBN) and 28 demographically matched healthy female controls (HC). Sham depletion administered identical capsules containing diphenhydramine. The study design consisted of a randomized, double-blind, placebo-controlled crossover, single-site experimental trial. The main outcome measures were reward learning in a probabilistic reward task analyzed using signal-detection theory. Secondary outcome measures included self-report assessments, including the Eating Disorder Examination-Questionnaire. Relative to healthy controls, rBN subjects were characterized by blunted reward learning in the AMPT--but not in placebo- condition. Highlighting the specificity of these findings, groups did not differ in their ability to perceptually distinguish between stimuli. Increased CD induced anhedonic (but not eating disorder) symptoms were associated with a reduced response bias toward a more frequently rewarded stimulus. In conclusion, under CD, rBN subjects showed reduced reward learning compared with healthy control subjects. These deficits uncover disturbance of the central reward processing systems in rBN related to altered brain catecholamine levels, which might reflect a trait-like deficit increasing vulnerability to BN. PMID- 22491354 TI - A functional Tph2 C1473G polymorphism causes an anxiety phenotype via compensatory changes in the serotonergic system. AB - The association of single-nucleotide polymorphisms (SNPs) in the human tryptophan hydroxylase 2 (TPH2) gene with anxiety traits and depression has been inconclusive. Observed inconsistencies might result from the fact that TPH2 polymorphisms have been studied in a genetically heterogeneous human population. A defined genetic background, control over environmental factors, and the ability to analyze the molecular and neurochemical consequences of introduced genetic alterations constitute major advantages of investigating SNPs in inbred laboratory mouse strains. To investigate the behavioral and neurochemical consequences of a functional C1473G SNP in the mouse Tph2 gene, we generated congenic C57BL/6N mice homozygous for the Tph2 1473G allele. The Arg(447) substitution in the TPH2 enzyme resulted in a significant reduction of the brain serotonin (5-HT) in vivo synthesis rate. Despite decreased 5-HT synthesis, we could detect neither a reduction of brain region-specific 5-HT concentrations nor changes in baseline and stress-induced 5-HT release using a microdialysis approach. However, using a [(35)S]GTP-gamma-S binding assay and 5-HT(1A) receptor autoradiography, a functional desensitization of 5-HT(1A) autoreceptors could be identified. Furthermore, behavioral analysis revealed a distinct anxiety phenotype in homozygous Tph2 1473G mice, which could be reversed with chronic escitalopram treatment. Alterations in depressive-like behavior could not be detected under baseline conditions or after chronic mild stress. These findings provide evidence for an involvement of functional Tph2 polymorphisms in anxiety related behaviors, which are likely not caused directly by alterations in 5-HT content or release but are rather due to compensatory changes during development involving functional desensitization of 5-HT(1A) autoreceptors. PMID- 22491355 TI - Acute tryptophan depletion increases translational indices of anxiety but not fear: serotonergic modulation of the bed nucleus of the stria terminalis? AB - Serotonin is strongly implicated in the mammalian stress response, but surprisingly little is known about its mode of action. Recent data suggest that serotonin can inhibit aversive responding in humans, but this remains underspecified. In particular, data in rodents suggest that global serotonin depletion may specifically increase long-duration bed nucleus of the stria terminalis (BNST)-mediated aversive responses (ie, anxiety), but not short duration BNST-independent responses (ie, fear). Here, we extend these findings to humans. In a balanced, placebo-controlled crossover design, healthy volunteers (n=20) received a controlled diet with and without the serotonin precursor tryptophan (acute tryptophan depletion; ATD). Aversive states were indexed by translational acoustic startle measures. Fear and anxiety were operationally defined as the increase in startle reactivity during short- and long-duration threat periods evoked by predictable shock (fear-potentiated startle) and by the context in which the shocks were administered (anxiety-potentiated startle), respectively. ATD significantly increased long-duration anxiety-potentiated startle but had no effect on short-duration fear-potentiated startle. These results suggest that serotonin depletion in humans selectively increases anxiety but not fear. Current translational frameworks support the proposition that ATD thus disinhibits dorsal raphe-originating serotonergic control of corticotropin releasing hormone-mediated excitation of the BNST. This generates a candidate neuropharmacological mechanism by which depleted serotonin may increase response to sustained threats, alongside clear implications for our understanding of the manifestation and treatment of mood and anxiety disorders. PMID- 22491356 TI - A new player in the puzzle of filovirus entry. AB - Viruses of the genera Ebolavirus and Marburgvirus are filoviruses that cause haemorrhagic fever in primates, with extremely high fatality rates. Studies have focused on elucidating how these viruses enter host cells, with the aim of developing therapeutics. The ebolavirus glycoprotein has been found to play key parts in all steps of entry. Furthermore, recent studies have identified Niemann Pick C1 (NPC1), a protein that resides deep in the endocytic pathway, as an important host factor in this process. PMID- 22491359 TI - Immune evasion: Influenza's sting in the tail. PMID- 22491362 TI - Bacterial transcription: Rho gets to grips with the riboswitch. PMID- 22491363 TI - Bacterial pathogenesis: A competitive edge for Salmonella. PMID- 22491365 TI - Simplification through complexity: the role of Ni-complexes in catalysed diyne cyclobutanone [4+2+2] cycloadditions, a comparative DFT study. AB - A series of density functional theory (DFT) experiments carried out on selected nickel((0))-catalysed diyne-cyclobutanone [4+2+2] cycloadditions provided quantitative confirmation of proposed multistep mechanisms, while clarifying the catalytic role of Ni in the reactions. Geometric and energetic results of the Ni catalysed process were compared to the one-step non-catalysed complement. Results show the first oxidation to be the rate-determining step, with the intramolecular reaction being the preferred one of the two competing pathways. Ligand-identity is also shown to greatly influence reaction barriers, leading to large deviation in product yields, in direct agreement with experimental observations. PMID- 22491358 TI - How glycan metabolism shapes the human gut microbiota. AB - Symbiotic microorganisms that reside in the human intestine are adept at foraging glycans and polysaccharides, including those in dietary plants (starch, hemicellulose and pectin), animal-derived cartilage and tissue (glycosaminoglycans and N-linked glycans), and host mucus (O-linked glycans). Fluctuations in the abundance of dietary and endogenous glycans, combined with the immense chemical variation among these molecules, create a dynamic and heterogeneous environment in which gut microorganisms proliferate. In this Review, we describe how glycans shape the composition of the gut microbiota over various periods of time, the mechanisms by which individual microorganisms degrade these glycans, and potential opportunities to intentionally influence this ecosystem for better health and nutrition. PMID- 22491366 TI - Culturing and applications of rotating wall vessel bioreactor derived 3D epithelial cell models. AB - Cells and tissues in the body experience environmental conditions that influence their architecture, intercellular communications, and overall functions. For in vitro cell culture models to accurately mimic the tissue of interest, the growth environment of the culture is a critical aspect to consider. Commonly used conventional cell culture systems propagate epithelial cells on flat two dimensional (2-D) impermeable surfaces. Although much has been learned from conventional cell culture systems, many findings are not reproducible in human clinical trials or tissue explants, potentially as a result of the lack of a physiologically relevant microenvironment. Here, we describe a culture system that overcomes many of the culture condition boundaries of 2-D cell cultures, by using the innovative rotating wall vessel (RWV) bioreactor technology. We and others have shown that organotypic RWV-derived models can recapitulate structure, function, and authentic human responses to external stimuli similarly to human explant tissues (1-6). The RWV bioreactor is a suspension culture system that allows for the growth of epithelial cells under low physiological fluid shear conditions. The bioreactors come in two different formats, a high-aspect rotating vessel (HARV) or a slow-turning lateral vessel (STLV), in which they differ by their aeration source. Epithelial cells are added to the bioreactor of choice in combination with porous, collagen-coated microcarrier beads (Figure 1A). The cells utilize the beads as a growth scaffold during the constant free fall in the bioreactor (Figure 1B). The microenvironment provided by the bioreactor allows the cells to form three-dimensional (3-D) aggregates displaying in vivo-like characteristics often not observed under standard 2-D culture conditions (Figure 1D). These characteristics include tight junctions, mucus production, apical/basal orientation, in vivo protein localization, and additional epithelial cell-type specific properties. The progression from a monolayer of epithelial cells to a fully differentiated 3-D aggregate varies based on cell type(1, 7-13). Periodic sampling from the bioreactor allows for monitoring of epithelial aggregate formation, cellular differentiation markers and viability (Figure 1D). Once cellular differentiation and aggregate formation is established, the cells are harvested from the bioreactor, and similar assays performed on 2-D cells can be applied to the 3-D aggregates with a few considerations (Figure 1E-G). In this work, we describe detailed steps of how to culture 3-D epithelial cell aggregates in the RWV bioreactor system and a variety of potential assays and analyses that can be executed with the 3-D aggregates. These analyses include, but are not limited to, structural/morphological analysis (confocal, scanning and transmission electron microscopy), cytokine/chemokine secretion and cell signaling (cytometric bead array and Western blot analysis), gene expression analysis (real-time PCR), toxicological/drug analysis and host-pathogen interactions. The utilization of these assays set the foundation for more in depth and expansive studies such as metabolomics, transcriptomics, proteomics and other array-based applications. Our goal is to present a non-conventional means of culturing human epithelial cells to produce organotypic 3-D models that recapitulate the human in vivo tissue, in a facile and robust system to be used by researchers with diverse scientific interests. PMID- 22491367 TI - Evidence-based practices and recovery-oriented services: is there a relationship? Should there be one? PMID- 22491368 TI - Service providers' experiences and perspectives on recovery-oriented mental health system reform. AB - OBJECTIVE: With the use of a qualitative approach, this study focuses on service providers' experiences and perspectives on recovery-oriented reform. METHODS: Nine focus groups were conducted with a sample of 68 service providers recruited from three Canadian sites. RESULTS: Three major themes were identified: 1) positive attitudes towards recovery-oriented reform; 2) skepticism towards recovery-oriented reform; and 3) challenges associated with implementing recovery oriented practice. These challenges pertained to conceptual uncertainty and consistency around the meanings of recovery; application of recovery-oriented practice with certain populations and in certain contexts; bureaucratization of recovery-oriented tools; limited leadership support; and, societal stigma and social exclusion of persons with mental illnesses. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The findings point towards challenges that might arise as system planners move ahead in their efforts toward implementing recovery within the mental health system. In this regard, we offer several recommendations for the planning of organizational and educational practices that support the implementation of recovery-oriented practice. PMID- 22491369 TI - Recovery in mental health: a movement towards well-being and meaning in contrast to an avoidance of symptoms. AB - OBJECTIVE: This paper examines the types of goals being set by individuals in the context of Australian mental health services and whether goal type differs across the stages of recovery. METHODS: Goal records of 144 individuals accessing services were reviewed to examine goal content, ratio of approach and avoidance oriented goals and changes across stages of psychological recovery. RESULTS: Individuals further along in their recovery set significantly more approach goals and types of goals set appeared to reflect broader life roles. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Setting approach goals and goals that reflect broader life roles tends to support the definition of psychological recovery as being "the movement towards" greater meaning and enhanced sense of self. PMID- 22491370 TI - Decision making in recovery-oriented mental health care. AB - OBJECTIVE: Patient-centered communication has been linked to patient satisfaction, treatment adherence and outcomes. Shared decision making (SDM) has been advocated as an important and ethically essential aspect of patient-centered care, but SDM has received relatively little attention in mental health care, despite studies indicating that consumers want to be involved in making decisions. This is particularly important in a recovery-oriented system, where consumers are active participants in their treatment and rehabilitation. Because medication management is a key component of recovery from severe mental illnesses, this study explores how consumers and providers make decisions in medication management consultations. METHODS: Four providers (3 psychiatrists, 1 nurse practitioner) and 40 consumers with severe mental illness (10 consumers per provider) were recruited from a community mental health center with a recovery oriented focus. We directly observed 40 medication management appointments. Observations were audio recorded and transcribed. We used emergent thematic analysis to characterize decision making processes. RESULTS: Providers initiated most decisions, although they often invited consumers to participate in decision making. Decisions initiated by consumers elicited a greater degree of discussion and disagreement, but also frequently resulted in consumers' preferences prevailing. Consultations generally exhibited more characteristics of person centeredness than SDM. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: While we observed a high degree of person-centeredness, SDM was not prevalent. Interventions helping consumers to take greater initiative when working with service providers may be helpful. For example, programs using tools such as peer instruction, Internet-based software, and individual case-manager instruction all have shown promise for enhancing SDM in mental health treatment. Further research is needed to determine the degree of SDM in other settings (e.g., with case managers) and the impact of SDM on consumers' recovery. PMID- 22491371 TI - Predictors of health services utilization among persons with psychiatric disabilities engaged in supported independent housing. AB - OBJECTIVE: Persons with psychiatric disabilities are at greater risk for medical comorbidity, and prior research suggests these persons may underutilize health services. In response, this study examined the impact of engagement in psychiatric rehabilitation services, including case management, on utilization of general health services among persons with psychiatric disabilities engaged in supported housing, while controlling for demographic and clinical characteristics. METHODS: Poisson regression analyses were used to examine the impact of socio-demographic, clinical, and service characteristics on reported utilization of general health services in the past year. RESULTS: Findings indicated supported housing residents receiving case management coupled with weekly contact with residential support services visited a general health practitioner more frequently than those with less support services. CONCLUSIONS AND IMPLICATIONS: Study results suggest psychiatric rehabilitation services provided to persons in the context of safe and affordable housing may represent an important mechanism for enabling persons with psychiatric disorders to access needed medical care. PMID- 22491372 TI - Implementation of individual placement and support: the Nottingham experience. AB - TOPIC: This case study describes the implementation of individual placement and support (IPS), an evidence-based approach to employment support for people with severe mental illnesses. The case study draws from the literature on implementation and describes lessons learned from the experience of a large mental health provider in urban Nottingham, United Kingdom. PURPOSE: To inform those who want to implement a new service or IPS in mental health settings. SOURCES USED: Research and policy documents published on implementation and employment support, local experience, and fidelity reviews. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This paper adds to the literature on IPS implementation and highlights issues arising from the current UK recession that affect the competition for available jobs and the service context into which the IPS development has been introduced. The future of IPS depends on its acceptance as an essential aspect of mental health services. IPS implementation also benefits with strong leadership, expert knowledge of implementing IPS in the UK context, commitment from senior managers and clinicians, a capacity to train staff according to IPS principles, and integration of rehabilitation services with mental health treatment. Ongoing funding is also a prerequisite to successful implementation. PMID- 22491373 TI - Recovery through the Lens of Cultural Diversity. AB - TOPIC: This Brief Report is based on a project entitled Recovery through the Lens of Cultural Diversity that sought to develop an enhanced model of recovery that accounts for culture. PURPOSE: The purpose of the project was to increase the ability of mental health organizations in Toronto, Canada to design and deliver culturally relevant and responsive recovery-oriented services to the diverse communities they serve. SOURCES USED: For the purposes of this report, sources used included an interdisciplinary and culturally diverse group of service providers; focus groups that included service users and family members; and a community forum. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: To assist practitioners to better meet the service needs of their culturally diverse service recipients, recommendations are available to guide the continuing advancement of culturally relevant recovery-promoting practices for service users and family members. PMID- 22491374 TI - Challenges faced by mental health peer support workers: peer support from the peer supporter's point of view. AB - OBJECTIVE: This study aimed to identify the various challenges encountered by peer support workers in Western Australia in the course of their work and to identify possible solutions to those challenges. METHOD: We used the nominal group technique to collect and analyze the data. RESULTS: The main challenge encountered by participants was a lack of understanding of the peer support worker role which caused them to experience a sense of exclusion. The main solution focused on strategies to educate consumers, managers, and health professionals about the peer support worker role. CONCLUSION AND IMPLICATIONS FOR PRACTICE: Managers have a responsibility to be informed about the peer support worker role and communicate role related information to other team members to ensure that peer support workers are included as part of the health team. Implications for practice therefore center on training for managers and inclusion of the peer support worker role in orientation programs. Further, if these steps are not undertaken, a valuable resource could be lost to a health service to the detriment of persons with a mental illness. PMID- 22491375 TI - Meso and micro level workforce challenges in psychiatric rehabilitation. AB - OBJECTIVE: Results of an exploratory study are presented which examined workforce challenges in Australia's most established psychiatric rehabilitation sector. The study had the two-fold aim of investigating workforce challenges at an organizational ("meso") level and at the level of direct-service workers' daily practice ("micro"). METHODS: Data from 23 key informant interviews conducted with service managers and long-serving staff were analyzed through basic descriptive and thematic analyses. RESULTS: Organizations faced significant annual staff turnover (25.6%), specific staff supply shortages, and challenges in recruiting staff with adequate experience and longevity to match the complexity of client issues. Workers equally encountered challenges in this increasingly complex and rapidly changing field of work. CONCLUSIONS & IMPLICATIONS FOR PRACTICE: Workforce strategies designed to attract/retain experienced staff can improve workforce cohesiveness and sustainability, as can training and support activities aimed at equipping staff to reflect on and operate in dynamic and changing work environments. PMID- 22491376 TI - The relationship between hope and symptoms. AB - OBJECTIVE: Hope is a critical aspect of the recovery process for persons with serious mental illnesses. The goal of this pilot study was to assess the relationship between hope and symptoms for a cohort of individuals with mental illnesses receiving supported employment services. METHOD: A total of 74 participants enrolled in supported employment were assessed on their level of hopefulness, hopelessness and psychiatric symptoms. Correlations were performed to determine the relationship between hope and psychiatric symptoms, and hopelessness and psychiatric symptoms. RESULTS: The findings indicated a significant inverse relationship between hope and symptoms, and a significant positive relationship between hopelessness and symptoms. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Hope and symptoms were inversely related, highlighting the importance of developing a wellness strategy that addresses managing symptoms as part of one's recovery process. Additionally, this finding highlights the critical role of PsyR providers in supporting people in recovery with developing a wellness strategy that will both help ameliorate symptoms and increase hope. PMID- 22491377 TI - A recovery mentor at work. PMID- 22491378 TI - Developing an integrated workforce development plan. PMID- 22491380 TI - Parenting style, locus of control, and oral hygiene in adolescents. AB - OBJECTIVE: The aim of the study was to test if variations in oral hygiene levels in adolescents were associated with locus of control and parenting styles after controlling for demographic factors. MATERIAL AND METHODS: The study sample comprised 237 adolescents aged 12-13 years. The structured questionnaire included demographic characteristics and items about parenting style and locus of control. The Individual Quantitative Plaque % Index (IQPI) and toothbrushing frequency were used as clinical outcome measures. RESULTS: In the bivariate analyses, socioeconomic status (P=0.012), number of children in the family (P=0.003), and frequency of toothbrushing (P=0.001) were related to dental plaque levels. Gender (P<0.001), socioeconomic status (P=0.022), and external locus of control (Spearman rho, -0.144, P=0.027) were statistically significantly associated with toothbrushing frequency. In the multivariate analyses, only socioeconomic status and toothbrushing frequency were statistically significantly related to the IQPI. When toothbrushing frequency as the second outcome variable was used, the IQPI and gender were statistically significant. The association with socioeconomic status did not reach statistical significance (P=0.07). CONCLUSIONS: Only socioeconomic status and toothbrushing frequency explained variation in dental plaque levels among adolescents. The expected relationship among parenting styles, locus of control, and oral hygiene levels was not confirmed. PMID- 22491381 TI - Two cases of takotsubo syndrome related to tracheal intubation/extubation. AB - Takotsubo cardiomyopathy is an acute, reversible left ventricular dysfunction with characteristic contractility disorder and is usually preceded by emotional or physical stress. Two cases of Takotsubo cardiomyopathy related to tracheal manipulation are presented. Both the patients had all the typical symptoms and signs of Takotsubo cardiomyopathy, and both of them recovered completely within weeks. Tracheal manipulation is a well-known stress factor during the perioperative period, and experience from these two cases stresses the crucial role of measures aimed to stress reduction. Proper premedication and calm environment are recommended to produce anxiolysis before intubation. The administration of alpha- and beta-blockers is also recommended to inhibit sympathetic stress caused by tracheal manipulation. PMID- 22491382 TI - Two dog-related infections leading to death: overwhelming Capnocytophaga canimorsus sepsis in a patient with cystic echinococcosis. AB - Capnocytophaga canimorsus is a fastidious, capnophilic, fusiform, and filamentous gram-negative rod. It is part of the normal oral flora of dogs and cats and can cause an infection in humans, but is of generally low virulence in healthy individuals. A case of fatal sepsis due to Capnocytophaga canimorsus in a 46-year old woman with clinically silent cystic echinococcosis discovered postmortem is present. She had been bitten by a dog 3 days before the symptoms appeared. The family had owned the dog for 4 years. A preliminary diagnosis of septic shock of unknown etiology with multisystem organ failure was established. Despite all the efforts, the patient died on the seventh day of hospitalization. Laboratory findings received postmortem showed Capnocytophaga canimorsus isolated from the blood culture after 7 incubation days. Autopsy showed a cyst in the liver with a fibrotic wall and necrotic eosinophilic interiors containing fragments of Echinococcus granulosus scolices. In conclusion, an interaction possibly established long ago between the host and Echinococcus granulosus conditioned immunosuppression mechanisms developed by the parasite in this case, which can explain such an aggressive course of the infection with Capnocytophaga. Two dog related infections were fatal in the middle-aged dog owner considered healthy before this hospitalization. Vigilance concerning recent exposure to dogs or cats and potential immunosuppression risk factors must be maintained in a patient presenting with clinical features of fulminant sepsis. PMID- 22491383 TI - Biomechanical aspects of locking reconstruction plate positioning in osteosynthesis of transverse clavicle fracture. AB - The aim of this study was to evaluate and compare the biomechanical effects of locking reconstruction plate positioning on the osteosynthesis of clavicle midshaft simulated transverse fractures. MATERIAL AND METHODS: Twelve synthetic clavicles with simulated midshaft transverse fractures were repaired with a 3.5 mm locking reconstruction plate in the anteroinferior or the superior position. The clavicles were randomly assigned to 2 groups (6 per group). Each repaired clavicle was tested in cantilever bending by using the universal testing machine. The maximal load and the displacement of the specimens at a load of 40 N were recorded for each group. RESULTS: The anteroinferior plating osteosynthesis with a 3.5-mm locking reconstruction plate could bear an average maximal load of 183.3 N (SD, 11.3); the corresponding load for the superior plating osteosynthesis with the identical implants was 444.8 N (SD, 102.3), and the mean displacement was 1.5 mm (SD, 0.5) and 0.7 mm (SD, 0.2), respectively. CONCLUSIONS: The superior plating osteosynthesis of simulated midshaft transverse clavicle fractures with the 7-hole 3.5-mm locking reconstruction plate had a significantly higher bending (from top to bottom) load to failure in comparison with the anteroinferior plating osteosynthesis of the clavicle with the identical implants. Clavicles plated with the 7-hole 3.5-mm locking reconstruction plate at the superior aspect exhibited a significantly greater biomechanical stability at a load of 40 N than those plated at the anteroinferior aspect. PMID- 22491384 TI - Escherichia coli colonization in neonates: prevalence, perinatal transmission, antimicrobial susceptibility, and risk factors. AB - Escherichia coli is one of the leading causes of early-onset neonatal sepsis in many industrialized countries. However, there is a lack of studies on Escherichia coli colonization in women and neonates. The study aimed at determining the prevalence Escherichia coli among pregnant women and newborns, perinatal transmission, antimicrobial susceptibility, and risk factors for neonatal colonization. MATERIAL AND METHODS: In this prospective, cross-sectional study, 827 infants born to 808 mothers were enrolled. The study was carried out from October 1, 2006, to June 30, 2007. Women were screened for E. coli carriage at 35 37 weeks of gestation or on admission for premature rupture of membranes and delivery; neonates, within 15 minutes of their lives. Risk factors for colonization were collected by a questionnaire and were recorded during labor. RESULTS: Maternal E. coli colonization rate was 19.9%; neonatal, 14.4%; and transmission rate, 21.4%. Less than one-fourth (22.7%) of neonatal E. coli strains were resistant to ampicillin. Logistic regression analysis revealed that anal sexual intercourse (OR, 3.91; 95% CI, 1.87-8.19), one sexual partner (OR, 2.01; 95% CI, 1.30-3.11), maternal vaginal Escherichia coli colonization (OR, 1.81; 95% CI, 1.12-2.93), maternal body mass index of <=27 (OR, 1.77; 95% CI, 1.15-2.73), and maternal education lower than university level (OR, 1.70; 95% CI, 1.06-2.74) were associated with neonatal Escherichia coli colonization. CONCLUSIONS: The prevalence of maternal Escherichia coli colonization was higher in this study than other studies (19.9%). Neonatal Escherichia coli colonization was 14.4%. The resistance of Escherichia coli isolates to ampicillin was not high (22.7%). Improvement of maternal education and modification of mothers' sexual habits need to be undertaken to prevent neonatal Escherichia coli colonization. PMID- 22491385 TI - Reliability and validity of DPA-1 testing after anterior cruciate ligament reconstruction. AB - There is a lack of equipment and methods for the reliable and valid measurements of human neuromuscular control. To overcome this limitation, an analyzer of dynamic parameters (DPA-1) of human hand and leg movements was constructed by Kaunas University of Technology and "Katra" engineers in collaboration with the Lithuanian Academy of Physical Education. The aim of the study was to determine the reliability and validity of the tests performed on the DPA-1 in healthy and injured subjects after the anterior cruciate ligament (ACL) reconstruction surgery. MATERIAL AND METHODS. The men who had undergone a unilateral ACL reconstruction (n=17, on the average 3.8 months [SD, 2.1] after the surgery) and healthy untrained men (n=17) performed the research protocol twice within 24 hours in between. Average reaction time, mean and maximal movement speed, time to reach maximal speed, and movement distance of the right and left feet for the patients and of the dominant foot for the healthy subjects using the DPA-1 as well as the scores of isokinetic muscle strength and self-assessment tests were registered. RESULTS. There was a significantly reduced concentric peak torque on the injured knee compared with the uninjured knee during knee extension, and the mean score of the Lysholm scale for the injured knee was 69.1 (SD, 13.7) (P<0.05, compared between legs). The test-retest reliability for all the DPA-1 tests varied from 0.68 to 0.94 (P<0.05). However, there were no significant differences in most variables measured by the DPA-1 between injured knee, uninjured knee, and control knee. CONCLUSIONS. The results revealed low validity of the DPA-1 tests for the evaluation of patients following ACL surgery, despite the reliability of these tests varied from moderate to very high. PMID- 22491386 TI - Quality of life in patients with age-related macular degeneration. AB - The aim of this study was to evaluate the quality of life in persons affected by age-related macular degeneration. MATERIAL AND METHODS: The study was performed in the Clinic of Ophthalmology, Hospital of Lithuanian University of Health Sciences. A total of 140 patients completed the Visual Functioning Questionnaire and the Hospital Anxiety and Depression Scale (HADS) during this prospective study. The patients were divided into two groups: patients with age-related macular degeneration (70 patients) and control patients (70 patients). RESULTS: There was a significant difference in the quality of life between groups (P<0.0001). Analyzing patients with age-related macular degeneration within the group (patients with monocular or binocular disorders), significant differences in near vision (P=0.003), far vision (P=0.04), color vision (P=0.01), and social functioning (P=0.02) were observed. Mental health (r=0.326, P=0.02), dependency (r=0.340, P=0.02), and role difficulties (r=0.355, P=0.01) were found to be significantly associated with general vision in the age-related macular degeneration group. CONCLUSIONS: Age-related macular degeneration appeared to have a great impact on the quality of life. General vision impairment caused by age-related macular degeneration affects patient's mental health, dependency, and role difficulties. PMID- 22491387 TI - Effect of gold nanoparticles in the treatment of established collagen arthritis in rats. AB - BACKGROUND AND OBJECTIVE: The role of gold nanoparticles (AuNPs) in the treatment of autoimmune diseases remains vague. Therefore, the aim of this study was to determine the effect of AuNPs in the treatment of rats with established collagen induced arthritis (CIA). MATERIAL AND METHODS: A total of 24 Wistar male rats with established CIA were used. AuNPs measuring 13-nm and 50-nm were prepared according to standard procedures, and their size was determined using transmission electron microscopy. These gold particles were injected intra articularly 5 times a week, 12 injections in total. Body and organ weight, arthritic profiles based on paw swelling, histological changes in the joints and internal organs, blood indices, and serum oxidative products were investigated. RESULTS: An examination of the course of the experimental disease and a subsequent histological analysis as well as hematological studies revealed a nontoxic effect of AuNPs on the vital organs. The treatment of the rats with established CIA by 13-nm and 50-nm gold nanoparticles decreased joint swelling by 49.7% (P<0.002) and 45.03% (P<0.01), respectively. That corresponded to the decrease in statistically significant histological changes in articular tissues. AuNPs showed their antioxidant effect by increasing the level of antioxidant enzyme catalase. CONCLUSIONS: The continuous intra-articular administration of AuNPs not only reduced the inflammation, joint swelling, and development of polyarthritis, but also reduced histological changes in articular tissues without toxic effects on the internal organs. The results obtained disclose the role of AuNPs as antioxidant agents. PMID- 22491388 TI - Bottle-weaning intervention tools: the "how" and "why" of a WIC-based educational flipchart, parent brochure, and website. AB - OBJECTIVE: This article describes the development of educational materials for a Women, Infants, and Children (WIC)-based randomized controlled trial of an intervention encouraging timely bottle weaning. METHOD: Following a systematic process to develop of patient education materials, messages were first tested in 4 focus groups with 26 caregivers of WIC toddlers aged 7 to 36 months of age at the 2 study sites. Following review and revision, the materials were retested in one-on-one nutritional counseling sessions with 10 clients at the WIC sites who met the study's eligibility criteria. RESULTS: Materials development was an iterative process requiring several levels of input, review, and revision. Use of a systematic process guided by steps adapted from the health education literature was crucial in ensuring continuous feedback from stakeholders, experts, and priority populations and to develop an intervention instrument that met the needs and expectations of all groups. CONCLUSIONS AND IMPLICATIONS: The content, theoretical orientation, and format of the materials were influenced at every turn by feedback from frontline WIC nutritionists, WIC policy staff at the state level, and WIC clients. Development of effective, easy to use materials requires constant input from key stakeholders. PMID- 22491390 TI - Kidney cancer: bad news for personalized therapy. PMID- 22491392 TI - Peripapillary choroidal thickness in healthy controls and patients with focal, diffuse, and sclerotic glaucomatous optic disc damage. AB - OBJECTIVE: To examine peripapillary choroidal thickness in healthy controls and in patients with glaucoma who have focal, diffuse, and sclerotic optic disc damage. METHODS: Healthy controls (n=92) and patients with glaucoma who have focal (n=34), diffuse (n=35), and sclerotic (n=34) optic disc damage were imaged with spectral-domain optical coherence tomography (12 degrees circular scan protocol centered on optic nerve head). Peripapillary choroidal thickness was measured as the distance between the automatically segmented retinal pigment epithelium/Bruch's membrane and the manually outlined interface between the posterior choroid and the anterior border of the sclera in eyes in which the anterior scleral border was visible over more than 85% of the scan circumference. RESULTS: The anterior scleral border was visible in 76 controls (83%) and 89 patients (86%). Peripapillary choroidal thickness in healthy controls decreased linearly with age (-11 MUm/decade; P.001; r2=0.16), with a predicted value of 137 MUm at age 70 years (95% prediction interval, 62-212 MUm). While this value was similar in patients with focal and diffuse optic disc damage (126 and 130 MUm, respectively; P=.22 compared with controls), it was approximately 30% lower in patients with sclerotic optic disc damage (96 MUm; P.001 compared with controls). CONCLUSIONS: The peripapillary choroid of patients with glaucoma who have sclerotic optic disc damage was approximately 25% to 30% thinner compared with that in patients with focal and diffuse optic disc damage and with that in healthy controls. The role of the choroid in the pathophysiology of sclerotic glaucomatous optic disc damage needs further investigation. PMID- 22491391 TI - Importance of early postnatal weight gain for normal retinal angiogenesis in very preterm infants: a multicenter study analyzing weight velocity deviations for the prediction of retinopathy of prematurity. AB - OBJECTIVE: To assess WINROP (https://winrop.com), an algorithm using postnatal weight measurements, as a tool for the prediction of retinopathy of prematurity (ROP) in a large geographically and racially diverse study population. METHODS: WINROP analysis was performed retrospectively on conventionally at-risk infants from 10 neonatal intensive careunits.Weight measurements were entered into WINROP, which signals an alarm for an abnormal weight gain rate. Infants were classified into categories of no alarm (unlikely to develop type 1ROP)and alarm (at risk for developing type 1ROP).Use of WINROP requires that an infant has (1) gestational age less than 32 weeks at birth, (2) weekly weight measurements,(3) physiologic weight gain,and(4)absence of other pathologic retinal vascular disease. RESULTS: A total of 1706 infants with a median gestational age of 28 weeks (range, 22-31 weeks) and median birth weight of 1016 g (range, 378-2240 g) were included in the study analysis. An alarm occurred in 1101 infants (64.5%), with a median time from birth to alarm of 3 weeks (range, 0-12 weeks) and from alarm to treatment of 8 weeks (range, 1 day to 22 weeks). The sensitivity of WINROP was 98.6% and the negative predictive value was 99.7%. Two infants with type 1 ROP requiring treatment after 40 weeks' postmenstrual age did not receive an alarm. CONCLUSION: The WINROP system is a useful adjunct for ROP screening that identifies high-risk infants early to optimize care and potentially reduce the overall number of diagnostic ROP examinations. PMID- 22491393 TI - Clinical evaluation of 3 families with basal laminar drusen caused by novel mutations in the complement factor H gene. AB - OBJECTIVES: To identify novel complement factor H (CFH) gene mutations and to specify the clinical characteristics in patients with basal laminar drusen (BLD), a clinical subtype of age-related macular degeneration. METHODS: Twenty-one probands with BLD were included in this study. The ophthalmic examination included nonstereoscopic 30 degrees color fundus photography, fluorescein angiography, and high-resolution spectral-domain optical coherence tomography. Renal function was tested by measurement of serum creatinine and urea nitrogen levels. Venous blood samples were drawn for genomic DNA, and all coding exons and splice junctions of the CFH gene were analyzed by direct sequencing. RESULTS: In 3 families, we identified novel heterozygous mutations in theCFHgene: p.Ile184fsX, p.Lys204fsX, and c.1697-17_-8del. Ten of 13 mutation carriers displayed the BLD phenotype with a wide variety in clinical presentation, ranging from limited macular drusen to extensive drusen in the posterior pole as well as the peripheral retina. Two patients with BLD developed endstage kidney disease as a result of membranoproliferative glomerulonephritis type II. CONCLUSIONS: The early-onset BLD phenotype can be caused by heterozygous mutations in the CFH gene. Because some patients with BLD are at risk to develop membranoproliferative glomerulonephritis type II, we recommend that patients with extensive BLD undergo screening for renal dysfunction. CLINICAL RELEVANCE: Elucidation of the clinical BLD phenotype will facilitate identification of individuals predisposed to developing disease-related comorbidity, such as membranoproliferative glomerulonephritis type II. Moreover, with upcoming treatment modalities targeting specific components of the complement system, early identification of patients with BLD and detection of the genetic defect become increasingly important. PMID- 22491394 TI - Reactivation of retinopathy of prematurity after bevacizumab injection. AB - OBJECTIVE: To report late reactivation and progression of retinopathy of prematurity (ROP) after intravitreal bevacizumab monotherapy. METHODS: Retrospective review of 9 patients (17 eyes) with recurrence of ROP after initial treatment with intravitreal bevacizumab monotherapy. Data collected included (1) location and stage of ROP activity, (2) number and timing of treatments, and (3) structural outcomes. RESULTS: Mean age at treatment-requiring recurrence was 49.3 weeks (SD, 9.1 weeks; minimum, 37 weeks; maximum, 69 weeks) postmenstrual age (PMA). The mean time between initial treatment and treatment-requiring recurrence was 14.4 weeks, with a minimum of 4 and maximum of 35 weeks. Fives eyes progressed to retinal detachment (4 eyes stage 5, 1 eye stage 4a). Age at retinal detachment ranged from 49 to 69 weeks PMA with a median of 55 weeks PMA and mean of 58.4 weeks PMA. No eye that received laser treatment for recurrence progressed to retinal detachment. CONCLUSIONS: Although intravitreal bevacizumab treatment is effective in inducing regression of ROP, the effect may be transient. Recurrence can occur later in the course than with conventional laser therapy. Late retinal detachment can occur despite early regression. Longterm favorable structural outcome may require extended observation and retreatment. Laser may be a useful treatment for recurrences. PMID- 22491395 TI - A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. AB - OBJECTIVE: To report the 2-year outcomes of the BOLT study, a prospective randomized controlled trial evaluating intravitreous bevacizumab and modified Early Treatment Diabetic Retinopathy Study (ETDRS) macular laser therapy (MLT) in patients with persistent clinically significant macular edema (CSME). METHODS: In a 2-year, single-center, randomized controlled trial, 80 patients with center involving CSME and visual acuity of 20/40 to 20/320 were randomized to receive either bevacizumab or MLT. MAIN OUTCOME MEASURES: PRIMARY OUTCOME: difference in ETDRS best-corrected visual acuity (BCVA) between arms. SECONDARY OUTCOMES: mean change in BCVA, proportion gaining at least 15 and at least 10 ETDRS letters, losing fewer than 15 and at least 30 letters, change in central macular thickness, ETDRS retinopathy severity, and safety outcomes. RESULTS: At 2 years, mean (SD) ETDRS BCVA was 64.4 (13.3) (ETDRS equivalent Snellen fraction: 20/50) in the bevacizumab arm and 54.8 (12.6) (20/80) in the MLT arm (P=.005). The bevacizumab arm gained a median of 9 ETDRS letters vs 2.5 letters for MLT (P=.005), with a mean gain of 8.6 letters for bevacizumab vs amean loss of 0.5 letters for MLT. Forty-nine percent of patients gained 10 or more letters (P=.001) and 32% gained at least 15 letters (P=.004) for bevacizumab vs 7% and 4% for MLT. Percentage who lost fewer than 15 letters in the MLT arm was 86% vs 100% for bevacizumab (P=.03). Mean reduction in central macular thickness was 146 MUm in the bevacizumab arm vs 118 MUm in the MLT arm. The median number of treatments over 24 months was 13 for bevacizumab and 4 for MLT. CONCLUSIONS: This study provides evidence supporting longer-term use of intravitreous bevacizumab for persistent center-involving CSME. APPLICATION TO CLINICAL PRACTICE: Improvements in BCVA and central macular thickness seen with bevacizumab at 1 year were maintained over the second year with a mean of 4 injections. TRIAL REGISTRATION: eudract.ema.europa.eu Identifier: 2007-000847-89 PMID- 22491396 TI - A motivational peer support program for type 2 diabetes prevention delivered by people with type 2 diabetes: the UEA-IFG feasibility study. AB - PURPOSE: The purpose of this study was to develop a peer support program for individuals at high risk of type 2 diabetes as part of a novel Diabetes Prevention Programme (The UEA-IFG Study). Lay members of the public with existing type 2 diabetes volunteered as peer supporters (termed type 2 trainers) for participants at high risk of developing type 2 diabetes. The feasibility of type 2 trainer recruitment, training, and retention was tested. METHODS: Between January and September 2009, 1500 potential type 2 trainers with existing type 2 diabetes were contacted and 168 (11%) expressed an interest. From this group, 26 type 2 trainers were appointed to begin training. All completed 7 training seminars, covering diabetes prevention, nutrition, physical activity, listening skills, motivation, and goal planning. Motivational calls were made every 12 weeks to each study participant by each type 2 trainer in addition to health care professional-delivered education sessions. RESULTS: Twenty-six type 2 trainers were recruited to enter the program. One type 2 trainer withdrew before beginning their role. The retention rate was high, with 22 (89%) of the type 2 trainers continuing until study end (July 2010; 20 months), with a total of 240 phone calls made. CONCLUSION: The recruiting and training of lay volunteers with existing type 2 diabetes as type 2 trainers to support study participants at risk of developing the same condition was a cost-effective strategy in comparison to employing salaried health care professionals and warrants further investigation on health outcomes. PMID- 22491397 TI - Building capacity to reduce disparities in diabetes: training community health workers using an integrated distance learning model. AB - PURPOSE: The purpose of this study is to determine whether an innovative interactive distance training program is an effective modality to train community health workers (CHWs) to become members of the diabetes health care team. The University of New Mexico Health Sciences Center has developed a rigorous diabetes training program for CHWs involving both distance and hands-on learning as part of Project ECHOTM (Extension for Community Healthcare Outcomes). METHODS: Twenty three diverse CHW participants from across New Mexico were enrolled in the first training session. Participants completed surveys at baseline and at the end of the program. They attended a 3-day hands-on training session, followed by weekly participation in tele/video conferences for 6 months. Wilcoxon signed-rank statistics were used to compare pre- and posttest results. RESULTS: Participants demonstrated significant improvements in diabetes knowledge (P = .002), diabetes attitudes (P = .04) and confidence in both clinical and nonclinical skills (P < .001 and P = .04, respectively). Additionally, during focus group discussions, participants reported numerous benefits from participation in the program. CONCLUSIONS: Community health worker participation in the Project ECHO diabetes training program resulted in significant increases in knowledge, confidence, and attitudes in providing care to patients with diabetes. Studies are ongoing to determine whether the training has a positive impact on patient outcomes. PMID- 22491399 TI - Mechanistic aspects of photo-induced formation of peroxide ions on the surface of cubic Ln2O3 (Ln = Nd, Sm, Gd) under oxygen. AB - The photo-induced formation of peroxide ions on the surface of cubic Ln2O3 (Ln = Nd, Sm, Gd) was studied by in situ microprobe Raman spectroscopy using a 325 nm laser as excitation source. It was found that the Raman bands of peroxide ions at 833-843 cm(-1) began to grow at the expense of the Ln(3+)-O(2-) bands at 333-359 cm(-1) when the Ln2O3 samples under O2 were continuously irradiated with a focused 325 nm laser beam at temperatures between 25-150 degrees C. The intensity of the peroxide Raman band was found to increase with increasing O2 partial pressure, whereas no peroxide band was detected on the Ln2O3 under N2 as well as on the samples first irradiated with laser under Ar or N2 followed by exposure to O2 in the dark. The experiments using (18)O as a tracer further confirmed that the peroxide ions are generated by a photo-induced reaction between O2 and the lattice oxygen (O(2-)) species in Ln2O3. Under the excitation of 325 nm UV light, the transformation of O2 to peroxide ions on the surface of the above lanthanide sesquioxides can even take place at room temperature. Basicity of the lattice oxygen species on Ln2O3 also has an impact on the peroxide formation. Higher temperature or laser irradiation power is required to initiate the reaction between O2 and O(2-) species of weaker basicity. PMID- 22491398 TI - Effect of a short-duration, culturally tailored, community-based diabetes self management intervention for Korean immigrants: a pilot study. AB - PURPOSE: The purpose of this pilot study was to assess the effectiveness, feasibility, and acceptability of a short-duration, culturally tailored, community-based diabetes self- management program (CTCDSP) for Korean immigrants with type 2 diabetes delivered at a non-clinic-affiliated community center. METHODS: Forty-one Korean adults with type 2 diabetes participated in a 2-session CTCDSP delivered by a bilingual nurse practitioner at a Korean community center. Outcome measures included biological, behavioral, and general health well-being; diabetes knowledge; and self-efficacy assessed at baseline, post-education, and 3 month follow-up. Repeated-measures analyses of variance were used to explore mean differences in outcomes across the 3 assessment points. RESULTS: From baseline to 3-month follow-up assessment, participants exhibited significant improvement on several physiological and behavioral measures. Mean levels of hemoglobin A1c and waist circumference decreased, whereas high-density lipoprotein levels increased. Additionally, participants reported an increase in weekly feet checks, and there was a trend increase in participants' reported frequency of exercise activities. The feasibility of the CTCDSP was established, and participant satisfaction with the program was high. CONCLUSIONS: A short-duration CTCDSP may be an effective, feasible, and favorably received approach to improving diabetes outcomes in Korean and potentially other underserved ethnic minority immigrants who have limited access to mainstream clinic-based diabetes self-management programs. PMID- 22491400 TI - Attenuated glial reaction in experimental proliferative vitreoretinopathy treated with liposomal doxorubicin. AB - PURPOSE: We investigated the therapeutic effect of liposomal doxorubicin (Lipo dox) on experimental proliferative vitreoretinopathy (PVR). METHODS: The toxicity of Lipo-dox was determined in vitro in cultured rabbit retinal pigment epithelium (RPE) cells by tetrazolium-based (MTT) assay for cell viability performed 48 and 96 hours after treatment, and in vivo by electroretinography and histopathology. The therapeutic effect of intravitreous injection of Lipo-dox was evaluated in a rabbit model of PVR induced by injection of rabbit RPE cells after gas compression of the vitreous. The presence of PVR was determined by indirect ophthalmoscopy on days 1, 7, 14, 21, and 28 after injection. Western blot and immunofluorescence studies were performed to evaluate the expression of the glial markers vimentin and glial fibrillary acidic protein (GFAP). A pharmacokinetic study also was performed and analyzed by liquid chromatography coupled with tandem mass spectrometry (LC-MS). RESULTS: The 50% inhibitory concentrations (IC50) of doxorubicin (Doxo) and Lipo-dox in RPE cells were 0.01-0.1 and 0.1-1.0 MUg/mL, respectively. Lipo-dox (10 MUg/mL) did not reduce the amplitude reduction in the ERG study or produce obvious retinal toxicity. Lipo-dox still could be detected in the vitreous 7 days after injection. The Lipo-dox (10 MUg/mL)-treated eyes showed lower grade PVR than did the untreated eyes. Lipo-dox also decreased the retinal expression levels of vimentin and GFAP. CONCLUSIONS: Lipo-dox can attenuate the severity of experimental PVR, and reduces the glial cell expression of intermediate filaments in PVR retinas. Lipo-dox has a wider safe dosage range and a longer half-life in the vitreous than does primary Doxo. PMID- 22491402 TI - Spectral transmission of the human crystalline lens in adult and elderly persons: color and total transmission of visible light. AB - PURPOSE: To experimentally measure the spectral transmission of human crystalline lenses belonging to adult and elderly persons, and to determine the color and total transmission of visible light of such crystalline lenses. METHODS: The spectral transmission curve of 32 human crystalline lenses was measured using a PerkinElmer 800UV/VIS spectrometer. Total transmission of visible light and the chromatic coordinates of these crystalline lenses were determined from these curves for solar illumination. RESULTS: The crystalline lens that filters UV and its transmission in the visible spectrum decreases with age; such a decrease is greater for short wavelengths. The total transmission of visible light decreases, especially after the age of 70 years, and the crystalline color becomes yellower and saturated. CONCLUSIONS: The great variability existing in the spectral transmission of the human crystalline lens is lesser between the ages of 40 and 59 years, but greater from the age of 60 and older. The decrement in transmittance between these two age groups varies from 40% for 420 nm to 18% for 580 nm. Nevertheless, it is proven that age is not the only parameter affecting crystalline transmission. In the range of 40 to 59 years, age does not bear an influence on total transmission of light, but from 60 years and older it does. Moreover, the light transmitted decreases with age. This total transmission of light is similar to or lower than the amount that the different intraocular lenses transmit, even with a yellow or orange filter. The color of the human lens becomes yellowish and saturated with age. PMID- 22491401 TI - Propranolol inhibition of beta-adrenergic receptor does not suppress pathologic neovascularization in oxygen-induced retinopathy. AB - PURPOSE: Retinopathy of prematurity (ROP) is a leading cause of blindness in children and is, in its most severe form, characterized by uncontrolled growth of vision-threatening pathologic vessels. Propranolol, a nonselective beta adrenergic receptor blocker, was reported to protect against pathologic retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Based on this single animal study using nonstandard evaluation of retinopathy, clinical trials are currently ongoing to evaluate propranolol treatment in stage 2 ROP patients who tend to experience spontaneous disease regression and are at low risk of blindness. Because these ROP patients are vulnerable premature infants who are still in a fragile state of incomplete development, the efficacy of propranolol treatment in retinopathy needs to be evaluated thoroughly in preclinical animal models of retinopathy and potential benefits weighed against potential adverse effects. METHODS: Retinopathy was induced by exposing neonatal mice to 75% oxygen from postnatal day (P) 7 to P12. Three routes of propranolol treatment were assessed from P12 to P16: oral gavage, intraperitoneal injection, or subcutaneous injection, with doses varying between 2 and 60 mg/kg/day. At P17, retinal flatmounts were stained with isolectin and quantified with a standard protocol to measure vasoobliteration and pathologic neovascularization. Retinal gene expression was analyzed with qRT-PCR using RNA isolated from retinas of control and propranolol-treated pups. RESULTS: None of the treatment approaches at any dose of propranolol (up to 60 mg/kg/day) were effective in preventing the development of retinopathy in a mouse model of OIR, evaluated using standard techniques. Propranolol treatment also did not change retinal expression of angiogenic factors including vascular endothelial growth factor. CONCLUSIONS: Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of beta-adrenergic receptors is an appropriate therapeutic approach for treating ROP. PMID- 22491403 TI - Time outdoors and physical activity as predictors of incident myopia in childhood: a prospective cohort study. AB - PURPOSE: Time spent in "sports/outdoor activity" has shown a negative association with incident myopia during childhood. We investigated the association of incident myopia with time spent outdoors and physical activity separately. METHODS: Participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) were assessed by noncycloplegic autorefraction at ages 7, 10, 11, 12, and 15 years, and classified as myopic (<=-1 diopters) or as emmetropic/hyperopic (>=-0.25 diopters) at each visit (N = 4,837-7,747). Physical activity at age 11 years was measured objectively using an accelerometer, worn for 1 week. Time spent outdoors was assessed via a parental questionnaire administered when children were aged 8-9 years. Variables associated with incident myopia were examined using Cox regression. RESULTS: In analyses using all available data, both time spent outdoors and physical activity were associated with incident myopia, with time outdoors having the larger effect. The results were similar for analyses restricted to children classified as either nonmyopic or emmetropic/hyperopic at age 11 years. Thus, for children nonmyopic at age 11, the hazard ratio (95% confidence interval, CI) for incident myopia was 0.66 (0.47 0.93) for a high versus low amount of time spent outdoors, and 0.87 (0.76-0.99) per unit standard deviation above average increase in moderate/vigorous physical activity. CONCLUSION: Time spent outdoors was predictive of incident myopia independently of physical activity level. The greater association observed for time outdoors suggests that the previously reported link between "sports/outdoor activity" and incident myopia is due mainly to its capture of information relating to time outdoors rather than physical activity. PMID- 22491404 TI - Integrin-linked kinase deletion in the developing lens leads to capsule rupture, impaired fiber migration and non-apoptotic epithelial cell death. AB - PURPOSE: The lens is a powerful model system to study integrin-mediated cell matrix interaction in an in vivo context, as it is surrounded by a true basement membrane, the lens capsule. To characterize better the function of integrin linked kinase (ILK), we examined the phenotypic consequences of its deletion in the developing mouse lens. METHODS: ILK was deleted from the embryonic lens either at the time of placode invagination using the Le-Cre line or after initial lens formation using the Nestin-Cre line. RESULTS: Early deletion of ILK leads to defects in extracellular matrix deposition that result in lens capsule rupture at the lens vesicle stage (E13.5). If ILK was deleted at a later time-point after initial establishment of the lens capsule, rupture was prevented. Instead, ILK deletion resulted in secondary fiber migration defects and, most notably, in cell death of the anterior epithelium (E18.5-P0). Remarkably, dying cells did not stain positively for terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) or activated-caspase 3, suggesting that they were dying from a non apoptotic mechanism. Moreover, cross to a Bax(fl/fl)/Bak-/- mouse line that is resistant to most forms of apoptosis failed to promote cell survival in the ILK deleted lens epithelium. Electron microscopy revealed the presence of numerous membranous vacuoles containing degrading cellular material. CONCLUSIONS. Our study reveals a role for ILK in extracellular matrix organization, fiber migration, and cell survival. Furthermore, to our knowledge we show for the first time that ILK disruption results in non-apoptotic cell death in vivo. PMID- 22491405 TI - Neurodegenerative differences in the retinas of male and female patients with type 2 diabetes. AB - PURPOSE: The purpose of our study is to determine whether neuroretinal function, measured by the multifocal electroretinogram, differs between males and females with type 2 diabetes and no retinopathy. METHODS: This study included 70 eyes from 70 adult subjects (14 control males, 22 control females, 16 males with type 2 diabetes, and 18 females with type 2 diabetes). A template-scaling technique was used to obtain first-order P1 implicit times and N1-P1 amplitudes from photopic multifocal electroretinograms within the central 45 degrees. RESULTS: The males with type 2 diabetes were significantly more abnormal than their female counterparts in two separate analyses of local neuroretinal function. First, the total number of retinal locations with an abnormally delayed implicit time (z score >= 2) was higher (P < 0.001) in the diabetic males (482 locations = 29.2%) compared to the diabetic females (298 locations = 16.1%). Second, in the response topographies that consisted of 103 means of local implicit times for each group, the diabetic males were significantly delayed (P < 0.025) at 23 corresponding positions (22.3%) compared to the diabetic females. At the same time, no corresponding stimulus locations were significantly delayed in the diabetic females compared to the diabetic males. CONCLUSIONS: Neuroretinal function is more abnormal in males than in females for adults with type 2 diabetes and no retinopathy. These results suggest that, relative to males, females may have some protection from, or resistance to, neurodegenerative changes that precede the development of background retinopathy in type 2 diabetes. PMID- 22491406 TI - Localized glaucomatous change detection within the proper orthogonal decomposition framework. AB - PURPOSE: To detect localized glaucomatous structural changes using proper orthogonal decomposition (POD) framework with false-positive control that minimizes confirmatory follow-ups, and to compare the results to topographic change analysis (TCA). METHODS: We included 167 participants (246 eyes) with >=4 Heidelberg Retina Tomograph (HRT)-II exams from the Diagnostic Innovations in Glaucoma Study; 36 eyes progressed by stereo-photographs or visual fields. All other patient eyes (n = 210) were non-progressing. Specificities were evaluated using 21 normal eyes. Significance of change at each HRT superpixel between each follow-up and its nearest baseline (obtained using POD) was estimated using mixed effects ANOVA. Locations with significant reduction in retinal height (red pixels) were determined using Bonferroni, Lehmann-Romano k-family-wise error rate (k-FWER), and Benjamini-Hochberg false discovery rate (FDR) type I error control procedures. Observed positive rate (OPR) in each follow-up was calculated as a ratio of number of red pixels within disk to disk size. Progression by POD was defined as one or more follow-ups with OPR greater than the anticipated false positive rate. TCA was evaluated using the recently proposed liberal, moderate, and conservative progression criteria. RESULTS: Sensitivity in progressors, specificity in normals, and specificity in non-progressors, respectively, were POD-Bonferroni = 100%, 0%, and 0%; POD k-FWER = 78%, 86%, and 43%; POD-FDR = 78%, 86%, and 43%; POD k-FWER with retinal height change >=50 MUm = 61%, 95%, and 60%; TCA-liberal = 86%, 62%, and 21%; TCA-moderate = 53%, 100%, and 70%; and TCA conservative = 17%, 100%, and 84%. CONCLUSIONS: With a stronger control of type I errors, k-FWER in POD framework minimized confirmatory follow-ups while providing diagnostic accuracy comparable to TCA. Thus, POD with k-FWER shows promise to reduce the number of confirmatory follow-ups required for clinical care and studies evaluating new glaucoma treatments. (ClinicalTrials.gov number, NCT00221897.). PMID- 22491407 TI - Effect of biopsy location and size on proliferative capacity of ex vivo expanded conjunctival tissue. AB - PURPOSE: To evaluate the effect of location and size of biopsy on phenotype and proliferative capacity of cultured rat conjunctival epithelial cells. METHODS: Pieces of conjunctiva were used from six areas: superior and inferior areas of bulbus, fornix, and tarsus of male Sprague-Dawley rats (n = 6). Explants were grown in RPMI 1640 with 10% fetal bovine serum on coverslips for 8 days or assayed for colony-forming efficiency (n = 9). Analysis included immunofluorescence microscopy and outgrowth measurements with ImageJ software. The Mann-Whitney test and Spearman's rank-order correlation test were used. RESULTS: Superior (23.9 +/- 2.9-fold growth) and inferior (22.4 +/- 1.2-fold growth) forniceal tissues yielded significantly more outgrowth with respect to explant size than superior bulbar (13.4 +/- 1.9-fold growth; P < 0.05 and P < 0.01, respectively), inferior bulbar (13.6 +/- 1.6-fold growth; P = 0.01 and P < 0.01, respectively), and inferior tarsal tissues (14.0 +/- 1.3-fold growth; P = 0.01). Outgrowth size correlated positively with explant size (r(s) = 0.54; P < 0.001), whereas explant size correlated negatively with fold growth (r(s) = 0.36; P < 0.001). Superior forniceal cells displayed higher colony-forming efficiency (3.6% +/- 0.9%) than superior bulbar (1.1% +/- 0.3%; P < 0.05) and inferior bulbar cells (1.6% +/- 0.8%; P < 0.05). Percentage of p63+ and PCNA+ cells correlated positively with explant and outgrowth size. CONCLUSIONS: Small forniceal conjunctival explants grow the most effectively; however, for transplantation purposes, the loss of p63+ and PCNA+ cells with small explants must be considered. PMID- 22491408 TI - Aquaporin changes during diabetic retinopathy in rats are accelerated by systemic hypertension and are linked to the renin-angiotensin system. AB - PURPOSE: We explored the relationship between the renin-angiotensin system (RAS) and aquaporins (AQP1 and AQP4 in Muller glia and astrocytes) in diabetic retinopathy (DR) with and without systemic hypertension. METHODS: Diabetes was induced in spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats by intraperitoneal injections of streptozotocin. The diabetic and control non-diabetic rats were assigned randomly to receive no anti hypertension treatment, or to be treated with the angiotensin II receptor blocker (ARB), valsartan (40 mg/kg/d) or the beta-blocker, metoprolol (50 mg/kg/day). Eight weeks later, retinas were evaluated by immunohistochemistry and Western blot to detect changes in the expression of AQP1, AQP4, and glial fibrillary acidic protein (GFAP). RESULTS: Hypertension increased expression of glial GFAP and AQP4 (P < 0.01), but not AQP1 (P > 0.05) in diabetic rats. Valsartan and metoprolol decreased GFAP, AQP1, and AQP4 expression in diabetic SHR rats (P < 0.01). Valsartan decreased GFAP and AQP1 expression in diabetic WKY rats (P < 0.01), while metoprolol did not. CONCLUSIONS: Activation of Muller glia and astrocytes was involved in the mechanism by which systemic hypertension affects DR. AQPs and macroglia were linked to changes in the RAS in DR. Changes in aquaporin expression in DR were increased by hypertension. This provides additional support for the early use of an ARB in the treatment of DR, especially in cases with retinal edema. PMID- 22491409 TI - Evaluation of lamina cribrosa and peripapillary sclera stiffness in pseudoexfoliation and normal eyes by atomic force microscopy. AB - PURPOSE: Pseudoexfoliation (PEX) syndrome is a systemic disorder of the elastic fiber system that can lead to PEX glaucoma. Elastotic alterations in the lamina cribrosa (LC) of PEX eyes suggested biomechanical implications predisposing to pressure-induced optic nerve damage. In this pilot study, the stiffness of LC and peripapillary sclera (ppSC) in eyes with and without PEX syndrome were analyzed by atomic force microscopy (AFM) nanoindentation. METHODS: Unfixed cryosections (5-MUm thick) were prepared from the optic nerve heads (ONH) of three donor eyes with PEX syndrome and three age-matched control eyes. AFM force mapping was performed in selected regions of the central, midperipheral, and peripheral LC and the ppSC using a spherical cantilever tip. To determine the local Young's modulus of elasticity (YME) as a measure of tissue stiffness, force curves were acquired and analyzed using the spherical Hertz model. RESULTS: For the LC, the median YME values calculated from single stiffness maps averaged 17.2 (+/-2.7) kPa in normal eyes and 10.1 (+/-1.4) kPa in PEX eyes, indicating a significant PEX-related decrease in stiffness by over 40% (P < 0.01). The corresponding YME values for the ppSC, which revealed a 9-fold higher tissue stiffness than in the LC, averaged 158.3 (+/-59.8) kPa for control and 85.8 (+/-16.9) kPa for PEX samples. CONCLUSIONS: AFM was proven suitable for determining the stiffness of ONH tissues, encouraging further large-scale analyses. The marked decrease in stiffness, implying an increased deformability of the ONH in PEX eyes, may reflect an inherent tissue weakness rendering these eyes more vulnerable to glaucomatous damage. PMID- 22491410 TI - Adherence to occlusion therapy in the first six months of follow-up and visual acuity among participants in the Infant Aphakia Treatment Study (IATS). AB - PURPOSE: Achieving good vision in infants born with a unilateral cataract is believed to require early surgery and consistent occlusion of the fellow eye. This article examines the relationship between adherence to patching and grating acuity. METHODS: Data came from the Infant Aphakia Treatment Study, a randomized clinical trial of treatment for unilateral congenital cataract. Infants were either left aphakic (n = 53) or had an intraocular lens implanted (n = 55). Patching was prescribed 1 hour per day per month of age until 8 months of age and 50% of waking hours thereafter. Adherence was measured as the mean percentage of prescribed patching reported in a 7-day diary completed 2 months after surgery, and 48-hour recall interviews conducted 3 and 6 months after surgery. Grating visual acuity was measured within 1 month of the infant's first birthday (n = 108) using Teller Acuity Cards by a tester masked to treatment. Nonparametric correlations were used to examine the relationship with grating acuity. RESULTS: On average, caregivers reported patching 84.3% (SD = 31.2%) of prescribed time and adherence did not differ by treatment (t = -1.40, df = 106, p = 0.16). Adherence was associated with grating acuity (r(Spearman) = -0.27, p < 0.01), but more so among pseudophakic (r(Spearman) = -0.41, p < 0.01) than aphakic infants (r(Spearman) = -0.10, p = 0.49). CONCLUSIONS: This study empirically has shown that adherence to patching during the first 6 months after surgery is associated with better grating visual acuity at 12 months of age after treatment for unilateral cataract and that implanting an intraocular lens is not associated with adherence. (ClinicalTrials.gov number, NCT00212134.). PMID- 22491411 TI - Activation of the hedgehog signaling pathway in the developing lens stimulates ectopic FoxE3 expression and disruption in fiber cell differentiation. AB - PURPOSE: The signaling pathways and transcriptional effectors responsible for directing mammalian lens development provide key regulatory molecules that can inform our understanding of human eye defects. The hedgehog genes encode extracellular signaling proteins responsible for patterning and tissue formation during embryogenesis. Signal transduction of this pathway is mediated through activation of the transmembrane proteins smoothened and patched, stimulating downstream signaling resulting in the activation or repression of hedgehog target genes. Hedgehog signaling is implicated in eye development, and defects in hedgehog signaling components have been shown to result in defects of the retina, iris, and lens. METHODS: We assessed the consequences of constitutive hedgehog signaling in the developing mouse lens using Cre-LoxP technology to express the conditional M2 smoothened allele in the embryonic head and lens ectoderm. RESULTS: Although initial lens development appeared normal, morphological defects were apparent by E12.5 and became more significant at later stages of embryogenesis. Altered lens morphology correlated with ectopic expression of FoxE3, which encodes a critical gene required for human and mouse lens development. Later, inappropriate expression of the epithelial marker Pax6, and as well as fiber cell markers c-maf and Prox1 also occurred, indicating a failure of appropriate lens fiber cell differentiation accompanied by altered lens cell proliferation and cell death. CONCLUSIONS: Our findings demonstrate that the ectopic activation of downstream effectors of the hedgehog signaling pathway in the mouse lens disrupts normal fiber cell differentiation by a mechanism consistent with a sustained epithelial cellular developmental program driven by FoxE3. PMID- 22491412 TI - The effect of Rho-associated protein kinase inhibitor on monkey Schlemm's canal endothelial cells. AB - PURPOSE: To investigate the effect of a specific inhibitor of Rho-associated protein kinase, Y-27632, on monkey Schlemm's canal endothelial (SCE) cells. METHODS: SCE cells were isolated from cynomolgus monkey eyes. The effects of Y 27632 on aqueous outflow facility were evaluated using enucleated monkey eyes and a constant-pressure perfusion system. The effect of Y-27632 on the barrier function of the confluent SCE-cell monolayer was evaluated by measuring transendothelial electrical resistance (TEER) and fluorescein permeability. Y 27632-induced changes in the intracellular localization of ZO-1, claudin-5, beta catenin, pan-cadherin, and filamentous actin (F-actin) were examined by immunofluorescence. Gene-expression changes induced by Y-27632 were analyzed with microarray, and the functional categories of changed genes were identified by gene ontology analysis. The concentrations of intracellular calcium ions were estimated using Fluo-4/AM and a fluorescence microscope system. RESULTS: Y-27632 significantly increased the outflow facility and the number of associated giant vacuoles, decreased TEER of the SCE-cell monolayer, and increased the transendothelial flux of fluorescein. Y-27632 disrupted ZO-1 and claudin-5 expression in a confluent SCE-cell monolayer. Among 12,544 genes, Y-27632 treatment increased the expression of 57 genes and decreased the expression of 15 genes. Gene ontology analysis revealed that changed genes were related to various cellular functions, including regulation of calcium ion transport into the cytosol. Y-27632 partially diminished the A23187-induced increase in intracellular calcium ions. CONCLUSIONS: Y-27632 increased the permeability of the SCE-cell monolayer in association with disruption of the tight junction, F actin depolymerization, and changes in various cell functions, including calcium transfer. PMID- 22491413 TI - Endoplasmic reticulum stress in retinal vascular degeneration: protective role of resveratrol. AB - PURPOSE: Endoplasmic reticulum (ER) stress has been demonstrated to contribute to neurodegeneration in multiple ocular diseases. However, whether ER stress can induce vascular degeneration in the retina remains unknown. We investigated the possible role of ER stress in retinal vascular degeneration in vivo, and the effects of resveratrol on tunicamycin and ischemia and reperfusion (I/R)-induced retinal vascular degeneration. METHODS: Different dosages of tunicamycin, an ER stress inducer, were injected into the vitreous of mouse eyes. Retinal I/R injury was induced by elevating the intraocular pressure for 60 minutes followed by reperfusion in mice. Two dosages of resveratrol (5 and 25 mg/kg body weight per day) were administrated 2 days before retinal I/R injury, while 100 MUM resveratrol were injected into the vitreous together with tunicamycin. Formation of acellular capillaries was assessed 7 days after I/R injury and tunicamycin injection, while cell bodies in ganglion cell layer and brain-specific homeobox/POU domain protein 3A (Brn3a) staining on retinal flat-mounts were analyzed 4 days after I/R injury. ER stress markers, including eukaryotic initiation factor 2alpha (eIF2alpha), CCAAT enhancer-binding protein homologous protein (CHOP), immunoglobulin binding protein (Bip), inositol requiring enzyme 1alpha (IRE1alpha), C-jun N-terminal kinase (JNK)1/2 and Xbp1 splicing, were examined by RT-PCR, or Western blots or immunostaining from retinas 1 or 2 days after tunicamycin injection and I/R injury. RESULTS: Tunicamycin caused ER stress and capillary degeneration in vivo, both of which were inhibited by resveratrol. Pretreatment of high dosage of resveratrol also significantly inhibited retinal I/R injury-induced capillary degeneration; however, neither of the dosages prevented the injury-induced neurodegeneration. Levels of CHOP, phosphorylated eIF2alpha, IRE1alpha, phosphorylated JNK1/2, Xbp1 splicing and Bip were elevated after I/R injury. High dosage of resveratrol pretreatment inhibited the injury induced up-regulation of eIF2alpha-CHOP and IRE1alpha-XBP1 pathways. CONCLUSIONS: ER stress is an important contributor to vascular degeneration in retina. Resveratrol suppresses I/R injury and tunicamycin-induced vascular degeneration by inhibiting ER stress. PMID- 22491414 TI - Anti-angiogenic effect of KR-31831 on corneal and choroidal neovascularization in rat models. AB - PURPOSE: We attempt to determine the effect and mechanism of KR-31831 in rat models of corneal neovascularization and choroidal neovascularization (CNV). METHODS: Corneal neovascularization was induced by silver nitrate cauterization. Balanced salt solution (for control), KR-31831 (0.1 mg/mL), and bevacizumab (10 mg/mL) were applied topically with or without subsequent subconjunctival injection (10 MUL). The degree of corneal neovascularization was compared among treatments. The effects of intravitreal (0.1 and 0.3 mg/mL) and intraperitoneal (25 mg/kg) of KR-31831, and intravitreal injection of bevacizumab (2.5 mg/mL) were compared in a laser-induced CNV model. FITC-dextran was used to observe the choroid vessels and to evaluate vessel leakage by fluorescence intensity. RESULTS: In the silver nitrate cauterized rat, topical KR-31831 (P = 0.008) or bevacizumab (P = 0.008) reduced effectively the area of corneal neovascularization compared to control on day 14. This was reduced further by additional subconjunctival injection of KR-31831 (P = 0.024) and bevacizumab (P = 0.016). After KR-31831 application, vascular endothelial growth factor (VEGF) receptor 2 and matrix metalloproteinase (MMP)-2 expression was decreased in the cornea. In the CNV model, intravitreal (0.3 mg/mL) and intraperitoneal KR-31831 inhibited significantly the CNV area (P = 0.008 and P = 0.008, respectively) and fluorescence leakage (P = 0.008 and P = 0.032, respectively). This effect was more significant compared to intravitreal bevacizumab in terms of the CNV area (P = 0.032 and P = 0.008, respectively) and fluorescence leakage (P = 0.016 and P = 0.008, respectively). CONCLUSIONS: The anti-angiogenic effect of KR-31831 was comparable in the cornea and more effective in the choroid compared to that of bevacizumab, and it may exert its effect by VEGF signaling and MMP-2. PMID- 22491415 TI - Association of vision loss in glaucoma and age-related macular degeneration with IADL disability. AB - PURPOSE: To determine if glaucoma and/or age-related macular degeneration (AMD) are associated with disability in instrumental activities of daily living (IADLs). METHODS: Glaucoma subjects (n = 84) with bilateral visual field (VF) loss and AMD subjects (n = 47) with bilateral or severe unilateral visual acuity (VA) loss were compared with 60 subjects with normal vision (controls). Subjects completed a standard IADL disability questionnaire, with disability defined as an inability to perform one or more IADLs unassisted. RESULTS: Disability in one or more IADLs was present in 18.3% of controls as compared with 25.0% of glaucoma subjects (P = 0.34) and 44.7% of AMD subjects (P = 0.003). The specific IADL disabilities occurring more frequently in both AMD and glaucoma subjects were preparing meals, grocery shopping, and out-of-home travelling (P < 0.05 for both). In multivariate logistic regression models run adjusting for age, sex, mental status, comorbidity, and years of education, AMD (odds ratio [OR] = 3.4, P = 0.02) but not glaucoma (OR = 1.4, P = 0.45) was associated with IADL disability. However, among glaucoma and control patients, the odds of IADL disability increased 1.6-fold with every 5 dB of VF loss in the better-seeing eye (P = 0.001). Additionally, severe glaucoma subjects (better-eye MD worse than 13.5 dB) had higher odds of IADL disability (OR = 4.2, P = 0.02). Among AMD and control subjects, every Early Treatment of Diabetic Retinopathy Study line of worse acuity was associated with a greater likelihood of IADL disability (OR = 1.3). CONCLUSIONS: VA loss in AMD and severe VF loss in glaucoma are associated with self-reported difficulties with IADLs. These limitations become more likely with increasing magnitude of VA or VF loss. PMID- 22491416 TI - Differentiation of exudative age-related macular degeneration and polypoidal choroidal vasculopathy in the ARMS2/HTRA1 locus. AB - PURPOSE: differentiate the associations of exudative age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) with the ARMS2/HTRA1 locus. METHODS: The entire ARMS2 sequence was sequenced and HTRA1 rs11200638 genotyped in 568 unrelated Chinese individuals: 156 exudative AMD patients, 164 PCV patients, and 248 controls. A meta-analysis was performed to examine the effects of rs10490924 and rs11200638 at the ARMS2/HTRA1 locus in PCV. RESULTS: In total, 31 polymorphisms in ARMS2 were identified. Significant associations with both exudative AMD and PCV were observed in 11 of them and HTRA1 rs11200638, with different genotypic distributions between exudative AMD and PCV (P < 0.001). After adjusting for rs11200638, ARMS2 rs10490924 remained significantly associated with exudative AMD (P = 0.011), but not with PCV (P = 0.077). Meta-analysis showed consistent allelic associations of rs10490924 and rs11200638 with PCV in different study populations. CONCLUSIONS: There is a strong and consistent association of the ARMS2/HTRA1 locus with both exudative AMD and PCV, suggesting the two disorders share, at least partially, similar molecular mechanisms. Different effect sizes indicate the existence of additional genetic and environmental factors affecting them to different extents. PMID- 22491417 TI - Visual function and vision-related quality of life after vitrectomy for epiretinal membranes: a 12-month follow-up study. AB - PURPOSE: Toevaluate the effect of removing epiretinal membranes (ERMs) on visual function and vision-related quality of life (VR-QOL) for 12 months postoperatively. METHODS: Idiopathic ERMs were removed during vitrectomy in 26 eyes. The VR-QOL was evaluated using a self-administered 25-item National Eye Institute Visual Function Questionnaire before (baseline) and 3 and 12 months postoperatively. During the same periods, the best-corrected visual acuity (BCVA), central macular thickness (CMT), and metamorphopsia score were recorded. RESULTS: At baseline and months 3 and 12, the logMAR BCVAs (mean +/- SEM) were 0.41 +/- 0.05, 0.17 +/- 0.04 (P = 0.0001 versus baseline), and 0.10 +/- 0.03 (P < 0.0001 versus baseline, P = 0.0016 versus month 3), respectively; the CMTs (MUm) were 402 +/- 18, 312 +/- 9 (P < 0.0001 versus baseline), and 300 +/- 7 (P < 0.0001 versus baseline, P = 0.0544 versus month 3); and the metamorphopsia scores were 202 +/- 29, 137 +/- 27 (P = 0.0186 versus baseline), and 108 +/- 26 (P = 0.0005 versus baseline, P = 0.0218 versus month 3). In 23 (88%) of 26 eyes, the BCVA improved more than 0.1 logMAR unit at month 12. The improved BCVA was correlated with improvements in two subscales (r = -0.405 to -0.574, P = 0.0041 0.0427) at month 3; the improved metamorphopsia score was correlated with the improved composite score (r = -0.552, P = 0.0058) and three subscales (r = -0.458 to -0.507, P = 0.0113-0.0219) at month 12. CONCLUSIONS: Removing ERMs improved visual function, anatomy, and the VR-QOL. Three months postoperatively, the improved BCVA was the most important factor related to the improved VR-QOL, although the simultaneous cataract surgery might have had a confounding effect. The improved metamorphopsia was the important factor associated with improved VR QOL 12 months postoperatively.(www.umin.ac.jp/ctr number, UMIN000000617). PMID- 22491418 TI - Phosphorylation of phosducin accelerates rod recovery from transducin translocation. AB - PURPOSE: In rods saturated by light, the G protein transducin undergoes translocation from the outer segment compartment, which results in the uncoupling of transducin from its innate receptor, rhodopsin. We measured the kinetics of recovery from this adaptive cellular response, while also investigating the role of phosducin, a phosphoprotein binding transducin betagamma subunits in its de phosphorylated state, in regulating this process. METHODS: Mice were exposed to a moderate rod-saturating light triggering transducin translocation, and then allowed to recover in the dark while free running. The kinetics of the return of the transducin subunits to the outer segments were compared in transgenic mouse models expressing full-length phosducin, and phosducin lacking phosphorylation sites serine 54 and 71, using Western blot analysis of serial tangential sections of the retina. RESULTS: In mice expressing normal phosducin, transducin alpha and betagamma subunits returned to the outer segments with a half-time (t(1/2)) of ~24 and 29 minutes, respectively. In the phosducin phosphorylation mutants, the transducin alpha subunit moved four times slower, with t(1/2) ~95 minutes, while the movement of transducin betagamma was less affected. CONCLUSIONS: We demonstrate that the recovery of rod photoreceptors from the ambient saturating levels of illumination, in terms of the return of the light-dispersed transducin subunits to the rod outer segments, occurs six times faster than reported previously. Our data also support the notion that the accumulation of transducin alpha subunit in the outer segment is driven by its re-binding to the transducin betagamma dimer, because this process is accelerated significantly by phosducin phosphorylation. PMID- 22491419 TI - Triazolothienopyrimidine inhibitors of urea transporter UT-B reduce urine concentration. AB - Urea transport (UT) proteins facilitate the concentration of urine by the kidney, suggesting that inhibition of these proteins could have therapeutic use as a diuretic strategy. We screened 100,000 compounds for UT-B inhibition using an optical assay based on the hypotonic lysis of acetamide-loaded mouse erythrocytes. We identified a class of triazolothienopyrimidine UT-B inhibitors; the most potent compound, UTB(inh)-14, fully and reversibly inhibited urea transport with IC(50) values of 10 nM and 25 nM for human and mouse UT-B, respectively. UTB(inh)-14 competed with urea binding at an intracellular site on the UT-B protein. UTB(inh)-14 exhibited low toxicity and high selectivity for UT B over UT-A isoforms. After intraperitoneal administration of UTB(inh)-14 in mice to achieve predicted therapeutic concentrations in the kidney, urine osmolality after administration of 1-deamino-8-D-arginine-vasopressin was approximately 700 mosm/kg H(2)O lower in UTB(inh)-14-treated mice than vehicle-treated mice. UTB(inh)-14 also increased urine output and reduced urine osmolality in mice given free access to water. UTB(inh)-14 did not reduce urine osmolality in UT-B knockout mice. In summary, these data provide proof of concept for the potential utility of UT inhibitors to reduce urinary concentration in high-vasopressin, fluid-retaining conditions. The diuretic mechanism of UT inhibitors may complement the action of conventional diuretics, which target sodium transport. PMID- 22491420 TI - CD8+ regulatory T cells induced by T cell vaccination protect against autoimmune nephritis. AB - Autoreactive T cells play a pivotal role in the pathogenesis of autoimmune kidney disease. T cell vaccination (TCV) may limit autoimmune disease and induce CD8+ regulatory T cells (Tregs). We used Heymann nephritis (HN), a rat model of human membranous nephritis, to study the effects of TCV on autoimmune kidney disease. We harvested CD4+ T cells from renal tubular antigen (Fx1A) -immunized rats and activated these cells in vitro to express the MHC Class Ib molecule Qa-1. Vaccination of Lewis rats with these autoreactive Fx1A-induced T cells protected against HN, whereas control-primed T cells did not. Rats that underwent TCV had lower levels of proteinuria and serum creatinine and significantly less glomerulosclerosis, tubular damage, and interstitial infiltrates. Furthermore, these rats expressed less IFN-gamma and IL-6 in splenocytes, whereas the numbers of Tregs and the expression of Foxp3 were unchanged. In vitro cytotoxicity assays showed CD8+ T cell-mediated elimination of Qa-1-expressing CD4+ T cells. In vivo, TCV abrogated the increase in Qa-1-expressing CXCR5+ TFH cells observed in HN compared with controls. Taken together, these results suggest that TCV protects against autoimmune kidney disease by targeting Qa-1-expressing autoreactive CD4+ cells. PMID- 22491421 TI - First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours. AB - BACKGROUND: PM00104 binds guanines at DNA minor grooves, impacting DNA replication and transcription. A phase I study was undertaken to investigate safety, dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), pharmacokinetics (PKs) and preliminary antitumour activity of PM00104 as a 1- or 3-h infusion three-weekly. METHODS: Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data. RESULTS: A total of 47 patients were treated; 27 patients on the 1-h schedule (0.23-3.6 mg m(-2)) and 20 patients on the 3-h schedule (1.8-3.5 mg m(-2)). Dose-limiting toxicities comprised reversible nausea, vomiting, fatigue, elevated transaminases and thrombocytopenia, establishing the 1-h schedule RP2D at 3.0 mg m(-2). With the 3-h schedule, DLTs of reversible hypotension and neutropenia established the RP2D at 2.8 mg m(-2). Common PM00104-related adverse events at the RP2D comprised grade 1-2 nausea, fatigue and myelosuppression. In both schedules, PKs increased linearly, but doses over the 1-h schedule RP2D resulted in higher than proportional increases in exposure. A patient with advanced urothelial carcinoma had RECIST shrinkage by 49%, and three patients had RECIST stable disease >=6 months. CONCLUSION: PM00104 is well tolerated, with preliminary evidence of antitumour activity observed. The 1-h 3-weekly schedule is being assessed in phase II clinical trials. PMID- 22491422 TI - Cross-suppression of EGFR ligands amphiregulin and epiregulin and de-repression of FGFR3 signalling contribute to cetuximab resistance in wild-type KRAS tumour cells. AB - BACKGROUND: In addition to the mutational status of KRAS, the epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG) might function as bona fide biomarkers of cetuximab (Ctx) sensitivity for most EGFR driven carcinomas. METHODS: Lentivirus-delivered small hairpin RNAs were employed to specifically reduce AREG or EREG gene expression in wild-type KRAS A431 squamous cell carcinoma cells. Colony-forming assays were used to monitor the impact of AREG and EREG knockdown on Ctx efficacy. Amphiregulin and EREG protein expression levels were assessed by quantitative ELISA in parental A431 cells and in pooled populations of A431 cells adapted to grow in the presence of Ctx. A phosphoproteomic platform was used to measure the relative level of phosphorylation of 42 distinct receptor tyrosine kinases before and after the acquisition of resistance to Ctx. RESULTS: Stable gene silencing of either ligand was found to notably reduce the expression of the other ligand. Parental A431 cells with normal expression levels of AREG/EREG exhibited significantly increased growth inhibition in response to Ctx, compared with derivatives that are engineered to produce minimal AREG/EREG. The parental A431 cells acutely treated with Ctx exhibited reduced basal expression levels of AREG/EREG. Pooled populations of Ctx-resistant A431 cells expressed significantly lower levels of AREG/EREG and were insensitive to the downregulatory effects of Ctx. Phosphoproteomic screen identified a remarkable hyperactivation of FGFR3 in Ctx resistant A431 cells, which gained sensitivity to the cytotoxic and apoptotic effects of the FGFR3 TK inhibitor PD173074. The A431 parental cells acutely treated with Ctx rapidly activated FGFR3 and their concomitant exposure to Ctx and PD173074 resulted in synergistic apoptosis. CONCLUSION: Cross-suppression of AREG/EREG expression may explain the tight co-expression of AREG and EREG, as well as their tendency to be more highly expressed than other EGFR ligands to determine Ctx efficacy. The positive selection for Ctx-resistant tumour cells exhibiting AREG/EREG cross-suppression may have an important role in the emergence of Ctx resistance. As de-repression of FGFR3 activity rapidly replaces the loss of EGFR-ligand signalling in terms of cell proliferation and survival, combinations of Ctx and FGFR3-targeted drugs may be a valuable strategy to enhance the efficacy of single Ctx while preventing or delaying acquired resistance to Ctx. PMID- 22491423 TI - Online doctor reviews: do they track surgeon volume, a proxy for quality of care? AB - BACKGROUND: Increasingly, consumers are accessing the Internet seeking health information. Consumers are also using online doctor review websites to help select their physician. Such websites tally numerical ratings and comments from past patients. To our knowledge, no study has previously analyzed whether doctors with positive online reputations on doctor review websites actually deliver higher quality of care typically associated with better clinical outcomes and better safety records. OBJECTIVE: For a number of procedures, surgeons who perform more procedures have better clinical outcomes and safety records than those who perform fewer procedures. Our objective was to determine if surgeon volume, as a proxy for clinical outcomes and patient safety, correlates with online reputation. METHODS: We investigated the numerical ratings and comments on 9 online review websites for high- and low-volume surgeons for three procedures: lumbar surgery, total knee replacement, and bariatric surgery. High-volume surgeons were randomly selected from the group within the highest quartile of claims submitted for reimbursement using the procedures' relevant current procedural terminology (CPT) codes. Low-volume surgeons were randomly selected from the lowest quartile of submitted claims for the procedures' relevant CPT codes. Claims were collated within the Normative Health Information Database, covering multiple payers for more than 25 million insured patients. RESULTS: Numerical ratings were found for the majority of physicians in our sample (547/600, 91.2%) and comments were found for 385/600 (64.2%) of the physicians. We found that high-volume (HV) surgeons could be differentiated from low-volume (LV) surgeons independently by analyzing: (1) the total number of numerical ratings per website (HV: mean = 5.85; LV: mean = 4.87, P<.001); (2) the total number of text comments per website (HV: mean = 2.74; LV: mean = 2.30, P=.05); (3) the proportion of glowing praise/total comments about quality of care (HV: mean = 0.64; LV: mean = 0.51, P=.002); and (4) the proportion of scathing criticism/total comments about quality of care (HV: mean = 0.14; LV: mean = 0.23, P= .005). Even when these features were combined, the effect size, although significant, was still weak. The results revealed that one could accurately identify a physician's patient volume via discriminant and classification analysis 61.6% of the time. We also found that high-volume surgeons could not be differentiated from low-volume surgeons by analyzing (1) standardized z score numerical ratings (HV: mean = 0.07; LV: mean = 0, P=.27); (2) proportion of glowing praise/total comments about customer service (HV: mean = 0.24; LV: mean = 0.22, P=.52); and (3) proportion of scathing criticism/total comments about customer service (HV: mean = 0.19; LV: mean = 0.21, P=.48). CONCLUSIONS: Online review websites provide a rich source of data that may be able to track quality of care, although the effect size is weak and not consistent for all review website metrics. PMID- 22491424 TI - Liver-specific loss of Atg5 causes persistent activation of Nrf2 and protects against acetaminophen-induced liver injury. AB - Autophagy is an evolutionarily conserved biological process that degrades intracellular proteins and organelles including damaged mitochondria through the formation of autophagosome. We have previously demonstrated that pharmacological induction of autophagy by rapamycin protects against acetaminophen (APAP)-induced liver injury in mice. In contrast, in the present study, we found that mice with the liver-specific loss of Atg5, an essential autophagy gene, were resistant to APAP-induced liver injury. Hepatocyte-specific deletion of Atg5 resulted in mild liver injury characterized by increased apoptosis and compensatory hepatocyte proliferation. The lack of autophagy in the Atg5-deficient mouse livers was confirmed by increased p62 protein levels and the absence of LC3-lipidation as well as autophagosome formation. Analysis of histological and clinical chemistry parameters indicated that the Atg5 liver-specific knockout mice are resistant to APAP overdose (500 mg/kg). Further investigations revealed that the bioactivation of APAP is normal in Atg5 liver-specific knockout mice although they had lower CYP2E1 expression. There was an increased basal hepatic glutathione (GSH) content and a faster recovery of GSH after APAP treatment due to persistent activation of Nrf2, a transcriptional factor regulating drug detoxification and GSH synthesis gene expression. In addition, we found significantly higher hepatocyte proliferation in the livers of Atg5 liver-specific knockout mice. Taken together, our data suggest that persistent activation of Nrf2 and increased hepatocyte proliferation protect against APAP-induced liver injury in Atg5 liver-specific knockout mice. PMID- 22491425 TI - Relationship of metabolism and cell proliferation to the mode of action of fluensulfone-induced mouse lung tumors: analysis of their human relevance using the IPCS framework. AB - Species-specific lung tumors in the mouse are induced by a number of chemicals. The underlying cause appears to be a high metabolic activity of mouse lung, due to relatively high abundance of Clara cells in mice compared with humans and the mouse-specific cytochrome P450 isoform 2f2 in the Clara cells. The chemicals are activated to reactive intermediates, leading to local cytotoxicity or mitogenicity resulting in increased cell proliferation and tumors. Rats have lower metabolic activity than mice (already below the threshold needed to cause lung tumors upon lifetime exposure) and activity in humans is lower than in rats. The carcinogenic risk for human lung is low for this mode of action (MOA). Fluensulfone has shown an increased incidence of lung adenomas in mice, but not in rats, at high doses. Fluensulfone is not genotoxic. MOA studies were conducted investigating key events of the postulated MOA. Fluensulfone is extensively metabolized by mouse lung microsomes, whereas no metabolic activity is seen with human lung microsomes. Cyp 2f2 is a major contributor in fluensulfone's metabolism and Cyp 2e1 is not involved. Furthermore, administration of fluensulfone to mice led to an early increase in Clara cell proliferation. The International Programme on Chemical Safety (IPCS) MOA and human relevance framework was used to evaluate the collective data on fluensulfone. We concluded that fluensulfone leads to species-specific mouse lung tumors and that these tumors are likely not relevant to human hazard or risk. PMID- 22491426 TI - Targets and intracellular signaling mechanisms for deoxynivalenol-induced ribosomal RNA cleavage. AB - The trichothecene mycotoxin deoxynivalenol (DON), a known translational inhibitor, induces ribosomal RNA (rRNA) cleavage. Here, we characterized this process relative to (1) specific 18S and 28S ribosomal RNA cleavage sites and (2) identity of specific upstream signaling elements in this pathway. Capillary electrophoresis indicated that DON at concentrations as low as 200 ng/ml evoked selective rRNA cleavage after 6 h and that 1000 ng/ml caused cleavage within 2 h. Northern blot analysis revealed that DON exposure induced six rRNA cleavage fragments from 28S rRNA and five fragments from 18S rRNA. When selective kinase inhibitors were used to identify potential upstream signals, RNA-activated protein kinase (PKR), hematopoietic cell kinase (Hck), and p38 were found to be required for rRNA cleavage, whereas c-Jun N-terminal kinase and extracellular signal-regulated kinase were not. Furthermore, rRNA fragmentation was suppressed by the p53 inhibitors pifithrin-alpha and pifithrin-MU as well as the pan caspase inhibitor Z-VAD-FMK. Concurrent apoptosis was confirmed by acridine orange/ethidium bromide staining and flow cytometry. DON activated caspases 3, 8, and 9, thus suggesting the possible coinvolvement of both extrinsic and intrinsic apoptotic pathways in rRNA cleavage. Satratoxin G (SG), anisomycin, and ricin also induced specific rRNA cleavage profiles identical to those of DON, suggesting that ribotoxins might share a conserved rRNA cleavage mechanism. Taken together, DON-induced rRNA cleavage is likely to be closely linked to apoptosis activation and appears to involve the sequential activation of PKR/Hck ->p38->p53 >caspase 8/9->caspase 3. PMID- 22491427 TI - Nongenotoxic apoptosis inducers do not produce misleading positive results in the TK6 cell-based GADD45a-GFP genotoxicity assay. AB - The in vitro mammalian genotoxicity tests identify some carcinogens not identified by the bacterial Ames test. However, historically they have produced rather more misleading predictions of carcinogenicity than the Ames test. This liability has been reduced in pharmaceutical testing by lowering the top-testing dose and rejecting data from excessively toxic doses. It also stimulated the development of new assays with inherently higher specificity. Among these, the GADD45a-GFP assay has been recognized as a maturing technology by the International Life Sciences Institute Health and Environmental Sciences Institute In Vitro Genetic Toxicity Emerging Technologies and New Strategies workgroup and has been concluded to be suitable for inclusion in a battery of high throughput screening by the U.K. Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment. GADD45a is induced by compounds that cause damage to or missegregation of chromosomes, and is implicated in the stimulation of repair or apoptosis where damage is overwhelming. It is therefore important to understand whether this causes a liability in the assay to produce misleading positives for nongenotoxic inducers of apoptosis. Compounds hypothesized to stimulate apoptosis in the GADD45a-GFP assay or to induce GADD45a in the absence of genotoxic stress, such as p53 activators, NF-kappaB and Bcl-2 inhibitors were selected. Apoptosis induction was monitored using Annexin V binding and caspase 3/7 activation assays. The majority of compounds tested were negative in the GADD45a-GFP assay. The few that generated positive data were also found positive in concurrent comet assay and/or micronucleus tests. The data presented here demonstrate that the GADD45a-GFP assay is not vulnerable to the generation of misleading positive results by apoptosis inducers. PMID- 22491428 TI - Physicochemical determinants in the cellular responses to nanostructured amorphous silicas. AB - Amorphous silicas, opposite to crystalline polymorphs, have been regarded so far as nonpathogenic, but few studies have addressed the toxicity of the wide array of amorphous silica forms. With the advent of nanotoxicology, there has been a rising concern about the safety of silica nanoparticles to be used in nanomedicine. Here, we report a study on the toxicity of amorphous nanostructured silicas obtained with two different preparation procedures (pyrolysis vs. precipitation), the pyrogenic in two very different particle sizes, in order to assess the role of size and origin on surface properties and on the cell damage, oxidative stress, and inflammatory response elicited in murine alveolar macrophages. A quartz dust was employed as positive control and monodispersed silica spheres as negative control. Pyrogenic silicas were remarkably more active than the precipitated one as to cytotoxicity, reactive oxygen species production, lipid peroxidation, nitric oxide synthesis, and production of tumor necrosis factor-alpha, when compared both per mass and per unit surface. Between the two pyrogenic silicas, the larger one was the more active. Silanols density is the major difference in surface composition among the three silicas, being much larger than the precipitated one as indicated by joint calorimetric and infrared spectroscopy analysis. We assume here that full hydroxylation of a silica surface, with consequent stable coverage by water molecules, reduces/inhibits toxic behavior. The preparation route appears thus determinant in yielding potentially toxic materials, although the smallest size does not always correspond to an increased toxicity. PMID- 22491429 TI - Non-dioxin-like AhR ligands in a mouse peanut allergy model. AB - Recently, we have shown that AhR activation by 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD) suppresses sensitization to peanut at least in part by inducing a functional shift toward CD4(+)CD25(+)Foxp3(+) T cells. Next to TCDD, numerous other AhR ligands have been described. In this study, we investigated the effect of three structurally different non-dioxin-like AhR ligands, e.g., 6 formylindolo[3,2-b]carbazole (FICZ), beta-naphthoflavone (beta-NF), and 6-methyl 1,3,8-trichlorodibenzofuran (6-MCDF), on peanut sensitization. Female C57BL/6 mice were sensitized by administering peanut extract (PE) by gavage in the presence of cholera toxin. Before and during peanut sensitization, mice were treated with FICZ, beta-NF, or 6-MCDF. AhR gene transcription in duodenum and liver was investigated on day 5, even as the effect of these AhR ligands on CD4(+)CD25(+)Foxp3(+) T(reg) cells in spleen and mesenteric lymph nodes (MLNs). Mice treated with TCDD were included as a positive control. Furthermore, the murine reporter cell line H1G1.1c3 (CAFLUX) was used to investigate the possible role of metabolism of TCDD, FICZ, beta-NF, and 6-MCDF on AhR activation in vitro. TCDD, but not FICZ, beta-NF, and 6-MCDF, suppressed sensitization to peanut (measured by PE-specific IgE, IgG1, IgG2a and PE-induced interleukin (IL)-5, IL 10, IL-13, IL-17a, IL-22, and interferon-gamma). In addition, FICZ, beta-NF, and 6-MCDF treatments less effectively induced AhR gene transcription (measured by gene expression of AhR, AhRR, CYP1A1, CYP1A2, CYP1B1) compared with TCDD-treated mice. Furthermore, FICZ, beta-NF and 6-MCDF did not increase the percentage of CD4(+)CD25(+)Foxp3(+) T(reg) cells in spleen and mesenteric lymph nodes compared with PE-sensitized mice, in contrast to TCDD. Inhibition of metabolism in vitro increased AhR activation. Together, these data shows that TCDD, but not FICZ, beta-NF, and 6-MCDF suppresses sensitization to peanut. Differences in metabolism, AhR binding and subsequent gene transcription might explain these findings and warrant further studies to investigate the role of the AhR in food allergic responses. PMID- 22491430 TI - Large para-articular osteochondroma of the knee joint: a case report. AB - A unique case of large intra-articular osteochondroma of the knee of a 15-year duration is presented along with a review of the literature. The tumor may have remained asymptomatic for such a long period because of its slow growth and stretch elongation of the quadriceps mechanism. PMID- 22491431 TI - Which hand outcome measurement is best for Turkish speaking patients? AB - OBJECTIVE: In determining treatment outcomes of the hand, the Disabilities of the Arm, Shoulder and Hand (DASH), Michigan Hand Outcomes Questionnaire (MHQ) and Milliken Activities of Daily Living Scale (MAS) questionnaires are the most commonly used. The aim of this study was to evaluate the relations, strengths and weaknesses of these questionnaires and determine the most appropriate outcome measure for the Turkish population. METHODS: The study included 74 patients with various types of hand injuries. Patients filled out the DASH-Turkish, MHQ and MAS questionnaires. Grip strength and pain intensity were also assessed. RESULTS: MAS parameters were well-correlated with DASH-Turkish and grip strength (p<0.05). MHQ was correlated with all other outcomes except the left hand part. CONCLUSION: The DASH, MHQ and MAS questionnaires are culturally compatible with the Turkish population and have revealed a good correlation. These results suggest that these outcome instruments can be used in the assessment of hand and wrist surgery outcomes in the Turkish population. PMID- 22491432 TI - The effects of osteoporosis on functional outcome in patients with distal radius fracture treated with plate osteosynthesis. AB - OBJECTIVE: The aim of this study was to evaluate the effect of osteoporosis on functional results in patients with distal radius fracture treated with plate osteosynthesis. METHODS: The study included 37 female patients who underwent osteosynthesis using volar locking plate for distal radius fracture between 2006 and 2008. Diagnosis of osteoporosis was made with bone mineral density measurement. Patients were divided into two groups; Group 1 patients (20 patients; mean age: 56.5 years) had osteoporosis and a mean T-score of -2.6 SD, and Group 2 patients (17 patients; mean age: 37.1 years) did not have osteoporosis and had a T-score of -0.7 SD. Radiological results were evaluated according to the Stewart's criteria and activities of daily living were assessed with the modified Gartland and Werley score, the modified Mayo wrist scoring system, and the DASH scoring system. RESULTS: According to the Stewart's radiological evaluation criteria and modified Gartland and Werley scores, there was no statistically significant difference between Group 1 and 2 (p>0.05). However, a statistically significant difference was found between Group 1 and 2 according to the modified Mayo wrist scoring system and DASH scoring system (p<0.05). CONCLUSION: There was no radiological difference between the osteoporotic and non-osteoporotic patients with distal radius fractures treated with plate osteosynthesis. However, osteoporosis had a negative effect on the results and range of motion of the wrist, and activities of daily living were significantly restricted. PMID- 22491433 TI - The effect of medial side repair in terrible triad injury of the elbow. AB - OBJECTIVE: The aim of this study was to evaluate the effect of surgical repair of the medial collateral ligament and ulnar nerve release in cases of terrible triad injuries of the elbow. METHODS: This study included 16 patients (average age: 34 years) who underwent surgery following a diagnosis of terrible triad injury of the elbow between 1996 and 2007. Average follow up was 34.5 months. In all cases, the radial head was first fixed or replaced and the anterior capsule/coronoid complex and lateral collateral ligament were repaired. The medial side of the elbow was addressed (medial collateral ligament repair and ulnar nerve release) in 8 cases and not addressed in the remaining 8 cases. Range of motion, pain, stability, ulnar nerve symptoms, functional Mayo Elbow Performance Index, and Disabilities of the Arm, Shoulder and Hand scores were documented. Serial X-rays were used to confirm ulnohumeral arthritis and development of ectopic calcification. Ultrasonography or MRI was used to detect ulnar nerve entrapment. RESULTS: Range of motion was slightly more limited in cases where the medial side was not addressed. Ulnohumeral range of motion and flexion degrees were higher in the cases where the medial side was addressed (p<0.05). Serial X-rays demonstrated impending ectopic calcification located at the proximal insertion of medial collateral ligament in patients who did not undergo medial side repair. MRI or ultrasonography confirmed these findings, revealing swollen displaced nerves resembling findings similar to cubital tunnel syndrome. CONCLUSION: Ulnar neuropathy is a common complication after medial collateral ligament injury and prophylactic release will facilitate overall results and postoperative patient satisfaction. PMID- 22491434 TI - Chair method: a simple and effective method for reduction of anterior shoulder dislocation. AB - OBJECTIVE: The ideal reduction method for anterior shoulder dislocation is defined as a practical technique applied without any assistance and minimizing patient interference. The aim of this study was to evaluate the outcomes of patients with shoulder dislocations reduced using the chair method in the emergency department and show that the chair method is one of the ideal methods. METHODS: Seventy-four patients with anterior shoulder dislocation were treated using the chair method. Data from patients were recorded and analyzed. RESULTS: All dislocated shoulders were successfully reduced using the chair method without any complication or difficulty. Thirty patients had first time dislocation and 44 patients had previous dislocation. Mean duration between dislocation and reduction was 3 (range: 1 to 6) hours. Mean duration of reduction was 13.9 (range: 3 to 45) seconds. CONCLUSION: The chair method is an effective and successful reduction method for shoulder dislocation. We believe that orthopedists and emergency department physicians should be familiar with this simple technique which does not have to be performed under general anesthesia. PMID- 22491435 TI - Intramedullary osteosynthesis of instable intertrochanteric femur fractures with Profin(r) nail in elderly patients. AB - OBJECTIVE: The aim of this study was to retrospectively analyze the radiologic and functional results of patients with instable intertrochanteric femur fractures treated with Profin(r) nails. METHODS: This study included 32 patients (24 female, 8 male; mean age: 70.7 years; range: 65 to 96 years) who were treated with Profin(r) nails for instable intertrochanteric fractures. Fractures were caused by a simple fall in 30 patients and pedestrian accident in two. Eleven patients had Type 31-A2 and 21 patients had Type 31-A3 fractures according to the AO/OTA classification. Results were evaluated clinically and radiologically. Mean follow-up period was 17.3 (range: 12 to 23) months. RESULTS: Good or acceptable reduction was achieved in 93.7% of our patients. Mean surgery duration was 28.2 (range: 22 to 75) minutes and mean blood loss was 215 (range: 150 to 320) cc. Complete union was achieved in all patients at a mean of 17.6 (range: 15 to 22) weeks. Postoperative mean collodiaphyseal angle was 125.5 (range: 122 to 130) degrees and there was no significant difference with follow-up values (p>0.05). Twenty-two patients were able to walk with support and 10 without support after surgery. Mean Oxford hip score was 23.70 (range: 14 to 39) points. One year mortality rate was 18.75%. CONCLUSION: Good functional and radiologic results can be achieved using Profin(r) nails for unstable intertrochanteric femur fractures in elderly patients. PMID- 22491436 TI - Comparison of reduction methods in intramedullary nailing of subtrochanteric femoral fractures. AB - OBJECTIVE: The aim of this study was to compare the outcomes of three reduction methods used during intramedullary nailing of the subtrochanteric femur fractures. METHODS: This study included 45 patients with subtrochanteric femur fractures who were treated with intramedullary nailing. Twenty-two patients underwent clamp-assisted reduction, 11 reduction with cable cerclage, and 12 with blocking screws. Reduction techniques were compared with respect to the early postoperative alignment, one year postoperative alignment, time to full weight bearing, time to union, Harris hip score at one year, operation and fluoroscopy times, blood transfusion amount, complications, and additional interventions. RESULTS: The clamp-assisted reduction group had a statistically high mean time to full weight-bearing (p=0.038) and a low mean Harris hip score at one year (p=0.002). The blocking screw group's operation times and fluoroscopy times were statistically long. There was no statistically significant difference between the clamp-assisted reduction and cable cerclage groups in terms of operation times and fluoroscopy times. On the other hand, there were statistically significant differences between the clamp-assisted reduction and blocking screw groups (p=0.0001 and p=0.0001, respectively) and between the cable cerclage and blocking screw groups (p=0.037 p=0.0001, respectively) in terms of operation times and fluoroscopy times. There was no statistically significant difference between the clamp-assisted reduction, cable cerclage and the blocking screw groups in terms of early postoperative alignment, one year postoperative alignment, time to union, complications or additional interventions. CONCLUSION: Clamp-assisted reduction leads to a longer time to weight-bearing and a poorer functional status at one year. Operation time and fluoroscopy time were longest in the blocking screw group. PMID- 22491437 TI - Acetabular reconstruction by impacted cancellous allografts in cementless total hip arthroplasty revision. AB - OBJECTIVE: The aim of this study was to evaluate the primary and secondary stability, where 100% or virtually 100% of the uncemented acetabular component contacted with impacted cancellous allografts, focusing especially on the amount of graft used and rim contact. METHODS: Fifteen cases of acetabular reconstruction using impacted cancellous allografts and cementless porous-coated component in which 100% or virtually 100% of the component contacted only with the allograft were reviewed. Mean follow-up was 97.5 (range: 58 to 130) months after revision. The Harris hip score was used to evaluate clinical results. Radiographic evaluations were done using standard anteroposterior views obtained at the final follow-up. RESULTS: Two patients underwent re-revision. The mean Harris hip score of the remaining 13 patients was 88.3+/-11.9 (range: 68 to 100) at the final follow-up. Early postoperative radiographs showed mean angle of inclination of 45 degrees (range: 30 degrees to 55 degrees ). There was a mean migration of 6.2+/-7.8 (range: 0 to 29) mm and the migration amount did not differ according to rim contact (p=0.054). There was no correlation between migration and amount of graft used (p>0.05). There was a significant correlation between migration and follow-up time (p<0.01). CONCLUSION: Our results imply that 50% host bone contact is not absolutely necessary to form a stable construct while restoring the centre of hip rotation. PMID- 22491438 TI - Adjunctive hyperbaric oxygen therapy in the treatment of atrophic tibial nonunion with Ilizarov external fixator: a radiographic and scintigraphic study in rabbits. AB - OBJECTIVE: The aim of this experimental study was to determine the effects of adjunctive hyperbaric oxygen therapy (HBO) on atrophic tibial nonunion treatment using Ilizarov external fixator. METHODS: Twenty New Zealand white rabbits were randomly divided into two equal groups. A circular external fixator was applied to the right tibia of all the rabbits. A 5-mm bone block was resected and a tibial pseudarthrosis was obtained after a 6-month waiting period. The experimental group rabbits (n=10) underwent daily 2.5 ATA HBO therapy for 2 hours for 20 days and the control group rabbits (n=10) did not receive any corresponding treatment. Osteoblastic activity was evaluated with bone scintigraphy on days 30 and 90. Fracture healing was evaluated by plain radiographs on days 30 and 90. RESULTS: On Day 30, radiological scores were statistically similar in both groups (p=0.167). However, on Day 90, the experimental group displayed significantly higher radiological scores (p<0.001). Osteoblastic activity was also higher in the experimental group on both scintigraphic assessments (p=0.005 and p=0.001). CONCLUSION: The results of this study suggest that HBO can be used as a supplementary therapy in the management of atrophic tibial nonunion. PMID- 22491439 TI - Accessory tendon slip arising from the extensor carpi ulnaris and its importance for wrist pain. AB - OBJECTIVE: The anatomical variations of the extensor carpi ulnaris (ECU) muscle can cause a functional impairment of the wrist and the little finger. The aim of this study was to determine the number, thickness and type of accessory tendon arising from the ECU. METHODS: The presence of an accessory tendinous slip from the ECU muscle was examined in terms of gross appearance, size, shape, thickness, location and distribution in 54 cadaveric forearms. RESULTS: The accessory slips arising from the ECU muscle were observed in three specimens (5.6%) (two left, one right). These slips ran to the ulnar side of the extensor digiti minimi tendon, originated from the head of the ECU, and ended on the extensor apparatus of the fifth finger. The mean width of the tendinous slips was 1.4+/-0.01 mm. CONCLUSION: This anatomic variation of the ECU should be considered in diagnostic and surgical procedures involving the dorsum of the hand. Its clinical importance in the treatment of tenosynovitis and subluxation of joints is also stressed. PMID- 22491440 TI - Neglected floating fifth metacarpal: a case report. AB - Simultaneous dislocation of the metacarpophalangeal and carpometacarpal joint has been previously reported. Floating metacarpals occur when the metacarpal head displaces volarly and the base displaces towards the dorsal side. A closed dislocation at both ends of the fifth ray is unusual. In this study, we report a neglected case of floating fifth ray and its management along with a review of the literature. PMID- 22491441 TI - Unusual localization of an aneurysmal bone cyst in ulnar coronoid process. AB - Aneurysmal bone cysts are non-neoplastic, expansile, osteolytic tumor-like conditions. All bones may be involved, but the most commonly affected is the metaphysis of the long bones, especially the tibia, humerus and femur. We present a 13-year-old female patient with a cystic lesion with cortical continuity and a large bone cyst in the coronoid process of the ulna. The bone cyst was treated with curettage, phenol application and cement implantation following cyst debulking. Aneurysmal bone tumors are rare tumor-like conditions and localization at the coronoid process of the ulna with mechanical block of the elbow motion has yet to be reported. Debulking and curettage of the lesion and bone cement implantation are useful methods for local control of aneurysmal bone cysts. PMID- 22491443 TI - From model to action: using a system dynamics model of chronic disease risks to align community action. AB - Health planners in Austin, Texas, are using a System Dynamics Model of Cardiovascular Disease Risks (SD model) to align prevention efforts and maximize the effect of limited resources. The SD model was developed using available evidence of disease prevalence, risk factors, local contextual factors, resulting health conditions, and their impact on population health. Given an interest in understanding opportunities for upstream health protection, the SD model focused on the portion of the population that has never had a cardiovascular event. Leaders in Austin used this interactive simulation model as a catalyst for convening diverse stakeholders in thinking about their strategic directions and policy priorities. Health officials shared insights from the model with a range of organizations in an effort to align actions and leverage assets in the community to promote healthier conditions for all. This article summarizes the results from several simulated intervention scenarios focusing specifically on conditions in East Travis County, an area marked by higher prevalence of adverse living conditions and related chronic diseases. The article also describes the formation of a new Chronic Disease Prevention Coalition in Austin, along with shifts in its members' perceived priorities for intervention both before and after interactions with the SD model. PMID- 22491444 TI - Selected new developments in vibrational structure theory: potential construction and vibrational wave function calculations. AB - This perspective addresses selected recent developments in the theoretical calculation of vibrational spectra, energies, wave functions and properties. The theoretical foundation and recently developed computational protocols for constructing hierarchies of vibrational Hamiltonian operators are reviewed. A many-mode second quantization (SQ) formulation is discussed prior to the discussion of anharmonic wave functions. Emphasis is put on vibrational self consistent field (VSCF) based methods and in particular vibrational coupled cluster (VCC) theory. Other issues are also reviewed briefly, such as inclusion of thermal effects, response theoretical calculation of spectra, and the difficulty in treating dense spectra. PMID- 22491445 TI - Cost-effective hearing rehabilitation: a role for self-fitting hearing aids? PMID- 22491446 TI - The removal of RNA primers from DNA synthesized by the reverse transcriptase of the retrotransposon Tf1 is stimulated by Tf1 integrase. AB - The Tf1 retrotransposon represents a group of long terminal repeat retroelements that use an RNA self-primer for initiating reverse transcription while synthesizing the minus-sense DNA strand. Tf1 reverse transcriptase (RT) was found earlier to generate the self-primer in vitro. Here, we show that this RT can remove from the synthesized cDNA the entire self-primer as well as the complete polypurine tract (PPT) sequence (serving as a second primer for cDNA synthesis). However, these primer removals, mediated by the RNase H activity of Tf1 RT, are quite inefficient. Interestingly, the integrase of Tf1 stimulated the specific Tf1 RT-directed cleavage of both the self-primer and PPT, although there was no general enhancement of the RT's RNase H activity (and the integrase by itself is devoid of any primer cleavage). The RTs of two prototype retroviruses, murine leukemia virus and human immunodeficiency virus, showed only a partial and nonspecific cleavage of both Tf1-associated primers with no stimulation by Tf1 integrase. Mutagenesis of Tf1 integrase revealed that the complete Tf1 integrase protein (excluding its chromodomain) is required for stimulating the Tf1 RT primer removal activity. Nonetheless, a double mutant integrase that has lost its integration functions can still stimulate the RT's activity, though heat inactivated integrase cannot enhance primer removals. These findings suggest that the enzymatic activity of Tf1 integrase is not essential for stimulating the RT mediated primer removal, while the proper folding of this protein is obligatory for this function. These results highlight possible new functions of Tf1 integrase in the retrotransposon's reverse transcription process. PMID- 22491447 TI - Foamy virus Pol protein expressed as a Gag-Pol fusion retains enzymatic activities, allowing for infectious virus production. AB - Foamy viruses (FV) synthesize Pol from a spliced pol mRNA independently of Gag, unlike orthoretroviruses, which synthesize Pol as a Gag-Pol protein that coassembles with Gag. We found that prototype FV (PFV) mutants expressing Gag and Pol only as a Gag-Pol protein without the spliced Pol contain protease activity equivalent to that of wild-type (WT) Pol. Regardless of the presence or absence of the spliced Pol, the PFV Gag-Pol proteins can assemble into virus-like particles (VLPs), in contrast to the orthoretroviral Gag-Pol proteins, which cannot form VLPs. However, the PFV Gag-Pol VLPs have aberrant morphologies and are not infectious. In the absence of the spliced Pol, coexpression of a PFV Gag Pol protein with Gag can produce infectious virions. Our results suggest that enzymes encoded by PFV pol (protease, reverse transcriptase, and integrase) are enzymatically active if they are synthesized as part of a Gag-Pol protein. PMID- 22491449 TI - CD44 participates in IP-10 induction in cells in which hepatitis C virus RNA is replicating, through an interaction with Toll-like receptor 2 and hyaluronan. AB - The mechanisms of induction of liver injury during chronic infection with hepatitis C virus (HCV) are not well understood. Gamma interferon (IFN-gamma) inducible protein 10 (IP-10), a member of the CXC chemokine family, is expressed in the liver of chronic hepatitis C (CHC) patients and selectively recruits activated T cells to the sites of inflammation. Recently, it was shown that a low plasma concentration of IP-10 in CHC patients was closely associated with the outcome of antiviral therapy. In this study, we examined the role of the Toll like receptor (TLR) pathway on IP-10 production in cells replicating HCV. Among the CXC chemokines, the expression of IP-10 was specifically increased in cells replicating HCV upon stimulation with conventional TLR2 ligands. The enhancement of IP-10 production upon stimulation with TLR2 ligands in cells replicating HCV induced CD44 expression. CD44 is a broadly distributed type I transmembrane glycoprotein and a receptor for the glycosaminoglycan hyaluronan (HA). In CHC patients, the expression of HA in serum has been shown to increase in accord with the progression of liver fibrosis, and HA also works as a ligand for TLR2. In the present study, IP-10 production upon HA stimulation was dependent on the expression of TLR2 and CD44, and a direct association between TLR2 and CD44 was observed. These results suggest that endogenous expression of HA in hepatocytes in CHC patients participates in IP-10 production through an engagement of TLR2 and CD44. PMID- 22491448 TI - Integrated clinical, pathologic, virologic, and transcriptomic analysis of H5N1 influenza virus-induced viral pneumonia in the rhesus macaque. AB - Viral pneumonia has been frequently reported during early stages of influenza virus pandemics and in many human cases of highly pathogenic avian influenza (HPAI) H5N1 virus infection. To better understand the pathogenesis of this disease, we produced nonlethal viral pneumonia in rhesus macaques by using an HPAI H5N1 virus (A/Anhui/2/2005; referred to as Anhui/2). Infected macaques were monitored for 14 days, and tissue samples were collected at 6 time points for virologic, histopathologic, and transcriptomic analyses. Anhui/2 efficiently replicated in the lung from 12 h to 3 days postinfection (p.i.) and caused temporal but severe pneumonia that began to resolve by day 14. Lung transcriptional changes were first observed at 6 h, and increased expression of vascular permeability regulators and neutrophil chemoattractants correlated with increased serum leakage and neutrophil infiltration in situ. Additional inflammatory, antiviral, and apoptotic genes were upregulated from 12 h, concurrent with viral antigen detection and increasing immune cell populations. A shift toward upregulation of acquired immunity was apparent after day 6. Expression levels of established immune cell molecular markers revealed remarkable similarity with pathological findings, indicating early and robust neutrophil infiltration, a slight delay in macrophage accumulation, and abundant late populations of T lymphocytes. We also characterized the putative mechanisms regulating a unique, pneumonia-associated biphasic fever pattern. Thus, this study is the first to use a comprehensive and integrative approach to delineate specific molecular mechanisms regulating influenza virus-induced pneumonia in nonhuman primates, an important first step toward better management of human influenza virus disease. PMID- 22491450 TI - Rescue of a porcine anellovirus (torque teno sus virus 2) from cloned genomic DNA in pigs. AB - Anelloviruses are a group of single-stranded circular DNA viruses infecting humans and other animal species. Animal models combined with reverse genetic systems of anellovirus have not been developed. We report here the construction and initial characterization of full-length DNA clones of a porcine anellovirus, torque teno sus virus 2 (TTSuV2), in vitro and in vivo. We first demonstrated that five cell lines, including PK-15 cells, are free of TTSuV1 or TTSuV2 contamination, as determined by a real-time PCR and an immunofluorescence assay (IFA) using anti-TTSuV antibodies. Recombinant plasmids harboring monomeric or tandem-dimerized genomic DNA of TTSuV2 from the United States and Germany were constructed. Circular TTSuV2 genomic DNA with or without introduced genetic markers and tandem-dimerized TTSuV2 plasmids were transfected into PK-15 cells, respectively. Splicing of viral mRNAs was identified in transfected cells. Expression of TTSuV2-specific open reading frame 1 (ORF1) in cell nuclei, especially in nucleoli, was detected by IFA. However, evidence of productive TTSuV2 infection was not observed in 12 different cell lines transfected with the TTSuV2 DNA clones. Transfection with circular DNA from a TTSuV2 deletion mutant did not produce ORF1 protein, suggesting that the observed ORF1 expression is driven by TTSuV2 DNA replication in cells. Pigs inoculated with either the tandem dimerized clones or circular genomic DNA of U.S. TTSuV2 developed viremia, and the introduced genetic markers were retained in viral DNA recovered from the sera of infected pigs. The availability of an infectious DNA clone of TTSuV2 will facilitate future study of porcine anellovirus pathogenesis and biology. PMID- 22491451 TI - Patterns of acute rhesus cytomegalovirus (RhCMV) infection predict long-term RhCMV infection. AB - We previously reported that long-term rhesus cytomegalovirus (RhCMV) excretion in infected macaques was related to UL/b' coding content. Acute biopsy specimens of the inoculation sites from the previous study have now been analyzed to determine whether there were acute phenotypic predictors of long-term RhCMV infection. Only in animals displaying acute endothelial tropism and neutrophilic inflammation was RhCMV excretion detected. The results imply that vaccinating against these early viral determinants would significantly impede long-term RhCMV infection. PMID- 22491452 TI - Serology-enabled discovery of genetically diverse hepaciviruses in a new host. AB - Genetic and biological characterization of new hepaciviruses infecting animals contributes to our understanding of the ultimate origins of hepatitis C virus (HCV) infection in humans and dramatically enhances our ability to study its pathogenesis using tractable animal models. Animal homologs of HCV include a recently discovered canine hepacivirus (CHV) and GB virus B (GBV-B), both viruses with largely undetermined natural host ranges. Here we used a versatile serology based approach to determine the natural host of the only known nonprimate hepacivirus (NPHV), CHV, which is also the closest phylogenetic relative of HCV. Recombinant protein expressed from the helicase domain of CHV NS3 was used as antigen in the luciferase immunoprecipitation system (LIPS) assay to screen several nonprimate animal species. Thirty-six samples from 103 horses were immunoreactive, and viral genomic RNA was present in 8 of the 36 seropositive animals and none of the seronegative animals. Complete genome sequences of these 8 genetically diverse NPHVs showed 14% (range, 6.4% to 17.2%) nucleotide sequence divergence, with most changes occurring at synonymous sites. RNA secondary structure prediction of the 383-base 5' untranslated region of NPHV was refined and extended through mapping of polymorphic sites to unpaired regions or (semi)covariant pairings. Similar approaches were adopted to delineate extensive RNA secondary structures in the coding region of the genome, predicted to form 27 regularly spaced, thermodynamically stable stem-loops. Together, these findings suggest a promising new nonprimate animal model and provide a database that will aid creation of functional NPHV cDNA clones and other novel tools for hepacivirus studies. PMID- 22491453 TI - Characterization of the viral O-glycopeptidome: a novel tool of relevance for vaccine design and serodiagnosis. AB - Viral envelope proteins mediate interactions with host cells, leading to internalization and intracellular propagation. Envelope proteins are glycosylated and are known to serve important functions in masking host immunity to viral glycoproteins. However, the viral infectious cycle in cells may also lead to aberrant glycosylation that may elicit immunity. Our knowledge of immunity to aberrant viral glycans and glycoproteins is limited, potentially due to technical limitations in identifying immunogenic glycans and glycopeptide epitopes. This work describes three different complementary methods for high-throughput screening and identification of potential immunodominant O-glycopeptide epitopes on viral envelope glycoproteins: (i) on-chip enzymatic glycosylation of scan peptides, (ii) chemical glycopeptide microarray synthesis, and (iii) a one-bead one-compound random glycopeptide library. We used herpes simplex virus type 2 (HSV-2) as a model system and identified a simple O-glycopeptide pan-epitope, (501)PPA(GalNAc)TAPG(507), on the mature gG-2 glycoprotein that was broadly recognized by IgG antibodies in HSV-2-infected individuals but not in HSV-1 infected or noninfected individuals. Serum reactivity to the extended sialyl-T glycoform was tolerated, suggesting that self glycans can participate in immune responses. The methods presented provide new insight into viral immunity and new targets for immunodiagnostic and therapeutic measures. PMID- 22491454 TI - The number of Toll-like receptor 9-agonist motifs in the adenovirus genome correlates with induction of dendritic cell maturation by adenovirus immune complexes. AB - Adenovirus serotype 5 (Ad5) vectors and specific neutralizing antibodies (NAbs) generate immune complexes (ICs) which are potent inducers of dendritic cell (DC) maturation. Here we show that ICs generated with rare Ad vector serotypes, such as Ad26 and Ad35, which are lead candidates in HIV vaccine development, are poor inducers of DC maturation and that their potency in inducing DC maturation strongly correlated with the number of Toll-like receptor 9 (TLR9)-agonist motifs present in the Ad vector's genome. In addition, we showed that antihexon but not antifiber antibodies are responsible for the induction of Ad IC-mediated DC maturation. PMID- 22491455 TI - Functions of the Epstein-Barr virus EBNA1 protein in viral reactivation and lytic infection. AB - EBNA1 is the only nuclear Epstein-Barr virus (EBV) protein expressed in both latent and lytic modes of infection. While EBNA1 is known to play several important roles in latent infection, the reason for its continued expression in lytic infection is unknown. Here we identified two roles for EBNA1 in the reactivation of latent EBV to the lytic cycle in epithelial cells. First, EBNA1 depletion in latently infected cells was shown to positively contribute to spontaneous EBV reactivation, showing that EBNA1 has a role in suppressing reactivation. Second, when the lytic cycle was induced, EBNA1 depletion decreased lytic gene expression and DNA amplification, showing that it positively contributed to lytic infection. Since we have previously shown that EBNA1 disrupts promyelocytic leukemia (PML) nuclear bodies, we investigated whether this function could account for the effects of EBNA1 on lytic infection by repeating the experiments with cells lacking PML proteins. In the absence of PML, EBNA1 did not promote lytic infection, indicating that the EBNA1-mediated PML disruption is responsible for promoting lytic infection. In keeping with this conclusion, PML silencing was found to be sufficient to induce the EBV lytic cycle. Finally, by generating cells with single PML isoforms, we showed that individual PML isoforms were sufficient to suppress EBV lytic reactivation, although PML isoform IV (PML IV) was ineffective because it was most efficiently degraded by EBNA1. Our results provide the first function for EBNA1 in lytic infection and show that EBNA1 interactions with PML IV lead to a loss of PML nuclear bodies (NBs) that promotes lytic infection. PMID- 22491456 TI - A pan-H1 anti-hemagglutinin monoclonal antibody with potent broad-spectrum efficacy in vivo. AB - Seasonal epidemics caused by antigenic variations in influenza A virus remain a public health concern and an economic burden. The isolation and characterization of broadly neutralizing anti-hemagglutinin monoclonal antibodies (MAb) have highlighted the presence of highly conserved epitopes in divergent influenza A viruses. Here, we describe the generation and characterization of a mouse monoclonal antibody designed to target the conserved regions of the hemagglutinin of influenza A H1 viruses, a subtype that has caused pandemics in the human population in both the 20th and 21st centuries. By sequentially immunizing mice with plasmid DNA encoding the hemagglutinin of antigenically different H1 influenza A viruses (A/South Carolina/1/1918, A/USSR/92/1977, and A/California/4/2009), we isolated and identified MAb 6F12. Similar to other broadly neutralizing MAb previously described, MAb 6F12 has no hemagglutination inhibition activity against influenza A viruses and targets the stalk region of hemagglutinins. As designed, it has neutralizing activity against a divergent panel of H1 viruses in vitro, representing 79 years of antigenic drift. Most notably, MAb 6F12 prevented gross weight loss against divergent H1 viruses in passive transfer experiments in mice, both in pre- and postexposure prophylaxis regimens. The broad but specific activity of MAb 6F12 highlights the potent efficacy of monoclonal antibodies directed against a single subtype of influenza A virus. PMID- 22491457 TI - Epitope insertion at the N-terminal molecular switch of the rabbit hemorrhagic disease virus T = 3 capsid protein leads to larger T = 4 capsids. AB - Viruses need only one or a few structural capsid proteins to build an infectious particle. This is possible through the extensive use of symmetry and the conformational polymorphism of the structural proteins. Using virus-like particles (VLP) from rabbit hemorrhagic disease virus (RHDV) as a model, we addressed the basis of calicivirus capsid assembly and their application in vaccine design. The RHDV capsid is based on a T=3 lattice containing 180 identical subunits (VP1). We determined the structure of RHDV VLP to 8.0-A resolution by three-dimensional cryoelectron microscopy; in addition, we used San Miguel sea lion virus (SMSV) and feline calicivirus (FCV) capsid subunit structures to establish the backbone structure of VP1 by homology modeling and flexible docking analysis. Based on the three-domain VP1 model, several insertion mutants were designed to validate the VP1 pseudoatomic model, and foreign epitopes were placed at the N- or C-terminal end, as well as in an exposed loop on the capsid surface. We selected a set of T and B cell epitopes of various lengths derived from viral and eukaryotic origins. Structural analysis of these chimeric capsids further validates the VP1 model to design new chimeras. Whereas most insertions are well tolerated, VP1 with an FCV capsid protein-neutralizing epitope at the N terminus assembled into mixtures of T=3 and larger T=4 capsids. The calicivirus capsid protein, and perhaps that of many other viruses, thus can encode polymorphism modulators that are not anticipated from the plane sequence, with important implications for understanding virus assembly and evolution. PMID- 22491458 TI - Suppression of antigen-specific T cell responses by the Kaposi's sarcoma associated herpesvirus viral OX2 protein and its cellular orthologue, CD200. AB - Regulating appropriate activation of the immune response in the healthy host despite continual immune surveillance dictates that immune responses must be either self-limiting and therefore negatively regulated following their activation or prevented from developing inappropriately. In the case of antigen specific T cells, their response is attenuated by several mechanisms, including ligation of CTLA-4 and PD-1. Through the study of the viral OX2 (vOX2) immunoregulator encoded by Kaposi's sarcoma-associated herpesvirus (KSHV), we have identified a T cell-attenuating role both for this protein and for CD200, a cellular orthologue of the viral vOX2 protein. In vitro, antigen-presenting cells (APC) expressing either native vOX2 or CD200 suppressed two functions of cognate antigen-specific T cell clones: gamma interferon (IFN-gamma) production and mobilization of CD107a, a cytolytic granule component and measure of target cell killing ability. Mechanistically, vOX2 and CD200 expression on APC suppressed the phosphorylation of ERK1/2 mitogen-activated protein kinase in responding T cells. These data provide the first evidence for a role of both KSHV vOX2 and cellular CD200 in the negative regulation of antigen-specific T cell responses. They suggest that KSHV has evolved to harness the host CD200-based mechanism of attenuation of T cell responses to facilitate virus persistence and dissemination within the infected individual. Moreover, our studies define a new paradigm in immune modulation by viruses: the provision of a negative costimulatory signal to T cells by a virus-encoded orthologue of CD200. PMID- 22491459 TI - Human papillomavirus type 16 genetic variants: phylogeny and classification based on E6 and LCR. AB - Naturally occurring genetic variants of human papillomavirus type 16 (HPV16) are common and have previously been classified into 4 major lineages; European-Asian (EAS), including the sublineages European (EUR) and Asian (As), African 1 (AFR1), African 2 (AFR2), and North-American/Asian-American (NA/AA). We aimed to improve the classification of HPV16 variant lineages by using a large resource of HPV16 positive cervical samples collected from geographically diverse populations in studies on HPV and/or cervical cancer undertaken by the International Agency for Research on Cancer. In total, we sequenced the entire E6 genes and long control regions (LCRs) of 953 HPV16 isolates from 27 different countries worldwide. Phylogenetic analyses confirmed previously described variant lineages and subclassifications. We characterized two new sublineages within each of the lineages AFR1 and AFR2 that are robustly classified using E6 and/or the LCR. We could differentiate previously identified AA1, AA2, and NA sublineages, although they could not be distinguished by E6 alone, requiring the LCR for correct phylogenetic classification. We thus provide a classification system for HPV16 genomes based on 13 and 32 phylogenetically distinguishing positions in E6 and the LCR, respectively, that distinguish nine HPV16 variant sublineages (EUR, As, AFR1a, AFR1b, AFR2a, AFR2b, NA, AA1, and AA2). Ninety-seven percent of all 953 samples fitted this classification perfectly. Other positions were frequently polymorphic within one or more lineages but did not define phylogenetic subgroups. Such a standardized classification of HPV16 variants is important for future epidemiological and biological studies of the carcinogenic potential of HPV16 variant lineages. PMID- 22491460 TI - Analysis of viral and cellular factors influencing herpesvirus-induced nuclear envelope breakdown. AB - Herpesvirus nucleocapsids are translocated from their assembly site in the nucleus to the cytosol by acquisition of a primary envelope at the inner nuclear membrane which subsequently fuses with the outer nuclear membrane. This transport through the nuclear envelope requires homologs of the conserved herpesviral pUL31 and pUL34 proteins which form the nuclear egress complex (NEC). In its absence, 1,000-fold less virus progeny is produced. We isolated a UL34-negative mutant of the alphaherpesvirus pseudorabies virus (PrV), PrV-DeltaUL34Pass, which regained replication competence after serial passages in cell culture by inducing nuclear envelope breakdown (NEBD) (B. G. Klupp, H. Granzow, and T. C. Mettenleiter, J. Virol. 85:8285-8292, 2011). To test whether this phenotype is unique, passaging experiments were repeated with a UL31 deletion mutant. After 60 passages, the resulting PrV-DeltaUL31Pass replicated similarly to wild-type PrV. Ultrastructural analyses confirmed escape from the nucleus via NEBD, indicating an inherent genetic disposition in herpesviruses. To identify the mutated viral genes responsible for this phenotype, the genome of PrV-DeltaUL34Pass was sequenced and compared to the genomes of parental PrV-Ka and PrV-DeltaUL34. Targeted sequencing of PrV-DeltaUL31Pass disclosed congruent mutations comprising genes encoding tegument proteins (pUL49, pUL46, pUL21, pUS2), envelope proteins (gI, pUS9), and protease pUL26. To investigate involvement of cellular pathways, different inhibitors of cellular kinases were tested. While induction of apoptosis or inhibition of caspases had no specific effect on the passaged mutants, roscovitine, a cyclin-dependent kinase inhibitor, and U0126, an inhibitor of MEK1/2, specifically impaired replication of the passaged mutants, indicating involvement of mitosis-related processes in herpesvirus-induced NEBD. PMID- 22491461 TI - Pathogenicity and transmission in pigs of the novel A(H3N2)v influenza virus isolated from humans and characterization of swine H3N2 viruses isolated in 2010 2011. AB - Swine influenza virus (SIV) H3N2 with triple reassorted internal genes (TRIG) has been enzootic in Unites States since 1998. Transmission of the 2009 pandemic H1N1 (pH1N1) virus to pigs in the United States was followed by reassortment with endemic SIV, resulting in reassorted viruses that include novel H3N2 genotypes (rH3N2p). Between July and December 2011, 12 cases of human infections with swine lineage H3N2 viruses containing the pandemic matrix (pM) gene [A(H3N2)v] were detected. Whole-genome analysis of H3N2 viruses isolated from pigs from 2009 to 2011 sequenced in this study and other available H3N2 sequences showed six different rH3N2p genotypes present in the U.S. swine population since 2009. The presence of the pM gene was a common feature among all rH3N2p genotypes, but no specific genotype appeared to predominate in the swine population. We compared the pathogenic, transmission, genetic, and antigenic properties of a human A(H3N2)v isolate and two swine H3N2 isolates, H3N2-TRIG and rH3N2p. Our in vivo study detected no increased virulence in A(H3N2)v or rH3N2p viruses compared to endemic H3N2-TRIG virus. Antibodies to cluster IV H3N2-TRIG and rH3N2p viruses had reduced cross-reactivity to A(H3N2)v compared to other cluster IV H3N2-TRIG and rH3N2p viruses. Genetic analysis of the hemagglutinin gene indicated that although rH3N2p and A(H3N2)v are related to cluster IV of H3N2-TRIG, some recent rH3N2p isolates appeared to be forming a separate cluster along with the human isolates of A(H3N2)v. Continued monitoring of these H3N2 viruses is necessary to evaluate the evolution and potential loss of population immunity in swine and humans. PMID- 22491462 TI - A 3-O-sulfated heparan sulfate binding peptide preferentially targets herpes simplex virus 2-infected cells. AB - Herpes simplex virus 2 (HSV-2) is the primary cause of genital herpes, which is one of the most common sexually transmitted viral infections worldwide and a major cofactor for human immunodeficiency virus infection. The lack of an effective vaccine or treatment and the emergence of drug-resistant strains highlight the need for developing new antivirals for HSV-2. Here, we demonstrate that a low-molecular-weight peptide isolated against 3-O-sulfated heparan sulfate (3-OS HS) can efficiently block HSV-2 infection. Treatment with the peptide inhibited viral entry and cell-to-cell spread both in vitro and in vivo using a mouse model of genital HSV-2 infection. Quite interestingly, the peptide showed a preferential binding to HSV-2-infected cells, with more than 200% increased binding compared to uninfected cells. Our additional results show that heparan sulfate expression is upregulated by 25% upon HSV-2 infection, which is a significant new finding that could be exploited for designing new diagnostic tests and treatment strategies against HSV-2-infected cells. In addition, our results also raise the possibility that 3-OS HS modifications within HS may be upregulated even more to accommodate for a significantly higher increase in the peptide binding to the infected cells. PMID- 22491463 TI - Determinants in the maturation of rubella virus p200 replicase polyprotein precursor. AB - Rubella virus (RUBV), a positive-strand RNA virus, replicates its RNA within membrane-associated replication complexes (RCs) in the cytoplasm of infected cells. RNA synthesis is mediated by the nonstructural proteins (NSPs) P200 and its cleavage products, P150 and P90 (N and C terminal within P200, respectively), which are processed by a protease residing at the C terminus of P150. In this study of NSP maturation, we found that early NSP localization into foci appeared to target the membranes of the endoplasmic reticulum. During maturation, P150 and P90 likely interact within the context of P200 and remain in a complex after cleavage. We found that P150-P90 interactions were blocked by mutational disruption of an alpha helix at the N terminus (amino acids [aa] 36 to 49) of P200 and that these mutations also had an effect on NSP targeting, processing, and membrane association. While the P150-P90 interaction also required residues 1700 to 1900 within P90, focus formation required the entire RNA-dependent RNA polymerase (aa 1700 to 2116). Surprisingly, the RUBV capsid protein (CP) rescued RNA synthesis by several alanine-scanning mutations in the N-terminal alpha helix, and packaged replicon assays showed that rescue could be mediated by CP in the virus particle. We hypothesize that CP rescues these mutations as well as internal deletions of the Q domain within P150 and mutations in the 5' and 3' cis acting elements in the genomic RNA by chaperoning the maturation of P200. CP's ability to properly target the otherwise aggregated plasmid-expressed P200 provides support for this hypothesis. PMID- 22491464 TI - Association of major histocompatibility complex class I haplotypes with disease progression after simian immunodeficiency virus challenge in burmese rhesus macaques. AB - Nonhuman primate AIDS models are essential for the analysis of AIDS pathogenesis and the evaluation of vaccine efficacy. Multiple studies on human immunodeficiency virus and simian immunodeficiency virus (SIV) infection have indicated the association of major histocompatibility complex class I (MHC-I) genotypes with rapid or slow AIDS progression. The accumulation of macaque groups that share not only a single MHC-I allele but also an MHC-I haplotype consisting of multiple polymorphic MHC-I loci would greatly contribute to the progress of AIDS research. Here, we investigated SIVmac239 infections in four groups of Burmese rhesus macaques sharing individual MHC-I haplotypes, referred to as A, E, B, and J. Out of 20 macaques belonging to A(+) (n = 6), E(+) (n = 6), B(+) (n = 4), and J(+) (n = 4) groups, 18 showed persistent viremia. Fifteen of them developed AIDS in 0.5 to 4 years, with the remaining three at 1 or 2 years under observation. A(+) animals, including two controllers, showed slower disease progression, whereas J(+) animals exhibited rapid progression. E(+) and B(+) animals showed intermediate plasma viral loads and survival periods. Gag-specific CD8(+) T-cell responses were efficiently induced in A(+) animals, while Nef specific CD8(+) T-cell responses were in A(+), E(+), and B(+) animals. Multiple comparisons among these groups revealed significant differences in survival periods, peripheral CD4(+) T-cell decline, and SIV-specific CD4(+) T-cell polyfunctionality in the chronic phase. This study indicates the association of MHC-I haplotypes with AIDS progression and presents an AIDS model facilitating the analysis of virus-host immune interaction. PMID- 22491466 TI - A reverse genetics approach to study feline infectious peritonitis. AB - Feline infectious peritonitis (FIP) is a lethal immunopathological disease caused by feline coronaviruses (FCoVs). Here, we describe a reverse genetics approach to study FIP by assessing the pathogenicity of recombinant type I and type II and chimeric type I/type II FCoVs. All recombinant FCoVs established productive infection in cats, and recombinant type II FCoV (strain 79-1146) induced FIP. Virus sequence analyses from FIP-diseased cats revealed that the 3c gene stop codon of strain 79-1146 has changed to restore a full-length open reading frame (ORF). PMID- 22491465 TI - A lentiviral vector-based, herpes simplex virus 1 (HSV-1) glycoprotein B vaccine affords cross-protection against HSV-1 and HSV-2 genital infections. AB - Genital herpes is caused by herpes simplex virus 1 (HSV-1) and HSV-2, and its incidence is constantly increasing in the human population. Regardless of the clinical manifestation, HSV-1 and HSV-2 infections are highly transmissible to sexual partners and enhance susceptibility to other sexually transmitted infections. An effective vaccine is not yet available. Here, HSV-1 glycoprotein B (gB1) was delivered by a feline immunodeficiency virus (FIV) vector and tested against HSV-1 and HSV-2 vaginal challenges in C57BL/6 mice. The gB1 vaccine elicited cross-neutralizing antibodies and cell-mediated responses that protected 100 and 75% animals from HSV-1- and HSV-2-associated severe disease, respectively. Two of the eight fully protected vaccinees underwent subclinical HSV-2 infection, as demonstrated by deep immunosuppression and other analyses. Finally, vaccination prevented death in 83% of the animals challenged with a HSV 2 dose that killed 78 and 100% naive and mock-vaccinated controls, respectively. Since this FIV vector can accommodate two or more HSV immunogens, this vaccine has ample potential for improvement and may become a candidate for the development of a truly effective vaccine against genital herpes. PMID- 22491467 TI - Oct4+ stem/progenitor swine lung epithelial cells are targets for influenza virus replication. AB - We isolated stem/progenitor epithelial cells from the lungs of 4- to 6-week-old pigs. The epithelial progenitor colony cells were surrounded by mesenchymal stromal cells. The progenitor epithelial colony cells expressed stem cell markers such as octamer binding transcription factor 4 (Oct4) and stage-specific embryonic antigen 1 (SSEA-1), as well as the epithelial markers pancytokeratin, cytokeratin-18, and occludin, but not mesenchymal (CD44, CD29, and CD90) and hematopoietic (CD45) markers. The colony cells had extensive self-renewal potential and had the capacity to undergo differentiation to alveolar type I- and type II-like pneumocytes. Additionally, these cells expressed sialic acid receptors and supported the active replication of influenza virus, which was accompanied by cell lysis. The lysis of progenitor epithelial cells by influenza virus may cause a marked reduction in the potential of progenitor cells for self renewal and for their ability to differentiate into specialized cells of the lung. These observations suggest the possible involvement of lung stem/progenitor cells in influenza virus infection. PMID- 22491468 TI - Residues within the C-terminal arm of the herpes simplex virus 1 glycoprotein B ectodomain contribute to its refolding during the fusion step of virus entry. AB - Herpesvirus entry into cells requires coordinated interactions among several viral glycoproteins. The final membrane fusion step of entry is executed by glycoprotein B (gB), a class III viral fusion protein that is conserved across all herpesviruses. Fusion proteins are metastable proteins that mediate fusion by inserting into a target membrane and refolding from a prefusion to postfusion conformation to bring the viral and cell membranes together. Although the structure of gB has been solved in a conformation that likely represents its postfusion form, its prefusion structure and the details of how it refolds to execute fusion are unknown. The postfusion gB structure contains a trimeric coiled-coil at its core and a long C-terminal arm within the ectodomain packs against this coil in an antiparallel manner. This coil-arm complex is reminiscent of the six-helix bundle that provides the energy for fusion in class I fusogens. To determine the role of the coil-arm complex, we individually mutated residues in the herpes simplex virus 1 gB coil-arm complex to alanine and assessed the contribution of each residue to cell-cell and virus-cell fusion. Several coil mutations resulted in a loss of cell surface expression, indicating that the coil residues are important for proper processing of gB. Three mutations in the arm region (I671A, H681A, and F683A) reduced fusion without affecting expression. Combining these three arm mutations drastically reduced the ability of gB to execute fusion; however, fusion function could be restored by adding known hyperfusogenic mutations to the arm mutant. We propose that the formation of the coil-arm complex drives the gB transition to a postfusion conformation and the coil-arm complex performs a function similar to that of the six-helix bundle in class I fusion. Furthermore, we suggest that these specific mutations in the arm may energetically favor the prefusion state of gB. PMID- 22491469 TI - Multifunctional CD4 cells expressing gamma interferon and perforin mediate protection against lethal influenza virus infection. AB - CD4 effectors generated in vitro can promote survival against a highly pathogenic influenza virus via an antibody-independent mechanism involving class II restricted, perforin-mediated cytotoxicity. However, it is not known whether CD4 cells activated during influenza virus infection can acquire cytolytic activity that contributes to protection against lethal challenge. CD4 cells isolated from the lungs of infected mice were able to confer protection against a lethal dose of H1N1 influenza virus A/Puerto Rico 8/34 (PR8). Infection of BALB/c mice with PR8 induced a multifunctional CD4 population with proliferative capacity and ability to secrete interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF alpha) in the draining lymph node (DLN) and gamma interferon (IFN-gamma) and IL 10 in the lung. IFN-gamma-deficient CD4 cells produced larger amounts of IL-17 and similar levels of TNF-alpha, IL-10, and IL-2 compared to wild-type (WT) CD4 cells. Both WT and IFN-gamma(-/-) CD4 cells exhibit influenza virus-specific cytotoxicity; however, IFN-gamma-deficient CD4 cells did not promote recovery after lethal infection as effectively as WT CD4 cells. PR8 infection induced a population of cytolytic CD4 effectors that resided in the lung but not the DLN. These cells expressed granzyme B (GrB) and required perforin to lyse peptide pulsed targets. Lethally infected mice given influenza virus-specific CD4 cells deficient in perforin showed greater weight loss and a slower time to recovery than mice given WT influenza virus-specific CD4 cells. Taken together, these data strengthen the concept that CD4 T cell effectors are broadly multifunctional with direct roles in promoting protection against lethal influenza virus infection. PMID- 22491470 TI - Role for TBC1D20 and Rab1 in hepatitis C virus replication via interaction with lipid droplet-bound nonstructural protein 5A. AB - Replication and assembly of hepatitis C virus (HCV) depend on the host's secretory and lipid-biosynthetic machinery. Viral replication occurs on endoplasmic reticulum (ER)-derived modified membranes, while viral assembly is thought to occur on lipid droplets (LDs). A physical association and coordination between the viral replication and assembly complexes are prerequisites for efficient viral production. Nonstructural protein 5A (NS5A), which localizes both to the ER and LDs, is an ideal candidate for this function. Here, the interaction of NS5A with host cell membranes and binding partners was characterized in living cells. The binding of NS5A to LDs is apparently irreversible, both in HCV infected cells and when ectopically expressed. In HCV-infected cells, NS5A fluorescence was observed around the LDs and in perinuclear structures that were incorporated into a highly immobile platform superimposed over the ER membrane. Moreover, TBC1D20 and its cognate GTPase Rab1 are recruited by NS5A to LDs. The NS5A-TBC1D20 interaction was shown to be essential for the viral life cycle. In cells, expression of the Rab1 dominant negative (Rab1DN) GTPase mutant abolished steady-state LDs. In infected cells, Rab1DN induced the elimination of NS5A from viral replication sites. Our results demonstrate the significance of the localization of NS5A to LDs and support a model whereby its interaction with TBC1D20 and Rab1 affects lipid droplet metabolism to promote the viral life cycle. PMID- 22491473 TI - Retraction: Defective heart development in hypomorphic LSD1 mice. PMID- 22491471 TI - Vicriviroc resistance decay and relative replicative fitness in HIV-1 clinical isolates under sequential drug selection pressures. AB - We previously described an HIV-1-infected individual who developed resistance to vicriviroc (VCV), an investigational CCR5 antagonist, during 28 weeks of therapy (Tsibris AM et al., J. Virol. 82:8210-8214, 2008). To investigate the decay of VCV resistance mutations, a standard clonal analysis of full-length env (gp160) was performed on plasma HIV-1 samples obtained at week 28 (the time of VCV discontinuation) and at three subsequent time points (weeks 30, 42, and 48). During 132 days, VCV-resistant HIV-1 was replaced by VCV-sensitive viruses whose V3 loop sequences differed from the dominant pretreatment forms. A deep sequencing analysis showed that the week 48 VCV-sensitive V3 loop form emerged from a preexisting viral variant. Enfuvirtide was added to the antiretroviral regimen at week 30; by week 48, enfuvirtide treatment selected for either the G36D or N43D HR-1 mutation. Growth competition experiments demonstrated that viruses incorporating the dominant week 28 VCV-resistant env were less fit than week 0 viruses in the absence of VCV but more fit than week 48 viruses. This week 48 fitness deficit persisted when G36D was corrected by either site-directed mutagenesis or week 48 gp41 domain swapping. The correction of N43D, in contrast, restored fitness relative to that of week 28, but not week 0, viruses. Virus entry kinetics correlated with observed fitness differences; the slower entry of enfuvirtide-resistant viruses corrected to wild-type rates in the presence of enfuvirtide. These findings suggest that while VCV and enfuvirtide select for resistance mutations in only one env subunit, gp120 and gp41 coevolve to maximize viral fitness under sequential drug selection pressures. PMID- 22491472 TI - Identification of a divalent metal cation binding site in herpes simplex virus 1 (HSV-1) ICP8 required for HSV replication. AB - Herpes simplex virus 1 (HSV-1) ICP8 is a single-stranded DNA-binding protein that is necessary for viral DNA replication and exhibits recombinase activity in vitro. Alignment of the HSV-1 ICP8 amino acid sequence with ICP8 homologs from other herpesviruses revealed conserved aspartic acid (D) and glutamic acid (E) residues. Amino acid residue D1087 was conserved in every ICP8 homolog analyzed, indicating that it is likely critical for ICP8 function. We took a genetic approach to investigate the functions of the conserved ICP8 D and E residues in HSV-1 replication. The E1086A D1087A mutant form of ICP8 failed to support the replication of an ICP8 mutant virus in a complementation assay. E1086A D1087A mutant ICP8 bound DNA, albeit with reduced affinity, demonstrating that the protein is not globally misfolded. This mutant form of ICP8 was also recognized by a conformation-specific antibody, further indicating that its overall structure was intact. A recombinant virus expressing E1086A D1087A mutant ICP8 was defective in viral replication, viral DNA synthesis, and late gene expression in Vero cells. A class of enzymes called DDE recombinases utilize conserved D and E residues to coordinate divalent metal cations in their active sites. We investigated whether the conserved D and E residues in ICP8 were also required for binding metal cations and found that the E1086A D1087A mutant form of ICP8 exhibited altered divalent metal binding in an in vitro iron-induced cleavage assay. These results identify a novel divalent metal cation-binding site in ICP8 that is required for ICP8 functions during viral replication. PMID- 22491474 TI - The inflammasome: a remote control for metabolic syndrome. PMID- 22491475 TI - NLRC5 regulates MHC class I antigen presentation in host defense against intracellular pathogens. AB - NOD-like receptors (NLRs) are a family of intracellular proteins that play critical roles in innate immunity against microbial infection. NLRC5, the largest member of the NLR family, has recently attracted much attention. However, in vitro studies have reported inconsistent results about the roles of NLRC5 in host defense and in regulating immune signaling pathways. The in vivo function of NLRC5 remains unknown. Here, we report that NLRC5 is a critical regulator of host defense against intracellular pathogens in vivo. NLRC5 was specifically required for the expression of genes involved in MHC class I antigen presentation. NLRC5 deficient mice showed a profound defect in the expression of MHC class I genes and a concomitant failure to activate L. monocytogenes-specific CD8(+) T cell responses, including activation, proliferation and cytotoxicity, and the mutant mice were more susceptible to the pathogen infection. NLRP3-mediated inflammasome activation was also partially impaired in NLRC5-deficient mice. However, NLRC5 was dispensable for pathogen-induced expression of NF-kappaB-dependent pro inflammatory genes as well as type I interferon genes. Thus, NLRC5 critically regulates MHC class I antigen presentation to control intracellular pathogen infection. PMID- 22491476 TI - K48-linked ubiquitination and protein degradation regulate 53BP1 recruitment at DNA damage sites. AB - Efficient DNA damage sensing and repair is crucial to preserve genomic integrity and failure to detect or repair DNA breaks can cause mutations, contributing to the formation of tumors. One key protein required for mediating DNA repair is the tumor suppressor 53BP1. Recent studies now demonstrate the crucial role of K48 linked ubiquitination and protein degradation for 53BP1 recruitment at sites of DNA damage. PMID- 22491477 TI - Bidirectional regulation between WDR83 and its natural antisense transcript DHPS in gastric cancer. AB - Natural antisense transcripts (NATs) exist ubiquitously in mammalian genomes and play roles in the regulation of gene expression. However, both the existence of bidirectional antisense RNA regulation and the possibility of protein-coding genes that function as antisense RNAs remain speculative. Here, we found that the protein-coding gene, deoxyhypusine synthase (DHPS), as the NAT of WDR83, concordantly regulated the expression of WDR83 mRNA and protein. Conversely, WDR83 also regulated DHPS by antisense pairing in a concordant manner. WDR83 and DHPS were capable of forming an RNA duplex at overlapping 3' untranslated regions and this duplex increased their mutual stability, which was required for the bidirectional regulation. As a pair of protein-coding cis-sense/antisense transcripts, WDR83 and DHPS were upregulated simultaneously and correlated positively in gastric cancer (GC), driving GC pathophysiology by promoting cell proliferation. Furthermore, the positive relationship between WDR83 and DHPS was also observed in other cancers. The bidirectional regulatory relationship between WDR83 and DHPS not only enriches our understanding of antisense regulation, but also provides a more complete understanding of their functions in tumor development. PMID- 22491478 TI - Time is of the essence: microRNAs and age-associated neurodegeneration. AB - Aging is a key risk factor in neurodegenerative disease; however, little is known about cellular pathways that mediate age-associated degeneration of the brain. The Bonini lab has identified a conserved microRNA, miR-34, that plays a neuroprotective role in the aging Drosophila brain and suggests that it functions in temporal control of gene expression. PMID- 22491480 TI - Effects of interferential therapy parameter combinations upon experimentally induced pain in pain-free participants: a randomized controlled trial. AB - BACKGROUND: Little evidence exists regarding parameter selection for hypoalgesia using interferential therapy (IFT). OBJECTIVE: This study investigated segmental and extrasegmental hypoalgesic effects of different IFT parameter combinations upon experimentally induced pressure pain threshold (PPT) in pain-free volunteers. DESIGN: The participants were randomly assigned to 6 groups: control, placebo, bipolar constant amplitude modulation frequency (AMF), bipolar sweep AMF, quadripolar constant AMF, and quadripolar sweep AMF. SETTING: The study was conducted in a university laboratory. PARTICIPANTS: One hundred eighty adults who were healthy and pain-free participated in the study. INTERVENTION: Interferential therapy was delivered to all groups at high, to-tolerance intensity and at high AMF. Stimulation to the dominant forearm was delivered for 30 minutes, with monitoring for a further 30 minutes. MEASUREMENTS: Pain pressure threshold was measured at the area of first dorsal interosseous muscle of the dominant and nondominant hands (segmental measurements) and over the tibialis anterior muscle (extrasegmental measurement) at baseline and at 10-minute intervals using a pressure algometer. Square root transformed PPT data were analyzed using repeated-measures analysis of variance. RESULTS: There was a significant change in PPT over time, but no significant between-subjects difference in segmental or extrasegmental PPT between any of the IFT groups and the placebo or control group. Thus, IFT delivered in any of these parameter combinations did not significantly affect the PPT of pain-free participants compared with the control or placebo group. LIMITATIONS: Success of blinding was not evaluated. CONCLUSIONS: This study showed that IFT delivered at high, to tolerance intensity and high AMF does not produce significant segmental and extrasegmental hypoalgesic effects on PPT in participants who were healthy compared with a control or placebo group. Further research is warranted to investigate the hypoalgesic effect of different IFT parameter combinations and to explain its possible mechanism of action. PMID- 22491481 TI - Physical therapy on the wards after early physical activity and mobility in the intensive care unit. AB - BACKGROUND: Weakness and debilitation are common following critical illness. Studies that assess whether early physical activity initiated in the intensive care unit (ICU) continues after a patient is transferred to a ward are lacking. OBJECTIVE: The purpose of this study was to assess whether physical activity and mobility initiated during ICU treatment were maintained after patients were discharged from a single ICU to a ward. DESIGN: This was a cohort study. METHODS: Consecutive patients who were diagnosed with respiratory failure and admitted to the respiratory ICU (RICU) at LDS Hospital underwent early physical activity and mobility as part of usual care. Medical data, the number of requests for a physical therapy consultation or nursing assistance with ambulation at ICU discharge, and mobility data were collected during the first 2 full days on the ward. RESULTS: Of the 72 patients who participated in the study, 65 had either a physical therapy consultation or a request for nursing assistance with ambulation at ward transfer. Activity level decreased in 40 participants (55%) on the first full ward day. Of the 61 participants who ambulated 100 ft (30.48 m) or more on the last full RICU day, 14 did not ambulate, 22 ambulated less than 100 ft, and 25 ambulated 100 ft or more on the first ward day. LIMITATIONS: Limitations include lack of data regarding why activity was not performed on the ward, lack of longitudinal follow-up to assess effects of activity, and lack of generalizability to patients not transferred to a ward or not treated in an ICU with an early mobility program. CONCLUSIONS: Despite the majority of participants having a physical therapy consultation or a request for nursing assistance with ambulation at the time of transfer to the medical ward, physical activity levels decreased in over half of participants on the first full ward day. The data suggest a need for education of ward staff regarding ICU debilitation, enhanced communication among care providers, and focus on the importance of patient centered outcomes during and following ICU treatment. PMID- 22491482 TI - Structural phase transitions induced by pressure in ammonium borohydride. AB - A combined experimental and theoretical study of hydrogen-rich ammonium borohydride (NH4BH4) subjected to pressures up to 10 GPa indicates two phase transitions, detected by synchrotron radiation powder X-ray diffraction, Raman spectroscopy and Car-Parrinello molecular dynamics calculations, at 1.5 and 3.4 GPa. The ambient pressure, face-centred cubic phase of NH4BH4 transforms into a highly disordered intermediate structure which then evolves upon increasing pressure into an orthorhombic, distorted CsCl structure. The structure of the latter phase was solved using ab initio computational techniques and from a Rietveld full pattern refinement of the powder X-ray diffraction data. PMID- 22491483 TI - The management of ingrowing toenails. PMID- 22491485 TI - Cancer treatment with patients in mind. PMID- 22491484 TI - Personalised medicine: not just in our genes. PMID- 22491486 TI - Primary care in Spain is underfunded and unattractive, says report. PMID- 22491487 TI - NHS looks set to save 20m pound as antipsychotic drug comes off patent. PMID- 22491488 TI - Whole genome sequencing fails to predict risk of most common diseases. PMID- 22491489 TI - Gas exchange and leaf aging in an evergreen oak: causes and consequences for leaf carbon balance and canopy respiration. AB - Leaves of Mediterranean evergreens experience large variations in gas exchange rates over their life span due to aging and seasonally changing environmental conditions. Accounting for the changing respiratory physiology of leaves over time will help improve estimations of leaf and whole-plant carbon balances. Here we examined seasonal variations in light-saturated net CO(2) assimilation (A(max)), dark respiration (R(d)) and the proportional change in R(d) per 10 degrees C change in temperature (Q(10) of R(d)) in previous-year (PY) and current year (CY) leaves of the broadleaved evergreen tree Quercus ilex L. A(max) and R(d) were lower in PY than in CY leaves. Differences in nitrogen between cohorts only partly explained such differences, and rates of A(max) and R(d) expressed per unit of leaf nitrogen were still significantly different between cohorts. The decline in A(max) in PY leaves did not result in the depletion of total non structural carbohydrates, whose concentration was in fact higher in PY than CY leaves. Leaf-level carbon balance modeled from gas exchange data was positive at all ages. Q(10) of R(d) did not differ significantly between leaf cohorts; however, failure to account for distinct R(d) between cohorts misestimated canopy leaf respiration by 13% across dates when scaling up leaf measurements to the canopy. In conclusion, the decline in A(max) in old leaves that are close to or exceed their mean life span does not limit the availability of carbohydrates, which are probably needed to sustain new growth, as well as R(d) and nutrient resorption during senescence. Accounting for leaf age as a source of variation of R(d) improves the estimation of foliar respiratory carbon release at the stand scale. PMID- 22491490 TI - Blunt cervical spine injury in children. AB - PURPOSE OF REVIEW: We present data from recently conducted research regarding the diagnosis of blunt cervical spine injury (CSI) in children. RECENT FINDINGS: Research in the prehospital setting to evaluate the need for cervical spine immobilization in children, regardless of clinical findings or mechanism of injury, suggests that low-risk prediction rules may be safely utilized by prehospital providers, although more data is needed. Their size, developing skeleton and unique anatomy leave children vulnerable to particular injury patterns, namely cephalad bony fractures and ligamentous and spinal cord injuries without radiographic abnormality. Low-risk clinical prediction rules have been developed but need to be further validated. For those children at higher risk of CSI, diagnostic imaging strategies are evolving, with computed tomography and MRI becoming more prominent. SUMMARY: Evidence in the management of children with CSI has expanded in recent years, but further large prospective studies are needed. We present a review of some recent developments influencing clinical practice. PMID- 22491491 TI - Recent advances in the management of congenital diaphragmatic hernia. AB - PURPOSE OF REVIEW: Congenital diaphragmatic hernia (CDH) is a rare developmental defect resulting in variable degrees of lung and pulmonary vasculature hypoplasia. Whereas many high-volume centers have recently reported increased survival rates, this has not been the collective trend. One potential explanation for this is inconsistent perinatal care among centers. RECENT FINDINGS: Significant efforts have been made to identify prenatally those fetuses that will be most severely affected. A number of radiologic features have shown promise for achieving this goal as well as identifying fetuses that may benefit from prenatal intervention. When CDH is antenatally diagnosed, early referral to a tertiary center is recommended. Centers that routinely use postnatal management protocols have demonstrated improved overall survival rates including increased survival in high-risk CDH patients. SUMMARY: As a result of advancements in perinatal care, more severely affected newborns with CDH are now surviving. These patients may experience a number of associated morbidities which affect not only their health but overall quality of life. A multidisciplinary approach to the long-term care of these patients will allow early identification and management of these morbidities. PMID- 22491492 TI - Adrenocortical function in the postoperative pediatric cardiac surgical patient. AB - PURPOSE OF REVIEW: Corticosteroids are frequently used in the postoperative care of children with congenital heart disease. This review describes the function of the adrenocortical axis in this population and the effects of corticosteroids on cardiovascular function. In addition, it examines the diagnosis of adrenal insufficiency in this population and provides an overview of recent studies on the use of steroids in treating hemodynamic instability in these children. RECENT FINDINGS: Corticosteroids improve hemodynamic parameters in children with shock following congenital heart surgery. This improvement may be due to treatment of adrenal insufficiency or from direct cardiovascular effects of corticosteroids. The diagnosis of adrenal insufficiency in this population is challenging as low cortisol levels do not consistently correlate with adverse outcomes. SUMMARY: Because of the lack of evidence delineating what the normal adrenocortical function is in this population, cortisol levels alone are not sufficient to justify treating with steroids in this population. Corticosteroids are beneficial in improving hemodynamics in children with shock after congenital heart surgery, but the adverse effects of the therapy in this context are not fully known. Prospective trials are necessary to clarify which patients may benefit from steroid therapy and to examine long-term effects of steroids. PMID- 22491493 TI - Newborn screening for cystic fibrosis. AB - PURPOSE OF REVIEW: Newborn screening for cystic fibrosis (CF) is now universal in the US and many other countries. The rapid expansion of screening has resulted in numerous publications identifying new challenges for healthcare providers. This review provides an overview of these publications and includes ideas on managing these challenges. RECENT FINDINGS: Most CF newborn screening algorithms involve DNA mutation analysis. As screening has expanded, new challenges have been identified related to carrier detection and inconclusive diagnoses. Early descriptions of infants with CF-related metabolic syndrome (CRMS) indicate that the natural history of this condition cannot be predicted. Early identification has also provided an opportunity to better understand the pathophysiology of CF. However, few studies have been conducted in infants with CF to determine optimal therapy and recommendations are largely anecdotal. SUMMARY: Newborn screening provides an opportunity to identify and begin treatment early in individuals with CF. Whereas a single, optimal approach to screening does not exist, all programs can benefit from new findings regarding sweat testing, carrier detection, early pathophysiology, and clinical outcomes. PMID- 22491494 TI - Modelling the health impact of environmentally sustainable dietary scenarios in the UK. AB - BACKGROUND/OBJECTIVES: Food is responsible for around one-fifth of all greenhouse gas (GHG) emissions from products consumed in the UK, the largest contributor of which is meat and dairy. The Committee on Climate Change have modelled the impact on GHG emissions of three dietary scenarios for food consumption in the UK. This paper models the impact of the three scenarios on mortality from cardiovascular disease and cancer. SUBJECTS/METHODS: A previously published model (DIETRON) was used. The three scenarios were parameterised by fruit and vegetables, fibre, total fat, saturated fat, monounsaturated fatty acids, polyunsaturated fatty acids, cholesterol and salt using the 2008 Family Food Survey. A Monte Carlo simulation generated 95% credible intervals. RESULTS: Scenario 1 (50% reduction in meat and dairy replaced by fruit, vegetables and cereals: 19% reduction in GHG emissions) resulted in 36,910 (30,192 to 43,592) deaths delayed or averted per year. Scenario 2 (75% reduction in cow and sheep meat replaced by pigs and poultry: 9% reduction in GHG emissions) resulted in 1999 (1739 to 2389) deaths delayed or averted. Scenario 3 (50% reduction in pigs and poultry replaced with fruit, vegetables and cereals: 3% reduction in GHG emissions) resulted in 9297 (7288 to 11,301) deaths delayed or averted. CONCLUSION: Modelled results suggest that public health and climate change dietary goals are in broad alignment with the largest results in both domains occurring when consumption of all meat and dairy products are reduced. Further work in real-life settings is needed to confirm these results. PMID- 22491497 TI - Comparison of explicitly correlated local coupled-cluster methods with various choices of virtual orbitals. AB - Explicitly correlated local coupled-cluster (LCCSD-F12) methods with pair natural orbitals (PNOs), orbital specific virtual orbitals (OSVs), and projected atomic orbitals (PAOs) are compared. In all cases pair-specific virtual subspaces (domains) are used, and the convergence of the correlation energy as a function of the domain sizes is studied. Furthermore, the performance of the methods for reaction energies of 52 reactions involving 58 small and medium sized molecules is investigated. It is demonstrated that for all choices of virtual orbitals much smaller domains are needed in the explicitly correlated methods than without the explicitly correlated terms, since the latter correct a large part of the domain error, as found previously. For PNO-LCCSD-F12 with VTZ-F12 basis sets on the average only 20 PNOs per pair are needed to obtain reaction energies with a root mean square deviation of less than 1 kJ mol(-1) from complete basis set estimates. With OSVs or PAOs at least 4 times larger domains are needed for the same accuracy. A new hybrid method that combines the advantages of the OSV and PNO methods is proposed and tested. While in the current work the different local methods are only simulated using a conventional CCSD program, the implications for low-order scaling local implementations of the various methods are discussed. PMID- 22491496 TI - Low social interactions in eating disorder patients in childhood and adulthood: a multi-centre European case control study. AB - The objective of this article was to examine lifestyle behaviours in eating disorder (ED) patients and healthy controls. A total of 801 ED patients and 727 healthy controls from five European countries completed the questions related to lifestyle behaviours of the Cross-Cultural Questionnaire (CCQ). For children, the ED sample exhibited more solitary activities (rigorously doing homework [p<0.001] and watching TV [p<0.05] and less socializing with friends [p<0.05]) than the healthy control group and this continued in adulthood. There were minimal differences across ED sub-diagnoses and various cross-cultural differences emerged. Reduced social activities may be an important risk and maintaining factor for ED symptomatology. PMID- 22491495 TI - MRI-measured pelvic bone marrow adipose tissue is inversely related to DXA measured bone mineral in younger and older adults. AB - BACKGROUND/OBJECTIVES: Recent research has shown an inverse relationship between bone marrow adipose tissue (BMAT) and bone mineral density (BMD). There is a lack of evidence at the macro-imaging level to establish whether increased BMAT is a cause or effect of bone loss. This cross-sectional study compared the BMAT and BMD relationship between a younger adult group at or approaching peak bone mass (PBM; age 18.0-39.9 years) and an older group with potential bone loss (PoBL; age 40.0-88.0 years). SUBJECTS/METHODS: Pelvic BMAT was evaluated in 560 healthy men and women with T1-weighted whole-body magnetic resonance imaging. BMD was measured using whole-body dual-energy X-ray absorptiometry. RESULTS: An inverse correlation was observed between pelvic BMAT and pelvic, total and spine BMD in the younger PBM group (r=-0.419 to -0.461, P<0.001) and in the older PoBL group (r=-0.405 to -0.500, P<0.001). After adjusting for age, sex, ethnicity, menopausal status, total body fat, skeletal muscle, subcutaneous and visceral adipose tissue, neither subject group (younger PBM vs older PoBL) nor its interaction with pelvic BMAT significantly contributed to the regression models with BMD as dependent variable and pelvic BMAT as independent variable (P=0.434 0.928). CONCLUSIONS: Our findings indicate that an inverse relationship between pelvic BMAT and BMD is present both in younger subjects who have not yet experienced bone loss and also in older subjects. These results provide support at the macro-imaging level for the hypothesis that low BMD may be a result of preferential differentiation of mesenchymal stem cells from osteoblasts to adipocytes. PMID- 22491498 TI - Exclusive rights in gastric cancer genomics. PMID- 22491499 TI - Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report. AB - Management of Helicobacter pylori infection is evolving and in this 4th edition of the Maastricht consensus report aspects related to the clinical role of H pylori were looked at again in 2010. In the 4th Maastricht/Florence Consensus Conference 44 experts from 24 countries took active part and examined key clinical aspects in three subdivided workshops: (1) Indications and contraindications for diagnosis and treatment, focusing on dyspepsia, non steroidal anti-inflammatory drugs or aspirin use, gastro-oesophageal reflux disease and extraintestinal manifestations of the infection. (2) Diagnostic tests and treatment of infection. (3) Prevention of gastric cancer and other complications. The results of the individual workshops were submitted to a final consensus voting to all participants. Recommendations are provided on the basis of the best current evidence and plausibility to guide doctors involved in the management of this infection associated with various clinical conditions. PMID- 22491500 TI - Editorial commentary: What did we learn from the emergency use authorization of peramivir in 2009? PMID- 22491501 TI - Emergency use authorization for intravenous peramivir: evaluation of safety in the treatment of hospitalized patients infected with 2009 H1N1 influenza A virus. AB - BACKGROUND: On 23 October 2009, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for intravenous peramivir, an unapproved antiviral, to treat suspected or confirmed 2009 H1N1 influenza A virus infection. Eligible hospitalized patients were unresponsive to or unable to tolerate available antivirals or lacked dependable oral or inhaled drug delivery routes. The EUA required healthcare providers to report medication errors, selected adverse events (AEs), serious AEs, and deaths to the FDA. METHODS: An FDA safety team analyzed reports submitted to the Adverse Event Reporting System (AERS) and sought follow-up in selected cases. RESULTS: The FDA received AERS reports for 344 patients (including 28 children and 3 pregnant women). Many patients were critically ill on mechanical ventilation (41%) and renal replacement therapies (19%); 38% had received oseltamivir. The most frequently reported serious AEs by MedDRA preferred term were death (15%), H1N1 influenza (8%), respiratory failure (8%), acute renal failure (7%), and acute respiratory distress syndrome (7%). Six medication errors were reported. Most deaths occurred among patients who were obese, immunosuppressed, aged >65 years, or received oseltamivir. Rash was the only treatment-emergent AE attributable to peramivir. Influenza severity, comorbidities, and concomitant medications confounded additional peramivir AE assessments. Missing clinical and laboratory data precluded evaluation of some reports. CONCLUSIONS: Many peramivir recipients under the EUA were critically ill and at risk for influenza-related complications. The safety data were insufficient to assess whether peramivir affected outcome or caused adverse reactions other than rash. Clinical trials in hospitalized patients with serious influenza infections should provide additional information. PMID- 22491502 TI - Editorial commentary: network epidemic models: assumptions and interpretations. PMID- 22491503 TI - Predicting trends in HIV-1 sexual transmission in sub-Saharan Africa through the Drug Resource Enhancement Against AIDS and Malnutrition model: antiretrovirals for 5 reduction of population infectivity, incidence and prevalence at the district level. AB - BACKGROUND: The use of antiretrovirals to reduce the incidence of human immunodeficiency virus (HIV) infection has been evaluated in mathematical models as potential strategies for curtailing the epidemic. Cohort data from the Drug Resource Enhancement Against AIDS and Malnutrition (DREAM) Program was used to generate a realistic model for the HIV epidemic in sub-Saharan Africa. METHODS: Two combined stochastic models were developed: patient and epidemic models. Models were combined using virus load as a parameter of infectivity. DREAM data that assessed patient care in Mozambique and Malawi were used to generate measures of infectivity, survival, and adherence. The Markov chain prediction model was used for the analysis of disease progression in treated and untreated patients. A partnership model was used to assess the probability that an infected individual would transmit HIV. RESULTS: Data from 26565 patients followed up from January 2002 through July 2009 were analyzed with the model; 63% of patients were female, the median age was 35 years, and the median observation time was 25 months. In the model, a 5-fold reduction in infectivity (from 1.6% to 0.3%) occurred within 3 years when triple ART was used. The annual incidence of HIV infection declined from 7% to 2% in 2 years, and the prevalence was halved, from 12% to 6%, in 11 years. Mortality in HIV-infected individuals declined by 50% in 5 years. A cost analysis demonstrated economic efficiency after 4 years. CONCLUSIONS: Our model, based on patient data, supports the hypothesis that treatment of all infected individuals translates into a drastic reduction in incident HIV infections. A targeted implementation strategy with massive population coverage is feasible in sub-Saharan Africa. PMID- 22491504 TI - Nocardia cyriacigeorgica infections attributable to unlicensed cosmetic procedures--an emerging public health problem? AB - We describe an outbreak of Nocardia cyriacigeorgica soft-tissue infections attributable to unlicensed cosmetic injections and the first report using multilocus sequence typing sequence data for determining Nocardia strain relatedness in an outbreak. All 8 cases identified had a common source exposure and required hospitalization, surgical debridement, and prolonged antimicrobial therapy. PMID- 22491505 TI - Does lipid emulsion reduce amphotericin B nephrotoxicity? A systematic review and meta-analysis. AB - This meta-analysis of 13 studies revealed that amphotericin B delivered as a locally prepared lipid emulsion or in liposomes reduced nephrotoxicity to a similar degree, by 18.4% (relative risk [RR], 0.40 [99% confidence interval, .25 .64]; n = 459) and 18.1% (RR, 0.48 [99% CI, .36-.64]); n = 1233), respectively. PMID- 22491506 TI - Peramivir use for treatment of hospitalized patients with influenza A(H1N1)pdm09 under emergency use authorization, October 2009-June 2010. AB - BACKGROUND: In response to the influenza A(H1N1)pdm09 (pH1N1) pandemic, peramivir, an investigational intravenous neuraminidase inhibitor, was made available for treatment of hospitalized patients with pH1N1 in the United States under an Emergency Use Authorization (EUA). The Centers for Disease Control and Prevention (CDC) implemented a program to manage peramivir distribution to requesting clinicians under EUA. We describe results of the CDC's peramivir program and 3 related surveys. METHODS: We analyzed data on peramivir requests made by clinicians to the CDC through an electronic request system. Three surveys were administered to enhance clinician compliance with adverse event reporting, to conduct product accountability, and to collect data on peramivir-treated patients. Descriptive analyses were performed, and 2-source capture-recapture analysis based on the 3 surveys was used to estimate the number of patients who received peramivir through the EUA. RESULTS: From 23 October 2009 to 23 June 2010, CDC received 1371 clinician requests for peramivir and delivered 2129 five day adult treatment course equivalents of peramivir to 563 hospitals. Based on survey responses, at least 1274 patients (median age, 43 years; range, 0-92 years; 49% male) received >=1 doses of peramivir (median duration, 6 days). Capture-recapture analysis yielded estimates for the potential total number of peramivir recipients ranging from 1185 (95% confidence interval [CI], 1076-1293) to 1490 (95% CI, 1321-1659). CONCLUSIONS: Approximately 1274 hospitalized patients received peramivir through EUA program during the pH1N1 pandemic. Further analyses are needed to assess the clinical effectiveness of peramivir treatment of hospitalized patients with pH1N1. PMID- 22491507 TI - Empowerment training and direct support professionals' attitudes about individuals with intellectual disabilities. AB - The purpose of this study was to determine if viewing a training video on empowerment of individuals with an intellectual and developmental disability would change the attitudes of direct support professionals (DSPs). Participants were 43 DSPs from a human service provider to individuals with intellectual and developmental disabilities. We randomly assigned them to one of two groups. A control group completed the Community Living Attitude Scale (CLAS-MR) without viewing a training video on empowerment until after CLAS-MR completion. The experimental group viewed the video on empowerment and then completed the CLAS MR. The hypothesis was supported in that DSPs who viewed the video prior to CLAS MR completion had significantly more empowering attitudes towards individuals with intellectual and developmental disabilities compared to the control group. PMID- 22491508 TI - Do less harm. PMID- 22491509 TI - Controversies section: introduction. PMID- 22491511 TI - Developments in nanostructured LiMPO4 (M = Fe, Co, Ni, Mn) composites based on three dimensional carbon architecture. AB - Nanostructured materials lie at the heart of fundamental advances in efficient energy storage and/or conversion, in which surface processes and transport kinetics play determining roles. This review describes recent developments in the synthesis and characterization of composites which consist of lithium metal phosphates (LiMPO(4), M = Fe, Co, Ni, Mn) coated on nanostructured carbon architectures (unordered and ordered carbon nanotubes, amorphous carbon, carbon foams). The major goal of this review is to highlight new progress in using different three dimensional nanostructured carbon architectures as support for the phosphate based cathode materials (e.g.: LiFePO(4), LiCoPO(4)) of high electronic conductivity to develop lithium batteries with high energy density, high rate capability and excellent cycling stability resulting from their huge surface area and short distance for mass and charge transport. PMID- 22491512 TI - Comparison of scattering and reflection SFG: a question of phase-matching. AB - We present a comparison between sum frequency scattering (SFS) and reflection mode sum frequency generation (R-SFG). We have used scattering theory to describe both scattering experiments as well as reflection mode experiments. The interfacial vibrational spectrum of nanoscopic oil droplets dispersed in water was probed with SFS as well as with R-SFG. Spectra recorded in phase-matched R SFG mode and spectra recorded with SFS from the same sample are different, which shows that different interfaces are measured. Scattering spectra at different scattering angles agree with nonlinear light scattering theory. We further present experiments with polymer films aimed at quantifying the comparative strength of R-SFG and SFS experiments. PMID- 22491513 TI - Secretory carcinoma of breast demonstrates nuclear or cytoplasmic expression in p63 immunohistochemistry. AB - The aim of this study was to evaluate the pattern of p63 expression and its implication in secretory carcinoma of the breast. Immunohistochemical staining for p63, p53, MDM2, and smooth muscle actin was performed in 7 cases of secretory carcinomas. Nuclear expression of p63 was observed in 3 cases, whereas staining against cytoplasmic and intraluminal secretory material were observed in 4 cases. p53 was expressed in 3 cases and MDM2 in 2 cases. The loss of myoepithelial cells was confirmed by immunohistochemical stain for smooth muscle actin in invasive secretory carcinomas. The pattern of expression of p63 in secretory carcinoma of the breast was revealed in nuclei or cytoplasm/secretory materials. PMID- 22491515 TI - Prevention of mutagenesis: new potential mechanisms of metformin action in neoplastic cells. AB - Several experimental and epidemiologic studies have shown that the antidiabetes drug metformin has antitumor properties. The report by Algire and colleagues in this issue of the journal (beginning on page 536) shows for the first time that metformin reduces mutagenesis induced by reactive oxygen species. This report offers new perspectives on metformin in cancer prevention and provides a new mechanism for the reduction of cancer risk in diabetic patients treated with this drug. PMID- 22491516 TI - Diagnosing Lynch syndrome: more light at the end of the tunnel. AB - Since the recognition of Lynch syndrome, which confers a high risk of colorectal, uterine, and other cancers, approaches to its diagnosis have included a family history of associated cancers and web-based algorithms. Identification of causative genes now allows a precise diagnosis, thus focusing present efforts on who should have genetic testing. Testing for cancer tissue changes can determine who should have germline genetic testing. Indeed, such tumor testing is now generally recommended for all newly diagnosed colorectal cancer cases. As reported in this issue of the journal by Yurgelun and colleagues (beginning on page 574), large colorectal adenomatous polyps (>=10 mm) from patients with Lynch syndrome exhibit findings similar to those in Lynch syndrome colorectal cancer tissues. This finding indicates that testing larger adenomas in persons at a significant risk for Lynch syndrome can now determine the need for germline genetic testing. Although further study is needed for general application, the present study justifies large polyp testing in high-risk families when cancer tissue is unavailable, albeit negative polyp tissue would not rule out Lynch syndrome, as would negative cancer tissue. PMID- 22491517 TI - Simplifying the energy balance message for breast cancer prevention. AB - Simple prevention messages based on understandable biologic principles are likely to be adopted. The long-held premise that postmenopausal obesity elevates, but premenopausal obesity reduces, risk for breast cancer is confusing to the public. Furthermore, decades of positive energy balance may be difficult to suddenly reverse at the time of the menopause. In this issue (beginning on page 583), Cecchini et al. suggest that obesity may also be a risk factor for pre-menopausal women 35 and older who have additional risk factors for breast cancer. Although the relative impact of dysregulated energy metabolism depends on many factors including age, hormonal milieu, and competing risk factors, as well as how it is measured, avoiding weight gain after age 30 is increasingly being recognized as a simple way to reduce risk of breast cancer. PMID- 22491518 TI - Genetic predisposition to chronic obstructive pulmonary disease and/or lung cancer: important considerations when evaluating risk. AB - Chronic obstructive pulmonary disease (COPD) is defined as a disease causing an airflow limitation that is not fully reversible. COPD is phenotypically complex and characterized by small-airway disease and/or emphysema that result from the interaction between host genetic susceptibility and environmental exposures. As in lung cancer, smoking exposure is the most important risk factor for the development of COPD, accounting for 80% to 90% of all cases. COPD affects an estimated 8% to 10% of the general adult population, 15% to 20% of the smoking population, and 50% to 80% of lung cancer patients (with substantial smoking histories). In prospective studies, COPD has been found to be an independent risk factor for lung cancer, conferring a three- to 10-fold increased risk of lung cancer when compared with smokers without COPD. These findings suggest that smokers have a host susceptibility to COPD alone, COPD and lung cancer (i.e., overlap), and lung cancer in the absence of COPD. This minireview focuses on important points that need to be addressed when studying genetic susceptibility factors for COPD and its complex relationship with susceptibility to lung cancer. PMID- 22491519 TI - Lung cancer risk prediction to select smokers for screening CT--letter. PMID- 22491521 TI - Phase relations and crystal structures in the system Ta-V-Ge. AB - Phase equilibria have been derived for the isothermal section of the Ta-V-Ge system at 1500 degrees C (for concentrations <45 at% Ge) on the basis of X-ray powder diffraction, EPMA and TEM analyses of argon arc melted alloys annealed in high vacuum at 1500 degrees C up to 200 hours. Four ternary phases have been identified within the isothermal section, out of which three were characterized by Rietveld refinement of X-ray powder diffraction data. tau(1)-(Ta(1 x)V(x))(5)Ge(3) (0.21 <= x <= 0.63) adopts the Mn(5)Si(3)-type and tau(2) Ta(Ta(x)V(1-x-y)Ge(y))(2), x = 0.02, y = 0.12 was found to be a MgZn(2)-type Laves phase. Detailed transmission electron microscopy (TEM) in several crystallographic directions confirmed lattice parameters and crystal symmetry of this phase and rejected the presence of any superstructure. tau(3)-Ta(9-x+y)V(4+x y-z)Ge(1+z), x = 0.32, y = 0.51, z = 0.98 crystallizes with the Nb(9)Co(4)Ge type, whereas the structure of tau(4) is not yet known. Although a MgCu(2)-type cubic Laves phase is not present in the Ta-V binary at this temperature, additions of Ge stabilize this phase in the ternary system: C15-Ta(Ta(x)V(1-x y)Ge(y))(2), x = 0.04, y = 0.05. V(11)Ge(8) (Cr(11)Ge(8) type) shows a large solubility up to (Ta(x)V(1-x))(11)Ge(8), x = 0.64 at 1500 degrees C. PMID- 22491522 TI - Manganese carbonyl fluorides: are they viable molecules? AB - The mononuclear Mn(CO)(5)X and binuclear Mn(2)(CO)(8)(MU-X)(2) manganese carbonyl halides have long been known for the halogens Cl, Br, and I. However, the corresponding manganese carbonyl fluorides (X = F) remain unknown. The structures and thermochemistry of such manganese carbonyl fluorides and their decarbonylation products have now been investigated using density functional theory. In all cases singlet structures were found to have lower energies than the corresponding triplet structures. The expected octahedral structure is predicted for Mn(CO)(5)F. Decarbonylation of Mn(CO)(5)F is predicted to give trigonal bipyramidal Mn(CO)(4)F with equatorial fluorine. Further, decarbonylation gives tetrahedral Mn(CO)(3)F. All of the binuclear Mn(2)(CO)(n)F(2) structures (n = 8, 7, 6) are predicted to have a central Mn(2)F(2) unit with two bridging F atoms, a non-bonding Mn...Mn distance of ~3.1 A, and exclusively terminal CO groups. The thermochemistry of these manganese carbonyl fluorides indicates that they are viable species. This suggests that the failure to date to synthesize the simple manganese carbonyl fluorides arises from a lack of a suitable synthetic method rather than from the instability of the desired products. PMID- 22491523 TI - Urban environment of New York City promotes growth in northern red oak seedlings. AB - Urbanization is accelerating across the globe, elevating the importance of studying urban ecology. Urban environments exhibit several factors affecting plant growth and function, including high temperatures (particularly at night), CO(2) concentrations and atmospheric nitrogen deposition. We investigated the effects of urban environments on growth in Quercus rubra L. seedlings. We grew seedlings from acorns for one season at four sites along an urban-rural transect from Central Park in New York City to the Catskill Mountains in upstate New York (difference in average maximum temperatures of 2.4 degrees C; difference in minimum temperatures of 4.6 degrees C). In addition, we grew Q. rubra seedlings in growth cabinets (GCs) mimicking the seasonal differential between the city and rural sites (based on a 5-year average). In the field experiment, we found an eightfold increase in biomass in urban-grown seedlings relative to those grown at rural sites. This difference was primarily related to changes in growth allocation. Urban-grown seedlings and seedlings grown at urban temperatures in the GCs exhibited a lower root: shoot ratio (urban ~0.8, rural/remote ~1.5), reducing below-ground carbon costs associated with construction and maintenance. These urban seedlings instead allocated more growth to leaves than did rural grown seedlings, resulting in 10-fold greater photosynthetic area but no difference in photosynthetic capacity of foliage per unit area. Seedlings grown at urban temperatures in both the field and GC experiments had higher leaf nitrogen concentrations per unit area than those grown at cooler temperatures (increases of 23% in field, 32% in GC). Lastly, we measured threefold greater (13)C enrichment of respired CO(2) (relative to substrate) in urban-grown leaves than at other sites, which may suggest greater allocation of respiratory function to growth over maintenance. It also shows that lack of differences in total R flux in response to environmental conditions may mask dramatic shifts in respiratory functioning. Overall, our findings indicating greater seedling growth and establishment at a critical regeneration phase of forest development may have important implications for the ecology of urban forests as well as the predicted growth of the terrestrial biosphere in temperate regions in response to climate change. PMID- 22491524 TI - Co-optimal distribution of leaf nitrogen and hydraulic conductance in plant canopies. AB - Leaf properties vary significantly within plant canopies, due to the strong gradient in light availability through the canopy, and the need for plants to use resources efficiently. At high light, photosynthesis is maximized when leaves have a high nitrogen content and water supply, whereas at low light leaves have a lower requirement for both nitrogen and water. Studies of the distribution of leaf nitrogen (N) within canopies have shown that, if water supply is ignored, the optimal distribution is that where N is proportional to light, but that the gradient of N in real canopies is shallower than the optimal distribution. We extend this work by considering the optimal co-allocation of nitrogen and water supply within plant canopies. We developed a simple 'toy' two-leaf canopy model and optimized the distribution of N and hydraulic conductance (K) between the two leaves. We asked whether hydraulic constraints to water supply can explain shallow N gradients in canopies. We found that the optimal N distribution within plant canopies is proportional to the light distribution only if hydraulic conductance, K, is also optimally distributed. The optimal distribution of K is that where K and N are both proportional to incident light, such that optimal K is highest to the upper canopy. If the plant is constrained in its ability to construct higher K to sun-exposed leaves, the optimal N distribution does not follow the gradient in light within canopies, but instead follows a shallower gradient. We therefore hypothesize that measured deviations from the predicted optimal distribution of N could be explained by constraints on the distribution of K within canopies. Further empirical research is required on the extent to which plants can construct optimal K distributions, and whether shallow within canopy N distributions can be explained by sub-optimal K distributions. PMID- 22491525 TI - PbS quantum dot sensitized anatase TiO2 nanocorals for quantum dot-sensitized solar cell applications. AB - Lead sulphide (PbS) quantum dot (QD) sensitized anatase TiO(2) nanocorals (TNC) were synthesized by SILAR and hydrothermal techniques. The TNC, PbS and PbS-TNC samples were characterized by optical absorption, XRD, FT-IR, FESEM and XPS. The results show that PbS QDs are coated on the TNCs, the optical absorption is found to be enhanced and the band edge is shifted to ~693 nm as compared with plain TNCs at 340 nm. The PbS-TNC sample exhibits an improved photoelectrochemical performance with a maximum short circuit current (J(sc)) of 3.84 mA cm(-2). The photocurrent density was found to be enhanced 2 fold, as compared with those of the bare PbS photoelectrode. The total power conversion efficiency of the PbS-TNC electrodes is 1.23%. PMID- 22491526 TI - Theoretical insight into the aggregation induced emission phenomena of diphenyldibenzofulvene: a nonadiabatic molecular dynamics study. AB - The diphenyldibenzofulvene (DPDBF) molecule appears in two forms: ring open and ring closed. The former fluoresces weakly in solution, but it becomes strongly emissive in the solid phase, exhibiting an exotic aggregation-induced emission phenomenon. The latter presents a normal aggregation quenching phenomenon, as is expected. We implement nonadiabatic molecular dynamics based on the combination of time-dependent Kohn-Sham (TDKS) and density functional tight binding (DFTB) methods with Tully's fewest switches surface hopping algorithm to investigate the excited state nonradiative decay processes. From the analysis of the nonadiabatic coupling vectors, it is found that the low frequency twisting motion in the ring open DPDBF couples strongly with the electronic excitation and dissipates the energy efficiently. While in the closed form, such motion is blocked by a chemical bond. This leads to the nonradiative decay rate for the open form (1.4 ps) becoming much faster than the closed form (24.5 ps). It is expected that, in the solid state, the low frequency motion of the open form will be hindered and the energy dissipation pathway by nonradiative decay will be slowed, presenting a remarkable aggregation enhanced emission phenomenon. PMID- 22491529 TI - On surgical disruption: rating, expected operative time or actual wasted time- some comments on Gillepsie et al (2012). PMID- 22491528 TI - Combining process indicators to evaluate quality of care for surgical patients with colorectal cancer: are scores consistent with short-term outcome? AB - OBJECTIVE: To determine if composite measures based on process indicators are consistent with short-term outcome indicators in surgical colorectal cancer care. DESIGN: Longitudinal analysis of consistency between composite measures based on process indicators and outcome indicators for 85 Dutch hospitals. SETTING: The Dutch Surgical Colorectal Audit database, the Netherlands. PARTICIPANTS: 4732 elective patients with colon carcinoma and 2239 with rectum carcinoma treated in 85 hospitals were included in the analyses. MAIN OUTCOME MEASURES: All available process indicators were aggregated into five different composite measures. The association of the different composite measures with risk-adjusted postoperative mortality and morbidity was analysed at the patient and hospital level. RESULTS: At the patient level, only one of the composite measures was negatively associated with morbidity for rectum carcinoma. At the hospital level, a strong negative association was found between composite measures and hospital mortality and morbidity rates for rectum carcinoma (p<0.05), and hospital morbidity rates for colon carcinoma. CONCLUSIONS: For individual patients, a high score on the composite measures based on process indicators is not associated with better short-term outcome. However, at the hospital level, a good score on the composite measures based on process indicators was consistent with more favourable risk adjusted short-term outcome rates. PMID- 22491530 TI - Checklists, safety, my culture and me. AB - The world is not flat. Hierarchy is a fact of life in society and in healthcare institutions. National, specialty-specific and institutional cultures may play an important role in shaping today's patient-safety climate. The influence of power distance on safety interventions is under-studied. Checklists may make power distance-hampered negotiations easier by providing a standardised aviation-like framework for communications and by democratising the environment. By using surveys and simulation, we might discover patterns of potentially hidden yet problematic interactions that might foster maintenance of the error swamp. We need to understand how people interact as members of a group as this is crucial for the development of generalisable safety interventions. PMID- 22491531 TI - Findings from a national improvement collaborative: are improvements sustained? AB - BACKGROUND: Despite considerable efforts to improve healthcare quality and patient safety, broad measures of patient outcomes show little improvement. Many factors, including limited programme evaluations and understanding of whether quality improvement (QI) efforts are sustained, potentially contribute to the lack of widespread improvements in quality. This study examines whether hospitals participating in a Veterans Health Affairs QI collaborative have made and then sustained improvements. METHODS: Separate patient-level risk-adjusted time-series models for two primary outcomes (hospital length of stay (LOS) and rate of discharges before noon) as well as three secondary outcomes (30-day all-cause hospital readmission, in-hospital mortality and 30-day mortality). The models considered 2 years of pre-intervention data, 1 year of data to measure improvements and then 2 years of post-intervention data to see whether improvements were sustained. RESULTS: Among 130 Veterans Affairs hospitals, 35% and 46% exhibited improvements beyond baseline trends on LOS and discharges before noon, respectively. 60% of improving LOS hospitals exhibited sustained improvements, but only 32% for discharges by noon. Additional subgroup analyses by hospital size and region found a similar performance across most groups. CONCLUSIONS: This quasi-experimental evaluation found lower rates of improvements than normally reported in studies of QI collaboratives. The most striking observation was that a majority of hospitals increased their rates of discharges before noon, but after completing the collaborative their performance declined. Future work needs to qualitatively and quantitatively assess what organisational features distinguish those hospitals that can improve and sustain quality. PMID- 22491533 TI - In vivo diagnosis of melanoma and nonmelanoma skin cancer using oblique incidence diffuse reflectance spectrometry. AB - Early detection and treatment of skin cancer can significantly improve patient outcome. However, present standards for diagnosis require biopsy and histopathologic examinations that are relatively invasive, expensive, and difficult for patients with many early-stage lesions. Here, we show an oblique incidence diffuse reflectance spectroscopic (OIDRS) system that can be used for rapid skin cancer detection in vivo. This system was tested under clinical conditions by obtaining spectra from pigmented and nonpigmented skin lesions, including melanomas, differently staged dysplastic nevi, and common nevi that were validated by standard pathohistologic criteria. For diagnosis of pigmented melanoma, the data obtained achieved 90% sensitivity and specificity for a blinded test set. In a second analysis, we showed that this spectroscopy system can also differentiate nonpigmented basal cell or squamous cell carcinomas from noncancerous skin abnormalities, such as actinic keratoses and seborrheic keratoses, achieving 92% sensitivity and specificity. Taken together, our findings establish how OIDRS can be used to more rapidly and easily diagnose skin cancer in an accurate and automated manner in the clinic. PMID- 22491534 TI - The impact of occupation on child health in a Palestinian refugee camp. AB - This article focuses on child health in the Palestinian refugee camp of Dheisheh in the West Bank region of the Occupied Palestinian Territories. Thirty in-depth interviews were carried out with parents to determine their perceptions of their children's health. The questions related to physical, mental and social well being, access to health facilities, factors that were likely to hinder health and measures that could be implemented to improve child health. The study was carried out prior to and during the Gaza War in December 2008 that resulted in the deaths of 1380 Palestinians including 431 children and 112 women [1]. The effects of occupation, conflict and being a refugee had a detrimental impact on perceptions of health. Interviewees revealed that their perceptions of their children's health were determined by the camp's conditions, the current economic climate, past and current political conflict and financial and social restrictions. The understanding of being healthy incorporated physical and mental health as well as social well-being. As a result, 70% of interviewees deemed that their children were not in good health. This finding accelerated to 100% after the Gaza War, showing the negative effect war has on health perceptions. Findings showed that perceptions of physical health are very much interlinked with mental well-being and parents' perceptions of their children's health, and are closely related to their state of mental health. Consequently, a clear correlation can be discerned between the ongoing occupation and its detrimental effects on mental health. Therapeutic and preventive health programmes such as child therapy and stress management that have already been implemented by the Gaza Community Mental Health Programme would be highly beneficial to both children and adults in Dheisheh refugee camp. PMID- 22491535 TI - The Journal's website: home tweet home. PMID- 22491536 TI - Effects on mortality, treatment, and time management as a result of routine use of total body computed tomography in blunt high-energy trauma patients. AB - BACKGROUND: Currently, total body computed tomography (TBCT) is rapidly implemented in the evaluation of trauma patients. With this review, we aim to evaluate the clinical implications-mortality, change in treatment, and time management-of the routine use of TBCT in adult blunt high-energy trauma patients compared with a conservative approach with the use of conventional radiography, ultrasound, and selective computed tomography. METHODS: A literature search for original studies on TBCT in blunt high-energy trauma patients was performed. Two independent observers included studies concerning mortality, change of treatment, and/or time management as outcome measures. For each article, relevant data were extracted and analyzed. In addition, the quality according to the Oxford levels of evidence was assessed. RESULTS: From 183 articles initially identified, the observers included nine original studies in consensus. One of three studies described a significant difference in mortality; four described a change of treatment in 2% to 27% of patients because of the use of TBCT. Five studies found a gain in time with the use of immediate routine TBCT. Eight studies scored a level of evidence of 2b and one of 3b. CONCLUSION: Current literature has predominantly suboptimal design to prove terminally that the routine use of TBCT results in improved survival of blunt high-energy trauma patients. TBCT can give a change of treatment and improves time intervals in the emergency department as compared with its selective use. PMID- 22491537 TI - Necrotizing fasciitis: classification, diagnosis, and management. AB - Necrotizing fasciitis (NF), a life-threatening rare infection of the soft tissues, is a medical and surgical emergency. It is characterized by subtle, rapid onset of spreading inflammation and necrosis starting from the fascia, muscles, and subcutaneous fat, with subsequent necrosis of the overlying skin. Once suspected, immediate and extensive radical debridement of necrotic tissues is mandatory. Appropriate antibiotics and intensive general support avoid massive systemic diffusion of the infective process and are the key for successful treatment. However, early diagnosis is missed or delayed in 85% to 100% of cases in large published series: because of the lack of specific clinical features in the initial stage of the disease, it is often underestimated or confused with cellulitis or abscess. Mortality rates are still high and have shown no tendency to decrease in the last 100 years. Unfortunately, the prevalence of the disease is such that physicians rarely become sufficiently confident with NF to be able to proceed with rapid diagnosis and management. This review covers the literature published in MEDLINE in the period 1970 to December 31, 2010. Particular attention is given to the clinical and laboratory elements to be considered for diagnosis. A wide variety of diagnostic tools have been described to facilitate and hasten the diagnosis of NF, but the most important tool for early diagnosis still remains a high index of clinical suspicion. PMID- 22491538 TI - Impact of prehospital mode of transport after severe injury: a multicenter evaluation from the Resuscitation Outcomes Consortium. AB - BACKGROUND: There is ongoing controversy about the relative effectiveness of air medical versus ground transportation for severely injured patients. In some systems, air medical crews may provide a higher level of care but may require longer transport times. We sought to evaluate the impact of mode of transport on outcome based on analysis of data from two randomized trials of prehospital hypertonic resuscitation. METHODS: Injured patients were enrolled based on prehospital evidence of hypovolemic shock (systolic blood pressure <=70 mm Hg or systolic blood pressure = 71-90 mm Hg with heart rate >=108 bpm) or severe traumatic brain injury (TBI; Glasgow Coma Scale score <=8). Patient demographics, injury severity, and physiology were compared based on mode of transport. Multivariate logistic regression was used to determine the impact of mode of transport on 24-hour and 28-day survival for all patients and 6-month extended Glasgow Outcome Scale for patients with TBI, adjusting for differences in injury severity. RESULTS: Included were 2,049 patients, of which 703 (34%) were transported by air. Patients transported by air were more severely injured (mean Injury Severity Score, 30.3 vs. 22.8; p < 0.001), more likely to be in the TBI cohort (70% vs. 55.4%; p < 0.001), and more likely blunt mechanism (94.0% vs. 78.1%; p < 0.001). Patients transported by air had higher rates of prehospital intubation (81% vs. 36%; p < 0.001), received more intravenous fluids (mean 1.3 L vs. 0.8 L; p < 0.001), and had longer prehospital times (mean 76.1 minutes vs. 43.5 minutes; p < 0.001). Adjusted analysis revealed no significant impact of mode of transport on survival or 6-month neurologic outcome (air transport-28-day survival: odds ratio, 1.11; 95% confidence interval, 0.82-1.51; 6-month extended Glasgow Outcome Scale score <=4: odds ratio, 0.94; 95% confidence interval, 0.68 1.31). CONCLUSION: There was no difference in the adjusted clinical outcome according to mode of transport. However, air medical transported more severely injured patients with more advanced life support procedures and longer prehospital time. LEVEL OF EVIDENCE: III. PMID- 22491539 TI - Evaluation of multidetector computed tomography for penetrating neck injury: a prospective multicenter study. AB - BACKGROUND: The purpose of this prospective multicenter study was to evaluate a clinical protocol integrating multidetector computed tomographic angiography (MDCTA) as the initial screening examination for the work-up of penetrating neck injury. METHODS: All penetrating neck injuries assessed at two Level I trauma centers (January 2009-July 2011) prospectively underwent a structured clinical examination. Those with hard signs of injury (active bleed, instability, expanding/pulsatile hematoma, bruit/thrill, hemoptysis, hematemesis, and air bubbling) underwent exploration, those who were asymptomatic were observed. The remainder, with soft signs underwent MDCTA. Sensitivity and specificity were tested against an aggregate gold standard of operative intervention, clinical follow-up, and when obtained, conventional angiography, bronchoscopy, esophagogram, and esophagoscopy. RESULTS: Four hundred fifty-three penetrating neck injuries were evaluated. Hard signs of vascular or aerodigestive tract injury were observed in 8.6% with an 89.7% incidence of clinically significant injury. 41.7% had no signs of injury and were observed with no missed injuries (follow-up, 2.6 days +/- 1.1 days [1-58 days]). The remaining 225 (49.7%) underwent MDCTA (stab wound, 61.3%; gunshot wound, 37.8%; shotgun, 0.9%). The external wounds were in zone II (38.2%), multiple (28.9%), zone I (16.9%), and zone III (16.0%). Twenty-eight injuries were found in 22 patients (5 internal jugular-V, 2 external jugular-V, 1 vertebral-A, 7 common carotid-A, 2 internal carotid-A, 3 external carotid-A, 2 subclavian-A, 3 esophagus, and 3 tracheas). Five patients had false-positive findings (2 vascular and 3 aerodigestive tract). The 194 negative studies (follow-up, 5.5 days +/- 7.5 days [1-27 days]) had no delayed diagnosis of injury. MDCTA was nondiagnostic in four patients (1.8%), secondary to artifact. One of these had a vertebral-A injury diagnosed at angiography. MDCTA achieved 100% sensitivity and 97.5% specificity in detecting all clinically significant injuries. CONCLUSION: In the initial evaluation of patients who have sustained penetrating neck trauma, physical examination can safely reduce unnecessary imaging. If imaging is required, MDCTA is a highly sensitive and specific screening modality for evaluating the vascular and aerodigestive structures in the neck. LEVEL OF EVIDENCE: II, prospective study. PMID- 22491540 TI - Barriers to compliance with evidence-based care in trauma. AB - BACKGROUND: We have preciously demonstrated that trauma patients receive less than two-thirds of the care recommended by evidence-based medicine. The purpose of this study was to identify patients least likely to receive optimal care. METHODS: Records of a random sample of 774 patients admitted to a Level I trauma center (2006-2008) with moderate to severe injuries (Abbreviated Injury Scale score >=3) were reviewed for compliance with 25 trauma-specific processes of care (T-POC) endorsed by Advanced Trauma Life Support, Eastern Association for the Surgery of Trauma, the Brain Trauma Foundation, Surgical Care Improvement Project, and the Glue Grant Consortium based on evidence or consensus. These encompassed all aspects of trauma care, including initial evaluation, resuscitation, operative care, critical care, rehabilitation, and injury prevention. Multivariate logistic regression was used to identify patients likely to receive recommended care. RESULTS: Study patients were eligible for a total of 2,603 T-POC, of which only 1,515 (58%) were provided to the patient. Compliance was highest for T-POC involving resuscitation (83%) and was lowest for neurosurgical interventions (17%). Increasing severity of head injuries was associated with lower compliance, while intensive care unit stay was associated with higher compliance. There was no relationship between compliance and patient demographics, socioeconomic status, overall injury severity, or daily volume of trauma admissions. CONCLUSION: Little over half of recommended care was delivered to trauma patients with moderate to severe injuries. Patients with increasing severity of traumatic brain injuries were least likely to receive optimal care. However, differences among patient subgroups are small in relation to the overall gap between observed and recommended care. LEVEL OF EVIDENCE: II. PMID- 22491541 TI - The forgotten trauma patient: outcomes for injured patients evaluated by emergency medical services but not transported to the hospital. AB - BACKGROUND: Injured patients who are not transported by an ambulance to the hospital are often not included in trauma registries. The outcomes of these patients have until now been unknown. Understanding what happens to nontransports is necessary to better understand triage validity, patient outcomes, and costs associated with injury. We hypothesized that a subset of patients who were not transported from the scene would later present for evaluation and that these patients would have a nonzero mortality rate. METHODS: This is a population based, retrospective cohort study of injured adults and children for three counties in California from 2006 to 2008. Prehospital data for injured patients for whom an ambulance was dispatched were probabilistically linked to trauma registry data from four trauma centers, state-level discharge data, emergency department records, and death files (1-year mortality). RESULTS: A total of 69,413 injured persons who were evaluated at the scene by emergency medical services were included in the analysis. Of them, 5,865 (8.5%) were not transported. Of those not transported, 1,616 (28%) were later seen in an emergency department and discharged and 92 (2%) were admitted. Seven (0.2%) patients later died. CONCLUSION: Patients evaluated by emergency medical services, but not initially transported from the field after injury, often present later to the hospital. The mortality rate in this population was not zero, and these patients may represent preventable deaths. LEVEL OF EVIDENCE: III, therapeutic study. PMID- 22491542 TI - The use of temporary abdominal closure in low-risk trauma patients: helpful or harmful? AB - BACKGROUND: Temporary abdominal closure (TAC) has become a widely used technique in severely injured patients. However, there is growing concern that TAC is being overutilized. We sought to identify less severely injured patients who underwent TAC and to compare their outcomes with patients managed with a single-stage laparotomy (SSL). METHODS: This is a analysis of all trauma patients who underwent immediate laparotomy from 2005 to 2009. Risk modeling identified TAC patients who met all low-risk criteria: systolic blood pressure >90, no severe head injury, no combined solid + hollow viscus injury, or vascular injury. The low-risk cohort (LR-TAC) was compared with a matched similarly injured cohort managed with SSL using univariate and multivariate regression analysis. RESULTS: Among the 282 patients undergoing TAC, 62 (22%) met low-risk criteria and were included in the LR-TAC group. There were 566 patients identified in the SSL group. There was no significant difference between groups for age, mechanism, Injury Severity Scores, associated injuries, base deficit, temperature, blood transfusion, solid organ injury, or bowel resection. The LR-TAC group had more hospital and ventilator days and increased complications rates (all p < 0.05). This included a higher rate of bowel ischemia/perforation with LR-TAC (7% vs. 0.7%). The use of TAC in the low-risk group was independently associated with increased complications (odds ratio 3.0, p = 0.01) and prolonged hospital stays (odds ratio 9.6, p < 0.01). CONCLUSIONS: TAC was associated with increased morbidity and resource utilization when applied to less severely injured patients. Further study is indicated to clarify populations that may be harmed or benefitted by TAC. LEVEL OF EVIDENCE: : III, therapeutic study. PMID- 22491543 TI - Who will cover the cost of undocumented immigrant trauma care? AB - BACKGROUND: Health care reform under the "Patient Protection and Affordable Care Act" (PPACA) will lead to changes in reimbursement. Although this legislation provides a mechanism for uninsured Americans to obtain coverage, it excludes undocumented immigrants (UDI). Reimbursement for UDIs comes from the disproportionate share hospital (DSH) program and was previously supported by Section-1011 of the 2003 Medicare Modernization Act (S1011). The PPACA details a cut of DSH funds starting in 2014. This could impose a significant financial burden on trauma centers. METHODS: From May 2005 to May 2008, we retrospectively reviewed all trauma-related emergency room visits by UDIs. We quantified charges for three entities: emergency department physicians, trauma surgeons, and the hospital. We applied our average institutional collection rate to these charges and compared these projected collections with the actual collections. RESULTS: Over a three-year period, we identified 1,325 trauma UDIs. The financial records revealed a projected emergency department physicians collection of $452,686, a projected trauma surgeons collection of $1.2 million, and a projected hospital collection of $6.9 million (total $8.6 million). Actual funding from S1011 provided $1.7 million and DSH provided $1.9 million (total $3.6 million). Texas State Funding and UDI self-payment contributed $611,082. Overall, our institution had a reimbursement discrepancy of $4.3 million with DSH/S1011 assistance. This increased to $6.0 million after the termination of S1011 and may increase to $7.9 million under PPACA. CONCLUSION: These figures underestimate the total cost of UDI trauma care as it only includes three entities. Our data represent a fraction of national figures. Failure to address these issues could result in ongoing financial problems for trauma centers. LEVEL OF EVIDENCE: II, economic and decision analysis. PMID- 22491544 TI - Host susceptibility to gram-negative pneumonia after lung contusion. AB - BACKGROUND: Lung contusion (LC) induces inflammation with high local concentrations of proinflammatory mediators stimulating chemotaxis and activation of neutrophils. LC is also a risk factor for development of pneumonia; however, the reason for this increased susceptibility is not clearly identified. We hypothesize that LC creates acute changes in the host pulmonary innate immune system that leads to vulnerability from a "second" hit bacterial infection. METHODS: Female C57Bl/6 mice underwent LC injury at time -6 hours. At 0 hours, these mice were inoculated intratracheally with 1,000 colony forming unit (CFU) of Klebsiella pneumoniae (LC+Pneu) or vehicle (LC). Control animals underwent a sham LC injury followed by pneumonia (Sham+Pneu). Bronchoalveolar lavage (BAL) fluid and lung tissue specimens were collected. Lung bacteria levels were quantified by serial dilution, plating, and counting CFUs. Cytokine levels were assayed by ELISA. Cell type identification and quantification was performed using flow cytometry. RESULTS: Survival at 72 hours was markedly different for the LC, Sham+Pneu, and LC+Pneu groups (100%, 80%, 20%, p < 0.05 Sham+Pneu vs. LC+Pneu). LC+Pneu animals had decreased pulmonary bacterial clearance at 24 hours compared with the Sham+Pneu group (4 * 10(7) vs. 8 * 10(6) CFUs, p < 0.05). BAL levels of IL-1beta, IL-6, and keratinocyte chemoattractant were all significantly elevated in LC+Pneu mice compared with the Sham+Pneu group at 24 hours. Conversely, the Sham+Pneu mice had increased levels of macrophage inflammatory protein-2, total cells, macrophages, and neutrophils in BAL compared with the LC+Pneu group at 24 hours. LC+Pneu animals demonstrated changes in macrophage apoptosis and necrosis in BAL samples obtained 2 hours after induction of pneumonia when compared with the Sham+Pneu group. Both Sham+Pneu and LC+Pneu animals demonstrated an increase in the level of IL-10 in BAL fluid compared with LC animals. CONCLUSION: Acute inflammation after LC acts to modulate the presence of inflammatory cells necessary to combat gram-negative bacteria. This results in decreased bacterial clearance and increased mortality from pneumonia. PMID- 22491545 TI - Lessons learned from airway pressure release ventilation. AB - BACKGROUND: The aim of this article is to review a single institution's experience with airway pressure release ventilation (APRV) with respect to safety, complications, and efficacy at correcting hypercarbia and hypoxemia. METHODS: Patients transitioned from either volume- or pressure-targeted ventilation to APRV in a university hospital surgical intensive care unit were retrospectively reviewed. Patients whose ventilator strategy started with APRV were excluded. Abstracted data included age, sex, diagnosis, ventilation parameters, indication for altering the ventilator strategy, laboratory values, and ventilator-associated complications. Data before and after transitioning to APRV were compared using a two-tailed unpaired t test or chi2 test as appropriate; significance assumed for p <= 0.05. RESULTS: Patient mix (n = 38) was 43% trauma, 32% sepsis, 8% cardiac surgery, 12% vascular surgery, and 5% other. Transitioning to APRV was undertaken most often for hypoxemia (88%) and less frequently for hypercarbia (12%). The mean time to correct hypoxemia (SA(O2) >92%) was 7 minutes +/- 4 minutes, while the mean time to correct P(CO2) (P(CO2) <=40 mm Hg) was 42 minutes +/- 7 minutes. The mean time to maximal CO2 clearance was 66 minutes +/- 12 minutes. The mean minute ventilation decreased on APRV by 3.3 L/min +/- 0.9 L/min but achieved superior CO2 clearance and oxygenation. The mean time to FIO2 <=0.6 was 5.2 hours +/- 0.9 hours. Four of the 38 patients developed a pneumothorax. Ninety-seven percent of patients on APRV who were transported out of the intensive care unit using bag-valve ventilation (with appropriate positive end-expiratory pressure valve settings) with P(high) >=20 cm H2O developed hypoxemia within 5 minutes. Hundred percent of patients with a P(high) <=20 cm H2O were safely hand ventilated during transport without developing hypoxemia. CONCLUSIONS: APRV is a safe mode of ventilation for hypoxemic or hypercarbic respiratory failure. Improvements in PO2 and PCO2 are achieved at lower minute ventilations than with volume- or pressure-targeted modes. LEVEL OF EVIDENCE: III. PMID- 22491546 TI - Predictors of acute posttraumatic stress disorder symptoms following civilian trauma: highest incidence and severity of symptoms after assault. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with significant morbidity following injury. The incidence and risk factors for PTSD are not well described in the civilian trauma population. We proposed to screen all trauma patients in the outpatient trauma clinic for acute PTSD symptoms and identify risk factors for PTSD. METHODS: We prospectively screened 1,386 injured patients who presented for follow-up in trauma clinic (January 2009 to September 2010) using an established PTSD screening test (PTSD Checklist-Civilian, PCL-C). A PCL C score of >=35, with a known sensitivity of >85% for PTSD, was considered screen positive (PCL-C-POS). Backward stepwise logistic regression was used to determine independent risk factors for PCL-C-POS. RESULTS: Over 25% of trauma clinic patients met the threshold for positive PTSD screen (PCL-C-POS). The highest incidence (43%) was in patients who sustained assault (blunt or penetrating). Regression analysis revealed that age <55 years, female gender, motor vehicle collision, and assaultive mechanism (blunt or penetrating, excluding self inflicted or accidental injury) were independent predictors of PCL-C-POS status. As the severity of symptoms increased (higher PCL-C scores), the risk associated with assaultive mechanism significantly increased in a dose-response fashion (p < 0.05). CONCLUSIONS: This study confirms the high incidence of acute PTSD symptoms in trauma patients and supports the feasibility of PTSD screening in the outpatient trauma clinic. Among all mechanisms of injury, patients who sustain interpersonal violence are at the highest risk of developing acute PTSD symptoms. These results suggest that PTSD screening in outpatient trauma clinic may allow early detection and referral of patients with PTSD. LEVEL OF EVIDENCE: II. PMID- 22491547 TI - Cervical spine injuries and helmet laws: a population-based study. AB - BACKGROUND: To assess the incidence of cervical spine (C-spine) injuries in patients admitted after motorcycle crash in states with mandatory helmet laws (MHL) compared with states without helmet laws or selective helmet laws. METHODS: The Nationwide Inpatient Sample from the Healthcare and Utilization Project for the year 2008 was analyzed. International Classification of Diseases and Health Related Problems, Ninth Edition codes were used to identify patients with a diagnosis of motorcycle crash and C-spine injuries. National estimates were generated based on weighted analysis of the data. Outcome variables investigated were as follows: length of stay (LOS), in-hospital mortality, hospital teaching status, and discharge disposition. States were then stratified into states with MHL or selective helmet laws. RESULTS: A total of 30,117 discharges were identified. Of these, 2,041 (6.7%) patients had a C-spine injury. Patients in MHL states had a lower incidence of C-spine injuries (5.6 vs. 6.4%; p = 0.003) and less in-hospital mortality (1.8 vs. 2.6%; p = 0.0001). Patients older than 55 years were less likely to be discharged home (57.5% vs. 72.5%; p = 0.0001), more likely to die in-hospital (3.0% vs. 2.1%; p = 0.0001), and more likely to have a hospital LOS more than 21 days (7.7% vs. 6.2%; p = 0.0001). CONCLUSION: Patients admitted to the hospital in states with MHLs have decreased rate of C-spine injuries than those patients admitted in states with more flexible helmet laws. Patients older than 55 years are more likely to die in the hospital, have a prolonged LOS, and require services after discharge. LEVEL OF EVIDENCE: III. PMID- 22491548 TI - Expression of HMGB1 and RAGE in rat and human brains after traumatic brain injury. AB - BACKGROUND: Increasing evidence suggests that an inflammatory reaction contributes to the secondary brain injury that plays a critical role in the clinical outcome of patients with traumatic brain injury (TBI). Recently, high mobility group box 1 (HMGB1) has been identified as a key cytokine in the inflammatory reaction and may represent a new target for the treatment of TBI. However, the expression of HMGB1 during this injury process has not yet been studied. METHODS: In this study, the levels of both HMGB1 and receptor for advanced glycation end products (RAGE) in the rat brain were analyzed by Western blot at different time points after TBI. Immunohistochemistry was also performed to examine the expression pattern of HMGB1 and RAGE in both the rat and the human brain after TBI. RESULTS: In the rat brain, HMGB1 levels significantly declined below the basal level at 6 hours after TBI and then gradually returned to the basal level 2 days later. RAGE expression increased 6 hours after TBI and reached its peak after 1 day; this level then slowly decreased but remained higher than the sham-injury group until 6 days after TBI. In both rat and human brains, HMGB1 either disappeared or was translocated from the nucleus to the cytoplasm at early stages after TBI and then was localized to the cytoplasm of phagocytic microglia at later stages. RAGE expression increased in the region surrounding the contused area after TBI in both rat and human brains. At later stages, RAGE was mainly expressed in microglia. CONCLUSION: HMGB1 is involved in both early and later stages after TBI. Targeting HMGB1 signaling may be a promising therapeutic approach for the treatment of TBI. PMID- 22491549 TI - Attenuating inflammation but stimulating both angiogenesis and neurogenesis using hyperbaric oxygen in rats with traumatic brain injury. AB - BACKGROUND: Inflammation, angiogenesis, neurogenesis, and gliosis are involved in traumatic brain injury (TBI). Several studies provide evidence supporting the neuroprotective effect of hyperbaric oxygen (HBO2) therapy in TBI. The aim of this study was to ascertain whether inflammation, angiogenesis, neurogenesis, and gliosis during TBI are affected by HBO2 therapy. METHODS: Rats were randomly divided into three groups: TBI + NBA (normobaric air: 21% O2 at 1 absolute atmospheres), TBI + HBO2, and Sham operation + NBA. TBI + HBO2 rats received 100% O2 at 2.0 absolute atmospheres for 1 hr/d for three consecutive days. Behavioral tests and biochemical and histologic evaluations were done 4 days after TBI onset. RESULTS: TBI + NBA rats displayed: (1) motor and cognitive dysfunction; (2) cerebral infarction and apoptosis; (3) activated inflammation (evidenced by increased brain myeloperoxidase activity and higher serum levels of tumor necrosis factor-alpha); (4) neuronal loss (evidenced by fewer NeuN-positive cells); and (5) gliosis (evidenced by more glial fibrillary protein-positive cells). In TBI + HBO2 rats, HBO2 therapy significantly reduced TBI-induced motor and cognitive dysfunction, cerebral infarction and apoptosis, activated inflammation, neuronal loss, and gliosis. In addition, HBO2 therapy stimulated angiogenesis (evidenced by more bromodeoxyuridine-positive endothelial and vascular endothelial growth factor-positive cells), neurogenesis (evidenced by more bromodeoxyuridine-NeuN double-positive and glial cells-derived neurotrophic factor-positive cells), and overproduction of interleukin-10 (an anti inflammatory cytokine). CONCLUSIONS: Collectively, these results suggest that HBO2 therapy may improve outcomes of TBI in rats by inhibiting activated inflammation and gliosis while stimulating both angiogenesis and neurogenesis in the early stage. PMID- 22491550 TI - Platonin mitigates lung injury in a two-hit model of hemorrhage/resuscitation and endotoxemia in rats. AB - BACKGROUND: Traumatic hemorrhagic shock and subsequent resuscitation may promote bacteria translocation and cause endotoxemia, a two-hit process that will induce severe lung injury. The pathogenesis involves oxidative stress, neutrophil infiltration, and inflammatory response. Platonin, a potent antioxidant, possesses potent anti-inflammation capacity. We sought to elucidate whether platonin could mitigate acute lung injury in a two-hit model of traumatic hemorrhage/resuscitation and subsequent endotoxemia. METHODS: Adult male rats were randomized to receive traumatic hemorrhage/resuscitation plus lipopolysaccharide (HS/L) alone or HS/L plus platonin (200 MUg/kg; n = 12 in each group). Sham groups were used simultaneously. At 6 hours after resuscitation, rats were killed and the levels of lung injury were assayed. RESULTS: Rats treated with HS/L alone had severe lung injury as evidenced by significant alterations in lung function (i.e., arterial blood gas and alveolar-arterial oxygen difference) and histology. Significant increases in polymorphonuclear leukocytes/alveoli ratio (neutrophil infiltration index) and significant increases in the concentrations of inflammatory molecules (including chemokine, cytokine, and prostaglandin E2) and malondialdehyde (lipid peroxidation index) revealed that HS/L caused significant oxidative stress, neutrophil infiltration, and inflammatory response in rat lungs. Moreover, our data revealed that the levels of functional and histologic alteration as well as polymorphonuclear leukocytes/alveoli ratio and the concentrations of inflammatory molecules and malondialdehyde in rats treated with HS/L plus platonin (200 MUg/kg) were significantly lower than those treated with HR/L alone. CONCLUSIONS: Platonin mitigates lung injury in a two-hit model of traumatic hemorrhage/resuscitation and endotoxemia in rats. PMID- 22491551 TI - A portable thoracic closed drainage instrument for hemopneumothorax. AB - BACKGROUND: Hemopneumothorax is a common sequelae of traumatic thoracic injury. The most effective treatment of this condition is thoracic drainage. Despite the common occurrence of this condition, available instruments are difficult to use emergently, particularly when large amounts of patients need to be drained. In the present experiment, a newly designed chest tube and thoracic closed drainage package is described and preliminarily evaluated with the goal to improve the treatment of traumatic hemopneumothorax. METHOD: Twenty canines were divided into two groups. In one group, the newly designed thoracic closed drainage package was used, whereas in the other group a currently available chest tube and bottle were used. Drainage test, ultrasound examination, flushing test, and tension test were performed to evaluate the effectiveness of the drainage package. RESULTS: We found that the newly-designed drainage tube is as effective as the common tube when evaluated using all of the chosen methods. In addition, the package is very lightweight and portable. CONCLUSION: The newly-designed thoracic drainage package is very effective in the emergency treatment of thoracic trauma and may be more suitable for the emergency treatment of hemopneumothorax. PMID- 22491552 TI - Recombinant human bone morphogenetic protein-2 use in the off-label treatment of nonunions and acute fractures: a retrospective review. AB - BACKGROUND: Recombinant human bone morphogenetic protein-2 (BMP-2) is Food and Drug Administration-approved for use in acute open tibial shaft fractures. Some surgeons, however, also use BMP-2 in an "off-label" application for other acute fractures and for nonunion care. This retrospective study was performed to assess radiographic outcomes of off-label uses of BMP-2 for acute fractures and nonunions at our institution. METHODS: All eligible off-label BMP-2 applications between 2004 and 2008 for acute fractures or nonunions were reviewed. Univariate and multivariate analyses were completed to identify patient and clinical factors that could predict radiographic success or failure of the procedure. RESULTS: One hundred sixteen of 145 BMP-2 applications in 104 of 128 patients met inclusion and exclusion criteria. The overall radiographic union rate was 66% (76 of 116). In the univariate analysis, five factors correlated with significantly higher union rate: volume of bone defect <4 cm3, >2 cortices in contact at the index procedure, male gender, body mass index <30, and history of closed fracture pattern. Within the multivariate analysis, factors independently predictive of radiographic union included open versus closed fracture, gender, and volume of bone defect. CONCLUSION: Off-label use of BMP-2 in acute fractures and nonunions resulted in a 66% success rate. It remains uncertain whether there is any clinical advantage to this approach, but it appears that female gender, open injury, and higher volumes of bone defect may be important negative prognostic factors for obtaining radiographic union. Appropriately powered prospective randomized trials are needed for further clarification, especially in light of the high cost of this treatment. PMID- 22491553 TI - Surgical management of acute odontoid fractures: surgery-related complications and long-term outcomes in a consecutive series of 97 patients. AB - BACKGROUND: The purpose of this study was to determine the incidence of surgery for odontoid fractures and to study surgical mortality, surgical morbidity, and long-term outcome in a large, contemporary, consecutive, single-institution, surgical series of odontoid fractures. METHODS: This is a retrospective study of all odontoid fractures treated by open surgery at our hospital during 2002 to 2009. The fractures were classified according to Grauer. Follow-up data, clinical examinations, and cervical computed tomographies were collected in 2010. RESULTS: This study included 97 consecutive patients with a median age of 73.0 years. The incidence of open fixation of odontoid fractures in this population was 0.45 per 100,000, and the incidence increased with age. The fractures were classified as type IIA in 3 patients, type IIB in 63 patients, type IIC in 8 patients, and type III in 23 patients. Anterior fixation and posterior fixation were performed in 41 and 56 patients, respectively. Immediate postoperative neurologic status was unchanged or improved in 97% of the patients. None of the patients developed postoperative hematoma, wound infection, deep venous thrombosis, or pulmonary embolism. Eleven patients underwent resurgery during the follow-up period; five had suboptimal reposition after the first surgery, one had suboptimal position of an anterior odontoid screw, two had rupture of fixation materials, and three developed pseudarthrosis. Overall survival (OS) rates after 1, 12, and 24 months were 96%, 84%, and 75%, respectively. Fifty-seven patients were available for follow-up evaluation with a mean time of 37 months. Radiologic follow-up showed definite bony fusion in 82% of the patients and uncertain bony fusion in 18% of the patients. Flexion-extension radiographs were obtained in 6 of the 10 patients with uncertain bony fusion; 5 of these were defined as stable (fibrous union) and 1 was unstable. Multivariate logistic regression demonstrated increased odds of nonbony fusion in more displaced fractures (OR, 1.44; 95% CI, 1.04-2.16; p = 0.04) and when using the anterior fusion technique (OR, 0.17; 95% CI, 0.03-0.75; p = 0.02). There was no significant association between neck pain and fusion method (Mann-Whitney U test, p = 0.86). Patients treated with a posterior fusion approach had significantly more neck stiffness than patients who underwent fusion with an anterior odontoid screw (Fisher's exact test, p = 0.04). CONCLUSIONS: The annual incidence of open fixation of odontoid fractures was 0.45 per 100,000 inhabitants, and the incidence increased with age. The median age at time of surgery was 73.0 years, and the surgical mortality was 4%. Increased odds of nonbony fusion were observed in more displaced fractures and after anterior screw fixations. There were no significant differences between patients treated with anterior screw fixation versus posterior wiring with respect to neck pain, but patients fused with a posterior approach reported significantly more neck stiffness. PMID- 22491554 TI - Evaluating contemporary antibiotics as a risk factor for Clostridium difficile infection in surgical trauma patients. AB - BACKGROUND: With most Clostridium difficile infections (CDI) occurring after exposure to antimicrobial treatment, specific antibiotics and duration of exposure were evaluated independently for increased risk of CDI in surgical patients. METHODS: A retrospective, case-control design was used to study surgical inpatients. The case group had a positive Clostridium difficile toxin assay, whereas the control group did not. RESULTS: Four antibiotics had a risk that was statistically significant for causing CDI in surgical patients: cefepime (odds ratio [OR], 5.7; 95% confidence interval [CI], 1.7-19.1; p = 0.0044), imipenem/cilastatin (OR, 3.2; 95% CI, 1.2-8.9; p = 0.0388), piperacillin/tazobactam (OR, 2.4; 95% CI, 1.3-4.5; p = 0.0067), and vancomycin (OR, 1.9; 95% CI, 1.0-3.5; p = 0.0439). Exposure longer than 7 days to cefepime (p = 0.0006), piperacillin/tazobactam (p = 0.0021), and imipenem/cilastatin (p = 0.0171) also increased risk for development of CDI. CONCLUSION: The use of cefepime, imipenem/cilastatin, piperacillin/tazobactam, and vancomycin and the use of multiple classes of antibiotics for at least 7 days significantly increased the risk of CDI in surgical inpatients. PMID- 22491555 TI - Retrograde intramedullary nailing of open femoral shaft fractures: a retrospective case series. AB - BACKGROUND: Nailing of open femur fractures has been described, but the literature on this subject often used antegrade nailing techniques. A retrograde nailing technique carries the risk of contamination and infection of the knee, infection, and nonunion. The purpose of this study was to have a case series examining the intermediate term outcome of retrograde nailing of open femur fractures. METHODS: A retrospective review of all open femur fractures treated between 2008 and 2010 at a Level II trauma center was performed. Demographic and injury patterns were reviewed for the 35 patients who were treated with retrograde nailing. The main outcome measures evaluated were infection (knee or femur) and nonunion. RESULTS: There were 11 grade I, 18 grade II, and 6 grade IIIA fractures (no IIIB or IIIC injuries). Healing occurred in 34 of 35 fractures with 1 (3%) nonunion and 2 (6%) deep infections, both occurring in IIIA fractures. There were no cases of knee joint infections, but two patients (6%) developed arthrofibrosis requiring manipulation. Implant removal of a prominent screw was required in one patient. CONCLUSION: Early retrograde nailing of open femur fractures has infection and healing rates consistent with existing literature. There seems to be little risk for knee infection, but the increased incidence of arthrofibrosis requiring manipulation is higher than previously published. These findings suggest that early retrograde nailing may be considered an acceptable treatment option for open femur fractures. LEVEL OF EVIDENCE: IV, case series. PMID- 22491556 TI - The value of cervical magnetic resonance imaging in the evaluation of the obtunded or comatose patient with cervical trauma, no other abnormal neurological findings, and a normal cervical computed tomography. AB - BACKGROUND: The value of magnetic resonance imaging (MRI) in the evaluation of the obtunded or comatose patient with a potential neck injury is a controversial subject. Some authors have suggested that MRI of the cervical spine adds no value in the evaluation of patients with a normal computed tomography (CT) of the neck. However, others have suggested that MRI is the gold standard for clearing the cervical spine in a clinically suspicious or unevaluatable blunt trauma patient. The purpose of this study is to evaluate our data in regard to these conflicting hypotheses. METHODS: Five consecutive years of data from 17,000 patients seen at our Level I trauma center yielded 512 individuals who underwent both CT and MRI of the cervical spine. Of the latter group, 150 individuals met three strict inclusion criteria for this study: (1) obtundation (Glasgow Coma Scale <=13, with 94 of this group comatose [Glasgow Coma Scale <=8]); (2) no obvious neurologic deficits; and (3) a normal cervical CT. The effect of MRI on the clinical management of these patients was evaluated. RESULTS: Among the 150 obtunded or comatose patients with a negative CT, the majority (51%) had a normal MRI. Among the patients with a positive MRI, the most common MRI-positive findings were ligamentous and soft tissue injury (81%). However, no MRI findings were deemed unstable, and no surgical intervention or change in the clinical management aside from collar immobilization of these individuals occurred after MRI. CONCLUSIONS: The addition of a cervical MRI to the evaluation protocol of obtunded or comatose patients with an otherwise normal neurologic examination and a normal cervical CT did not provide any additional useful information to change the management of these patients. PMID- 22491557 TI - Utility of a point-of-care device for rapid determination of prothrombin time in trauma patients: a preliminary study. AB - BACKGROUND: Rapid and accurate determination of prothrombin time in trauma patients may help to faster control of bleeding induced coagulopathy. The goal of this prospective observational study was to investigate the accuracy of bedside measurements of prothrombin time by the mean of a point-of-care device (INRatio) in trauma patients. METHODS: Fifty blood samples were drawn at admission and during the acute care phase for standard coagulation assays (prothrombin time, International Normalized Ratio [INR], and fibrinogen) and INRatio testing (INR(A)) from 48 trauma patients. RESULTS: Standard coagulation assays were available after a mean of 66 minutes. Median Injury Severity Score was 18, and 16 patients (33%) had a coagulopathy. Significant correlation was found between INR and INR(A) (r: 0.93, 95% confidence interval: 0.87-0.96). The mean difference (bias) for INR was 0.00, and standard deviation (precision) of the difference was 0.78. However, in cases where there was decreased hemoglobin (<10 gr . L(-1)) and fibrinogen (<1.5 gr . L(-1)), bias and precision were increased. To predict the need for fresh frozen plasma transfusion (INR > 1.5), INR(A) cutoff value of 1.3 resulted in a sensitivity of 92% and a specificity of 79%. The area under the receiver operating characteristic curve was 0.946 (95% confidence interval: 0,845 0,982). CONCLUSION: INRatio may be a useful device in the management of trauma patients with ongoing or suspected coagulopathy that may help to save at least 60 minutes in the process of obtaining a prothrombin time result. It may allow earlier detection of coagulopathy and, together with vital sign and hemoglobin, may help to guide fresh frozen plasma transfusion. PMID- 22491558 TI - A questionable association of stroke volume and arterial pulse pressure under gravitational stress. AB - BACKGROUND: The purpose of this study was to examine individual stroke volume pulse pressure (PP) relationships in healthy young men and women. METHODS: Sixteen healthy men and women were assessed at baseline and during four 12-minute stages of progressive lower body negative pressure (LBNP) at -15, -30, -45, and 60 mm Hg. RESULTS: Throughout staged LBNP, systolic blood pressure (105 +/- 7.8 vs. 103 +/- 8.3 mm Hg) and mean arterial pressure were not statistically different (81 +/- 5.6 vs. 83 +/- 5.9 mm Hg). There was also a significant increase in diastolic blood pressure (69 +/- 5.3 vs. 72 +/- 5.9 mm Hg) and heart rate (63 +/- 8.3 vs. 86 +/- 14.2 bpm) as well as a decrease in PP (37 +/- 5.7 vs. 31 +/- 7.0 mm Hg) and stroke volume (80 +/- 17.0 vs. 26.6 +/- 10.0 mL). There was a strong positive relationship for LBNP versus stroke volume (r2 = 0.99), PP (r2 = 0.96), and heart rate (r2 = -0.92), as well as for stroke volume versus PP (r2 = 0.98) and stroke volume versus heart rate (r = -0.94). Substantial intersubject variability in the stroke volume and PP correlations were presented. Strong, significant correlations were only displayed for 38% of the participants, while heart rate and stroke volume was strongly associated in 63% of these individuals. CONCLUSIONS: This work highlights the limitations of using PP when assessing trauma patients because of large interindividual differences. PMID- 22491559 TI - Ventilator-associated pneumonia: bacteremia and death after traumatic injury. AB - BACKGROUND: The implications of bacteremia in critically ill patients are uncertain. Some reports suggest bacteremia is linked to higher mortality whereas others do not. These differences may, in part, be because of differences in patient cohorts. To address the potential independent relationship between bacteremia and outcome, we focused on critically ill trauma patients with ventilator-associated pneumonia (VAP), of whom a significant proportion had concomitant bacteremia. We tested the hypothesis that bacteremia was associated with death in trauma patients who developed VAP. METHODS: In this retrospective cohort study, we measured the incidence of bacteremia associated with VAP and compared the case-fatality rates between patients with and without bacteremia. We adjusted for other mortality risk factors and possible confounders in two ways. First, using forward conditional logistic regression and second, we calculated propensity scores and then adjusted for this score in a regression model. RESULTS: There were 554 with VAP. Patients with bacteremia had a 26% case fatality rate (19 of 74 patients). Patients with VAP alone had a case-fatality rate of 12% (56 of 480 patients). The unadjusted relative risk (RR) for death associated with bacteremia was 2.2 (95% confidence interval = 1.4-3.5). After adjusting for age, acute physiology score, and severity of injury, patients with bacteremia had an increased risk of death compared with patients with VAP alone (adjusted odds ratio = 2.65, 95% confidence interval = 1.36-5.17). Our propensity score analysis resulted in a similar association between bacteremia and mortality. CONCLUSIONS: VAP with bacteremia is associated with an increased mortality in comparison with VAP alone after severe traumatic injury. PMID- 22491560 TI - Targeting the lateral but not the third ventricle induces bone loss in ewe: an experimental approach to generate an improved large animal model of osteoporosis. AB - BACKGROUND: Osteoporosis is a chronic disease characterized by bone loss and increased skeletal fragility. Large animal models are required for preclinical testing of new therapeutic approaches. We have recently demonstrated that continuous intracerebroventricular (ICV) application of leptin into the lateral ventricle (LV) induces bone loss in ewe. On the basis of these findings, we reasoned that the third ventricle (TV) is an even better target because of its closer location to the hypothalamus that mediates leptin effects on bone. METHODS: Corriedale sheep were randomly mixed to four groups of four ewe each: control entire (control), ovarectomy plus ICV application of cerebrospinal fluid (OVX), OVX plus ICV application of leptin into the LV (leptin-LV); and ICV application of leptin into the TV (leptin-TV). After 3 months, histomorphometric characterization and bone turnover parameters were analyzed. RESULTS: Highly significant loss of trabecular bone was observed only in leptin-LV group. Increased osteoclast indices and urinary cross-lap excretion were observed in OVX and leptin-TV group. In contrast, serum parameters of osteoblast activity were only significantly decreased in leptin-LV group. Autopsy of ewe brain showed fibrosis around the stainless steel cannula in leptin-TV group. CONCLUSIONS: ICV application of leptin into the LV strongly reduces bone formation and leads to a highly significant trabecular bone loss in ewe. In contrast, ICV application of leptin into the TV is technically more demanding and results are unpredictable, because the required use of stainless steel cannula induces peri-implant fibrosis that might prevent leptin to enter the cerebrospinal fluid. PMID- 22491561 TI - Experimental multiscale analysis of liver damage and failure process under compression. AB - BACKGROUND: To prevent abdominal organs' traumas in crash situations, the definition of efficient safety devices should be based on a detailed knowledge of human tolerance, i.e., injury mechanisms and related injury criteria. This knowledge should be based on experimental observation of these mechanisms through damage and failure analysis. METHODS: In this study, 10 human cadaveric livers are uniaxially compressed using three different loading velocities (0.0013, 0.2, and 1 m/s). Injuries induced are analyzed at two observation levels through a macroscopic study of internal and external cracks and a histologic study of damage initiation. RESULTS: Liver global behavior is similar for the three loading velocities, but loading rate seems to influence the stiffness and the severity of failure process. Macroscopic injury analysis showed four patterns of laceration because of organ spreading during its compression exhibiting liver structure incidence. Histologic analysis shows two different damage occurrences: microcracking and cavitation. The crack propagation is observed to occur preferentially within the lobules. Influence of the vascular system is also highlighted. Both macroscopic and histologic injuries obtained are relevant with those clinically observed under trauma situations. CONCLUSION: Based on experimental investigation of human liver under compression, this work provides a multiscale evaluation of injury process coupling mechanical and histologic analysis. Injury mechanisms postulated involve vascular structures and capsule. All this information is essential for the design of dedicated behavior laws and finite element models. PMID- 22491562 TI - Management of contaminated open fractures: a comparison of two types of irrigation in a porcine model. AB - BACKGROUND: Treatment of open fractures demands rapid intervention consisting of intravenous antibiotics, aggressive debridement, fracture immobilization, and soft tissue management including additional debridements and soft tissue coverage. Despite this approach, infection, particularly osteomyelitis, after open fracture continues to be a source of significant morbidity. Recent literature has provided several studies that performed clinical trials in superficial wounds. These investigations compared sterile solutions with tap water for wound decontamination. The results suggest that tap water washouts are cost-effective for these specific wounds. MATERIAL: An established protocol using sterile porcine hind limb tibias, as reported by Bhandari et al., was applied with modification. There were then 15 specimens and 5 controls (no irrigation) for each condition. The conditions were potable water and sterile water. A representative bacterium of gram-positive, Staphylococcus aureus, or gram negative, Escherichia coli, acted as the contaminant. Sectioned, sterile porcine hind limb tibias were inoculated with 1 mL of a known concentration (1 * 10(10)) of bacterium and incubated. Each specimen was then irrigated, with bulb irrigation at a standardized distance of 15 cm, with 500 mL of irrigation. The specimen, along with 0.5 mL of wash (irrigant collected after it was placed over the specimen), was placed in 5 mL of Brain Heart Infusion broth. All specimens were incubated in this broth at 37 degrees C for 2 hours. At 2 hours, a 100-MUL supernatant was plated on blood agar plates and incubated for 24 hours. Colony counts for each specimen and controls were then performed. RESULTS: The number of colony forming units (CFUs) for each type of bacterium was different. The average CFUs from bone samples contaminated with E. coli was 5.18 * 10(8) after irrigation with sterile water and 6.24 * 10(8) after irrigation with tap water. The average CFUs from bone samples contaminated with S. aureus was 18 * 10(6) after irrigation with sterile water and 12 * 10(6) after irrigation with tap water. The average CFUs from the irrigation samples from E. coli contamination treated with sterile water was 1.3 * 10(6) and the CFUs from E. coli contamination treated with tap water was 2.2 * 10(6). The average CFUs from the irrigation samples from S. aureus contamination treated with sterile water was 1.57 * 10(6) and the CFUs from S. aureus contamination treated with tap water was 1.56 * 10(6). CONCLUSION: There was no significant difference between the CFUs for the sterile and potable water (p = 0.201) for each bacterium (p = 0.871). PMID- 22491563 TI - Primary free functioning muscle transfer for fingers with accompanying tendon transfer for thumb provide one-stage upper extremity composite reconstruction in acute open wound. AB - BACKGROUND: Upper limb trauma may present as both soft tissue and muscle defects necessitating a free skin flap to effect a repair. The limb's core (basic) functionality can be returned with a secondary tendon transfer or a functioning muscle transfer. A functioning muscle flap can provide for soft tissue repair and functional restoration in a single procedure, but the success of such procedures requires further clarification. MATERIAL: From 1997 to 2006, nine patients underwent free functioning muscle transfer performed for upper extremity composite structure and functional defects, including four flexor digitorum profundus muscle and three extensor digitorum comminis muscle defects. Seven thumb tendon defects were managed with simultaneous tendon and free functioning muscle transfer. In addition, two opponensplasties and one thumb basal joint arthrodesis were performed for thumb function revision. RESULT: In all nine patients, procedures were completed without complications, the flaps surviving, enabling the patients to achieve opposable hand function. The muscle strength accomplished M4.2 (M3-5). The grip power was 41.7, and pinch power 55.3%, when compared with the other hand. CONCLUSION: Primary functioning muscle transfer can provide a one-stage composite functional restoration in an open wound. The thumb can be reconstructed with tendon transfer followed by opponensplasty to achieve a satisfactory range of opposable function. PMID- 22491564 TI - Influence of flap factors on partial necrosis of reverse sural artery flap: a study of 179 consecutive flaps. AB - BACKGROUND: Partial necrosis is a main complication of reverse sural artery flap. The purpose of this article is to evaluate effect of flap factors on partial necrosis in the flap. PATIENTS AND METHODS: We retrospectively reviewed data of 175 patients with 179 flaps used to reconstruct soft tissue defects in the distal lower leg, heel, and foot between April 2001 and April 2010. Posterior aspect of the lower leg was equally divided into nine zones. The flap factors were compared between the survival flaps and the partial-necrosis flaps. RESULTS: There were 141 flaps surviving completely; distal de-epithelialization and wound dehiscence developed in 12 flaps and 6 flaps, respectively; partial necrosis occurred in 20 (11.2%) flaps. Partial-necrosis rate was significantly higher in the flaps with top-edge locating in the upper 1/9 of the calf (32.3%, 10 of 31), in the flaps with length-width ratio (LWR) >=5:1 (17.8%, 13 of 73), or in the flaps with width of skin island (width) >=8 cm (15.2%, 16 of 105); it was significantly lower in the flaps with top-edge locating in the lower 7/9 of the calf (3.8%, 3 of 80). Seventeen (80.9%) of 21 flaps with LWR >=6:1 survived, and the maximal LWR of completely survival flap was 7.00:1. CONCLUSION: Probability of partial necrosis occurring in reverse sural artery flap significantly increase when top-edge of the flap locates in the upper 1/9 of the calf, when LWR of the flap is 5:1 or more, or when width is 8 cm or more. The flap with top-edge locating lower 7/9 of the calf is safe and reliable. PMID- 22491565 TI - Effect of divergent screw fixation in vertical medial malleolus fractures. AB - BACKGROUND: This study qualified and evaluated the mechanical properties of three different screw orientations used for fixation of vertical shear fractures of the medial malleolus. METHODS: Identical vertical osteotomies were created in synthetic distal tibiae using a jig. The specimens were assigned to one of the three fixation groups (n = 8 per group): (1) parallel: two 40 mm length, 4.0 mm diameter screws placed parallel to each other in the transverse plane; (2) convergent: two 40 mm length, 4.0 mm diameter screws placed 25 degree convergent to each other in the transverse plane; and (3) divergent: two 40 mm length, 4.0 mm diameter screws placed 15 degree divergent to each other in the transverse plane. The specimens were tested using offset axial loading at 1 mm/s until 2 mm of displacement. RESULTS: The average stiffness was 102 N/mm +/- 51 N/mm for the parallel group, 109 N/mm +/- 37 N/mm for the convergent group, and 185 N/mm +/- 73 N/mm for the divergent group. The average stiffness of the divergent group was significantly greater than either the parallel (p < 0.05) or convergent (p < 0.05) groups. The divergent group was 81.4% more stiff than the parallel group and 69.7% more stiff than the convergent group. The average load at 2 mm of displacement was 324 N +/- 87 N for the parallel group, 373 N +/- 95 N for the convergent group, and 512 N +/- 170 N for the divergent group. The average load at failure of the divergent group was significantly (p < 0.05) greater than the parallel groups. The divergent group was required 58.0% more force at 2 mm of displacement than the parallel group and 37.3% more force at 2 mm of displacement than the convergent group. CONCLUSION: The use of a divergent screw pattern resulted in a stiffer fixation construct that requires more force for 2 mm of displacement when used to stabilize an osteotomy model of vertical shear medial malleolus fractures. PMID- 22491566 TI - Safety of prehospital intravenous fentanyl for adult trauma patients. AB - BACKGROUND: Little is known about the safety of intravenous fentanyl for adult trauma patients in the prehospital setting. Our objective was to study the hemodynamic effect of prehospital intravenous fentanyl in initially normotensive adult trauma patients. METHODS: A quasi-experimental design was used to compare adult trauma patients who received intravenous fentanyl and those who did not receive fentanyl in a large regional prehospital system and its affiliated Level I trauma center. Emergent adult trauma patients were included with an initial prehospital Glasgow Coma Scale score of >=13 and systolic blood pressure >90 mm Hg. Patients were stratified into two groups, those who received a single dose of intravenous fentanyl (100 MUg) and those who did not. The outcome was initial emergency department (ED) shock index (heart rate divided by systolic blood pressure). Multivariable linear regression was used to estimate the effect of fentanyl on ED shock index while adjusting for prehospital shock index, age, gender, Trauma Injury Severity Score, and the propensity for receiving fentanyl. RESULTS: Seven hundred sixty-three patients were included, of whom 217 (28%) received fentanyl. The groups had comparable demographics (age, gender, and race/ethnicity) but different clinical characteristics (ED vital signs, Injury Severity Score, mechanism, and ED disposition). The adjusted ED shock index of fentanyl patients improved (-0.03; 95% confidence interval: -0.05 to 0.00; p = 0.02) compared with no fentanyl. CONCLUSION: Prehospital intravenous fentanyl did not adversely affect the initial ED shock index in adult trauma patients. Additional research should be performed to confirm and extend our findings. LEVEL OF EVIDENCE: III. PMID- 22491567 TI - Bacteria on external fixators: which prep is best? AB - BACKGROUND: There are no established guidelines for the surgical prep of an external fixator in the operative field. This study investigates the effectiveness of different prep solutions and methods of application. METHODS: Forty external fixator constructs, consisting of a rod, pin, and pin to rod coupling device, were immersed in a broth of Staphylococcus aureus (lux) for 12 hours. Constructs were then randomized into four treatment groups: chlorhexidine gluconate (CHG) (4%) scrub, CHG (4%) spray, povidone-iodine (PI) (10%) scrub, and PI (10%) spray. Each construct was imaged with a specialized photon capturing camera system yielding the quantitative and spatial distribution of bacteria both before and after the prep. Each pin to bar clamp was loosened and moved 2 cm down the construct, simulating an external fixator adjustment, and reimaged. Spatial distribution of bacteria and total bacteria counts were compared. RESULTS: There was a similar reduction in bacteria after surgical prep when comparing all four groups independently (p = 0.19), method of application (spray vs. scrub, p = 0.27), and different solutions (CHG vs. PI, p = 0.41). Although bacteria were evident in newly exposed areas after external fixator adjustment, most notably within the loosened pin to bar clamp, it did not result in an increase in bacteria counts (all four groups, p = 0.11; spray vs. scrub, p = 0.18; CHG vs. PI, p = 0.99). CONCLUSIONS: Although there was no increase in bacteria counts after the simulated external fixator adjustment, it did expose additional bacteria previously unseen. Although there was no difference in surgical prep solution or method of application, consideration must be given to performing an additional surgical prep of the newly exposed surface after loosening of each individual external fixator component as this may further minimize potential bacteria exposure. PMID- 22491568 TI - Prehospital injury deaths--strengthening the case for prevention: nationwide cohort study. AB - BACKGROUND: To determine the frequency and characteristics of prehospital deaths compared with hospital deaths in different subpopulations with severe injuries. METHODS: Population-based cohort study using person-based linkage of the Swedish nationwide hospital discharge register with death certificate data. In all, 28,715 injury deaths were identified among 419,137 cases of severe injury during 1998 to 2004. Prehospital deaths were defined as autopsied out-of-hospital deaths with injury as the underlying cause. Their impact on mortality prediction was assessed using the International Classification of Disease Injury Severity Score with the C statistic as a measure of discrimination. RESULTS: The majority of all injury deaths occurred either at the scene or before hospitalization. Among persons younger than 65 years, for each hospital death there were nine prehospital deaths. A high proportion of deaths from drowning, suffocation, and firearm injuries were prehospital (85, 82, and 67% of all cases, respectively). More than 90% of hospital deaths resulted from unintentional injuries, while only 43% of prehospital deaths were unintentional. The largest increase in a cause specific case fatality risk estimate was seen for poisoning, where inclusion of prehospital deaths increased the risk estimate from 1.6% to 22.8%. Injury mortality prediction based on International Classification of Disease Injury Severity Score improved when prehospital deaths were added to hospital data (C statistic increased from 0.86 to 0.93). CONCLUSIONS: Prehospital deaths constitute the majority of trauma deaths and differ in major characteristics from hospital deaths. The high proportion of prehospital deaths among young and middle aged people highlights the potential impact of preventive efforts. LEVEL OF EVIDENCE: III. PMID- 22491569 TI - Homicide as a medical outcome: racial disparity in deaths from assault in US Level I and II trauma centers. AB - BACKGROUND: Since 1900, thousands of medical journal articles have been published on the topic of racial disparities in health and medical outcomes in the United States, including overlapping disparities based on health insurance status. But research on the question of such disparities in the medical treatment of injury from assault-matters of public safety, considerable public expense, and policy debate-is lacking. METHODS: To determine differences by race and insurance status on death from intentional injury by others on and after trauma center arrival, propensity score matching is used to estimate adjusted mortality risk ratios by race and medical insurance controlling for facility, case, and injury characteristics. Analysis is based on a nationally representative sample of 100 Level I and II US trauma centers (National Trauma Data Bank 2005-2008) and includes 137,618 black and white assault cases aged 15 years and older: 35% white, and 65% black, with 46% of the whites and 60% of the blacks coded as uninsured. RESULTS: Black patients showed higher overall raw mortality rates from assault than whites (8.9% vs. 5.1%), but after propensity score matching, the black to white adjusted risk ratio for death from assault (homicide) dropped significantly across firearm, cutting/piercing, and blunt injuries. After adjustment, estimated black deaths were 29% in excess of white deaths for firearm injuries, 36% in excess for cutting/piercing injuries, and 61% in excess for blunt injuries. Uninsured blacks comprised 76% of all excess trauma center deaths from assault. CONCLUSIONS: Along with insurance status, and after excluding on scene deaths, among patients brought to the Level I and II trauma centers, race is a substantial independent predictor of who dies from assault. Blacks, especially the uninsured, have significantly worse outcomes overall, but there is some evidence that this pattern is minimized at higher levels of injury severity. LEVEL OF EVIDENCE: I, prognostic study. PMID- 22491570 TI - The PHILOS plate for proximal humeral fractures--risk factors for complications at one year. AB - BACKGROUND: Since 2003, we have used the Proximal Humerus Interlocking System plate for treatment of proximal humeral fractures. Although many patients have good and excellent results, the reported rate of complications varies. We have focused on the complication rate and risk factors for complications 1 year after surgery. METHODS: From 2003 until 2008, a total of 294 (223 women; 71 men; median age, 72.9) patients were included. General data were collected at the time of injury (Charlson Index, smoking, and steroid therapy). Fractures were classified (AO/OTA) retrospectively. The follow-up of 1 year included radiographs and Constant-Murley score for functionality. Complications and revision surgeries were analyzed specifically. RESULTS: We found 83 (28.2%) patients with a total of 105 complications, requiring a total of 72 (24.5%) revision surgeries. The most frequent complication was screw cutout (33 of 294, 11.2%), because of secondary fracture displacement or avascular necrosis (AVN). AVN (20 of 294, 6.8%) was the main reason for secondary arthroplasty. Smoking more than 20 pack years had a significant impact on the complication rate. Fractures classified 11-A3 showed more implant failures. Fracture dislocations predisposed to secondary screw cutout and AVN. Patients without complications (211, 71.8%) achieved a median Constant-Murley score of 89 (40-100) points. CONCLUSION: This study points out several predisposing factors for negative outcome after open reduction and internal fixation with the Proximal Humerus Interlocking System plate (fracture type: 11-A3, fracture dislocations, and smoking). Accounting for these, patient's risk for complications can be evaluated more individually and taken into consideration for the concept of treatment. Altering the surgical technique was associated with a significant reduction in the incidence of secondary screw cutout. PMID- 22491571 TI - Pressure ulcers in the trauma population: are reimbursement penalties appropriate? PMID- 22491572 TI - BioGlue hemostasis of penetrating cardiac wounds in proximity to the left anterior descending coronary artery. AB - BACKGROUND: Penetrating cardiac injuries necessitate rapid resuscitation and repair, most commonly with the use of pledgeted sutures. Hemostasis can be difficult to obtain with injuries near coronary vessels or with friable tissue that does not hold suture. We describe the use of BioGlue, a synthetic bovine albumin and glutaraldehyde mix, as a hemostatic adjunct in these challenging cases. METHODS: Patients sustaining penetrating cardiac injury undergoing emergent operation from January 2000 to January 2010 were reviewed. RESULTS: During the 10-year study period, 67 patients required emergent operation for a cardiac injury, with three patients undergoing BioGlue repair of their ventricle. All patients were male with a mean age of 40 years +/- 8 years. In two patients, BioGlue was used in addition to suture repair to control hemorrhage, while in one patient BioGlue was used as the only cardiac repair. Hemostasis was achieved in all cases, and there were no cardiac complications in 20 months (range 15-26 months) of follow-up. CONCLUSIONS: To our knowledge, this is the first description of the use of BioGlue for repair of penetrating cardiac injuries. This technique should be added to the armamentarium in managing complex cardiac wounds. LEVEL OF EVIDENCE: III. PMID- 22491573 TI - The relationship between dexmedetomidine dosing and hypotension. PMID- 22491574 TI - An evaluation of two tourniquet systems for the control of prehospital lower limb hemorrhage. PMID- 22491575 TI - Prehospital cardiopulmonary resuscitation time in traumatic arrest. PMID- 22491577 TI - Discrepency between heart rate and markers of hypoperfusion. PMID- 22491582 TI - Pulmonary artery missile embolus after a gunshot wound to the upper extremity. PMID- 22491583 TI - Pentacam-aided diagnosis of traumatic lens subluxation. PMID- 22491584 TI - Alligator wrestling: the ultimate wrestling match. PMID- 22491585 TI - Emphysematous cholecystitis treated by percutaneous transheptic biliary drainage. PMID- 22491586 TI - Traumatic pseudoaneurysm of the superior cerebellar artery. PMID- 22491587 TI - Multiple symptomatic traumatic cerebral vasospasm treated by percutaneous transluminal angioplasty. PMID- 22491590 TI - Resection and primary anastomosis with proximal diversion instead of Hartmann's: evolving the management of diverticulitis using NSQIP data. AB - BACKGROUND: The emergency surgical treatment of acute diverticulitis with feculent or purulent peritonitis has traditionally been the Hartmann's procedure (HP). Debate continues over whether primary resection with anastomosis and proximal diversion may be performed in the setting of a high-risk anastomosis in complicated diverticular disease. In contrast to a loop ileostomy takedown, the morbidity of a Hartmann's reversal is preventative for many patients, leaving them with a permanent stoma. Our study compared the surgical outcomes of patients with perforated diverticulitis who underwent a HP to primary anastomosis with proximal diversion (PAPD). METHODS: The National Surgical Quality Improvement Program (NSQIP) database was queried from 2005 to 2009 to identify all cases of perforated diverticulitis classified as contaminated or dirty/infected. Patients were stratified into HP or PAPD, and logistic regression models were created to control for patient demographics, comorbidities, perioperative risk, and illness severity to determine the impact of surgical procedure on outcome. RESULTS: There were 2,018 patients meeting the inclusion criteria of which 340 (17%) underwent PAPD and the remainder underwent HP. Significant independent predictors of infectious outcomes were alcohol use, preoperative sepsis, and operative time. There was no significant difference in risk of infectious complications, return to the operating room, prolonged ventilator use, death, or hospital length of stay between the two procedures. When considering only dirty/infected cases, the mortality risk was twofold greater when PAPD was performed. CONCLUSION: The treatment of acute diverticulitis in the setting of contamination can be safely treated with resection, primary anastomosis, and proximal diversion as opposed to a HP in certain circumstances. Given the decreased morbidity of subsequent loop ileostomy takedown compared with a Hartmann's reversal, this procedure should be given consideration in the management of acute, perforated diverticulitis but may not be warranted in cases of feculent peritonitis. PMID- 22491589 TI - Nanocytology of rectal colonocytes to assess risk of colon cancer based on field cancerization. AB - Developing a minimally invasive and cost-effective prescreening strategy for colon cancer is critical because of the impossibility of conducting colonoscopy on the entire at-risk population. The concept of field carcinogenesis, in which normal-appearing tissue away from a tumor has molecular and, consequently, nano architectural abnormalities, offers one attractive approach to identify high-risk patients. In this study, we investigated whether the novel imaging technique partial wave spectroscopic (PWS) microscopy could risk-stratify patients harboring precancerous lesions of the colon, using an optically measured biomarker (L(d)) obtained from microscopically normal but nanoscopically altered cells. Rectal epithelial cells were examined from 146 patients, including 72 control patients, 14 patients with diminutive adenomas, 20 patients with nondiminutive/nonadvanced adenomas, 15 patients with advanced adenomas/high-grade dysplasia, 12 patients with genetic mutation leading to Lynch syndrome, and 13 patients with cancer. We found that the L(d) obtained from rectal colonocytes was well correlated with colon tumorigenicity in our patient cohort and in an independent validation set of 39 additional patients. Therefore, our findings suggest that PWS-measured L(d) is an accurate marker of field carcinogenesis. This approach provides a potential prescreening strategy for risk stratification before colonoscopy. PMID- 22491591 TI - Anticoagulation management around percutaneous bedside procedures: is adjustment required? AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) and percutaneous dilatational tracheostomy (PDT) are frequently performed bedside in the intensive care unit. Critically ill patients frequently require anticoagulant (AC) and antiplatelet (AP) therapies for myriad indications. There are no societal guidelines proffering strategies to manage AC/AP therapies periprocedurally for bedside PEG or PDT. The aim of this study is to evaluate the management of AC/AP therapies around PEG/PDT, assess periprocedural bleeding complications, and identify risk factors associated with bleeding. METHODS: A retrospective, observational study of all adult patients admitted from October 2004 to December 2009 receiving a bedside PEG or PDT was conducted. Patients were identified by procedure codes via an in-hospital database. A medical record review was performed for each included patient. RESULTS: Four hundred fifteen patients were included, with 187 PEGs and 352 PDTs being performed. Prophylactic anticoagulation was held for approximately one dose before and two doses or less after the procedure. There was wide variation in patterns of holding therapy in patients receiving anticoagulation via continuous infusion. There were 19 recorded minor bleeding events, 1 (0.5%) with PEG and 18 (5.1%) with PDT, with no hemorrhagic events. No association was found between international normalized ratio, prothrombin time, or activated partial thromboplastin time values and bleed risk (p = 0.853, 0.689, and 0.440, respectively). Platelet count was significantly lower in patients with a bleeding event (p = 0.006). CONCLUSIONS: We found that while practice patterns were quite consistent in regard to the management of prophylactic anticoagulation, it varied widely in patients receiving therapeutic anticoagulation. It seems that prophylactic anticoagulation use did not affect bleed risk with PEG/PDT. PMID- 22491592 TI - Fresh frozen plasma/red blood cell resuscitation regimen that restores procoagulants without causing adult respiratory distress syndrome. AB - BACKGROUND: Controversy exists about the ideal fresh frozen plasma/red blood cell (FFP/RBC) ratio for resuscitation of patients requiring massive transfusion (MT). This study correlates the FFP/RBC with clotting time (CT), prothrombin time (PT), partial thromboplastin time (PTT), and thrombin time (TT); with procoagulants (fibrinogen [FI], factor 5 [FV], and factor 8 [FVIII]); and with adult respiratory distress syndrome (pO2/FIO2). METHODS: The 32 patients studied in operating room (OR) were in shock for 47 minutes and received an average of 17.6 units RBC, 4.2 units FFP, and 14.2 L balanced electrolyte solution. The 53 patients (including 22 of the OR patients), studied an average of 9.5 hours after operation, had an average shock time of 42 minutes, and received 17.4 units RBC, 4.6 units FFP, and 12.3 L balanced electrolyte solution in OR. RESULTS: The FFP/RBC in OR averaged 0.3:1 (range: 0.1:1 to 0.9:1). The OR study, done after a minimum of 10 RBC units at 3.8 hours, showed a PT of 3.5 seconds off normal (international normalized ratio < 1.3), a PTT of 34 seconds, and TT of 7.9 seconds off normal. FI, FV, and FVIII were restored to 148 mg/dL, 54%, and 81%. The pO2/FIO2 was 282. The early post-OR study showed a PT of 2.3 seconds off normal (international normalized ratio = 1.2), a PTT of 32 seconds, a TT of 7.2 seconds off normal, an FI of 207 mg/dL, an FV of 64%, an FVIII of 102%, and a pO2/FIO2 of 332. Both OR and early post-OR CTs and procoagulant levels are associated with adequate coagulation. All patients with a 0.31:1 or higher FFP/RBC had sufficient restoration of CTs and procoagulants. CONCLUSION: These data show that an FFP/RBC ratio above 0.31:1 in injured patients requiring MT restores CTs and procoagulant to clinically effective levels while not causing adult respiratory distress syndrome. Future studies on defining the ideal FFP/RBC ratio for MT should monitor CTs, procoagulants, and organ function. PMID- 22491593 TI - Factor IX complex for the correction of traumatic coagulopathy. AB - BACKGROUND: Damage control resuscitation advocates correction of coagulopathy; however, options are limited and expensive. The use of prothrombin complex concentrate (PCC), also known as factor IX complex, can quickly accelerate reversal of coagulopathy at relatively low cost. The purpose of this study is to describe our experience in the use of factor IX complex in coagulopathic trauma patients. METHODS: All patients receiving PCC at our Level I trauma center over a two-year period (2008-2010) were reviewed. PCC was used at the discretion of the trauma attending for treatment of coagulopathy, reversal of coumadin, and when recombinant factor VIIa was indicated. RESULTS: Forty-five trauma patients received 51 doses of PCC. Sixty-two per cent were male and mean Injury Severity Score was 23 (+/- 14.87). Standard dose was 25 units per kg and mean cost per patient was $1,022 ($504-3,484). Fifty-eight per cent of patients were on warfarin before admission. Mean international normalized ratio (INR) was decreased after PCC administration (p = 0.001). Packed red blood cell transfusion was also reduced after factor IX complex (p = 0.018). Mean INR was reduced in both the nonwarfarin (p = 0.001) and warfarin (p = 0.001) groups. Packed red blood cell transfusion was less in the nonwarfarin group (p = 0.002) however was not significant in the warfarin group. Subsequent thromboembolic events were observed in 3 of the 45 patients (7%). Mortality was 16 of 45 (36%). CONCLUSION: PCC rapidly and effectively treats coagulopathy after traumatic injury. PCC therapy leads to a significant correction in INR in all trauma patients, regardless of coumadin use, and concomitant reduction in blood product transfusion. PCC should be considered as an effective tool to treat acute coagulopathy of trauma. Further prospective studies examining the safety, efficacy, cost, and outcomes comparing PCC and recombinant factor VIIa are needed. PMID- 22491594 TI - Targeted resuscitation improves coagulation and outcome. AB - BACKGROUND: Acute trauma coagulopathy in seriously injured casualties may be initiated by tissue hypoperfusion. A targeted (or novel hybrid [NH]) resuscitation strategy was developed to overcome poor tissue oxygen delivery associated with prolonged hypotension. METHODS: Under the Animals (Scientific Procedures) Act 1986, terminally anesthetized large white pigs were divided into four groups (n = 6). Groups 1 and 2 received blast injury and 3 and 4 no blast (sham). All were given a controlled hemorrhage (35% blood volume) and an uncompressed grade IV liver injury. Five minutes later, all were resuscitated with 0.9% saline to a systolic arterial pressure (SAP) of 80 mm Hg. After 60 minutes, the NH groups (1 and 3) were resuscitated to a SAP (110 mm Hg), whereas hypotensive groups (2 and 4) continued with SAP 80 mm Hg for up to 8 hours from onset of resuscitation. RESULTS: Mean survival time was shorter in group 2 (258 minutes) compared with groups 1, 3, and 4 (452 minutes, 448 minutes, and 369 minutes). By the end of the study, hypotension was associated with a significantly greater prothrombin time (1.73 +/- 0.10 and 1.87 +/- 0.15 times presurgery, groups 2 and 4) compared with NH (1.44 +/- 0.09 and 1.36 +/- 0.06, groups 1 and 3, p = 0.001). Blast versus sham had no significant effect on prothrombin time (p = 0.56). Peak levels of interleukin 6 were significantly lower in NH groups. Arterial base excess was significantly lower with hypotension (-18.4 mmol/L +/- 2.7 mmol/L and -12.1 mmol/L +/- 3.2 mmol/L) versus NH (-3.7 mmol/L +/- 2.8 mmol/L and -1.8 mmol/L +/- 1.8 mmol/L, p = 0.0001). Hematocrit was not significantly different between groups (p = 0.16). CONCLUSION: Targeted resuscitation (NH) attenuates the development of acute trauma coagulopathy and systemic inflammation with improved tissue perfusion and reduced metabolic acidosis in a model of complex injury. This emphasizes the challenge of choosing a resuscitation strategy for trauma patients where the needs of tissue perfusion must be balanced against the risk of rebleeding during resuscitation. PMID- 22491596 TI - Comparison of hemodynamic measurements from invasive and noninvasive monitoring during early resuscitation. AB - BACKGROUND: Measurements obtained from the insertion of a pulmonary artery catheter (PAC) in critically ill and/or injured patients have traditionally assisted with resuscitation efforts. However, with the recent utilization of ultrasound in the intensive care unit setting, transthoracic echocardiography (TTE) has gained popularity. The purpose of this study is to compare serial PAC and TTE measurements and document levels of serum biomarkers during resuscitation. METHODS: Over a 25-month period, critically ill and/or injured patients admitted to a Level I adult trauma center were enrolled in this 48-hour intensive care unit study. Serial PAC and TTE measurements were obtained every 12 hours (total = 5 points/patient). Serial levels of lactate, Delta base, troponin 1, and B-type natriuretic peptide were obtained. Pearson correlation coefficient and intraclass correlation (ICC) assessed relationship and agreement, respectively, between PAC and TTE measures of cardiac output (CO) and stroke volume (SV). Analysis of variance with post hoc pairwise determined differences over time. RESULTS: Of the 29 patients, 69% were male, with a mean age of 47.4 years +/- 19.5 years and 79.3% survival. Of these, 25 of 29 were trauma with a mean Injury Severity Score of 23.5 +/- 10.7. CO from PAC and TTE was significantly related (Pearson correlations, 0.57-0.64) and agreed with moderate strength (ICC, 0.66-0.70). SV from PAC and TTE was significantly related (Pearson correlations, 0.40-0.58) and agreed at a weaker level (ICC, 0.41-0.62). Tricuspid regurgitation was noted in 80% and mitral regurgitation in 50% to 60% of patients. CONCLUSION: Measurements of CO and SV were moderately strong in correlation and agreement which may suggest PAC measurements overestimate actual values. The significance of tricuspid regurgitation and mitral regurgitation during early resuscitation is unknown. PMID- 22491595 TI - Base deficit as a marker of survival after traumatic injury: consistent across changing patient populations and resuscitation paradigms. AB - BACKGROUND: Damage control resuscitation (DCR) has improved outcomes in severely injured patients. In civilian centers, massive transfusion protocols (MTPs) represent the most formal application of DCR principles, ensuring early, accurate delivery of high fixed ratios of blood components. Recent data suggest that DCR may also help address early trauma-induced coagulopathy. Finally, base deficit (BD) is a long-recognized and simple early prognostic marker of survival after injury. METHODS: Outcomes of patients with admission BD data resuscitated during the DCR era (2007-2010) were compared with previously published data (1995-2003) of patients cared for before the DCR era (pre-DCR). Patients were considered to have no hypoperfusion (BD, >-6), mild (BD, -6 to -14.9), moderate (BD, -15 to 23.9), or severe hypoperfusion (BD, <-24). RESULTS: Of 6,767 patients, 4,561 were treated in the pre-DCR era and 2,206 in the DCR era. Of the latter, 218 (9.8%) represented activations of the MTP. DCR patients tended to be slightly older, more likely victims of penetrating trauma, and slightly more severely injured as measured by trauma scores and BD. Despite these differences, overall survival was unchanged in the two eras (86.4% vs. 85.7%, p = 0.67), and survival curves stratified by mechanism of injury were nearly identical. Patients with severe BD who were resuscitated using the MTP, however, experienced a substantial increase in survival compared with pre-DCR counterparts. CONCLUSION: Despite limited adoption of formal DCR, overall survival after injury, stratified by BD, is identical in the modern era. Patients with severely deranged physiology, however, experience better outcomes. BD remains a consistent predictor of mortality after traumatic injury. Predicted survival depends more on the energy level of the injury (stab wound vs. nonstab wound) than the mechanism of injury (blunt vs. penetrating). PMID- 22491597 TI - Milk fat globule epidermal growth factor-factor 8 mitigates inflammation and tissue injury after hemorrhagic shock in experimental animals. AB - BACKGROUND: Insufficient clearance of apoptotic cells leads to increased inflammation and exaggerated organ injury. The opsonizing protein, milk fat globule epidermal growth factor-factor 8 (MFG-E8), upregulates apoptotic cell clearance. The purpose of this study was to determine the degree of apoptotic cell clearance, and whether inflammation, organ injury, and survival are improved after treatment with recombinant human MFG-E8 (rhMFG-E8) after hemorrhagic shock. METHODS: Male mice underwent a pressure-controlled (25 mm Hg +/- 5 mm Hg) model of hemorrhagic shock for 90 minutes. They were resuscitated with normal saline with or without recombinant human MFG-E8 (rhMFG-E8) over 30 minutes. At 3.5-hour postresuscitation, blood and tissue were collected. MFG-E8 levels in the plasma, lungs, and spleen were measured. Apoptotic cell clearance was measured by cleaved caspase-3 levels and TUNEL staining. Neutrophil infiltration was assessed using myeloperoxidase activity in the lungs and spleen. Plasma and tissue levels of proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) were measured by ELISA. Finally, a seven-day survival study was also conducted. RESULTS: MFG-E8 levels in the plasma, lungs, and spleen significantly decreased by 33%, 44%, and 55%, respectively, at 3.5 hour after hemorrhage and resuscitation with rhMFG-E8. Treatment with rhMFG-E8 significantly improved apoptosis, by reducing TUNEL+ cells after treatment and restoring cleaved caspase-3 expression back to baseline. Neutrophil infiltration was blunted by 29% and 41% in the lungs and spleen, respectively. Cytokine expression was also reduced significantly, by 64% to 73% in plasma, 24% to 58% in the lungs, and 49% to 76% in the spleen. Finally, animals demonstrated a superior survival rate over 7 days after treatment with rhMFG-E8. CONCLUSION: The administration of rhMFG-E8 is a potent treatment in animals after hemorrhagic shock. PMID- 22491598 TI - Moving from "optimal resources" to "optimal care" at trauma centers. AB - BACKGROUND: The Trauma Quality Improvement Program has shown that risk-adjusted mortality rates at some centers are nearly 50% higher than at others. This "quality gap" may be due to different clinical practices or processes of care. We have previously shown that adoption of processes called core measures by the Joint Commission and Centers for Medicare and Medicaid Services does not improve outcomes of trauma patients. We hypothesized that improved compliance with trauma specific clinical processes of care (POC) is associated with reduced in-hospital mortality. METHODS: Records of a random sample of 1,000 patients admitted to a Level I trauma center who met Trauma Quality Improvement Program criteria (age >= 16 years and Abbreviated Injury Scale score 3) were retrospectively reviewed for compliance with 25 trauma-specific POC (T-POC) that were evidence-based or expert consensus panel recommendations. Multivariate regression was used to determine the relationship between T-POC compliance and in-hospital mortality, adjusted for age, gender, injury type, and severity. RESULTS: Median age was 41 years, 65% were men, 88% sustained a blunt injury, and mortality was 12%. Of these, 77% were eligible for at least one T-POC and 58% were eligible for two or more. There was wide variation in T-POC compliance. Every 10% increase in compliance was associated with a 14% reduction in risk-adjusted in-hospital mortality. CONCLUSION: Unlike adoption of core measures, compliance with T-POC is associated with reduced mortality in trauma patients. Trauma centers with excess in-hospital mortality may improve patient outcomes by consistently applying T-POC. These processes should be explored for potential use as Core Trauma Center Performance Measures. PMID- 22491599 TI - Predictors of critical care-related complications in colectomy patients using the National Surgical Quality Improvement Program: exploring frailty and aggressive laparoscopic approaches. AB - BACKGROUND: Colectomy patients experience a broad set of adverse outcomes. Complications requiring critical care support are common in this group. We hypothesized that as frailty increases, the risk of Clavien class IV and V complications will increase in colectomy patients. METHODS: Using the National Surgical Quality Improvement Program (NSQIP) participant use files for 2005-2009, we identified patients who underwent laparoscopic and open colectomies by Current Procedural Terminology code. Using the Clavien classification for postoperative complications, we identified NSQIP data points most consistent with Clavien class IV requiring intensive care unit (ICU) care or class V complications (death). We used a modified frailty index with 11 variables based on mapping the Canadian Study of Health and Aging Frailty Index and existing NSQIP variables. Logistic regression was performed to acuity adjust the findings. RESULTS: A total of 58,448 colectomies were identified. As frailty index increased from 0 to 0.55, the proportion of those experiencing Clavien class IV or V complications increased from 3.2% at baseline to 56.3%. Variables found to be significant by logistic regression (odds ratio) were frailty index (14.4; p = 0.001), open procedure (2.35; p < 0.001), and American Society of Anesthesiologists class 4 (3.2; p = 0.038) or 5 (7.1; p = 0.001) while emergency operation and wound classification 3 or 4 were not. CONCLUSIONS: Complications requiring ICU care represent a significant morbidity in the colectomy patient population. Frailty index seems to be an important predictor of ICU-level complications and death, and laparoscopy seems to be protective. PMID- 22491600 TI - Prospective evaluation of selective nonoperative management of torso gunshot wounds: when is it safe to discharge? AB - BACKGROUND: Selective nonoperative management (NOM) has been increasingly used for torso gunshot wounds (GSWs). The optimal observation time required to exclude a hollow viscus injury is not clear. The purpose of this study was to determine the safe period of observation before discharge. METHODS: All patients aged 16 years and older sustaining a torso GSW undergoing a trial of NOM were prospectively enrolled (January 2009 to January 2011). Patient demographics, initial computed tomography (CT) results, time to failure of NOM, operative procedures, and outcomes were collected. Failure of NOM was defined as the need for operation. RESULTS: A total of 270 patients sustained a GSW to the torso. Of those, 25 patients (9.3%) died in the emergency department and were excluded leaving 245 patients available for the analysis. Mean age was 26.5 years +/- 9.9 years (16-62 years), 92.7% (227) were men, and mean Injury Severity Score scale was 13.8 +/- 11.3 (1-45). Overall, 115 patients (46.9%) underwent immediate exploratory laparotomy based on clinical criteria (72.2% had peritonitis, 27.8% hypotension, 10.4% unevaluable, and 4.3% evisceration), and 130 patients (53.1%) underwent evaluation with CT for possible NOM. Of those, 39 patients (30.0%) had a positive CT and were subsequently operated on. All had significant intra abdominal injuries requiring surgical management. A total of 91 patients (70.0%) underwent a trial of NOM (47 had equivocal CT findings and 44 had a negative examination). Of these, 8 patients (8.8%) failed NOM and underwent laparotomy (all had equivocal CT scans). Two patients had a nontherapeutic laparotomy; the remainder had stomach (50.0%), colon (25.5%), and rectal (12.5%) injuries. The mean time from admission to development of clinical or laboratory signs of NOM failure was 2 hours:43 minutes +/- 2 hours:23 minutes (0 hour:31 minutes-6 hours:58 minutes). All patients failed within 24 hours of admission. CONCLUSION: In the initial evaluation of patients sustaining a GSW to the torso, clinical examination is essential for identifying those who will require emergency operation. For those undergoing a trial of NOM, all failures occurred within 24 hours of hospital admission, setting a minimum required observation period before discharge. PMID- 22491601 TI - Crystalloid to packed red blood cell transfusion ratio in the massively transfused patient: when a little goes a long way. AB - BACKGROUND: Massive transfusion (MT) protocols have emphasized the importance of ratio-based transfusion of plasma and platelets relative to packed red blood cells (PRBCs); however, the risks attributable to crystalloid resuscitation in patients requiring MT remain largely unexplored. We hypothesized that an increased crystalloid:PRBC (C:PRBC) ratio would be associated with increased morbidity and poor outcome after MT. METHODS: Data were obtained from a multicenter prospective cohort study evaluating outcomes in blunt injured adults with hemorrhagic shock. Patients requiring MT (>= 10 units PRBCs in first 24 hours) were analyzed. The C:PRBC ratio was computed by the ratio of crystalloid infused in liters (L) to the units of PRBCs transfused in the first 24 hours postinjury. Logistic regression modeling was used to characterize the independent risks associated with the 24-hour C:PRBC ratio, after controlling for important confounders and other blood component transfusion requirements. RESULTS: Logistic regression revealed that the 24-hour C:PRBC ratio was significantly associated with a greater independent risk of multiple organ failure (MOF), acute respiratory distress syndrome (ARDS), and abdominal compartment syndrome (ACS). No association with mortality or nosocomial infection was found. A dose-response analysis revealed that patients with a C:PRBC ratio >1.5:1 had over a 70% higher independent risk of MOF and over a twofold higher risk of ARDS and ACS. CONCLUSION: In patients requiring MT, crystalloid resuscitation in a ratio greater than 1.5:1 per unit of PRBCs transfused was independently associated with a higher risk of MOF, ARDS, and ACS. These results suggest overly aggressive crystalloid resuscitation should be minimized in these severely injured patients. Further research is required to determine whether incorporation of the C:PRBC ratio into MT protocols improves outcome. PMID- 22491602 TI - Determination of efficacy of novel modified chitosan sponge dressing in a lethal arterial injury model in swine. AB - BACKGROUND: Chitosan is a functional biopolymer that has been widely used as a hemostat. Recently, its efficacy has been questioned due to clinical failures as a result of poor adhesiveness. The purpose of this study was to compare, in a severe groin injury model in swine, the hemostatic properties of an unmodified standard chitosan sponge with standard gauze dressing and a novel hydrophobically modified (hm) chitosan sponge. Previous studies have demonstrated that hm chitosan provides greatly enhanced cellular adhesion and hemostatic effect via noncovalent insertion of hydrophobic pendant groups into cell membranes. METHODS: Twenty-four Yorkshire swine were randomized to receive hm-chitosan (n = 8), unmodified chitosan (n = 8), or standard Accu-Sorb gauze dressing (n = 8) for hemostatic control. A complex groin injury involving arterial puncture (4.4-mm punch) of the femoral artery was made after splenectomy. After 30 seconds of uncontrolled hemorrhage, the randomized dressing was applied and compression was held for 3 minutes. Fluid resuscitation was initiated to achieve and maintain the baseline mean arterial pressure and the wound was inspected for bleeding. Failure of hemostasis was defined as pooling of blood outside the wound. Animals were then monitored for 180 minutes and surviving animals were killed. RESULTS: Blood loss before treatment was similar between groups (p < 0.1). Compared with the hm chitosan sponge group, which had no failures, the unmodified chitosan sponge group and the standard gauze group each had eight failures over the 180-minute observation period. For the unmodified chitosan sponge failures, six of which provided initial hemostasis, secondary rebleeding was observed 44 minutes +/- 28 minutes after application. Standard gauze provided no initial hemostasis after the 3-minute compression interval. CONCLUSIONS: Hm-chitosan is superior to unmodified chitosan sponges (p < 0.001) or standard gauze for controlling bleeding from a lethal arterial injury. The hm-chitosan technology may provide an advantage over native chitosan-based dressings for control of active hemorrhage. PMID- 22491603 TI - Estrogen modulation of pneumonia? An immunoglobulin A effect. AB - BACKGROUND: Laboratory and clinical studies demonstrated a salutary effect of estradiol (E2) on pneumonia and other infectious complications after trauma, while dihydrotestosterone (DHT) failed to show a similar effect. Secretory immunoglobulin A is the principle antibody in the respiratory and other mucosal secretions. Immunoglobulin A (IgA) production and transport into the mucosal secretion is regulated by Toll-like receptor 4 (TLR-4). In addition, E2 may influence immune regulatory cells via TLR-4. We hypothesized that the protective effect of E2 on the development of pneumonia may be related to modulation of IgA transport into respiratory secretions. METHODS: Calu-3 respiratory epithelial cell monolayers were established in a two-chamber cell culture system. Calu-3 cells were then treated with either E2 or DHT for 3 days for maximal cell stimulation. Dimeric IgA was added to the basal chamber of Calu-3 cells, and IgA transcellular transport was indexed by recovery of secretory immunoglobulin A in the apical chamber media. In separate experiments, Klebsiella pneumonia (10(5) CFU/mL) was added to the apical chamber of treated Calu-3 cell monolayers, and bacterial passage across Calu-3 cells was determined by bacterial recovery from the basal chamber. Calu-3 cells not treated with E2 or DHT served as control. RESULTS: Calu-3 cells pretreated with E2 significantly increased IgA transport, and this effect was augmented in a dose-dependent fashion. Only cells pretreated with E2 significantly decreased bacterial passage, and this effect was exhibited in a dose- and time-dependent fashion. E2 led to a significant increase in TLR-4 expression. CONCLUSION: The protective effect of E2 against pneumonia may be related to augmented transport of IgA into the respiratory mucosal secretions. PMID- 22491604 TI - Editorial critique. PMID- 22491605 TI - Advanced endotracheal tube biofilm stage, not duration of intubation, is related to pneumonia. AB - BACKGROUND: Biofilms are complex communities of living bacteria surrounded by a protective glycocalyx. Biofilms have been implicated in the development of infections such as dental caries and hardware infections. Biofilms form on endotracheal tubes (ETT) and can impact airway resistance. The lifecycle of a biofilm has four stages. We hypothesize that there is a relationship between the stage of biofilm on the ETT and development of pneumonia. METHODS: Thirty-two ETT were analyzed for biofilms and staged. Staging was performed by a microbiologist blinded to all patient information. Data included development of pneumonia, duration of intubation, comorbidities, and microbiology. Pneumonia was defined as presence of fever, WBC >12 K or <4 K, infiltrate on chest X-ray, and purulent sputum with +lower airway culture (bronchoalveolar lavage or brush). Statistics were performed by a biostatistician; p < 0.05 defined significance. RESULTS: There were 11 women and 21 men with a mean age of 50 years. Mean intensive care unit days were 13 (standard deviation +/- 9.9) and mean length of intubation was 7.4 days (standard deviation +/- 5.0). Half (16 of 32) the patients developed pneumonia while intubated. Eight of 10 patients with a stage IV biofilm had pneumonia. There was a relationship between increasing biofilm stage with the incidence of pneumonia (p < 0.05). Stage IV biofilms were associated with pneumonia (p < 0.02). There was no relationship to duration of intubation, patient age or hospital stay and biofilm stage. CONCLUSIONS: Advanced biofilm stage (stage IV) is associated with pneumonia. Duration of intubation does not predict biofilm stage. PMID- 22491606 TI - Single-drug sedation with fentanyl for prehospital postintubation sedation in trauma patients. AB - BACKGROUND: A fentanyl-only (FO) regimen for prehospital postintubation sedation in trauma patients was compared with the standard protocol (SP) of fentanyl + benzodiazepine. METHODS: Intubated patients transported to a Level I trauma center from December 1, 2005, to April 30, 2009, were retrospectively reviewed. Before 2007, only SP was used; afterward both regimens were used. Groups were compared for hemodynamic and neurologic parameters in the prehospital setting and trauma bay, fluid volumes, time until general or neurosurgical intervention (NSI), and other outcomes. RESULTS: Groups were comparable with respect to age, sex, mechanism, alcohol level, intensive care unit length of stay, and hospital length of stay. Comorbidities were similar except hypertension (p = 0.019), and stroke (p = 0.029) were more frequent in FO patients. Prehospital heart rate and Glasgow Coma Scale (GCS) were similar. Trauma bay hemodynamic parameters and fluid resuscitation volumes were comparable, but pupil nonreactivity was more frequent in the FO group both overall (p = 0.032) and when comparing only patients with traumatic brain injury (TBI; p = 0.014). The incidence of TBI was comparable. Although the frequency of craniotomy (13% FO vs. 7% SP) and mortality (17% FO vs. 11% SP) were not statistically different overall, in patients with TBI, there was a higher incidence of NSI (28% vs. 14%, p = 0.015), craniotomy (14% vs. 3%, p = 0.02), and time to initial NSI (446 minutes vs. 193 minutes, p = 0.042) in the FO patients. CONCLUSIONS: In this study, an FO regimen was associated with similar hemodynamic but worse neurologic variables compared with the SP regimen. Prospective evaluation is warranted before adoption of this regimen, especially in TBI patients. PMID- 22491607 TI - Prehospital dynamic tissue oxygen saturation response predicts in-hospital lifesaving interventions in trauma patients. AB - BACKGROUND: Tissue oximetry (StO2) plus a vascular occlusion test is a noninvasive technology that targets indices of oxygen uptake and delivery. We hypothesize that prehospital tissue oximetric values and vascular occlusion test response can predict the need for in-hospital lifesaving interventions (LSI). METHODS: We conducted a prospective, blinded observational study to evaluate StO2 slopes to predict the need for LSI. We calculated the DeO2 slope using Pearson's coefficients of regression (r2) for the first 25% of descent and the ReO2 slope using the entire recovery interval. The primary outcome was LSI defined as the need for emergent operation or transfusion in the first 24 hours of hospitalization. We created multivariable logistic regression models using covariates of age, sex, vital signs, lactate, and mental status. RESULTS: We assessed StO2 in a convenience sample of 150 trauma patients from April to November of 2009. In-hospital mortality was 3% (95% confidence interval [CI], 1.1 7.6); 31% (95% CI, 24-39) were admitted to the intensive care unit, 6% (95% CI, 2.8-11.1) had an emergent operation, and 10% (95% CI, 5.7-15.9) required transfusion. Decreasing DeO2 was associated with a higher proportion of patients requiring LSI. In the multivariate model, the association between the need for LSI and DeO2, Glasgow Coma Scale, and age persists. CONCLUSION: Prehospital DeO2 is associated with need for LSI in our trauma population. Further study of DeO2 is warranted to determine whether it can be used as an adjunct triage criterion or an endpoint for resuscitation. PMID- 22491608 TI - Coagulation management of bleeding trauma patients is changing in German trauma centers: an analysis from the trauma registry of the German Society for Trauma Surgery. AB - BACKGROUND: Recent findings have emphasized the need for early and aggressive coagulation support in bleeding trauma patients. This study aimed to examine whether blood component transfusion and hemostatic drug administration during acute trauma care have changed in daily practice during the recent years. METHODS: The multicenter trauma registry of the German Society for Trauma was retrospectively analyzed for primarily admitted patients older than 16 years with an Injury Severity Score >= 16 who had received at least five red blood cell (RBC) units between emergency room arrival and intensive care unit admission. Administration of fresh frozen plasma and platelet units has been documented since 2002, and use of hemostatic drugs since 2005. RESULTS: From 2002 until 2009 (n = 2,813), the fresh frozen plasma:RBC ratio increased from 0.65 to 0.75 (p = 0.02) and the platelet:RBC ratio from 0.04 to 0.09 (p < 0.0001). A constant increase was also observed regarding the overall use of hemostatic drugs (n = 1,811; 2005-2009) as these were administered to 43.4% of the patients in 2005 and to 60.7% in 2009 (p < 0.0001). Especially, the administration of fibrinogen concentrate (2005: 17.0%, 2009: 45.6%; p < 0.0001) and recombinant factor VIIa (2005: 1.9%, 2009: 6.3%; p = 0.04) showed a marked increase. However, mortality rates remained unchanged during the 8-year study period. CONCLUSIONS: The therapy of bleeding trauma patients has changed in Germany during the recent years toward more aggressive coagulation support. This development continues although grades of evidence are still low regarding most of the changes reported in our study. Randomized controlled trials are needed with respect to blood component therapy using predefined ratios and to the administration of hemostatic drugs commonly used for the severely injured. PMID- 22491609 TI - Admission heart rate is a predictor of mortality. AB - BACKGROUND: The association between admission heart rate (AHR) and mortality after trauma can assist initial emergency department triage and resuscitation. In addition, increased AHR is often associated with sympathetic hyperactivity which may require targeted treatment. We determined whether AHR was a predictor for mortality in trauma patients. METHODS: The Los Angeles County Trauma System Database was queried for all injured patients admitted between 1998 and 2005 (n = 147,788). Traumatic brain injury (TBI) patients (head Abbreviated Injury Scale score >= 3) were excluded. Demographics were compared at various AHR subgroups (<50, 50-59, 60-69, 70-79, 80-89, 90-99, 100-109, and >= 110). Mortality was compared at various AHR ranges, and logistic regression was performed to determine significance. RESULTS: After exclusions, 103,799 trauma patients requiring admission were identified; overall mortality was 1.4%. AHR 80 to 89 demonstrated a statistically significant lower mortality (0.5%) compared with all other AHR ranges, except AHR 70 to 79 (0.6%). In trauma patients who required admission, AHR 70 to 79 and 80 to 89 were predictors of lower mortality. Mortality for 22,232 moderate to severely injured patients was 5.5% and AHR 80 to 89 demonstrated a statistically lower mortality (2.0%) than all other AHR ranges, except AHR 70 to 79 (1.9%). After moderate to severe trauma, AHR <60 and >= 100 were associated with significantly higher mortality. CONCLUSION: Mortality after trauma increases outside the AHR range of 70 to 89 beats per minute. AHR ranges previously considered "normal" were associated with significantly increased mortality. Prospective research is required to evaluate if resuscitation goals should target heart rate at the 70 to 89 range. PMID- 22491610 TI - Effect of mini-fragment fixation on the stabilization of medial malleolus fractures. AB - BACKGROUND: Oblique fractures of the medial malleolus can arise from the application of axial force at various anatomic positions of the ankle, including supination-external rotation, pronation-external rotation, or pronation abduction. Although a variety of techniques exist to provide fixation of horizontal medial malleolus fractures, the optimal technique and pattern for internal fixation remains unclear. The aim of this study was to evaluate the mechanical properties of four different fixation methods for fractures of the medial malleolus. METHODS: Identical oblique osteotomies were created in synthetic distal tibiae using a jig. The specimens were divided into four fixation groups: contoured 2.0 mm mini-fragment T-plate, figure-of-eight tension band wire, construct two parallel 4.0 mm cancellous screws, and two divergent 4.0 mm cancellous screws. The specimens were tested using offset axial tension at 10 mm/min until 2 mm of joint line displacement. RESULTS: The average stiffness in tension and force at 2 mm of joint line displacement of the plate construct was significantly greater than any of the other constructs (p < 0.05), whereas the average stiffness in tension of the other three groups were not significantly different from each other (p > 0.05). CONCLUSION: Using a contoured 2.0 mm mini fragment T-plate as the method of fixation resulted in an at least 25% stiffer construct during tension and required at least 24% more force for 2 mm of joint line displacement when compared with more traditional methods of fixation in an osteotomy model of an oblique medial malleolus fracture. PMID- 22491611 TI - The impact of plasma preparations and their storage time on short-term posttransfusion mortality: a population-based study using the Scandinavian Donation and Transfusion database. AB - BACKGROUND: The treatment of coagulopathy and bleeding in severe trauma requires rapid delivery of large amounts of plasma to emergency wards. The resulting need for adequate supplies of nonfrozen or thawed plasma has consequences for storage strategies. Using extensive population data from a setting where both fresh frozen plasma (FFP) and cold-stored liquid plasma were used, this study investigates whether there is an association between short-term mortality after receipt of FFP or liquid plasma of different storage times. METHODS: A cohort of 84,986 Swedish patients was followed up from first recorded allogenic plasma transfusion for 14-day mortality. Associations with exposure to FFP were expressed as relative risks adjusted for patient characteristics, total transfusions, hospital, and calendar year. For non-FFP, the units given to patients who died and matched patients who survived were compared for their duration of storage. RESULTS: The relative risk of exposure to FFP was 1.19 (95% confidence interval: 1.12-1.27, p < 0.0001), with the risk elevation confined to the earlier calendar years of the study. There was no evidence of any effect of storage time of non-FFP. In analyses of all plasma types, FFP from male donors had lowest risk. CONCLUSIONS: Compared with exclusive use of never-frozen plasma, FFP was associated with increased short-term mortality in the era before leukocyte depletion. FFP from female donors had a significantly higher risk than male FFP. For non-FFP, duration of storage was unrelated to mortality. These findings can help to inform policies for managing high plasma demand in critical care. PMID- 22491612 TI - Trauma center volume and quality improvement programs. AB - BACKGROUND: Growing evidence suggests that for many treatments, a relationship exists between provider volume and patient outcomes. This relationship is less clear in injury management. We sought to evaluate whether a relationship exists between trauma center volume and the nature of quality improvement (QI) programs. METHODS: This is a survey of 154 verified adult trauma centers in the United States, Canada, Australia, and New Zealand (76% response rate) regarding their QI programs. Centers were classified according to American College of Surgeons annual volume requirements for a Level I center (low volume vs. high volume) and QI programs compared. RESULTS: All participating trauma centers reported using a trauma registry and measuring quality of care. Low-volume centers were more likely than high-volume centers to use quality indicators for evaluating triage and patient flow (18% vs. 13%, p < 0.001), effectiveness of care (33% vs. 30%, p = 0.016), and efficiency of care (29% vs. 23%, p < 0.001). High-volume centers were more likely to use quality indicators for evaluating medical errors and adverse events (30% vs. 36%, p < 0.001) and the use of guidelines/protocols (2% vs. 3%, p = 0.001). Report cards (41% vs. 59%, p = 0.025) and internal benchmarking (79% vs. 91%, p = 0.040) were less frequently reported to be used by low-volume than high-volume centers. CONCLUSIONS: Both low- and high-volume centers reported being engaged in QI. Small differences in the types of quality indicators used by centers were observed according to volume, with high-volume centers more likely than low-volume centers to use report cards and benchmarking as QI tools. PMID- 22491613 TI - Mortality and morbidity from combat neck injury. AB - BACKGROUND: Neck injury represents 11% of battle injuries in UK forces in comparison with 2% to 5% in US forces. The aim of this study was to determine the causes of death and long-term morbidity from combat neck injury in an attempt to recommend new methods of protecting the neck. METHOD: Hospital and postmortem records for all UK servicemen sustaining battle injuries to the neck between January 1, 2006 and December 31, 2010 were analyzed. RESULTS: Neck wounds were found in 152 of 1,528 (10%) of battle injured service personnel. Seventy-nine percent of neck wounds were caused by explosions and were associated with a mortality rate of 41% compared with 78% from gunshot wounds (GSWs). Although current UK OSPREY neck collars can potentially protect zone I from explosive fragments, in the 58% in which the wearing of a neck collar was known, all service personnel chose not to wear the collar. The most common cause of death from explosive fragments was vascular injury (85%). Zone II was the most commonly affected area overall by explosive fragments and had the highest mortality but zone I was associated with the highest morbidity in survivors. CONCLUSIONS: Nape protectors, that cover zone III of the neck posteriorly, would only have potentially prevented 3% of injuries and therefore this study does not support their use. Current UK OSPREY neck collars potentially protect against the majority of explosive fragments to zones I and II and had these collars been worn potentially 16 deaths may have been prevented. Reasons for their lack of uptake by UK servicemen is therefore being evaluated. Surface wound mapping of penetrating explosive fragments in our series has been used to validate the area of coverage required for future designs of neck protection. PMID- 22491614 TI - Epidemiology and predictors of cervical spine injury in adult major trauma patients: a multicenter cohort study. AB - BACKGROUND: Patients with cervical spine injuries are a high-risk group, with the highest reported early mortality rate in spinal trauma. METHODS: This cohort study investigated predictors for cervical spine injury in adult (>= 16 years) major trauma patients using prospectively collected data of the Trauma Audit and Research Network from 1988 to 2009. Univariate and multivariate logistic regression analyses were used to determine predictors for cervical fractures/dislocations or cord injury. RESULTS: A total of 250,584 patients were analyzed. Median age was 47.2 years (interquartile range, 29.8-66.0) and Injury Severity Score 9 (interquartile range, 4-11); 60.2% were male. Six thousand eight hundred two patients (2.3%) sustained cervical fractures/dislocations alone. Two thousand sixty-nine (0.8%) sustained cervical cord injury with/without fractures/dislocations; 39.9% of fracture/dislocation and 25.8% of cord injury patients suffered injuries to other body regions. Age >= 65 years (odds ratio [OR], 1.45-1.92), males (females OR, 0.91; 95% CI, 0.86-0.96), Glasgow Coma Scale (GCS) score <15 (OR, 1.26-1.30), LeFort facial fractures (OR, 1.29; 95% confidence interval [CI], 1.05-1.59), sports injuries (OR, 3.51; 95% CI, 2.87 4.31), road traffic collisions (OR, 3.24; 95% CI, 3.01-3.49), and falls >2 m (OR, 2.74; 95% CI, 2.53-2.97) were predictive for fractures/dislocations. Age <35 years (OR, 1.25-1.72), males (females OR, 0.59; 95% CI, 0.53-0.65), GCS score <15 (OR, 1.35-1.85), systolic blood pressure <110 mm Hg (OR, 1.16; 95% CI, 1.02 1.31), sports injuries (OR, 4.42; 95% CI, 3.28-5.95), road traffic collisions (OR, 2.58; 95% CI, 2.26-2.94), and falls >2 m (OR, 2.24; 95% CI, 1.94-2.58) were predictors for cord injury. CONCLUSIONS: 3.5% of patients suffered cervical spine injury. Patients with a lowered GCS or systolic blood pressure, severe facial fractures, dangerous injury mechanism, male gender, and/or age >= 35 years are at increased risk. Contrary to common belief, head injury was not predictive for cervical spine involvement. PMID- 22491615 TI - Leptin administration alleviates ischemic brain injury in mice by reducing oxidative stress and subsequent neuronal apoptosis. AB - BACKGROUND: Recent research has indicates that leptin plays a protective role in traumatic brain injury. We studied the protective effect of leptin on cerebral ischemia/reperfusion injury by using mice transient focal cerebral ischemia/reperfusion injury model. METHODS: The distribution of 125I-leptin in the mouse brain was assessed by radioimmunoassay method. Mouse models of transient focal cerebral ischemia were established by occlusion of the right middle cerebral artery for two hours followed by 24 hours reperfusion. The neurologic deficits and infarct volume were determined using the Longa's score and 2,3,5-triphenyltetrazolium chloride staining, respectively. Regional cerebral blood flow was monitored by a laser-Doppler blood flowmeter. The levels of malondialdehyde, nitric oxide, nitric oxide synthase, and superoxide dismutase were detected according to respective assay kit. The histologic changes and neuronal apoptosis were observed with hematoxylin and eosin and transferase mediated dUTP-biotin nick end labeling staining, respectively. The expression of B-cell lymphoma/leukemia-2 (Bcl-2) and cysteineasparateprotease-3 (caspase-3) were investigated by Western blot and real-time polymerase chain reaction assay. RESULTS: Leptin decreased infarct volume and neurologic defects and improved regional cerebral blood flow and microvascular branch blood flow after injury. The malondialdehyde and nitric oxide levels were reduced, and superoxide dismutase level was increased after leptin treatment, which also minimized histologic changes and neuronal apoptosis, led to the upregulation of Bcl-2 and downregulation of caspase-3 expression after injury. CONCLUSIONS: Peripherally administered leptin crossed the blood-brain barrier and was distributed into multiple regions of the brain; in the brain, leptin directly alleviated the injury-evoked damages by reducing oxidative stress and neuronal apoptosis. PMID- 22491616 TI - Persistent and progressive pulmonary fibrotic changes in a model of fat embolism. AB - BACKGROUND: Fat embolism (FE) after trauma and some orthopedic procedures is known to cause acute lung injury, including acute respiratory distress syndrome. However, its potential long-term effects on the lung are unknown. A previous study using a rat model of FE found significant histopathologic changes in the lungs after intravenous injection of triolein for up to 11 days. This study detailed the persistence of the lung damage and investigated the input of the renin-angiotensin system in its pathology. METHODS: Unanesthetized rats were injected via the tail vein with 0.2 mL saline or triolein. After euthanasia, at 3 weeks or 6 weeks, lung sections were stained to highlight cellular structure, presence of collagen and fat, or immunolabeled for smooth muscle actin or angiotensin peptides. RESULTS: At 3 weeks or 6 weeks after triolein injection, there was no dilatation of the heart or inferior vena cava, no congestion of the liver or spleen, no adventitial edema, nor was fluid present in alveoli or pleural cavity as reported in animals at earlier time points. Persisting pathology included reduced lumen patency, thickening of the media of small arteries and arterioles, and vascular and septal inflammation. Although the fat content of the lung decreased from week 3 to week 6, there was a progressive increase in collagen, smooth muscle actin, and angiotensin peptides. CONCLUSIONS: This model extends the effect of FE on pulmonary pathology to 6 weeks, revealing persistent vasculitis, septal inflammation, and progressive fibrotic changes which are associated with increased presence of angiotensin peptides. PMID- 22491617 TI - Prediction of clinical outcomes for massively-burned patients via serum transthyretin levels in the early postburn period. AB - BACKGROUND: We observed that serum transthyretin (TTR) levels consistently remain low when patients' general conditions are poor, despite adequate nutritional support. We conducted this study to analyze the changes of serum TTR over time from injury in massively-burned patients and verify the validity of prediction by clinical outcomes, which are assessed via serum TTR in the early postburn period. METHODS: From January 2005 to December 2010, the samples of serum TTR from 471 burn patients (mean % total body surface area [TBSA] burned, 51% +/- 20%) were analyzed with time frames from injury retrospectively. RESULTS: Serum TTR significantly decreased during the period from day 5 to day 10 postinjury in both the survival group (n = 290, mean %TBSA burned, 42.9% +/- 14.2%) and nonsurvival group (n = 181, mean %TBSA burned, 64.6% +/- 20.8%). However, after this period, the serum TTR constantly increased in the survival group but remained low in nonsurvivors. At all time, the levels of serum TTR obtained from survivors were significantly higher than those of nonsurvivors. The serum TTR had weak correlation with the extent of the burn injury (r = -0.234). Survival rates of the patients increased significantly by the increase of the serum TTR of early postburn period. In multivariable model, age (odds ratio [OR], 1.054; 95% confidence interval [CI], 1.043-1.066; p = 0.000), TBSA burned (OR, 1.058; 95% CI, 1.051-1.066; p = 0.000), sex (OR, 0.720; 95% CI, 0.547-0.947; p = 0.019), and serum TTR during early postburn period (OR, 1.05; 95% CI, 0.873-0.972; p = 0.003) were independently associated with mortality. CONCLUSIONS: The serum TTR of early postburn period can be used as a prognostic markers, and low serum TTR can be used as a signal for screening out the patients at risk who need careful assessment and monitoring at an early stage. PMID- 22491618 TI - Continuously recorded oxygen saturation and heart rate during prehospital transport outperform initial measurement in prediction of mortality after trauma. AB - INTRODUCTION: Available trauma scoring systems that predict need for higher echelons of care require data not available in the field. We hypothesized that analysis of continuous vital sign data in comparison to trauma registry data predicts mortality early in trauma patient management. METHODS: A real-time vital signs wave form and data capture system collected trauma patient data during prehospital management from Propaq 206E physiologic monitors. Analysis using statistical and mathematical software calculated receiver operator characteristic curves to evaluate the sensitivity and specificity of continuous vital sign waveforms in predicting mortality. The area under the curve (AUC) was calculated to determine nonsurvival by a particular vital sign (oxygen saturation [SpO2], heart rate, and systolic blood pressure) from these data, compared with a single value in the trauma registry, and to standard trauma scoring systems. RESULTS: The average transport time from field to hospital for all patients was 25 minutes. Eight of 120 patients (7%) died; 5 of 8 patients (62%) died within the first 24 hours. Receiver operator characteristic analysis of mean SpO2 <90% versus mortality yielded an AUC of 0.76 (p = 0.005) with a sensitivity of 62% and specificity of 86% The initial SpO2 <90% measurement from the trauma registry yielded an AUC of 0.59. Preadmission Glasgow Coma Scale score yielded an AUC of 0.74 (p = 0.009). Injury Severity Score and Trauma-Injury Severity Score produced AUCs of 0.91 and 0.96, respectively. Revised Trauma Score gave an AUC of 0.73, no different from automated predictions of mortality from SpO2. CONCLUSION: Injury Severity Score and Trauma-Injury Severity Score are predictive of mortality but rely on the inclusion of intra-abdominal and intrathoracic diagnostic data that are not readily available during field assessment. Automated vital signs data collection and analysis from a single noninvasive device with decision support has the potential to alleviate the dual burdens of patient triage and documentation required of the prehospital provider. PMID- 22491619 TI - Efficacy of beta-blockade after isolated blunt head injury: does race matter? AB - BACKGROUND: Several retrospective clinical studies and recent prospective animal models demonstrate improved outcomes with beta-blocker administration after isolated blunt head injury. However, no investigations to date have examined the influence of race on the potential therapeutic effectiveness of these medications. Our hypothesis was that mortality benefits associated with beta blocker exposure after isolated blunt head injury varies based on ethnicity. METHODS: The trauma registry and the surgical intensive care unit (ICU) databases of an academic Level I trauma center were used to identify all patients sustaining blunt head injury requiring ICU admission from July 1998 to December 2009. Patients sustaining major associated extracranial injuries (Abbreviated Injury Scale [AIS] score >= 3 in any body region) were excluded. Patient demographics, injury profile, Injury Severity Score, and beta-blocker exposure were abstracted. The primary outcome evaluated was in-hospital mortality stratified by ethnicity. RESULTS: During the 11-year study period, 3,750 patients were admitted to the Los Angeles County + University of Southern California Medical Center trauma ICU because of blunt trauma. Of these, 65% (n = 2,446) had an "isolated" head injury. When stratified by race, most patients were Hispanics (60%), followed by Whites (21%), Asians (11%), and African Americans (8%). After adjusting for confounding variables with multivariate regression, only those of Asian and Hispanic descent demonstrated significantly improved outcomes associated with beta-blocker administration. CONCLUSIONS: Our results indicate that beta-blockade after traumatic brain injury may not benefit all races equally. Further prospective research is necessary to assess this discrepancy in treatment benefit and explore other possible therapeutic interventions. PMID- 22491620 TI - Nonsurgical management of delayed splenic rupture after blunt trauma. AB - BACKGROUND: Delayed splenic rupture (DSR) is a rare manifestation of blunt splenic trauma, and splenectomy remains the primary treatment for patients with DSR. The purpose of this study was to review our experience with nonsurgical management of DSR with the use of splenic artery embolization (SAE) as an adjunct treatment. METHODS: This retrospective study included patients with DSR treated at our institution from January 2001 to December 2008. Management included initial resuscitation and close observation in the intensive care unit. Further interventions were based on the patient's hemodynamic status and followed a treatment protocol. These interventions included SAE or surgery. RESULTS: There were 15 patients included in the analysis. Three patients underwent emergent surgery, and 12 patients received nonsurgical management initially. Of these 12 patients, five underwent SAE. One of these five patients subsequently underwent splenectomy because of recurrent bleeding. Of the remaining seven patients who received nonoperative management, one required a splenectomy because of recurrent hemorrhage and hypotension. There were no mortalities; however, two surgery associated complications occurred. The success rate of nonsurgical therapy was 83%. SAE was used for splenic salvage with a success rate of 80% (4 of 5). The overall failure rate of DSR was 33% (5 of 15). CONCLUSIONS: Nonsurgical management can safely be used in selected patients with DSR, especially for those with a good response to resuscitation. SAE is as effective for DSR as it is for acute splenic injury. Physicians should consider SAE as an option for the treatment of DSR. PMID- 22491621 TI - Prediction of minimally conscious state with somatosensory evoked potentials in long-term unconscious patients after traumatic brain injury. AB - BACKGROUND: To evaluate the predictive power of somatosensory evoked potentials (SEPs) for minimally conscious state (MCS) in long-term unconscious patients after traumatic brain injury (TBI). METHODS: SEPs were recorded in 58 patients with duration of unconsciousness >30 days after TBI. SEPs were classified into three grades. Predictors including age, sex, Glasgow Coma Scale (GCS), and cause of injury were also analyzed, respectively. The outcome was divided into two groups including unconscious group and MCS group. The outcome was assessed at 12 months after TBI. RESULTS: In 58 patients, 22 of 58 were minimally conscious, 3 of 58 dead, and 33 of 57 were still in vegetative state at 12 months after TBI. SEPs grade (p = 0.001) and GCS (p = 0.010) were significantly associated with the outcome. The area under the receiver operator characteristic curve of SEPs was 0.891 +/- 0.048 (p < 0.001; 95% confidence interval, 0.798-0.984) for predicting outcome, and of GCS score was only 0.746 +/- 0.066 (p = 0.002; 95% confidence interval, 0.616-0.876). The accuracy of the whole model for predicting unconscious and MCS was 91.7% and 86.4%, respectively. The overall correct prediction was as high as 89.7% (p < 0.001). CONCLUSIONS: SEPs are excellent in predicting the outcome of long-term unconscious patients after TBI. SEPs should be considered more often and more routinely used after TBI. PMID- 22491622 TI - Focus on pediatric intentional trauma. AB - BACKGROUND: Based on our previous study, pediatric intentional trauma injuries with Injury Severity Scores (ISS) >= 12 were more commonly observed in the urban than the rural setting (15.2% vs. 5.5%) in Alberta from 1996 to 2006. We wish to understand differences between urban and rural pediatric intentional trauma to plan for prevention and supportive strategies. METHODS: Data were extracted from the Alberta Trauma Registry on pediatric patients (0-17 years) with ISS >= 12, treated from 1996 to 2010 at the Stollery Children's Hospital. Statistical analysis was made comparing urban versus rural groups using t test and chi2 with p < 0.05 considered significant. RESULTS: There were 170 pediatric patients who suffered intentional injury (urban = 58.3%; rural = 41.8%; not significant), with a majority of males (72.4%). Two groups were predominant: the very young (<1 year) at 17.1% of all injuries and the teens (>= 15 years) at 54.1%. The cause of intent injury was child abuse (31.2%), assault with blunt object (24.6%), assault with a sharp object (22.9%), and suicide (18.2%). The mean ISS was 22.9 +/- 7.8 standard deviation. Tragically, 29 patients (17.1%) died. There were no differences between urban and rural pediatric trauma in terms of age, gender, cause of injury, ISS, survival, length of stay, pediatric intensive care unit length of stay, number of operations needed, or alcohol. CONCLUSION: An important pattern of intentional injuries can be seen where preventative efforts can be strengthened regardless of urban or rural area: the very young as shaken baby cases and the teens, who unfortunately, accounted for the majority of suicidal attempts. PMID- 22491623 TI - Responses of distraction regenerate to high-frequency traction at a rapid rate. AB - BACKGROUND: Continuous traction is capable of creating an optimal biological environment for bone healing which may finally compensate for the rapid distraction rate in distraction osteogenesis. This study was designed to investigate the response of distraction callus to continuous distraction at a rapid rate using a rabbit model of mandibular lengthening. METHODS: Thirty adult New Zealand white rabbits were randomly assigned to the intermittent (1 step/d) or continuous distraction (8 steps/s) group, with 15 in each. After osteotomy, manual-driven or autodriven distractor was adapted accordingly. The distraction was activated at a rate of 3.0 mm/d for 4 days. Five rabbits in each group were killed at week 2, week 4, and week 12 of consolidation, respectively. Plain radiography, microcomputed tomography, and histology examinations were used to evaluate the bone regeneration status. RESULTS: Plain radiographs and histologic studies demonstrated more advanced bone healing in continuous distraction group than that in intermittent distraction group at all the examined time points. Quantitative microcomputed tomography analysis showed significantly higher bone volume in continuous distraction group at week 2 (p < 0.01) and week 4 (p < 0.05) of consolidation. CONCLUSIONS: Continuous traction by autodriven distractor could be a promising clinical alternative to shorten the treatment course of distraction osteogenesis. Further studies to test its clinical potential using large animals that have similar metabolic rate and muscular resistance with human being are necessary. PMID- 22491624 TI - Vascularized periosteal transfer from the medial femoral condyle: is it compulsory to include the cortical bone? AB - BACKGROUND: The corticoperiosteal flap from the medial femoral condyle has become the workhorse in the management of recalcitrant nonunions with vascularized periosteum. Inclusion of the outer condylar cortex has been advocated to avoid damaging the osteogenic capacity of the periosteum and is at present an ordinary technical step in the procedure. PATIENTS: A clinical prospective study was undertaken to evaluate the effectiveness of periosteal-only microvascular transfers from the medial femoral condyle associated with bone grafts in the treatment of recalcitrant nonunions. A group of 8 patients with periosteal-only flaps (study group) is compared with a corticoperiosteal control group (13 patients). A statistical analysis is made of the results. RESULTS: We had 100% union rate in both the study and control groups. Evaluation of early signs of bone healing by two independent evaluators did not found differences between the groups (4.5 months in the study and 4.9 months in the control group). CONCLUSIONS: Although not statistically significant because of the small sample size, our study might support the idea that both periosteal and corticoperiosteal flaps from the medial femoral condyle are effective, when associated with a bone graft, in the treatment of recalcitrant nonunions with small gaps. A further analysis of the results suggests, albeit no statistical significant, that structural and nonstructural bone grafts are both effective when associated with a vascularized periosteal or corticoperiosteal transfer from the medial femoral condyle. PMID- 22491625 TI - Risk factors for postoperative complications of displaced clavicular midshaft fractures. AB - BACKGROUND: This study evaluated the risk factors of the complications following operative treatment of an acute displaced clavicular midshaft fracture using a reconstruction plate. METHODS: One hundred twenty-five patients with an acute displaced clavicular midshaft fracture underwent open reduction and plate fixation using a reconstruction plate. Cerclage wires or interfragmentary screws were used for additional comminuted fragment fixation. Clinical outcomes and radiologic evaluation were assessed. Risk factors for postoperative complications requiring reoperation were analyzed by univariate analysis. RESULTS: Bony union was achieved in 110 patients without any complications within 10.6 weeks postoperatively. Fifteen patients (12%) had a complication requiring reoperation. Implant-related complications occurred in 10 patients (plate breakage in 6 and plate loosening in 4). Deep infection and intractable adhesive capsulitis occurred in one and two patients, respectively. Refracture of the same clavicle after plate removal occurred in two patients. All patients with plate breakage demonstrated nonunion at the time of second operation. Unlike plate breakage, plate loosening was found to be associated with technical errors. Preoperative fracture pattern (p = 0.012) and usage of cerclage wires for additional fragment fixation were found to be significantly related to implant failure (p = 0.009). CONCLUSIONS: Open reduction and internal fixation using a reconstruction plate for acute displaced clavicular midshaft fractures demonstrated satisfactory clinical outcomes and favorable bony union rates. However, hardware-related complications because of fracture pattern, nonunion, and inadequate surgical techniques require detailed consideration. Furthermore, when additional fixation is needed for comminuted fracture fragments, interfragmentary screw fixation is recommended before cerclage wiring. PMID- 22491626 TI - Factors predicting failure of patella fixation. AB - BACKGROUND: Surgical fixation of patella fractures is frequently indicated due to disruption of the quadriceps mechanism. Operative technique varies; however, failure rates can be high. The purpose of this study was to compare the effectiveness of various techniques for the fixation of patella fractures and the etiology of fixation failure. METHODS: We retrospectively reviewed 173 patella fractures treated operatively at two Level I trauma centers. Patients with less than 90 days of follow-up, inadequate radiographic studies, and partial or total excision were excluded. Failure was defined as hardware breakage, nonunion, or displacement of fragments from their initial reduced position. Twelve factors were examined independently for predictive value using both univariate and multivariate analyses. A comparison between groups based on reoperation and hardware removal was also performed. RESULTS: One hundred nine patients met the inclusion criteria, and 13 were found to have failed (12%). Both older patient age (p < 0.02) and use of K-wires, with or without tension-band wires (p < 0.04), were found to be significant predictors of failure. Increasing follow-up time was the only significant predictor of reoperation (p < 0.001) and hardware removal (p < 0.001). CONCLUSIONS: As anticipated, increasing age was found to correlate with higher failure rates. Use of K-wires with or without tension-band wires correlated with higher failure rates, compared with the use of screws, both K wires and screws, or other fixation. Increasing follow-up time predicted both reoperation and hardware removal, with patients having symptomatic hardware and other complications naturally returning to clinic for evaluation and treatment. PMID- 22491627 TI - Surgical treatment of transverse patella fractures by the cable pin system with a minimally invasive technique. AB - BACKGROUND: Transverse patella fractures are the most common type of patella fractures. Minimally invasive surgical technique for treatment of transverse patella fractures with the Cable Pin System has not been previously reported. METHODS: Thirty-four patients with displaced transverse fractures of the patella were included in this prospective study and were operatively treated by the Cable Pin System with a minimally invasive technique. Postoperative evaluation was based on radiographs, Visual Analog Scale of pain, range of motion, and Bostman grading scale. RESULTS: A total of 31 patients were finally included, with an average follow-up period of 21 months. The average operation time was 48 minutes. Intraoperative fluoroscopy was used for 2 to 4 times (average: 2.4 times). Radiographic evidence of solid fracture union was observed in all cases in a mean period of 7.2 weeks. The Visual Analog Scale score for pain was 3.3 +/- 1.4 and 1.5 +/- 1.3 at 4 weeks after surgery and when radiographic fracture healing was achieved, respectively. Twenty-nine patients achieved full knee range of motion, while two patients had 10 degrees loss of full flexion at the final follow-up visit. The average Bostman score was 29.1/30 (range, 27-30) at 1 year after surgery, and an evaluation of "excellent" was observed in 30 patients at the final follow-up visit. CONCLUSION: Surgical treatment of transverse patella fractures by the Cable Pin System with a minimally invasive technique was shown to provide satisfactory clinical results and excellent knee functions, with less pain and low incidence of complications. It could be a new option for treatment of transverse patella fractures. PMID- 22491628 TI - Microbiology and injury characteristics in severe open tibia fractures from combat. AB - BACKGROUND: Type III open tibia fractures are common combat injuries. The purpose of the study was to evaluate the effect of injury characteristics and surveillance cultures on outcomes in combat-related severe open tibia fractures. METHODS: We conducted a retrospective study of all combat-related open Gustilo and Anderson (G/A) type III diaphyseal tibia fractures treated at our centers between March 2003 and September 2007. RESULTS: One hundred ninety-two Operation Iraqi Freedom/Operation Enduring Freedom military personnel with 213 type III open tibial shaft fractures were identified. Fifty-seven extremities (27%) developed a deep infection and 47 extremities (22%) ultimately underwent amputation at an average follow-up of 24 months. Orthopedic Trauma Association type C fractures took significantly longer to achieve osseous union (p = 0.02). G/A type III B and III C fractures were more likely to undergo an amputation and took longer to achieve fracture union. Deep infection and osteomyelitis were significantly associated with amputation, revision operation, and prolonged time to union. Surveillance cultures were positive in 64% of extremities and 93% of these cultures isolated gram-negative species. In contrast, infecting organisms were predominantly gram-positive. CONCLUSIONS: Type III open tibia fractures from combat unite in 80.3% of cases at an average of 9.2 months. We recorded a 27% deep infection rate and a 22% amputation rate. The G/A type is associated with development of deep infection, need for amputation, and time to union. Positive surveillance cultures are associated with development of deep infection, osteomyelitis, and ultimate need for amputation. Surveillance cultures were not predictive of the infecting organism if a deep infection subsequently develops. PMID- 22491629 TI - Pain and satisfaction in hospitalized trauma patients: the importance of self efficacy and psychological distress. AB - BACKGROUND: Unmanaged pain has been found to predict delayed return to work, psychologic distress, and chronic pain and disability in patients with traumatic injury. However, little is known about the pain experience during hospitalization. The primary objective of this study was to determine pain intensity, pain interference, and satisfaction with pain treatment in orthopedic trauma patients at hospital discharge. A secondary objective was to examine whether patient self-efficacy and psychologic distress were associated with pain and satisfaction. METHODS: Two hundred thirty-three orthopedic trauma patients were enrolled and completed a discharge assessment at a Level I trauma center. Pain was measured with the Brief Pain Inventory and satisfaction with the American Pain Society Patient Outcome Questionnaire. RESULTS: Ninety-seven percent of patients reported pain at the time of hospital discharge, with 59% and 73% reporting moderate to severe pain intensity and interference, respectively. Overall, 86% of patients were satisfied with pain treatment. Multivariable regression analyses demonstrated that decreased self-efficacy was associated with moderate to severe pain intensity, increased depression was associated with moderate to severe pain intensity and interference, and increased pain intensity was associated with decreased satisfaction (p < 0.05). CONCLUSIONS: Results suggest that orthopedic trauma patients have a significant pain burden but are satisfied with pain treatment during the hospital stay. Efforts are needed to improve pain assessment and management and findings imply that addressing self efficacy and depressive symptoms may decrease pain and increase satisfaction at hospital discharge. Brief educational interventions that incorporate pain coping skills and self-management techniques may be a feasible approach to improving self-efficacy in the acute care setting. Additional recommendations include routine hospital screening for depression and increased communication between surgeons and mental health providers to identify patients at high risk for unmanaged pain and facilitate provision of early mental health services. PMID- 22491630 TI - A systematic review of early versus delayed wound closure in patients with open fractures requiring flap coverage. AB - BACKGROUND: Wound management in open fractures remains an area of controversy. Although numerous protocols for soft tissue coverage and fracture fixation have been proposed, problems with infection, delayed healing, and prolonged disability have remained. The purpose of this systematic review was to critically examine the timing of flap coverage in open fractures and its impact on bone union, infections, complication rates, and duration of hospital stay. METHODS: We comprehensively searched the literature for relevant studies across CINAHL, EMBASE, MEDLINE, and the Cochrane databases. The Orthopaedic Trauma Association and Canadian Orthopedic Association proceedings were also searched. Two independent reviewers screened and assessed abstracts. Articles were selected using specific inclusion criteria and were categorized as "early," "intermediate," or "late" based on their timing of flap coverage. Methodological quality of included studies was assessed using the Newcastle-Ottawa Scale for Cohort Studies. RESULTS: Of 83 potentially eligible studies, 20 articles were included in the final analysis (agreement kappa = 0.83). Of these, eight studies evaluated "early" flap coverage, nine studies evaluated "intermediate" flap coverage, and nine studies evaluated "late" flap coverage. Early flap coverage was associated with lower infection rates (p < 0.0001) and lower complications (p = 0.15). CONCLUSIONS: The results of this systematic review (level III evidence) suggest that any delay in flap coverage may provide suboptimal bone healing, infection, and complication rates. It is recommended that methodologically sound randomized controlled trials be performed comparing "early" flap coverage time points to determine optimal outcomes for bone union, infection, and hospital stay as none exist to date. PMID- 22491631 TI - The medial transepicondylar approach to the elbow: a little-known technique. PMID- 22491632 TI - The smart screw: a fancy skill for sacroiliac screw insertion. PMID- 22491633 TI - Treatment of torus fractures in the forearm in children using bandage therapy. AB - BACKGROUND: In a torus fracture, there is an intact cortex at the side of the fracture which gives more intrinsic stability than in greenstick fractures, where one side of the cortex is disrupted. Two previously done studies compared soft bandage therapy (BT) with cast therapy in the treatment of torus forearm fractures in children and showed this is safe and does not cause any complications. The aim of our study was to validate these studies by treating all patients presenting to emergency department with a torus fracture with BT and investigate whether any complications occur. METHODS: At a single-center from January 2009 to June 2009, all patients with an impacted greenstick fracture of the distal radius and/or ulna without exception were treated using BT. Primary endpoint was secondary angulation; secondary endpoint was pain on Visual Analog Score. RESULTS: Seven patients were misdiagnosed as torus fractures but were actually greenstick fractures and had to be excluded. A total of 49 patients with a torus fracture were included in statistical analysis. No fracture displacement was seen. Four patients needed an additional nonsteroidal antiinflammatory drug or an antalgic plaster cast. The overall Visual Analog Score of the patients was lower than in previous studies. CONCLUSIONS: Soft BT is safe in all children without risk of further angulation and with a pain score equal to cast therapy. Important is that misdiagnosis of the torus fracture at initial presentation should be minimized. PMID- 22491634 TI - Ex vivo evaluation of the polymerization temperatures during cement augmentation of proximal femoral nail antirotation blades. AB - BACKGROUND: Previous studies have clearly demonstrated superior biomechanical behavior of augmented proximal femoral nail antirotation (PFNA) blades compared with nonaugmented ones with respect to implant cutout. Nevertheless, there is concern about thermal bone necrosis due to exothermic curing of polymethylmethacrylate (PMMA)-based bone cements. The objective of this study was to quantify the temperatures arising around perforated titanium PFNA blades when augmenting with PMMA. METHODS: Cylindrical samples from six pairs of fresh frozen human cadaveric femoral heads implanted with a PFNA blade were placed in a 37 degrees C water bath and augmented with 3 mL and 6 mL PMMA. During augmentation, temperatures were measured using six K-type thermocouples that were placed at controlled distances around the implant. With the help of high-resolution quantitative computed tomography images, the locations of all thermocouples with respect to the cement-bone interface were reconstructed. RESULTS: No temperatures higher than 45 degrees C were measured in the interface region and the surrounding cement-free cancellous bone. In the same regions, the longest exposure time above 41 degrees C was 8.5 minutes and was measured in a 6-mL sample. Average maximum temperature was significantly lower for the 3-mL group compared with the 6-mL group (p = 0.017). CONCLUSION: The results of this study suggest that augmentation of titanium PFNA blades is not associated with a risk of thermal bone necrosis when using up to 6 mL of PMMA. However, larger amounts of cement lead to higher temperatures. PMMA application should therefore be kept low to minimally alter the biological system. PMID- 22491635 TI - Level of agreement between patient and proxy responses to the EQ-5D health questionnaire 12 months after injury. AB - BACKGROUND: Health-related quality of life represents a patient's experiences and expectations and should be collected from the patient. In trauma, collection of information from the patient can be challenging, particularly for subgroups where cognitive impairment is prevalent, increasing reliance on proxy reporting. This study assessed the agreement between patient and proxy reporting of health related quality of life 12 months after injury. METHODS: The Victorian State Trauma Registry and Victorian Orthopaedic Trauma Outcomes Registry collect EQ-5D data at 12 months after injury. Cases where data were collected from the patient and proxy were extracted. Agreement between patient and proxy responses was compared using kappa (K) coefficients for the individual EQ-5D items, and Bland Altman plots and Wilcoxon signed-rank tests for the EQ-5D summary score and visual analog scale (VAS). RESULTS: Agreement between patient and proxy respondents was substantial for the mobility (K = 0.61) and personal care items (K = 0.67) and moderate for the usual activities (K = 0.50), pain/discomfort (K = 0.42), and anxiety/depression items (K = 0.47). The mean difference between proxy and patient-reported scores for the VAS (0.74, 95% confidence interval: -2.73, 4.21) and the EQ-5D summary score (-0.02, 95% confidence interval: -0.07, 0.03) was small, but the limits of agreement were wide (-34.22 to 35.71 for VAS and 0.55 to 0.51 for summary score), suggesting no systematic bias. CONCLUSIONS: Although proxy and patient responses for the EQ-5D VAS may differ, the differences show random variability rather than systematic bias. Group comparisons using proxy responses are unlikely to be biased, but proxy responses should be used with caution when assessing individual patient recovery. PMID- 22491636 TI - Anarchy and the surgical care of President William McKinley. PMID- 22491637 TI - Epidemiology of cheerleading injuries presenting to NEISS hospitals. PMID- 22491638 TI - An analysis of phenytoin vs. levetiracetam for early seizure pharmacoprophylaxis following TBI. PMID- 22491639 TI - An inconvenient epidemic. PMID- 22491640 TI - Pulmonary embolus in combat extremity injury: influence of the fresh frozen plasma to red blood cells ratio? PMID- 22491643 TI - Necessity of defining new diagnostic and management protocols for trauma patients. PMID- 22491641 TI - Re: Annual pediatric pedestrian education does not improve pedestrian behavior. PMID- 22491644 TI - Blunt cerebrovascular injuries in children: broadened screening guidelines are warranted. PMID- 22491645 TI - Re: An evaluation of two tourniquet systems for the control of prehospital lower limb hemorrhage. PMID- 22491646 TI - Coagulopathy after burn and smoke inhalation injury: the evidence is there, let's take advantage of it! PMID- 22491648 TI - The case for brain death determination by CTA: where are the results? PMID- 22491652 TI - Split down the middle: a functional survivor of complete traumatic hemipelvectomy. PMID- 22491653 TI - Huge extrapleural hematoma by blunt trauma mimicking traumatic hemothorax. PMID- 22491655 TI - Estimation of body weight in hospitalized patients. AB - AIM: To examine the bias and precision of different methods of estimating body mass and height in hospitalized adult patients. METHODS: Patients were enrolled at the Alfred and Caulfield hospitals, Melbourne, Australia following verbal consent. Estimates were made using the Lorenz formula (that utilizes height, waist and hip circumference), the Crandell formula (that utilizes height and arm circumference) and visual estimation of weight based on the average results obtained by two pharmacy interns. Statistical error was calculated as the ratio of estimated to actual weight; bias was assessed as the mean error and precision as the proportion of estimates within 10 and 20% of measured weight and standard deviation of the error. RESULTS: In a 5-week period July to August 2010, 198 patients were enrolled. The median age was 64 years (range 19-91) and 52% were female. Thirty-four (17%) patients were obese (BMI >30 kg/m(2)) and 8 (4%) were underweight (BMI <18 kg/m(2)). With the Lorenz formula an estimate within 10% was obtained for 56% of patients; with the Crandell formula prediction was poor. Documentation of body weight in notes and patient self-reporting were both accurate. Seventy-two patients (43%) were prescribed one or more drugs for which dosing potentially should be adjusted for body weight. CONCLUSION: In adult hospitalized patients, the estimation of body weight by anthropomorphic measures is not accurate. This supports the need for equipment to be made widely available to accurately weigh patients directly in hospital, including in unconscious and immobile patients. PMID- 22491656 TI - Hypertension, arterial haemodynamics and left ventricular disease: historical observations. PMID- 22491657 TI - Kidney volume changes in patients with autosomal dominant polycystic kidney disease after renal transplantation. AB - BACKGROUND: Few studies have investigated whether the volume of native kidney and liver (when combined with polycystic disease) in patients with autosomal dominant polycystic kidney disease (ADPKD) decreases after renal transplantation. METHODS: Changes in the volume of native kidney (bilateral: n=28; unilateral: n=5) and liver (concomitant polycystic disease: n=18) were analyzed in 33 patients with ADPKD, who underwent renal transplantation. Volumetry was retrospectively conducted using simple computed tomography scan data 6 months before transplantation, at the time of transplantation, and 1, 3, and 5 years after transplantation. Volume change was calculated on the basis of the value at the time of transplantation. RESULTS: Mean+/-standard deviation values of bilateral native kidney volume were 3100+/-1417 (range: 756 to 6525; median: 2499) cm at the time of transplantation. Kidney volumes were significantly reduced in all but one patient after renal transplantation, decreasing by 37.7% and 40.6% at 1 and 3 years, respectively. The major proportion of the decrease was observed within the first year posttransplantation. In contrast, 16 of 18 patients showed significant increase of liver volumes after renal transplantation. The mean rates of increase were 8.6% and 21.4% at 1 and 3 years, respectively. CONCLUSIONS: As the volume of native polycystic kidneys could be reduced after renal transplantation, resection would be unnecessary if the space for kidney graft is available in the absence of infection, bleeding, or malignancy. When ADPKD is combined with polycystic liver disease, the possibility of intolerable symptoms caused by growing liver cysts should also be taken into account. PMID- 22491658 TI - Risk of tacrolimus toxicity in CYP3A5 nonexpressors treated with intravenous nicardipine after kidney transplantation. AB - BACKGROUND: Tacrolimus is commonly prescribed for immunosuppression, yet it can cause acute and chronic kidney injury. Continuous intravenous nicardipine (CIVN), prescribed for posttransplant hypertension, inhibits tacrolimus metabolism by cytochrome P450 (CYP) 3A4 and could lead to tacrolimus overexposure in patients genetically lacking the alternative pathway for tacrolimus metabolism, CYP3A5. METHODS: We compared maximum 12-hr tacrolimus trough levels (MaxC0) and dose adjusted MaxC0 in 12 cases treated with CIVN immediately after kidney transplantation with 26 controls (no CIVN). CYP3A5 genotype was determined for all cases. RESULTS: Eight cases not expressing CYP3A5 (CYP3A5*3/*3) had higher median MaxC0 (24.3 ng/mL) than four cases expressing CYP3A5 (CYP3A5*1/*1; 13.9 ng/mL, P=0.028) and controls (14.6 ng/mL, P=0.003). Compared with the other two groups combined, CYP3A5*3/*3 cases had higher median dose-adjusted MaxC0 (330 vs. 175, P=0.012), less time to MaxC0 (42 vs. 72 hr, P<0.001), and more scheduled tacrolimus doses held per patient (1.75 vs. 0.4, P=0.007). Six of eight (75%) CYP3A5*3/*3 cases had potentially toxic MaxC0 (>20 ng/mL) compared with none of four CYP3A5*1/*1 cases and 3 of 26 (11.5%) controls (P<0.001, CYP3A5*3/*3 cases vs. all others). CONCLUSION: CYP3A5 nonexpressors simultaneously treated with tacrolimus and CIVN may be at increased risk for tacrolimus toxicity. PMID- 22491660 TI - Cancer of the oesophagus and gastrooesophageal junction: neoadjuvant therapy should not be a surrogate for suboptimal lymphadenectomy. PMID- 22491659 TI - Direct access transcatheter mitral annuloplasty with a sutureless and adjustable device: preclinical experience. AB - OBJECTIVES: The aim of the study was to evaluate the technical feasibility and performance of a transcatheter mitral annuloplasty system. METHODS: Adult swines (n = 15) underwent left thoracotomy through the 4th-5th intercostal space. A transcatheter device (CardioBand, Valtech-Cardio Ltd) was introduced through an 18F sheath through the left atrium and attached to the annulus between the posterior and anterior commissures using echocardiographic and fluoroscopic guidance, on the beating heart. The sutureless device was implanted using a steerable delivery system to deploy sequential fixation elements. Following implantation, the device length was adjusted on the beating heart to reduce the intercommissural and septolateral dimension, under echocardiographic guidance. Finally, the flexible adjustment tool was withdrawn from the working sheath and the atrial purse-string closed. All but five animals were sacrificed acutely by intent, while the others were sacrificed at 90 days. RESULTS: All animals survived the acute implant. One animal died at the third post-operative day due to bleeding. The annuloplasty system was successfully implanted in all animals. A mean of 12 +/- 3 fixation elements were deployed. The band length was reduced up to 20% after implantation in each animal. At necropsy, the location of the implant was within a few millimetres of the annulus (3.5 +/- 4 mm). In three animals, fixation elements were implanted inadvertently in the leaflets, but no coronary lesions were observed. All animals survived the acute implant. One animal died on the third post-operative day due to bleeding. In the four long term survivors, the implanted annuloplasty device showed satisfactory healing and no ring dehiscence. CONCLUSIONS: Transcatheter minimally invasive, beating-heart implantation of an adjustable annuloplasty band is feasible in the animal model. This approach may be an alternative to open surgical procedures in high-risk patients. PMID- 22491663 TI - Transapical aortic valve implantation using a new self-expandable bioprosthesis (ACURATE TATM): 6-month outcomes. AB - OBJECTIVES: The ACURATE TA(TM) Aortic Bioprosthesis and Delivery System (Symetis S.A., Ecublens, Switzerland) is a new transcatheter aortic valve designed for transapical implantation. The six-month results from the completed first-in-man study are reported. METHODS: The Symetis ACURATE TA(TM) is composed of a porcine biological tissue valve attached to a self-expandable nitinol stent. It allows for anatomical orientation and facilitates intuitive implantation providing tactile feedback. Since November 2009, a total of 40 high-risk elderly patients have been treated. RESULTS: The mean age of enrolled patients was 83.2 +/- 4.0; 60.0% were female, with a mean logistic EuroSCORE of 21.2 +/- 10.8% and a mean Society of Thoracic Surgeons (STS) score of 9.0 +/- 4.7%. All implants were delivered successfully in the intra-annular and subcoronary position. One patient was converted to conventional surgery due to coronary impingement (after valve-in valve implantation). One additional patient received valve-in-valve treatment (SAPIEN THV TA(TM)). Five patients expired within 30 days and two additional patients expired during the 6-month follow-up due to non-valve-related causes resulting in a mid-term survival rate of 82.5%. Two patients suffered a stroke and another three required new onset pacemaker implantation. The mean aortic gradient significantly improved and remained stable throughout the follow-up (baseline: 51.9 +/- 14.3 mmHg, 30 days: 12.3 +/- 5.1 mmHg, 6 months: 11.9 +/- 5.8 mmHg). At the 6-month follow-up, 96.7% of patients demonstrated either none/trace or mild (1+/4) paravalvular leakage only. According to the Valve Academic Research Council the device's success rate was 92.5%, with a 30-day safety profile of 25%. CONCLUSIONS: At the 6-month follow-up, the ACURATE TA(TM) device showed stable valve function with low rates of paravalvular leakages. The cohort of high-risk patients demonstrated good clinical outcomes and 6-month survival. PMID- 22491664 TI - Evaluation of the Aristotle complexity models in adult patients with congenital heart disease. AB - OBJECTIVES: The adult congenital heart disease (CHD) population has surpassed the paediatric CHD population. Half of all mortality caused by CHD occurs in adulthood; in some patients, it occurs during surgery. We sought to assess the potential risk factors for adverse outcome after cardiac operations in adults with CHD, and to evaluate the predictive power of the Aristotle score models for hospital mortality. METHODS: Procedure-dependent and independent factors, as well as the outcome factors of all consecutive patients aged 16 or more who underwent surgery for CHD between 2005 and 2008 at our institution were evaluated according to the European Association for Cardio-Thoracic Surgery Congenital Database nomenclature. An Aristotle basic complexity (ABC) and an Aristotle comprehensive complexity (ACC) score were assigned to each operation. The discriminatory power of the scores was assessed using the area under the receiver operating characteristics (AuROC) curve. RESULTS: During 542 operations, 773 procedures were performed. The early mortality rate was 2.4%, and the early complication rate was 53.7%. Tricuspid valve replacement (P = 0.009), mitral valve replacement (P < 0.001), elevated lung resistances (P = 0.002), hypothyroidism (P = 0.002) and redosternotomy (P = 0.003) emerged as risk factors for 30-day mortality. Tricuspid valve replacement (P < 0.001), tricuspid valvuloplasty (P = 0.006), mitral valve replacement (P = 0.003), shunt implantation (P = 0.009), surgical ablation (P = 0.024), myocardial dysfunction (P = 0.014), elevated lung resistances (P = 0.004), hypothyroidism (P = 0.002) and redosternotomy (P < 0.001) emerged as risk factors for complications. Mean ABC and ACC scores were 6.6 +/- 2.3, and 9.0 +/- 3.7, respectively. The AuROCs of the ABC and the ACC scores for 30-day mortality were 0.663 (P = 0.044), and 0.755 (P = 0.002), respectively. The AuROCs of the ABC and the ACC scores for complications were 0.634 (P < 0.001), and 0.670 (P < 0.001), respectively. CONCLUSIONS: Surgery for adults with CHD can be performed with low early mortality. However, complications are frequent, especially in patients who require repeat operations for atrioventricular valve incompetence. The ACC score may be helpful to estimate the risk of early mortality. PMID- 22491665 TI - Complications following lung surgery in the Dutch-Belgian randomized lung cancer screening trial. AB - OBJECTIVES: To assess the complication rate in participants of the screen arm of the NELSON lung cancer screening trial who underwent surgical resection and to investigate, based on a literature review, whether the complication rate, length of hospital stay, re-thoracotomy and mortality rates after a surgical procedure were different from those of the non-screening series, taking co-morbidity into account. METHODS: Between April 2004 and December 2008, 198 subjects underwent thoracic surgery. Co-morbid conditions were retrieved from the medical records. Postoperative complications were classified as minor and major. RESULTS: In total, 182 thoracotomies, 5 thoracotomies after video-assisted thoracoscopic surgery (VATS) and 11 VATS procedures were performed. In these patients, 36% had chronic obstructive lung disease, 16% coronary artery disease, 14% diabetes mellitus and 11% peripheral vascular disease. Following thoracotomy, 47% (88/187) had >=1 minor (7-57% in literature) and 10% (18/187) >=1 major complication (2 26% in literature); following VATS, 38% (6/16) had >=1 minor complication, but no major complications. Seventeen per cent (3/18) of major complications and 21% (20/96) of minor complications were seen in subjects operated for benign disease. The re-thoracotomy rate was 3% and there was no 30-day mortality after thoracotomy or VATS (0-8.3% in literature). The mortality rate of 0% after surgical procedures is low when compared with the non-screening series (0-8.3%); the rate of complications (53%) is within range when compared with the non screening series (8.5-58%). CONCLUSIONS: In conclusion, mortality rates after surgical procedures are lower in the NELSON lung cancer screening trial than those in the non-screening series. The rate of complications is within the same range as in the non-screening series. TRIAL REGISTRATION NUMBER: ISR CTN 63545820. PMID- 22491666 TI - Prognostic significance of cardiac troponin I on admission for surgical treatment of acute pulmonary embolism: a single-centre experience over more than 10 years. AB - OBJECTIVES: Cardiac troponin I (cTnI) is a highly sensitive, specific marker for myocardial cell injury. We sought to determine whether cTnI on admission may help to identify patients with increased risk of open surgical embolectomy with acute pulmonary embolism (PE). METHODS: Forty-six consecutive patients with confirmed acute PE were enrolled in this prospective study. PE was confirmed by pulmonary angiography, computed tomography (CT) scan or echocardiography. Severity of PE was assessed by clinical data, and cTnI was measured within 12 h after admission. RESULTS: cTnI was elevated in 28 patients with acute PE. Preoperative right ventricular dysfunction [odds ratio (OR): 15.2; 95% confidence interval (CI): 2.02-144.8; P < 0.002], prolonged hypotension with cardiogenic shock (OR: 14.9; 95% CI: 2.2-131.1; P < 0.002) and preoperative need for resuscitation (OR: 6.0; 95% CI: 0.6-143.8; P = 0.12) were more prevalent in patients with elevated cTnI serum concentrations. cTnI-positive patients were also more likely to require inotropic support (OR: 10.0; 95% CI: 1.8-65.1; P < 0.005) and mechanical ventilation (OR: 13.5; 95% CI: 2.2-95.6; P < 0.005). Moreover, an elevated cTnI level on admission significantly correlated with both primary endpoints, in hospital mortality (OR: 9.0; 95% CI: 1.0-215.2; P = 0.03) and major adverse clinical events (OR: 8.3; 95% CI: 1.5-62.5; P = 0.006). After multivariable risk adjustment, a positive cTnI value remained an independent predictor of in hospital mortality (OR: 13.6; 95% CI: 3.22-145.8; P = 0.014) and major adverse clinical events (OR: 15.7; 95% CI: 4.15-133.7; P = 0.031). CONCLUSIONS: cTnI on admission may improve risk assessment of patients undergoing open surgical embolectomy due to acute PE. PMID- 22491667 TI - Worldwide Oesophageal Cancer Collaboration guidelines for lymphadenectomy predict survival following neoadjuvant therapy. AB - OBJECTIVES: The Worldwide Oesophageal Cancer Collaboration (WECC) reported recommendations regarding the optimum number of lymph nodes to be removed during oesophagectomy based upon patients undergoing surgery alone. We sought to determine whether these recommendations are relevant in the case of oesophageal cancer (EC) patients receiving neoadjuvant therapy. METHODS: Patients undergoing neoadjuvant chemotherapy followed by transthoracic en bloc oesophagectomy were reviewed. Patients were grouped by optimal versus suboptimal lymphadenectomy per WECC recommendations (pTis/T0/T1 >= 10; pT2 >= 20; pT3/T4 >= 30). Cohorts were compared for factors predicting optimal lymphadenectomy and for overall survival (OS). RESULTS: During the time period, 135 patients (adeno = 100, squamous = 35) met the study criteria, of whom 94 patients (70%) had optimal lymphadenectomy. Optimal lymphadenectomy was more likely for tumours with lower ypT (P <= 0.001). Optimal lymphadenectomy predicted the OS (0.50, confidence intervals 0.29-0.85, P = 0.011), although it was collinear with ypT classification, which was also predictive. Patients not down-staged in ypT (n = 66, 49%) particularly experienced a trend towards improved 3-year survival with optimal lymphadenectomy (51 versus 29%, P = 0.144). Similarly, of patients with persistent nodal disease (n = 79, 59%), those who had optimal lymphadenectomy (n = 51) experienced improved 3-year OS compared with those with suboptimal lymphadenectomy (n = 28), (55 versus 36%, P = 0.087). CONCLUSIONS: WECC recommendations regarding lymphadenectomy for EC may be applicable to patients undergoing oesophagectomy following neoadjuvant therapy, particularly those who are not down-staged by pathological tumour depth (T) classification and those with persistent nodal metastases. Techniques to enhance the extent of LAN should be pursued in this patient population. PMID- 22491668 TI - In vitro haemocompatibility of a novel bioprosthetic total artificial heart. AB - OBJECTIVES: The CARMAT total artificial heart (TAH) is an implantable, electro hydraulically driven, pulsatile flow device with four bioprosthetic valves. Its blood-pumping surfaces consist of processed bioprosthetic pericardial tissue and expanded polytetrafluorethylene (ePTFE), potentially allowing for the reduction of anti-coagulation. This pre-clinical study assessed the in vitro haemocompatibility of these surfaces. METHODS: Coupons of pericardial tissue and ePTFE were placed in closed tubular circuits filled with 12.5 ml of fresh human blood exposed to the pulsatile flow at 120 ml/min for 4 h (37 degrees C). Silicone- and heparin-coated polyvinyl chloride (PVC) tubes served as positive and negative controls, respectively. Fresh blood from six donors was used to fill four sets of 12 circuits. Blood samples were taken at baseline and from each circuit after 4 h. Coupons of materials were examined with scanning electron microscopy. RESULTS: The platelet count was 202 +/- 45 10(9) l(-1) at baseline. Four hours after circulation, the platelet counts were 161 +/- 30 10(9) l(-1) (compared with baseline, P = 0.0207) for pericardial tissue, 162 +/- 35 10(9) l( 1) (P = 0.0305) for ePTFE and 136 +/- 42 10(9) l(-1) for positive controls (P = 0.0021). Baseline plasma fibrinogen was 2.9 +/- 0.5 mg/dl compared with 3.0 +/- 0.5 mg/dl for pericardial tissue and 3.1 +/- 0.7 mg/dl for ePTFE, indicating no marked fibrinogen consumption. Thromboxane B2 levels for positive controls were 33.3 +/- 8.7 ng/ml compared with 16.2 +/- 11.5 ng/ml for pericardial tissue (P = 0.0015) and 15.2 +/- 4.7 ng/ml for ePTFE (P < 0.0001). Platelet adhesion was 2.87 +/- 1.01 10(9) cm(-2) for positive controls compared with 1.06 +/- 0.73 10(9) cm( 2) for pericardial tissue (P < 0.0001) and 0.79 +/- 0.75 10(9) cm(-2) for ePTFE (P < 0.0001). Thrombin-antithrombin III complex levels were 3.8 +/- 0.5 MUg/ml for positive controls compared with 1.9 +/- 0.9 for pericardial tissue (P < 0.0001) and 2.1 +/- 1.0 for ePTFE (P < 0.0001). With an electro-microscopic examination at *600, only small depositions of platelets, erythrocytes and fibrin were noticed on the pericardial tissue samples and ePTFE samples. Silicone surfaces showed marked areas of thrombi, and PVC tubings a thin protein layer. CONCLUSIONS: Haemocompatibility of the TAH blood-contacting surfaces was confirmed by in vitro studies showing a limited consumption of fibrin, limited thromboxane B2 release and platelet adhesion, and minor blood cell depositions on the surfaces. These results will be validated in clinical studies, with the aim of reducing anti-coagulation when using the CARMAT TAH. PMID- 22491669 TI - Aortic arch surgery with a mild-to-moderate circulatory arrest: the significance of aortic arch pathology. PMID- 22491670 TI - Mid-term experience with the Hancock porcine-valved Dacron conduit for right ventricular outflow tract reconstruction. AB - OBJECTIVES: Surgical reconstruction of the right ventricular outflow tract (RVOT) often requires implantation of a valved conduit. A single-centre 10-year experience with the Hancock porcine-valved Dacron conduit was retrospectively assessed. METHODS: The records of 63 patients who underwent RVOT reconstruction with Hancock conduit implantation between August 2000 and July 2010 were retrospectively reviewed. The median age was 13 years (range, 4 months to 64 years) and the median weight 44 kg (range, 6.5-75 kg). Fifty-one patients (83%) had previous cardiac surgery, and conduit replacement was performed in 31 patients (49%). Patient and conduit survivals with respect to factors precipitating conduit degeneration were analysed. Conduit failure was defined as severe conduit regurgitation or stenosis with a main pulmonary artery systolic gradient over 60 mmHg. RESULTS: Early mortality was 4.8% and not related to conduit failure. Follow-up was complete with a mean duration of 3.5 +/- 2.6 years. Patient survival after conduit implantation was 93 [95% confidence interval (CI), 87-100], 90 (95% CI, 81-100) and 85% (95% CI, 74-98) after 1, 3 and 5 years, respectively. Conduit failure occurred in six patients after a median of 5.6 years (range, 2.7-9.0 years). Freedom from conduit failure was 100, 96 (95% CI, 89-100) and 83% (95% CI, 62-100%) after 1, 3 and 5 years, respectively. Mean systolic gradient over the stenotic conduit valve was 87 +/- 11 mmHg. Neither RVOT-aneurysm formation nor distal conduit stenosis occurred. Univariate analysis revealed younger age and absent pulmonary valve syndrome as risk factors for conduit failure (P = 0.01 and P < 0.01). Stepwise logistic regression identified higher white blood cell count at postoperative day 8 as a significant risk factor for conduit failure (odds ratio, 0.7; 95% CI, 0.52-0.89; P < 0.01). CONCLUSIONS: The Hancock conduit is a valuable option for pulmonary valve replacement. It is not associated with RVOT-aneurysm formation or distal conduit stenosis. A persisting perioperative inflammatory reaction may be a predictor for later conduit failure. PMID- 22491671 TI - Sea urchin spine-associated tenosynovitis-- recovery with hand therapy. PMID- 22491673 TI - Smac mimetic LBW242 sensitizes XIAP-overexpressing neuroblastoma cells for TNF alpha-independent apoptosis. AB - Despite intensive treatment regimens, high-risk and late-stage neuroblastoma tends to have a poor survival outcome. Overexpression of the apoptotic regulator, X-linked inhibitor of apoptosis protein (XIAP), has been associated with chemotherapy resistance in several cancers including neuroblastoma. Here, we report preclinical evidence that XIAP offers an effective therapeutic target in neuroblastoma. Human and murine neuroblastoma cells were treated with the Smac mimetic LBW242 alone or in combination with cytotoxic drugs used clinically to treat neuroblastoma. Expression of XIAP protein, but not mRNA, was highly increased in neuroblastoma cells compared to healthy adrenal gland tissue, consistent with a posttranscriptional regulation of XIAP expression. Treatment with LBW242 sensitized human and murine neuroblastoma cells to chemotherapy induced apoptosis, which was mediated by activation of both the intrinsic and extrinsic apoptosis pathways. Although Smac mimetics have been reported to stimulate TNF-alpha-induced apoptosis by degradation of cellular IAP (cIAP)-1/2, we found that LBW242-mediated sensitization in neuroblastoma cells occurred in a TNF-alpha-independent manner, despite induction of cIAP-1/2 degradation and TNF alpha expression. Together, our findings show that XIAP targeting sensitizes neuroblastoma to chemotherapy-induced apoptosis, suggesting a novel therapeutic approach to treat this childhood malignancy. PMID- 22491672 TI - Human nuclease/helicase DNA2 alleviates replication stress by promoting DNA end resection. AB - In precancerous and cancerous lesions, excessive growth signals resulting from activation of oncogenes or loss of tumor suppressor genes lead to intensive replication stress, which is recognized by a high level of replication-associated DNA double-strand breaks (DSB). However, the molecular mechanism by which cells alleviate excessive replication stress remains unclear. In this study, we report that the human nuclease/helicase DNA2 facilitates homologous recombination to repair replication-associated DNA DSBs, thereby providing cells with survival advantages under conditions of replication stress. The nuclease activity of DNA2 was required for DSB end resection, which allowed subsequent recruitment of RPA and RAD51 to repair DSBs and restart replication. More importantly, DNA2 expression was significantly increased in human cancers and its expression correlated with patient outcome. Our findings therefore indicate that enhanced activity of DSB resection likely constitutes one mechanism whereby precancerous and cancerous cells might alleviate replication stress. PMID- 22491674 TI - Enantioseparation and absolute configuration determination of angular-type pyranocoumarins from peucedani radix using enzymatic hydrolysis and chiral HPLC MS/MS analysis. AB - Angular-type pyranocoumarins from Peucedani Radix (Chinese name: Qian-hu) have exhibited potential for use on treatment of cancer and pulmonary hypertension. Due to the existence of C-3' and C-4' chiral centers, compounds belonging to this chemical type commonly exist in enantiomers and/or diastereoisomers, which may elicit distinct activities during their interactions with the human body. In the present study, a new method, which combines enzymatic hydrolysis with chiral LC MS/MS analysis, has been developed to determine the absolute configurations of these angular-type pyranocoumarins. Pyranocoumarins isolated from Qian-hu, their enantiomers, or metabolites were individually incubated with rat liver microsomes. As the common end product from enzymatic hydrolysis of all tested pyranocoumarins, cis-khellactone was collected and its absolute configuration was determined by comparison with (+)-cis-khellactone and (-)-cis-khellactone using chiral LC-MS/MS. The absolute configurations of all tested parent pyranocoumarins were determined by combination of LC-MS/MS, NMR and polarimetric analysis. The results revealed that the metabolite cis-khellactone retained the same absolute configurations of the stereogenic carbons as the respective parent compound. This method was proven to be rapid and sensitive and also has advantages in discriminating single enantiomers and mixtures of optical isomers with different ratios. PMID- 22491675 TI - (E)-5-styryl-1H-indole and (E)-6-styrylquinoline derivatives serve as probes for beta-amyloid plaques. AB - We report the synthesis and biological evaluation of novel (E)-5-styryl-1H-indole and (E)-6-styrylquinoline derivatives as probes for imaging beta-amyloid (Abeta) plaques. These derivatives showed binding affinities for Abeta1-40 aggregates with K(i) values varying from 4.1 to 288.4 nM. (E)-5-(4-iodostyryl)-1H-indole (8) clearly stained Abeta plaques in the brain sections of Alzheimer's disease (AD) model mice (APP/PS1). Furthermore, autoradiography for [125I]8 displayed intense and specific labeling of Abeta plaques in the brain sections mentioned above with low background. In biodistribution experiments using normal mice [125I]8 showed high initial brain uptake followed by rapid washout (4.27 and 0.64% ID/g at 2 and 30 min post injection, respectively). These findings suggests that [123I]8 may be a potential SPECT imaging agent for detecting Abeta plaques in AD brain. PMID- 22491676 TI - One-pot synthesis of disperse dyes under microwave irradiation: dyebath reuse in dyeing of polyester fabrics. AB - A series of 4-hydroxyphenylazopyrazolopyrimidine disperse dyes were prepared via one-pot reactions of p-hydroxyphenylhydrazone, hydrazine hydrate, and acetylacetone or enaminones using microwave irradiation as an energy source. Structural assignments of the dyes were confirmed by X-ray crystallographic structure determination. Instead of discharging the dyebath after each dyeing cycle, the residual dyebath was spectrophotometrically analyzed and then pH readjusted for a repeat dyeing with longer time. Fastness of the dyed samples was measured after each recycle. Most of the dyed fabrics tested displayed good light fastness and excellent fastness to washing and perspiration. Finally, the biological activity of the synthesized dyes against Gram positive bacteria, Gram negative bacteria and yeast were evaluated. PMID- 22491677 TI - Evaluation of antioxidant and immunity activities of quercetin in isoproterenol treated rats. AB - The present study was designed to evaluate the effect of quercetin on myocardial oxidative stress and immunity function impairment induced by isoproterenol in rats. To induce myocardial ischemia, Wistar rats were subcutaneously injected with isoproterenol (70 mg/kg). Blood immunity index, cardiac marker enzymes and antioxidative parameters in hearts were measured. It was found that the levels of blood AST, creatine kinase, NO, NOS, IL-10, IL-1, IL-8 and lactate dehydrogenase in isoproterenol-treated rats were significantly increased. The rats administrated with isoproterenol showed the declines in myocardial antioxidant enzymes activities. Administration of quercetin significantly ameliorated myocardial oxidative injury and immunity function impairment induced by isoproterenol. The results indicated that quercetin possesses activity against isoproterenol-induced myocardial oxidative injury and immunity function impairment, and that the mechanism of pharmacological action was related at least in part to the antioxidant activity of quercetin. PMID- 22491678 TI - Anti-inflammatory activity of hautriwaic acid isolated from Dodonaea viscosa leaves. AB - The aim of this study was to identify an anti-inflammatory compound from D. viscosa leaves. The structure of this bioactive substance was elucidated by IR and NMR studies, which indicated that this natural product corresponds to hautriwaic acid (HA). This diterpene exhibited good anti-inflammatory activity in 12-O-tetradecanoylphorbol 13-acetate (TPA) mice ear edema models by applications at doses of 0.25, 0.5 and 1.0 mg/ear (60.2, 70.2 and 87.1% inhibition, respectively); additionally Dodonaea viscosa dichloro-methane extract (DvDE) displays a 97.8% anti-inflammatory effect at 3 mg/kg. Multiple applications of DvDE at doses of 100 mg/kg on TPA mice ear edema inhibited the edema-associated inflammation by 71.8%, while HA at doses of 15 mg/kg, reduced edema to 64% and indomethacin 40%. PMID- 22491679 TI - Organocatalysis in synthesis: L-proline as an enantioselective catalyst in the synthesis of pyrans and thiopyrans. AB - The multicomponent reaction (MCR) of aromatic aldehydes 1 and malononitrile (2) with active methylenes 5a-h in the presence of L-proline produced pyrans and thiopyrans 6a-h stereospecifically and in good yields. Moreover a novel MCR of ethyl propiolate (8) with 1 and 2 in the presence of L-proline to afford (R) polysubstituted pyran is also reported. X-ray structures, e.e. and optical activity of the synthesized compounds indicated that L-proline as a catalyst is responsible for the observed enantioselectivity in the studied reactions. PMID- 22491680 TI - New methodology for the synthesis of thiobarbiturates mediated by manganese(III) acetate. AB - A three step synthesis of various thiobarbiturate derivatives 17-24 was established. The first step is mediated by Mn(OAc)3, in order to generate a carbon-carbon bond between a terminal alkene and malonate. Derivatives 1-8 were obtained in moderate to good yields under mild conditions. This key step allows synthesis of a wide variety of lipophilic thiobarbiturates, which could be tested for their anticonvulsive or anesthesic potential. PMID- 22491681 TI - Repeated dose 28-days oral toxicity study of Carica papaya L. leaf extract in Sprague Dawley rats. AB - Carica papaya L. leaves have been used in ethnomedicine for the treatment of fevers and cancers. Despite its benefits, very few studies on their potential toxicity have been described. The aim of the present study was to characterize the chemical composition of the leaf extract from 'Sekaki' C. papaya cultivar by UPLC-TripleTOF-ESI-MS and to investigate the sub-acute oral toxicity in Sprague Dawley rats at doses of 0.01, 0.14 and 2 g/kg by examining the general behavior, clinical signs, hematological parameters, serum biochemistry and histopathology changes. A total of twelve compounds consisting of one piperidine alkaloid, two organic acids, six malic acid derivatives, and four flavonol glycosides were characterized or tentatively identified in the C. papaya leaf extract. In the sub acute study, the C. papaya extract did not cause mortality nor were treatment related changes in body weight, food intake, water level, and hematological parameters observed between treatment and control groups. Some biochemical parameters such as the total protein, HDL-cholesterol, AST, ALT and ALP were elevated in a non-dose dependent manner. Histopathological examination of all organs including liver did not reveal morphological alteration. Other parameters showed non-significant differences between treatment and control groups. The present results suggest that C. papaya leaf extract at a dose up to fourteen times the levels employed in practical use in traditional medicine in Malaysia could be considered safe as a medicinal agent. PMID- 22491682 TI - Synthesis and calcium mobilization activity of cADPR analogues which integrate nucleobase, northern and southern ribose modifications. AB - Novel cADPR mimics, which integrate nucleobase, northern and southern ribose modifications were synthesized. The key steps of the synthesis were a Cu(I) catalyzed Huisgen [3+2] cycloaddition and a microwave-assisted intramolecular pyrophosphorylation. Preliminary biological investigations showed that these cADPR mimics are membrane-permeating agonists of the calcium signaling pathway. The introduction of chlorine or fluorine at the 2'-position of the southern riboses led to a decrease of activity. The existence of a hydrophobic group on the 3'-OH of the southern riboses does not obviously alter the agonistic activity. PMID- 22491683 TI - Bio-functional constituents from the stems of Liriodendron tulipifera. AB - Four known compounds have been isolated from the stems of Liriodendron tulipifera, and the structures of these pure constituents were determined using spectroscopic analysis. Isolated compounds were screened for free radical scavenging ability, metal chelating power assay and ferric reducing antioxidant power assay (FRAP). The anti-tyrosinase effects of L. tulipifera compounds were calculated the inhibition of hydroxylation of L-tyrosine to L-dopa according to an in vitro mushroom tyrosinase assay. The study also examined the bio-effects of the four compounds on the human melanoma A375.S2, and showed that liriodenine (1) and (-)-norglaucine (4) significantly inhibited the proliferation of melanoma cells in the cell viability assay. Wound healing results indicated that liriodenine (1), (-)-glaucine (3) and (-)-norglaucine (4) exerted anti-migration potential. Interestingly, (-)-glaucine (3), neither liriodenine (1) nor (-) norglaucine (4) showed promising anti-migration potential without inducing significant cytotoxicity. Furthermore, a dramatically increased level of intracellular reactive oxygen species (ROS) was detected from (-)-glaucine (3). The cell cycle assessment demonstrated a moderate G2/M accumulation by (-) glaucine (3). The above results revealed the anti-cancer effects of L. tulipifera compounds, especially on the anti-migration ability indicating the promising chemopreventive agents to human skin melanoma cells. PMID- 22491684 TI - Trends in susceptibility of vancomycin-resistant Enterococcus faecium to tigecycline, daptomycin, and linezolid and molecular epidemiology of the isolates: results from the Tigecycline In Vitro Surveillance in Taiwan (TIST) study, 2006 to 2010. AB - Among the 219 vancomycin-resistant Enterococcus faecium isolates collected in 20 Taiwanese hospitals from 2006 to 2010, all were susceptible to linezolid and daptomycin, and 98.6% were susceptible to tigecycline. There was a shift toward higher tigecycline MIC values (MIC(90)s) from 2006-2007 (0.06 MUg/ml) to 2008 2010 (0.12 MUg/ml). The MIC(90)s of daptomycin and linezolid remained stationary. Although pulsotypes among the isolates from the 20 hospitals varied, intrahospital spreading of several clones was identified in 13 hospitals. PMID- 22491685 TI - Efficacy of OH-CATH30 and its analogs against drug-resistant bacteria in vitro and in mouse models. AB - Antimicrobial peptides (AMPs) have been considered alternatives to conventional antibiotics for drug-resistant bacterial infections. However, their comparatively high toxicity toward eukaryotic cells and poor efficacy in vivo hamper their clinical application. OH-CATH30, a novel cathelicidin peptide deduced from the king cobra, possesses potent antibacterial activity in vitro. The objective of this study is to evaluate the efficacy of OH-CATH30 and its analog OH-CM6 against drug-resistant bacteria in vitro and in vivo. The MICs of OH-CATH30 and OH-CM6 ranged from 1.56 to 12.5 MUg/ml against drug-resistant clinical isolates of several pathogenic species, including Escherichia coli, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. The MICs of OH-CATH30 and OH-CM6 were slightly altered in the presence of 25% human serum. OH-CATH30 and OH-CM6 killed E. coli quickly (within 60 min) by disrupting the bacterial cytoplasmic membrane. Importantly, the 50% lethal doses (LD(50)) of OH-CATH30 and OH-CM6 in mice following intraperitoneal (i.p.) injection were 120 mg/kg of body weight and 100 mg/kg, respectively, and no death was observed at any dose up to 160 mg/kg following subcutaneous (s.c.) injection. Moreover, 10 mg/kg OH-CATH30 or OH-CM6 significantly decreased the bacterial counts as well as the inflammatory response in a mouse thigh infection model and rescued infected mice in a bacteremia model induced by drug-resistant E. coli. Taken together, our findings demonstrate that the natural cathelicidin peptide OH-CATH30 and its analogs exhibit relatively low toxicity and potent efficacy in mouse models, indicating that they may have therapeutic potential against the systemic infections caused by drug-resistant bacteria. PMID- 22491686 TI - In vitro activity of telavancin in combination with colistin versus Gram-negative bacterial pathogens. AB - The treatment of Gram-negative infections is increasingly compromised by the spread of resistance. With few agents currently in development, clinicians are now considering the use of unorthodox combination therapies for multidrug resistant strains. Here we assessed the in vitro activity of the novel lipoglycopeptide telavancin (TLV) when combined with colistin (COL) versus 13 Gram-negative type strains and 66 clinical isolates. Marked synergy was observed in either checkerboard (fractional inhibitory concentration index [FICI], <0.5; susceptibility breakpoint index [SBPI], >2) or time-kill assays (>2-log reduction in viable counts compared with starting inocula at 24 h) versus the majority of COL-susceptible enterobacteria, Stenotrophomonas maltophilia, and Acinetobacter baumannii isolates, but only limited effects were seen against Pseudomonas aeruginosa or strains with COL resistance. Using an Etest/agar dilution method, the activity of TLV was potentiated by relatively low concentrations of COL (0.25 to 0.75 MUg/ml), reducing the MIC of TLV from >32 MUg/ml to <= 1 MUg/ml for 35% of the clinical isolates. This provides further evidence that glycopeptide polymyxin combinations may be a useful therapeutic option in the treatment of Gram-negative infections. PMID- 22491687 TI - In vitro activity of ceftaroline against clinical isolates of Streptococcus pneumoniae recovered in 43 U.S. medical centers during 2010-2011. AB - The in vitro activity of ceftaroline, a recently introduced parenteral cephalosporin, was assessed versus 1,750 isolates of Streptococcus pneumoniae recovered from patients with a variety of pneumococcal infections in 43 U.S. medical centers during 2010-2011. Using a breakpoint of <= 0.5 MUg/ml for susceptibility, all of the isolates were found to be susceptible to ceftaroline. Ceftaroline MICs were consistently 16-fold lower than ceftriaxone MICs. Among the isolates characterized in this investigation, 38.9% were found to be nonsusceptible to penicillin (oral penicillin breakpoints) and 9.1% were nonsusceptible to ceftriaxone (nonmeningitis breakpoints). PMID- 22491688 TI - Prospective screening of novel antibacterial inhibitors of dihydrofolate reductase for mutational resistance. AB - Resistance to trimethoprim (TMP) resulting from point mutations in the enzyme drug target dihydrofolate reductase (DHFR) drives the development of new antifolate inhibitors effective against methicillin-resistant Staphylococcus aureus (MRSA). For the past several years we have used structure-based design to create propargyl-linked antifolates that are highly potent antibacterial agents. In order to focus priority on the development of lead compounds with a low propensity to induce resistance, we prospectively evaluated resistance profiles for two of these inhibitors in an MRSA strain. By selection with the lead inhibitors, we generated resistant strains that contain single point mutations F98Y and H30N associated with TMP resistance and one novel mutation, F98I, in DHFR. Encouragingly, the pyridyl propargyl-linked inhibitor selects mutants at low frequency (6.85 * 10(-10) to 1.65 * 10(-9)) and maintains a low MIC (2.5 MUg/ml) and a low mutant prevention concentration (1.25 MUg/ml), strongly supporting its position as a lead compound. Results from this prospective screening method inform the continued design of antifolates effective against mutations at the Phe 98 position. Furthermore, the method can be used broadly to incorporate ideas for overcoming resistance early in the development process. PMID- 22491689 TI - "tet(U)" is not a tetracycline resistance determinant. AB - The enterococcal plasmid pKQ10 has been reported to carry a poorly characterized tetracycline resistance determinant designated tet(U). However, in a series of studies intended to further characterize this determinant, we have been unable to substantiate the claim that tet(U) confers resistance to tetracyclines. In line with these results, bioinformatic analysis provides compelling evidence that "tet(U)" is in fact the misannotated 3' end of a gene encoding a rolling-circle replication initiator (Rep) protein. PMID- 22491690 TI - Efficacy of bacteriophage therapy in experimental sepsis and meningitis caused by a clone O25b:H4-ST131 Escherichia coli strain producing CTX-M-15. AB - We evaluated phage therapy in experimental infections due to S242, a fatal neonatal meningitis Escherichia coli strain belonging to the worldwide distributed O25b:H4-ST131 clone that produces extended-spectrum beta-lactamase CTX-M-15. A lytic phage, EC200(PP), active against S242, was isolated from environmental water. After determining in vitro and ex vivo stabilities and pharmacokinetic properties of EC200(PP) in rat pups, we assessed the therapeutic efficacy of a single dose of 10(8) PFU using models of sepsis and meningitis in which fatality was 100%. EC200(PP) was partially neutralized by human serum. In contrast to the high concentration of phage in the spleen and the kidney, low titers in urine and the central nervous system were observed. Nevertheless, in the sepsis model, EC200(PP) administered 7 h or 24 h postinfection resulted in 100% and 50% pup survival, respectively. In the meningitis model, EC200(PP) administered 1 h or 7 h postinfection rescued 100% of the animals. The most delayed treatments were associated with the selection of phage-resistant S242 mutants. However, a representative mutant was highly sensitive to killing serum activity and avirulent in an animal model. EC200(PP) is a potential therapeutic agent for sepsis and meningitis caused by the widespread E. coli O25:H4-ST131 multidrug-resistant clone. PMID- 22491691 TI - Transferable plasmid-mediated resistance to linezolid due to cfr in a human clinical isolate of Enterococcus faecalis. AB - Nonmutational resistance to linezolid is due to the presence of cfr, which encodes a methyltransferase responsible for methylation of A2503 in the 23S rRNA. The cfr gene was first described in animal isolates of staphylococci, and more recently, it has been identified in Staphylococcus aureus from human clinical infections, including in an outbreak of methicillin-resistant S. aureus. In enterococci, cfr has been described in an animal isolate of Enterococcus faecalis from China. Here, we report an isolate of linezolid-resistant E. faecalis (603 50427X) recovered from a patient in Thailand who received prolonged therapy with the antibiotic for the treatment of atypical mycobacterial disease. The isolate lacked mutations in the genes coding for 23S rRNA and L3 and L4 ribosomal proteins and belonged to the multilocus sequence type (MLST) 16 (ST16), which is commonly found in enterococcal isolates from animal sources. Resistance to linezolid was associated with the presence of cfr on an ~97-kb transferable plasmid. The cfr gene environment exhibited DNA sequences similar to those of other cfr-carrying plasmids previously identified in staphylococci (nucleotide identity, 99 to 100%). The cfr-carrying plasmid was transferable by conjugation to a laboratory strain of E. faecalis (OG1RF) but not to Enterococcus faecium or S. aureus. The cfr gene was flanked by IS256-like sequences both upstream and downstream. This is the first characterization of the potential horizontal transferability of the cfr gene from a human linezolid-resistant isolate of E. faecalis. PMID- 22491692 TI - Spanish multicenter study of the epidemiology and mechanisms of amoxicillin clavulanate resistance in Escherichia coli. AB - We conducted a prospective multicenter study in Spain to characterize the mechanisms of resistance to amoxicillin-clavulanate (AMC) in Escherichia coli. Up to 44 AMC-resistant E. coli isolates (MIC >= 32/16 MUg/ml) were collected at each of the seven participant hospitals. Resistance mechanisms were characterized by PCR and sequencing. Molecular epidemiology was studied by pulsed-field gel electrophoresis (PFGE) and by multilocus sequence typing. Overall AMC resistance was 9.3%. The resistance mechanisms detected in the 257 AMC-resistant isolates were OXA-1 production (26.1%), hyperproduction of penicillinase (22.6%), production of plasmidic AmpC (19.5%), hyperproduction of chromosomic AmpC (18.3%), and production of inhibitor-resistant TEM (IRT) (17.5%). The IRTs identified were TEM-40 (33.3%), TEM-30 (28.9%), TEM-33 (11.1%), TEM-32 (4.4%), TEM-34 (4.4%), TEM-35 (2.2%), TEM-54 (2.2%), TEM-76 (2.2%), TEM-79 (2.2%), and the new TEM-185 (8.8%). By PFGE, a high degree of genetic diversity was observed although two well-defined clusters were detected in the OXA-1-producing isolates: the C1 cluster consisting of 19 phylogroup A/sequence type 88 [ST88] isolates and the C2 cluster consisting of 19 phylogroup B2/ST131 isolates (16 of them producing CTX-M-15). Each of the clusters was detected in six different hospitals. In total, 21.8% of the isolates were serotype O25b/phylogroup B2 (O25b/B2). AMC resistance in E. coli is widespread in Spain at the hospital and community levels. A high prevalence of OXA-1 was found. Although resistant isolates were genetically diverse, clonality was linked to OXA-1-producing isolates of the STs 88 and 131. Dissemination of IRTs was frequent, and the epidemic O25b/B2/ST131 clone carried many different mechanisms of AMC resistance. PMID- 22491693 TI - Characterization of globally spread Escherichia coli ST131 isolates (1991 to 2010). AB - The characterization of a broad representative sample of ST131 Escherichia coli isolates from different origins and settings (1991 to 2010) revealed that this clonal group has likely diversified recently and that the expansion of particular variants has probably been favored by the capture of diverse, multidrug-resistant IncFII plasmids (pC15-1a, pEK499, pKF3-140-like). The low ability to adhere and to grow as biofilm that was detected in this study suggests unknown mechanisms for the persistence of this clonal group which need to be further explored. PMID- 22491694 TI - Alanyl-phosphatidylglycerol and lysyl-phosphatidylglycerol are translocated by the same MprF flippases and have similar capacities to protect against the antibiotic daptomycin in Staphylococcus aureus. AB - The lysinylation of negatively charged phosphatidylglycerol by MprF proteins reduces the affinity of cationic antimicrobial peptides (CAMPs) for bacterial cytoplasmic membranes and reduces the susceptibility of several Gram-positive bacterial pathogens to CAMPs. MprF of Staphylococcus aureus encompasses a lysyl phosphatidylglycerol (Lys-PG) synthase and a Lys-PG flippase domain. In contrast, Clostridium perfringens encodes two MprF homologs which specifically synthesize alanyl-phosphatidylglycerol (Ala-PG) or Lys-PG, while only the Lys-PG synthase is fused to a putative flippase domain. It remains unknown whether cationic Lys-PG and zwitterionic Ala-PG differ in their capacities to be translocated by MprF flippases and if both can reduce CAMP susceptibility in Gram-positive bacteria. By expressing the MprF proteins of C. perfringens in an S. aureus mprF deletion mutant, we found that both lipids can be efficiently produced in S. aureus. Simultaneous expression of the Lys-PG and Ala-PG synthases led to the production of both lipids and slightly increased the overall amounts of aminoacyl phospholipids. Ala-PG production by the corresponding C. perfringens enzyme did not affect susceptibility to CAMPs such as nisin and gallidermin or to the CAMP like antibiotic daptomycin. However, coexpression of the Ala-PG synthase with flippase domains of Lys-PG synthesizing MprF proteins led to a wild-type level of daptomycin susceptibility, indicating that Ala-PG can also protect bacterial membranes against daptomycin and suggesting that Lys-PG flippases can also translocate the related lipid Ala-PG. Thus, bacterial aminoacyl phospholipid flippases exhibit more relaxed substrate specificity and Ala-PG and Lys-PG are more similar in their capacities to modulate membrane functions than anticipated. PMID- 22491695 TI - Quality of life of patients who have undergone the minimally invasive repair of pectus carinatum. AB - OBJECTIVES: Several studies previously demonstrated an improvement in the quality of life (QoL) of the patients undergoing a minimally invasive repair of pectus excavatum, but there are no data about such improvement following the minimally invasive repair of pectus carinatum (PC) deformity. The purpose of this study was to investigate the effects of the minimally invasive repair of PC deformity on the psychosocial and physical functioning of the patients. METHODS: Among 40 patients who underwent minimally invasive repair for PC deformity from July 2008 to March 2011, 35 patients accepted to answer the QoL questionnaires, and 30 of them who had completed the postoperative 6th month were evaluated in this study. The modified two-step Nuss questionnaire was used for the QoL assessment. All patients and their parents completed the appropriate questionnaires regarding the patients' preoperative psychosocial and physical functioning, and they were asked to answer the same questions on the postoperative 6th month. The results from these questionnaires were analysed using Wilcoxon signed rank test to investigate the effects of the minimally invasive repair of PC deformity on psychosocial and physical functioning of the patients. RESULTS: The questionnaires used in the study confirmed the positive impact of the surgical correction on psychosocial and physical well-being in the patients and their parents. Spearman's rho correlation coefficient determined how well the answers to the same question at two different times correlated with each other, and Cronbach's alpha demonstrated the internal consistency of these answers. These two parameters showed that the statistical results of the study were reliable enough. Statistical analysis of the scoring of the individual questions and the total scoring of individual patients revealed a statistically significant improvement (P < 0.05) following surgery. Similar significant improvements were observed in the total scoring of individual parents and in most scoring of the individual questions (10 of 13, 77%) in the parental questionnaire (P < 0.05). CONCLUSIONS: The results of this study confirm for the first time that minimally invasive repair of PC deformity has a positive impact on both psychosocial and physical functioning of the patient, which is supported by parental assessment. PMID- 22491696 TI - Acute headache and visual field defect. PMID- 22491697 TI - Is it time for a new kind of hospital physician? PMID- 22491698 TI - We need female doctors at all levels and in all specialties. PMID- 22491699 TI - Lansley has pulled off one of the profoundest reforms ever. PMID- 22491702 TI - Medical heresy: ditch the eponyms. PMID- 22491703 TI - Doctor is struck off for failing to disclose manslaughter conviction in Spain. PMID- 22491704 TI - A 90 year old man with difficulty swallowing and proximal muscle weakness. PMID- 22491705 TI - Functional tolerance in an isoreticular series of highly porous metal-organic frameworks. AB - A series of highly porous University of Michigan Crystalline Material (UMCM-1) type Zn-based metal-organic frameworks (MOFs) were synthesized from mono- and bi functionalized benzenedicarboxylate (BDC) ligands. In total, 16 new functionalized UMCM-1 derivatives were obtained by a combination of pre- and postsynthetic functionalization. Through postsynthetic modification (PSM), amino halo bifunctional MOFs were converted into amide-halo materials via solid-state acylation reactions. A series of bifunctional MOFs containing Cl, Br, and I groups revealed that PSM conversion is not affected by the size of the halide, only by the steric bulk of the reagent used in these solid-state organic transformations. PMID- 22491706 TI - Anatomic study of the attachment of the medial patellofemoral ligament and its characteristic relationships to the vastus intermedius. AB - PURPOSE: The aim of this study was to investigate the attachment of the medial patellofemoral ligament (MPFL) using cadaver specimens and establish an anatomic basis for optimal MPFL reconstruction to achieve better patella stability. METHODS: Sixteen knees of eight cadavers were used in this study. The relationship of the MPFL with quadriceps muscles was investigated from outside after removal of the distal part of the vastus medialis and the rectus femoris and then evaluated from intra-articular side after release of lateral margin of the vastus lateralis muscle, patella and patella tendon. RESULTS: The proximal fibres of MPFL were mainly attached to the vastus intermedius tendon, without tight adhesion to the vastus medialis. The distal fibres of MPFL were interdigitated with the deep layer of the medial retinaculum that was attached to the medial margin of the patella tendon. CONCLUSION: These findings imply that MPFL, which was directly attached to the vastus intermedius and patella and indirectly continued to the patella tendon, could keep pulling them medially as one unit and consequently make the patella move smoothly on the trochlea during whole movement of the knee. Clinically, dysfunction of both proximal and distal MPFL fibres should be considered in the diagnosis and treatment of patella instability after traumatic patella dislocation. MPFL reconstruction with both fibres has a possibility to lead ideal function of MPFL and better instability of the patella. PMID- 22491707 TI - Cyclic long-term loading of a bilateral fixed-angle plate in comparison with tension band wiring with K-wires or cannulated screws in transverse patella fractures. AB - PURPOSE: A bilateral fixed-angle plate was biomechanically compared to the two currently preferred methods of osteosynthesis for transverse patella fractures. It was hypothesized that the new angle-stable implant would provide a secure and sustainable fracture fixation, superior to the established standard techniques. METHODS: Twenty-one identical patellae made of polyurethane foam (Sawbones((r))), osteotomized to create a transverse two-part fracture, were fixed with modified anterior tension wiring, cannulated lag screws with anterior tension wiring or bilateral polyaxial 2.7-mm fixed-angle plates. The testing protocol consisted of 10,000 repetitive cycles using a non-destructive physiological load between 100 and 300 N at a simulated knee flexion of 60 degrees . RESULTS: All 21 Sawbone((r))-patellae sustained repetitive loading up to 10,000 cycles without failing. The anterior tension wire group displayed significant displacement of the fracture gap (0.7 +/- 0.2 mm) during cyclic loading, while both lag screws with tension wiring and bilateral fixed-angle plates showed no fracture gap widening at all (p < 0.01). CONCLUSION: The bilateral fixed-angle plate and cannulated lag screws with anterior tension wiring preserved a constantly reduced fracture gap over 10,000 tensile cycles in contrast to modified anterior tension wiring, which exhibited significant widening of the gap after initial loading. Results of in vitro testing indicate that bilateral fixed-angle plates provide sustainable fixation stability offering a promising new option in the treatment for transverse patella fractures. PMID- 22491708 TI - Local infusion analgesia using intra-articular double lumen catheter after total knee arthroplasty: a double blinded randomized control study. AB - PURPOSE: Although intra-operative local infiltration analgesia has gained increasing popularity in joint replacement surgery, it is not clear whether postoperative local infusion analgesia using an indwelling catheter provides clinically important additional effects. We, therefore, conducted a randomized controlled trial to clarify the efficacy of the originally developed local infusion analgesia technique in total knee arthroplasty. METHODS: Forty patients were randomly allocated to the local infusion analgesia or control group. Patients in the local infusion analgesia group received intermittent bolus intra articular injection of analgesics consisting of ropivacaine, dexamethasone, and isepamicin until postoperative 48 h. Primary outcome was pain severity at rest using 100-mm visual analogue scale. RESULTS: Pain severity in patients of the local infusion analgesia group was lower than control group, and there were significant differences between groups at POD1 (p = 0.025) and POD3 (p = 0.007). Reduction of postoperative pain was associated with a decrease in C-reactive protein level and earlier achievement of straight leg raise. In addition, postoperative drain volume was reduced in the local infusion analgesia group. CONCLUSION: Although larger studies are needed to examine its safety, the local infusion analgesia alone provided clinically significant analgesic effects and rapid recovery in total knee arthroplasty. PMID- 22491710 TI - MicroRNA-193b modulates proliferation, migration, and invasion of non-small cell lung cancer cells. AB - MicroRNAs have been reported to be closely related to the development of human lung cancers. However, the functions of microRNAs in non-small cell lung cancer (NSCLC) remain largely undefined. Here, we investigated the role of microRNA-193b (miR-193b) in NSCLC. Our data showed that miR-193b was markedly down-regulated in NSCLC cancer tissues compared with adjacent normal tissues. The NSCLC cell line (A549) transfected with the miR-193b exhibited significantly decreased proliferation, migration, and invasion capacities when compared with the control cells. In contrast, inhibition of miR-193b increased the proliferation, migration, and invasion of A549 cells. Moreover, miR-193b repressed the expressions of cyclin D1 and urokinase-type plasminogen activator in A549 cells. These data suggest that miR-193b is a tumor suppressor in NSCLC. PMID- 22491711 TI - Quantifying factors that influence metal ion release in photocaged complexes using ZinCast derivatives. AB - Two generations of nitrobenzhydrol-based photocages for Zn(2+) have been prepared and characterized. The first series includes the tridentate ZinCast-1 utilizes a bis-pyridin-2-ylmethyl-aniline ligand that forms a 5,5-chelate ring upon metal binding. The related photocages ZinCast-2 with a N-[2-(pyridine-2-yl)ethyl]-N (pyridine-2-ylmethyl)aniline (5,6-chelate ring) and ZinCast-3 with a N,N-bis[2 (pyridine-2-yl)ethyl]aniline (6,6-chelate ring) were synthesized for comparative studies. The complexes formed by the ions Cu(2+), Zn(2+) and Cd(2+) with three ZinCast and their photoproducts (ZinUnc) were interrogated by UV-Vis spectroscopy. The studies indicate that ZinCast-1 forms complexes of the highest stability and ZinCast-3 exhibits the most significant changes in metal affinity upon uncaging. These results suggest that the changes in nitrogen atom donor ability as well as the initial complex stability must be considered to design a photocage with the desired properties. The composite results were used to design ZinCast-4 and ZinCast-5, the second generation photocages that incorporate an additional adjacent ether ligand into the Zn(2+) chelator. PMID- 22491713 TI - An unusual coronary to LV cavitary fistula in a young patient. PMID- 22491714 TI - The importance of knowing context of hospital episode statistics when reconfiguring the NHS. PMID- 22491716 TI - Alterations of heart rate variability in women with overactive bladder syndrome. AB - INTRODUCTION AND HYPOTHESIS: Our objective was to compare autonomic nervous system function between women with an overactive bladder (OAB) and control participants during regulated bladder filling. METHODS: Twenty-four women, nine with OAB and 15 without (control), were instructed to drink 1.5 l of water at a rate of 250 ml every 5 min during continuous electrocardiogram (ECG) monitoring. Participants were asked to indicate first sensations of filling (FSF), first desire to void (FDV), strong desire to void (SDV), and maximal bladder capacity (MC). ECG signals were used to assess heart rate variability, which were analyzed in time and frequency domains using the fast Fourier transform. The low-frequency (LF)and high-frequency (HF) spectral bands were used to asses sympathetic and parasympathetic pathways, respectively. RESULTS: During the bladder-filling phase, women with OAB had significantly lower LF values (at the MC phase 5.4 +/- 1.4 ms(2)/Hz vs. 6.4 +/- 0.6 ms(2)/Hz in the control group, p = 0.02). In the control group, LF increased continuously, whereas in the OAB group, LF increased until the sensation of SDV and then abruptly decreased to baseline values. MC was lower in women with OAB (372 +/- 153 ml vs. 592 +/- 298 ml, p < 0.05, respectively). CONCLUSIONS: Reduced sympathetic tone in women with OAB may explain their attainment of lower volumes of MC and their sensation of urgency. The rapid decrease in sympathetic neural activity that accompanies the sensation of an SDV may be related to the pathophysiology of the urgency symptom in these women. PMID- 22491717 TI - Evaluation of a new multi-parallel line immunoassay for systemic sclerosis associated antibodies in an Asian population. AB - OBJECTIVES: To compare the SSc-line immunoassay (LIA) with conventional techniques of antibody detection, to evaluate its diagnostic utility and to describe clinical associations of antibodies in Asian SSc patients. METHODS: Stored sera from patients with SSc (n = 68), SLE (n = 49), OA (n = 41) and normal controls (NCs, n = 32) were evaluated. Cohen's kappa and Bland-Altman plots were used to evaluate agreement. RESULTS: There was good agreement between LIA and ELISA for anti-Scl-70 (kappa = 0.97), anti-CENPA (kappa = 0.83), anti-CENPB (kappa = 0.96) and anti-PmScl100 (kappa = 1.00) (5.48-8.22% of values outside the 95% limits of agreement using Bland-Altman plots), and between LIA and IIF for anti-CENPA (kappa = 0.81) and anti-CENPB (kappa = 0.77) (P < 0.001). Using LIA, of 32 (32/68, 47%) SSc patients negative for anti-Scl-70 and anti-CENPA/B, 5 (5/32, 15%) were positive for anti-Ku, -Nor90, -fibrillarin and -RP155. Specificity of each antibody for SSc was at least 97% (vs OA/NC) and 94% (vs SLE), except for anti-Ro52 (63%). Anti-CENPB was associated with joint pain [odds ratio (OR) 0.17], interstitial lung disease (OR 0.24) and telangiectasia (OR 4.00) (P < 0.05). Anti-Ro60 was associated with pulmonary arterial hypertension (OR 3.89, P = 0.041). CONCLUSION: The SSc-LIA has good agreement with conventional techniques for selected antibodies and has good diagnostic utility. PMID- 22491715 TI - microRNA involvement in human cancer. AB - When, ~20 years ago, investigators first determined that components of the genome considered nonfunctional had, in fact, gene regulatory capacity, they probably had no idea of their potential in controlling cell fate and were forced to revise and somehow reorganize their view of the molecular biology. Indeed, it is currently well documented how a class of small non-coding RNAs, microRNAs, are conserved among the species, expressed in different tissues and cell types and involved in almost every biological process, including cell cycle, growth, apoptosis, differentiation and stress response, exerting a finely tuned regulation of gene expression by targeting multiple molecules. As a consequence of the widespread range of processes they are able to influence, it is not surprising that miRNA deregulation is a hallmark of several pathological conditions, including cancer. Indeed, the aberrant expression of these tiny molecules in human tumors is not just a casual association, but they can exert a causal role, as oncogenes or tumor suppressors, in different steps of the tumorigenic process, from initiation and development to progression toward the acquisition of a metastatic phenotype. An increasing body of evidence has indeed proved the importance of miRNAs in cancer, suggesting their possible use as diagnostic, prognostic and predictive biomarkers and leading to exploit miRNA based anticancer therapies, either alone or in combination with current targeted therapies, with the goal to improve disease response and increase cure rates. Here, we review our current knowledge about miRNA involvement in cancer. PMID- 22491718 TI - Concomitant cyclophosphamide and oral immunosuppressants with rituximab for systemic lupus erythematosus. PMID- 22491719 TI - Juvenile idiopathic arthritis-associated uveitis complicated by glaucoma and Brown's syndrome. PMID- 22491720 TI - Effects of ebselen on radiocontrast media-induced hepatotoxicity in rats. AB - Oxidative stress is accepted as a potential responsible mechanism in the pathogenesis of radiocontrast media (RCM)-induced hepatotoxicity. Therefore, we aimed to investigate the protective effects of ebselen against RCM-induced hepatotoxicity by measuring tissue oxidant/antioxidant parameters and histological changes in rats. Wistar albino rats were randomly separated into four groups consisting of eight rats per group. Normal saline was given to the rats in control group (group 1). RCM was given to the rats in group 2, and both RCM and ebselen were given to the rats in group 3. Only ebselen was given to the rats in group 4. Liver sections of the killed animals were analyzed to measure the levels of malondialdehyde (MDA) and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), as well as histopathological changes. In RCM group, SOD and CAT levels were found increased. In RCM-ebselen group, MDA, SOD and CAT levels were found decreased. In RCM-ebselen group, however, GSH-Px activities of liver tissue increased. All these results indicated that ebselen produced a protective mechanism against RCM-induced hepatotoxicity and took part in oxidative stress. PMID- 22491721 TI - The apoptotic effect of a high dose of toluene on liver tissue during the acute phase: an experimental study. AB - The aim of this study is to investigate the acute toxic effects of high-dose toluene and its mechanisms on the liver tissue of toluene-treated rats. In this study, 16 adult male Wistar albino rats (200-220 g) were divided into two equal groups. Group I was used as a control group, while group II was exposed to high dose of toluene, 5200 mg/kg (6 ml/kg per gavage). After the 3-hour experimental period, blood samples and liver tissues were taken from the euthanized animals. Serum aspartate and alanine aminotransferase levels were assayed. Liver tissues were fixed in 10% neutral formalin, then embedded in paraffin and sectioned (5 MUm thickness). Sections were stained with hematoxylin and eosin for histopathological examination. A terminal transferase dUTP nick end labeling assay was also done for the determination of apoptosis in liver tissues. For the determination of Bax and caspase-3 immunoreactivity, the sections were stained using avidin-biotin-peroxidase immunohistochemical method. The level of plasma transaminase was found to be increased in toluene administered rats. Additionally, slight degeneration of hepatocyte and mononuclear cell infiltration was observed in the liver tissue sections and a high (+++) immunoreactivity for Bax and caspase-3 protein was observed in the toluene group. This study showed that the high dose of toluene triggers apoptosis in the liver of rats via the mitochondrial pathway in acute period. PMID- 22491722 TI - Hypothyroidism maintained reactive oxygen species-steady state in the kidney of rats intoxicated with ethylene glycol: effect related to an increase in the glutathione that maintains the redox environment. AB - Our objective was to determine whether hypothyroidism protects against ethylene glycol (EG)-induced renal damage and whether the redox environment participates in the protection process. We used 36 male Wistar rats divided into four groups: (1) euthyroid, (2) euthyroid + 0.75% EG, (3) hypothyroid, and (4) hypothyroid + 0.75% EG. Hypothyroidism occurred 2 weeks after thyroidectomy. The parathyroid gland was reimplanted. EG was administrated for 21 days in drinking water. On day 21, the renal function was assessed and then the rats were decapitated. The left kidney was processed for histology, and the right kidney was used to determine the redox environment, oxidative stress, and the testing of the antioxidant enzymatic system. EG in euthyroid rats reduced the hydric and electrolytic balance and it also caused oxidative stress and renal damage. Hypothyroidism per se modifies the renal function causing a low osmolal and potassium clearance and the filtered load of potassium and sodium. In addition, there was an enhanced redox state because hypothyroidism increases the reduced glutathione concentration caused by a high activity of gamma-glutamylcysteine synthase. Hypothyroidism is a protective state against EG because the changes in the renal function were smaller than in the euthyroid state. The oxidative stress and cellular damage were ameliorated by the hypothyroid condition. Also, the hypothyroidism-enhanced redox environment protects against EG-induced oxidative stress, renal damage, and renal dysfunction. PMID- 22491723 TI - Toxic effects of boron on growth and antioxidant system parameters of maize (Zea mays L.) roots. AB - The aim of this study was to investigate the possible oxidative stress and the antioxidant response, which were caused on maize by boron (B). For this, 11- and 15-day-old maize seedlings were subjected to 2 or 4 mM B in the form of boric acid (H3BO3) for 2 and/or 6 days. At the end of the treatment period, root length, hydrogen peroxide (H2O2) content, malondialdehyde (MDA) content and the antioxidant enzymes superoxide dismutase (SOD), peroxidase (POX) and catalase (CAT) were measured. The results revealed that root length of plants, activity of antioxidative enzymes such as SOD, POX and CAT and also H2O2 contents and MDA levels were seriously affected by excess B. These results suggested that the oxidative stress occurred due to the toxic effect of B. PMID- 22491724 TI - Determination of antimutagenic properties of apigenin-7-O-rutinoside, a flavonoid isolated from Mentha longifolia (L.) Huds. ssp. longifolia with yeast DEL assay. AB - Lamiaceae is an important plant family that has been investigated for its medicinal properties due to its large amounts of phenolic acids and flavonoids. Flavonoids have been shown to have antioxidant and antimutagenic activities in different test systems, but their certain mechanisms are still unclear. This study was designed to evaluate the mutagenic and antimutagenic activities of apigenin 7-O-rutinoside, a flavonoid isolated from Mentha longifolia (L.) Huds. ssp. longifolia. The possible antimutagenic potential of apigenin 7-O-rutinoside (A7R) was examined against mutagens ethyl methanesulfonate (EMS) and acridine (AC) in a eukaryotic cell system Saccharomyces cerevisiae RS112. The results showed that A7R has different inhibition rates against EMS and AC-induced mutagenicity. Thus, the properties of A7R are of great pharmacological importance and might be beneficial for reducing the risk of reactive oxygen species-related diseases. PMID- 22491725 TI - Paraquat-induced convulsion and death: a report of five cases. AB - Paraquat (PQ) is a potent toxicant for humans, and poisoning with PQ is associated with high mortality. Patients with severe PQ-induced poisoning may die of multiple organ failure involving the circulatory and respiratory systems. Death resulting from epilepsy-like convulsions, which are infrequently noted reported with PQ poisoning, is observed clinically with this condition. This study presents the clinical data of five patients with severe PQ-induced poisoning who died of epilepsy-like convulsions, and related publications were reviewed in order to investigate the pathogenesis, clinical manifestations, and prognosis of these convulsions. Our results may help prevent this event and improve the success of treatment. PMID- 22491726 TI - Borax counteracts genotoxicity of aluminum in rat liver. AB - This study was carried out to evaluate the protective role of borax (BX) on genotoxicity induced by aluminum (Al) in rat liver, using liver micronucleus assay as an indicator of genotoxicity. Sprague-Dawley rats were randomly separated into six groups and each group had four animals. Aluminum chloride (AlCl3; 5 mg/kg b.w.) and BX (3.25 and 13 mg/kg b.w.) were injected intraperitoneally to rats. Besides, animals were also treated with Al for 4 consecutive days followed by BX for 10 days. Rats were anesthetized after Al and BX injections and the hepatocytes were isolated for counting the number of micronucleated hepatocytes (MNHEPs). AlCl3 was found to significantly (p < 0.05) increase the number of MNHEPs. Rats treated with BX, however, showed no increase in MNHEPs. Moreover, simultaneous treatments with BX significantly modulated the genotoxic effects of AlCl3 in rats. It can be concluded that BX has beneficial influences and has the ability to antagonize Al toxicity. PMID- 22491727 TI - Persistent organic chemicals stage a return...but the stage has changed. PMID- 22491729 TI - Stress management and multiple sclerosis: a randomized controlled trial. AB - There is a well-established adverse reciprocal relationship between stress and multiple sclerosis (MS). However, stress management in these patients has been parsimoniously studied. In this parallel randomized controlled trial, relapsing remitting MS patients were randomly assigned to undergo either an 8-week stress management program (n=31; relaxation breathing and progressive muscle relaxation, twice a day) or not (n=30). Self-reported validated measures were used to evaluate perceived stress, health locus of control, anxiety, and depression. Daily diaries of MS symptoms were also kept by patients. In patients in the intervention group, perceived stress and symptoms of depression were significantly decreased after 8 weeks of relaxation. Repeated measures analyses showed significant group-by-time interactions for both the number of weekly symptoms and the mean intensity per symptom. No other significant change was reported. We deem that our results should encourage future studies that will incorporate more objective clinical and laboratory outcomes. PMID- 22491730 TI - Assessment of acute concussion in the combat environment. AB - Despite the prevalence of concussion in soldiers deployed to Iraq and Afghanistan, neuropsychological tests used to assist in concussion management have not been validated on the battlefield. This study evaluated the validity of the Automated Neuropsychological Assessment Metrics (ANAM) in the combat environment. Cases meeting criteria for concussion, healthy controls, and injured controls were assessed. Soldiers were administered the ANAM, traditional neuropsychological tests, and a background questionnaire. Cases were enrolled within 72 h of concussion. Cases exhibited poorer performance than controls on all ANAM subtests, with significant differences on simple reaction time (SRT), procedural reaction time (PRT), code substitution, and matching to sample (p<.001). Discriminant ability of scores on SRT and PRT subtests was 71%, which improved to 76% when pre-deployment baseline scores were available. An exploratory clinical decision tool incorporating ANAM scores and symptoms improved discriminant ability to 81%. Results provide initial validation of the ANAM for detecting acute effects of battlefield concussion. PMID- 22491731 TI - Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: a phase II study. AB - BACKGROUND: We report a prospective multicenter phase II study of haploidentical hematopoietic stem cell transplantation using CD3/CD19-depleted grafts after reduced intensity conditioning with fludarabine, thiotepa, melphalan and OKT-3. DESIGN AND METHODS: Sixty-one adults with a median age of 46 years (range 19-65 years) have been enrolled. Diagnoses were acute myeloid leukemia (n=38), acute lymphoblastic leukemia (n=8), non-Hodgkin's lymphoma (n=6), myeloma (n=4), chronic myeloid leukemia (n=3), chronic lymphatic leukemia (n=1) and myelodysplastic syndrome (n=1). Patients were considered high risk because of refractory disease (n=18), cytogenetics (n=6), complete remission (>= 2) (n=9), chemosensitive relapse in partial remission (n=4) or relapse after prior hematopoietic stem cell transplantation (n=15 allogeneic, n=8 autologous, n=1 both). At haploidentical hematopoietic stem cell transplantation, 30 patients were in complete remission and 31 in partial remission. Grafts contained a median of 7.0 * 10(6) (range 3.2-22) CD34(+) cells/kg, 4.2 * 10(4) (range 0.6-44) CD3(+) T cells/kg and 2.7 * 10(7) (range 0.00-37.3) CD56(+) cells/kg. RESULTS: Engraftment was rapid with a median of 12 days to granulocytes more than 0.5 * 10(9)/L (range 9-50 days) and 11 days to platelets more than 20 * 10(9) (range 7 38 days). Incidence of grade IIIV acute graft-versus-host-disease and chronic graft-versus-host-disease was 46% and 18%, respectively. Non-relapse mortality on Day 100 was 23% and 42% at two years. Cumulative incidence of relapse/progression at two years was 31%. Kaplan-Meier estimated 1-year and 2-year overall survival with median follow up of 869 days (range 181-1932) is 41% and 28%, respectively. CONCLUSIONS: This regimen allows successful haploidentical hematopoietic stem cell transplantation with reduced intensity conditioning in high-risk patients lacking a suitable donor. (clinicaltrials.gov identifier:NCT00202917). PMID- 22491732 TI - Gla-domainless factor Xa: molecular bait to bypass a blocked tenase complex. AB - BACKGROUND: Hemophilia is caused by deficiencies in coagulation factor VIII or IX, resulting in direct blockade of the intrinsic tenase complex and indirect blockade of the extrinsic tenase complex which is rapidly inhibited upon binding of factor Xa to tissue factor pathway inhibitor. We evaluated the ability of Gla domainless factor Xa, a truncated form of factor Xa devoid of procoagulant properties, to bind to tissue factor pathway inhibitor and to alleviate the physiological inhibition of the extrinsic tenase. DESIGN AND METHODS: Using a thrombin generation assay triggered by a low concentration of tissue factor, we evaluated the ability of Gla-domainless factor Xa to restore blood coagulation in plasma from hemophilia A and B patients without and with inhibitors. We then compared its efficacy to generate thrombin to depletion of antithrombin or tissue factor pathway inhibitor by specific antibodies. Finally, we compared the kinetics of neutralization of factor Xa and Gla-domainless factor Xa by antithrombin and tissue factor pathway inhibitor. RESULTS: Gla-domainless factor Xa was able to restore thrombin generation in plasma samples from hemophiliacs. This effect was observed for plasma from hemophilia A patients without or with inhibitors and for plasma from hemophilia B patients. Gla-domainless factor Xa had a lower affinity than factor Xa for tissue factor pathway inhibitor whereas the affinities of both proteins for antithrombin were similar. Finally, despite a short half-life in plasma, the effect of Gla-domainless factor Xa on thrombin generation was sustained for at least 1 hour. CONCLUSIONS: As Gla-domainless factor Xa was able to restore thrombin generation in plasma from hemophilia patients, our results suggest that it may be an effective alternative to current treatments for hemophilia with or without an inhibitor. PMID- 22491733 TI - A critical appraisal of tools available for monitoring epigenetic changes in clinical samples from patients with myeloid malignancies. AB - Research over the past decade has confirmed that epigenetic alterations act in concert with genetic lesions to deregulate gene expression in acute myeloid leukemia and myelodysplastic syndromes. Epigenetic alterations may serve as markers of disease, and may potentially be used for classification, prognostication and to monitor minimal residual disease. In addition, we now have the capability to pharmaceutically target epigenetic modifications, and there is an urgent need for early validation of the efficacy of the drugs. Also, an improved understanding of the functionality of epigenetic modifications may further pave the road towards individualized therapy. The recent advances in biotechnology and bioinformatics provide a plethora of novel tools for characterizing the epigenome in clinical samples, but at this point the practical, clinical utility of these methodologies needs further exploration. Here, we provide the pros and cons of the currently most feasible methods used for characterizing the methylome in clinical samples, and give a brief introduction to novel approaches to sequencing that may revolutionize our abilities to characterize the genomes and epigenomes in acute myeloid leukemia and myelodysplastic syndrome patients. PMID- 22491734 TI - An observational, prospective, two-cohort comparison of a fixed versus variable dosing strategy of prothrombin complex concentrate to counteract vitamin K antagonists in 240 bleeding emergencies. AB - BACKGROUND: Despite years of experience with vitamin K antagonist-associated bleeding events, there is still no evidence to help identify the optimal treatment with prothrombin complex concentrates. Variable dosing and fixed dose strategies are being used. In this observational prospective two-cohort study, we aimed to assess the non-inferiority of a low fixed PCC dose (1,040 IU Factor IX) compared to the registered variable dosing regimen based on baseline International Normalized Rate, bodyweight, and target International Normalized Rate, to counteract vitamin K antagonists in a bleeding emergency in a daily clinical practice setting. DESIGN AND METHODS: Non-inferiority of the fixed prothrombin complex concentrate dose was hypothesized with a margin of 4%. Main end points were proportion of patients reaching the target International Normalized Rate (< 2.0) after prothrombin complex concentrate treatment, and successful clinical outcome. RESULTS: Target International Normalized Rate was reached in 92% of the fixed dose patients (n=101) versus 95% of variable dose patients (n=139) resulting in a risk difference of -2.99% (90% CI: - 8.6 to 2.7) (non-inferiority not confirmed). Clinical outcome was successful in 96% and 88% of fixed versus variable dose, respectively, with a risk difference of 8.3% (90% CI: 2.7-13.9; non-inferiority confirmed). CONCLUSIONS: Although a lower fixed prothrombin complex concentrate dose was associated with successful clinical outcome, fewer patients reached the target International Normalized Rate. PMID- 22491735 TI - Human microRNA-1245 down-regulates the NKG2D receptor in natural killer cells and impairs NKG2D-mediated functions. AB - BACKGROUND: NKG2D is an activating receptor expressed by natural killer and T cells, which have crucial functions in tumor and microbial immunosurveillance. Several cytokines have been identified as modulators of NKG2D receptor expression. However, little is known about NKG2D gene regulation. In this study, we found that microRNA 1245 attenuated the expression of NKG2D in natural killer cells. DESIGN AND METHODS: We investigated the potential interactions between the 3'-untranslated region of the NKG2D gene and microRNA as well as their functional roles in the regulation of NKG2D expression and cytotoxicity in natural killer cells. RESULTS: Transforming growth factor-beta1, a major negative regulator of NKG2D expression, post-transcriptionally up-regulated mature microRNA-1245 expression, thus down-regulating NKG2D expression and impairing NKG2D-mediated immune responses in natural killer cells. Conversely, microRNA-1245 down regulation significantly increased the expression of NKG2D expression in natural killer cells, resulting in more efficient NKG2D-mediated cytotoxicity. CONCLUSIONS These results reveal a novel NKG2D regulatory pathway mediated by microRNA-1245, which may represent one of the mechanisms used by transforming growth factor-beta1 to attenuate NKG2D expression in natural killer cells. PMID- 22491736 TI - A molecular and computational diagnostic approach identifies FOXP3, ICOS, CD52 and CASP1 as the most informative biomarkers in acute graft-versus-host disease. AB - BACKGROUND: Acute graft-versus-host disease is a severe complication of allogeneic stem cell transplantation in which the functional immune cells of the donor recognize the recipient as foreign and mount an immunological attack. There is an urgent need for better diagnostic instruments for the assessment of acute graft-versus-host disease. In the present study, a novel bioinformatics framework was used to identify gene expression patterns associated with acute graft versushost disease in patients undergoing allogeneic hematopoietic stem cell transplantation. DESIGN AND METHODS: Peripheral blood cells were collected prospectively from patients who did develop acute graftversus-host disease (YES) and from those who did not (NO). Gene expression profiling was performed using a panel of 47 candidate genes potentially involved in alloreactive responses. The entire population of YES/NO acute graft-versus-host disease patients formed the experimental validation set. Personalized modeling based on a gene selection technique was applied to identify the most significant mRNA transcripts, which were then used to profile individual data samples for training and testing the classification/prediction framework. RESULTS: A leave-one-out cross-validation procedure was performed to investigate the robustness of the classification framework producing the following results: 100% on the training dataset and 97% on the testing dataset. According to our integrated methodology, transcripts for FOXP3, ICOS, CD52 and CASP1, genes involved in immune alloreactive responses and participating in immune cell interactions, were identified as the most informative biomarkers in allogeneic stem cell transplant recipients experiencing acute graft-versus-host disease. CONCLUSIONS: This study demonstrates that the integrated methodology proposed is useful for the selection of valid gene targets for the diagnosis of acute graft-versus-host disease, producing satisfactory accuracy over independent clinical features of the allogeneic transplanted population. PMID- 22491737 TI - Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome. AB - BACKGROUND: Patients with the Shwachman-Diamond syndrome often develop hematologic complications. No risk factors for these complications have so far been identified. The aim of this study was to classify the hematologic complications occurring in patients with Shwachman-Diamond syndrome and to investigate the risk factors for these complications. DESIGN AND METHODS: One hundred and two patients with Shwachman-Diamond syndrome, with a median follow-up of 11.6 years, were studied. Major hematologic complications were considered in the case of definitive severe cytopenia (i.e. anemia <7 g/dL or thrombocytopenia <20 * 10(9)/L), classified as malignant (myelodysplasia/leukemia) according to the 2008 World Health Organization classification or as non-malignant. RESULTS: Severe cytopenia was observed in 21 patients and classified as malignant severe cytopenia (n=9), non-malignant severe cytopenia (n=9) and malignant severe cytopenia preceded by non-malignant severe cytopenia (n=3). The 20-year cumulative risk of severe cytopenia was 24.3% (95% confidence interval: 15.3% 38.5%). Young age at first symptoms (<3 months) and low hematologic parameters both at diagnosis of the disease and during the follow-up were associated with severe hematologic complications (P<0.001). Fifteen novel SBDS mutations were identified. Genotype analysis showed no discernible prognostic value. CONCLUSIONS Patients with Shwachman-Diamond syndrome with very early symptoms or cytopenia at diagnosis (even mild anemia or thrombocytopenia) should be considered at a high risk of severe hematologic complications, malignant or non-malignant. Transient severe cytopenia or an indolent cytogenetic clone had no deleterious value. PMID- 22491738 TI - The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia. AB - BACKGROUND: PI3K/AKT pathway mutations are found in T-cell acute lymphoblastic leukemia, but their overall impact and associations with other genetic aberrations is unknown. PTEN mutations have been proposed as secondary mutations that follow NOTCH1-activating mutations and cause cellular resistance to gamma secretase inhibitors. DESIGN AND METHODS: The impact of PTEN, PI3K and AKT aberrations was studied in a genetically well-characterized pediatric T-cell leukemia patient cohort (n=146) treated on DCOG or COALL protocols. RESULTS: PTEN and AKT E17K aberrations were detected in 13% and 2% of patients, respectively. Defective PTEN-splicing was identified in incidental cases. Patients without PTEN protein but lacking exon-, splice-, promoter mutations or promoter hypermethylation were present. PTEN/AKT mutations were especially abundant in TAL or LMO-rearranged leukemia but nearly absent in TLX3-rearranged patients (P=0.03), the opposite to that observed for NOTCH1-activating mutations. Most PTEN/AKT mutant patients either lacked NOTCH1-activating mutations (P=0.006) or had weak NOTCH1-activating mutations (P=0.011), and consequently expressed low intracellular NOTCH1, cMYC and MUSASHI levels. T-cell leukemia patients without PTEN/AKT and NOTCH1-activating mutations fared well, with a cumulative incidence of relapse of only 8% versus 35% for PTEN/AKT and/or NOTCH1-activated patients (P=0.005). CONCLUSIONS: PI3K/AKT pathway aberrations are present in 18% of pediatric T-cell acute lymphoblastic leukemia patients. Absence of strong NOTCH1 activating mutations in these cases may explain cellular insensitivity to gamma secretase inhibitors. PMID- 22491739 TI - Chimeric antisense RNA derived from chromosomal translocation modulates target gene expression. PMID- 22491740 TI - Induction of insulin resistance by the adipokines resistin, leptin, plasminogen activator inhibitor-1 and retinol binding protein 4 in human megakaryocytes. AB - BACKGROUND: In normal platelets, insulin inhibits agonist-induced Ca(2+) mobilization by raising cyclic AMP. Platelet from patients with type 2 diabetes are resistant to insulin and show increased Ca(2+) mobilization, aggregation and procoagulant activity. We searched for the cause of this insulin resistance. DESIGN AND METHODS: Platelets, the megakaryocytic cell line CHRF-288-11 and primary megakaryocytes were incubated with adipokines and with plasma from individuals with a disturbed adipokine profile. Thrombin-induced Ca(2+) mobilization and signaling through the insulin receptor and insulin receptor substrate 1 were measured. Abnormalities induced by adipokines were compared with abnormalities found in platelets from patients with type 2 diabetes. RESULTS: Resistin, leptin, plasminogen activator inhibitor-1 and retinol binding protein 4 left platelets unchanged but induced insulin resistance in CHRF-288-11 cells. Interleukin-6, tumor necrosis factor-alpha and visfatin had no effect. These results were confirmed in primary megakaryocytes. Contact with adipokines for 2 hours disturbed insulin receptor substrate 1 Ser(307)-phosphorylation, while contact for 72 hours caused insulin receptor substrate 1 degradation. Plasma with a disturbed adipokine profile also made CHRF-288-11 cells insulin-resistant. Platelets from patients with type 2 diabetes showed decreased insulin receptor substrate 1 expression. CONCLUSIONS: Adipokines resistin, leptin, plasminogen activator-1 and retinol binding protein 4 disturb insulin receptor substrate 1 activity and expression in megakaryocytes. This might be a cause of the insulin resistance observed in platelets from patients with type 2 diabetes. PMID- 22491741 TI - A novel role for survivin in erythroblast enucleation. AB - BACKGROUND: Nucleus free red blood cells are unique to mammals. During their terminal stage of differentiation, mammalian erythroblasts exit the cell cycle and enucleate. We previously found that survivin, a member of the chromosomal passenger complex that is required for cytokinesis, is highly expressed in late non-dividing cells. The role of survivin in enucleating erythroblasts is not known. DESIGN AND METHODS: In order to identify the role of survivin in these late erythroblasts, we performed proteomic analysis on survivin-bound protein complexes purified from murine erythroleukemia cells. Various molecular and cell biological techniques were used to confirm the presence and function of this novel complex. Furthermore, we used survivin(fl/fl) mice to study the effect of loss of survivin in enucleating erythroblasts. RESULTS: We found that survivin failed to co-localize with its known partners' inner centromere protein or Aurora B in enucleating erythroblasts but rather exists in a multi-protein complex with epidermal growth factor receptor substrate15 and clathrin, two proteins that mediate endocytic vesicle trafficking. As evidence for a direct role of this latter complex in enucleation, we found that knockdown of the genes reduced the efficiency of enucleation of primary human erythroblasts. We also observed that loss of survivin in murine erythroblasts inhibited enucleation and that survivin deficient cells harbored smaller cytoplasmic vacuoles. Interestingly, vacuolin-1, a small molecule that induces vacuole fusion, rescued the defective enucleation caused by survivin deficiency. CONCLUSIONS: This study identified a novel role for survivin in erythroblast enucleation through previously unknown protein partners. PMID- 22491742 TI - Dynamic International Prognostic Scoring System scores, pre-transplant therapy and chronic graft-versus-host disease determine outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis. AB - BACKGROUND: Myelofibrosis is a myeloproliferative stem cell disorder curable exclusively by allogeneic hematopoietic stem cell transplantation and is associated with substantial mortality and morbidity. The aim of this study was to assess disease-specific and transplant-related risk factors that influence post transplant outcome in patients with myelofibrosis. DESIGN AND METHODS: We retrospectively assessed 76 consecutive patients with primary (n=47) or secondary (n=29) myelofibrosis who underwent bone marrow (n=6) or peripheral blood stem cell (n=70) transplantation from sibling (n=30) or unrelated (n=46) donors between January 1994 and December 2010. The median follow-up of surviving patients was 55 +/- 7.5 months. RESULTS: Primary graft failure occurred in 5% and the non-relapse mortality rate at 1 year was 28%. The relapse-free survival rate was 50% with a relapse rate of 19% at 5 years. The use of pharmacological pre treatment and the post-transplant occurrence of chronic graft-versus-host disease were significant independent unfavourable risk factors for post-transplant survival in multivariate analysis. Using the Dynamic International Prognostic Scoring System for risk stratification, low-risk patients had significantly better overall survival (P=0.014, hazard ratio 1.4) and relapse-free survival (P=0.02, hazard ratio 1.3) compared to the other risk groups of patients. The additional inclusion of thrombocytopenia, abnormal karyotype and transfusion need (Dynamic International Prognostic Scoring System Plus) resulted in a predicted 5 year overall survival of 100%, 51%, 54% and 30% for low, intermediate-1, intermediate-2 and high-risk groups, respectively. The relapse incidence was significantly higher in the absence of chronic graft-versus-host disease (P=0.006), and pharmacological pre-treatment (n=43) was associated with reduced relapse-free survival (P=0.001). CONCLUSIONS: The data corroborate a strong correlation between alloreactivity and long-term post-transplant disease control and confirm an inverse relationship between disease stage, pharmacotherapy and outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis. The Dynamic International Prognostic Scoring System was demonstrated to be useful for risk stratification of patients with myelofibrosis who are to undergo hematopoietic stem cell transplantation. PMID- 22491744 TI - Coordination site-dependent cation binding and multi-responsible redox properties of Janus-head metalloligand, [Mo(V)(1,2-mercaptophenolato)3]. AB - The redox-active fac-[Mo(V)(mp)(3)](-) (mp: o-mercaptophenolato) bearing asymmetric O- and S-cation binding sites can bind with several kinds of metal ions such as Na(+), Mn(II), Fe(II), Co(II), Ni(II), and Cu(I). The fac [Mo(V)(mp)(3)](-) metalloligand coordinates to Na(+) to form the contact ion pair {Na(+)(THF)(3)[fac-Mo(V)(mp)(3)]} (1), while a separated ion pair, n-Bu(4)N[fac Mo(V)(mp)(3)] (2), is obtained by exchanging Na(+) with n-Bu(4)N(+). In the presence of asymmetric binding-sites, the metalloligand reacts with Mn(II)Cl(2).4H(2)O, Fe(II)Cl(2).4H(2)O, Co(II)Cl(2).6H(2)O, and Ni(II)Cl(2).6H(2)O to afford UV-vis-NIR spectra, indicating binding of these guest metal cations. Especially, for the cases of the Mn(II) and Co(II) products, trinuclear complexes, {M(H(2)O)(MeOH)[fac-Mo(V)(mp)(3)](2)}.1.5CH(2)Cl(2) (3.1.5CH(2)Cl(2) (M = Mn(II)), 4.1.5CH(2)Cl(2) (M = Co(II))), are successfully isolated and structurally characterized where the M are selectively bound to the hard O-binding sites of the fac-[Mo(V)(mp)(3)](-). On the other hand, a coordination polymer, {Cu(I)(CH(3)CN)[mer-Mo(V)(mp)(3)]}(n) (5), is obtained by the reaction of fac-[Mo(V)(mp)(3)](-) with [Cu(I)(CH(3)CN)(4)]ClO(4). In sharp contrast to the cases of 1, 3.1.5CH(2)Cl(2), and 4.1.5CH(2)Cl(2), the Cu(I) in 5 are selectively bound to the soft S-binding sites, where each Cu(I) is shared by two [Mo(V)(mp)(3)](-) with bidentate or monodentate coordination modes. The second notable feature of 5 is found in the geometric change of the [Mo(V)(mp)(3)](-), where the original fac-form of 1 is isomerized to the mer [Mo(V)(mp)(3)](-) in 5, which was structurally and spectroscopically characterized for the first time. Such isomerization demonstrates the structural flexibility of the [Mo(V)(mp)(3)](-). Spectroscopic studies strongly indicate that the association/dissociation between the guest metal ions and metalloligand can be modulated by solvent polarity. Furthermore, it was also found that such association/dissociation features are significantly influenced by coexisting anions such as ClO(4)(-) or B(C(6)F(5))(4)(-). This suggests that coordination bonds between the guest metal ions and metalloligand are not too static, but are sufficiently moderate to be responsive to external environments. Moreover, electrochemical data of 1 and 3.1.5CH(2)Cl(2) demonstrated that guest metal ion binding led to enhance electron-accepting properties of the metalloligand. Our results illustrate the use of a redox-active chalcogenolato complex with a simple mononuclear structure as a multifunctional metalloligand that is responsive to chemical and electrochemical stimuli. PMID- 22491745 TI - New insights into the mechanism of oxodiperoxomolybdenum catalysed olefin epoxidation and the crystal structures of several oxo-peroxo molybdenum complexes. AB - [Mo(O)(O(2))(2)(L)(2)] compounds (L = pz, pyrazole; dmpz, 3,5-dimethylpyrazole) were reacted stoichiometrically, in the absence of an oxidant, with cis cyclooctene in an ionic liquid medium where selective formation of the corresponding epoxide was observed. However, this oxo-transfer reaction was not observed for some other olefins, suggesting that alternative reaction pathways exist for these epoxidation processes. Subsequently, DFT studies investigating the oxodiperoxomolybdenum catalysed epoxidation model reaction for ethylene with hydrogen peroxide oxidant were performed. The well known Sharpless mechanism was first analysed for the [Mo(O)(O(2))(2)(dmpz)(2)] model catalyst and a low energy reaction pathway was found, which fits well with the observed experimental results for cis-cyclooctene. The structural parameters of the computed dioxoperoxo intermediate [Mo(O)(2)(O(2))(dmpz)(2)] in the Sharpless mechanism compare well with those found for the same moiety within the [Mo(4)O(16)(dmpz)(6)] complex, for which the full X-ray report is presented here. A second mechanism for the model epoxidation reaction was theoretically investigated in order to clarify why some olefins, which do not react stoichiometrically in the absence of an oxidant, showed low level conversions in catalytic conditions. A Thiel-type mechanism, in which the oxidant activation occurs prior to the oxo-transfer step, was considered. The olefin attack of the hydroperoxide ligand formed upon activation of hydrogen peroxide with the [Mo(O)(O(2))(2)(dmpz)(2)] model catalyst was not possible to model. The presence of two dmpz ligands coordinated to the molybdenum centre prevented the olefin attack for steric reasons. However, a low energy reaction pathway was identified for the [Mo(O)(O(2))(2)(dmpz)] catalyst, which can be formed from [Mo(O)(2)(O(2))(dmpz)(2)] by ligand dissociation. Both mechanisms, Sharpless- and Thiel-type, were found to display comparable energy barriers and both are accessible alternative pathways in the oxodiperoxomolybdenum catalysed olefin epoxidation. Additionally, the molecular structures of [Mo(O)(O(2))(2)(H(2)O)(pz)] and [Hdmpz](4)[Mo(8)O(22)(O(2))(4)(dmpz)(2)].2H(2)O and the full X-ray report of [Mo(O)(O(2))(2)(pz)(2)] are also presented. PMID- 22491746 TI - Controlled growth of ZnO/Zn1-xPbxSe core-shell nanowires and their interfacial electronic energy alignment. AB - ZnO/Zn(1-x)Pb(x)Se core-shell nanowires (NWs) have been synthesized by a solution based surface ion transfer method at various temperatures. The energy dispersive spectroscopic (EDS) mapping of single NWs suggests that the Zn, Pb and Se atoms are uniformly distributed in their shell layers. The ternary Zn(1-x)Pb(x)Se layers with tunable bandgaps extend the band-edge of optical absorption from 450 nm to 700 nm contrasting with the binary ZnSe layers. The ultraviolet photoelectron spectroscopic (UPS) analysis reveals a transition from the type I to type II band alignment when the x fraction decreases from 0.66 to the value of 0.36 in the nanoshell layers. This quantitative investigation of electronic energy levels at ZnO and Zn(1-x)Pb(x)Se interfaces indicates that the proper type II band alignment is well suited for photovoltaic energy conversion. The photovoltaic cells comprising a ZnO/Zn(1-x)Pb(x)Se nano-heterojunction with the optimized Pb content are expected to be more efficient than the devices sensitized by binary ZnSe or PbSe. PMID- 22491747 TI - The origin of the 5S ribosomal RNA molecule could have been caused by a single inverse duplication: strong evidence from its sequences. AB - The secondary structure of the 5S ribosomal RNA (5S rRNA) molecule shows a high degree of symmetry. In order to explain the origin of this symmetry, it has been conjectured that one half of the 5S rRNA molecule was its precursor and that an indirect duplication of this precursor created the other half and thus the current symmetry of the molecule. Here, we have subjected to an empirical test both the indirect duplication model, analysing a total of 684 5S rRNA sequences for complementarity between the two halves of the 5S rRNA, and the direct duplication model analysing in this case the similarity between the two halves of this molecule. In intra- and inter-molecule and intra- and inter-domain comparisons, we find a high statistical support to the hypothesis of a complementarity relationship between the two halves of the 5S rRNA molecule, denying vice versa the hypothesis of similarity between these halves. Therefore, these observations corroborate the indirect duplication model at the expense of the direct duplication model, as reason of the origin of the 5S rRNA molecule. More generally, we discuss and favour the hypothesis that all RNAs and proteins, which present symmetry, did so through gene duplication and not by gradualistic accumulation of few monomers or segments of molecule into a gradualistic growth process. This would be the consequence of the very high propensity that nucleic acids have to be subjected to duplications. PMID- 22491748 TI - Research paper of the year: interventions to improve health. PMID- 22491749 TI - Most laboratory cancer studies cannot be replicated, study shows. PMID- 22491750 TI - Prescribing for women patients is less likely to follow guidelines than prescribing for their male counterparts. PMID- 22491751 TI - Free-standing nickel oxide nanoflake arrays: synthesis and application for highly sensitive non-enzymatic glucose sensors. AB - We report a seed-mediated hydrothermal growth of free-standing nickel hydroxide [Ni(OH)(2)] and nickel oxide (NiO) nanoflake arrays and their implementation as electrodes for non-enzymatic glucose sensors. Ni(OH)(2) nanoflakes were converted into porous NiO nanoflakes upon thermal annealing in air at temperatures of 300 degrees C or above. NiO nanoflake-arrayed sensors achieve an excellent glucose sensitivity of ~8500 MUA cm(-2) mM(-1) and a low detection limit of 1.2 MUM glucose at an applied bias of 0.5 V vs. Ag/AgCl. The fabrication of the nanoflake electrode avoids the use of polymer binders representing additional advantage over the conventional powder based glucose sensors. Furthermore, they show good specificity to glucose in the presence of ascorbic acid, d-lactose and d fructose. PMID- 22491752 TI - Deficiency of the Kruppel-like factor KLF4 correlates with increased cell proliferation and enhanced skin tumorigenesis. AB - Kruppel-like factor 4 (KLF4) is a transcription factor that is highly expressed in differentiated epithelial cells including that of the skin. It is critical for specification or function of differentiated epithelial cells. Moreover, KLF4 functions either as a tumor suppressor or an oncogene depending on different cellular contexts. However, the role of KLF4 in skin tumorigenesis remains controversial. To address this issue, we first examined KLF4 expression using a cohort of samples from patients with skin squamous cell carcinoma and basal cell carcinoma and found that in 21 of 24 tumor tissues (87.5%), KLF4 expression as assayed by immunohistochemistry was absent when compared with that in normal tissues. In addition, knockdown of KLF4 in human epidermal squamous cell carcinoma SCC13 cells was accompanied by increased cell growth. Further analysis revealed that KLF4 deficiency promoted cell migration and adhesion, which are the important properties of tumor cells. These observations were supported by the effect upon overexpression of KLF4 in SCC13 cells. Furthermore, we generated a novel tamoxifen-inducible KLF4/CreER and KLF4(flox) double transgenic mouse model to examine the role of KLF4 in skin cancer development. Consistent with in vitro studies, KLF4 deficiency increased the ability of migration and adhesion of mouse primary skin keratinocytes. Moreover, KLF4 knockout led to increased cell proliferation and skin carcinogenesis in a classical DMBA/TPA mouse skin cancer model. Taken together, our data suggest that KLF4 inhibits cell proliferation, migration and adhesion and that loss of KLF4 promotes skin tumorigenesis. PMID- 22491753 TI - A prospective trial on ureteral stenting combined with secondary ureteroscopy after an initial failed procedure. AB - The aim of this study is to investigate the impact of the intentional ureteral stenting on the success rate of calculus extraction by second ureteroscopy, when the initial ureteroscopy failed. We prospectively enrolled 512 patients with ureteral calculi who underwent ureteroscopies from April 2005 to May 2011. The patients with failed initial ureteroscopies were classified into two groups depending on the stent type: the Double-J stent and the ureteral catheter group. The secondary ureteroscopies were performed in a short period (3-22 days). Data were abstracted on stone size, location, patient demographics, outcome and complications. A total of 453 patients had success after the initial ureteroscopy and the success rate was 88.5%. Of the 59 failed patients, 40 were managed by reureteroscopy with Double-J stent placement and 19 with ureteral catheters. There were no statistically significant differences between patients in Double-J stent and ureteral catheter group in the aspects of age, primary stone size, gender, stone location and stone-free rate [39/40 (97.5%) versus 19/19 (100%), p > 0.05]. Moreover, the mean stents retaining period before the second ureteroscopy was significantly shorter in the ureteral catheter group, when compared with the Double-J stent group (3.9 versus 16.9 days, p < 0.01). The complications were moderate and not significantly different between the two groups (p > 0.05). Indwelling a ureteral stent leads to a high subsequent success rate for second ureteroscopy following an initial failed procedure. In addition to Double-J stent, the ureteral catheter stent was an effective alternative with shorter retaining period, especially for impacted stones. PMID- 22491755 TI - Social inequalities in adolescent depression: the role of parental social support and optimism. AB - AIMS: Interpersonal theory suggests relationships between socio-economic status (SES) and adolescent psychopathology mediated by negative parenting. This study examines the role of perceived parental social support and optimism in understanding adolescents' depression and self-rated health among a sample of Hungarian youth. METHODS: Using a self-administered questionnaire, data (N = 881) were collected from high-school students (14-20 years old) in Szeged, Hungary (a regional centre in the southeastern region, near to the Serbian border, with a population of 170,000 inhabitants). To analyse the overall structure of the relationship between objective/subjective SES, parental support, optimism and health outcomes (depression, self-perceived health), structural equation modelling (SEM) was employed. RESULTS: Findings suggest the following: (1) SES variables generate social inequalities in adolescent depression through parental social support, particularly maternal support; and (2) parents provide youths with different levels of social support that in turn may strengthen or weaken optimism during the socialization process. CONCLUSIONS: In addressing depression prevention and treatment, we may want to take into account socio-economic differences in social networks and levels of optimism, which may influence youths' psychosocial adjustment and development of psychopathology. PMID- 22491756 TI - Disaster-related psychiatric disorders among survivors of flooding in Ladakh, India. AB - BACKGROUND: Heavy rainfall in northern India in August 2010 caused flash floods, seriously damaging homes and infrastructure. There have been no major disasters in the history of Ladakh, and no surveys on post-disaster psychiatric disorders have been conducted in this area. AIMS AND METHODS: To examine the impact of this disaster in Ladakh one month post-disaster, we visited Choglamsar, located near the town of Leh, where the flood had the most severe impact. In total, 318 survivors (mean age: 58.6 years; female-male ratio: 59.7%; Tibetan refugees: 86.2%) participated in the survey. We used the two-item Patient Health Questionnaire (PHQ-2) along with questions covering background characteristics and disaster exposure. A psychiatrist interviewed the survivors with a single or double positive score in the PHQ-2 or with post-traumatic stress disorder (PTSD) symptoms. RESULTS AND CONCLUSION: There were only two PTSD cases and five of major depressive disorders. PTSD and depression were less common in the Tibetan cultural areas than in other areas. The social background and temperamental characteristics of the Tibetan culture may play a suppressive role in psychiatric disorders. PMID- 22491757 TI - Quality of life and social determinants of anxiolytics and hypnotics use in women in Poland: a population-based study. AB - BACKGROUND: The majority of studies show a substantially higher consumption of anxiolytics and antidepressants among women than among men and in the age bracket above 45 years. AIMS: To analyse association between the use of hypnotics/anxiolytics, and various characteristics of Polish women, including health-related quality of life. METHOD: One thousand, five hundred and sixty (1,560) women aged 45-60 years completed a questionnaire dealing with the use of hypnotics/anxiolytics, demographic characteristics, environmental and work stress exposure, and self-reported quality of life (SF-36 form). RESULTS: The following variables were revealed as the predictors of hypnotic/anxiolytic use on univariate analysis: age; social pension; stress at work and environmental stress; hormone replacement therapy; headache; palpitations; mood swings or increased muscular tension; anger; duration of symptoms longer than one week; consulting a specialist; and low physical and mental health-related quality of life. The significant protective factors included: vocational and tertiary education; job satisfaction; and home as place of rest. The independent predictors of anxiolytic/hypnotic use included consulting a specialist and symptoms lasting more than one week, while job satisfaction and home as place of rest were the independent protective factors. CONCLUSIONS: The use of hypnotic/anxiolytic medication is strongly associated with environmental and psychosocial characteristics of women between 40 and 65 years of age. PMID- 22491758 TI - Exploration of factors associated with social worker attitudes toward suicide. AB - BACKGROUND: Social workers are expected to play important roles in suicide intervention. Caregiving behaviours of medical personnel to suicidal individuals have been reported to be influenced by their own attitudes toward suicide. In this context, only a limited number of studies have examined social workers' attitudes toward suicide. AIM: The purpose of this study was to explore associations between personal or occupational factors of social workers and their attitudes toward suicide. METHODS: A self-administered questionnaire was mailed to 2,999 study participants registered with the Tokyo chapter of the Japanese Association of Certified Social Workers. We adopted the Attitudes Toward Suicide Scale (ATTS) to measure attitudes toward suicide. MANCOVA was used to test for the effects of demographic, personal and occupational factors on ATTS sub-scale scores. RESULTS: Participants with a history of suicidal thoughts had stronger attitudes regarding the right to suicide than those with no history; these attitudes were not affected by a history of participating in suicide-prevention training. CONCLUSIONS: Our findings suggest that suicide education should incorporate programmes directed at altering permissive attitudes toward suicide. PMID- 22491759 TI - Thiol-yne coupling: revisiting old concepts as a breakthrough for up-to-date applications. AB - Radical thiol-yne coupling (TYC) has emerged as one of the most appealing click chemistry procedures, appearing as a sound candidate for replacing/complementing other popular click reactions such as the thiol-ene coupling (TEC) and the Cu catalysed azide-alkyne cycloaddition (CuAAC). Radical TYC is indeed a metal-free reaction suitable for biomedical applications, and its mechanistic features often make it more efficient than its TEC sister reaction and more suitable for multifaceted derivatisations in the materials chemistry and bioconjugation realms. This article reviews the fascinating results obtained in those fields in very recent years. PMID- 22491760 TI - Impact of Quaternary climatic changes and interspecific competition on the demographic history of a highly mobile generalist carnivore, the coyote. AB - Recurrent cycles of climatic change during the Quaternary period have dramatically affected the population genetic structure of many species. We reconstruct the recent demographic history of the coyote (Canis latrans) through the use of Bayesian techniques to examine the effects of Late Quaternary climatic perturbations on the genetic structure of a highly mobile generalist species. Our analysis reveals a lack of phylogeographic structure throughout the range but past population size changes correlated with climatic changes. We conclude that even generalist carnivorous species are very susceptible to environmental changes associated with climatic perturbations. This effect may be enhanced in coyotes by interspecific competition with larger carnivores. PMID- 22491761 TI - A test of the oxidative damage hypothesis for discontinuous gas exchange in the locust Locusta migratoria. AB - The discontinuous gas exchange cycle (DGC) is a breathing pattern displayed by many insects, characterized by periodic breath-holding and intermittently low tracheal O(2) levels. It has been hypothesized that the adaptive value of DGCs is to reduce oxidative damage, with low tracheal O(2) partial pressures (PO(2) ~ 2-5 kPa) occurring to reduce the production of oxygen free radicals. If this is so, insects displaying DGCs should continue to actively defend a low tracheal PO(2) even when breathing higher than atmospheric levels of oxygen (hyperoxia). This behaviour has been observed in moth pupae exposed to ambient PO(2) up to 50 kPa. To test this observation in adult insects, we implanted fibre-optic oxygen optodes within the tracheal systems of adult migratory locusts Locusta migratoria exposed to normoxia, hypoxia and hyperoxia. In normoxic and hypoxic atmospheres, the minimum tracheal PO(2) that occurred during DGCs varied between 3.4 and 1.2 kPa. In hyperoxia up to 40.5 kPa, the minimum tracheal PO(2) achieved during a DGC exceeded 30 kPa, increasing with ambient levels. These results are consistent with a respiratory control mechanism that functions to satisfy O(2) requirements by maintaining PO(2) above a critical level, not defend against high levels of O(2). PMID- 22491762 TI - Habitat associations of species show consistent but weak responses to climate. AB - Different vegetation types can generate variation in microclimates at local scales, potentially buffering species from adverse climates. To determine if species could respond to such microclimates under climatic warming, we evaluated whether ectothermic species (butterflies) can exploit favourable microclimates and alter their use of different habitats in response to year-to-year variation in climate. In both relatively cold (Britain) and warm (Catalonia) regions of their geographical ranges, most species shifted into cooler, closed habitats (e.g. woodland) in hot years, and into warmer, open habitats (e.g. grassland) in cooler years. Additionally, three-quarters of species occurred in closed habitats more frequently in the warm region than in the cool region. Thus, species shift their local distributions and alter their habitat associations to exploit favourable microclimates, although the magnitude of the shift (approx. 1.3% of individuals from open to shade, per degree Celsius) is unlikely to buffer species from impacts of regional climate warming. PMID- 22491763 TI - Reassessment of genome size in turtle and crocodile based on chromosome measurement by flow karyotyping: close similarity to chicken. AB - The genome size in turtles and crocodiles is thought to be much larger than the 1.2 Gb of the chicken (Gallus gallus domesticus, GGA), according to the animal genome size database. However, GGA macrochromosomes show extensive homology in the karyotypes of the red eared slider (Trachemys scripta elegans, TSC) and the Nile crocodile (Crocodylus niloticus, CNI), and bird and reptile genomes have been highly conserved during evolution. In this study, size and GC content of all chromosomes are measured from the flow karyotypes of GGA, TSC and CNI. Genome sizes estimated from the total chromosome size demonstrate that TSC and CNI are 1.21 Gb and 1.29 Gb, respectively. This refines previous overestimations and reveals similar genome sizes in chicken, turtle and crocodile. Analysis of chromosome GC content in each of these three species shows a higher GC content in smaller chromosomes than in larger chromosomes. This contrasts with mammals and squamates in which GC content does not correlate with chromosome size. These data suggest that a common ancestor of birds, turtles and crocodiles had a small genome size and a chromosomal size-dependent GC bias, distinct from the squamate lineage. PMID- 22491764 TI - Model analysis for plant disease dynamics co-mediated by herbivory and herbivore borne phytopathogens. AB - Plants are subject to diseases caused by pathogens, many of which are transmitted by herbivorous arthropod vectors. To understand plant disease dynamics, we studied a minimum hybrid model combining consumer-resource (herbivore-plant) and susceptible-infected models, in which the disease is transmitted bi-directionally between the consumer and the resource from the infected to susceptible classes. Model analysis showed that: (i) the disease is more likely to persist when the herbivore feeds on the susceptible plants rather than the infected plants, and (ii) alternative stable states can exist in which the system converges to either a disease-free or an endemic state, depending on the initial conditions. The second finding is particularly important because it suggests that the disease may persist once established, even though the initial prevalence is low (i.e. the R(0) rule does not always hold). This situation is likely to occur when the infection improves the plant nutritive quality, and the herbivore preferentially feeds on the infected resource (i.e. indirect vector-pathogen mutualism). Our results highlight the importance of the eco-epidemiological perspective that integration of tripartite interactions among host plant, plant pathogen and herbivore vector is crucial for the successful control of plant diseases. PMID- 22491765 TI - Forensic pharmacists engage in work relating to litigation, the regulatory process, or the criminal justice system. Introduction. PMID- 22491766 TI - Anticoagulants: therapeutics, risks, and toxicity--special emphasis on heparin induced thrombocytopenia (HIT). AB - Anticoagulants are powerful and unavoidably dangerous drugs that must be carefully selected, monitored, and evaluated. Every patient undergoing treatment is at risk of excess bleeding, since the primary purpose of this class of drugs is to decrease clotting through a variety of biochemical and pharmacological mechanisms. Under the best of circumstances, significant numbers of patients (~10%) experience toxicity on traditional warfarin oral anticoagulants. Beyond the obvious type A pharmacological toxicity, heparin products carry a seemingly paradoxical/novel risk of increased coagulopathy with limb- and life-threatening thromboembolic injuries (heparin-induced thrombocytopenia [HIT]). As a result of the great toxicity risk, many patients suffer injuries, and litigation is threatened or initiated, frequently against pharmacists and their employers. This article reviews the therapeutic use of old and novel anticoagulants, lists the types of litigation related thereto, and discusses the HIT risk associated with heparin products treatment. Litigation can result from adverse drug reactions and toxicity from anticoagulants. PMID- 22491767 TI - Factors affecting warfarin related knowledge and INR control of patients attending physicians and pharmacists' managed anticoagulation clinics. PMID- 22491770 TI - Epithelial cell responses to infection with human papillomavirus. AB - Human papillomavirus (HPV) infection of the genital tract is common in young sexually active individuals, the majority of whom clear the infection without overt clinical disease. Most of those who do develop benign lesions eventually mount an effective cell-mediated immune (CMI) response, and the lesions regress. Regression of anogenital warts is accompanied histologically by a CD4(+) T cell dominated Th1 response; animal models support this and provide evidence that the response is modulated by antigen-specific CD4(+) T cell-dependent mechanisms. Failure to develop an effective CMI response to clear or control infection results in persistent infection and, in the case of the oncogenic HPVs, an increased probability of progression to high-grade intraepithelial neoplasia and invasive carcinoma. Effective evasion of innate immune recognition seems to be the hallmark of HPV infections. The viral infectious cycle is exclusively intraepithelial: there is no viremia and no virus-induced cytolysis or cell death, and viral replication and release are not associated with inflammation. HPV globally downregulates the innate immune signaling pathways in the infected keratinocyte. Proinflammatory cytokines, particularly the type I interferons, are not released, and the signals for Langerhans cell (LC) activation and migration, together with recruitment of stromal dendritic cells and macrophages, are either not present or inadequate. This immune ignorance results in chronic infections that persist over weeks and months. Progression to high-grade intraepithelial neoplasia with concomitant upregulation of the E6 and E7 oncoproteins is associated with further deregulation of immunologically relevant molecules, particularly chemotactic chemokines and their receptors, on keratinocytes and endothelial cells of the underlying microvasculature, limiting or preventing the ingress of cytotoxic effectors into the lesions. Recent evidence suggests that HPV infection of basal keratinocytes requires epithelial wounding followed by the reepithelization of wound healing. The wound exudate that results provides a mechanistic explanation for the protection offered by serum neutralizing antibody generated by HPV L1 virus-like particle (VLP) vaccines. PMID- 22491772 TI - Epidemiology of and diagnostic strategies for toxoplasmosis. AB - The apicomplexan parasite Toxoplasma gondii was discovered a little over 100 years ago, but knowledge of its biological life cycle and its medical importance has grown in the last 40 years. This obligate intracellular parasite was identified early as a pathogen responsible for congenital infection, but its clinical expression and the importance of reactivations of infections in immunocompromised patients were recognized later, in the era of organ transplantation and HIV infection. Recent knowledge of host cell-parasite interactions and of parasite virulence has brought new insights into the comprehension of the pathophysiology of infection. In this review, we focus on epidemiological and diagnostic aspects, putting them in perspective with current knowledge of parasite genotypes. In particular, we provide critical information on diagnostic methods according to the patient's background and discuss the implementation of screening tools for congenital toxoplasmosis according to health policies. PMID- 22491775 TI - Update on influenza diagnostics: lessons from the novel H1N1 influenza A pandemic. AB - The menu of diagnostic tools that can be utilized to establish a diagnosis of influenza is extensive and includes classic virology techniques as well as new and emerging methods. This review of how the various existing diagnostic methods have been utilized, first in the context of a rapidly evolving outbreak of novel influenza virus and then during the different subsequent phases and waves of the pandemic, demonstrates the unique roles, advantages, and limitations of each of these methods. Rapid antigen tests were used extensively throughout the pandemic. Recognition of the low negative predictive values of these tests is important. Private laboratories with preexisting expertise, infrastructure, and resources for rapid development, validation, and implementation of laboratory-developed assays played an unprecedented role in helping to meet the diagnostic demands during the pandemic. FDA-cleared assays remain an important element of the diagnostic armamentarium during a pandemic, and a process must be developed with the FDA to allow manufacturers to modify these assays for detection of novel strains in a timely fashion. The need and role for subtyping of influenza viruses and antiviral susceptibility testing will likely depend on qualitative (circulating subtypes and their resistance patterns) and quantitative (relative prevalence) characterization of influenza viruses circulating during future epidemics and pandemics. PMID- 22491773 TI - Colonization by Pneumocystis jirovecii and its role in disease. AB - Although the incidence of Pneumocystis pneumonia (PCP) has decreased since the introduction of combination antiretroviral therapy, it remains an important cause of disease in both HIV-infected and non-HIV-infected immunosuppressed populations. The epidemiology of PCP has shifted over the course of the HIV epidemic both from changes in HIV and PCP treatment and prevention and from changes in critical care medicine. Although less common in non-HIV-infected immunosuppressed patients, PCP is now more frequently seen due to the increasing numbers of organ transplants and development of novel immunotherapies. New diagnostic and treatment modalities are under investigation. The immune response is critical in preventing this disease but also results in lung damage, and future work may offer potential areas for vaccine development or immunomodulatory therapy. Colonization with Pneumocystis is an area of increasing clinical and research interest and may be important in development of lung diseases such as chronic obstructive pulmonary disease. In this review, we discuss current clinical and research topics in the study of Pneumocystis and highlight areas for future research. PMID- 22491771 TI - Two years after pandemic influenza A/2009/H1N1: what have we learned? AB - The world had been anticipating another influenza pandemic since the last one in 1968. The pandemic influenza A H1N1 2009 virus (A/2009/H1N1) finally arrived, causing the first pandemic influenza of the new millennium, which has affected over 214 countries and caused over 18,449 deaths. Because of the persistent threat from the A/H5N1 virus since 1997 and the outbreak of the severe acute respiratory syndrome (SARS) coronavirus in 2003, medical and scientific communities have been more prepared in mindset and infrastructure. This preparedness has allowed for rapid and effective research on the epidemiological, clinical, pathological, immunological, virological, and other basic scientific aspects of the disease, with impacts on its control. A PubMed search using the keywords "pandemic influenza virus H1N1 2009" yielded over 2,500 publications, which markedly exceeded the number published on previous pandemics. Only representative works with relevance to clinical microbiology and infectious diseases are reviewed in this article. A significant increase in the understanding of this virus and the disease within such a short amount of time has allowed for the timely development of diagnostic tests, treatments, and preventive measures. These findings could prove useful for future randomized controlled clinical trials and the epidemiological control of future pandemics. PMID- 22491777 TI - MRI of superficial soft tissue masses: analysis of features useful in distinguishing between benign and malignant lesions. AB - AIM: To identify the MRI features of superficial soft tissue masses, that may allow differentiation between malignant and non-malignant lesions. METHOD: A total of 136 consecutive patients referred to a supra-regional musculoskeletal oncology center over a 10-year period with the diagnosis of a superficial soft tissue mass were included in this retrospective study. Features analyzed included patient demographics, lesion size, MRI signal characteristics, margins, lobulation, hemorrhage, necrosis, fascial edema, relationship to the fascia, as well as involvement of the skin. Comparison was then made with the final histological diagnosis. RESULTS: Of the patients reviewed, 58 were male and 78 were female, and the mean age was 49.9 years. The mean age for malignant lesions was 57.9 years, and that for non-neoplastic and benign conditions 41.9 years (p < 0.001). A significant relationship was identified between malignancy and lobulation (p < 0.01), hemorrhage (p < 0.001), fascial edema (p < 0.001), hemorrhage (p < 0.0001) and necrosis (p < 0.001). The relationship between skin thickening and skin contact and malignancy was also found to be significant. However, size was not found to be an important determining factor for malignancy, with a significant proportion of malignant superficial sarcomas measuring less than 5 cm in maximal diameter. CONCLUSIONS: This study has shown that a significant proportion of malignant superficial sarcomas measured less than 5 cm in maximal diameter. Fascial edema, skin thickening, skin contact, hemorrhage, and necrosis were found to be highly significant factors indicative of malignancy. Lobulation and peritumoral edema were also significant MRI features. PMID- 22491774 TI - Infection barriers to successful xenotransplantation focusing on porcine endogenous retroviruses. AB - Xenotransplantation may be a solution to overcome the shortage of organs for the treatment of patients with organ failure, but it may be associated with the transmission of porcine microorganisms and the development of xenozoonoses. Whereas most microorganisms may be eliminated by pathogen-free breeding of the donor animals, porcine endogenous retroviruses (PERVs) cannot be eliminated, since these are integrated into the genomes of all pigs. Human-tropic PERV-A and B are present in all pigs and are able to infect human cells. Infection of ecotropic PERV-C is limited to pig cells. PERVs may adapt to host cells by varying the number of LTR-binding transcription factor binding sites. Like all retroviruses, they may induce tumors and/or immunodeficiencies. To date, all experimental, preclinical, and clinical xenotransplantations using pig cells, tissues, and organs have not shown transmission of PERV. Highly sensitive and specific methods have been developed to analyze the PERV status of donor pigs and to monitor recipients for PERV infection. Strategies have been developed to prevent PERV transmission, including selection of PERV-C-negative, low-producer pigs, generation of an effective vaccine, selection of effective antiretrovirals, and generation of animals transgenic for a PERV-specific short hairpin RNA inhibiting PERV expression by RNA interference. PMID- 22491778 TI - Short- and long-term dynamic responses of the metabolic network and gene expression in yeast to a transient change in the nutrient environment. AB - Quantitative data on the dynamic changes in the transcriptome and the metabolome of yeast in response to an impulse-like perturbation in nutrient availability was integrated with the metabolic pathway information in order to elucidate the long term dynamic re-organization of the cells. This study revealed that, in addition to the dynamic re-organization of the de novo biosynthetic pathways, salvage pathways were also re-organized in a time-dependent manner upon catabolite repression. The transcriptional and the metabolic responses observed for nitrogen catabolite repression were not as severe as those observed for carbon catabolite repression. Selective up- or down regulation of a single member of a paralogous gene pair during the response to the relaxation from nutritional limitation was identified indicating a differentiation of functions among paralogs. Our study highlighted the role of inosine accumulation and recycling in energy homeostasis and indicated possible bottlenecks in the process. PMID- 22491779 TI - Insertion of T4-lysozyme (T4L) can be a useful tool for studying olfactory related GPCRs. AB - The detergents used to solubilize GPCRs can make crystal growth the rate-limiting step in determining their structure. The Kobilka laboratory showed that insertion of T4-lysozyme (T4L) in the 3rd intracellular loop is a promising strategy towards increasing the solvent-exposed receptor area, and hence the number of possible lattice-forming contacts. The potential to use T4L with the olfactory related receptors hOR17-4 and hVN1R1 was thus tested. The structure and function of native and T4L-variants were compared. Both receptors localized to the cell membrane, and could initiate ligand-activated signaling. Purified receptors not only had the predicted alpha-helical structures, but also bound their ligands canthoxal (M(W) = 178.23) and myrtenal (M(W) = 150.22). Interestingly, the T4L variants had higher percentages of soluble monomers compared to protein aggregates, effectively increasing the protein yield that could be used for structural and function studies. They also bound their ligands for longer times, suggesting higher receptor stability. Our results indicate that a T4L insertion may be a general method for obtaining GPCRs suitable for structural studies. PMID- 22491780 TI - The prognostic value of amyloid imaging. AB - Mild cognitive impairment is characterized by a decline in cognitive performance without interference with activities of daily living. The amnestic subtype of mild cognitive impairment progresses to Alzheimer's disease at a rate of 10-15% per year and in the majority the neuropathology is intermediate between the neuropathological changes of typical ageing and Alzheimer's disease. Amyloid deposition occurs over a decade before the development of noticeable cognitive symptoms in a continuous process that starts in healthy elderly individuals. Newly developed PET amyloid imaging agents provide noninvasive biomarkers for the early in vivo detection of Alzheimer's pathology in healthy elderly individuals and those with mild cognitive impairment. Exclusion of amyloid pathology should allow a more accurate prognosis to be given and ensure appropriate recruitment into clinical trials testing the efficacy of new putative antiamyloid agents at an earlier disease stage. The development of (18)F-labelled amyloid imaging agents has increased the availability of this new technology for clinical and research use since they can be used in PET centres where a cyclotron and radiochemistry are not available. This review discusses the role of PET imaging for assessing the amyloid load in cognitively normal elderly subjects and subjects with mild cognitive impairment at risk of conversion to Alzheimer's disease. PMID- 22491776 TI - Predictors of mortality in Staphylococcus aureus Bacteremia. AB - Staphylococcus aureus bacteremia (SAB) is an important infection with an incidence rate ranging from 20 to 50 cases/100,000 population per year. Between 10% and 30% of these patients will die from SAB. Comparatively, this accounts for a greater number of deaths than for AIDS, tuberculosis, and viral hepatitis combined. Multiple factors influence outcomes for SAB patients. The most consistent predictor of mortality is age, with older patients being twice as likely to die. Except for the presence of comorbidities, the impacts of other host factors, including gender, ethnicity, socioeconomic status, and immune status, are unclear. Pathogen-host interactions, especially the presence of shock and the source of SAB, are strong predictors of outcomes. Although antibiotic resistance may be associated with increased mortality, questions remain as to whether this reflects pathogen-specific factors or poorer responses to antibiotic therapy, namely, vancomycin. Optimal management relies on starting appropriate antibiotics in a timely fashion, resulting in improved outcomes for certain patient subgroups. The roles of surgery and infectious disease consultations require further study. Although the rate of mortality from SAB is declining, it remains high. Future international collaborative studies are required to tease out the relative contributions of various factors to mortality, which would enable the optimization of SAB management and patient outcomes. PMID- 22491781 TI - MRI-suspected low-grade glioma: is there a need to perform dynamic FET PET? AB - PURPOSE: Since differentiation between low-grade glioma (LGG) and high-grade glioma (HGG) remains challenging according to MRI criteria alone, we investigated the discriminative value of additional dynamic FET PET in patients with MRI suspected LGG. METHODS: Included in this retrospective study were 127 patients with newly diagnosed MRI-suspected LGG and dynamic FET PET prior to histopathological assessment. FET PET lesions were visually classified as having reduced, normal, or increased tracer uptake. Maximal tumour uptake scaled to the mean background uptake (SUV(max)/BG), mean tumour uptake (SUV(mean)/BG), biological tumour volume and kinetics were evaluated and correlated with individual histopathological findings. RESULTS: Histopathological analysis revealed 71 patients with LGG, 47 patients with HGG (including 5 glioblastoma multiforme), 2 patients with low-grade ganglioglioma and 7 patients with non neoplastic lesions. Of the 127 patients, 97 had lesions with increased FET uptake, of which 93 were neoplastic. Increased uptake was found in 49/71 LGG (69 %) and 42/47 HGG (89 %). None of the conventional uptake parameters differed significantly between the HGG and LGG groups. Kinetic analysis reliably identified HGG (sensitivity 95 %, specificity 72 %, PPV 74 %, NPV 95 %). Normal tracer uptake was observed in 19 patients (15 with LGG, 1 with HGG and 3 with non neoplastic lesions) and reduced uptake in 11 patients (7 with LGG and 4 with HGG). CONCLUSION: Among the MRI-suspected LGG, kinetic but not conventional analysis of FET uptake enabled remarkably high sensitivity for detection of HGG. This held true even for lesions with low or diffuse tracer uptake. Lesions with reduced tracer uptake must be interpreted with caution, as they can also harbour HGG tissue. PMID- 22491783 TI - Acidification in Arabian Gulf--insights from pH and temperature measurements. AB - The detrimental effects of increasing atmospheric levels of carbon dioxide (CO(2)) and other greenhouse gases since the industrial revolution has led to a concerted international effort to control their release and abate the environmental and human health impacts. CO(2) is removed from the atmosphere by photosynthesis of plants in the terrestrial environment and by aquatic sequestration. In the Middle East and other arid countries, terrestrial removal is minimal. The most likely removal pathway for CO(2) in arid regions around the world is by aquatic sequestration. In the Middle East the major sink is the Arabian Gulf which leads to acidification of the marine environment. Biweekly pH concentration measurements in surface waters of the northern Arabian Gulf over a four year period in this study suggest that the Arabian Gulf waters are becoming increasingly acidic with time. Supporting evidence for increased CO(2) sequestration comes from increased marine primary productivity over the past decade. Biological effects, such as coral bleaching, observed during this period suggest that urgent action is required to reverse the trend and protect marine life. The data highlight the fact that this semi-enclosed sea is undergoing a rapid degradation which may affect the oceanic chemistry and biogeochemical cycle much earlier than predicted for most oceanic waters. PMID- 22491786 TI - E. coli LoiP (YggG), a metalloprotease hydrolyzing Phe-Phe bonds. AB - YggG is a conserved lipoprotein localized to the outer membrane of Gram negative bacteria. Even though the expressed open reading frame has been identified previously, the Escherichia coli protein remained uncharacterized. We report that YggG of E. coli is a metalloprotease that cleaves its targets preferentially between Phe-Phe residues. Since the yggG promoter is upregulated when bacteria are subjected to media of low osmolarity, YggG was named LoiP (low osmolarity induced protease). LoiP has an intramolecular disulfide (S-S) bond that is formed even in the absence of the periplasmic oxido-reductase DsbA and proper membrane localization of LoiP can depend on another putative metalloprotease, YfgC. PMID- 22491782 TI - Synapses and Alzheimer's disease. AB - Alzheimer's disease (AD) is a major cause of dementia in the elderly. Pathologically, AD is characterized by the accumulation of insoluble aggregates of Abeta-peptides that are proteolytic cleavage products of the amyloid-beta precursor protein ("plaques") and by insoluble filaments composed of hyperphosphorylated tau protein ("tangles"). Familial forms of AD often display increased production of Abeta peptides and/or altered activity of presenilins, the catalytic subunits of gamma-secretase that produce Abeta peptides. Although the pathogenesis of AD remains unclear, recent studies have highlighted two major themes that are likely important. First, oligomeric Abeta species have strong detrimental effects on synapse function and structure, particularly on the postsynaptic side. Second, decreased presenilin function impairs synaptic transmission and promotes neurodegeneration. The mechanisms underlying these processes are beginning to be elucidated, and, although their relevance to AD remains debated, understanding these processes will likely allow new therapeutic avenues to AD. PMID- 22491787 TI - Hypomagnesemia after spinal fusion. AB - OBJECTIVES: To determine the frequency of hypomagnesemia in pediatric patients after spinal fusion, to verify whether postoperative magnesium levels were lower than preoperative levels and, if so, to identify possible causes and assess the clinical repercussions for patients. METHODS: This was a retrospective descriptive study of pediatric patients admitted to a pediatric intensive care unit (ICU) after spine fusion surgery, between March 1 and August 31, 2011. Preoperative magnesium, phosphorus and total and ionized calcium concentrations were compared with the results of tests conducted during the first 24 hours after admission to the ICU. RESULTS: A total of 45 patients were enrolled on the study. Median age was 13.1 years. Preoperative mean serum magnesium was 1.8 +/- 0.2 mg/dL and postoperative serum magnesium was 1.4 +/- 0.2 mg/dL, which was a significant reduction between the two periods (p < 0.001). The frequency of hypomagnesemia rose from 1 patient (2%) in the preoperative period to 31 patients (68%) during the postoperative period. There were also significant reductions in concentrations of phosphorus (p < 0.001) and total calcium (p < 0.001). There was a significant correlation between magnesium reductions and the volume of fluids administered during the surgery (p = 0.03), transfused blood volume (p < 0.001) and number of vertebrae fused (p < 0.05). Seven of the 31 patients with hypomagnesemia exhibited symptoms (22%). CONCLUSION: There was an elevated frequency of hypomagnesemia in patients who underwent spinal fusion. Serum magnesium should be assayed when patients are admitted to the pediatric ICU, so that appropriate supplementation can be initiated immediately, minimizing the risk of complications. PMID- 22491788 TI - The simultaneous ex vivo detection of low-frequency antigen-specific CD4+ and CD8+ T-cell responses using overlapping peptide pools. AB - The ability to measure antigen-specific T cells at the single-cell level by intracellular cytokine staining (ICS) is a promising immunomonitoring tool and is extensively applied in the evaluation of immunotherapy of cancer. The protocols used to detect antigen-specific CD8+ T-cell responses generally work for the detection of antigen-specific T cells in samples that have undergone at least one round of in vitro pre-stimulation. Application of a common protocol but now using long peptides as antigens was not suitable to simultaneously detect antigen specific CD8+ and CD4+ T cells directly ex vivo in cryopreserved samples. CD8 T cell reactivity to monocytes pulsed with long peptides as antigens ranged between 5 and 25 % of that observed against monocytes pulsed with a direct HLA class I fitting minimal CTL peptide epitope. Therefore, we adapted our ICS protocol and show that the use of tenfold higher concentration of long peptides to load APC, the use of IFN-alpha and poly(I:C) to promote antigen processing and improve T cell stimulation, does allow for the ex vivo detection of low-frequency antigen specific CD8+ and CD4+ T cells in an HLA-independent setting. While most of the improvements were related to increasing the ability to measure CD8+ T-cell reactivity following stimulation with long peptides to at least 50 % of the response detected when using a minimal peptide epitope, the final analysis of blood samples from vaccinated patients successfully showed that the adapted ICS protocol also increases the ability to ex vivo detect low-frequency p53-specific CD4+ T-cell responses in cryopreserved PBMC samples. PMID- 22491789 TI - Safety and efficacy of antibiotics compared with appendicectomy for treatment of uncomplicated acute appendicitis: meta-analysis of randomised controlled trials. AB - OBJECTIVE: To compare the safety and efficacy of antibiotic treatment versus appendicectomy for the primary treatment of uncomplicated acute appendicitis. DESIGN: Meta-analysis of randomised controlled trials. POPULATION: Randomised controlled trials of adult patients presenting with uncomplicated acute appendicitis, diagnosed by haematological and radiological investigations. INTERVENTIONS: Antibiotic treatment versus appendicectomy. OUTCOME MEASURES: The primary outcome measure was complications. The secondary outcome measures were efficacy of treatment, length of stay, and incidence of complicated appendicitis and readmissions. RESULTS: Four randomised controlled trials with a total of 900 patients (470 antibiotic treatment, 430 appendicectomy) met the inclusion criteria. Antibiotic treatment was associated with a 63% (277/438) success rate at one year. Meta-analysis of complications showed a relative risk reduction of 31% for antibiotic treatment compared with appendicectomy (risk ratio (Mantel Haenszel, fixed) 0.69 (95% confidence interval 0.54 to 0.89); I(2)=0%; P=0.004). A secondary analysis, excluding the study with crossover of patients between the two interventions after randomisation, showed a significant relative risk reduction of 39% for antibiotic therapy (risk ratio 0.61 (0.40 to 0.92); I(2)=0%; P=0.02). Of the 65 (20%) patients who had appendicectomy after readmission, nine had perforated appendicitis and four had gangrenous appendicitis. No significant differences were seen for treatment efficacy, length of stay, or risk of developing complicated appendicitis. CONCLUSION: Antibiotics are both effective and safe as primary treatment for patients with uncomplicated acute appendicitis. Initial antibiotic treatment merits consideration as a primary treatment option for early uncomplicated appendicitis. PMID- 22491791 TI - Should conservative treatment of appendicitis be first line? PMID- 22491790 TI - Early detection and intervention evaluation for people at risk of psychosis: multisite randomised controlled trial. AB - OBJECTIVE: To determine whether cognitive therapy is effective in preventing the worsening of emerging psychotic symptoms experienced by help seeking young people deemed to be at risk for serious conditions such as schizophrenia. DESIGN: Multisite single blind randomised controlled trial. SETTING: Diverse services at five UK sites. PARTICIPANTS: 288 participants aged 14-35 years (mean 20.74, SD 4.34 years) at high risk of psychosis: 144 were assigned to cognitive therapy plus monitoring of mental state and 144 to monitoring of mental state only. Participants were followed-up for a minimum of 12 months and a maximum of 24 months. INTERVENTION: Cognitive therapy (up to 26 (mean 9.1) sessions over six months) plus monitoring of mental state compared with monitoring of mental state only. MAIN OUTCOME MEASURES: Primary outcome was scores on the comprehensive assessment of at risk mental states (CAARMS), which provides a dichotomous transition to psychosis score and ordinal scores for severity of psychotic symptoms and distress. Secondary outcomes included emotional dysfunction and quality of life. RESULTS: Transition to psychosis based on intention to treat was analysed using discrete time survival models. Overall, the prevalence of transition was lower than expected (23/288; 8%), with no significant difference between the two groups (proportional odds ratio 0.73, 95% confidence interval 0.32 to 1.68). Changes in severity of symptoms and distress, as well as secondary outcomes, were analysed using random effects regression (analysis of covariance) adjusted for site and baseline symptoms. Distress from psychotic symptoms did not differ (estimated difference at 12 months -3.00, 95% confidence interval -6.95 to 0.94) but their severity was significantly reduced in the group assigned to cognitive therapy (estimated between group effect size at 12 months -3.67, -6.71 to -0.64, P=0.018). CONCLUSIONS: Cognitive therapy plus monitoring did not significantly reduce transition to psychosis or symptom related distress but reduced the severity of psychotic symptoms in young people at high risk. Most participants in both groups improved over time. The results have important implications for the at risk mental state concept. TRIAL REGISTRATION: Current Controlled Trials ISRCTN56283883. PMID- 22491792 TI - Cost-effectiveness analysis of autologous chondrocyte implantation: a comparison of periosteal patch versus type I/III collagen membrane. AB - BACKGROUND: Autologous chondrocyte implantation (ACI) involves the use of a periosteal patch (ACI-P) as a cover for transplanted chondrocytes. Theoretically, this periosteal patch provides mesenchymal stem cells and growth factors that encourage chondrocyte development/differentiation. However, there is a significant rate of graft hypertrophy with the use of periosteum compared with using a type I/III collagen patch (ACI-C). This type I/III collagen patch, although not approved by the United States Food and Drug Administration for ACI, has been used extensively in Europe and in an "off-label" nature in the United States as a cover during ACI. PURPOSE: To examine the cost effectiveness of ACI and determine whether ACI-C is more cost effective than ACI-P. STUDY DESIGN: Economic and decision analysis; Level of evidence, 2. METHODS: Outcome data and complication rates from patients undergoing ACI (ACI-P and ACI-C) were derived from the best evidence in the literature. Costs were determined by examining the typical patient charges undergoing ACI at a local orthopaedic hospital. The costs, results, and complication rates were used to develop a decision analysis model comparing ACI-P to ACI-C. RESULTS: The cost of ACI-P was $66,752 and for ACI-C was $66,939.50 ($187.50 difference). The cost per quality-adjusted life year (QALY) for ACI-P was $9466 compared with $9243 for ACI-C. Sensitivity analysis was performed regarding the additional cost of the type I/III collagen patch ($780) in ACI-C as well as the rate of graft hypertrophy after ACI-P (25%). This analysis revealed that the cost of the type I/III collagen patch would have to reach $1721, or the rate of graft hypertrophy after ACI-P reduced to almost 11%, before ACI-P became more cost effective than ACI-C. CONCLUSION: This cost effectiveness analysis reveals that, while both ACI-P and ACI-C are cost effective, ACI-C is slightly more cost effective than ACI-P. This is likely secondary to the significant rate of patch-related complications associated with ACI-P, which is significantly reduced with ACI-C. Although the model is very sensitive to differences in outcomes between ACI-P and ACI-C, there is no high quality evidence to suggest that there is a significant difference between the two. Thus, ACI-P becomes more cost effective if the cost of the type I/III collagen membrane is significantly increased or if the rate of graft hypertrophy after ACI-P were to be markedly reduced. PMID- 22491793 TI - Synthetic resorbable scaffolds for the treatment of isolated patellofemoral cartilage defects in young patients: magnetic resonance imaging and clinical evaluation. AB - BACKGROUND: Surgical management of patellar cartilage defects remains controversial. The ideal technique to regenerate hyaline cartilage is not yet defined. However, a synthetic resorbable osteochondral scaffold plug (TruFit CB) seems to offer a treatment option with good results at short-term follow-up, at least in the condylar setting. HYPOTHESIS: A synthetic implant provides a simple and efficacious means of treating the cartilage defects of the patellofemoral joint in young patients. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A study was designed to evaluate prospectively short- and medium-term results in patients with osteochondral patellar defects treated with synthetic reabsorbable scaffolds. Patient outcome scores (Short Form 36 [SF-36] and Knee injury and Osteoarthritis Outcome Score [KOOS]), demographics, prior surgeries, and data from a physical examination were collected at baseline (before implantation) and at 6, 12, and 24 months after surgery. Defect characteristics were collected during implantation. Diagnosis and monitoring were performed by magnetic resonance imaging. RESULTS: Ten patients with a mean age of 33.3 years (range, 16-49 years) were evaluated prospectively at 24 months' follow-up. The number of plugs used for each patient ranged from 1 to 4. At 1-year follow-up, the results were satisfactory in 8 of 10 patients, and poor in 2, according to clinical assessment (KOOS, visual analog scale, and SF-36). At 18 months of follow-up, all patients except one complained of pain and knee swelling. Reoperation rate for implant failure at final follow-up was 70%. Magnetic resonance imaging at final follow-up showed a cylindrical cavity of fibrous tissue instead of subchondral bone restoration. CONCLUSION: A synthetic implant can improve symptoms and joint function, especially for small lesions, only for a short period of time. However, 2 years of monitoring has shown its failure in restoring the subchondral bone despite the formation of predominant hyaline cartilage from synthetic resorbable scaffolds. Under current conditions and according to our experience, we do not recommend TruFit synthetic implants for osteochondral patellar defects in active patients. PMID- 22491794 TI - Incidence and risk factors for injuries to the anterior cruciate ligament in National Collegiate Athletic Association football: data from the 2004-2005 through 2008-2009 National Collegiate Athletic Association Injury Surveillance System. AB - BACKGROUND: Injuries to the anterior cruciate ligament (ACL) are common in athletic populations, particularly in athletes participating in football, soccer, and skiing. PURPOSE: The purpose of this study was to analyze the National Collegiate Athletic Association (NCAA) Injury Surveillance System (ISS) men's football ACL injury database from the playing seasons of 2004-2005 through 2008 2009 to determine the incidence and epidemiology of complete injury to the ACL in NCAA football athletes. STUDY DESIGN: Descriptive epidemiology study. METHODS: The NCAA ISS men's football database was reviewed from the 2004-2005 through 2008 2009 seasons using the specific injury code, "Anterior cruciate ligament (ACL) complete tear." The injury rate was computed for competition and practice exposures. Ninety-five percent confidence intervals (CIs) for the incident rates were calculated using assumptions of a Poisson distribution. Pairwise, 2-sample tests of equality of proportions with a continuity correction were used to estimate the associations of risk factors such as event type, playing surface, season segment, and football subdivision. Descriptive data were also described. RESULTS: The ACL injury rate during games (8.06 per 10,000 athlete-exposures [AEs] 95% CI, 6.80-9.42) was significantly greater than the rate during practice (0.8 per 10,000 AEs 95% CI, 0.68-0.93). Players were 10.09 (95% CI, 8.08-12.59) times more likely to sustain an ACL injury in competition when compared with practices. When practice exposures were analyzed separately, the injury rate was significantly greater during scrimmages (3.99 per 10,000 AEs 95% CI, 2.29-5.94) compared with regular practices (0.83 per 10,000 AEs 95% CI, 0.69-0.97) and walk throughs (0 per 10,000 AEs 95% CI, 0-0.14). There was an incidence rate of 1.73 ACL injuries per 10,000 AEs (95% CI, 1.47-2.0) on artificial playing surfaces compared with a rate of 1.24 per 10,000 AEs (95% CI, 1.05-1.45) on natural grass. The rate of ACL injury on artificial surfaces is 1.39 (95% CI, 1.11-1.73) times higher than the injury rate on grass surfaces. CONCLUSION: Between 2004 and 2009, NCAA football players experienced a greater number of ACL injuries in games compared with practices, in scrimmages compared with regular practices, and when playing on artificial turf surfaces. This latter finding will need to be confirmed by additional studies. PMID- 22491795 TI - Morphologic changes in fresh-frozen meniscus allografts over 1 year: a prospective magnetic resonance imaging study on the width and thickness of transplants. AB - BACKGROUND: Little is known about morphologic changes in the remodeling period after human meniscal allograft transplantation (MAT). HYPOTHESIS: The gross structure of meniscal transplants may be altered significantly in width and thickness during early remodeling periods. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Thirty-one patients who underwent MAT (9 medial and 22 lateral menisci) between 2008 and 2009 were prospectively evaluated by serial magnetic resonance imaging scans 2 days, 6 weeks, and 3, 6, and 12 months after surgery. At each time point, the width and thickness of the menisci were measured. The relative degree of shrinkage after 1 year was categorized as minimal (<10%), mild (10%-25%), moderate (25%-50%), or severe (>50%). The Lysholm score and Tegner activity level were used for clinical outcome scales. RESULTS: More apparent changes were observed at mid-body rather than at the posterior horn. Meniscal width at the mid-body decreased to 89% (P < .01), whereas thickness increased to 115% (P < .01) at 12 months. Shrinkage was observed for 3 months after MAT, but there were no significant changes thereafter. The thickness of the meniscal peripheral rim did not change before 3 months but increased afterward, for up to 1 year. Of the 31 patients, 20 (64.5%) had minimal shrinkage, 6 (19.4%) had mild shrinkage, 5 (16.1%) had moderate shrinkage, and none had severe shrinkage over 1 year. In the 5 cases of moderate shrinkage, the reduction occurred progressively for 1 year. However, the relative morphologic changes did not correlate with clinical outcome scales at postoperative 1 and 2 years (P > .05). The preoperative alignment deviation, cartilage status (Outerbridge grade), age, gender, amount of extrusion, and time from previous meniscectomy did not affect the degree of shrinkage. CONCLUSION: Gross morphologic alterations, as determined by width and thickness, were observed during the first postoperative year. Substantial shrinkage at the mid-body occurred progressively for 1 year in 16.1% of the cases. No association was found between morphologic changes and short-term clinical outcomes. PMID- 22491796 TI - MSV3d: database of human MisSense Variants mapped to 3D protein structure. AB - The elucidation of the complex relationships linking genotypic and phenotypic variations to protein structure is a major challenge in the post-genomic era. We present MSV3d (Database of human MisSense Variants mapped to 3D protein structure), a new database that contains detailed annotation of missense variants of all human proteins (20 199 proteins). The multi-level characterization includes details of the physico-chemical changes induced by amino acid modification, as well as information related to the conservation of the mutated residue and its position relative to functional features in the available or predicted 3D model. Major releases of the database are automatically generated and updated regularly in line with the dbSNP (database of Single Nucleotide Polymorphism) and SwissVar releases, by exploiting the extensive Decrypthon computational grid resources. The database (http://decrypthon.igbmc.fr/msv3d) is easily accessible through a simple web interface coupled to a powerful query engine and a standard web service. The content is completely or partially downloadable in XML or flat file formats. Database URL: http://decrypthon.igbmc.fr/msv3d. PMID- 22491797 TI - Combination of Rad001 (everolimus) and propachlor synergistically induces apoptosis through enhanced autophagy in prostate cancer cells. AB - PI3K/AKT/mTOR pathway plays a key role in the tumorigenesis of many human cancers including prostate cancer. However, inhibitors of this pathway, such as Rad001, have not shown therapeutic efficacy as a single agent. Through a high-throughput screen of 5,000 widely used small molecules, we identified compounds that can synergize with Rad001 to inhibit prostate cancer cells. One of the compounds, propachlor, synergizes with Rad001 to induce apoptosis of castration-resistant prostate cancer cells via enhanced autophagy. This enhanced autophagic cell death is accompanied by increased Beclin1 expression as well as upregulation of Atg5 Atg12 conjugate and LC3-2. Rad001 and propachlor can also synergistically inhibit tumors in a xenograft animal model of prostate cancer. These findings provide a novel direction to develop combination therapies for advanced and metastatic prostate cancer that has failed the currently available therapies. PMID- 22491798 TI - Overcoming platinum resistance through the use of a copper-lowering agent. AB - Low levels of human copper transporter 1 (hCtr1) mRNA are associated with a shorter progression-free survival after platinum-based therapy. Pretreatment with a copper-lowering agent such as trientine enhanced hCtr1-mediated platinum uptake. Therefore, we conducted a pilot study (NCT01178112) of carboplatin and trientine with the goal of resensitizing patients with advanced cancer to platinum chemotherapy. This case report reviews the outcomes of 5 patients with platinum-resistant high-grade epithelial ovarian cancer enrolled on the study to date. Overall, they tolerated treatment well. Severe adverse events that occurred in 2 patients were myelosuppression, notably anemia requiring transfusion. Dose limiting toxicity was not observed within the first 28 days (cycle 1). After 2 cycles of therapy, partial remission was achieved in 1 patient (10+ months), stable disease in 3 patients (2, 3.5+, and 5 months, respectively), and 1 patient had progressive disease. These cases provide preliminary clinical evidence that the role of decreasing copper levels in reversing platinum resistance merits additional clinical investigation. Evaluation of this novel strategy is warranted in larger studies to assess the efficacy of this approach for treating platinum resistant advanced epithelial ovarian cancer in patients with high copper levels. PMID- 22491799 TI - Effect of small-molecule-binding affinity on tumor uptake in vivo: a systematic study using a pretargeted bispecific antibody. AB - Small-molecule ligands specific for tumor-associated surface receptors have wide applications in cancer diagnosis and therapy. Achieving high-affinity binding to the desired target is important for improving detection limits and for increasing therapeutic efficacy. However, the affinity required for maximal binding and retention remains unknown. Here, we present a systematic study of the effect of small-molecule affinity on tumor uptake in vivo with affinities spanning a range of three orders of magnitude. A pretargeted bispecific antibody with different binding affinities to different DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid)-based small molecules is used as a receptor proxy. In this particular system targeting carcinoembryonic antigen, a small-molecule-binding affinity of 400 pmol/L was sufficient to achieve maximal tumor targeting, and an improvement in affinity to 10 pmol/L showed no significant improvement in tumor uptake at 24 hours postinjection. We derive a simple mathematical model of tumor targeting using measurable parameters that correlates well with experimental observations. We use relations derived from the model to develop design criteria for the future development of small-molecule agents for targeted cancer therapeutics. PMID- 22491801 TI - Fabrication of nanostructures through molecular self-assembly of small amphiphilic glyco-dehydropeptides. AB - Self-assembled peptide-based nanostructures have been the focus of research in the past decade because of their potential applications in various biological systems. Normally, small self-assembled peptide nanostructures contain hydrophobic moieties, therefore, their solubility in aqueous systems poses the important challenge in the field of molecular self-assembly in order to make effective use of these in a wide variety of applications. To improve their aqueous solubility, the self-assembled amphiphilic alpha,beta dehydrophenylalanine containing small glyco-dehydropeptides, Boc-Phe-DeltaPhe epsilonAhx-GA (I) and H-Phe-DeltaPhe-epsilonAhx-GA (II) with glucosamine (GA) attached at the C-terminal through a 6-aminocaproic acid linker, were synthesized, demonstrating the formation of nanostructures in aqueous media, which were characterized by DLS, AFM and TEM. Further, nanostructure II reduced auric chloride to gold nanoparticles and formed a peptide-gold conjugate (VII). The feasibility of using the nanostructures I and II as nanovectors for drug delivery was demonstrated by loading hydrophobic molecules, eosin and N fluoresceinyl-2-aminoethanol (FAE) dyes. Besides, these peptides displayed antimicrobial activity against Micrococcus flavus, Bacillus subtilis and Pseudomonas aeruginosa. All these results advocate the potential of these nanostructures as efficient vectors for drug delivery applications. PMID- 22491800 TI - Antitumor mechanisms of targeting the PDK1 pathway in head and neck cancer. AB - G-protein-coupled receptors (GPCR) activate the epidermal growth factor receptor (EGFR) and mediate EGFR-independent signaling pathways to promote the growth of a variety of cancers, including head and neck squamous cell carcinoma (HNSCC). Identification of the common signaling mechanisms involved in GPCR-induced EGFR dependent and EGFR-independent processes will facilitate the development of more therapeutic strategies. In this study, we hypothesized that phosphoinositide dependent kinase 1 (PDK1) contributes to GPCR-EGFR cross-talk and signaling in the absence of EGFR and suggests that inhibition of the PDK1 pathway may be effective in the treatment of HNSCC. The contribution of PDK1 to the EGFR dependent and EGFR-independent signaling in HNSCC was determined using RNA interference, a kinase-dead mutant, and pharmacologic inhibition. In vivo xenografts studies were also carried out to determine the efficacy of targeting PDK1 alone or in combination with the U.S. Food and Drug Administration-approved EGFR inhibitor cetuximab. PDK1 contributed to both GPCR-induced EGFR activation and cell growth. PDK1 also mediated activation of p70S6K in the absence of EGFR. Blockade of PDK1 with a small molecule inhibitor (AR-12) abrogated HNSCC growth, induced apoptosis, and enhanced the antiproliferative effects of EGFR tyrosine kinase inhibitors in vitro. HNSCC xenografts expressing kinase-dead PDK1 showed increased sensitivity to cetuximab compared with vector-transfected controls. Administration of AR-12 substantially decreased HNSCC tumor growth in vivo. These cumulative results show that PDK1 is a common signaling intermediate in GPCR-EGFR cross-talk and EGFR-independent signaling, and in which targeting the PDK1 pathway may represent a rational therapeutic strategy to enhance clinical responses to EGFR inhibitors in HNSCC. PMID- 22491802 TI - Fluoroscopy-guided retrograde core drilling and cancellous bone grafting in osteochondral defects of the talus. AB - PURPOSE: In undetached osteochondral lesions (OCL) of the talus both revitalisation of the subchondral necrosis and cartilage preservation are essential. For these cases, we assess the results of minimally invasive retrograde core drilling and cancellous bone grafting. METHODS: Forty-one osteochondral lesions of the talus (12x grade I, 22x grade II and 7x grade III according to the Pritsch classification, defect sizes 7-14 mm) in 38 patients (mean age 33.2 years) treated by fluoroscopy-guided retrograde core drilling and autologous cancellous bone grafting were evaluated by clinical scores and MRI. The mean follow-up was 29.0 (+/-13) months. RESULTS: The AOFAS score increased significantly from 47.3 (+/-15.3) to 80.8 (+/-18.6) points. Lesions with intact cartilage (grades I and II) had a tendency to superior results than grade III lesions (83.1 +/- 17.3 vs. 69.4 +/- 22.2 points, p = 0.07). First-line treatments and open distal tibial growth plates led to significantly better outcomes (each p < 0.05). Age, gender, BMI, time to follow-up, defect localisation or a traumatic origin did not influence the score results. On a visual analogue scale pain intensity reduced from 7.5 (+/-1.5) to 3.7 (+/-2.6) while subjective function increased from 4.6 (+/-2.0) to 8.2 (+/-2.3) (each p < 0.001). In MRI follow-ups, five of the 41 patients showed a complete bone remodelling. In two cases demarcation was detectable. CONCLUSIONS: The technique reported is a highly effective therapeutic option in OCL of the talus with intact cartilage grades I and II. However, second-line treatments and grade III lesions with cracked cartilage surface can not be generally recommended for this procedure. PMID- 22491803 TI - Biologic therapy and risk of infection. AB - Biologic compounds are being used more frequently to treat a multitude of systemic inflammatory conditions. These novel compounds are composed of antibodies or other peptides that act through one of three mechanisms: inhibiting inflammatory cytokine signaling (typically tumor necrosis factor or TNF), inhibiting T-cell activation, or depleting B-cells. The increase in use and ever expanding list of new immune modulating therapies make knowledge of the infectious complications associated with immune modulation even more important. Of particular concern is the risk for developing atypical and opportunistic infections including tuberculosis, herpes zoster, Legionella pneumophila, and Listeria monocytogenes. PMID- 22491804 TI - The role of imiquimod 3.75% cream in the treatment of external genital warts. AB - Imiquimod 3.75% cream has recently been approved by both the U.S. Federal Drug Administration and Health Canada for the treatment of external genital warts. Herein, we provide an overview of external genital warts, review the phase 3 clinical trials leading to the approval of imiquimod 3.75% cream, and compare its efficacy and clinical use with imiquimod 5% cream. Moreover, therapeutic options have further expanded with the relatively recent introduction of sinecatechins 15% ointment, an extract of green tea leaves. PMID- 22491805 TI - Prevalences of illicit drug use in people aged 50 years and over from two surveys. AB - BACKGROUND: little is known about illicit drug use in older people. Prevalences may rise as populations for whom illicit drug use has been more common and acceptable become older. OBJECTIVES: to quantify illicit drug use in people aged 50 years and over in England and inner London and to compare this between 50 and 64 and 65+ age groups. METHODS: primary analyses used data from the 2007 Adult Psychiatric Morbidity Survey (APMS) and the 2008-10 South East London Community Health (SELCoH) Survey. Secondary analyses included additional data on 50-64 year olds from the 1993, 2000 and 2007 APMS, and on 65-74 year olds from the 2000 and 2007 APMS. RESULTS: cannabis was the drug most commonly used in all samples. Prevalences of use within the last 12 months in 50-64 and 65+ age groups were 1.8 and 0.4%, respectively, in England and 9.0 and 1.1%, respectively, in inner London. Prevalences of use at any time previously were 11.4, 1.7, 42.8 and 9.4%, respectively. Lifetime cannabis, amphetamine, cocaine and LSD use in 50-64 year olds had increased approximately tenfold in England from 1993. Lifetime and 12 month trends in tranquilisers were relatively stable. CONCLUSIONS: use of some illicit drugs, particularly cannabis, has increased rapidly in mid- and late life. PMID- 22491806 TI - Characteristics and therapy of premenopausal patients with early-onset breast cancer in Germany. AB - PURPOSE: The objective of the study is to investigate what kind of tumors young, premenopausal breast cancer patients in Germany show at diagnosis and how they are treated adjuvantly in comparison with a normally distributed cohort. METHODS: The study describes the data of 535 patients who were treated adjuvantly between 2002 and 2006 and participated in a resident mother-child program for rehabilitation (Groemitz cohort). The data includes TNM categories, biology of tumor and therapies. This population is being compared to an age-heterogeneous cohort from the state of Schleswig-Holstein and the DMP-report of the state of North Rhine-Westphalia. RESULTS: 45.8 % of the patients were diagnosed with tumor category pT1, 37 % pT2, 7.3 % pT3 and 1.9 % pT4. 5 % had merely DCIS. 48.8 % of the patients were pN0, 31.4 % pN1 and 17.4 % had a more intense manifestation of lymph nodes. 43.5 % of the tumors showed a grading classified as G3, 64.3 % were estrogen and progesterone hormone receptor positive and 26.2 % Her2 positive. 21 % of the examined cohort members/patients showed a triple negative carcinoma. 59.1 % of the patients with pT1 underwent breast-conserving surgery, 56.1 % of those with pT2 and 25.6 % of those with pT3. Overall 31.0 % of the women received mastectomy and 14.8 % received mastectomy with subsequent reconstruction. 97.6 % of the patients received axillary surgery, 89.9 % chemotherapy. Overall 23.7 % of the patients received their treatment in connection with clinical studies. 95.3 % of the patients with hormone receptor positive tumor received endocrine therapy, 61.3 % of them with GnRH-analogs. In comparison with the OVIS and DMP cohorts patients of the Groemitz cohort were on average 20 years younger. Their tumors were of bigger size and had more often reached the axillary lymph nodes (pN0 48.8 % Groemitz/62.0 % OVIS/66.7 % DMP). The hormone receptor status was more often negative (35.7/16.6/16.5 %) and tumor grading higher (G3 43.5/29.0/28.5 %). Surgery was more extensive even with small tumors (breast conserving surgery with tumor stage pT1 59.1/81.2/77.6 %) and axillary surgery was performed more often in the young collective (97.6/89.3/62.5 %). More patients of the young collective received chemotherapy (89.9/58.4 %/unknown) and more patients of the young collective with hormone receptor positive tumor received endocrine therapy (95.3/77.4/90.6 %). CONCLUSION: Our study shows that young breast cancer patients in Germany can be regarded as a special group. At the time of diagnosis the tumor has frequently reached a more advanced stage, and carcinomas are more aggressive. Operative and medical treatment will often be more aggressive. PMID- 22491807 TI - Effects of the menstrual cycle phases on the tilt testing results in vasovagal patients. AB - PURPOSE: The aim of the study was to assess the distribution of positive tilt testing (TT) throughout the menstrual cycle and to determine if the phase of menstrual cycle contributes to the duration of the loss of consciousness. METHODS: TT results of 183 premenopausal women, aged 29.5 +/- 9.8 years, were studied. The menstrual cycle was divided into four phases based on the first day of the last menstrual bleeding: perimenstrual (M), preovulatory (F), periovulatory (O) and postovulatory (L). RESULTS: Positive TT results were equally distributed. In patients with TT in O phase, the highest percentage of NTG provocation was needed. Patients in L phase had significantly lower incidence of cardioinhibitory reaction. The longest duration of loss of consciousness was in the M phase. Multiple regression analysis revealed that the duration of loss of consciousness during positive TT was significantly associated with higher number of syncopal events, TT performed in M phase and lower heart rate at TT termination. Cardiodepressive type of neurocardiogenic reaction was more frequent during M and O phase than during L phase. CONCLUSIONS: The distribution of positive TT results as well as syncope and presyncope does not differ throughout the menstrual cycle. Diagnostic TT in premenopausal women with unexplained syncope could be performed irrespective of the phase of menstrual cycle. TT has similar sensitivity throughout the menstrual cycle. During the postovulatory phase, cardioinhibitory reaction is less frequent than in M and O phases. The duration of loss of consciousness is longer during the M phase of the menstrual cycle independently of the higher syncope number and lower heart rate at TT termination. PMID- 22491808 TI - Prevalence of female genital mutilation among female infants in Kano, Northern Nigeria. AB - OBJECTIVES: To determine the prevalence and type of female genital mutilation (FGM) among female infants, reasons and attitude of the mothers to the practice. DESIGN: A cross sectional descriptive study. SETTING: Tertiary centre in Kano Northern Nigeria. METHOD: A Pretested questionnaire was administered for mothers of female infants presenting for routine immunization in Aminu Kano Teaching Hospital (AKTH). A total of 250 questionnaires were administered, but only 200 were properly filled and this was used for the analysis. MAIN OUTCOME MEASURES: Prevalence and type of FGM, reason for and attitude of mothers towards FGM. RESULTS: Twenty-six infants had FGM during the period of study, giving a prevalence rate of 13 %. The mean age at cutting was 8 days +/- 7.3. The commonest type of FGM was type I accounting for 96.2 % of the cases. Tradition/culture was the commonest reason for mutilation accounting for 73.1 %, other reasons included; religious in 11.5 %, hygienic in 11.5 % and to preserve virginity in 3.8 %. Traditional barbers were the commonest operators in 80.8 % of cases, followed by the nurse/midwife in 15.4 % of cases. The fathers were the main decision makers in 46.2 %, followed by both parents in 26.9 % and grandparents in 15.4 % of the cases. 84 % of mothers were not in support of the practice. Thirteen percent of the clients would circumcise all their daughters. Forty-eight percent of the clients were of the opinion that FGM cause harm to the victims. Four percent of those whose daughters were yet to be circumcised will do so later. CONCLUSION: Female genital cutting is still practiced in our environment. Educational enlightenment is fundamental in changing public opinion as well as in offering reasonable alternative to FGM. Campaign against the practice of FGM should be encouraged to eradicate its practice. PMID- 22491810 TI - Accelerating chronically unresponsive children to tier 3 instruction: what level of data is necessary to ensure selection accuracy? AB - Response-to-intervention (RTI) approaches to disability identification are meant to put an end to the so-called wait-to-fail requirement associated with IQ discrepancy. However, in an unfortunate irony, there is a group of children who wait to fail in RTI frameworks. That is, they must fail both general classroom instruction (Tier 1) and small-group intervention (Tier 2) before becoming eligible for the most intensive intervention (Tier 3). The purpose of this article was to determine how to predict accurately which at-risk children will be unresponsive to Tiers 1 and 2, thereby allowing unresponsive children to move directly from Tier 1 to Tier 3. As part of an efficacy study of a multitier RTI approach to prevention and identification of reading disabilities (RD), 129 first grade children who were unresponsive to classroom reading instruction were randomly assigned to 14 weeks of small-group, Tier 2 intervention. Nonresponders to this instruction (n = 33) were identified using local norms on first-grade word identification fluency growth linked to a distal outcome of RD at the end of second grade. Logistic regression models were used to predict membership in responder and nonresponder groups. Predictors were entered as blocks of data from least to most difficult to obtain: universal screening data, Tier 1 response data, norm referenced tests, and Tier 2 response data. Tier 2 response data were not necessary to classify students as responders and nonresponders to Tier 2 instruction, suggesting that some children can be accurately identified as eligible for Tier 3 intervention using only Tier 1 data, thereby avoiding prolonged periods of failure to instruction. PMID- 22491809 TI - The early prevention of mathematics difficulty: its power and limitations. AB - In this article, the authors consider the power and limitations of responsiveness to-intervention (RTI) for reducing the need for ongoing and intensive services for the segment of the school population traditionally identified as having a learning disability in mathematics. To assess the robustness of RTI, the authors describe four studies with strong demonstrations of efficacy, as they considered the percentage of students who failed to respond, the post-tutoring achievement gap between tutored and not-at-risk students, and the extent of transfer across components of the mathematics curriculum. The authors then discuss implications and additional research questions pertaining to mathematics intervention generally and within the context of RTI. They conclude with a proposal for an expanded conceptualization of RTI. PMID- 22491811 TI - Response to intervention with secondary school students with reading difficulties. AB - The authors summarize evidence from a multiyear study with secondary students with reading difficulties on (a) the potential efficacy of primary-level (Tier 1), secondary-level (Tier 2), and tertiary-level (Tier 3) interventions in remediating reading difficulties with middle school students, (b) the likelihood of resolving reading disabilities with older students with intractable reading disabilities, (c) the reliability, validity, and use of screening and progress monitoring measures with middle school students, and (d) the implications of implementing response to intervention (RTI) practices at the middle school level. The authors provide guidance about prevailing questions about remediating reading difficulties with secondary students and discuss future directions for research using RTI frameworks for students at the secondary level. PMID- 22491812 TI - Response to intervention for reading difficulties in the primary grades: some answers and lingering questions. AB - The purpose of this article is to describe the current research base and identify research needs related to response to intervention (RTI) frameworks in primary grade reading. Research is reviewed on early reading instruction and intervention, the implementation of multitiered reading interventions, and the determination of intervention responsiveness. Areas identified as in need of research include (a) the conditions under which early reading interventions are most effective in RTI contexts, (b) multitiered interventions for students with limited English proficiency, (c) reading instruction for students who make limited progress in Tier 3 intensive interventions, (d) criteria for determining intervention responsiveness, and (e) the effects of fully implemented RTI frameworks. Although RTI research may be expensive and difficult to implement, it may contribute to improved reading outcomes for many students who are otherwise at risk of serious negative life consequences. PMID- 22491813 TI - Behavioral factors in assessing impact of HIV treatment as prevention. AB - The recent NIH HPTN 052 study of using HIV treatment to prevent HIV transmission in serostatus discordant heterosexual partnerships has garnered much attention. In subsequent discussions, however, the topic of HIV-related risk behavior has been nearly absent. Here, we identify the critical roles that HIV-related risk behavior plays in determining the unmet needs, optimal targeting, and ultimate impact of treatment as prevention. We describe the size of the population at risk of HIV and three subgroups of persons living with HIV (PLWH) based on awareness of serostatus and risk behavior, and the corresponding HIV transmission rates to seronegative partners. For each of the subgroups of PLWH, we identify which approach is most relevant ("testing and linkage to care," "treatment as prevention," and/or "treatment as clinical care"). We observe that the impact of "treatment as prevention" on HIV incidence will depend heavily on which subgroup of PLWH is targeted for services. PMID- 22491814 TI - (-)-Epigallocatechin-3-gallate inhibits the replication cycle of hepatitis C virus. AB - (-)-Epigallocatechin-3-gallate (EGCG) is the most abundant catechin in green tea. In this study, we found that hepatitis C virus (HCV) infection was significantly suppressed by EGCG in an HCV cell culture (HCVcc) system using a JFH1-GFP chimeric virus, with a 50 % effective concentration (EC(50)) of 17.9 MUM. The inhibitory activity of EGCG was confirmed by monitoring HCV RNA and protein expression levels in Huh7.5.1 cells infected with the JFH1 virus. Moreover, we demonstrated that the inhibitory mechanisms of EGCG were attributable to the suppression of both the HCV entry and RNA replication steps, although EGCG had little effect on translation directed by the viral internal ribosome entry site (IRES). Furthermore, HCV could be rapidly eliminated from cell cultures after two and five passages in the presence of 50 and 25 MUM EGCG, respectively. These results indicate that EGCG is a potential candidate as a preventive and antiviral drug for HCV infection. PMID- 22491815 TI - In vivo expression and binding activity of scFv-RWAV, which recognizes the coat protein of tomato leaf curl New Delhi virus (family Geminiviridae). AB - Recombinant antibodies expressed in plants have the potential to interrupt virus infections by blocking essential stages of the infection cycle. Here, we show that the expression of a recombinant single-chain variable fragment (scFv) that recognizes the coat protein of tomato leaf curl New Delhi virus (ToLCNDV) in vitro can also bind to a recombinant coat protein in vivo in the reducing environment of the plant cytosol. The scFv and its target were both expressed as fluorescent protein fusions, one incorporating green fluorescent protein (GFP) and the other DsRed. We found that the incorporation of a nuclear localization signal into the scFv construct resulted in the nuclear import of the antibody antigen complex, as shown by colocalization of the two fluorescent signals. This demonstrates that recombinant antibodies can be targeted to the nucleus and will bind to geminivirus coat proteins therein, allowing the virus infection cycle to be interrupted during its critical replicative phase. PMID- 22491816 TI - Effects of abdominal fat distribution parameters on severity of acute pancreatitis. AB - BACKGROUND: Obesity is a well-established risk factor for acute pancreatitis. Increased visceral fat has been shown to exacerbate the pro-inflammatory milieu experienced by patients. This study aimed to investigate the relationship between the severity of acute pancreatitis and abdominal fat distribution parameters measured on computed tomography (CT) scan. METHODS: Consecutive patients admitted to Cork University Hospital with acute pancreatitis between January 2005 and December 2010 were evaluated for inclusion in the study. An open source image analysis software (Osirix, v 3.9) was used to calculate individual abdominal fat distribution parameters from CT scans by segmentation of abdominal tissues. RESULTS: A total of 214 patients were admitted with pancreatitis between January 2005 and December 2010. Sixty-two of these patients underwent a CT scan and were thus eligible for inclusion. Visceral fat volume was the volumetric fat parameter that had the most significant association with severe acute pancreatitis (P = 0.003). There was a significant association between visceral fat volume and subsequent development of systemic complications of severe acute pancreatitis (P = 0.003). There was a strong association between mortality and visceral fat volume (P = 0.019). Multivariate regression analysis, adjusted for gender, did not identify any individual abdominal fat distribution index as an independent risk factor for severe acute pancreatitis. CONCLUSIONS: Overall, estimation of abdominal fat distribution parameters from CT scans performed on patients with acute pancreatitis indicates a strong association between visceral fat, severe acute pancreatitis, and the subsequent development of systemic complications. These data suggest that visceral fat volume should be incorporated into future predictive scoring systems. PMID- 22491817 TI - Diagnostic role of procalcitonin in patients with suspected appendicitis. AB - BACKGROUND: The aim of this study was to assess the diagnostic value of procalcitonin (PCT) in emergency department (ED) patients with suspected appendicitis. METHODS: A prospective observational study was carried out in the emergency department of a university hospital between July 2007 and June 2008. Adult patients who presented to the ED with clinically suspected appendicitis were enrolled. Each patient underwent serum PCT, C-reactive protein (CRP), and Alvarado score evaluation on admission. The results of these three measurements were analyzed in relation to the final diagnosis determined by histopathological findings or compatible computed tomography findings. RESULTS: Of the 214 study patients, 113 (52.8 %) had a confirmed diagnosis of appendicitis and 58 had complicated appendicitis (phlegmon, perforation, or gangrene). For the diagnosis of appendicitis, the area under the receiving operating characteristic (ROC) curve is 0.74 for Alvarado score, 0.69 for PCT, and 0.61 for CRP. Overall, the Alvarado score has the best discriminative capability among the three tested markers. We adopted two cutoff point approaches to harness both ends of the diagnostic value of a biomarker. PCT levels were significantly higher in patients with complicated appendicitis. For diagnosis of complicated appendicitis, a cutoff value of 0.5 ng/mL had a sensitivity of 29 % and a specificity of 95 %, while a cutoff value of 0.05 ng/ml had a sensitivity of 85 % and a specificity of 30 % in diagnosing complicated appendicitis. For those with a PCT value in the gray zone, clinical findings may play a more important role. CONCLUSION: The study does not support the hypothesis that the PCT test may be useful for screening ED patients for appendicitis. However, determination of the PCT level may be useful for risk assessment of ED patients with suspected complicated appendicitis. PMID- 22491818 TI - Do we overtreat post-thyroidectomy hypocalcemia? AB - BACKGROUND: Calcium and calcitriol supplements are standard for patients with post-thyroidectomy serum calcium <2.0 mmol/L; however, we wondered whether we overtreat post-thyroidectomy hypocalcemia with intraoperative parathyroid hormone (PTH). We examined quick-intraoperative intact PTH (QiPTH) assay results to find a suitable treatment for post-thyroidectomy hypocalcemia. METHODS: We studied 197 bilateral thyroidectomy patients. Post-thyroidectomy hypocalcemia was defined as serum calcium <2.0 mmol/L. A QiPTH assay was done 15 min after the thyroidectomy (QiPTH(15)), and hypoparathyroidism was defined as PTH <15 ng/L. The QiPTH(15) assay was used to determine the effects of the thyroidectomy on postoperative PTH levels and serum calcium levels. The natural course and medical response of hypocalcemia was observed in patients with a QiPTH(15) >= 15 ng/L. RESULTS: None of the 187 patients with a QiPTH(15) >= 15 ng/L developed postoperative hypoparathyroidism. However, 79 patients developed transient hypocalcemia, and those with Graves' disease (47/94) had significantly (p < 0.05) higher hypocalcemia than those with non-Graves' thyroid disease (32/93). The serum calcium of these 79 patients declined to its lowest level within the first postoperative 18 h. Seven patients with serum calcium <1.75 mmol/L were successfully treated using a calcium supplement only, and the others recovered spontaneously without treatment. CONCLUSIONS: When post-thyroidectomy QiPTH(15) was >= 15 ng/L, postoperative hypoparathyroidism was excluded, but more than one third of the patients developed post-thyroidectomy hypocalcemia. However, most of them recovered without treatment, and a few recovered after taking only a calcium supplement. We believe that using QiPTH(15) results as a guide will prevent overtreatment of post-thyroidectomy hypocalcemia. PMID- 22491819 TI - A survey of arsenic, manganese, boron, thorium, and other toxic metals in the groundwater of a West Bengal, India neighbourhood. AB - Around 150 million people are at risk from arsenic-contaminated groundwater in India and Bangladesh. Multiple metal analysis in Bangladesh has found other toxic elements above the World Health Organization (WHO) health-based drinking water guidelines which significantly increases the number of people at risk due to drinking groundwater. In this study, drinking water samples from the Bongaon area (North 24 Parganas district, West Bengal, India) were analyzed for multiple metal contamination in order to evaluate groundwater quality on the neighbourhood scale. Each sample was analyzed for arsenic (As), boron (B), barium (Ba), chromium (Cr), manganese (Mn), molybdenum (Mo), nickel (Ni), lead (Pb), and uranium (U). Arsenic was found above the WHO health-based drinking water guideline in 50% of these tubewells. Mn and B were found at significant concentrations in 19% and 6% of these tubewells, respectively. The maps of As, Mn, and B concentrations suggest that approximately 75% of this area has no safe tubewells. The concentrations of As, Mn, B, and many other toxic elements are independent of each other. The concentrations of Pb and U were not found above WHO health-based drinking water guidelines but they were statistically related to each other (p-value = 0.001). An analysis of selected isotopes in the Uranium, Actinium, and Thorium Radioactive Decay Series revealed the presence of thorium (Th) in 31% of these tubewells. This discovery of Th, which does not have a WHO health-based drinking water guideline, is a potential public health challenge. In sum, the widespread presence and independent distribution of other metals besides As must be taken into consideration for drinking water remediation strategies involving well switching or home-scale water treatment. PMID- 22491821 TI - Rotator cuff regeneration using a bioabsorbable material with bone marrow-derived mesenchymal stem cells in a rabbit model. AB - BACKGROUND: Rotator cuff regeneration using tissue engineering techniques is a challenging treatment in elderly patients with irreparable rotator cuff tears. HYPOTHESIS: A polyglycolic acid sheet scaffold with seeded mesenchymal stem cells (MSCs) may enhance the expression of type I collagen products and increase the mechanical strength of the regenerated tendon in vivo. STUDY DESIGN: Controlled laboratory study. METHODS: A surgically created defect of infraspinatus tendons of rabbits was reconstructed with 2 different materials, a polyglycolic acid (PGA) sheet alone (PGA group) (n = 34) and a PGA sheet seeded with autologously cultured MSCs (MSC group) (n = 34). The authors created a tendon defect model without embedding any graft as the control model (control group) (n = 34). The rabbits were sacrificed at 4, 8, and 16 weeks after the operation and then were histologically evaluated. The rabbits were also biomechanically evaluated by measuring the ultimate failure loads and Young's modulus at 4 and 16 weeks following implantation. RESULTS: In the MSC group, the fibrocartilage layers and Sharpey fibers were found regularly in the insertion site at 8 weeks compared with the PGA group. In control group, thin membranes with many fibroblasts arranged in an irregular pattern linked the end of the torn cuff to the bone without any Sharpey fibers and type I collagen. A large volume of type I collagen was found in comparison with type III collagen at 16 weeks in the MSC group, whereas type III collagen was more prevalent than type I in the PGA group. The tendon maturing score in the MSC group had higher values than the PGA and control groups at 8 and 16 weeks (mean values were 21.0 +/- 0.89, 24.0 +/- 2.53 in the MSC group; 16.7 +/- 2.25, 21.3 +/- 2.42 in the PGA group; and 10.2 +/- 0.98, 12.2 +/- 1.72 in the control group, respectively) (P < .05). The results of the mechanical analysis revealed that the regenerated tendons in the MSC group had better tensile strength than in the PGA and control groups at 16 weeks (mean values were 3.04 +/- 0.54 in the MSC group, 2.38 +/- 0.63 in the PGA group, and 1.58 +/- 0.13 in the control group) (P < .05). CONCLUSION: Bone marrow-derived MSCs were able to regenerate tendon-bone insertions and the tendon belly, including the production of type I collagen, and increased the mechanical strength of the regenerated rotator cuff tendon. CLINICAL RELEVANCE: Rotator cuff regeneration using MSCs is a promising treatment for massive rotator cuff defects. PMID- 22491822 TI - Boron uptake in normal melanocytes and melanoma cells and boron biodistribution study in mice bearing B16F10 melanoma for boron neutron capture therapy. AB - Information on (10)B distribution in normal tissues is crucial to any further development of boron neutron capture therapy (BNCT). The goal of this study was to investigate the in vitro and in vivo boron biodistribution in B16F10 murine melanoma and normal tissues as a model for human melanoma treatment by a simple and rapid colorimetric method, which was validated by HR-ICP-MS. The B16F10 melanoma cell line showed higher melanin content than human melanocytes, demonstrating a greater potential for boronophenylalanine uptake. The melanocytes showed a moderate viability decrease in the first few minutes after BNCT application, stabilizing after 75 min, whereas the B16F10 melanoma showed the greatest intracellular boron concentration at 150 min after application, indicating a different boron uptake of melanoma cells compared to normal melanocytes. Moreover, at this time, the increase in boron uptake in melanoma cells was approximately 1.6 times higher than that in normal melanocytes. The (10)B concentration in the blood of mice bearing B16F10 melanoma increased until 90 min after BNCT application and then decreased after 120 min, and remained low until the 240th minute. On the other hand, the (10)B concentration in tumors was increased from 90 min and maximal at 150 min after application, thus confirming the in vitro results. Therefore, the present in vitro and in vivo study of (10)B uptake in normal and tumor cells revealed important data that could enable BNCT to be possibly used as a treatment for melanoma, a chemoresistant cancer associated with high mortality. PMID- 22491823 TI - An antibody fusion protein for cancer immunotherapy mimicking IL-15 trans presentation at the tumor site. AB - Cytokines driving the immune response are powerful tools for cancer immunotherapy, but their application is generally limited by severe systemic toxicity. Targeted approaches by means of antibody-cytokine fusion proteins might enable focus on the cytokine activity to the tumor site, thereby reducing unwanted side effects. Here, we investigated the possibility to improve the efficiency of interleukin (IL)-15 presentation in a targeted approach by the incorporation of an IL-15Ralpha chain fragment, mimicking physiologic trans presentation. Therefore, an antibody cytokine fusion protein (scFv_RD_IL-15) composed of an antibody moiety targeting the tumor stromal fibroblast activation protein (FAP), an extended IL-15Ralphasushi domain (RD) and IL-15 was generated, exhibiting antibody-mediated specific binding and cytokine activity in soluble and targeted form. Comparative analysis with a corresponding antibody fusion protein devoid of RD (scFv_IL-15) showed for scFv_RD_IL-15 in solution enhanced stimulatory activity on Mo7e (IL-15Rbetagamma) cells and reduced proliferation response on CTLL-2 (IL-15Ralphabetagamma) cells, while in FAP-targeted, that is, membrane-bound form, comparable proliferation of CTLL-2 (IL-15Ralphabetagamma) cells was obtained. In addition, scFv_RD_IL-15 achieved in its soluble and target bound form stronger proliferation and cytotoxicity on unstimulated and activated T cells, respectively. Furthermore, in vivo analysis in a lung metastasis tumor mouse model revealed a superior antitumor effect for scFv_RD_IL-15 in comparison with that obtained by an untargeted or RD missing version of IL-15 fusion protein. Thus, tumor-directed trans-presentation of IL-15 in association with RD in form of an antibody fusion protein seems to be a promising approach to further improve the antitumor effect of IL-15. PMID- 22491824 TI - Developing a prevention synthesis and translation system to promote science-based approaches to teen pregnancy, HIV and STI prevention. AB - The Interactive Systems Framework for Dissemination and Implementation (ISF) is a multi-system framework that can guide research-to-practice efforts by building and supporting the work of three interacting systems: the Prevention Delivery, Support, and Synthesis and Translation Systems. The Synthesis and Translation system is vital to bridging science and practice, yet how to develop it and train support system partners to use it is under-researched. This article bridges this gap by offering a case example of the planning, development, and use of a synthesis and translation product called Promoting Science-based Approaches to Teen Pregnancy Prevention using Getting To Outcomes. The case presented documents the process used for developing the synthesis and translation product, reports on efforts to engage the Prevention Support system to use the product, and how we approached building interaction between the Synthesis and Translation System and the Support System partners. Practice-oriented evaluation data are also presented. Implications for practice, policy and research are discussed. PMID- 22491825 TI - Recent discovery of plant-derived anti-diabetic natural products. AB - Covering: 2005 to 2010. This review covers recent discoveries of anti-diabetic compounds. Diabetes mellitus (DM) is a complex disease affecting patients' daily life and elevating patients' risk of developing other diseases. There are several forms of diabetes, including type-1 diabetes (insulin-dependent), type-2 diabetes (noninsulin-dependent), and gestational diabetes. Type-2 diabetes is the most common form and the patient population with type-2 DM rises every year. Current treatments meet some but not all patients' needs. Therefore, new anti-diabetic drugs are in great demand. Traditional herbal medicine provides a rich source for new drug discovery. In this review, recent discoveries of anti-diabetic compounds have been summarized according to their chemical structures and mechanisms of action. Anti-diabetic plant extracts, many of which have been used and marketed as dietary supplements, were also included and discussed, and are classified according to the positive control used in the anti-diabetic animal studies. New anti-diabetic natural products found in the recent patent literature are also summarized. PMID- 22491826 TI - Investigating the parameters affecting the adsorption of amino acids onto AgCl nanoparticles with different surface charges. AB - In this paper, adsorption behaviors of typical neutral (alanine), acidic (glutamic acid) and basic (lysine) amino acids onto the surfaces of neutral as well as positively and negatively charged silver chloride nanoparticles were examined. Silver chloride nanoparticles with different charges and different water content were synthesized by reverse micelle method. The adsorptions of the above mentioned amino acids onto the surfaces of differently charged silver chloride nanoparticles were found to depend strongly on various parameters including pH of the aqueous solution, type of amino acid, water to surfactant mole ratio, and type of charges on the surfaces of silver chloride nanoparticles. It was found that the interaction of -NH(3) (+) groups of the amino acids with silver ion could be a driving force for adsorption of amino acids. Alanine and Glutamic acid showed almost similar trend for being adsorbed on the surface of silver chloride nanoparticles. Electrostatic interaction, hydrophobicity of both nanoparticle and amino acid, complex formation between amine group and silver ion, interaction between protonated amine and silver ion as well as the number of nanoparticles per unit volume of solution were considered for interpreting the observed results. PMID- 22491828 TI - Why statistics? PMID- 22491820 TI - An eicosanoid-centric view of atherothrombotic risk factors. AB - Cardiovascular disease is the foremost cause of morbidity and mortality in the Western world. Atherosclerosis followed by thrombosis (atherothrombosis) is the pathological process underlying most myocardial, cerebral, and peripheral vascular events. Atherothrombosis is a complex and heterogeneous inflammatory process that involves interactions between many cell types (including vascular smooth muscle cells, endothelial cells, macrophages, and platelets) and processes (including migration, proliferation, and activation). Despite a wealth of knowledge from many recent studies using knockout mouse and human genetic studies (GWAS and candidate approach) identifying genes and proteins directly involved in these processes, traditional cardiovascular risk factors (hyperlipidemia, hypertension, smoking, diabetes mellitus, sex, and age) remain the most useful predictor of disease. Eicosanoids (20 carbon polyunsaturated fatty acid derivatives of arachidonic acid and other essential fatty acids) are emerging as important regulators of cardiovascular disease processes. Drugs indirectly modulating these signals, including COX-1/COX-2 inhibitors, have proven to play major roles in the atherothrombotic process. However, the complexity of their roles and regulation by opposing eicosanoid signaling, have contributed to the lack of therapies directed at the eicosanoid receptors themselves. This is likely to change, as our understanding of the structure, signaling, and function of the eicosanoid receptors improves. Indeed, a major advance is emerging from the characterization of dysfunctional naturally occurring mutations of the eicosanoid receptors. In light of the proven and continuing importance of risk factors, we have elected to focus on the relationship between eicosanoids and cardiovascular risk factors. PMID- 22491827 TI - Dopamine receptor antagonism disrupts social preference in zebrafish: a strain comparison study. AB - Zebrafish form shoals in nature and in the laboratory. The sight of conspecifics has been found reinforcing in zebrafish learning tasks. However, the mechanisms of shoaling, and those of its reinforcing properties, are not known. The dopaminergic system has been implicated in reward among other functions and it is also engaged by drugs of abuse as shown in a variety of vertebrates including zebrafish. The ontogenetic changes in dopamine levels and, to a lesser degree, in serotonin levels, have been found to accompany the maturation of shoaling in zebrafish. Thus, we hypothesized that the dopaminergic system may contribute to shoaling in zebrafish. To test this we employed a D1-receptor antagonist and quantified behavioral responses of our subjects using a social preference (shoaling) paradigm. We found significant reduction of social preference induced by the D1-R antagonist, SCH23390, in the AB strain of zebrafish, an alteration that was not accompanied by changes in motor function or vision. We also detected D1-R antagonist-induced changes in the level of dopamine, DOPAC, serotonin and 5HIAA, respectively, in the brain of AB zebrafish as quantified by HPLC with electrochemical detection. We found the antagonist-induced behavioral changes to be absent and the levels of these neurochemicals to be lower in another zebrafish population, SF, demonstrating naturally occurring genetic variability in these traits. We conclude that this variability may be utilized to unravel the mechanisms of social behavior in zebrafish, a line of research that may be extended to other vertebrates including our own species. PMID- 22491833 TI - Avian influenza. On second thought, flu papers get go-ahead. PMID- 22491834 TI - Science and security. U.S. agencies to start screening biomedical proposals for dual use. PMID- 22491836 TI - Arms control. Updated review finds little U.S. military risk in nuclear test ban. PMID- 22491835 TI - U.S. science policy. Agencies rally to tackle big data. PMID- 22491837 TI - Balkans. In former Yugoslavia, academies keep fighting. PMID- 22491839 TI - NextGen speaks. PMID- 22491838 TI - Scientific community. A week in Stockholm. PMID- 22491840 TI - Science in Asia. Improving Asia-Pacific science collaboration. PMID- 22491841 TI - Immunology. Rebuilding the thymus. PMID- 22491842 TI - Applied physics. Stressing ferroelectrics. PMID- 22491843 TI - Medicine. Irisin, light my fire. PMID- 22491844 TI - Materials science. Watching solution growth of nanoparticles in graphene cells. PMID- 22491845 TI - Ecology. How bacterial lineages emerge. PMID- 22491846 TI - Paleontology. Reading Pliocene bones. PMID- 22491848 TI - Mechanical writing of ferroelectric polarization. AB - Ferroelectric materials are characterized by a permanent electric dipole that can be reversed through the application of an external voltage, but a strong intrinsic coupling between polarization and deformation also causes all ferroelectrics to be piezoelectric, leading to applications in sensors and high displacement actuators. A less explored property is flexoelectricity, the coupling between polarization and a strain gradient. We demonstrate that the stress gradient generated by the tip of an atomic force microscope can mechanically switch the polarization in the nanoscale volume of a ferroelectric film. Pure mechanical force can therefore be used as a dynamic tool for polarization control and may enable applications in which memory bits are written mechanically and read electrically. PMID- 22491847 TI - Population genomics of early events in the ecological differentiation of bacteria. AB - Genetic exchange is common among bacteria, but its effect on population diversity during ecological differentiation remains controversial. A fundamental question is whether advantageous mutations lead to selection of clonal genomes or, as in sexual eukaryotes, sweep through populations on their own. Here, we show that in two recently diverged populations of ocean bacteria, ecological differentiation has occurred akin to a sexual mechanism: A few genome regions have swept through subpopulations in a habitat-specific manner, accompanied by gradual separation of gene pools as evidenced by increased habitat specificity of the most recent recombinations. These findings reconcile previous, seemingly contradictory empirical observations of the genetic structure of bacterial populations and point to a more unified process of differentiation in bacteria and sexual eukaryotes than previously thought. PMID- 22491849 TI - High-resolution EM of colloidal nanocrystal growth using graphene liquid cells. AB - We introduce a new type of liquid cell for in situ transmission electron microscopy (TEM) based on entrapment of a liquid film between layers of graphene. The graphene liquid cell facilitates atomic-level resolution imaging while sustaining the most realistic liquid conditions achievable under electron-beam radiation. We employ this cell to explore the mechanism of colloidal platinum nanocrystal growth. Direct atomic-resolution imaging allows us to visualize critical steps in the process, including site-selective coalescence, structural reshaping after coalescence, and surface faceting. PMID- 22491850 TI - Copper systematics in arc magmas and implications for crust-mantle differentiation. AB - Arc magmas are important building blocks of the continental crust. Because many arc lavas are oxidized, continent formation is thought to be associated with oxidizing conditions. On the basis of copper's (Cu's) affinity for reduced sulfur phases, we tracked the redox state of arc magmas from mantle source to emplacement in the crust. Primary arc and mid-ocean ridge basalts have identical Cu contents, indicating that the redox states of primitive arc magmas are indistinguishable from that of mid-ocean ridge basalts. During magmatic differentiation, the Cu content of most arc magmas decreases markedly because of sulfide segregation. Because a similar depletion in Cu characterizes global continental crust, the formation of sulfide-bearing cumulates under reducing conditions may be a critical step in continent formation. PMID- 22491851 TI - The role and implications of bassanite as a stable precursor phase to gypsum precipitation. AB - Calcium sulfate minerals such as gypsum play important roles in natural and industrial processes, but their precipitation mechanisms remain largely unexplored. We used time-resolved sample quenching and high-resolution microscopy to demonstrate that gypsum forms via a three-stage process: (i) homogeneous precipitation of nanocrystalline hemihydrate bassanite below its predicted solubility, (ii) self-assembly of bassanite into elongated aggregates co-oriented along their c axis, and (iii) transformation into dihydrate gypsum. These findings indicate that a stable nanocrystalline precursor phase can form below its bulk solubility and that in the CaSO(4) system, the self-assembly of nanoparticles plays a crucial role. Understanding why bassanite forms prior to gypsum can lead to more efficient anti-scaling strategies for water desalination and may help to explain the persistence of CaSO(4) phases in regions of low water activity on Mars. PMID- 22491852 TI - Late accretion on the earliest planetesimals revealed by the highly siderophile elements. AB - Late accretion of primitive chondritic material to Earth, the Moon, and Mars, after core formation had ceased, can account for the absolute and relative abundances of highly siderophile elements (HSEs) in their silicate mantles. Here we show that smaller planetesimals also possess elevated HSE abundances in chondritic proportions. This demonstrates that late addition of chondritic material was a common feature of all differentiated planets and planetesimals, irrespective of when they accreted; occurring <=5 to >=150 million years after the formation of the solar system. Parent-body size played a role in producing variations in absolute HSE abundances among these bodies; however, the oxidation state of the body exerted the major control by influencing the extent to which late-accreted material was mixed into the silicate mantle rather than removed to the core. PMID- 22491854 TI - Neural mechanisms of foraging. AB - Behavioral economic studies involving limited numbers of choices have provided key insights into neural decision-making mechanisms. By contrast, animals' foraging choices arise in the context of sequences of encounters with prey or food. On each encounter, the animal chooses whether to engage or, if the environment is sufficiently rich, to search elsewhere. The cost of foraging is also critical. We demonstrate that humans can alternate between two modes of choice, comparative decision-making and foraging, depending on distinct neural mechanisms in ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) using distinct reference frames; in ACC, choice variables are represented in invariant reference to foraging or searching for alternatives. Whereas vmPFC encodes values of specific well-defined options, ACC encodes the average value of the foraging environment and cost of foraging. PMID- 22491853 TI - A major genome region underlying artemisinin resistance in malaria. AB - Evolving resistance to artemisinin-based compounds threatens to derail attempts to control malaria. Resistance has been confirmed in western Cambodia and has recently emerged in western Thailand, but is absent from neighboring Laos. Artemisinin resistance results in reduced parasite clearance rates (CRs) after treatment. We used a two-phase strategy to identify genome region(s) underlying this ongoing selective event. Geographical differentiation and haplotype structure at 6969 polymorphic single-nucleotide polymorphisms (SNPs) in 91 parasites from Cambodia, Thailand, and Laos identified 33 genome regions under strong selection. We screened SNPs and microsatellites within these regions in 715 parasites from Thailand, identifying a selective sweep on chromosome 13 that shows strong association (P = 10(-6) to 10(-12)) with slow CRs, illustrating the efficacy of targeted association for identifying the genetic basis of adaptive traits. PMID- 22491855 TI - RNA aptamers: a review of recent trends and applications. AB - RNA aptamers, small oligonucleotides derived by an in-vitro selection process called SELEX (Systematic Evolution of Ligands by EXperimental enrichment), are important candidates for therapeutic and diagnostic applications. RNA aptamers have high affinity and specificity for their target molecules. In this review, we describe methods for generating RNA aptamers (the SELEX technique and modified SELEX processes) and therapeutic applications for diseases such as neovascular age-related macular degeneration (AMD), inflammatory diseases, and obesity. We also analyze the social networks among researchers and organizations (universities, research institutes, firms, etc.) that are active in the pursuit of aptamer-based therapeutic approaches. This study provides relevant information on recent research trends in RNA aptamers. PMID- 22491856 TI - Hypoglycemic encephalopathy: a case series and literature review on outcome determination. AB - Data on clinical long-term outcome after the acute phase of hypoglycemic encephalopathy (HE) using validated outcome scales is currently unavailable. Here we report the results of a systematic literature search for studies on HE and data on long-term outcome in patients with HE admitted to three Charite hospitals between January 2005 and July 2010. HE was defined as coma/stupor and blood glucose levels <50 mg/dl on admission, persistence of coma/stupor for >=24 h despite normalization of blood glucose levels, and exclusion of any other cause of coma/stupor. Outcome was assessed using the modified Rankin scale (mRS), Glasgow Outcome Scale (GOS), and Barthel index (BI). Fifteen patients were included, with a mean age of 60 years (range 29-79). Two were lost to follow-up. Of the remaining 13 patients, six had died (46 %). In the seven survivors, the median mRS score was 0 (range 0-5), median GOS score was 5 (range 2-5), and median BI was 100 (range 0-100). MRIs made in the acute phase were available for three patients and revealed no obvious relation between lesion size or pattern and clinical outcome. To our knowledge, this is the first case series using validated clinical scoring systems to determine clinical long-term outcome after HE. The results suggest that mortality is high, but long-term survival with little or no disability is possible and can be observed in the majority of survivors. Risk of death or poor outcome does not seem to be related to MRI features in the acute phase but rather to other presumably medical factors. PMID- 22491857 TI - Importance and challenge of making an early diagnosis in LMNA-related muscular dystrophy. AB - OBJECTIVE: To identify the most useful clinical and histologic markers that facilitate early diagnosis in LMNA-related muscular dystrophy and to assess the usefulness of Western blotting (WB) for lamin A/C. METHODS: We analyzed the clinical and histologic features and WB results of all patients with laminopathies diagnosed in a research-based diagnostic service over 8 years. RESULTS: Although patients with congenital muscular dystrophy (MDCL) (n = 5) and Emery-Dreifuss muscular dystrophy (EDMD) (n = 5) had distinctive early clinical features, the lack of a suggestive clinical phenotype significantly delayed diagnosis in 2 of 3 patients with limb-girdle muscular dystrophy (LGMD) (n = 3). In addition, 6 of 20 muscle biopsy samples were considered nondystrophic, which contributed to delays in diagnosis in some patients. Neck extensor involvement (weakness or contractures) was the most consistent clinical sign, present in all patients. Reduced lamin A/C levels on WB were seen in 5 of 9 patients with laminopathies. CONCLUSION: Clinical features provide the best clues for diagnosing MDCL and EDMD early in the disease, and we urge clinicians to become familiar with those phenotypes. WB for lamin A/C may contribute to diagnosis but requires technical expertise, and results are normal in many individuals with LMNA mutations. Because of the survival benefit of early diagnosis and treatment, we recommend that LMNA gene sequencing be performed in all patients with undiagnosed congenital muscular dystrophy and neck extensor weakness, all patients with genetically undiagnosed LGMD, and those with suggestive clinical signs and nonspecific histologic abnormalities. PMID- 22491858 TI - Terminal dedifferentiation of cognitive abilities. AB - OBJECTIVE: To test the cognitive dedifferentiation hypothesis that cognitive abilities become increasingly correlated in late life. METHODS: Participants are 174 older persons without dementia at the beginning of a longitudinal clinical pathologic cohort study. At annual intervals for 6 to 15 years prior to death, they completed a battery of cognitive performance tests from which previously established composite measures of episodic memory, semantic memory, working memory, and perceptual speed were derived. At death, there was a uniform neuropathologic assessment and levels of diffuse plaques, neuritic plaques, and neurofibrillary tangles were summarized in a composite measure. Change in the 4 cognitive outcomes was analyzed simultaneously in a mixed-effects model that allowed rate of decline to accelerate at a variable point before death. RESULTS: On average, cognitive decline before the terminal period was relatively gradual, and rates of change in different cognitive domains were moderately correlated, ranging from 0.25 (episodic memory-working memory) to 0.46 (episodic memory semantic memory). By contrast, cognition declined rapidly during the terminal period, and rates of change in different cognitive functions were strongly correlated, ranging from 0.83 (working memory-perceptual speed) to 0.89 (episodic memory-semantic memory, semantic memory-working memory). Higher level of plaques and tangles on postmortem examination was associated with faster preterminal decline and earlier onset of terminal decline but not with rate of terminal decline or correlations between rates of change in different cognitive functions. CONCLUSION: In the last years of life, covariation among cognitive abilities sharply increases consistent with the cognitive dedifferentiation hypothesis. PMID- 22491859 TI - An apple a day to prevent Parkinson disease: reduction of risk by flavonoids. PMID- 22491860 TI - Role of common and rare APP DNA sequence variants in Alzheimer disease. AB - OBJECTIVES: More than 30 different rare mutations, including copy number variants (CNVs), in the amyloid precursor protein gene (APP) cause early-onset familial Alzheimer disease (EOFAD), whereas the contribution of common APP variants to disease risk remains controversial. In this study we systematically assessed the role of both rare and common APP DNA variants in Alzheimer disease (AD) families. METHODS: Families with EOFAD genetically linked to the APP region were screened for missense mutations and locus duplications of APP. Further, using genome-wide DNA microarray data, we examined the APP locus for CNVs in a total of 797 additional early- and late-onset AD pedigrees. Finally, 423 single nucleotide polymorphisms (SNPs) in the APP locus, including 2 promoter polymorphisms previously associated with AD risk, were tested in up to 4,200 individuals from multiplex AD families. RESULTS: Analyses of 8 21q21-linked families revealed one family carrying a nonsynonymous mutation in exon 17 (Val717Leu) and another family with a partially penetrant 3.5-Mb locus duplication encompassing APP. CNV analysis in the APP locus revealed an additional family carrying a fully penetrant 380-kb duplication, merely spanning APP. Last, contrary to previous reports, association analyses of more than 400 different SNPs in or near APP failed to show significant effects on AD risk. CONCLUSION: Our study shows that APP mutations and locus duplications are a very rare cause of EOFAD and that the contribution of common APP variants to AD susceptibility is insignificant. Furthermore, duplications of APP may not be fully penetrant, possibly indicating the existence of hitherto unknown protective genetic factors. PMID- 22491861 TI - Network correlates of disease severity in multiple system atrophy. AB - OBJECTIVE: Multiple system atrophy (MSA), the most common of the atypical parkinsonian disorders, is characterized by the presence of an abnormal spatial covariance pattern in resting state metabolic brain images from patients with this disease. Nonetheless, the potential utility of this pattern as a MSA biomarker is contingent upon its specificity for this disorder and its relationship to clinical disability in individual patients. METHODS: We used [(18)F]fluorodeoxyglucose PET to study 33 patients with MSA, 20 age- and severity matched patients with idiopathic Parkinson disease (PD), and 15 healthy volunteers. For each subject, we computed the expression of the previously characterized metabolic covariance patterns for MSA and PD (termed MSARP and PDRP, respectively) on a prospective single-case basis. The resulting network values for the individual patients were correlated with clinical motor ratings and disease duration. RESULTS: In the MSA group, disease-related pattern (MSARP) values were elevated relative to the control and PD groups (p < 0.001 for both comparisons). In this group, MSARP values correlated with clinical ratings of motor disability (r = 0.57, p = 0.0008) and with disease duration (r = -0.376, p = 0.03). By contrast, MSARP expression in the PD group did not differ from control values (p = 1.0). In this group, motor ratings correlated with PDRP (r = 0.60, p = 0.006) but not with MSARP values (p = 0.88). CONCLUSIONS: MSA is associated with elevated expression of a specific disease-related metabolic pattern. Moreover, differences in the expression of this pattern in patients with MSA correlate with clinical disability. The findings suggest that the MSARP may be a useful biomarker in trials of new therapies for this disorder. PMID- 22491862 TI - Influence of pregnancy on neuromyelitis optica spectrum disorder. AB - OBJECTIVE: To investigate the influence of pregnancy on patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: A total of 190 women with NMOSD were enrolled from 7 referral hospitals in 4 countries. We reviewed medical records and used a structured questionnaire to investigate gravidity, parity, and the number of relapses during the 2 years before pregnancy, during each trimester of pregnancy, during the first and second trimesters after delivery, and for 6 months thereafter. The annualized relapse rate (ARR) was calculated for each period. RESULTS: Of the 190 women with NMOSD, 40 patients experienced 54 informative pregnancies, and all of them were seropositive for aquaporin-4 antibody. Fourteen patients developed the first symptoms of NMOSD either during the pregnancy (3 patients) or within a year after delivery or abortion (8 and 3 patients, respectively). Twenty-six patients experienced 40 pregnancies after the onset of NMOSD (26 deliveries and 14 abortions [1 spontaneous and 13 elective]). There was one preterm delivery with birth defects and no stillbirths. The ARR during pregnancy did not differ from that before pregnancy, but it increased significantly during the first and second trimesters after delivery (5.3 and 3.7 times, respectively). Moreover, 77% of the deliveries were associated with postpartum relapses. CONCLUSION: The significantly increased relapse rate and numerous cases of NMOSD onset after pregnancy suggest that delivery adversely affects the course of NMOSD. Prospective studies are needed to confirm our findings. PMID- 22491863 TI - Illuminating cognitive dedifferentiation at the end of life. PMID- 22491864 TI - Influence of late-life cognitive activity on cognitive health. AB - OBJECTIVE: To test the hypothesis that late-life participation in mentally stimulating activities affects subsequent cognitive health. METHODS: Analyses are based on 1,076 older persons without dementia at study onset participating in a longitudinal cohort study. They completed annual clinical evaluations for a mean of 4.9 years. Each evaluation included administration of a self-report scale about participation in mentally stimulating activities and a battery of cognitive performance tests. Previously established measures of cognitively stimulating activity and cognitive function were derived. We assessed the temporal sequence of activity changes in relation to functional changes in a series of cross-lagged panel models adjusted for age, sex, and education. RESULTS: During the observation period, cognitive activity participation (estimate of mean annual change = -0.066, SE = 0.005, p < 0.001) and cognitive functioning (estimate = 0.077, SE = 0.005, p < 0.001) declined at rates that were moderately correlated (r = 0.44, p < 0.001). The level of cognitive activity in a given year predicted the level of global cognitive function in the following year, but the level of global cognition did not predict the subsequent level of cognitive activity participation. Cognitive activity showed the same pattern of unidirectional associations with measures of episodic and semantic memory, but its associations with working memory were bidirectional. CONCLUSIONS: The results suggest that more frequent mental stimulation in old age leads to better cognitive functioning. PMID- 22491866 TI - Similar clinical and neuroimaging features in monozygotic twin pair with mutation in progranulin. AB - OBJECTIVE: To report the phenotypic characterization of monozygotic twins with mutations encoding progranulin (PGRN). METHODS: We studied a twin pair with an exon 4 gene deletion in the PGRN gene. Both twins had clinical and neuropsychological examinations as well as structural MRI and fluorodeoxyglucose PET (FDG-PET) scans. PGRN gene sequencing was performed followed by progranulin ELISA in plasma. RESULTS: Both twins manifested symptoms within 3 years of each other, with early behavioral, language, dysexecutive, and memory problems. MRI and FDG-PET imaging demonstrated a strikingly similar topography of findings with clear left hemisphere predominance. Serum progranulin levels in both were well below those from a normal population sample. CONCLUSIONS: Compared with the heterogeneity seen in many families with PGRN mutations, these monozygotic twins demonstrated strong clinical, neuroimaging, and serum progranulin level similarities, demonstrating the importance of shared genetic profiles beyond environmental influences in the symptomatic expression of the disease. PMID- 22491865 TI - Effects of fetal antiepileptic drug exposure: outcomes at age 4.5 years. AB - OBJECTIVE: To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure. METHODS: The NEAD Study is an ongoing prospective observational multicenter study, which enrolled pregnant women with epilepsy on AED monotherapy (1999-2004) to determine if differential long-term neurodevelopmental effects exist across 4 commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). The primary outcome is IQ at 6 years of age. Planned analyses were conducted using Bayley Scales of Infant Development (BSID at age 2) and Differential Ability Scale (IQ at ages 3 and 4.5). RESULTS: Multivariate intent-to-treat (n = 310) and completer (n = 209) analyses of age 4.5 IQ revealed significant effects for AED group. IQ for children exposed to valproate was lower than each other AED. Adjusted means (95% confidence intervals) were carbamazepine 106 (102-109), lamotrigine 106 (102 109), phenytoin 105 (102-109), valproate 96 (91-100). IQ was negatively associated with valproate dose, but not other AEDs. Maternal IQ correlated with child IQ for children exposed to the other AEDs, but not valproate. Age 4.5 IQ correlated with age 2 BSID and age 3 IQ. Frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ <70 at 4.5 years). Verbal abilities were impaired for all 4 AED groups compared to nonverbal skills. CONCLUSIONS: Adverse cognitive effects of fetal valproate exposure persist to 4.5 years and are related to performances at earlier ages. Verbal abilities may be impaired by commonly used AEDs. Additional research is needed. PMID- 22491867 TI - Migraine in cervical artery dissection and ischemic stroke patients. AB - OBJECTIVE: Several small to medium-sized studies indicated a link between cervical artery dissection (CeAD) and migraine. Migrainous CeAD patients were suggested to have different clinical characteristics compared to nonmigraine CeAD patients. We tested these hypotheses in the large Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) population. METHODS: A total of 968 CeAD patients and 653 patients with an ischemic stroke of a cause other than CeAD (non CeAD IS) were recruited. CeAD patients with stroke (CeAD(stroke), n = 635) were compared with non-CeAD IS patients regarding migraine, clinical characteristics, and outcome. CeAD patients with and without migraine were compared in terms of clinical characteristics and outcome. RESULTS: Migraine was more common among CeAD(stroke) patients compared to non-CeAD IS patients (35.7 vs 27.4%, p = 0.003). The difference was mainly due to migraine without aura (20.2 vs 11.2%, p < 0.001). There were no differences in prevalence of strokes, arterial distribution, or other clinical or prognostic features between migrainous and nonmigrainous CeAD patients. CONCLUSION: Migraine without aura is more common among CeAD(stroke) patients compared to non-CeAD IS patients. The mechanisms and possible causative link remain to be proved. Although CeAD is often complicated by stroke, our data do not support increased risk of stroke in migrainous CeAD patients. PMID- 22491868 TI - Investigating missing data in Alzheimer disease studies. PMID- 22491870 TI - Cyclophosphamide treatment for unrelenting CNS vasculitis secondary to tuberculous meningitis. PMID- 22491871 TI - Habitual intake of dietary flavonoids and risk of Parkinson disease. AB - OBJECTIVE: To prospectively examine whether higher intakes of total flavonoids and their subclasses (flavanones, anthocyanins, flavan-3-ols, flavonols, flavones, and polymers) were associated with a lower risk of developing Parkinson disease (PD). METHODS: In the current analysis, we included 49,281 men in the Health Professional Follow-up Study and 80,336 women from the Nurses' Health Study. Five major sources of flavonoid-rich foods (tea, berry fruits, apples, red wine, and orange/orange juice) were also examined. Flavonoid intake was assessed using an updated food composition database and a validated food frequency questionnaire. RESULTS: We identified 805 participants (438 men and 367 women) who developed PD during 20-22 years of follow-up. In men, after adjusting for multiple confounders, participants in the highest quintile of total flavonoids had a 40%lower PD risk than those in the lowest quintile (hazard ratio [HR] = 0.60; 95% confidence interval 0.43, 0.83; p trend = 0.001). No significant relationship was observed in women (p trend = 0.62) or in pooled analyses (p trend = 0.23). In the pooled analyses for the subclasses, intakes of anthocyanins and a rich dietary source, berries, were significantly associated with a lower PD risk (HR comparing 2 extreme intake quintiles were 0.76 for anthocyanins and 0.77 for berries, respectively; p trend < 0.02 for both). CONCLUSIONS: Our findings suggest that intake of some flavonoids may reduce PD risk, particularly in men, but a protective effect of other constituents of plant foods cannot be excluded. PMID- 22491872 TI - Isolation and characterization of two YUCCA flavin monooxygenase genes from cultivated strawberry (Fragaria * ananassa Duch.). AB - In strawberry (Fragaria * ananassa Duch.), auxin has been recognized as the main signal molecule coordinating the growth and initiation of ripening of fruits. The molecular mechanism regulating auxin biosynthesis in strawberry remains unknown. This project reports two YUCCA flavin monooxygenase genes FaYUC1-2 isolated from cultivated strawberry. FaYUC1 and FaYUC2 are most homologous to AtYUC6 and AtYUC4, respectively. Significant expression of FaYUC1-2 is found in vegetative meristems and reproductive organs, with overlapping but distinct patterns. During fruit development, both transcripts of FaYUC1 and FaYUC2 in achenes reach a peak around large green fruit (G2) stage, but the sudden rise in FaYUC2 transcript level is much steeper and begins earlier than that in FaYUC1. FaYUC2 is also obviously expressed in the receptacles from green fruits, hinting another auxin source for receptacle development, other than achenes. FaYUC1 over-expression Arabidopsis exhibits typical auxin hyper-accumulation phenotype in many aspects, such as the narrow and downward curled leaves, strong apical dominance, short and hairy root. It is also severely sterile, due to the disruption of floral meristems initiation and floral organs development. Transgenic analysis indicates that strawberry YUC gene may hold conserved role in auxin biosynthesis like their homologs in other plants. Integrated with the spatiotemporal expression features, these results led us to propose that FaYUC1-2 may involve in many developmental processes including flower and fruit development in strawberry. KEY MESSAGE: This paper is the first report of isolation and characterization of strawberry auxin biosynthesis genes. And their conserved functions in auxin biosynthesis were confirmed after ectopic expression. PMID- 22491869 TI - Predicting missing biomarker data in a longitudinal study of Alzheimer disease. AB - OBJECTIVE: To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD). METHODS: The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005-2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI. RESULTS: CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Abeta(42). Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD. CONCLUSION: The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD. PMID- 22491873 TI - Thirteen Chinese patients with sporadic Paget's disease of bone: clinical features, SQSTM1 mutation identification, and functional analysis. AB - To increase awareness of the rarity of Paget's disease of bone (PDB) in the Chinese population, we characterized the clinical manifestations and features of 13 Chinese sporadic PDB patients. The clinical features of our Chinese PDB patients show similarities with cases reported in Western countries. The most common lesion sites were the pelvis, femur, and tibia; the next most common lesion sites were the spine and skull. Most patients had a higher serum alkaline phosphatase (ALP) level. Treatment with bisphosphonates was effective. In addition, we screened for PDB-causing mutations and performed a functional analysis in an attempt to elucidate the molecular pathogenesis of PDB. A total of 216 persons, including 13 sporadic PDB patients, three unaffected relatives of 1 patient, and 200 healthy donors, were recruited. All eight exons and exon-intron boundaries of the SQSTM1 gene were amplified by polymerase chain reaction (PCR) and directly sequenced. We identified a 53-year-old man who harbored a heterozygous T-to-C transversion at position 1250 in exon 8 (1250T > C), which resulted in a methionine-to-threonine (ATG > ACG) substitution at codon 404 (M404T). The M404T mutant SQSTM1 protein exhibited increased NF-kappaB activation and drove a significantly increased number of osteoclast-like cells (OLCs) that formed in response to RANKL and an increased number of OLC nuclei. This is the first report of an SQSTM1 genetic mutation that contributes to the pathogenesis of PDB in Chinese patients. These results may partially explain the mechanism by which this SQSTM1 mutation contributes to the pathogenesis of sporadic PDB in Chinese patients. PMID- 22491874 TI - An altered hormonal profile and elevated rate of bone loss are associated with low bone mass in professional horse-racing jockeys. AB - Horse-racing jockeys are a group of weight-restricted athletes, who have been suggested as undertaking rapid and extreme weight cycling practices in order to comply with stipulated body-mass standards. The aim of this study was to examine bone mass, turnover and endocrine function in jockeys and to compare this group with age, gender and body mass index matched controls. Twenty male professional jockeys and 20 healthy male controls participated. Dual energy X-ray absorptiometry scans and early morning fasting blood and urine samples were used to measure bone mass, turnover and a hormonal profile. Total body bone mineral density (BMD) was significantly lower in jockeys (1.143 +/- 0.05 vs. 1.27 +/- 0.06 g cm(-3), p < 0.01). Bone resorptive activity was elevated in the jockey group as indicated by significantly higher urinary NTx/creatinine (76.94 +/- 29.52 vs. 55.9 +/- 13.9 nmol mmol(-1), p < 0.01), resulting in a significantly negative uncoupling index between bone resorption and formation. Sex hormone binding globulin (SHBG) levels were significantly higher in jockeys (41.21 +/- 9.77 vs. 28.24 +/- 9.98 nmol L(-1), p < 0.01) with a lower percentage of bioavailable testosterone (48.89 +/- 7.38 vs. 59.18 +/- 6.74 %, p < 0.01). SHBG and insulin-like growth factor-1 were independent predictors of total body and femoral neck BMD, respectively (p < 0.05). In conclusion, it appears that professional jockeys have an elevated rate of bone loss and reduced bone mass that appears to be associated with disrupted hormonal activity. It is likely that this may have occurred in response to the chronic weight cycling habitually experienced by this group. PMID- 22491875 TI - [The relevance of head and neck surgery for ear, nose and throat medicine: the 83rd annual meeting of the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery in Mainz, 16-20 May 2012]. PMID- 22491876 TI - [Sleep medicine]. PMID- 22491877 TI - [Randomized controlled trials in the surgical treatment of obstructive sleep apnea]. AB - The need for surgical treatment alternatives for obstructive sleep apnea is unchanged. However, recommendations regarding these treatments can often only be given with caution as there are only a limited number of controlled studies available. To perform controlled trials and even more so placebo controlled trials in the field of sleep surgery is challenging, especially in comparison to studies evaluating conservative approaches. Nevertheless, these studies can be carried out also in the field of sleep surgery. In this review we present recent concepts and high-quality surgical trials with innovative study designs. A Medline search revealed 310 studies regarding surgical treatment of sleep apnea. These studies were assessed regarding quality, execution and number of subjects. A total of 12 randomized controlled studies were identified addressing palatal implants, radio-frequency surgery, nasal surgery, maxillomandibular advancement and laser-assisted uvulopalatoplasty (LAUP). Furthermore this review addresses the limitations of surgical studies and the differences compared to trials dealing with conservative approaches. The studies presented in this review demonstrate that high-quality trials regarding surgical treatment of obstructive sleep apnea are feasible and can lead to recommendations with high evidence levels. PMID- 22491878 TI - [Acoustic analyses of snoring sounds: the possibilities and outlook]. AB - Acoustic analyses of snoring sounds have been performed for 30 years in the diagnostic procedure for sleep disordered breathing and can be categorized according to the frequency spectrum. Snoring with dominant deep frequencies below 500 Hz is predominately caused by velar vibrations without obstruction in simple snoring. High frequency snoring above 500 Hz is caused by partial or complete obstruction of the upper airway in patients with obstructive sleep-apnea syndrome. Combined snoring noises with deep and high frequency components are still a diagnostic challenge. The human hearing is still better in rating threatening characters of snoring noises than any acoustic analysis. New approaches by means of psychoacoustic analysis might contribute to decoding the acoustic fingerprint of snoring. By applying adequate analysis algorithms acoustic screening devices might be able to shed light on the extent of sleep disordered breathing in the future. Moreover an improved topodiagnostic approach in snoring might contribute to a better outcome in the treatment of snoring. PMID- 22491879 TI - [Health-related consequences of obstructive sleep apnea: daytime sleepiness, accident risk and legal aspects]. AB - Daytime sleepiness for any reason leads to impairment of daytime performance and an increased accident rate. The consequences are an increase of illness- and accident-related costs for the health system. Obstructive sleep apnea (OSA) is one of the major reasons for increased daytime sleepiness, especially in professional drivers. The accident frequency in OSA can be significantly reduced by adequate continuous positive airway pressure (CPAP) therapy. Up till now there are no uniform legal regulations about the handling of OSAS patients or patients with daytime sleepiness due to other diseases as far as driving ability is concerned. PMID- 22491880 TI - [Perioperative risk management of patients with obstructive sleep apnea]. AB - Obstructive sleep apnea (OSA) has a relatively high prevalence of 3-7% in the general population in western industrialized countries. The prevalence is higher in older patients and in patients with cardiac or metabolic disorders. In the general surgical population patients with OSA are often unrecognized prior to surgery so that unexpected problems can occur due to the higher risk of airway collapse. Severe apnea can result even hours later and especially after surgery of the upper airway. Anesthesists and ear nose and throat surgeons are equally responsible for the perioperative surveillance. The article will show the importance of the preoperative identification of OSA patients and the perioperative risk management in the different risk phases apart from surgery. Although the importance of guidelines is very high there are no mandatory guidelines in Germany in contrast to the USA and the implementation should be given priority. PMID- 22491881 TI - [Diagnosis of otolith function and estimation of subjective visual vertical]. PMID- 22491882 TI - [Medical examination: preparation for ENT specialisation: Part 4]. PMID- 22491883 TI - [Auditory processing and perception disorders: proposed treatment and management: guidelines of the German Society for Phoniatry and Pedaudiology]. PMID- 22491884 TI - [Aspirin desensitization: therapy options in patients with aspirin-exacerbated respiratory disease]. AB - Aspirin desensitization has established itself as an additional therapy option in the treatment of aspirin- exacerbated respiratory disease, recurrent chronic rhinosinusitis and nasal polyps. Inpatient treatment is strongly recommended due to the risk of life-threatening side effects. In addition, the necessary requirements, indications and contraindications should be carefully considered from a medicolegal perspective. A maintenance dose of 300 (-500) mg ASS is currently recommended. Indications include persisting symptoms despite intensive medical care and/or recurrent nasal polyps, leading to recurrent sinus operations and/or the need to take systemic corticosteroids in order to control nasal symptoms or asthma. If ASS intake is interrupted for more than 48 h, aspirin desensitization should be resumed to prevent renewed intolerance reactions. PMID- 22491885 TI - Adult neurogenesis in the brain of the Mozambique tilapia, Oreochromis mossambicus. AB - Although the generation of new neurons in the adult nervous system ('adult neurogenesis') has been studied intensively in recent years, little is known about this phenomenon in non-mammalian vertebrates. Here, we examined the generation, migration, and differentiation of new neurons and glial cells in the Mozambique tilapia (Oreochromis mossambicus), a representative of one of the largest vertebrate taxonomic orders, the perciform fish. The vast majority of new cells in the brain are born in specific proliferation zones of the olfactory bulb; the dorsal and ventral telencephalon; the periventricular nucleus of the posterior tuberculum, optic tectum, and nucleus recessi lateralis of the diencephalon; and the valvula cerebelli, corpus cerebelli, and lobus caudalis of the cerebellum. As shown in the olfactory bulb and the lateral part of the valvula cerebelli, some of the young cells migrate from their site of origin to specific target areas. Labeling of mitotic cells with the thymidine analog 5 bromo-2'-deoxyuridine, combined with immunostaining against the neuron-specific marker protein Hu or against the astroglial marker glial fibrillary acidic protein demonstrated differentiation of the adult-born cells into both neurons and glia. Taken together, the present investigation supports the hypothesis that adult neurogenesis is an evolutionarily conserved vertebrate trait. PMID- 22491886 TI - Neural mechanisms underlying deafferentation pain: a hypothesis from a neuroimaging perspective. AB - Deafferentation pain following nerve injury annoys patients, and its management is a challenge in clinical practice. Although the mechanisms underlying deafferentation pain remain poorly understood, progress in the development of multidimensional neuroimaging techniques is casting some light on these issues. Deafferentation pain likely results from reorganization of the nervous system after nerve injury via processes that interact with the substrates for pain perception (the pain matrix). Therapeutic effects of motor cortex stimulation on deafferentation pain suggest that the core mechanisms underlying deafferentation pain also interact with the motor system. Therefore, simultaneous neuroimaging and brain stimulation, an emerging neuroimaging technique, was developed to investigate complicated interactions among motor, somatosensory, and pain systems. In healthy participants, parts of the pain matrix (the anterior cingulate cortex, parietal operculum, and thalamus) show activity during both somatosensory stimulation and brain stimulation to the motor cortex. This finding indicates that motor, somatosensory, and pain systems communicate among each other via the neural network. A better understanding of the plastic mechanisms influencing such cross-talk among these systems will help develop therapeutic interventions using brain stimulation and neurofeedback. PMID- 22491887 TI - Setting the standard: a special focus on genomic selection in GENETICS and G3. PMID- 22491888 TI - Where's the money? Inversions, genes, and the hunt for genomic targets of selection. PMID- 22491891 TI - Denicotinized versus average nicotine tobacco cigarette smoking differentially releases striatal dopamine. AB - INTRODUCTION: Nicotine has long been recognized as a necessary but insufficient component of tobacco cigarettes to maintain a psychophysiological need to smoke. This study examined venous plasma concentrations effects of nicotine in cigarette smoking after overnight abstinence to release striatal dopamine (DA). METHODS: Twenty-two male smokers smoked either denicotinized (denic) or average nicotine (nic) cigarettes under single blind conditions. Each was given [(11)C]raclopride and scanned in a positron emission tomography (PET) facility. RESULTS: Smoking either denic or nic cigarettes released striatal DA. Denic cigarette smoking released DA primarily in the right striatum, whereas nic cigarette smoking released DA in both striata, but especially in the left. Increases in venous plasma nicotine concentrations correlated positively with increased DA release in the left caudate nucleus. Smoking denic cigarettes reduced craving as much as smoking nic cigarettes. Craving reduction after nic tobacco smoking correlated with increases in plasma nicotine. CONCLUSIONS: Nonnicotine factors in tobacco smoking produce important right brain effects. Nicotine is a pharmacological factor during tobacco smoking that releases bilateral striatal DA, but more in the left brain. PMID- 22491892 TI - Pathways of change explaining the effect of smoke-free legislation on smoking cessation in The Netherlands. An application of the international tobacco control conceptual model. AB - INTRODUCTION: This study aims to test the pathways of change from individual exposure to smoke-free legislation on smoking cessation, as hypothesized in the International Tobacco Control (ITC) Conceptual Model. METHODS: A nationally representative sample of Dutch smokers aged 15 years and older was surveyed during 4 consecutive annual surveys. Of the 1,820 baseline smokers, 1,012 participated in the fourth survey. Structural Equation Modeling was employed to test a model of the effects of individual exposure to smoke-free legislation through policy-specific variables (support for smoke-free legislation and awareness of the harm of [secondhand] smoking) and psychosocial mediators (attitudes, subjective norm, self-efficacy, and intention to quit) on quit attempts and quit success. RESULTS: The effect of individual exposure to smoke free legislation on smoking cessation was mediated by 1 pathway via support for smoke-free legislation, attitudes about quitting, and intention to quit smoking. Exposure to smoke-free legislation also influenced awareness of the harm of (secondhand) smoking, which in turn influenced the subjective norm about quitting. However, only attitudes about quitting were significantly associated with intention to quit smoking, whereas subjective norm and self-efficacy for quitting were not. Intention to quit predicted quit attempts and quit success, and self-efficacy for quitting predicted quit success. CONCLUSIONS: Our findings support the ITC Conceptual Model, which hypothesized that policies influence smoking cessation through policy-specific variables and psychosocial mediators. Smoke-free legislation may increase smoking cessation, provided that it succeeds in influencing support for the legislation. PMID- 22491889 TI - Mitotic spindle form and function. AB - The Saccharomyces cerevisiae mitotic spindle in budding yeast is exemplified by its simplicity and elegance. Microtubules are nucleated from a crystalline array of proteins organized in the nuclear envelope, known as the spindle pole body in yeast (analogous to the centrosome in larger eukaryotes). The spindle has two classes of nuclear microtubules: kinetochore microtubules and interpolar microtubules. One kinetochore microtubule attaches to a single centromere on each chromosome, while approximately four interpolar microtubules emanate from each pole and interdigitate with interpolar microtubules from the opposite spindle to provide stability to the bipolar spindle. On the cytoplasmic face, two to three microtubules extend from the spindle pole toward the cell cortex. Processes requiring microtubule function are limited to spindles in mitosis and to spindle orientation and nuclear positioning in the cytoplasm. Microtubule function is regulated in large part via products of the 6 kinesin gene family and the 1 cytoplasmic dynein gene. A single bipolar kinesin (Cin8, class Kin-5), together with a depolymerase (Kip3, class Kin-8) or minus-end-directed kinesin (Kar3, class Kin-14), can support spindle function and cell viability. The remarkable feature of yeast cells is that they can survive with microtubules and genes for just two motor proteins, thus providing an unparalleled system to dissect microtubule and motor function within the spindle machine. PMID- 22491893 TI - Metabolic rate regulation by the renin-angiotensin system: brain vs. body. AB - Substantial evidence supports a role for the renin-angiotensin system (RAS) in the regulation of metabolic function, but an apparent paradox exists where genetic or pharmacological inhibition of the RAS occasionally has similar physiological effects as chronic angiotensin infusion. Similarly, while RAS targeting in animal models has robust metabolic consequences, effects in humans are more subtle. Here, we review the data supporting a role for the RAS in metabolic rate regulation and propose a model where the local brain RAS works in opposition to the peripheral RAS, thus helping to explain the paradoxically similar effects of RAS supplementation and inhibition. Selectively modulating the peripheral RAS or brain RAS may thus provide a more effective treatment paradigm for obesity and obesity-related disorders. PMID- 22491894 TI - Specific mitochondrial functions in separate sub-cellular domains of pancreatic acinar cells. AB - The pancreatic acinar cell synthesizes many digestive proenzymes, which are packaged into secretory (zymogen) granules and secreted by exocytosis upon the action of the neurotransmitter acetylcholine, released from vagal nerve endings, or the hormone cholecystokinin. These secretagogues mobilize Ca(2+) from internal stores and thereby create the cytosolic Ca(2+) signals that control exocytosis. Exocytosis requires Ca(2+), Mg(2+) and ATP. Mg(2+) is present in millimolars concentration throughout the cytosol, but high cytosolic Ca(2+) concentrations need to be created in the local domains near the apical plasma membrane. A special group of mitochondria surrounding the apical granular area play a crucial role in confining cytosolic Ca(2+) elevations to this part of the cell by acting as a Ca(2+) buffer barrier. The Ca(2+) uptake into these mitochondria during apical Ca(2+) spiking stimulates mitochondrial ATP synthesis. ATP is also required for Ca(2+) extrusion via the plasma membrane Ca(2+) pumps, mainly located in the apical area, as well as for Ca(2+) reuptake into the endoplasmic reticulum. Because Ca(2+) extrusion occurs during Ca(2+) spiking, there is a need for compensatory Ca(2+) entry via store-operated Ca(2+) channels. Sub plasmalemmal (peripheral) mitochondria play an important role in supporting both store-operated Ca(2+) entry at the base as well as the subsequent Ca(2+) pumping into the endoplasmic reticulum. A third group of mitochondria surround the nucleus. They protect the nucleus against unwarranted Ca(2+) signals generated elsewhere and are capable of confining Ca(2+) signals primarily generated inside the nucleus to this part of the cell. PMID- 22491895 TI - Polysaccharide nanofibrous scaffolds as a model for in vitro skin tissue regeneration. AB - Tissue engineering and nanotechnology have advanced a general strategy combining the cellular elements of living tissue with sophisticated functional biocomposites to produce living structures of sufficient size and function at a low cost for clinical relevance. Xylan, a natural polysaccharide was electrospun along with polyvinyl alcohol (PVA) to produce Xylan/PVA nanofibers for skin tissue engineering. The Xylan/PVA glutaraldehyde (Glu) vapor cross-linked nanofibers were characterized by SEM, FT-IR, tensile testing and water contact angle measurements to analyze the morphology, functional groups, mechanical properties and wettability of the fibers for skin tissue regeneration. The cell biomaterial interactions were studied by culturing human foreskin fibroblasts on Xylan/PVA Glu vapor cross-linked and Xylan/PVA/Glu blend nanofibrous scaffolds. The observed results showed that the mechanical properties (72 %) and fibroblast proliferation significantly increased up to 23 % (P < 0.05) in 48 h Glu vapor cross-linked nanofibers compared to 24 h Glu vapor cross-linked Xylan/PVA nanofibers. The present study may prove that the natural biodegradable Xylan/PVA nanofibrous scaffolds have good potential for fibroblast adhesion, proliferation and cell matrix interactions relevant for skin tissue regeneration. PMID- 22491896 TI - Genetic linkage map construction and QTL mapping of cadmium accumulation in radish (Raphanus sativus L.). AB - Cadmium (Cd) is a widespread soil pollutant and poses a significant threat to human health via the food chain. Large phenotypic variations in Cd concentration of radish roots and shoots have been observed. However, the genetic and molecular mechanisms of Cd accumulation in radish remain to be elucidated. In this study, a genetic linkage map was constructed using an F(2) mapping population derived from a cross between a high Cd-accumulating cultivar NAU-Dysx and a low Cd accumulating cultivar NAU-Yh. The linkage map consisted of 523 SRAP, RAPD, SSR, ISSR, RAMP, and RGA markers and had a total length of 1,678.2 cM with a mean distance of 3.4 cM between two markers. All mapped markers distributed on nine linkage groups (LGs) having sizes between 134.7 and 236.8 cM. Four quantitative trait loci (QTLs) for root Cd accumulation were mapped on LGs 1, 4, 6, and 9, which accounted for 9.86 to 48.64 % of all phenotypic variance. Two QTLs associated with shoot Cd accumulation were detected on LG1 and 3, which accounted for 17.08 and 29.53 % of phenotypic variance, respectively. A major-effect QTL, qRCd9 (QTL for root Cd accumulation on LG9), was identified on LG 9 flanked by NAUrp011_754 and EM5me6_286 markers with a high LOD value of 23.6, which accounted for 48.64 % of the total phenotypic variance in Cd accumulation of F(2) lines. The results indicated that qRCd9 is a novel QTL responsible for controlling root Cd accumulation in radish, and the identification of specific molecular markers tightly linked to the major QTL could be further applied for marker-assisted selection (MAS) in low-Cd content radish breeding program. PMID- 22491897 TI - The value of preoperative CT scan in newborns with type C esophageal atresia. AB - PURPOSE: This study was designed to evaluate the accuracy of preoperative CT scan in depicting the structure of type C esophageal atresia (EA) and determine its role in planning the surgical strategy by digitally measuring the interpouch distance. METHODS: Thirty-five neonates (20 males, 15 females) born with type C EA were enrolled in this study. A helical CT scan was performed after chest radiographs of the neonates with a coiled oroesophageal tube in the upper esophageal pouch. The interpouch distances measured on CT images were compared with the findings at surgery. RESULTS: With the use of helical CT scan, the structure of EA-TEF was accurately depicted; the origins of the fistula and the interpouch distance were defined. The interpouch distance detected by CT scan correlated well with the findings at surgery. Statistical analysis demonstrated no significant difference (R = 0.99, P < 0.001). CT scan findings were crucial in planning the surgical strategy in 14 patients (40%). CONCLUSION: Preoperative CT scan could provide more accurate information about the origin of the fistula and the interpouch distance in type C EA and played a crucial role in planning the surgical strategy. PMID- 22491898 TI - Secondary structure of antisense RNAbeta, an internal transcriptional terminator of the plasmid-encoded iron transport-biosynthesis operon of Vibrio anguillarum. AB - RNAbeta affects the transcription process of the iron transport-biosynthesis operon encoded in the pJM1 plasmid of Vibrio anguillarum at a stem-loop structure located in the intergenic region between the fatA and angR genes. The net result is a higher level of the fatD, fatC, fatB, and fatA moiety as compared with the longer transcript encoding those genes as well as the angR and angT genes. In this work we report the secondary structure of RNAbeta determined by treatment with single and double strand specific ribonucleases as well as lead acetate followed by sequencing. The generated in vitro structural data indicated that three of the four previously described loops are in agreement with the original model, however, the alteration of loop IV as well as several other structural differences in the overall shape of the molecule led to the necessity of creating a new in silico model. Using the sites of mutations in the various loops we modeled the change in the RNAbeta secondary structure induced by those mutations. Mutations of loops III and IV to their complementary bases alter the overall structure of the RNAbeta significantly and increase its function while mutations in loops I and II have the opposite effect, the structure is unchanged but the activity of RNAbeta decreases. This indicates that loops I and II are necessary for interaction with the target mRNA. It is possible that the structural rearrangement introduced by mutations in loops III and IV promote activity and binding in loops I and II through reducing steric hindrance or increased binding to the target. This result also indicates that the exact relative positions of the critical loops are unimportant for activity. PMID- 22491899 TI - Nipah and hendra virus interactions with the innate immune system. AB - Nipah virus and Hendra virus are related, highly pathogenic paramyxoviruses with unusually broad host ranges. Henipaviruses encode several proteins that block innate immune responses, and these are likely to serve as virulence factors. Specfically, four virus-encoded proteins, the phosphoprotein (P), the V protein, the W protein, and the C protein have each been demonstrated to counteract aspects of the interferon (IFN)-alpha/beta response, a key component of the innate immune response to virus infection. The available data indicate that V and W can inhibit the production of IFNalpha/beta in response to various stimuli, while the P, V, and W proteins also block the ability of IFNs to signal and induce an antiviral state in cells. The C protein also inhibits the antiviral effects of IFNalpha/beta by a poorly characterized mechanism. Reverse genetics systems, which allow the generation of recombinant viruses bearing specific mutations, have demonstrated the importance of the viral IFN-antagonists for replication. With these systems in hand, the field is now poised to define how specific viral IFN-antagonist functions influence viral pathogenesis. PMID- 22491901 TI - Analysis of microRNAs and their precursors in bovine early embryonic development. AB - In animals, the maternal-to-embryonic transition (MET) occurs in the first days of early development and involves the degradation of maternal transcripts that have been stored during oogenesis. Moreover, precise and specific control mechanisms govern the adequate synchronization of the MET events to promote the activation of the embryonic genome. These mechanisms are not well understood, but it is believed that microRNAs (miRNAs) could be one of the mechanisms involved. After a microarray screening study, we analysed the expression of specific miRNA during oocyte maturation and early embryo development until preimplantation stages. Two differentially expressed candidates were selected for further analysis. Mature and precursor forms of miR-21 and miR-130a were quantified by qRT-PCR in pools of 20 oocytes at GV (germinal vesicle), GV breakdown and metaphase II stages as well as in pools of embryos at the 2-cell, 4-cell, 8-cell and blastocyst stages. The results showed a linear increase during the 1-8 cell stage for the mature forms of miR-130a and miR-21 (P < 0.05 and P < 0.003, respectively) and for the precursor form of miR-130a (P < 0.002). To see if this increase was due to minor transcriptional activity, 2-cell embryos were exposed to alpha-amanitin for 30-34 h. Results showed a significant decrease in miR-21, pre-miR-21, miR-130a and SRFS3 in alpha-amanitin-treated embryos (P < 0.05). Considering the potential regulatory role of these miRNA, the bovine genome was screened to identify putative targets with a 3'UTR exact seed match. This study suggests that miRNAs could be important players in the MET, as expression profiles suggest a potential regulation role during early development steps. PMID- 22491902 TI - The interaction between the maternal BMI and angiogenic gene polymorphisms associates with the risk of spontaneous preterm birth. AB - Obesity is associated with an increased level of inflammation. Interactions between inflammatory and angiogenic pathways are implicated in the major pregnancy disorders. The aim of this study was to investigate whether functional polymorphisms in angiogenesis-regulating genes (VEGFA rs699947, VEGFA rs3025039, KDR rs2071559 and ANGPT1 rs2507800) interact with the maternal BMI to modify the risk of a spontaneous preterm birth (sPTB). We conducted a nested case-control study of 1190 nulliparous Caucasian women (107 sPTBs and 1083 controls). Spontaneous PTB was defined as spontaneous preterm labour or a preterm premature rupture of membranes resulting in a preterm birth at <37 weeks of gestation. DNA was extracted from the peripheral blood and genotyped using the Sequenom MassARRAY system. Among overweight or obese women (BMI >=25), the VEGFA rs699947 AA genotype was associated with a higher risk of sPTBs [odds ratio (OR) = 2.4, 95% confidence interval (CI): 1.4-4.6, P = 0.001] and a significant interaction between the BMI and the polymorphism was detected (OR = 4.2, 95% CI: 1.7-10.9, P = 0.003). Among women with a BMI <25, ANGPT1 rs2507800 AA genotype was associated with a higher risk of sPTB (OR = 2.3, 95% CI: 1.2-4.4, P= 0.02) and a significant interaction between BMI and the polymorphism was detected (OR = 3.3, 95% CI: 1.1 9.3, P = 0.02). All results remained significant after adjusting for potential confounding factors. The maternal BMI interacts with angiogenesis-regulating gene polymorphisms to modify the risk of sPTBs. PMID- 22491903 TI - The prevalence and correlates of neurotic disorders among undergraduates at a mainland Chinese university. AB - OBJECTIVES: To study the prevalence and risk factors of neurotic disorders (NDs) among Chinese university students. METHODS: Stratified random sampling was used to select students who were interviewed using the World Health Organization Composite International Diagnostic Interview Version 3.0 to diagnose psychiatric disorder and collected socio-demographic, and family structure and environment data. The response rate was 90 % (N = 1,843). The International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) criteria were used to diagnose NDs. We used logistical regression to evaluate the links between NDs and selected correlates. RESULTS: The prevalence of NDs was 25.6 % (lifetime), 15.7 % (12-month), and 6.8 % (30-day) among the university students with no significant gender differences in these rates. No family structure characteristics were related to 12-month prevalence of NDs (P > 0.05). In contrast, family environment factors including a history of family disputes (OR 1.562, CI 1.108-2.203), parental mental health problems (OR 1.800, CI 1.379 2.349), and absence of care in childhood (OR 1.916, 95 % CI 1.331-2.759) were associated with higher prevalence rates of NDs. CONCLUSIONS: Our findings show a high prevalence of NDs in this sample of Chinese undergraduates. Social environment factors, in the student's family of orientation, were significantly associated with the prevalence of NDs. These findings support the importance of negative family experiences during childhood and adolescence and increasing vulnerability to NDs. PMID- 22491904 TI - Recognition and treatment of psychological disorders during military service in the UK armed forces: a study of war pensioners. AB - PURPOSE: Little is known about the detection and treatment of psychological disorders arising during military service. We investigated whether personnel who developed disorders while serving in the UK armed forces came to the attention of medical services for these problems, received corresponding diagnoses, and were treated. METHODS: For this retrospective record-based study 132 veterans in receipt of a war pension for psychological or physical problems received a lifetime diagnostic interview. Those with onsets of PTSD, depression, or alcohol abuse while in service were compared with those who never developed any condition or only developed it after discharge. Their medical records were inspected for contemporaneous contacts, diagnoses, and treatment. RESULTS: PTSD and depression, but not alcohol abuse, were independently associated with mental health contacts while in service. The median time from PTSD onset to first contact was 1 month. Under half of personnel meeting criteria for these disorders received a corresponding diagnosis, and alcohol abuse was more likely to be recognised in the context of comorbid PTSD. PTSD was as well recognised in earlier as in later years covered by the study. Most personnel with disorders received treatment, and those treated were more likely to be medically downgraded or discharged. CONCLUSIONS: War pensioners are more likely than not to have had their psychological problems acknowledged and treated while in service. The fact that these problems are still largely present 10 years later raises questions over the continuity of care associated with the transition to civilian life. PMID- 22491905 TI - Responses to suicidal messages in an online support group: comparison between trained volunteers and lay individuals. AB - PURPOSE: Although trained volunteers are considered to be a valuable source of emotional first aid for individuals in crisis, there is a paucity of empirical evidence comparing them to lay individuals. The current study exploits a methodological opportunity engendered by an online support group in which both trained volunteers and lay individuals responded to the same distressful messages within the same naturally occurring setting. METHOD: The two groups were compared on the basis of the types of strategies they employed in response to 111 suicidal messages retrieved from an online support group operated by the Israeli Association of Emotional First Aid (ERAN). RESULTS: Trained volunteers used a wider variety of strategies. They also employed more emotion-focused strategies and more therapeutic-like cognitive-focused strategies than the lay individuals. Self-disclosure was more prevalent among the responses of the lay individuals. CONCLUSIONS: Trained volunteers constitute a valuable community source of suicide prevention. The implications of the findings regarding the provision of crisis intervention and suicide prevention via an online support groups are discussed. PMID- 22491906 TI - Father mental health during the early parenting period: results of an Australian population based longitudinal study. AB - PURPOSE: The primary objective of this study was to report on the occurrence of mental health difficulties for a large national sample of Australian fathers of children aged 0-5 years (n = 3,471). Secondary objectives were to compare fathers' mental health against normative data for the general male adult population, and to examine the course of mental health problems for fathers across the early childhood period. METHODS: Secondary analysis of data from the infant cohort of the Longitudinal Study of Australian Children at three waves when children were 0-12 months, 2-3 and 4-5 years. Comparative data on the prevalence of psychological distress in the Australian adult male population sourced from the National Survey of Mental Health and Wellbeing. RESULTS: Approximately nine per cent of fathers reported symptomatic or clinical psychological distress at each wave, as measured by the Kessler-6. Approximately 30 % reporting distress at wave 1 continued to report distress at a similar or worse level across waves 2 and 3. Fathers not living with their children also had high rates of distress (14 % at wave 1 and 10 % at wave 2). Finally, fathers in the present study had 1.38 increased odds (95 % CI 1.12-1.69) for psychological distress compared with the Australian adult male population. CONCLUSIONS: Fathers are at risk of experiencing postnatal mental health difficulties, which may persist across the early childhood period for some fathers. The results suggest routine assessment of fathers' wellbeing should be undertaken in the postnatal period with mental health interventions and support provided across the early childhood period. PMID- 22491911 TI - Osmotic demyelination syndrome: variable clinical and radiologic response to intravenous immunoglobulin therapy. PMID- 22491912 TI - Germline mutations 657del5 and 643C>T (R215W) in NBN are not likely to be associated with increased risk of breast cancer in Czech women. PMID- 22491914 TI - Botulinum toxin injection for the management of refractory filamentary keratitis. AB - OBJECTIVE: To evaluate the efficacy of onabotulinumtoxinA injection for the treatment of refractory filamentary keratitis. METHODS: A retrospective review of treatment response of 33 eyes of 17 patients with filamentary keratitis resistant to conventional medical therapy who were treated with onabotulinumtoxinA injection was performed. Ocular surface findings, symptom improvement, and the number and location of filaments before and after the injections were recorded. All eyelids were injected subcutaneously with onabotulinumtoxinA (10 U/0.1 mL). All treatments were performed in accordance with an individualized treatment plan using precise localizing treatment maps, with adjustments to dosage based on treatment response. RESULTS: Objective and subjective improvement was noted after the initial onabotulinumtoxinA injection in all patients. Filaments completely resolved after the onabotulinumtoxinA injection in 29 eyes (88%). In 20 of these eyes, filaments and punctate fluorescein staining resolved, whereas in 9 eyes, filaments resolved but punctate fluorescein staining persisted. Three eyes (9%) had partial improvement: 2 residual microfilaments were noted in one eye and 1 in the other eye. In 1 eye, filaments resolved after initial and subsequent injections but recurred within 8 weeks of each injection. Although 14 treated eyes (42%) showed sustained improvement after 1 onabotulinumtoxinA injection, additional injections were necessary in 19 eyes (58%) during the follow-up period because of the recurrence of symptoms and filaments on the cornea. CONCLUSIONS: OnabotulinumtoxinA injection should be considered an effective option for treating refractory filamentary keratitis. Because of the likelihood of recurrence, serial onabotulinumtoxinA injections may be necessary in some cases. PMID- 22491915 TI - Increased risk of anterior uveitis following herpes zoster: a nationwide population-based study. AB - OBJECTIVE: To investigate the relationship between herpes zoster (HZ) and the subsequent risk of anterior uveitis during the year following an HZ diagnosis, using a nationwide population-based data set. METHODS: This study used the Taiwan National Health Insurance Research Database. The study cohort consisted of 314,405 patients who received a diagnosis of HZ. The comparison cohort comprised 943,215 randomly selected patients. We tracked each patient for a 1-year period from their index ambulatory care visit to identify those who subsequently received a diagnosis of anterior uveitis. Stratified Cox proportional hazard regressions were performed to compute the adjusted 1-year uveitis-free survival rate, after adjusting for patient's age, sex, and geographic region and the presence of rheumatoid arthritis, psoriasis, mumps, systemic lupus erythematosus, tuberculosis, ankylosing spondylitis, and human immunodeficiency syndrome/AIDS. RESULTS: During the 1-year follow-up period, 2515 (0.2%) of 1,257,620 sampled patients were diagnosed with anterior uveitis: 908 from the study cohort (0.3% of the patients with HZ) and 1607 from the comparison cohort (0.2% of patients without HZ). After adjusting for potential confounders, the hazard ratio of anterior uveitis during the 1-year follow-up period was 1.67 for patients with HZ (P < .001) compared with the comparison cohort. In addition, the hazard ratio of anterior uveitis for patients with HZ ophthalmicus was 13.06 (P < .001) when compared with patients without HZ. CONCLUSIONS: The risk of anterior uveitis increased in the year following a diagnosis of HZ. We suggest that patient eye condition be evaluated following diagnosis with HZ. PMID- 22491913 TI - Relationship of Fuchs endothelial corneal dystrophy severity to central corneal thickness. AB - OBJECTIVE: To define the relationship between Fuchs endothelial corneal dystrophy (FECD) severity and central corneal thickness (CCT). METHODS: We examined 1610 eyes from a subset of index cases, family members, and unrelated control subjects with normal corneas from the FECD Genetics Multi-Center Study. To estimate the association between FECD severity grade (7-point severity scale based on guttae confluence) and CCT measured by ultrasonographic pachymetry, a multivariable model was used that adjusted for eye, age, race, sex, history of glaucoma or ocular hypertension, diabetes mellitus, contact lens wear, intraocular pressure, and familial relationship to the index case. An interaction between FECD severity grade and edema (stromal or epithelial) on slitlamp examination findings was used to investigate whether the effect of FECD severity grade on CCT differed between those with and without edema. RESULTS: Average CCT was thicker in index cases for all FECD grades compared with unaffected controls (P <= .003) and in affected family members with an FECD grade of 4 or greater compared with unaffected family members (P <= .04). Similar results were observed for subjects without edema. Average CCT of index cases was greater than that of affected family members with grades 4, 5, and 6 FECD (P <= .02). Intraocular pressure was also associated with CCT (P = .01). CONCLUSIONS: An increase in CCT occurs with increasing severity of FECD, including at lower FECD grades in which clinically observable edema is not present. Monitoring CCT changes serially could be a more sensitive measure of disease progression with surgical therapeutic implications. PMID- 22491916 TI - Intravitreal ketorolac for chronic uveitis and macular edema: a pilot study. AB - OBJECTIVE: To investigate the adverse ocular effects of intravitreal ketorolac (4 mg) in patients with chronic uveitis and complications of chronic inflammation (macular edema). METHODS: We conducted a prospective phase 1 clinical trial involving 10 eyes of 10 adult patients with chronic inflammation and/or macular edema for whom previous treatment failed or who could not tolerate corticosteroids because of adverse ocular effects. Baseline (day 0) electroretinography, fluorescein angiogram, spectral domain optical coherence tomography (OCT), Goldmann visual field, and complete ophthalmic examination were performed, and then a single intravitreal injection of ketorolac (4 mg) was administered. Another ophthalmic examination with OCT was performed on day 3. Ophthalmic examination with fluorescein angiogram and OCT was repeated on days 7 and 30, and ophthalmic examination with fluorescein angiogram, OCT, electroretinography, and Goldmann visual field was performed on day 90. The study took place from March 1, 2010, through February 28, 2011. RESULTS: On the basis of ophthalmic examination findings, visual field, and electroretinography testing, there were no observed adverse ocular effects of intravitreal ketorolac. In 2 of 2 eyes with active intraocular inflammation, there was early resolution of inflammation, and in 4 of 8 eyes with macular edema, there appeared to be transient reduction in OCT thickness and/or fluorescein angiogram leakage. CONCLUSION: A single intravitreal injection of ketorolac (4 mg) appeared to be well tolerated. CLINICAL RELEVANCE: Intravitreal ketorolac requires further clinical trials to determine whether it is an effective means to treat posterior segment inflammation as a safer alternative to corticosteroids in patients at increased risk of cataract formation and increased intraocular pressure. PMID- 22491917 TI - Vitreoretinal surgery in the setting of permanent keratoprosthesis. AB - OBJECTIVES: To evaluate the surgical management of vitreoretinal pathology in patients with a permanent Boston Type 1 keratoprosthesis (hereafter referred to as a KPro) in the era of small-gauge vitrectomy techniques. METHODS: Retrospective review of 23 small-gauge vitreoretinal surgical procedures during or after Dohlman-Doane KPro placement in 14 eyes. RESULTS: Established and innovative techniques were used, including sutureless small-gauge vitrectomy, temporal positioning of surgeon, long-term tamponades, and exploratory endoscopy. Retro-KPro membranes formed less frequently when vitrectomy was performed during KPro placement. Anatomical goals were achieved, and no serious complications directly resulted from these techniques. Visual acuity, frequently limited by preexisting pathology, improved in most cases. CONCLUSIONS: Modern posterior segment surgical techniques, including small-gauge sutureless vitrectomy, can be effectively used for patients with a permanent KPro. Vitrectomy and glaucoma tube revision by a team of subspecialists at the time of KPro placement may reduce subsequent complications. PMID- 22491918 TI - Transocular removal of a retrobulbar foreign body and internal patch of the posterior exit wound with autologous tenon capsule. AB - A case of perforating ocular injury with a retrobulbar foreign body and a large full-thickness posterior pole defect near the optic disc was scheduled for vitrectomy after primary corneal suturing. Because it was difficult to remove the retrobulbar foreign body by orbitotomy and perform the outside suture, the retrobulbar foreign body was removed through the posterior hole by a transocular approach, and an autologous Tenon capsule flap was used to internally patch the large full-thickness posterior pole defect, thus enabling silicon tamponade. After 3 months of follow-up, there was no immune response around the patch. The retina remained mostly attached with a maintained peripheral visual field, normal intraocular pressure, and good cosmetic appearance. This surgical technique may be valuable in patients with a perforating retrobulbar foreign body and a large full-thickness posterior pole defect. PMID- 22491919 TI - Comparative effectiveness: insights on treatment options for open-angle glaucoma. PMID- 22491920 TI - The potential role of epigenetics in ocular diseases. PMID- 22491921 TI - Insight into glaucoma treatment in the early 1900s: Harvey Cushing's 1905 operation. AB - Rapid advances in understanding glaucoma occurred following the invention of the ophthalmoscope in the mid-19th century. To our knowledge, attempts by neurosurgeon Harvey Cushing, MD, to cure the condition during his years at Johns Hopkins Hospital have never been previously reported. The Johns Hopkins Hospital surgical records from 1896 through 1912 were reviewed. A case in which Cushing attempted a surgical cure for a patient diagnosed as having glaucoma was selected for review. In 1905, Cushing performed extirpation of the superior cervical ganglion of a patient believed to have chronic glaucoma experiencing an acute episode who had previously underwent bilateral iridectomies. The patient reported stabilization of vision and decreased pain after the procedure. Respected neurosurgeon Cushing undertook surgical treatment of glaucoma at the turn of the 20th century. His approach provides insight into contemporary glaucoma therapies and pathophysiology. PMID- 22491922 TI - Central retinal vascular occlusion associated with acute retinal necrosis. PMID- 22491923 TI - Adaptive optics and spectral- domain optical coherence tomography of human photoreceptor structure after short-duration [corrected] pascal macular grid and panretinal laser photocoagulation. PMID- 22491924 TI - Why visual function does not correlate with optic glioma size or growth. PMID- 22491925 TI - Substance P concentration in human amniotic membrane. PMID- 22491926 TI - Epstein-Barr virus-positive T-cell lymphoma involving the lacrimal gland of an adult. PMID- 22491927 TI - Treatment of congenital cytomegalovirus retinitis with intravitreous ganciclovir. PMID- 22491928 TI - Incidence of cytomegalovirus retinitis in patients with human immunodeficiency virus following negative initial screening examination results. PMID- 22491930 TI - Painful traumatic neuroma after orbital decompression surgery. PMID- 22491929 TI - Cost of selective laser trabeculoplasty vs topical medications for glaucoma. PMID- 22491931 TI - Visual observations of an American patient with Leber hereditary optic neuropathy after purported injections of stem cells in China. PMID- 22491932 TI - Ciliary body clefting accompanied by rupture of the trabecular meshwork in congenital glaucoma. PMID- 22491933 TI - Evaluation of novel renal biomarkers with a cisplatin model of kidney injury: gender and dosage differences. AB - A number of novel urinary biomarkers have been identified and partially qualified for use as markers for renal injury in rats. We use two novel multiplex assays to quantify biomarker concentration in multiple urine collections made prior to and following administration of cisplatin, a common nephrotoxicant, to rats. We investigate the correlation of the magnitude of biomarker changes with the severity of histopathological observations and explore the relationship of these to both dose and sex. The novel biomarkers evaluated are urinary albumin, alpha glutathione s-transferase (alpha-GST), glutathione S-transferase-yb1 (GSTYb1), lipocalin-2, kidney injury molecule-1 (KIM-1), osteopontin, and renal papillary antigen 1 (RPA-1) and plasma cystatin C, alongside the traditional biomarkers of plasma urea, creatinine, and urinary n-acetyl-beta-d-glucosaminidase (NAG), total protein, and glucose. We show for all time points, and for almost all doses, that male rats consistently had either more severely graded or a higher incidence of histologically observed lesions than females; that changes in urinary glucose, total urinary protein, NAG, and the novel urinary biomarkers albumin, osteopontin, and KIM-1 are clearly temporally associated; and that changes are related to the severity of injury. We also found that receiver operating characteristic curve analysis and area under the curve are significantly higher than urea or creatinine for all new biomarkers except aGST, GSTYb1, cystatin c, and total protein in both sexes. PMID- 22491935 TI - Neratinib reverses ATP-binding cassette B1-mediated chemotherapeutic drug resistance in vitro, in vivo, and ex vivo. AB - Neratinib, an irreversible inhibitor of epidermal growth factor receptor and human epidermal receptor 2, is in phase III clinical trials for patients with human epidermal receptor 2-positive, locally advanced or metastatic breast cancer. The objective of this study was to explore the ability of neratinib to reverse tumor multidrug resistance attributable to overexpression of ATP-binding cassette (ABC) transporters. Our results showed that neratinib remarkably enhanced the sensitivity of ABCB1-overexpressing cells to ABCB1 substrates. It is noteworthy that neratinib augmented the effect of chemotherapeutic agents in inhibiting the growth of ABCB1-overexpressing primary leukemia blasts and KBv200 cell xenografts in nude mice. Furthermore, neratinib increased doxorubicin accumulation in ABCB1-overexpressing cell lines and Rhodamine 123 accumulation in ABCB1-overexpressing cell lines and primary leukemia blasts. Neratinib stimulated the ATPase activity of ABCB1 at low concentrations but inhibited it at high concentrations. Likewise, neratinib inhibited the photolabeling of ABCB1 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner (IC(50) = 0.24 MUM). Neither the expression of ABCB1 at the mRNA and protein levels nor the phosphorylation of Akt was affected by neratinib at reversal concentrations. Docking simulation results were consistent with the binding conformation of neratinib within the large cavity of the transmembrane region of ABCB1, which provides computational support for the cross-reactivity of tyrosine kinase inhibitors with human ABCB1. In conclusion, neratinib can reverse ABCB1-mediated multidrug resistance in vitro, ex vivo, and in vivo by inhibiting its transport function. PMID- 22491936 TI - Comment on Rubulotta et al.: Intensive care medicine: finding its way in the "European labyrinth". PMID- 22491938 TI - Seizures in 204 comatose children: incidence and outcome. AB - PURPOSE: Seizures are common in comatose children, but may be clinically subtle or only manifest on continuous electroencephalographic monitoring (cEEG); any association with outcome remains uncertain. METHODS: cEEG (one to three channels) was performed for a median 42 h (range 2-630 h) in 204 unventilated and ventilated children aged <=15 years (18 neonates, 61 infants) in coma with different aetiologies. Outcome at 1 month was independently determined and dichotomized for survivors into favourable (normal or moderate neurological handicap) and unfavourable (severe handicap or vegetative state). RESULTS: Of the 204 patients, 110 had clinical seizures (CS) before cEEG commenced. During cEEG, 74 patients (36%, 95% confidence interval, 95% CI, 32-41%) had electroencephalographic seizures (ES), the majority without clinical accompaniment (non-convulsive seizures, NCS). CS occurred before NCS in 69 of the 204 patients; 5 ventilated with NCS had no CS observed. Death (93/204; 46%) was independently predicted by admission Paediatric Index of Mortality (PIM; adjusted odds ratio, aOR, 1.027, 95% CI 1.012-1.042; p < 0.0005), Adelaide coma score (aOR 0.813, 95% CI 0.700-0.943; p = 0.006), and EEG grade on admission (excess slow with >3% fast, aOR 5.43, 95% CI 1.90-15.6; excess slow with <3% fast, aOR 8.71, 95% CI 2.58-29.4; low amplitude, 10th centile <9 uV, aOR 3.78, 95% CI 1.23-11.7; and burst suppression, aOR 10.68, 95% CI 2.31-49.4) compared with normal cEEG, as well as absence of CS at any time (aOR 2.38, 95% CI 1.18-4.81). Unfavourable outcome (29/111 survivors; 26%) was independently predicted by the presence of ES (aOR 15.4, 95% CI 4.7-49.7) and PIM (aOR 1.036, 95% CI 1.013-1.059). CONCLUSION: Seizures are common in comatose children, and are associated with an unfavourable outcome in survivors. cEEG allows the detection of subtle CS and NCS and is a prognostic tool. PMID- 22491940 TI - Less blood loss with tetrastarch. PMID- 22491942 TI - The effect of erbium family laser on tensile bond strength of composite to dentin in comparison with conventional method. AB - The purpose of this study was to evaluate the effect of Er:YAG and Er,Cr:YSGG laser on tensile bond strength of composite resin to dentine in comparison with bur-prepared cavities. Fifteen extracted caries-free human third molars were selected. The teeth were cut at a level below the occlusal pit and fissure plan and randomly divided into three groups. Five cavities were prepared by diamond bur, five cavities prepared by Er:YAG laser, and the other group prepared by Er,Cr:YSGG laser. Then, all the cavities were restored by composite resin. The teeth were sectioned longitudinally with Isomet and the specimens prepared in dumbbelled shape (n = 36). The samples were attached to special jigs, and the tensile bond strength of the three groups was measured by universal testing machine at a speed of 0.5 mm/min. The results of the three groups were analyzed with one-way ANOVA and Tamhane test. The means and standard deviations of tensile bond strength of bur-cut, Er:YAG laser-ablated, and Er,Cr:YSGG laser-ablated dentine were 5.04 +/- 0.93, 13.37 +/- 3.87, and 4.85 +/- 0.93 MPa, respectively. There is little difference in tensile bond strength of composite resin in Er,Cr:YSGG lased-prepared cavities in comparison with bur-prepared cavities, but the Er:YAG laser group showed higher bond strength than the other groups. PMID- 22491939 TI - Prognostic value of chromogranin A in severe sepsis: data from the FINNSEPSIS study. AB - PURPOSE: To assess the prognostic information of chromogranin A (CgA), a marker associated with adrenergic tone and myocardial function, in patients with severe sepsis. METHODS: CgA levels were measured at the time of study inclusion and 72 h later in 232 patients with severe sepsis recruited from 24 ICUs in Finland (FINNSEPSIS study). RESULTS: Sixty-five patients (28%) died during the index hospitalization. CgA levels at inclusion and after 72 h correlated with several established indices of risk in sepsis. Patients who died during the hospitalization had higher baseline CgA levels than hospital survivors: 14.0 (Q1 3, 7.4-27.4) versus 9.1 (5.9-15.8) nmol/l, P = 0.002, and after 72 h: 16.2 (9.0 31.1) versus 9.8 (6.0-18.0) nmol/l, P = 0.001. Prior cardiovascular disease (P = 0.04) and cardiovascular SOFA levels on day 3 (P = 0.03) were associated with higher CgA levels after 72 h by linear regression. CgA levels on study inclusion and after 72 h were independently associated with hospital mortality by logistic regression: OR (logarithmically transformed CgA levels) 1.95 (95% CI 1.01-3.77), P = 0.046 and OR 2.03 (95% CI 1.18-3.49), P = 0.01, respectively. The prognostic accuracy was comparable for CgA measurements and SAPS II score, and the addition of CgA measurements to the SAPS II score improved risk stratification of the patients as assessed by the category-free net reclassification index. A CgA level >6.6 nmol/l on study inclusion was associated with septic shock during the hospitalization. CONCLUSION: CgA levels measured during hospitalization for severe sepsis are associated with cardiovascular dysfunction and may provide additional prognostic information in patients with severe sepsis. PMID- 22491943 TI - DE-Cadherin regulates unconventional Myosin ID and Myosin IC in Drosophila left right asymmetry establishment. AB - In bilateria, positioning and looping of visceral organs requires proper left right (L/R) asymmetry establishment. Recent work in Drosophila has identified a novel situs inversus gene encoding the unconventional type ID myosin (MyoID). In myoID mutant flies, the L/R axis is inverted, causing reversed looping of organs, such as the gut, spermiduct and genitalia. We have previously shown that MyoID interacts physically with beta-Catenin, suggesting a role of the adherens junction in Drosophila L/R asymmetry. Here, we show that DE-Cadherin co immunoprecipitates with MyoID and is required for MyoID L/R activity. We further demonstrate that MyoIC, a closely related unconventional type I myosin, can antagonize MyoID L/R activity by preventing its binding to adherens junction components, both in vitro and in vivo. Interestingly, DE-Cadherin inhibits MyoIC, providing a protective mechanism to MyoID function. Conditional genetic experiments indicate that DE-Cadherin, MyoIC and MyoID show temporal synchronicity for their function in L/R asymmetry. These data suggest that following MyoID recruitment by beta-Catenin at the adherens junction, DE-Cadherin has a twofold effect on Drosophila L/R asymmetry by promoting MyoID activity and repressing that of MyoIC. Interestingly, the product of the vertebrate situs inversus gene inversin also physically interacts with beta-Catenin, suggesting that the adherens junction might serve as a conserved platform for determinants to establish L/R asymmetry both in vertebrates and invertebrates. PMID- 22491944 TI - Post-translational modification of Ngn2 differentially affects transcription of distinct targets to regulate the balance between progenitor maintenance and differentiation. AB - Neurogenin 2 (Ngn2) controls neuronal differentiation cell-autonomously by transcriptional activation of targets such as NeuroD, while simultaneously controlling progenitor maintenance non-cell-autonomously by upregulating Delta expression and Notch signalling. Reduction in Cdk-dependent multisite phosphorylation of Ngn2 enhances its promoter binding affinity. This leads specifically to an increase in neuronal differentiation without an apparent increase in progenitor maintenance via Delta-Notch signalling, although the mechanism underlying this imbalance remains unclear. Here we show in Xenopus embryos and mouse P19 cells that the NeuroD promoter is substantially more sensitive to the phosphorylation status of Ngn2 than the Delta promoter, and that this can be attributed to differences in the ease of promoter activation. In addition, we also show that the phosphorylation status of Ngn2 regulates sensitivity to Notch signalling. These observations explain how Ngn2 post translational modification in response to changes in the cell cycle kinase environment results in enhanced neuronal differentiation upon cell cycle lengthening. PMID- 22491945 TI - Bcl11a is required for neuronal morphogenesis and sensory circuit formation in dorsal spinal cord development. AB - Dorsal spinal cord neurons receive and integrate somatosensory information provided by neurons located in dorsal root ganglia. Here we demonstrate that dorsal spinal neurons require the Kruppel-C(2)H(2) zinc-finger transcription factor Bcl11a for terminal differentiation and morphogenesis. The disrupted differentiation of dorsal spinal neurons observed in Bcl11a mutant mice interferes with their correct innervation by cutaneous sensory neurons. To understand the mechanism underlying the innervation deficit, we characterized changes in gene expression in the dorsal horn of Bcl11a mutants and identified dysregulated expression of the gene encoding secreted frizzled-related protein 3 (sFRP3, or Frzb). Frzb mutant mice show a deficit in the innervation of the spinal cord, suggesting that the dysregulated expression of Frzb can account in part for the phenotype of Bcl11a mutants. Thus, our genetic analysis of Bcl11a reveals essential functions of this transcription factor in neuronal morphogenesis and sensory wiring of the dorsal spinal cord and identifies Frzb, a component of the Wnt pathway, as a downstream acting molecule involved in this process. PMID- 22491946 TI - A new asymmetric division contributes to the continuous production of infective trypanosomes in the tsetse fly. AB - African trypanosomes are flagellated protozoan parasites that cause sleeping sickness and are transmitted by the bite of the tsetse fly. To complete their life cycle in the insect, trypanosomes reach the salivary glands and transform into the metacyclic infective form. The latter are expelled with the saliva at each blood meal during the whole life of the insect. Here, we reveal a means by which the continuous production of infective parasites could be ensured. Dividing trypanosomes present in the salivary glands of infected tsetse flies were monitored by live video-microscopy and by quantitative immunofluorescence analysis using molecular markers for the cytoskeleton and for surface antigens. This revealed the existence of two distinct modes of trypanosome proliferation occurring simultaneously in the salivary glands. The first cycle produces two equivalent cells that are not competent for infection and are attached to the epithelium. This mode of proliferation is predominant at the early steps of infection, ensuring a rapid colonization of the glands. The second mode is more frequent at later stages of infection and involves an asymmetric division. It produces a daughter cell that matures into the infective metacyclic form that is released in the saliva, as demonstrated by the expression of specific molecular markers - the calflagins. The levels of these calcium-binding proteins increase exclusively in the new flagellum during the asymmetric division, showing the commitment of the future daughter cell to differentiation. The coordination of these two alternative cell cycles contributes to the continuous production of infective parasites, turning the tsetse fly into an efficient and long-lasting vector for African trypanosomes. PMID- 22491947 TI - FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5 and Bcl6b through MAP2K1 activation. AB - Fibroblast growth factor 2 (FGF2) and glial cell line-derived neurotrophic factor (GDNF) are required to recapitulate spermatogonial stem cell (SSC) self-renewal in vitro. Although studies have revealed the role of the GDNF signaling pathway in SSCs, little is known about how FGF2 is involved. In the present study, we assessed the role of the FGF2 signaling pathway using a mouse germline stem (GS) cell culture system that allows in vitro expansion of SSCs. Adding GDNF or FGF2 induced phosphorylation of MAPK1/3, and adding the MAP2K1 inhibitor PD0325091 reduced GS cell proliferation and MAPK1/3 phosphorylation. Moreover, GS cells transfected with an activated form of Map2k1 not only upregulated Etv5 and Bcl6b gene expression, but also proliferated in an FGF2-independent manner, suggesting that they act downstream of MAP2K1 signaling to drive SSC self-renewal. Although GS cells transfected with Map2k1, Etv5 or Bcl6b showed normal spermatogonial markers, transplanting GS cells expressing Bcl6b into infertile mouse testes resulted in the formation of a germ cell tumor, suggesting that excessive self renewal signals causes tumorigenic conversion. These results show that FGF2 depends on MAP2K1 signaling to drive SSC self-renewal via upregulation of the Etv5 and Bcl6b genes. PMID- 22491948 TI - ADITEC: joining forces for next-generation vaccines. AB - Scientists sit poised at a singular moment in the history of vaccine research. Genomics and systems biology have fueled advances in our understanding of human immunology. Together with adjuvant development and structure-based design of immunogens, these next-generation technologies are transforming the field of vaccinology and shaping the future of medicine. However, the sophisticated science behind the development of modern vaccines and the resulting knotty ethical issues have become so complex that scientists and policy-makers need a new model for vaccine research. The European Commission-sponsored Advanced Immunization Technologies project--ADITEC--brings together some of the leading laboratories in the field to tackle the problems that no lab can tackle in isolation. PMID- 22491949 TI - Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. AB - We describe the development and clinical translation of a targeted polymeric nanoparticle (TNP) containing the chemotherapeutic docetaxel (DTXL) for the treatment of patients with solid tumors. DTXL-TNP is targeted to prostate specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors. DTXL-TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading, and drug release properties. Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half-life of about 20 hours and minimal liver accumulation. In tumor-bearing mice, DTXL-TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent-based DTXL formulation (sb-DTXL). In tumor-bearing mice, rats, and nonhuman primates, DTXL TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL, with total DTXL plasma concentrations remaining at least 100-fold higher than sb DTXL for more than 24 hours. Finally, initial clinical data in patients with advanced solid tumors indicated that DTXL-TNP displays a pharmacological profile differentiated from sb-DTXL, including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb-DTXL dose typically used in the clinic. PMID- 22491950 TI - A noncoding RNA antisense to moesin at 5p14.1 in autism. AB - People with autism spectrum disorder (ASD) are characterized by deficits in social interaction, language, and behavioral flexibility. Rare mutations and copy number variations have been identified in individuals with ASD, but in most patients, the causal variants remain unknown. A genome-wide association study (GWAS), designed to identify genes and pathways that contribute to ASD, indicated a genome-wide significant association of ASD with the single-nucleotide polymorphism (SNP) rs4307059 (P = 10-10), which is located in a gene-poor region of chromosome 5p14.1. We describe here a 3.9-kb noncoding RNA that is transcribed from the region of the chromosome 5p14.1 ASD GWAS association SNP. The noncoding RNA was encoded by the opposite (antisense) strand of moesin pseudogene 1 (MSNP1), and we therefore designated it as MSNP1AS (moesin pseudogene 1, antisense). Chromosome 5p14.1 MSNP1AS was 94% identical and antisense to the X chromosome transcript of MSN, which encodes a protein (moesin) that regulates neuronal architecture. Individuals who carry the ASD-associated rs4307059 T allele showed increased expression of MSNP1AS. The MSNP1AS noncoding RNA bound to MSN, was highly overexpressed (12.7-fold) in postmortem cerebral cortex of individuals with ASD, and could regulate levels of moesin protein in human cell lines. These data reveal a biologically functional element that may contribute to ASD risk. PMID- 22491951 TI - Serotonin neuron loss and nonmotor symptoms continue in Parkinson's patients treated with dopamine grafts. AB - Cell therapy studies in patients with Parkinson's disease (PD) have been confined to intrastriatal transplantation of dopamine-rich fetal mesencephalic tissue in efforts to improve motor performance. Although some PD patients receiving the dopamine-rich grafts showed improvements in motor symptoms due to replacement of dopaminergic neurons, they still suffered from nonmotor symptoms including depression, fatigue, visual hallucinations, and sleep problems. Using functional imaging and clinical evaluation of motor and nonmotor symptoms in three PD patients transplanted with intrastriatal fetal grafts 13 to 16 years previously, we assessed whether reestablishment of dopaminergic neuronal networks is sufficient to improve a broad range of symptoms. At 13 to 16 years after transplantation, dopaminergic innervation was restored to normal levels in basal ganglia and preserved in a number of extrabasal ganglia areas. These changes were associated with long-lasting relief of motor symptoms. Then, we assessed the integrity of their serotonergic and norepinephrine neuronal systems using [11C]DASB {[11C]3-amino-4-(2-dimethylaminomethylphenylthio) benzonitrile} positron emission tomography (PET) and 18F-dopa PET, respectively. 18F-dopa uptake in the locus coeruleus was within the normal range. In contrast, [11C]DASB uptake in the raphe nuclei and regions receiving serotonergic projections was markedly reduced. These results indicate ongoing degeneration of serotonergic raphe nuclei and their projections to regions involved in the regulation of sleep, arousal, feeding, satiety, mood, and emotion. Our findings indicate that future cell-based therapies using fetal tissue or stem cells in PD patients may require additional grafts of serotonergic neurons to relieve nonmotor symptoms by restoring serotonergic neurotransmission in specific cerebral targets. PMID- 22491952 TI - T cell receptor alphabeta diversity inversely correlates with pathogen-specific antibody levels in human cytomegalovirus infection. AB - A diverse T cell receptor (TCR) repertoire capable of recognizing a broad range of antigenic peptides is thought to be central to effective pathogen-specific immunity by counteracting escape mutations, selecting high-avidity T cells, and providing T cell specificities with comprehensive functional characteristics. However, evidence that TCR diversity is important for the successful control of human infections is limited. A single-cell strategy for the clonotypic analysis of human CD8+ TCRalphabeta repertoires was used to probe the diversity and magnitude of individual human cytomegalovirus (CMV)-specific CD8+ T cells recovered directly ex vivo. We found that CD8+ TCRalphabeta repertoire diversity, but not the size of the CD8+ T cell response, was inversely related to circulating CMV-specific antibody levels, a measure that has been correlated epidemiologically with differential mortality risks and found here to be higher in persons with detectable (versus undetectable) CMV viral loads. Overall, our findings indicate that CD8+ T cell diversity may be more important than T cell abundance in limiting the negative consequences of CMV persistence, demonstrate high prevalence of both TCRalpha and TCRbeta public motif usage, and suggest that a highly diverse TCRalphabeta repertoire may be an important benchmark and target in the success of immunotherapeutic strategies. PMID- 22491953 TI - Lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study. AB - OBJECTIVE: To evaluate the association of volume limited and pressure limited (lung protective) mechanical ventilation with two year survival in patients with acute lung injury. DESIGN: Prospective cohort study. SETTING: 13 intensive care units at four hospitals in Baltimore, Maryland, USA. PARTICIPANTS: 485 consecutive mechanically ventilated patients with acute lung injury. MAIN OUTCOME MEASURE: Two year survival after onset of acute lung injury. RESULTS: 485 patients contributed data for 6240 eligible ventilator settings, as measured twice daily (median of eight eligible ventilator settings per patient; 41% of which adhered to lung protective ventilation). Of these patients, 311 (64%) died within two years. After adjusting for the total duration of ventilation and other relevant covariates, each additional ventilator setting adherent to lung protective ventilation was associated with a 3% decrease in the risk of mortality over two years (hazard ratio 0.97, 95% confidence interval 0.95 to 0.99, P=0.002). Compared with no adherence, the estimated absolute risk reduction in two year mortality for a prototypical patient with 50% adherence to lung protective ventilation was 4.0% (0.8% to 7.2%, P=0.012) and with 100% adherence was 7.8% (1.6% to 14.0%, P=0.011). CONCLUSIONS: Lung protective mechanical ventilation was associated with a substantial long term survival benefit for patients with acute lung injury. Greater use of lung protective ventilation in routine clinical practice could reduce long term mortality in patients with acute lung injury. TRIAL REGISTRATION: Clinicaltrials.gov NCT00300248. PMID- 22491954 TI - Interpreting and investigating proteinuria. PMID- 22491955 TI - How collaboration is providing new drugs for neglected diseases. PMID- 22491956 TI - Lung protective ventilation. PMID- 22491957 TI - Guidelines mean that you can have a DIY assisted suicide, but not a professional one. PMID- 22491958 TI - Fertility regulator tells clinics to treat egg and sperm donors better to boost numbers. PMID- 22491959 TI - Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. AB - Multiple system atrophy (MSA) is a progressive late onset neurodegenerative alpha synucleinopathy with unclear pathogenesis. Recent genetic and pathological studies support a central role of alpha-synuclein (alphaSYN) in MSA pathogenesis. Oligodendroglial cytoplasmic inclusions of fibrillar alphaSYN and dysfunction of the ubiquitin-proteasome system are suggestive of proteolytic stress in this disorder. To address the possible pathogenic role of oligodendroglial alphaSYN accumulation and proteolytic failure in MSA we applied systemic proteasome inhibition (PSI) in transgenic mice with oligodendroglial human alphaSYN expression and determined the presence of MSA-like neurodegeneration in this model as compared to wild-type mice. PSI induced open field motor disability in transgenic alphaSYN mice but not in wild-type mice. The motor phenotype corresponded to progressive and selective neuronal loss in the striatonigral and olivopontocerebellar systems of PSI-treated transgenic alphaSYN mice. In contrast no neurodegeneration was detected in PSI-treated wild-type controls. PSI treatment of transgenic alphaSYN mice was associated with significant ultrastructural alterations including accumulation of fibrillar human alphaSYN in the cytoplasm of oligodendroglia, which resulted in myelin disruption and demyelination characterized by increased g-ratio. The oligodendroglial and myelin pathology was accompanied by axonal degeneration evidenced by signs of mitochondrial stress and dysfunctional axonal transport in the affected neurites. In summary, we provide new evidence supporting a primary role of proteolytic failure and suggesting a neurodegenerative pathomechanism related to disturbed oligodendroglial/myelin trophic support in the pathogenesis of MSA. PMID- 22491960 TI - The evolution of eProtocols that enable reproducible clinical research and care methods. AB - Unnecessary variation in clinical care and clinical research reduces our ability to determine what healthcare interventions are effective. Reducing this unnecessary variation could lead to further healthcare quality improvement and more effective clinical research. We have developed and used electronic decision support tools (eProtocols) to reduce unnecessary variation. Our eProtocols have progressed from a locally developed mainframe computer application in one clinical site (LDS Hospital) to web-based applications available in multiple languages and used internationally. We use eProtocol-insulin as an example to illustrate this evolution. We initially developed eProtocol-insulin as a local quality improvement effort to manage stress hyperglycemia in the adult intensive care unit (ICU). We extended eProtocol-insulin use to translate our quality improvement results into usual clinical care at Intermountain Healthcare ICUs. We exported eProtocol-insulin to support research in other US and international institutions, and extended our work to the pediatric ICU. We iteratively refined eProtocol-insulin throughout these transitions, and incorporated new knowledge about managing stress hyperglycemia in the ICU. Based on our experience in the development and clinical use of eProtocols, we outline remaining challenges to eProtocol development, widespread distribution and use, and suggest a process for eProtocol development. Technical and regulatory issues, as well as standardization of protocol development, validation and maintenance, need to be addressed. Resolution of these issues should facilitate general use of eProtocols to improve patient care. PMID- 22491961 TI - Visual estimation of pulse pressure variation is not reliable: a randomized simulation study. AB - Pulse pressure variation (PPV) can be monitored several ways, but according to recent survey data it is most often visually estimated ("eyeballed") by practitioners. It is not known how accurate visual estimation of PPV is, or whether eyeballing of PPV in goal-directed fluid therapy studies may limit the ability to blind the control group to PPV value. The goal of this study was to test the accuracy of visual estimation of PPV. Using a simulator program designed by the authors that runs on a PC, 20 residents and 19 attendings were shown five arterial pressure waveforms each with different PPV values (range 1-30 %) moving at one of three sweep speeds (6.25, 12.5, or 25 mm/s) and asked to determine the PPV. There was a weak but significant relationship between true PPV and eyeball PPV (r (2) = 0.22; p < 0.01). The agreement between true PPV and eyeball PPV was 3.3 +/- 8.7 %. The mean percent error was 122 %. The rate of correct response group classification was 65 %. Mean percent error was higher the faster the waveform sweep speed (130 % at 25 mm/s vs. 117 % at 6.25 mm/s), and correct responsiveness classification lower (58 % at 25 mm/s vs. 69 % at 6.25 mm/s). The results from this study show that eyeballing the arterial pressure waveform in order to evaluate pulse pressure variation is not accurate. PMID- 22491962 TI - A nonparametric approach for determining significance of county cancer rates compared to the overall state rate: illustrated with Minnesota data. AB - BACKGROUND: The study of the geographical distribution of disease has expanded greatly with GIS technology and its application to increasingly available public health data. The emergence of this technology has increased the challenges for public health practitioners to provide meaningful interpretations for county based state cancer maps. METHODS: One of these challenges-spurious inferences about the significance of differences between county and overall state cancer rates-can be addressed through a nonparametric statistical method. The Wilcoxon's signed rank test (WSRT) has a practical application for determining the significance of county cancer rates compared to the statewide rate. This extension of the WSRT, developed by John Tukey, forms the basis for constructing a single confidence interval for all differences in county and state directly age adjusted cancer rates. Empirical evaluation of this WSRT application was conducted using Minnesota cancer incidence data. RESULTS: The WSRT procedure reduced the impact of statistical artifacts that are frequently encountered with standard normal significance testing of the difference between directly age adjusted county and the overall state cancer rates. CONCLUSION: Although further assessment of its performance is required, the WSRT procedure appears to be a useful complement for mapping directly age-adjusted state cancer rates by county. PMID- 22491963 TI - Treating ADHD with agomelatine. AB - OBJECTIVE: Agomelatine is a relatively new antidepressant, with affinities to MT1 and MT2 (responsible for the circadian rhythm) as well as to 5-HT2C receptors. Since antidepressants have demonstrated some benefit in the treatment of ADH and because of the fact, that ADHD is often associated with sleep disorders, we assumed, that it might be a therapeutic alternative also for ADHD. METHOD: We proved this assumption in ten ADHD patients in a placebo controlled manner. RESULTS: Agomelatine's effect was superior to that of placebo, but seems to be less than that of Methylphenidate or placebo. CONCLUSION: If ADHD therapy with Methylphenidate or Atomoxetine is not indicated e.g. because of adverse side effects and if an ADHD patient suffers from additional sleep disorders, Agomelatine might be a helpful therapeutic alternative. PMID- 22491964 TI - From the editors' desk: Why NCATS should read this issue of JGIM. PMID- 22491966 TI - Response to debate on the self-report habit index. PMID- 22491967 TI - Differential effects of Bcl-2 and caspases on mitochondrial permeabilization during endogenous or exogenous reactive oxygen species-induced cell death: a comparative study of H2O2, paraquat, t-BHP, etoposide and TNF-alpha-induced cell death. AB - In this study, we have compared several features of cell death triggered by classical inducers of apoptotic pathways (etoposide and tumour necrosis factor (TNF)-alpha) versus exogenous reactive oxygen species (ROS; hydrogen peroxide (H2O2), tert-butyl hydroperoxide (t-BHP)) or a ROS generator (paraquat). Our aim was to characterize relationships that exist between ROS, mitochondrial perturbations, Bcl-2 and caspases, depending on source and identity of ROS. First, we have found that these five inducers trigger oxidative stress, mitochondrial membrane permeabilization (MMP), cytochrome c (cyt c) release from mitochondria and cell death. In each case, cell death could be inhibited by several antioxidants, showing that it is primarily ROS dependent. Second, we have highlighted that during etoposide or TNF-alpha treatments, intracellular ROS level, MMP and cell death are all regulated by caspases and Bcl-2, with caspases acting early in the process. Third, we have demonstrated that H2O2-induced cell death shares many of these characteristics with etoposide and TNF-alpha, whereas t-BHP induces both caspase-dependent and caspase-independent cell death. Surprisingly, paraquat-induced cell death, which harbours some characteristics of apoptosis such as cyt c release and caspase-3 activation, is not modulated by Bcl 2 and caspase inhibitors, suggesting that paraquat also triggers non-apoptotic cell death signals. On the one hand, these results show that endogenous or exogenous ROS can trigger multiple cell death pathways with Bcl-2 and caspases acting differentially. On the other hand, they suggest that H2O2 could be an important mediator of etoposide and TNF-alpha-dependent cell death since these inducers trigger similar phenotypes. PMID- 22491968 TI - Correlation of low back pain caused by lumbar spinal stenosis and depression in women: a clinical study. AB - OBJECTIVE: Low back pain (LBP) due to spinal stenosis may be one of the most debilitating symptoms to decrease the quality of life. The cause and effect association of LBP and depression is vague. Pain may also be a somatization symptom of depression. This is more frequent in the female population. This clinical study was designed to evaluate the correlation between the level of back pain caused by lumbar spinal stenosis and depression in the female population. METHOD: The study included 50 consecutive female patients with spinal stenosis. The stenosis diagnosis is made by neurological examination and neuro-imaging. The study group was psychiatrically evaluated and grouped as those with and without depression. Visual analog scale (VAS), Oswestry disability index (ODI) and Hamilton Depression Scale (HDS) were utilized in initial evaluation of the group. RESULTS: Twenty-one patients with lumbar spinal stenosis had depression (DLS Group) and 29 did not (LSS Group). Mean HDS scores were 8.97 and 32.48 for Group LSS and Group DLS, respectively. There was a statistically significant difference between the VAS scores of the groups (the mean VAS scores were 5.6 and 7.6, for groups LSS and DLS, respectively). The mean ODI values for LSS (65.24 +/- 4.58) and DLS (75.1 +/- 6.7) groups were also significantly different. In Group DLS, there were positive correlations between ODI and VAS with HDS (p < 0.001). CONCLUSION: Our findings indicated a relationship between lumbar spinal stenosis associated pain levels and depression. However, the cause and result relationship still needs to be established yet. PMID- 22491965 TI - Aging, atherosclerosis, and IGF-1. AB - Insulin-like growth factor 1 (IGF-1) is an endocrine and autocrine/paracrine growth factor that circulates at high levels in the plasma and is expressed in most cell types. IGF-1 has major effects on development, cell growth and differentiation, and tissue repair. Recent evidence indicates that IGF-1 reduces atherosclerosis burden and improves features of atherosclerotic plaque stability in animal models. Potential mechanisms for this atheroprotective effect include IGF-1-induced reduction in oxidative stress, cell apoptosis, proinflammatory signaling, and endothelial dysfunction. Aging is associated with increased vascular oxidative stress and vascular disease, suggesting that IGF-1 may exert salutary effects on vascular aging processes. In this review, we will provide a comprehensive update on IGF-1's ability to modulate vascular oxidative stress and to limit atherogenesis and the vascular complications of aging. PMID- 22491969 TI - You want to do what? My mother's choice to have direct-to-consumer genetic testing. AB - As a genetic counselor, I had mixed opinions when my mother told me of her intent to undergo genomewide, SNP-based direct-to-consumer (DTC) genetic testing. I cautioned her that results could be misleading, could increase anxiety and were often of limited clinical validity or utility. I warned of the possibility of learning unintended health information and expressed concerns about how the information might be used by a private company. I told her about the variability in results among companies. Yet, she persisted in her desire, reminding me that she was an informed consumer. After reviewing her goals and understanding of the information she might receive, she elected to proceed. Despite my insistence that I would not be her personal genetic counselor, when the results came back, I found myself immersed in her genetic data. In this manuscript, I will examine how this personal experience challenged my perceptions of DTC testing. PMID- 22491970 TI - Child maltreatment research, policy, and practice for the next decade. Highlights from an Institute of Medicine/National Research Council workshop. PMID- 22491971 TI - Identifying domestic and international sex-trafficking victims during human service provision. AB - Children, youth, and adults of both genders are sex trafficked into and throughout the United States every day. Regrettably, little attention has been given to how human service providers might identify the sex-trafficking victims they are likely to encounter. To address this knowledge gap, the authors review 20 documents with the aim of detecting and synthesizing service identification recommendations in the scientific literature, government reports, and documents produced by organizations working with sex-trafficking victims. The review shows consensus regarding identification recommendations, including (a) trafficking indicators, (b) victim interaction strategies, (c) immediate response strategies, and (d) child-specific information. The review also shows consensus regarding screening questions that are important for service providers to use in identifying sex-trafficking victims. These questions relate to the victims' safety, employment, living environment, and travel and immigration status in addition to specific questions used with children and youth. The review results offer human service providers a preliminary set of screening strategies and questions that can be used to identify sex-trafficking victims in the context of human services. Building on the review findings, the authors offer policy and research recommendations. PMID- 22491972 TI - Synchrotron-based dynamic computed tomography of tissue motion for regional lung function measurement. AB - During breathing, lung inflation is a dynamic process involving a balance of mechanical factors, including trans-pulmonary pressure gradients, tissue compliance and airway resistance. Current techniques lack the capacity for dynamic measurement of ventilation in vivo at sufficient spatial and temporal resolution to allow the spatio-temporal patterns of ventilation to be precisely defined. As a result, little is known of the regional dynamics of lung inflation, in either health or disease. Using fast synchrotron-based imaging (up to 60 frames s(-1)), we have combined dynamic computed tomography (CT) with cross correlation velocimetry to measure regional time constants and expansion within the mammalian lung in vivo. Additionally, our new technique provides estimation of the airflow distribution throughout the bronchial tree during the ventilation cycle. Measurements of lung expansion and airflow in mice and rabbit pups are shown to agree with independent measures. The ability to measure lung function at a regional level will provide invaluable information for studies into normal and pathological lung dynamics, and may provide new pathways for diagnosis of regional lung diseases. Although proof-of-concept data were acquired on a synchrotron, the methodology developed potentially lends itself to clinical CT scanning and therefore offers translational research opportunities. PMID- 22491973 TI - Identification of intermittent control in man and machine. AB - Regulation by negative feedback is fundamental to engineering and biological processes. Biological regulation is usually explained using continuous feedback models from both classical and modern control theory. An alternative control paradigm, intermittent control, has also been suggested as a model for biological control systems, particularly those involving the central nervous system. However, at present, there is no identification method explicitly formulated to distinguish intermittent from continuous control; here, we present such a method. The identification experiment uses a special paired-step set-point sequence. The corresponding data analysis use a conventional ARMA model to relate a theoretically derived equivalent set-point to control signal; the novelty lies in sequentially and iteratively adjusting the timing of the steps of this equivalent set-point to optimize the linear time-invariant fit. The method was verified using realistic simulation data and was found to robustly distinguish not only between continuous and intermittent control but also between event-driven intermittent and clock-driven intermittent control. When applied to human pursuit tracking, event-driven intermittent control was identified, with an intermittent interval of 260-310 ms (n = 6, p < 0.05). This new identification method is applicable for machine and biological applications. PMID- 22491974 TI - Effect of solid surface charge on the binding behaviour of a metal-binding peptide. AB - Over the last decade, solid-binding peptides have been increasingly used as molecular building blocks coupling bio- and nanotechnology. Despite considerable research being invested in this field, the effects of many surface-related parameters that define the binding of peptide to solids are still unknown. In the quest to control biological molecules at solid interfaces and, thereby, tailoring the binding characteristics of the peptides, the use of surface charge of the solid surface may probably play an important role, which then can be used as a potential tuning parameter of peptide adsorption. Here, we report quantitative investigation on the viscoelastic properties and binding kinetics of an engineered gold-binding peptide, 3RGBP(1), adsorbed onto the gold surface at different surface charge densities. The experiments were performed in aqueous solutions using an electrochemical dissipative quartz crystal microbalance system. Hydrodynamic mass, hydration state and surface coverage of the adsorbed peptide films were determined as a function of surface charge density of the gold metal substrate. Under each charged condition, binding of 3rGBP(1) displayed quantitative differences in terms of adsorbed peptide amount, surface coverage ratio and hydration state. Based on the intrinsically disordered structure of the peptide, we propose a possible mechanism for binding of the peptide that can be used for tuning surface adsorption in further studies. Controlled alteration of peptide binding on solid surfaces, as shown here, may provide novel methods for surface functionalization used for bioenabled processing and fabrication of future micro- and nanodevices. PMID- 22491975 TI - Importance of initial aortic properties on the evolving regional anisotropy, stiffness and wall thickness of human abdominal aortic aneurysms. AB - Complementary advances in medical imaging, vascular biology and biomechanics promise to enable computational modelling of abdominal aortic aneurysms to play increasingly important roles in clinical decision processes. Using a finite element-based growth and remodelling model of evolving aneurysm geometry and material properties, we show that regional variations in material anisotropy, stiffness and wall thickness should be expected to arise naturally and thus should be included in analyses of aneurysmal enlargement or wall stress. In addition, by initiating the model from best-fit material parameters estimated for non-aneurysmal aortas from different subjects, we show that the initial state of the aorta may influence strongly the subsequent rate of enlargement, wall thickness, mechanical behaviour and thus stress in the lesion. We submit, therefore, that clinically reliable modelling of the enlargement and overall rupture-potential of aneurysms may require both a better understanding of the mechanobiological processes that govern the evolution of these lesions and new methods of determining the patient-specific state of the pre-aneurysmal aorta (or correlation to currently unaffected portions thereof) through knowledge of demographics, comorbidities, lifestyle, genetics and future non-invasive or minimally invasive tests. PMID- 22491976 TI - A methodology for global-sensitivity analysis of time-dependent outputs in systems biology modelling. AB - One of the main challenges in the development of mathematical and computational models of biological systems is the precise estimation of parameter values. Understanding the effects of uncertainties in parameter values on model behaviour is crucial to the successful use of these models. Global sensitivity analysis (SA) can be used to quantify the variability in model predictions resulting from the uncertainty in multiple parameters and to shed light on the biological mechanisms driving system behaviour. We present a new methodology for global SA in systems biology which is computationally efficient and can be used to identify the key parameters and their interactions which drive the dynamic behaviour of a complex biological model. The approach combines functional principal component analysis with established global SA techniques. The methodology is applied to a model of the insulin signalling pathway, defects of which are a major cause of type 2 diabetes and a number of key features of the system are identified. PMID- 22491977 TI - Single and mixed poloxamine micelles as nanocarriers for solubilization and sustained release of ethoxzolamide for topical glaucoma therapy. AB - Polymeric micelles of single and mixed poloxamines (Tetronic) were evaluated regarding their ability to host the antiglaucoma agent ethoxzolamide (ETOX) for topical ocular application. Three highly hydrophilic varieties of poloxamine (T908, T1107 and T1307) and a medium hydrophilic variety (T904), possessing a similar number of propylene oxide units but different contents in ethylene oxide, were chosen for the study. The critical micellar concentration and the cloud point of mixed micelles in 0.9 per cent NaCl were slightly greater than the values predicted from the additive rule, suggesting that the co-micellization is hindered. Micellar size ranged between 17 and 120 nm and it was not altered after the loading of ETOX (2.7-11.5 mg drug g(-1) poloxamine). Drug solubilization ability ranked in the order: T904 (50-fold increase in the apparent solubility) > T1107 is approximately equal to T1307 > T908. Mixed micelles showed an intermediate capability to host ETOX but a greater physical stability, maintaining almost 100 per cent drug solubilized after 28 days. Furthermore, the different structural features of poloxamines and their combination in mixed micelles enabled the tuning of drug release profiles, sustaining the release in the 1-5 days range. These findings together with promising hen's egg test chorioallantoic membrane biocompatibility tests make poloxamine micelles promising nanocarriers for carbonic anhydrase inhibitors in the treatment of glaucoma. PMID- 22491978 TI - Energetically optimal running requires torques about the centre of mass. AB - Bipedal animals experience ground reaction forces (GRFs) that pass close to the centre of mass (CoM) throughout stance, first decelerating the body, then re accelerating it during the second half of stance. This results in fluctuations in kinetic energy, requiring mechanical work from the muscles. However, here we show analytically that, in extreme cases (with a very large body pitch moment of inertia), continuous alignment of the GRF through the CoM requires greater mechanical work than a maintained vertical force; we show numerically that GRFs passing between CoM and vertical throughout stance are energetically favourable under realistic conditions; and demonstrate that the magnitude, if not the precise form, of actual CoM-torque profiles in running is broadly consistent with simple mechanical work minimization for humans with appropriate pitch moment of inertia. While the potential energetic savings of CoM-torque support strategies are small (a few per cent) over the range of human running, their importance increases dramatically at high speeds and stance angles. Fast, compliant runners or hoppers would benefit considerably from GRFs more vertical than the zero-CoM torque strategy, especially with bodies of high pitch moment of inertia- suggesting a novel advantage to kangaroos of their peculiar long-head/long-tail structure. PMID- 22491979 TI - Quantitative three-dimensional microtextural analyses of tooth wear as a tool for dietary discrimination in fishes. AB - Resource polymorphisms and competition for resources are significant factors in speciation. Many examples come from fishes, and cichlids are of particular importance because of their role as model organisms at the interface of ecology, development, genetics and evolution. However, analysis of trophic resource use in fishes can be difficult and time-consuming, and for fossil fish species it is particularly problematic. Here, we present evidence from cichlids that analysis of tooth microwear based on high-resolution (sub-micrometre scale) three dimensional data and new ISO standards for quantification of surface textures provides a powerful tool for dietary discrimination and investigation of trophic resource exploitation. Our results suggest that three-dimensional approaches to analysis offer significant advantages over two-dimensional operator-scored methods of microwear analysis, including applicability to rough tooth surfaces that lack distinct scratches and pits. Tooth microwear textures develop over a longer period of time than is represented by stomach contents, and analyses based on textures are less prone to biases introduced by opportunistic feeding. They are more sensitive to subtle dietary differences than isotopic analysis. Quantitative textural analysis of tooth microwear has a useful role to play, complementing existing approaches, in trophic analysis of fishes-both extant and extinct. PMID- 22491980 TI - Floquet stability analysis of the longitudinal dynamics of two hovering model insects. AB - Because of the periodically varying aerodynamic and inertial forces of the flapping wings, a hovering or constant-speed flying insect is a cyclically forcing system, and, generally, the flight is not in a fixed-point equilibrium, but in a cyclic-motion equilibrium. Current stability theory of insect flight is based on the averaged model and treats the flight as a fixed-point equilibrium. In the present study, we treated the flight as a cyclic-motion equilibrium and used the Floquet theory to analyse the longitudinal stability of insect flight. Two hovering model insects were considered-a dronefly and a hawkmoth. The former had relatively high wingbeat frequency and small wing-mass to body-mass ratio, and hence very small amplitude of body oscillation; while the latter had relatively low wingbeat frequency and large wing-mass to body-mass ratio, and hence relatively large amplitude of body oscillation. For comparison, analysis using the averaged-model theory (fixed-point stability analysis) was also made. Results of both the cyclic-motion stability analysis and the fixed-point stability analysis were tested by numerical simulation using complete equations of motion coupled with the Navier-Stokes equations. The Floquet theory (cyclic motion stability analysis) agreed well with the simulation for both the model dronefly and the model hawkmoth; but the averaged-model theory gave good results only for the dronefly. Thus, for an insect with relatively large body oscillation at wingbeat frequency, cyclic-motion stability analysis is required, and for their control analysis, the existing well-developed control theories for systems of fixed-point equilibrium are no longer applicable and new methods that take the cyclic variation of the flight dynamics into account are needed. PMID- 22491981 TI - A photonic heterostructure produces diverse iridescent colours in duck wing patches. AB - The colours of birds are diverse but limited relative to the colours they can perceive. This mismatch may be partially caused by the properties of their colour production mechanisms. Aside from pigments, several classes of highly ordered nanostructures (thin films, amorphous three-dimensional arrays) can produce a range of colours. However, the variability of any single nanostructural class has rarely been explored. Dabbling ducks are a speciose clade with substantial interspecific variation in the iridescent coloration of their wing patches (specula). Here, we use electron microscopy, spectrophotometry, polarization and refractive index-matching experiments, and optical modelling to examine these colours. We show that, in all species examined, speculum colour is produced by a photonic heterostructure consisting of both a single thin-film of keratin and a two-dimensional hexagonal lattice of melanosomes in feather barbules. Although the range of possible variations of this heterostructure is theoretically broad, only relatively close-packed, energetically stable variants producing more saturated colours were observed, suggesting that ducks are either physically constrained to these configurations or are under selection for the colours that they produce. These data thus reveal a previously undescribed biophotonic structure and suggest that both physical variability and constraints within single nanostructural classes may help explain the broader patterns of colour across Aves. PMID- 22491982 TI - Possible anti-tumor activity of initial treatment with zoledronic acid with hormonal therapy for bone-metastatic prostate cancer in multicenter clinical trial. AB - BACKGROUND: To ascertain the anti-tumor effect of zoledronic acid (ZOL) treatment on clinical outcomes in patients with bone metastatic prostate cancer, we examined the effect of ZOL started simultaneously with hormonal therapy as initial treatment in these patients. METHODS: Forty-seven patients with bone metastatic prostate cancer who received a luteinizing hormone releasing-hormone (LHRH) analogue and an anti-androgen [maximal androgen blockade (MAB)] were assigned to receive ZOL (4 mg intravenous administration every month for 2 years). The time to progression (TTP) of the prostate-specific antigen (PSA), the overall survival (OS), and the rate of PSA decrease in patients with MAB and ZOL treatment (ZOL group) were compared with these parameters in patients who received only MAB at one institute as a control group (non-ZOL group). RESULTS: Although the nadir PSA level and the rate of PSA normalization showed no significant differences between the ZOL and non-ZOL groups, the time to nadir PSA in the ZOL group was significantly shorter than that in the non-ZOL group (P < 0.05, Mann-Whitney U-test). There was a significant difference in TTP (P = 0.017, log-rank test) between the ZOL and non-ZOL groups, and statistically significant differences in TTP and OS between the ZOL and non-ZOL groups (P = 0.044 and 0.035, log-rank test) were recognized particularly in patients with advanced disease (extension of disease, grade 3 and 4). CONCLUSIONS: Simultaneous administration of ZOL and MAB as initial treatment delayed TTP in bone-metastatic prostate cancer patients. Initial treatment with ZOL has the possibility of anti tumor activity to delay disease progression. PMID- 22491983 TI - Sodium nitroprusside, a nitric oxide donor, fails to bypass the block of neuronal differentiation in PC12 cells imposed by a dominant negative Ras protein. AB - Nitric oxide (NO) is a mediator of a diverse array of inter- and intracellular signal transduction processes. The aim of the present study was to analyze its possible role as a second messenger in the process of neuronal differentiation of PC12 pheochromocytoma cells. Upon NGF treatment wildtype PC12 cells stop dividing and develop neurites. In contrast, a PC12 subclone (designated M-M17-26) expressing a dominant-negative mutant Ras protein keeps proliferating and fails to grow neurites after NGF treatment. Sodium nitroprusside (SNP), an NO donor, was found to induce the p53 protein and to inhibit proliferation of both PC12 and M-M17-26 cells, but failed to induce neuronal differentiation in these cell lines. Key signaling pathways (the ERK and Akt pathways) were also not affected by SNP treatment, and the phosphorylation of CREB transcription factor was only slightly stimulated. It is thus concluded from the results presented in this paper that NO is unable to activate signaling proteins acting downstream or independent of Ras that are required for neuronal differentiation. PMID- 22491984 TI - Stabilization of erythrocytes against oxidative and hypotonic stress by tannins isolated from sumac leaves (Rhus typhina L.) and grape seeds (Vitis vinifera L.). AB - Erythrocytes are constantly exposed to ROS due to their function in the organism. High tension of oxygen, presence of hemoglobin iron and high concentration of polyunsaturated fatty acids in membrane make erythrocytes especially susceptible to oxidative stress. A comparison of the antioxidant activities of polyphenol rich plant extracts containing hydrolysable tannins from sumac leaves (Rhus typhina L.) and condensed tannins from grape seeds (Vitis vinifera L.) showed that at the 5-50 MUg/ml concentration range they reduced to the same extent hemolysis and glutathione, lipid and hemoglobin oxidation induced by erythrocyte treatment with 400 MUM ONOO(-) or 1 mM HClO. However, extract (condensed tannins) from grape seeds in comparison with extract (hydrolysable tannins) from sumac leaves stabilized erythrocytes in hypotonic NaCl solutions weakly. Our data indicate that both hydrolysable and condensed tannins significantly decrease the fluidity of the surface of erythrocyte membranes but the effect of hydrolysable ones was more profound. In conclusion, our results indicate that extracts from sumac leaves (hydrolysable tannins) and grape seeds (condensed tannins) are very effective protectors against oxidative damage in erythrocytes. PMID- 22491985 TI - Study identifies behaviours in young children that might prevent obesity. PMID- 22491986 TI - The effect of maize silage as co-substrate for swine manure on the bacterial community structure in biogas plants. AB - The qualitative and quantitative changes in the bacterial community composition in two mesophilic, commercially used biogas plants were monitored by denaturing gradient gel electrophoresis (DGGE) and real-time PCR. The main objective was to evaluate the influence of the co-substrate maize silage on total bacteria and some selected bacterial groups by comparing full-scale reactors fed solely with pig manure or additionally with maize silage. DGGE fingerprints reflected shifts in the bacterial community structure associated with maize silage as co-substrate and the real-time PCR results showed clear changes in the quantitative composition of the bacterial consortia of each fermenter. A clear dominance of Clostridia in all surveyed fermenters and considerably lower abundance of Bacteroidetes in the biogas plant fed with maize silage was shown. PMID- 22491987 TI - Antimicrobial susceptibility of microflora from ovine cheese. AB - Strains identified in ovine cheese and bryndza by matrix-assisted laser desorption/ionization time-of-flight analysis belonged to ten species of non enterococcal lactic acid bacteria and included Lactobacillus casei/Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus rhamnosus, Lactobacillus helveticus, Lactobacillus delbrueckii, Lactobacillus fermentum, Lactobacillus brevis, Lactococcus lactis, Pediococcus pentosaceus and Pediococcus acidilactici. The susceptibility toward antibiotics was determined in lactobacilli, lactococci and pediococci and also in Escherichia coli for comparison. Analysis of L. fermentum and pediococci revealed the presence of non-wild-type epidemiological cut-offs in streptomycin, clindamycin or gentamicin. E. coli were resistant to ampicillin, tetracycline, enrofloxacin and florfenicol. No extended spectrum beta lactamases were detected. PMID- 22491989 TI - PLFA profiles for microbial community monitoring in anaerobic digestion. AB - The use of municipal solid waste as feedstock for biogas production offers an interesting possibility for waste treatment with the beneficial effect of gaining a green energy source. The involved processes are very complex, and many different organisms connected via a dynamic food web are associated with them. These complex interactions within these microbial communities are still not clearly understood. Therefore, a phospholipid fatty acid (PLFA) profile analysis method, well established in aerobic but still not as common in anaerobic systems, was used to throw some light on this matter. In the present investigation, a 750 m3 biogas reactor (Roppen, Austria) was monitored over a half-year period. During this period, four different phases in terms of gas production could be determined: low (I), increasing (II), high (III), and decreasing (IV) gas production. In combination with the PLFA profiles, we were able to identify changes in the microbial community associated with these phases. PMID- 22491988 TI - Inter-species differences in the growth of bifidobacteria cultured on human milk oligosaccharides. AB - Human milk (HM) contains as the third most abundant component around 200 different structures of human milk oligosaccharides (HMOs). HMOs are the first and irreplaceable prebiotics for infants, supporting bifidobacteria as the most important bacterial group in an infant intestine. The aim of our study was to test the growth of bifidobacteria in HM and on HMOs. Bifidobacteria were isolated from two groups of infants. The first one (eight strains) were isolated from infants who had bifidobacteria in their feces but, after a short period of time (4 to 24 days), bifidobacteria were no longer detected in their feces (disappeared bifidobacteria [DB]). The second group of bifidobacteria (eight strains) originated from infants with continual presence of bifidobacteria in their feces (persistent bifidobacteria [PB]). There were significant differences (p < 0.05) between DB and PB groups in the ability of the strains to grow in HM. PB grew in HM, reaching counts higher than 7 log CFU/ml. In contrast, counts of DB decreased from 5 to 4.3 log CFU/ml after cultivation in HM. The final pH after cultivation of bifidobacteria on HMOs was 6.2 and 4.9 in DP and PB groups, respectively. In general, Bifidobacterium bifidum and B. breve species were able to utilize HMOs, while B. adolescentis and B. longum subsp. longum species did not. The ability to grow in HM and to utilize HMOs seem to be important properties of bifidobacteria which are able to colonize infant intestinal tract. PMID- 22491990 TI - Growth and survival of lactic acid bacteria in lucerne silage. AB - A rifampicin-resistant variant of two strains of Lactobacillus plantarum, one strain of Pediococcus acidilactici, and one strain of Enterococcus faecium were used for the experimental production of lucerne silage. Laboratory silage without inoculants served as a control. Counts of total anaerobes, total lactic acid bacteria (LAB), lactobacilli, pediococci, and enterococci were determined on days 14, 21, 30, 49, and 60 of lucerne fermentation. LAB dominated in silage microflora, reaching a percentage between 59 and 95 % of total anaerobes. Lactobacilli were found as a predominant group of LAB during the whole study. Lactobacilli reached numbers 8.74 log CFU/g in treated silage and 8.89 log CFU/g in the control at the first observation. Their counts decreased to 4.23 and 4.92 log CFU/g in treated silage and the control, respectively, on day 63 of fermentation. Similar decreases were observed in all bacterial groups. The treated silage samples possessed lower pH (4.2 vs. 4.5 in control samples) and contained more lactic acid compared to control silage. The identity of re isolated rifampicin-resistant bacteria with those inoculated to the lucerne was evaluated by fingerprinting techniques. The fingerprint profiles of re-isolated bacteria corresponded to the profiles of strains used for the treatment. It could be concluded that supplemented LAB dominated in laboratory silage and overgrew naturally occurring LAB. PMID- 22491992 TI - [The challenge of adequate reimbursement for the seriously injured patient in the German DRG system]. AB - BACKGROUND: Critically injured patients are a very heterogeneous group, medically and economically. Their treatment is a major challenge for both the medical care and the appropriate financial reimbursement. Systematic underfunding can have a significant impact on the quality of patient care. In 2009 the German Trauma Society and the DRG-Research Group of the University Hospital Muenster initialised a DRG evaluation project to analyse the validity of case allocation of critically injured patients within the German DRG system versions 2008 and 2011 with additional consideration of clinical data from the trauma registry of the German Trauma Society. Severe deficits within the G-DRG structure were identified and specific solutions were designed and realised. METHODS: A retrospective analysis was undertaken of standardised G-DRG data (S 21 KHEntgG) including case-related cost data from 3 362 critically injured patients in the periods 2007 and 2008 from 10 university hospitals and 7 large municipal hospitals. For 1 241 cases of the sample, complementary detailed information was available from the trauma registry of the German Trauma Society to monitor the case allocation of critically injured patients within the G-DRG system. Analyses of coding and grouping, performance of case allocation, and the homogeneity of costs in the G-DRG versions 2008 and 2011 were done. RESULTS: The following situations were found: (i) systematic underfunding of trauma patients in the G DRG-Version 2008, especially trauma patients with acute paraplegia; (ii) participation in the official G-DRG development for 2011 with 13 proposals which were largely realised; (ii) the majority of cases with cost-covering in the G-DRG version 2011; (iv) significant improvements in the quality of statistical criteria; (v) overfunded trauma patients with high intensive care costs; (vi) underfunding for clinically relevant critically injured patients not identified in the G-DRG system. CONCLUSION: The quality of the G-DRG system is measured by the ability to obtain adequate case allocations for highly complex and heterogeneous cases. Specific modifications of the G-DRG structures could increase the appropriateness of case allocation of critically injured patients. Additional consideration of the ISS clinical data must be further evaluated. Data based analysis is an essential prerequisite for a constructive development of the G-DRG system and a necessary tool for the active participation of medical societies in this process. PMID- 22491991 TI - Investigating tonic Wnt signaling throughout the adult CNS and in the hippocampal neurogenic niche of BatGal and ins-TopGal mice. AB - Wnt/beta-catenin signaling has a well-established role in the development of the central nervous system (CNS), and recent evidence is extending this role to include the regulation of adult hippocampal function, including neurogenesis within the dentate gyrus. While the neuroanatomical expression pattern of many canonical Wnt signaling components have been investigated, the sites of signal integration and functional downstream beta-catenin activation remain comparatively less characterized in the adult CNS. Using two independent transgenic beta-catenin-activated LacZ reporter mouse lines (BatGal and ins TopGal), we demonstrate that Wnt/beta-catenin signaling is active in discrete regions of the adult mouse CNS. Intriguingly, BatGal mice exhibit a broad pattern of reporter expression in the CNS, while expression in ins-TopGal mice is more restricted. Further investigation of these two lines reveals temporal differences in beta-catenin-activated reporter expression during neurogenesis within the adult hippocampus. Ins-TopGal mice display peaks of Wnt/beta-catenin-activated reporter expression during early and later stages of neurogenesis suggesting Wnt/beta-catenin signaling plays an important role during both progenitor cell amplification as well as neuronal maturation, integration, and/or maintenance; however, results from BatGal mice are not as convincing. Thus our data using ins TopGal mice are consistent with the idea that Wnt signaling plays diverse roles during adult hippocampal neurogenesis and support the idea that multiple transgenic reporter lines must be rigorously compared during scientific investigations. PMID- 22491993 TI - Heterogeneity in depression symptoms and health status among older adults. AB - OBJECTIVES: We assessed whether distinct classes of depression symptoms could be identified. In addition, we determined how these classes differed in terms of health status. METHODS: Data were analyzed with latent profile analysis. MANOVA tests were used to compare the health status of the various classes. RESULTS: A four-class model had the best fit. Classes were labeled according to participants' responses to the Center for Epidemiologic Studies-Depression Scale (CES-D) items and their overall score: low depression symptoms, high depression symptoms, subthreshold with anhedonia, and subthreshold with anhedonia and negative interpersonal feelings. Cross-sectional and longitudinal analyses showed that health status differed across classes. CONCLUSIONS: The results provide support for the idea that there is heterogeneity in the presentation of depression symptoms among older adults. These data showed that about a third of our sample of older adults reported increased levels of anhedonia and that negative interpersonal feelings were uncommon. PMID- 22491994 TI - Prevalence of pharyngeal Chlamydia trachomatis and Neisseria gonorrhoeae among heterosexual men in Japan. AB - Pharyngeal chlamydial and gonococcal infections can occur as a consequence of oral sex, and they also can be transmitted from the pharynx to the genital tract of sex partners. There have been many reports on the prevalence of pharyngeal Chlamydia trachomatis and Neisseria gonorrhoeae in men who have sex with men; however, there have been few reports on the prevalence of these pathogens in the pharynges of heterosexual men. In this study, we determined the prevalence of pharyngeal C. trachomatis and N. gonorrhoeae in 42 heterosexual men diagnosed with urethritis. Pharyngeal swabs and first-voided urine specimens were tested using the Gen-Probe APTIMA Combo 2 transcription-mediated amplification assay. The prevalence of pharyngeal C. trachomatis and N. gonorrhoeae in patients with urethritis was 2.4 % (1/42) and 11.9 % (5/42), respectively. Among patients with either chlamydial or gonococcal urethritis, 9.1 % (1/11) and 25.0 % (5/20) had pharyngeal C. trachomatis or N. gonorrhoeae, respectively. Our results suggest that screening for pharyngeal colonization by N. gonorrhoeae and C. trachomatis using validated nucleic acid amplification tests should be performed in heterosexual men diagnosed with urethritis. PMID- 22491995 TI - Hospital-acquired pneumonia in Japan may have a better mortality profile than HAP in the United States: a retrospective study. AB - The characteristics of hospital-acquired pneumonia (HAP) are not well documented. In the present study we investigated the severity and mortality, microbiological profile, and the value of Gram staining in culture-confirmed HAP in a Japanese hospital by retrospective review conducted at a Japanese university hospital. Only culture-confirmed cases with good specimen quality were included in the analysis. The clinical characteristics of HAP, as well as the causative organisms, were investigated. Furthermore, the prognostic ability of existing prediction rules were evaluated for prediction of overall mortality. Forty-two cases were enrolled in this analysis. The majority of patients were admitted to the ICU (61.9 %), and 40.5 % had ventilator-associated pneumonia (VAP). The 30 day mortality was 23.8 %, which is less than that reported in the United States. Factors commonly known to be associated with worse outcome in the USA did not appear to influence the mortality from HAP in Japan. The most frequent causative organisms were methicillin-resistant Staphylococcus aureus (MRSA), followed by Pseudomonas spp. Sensitivity and negative predictive value of Gram staining were 89.4 and 85.7 %, respectively. SMART-COP predicted 30-day mortality with an area under the ROC curve (AUC) >0.7. The characteristics of HAP in Japan differ from HAP reported in the USA. In addition to lower mortality, we found both fewer ICU cases and VAP. Gram staining of good-quality specimens demonstrated promising sensitivity to predict the causative organisms. SMART-COP predicted mortality with appropriate ROC curve (AUC). PMID- 22491996 TI - Opportunities and challenges associated with engaging immigrant women in participatory action research. AB - With increasing recognition of the importance of knowledge exchange between researchers and research stakeholders, community member involvement remains poorly accessed. A promising community-based research methodology for knowledge exchange is participatory action research (PAR). This review examines opportunities and challenges associated with using PAR to examine issues related to community health, specifically that of immigrant women. The literature search included published and grey literature relevant to immigrant women and PAR. PAR actively engages community members of the study population throughout the research process. The involvement of immigrant women in research that explores issues pertinent to their health is essential to conducting relevant research to subsequently inform policies and programs. There are numerous advantages to using a PAR approach, including enhanced research relevance and utilization; notwithstanding, there are challenges to overcome in order to engage community based immigrant women in research. Ultimately, policies that have contextual grounding through PAR have better likelihood of effectively addressing priority issues for immigrant women. PMID- 22491997 TI - Effect of laparoscopic adjustable gastric banding on modifiable cardiovascular risk factors in extremely obese adolescents. AB - Recently, surgical intervention has gained increasing support in adolescents with extreme obesity. This study summarizes the analysis into the effect of laparoscopic adjustable gastric bands (LAGB) on cardiovascular risk factors in 14 extremely obese Portuguese adolescent patients. Data collected both pre- and postoperatively included age, gender, body mass index (BMI), percentage of excess weight loss, cardiovascular risk factors, and cardiovascular outcomes. Ten girls and four boys aged from 13.5 to 17.5 years underwent LABG. The mean preoperative weight and BMI were 127.4 kg and 46.1 kg/m(2), respectively. The average percentage of weight loss calculated was 32 % at 1 year, 38.8 % at 2 years, and 48.1 % at 3 years of follow-up. Simultaneously, blood pressure and insulin resistance index returned to normal, and there was an increase in high-density lipoprotein levels, 3 years after the LABG was fitted. LABG fitting is a safe and effective treatment strategy for the improvement of cardiovascular status following weight loss. PMID- 22491998 TI - Genetic modification of baculovirus expression vectors. AB - As a protein expression vector, the baculovirus demonstrates many advantages over other vectors. With the development of biotechnology, baculoviral vectors have been genetically modified to facilitate high level expression of heterologous proteins in both insect and mammalian cells. These modifications include utilization of different promoters and signal peptides, deletion or replacement of viral genes for increasing protein secretion, integration of polycistronic expression cassette for producing protein complexes, and baculovirus pseudotyping, promoter accommodation or surface display for enhancing mammalian cell targeting gene delivery. This review summarizes the development and the current state of art of the baculovirus expression system. Further development of baculovirus expression systems will make them even more feasible and accessible for advanced applications. PMID- 22491999 TI - Expression of endogenous beta retroviruses and Hyal-2 mRNA in immune organs of fetuses and lambs. AB - Endogenous beta retroviruses (enJSRV) are highly homologous with Jaagsiekte sheep retrovirus (exJSRV), this exogenous retrovirus is the aetiological agent of ovine pulmonary adenocarcinoma (OPA). The aim of this study was to clarify the function of enJSRV and the immunological mechanisms of its corresponding antibody, that is undetectable in JSRV-infected ovine serum. The expression of enJSRV envelope protein and Hyal-2 mRNA in immune organs and lungs of ovine fetuses and lambs were analyzed by Real-Time reverse transcription PCR and In Situ Hybridization using specific probes. In Situ Hybridization results indicated that the enJSRV envelope protein and Hyal-2 mRNA were expressed in thymus, spleen, mesenteric lymph nodes and lungs at different times, while no positive signals were detected in the negative controls. On the other hand, results from Real-Time reverse transcription PCR analysis showed that in 130d fetuses and 3d newborn lambs the enJSRV mRNA levels were much higher in organs associated with the immune system than that in lungs, especially in the thymus and spleen, but levels of Hyal-2 mRNA expression was not significantly different in all collected tissue. These results provided evidence from an immunology point of view to understand why the circulating antibodies against exJSRV are undetectable in JSRV-infected ovine, and will help to unravel the pathogenesis of JSRV-infected ovine. PMID- 22492000 TI - Characterization of pigeon paramyxoviruses (Newcastle disease virus) isolated in Kazakhstan in 2005. AB - Isolates of Newcastle disease virus (NDV) from deceased wild and domestic pigeons in Kazakhstan were obtained from the Almaty region during 2005 and were genotypically analyzed by using reverse transcription polymerase chain reaction (RT-PCR) with primers specific to the viral fusion (F) protein gene. Part of the amplified F protein DNA product (nucleotide sequence 47-422) and the deduced amino acid sequences were compared phylogenetically with those from strains previously reported in other geographic regions. Phylogenetic analysis indicated that the Kazakhstanian pigeon paramyxovirus type 1 (PPMV-1) isolates belong to genotype VI or 4bii. To our knowledge, this is the first reported VI isolates that possess the sequences of 112GKRQKR116 * F117 within the F0 protein. The information is fundamental to improving the efficiency of control strategies and vaccine development for NDV. PMID- 22492001 TI - Surface display of rice stripe virus NSvc2 and analysis of its membrane fusion activity. AB - Rice stripe virus (RSV) infects rice and is transmitted in a propagative manner by the small brown planthopper. How RSV enters an insect cell to initiate the infection cycle is poorly understood. Sequence analysis revealed that the RSV NSvc2 protein was similar to the membrane glycoproteins of several members in the family Bunyaviridae and might induce cell membrane fusion. To conveniently study the membrane fusion activity of NSvc2, we constructed cell surface display vectors for expressing Nsvc2 on the insect cell surface as the membrane glycoproteins of the enveloped viruses. Our results showed that NSvc2 was successfully expressed and displayed on the surface of insect Sf9 cells. When induced by low pH, the membrane fusion was not observed in the cells that expressed NSvc2. Additionally, the membrane fusion was also not detected when co expressing Nsvc2 and the viral capsid protein on insect cell surface. Thus, RSV NSvc2 is probably different from the phlebovirus counterparts, which could suggest different functions. RSV might enter insect cells other than by fusion with plasma or endosome membrane. PMID- 22492002 TI - Suppression of RNA interference pathway in vitro by Grass carp reovirus. AB - The means of survival of genomic dsRNA of reoviruses from dsRNA-triggered and Dicer-initiated RNAi pathway remains to be defined. The present study aimed to investigate the effect of Grass carp reovirus (GCRV) replication on the RNAi pathway of grass carp kidney cells (CIK). The dsRNA-triggered RNAi pathway was demonstrated unimpaired in CIK cells through RNAi assay. GCRV-specific siRNA was generated in CIK cells transfected with purified GCRV genomic dsRNA in Northern blot analysis; while in GCRV-infected CIK cells, no GCRV-specific siRNA could be detected. Infection and transfection experiments further indicated that replication of GCRV correlated with the increased transcription level of the Dicer gene and functional inhibition of in vitro synthesized egfp-siRNA in silencing the EGFP reporter gene. These data demonstrated that although only the genomic dsRNA of GCRV was sensitive to the cellular RNAi pathway, unidentified RNAi suppressor protein(s) might contribute to the survival of the viral genome and efficient viral replication. PMID- 22492003 TI - Subtyping animal influenza virus with general multiplex RT-PCR and Liquichip high throughput (GMPLex). AB - This study developed a multiplex RT-PCR integrated with luminex technology to rapidly subtype simultaneously multiple influenza viruses. Primers and probes were designed to amplify NS and M genes of influenza A viruses HA gene of H1, H3, H5, H7, H9 subtypes, and NA gene of the N1 and N2 subtypes. Universal super primers were introduced to establish a multiplex RT-PCR (GM RT-PCR). It included three stages of RT-PCR amplification, and then the RT-PCR products were further tested by LiquiChip probe, combined to give an influenza virus (IV) rapid high throughput subtyping test, designated as GMPLex. The IV GMPLex rapid high throughput subtyping test presents the following features: high throughput, able to determine the subtypes of 9 target genes in H1, H3, H5, H7, H9, N1, and N2 subtypes of the influenza A virus at one time; rapid, completing the influenza subtyping within 6 hours; high specificity, ensured the specificity of the different subtypes by using two nested degenerate primers and one probe, no cross reaction occurring between the subtypes, no non-specific reactions with other pathogens and high sensitivity. When used separately to detect the product of single GM RT-PCR for single H5 or N1 gene, the GMPLex test showed a sensitivity of 10-5(= 280ELD50) forboth tests and the Luminex qualitative ratio results were 3.08 and 3.12, respectively. When used to detect the product of GM RT-PCR for H5N1 strain at the same time, both showed a sensitivity of 10-4(=2800 ELD50). The GMPLex rapid high throughput subtyping test can satisfy the needs of influenza rapid testing. PMID- 22492004 TI - Analysis on factors related to rabies epidemic in China from 2007-2011. AB - To analyze features of the rabies epidemic in China between 2007 and 2011, identify factors influencing the epidemic and to provide a scientific basis for further control and prevention of rabies, Descriptive epidemiological methods and statistical analysis was used on data collected from the National Disease Reporting Information System between 2007 to 2011 and the National Active Surveillance System between 2007 and 2010. Our analysis shows that while the number of human rabies cases decreased year by year, the number of districts reporting cases did not show significant change. The situations in Guangdong, Guangxi, Guizhou and Hunan provinces clearly improved over the period but they remain provinces with high-incidence, and consequently influence the epidemic situation of surrounding provinces and possibly the whole country. Summer and autumn were high-incidence seasons. Farmers, students and pre-school children represent the high-risk populations, and rates of cases in farmers increased, those for students decreased, and pre-school children remained unchanged. Provinces with active surveillance programs reported a total of 2346 individual cases, of which 88.53% were associated with canines. Postexposure prophylaxis (PEP) of rabies cases was not significantly improved, whereas PEP in post exposure population was good. In rural regions of China, canine density was reduced somewhat, and the immunization rate increased slightly. Finally we show that while the epidemic decreased 2007 to 2011 in China, cases continued to be diffused in certain regions. Lack of standardization of PEP on rabies cases was the main reason of morbidity. The high density and low immunization of dog in rural areas and the defective situation of PEP are still continuous occurrences in China and remain a cause for concern. PMID- 22492005 TI - Viability of the skin paddle does not predict the functional outcome in free muscle transfers with a second ischemic event: a report of three cases. AB - Conventional skin flap monitoring is one of the widely used methods to assess postoperative circulation in innervated free muscle transfer (IFMT). However, following reexploration for vascular compromise and reestablishing circulation, functional recovery of the muscle despite surviving skin flap is not clear. The purpose of this article is to report three such cases and determine the reliability of viable skin flap in an IFMT with a second ischemic event. Long term functional results were assessed in terms of reinnervation time, elbow range of motion, strength of elbow flexion, finger function in terms of total active motion, and power lifting with hook grip. These IFMTs developed complete or partial necrosis of the muscle and could not obtain satisfactory function. The conventional monitoring of the skin flap did not promptly reflect vascularity of IFMT, and a surviving skin flap after reexploration for compromised vascularity does not guarantee complete survival of the muscle. There is a need for earlier and rapid detection of vascular compromise in IFMTs. PMID- 22492006 TI - Intraoperative hemodynamic evaluation of the latissimus dorsi muscle flap: a prospective study. AB - The aim of this study was to assess intraoperatively the hemodynamic changes in the donor vessel of free latissimus dorsi (LD) flap before and after denervation and to analyze flow changes after flap transfer. Twenty-seven patients underwent LD muscle microvascular reconstruction for lower-limb soft tissue defects. Measurements of blood flow were performed intraoperatively by using a 2- to 5-mm probe ultrasonic transit-time flowmeter around the dissected vessels. Registrations were made in the thoracodorsal artery before and after harvesting the flap, after compressing and cutting the motor nerve, and after anastomosis. Mean blood flow of in situ harvested thoracodorsal artery as measured intraoperatively by transit-time flowmeter was (mean +/- standard deviation) 16.6 +/- 11 mL/min and was significantly increased after raising the flap to 24.0 +/- 22 mL/min (p <0.05); it was 25.6 +/- 23 mL/min after compressing the motor nerve and was significantly increased after cutting the motor nerve to 32.5 +/- 26 mL/min (p <0.05). A significant increase of blood flow to 28.1 +/- 19 mL/min was also detected in the thoracodorsal artery after flap transplantation with end-to side anastomosis (p <0.05). Vascular resistance in the thoracodorsal artery significantly decreased after flap raising and anastomosis (from 7.5 +/- 3.4 to 4.0 +/- 1.9 and to 4.5 +/- 2.4, respectively, p <0.05). LD flap harvesting increases blood flow and decreases resistance in the thoracodorsal artery, especially after denervation. PMID- 22492007 TI - Microneurosurgical planning in toe-to-hand transplantation: axonal population of digital nerves in the fingers and toes. AB - Although toe-to-hand microvascular transplantation is now an accepted and successful reconstructive strategy for the thumb, there remains varying success in recovery of sensibility. The purpose of the present study was to provide an anatomic basis for analyzing neurotization of the great toe or the second toe with the digital nerves of the fingers and hand. Axon counts were obtained from donor and recipient nerves during reconstructive procedures. Sixty-seven upper- and eighty lower-extremity nerves were analyzed. No statistical difference was found between the mean number of axons between the thumb and the index finger; however, the thumb had significantly more (p < 0.001) axons than the middle or the ring finger. The great toe had significantly more axons than the second toe (p < 0.001). The common plantar digital nerve had significantly more axons than a digital nerve (p < 0.001). The thumb had significantly more axons than the great toe (p < 0.001). The thumb had significantly more axons than the second toe (p < 0.001). Numerical data are now available for strategic planning of toe transplantation, and direct neurotization from the dorsum of the hand to the digits. PMID- 22492008 TI - Is magnetic resonance safe in implanted cardiac devices patients? AB - Nazarian et al. [1] evaluate in a prospective non-randomized trial the safety of a 1.5 T MRI protocol for patients with implanted cardiac devices (ICD and PM). 438 participants (54 % with PM and 46 % with ICD implanted, respectively,after the 1998 and 2000) were enrolled and underwent 555MRI examinations. Patients with a recent implant(?6 weeks), those with abandoned or epicardiac leads, and PM dependent patients with an ICD were excluded.According to the experimental protocol, an asynchronous pacing mode (VOO/DOO) was programmed in the pacemaker dependent patients, while an inhibited pacing mode(VVI/DDI) was used for the other patients. The ICD function of non-PM-dependent patients was disabled. During the MRI examination, blood pressure, electrocardiography, pulse oximetry and symptoms were monitored by a nurse with experience in cardiac life support and device programming who had an immediate backup from an electrophysiologist.Device variables including sensing, impedance, capture threshold and battery voltage were evaluated before MRI examination, immediately after MRI and after 3-6 months.Variations exceeding 30, 40 and 50 %for, respectively, lead impedance, sensing and capture threshold were considered as significant changes in lead performance.Baseline and immediate follow-up interrogations were performed in all 438. Long-term follow-up device variables were available for 266 patients (61 %). 3 of 438 patients(0.7 %) experienced acute power-on-reset events. None of them had device dysfunction during long-term follow-up(3-6 months). Right ventricular sensing and atrial, right and left ventricular impedances were reduced immediately after MRI. At long-term follow-up in 61 % of the patients,decreased right ventricular (RV) sensing and lead impedance,increased RV capture threshold and decreased battery voltage were noted. The observed changes did not require device revision or reprogramming. The distributions of changes in device variables were within the 20 % at baseline for most participants. Thoracic MRI sequences had a greater effect on device variables and were more likely to result in artifacts (for instance, image distortion,signal voids or bright areas and poor fat suppression). PMID- 22492009 TI - Edematous striae distensae. PMID- 22492010 TI - Relationship between renal hemodynamic status and aging in patients without diabetes evaluated by renal Doppler ultrasonography. AB - BACKGROUND: Aging is well known as one of the major causes of a reduced glomerular filtration rate (GFR). The resistive index (RI) measured by renal Doppler ultrasonography (RDU) is thought to be a good indicator of renal vascular resistance induced by arteriosclerosis. In this study, we investigated whether RI could be used to evaluate the pathogenesis of renal damage or the mechanisms of reduction of renal function by aging. METHODS: We investigated the correlation between RI and multiple clinical parameters and the influence of aging on the renal hemodynamic status of 194 in-patients (mean age 66.2 years) who underwent RDU at our hospital between February 2009 and July 2010. RESULTS: RI was significantly correlated with the age, estimated GFR (eGFR), diastolic blood pressure, pulse pressure, and degree of albuminuria. Subjects aged >=75 years showed a significantly higher correlation coefficient between eGFR and RI. RI showed a stronger correlation with age in subjects aged >=75 years compared to eGFR. CONCLUSION: The present study showed that renal vascular resistance and intra-renal arteriosclerosis had a greater impact on renal function in older than younger subjects, reflecting the possible mechanisms of renal function reduction due to aging. PMID- 22492011 TI - Differences in the local and national prevalences of chronic kidney disease based on annual health check program data. AB - BACKGROUND: Chronic kidney disease (CKD) is now recognized as a global public health problem, and evaluating the prevalence of CKD at the local level is important and helpful for assessing health care needs and targeted interventions. To assess the current picture concerning CKD in a local area, local and national prevalences of CKD were compared by calculating standardized rate ratios (SRRs) and confidence intervals (CIs). METHODS: For the national prevalence of CKD, the data from a previous report that showed age- and sex-specific prevalence of each stage of CKD on the basis of a large dataset from the Japanese annual health check program were used. Using annual health check program data in Sado City, the SRRs and CIs were calculated. RESULTS: The SRRs were 0.70 for males and 0.60 for females, indicating that Sado City had a 30 % lower prevalence of CKD for males and a 40 % lower for females than the national average. The 95 % CIs of the SRRs were calculated as 0.64-0.72 for males and 0.55-0.64 for females. Thus, the prevalence of CKD for both males and females in Sado City is significantly lower than the national average for Japan. CONCLUSIONS: Because this methodology adjusts for age and sex, it can serve as a useful tool to assess the current picture related to CKD in a local area. We believe that this could be an important step for improving local care to prevent the development of CKD. PMID- 22492012 TI - Long-term effect of radiocontrast-enhanced computed tomography on the renal function of chronic kidney disease patients. AB - BACKGROUND: The risk of acute kidney injury produced by intravenous radiocontrast in patients with chronic kidney disease (CKD) has been well known, but little is known about the long-term effects on renal function. METHODS: We retrospectively reviewed the medical records of 176 CKD patients with estimated glomerular filtration rates (eGFR) <60 ml/min/1.73 m(2) who underwent computed tomography (CT) with intravenous radiocontrast at Pusan National University Hospital. Patients were divided into 3 groups (CKD stage 3, n = 104; CKD stage 4, n = 52; peritoneal dialysis, n = 20). Follow-up eGFR values were assessed on a monthly basis for up to 8 months. RESULTS: In baseline characteristics, there were no significant differences between the 3 groups (i.e., CKD stage 3, stage 4, and PD) in the variables of age, sex, presence of diabetes and follow-up period. There were no significant differences between eGFR before and after CT in all patients and each of the 3 investigated groups. In each group, data analysis according to the presence of diabetes mellitus (DM) did not show significant differences of eGFR before and after CT. CONCLUSION: Overall, these results illustrate that intravenous contrast media used in the standard CT scan have no significant long term effects on renal function in CKD patients, irrespective of DM. Therefore, from a long-term perspective, contrast-enhanced CT might be a better option than gadolinium-based magnetic resonance imaging, which is known to be associated with fatal nephrogenic systemic fibrosis in CKD patients. PMID- 22492013 TI - Mizoribine, tacrolimus, and corticosteroid combination therapy successfully induces remission in patients with lupus nephritis. AB - BACKGROUND: Conventional cyclophosphamide-based treatment regimens for lupus nephritis (LN) are still not considered to be optimal. The aim of this study was to evaluate the efficacy and safety of mizoribine, tacrolimus, and corticosteroid combination therapy for LN. METHODS: We retrospectively evaluated a combination treatment of mizoribine and tacrolimus with corticosteroids as induction therapy in eight newly diagnosed systemic lupus erythematosus (SLE) patients with biopsy proven LN. RESULTS: All patients were women, and their mean [standard deviation (SD)] age was 48.5 (20) years. All patients (100 %) had positive anti-double stranded DNA (anti-dsDNA) antibody titers, and four (50.0 %) were nephrotic. Mean (SD) serum creatinine and daily proteinuria levels were 0.72 (0.4) mg/dl (range 0.33-1.55 mg/dl) and 4.56 (2.8) g (range 0.77-8.2 g), respectively. By month 2, significant improvements in the anti-dsDNA antibody titers, levels of proteinuria, serum albumin, and C3, and SLE disease activity index score were observed. By month 6, seven patients (87.5 %) were in complete remission, with normalized levels of both proteinuria and serum creatinine. CONCLUSIONS: This pilot study suggests that mizoribine and tacrolimus treatment with corticosteroids is well tolerated and may prove to be an optimal alternative remission-inducing regimen for LN. PMID- 22492014 TI - Death, nasomaxillary complex, and sleep in young children. AB - This is an investigation of anatomical and sleep history risk factors that were associated with abrupt sleep-associated death in seven children with good pre mortem history. Seven young children with abrupt deaths and information on health status, sleep history, death scene report, and autopsy performed in a specialized unit dedicated to investigation of abrupt death in young children were investigated Seven age and gender matched living children with obstructive-sleep apnea (OSA) were compared to the findings obtained from the dead children. Two deaths results from accidents determined by the death scene and five were unexplained at the death scene. History revealed presence of chronic indicators of abnormal sleep in all cases prior death and history of an acute, often mild, rhinitis just preceding death in several. Four children, including three infants, were usually sleeping in a prone position. Autopsy demonstrated variable enlargement of upper airway soft tissues in all cases, and in all cases, there were features consistent with a narrow, small nasomaxillary complex, with or without mandibular retroposition. All children were concluded to have died of hypoxia during sleep. Our OSA children presented similar complaints and similar facial features. Anatomic risk factors for a narrow upper airway can be determined early in life, and these traits are often familial. Their presence should lead to greater attention to sleep-related complaints that may be present very early in life and indicate impairment of well been and presence of sleep disruption. Further investigation should be performed to understand the role of upper airway infection in the setting of anatomically small airway in apparently abrupt death of infants and toddlers. PMID- 22492015 TI - Role of the transporter regulator protein (RS1) in the modulation of concentrative nucleoside transporters (CNTs) in epithelia. AB - SLC28 genes encode three plasma membrane transporter proteins, human concentrative nucleoside transporter (CNT)1, CNT2, and CNT3, all of which are implicated in the uptake of natural nucleosides and a variety of nucleoside analogs used in the chemotherapy of cancer and viral and inflammatory diseases. Mechanisms determining their trafficking toward the plasma membrane are not well known, although this might eventually become a target for therapeutic intervention. The transporter regulator RS1, which was initially identified as a short-term, post-transcriptional regulator of the high-affinity, Na(+)-coupled, glucose transporter sodium-dependent glucose cotransporter 1, was evaluated in this study as a candidate for coordinate regulation of membrane insertion of human CNT-type proteins. With a combination of studies with mammalian cells, Xenopus laevis oocytes, and RS1-null mice, evidence that RS1 down-regulates the localization and activity at the plasma membrane of the three members of this protein family (CNT1, CNT2, and CNT3) is provided, which indicates the biochemical basis for coordinate regulation of nucleoside uptake ability in epithelia and probably in other RS1-expressing cell types. PMID- 22492016 TI - Comparison of bone-implant contact and bone-implant volume between 2D histological sections and 3D-SRuCT slices. AB - Histological imaging is still considered the gold standard for analysing bone formation around metallic implants. Generally, a limited number of histological sections per sample are used for the approximation of mean values of peri-implant bone formation. In this study we compared statistically the results of bone implant contact (BIC) and bone-implant volume (BIV) obtained by histological sections, with those obtained by X-ray absorption images from synchrotron radiation micro-computed tomography (SRuCT) using osseointegrated screw-shaped implants from a mini-pig study. Comparing the BIC results of 3-4 histological sections per implant sample with the appropriate 3-4 SRuCT slices showed a non significant difference of 1.9 % (p = 0.703). The contact area assessed by the whole 3D information from the SRuCT measurement in comparison to the histomorphometric results showed a non-significant difference in BIC of 4.9 % (p = 0.171). The amount of the bone-implant volume in the histological sections and the appropriate SRuCT slices showed a non-significant difference by only 1.4 % (p = 0.736) and also remains non-significant with 2.6 % (p = 0.323) using the volumetric SRuCT information. We conclude that for a clinical evaluation of implant osseointegration with histological imaging at least 3-4 sections per sample are sufficient to represent the BIC or BIV for a sample. Due to the fact that in this study we have found a significant intra-sample variation in BIC of up to +/- 35 % the selection of only one or two histological sections per sample may strongly influence the determined BIC. PMID- 22492017 TI - Mesenchymal stem cell recruitment by stromal derived factor-1-delivery systems based on chitosan/poly(gamma-glutamic acid) polyelectrolyte complexes. AB - Human mesenchymal stem cells (hMSCs) have an enormous potential for tissue engineering and cell-based therapies. With a potential of differentiation into multiple lineages and immune-suppression, these cells play a key role in tissue remodelling and regeneration. Here a method of hMSC recruitment is described, based on the incorporation of a chemokine in Chitosan (Ch)/Poly(gamma-glutamic acid) (gamma-PGA) complexes. Ch is a non-toxic, cationic polysaccharide widely investigated. gamma-PGA is a hydrophilic, non-toxic, biodegradable and negatively charged poly-amino acid. Ch and gamma-PGA, being oppositely charged, can be combined through electrostatic interactions. These biocompatible structures can be used as carriers for active substances and can be easily modulated in order to control the delivery of drugs, proteins, DNA, etc. Using the layer-by-layer method, Ch and gamma-PGA were assembled into polyelectrolyte multilayers films (PEMs) with thickness of 120 nm. The chemokine stromal-derived factor-1 (SDF-1) was incorporated in these complexes and was continuously released during 120 h. The method of SDF-1 incorporation is of crucial importance for polymers assembly into PEMs and for the release kinetics of this chemokine. The Ch/gamma-PGA PEMs with SDF-1 were able to recruit hMSCs, increasing the cell migration up to 6 fold to a maximum of 16.2 +/- 4.9 cells/mm2. The controlled release of SDF-1 would be of great therapeutic value in the process of hMSC homing to injured tissues. This is the first study suggesting Ch/gamma-PGA PEMs as SDF-1 reservoirs to recruit hMSCs, describing an efficient method of chemokine incorporation that allows a sustained released up to 5 days and that can be easily scaled-up. PMID- 22492018 TI - An experimental setup to evaluate innovative therapy options for the enhancement of bone healing using BMP as a benchmark--a pilot study. AB - Critical or delayed bone healing in rat osteotomy (OT) models is mostly achieved through large defects or instability. We aimed to design a rat OT model for impaired bone healing based on age, gender and parity. The outcome should be controllable through variations of the haematoma in the OT including a bone morphogenetic protein (BMP) 2 guided positive control. Using external fixation to stabilise femoral a 2 mm double OT in 12 month old, female Sprague Dawley rats after a minimum of 3 litters healing was characterised following in situ haematoma formation (ISH-group)), transplantation of a BMP charged autologous blood clot (BMP-group) and the artificial blood clot only (ABC-group) into the OT gap. In vivo micro-computer tomography (uCT) scans were performed after 2, 4 and 6 weeks. After 6 weeks specimens underwent histological analyses. In uCT examinations and histological analyses no bony bridging was observed in all but one animal in the ISH-group. In the BMP group complete bridging was achieved in all animals. The ABC-group showed less mineralised tissue formation and smaller bridging scores during the course of healing than the ISH-group. In this pilot study we introduce a model for impaired bone healing taking the major biological risk factors into account. We could show that the in situ fracture haematoma is essential for bone regeneration. Using BMP as a positive control the presented experimental setup can serve to evaluate innovative therapeutical concepts in long bone application. PMID- 22492019 TI - Bone apposition to a titanium-zirconium alloy implant, as compared to two other titanium-containing implants. AB - Implants made of commercially pure titanium (cpTi) are widely and successfully used in dentistry. For certain indications, diameter-reduced Ti alloy implants with improved mechanical strength are highly desirable. The aim was to compare the osseointegration of titanium-zirconium (TiZr) and cpTi implants with a modified sandblasted and acid-etched (SLActive) surface and with a Ti6Al4V alloy that was sand-blasted and acid-washed. Cylindrical implants with two, 0.75 mm deep, circumferential grooves were placed in the maxilla of miniature pigs and allowed to heal for 1, 2, 4 and 8 weeks. Undecalcified toluidine blue-stained ground sections were produced. Surface topography, area fraction of tissue components, and bone-to-implant contact (BIC) were determined. All materials showed significantly different surface roughness parameters. The amount of new bone within the implant grooves increased over time, without significant differences between materials. However, BIC values were significantly related to the implant material and the healing period. For TiZr and cpTi implants, the BIC increased over time, reaching values of 59.38 % and 76.15 % after 2 weeks, and 74.50 % and 84.67 % after 8 weeks, respectively. In contrast, the BIC for Ti6Al4V implants peaked with 42.29 % after 2 weeks followed by a decline to 28.60 % at 8 weeks. Significantly more surface was covered by multinucleated giant cells on Ti6Al4V implants after 4 and 8 weeks. In conclusion, TiZr and cpTi implants showed faster osseointegration than Ti6Al4V implants. Both chemistry and surface topography might have influenced the results. The use of diameter-reduced TiZr implants in more challenging clinical situations warrants further documentation in long-term clinical studies. PMID- 22492020 TI - Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m(2) every 21 days in patients with cancer. AB - PURPOSE: This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. EXPERIMENTAL DESIGN: This was an open-label, multicenter, dose escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40-195 mg/m(2)) were combined with 500 mg/m(2) of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Antitumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. RESULTS: A total of 31 patients were enrolled into six cohorts (three at 40 mg/m(2) over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m(2), 70 mg/m(2), and 195 mg/m(2); 13 at 105 mg/m(2); six at 150 mg/m(2)). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m(2)); reversible infusion-related reaction (150 mg/m(2)); thrombocytopenia (195 mg/m(2)); and fatigue (195 mg/m(2)). The maximum tolerated dose was defined as 150 mg/m(2). The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses >=105 mg/m(2). CONCLUSION: LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles. PMID- 22492021 TI - Sunlight exposure may be a risk factor of hearing impairment: a community-based study in Japanese older men and women. AB - BACKGROUND: Oxidative stress is an important factor in the pathology of age related hearing loss. Recent animal studies have reported that ultraviolet radiation in sunlight is related to systemic induction of oxidative stress. Chronic sun exposure leads to photodamaged skin, which is manifested as facial skin wrinkling and hyperpigmentation. We hypothesized that sunlight exposure, as assessed by the severity of facial skin photodamage, might be associated with hearing impairment through an oxidative stress mechanism. To examine this, we performed a cross-sectional analysis by using the baseline data from a community based cohort study of older Japanese. METHODS: A total of 805 residents (342 men and 463 women) aged 65 years or older living in Kurabuchi Town, Gunma prefecture, Japan, were examined between 2005 and 2006. Facial skin condition was quantified by image analysis of standardized facial images. Hearing impairment was defined as a failure to hear a 30-dB signal at 1 kHz and a 40-dB signal at 4 kHz in the better ear in pure-tone audiometric tests. RESULTS: In men, facial wrinkle was positively associated with hearing impairment (for highest vs lowest: multivariate-adjusted odds ratio, 2.16; 95% confidence interval, 1.00-4.66; p for trend = .01). Stratified analysis by age, educational level, smoking status, sunscreen or foundation use, and diabetes showed results similar to those for men as a whole. This association was particularly pronounced in men with the low levels of antioxidants and without occupational noise exposure. We observed no apparent association in women. CONCLUSIONS: The results support the hypothesis that chronic sun exposure is a risk factor of hearing impairment. PMID- 22492022 TI - Clinical complexity and mortality in middle-aged and older adults with diabetes. AB - BACKGROUND: Middle-aged and older adults with diabetes are heterogeneous and may be characterized as belonging to one of three clinical groups: a relatively healthy group, a group having characteristics likely to make diabetes self management difficult, and a group with poor health status for whom current management targets have uncertain benefit. METHODS: We analyzed waves 2004-2008 of the Health and Retirement Study and the supplemental Health and Retirement Study 2003 Diabetes Study. The sample included adults with diabetes 51 years and older (n = 3,507, representing 13.6 million in 2004). We investigated the mortality outcomes for the three clinical groups, using survival analysis and Cox proportional hazard models. RESULTS: The 5-year survival probabilities were Relatively Healthy Group, 90.8%; Self-Management Difficulty Group, 79.4%; and Uncertain Benefit Group, 52.5%. For all age groups and clinical groups, except those 76 years and older in the Uncertain Benefit Group, survival exceeded 50%. CONCLUSIONS: This study reveals the substantial survival of middle-aged and older adults with diabetes, regardless of health status. These findings have implications for the clinical management of and future research about diabetes patients with multiple comorbidities. PMID- 22492023 TI - A series of patients on anti-TNF therapy referred to a multidisciplinary lung cancer service. AB - BACKGROUND: Biological therapies have significantly improved the quality of life of patients with aggressive collagen vascular diseases. Blocking TNF activity may potentially confer a higher malignant potential for patients. AIMS: To identify patients to whom anti-TNF therapies were recently prescribed and were referred to a multidisciplinary lung cancer service. METHODS: Retrospective review of patients over an 18-month period who were referred to a multidisciplinary lung cancer service. RESULTS: Three patients who underwent recent anti-TNF therapies and presented with solid organ tumours. All had significant additional risks for cancer including smoking and family history and active connective tissue diseases with a past history of immunosuppressive therapies. CONCLUSIONS: Our series highlights the potential malignant risk of anti-TNF theraphy to a general medical audience. PMID- 22492024 TI - Follicular neoplasm involving one lobe of thyroid: is hemithyroidectomy the adequate initial procedure? AB - AIM: Ultrasound-guided fine-needle aspiration cytology (FNAC), intraoperative frozen section, elastography and molecular markers have been tried to predict malignancy in indeterminate thyroid lesions. However, only histopathological evidence of capsular and vascular invasion can confirm malignancy. The aim of this study is to determine the effectiveness of hemithyroidectomy (HT) as an adequate surgical intervention in patients having cytologically proven follicular neoplasm limited to one lobe of the thyroid in a resource-limited country like India. MATERIALS AND METHODS: A retrospective study was conducted. The data of all patients operated for FNAC-proven follicular neoplasm (2008-2011) were analysed. RESULTS: A total of 123 cases had FNAC-proven follicular neoplasm. Fourteen were male and 109 female. Forty-six patients with multiple nodules involving both lobes (MNG) underwent total thyroidectomy (TT), whereas 77 who had solitary thyroid nodule (STN) underwent HT. Among patients who had HT (n = 77), histopathology revealed malignancy in 3.6% (n = 3). Patients who needed completion thyroidectomy (CT) were older females (p = 0.02) with higher TSH levels (p = 0.0001), shorter duration of goitre (p = 0.01) and smaller nodules (p = 0.04). CONCLUSIONS: Hemithyroidectomy is an adequate initial surgical procedure for FNAC-proven follicular neoplasm. The incidence of carcinoma is 3.9%. Older subjects with high normal TSH are likely to have malignancy. Routine employment of intraoperative frozen section, elastography and molecular markers is not necessary if locally unavailable, since the incidence of malignancy in FNAC proven follicular neoplasm is low. PMID- 22492026 TI - How to reach: movement planning in the posterior parietal cortex. PMID- 22492025 TI - A review of genetics, arterial stiffness, and blood pressure in African Americans. AB - The prevalence of hypertension in African Americans in the USA is among the highest in the world and increasing. The identification of genes and pathways regulating blood pressure in African Americans has been challenging. An early predictor of hypertension is arterial stiffness. The prevalence of arterial stiffness is significantly higher in African Americans compared to Caucasians. Approximately 20 % of the variance in arterial stiffness is estimated to be heritable. Identifying genes and biological pathways regulating arterial stiffness may provide insight into the genetics underlying the increased risk of hypertension in African Americans. This paper reviews the genetic findings to date in the area of arterial stiffness and blood pressure in African Americans with an emphasis on the current limitations and new efforts to move the field forward. PMID- 22492027 TI - Age-dependent rescue by simvastatin of Alzheimer's disease cerebrovascular and memory deficits. AB - Alzheimer's disease (AD) is now established as a progressive compromise not only of the neurons but also of the cerebral vasculature. Increasing evidence also indicates that cerebrovascular dysfunction may be a key or an aggravating pathogenic factor in AD, emphasizing the importance to properly control this deficit when aiming for effective therapy. Here, we report that simvastatin (3-6 months, 40 mg/kg/d) completely rescued cerebrovascular reactivity, basal endothelial nitric oxide synthesis, and activity-induced neurometabolic and neurovascular coupling in adult (6 months) and aged (12 months) transgenic mice overexpressing the Swedish and Indiana mutations of the human amyloid precursor protein (AD mice). Remarkably, simvastatin fully restored short- and long-term memory in adult, but not in aged AD mice. These beneficial effects occurred without any decreasing effect of simvastatin on brain amyloid-beta (Abeta) levels or plaque load. However, in AD mice with recovered memory, protein levels of the learning- and memory-related immediate early genes c-Fos and Egr-1 were normalized or upregulated in hippocampal CA1 neurons, indicative of restored neuronal function. In contrast, the levels of phospholipase A2, enkephalin, PSD 95, synaptophysin, or glutamate NMDA receptor subunit type 2B were either unaltered in AD mice or unaffected by treatment. These findings disclose new sites of action for statins against Abeta-induced neuronal and cerebrovascular deficits that could be predictive of therapeutic benefit in AD patients. They further indicate that simvastatin and, possibly, other brain penetrant statins bear high therapeutic promise in early AD and in patients with vascular diseases who are at risk of developing AD. PMID- 22492028 TI - Direct evidence for domain-sensitive functional subregions in human entorhinal cortex. AB - The medial temporal lobes (MTL) are known to play a crucial role in memory processes. Anatomical findings from animal studies suggest partially segregated MTL pathways converge in the hippocampus, with a posterior stream including parahippocampal and medial lateral entorhinal cortex and an anterior stream including perirhinal and lateral entorhinal cortex. These streams may operate on spatial and nonspatial information, respectively. In humans, such a functional dissociation has been suggested between parahippocampal and perirhinal cortex. Data from rodents and nonhuman primates suggest a similar dissociation between medial and lateral entorhinal cortex, which are reciprocally connected to parahippocampal and perirhinal cortex, but evidence for functional subregions within entorhinal cortex in humans is lacking. We addressed this issue using high resolution fMRI with improved spatial normalization. Volunteers (n = 28) performed a working memory paradigm involving the retrieval of spatial (scenes) and nonspatial (faces) information after distraction. A clear dissociation between MTL subcircuits emerged. A perirhinal-lateral entorhinal pathway was more involved in the retrieval of faces after distraction, whereas a parahippocampal medial entorhinal pathway was more involved in the retrieval of scenes after distraction. A cluster in posterior hippocampus showed a deactivation for the retrieval of faces after distraction. Our data thus provide direct evidence for a functional specialization within human entorhinal cortex and thereby strongly support MTL models that emphasize the importance of partially segregated parallel processing streams. PMID- 22492029 TI - Pinceau organization in the cerebellum requires distinct functions of neurofascin in Purkinje and basket neurons during postnatal development. AB - Basket axon collaterals synapse onto the Purkinje soma/axon initial segment (AIS) area to form specialized structures, the pinceau, which are critical for normal cerebellar function. Mechanistic details of how the pinceau become organized during cerebellar development are poorly understood. Loss of cytoskeletal adaptor protein Ankyrin G (AnkG) results in mislocalization of the cell adhesion molecule Neurofascin (Nfasc) at the Purkinje AIS and abnormal organization of the pinceau. Loss of Nfasc in adult Purkinje neurons leads to slow disorganization of the Purkinje AIS and pinceau morphology. Here, we used mouse conditional knock-out techniques to show that selective loss of Nfasc, specifically in Purkinje neurons during early development, prevented maturation of the AIS and resulted in loss of Purkinje neuron spontaneous activity and pinceau disorganization. Loss of Nfasc in both Purkinje and basket neurons caused abnormal basket axon collateral branching and targeting to Purkinje soma/AIS, leading to extensive pinceau disorganization, Purkinje neuron degeneration, and severe ataxia. Our studies reveal that the Purkinje Nfasc is required for AIS maturation and for maintaining stable contacts between basket axon terminals and the Purkinje AIS during pinceau organization, while the basket neuron Nfasc in combination with Purkinje Nfasc is required for proper basket axon collateral outgrowth and targeting to Purkinje soma/AIS. Thus, cerebellar pinceau organization requires coordinated mechanisms involving specific Nfasc functions in both Purkinje and basket neurons. PMID- 22492030 TI - Deterministic and stochastic neuronal contributions to distinct synchronous CA3 network bursts. AB - Computational studies have suggested that stochastic, deterministic, and mixed processes all could be possible determinants of spontaneous, synchronous network bursts. In the present study, using multicellular calcium imaging coupled with fast confocal microscopy, we describe neuronal behavior underlying spontaneous network bursts in developing rat and mouse hippocampal area CA3 networks. Two primary burst types were studied: giant depolarizing potentials (GDPs) and spontaneous interictal bursts recorded in bicuculline, a GABA(A) receptor antagonist. Analysis of the simultaneous behavior of multiple CA3 neurons during synchronous GDPs revealed a repeatable activation order from burst to burst. This was validated using several statistical methods, including high Kendall's coefficient of concordance values for firing order during GDPs, high Pearson's correlations of cellular activation times between burst pairs, and latent class analysis, which revealed a population of 5-6% of CA3 neurons reliably firing very early during GDPs. In contrast, neuronal firing order during interictal bursts appeared homogeneous, with no particular cells repeatedly leading or lagging during these synchronous events. We conclude that GDPs activate via a deterministic mechanism, with distinct, repeatable roles for subsets of neurons during burst generation, while interictal bursts appear to be stochastic events with cells assuming interchangeable roles in the generation of these events. PMID- 22492031 TI - The fraction of cortical GABAergic neurons is constant from near the start of cortical neurogenesis to adulthood. AB - Approximately one in five neurons is GABAergic in many neocortical areas and species, forming a critical balance between inhibition and excitation in adult circuits. During development, cortical GABAergic neurons are generated in ventral telencephalon and migrate up to developing cortex where the excitatory glutamatergic neurons are born. We ask here: when during development is the adult GABAergic/glutamatergic neuron ratio first established? To answer this question, we have determined the fraction of all neocortical GABAergic neurons that will become inhibitory (GAD67(+)) in mice from embryonic day 10.5 (E10.5) to postnatal day 28 (P28). We find that this fraction is close to 1/5, the adult value, starting from early in corticogenesis (E14.5, when GAD67(+) neurons are still migrating tangentially to the cortex) and continuing at the same 1/5 value throughout the remainder of brain development. Thus our data indicate the one-in five fraction of GABAergic neurons is already established during their neuronal migration and well before significant synapse formation. PMID- 22492032 TI - Coincident generation of pyramidal neurons and protoplasmic astrocytes in neocortical columns. AB - Astrocytes, one of the most common cell types in the brain, are essential for processes ranging from neural development through potassium homeostasis to synaptic plasticity. Surprisingly, the developmental origins of astrocytes in the neocortex are still controversial. To investigate the patterns of astrocyte development in the neocortex we examined cortical development in a transgenic mouse in which a random, sparse subset of neural progenitors undergoes CRE/lox recombination, permanently labeling their progeny. We demonstrate that neural progenitors in neocortex generate discrete columnar structures that contain both projection neurons and protoplasmic astrocytes. Ninety-five percent of developmental cortical columns labeled in our system contained both astrocytes and neurons. The astrocyte to neuron ratio of labeled cells in a developmental column was 1:7.4, similar to the overall ratio of 1:8.4 across the entire gray matter of the neocortex, indicating that column-associated astrocytes account for the majority of protoplasmic astrocytes in neocortex. Most of the labeled columns contained multiple clusters of several astrocytes. Dividing cells were found at the base of neuronal columns at the beginning of gliogenesis, and later within the cortical layers, suggesting a mechanism by which astrocytes could be distributed within a column. These data indicate that radial glia are the source of both neurons and astrocytes in the neocortex, and that these two cell types are generated in a spatially restricted manner during cortical development. PMID- 22492033 TI - Spike encoding of neurotransmitter release timing by spiral ganglion neurons of the cochlea. AB - Mammalian cochlear spiral ganglion neurons (SGNs) encode sound with microsecond precision. Spike triggering relies upon input from a single ribbon-type active zone of a presynaptic inner hair cell (IHC). Using patch-clamp recordings of rat SGN postsynaptic boutons innervating the modiolar face of IHCs from the cochlear apex, at room temperature, we studied how spike generation contributes to spike timing relative to synaptic input. SGNs were phasic, firing a single short latency spike for sustained currents of sufficient onset slope. Almost every EPSP elicited a spike, but latency (300-1500 MUs) varied with EPSP size and kinetics. When current-clamp stimuli approximated the mean physiological EPSC (~300 pA), several times larger than threshold current (rheobase, ~50 pA), spikes were triggered rapidly (latency, ~500 MUs) and precisely (SD, <50 MUs). This demonstrated the significance of strong synaptic input. However, increasing EPSC size beyond the physiological mean resulted in less-potent reduction of latency and jitter. Differences in EPSC charge and SGN baseline potential influenced spike timing less as EPSC onset slope and peak amplitude increased. Moreover, the effect of baseline potential on relative threshold was small due to compensatory shift of absolute threshold potential. Experimental first-spike latencies in response to a broad range of stimuli were predicted by a two-compartment exponential integrate-and-fire model, with latency prediction error of <100 MUs. In conclusion, the close anatomical coupling between a strong synapse and spike generator along with the phasic firing property lock SGN spikes to IHC exocytosis timing to generate the auditory temporal code with high fidelity. PMID- 22492034 TI - Dendritic BDNF synthesis is required for late-phase spine maturation and recovery of cortical responses following sensory deprivation. AB - Sensory experience in early postnatal life shapes neuronal connections in the brain. Here we report that the local synthesis of brain-derived neurotrophic factor (BDNF) in dendrites plays an important role in this process. We found that dendritic spines of layer 2/3 pyramidal neurons of the visual cortex in mutant mice lacking dendritic Bdnf mRNA and thus local BDNF synthesis were normal at 3 weeks of age, but thinner, longer, and more closely spaced (morphological features of immaturity) at 4 months of age than in wild-type (WT) littermates. Layer 2/3 of the visual cortex in these mutant animals also had fewer GABAergic presynaptic terminals at both ages. The overall size and shape of dendritic arbors were, however, similar in mutant and WT mice at both ages. By using optical imaging of intrinsic signals and single-unit recordings, we found that mutant animals failed to recover cortical responsiveness following monocular deprivation (MD) during the critical period, although they displayed normally the competitive loss of responsiveness to an eye briefly deprived of vision. Furthermore, MD still induced a loss of responsiveness to the closed eye in adult mutant mice, but not in adult WT mice. These results indicate that dendritic BDNF synthesis is required for spine pruning, late-phase spine maturation, and recovery of cortical responsiveness following sensory deprivation. They also suggest that maturation of dendritic spines is required for the maintenance of cortical responsiveness following sensory deprivation in adulthood. PMID- 22492036 TI - The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors. AB - The glucagon-like peptide 1 (GLP-1) system is a recently established target for type 2 diabetes treatment. In addition to regulating glucose homeostasis, GLP-1 also reduces food intake. Previous studies demonstrate that the anorexigenic effects of GLP-1 can be mediated through hypothalamic and brainstem circuits which regulate homeostatic feeding. Here, we demonstrate an entirely novel neurobiological mechanism for GLP-1-induced anorexia in rats, involving direct effects of a GLP-1 agonist, Exendin-4 (EX4) on food reward that are exerted at the level of the mesolimbic reward system. We assessed the impact of peripheral, central, and intramesolimbic EX4 on two models of food reward: conditioned place preference (CPP) and progressive ratio operant-conditioning. Food-reward behavior was reduced in the CPP test by EX4, as rats no longer preferred an environment previously paired to chocolate pellets. EX4 also decreased motivated behavior for sucrose in a progressive ratio operant-conditioning paradigm when administered peripherally. We show that this effect is mediated centrally, via GLP-1 receptors (GLP-1Rs). GLP-1Rs are expressed in several key nodes of the mesolimbic reward system; however, their function remains unexplored. Thus we sought to determine the neurobiological substrates underlying the food-reward effect. We found that the EX4-mediated inhibition of food reward could be driven from two key mesolimbic structures-ventral tegmental area and nucleus accumbens-without inducing concurrent malaise or locomotor impairment. The current findings, that activation of central GLP-1Rs strikingly suppresses food reward/motivation by interacting with the mesolimbic system, indicate an entirely novel mechanism by which the GLP-1R stimulation affects feeding-oriented behavior. PMID- 22492035 TI - Reducing human apolipoprotein E levels attenuates age-dependent Abeta accumulation in mutant human amyloid precursor protein transgenic mice. AB - Apolipoprotein E4 (apoE4) plays a major role in the pathogenesis of Alzheimer's disease. Brain amyloid-beta (Abeta) accumulation depends on age and apoE isoforms (apoE4 > apoE3) both in humans and in transgenic mouse models. Brain apoE levels are also isoform dependent, but in the opposite direction (apoE4 < apoE3). Thus, one prevailing hypothesis is to increase brain apoE expression to reduce Abeta levels. To test this hypothesis, we generated mutant human amyloid precursor protein transgenic mice expressing one or two copies of the human APOE3 or APOE4 gene that was knocked in and flanked by LoxP sites. We report that reducing apoE3 or apoE4 expression by 50% in 6-month-old mice results in efficient Abeta clearance and does not increase Abeta accumulation. However, 12-month-old mice with one copy of the human APOE gene had significantly reduced Abeta levels and plaque loads compared with mice with two copies, regardless of which human apoE isoform was expressed, suggesting a gene dose-dependent effect of apoE on Abeta accumulation in aged mice. Additionally, 12-month-old mice expressing one or two copies of the human APOE4 gene had significantly higher levels of Abeta accumulation and plaque loads than age-matched mice expressing one or two copies of the human APOE3 gene, suggesting an isoform-dependent effect of apoE on Abeta accumulation in aged mice. Moreover, Cre-mediated APOE4 gene excision in hippocampal astrocytes significantly reduced insoluble Abeta in adult mice. Thus, reducing, rather than increasing, apoE expression is an attractive approach to lowering brain Abeta levels. PMID- 22492037 TI - Eye-specific projections of retinogeniculate axons are altered in albino mice. AB - The divergence of retinal ganglion cell (RGC) axons into ipsilateral and contralateral projections at the optic chiasm and the subsequent segregation of retinal inputs into eye-specific domains in their target, the dorsal lateral geniculate nucleus (dLGN), are crucial for binocular vision. In albinism, affected individuals exhibit a lack or reduction of pigmentation in the eye and skin, a concomitant reduced ipsilateral projection, and diverse visual defects. Here we investigate how such altered decussation affects eye-specific retinogeniculate targeting in albino mice using the C57BL/6 Tyr(c-2J/c-2J) strain, in which tyrosinase, necessary for melanogenesis, is mutated. In albino mice, fewer RGCs from the ventrotemporal (VT) retina project ipsilaterally, reflected in a decrease in cells expressing ipsilateral markers. In addition, a population of RGCs from the VT retina projects contralaterally and, within the dLGN, their axons cluster into a patch separated from the contralateral termination area. Furthermore, eye-specific segregation is not complete in the albino dLGN and, upon perturbing postnatal retinal activity with epibatidine, the ipsilateral projection fragments and the aberrant contralateral patch disappears. These results suggest that the defects in afferent targeting and activity dependent refinement in the albino dLGN arise from RGC misspecification together with potential perturbations of early activity patterns in the albino retina. PMID- 22492038 TI - Differential association of receptor-Gbetagamma complexes with beta-arrestin2 determines recycling bias and potential for tolerance of delta opioid receptor agonists. AB - Opioid tendency to generate analgesic tolerance has been previously linked to biased internalization. Here, we assessed an alternative possibility; whether tolerance of delta opioid receptor agonists (DORs) could be related to agonist specific recycling. A first series of experiments revealed that DOR internalization by DPDPE and SNC-80 was similar, but only DPDPE induced recycling. We then established that the non-recycling agonist SNC-80 generated acute analgesic tolerance that was absent in mice treated with DPDPE. Furthermore, both agonists stabilized different conformations, whose distinct interaction with Gbetagamma subunits led to different modalities of beta arrestin2 (betaarr2) recruitment. In particular, bioluminescence resonance energy transfer (BRET) assays revealed that sustained activation by SNC-80 drew the receptor C terminus in close proximity of the N-terminal domain of Ggamma2, causing betaarr2 to interact with receptors and Gbetagamma subunits. DPDPE moved the receptor C-tail away from the Gbetagamma dimer, resulting in betaarr2 recruitment to the receptor but not in the vicinity of Ggamma2. These differences were associated with stable DOR-betaarr2 association, poor recycling, and marked desensitization following exposure to SNC-80, while DPDPE promoted transient receptor interaction with betaarr2 and effective recycling, which conferred protection from desensitization. Together, these data indicate that DORs may adopt ligand-specific conformations whose distinct recycling properties determine the extent of desensitization and are predictive of analgesic tolerance. Based on these findings, we propose that the development of functionally selective DOR ligands that favor recycling could constitute a valid strategy for the production of longer acting opioid analgesics. PMID- 22492039 TI - Iron efflux from astrocytes plays a role in remyelination. AB - How iron is delivered to the CNS for myelination is not well understood. We assessed whether astrocytes can provide iron to cells in the CNS for remyelination. To study this we generated a conditional deletion of the iron efflux transporter ferroportin (Fpn) in astrocytes, and induced focal demyelination in the mouse spinal cord dorsal column by microinjection of lysophosphatidylcholine (LPC). Remyelination assessed by electron microscopy was reduced in astrocyte-specific Fpn knock-out mice compared with wild-type controls, as was proliferation of oligodendrocyte precursor cells (OPCs). Cell culture work showed that lack of iron reduces the ability of microglia to express cytokines (TNF-alpha and IL-1beta) involved in remyelination. Furthermore, astrocytes in culture express high levels of FGF-2 in response to IL-1beta, and IGF-1 in response to TNF-alpha stimulation. FGF-2 and IGF-1 are known to be important for myelination. Reduction in IL-1beta and IGF-1 were also seen in astrocyte-specific Fpn knock-out mice after LPC-induced demyelination. These data suggest that iron efflux from astrocytes plays a role in remyelination by either direct effects on OPCs or indirectly by affecting glial activation. PMID- 22492040 TI - Neural mechanisms of object naming and word comprehension in primary progressive aphasia. AB - Primary progressive aphasia (PPA) is a neurodegenerative syndrome that causes a gradual atrophy of the left hemisphere language network, leading to impairments of object naming (anomia) and word comprehension. In 33 human subjects with PPA, object naming and word comprehension were explored with N400 potentials elicited by picture-word or picture-picture matching tasks. Two mechanisms of impairment were identified. In one group of patients, where the object name could be recognized but not retrieved during verbal naming, N400s in picture-word trials were also abnormal, revealing an associative basis for retrieval anomia. In these patients, a putative prephonological signal (i.e., lemma) evoked by the object picture appears to have become too weak to elicit retrieval, but not necessarily too weak to support the informationally less taxing process of recognition. A second group of PPA patients showed more severe naming deficits-the object name was neither verbalized nor recognized. Furthermore, nouns of the same category (but not those of other object categories) could not be identified as mismatches. This blurring of intracategory but not intercategory differentiation of word meaning was correlated with anterior temporal atrophy, predominantly in the left hemisphere, especially along the superior temporal gyrus. Although not part of the classic language network, this area appears critical for proceeding from generic to specific levels of word comprehension and object naming. N400 abnormalities emerged for lexical (picture-word) but not nonverbal (picture picture) associations, supporting a dual-route rather than amodal organization of object concepts. PMID- 22492041 TI - Distinct cortical correlates of autistic versus antisocial traits in a longitudinal sample of typically developing youth. AB - In humans, behaviors associated with autism and antisociality, disorders characterized by distinct social impairments, can be viewed as quantitative traits that range from frank impairment to normal variation, as found in the general population. Neuroimaging investigations of autism and antisociality demonstrate diagnostically specific aberrant cortical brain structure. However, little is known about structural brain correlates of social behavior in nonclinical populations. Therefore, we sought to determine whether autistic and antisocial traits exhibit dissociable cortical correlates and whether these associations are stable across development among typically developing youth. Three hundred twenty-three typically developing youth (age at first scan: mean = 10.63, SD = 3.71 years) underwent anatomic magnetic resonance imaging (1-6 scans each; total = 742 scans), and provided ratings of autistic and antisocial traits. Higher autistic trait ratings were associated with thinner cortex most prominently in right superior temporal sulcus while higher antisocial trait ratings were associated with thinner cortex in primarily bilateral anterior prefrontal cortices. There was no interaction with age, indicating that these brain-behavior associations were stable across development. Using assessments of both subclinical autistic and subclinical antisocial traits within a large longitudinal sample of typically developing youth, we demonstrate dissociable neuroanatomic correlations that parallel those found in the frank clinical disorders of autism (e.g., superior temporal cortex) and antisociality (e.g., anterior prefrontal cortex). Moreover, these correlations appear to be established in early childhood and remain fixed into early adulthood. These results support the dimensional view of psychopathology and provide neural signatures that can serve as informative endophenotypes for future genetic studies. PMID- 22492042 TI - BK channels mediate pathway-specific modulation of visual signals in the in vivo mouse retina. AB - The modulatory role of large-conductance Ca(2+)-activated K(+) (BK) channels in the nervous system has been extensively studied. In the retina, it has been shown that BK channels play a pivotal role in modulating feedback from A17 amacrine cells to rod bipolar cells (RBCs). Here, we used electroretinography to examine the functional role of BK channels for rod and cone vision in the retina in vivo using a genetically engineered mouse lacking functional BK channels (Bk(-/-)). Under dark-adapted and light-adapted conditions, the lack of BK channels had no effect on photoreceptor activity, suggesting that these ion channels do not modulate photoreceptor responses. At the bipolar cell level, the ERG signals attributed to RBCs in Bk(-/-) mice were not different from those in wild-type mice at low scotopic stimulus intensities. However, at high scotopic and low mesopic stimulus intensities, close to RBC saturation, a significant reduction of ERG signals reflecting RBC activity was present in the Bk(-/-) retina. At higher mesopic stimulus intensities activating both RBCs and cone bipolar cells (CBCs), no difference in ERG signals between Bk(-/-) and wild-type mice was found. In photopic stimulus paradigms, activity of ON- and OFF-CBCs in Bk(-/-) and wild type retinae was indistinguishable. These findings demonstrate that BK channels modulate visual responses in vivo at the bipolar cell level at intermediate stimulus conditions. PMID- 22492043 TI - Regulation of MAPK/ERK signaling and photic entrainment of the suprachiasmatic nucleus circadian clock by Raf kinase inhibitor protein. AB - Activation of the MAPK/ERK signaling cascade in the suprachiasmatic nucleus (SCN) is a key event that couples light to circadian clock entrainment. However, we do not fully understand the mechanisms that shape the properties of MAPK/ERK signaling in the SCN, and how these mechanisms may influence overt circadian rhythms. Here we show that Raf kinase inhibitor protein (RKIP) controls the kinetics of light-induced MAPK/ERK activity in the SCN and photic entrainment of behavioral rhythms. Light triggers robust phosphorylation of RKIP in the murine SCN and dissociation of RKIP and c-Raf. Overexpression of a nonphosphorylatable form of RKIP in the SCN of transgenic mice blocks light-induced ERK1/2 activation in the SCN and severely dampens light-induced phase delays in behavioral rhythms. Conversely, in RKIP knock-out (RKIP(-/-)) mice, light-induced ERK1/2 activity in the SCN is prolonged in the early and late subjective night, resulting in augmentation of the phase-delaying and -advancing effects of light. Reentrainment to an advancing light cycle was also accelerated in RKIP(-/-) mice. In relation to the molecular clockwork, genetic deletion of RKIP potentiated light-evoked PER1 and PER2 protein expression in the SCN in the early night. Additionally, RKIP(-/-) mice displayed enhanced transcriptional activation of mPeriod1 and the immediate early gene c-Fos in the SCN in response to a phase-delaying light pulse. Collectively, our data reveal an important role of RKIP in the regulation of MAPK/ERK signaling in the SCN and photic entrainment of the SCN clock. PMID- 22492044 TI - Central cardiovascular circuits contribute to the neurovascular dysfunction in angiotensin II hypertension. AB - Hypertension, a powerful risk factor for stroke and dementia, has damaging effects on the brain and its vessels. In particular, hypertension alters vital cerebrovascular control mechanisms linking neural activity to cerebral perfusion. In experimental models of slow-developing hypertension, free radical signaling in the subfornical organ (SFO), one of the forebrain circumventricular organs, is critical for the hormonal release and sympathetic activation driving the elevation in arterial pressure. However, the contribution of this central mechanism to the cerebrovascular alterations induced by hypertension remains uncertain. We tested the hypothesis that free radical production in the SFO is involved in the alterations in cerebrovascular regulation produced by hypertension. In a mouse model of gradual hypertension induced by chronic administration of subpressor doses of angiotensin II (AngII), suppression of free radicals in the SFO by overexpression of CuZn-superoxide dismutase (CuZnSOD) prevented the alteration in neurovascular coupling and endothelium-dependent responses in somatosensory cortex induced by hypertension. The SFO mediates the dysfunction via two signaling pathways. One involves SFO-dependent activation of the paraventricular hypothalamic nucleus, elevations in plasma vasopressin, upregulation of endothelin-1 in cerebral resistance arterioles and activation of endothelin type A receptors. The other pathway depends on activation of cerebrovascular AngII type 1 (AT1) receptors by AngII. Both pathways mediate vasomotor dysfunction by inducing vascular oxidative stress. The findings implicate for the first time the SFO and its efferent hypothalamic pathways in the cerebrovascular alterations induced by AngII, and identify vasopressin and endothelin-1 as potential therapeutic targets to counteract the devastating effects of hypertension on the brain. PMID- 22492045 TI - G-protein-coupled receptor 30 mediates rapid neuroprotective effects of estrogen via depression of NR2B-containing NMDA receptors. AB - 17-beta-estradiol (E2) is a steroid hormone involved in neuroprotection against excitotoxicity and other forms of brain injury. Through genomic and nongenomic mechanisms, E2 modulates neuronal excitability and signal transmission by regulating NMDA and non-NMDA receptors. However, the mechanisms and identity of the receptors involved remain unclear, even though studies have suggested that estrogen G-protein-coupled receptor 30 (GPR30) is linked to protection against ischemic injury. In the culture cortical neurons, treatment with E2 and the GPR30 agonist G1 for 45 min attenuated the excitotoxicity induced by NMDA exposure. The acute neuroprotection mediated by GPR30 is dependent on G-protein-coupled signals and ERK1/2 activation, but independent on transcription or translation. Knockdown of GPR30 using short hairpin RNAs (shRNAs) significantly reduced the E2-induced rapid neuroprotection. Patch-clamp recordings revealed that GPR30 activation depressed exogenous NMDA-elicited currents. Short-term GPR30 activation did not affect the expression of either NR2A- or NR2B-containing NMDARs; however, it depressed NR2B subunit phosphorylation at Ser-1303 by inhibiting the dephosphorylation of death-associated protein kinase 1 (DAPK1). DAPK1 knockdown using shRNAs significantly blocked NR2B subunit phosphorylation at Ser-1303 and abolished the GPR30-mediated depression of exogenous NMDA-elicited currents. Lateral ventricle injection of the GPR30 agonist G1 (0.2 MUg) provided significant neuroprotection in the ovariectomized female mice subjected to middle cerebral artery occlusion. These findings provide direct evidence that fast neuroprotection by estradiol is partially mediated by GPR30 and the subsequent downregulation of NR2B-containing NMDARs. The modulation of DAPK1 activity by GPR30 may be an important mediator of estradiol-dependent neuroprotection. PMID- 22492046 TI - Reduced calreticulin levels link endoplasmic reticulum stress and Fas-triggered cell death in motoneurons vulnerable to ALS. AB - Cellular responses to protein misfolding are thought to play key roles in triggering neurodegeneration. In the mutant superoxide dismutase (mSOD1) model of amyotrophic lateral sclerosis (ALS), subsets of motoneurons are selectively vulnerable to degeneration. Fast fatigable motoneurons selectively activate an endoplasmic reticulum (ER) stress response that drives their early degeneration while a subset of mSOD1 motoneurons show exacerbated sensitivity to activation of the motoneuron-specific Fas/NO pathway. However, the links between the two mechanisms and the molecular basis of their cellular specificity remained unclear. We show that Fas activation leads, specifically in mSOD1 motoneurons, to reductions in levels of calreticulin (CRT), a calcium-binding ER chaperone. Decreased expression of CRT is both necessary and sufficient to trigger SOD1(G93A) motoneuron death through the Fas/NO pathway. In SOD1(G93A) mice in vivo, reductions in CRT precede muscle denervation and are restricted to vulnerable motor pools. In vitro, both reduced CRT and Fas activation trigger an ER stress response that is restricted to, and required for death of, vulnerable SOD1(G93A) motoneurons. Our data reveal CRT as a critical link between a motoneuron-specific death pathway and the ER stress response and point to a role of CRT levels in modulating motoneuron vulnerability to ALS. PMID- 22492047 TI - Encoding of sensory prediction errors in the human cerebellum. AB - A central tenet of motor neuroscience is that the cerebellum learns from sensory prediction errors. Surprisingly, neuroimaging studies have not revealed definitive signatures of error processing in the cerebellum. Furthermore, neurophysiologic studies suggest an asymmetry, such that the cerebellum may encode errors arising from unexpected sensory events, but not errors reflecting the omission of expected stimuli. We conducted an imaging study to compare the cerebellar response to these two types of errors. Participants made fast out-and back reaching movements, aiming either for an object that delivered a force pulse if intersected or for a gap between two objects, either of which delivered a force pulse if intersected. Errors (missing the target) could therefore be signaled either through the presence or absence of a force pulse. In an initial analysis, the cerebellar BOLD response was smaller on trials with errors compared with trials without errors. However, we also observed an error-related decrease in heart rate. After correcting for variation in heart rate, increased activation during error trials was observed in the hand area of lobules V and VI. This effect was similar for the two error types. The results provide evidence for the encoding of errors resulting from either the unexpected presence or unexpected absence of sensory stimulation in the human cerebellum. PMID- 22492048 TI - Logarithmic compression of sensory signals within the dendritic tree of a collision-sensitive neuron. AB - Neurons in a variety of species, both vertebrate and invertebrate, encode the kinematics of objects approaching on a collision course through a time-varying firing rate profile that initially increases, then peaks, and eventually decays as collision becomes imminent. In this temporal profile, the peak firing rate signals when the approaching object's subtended size reaches an angular threshold, an event which has been related to the timing of escape behaviors. In a locust neuron called the lobula giant motion detector (LGMD), the biophysical basis of this angular threshold computation relies on a multiplicative combination of the object's angular size and speed, achieved through a logarithmic-exponential transform. To understand how this transform is implemented, we modeled the encoding of angular velocity along the pathway leading to the LGMD based on the experimentally determined activation pattern of its presynaptic neurons. These simulations show that the logarithmic transform of angular speed occurs between the synaptic conductances activated by the approaching object onto the LGMD's dendritic tree and its membrane potential at the spike initiation zone. Thus, we demonstrate an example of how a single neuron's dendritic tree implements a mathematical step in a neural computation important for natural behavior. PMID- 22492049 TI - Returning from oblivion: imaging the neural core of consciousness. AB - One of the greatest challenges of modern neuroscience is to discover the neural mechanisms of consciousness and to explain how they produce the conscious state. We sought the underlying neural substrate of human consciousness by manipulating the level of consciousness in volunteers with anesthetic agents and visualizing the resultant changes in brain activity using regional cerebral blood flow imaging with positron emission tomography. Study design and methodology were chosen to dissociate the state-related changes in consciousness from the effects of the anesthetic drugs. We found the emergence of consciousness, as assessed with a motor response to a spoken command, to be associated with the activation of a core network involving subcortical and limbic regions that become functionally coupled with parts of frontal and inferior parietal cortices upon awakening from unconsciousness. The neural core of consciousness thus involves forebrain arousal acting to link motor intentions originating in posterior sensory integration regions with motor action control arising in more anterior brain regions. These findings reveal the clearest picture yet of the minimal neural correlates required for a conscious state to emerge. PMID- 22492050 TI - The RNA-binding protein human antigen R controls global changes in gene expression during Schwann cell development. AB - An important prerequisite to myelination in peripheral nerves is the establishment of one-to-one relationships between axons and Schwann cells. This patterning event depends on immature Schwann cell proliferation, apoptosis, and morphogenesis, which are governed by coordinated changes in gene expression. Here, we found that the RNA-binding protein human antigen R (HuR) was highly expressed in immature Schwann cells, where genome-wide identification of its target mRNAs in vivo in mouse sciatic nerves using ribonomics showed an enrichment of functionally related genes regulating these processes. HuR coordinately regulated expression of several genes to promote proliferation, apoptosis, and morphogenesis in rat Schwann cells, in response to NRG1, TGFbeta, and laminins, three major signals implicated in this patterning event. Strikingly, HuR also binds to several mRNAs encoding myelination-related proteins but, contrary to its typical function, negatively regulated their expression, likely to prevent ectopic myelination during development. These functions of HuR correlated with its abundance and subcellular localization, which were regulated by different signals in Schwann cells. PMID- 22492051 TI - Synaptic activity unmasks dopamine D2 receptor modulation of a specific class of layer V pyramidal neurons in prefrontal cortex. AB - Dopamine D2 receptors (D2Rs) play a major role in the function of the prefrontal cortex (PFC), and may contribute to prefrontal dysfunction in conditions such as schizophrenia. Here we report that in mouse PFC, D2Rs are selectively expressed by a subtype of layer V pyramidal neurons that have thick apical tufts, prominent h-current, and subcortical projections. Within this subpopulation, the D2R agonist quinpirole elicits a novel afterdepolarization that generates voltage fluctuations and spiking for hundreds of milliseconds. Surprisingly, this afterdepolarization is masked in quiescent brain slices, but is readily unmasked by physiologic levels of synaptic input which activate NMDA receptors, possibly explaining why this phenomenon has not been reported previously. Notably, we could still elicit this afterdepolarization for some time after the cessation of synaptic stimulation. In addition to NMDA receptors, the quinpirole-induced afterdepolarization also depended on L-type Ca(2+) channels and was blocked by the selective L-type antagonist nimodipine. To confirm that D2Rs can elicit this afterdepolarization by enhancing Ca(2+) (and Ca(2+)-dependent) currents, we measured whole-cell Ca(2+) potentials that occur after blocking Na(+) and K(+) channels, and found quinpirole enhanced these potentials, while the selective D2R antagonist sulpiride had the opposite effect. Thus, D2Rs can elicit a Ca(2+) channel-dependent afterdepolarization that powerfully modulates activity in specific prefrontal neurons. Through this mechanism, D2Rs might enhance outputs to subcortical structures, contribute to reward-related persistent firing, or increase the level of noise in prefrontal circuits. PMID- 22492052 TI - Thalamocortical dysfunction and thalamic injury after asphyxial cardiac arrest in developing rats. AB - Global hypoxia-ischemia interrupts oxygen delivery and blood flow to the entire brain. Previous studies of global brain hypoxia-ischemia have primarily focused on injury to the cerebral cortex and to the hippocampus. Susceptible neuronal populations also include inhibitory neurons in the thalamic reticular nucleus. We therefore investigated the impact of global brain hypoxia-ischemia on the thalamic circuit function in the somatosensory system of young rats. We used single neuron recordings and controlled whisker deflections to examine responses of thalamocortical neurons to sensory stimulation in rat survivors of 9 min of asphyxial cardiac arrest incurred on postnatal day 17. We found that 48-72 h after cardiac arrest, thalamocortical neurons demonstrate significantly elevated firing rates both during spontaneous activity and in response to whisker deflections. The elevated evoked firing rates persist for at least 6-8 weeks after injury. Despite the overall increase in firing, by 6 weeks, thalamocortical neurons display degraded receptive fields, with decreased responses to adjacent whiskers. Nine minutes of asphyxial cardiac arrest was associated with extensive degeneration of neurites in the somatosensory nucleus as well as activation of microglia in the reticular nucleus. Global brain hypoxia-ischemia during cardiac arrest has a long-term impact on processing and transfer of sensory information by thalamic circuitry. Thalamic circuitry and normalization of its function may represent a distinct therapeutic target after cardiac arrest. PMID- 22492053 TI - Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking. AB - In humans, exposure to contexts previously associated with heroin use can provoke relapse. In rats, exposure to heroin-paired contexts after extinction of drug reinforced responding in different contexts reinstates heroin seeking. This effect is attenuated by inhibition of glutamate or dopamine transmission in nucleus accumbens shell, or inactivation of ventral medial prefrontal cortex (mPFC). Here, we used an anatomical asymmetrical disconnection procedure to demonstrate that an interaction between glutamatergic projections from ventral mPFC to accumbens shell and local dopamine D(1) postsynaptic receptors contributes to context-induced reinstatement of heroin seeking. We also combined the marker of neuronal activity, Fos, with the retrograde tracer Fluoro-Gold to assess activation in this pathway during context-induced reinstatement. Rats were trained to self-administer heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Lever pressing was subsequently extinguished in a nondrug-associated context in the presence of the discrete cue. Rats were then tested in the heroin- or extinction-associated contexts under extinction conditions. Injections of muscimol + baclofen into ventral mPFC in one hemisphere and D(1)-family receptor antagonist SCH 23390 into the contralateral or ipsilateral accumbens shell decreased context-induced reinstatement. Unilateral injections of muscimol + baclofen into ventral mPFC or SCH 23390 into the accumbens shell had no effect. Context-induced reinstatement was associated with increased Fos expression in ventral mPFC neurons, including those projecting to accumbens shell, with higher double-labeling in the ipsilateral projection than in the contralateral projection. Our results demonstrate that activation of glutamatergic projections from ventral mPFC to accumbens shell, previously implicated in inhibition of cocaine relapse, promotes heroin relapse. PMID- 22492054 TI - Hierarchical connectivity and connection-specific dynamics in the corticospinal corticostriatal microcircuit in mouse motor cortex. AB - The generation of purposive movement by mammals involves coordinated activity in the corticospinal and corticostriatal systems, which are involved in different aspects of motor control. In the motor cortex, corticospinal and corticostriatal neurons are closely intermingled, raising the question of whether and how information flows intracortically within and across these two channels. To explore this, we developed an optogenetic technique based on retrograde transfection of neurons with deletion-mutant rabies virus encoding channelrhodopsin-2, and used this in conjunction with retrograde anatomical labeling to stimulate and record from identified projection neurons in mouse motor cortex. We also used paired recordings to measure unitary connections. Both corticospinal and callosally projecting corticostriatal neurons in layer 5B formed within-class (recurrent) connections, with higher connection probability among corticostriatal than among corticospinal neurons. In contrast, across-class connectivity was extraordinarily asymmetric, essentially unidirectional from corticostriatal to corticospinal. Corticostriatal neurons in layer 5A and corticocortical neurons (callosal projection neurons similar to corticostriatal neurons) similarly received a paucity of corticospinal input. Connections involving presynaptic corticostriatal neurons had greater synaptic depression, and those involving postsynaptic corticospinal neurons had faster decaying EPSPs. Consequently, the three connections displayed a diversity of dynamic properties reflecting the different combinations of presynaptic and postsynaptic projection neurons. Collectively, these findings delineate a four-way specialized excitatory microcircuit formed by corticospinal and corticostriatal neurons. The "rectifying" corticostriatal-to-corticospinal connectivity implies a hierarchical organization and functional compartmentalization of corticospinal activity via unidirectional signaling from higher-order (corticostriatal) to lower-order (corticospinal) output neurons. PMID- 22492055 TI - Cooperative roles of BDNF expression in neurons and Schwann cells are modulated by exercise to facilitate nerve regeneration. AB - After peripheral nerve injury, neurotrophins play a key role in the regeneration of damaged axons that can be augmented by exercise, although the distinct roles played by neurons and Schwann cells are unclear. In this study, we evaluated the requirement for the neurotrophin, brain-derived neurotrophic factor (BDNF), in neurons and Schwann cells for the regeneration of peripheral axons after injury. Common fibular or tibial nerves in thy-1-YFP-H mice were cut bilaterally and repaired using a graft of the same nerve from transgenic mice lacking BDNF in Schwann cells (BDNF(-/-)) or wild-type mice (WT). Two weeks postrepair, axonal regeneration into BDNF(-/-) grafts was markedly less than WT grafts, emphasizing the importance of Schwann cell BDNF. Nerve regeneration was enhanced by treadmill training posttransection, regardless of the BDNF content of the nerve graft. We further tested the hypothesis that training-induced increases in BDNF in neurons allow regenerating axons to overcome a lack of BDNF expression in cells in the pathway through which they regenerate. Nerves in mice lacking BDNF in YFP(+) neurons (SLICK) were cut and repaired with BDNF(-/-) and WT nerves. SLICK axons lacking BDNF did not regenerate into grafts lacking Schwann cell BDNF. Treadmill training could not rescue the regeneration into BDNF(-/-) grafts if the neurons also lacked BDNF. Both Schwann cell- and neuron-derived BDNF are thus important for axon regeneration in cut peripheral nerves. PMID- 22492056 TI - Iron deficiency disrupts axon maturation of the developing auditory nerve. AB - Iron is critical in multiple aspects of CNS development, but its role in neurodevelopment--the ability of iron deficiency to alter normal development--is difficult to dissociate from the effects of anemia. We developed a novel dietary restriction model in the rat that allows us to study the effects of iron deficiency in the absence of severe anemia. Using a combination of auditory brainstem response analyses (ABR) and electron microscopy, we identified an unexpected impact of nonanemic iron deficiency on axonal diameter and neurofilament regulation in the auditory nerve. These changes are associated with altered ABR latency during development. In contrast to models of severe iron deficiency with anemia, we did not find consistent or prolonged defects in myelination. Our data demonstrate that iron deficiency in the absence of anemia disrupts normal development of the auditory nerve and results in altered conduction velocity. PMID- 22492057 TI - Distribution of hip pain in osteoarthritis patients secondary to developmental dysplasia of the hip. AB - OBJECTIVES: Our aim was to clarify the distribution of hip pain in patients with osteoarthritis of the hip secondary to developmental dysplasia of the hip (DDH). METHODS: We retrospectively studied 443 hips in 369 patients with osteoarthritis secondary to DDH; mean age was 61 years, and follow-up rate was 84 %. Hip pain was defined as preoperative pain that was relieved 3 months after total hip arthroplasty. RESULTS: Distribution of pain originating in the hip was 89 % (393 hips) to the groin, 38 % (170 hips) to the buttock, 33 % (144 hips) to the anterior thigh, 29 % (130 hips) to the knee, 27 % (118 hips) to the greater trochanter, 17 % (76 hips) to the low back, and 8 % (34 hips) to the lower leg. When the groin, buttock, and greater trochanter were combined as the hip region, 95 % (421 hips) of pain was located in the hip region. On the other hand, when the anterior thigh, knee, lower leg, and low back were combined as the referral region, 55 % (242 hips) showed referred pain. CONCLUSIONS: We suggest that rheumatologists be aware of hip disease masquerading as knee pain or low back pain. PMID- 22492058 TI - A common genetic network underlies substance use disorders and disruptive or externalizing disorders. AB - Here we summarize evidence obtained by our group during the last two decades, and contrasted it with a review of related data from the available literature to show that behavioral syndromes involving attention deficit/hyperactivity disorder (ADHD), externalizing disorders, and substance-use disorder (SUD) share similar signs and symptoms (i.e., have a biological basis as common syndromes), physiopathological and psychopathological mechanisms, and genetic factors. Furthermore, we will show that the same genetic variants harbored in different genes are associated with different syndromes and that non-linear interactions between genetic variants (epistasis) best explain phenotype severity, long-term outcome, and response to treatment. These data have been depicted in our studies by extended pedigrees, where ADHD, externalizing symptoms, and SUD segregate and co-segregate. Finally, we applied here a new formal network analysis using the set of significantly replicated genes that have been shown to be either associated and/or linked to ADHD, disruptive behaviors, and SUD in order to detect significantly enriched gene categories for protein and genetic interactions, pathways, co-expression, co-localization, and protein domain similarity. We found that networks related to pathways involved in axon guidance, regulation of synaptic transmission, and regulation of transmission of nerve impulse are overrepresented. In summary, we provide compiled evidence of complex networks of genotypes underlying a wide phenotype that involves SUD and externalizing disorders. PMID- 22492059 TI - The interplay of genes and adolescent development in substance use disorders: leveraging findings from GWAS meta-analyses to test developmental hypotheses about nicotine consumption. AB - The present study evaluated gene by development interaction in cigarettes smoked per day (CPD) in a longitudinal community-representative sample (N = 3,231) of Caucasian twins measured at ages 14, 17, 20, and 24. Biometric heritability analyses show strong heritabilities and shared environmental influences, as well as cross-age genetic and shared environmental correlations. Single nucleotide polymorphisms (SNPs) previously associated with CPD according to meta-analysis were summed to create a SNP score. At best, the SNP score accounted for 1 % of the variance in CPD. The results suggest developmental moderation with a larger significant SNP score effect on CPD at ages 20 and 24, and smaller non significant effect at ages 14 and 17. These results are consistent with the notion that nicotine-specific genetic substance use risk is less important at younger ages, and becomes more important as individuals age into adulthood. In a complementary analysis, the same nicotine-relevant SNP score was unrelated to the frequency of alcohol use at ages 14, 17, 20, or 24. These results indicate that the SNP score is specific to nicotine in this small sample and that increased exposure to nicotine at ages 20 and 24 does not influence the extent of concurrent or later alcohol use. Increased sample sizes and replication or meta analysis are necessary to confirm these results. The methods and results illustrate the importance and difficulty of considering developmental processes in understanding the interplay of genes and environment. PMID- 22492060 TI - The distinctive nature of atherosclerotic vascular disease in diabetes: pathophysiological and morphological insights. AB - As the incidence of diabetes mellitus continues to rise, parallel increases in the rates of diabetic atherosclerotic vascular disease are projected to impart major health and socioeconomic challenges for authorities worldwide. Diabetes results in a proatherogenic phenotype, manifesting in an accelerated, diffuse, polyvascular fashion. In this review, we highlight the pathophysiological and morphological hallmarks of diabetic atherosclerosis. PMID- 22492062 TI - The development of efficient plant promoters for transgene expression employing plant virus promoters. PMID- 22492061 TI - The diagnosis and management of cerebrovascular disease in diabetes. AB - Cerebrovascular disease is a leading cause of morbidity and mortality in diabetes. Compared with nondiabetic patients, diabetic patients have at least twice the risk for stroke, earlier onset of symptoms, and worse functional outcomes. Approximately 20 % of diabetic patients will die from stroke, making it one of the leading causes of death in this population. Effective strategies for primary and secondary prevention of stroke have been developed in research cohorts that included both diabetic and nondiabetic patients. Nevertheless, prevention in diabetes has some specific considerations. In this paper, we summarize evidence to guide the diagnosis and management of stroke in diabetic patients. We propose that diabetic stroke patients should have a robust risk assessment to target interventions, like other patients with cerebrovascular disease, but with special attention to glycemic control and lifestyle modification. PMID- 22492063 TI - Impaired immune evasion in HIV through intracellular delays and multiple infection of cells. AB - With its high mutation rate, HIV is capable of escape from recognition, suppression and/or killing by CD8(+) cytotoxic T lymphocytes (CTLs). The rate at which escape variants replace each other can give insights into the selective pressure imposed by single CTL clones. We investigate the effects of specific characteristics of the HIV life cycle on the dynamics of immune escape. First, it has been found that cells in HIV-infected patients can carry multiple copies of proviruses. To investigate how this process affects the emergence of immune escape, we develop a mathematical model of HIV dynamics with multiple infections of cells. Increasing the frequency of multiple-infected cells delays the appearance of immune escape variants, slows down the rate at which they replace the wild-type variant and can even prevent escape variants from taking over the quasi-species. Second, we study the effect of the intracellular eclipse phase on the rate of escape and show that escape rates are expected to be slower than previously anticipated. In summary, slow escape rates do not necessarily imply inefficient CTL-mediated killing of HIV-infected cells, but are at least partly a result of the specific characteristics of the viral life cycle. PMID- 22492064 TI - Host modulation of parasite competition in multiple infections. AB - Parasite diversity is a constant challenge to host immune systems and has important clinical implications, but factors underpinning its emergence and maintenance are still poorly understood. Hosts typically harbour multiple parasite genotypes that share both host resources and immune responses. Parasite diversity is thus shaped not only by resource competition between co-infecting parasites but also by host-driven immune-mediated competition. We investigated these effects in an insect-trypanosome system, combining in vivo and in vitro single and double inoculations. In vivo, a non-pathogenic, general immune challenge was used to manipulate host immune condition and resulted in a reduced ability of hosts to defend against a subsequent exposure to the trypanosome parasites, illustrating the costs of immune activation. The associated increase in available host space benefited the weaker parasite strains of each pair as much as the otherwise more competitive strains, resulting in more frequent multiple infections in immune-challenged hosts. In vitro assays showed that in the absence of a host, overall parasite diversity was minimal because the outcome of competition was virtually fixed and resulted in strain extinction. Altogether, this shows that parasite competition is largely host-mediated and suggests a role for host immune condition in the maintenance of parasite diversity. PMID- 22492066 TI - Appropriate evaluation of and risk factors for radiation dermatitis in breast cancer patients receiving hypofractionated whole-breast irradiation after breast conserving surgery. AB - BACKGROUND: In grading radiation-induced dermatitis (RID), there are not only inter-evaluator differences but also intra-evaluator variations. We retrospectively analyzed the advantages of establishing a more precise evaluation method using photographs to minimize intra-evaluator variations and RID risk factors. METHODS: We analyzed 301 breasts, including those of 3 patients with bilateral breast cancer who underwent hypofractionated whole-breast irradiation (WBI) after breast-conserving surgery. Four radiation oncologists (A, B, C and D) evaluated photographs taken before, during and after radiation therapy and graded RID using two methods. RESULTS: The percentages of maximum grades between the two methods varied widely. Kappa statistics revealed that the inter- and intra evaluator agreements were mostly fair. In multivariate analysis, age (<=60 years old), boost irradiation, concurrent hormonal therapy and chemotherapy prior to WBI are statistically significant risk factors for >= grade 2 RID according to two evaluators (B and D), two evaluators (A and B), one evaluator (B) and one evaluator (D), respectively. CONCLUSIONS: The assessment of serial skin change in photographs is useful for judging RID. No risk factor was statistically significant for all evaluators because of wide intra-evaluator variations and large inter-evaluator differences. More objective criteria are needed for appropriate evaluation of RID. PMID- 22492065 TI - Polyploidy in fungi: evolution after whole-genome duplication. AB - Polyploidy is a major evolutionary process in eukaryotes-particularly in plants and, to a less extent, in animals, wherein several past and recent whole-genome duplication events have been described. Surprisingly, the incidence of polyploidy in other eukaryote kingdoms, particularly within fungi, remained largely disregarded by the scientific community working on the evolutionary consequences of polyploidy. Recent studies have significantly increased our knowledge of the occurrence and evolutionary significance of fungal polyploidy. The ecological, structural and functional consequences of polyploidy in fungi are reviewed here and compared with the knowledge acquired with conventional plant and animal models. In particular, the genus Saccharomyces emerges as a relevant model for polyploid studies, in addition to plant and animal models. PMID- 22492070 TI - [Palpitations: help, my heart is stumbling!]. PMID- 22492069 TI - Primary caregiver characteristics and transitions in community-based care. AB - OBJECTIVES: To identify informal primary caregiver characteristics associated with care transitions of community-dwelling older persons with impairments in daily living activities. METHOD: Data for this study were pooled to observe transitions from Wave 1-Wave 2 and Wave 2-Wave 3 of the Second Longitudinal Survey on Aging (LSOA II). The sample includes respondents with at least one impairment in daily living activities and with an informal caregiver at baseline of each transition period (n = 2,990). Primary caregiver transitions to another informal caregiver, to formal care, to a nursing home, or to no care were modeled using multinomial logistic regression. RESULTS: More than half (54%) of the surviving respondents experienced a care transition for a period of 2 years. Multivariate results indicate that husband and son primary caregivers are more likely to transfer care than wives and daughters, although children caring for same-gender parents were less likely to transfer out of the primary caregiver role than children caring for parents of the opposite sex. Respondents with primary caregivers who are "other" relatives or nonrelatives, who are not coresident with the care receiver, or who are assisted by secondary helpers were at elevated risk for care transitions over the 2-year study period. DISCUSSION: The results of this study suggest that older persons' care transitions result from complex informal network dynamics, with primary caregiver gender and relationship to the care receiver playing key roles. PMID- 22492072 TI - [Do advance directives facilitate the process of dying in dignity?]. AB - The benefit of an advance directive was evaluated by written questionnaires and personal interviews with relatives, nurses and physicians of recently deceased patients. The results indicate that a written advance directive is less important than ongoing communication between relatives or a designated person of trust, physicians and nurses. A standard advance directive however is helpful to initiate the discussion about the last will of a person. A further result of this survey is, that physicians and nurses do not feel confident in decision making regarding treatment and care of the dying. A written advance directive or a designated person of trust helping decisions making in the presumptive will of the patient, is seen as helpful. PMID- 22492073 TI - [My patient is anxious - what's next?]. AB - Anxiety disorders are common disorders associated with marked impairment and reduced quality of life. In the general practitioner's office as well as in the specialist's consultation, patients with anxiety disorders frequently present primarily somatic complaints. Many patients run through numerous checkups prior to be referred to psychiatric treatment. Some basic aspects can help to earlier identify patients suffering from anxiety disorders and to initiate sufficient therapy. With evidence-based treatment with cognitive-behavioral therapy and adequate psychopharmacotherapy, many patients can achieve complete remission of symptoms. Initial treatment can comprise specific psycho-education as well as first-line psychopharmacological treatment with e.g. SSRI. PMID- 22492074 TI - [Preeclampsia - a life-time risk for the mother]. AB - Preeclampsia is a pregnancy-induced disease associated with considerable maternal and fetal morbidity and mortality. While delivery usually results in a complete healing there is growing evidence that preeclampsia is a significant risk factor for cardiovascular and metabolic diseases in later life of these mothers. Especially early-onset, severity and number of deliveries with preeclampsia are relevant risk-factors. Preeclampsia itself could play a causative role or may just be a transient early symptom. An increasing understanding of these correlations is of major importance concerning health prevention and early detection of diseases in these young women. PMID- 22492075 TI - [How can successful weight reduction be maintained the best?]. PMID- 22492076 TI - [Electric blue finger nail]. AB - Glomus tumors are benign tumors and are most often localized acral. They usually are diagnosed non-invasively by patient's history, clinical examination, duplex ultrasound and MRI-angiography. Need for intervention depends on the symptoms. PMID- 22492077 TI - [Four drug groups cause two thirds of all adverse drug effect-induced emergency hospitalizations in the elderly]. PMID- 22492078 TI - [Added niacin administration to statins in low HDL has no additive effect in nonacute cardiovascular diseases]. PMID- 22492080 TI - [CME ultrasonography. Refractory arterial hypertension. Renal artery stenosis in fibromuscular dysplasia]. PMID- 22492083 TI - Availability and costs of single cigarettes in Guatemala. AB - INTRODUCTION: Single-cigarette sales have been associated with increased cigarette accessibility to less educated, lower-income populations, and minors; lower immediate cost, and increased smoking cues. Since 1997, Guatemalan Law bans the sale of single cigarettes and packs with fewer than 20 cigarettes. In 2005, Guatemala ratified the World Health Organization Framework Convention on Tobacco Control (WHO FCTC); it is therefore obliged to "prohibit sale of cigarettes individually or in small packets." METHODS: Blocks were numbered and randomly selected in Guatemala City and 3 neighboring towns. All stores in each block were surveyed. Single-cigarette and fewer than 20-cigarette pack sales were assessed by observation and purchase attempts. Cigarette brands and manufacturers (Philip Morris, PM or British American Tobacco, BAT) were also recorded. Percentages and means were used to describe data. Analyses were done using STATA 11.0. RESULTS: Of 398 stores and street vendors surveyed, 75.6% (301) sold cigarettes. Of these, 91% (275) sold single cigarettes and none sold fewer than 20-cigarette packs. Only informal economic sectors sold singles. There was no difference on sales between Guatemala City and neighboring towns and by store type. Buying 20 single cigarettes was US$ 0.83 more expensive than buying a 20-cigarette pack. The most prevalent brands were Rubios (PM), Marlboro (PM), Payasos (BAT), and After Hours (BAT). CONCLUSIONS: Single-cigarettes sales are highly prevalent among informal economic sectors in Guatemala City and its neighboring towns. Our data should prove useful to advocate for FCTC Article 16 enforcement in Guatemala. PMID- 22492084 TI - Preclinical evidence that activation of mesolimbic alpha 6 subunit containing nicotinic acetylcholine receptors supports nicotine addiction phenotype. AB - INTRODUCTION: Nicotine is a major psychoactive ingredient in tobacco yet very few individuals quit smoking with the aid of nicotine replacement therapy. Targeted therapies with more selective action at nicotinic acetylcholine receptors (nAChRs) that contain a beta2 subunit (beta2*nAChRs; *denotes assembly with other subunits) have enjoyed significantly greater success, but exhibit potential for unwanted cardiac, gastrointestinal, and emotive side effects. DISCUSSION: This literature review focuses on the preclinical evidence that suggests that subclasses of beta2*nAChRs that assemble with the alpha6 subunit may provide an effective target for tobacco cessation. alpha6beta2*nAChRs have a highly selective pattern of neuroanatomical expression in catecholaminergic nuclei including the ventral tegmental area and its projection regions. alpha6beta2*nAChRs promote dopamine (DA) neuron activity and DA release in the mesolimbic dopamine system, a brain circuitry that is well-studied for its contributions to addiction behavior. A combination of genetic and pharmacological studies indicates that activation of alpha6beta2*nAChRs is necessary and sufficient for nicotine psychostimulant effects and nicotine self-administration. alpha6beta2*nAChRs support maintenance of nicotine use, support the conditioned reinforcing effects of drug-associated cues, and regulate nicotine withdrawal. CONCLUSIONS: These data suggest that alpha6beta2*nAChRs represent a critical pool of high affinity beta2*nAChRs that regulates nicotine dependence phenotype and suggest that inhibition of these receptors may provide an effective strategy for tobacco cessation therapy. PMID- 22492085 TI - Developing and validating a human laboratory model to screen medications for smoking cessation. AB - INTRODUCTION: To facilitate translational work in medications development for smoking cessation, we have developed a human laboratory analogue of smoking lapse behavior. Our paradigm models 2 critical features of smoking lapse: the ability to resist the first cigarette and subsequent ad libitum smoking. In this paper we present the results of 2 studies designed to develop and validate the effect of nicotine deprivation on smoking lapse behavior. METHODS: Study 1 (n = 30) was designed to develop the model parameters by examining varying levels of nicotine deprivation (1, 6, and 18 hr; within-subject) and identifying optimum levels of monetary reinforcement to provide while modeling the ability to resist smoking. Study 2 was designed to validate the model by screening smoking cessation medications with known clinical efficacy. Subjects (n = 62) were randomized to either varenicline 2 mg/day, bupropion 300 mg/day, or placebo, and we then modeled their ability to resist smoking and subsequent ad libitum smoking. RESULTS: In Study 1, increasing levels of nicotine deprivation and decreasing levels of monetary reinforcement decreased the ability to resist smoking. In Study 2, the lapse model was found to be sensitive to medication effects among smokers who demonstrated a pattern of heavy, uninterrupted, and automated smoking (i.e., smoked within 5 min of waking). Ratings of craving, mood, withdrawal, and subjective cigarette effects are presented as secondary outcomes with results mirroring clinical findings. CONCLUSIONS: Our smoking lapse model demonstrates promise as a translational tool to screen novel smoking cessation medications. Next steps in this line of research will focus on evaluating predictive validity. PMID- 22492086 TI - Tobacco smoking among migrant factory workers in Shenzhen, China. AB - BACKGROUND: While several studies of smoking behaviors in rural-to-urban Chinese migrants exist, none to our knowledge have focused on factory workers, estimated to represent between 10% and 20% of China's total rural-to-urban migratory population. This paper assesses factors associated with smoking behavior among rural-to-urban migrant factory workers in Shenzhen, China. METHODS: A cross sectional survey of migrant workers from 44 randomly selected factories in Shenzhen, China. Participants were migrant factory workers aged 16-59 years and holding nonlocal household registration. The main outcome measures were demographic, migration-related, and behavioral factors associated with smoking status. RESULTS: Four thousand and eighty-eight completed questionnaires were obtained (response rate 95.5%). Overall smoking prevalence (including occasional, daily, and heavy daily smoking) was 19.1%. The prevalence of daily smoking (including heavy daily smoking) was higher in men (27.3%) than women (0.7%). These rates are significantly lower than national smoking rates (59.5% in men, 3.7% in women) and rates found in a similar study. A high-risk group of men who smoke heavily and consume alcohol frequently was identified. Longer working hours and less rest were associated with higher rates of smoking. Frequent Internet use and lack of insurance were associated with lifetime smoking. Gender-adjusted models showed that poorer mental health and an accumulated working time in Shenzhen of 2-3 years increased female workers' likelihood of smoking. CONCLUSIONS: Migrant factory workers in Shenzhen had lower rates of smoking than other population groups in China. The identification of risk factors for heavy smoking may help to effectively target health promotion interventions. PMID- 22492087 TI - Cardiac ultrasound imaging in heart failure: recent advances. AB - Several new imaging modalities are being utilized in the management of heart failure. Echocardiography and speckle tracking imaging offer clinician the benefits of easy accessibility, real time data interpretation and objective quantification of heart function. Accordingly, this article reviews the current evidence base related to the use of echocardiography and other advanced ultrasonography techniques in heart failure, and discusses applications as well as limitations of these emerging technologies. The role of cardiac resynchronization therapy (CRT) and implications of the PROSPECT (Predictors of Response to CRT) trial in management of heart failure are also reviewed. The article concludes with a discussion about the evolving role of echocardiography in diagnosis and management of subclinical heart disease, so that preventive strategies may be devised. PMID- 22492088 TI - Right hepatic artery traveling anteriorly to the common bile duct. AB - The topographic relationship between arteries and hepatobiliary ducts can be crucial during cholecystectomy. We observed the right hepatic artery traveling a rare route in a 91-year-old male. The common hepatic artery gave off the left hepatic, the right gastric, the gastroduodenal, and the right hepatic arteries consecutively without forming the proper hepatic artery. The right hepatic artery crossed the common bile duct anteriorly, ascended on the right side of the duct, passed the cystic duct posteriorly, and entered the right lobe of the liver. The so-called 9 o'clock artery running on the right side of the common hepatic and common biliary is reasonably speculated to be the aberrant right hepatic artery as presently shown. Developmental and clinical issues are discussed. PMID- 22492089 TI - Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo. AB - OBJECTIVE: Thrombin induces CD40 ligand (CD40L) and matrix metalloproteinases (MMPs) under inflammatory/prothrombotic conditions. Thrombin and CD40L could modulate endothelial MMP-10 expression in vitro and in vivo. METHODS AND RESULTS: Human endothelial cells were stimulated with thrombin (0.1-10 U/mL), CD40L (0.25 1 MUg/mL), or their combination (thrombin/CD40L) to assess MMP-10 expression and microparticle generation. Thrombin/CD40L elicited higher MMP-10 mRNA (5-fold; P<0.001) and protein levels (4.5-fold; P<0.001) than either stimulus alone. This effect was mimicked by a protease-activated receptor-1 agonist and antagonized by hirudin, a-protease-activated receptor-1, alpha-CD40L, and alpha-CD40 antibodies. The synergistic effect was dependent on p38 mitogen-activated protein kinase and c-Jun N-terminal kinase-1 pathways. Thrombin also upregulated the expression of CD40 in endothelial cell surface increasing its availability, thereby favoring its synergistic effects with CD40L. In mice, thrombin/CD40L further increased the aortic MMP-10 expression. Septic patients with systemic inflammation and enhanced thrombin generation (n=60) exhibited increased MMP-10 and soluble CD40L levels associated with adverse clinical outcome. Endothelial and systemic activation by thrombin/CD40L and lipopolysaccharide also increased microparticles harboring MMP 10 and CD40L. CONCLUSIONS: Thrombin/CD40L elicited a strong synergistic effect on endothelial MMP-10 expression and microparticles containing MMP-10 in vitro and in vivo, which may represent a new link between inflammation/thrombosis with prognostic implications. PMID- 22492092 TI - Experiments, causation, and the uses of vivisection in the first half of the seventeenth century. AB - Defining experiment was particularly vexed in the realm of anatomical dissection and vivisection. Was dissection merely descriptive, or something more? Harvey's discovery of the circulation of the blood and Aselli's discovery of the so-called lacteal veins shaped much anatomical research between the late 1620s and the 1650s. While the techniques of dissection and vivisection gained wide use, there was much debate on the validity of the circulation in particular, and its relationship to the lacteal veins. Critics, particularly the French anatomist Jean Riolan, but also the natural philosopher Pierre Gassendi, focused on the lack of causation in Harvey's method and the lack of medical use and not on his use of vivisection. Jean Pecquet's discovery of the thoracic duct in 1651 changed the terms of the debate by definitively connecting the circulation with the lacteals. Riolan's critiques of Pecquet in the 1650s show profoundly differing notions of the purpose of dissection. While Gassendi eventually accepted Harvey's concept of the circulation, Riolan never did. PMID- 22492091 TI - Exenatide, a glucagon-like peptide-1 receptor agonist, acutely inhibits intestinal lipoprotein production in healthy humans. AB - OBJECTIVE: Incretin-based therapies for the treatment of type 2 diabetes mellitus improve plasma lipid profiles and postprandial lipemia, but their exact mechanism of action remains unclear. Here, we examined the acute effect of the glucagon like peptide-1 receptor agonist, exenatide, on intestinal and hepatic triglyceride-rich lipoprotein production and clearance in healthy humans. METHODS AND RESULTS: Fifteen normolipidemic, normoglycemic men underwent 2 studies each (SC 10 MUg exenatide versus placebo), 4 to 6 weeks apart, in random order, in which triglyceride-rich lipoprotein particle kinetics were examined with a primed, constant infusion of deuterated leucine and analyzed by multicompartmental modeling under pancreatic clamp conditions. A fed state was maintained during each study by infusing a high-fat, mixed macronutrient, liquid formula at a constant rate directly into the duodenum via a nasoduodenal tube. Exenatide significantly suppressed the plasma concentration and production rate of triglyceride-rich lipoprotein-apolipoprotein B-48, but not of triglyceride rich lipoprotein-apolipoprotein B-100. CONCLUSIONS: These results suggest a possible direct effect of exenatide on intestinal lipoprotein particle production, independent of changes in weight gain and satiety as seen in long term studies and independent of changes in gastric emptying. This finding expands our understanding of the effects of exenatide in metabolic regulation beyond its primary therapeutic role in regulation of glucose homeostasis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov, NCT01056549. PMID- 22492090 TI - Reactive oxygen species regulate osteopontin expression in a murine model of postischemic neovascularization. AB - OBJECTIVE: Previous findings from our laboratory demonstrated that neovascularization was impaired in osteopontin (OPN) knockout animals. However, the mechanisms responsible for the regulation of OPN expression in the setting of ischemia remain undefined. Therefore, we sought to determine whether OPN is upregulated in response to ischemia and hypothesized that hydrogen peroxide (H(2)O(2)) is a critical component of the signaling mechanism by which OPN expression is upregulated in response to ischemia in vivo. METHODS AND RESULTS: To determine whether ischemic injury upregulates OPN, we used a murine model of hindlimb ischemia. Femoral artery ligation in C57BL/6 mice significantly increased OPN expression and H(2)O(2) production. Infusion of C57BL/6 mice with polyethylene glycol-catalase (10 000 U/kg per day) or the use of transgenic mice with smooth muscle cell-specific catalase overexpression blunted ischemia-induced OPN, suggesting ischemia-induced OPN expression is H(2)O(2)-dependent. Decreased H(2)O(2)-mediated OPN blunted reperfusion and collateral formation in vivo. In contrast, the overexpression of OPN using lentivirus restored neovascularization. CONCLUSIONS: Scavenging H(2)O(2) blocks ischemia-induced OPN expression, providing evidence that ischemia-induced OPN expression is H(2)O(2) dependent. Decreased OPN expression impaired neovascularization, whereas overexpression of OPN increased angiogenesis, supporting our hypothesis that OPN is a critical mediator of postischemic neovascularization and a potential novel therapeutic target for inducing new vessel growth. PMID- 22492093 TI - Clinical significance of peritumoral lymphatic vessel density and lymphatic vessel invasion detected by D2-40 immunostaining in FIGO Ib1-IIa squamous cell cervical cancer. AB - The clinical significance of lymphangiogenesis in cervical cancer remains controversial. Our aim was to investigate the correlation between lymphangiogenesis, lymphatic vessel invasion (LVI) and tumor metastasis, invasion and prognosis in squamous cell cervical cancer. Paraffin sections of 90 patients with FIGO (Federation Internationale de Gynecologie et d'Obstetrique) Ib1-IIa squamous cell cervical cancer were stained for immunohistochemistry with a D2-40 monoclonal antibody against the carcinoembryonic antigen M2A. The lymphatic vessel density (LVD) and LVI were measured, and their relationship with the clinicopathological data was analyzed. D2-40-positive lymphatic vessels were found in 75 of the 90 patients (83.3 %). All D2-40-positive vessels were located in peritumoral areas. The mean+/-SD of the peritumoral LVD was 10.08+/-4.16. The positive rate of LVI was 32.0 % (24/75). The recurrence rate of patients with LVD >10 (62.1 %, 18/29) was significantly higher than that of patients with LVD <=10 (34.8 %, 16/46, P = 0.021). The 5-year recurrence-free survival rate of patients with LVD >10 (41.0 %) was significantly lower than that of patients with LVD <=10 (67.0 %, P = 0.045). Univariate analysis showed that the peritumoral LVD (<=10 vs >10) was correlated with LVI (absent vs present, P = 0.016). The peritumoral LVD and LVI showed no correlation with age, FIGO stage, tumor size, tumor grade, depth of invasion, or pelvic lymph node metastasis (all: P > 0.05). Peritumoral lymphangiogenesis was correlated with the recurrence and recurrence-free survival in patients with squamous cell cervical cancer. Examination of peritumoral LVD in these patients might therefore help to estimate the risk of recurrence. PMID- 22492094 TI - Baroreceptor sensitivity after Valsalva maneuver in women with chronic obstructive pulmonary disease. AB - PURPOSE: Reduced baroreceptor sensitivity (BRS) results in changes in autonomic modulation. Patients with chronic obstructive pulmonary disease (COPD) may have altered BRS. Therefore, we compared BRS between COPD patients and normal controls. METHODS: We compared 14 COPD patients [mean (+/-SD) age, 62 +/- 8 years] to 14 healthy controls [mean (+/-SD) age, 59 +/- 6 years] for the loss of BRS. All patients received beta(2)-agonist therapy but were free from any other type of medication that would interfere with autonomic responses, all controls were free from cardiopulmonary disease, and none was taking medications. All participants were female, post-menopausal, had no known cardiac disease and were ex-smokers. Reduced baroreceptor sensitivity was determined using the slope of the magnitude of R-R widening over the increase in systolic blood pressure following Valsalva maneuver. RESULTS: The mean BRS in controls versus COPD patients showed a mean value of 6.15 +/- 2.26 versus 1.91 +/- 2.92 ms/mmHg (p < 0.001). CONCLUSIONS: These findings are consistent with other abnormalities of autonomic disruption as previously reported, and demonstrate a severe blunting of the baroreceptor response in individuals with COPD. The cause of this altered BRS response in COPD is not fully clear, we postulate that air trapping with persistent elevation of intrathoracic pressure may lead to a subsequent blunting of the sensitivity of the baroreceptors. PMID- 22492095 TI - Sympathetic nerve activity in stress-induced cardiomyopathy. AB - PURPOSE: To evaluate directly recorded efferent sympathetic nerve traffic in patients with stress-induced cardiomyopathy (SIC). BACKGROUND: SIC is a syndrome affecting mostly postmenopausal women following severe emotional stress. Though the precise pathophysiology is not well understood, a catecholamine overstimulation of the myocardium is thought to underlie the pathogenesis. METHODS: Direct recordings of multiunit efferent postganglionic muscle sympathetic nerve activity (MSNA) were obtained from 12 female patients, 5 in the acute (24-48 h) and 7 in the recovery phase (1-6 months), with apical ballooning pattern and 12 healthy matched controls. MSNA was expressed as burst frequency (BF), burst incidence (BI) and relative median burst amplitude (RMBA %). One of the twelve patients in this study was on beta blockade treatment due to a different illness, at time of onset of SIC. All patients were investigated with ongoing medication. RESULTS: MSNA was lower in patients with SIC as compared to matched controls, but did not differ between the acute and recovery phase of SIC. RMBA %, blood pressure and heart rate did not differ between the groups. CONCLUSION: MSNA is shown to be lower in patients with SIC compared to healthy controls, suggesting that sympathetic neuronal outflow is rapidly reduced following the initial phase of SIC. A distension of the ventricular myocardium, due to excessive catecholamine release over the heart in the acute phase, may increase the firing rate of unmyelinated cardiac c-fibre afferents resulting in widespread sympathetic inhibition. Such a mechanism may underlie the lower MSNA reported in our patients. PMID- 22492096 TI - [Natalizumab and reduction of carbonylated proteins in patients with multiple sclerosis]. AB - INTRODUCTION: The sensitivity of the central nervous system to oxidative damage and its relationship with inflammatory response are well known. Recent studies have shown that oxidative stress is present in the establishment and development of multiple sclerosis (MS). One of the most recent treatments in this process is natalizumab, a monoclonal antibody. AIM: To evaluate whether the therapeutic effect of natalizumab is associated with the severity of the disease and the oxidative damage. PATIENTS AND METHODS: Researchers recruited twenty patients with relapsing-remitting MS (RRMS) undergoing therapy with natalizumab and distributed, according to the Expanded Disability Status Scale (EDSS), in two groups: RRMS-1 (EDSS < 5) and RRMS-2 (EDSS >= 5). Blood samples were taken for an oxidative profile study. RESULTS: Data showed a decrease in carbonylated proteins following treatment with natalizumab. The reduction in oxidative damage rated as protein oxidation is significant between the previous (baseline) situation of the patient and after 14 months' treatment. The most significant decrease coincided with the patients with the highest levels of severity in the process. Although it has not been possible to establish a correlation, the statistical significance is higher for patients in the RRMS-2 group treated with natalizumab. The antioxidant systems, on the other hand, did not display any statistically significant changes. CONCLUSIONS: Natalizumab brings about a reduction in carbonylated protein levels. PMID- 22492097 TI - [Contribution of diffusion tensor magnetic resonance imaging to the diagnosis of focal cortical dysplasias]. AB - INTRODUCTION: Focal cortical dysplasias (FCD) are cortical malformations and, although they display typical characteristics in conventional magnetic resonance imaging (MRI), the precise determination of the epileptogenic zone remains a controversial issue. The less favourable progress during the post-operative period with respect to other symptomatic epilepsies could be explained by the existence of epileptogenic areas that do not show up in conventional MRI. Diffusion tensor imaging (DTI) is sensitive to subtle microstructural abnormalities, and fractional anisotropy, which is an indirect indicator, shows areas with reductions in the underlying white matter that go beyond the alterations detected with conventional MRI in isolated cases in previous works. AIM: In this study we analyse the characteristics of fractional anisotropy in a series of patients with FCD in order to evaluate the contribution made to diagnosis by MRI by DTI. SUBJECTS AND METHODS: Twenty-one controls and eleven patients with FCD that was visible in MRI were scanned, and clinical and imaging variables were both recorded. A visual analysis of the fractional anisotropy maps was conducted to search for asymmetries between hemispheres and biases in the clinical or structural MRI data. RESULTS: Two females and nine males, aged 30 +/- 9.7 years took part in the study; time to progression of epilepsy: 22 +/- 9.3 years; average frequency of the seizures: 3/month (range: 0.16-8/month). All of them showed inter-hemispheric asymmetries, which went beyond the structural limits of FCD in the case of 10 of the patients (90%). None of the controls displayed asymmetries in the fractional anisotropy. No significant relation was found with the variables that were compared. CONCLUSIONS: Further studies need to be conducted with larger numbers of patients in order to evaluate the usefulness of DTI in defining the location and extension of the epileptogenic zone in this population. PMID- 22492099 TI - [Minor physical abnormalities and clinical features in patients with schizophrenia spectrum disorders]. AB - INTRODUCTION: Minor physical anomalies are nonspecific morphologic variants generated during gestation. They are markers of events (inherited and/or acquired) related with the 'neuroprogression' of the schizophrenia spectrum disorders and may be differentially involved with their symptom profiles. The aim of the study was to explore the relationship of minor physical anomalies with positive syndrome, negative syndrome and general psychopathology in patients with schizophrenia or other functional psychoses. PATIENTS AND METHODS: Cross sectional study of patients with schizophrenia or other functional psychoses consecutively hospitalized with an acute psychotic episode. Minor physical anomalies were evaluated with the Waldrop scale and clinical characteristics of psychosis were measured with the Positive and Negative Syndrome Scale (PANSS). RESULTS: 41 patients with functional psychoses were evaluated: 32 (78%) with schizophrenia, 9 (21.9%) with psychotic disorder not otherwise specified. There was no relationship between the Waldrop scale score and score on the PANSS, its negative scale and its general psychopathology scale. The positive scale of the PANSS and the Waldrop scale were correlated in the whole sample (Spearman rho = 0.356; p = 0.022). In the group of patients with schizophrenia, the correlation was even greater (Spearman rho = 0.420; p = 0.017). CONCLUSIONS: The path from apparently premorbid stages to specific clinical pictures in patients with schizophrenia spectrum disorders is determined by the neurodevelopment, a dynamic process influenced by genetic inheritance and environmental injuries. PMID- 22492100 TI - [Encephalitis associated to anti-NMDA receptor antibodies: a description of two cases in the child/youth population]. AB - INTRODUCTION: The clinical diagnosis of encephalitis due to anti-glutamate receptor N-methyl D-aspartate (NMDA) antibodies (anti-NMDA encephalitis) is made more complex by the fact that psychiatric clinical features are usually predominant in the early stages. This can lead to a delay in the diagnosis, treatment and prognosis of the disease. CASE REPORTS: We report on two clinical cases attended by the Child/Youth Psychiatry Section of our hospital, in collaboration with the Paediatric and Neurology services. Case 1: a 4-year-old male who was referred owing to behavioural alterations and the regression of previously acquired skills. Case 2: a 13-year-old female who was admitted due to a behavioural disorder within the context of a possible initial psychotic episode. In both cases appropriate complementary tests were performed, including lumbar puncture and anti-NMDA antibodies, which were positive. Once the diagnosis of anti-NMDA encephalitis had been reached, treatment was started: in the first case, with intravenous perfusion of corticoids and immunoglobulins, while in the second rituximab had to be associated. Both patients progressed towards clinical improvement. CONCLUSIONS: Over the last two years there has been an increase in the number of cases of anti-NMDA encephalitis diagnosed in the child/youth population. It is a neuropsychiatric, autoimmune condition, which can correspond to a paraneoplastic syndrome. Follow-up and transvaginal ultrasonography as well as thoracoabdominal computerised axial tomography scans are recommended for at least two years after diagnosis. Early diagnosis and treatment are important, which means that a multi- and interdisciplinary approach is required. PMID- 22492101 TI - [Recognition of facial expression of emotions in Parkinson's disease: a theoretical review]. AB - INTRODUCTION: Emotional facial expression is a basic guide during social interaction and, therefore, alterations in their expression or recognition are important limitations for communication. AIM: To examine facial expression recognition abilities and their possible impairment in Parkinson's disease. DEVELOPMENT: First, we review the studies on this topic which have not found entirely similar results. Second, we analyze the factors that may explain these discrepancies and, in particular, as third objective, we consider the relationship between emotional recognition problems and cognitive impairment associated with the disease. Finally, we propose alternatives strategies for the development of studies that could clarify the state of these abilities in Parkinson's disease. CONCLUSIONS: Most studies suggest deficits in facial expression recognition, especially in those with negative emotional content. However, it is possible that these alterations are related to those that also appear in the course of the disease in other perceptual and executive processes. To advance in this issue, we consider necessary to design emotional recognition studies implicating differentially the executive or visuospatial processes, and/or contrasting cognitive abilities with facial expressions and non emotional stimuli. The precision of the status of these abilities, as well as increase our knowledge of the functional consequences of the characteristic brain damage in the disease, may indicate if we should pay special attention in their rehabilitation inside the programs implemented. PMID- 22492098 TI - [Hospital arrival times and delay before acute stroke patients receive neurological care. Analysis of a national multi-centre registry: EPICES registry (II)]. AB - INTRODUCTION: Delays on arrival time and specialized care at hospital are still the first cause that hampers the application of best possible treatments to the stroke patients. AIM: To analyze the arrival time to the hospital up to the neurological care of patients, in a multicentric series of stroke patients. PATIENTS AND METHODS: The EPICES registry is an observational and prospective study performed with a methodology of registering consecutive clinical records of stroke patients admitted to the hospital under neurological attention. The sample used to analyze starting-door times it was 5,454 patients, for the door neurologist time it was 5,379 patients, and for the time of stay at ER room it was 5,825 patients. RESULTS: 90% of the patients presented a stroke between 8 and 24 h. The season of the year had no influence on the frequency, neither on the distribution of stroke type. onset-door time was 264.1 +/- 318.3 minutes; 34.7% of the patients arrived to the hospital during the first hour after the onset of the symptoms, and 63.7% of them arrived during the first three hours. Door neurologist time was 378.1 +/- 731.4 minutes; patients' age (p < 0.0001) and previous strokes (p < 0.0001) significantly prolonged such time. The availability of neurologist on call at the emergency service and of stroke units were associated to a significant reduction of hospital indoor times. CONCLUSION: In relation to previous data, current study shows an important reduction of onset door and door-neurologist times. PMID- 22492102 TI - [Neurophysiological advances in carpal tunnel syndrome: process of central sensitisation or local neuropathy]. AB - INTRODUCTION: Carpal tunnel syndrome (CTS) is considered a simple entrapment of the median nerve at the carpal tunnel. In the last years, several studies have demonstrated the presence of peripheral and central sensitization mechanisms. AIM: To review the basis neurophysiology of peripheral and central sensitization by applying them to CTS and to determine their clinical repercussions. DEVELOPMENT: Several studies have revealed that patients with CTS exhibit somato sensory changes in areas innervated by the median nerve and also in areas non related with the median nerve. Individuals with CTS exhibited widespread mechanical and thermal pain hyperalgesia, although they suffered from unilateral symptoms. Further, patients also showed wide-spread impairments in vibration conduction, deficits in fine motor control and changes in the somato-sensory cortex. These evidences support the presence of a complex process of peripheral and central sensitization in patients with CTS which may constitute a negative prognosis factor for the management of these patients. CONCLUSIONS: The advances in neurosciences in the last years support the presence of peripheral and central sensitization mechanisms in CTS. These mechanisms justify the necessity of conceptual changes and in the management, both conservative and surgical, of this syndrome. Additionally, central sensitization can also play a relevant role in the prognosis of CTS since it can constitute a negative prognosis factor for its treatment. PMID- 22492103 TI - Clinical guidelines for late-onset Pompe disease. AB - Before 2006, Pompe disease or glycogenosis storage disease type II was an incurable disease whose treatment was merely palliative. The development of a recombinant human alpha-glucosidase enzymatic replacement therapy has become the first specific treatment for this illness. The aim of this guide is to serve as reference for the management of the late-onset Pompe disease, the type of Pompe disease that develops after one year of age. In the guide a group of Spanish experts make specific recommendations about diagnosis, follow-up and treatment of this illness. With regard to diagnosis, the dried blood spots method is essential as the first step for the diagnosis of Pompe disease. The confirmation of the diagnosis of Pompe disease must be made by means of an study of enzymatic activity in isolated lymphocytes or a mutation analysis of the alpha-glucosidase gene. With regard to treatment with enzymatic replacement therapy, the experts say that is effective improving or stabilizating the motor function and the respiratory function and it must be introduced when the first symptoms attributable to Pompe disease appear. PMID- 22492104 TI - [Musical obsessions in obsessive-compulsive disorder]. PMID- 22492105 TI - [Othello syndrome induced by pramipexole]. PMID- 22492106 TI - [Some considerations on the analysis of publications in clinical neurology in different European countries over the period 2000-2009]. PMID- 22492108 TI - Anemia is associated with mortality following endovascular repair of abdominal aortic aneurysm. AB - AIM: The aim of this study was to compare midterm mortality between anemic and nonanemic patients undergoing endovascular repair of abdominal aortic aneurysm and to assess a correlation with markers of inflammation. METHODS: Anemia was defined as hemoglobin <13 (men) and <12 g/dL (women). The impact of anemia and inflammatory markers on mortality was assessed using Kaplan-Meier curves and Cox regression. RESULTS: A total of 224 patients (12 females [5.36%]; age: 69.73 +/- 8.72 years) were included; 102 (45.53%) were anemic. Median follow-up was 17 months (interquartile range: 7-25 months). Nine patients died (1.79%; 8 anemic vs 1 nonanemic). Survival was lower for patients with anemia (log-rank, P = .01). White blood cell count and C-reactive protein (CRP) differed significantly (P < .001 and P = .01). Anemia and CRP were associated with decreased survival (Cox regression, P = .01, hazard ratio [HR]: 0.35, 95% confidence interval: 0.14-0.84 and P = .002, HR: 1.18, 95% CI: 1.06-1.31). CONCLUSION: Patients with anemia had decreased survival over the midterm; inflammatory markers were higher among this group. PMID- 22492109 TI - Aortic aneurysmal repair with surtureless visceral revascularization using novel hybrid vascular graft and a gradual funneling technique. AB - This article details a novel technique in the treatment of a symptomatic thoracoabdominal aneurysm (TAA) involving the visceral segment and an infrarenal abdominal aortic aneurysm. The patient was treated in a 2-staged hybrid approach combining an endovascular repair of the infrarenal segment, followed by open TAA repair. The large visceral arteries were revascularized using expanded polytetrafluoroethylene GORE Hybrid Vascular Graft (GHVG) and a Gradual Funneling Technique with Dacron graft. This method assured a complete hemostatic seal and minimized visceral ischemic time. To our knowledge, this is the first case of sutureless visceral artery revascularization using GHVG reported in the literature. PMID- 22492110 TI - External iliac artery stenting: high incidence of concomitant revascularization procedures. AB - OBJECTIVES: To review immediate results, patency rates, hemodynamic success, and incidence of concomitant procedures with external iliac artery stenting (EIAS). METHODS: Demographic features, category and clinical grade, Trans-Atlantic Inter Society Consensus II classification lesion type, pre- and postprocedure ankle brachial indices, and primary patency were compared between group 1 (EIAS without distal revascularization) and group 2 (EIAS with concomitant distal revascularization). RESULTS: No mortality and a 100% immediate technical success rate was recorded in group 1 (n = 12) and group 2 (n = 24). Eleven patients (30.6%) also had stenting of the adjacent common iliac artery. Two thirds of group 2 patients required concomitant femoral or distal revascularization. CONCLUSIONS: No difference in stent patency rates was found between patients in group 1 versus group 2. Patients requiring EIAS tend to have more diffuse arterial disease necessitating complicated open reconstruction and/or distal revascularization, as well as more proximal iliac stenting. PMID- 22492111 TI - Treatment of type II endoleaks with ethylene-vinyl-alcohol copolymer (Onyx). AB - We report our single-center experience in treating 101 type II endoleaks with ethylene-vinyl-alcohol copolymer (EVOH, Onyx). In all, 65 endoleaks were embolized transarterially, and 36 were treated through a translumbar approach. Since the first transarterial embolization, when we began attempts to treat all patients initially via common femoral access, 58 (65.9%) of 88 patients were successfully embolized transarterially. All endoleaks in the translumbar group were successfully treated. At a median follow-up length of 15 weeks, a decrease or stabilization in aneurysm size was observed in 39 (73.6%) of the 53 endoleaks that had adequate follow-up computed tomography imaging. The overall residual endoleak rate was 34.0%. There was no difference in efficacy when comparing transarterial and translumbar approaches. We demonstrate that in most cases, transarterial access of the endoleak nidus is feasible, and controlled embolization is possible using EVOH. Furthermore, EVOH appears effective in long term stabilization of aneurysm size and in preventing residual endoleaks. PMID- 22492112 TI - Endovascular management of vascular complications in pancreatic transplants. AB - Vascular complications after pancreatic transplantation carry a high rate of graft loss. Endovascular management of these complications is confined to stent placement for iliac artery inflow disease and embolization for arteriovenous fistulae (AVFs), pseudoaneurysms, or active bleeding. The current study describes the endovascular management of pancreatic transplant venous thrombosis (N = 1), arterial stenosis (N = 5), thrombosis (N = 3), pseudoaneurysms (N = 1), and AVF (N = 2). In addition, embolization of nonfunctioning grafts is described as an endovascular alternative to pancreatectomy. PMID- 22492114 TI - GP practices abandon boundaries to widen choice for patients. PMID- 22492113 TI - "Feeling younger, being stronger": an experimental study of subjective age and physical functioning among older adults. AB - OBJECTIVES: The present study is an attempt to experimentally induce a younger subjective age among older adults and to test whether they show better physical functioning when they are induced to feel younger. METHOD: Participants were 49 older adults aged between 52 and 91 years. Following an initial measure of handgrip performance as an indicator of physical functioning, participants in the experimental condition received positive feedback regarding their performance compared with their same-aged peers, whereas participants in the control condition did not receive any information. Participants in both groups then completed a second handgrip measure. Subjective age was assessed before the initial handgrip task and after the experimental manipulation. RESULTS: Participants in the experimental group felt younger than their age and showed a significant increase in grip strength, whereas no changes in subjective age and grip strength were observed in the control condition. DISCUSSION: This study is among the first to induce a younger subjective age. It supports the notion that redirecting older adults' attention to downward social comparison with same-aged peers is a promising strategy to maintain a sense of feeling younger. In addition, our results provide an initial positive answer to the question of whether feeling younger translates into better physical functioning. PMID- 22492115 TI - Virgin Care is set to take over two NHS community health services in Surrey. PMID- 22492116 TI - Private healthcare market may be anti-competitive with poor returns for patients. PMID- 22492117 TI - Governments needs to explore alternative to prohibitionist drug policies, says report. PMID- 22492118 TI - Government's demand for raids on abortion clinics cost 580 inspections and 1m pound, says regulator. PMID- 22492119 TI - Trabecular architecture and vertebral fragility in osteoporosis. AB - Osteoporosis heightens vertebral fragility owing to the biomechanical effects of diminished bone structure and composition. These biomechanical effects are only partially explained by loss in bone mass, so additional factors that are independent of bone mass are also thought to play an important role in vertebral fragility. Recent advances in imaging equipment, imaging-processing methods, and computational capacity allow researchers to quantify trabecular architecture in the vertebra at the level of the individual trabecular elements and to derive biomechanics-based measures of architecture that are independent of bone mass and density. These advances have shed light on the role of architecture in vertebral fragility. In addition to the adverse biomechanical consequences associated with trabecular thinning and loss of connectivity, a reduction in the number of vertical trabecular plates appears to be particularly harmful to vertebral strength. In the clinic, detailed architecture analysis is primarily applied to peripheral sites such as the distal radius and tibia. Analysis of trabecular architecture at these peripheral sites has shown mixed results for discriminating between patients with and without a vertebral fracture independent of bone mass, but has the potential to provide unique insight into the effects of therapeutic treatments. Overall, it does appear that trabecular architecture has an independent role on vertebral strength. Additional research is required to determine how and where architecture should be measured in vivo and whether assessment of trabecular architecture in a clinical setting improves prospective fracture risk assessment for the vertebra. PMID- 22492121 TI - Quantitative changes in microtubule distribution correlate with guard cell function in Arabidopsis. AB - Radially arranged cortical microtubules are a prominent feature of guard cells. We observed guard cells expressing GFP-tubulin (GFP-TUA6) with confocal microscopy and found recognizable changes in the appearance of microtubules when stomata open or close (Eisinger et al., 2012). In the present study, analysis of fluorescence distribution showed a dramatic increase in peak intensities of microtubule bundles within guard cells as stomata open. This increase was correlated with an increase in the total fluorescence that could be attributed to polymerized tubulin. Adjacent pavement cells did not show similar changes in peak intensities or integrated fluorescence when stomatal apertures changed. Imaging of RFP-tagged end binding protein 1 (EB1) and YFP-tagged alpha-tubulin expressed in the same cell revealed that the number of microtubules with growing ends remained constant, although the total amount of polymerized tubulin was higher in open than in closed guard cells. Taken together, these results indicate that the changes in microtubule array organization that are correlated with and required for normal guard cell function are characterized by changes in microtubule clustering or bundling. PMID- 22492120 TI - Phytochrome signaling in green Arabidopsis seedlings: impact assessment of a mutually negative phyB-PIF feedback loop. AB - The reversibly red (R)/far-red (FR)-light-responsive phytochrome (phy) photosensory system initiates both the deetiolation process in dark-germinated seedlings upon first exposure to light, and the shade-avoidance process in fully deetiolated seedlings upon exposure to vegetational shade. The intracellular signaling pathway from the light-activated photoreceptor conformer (Pfr) to the transcriptional network that drives these responses involves direct, physical interaction of Pfr with a small subfamily of bHLH transcription factors, termed Phy-Interacting Factors (PIFs), which induces rapid PIF proteolytic degradation. In addition, there is evidence of further complexity in light-grown seedlings, whereby phyB-PIF interaction reciprocally induces phyB degradation, in a mutually negative, feedback-loop configuration. Here, to assess the relative contributions of these antagonistic activities to the net phenotypic readout in light-grown seedlings, we have examined the magnitude of the light- and simulated-shade induced responses of a pentuple phyBpif1pif3pif4pif5 (phyBpifq) mutant and various multiple pif-mutant combinations. The data (1) reaffirm that phyB is the predominant, if not exclusive, photoreceptor imposing the inhibition of hypocotyl elongation in deetiolating seedlings in response to prolonged continuous R irradiation and (2) show that the PIF quartet (PIF1, PIF3, PIF4, and PIF5) retain and exert a dual capacity to modulate hypocotyl elongation under these conditions, by concomitantly promoting cell elongation through intrinsic transcriptional-regulatory activity, and reducing phyB-inhibitory capacity through feedback-loop-induced phyB degradation. In shade-exposed seedlings, immunoblot analysis shows that the shade-imposed reduction in Pfr levels induces increases in the abundance of PIF3, and mutant analysis indicates that PIF3 acts, in conjunction with PIF4 and PIF5, to promote the known shade-induced acceleration of hypocotyl elongation. Conversely, although the quadruple pifq mutant displays clearly reduced hypocotyl elongation compared to wild-type in response to prolonged shade, immunoblot analysis detects no elevation in phyB levels in the mutant seedlings compared to the wild-type during the majority of the shade-induced growth period, and phyB levels are not robustly correlated with the growth phenotype across the pif-mutant combinations compared. These results suggest that PIF feedback modulation of phyB abundance does not play a dominant role in modulating the magnitude of the PIF-promoted, shade-responsive phenotype under these conditions. In seedlings grown under diurnal light-dark cycles, the data show that FR-pulse-induced removal of Pfr at the beginning of the dark period (End-of-Day-FR (EOD-FR) treatment) results in longer hypocotyls relative to no EOD-FR treatment and that this effect is attenuated in the pif-mutant combinations tested. This result similarly indicates that the PIF quartet members are capable of intrinsically promoting hypocotyl cell elongation in light-grown plants, independently of the effects of PIF feedback modulation of photoactivated phyB abundance. PMID- 22492122 TI - High endogenous salivary amylase activity is associated with improved glycemic homeostasis following starch ingestion in adults. AB - In the current study, we determined whether increased digestion of starch by high salivary amylase concentrations predicted postprandial blood glucose following starch ingestion. Healthy, nonobese individuals were prescreened for salivary amylase activity and classified as high (HA) or low amylase (LA) if their activity levels per minute fell 1 SD higher or lower than the group mean, respectively. Fasting HA (n = 7) and LA (n = 7) individuals participated in 2 sessions during which they ingested either a starch (experimental) or glucose solution (control) on separate days. Blood samples were collected before, during, and after the participants drank each solution. The samples were analyzed for plasma glucose and insulin concentrations as well as diploid AMY1 gene copy number. HA individuals had significantly more AMY1 gene copies within their genomes than did the LA individuals. We found that following starch ingestion, HA individuals had significantly lower postprandial blood glucose concentrations at 45, 60, and 75 min, as well as significantly lower AUC and peak blood glucose concentrations than the LA individuals. Plasma insulin concentrations in the HA group were significantly higher than baseline early in the testing session, whereas insulin concentrations in the LA group did not increase at this time. Following ingestion of the glucose solution, however, blood glucose and insulin concentrations did not differ between the groups. These observations are interpreted to suggest that HA individuals may be better adapted to ingest starches, whereas LA individuals may be at greater risk for insulin resistance and diabetes if chronically ingesting starch-rich diets. PMID- 22492123 TI - Morbidity in adults with a normal limited scaphoid MRI: a retrospective cohort study and follow-up questionnaire. AB - INTRODUCTION: The scaphoid bone is the most commonly fractured carpal bone. MRI is now recognised to be more sensitive and specific than serial plain films in the diagnosis of occult scaphoid fracture. What is not known is whether it is safe to discharge, without follow-up, those with a normal limited extremity MRI. The primary objective of this study was to determine whether a normal limited scaphoid MRI safely excludes clinically significant injury. The secondary objectives were to determine morbidity and patient experiences of those without fracture on MRI. METHODS: This is a cohort study with retrospective case note review and a written follow-up questionnaire conducted in a South of England emergency department soft tissue review clinic. RESULTS: 214 limited extremity MRIs were performed between January 2006 and July 2008 for suspected scaphoid injury. 152 participants were included in the study. 122 (80%) MRIs showed no fracture. In 72 (47%), there were no traumatic findings. The most significant finding in 33 (22%) was bony bruising and joint oedema in 17 (11%). One (0.9%) clinically important injury was missed. There was significant morbidity in those with normal MRIs. Worst-case scenario analysis shows that at least 12.5% of patients with a normal MRI still had symptoms and 14% still had abnormal function a year or more after injury. DISCUSSION: This study shows that limited extremity MRI can safely exclude clinically important injury. Significant symptoms do persist, however, for many patients with a normal MRI. PMID- 22492124 TI - Looking beyond Morison's pouch in focused assessment with sonography for trauma: penetrating hepatobiliary trauma and a new sign for emergency physicians. PMID- 22492125 TI - The impact of implementing the single provider model of emergency medicine in a paediatric hospital: a retrospective cohort analysis. AB - STUDY OBJECTIVE: The Meyer Pediatric Hospital in Florence, Italy recently implemented the single provider model of emergency medicine. Prior to these changes, patients were triaged to a paediatric surgeon or paediatrician based on the complaint. The authors assess the outcomes of patients evaluated by surgeons prior to this change and compare them with those of patients seen by emergency physicians. METHODS: A retrospective, cohort study was performed reviewing patients seen in the emergency department between 2005 and 2008 for the three most common surgical complaints encountered before the systems change: head trauma, testicular pain and abdominal pain. Outcomes include misdiagnoses, consultation rates, dispositions, imaging, interventions and surgeries. RESULTS: A total of 2415 patient visits were included. Emergency physicians saw more patients (1388 vs 1027) and obtained more consultations (25.6% vs 8.1%) than surgeons. Patients triaged directly to surgeons were more likely to be admitted to the hospital (10.3% vs 7.6%), undergo urgent interventions (9.5% vs 6.7%), undergo surgery (8.0% vs 4.8%), have more radiographic images to evaluate head trauma (12.1% vs 5.3%), be misdiagnosed (1.0% vs 0.3%) and have more plain films for abdominal pain (3.1% vs 1.3%). There is an overall trend towards fewer missed diagnoses by emergency physicians (0.3% vs 0.9%), but this difference is only statistically significant in the abdominal pain subset analysis (p=0.032, combined data p=0.052). CONCLUSIONS: The single provider model of emergency medicine where emergency physicians manage all patients presenting to the emergency department appears to be a safe and efficient model of emergency medical care. PMID- 22492126 TI - Short answer question case series: Controversies in the diagnosis and management of diverticulitis. PMID- 22492127 TI - Effects of interferon beta-1b on cognitive performance in patients with a first event suggestive of multiple sclerosis. AB - BACKGROUND: Cognitive dysfunction occurs at the earliest stages of multiple sclerosis (MS), including the stage of clinically isolated syndrome (CIS). METHODS: We evaluated the impact of interferon beta-1b (IFNbeta-1b) 250 ug on cognitive performance during the CIS stage in the BENEFITstudy. Cognition was assessed by Paced Auditory Serial Addition Test-3" (PASAT-3") scores. RESULTS: Improvement in PASAT-3" score from baseline to year two was greater for IFNbeta 1b treatment than placebo in patients not reaching clinically definite MS (CDMS) by year two. The treatment effect was maintained at year five and was statistically significant. CONCLUSIONS: To conclude, early IFNbeta-1b treatment had a sustained positive effect on PASAT-3" score over the 5-year BENEFIT study. PMID- 22492128 TI - Association of SNPs rs6498169 and rs10984447 with multiple sclerosis in Saudi patients: a model of the usefulness of familial aggregates in identifying genetic linkage in a multifactorial disease. AB - OBJECTIVE: Genome-Wide association studies (GWAS) showed an association between subset of single-nucleotide polymorphism (SNPs) and multiple sclerosis. Our study aims to study this association in Saudi familial multiple sclerosis patients. METHODS: Four subject groups were used in this study: sporadic MS (MS patients without family history), FMS (MS patients who have at least one family member diagnosed with MS), related controls (relatives of FMS patients who appear to be free of the disease) and independent controls (healthy volunteers). Subjects were genotyped for 15 SNPs. The variation in the genotype distribution was analyzed across study groups by using logistic regression. RESULTS: 342 subjects were included. 99 were in the sporadic MS group, 22 were FMS, 89 were related control, and 132 were independent control. SNPS rs3135388, rs7577363, rs1321172, rs6897932, rs6498169, rs12487066, and rs4763655were associated with MS when MS and independent control groups were compared. Same SNPS were identified but with stronger association when the FMS and independent control groups were compared. Finally, when the patients and the controls were selected from a much more homogenous genetic pool from which it would be expected that only SNPs highly linked to MS would persist, only two SNPs rs6498169[OR 4.26, CI (1.17 - 15.51)];, and rs10984447 [OR 13.63, CI(1.54, 120.83) ][were associated with MS. CONCLUSIONS: Our results suggest that using a more homogenous genetic pool of cases and controls could help to identify the most significant MS-associated SNPs. Our finding is in agreement with other studies including larger sample size and more diverse populations. PMID- 22492129 TI - Towards establishing MS prevalence in Latin America and the Caribbean. AB - A very high prevalence of multiple sclerosis (MS) has been reported in some Western European and North American countries. The few surveys of MS epidemiology in South America reveal lower prevalence rates, implying that susceptibility varies between distinct ethnic groups, thus forming an important determinant of the geographic distribution of the disease. The objective of this study is to review MS prevalence estimates in different Latin American and Caribbean countries. We reviewed surveys of regional MS prevalence from 1991 to 2011. Sources included an online database, authors' reports and proceedings or specific lectures from regional conferences. We obtained a total of 30 prevalence surveys from 15 countries, showing low/medium MS prevalence rates. Both the number and the quality of prevalence surveys have greatly improved in this region over recent decades. This is the first collaborative study to map the regional frequency of MS. Establishment of standardized methods and joint epidemiological studies will advance future MS research in Latin America and the Caribbean. PMID- 22492130 TI - Intramuscular interferon beta-1a is effective in Japanese patients with relapsing remitting multiple sclerosis: a pre-treatment versus treatment comparison study of gadolinium-enhanced MRI brain lesions. AB - BACKGROUND AND OBJECTIVE: Interferon beta (IFNbeta) is standard therapy for multiple sclerosis (MS). The efficacy of intramuscular (IM) IFNbeta-1a (AVONEX((r))) was assessed in 25 Japanese patients with relapsing-remitting MS (RRMS). METHODS: Patients with RRMS not previously treated with IFNbeta or other disease-modifying therapies were included in this 36-week study. The primary outcome was the average total number of gadolinium-enhanced lesions detected on four brain MRI scans during the last 12 weeks of 24 weeks' treatment with IM IFNbeta-1a 30 MUg once weekly compared with the number during the 12-week pre treatment period. Lesions were counted by blinded investigators. RESULTS: IM IFNbeta-1a significantly decreased the median number of gadolinium-enhanced lesions from 2.5 to 0.3 (p < 0.0001) compared with pre-treatment values. The median number of new gadolinium-enhanced lesions also decreased significantly from 2.0 to 0.3 (p = 0.0002). Serum neopterin was induced in a manner similar to that observed previously in a Caucasian RRMS population. No new adverse events occurred during the study. CONCLUSION: This first study of IM IFNbeta-1a in Japanese patients with RRMS demonstrated a level of efficacy similar to that reported in Caucasian patients based on an assessment of pre-treatment and post treatment gadolinium-enhanced lesions. PMID- 22492131 TI - Neurofilaments as biomarkers in multiple sclerosis. AB - Neurodegeneration is the correlate of disease progression in multiple sclerosis (MS) and thus biological biomarkers that sensitively reflect this process are much needed. Neurofilament protein subunits are potential cerebrospinal fluid (CSF) biomarkers for disease progression in MS. We argue that the neurofilament light subunit can reflect acute axonal damage mediated by inflammatory mechanisms and can imply prognostic value for conversion from clinically isolated syndrome (CIS) to definite MS. The neurofilament heavy subunit may rather reflect chronic irreversible damage and has prognostic value for disease progression or disability. The neurofilament intermediate subunit has not yet been studied. Recent studies showing higher neurofilament light or heavy subunit levels to be altered upon treatment regimes indicate their potential clinical value in monitoring treatment or side effects. Future studies should be aimed at the optimisation, standardisation and interlaboratory implementation of the assays and address the predictive value of these biomarkers. PMID- 22492132 TI - The unidimensional self-efficacy scale for MS (USE-MS): developing a patient based and patient reported outcome. AB - BACKGROUND: Self-efficacy concerns the individual's belief that he or she is capable of performing a certain task and producing a desired effect, i.e. it reflects the person's perceptions of their capability for specific tasks, as distinct from their actual ability. Self-efficacy has been shown to influence motivation, psychological well-being, adherence with treatment regimes and quality of life in multiple sclerosis and other conditions. OBJECTIVE: To develop a unidimensional scale of MS self-efficacy with robust psychometric properties, suitable for patient self report. METHODS: A questionnaire pack covering three MS self-efficacy scales, the Dispositional Resilience Scale and demographic data was posted to MS patients from two MS databases. Data underwent Rasch analysis. RESULTS: Response rate was 309/600 (51.5%). None of the existing MS self-efficacy scales were unidimensional. A new 12-item scale, created by combining items from our two scales, was shown to fit the Rasch model, was unidimensional, and invariant for gender, education and disease duration. CONCLUSION: The Unidimensional Self-Efficacy scale for MS (USE-MS) provides a simple summated scale for an ordinal estimate of a persons' self efficacy. A transformation to interval scaling is available for use in the calculation of change scores and effect sizes. PMID- 22492133 TI - Magnetization transfer imaging in multiple sclerosis treated with alemtuzumab. AB - The magnetization transfer ratio reflects the integrity of tissue structure, including myelination and axonal density. Mean magnetization transfer ratio fell in 18 untreated patients with multiple sclerosis both in normal appearing grey ( 0.25 pu/year, p < 0.001) and white matter (-0.12 pu/year, p = 0.004). Conversely, mean magnetization transfer ratio was stable in 20 alemtuzumab-treated patients (grey matter: -0.01 pu/year, p = 0.87; white matter: -0.02 pu/year, p = 0.51). The gradient difference in grey matter was 0.25 pu/year (p < 0.001) after age adjustment. These data suggest that in multiple sclerosis alemtuzumab protects against tissue damage in normal-appearing grey matter, perhaps by preventing new lesion formation. PMID- 22492134 TI - Scrub typhus without eruption. PMID- 22492135 TI - Pleural involvement in spinal tuberculosis. AB - Spinal tuberculosis or Pott's disease of the spine associated with pleural involvement has long intrigued researchers regarding the nature and pathogenesis of their occurrence. We describe two interesting patients of spinal tuberculosis, one with cervical and another with thoracic spine disease, with pleural involvement, which developed after lateral extension of cold abscess involving the parietal pleura, and without any evidence of pulmonary disease. PMID- 22492136 TI - Controlled human blood stage malaria infection: current status and potential applications. AB - Controlled human malaria infection by blood stage parasite (BSP) inoculation is an alternative to the well-established model of infection with Plasmodium falciparum sporozoites delivered by mosquito bites. The BSP model has been utilized less frequently, but its use is increasing. Advantages of BSP challenge include greater ease of administration, better standardization of the infecting dose per volunteer, and good inter-study reproducibility of in vivo parasite dynamics. Recently, a surprising reduction in clinical symptoms at microscopic patency in the BSP model has been identified, which has an undefined and intriguing pathophysiologic basis, but may make this approach more acceptable to volunteers. We summarize clinical, parasitologic, and immunologic data from all BSP challenges to date, explore differences between the BSP and sporozoite models, and propose future applications for BSP challenge. PMID- 22492137 TI - Using limes and synthetic psoralens to enhance solar disinfection of water (SODIS): a laboratory evaluation with norovirus, Escherichia coli, and MS2. AB - We investigated the use of psoralens and limes to enhance solar disinfection of water (SODIS) using an UV lamp and natural sunlight experiments. SODIS conditions were replicated using sunlight, 2 L polyethylene terephthalate (PET) bottles, and tap water with Escherichia coli, MS2 bacteriophage, and murine norovirus (MNV). Psoralens and lime acidity both interact synergistically with UV radiation to accelerate inactivation of microbes. Escherichia coli was ablated > 6.1 logs by SODIS + Lime Slurry and 5.6 logs by SODIS + Lime Juice in 30-minute solar exposures, compared with a 1.5 log reduction with SODIS alone (N = 3; P < 0.001). MS2 was inactivated > 3.9 logs by SODIS + Lime Slurry, 1.9 logs by SODIS + Lime Juice, and 1.4 logs by SODIS in 2.5-hour solar exposures (N = 3; P < 0.05). MNV was resistant to SODIS, with < 2 log reductions after 6 hours. Efficacy of SODIS against human norovirus should be investigated further. PMID- 22492138 TI - Promoting good clinical laboratory practices and laboratory accreditation to support clinical trials in sub-Saharan Africa. AB - Laboratory capacity in the developing world frequently lacks quality management systems (QMS) such as good clinical laboratory practices, proper safety precautions, and adequate facilities; impacting the ability to conduct biomedical research where it is needed most. As the regulatory climate changes globally, higher quality laboratory support is needed to protect study volunteers and to accurately assess biological parameters. The University of Bamako and its partners have undertaken a comprehensive QMS plan to improve quality and productivity using the Clinical and Laboratory Standards Institute standards and guidelines. The clinical laboratory passed the College of American Pathologists inspection in April 2010, and received full accreditation in June 2010. Our efforts to implement high-quality standards have been valuable for evaluating safety and immunogenicity of malaria vaccine candidates in Mali. Other disease specific research groups in resource-limited settings may benefit by incorporating similar training initiatives, QMS methods, and continual improvement practices to ensure best practices. PMID- 22492139 TI - High degree of Plasmodium vivax diversity in the Peruvian Amazon demonstrated by tandem repeat polymorphism analysis. AB - Molecular tools to distinguish strains of Plasmodium vivax are important for studying the epidemiology of malaria transmission. Two sets of markers-tandem repeat (TR) polymorphisms and MSP3alpha-were used to study Plasmodium vivax in patients in the Peruvian Amazon region of Iquitos. Of 110 patients, 90 distinct haplotypes were distinguished using 9 TR markers. An MSP3alpha polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using HhaI and AluI revealed 8 and 9 profiles, respectively, and 36 profiles when analyzed in combination. Combining TR and PCR-RFLP markers, 101 distinct molecular profiles were distinguished among these 110 patients. Nine TR markers arrayed along a 100 kB stretch of a P. vivax chromosome containing the gene for circumsporozoite protein showed non-linear linkage disequilibrium (I(SA) = 0.03, P = 0.001). These findings demonstrate the potential use of TR markers for molecular epidemiology studies. PMID- 22492140 TI - Compliance with antimalaria chemoprophylaxis in a combat zone. AB - Compliance with malaria chemoprophylaxis by military service members (MSMs) is notoriously low, ranging from 30% to 56%. Our objective was to determine the rate of compliance and reasons for non-compliance with malaria chemoprophylaxis among healthy US MSMs in Afghanistan. An eight-question, anonymous online survey was used to collect data regarding the compliance of healthy MSMs with malaria chemoprophylaxis. E-mail surveys were sent to 1,200 MSMs; 528 (44%) MSMs completed the survey. One-time daily doxycycline was the most commonly prescribed chemoprophylaxis (90%); 60% (N = 318) responded that they were compliant with their chemoprophylaxis as prescribed, whereas 40% (N = 221) indicated that they were not compliant. Compliance with daily dosing was 61% and weekly dosing was 38%. The most common reasons for non-compliance were gastrointestinal effects (39%), forgetfulness (31%), and low perception of risk (24%). Malaria chemoprophylaxis compliance by healthy MSMs in Afghanistan is poor. Side effects, forgetfulness, and lack of education are contributing factors. Commanders bear the primary responsibility for the health of their soldiers, and the individual MSM bears personal responsibility; however, additional public health interventions could possibly have a positive impact on prevention. PMID- 22492141 TI - Investigation of a sudden malaria outbreak in the isolated Amazonian village of Saul, French Guiana, January-April 2009. AB - Malaria is endemic in French Guiana. Plasmodium falciparum and Plasmodium vivax are the predominant species responsible and Anopheles darlingi is described as the major vector. In mid-August 2008, an increase in malaria incidence was observed in Saul. A retrospective cohort survey was performed. In vitro susceptibility profiles to antimalarials were determined on P. falciparum isolates. Collections of mosquitoes were organized. The malaria attack rate reached 70.6/100. The risk of malaria increased for people between 40 and 49 years of age, living in a house not subjected to a recent indoor residual insecticide spraying or staying overnight in the surrounding forest. All isolates were susceptible. Anopheles darlingi females and larvae were collected in the village suggesting a local transmission. Our results strongly support a role of illegal mining activities in the emergence of new foci of malaria. Therefore, public health authorities should define policies to fight malaria at a transborder level. PMID- 22492142 TI - rK39 antigen for the diagnosis of visceral leishmaniasis by using human saliva. AB - The rK39 rapid immunochromatographic test (ICT) is now being widely used in the diagnosis of visceral leishmaniasis (VL) using serum. We evaluated the presence of anti-rK-39 antibody in human saliva being noninvasive to replace the invasive procedures of diagnosis. Enzyme-linked immunosorbent assay (ELISA) and ICT assays were performed in 300 subjects: 114-confirmed VL patients, 95 and 47 healthy controls from endemic and nonendemic regions, respectively, and 44 subjects with different diseases. Sensitivity in saliva was 83.3% by ELISA and 82.5% by ICT, compared with 100% for both ICT and ELISA in serum. Specificity in saliva was 100%, 90.5%, and 88.6% with ELISA, and 91.48%, 91.57%, and 84.06% using ICT, in nonendemic, endemic, and different diseases, respectively. In serum, specificity was 97%, 88.5%, and 89% by ELISA and 100%, 94.7%, and 95.5% by ICT in nonendemic, endemic, and different diseases, respectively. Saliva is not suitable for diagnosis of VL because of low sensitivity. PMID- 22492143 TI - Identification and characterization of a novel Leishmania donovani antigen for serodiagnosis of visceral leishmaniasis. AB - Despite several drawbacks, rK39-based rapid immunochromatographic test is widely used for the diagnosis of visceral leishmaniasis (VL) in the Indian subcontinent. There is an urgent need to develop a better antigen. In this study we separated crude soluble antigens of Leishmania donovani by sodium dodecyl sulfate polyacrylamide gel electrophoresis and hybridized with pool sera from pre- and post-treated VL patients, 6 months follow-up, endemic healthy (EHC), and nonendemic healthy controls (NEHC) by Western blotting. The sensitivity of enzyme linked immunosorbent assay with identified protein was 95% (confidence interval [CI] = 89.6-98.01%), whereas the specificity for EHC, NEHC, and different disease groups were 96.3% (CI = 89.8-98.6%), 100% (CI = 95.8-100%), and 97.4% (CI = 91.02 99.3%), respectively. This specific antigen was subjected to two-dimensional gel electrophoresis and after tryptic digestion, antigen was characterized by matrix assisted laser desorption/ionization time-of-flight mass spectrometry. Further analysis showed that it is a member of the heat shock protein family of 70 kDa, designated as BHUP1, and has great potential in the diagnosis of VL. PMID- 22492144 TI - Development of Leishmania (Leishmania) infantum chagasi in its natural sandfly vector Lutzomyia longipalpis. AB - We analyzed the development of Leishmania (Leishmania) infantum chagasi in its natural sandfly vector Lutzomyia longipalpis. In addition, we compared sandfly infections initiated with axenic amastigotes or promastigotes. Our data showed no important difference between Lu. longipalpis infection rates resulting from either type of infections. Furthermore, development of infection was equivalent in both cases. All promastigote forms were found inside the sandfly and, after blood digestion, most of the population consisted of procyclics and nectomonads. A low percentage of metacyclic forms was coincident with a high number of nectomonads during late stages of infection, but which form gives rise to metacyclic forms in L. infantum chagasi is unknown. These results also show that the promastigote infection model, at least for this situation, is suitable for obtaining of infected sandflies because it is easier and less laborious. PMID- 22492145 TI - Association of in utero sensitization to Schistosoma haematobium with enhanced cord blood IgE and increased frequencies of CD5- B cells in African newborns. AB - This study investigated in utero priming as a consequence of maternal parasitic infections. Cord blood plasma samples of 63 African newborns were assessed by enzyme-linked immunosorbent assay for their content of total and schistosome specific or filaria-specific IgE and IgG4. The frequencies of lymphocyte phenotypes in cord blood were also determined by using flow cytometry, and were compared with those of European newborns. We found significantly increased schistosome soluble egg antigen (SEA)-specific IgE in cord plasma of those born to mothers with schistosome infections and correlations between fetal and maternal SEA-specific and filaria antigen-specific IgE. These data are evidence for in utero priming of the fetal immune system to maternal helminth infections. Furthermore, we show significantly enhanced percentages of CD5- B cells in African newborns cord blood compared with Europeans, which is consistent with earlier maturation of the African fetal immune system. PMID- 22492146 TI - Intraocular gnathostomiasis: report of a case and review of literature. AB - Intraocular gnathostomiasis is a rare parasitic infection caused by the third stage larvae of spiruroid nematode Gnanthostoma spp. seen mostly in tropical and subtropical regions. It is a food-borne zoonosis caused by ingestion of raw or undercooked freshwater fish, amphibians, reptiles, birds, and mammals, all of which are known to harbor advanced third-stage larvae of Gnanthostoma spp. To date, 74 cases of intraocular gnathostomiasis have been reported from 12 different countries. Only four countries have reported more than 10 cases each, and India shares the rare distinction of being one of them, with 14 cases. Surprisingly, not a single case of cutaneous gnanthostomiasis has ever been reported from India. We present one such case of intraocular gnathostomiasis in a 41-year-old male who presented with an actively motile worm attached to the iris, and we review the pertinent literature of all such cases reported from India. PMID- 22492147 TI - Soil-transmitted helminthiasis in Laos: a community-wide cross-sectional study of humans and dogs in a mass drug administration environment. AB - We conducted a community cross-sectional survey of soil-transmitted helminthiasis in humans and dogs in four provinces in northern Laos. We collected and tested human and dog fecal samples and analyzed results against sociodemographic data. The prevalence of Ascaris lumbricoides, Trichuris trichiura, hookworm, and Strongyloides stercoralis was 26.1% (95% confidence interval [CI] = 23.7-28.4%), 41.5% (95% CI = 38.8-44.1%), 46.3% (95% CI = 43.3-49.0%), and 8.9% (95% CI = 7.4 10.4%), respectively. We observed strong heterogeneity for helminthiasis by ethnicity, province, and wealth status, which coincided with a risk profile demonstrating that Mon-Khmer persons and the poorest households are highly vulnerable. Necator americanus was the dominant hookworm species infecting humans and Ancylostoma ceylanicum was the only Ancylostoma species detected. Hookworm prevalence in village dogs was 94%, and the dominant species was A. ceylanicum. Necator americanus was also detected in dogs. It appears that dogs have a role in human hookworm transmission and warrant further investigation. PMID- 22492148 TI - Evidence of polyandry for Aedes aegypti in semifield enclosures. AB - Female Aedes aegypti are assumed to be primarily monandrous (i.e., mate only once in their lifetime), but true estimates of mating frequency have not been determined outside the laboratory. To assess polyandry in Ae. aegypti with first generation progeny from wild mosquitoes, stable isotope semen-labeled males ((15)N or (13)C) were allowed to mate with unlabeled females in semifield enclosures (22.5 m(3)) in a dengue-endemic area in southern Mexico. On average, 14% of females were positive for both labels, indicating that they received semen from more than one male. Our results provide evidence of a small but potentially significant rate of multiple mating within a 48-hour period and provide an approach for future open-field studies of polyandry in this species. Polyandry has implications for understanding mosquito ecology, evolution, and reproductive behavior as well as genetic strategies for mosquito control. PMID- 22492149 TI - Efficacy of mosquito traps for collecting potential West Nile mosquito vectors in a natural Mediterranean wetland. AB - Surveillance, research, and control of mosquito-borne diseases such as West Nile virus require efficient methods for sampling mosquitoes. We compared the efficacy of BG-Sentinel and Centers for Disease Control and Prevention (CDC)-CO(2) traps in terms of the abundances of host-seeking and blood-fed female mosquitoes and the origin of mosquito bloodmeals. Our results indicate that BG-Sentinel traps that use CO(2) and attractants are as effective as CDC-CO(2) traps for Culex mosquito species, Ochlerotatus caspius, and they are also highly efficient at capturing Anopheles atroparvus host-seeking and blood-fed females with or without CO(2). The CDC-CO(2) trap is the least efficient method for capturing blood-fed females. BG-Sentinel traps with attractants and CO(2) were significantly better at capturing mosquitoes that had fed on mammals than the unbaited BG-Sentinel and CDC-CO(2) traps in the cases of An. atroparvus and Cx. theileri. These results may help researchers to optimize trapping methods by obtaining greater sample sizes and saving time and money. PMID- 22492150 TI - Collapse of Anopheles darlingi populations in Suriname after introduction of insecticide-treated nets (ITNs); malaria down to near elimination level. AB - A longitudinal study of malaria vectors was carried out in three villages in Suriname between 2006 and 2010. During 13,392 man hours of collections, 3,180 mosquitoes were collected, of which 33.7% were anophelines. Of these, Anopheles darlingi accounted for 88.1%, and An. nuneztovari accounted for 11.1%. The highest mean An. darlingi human biting rate (HBR) observed per survey was 1.43 bites/man per hour outdoor and 1.09 bites/man per hour indoor; 2 An. darlingi of the 683 tested were infected with Plasmodium falciparum. The anopheline HBR decreased to zero after the onset of malaria intervention activities, including insecticide-treated net (ITN) distribution, in 2006. Malaria transmission decreased to pre-elimination levels. It is concluded that the combination of ITN and climatic events has led to the collapse of malaria vector populations in the study sites in the interior of the country. The results are discussed in relation to the stability of malaria transmission in areas with low-density human populations. PMID- 22492151 TI - Effects of Beauveria bassiana on survival, blood-feeding success, and fecundity of Aedes aegypti in laboratory and semi-field conditions. AB - The fungus Beauveria bassiana reduces Aedes aegypti longevity in laboratory conditions, but effects on survival, blood-feeding behavior, and fecundity in realistic environmental conditions have not been tested. Adult, female Ae. aegypti infected with B. bassiana (FI-277) were monitored for blood-feeding success and fecundity in the laboratory. Fungal infection reduced mosquito-human contact by 30%. Fecundity was reduced by (mean +/- SD) 29.3 +/- 8.6 eggs per female per lifetime in the laboratory; egg batch size and viability were unaffected. Mosquito survival, blood-feeding behavior, and fecundity were also tested in 5 meter * 7 meter * 4 meter semi-field cages in northern Queensland, Australia. Fungal infection reduced mosquito survival in semi-field conditions by 59-95% in large cages compared with 61-69% in small cages. One semi-field cage trial demonstrated 80% reduction in blood-feeding; a second trial showed no significant effect. Infection did not affect fecundity in large cages. Beauveria bassiana can kill and may reduce biting of Ae. aegypti in semi-field conditions and in the laboratory. These results further support the use of B. bassiana as a potential biocontrol agent against Ae. aegypti. PMID- 22492152 TI - Dispersal of male Aedes aegypti in a coastal village in southern Mexico. AB - Most Aedes aegypti dispersal studies have focused on females because of their central role in dengue virus transmission. Only a few mark-release-recapture (MRR) studies provided insights into male Ae. aegypti dispersal. To fill this knowledge gap, we conducted five male Ae. aegypti MRR experiments in a coastal village in southern Mexico. Small and large male cohorts were marked with fluorescent dusts, released outside buildings, and recaptures were carried out by using backpack aspirators. Recapture rates ranged between 0.35% and 6.55% and median distance traveled was 12-166 meters. A statistically significant difference in median distance traveled with large males dispersing farther than small ones was detected only in one experiment (MRR5: U = 3.5, P < 0.01). Male dispersal data will be useful for constructing and estimating parameter values and validating models that will be used to plan the most effective release strategies for genetically modified male Ae. aegypti. PMID- 22492153 TI - House infestation dynamics and feeding sources of Triatoma dimidiata in central Veracruz, Mexico. AB - Chagas disease is endemic in the state of Veracruz, Mexico, and we investigated here the dynamics of house infestation by Chagas disease vectors to understand disease transmission and design effective control interventions. Bug collections in 42 rural villages confirmed the widespread distribution of Triatoma dimidiata in central Veracruz. Unexpectedly, collection data further indicated a clear pattern of seasonal infestation by mostly adult bugs. Analysis of feeding sources with a polymerase chain reaction-heteroduplex assay indicated a frequent feeding on humans, in agreement with the high seroprevalence previously observed. Feeding sources also confirmed a significant dispersal of bugs between habitats. High dispersal capabilities and seasonal infestation may thus be a shared characteristic of several of the T. dimidiata sibling species from this complex. It would thus be critical to adapt vector control interventions to this behavior to improve their efficacy and sustainability, as the control of T. dimidiata has been notoriously challenging. PMID- 22492154 TI - Training laboratory technicians from the Ethiopian periphery in the MODS technique enables rapid and low-cost diagnosis of Mycobacterium tuberculosis infection. AB - Tuberculosis (TB) is a leading cause of morbidity and mortality and is frequently complicated by emergence of drug-resistant strains. Diagnosis of TB in developing countries is often based on the relatively insensitive acid-fast staining that does not enable susceptibility profiling. Microscopic observation drug susceptibility assay (MODS) is an inexpensive, simple method that enables rapid TB culture coupled with susceptibility testing. A 3-week MODS training of three Ethiopian laboratory technicians was conducted at Hadassah-Hebrew University Medical Center, Israel. Results of the trainee readings were blindly assessed by an experienced instructor. Two hundred fifty-five (255) trainee culture readings were evaluated throughout the course. The sensitivity and specificity were 75 100% and 31.5-100%, respectively. Multivariate analysis revealed that sensitivity and duration of incubation were positively correlated, although specificity was positively correlated with the length of training. MODS can be reliably performed by laboratory technicians inexperienced in culture techniques in developing countries, with high sensitivity and specificity reached after a brief learning period. PMID- 22492155 TI - Innate and adaptive immune responses during acute M. tuberculosis infection in adult household contacts in Kampala, Uganda. AB - Contacts of active pulmonary tuberculosis (TB) patients are at risk for Mycobacterium tuberculosis (MTB) infection. Because most infections are controlled, studies during MTB infection provide insight into protective immunity. We compared immune responses of adult household contacts that did and did not convert the tuberculin skin test (TST). Innate and adaptive immune responses were measured by whole blood assay. Responses of TST converters (TSTC) were compared with persistently TST negative contacts (PTST-) and contacts who were TST+ at baseline (TST+). TLR-2, TLR-4, and IFN-gammaR responses to IFN-gamma did not differ between the groups, nor did gammadelta T cell responses. T cell responses to MTB antigens differed markedly among TSTC, PTST-, and TST+ contacts. Thus, no differences in innate responses were found among the three household contact groups. However, adaptive T cell responses to MTB antigens did differ before and during MTB infection among PTST-, TSTC, and TST+ contacts. PMID- 22492156 TI - Factors associated with encephalopathy in patients with Salmonella enterica serotype Typhi bacteremia presenting to a diarrheal hospital in Dhaka, Bangladesh. AB - To characterize clinical correlates of typhoid fever-associated encephalopathy, we performed a retrospective chart review of patients with Salmonella enterica serotype Typhi bacteremia who were hospitalized at the International Centre for Diarrhoeal Disease Research, Bangladesh, from February of 2009 to June of 2011. Of 207 patients bacteremic with Salmonella Typhi who were >= 5 years of age, we identified 43 (21%) patients with encephalopathy. Univariate analysis revealed that patients with encephalopathy more often presented at ages of 10-24 years and had severe dehydration, low oxygen saturation, high respiratory rate, low leukocyte count, low platelet count, and Widal flagellar H agglutinin (TH) titer >= 1:640 compared with typhoid patients without encephalopathy. Multivariate analysis using logistic regression showed that age, dehydration, leukocyte count, and Widal TH titer were independently associated with encephalopathy. Our findings suggest that age, severity of disease, and immune responses are associated with encephalopathy during Salmonella Typhi bacteremia, perhaps reflecting the impact of prominent inflammatory responses. PMID- 22492157 TI - Anthrax outbreaks in Bangladesh, 2009-2010. AB - During August 2009-October 2010, a multidisciplinary team investigated 14 outbreaks of animal and human anthrax in Bangladesh to identify the etiology, pathway of transmission, and social, behavioral, and cultural factors that led to these outbreaks. The team identified 140 animal cases of anthrax and 273 human cases of cutaneous anthrax. Ninety one percent of persons in whom cutaneous anthrax developed had history of butchering sick animals, handling raw meat, contact with animal skin, or were present at slaughtering sites. Each year, Bacillus anthracis of identical genotypes were isolated from animal and human cases. Inadequate livestock vaccination coverage, lack of awareness of the risk of anthrax transmission from animal to humans, social norms and poverty contributed to these outbreaks. Addressing these challenges and adopting a joint animal and human health approach could contribute to detecting and preventing such outbreaks in the future. PMID- 22492158 TI - Detection of rickettsioses and Q fever in Sri Lanka. AB - Current serological evidence suggests the presence of scrub typhus and spotted fever group (SFG) rickettsiosis in Sri Lanka. Our objective was to identify rickettsial agents/Q fever as aetiological causes for patients who were presumed having rickettsioses by the presence of an eschar or a rash. Sera from patients with unknown origin fever from Matara were tested by immunofluorescence for SFG rickettsial antigens, typhus group rickettsiae, Orientia tsutsugamushi, and Coxiella burnetii antigens. Thirteen (7.3%) of the patients presented with a rash, 11 (6.1%) had an inoculation eschar, and 16 patients recalled a tick or flea bite. We found that 25 (14%) patients had scrub typhus, 6 (3%) SFG rickettsioses, 3 (1.6%) acute Q fever, 3 (1.6%) murine typhus, and 3 (1.6%) were infected by Rickettsia felis. In addition to already described scrub and murine typhus, we found that R. felis and C. burnetii infections should be considered in Sri Lanka. PMID- 22492159 TI - Fatal Rocky Mountain spotted fever in the United States, 1999-2007. AB - Death from Rocky Mountain spotted fever (RMSF) is preventable with prompt, appropriate treatment. Data from two independent sources were analyzed to estimate the burden of fatal RMSF and identify risk factors for fatal RMSF in the United States during 1999-2007. Despite increased reporting of RMSF cases to the Centers for Disease Control and Prevention, no significant changes in the estimated number of annual fatal RMSF cases were found. American Indians were at higher risk of fatal RMSF relative to whites (relative risk [RR] = 3.9), and children less than 10 years of age (RR=5.1) [corrected] and adults >= 70 years of age (RR = 3.0) were also at increased risk relative to other ages. Persons with cases of RMSF with an immunosuppressive condition were at increased risk of death (RR = 4.4). Delaying treatment of RMSF was also associated with increased deaths. These results may indicate a gap between recommendations and practice. PMID- 22492160 TI - A comparative study of clinical features between monotypic and dual infection cases with Chikungunya virus and dengue virus in West Bengal, India. AB - Chikungunya virus (CHIKV) and dengue virus (DENV) are circulating individually in the state of West Bengal, India. However, after 1965 the dual-infection caused by both viruses had not been recorded until 2010. In 2010, an investigation of the febrile cases was carried out to confirm the involvement of both viruses simultaneously. A total of 550 blood samples were tested for the detection of immunoglobulin M (IgM) antibody against both CHIKV and DENV. Serology by the enzyme-linked immunosorbent assay method confirmed that 131 (23.8%) and 104 (18.9%) patients had IgM antibody against CHIKV and DENV, respectively, whereas 68 (12.4%) had IgM antibodies against both CHIKV and DENV. Fever, joint pain, rashes, headache, myalgia, and nausea/vomiting are the common features in the case of both monotypic and dual-infection. Severe arthralgia and swelling of joints were common only in CHIKV-positive cases and abdominal pain was mainly associated with DENV infection. Diarrhea was reported only by the dual-infected patients (16.2%). PMID- 22492161 TI - Landscape-level spatial patterns of West Nile virus risk in the northern Great Plains. AB - Understanding the landscape-level determinants of West Nile virus (WNV) can aid in mapping high-risk areas and enhance disease control and prevention efforts. This study analyzed the spatial patterns of human WNV cases in three areas in South Dakota during 2003-2007 and investigated the influences of land cover, hydrology, soils, irrigation, and elevation by using case-control models. Land cover, hydrology, soils, and elevation all influenced WNV risk, although the main drivers were different in each study area. Risk for WNV was generally higher in areas with rural land cover than in developed areas, and higher close to wetlands or soils with a high ponding frequency. In western South Dakota, WNV risk also decreased with increasing elevation and was higher in forested areas. Our results showed that the spatial patterns of human WNV risk were associated with landscape level features that likely reflect variability in mosquito ecology, avian host communities, and human activity. PMID- 22492162 TI - Identification of Oropouche Orthobunyavirus in the cerebrospinal fluid of three patients in the Amazonas, Brazil. AB - Oropouche fever is the second most frequent arboviral infection in Brazil, surpassed only by dengue. Oropouche virus (OROV) causes large and explosive outbreaks of acute febrile illness in cities and villages in the Amazon and Central-Plateau regions. Cerebrospinal fluid (CSF) samples from 110 meningoencephalitis patients were analyzed. The RNA extracted from fluid was submitted to reverse transcription-polymerase chain reaction and sequencing to identify OROV. Three CSF samples showed the presence of OROV causing infection in the central nervous system (CNS). These patients are adults. Two of the patients had other diseases affecting CNS and immune systems: neurocysticercosis and acquired immunodeficiency syndrome, respectively. Nucleotide sequence analysis showed that the OROV from the CSF of these patients belonged to genotype I. We show here that severe Oropouche disease is occurring during outbreaks of this virus in Brazil. PMID- 22492163 TI - Evaluation of a monoclonal antibody-based rapid immunochromatographic test for direct detection of rabies virus in the brain of humans and animals. AB - Rabies diagnosis uses a direct fluorescent antibody test (FAT) that is difficult, costly, and time-consuming, and requires trained personnel. We developed a rapid immunochromatographic test (RICT) for the diagnosis of rabies. The efficacy of the RICT was compared with that of the FAT. Brain samples were collected from humans, dogs, cats, and other animals in Sri Lanka (n = 248), Bhutan (n = 27), and Thailand (n = 228). The sensitivity (0.74-0.95), specificity (0.98-1.0), positive predictive value (0.98-1.0), negative predictive value (0.75-0.97), accuracy (0.91-0.98), and kappa measure of agreement (0.79-0.93) were all satisfactory for animal samples and samples preserved in 50% glycerol saline solution. Because the RICT showed high sensitivity but low specificity with human brain samples, it is unsuitable for confirming rabies in humans. No amino acid substitutions were found in the antibody attachment sites of the nucleoprotein gene with FAT-positive, RICT-negative samples. The RICT is reliable, user friendly, rapid, robust, and can be used in laboratories with a modest infrastructure. PMID- 22492164 TI - A comparison of the prevalence of lead-contaminated imported Chinese ceramic dinnerware purchased inside versus outside Philadelphia's Chinatown. AB - Lead-contaminated ceramics can be a clinically significant source of lead poisoning, with the potential to cause illness in children and adults; one death in a child has been described. We hypothesized that the prevalence of lead contaminated ceramics would be higher within Chinatown versus outside of Chinatown. The study was a prospective observational cross-sectional study. Two areas were defined geographically as being within and outside of Philadelphia's Chinatown, and a predefined number of items were purchased in each area. Each item was screened for lead utilizing a colorimetric testing swab. Positive items were leached for lead using the ASTM C738-94 protocol for lead level quantification. The primary outcome was the prevalence of ceramics not compliant with the FDA standard for leachable lead within and outside of Philadelphia's Chinatown. A total of 132 items were purchased, 46 outside of and 86 within Chinatown. More lead-positive items originated within Chinatown than outside of Chinatown [five positive items, 5.8 % prevalence within Chinatown (95 % confidence interval, CI, 2.5-12.9 %), and zero positive, 0 % prevalence outside of Chinatown (95 % CI 0-7.5 %)]. However, this difference was not found to be statistically significant (P = 0.1624). The leachable lead-positive items were up to 40-fold the acceptable FDA levels. Testing a larger number of items may demonstrate a significant source of lead exposure. PMID- 22492165 TI - Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation. AB - OBJECTIVE: Enhanced adhesive signaling, including activation of focal adhesion kinase (FAK), is a hallmark of fibroblasts from lung fibrosis patients, and FAK has therefore been hypothesized to be a key mediator of this disease. This study was undertaken to characterize the contribution of FAK to the development of pulmonary fibrosis both in vivo and in vitro. METHODS: FAK expression and activity were analyzed in lung tissue samples from lung fibrosis patients by immunohistochemistry. Mice orally treated with the FAK inhibitor PF-562,271, or with small interfering RNA (siRNA)-mediated silencing of FAK were exposed to intratracheally instilled bleomycin to induce lung fibrosis, and lungs were harvested for histologic and biochemical analysis. Using endothelin 1 (ET-1) as a stimulus, cell adhesion and contraction, as well as profibrotic gene expression, were studied in fibroblasts isolated from wild-type and FAK-deficient mouse embryos. ET-1-mediated FAK activation and gene expression were studied in primary mouse lung fibroblasts, as well as in wild-type and beta1 integrin-deficient mouse fibroblasts. RESULTS: FAK expression and activity were up-regulated in fibroblast foci and remodeled vessels from lung fibrosis patients. Pharmacologic or siRNA-mediated targeting of FAK resulted in marked abrogation of bleomycin induced lung fibrosis in mice. Loss of FAK impaired the acquisition of a profibrotic phenotype in response to ET-1. Profibrotic gene expression leading to myofibroblast differentiation required cell adhesion, and was driven by JNK activation through beta1 integrin/FAK signaling. CONCLUSION: These results implicate FAK as a central mediator of fibrogenesis, and highlight this kinase as a potential therapeutic target in fibrotic diseases. PMID- 22492166 TI - Degradation kinetics of 4-amino naphthalene-1-sulfonic acid by a biofilm-forming bacterial consortium under carbon and nitrogen limitations. AB - By decolorization of azo dyes, caused by reductive cleavage of the azo linkage, toxic or recalcitrant amines are generated. The present study deals with the effect of the inflowing medium composition (C:N ratio) on the kinetic behavior of a bacterial biofilm-forming consortium, able to use as carbon, nitrogen and sulfur source, the molecule of 4-aminonaphthalene-1-sulfonic acid (4ANS), which is one of the most recalcitrant byproducts generated by decolorization of azo dyes. All the experiments were carried out at room temperature in a lab-scale packed-bed biofilm reactor. Because environmental conditions affect the bioreactor performance, two mineral salts media containing 4ANS, with distinct C:N ratios; 0.68 (carbon as the limiting nutrient) and 8.57 (nitrogen as the limiting nutrient) were used to evaluate their effect on 4ANS biodegradation. By HPLC and COD measurements, the 4ANS removal rates and removal efficiencies were determined. The cultivable bacterial strains that compose the consortium were identified by their 16S rDNA gene sequence. With the enrichment technique used, a microbial consortium able to use efficiently 4ANS as the sole carbon source and energy, nitrogen and sulfur, was selected. The bacterial strains that constitute the consortium were isolated and identified. They belong to the following genera: Bacillus, Arthrobacter, Microbacterium, Nocardioides, and Oleomonas. The results obtained with this consortium showed, under nitrogen limitation, a remarkable increase in the 4ANS removal efficiency eta(ANS), and in the 4ANS volumetric removal rates R (V,4ANS), as compared to those obtained under carbon limitation. Differences observed in bioreactor performance after changing the nutrient limitation could be caused by changes in biofilm properties and structure. PMID- 22492167 TI - Pollen limitation in a narrow endemic plant: geographical variation and driving factors. AB - Pollen limitation may have important consequences for the reproduction and abundance of plant species. It may be especially harmful to endangered and endemic plants with small populations. In this study, we quantify the effect of pollen limitation on seed production and seedling emergence in an endangered narrow endemic crucifer, Erysimum popovii. We conducted a pollen addition experiment across the entire geographic distribution of the species, and explored the effect of pollinator assemblage, plant population size and density, and other habitat variables on pollen limitation intensity in 13 populations. We supplemented flowers in 20 plants per population with allogamous pollen. To account for potential resource reallocation, we used two types of control untreated flowers: internal control flowers from the same individual as the supplemented flowers, and external control flowers from other individuals. Our results indicate that E. popovii is pollen-limited in most of the populations studied, but only through seed production, since pollen supplementation did not enhance seedling emergence. Beefly abundance was associated with among-population differences in pollen limitation intensity. Populations in which beeflies were more abundant were less pollen-limited. In contrast, the abundance of other flower visitors, such as large bees or butterflies, was not associated with pollen limitation. Annual rainfall and bare soil cover were associated with the intensity of pollen limitation across populations. PMID- 22492168 TI - Higher nest predation risk in association with a top predator: mesopredator attraction? AB - Breeding close to top predators is a widespread reproductive strategy. Breeding animals may gain indirect benefits if proximity to top predators results in a reduction of predation due to suppression of mesopredators. We tested if passerine birds gain protection from mesopredators by nesting within territories of a top predator, the Ural owl (Strix uralensis). We placed nest boxes for pied flycatchers (Ficedula hypoleuca) in Ural owl nest sites and in control sites (currently unoccupied by owls). The nest boxes were designed so that nest predation risk could be altered (experimentally increased) after flycatcher settlement; we considered predation rate as a proxy of mesopredator abundance. Overall, we found higher nest predation rates in treatment than in control sites. Flycatcher laying date did not differ between sites, but smaller clutches were laid in treatment sites compared to controls, suggesting a response to perceived predation risk. Relative nest predation rate varied between years, being higher in owl nest sites in 2 years but similar in another; this variation might be indirectly influenced by vole abundance. Proximity to Ural owl nests might represent a risky habitat for passerines. High predation rates within owl territories could be because small mesopredators that do not directly threaten owl nests are attracted to owl nest sites. This could be explained if some mesopredators use owl territories to gain protection from their own predators, or if top predators and mesopredators independently seek similar habitats. PMID- 22492169 TI - Changes to the N cycle following bark beetle outbreaks in two contrasting conifer forest types. AB - Outbreaks of Dendroctonus beetles are causing extensive mortality in conifer forests throughout North America. However, nitrogen (N) cycling impacts among forest types are not well known. We quantified beetle-induced changes in forest structure, soil temperature, and N cycling in Douglas-fir (Pseudotsuga menziesii) forests of Greater Yellowstone (WY, USA), and compared them to published lodgepole pine (Pinus contorta var. latifolia) data. Five undisturbed stands were compared to five beetle-killed stands (4-5 years post-outbreak). We hypothesized greater N cycling responses in Douglas-fir due to higher overall N stocks. Undisturbed Douglas-fir stands had greater litter N pools, soil N, and net N mineralization than lodgepole pine. Several responses to disturbance were similar between forest types, including a pulse of N-enriched litter, doubling of soil N availability, 30-50 % increase in understory cover, and 20 % increase in foliar N concentration of unattacked trees. However, the response of some ecosystem properties notably varied by host forest type. Soil temperature was unaffected in Douglas-fir, but lowered in lodgepole pine. Fresh foliar %N was uncorrelated with net N mineralization in Douglas-fir, but positively correlated in lodgepole pine. Though soil ammonium and nitrate, net N mineralization, and net nitrification all doubled, they remained low in both forest types (<6 MUg N g soil(-1) NH(4) (+)or NO(3) (-); <25 MUg N g soil(-1) year(-1) net N mineralization; <8 MUg N g soil( 1) year(-1) net nitrification). Results suggest that beetle disturbance affected litter and soil N cycling similarly in each forest type, despite substantial differences in pre-disturbance biogeochemistry. In contrast, soil temperature and soil N-foliar N linkages differed between host forest types. This result suggests that disturbance type may be a better predictor of litter and soil N responses than forest type due to similar disturbance mechanisms and disturbance legacies across both host-beetle systems. PMID- 22492170 TI - Interactive effects of herbivory and competition intensity determine invasive plant performance. AB - Herbivory can reduce plant fitness, and its effects can be increased by competition. Though numerous studies have examined the joint effects of herbivores and competitors on plant performance, these interactive effects are seldom considered in the context of plant invasions. Here, we examined variation in plant performance within a competitive environment in response to both specialist and generalist herbivores using Chinese tallow as a model species. We combined tallow plants from native and invasive populations to form all possible pairwise combinations, and designated invasive populations as stronger neighbours and native populations as weaker neighbours. We found that when no herbivory was imposed, invasive populations always had higher total biomass than natives, regardless of their neighbours, which is consistent with our assumption of increased competitive ability. Defoliation by either generalist or specialist herbivores suppressed plant growth but the effects of specialists were generally stronger for invasive populations. Invasive populations had their lowest biomass when fed upon by specialists while simultaneously competing with stronger neighbours. The root/shoot ratios of invasive populations were lower than those of native populations under almost all conditions, and invasive plants were taller than native plants overall, especially when herbivores were present, suggesting that invasive populations may adopt an "aboveground first" strategy to cope with herbivory and competition. These results suggest that release from herbivores, especially specialists, improves an invader's performance and helps to increase its competitive ability. Therefore, increasing interspecific competition intensity by planting a stronger neighbour while simultaneously releasing a specialist herbivore may be an especially effective method of managing invasive plants. PMID- 22492171 TI - Surgical technique: a percutaneous method of subcutaneous fixation for the anterior pelvic ring: the pelvic bridge. AB - BACKGROUND: Management of pelvic ring injuries using minimally invasive techniques may be desirable if reduction and stability can be achieved. We present a new technique, the anterior pelvic bridge, which is a percutaneous method of fixing the anterior pelvis through limited incisions over the iliac crest(s) and pubic symphysis. DESCRIPTION OF TECHNIQUE: An incision is made over each anterior iliac crest and a 6- to 8-cm incision is centered over the symphysis. Either a locking reconstruction plate or a spinal rod is placed through a subcutaneous tunnel overlying the external oblique fascia in the subcutaneous tissue, and fixation into the iliac crest and pubis is achieved to effect stability. METHODS: A randomized controlled trial comparing anterior pelvic external fixation (APEF) versus anterior pelvic internal fixation (APIF) for unstable pelvic ring injuries was begun in October 2010. Patients with unstable pelvic ring injuries were enrolled and followed with respect to fracture reduction, surgical pain, complications, and functional outcome scores. RESULTS: As of January 2012, 23 patients met inclusion; however, 12 patients refused participation because of the possibility of external fixation, leaving 11 patients (four male, seven female) enrolled. At 6-month followup, there was a single pin tract infection in the APEF cohort and no complications or pain in the APIF cohort. CONCLUSIONS: This clinical experience lends support to the use of a new minimally invasive technique to stabilize the anterior pelvis, particularly given the resistance on the part of patients to consider external fixation. LEVEL OF EVIDENCE: Level II, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 22492172 TI - LCPD: reduced range of motion resulting from extra- and intraarticular impingement. AB - BACKGROUND: Legg-Calve-Perthes disease (LCPD) often results in a deformity that can be considered as a complex form of femoroacetabular impingement (FAI). Improved preoperative characterization of the FAI problem based on a noninvasive three-dimensional computer analysis may help to plan the appropriate operative treatment. QUESTIONS/PURPOSES: We asked whether the location of impingement zones, the presence of additional extraarticular impingement, and the resulting ROM differ between hips with LCPD and normal hips or hips with FAI. METHODS: We used a CT-based virtual dynamic motion analysis based on a motion algorithm to simulate the individual motion for 13 hips with LCPD, 22 hips with FAI, and 27 normal hips. We then determined the motion and impingement pattern of each hip for the anterior (flexion, adduction, internal rotation) and the posterior impingement tests (extension, adduction, external rotation). RESULTS: The location of impingement zones in hips with LCPD differed compared with the FAI/normal groups. Intra- and extraarticular impingement was more frequent in LCPD (79% and 86%, respectively) compared with normal (15%, 15%) and FAI hips (36%, 14%). Hips with LCPD had decreased amplitude for all hip motions (flexion, extension, abduction, adduction, internal and external rotation) compared with FAI or normal. CONCLUSIONS: Hips with LCPD show a decreased ROM as a result of a higher prevalence of intra- and extraarticular FAI. Noninvasive assessment of impingement characteristics in hips with LCPD may be helpful in the future for establishment of a surgical plan. PMID- 22492173 TI - High survivorship of cemented sockets with roof graft for severe acetabular dysplasia. AB - BACKGROUND: Socket fixation in patients with acetabular dysplasia can be technically demanding but the use of structural grafts can help to reconstruct the original center of hip rotation. Because reported survival rates differ, construct survival seems to depend on the technique of graft preparation and fixation. QUESTIONS/PURPOSES: What is the survivorship of cemented sockets with acetabular roof graft in patients with severe acetabular dysplasia? Do clinical scores equal those of patients without acetabular grafting? METHODS: We retrospectively reviewed 62 patients (74 hips) who had undergone cemented THA with acetabular roof graft. Mean age at surgery was 45 years (range, 19-71 years). Revisions and radiographic failures were determined and clinical scores (Oxford, SF-12) were obtained and matched to a control group. Kaplan-Meier analysis was used to determine survivorship at a minimum followup of 5 years (mean, 10.4 years; range, 5-16 years). RESULTS: Survivorship for all-cause revision was 98% (95% CI, 92.5%-100.0%) at 10 years followup. Two hips were revised for aseptic acetabular loosening and one hip for polyethylene wear. All grafts incorporated and no additional radiographic loosenings were seen. Patients with grafting had higher Oxford scores compared with the control group but other scores were equal. CONCLUSIONS: In contrast to reported series and the common use of cementless cups in patients with developmental dysplasia of the hip, we found high survivorship of cemented sockets with roof graft in severe acetabular dysplasia at a mean followup of more than 10 years. These patients showed higher Oxford scores than patients in a control group. This technique that restores bone stock is a reasonable solution for often young patients with dysplasia. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 22492174 TI - Differential migratory properties of monocytes isolated from human subjects naive and non-naive to Cannabis. AB - This study evaluates the migratory potential of monocytes isolated from two groups of human subjects: naive and non-naive to Cannabis. Phytocannabinoids (pCB), the bioactive agents produced by the plant Cannabis, regulate the phenotype and function of immune cells by interacting with CB1 and CB2 receptors. It has been shown that agents influencing the phenotype of circulating monocytes influence the phenotype of macrophages and the outcome of immune responses. To date, nothing is known about the acute and long-term effects of pCB on human circulating monocytes. Healthy subjects were recruited for a single blood draw. Monocytes were isolated, fluorescently labeled and their migration quantified using a validated assay that employs near infrared fluorescence and modified Boyden chambers. CB1 and CB2 receptor mRNA expression was quantified by qPCR. Monocytes from all subjects (n = 10) responded to chemokine (c-c motif) ligand 2 (CCL2) and human serum stimuli. Acute application of pCB significantly inhibited both the basal and CCL2-stimulated migration of monocytes, but only in subjects non-naive to Cannabis. qPCR analysis indicates that monocytes from subjects non naive to Cannabis express significantly more CB1 mRNA. The phenotype of monocytes isolated from subjects non-naive to Cannabis is significantly different from monocytes isolated from subjects naive to Cannabis. Only monocytes from subjects non-naive to Cannabis respond to acute exposure to pCB by reducing their overall migratory capacity. Our study suggests that chronic exposure to Cannabis affects the phenotype of circulating monocytes and accordingly could influence outcome of inflammatory responses occurring in injured tissues. PMID- 22492175 TI - Foveal sensitivity and visual acuity in macular thickening disorders. AB - PURPOSE: To study the relationship between foveal sensitivity and visual acuity in eyes with macular disorders exhibiting macular thickening. METHODS: We studied the relationship between foveal sensitivity, obtained as the "foveal threshold" by use of Humphrey perimetry, and best-corrected visual acuity, converted to the logarithm of the minimum angle of resolution (logMAR), for 117 eyes with epiretinal membrane (ERM), 197 eyes with retinal vein occlusion associated with macular edema (RVOME), and 158 eyes with central serous chorioretinopathy (CSC). RESULTS: Foveal sensitivity and logMAR correlated significantly for the eyes with ERM, RVOME, and CSC. Although mean foveal sensitivity was no different among the three diseases, mean logMAR was lower in eyes with CSC, i.e., visual acuity was better, than in those with ERM or RVOME (P < 0.001). CONCLUSIONS: Light sense (foveal sensitivity) is related to spatial resolution (logMAR) at the center of the fovea, in eyes with ERM, RVOME, and CSC at different strengths depending on the disease. Less pronounced reduction of visual acuity compared with foveal sensitivity in eyes with CSC could explain the tendency of these patients to complain of dimness rather than acuity loss. PMID- 22492176 TI - Improved particle swarm optimization algorithm for android medical care IOT using modified parameters. AB - This study examines wireless sensor network with real-time remote identification using the Android study of things (HCIOT) platform in community healthcare. An improved particle swarm optimization (PSO) method is proposed to efficiently enhance physiological multi-sensors data fusion measurement precision in the Internet of Things (IOT) system. Improved PSO (IPSO) includes: inertia weight factor design, shrinkage factor adjustment to allow improved PSO algorithm data fusion performance. The Android platform is employed to build multi-physiological signal processing and timely medical care of things analysis. Wireless sensor network signal transmission and Internet links allow community or family members to have timely medical care network services. PMID- 22492177 TI - Analysis of cloud-based solutions on EHRs systems in different scenarios. AB - Nowadays with the growing of the wireless connections people can access all the resources hosted in the Cloud almost everywhere. In this context, organisms can take advantage of this fact, in terms of e-Health, deploying Cloud-based solutions on e-Health services. In this paper two Cloud-based solutions for different scenarios of Electronic Health Records (EHRs) management system are proposed. We have researched articles published between the years 2005 and 2011 about the implementation of e-Health services based on the Cloud in Medline. In order to analyze the best scenario for the deployment of Cloud Computing two solutions for a large Hospital and a network of Primary Care Health centers have been studied. Economic estimation of the cost of the implementation for both scenarios has been done via the Amazon calculator tool. As a result of this analysis two solutions are suggested depending on the scenario: To deploy a Cloud solution for a large Hospital a typical Cloud solution in which are hired just the needed services has been assumed. On the other hand to work with several Primary Care Centers it's suggested the implementation of a network, which interconnects these centers with just one Cloud environment. Finally it's considered the fact of deploying a hybrid solution: in which EHRs with images will be hosted in the Hospital or Primary Care Centers and the rest of them will be migrated to the Cloud. PMID- 22492179 TI - Last observation carried forward approach threatens the validity of intent-to treat analysis in fibromyalgia trials: comment on the article by Arnold et al. PMID- 22492180 TI - System approaches reveal the molecular networks involved in neural stem cell differentiation. AB - The self-renewal and multipotent potentials in neural stem cells (NSCs) maintain the normal physiological functions of central nervous system (CNS). The abnormal differentiation of NSCs would lead to CNS disorders. However, the mechanisms of how NSCs differentiate into astrocytes, oligodendrocytes (OLs) and neurons are still unclear, which is mainly due to the complexity of differentiation processes and the limitation of the cell separation method. In this study, we modeled the dynamics of neural cell interactions in a systemic approach by mining the high throughput genomic and proteomic data, and identified 8615 genes that are involved in various biological processes and functions with significant changes during the differentiation processes. A total of 1559 genes are specifically expressed in neural cells, in which 242 genes are NSC specific, 215 are astrocyte specific, 551 are OL specific, and 563 are neuron specific. In addition, we proposed 57 transcriptional regulators specifically expressed in NSCs may play essential roles in the development courses. These findings provide more comprehensive analysis for better understanding the endogenous mechanisms of NSC fate determination. PMID- 22492181 TI - Hippo pathway in intestinal homeostasis and tumorigenesis. AB - The Hippo pathway plays a crucial role in controlling organ size by inhibiting cell proliferation and promoting cell death. Recent findings implicate that this pathway is involved in the process of intestinal regeneration and tumorigenesis. Here we summarize current studies for the function of the Hippo signaling pathway in intestinal homeostasis, regeneration and tumorigenesis, and the crosstalk between the Hippo signaling pathway and other major signaling pathways, i.e. Wnt, Notch and Jak/Stat signaling pathways in intestinal compartment. PMID- 22492182 TI - Computational prediction and experimental assessment of an HLA-A*0201-restricted cytotoxic T lymphocyte epitope from neutral endopeptidase. AB - Neutral endopeptidase (NEP) is the first target antigen identified on podocytes in human membranous nephropathy (MN). Cytotoxic T lymphocytes (CTLs) are considered essential for glomerular destruction in MN model. The aim of this study was to show that the CTL epitopes of NEP could be used to design more effective and better tolerated therapies. The CTL epitopes of NEP were screened using the long-distance prediction system SYFPEITHI and the Bioinformatics and Molecular Analysis Section of the MHC Peptide Binding Predictions program. Peptides were synthesized and immunoreactivity was assessed by peptide-MHC binding affinity assay, cytotoxicity assay and HLA-A2.1/Kb transgenic mice immunization. Five candidates were identified according to the high scores generated by the computer predicting system. Peptide NEP(375-383) (FIMDLVSSL), which up-regulated HLA-A2.1 molecular expression, showed a high affinity to HLA A2.1, whereas NEP(268-276), NEP(297--305) and NEP(492-500) (QLALEMNKV, MLLYNKMRL and KLNNEYLEL) showed a moderate affinity and NEP(559-567) (ILQPPFFSA) only had a low affinity. Cytotoxicity assay further showed that NEP(268-276) and NEP(375 383) could induce NEP-specific CTL responses in vitro. Unexpectedly, we found that a single CTL epitope, NEP(375-383), could induce proteinuria and glomerular injury in HLA-A2.1/K(b) transgenic mice in vivo. HLA-A*0201-restricted CTL epitope NEP(375-383) can serve as a potential candidate for designing MN vaccine. PMID- 22492183 TI - Technology adoption and implementation in organisations: comparative case studies of 12 English NHS Trusts. AB - OBJECTIVES: To understand organisational technology adoption (initiation, adoption decision, implementation) by looking at the different types of innovation knowledge used during this process. DESIGN: Qualitative, multisite, comparative case study design. SETTING: One primary care and 11 acute care organisations (trusts) across all health regions in England in the context of infection prevention and control. PARTICIPANTS AND DATA ANALYSIS: 121 semistructured individual and group interviews with 109 informants, involving clinical and non-clinical staff from all organisational levels and various professional groups. Documentary evidence and field notes were also used. 38 technology adoption processes were analysed using an integrated approach combining inductive and deductive reasoning. MAIN FINDINGS: Those involved in the process variably accessed three types of innovation knowledge: 'awareness' (information that an innovation exists), 'principles' (information about an innovation's functioning principles) and 'how-to' (information required to use an innovation properly at individual and organisational levels). Centralised (national, government-led) and local sources were used to obtain this knowledge. Localised professional networks were preferred sources for all three types of knowledge. Professional backgrounds influenced an asymmetric attention to different types of innovation knowledge. When less attention was given to 'how to' compared with 'principles' knowledge at the early stages of the process, this contributed to 12 cases of incomplete implementation or discontinuance after initial adoption. CONCLUSIONS: Potential adopters and change agents often overlooked or undervalued 'how-to' knowledge. Balancing 'principles' and 'how-to' knowledge early in the innovation process enhanced successful technology adoption and implementation by considering efficacy as well as strategic, structural and cultural fit with the organisation's context. This learning is critical given the policy emphasis for health organisations to be innovation-ready. PMID- 22492184 TI - A comparison of reusable and disposable perioperative textiles: sustainability state-of-the-art 2012. AB - Contemporary comparisons of reusable and single-use perioperative textiles (surgical gowns and drapes) reflect major changes in the technologies to produce and reuse these products. Reusable and disposable gowns and drapes meet new standards for medical workers and patient protection, use synthetic lightweight fabrics, and are competitively priced. In multiple science-based life cycle environmental studies, reusable surgical gowns and drapes demonstrate substantial sustainability benefits over the same disposable product in natural resource energy (200%-300%), water (250%-330%), carbon footprint (200%-300%), volatile organics, solid wastes (750%), and instrument recovery. Because all other factors (cost, protection, and comfort) are reasonably similar, the environmental benefits of reusable surgical gowns and drapes to health care sustainability programs are important for this industry. Thus, it is no longer valid to indicate that reusables are better in some environmental impacts and disposables are better in other environmental impacts. It is also important to recognize that large-scale studies of comfort, protection, or economics have not been actively pursued in the last 5 to 10 years, and thus the factors to improve both reusables and disposable systems are difficult to assess. In addition, the comparison related to jobs is not well studied, but may further support reusables. In summary, currently available perioperative textiles are similar in comfort, safety, and cost, but reusable textiles offer substantial opportunities for nurses, physicians, and hospitals to reduce environmental footprints when selected over disposable alternatives. Evidenced-based comparison of environmental factors supports the conclusion that reusable gowns and drapes offer important sustainability improvements. The benefit of reusable systems may be similar for other reusables in anesthesia, such as laryngeal mask airways or suction canisters, but life cycle studies are needed to substantiate these benefits. PMID- 22492185 TI - A life cycle assessment of reusable and single-use central venous catheter insertion kits. AB - BACKGROUND: For most items used in operating rooms, it is unclear whether reusable items are environmentally and financially advantageous in comparison with single-use variants. We examined the life cycles of reusable and single-use central venous catheter kits used to aid the insertion of single-use, central venous catheters in operating rooms. We did not examine the actual disposable catheter sets themselves. We assessed the entire financial and environmental costs for the kits, including the influence of the energy source used for sterilization. METHODS: For the reusable central venous catheter kit, we performed a "time-in-motion" study to determine the labor costs and measured the energy and water consumption for cleaning and sterilization at Western Health, Melbourne, Australia. For the majority of the inputs for the single-use kit, we relied upon industry and inventory-sourced databases. We modeled the life cycles of the reusable and single-use central venous catheter kits with Monte Carlo analysis. RESULTS: Inclusive of labor, the reusable central venous catheter insertion kits cost $6.35 Australian ($A) (95% confidence interval [CI], $A5.89 to $A6.86), and the single-use kits cost $A8.65. For the reusable kit, CO(2) emissions were 1211 g (95% CI, 1099 to 1323 g) and for the single-use kit 407 g (95% CI, 379 to 442 g). Water use was 27.7 L (95% CI, 27.0 to 28.6 l) for the reusable kit and 2.5 L (95% CI, 2.1 to 2.9 l) for the single-use kit. For the reusable kit, sterilization had the greatest environmental cost, and for the single-use kit, the manufacture of plastic and metal components had the largest environmental costs. Different sources of electricity to make the reusable kits patient-ready again affected the CO(2) emissions: electricity from hospital gas cogeneration resulted in 436 g CO(2) (95% CI, 410 to 473 g CO(2)), from the United States electricity grid 764 g CO(2) (95% CI, 509 to 1174 g CO(2)), and from the European electricity grid 572 g (95% CI, 470 to 713 g CO(2)). CONCLUSIONS: Inclusive of labor, the reusable central venous catheter insertion kits were less expensive than were the single-use kits. For our hospital, which uses brown coal-sourced electricity, the environmental costs of the reusable kit were considerably greater than those of the single-use kit. Efforts to reduce the environmental footprint of reusable items should be directed towards decreasing the water and energy consumed in cleaning and sterilization. The source of hospital electricity significantly alters the relative environmental effects of reusable items. PMID- 22492186 TI - Life cycle greenhouse gas emissions of anesthetic drugs. AB - BACKGROUND: Anesthesiologists must consider the entire life cycle of drugs in order to include environmental impacts into clinical decisions. In the present study we used life cycle assessment to examine the climate change impacts of 5 anesthetic drugs: sevoflurane, desflurane, isoflurane, nitrous oxide, and propofol. METHODS: A full cradle-to-grave approach was used, encompassing resource extraction, drug manufacturing, transport to health care facilities, drug delivery to the patient, and disposal or emission to the environment. At each stage of the life cycle, energy, material inputs, and emissions were considered, as well as use-specific impacts of each drug. The 4 inhalation anesthetics are greenhouse gases (GHGs), and so life cycle GHG emissions include waste anesthetic gases vented to the atmosphere and emissions (largely carbon dioxide) that arise from other life cycle stages. RESULTS: Desflurane accounts for the largest life cycle GHG impact among the anesthetic drugs considered here: 15 times that of isoflurane and 20 times that of sevoflurane on a per MAC-hour basis when administered in an O(2)/air admixture. GHG emissions increase significantly for all drugs when administered in an N(2)O/O(2) admixture. For all of the inhalation anesthetics, GHG impacts are dominated by uncontrolled emissions of waste anesthetic gases. GHG impacts of propofol are comparatively quite small, nearly 4 orders of magnitude lower than those of desflurane or nitrous oxide. Unlike the inhaled drugs, the GHG impacts of propofol primarily stem from the electricity required for the syringe pump and not from drug production or direct release to the environment. DISCUSSION: Our results reiterate previous published data on the GHG effects of these inhaled drugs, while providing a life cycle context. There are several practical environmental impact mitigation strategies. Desflurane and nitrous oxide should be restricted to cases where they may reduce morbidity and mortality over alternative drugs. Clinicians should avoid unnecessarily high fresh gas flow rates for all inhaled drugs. There are waste anesthetic gas capturing systems, and even in advance of reprocessed gas applications, strong consideration should be given to their use. From our results it appears likely that techniques other than inhalation anesthetics, such as total i.v. anesthesia, neuraxial, or peripheral nerve blocks, would be least harmful to the environment. PMID- 22492187 TI - Technical communication: design and in vitro testing of a pressure-sensing syringe for endotracheal tube cuffs. AB - Endotracheal intubation is a frequently performed procedure in the prehospital setting, intensive care unit, and for patients undergoing surgery. The endotracheal tube cuff must be inflated to a pressure that prevents air leaks without compromising tracheal mucosal blood flow. For simultaneous endotracheal tube cuff inflation and measurement, we designed and tested a novel pressure sensing syringe in vitro. The prototype was developed using a standard 10-mL polycarbonate syringe body that houses a plunger and a silicone rubber bellows, the pressure-sensing element. Bellow feasibility was determined and modeled using finite element analysis. Repeatability testing at each pressure measurement for each bellows (pressure versus deflection) was within an average standard deviation of 0.3 cm to 1.61 cm (1%-5% error). Using an aneroid manometer for comparison, there was excellent linear correlation with a Spearman rank of 0.99 (P < 0.001), up to 30 cm H(2)O. PMID- 22492188 TI - Hemoglobin desaturation after propofol/remifentanil-induced apnea: a study of the recovery of spontaneous ventilation in healthy volunteers. AB - BACKGROUND: In an earlier study investigating the "can't ventilate/can't intubate" clinical scenario, induction of anesthesia with thiopental 5 mg/kg and succinylcholine 1.0 mg/kg was associated with a significant risk of hemoglobin desaturation. It appeared that succinylcholine-induced apnea was responsible for the prolonged apnea. Our hypothesis was that using propofol and remifentanil for tracheal intubation might avoid prolonged apnea and subsequent desaturation attributable to muscle relaxation. METHODS: Twenty-four healthy volunteers ages 18 to 45 years participated. After oxygen administration to end-tidal oxygen >90%, volunteers received 2 mg/kg propofol and remifentanil either 2 mcg/kg (group 1; n = 12) or 1.5 mcg/kg (group 2; n = 12). Oxygen saturation (SpO(2)) was measured at a finger, an ear lobe, and the forehead. If SpO(2) decreased below 80%, volunteers received chin lift and, if persistent, assisted ventilation. RESULTS: Desaturation (SpO(2) < 80%) occurred in 5 volunteers: 4 in the higher remifentanil dose (2 mcg/kg) group and 1 in the lower dose (1.5 mcg/kg) group. Chin lift and assisted ventilation was necessary in 3 volunteers. The lowest SpO(2) was 82.4 +/- 10.5 (mean +/- SD) in the higher-dose group vs. 92.4 +/- 8.6 with the lower dose of remifentanil (P = 0.019). Apnea time was shorter (P = 0.0093) with the lower dose (4.7 +/- 1.5) than with the higher dose of remifentanil (6.1 +/- 1.0). Conditions for intubation were excellent or acceptable in 11 volunteers (92%; 95% confidence interval [CI], 65%-99%) in the higher-dose group, and in 8 (67%; 95% CI, 39%-86%) with the lower dose. CONCLUSIONS: Administered with propofol 2 mg/kg, the remifentanil dose necessary to produce acceptable intubating conditions, 2 mcg/kg, produces apnea that carries a significant risk of desaturation, whereas a remifentanil dose of 1.5 mcg/kg does not reliably produce acceptable intubating conditions and does not eliminate the risk of desaturation. PMID- 22492189 TI - Medical intelligence article: assessing the impact on global climate from general anesthetic gases. AB - Although present in the atmosphere with a combined concentration approximately 100,000 times lower than carbon dioxide (i.e., the principal anthropogenic driver of climate change), halogenated organic compounds are responsible for a warming effect of approximately 10% to 15% of the total anthropogenic radiative forcing of climate, as measured relative to the start of the industrial era (approximately 1750). The family of anesthetic gases includes several halogenated organic compounds that are strong greenhouse gases. In this short report, we provide an overview of the state of knowledge regarding the impact of anesthetic gas release on the environment, with particular focus on its contribution to the radiative forcing of climate change. PMID- 22492190 TI - Comparative life cycle assessment of disposable and reusable laryngeal mask airways. AB - BACKGROUND: Growing awareness of the negative impacts from the practice of health care on the environment and public health calls for the routine inclusion of life cycle criteria into the decision-making process of device selection. Here we present a life cycle assessment of 2 laryngeal mask airways (LMAs), a one-time use disposable UniqueTM LMA and a 40-time-use reusable ClassicTM LMA. METHODS: In life cycle assessment, the basis of comparison is called the "functional unit." For this report, the functional unit of the disposable and reusable LMAs was taken to be maintenance of airway patency by 40 disposable LMAs or 40 uses of 1 reusable LMA. This was a cradle-to-grave study that included inputs and outputs for the manufacture, transport, use, and waste phases of the LMAs. The environmental impacts of the 2 LMAs were estimated using SimaPro life cycle assessment software and the Building for Environmental and Economic Sustainability impact assessment method. Sensitivity and simple life cycle cost analyses were conducted to aid in interpretation of the results. RESULTS: The reusable LMA was found to have a more favorable environmental profile than the disposable LMA as used at Yale New Haven Hospital. The most important sources of impacts for the disposable LMA were the production of polymers, packaging, and waste management, whereas for the reusable LMA, washing and sterilization dominated for most impact categories. DISCUSSION: The differences in environmental impacts between these devices strongly favor reusable devices. These benefits must be weighed against concerns regarding transmission of infection. Health care facilities can decrease their environmental impacts by using reusable LMAs, to a lesser extent by selecting disposable LMA models that are not made of certain plastics, and by ordering in bulk from local distributors. Certain practices would further reduce the environmental impacts of reusable LMAs, such as increasing the number of devices autoclaved in a single cycle to 10 (-25% GHG emissions) and improving the energy efficiency of the autoclaving machines by 10% (-8% GHG emissions). For both environmental and cost considerations, management and operating procedures should be put in place to ensure that reusable LMAs are not discarded prematurely. PMID- 22492191 TI - Semantic Web meets Integrative Biology: a survey. AB - Integrative Biology (IB) uses experimental or computational quantitative technologies to characterize biological systems at the molecular, cellular, tissue and population levels. IB typically involves the integration of the data, knowledge and capabilities across disciplinary boundaries in order to solve complex problems. We identify a series of bioinformatics problems posed by interdisciplinary integration: (i) data integration that interconnects structured data across related biomedical domains; (ii) ontology integration that brings jargons, terminologies and taxonomies from various disciplines into a unified network of ontologies; (iii) knowledge integration that integrates disparate knowledge elements from multiple sources; (iv) service integration that build applications out of services provided by different vendors. We argue that IB can benefit significantly from the integration solutions enabled by Semantic Web (SW) technologies. The SW enables scientists to share content beyond the boundaries of applications and websites, resulting into a web of data that is meaningful and understandable to any computers. In this review, we provide insight into how SW technologies can be used to build open, standardized and interoperable solutions for interdisciplinary integration on a global basis. We present a rich set of case studies in system biology, integrative neuroscience, bio-pharmaceutics and translational medicine, to highlight the technical features and benefits of SW applications in IB. PMID- 22492192 TI - A survey of error-correction methods for next-generation sequencing. AB - Error Correction is important for most next-generation sequencing applications because highly accurate sequenced reads will likely lead to higher quality results. Many techniques for error correction of sequencing data from next-gen platforms have been developed in the recent years. However, compared with the fast development of sequencing technologies, there is a lack of standardized evaluation procedure for different error-correction methods, making it difficult to assess their relative merits and demerits. In this article, we provide a comprehensive review of many error-correction methods, and establish a common set of benchmark data and evaluation criteria to provide a comparative assessment. We present experimental results on quality, run-time, memory usage and scalability of several error-correction methods. Apart from providing explicit recommendations useful to practitioners, the review serves to identify the current state of the art and promising directions for future research. AVAILABILITY: All error-correction programs used in this article are downloaded from hosting websites. The evaluation tool kit is publicly available at: http://aluru-sun.ece.iastate.edu/doku.php?id=ecr. PMID- 22492193 TI - Auditory spatial processing in the human cortex. AB - The auditory system codes spatial locations in a way that deviates from the spatial representations found in other modalities. This difference is especially striking in the cortex, where neurons form topographical maps of visual and tactile space but where auditory space is represented through a population rate code. In this hemifield code, sound source location is represented in the activity of two widely tuned opponent populations, one tuned to the right and the other to the left side of auditory space. Scientists are only beginning to uncover how this coding strategy adapts to various spatial processing demands. This review presents the current understanding of auditory spatial processing in the cortex. To this end, the authors consider how various implementations of the hemifield code may exist within the auditory cortex and how these may be modulated by the stimulation and task context. As a result, a coherent set of neural strategies for auditory spatial processing emerges. PMID- 22492194 TI - Information processing in decision-making systems. AB - Decisions result from an interaction between multiple functional systems acting in parallel to process information in very different ways, each with strengths and weaknesses. In this review, the authors address three action-selection components of decision-making: The Pavlovian system releases an action from a limited repertoire of potential actions, such as approaching learned stimuli. Like the Pavlovian system, the habit system is computationally fast but, unlike the Pavlovian system permits arbitrary stimulus-action pairings. These associations are a "forward'' mechanism; when a situation is recognized, the action is released. In contrast, the deliberative system is flexible but takes time to process. The deliberative system uses knowledge of the causal structure of the world to search into the future, planning actions to maximize expected rewards. Deliberation depends on the ability to imagine future possibilities, including novel situations, and it allows decisions to be taken without having previously experienced the options. Various anatomical structures have been identified that carry out the information processing of each of these systems: hippocampus constitutes a map of the world that can be used for searching/imagining the future; dorsal striatal neurons represent situation action associations; and ventral striatum maintains value representations for all three systems. Each system presents vulnerabilities to pathologies that can manifest as psychiatric disorders. Understanding these systems and their relation to neuroanatomy opens up a deeper way to treat the structural problems underlying various disorders. PMID- 22492195 TI - Hydroxyapatite nanorods: soft-template synthesis, characterization and preliminary in vitro tests. AB - Synthetic hydroxyapatite nanorods are excellent candidates for bone tissue engineering applications. In this study, hydroxyapatite nanorods resembling bone minerals were produced by using soft-template method with cetyltrimethylammonium bromide. Composite hydroxyapatite/poly(D, L)lactic acid films were prepared to evaluate the prepared hydroxyapatite nanorods in terms of cell affinity. Preliminary in vitro experiments showed that aspect ratio and film surface roughness play a vital role in controlling adhesion and proliferation of human osteoblast cell line MG 63. The hydroxyapatite nanorods with aspect ratios in the range of 5.94-7 were found to possess distinctive properties, with the corresponding hydroxyapatite/poly(D, L)lactic acid films promoting cellular confluence and a fast formation of collagen fibers as early as after 7 days of culture. PMID- 22492196 TI - CAD-CAM-generated hydroxyapatite scaffold to replace the mandibular condyle in sheep: preliminary results. AB - In this study, rapid CAD-CAM prototyping of pure hydroxyapatite to replace temporomandibular joint condyles was tested in sheep. Three adult animals were implanted with CAD-CAM-designed porous hydroxyapatite scaffolds as condyle substitutes. The desired scaffold shape was achieved by subtractive automated milling machining (block reduction). Custom-made surgical guides were created by direct metal laser sintering and were used to export the virtual planning of the bone cut lines into the surgical environment. Using the same technique, fixation plates were created and applied to the scaffold pre-operatively to firmly secure the condyles to the bone and to assure primary stability of the hydroxyapatite scaffolds during masticatory function. Four months post-surgery, the sheep were sacrificed. The hydroxyapatite scaffolds were explanted, and histological specimens were prepared. Different histological tissues penetrating the scaffold macropores, the sequence of bone remodeling, new apposition of bone and/or cartilage as a consequence of the different functional anatomic role, and osseointegration at the interface between the scaffold and bone were documented. This animal model was found to be appropriate for testing CAD-CAM customization and the biomechanical properties of porous, pure hydroxyapatite scaffolds used as joint prostheses. PMID- 22492197 TI - Limited V-shaped cement augmentation of the proximal femur to prevent secondary hip fractures. AB - Patients with a femoral fracture due to osteoporosis are at high risk of sustaining a secondary fracture on the contralateral side. A prophylactic mechanical reinforcement of the contralateral side during operation of the initial fracture could be of interest for such patients. This biomechanical in vitro study investigates the potential of a limited V-shaped bone cement augmentation to prevent secondary hip fractures by targeting the areas of the proximal femur with the highest stresses during a fall. Five pairs of human cadaveric proximal femora were tested in a configuration simulating a fall on the greater trochanter. The femoral neck of one specimen of each pair was augmented with 8-14 ml polymethylmethacrylate from the lateral cortex towards inferior and superior, spanning a V-shaped cement pattern. Clinical relevant fractures were generated with a 45 kg mass in controlled free fall. Load-displacement data were recorded and energy to fracture, fracture load, yield load and stiffness were statistically evaluated. Augmented samples absorbed 124% more energy until fracture compared to their controls (p = 0.043). No significant differences were found between the two groups for fracture load (p = 0.5), yield load (p = 0.35) and stiffness (p = 0.5). Biomechanically, a limited V-shaped prophylactic cement augmentation carries potential to prevent secondary hip fractures indicated by increased energy absorption until fracture. Further investigations are necessary to minimize interference with the biology and to maximize the mechanical benefit of prophylactic augmentation. PMID- 22492198 TI - Clinical assessment of calcium phosphate cement to treat tibial plateau fractures. AB - The aim of this study was to examine histological changes in bone morphology after surgical treatment of tibial plateau fractures using calcium phosphate cement as a substitute for autologous bone grafting. A total of 42 patients with tibial plateau fractures were treated with open reduction, internal fixation, and calcium phosphate cement. A further 34 control patients underwent open reduction and internal fixation. Bone samples for histology were obtained during the surgery. Bone healing and functional recovery were assessed. Bone cell counts were significantly higher in samples obtained during the second surgery (81.2) compared with the first surgery (45.4, p < 0.001). Bone healing scores significantly increased with time after surgery (p < 0.001). Mean Hospital for Special Surgery knee scores were rated "good" for both the calcium phosphate cement group (82.3) and control group (79.4) in 12 months, and were not significantly different between groups. Histological examination of samples obtained during the second surgery revealed well-arranged trabeculae, in addition to new bone and blood vessel formation. These histological, radiological, and functional findings suggest that calcium phosphate cement may be an effective substitute for autologous bone grafting to treat tibial plateau fractures. PMID- 22492199 TI - Biofunctionalisation of polymeric scaffolds for neural tissue engineering. AB - Patients who experience injury to the central or peripheral nervous systems invariably suffer from a range of dysfunctions due to the limited ability for repair and reconstruction of damaged neural tissue. Whilst some treatment strategies can provide symptomatic improvement of motor and cognitive function, they fail to repair the injured circuits and rarely offer long-term disease modification. To this end, the biological molecules, used in combination with neural tissue engineering scaffolds, may provide feasible means to repair damaged neural pathways. This review will focus on three promising classes of neural tissue engineering scaffolds, namely hydrogels, electrospun nanofibres and self assembling peptides. Additionally, the importance and methods for presenting biologically relevant molecules such as, neurotrophins, extracellular matrix proteins and protein-derived sequences that promote neuronal survival, proliferation and neurite outgrowth into the lesion will be discussed. PMID- 22492200 TI - Effectiveness of antibacterial copper additives in silicone implants. AB - Staphylococcus epidermidis plays a major role in capsular contractures of silicone breast implants. This in vitro study evaluates the antibacterial effect of copper on S. epidermidis in silicone implants. Specimens of a silicone material used for breast augmentation (Cu0) and specimens coated with different copper concentrations (Cu1, Cu2) were artificially aged. Surface roughness and surface free energy were assessed. The specimens were incubated in an S. epidermidis suspension. We assessed the quantification and the viability of adhering bacteria by live/dead cell labeling with fluorescence microscopy. Additionally, inhibition of bacterial growth was evaluated by agar diffusion, broth culture, and quantitative culture of surface bacteria. No significant differences in surface roughness and surface free energy were found between Cu0, Cu1 and Cu2. Aging did not change surface characteristics and the extent of bacterial adhesion. Fluorescence microscopy showed that the quantity of bacteria on Cu0 was significantly higher than that on Cu1 and Cu2. The ratio of dead to total adhering bacteria was significantly lower on Cu0 than on Cu1 and Cu2, and tended to be higher for Cu2 than for Cu1. Quantitative culture showed equal trends. Copper additives seem to have anti-adherence and bactericidal effects on S. epidermidis in vitro. PMID- 22492201 TI - Enhanced visualization of biodegradable polymeric vascular scaffolds by incorporation of gold, silver and magnetite nanoparticles. AB - Due to improved tissue regeneration and the enabling of post-operative minimally invasive interventions in the same vessel segment, biodegradable polymeric scaffolds represent a competitive approach to permanent metallic stents in vascular applications. Despite these advantages some challenges, such as the improvement of the scaffold mechanics and enhancement of scaffold visibility during the implantation procedure, are persisting. Therefore, the scope of our studies was to investigate the potential of gold, silver and magnetite nanoparticles incorporated in a polymeric blend of poly(L-lactide)/poly(4 hydroxybutyrate) for image enhancement in X-ray, magnetic resonance or near infrared imaging. Their impact on mechanical properties of such modified scaffold materials was also evaluated. PMID- 22492202 TI - Quantitative changes in endogenous DNA adducts correlate with conazole in vivo mutagenicity and tumorigenicity. AB - The mouse liver tumorigenic conazole fungicides triadimefon and propiconazole have previously been shown to be in vivo mouse liver mutagens in the Big BlueTM transgenic mutation assay when administered in feed at tumorigenic doses, whereas the nontumorigenic conazole myclobutanil was not mutagenic. DNA sequencing of the mutants recovered from each treatment group as well as from animals receiving control diet revealed that propiconazole- and triadimefon-induced mutations do not represent general clonal expansion of background mutations, and support the hypothesis that they arise from the accumulation of endogenous reactive metabolic intermediates within the liver in vivo. We therefore measured the spectra of endogenous DNA adducts in the livers of mice from these studies to determine if there were quantitative or qualitative differences between mice receiving tumorigenic or nontumorigenic conazoles compared to concurrent control animals. We resolved and quantitated 16 individual adduct spots by (32)P postlabelling and thin layer chromatography using three solvent systems. Qualitatively, we observed the same DNA adducts in control mice as in mice receiving conazoles. However, the 13 adducts with the highest chromatographic mobility were, as a group, present at significantly higher amounts in the livers of mice treated with propiconazole and triadimefon than in their concurrent controls, whereas this same group of DNA adducts in the myclobutanil-treated mice was not different from controls. This same group of endogenous adducts were significantly correlated with mutant frequency across all treatment groups (P = 0.002), as were total endogenous DNA adduct levels (P = 0.005). We hypothesise that this treatment-related increase in endogenous DNA adducts, together with concomitant increases in cell proliferation previously reported to be induced by conazoles, explain the observed increased in vivo mutation frequencies previously reported to be induced by treatment with propiconazole and triadimefon. PMID- 22492203 TI - Chromosome aberration frequency in rat peripheral lymphocytes increases with repeated dosing with hexamethylphosphoramide or cyclophosphamide. AB - Although there are several in vivo tests for potential genotoxicity, with the possible exception of the transgenic rodent mutation models, none is specifically intended to assess increasing damage with chronic administration. In principle, peripheral blood lymphocytes would be expected to accumulate DNA damage with repeated dosing because the majority are not in active division and appear to have limited DNA repair capability, and they are exposed to plasma levels of test materials and metabolites. However, there appear to be no published reports confirming this principle. Therefore, in the current study, after optimising culture conditions for rat lymphocytes in this laboratory, rats were given oral doses of cyclophosphamide or hexamethylphosphoramide (HMPA) for up to 28 days and peripheral lymphocytes analysed for chromosome aberrations at various time points. The results clearly show that, for both compounds, doses that gave no significant increases in aberration frequency after 2 days induced clear increases after 15 days with further damage detectable after 28 doses. With HMPA, it was shown that DNA damage persisted for at least 10 days after cessation of treatment. These data show that repeat dose studies in the rat measuring chromosome aberration frequency in lymphocytes can give a genuine indication that genotoxicity may increase with chronic administration and, therefore, maybe useful in assessing the risk of potentially genotoxic substances. PMID- 22492204 TI - Hypersialylated type-I lactosamine-containing N-glycans found in Artiodactyla sera are potential xenoantigens. AB - There is increasing interest in biologics, i.e. human-originated biological pharmaceutics. Most of the protein drugs developed so far, such as immunoglobulins and erythropoietin, are secreted glycoproteins; as a result, any non-human-type glycans, such as alphaGal and NeuGc, derived from animal cells and sera must be removed to circumvent undesirable immunogenic reactions. In this study, we made an extensive search for potential xenoantigenic glycans among a panel of mammalian sera. As a result, sera belonging to the order Artiodactyla, i.e. bovine, lamb and goat sera, were found to contain substantial amounts of hypersialylated biantennary glycans closely associated with a type-I lactosamine structure containing a unique tetrasaccharide, Siaalpha2-3Galbeta1-3(Siaalpha2 6)GlcNAc. In all three Artiodactyla sera, the most abundant structure was Siaalpha2-3Galbeta1-3(Siaalpha2-6)GlcNAcbeta1-2Manalpha1-3[Siaalpha2-6Galbeta1 4GlcNAcbeta1-2Manalpha1-6]Manbeta1-4GlcNAcbeta1-4GlcNAc. A dually hypersialylated biantennary structure, Siaalpha2-3Galbeta1-3(Siaalpha2-6)GlcNAcbeta1-2Manalpha1 3[Siaalpha2-3Galbeta1-3(Siaalpha2-6)GlcNAcbeta1-2Manalpha1-6]Manbeta1 4GlcNAcbeta1-4GlcNAc, was also abundant (10%) in bovine serum. The amount of hypersialylated glycans among total sialylated glycans was 46, 26 and 23% in bovine, lamb and goat sera, respectively. On the other hand, such structures could not be detected in the sera of other animals including human. The biological functions and the immunogenicity of the hypersialylated glycans in these animals remain to be elucidated; however, it is worth noting that glycoproteins biosynthesized from Artiodactyla cells and those contaminated with bovine serum might enhance undesirable antigenicity in human patients. PMID- 22492205 TI - The essential endoplasmic reticulum chaperone Rot1 is required for protein N- and O-glycosylation in yeast. AB - Rot1 is an essential yeast protein originally shown to be implicated in such diverse processes such as beta-1,6-glucan synthesis, actin cytoskeleton dynamics or lysis of autophagic bodies. More recently also a role as a molecular chaperone has been discovered. Here, we report that Rot1 interacts in a synthetic manner with Ost3, one of the nine subunits of the oligosaccharyltransferase (OST) complex, the key enzyme of N-glycosylation. The deletion of OST3 in the rot1-1 mutant causes a temperature sensitive phenotype as well as sensitivity toward compounds interfering with cell wall biogenesis such as Calcofluor White, caffeine, Congo Red and hygromycin B, whereas the deletion of OST6, a functional homolog of OST3, has no effect. OST activity in vitro determined in membranes from rot1-1ost3Delta cells was found to be decreased to 45% compared with wild type membranes, and model glycoproteins of N-glycosylation, like carboxypeptidase Y, Gas1 or dipeptidyl aminopeptidase B, displayed an underglycosylation pattern. By affinity chromatography, a physical interaction between Rot1 and Ost3 was demonstrated. Moreover, Rot1 was found to be involved also in the O-mannosylation process, as the glycosylation of distinct glycoproteins of this type were affected as well. Altogether, the data extend the role of Rot1 as a chaperone required to ensure proper glycosylation. PMID- 22492206 TI - Aspectual coercion in eye movements. AB - Comprehension includes interpreting sentences in terms of aspectual categories such as processes (Harry climbed) and culminations (Harry reached the top). Adding a verbal modifier such as for many years to a culmination coerces its interpretation from one to many culminations. Previous studies have found that coercion increases lexical decision and meaning judgment time, but not eye fixation time. This study recorded eye movements as participants read sentences in which a coercive adverb increased the interpretation of multiple events. Adverbs appeared at the end of a clause and line; the post-adverb region appeared at the beginning of the next line; follow-up questions occasionally asked about aspectual meaning; and clause type varied systematically. Coercive adverbs increased eye fixation time in the post-adverb region and in the adverb and post adverb regions combined. Factors that influence the appearance of aspectual coercion may include world knowledge, follow-up questions, and the location and ambiguity of adverbs. PMID- 22492207 TI - Egg oiling to reduce hatch-year ring-billed gull numbers on Chicago's beaches during swim season and water quality test results. AB - A burgeoning ring-billed gull population along Chicago's Lake Michigan beaches contributes to degraded water quality through fecal contamination. Egg oiling was conducted at Chicago's gull colonies to reduce production and the influx of hatch year (HY) gulls using Chicago's beaches, with a second, long-term objective of eventually reducing adult gull numbers through attrition. We also investigated swim season water quality trends through the course of this work. From 2007 to 2009, 52, 80, and 81%, of nests at the two primary nest colonies had their eggs rendered inviable by corn oil application. Counts of HY and after hatch-year (AHY) gulls were analyzed during treatment years for 10 beaches. Water quality data were available from the Chicago Park District during our three treatment years and the prior year (baseline) for 19 beaches. HY counts declined at all 10 surveyed beaches from the initial year (52% nests with oiled eggs) to subsequent years with ~80% of nests oiled. Overall, HY gulls numbers on beaches decreased 86% from 2007 to 2009. Decreases in beach usage by AHY gulls were not detected. Compared to pretreatment, the number of beaches with improved water quality test rates increased each year through the course of the study. The frequency of water quality tests showing bacterial exceedances compared to 2006 declined at 18 of 19 beaches by 2009. Egg oiling resulted in fewer HY gulls using Chicago's beaches and was likely a beneficial factor for reduced frequencies of swim advisories and swim bans. PMID- 22492208 TI - Immunohistochemical characterization of feline mast cell tumors. AB - Expression of histamine, serotonin, and KIT was evaluated in 61 archived feline mast cell tumors (MCTs) from the skin (n = 29), spleen (n = 17), and gastrointestinal (GI) tract (n = 15) using immunohistochemistry. Twenty-eight percent of cutaneous MCTs, 18% of splenic MCTs, and 53% of GI MCTs displayed histamine immunoreactivity. Serotonin immunoreactivity was detected in 3 GI and 1 cutaneous MCT. Sixty-nine percent of cutaneous MCTs, 35% of splenic MCTs, and 33% of GI MCTs were positive for KIT. Expression of these biogenic amines and KIT was less common than expected. Results of this study suggest heterogeneity in feline MCTs based on anatomic location. Further studies are needed to explain the significance of these differences. PMID- 22492209 TI - Hepatic encephalopathy associated with hepatic lipidosis in llamas (Lama glama). AB - Hepatic encephalopathy has been listed as a differential for llamas displaying neurologic signs, but it has not been histopathologically described. This report details the neurologic histopathologic findings associated with 3 cases of hepatic lipidosis with concurrent neurologic signs and compares them to 3 cases of hepatic lipidosis in the absence of neurologic signs and 3 cases without hepatic lipidosis. Brain from all 3 llamas displaying neurologic signs contained Alzheimer type II cells, which were not detected in either subset of llamas without neurologic signs. Astrocytic immunohistochemical staining intensity for glial fibrillary acid protein was decreased in llamas with neurologic signs as compared to 2 of 3 llamas with hepatic lipidosis and without neurologic signs and to 2 of 3 llamas without hepatic lipidosis. Immunohistochemical staining for S100 did not vary between groups. These findings suggest that hepatic encephalopathy may be associated with hepatic lipidosis in llamas. PMID- 22492210 TI - Unresectable Hepatocellular Carcinoma Due to Portal Venous Thrombosis: Focal Stereotactic Body Radiation Therapy Can Promote Resectability. PMID- 22492211 TI - Joint trajectories of symptoms of disruptive behavior problems and depressive symptoms during early adolescence and adjustment problems during emerging adulthood. AB - The joint, longitudinal trajectories of symptoms of disruptive behavior problems and of depression were examined in a community sample drawn from neighborhoods with elevated rates of delinquency. Growth mixture modeling was applied to a 6 year transition period from childhood to adolescence, age 10 to 16 years, to identify latent classes of trajectories for each symptom type. Several classes emerged for the two types of symptoms, namely a group of youth with high levels of disruptive behavior, a group with increasing levels, and a group with low levels, as well as a group with increasing levels of depression, a group with high levels, a group with decreasing levels, and a group with low levels. Within each symptom type, membership in either the high or in the increasing classes was related to a variety of problematic outcomes during emerging adulthood. The co occurrence of the disruptive behavior and depression classes was then evaluated using parallel process analysis. Youth exhibiting high depressive symptoms were at increased risk for disruptive behavior problems, and youth with increasing disruptive behavior problems were at risk for depressive symptoms. However, only a very small number of youth had both a high depression trajectory and a high disruptive behavior trajectory. Implications of the findings for the design of prevention and treatment programs are discussed. PMID- 22492212 TI - Anterior choroidal artery ischaemic patterns predict outcome of carotid occlusion. AB - OBJECTIVE: To investigate whether anterior choroidal artery (AChA) territory sparing or AChA infarction restricted to the medial temporal lobe (MT), implying good collateral status, predicts good outcome, defined as modified Rankin Scale 0 2, at discharge in acute internal carotid artery (ICA) occlusion. METHODS: The authors studied consecutive patients with acute ICA occlusion admitted to an academic medical centre between January 2002 and August 2010, who underwent MRI followed by conventional angiography. The pattern of AChA involvement on initial diffusion-weighted imaging was dichotomised as spared or MT only versus other partial or full. The association of AChA infarct patterns and good outcome at discharge was calculated by multivariate logistic regression with adjustment. RESULTS: For the 60 patients meeting entry criteria, mean age was 68.3 years and median admission NIH Stroke Scale score was 19. AChA territory was spared or restricted to the MT in 27 patients and other partially involved or fully involved in 33 patients. AChA territory spared or ischaemia restricted to MT only, compared with other partial infarct patterns or full infarct, was independently associated with good discharge outcome (44.4% vs 12.1%, OR 7.24, 95% CI 1.32 to 39.89, p=0.023). CONCLUSION: In acute ICA occlusion, the absence of AChA infarction or restriction to the MT is an independent predictor of good discharge outcome. Analysis of AChA infarct patterns may improve early prognostication and decision-making. PMID- 22492213 TI - Impact of DaTscan SPECT imaging on clinical management, diagnosis, confidence of diagnosis, quality of life, health resource use and safety in patients with clinically uncertain parkinsonian syndromes: a prospective 1-year follow-up of an open-label controlled study. AB - BACKGROUND: This study assessed the impact of DaTscan on clinical management, diagnosis, confidence of diagnosis (CoD), quality of life (QoL), health resource use (HRU) and safety during a 1-year follow-up in patients with clinically uncertain parkinsonian syndromes (CUPS). METHODS: A total of 19 university hospital centres in Europe and the USA participated in this open-label, single dose, prospective, clinical trial in patients with CUPS who were randomised to a DaTscan imaging group or to a no-imaging (control) group. The proportion of patients with changes in clinical management, diagnosis, CoD, QoL and HRU from baseline through 1 year post-DaTscan was compared between groups. RESULTS: There were 273 patients randomised (135 DaTscan, 138 control). Significantly more patients in the DaTscan imaging group had at least one change in their actual clinical management after 12 weeks (p=0.002) and after 1 year (p<0.001) compared with patients in the control group. In addition, significantly more DaTscan patients had changes in diagnosis and an increased CoD at 4 weeks, 12 weeks and 1 year (all p<0.001) compared with control patients. No significant differences in total score for QoL or HRU were observed between groups during the 1-year follow up period. DaTscan was safe and well tolerated. One patient in the imaging group had an adverse event (headache) with suspected relationship to DaTscan post administration. CONCLUSIONS: DaTscan had a significant impact on clinical management, diagnosis and CoD in patients with CUPS. DaTscan is safe and well tolerated, and is a useful adjunct to differentiate a diagnosis of CUPS. Trial registration number http://ClinicalTrials.gov Identifier: NCT00382967. PMID- 22492214 TI - Axonal integrity predicts cortical reorganisation following cervical injury. AB - BACKGROUND: Traumatic spinal cord injury (SCI) leads to disruption of axonal architecture and macroscopic tissue loss with impaired information flow between the brain and spinal cord-the presumed basis of ensuing clinical impairment. OBJECTIVE: The authors used a clinically viable, multimodal MRI protocol to quantify the axonal integrity of the cranial corticospinal tract (CST) and to establish how microstructural white matter changes in the CST are related to cross-sectional spinal cord area and cortical reorganisation of the sensorimotor system in subjects with traumatic SCI. METHODS: Nine volunteers with cervical injuries resulting in bilateral motor impairment and 14 control subjects were studied. The authors used diffusion tensor imaging to assess white matter integrity in the CST, T1-weighted imaging to measure cross-sectional spinal cord area and functional MRI to compare motor task-related brain activations. The relationships among microstructural, macrostructural and functional measures were assessed using regression analyses. Results Diffusion tensor imaging revealed significant differences in the CST of SCI subjects-compared with controls-in the pyramids, the internal capsule, the cerebral peduncle and the hand area. The microstructural white matter changes observed in the left pyramid predicted increased task-related responses in the left M1 leg area, while changes in the cerebral peduncle were predicted by reduced cord area. CONCLUSION: The observed microstructural changes suggest trauma-related axonal degeneration and demyelination, which are related to cortical motor reorganisation and macrostructure. The extent of these changes may reflect the plasticity of motor pathways associated with cortical reorganisation. This clinically viable multimodal imaging approach is therefore appropriate for monitoring degeneration of central pathways and the evaluation of treatments targeting axonal repair in SCI. PMID- 22492215 TI - Headache in three new cases of Harlequin syndrome with accompanying pharmacological comparison with migraine. AB - BACKGROUND: Harlequin syndrome (HS) is a rare autonomic disorder characterised by unilateral diminished sweating and flushing of the face in response to heat or exercise. Some patients with HS complain of headache. METHODS: We present three new cases to characterise their headache phenotype and pharmacology and review the literature of cases where headache was described. RESULTS Two out of the three patients presented with episodes of unilateral headache associated with exercise: in one case the headache had migrainous features and was contralateral to the side where the flushing occurred, whereas the second patient, who had had migraine attacks in the past, had a brief throbbing headache, with no associated symptoms, ipsilateral to the facial flushing. The third woman had migraine but the attacks were not associated with HS. Pharmacological characterisation suggested the HS and migraine were biologically distinct. HS was not triggered by nitroglycerin and was unaffected by sumatriptan, dihydroergotamine and ergotamine. HS and migraine did not occur together. In the literature, we found six patients with both HS and headache, five of whom had migraine. CONCLUSIONS: These data do not show any correlation between the phenotypic expression of migraine and HS suggesting the syndromes are pathogenetically independent. PMID- 22492216 TI - Mild cognitive impairment and cognitive-motor relationships in newly diagnosed drug-naive patients with Parkinson's disease. AB - BACKGROUND AND AIMS: (1) To establish the prevalence of mild cognitive impairment (MCI) in newly diagnosed drug-naive patients with Parkinson's disease adopting recently proposed and more conservative preliminary research criteria. (2) To investigate the relation between cognitive performances, MCI and motor dysfunction. METHODS: 132 consecutive newly diagnosed drug-naive PD patients and 100 healthy controls (HCs) underwent a neuropsychological evaluation covering different cognitive domains. Moreover, on the basis of the Unified Parkinson's Disease Rating Scale II/III, different motor scores were calculated and patients were classified in motor subtypes. 11 patients were excluded from the analysis during clinical follow-up which was continued at least 3 years from the diagnosis; therefore, the final sample included 121 patients. RESULTS: MCI prevalence was higher in PD (14.8%) patients than in HCs (7.0%). PD patients reported lower cognitive performances than HCs in several cognitive domains; HCs also outperformed cognitively preserved PD patients in tasks of episodic verbal memory and in a screening task of executive functions. MCI-PD patients presented a more severe bradykinesia score than non-MCI PD patients and patients mainly characterised by tremor had better performances in some cognitive domains, and specific cognitive-motor relationships emerged. CONCLUSIONS: Although the adoption of more conservative diagnostic criteria identified a lower MCI prevalence, we found evidence that newly diagnosed drug-naive PD patients present a higher risk of MCI in comparison with HCs. Axial symptoms and bradykinesia represent risk factors for MCI in PD patients and a classification of PD patients that highlights the presence/absence of tremor, as proposed in this study, is probably better tailored for the early stages of PD than classifications proposed for more advanced PD stages. PMID- 22492217 TI - Suppression of dendritic cell maturation and T cell proliferation by synovial fluid myeloid cells from mice with autoimmune arthritis. AB - OBJECTIVE: To determine whether myeloid cells (such as granulocytes) present in the synovial fluid (SF) of arthritic joints have an impact on adaptive immunity. Specifically, we investigated the effects of SF cells harvested from the joints of mice with proteoglycan-induced arthritis (PGIA), on dendritic cell (DC) maturation and antigen-specific T cell proliferation. METHODS: We monitored DC maturation (MHCII and CD86 expression) by flow cytometry upon coculture of DCs with SF cells or spleen myeloid cells from mice with PGIA. The effects of these myeloid cells on T cell proliferation were studied using T cells purified from PG specific T cell receptor (TCR)-transgenic (Tg) mice. Phenotype analysis of myeloid cells was performed by immunostaining, reverse transcription-polymerase chain reaction, Western blotting, and biochemical assays. RESULTS: Inflammatory SF cells significantly suppressed the maturation of DCs upon coculture. PG-TCR-Tg mouse T cells cultured with antigen-loaded DCs showed dramatic decreases in proliferation in the presence of SF cells. Spleen myeloid cells from arthritic mice did not have suppressive effects. SF cells were unable to suppress CD3/CD28 stimulated proliferation of the same T cells, suggesting a DC-dependent mechanism. SF cells exhibited all of the characteristics of myeloid-derived suppressor cells (MDSCs) and exerted suppression primarily through the production of nitric oxide and reactive oxygen species by granulocyte-like cells. CONCLUSION: SF in the joints of mice with PGIA contains a population of granulocytic MDSCs that potently suppress DC maturation and T cell proliferation. These MDSCs have the potential to limit the expansion of autoreactive T cells, thus breaking the vicious cycle of autoimmunity and inflammation. PMID- 22492218 TI - Comparison of organ dosimetry methods and effective dose calculation methods for paediatric CT. AB - Computed tomography (CT) is the single biggest ionising radiation risk from anthropogenic exposure. Reducing unnecessary carcinogenic risks from this source requires the determination of organ and tissue absorbed doses to estimate detrimental stochastic effects. In addition, effective dose can be used to assess comparative risk between exposure situations and facilitate dose reduction through optimisation. Children are at the highest risk from radiation induced carcinogenesis and therefore dosimetry for paediatric CT recipients is essential in addressing the ionising radiation health risks of CT scanning. However, there is no well-defined method in the clinical environment for routinely and reliably performing paediatric CT organ dosimetry and there are numerous methods utilised for estimating paediatric CT effective dose. Therefore, in this study, eleven computational methods for organ dosimetry and/or effective dose calculation were investigated and compared with absorbed doses measured using thermoluminescent dosemeters placed in a physical anthropomorphic phantom representing a 10 year old child. Three common clinical paediatric CT protocols including brain, chest and abdomen/pelvis examinations were evaluated. Overall, computed absorbed doses to organs and tissues fully and directly irradiated demonstrated better agreement (within approximately 50 %) with the measured absorbed doses than absorbed doses to distributed organs or to those located on the periphery of the scan volume, which showed up to a 15-fold dose variation. The disparities predominantly arose from differences in the phantoms used. While the ability to estimate CT dose is essential for risk assessment and radiation protection, identifying a simple, practical dosimetry method remains challenging. PMID- 22492219 TI - Infection of Helicobacter species and liver disease. PMID- 22492220 TI - Luteal phase GnRHa trigger in random start fertility preservation cycles. PMID- 22492221 TI - Serum anti-mullerian hormone, follicle stimulating hormone and antral follicle count measurement cannot predict pregnancy rates in IVF/ICSI cycles. AB - PURPOSE: To investigate whether serum anti-mullerian hormone (AMH), follicle stimulating hormone (FSH), or antral follicle count (AFC) are predictive for clinical pregnancy in in vitro fertilization (IVF) patients. METHODS: Serum AMH, inhibin B, FSH, luteinizing hormone (LH), estradiol (E2), prolactin, and thyroid stimulating hormone (TSH) levels and AFC of 189 women under 40 years of age were investigated. Pregnant and non-pregnant women were compared. RESULTS: Forty-seven (24.8 %) clinical pregnancies were observed in 189 women. There was no significant difference in terms of mean age, duration of infertility, body mass index, AMH, LH, FSH, E2, TSH, Inhibin B, AFC and total oocyte number between women who did and who did not become pregnant. Additionally, there was no significant difference in clinical pregnancy rates between the quartiles of AMH, FSH and AFC. (P values were 0.668, 0.071, and 0.252, respectively.) CONCLUSION: Serum AMH and FSH, and AFC cannot predict clinical pregnancy in IVF patients under 40; the pregnancy rate tends to increase as AMH increases, although this remains non-significant. PMID- 22492222 TI - Importance of sperm gluthatione treatment in ART. AB - PURPOSE: The aim of this study was to investigate whether treatment of sperm from infertile patients would gluthatione could reduce sperm premature chromosome condensation (PCC). To reach the goals of this study, the frequency of sperm PCC formation in sperm of normal and sub-fertile men with/without glutathione treatment were compared and analyzed. METHODS: Hamster oocytes were retrieved after super ovulation by PMSG and HCG injection. Following treatment with hyaluronidase, zonae was removed by trypsin digestion. Sperm were classified into 3 groups according to morphology, movement and counts, treated with glutathione(10 MUg/ml) and then processed by swim up method. After capacitation, zona-free oocytes were incubated with sperm then transferred to fresh media containing colcemid. Cells were fixed and slides prepared using Tarkowskie's standard air drying technique and after staining in 5% Giemsa, oocytes were analyzed at high magnification. RESULTS: Sperm penetration rate was higher and the rate of intact sperm head and PCC was lower in GSH treated samples compared to non treated groups. Sperm penetration rate was significantly higher in treated astheno sperm samples compared to non-treated ones (66.4% and 50. 97% respectively) (P < 0.001). We observed a significantly higher PCC frequency in infertile patients (P < 0.001). In addition, there was a significantly lower rate of intact sperm head in treated astheno sperm samples (17.49%) compared to non treated ones (26.79%) (P < 0.001). Finally, a significantly lower rate of PCC in treated astheno sperm samples comparing to non treated ones was seen (51.06% and 72.96% respectively) (P < 0. 001). CONCLUSIONS: Our results show that sperm PCC formation could be one of the major causes of failed fertilization in individuals with sperm abnormalities. Also sperm PCC formation may be involved in the etiology of some cases of idiopathic infertility. Given that the susceptibility of sperm to oxidative stress is significantly greater in idiopathic infertile men, our results show that treatment with glutathione could significantly reduce these stress factors and increase ART outcome. PMID- 22492224 TI - Unnecessary life threatening complications after IVF in mixed connective tissue disease. PMID- 22492223 TI - Assessment of long term endocrine function after transplantation of frozen-thawed human ovarian tissue to the heterotopic site: 10 year longitudinal follow-up study. AB - PURPOSE: To assess the longevity of ovarian grafts in five cancer patients who underwent heterotopic autotransplantation of frozen-thawed ovarian tissue. METHOD(S): Five cancer survivors underwent heterotopic ovarian transplantation between 2001 and 2011. Stored ovarian tissue (for 1-10 years) was rapidly thawed and transplanted into the space between the rectus sheath and the rectus muscle (8-20 cortical sections per patient). Endocrine function was assessed by monthly blood tests (FSH, LH, E2, progesterone and testosterone) and ultrasound after transplantation. The monitoring was continued until the cessation of endocrine function by consecutive blood tests (E2 < 20 pg/ml; FSH >= 35 IU/L). RESULT(S): Endocrine function was restored in all patients between 12-20 weeks after transplantation. Four patients required the second transplantation one to two years after the first transplantation. The duration of endocrine function after the second transplantation was much longer (9 months-84 months). The longest duration of endocrine function was seen in a woman who underwent ovarian transplantation in 2003 and 2004 after radiotherapy for cervical cancer. Even more than seven years after transplantation, endocrine function has not ceased (FSH 9.5, E2 108, on July 1, 2011). Of note, this patient underwent three IVF cycles in 2004 which resulted in four embryos. CONCLUSION(S): Long-term endocrine function lasting for seven years can be established with heterotopic transplantation of cryobanked human ovarian tissue. Re-establishment of long-term endocrine function after ovarian transplantation will benefit young cancer survivors with premature ovarian failure. PMID- 22492225 TI - Discrimination of benign and neoplastic mucosa with a high-resolution microendoscope (HRME) in head and neck cancer. AB - BACKGROUND: The efficacy of ablative surgery for head and neck squamous cell carcinoma (HNSCC) depends critically on obtaining negative margins. Although intraoperative "frozen section" analysis of margins is a valuable adjunct, it is expensive, time-consuming, and highly dependent on pathologist expertise. Optical imaging has potential to improve the accuracy of margins by identifying cancerous tissue in real time. Our goal was to determine the accuracy and inter-rater reliability of head and neck cancer specialists using high-resolution microendoscopic (HRME) images to discriminate between cancerous and benign mucosa. METHODS: Thirty-eight patients diagnosed with head and neck squamous cell carcinoma (HNSCC) were enrolled in this single-center study. HRME was used to image each specimen after application of proflavine, with concurrent standard histopathologic analysis. Images were evaluated for quality control, and a training set containing representative images of benign and neoplastic tissue was assembled. After viewing training images, seven head and neck cancer specialists with no previous HRME experience reviewed 36 test images and were asked to classify each. RESULTS: The mean accuracy of all reviewers in correctly diagnosing neoplastic mucosa was 97% (95% confidence interval (CI), 94-99%). The mean sensitivity and specificity were 98% (97-100%) and 92% (87-98%), respectively. The Fleiss kappa statistic for inter-rater reliability was 0.84 (0.77-0.91). CONCLUSIONS: Medical professionals can be quickly trained to use HRME to discriminate between benign and neoplastic mucosa in the head and neck. With further development, the HRME shows promise as a method of real-time margin determination at the point of care. PMID- 22492226 TI - The significance of visceral pleural surface invasion in 321 cases of non-small cell lung cancers with pleural retraction. AB - BACKGROUND: In order to improve prognostic applications and treatment decisions, we report our experiences of visceral pleural surface invasion (VPSI) in non small cell lung cancers (NSCLCs) with pleural retraction. METHODS: A total of 321 NSCLCs with pleural retraction were identified by carefully inspecting surgically resected specimens. The extent of pleural invasion, including the use of elastic stain, was evaluated. Patients with and without VPSI were compared for clinicopathologic parameters and survival. RESULTS: VPSI was identified in 170 (53.0 %) of the stage I-III cases and 98 (43.4 %) of the patients with stage I disease. VPSI was associated with a higher frequency of tumor size greater than 3 cm, moderate/poor differentiation, vascular invasion, mediastinal lymph node metastasis, extranodal involvement, and higher TNM stages. Multivariate analysis revealed VPSI to be a significant independent predictor of unfavorable prognosis. The 5-year survival of patients with and without VPSI was 57.9 and 83.0 %, respectively (P = 0.001), and was 74.3 and 88.5 % (P = 0.005) in stages I-III and stage I disease, respectively. CONCLUSIONS: VPSI is an independent factor for poor prognosis in NSCLCs, regardless of lymph node status. Stage IB NSCLCs with PL1 pleural invasion are associated with a survival rate similar to that of stage IA NSCLCs and could be classified as T1 lesions. While surgical treatment is adequate in these patients, stage IB NSCLCs with VPSI have poor prognosis, and these patients should be considered for adjuvant chemotherapy. PMID- 22492227 TI - Association of head circumference and shoulder dystocia in macrosomic neonates. AB - To determine whether asymmetric macrosomia (disproportionately large body size in comparison to head circumference) could be demonstrated in a population of infants suffering shoulder dystocia during delivery relative to those that did not suffer from shoulder dystocia. A case-control study was conducted as a retrospective chart review over 3 years at a large maternity hospital in an urban setting. Among infants over 4,000 g, those that suffered from shoulder dystocia during delivery had a smaller mean head circumference than infants of a similar size that did not suffer from shoulder dystocia. A statistically significant difference was also present when cases of documented gestational diabetes were excluded. Asymmetric macrosomia is more likely to be present in a population of infants who suffered shoulder dystocia during delivery. This knowledge could be used in designing tools to predict which pregnancies are at highest risk for shoulder dystocia during delivery. PMID- 22492228 TI - The Western Surgical Concern Inventory-Thyroid: development and initial validation. AB - OBJECTIVE: Patients considering surgery face many uncertainties and concerns. This investigation sought to develop an objective assessment tool for characterizing the areas of greatest concern among those considering thyroidectomy. STUDY DESIGN: Prospective cohort design. SETTING: Tertiary-care otolaryngology practice. SUBJECTS: Participants included individuals presenting with a thyroid nodule found to be of intermediate risk (15%-20%) of cancer based on fine-needle aspiration (FNA) biopsy and amendable to hemithyroidectomy. METHODS: As part of validating a clinical measure concerning perioperative concerns, patients presenting with thyroid nodules amendable to hemithyroidectomy were voluntarily recruited. Thirty individuals (6 men, 24 women) completed a novel 18-item questionnaire during their initial clinical visit and again 3 days later. Outcome measures included descriptive statistics and test-retest reliability. RESULTS: Individual patients have both general and specific preoperative concerns. A wide range of responses was obtained across the entire spectrum of the survey. The questionnaire demonstrated fair-to-excellent test retest reliability, with correlation values from 0.467 to 0.954. Between-rater reliability was consistent with intraclass correlation coefficient values of 0.52 to 0.86. No relationship between question order and patient response was identified. Women were found to be more concerned about scar appearance (P = .028), and men were conversely more concerned about resuming daily activities (P = .026). CONCLUSIONS: Patients considering thyroidectomy have concerns that remain stable in the early preoperative period. This is the first study to evaluate preoperative patient concerns and preliminarily establishes the Western Surgical Concern Inventory-Thyroid as a means of ensuring adequate patient counseling and a method of evaluating preoperative patient education. PMID- 22492229 TI - A role of the mammalian target of rapamycin (mTOR) in glutamate-induced down regulation of tuberous sclerosis complex proteins 2 (TSC2). AB - Mammalian target of rapamycin (mTOR) signaling plays a critical role in the regulation of activity-dependent protein synthesis in neurons. It is well established that the GTPase-activating protein tuberous sclerosis complex proteins (2TSC2) is an upstream inhibitor of mTOR. In this study, we show that glutamate stimulation down-regulates TSC2 protein in cortical cultures via NMDA receptor (NMDAR) activation. Interestingly, the mTOR-specific inhibitor rapamycin blocks the glutamate-induced TSC2 down-regulation. This finding suggests that NMDAR activation evokes an mTOR-mediated negative regulation of TSC2. In addition, we also show that the glutamate-induced down-regulation of TSC2 protein is blocked by proteasome inhibitor MG132, indicating the involvement of proteasome-mediated protein degradation. We propose that the NMDAR activation stimulates an mTOR-proteasome pathway to degrade TSC2 protein. PMID- 22492230 TI - High-content analysis of proapoptotic EphA4 dependence receptor functions using small-molecule libraries. AB - Small-molecule compounds (SMCs) can provide an inexpensive and selective approach to modifying biological responses. High-content analysis (HCA) of SMC libraries can help identify candidate molecules that inhibit or activate cellular responses. In particular, regulation of cell death has important implications for many pathological conditions. Dependence receptors are a new classification of proapoptotic membrane receptors that, unlike classic death receptors, initiate apoptotic signals in the absence of their ligands. EphA4 has recently been identified as a dependence receptor that may have important functions in conditions as disparate as cancer biology and CNS injury and disease. To screen potential candidate SMCs that inhibit or activate EphA4-induced cell death, HCA of an SMC library was performed using stable EphA4-expressing NIH 3T3 cells. Our results describe a high-content method for screening dependence receptor signaling pathways and demonstrate that several candidate SMCs can inhibit EphA4 mediated cell death. PMID- 22492231 TI - Enzymological evidence for the function of a plastid-located pyruvate carboxylase in the Haptophyte alga Emiliania huxleyi: a novel pathway for the production of C4 compounds. AB - Pyruvate carboxylase (PYC) catalyzes the beta-carboxylation of pyruvate to yield oxaloacetate (OAA). We previously isolated a cDNA encoding a putative PYC (EhPYC1) from the haptophyte alga Emiliania huxleyi and then proposed that EhPYC1 contributes to active anaplerotic beta-carboxylation during photosynthesis although PYC activity was not detected in the cell extracts. Involvement of PYC in photosynthetic carbon metabolism is unique, since PYC generally functions in non-photosynthetic organisms. In the present study, we demonstrate that EhPYC1 is highly sensitive to endogenous proteases and therefore is easily degraded in cell extracts. By avoiding proteolytic degradation, PYC activity can be detected in the cell extracts of E. huxleyi. The activity of a recombinant His-tagged EhPYC1 expressed in Streptomyces lividans was inhibited by l-malate in a mixed non competitive manner. Immunofluorescence labeling showed that EhPYC1 is located in the plastid. This result agrees with the prediction that a bipartite plastid targeting signal is present that functions to deliver proteins into the four membrane plastid of haptophyte algae. This is the first finding of a plastid located PYC. These results indicate that E. huxleyi possesses a unique pathway to produce OAA catalyzed by PYC, and the pathway may provide carbon skeletons for amino acid biosynthesis in the plastid. A database search indicates that PYC genes are widespread in green algae, diatoms and brown algae, suggesting the crucial role of PYC in various aquatic phototrophs. PMID- 22492232 TI - Plant imprinted genes identified by genome-wide approaches and their regulatory mechanisms. AB - Genomic imprinting is an epigenetic phenomenon found in mammals and flowering plants that leads to differential allelic gene expression depending on their parent of origin. In plants, genomic imprinting primarily occurs in the endosperm, and it is associated with seed development. The imprinted expression is driven by the epigenetic memory programmed in each lineage of female and male germlines. Several imprinted genes have been identified based on genetic studies in maize and Arabidopsis. Recent advances in genome-wide analyses made it possible to identify multiple imprinted genes including many nuclear proteins, such as transcription factors and chromatin-related proteins in different plant species. Some of these genes are conserved in Arabidopsis, rice and maize, but many are species specific. Genome-wide analyses also clarified the regulation mechanism of imprinted genes orchestrated by DNA methylation and histone methylation marks. Additionally, genetic analyses using Arabidopsis revealed new regulatory factors of DNA demethylation and imprinting and shed light on the more precise mechanisms. PMID- 22492233 TI - Changes in the contents of metabolites and enzyme activities in rice plants responding to Rhizoctonia solani Kuhn infection: activation of glycolysis and connection to phenylpropanoid pathway. AB - Rhizoctonia solani Kuhn causes sheath blight disease in rice, and genetic resistance against it is the most desirable characteristic. Current improvement efforts are based on analysis of polygenic quantitative trait loci (QTLs), but interpretation is limited by the lack of information on the changes in metabolic pathways. Our previous studies linked activation of the glycolytic pathway to enhanced generation of lignin in the phenylpropanoid pathway. The current studies investigated the regulation of glycolysis by examining the time course of changes in enzymatic activities and metabolite contents. The results showed that the activities of all glycolytic enzymes as well as fructose-6-phosphate (F-6-P), fructose-1,6-bisphosphate (F-1,6-P(2)), dihydroxyacetone phosphate (DHAP), glyceraldehyde-3-phosphate (GAP), 3-phosphoglycerate (3-PG), phosphoenolpyruvate (PEP) and pyruvate contents increased. These results combined with our previous findings that the expression of phosphoglucomutase (PGM), triosephosphate isomerase (TPI), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), enolase and pyruvate kinase (PK) increased after infection suggested that the additional establishment of glycolysis in the cytosol compartment occurred after infection. Further evidence for this was our recent findings that the increase in expression of the 6-phosphofructokinase (PFK) plastid isozyme Os06g05860 was accompanied by an increase in expression of three cytosolic PFK isozymes, i.e. Os01g09570, Os01g53680 and Os04g39420, as well as pyrophosphate-dependent phosphofrucokinase (PFP) isozymes Os08g25720 (alpha-subunit) and Os06g13810 (beta-subunit) in infected rice plants of the resistant line. The results also showed that the reactions catalysed by PFK/PFP, aldolase, GAPDH + phosphoglycerate kinase (PGK) and PK in leaf sheaths of R. solani-infected rice plants were non-equilibrium reactions in vivo. This study showed that PGM, phosphoglucose isomerase (PGI), TPI and phosphoglycerate mutase (PGmu) + enolase could be regulated through coarse control whereas, PFK/PFP, aldolase, GAPDH + PGK and PK could be regulated through coarse and fine controls simultaneously. PMID- 22492235 TI - Identification of functional elements of the GDP-fucose transporter SLC35C1 using a novel Chinese hamster ovary mutant. AB - The GDP-fucose transporter SLC35C1 critically regulates the fucosylation of glycans. Elucidation of its structure-function relationships remains a challenge due to the lack of an appropriate mutant cell line. Here we report a novel Chinese hamster ovary (CHO) mutant, CHO-gmt5, generated by the zinc-finger nuclease technology, in which the Slc35c1 gene was knocked out from a previously reported CHO mutant that has a dysfunctional CMP-sialic acid transporter (CST) gene (Slc35a1). Consequently, CHO-gmt5 harbors double genetic defects in Slc35a1 and Slc35c1 and produces N-glycans deficient in both sialic acid and fucose. The structure-function relationships of SLC35C1 were studied using CHO-gmt5 cells. In contrast to the CST and UDP-galactose transporter, the C-terminal tail of SLC35C1 is not required for its Golgi localization but is essential for generating glycans that are recognized by a fucose-binding lectin, Aleuria aurantia lectin (AAL), suggesting an important role in the transport activity of SLC35C1. Furthermore, we found that this impact can be independently contributed by a cluster of three lysine residues and a Glu-Met (EM) sequence within the C terminus. We also showed that the conserved glycine residues at positions 180 and 277 of SLC35C1 have significant impacts on AAL binding to CHO-gmt5 cells, suggesting that these conserved glycine residues are required for the transport activity of Slc35 proteins. The absence of sialic acid and fucose on Fc N-glycan has been independently shown to enhance the antibody-dependent cellular cytotoxicity (ADCC) effect. By combining these features into one cell line, we postulate that CHO-gmt5 may represent a more advantageous cell line for the production of recombinant antibodies with enhanced ADCC effect. PMID- 22492234 TI - Infection, inflammation and host carbohydrates: a Glyco-Evasion Hypothesis. AB - Microbial immune evasion can be achieved through the expression, or mimicry, of host-like carbohydrates on the microbial cell surface to hide from detection. However, disparate reports collectively suggest that evasion could also be accomplished through the modulation of the host glycosylation pathways, a mechanism that we call the "Glyco-Evasion Hypothesis". Here, we will summarize the evidence in support of this paradigm by reviewing three separate bodies of work present in the literature. We review how infection and inflammation can lead to host glycosylation changes, how host glycosylation changes can increase susceptibility to infection and inflammation and how glycosylation impacts molecular and cellular function. Then, using these data as a foundation, we propose a unifying hypothesis in which microbial products can hijack host glycosylation to manipulate the immune response to the advantage of the pathogen. This model reveals areas of research that we believe could significantly improve our fight against infectious disease. PMID- 22492236 TI - EarlyCDT(r)-Lung test: improved clinical utility through additional autoantibody assays. AB - Tumor-associated autoantibodies (AAbs) have been described in patients with lung cancer, and the EarlyCDT(r)-Lung test that measures such AAbs is available as an aid for the early detection of lung cancer in high-risk populations. Improvements in specificity would improve its cost-effectiveness, as well as reduce anxiety associated with false positive tests. Samples from 235 patients with newly diagnosed lung cancer and matched controls were measured for the presence of AAbs to a panel of six (p53, NY-ESO-1, CAGE, GBU4-5, Annexin I, and SOX2) or seven (p53, NY-ESO-1, CAGE, GBU4-5, SOX2, HuD, and MAGE A4) antigens. Data were assessed in relation to cancer type and stage. The sensitivity and specificity of these two panels were also compared in two prospective consecutive series of 776 and 836 individuals at an increased risk of developing lung cancer. The six-AAb panel gave a sensitivity of 39% with a specificity of 89 %, while the seven-AAb panel gave a sensitivity of 41 % with a specificity of 91 % which, once adjusted for occult cancers in the population, resulted in a specificity of 93 %. Analysis of these AAb assays in the at-risk population confirmed that the seven-AAb panel resulted in a significant increase in the specificity of the test from 82 to 90 %, with no significant change in sensitivity. The change from a six- to a seven AAb assay can improve the specificity of the test and would result in a PPV of 1 in 8 and an overall accuracy of 92 %. PMID- 22492237 TI - Antitumor effect of the mTOR inhibitor everolimus in combination with trastuzumab on human breast cancer stem cells in vitro and in vivo. AB - This study evaluated the effects of a mammalian target of mTOR inhibitor everolimus alone or in combination with trastuzumab on stem cells from HER2 overexpressing primary breast cancer cells and the BT474 breast cancer cell line in vitro and in vivo. For the in vitro studies, we sorted ESA(+)CD44(+)CD24( /low) cells as stem cells from primary breast cancer cells and BT474 cells using flow cytometry. The MTT assay was used to quantify the inhibitory effect of the drugs on total cells and stem cells specifically. Stem cell apoptosis, cell cycle distributions, and their tumorigenicity after treatment were investigated by flow cytometry or soft agar colony formation assays. For the in vivo studies, BALB/c mice were injected with BT474 stem cells, and the different treatments were administered. After necropsy, the expression of Ki67, CD31, AKT1, and phospho-AKT (Thr308) was analyzed by immunohistochemistry. For the in vitro studies, Treatment with everolimus resulted in stem cell growth inhibition in a dose dependent manner. The combination of everolimus with trastuzumab was more effective at inhibiting cell growth (P < 0.001) and tumorigenicity (P < 0.001) compared with single-agent therapy. In addition, an increase in G1 cell cycle arrest and an increased population of cells in early apoptosis were seen in the combination treatment group compared with either of the single-agent groups (P < 0.01). For the in vivo studies, everolimus plus trastuzumab therapy was much more effective at reducing tumor volume in mice compared with either single agent alone (P < 0.05). Compared with everolimus alone, the combination of everolimus and trastuzumab reduced the expression of Ki67, AKT1, and phospho-AKT (Thr308) (P < 0.05). We conclude that everolimus has effective inhibitory effects on HER2 overexpressing stem cells in vitro and vivo. Everolimus plus trastuzumab is a rational combination treatment that may be promising in human clinical trials. PMID- 22492238 TI - Evolving models of tumor origin and progression. AB - History of cancer disease models clearly illustrates the evolving nature of these concepts. Since such models undergo continual revisions and additions as a result of underlying medical research, they also tend to reorganize knowledge and allow perceiving previously unseen relationships. Growth of medical thought has been influenced for many centuries by an ancient Hippocratic concept of disease seen as a disturbance in bodily "humors." True mechanisms of cell and tissue injury started to be elucidated only with the advent of postmortem pathological findings. Concerning cancer, when first disease-producing bacteria were identified in the nineteenth century, also neoplasms were treated as infectious diseases. Foreign organisms were thought to be present inside tumors. However, this hypothesis could not be confirmed by microscopic or histochemical studies. The latter suggested, instead, that tumors were rather formed by abnormal cells. Cancer was then started to be regarded as a disease of cells. This interpretation was radically altered by later developments in genetics which suggested that neoplasms can be treated as genetic diseases as pathologic cellular lesions are caused by mutations in specific genes. More recent models have compared carcinogenesis to evolutionary processes. Due to genetic instability, successive mutations, appearing in cells, lead to selection of cancer cells which feature specific phenotypic traits. The newest data indicate that there may be also a link between cancer and mutated stem cells. The review discusses main concepts of tumor origin forwarded since the beginnings of the nineteenth century. PMID- 22492239 TI - Introduction to this special issue on tumor targeting. PMID- 22492240 TI - Social implications of balloon kyphoplasty: prospective study from a single UK centre. AB - PURPOSE: The incidence of osteoporotic fractures is increasing with an ageing population. This has potential consequences for health services, patients and their families. Treatment of osteoporotic vertebral compression fractures (OVCFs) has been limited to non-surgical measures so far. The social and functional consequences of balloon kyphoplasty, a recent development for the treatment of VCF, were assessed in this cohort study. METHODS: Data collected prospectively from 53 patients undergoing balloon kyphoplasty for symptomatic OVCF in our hospital's spinal unit were compared with data from an historical age-matched group of 51 consecutive patients treated conservatively for symptomatic OVCF. Social functionality was recorded prior to the injury, and at 6-month and 1-year follow-up; mortality was recorded at 6 months and 1 year. RESULTS: The mortality rate in the balloon kyphoplasty group was 11 % (6/53) at 1 year post-OVCF, versus 22 % (11/51) in the conservatively treated controls. A drift to a lower level of social functionality (defined by a lower level of independence) was observed at 1 year in 21 % of patients in the balloon kyphoplasty group versus 53 % of patients in the conservatively treated group. A drift to a lower level of independence was noted in 67 % of the conservatively treated patients who started at a lower level of functionality versus 20 % drift in a similar group who were treated with balloon kyphoplasty. CONCLUSIONS: The reduction in mortality and drift in social functionality at 1 year following treatment with balloon kyphoplasty suggests that it is a viable option for the management of OVCFs. PMID- 22492242 TI - Biomechanical assessment of the effects of decompressive surgery in non chondrodystrophic and chondrodystrophic canine multisegmented lumbar spines. AB - PURPOSE: Dogs are often used as an animal model in spinal research, but consideration should be given to the breed used as chondrodystrophic (CD) dog breeds always develop IVD degeneration at an early age, whereas non chondrodystrophic (NCD) dog breeds may develop IVD degeneration, but only later in life. The aim of this study was to provide a mechanical characterization of the NCD [non-degenerated intervertebral discs (IVDs), rich in notochordal cells] and CD (degenerated IVDs, rich in chondrocyte-like cells) canine spine before and after decompressive surgery (nucleotomy). METHODS: The biomechanical properties of multisegmented lumbar spine specimens (T13-L5 and L5-Cd1) from 2-year-old NCD dogs (healthy) and CD dogs (early degeneration) were investigated in flexion/extension (FE), lateral bending (LB), and axial rotation (AR), in the native state and after nucleotomy of L2-L3 or dorsal laminectomy and nucleotomy of L7-S1. The range of motion (ROM), neutral zone (NZ), and NZ stiffness (NZS) of L1-L2, L2-L3, L6-L7, and L7-S1 were calculated. RESULTS: In native spines in both dog groups, the greatest mobility in FE was found at L7-S1, and the greatest mobility in LB at L2-L3. Surgery significantly increased the ROM and NZ, and significantly decreased the NZS in FE, LB, and AR in both breed groups. However, surgery at L2-L3 resulted in a significantly larger increase in NZ and decrease in NZS in the CD spines compared with the NCD spines, whereas surgery at L7-S1 induced a significantly larger increase in ROM and decrease in NZS in the NCD spines compared with the CD spines. CONCLUSIONS: Spinal biomechanics significantly differ between NCD and CD dogs and researchers should consider this aspect when using the dog as a model for spinal research. PMID- 22492243 TI - Synovial fluid from patients with early osteoarthritis modulates fibroblast-like synoviocyte responses to toll-like receptor 4 and toll-like receptor 2 ligands via soluble CD14. AB - OBJECTIVE: Synovial inflammation, a feature of both osteoarthritis (OA) and meniscal injury, is hypothesized to be triggered in part via stimulation of Toll like receptors (TLRs). We undertook this study to test whether a TLR-2- or TLR-4 stimulating factor in synovial fluid (SF) from patients with early knee OA with meniscal injury could lead to inflammatory activation of synoviocytes. METHODS: SF was obtained from patients with early OA cartilage damage undergoing arthroscopic meniscal procedures. SF was used to stimulate primary cultures of fibroblast-like synoviocytes (FLS) and cell lines transfected with TLR-2 or TLR 4. SF was used either alone or in combination with a TLR-2 stimulus (palmitoyl-3 cysteine-serine-lysine-4 [Pam3CSK4]) or a TLR-4 stimulus (lipopolysaccharide [LPS]). In blocking experiments, SF was preincubated with anti-CD14 antibody. RESULTS: SF from these patients did not stimulate interleukin-8 (IL-8) release from TLR transfectants. Compared with SF on its own, SF (at concentrations of 0.09-25%) in combination with TLR-2 or TLR-4 ligands resulted in significant augmentation of IL-8 release from both transfectants and primary FLS. Soluble CD14 (sCD14), a coreceptor for TLRs, was measured in SF from patients with early OA at levels comparable to those in patients with advanced OA and patients with rheumatoid arthritis. Blockade with anti-CD14 antibody abolished the ability of SF to augment IL-8 production in response to LPS, and diminished Pam3CSK4 responses. CONCLUSION: SF augments FLS responses to TLR-2 and TLR-4 ligands. This effect was largely due to sCD14. Our results demonstrate that sCD14 in the setting of OA and meniscal injury sensitizes FLS to respond to inflammatory stimuli such as TLR ligands. PMID- 22492244 TI - Occurrence of vaccine and non-vaccine human papillomavirus types in adolescent Finnish females 4 years post-vaccination. AB - Control of human papillomavirus (HPV)-related cancers by inclusion of HPV vaccination into national vaccination programmes is likely. One open question is replacement of the vaccine types with other high-risk (hr) HPV types in the vaccination era. We studied occurrence of HPV types in adolescent females participating in a population-based vaccination trial. A total of 4,808 16- to 17 year-old females from Finland were enrolled in the 1:1 randomized phase III (PATRICIA) trial of the efficacy of vaccination with the AS04-adjuvanted HPV 16/18 virus-like particle vaccine as compared to hepatitis A virus (HAV) vaccine. HPV infection was assessed from cervical samples taken every 6 months for 4 years post-vaccination by polymerase chain reaction (PCR) for genital oncogenic HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 58, 59, 66, 68, and 73 as well as low risk types HPV-6 and HPV-11. The HPV-16/18 vaccine coverage ranged between 1 and 22% by age-cohort and study community. Odds ratios (ORs) for infections with different HPV types in baseline PCR negative HPV-16/18 vs. HAV vaccinated women, and Poisson regression derived HPV incidence rate ratios (IRRs) in baseline positive vs. negative women were calculated. The OR and IRR estimates for acquisition of any genital HPV types showed no excess risk neither in baseline HPV DNA-negative HPV-16/18-vaccinated women compared to baseline HPV DNA-negative HAV vaccinated women nor in HPV-16/18-vaccinated baseline HPV-16/18-positive women compared to baseline HPV-16/18-negative women. In the HAV-vaccinated, baseline HPV-18-positive women showed an increased risk of acquiring other clade A7 HPV types (39, 45, 59, 68) (IRR 1.8, 95% confidence interval = 1.01.-3.1). We found no increased occurrence of non-vaccine HPV types suggestive of type replacement 1-4 years post-vaccination among HPV-16/18-vaccinated Finnish adolescents. PMID- 22492245 TI - Stereotactic radiosurgery for intracranial chondrosarcoma. AB - To assess outcomes after stereotactic radiosurgery (SRS) for chondrosarcomas of the skull base, we reviewed 22 patients with cranial base chondrosarcomas who underwent SRS between 1987 and 2009. The median patient age was 42 years (range, 15-75). The median SRS target volume was 8.0 cc (range, 0.9-28.2) and median margin dose was 15.0 Gy (range, 10.5-20). 15 patients (68 %) underwent one or more tumor resections and 3 of these patients also had fractionated radiation therapy. At a median follow-up of 75 months after SRS, seven patients died due to tumor progression. The actuarial overall survival after SRS for the entire group of chondrosarcoma patients was 95, 76, 70 and 56 % at 1, 3, 5 and 10 years, respectively. Factors associated with longer survival after SRS included patient age >40 years, a shorter interval (<6 months) between diagnosis and SRS, and either no or a single prior resection. Treated tumor control rates were 91, 72, 72 and 54 % at 1, 3, 5 and 10 years, respectively. Factors associated with longer progression-free survival after SRS included patient age >40 years and no prior RT. Symptomatic adverse radiation effects occurred in two patients (10 %). Stereotactic radiosurgery may provide a benefit to patients as either a primary or adjuvant therapy. The ability to achieve tumor control in patients with chondrosarcoma is likely to be enhanced by earlier timing of SRS after diagnosis and multimodal management, beginning with resection when feasible followed by early SRS for progressive residual tumor. PMID- 22492246 TI - Pre- and post-operative plasma glial fibrillary acidic protein levels in patients with newly diagnosed gliomas. AB - Therapies that disrupt or repair blood-brain barrier integrity can result in major changes in MRI images even when the tumor volume remains constant. Thus, a reliable blood-based tumor biomarker could significantly improve clinical care and research studies in these patients. This study was performed to assess plasma concentrations of glial fibrillary acidic protein (GFAP) in patients with high- and low-grade gliomas before and after debulking surgery. Pre-operative plasma was collected from 33 patients with radiation- and chemotherapy-naive gliomas. Additional plasma was collected 24-48 h post-operatively from 23 of these patients. Plasma GFAP (pGFAP) concentrations were determined using an electrochemiluminescent immunoassay and were analyzed as a function of tumor grade, tumor GFAP expression, the integrity of the blood-brain barrier, and post operative status. Detectable pGFAP levels (>= 0.04 ng/mL) were found pre operatively in 52 % of patients and post-operatively in 96 %. Detectable pGFAP was more common in patients with WHO grade IV (100 %) than WHO grade III (56 %) or WHO grade II gliomas (20 %). No patient with undetectable GFAP had WHO grade IV glioma. Higher pGFAP concentrations were also associated with contrast enhancement but not related to tumor GFAP expression. GFAP is commonly detected in the plasma of patients with high-grade gliomas. pGFAP levels rise rather than fall following debulking surgery which is probably a result of surgical trauma. GFAP remains a potentially informative plasma biomarker for gliomas. Longitudinal studies are required to correlate pGFAP levels with patient outcomes. PMID- 22492248 TI - Prevalence of mitochondrial diabetes in southwestern Finland: a molecular epidemiological study. AB - Mitochondrial diabetes and deafness (MIDD) is a subtype of diabetes mellitus (DM) that most commonly results from the m.3243A > G mutation in mitochondrial DNA (mtDNA). Sensorineural hearing loss is a typical accompanying feature. Previous studies have suggested a prevalence of ~1-1.5 % for MIDD. We studied the molecular epidemiology of MIDD among young (aged 18-45 years) adults in a defined population in southwestern Finland. Of the identified cohort of 1,532 patients with DM, we received blood samples of 299 patients and analyzed them for the m.3243A > G mutation and for mtDNA haplogroups. We found three DM patients (1.0 %) with the m.3243A > G mutation. All the three patients with DM and m.3243A > G also had severe hearing impairment that required use of hearing aid. MtDNA haplogroup U was more prevalent among patients with maternal family history of DM. We conclude that among young adults, ~1 % of all DM is associated with the m.3243A > G mutation. We suggest that all patients with both DM and hearing impairment, at least in this age group, should undergo investigation for this mutation. Furthermore, our results suggest that mtDNA haplogroup U is associated with maternal family history of DM. PMID- 22492247 TI - Use of pooled samples from the National Health and Nutrition Examination Survey. AB - The National Centers for Disease Control and Prevention (CDC) provides an ongoing assessment of the US population's exposure to environmental chemicals by using biomonitoring in conjunction with CDC's National Health and Nutrition Examination Survey (NHANES). Characterizing the distributions of concentrations of environmental compounds or their metabolites in the US population is a primary objective of CDC's biomonitoring program. Historically, this characterization has been based on individual measurements of these compounds in body fluid or tissue from representative samples of the population. Pooling samples before making analytical measurements can reduce the costs of biomonitoring by reducing the number of analyses. For the first time in NHANES 2005-2006, a weighted pooled sample design was implemented to facilitate pooling samples before making analytical measurements. This paper describes this design and the estimation method being developed in the National Center for Environmental Health, Division of Laboratory Sciences (NCEH/DLS) to characterize concentrations of polychlorinated and polybrominated compounds. We present percentile estimates for 2,2 ( ' ) ,4,4 ( ' ) ,5,5 ( ' ) -hexachlorobiphenyl (PCB153) in specific subpopulations of the US based on the NHANES 2005-2006 pooled-sample design. We also compare estimates based on individual samples from NHANES 2003-2004 with estimates based on artificially created pools from NHANES 2003-2004 using a pooled-sample design similar to the one used for NHANES 2005-2006. For NHANES 2005-2006 the number of analyses required to characterize the levels of 61 polychlorinated and 13 polybrominated compounds in the US population was reduced from 2201 to 228. At a cost of $1400 per analytical measurement, this represents a savings of approximately $2.78 million. Published 2012. This article is a US Government work and is in the public domain in the USA. PMID- 22492249 TI - Efficacy and tolerability of hyaluronic acid, tea tree oil and methyl-sulfonyl methane in a new gel medical device for treatment of haemorrhoids in a double blind, placebo-controlled clinical trial. AB - Topical formulations are widely used in anti-haemorrhoidal treatment, but often lacking controlled clinical trials. Here, we report the results from a controlled clinical trial performed with a new gel medical device (Proctoial) containing hyaluronic acid with tea tree oil and methyl-sulfonyl-methane as major components. The total number of 36 haemorrhoidal patients (grade 1-3) was enrolled in a double-blind, placebo-controlled clinical trial and divided into 2 equal parallel groups. The anal pain, pain during defecation, visible bleeding, pruritus and irritation/inflammation were recorded before and after 14-day treatment using a visual analogue scale both by the investigators and by the patients. Safety and tolerability of the treatments were also recorded. The new gel medical device statistically significantly reduced all the symptoms after the treatment compared to placebo. The results indicated also a very good tolerability and safety of the treatments. PMID- 22492250 TI - Serum gamma-glutamyltransferase activity in patients with nonvalvular atrial fibrillation. AB - Procoagulant and prothrombotic states in patients with chronic atrial fibrillation (AF) are higher than those in patients with normal sinus rhythm. We assessed and compared serum gamma-glutamyltranferase (GGT) activity in elderly patients with nonvalvular AF and control participants with normal sinus rhythm. Consecutive patients (n = 81) with nonvalvular chronic AF and 210 age- and gender matched control participants with normal sinus rhythm were retrospectively included in the study from the outpatient cardiology clinic. Presence of coronary artery disease, hypertension, gender, hyperlipidemia, diabetes mellitus, smoking status, glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and ejection fraction were comparable between the 2 groups (P > .05 for all). However, serum gamma-GGT activity was significantly higher (P = .003) in patients with AF compared with those without AF. We have shown that serum gamma-GGT activity is independently associated with chronic nonvalvular AF. PMID- 22492251 TI - Clinical presentation and cardiovascular risk profiles in patients with left main coronary artery disease in a middle eastern country. AB - We evaluated the prevalence and clinical profile of patients with left main coronary artery disease (LMCA) in Qatar between 2006 and 2010. Patients were divided into 2 groups: patients with LMCA and patients without LMCA but had severe 3-vessel disease (VeD) eligible for surgical revascularization. Among 7000 patients who underwent coronary angiography, 210 patients had significant LMCA and 200 patients with severe 3VeD were matched for age and sex. Diabetes mellitus and hypertension were comparable in the 2 groups. Presentations with myocardial infarction or heart failure were comparable in both groups. Isolated LMCA was 4 fold higher in women (P = .02). Dyslipidemia and smoking were more prevalent in patients with distal and proximal lesions, respectively. Renal failure was independent predictor of LMCA (adjusted odds ratio: 2.6; 95% confidence interval: 1.43-4.69). One-year mortality was higher in LMCA (P = .01). The LMCA carries high mortality. Certain cardiovascular risk factors were important predictors of stenosis site. PMID- 22492252 TI - Bilirubin levels and the burden of coronary atherosclerosis in patients with STEMI. AB - We investigated whether serum bilirubin level (a marker of heme oxygenase activity) is a predictor of high levels of SYNTAX score (SXscore) in patients with acute myocardial infarction. Patients (n = 281; male 77%; mean age 60 +/- 12) who were admitted with ST-elevation myocardial infarctions (STEMIs) were enrolled. Patients were divided into 2 groups. Group 1 was defined as SXscore <22 and group 2 was defined as SXscore >=22. Total bilirubin levels were significantly higher in the high-SXscore group than in the low-SXscore group (0.86 +/- 0.42 vs 1.02 +/- 0.51, P = .005). A significant correlation was detected between total bilirubin and SXscore (r = .42; P = .001). At multivariate analysis, total bilirubin (odds ratio: 1.86, 95% confidence interval 1.04-3.35; P = .038) was an independent risk factor for high SXscore in patients with STEMI. In conclusion, serum bilirubin level is independently associated with SXscore in patients with STEMI. PMID- 22492253 TI - Prevalence of noncalcified coronary plaque in patients with calcium score of 0: the silent enemy. AB - Noncalcified coronary artery plaques (NCAPs) are susceptible to rupture, resulting in coronary artery thrombosis. Using computer tomography coronary angiography (CTCA), we evaluated the prevalence and degree of stenosis caused by NCAP in patients without coronary artery calcification (CAC). A retrospective analysis of 447 symptomatic patients with 0 CAC score revealed negative CTCA in 400 (89.5%). Noncalcified coronary artery plaques were demonstrated in 47 (10.5%), with 4 presenting stenosis >50%. Patients with positive CTCA, compared to those with normal CTCA, had significantly higher mean age (56.2 years vs 50.6 years, P < .004) and higher pretest coronary artery disease (CAD) probability (26% vs 34%, P < .0001). Noncalcified coronary artery plaque was predominantly developed in the proximal segment of the left anterior descending artery. Noncalcified coronary artery plaque is present in up to 10% of patients with a CAC score of 0. Computer tomography coronary angiography could be of diagnostic value in symptomatic patients with multiple risk factors for CAD, even in the absence of CAC. PMID- 22492254 TI - Monocyte chemoattractant protein 1 is correlated with glycemic control and peripheral arterial disease in type 2 diabetic patients with metabolic syndrome. AB - We evaluated the serum levels of monocyte chemoattractant protein 1 (MCP-1) and their association with peripheral arterial disease (PAD) in 199 patients with type 2 diabetes mellitus (T2DM) and metabolic syndrome ([MetS], group A) in comparison with 109 healthy controls (group B). In group A, MCP-1 levels were significantly (P < .001) higher than group B and exhibited a positive correlation with HbA1c (P < .001) and a negative correlation with ankle-brachial index (P < .001). In the same group, patients with PAD had significantly higher MCP-1 levels compared with those without PAD (P < .001). In conclusion, T2DM patients with MetS exhibit higher serum MCP-1 levels. The latter is associated with worse glycemic control and PAD. These results suggest a potential contributory role for MCP-1 in the pathogenesis of PAD in the presence of hyperglycemia and MetS in T2DM. PMID- 22492255 TI - Tobacco use and cancer survival: a cohort study of 40,230 Swedish male construction workers with incident cancer. AB - On theoretical grounds, nicotine has been implicated as a modifier of cancer progression. We investigated possible associations of smoking or use of Scandinavian moist snuff (snus) with survival after cancer among Swedish male construction workers. Snus use is associated with substantial exposure to nicotine but not to the combustion products in smoke. Among 336,381 workers with detailed information on tobacco use in 1971-1992, we observed 40,230 incident cancers. Complete follow-up through 2007 was accomplished through linkage to population and health registers. Hazard ratios (HRs) and 95% confidence intervals (CIs) for death from any cause, cancer-specific death and death from other causes were derived from Cox proportional hazards regression models adjusted for age at diagnosis, body mass index at study entry and period of diagnosis. Never users of any tobacco served as reference. Increased risks of cancer-specific death were observed both among exclusive smokers (HR(all cancer) 1.15, 95% CI: 1.10-1.21) and never-smoking snus users (1.15, 95% CI: 1.05-1.26). As regards deaths due to other causes, exclusive smokers had higher relative risks than exclusive snus users (p = 0.03). A history of tobacco use, even exclusive use of the seemingly benign snus, is associated with moderately increased cancer-specific mortality. Although nicotine might play a role, the mechanisms warrant further investigation. PMID- 22492256 TI - Combined subunit-specific and unspecific inhibition of NMDA receptors triggers distinct cortical c-fos expression patterns. PMID- 22492257 TI - Functional classification of membrane transporters and channels based on filtered TM/non-TM amino acid composition. AB - Membrane transporters catalyze the transport of small solute molecules across biological barriers such as lipid bilayer membranes. As the experimental annotation of which proteins transport which substrates is incomplete it is highly desirable to develop computational methods that can assist in the classification and substrate annotation of putative membrane transport proteins. Here, we determined the similarity of membrane transporter sequences annotated in the Transport Classification Database (Saier et al., Nucleic Acids Res 2006, 34, D181-D186) and Arabidopsis thaliana membrane transporters annotated in the database Aramemnon (Schwacke et al., Plant Physiol 2003, 131, 16-26). The similarity measure was based on the amino acid composition either considering the full sequences or separately in the transmembrane (TM) and external parts of the sequences. We considered four different substrate sets and three different subfamilies and tried to classify the given proteins into these classes. Family or substrate prediction based on the simple amino acid frequency had an average accuracy of 76%. The differentiation between TM and non-TM regions led to an improved accuracy of 80% on average. PMID- 22492259 TI - Parental environment changes the dormancy state and karrikinolide response of Brassica tournefortii seeds. AB - BACKGROUND AND AIMS: The smoke-derived chemical karrikinolide (KAR(1)) shows potential as a tool to synchronize the germination of seeds for weed management and restoration. To assess its feasibility we need to understand why seeds from different populations of a species exhibit distinct responses to KAR(1). Environmental conditions during seed development, known as the parental environment, influence seed dormancy so we predicted that parental environment would also drive the KAR(1)-responses of seeds. Specifically, we hypothesized that (a) a common environment will unify the KAR(1)-responses of different populations, (b) a single population grown under different environmental conditions will exhibit different KAR(1)-responses, and (c) drought stress, as a particular feature of the parental environment, will make seeds less dormant and more responsive to KAR(1). METHODS: Seeds of the weed Brassica tournefortii were collected from four locations in Western Australia and were sown in common gardens at two field sites, to test whether their KAR(1)-responses could be unified by a common environment. To test the effects of drought on KAR(1) response, plants were grown in a glasshouse and subjected to water stress. For each trial, the germination responses of the next generation of seeds were assessed. KEY RESULTS: The KAR(1)-responses of seeds differed among populations, but this variation was reduced when seeds developed in a common environment. The KAR(1)-responses of each population changed when seeds developed in different environments. Different parental environments affected germination responses of the populations differently, showing that parental environment interacts with genetics to determine KAR(1)-responses. Seeds from droughted plants were 5 % more responsive to KAR(1) and 5 % less dormant than seeds from well-watered plants, but KAR(1)-responses and dormancy state were not intrinsically linked in all experiments. CONCLUSIONS: The parental environment in which seeds develop is one of the key drivers of the KAR(1)-responses of seeds. PMID- 22492260 TI - The effects of large herbivores on the landscape dynamics of a perennial herb. AB - BACKGROUND AND AIMS: Models assessing the prospects of plant species at the landscape level often focus primarily on the relationship between species dynamics and landscape structure. However, the short-term prospects of species with slow responses to landscape changes depend on the factors affecting local population dynamics. In this study it is hypothesized that large herbivores may be a major factor affecting the short-term prospects of slow-responding species in the European landscape, because large herbivores have increased in number in this region in recent decades and can strongly influence local population dynamics. METHODS: The impact of browsing by large herbivores was simulated on the landscape-level dynamics of the dry grassland perennial polycarpic herb Scorzonera hispanica. A dynamic, spatially explicit model was used that incorporated information on the location of patches suitable for S. hispanica, local population dynamics (matrices including the impact of large herbivores), initial population sizes and dispersal rate of the species. Simulations were performed relating to the prospects of S. hispanica over the next 30 years under different rates of herbivory (browsing intensity) and varying frequencies of population destruction (e.g. by human activity). KEY RESULTS: Although a high rate of herbivory was detected in most populations of S. hispanica, current landscape-level dynamics of S. hispanica were approximately in equilibrium. A decline or increase of over 20 % in the herbivory rate promoted rapid expansion or decline of S. hispanica, respectively. This effect was much stronger in the presence of population destruction. CONCLUSIONS: Browsing by large herbivores can have a dramatic effect on the landscape dynamics of plant species. Changes in the density of large herbivores and the probability of population destruction should be incorporated into models predicting species abundance and distribution. PMID- 22492261 TI - A review of energy recovery from waste in China. AB - Although municipal solid waste (MSW) disposal in Europe and other developed countries has led to a widespread production of solid recovered fuel (SRF) and its incineration in various technical combustion processes, such developments have not yet occurred that widely in developing and transitional economies. This article puts mass-burn technologies and SRF into a China perspective, reviewing issues from technology application problems to emerging trends and future perspectives. Over the last two decades, growing waste volumes have prompted a move to waste incineration, especially in the large densely populated first-tier cities. However, with an organic fraction above 70% and a resulting water content of up to 65%, it is still argued that MSW in China is too moist for incineration. The introduction of mechanical biological treatment (MBT) or mechanical physical stabilization (MPS) technology for SRF production could provide the solution, either by offering further pre-drying options to mass-burn incinerators or by creating SRF to be burnt in co-incineration plants. First experiences of MBT and MPS technologies show promising results in terms of the capacity to deal with organic waste fractions, but the further disposal/utilization of the plants' output stream has not yet been fully addressed. PMID- 22492262 TI - How can a successful multi-family residential recycling programme be initiated within Baltimore City, Maryland? AB - Baltimore City formally began recycling in 1989 with all neighbourhoods having residential collection by 1992. Although the city of 637 000 has recycled for approximately 20 years, almost all residents in multi-family residential (MFR) housing have been and are still barred from participating at their residences. Discussions with City officials and residents have verified this antiquated policy of exclusion within MFR housing. Yet, the policy is still observed by the Department of Public Works even though the updated single-stream Code states that the 'Director of Public Works must collect all. . .recyclable materials. . .from all dwellings, including multiple-family dwellings'. The purpose of this study's is to provide policies, regulations, and recommendations for implementing requisite MFR recycling within Baltimore City. The study's methodology follows a case study approach by examining three cities in the United States that currently mandate MFR recycling: Chicago, Illinois; Boston, Massachusetts; and Arlington, Virginia. Post-analysis suggests that while some cities' MFR programmes perform poorly, each city's strengths aid in creating specific proposals that can produce a successful MFR recycling program in Baltimore City. These tenets of a future MFR recycling program form the basis of a successful MFR recycling program that will allow all city residents to participate via initiatives in the categories of both programme, accessibility, and informing and self-review. PMID- 22492263 TI - Estimating the impact of the home appliances trade-in policy on WEEE management in China. AB - The ever-increasing amount of waste electric and electronic equipment (WEEE) has become a global problem. In view of the deleterious effects of WEEE on the environment and the valuable materials that can be reused in them, many countries have focused their attention on the management of WEEE and the recovery technologies of WEEE. The Chinese government has been active in creating a legislative and institutional framework to realize WEEE recycling. In June 2009, Chinese government launched home appliances and electronics trade-in implementation solution. This paper elaborates the home appliances trade-in policy and its significant impact on the WEEE management. The trade-in policy is not only conducive to expanding the consumption demand and promoting the balance of domestic and overseas demand, but also favorable to improving the energy efficiency and reducing environmental pollution. Under this policy, China has successfully established an effective WEEE recycling system, using the financial means and network design. Experiences gained from the trade-in policy have shown that management systems of WEEE need to be designed and implemented in a multi stakeholder dialogue. PMID- 22492265 TI - Unusual cause of primary amenorrhea due to kissing internal carotid arteries. PMID- 22492266 TI - Electroencephalographic activity in neonatal ventral hippocampus lesion in adult rats. AB - A neonatal ventral hippocampal lesion (NVHL) in rats has been commonly used as a neurodevelopmental model to mimic schizophrenia-like behaviors. Recently, we reported that NVHL resulted in dendritic retraction and spine loss in pyramidal neurons of the prefrontal cortex (PFC). In addition, the hippocampus and PFC are important structures in the regulation of the electroencephalographic (EEG) activity. Patients with PFC lesions show deficits in the EEG activity. This study aimed to determine whether the EEG activity was altered in NVHL rats. In addition, we also analyzed the locomotor activity induced by a novel environment and exploratory behavior using the hole-board test. Consistent with the behavioral findings, the EEG analysis of the cortical regions showed that the NVHL rats displayed a lower power in cortical bands. At 1-8 Hz, 9-14 Hz, and 15 30 Hz bands, our findings showed a decrease in the absolute power of the parietal and occipital cortices recordings. In addition, the NVHL rats also showed a reduction in the exploratory behavior tested using the hole-board test. In conclusion, this study demonstrated that the EEG activity was reduced in adult NVHL rats and suggests that this may play a role in the behavioral changes observed in this neurodevelopmental model of schizophrenia. PMID- 22492267 TI - QTc prolongation and clozapine: fact or artefact? PMID- 22492268 TI - Comparative proteomic analysis of differentiation of mouse F9 embryonic carcinoma cells induced by retinoic acid. AB - The multipotent mouse F9 embryonic carcinoma cell is an ideal model system to investigate the mechanism of retinoic acid (RA) in cell differentiation and cell growth control and the biochemical basis of early embryonic development. We reported here a proteomics approach to study protein expression changes during the differentiation of F9 cells into the visceral endoderm. F9 cells were incubated with or without RA at 0, 24, 48, and 72 h. Total proteins extracted were separated by two-dimensional electrophoresis (2-DE) and the protein patterns on the gels were comparatively analyzed by computer. Approximately 1,100 protein spots were detected in the F9 proteome, within the pH 3-10 range. Fourteen protein spots which the levels of expression were found to be altered dramatically during the F9 cells differentiating, and were identified by MALDI TOF MS or ESI-MS/MS. These proteins included metabolism enzymes, HSP60s, RAN, hnRNP K, FUBP1, VDAC1, STI1, and prohibitin. These proteins are involved in cellar metabolism, gene expression regulation, stress response, and apoptosis, respectively. The data from proteomic analyze are consistent with the result obtained from Western blot analysis. This study increases our understanding of the proteomics changes during F9 cells differentiation induced by RA. PMID- 22492269 TI - Phosphorylation target site specificity for AGC kinases DMPK E and Lats2. AB - Serine/threonine kinases of the AGC group are important regulators of cell growth and motility. To examine the candidate substrate profile for two members of this group, DMPK E and Lats2, we performed in vitro kinase assays on peptide arrays. Substrate peptides for both kinases exhibited a predominance of basic residues surrounding the phosphorylation target site. 3D homology modeling of the kinase domains of DMPK E and Lats2 indicated that presence of two negative pockets in the peptide binding groove provides an explanation for the substrate preference. These findings will aid future research toward signaling functions of Lats2 and DMPK E within cells. PMID- 22492270 TI - HDAC2 overexpression confers oncogenic potential to human lung cancer cells by deregulating expression of apoptosis and cell cycle proteins. AB - Histone deacetylase 2 (HDAC2) is crucial for embryonic development, affects cytokine signaling relevant for immune responses, and is often significantly overexpressed in solid tumors, but little is known of its role in human lung cancer. In this study, we demonstrated the aberrant expression of HDAC2 in lung cancer tissues and investigated oncogenic properties of HDAC2 in human lung cancer cell lines. HDAC2 inactivation resulted in regression of tumor cell growth and activation of cellular apoptosis via p53 and Bax activation and Bcl2 suppression. In cell cycle regulation, HDAC2 inactivation caused induction of p21WAF1/CIP1 expression, and simultaneously suppressed the expressions of cyclin E2, cyclin D1, and CDK2, respectively. Consequently, this led to the hypophosphorylation of pRb protein in G1/S transition and thereby inactivated E2F/DP1 target gene transcriptions of A549 cells. In addition, we demonstrated that HDAC2 directly regulated p21WAF1/CIP1 expression in a p53-independent manner. However, HDAC1 was not related to p21WAF1/CIP1 expression and tumorigenesis of lung cancer. Lastly, we observed that sustained-suppression of HDAC2 in A549 lung cancer cells attenuated in vitro tumorigenic properties and in vivo tumor growth of the mouse xenograft model. Taken together, we suggest that the aberrant regulation of HDAC2 and its epigenetic regulation of gene transcription in apoptosis and cell cycle components play an important role in the development of lung cancer. PMID- 22492273 TI - Total and soluble oxalate content of some Indian spices. AB - Spices, such as cinnamon, cloves, cardamom, garlic, ginger, cumin, coriander and turmeric are used all over the world as flavouring and colouring ingredients in Indian foods. Previous studies have shown that spices contain variable amounts of total oxalates but there are few reports of soluble oxalate contents. In this study, the total, soluble and insoluble oxalate contents of ten different spices commonly used in Indian cuisine were measured. Total oxalate content ranged from 194 (nutmeg) to 4,014 (green cardamom) mg/100 g DM, while the soluble oxalate contents ranged from 41 (nutmeg) to 3,977 (green cardamom) mg/100 g DM. Overall, the percentage of soluble oxalate content of the spices ranged from 4.7 to 99.1% of the total oxalate content which suggests that some spices present no risk to people liable to kidney stone formation, while other spices can supply significant amounts of soluble oxalates and therefore should be used in moderation. PMID- 22492274 TI - Enhancement of folate content and its stability using food grade elicitors in coriander (Coriandrum sativum L.). AB - Folate (vitamin B9) content was evaluated in 10 varieties of coriander with the aim of enhancing its concentration and stability, because of three reasons: 1) coriander is among a few widely used greens in the world and suits many cuisines, 2) folate deficiency is prevalent in developing countries causing anaemia, infant mortality and neural tube closure defects, and 3) natural folate is preferred due to doubts about health risks associated with the synthetic form. In C. sativum, the highest folate content of 1,577 MUg/100 g DW was found in var. GS4 Multicut foliage of mature plants (marketable stage) with an insignificantly higher content (1,599.74 MUg/100 g DW) at flowering, which is a stage not preferred in markets. In callus cultures treated with plant growth regulators (GRs) (6 benzylaminopurine, kinetin and abscisic acid) substantial increase in folate occurred after 6 h, whereas elicitors (methyl jasmonate and salicylic acid) caused rapid 2-fold increase of folate, particularly in response to salicylic acid. Based on these observations, foliar applications were done for in vivo plants, where salicylic acid (250 MUM, 24 h) also enhanced folate level by 2 folds (3,112.33 MUg/100 g DW), although the content varied with diurnal rhythms. Stability of folates in treated coriander foliage was 10 % higher than in untreated foliage when stored at 25 degrees C and 4 degrees C. This study has established for the first time that coriander foliage is rich in folates, which can be doubled by elicitation and impart 10 % more stability than control during processing and storage. PMID- 22492275 TI - Portal vein infusion chemotherapy with gemcitabine after surgery for pancreatic cancer. AB - PURPOSES: Pancreatic cancer still has a poor prognosis even after curative resection because of the high incidence of postoperative liver metastasis. This study prospectively evaluated the feasibility and tolerability of portal vein infusion chemotherapy of gemcitabine (PVIG) as an adjuvant setting after pancreatic resection. METHODS: Thirteen patients enrolled in this study received postoperative chemotherapy with PVIG. The patients received intermittent administration of gemcitabine (800 mg/m(2)) via the portal vein on days 1, 8, and 15 after surgery. The tolerability and the toxicity of PVIG were closely monitored. RESULTS: The PVIG was started on an average of 3.1 days after surgery. Complete doses of chemotherapy (three sessions of portal infusion) were accomplished in 11 of the 13 patients. Grade 3 or 4 leukocytopenia was observed in three patients (23 %), and liver dysfunction was found in one patient (7.7 %). Grade 2 sepsis developed in two cases due to bloodstream infection. Liver metastasis was the first site of recurrence in only two patients. CONCLUSIONS: PVIG can be administered to the liver with acceptable toxicity, but myelosuppression is similar to the systemic use of gemcitabine. Careful observation is required even for locoregional chemotherapy. PMID- 22492276 TI - Anti-biofilm dentin primer with quaternary ammonium and silver nanoparticles. AB - Antibacterial bonding agents could combat recurrent caries at the tooth-composite margins. The objectives of this study were to develop novel antibacterial dentin primers containing quaternary ammonium dimethacrylate (QADM) and nanoparticles of silver (NAg), and to investigate the effects on dentin bond strength and dental plaque microcosm biofilms for the first time. Scotchbond Multi-Purpose ("SBMP") bonding agent was used. QADM and NAg were incorporated into SBMP primer, yielding 4 primers: SBMP primer (control), control + 10% QADM (mass), control + 0.05% NAg, and control + 10% QADM + 0.05% NAg. Human saliva was collected to grow microcosm biofilms. The NAg particle size (mean +/- SD; n = 100) was 2.7 +/- 0.6 nm. Dentin shear bond strengths (n = 10) with human third molars were approximately 30 MPa for all groups (p > 0.1). QADM-NAg-containing primer increased the bacteria inhibition zone by 9-fold, compared with control primer (p < 0.05). QADM-NAg containing primer reduced lactic acid production and colony-forming units of total micro-organisms, total streptococci, and mutans streptococci by an order of magnitude. In conclusion, novel QADM-NAg-containing primers were strongly antibacterial without compromising dentin bond strength, and hence are promising to inhibit biofilms and secondary caries. The processing method of incorporating QADM and NAg together into the same primer produced the strongest antibacterial effect, which could have a wide applicability to other bonding systems. PMID- 22492277 TI - Cognitive behavioral therapy for orthodontic pain control: a randomized trial. AB - The objective of this study was to evaluate the efficacy of cognitive behavioral therapy intervention for patients who experienced pain during orthodontic treatment. The baseline characteristics were assessed via questionnaires and oral examinations. Four hundred and fifty eligible individuals were recruited and randomized by computer-generated block randomization into three groups: cognitive behavioral therapy intervention (n = 150), ibuprofen intervention (n = 150), and no intervention (control; n = 150). Primary outcomes were the change from baseline in pain intensity measured with 100-mm Visual Analog Scale (VAS) scores at 1, 2, 3, 7, 14, and 30 days after initial archwire placement. Outcomes assessment was blinded and followed the intention-to-treat principle. One hundred forty-three (95.30%), 145 (96.70%), and 141 (94.00%) individuals in the cognitive behavioral therapy, the ibuprofen, and the control groups, respectively, completed the one-month follow-up evaluations. Those in the cognitive behavioral therapy group showed a greater decrease in mean VAS scores than did those in the control group over the previous five time-points (p < 0.001). Cognitive behavioral therapy was shown to be effective in pain control during the initial stage of orthodontic treatment. The study registration number was ChiCTR-TRC 00000556. PMID- 22492278 TI - Expression of Spy1 protein in human non-Hodgkin's lymphomas is correlated with phosphorylation of p27 Kip1 on Thr187 and cell proliferation. AB - Aberrations in cell cycle control are often observed in tumors and might even be necessary in tumor development. Spy1, a novel cell cycle regulatory protein, can control cell progression and survival through the atypical activation of cyclin dependent kinases (CDKs). In this progression, the phosphorylation of p27(Kip1) at Thr187 by CDK2 was shown to be a chief role. In this study, we studied 183 human specimens including reactive lymphoid and Non-Hodgkin's Lymphomas (NHLs) tissues. Immunohistochemistry (IHC) analysis suggested that Spy1 and pThr187-p27 were overexpressed in NHLs. The expression of Spy1 was positively related to pThr187-p27 and proliferation marker Ki-67 expression. In a multivariate analysis, high Spy1 and pThr187-p27 expressions were showed to be associated with poor prognosis in NHLs. While in vitro, following release of Jurkat cells from serum starvation, the expression of Spy1 was upregulated, as well as pThr187-p27 and CDK2. And an increased interaction between Spy1 and pThr187-p27 was demonstrated at 4 h after serum stimulation. Additionally, transfecting cells with Spy1-siRNA could diminish the expression of pThr187-p27 and arrest cell growth. Our results suggest that Spy1 may be a possible prognostic indicator in NHLs, and it was correlated with phosphorylation of p27(Kip1) on Thr187. These findings provide a rational framework for further development of Spy1 inhibitors as a novel class of anti-tumor agents. PMID- 22492279 TI - Clinical significance of miR-22 expression in patients with colorectal cancer. AB - MicroRNAs (miRNAs) are non-coding RNAs that have been shown to be aberrantly expressed in several tumor types. Of these miRNAs, miR-22 as tumor suppressor has been shown to play a crucial role in human carcinogenesis. However, its association with the clinicopathological features of colorectal cancer has yet to be addressed. In this study, we compared the expression of miR-22 between colorectal cancer tissues and the normal adjacent mucosa using a quantitative real-time RT-PCR. The association of miR-22 expression with clinicopathological characters was analyzed by appropriate statistical analysis. Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the associations of miR-22 expression with survival of patients. Results showed that the relative expression levels of miR-22 were significantly lower in colorectal cancer tissues than those in the normal adjacent mucosa, and low expression of miR-22 correlated with liver metastasis. Kaplan-Meier analysis indicated that patients with reduced miR-22 had a poor overall survival. Moreover, the multivariate analysis showed that reduced expression of miR-22 was an independent predictor of overall survival. Our data indicate the potential of miR-22 as a novel prognostic biomarker for CRC. PMID- 22492280 TI - Downregulation of GRIM-19 is associated with hyperactivation of p-STAT3 in hepatocellular carcinoma. AB - Accumulating evidence has implicated that constitutive activation of signal transducer and activator of transcription protein 3 (STAT3) may be a major oncogenic factor involved in hepatocellular carcinoma (HCC) development. Gene associated with retinoid-interferon-induced mortality-19 (GRIM-19) has been shown to be a tumor suppressor associated with growth control and suppression of STAT3 activity. The downregulation of GRIM-19 expression has been shown in a number of human tumor types, and it has been correlated with hyperactivation of STAT3. However, the role of GRIM-19 in the pathogenesis of HCC has not been evaluated. The aim of our study was to evaluate GRIM-19 expression levels and investigate their correlation with phosphorylated STAT3 (p-STAT3) levels in HCC. GRIM-19 and p-STAT3 expression levels were analyzed in HCC and adjacent nontumorous liver tissues (ANLT) by immunohistochemistry, western blot analysis, and RT-PCR. GRIM 19 protein expression was predominantly located in the cytoplasm with weak staining in the nucleus in ANLT, but only located in the cytoplasm in HCC tissues. HCC samples exhibited low levels of GRIM-19 and moderate to high levels of p-STAT3 expression. In contrast, ANLT was characterized by high levels of GRIM 19 and low levels of p-STAT3 expression. Downregulation of GRIM-19 was closely correlated with increased histological grade in HCC. GRIM-19 expression is closely correlated with histological grading and p-STAT3 in HCC. Thus, the potential role of GRIM-19 in HCC development may be through these correlations. PMID- 22492282 TI - Adiponectin, adiponectin receptors, and epigenetic regulation of adipogenesis. AB - We studied the molecular mechanism of obesity-induced insulin resistance and adipogenesis. Plasma adiponectin and adiponectin receptor (AdipoR1) in muscle are down-regulated in obesity. Analysis of muscle-specific AdipoR1 knockout mice revealed the pivotal role of adiponectin/AdipoR1 in the regulation of mitochondrial biogenesis via AMPK- and SIRT1-mediated PGC-1alpha activation as well as Ca(2+)-dependent up-regulation of PGC-1alpha expression. Reduced adiponectin/AdipoR1 signals in muscle in obesity appear to cause PGC-1alpha inactivation as well as down-regulation and consequently impaired mitochondrial biogenesis and insulin resistance. In the epigenetic analysis of adipogenesis, we demonstrated that adipocyte-specific formaldehyde-assisted isolation of regulatory elements (FAIRE) peaks are associated with genes up-regulated by adipogenesis, whereas preadipocyte-specific FAIRE peaks are associated with genes down-regulated by adipogenesis. Computational motif analyses of adipocyte specific FAIRE peaks confirmed PPARgamma and CCAAT-enhancer binding proteins (C/EBPs) on the top list, consistent with their crucial roles in adipogenic transcription, and also revealed NFIA and NFIB to be important regulators of proper adipocyte differentiation. PMID- 22492281 TI - Association between vascular-poor area of primary tumors and epidermal growth factor receptor gene status in advanced lung adenocarcinoma. AB - Mutation of the epidermal growth factor receptor gene (EGFR mutation) is a very important marker in the treatment for non-small cell lung cancer. Since signaling from this receptor induces tumor-associated angiogenesis, we hypothesized that lung cancers with EGFR mutations tend to develop locally with increased angiogenesis. Thus, the association between vascular-poor area of primary tumors and EGFR status was retrospectively investigated in advanced lung adenocarcinomas. To assess vascular-poor area, contrast-enhanced computed tomography scans taken before initial treatment for lung cancer were analyzed, together with primary tumor location (peripheral or central) and size. We analyzed 178 patients with advanced lung adenocarcinoma. EGFR mutations were detected in 95 of the 178 patients (53.4 %). EGFR mutation was found to be significantly related to women (P = 0.0070), never-smokers (P < 0.0001), and tumors without vascular-poor area (P < 0.0001). Based on a multivariate analysis, presence of EGFR mutations was independently associated with never-smokers (P = 0.0046), lack of vascular-poor area (P = 0.0001), and tumor size >30 mm (P = 0.0080). EGFR mutations were found in 41 of 51 never-smokers without vascular poor area (80.4 %), 19 of 36 never-smokers with vascular-poor area (52.8 %), 19 of 37 current or former-smokers without vascular-poor area (51.4 %), and 16 of 54 current or former-smokers with vascular-poor area (29.6 %). This study showed an association between vascular-poor area of primary tumors and EGFR status. As a consequence, evaluation using a combination of smoking status and vascular-poor area allows us to predict presence of EGFR mutations at a high frequency. PMID- 22492283 TI - The transient receptor potential vanilloid-2 cation channel impairs glioblastoma stem-like cell proliferation and promotes differentiation. AB - Malignant transformation of cells resulting from enhanced proliferation and aberrant differentiation is often accompanied by changes in transient receptor potential vanilloid (TRPV) channels expression. In gliomas, recent evidence indicates that TRPV type 2 (TRPV2) negatively controls glioma cell survival and proliferation. In addition, cannabinoids, the ligands of both cannabinoid and TRPV2 receptors, promote glioblastoma stem-like cells (GSCs) differentiation and inhibit gliomagenesis. Herein, we provide evidence on the expression of TRPV2 in human GSCs and that GSCs differentiation reduces nestin and progressively increases both the glial fibrillary acidic protein (GFAP) and TRPV2 expression. Therefore, we evaluated the role of TRPV2 cation channel in GSC lines differentiation. Treatment of GSC lines with the TRPV antagonist Ruthenium Red, with ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid or knockdown of TRPV2 gene during differentiation, decreases GFAP and class III beta tubulin (beta(III)-tubulin) expression; conversely, phorbol-12-myristate-13 acetate stimulates GSCs proliferation, reduces TRPV2 expression and partially reverts astroglial differentiation. In addition, forced TRPV2 expression in GSC lines by stable TRPV2 transfection increases GFAP and beta(III)-tubulin expression and parallelly reduces proliferation. Finally, TRPV2 overexpression inhibits GSCs proliferation in a xenograft mouse model, as shown by reduced tumor diameter and mitotic index, and promotes the differentiation of GSCs toward a more mature glial phenotype. Overall, our results demonstrate that TRPV2 promotes in vitro and in vivo GSCs differentiation and inhibits their proliferation. Better understanding of the molecular mechanisms that regulate the balance between proliferation and differentiation of GSCs would lead to more specific and efficacious pharmacological approaches. PMID- 22492284 TI - Aggregatibacter actinomycetemcomitans lipopolysaccharide regulates bone sialoprotein gene transcription. AB - Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) is believed to be associated with aggressive periodontitis characterized by a rapid bone loss. A. actinomycetemcomitans lipopolysaccharide (LPS) has a similar structure to Escherichia coli LPS, and they are Toll-like receptor 4 agonists. Bone sialoprotein (BSP) is an early marker of osteoblast differentiation. To investigate the effects of A. actinomycetemcomitans LPS on bone formation, we targeted BSP as a marker for osteogenic differentiation and bone formation. BSP mRNA levels were decreased by 0.1 ug/ml and increased by 0.01 ug/ml A. actinomycetemcomitans LPS at 6 h in osteoblast-like ROS17/2.8 cells. In transient transfection analyses, 0.1 ug/ml decreased and 0.01 ug/ml A. actinomycetemcomitans LPS increased luciferase activities of the construct (-116 to +60). Introduction of 2 bp mutations to the constructs showed that the effects of A. actinomycetemcomitans LPS were mediated by a cAMP response element (CRE), a FGF2 response element (FRE), and a homeodomain protein-binding site (HOX). Tyrosine kinase, ERK1/2, and PI3-kinase/Akt participated in the effects of both 0.1 and 0.01 ug/ml A. actinomycetemcomitans LPS. The results of gel shift showed that 0.1 ug/ml decreased while 0.01 ug/ml A. actinomycetemcomitans LPS increased CRE-, FRE-, and HOX-binding protein complexes formation at 6 h, and revealed that 0.01 ug/ml A. actinomycetemcomitans LPS induced BSP transcription through CREB1, JunD, Fra2, c-Fos, Runx2, Dlx5, and Smad1 targeting those response elements. These studies therefore indicated that 0.1 ug/ml suppressed and 0.01 ug/ml A. actinomycetemcomitans LPS increased BSP gene transcription mediated through CRE, FRE, and HOX elements in the rat BSP gene promoter. PMID- 22492285 TI - Time trend analysis of return to work after stroke in Denmark 1996-2006. AB - BACKGROUND: In the period 1997-2005, the Danish government initiated a series of legislative changes aimed at facilitating RTW (return to work) in the Danish population. In the present study, we investigated the odds of being gainfully occupied ca. two years after stroke as a function of onset calendar year, 1996 2006. METHODS: All previously employed 20-57 year-old stroke patients in Denmark 1996-2006 (N = 19985) were followed prospectively through national registers. The analysis was controlled for the type of stroke and a series of demographic, structural and occupational variables. RESULTS: The odds for RTW increased significantly during the study period (P < 0.0001). The odds at the end of the period were more than twice as high as they were at the beginning, even after post hoc control for improved survival and decreased unemployment rates. The most conspicuous increase coincided with a change in the sickness benefit act that took place in 2005. CONCLUSION: The study provides quite strong circumstantial evidence that the legislative changes had an effect on the odds of return to work after stroke. More direct evidence is desirable, but such can only be obtained through a randomized controlled study. PMID- 22492286 TI - Contact blepharoconjunctivitis due to black henna--a case report. AB - Para-phenylenediamine (PPD) can induce immediate or - more often - delayed hypersensitivity. We report the case of 48-year old female admitted to the out patient allergy clinic a day after her visit in a beauty parlour, where she had her eyelashes and eyebrows dyed with henna. Physical examination revealed prominent edema of the upper part of the face including forehead, cheeks and eyes causing severe narrowing of the palpebral chink. Skin prick tests (SPT) with common allergens were positive for Dermatophagoides pteronyssinus, Dermatophagoides farinae and moulds, while the SPT with PPD was negative. Patch test to PPD was positive. Further investigations revealed eosinophilia in the tear fluid. To our knowledge, this is the first case of PPD-induced contact blepharoconjunctivitis (CB) with concomitant increased eosinophilia in the tear fluid. PMID- 22492287 TI - Relationship between person-organization fit and objective and subjective health status (person-organization fit and health). AB - OBJECTIVE: [corrected] Person-Environment fit (P-E fit) paradigm, seems to be especially useful in explaining phenomena related to work attitudes and occupational health. The study explores the relationship between a specific facet of P-E fit as Person-Organization fit (P-O fit) and health. MATERIALS AND METHODS: Research was conducted on the random sample of 600 employees. Person Organization Fit Questionnaire was used to asses the level of Person-Organization fit; mental health status was measured by General Health Questionnaire (GHQ-28); and items from Work Ability Index allowed for evaluation of somatic health. Data was analyzed using non parametric statistical tests. The predictive value of P-O fit for various aspects of health was checked by means of linear regression models. RESULTS: A comparison between the groups distinguished on the basis of their somatic and mental health indicators showed significant differences in the level of overall P-O fit (chi(2) = 23.178; p < 0.001) and its subdimensions: for complementary fit (chi(2) = 29.272; p < 0.001), supplementary fit (chi(2) = 23.059; p < 0.001), and identification with organization (chi(2) = 8.688; p = 0.034). From the perspective of mental health, supplementary P-O fit seems to be important for men's well-being and explains almost 9% of variance in GHQ-28 scores, while in women, complementary fit (5% explained variance in women's GHQ score) and identification with organization (1% explained variance in GHQ score) are significant predictors of mental well-being. Interestingly, better supplementary and complementary fit are related to better mental health, but stronger identification with organization in women produces adverse effect on their mental health. CONCLUSIONS: The results show that obtaining the optimal level of P-O fit can be beneficial not only for the organization (e.g. lower turnover, better work effectiveness and commitment), but also for the employees themselves. Optimal level of P-O fit can be considered as a factor maintaining workers' health. However, prospective research is needed to confirm the results obtained in this exploratory study. PMID- 22492288 TI - The different faces of Janus kinase inhibition. PMID- 22492289 TI - Raising hematology's European voice: the importance of calling yourself a hematologist. PMID- 22492290 TI - Conceiving a hematopoietic stem cell donor: twenty-five years after our decision to save a child. PMID- 22492291 TI - Low frequency of type-I and type-II aberrations in myeloid leukemia of Down syndrome, underscoring the unique entity of this disease. PMID- 22492293 TI - MonoMAC versus idiopathic CD4+ lymphocytopenia. Comment to Haematologica. 2011;96(8):1221-5. PMID- 22492294 TI - Reliability and validity of the Cystic Fibrosis Questionnaire-Revised for children and parents in Turkey: cross-sectional study. AB - PURPOSE: The purpose of study was to translate Cystic Fibrosis Questionnaire Revised (CFQ-R) into Turkish for children with cystic fibrosis (CF) and evaluate its reliability and validity. This is the first CF-specific health-related quality of life (HRQOL) measure validated in a Muslim country. METHODS: Fifty-one children aged 6-13 years treated at four centers in Turkey and 30 parents participated in this cross-sectional study. Demographic characteristics and disease severity parameters were recorded for all participants. All participants completed the parent or child versions of CFQ-R and KINDL questionnaires at enrollment. Reliability and construct validity analysis were carried out. RESULTS: Both children and parents endorsed a range of responses, with no evidence of floor or ceiling effects. Item-to-total correlations indicated that most items were more highly correlated with their intended scale than competing scales. Good internal consistency was found for majority of child and parent scales. CFQ-R scales correlated significantly with clinical indices of disease severity. Good evidence of convergent validity with a generic HRQOL scale was found. CONCLUSION: Turkish versions of CFQ-R Child and Parent instruments have demonstrated adequate reliability and validity and can be utilized in clinical trials or integrated into clinical evaluation and follow-up of Turkish children with CF. PMID- 22492295 TI - Cerebral arteriovenous malformations and seizures: differential impact on the time to seizure-free state according to the treatment modalities. AB - BACKGROUND: To determine the prognostic factors for the incidence and the outcome of seizure in patients with cerebral arteriovenous malformation (AVM) and to identify the time to seizure-free state according to the treatment modalities. MATERIAL AND METHODS: Between 1995 and 2008, the multidisciplinary team at our institution treated 399 patients with cerebral AVMs. Treatment consisted of surgical resection, radiosurgery, and embolization, either alone or in combination. The median follow-up period was 6.0 years (range, 3.0-16.2 years). Eighty-six patients (21.5 %) experienced seizures before treatment. We investigated the variables associated with seizure incidence and seizure outcome and analyzed the outcomes of seizure among each treatment modality. RESULTS: After treatment, 60 (70 %) patients were seizure-free. Compared with 313 patients who did not experience seizures, we found that younger age (<= 35 years), size >= 3 cm, and location of temporal lobe were associated with seizures (p < 0.05). Short seizure history, accompanying intracerebral hemorrhage, generalized tonic clonic type seizure, deep-seated or infratentorial AVM, complete obliteration of AVM, and a favorable neurological outcome at 12 months were closely associated with Engel Class I outcomes (p < 0.05). Seizure-free outcomes after microsurgery, radiosurgery, or embolization were 78 %, 66 %, and 50 %, respectively. The overall annual bleeding rate was 1.0 % and 2.2 % in microsurgery-treated and radiosurgery-treated AVMs, respectively. In the surgery group, the median time to seizure-free status was 1.1 months (95 % CI, 0.7-1.2 months), whereas the radiosurgery group and embolization-alone group showed 20.5 months (95 % CI, 18.3 23.8 months), and 8.1 months (95 % CI, 6.0-13.5 months), respectively. CONCLUSIONS: A multidisciplinary team approach for cerebral AVMs achieved satisfactory seizure control results. Microsurgery led to the highest percentage of seizure-free outcomes and had the lowest annual bleeding rate, whereas radiosurgery had a higher bleeding rate. Median time to seizure-free status in surgically treated patients was shorter than in patients who underwent radiosurgical or endovascular treatment. PMID- 22492296 TI - Emil Theodor Kocher: the first Swiss neurosurgeon. AB - BACKGROUND: Emil Theodor Kocher (1841-1917) was elected as head of the university clinic for surgery in Berne, Switzerland at the age of 31 years. During the 45 years of his professorship he became one of the outstanding surgeons of Europe by using surgical techniques based predominately on physiological and biological ideas. The aim of this article was to highlight his neurosurgical achievements published in the German language. METHODS: The illustrations of Kocher's works in the field of neurosurgery are exclusively based on his publications and works published by his co-workers. RESULTS: Kocher received the Nobel Prize in Physiology or Medicine in 1909 because he devoted himself to intense research and development in the pathophysiology and surgical treatment of diseases of the thyroid gland. His particular neurosurgical interests were in cerebral and spinal trauma, operative treatment of epilepsy and the pathophysiology of elevated intracranial pressure. CONCLUSION: Studies of Kocher's contributions, published exclusively in the German language, lead to the conclusion that Kocher must be designated as the first Swiss neurosurgeon. PMID- 22492297 TI - Minimizing morbidity in endoscopic pituitary surgery: outcomes of the novel nasoseptal rescue flap technique. AB - OBJECTIVE: The novel nasoseptal rescue flap has been proven to provide complete coverage of dural defects that may be encountered during endoscopic pituitary surgery through cadaveric studies. In this case series, the authors report outcomes from the first cohort of patients who had a nasoseptal rescue flap raised prior to surgery. STUDY DESIGN: Case series with chart review. SETTING: University of North Carolina-Chapel Hill. SUBJECTS AND METHODS: Patients requiring nasoseptal rescue flaps were identified from the senior author's database. RESULTS: Nasoseptal rescue flaps were harvested in 26 consecutive patients, with only 7 (27%) patients actually requiring use of the rescue flap for skull base reconstruction due to intraoperative cerebrospinal fluid (CSF) leak. Six patients had low-flow CSF leaks, whereas 1 patient had a high-flow CSF leak. Nineteen patients had pituitary adenomas, whereas 7 patients had Rathke cleft cyst. Mean follow-up time was 6 months (range, 1-16 months). Since surgery, no patients have presented with CSF leak or septal perforation. The success rate in those 7 patients with rescue flap utilization was 100%. CONCLUSION: The nasoseptal rescue flap is an effective surgical technique for patients undergoing pituitary surgery without a planned nasoseptal flap. It allows for vascularized skull base reconstruction if an intraoperative CSF leak is encountered and minimizes donor site morbidity if a leak is not encountered. PMID- 22492298 TI - A chitosan-based sinus sealant for reduction of adhesion formation in rabbit and sheep models. AB - OBJECTIVE: Chronic sinusitis is the most prevalent chronic disease in the United States in adults aged 18 to 44 years, with approximately 250,000 operations performed annually. Although often successful, sinus surgery fails in greater than 15% of patients. Adhesion formation is a common complication and cause for subsequent revision surgery. Here, the authors evaluate a sprayable chitosan/starch-based sinus sealant and demonstrate its ability to reduce adhesion formation both in vitro and in 2 animal models. STUDY DESIGN: Randomized, controlled, animal trials. SETTING: Academic medical center (fibroblast experiments) and animal laboratories (sheep and rabbit studies). SUBJECTS AND METHODS: This sinus sealant was applied to human cultured fibroblasts obtained from surgically removed polyps to examine its ability to inhibit fibroblast migration and proliferation. The sinus sealant was applied to New Zealand White rabbits (n = 20) in an established cecal-sidewall abrasion model and to sheep (n = 10) in a sinus surgical adhesion model to examine its ability to reduce adhesion formation. RESULTS: This sinus sealant inhibited migration and proliferation of human cultured fibroblasts and reduced the total adhesion score from 4.9 to 0.3 for a total reduction of 94% (95th percentile confidence interval [CI], 78%, 100%; P < .001) in a well-established rabbit cecal sidewall model commonly used for adhesion testing. Moreover, this sealant reduced adhesion formation from 80% to 10% for a total reduction of 70% (95th percentile CI, 57%, 93%; P = .003) in a sheep sinus adhesion surgical model. CONCLUSION: This chitosan-based sealant demonstrates promise for reducing adhesion formation in sinus surgery. PMID- 22492299 TI - Histomorphological changes of Tutoplast-processed fascia lata grafts in a rabbit rhinoplasty model. AB - OBJECTIVES: Tutoplast-processed fascia lata (TPFL) is a commercially available homograft that has been successfully used as graft tissue for rhinoplasty. The present study evaluates the histomorphological changes of TPFL in a rabbit rhinoplasty model. STUDY DESIGN: Prospective study using a rabbit model. SETTING: Animal laboratory of the Asan Medical Center. SUBJECTS AND METHODS: The study used 15 New Zealand White rabbits. Each rabbit was implanted with a TPFL (experimental group) and autologous fascia lata (control group) graft of equal size into the nasal dorsum. Rabbits were killed at 1, 3, and 6 months, and the grafts were removed and microscopically assessed for fibroblast proliferation, neovascularization, inflammation, and thickness. RESULTS: For TPFL grafts, the degree of inflammation significantly decreased between 1 and 3 months (P = .041). The degree of fibroblast proliferation continually increased over time. There was a mild degree of neovascularization for the TPFL graft at 1 month. The degree of neovascularization increased between 3 and 6 months (P = .041). For the degree of inflammation, fibroblast proliferation, and neovascularization, there was no significant difference between TPFL and autologous fascia lata at 6 months. Mean thickness analysis showed that there was no significant thickness reduction in both TPFL and autologous fascia lata grafts at 6 months. CONCLUSION: The TPFL grafts showed negligible resorption rates and favorable tissue reactions in the rabbit rhinoplasty model. PMID- 22492300 TI - Long-term engraftment and angiogenic properties of lentivirally transduced adipose tissue-derived stromal cells. AB - Human adipose tissue-derived stromal cells (ADSCs) are being evaluated for cardiovascular repair. We developed an ex vivo method for producing angiogenic ADSCs transduced with a self-inactivating lentiviral vector (LV) expressing the enhanced green fluorescence protein (EGFP) from an internal cytomegalovirus (CMV) promoter to track these cells after in vivo engraftment. ADSCs from visceral adipose tissue were transduced using a LV incorporating the Rous Sarcoma Virus (RSV) long terminal repeat (LTR) sequences and the Woodchuck hepatitis virus post transcriptional regulatory element (WPRE) to enhance EGFP gene expression. We compared infection protocols with non-concentrated lentiviral supernatant or pellet fractions after ultracentrifugation, testing transduction efficiency, and reporter gene expression by quantitative flow cytometry at 5 and 28 days. Transduction of ADSCs with pellet after ultracentrifugation provided the highest transduction rate [flow cytometry titers: 6.5 +/- 0.3 * 10(5) transduction units (TU)/mL and 20 +/- 1.2 * 10(6) TU/mL at day 5 with non-concentrated lentiviral supernatant and pellet, respectively, with titer in the supernatant after ultracentrifugation remaining undetectable]. Reporter gene expression did not affect cell viability, morphology, proliferation, differentiation, self-renewal, or angiogenic activity. Furthermore, reporter gene expression did not significantly affect Fas/CD95-induced apoptosis. The in vivo implantation of transduced ADSCs into a mouse ischemic leg model resulted in efficient engraftment and angiogenesis. ADSC gene labeling using LVs is feasible and efficient, without impairment of stem cell characteristics, cell engraftment, and angiogenic activity. Such transduced ADSCs can be efficiently tracked in vitro and in vivo and may serve as vehicle for therapeutic genes. PMID- 22492301 TI - Lasing from epitaxially oriented needle crystals of a thiophene/phenylene co oligomer. AB - Optically pumped lasing of epitaxially oriented molecular crystals is presented. Needle-like crystals of a thiophene/phenylene co-oligomer is grown along the [110] direction of a KCl substrate. The fluorescence light is one-dimensionally confined and amplified by the self-waveguiding effect in the elongated needles. The Fabry-Perot resonation by the terminated ends results in laser oscillations corresponding to the needle length. PMID- 22492302 TI - Accelerated proliferation and differential global gene expression in pancreatic islets of five-week-old heterozygous Men1 mice: Men1 is a haploinsufficient suppressor. AB - Individuals carrying heterozygous (hz) MEN1 (Multiple Endocrine Neoplasia Syndrome Type 1) germ line mutations develop endocrine tumors as a result of somatic loss of the wild-type (wt) allele. However, endocrine cell proliferation has been observed despite wt allele retention, indicating haploinsufficiency. To study downstream molecular effects of the hz haplotype, a germ line Men1 hz mouse model was used to explore differences in global endocrine pancreatic gene expression. Because islet cells of 5-wk-old hz mice express Menin from the retained wt Men1 allele, these were isolated after collagenase digestion of the pancreas, and used for global gene expression array. Wild-type littermates were used for comparison. Array findings were corroborated by quantitative PCR, Western blotting, in situ proximity ligation assay, and immunohistochemistry. The hz islets show increased proliferation: the Ki-67 index was twice as high as in wt islets (3.48 vs. 1.74%; P = 0.024). The microarray results demonstrated that several genes were differentially expressed. Some selected genes were studied on the protein level, e.g. the cytoskeletal regulator myristoylated alanine-rich protein kinase C substrate (Marcks) was significantly less expressed in hz islets, using in situ proximity ligation assay and Western blotting (P < 0.001 and P < 0.01, respectively). Further, gene ontology analysis showed that genes with higher mRNA expression in the hz endocrine pancreas were associated with e.g. chromatin maintenance and apoptosis. Lower mRNA was observed for genes involved in growth factor binding. In conclusion, despite retained Menin expression, proliferation was accelerated, and numerous genes were differentially expressed in the endocrine pancreas of 5-wk-old hz Men1 mice, corroborating the hypothesis that MEN1 is a haploinsufficient suppressor. PMID- 22492303 TI - Dose-dependent effects of androgens on the circadian timing system and its response to light. AB - The hypothalamic suprachiasmatic nucleus (SCN) is the locus of a master clock that regulates circadian rhythms in physiology and behavior. Gonadectomy in male mice lengthens the period of circadian rhythms and increases the day-to-day variability of activity onset time. Both of these responses are rescued by the nonaromatizable androgen dihydrotestosterone. Androgen receptors (AR) are localized in SCN neurons that receive direct retinal input. To explore how androgens affect circadian clock function and its responsiveness to photic cues, we measured wheel-running behavior and SCN AR expression in intact, gonadectomized, and testosterone-replaced mice, held under various photic conditions. Gonadectomy lengthened circadian period in constant dim light but not in constant darkness. Increasing intensities of constant light parametrically increased circadian period, and this was potentiated at all intensities by gonadectomy. In contrast, gonadectomy did not alter light-induced pupil constriction, suggesting a nonretinal locus of hormone action. In hormone replaced animals housed in constant darkness, T concentration was positively correlated with precision of activity onset and with SCN AR expression and negatively correlated with duration of activity. We infer the existence of two androgenic mechanisms: one modulates SCN responsiveness to light, and the second modulates SCN timekeeping and locomotor activity in a dose-dependent manner. Finally, the effects of androgens on period are a result of hormonal modulation of the SCN's response to photic input rather than to a change in the inherent period of oscillators in the absence of light. PMID- 22492305 TI - Interleukin-1beta promotes proliferation and inhibits differentiation of chondrocytes through a mechanism involving down-regulation of FGFR-3 and p21. AB - The proinflammatory cytokine IL-1beta is elevated in many childhood chronic inflammatory diseases as well as obesity and can be associated with growth retardation. Here we show that IL-1beta affects bone growth by directly disturbing the normal sequence of events in the growth plate, resulting in increased proliferation and widening of the proliferative zone, whereas the hypertrophic zone becomes disorganized, with impaired matrix structure and increased apoptosis and osteoclast activity. This was also evident in vitro: IL 1beta increased proliferation and caused a G1-to-S phase shift in the cell cycle in ATDC5 chondrocytes, accompanied by a reduction in fibroblast growth factor receptor-3 (FGFR-3) and its downstream gene, the cell-cycle inhibitor p21 and its family member p57, whereas the cell-cycle promoter E2F-2 was increased. The reduction in FGFR-3, p21, and p57 was followed by delayed cell differentiation, manifested by decreases in proteoglycan synthesis, mineralization, alkaline phosphatase activity, and the expression of Sox9, RunX2, collagen type II, collagen type X, and other matrix proteins. Taken together, we suggest that IL 1beta alters normal chondrogenesis and bone growth through a mechanism involving down-regulation of FGFR-3 and p21. PMID- 22492304 TI - A lack of ovarian function increases neuroinflammation in aged mice. AB - Although several lines of evidence have indicated that menopause is associated with increased susceptibility to neurological disorders, the mechanisms involved in this phenomenon remain to be elucidated. Because neuroinflammation is a common feature of a number of brain diseases, we hypothesized that the cessation of ovarian functions and the consequent decrease in estrogen receptor (ER)-mediated antiinflammatory activity may represent a trigger for postmenopausal brain dysfunctions. The aim of the present study was to investigate the effects of aging and surgical menopause on the activity of ER in neuroinflammation. The present study shows that ER genes are expressed in the hippocampus, but ER transcriptional activity decreases significantly beginning at 12 months of age in intact and ovariectomized mice. With ovariectomy, we observe an age-dependent accumulation of mRNA encoding inflammatory mediators (e.g. TNFalpha, IL1beta, and macrophage inflammatory protein-2) and changes in the morphology of astroglia and microglia. In addition, we show that aging itself is coupled with an exaggerated response to acute inflammatory stimuli with a major accumulation of TNFalpha, IL1beta, macrophage inflammatory protein-2, and macrophage chemoattractant protein-1 mRNA in response to lipopolysaccharide administration. The response to acute inflammatory stimuli appears to be differentially modulated by the duration of hormone deprivation in 12-month-old mice. Taken together, the present results show that aging is associated with decreased ER activity, despite continuous ER synthesis, and that age-dependent neuroinflammation is strongly influenced by hormone deprivation. PMID- 22492306 TI - Involvement of doublecortin-expressing cells in the arcuate nucleus in body weight regulation. AB - Hypothalamic functions, including feeding behavior, show a high degree of plasticity throughout life. Doublecortin (DCX) is a marker of plasticity and neuronal migration expressed in the hypothalamus. Therefore, we wanted to map the fate of DCX(+) cells in the arcuate nucleus (ARC) of the hypothalamus. For this purpose, we generated a BAC transgenic mouse line that expresses the inducible recombinase CreER(T2) under control of the DCX locus. Crossing this line with the Rosa26 or Ai14 reporter mouse lines, we found reporter(+) cells in the ARC upon tamoxifen treatment. They were born prenatally and expressed both DCX and the plasticity marker TUC-4. Immediately after labeling, reporter(+) cells had an enlarged soma that normalized over time, suggesting morphological remodeling. Reporter(+) cells expressed beta-endorphin and BSX, neuronal markers of the feeding circuit. Furthermore, leptin treatment led to phosphorylation of STAT3 in reporter(+) cells in accordance with the concept that they are part of the feeding circuits. Indeed, we found a negative correlation between the number of reporter(+) cells and body weight and epididymal fat pads. Our data suggest that DCX(+) cells in the ARC represent a cellular correlate of plasticity that is involved in controlling energy balance in adult mice. PMID- 22492307 TI - A half-truth is a whole lie: on the necessity of investigating sex influences on the brain. AB - Sex influences are proving to be extremely widespread on brain function, including the human brain. Ample evidence now proves that the sex of subjects can influence, ever reverse, findings, hence conclusions, at all levels of brain science, down to the molecular level, often in completely unanticipated ways. Thus the still-prominent assumption that sex influences may be safely ignored by neurobiologists is invalid and must be abandoned. The failure to properly consider the issue fills the literature with conclusions tenuous at best, false at worst. The continuing, widespread resistance to investigating sex influences among brain scientists, a resistance largely rooted in deeply entrenched biases against the topic, is becoming increasingly scientifically indefensible and strongly retards progress in our field. PMID- 22492308 TI - Minireview: CRF and Wylie Vale: a story of 41 amino acids and a Texan with grit. PMID- 22492309 TI - Sulfuretin from heartwood of Rhus verniciflua triggers apoptosis through activation of Fas, Caspase-8, and the mitochondrial death pathway in HL-60 human leukemia cells. AB - Sulfuretin, a flavonoid isolated from heartwood of Rhus verniciflua, has been reported to have anti-cancer activities but the underlying molecular mechanism was not clear. In this study, sulfuretin induced apoptosis by activating caspases 8, -9, and -3 as well as cleavage of poly(ADP-ribose) polymerase. Furthermore, treatment with sulfuretin caused mitochondrial dysfunctions, including the loss of mitochondrial membrane potential (DeltaPsi(m)), the release of cytochrome c to the cytosol, and the translocations of Bax and tBid. Sulfuretin also activated the extrinsic apoptosis pathway, that is, it increased the expressions of Fas and FasL, the activation of caspase-8, and the cleavage of Bid. Furthermore, blocking the FasL-Fas interaction with NOK-1 monoclonal antibody prevented the sulfuretin induced apoptosis. The therapeutical effect of sulfuretin in leukemia is due to its potent apoptotic activity through the extrinsic pathway driven by a Fas mediated caspase-8-dependent pathway. PMID- 22492310 TI - Adherence to treatment guidelines and survival in patients with early-stage breast cancer by age at diagnosis. AB - BACKGROUND: Elderly patients with breast cancer are under-represented in clinical studies. It is not known whether treatment guidelines, based on clinical trials, can be extrapolated to this population. The aim of this study was to assess adherence to treatment guidelines by age at diagnosis, and to examine age specific survival in relation to adherence to guidelines. METHODS: Patients with early-stage breast cancer aged either less than 65 years, or 75 years or more, diagnosed between 2005 and 2008, were identified from the Netherlands Cancer Registry. Adherence to treatment guidelines for breast and axillary surgery, radiotherapy, chemotherapy and endocrine therapy was determined. Non-adherence to the guidelines was defined as overtreatment or undertreatment. The primary endpoint was overall survival, assessed by means of an instrumental variable, the comprehensive cancer centre region. RESULTS: Some 24 959 patients younger than 65 years and 6561 patients aged 75 years or more were included in the analysis. Median follow-up was 2.8 years. Compared with patients younger than 65 years, those aged at least 75 years were less frequently treated in concordance with guidelines: 62.0 per cent (15 487 patients) versus 55.6 per cent (3647 patients) (P < 0.001). In both age groups, most patients received at least three of five treatment modalities in concordance with guidelines: 98.8 per cent (24 652 patients) and 93.8 per cent (6152 patients) respectively. Analysis of survival using the instrumental variable showed that adherence to guidelines was not associated with overall survival in patients younger than 65 years (P = 0.601) or those aged at least 75 years (P = 0.190). CONCLUSION: Adherence to treatment guidelines was affected by age at diagnosis. However, adherence to the guidelines was not associated with overall survival in either age group. PMID- 22492311 TI - Rknots: topological analysis of knotted biopolymers with R. AB - MOTIVATION: Rknots is a flexible R package providing tools for the detection and characterization of topological knots in biological polymers. The package is well documented and provides a simple syntax for data import and preprocessing, structure reduction, topological analyses and 2D and 3D visualization. Remarkably, Rknots is not limited to protein knots and allows researchers from interdisciplinary fields to analyze different topological structures and to develop simple yet fully custom pipelines. PMID- 22492312 TI - LOESS correction for length variation in gene set-based genomic sequence analysis. AB - MOTIVATION: Sequence analysis algorithms are often applied to sets of DNA, RNA or protein sequences to identify common or distinguishing features. Controlling for sequence length variation is critical to properly score sequence features and identify true biological signals rather than length-dependent artifacts. RESULTS: Several cis-regulatory module discovery algorithms exhibit a substantial dependence between DNA sequence score and sequence length. Our newly developed LOESS method is flexible in capturing diverse score-length relationships and is more effective in correcting DNA sequence scores for length-dependent artifacts, compared with four other approaches. Application of this method to genes co expressed during Drosophila melanogaster embryonic mesoderm development or neural development scored by the Lever motif analysis algorithm resulted in successful recovery of their biologically validated cis-regulatory codes. The LOESS length correction method is broadly applicable, and may be useful not only for more accurate inference of cis-regulatory codes, but also for detection of other types of patterns in biological sequences. AVAILABILITY: Source code and compiled code are available from http://thebrain.bwh.harvard.edu/LM_LOESS/ PMID- 22492313 TI - Approximate probabilistic analysis of biopathway dynamics. AB - MOTIVATION: Biopathways are often modeled as systems of ordinary differential equations (ODEs). Such systems will usually have many unknown parameters and hence will be difficult to calibrate. Since the data available for calibration will have limited precision, an approximate representation of the ODEs dynamics should suffice. One must, however, be able to efficiently construct such approximations for large models and perform model calibration and subsequent analysis. RESULTS: We present a graphical processing unit (GPU) based scheme by which a system of ODEs is approximated as a dynamic Bayesian network (DBN). We then construct a model checking procedure for DBNs based on a simple probabilistic linear time temporal logic. The GPU implementation considerably extends the reach of our previous PC-cluster-based implementation (Liu et al., 2011b). Further, the key components of our algorithm can serve as the GPU kernel for other Monte Carlo simulations-based analysis of biopathway dynamics. Similarly, our model checking framework is a generic one and can be applied in other systems biology settings. We have tested our methods on three ODE models of bio-pathways: the epidermal growth factor-nerve growth factor pathway, the segmentation clock network and the MLC-phosphorylation pathway models. The GPU implementation shows significant gains in performance and scalability whereas the model checking framework turns out to be convenient and efficient for specifying and verifying interesting pathways properties. AVAILABILITY: The source code is freely available at http://www.comp.nus.edu.sg/~rpsysbio/pada-gpu/ PMID- 22492314 TI - Eoulsan: a cloud computing-based framework facilitating high throughput sequencing analyses. AB - We developed a modular and scalable framework called Eoulsan, based on the Hadoop implementation of the MapReduce algorithm dedicated to high-throughput sequencing data analysis. Eoulsan allows users to easily set up a cloud computing cluster and automate the analysis of several samples at once using various software solutions available. Our tests with Amazon Web Services demonstrated that the computation cost is linear with the number of instances booked as is the running time with the increasing amounts of data. AVAILABILITY AND IMPLEMENTATION: Eoulsan is implemented in Java, supported on Linux systems and distributed under the LGPL License at: http://transcriptome.ens.fr/eoulsan/ PMID- 22492315 TI - Rigorous assessment of gene set enrichment tests. AB - MOTIVATION: Several statistical tests are available to detect the enrichment of differential expression in gene sets. Such tests were originally proposed for analyzing gene sets associated with biological processes. The objective evaluation of tests on real measurements has not been possible as it is difficult to decide a priori, which processes will be affected in given experiments. RESULTS: We present a first large study to rigorously assess and compare the performance of gene set enrichment tests on real expression measurements. Gene sets are defined based on the targets of given regulators such as transcription factors (TFs) and microRNAs (miRNAs). In contrast to processes, TFs and miRNAs are amenable to direct perturbations, e.g. regulator over-expression or deletion. We assess the ability of 14 different statistical tests to predict the perturbations from expression measurements in Escherichia coli, Saccharomyces cerevisiae and human. We also analyze how performance depends on the quality and comprehensiveness of the regulator targets via a permutation approach. We find that ANOVA and Wilcoxons test consistently perform better than for instance Kolmogorov-Smirnov and hypergeometric tests. For scenarios where the optimal test is not known, we suggest to combine all evaluated tests into an unweighted consensus, which also performs well in our assessment. Our results provide a guide for the selection of existing tests as well as a basis for the development and assessment of novel tests. PMID- 22492316 TI - Genetically engineered oncolytic adenovirus induces autophagic cell death through an E2F1-microRNA-7-epidermal growth factor receptor axis. AB - Autophagy is known to have a cytoprotective role under various cellular stresses; however, it also results in robust cell death as an important safeguard mechanism that protects the organism against invading pathogens and unwanted cancer cells. Autophagy is regulated by cell signalling including microRNA (miRNA), a post transcriptional regulator of gene expression. Here, we show that genetically engineered telomerase-specific oncolytic adenovirus induced miR-7 expression, which is significantly associated with its cytopathic activity in human cancer cells. Virus-mediated miR-7 upregulation depended on enhanced expression of the E2F1 protein. Ectopic expression of miR-7 suppressed cell viability and induced autophagy by inhibiting epidermal growth factor receptor (EGFR) expression. Our results suggest that oncolytic adenovirus induces autophagic cell death through an E2F1-miR-7-EGFR pathway in human cancer cells, providing a novel insight into the molecular mechanism of an anticancer virotherapy. PMID- 22492319 TI - Photo quiz. Lip lesion in a solid organ transplant recipient. PMID- 22492318 TI - "Silent" dissemination of Klebsiella pneumoniae isolates bearing K. pneumoniae carbapenemase in a long-term care facility for children and young adults in Northeast Ohio. AB - BACKGROUND: Klebsiella pneumoniae isolates harboring the K. pneumoniae carbapenemase gene (bla(KPC)) are creating a significant healthcare threat in both acute and long-term care facilities (LTCFs). As part of a study conducted in 2004 to determine the risk of stool colonization with extended-spectrum cephalosporin-resistant gram-negative bacteria, 12 isolates of K. pneumoniae that exhibited nonsusceptibility to extended-spectrum cephalosporins were detected. All were gastrointestinal carriage isolates that were not associated with infection. METHODS: Reassessment of the carbapenem minimum inhibitory concentrations using revised 2011 Clinical Laboratory Standards Institute breakpoints uncovered carbapenem resistance. To further investigate, a DNA microarray assay, PCR-sequencing of bla genes, immunoblotting, repetitive sequence-based PCR (rep-PCR) and multilocus sequence typing (MLST) were performed. RESULTS: The DNA microarray detected bla(KPC) in all 12 isolates, and bla(KPC-3) was identified by PCR amplification and sequencing of the amplicon. In addition, a bla(SHV-11) gene was detected in all isolates. Immunoblotting revealed "low-level" production of the K. pneumoniae carbapenemase, and rep-PCR indicated that all bla(KPC-3)-positive K. pneumoniae strains were genetically related (>=98% similar). According to MLST, all isolates belonged to sequence type 36. This sequence type has not been previously linked with bla(KPC) carriage. Plasmids from 3 representative isolates readily transferred the bla(KPC 3) to Escherichia coli J-53 recipients. CONCLUSIONS: Our findings reveal the "silent" dissemination of bla(KPC-3) as part of Tn4401b on a mobile plasmid in Northeast Ohio nearly a decade ago and establish the first report, to our knowledge, of K. pneumoniae containing bla(KPC-3) in an LTCF caring for neurologically impaired children and young adults. PMID- 22492321 TI - Totally drug-resistant and extremely drug-resistant tuberculosis: the same disease? PMID- 22492330 TI - Roots affect the response of heterotrophic soil respiration to temperature in tussock grass microcosms. AB - AIMS AND BACKGROUND: While the temperature response of soil respiration (R(S)) has been well studied, the partitioning of heterotrophic respiration (R(H)) by soil microbes from autotrophic respiration (R(A)) by roots, known to have distinct temperature sensitivities, has been problematic. Further complexity stems from the presence of roots affecting R(H), the rhizosphere priming effect. In this study the short-term temperature responses of R(A) and R(H) in relation to rhizosphere priming are investigated. METHODS: Temperature responses of R(A), R(H) and rhizosphere priming were assessed in microcosms of Poa cita using a natural abundance delta(13)C discrimination approach. RESULTS: The temperature response of R(S) was found to be regulated primarily by R(A), which accounted for 70 % of total soil respiration. Heterotrophic respiration was less sensitive to temperature in the presence of plant roots, resulting in negative priming effects with increasing temperature. CONCLUSIONS: The results emphasize the importance of roots in regulating the temperature response of R(S), and a framework is presented for further investigation into temperature effects on heterotrophic respiration and rhizosphere priming, which could be applied to other soil and vegetation types to improve models of soil carbon turnover. PMID- 22492331 TI - Response to enemies in the invasive plant Lythrum salicaria is genetically determined. AB - BACKGROUND AND AIMS: The enemy release hypothesis assumes that invasive plants lose their co-evolved natural enemies during introduction into the new range. This study tested, as proposed by the evolution of increased competitive ability (EICA) hypothesis, whether escape from enemies results in a decrease in defence ability in plants from the invaded range. Two straightforward aspects of the EICA are examined: (1) if invasives have lost their enemies and their defence, they should be more negatively affected by their full natural pre-invasion herbivore spectrum than their native conspecifics; and (2) the genetic basis of evolutionary change in response to enemy release in the invasive range has not been taken sufficiently into account. METHODS: Lythrum salicaria (purple loosestrife) from several populations in its native (Europe) and invasive range (North America) was exposed to all above-ground herbivores in replicated natural populations in the native range. The experiment was performed both with plants raised from field-collected seeds as well as with offspring of these where maternal effects were removed. KEY RESULTS: Absolute and relative leaf damage was higher for introduced than for native plants. Despite having smaller height growth rate, invasive plants attained a much larger final size than natives irrespective of damage, indicating large tolerance rather than effective defence. Origin effects on response to herbivory and growth were stronger in second generation plants, suggesting that invasive potential through enemy release has a genetic basis. CONCLUSIONS: The findings support two predictions of the EICA hypothesis - a genetically determined difference between native and invasive plants in plant vigour and response to enemies - and point to the importance of experiments that control for maternal effects and include the entire spectrum of native range enemies. PMID- 22492317 TI - Preeminence of Staphylococcus aureus in infective endocarditis: a 1-year population-based survey. AB - BACKGROUND: Observational studies showed that the profile of infective endocarditis (IE) significantly changed over the past decades. However, most studies involved referral centers. We conducted a population-based study to control for this referral bias. The objective was to update the description of characteristics of IE in France and to compare the profile of community-acquired versus healthcare-associated IE. METHODS: A prospective population-based observational study conducted in all medical facilities from 7 French regions (32% of French individuals aged >=18 years) identified 497 adults with Duke-Li definite IE who were first admitted to the hospital in 2008. Main measures included age-standardized and sex-standardized incidence of IE and multivariate Cox regression analysis for risk factors of in-hospital death. RESULTS: The age standardized and sex-standardized annual incidence of IE was 33.8 (95% confidence interval [CI], 30.8-36.9) cases per million inhabitants. The incidence was highest in men aged 75-79 years. A majority of patients had no previously known heart disease. Staphylococci were the most common causal agents, accounting for 36.2% of cases (Staphylococcus aureus, 26.6%; coagulase-negative staphylococci, 9.7%). Healthcare-associated IE represented 26.7% of all cases and exhibited a clinical pattern significantly different from that of community-acquired IE. S. aureus as the causal agent of IE was the most important factor associated with in hospital death in community-acquired IE (hazard ratio [HR], 2.82 [95% CI, 1.72 4.61]) and the single factor in healthcare-associated IE (HR, 2.54 [95% CI, 1.33 4.85]). CONCLUSIONS: S. aureus became both the leading cause and the most important prognostic factor of IE, and healthcare-associated IE appeared as a major subgroup of the disease. PMID- 22492333 TI - Wheelchair research progress, perspectives, and transformation. PMID- 22492332 TI - Contemporary gene flow and mating system of Arabis alpina in a Central European alpine landscape. AB - BACKGROUND AND AIMS: Gene flow is important in counteracting the divergence of populations but also in spreading genes among populations. However, contemporary gene flow is not well understood across alpine landscapes. The aim of this study was to estimate contemporary gene flow through pollen and to examine the realized mating system in the alpine perennial plant, Arabis alpina (Brassicaceae). METHODS: An entire sub-alpine to alpine landscape of 2 km(2) was exhaustively sampled in the Swiss Alps. Eighteen nuclear microsatellite loci were used to genotype 595 individuals and 499 offspring from 49 maternal plants. Contemporary gene flow by pollen was estimated from paternity analysis, matching the genotypes of maternal plants and offspring to the pool of likely father plants. Realized mating patterns and genetic structure were also estimated. KEY RESULTS: Paternity analysis revealed several long-distance gene flow events (<=1 km). However, most outcrossing pollen was dispersed close to the mother plants, and 84 % of all offspring were selfed. Individuals that were spatially close were more related than by chance and were also more likely to be connected by pollen dispersal. CONCLUSIONS: In the alpine landscape studied, genetic structure occurred on small spatial scales as expected for alpine plants. However, gene flow also covered large distances. This makes it plausible for alpine plants to spread beneficial alleles at least via pollen across landscapes at a short time scale. Thus, gene flow potentially facilitates rapid adaptation in A. alpina likely to be required under ongoing climate change. PMID- 22492334 TI - Dynamic stiffness and transmissibility of commercially available wheelchair cushions using a laboratory test method. AB - Evidence suggests that wheelchair (WC) users are exposed to unhealthy levels of vibration during WC use. Health risks associated with vibration exposure include vertebral disc degeneration and back pain, which may consequently decrease the function and independence of WC users. Some evidence suggests that the cushions used in WCs may amplify vibrations, although conclusive evidence has not been presented in the literature. This study evaluated and compared the transmissibility of commercially available WC cushions with two laboratory test methods: (1) direct measurement of transmissibility while human subjects propelled a WC over a road course with different cushions and (2) characterization of cushions with a material testing system (MTS) combined with mathematical models of the apparent mass of the human body. Results showed that although dynamic characterization of WC cushions is possible with an MTS, the results did not correlate well with the transmissibility obtained in the WC road course. Significant differences were found for transmissibility among the cushions tested, with the air-based cushions having lower transmissibility than the foam- or gel-based cushions. PMID- 22492335 TI - Changes in surface electromyography signals and kinetics associated with progression of fatigue at two speeds during wheelchair propulsion. AB - The purpose of this study was to determine whether muscle balance is influenced by fatigue in a recordable way, toward creating novel defensive activity strategies for manual wheelchair users (MWUs). Wheelchair propulsion to a point of mild fatigue, level 15 on the Rating of Perceived Exertion scale, was investigated at two different speeds. Surface electromyographic (EMG) activity of 7 muscles was recorded on 14 nondisabled participants. Kinetic variables were measured using a SmartWheel. No significant effect was found of percentage endurance time on kinetic variables for the two propulsion speeds. Fatigue related changes in the EMG spectra were identified as an increase of EMG intensity and a decrease of mean power frequency as a function of percent endurance time for the tested muscles under both fast and slow speed conditions. The greater increases in activity for propulsive muscles compared with recovery muscles during fast speed wheelchair propulsion indicated muscle imbalance associated with fatiguing wheelchair propulsion. This study shows how kinetic and EMG information might be used as feedback to MWUs to ensure that they conduct activity in ways that do not precipitate injury. PMID- 22492336 TI - Clinical evaluation of semiautonomous smart wheelchair architecture (Drive-Safe System) with visually impaired individuals. AB - Nonambulatory, visually impaired individuals mostly rely on caregivers for their day-to-day mobility needs. The Drive-Safe System (DSS) is a modular, semiautonomous smart wheelchair system aimed at providing independent mobility to people with visual and mobility impairments. In this project, clinical evaluation of the DSS was performed in a controlled laboratory setting with individuals who have visual impairment but no mobility impairment. Their performance using DSS was compared with their performance using a standard cane for navigation assistance. Participants rated their subjective appraisal of the DSS by using the National Aeronautics and Space Administration-Task Load Index inventory. DSS significantly reduced the number and severity of collisions compared with using a cane alone and without increasing the time required to complete the task. Users rated DSS favorably; they experienced less physical demand when using the DSS, but did not feel any difference in perceived effort, mental demand, and level of frustration when using the DSS alone or along with a cane in comparison with using a cane alone. These findings suggest that the DSS can be a safe, reliable, and easy-to-learn and operate independent mobility solution for visually impaired wheelchair users. PMID- 22492337 TI - Test method for empirically determining inertial properties of manual wheelchairs. AB - The iMachine is a spring-loaded turntable used to measure inertial properties of irregularly shaped rigid bodies, specifically manual wheelchairs. We used a Newton-Euler approach to calculate wheelchair mass and center of mass (CM) location from static force measurements using load cells. We determined the moment of inertia about the vertical axis from the natural frequency of the system in simple harmonic motion. The device was calibrated to eliminate the effects of platform components on measurement error. For objects with known inertial properties, the average relative error of the mass and the CM coordinates (x and y) were 0.76%, 0.89%, and 1.99%, respectively. The resolution of the moment of inertia calculation depends on the ratio of test piece inertia to system inertia, such that the higher the ratio, the more accurate the measurements. We conducted a Gage Repeatability and Reproducibility (Gage R&R) test using three manual wheelchairs measured three times by three operators; the results showed that over 90% of the variance in inertia was caused by differences in the wheelchairs being measured. Gage R&R analysis indicated that measurement system operation was acceptable using criteria from the Automobile Industry Action Group for both inertia and mass measurements. PMID- 22492338 TI - Assessment of field rolling resistance of manual wheelchairs. AB - This article proposes a simple and convenient method for assessing the subject specific rolling resistance acting on a manual wheelchair, which could be used during the provision of clinical service. This method, based on a simple mathematical equation, is sensitive to both the total mass and its fore-aft distribution, which changes with the subject, wheelchair properties, and adjustments. The rolling resistance properties of three types of front casters and four types of rear wheels were determined for two indoor surfaces commonly encountered by wheelchair users (a hard smooth surface and carpet) from measurements of a three-dimensional accelerometer during field deceleration tests performed with artificial load. The average results provided by these experiments were then used as input data to assess the rolling resistance from the mathematical equation with an acceptable accuracy on hard smooth and carpet surfaces (standard errors of the estimates were 4.4 and 3.9 N, respectively). Thus, this method can be confidently used by clinicians to help users make trade offs between front and rear wheel types and sizes when choosing and adjusting their manual wheelchair. PMID- 22492339 TI - Pilot study for quantifying driving characteristics during power wheelchair soccer. AB - This study determined the driving characteristics of wheelchair users during power wheelchair soccer games. Data for this study were collected at the 28th and 29th National Veterans Wheelchair Games. Nineteen veterans who were 18 years or older and power wheelchair soccer players completed a brief demographic survey and provided information about their power wheelchairs. A customized data-logging device was placed on each participant's wheelchair before power soccer game participation. The data logger was removed at the end of the final game for each participant. The average distance traveled during the games was 899.5 +/- 592.5 m, and the average maximum continuous distance traveled was 256.0 +/- 209.4 m. The average wheelchair speed was 0.8 +/- 0.2 m/s, and the average duration of driving time was 17.6 +/- 8.3 min. Average proportion of time spent at a speed >1 m/s was 30.7% +/- 33.8%, between 0.5 and 1 m/s was 16.2% +/- 34.4%, and <0.5 m/s was 21.4% +/- 24.3%. The information from this descriptive study provides insight for future research in the field of adapted sports for people with high levels of impairments who use power wheelchairs for their mobility. PMID- 22492340 TI - Rehabilitation Research and Development state-of-the-art conference on outcome measures in rehabilitation. PMID- 22492341 TI - Issues in defining and measuring veteran community reintegration: proceedings of the Working Group on Community Reintegration, VA Rehabilitation Outcomes Conference, Miami, Florida. AB - In January 2010, the Department of Veterans Affairs (VA) Rehabilitation Research and Development Service convened a State of the Art (SOTA) conference to advance the field of outcome measurement for rehabilitation-related studies. This article reports on the proceedings of the SOTA Working Group on Community Reintegration. We explored the use of the International Classification of Health, Disability, and Functioning as a theoretical framework for measuring community reintegration; identified key dimensions of community reintegration that could and/or should be measured; discussed challenges in measuring community reintegration; suggested steps to enhance community reintegration measurement; proposed future research that focuses on outcomes measures for community reintegration and the study of community reintegration outcomes; and made policy recommendations that would facilitate community reintegration research within the VA. PMID- 22492342 TI - Vocational services research: recommendations for next stage of work. AB - As the field of vocational services (VS) research matures, it is necessary to review its progress and identify any important gaps in measurement and methodology that may hamper future efforts. To encourage progress, we have identified (1) ways to increase consistency in measuring employment outcomes, (2) emerging patterns and lingering gaps in the range of variables and measures commonly used in VS research, (3) broader methodological patterns and needs in the area of study design and sampling, (4) interventions that warrant additional study, and (5) broad strategies to increase the overall amount and quality of VS research. The goal of this article is to assist the field in achieving clearer coherence in shared expectations and standards for research so that the field can consolidate its gains as it helps people successfully return to rewarding jobs in the community. PMID- 22492343 TI - Mental health assessment in rehabilitation research. AB - Assessment in mental health research has evolved from focusing on symptoms and diagnosis to addressing a broad range of change, including psychosocial functioning. This is consistent with developments in the areas of psychosocial rehabilitation and the increase in recovery-oriented intervention models for mental disorders. We reviewed the status of assessment in mental health research, providing an overview of symptom and diagnostic assessment that is the cornerstone of most mental health research assessment. We then focused on measurement that can be applied across diagnostic groups and on functioning as a key mental health outcome. We reviewed the International Classification of Functioning, Disability, and Health and its implications for improvements in assessment. We provided an example of a new assessment, the Inventory of Psychosocial Functioning, which highlights key issues in the measurement of functioning. We then addressed improving research assessment, including issues of assessment in diverse populations and the need to capitalize on new data sources and new assessment technologies to advance assessment in mental health research. Finally, we reviewed and discussed areas for research and quality improvement, drawing on examples from the Department of Veterans Affairs to illustrate potential opportunities. PMID- 22492344 TI - Measurement of social participation outcomes in rehabilitation of veterans with traumatic brain injury. AB - Traumatic brain injury (TBI) is a significant concern in the veteran population, and the Department of Veteran Affairs (VA) has devoted substantial healthcare resources to the rehabilitation of veterans with TBI. Evaluating the outcomes of these rehabilitation activities requires measuring whether they meaningfully improve veterans' lives, especially with regard to community and vocational participation, which are strongly linked to perceived quality of life. In January 2010, the VA Rehabilitation Research and Development Service convened an invitational conference focused on outcome measurement in rehabilitation with a specific focus on veterans' community and vocational participation. This article reports on the working group, addressing the issues of conceptualizing and operationalizing such participation outcome measures for veterans with TBI; we discuss conceptual models of participation, review participation subdomains and their instruments of measurement, and identify current research issues and needs. Two avenues are identified for advancing participation measurement in veterans with TBI. First, we describe suggestions to facilitate the immediate implementation of participation measurement into TBI clinical practice and rehabilitation (cont) research within the VA healthcare system. Second, we describe recommendations for future VA research funding initiatives specific to improving the measurement of participation in veterans with TBI. PMID- 22492345 TI - Activity and participation after spinal cord injury: state-of-the-art report. AB - The importance of activities and community participation for persons with spinal cord injury (SCI) has been recognized for decades and yet theoretical and empirical advances have been limited. This report summarizes the recommendations for researchers on the topic of measuring activity and participation among persons with SCI formulated by the Spinal Cord Injury workgroup at the State-of the-Art Conference on Outcome Measures in Rehabilitation held in January 2010. Activity and participation were defined as independent constructs ideally measured in reference to personal values and environmental influences. Measures of activity, participation, and factors influencing activity and participation are reviewed and critiqued. Gaps in available measures are described, measures in development are discussed, and suggestions for future research are made. PMID- 22492346 TI - Small N designs for rehabilitation research. AB - Rehabilitation research presents unique and challenging problems to investigators during both the design and analysis periods. Statistical issues regarding sample size requirements for an adequately powered study may be in direct conflict with realistic recruitment and subject retention goals. Issues of underpowered studies, sample size requirements, and recruitment goals plague rehabilitation research. Randomized clinical trials (RCTs) are typically narrow in scope and thus lack generalizability to everyday, yet specific, clinical problems; they are also costly and time-consuming and require large numbers of participants for randomization to have optimal, desired effects. Further, the RCT design may not be applicable to assistive technologies and environmental modifications-vital components of disability and rehabilitation research-nor is it appropriate in situations in which theoretical models of change are lacking or premature. Single case designs are better suited for studies in which understanding and changing patient behavior and functional status are primary goals and the targeted sample sizes are less than 30 and frequently less than 10. Theoretical, methodological, and clinical reasons for using experimental and quasi-experimental single-case designs are presented. Recommendations for designing and conducting single-case studies that contribute to the evidence base are also discussed. PMID- 22492347 TI - Prevalence of feline leukemia virus infection in domestic cats in Rio de Janeiro. AB - Peripheral blood smears of 1094 domestic cats were collected and tested by indirect immunofluorescence antibody assay for p27 antigen in cells to study the prevalence and risk factors for feline leukemia virus (FeLV) in the state of Rio de Janeiro. Sex, age, breed, outdoor access, neutering status, type of habitation (household, shelter, veterinary clinics and other places), number of household cats and clinical signs were registered on a form. Among the tested samples, 11.52% were positive. Risk factors for FeLV infection included outdoor access, age range between 1 and 5 years old, and cohabitation with numerous cats. PMID- 22492348 TI - Bilateral radial hemimelia and multiple malformations in a kitten. AB - Hemimelia is a congenital disease of complete or partial absence of one or more bones. The most important hypothesis is that radial agenesis is a consequence of neural crest injury. Treatment selection depends on the degree of the deformity and the reduction of limb function. This report describes a case of bilateral radial hemimelia and multiple malformations in a kitten aged 2 months treated conservatively with splint bandage, until bone maturity. The re-evaluation was performed 4 years later. PMID- 22492349 TI - Prevalence and pattern of congenital heart disease in Uttarakhand, India. AB - OBJECTIVE: To find the prevalence and pattern of congenital heart disease (CHD) at a tertiary care hospital in Uttarakhand, India. METHODS: A thorough history and clinical examination was done for all the live births and children up to 18 y of age who presented to the institute over a period of 3 y from July 2008 through June 2011. Those suspected of having a CHD, were further evaluated with ECG, chest radiography and the diagnosis was confirmed by color Doppler echocardiography. RESULTS: Of the 36541 children examined, 312 were identified as having congenital heart defects, thus giving a prevalence of 8.54 per 1000 children attending hospital. Only one fifth cases were diagnosed in neonatal period and the diagnosis was delayed beyond infancy in more than half of the cases. Ventricular septal defect (30.45%), atrial septal defect (17.63%), patent ductus arteriosus (9.62%), pulmonary stenosis (6.41%), tetralogy of Fallot (5.45%) and transposition of great arteries (5.13%) were the commonest defects observed. Only 9.29% of children with CHD underwent definitive treatment. CONCLUSION: The prevalence of CHD at a tertiary referral hospital in Uttarakhand India is 8.54 per 1000 children. VSD and TOF are the most common acyanotic and cyanotic congenital heart defects respectively. PMID- 22492351 TI - Different levels of Notch signaling regulate quiescence, renewal and differentiation in pancreatic endocrine progenitors. AB - Genetic studies have implicated Notch signaling in the maintenance of pancreatic progenitors. However, how Notch signaling regulates the quiescent, proliferative or differentiation behaviors of pancreatic progenitors at the single-cell level remains unclear. Here, using single-cell genetic analyses and a new transgenic system that allows dynamic assessment of Notch signaling, we address how discrete levels of Notch signaling regulate the behavior of endocrine progenitors in the zebrafish intrapancreatic duct. We find that these progenitors experience different levels of Notch signaling, which in turn regulate distinct cellular outcomes. High levels of Notch signaling induce quiescence, whereas lower levels promote progenitor amplification. The sustained downregulation of Notch signaling triggers a multistep process that includes cell cycle entry and progenitor amplification prior to endocrine differentiation. Importantly, progenitor amplification and differentiation can be uncoupled by modulating the duration and/or extent of Notch signaling downregulation, indicating that these processes are triggered by distinct levels of Notch signaling. These data show that different levels of Notch signaling drive distinct behaviors in a progenitor population. PMID- 22492350 TI - Transcriptional co-regulation of neuronal migration and laminar identity in the neocortex. AB - The cerebral neocortex is segregated into six horizontal layers, each containing unique populations of molecularly and functionally distinct excitatory projection (pyramidal) neurons and inhibitory interneurons. Development of the neocortex requires the orchestrated execution of a series of crucial processes, including the migration of young neurons into appropriate positions within the nascent neocortex, and the acquisition of layer-specific neuronal identities and axonal projections. Here, we discuss emerging evidence supporting the notion that the migration and final laminar positioning of cortical neurons are also co-regulated by cell type- and layer-specific transcription factors that play concomitant roles in determining the molecular identity and axonal connectivity of these neurons. These transcriptional programs thus provide direct links between the mechanisms controlling the laminar position and identity of cortical neurons. PMID- 22492352 TI - STUNTED mediates the control of cell proliferation by GA in Arabidopsis. AB - Gibberellins (GA) are an important family of plant growth regulators, which are essential for many aspects of plant growth and development. In the GA signaling pathway, the action of GA is opposed by a group of DELLA family repressors, such as RGA. Although the mechanisms of action of the DELLA proteins have been studied in great detail, the effectors that act downstream of DELLA proteins and bring about GA-responsive growth and development remain largely unknown. In this study, we have characterized STUNTED (STU), a receptor-like cytoplasmic kinase (RLCK) VI family gene, which is ubiquitously detectable in all the tissues examined. RGA activity and GA signaling specifically mediate the levels of STU transcripts in shoot apices that contain actively dividing cells. stu-1 loss-of-function mutants exhibit retarded growth in many aspects of plant development. During the vegetative phase, stu-1 seedlings develop smaller leaves and shorter roots than wild-type seedlings, while during the reproductive phase, stu-1 exhibits delayed floral transition and lower fertility. The reduced stature of stu-1 partly results from a reduction in cell proliferation. Furthermore, we present evidence that STU serves as an important regulator mediating the control of cell proliferation by GA possibly through two cyclin-dependent kinase inhibitors, SIM and SMR1. Taken together, our results suggest that STU acts downstream of RGA and promotes cell proliferation in the GA pathway. PMID- 22492353 TI - SOX7 regulates the expression of VE-cadherin in the haemogenic endothelium at the onset of haematopoietic development. AB - At early stages of vertebrate ontogeny, blood and endothelial cells develop from a common mesodermal progenitor, the haemangioblast. Upon haematopoietic commitment, the haemangioblast generates blood precursors through populations of endothelial cells with haemogenic properties. Although several transcription factors have been implicated in haemangioblast differentiation, the precise mechanisms governing cell fate decisions towards the generation of haemogenic endothelium precursors remain largely unknown. Under defined conditions, embryonic stem (ES) cells can be differentiated into haemangioblast-like progenitors that faithfully recapitulate early embryonic haematopoiesis. Here, we made use of mouse ES cells as a model system to understand the role of SOX7, a member of a large family of transcription factors involved in a wide range of developmental processes. During haemangioblast differentiation, SOX7 is expressed in haemogenic endothelium cells and is downregulated in nascent blood precursors. Gain-of-function assays revealed that the enforced expression of Sox7 in haemangioblast-derived blast colonies blocks further differentiation and sustains the expression of endothelial markers. Thus, to explore the transcriptional activity of SOX7, we focused on the endothelial-specific adhesion molecule VE cadherin. Similar to SOX7, VE-cadherin is expressed in haemogenic endothelium and is downregulated during blood cell formation. We show that SOX7 binds and activates the promoter of VE-cadherin, demonstrating that this gene is a novel downstream transcriptional target of SOX7. Altogether, our findings suggest that SOX7 is involved in the transcriptional regulation of genes expressed in the haemogenic endothelium and provide new clues to decipher the molecular pathways that drive early embryonic haematopoiesis. PMID- 22492354 TI - Loss of Llgl1 in retinal neuroepithelia reveals links between apical domain size, Notch activity and neurogenesis. AB - To gain insights into the cellular mechanisms of neurogenesis, we analyzed retinal neuroepithelia deficient for Llgl1, a protein implicated in apicobasal cell polarity, asymmetric cell division, cell shape and cell cycle exit. We found that vertebrate retinal neuroepithelia deficient for Llgl1 retained overt apicobasal polarity, but had expanded apical domains. Llgl1 retinal progenitors also had increased Notch activity and reduced rates of neurogenesis. Blocking Notch function by depleting Rbpj restored normal neurogenesis. Experimental expansion of the apical domain, through inhibition of Shroom3, also increased Notch activity and reduced neurogenesis. Significantly, in wild-type retina, neurogenic retinal progenitors had smaller apical domains compared with proliferative neuroepithelia. As nuclear position during interkinetic nuclear migration (IKNM) has been previously linked with cell cycle exit, we analyzed this phenomenon in cells depleted of Llgl1. We found that although IKNM was normal, the relationship between nuclear position and neurogenesis was shifted away from the apical surface, consistent with increased pro-proliferative and/or anti-neurogenic signals associated with the apical domain. These data, in conjunction with other findings, suggest that, in retinal neuroepithelia, the size of the apical domain modulates the strength of polarized signals that influence neurogenesis. PMID- 22492355 TI - COUP-TFII controls amygdala patterning by regulating neuropilin expression. AB - The development of the progenitor zones in the pallium, lateral ganglionic eminence (LGE) and medial ganglionic eminence (MGE) in the subpallium has been well studied; however, so far the role of the caudal ganglionic eminence (CGE), a posterior subpallial domain, in telencephalon patterning remains poorly understood. COUP-TFII, an orphan nuclear receptor, is preferentially expressed in the CGE. We generated COUP-TFII mouse mutants, using Rx-Cre (RxCre;COUP TFII(F/F)), to study its function in telencephalon development. In these mutants, we found severe defects in the formation of the amygdala complex, including the lateral (LA), basolateral (BLA) and basomedial (BMA) amygdala nuclei. Molecular analysis provided evidence that the migration of CGE-derived Pax6(+) cells failed to settle into the BMA nucleus, owing to reduced expression of neuropilin 1 (Nrp1) and Nrp2, two semaphorin receptors that regulate neuronal cell migration and axon guidance. Our ChIP assays revealed that Nrp1 and Nrp2 genes are the direct targets of COUP-TFII in the telencephalon in vivo. Furthermore, our results showed that the coordinated development between the CGE originated subpallial population (Pax6(+) cells) and pallial populations (Tbr1(+) and Lhx2(+) cells) was essential for patterning the amygdala assembly. Our study presented novel genetic evidence that the caudal ganglionic eminence, a distinct subpallial progenitor zone, contributes cells to the basal telencephalon, such as the BMA nucleus. PMID- 22492356 TI - Dynamic in vivo binding of transcription factors to cis-regulatory modules of cer and gsc in the stepwise formation of the Spemann-Mangold organizer. AB - How multiple developmental cues are integrated on cis-regulatory modules (CRMs) for cell fate decisions remains uncertain. The Spemann-Mangold organizer in Xenopus embryos expresses the transcription factors Lim1/Lhx1, Otx2, Mix1, Siamois (Sia) and VegT. Reporter analyses using sperm nuclear transplantation and DNA injection showed that cerberus (cer) and goosecoid (gsc) are activated by the aforementioned transcription factors through CRMs conserved between X. laevis and X. tropicalis. ChIP-qPCR analysis for the five transcription factors revealed that cer and gsc CRMs are initially bound by both Sia and VegT at the late blastula stage, and subsequently bound by all five factors at the gastrula stage. At the neurula stage, only binding of Lim1 and Otx2 to the gsc CRM, among others, persists, which corresponds to their co-expression in the prechordal plate. Based on these data, together with detailed expression pattern analysis, we propose a new model of stepwise formation of the organizer, in which (1) maternal VegT and Wnt-induced Sia first bind to CRMs at the blastula stage; then (2) Nodal inducible Lim1, Otx2, Mix1 and zygotic VegT are bound to CRMs in the dorsal endodermal and mesodermal regions where all these genes are co-expressed; and (3) these two regions are combined at the gastrula stage to form the organizer. Thus, the in vivo dynamics of multiple transcription factors highlight their roles in the initiation and maintenance of gene expression, and also reveal the stepwise integration of maternal, Nodal and Wnt signaling on CRMs of organizer genes to generate the organizer. PMID- 22492357 TI - Analysis of centriole elimination during C. elegans oogenesis. AB - Centrosomes are the principal microtubule organizing centers (MTOCs) of animal cells and comprise a pair of centrioles surrounded by pericentriolar material (PCM). Centriole number must be carefully regulated, notably to ensure bipolar spindle formation and thus faithful chromosome segregation. In the germ line of most metazoan species, centrioles are maintained during spermatogenesis, but eliminated during oogenesis. Such differential behavior ensures that the appropriate number of centrioles is present in the newly fertilized zygote. Despite being a fundamental feature of sexual reproduction in metazoans, the mechanisms governing centriole elimination during oogenesis are poorly understood. Here, we investigate this question in C. elegans. Using antibodies directed against centriolar components and serial-section electron microscopy, we establish that centrioles are eliminated during the diplotene stage of the meiotic cell cycle. Moreover, we show that centriole elimination is delayed upon depletion of the helicase CGH-1. We also find that somatic cells make a minor contribution to this process, and demonstrate that the germ cell karyotype is important for timely centriole elimination. These findings set the stage for a mechanistic dissection of centriole elimination in a metazoan organism. PMID- 22492358 TI - Not just inductive: a crucial mechanical role for the endoderm during heart tube assembly. AB - The heart is the first functioning organ to form during development. During gastrulation, the cardiac progenitors reside in the lateral plate mesoderm but maintain close contact with the underlying endoderm. In amniotes, these bilateral heart fields are initially organized as a pair of flat epithelia that move towards the embryonic midline and fuse above the anterior intestinal portal (AIP) to form the heart tube. This medial motion is typically attributed to active mesodermal migration over the underlying endoderm. In this model, the role of the endoderm is twofold: to serve as a mechanically passive substrate for the crawling mesoderm and to secrete various growth factors necessary for cardiac specification and differentiation. Here, using computational modeling and experiments on chick embryos, we present evidence supporting an active mechanical role for the endoderm during heart tube assembly. Label-tracking experiments suggest that active endodermal shortening around the AIP accounts for most of the heart field motion towards the midline. Results indicate that this shortening is driven by cytoskeletal contraction, as exposure to the myosin-II inhibitor blebbistatin arrested any shortening and also decreased both tissue stiffness (measured by microindentation) and mechanical tension (measured by cutting experiments). In addition, blebbistatin treatment often resulted in cardia bifida and abnormal foregut morphogenesis. Moreover, finite element simulations of our cutting experiments suggest that the endoderm (not the mesoderm) is the primary contractile tissue layer during this process. Taken together, these results indicate that contraction of the endoderm actively pulls the heart fields towards the embryonic midline, where they fuse to form the heart tube. PMID- 22492360 TI - Extracts from The Cochrane Library: Topical anaesthetic or vasoconstrictor preparations for flexible fibre-optic nasal pharyngoscopy and laryngoscopy. AB - The "Cochrane Corner" is a quarterly section in the Journal that highlights systematic reviews relevant to otolaryngology- head and neck surgery, with invited commentary to aid clinical decision making. This installment features a Cochrane Review, "Topical Anaesthetic or Vasoconstrictor Preparations for Flexible Fibre-optic Nasal Pharyngoscopy and Laryngoscopy," that finds no evidence of reduced pain or discomfort for topical treatment prior to endoscopy. PMID- 22492359 TI - Turning gene function ON and OFF using sense and antisense photo-morpholinos in zebrafish. AB - To understand the molecular mechanisms of development it is essential to be able to turn genes on and off at will and in a spatially restricted fashion. Morpholino oligonucleotides (MOs) are very common tools used in several model organisms with which it is possible to block gene expression. Recently developed photo-activated MOs allow control over the onset of MO activity. However, deactivation of photo-cleavable MO activity has remained elusive. Here, we describe photo-cleavable MOs with which it is possible to activate or de-activate MO function by UV exposure in a temporal and spatial manner. We show, using several different genes as examples, that it is possible to turn gene expression on or off both in the entire zebrafish embryo and in single cells. We use these tools to demonstrate the sufficiency of no tail expression as late as tailbud stage to drive medial precursor cells towards the notochord cell fate. As a broader approach for the use of photo-cleavable MOs, we show temporal control over gal4 function, which has many potential applications in multiple transgenic lines. We demonstrate temporal manipulation of Gal4 transgene expression in only primary motoneurons and not secondary motoneurons, heretofore impossible with conventional transgenic approaches. In another example, we follow and analyze neural crest cells that regained sox10 function after deactivation of a photo cleavable sox10-MO at different time points. Our results suggest that sox10 function might not be critical during neural crest formation. PMID- 22492361 TI - A new ammine dual-cation (Li, Mg) borohydride: synthesis, structure, and dehydrogenation enhancement. AB - A new ammine dual-cation borohydride, LiMg(BH(4))(3)(NH(3))(2), has been successfully synthesized simply by ball-milling of Mg(BH(4))(2) and LiBH(4).NH(3). Structure analysis of the synthesized LiMg(BH(4))(3)(NH(3))(2) revealed that it crystallized in the space group P6(3) (no. 173) with lattice parameters of a=b=8.0002(1) A, c=8.4276(1) A, alpha=beta=90 degrees , and gamma=120 degrees at 50 degrees C. A three-dimensional architecture is built up through corner-connecting BH(4) units. Strong N-H...H-B dihydrogen bonds exist between the NH(3) and BH(4) units, enabling LiMg(BH(4))(3)(NH(3))(2) to undergo dehydrogenation at a much lower temperature. Dehydrogenation studies have revealed that the LiMg(BH(4))(3)(NH(3))(2)/LiBH(4) composite is able to release over 8 wt% hydrogen below 200 degrees C, which is comparable to that released by Mg(BH(4))(3)(NH(3))(2). More importantly, it was found that release of the byproduct NH(3) in this system can be completely suppressed by adjusting the ratio of Mg(BH(4))(2) and LiBH(4).NH(3). This chemical control route highlights a potential method for modifying the dehydrogenation properties of other ammine borohydride systems. PMID- 22492362 TI - Rightward convexity of the great vessel arising from the anterior ventricle: a novel fetal marker for transposition of the great arteries. AB - OBJECTIVES: Traditionally transposition of the great arteries (TGA) is suggested by bifurcation of the great vessel arising from the posterior ventricle and the parallel course of the great vessels as they leave the heart. These findings may be difficult to demonstrate, requiring additional fetal echocardiographic features to indicate TGA. In this study, we investigated a new marker of TGA, namely rightward convexity of the great vessel arising from the anterior ventricle. METHODS: We reviewed fetal studies from 2006 to 2010 in which an antenatal diagnosis of TGA was confirmed postnatally. We specifically viewed images obtained by scanning the great vessel arising from the anterior ventricle cranially to the superior mediastinum at the level of the three vessels and trachea view and compared them with similar views in normal hearts. RESULTS: In 21 cases of confirmed TGA, the great vessel arising from the anterior ventricle (aorta) coursing cranially demonstrated an abnormal convexity to the right. This was in contrast to convexity to the left or lack of convexity of the great vessel (pulmonary artery) arising from the anterior ventricle in fetuses with a normal heart. In two fetuses rightward vessel convexity from the anterior ventricle was the clue on the initial scan suggesting TGA, which was subsequently confirmed. In addition, only two vessels, the superior vena cava and aorta, were demonstrated in fetuses with TGA, the pulmonary artery and ductus arteriosus lying below (caudal to) the transverse arch. CONCLUSIONS: Noting the rightward convexity of the great vessel arising from the anterior ventricle may aid in the prenatal diagnosis of TGA. Furthermore, the relative simplicity of this sign may make it valuable in fetal screening for this cardiac defect. PMID- 22492363 TI - Dental x-rays and risk of meningioma. AB - BACKGROUND: Ionizing radiation is a consistently identified and potentially modifiable risk factor for meningioma, which is the most frequently reported primary brain tumor in the United States. The objective of this study was to examine the association between dental x-rays-the most common artificial source of ionizing radiation-and the risk of intracranial meningioma. METHODS: This population-based case-control study included 1433 patients who had intracranial meningioma diagnosed at ages 20 to 79 years and were residents of the states of Connecticut, Massachusetts, North Carolina, the San Francisco Bay Area, and 8 counties in Houston, Texas between May 1, 2006 and April 28, 2011 (cases). A control group of 1350 individuals was frequency matched on age, sex, and geography (controls). The main outcome measure for the study was the association between a diagnosis of intracranial meningioma and self-reported bitewing, full mouth, and panorex dental x-rays. RESULTS: Over a lifetime, cases were more than twice as likely as controls (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.4-2.9) to report having ever had a bitewing examination. Regardless of the age at which the films were obtained, individuals who reported receiving bitewing films on a yearly basis or with greater frequency had an elevated risk for ages <10 years (OR, 1.4; 95% CI, 1.0-1.8), ages 10 to 19 years (OR, 1.6; 95% CI, 1.2 2.0), ages 20 to 49 years (OR, 1.9; 95% CI, 1.4-2.6), and ages >=40 years (OR, 1.5; 95% CI, 1.1-2.0). An increased risk of meningioma also was associated with panorex films taken at a young age or on a yearly basis or with greater frequency, and individuals who reported receiving such films at ages <10 years had a 4.9 times increased risk (95% CI, 1.8-13.2) of meningioma. No association was appreciated for tumor location above or below the tentorium. CONCLUSIONS: Exposure to some dental x-rays performed in the past, when radiation exposure was greater than in the current era, appears to be associated with an increased risk of intracranial meningioma. As with all sources of artificial ionizing radiation, considered use of this modifiable risk factor may be of benefit to patients. PMID- 22492365 TI - Association of plasma B-6 vitamers with systemic markers of inflammation before and after pyridoxine treatment in patients with stable angina pectoris. AB - BACKGROUND: A negative association between systemic markers of inflammation and plasma vitamin B-6 has been observed in population-based and patient cohorts; however, vitamin B-6 (pyridoxine) treatment has mostly failed to improve inflammatory indexes. OBJECTIVE: We aimed to assess the effect of pyridoxine treatment on B-6 vitamer and inflammatory marker relations. DESIGN: We measured pyridoxal 5'-phosphate (PLP), pyridoxal, 4-pyridoxic acid (PA), C-reactive protein (CRP), neopterin, and the kynurenine-to-tryptophan ratio (KTR) in plasma and the white blood cell count (WBC). A partial Spearman's correlation was used to assess associations of B-6 vitamers with inflammatory markers before and after daily treatment with 40 mg pyridoxine hydrochloride. Generalized additive models and segmented regression analysis were used for nonlinear relations. RESULTS: A 9 60-fold increase in B-6 vitamer concentrations over baseline values was observed after 28 d of treatment with pyridoxine. PLP was negatively associated with all 4 inflammatory markers at baseline and, predominantly, with CRP and KTR at day 28. The catabolite PA was positively associated with neopterin and KTR before and after treatment. The dose-response relation between CRP and B-6 vitamers at day 28 was nonlinear, with an increased steepness of slope at CRP >7 mg/L. Finally, changes in B-6 vitamer concentrations were correlated with changes in inflammatory marker concentrations over a time span of 4 wk. CONCLUSIONS: The associations between plasma vitamin B-6 and inflammatory markers were preserved or even increased after pyridoxine treatment. The results suggest that the acute phase and activated cellular immunity are associated with increased cellular uptake and catabolism of vitamin B-6, respectively. PMID- 22492364 TI - Effects of vitamin C supplementation on blood pressure: a meta-analysis of randomized controlled trials. AB - BACKGROUND: In observational studies, increased vitamin C intake, vitamin C supplementation, and higher blood concentrations of vitamin C are associated with lower blood pressure (BP). However, evidence for blood pressure-lowering effects of vitamin C in clinical trials is inconsistent. OBJECTIVE: The objective was to conduct a systematic review and meta-analysis of clinical trials that examined the effects of vitamin C supplementation on BP. DESIGN: We searched Medline, EMBASE, and Central databases from 1966 to 2011. Prespecified inclusion criteria were as follows: 1) use of a randomized controlled trial design; 2) trial reported effects on systolic BP (SBP) or diastolic BP (DBP) or both; 3) trial used oral vitamin C and concurrent control groups; and 4) trial had a minimum duration of 2 wk. BP effects were pooled by random-effects models, with trials weighted by inverse variance. RESULTS: Twenty-nine trials met eligibility criteria for the primary analysis. The median dose was 500 mg/d, the median duration was 8 wk, and trial sizes ranged from 10 to 120 participants. The pooled changes in SBP and DBP were -3.84 mm Hg (95% CI: -5.29, -2.38 mm Hg; P < 0.01) and -1.48 mm Hg (95% CI: -2.86, -0.10 mm Hg; P = 0.04), respectively. In trials in hypertensive participants, corresponding reductions in SBP and DBP were -4.85 mm Hg (P < 0.01) and -1.67 mm Hg (P = 0.17). After the inclusion of 9 trials with imputed BP effects, BP effects were attenuated but remained significant. CONCLUSIONS: In short-term trials, vitamin C supplementation reduced SBP and DBP. Long-term trials on the effects of vitamin C supplementation on BP and clinical events are needed. PMID- 22492366 TI - Selling Sprinkles micronutrient powder reduces anemia, iron deficiency, and vitamin A deficiency in young children in Western Kenya: a cluster-randomized controlled trial. AB - BACKGROUND: Although the efficacy of micronutrient powders [MNPs; eg, Sprinkles MNP (Sprinkles Global Health Initiative)] in the reduction of anemia has been established, the effectiveness of these powders in real-world programs has seldom been assessed. OBJECTIVE: In this study, we evaluated the effect of community based marketing and distribution of Sprinkles MNP on childhood rates of anemia and iron and vitamin A deficiency. DESIGN: In a cluster-randomized trial in children aged 6-35 mo in Western Kenya, 60 villages were randomly assigned to either intervention or control groups. Community vendors marketed and sold sachets of Sprinkles MNP in intervention villages. Biweekly household visits monitored the use of Sprinkles MNP. Hemoglobin, ferritin, retinol binding protein, malaria, and anthropometric measures were assessed at baseline (n = 1063) and 12 mo of follow-up (n = 862). Data were analyzed by using an intention to-treat analysis and generalized linear mixed models. RESULTS: On average, 33% of households in intervention villages purchased Sprinkles MNP; the average weekly intake per child was 0.9 sachets (~11.3 mg Fe and ~328 MUg vitamin A). Compared with control subjects, intervention children had greater improvements in hemoglobin concentrations (increase of 0.9 compared with 0.6 g/dL, respectively; P = 0.02), iron deficiency (decrease of 19.3% compared with 5.3%, respectively; P = 0.001), and vitamin A deficiency (decrease of 7.5% compared with an increase of 2.5%, respectively; P = 0.01). Results adjusted for age, sex, socioeconomic status, and maternal education showed a significant association between the hemoglobin, iron, and vitamin A concentrations of children and the number of Sprinkles MNP sachets the children consumed. The prevalence of malaria, wasting, and stunting did not change significantly in either group. CONCLUSION: Even with relatively low and infrequent use, Sprinkles MNP sales through community vendors were associated with decreased rates of anemia and iron and vitamin A deficiency in children in a resource-poor setting. This trial was registered at clinicaltrials.gov as NCT01088958. PMID- 22492367 TI - Long-term consumption of high energy-dense snack foods on sensory-specific satiety and intake. AB - BACKGROUND: The sensory attributes of foods may have an important influence on intake because of sensory-specific satiety (SSS). Foods with high SSS may aid in body weight maintenance as a result of termination of consumption before metabolic satiety. No studies have investigated whether long-term exposure to a food might change SSS or how this affects food intake. OBJECTIVE: The objective was to compare the effects of daily consumption of 3 energy-dense snack foods (hazelnuts, chocolate, and potato chips) for 12 wk on SSS and ad libitum intake during a tasting session. DESIGN: One hundred eighteen participants took part in this randomized, controlled, parallel study with 4 arms: control group (no additional food) or ~1100 kJ/d for each snack. SSS, food intake, and body composition were measured at baseline and at week 12. RESULTS: Daily consumption of snacks for 12 wk resulted in a statistically significant reduction in SSS in all 3 snack groups (P = 0.015). However, no such changes were seen in the control group (P = 0.608). Ad libitum energy intake increased over the study during the tasting sessions for the snack food across all groups, including the control group (P = 0.039). Inverse associations were found between baseline SSS and BMI (P = 0.039), percentage body fat (P = 0.013), and fat mass (P = 0.004). CONCLUSION: Habitual consumption of a high energy-dense snack food results in a decrease in SSS, which could lead to a higher energy intake of the snack. This trial was registered at www.anzctr.org.au as ACTRN12609000265279. PMID- 22492368 TI - Effects of red orange juice intake on endothelial function and inflammatory markers in adult subjects with increased cardiovascular risk. AB - BACKGROUND: Oxidative and inflammatory stresses are involved in the pathogenesis of atherosclerosis. The consumption of fruit and vegetables is associated with improved health and reduced cardiovascular risk. Red oranges have a high content of antioxidant and antiinflammatory substances, but there is a paucity of data concerning their effects on cardiovascular biomarkers in subjects with increased cardiovascular risk. OBJECTIVE: We investigated the effect of red orange juice intake on endothelial function, oxidative stress, and markers of inflammation in subjects with increased cardiovascular risk. DESIGN: Nineteen nondiabetic subjects with increased cardiovascular risk (aged 27-56 y) were included in a randomized, placebo-controlled, single-blind crossover study and compared with 12 healthy, nonobese control subjects. In 2 periods of 7 d each with a 3-d interval, each participant alternatively received 500 mL red orange juice/d and 500 mL placebo/d in a random sequence. All measurements were performed in the morning after overnight fasting. RESULTS: Endothelial function, which was measured as flow-mediated dilation, significantly improved and was normalized (5.7% compared with 7.9%; P < 0.005) after 1 wk of red orange juice consumption. Similarly, concentrations of high-sensitivity C-reactive protein, IL-6, and TNF-alpha significantly decreased (P < 0.001). Red orange juice had no significant effect on nitric oxide plasma concentrations. CONCLUSION: A 7-d consumption of red orange juice ameliorates endothelial function and reduces inflammation in nondiabetic subjects with increased cardiovascular risk. This trial was registered at biomedcentral.com as ISRCTN39987296. PMID- 22492369 TI - Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial. AB - BACKGROUND: Replacing SFAs with vegetable PUFAs has cardiometabolic benefits, but the effects on liver fat are unknown. Increased dietary n-6 PUFAs have, however, also been proposed to promote inflammation-a yet unproven theory. OBJECTIVE: We investigated the effects of PUFAs on liver fat, systemic inflammation, and metabolic disorders. DESIGN: We randomly assigned 67 abdominally obese subjects (15% had type 2 diabetes) to a 10-wk isocaloric diet high in vegetable n-6 PUFA (PUFA diet) or SFA mainly from butter (SFA diet), without altering the macronutrient intake. Liver fat was assessed by MRI and magnetic resonance proton (1H) spectroscopy (MRS). Proprotein convertase subtilisin/kexin type-9 (PCSK9, a hepatic LDL-receptor regulator), inflammation, and adipose tissue expression of inflammatory and lipogenic genes were determined. RESULTS: A total of 61 subjects completed the study. Body weight modestly increased but was not different between groups. Liver fat was lower during the PUFA diet than during the SFA diet [between-group difference in relative change from baseline; 16% (MRI; P < 0.001), 34% (MRS; P = 0.02)]. PCSK9 (P = 0.001), TNF receptor-2 (P < 0.01), and IL-1 receptor antagonist (P = 0.02) concentrations were lower during the PUFA diet, whereas insulin (P = 0.06) tended to be higher during the SFA diet. In compliant subjects (defined as change in serum linoleic acid), insulin, total/HDL cholesterol ratio, LDL cholesterol, and triglycerides were lower during the PUFA diet than during the SFA diet (P < 0.05). Adipose tissue gene expression was unchanged. CONCLUSIONS: Compared with SFA intake, n-6 PUFAs reduce liver fat and modestly improve metabolic status, without weight loss. A high n-6 PUFA intake does not cause any signs of inflammation or oxidative stress. Downregulation of PCSK9 could be a novel mechanism behind the cholesterol-lowering effects of PUFAs. This trial was registered at clinicaltrials.gov as NCT01038102. PMID- 22492370 TI - Effect of a tomato-rich diet on markers of cardiovascular disease risk in moderately overweight, disease-free, middle-aged adults: a randomized controlled trial. AB - BACKGROUND: Cardiovascular disease (CVD) is a major cause of mortality in the United Kingdom. Epidemiologic studies suggest that consumption of tomato-based foods may lower CVD risk. Such potential benefits have been ascribed in part to high concentrations of lycopene in the tomatoes. However, these findings have not yet been validated by comprehensive intervention trials. OBJECTIVE: The aim of this study was to conduct a single-blind, randomized controlled intervention trial with healthy middle-aged volunteers to assess whether the consumption of tomato-based foods affects recognized biomarkers of CVD risk. DESIGN: After a 4 wk run-in period with a low-tomato diet, 225 volunteers (94 men and 131 women) aged 40-65 y were randomly assigned into 1 of 3 dietary intervention groups and asked to consume a control diet (low in tomato-based foods), a high-tomato-based diet, or a control diet supplemented with lycopene capsules (10 mg/d) for 12 wk. Blood samples were collected at baseline, at 6 wk, and after the intervention and were analyzed for carotenoid and lipid profiles and inflammatory markers. Blood pressure, weight, and arterial stiffness were also measured. Dietary intake was also determined during the intervention. RESULTS: None of the systemic markers (inflammatory markers, markers of insulin resistance and sensitivity) changed significantly after the dietary intervention. Moreover, lipid concentrations and arterial stiffness were also unaffected by the interventions. CONCLUSION: These data indicate that a relatively high daily consumption of tomato-based products (equivalent to 32-50 mg lycopene/d) or lycopene supplements (10 mg/d) is ineffective at reducing conventional CVD risk markers in moderately overweight, healthy, middle-aged individuals. This trial was registered at isrctn.org as ISRCTN34203810. PMID- 22492371 TI - Folate intake and incidence of hypertension among American young adults: a 20-y follow-up study. AB - BACKGROUND: Laboratory studies suggest that folate intake may decrease blood pressure (BP) through increasing nitric oxide synthesis in endothelial cells and/or reducing plasma homocysteine concentrations. However, human studies, particularly longitudinal data, are limited. OBJECTIVE: Our objective was to investigate whether dietary folate intake is associated with the 20-y incidence of hypertension. DESIGN: We prospectively followed 4400 men and women (African Americans and whites aged 18-30 y) without hypertension at baseline (1985) in the Coronary Artery Risk Development in Young Adults study 6 times, in 1987, 1990, 1992, 1995, 2000, and 2005. Diet was assessed by dietary-history questionnaire at baseline and in 1992 and 2005. Incident hypertension was defined as the first occurrence at any follow-up examination of systolic BP >= 140 mm Hg, diastolic BP >= 90 mm Hg, or use of antihypertensive medication. RESULTS: A total of 989 incident cases were identified during the 20-y follow-up. After adjustment for potential confounders, participants in the highest quintile of total folate intake had a significantly lower incidence of hypertension (HR: 0.48; 95% CI: 0.38, 0.62; P-trend < 0.01) than did those in the lowest quintile. The multivariable HRs for the same comparison were 0.33 (95% CI: 0.22, 0.51; P-trend < 0.01) in whites and 0.54 (95% CI: 0.40, 0.75; P-trend < 0.01) in African Americans (P-interaction = 0.047). The inverse associations were confirmed in a subset of the cohort (n = 1445) with serum folate measured at baseline and in 1992 and 2000. CONCLUSIONS: Higher folate intake in young adulthood was longitudinally associated with a lower incidence of hypertension later in life. This inverse association was more pronounced in whites. Additional studies are warranted to establish the causal inference. PMID- 22492372 TI - Methionine requirement of the enterally fed term infant in the first month of life in the presence of cysteine. AB - BACKGROUND: The essential amino acid methionine can be used for protein synthesis but also serves as a precursor for homocysteine and cysteine. OBJECTIVE: The objective of this study was to determine the minimal obligatory methionine requirement of infants in the presence of excess cysteine (91 mg ? kg(-1) ? d( 1)) by using the indicator amino acid oxidation (IAAO) method with l-[1 (13)C]phenylalanine as the indicator. DESIGN: Fully enterally fed term infants <1 mo of age were randomly assigned to methionine intakes that ranged from 3 to 59 mg ? kg(-1) ? d(-1) as part of an elemental formula. After 1 d of adaptation to the test diet, [(13)C]bicarbonate and l-[1-(13)C]phenylalanine tracers were given enterally. Breath samples were collected at baseline and during isotopic plateaus. The mean methionine requirement was determined by using biphasic linear regression crossover analysis on the fraction of (13)CO(2) recovery from l-[1 (13)C]phenylalanine oxidation (F(13)CO(2)). Data are presented as means +/- SDs. RESULTS: Thirty-three neonates (gestational age: 39 +/- 1 wk) were studied at 13 +/- 6 d. With increasing methionine intakes, F(13)CO(2) decreased until a methionine intake of 38 mg ? kg(-1) ? d(-1); additional increases in methionine intake did not affect F(13)CO(2). The mean methionine requirement was determined at 38 mg ? kg(-1) ? d(-1), and the upper and lower CIs were 48 and 27 mg ? kg(-1) ? d(-11), respectively (P < 0.0001, r(2) = 0.59). CONCLUSIONS: Although the current recommended methionine intake of 28 mg ? kg(-1) ? d(-1) is within the CIs of our study, the estimated mean requirement is substantially higher. However, most of the infant formulas provide a methionine intake of 49-80 mg ? kg(-1) ? d( 1), which is above the upper CI of our study. This trial was registered at www.trialregister.nl as NTR1610. PMID- 22492373 TI - Contrasting effects of Bifidobacterium breve NCIMB 702258 and Bifidobacterium breve DPC 6330 on the composition of murine brain fatty acids and gut microbiota. AB - BACKGROUND: We previously showed that microbial metabolism in the gut influences the composition of bioactive fatty acids in host adipose tissue. OBJECTIVE: This study compared the effect of dietary supplementation for 8 wk with human-derived Bifidobacterium breve strains on fat distribution and composition and the composition of the gut microbiota in mice. METHODS: C57BL/6 mice (n = 8 per group) received B. breve DPC 6330 or B. breve NCIMB 702258 (10(9) microorganisms) daily for 8 wk or no supplement (controls). Tissue fatty acid composition was assessed by gas-liquid chromatography while 16S rRNA pyrosequencing was used to investigate microbiota composition. RESULTS: Visceral fat mass and brain stearic acid, arachidonic acid, and DHA were higher in mice supplemented with B. breve NCIMB 702258 than in mice in the other 2 groups (P < 0.05). In addition, both B. breve DPC 6330 and B. breve NCIMB 702258 supplementation resulted in higher propionate concentrations in the cecum than did no supplementation (P < 0.05). Compositional sequencing of the gut microbiota showed a tendency for greater proportions of Clostridiaceae (25%, 12%, and 18%; P = 0.08) and lower proportions of Eubacteriaceae (3%, 12%, and 13%; P = 0.06) in mice supplemented with B. breve DPC 6330 than in mice supplemented with B. breve NCIMB 702258 and unsupplemented controls, respectively. CONCLUSION: The response of fatty acid metabolism to administration of bifidobacteria is strain-dependent, and strain-strain differences are important factors that influence modulation of the gut microbial community by ingested microorganisms. PMID- 22492374 TI - Prospective study of methylenetetrahydrofolate reductase (MTHFR) variant C677T and risk of all-cause and cardiovascular disease mortality among 6000 US adults. AB - BACKGROUND: The association between blood homocysteine concentration and the risk of cardiovascular disease (CVD) remains controversial, but few studies have examined the association between MTHFR C677T (a proxy for high homocysteine concentration) and death from CVD. OBJECTIVE: The objective was to examine associations of MTHFR C677T, a proxy for high homocysteine concentrations, with CVD mortality and with all-cause mortality in a national representative prospective cohort of the US adult population before the introduction of mandatory folic acid fortification of flour. DESIGN: We used Mendelian randomization to examine the association of MTHFR C677T with cause-specific mortality in 5925 participants by accessing the NHANES III (1991-1994) Linked Mortality File (through 2006). RESULTS: A comparison of homozygotes at baseline showed that individuals with a TT genotype had a 2.2-MUmol/L higher homocysteine and a 1.4-ng/mL lower folate concentration, respectively, than did those with a CC genotype. The TT genotype frequency varied from 1.2% (95% CI: 0.7, 2.0) in non Hispanic blacks and 11.6% (95% CI: 9.6, 14.0) in non-Hispanic whites to 19.4% (95% CI: 16.7, 22.3) in Mexican Americans. After adjustment for ethnic group and other CVD risk factors, the MTHFR C677T TT genotype was associated with significantly lower CVD mortality (HR: 0.69; 95% CI: 0.50, 0. 95) but had no significant effect on all-cause mortality (HR: 0.79; 95% CI: 0.59, 1.05). After stratification by period of follow-up, the inverse association of MTHFR with CVD mortality was significant only in the period after introduction of mandatory folic acid fortification. CONCLUSION: The inverse association of MTHFR with CVD mortality was unexpected and highlights the need for caution in interpretation of Mendelian randomization studies, which, like other observational studies, can be influenced by chance, bias, or confounding. PMID- 22492375 TI - What is the evidence that vitamin C supplements lower blood pressure? PMID- 22492376 TI - Secular trends in pediatric BMI. PMID- 22492377 TI - Complex relations of genetic polymorphisms with nutritionally influenced biomarkers. PMID- 22492378 TI - Soda consumption and the risk of stroke in men and women. AB - BACKGROUND: Consumption of sugar-sweetened soda has been associated with an increased risk of cardiometabolic disease. The relation with cerebrovascular disease has not yet been closely examined. OBJECTIVE: Our objective was to examine patterns of soda consumption and substitution of alternative beverages for soda in relation to stroke risk. DESIGN: The Nurses' Health Study, a prospective cohort study of 84,085 women followed for 28 y (1980-2008), and the Health Professionals Follow-Up Study, a prospective cohort study of 43,371 men followed for 22 y (1986-2008), provided data on soda consumption and incident stroke. RESULTS: We documented 1416 strokes in men during 841,770 person-years of follow-up and 2938 strokes in women during 2,188,230 person-years of follow-up. The pooled RR of total stroke for >= 1 serving of sugar-sweetened soda/d, compared with none, was 1.16 (95% CI: 1.00, 1.34). The pooled RR of total stroke for >= 1 serving of low-calorie soda/d, compared with none, was 1.16 (95% CI: 1.05, 1.28). Compared with 1 serving of sugar-sweetened soda/d, 1 serving of decaffeinated coffee/d was associated with a 10% (95% CI: 1%, 19%) lower risk of stroke and 1 serving of caffeinated coffee/d with a 9% (95% CI: 0%, 17%) lower risk. Similar estimated reductions in risk were seen for substitution of caffeinated or decaffeinated coffee for low-calorie soda. CONCLUSIONS: Greater consumption of sugar-sweetened and low-calorie sodas was associated with a significantly higher risk of stroke. This risk may be reduced by substituting alternative beverages for soda. PMID- 22492379 TI - Impaired fracture healing associated with amino acid disturbances. AB - BACKGROUND: Five percent to 10% of all fracture patients experience an inadequate healing process that results in a nonunion of fracture parts. Previous experimental studies have indicated the importance of sufficient nitric oxide production from arginine during normal fracture healing. However, during conditions of stress, such as inflammation, arginine availability can become limited, which may lead to a nonunion as a result of insufficient callus formation. OBJECTIVE: The aim of this study was to measure callus and plasma amino acid concentrations in patients with and without a fracture nonunion. DESIGN: Amino acid concentrations in plasma and callus were measured with HPLC in atrophic nonunions (n = 12) and compared with those in hypertrophic nonunions (n = 12), acute fractures (n = 15), and healed fractures (n = 8). RESULTS: Arginine (61 compared with 180 MUmol/mg; P < 0.0001), citrulline (13 compared with 44 MUmol/mg; P < 0.0001), and ornithine (25 compared with 149 MUmol/mg; P < 0.0001) in callus were significantly lower in atrophic-nonunion patients than in healed fracture patients. In hypertrophic nonunions, arginine was significantly higher and ornithine was lower than in healed fractures. Plasma arginine concentrations were significantly lower in patients with hypertrophic nonunions (62 MUmol/L; P < 0.001) and acute-fracture patients (41 MUmol/L; P < 0.001) but not in atrophic nonunion patients. Plasma ornithine concentrations were lower in all groups than in acute-fracture patients. CONCLUSIONS: Amino acid concentrations were significantly changed in nonunion patients. Atrophic nonunions had lower concentrations of all amino acids, whereas hypertrophic nonunions had higher arginine and lower ornithine concentrations at fracture sites than did healed fracture and acute-fracture patients. PMID- 22492380 TI - Maternal vitamin D status and calcium intake interact to affect fetal skeletal growth in utero in pregnant adolescents. AB - BACKGROUND: Maternal calcium intake and vitamin D status may affect fetal bone development. OBJECTIVE: This study was designed to examine relations between maternal calcium intake, 25-hydroxyvitamin D [25(OH)D] status, and fetal bone growth across pregnancy. DESIGN: This was a prospective longitudinal design. Maternal 25(OH)D, parathyroid hormone, and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were determined at midgestation (~26 wk) and at delivery in 171 adolescents (<= 18 y). Dietary recalls and fetal sonograms were performed up to 3 times across gestation, and fetal femur and humerus z scores were generated. RESULTS: Fetal femur and humerus z scores and neonatal birth length were significantly greater (P < 0.03) in adolescents consuming >= 1050 mg than in those consuming <1050 mg Ca/d. Maternal 25(OH)D > 50 nmol/L was significantly positively associated with fetal femur and humerus z scores (P < 0.01). When maternal smoking, height, race, weight gain, and gestational age were controlled for, these relations remained significant. Interactions between calcium intake and 25(OH)D were evident. Calcium intake was associated with fetal femur z scores and birth length only when maternal 25(OH)D was <= 50 nmol/L (P < 0.05). Similarly, maternal 25(OH)D was associated with fetal femur and humerus z scores only when maternal calcium intake was <1050 mg/d (P < 0.03). CONCLUSIONS: Optimal calcium intake and adequate maternal vitamin D status are both needed to maximize fetal bone growth. Interactions between these nutrients were evident when either calcium or vitamin D status was limited. Improving maternal calcium intake and/or vitamin D status during pregnancy may have a positive effect on fetal skeletal development in pregnant adolescents. PMID- 22492381 TI - Analyses of single nucleotide polymorphisms in selected nutrient-sensitive genes in weight-regain prevention: the DIOGENES study. AB - BACKGROUND: Differences in the interindividual response to dietary intervention could be modified by genetic variation in nutrient-sensitive genes. OBJECTIVE: This study examined single nucleotide polymorphisms (SNPs) in presumed nutrient sensitive candidate genes for obesity and obesity-related diseases for main and dietary interaction effects on weight, waist circumference, and fat mass regain over 6 mo. DESIGN: In total, 742 participants who had lost >= 8% of their initial body weight were randomly assigned to follow 1 of 5 different ad libitum diets with different glycemic indexes and contents of dietary protein. The SNP main and SNP-diet interaction effects were analyzed by using linear regression models, corrected for multiple testing by using Bonferroni correction and evaluated by using quantile-quantile (Q-Q) plots. RESULTS: After correction for multiple testing, none of the SNPs were significantly associated with weight, waist circumference, or fat mass regain. Q-Q plots showed that ALOX5AP rs4769873 showed a higher observed than predicted P value for the association with less waist circumference regain over 6 mo (-3.1 cm/allele; 95% CI: -4.6, -1.6; P/Bonferroni corrected P = 0.000039/0.076), independently of diet. Additional associations were identified by using Q-Q plots for SNPs in ALOX5AP, TNF, and KCNJ11 for main effects; in LPL and TUB for glycemic index interaction effects on waist circumference regain; in GHRL, CCK, MLXIPL, and LEPR on weight; in PPARC1A, PCK2, ALOX5AP, PYY, and ADRB3 on waist circumference; and in PPARD, FABP1, PLAUR, and LPIN1 on fat mass regain for dietary protein interaction. CONCLUSION: The observed effects of SNP-diet interactions on weight, waist, and fat mass regain suggest that genetic variation in nutrient-sensitive genes can modify the response to diet. This trial was registered at clinicaltrials.gov as NCT00390637. PMID- 22492382 TI - Randomized controlled trial of the effectiveness of a soybean-maize-sorghum-based ready-to-use complementary food paste on infant growth in South Kivu, Democratic Republic of Congo. AB - BACKGROUND: Evidence of the effectiveness of lipid-based ready-to-use complementary foods (RUCF) at improving linear growth among infants aged 6-12 mo is scarce, and further work is warranted. OBJECTIVE: The objective was to assess the effectiveness of a fortified soybean-maize-sorghum RUCF paste compared with a fortified corn soy blend (UNIMIX) porridge on the prevalence of underweight and stunting among infants in South Kivu Province, Democratic Republic of Congo. DESIGN: Infants were randomly assigned at 6 mo of age to receive either RUCF (n = 691) or UNIMIX (n = 692) for 6 mo. In addition to admission and monthly anthropometric measurements, hemoglobin, triglyceride, and cholesterol were measured at enrollment and at the end of the study. RESULTS: No significant differences in the prevalence of stunting (RUCF: 48.6%; UNIMIX: 46.4%; P = 0.31), the prevalence of underweight (RUCF: 20.4%; UNIMIX: 18.2%; P = 0.42), or weight gain (RUCF: 1.2 +/- 0.7 kg; UNIMIX: 1.3 +/- 0.7 kg; P = 0.08) were found. A small but statistically significant difference in length gain (RUCF: 5.2 +/- 2.0; UNIMIX: 5.4 +/- 2.0; P = 0.03) was found. No significant differences in the concentrations of hemoglobin, serum triglyceride, and serum cholesterol were found between the 2 groups. CONCLUSION: No significant differences were found between the RUCF and UNIMIX in the reduction of the prevalence of stunting and underweight at 12 mo of age among rural Congolese infants. This trial was registered at controlled-trials.com as ISRCTN20267635. PMID- 22492383 TI - A meta-analysis to determine the effect on survival of platelet transfusions in patients with either spontaneous or traumatic antiplatelet medication-associated intracranial haemorrhage. AB - OBJECTIVES: The aim of this study was to evaluate by meta-analysis the current level of evidence in order to establish the impact of a platelet transfusion on survival in patients on pre-injury antiplatelet agents who sustain an intracranial haemorrhage (either spontaneous or traumatic). DESIGN: This was a meta-analysis; the MEDLINE Database was searched using the PubMed interface and the Ovid interface. CINAHL and EMBASE Databases were also searched. The search was performed to identify randomised controlled trials (RCT)'s case-controlled studies or nested case-controlled studies. Comparing the outcome (death or survival) of patients with intracranial haemorrhage (ICH) and pre-injury antiplatelet agents who received a platelet transfusion against a similar cohort of patients who did not receive a platelet transfusion. RESULTS: 499 citations were obtained from the PubMed search. 31 full articles were reviewed from 34 abstracts. 6 studies were found suitable for the meta-analysis. No randomised controlled studies were identified. 2 of the six studies were in patients with spontaneous ICH. The remaining four studies were in patients with traumatic intracranial haemorrhage. Significant heterogeneity was present between the studies, I(2)=58.276. The random effects model was therefore the preferred model, this produced a pooled OR for survival of 0.773 (95% CI 0.414 to 1.442). CONCLUSIONS: The results of this meta-analysis has shown, based upon six small studies, that there was no clear benefit in terms of survival in the administration of a platelet transfusion to patients with antiplatelet-associated ICH. Further work is required in order to establish any potential benefit in the administration of a platelet transfusion in patients with spontaneous or traumatic intracranial haemorrhage who were on pre-injury antiplatelet agents. PMID- 22492384 TI - Intimate partner violence and prescription of potentially addictive drugs: prospective cohort study of women in the Oslo Health Study. AB - OBJECTIVES: To investigate the prescription of potentially addictive drugs, including analgesics and central nervous system depressants, to women who had experienced intimate partner violence (IPV). DESIGN: Prospective population-based cohort study. SETTING: Information about IPV from the Oslo Health Study 2000/2001 was linked with prescription data from the Norwegian Prescription Database from 1 January 2004 through 31 December 2009. PARTICIPANTS: The study included 6081 women aged 30-60 years. MAIN OUTCOME MEASURES: Prescription rate ratios (RRs) for potentially addictive drugs derived from negative binomial models, adjusted for age, education, paid employment, marital status, chronic musculoskeletal pain, mental distress and sleep problems. RESULTS: Altogether 819 (13.5%) of 6081 women reported ever experiencing IPV: 454 (7.5%) comprised physical and/or sexual IPV and 365 (6.0%) psychological IPV alone. Prescription rates for potentially addictive drugs were clearly higher among women who had experienced IPV: crude RRs were 3.57 (95% CI 2.89 to 4.40) for physical/sexual IPV and 2.13 (95% CI 1.69 to 2.69) for psychological IPV alone. After full adjustment RRs were 1.83 (1.50 to 2.22) for physical/sexual IPV, and 1.97 (1.59 to 2.45) for psychological IPV alone. Prescription rates were increased both for potentially addictive analgesics and central nervous system depressants. Furthermore, women who reported IPV were more likely to receive potentially addictive drugs from multiple physicians. CONCLUSIONS: Women who had experienced IPV, including psychological violence alone, more often received prescriptions for potentially addictive drugs. Researchers and clinicians should address the possible adverse health and psychosocial impact of such prescription and focus on developing evidence-based healthcare for women who have experienced IPV. PMID- 22492385 TI - Oral phenotype and scoring of vascular Ehlers-Danlos syndrome: a case-control study. AB - OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare genetic condition related to mutations in the COL3A1 gene, responsible of vascular, digestive and uterine accidents. Difficulty of clinical diagnosis has led to the design of diagnostic criteria, summarised in the Villefranche classification. The goal was to assess oral features of vEDS. Gingival recession is the only oral sign recognised as a minor diagnostic criterion. The authors aimed to check this assumption since bibliographical search related to gingival recession in vEDS proved scarce. DESIGN: Prospective case-control study. SETTING: Dental surgery department in a French tertiary hospital. PARTICIPANTS: 17 consecutive patients with genetically proven vEDS, aged 19-55 years, were compared with 46 age- and sex-matched controls. OBSERVATIONS: Complete oral examination (clinical and radiological) with standardised assessment of periodontal structure, temporomandibular joint function and dental characteristics were performed. COL3A1 mutations were identified by direct sequencing of genomic or complementary DNA. RESULTS: Prevalence of gingival recession was low among patients with vEDS, as for periodontitis. Conversely, patients showed marked gingival fragility, temporomandibular disorders, dentin formation defects, molar root fusion and increased root length. After logistic regression, three variables remained significantly associated to vEDS. These variables were integrated in a diagnostic oral score with 87.5% and 97% sensitivity and specificity, respectively. CONCLUSIONS: Gingival recession is an inappropriate diagnostic criterion for vEDS. Several new specific oral signs of the disease were identified, whose combination may be of greater value in diagnosing vEDS. PMID- 22492386 TI - Thirty-day mortality after elective and emergency total colectomy in Danish patients with inflammatory bowel disease: a population-based nationwide cohort study. AB - OBJECTIVES: The purpose of this investigation was to assess 30-day mortality among Danish inflammatory bowel diseases (IBD) patients and to examine the prognostic impact of hospital total colectomy volume, age, gender and comorbidity. DESIGN: Cohort study. SETTING: The authors compared 30-day survival over the period 1996-2010 among 2889 IBD patients with total colectomy identified in the Danish National Registry of Patients. This registry covers all hospitals in Denmark. Postoperative survival patterns for patients with ulcerative colitis and Crohn's disease were compared, using proportional hazard regression. The regression model accounted for the timing of surgery, hospital total colectomy volume, age, gender and comorbidity. PARTICIPANTS: Patients were enrolled in the study if they had a hospital registry diagnosis of IBD, with accompanying procedure codes for total colectomy (see codes in online appendix table 1). Hospitalisations were described as elective or emergency, and patients were categorised as having Crohn's disease, ulcerative colitis or as a mixed group. OUTCOME MEASURES: Primary outcome measure was 30-day mortality. RESULTS: Among 2889 IBD patients with total colectomy, 1439 (50%) underwent surgery during an emergency hospitalisation. Thirty-day mortality was 5.3% (76/1439) among emergency cases compared with 1% (14/1450) among elective cases. The highest mortality (8.1%; 11 of 136) was observed among Crohn's patients undergoing emergency surgery. The mortality of patients with ulcerative colitis undergoing emergency surgery was 5.2% (55/1056). After elective surgery, the 30-day mortality was 0.9% (8/938) among patients with ulcerative colitis and 1.5% (3/201) among Crohn's disease patients. Low hospital total colectomy volume, comorbidity and high age were associated with increased 30-day mortality in ulcerative colitis patients undergoing emergency surgery. CONCLUSION: Emergency total colectomy among patients with ulcerative colitis and particularly Crohn's disease is associated with substantial 30-day mortality. PMID- 22492387 TI - How does a history of psychiatric hospital care influence access to coronary care: a cohort study. AB - OBJECTIVES: Equity in physical health of patients with severe mental disorders is a major public health concern. The aim of this cohort study was to examine equity in access to coronary care among persons with a history of severe mental disorder in 1998-2009. DESIGN: Nationwide register linkage cohort study. SETTING: Hospital care in the Finnish healthcare system. POPULATION: The study population consisted of all residents in Finland aged 40 years or older. All hospital discharges in 1998-2009 with a diagnosis of coronary heart disease or severe mental disorder were obtained from the Care Register. PRIMARY OUTCOME MEASURES: Data on deaths, hospitalisations and coronary revascularisations were linked to the data set using unique personal identifiers. RESULTS: Patients with severe mental disorders had increased likelihood of hospital care due to coronary heart disease (RR between 1.22, 95% CI 1.18 to 1.25 and 1.93, 1.84 to 2.03 in different age groups) and in 40-49-year-olds also increased likelihood of revascularisation (1.26, 1.16 to 1.38) compared with persons without mental disorders. Access to revascularisation was poorer among older persons with severe mental disorders in relation to need suggested by increased coronary mortality. In spite of excess coronary mortality (ranging from 0.95, 0.89 to 1.01 to 3.16, 2.82 to 3.54), worst off were people with a history of psychosis, who did not have increased use of hospital care and had lower likelihood of receiving revascularisations (ranging from 0.44, 0.37 to 0.51 to 0.74, 0.59 to 0.93) compared with persons without mental disorders. CONCLUSIONS: Selective mechanisms seem to be at work in access to care and revascularisations among people with severe mental disorders. Healthcare professionals need to be aware of the need for targeted measures to address challenges in provision of somatic care among people with severe mental health problems, especially among people with psychoses and old people. PMID- 22492388 TI - The apparent breastfeeding paradox in very preterm infants: relationship between breast feeding, early weight gain and neurodevelopment based on results from two cohorts, EPIPAGE and LIFT. AB - CONTEXT: Supplementation of breast milk is difficult once infants suckle the breast and is often discontinued at end of hospitalisation and after discharge. Thus, breastfed preterm infants are exposed to an increased risk of nutritional deficit with a possible consequence on neurodevelopmental outcome. OBJECTIVE: To assess the relationship between breast feeding at time of discharge, weight gain during hospitalisation and neurodevelopmental outcome. DESIGN: Observational cohort study. SETTING: Two large, independent population-based cohorts of very preterm infants: the Loire Infant Follow-up Team (LIFT) and the EPIPAGE cohorts. PATIENTS: 2925 very preterm infants alive at discharge. MAIN OUTCOME MEASURE: Suboptimal neurodevelopmental outcome, defined as a score in the lower tercile, using Age and Stages Questionnaire at 2 years in LIFT and Kaufman Assessment Battery for Children Test at 5 years in EPIPAGE. Two propensity scores for breast feeding at discharge, one for each cohort, were used to reduce bias. RESULTS: Breast feeding at time of discharge concerned only 278/1733 (16%) infants in LIFT and 409/2163 (19%) infants in EPIPAGE cohort. Breast feeding is significantly associated with an increased risk of losing one weight Z-score during hospitalisation (LIFT: n=1463, adjusted odd ratio (aOR)=2.51 (95% CI 1.87 to 3.36); EPIPAGE: n=1417, aOR=1.55 (95% CI 1.14 to 2.12)) and with a decreased risk for a suboptimal neurodevelopmental assessment (LIFT: n=1463, aOR=0.63 (95% CI 0.45 to 0.87); EPIPAGE: n=1441, aOR=0.65 (95% CI 0.47 to 0.89) and an increased chance of having a head circumference Z-score higher than 0.5 at 2 years in LIFT cohort (n=1276, aOR=1.43 (95% CI 1.02 to 2.02)) and at 5 years in EPIPAGE cohort (n=1412, aOR=1.47 (95% CI 1.10 to 1.95)). CONCLUSIONS: The observed better neurodevelopment in spite of suboptimal initial weight gain could be termed the 'apparent breastfeeding paradox' in very preterm infants. Regardless of the mechanisms involved, the current data provide encouragement for the use of breast feeding in preterm infants. PMID- 22492389 TI - Loss of epithelial membrane protein-2 expression confers an independent prognosticator in nasopharyngeal carcinoma: a cohort study. AB - OBJECTIVE: To evaluate the expression of epithelial membrane protein-2 (EMP2) protein and its clinicopathological associations in patients with nasopharyngeal carcinoma. DESIGN: Retrospective population-based cohort study. SETTING: This study was based on a biobank in Chi-Mei Medical Center (Tainan, Taiwan) from 1993 to 2002. PARTICIPANTS: Biopsies of 124 consecutive nasopharyngeal carcinoma patients without initial distant metastasis and treated with consistent guidelines were assessed. Immunoexpressions of EMP2 were analysed and the outcomes were correlated with clinicopathological features and patient survivals. PRIMARY AND SECONDARY OUTCOME MEASURES: Immunoexpressions of EMP2 were analyzed and the outcomes were correlated with clinicopathological features and patient survivals. RESULTS: Loss of EMP2 expression (49.2%) was correlated with advanced primary tumour (p=0.044), nodal status (p=0.045) and the 7th American Joint Committee on Cancer stage (p=0.027). In multivariate analyses, loss of EMP2 expression emerged as an independent prognosticator for worse disease-specific survival (DSS; p=0.015) and local recurrence-free survival (LRFS; p=0.030), along with the American Joint Committee on Cancer stages III-IV (p=0.034, DSS; p=0.023, LRFS). CONCLUSIONS: Loss of EMP2 expression is common and associated with adverse prognosticators and might confer tumour aggressiveness through hampering its interaction with specific membrane protein(s) and hence the downstream signal transduction pathway(s). PMID- 22492390 TI - Societal preferences for standard health insurance coverage in the Netherlands: a cross-sectional study. AB - INTRODUCTION: Cost-effectiveness is an important criterion in the decision to cover interventions in health insurance packages. One of the outcome measures, the quality-adjusted life year, has been criticised on its assumptions and implications concerning life expectancy and quality of life. Several studies have been conducted that measured societal preferences concerning healthcare rationing decisions. These studies mainly focused on one attribute. To adjust quality adjusted life year maximisation in accordance with societal preferences, the relative importance of attributes should be studied. The present study aims to measure the relative importance of age, gender, socioeconomic status, pre intervention health state, treatment effect, chance of treatment success and number of people in need of the intervention. A secondary objective is to compare the validity of the willingness to pay method with the validity of a relatively new preference elicitation method, best-worst scaling. METHODS AND ANALYSIS: A representative sample of 2000 Dutch citizens, over 18 years of age, are recruited to complete a web-based survey containing treatment scenarios. The scenarios present different levels of attributes. Respondents are asked to select one of the four scenarios that they prefer to be covered by the Dutch standard health insurance package and one that they prefer not to be covered. They are also asked to indicate how much they are willing to pay for each treatment scenario. At the end of the survey, respondents are asked to rate every attribute on a 1-10 scale. Two versions of the questionnaire are developed which differ on the framing, that is, treatments can be added to or removed from the insurance package. The data will be analysed by means of sequential conditional logit analysis (best-worst scaling) and analysis of variance (willingness to pay). ETHICS AND DISSEMINATION: The protocol is reviewed and approved by the medical ethical committee of the University Medical Center Leiden. PMID- 22492391 TI - Individual neurons in the rat lateral habenular complex project mostly to the dopaminergic ventral tegmental area or to the serotonergic raphe nuclei. AB - The lateral habenular complex (LHb) is a bilateral epithalamic brain structure involved in the modulation of ascending monoamine systems in response to afferents from limbic regions and basal ganglia. The LHb is implicated in various biological functions, such as reward, sleep-wake cycle, feeding, pain processing, and memory formation. The modulatory role of the LHb is partially assumed by putative spontaneously active LHb neurons projecting to the dopaminergic ventral tegmental area (VTA) and to the serotonergic median (MnR) and dorsal raphe nuclei (DR). All four nuclei form a complex and coordinated network to evoke appropriate responses to reward-related stimuli. At present it is not known whether individual LHb neurons project to only one or to more than one monoaminergic nucleus. To answer this question, we made dual injections of two different retrograde tracers into the rat VTA and either DR or MnR. Tracers were visualized by immunohistochemistry. In coronal sections, the different retrogradly labeled habenular neurons were quantified and assigned to the corresponding habenular subnuclei. Our results show that 1) the distribution of neurons in the LHb projecting to the three monoamine nuclei is similar and exhibits a great overlap, 2) the vast majority of LHb projection neurons target one monoaminergic nucleus only, and 3) very few, heterogeneously distributed LHb neurons project to both dopaminergic and serotonergic nuclei. These results imply that the LHb forms both separate and interconnected circuits with each monoaminergic nucleus, permitting the LHb to modulate its output to different monoamine systems either independently or jointly. PMID- 22492392 TI - Dual-time-point 18F-FDG PET/CT in patients with colorectal cancer: clinical value of early delayed scanning. AB - OBJECTIVE: In dual-time-point PET/CT, early delayed scanning (D-1) just after the completion of whole body scanning (E) is easy to perform without additional radiation exposure and repositioning. Our aim was to assess the clinical value of D-1 compared with conventional delayed scanning (D-2). METHODS: Our institutional review board approved this retrospective study. Fifty-four patients with known or suspected colorectal cancer underwent (18)F-FDG PET/CT at our institution. The E scan at 1-h post-injection was followed by D-1 at 85 +/- 7 min post-injection and D-2 at 124 +/- 7 min post-injection. The clinical value of D-1 was evaluated by comparing diagnostic performance with D-2 for differentiating physiologic from pathological uptake and for staging colorectal cancer. Colonoscopic findings, histopathological results and clinical follow-up including radiological findings were used as reference standards. RESULTS: Thirty-two, eight and 73 focal or short segmental FDG foci by physiologic processes in the colon/rectum, the small intestine and the ureter, respectively, noted in the E scan were evaluated in this study. Using D-1 and D-2, 14/32 (44%) and 17/32 (53%) in the colon/rectum, 5/8 (63%) and 8/8 (100%) in the small intestine, and 55/73 (75%) and 69/73 (95%) in the ureter, respectively, were accurately interpreted as physiologic with the change of intensity and/or shape/location. A significant difference between D-1 and D-2 was observed in the ureter, but not in the bowel. The 55 colorectal cancers were finally diagnosed in 52 patients. In the staging of colorectal cancer, there were no significant differences among the three scans in the lesion based detectability, the patient-based sensitivity, specificity and accuracy for the identification of primary tumors, nodal and hepatic metastases, and dissemination. CONCLUSIONS: Neither D-1 nor D-2 improved staging of colorectal cancer. However, delayed scans yielded information useful for differentiating physiologic uptake from pathological uptake and D-1 may provide comparable efficacy with D-2 in the bowel. Because of the ease of acquisition, the D-1 scan was considered a practical way to reduce false-positives in the abdomen and possibly helpful to avoid unnecessary additional invasive examinations, such as colonoscopy. PMID- 22492393 TI - [Virtual versus traditional autopsy]. PMID- 22492394 TI - RT-PCR test for detecting porcine sapovirus in weanling piglets in Hunan Province, China. AB - The prevalence of porcine sapovirus infection in weanling pigs was investigated in Hunan Province, China, between August 2006 and October 2007. A total of 153 diarrheic fecal samples from ten intensive pig farms from ten representative administrative regions in Hunan province were examined for porcine sapoviruses using RT-PCR. Twenty-two of 153 (14.37 %) samples were found to contain porcine sapoviruses. Phylogenetic analysis showed that all the porcine sapovirus isolates in Hunan Province belonged to the porcine sapovirus genogroup III. The results of the present investigation have implications for the control of porcine sapovirus infection in pigs in Hunan Province, China. PMID- 22492395 TI - Temporary silicon-tethered ring-closing metathesis: recent advances in methodology development and natural product synthesis. AB - Temporary silicon-tethered ring-closing metathesis represents an important cross coupling strategy for the formation of medium-sized silacycles. These intermediates are valuable synthons in organic synthesis due to their propensity to undergo a facile refunctionalization through protodesilylation, oxidation, silane-group transfer or transmetallation. A particularly attractive utility of this methodology is an application in the synthesis of biologically important natural products. The purpose of this review article is to highlight the recent progress in methodology development and its strategic application toward the target-directed synthesis. PMID- 22492397 TI - SABER: a computational method for identifying active sites for new reactions. AB - A software suite, SABER (Selection of Active/Binding sites for Enzyme Redesign), has been developed for the analysis of atomic geometries in protein structures, using a geometric hashing algorithm (Barker and Thornton, Bioinformatics 2003;19:1644-1649). SABER is used to explore the Protein Data Bank (PDB) to locate proteins with a specific 3D arrangement of catalytic groups to identify active sites that might be redesigned to catalyze new reactions. As a proof-of principle test, SABER was used to identify enzymes that have the same catalytic group arrangement present in o-succinyl benzoate synthase (OSBS). Among the highest-scoring scaffolds identified by the SABER search for enzymes with the same catalytic group arrangement as OSBS were L-Ala D/L-Glu epimerase (AEE) and muconate lactonizing enzyme II (MLE), both of which have been redesigned to become effective OSBS catalysts, demonstrated by experiments. Next, we used SABER to search for naturally existing active sites in the PDB with catalytic groups similar to those present in the designed Kemp elimination enzyme KE07. From over 2000 geometric matches to the KE07 active site, SABER identified 23 matches that corresponded to residues from known active sites. The best of these matches, with a 0.28 A catalytic atom RMSD to KE07, was then redesigned to be compatible with the Kemp elimination using RosettaDesign. We also used SABER to search for potential Kemp eliminases using a theozyme predicted to provide a greater rate acceleration than the active site of KE07, and used Rosetta to create a design based on the proteins identified. PMID- 22492399 TI - Establishing early enteral nutrition with the use of self-advancing postpyloric feeding tube in critically ill children. AB - INTRODUCTION: Early nutrition support is an integral part of the care of critically ill children. Early enteral nutrition (EN) improves nitrogen balance and prevents bacterial translocation and gut mucosal atrophy. Adequate EN is often not achieved as gastric feeds are not tolerated and placing postpyloric feeding tubes can be difficult. Spontaneous transpyloric passage of standard feeding tubes without endoscopic intervention or use of anesthesia can range from 30%-80%. The authors report on their experience with a 14Fr polyurethane self advancing jejunal feeding tube in a pediatric population. These tubes have been used in the adult population with success, but to the authors' knowledge, there have been no reports of its use in the pediatric age group. CASE SERIES: The authors present 7 critically ill patients 8-19 years old, admitted to the pediatric intensive care unit, in whom prolonged recovery, inability to tolerate gastric feeds, and dependence on ventilator were predicted at the outset. The jejunal feeding tube was successfully placed on first attempt at the bedside in all 7 patients within the first 24 hours without the use of a promotility agent or endoscopic intervention. Nutrition goal achieved within 48 hours of feeding tube placement was reported for each patient. This case series demonstrates that children fed via the small bowel reached their nutrition goal earlier and did not require parenteral nutrition. CONCLUSION: The self-advancing jejunal feeding tube can be used effectively to establish early EN in critically ill children. PMID- 22492400 TI - In-vivo patellar tendon kinematics during weight-bearing deep knee flexion. AB - This study quantified in-vivo 3D patellar tendon kinematics during weight-bearing deep knee bend beyond 150 degrees . Each knee was MRI scanned to create 3D bony models of the patella, tibia, femur, and the attachment sites of the patellar tendon on the distal patella and the tibial tubercle. Each attachment site was divided into lateral, central, and medial thirds. The subjects were then imaged using a dual fluoroscopic image system while performing a deep knee bend. The knee positions were determined using the bony models and the fluoroscopic images. The patellar tendon kinematics was analyzed using the relative positions of its patellar and tibial attachment sites. The relative elongations of all three portions of the patellar tendon increased similarly up to 60 degrees . Beyond 60 degrees , the relative elongation of the medial portion of the patellar tendon decreased as the knee flexed from 60 degrees to 150 degrees while those of the lateral and central portions showed continuous increases from 120 degrees to 150 degrees . At 150 degrees , the relative elongation of the medial portion was significantly lower than that of the central portion. In four of seven knees, the patellar tendon impinged on the tibial bony surface at 120 degrees and 150 degrees of knee flexion. These data may provide useful insight into the intrinsic patellar tendon biomechanics during a weight-bearing deep knee bend and could provide biomechanical guidelines for future development of total knee arthroplasties that are intended to restore normal knee function. PMID- 22492401 TI - Arbuscular mycorrhizal colonization of giant sequoia (Sequoiadendron giganteum) in response to restoration practices. AB - Interactions with soil microbiota determine the success of restoring plants to their native habitats. The goal of our study was to understand the effects of restoration practices on interactions of giant sequoia Sequoiadendron giganteum with arbuscular mycorrhizal (AM) fungi (Glomeromycota). Natural regeneration of Sequoiadendron is threatened by the absence of severe fires that create forest canopy gaps. Generating artificial canopy gaps offers an alternative tool for giant sequoia restoration. We investigated the effect of regeneration practices, including (i) sapling location within gaps, (ii) gap size and (iii) soil substrate, on AM fungal colonization of giant sequoia sapling roots in a native giant sequoia grove of the Sierra Nevada, California. We found that the extent of AM fungal root colonization was positively correlated with sapling height and light availability, which were related to the location of the sapling within the gap and the gap size. While colonization frequency by arbuscules in saplings on ash substrate was higher relative to saplings in mineral soil, the total AM fungal root colonization was similar between the substrates. A negative correlation between root colonization by Glomeromycota and non-AM fungal species indicated antagonistic interactions between different classes of root-associated fungi. Using DNA genotyping, we identified six AM fungal taxa representing genera Glomus and Ambispora present in Sequoiadendron roots. Overall, we found that AM fungal colonization of giant sequoia roots was associated with availability of plant-assimilated carbon to the fungus rather than with the AM fungal supply of mineral nutrients to the roots. We conclude that restoration practices affecting light availability and carbon assimilation alter feedbacks between sapling growth and activity of AM fungi in the roots. PMID- 22492402 TI - Anthracnose disease of centipedegrass turf caused by Colletotrichum eremochloae, a new fungal species closely related to Colletotrichum sublineola. AB - Colletotrichum is a cosmopolitan, anamorphic fungal genus responsible for anthracnose disease in hundreds of plant species worldwide, including members of the Poaceae. Anthracnose disease of the widely planted, non-native, warm-season lawn grass, Eremochloae ophiuroides (centipedegrass), is commonly encountered in the southern United States, but the causal agent has never been identified. We use DNA sequence data from modern cultures and archival fungarium specimens in this study to determine the identity of the fungus responsible for centipedegrass anthracnose disease and provide experimental confirmation of pathogenicity. C. eremochloae sp. nov., a pathogen of centipedegrass, is proposed based on phylogenetic evidence from four sequence markers (Apn2, Apn2/ Mat1, Sod2, ITS). C. eremochloae isolates from centipedegrass shared common morphology and phenotype with C. sublineola, a destructive pathogen of cultivated sorghum and Johnsongrass weeds (Sorghum halepense, S. vulgaris). Molecular phylogenetic analysis identified C. eremochloae and C. sublineola as closely related sister taxa, but genealogical concordance supported their distinction as unique phylogenetic species. Fixed nucleotide differences between C. eremochloae and C. sublineola were observed from collections of these fungi spanning 105 y, including the 1904 lectotype specimen of C. sublineola. C. eremochloae was identified from a fungarium specimen of centipedegrass intercepted at a USA port from a 1923 Chinese shipment; the multilocus sequence from this specimen was identical to modern samples of the fungus. Thus, it appears that the fungus might have migrated to the USA around the same time that centipedegrass first was introduced to the USA in 1916 from China, where the grass is indigenous. The new species C. eremochloae is described and illustrated, along with a description and discussion of C. sublineola based on the lectotype and newly designated epitype. PMID- 22492403 TI - Fusarium azukicola sp. nov., an exotic azuki bean root-rot pathogen in Hokkaido, Japan. AB - We report on the phenotypic, molecular phylogenetic and pathogenic characterization of a novel azuki bean (Vigna angularis) root-rot (BRR) pathogen from Hokkaido, Japan, which formally is described herein as Fusarium azukicola. This species can be distinguished phenotypically from the other Phaseolus/Vigna BRR and soybean sudden-death syndrome (SDS) pathogens by the production of wider and longer four-septate conidia cultured on SNA. Molecular phylogenetic analyses of four anonymous intergenic loci, a portion of the translation elongation factor (EF-1alpha) gene and the nuclear ribosomal intergenic spacer region (IGS rDNA) strongly support the genealogical exclusivity of F. azukicola with respect to the other soybean SDS and BRR pathogens within Clade 2 of the F. solani species complex (FSSC). Evolutionary relationships of F. azukicola to other members of the SDS-BRR clade, however, are unresolved by phylogenetic analyses of the individual and combined datasets, with the exception of the IGS rDNA partition, which strongly supports it as a sister of the soybean SDS pathogen F. brasiliense. A multilocus genotyping assay is updated to include primer probes that successfully distinguish F. azukicola from the other soybean SDS and BRR pathogens. Results of a pathogenicity experiment reveal that the F. azukicola isolates are able to induce root-rot symptoms on azuki bean, mung bean (Vigna radiata), kidney bean (Phaseolus vulgaris) and soybean (Glycine max), as well as typical SDS foliar symptoms on soybean. Our hypothesis is that F. azukicola evolved in South America and was introduced to Hokkaido, Japan, on azuki bean but its possible route of introduction remains unknown. PMID- 22492404 TI - Phytophthora aquimorbida sp. nov. and Phytophthora taxon 'aquatilis' recovered from irrigation reservoirs and a stream in Virginia, USA. AB - Two distinct subgroups (L2 and A(-2)) were recovered from irrigation reservoirs and a stream in Virginia, USA. After molecular, morphological and physiological examinations, the L2 subgroup was named Phytophthora aquimorbida and the A(-2) designated as Phytophthora taxon 'aquatilis'. Both taxa are homothallic. P. aquimorbida is characterized by its noncaducous and nonpapillate sporangia, catenulate and radiating hyphal swellings and thick-walled plerotic oospores formed in globose oogonia mostly in the absence of an antheridium. P. taxon 'aquatilis' produces plerotic oospores in globose oogonia mostly with a paragynous antheridium. It has semi-papillate, caducous sporangia with variable pedicels, but it does not have hyphal swelling. Analyses of ITS, CO1, beta tubulin and NADH1 sequences revealed that P. aquimorbida is closely related to P. hydropathica, P. irrigata and P. parsiana, and P. taxon 'aquatilis' is related to P. multivesiculata. The optimum temperature for culture growth is 30 and 20 C for P. aquimorbida and P. taxon 'aquatilis' respectively. Both taxa were pathogenic to rhododendron plants and caused root discoloration, pale leaves, wilting, tip necrosis and dieback. Their plant biosecurity risk also is discussed. PMID- 22492405 TI - Molecular, proteomic and morphological characterization of the ascomycete Guignardia bidwellii, agent of grape black rot: a polyphasic approach to fungal identification. AB - Guignardia bidwellii is the etiological agent of grape black rot, a disease affecting Vitis and other Vitaceae that can cause heavy crop losses in vineyards. Its identification is based mainly on morphological characters and the symptoms on plants but, due to their variability, they may be difficult to interpret to reliably distinguish the pathogen to species. To date, despite the economic importance of G. bidwellii, no molecular investigations have been carried out on Vitis isolates and few sequence data are available for cultures derived from ornamental host plants. We analyzed samples of G. bidwellii collected from grapevine cultivars and ornamental plants of various geographic origins by morphological, molecular and proteomic techniques, including ITS1-ITS2 regions and calmodulin gene sequencing, as well as matrix-assisted laser desorption/ionization analysis by time-of-flight mass spectrometry (MALDI-TOF MS). This polyphasic approach allowed assessing the phylogenetic relationships among the different isolates and suggested the existence of two distinct species. The advantages of a polyphasic approach for the identification of G. bidwellii are highlighted. PMID- 22492406 TI - Development and application of a TaqMan real-time PCR assay for rapid detection of Magnaporthe poae. AB - In North America, one of the most important root diseases of Poa and Festuca turf is summer patch, caused by Magnaporthe poae. Detection and identification of M. poae in infected roots by conventional culture-based methods is difficult and time consuming, typically taking 3 wk or longer to accomplish. In this study, a culture-independent, TaqMan real-time PCR assay was developed for the detection of M. poae from the roots of fungicide treated and non-treated Kentucky bluegrass (Poa pratensis) turf. The assay was validated with the target pathogen, closely related fungal species and a number of other microorganisms that inhabit the same host and soil environment. This assay was more sensitive (could detect as little as 3.88 pg genomic DNA of M. poae), rapid and accurate compared to direct microscopic observation and isolation on a selective medium. The real-time PCR detection results corresponded closely to visual assessments of disease severity in the field. Utilization of this assay in diagnostic laboratories will enable turfgrass managers to more quickly and effectively detect and potentially reduce fungicide usage through early and accurate identification of the pathogen. PMID- 22492407 TI - Stipitate stereoid basidiocarps have evolved multiple times. AB - Stipitate stereoid fungi are Basidiomycetes with a stipe, a spathulate-to funnel shaped pileus, a smooth hymenophore, and hyaline, smooth spores. Representatives of the genera Cotylidia, Cymatoderma, Muscinupta, Podoscypha and Stereopsis were subjected to molecular phylogenetic analyses based on nuclear ribosomal large subunit, 5.8S and ITS sequences. For four of the genera the type species was included in analyses. Stereopsis radicans, the type species of Stereopsis, forms a lineage with the corticioid species Clavulicium globosum but could not be placed in any of the presently accepted orders within Agaricomycotina. Stereopsis vitellina falls within the Atheliales, making it the first pileus- and stipe forming fungus recovered in this order. Cotylidia and Muscinupta again are shown to be members of the Hymenochaetales, whereas Cymatoderma and Podoscypha belong in the Polyporales. Cymatoderma is polyphyletic and Cymatoderma sensu stricto is separated from other stipitate stereoid fungi in the Polyporales, whereas the remaining Cymatoderma species are nested within a well supported clade holding all Podoscypha species but also Abortiporus biennis. PMID- 22492408 TI - Puccinia chunjii, a close relative of the cereal stem rusts revealed by molecular phylogeny and morphological study. AB - A rust specimen with macroscopic similarities to the cereal stem rusts was collected on Elymus sp. from Gansu province, China. Phylogenetic analyses of ITS and COI DNA sequences indicated the fungus was closely related but distinct as a strongly supported sister taxon to the Puccinia graminis species complex. Microscopic examination revealed diagnostic teliospore characteristics, differentiating it from P. graminis and other morphologically similar rusts. Herein, we designate a name for this new lineage, Puccinia chunjii sp. nov. PMID- 22492409 TI - Description and life cycle of a new Physarum (Myxomycetes) from the Atacama Desert in Chile. AB - A new species of Physarum (Myxomycetes), Physarum atacamense is described in this paper, and details are provided on its life cycle as observed in spore-to-spore culture in agar. The new species was collected during studies of the Atacama Desert in Chile. It has been collected directly in the field and isolated in moist chamber cultures prepared with material from an endemic cactus. The combination of characters that make this species unique in the genus are its large fusiform nodes of the capillitium, its long, bicolored stalk and the very dark brown and densely warted angular spores. The morphology of specimens of this myxomycete was examined with scanning electron microscopy and light microscopy, and micrographs of relevant details and life cycle stages are included in this paper. The importance of resistant stages in the life cycle of this myxomycete is stressed, and the close association of this myxomycete with its plant substrates is discussed. PMID- 22492410 TI - [The wide focus of internal medicine]. PMID- 22492411 TI - [Knowledge and management of hepatitis B virus infected patients in Germany]. AB - BACKGROUND AND AIM: Hepatitis B is a significant health burden in Germany. The aim of this study was (I) to gain more information on knowledge of hepatitis B patients and patient management considering epidemiologic and socio-economic factors, (II) to investigate the knowledge of relatives of patients with hepatitis B about liver disease, modes of infection and possibilities of prevention. PATIENTS AND METHODS: Structured questionnaires were sent to 1000 patients with hepatitis B as a project of the Model Region North of the German network of excellence for viral hepatitis. The patients were asked to forward additional questionnaires to their relatives and household members. RESULTS: 312 (31 %) questionnaires were sent back and evaluated. The majority of responding patients had an immigration background (75 %). The knowledge of hepatitis B patients about their disease status was very heterogeneous. While most of them were aware of their ALT-values, only some patients knew their HBV viral loads. Patients with a low socio-economic status consulted physicians more often but did not receive medical examinations more frequently. The knowledge of relatives (384 relatives from families of 216 patients) about the mode of transmission and the possibilities of prevention were also heterogeneous. Only 84 % of the partners and children were vaccinated against hepatitis B and only 75 % of relatives knew that condoms protect against HBV infection. CONCLUSION: Not only patients with hepatitis B but also relatives and household members should be informed about consequences of liver disease and HBV infection. The poor vaccination coverage even of sexual partners of HBV-infected individuals requires attention and should lead to a better education. PMID- 22492412 TI - [Digital necrosis in a patient with atherosclerosis: also a paraneoplasia?]. AB - HISTORY AND ADMISSION FINDINGS: A 59-year-old man was admitted with an acral necrosis of the left 3rd finger, which had developed during several weeks. Furthermore, the patient complained of diarrhoea. INVESTIGATIONS: Acral light plethysmography showed critical ischemia of digitus II and V, and impaired distal perfusion of digitus I and IV. Duplex sonography revealed atherosclerotic plaques in the supraaortal vessels with stenosis of the left axillary artery which was confirmed by ultrasound. However, no differences in the pressure of ulnar and radial arteries existed. Colonoscopy and abdominal computed tomography revealed two colon neoplasms, including hepatic metastasis. TREATMENT AND COURSE: The stenosis of the left axillary artery was considered as the source of distal embolisation. However, after morphologically successful angioplasty distal necrosis worsened with involvement of additional fingers. Later in the course, diagnostic work-up of diarrhoa established the diagnosis of metastatic colorectal cancer. Finally, the patient died because of intercurrent pneumonia. CONCLUSION: Spontaneous acral necrosis may develop due to embolisation or local thrombotic vessel occlusion. Progression despite successful treatment of a potential source of embolism points to a significant coagulopathy, as in metastatic cancer. PMID- 22492413 TI - [42-year-old woman with progressive dyspnea, lower limb swelling and skin lesions]. PMID- 22492414 TI - [Vaccination against rabies: how and when?]. AB - Each year, more than 55,000 people die from rabies. Rabies virus (RABV) is transmitted via bites from infected animals. Dogs represent the most important source of infections worldwide. In Germany, the last case of terrestrial rabies was reported in 2006. Therefore, the country has been considered rabies-free since September 2008 (as defined by World Organization of Animal Health, OIE). Bat rabies, however, is still endemic and mostly occurs in northern Germany. It is caused by the European Bat Lyssa Virus (EBLV), which is closely related to RABV. Cases of rabies in humans are almost 100 % lethal, therefore, the correct choice of prophylactic measures is essential. Pre-exposition vaccination is recommended for individuals at risk of contact to Rabies Virus. If used together with post-exposure measures, it confers high-grade protection against disease manifestation. Even non-vaccinated individuals exposed to Rabies Virus can be protected from overt disease in almost all cases with timely and accurate application of post-exposure vaccination. The mode and intensity of exposure determine the choice of regimen (wound treatment, active and passive vaccination). PMID- 22492415 TI - [Inflammatory rheumatic diseases in the elderly]. PMID- 22492416 TI - [Platelet inhibitors and proton pump inhibitors: no more uncertainties?]. PMID- 22492417 TI - [Bariatric surgery: pro]. PMID- 22492418 TI - [Bariatric surgery - contra]. PMID- 22492419 TI - [Interactions of proton pump inhibitors with oral bisphosphonates and fracture risk]. PMID- 22492420 TI - [Steviol glycosides as sweetener in diabetes?]. PMID- 22492421 TI - When bigger is better: intermolecular hydrofunctionalizations of activated alkenes catalyzed by heteroleptic alkaline Earth complexes. AB - New alkaline-earth amido complexes catalyze the regioselective intermolecular hydroamination (see scheme; Ae=alkaline earth) and hydrophosphination of styrene and isoprene with unprecedented activities. The catalytic performances increased linearly with the size of the metal. PMID- 22492422 TI - Aortic root pathology in Marfan syndrome increases the risk of migraine with aura. AB - AIM: To assess the lifetime prevalence of migraine in patients with Marfan syndrome (MFS) and to investigate a history of aortic root replacement (AR) as a possible risk factor. METHODS: In a multicentre study 123 MFS patients (n = 52 with AR, n = 71 without AR), 82 age- and sex-matched controls and 51 patients with AR but without MFS, were interviewed using a semi-structured headache questionnaire. A multinomial logistic regression model was used to investigate risk factors for migraine with and without aura, adjusting for age and gender. RESULTS: Lifetime migraine prevalence was increased in female MFS patients (51%) compared to healthy female controls (29%), p = 0.017. In males lifetime migraine prevalence among MFS patients was only numerically increased. Lifetime prevalence of migraine with aura was increased among MFS patients compared to healthy controls both in males (19% vs. 3%, p = 0.048) and females (30% vs. 14%, p = 0.049). A history of AR, independently from MFS, gender and age, increased the lifetime prevalence of migraine with aura (OR 3.1 [1.2-8.0]). In all but one patient migraine started before the AR. CONCLUSIONS: The lifetime prevalence of migraine with aura, but not migraine without aura, is increased in patients with MFS. This association is driven by a history of AR. The replacement procedure itself is unlikely to be causally associated with migraine as in nearly all subjects, migraine started before the procedure. However this study adds to the evidence that underlying vessel wall pathology may be involved in migraine with aura. PMID- 22492423 TI - Altered interictal saccadic reaction time in migraine: a cross-sectional study. AB - AIMS: The underlying mechanisms of migraine remain poorly understood, partly because we lack objective methods for quantitative analysis of neurological function. To address this issue, we measured interictal saccadic latency in migraineurs and controls. METHODS: In a cross-sectional study, we compared interictal saccadic latency distributions of 12,800 saccades in 32 migraineurs with 32 age- and sex-matched controls. RESULTS: The variability of migraineurs' reaction time distributions was significantly smaller (sigma = 1.01 vs. 1.13; p < 0.05) compared with controls. In addition, a smaller proportion of migraineurs generated 'early' saccades (31% vs. 56%: p < 0.05). Sensitivity/specificity analysis demonstrated the potential benefit of this technique to diagnostic discrimination. CONCLUSIONS: The migraineur's brain behaves significantly differently from that of a control during the interictal period. By analysing whole distributions, rather than just means, data can be related directly to current neurophysiological models: specifically, the observed decrease in variability suggests a functional deficit in the noradrenergic systems influencing the cerebral cortex. From a clinical perspective, this novel method of characterising neurological function in migraine is more rapid, practicable, inexpensive, objective and quantitative than previous methods such as evoked potentials and transcranial magnetic stimulation, and has the potential both to improve current diagnostic discrimination and to help guide future research into the underlying neural mechanisms. PMID- 22492424 TI - Botulinum toxin type A for the treatment of trigeminal neuralgia: results from a randomized, double-blind, placebo-controlled trial. AB - AIM: To investigate the efficacy, safety and tolerability of intradermal and/or submucosal administration of botulinum toxin type A (BTX-A) for patients with trigeminal neuralgia (TN). METHODS: In this randomized, double-blind, placebo controlled study, 42 TN patients were randomly allocated into two groups, namely, intradermal and/or submucosal injection of BTX-A (75 U/1.5 mL; n = 22) or saline (1.5 mL; n = 20) in the skin and/or mucosa where pain was experienced. The primary endpoints were pain severity (assessed by the visual analogue scale) and pain attack frequency per day. The secondary endpoint was the patient's overall response to treatment, assessed using the Patient Global Impression of Change scale. Patients with >= 50% reduction in mean pain score at week 12 were defined as responders. RESULTS: A total of 40 patients completed the study. BTX-A significantly reduced pain intensity at week 2 and pain attack frequency at week 1. The efficacy was maintained throughout the course of the study. More BTX-A treated patients reported that pain had improved by the end of the study. Significantly more responders were present in the BTX-A group (68.18%) than in the placebo group (15.00%). BTX-A was well tolerated, with few treatment-related adverse events. CONCLUSIONS: BTX-A may be an efficient, safe and novel strategy for TN treatment. PMID- 22492425 TI - Headache attributed to airplane travel ('airplane headache'): clinical profile based on a large case series. AB - BACKGROUND: The 'headache attributed to airplane travel', also named 'airplane headache' (AH), is a recently described headache disorder that appears exclusively in relation to airplane flights, in particular during the landing phase. Based on the stereotypical nature of the attacks in all reported cases, we proposed provisional diagnostic criteria for AH in a previously published paper. Up to now 37 cases have been described in the literature. METHODS: After our paper was disseminated via the Internet, we received several email messages from subjects around the world who had experienced such a peculiar headache. Their cooperation, by completing a structured questionnaire and allowing the direct observation of three subjects, enabled us to carry out a study on a total of 75 patients suffering from AH. RESULTS: Our survey confirmed the stereotypical nature of the attacks, in particular with regard to the short duration of the pain (lasting less than 30 minutes in up to 95% of the cases), the clear relationship with the landing phase, the unilateral pain, the male preponderance, and the absence of accompanying signs and/or symptoms. It is conceivable to consider barotrauma as one of the main mechanisms involved in the pathophysiology of AH. The observation that the pain appears inconstantly in the majority of cases, without any evident disorder affecting the paranasal sinuses, could be consistent with a multimodal pathogenesis underlying this condition, possibly resulting in the interaction between anatomic, environmental and temporary concurrent factors. CONCLUSIONS: This is by far the largest AH case series ever reported in the literature. The diagnostic criteria that we previously proposed proved to be valid when applied to a large number of patients suffering from this condition. We support its recognition as a new form of headache, to be included in the forthcoming update of the International Headache Society Classification, within '10. Headache attributed to disorder of homoeostasis'. Its formal validation would favour further studies aimed at improving the understanding of its pathophysiology and implementing preventative measures. PMID- 22492426 TI - Delayed development of visual motion processing in childhood migraine. AB - INTRODUCTION: Altered visual processing has been observed in adult migraineurs. But because visual processing has not been studied in paediatric cases, it is not known whether such visual system alterations are already present in early development. We therefore used a dynamic visual task to investigate motion detection threshold in paediatric migraine. METHODS: Fourteen migraineurs and 21 controls participated in the study (age range: 8-17 years). The minimal percentage of coherently moving dot stimuli at which subjects were still able to detect coherent movement (absolute threshold) was determined using a random dot kinematogram paradigm. RESULTS: Motion coherence detection threshold was higher in migraineurs (p < 0.05). This difference between groups was more pronounced at younger ages, but migraineurs seem to catch up with healthy controls over the years. CONCLUSIONS: Children with migraine exhibit a delayed development of visual motion processing. This might be a useful supplementary biomarker in paediatric migraine. PMID- 22492427 TI - Learning curves of basic laparoscopic psychomotor skills in SINERGIA VR simulator. AB - PURPOSE: Surgical simulators are currently essential within any laparoscopic training program because they provide a low-stakes, reproducible and reliable environment to acquire basic skills. The purpose of this study is to determine the training learning curve based on different metrics corresponding to five tasks included in SINERGIA laparoscopic virtual reality simulator. METHODS: Thirty medical students without surgical experience participated in the study. Five tasks of SINERGIA were included: Coordination, Navigation, Navigation and touch, Accurate grasping and Coordinated pulling. Each participant was trained in SINERGIA. This training consisted of eight sessions (R1-R8) of the five mentioned tasks and was carried out in two consecutive days with four sessions per day. A statistical analysis was made, and the results of R1, R4 and R8 were pair-wise compared with Wilcoxon signed-rank test. Significance is considered at P value <0.005. RESULTS: In total, 84.38% of the metrics provided by SINERGIA and included in this study show significant differences when comparing R1 and R8. Metrics are mostly improved in the first session of training (75.00% when R1 and R4 are compared vs. 37.50% when R4 and R8 are compared). In tasks Coordination and Navigation and touch, all metrics are improved. On the other hand, Navigation just improves 60% of the analyzed metrics. Most learning curves show an improvement with better results in the fulfillment of the different tasks. CONCLUSIONS: Learning curves of metrics that assess the basic psychomotor laparoscopic skills acquired in SINERGIA virtual reality simulator show a faster learning rate during the first part of the training. Nevertheless, eight repetitions of the tasks are not enough to acquire all psychomotor skills that can be trained in SINERGIA. Therefore, and based on these results together with previous works, SINERGIA could be used as training tool with a properly designed training program. PMID- 22492428 TI - The German and the French studies on childhood leukemia and nuclear power: differences and similarities. PMID- 22492429 TI - Myocardial lesion depth with circular electroporation ablation. AB - BACKGROUND: Recently, we demonstrated the feasibility and safety of circular electroporation ablation in porcine pulmonary vein ostia, but the relationship between the magnitude of the application and lesion dimensions is still unknown. METHODS AND RESULTS: An in vivo porcine study was performed on left ventricular epicardium submerged under 10 mm of blood, using devices that mimic a 20-mm diameter 7F circular ablation catheter. Model D contained 10 separate electrodes, whereas model M consisted of 1 circular electrode. Ablations were performed at 50, 100, and 200 J with model D and at 100 J with model M. Lesion dimensions were measured after 3-week survival. All applications resulted in smooth voltage waveforms demonstrating the absence of vapor globe formation, arcing, and a pressure wave. Applications up to 100 J with model D resulted in separate lesions under the electrodes. At 200 J, continuous deep circular lesions were created despite the use of separate electrodes. There was a significant relationship between applied current and median lesion depth, with a slope of 0.17 mm/A. At 100 J, there was no difference in lesion depth or width between models D and M. The electrodes and ablation site directly after ablation showed no signs of thermal damage. CONCLUSIONS: In an epicardial porcine model with blood around the application site, continuous circular lesions, deep enough for electric pulmonary vein isolation, were created with a single circular 200-J application. Lesions were continuous despite the use of separate electrodes. Lesion depth increased with the magnitude of the application. PMID- 22492430 TI - Outcomes of catheter ablation of ventricular tachycardia in arrhythmogenic right ventricular dysplasia/cardiomyopathy. AB - BACKGROUND: Prior studies evaluating the efficacy of catheter ablation of ventricular tachycardia (VT) among patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) have reported varied outcomes. More recently, studies have suggested that an epicardial ablation is necessary for improved outcomes after catheter ablation of VT. The overall objective of the present study was to assess the efficacy of radiofrequency catheter ablation (RFA) of VT in ARVD/C, with particular focus on newer ablation strategies, including epicardial catheter ablation. METHODS AND RESULTS: The study population included 87 patients with ARVD/C who underwent a total of 175 RFA procedures between 1992 and 2011 at 80 different electrophysiology centers. Recurrence of VT following RFA and effect of RFA on the burden of VT were assessed. The mean age of the cohort was 38+/-13 years. Over a mean follow-up of 88.3+/-66 months, the overall freedom from VT of the 175 procedures was 47%, 21%, and 15%, at 1, 5, and 10 years, respectively. The cumulative freedom from VT following epicardial RFA was 64% and 45% at 1 and 5 years, respectively, which was significantly longer than endocardial RFA (P=0.021). Survival free of VT among procedures with 3D electroanatomic mapping was significantly longer compared to those without (P=0.016). Burden of VT was reduced irrespective of the ablation strategy (P<0.001). CONCLUSIONS: Although VT recurrences are common, RFA results in a significant reduction in the burden of VT in patients with ARVD/C. Further, although the use of 3D electroanatomic mapping systems and epicardial ablation strategies are associated with longer survival free of VT, recurrence rates remain considerable. PMID- 22492431 TI - Interventions in sports settings to reduce alcohol consumption and alcohol related harm: a systematic review protocol. AB - INTRODUCTION: Alcohol consumption is a primary cause of physical, psychological and social harm to both the user and others. At both the professional and non professional level, sports players and fans report consuming alcohol at greater levels than people not involved in sports. Limited systematic reviews have been conducted assessing interventions targeting alcohol consumption behaviour and related harms in the sporting context. METHODS AND ANALYSIS: The review aims to determine if interventions implemented in the sport setting decrease alcohol consumption and related harms. Participants may include all persons regardless of age or other characteristics. Studies will be included which have implemented interventions within the sport setting and have either measured: alcohol consumption, excessive alcohol consumption or intoxication or alcohol-related injury or violence. Randomised controlled trials, staggered enrolment trials, stepped-wedged trials, quasi-randomised trials, quasi-experimental trials and natural experiments will be included. Studies without a parallel comparison group will be excluded. Data will be sourced from a range of electronic databases and sources of grey literature. Two authors will independently screen all titles and abstracts of papers identified through the search strategy. Two authors will independently examine the full text of all remaining papers to determine eligibility. Two authors will independently extract data from eligible studies and independently assess risk of bias by assessing the adequacy of study characteristics. Where studies are sufficiently homogeneous, trial results will be synthesised using a fixed-effects meta-analysis. Standardised mean differences will be used for continuous outcomes and RRs will be used for binary outcomes. DISSEMINATION: The findings of this study will be disseminated widely through mechanisms including peer-reviewed publications and conference presentations. PMID- 22492432 TI - Promoting nurse interventionist fidelity to motivational interviewing in a diabetes self-care intervention. AB - We describe interventionist training procedures for a pilot intervention study that tested the effects of a nurse-delivered Motivational Interviewing (MI) intervention on diabetes self-care among adults diagnosed with type 2 diabetes mellitus. It reports on findings from MI fidelity assessments. Training consisted of didactic workshops plus practicum. Fidelity of MI was assessed using the MI Treatment Integrity (MITI) Scale. Fidelity assessments were conducted on 18 (25%) audiotaped MI sessions, which were randomly selected from a total of 72 sessions with 26 participants. Scores of the MITI were in the proficient and competent range. Results suggest that training strategies were sufficient to promote satisfactory interventionist fidelity to MI. PMID- 22492433 TI - A positive correlation between bacterial autoaggregation and biofilm formation in native Sinorhizobium meliloti isolates from Argentina. AB - Sinorhizobium meliloti is a symbiotic nitrogen-fixing bacterium that elicits nodule formation on roots of alfalfa plants. S. meliloti produces two exopolysaccharides (EPSs), termed EPS I and EPS II, that are both able to promote symbiosis. EPS I and EPS II are secreted in two major fractions that reflect differing degrees of subunit polymerization, designated high- and low-molecular weight fractions. We reported previously that EPSs are crucial for autoaggregation and biofilm formation in S. meliloti reference strains and isogenic mutants. However, the previous observations were obtained by use of "domesticated" laboratory strains, with mutations resulting from successive passages under unnatural conditions, as has been documented for reference strain Rm1021. In the present study, we analyzed the autoaggregation and biofilm formation abilities of native S. meliloti strains isolated from root nodules of alfalfa plants grown in four regions of Argentina. 16S rRNA gene analysis of all the native isolates revealed a high degree of identity with reference S. meliloti strains. PCR analysis of the expR gene of all the isolates showed that, as in the case of reference strain Rm8530, this gene is not interrupted by an insertion sequence (IS) element. A positive correlation was found between autoaggregation and biofilm formation abilities in these rhizobia, indicating that both processes depend on the same physical adhesive forces. Extracellular complementation experiments using mutants of the native strains showed that autoaggregation was dependent on EPS II production. Our results indicate that a functional EPS II synthetic pathway and its proper regulation are essential for cell-cell interactions and surface attachment of S. meliloti. PMID- 22492434 TI - Functional specificity of extracellular nucleases of Shewanella oneidensis MR-1. AB - Bacterial species such as Shewanella oneidensis MR-1 require extracellular nucleolytic activity for the utilization of extracellular DNA (eDNA) as a source of nutrients and for the turnover of eDNA as a structural matrix component during biofilm formation. We have previously characterized two extracellular nucleases of S. oneidensis MR-1, ExeM and ExeS. Although both are involved in biofilm formation, they are not specifically required for the utilization of eDNA as a nutrient. Here we identified and characterized EndA, a third extracellular nuclease of Shewanella. The heterologously overproduced and purified protein was highly active and rapidly degraded linear and supercoiled DNAs of various origins. Divalent metal ions (Mg(2+) or Mn(2+)) were required for function. endA is cotranscribed with phoA, an extracellular phosphatase, and is not upregulated upon phosphostarvation. Deletion of endA abolished both extracellular degradation of DNA by S. oneidensis MR-1 and the ability to use eDNA as a sole source of phosphorus. PhoA is not strictly required for the exploitation of eDNA as a nutrient. The activity of EndA prevents the formation of large cell aggregates during planktonic growth. However, in contrast to the findings for ExeM, endA deletion had only minor effects on biofilm formation. The findings strongly suggest that the extracellular nucleases of S. oneidensis exert specific functions required under different conditions. PMID- 22492435 TI - Life under multiple extreme conditions: diversity and physiology of the halophilic alkalithermophiles. AB - Around the world, there are numerous alkaline, hypersaline environments that are heated either geothermally or through intense solar radiation. It was once thought that such harsh environments were inhospitable and incapable of supporting a variety of life. However, numerous culture-dependent and independent studies revealed the presence of an extensive diversity of aerobic and anaerobic bacteria and archaea that survive and grow under these multiple harsh conditions. This diversity includes the halophilic alkalithermophiles, a novel group of polyextremophiles that require for growth and proliferation the multiple extremes of high salinity, alkaline pH, and elevated temperature. Life under these conditions undoubtedly involves the development of unique physiological characteristics, phenotypic properties, and adaptive mechanisms that enable control of membrane permeability, control of intracellular osmotic balance, and stability of the cell wall, intracellular proteins, and other cellular constituents. This minireview highlights the ecology and growth characteristics of the extremely halophilic alkalithermophiles that have been isolated thus far. Biochemical, metabolic, and physiological properties of the extremely halophilic alkalithermophiles are described, and their roles in resistance to the combined stressors of high salinity, alkaline pH, and high temperature are discussed. The isolation of halophilic alkalithermophiles broadens the physicochemical boundaries for life and extends the boundaries for the combinations of the maximum salinity, pH, and temperature that can support microbial growth. PMID- 22492436 TI - No evidence for transmission of antibiotic-resistant Escherichia coli strains from humans to wild western lowland gorillas in Lope National Park, Gabon. AB - The intensification of human activities within the habitats of wild animals is increasing the risk of interspecies disease transmission. This risk is particularly important for great apes, given their close phylogenetic relationship with humans. Areas of high human density or intense research and ecotourism activities expose apes to a high risk of disease spillover from humans. Is this risk lower in areas of low human density? We determined the prevalence of Escherichia coli antibiotic-resistant isolates in a population of the critically endangered western lowland gorilla (Gorilla gorilla gorilla) and other wild mammals in Lope National Park (LNP), Gabon, and we tested whether the observed pattern could be explained by bacterial transmission from humans and domestic animals into wildlife populations. Our results show a high prevalence of antibiotic-resistant bacterial isolates in humans and low levels in gorillas and other wildlife. The significant differences in the genetic background of the resistant bacteria isolated from humans and gorillas suggest that transmission is low or does not occur between these two species. These findings indicate that the presence of antibiotic-resistant strains in wildlife do not imply direct bacteria transmission from humans. Thus, in areas of low human density, human-wildlife E. coli transmission seems to be low. The presence of antibiotic-resistant isolates in gorillas may be better explained by other mechanisms for resistance acquisition, such as horizontal gene exchange among bacteria or naturally acquired resistance. PMID- 22492437 TI - Development and evaluation of a quantitative PCR assay targeting sandhill crane (Grus canadensis) fecal pollution. AB - While the microbial water quality in the Platte River is seasonally impacted by excreta from migrating cranes, there are no methods available to study crane fecal contamination. Here we characterized microbial populations in crane feces using phylogenetic analysis of 16S rRNA gene fecal clone libraries. Using these sequences, a novel crane quantitative PCR (Crane1) assay was developed, and its applicability as a microbial source tracking (MST) assay was evaluated by determining its host specificity and detection ability in environmental waters. Bacteria from crane excreta were dominated by bacilli and proteobacteria, with a notable paucity of sequences homologous to Bacteroidetes and Clostridia. The Crane1 marker targeted a dominant clade of unclassified Lactobacillales sequences closely related to Catellicoccus marimammalium. The host distribution of the Crane1 marker was relatively high, being positive for 69% (66/96) of the crane excreta samples tested. The assay also showed high host specificity, with 95% of the nontarget fecal samples (i.e., n = 553; 20 different free-range hosts) being negative. Of the presumed crane-impacted water samples (n = 16), 88% were positive for the Crane1 assay, whereas none of the water samples not impacted by cranes were positive (n = 165). Bayesian statistical models of the Crane1 MST marker demonstrated high confidence in detecting true-positive signals and a low probability of false-negative signals from environmental water samples. Altogether, these data suggest that the newly developed marker could be used in environmental monitoring studies to study crane fecal pollution dynamics. PMID- 22492438 TI - Biosynthesis of fusarubins accounts for pigmentation of Fusarium fujikuroi perithecia. AB - Fusarium fujikuroi produces a variety of secondary metabolites, of which polyketides form the most diverse group. Among these are the highly pigmented naphthoquinones, which have been shown to possess different functional properties for the fungus. A group of naphthoquinones, polyketides related to fusarubin, were identified in Fusarium spp. more than 60 years ago, but neither the genes responsible for their formation nor their biological function has been discovered to date. In addition, although it is known that the sexual fruiting bodies in which the progeny of the fungus develops are darkly colored by a polyketide synthase (PKS)-derived pigment, the structure of this pigment has never been elucidated. Here we present data that link the fusarubin-type polyketides to a defined gene cluster, which we designate fsr, and demonstrate that the fusarubins are the pigments responsible for the coloration of the perithecia. We studied their regulation and the function of the single genes within the cluster by a combination of gene replacements and overexpression of the PKS-encoding gene, and we present a model for the biosynthetic pathway of the fusarubins based on these data. PMID- 22492439 TI - Purification and characterization of the acetone carboxylase of Cupriavidus metallidurans strain CH34. AB - Acetone carboxylase (Acx) is a key enzyme involved in the biodegradation of acetone by bacteria. Except for the Helicobacteraceae family, genome analyses revealed that bacteria that possess an Acx, such as Cupriavidus metallidurans strain CH34, are associated with soil. The Acx of CH34 forms the heterohexameric complex alpha(2)beta(2)gamma(2) and can carboxylate only acetone and 2-butanone in an ATP-dependent reaction to acetoacetate and 3-keto-2-methylbutyrate, respectively. PMID- 22492440 TI - Molecular identification and characterization of a new type of bovine enterovirus. AB - Bovine enteroviruses belong to the family Picornaviridae. Little is known about their pathogenic potential; however, they cause asymptomatic infections in cattle and are excreted in feces. In the present study, viruses isolated from environmental samples were sequenced. According to phylogenetic analyses and standard picornavirus nomenclature, these isolates constitute a new type of bovine enterovirus serogroup A. PMID- 22492441 TI - Quantitative PCR for tracking the megaplasmid-borne biodegradation potential of a model sphingomonad. AB - We developed a quantitative PCR method for tracking the dxnA1 gene, the initial, megaplasmid-borne gene in Sphingomonas wittichii RW1's dibenzo-p-dioxin degradation pathway. We used this method on complex environmental samples and report on growth of S. wittichii RW1 in landfill leachate, thus furnishing a novel tool for monitoring megaplasmid-borne, dioxygenase-encoding genes. PMID- 22492442 TI - Distribution of monoclonal antibody subgroups and sequence-based types among Legionella pneumophila serogroup 1 isolates derived from cooling tower water, bathwater, and soil in Japan. AB - Legionella pneumophila serogroup (SG) 1 is the most frequent cause of legionellosis. This study analyzed environmental isolates of L. pneumophila SG 1 in Japan using monoclonal antibody (MAb) typing and sequence-based typing (SBT). Samples were analyzed from bathwater (BW; n = 50), cooling tower water (CT; n = 50), and soil (SO; n = 35). The distribution of MAb types varied by source, with the most prevalent types being Bellingham (42%), Oxford (72%), and OLDA (51%) in BW, CT, and SO, respectively. The ratios of MAb 3/1 positive isolates were 26, 2, and 14% from BW, CT, and SO, respectively. The environmental isolates from BW, CT, and SO were divided into 34 sequence types (STs; index of discrimination [IOD] = 0.973), 8 STs (IOD = 0.448), and 11 STs (IOD = 0.879), respectively. Genetic variation among CT isolates was smaller than seen in BW and SO. ST1 accounted for 74% of the CT isolates. The only common STs between (i) BW and CT, (ii) BW and SO, and (iii) CT and SO were ST1, ST129, and ST48, respectively, suggesting that each environment constitutes an independent habitat. PMID- 22492443 TI - Resistance to broad-spectrum antibiotics in aquatic systems: anthropogenic activities modulate the dissemination of bla(CTX-M)-like genes. AB - We compared the resistomes within polluted and unpolluted rivers, focusing on extended-spectrum beta-lactamase (ESBL) genes, in particular bla(CTX-M). Twelve rivers from a Portuguese hydrographic basin were sampled. Physicochemical and microbiological parameters of water quality were determined, and the results showed that 9 rivers were classified as unpolluted (UP) and that 3 were classified as polluted (P). Of the 225 cefotaxime-resistant strains isolated, 39 were identified as ESBL-producing strains, with 18 carrying a bla(CTX-M) gene (15 from P and 3 from UP rivers). Analysis of CTX-M nucleotide sequences showed that 17 isolates produced CTX-M from group 1 (CTX-M-1, -3, -15, and -32) and 1 CTX-M that belonged to group 9 (CTX-M-14). A genetic environment study revealed the presence of different genetic elements previously described for clinical strains. ISEcp1 was found in the upstream regions of all isolates examined. Culture independent bla(CTX-M)-like libraries were comprised of 16 CTX-M gene variants, with 14 types in the P library and 4 types in UP library, varying from 68% to 99% similarity between them. Besides the much lower level of diversity among CTX-M like genes from UP sites, the majority were similar to chromosomal ESBLs such as bla(RAHN-1). The results demonstrate that the occurrence and diversity of bla(CTX M) genes are clearly different between polluted and unpolluted lotic ecosystems; these findings favor the hypothesis that natural environments are reservoirs of resistant bacteria and resistance genes, where anthropogenic-driven selective pressures may be contributing to the persistence and dissemination of genes usually relevant in clinical environments. PMID- 22492444 TI - Production of a novel quercetin glycoside through metabolic engineering of Escherichia coli. AB - Most flavonoids exist as sugar conjugates. Naturally occurring flavonoid sugar conjugates include glucose, galactose, glucuronide, rhamnose, xylose, and arabinose. These flavonoid glycosides have diverse physiological activities, depending on the type of sugar attached. To synthesize an unnatural flavonoid glycoside, Actinobacillus actinomycetemcomitans gene tll (encoding dTDP-6-deoxy-L lyxo-4-hexulose reductase, which converts the endogenous nucleotide sugar dTDP-4 dehydro-6-deoxy-L-mannose to dTDP-6-deoxytalose) was introduced into Escherichia coli. In addition, nucleotide-sugar dependent glycosyltransferases (UGTs) were screened to find a UGT that could use dTDP-6-deoxytalose. Supplementation of this engineered strain of E. coli with quercetin resulted in the production of quercetin-3-O-(6-deoxytalose). To increase the production of quercetin 3-O-(6 deoxytalose) by increasing the supplement of dTDP-6-deoxytalose in E. coli, we engineered nucleotide biosynthetic genes of E. coli, such as galU (UTP-glucose 1 phosphate uridyltransferase), rffA (dTDP-4-oxo-6-deoxy-d-glucose transaminase), and/or rfbD (dTDP-4-dehydrorahmnose reductase). The engineered E. coli strain produced approximately 98 mg of quercetin 3-O-(6-deoxytalose)/liter, which is 7 fold more than that produced by the wild-type strain, and the by-products, quercetin 3-O-glucose and quercetin 3-O-rhamnose, were also significantly reduced. PMID- 22492445 TI - Catalytic efficiency diversification of duplicate beta-1,3-1,4-glucanases from Neocallimastix patriciarum J11. AB - Four types of beta-1,3-1,4 glucanase (beta-glucanase, EC 3.2.1.73) genes, designated bglA13, bglA16, bglA51, and bglM2, were found in the cDNA library of Neocallimastix patriciarum J11. All were highly homologous with each other and demonstrated a close phylogenetic relationship with and a similar codon bias to Streptococcus equinus. The presence of expansion and several predicted secondary structures in the 3' untranslated regions (3'UTRs) of bglA16 and bglM2 suggest that these two genes were duplicated recently, whereas bglA13 and bglA16, which contain very short 3'UTRs, were replicated earlier. These findings indicate that the beta-glucanase genes from N. patriciarum J11 may have arisen by horizontal transfer from the bacterium and subsequent duplication in the rumen fungus. beta Glucanase genes of Streptococcus equinus, Ruminococcus albus 7, and N. patriciarum J11 were cloned and expressed by Escherichia coli. The recombinant beta-glucanases cloned from S. equinus, R. albus 7, and N. patriciarum J11 were endo-acting and had similar substrate specificity, but they demonstrated different properties in other tests. The specific activities and catalytic efficiency of the bacterial beta-glucanases were also significantly lower than those of the fungal beta-glucanases. Our results also revealed that the activities and some characteristics of enzymes were changed during the horizontal gene transfer event. The specific activities of the fungal beta-glucanases ranged from 26,529 to 41,209 U/mg of protein when barley-derived beta-glucan was used as the substrate. They also demonstrated similar pH and temperature optima, substrate specificity, substrate affinity, and hydrolysis patterns. Nevertheless, BglA16 and BglM2, two recently duplicated beta-glucanases, showed much higher k(cat) values than others. These results support the notion that duplicated beta glucanase genes, namely, bglA16 and bglM2, increase the reaction efficiency of beta-glucanases and suggest that the catalytic efficiency of beta-glucanase is likely to be a criterion determining the evolutionary fate of duplicate forms in N. patriciarum J11. PMID- 22492446 TI - Genetic complementation of the obligate marine actinobacterium Salinispora tropica with the large mechanosensitive channel gene mscL rescues cells from osmotic downshock. AB - Marine actinomycetes in the genus Salinispora fail to grow when seawater is replaced with deionized (DI) water in complex growth media. While bioinformatic analyses have led to the identification of a number of candidate marine adaptation genes, there is currently no experimental evidence to support the genetic basis for the osmotic requirements associated with this taxon. One hypothesis is that the lineage-specific loss of mscL is responsible for the failure of strains to grow in media prepared with DI water. The mscL gene encodes a conserved transmembrane protein that reduces turgor pressure under conditions of acute osmotic downshock. In the present study, the mscL gene from a Micromonospora strain capable of growth on media prepared with DI water was transformed into S. tropica strain CNB-440. The single-copy, chromosomal genetic complementation yielded a recombinant Salinispora mscL(+) strain that demonstrated an increased capacity to survive osmotic downshock. The enhanced survival of the S. tropica transformant provides experimental evidence that the loss of mscL is associated with the failure of Salinispora spp. to grow in low osmotic-strength media. PMID- 22492447 TI - Diversity and expression of RubisCO genes in a perennially ice-covered Antarctic lake during the polar night transition. AB - The autotrophic communities in the lakes of the McMurdo Dry Valleys, Antarctica, have generated interest since the early 1960s owing to low light transmission through the permanent ice covers, a strongly bimodal seasonal light cycle, constant cold water temperatures, and geographical isolation. Previous work has shown that autotrophic carbon fixation in these lakes provides an important source of organic matter to this polar desert. Lake Bonney has two lobes separated by a shallow sill and is one of several chemically stratified lakes in the dry valleys that support year-round biological activity. As part of an International Polar Year initiative, we monitored the diversity and abundance of major isoforms of RubisCO in Lake Bonney by using a combined sequencing and quantitative PCR approach during the transition from summer to polar winter. Form ID RubisCO genes related to a stramenopile, a haptophyte, and a cryptophyte were identified, while primers specific for form IA/B RubisCO detected a diverse autotrophic community of chlorophytes, cyanobacteria, and chemoautotrophic proteobacteria. Form ID RubisCO dominated phytoplankton communities in both lobes of the lake and closely matched depth profiles for photosynthesis and chlorophyll. Our results indicate a coupling between light availability, photosynthesis, and rbcL mRNA levels in deep phytoplankton populations. Regulatory control of rbcL in phytoplankton living in nutrient-deprived shallow depths does not appear to be solely light dependent. The distinct water chemistries of the east and west lobes have resulted in depth- and lobe-dependent variability in RubisCO diversity, which plays a role in transcriptional activity of the key gene responsible for carbon fixation. PMID- 22492448 TI - Fungal endophytic communities in grapevines (Vitis vinifera L.) respond to crop management. AB - We studied the distribution of fungal endophytes of grapevine (Vitis vinifera L.) plants in a subalpine area of northern Italy, where viticulture is of high economic relevance. We adopted both cultivation-based and cultivation-independent approaches to address how various anthropic and nonanthropic factors shape microbial communities. Grapevine stems were harvested from several locations considering organic and integrated pest management (IPM) and from the cultivars Merlot and Chardonnay. Cultivable fungi were isolated and identified by internal transcribed-spacer sequence analysis, using a novel colony-PCR method, to amplify DNA from fungal specimens. The composition of fungal communities was assessed using a cultivation-independent approach, automated ribosomal intergenic spacer analysis (ARISA). Multivariate statistical analysis of both culture-dependent and culture-independent data sets was convergent and indicated that fungal endophytic communities in grapevines from organically managed farms were different from those from farms utilizing IPM. Fungal communities in plants of cv. Merlot and cv. Chardonnay overlapped when analyzed using culture-dependent approaches but could be partially resolved using ARISA fingerprinting. PMID- 22492449 TI - Biofilm roughness determines Cryptosporidium parvum retention in environmental biofilms. AB - The genus Cryptosporidium is a group of waterborne protozoan parasites that have been implicated in significant outbreaks of gastrointestinal infections throughout the world. Biofilms trap these pathogens and can contaminate water supplies through subsequent release. Biofilm microbial assemblages were collected seasonally from three streams in eastern Pennsylvania and used to grow biofilms in laboratory microcosms. Daily oocyst counts in the influx and efflux flow allowed the calculation of daily oocyst retention in the biofilm. Following the removal of oocysts from the influx water, oocyst attachment to the biofilm declined to an equilibrium state within 5 days that was sustained for at least 25 days. Varying the oocyst loading rate for the system showed that biofilm retention could be saturated, suggesting that discrete binding sites determined the maximum number of oocysts retained. Oocyst retention varied seasonally but was consistent across all three sites; however, seasonal oocyst retention was not consistent across years at the same site. No correlation between oocyst attachment and any measured water quality parameter was found. However, oocyst retention was strongly correlated with biofilm surface roughness and roughness varied among seasons and across years. We hypothesize that biofilm roughness and oocyst retention are dependent on environmentally driven changes in the biofilm community rather than directly on water quality conditions. It is important to understand oocyst transport dynamics to reduce risks of human infection. Better understanding of factors controlling biofilm retention of oocysts should improve our understanding of oocyst transport at different scales. PMID- 22492450 TI - Low-temperature decontamination with hydrogen peroxide or chlorine dioxide for space applications. AB - The currently used microbial decontamination method for spacecraft and components uses dry-heat microbial reduction at temperatures of >110 degrees C for extended periods to prevent the contamination of extraplanetary destinations. This process is effective and reproducible, but it is also long and costly and precludes the use of heat-labile materials. The need for an alternative to dry-heat microbial reduction has been identified by space agencies. Investigations assessing the biological efficacy of two gaseous decontamination technologies, vapor hydrogen peroxide (Steris) and chlorine dioxide (ClorDiSys), were undertaken in a 20-m(3) exposure chamber. Five spore-forming Bacillus spp. were exposed on stainless steel coupons to vaporized hydrogen peroxide and chlorine dioxide gas. Exposure for 20 min to vapor hydrogen peroxide resulted in 6- and 5-log reductions in the recovery of Bacillus atrophaeus and Geobacillus stearothermophilus, respectively. However, in comparison, chlorine dioxide required an exposure period of 60 min to reduce both B. atrophaeus and G. stearothermophilus by 5 logs. Of the three other Bacillus spp. tested, Bacillus thuringiensis proved the most resistant to hydrogen peroxide and chlorine dioxide with D values of 175.4 s and 6.6 h, respectively. Both low-temperature decontamination technologies proved effective at reducing the Bacillus spp. tested within the exposure ranges by over 5 logs, with the exception of B. thuringiensis, which was more resistant to both technologies. These results indicate that a review of the indicator organism choice and loading could provide a more appropriate and realistic challenge for the sterilization procedures used in the space industry. PMID- 22492451 TI - Effects of essential oils on methane production and fermentation by, and abundance and diversity of, rumen microbial populations. AB - Five essential oils (EOs), namely, clove oil (CLO), eucalyptus oil (EUO), garlic oil (GAO), origanum oil (ORO), and peppermint oil (PEO), were tested in vitro at 3 different doses (0.25, 0.50, and 1.0 g/liter) for their effect on methane production, fermentation, and select groups of ruminal microbes, including total bacteria, cellulolytic bacteria, archaea, and protozoa. All the EOs significantly reduced methane production with increasing doses, with reductions by 34.4%, 17.6%, 42.3%, 87%, and 25.7% for CLO, EUO, GAO, ORO, and PEO, respectively, at 1.0 g/liter compared with the control. However, apparent degradability of dry matter and neutral detergent fiber also decreased linearly with increasing doses by all EOs except GAO. The concentrations of total volatile fatty acids were not affected by GAO, EUO, or PEO but altered linearly and quadratically by CLO and ORO, respectively. All the EOs also differed in altering the molar proportions of acetate, propionate, and butyrate. As determined by quantitative real-time PCR, all the EOs decreased the abundance of archaea, protozoa, and major cellulolytic bacteria (i.e., Fibrobacter succinogenes, Ruminococcus flavefaciens, and R. albus) linearly with increasing EO doses. On the basis of denaturing gradient gel electrophoresis analysis, different EOs changed the composition of both archaeal and bacterial communities to different extents. The Shannon-Wiener diversity index (H') was reduced for archaea by all EOs in a dose-dependent manner but increased for bacteria at low and medium doses (0.25 and 0.50 g/liter) for all EOs except ORO. Due to the adverse effects on feed digestion and fermentation at high doses, a single EO may not effectively and practically mitigate methane emission from ruminants unless used at low doses in combinations with other antimethanogenic compounds. PMID- 22492452 TI - Novel genes involved in Pseudomonas fluorescens Pf0-1 motility and biofilm formation. AB - AdnA in Pseudomonas fluorescens, an ortholog of FleQ in P. aeruginosa, regulates both motility and flagellum-mediated attachment to various surfaces. A whole genome microarray determined the AdnA transcriptome by comparing the gene expression pattern of wild-type Pf0-1 to that of Pf0-2x (adnA deletion mutant) in broth culture. In the absence of AdnA, expression of 92 genes was decreased, while 11 genes showed increased expression. Analysis of 16 of these genes fused to lacZ confirmed the microarray results. Several genes were further evaluated for their role in motility and biofilm formation. Two genes, Pfl01_1508 and Pfl01_1517, affected motility and had different effects on biofilm formation in Pf0-1. These two genes are predicted to specify proteins similar to the glycosyl transferases FgtA1 and FgtA2, which have been shown to be involved in virulence and motility in P. syringae. Three other genes, Pfl01_1516, Pfl01_1572, and Pfl01_1573, not previously associated with motility and biofilm formation in Pseudomonas had similar effects on biofilm formation in Pf0-1. Deletion of each of these genes led to different motility defects. Our data revealed an additional level of complexity in the control of flagellum function beyond the core genes known to be required and may yield insights into processes important for environmental persistence of P. fluorescens Pf0-1. PMID- 22492453 TI - Inclusion of chicory (Cichorium intybus L.) in pigs' diets affects the intestinal microenvironment and the gut microbiota. AB - The content and composition of prebiotic plant fiber in the diet is important in promoting gut-related health. This study investigated the effects of the dietary inclusion of chicory forage and roots on the intestinal microenvironment of pigs. Thirty-seven-week-old pigs were fed 1 of 5 diets for 18 days, including a cereal based control diet and 4 diets with the inclusion of 80 and 160 g kg(-1) of body weight chicory forage (CF80 and CF160), 80 g kg(-1) chicory root (CR80), and a mix of 80 g kg(-1) forage and 80 g kg(-1) chicory root (CFR). The animals maintained good performance and health irrespective of diet. Bacterial community structure and diversity in ileal and colonic samples was assessed using terminal restriction fragment length polymorphism (T-RFLP), combined with cloning and sequencing. Samples clustered perfectly according to gut segment with a higher bacterial diversity in colon than ileum. Distal ileum was dominated by lactic acid bacteria (LAB), and the relative amount of this group was increased by the CF160 and CFR diets. The colonic bacterial community was dominated by butyrate producing bacteria and Prevotella. The increased relative abundance of butyrate producing bacteria in the colon was positively correlated with the molar proportion of acetic acid and furthermore linked to the chicory forage diets (CF80 and CF160). Diets including chicory roots (CR80 and CFR) were correlated with a higher colonic abundance of Megasphaera elsdenii. The fermentation products and pH in digesta responded to diet type and were correlated with shifts in the microbiota, showing that chicory influences the intestinal microenvironment of pigs. PMID- 22492454 TI - Comparative analysis of Lactobacillus plantarum WCFS1 transcriptomes by using DNA microarray and next-generation sequencing technologies. AB - RNA sequencing is starting to compete with the use of DNA microarrays for transcription analysis in eukaryotes as well as in prokaryotes. The application of RNA sequencing in prokaryotes requires additional steps in the RNA preparation procedure to increase the relative abundance of mRNA and cannot employ the poly(T)-primed approach in cDNA synthesis. In this study, we aimed to validate the use of RNA sequencing (direct cDNA sequencing and 3'-untranslated region [UTR] sequencing) using Lactobacillus plantarum WCFS1 as a model organism, employing its established microarray platform as a reference. A limited effect of mRNA enrichment on genome-wide transcript quantification was observed, and comparative transcriptome analyses were performed for L. plantarum WCFS1 grown in two different laboratory media. Microarray analyses and both RNA sequencing methods resulted in similar depths of analysis and generated similar fold-change ratios of differentially expressed genes. The highest overall correlation was found between microarray and direct cDNA sequencing-derived transcriptomes, while the 3'-UTR sequencing-derived transcriptome appeared to deviate the most. Overall, a high similarity between patterns of transcript abundance and fold change levels of differentially expressed genes was detected by all three methods, indicating that the biological conclusions drawn from the transcriptome data were consistent among the three technologies. PMID- 22492455 TI - Genome-based cluster deletion reveals an endocrocin biosynthetic pathway in Aspergillus fumigatus. AB - Endocrocin is a simple anthraquinone frequently identified in extracts of numerous fungi. Several biosynthetic schemes for endocrocin synthesis have been hypothesized, but to date, no dedicated secondary metabolite gene cluster that produces this polyketide as its major metabolite has been identified. Here we describe our biosynthetic and regulatory characterization of the endocrocin gene cluster in Aspergillus fumigatus. This is the first report of this anthraquinone in this species. The biosynthetic genes required for endocrocin production are regulated by the global regulator of secondary metabolism, LaeA, and encode an iterative nonreducing polyketide synthase (encA), a physically discrete metallo beta-lactamase type thioesterase (encB), and a monooxygenase (encC). Interestingly, the deletion of a gene immediately adjacent to encC, termed encD and encoding a putative 2-oxoglutarate-Fe(II) type oxidoreductase, resulted in higher levels of endocrocin production than in the wild-type strain, whereas overexpression of encD eliminated endocrocin accumulation. We found that overexpression of the encA transcript resulted in higher transcript levels of encA-D and higher production of endocrocin. We discuss a model of the enc cluster as one evolutionary origin of fungal anthraquinones derived from a nonreducing polyketide synthase and a discrete metallo-beta-lactamase-type thioesterase. PMID- 22492456 TI - Freeze-coring method for characterization of microbial community structure and function in wetland soils at high spatial resolution. AB - A simple freeze-coring method was developed to obtain structurally intact cores from wetland soils. A copper tube was inserted into the wetland and filled with ethanol and dry ice to freeze the surrounding soil. Biological structure and function could be analyzed, and labile compounds such as mRNA were recovered. PMID- 22492457 TI - Norwegian sheep are an important reservoir for human-pathogenic Escherichia coli O26:H11. AB - A previous national survey of Escherichia coli in Norwegian sheep detected eae positive (eae(+)) E. coli O26:H11 isolates in 16.3% (80/491) of the flocks. The purpose of the present study was to evaluate the human-pathogenic potential of these ovine isolates by comparing them with E. coli O26 isolates from humans infected in Norway. All human E. coli O26 isolates studied carried the eae gene and shared flagellar type H11. Two-thirds of the sheep flocks and 95.1% of the patients harbored isolates containing arcA allele type 2 and espK and were classified as enterohemorrhagic E. coli (EHEC) (stx positive) or EHEC-like (stx negative). These isolates were further divided into group A (EspK2 positive), associated with stx(2-EDL933) and stcE(O103), and group B (EspK1 positive), associated with stx(1a). Although the stx genes were more frequently present in isolates from patients (46.3%) than in those from sheep flocks (5%), more than half of the ovine isolates in the EHEC/EHEC-like group had multiple-locus variable number of tandem repeat analysis (MLVA) profiles that were identical to those seen in stx-positive human O26:H11 isolates. This indicates that EHEC-like ovine isolates may be able to acquire stx-carrying bacteriophages and thereby have the possibility to cause serious illness in humans. The remaining one-third of the sheep flocks and two of the patients had isolates fulfilling the criteria for atypical enteropathogenic E. coli (aEPEC): arcA allele type 1 and espK negative (group C). The majority of these ovine isolates showed MLVA profiles not previously seen in E. coli O26:H11 isolates from humans. However, according to their virulence gene profile, the aEPEC ovine isolates should be considered potentially pathogenic for humans. In conclusion, sheep are an important reservoir of human-pathogenic E. coli O26:H11 isolates in Norway. PMID- 22492458 TI - Regulation of polyphosphate kinase production by antisense RNA in Pseudomonas fluorescens Pf0-1. AB - Pseudomonas spp. adapt rapidly to environmental fluctuations. Loss or overproduction of polyphosphate reduces the fitness of Pseudomonas fluorescens Pf0-1, indicating the importance of the fine-tuning of polyphosphate production. An antisense RNA was investigated and shown to regulate the polyphosphate kinase gene (ppk) by a posttranscriptional mechanism reducing ppk transcript abundance. PMID- 22492459 TI - Simple absolute quantification method correcting for quantitative PCR efficiency variations for microbial community samples. AB - Real-time quantitative PCR (qPCR) is a widely used technique in microbial community analysis, allowing the quantification of the number of target genes in a community sample. Currently, the standard-curve (SC) method of absolute quantification is widely employed for these kinds of analysis. However, the SC method assumes that the amplification efficiency (E) is the same for both the standard and the sample target template. We analyzed 19 bacterial strains and nine environmental samples in qPCR assays, targeting the nifH and 16S rRNA genes. The E values of the qPCRs differed significantly, depending on the template. This has major implications for the quantification. If the sample and standard differ in their E values, quantification errors of up to orders of magnitude are possible. To address this problem, we propose and test the one-point calibration (OPC) method for absolute quantification. The OPC method corrects for differences in E and was derived from the DeltaDeltaC(T) method with correction for E, which is commonly used for relative quantification in gene expression studies. The SC and OPC methods were compared by quantifying artificial template mixtures from Geobacter sulfurreducens (DSM 12127) and Nostoc commune (Culture Collection of Algae and Protozoa [CCAP] 1453/33), which differ in their E values. While the SC method deviated from the expected nifH gene copy number by 3- to 5-fold, the OPC method quantified the template mixtures with high accuracy. Moreover, analyzing environmental samples, we show that even small differences in E between the standard and the sample can cause significant differences between the copy numbers calculated by the SC and the OPC methods. PMID- 22492460 TI - Expression of chlorite dismutase and chlorate reductase in the presence of oxygen and/or chlorate as the terminal electron acceptor in Ideonella dechloratans. AB - The ability of microorganisms to perform dissimilatory (per)chlorate reduction is, for most species, known to be oxygen sensitive. Consequently, bioremediation processes for the removal of oxochlorates will be disturbed if oxygen is present. We measured the expression of chlorite dismutase and chlorate reductase in the presence of different terminal electron acceptors in the chlorate reducer Ideonella dechloratans. Enzyme activity assays and mRNA analyses by real-time quantitative reverse transcription (qRT)-PCR were performed on cell extracts from cells grown aerobically with and without chlorate and on cells grown anaerobically in the presence of chlorate. Our results showed that both chlorite dismutase and chlorate reductase are expressed during aerobic growth. However, transfer to anaerobic conditions with chlorate resulted in significantly enhanced enzyme activities and mRNA levels for both enzymes. Absence of oxygen was necessary for the induction to occur, since chlorate addition under aerobic conditions produced neither increased enzyme activities nor higher relative levels of mRNA. For chlorite dismutase, the observed increase in activity was on the same order of magnitude as the increase in the relative mRNA level, indicating gene regulation at the transcriptional level. However, chlorate reductase showed about 200 times higher enzyme activity in anaerobically induced cells, whereas the increase in mRNA was only about 10-fold, suggesting additional mechanisms influence the enzyme activity. PMID- 22492462 TI - Deciphering the activation sequence of ferrociphenol anticancer drug candidates. AB - The complete oxidation sequence of a model for ferrociphenols, a new class of anticancer drug candidate, is reported. Cyclic voltammetry was used to monitor the formation of oxidation intermediates on different timescales, thereby allowing the electrochemical characterization of both the short-lived and stable species obtained from the successive electron-transfer and deprotonation steps. The electrochemical preparation of the ferrocenium intermediate enabled a stepwise voltammetric determination of the stable oxidation compounds obtained upon addition of a base as well as the electron stoichiometry observed for the overall oxidation process. A mechanism has been established from the electrochemical data, which involves a base-promoted intramolecular electron transfer between the phenol and the ferrocenium cation. The resulting species is further oxidized then deprotonated to yield a stable quinone methide. To further characterize the transient species successively formed during the two-electron oxidation of the ferrociphenol to its quinone methide, EPR was used to monitor the fate of the paramagnetic species generated upon addition of imidazole to the electrogenerated ferrocenium. The study revealed the passage from an iron centered to a carbon-centered radical, which is then oxidized to yield the quinone methide, namely, the species that interacts with proteins and so forth under biological conditions. PMID- 22492461 TI - Shell biofilm nitrification and gut denitrification contribute to emission of nitrous oxide by the invasive freshwater mussel Dreissena polymorpha (zebra mussel). AB - Nitrification in shell biofilms and denitrification in the gut of the animal accounted for N(2)O emission by Dreissena polymorpha (Bivalvia), as shown by gas chromatography and gene expression analysis. The mussel's ammonium excretion was sufficient to sustain N(2)O production and thus potentially uncouples invertebrate N(2)O production from environmental N concentrations. PMID- 22492463 TI - Solidified liquid layer model expands the application fields of quartz crystal microbalance. AB - The application of a quartz crystal microbalance (QCM) in liquid is hindered by the complexity of data analysis. Recently, a "solidified liquid layer" (SLL) model has been proposed to simplify the data analysis. Here, missing evidence to support the SLL model is provided: 1) the SLL model is responsive to the density change of the liquid environment, 2) thickness values from the SLL model (T(SLL) ) are in agreement with values measured by ellipsometry. The SLL model predicts that a 0.18 nm change of T(SLL) will lead to a 1 Hz signal, which is the resolution that most commercial QCMs could easily achieve. Using the SLL model, Au-S bond breakage has been successful. Biosensor applications are also being designed according to the SLL model. It is believed that with these results, the SLL model will bring QCM back to the radar screen of scientists. PMID- 22492464 TI - Compromised trabecular microarchitecture and lower finite element estimates of radius and tibia bone strength in adults with turner syndrome: a cross-sectional study using high-resolution-pQCT. AB - Although bone mass appear ample for bone size in Turner syndrome (TS), epidemiological studies have reported an increased risk of fracture in TS. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to measure standard morphological parameters of bone geometry and microarchitecture, as well as estimated bone strength by finite element analysis (FEA) to assess bone characteristics beyond bone mineral density (BMD) that possibly contribute to the increased risk of fracture. Thirty-two TS patients (median age 35, range 20-61 years) and 32 healthy control subjects (median age 36, range 19-58 years) matched with the TS participants with respect to age and body-mass index were studied. A full region of interest (ROI) image analysis and a height-matched ROI analysis adjusting for differences in body height between groups were performed. Mean bone cross-sectional area was lower in TS patients in radius (-15%) and tibia (-13%) (both p < 0.01) whereas cortical thickness was higher in TS patients in radius (18%, p < 0.01) but not in tibia compared to controls. Cortical porosity was lower in TS patients at both sites (-32% in radius, -36% in tibia, both p < 0.0001). Trabecular integrity was compromised in TS patients with lower bone volume per tissue volume (BV/TV) (-27% in radius, -22% in tibia, both p < 0.0001), trabecular number (-27% in radius, -12% in tibia, both p < 0.05), and higher trabecular spacing (54% in radius, 23% in tibia, both p < 0.01). In the height-matched ROI analysis, differences remained significant apart from total area at both sites, cortical thickness in radius, and trabecular number in tibia. FEA estimated failure load was lower in TS patients in both radius (-11%) and tibia (-16%) (both p < 0.01) and remained significantly lower in the height matched ROI analysis. Conclusively, TS patients had compromised trabecular microarchitecture and lower bone strength at both skeletal sites, which may partly account for the increased risk of fracture observed in these patients. PMID- 22492465 TI - Three-dimensional evaluation of facial morphology in children aged 5-6 years with a Class III malocclusion. AB - The aim of this study was to evaluate facial morphology in 25 Class III and 46 non-Class III children aged 5-6 years using three-dimensional (3D) laser imaging; 3D facial images were obtained, two average facial templates were constructed for the non-Class III male and female groups, each individual face was superimposed on the corresponding average template and group comparisons were evaluated (facial height, facial convexity, mandibular position and facial surface morphology). Differences between parameters were evaluated by using an analysis of variance and colour deviation maps. The results showed that Class III children had less mid-face prominence and a concave facial profile when compared to non Class III children (P = 0.002 and P = 0.018). The position of the pg point in the z-axis just failed to reach statistical significance when comparing the two groups (P = 0.051). A vertical analysis showed no statistical significance between the groups, when evaluating middle (n-sn) and lower (sn-pg) facial height. Coincidence of the Class III faces to normal templates with a tolerance set as 0.5 mm was low (less than 30%). The soft tissue characteristics of a Class III face differ significantly from the non-Class III face in the mid-face region and in the facial profile. A 3D laser imaging method evaluated and identified morphological characteristics of Class III children in deciduous dentition, which could in the future become an important diagnostic tool in small children. The most important clinical advantage of this study is the non-invasiveness of the method. PMID- 22492466 TI - The impact of refeeding on blood fatty acids and amino acid profiles in elderly patients: a metabolomic analysis. AB - BACKGROUND: Refeeding of elderly frail patients after food deprivation is commonly associated with a high mortality rate. OBJECTIVE: To evaluate the effect of refeeding on metabolite fluctuation of blood carnitine fatty acids (15 compounds) and free amino acids (14 compounds). METHODS: Metabolite fluctuation was followed up in an exploratory, cohort, and noninterventional study in elderly and frail patients (84.5 +/- 5 years) after a long period of food deprivation. Patients in the study group were refed by enteral nutrition (EN) and were followed up during 7 days for blood metabolites (n = 27). Patients in the control group (n = 26) had been fed by EN for more than 3 months. Refeeding was initiated with 10 kcal/kg/d and gradual increases of 200 kcal/d for 3 days afterwards. Blood metabolites were assayed in a sample of 25 uL. RESULTS: On food deprivation, the concentrations of all even monocarboxylic carnitine fatty acids were much higher in the study group than in the EN control group (P < .01). Upon refeeding, a remarkable decrease in all carnitine fatty acids was observed. In addition, significant daily fluctuations were observed for most metabolites in the study group of the refed patients as compared with the EN control group (P < .01). The highest fluctuations were observed following refeeding in the 7 patients who later died. CONCLUSION: A significant metabolic instability is observed on refeeding even with a slow refeeding schedule of 10 kcal/kg/d. Measurement of metabolomics parameters may be used for the evaluation of malnutrition, refeeding status, and optimization of the enteral formula. PMID- 22492467 TI - Heteroleptic silylamido phenolate complexes of calcium and the larger alkaline earth metals: beta-agostic Ae???Si-H stabilization and activity in the ring opening polymerization of L-lactide. AB - The factors governing the stability and the reactivity towards cyclic esters of heteroleptic complexes of the large alkaline earth metals (Ae) have been probed. The synthesis and stability of a family of heteroleptic silylamido and alkoxide complexes of calcium [{LO(i)}Ca-Nu(thf)(n)] supported by mono-anionic amino ether phenolate ligands (i = 1, {LO(1)}(-) = 4-(tert-butyl)-2,6 bis(morpholinomethyl)phenolate, Nu(-) = N(SiMe(2)H)(2)(-), n = 0, 4; i = 2, {LO(2)}(-) = 2,4-di-tert-butyl-6-{[2-(methoxymethyl)pyrrolidin-1 yl]methyl}phenolate, Nu(-) = N(SiMe(2)H)(2)(-), n = 0, 5; i = 4, {LO(4)}(-) = 2 {[bis(2-methoxyethyl)amino]methyl}-4,6-di-tert-butylphenolate, Nu(-) = N(SiMe(2)H)(2)(-), n = 1, 6; Nu(-) = HC=CCH(2)O(-), n = 0, 7) and those of the related [{LO(3)}Ae-N(SiMe(2)H)(2)] ({LO(3)}(-) = 2-[(1,4,7,10-tetraoxa-13 azacyclopentadecan-13-yl)methyl]-4,6-di-tert-butylphenolate Ae = Ca, 1; Sr, 2; Ba, 3) have been investigated. The molecular structures of 1, 2, [(4)(2)], 6, and [(7)(2)] have been determined by X-ray diffraction. These highlight Ae???H-Si internal beta-agostic interactions, which play a key role in the stabilization of [{LO(i)}Ae-N(SiMe(2)H)(2)] complexes against ligand redistribution reactions, in contrast to regular [{LO(i)}Ae-N(SiMe(3))(2)]. Pulse-gradient spin-echo (PGSE) NMR measurements showed that 1, 4, 6, and 7 are monomeric in solution. Complexes 1-7 mediate the ring-opening polymerization (ROP) of L-lactide highly efficiently, converting up to 5000 equivalents of monomer at 25 degrees C in a controlled fashion. In the immortal ROP performed with up to 100 equivalents of exogenous 9-anthracenylmethanol or benzyl or propargyl alcohols as a transfer agent, the activity of the catalyst increased with the size of the metal (1<2<3). For Ca-based complexes, the enhanced electron-donating ability of the ancillary ligand favored catalyst activity (1>6>4~5). The nature of the alcohol had little effect over the activity of the binary catalyst system 1/ROH; in all cases, both the control and end-group fidelity were excellent. In the living ROP of L-LA, the HC=CCH(2)O(-) initiating group (as in 7) proved superior to N(SiMe(2)H)(2)(-) or N(SiMe(3))(2)(-) (as in 6 or [{LO(4)}Ca-N(SiMe(3))(2)] (B), respectively). PMID- 22492468 TI - Reversal of endothelial progenitor cell dysfunction in patients with type 2 diabetes using a conditioned medium of human embryonic stem cell-derived endothelial cells. AB - BACKGROUND: The potential clinical application of bone marrow or peripheral blood derived progenitor cells for cardiovascular regeneration in patients with diabetes mellitus (DM) is limited by their functional impairment. We sought to determine the mechanisms of impaired therapeutic efficacy of peripheral blood derived progenitor cells in type 2 DM patients and evaluated the use of cell-free conditioned medium obtained from human embryonic stem cell-derived endothelial like cells (ESC-ECs) to reverse their functional impairment. METHODS: The angiogenic potential of late outgrowth endothelial cells (OECs) and cytokine profile of the conditional medium of proangiogenic cells (PACs) derived from peripheral blood-mononuclear cells of healthy control and DM patients and ESC-ECs was compared by in vitro tube formation assay and a multiplex bead-based immunoassay kit, respectively. The in vivo angiogenic potential of ESC-ECs derived conditioned medium in rescuing the functional impairment of PB-PACs in DM patients was investigated using a hindlimb ischemia model. RESULTS: Human ESC-ECs had similar functional and phenotypic characteristics as OECs in healthy controls. Cytokine profiling showed that vascular endothelial growth factor, stromal cell-derived factor 1 and placental growth factor were down-regulated in PACs from DM patients. Tube formation assay that revealed functional impairment of OECs from DM patients could be rescued by ESC-ECs conditioned medium. Administration of ESC-ECs conditioned medium restored the therapeutic efficacy of PB-PACs from DM patients in a mouse model of hindlimb ischemia. CONCLUSIONS: Our results showed that peripheral blood-derived progenitor cells from DM patients have impaired function because of defective secretion of angiogenic cytokines, which could be restored by supplementation of ESC-ECs conditioned medium. PMID- 22492469 TI - A quantitative index measured on 99mTc GSA SPECT/CT 3D fused images to evaluate severe fibrosis in patients with chronic liver disease. AB - PURPOSE: We compared quantitative indices estimated by use of technetium-(99m) galactosyl human serum albumin ((99m)Tc-GSA) single-photon emission computed tomography (SPECT)/computed tomography (CT) fused imaging and hepatic fibrosis in patients with chronic liver disease. MATERIALS AND METHODS: On the basis of pathological findings we divided 161 patients into non-severe and severe fibrosis groups (n = 81 and n = 80, respectively). We measured 2 indices by (99m)Tc-GSA SPECT/CT fused imaging: liver uptake value (LUV) = [radioactivity (whole liver)/radioactivity (injected)] * 100/body surface area, and functional liver index (FLI) = [radioactivity (hepatocytes)/radioactivity (injected)] * 100/liver volume. We compared these indices with biochemical and histopathological results. RESULTS: Univariate and multivariate analyses showed that FLI, LUV, LHL15, and prothrombin time were significant independent predictors of severe fibrosis. On the basis of receiver operating characteristics analysis, the areas under curve values of FLI, LUV, LHL15, and prothrombin time for predicting severe fibrosis were 0.83, 0.73, 0.69, and 0.68, respectively. Using an FLI value of 0.053, it was possible to predict severe fibrosis with 65 % sensitivity, 88 % specificity, and 76 % accuracy. CONCLUSION: Assessment of functional hepatocytes by use of (99m)Tc-GSA SPECT/CT fused images is useful for identifying pathological liver fibrosis. PMID- 22492470 TI - Follow-up CT and MR findings of osteoblastic spinal metastatic lesions after stereotactic radiotherapy. AB - PURPOSE: We retrospectively analyzed pre and post-stereotactic radiotherapy CT and MRI findings and volume changes for osteoblastic spinal metastatic lesions. MATERIALS AND METHODS: Of 114 lesions in 72 patients, 11 were osteoblastic. CT and MR images were reviewed to determine tumor volume, CT attenuation, T2 signal intensities, and contrast enhancement. RESULTS: Tumor volume did not change for 10 lesions and increased for 1 lesion. CT attenuation increased for 8 lesions with heterogeneous T2 signal intensities. Of these 8 lesions, 4 had patterns of dark signal foci and the other 4 had patterns of both dark and bright signal foci. T2 signal intensity became heterogenous, with dark and bright foci, for 2 of 3 lesions for which CT attenuation decreased, and normalized for the third lesion. The degree of contrast enhancement decreased for 6 lesions and did not change for 5 lesions. CONCLUSION: There were no changes in volume except for one case. On CT images, sclerotic changes were more common than loss of sclerotic foci. On T2-weighted images, dark signal intensities with or without bright signal foci developed and the degree of enhancement decreased for more than half of the cases. PMID- 22492471 TI - Pelvic arteriovenous malformation treated by superselective transcatheter venous and arterial embolization. AB - We describe a rare case of hematuria and hemospermia associated with pelvic arteriovenous malformation (AVM) in a male patient treated by transcatheter embolization. Understanding AVM hemodynamics contributes to the elucidation of its pathology and improves the outcome of embolization. In the present case, multiple arteriolar components shunted to the initial part of a single dominant outflow vein. Superselective embolization of a draining vein and feeding artery with an n-butyl cyanoacrylate/lipiodol mixture and polyvinyl alcohol particles was effective in terms of shunt disappearance and minimizing the need for subsequent arterial embolization. PMID- 22492472 TI - Polydiacetylene-based electrospun fibers for detection of HCl gas. AB - Polydiacetylenes (PDAs), a family of conjugated polymers, are very intriguing materials in several aspects. Especially, the stimulus-induced apparent blue-to red transition of the PDAs has led to the development of a variety of PDA-based chemosensors. In the current work, we synthesized PDA monomers bearing trimethyl amine (PCDA-DMEDA) and incorporated them with Poly(ethylene oxide) (PEO) into electrospun fibers. For the first time, we successfully demonstrated that PDA based electrospun fibers can be used for the naked-eye detection of HCl gas by simple color change (blue to red). PMID- 22492473 TI - Visualizing chemical reactions confined under graphene. AB - An undercover agent: graphene has been used as an imaging agent to visualize interfacial reactions under its cover, and exhibits a strong confinement effect on the chemistry of molecules underneath. In a CO atmosphere, CO penetrates into the graphene/Pt(111) interface and reacts with O(2) therein, whereas intercalated CO desorbs from the Pt surface. PMID- 22492474 TI - Nurses' treatment of tobacco dependence in hospitalized smokers in three states. AB - Hospital-based nurses (N = 1,790) from three states reported their interventions to help patients quit smoking. Frequency of nurses' interventions in one low tobacco use state, California (n = 651), were compared to nurses' interventions in two high tobacco use states, Indiana (n = 720) and West Virginia (n = 419). Nurses in California were significantly more likely to Advise smokers to quit (OR 1.34, 95% CI [1.06, 1.69]) and Refer smokers to a Quitline (OR 2.82, 95% CI [1.36, 5.88]) compared with nurses in the high tobacco prevalence states. Other aspects of their interventions did not differ by state. Quitline referral was infrequent (16%) but was quadrupled if nurses arranged for smokers to quit (OR 4.07, 95% CI [3.11, 5.32]). PMID- 22492475 TI - French Geocap study confirms increased leukemia risks in young children near nuclear power plants. PMID- 22492476 TI - [2012: Update on diagnosis and treatment of multiple sclerosis]. PMID- 22492477 TI - [Vitamin D for prevention of diseases?]. AB - Vitamin D3 shows a multitude of possible preventive effects in various diseases. Calcitriol, the biologically active form of vitamin D3, affects not only bone metabolism but also acts on the renal renin secretion, the pancreatic insulin production in the beta cells, growth and proliferation of smooth and cardiac muscle cells and the function of lymphocytes and macrophages. Although the human body can synthesise vitamin D3 itself, vitamin D deficiency is common in the German population. Numerous trials studied the association between vitamin D deficiency and different diseases. It is known that even mild forms of vitamin D deficiency increase the risk for cardiovascular diseases or diabetes mellitus. Furthermore, an association with cancer such as pancreatic or colorectal cancer was observed. This is attributed to the influence of vitamin D on cell differentiation, angiogenesis, DNA repair mechanisms and the transcription of numerous genes. In addition, effects of vitamin D deficiency in diseases such as Parkinson's disease, multiple sclerosis and autoimmune diseases are discussed. However, up to now the level of evidence of all these observations is low. There are missing confirmatory randomized controlled trials. Noting the possible preventive effects of vitamin D, a moderate exposure to sunlight to increase vitamin D synthesis can be recommended. Even a controlled supplementation of vitamin D in patients with vitamin D deficiency is considered as reasonable. However, an uncritical substitution of high-dose vitamin D should be avoided because of the risk of hypercalcaemia. PMID- 22492478 TI - [Effectiveness and safety of varenicline for smoking cessation]. AB - Smoking is one of the major avoidable risks for mortality and morbidity. Thus developing new strategies for smoking cessation is a crucial medical challenge. Varenicline is an alpha4beta2 nicotinic acetylcholine receptor partial agonist developed especially for smoking cessation. Several trials proved the efficacy of varenicline and its superiority to other medications for smoking cessation (bupropion and nicotine replacement therapy). Varenicline was associated with severe cardiovascular and neuro-psychiatric side effects. This article discusses the current research data on efficacy and safety of varenicline therapy for smoking cessation. PMID- 22492479 TI - Effect of alendronate for reducing fracture by FRAX score and femoral neck bone mineral density: the Fracture Intervention Trial. AB - The WHO Fracture Risk Assessment Tool (FRAX; http://www.shef.ac.uk/FRAX) estimates the 10-year probability of major osteoporotic fracture. Clodronate and bazedoxifene reduced nonvertebral and clinical fracture more effectively on a relative scale in women with higher FRAX scores. We used data from the Fracture Intervention Trial (FIT) to evaluate the interaction between FRAX score and treatment with alendronate. We combined the Clinical Fracture (CF) arm and Vertebral Fracture (VF) arm of FIT. The CF and VF arm of FIT randomized 4432 and 2027 women, respectively, to placebo or alendronate for 4 and 3 years, respectively. FRAX risk factors were assessed at baseline. FRAX scores were calculated by WHO. We used Poisson regression models to assess the interaction between alendronate and FRAX score on the risk of nonvertebral, clinical, major osteoporotic, and radiographic vertebral fractures. Overall, alendronate significantly reduced the risk of nonvertebral fracture (incidence rate ratio [IRR] 0.86; 95% confidence interval [CI], 0.75-0.99), but the effect was greater for femoral neck (FN) bone mineral density (BMD) T-score <= -2.5 (IRR 0.76; 95% CI, 0.62-0.93) than for FN T-score > -2.5 (IRR 0.96; 95% CI, 0.80-1.16) (p = 0.02, interaction between alendronate and FN BMD). However, there was no evidence of an interaction between alendronate and FRAX score with FN BMD for risk of nonvertebral fracture (interaction p = 0.61). The absolute benefit of alendronate was greatest among women with highest FRAX scores. Results were similar for clinical fractures, major osteoporotic fractures, and radiographic vertebral fractures and whether or not FRAX scores included FN BMD. Among this cohort of women with low bone mass there was no significant interaction between FRAX score and alendronate for nonvertebral, clinical or major osteoporotic fractures, or radiographic vertebral fractures. These results suggest that the effect of alendronate on a relative scale does not vary by FRAX score. A randomized controlled trial testing the effect of antifracture agents among women with high FRAX score but without osteoporosis is warranted. PMID- 22492480 TI - Circulating microRNAs: macro-utility as markers of prostate cancer? AB - The realization that microRNAs (miRNAs) are frequently deregulated in malignancy has had a major impact on cancer research. In particular, the recent finding that highly stable forms of miRNAs can be accurately measured in body fluids, including blood, has generated considerable excitement. Here, we discuss the potential of blood-based circulating miRNAs as diagnostic, prognostic, and predictive biomarkers of prostate cancer. We also describe practical considerations that may influence identification and/or measurement of miRNA biomarkers in the circulation. Finally, evidence is prevented for the emerging concept that circulating miRNAs are actively released by their cells of origin and can modulate gene expression at distal sites. These mobile miRNAs, which we term 'hormomirs' because of their hormone-like characteristics, could act as local or long-range signals to maintain normal homeostasis or influence the development and progression of diseases such as cancer. PMID- 22492481 TI - The association between in-patient death, utilization of hospital resources and availability of palliative home care for cancer patients. AB - BACKGROUND: The impact of palliative home care programs on in-patient admissions and deaths has not been appropriately established. AIM: The main objectives of this study have been to evaluate the frequency of in-patient hospital deaths and the use of hospital resources among cancer patients in two areas of the Madrid Region, as well as to assess differences between one area with and one without a palliative home care team (PHCT) in those variables. DESIGN AND SETTING: We conducted a population-based study comparing two adjacent metropolitan areas of approximately 200,000 inhabitants each in the Madrid Region, Spain, measuring in patient deaths, emergency room admissions and in-patient days among cancer patients who died in 2005. Only one of the two areas had a fully established PHCT. RESULTS: 524/549 cancer patients (95%) had an identified place of death: 74% died in hospital, 17% at home, 6% in an in-patient hospice and 3% in a nursing home. The frequency of hospital deaths was significantly lower among patients of the PHCT area (61% versus 77%, p < 0.001), as well as the number of patients using emergency and in-patient services (68% versus 79%, p = 0.004, and 66 versus 76%, p = 0.012, respectively). After adjusting for other factors, the risk of hospital death was lower among patients older than 80 (OR, 95% CI, 0.3, 0.1-0.5), higher among patients with hematological malignancies (OR 6.1, 2.0 18.9) and lower among patients of the PHCT area (OR 0.4, 0.2-0.6). CONCLUSIONS: Our findings suggest that a PHCT is associated with reduced in-patient deaths and overall hospitalization over the last two months of life. PMID- 22492482 TI - Medium-sized rings versus macrocycles through rhodium-catalyzed ring-expansion reactions of cyclic acetals. AB - alpha-Diazo beta-ketoesters and diketones react with cyclic acetals under Rh(II) catalysis to yield unprecedented polyoxygenated 8- and 9-membered rings in one pot. The reactions occur under mild conditions with yields up to 90%. A perfect regioselectivity is obtained, which can be rationalized through a mechanistic hypothesis that considers 1) the formation of an oxonium ylide, 2) its transformation into an unsaturated acyclic oxocarbenium electrophilic intermediate, and 3) an intramolecular nucleophilic attack in a direct application of Baldwin's rules. PMID- 22492483 TI - Regional coronary endothelial function is closely related to local early coronary atherosclerosis in patients with mild coronary artery disease: pilot study. AB - BACKGROUND: Coronary endothelial function is abnormal in patients with established coronary artery disease and was recently shown by MRI to relate to the severity of luminal stenosis. Recent advances in MRI now allow the noninvasive assessment of both anatomic and functional (endothelial function) changes that previously required invasive studies. We tested the hypothesis that abnormal coronary endothelial function is related to measures of early atherosclerosis such as increased coronary wall thickness. METHODS AND RESULTS: Seventeen arteries in 14 healthy adults and 17 arteries in 14 patients with nonobstructive coronary artery disease were studied. To measure endothelial function, coronary MRI was performed before and during isometric handgrip exercise, an endothelial-dependent stressor, and changes in coronary cross sectional area and flow were measured. Black blood imaging was performed to quantify coronary wall thickness and indices of arterial remodeling. The mean stress-induced change in cross-sectional area was significantly higher in healthy adults (13.5%+/-12.8%, mean+/-SD, n=17) than in those with mildly diseased arteries (-2.2%+/-6.8%, P<0.0001, n=17). Mean coronary wall thickness was lower in healthy subjects (0.9+/-0.2 mm) than in patients with coronary artery disease (1.4+/-0.3 mm, P<0.0001). In contrast to healthy subjects, stress-induced changes in cross-sectional area, a measure of coronary endothelial function, correlated inversely with coronary wall thickness in patients with coronary artery disease (r=-0.73, P=0.0008). CONCLUSIONS: There is an inverse relationship between coronary endothelial function and local coronary wall thickness in patients with coronary artery disease but not in healthy adults. These findings demonstrate that local endothelial-dependent functional changes are related to the extent of early anatomic atherosclerosis in mildly diseased arteries. This combined MRI approach enables the anatomic and functional investigation of early coronary disease. PMID- 22492484 TI - Increasing plasma free fatty acids in healthy subjects induces aortic distensibility changes seen in obesity. AB - BACKGROUND: Elevated free fatty acid (FFA) levels are known to impair aortic elastic function. In obesity, FFA levels are elevated and aortic distensibility (AD) reduced in a pattern that predominantly affects the distal aorta. Despite this, the role of FFAs in obesity-related aortic stiffness remains unclear. METHODS AND RESULTS: Using vascular MRI, we aimed to determine if (1) FFA level correlated with AD in obesity; and (2) whether elevating FFA acutely and subacutely in normal-weight subjects reproduced the distal pattern of AD change in obesity. To do this, regional AD was recorded in 35 normal-weight and 70 obese subjects and then correlated with FFA levels. When compared with normal weight, obesity was associated with reduced AD in a pattern predominantly affecting the distal aorta (ascending aorta by -22%, proximal descending aorta by -25%, and abdominal aorta by -35%; P<0.001). After controlling for age, blood pressure, and body mass index, FFA levels remained negatively correlated with abdominal AD (r= 0.43, P<0.01). In 2 further normal-weight groups, AD was recorded before and after elevation of FFA levels with intralipid infusion (by +535%, n=9) and a 5 day high-fat, low-carbohydrate diet (by +48%, n=14). CONCLUSIONS: Both intralipid infusion and a low-carbohydrate diet resulted in reduced abdominal AD (infusion 22%, diet -28%; both P<0.05), reproducing the distal pattern AD reduction seen in obesity. These findings suggest that elevated FFA impair AD in obesity and provide a potential therapeutic target to improve aortic elastic function in obesity. PMID- 22492485 TI - Performance of a multi-marker diabetes risk score in the Insulin Resistance Atherosclerosis Study (IRAS), a multi-ethnic US cohort. AB - BACKGROUND: This study compares a previously developed Diabetes Risk Score to commonly used clinical tools for type 2 diabetes risk evaluation in the Insulin Resistance Atherosclerosis Study (IRAS) cohort, a multi-ethnic US cohort. Available as a clinical test, the PreDx(r) Diabetes Risk Score uses fasting concentrations of adiponectin, C-reactive protein, ferritin, interleukin-2 receptor alpha, HbA(1c) , glucose and insulin, plus age and gender to predict 5 year risk of diabetes. It was developed in a Northern European population. METHODS: The Diabetes Risk Score was measured using archived fasting plasma specimens from 722 non-diabetic IRAS participants, 17.6% of whom developed diabetes during 5.2 years median follow-up (inter-quartile range: 5.1-5.4 years). The study included non-Hispanic whites (41.8%), Hispanics (34.5%) and African Americans (23.7%). Performance of the algorithm was evaluated by area under the receiver operating characteristic curve (AROC) and risk reclassification against other tools. RESULTS: The Diabetes Risk Score discriminates participants who developed diabetes from those who did not significantly better than fasting glucose (AROC = 0.763 versus 0.710, p = 0.003). The Diabetes Risk Score performed equally well in subpopulations defined by race/ethnicity or gender. The Diabetes Risk Score provided a significant net reclassification improvement of 0.24 (p = 0.01) when comparing predefined low/moderate/high Diabetes Risk Score categories to metabolic syndrome risk factor counting. The Diabetes Risk Score complemented the use of the oral glucose tolerance test by identifying high risk patients with impaired fasting glucose but normal glucose tolerance, 33% of whom converted. CONCLUSIONS: Measuring the Diabetes Risk Score of elevated-risk US patients could help physicians decide which patients warrant more intensive intervention. The Diabetes Risk Score performed equally well across the ethnic subpopulations present in this cohort. PMID- 22492486 TI - Facile iron-mediated AGET ATRP for water-soluble poly(ethylene glycol) monomethyl ether methacrylate in water. AB - An environmentally friendly iron catalyst system was successfully developed in water for the AGET ATRP (activator generated by electron transfer for atom transfer radical polymerization) of water-soluble monomer poly(ethylene glycol) monomethyl ether methacrylate (PEGMA) for the first time. A kinetic study indicated that the polymerization was a living/controlled process in which molecular weight increased linearly with monomer conversion. A lower molecular weight distribution (M(w)/M(n) < 1.5) was maintained. The nontoxic and biocompatible characteristics of the iron catalyst facilitate its mediated polymerization to be used in the preparation of functional polymer materials for biomedical use. PMID- 22492487 TI - Synthesis and enzymatic deprotection of fully protected 2'-5' oligoadenylates (2 5A): towards a prodrug strategy for short 2-5A. AB - Fully protected pA2'p5'A2'p5'A trimers 1a and 1b have been prepared as prodrug candidates for a short 2'-5' oligoadenylate, 2-5A, and its 3'-O-Me analog, respectively. The kinetics of hog liver carboxyesterase (HLE)-triggered deprotection in HEPES buffer (pH 7.5) at 37 degrees has been studied. The deprotection of 1a turned out to be very slow, and 2-5A never appeared in a fully deprotected form. By contrast, a considerable proportion of 1b was converted to the desired 2-5A trimer, although partial removal of the 3'-O-[(acetyloxy)methyl] group prior to exposure of the adjacent phosphodiester linkage resulted in 2',5' >3',5' phosphate migration and release of adenosine as side reactions. PMID- 22492488 TI - Stabilized hemiacetal complexes as precursors for the controlled release of bioactive volatile alcohols. AB - Hemiacetals of pyridine-2-carbaldehyde derivatives and volatile alcohols can be stabilized in organic solution in the presence of protons or different metal cations. Despite the inherent instability of hemiacetals in H(2) O, stabilizing them with zinc(II) triflate and adding them to a cationic surfactant formulation resulted in the slow release of the alcohol from cotton surfaces being treated with the hemiacetal complex. Stabilized hemiacetals might thus be suitable delivery systems of bioactive volatiles by rapid hydrolysis in H(2) O-based media. PMID- 22492489 TI - Similarity in venom alkaloid chemistry of alate queens of imported fire ants: implication for hybridization between Solenopsis richteri and S. invicta in the Southern United States. AB - Both cis- and trans-2-methyl-6-undecylpiperidines, MC11P, have been previously reported as the major components of the venom of alate queens of the imported fire ants, Solenopsis richteri (black) and S. invicta (red). To identify the minor components of venom alkaloids from alate queens and compare the venom alkaloid chemistry of alate queen of their hybrid (S. richteri*S. invicta) with that of the two parental fire ant species (S. richteri and S. invicta), silica gel short-column chromatography was utilized for separating cis-stereoisomers of venom alkaloids from trans-stereoisomers. GC/MS Analyses of venom-alkaloid chemistry of alate queens demonstrated that fewer alkaloid peaks were detected in the chromatograms of the alate queens compared to those of workers. Three new compounds, 7, 12, and 13, were detected as minor components in the venom of alate queens of all three fire ant species. Alate queens of hybrid fire ants showed cis and trans-alkaloid patterns similar to those of the parental species. Similarity in venom-alkaloid chemistry of alate queens of S. richteri and S. invicta, and their hybrid may indicate their reproductive compatibility in the hybrid zone in southern United States, where all three species occur sympatrically. PMID- 22492490 TI - Reductive coupling of aldehydes by h(2) s in aqueous solutions, a C--C bond forming reaction of prebiotic interest. AB - We report here a novel reductive coupling reaction of conjugated, non- or poorly enolizable aldehydes induced by H(2) S and operative in aqueous solutions under prebiotically relevant conditions. This reaction leads from retinal to beta carotene, and from benzylic aldehydes to the corresponding diarylethylenes. This novel reaction also opens a new potentially prebiotic pathway leading from glyoxylic acid to various compounds that are involved in the reductive tricarboxylic acid cycle. This C--C bond forming reaction of prebiotic interest might have been operative, notably, in the sulfide-rich environments of hydrothermal vents, which have been postulated as possible sites for the first steps of organic chemical evolution. PMID- 22492491 TI - Chemical diversity of essential oils from Asteriscus graveolens (Forssk.) less.: identification of cis-8-Acetoxychrysanthenyl acetate as a new natural component. AB - Asteriscus graveolens is an endemic medicinal plant mainly distributed in south western Algeria and south-eastern Morocco. The essential oils of leaves, stems, and flowers of A. graveolens had been studied by GC, GC/MS, and (13) C-NMR. The spectral data of two nerolidol derivatives, 6-oxo- and 6-hydroxycyclonerolidol, were reassigned by 1D- and 2D-NMR spectroscopy. These compounds can be considered as chemical markers of this genus. The structure of a monoterpenic diester with a chrysanthenane skeleton, i.e., cis-8-acetoxychrysanthenyl acetate, was determined for the first time on the basis of GC/MS, and 1D- and 2D-NMR. The stem and leaf oils were characterized by high content of oxygenated sesquiterpenes with 6-oxo- and 6-hydroxycyclonerolidol as major components, and the flower essential oils were dominated by the new monoterpenic compound cis-8-acetoxychrysanthenyl acetate. PMID- 22492492 TI - Concomitant induction of heme oxygenase-1 attenuates the cytotoxicity of arsenic species from lumbricus extract in human liver HepG2 cells. AB - Heme oxygenase-1 (HO-1) is an inducible antioxidant enzyme that degrades heme to three products, biliverdin, carbon monoxide (CO), and iron ion. The present study was originally designed to characterize the HO-1 induction by Lumbricus extract as a potential cytoprotective mechanism. Through bioactivity-guided fractionation, with human HepG2 cells as the cellular detector, surprisingly, we found that arsenic was enriched in the active fractions isolated from Lumbricus extract. Arsenic speciation was further carried out by liquid chromatography with inductively coupled plasma mass spectrometry (LC/ICP-MS). Our results showed that Lumbricus extract contained two major arsenic species, arsenite (As(III) ; 53.7%) and arsenate (As(V) ; 34.2%), and six minor arsenic species. Commercial sodium arsenite (NaAsO(2) ) was used to verify the effects of Lumbricus extract on HO-1 expression and related intracellular signaling pathways. Both p38 MAP kinase and NF-E2-related factor 2 (Nrf2) pathways were found to modulate HO-1 induction by Lumbricus extract and NaAsO(2) . The cytotoxicity of arsenite was augmented by p38 MAP kinase inhibitor SB202190 and HO-1 inhibitor tin protoporphyrin IX (SnPP), whereas p38 MAP kinase inhibitor SB202190 also inhibited HO-1 induction by NaAsO(2) . These results suggest that arsenic-containing compounds are responsible for HO-1 induction by Lumbricus extract. Although the exact role of toxic arsenic compounds in the treatment of oxidative injury remains unclear, concomitant HO-1 induction may be a key mechanism to antagonize the cytotoxicity of arsenic compounds in human cells. PMID- 22492493 TI - Micromorphological and chemotaxonomical traits of Micromeria croatica (Pers.) Schott. AB - A study on the types and distribution of trichomes, pollen morphology, chemical composition of essential oil (analyzed by GC-FID and GC/MS), and the content of macroelements (Na, K, Ca, and Mg) and trace elements (B, Fe, Cu, Mn, Zn, Al, Pb, Cr, Cd, Ni, Hg, and As) analyzed by ICP-AES (=inductively coupled plasma atomic emission spectroscopy) was conducted on Micromeria croatica (Pers.) Schott. Non glandular trichomes, peltate trichomes (typical hairs of Lamiaceae), small capitate trichomes (composed of one basal epidermal cell and one head cell), and larger capitate trichomes (composed of one basal epidermal cell, two to three stalk cells, and one head cell with subcuticular space) were observed on leaves, stems, the calyx, and corolla. Pollen of M. croatica had six apertures (hexacolpate) which were set in the equatorial pollen belt (zonocolpate) and showed medium reticulate ornamentation (hetrobrochate type). The essential oil contained from 27 to 39 constituents, the most representative of which were caryophyllene oxide and E-caryophyllene. Among the investigated macroelements, the content of K was highest (8730-10080 mg/kg). The content of trace elements ranged from 0.12 mg/kg (Cr) to 78.00 mg/kg (Fe), while the content of Cd, Ni, Hg, and As were lower than the limit of quantification. PMID- 22492494 TI - Two New Norlignans and a New Lignanamide from Peperomia tetraphylla. AB - Two new cyclobutane-type norlignans, methyl rel-(1R,2S,3S)-2-(7-methoxy-1,3 benzodioxol-5-yl)-3-(2,4,5-trimethoxyphenyl)cyclobutanecarboxylate (1), and methyl rel-(1R,2R,3S)-2-(7-methoxy-1,3-benzodioxol-5-yl)-3-(2,4,5 trimethoxyphenyl)cyclobutanecarboxylate (2), and a new lignanamide, 3-hydroxy-N [2-(4-hydroxyphenyl)ethyl]-alpha-[4-(2-{N-[2-(4 hydroxyphenyl)ethyl]carbamoyl}ethenyl)-3-methoxyphenoxy]-4-methoxycinnamamide 4,8"-ether (3), along with five known amides, 4-8, were obtained from the whole plant of Peperomia tetraphylla. Their structures were elucidated mainly by the analysis of NMR and MS data. The new compounds 1-3 and the known compound 4 were tested for their cytotoxic activities against the HepG2 (human hepatocarcinoma), A549 (human lung cancer), and HeLa (human cervical cancer) cell lines. Compound 4 showed significant cytotoxicity against HepG2 cell lines with an IC(50) value of 9.4 +/- 1.0 MUM. PMID- 22492495 TI - Synthesis and immunostimulating properties of novel adamant-1-yl tripeptides. AB - The aim of this work was to prepare L- and D-(adamant-1-yl)-Gly-L-Ala-D-isoGln peptides in order to study their adjuvant (immunostimulating) activities. Adjuvant activity of adamant-1-yl tripeptides was tested in the mouse model using ovalbumin as an antigen and in comparison to the peptidoglycan monomer (PGM; beta D-GlcNAc-(1->4)-D-MurNAc-L-Ala-D-isoGln-mesoDAP(epsilonNH(2) )-D-Ala-D-Ala) and structurally related adamant-2-yl tripeptides. PMID- 22492497 TI - Chemical composition and intraspecific variability of the essential oils of five populations of Hypericum triquetrifolium Turra growing in North Tunisia. AB - The chemical composition of the essential oils of five populations of Hypericum triquetrifolium Turra from Tunisia and their intraspecific variability were analyzed in detail by GC/MS. One hundred seventy-four compounds were identified, representing averages of 87.9 to 98.7% of the oil composition. The components are represented here by homologous series of monoterpene hydrocarbons, oxygenated monoterpenes, sesquiterpenes hydrocarbons, oxygenated sesquiterpenes, non terpenic hydrocarbons, and others. Sesquiterpene hydrocarbons were the most abundant chemical compounds. Multivariate chemometric techniques, such as cluster analysis (CA) and principal-component analysis (PCA), were used to characterize the samples according to the geographical origin. By statistical analysis, the analyzed populations were classified into four chemotype groups. PMID- 22492496 TI - Chemical and genetic study of Ligularia duciformis and related species in Sichuan and Yunnan Provinces of China. AB - The chemical constituents of the root extracts and the evolutionarily neutral DNA base sequences were studied for 28 samples of Ligularia duciformis, L. kongkalingensis, and L. nelumbifolia collected in Sichuan and Yunnan Provinces of China. The samples could be classified into four chemotypes (1-4). Sesquiterpenoids having eremophilane and oplopane skeletons were isolated from two (Chemotype 1) and three (Chemotype 2) samples, respectively. Two new oplopane derivatives were isolated and their structures were determined. In 18 samples, phenylpropenoids were the major components (Chemotype 3). In five samples, neither phenylpropenoids nor sesquiterpenoids were found (Chemotype 4). Despite this large chemical variety, no correlation was found between the chemotype and the morphological criteria of species identification. The analysis of the evolutionarily neutral DNA regions also indicated that the samples were not separated into distinct clades and that introgression was extensive. PMID- 22492498 TI - Structural characteristics and biological activity of Fucoidans from the brown algae Alaria sp. and Saccharina japonica of different reproductive status. AB - Structural characteristics and the antitumor activity of fucoidans isolated from vegetative and reproductive tissue of the brown algae Alaria sp. and Saccharina japonica were studied. The reproductive status of the brown algae affected the yield of fucoidans and their structural characteristics. The fucoidan yield was 5.7% (w/w on the basis of the dried algae weight) for fertile and 3.8% for sterile Alaria sp. and 1.42 and 0.71% for fertile and sterile S. japonica, respectively. The fucoidans from fertile Alaria sp. and S. japonica had a slightly higher degree of sulfation and a somewhat more homogeneous monosaccharide composition, with predominate amounts of fucose and galactose, than those isolated from sterile algae tissue. The fucoidans from both the sterile and fertile brown algae tissue tested possessed selective cytotoxicity towards human breast cancer (T-47D) and melanoma (RPMI-7951) cell lines, but not to normal mouse epidermal cells (JB6 Cl41), and effectively inhibited the proliferation and colony formation of the breast cancer and melanoma cell lines. The fucoidans from reproductive tissue of brown algae possessed higher antitumor activity than those from vegetative plants. PMID- 22492499 TI - Chemical composition and antimicrobial activity of essential oils from Scabiosa arenaria Forssk: growing wild in Tunisia. AB - The essential oils isolated from three organs, i.e., fruits, stems and leaves, and flowers, of the endemic North African plant Scabiosa arenaria Forssk. were screened for their chemical composition, as well as their possible antibacterial, anticandidal, and antifungal properties. According to the GC-FID and GC/MS analyses, 61 (99.26% of the total oil composition), 79 (98.43%), and 51 compounds (99.9%) were identified in the three oils, respectively. While alpha-thujone (34.39%), camphor (17.48%), and beta-thujone (15.29%) constituted the major compounds of the fruit oil, chrysanthenone (23.43%), together with camphor (12.98%) and alpha-thujone (10.7%), were the main constituents of the stem and leaf oil. In the case of the flower oil, also chrysanthenone (38.52%), camphor (11.75%), and alpha-thujone (9.5%) were identified as the major compounds. Furthermore, the isolated oils were tested against 16 Gram-positive and Gram negative bacteria, four Candida species, and nine phytopathogenic fungal strains. It was found that the oils exhibited interesting antibacterial and anticandidal activities, comparable to those of thymol, which was used as positive control, but no activity against the phytopathogenic fungal strains was observed. PMID- 22492500 TI - Readability of hospice materials to prepare families for caregiving at the time of death. AB - Many health care materials are not written at levels that can be understood by most lay people. In this descriptive study, we examined the readability of documents used by hospices to prepare families for caregiving at the time of death. We used two common formulae to examine the documents. The mean Flesch Kincaid grade level was 8.95 (SD 1.80). The mean Simple Measure of Gobbledygook grade level was 11.06 (SD 1.36). When we used the Colors Label Ease for Adult Readers instrument, it became evident that medical terminology was the primary reason for the high-grade levels. Most documents (78%) included medical terms that were directly (46.2%) or indirectly (25.6%) explained in the text. Modification of hospice materials could improve families' comprehension of information important for optimal end-of-life care. PMID- 22492501 TI - Daily parathyroid hormone 1-34 replacement therapy for hypoparathyroidism induces marked changes in bone turnover and structure. AB - Parathyroid hormone (PTH) has variable actions on bone. Chronically increased PTH is catabolic and leads to osteoporosis; yet intermittent administration is anabolic and increases bone mass. PTH deficiency is associated with decreased bone remodeling and increased bone mass. However, the effects of PTH replacement therapy on bone in hypoparathyroidism are not well known. We discontinued calcitriol therapy and treated 5 hypoparathyroid subjects (2 adults and 3 adolescents) with synthetic human PTH 1-34 (hPTH 1-34), injected two to three times daily for 18 months, with doses individualized to maintain serum calcium at 1.9 to 2.25 mmol/L. Biochemical markers and bone mineral density (BMD) were assessed every 6 months; iliac-crest biopsies were performed before and after 1 year of treatment. hPTH 1-34 therapy significantly increased bone markers to supranormal levels. Histomorphometry revealed that treatment dramatically increased cancellous bone volume and trabecular number and decreased trabecular separation. Changes in trabecular width were variable, suggesting that the increase in trabecular number was due to the observed intratrabecular tunneling. Cortical width remained unchanged; however, hPTH 1-34 treatment increased cortical porosity. Cancellous bone remodeling was also stimulated, inducing significant changes in osteoid, mineralizing surface, and bone formation rate. Similar changes were seen in endocortical and intracortical remodeling. BMD Z scores were unchanged at the spine and femoral neck. Total hip Z-scores increased; however, total body BMD Z-scores decreased during the first 6 months of treatment and then stabilized, remaining significantly decreased compared to baseline. Radial Z-scores also decreased with treatment; this was most pronounced in the growing adolescent. Daily hPTH 1-34 therapy for hypoparathyroidism stimulated bone turnover, increased bone volume, and altered bone structure in the iliac crest. These findings suggest that treatment with hPTH 1-34 in hypoparathyroid adults and adolescents has varying effects in the different skeletal compartments, leading to an increase in trabecular bone and an apparent trabecularization of cortical bone. PMID- 22492502 TI - Cell-adhesive thermogelling PNIPAAm/hyaluronic acid cell delivery hydrogels for potential application as minimally invasive retinal therapeutics. AB - Copolymers of N-isopropylacrylamide (NIPAAm) and acrylic acid N hydroxysuccinimide (NAS) were synthesized via free radical polymerization and conjugated with amine-functionalized hyaluronic acid (HA) and cell adhesive RGDS peptides. These novel copolymers were designed to facilitate noninvasive delivery of a liquid suspension of cells into the delicate subretinal space for treatment of retinal degenerative diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. The various synthesized copolymers all displayed subphysiological phase transition temperatures, thereby allowing temperature induced scaffold formation and subsequent entrapment of transplanted cells within an adhesive support matrix. Successful grafting of HA and RGDS peptides were confirmed with Fourier Transform Infrared (FTIR) spectroscopy and quantified with (1)H Nuclear Magnetic Resonance (NMR) spectroscopy. All copolymers demonstrated excellent compatibility with retinal pigment epithelial (RPE) cells in culture and minimal host response was observed following subcutaneous implantation into hairless SKH1-E mice (strain code 447). PMID- 22492503 TI - Asymmetric N-allylation of indoles through the iridium-catalyzed allylic alkylation/oxidation of indolines. PMID- 22492504 TI - Gated photochromism and acidity photomodulation of a diacid dithienylethene dye. AB - The present study quantitatively analyses the gated photochromism and the acidity photomodulation properties of a diacid dithienylethene compound. Photoisomerisation between the open and closed isomers was investigated by UV/visible and (1)H NMR spectroscopy. It was found that the photocyclisation quantum yield of the diacid form was remarkably high (around 90%). Partial neutralisation of the open isomer revealed a gated photochromism as the photocyclisation quantum yield of the mono- and dianion were 50 and 67%, respectively. A considerable photomodulation of the acidity was observed: the closed isomer is more acid than the open one by more than one pK(a) unit. This effect has been shown to be exploitable for a reversible photo-acid generation. This is the first time that a complete quantitative investigation that allows for the determination of the main photochromic, spectral and thermodynamic parameters of a base-sensitive photochromic diarylethene has been carried out. PMID- 22492505 TI - Recognition of heat shock protein 60 epitopes in children with type 1 diabetes. AB - BACKGROUND: Treatment with a specific HSP60 epitope in new onset of type 1 diabetes (T1D) patients has been shown to preserve endogenous insulin production. Previously, recognition of pan HLA-DR-binding HSP60 epitopes in various autoimmune diseases was found; this study investigated recognition of these epitopes in newly diagnosed T1D patients and correlated findings to the occurrence of a partial remission. METHODS: Peripheral blood mononuclear cells of 18 children with T1D were prospectively collected at disease onset and a few months after diagnosis. Epitope-specific T-cell proliferation and cytokine production (intracellular and in culture supernatants) were measured. Results were compared with 31 longstanding T1D patients and ten healthy controls. RESULTS: Although HSP60 epitope-specific T-cell proliferative responses were detected, overall proliferative responses were low. At onset, epitope-specific intracellular IFN-gamma production was higher in T1D patients compared with healthy controls (p < 0.05). At follow-up, both IL-10 and IFN-gamma production were higher in those without a partial remission than in those with a partial remission (both p < 0.05). Also, IL-10 and IFN-gamma production were higher compared with onset for patients without a PR (both p < 0.01). In supernatants of HSP60 epitope-specific T-cell cultures, no substantial differences in cytokine production were found between T1D patients with and without a partial remission, either at onset or a few months after onset. As patient numbers were small, results should be interpreted with caution. CONCLUSIONS: Pan-DR-binding HSP60 peptides induced low peptide-specific proliferative responses and peptide specific production of some, mainly intracellular, cytokines in T1D patients. Recognition did not differ significantly between patient groups and various time points. PMID- 22492506 TI - Formation of a polypseudorotaxane via self-assembly of gamma-cyclodextrin with poly(N-isopropylacrylamide). AB - A polypseudorotaxane (PPR) comprising gamma-cyclodextrin (gamma-CD) as host molecules and poly(N-isopropylacrylamide) (PNIPAM) as a guest polymer is prepared via self-assembly in aqueous solution. Due to the bulky pendant isopropylamide group, PNIPAM exhibits size-selectivity toward self-assembly with alpha-, beta-, and gamma-CDs. It can fit into the cavity of gamma-CD to give rise to a PPR, but cannot pass through alpha-CD and beta-CD under the same conditions. The ratio of the number of gamma-CD molecules to entrapped NIPAM repeat units is kept at 1:2.2 or 1:2.4, determined by (1) H NMR spectroscopy and TGA analysis, respectively, indicating that there are more than 2 but less than 3 NIPAM repeat units included by one gamma-CD molecule. This finding opens new avenues to PPR-based supramolecular polymers to be used as solid, stimuli-responsive materials. PMID- 22492507 TI - Overexpression of S4D mutant of Leishmania donovani ADF/cofilin impairs flagellum assembly by affecting actin dynamics. AB - Leishmania, like other eukaryotes, contains large amounts of actin and a number of actin-related and actin binding proteins. Our earlier studies have shown that deletion of the gene corresponding to Leishmania actin-depolymerizing protein (ADF/cofilin) adversely affects flagellum assembly, intracellular trafficking, and cell division. To further analyze this, we have now created ADF/cofilin site specific point mutants and then examined (i) the actin-depolymerizing, G-actin binding, and actin-bound nucleotide exchange activities of the mutant proteins and (ii) the effect of overexpression of these proteins in wild-type cells. Here we show that S4D mutant protein failed to depolymerize F-actin but weakly bound G actin and inhibited the exchange of G-actin-bound nucleotide. We further observed that overexpression of this protein impaired flagellum assembly and consequently cell motility by severely impairing the assembly of the paraflagellar rod, without significantly affecting vesicular trafficking or cell growth. Taken together, these results indicate that dynamic actin is essentially required in assembly of the eukaryotic flagellum. PMID- 22492508 TI - Bicyclic peptides with optimized ring size inhibit human plasma kallikrein and its orthologues while sparing paralogous proteases. PMID- 22492509 TI - A rapid method for assessing the RNA-binding potential of a protein. AB - In recent years, evidence has emerged for the existence of many diverse types of RNA, which play roles in a wide range of biological processes in all kingdoms of life. These molecules generally do not, however, act in isolation, and identifying which proteins partner with RNA is a major challenge. Many methods, in vivo and in vitro, have been used to address this question, including combinatorial or high-throughput approaches, such as systematic evolution of ligands, cross-linking and immunoprecipitation and RNA immunoprecipitation combined with deep sequencing. However, most of these methods are not trivial to pursue and often require substantial optimization before results can be achieved. Here, we demonstrate a simple technique that allows one to screen proteins for RNA-binding properties in a gel-shift experiment and can be easily implemented in any laboratory. This assay should be a useful first-pass tool for assessing whether a protein has RNA- or DNA-binding properties, prior to committing resources to more complex procedures. PMID- 22492510 TI - Master regulatory GATA transcription factors: mechanistic principles and emerging links to hematologic malignancies. AB - Numerous examples exist of how disrupting the actions of physiological regulators of blood cell development yields hematologic malignancies. The master regulator of hematopoietic stem/progenitor cells GATA-2 was cloned almost 20 years ago, and elegant genetic analyses demonstrated its essential function to promote hematopoiesis. While certain GATA-2 target genes are implicated in leukemogenesis, only recently have definitive insights emerged linking GATA-2 to human hematologic pathophysiologies. These pathophysiologies include myelodysplastic syndrome, acute myeloid leukemia and an immunodeficiency syndrome with complex phenotypes including leukemia. As GATA-2 has a pivotal role in the etiology of human cancer, it is instructive to consider mechanisms underlying normal GATA factor function/regulation and how dissecting such mechanisms may reveal unique opportunities for thwarting GATA-2-dependent processes in a therapeutic context. This article highlights GATA factor mechanistic principles, with a heavy emphasis on GATA-1 and GATA-2 functions in the hematopoietic system, and new links between GATA-2 dysregulation and human pathophysiologies. PMID- 22492511 TI - Estrogen receptor-alpha recruits P-TEFb to overcome transcriptional pausing in intron 1 of the MYB gene. AB - The MYB proto-oncogene is expressed in most estrogen receptor-positive (ERalpha(+)) breast tumors and cell lines. Expression of MYB is controlled, in breast cancer and other cell types, by a transcriptional pausing mechanism involving an attenuation site located ~1.7 kb downstream from the transcription start site. In breast cancer cells, ligand-bound ERalpha binds close to, and drives transcription beyond this attenuation site, allowing synthesis of complete transcripts. However, little is known, in general, about the factors involved in relieving transcriptional attenuation, or specifically how ERalpha coordinates such factors to promote transcriptional elongation. Using cyclin dependent kinase 9 (CDK9) inhibitors, reporter gene assays and measurements of total and intronic MYB transcription, we show that functionally active CDK9 is required for estrogen dependent transcriptional elongation. We further show by ChIP and co immunoprecipitation studies that the P-TEFb complex (CDK9/CyclinT1) is recruited to the attenuation region by ligand-bound ERalpha, resulting in increased RNA polymerase II Ser-2 phosphorylation. These data provide new insights into MYB regulation, and given the critical roles of MYB in tumorigenesis, suggest targeting MYB elongation as potential therapeutic strategy. PMID- 22492512 TI - Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs. AB - The recent discovery that the human and other mammalian genomes produce thousands of long non-coding RNAs (lncRNAs) raises many fascinating questions. These mRNA like molecules, which lack significant protein-coding capacity, have been implicated in a wide range of biological functions through diverse and as yet poorly understood molecular mechanisms. Despite some recent insights into how lncRNAs function in such diverse cellular processes as regulation of gene expression and assembly of cellular structures, by and large, the key questions regarding lncRNA mechanisms remain to be answered. In this review, we discuss recent advances in understanding the biology of lncRNAs and propose avenues of investigation that may lead to fundamental new insights into their functions and mechanisms of action. Finally, as numerous lncRNAs are dysregulated in human diseases and disorders, we also discuss potential roles for these molecules in human health. PMID- 22492513 TI - A flexible integrative approach based on random forest improves prediction of transcription factor binding sites. AB - Transcription factor binding sites (TFBSs) are DNA sequences of 6-15 base pairs. Interaction of these TFBSs with transcription factors (TFs) is largely responsible for most spatiotemporal gene expression patterns. Here, we evaluate to what extent sequence-based prediction of TFBSs can be improved by taking into account the positional dependencies of nucleotides (NPDs) and the nucleotide sequence-dependent structure of DNA. We make use of the random forest algorithm to flexibly exploit both types of information. Results in this study show that both the structural method and the NPD method can be valuable for the prediction of TFBSs. Moreover, their predictive values seem to be complementary, even to the widely used position weight matrix (PWM) method. This led us to combine all three methods. Results obtained for five eukaryotic TFs with different DNA-binding domains show that our method improves classification accuracy for all five eukaryotic TFs compared with other approaches. Additionally, we contrast the results of seven smaller prokaryotic sets with high-quality data and show that with the use of high-quality data we can significantly improve prediction performance. Models developed in this study can be of great use for gaining insight into the mechanisms of TF binding. PMID- 22492514 TI - Subacute ischemic stroke is associated with focal 11C PiB positron emission tomography retention but not with global neocortical Abeta deposition. AB - BACKGROUND AND PURPOSE: Conflicting evidence exists as to whether focal cerebral ischemia contributes to cerebral amyloid deposition. We aimed to look at Abeta deposits, detected by N-methyl-2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (PiB) positron emission tomography, in patients with recent ischemic stroke. Specifically, we hypothesized that patients with recent ischemic stroke have higher local and neocortical PiB positron emission tomography retention and that this may be associated with major vascular risk factors. METHODS: Ischemic stroke patients were studied using PiB positron emission tomography within 30 days and compared to age-matched controls. Distribution volume ratio maps were created using Logan graphical analysis with the cerebellar cortex as a reference. RESULTS: Among the 21 ischemic stroke patients (median age, 76 years; interquartile range, 68-77), the ipsilateral peri-infarct region PiB retention was higher compared to the contralateral mirror region, with a PiB distribution volume ratio difference of 0.29 (95% CI, 0.2-0.44; P=0.001) at median 10 (interquartile range, 7-14) days after stroke. Two patients also had higher PiB retention within the infarct compared to the contralateral side. There was no difference in the neocortical PiB retention elsewhere in the brain among ischemic stroke patients compared with 22 age-matched normal controls (P=0.22). Among the risk factors in the ischemic stroke patients, diabetes was associated with a higher neocortical PiB retention (Spearman Rho=0.48; 95% CI, 0.28-0.72). CONCLUSIONS: PiB retention was higher in the peri-infarct region among patients with recent ischemic stroke. This did not translate into a higher global neocortical PiB retention except possibly in patients with diabetes. The cause of the focal PiB retention is uncertain and requires further investigation. PMID- 22492515 TI - Secondary neurodegeneration in remote regions after focal cerebral infarction: a new target for stroke management? PMID- 22492516 TI - Letter by Martinez-Martinez et al regarding article, "variable presentations of postpartum angiopathy". PMID- 22492517 TI - Relationship between neurologic deficit severity and final functional outcome shifts and strengthens during first hours after onset. AB - BACKGROUND AND PURPOSE: Early neurological deficit severity is the most important determinant of final functional outcome in acute ischemic stroke. However, deficit severity frequently changes during the first hours and days postonset. METHODS: Analysis of control group patients enrolled in the 2 National Institute of Neurological Disorders and Stroke tissue-type plasminogen activator trials. Neurological deficit severity was measured serially using the National Institutes of Health Stroke Scale (NIHSS) at 1 to 3 hours postonset, 3 to 5 hours, 24 hours, 7 to 10 days, and 90 days. Final global disability outcome was assessed at 90 days using the modified Rankin Scale. RESULTS: Among the 312 patients, median neurological deficit severity on the NIHSS improved throughout the 90-day observation period, from 15 (interquartile range, 9.5-20) at 1 to 3 hours, to 12 (interquartile range, 6-19) at 24 hours, to 7 (interquartile range, 2-19) at 90 days. Between 1-to-3-hours to 24 hours, more patients spontaneously improved than worsened: 39.1% versus 17.6% (P<0.001). NIHSS scores associated with individual final modified Rankin Scale global disability ranks shifted to lower values over time; eg, patients with a final modified Rankin Scale of 2 had the following median NIHSS scores: 12 at 1 to 3 hours, 10 at 3 to 5 hours, 9 at 24 hours, and 3 at 90 days. Correlation coefficients between NIHSS and the final modified Rankin Scale increased over time, from 0.51 at 1 to 3 hours, to 0.72 at 24 hours, to 0.87 at 90 days. CONCLUSIONS: During the first 24 hours after onset, spontaneous improvement occurs in 2 of 5 acute ischemic stroke patients. The NIHSS scores associated with individual global disability ranks decrease over time. Neurological deficit severity increasingly predicts final disability outcome, accounting for one quarter of the variance at 1 to 3 hours, one half at 24 hours, and three quarters at 90 days. PMID- 22492518 TI - Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. AB - BACKGROUND AND PURPOSE: Intracranial hemorrhage is the most devastating complication of anticoagulation. Outcomes associated with different sites of intracranial bleeding occurring with warfarin versus dabigatran have not been defined. METHODS: Analysis of 18 113 participants with atrial fibrillation in the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial assigned to adjusted-dose warfarin (target international normalized ratio, 2-3) or dabigatran (150 mg or 110 mg, both twice daily). RESULTS: During a mean of 2.0 years of follow-up, 154 intracranial hemorrhages occurred in 153 participants: 46% intracerebral (49% mortality), 45% subdural (24% mortality), and 8% subarachnoid (31% mortality). The rates of intracranial hemorrhage were 0.76%, 0.31%, and 0.23% per year among those assigned to warfarin, dabigatran 150 mg, and dabigatran 110 mg, respectively (P<0.001 for either dabigatran dose versus warfarin). Fewer fatal intracranial hemorrhages occurred among those assigned dabigatran 150 mg and 110 mg (n=13 and n=11, respectively) versus warfarin (n=32; P<0.01 for both). Fewer traumatic intracranial hemorrhages occurred among those assigned to dabigatran (11 patients with each dose) compared with warfarin (24 patients; P<0.05 for both dabigatran doses versus warfarin). Independent predictors of intracranial hemorrhage were assignment to warfarin (relative risk, 2.9; P<0.001), aspirin use (relative risk, 1.6; P=0.01), age (relative risk, 1.1 per year; P<0.001), and previous stroke/transient ischemic attack (relative risk, 1.8; P=0.001). CONCLUSIONS: The clinical spectrum of intracranial hemorrhage was similar for patients given warfarin and dabigatran. Absolute rates at all sites and both fatal and traumatic intracranial hemorrhages were lower with dabigatran than with warfarin. Concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage. PMID- 22492519 TI - Baseline cardiovascular risk predicts subsequent changes in resting brain function. AB - BACKGROUND AND PURPOSE: The Framingham Heart Study group cardiovascular disease risk profile (FCRP) score was used to assess the relationship between baseline cardiovascular risk and subsequent changes in resting state cerebral blood flow (CBF) in cognitively normal older participants from the Baltimore Longitudinal Study of Aging. METHODS: Ninty-seven cognitively normal participants underwent annual resting-state positron emission tomography scans at baseline and over a period of up to 8 years (mean interval, 7.4 years). Images quantifying voxel-wise longitudinal rates of CBF change were calculated and used to examine the relationship between baseline FCRP score and changes over time in regional CBF. Individual components of the FCRP score (age, cholesterol, blood pressure, smoking status, and type 2 diabetes) were also correlated with changes in regional CBF to examine the independent contributions of each component to the overall pattern of change. RESULTS: Higher baseline FCRP scores were associated with accelerated longitudinal decline in CBF in orbitofrontal, medial frontal/anterior cingulate, insular, precuneus, and brain stem regions. Of the components that comprise the FCRP score, higher diastolic blood pressure and diabetes were associated independently with greater decline in the medial frontal/anterior cingulate and insular regions, respectively. CONCLUSIONS: Baseline cardiovascular risk factors are associated with greater rates of decline in resting state regional brain function. The regions showing accelerated decline participate in higher-order cognitive processes and are also vulnerable to age related neuropathology. These results, in conjunction with other studies, encourage early treatment of cardiovascular risk factors in older individuals. PMID- 22492521 TI - Introspection: an analysis of the citation impact of stroke. PMID- 22492520 TI - Relationship between angiographic vasospasm and regional hypoperfusion in aneurysmal subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: Angiographic vasospasm frequently complicates subarachnoid hemorrhage and has been implicated in the development of delayed cerebral ischemia. Whether large-vessel narrowing adequately accounts for the critical reductions in regional cerebral blood flow underlying ischemia is unclear. We sought to clarify the relationship between angiographic vasospasm and regional hypoperfusion. METHODS: Twenty-five patients with aneurysmal subarachnoid hemorrhage underwent cerebral catheter angiography and 15O-positron emission tomographic imaging within 1 day of each other (median of 7 days after subarachnoid hemorrhage). Severity of vasospasm was assessed in each intracranial artery, whereas cerebral blood flow and oxygen extraction fraction were measured in 28 brain regions distributed across these vascular territories. We analyzed the association between vasospasm and perfusion and compared frequency of hypoperfusion (cerebral blood flow<25 mL/100 g/min) and oligemia (low oxygen delivery with oxygen extraction fraction>=0.5) in territories with versus without significant vasospasm. RESULTS: Twenty-four percent of 652 brain regions were supplied by vessels with significant vasospasm. Cerebral blood flow was lower in such regions (38.6+/-12 versus 48.7+/-16 mL/100 g/min), whereas oxygen extraction fraction was higher (0.48+/-0.19 versus 0.37+/-0.14, both P<0.001). Hypoperfusion was seen in 46 regions (7%), but 66% of these were supplied by vessels with no significant vasospasm; 24% occurred in patients without angiographic vasospasm. Similarly, oligemia occurred more frequently outside territories with vasospasm. CONCLUSIONS: Angiographic vasospasm is associated with reductions in cerebral perfusion. However, regional hypoperfusion and oligemia frequently occurred in territories and patients without vasospasm. Other factors in addition to large vessel narrowing must contribute to critical reductions in perfusion. PMID- 22492522 TI - Clinical and pathological improvement in stroke-prone spontaneous hypertensive rats related to the pleiotropic effect of cilostazol. AB - BACKGROUND AND PURPOSE: Cerebral infarction is a major cause of death or decreasing activities of daily living. This study aimed to investigate the efficacy of commonly used antiplatelet drugs on stroke and motor and cognitive functions in relation to oxidative stress markers and insulin-like growth factor 1 receptor (IGF-1R). METHODS: Stroke-prone spontaneously hypertensive rats were treated with vehicle, aspirin, clopidogrel, and cilostazol from 8 to 10 weeks of age. Physiological parameters, regional cerebral blood flow, and serum lipids were examined. Motor and cognitive functions were evaluated weekly by the Rotorod and water maze task. Spontaneous infarct volume, oxidative stress markers for lipid, protein, and DNA at the ischemic boundary zone of spontaneous infarction, and the IGF-1R-positive cell ratio in the hippocampus were immunohistochemically examined in brain sections. IGF-1Rbeta expression in the hippocampus was assessed by Western blotting. RESULTS: The antiplatelet drugs, cilostazol and clopidogrel, reduced the spontaneous infarct volume more than aspirin. Only cilostazol improved motor and cognitive functions with a significant increase (P<0.05) in the memory-related IGF-1R-positive ratio and IGF-1Rbeta expression in the hippocampus. Cilostazol reduced the 4 oxidative stress markers in affected neurons in stroke-prone spontaneously hypertensive rats regardless of blood pressure, regional cerebral blood flow, or serum lipid levels. CONCLUSIONS: The present results suggest that a possible pleiotropic effect of cilostazol resulted in the reduction of spontaneous infarct volume and preservation of motor and spatial cognitive functions. The increase of IGF-1R-positive cells in the hippocampal CA1 region could partly explain the preservation of spatial cognitive function in stroke-prone spontaneously hypertensive rats. PMID- 22492523 TI - From MST to PTSD. PMID- 22492524 TI - Cellular responses to the metal-binding properties of metformin. AB - In recent decades, the antihyperglycemic biguanide metformin has been used extensively in the treatment of type 2 diabetes, despite continuing uncertainty over its direct target. In this article, using two independent approaches, we demonstrate that cellular actions of metformin are disrupted by interference with its metal-binding properties, which have been known for over a century but little studied by biologists. We demonstrate that copper sequestration opposes known actions of metformin not only on AMP-activated protein kinase (AMPK)-dependent signaling, but also on S6 protein phosphorylation. Biguanide/metal interactions are stabilized by extensive pi-electron delocalization and by investigating analogs of metformin; we provide evidence that this intrinsic property enables biguanides to regulate AMPK, glucose production, gluconeogenic gene expression, mitochondrial respiration, and mitochondrial copper binding. In contrast, regulation of S6 phosphorylation is prevented only by direct modification of the metal-liganding groups of the biguanide structure, supporting recent data that AMPK and S6 phosphorylation are regulated independently by biguanides. Additional studies with pioglitazone suggest that mitochondrial copper is targeted by both of these clinically important drugs. Together, these results suggest that cellular effects of biguanides depend on their metal-binding properties. This link may illuminate a better understanding of the molecular mechanisms enabling antihyperglycemic drug action. PMID- 22492525 TI - Gluteofemoral adipose tissue plays a major role in production of the lipokine palmitoleate in humans. AB - The expansion of lower-body adipose tissue (AT) is paradoxically associated with reduced cardiovascular disease and diabetes risk. We examined whether the beneficial metabolic properties of lower-body AT are related to the production and release of the insulin-sensitizing lipokine palmitoleate (16:1n-7). Using venoarterial difference sampling, we investigated the relative release of 16:1n-7 from lower-body (gluteofemoral) and upper-body (abdominal subcutaneous) AT depots. Paired gluteofemoral and abdominal subcutaneous AT samples were analyzed for triglyceride fatty acid composition and mRNA expression. Finally, the triglyceride fatty acid composition of isolated human preadipocytes was determined. Relative release of 16:1n-7 was markedly higher from gluteofemoral AT compared with abdominal subcutaneous AT. Stearoyl-CoA desaturase 1 (SCD1), the key enzyme involved in endogenous 16:1n-7 production, was more highly expressed in gluteofemoral AT and was associated with greater enrichment of 16:1n-7. Furthermore, isolated human preadipocytes from gluteofemoral AT displayed a higher content of SCD1-derived fatty acids. We demonstrate that human gluteofemoral AT plays a major role in determining systemic concentrations of the lipokine palmitoleate. Moreover, this appears to be an inherent feature of gluteofemoral AT. We propose that the beneficial metabolic properties of lower body AT may be partly explained by the intrinsically greater production and release of palmitoleate. PMID- 22492526 TI - Transient receptor potential vanilloid type 1-dependent regulation of liver related neurons in the paraventricular nucleus of the hypothalamus diminished in the type 1 diabetic mouse. AB - The paraventricular nucleus (PVN) of the hypothalamus controls the autonomic neural output to the liver, thereby participating in the regulation of hepatic glucose production (HGP); nevertheless, mechanisms controlling the activity of liver-related PVN neurons are not known. Transient receptor potential vanilloid type 1 (TRPV1) is involved in glucose homeostasis and colocalizes with liver related PVN neurons; however, the functional role of TRPV1 regarding liver related PVN neurons has to be elucidated. A retrograde viral tracer was used to identify liver-related neurons within the brain-liver circuit in control, type 1 diabetic, and insulin-treated mice. Our data indicate that TRPV1 regulates liver related PVN neurons. This TRPV1-dependent excitation diminished in type 1 diabetic mice. In vivo and in vitro insulin restored TRPV1 activity in a phosphatidylinositol 3-kinase/protein kinase C-dependent manner and stimulated TRPV1 receptor trafficking to the plasma membrane. There was no difference in total TRPV1 protein expression; however, increased phosphorylation of TRPV1 receptors was observed in type 1 diabetic mice. Our data demonstrate that TRPV1 plays a pivotal role in the regulation of liver-related PVN neurons. Moreover, TRPV1-dependent excitation of liver-related PVN neurons diminishes in type 1 diabetes, thus indicating that the brain-liver autonomic circuitry is altered in type 1 diabetes and may contribute to the autonomic dysfunction of HGP. PMID- 22492527 TI - Reduced insulin exocytosis in human pancreatic beta-cells with gene variants linked to type 2 diabetes. AB - The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet function remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features in relation to genetic risk profiles in diabetic and nondiabetic donors. Islets from donors with T2D exhibited impaired insulin secretion, which was more pronounced in lean than obese diabetic donors. We assessed the impact of 14 disease susceptibility variants on measures of glucose sensing, exocytosis, and structure. Variants near TCF7L2 and ADRA2A were associated with reduced glucose-induced insulin secretion, whereas susceptibility variants near ADRA2A, KCNJ11, KCNQ1, and TCF7L2 were associated with reduced depolarization-evoked insulin exocytosis. KCNQ1, ADRA2A, KCNJ11, HHEX/IDE, and SLC2A2 variants affected granule docking. We combined our results to create a novel genetic risk score for beta-cell dysfunction that includes aberrant granule docking, decreased Ca(2+) sensitivity of exocytosis, and reduced insulin release. Individuals with a high risk score displayed an impaired response to intravenous glucose and deteriorating insulin secretion over time. Our results underscore the importance of defects in beta-cell exocytosis in T2D and demonstrate the potential of cellular phenotypic characterization in the elucidation of complex genetic disorders. PMID- 22492528 TI - Bile acids acutely stimulate insulin secretion of mouse beta-cells via farnesoid X receptor activation and K(ATP) channel inhibition. AB - Type 2 diabetes mellitus is associated with alterations in bile acid (BA) signaling. The aim of our study was to test whether pancreatic beta-cells contribute to BA-dependent regulation of glucose homeostasis. Experiments were performed with islets from wild-type, farnesoid X receptor (FXR) knockout (KO), and beta-cell ATP-dependent K(+) (K(ATP)) channel gene SUR1 (ABCC8) KO mice, respectively. Sodium taurochenodeoxycholate (TCDC) increased glucose-induced insulin secretion. This effect was mimicked by the FXR agonist GW4064 and suppressed by the FXR antagonist guggulsterone. TCDC and GW4064 stimulated the electrical activity of beta-cells and enhanced cytosolic Ca(2+) concentration ([Ca(2+)](c)). These effects were blunted by guggulsterone. Sodium ursodeoxycholate, which has a much lower affinity to FXR than TCDC, had no effect on [Ca(2+)](c) and insulin secretion. FXR activation by TCDC is suggested to inhibit K(ATP) current. The decline in K(ATP) channel activity by TCDC was only observed in beta-cells with intact metabolism and was reversed by guggulsterone. TCDC did not alter insulin secretion in islets of SUR1-KO or FXR-KO mice. TCDC did not change islet cell apoptosis. This is the first study showing an acute action of BA on beta-cell function. The effect is mediated by FXR by nongenomic elements, suggesting a novel link between FXR activation and K(ATP) channel inhibition. PMID- 22492529 TI - Monounsaturated fatty acids prevent the aversive effects of obesity on locomotion, brain activity, and sleep behavior. AB - Fat and physical inactivity are the most evident factors in the pathogenesis of obesity, and fat quality seems to play a crucial role for measures of glucose homeostasis. However, the impact of dietary fat quality on brain function, behavior, and sleep is basically unknown. In this study, mice were fed a diet supplemented with either monounsaturated fatty acids (MUFAs) or saturated fatty acids (SFAs) and their impact on glucose homeostasis, locomotion, brain activity, and sleep behavior was evaluated. MUFAs and SFAs led to a significant increase in fat mass but only feeding of SFAs was accompanied by glucose intolerance in mice. Radiotelemetry revealed a significant decrease in cortical activity in SFA-mice whereas MUFAs even improved activity. SFAs decreased wakefulness and increased non-rapid eye movement sleep. An intracerebroventricular application of insulin promoted locomotor activity in MUFA-fed mice, whereas SFA-mice were resistant. In humans, SFA-enriched diet led to a decrease in hippocampal and cortical activity determined by functional magnetic resonance imaging techniques. Together, dietary intake of MUFAs promoted insulin action in the brain with its beneficial effects for cortical activity, locomotion, and sleep, whereas a comparable intake of SFAs acted as a negative modulator of brain activity in mice and humans. PMID- 22492530 TI - Changing metabolic signatures of amino acids and lipids during the prediabetic period in a pig model with impaired incretin function and reduced beta-cell mass. AB - Diabetes is generally diagnosed too late. Therefore, biomarkers indicating early stages of beta-cell dysfunction and mass reduction would facilitate timely counteraction. Transgenic pigs expressing a dominant-negative glucose-dependent insulinotropic polypeptide receptor (GIPR(dn)) reveal progressive deterioration of glucose control and reduction of beta-cell mass, providing a unique opportunity to study metabolic changes during the prediabetic period. Plasma samples from intravenous glucose tolerance tests of 2.5- and 5-month-old GIPR(dn) transgenic and control animals were analyzed for 163 metabolites by targeted mass spectrometry. Analysis of variance revealed that 26 of 163 parameters were influenced by the interaction Genotype * Age (P <= 0.0001) and thus are potential markers for progression within the prediabetic state. Among them, the concentrations of seven amino acids (Phe, Orn, Val, xLeu, His, Arg, and Tyr) were increased in 2.5-month-old but decreased in 5-month-old GIPR(dn) transgenic pigs versus controls. Furthermore, specific sphingomyelins, diacylglycerols, and ether phospholipids were decreased in plasma of 5-month-old GIPR(dn) transgenic pigs. Alterations in plasma metabolite concentrations were associated with liver transcriptome changes in relevant pathways. The concentrations of a number of plasma amino acids and lipids correlated significantly with beta-cell mass of 5 month-old pigs. These metabolites represent candidate biomarkers of early phases of beta-cell dysfunction and mass reduction. PMID- 22492533 TI - First seconds in a building's life-in situ synchrotron X-ray diffraction study of cement hydration on the millisecond timescale. AB - Setting cement: highly dynamic hydration processes that occur during the first seconds of cement hydration were studied by time-resolved synchrotron X-ray diffraction. Polycarboxylate ether additives were found to influence the formation of the initial crystalline hydration products on a molecular level. PMID- 22492532 TI - Osteoblast maturation and new bone formation in response to titanium implant surface features are reduced with age. AB - The surface properties of materials contribute to host cellular response and play a significant role in determining the overall success or failure of an implanted biomaterial. Rough titanium (Ti) surface microtopography and high surface free energy have been shown to enhance osteoblast maturation in vitro and increase bone formation in vivo. Whereas the surface properties of Ti are known to affect osteoblast response, host bone quality also plays a significant role in determining successful osseointegration. One factor affecting host bone quality is patient age. We examined both in vitro and in vivo whether response to Ti surface features was affected by animal age. Calvarial osteoblasts isolated from 1-, 3-, and 11-month-old rats all displayed a reduction in cell number and increases in alkaline phosphatase-specific activity and osteocalcin in response to increasing Ti surface microtopography and surface energy. Further, osteoblasts from the three ages examined displayed increased production of osteocalcin and local factors osteoprotegerin, vascular endothelial growth factor (VEGF)-A, and active transforming growth factor (TGF)-beta1 in response to increasing Ti surface roughness and surface energy. Latent TGF-beta1 only increased in cultures of osteoblasts from 1- and 3-month-old rats. Treatment with the systemic osteotropic hormone 1alpha,25(OH)(2)D(3) further enhanced the response of osteoblasts to Ti surface features for all three age groups. However, osteoblasts derived from 11-month-old animals had a reduced response to 1alpha,25(OH)(2)D(3) compared to osteoblasts derived from 1- or 3-month-old animals. These results were confirmed in vivo. Ti implants placed in the femoral intramedullary canal of old (9-month-old) mice yielded lower bone-to-implant contact and neovascularization in response to Ti surface roughness and energy compared to younger (2-month-old) mice. These results show that rodent osteoblast maturation in vitro as well as new bone formation in vivo is reduced with age. Whether comparable age differences exist in humans needs to be determined. PMID- 22492531 TI - Tuning electrical conduction along endothelial tubes of resistance arteries through Ca(2+)-activated K(+) channels. AB - RATIONALE: Electrical conduction through gap junction channels between endothelial cells of resistance vessels is integral to blood flow control. Small and intermediate-conductance Ca(2+)-activated K(+) channels (SK(Ca)/IK(Ca)) initiate electrical signals in endothelial cells, but it is unknown whether SK(Ca)/IK(Ca) activation alters signal transmission along the endothelium. OBJECTIVE: We tested the hypothesis that SK(Ca)/IK(Ca) activity regulates electrical conduction along the endothelium of resistance vessels. METHODS AND RESULTS: Freshly isolated endothelial cell tubes (60 MUm wide; 1-3 mm long; cell length, ~35 MUm) from mouse skeletal muscle feed (superior epigastric) arteries were studied using dual intracellular microelectrodes. Current was injected (+/ 0.1-3 nA) at site 1 while recording membrane potential (V(m)) at site 2 (separation distance=50-2000 MUm). SK(Ca)/IK(Ca) activation (NS309, 1 MUmol/L) reduced the change in V(m) along endothelial cell tubes by >=50% and shortened the electrical length constant (lambda) from 1380 to 850 MUm (P<0.05) while intercellular dye transfer (propidium iodide) was maintained. Activating SK(Ca)/IK(Ca) with acetylcholine or SKA-31 also reduced electrical conduction. These effects of SK(Ca)/IK(Ca) activation persisted when hyperpolarization (>30 mV) was prevented with 60 mmol/L [K(+)](o). Conversely, blocking SK(Ca)/IK(Ca) (apamin+charybdotoxin) depolarized cells by ~10 mV and enhanced electrical conduction (ie, changes in V(m)) by ~30% (P<0.05). CONCLUSIONS: These findings illustrate a novel role for SK(Ca)/IK(Ca) activity in tuning electrical conduction along the endothelium of resistance vessels by governing signal dissipation through changes in membrane resistance. Voltage-insensitive ion channels can thereby tune intercellular electrical signaling independent from gap junction channels. PMID- 22492535 TI - Copper-catalyzed formation of C-O bonds by direct alpha-C-H bond activation of ethers using stoichiometric amounts of peroxide in batch and continuous-flow formats. AB - Peroxides and ethers in flow: 2-Carbonyl-substituted phenols and beta-ketoesters react safely with ethers in a microreactor environment using a copper catalyst and an organic peroxide (TBHP). This protocol results in unsymmetrical acetal scaffolds not easily available otherwise (see scheme). PMID- 22492534 TI - Experimental model of biofilm implant-related osteomyelitis to test combination biomaterials using biofilms as initial inocula. AB - Currently, the majority of animal models that are used to study biofilm-related infections use planktonic bacterial cells as initial inocula to produce positive signals of infection in biomaterials studies. However, the use of planktonic cells has potentially led to inconsistent results in infection outcomes. In this study, well-established biofilms of methicillin-resistant Staphylococcus aureus were grown and used as initial inocula in an animal model of a Type IIIB open fracture. The goal of the work was to establish, for the first time, a repeatable model of biofilm implant-related osteomyelitis, wherein biofilms were used as initial inocula to test combination biomaterials. Results showed that 100% of animals that were treated with biofilms developed osteomyelitis, whereas 0% of animals not treated with biofilm developed infection. The development of this experimental model may lead to an important shift in biofilm and biomaterials research by showing that when biofilms are used as initial inocula, they may provide additional insights into how biofilm-related infections in the clinic develop and how they can be treated with combination biomaterials to eradicate and/or prevent biofilm formation. PMID- 22492536 TI - Impact of polymer network inhomogeneities on the volume phase transition of thermoresponsive microgels. AB - Thermoresponsive polymer gels exhibit pronounced swelling and deswelling upon changes in temperature, rendering them attractive for various applications. This transition has been studied extensively, but only little is known about how it is affected by nano- and micrometer-scale inhomogeneities in the polymer gel network. In this work, droplet microfluidics is used to fabricate microgel particles of strongly varying inner homogeneity to study their volume phase behavior. These particles exhibit very similar equilibrium swelling and deswelling independent of their inner inhomogeneity, but the kinetics of their volume phase transition is markedly different: while gels with pronounced micrometer-scale inhomogeneity show fast and affine deswelling, homogeneous gels shrink slowly and in multiple steps. PMID- 22492537 TI - Self-assembled aptamer-based drug carriers for bispecific cytotoxicity to cancer cells. AB - Monovalent aptamers can deliver drugs to target cells by specific recognition. However, different cancer subtypes are distinguished by heterogeneous biomarkers and one single aptamer is unable to recognize all clinical samples from different patients with even the same type of cancers. To address heterogeneity among cancer subtypes for targeted drug delivery, as a model, we developed a drug carrier with a broader recognition range of cancer subtypes. This carrier, sgc8c sgd5a (SD), was self-assembled from two modified monovalent aptamers. It showed bispecific recognition abilities to target cells in cell mixtures; thus broadening the recognition capabilities of its parent aptamers. The self-assembly of SD simultaneously formed multiple drug loading sites for the anticancer drug doxorubicin (Dox). The Dox-loaded SD (SD-Dox) also showed bispecific abilities for target cell binding and drug delivery. Most importantly, SD-Dox induced bispecific cytotoxicity in target cells in cell mixtures. Therefore, by broadening the otherwise limited recognition capabilities of monovalent aptamers, bispecific aptamer-based drug carriers would facilitate aptamer applications for clinically heterogeneous cancer subtypes that respond to the same cancer therapy. PMID- 22492539 TI - Impairment of activities of daily living and incident heart failure in community dwelling older adults. AB - AIMS: Instrumental activities of daily living (IADLs) are tasks that are necessary for independent community living. These tasks often require intact physical and cognitive function, the impairment of which may adversely affect health in older adults. In the current study, we examined the association between IADL impairment and incident heart failure (HF) in community-dwelling older adults. METHODS AND RESULTS: Of the 5795 community-dwelling adults, aged >=65 years, in the Cardiovascular Health Study, 5511 had data on baseline IADL and were free of prevalent HF. Of these, 1333 (24%) had baseline IADL impairment, defined as self-reported difficulty with one or more of the following tasks: using the telephone, preparing food, performing light and heavy housework, managing finances, and shopping. Propensity scores for IADL impairment, estimated for each of the 5511 participants, were used to assemble a cohort of 1038 pairs of participants with and without IADL impairment who were balanced on 42 baseline characteristics. Centrally adjudicated incident HF occurred in 26% and 21% of matched participants with and without IADL impairment, respectively, during >12 years of follow-up [matched hazard ratio (HR) 1.33; 95% confidence interval (CI) 1.11-1.59; P = 0.002]. Unadjusted and multivariable-adjusted HRs for incident HF before matching were 1.77 (95% CI 1.56-2.01; P < 0.001) and 1.33 (95% CI 1.15 1.54; P < 0.001), respectively. IADL impairment was also associated with all cause mortality (matched HR 1.19; 95% CI 1.06-1.34; P = 0.004). CONCLUSION: Among community-dwelling older adults free of baseline HF, IADL impairment is a strong and independent predictor of incident HF and mortality. PMID- 22492540 TI - Systematics Agenda 2020: the mission evolves. PMID- 22492541 TI - Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass. AB - Osteoclast differentiation is critically dependent on calcium (Ca(2+)) signaling. Transient receptor potential vanilloid 4 (TRPV4), mediates Ca(2+) influx in the late stage of osteoclast differentiation and thereby regulates Ca(2+) signaling. However, the system-modifying effect of TRPV4 activity remains to be determined. To elucidate the mechanisms underlying TRPV4 activation based on osteoclast differentiation, TRPV4 gain-of-function mutants were generated by the amino acid substitutions R616Q and V620I in TRPV4 and were introduced into osteoclast lineage in Trpv4 null mice to generate Trpv4(R616Q/V620I) transgenic mice. As expected, TRPV4 activation in osteoclasts increased the number of osteoclasts and their resorption activity, thereby resulting in bone loss. During in vitro analysis, Trpv4(R616Q/V620I) osteoclasts showed activated Ca(2+)/calmodulin signaling compared with osteoclasts lacking Trpv4. In addition, studies of Trpv4(R616Q/V620I) mice that lacked the calmodulin-binding domain indicated that bone loss due to TRPV4 activation was abrogated by loss of interactions between Ca(2+)/calmodulin signaling and TRPV4. Finally, modulators of TRPV4 interactions with the calmodulin-binding domain were investigated by proteomic analysis. Interestingly, nonmuscle myosin IIa was identified by liquid chromatography tandem mass spectroscopy (LC-MS/MS) analysis, which was confirmed by immunoblotting following coimmunoprecipitation with TRPV4. Furthermore, myosin IIa gene silencing significantly reduced TRPV4 activation concomitant with impaired osteoclast maturation. These results indicate that TRPV4 activation reciprocally regulates Ca(2+)/calmodulin signaling, which involves an association of TRPV4 with myosin IIa, and promotes sufficient osteoclast function. PMID- 22492542 TI - Oligopyrenotides: chiral nanoscale templates for chromophore assembly. AB - Getting organized: DNA-like supramolecular polymers formed of short oligopyrenotides serve as a helical scaffold for the molecular assembly of ligands. The cationic porphyrin meso-tetrakis(1-methylpyridin-4-yl)porphyrin interacts with the helical polymers in a similar way as with poly(dA:dT). PMID- 22492543 TI - Argon-based atmospheric pressure plasma enhances early bone response to rough titanium surfaces. AB - This study investigated the effect of an Argon-based atmospheric pressure plasma (APP) surface treatment operated chairside at atmospheric pressure conditions applied immediately prior to dental implant placement in a canine model. Surfaces investigated comprised: rough titanium surface (Ti) and rough titanium surface + Argon-based APP (Ti-Plasma). Surface energy was characterized by the Owens-Wendt Rabel-Kaelble method and chemistry by X-ray photoelectron spectroscopy (XPS). Six adult beagles dogs received two plateau-root form implants (n = 1 each surface) in each radii, providing implants that remained 1 and 3 weeks in vivo. Histometric parameters assessed were bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO). Statistical analysis was performed by Kruskall-Wallis (95% level of significance) and Dunn's post-hoc test. The XPS analysis showed peaks of Ti, C, and O for the Ti and Ti- Plasma surfaces. Both surfaces presented carbon primarily as hydrocarbon (C-C, C-H) with lower levels of oxidized carbon forms. The Ti-Plasma presented large increase in the Ti (+11%) and O (+16%) elements for the Ti- Plasma group along with a decrease of 23% in surface adsorbed C content. At 1 week no difference was found in histometric parameters between groups. At 3 weeks significantly higher BIC (>300%) and mean BAFO (>30%) were observed for Ti-Plasma treated surfaces. From a morphologic standpoint, improved interaction between connective tissue was observed at 1 week, likely leading to more uniform and higher bone formation at 3 weeks for the Ti-Plasma treated implants was observed. PMID- 22492544 TI - Residual toxicity and sublethal effects of chlorantraniliprole on Plutella xylostella (lepidoptera: plutellidae). AB - BACKGROUND: The diamondback moth (DBM), Plutella xylostella (L.), is the most important pest of cruciferous vegetables in the world. Chlorantraniliprole is a novel anthranilic diamide insecticide registered for the control of lepidopteran pests. The dose response, residual toxicity and sublethal effects of chlorantraniliprole applied for 48 h at LC10 (0.02 mg L(-1) ) and LC25 (0.06 mg L(-1) ) on P. xylostella were investigated. RESULTS: Leaf-dip bioassays showed that chlorantraniliprole had a high level of toxicity against larvae of P. xylostella, and the 48 h LC50 values were 0.23 and 0.25 mg L(-1) for a susceptible and field strain respectively. Chlorantraniliprole also had a long lasting effect when the larvae were exposed to chlorantraniliprole field sprayed on radish seedlings. Sublethal effects of chlorantraniliprole were indicated by reduced pupation, pupal weight and adult emergence rates. There was also an increase in the duration of female preoviposition period, decreased fecundity and egg hatch and decreased survival rates of the offspring. The mean values of the net reproductive rate (R0), intrinsic rate of increase (r(m)), finite rate of increase (lambda) were significantly lower in the treatment than in control groups. CONCLUSIONS: These results indicate that chlorantraniliprole is effective against P. xylostella. The sublethal concentrations of chlorantraniliprole may reduce the population growth of P. xylostella by decreasing its survival and reproduction, and by delaying its development. PMID- 22492545 TI - Identification of MicroRNAs associated with early relapse after nephrectomy in renal cell carcinoma patients. AB - Renal cell carcinoma (RCC) is the most common neoplasm of adult kidney. One of the important unmet medical needs in RCC is prognostic biomarker enabling identification of patients at high risk of relapse after nephrectomy. MicroRNAs (miRNAs) constitute a robust regulatory network with posttranscriptional regulatory efficiency for almost one-half of human coding genes, including oncogenes and tumor suppressors. To identify potential prognostic miRNAs, we analyzed expression profiles in tumors of different prognostic groups of RCC patients. Seventy-seven patients with clear cell RCC and detailed clinicopathological data were enrolled in a single-center study. Global miRNA expression profiles were obtained by use of TaqMan Low Density Arrays (754 parallel quantitative reverse-transcriptase polymerase chain reactions (qRT-PCR) reactions). For validation of identified miRNAs individual miRNA TaqMan assays were performed in an independent group of patients. We identified tumor relapse signature based on the expression of 64 miRNAs differentially expressed between relapse-free RCC patients and RCC patients who developed relapse (20 miRNAs were increased, 44 miRNAs were decreased). In the validation phase of the study, we successfully confirmed that expression levels of miR-143, miR-26a, miR-145, miR 10b, miR-195, and miR-126 are lower in the tumors of RCC patients who developed tumor relapse, moreover, the lowest levels of these miRNAs we observed in primary metastatic tumors. By using Kaplan-Meier analysis, we identified that miR-127-3p, miR-145, and miR-126 are significantly correlated with relapse-free survival of nonmetastatic RCC patients. If further validated, we suggest that identified miRNAs might be used for identification of RCC patients at high risk of early relapse after nephrectomy in clinical practice. PMID- 22492546 TI - Unsymmetric platinum(II) bis(aryleneethynylene) complexes as photosensitizers for dye-sensitized solar cells. AB - Four new unsymmetric platinum(II) bis(aryleneethynylene) derivatives have been designed and synthesized, which showed good light-harvesting capabilities for application as photosensitizers in dye-sensitized solar cells (DSSCs). The absorption, electrochemical, time-dependent density functional theory (TD-DFT), impedance spectroscopic, and photovoltaic properties of these platinum(II)-based sensitizers have been fully characterized. The optical and TD-DFT studies show that the incorporation of a strongly electron-donating group significantly enhances the absorption abilities of the complexes. The maximum absorption wavelength of these four organometallic dyes can be tuned by various structural modifications of the triphenylamine and/or thiophene electron donor, improving the light absorption range up to 650 nm. The photovoltaic performance of these dyes as photosensitizers in mesoporous TiO(2) solar cells was investigated, and a power conversion efficiency as high as 1.57% was achieved, with an open-circuit voltage of 0.59 V, short-circuit current density of 3.63 mA cm(-2), and fill factor of 0.73 under simulated AM 1.5G solar illumination. PMID- 22492547 TI - Repression of osteocyte Wnt/beta-catenin signaling is an early event in the progression of renal osteodystrophy. AB - Chronic kidney disease-mineral bone disorder (CKD-MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft-tissue calcification. Emerging evidence suggests that features of CKD-MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild-type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD-MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild type mice. To capture the early molecular and cellular events in the progression of CKD-MBD we examined cell-specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor-Ser33/37-beta-catenin was observed both in mouse and human bones. Overall repression of Wnt/beta-catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF-kappaB ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late-stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD-MBD and suggest that repression of the Wnt/beta catenin pathway is involved in the pathogenesis of renal osteodystrophy. PMID- 22492550 TI - When does feeling moral actually make you a better person? Conceptual abstraction moderates whether past moral deeds motivate consistency or compensatory behavior. AB - According to the moral licensing literature, moral self-perceptions induce compensatory behavior: People who feel moral act less prosocially than those who feel immoral. Conversely, work on moral identity indicates that moral self perceptions motivate behavioral consistency: People who feel moral act more prosocially than those who feel less so. In three studies, the authors reconcile these propositions by demonstrating the moderating role of conceptual abstraction. In Study 1, participants who recalled performing recent (concrete) moral or immoral behavior demonstrated compensatory behavior, whereas participants who considered temporally distant (abstract) moral behavior demonstrated behavioral consistency. Study 2 confirmed that this effect was unique to moral self-perceptions. Study 3 manipulated whether participants recalled moral or immoral actions concretely or abstractly, and replicated the moderation pattern with willingness to donate real money to charity. Together, these findings suggest that concrete moral self-perceptions activate self regulatory behavior, and abstract moral self-perceptions activate identity concerns. PMID- 22492551 TI - Blaming for a better future: future orientation and associated intolerance of personal uncertainty lead to harsher reactions toward innocent victims. AB - People are often encouraged to focus on the future and strive for long-term goals. This noted, the authors argue that this future orientation is associated with intolerance of personal uncertainty, as people usually cannot be certain that their efforts will pay off. To be able to tolerate personal uncertainty, people adhere strongly to the belief in a just world, paradoxically resulting in harsher reactions toward innocent victims. In three experiments, the authors show that a future orientation indeed leads to more negative evaluations of an innocent victim (Study 1), enhances intolerance of personal uncertainty (Study 2), and that experiencing personal uncertainty leads to more negative evaluations of a victim (Study 3). So, while a future orientation enables people to strive for long-term goals, it also leads them to be harsher toward innocent victims. One underlying mechanism causing these reactions is intolerance of personal uncertainty, associated with a future orientation. PMID- 22492552 TI - Heparin-modified dendrimer crosslinked collagen matrices for the delivery of heparin-binding epidermal growth factor. AB - A tissue engineered corneal equivalent (TECEs) requires host integration to achieve adequate anchorage and long-term device stability. Corneal integration through epithelialization and stromal integration can be manipulated by growth factors. We investigated the potential of heparin-binding epidermal growth factor (HB-EGF) for mediating interactions with human corneal epithelial cells (HCEC) and compared its efficacy to epidermal growth factor (EGF) in vitro. Furthermore, we utilized heparinized dendrimer crosslinked collagen gels, intended for use as TECE, for delivery of HB-EGF in a sustained manner. HCEC were exposed to HB-EGF at varying concentrations between 0.1 and 1000 ng/mL. Cell proliferation increased with growth factor concentration up to a concentration of 50 ng/mL, suggesting growth factor receptor down-regulation at higher HB-EGF concentrations. Response to HB-EGF was comparable to EGF at low concentrations of 0.1 and 1 ng/mL but at a concentration of 10 ng/mL, HB-EGF induced significantly better proliferation than EGF. Proliferation was found to be dependent on the initial seeding density. Heparinized dendrimer crosslinked collagen (CHG) gels were capable of HB-EGF uptake, which was influenced by heparin concentration within the gel, growth factor concentration and exposure time to the growth factor. HB-EGF release followed first order kinetics, with ~90% of the growth factor released after 2 weeks. Growth factor stability was verified with in vitro HCEC culture studies. Bioavailability was maintained in the gels through heparin interaction. Overall, HB-EGF induced proliferation of HCEC in vitro and can be released from heparinized collagen gels making it potentially suitable for promoting epithelialization of TECEs. PMID- 22492553 TI - Cognitive set-shifting in anorexia nervosa. AB - OBJECTIVE: Adult anorexia nervosa (AN) is associated with inefficient cognitive flexibility and set-shifting. Whether such inefficiencies also characterize adolescent AN is an important area of research. METHOD: Adolescents with AN and matched controls were administered a computerized task that required initial learning of an explicit rule using corrective feedback and learning of a new rule after a set number of trials. Adult patients with AN and controls were also examined. RESULTS: Adolescents with AN did not differ from matched controls with respect to set-shifting cost (decrease in performance after rule change), whereas adults with AN had significantly greater set-shifting cost compared with controls. DISCUSSION: This study suggests that set-shifting inefficiencies may not be a vulnerability factor for AN development in adolescents with AN, but might become an important aspect of the disorder at later age, and could point towards developmental neurobiologic brain changes that could affect AN at different ages. PMID- 22492554 TI - Three rings in one step: a quick approach to IKD-8344. AB - A highly efficient enantioselective total synthesis of the natural antibiotic IKD 8344 is achieved through a convergent route. This route features an otherwise impossible concurrent formation of the THF rings from a linear polyketide precursor through intramolecular O alkylations of mesylates in competition with normally rather facile beta elimination and/or alpha racemization reactions (see scheme, Ms=methanesulfonyl). PMID- 22492555 TI - Amide-directed tandem C-C/C-N bond formation through C-H activation. AB - The transformation of C-H bonds into other chemical bonds is of great significance in synthetic chemistry. C-H bond-activation processes provide a straightforward and atom-economic strategy for the construction of complex structures; as such, they have attracted widespread interest over the past decade. As a prevalent directing group in the field of C-H activation, the amide group not only offers excellent regiodirecting ability, but is also a potential C N bond precursor. As a consequence, a variety of nitrogen-containing heterocycles have been obtained by using these reactions. This Focus Review addresses the recent research into the amide-directed tandem C-C/C-N bond-formation process through C-H activation. The large body of research in this field over the past three years has established it as one of the most-important topics in organic chemistry. PMID- 22492556 TI - Conservative management in a case of iatrogenic twin anemia-polycythemia sequence. PMID- 22492557 TI - Habitual levels of high, but not moderate or low, impact activity are positively related to hip BMD and geometry: results from a population-based study of adolescents. AB - Whether a certain level of impact needs to be exceeded for physical activity (PA) to benefit bone accrual is currently unclear. To examine this question, we performed a cross-sectional analysis between PA and hip BMD in 724 adolescents (292 boys, mean 17.7 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC), partitioning outputs from a Newtest accelerometer into six different impact bands. Counts within 2.1 to 3.1g, 3.1 to 4.2g, 4.2 to 5.1g, and >5.1g bands were positively related to femoral neck (FN) BMD, in boys and girls combined, in our minimally adjusted model including age, height, and sex (0.5 1.1g: beta = -0.007, p = 0.8; 1.1-2.1g: beta = 0.003, p = 0.9; 2.1-3.1g: beta = 0.042, p = 0.08; 3.1-4.2g: beta = 0.058, p = 0.009; 4.2-5.1g: beta = 0.070, p = 0.001; >5.1g: beta = 0.080, p < 0.001) (beta = SD change per doubling in activity). Similar positive relationships were observed between high-impact bands and BMD at other hip sites (ward's triangle, total hip), hip structure indices derived by hip structural analysis of dual-energy X-ray absorptiometry (DXA) scans (FN width, cross-sectional area, cortical thickness), and predicted strength (cross-sectional moment of inertia). In analyses where adjacent bands were combined and then adjusted for other impacts, high impacts (>4.2g) were positively related to FN BMD, whereas, if anything, moderate (2.1-4.2g) and low impacts (0.5-2.1g) were inversely related (low: beta = -0.052, p = 0.2; medium: beta = -0.058, p = 0.2; high: beta = 0.137, p < 0.001). Though slightly attenuated, the positive association between PA and FN BMD, confined to high impacts, was still observed after adjustment for fat mass, lean mass, and socioeconomic position (high: beta = 0.096, p = 0.016). These results suggest that PA associated with impacts >4.2g, such as jumping and running (which further studies suggested requires speeds >10 km/h) is positively related to hip BMD and structure in adolescents, whereas moderate impact activity (eg, jogging) is of little benefit. Hence, PA may only strengthen lower limb bones in adolescents, and possibly adults, if this comprises high-impact activity. PMID- 22492558 TI - Investigation of SUMO pathway genes in the etiology of nonsyndromic cleft lip with or without cleft palate. AB - BACKGROUND: SUMO1 has been implicated as having a role in the causation of cleft lip with or without cleft palate (CLP), both directly and through association studies in humans and, perhaps more controversially, in transgenic mouse studies. METHODS: To screen for sequence variants that might be responsible for human CLP, we performed direct DNA sequence analysis in a well-characterized white European cohort of 192 patients. We screened the genes encoding SUMO1, SUMO2, and SUMO3, as well as the E3 ligases PIAS1 and PIAS2, which are required for sumoylation. Variants were analyzed in a cohort of 192 unaffected white European controls. RESULTS: Only two missense variants were identified, both within SUMO3, however, these were both present in multiple affected individuals and a similar number of controls. Other variants identified, apart from a single synonymous change in PIAS1, were all present within flanking intronic regions distant from splice consensus sites. Moreover, most other variants were previously reported in dbSNP and were shown to be present at a similar frequency in cases and controls. CONCLUSIONS: Our findings indicate that mutations identified in the SUMO-related genes tested, including three novel coding SNPs, do not directly contribute to the incidence of CLP. PMID- 22492559 TI - 'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization. AB - Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG repeat expansion in intron 1 of NOP56. Family interview and document research allowed us to reconstruct two extensive, multigenerational kindreds stemming from the same village (Costa da Morte in Galicia, Spain), in the 17th century. We found the presence of the spinocerebellar ataxia 36 mutation co segregating with disease in these families in whom we had previously identified an ~0.8 Mb linkage region to chromosome 20 p. Subsequent screening revealed the NOP56 expansion in eight additional Galician ataxia kindreds. While normal alleles contain 5-14 hexanucleotide repeats, expanded alleles range from ~650 to 2500 repeats, within a shared haplotype. Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions. We found a total of 63 individuals carrying the mutation, 44 of whom were confirmed to be clinically affected; over 400 people are at risk. We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss. There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis. Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto cerebellar atrophy. We estimated the origin of the founder mutation in Galicia to have occurred ~1275 years ago. Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36, while 15 (9.4%) showed other of the routinely tested dominant spinocerebellar ataxia types. Spinocerebellar ataxia 36 is thus, so far, the most frequent dominant spinocerebellar ataxia in this region, which may have implications for American countries associated with traditional Spanish emigration. PMID- 22492560 TI - Cortical inhibition in attention deficit hyperactivity disorder: new insights from the electroencephalographic response to transcranial magnetic stimulation. AB - Attention deficit hyperactivity disorder is one of the most frequent neuropsychiatric disorders in childhood. Transcranial magnetic stimulation studies based on muscle responses (motor-evoked potentials) suggested that reduced motor inhibition contributes to hyperactivity, a core symptom of the disease. Here we employed the N100 component of the electroencephalographic response to transcranial magnetic stimulation as a novel marker for a direct assessment of cortical inhibitory processes, which has not been examined in attention deficit hyperactivity disorder so far. We further investigated to what extent affected children were able to regulate motor cortical inhibition, and whether effects of age on the electroencephalographic response to transcranial magnetic stimulation were compatible with either a delay in brain maturation or a qualitatively different development. N100 amplitude evoked by transcranial magnetic stimulation and its age-dependent development were assessed in 20 children with attention deficit hyperactivity disorder and 19 healthy control children (8-14 years) by 64-channel electroencephalography. Amplitude and latency of the N100 component were compared at rest, during response preparation in a forewarned motor reaction time task and during movement execution. The amplitude of the N100 component at rest was significantly lower and its latency tended to be shorter in children with attention deficit hyperactivity disorder. Only in controls, N100 amplitude to transcranial magnetic stimulation was reduced by response preparation. During movement execution, N100 amplitude decreased while motor evoked potential amplitudes showed facilitation, indicating that the electroencephalographic response to transcranial magnetic stimulation provides further information on cortical excitability independent of motor evoked potential amplitudes and spinal influences. Children with attention deficit hyperactivity disorder showed a smaller N100 amplitude reduction during movement execution compared with control children. The N100 amplitude evoked by transcranial magnetic stimulation decreased with increasing age in both groups. The N100 reduction in children with attention deficit hyperactivity disorder at all ages suggests a qualitative difference rather than delayed development of cortical inhibition in this disease. Findings further suggest that top-down control of motor cortical inhibition is reduced in children with attention deficit hyperactivity disorder. We conclude that evoked potentials in response to transcranial magnetic stimulation are a promising new marker of cortical inhibition in attention deficit hyperactivity disorder during childhood. PMID- 22492562 TI - Leukoencephalopathy with thalamus and brainstem involvement and high lactate 'LTBL' caused by EARS2 mutations. AB - In the large group of genetically undetermined infantile-onset mitochondrial encephalopathies, multiple defects of mitochondrial DNA-related respiratory-chain complexes constitute a frequent biochemical signature. In order to identify responsible genes, we used exome-next-generation sequencing in a selected cohort of patients with this biochemical signature. In an isolated patient, we found two mutant alleles for EARS2, the gene encoding mitochondrial glutamyl-tRNA synthetase. The brain magnetic resonance imaging of this patient was hallmarked by extensive symmetrical cerebral white matter abnormalities sparing the periventricular rim and symmetrical signal abnormalities of the thalami, midbrain, pons, medulla oblongata and cerebellar white matter. Proton magnetic resonance spectroscopy showed increased lactate. We matched this magnetic resonance imaging pattern with that of a cohort of 11 previously selected unrelated cases. We found mutations in the EARS2 gene in all. Subsequent detailed clinical and magnetic resonance imaging based phenotyping revealed two distinct groups: mild and severe. All 12 patients shared an infantile onset and rapidly progressive disease with severe magnetic resonance imaging abnormalities and increased lactate in body fluids and proton magnetic resonance spectroscopy. Patients in the 'mild' group partially recovered and regained milestones in the following years with striking magnetic resonance imaging improvement and declining lactate levels, whereas those of the 'severe' group were characterized by clinical stagnation, brain atrophy on magnetic resonance imaging and persistent lactate increases. This new neurological disease, early-onset leukoencephalopathy with thalamus and brainstem involvement and high lactate, is hallmarked by unique magnetic resonance imaging features, defined by a peculiar biphasic clinical course and caused by mutations in a single gene, EARS2, expanding the list of medically relevant defects of mitochondrial DNA translation. PMID- 22492561 TI - Essential role of interleukin-6 in post-stroke angiogenesis. AB - Ambivalent effects of interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of interleukin-6 after stroke have not been investigated. Here, we subjected interleukin-6 knockout (IL 6(-/-)) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion. While ischaemic tissue damage was comparable at early time points, IL-6(-/-) mice showed significantly increased chronic lesion volumes as well as worse long-term functional outcome. In particular, IL-6(-/-) mice displayed an impaired angiogenic response to brain ischaemia with reduced numbers of newly generated endothelial cells and decreased density of perfused microvessels along with lower absolute regional cerebral blood flow and reduced vessel responsivity in ischaemic striatum at 4 weeks. Similarly, the early genomic activation of angiogenesis-related gene networks was strongly reduced and the ischaemia-induced signal transducer and activator of transcription 3 activation observed in wild-type mice was almost absent in IL-6( /-) mice. In addition, systemic neoangiogenesis was impaired in IL-6(-/-) mice. Transplantation of interleukin-6 competent bone marrow into IL-6(-/-) mice (IL 6(chi)) did not rescue interleukin-6 messenger RNA expression or the early transcriptional activation of angiogenesis after stroke. Accordingly, chronic stroke outcome in IL-6(chi) mice recapitulated the major effects of interleukin-6 deficiency on post-stroke regeneration with significantly enhanced lesion volumes and reduced vessel densities. Additional in vitro experiments yielded complementary evidence, which showed that after stroke resident brain cells serve as the major source of interleukin-6 in a self-amplifying network. Treatment of primary cortical neurons, mixed glial cultures or immortalized brain endothelia with interleukin 6-induced robust interleukin-6 messenger RNA transcription in each case, whereas oxygen-glucose deprivation did not. However, oxygen-glucose deprivation of organotypic brain slices resulted in strong upregulation of interleukin-6 messenger RNA along with increased transcription of key angiogenesis-associated genes. In conclusion, interleukin-6 produced locally by resident brain cells promotes post-stroke angiogenesis and thereby affords long term histological and functional protection. PMID- 22492563 TI - MFN2 mutations cause compensatory mitochondrial DNA proliferation. PMID- 22492564 TI - Rhombencephalosynapsis: new findings in a larger study. PMID- 22492565 TI - Comparison of obese and nonobese individuals with binge eating disorder: delicate boundary between binge eating disorder and non-purging bulimia nervosa. AB - OBJECTIVE: To compare obese and nonobese individuals with binge eating disorder (BED) on demographic data, illness history, eating disorders and psychological health. METHODS: This study used baseline data from a randomized controlled study on the efficacy of an online cognitive behavioural self-help treatment. Seventy four women aged between 18 and 60 years were recruited in the community. They had to meet full or subthreshold diagnostic criteria for BED according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. RESULTS: Forty per cent of the sample had a body mass index higher than 30 kg/m(2) . Mean age and severity of eating disorders were similar between obese and nonobese individuals. A statistically significant difference emerged regarding dietary restraint, with nonobese BED individuals exhibiting higher scores than obese BED individuals. CONCLUSIONS: Dietary restraint might be one of the factors explaining body mass index differences among BED individuals. This raises the question of the boundary between non-purging bulimia nervosa and BED in nonobese people. PMID- 22492566 TI - Angiographic CT for intraprocedural monitoring of complex neuroendovascular procedures. AB - SUMMARY Evolving techniques in interventional neuroradiology have widened therapeutic options, allowing treatment even in complex cases. Complex neuroendovascular procedures (eg, stent-assisted coiling, stent placement in X- or Y-techniques) require precise delineation of cerebral vasculature and devices. However, because of the complex anatomy or if an ideal projection is not possible, visualization of the parent artery might be difficult. We present 2 complex cases of basilar tip aneurysm in which ACT proved to be beneficial in the intraprocedural monitoring of stent-assisted coil embolization. PMID- 22492567 TI - Use of onyx for transarterial balloon-assisted embolization of traumatic carotid cavernous fistulas: a report of 23 cases. AB - BACKGROUND AND PURPOSE: TCCFs are a common complication following craniofacial trauma and are usually treated by coils or detachable balloons. The use of the liquid embolic agent Onyx as the sole agent for the treatment of TCCFs has been rarely reported. Herein, we summarized the preliminary experience and effectiveness of treating TCCFs with Onyx in 23 patients. MATERIALS AND METHODS: From the 36 type A CCFs treated in our department between September 2005 and March 2011, a total of 23 posttraumatic direct CCFs were treated by using Onyx only via transarterial approach. RESULTS: Immediate postprocedural angiograms demonstrated complete occlusion in all patients. All the patients underwent a single procedure except 1 with bilateral TCCFs. Up to 24-month clinical and 3 month angiographic follow-ups revealed an ongoing complete occlusion without any complications. CONCLUSIONS: In this series, the use of Onyx for the transarterial embolization of TCCFs was feasible and effective. Associated adverse events were rare. PMID- 22492568 TI - Common and expected postmortem CT observations involving the brain: mimics of antemortem pathology. AB - BACKGROUND AND PURPOSE: Postmortem imaging with CT or MR is emerging as an effective technique to augment forensic autopsy. Expected findings on postmortem imaging of the brain may mimic pathologic processes in the living brain, leading to potential misdiagnosis. The purpose of this study is to describe the array of CT findings that can be expected to be present within the brain after death. MATERIALS AND METHODS: A retrospective review was performed using an anonymized data base of 33 postmortem head CTs with no evidence of trauma to the face or scalp. Head CTs were assessed for 1) loss of gray-white differentiation, 2) effacement of the ventricles and cisterns, 3) postmortem intravascular blood distribution, 4) presence of intracranial or intravascular air, and 5) an irregular appearance of the falx. Imaging findings were correlated with autopsy findings. RESULTS: Visualization of the basal ganglia was noted in 30 (91%) subjects, and the cortical ribbon was appreciated in 14 (42%). The ventricles and cisterns were effaced in 19 (58%) cases. An "expected postmortem blood distribution" was seen in 27 (82%) instances. Intravascular air was present in 14 cases (42%). A "lumpy" falx was present in 20 cases (61%). In 4 cases of subdural or subarachnoid hemorrhage noted on autopsy, but not on CT, retrospective review confirmed that a true discrepancy between the radiology and pathology findings persisted. CONCLUSIONS: Recognition of expected postmortem patterns is required before pathology can be accurately diagnosed. A limitation of CT virtual autopsy is the possibility of missing small blood collections. PMID- 22492569 TI - A 5-item prediction rule to identify severe renal dysfunction in patients with acute stroke. AB - BACKGROUND AND PURPOSE: Although patients with severe renal dysfunction who receive iodinated contrast are at high risk of CIN, contrast-enhanced CT scans are often obtained without prior knowledge of kidney function in patients with acute stroke. We aimed to develop a tool to identify patients with acute stroke at a high risk of CIN in the absence of a recent GFR. MATERIALS AND METHODS: We used the RCSN (9872 patients) and OSA (2544 patients) for our derivation and validation cohort, respectively. A multivariable logistic regression model was performed to develop a predictive tool to identify severe renal dysfunction (defined as a GFR < 30 mL/min/1.73 m(2)). RESULTS: The overall prevalence of severe renal dysfunction was 4.9% and 5.2% in the derivation and validation cohort, respectively. The prediction rule was designed as follows: (age in years) + (5 points for women) + (5 points for history of diabetes mellitus) + (15 points for preadmission insulin use) + (10 points for history of hypertension). The prevalence of severe renal dysfunction is negligible in patients with a total score of <=70 (<=0.005%-0.7%) but increases with higher Renal Risk Scores (eg, scores 71-80: 2.1%-2.2%; scores 91-100: 6.6%-7.1%; scores 111-120: 15.9%-28.1%). CONCLUSIONS: The Renal Risk Score is a validated tool that helps clinicians select which patients with stroke can safely proceed to contrast-enhanced brain imaging without waiting for laboratory evidence of good renal function. PMID- 22492570 TI - Closed-cell stent for coil embolization of intracranial aneurysms: clinical and angiographic results. AB - BACKGROUND AND PURPOSE: Recanalization is observed in 20-40% of endovascularly treated intracranial aneurysms. To further reduce the recanalization and expand endovascular treatment, we evaluated the safety and efficacy of closed-cell SACE. MATERIALS AND METHODS: Between 2007 and 2010, 147 consecutive patients (110 women; mean age, 54 years) presenting at 2 centers with 161 wide-neck ruptured and unruptured aneurysms were treated by using SACE. Inclusion criteria were wide neck aneurysms (>4 mm or a dome/neck ratio <= 2). Clinical outcomes were assessed by the mRS score at baseline, discharge, and follow-up. Aneurysm occlusion was assessed on angiograms by using the RS immediately after SACE and at follow-up. RESULTS: Eighteen aneurysms (11%) were treated following rupture. Procedure related mortality and permanent neurologic deficits occurred in 2 (1.4%) and 5 patients (3.4%), respectively. In total, 7 patients (4.8%) died, including 2 with reruptures. Of the 140 surviving patients, 113 (80.7%) patients with 120 aneurysms were available for follow-up neurologic examination at a mean of 11.8 months. An increase in mRS score from admission to follow-up by 1, 2, or 3 points was seen in 7 (6.9%), 1 (1%), and 2 (2%) patients, respectively. Follow-up angiography was performed in 120 aneurysms at a mean of 11.9 months. Recanalization occurred in 12 aneurysms (10%), requiring retreatment in 7 (5.8%). Moderate in-stent stenosis was seen in 1 (0.8%), which remained asymptomatic. CONCLUSIONS: This series adds to the evidence demonstrating the safety and effectiveness of SACE in the treatment of intracranial aneurysms. However, SACE of ruptured aneurysms and premature termination of antiplatelet treatment are associated with increased morbidity and mortality. PMID- 22492571 TI - The fate of injured corticospinal tracts in patients with intracerebral hemorrhage: diffusion tensor imaging study. AB - BACKGROUND AND PURPOSE: Little is known about the fate of the injured CST for a large number of patients with ICH. Using DTT, we investigated the longitudinal changes of injured CSTs in patients with an ICH. MATERIALS AND METHODS: We recruited 45 patients with CST injury by an ICH in the supratentorial subcortical area. Two longitudinal DTTs were acquired: 1 within 30 days and the other after 3 months from onset. DTTs for the CST were classified into 3 types: type A, the CST was preserved around the hematoma; type B, the CST was interrupted around the hematoma; and type C, the CST did not reach the hematoma. RESULTS: At the first DTT, the motor functions of type C were worse than those of types A and B (P < .01), and motor functions of type A were better than those of type C at the second DTT (P < .01). Of 14 type A, 2 changed to type B (14.3%) and 12 did not change (85.7%); of 12 type B, 11 changed to type A (91.7%) and 1 changed to type C (8.3%); of 19 type C, 3 changed to type A (15.8%) and 16 did not change (84.2%). CONCLUSIONS: We found that the injured CST could change from the early stage to the chronic stage during the motor recovery phase in patients with an ICH. These results would be helpful in prediction of longitudinal DTT changes from the early stage to the chronic stage following ICH. PMID- 22492572 TI - The characteristics and risk factors of headache development after the coil embolization of an unruptured aneurysm. AB - BACKGROUND AND PURPOSE: Development of a headache after aneurysm coil embolization is not uncommon but has received little attention. The authors prospectively analyze the characteristics and risk factors of a headache after coiling in patients treated for an unruptured cerebral aneurysm. MATERIALS AND METHODS: Ninety patients treated for an unruptured cerebral aneurysm over a period of 1 year, and without a headache history within a month before coiling, were enrolled in this study. All coilings were successfully performed without neurologic complications. After coiling, headache development and intensities were recorded. RESULTS: Fifty (55.6%) patients experienced a headache (VAS score, 4.5 +/- 2.02) at 7.9 (range, 0-72) hours, on average, after coiling, and all headaches resolved within an average of 73.0 (range, 3-312) hours. Univariate analysis showed that the following were significantly associated with the development of a headache: age <= 50 years (OR 4.636, 95% CI, 1.414-15.198), hypertension (OR 0.232, 95% CI, 0.095-0.571), a packing attenuation of >25% (OR 3.619, 95% CI, 1.428-9.174), and a previous headache history (OR 2.769, 95% CI, 1.120-6.849). However, binary logistic regression showed that only a packing attenuation of >25% (P = .013, adjusted OR 3.774, 95% CI, 1.320-10.790) and no history of hypertension (P = .019, adjusted OR 3.515, 95% CI, 1.233-10.021) were independently associated with the development of a headache. CONCLUSIONS: A headache frequently developed after the coiling of unruptured aneurysms. However, headaches were relatively benign and resolved within several days. The present study shows that no hypertension history and a packing attenuation of >25% are risk factors of headache development. PMID- 22492573 TI - Elevated mean diffusivity in the left hemisphere superior longitudinal fasciculus in autism spectrum disorders increases with more profound language impairment. AB - BACKGROUND AND PURPOSE: Language impairments are observed in a subset of individuals with ASD. To examine microstructural brain white matter features associated with language ability in ASD, we measured the DTI parameters of language-related white matter tracts (SLF) as well as non-language-related white matter tracts (CST) in children with ASD/+LI and ASD/-LI) and in TD. MATERIALS AND METHODS: Eighteen children with ASD/-LI (age range, 6.7-17.5 years), 17 with ASD/+LI (age range, 6.8-14.8 years), and 25 TD (age range, 6.5-18 years) were evaluated with DTI and tractography. Primary DTI parameters considered for analysis were MD and FA. RESULTS: There was a main effect of diagnostic group on age-corrected MD (P < .05) with ASD/+LI significantly elevated compared with TD. This was most pronounced for left hemisphere SLF fiber tracts and for the temporal portion of the SLF. There was significant negative correlation between left hemisphere SLF MD values and the clinical assessment of language ability. There was no main effect of diagnostic group or diagnostic group X hemisphere interaction for FA. Although there was a main effect of diagnostic group on values of MD in the CST, this did not survive hemispheric subanalysis. CONCLUSIONS: Abnormal DTI parameters (specifically significantly elevated MD values in ASD) of the SLF appear to be associated with language impairment in ASD. These elevations are particularly pronounced in the left cerebral hemisphere, in the temporal portion of the SLF, and in children with clinical language impairment. PMID- 22492574 TI - Improved MR imaging detection of cerebral microbleeds more accurately identifies persons with vasculopathy. AB - BACKGROUND AND PURPOSE: The clinical relevance of improved detection of cerebral microbleeds by using advanced-versus-conventional MR imaging techniques remains uncertain. As part of the population-based Rotterdam Scan Study, we compared whether participants whose microbleeds were only demonstrated on a high resolution MR imaging sequence differed with respect to risk profile and risk of new microbleeds from participants whose microbleeds were also depicted on a conventional MR imaging sequence. MATERIALS AND METHODS: Two hundred participants (mean age, 79.2 years) underwent both conventional 2D T2*-weighted MR imaging and high-resolution 3D T2*-weighted MR imaging at 1.5T. Vascular risk factors, APOE allele status, and markers of small vessel disease and risk of incident microbleeds were compared for microbleed status by using logistic regression models adjusted for age and sex. RESULTS: There were no significant associations between any of the factors and microbleed presence in participants whose microbleeds were only demonstrated on a high-resolution MR imaging sequence. However, the estimates in these participants were more similar to those in participants whose microbleeds were also depicted on a conventional MR imaging sequence than to those in participants without microbleeds. Moreover, significantly more participants whose microbleeds were only demonstrated on high resolution MR imaging developed new CMBs during follow-up compared with participants without CMBs (25.0% versus 5.9%; OR, 5.98; 95% CI, 1.35-26.49). CONCLUSIONS: Improved detection of microbleeds may contribute to more accurate identification of persons with underlying small-vessel pathology in the general elderly population. Further studies are needed to replicate these findings and firmly establish the role of improved detection of CMBs in the identification of persons with vasculopathy. PMID- 22492575 TI - Does the tissue engineering architecture of poly(3-hydroxybutyrate) scaffold affects cell-material interactions? AB - A critical element in tissue engineering involves the fabrication of a three dimensional scaffold. The scaffold provides a space for new tissue formation, supports cellular ingrowth, and proliferation and mimics many roles of the extracellular matrix. Poly(3-hydroxybutyrate) (PHB) is the most thoroughly investigated member of the polyhydroxyalkanoates (PHAs) family that has various degrees of biocompatibility and biodegradability for tissue engineering applications. In this study, we fabricated PHB scaffolds by utilizing electrospinning and salt-leaching procedures. The behavior of monkey epithelial kidney cells (Vero) and mouse mesenchymal stem cells (mMSCs) on these scaffolds was compared by the MTS assay and scanning electron microscopy. Additionally, this study investigated the mechanical and physical properties of these scaffolds by measuring tensile strength and modulus, dynamic contact angle and porosity. According to our results, the salt-leached scaffolds showed more wettability and permeability, but inferior mechanical properties when compared with nanofibrous scaffolds. In terms of cell response, salt-leached scaffolds showed enhanced Vero cell proliferation, whereas both scaffolds responded similarly in the case of mMSCs proliferation. In brief, nanofibrous scaffolds can be a better substrate for cell attachment and morphology. PMID- 22492576 TI - Catalytic activation of diazo compounds using electron-rich, defined iron complexes for carbene-transfer reactions. PMID- 22492577 TI - A comparative review of petroleum-based and bio-based acrolein production. AB - Acrolein is an important chemical intermediate for many common industrial chemicals, leading to an array of useful end products. This paper reviews all the synthetic methods, including the former (aldol condensation) and contemporary (partial oxidation of propylene) manufacturing methods, the partial oxidation of propane, and most importantly, the bio-based glycerol-dehydration route. Emphasis is placed on the petroleum-based route from propylene and the bio-based route from glycerol, an abundantly available and relatively inexpensive raw material available from biodiesel production. This review provides technical details and incentives for industrial proyduction that justify a transition toward bio-based acrolein production. PMID- 22492578 TI - Elimination of local abnormal ventricular activities: a new end point for substrate modification in patients with scar-related ventricular tachycardia. AB - BACKGROUND: Catheter ablation of ventricular tachycardia (VT) is effective and particularly useful in patients with frequent defibrillator interventions. Various substrate modification techniques have been described for unmappable or hemodynamically intolerable VT. Noninducibility is the most frequently used end point but is associated with significant limitations, so the optimal end point remains unclear. We hypothesized that elimination of local abnormal ventricular activities (LAVAs) during sinus rhythm or ventricular pacing would be a useful and effective end point for substrate-based VT ablation. As an adjunct to this strategy, we used a new high-density mapping catheter and frequently used epicardial mapping. METHODS AND RESULTS: Seventy patients (age, 67+/-11 years; 7 female) with VT and structurally abnormal ventricle(s) were prospectively enrolled. Conventional mapping was performed in sinus rhythm in all, and a high density Pentaray mapping catheter was used in the endocardium (n=35) and epicardially. LAVAs were recorded in 67 patients (95.7%; 95% confidence interval, 89.2-98.9). Catheter ablation was performed targeting LAVA with an irrigated-tip catheter placed endocardially via a transseptal or retrograde aortic approach or epicardially via the subxiphoid approach. LAVAs were successfully abolished or dissociated in 47 of 67 patients (70.1%; 95% confidence interval, 58.7-80.1). In multivariate analysis, LAVA elimination was independently associated with a reduction in recurrent VT or death (hazard ratio, 0.49; 95% confidence interval, 0.26-0.95; P=0.035) during long-term follow-up (median, 22 months). CONCLUSIONS: LAVAs can be identified in most patients with scar-related VT. Elimination of LAVAs is feasible and safe and is associated with superior survival free from recurrent VT. PMID- 22492579 TI - Ablation for ventricular tachycardia during stable sinus rhythm. PMID- 22492580 TI - The age associations of blood pressure, cholesterol, and glucose: analysis of health examination surveys from international populations. AB - BACKGROUND: The age association of cardiovascular disease may be in part because its metabolic risk factors tend to rise with age. Few studies have analyzed age associations of multiple metabolic risks in the same population, especially in nationally representative samples. We examined worldwide variations in the age associations of systolic blood pressure (SBP), total cholesterol (TC), and fasting plasma glucose (FPG). METHODS AND RESULTS: We used individual records from 83 nationally or subnationally representative health examination surveys in 52 countries to fit a linear model to risk factor data between ages 30 and 64 years for SBP and FPG, and between 30 and 54 years for TC. We report the cross country variation of the slope and intercept of this relationship. We also assessed nonlinear associations in older ages. Between 30 and 64 years of age, SBP increased by 1.7 to 11.6 mm Hg per 10 years of age, and FPG increased by 0.8 to 20.4 mg/dL per 10 years of age in different countries and in the 2 sexes. Between 30 and 54 years of age, TC increased by 0.2 to 22.4 mg/dL per 10 years of age in different surveys and in the 2 sexes. For all risk factors and in most countries, risk factor levels rose more steeply among women than among men, especially for TC. On average, there was a flattening of age-SBP relationship in older ages; TC and FPG age associations reversed in older ages, leading to lower levels in older ages than in middle ages. CONCLUSIONS: The rise with age of major metabolic cardiovascular disease risk factors varied substantially across populations, especially for FPG and TC. TC rose more steeply in high-income countries and FPG in the Oceania countries, the Middle East, and the United States. The SBP age association had no specific income or geographical pattern. PMID- 22492581 TI - DICAM inhibits osteoclast differentiation through attenuation of the integrin alphaVbeta3 pathway. AB - Dual immunoglobulin (Ig) domain-containing adhesion molecule (DICAM) is involved in cell-cell adhesion through a heterophilic interaction with alphaVbeta3 integrin, which suggests that DICAM may participate in osteoclast differentiation. DICAM was localized in the plasma membrane of RAW264.7 and THP-1 cells, and its expression gradually increased during osteoclastogenesis in mouse bone marrow-derived macrophages (BMMs) treated with receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Forced expression of DICAM in BMMs and RAW264.7 cells blocked the generation of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts. Conversely, knockdown of DICAM by small hairpin RNA (shRNA) increased osteoclast formation in RAW264.7 cells. DICAM-mediated suppression of osteoclast differentiation was in part due to the inhibition of the p38 mitogen-activated protein (MAP) kinase pathway, which was corroborated by a decrease in the expression of c-Fos and nuclear factor of activated T cells (NFAT)c1. Mechanistically, DICAM directly interacted with integrin beta3, which inhibited heterodimerization between integrin alphaV and beta3. Exogenous expression of integrin beta3 or high-dose M CSF rescued DICAM-mediated inhibition of osteoclastogenesis, suggesting crosstalk between the integrin beta3 and c-Fms pathways. Finally, recombinant DICAM ectodomain suppressed the RANKL- and M-CSF-induced osteoclastogenesis of BMMs. Collectively, these results indicate that DICAM acts as a negative regulator of osteoclast differentiation by suppressing the integrin alphaVbeta3 pathway. PMID- 22492582 TI - Site-specific fluorescein labeling of human insulin. AB - Three fluorescein derivatives of human insulin (HI, 1) labeled at positions N(alphaA1) , N(alphaB1) and N(epsilonB29) respectively, were synthesized using an N-trifluoroacetyl-based protecting group scheme. The Tfa protecting group introduced by reaction with ethyl trifluoroacetate was found to be stable in aqueous and organic media and efficiently removed under mild basic conditions. PMID- 22492584 TI - Metabolic effects of replacing sucrose by isomaltulose in subjects with type 2 diabetes: a randomized double-blind trial. AB - OBJECTIVE: To test the hypothesis that replacement of sucrose with isomaltulose in sweet foods and beverages improves metabolic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: One hundred ten patients with type 2 diabetes were randomized to receive sweet foods containing either 50 g/day isomaltulose or sucrose for 12 weeks as part of their habitual diet under free living conditions. HbA(1c) at 12 weeks was the primary outcome parameter. RESULTS: In the final analysis comprising 101 patients, isomaltulose did not significantly affect HbA(1c) at 12 weeks (sucrose: 7.39 +/- 0.78%; isomaltulose: 7.24 +/- 0.76%; regression coefficient [b]: 0.02 [95% CI: -0.21 to 0.25], P = 0.844). Triglycerides at 12 weeks were significantly lower in the isomaltulose versus the sucrose group (b: 34.01 [6.59-61.44], P = 0.016). Other secondary parameters did not significantly differ between groups. CONCLUSIONS: Isomaltulose did not influence glycemic control assessed as HbA(1c) in type 2 diabetes under free-living conditions but was associated with lower triglyceride levels. PMID- 22492585 TI - How are physical activity, fitness, and sedentary behavior associated with insulin sensitivity in children? AB - OBJECTIVE: To describe the associations among moderate-to-vigorous physical activity (MVPA), fitness, sedentary behavior (SB), and insulin sensitivity (IS). RESEARCH DESIGN AND METHODS: Data were drawn from the baseline assessment of the QUALITY cohort, which included 630 white youth (aged 8-10 years at recruitment), with at least one obese biological parent. IS was measured by two fasting indices (insulin, homeostasis model assessment of insulin resistance) and an oral glucose tolerance test (OGTT)-based index (Matsuda IS index [Matsuda-ISI]). Fitness was measured by Vo(2peak); percent fat mass (PFM) was measured by dual-energy X-ray absorptiometry; 7-day MVPA was measured with accelerometry. SB indicators included average hours daily of self-report screen time (SBst), and average minutes daily at <100 counts/min from accelerometry (SBacc). Multivariable linear regression models were adjusted for age, sex, season, and puberty. RESULTS: MVPA and SBacc were independently associated with IS, but this was no longer statistically significant after accounting for PFM. SBst was negatively associated with IS in girls only, even after controlling for physical activity (PA), fitness, and adiposity; for each additional hour of SBst daily, IS decreased by 4.6-5.6% across all IS indices. Fitness was positively associated with IS (measured by Matsuda-ISI) after accounting for PA, SB, and PFM; for every 1 unit increase in Vo(2peak), Matsuda-ISI increased by approximately 1.0% (P < 0.05). CONCLUSIONS: In children with an obese parent, PA and SBacc are associated with IS, but this association is mediated by adiposity. SBst is negatively associated with IS in girls, beyond its known impact on adiposity. Finally, fitness is independently associated with better IS measured by OGTT. PMID- 22492587 TI - Nanoroses of nickel oxides: synthesis, electron tomography study, and application in CO oxidation and energy storage. AB - Nickel oxide and mixed-metal oxide structures were fabricated by using microwave irradiation in pure water. The nickel oxide self-assembled into unique rose shaped nanostructures. These nickel oxide roses were studied by performing electron tomography with virtual cross-sections through the particles to understand their morphology from their interior to their surface. These materials exhibited promising performance as nanocatalysts for CO oxidation and in energy storage devices. PMID- 22492588 TI - Toxicity of hyperthermic intraperitoneal chemotherapy (HIPEC) in pediatric patients with sarcomatosis/carcinomatosis: early experience and phase 1 results. AB - BACKGROUND: Intra-abdominal metastasis is a rare form of tumor dissemination in children. Complete surgical resection is usually deemed impossible. Children are frequently offered palliative care only. We adopted an aggressive approach for these cases which includes removal of dozens to hundreds of tumor nodules followed by perfusion of the abdominal cavity with hyperthermic chemotherapy (HIPEC) with a curative intent. METHODS: We evaluated toxicity in 23 children and young adults undergoing 27 HIPEC procedures using cisplatin. Disease diagnoses included rhabdomyosarcoma (RMS), non-RMS soft tissue sarcoma, (NRSTS), desmoplastic small round cell tumor, (DSRCT), mesothelioma, Wilms tumor, melanomatosis, and adenocarcinoma. Patients underwent cytoreductive surgery followed by cisplatin at 40.5-41 degrees C, for 90 minutes. A subset of these patients was enrolled on our phase 1 study and as part of dose escalation cohort received 150 mg/m(2) of cisplatin. All toxicities were recorded. RESULTS: Maximum tolerated dose was 100 mg/m(2). Dose limiting toxicity was grade 3 renal failure. In five of 27, 18% had grade 3 or higher renal failure. One patient developed a subclinical decrease in hearing and there were 2 grade 3 hematologic toxicities, 2 grade 3 hepatic toxicities, and one grade 3 ileus. One patient suffered grade3 cardiotoxicity. There were no operative/perioperative mortalities. Surgical complications occurred in 5/27 (18%) of patients. With a follow-up of 6-60 months, seven patients (26%) had no recurrence. CONCLUSIONS: HIPEC is reasonably tolerated in pediatric patients with extensive abdominal metastasis. More study is needed to determine for which histologies HIPEC is most efficacious. PMID- 22492586 TI - Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. AB - OBJECTIVE: To evaluate the effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in type 2 diabetes mellitus inadequately controlled with metformin monotherapy. RESEARCH DESIGN AND METHODS: This was a double-blind, placebo-controlled, parallel-group, multicenter, dose-ranging study in 451 subjects randomized to canagliflozin 50, 100, 200, or 300 mg once daily (QD) or 300 mg twice daily (BID), sitagliptin 100 mg QD, or placebo. Primary end point was change in A1C from baseline through week 12. Secondary end points included change in fasting plasma glucose (FPG), body weight, and overnight urinary glucose-to-creatinine ratio. Safety and tolerability were also assessed. RESULTS: Canagliflozin was associated with significant reductions in A1C from baseline (7.6-8.0%) to week 12: -0.79, -0.76, -0.70, -0.92, and -0.95% for canagliflozin 50, 100, 200, 300 mg QD and 300 mg BID, respectively, versus -0.22% for placebo (all P < 0.001) and -0.74% for sitagliptin. FPG was reduced by -16 to -27 mg/dL, and body weight was reduced by -2.3 to -3.4%, with significant increases in urinary glucose-to-creatinine ratio. Adverse events were transient, mild to moderate, and balanced across arms except for a non-dose-dependent increase in symptomatic genital infections with canagliflozin (3-8%) versus placebo and sitagliptin (2%). Urinary tract infections were reported without dose dependency in 3-9% of canagliflozin, 6% of placebo, and 2% of sitagliptin arms. Overall incidence of hypoglycemia was low. CONCLUSIONS: Canagliflozin added onto metformin significantly improved glycemic control in type 2 diabetes and was associated with low incidence of hypoglycemia and significant weight loss. The safety/tolerability profile of canagliflozin was favorable except for increased frequency of genital infections in females. PMID- 22492589 TI - Memantine effects measured with the Relevant Outcome Scale for Alzheimer's disease in an open-label, single-arm, multicenter clinical study. AB - OBJECTIVE: The Relevant Outcome Scale for Alzheimer's disease (ROSA) is a novel, valid, and reliable instrument for multidimensional assessment of Alzheimer's disease (AD) symptoms across all severity stages. The ROSA and four standard instruments -- the Alzheimer's disease Assessment Scale-cognitive (ADAS-cog), Severe Impairment Battery (SIB), Disability Assessment for Dementia (DAD), and the Neuropsychiatric Inventory (NPI) -- were used in an open-label, multicenter, single-arm clinical study to assess treatment-induced changes in cognitive, functional, and behavioral symptoms in patients with AD at different severity stages. METHODS: A total of 451 patients were treated with memantine (initiated at 5 mg/day and up-titrated with 5 mg weekly to a final dose of 20 mg/day) for 12 weeks. The study endpoints comprised changes from baseline in the scores of the ROSA, ADAS-cog, SIB, DAD, and NPI as well as global changes on the Clinical Global Impression of Change (CGI-C). Analyses were performed for the overall population and by AD severity stage (early, middle, late). RESULTS: The ROSA scores increased significantly after a 12-week treatment in all study groups except for early stage. Mean changes in the ADAS-cog score indicated a trend towards worsening in early and middle stages. Non-significant changes were shown by the SIB, NPI, and DAD assessments at week 12. The CGI-C demonstrated 'minimal improvement' or 'no change' for most of the patients. Overall, memantine treatment was safe and well tolerated. CONCLUSION: The results demonstrated the ROSA feasibility in daily practice for assessment of memantine effects over time in patients with moderate and late AD. PMID- 22492590 TI - Mechanical properties of biodegradable small-diameter chitosan artificial vascular prosthesis. AB - Initial clinical feasibility with the small-diameter chitosan artificial vascular prosthesis has been reported previously. Here, we present the results of mechanical properties of artificial vascular prosthesis with 2, 3, and 4 mm inner diameter (ID) and compare some of the properties with the native blood vessel of dog femoral artery. Thickness wall measurement demonstrated the average wall thickness of the artificial vascular prosthesis with 2, 3, and 4 mm ID and the native blood vessel of the dog femoral artery with 3 mm ID were 0.54 +/- 0.022 mm, 0.71 +/- 0.032 mm, 0.79 +/- 0.026 mm, and 0.67 +/- 0.22 mm (n = 20). Water absorption rate of 226.02% +/- 8.17%, 216.13% +/- 4.86%, and 205.69% +/- 4.34% were obtained from 2-, 3-, and 4-mm-diameter artificial vascular prosthesis (n = 12), respectively. Water osmotic pressure of the 2-, 3-, and 4-mm-diameter artificial vascular prosthesis was 39.25 +/- 3.35 mmHg, 34.2 +/- 4.54 mmHg, and 28.00 +/- 2.72 mmHg (n = 20), respectively. Water osmotic amount of the 2-, 3-, and 4-cm-diameter artificial vascular prosthesis (n = 20) was 4.90 +/- 0.47 mL/(min cm(2) ), 5.51 +/- 0.21 mL/(min cm(2) ), and 6.24 +/- 0.71 mL/(min cm(2) ), respectively. The ruptured stretching rate of the artificial vascular prosthesis (n = 20) with 2, 3, and 4 mm ID and the native blood vessel was 1.59% +/- 0.14%, 1.99% +/- 0.24%, 2.52% +/- 0.21%, and 32.16% +/- 2.15%, respectively. The longitudinal tensile strength of the artificial vascular prosthesis (n = 20) with 2, 3, and 4 mm ID and the native blood vessel was 8.58 +/- 1.98 N, 19.75 +/- 4.07 N, 22.92 +/- 3.85 N, and 18.76 +/- 2.05 N, respectively. The suture retention of the artificial vascular prosthesis (n = 20) with 2, 3, and 4 mm ID and the native blood vessel in dry condition is 5.80 +/- 0.51 N, 7.01 +/- 0.32 N, 8.49 +/- 0.56 N, and 7.92 +/- 0.39 N, respectively. The suture retention of the artificial vascular prosthesis (n = 20) with 2, 3, and 4 mm ID in wet condition is 3.87 +/- 0.43 N, 4.73 +/- 0.37 N, 5.63 +/- 0.36 N, and 7.92 +/- 0.39 N, respectively. The compliance of the artificial vascular prosthesis with 2, 3, and 4 mm ID and the native blood vessel was 6.5% +/- 2.6%/100 mmHg, 5.2% +/- 1.5%/100 mmHg, 4.7% +/- 1.3%/100 mmHg, and 10.3% +/- 2.3%/100 mmHg, respectively. The data reported here fulfill the quality requirement of clinical use of this kind of biodegradable small diameter artificial vascular prosthesis. PMID- 22492591 TI - Gold(I)-catalyzed stereoconvergent, intermolecular enantioselective hydroamination of allenes. PMID- 22492592 TI - Teaching and learning normal gynecological ultrasonography using simple virtual reality objects: a proposal for a standardized approach. PMID- 22492593 TI - Changes Are Coming and PDA Will Be There To Help. PMID- 22492594 TI - Letter to the editor. PMID- 22492595 TI - Author response. PMID- 22492596 TI - A case study: application of statistical process control tool for determining process capability and sigma level. AB - Statistical process control is the application of statistical methods to the measurement and analysis of variation process. Various regulatory authorities such as Validation Guidance for Industry (2011), International Conference on Harmonisation ICH Q10 (2009), the Health Canada guidelines (2009), Health Science Authority, Singapore: Guidance for Product Quality Review (2008), and International Organization for Standardization ISO-9000:2005 provide regulatory support for the application of statistical process control for better process control and understanding. In this study risk assessments, normal probability distributions, control charts, and capability charts are employed for selection of critical quality attributes, determination of normal probability distribution, statistical stability, and capability of production processes, respectively. The objective of this study is to determine tablet production process quality in the form of sigma process capability. By interpreting data and graph trends, forecasting of critical quality attributes, sigma process capability, and stability of process were studied. The overall study contributes to an assessment of process at the sigma level with respect to out-of-specification attributes produced. Finally, the study will point to an area where the application of quality improvement and quality risk assessment principles for achievement of six sigma-capable processes is possible. LAY ABSTRACT: Statistical process control is the most advantageous tool for determination of the quality of any production process. This tool is new for the pharmaceutical tablet production process. In the case of pharmaceutical tablet production processes, the quality control parameters act as quality assessment parameters. Application of risk assessment provides selection of critical quality attributes among quality control parameters. Sequential application of normality distributions, control charts, and capability analyses provides a valid statistical process control study on process. Interpretation of such a study provides information about stability, process variability, changing of trends, and quantification of process ability against defective production. Comparative evaluation of critical quality attributes by Pareto charts provides the least capable and most variable process that is liable for improvement. Statistical process control thus proves to be an important tool for six sigma-capable process development and continuous quality improvement. PMID- 22492597 TI - Delamination propensity of pharmaceutical glass containers by accelerated testing with different extraction media. AB - The delamination of pharmaceutical glass is a serious issue, as it can cause glass particles to appear in vials, a problem that has forced a number of drug product recalls in recent years. In Type I pharmaceutical glass vials, delamination occurs generally at the bottom and shoulder, where extensive flaming during the conversion process can favor a strong evaporation of alkali and borate species and the formation of heavily enriched silica layers. The contact with parenteral preparations dissolved in an alkaline medium increases the rate of glass corrosion, while the differential hydration of these layers can cause the detachment of flakes. The purpose of this study was to investigate the effect of the pH and the composition of the extraction solutions on the propensity of different glass types to delaminate. Repeated autoclave extractions at 121 degrees C were carried out on different glass types with different extraction media, including organic extractants like citric and glutaric acid. When vials were in contact with alkaline solutions and similarly aggressive media, an increase in silica extraction values indicated glass corrosion and an increasing risk for further delamination. Under such conditions expansion 33 glass is extensively corroded, showing high silica concentration and heavy flaking as compared to other glass types. Sulfur-treated glass also showed early flaking, even if SiO(2) concentration was very low. A similar ranking was observed with extractions carried out with glutaric and citric acids, but at far much higher SiO(2) concentration levels. Extractions with 0.9% KCl solution can be used as an accelerated test to highlight the propensity of a glass to delaminate, but in no case it can be taken as a guarantee that the glass will not delaminate when exposed to the pharmaceutical drug, whose extraction ability requires case-by case study. LAY ABSTRACT: How can injectable drug manufacturers prevent glass delamination? The issue of delamination is a serious one, as it can cause glass particles to appear in vials, a problem that has forced a number of drug product recalls in recent years. To combat this, pharmaceutical and biopharmaceutical manufacturers need to understand the reasons for glass delamination. The most recent cases of product recall due to the presence of particles in the filling liquid have involved borosilicate glass containers carrying drugs made of active components with known ability to corrode glass and to dissolve the silica matrix. Sometimes these ingredients are dissolved in an alkaline medium that dramatically increases the glass corrosion and potentially causes the issue. As this action is strongly affected by time and temperature, flaking may become visible only after a long incubation during storage and requires systematic monitoring to be detected at its early stage. If the nature of the filling liquid is the driving force of the phenomenon, other factors are of primary importance. The surface morphology created during vial forming is a key issue, being a function of the forming temperature that is higher in the cutting step and the forming of the bottom. Delamination occurs generally on the vial's bottom and shoulder, where extensive flaming can favor a strong evaporation of alkali and borate species and the formation of heavily enriched silica layers. When these layers are in contact with a solution, they are subject to a differential re-hydration that may result in cracking and detachment of scales. The purpose of this investigation is to identify testing conditions and parameters that can be used as indicators of an incipient delamination process. Extractions with 0.9% KCl solution for 1 h at 121 degrees C can be used to simulate a long-term contact with aggressive pharmaceutical preparations, while SiO(2) concentration in the extract solution can be taken as an index of glass dissolution. The conclusions developed by this study can provide pharmaceutical manufacturers with information needed to help prevent glass delamination in their processes. PMID- 22492598 TI - Design and evaluation of patches for transdermal delivery of losartan potassium. AB - The present work comprises the formulation and evaluation of losartan potassium with a view to developing and preparing a losartan potassium releasing system for transdermal applications. The aim of the study was to prepare the transdermal patch of drug using different blends of polymers. Transdermal patches of losartan potassium were prepared using ethyl cellulose (EC): polyvinyl pyrrolidone (PVP), Eudragit RL-100: Eudragit RS-100 and polyvinyl alcohol (PVA): polyvinyl pyrrolidone (PVP) using different ratios by the solvent casting technique. Physicochemical parameters like flexibility, thickness, smoothness, moisture content, hardness, and tensile strength were studied. The in vitro permeation study was carried out using a modified Keshery diffusion cell, and the formulation followed the Higuchi diffusion mechanism. The blood pressure lowering response of all formulations was studied using hypertension-induced rats by the chronic renal hypertension method. The formulation containing Eudragit RL-100: Eudragit RS-100 as polymers showed satisfactory drug release pattern (hydrophobic polymers) compared to combination of hydrophobic and hydrophilic polymers (EC: PVP) and PVA: PVP (hydrophilic polymers). The amount of drug release from formulations containing hydrophilic polymers and combination of both hydrophobic and hydrophilic polymers were found to be less in comparison to the patches of hydrophobic polymers. LAY ABSTRACT: The aim of the present study was to prepare and evaluate the transdermal patch of drug using different polymers such as hydrophobic, combination of hydrophobic: hydrophilic, and hydrophilic. Losartan potassium (hydrophilic) is the antihypertensive drug used for lowering increased blood pressure. Transdermal patches of losartan potassium were prepared using different ratios of polymers by the solvent casting technique. The prepared patches were evaluated for their flexibility, thickness, smoothness, moisture content, hardness, and tensile strength. The in vitro permeation study was carried out using a diffusion cell. The blood lowering response of all formulations was studied using hypertension-induced rats. The formulation containing hydrophobic polymers showed a satisfactory drug release pattern compared to the combination of hydrophobic: hydrophilic polymers and the hydrophilic polymers. Hence, the present study reveals that formulation of hydrophilic drug (losartan potassium) withhydrophobic polymers exhibit good release properties as compared to that of hydrophilic polymers and combination of both hydrophobic and hydrophilic polymers. PMID- 22492599 TI - Syringe siliconization process investigation and optimization. AB - The interior barrel of the prefilled syringe is often lubricated/siliconized by the syringe supplier or at the syringe filling site. Syringe siliconization is a complex process demanding automation with a high degree of precision; this information is often deemed "know-how" and is rarely published. The purpose of this study is to give a detailed account of developing and optimizing a bench-top siliconization unit with nozzle diving capabilities. This unit comprises a liquid dispense pump unit and a nozzle integrated with a Robo-cylinder linear actuator. The amount of coated silicone was determined by weighing the syringe before and after siliconization, and silicone distribution was visually inspected by glass powder coating or characterized by glide force testing. Nozzle spray range, nozzle retraction speed, silicone-coated amount, and air-to-nozzle pressure were found to be the key parameters affecting silicone distribution uniformity. Distribution uniformity is particularly sensitive to low-target silicone amount where the lack of silicone coating on the barrel near the needle side often caused the syringes to fail the glide force test or stall when using an autoinjector. In this bench-top unit we identified optimum coating conditions for a low silicone dose, which were also applicable to a pilot-scale siliconization system. The pilot unit outperformed the bench-top unit in a tighter control (standard deviation) in coated silicone amount due to the elimination of tubing flex. Tubing flex caused random nozzle mis-sprays and was prominent in the bench top unit, while the inherent design of the pilot system substantially limited tubing flux. In summary, this bench-top coating unit demonstrated successful siliconization of the 1 mL long syringe with ~0.2 mg of silicone oil using a spraying cycle also applicable to larger-scale siliconization. LAY ABSTRACT: Syringe siliconization can be considered a well-established manufacturing process and has been implemented by numerous syringe providers. However, its technical details and associated critical process parameters are rarely published. The purpose of this study is three-fold: (1) to reveal design details of a bench-top siliconization unit, (2) to identify critical process parameters and determine their optimum range to provide consistent and even silicone coating, and (3) to demonstrate the applicability of the optimum process condition derived from the bench-top unit to a pilot siliconization unit. The outcomes of this study will benefit scientists and engineers developing pre-filled syringe products by helping them to better understanding silicone spray coating principles and their relationship to siliconization processes in a large-scale manufacturing setting. PMID- 22492600 TI - Formulation and evaluation of bilayer tablets of metoclopramide hydrochloride and diclofenac sodium. AB - The main objective of the present research work was to develop a bilayer tablet of metoclopramide hydrochloride (MTH) and diclofenac sodium (DS) in separate layers to avoid incompatibility and thus to maximize the efficacy of both drugs in combination for the effective treatment of migraine headaches. MTH and DS were formulated as immediate and sustained release layers respectively. In vitro dissolution kinetic studies of an optimized (D10) batch of DS in both sustained release layer and bilayer tablet forms show good linearity of regression coefficient 0.9773 (first order equation). The results reveal that an optimized immediate release layer (M5) of MTH and a sustained release layer (D10) of DS might be suitable for the treatment of migraine by sequential release of the two drugs in a bilayer tablet. LAY ABSTRACT: Migraine is a type of recurring headache of moderate to severe intensity associated with gastrointestinal, neurological, and autonomic symptoms. In migraine, a combination of pretreatment with antiemetics is required for symptomatic treatment, when nausea and vomiting are severe. In our present research, we have selected the metoclopramide hydrochloride (MTH) active ingredient for study because it has an antiemetic effect and is a prokinetic agent. MTH is more effective to counteract gastric stasis associated with migraine, and it enhances the rate of absorption of non steroidal anti-inflammatory drugs (NSAIDs). In the present investigation we combine MTH and a second active ingredient, diclofenac sodium, as a formulated bilayer tablet to prevent degradation of MTH. PMID- 22492601 TI - Sterilizing filtration of liposome and related lipid-containing solutions: enhancing successful filter qualification. AB - Bacterial penetration of integral sterilizing-grade 0.2 MUm rated filters, although rare, is not a new phenomenon in the biopharmaceutical industry. It is recognized by both the Parenteral Drug Association and the Food and Drug Administration via recommended bacterial retention qualification (also commonly called filter validation) performed in relevant product fluids or suitable surrogates when necessary (1-3). As noted in recent work, formulations such as some adjuvanted vaccines, liposome-based drug delivery solutions, and similar surfactant or emulsion-based product fluids increase the likelihood of such penetration events (4). Here we demonstrate that some 0.2 MUm rated sterilizing grade filters from different filter manufacturers may perform less effectively than expected when their membranes are challenged with one of these bacterial penetration risk-related solutions. Some filters provided very little sterility assurance (titer reductions < 6 logs) and others provided substantial sterility assurance (titer reduction > 8 log). From this, it is clear that the product formulation most likely to lead to filter penetration must be identified early in the design process to facilitate process design and minimize qualification costs. In this way, the solution can be matched with the appropriate sterilizing-grade filter and the appropriate process conditions. LAY ABSTRACT: Bacterial penetration of intact sterilizing-grade filters during filter qualification, although rare, is not a new phenomenon in the biopharmaceutical industry. Because these incidences are identified in the filter validation process, there is no risk to the drug product end-user, but these failures do incur additional expense to the pharmaceutical manufacturer and could prevent the manufacture of very important drug formulations. Formulations such as some adjuvanted vaccines, liposome-based drug delivery solutions, and similar surfactant or emulsion-based product fluids have been documented to lead to an increased risk of penetration events. Here we demonstrate that some sterilizing-grade filters may perform differently from expected when their membranes are challenged with one of these solutions related to bacterial penetration risk. Some filters provided very little sterility assurance and others provided substantial sterility assurance. From this, it is clear that the pharmaceutical products and product formulation most likely to lead to filter penetration must be identified early in the design process to facilitate process design and minimize qualification costs. Moreover, that solution should be matched with the appropriate sterilizing-grade filter and process conditions to ensure expected sterility. PMID- 22492602 TI - A general strategy for the chemical aspects of the safety assessment of extractables and leachables in pharmaceutical drug products: the chemical assessment triad. AB - During the course of their manufacturing, storage, and administration, pharmaceutical drug products come in contact with materials, components, and systems. Such contact may result in an interaction between the drug product and these entities. One such interaction is the migration of substances from these entities and into the drug product, which is of concern due to the potential toxicity of the migrating substances. In order to properly assess the risk and manage the hazard posed by migratory substances, it is necessary to establish the identities of the migratory substances and the levels to which they will accumulate in the finished drug product, as these two pieces of information establish the hazard posed by an individual substance and the magnitude of the patient exposure (dose). The process by which migrating compounds are discovered and identified, and by which their accumulation levels in a finished drug product are established, is termed chemical assessment. Because the development of a finished drug product is a long and complicated process, chemical assessment is most typically not a single action but rather a series of actions that together establish a process of risk management. It is the purpose of this manuscript to establish a high-level strategy, illustrated in the chemical assessment triad, which can be applied to such a risk management process. LAY ABSTRACT: During the course of their manufacturing, storage, and administration, pharmaceutical drug products come in contact with materials, components, and systems. Such contact may result in an interaction between the drug product and these entities. One such interaction is the migration of substances from these entities and into the drug product, which is of concern due to the potential toxicity of the migrating substances. It is the purpose of this manuscript to outline a high-level strategy, illustrated in the chemical assessment triad, to chemically establish the safety risk related to the migrating substances. PMID- 22492603 TI - The effect of radiation on a variety of pharmaceuticals and materials containing polymers. AB - The interaction of radiation, whether it has natural or artificial, electromagnetic or particle-type characterizations, with materials causes different effects depending on the dose and type of radiation and physicochemical properties of the material. In the medical field, understanding the effect of radiation on a variety of materials including pharmaceuticals, medical devices, polymers as biomaterials, and packaging is crucial. Although there are many kinds of sterilization methods, the use of radiation in sterilization has many advantages such as being a substantially less toxic, safer terminal sterilization method. Radiosterilization is sterilization with an ionizing radiation such as gamma rays or electron beam (e-beam), the latter being a newer but less frequently used technique. However, the need for large facilities with proper radiation protections for personnel and the environment from the effects of radiation and radioactive wastes makes this procedure highly costly. The effects of radiation on materials, especially pharmaceuticals and polymer-containing medical devices, cause degradation or chemical changes. The effects of radiation on a variety of different materials is a growing research area that can create safer techniques that reduce radiation damage and increase cost-effectiveness in the future. LAY ABSTRACT: Radiation can be used for positive purposes such as medical applications and the sterilization of pharmaceutical products, medical devices, and food and agricultural products as well as clinical applications such as diagnosis and/or therapy of a variety of diseases. The dose rate, time, type and emitted energy of the radiation are critical issues for determining its benefit/damage ratio. The sterilization of pharmaceuticals and medical devices that contain polymers can be achieved safely and effectively by irradiation. The sterilization of materials at the terminal phase-that is, in its final packaging materials-and its suitability to a variety of different kinds of packaging materials have brought additional value to radiosterilization. However, radiation sterilization is more expensive than the other sterilization methods that require large facilities. Although this method is safe in application, the effects of radiation on drugs and polymers must be evaluated by various analytical methods. In the nuclear chemistry and radiochemistry field, more effective and novel methods are being developed to decrease the harmful effects of radiation on materials. PMID- 22492604 TI - Acupuncture points are large fields: the fuzziness of acupuncture point localization by doctors in practice. AB - BACKGROUND: Acupuncture textbooks, schools, practitioners and clinical researchers designing randomized controlled trials on acupuncture all assume that acupuncture points are small and must be located precisely. METHOD: Seventy-one medical doctors with >=200 h acupuncture training and >=2 years of clinical experience independently identified 23 commonly used acupuncture points on a male volunteer, using sticky transparent films with an X/Y grid placed asymmetrically around acupuncture points. RESULTS: For each acupuncture point, the field covering 95% (68%) of all point locations varied from 2.7 (0.7) cm(2) for PC-6 up to 41.4 (10.2) cm(2) for ST-38. Commonly-used acupuncture points showed unexpectedly large variance in location: 95% (or 68%) areas were SP-6: 12.2 cm(2) (3.0 cm(2) ), ST-36: 20.7 cm(2) (5.1 cm(2) ), LI-15: 18.7 cm(2) (4.6 cm(2) ), BL 23: 22.4 cm(2) (5.6 cm(2) ) and BL-54: 22.5 cm(2) (5.6 cm(2) ). Points close to anatomical landmarks (forearm, ankle, poplitea; BL-60, BL-40, TW-5, PC-6) were located with less variance. Precision of point location was independent of length of acupuncture experience, kind of training or medical specialty. CONCLUSIONS: In respect to the high degree of variation in the localization of acupuncture points, we suggest that the term 'acupuncture field' is more appropriate than 'acupuncture points' to describe the clinical reality; for the design of sham controlled acupuncture trials, we recommend a minimum distance of 6 cm between verum and sham points on face, hands and feet, and up to 12 cm for all other parts of the body. PMID- 22492612 TI - Tolerance and efficacy of preventive gastrostomy feeding in pediatric oncology. AB - BACKGROUND: Malnutrition in pediatric oncology remains underestimated, although having a negative impact on outcome. Enteral nutrition (EN) using percutaneous endoscopic gastrostomy (PEG) may prevent or reverse malnutrition consequences. We aimed to evaluate both efficacy and safety of early EN during tumors treatment in children. PROCEDURES: Medical records of pediatric patients having a PEG tube inserted between 1995 and 2009 were retrospectively reviewed. We compared type and incidence of complications in Group 1, including 74 patients suffering from cancer, and control Group 2, including 57 patients with neurological impairment. Efficacy of EN was evaluated through nutritional parameters [Z-scores weight for height (W/H) and height for age (H/A)], post-operative complications and relapse rates. Statistical significance was set for P < 0.05. RESULTS: PEG tolerance was similar in both groups, as shown by comparable complication rates (62% vs. 76%, NS). EN allowed improvement or stabilization of Z-score W/H in 76% of oncologic patients. The final height loss was lower (-0.5 vs. -1.2 SD of Z-scores H/A) when EN was started at the beginning of the oncologic treatment. In bone tumors, EN prevented weight loss during chemotherapy, and tended to lessen surgical complications, relapses and deaths. CONCLUSIONS: Early gastrostomy feeding represents a relatively safe way to prevent malnutrition in children with cancer, and might play a role in bone tumors oncological outcome. Further prospective studies are needed to confirm these results and assess the impact of EN and PEG on quality of life. PMID- 22492613 TI - Obesity and depressive symptoms in the elderly: a survey in the rural area of Chizhou, Anhui province. AB - OBJECTIVE: The aim of the present study is to examine the relationship between obesity and depressive symptoms and to test the "Jolly Fat" hypothesis among older Chinese. METHODS: A total of 736 rural Chinese aged 60 years and older participated in this cross-sectional study. Body mass index (BMI = kg/m(2) ) was calculated from the subjects' measured weight (kg) and height (meter). Depressive symptoms were assessed using the 30-item Geriatric Depression Scale (GDS-30), with a cut-off point of 11. RESULTS: Among 736 total participants, the prevalence of depressive symptoms was 24.1% in men and 27.9% in women. A trend about depressive symptoms decreased with increasing BMI was found in men (chi(2) trend = 5.74, df = 1, p = 0.01). A weak inverse linear trend between obesity and depressive symptoms was observed among subjects. In men, obese group was less likely to suffer from depressive symptoms compared with normal weight group before or after adjustment for confounders, with odds ratios of 0.32 (95% confidence interval (CI): 0.12-0.85) and 0.28 (95% CI: 0.09-0.85), respectively. However, the association between BMI and depressive symptoms in women showed no significant differences. CONCLUSIONS: Our results supported the "Jolly Fat" hypothesis only in rural older Chinese men, but not in women. Gender differences existed in the relationship between obesity and depressive symptoms. PMID- 22492614 TI - Selective reduction of biomass by hydriodic acid and its in situ regeneration from iodine by metal/hydrogen. AB - HI returns: Hydroiodic acid is a highly selective reducing reagent for a wide variety of substrates. Its application is limited by the formation of iodine and the difficulty in reconverting that iodione back to HI in situ. We report the facile conversion of I(2) to HI by metal-catalyzed hydrogenation in the presence of water, and demonstrate the utility of this process in the conversion of fructose to 5-methyfurfural and glycerol to 2-iodopropane. PMID- 22492615 TI - Metabolite profiling of bendamustine in urine of cancer patients after administration of [14C]bendamustine. AB - Bendamustine is an alkylating agent consisting of a mechlorethamine derivative, a benzimidazole group, and a butyric acid substituent. A human mass balance study showed that bendamustine is extensively metabolized and subsequently excreted in urine. However, limited information is available on the metabolite profile of bendamustine in human urine. The objective of this study was to elucidate the metabolic pathways of bendamustine in humans by identification of its metabolites excreted in urine. Human urine samples were collected up to 168 h after an intravenous infusion of 120 mg/m(2) (80-95 MUCi) [(14)C]bendamustine. Metabolites of [(14)C]bendamustine were identified using liquid chromatography (high resolution)-tandem mass spectrometry with off-line radioactivity detection. Bendamustine and a total of 25 bendamustine-related compounds were detected. Observed metabolic conversions at the benzimidazole and butyric acid moiety were N-demethylation and gamma-hydroxylation. In addition, various other combinations of these conversions with modifications at the mechlorethamine moiety were observed, including hydrolysis (the primary metabolic pathway), cysteine conjugation, and subsequent biotransformation to mercapturic acid and thiol derivatives, N-dealkylation, oxidation, and conjugation with phosphate, creatinine, and uric acid. Bendamustine-derived products containing phosphate, creatinine, and uric acid conjugates were also detected in control urine incubated with bendamustine. Metabolites that were excreted up to 168 h after the infusion included products of dihydrolysis and cysteine conjugation of bendamustine and gamma-hydroxybendamustine. The range of metabolic reactions is generally consistent with those reported for rat urine and bile, suggesting that the overall processes involved in metabolic elimination are qualitatively the same in rats and humans. PMID- 22492616 TI - To include plasmalemmal VDAC/porin pays. PMID- 22492618 TI - The structural basis of iron sensing by the human F-box protein FBXL5. PMID- 22492619 TI - Chain elongation and cyclization in type III PKS DpgA. AB - Chain elongation and cyclization of precursors of dihydroxyphenylacetyl-CoA (DPA CoA) catalyzed by the bacterial type III polyketide synthase DpgA were studied. Two labile intermediates, di- and tri-ketidyl-CoA (DK- and TK-CoA), were proposed and chemically synthesized. In the presence of DpgABD, each of these with [(13)C(3)]malonyl-CoA (MA-CoA) was able to form partially (13)C-enriched DPA-CoA. By NMR and MS analysis, the distribution of (13)C atoms in the partially (13)C enriched DPA-CoA shed light on how the polyketide chain elongates and cyclizes in the DpgA-catalyzed reaction. Polyketone intermediates elongate in a manner different from that which had been believed: two molecules of DK-CoA, or one DK CoA plus one acetoacetyl-CoA (AA-CoA), but not two molecules of AA-CoA can form one molecule of DPA-CoA. As a result, polyketidyl-CoA serves as both the starter and extender, whereas polyketone-CoA without the terminal carboxyl group can only act as an extender. The terminal carboxyl group is crucial for the cyclization that likely takes place on CoA. PMID- 22492620 TI - Insertion of heme b into the structure of the Cys34-carbamidomethylated human lipocalin alpha(1)-microglobulin: formation of a [(heme)(2) (alpha(1) Microglobulin)](3) complex. AB - alpha(1)-Microglobulin (alpha(1)m) is a 26 kDa plasma and tissue protein belonging to the lipocalin protein family. Previous investigations indicate that the protein interacts with heme and suggest that it has a function in heme metabolism. However, detailed characterizations of the alpha(1)m-heme interactions are lacking. Here, we report for the first time the preparation and analysis of a stable alpha(1)m-heme complex upon carbamidomethylation of the reactive Cys34 by using recombinantly expressed human alpha(1)m. Analytical size exclusion chromatography coupled with a diode-array absorbance spectrophotometry demonstrates that at first an alpha(1)m-heme monomer is formed. Subsequently, a second heme triggers oligomerization that leads to trimerization. The resulting (alpha(1)m[heme](2))(3) complex was characterized by resonance Raman and EPR spectroscopy, which support the presence of two ferrihemes, thus indicating an unusual spin-state admixed ground state with S=(3)/(2), (5)/(2). PMID- 22492621 TI - Site-specific protein modification using lipoic acid ligase and bis-aryl hydrazone formation. AB - A screen of Trp37 mutants of Escherichia coli lipoic acid ligase (LplA) revealed enzymes capable of ligating an aryl-aldehyde or aryl-hydrazine substrate to LplA's 13-residue acceptor peptide. Once site-specifically attached to recombinant proteins fused to this peptide, aryl-aldehydes could be chemoselectively derivatized with hydrazine-probe conjugates, and aryl-hydrazines could be derivatized in an analogous manner with aldehyde-probe conjugates. Such two-step labeling was demonstrated for AlexaFluor568 targeting to monovalent streptavidin in vitro, and to neurexin-1beta on the surface of living mammalian cells. To further highlight this technique, we labeled the low-density lipoprotein receptor on the surface of live cells with fluorescent phycoerythrin protein to allow single-molecule imaging and tracking over time. PMID- 22492623 TI - From dynamic combinatorial 'hit' to lead: in vitro and in vivo activity of compounds targeting the pathogenic RNAs that cause myotonic dystrophy. AB - The myotonic dystrophies (DM) are human diseases in which the accumulation of toxic RNA (CUG or CCUG) repeats in the cell causes sequestration of splicing factors, including MBNL1, leading to clinical symptoms such as muscle wasting and myotonia. We previously used Dynamic Combinatorial Chemistry to identify the first compounds known to inhibit (CUG)-MBNL1 binding in vitro. We now report transformation of those compounds into structures with activity in vivo. Introduction of a benzo[g]quinoline substructure previously unknown in the context of RNA recognition, as well as other modifications, provided several molecules with enhanced binding properties, including compounds with strong selectivity for CUG repeats over CAG repeats or CAG-CUG duplex RNA. Compounds readily penetrate cells, and improve luciferase activity in a mouse myoblast assay in which enzyme function is coupled to a release of nuclear CUG-RNA retention. Most importantly, two compounds are able to partially restore splicing in a mouse model of DM1. PMID- 22492624 TI - Combining H/D exchange mass spectroscopy and computational docking reveals extended DNA-binding surface on uracil-DNA glycosylase. AB - X-ray crystallography provides excellent structural data on protein-DNA interfaces, but crystallographic complexes typically contain only small fragments of large DNA molecules. We present a new approach that can use longer DNA substrates and reveal new protein-DNA interactions even in extensively studied systems. Our approach combines rigid-body computational docking with hydrogen/deuterium exchange mass spectrometry (DXMS). DXMS identifies solvent exposed protein surfaces; docking is used to create a 3-dimensional model of the protein-DNA interaction. We investigated the enzyme uracil-DNA glycosylase (UNG), which detects and cleaves uracil from DNA. UNG was incubated with a 30 bp DNA fragment containing a single uracil, giving the complex with the abasic DNA product. Compared with free UNG, the UNG-DNA complex showed increased solvent protection at the UNG active site and at two regions outside the active site: residues 210-220 and 251-264. Computational docking also identified these two DNA binding surfaces, but neither shows DNA contact in UNG-DNA crystallographic structures. Our results can be explained by separation of the two DNA strands on one side of the active site. These non-sequence-specific DNA-binding surfaces may aid local uracil search, contribute to binding the abasic DNA product and help present the DNA product to APE-1, the next enzyme on the DNA-repair pathway. PMID- 22492625 TI - Identification of differentially expressed non-coding RNAs in embryonic stem cell neural differentiation. AB - Protein-coding genes, guiding differentiation of ES cells into neural cells, have extensively been studied in the past. However, for the class of ncRNAs only the involvement of some specific microRNAs (miRNAs) has been described. Thus, to characterize the entire small non-coding RNA (ncRNA) transcriptome, involved in the differentiation of mouse ES cells into neural cells, we have generated three specialized ribonucleo-protein particle (RNP)-derived cDNA libraries, i.e. from pluripotent ES cells, neural progenitors and differentiated neural cells, respectively. By high-throughput sequencing and transcriptional profiling we identified several novel miRNAs to be involved in ES cell differentiation, as well as seven small nucleolar RNAs. In addition, expression of 7SL, 7SK and vault 2 RNAs was significantly up-regulated during ES cell differentiation. About half of ncRNA sequences from the three cDNA libraries mapped to intergenic or intragenic regions, designated as interRNAs and intraRNAs, respectively. Thereby, novel ncRNA candidates exhibited a predominant size of 18-30 nt, thus resembling miRNA species, but, with few exceptions, lacking canonical miRNA features. Additionally, these novel intraRNAs and interRNAs were not only found to be differentially expressed in stem-cell derivatives, but also in primary cultures of hippocampal neurons and astrocytes, strengthening their potential function in neural ES cell differentiation. PMID- 22492626 TI - Identification of high-confidence somatic mutations in whole genome sequence of formalin-fixed breast cancer specimens. AB - The utilization of archived, formalin-fixed paraffin-embedded (FFPE) tumor samples for massive parallel sequencing has been challenging due to DNA damage and contamination with normal stroma. Here, we perform whole genome sequencing of DNA isolated from two triple-negative breast cancer tumors archived for >11 years as 5 um FFPE sections and matched germline DNA. The tumor samples show differing amounts of FFPE damaged DNA sequencing reads revealed as relatively high alignment mismatch rates enriched for C . G > T . A substitutions compared to germline samples. This increase in mismatch rate is observable with as few as one million reads, allowing for an upfront evaluation of the sample integrity before whole genome sequencing. By applying innovative quality filters incorporating global nucleotide mismatch rates and local mismatch rates, we present a method to identify high-confidence somatic mutations even in the presence of FFPE induced DNA damage. This results in a breast cancer mutational profile consistent with previous studies and revealing potentially important functional mutations. Our study demonstrates the feasibility of performing genome-wide deep sequencing analysis of FFPE archived tumors of limited sample size such as residual cancer after treatment or metastatic biopsies. PMID- 22492627 TI - SAVoR: a server for sequencing annotation and visualization of RNA structures. AB - RNA secondary structure is required for the proper regulation of the cellular transcriptome. This is because the functionality, processing, localization and stability of RNAs are all dependent on the folding of these molecules into intricate structures through specific base pairing interactions encoded in their primary nucleotide sequences. Thus, as the number of RNA sequencing (RNA-seq) data sets and the variety of protocols for this technology grow rapidly, it is becoming increasingly pertinent to develop tools that can analyze and visualize this sequence data in the context of RNA secondary structure. Here, we present Sequencing Annotation and Visualization of RNA structures (SAVoR), a web server, which seamlessly links RNA structure predictions with sequencing data and genomic annotations to produce highly informative and annotated models of RNA secondary structure. SAVoR accepts read alignment data from RNA-seq experiments and computes a series of per-base values such as read abundance and sequence variant frequency. These values can then be visualized on a customizable secondary structure model. SAVoR is freely available at http://tesla.pcbi.upenn.edu/savor. PMID- 22492628 TI - A novel method to fabricate thermoresponsive microstructures with improved cell attachment/detachment properties. AB - A novel, simple, and rapid method to fabricate thermoresponsive micropatterned substrate for cell adhesion, growth, and thermally induced detachment was developed. Thermoresponsive polymer, poly(N-isopropylacrylamide) (PNIPAAm), was grafted onto the surface of polystyrene (PS) film with microstructure by plasma induced graft polymerization technique. The thermoresponsive micropatterned films were characterized by attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, hydrogen nuclear magnetic resonance ((1) H NMR) spectroscopy, X-ray photoelectron spectroscopy (XPS) and scanning electron microscope (SEM). These results indicated that the grafting ratio of PNIPAAm increased with increasing roughness of PS film. However, the microstructures on the substrate were not affected by grafted PNIPAAm. The optimal grafting conditions, such as plasma treatment time, monomer concentration, graft polymerization time, and graft medium were investigated. The thermoresponsive micropatterned films were investigated with the fibroblast cell (L929) adhesion, proliferation, and thermally induced detachment assay. The microstructure on the thermoresponsive micropatterned substrate facilitated cell adhesion above the lower critical solution temperature (LCST) of PNIPAAm and cell detachment below the LCST. Moreover, it can be used to regulate cell organization and tissue growth. PMID- 22492631 TI - Micronutrients and sickle cell disease, effects on growth, infection and vaso occlusive crisis: a systematic review. AB - Patients with Sickle cell disease (SCD) exhibit signs of poor growth, increased susceptibility to infection and recurrent episodes of painful vaso-occlusive crises. Micronutrient deficiencies may increase susceptibility to these outcomes. We conducted a systematic review to assess the strength of evidence for improved outcomes related to micronutrient interventions. Six randomized-controlled trials of moderate quality met the inclusion criteria. Zinc supplementation was associated with improved growth and decreased incidence of infection and is a promising intervention in the management of SCD patients. Omega-3 fatty acid supplementation was associated with limited reduction in vaso occlusive crises. This review identifies key knowledge gaps, which are important research priorities for nutritional interventions. PMID- 22492634 TI - Klotho: a master regulator of cardiovascular disease? PMID- 22492635 TI - Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23. AB - BACKGROUND: Klotho is known to function as a cofactor for the phosphatonin, fibroblast growth factor (FGF)-23 at the kidney. FGF-23 levels rise in chronic kidney disease (CKD) despite progression of accelerated vascular calcification. There are currently conflicting data on whether FGF-23 may exhibit direct vasculoprotective effects in CKD. METHODS AND RESULTS: In this study, we describe for the first time endogenous Klotho expression in human arteries and human aortic smooth muscle cells. We show that CKD is a state of vascular Klotho deficiency promoted by chronic circulating stress factors, including proinflammatory, uremic, and disordered metabolic conditions. Mechanistic studies demonstrated that Klotho knockdown potentiated the development of accelerated calcification through a Runx2 and myocardin-serum response factor-dependent pathway. Klotho knockdown studies further revealed that vascular cells are a Klotho-dependent target tissue for FGF-23. FGF-23 mediated cellular activation of p-ERK, p-AKT, and cellular proliferative effects, which were abrogated following Klotho knockdown. We next showed that vascular Klotho deficiency driven by procalcific stressors could be restored by vitamin D receptor activators, in vitro and further confirmed using human arterial organ cultures from CKD patients, in vivo. Furthermore, restoration of suppressed Klotho expression by vitamin D receptor activators conferred human aortic smooth muscle cells responsive to FGF-23 signaling and unmasked potential anticalcific effects. CONCLUSIONS: Chronic metabolic stress factors found in CKD promote vascular Klotho deficiency. Mechanistic studies revealed a bifunctional role for local vascular Klotho, first, as an endogenous inhibitor of vascular calcification and, second, as a cofactor required for vascular FGF-23 signaling. Furthermore, vitamin D receptor activators can restore Klotho expression and unmask FGF-23 anticalcific effects. PMID- 22492636 TI - Deciphering the complexities of human diseases and disorders by coupling induced pluripotent stem cells and systems genetics. AB - The recent discovery that adult mouse and human somatic cells can be 'reprogrammed' to a state of pluripotency by ectopic expression of only a few transcription factors has already made a major impact on the biomedical community. For the first time, it is possible to study diseases on an individual patient basis, which may eventually lead to the realization of personalized medicine. The utility of induced-pluripotent stem cells (iPSCs) for modeling human diseases has greatly benefitted from established human embryonic stem cell (ESC) differentiation and tissue engineering protocols developed to generate many different cell and tissue types. The limited access to preimplantation genetic tested embryos and the difficulty in gene targeting human ESCs have restricted the use of human ESCs in modeling human disease. Afforded by iPSC technology is the ability to study disease pathogenesis as it unfolds during tissue morphogenesis. The complexities of molecular signaling and interplay with protein transduction during disease progression necessitate a systems approach to studying human diseases, whereby data can be statistically integrated by sorting out the signal to noise issues that arise from global biological changes associated with disease versus experimental noise. Using a systems approach, biomarkers can be identified that define the initiation or progression of disease and likewise can serve as putative therapeutic targets. PMID- 22492637 TI - On the calculation of signal transduction ability of signaling transduction pathways in intracellular communication: systematic approach. AB - MOTIVATION: The major function of signal transduction pathways in cells is to sense signals from the environment and process the information through signaling molecules in order to regulate the activity of transcription factors. On the molecular level, the information transmitted by a small number of signal molecules is amplified in the internal signaling pathway through enzyme catalysis, molecular modification and via the activation or inhibition of interactions. However, the dynamic system behavior of a signaling pathway can be complex and, despite knowledge of the pathway components and interactions, it is still a challenge to interpret the pathways behavior. Therefore, a systematic method is proposed in this study to quantify the signal transduction ability. RESULTS: Based on the non-linear signal transduction system, signal transduction ability can be investigated by solving a Hamilton-Jacobi inequality (HJI) constrained optimization problem. To avoid difficulties associated with solving a complex HJI-constrained optimization problem for signal transduction ability, the Takagi-Sugeno fuzzy model is introduced to approximate the non-linear signal transduction system by interpolating several local linear systems so that the HJI constrained optimization problem can be replaced by a linear matrix inequality (LMI)-constrained optimization problem. The LMI problem can then be efficiently solved for measuring signal transduction ability. Finally, the signal transduction ability of two important signal transduction pathways was measured by the proposed method and confirmed using experimental data, which is useful for biotechnological and therapeutic application and drug design. PMID- 22492638 TI - Detection of differentially expressed segments in tiling array data. AB - MOTIVATION: Tiling arrays have been a mainstay of unbiased genome-wide transcriptomics over the last decade. Currently available approaches to identify expressed or differentially expressed segments in tiling array data are limited in the recovery of the underlying gene structures and require several parameters that are intensity-related or partly dataset-specific. RESULTS: We have developed TileShuffle, a statistical approach that identifies transcribed and differentially expressed segments as significant differences from the background distribution while considering sequence-specific affinity biases and cross hybridization. It avoids dataset-specific parameters in order to provide better comparability of different tiling array datasets, based on different technologies or array designs. TileShuffle detects highly and differentially expressed segments in biological data with significantly lower false discovery rates under equal sensitivities than commonly used methods. Also, it is clearly superior in the recovery of exon-intron structures. It further provides window z-scores as a normalized and robust measure for visual inspection. AVAILABILITY: The R package including documentation and examples is freely available at http://www.bioinf.uni leipzig.de/Software/TileShuffle/ PMID- 22492639 TI - Fast protein binding site comparisons using visual words representation. AB - MOTIVATION: Finding geometrically similar protein binding sites is crucial for understanding protein functions and can provide valuable information for protein protein docking and drug discovery. As the number of known protein-protein interaction structures has dramatically increased, a high-throughput and accurate protein binding site comparison method is essential. Traditional alignment-based methods can provide accurate correspondence between the binding sites but are computationally expensive. RESULTS: In this article, we present a novel method for the comparisons of protein binding sites using a 'visual words' representation (PBSword). We first extract geometric features of binding site surfaces and build a vocabulary of visual words by clustering a large set of feature descriptors. We then describe a binding site surface with a high dimensional vector that encodes the frequency of visual words, enhanced by the spatial relationships among them. Finally, we measure the similarity of binding sites by utilizing metric space operations, which provide speedy comparisons between protein binding sites. Our experimental results show that PBSword achieves a comparable classification accuracy to an alignment-based method and improves accuracy of a feature-based method by 36% on a non-redundant dataset. PBSword also exhibits a significant efficiency improvement over an alignment based method. PMID- 22492640 TI - PaGeFinder: quantitative identification of spatiotemporal pattern genes. AB - Pattern Gene Finder (PaGeFinder) is a web-based server for on-line detection of gene expression patterns from serial transcriptomic data generated by high throughput technologies like microarray or next-generation sequencing. Three particular parameters, the specificity measure, the dispersion measure and the contribution measure, were introduced and implemented in PaGeFinder to help quantitative and interactive identification of pattern genes like housekeeping genes, specific (selective) genes and repressed genes. Besides the on-line computation service, the PaGeFinder also provides downloadable Java programs for local detection of gene expression patterns. AVAILABILITY: http://bioinf.xmu.edu.cn:8080/PaGeFinder/index.jsp PMID- 22492641 TI - Differential variability improves the identification of cancer risk markers in DNA methylation studies profiling precursor cancer lesions. AB - MOTIVATION: The standard paradigm in omic disciplines has been to identify biologically relevant biomarkers using statistics that reflect differences in mean levels of a molecular quantity such as mRNA expression or DNA methylation. Recently, however, it has been proposed that differential epigenetic variability may mark genes that contribute to the risk of complex genetic diseases like cancer and that identification of risk and early detection markers may therefore benefit from statistics based on differential variability. RESULTS: Using four genome-wide DNA methylation datasets totalling 311 epithelial samples and encompassing all stages of cervical carcinogenesis, we here formally demonstrate that differential variability, as a criterion for selecting DNA methylation features, can identify cancer risk markers more reliably than statistics based on differences in mean methylation. We show that differential variability selects features with heterogeneous outlier methylation profiles and that these play a key role in the early stages of carcinogenesis. Moreover, differentially variable features identified in precursor non-invasive lesions exhibit significantly increased enrichment for developmental genes compared with differentially methylated sites. Conversely, differential variability does not add predictive value in cancer studies profiling invasive tumours or whole-blood tissue. Finally, we incorporate the differential variability feature selection step into a novel adaptive index prediction algorithm called EVORA (epigenetic variable outliers for risk prediction analysis), and demonstrate that EVORA compares favourably to powerful prediction algorithms based on differential methylation statistics. CONCLUSIONS: Statistics based on differential variability improve the detection of cancer risk markers in the context of DNA methylation studies profiling epithelial preinvasive neoplasias. We present a novel algorithm (EVORA) which could be used for prediction and diagnosis of precursor epithelial cancer lesions. AVAILABILITY: R-scripts implementing EVORA are available from CRAN (www.r-project.org). PMID- 22492642 TI - GRASS: a generic algorithm for scaffolding next-generation sequencing assemblies. AB - MOTIVATION: The increasing availability of second-generation high-throughput sequencing (HTS) technologies has sparked a growing interest in de novo genome sequencing. This in turn has fueled the need for reliable means of obtaining high quality draft genomes from short-read sequencing data. The millions of reads usually involved in HTS experiments are first assembled into longer fragments called contigs, which are then scaffolded, i.e. ordered and oriented using additional information, to produce even longer sequences called scaffolds. Most existing scaffolders of HTS genome assemblies are not suited for using information other than paired reads to perform scaffolding. They use this limited information to construct scaffolds, often preferring scaffold length over accuracy, when faced with the tradeoff. RESULTS: We present GRASS (GeneRic ASsembly Scaffolder)-a novel algorithm for scaffolding second-generation sequencing assemblies capable of using diverse information sources. GRASS offers a mixed-integer programming formulation of the contig scaffolding problem, which combines contig order, distance and orientation in a single optimization objective. The resulting optimization problem is solved using an expectation maximization procedure and an unconstrained binary quadratic programming approximation of the original problem. We compared GRASS with existing HTS scaffolders using Illumina paired reads of three bacterial genomes. Our algorithm constructs a comparable number of scaffolds, but makes fewer errors. This result is further improved when additional data, in the form of related genome sequences, are used. AVAILABILITY: GRASS source code is freely available from http://code.google.com/p/tud-scaffolding/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22492643 TI - Metab2MeSH: annotating compounds with medical subject headings. AB - SUMMARY: Progress in high-throughput genomic technologies has led to the development of a variety of resources that link genes to functional information contained in the biomedical literature. However, tools attempting to link small molecules to normal and diseased physiology and published data relevant to biologists and clinical investigators, are still lacking. With metabolomics rapidly emerging as a new omics field, the task of annotating small molecule metabolites becomes highly relevant. Our tool Metab2MeSH uses a statistical approach to reliably and automatically annotate compounds with concepts defined in Medical Subject Headings, and the National Library of Medicine's controlled vocabulary for biomedical concepts. These annotations provide links from compounds to biomedical literature and complement existing resources such as PubChem and the Human Metabolome Database. PMID- 22492644 TI - A comprehensive computational model of facilitated diffusion in prokaryotes. AB - MOTIVATION: Gene activity is mediated by site-specific transcription factors (TFs). Their binding to defined regions in the genome determines the rate at which their target genes are transcribed. RESULTS: We present a comprehensive computational model of the search process of TF for their genomic target site(s). The computational model considers: the DNA sequence, various TF species and the interaction of the individual molecules with the DNA or between themselves. We also demonstrate a systematic approach how to parametrize the system using available experimental data. PMID- 22492645 TI - PhyLAT: a phylogenetic local alignment tool. AB - MOTIVATION: The expansion of DNA sequencing capacity has enabled the sequencing of whole genomes from a number of related species. These genomes can be combined in a multiple alignment that provides useful information about the evolutionary history at each genomic locus. One area in which evolutionary information can productively be exploited is in aligning a new sequence to a database of existing, aligned genomes. However, existing high-throughput alignment tools are not designed to work effectively with multiple genome alignments. RESULTS: We introduce PhyLAT, the phylogenetic local alignment tool, to compute local alignments of a query sequence against a fixed multiple-genome alignment of closely related species. PhyLAT uses a known phylogenetic tree on the species in the multiple alignment to improve the quality of its computed alignments while also estimating the placement of the query on this tree. It combines a probabilistic approach to alignment with seeding and expansion heuristics to accelerate discovery of significant alignments. We provide evidence, using alignments of human chromosome 22 against a five-species alignment from the UCSC Genome Browser database, that PhyLAT's alignments are more accurate than those of other commonly used programs, including BLAST, POY, MAFFT, MUSCLE and CLUSTAL. PhyLAT also identifies more alignments in coding DNA than does pairwise alignment alone. Finally, our tool determines the evolutionary relationship of query sequences to the database more accurately than do POY, RAxML, EPA or pplacer. PMID- 22492646 TI - CRNreals: a toolbox for distinguishability and identifiability analysis of biochemical reaction networks. AB - Chemical reaction network theory is widely used in modeling and analyzing complex biochemical systems such as metabolic networks and cell signalling pathways. Being able to produce all the biologically and chemically important qualitative dynamical features, chemical reaction networks (CRNs) have attracted significant attention in the systems biology community. It is well-known that the reliable inference of CRN models generally requires thorough identifiability and distinguishability analysis together with carefully selected prior modeling assumptions. Here, we present a software toolbox CRNreals that supports the distinguishability and identifiability analysis of CRN models using recently published optimization-based procedures. AVAILABILITY AND IMPLEMENTATION: The CRNreals toolbox and the associated documentation are available at http://www.iim.csic.es/~gingproc/CRNreals/. The toolbox runs under the popular MATLAB computational environment and supports several free and commercial linear programming and mixed integer linear programming solvers. PMID- 22492647 TI - Bayesian integration of networks without gold standards. AB - MOTIVATION: Biological experiments give insight into networks of processes inside a cell, but are subject to error and uncertainty. However, due to the overlap between the large number of experiments reported in public databases it is possible to assess the chances of individual observations being correct. In order to do so, existing methods rely on high-quality 'gold standard' reference networks, but such reference networks are not always available. RESULTS: We present a novel algorithm for computing the probability of network interactions that operates without gold standard reference data. We show that our algorithm outperforms existing gold standard-based methods. Finally, we apply the new algorithm to a large collection of genetic interaction and protein-protein interaction experiments. AVAILABILITY: The integrated dataset and a reference implementation of the algorithm as a plug-in for the Ondex data integration framework are available for download at http://bio nexus.ncl.ac.uk/projects/nogold/ PMID- 22492648 TI - Matrix eQTL: ultra fast eQTL analysis via large matrix operations. AB - MOTIVATION: Expression quantitative trait loci (eQTL) analysis links variations in gene expression levels to genotypes. For modern datasets, eQTL analysis is a computationally intensive task as it involves testing for association of billions of transcript-SNP (single-nucleotide polymorphism) pair. The heavy computational burden makes eQTL analysis less popular and sometimes forces analysts to restrict their attention to just a small subset of transcript-SNP pairs. As more transcripts and SNPs get interrogated over a growing number of samples, the demand for faster tools for eQTL analysis grows stronger. RESULTS: We have developed a new software for computationally efficient eQTL analysis called Matrix eQTL. In tests on large datasets, it was 2-3 orders of magnitude faster than existing popular tools for QTL/eQTL analysis, while finding the same eQTLs. The fast performance is achieved by special preprocessing and expressing the most computationally intensive part of the algorithm in terms of large matrix operations. Matrix eQTL supports additive linear and ANOVA models with covariates, including models with correlated and heteroskedastic errors. The issue of multiple testing is addressed by calculating false discovery rate; this can be done separately for cis- and trans-eQTLs. PMID- 22492649 TI - Estimating the order of mutations during tumorigenesis from tumor genome sequencing data. AB - MOTIVATION: Tumors are thought to develop and evolve through a sequence of genetic and epigenetic somatic alterations to progenitor cells. Early stages of human tumorigenesis are hidden from view. Here, we develop a method for inferring some aspects of the order of mutational events during tumorigenesis based on genome sequencing data for a set of tumors. This method does not assume that the sequence of driver alterations is the same for each tumor, but enables the degree of similarity or difference in the sequence to be evaluated. RESULTS: To evaluate the new method, we applied it to colon cancer tumor sequencing data and the results are consistent with the multi-step tumorigenesis model previously developed based on comparing stages of cancer. We then applied the new method to DNA sequencing data for a set of lung cancers. The model may be a useful tool for better understanding the process of tumorigenesis. AVAILABILITY: The software is available at: http://linus.nci.nih.gov/Data/YounA/OrderMutation.zip. PMID- 22492650 TI - Fast automated NMR spectroscopy of short-lived biological samples. AB - Faster than death: NMR techniques that make use of nonlinear sampling and hyperdimensional processing enable the recording of complete NMR data sets for the automated assignment of the backbone and side-chain resonances of short-lived protein samples of cell lysates. PMID- 22492653 TI - Letter to the editor: "Interpretation of (31)P NMR saturation transfer experiments: do not forget the spin relaxation properties". PMID- 22492652 TI - TRPV4 in porcine lens epithelium regulates hemichannel-mediated ATP release and Na-K-ATPase activity. AB - In several tissues, transient receptor potential vanilloid 4 (TRPV4) channels are involved in the response to hyposmotic challenge. Here we report TRPV4 protein in porcine lens epithelium and show that TRPV4 activation is an important step in the response of the lens to hyposmotic stress. Hyposmotic solution (200 mosM) elicited ATP release from intact lenses and TRPV4 antagonists HC 067047 and RN 1734 prevented the release. In isosmotic solution, the TRPV4 agonist GSK1016790A (GSK) elicited ATP release. When propidium iodide (PI) (MW 668) was present in the bathing medium, GSK and hyposmotic solution both increased PI entry into the epithelium of intact lenses. Increased PI uptake and ATP release in response to GSK and hyposmotic solution were abolished by a mixture of agents that block connexin and pannexin hemichannels, 18alpha-glycyrrhetinic acid and probenecid. Increased Na-K-ATPase activity occurred in the epithelium of lenses exposed to GSK and 18alpha-glycyrrhetinic acid + probenecid prevented the response. Hyposmotic solution caused activation of Src family kinase and increased Na-K ATPase activity in the lens epithelium and TRPV4 antagonists prevented the response. Ionomycin, which is known to increase cytoplasmic calcium, elicited ATP release, the magnitude of which was no greater when lenses were exposed simultaneously to ionomycin and hyposmotic solution. Ionomycin-induced ATP release was significantly reduced in calcium-free medium. TRPV4-mediated calcium entry was examined in Fura-2-loaded cultured lens epithelium. Hyposmotic solution and GSK both increased cytoplasmic calcium that was prevented by TRPV4 antagonists. The cytoplasmic calcium rise in response to hyposmotic solution or GSK was abolished when calcium was removed from the bathing solution. The findings are consistent with hyposmotic shock-induced TRPV4 channel activation which triggers hemichannel-mediated ATP release. The results point to TRPV4 mediated calcium entry that causes a cytoplasmic calcium increase which is an essential early step in the mechanism used by the lens to sense and respond to hyposmotic stress. PMID- 22492651 TI - Evolving insights regarding mechanisms for the inhibition of insulin release by norepinephrine and heterotrimeric G proteins. AB - Norepinephrine has for many years been known to have three major effects on the pancreatic beta-cell which lead to the inhibition of insulin release. These are activation of K(+) channels to hyperpolarize the cell and prevent the gating of voltage-dependent Ca(2+) channels that increase intracellular Ca(2+) concentration ([Ca(2+)](i)) and trigger release; inhibition of adenylyl cyclases, thus preventing the augmentation of stimulated insulin release by cyclic AMP; and a "distal" effect that occurs downstream of increased [Ca(2+)](i) to inhibit exocytosis. All three are mediated by the pertussis toxin (PTX)-sensitive heterotrimeric Gi and Go proteins. The distal inhibitory effect on exocytosis is now known to be due to the binding of G protein betagamma subunits to the synaptosomal-associated protein of 25 kDa (SNAP-25) on the soluble NSF attachment protein receptor (SNARE) complex. Recent studies have uncovered two more actions of norepinephrine on the beta-cell: 1) retardation of the refilling of the readily releasable granule pool after it has been discharged, an action that is mediated by Galphai(1) and/or Galphai(2); and 2) inhibition of endocytosis that is mediated by Gz. Of importance also are new findings that Galphao regulates the number of docked granules in the beta-cell, and that Galphao(2) maintains a tonic inhibitory influence on secretion. The latter provides another explanation as to why PTX, which blocks the effect of Galphao(2), was initially called "islet activating protein." Finally, there is clear evidence that overexpression of alpha(2A)-adrenergic receptors in beta-cells can cause type 2 diabetes. PMID- 22492655 TI - Neonatal development of hepatic UGT1A9: implications of pediatric pharmacokinetics. AB - This article reports on the development of UDP-glucuronosyltransferase 1A9 (UGT1A9) in neonatal and pediatric liver. The substrate 4-methylumbelliferone (4MU) with specific inhibition by niflumic acid was used to define specific UGT1A9 activity. Subsequently, in silico pharmacokinetic (PK) and physiology based pharmacokinetic (PBPK) modeling was used to determine UGT1A9 maturation and hepatic clearance. Modeled maximal enzyme activity was 27.9 nmol . min(-1) . mg protein(-1) at 4 months of age, which had high concordance with the average V(max) in 45 individual adult (>20 years) livers of 29.0 nmol . min(-1) . mg protein(-1). The activity of UGT1A9 ranged 7.5-fold in the adult population (4.1 54.5 nmol . min(-1) . mg protein(-1)). Expression of UGT1A9 correlated with age only in children younger than 1 year (Spearman r = 0.70). Activity correlated with expression up to 18 years of age (Spearman r = 0.76). Furthermore, scaling intrinsic hepatic clearance of 4MU with an allometric PK model yielded a high clearance at birth and then fell to adult levels (1.3 l . h(-1) . kg(-1) at 18.1 years for well stirred or 1.4 l . h(-1) . kg(-1) at 18.7 years for parallel tube). The Simcyp PBPK models did not converge but showed an increase in clearance at under 1 year of age and then decreased to adult levels at approximately 20 years of age. Allometric scaling may be more accurate in cases of high-extraction drugs. Enzyme activities or hepatic clearances did not differ with gender or ethnicity. The UGT1A9 isoform has higher normalized clearance for 4MU at young ages, which may explain how other UGT1A9 substrates, such as propofol, have higher clearances in children than in adults. PMID- 22492656 TI - Parent-child communication and psychological adjustment in children with a brain tumor. AB - BACKGROUND: Internalizing problems, anxiety, depression, withdrawal, and consequent social problems are frequently observed in children with brain tumors. The objective of this work is to describe the relationship between these psychological problems and the type of parent-child communication established about the disease. PROCEDURES: A group of 64 children surviving a brain tumor (aged 4-18 years) underwent psychological assessment by means of parent reports on the Child Behavior Checklist (CBCL) and the Vineland Adaptive Behavior Scales (VABS). A semi-structured interview with each child and their parents enabled us to classify the method of communication regarding the disease as "avoidance," "ineffective," and "effective." Demographic, clinical, and functional data relating to the disease were also collected. RESULTS: A significant relationship between the onset of Internalizing problems, withdrawal, anxiety-depression, and social problems and the presence of avoidance or ineffective communication about the disease was observed (P = 0.001, P = 0.001, P = 0.001, and P = 0.01, respectively). These psychological problems did not prove to be associated to demographic or clinical variables; however, they were found to be related to the children's residual functional problems. By contrast, the method of communication proved to be unrelated to clinical or functional variables, but it was associated to demographic variables such as sex and age at assessment. CONCLUSIONS: Effective (complete, truthful, consistent, comprehensible, gradual and continuous, and tailored) communication to the child about his/her condition proved to be associated with a better psychological outcome. PMID- 22492659 TI - Family-health professional relations in pediatric weight management: an integrative review. AB - In this integrative review, we examined contemporary literature in pediatric weight management to identify characteristics that contribute to the relationship between families and health professionals and describe how these qualities can inform healthcare practices for obese children and families receiving weight management care. We searched literature published from 1980 to 2010 in three electronic databases (MEDLINE, PsycINFO and CINAHL). Twenty-four articles identified family-health professional relationships were influenced by the following: health professionals' weight-related discussions and approaches to care; and parents' preferences regarding weight-related terminology and expectations of healthcare delivery. There was considerable methodological heterogeneity in the types of reports (i.e. qualitative studies, review articles, commentaries) included in this review. Overall, the findings have implications for establishing a positive clinical relationship between families and health professionals, which include being sensitive when discussing weight-related issues, using euphemisms when talking about obesity, demonstrating a non judgmental and supportive attitude and including the family (children and parents) in healthcare interactions. Experimental research, clinical interventions and longitudinal studies are needed to build on the current evidence to determine how best to establish a collaborative partnership between families and health professionals and whether such a partnership improves treatment adherence, reduces intervention attrition and enhances pediatric weight management success. PMID- 22492661 TI - Structurally diverse cyclisation linkers impose different backbone conformations in bicyclic peptides. AB - Combinatorial libraries of structurally diverse peptide macrocycles offer a rich source for the development of high-affinity ligands to targets of interest. In this work we have developed linkers for the generation of genetically encoded bicyclic peptides and tested whether the peptides cyclised by them have significant variations in their backbone conformations. Two new cyclisation reagents, each containing three thiol-reactive groups, efficiently and selectively cyclised linear peptides containing three cysteine moieties. When the mesitylene linker of the bicyclic peptide PK15, a potent inhibitor of plasma kallikrein (K(i)=2 nM), was replaced by the new linkers, its inhibitory activity dropped by a factor of more than 1000, suggesting that the linkers impose different conformations on the peptide. Indeed, structural analysis by solution state NMR revealed different NOE constraints in the three bicyclic peptides, indicating that these relatively small linkers at the centres of bicyclic peptide structures significantly influence the conformations of the peptides. These results demonstrate the prominent structural role of linkers in peptide macrocycles and suggest that application of different cyclisation linkers in a combinatorial fashion could be an attractive means to generate topologically diverse macrocycle libraries. PMID- 22492660 TI - A simulation study of finite-sample properties of marginal structural Cox proportional hazards models. AB - Motivated by a previously published study of HIV treatment, we simulated data subject to time-varying confounding affected by prior treatment to examine some finite-sample properties of marginal structural Cox proportional hazards models. We compared (a) unadjusted, (b) regression-adjusted, (c) unstabilized, and (d) stabilized marginal structural (inverse probability-of-treatment [IPT] weighted) model estimators of effect in terms of bias, standard error, root mean squared error (MSE), and 95% confidence limit coverage over a range of research scenarios, including relatively small sample sizes and 10 study assessments. In the base-case scenario resembling the motivating example, where the true hazard ratio was 0.5, both IPT-weighted analyses were unbiased, whereas crude and adjusted analyses showed substantial bias towards and across the null. Stabilized IPT-weighted analyses remained unbiased across a range of scenarios, including relatively small sample size; however, the standard error was generally smaller in crude and adjusted models. In many cases, unstabilized weighted analysis showed a substantial increase in standard error compared with other approaches. Root MSE was smallest in the IPT-weighted analyses for the base-case scenario. In situations where time-varying confounding affected by prior treatment was absent, IPT-weighted analyses were less precise and therefore had greater root MSE compared with adjusted analyses. The 95% confidence limit coverage was close to nominal for all stabilized IPT-weighted but poor in crude, adjusted, and unstabilized IPT-weighted analysis. Under realistic scenarios, marginal structural Cox proportional hazards models performed according to expectations based on large-sample theory and provided accurate estimates of the hazard ratio. PMID- 22492663 TI - Mitochondrial P5, a member of protein disulphide isomerase family, suppresses oxidative stress-induced cell death. AB - P5, one of the protein disulphide isomerase (PDI) family members, catalyses disulphide bond formation in proteins and exhibits molecular chaperone and calcium binding activities in vitro, whereas its physiological significance remains controversial. Recently, we have reported that P5 localizes not only in the ER but also in mitochondria, although it remains unclear so far about its physiological significance(s) of its dual localization. Here we report that H(2)O(2)- or rotenone-induced cell death is suppressed in MTS-P5 cells, which stably express P5 in mitochondria. H(2)O(2)-induced cell death in Saos-2 cells occurred, in large part, through caspase-independent and poly(ADP-ribose) polymerase (PARP)-dependent manner. In MTS-P5 cells challenged with H(2)O(2) treatment, PARP was still activated, whereas release of cytochrome c or apoptosis inducing factor and intramitochondrial superoxide generation were suppressed. We also found that mitochondrial P5 was in close contact with citrate synthase and maintained large parts of its activity under H(2)O(2) exposure. These results suggest that mitochondrial P5 may upregulate tricarboxylic acid cycle and possibly, other intramitochondrial metabolism. PMID- 22492664 TI - A general Pd-catalyzed decarboxylative cross-coupling reaction between aryl carboxylic acids: synthesis of biaryl compounds. PMID- 22492662 TI - Screening for psychosocial risk in pediatric cancer. AB - Major professional organizations have called for psychosocial risk screening to identify specific psychosocial needs of children with cancer and their families and facilitate the delivery of appropriate evidence-based care to address these concerns. However, systematic screening of risk factors at diagnosis is rare in pediatric oncology practice. Subsequent to a brief summary of psychosocial risks in pediatric cancer and the rationale for screening, this review identified three screening models and two screening approaches [Distress Thermometer (DT), Psychosocial Assessment Tool (PAT)], among many more articles calling for screening. Implications of broadly implemented screening for all patients across treatment settings are discussed. PMID- 22492665 TI - Modulation of cellular responses on engineered polyurethane implants. AB - An in vivo rat cage implant system was used to study the effect of polyurethane surface chemistries on protein adsorption, macrophage adhesion, foreign-body giant cell formation (FBGCs), cellular apoptosis, and cytokine response. Polyurethanes with zwitterionic, anionic, and cationic chemistries were developed. The changes in the surface topography of the materials were determined using atomic force microscopy and the wettability by dynamic contact angle measurements. The in vitro protein adsorption studies revealed higher protein adsorption on cationic surfaces when compared with the base, while adsorption was significantly reduced on zwitterionic (**p < 0.01) and anionic (*p < 0.05) polyurethanes. Analysis of the exudates surrounding the materials revealed no differences between surfaces in the types or levels of cells present. Conversely, the proportion of adherent cells undergoing apoptosis, as determined by annexin V FITC staining, increased significantly on anionic followed by zwitterionic surfaces (60 + 5.0 and 38 + 3.7%) when compared with the base. Additionally, zwitterionic and anionic substrates provided decreased rates of macrophage adhesion and fusion into FBGCs, whereas cationic surfaces promoted macrophage adhesion and FBGC formation. Visualization of the F-actin cytoskeleton by Alexa Fluor 488 phalloidin showed a significant delay in the cytoskeletal fusion response on zwitterionic and the anionic surfaces. The real-time polymerase chain reaction (PCR) analysis of proinflammatory cytokines (tumor necrosis factor (TNF) alpha and interleukin (IL)-10) and pro-wound healing cytokines (IL-4 and TGF beta) revealed differential cytokine responses. Cationic substrates that triggered stimulation of TNF-alpha and IL-4 were associated with more spread cells and higher FBGCs, whereas zwitterionic and anionic substrates that suppressed these cytokines levels were associated with less spread cells and few FBGCs. These studies have revealed that zwitterionic and anionic polyurethane surface chemistries can not only reduce nonspecific adhesion, fusion, and inflammatory events but also effectively promote cellular apoptosis in vivo. PMID- 22492667 TI - Global variation in the prevalence of elevated cholesterol in outpatients with established vascular disease or 3 cardiovascular risk factors according to national indices of economic development and health system performance. AB - BACKGROUND: Elevated serum cholesterol accounts for a considerable proportion of cardiovascular disease worldwide. An understanding of the relationship between country-level economic and health system factors and elevated cholesterol may provide insight for prioritization of cardiovascular prevention programs. METHODS AND RESULTS: Using hierarchical models, we examined the relationship between elevated total cholesterol (>200 mg/dL) in 53 570 outpatients from 36 countries, and tertiles of several country-level indices: (1) gross national income, (2) total expenditure on health as percentage of gross domestic product, (3) government expenditure on health as percentage of total expenditure on health, (4) out-of-pocket expenditures as percentage of private expenditure on health, and the World Health Organization indices of (5) Health System Achievement and (6) Performance/Efficiency. Overall, 38% of outpatients had total cholesterol >200 mg/dL (>5.18 mmol/L), and 9.3% of the total variability in elevated cholesterol was at the country level; this proportion was higher for patients with (12.1%) versus without (7.4%) history of hyperlipidemia. Among patients with history of hyperlipidemia, countries in the highest tertile of gross national income or World Health Organization Health System Achievement had lower odds of elevated cholesterol than lower tertiles (P<0.001, for both). Countries in the highest tertile of out-of-pocket health expenditures had higher odds of elevated cholesterol than those in the lowest tertile (P<0.001). No significant associations were found for patients without history of hyperlipidemia. CONCLUSIONS: Global variations in the prevalence of elevated cholesterol among patients with history of hyperlipidemia are associated with country-level economic development and health system indices. These results support the need for strengthening efforts toward effective cardiovascular disease prevention and control and may provide insight for health policy setting at the national level. PMID- 22492666 TI - Photochemical modulation of Ras-mediated signal transduction using caged farnesyltransferase inhibitors: activation by one- and two-photon excitation. AB - The creation of caged molecules involves the attachment of protecting groups to biologically active compounds such as ligands, substrates and drugs that can be removed under specific conditions. Photoremovable caging groups are the most common due to their ability to be removed with high spatial and temporal resolution. Here, the synthesis and photochemistry of a caged inhibitor of protein farnesyltransferase is described. The inhibitor, FTI, was caged by alkylation of a critical thiol group with a bromohydroxycoumarin (Bhc) moiety. While Bhc is well established as a protecting group for carboxylates and phosphates, it has not been extensively used to cage sulfhydryl groups. The resulting caged molecule, Bhc-FTI, can be photolyzed with UV light to release the inhibitor that prevents Ras farnesylation, Ras membrane localization and downstream signaling. Finally, it is shown that Bhc-FTI can be uncaged by two photon excitation to produce FTI at levels sufficient to inhibit Ras localization and alter cell morphology. Given the widespread involvement of Ras proteins in signal transduction pathways, this caged inhibitor should be useful in a plethora of studies. PMID- 22492669 TI - The effect of a short message service maintenance treatment on body mass index and psychological well-being in overweight and obese children: a randomized controlled trial. AB - OBJECTIVE: Maintaining weight loss results in childhood obesity treatment is difficult to achieve. Self-management techniques such as self-monitoring are associated with increased weight loss and maintenance. This study analyzes whether self-monitoring of lifestyle behaviours through a short message service maintenance treatment (SMSMT) via mobile phones with personalized feedback positively effects weight, lifestyle behaviours and psychological well-being in obese children. METHODS: After 3 months of behavioural lifestyle treatment, 141 overweight and obese children (7-12 years) were randomly assigned to an intervention group receiving SMSMT for 9 months (n = 73) or to the control group (n = 68). The intervention group sent weekly self-monitoring data on exercise and eating behaviour and their mood via mobile phones. In return, they received tailored feedback messages. Primary treatment outcomes were weight, eating behaviour and psychological well-being, i.e. competence, self-esteem and quality of life. Secondary outcome was adherence to the SMSMT. Data were analyzed with mixed modelling. RESULTS: SMSMT did not improve treatment outcomes. Controls gained temporarily in physical health scores (P = 0.01). SMSMT completers sent on average every 2 weeks an SMS. Children who had greater weight loss during the first 3 months of lifestyle treatment sent more SMSs (P = 0.04). CONCLUSIONS: We did not find a positive effect of SMSMT on weight, eating behaviour or psychological well-being in obese children. SMSMT seems to be a feasible method of treatment delivery. Future research should study variations of SMSMT to investigate how SMSMT can be more effective. PMID- 22492670 TI - MicroRNA expression and activity in pediatric acute lymphoblastic leukemia (ALL). AB - Acute lymphoblastic leukemia (ALL) is the most common type of pediatric neoplasia. Highly heterogeneous, ALL includes several genetic subtypes with varying clinical outcome. Although, some features are well established as prognostic predictors, the details of the molecular mechanisms underlying different phenotypes are only beginning to emerge. Recently, microRNAs (miRNAs) have been shown to influence a range of physiological processes and, consequently, alterations in their expression and functions have been associated with the development of many cancers, including leukemia. This article aims to review the current state of knowledge of the role of miRNAs on the biology of childhood ALL, also including relevant findings from the adult leukemia literature. PMID- 22492668 TI - Serum lipids and lipoproteins in Chinese men and women. AB - BACKGROUND: Because of rapid change in lifestyle risk factors, cardiovascular disease has become the leading cause of death in China. We sought to estimate the national levels of serum lipids and lipoproteins among the Chinese adult population. METHODS AND RESULTS: We conducted a cross-sectional study in a nationally representative sample of 46 239 adults aged >=20 years. Fasting serum total, high-density lipoprotein, and low-density lipoprotein cholesterol and triglycerides were measured by standard methods. The age-standardized estimates of total, high-density lipoprotein, and low-density lipoprotein cholesterol and triglycerides were 4.72 (95% confidence interval, 4.70-4.73), 1.30 (1.29-1.30), 2.68 (2.67-2.70), and 1.57 (1.55-1.58) mmol/L, respectively, in the Chinese adult population. In addition, 22.5% (21.8-23.3%) or 220.4 million (212.1-228.8) Chinese adults had borderline high total cholesterol (5.18-6.21 mmol/L), and 9.0% (8.5-9.5%) or 88.1 million (83.4-92.8) had high total cholesterol (>=6.22 mmol/L). The population estimates for borderline high (3.37-4.13 mmol/L), high (4.14-4.91 mmol/L), and very high (>=4.92 mmol/L) low-density lipoprotein cholesterol were 13.9% (13.3-14.5%) or 133.5 million (127.0-140.1), 3.5% (3.3 3.8%) or 33.8 million (31.2-36.5), and 3.0% (2.8-3.3%) or 29.0 million (26.3 31.8) persons, respectively. In addition, 22.3% (21.6-23.1%) or 214.9 million (207.0-222.8) persons had low high-density lipoprotein cholesterol (<1.04 mmol/L). The awareness, treatment, and control of borderline high or high total cholesterol were 11.0%, 5.1%, and 2.8%, respectively, in the Chinese adult population. CONCLUSIONS: Serum total and low-density lipoprotein cholesterol levels were high and increasing in the Chinese population. Without effective intervention, atherosclerotic cardiovascular diseases may soar in the near future in China. PMID- 22492671 TI - A buckybowl with a lot of potential: C5-C20H5(CF3)5. AB - Lots of potential: a trifluoromethylated corannulene, C(5)-C(20)H(5)(CF(3))(5), has been prepared and characterized spectroscopically and by X-ray crystallography. The structure exhibits a highly ordered bowl stacking that is unusual for corannulenes with acyclic substituents. The first reduction of C(5) C(20)H(5)(CF(3))(5) is anodically shifted by 0.95 V, making it the strongest corannulene-based electron acceptor to date. PMID- 22492673 TI - Increased plasma S-adenosyl-homocysteine levels induce the proliferation and migration of VSMCs through an oxidative stress-ERK1/2 pathway in apoE(-/-) mice. AB - AIMS: Although S-adenosyl-homocysteine (SAH) is considered to be a more sensitive predictor of cardiovascular disease than homocysteine, the underlying mechanisms of its effects remain unknown. We investigated the in vivo and in vitro effects of SAH on vascular smooth muscle cells (VSMCs) proliferation and migration related to the development of atherogenesis in apolipoprotein E-deficient (apoE( /-)) mice. METHODS AND RESULTS: A total of 72 apoE(-/-) mice were randomly divided into six groups (n= 12 for each group). The control group was fed a conventional diet, the M group was fed a 1% methionine-supplemented diet, the A group was fed a diet that was supplemented with the SAH hydrolase (SAHH) inhibitor adenosine-2, 3-dialdehyde (ADA), the M+A group was fed a diet that was supplemented with methionine plus ADA, and two of the groups were intravenously injected with retrovirus that expressed either SAHH shRNA (SAHH(+/-)) or scrambled shRNA semi-weekly for 8 weeks. Compared with the controls, the mice in the A, M+A, and SAHH(+/-) groups had higher plasma SAH levels, larger atheromatous plaques, elevated VSMC proliferation, and higher aortic reactive oxygen species and malondialdehyde levels. In cultured VSMCs, 5 MUM ADA or SAHH shRNA caused SAH accumulation, which resulted in increased cell proliferation, migration, oxidative stress, and extracellular-regulated kinase 1/2 (ERK1/2) activation. These effects were significantly attenuated by preincubation with superoxide dismutase (300 U/mL). CONCLUSION: Our results suggest that elevated SAH induces VSMC proliferation and migration through an oxidative stress dependent activation of the ERK1/2 pathway to promote atherogenesis. PMID- 22492674 TI - Monocyte chemotactic protein 3 is a homing factor for circulating angiogenic cells. AB - AIMS: Circulating angiogenic cells (CAC) participate in cardiac repair. CAC recruitment to the ischaemic heart is mainly induced by the chemokine (C-X-C motif) receptor 4 (CXCR4)/stromal-cell derived factor-1alpha axis. However, CAC mobilization is only partly prevented by CXCR4 blockade, indicating that other mechanisms are involved. Since the expression of monocyte chemotactic protein 3 (MCP3) is increased in ischaemic hearts, we hypothesized that it may participate in CAC mobilization. METHODS AND RESULTS: CAC were obtained from peripheral blood mononuclear cells of healthy volunteers. In vitro migration of CAC was concentration-dependently increased by recombinant MCP3 (one-fold increase, P= 0.001), and this effect was inhibited by antibodies neutralizing the chemokine (C C motif) receptor 1 (CCR1). CCR1 expression at the surface of CAC was confirmed by flow cytometry. Conditioned medium from heparan sulfate-activated macrophages, which contained MCP3, induced the migration of CAC (one-fold increase, P= 0.01). This increase was partly inhibited by CCR1 antibodies. The migration of CAC was also stimulated by macrophage inflammatory protein 3beta. This effect was blocked by CCR7 antibodies and was of lower magnitude than that of MCP3. MCP3 induced the formation of blood vessels in Matrigel plugs implanted in mice (1.5-fold increase, P< 0.001). This effect was abrogated by anti-CCR1 antibodies. CONCLUSION: This study shows that MCP3 stimulates the migration of CAC and angiogenesis, suggesting that MCP3 may be useful to improve cardiac repair. PMID- 22492675 TI - Wnt signalling in smooth muscle cells and its role in cardiovascular disorders. AB - Vascular smooth muscle cells (SMCs) are the major cell type within blood vessels. SMCs exhibit low rates of proliferation, migration, and apoptosis in normal blood vessels. However, increased SMC proliferation, migration, and apoptosis rates radically alter the composition and structure of the blood vessel wall and contribute to cardiovascular diseases, such as atherosclerosis, and restenosis that occur after coronary artery vein grafting and stent implantation. Consequently, therapies that modulate SMC proliferation, migration, and apoptosis may be useful for treating cardiovascular diseases. The family of Wnt proteins, which were first identified in the wingless drosophila, has a well-established role in embryogenesis and development. It is now emerging that Wnt proteins also regulate SMC proliferation, migration, and survival. In this review article, we discuss recently emerging research that has revealed that Wnt proteins are important regulators of SMC behaviour via activation of beta-catenin-dependent and beta-catenin-independent Wnt signalling pathways. PMID- 22492672 TI - Emerging role of PKA/eNOS pathway in therapeutic angiogenesis for ischaemic tissue diseases. AB - Although an abundant amount of research has been devoted to the study of angiogenesis, its precise mechanisms are incompletely understood. Numerous clinical trials focused on therapeutic angiogenesis for the treatment of tissue ischaemia have not been as successful as those of preclinical studies. Thus, additional studies are needed to better understand critical molecular mechanisms regulating ischaemic neovascularization to identify novel therapeutic agents. Nitric oxide (NO) plays a central role in ischaemic neovascularization through the generation of cyclic guanosine monophosphate (cGMP) and the activation of several other signalling responses. Accumulated evidence suggests that endothelial protein kinase A/endothelial NO synthase (PKA/eNOS) signalling may play an important role in ischaemic disorders by promoting neovascularization. This review highlights recent advances in the role of the PKA/eNOS and NO-cGMP kinase cascade pathway in ischaemic neovascularization. We also discuss molecular relationships of PKA/eNOS with other angiogenic pathways and explore the possibility of activation of the NO/nitrite endocrine system as potential therapeutic targets for ischaemic angiogenesis. PMID- 22492676 TI - Post-myocardial infarct p27 fusion protein intravenous delivery averts adverse remodelling and improves heart function and survival in rodents. AB - AIMS: P27Kip1 (p27) blocks cell proliferation through the inhibition of cyclin dependent kinase 2 (cdk-2). Despite robust expression in the heart, little is known about the regulation and function of p27 in this terminally differentiated tissue. Previously, we demonstrated that p27 exerts anti-apoptotic and growth inhibitory effects through interaction with casein kinase 2 (ck2) in neonatal rat cardiomyocytes. Here, we test the hypothesis that delivery of a transactivator of transcription (TAT)-p27 fusion protein (TAT.p27) will improve cardiac function and survival in a rat model of myocardial infarction (MI). METHODS AND RESULTS: Fisher rats underwent permanent left anterior descending ligation-induced MI followed by iv injection of TAT.p27 or TAT.LacZ (20 mg/kg) on Days 1 and 7 post MI. Delivery of TAT.p27 was evaluated by western blot (WB) and immunofluorescence microscopy. Heart function was assessed by echocardiography and pressure-volume catheter. Apoptosis, hypertrophy, and fibrosis were detected by histochemistry and morphometry. WB confirmed gradual reduction in endogenous cardiac p27 levels following MI, with immunohistochemistry demonstrating successful delivery of TAT.p27 to the heart. At 48 h post-MI, cardiac apoptosis was decreased in rats treated with TAT.p27 when compared with saline- and TAT.LacZ-treated controls. At 28 days post-MI, rats treated with TAT.p27 manifested less cardiomyocyte hypertrophy and fibrosis, less diminished cardiac function, and greater survival. Additionally, p27KO mice undergoing experimental MI suffered an early increase in apoptosis with a larger infarct size and markedly reduced survival when compared with wild-type (WT) controls. CONCLUSION: These gain- and loss-of-function studies reveal a critical role for p27 in cardiac remodelling post-MI. PMID- 22492677 TI - Functional biomaterials for cartilage regeneration. AB - The injury and degeneration of articular cartilage and associated arthritis are leading causes of disability worldwide. Cartilage tissue engineering as a treatment modality for cartilage defects has been investigated for over 20 years. Various scaffold materials have been developed for this purpose, but has yet to achieve feasibility and effectiveness for widespread clinical use. Currently, the regeneration of articular cartilage remains a formidable challenge, due to the complex physiology of cartilage tissue and its poor healing capacity. Although intensive research has been focused on the developmental biology and regeneration of cartilage tissue and a diverse plethora of biomaterials have been developed for this purpose, cartilage regeneration is still suboptimal, such as lacking a layered structure, mechanical mismatch with native cartilage and inadequate integration between native tissue and implanted scaffold. The ideal scaffold material should have versatile properties that actively contribute to cartilage regeneration. Functional scaffold materials may overcome the various challenges faced in cartilage tissue engineering by providing essential biological, mechanical, and physical/chemical signaling cues through innovative design. This review thus focuses on the complex structure of native articular cartilage, the critical properties of scaffolds required for cartilage regeneration, present strategies for scaffold design, and future directions for cartilage regeneration with functional scaffold materials. PMID- 22492678 TI - Early recognition of POEMS syndrome: what is the role of clinical neurophysiology? PMID- 22492679 TI - Impact commentaries. Polyneuropathy in critically ill patients. PMID- 22492680 TI - A workspace-orientated needle-guiding robot for 3T MRI-guided transperineal prostate intervention: evaluation of in-bore workspace and MRI compatibility. AB - BACKGROUND: Magnetic resonance imaging (MRI)-guided prostate interventions have been introduced to enhance the cancer detection. For accurate needle positioning, in-bore-operated robotic systems have been developed and optimal use of the confined in-bore space become a critical engineering challenge. METHODS: As preliminary evaluation of our prostate intervention robot, we conducted a workspace design analysis, using a new evaluation method that we developed for in bore-operated robots for transperineal prostate interventions, and an MRI compatibility study. RESULTS: The workspace analysis resulted in the effective workspace (VW ) of 0.32, which is greater than that of our early prototype, despite the current robot being ca. 50% larger than the early prototype in sectional space. The MRI compatibility study resulted in < 15% signal:noise ratio (SNR) reduction. CONCLUSIONS: The new workspace evaluation method quantifies the workspace utilization of the in-bore-operated robots for MRI-guided transperineal prostate interventions, providing a useful tool for evaluation and new robot design. The robot creates insignificant electromagnetic noise during typical prostate imaging sequences. PMID- 22492681 TI - Improving physical self-perception in adolescent boys from disadvantaged schools: psychological outcomes from the Physical Activity Leaders randomized controlled trial. AB - OBJECTIVES: To evaluate the effect of a school-based obesity prevention programme on physical self-perception and key physical-activity related cognitions in adolescent boys from disadvantaged secondary schools. A secondary objective was to determine if any psychological changes were associated with improved weight status. METHODS: Participants (n = 100, age = 14.3[0.6]) were randomized to the PALS (Physical Activity Leaders) intervention (n = 50) or a control group (n = 50) and assessed at baseline, 3- and 6-month follow up. Measures included BMI, BMI z-score and % body fat (bioelectrical impedance analysis). Students also completed the Children's Physical Self-Perception Profile and a physical activity related cognitions questionnaire. The findings include secondary data analyses. RESULTS: Relative to the controls, the PALS group significantly increased their physical self worth (p = .01), perceived physical condition (p = .02), resistance training self efficacy (p < .001) and their use of physical activity behavioural strategies (p = .02). CONCLUSIONS: A school-based obesity prevention programme that targeted leadership skills improved psychological health in the physical domain in adolescent boys from disadvantaged schools. PMID- 22492683 TI - Structural and mechanistic revelations on an iron conversion reaction from pair distribution function analysis. AB - Not simply small particles: pair distribution function analysis yields comprehensive insights into the electrochemical reaction of alpha-Fe(2)O(3) with lithium. The metallic Fe formed in this reaction was found to be defect-rich nanoparticles that restructure continuously without growing-an unusual characteristic likely linked to its highly reversible capacity. PMID- 22492682 TI - "Accelerated ear-age": a new measure of chemotherapy-induced ototoxicity. AB - Currently, there are several different scales that grade chemotherapy-induced ototoxicity. This report highlights how the implications of the conclusions drawn from each scale differ and compare these prior scales to a more functionally based scale developed at Children's Hospital Boston. Additionally, this report introduces the concept of "ear-age," akin to the age at which one would expect the observed decrease in hearing as a consequence of normative aging (but documented in a child or young adult following chemotherapy). PMID- 22492684 TI - A pro-fibrotic role for interleukin-4 in cardiac pressure overload. AB - AIMS: The mechanisms underlying cardiac fibrosis in hypertension are yet to be defined, although inflammatory cells, fibroblasts, and cytokines have been implicated. Here, we investigated the role of interleukin-4 (IL-4) in cardiac fibrosis, which is elevated in the hypertensive heart. IL-4 has been shown to be pro-fibrotic in the liver and the lung, but its role in cardiac fibrosis has not been investigated. METHODS AND RESULTS: Cardiac fibrosis was induced in mice by constricting the aorta between the two carotid arteries. Fourteen days later marked left ventricular fibrosis developed together with expression of IL-4. Anti IL-4 neutralizing antibodies attenuated this fibrosis without affecting blood pressure or expression of the transforming growth factor-beta system. The reduction in fibrosis was associated with reductions in interstitial fibroblasts and macrophages together with reductions in proliferating cells and expression of monocyte chemoattractant protein-1 (MCP-1). Since mast cells are a source of IL 4, we also assessed their role in fibrosis. Cromolyn, a mast cell inhibitor attenuated mast cell degranulation as well as IL-4 mRNA expression and cardiac fibrosis without affecting blood pressure. Treatment with Cromolyn also reduced interstitial fibroblasts and macrophages in regions of developing fibrosis as well MCP-1 expression. CONCLUSION: This study demonstrates for the first time that IL-4, most likely produced by mast cells in the heart during pressure overload, is a significant contributor to cardiac fibrosis. Targeting this cytokine may be a useful therapeutic strategy to limit cardiac fibrosis. PMID- 22492685 TI - An evolutionary view of the mechanism for immune and genome diversity. AB - An ortholog of activation-induced cytidine deaminase (AID) was, evolutionarily, the first enzyme to generate acquired immune diversity by catalyzing gene conversion and probably somatic hypermutation (SHM). AID began to mediate class switch recombination (CSR) only after the evolution of frogs. Recent studies revealed that the mechanisms for generating immune and genetic diversity share several critical features. Meiotic recombination, V(D)J recombination, CSR, and SHM all require H3K4 trimethyl histone modification to specify the target DNA. Genetic instability related to dinucleotide or triplet repeats depends on DNA cleavage by topoisomerase 1, which also initiates DNA cleavage in both SHM and CSR. These similarities suggest that AID hijacked the basic mechanism for genome instability when AID evolved in jawless fish. Thus, the risk of introducing genome instability into nonimmunoglobulin loci is unavoidable but tolerable compared with the advantage conferred on the host of being protected against pathogens by the enormous Ig diversification. PMID- 22492686 TI - T cell factor-1 and beta-catenin control the development of memory-like CD8 thymocytes. AB - Innate memory-like CD8 thymocytes develop and acquire effector function during maturation in the absence of encounter with Ags. In this study, we demonstrate that enhanced function of transcription factors T cell factor (TCF)-1 and beta catenin regulate the frequency of promyelocytic leukemia zinc finger (PLZF) expressing, IL-4-producing thymocytes that promote the generation of eomesodermin expressing memory-like CD8 thymocytes in trans. In contrast, TCF1-deficient mice do not have PLZF-expressing thymocytes and eomesodermin-expressing memory-like CD8 thymocytes. Generation of TCF1 and beta-catenin-dependent memory-like CD8 thymocytes is non-cell-intrinsic and requires the expression of IL-4 and IL-4R. CD8 memory-like thymocytes migrate to the peripheral lymphoid organs, and the memory-like CD8 T cells rapidly produce IFN-gamma. Thus, TCF1 and beta-catenin regulate the generation of PLZF-expressing thymocytes and thereby facilitate the generation of memory-like CD8 T cells in the thymus. PMID- 22492687 TI - Self-supporting nanoporous alumina membranes as substrates for hepatic cell cultures. AB - Membranes made from nanoporous alumina exhibit interesting properties for their use in biomedical research. They show high porosity and the pore diameters can be easily adjusted in a reproducible manner. Nanoporous alumina membranes are thus ideal substrates for the cultivation of polar cells (e.g., hepatocytes) or the establishment of indirect co-cultures. The porous nature of the material allows supply of nutrients to both sides of adherent cells and the exchange of molecules across the membrane. However, it is well-known that surface features in the nanometer range affect cellular behavior. In this study, the response of HepG2 cells to nanoporous alumina membranes with three different pore diameters, ranging from 50 to 250 nm, has been evaluated. The cellular interactions with the nanoporous materials were assessed by investigating cell adhesion, morphology, and proliferation. Cell functionality was measured by means of albumin production. The membranes supported good cell adhesion and spreading. Compared to tissue culture plastic, the cells on the porous substrates developed distinct focal adhesion sites and actin stress fibers. Additionally, electron microscopical investigations revealed the penetration of cellular extensions into pores with diameters bigger than 200 nm. Furthermore, cell proliferation significantly increased with an increase in pore diameter, whereas the albumin production followed a reverse trend. Thus, it seems to be possible to direct cellular behavior of HepG2 cells growing on nanoporous alumina by changing the pore diameter of the material. Hence, nanoporous alumina membranes can be useful culture substrates to develop new approaches in the field of liver tissue engineering. PMID- 22492688 TI - Conceptual design of a novel multi-DoF manual instrument for laparoscopic surgery. AB - BACKGROUND: Laparoscopic surgery is becoming increasingly popular throughout the world. But the conventional instruments used in many surgeries are not flexible enough to be operated. Challenging tasks, such as suturing and knot-tying tasks are difficult to complete using conventional instruments with limited degrees of freedom (DoFs). In the paper, a novel cable-driven multi-DoF manual instrument is presented with a simple structure but strong functionality. METHODS: The proposed instrument has been developed with a wristlike operation end (OE), a wristlike end effector (EE), and the transmission system. It can be operated intuitively. The orientation and the position of the EE are directly controlled by surgeons due to the one-to-one motion mapping structure. The clamp structure and tension device are reasonably designed. The pitch, yaw, and the open and close motion are actuated by cables. Based on the optimization index Global Condition Index (GCI), four cables are used to actuate the pitch and yaw motions, while other two are used for the open and close motion. The layout of the cables is also determined by the GCI. RESULTS: Experiments carried out with a prototype show that tasks such as suturing and knot-tying can be completed comfortably. Due to the intuitive control and multi-DoFs, surgeons can use the prototype to finish the tasks with ease. CONCLUSIONS: The instrument developed herein with intuitive control and dexterity can be used alone or together with a robotic system to accomplish some challenging tasks that are difficult for conventional instruments. PMID- 22492689 TI - Ophthalmic artery chemosurgery for the management of retinoblastoma in eyes with extensive (>50%) retinal detachment. AB - BACKGROUND: Superselective delivery of chemotherapy through the ophthalmic artery, i.e. ophthalmic artery chemosurgery, has been used for the treatment of advanced intraocular retinoblastoma. Herein, we evaluate the efficacy of ophthalmic artery chemosurgery for retinoblastoma associated with >50% retinal detachment. PROCEDURE: Retrospective review of 37 eyes of 34 retinoblastoma patients who had extensive (>50%) bullous non-rhegmatogenous retinal detachments and received ophthalmic artery chemosurgery either as primary treatment or as "salvage" treatment after failed multi-cycle intravenous chemotherapy and/or external beam radiation (mean follow-up, 21 months). Data on patient and ocular survival, complications of ophthalmic artery chemosurgery treatments, time course of retinal reattachment, and serial electroretinograms (ERG) were collected. RESULTS: A total of 134 ophthalmic artery chemosurgery injections were performed. All children survive. Five eyes (5/37; 14%) were enucleated for progression of disease. The Kaplan-Meier enucleation-free survival rate at 2 years was 87.9% (95% confidence interval, 76.5-99.3%). The retina reattached in 28 eyes (28/37; 76%) and the 30-Hz flicker ERGs improved by >25 uV in seven eyes (7/37; 19%), remained stable (change < 25 uV) in 26 eyes (26/37; 70%), and decreased by >25 uV in four eyes (4/37; 11%). The Kaplan-Meier retinal reattachment rate was 58% after 3 months and three ophthalmic artery chemosurgery infusions (95% confidence interval, 41.9-74.1%). CONCLUSIONS: Ophthalmic artery chemosurgery is effective in preventing enucleation, promoting retinal reattachment and preserving or improving retinal function in the majority of eyes with advanced retinoblastoma and >50% retinal detachment that would otherwise be considered for enucleation. PMID- 22492690 TI - Lung function in hyper IgE syndrome. AB - Pneumatoceles and bronchiectasis are secondary complications of respiratory infections in patients with hyper IgE syndrome (HIgES). We report on a patient with HIgES and recurrent pneumonias since 1 year of age, with progression to pneumatoceles and bronchiectasis and fatal outcome, with disseminated infection and suspected allergic bronchopulmonary aspergillosis, who was subjected to sequential spirometric assessment. We describe the early beginning of respiratory infections, difficulties in the management of pulmonary sequelae and the impact of an early functional diagnosis and follow-up of the patient regarding a disease for which lung function has not been fully described. PMID- 22492691 TI - Insulin resistance in patients with cirrhosis and portal hypertension. AB - Insulin resistance (IR) is involved in the pathogenesis of endothelial dysfunction and is also present in patients with cirrhosis. Intrahepatic endothelial dysfunction plays a major role, increasing hepatic vascular resistance and promoting portal hypertension (PH). In addition, beta-adrenergic agonists and insulin share several intracellular signaling pathways. Thus IR may influence the response to beta-blockers. This study aimed at evaluating the relationship between IR and hepatic hemodynamics in patients with cirrhosis and with the portal pressure response to acute beta-blockade. Forty-nine patients with cirrhosis and PH were included. Hepatic and systemic hemodynamics were measured, and IR was estimated by using the updated homeostasis model assessment (HOMA)-2 index. Patients with HOMA-2 > 2.4 were considered IR. In patients with hepatic venous pressure gradient (HVPG) >= 10 mmHg) [clinically significant PH (CSPH)], hemodynamic measurements were performed again 20 min after intravenous propranolol. Mean HOMA-2 index was 3 +/- 1.4. Fifty-seven percent of patients had IR. A weak correlation between HOMA-2 index and HVPG was observed. Eighty-six percent of patients had CSPH. HOMA-2 index was an independent predictor of CSPH. However, in patients with CSPH, the correlation between HOMA-2 index and HVPG was lost. HVPG, but not IR, predicted the presence of esophageal varices. Response to propranolol was not different between patients with or without IR. In nondiabetic patients with cirrhosis, HOMA-2 index is directly associated with the presence of CSPH and indirectly with varices, but does not allow either grading HVPG or predicting its response to propranolol. PMID- 22492692 TI - Butyrate enemas enhance both cholinergic and nitrergic phenotype of myenteric neurons and neuromuscular transmission in newborn rat colon. AB - Postnatal changes in the enteric nervous system (ENS) are involved in the establishment of colonic motility. In adult rats, butyrate induced neuroplastic changes in the ENS, leading to enhanced colonic motility. Whether butyrate can induce similar changes during the postnatal period remains unknown. Enemas (Na butyrate) were performed daily in rat pups between postnatal day (PND) 7 and PND 17. Effects of butyrate were evaluated on morphological and histological parameters in the distal colon at PND 21. The neurochemical phenotype of colonic submucosal and myenteric neurons was analyzed using antibodies against Hu, choline acetyltransferase (ChAT), and neuronal nitric oxide synthase (nNOS). Colonic motility and neuromuscular transmission was assessed in vivo and ex vivo. Butyrate (2.5 mM) enemas had no impact on pup growth and histological parameters compared with control. Butyrate did not modify the number of Hu-immunoreactive (IR) neurons per ganglia. A significant increase in the proportion (per Hu-IR neurons) of nNOS-IR myenteric and submucosal neurons and ChAT-IR myenteric neurons was observed in the distal colon after butyrate enemas compared with control. In addition, butyrate induced a significant increase in both nitrergic and cholinergic components of the neuromuscular transmission compared with control. Finally, butyrate increased distal colonic transit time compared with control. We concluded that butyrate enemas induced neuroplastic changes in myenteric and submucosal neurons, leading to changes in gastrointestinal functions. Our results support exploration of butyrate as potential therapy for motility disorders in preterm infants with delayed maturation of the ENS. PMID- 22492693 TI - The role of the anteriolateral bed nucleus of the stria terminalis in stress induced nociception. AB - Activation of the central amygdala (CeA) by corticosterone (CORT) induces somatic and colonic hypersensitivity through corticotrophin-releasing factor (CRF) dependent mechanisms. However, the importance of the bed nucleus of the stria terminalis (BNST), part of the extended amygdala, on nociception remains unexplored. In the present study, we test the hypothesis that stimulation of the CeA by CORT induces somatic and colonic hypersensitivity through activation of the anteriolateral BNST (BNST(AL)). Animals were implanted with micropellets of CORT or cholesterol (CHOL) onto the CeA or the BNST(AL). Mechanical sensitivity was quantified using electronic von Frey filaments, and colonic nociception was measured by quantifying a visceromotor response to graded colorectal distension. In situ hybridization was used to determine mRNA levels for CRF, CRF(1), and CRF(2) receptors in the BNST(AL). In a second group, animals were implanted bilaterally with 1) CORT or CHOL micropellets onto the CeA; and 2) cannulas localized to the BNST(AL) to administer a CRF(1) receptor antagonist (CP376395). Animals implanted with CORT onto the CeA, but not the BNST(AL), exhibited increased expression of CRF mRNA and increased CRF(1)-to-CRF(2) receptor ratio in the BNST, as well as somatic and colonic hypersensitivity compared with CHOL controls. Infusion of CP376395 into the BNST(AL) inhibited somatic and colonic hypersensitivity in response to elevated amygdala CORT. Somatic and colonic hypersensitivity induced by elevated amygdala CORT is mediated via a CRF(1) receptor-dependent mechanism in the BNST(AL). The CeA through a descending pathway involving the BNST(AL) plays a pivotal role in somatic and colonic nociception. PMID- 22492694 TI - Inhibition of Syk activity by R788 in platelets prevents remote lung tissue damage after mesenteric ischemia-reperfusion injury. AB - Tissue injury following ischemia-reperfusion (I/R) occurs as a consequence of actions of soluble factors and immune cells. Growing evidence supports a role for platelets in the manifestation of tissue damage following I/R. Spleen tyrosine kinase has been well documented to be important in lymphocyte activation and more recently in platelet activation. We performed experiments to evaluate whether inhibition of platelet activation through inhibition of spleen tyrosine kinase prevents tissue damage after mesenteric I/R injury. Platelets isolated from C57BL/6J mice fed with R788 for 10 days were transfused into C57BL/6J mice depleted of platelets 2 days before mesenteric I/R injury. Platelet-depleted mice transfused with platelets from R788-treated mice before mesenteric I/R displayed a significant reduction in the degree of remote lung damage, but with little change in the degree of local intestinal damage compared with control I/R mice. Transfusion of R788-treated platelets also decreased platelet sequestration, C3 deposition, and immunoglobulin deposition in lung, but not in the intestine, compared with control groups. These findings demonstrate that platelet activation is a requisite for sequestration in the pulmonary vasculature to mediate remote tissue injury after mesenteric I/R. The use of small-molecule inhibitors may be valuable to prevent tissue damage in remote organs following I/R injury. PMID- 22492695 TI - Predicting and accounting for VTE in phase I cancer studies. PMID- 22492696 TI - Chemotherapy treatment patterns and clinical outcomes in patients with metastatic soft tissue sarcoma. The SArcoma treatment and Burden of Illness in North America and Europe (SABINE) study. AB - BACKGROUND: To describe chemotherapy treatment patterns and clinical outcomes in metastatic soft tissue sarcoma (mSTS) patients with favorable response to chemotherapy. PATIENTS AND METHODS: Multicenter (25) multi-country (9) retrospective chart review of mSTS patients with favorable response to chemotherapy, defined as stable disease or better following four cycles. RESULTS: Two hundred and thirteen patients (58% female; mean age 54.7 years) received a mean of 2.7 lines of chemotherapy and 5.2 cycles per line. The most common first line regimens were doxorubicin (34%) and anthracycline plus ifosfamide (30%). Favorable response was achieved by 83% to first-line and 42% and 38% in second- and third-line chemotherapy. The most common reason for chemotherapy discontinuation in lines with a favorable response was reaching a predefined number of cycles in first line (64% of 213) and disease progression in second or later lines (41% of 138). The mean time off chemotherapy was 38.0 weeks after first line, falling to 2.7-6.4 weeks in second or later lines. Median overall and progression-free survival were 23.5 (95% confidence interval 20.5-28.1) and 8.3 (7.4-9.9) months from first favorable response to chemotherapy. CONCLUSIONS: mSTS patients achieving favorable response to chemotherapy have poor outcomes. Additional treatment options are needed. PMID- 22492697 TI - Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. AB - BACKGROUND: We report the 10-year results of the EORTC trial 24891 comparing a larynx-preservation approach to immediate surgery in hypopharynx and lateral epilarynx squamous cell carcinoma. MATERIAL AND METHODS: Two hundred and two patients were randomized to either the surgical approach (total laryngectomy with partial pharyngectomy and neck dissection, followed by irradiation) or to the chemotherapy arm up to three cycles of induction chemotherapy (cisplatin 100 mg/m(2) day 1 + 5-FU 1000 mg/m(2) day 1-5) followed for complete responders by irradiation and otherwise by conventional treatment. The end points were overall survival [OS, noninferiority: hazard ratio (preservation/surgery) <= 1.428, one sided alpha = 0.05], progression-free survival (PFS) and survival with a functional larynx (SFL). RESULTS: At a median follow-up of 10.5 years on 194 eligible patients, disease evolution was seen in 54 and 49 patients in the surgery and chemotherapy arm, respectively, and 81 and 83 patients had died. The 10-year OS rate was 13.8% in the surgery arm and 13.1% in the chemotherapy arm. The 10-year PFS rates were 8.5% and 10.8%, respectively. In the chemotherapy arm, the 10-year SFL rate was 8.7%. CONCLUSION: This strategy did not compromise disease control or survival (that remained poor) and allowed more than half of the survivors to retain their larynx. PMID- 22492698 TI - Applying the 2011 St Gallen panel of prognostic markers on a large single hospital cohort of consecutively treated primary operable breast cancers. AB - BACKGROUND: Many easily measurable and readily available factors are now established as being prognostic in primary operable breast cancer. We here applied the 2011 St Gallen surrogate definition for breast cancer subclassification using tumor grade instead of Ki67. PATIENTS AND METHODS: Four thousand three hundred and eighteen consecutive patients who had surgery for primary operable breast cancer (1 January 2000 and 31 December 2009) in UZ Leuven excluding primary metastastic male breast cancers and those receiving neoadjuvant therapy. Five different surrogate phenotypes were created using the combined expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 together with tumor grade. Disease-free interval (DFI), distant metastastis-free interval (DMFI), locoregional relapse-free interval (LRRFI), breast cancer-specific survival (BCSS) and overall survival (OS) were calculated. RESULTS: Surrogate phenotypes present with significant differences in DFI, DMFI, LRRFI, BCSS and OS. 'Luminal A' tumors presented with the best outcome parameters but the effect weakened at longer follow-up. CONCLUSIONS: The four surrogate markers, agreed upon by the 2011 St Gallen consensus, defined five prognostic surrogate phenotypes in a large series of consecutively treated breast cancer patients. Their prognostic value changed with longer follow-up. The added value of gene expression profile over classical pathological assessment remains to be defined. PMID- 22492699 TI - Circulating activin-A is elevated in patients with advanced multiple myeloma and correlates with extensive bone involvement and inferior survival; no alterations post-lenalidomide and dexamethasone therapy. AB - BACKGROUND: Activin-A is a transforming growth factor -beta superfamily member, which seems to be implicated in the biology of osteolytic disease in multiple myeloma. DESIGN AND METHODS: Circulating activin-A was evaluated in 98 newly diagnosed myeloma patients (85 with symptomatic disease), in 40 patients with relapsed myeloma before and after four cycles of lenalidomide and dexamethasone (RD), in 27 healthy controls and in 10 monoclonal gammopathy of undetermined significance patients. RESULTS: Patients with newly diagnosed symptomatic myeloma had increased circulating activin-A compared with controls (P < 0.001), while patients with relapsed disease had elevated activin-A even compared with symptomatic patients at diagnosis (P < 0.001). High activin-A correlated with advanced International Staging System stage (P = 0.002), increased bone resorption (P < 0.001) and extensive bone disease (P = 0.03). Low levels of activin-A (<442 pg/ml) were associated with superior median overall survival: not reached versus 59 months (P = 0.04), while activin-A inversely correlated with survival as a continuous variable (P < 0.001). RD did not alter circulating activin-A after four cycles of treatment, even in responders. CONCLUSIONS: High circulating activin-A correlates with advanced features of myeloma, supporting the rationale for the use of activin-A antagonists, such as sotatercept in myeloma. The inability of RD to reduce activin-A reveals RD as a good candidate for combination therapies with activin-A antagonists in myeloma. PMID- 22492700 TI - Trends in cancer mortality in China: an update. AB - BACKGROUND: Cancer deaths of China with the world population nearly a quarter will have a severe impact on global cancer trend and burden. The study aims to provide a comprehensive overview of long-term trends in cancer mortality in China. MATERIALS AND METHODS: We used joinpoint analysis to detect changes in trends and generalized additive models to study birth cohort effect of risk factors between 1987 and 2009. RESULTS: Mortality of all cancers declined steadily in urban areas, but not in rural areas. Decreasing mortality from cancers of the stomach, esophagus, nasopharynx, and cervix uteri was observed, while lung and female breast cancer mortality increased. Mortality from leukemia remained relatively stable, and cancer of liver, colorectal, and bladder had different trends between the rural and urban areas. Generational risks peaked in the cohorts born around 1925-1930 and tended to decline in successive cohorts for most cancers except for leukemia, whose relative risks were rising in the very recent cohorts. CONCLUSION: The observed trends primarily reflect dramatic changes in socioeconomic development and lifestyle in China over the past two decades, and mortality from cancers of lung and female breast still represents a major public health priority for the government. PMID- 22492701 TI - Building an innovative model for personalized healthcare. PMID- 22492702 TI - Effect of sodium butyrate on autophagy and apoptosis in Chinese hamster ovary cells. AB - Sodium butyrate (NaBu), which is widely used in recombinant Chinese hamster ovary cell (rCHO) cultures for high-level expression of therapeutic proteins, is known to induce apoptosis in a dose-dependent manner. Lately, the significance of autophagy has increased in the field of CHO cell culture due to the fact that autophagy is related to the programmed cell death mechanism. To determine the effect of NaBu on autophagy as well as apoptosis of rCHO cells, rCHO cells producing erythropoietin were subjected to NaBu treatment. NaBu treatment up to 5 mM increased cleaved forms of PARP, caspase-3, and Annexin V positive population, confirming the previous results that NaBu induces apoptosis. Concurrently, NaBu treatment increased the level of accumulation of the autophagic marker, LC3-II, independently of nutrient depletion, suggesting that NaBu induces autophagy. To elucidate the potential role of autophagy induced by NaBu, a representative autophagy inducer (rapamycin) or an inhibitor (bafilomycin A1) was added to cultures together with NaBu. It was found that autophagy had the potential role of a positive cell survival mechanism under NaBu treatment. Furthermore, gradual reduction in mitochondrial membrane potential/mass and recruitment of a mitophagy protein, Parkin, to the mitochondria were observed under NaBu treatment, suggesting that this positive function of autophagy might be mediated by the autophagic removal of damaged mitochondria. Taken together, autophagy was observed in rCHO cell culture under NaBu treatments and the results obtained here support the positive effects of autophagy induced by NaBu treatments. PMID- 22492703 TI - Sorafenib and bevacizumab for recurrent metastatic hepatoblastoma: stable radiographic disease with decreased AFP. AB - We report the use of sorafenib and bevacizumab in combination for a patient with recurrent metastatic hepatoblastoma (HB). This combination demonstrated activity against our patient's refractory HB that had been extensively treated with multiple prior chemotherapeutic regimens. The patient had stabilization of radiographic disease coupled with an 83% decrease in his alpha-fetoprotein level. Given the response in this setting and the paucity of other available options, consideration could be given to using this combination as therapy in patients with recurrent HB who have failed more traditional agents. PMID- 22492704 TI - Stabilization of collagen tissues by photocrosslinking. AB - Photocrosslinking, using 2 mM Ru(II)(bpy)(3)Cl(2) and various concentrations of sodium persulfate with irradiation by blue light, ~455 nm, has been shown to be a rapid and effective method for crosslinking various tissues: tendon, amnion membrane, pericardium, and heart valve leaflet. The presence of new crosslinking was demonstrated by the increase in the shrinkage temperature of these tissues. In all the cases, increase in the shrinkage temperatures were seen, although at higher sodium persulfate concentrations, for example, 100 mM, both with and without the Ru(II)(bpy)(3)Cl(2) catalyst, some degradation of the collagenous tissues was found. The effectiveness of this photocrosslinking method when used with tissues was also shown through the increase in the break strength of tissues after crosslinking, and by the reduction of protein that could be extracted by urea. In solution studies, dityrosine has been shown to be formed during photocrosslinking. With tissues, Western blotting showed the presence of new dityrosine crosslinked proteins. PMID- 22492705 TI - The impact of effective continuous positive airway pressure on homeostasis model assessment insulin resistance in non-diabetic patients with moderate to severe obstructive sleep apnea. AB - Previous studies on the effects of continuous positive airway pressure (CPAP) on homeostasis model assessment insulin resistance (HOMA-IR) in obstructive sleep apnea patients have yielded conflicting results. Therefore, we conducted this meta-analysis to evaluate the impact of effective CPAP on HOMA-IR in non-diabetic patients with moderate to severe obstructive sleep apnea. We searched PubMed, HighWire Press, Ovid Medline (R), Cochrane library and EMBASE before December 2011 on original English language studies. The data on HOMA-IR and body mass index (BMI) were extracted from these studies. As compared with baseline values, 8 to 24 weeks of effective CPAP (>4 h/night) treatment significantly reduced HOMA IR by an average of 0.75(95% CI, from -0.96 to -0.53; p < 0.001). However, in subjects with irregular CPAP (<4 h/night), this effect was not observed (-0.22; 95%CI, from -2.24 to 1.80; p = 0.83). There were no intervention-related changes in BMI in both regular and irregular CPAP. Our analysis showed that 8 to 24 weeks of effective CPAP could significantly improve HOMA-IR in non-diabetic patients with moderate to severe obstructive sleep apnea, while no significant changes in BMI were detected. Further large scale, randomized and controlled trials are needed to evaluate the longer treatment and its possible effects on weight control and cardiovascular disease. PMID- 22492706 TI - Extensive terminal and asymmetric processing of small RNAs from rRNAs, snoRNAs, snRNAs, and tRNAs. AB - Deep sequencing studies frequently identify small RNA fragments of abundant RNAs. These fragments are thought to represent degradation products of their precursors. Using sequencing, computational analysis, and sensitive northern blot assays, we show that constitutively expressed non-coding RNAs such as tRNAs, snoRNAs, rRNAs and snRNAs preferentially produce small 5' and 3' end fragments. Similar to that of microRNA processing, these terminal fragments are generated in an asymmetric manner that predominantly favors either the 5' or 3' end. Terminal specific and asymmetric processing of these small RNAs occurs in both mouse and human cells. In addition to the known processing of some 3' terminal tRNA-derived fragments (tRFs) by the RNase III endonuclease Dicer, we show that several RNase family members can produce tRFs, including Angiogenin that cleaves the TpsiC loop to generate 3' tRFs. The 3' terminal tRFs but not the 5' tRFs are highly complementary to human endogenous retroviral sequences in the genome. Despite their independence from Dicer processing, these tRFs associate with Ago2 and are capable of down regulating target genes by transcript cleavage in vitro. We suggest that endogenous 3' tRFs have a role in regulating the unwarranted expression of endogenous viruses through the RNA interference pathway. PMID- 22492707 TI - Rad51 presynaptic filament stabilization function of the mouse Swi5-Sfr1 heterodimeric complex. AB - Homologous recombination (HR) represents a major error-free pathway to eliminate pre-carcinogenic chromosomal lesions. The DNA strand invasion reaction in HR is mediated by a helical filament of the Rad51 recombinase assembled on single stranded DNA that is derived from the nucleolytic processing of the primary lesion. Recent studies have found that the human and mouse Swi5 and Sfr1 proteins form a complex that influences Rad51-mediated HR in cells. Here, we provide biophysical evidence that the mouse Swi5-Sfr1 complex has a 1:1 stoichiometry. Importantly, the Swi5-Sfr1 complex, but neither Swi5 nor Sfr1 alone, physically interacts with Rad51 and stimulates Rad51-mediated homologous DNA pairing. This stimulatory effect stems from the stabilization of the Rad51-ssDNA presynaptic filament. Moreover, we provide evidence that the RSfp (rodent Sfr1 proline rich) motif in Sfr1 serves as a negative regulatory element. These results thus reveal an evolutionarily conserved function in the Swi5-Sfr1 complex and furnish valuable information as to the regulatory role of the RSfp motif that is specific to the mammalian Sfr1 orthologs. PMID- 22492708 TI - Chimeric piggyBac transposases for genomic targeting in human cells. AB - Integrating vectors such as viruses and transposons insert transgenes semi randomly and can potentially disrupt or deregulate genes. For these techniques to be of therapeutic value, a method for controlling the precise location of insertion is required. The piggyBac (PB) transposase is an efficient gene transfer vector active in a variety of cell types and proven to be amenable to modification. Here we present the design and validation of chimeric PB proteins fused to the Gal4 DNA binding domain with the ability to target transgenes to pre determined sites. Upstream activating sequence (UAS) Gal4 recognition sites harbored on recipient plasmids were preferentially targeted by the chimeric Gal4 PB transposase in human cells. To analyze the ability of these PB fusion proteins to target chromosomal locations, UAS sites were randomly integrated throughout the genome using the Sleeping Beauty transposon. Both N- and C-terminal Gal4-PB fusion proteins but not native PB were capable of targeting transposition nearby these introduced sites. A genome-wide integration analysis revealed the ability of our fusion constructs to bias 24% of integrations near endogenous Gal4 recognition sequences. This work provides a powerful approach to enhance the properties of the PB system for applications such as genetic engineering and gene therapy. PMID- 22492709 TI - Genome-wide analysis of EGR2/SOX10 binding in myelinating peripheral nerve. AB - Myelin is essential for the rapidity of saltatory nerve conduction, and also provides trophic support for axons to prevent axonal degeneration. Two critical determinants of myelination are SOX10 and EGR2/KROX20. SOX10 is required for specification of Schwann cells from neural crest, and is required at every stage of Schwann cell development. Egr2/Krox20 expression is activated by axonal signals in myelinating Schwann cells, and is required for cell cycle arrest and myelin formation. To elucidate the integrated function of these two transcription factors during peripheral nerve myelination, we performed in vivo ChIP-Seq analysis of myelinating peripheral nerve. Integration of these binding data with loss-of-function array data identified a range of genes regulated by these factors. In addition, although SOX10 itself regulates Egr2/Krox20 expression, leading to coordinate activation of several major myelin genes by the two factors, there is a large subset of genes that are activated independent of EGR2. Finally, the results identify a set of SOX10-dependent genes that are expressed in early Schwann cell development, but become subsequently repressed by EGR2/KROX20. PMID- 22492710 TI - Non-specific binding of Na+ and Mg2+ to RNA determined by force spectroscopy methods. AB - RNA duplex stability depends strongly on ionic conditions, and inside cells RNAs are exposed to both monovalent and multivalent ions. Despite recent advances, we do not have general methods to quantitatively account for the effects of monovalent and multivalent ions on RNA stability, and the thermodynamic parameters for secondary structure prediction have only been derived at 1M [Na(+)]. Here, by mechanically unfolding and folding a 20 bp RNA hairpin using optical tweezers, we study the RNA thermodynamics and kinetics at different monovalent and mixed monovalent/Mg(2+) salt conditions. We measure the unfolding and folding rupture forces and apply Kramers theory to extract accurate information about the hairpin free energy landscape under tension at a wide range of ionic conditions. We obtain non-specific corrections for the free energy of formation of the RNA hairpin and measure how the distance of the transition state to the folded state changes with force and ionic strength. We experimentally validate the Tightly Bound Ion model and obtain values for the persistence length of ssRNA. Finally, we test the approximate rule by which the non-specific binding affinity of divalent cations at a given concentration is equivalent to that of monovalent cations taken at 100-fold concentration for small molecular constructs. PMID- 22492711 TI - An analysis of substitution, deletion and insertion mutations in cancer genes. AB - Cancer-associated mutations in cancer genes constitute a diverse set of mutations associated with the disease. To gain insight into features of the set, substitution, deletion and insertion mutations were analysed at the nucleotide level, from the COSMIC database. The most frequent substitutions were c -> t, g > a, g -> t, and the most frequent codon changes were to termination codons. Deletions more than insertions, FS (frameshift) indels more than I-F (in-frame) ones, and single-nucleotide indels, were frequent. FS indels cause loss of significant fractions of proteins. The 5'-cut in FS deletions, and 5'-ligation in FS insertions, often occur between pairs of identical bases. Interestingly, the cut-site and 3'-ligation in insertions, and 3'-cut and join-pair in deletions, were each found to be the same significantly often (p < 0.001). It is suggested that these features aid the incorporation of indel mutations. Tumor suppressors undergo larger numbers of mutations, especially disruptive ones, over the entire protein length, to inactivate two alleles. Proto-oncogenes undergo fewer, less disruptive mutations, in selected protein regions, to activate a single allele. Finally, catalogues, in ranked order, of genes mutated in each cancer, and cancers in which each gene is mutated, were created. The study highlights the nucleotide level preferences and disruptive nature of cancer mutations. PMID- 22492712 TI - Combinatorial targeting of ribbon-helix-helix artificial transcription factors to chimeric recognition sites. AB - Artificial transcription factors (ATFs) are potent synthetic biology tools for modulating endogenous gene expression and precision genome editing. The ribbon helix-helix (RHH) superfamily of transcription factors are widespread in bacteria and archaea. The principal DNA binding determinant in this family comprises a two stranded antiparallel beta-sheet (ribbons) in which a pair of eight-residue motifs insert into the major groove. Here, we demonstrate that ribbons of divergent RHH proteins are compact and portable elements that can be grafted into a common alpha-helical scaffold producing active ATFs. Hybrid proteins cooperatively recognize DNA sites possessing core tetramer boxes whose functional spacing is dictated by interactions between the alpha-helical backbones. These interactions also promote combinatorial binding of chimeras with different transplanted ribbons, but identical backbones, to synthetic sites bearing cognate boxes for each protein either in vitro or in vivo. The composite assembly of interacting hybrid proteins offers potential advantages associated with combinatorial approaches to DNA recognition compared with ATFs that involve binding of a single protein. Moreover, the new class of RHH ATFs may be utilized to re-engineer transcriptional circuits, or may be enhanced with affinity tags, fluorescent moieties or other elements for targeted genome marking and manipulation in bacteria and archaea. PMID- 22492713 TI - Poly(2-acrylamido-2-methylpropanesulfonic acid) gel induces articular cartilage regeneration in vivo: comparisons of the induction ability between single- and double-network gels. AB - The purpose of this study was to determine the in vivo cartilage induction effect of the poly(2-acrylamido-2-methylpropanesulfonic acid) (PAMPS) single-network (SN) gel and poly(N,N'-dimethyl acrylamide) (PDMAAm) SN gel in comparison with that of the PAMPS/PDMAAm double-network (DN) gel. An osteochondral defect created in rabbit trochlea was treated with PAMPS/PDMAAm DN, PAMPS SN, or PDMAAm SN gel implantation or left untreated. The gel was implanted into the defect so that a 2 mm depth remained. The defects were examined by histologic and immunohistochemical evaluations, surface assessment using confocal laser scanning microscopy, and real-time polymerase chain reaction analysis at 4 weeks. Samples were quantitatively evaluated with a scoring system reported by Wayne et al. The PAMPS/PDMAAm DN gel-implanted defect was filled with the hyaline-like cartilage tissue. The PAMPS SN gel-implanted defect was filled inhomogenously with hyaline/fibrocartilage tissue. The histology score of the defect treated with PAMPS/PDMAAm DN gel was significantly higher than those treated with PAMPS and PDMAAm SN gels, and the untreated defect (p = 0.0408, p < 0.0001, and p < 0.0001, respectively) and the scores of the defect treated with PAMPS SN gel were significantly higher than those treated with PDMAAm SN gel and the untreated defect (p = 0.0026 and p = 0.0026, respectively). These results suggested that the PAMPS SN gel has an ability that can induce hyaline cartilage regeneration in vivo, but that the PDMAAm SN gel does not. The current study indicates that the chondrogenic potential of a negatively charged PAMPS gel component plays an important role in the cartilage regeneration ability of the PAMPS/PDMAAm DN gel in vivo. PMID- 22492714 TI - Thiotepa and melphalan based single, tandem, and triple high dose therapy and autologous stem cell transplantation for high risk neuroblastoma. AB - BACKGROUND: Outcome of high risk neuroblastoma (NBL) remains unsatisfactory in spite of intensive treatment efforts. Consolidation with high-dose (HD) chemotherapy and autologous stem cell transplantation (ASCT) has been intensified with tandem and triple cycles with promising results. Our purpose was to improve the outcome with two or three HD-consolidations. METHODS: Thirty six children with high risk NBL, diagnosed 1995-2010, had intensive induction and surgery, and were stratified to single, tandem or triple HD-therapy and ASCT, followed by local irradiation and cis-retinoic acid. In inoperable patients surgery was facilitated by preoperative HD-melphalan. Long-term outcome of our old cohort from 1987-1994 was updated. RESULTS: Ten year event-free survival (EFS) from diagnosis was 0.44+/-0.10 of the old and 0.43+/-0.085 of the new cohort. EFS from the last ASCT was 0.53 +/-0.12 and 0.48+/-0.091, respectively. Preoperative HD melphalan rendered 73% of bulky primaries operable in the new cohort. The 5-yr EFS from ASCT was 0.46+/-0.15 for single and 0.73+/-0.15 for tandem ASCT (P = 0.19). All triple ASCT patients, selected by poor/slow response, relapsed or died. CONCLUSIONS: Thiotepa- and melphalan based HD regimens, with or without total body irradiation (TBI), appeared to give an outcome comparable to major NBL study groups with acceptable toxicity. Tandem HD therapy gave a 5-year EFS of 73%, whereas a third HD consolidation did not offer any additional advantage for ultra high risk patients with slow response. Pediatr Blood Cancer 2012; 59: 1190 1197. (c) 2012 Wiley Periodicals, Inc. PMID- 22492715 TI - Obesity is associated with activated and insulin resistant immune cells. AB - BACKGROUND: Obesity and type 2 diabetes mellitus are characterized by insulin resistance and 'low-grade inflammation'; however, the pathophysiological link is poorly understood. To determine the relative contribution of obesity and insulin resistance to systemic 'inflammation', this study comprehensively characterized circulating immune cells in different grades of obesity. METHODS: Immune cell phenotypes and activation status were analysed by flow cytometry cross sectionally in morbidly obese (n = 16, body mass index (BMI) 42.2 +/- 5.4 kg/m2), overweight (n = 13, BMI 27.4 +/- 1.6 kg/m2) and normal weight (n = 12, BMI 22.5 +/- 1.9 kg/m2) subjects. RESULTS: Obese, but not overweight subjects, had increased activation marker expression on neutrophils, monocytes, T-lymphocytes and polarization of T helper cells towards a pro-inflammatory type 1-phenotype (Th1). Th1 numbers correlated positively with the degree of insulin resistance (homeostasis model assessment, p < 0.05). Lymphocytes from obese subjects showed reduced insulin-stimulated AKT-phosphorylation in vitro. Supra-physiological insulin concentrations did not affect T-cell differentiation, which under normal circumstances would promote an anti-inflammatory T helper type 2-phenotype. CONCLUSIONS: These results show that morbid obesity is characterized by circulating immune cells that are activated and insulin resistant, with the T cell balance polarized towards a pro-inflammatory Th1 phenotype. The loss of insulin-induced suppression of inflammatory phenotypes in circulating immune cells could contribute to the systemic and adipose tissue inflammation found in morbid obesity. PMID- 22492716 TI - Upregulation of anticoagulant proteins, protein S and tissue factor pathway inhibitor, in the mouse myocardium with cardio-specific TNF-alpha overexpression. AB - Heart failure (HF) has been recognized as a hypercoagulable state. However, the natural anticoagulation systems in the failing heart have not been studied. Recent experimental and clinical data have indicated that not only the thrombomodulin (TM)/protein C (PC) pathway but also the protein S (PS)/tissue factor pathway inhibitor (TFPI) system function as potent natural anticoagulants. To investigate the balance between procoagulant and anticoagulant activities in the failing heart, we measured the cardiac expression of tissue factor (TF), type 1 plasminogen activator inhibitor (PAI-1), TM, PC, PS, and TFPI by RT-PCR and/or Western blot analysis in male transgenic (TG) mice with heart-specific overexpression of TNF-alpha. Both procoagulant (TF and PAI-1) and anticoagulant (PS and TFPI) factors were upregulated in the myocardium of 24-wk-old TG (end stage HF) but not in that of 4-wk-old TG (early decompensated HF) compared with the wild-type mice. Both factors were also upregulated in the infarcted myocardium at 3 days after coronary ligation in the wild-type mice. The expression of TM was downregulated in the TG heart, and PC was not detected in the hearts. The transcript levels of PS orphan receptors, Mer and Tyro3, but not Axl, were significantly upregulated in the TG heart. Double immunohistochemical staining revealed that myocardial infiltrating CD3-positive T cells may produce PS in the TG myocardium. In conclusion, the PS/TFPI was upregulated in the myocardium of a different etiological model of HF, thus suggesting a role for the PS/TFPI system in the protection of the failing heart under both inflammatory and hypercoagulable states. PMID- 22492717 TI - Impaired cerebrovascular autoregulation and reduced CO2 reactivity after long duration spaceflight. AB - Long duration habitation on the International Space Station (ISS) is associated with chronic elevations in arterial blood pressure in the brain compared with normal upright posture on Earth and elevated inspired CO(2). Although results from short-duration spaceflights suggested possibly improved cerebrovascular autoregulation, animal models provided evidence of structural and functional changes in cerebral vessels that might negatively impact autoregulation with longer periods in microgravity. Seven astronauts (1 woman) spent 147 +/- 49 days on ISS. Preflight testing (30-60 days before launch) was compared with postflight testing on landing day (n = 4) or the morning 1 (n = 2) or 2 days (n = 1) after return to Earth. Arterial blood pressure at the level of the middle cerebral artery (BP(MCA)) and expired CO(2) were monitored along with transcranial Doppler ultrasound assessment of middle cerebral artery (MCA) blood flow velocity (CBFV). Cerebrovascular resistance index was calculated as (CVRi = BP(MCA)/CBFV). Cerebrovascular autoregulation and CO(2) reactivity were assessed in a supine position from an autoregressive moving average (ARMA) model of data obtained during a test where two breaths of 10% CO(2) were given four times during a 5-min period. CBFV and Doppler pulsatility index were reduced during -20 mmHg lower body negative pressure, with no differences pre- to postflight. The postflight indicator of dynamic autoregulation from the ARMA model revealed reduced gain for the CVRi response to BP(MCA) (P = 0.017). The postflight responses to CO(2) were reduced for CBFV (P = 0.056) and CVRi (P = 0.047). These results indicate that long duration missions on the ISS impaired dynamic cerebrovascular autoregulation and reduced cerebrovascular CO(2) reactivity. PMID- 22492718 TI - Dietary obesity increases NO and inhibits BKCa-mediated, endothelium-dependent dilation in rat cremaster muscle artery: association with caveolins and caveolae. AB - Obesity is a risk factor for hypertension and other vascular disease. The aim of this study was to examine the effect of diet-induced obesity on endothelium dependent dilation of rat cremaster muscle arterioles. Male Sprague-Dawley rats (213 +/- 1 g) were fed a cafeteria-style high-fat or control diet for 16-20 wk. Control rats weighed 558 +/- 7 g compared with obese rats 762 +/- 12 g (n = 52 56; P < 0.05). Diet-induced obesity had no effect on acetylcholine (ACh)-induced dilation of isolated, pressurized (70 mmHg) arterioles, but sodium nitroprusside (SNP)-induced vasodilation was enhanced. ACh-induced dilation of arterioles from control rats was abolished by a combination of the K(Ca) blockers apamin, 1-[(2 chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), and iberiotoxin (IBTX; all 0.1 MUmol/l), with no apparent role for nitric oxide (NO). In arterioles from obese rats, however, IBTX had no effect on responses to ACh while the NO synthase (NOS)/guanylate cyclase inhibitors N(omega)-nitro-L-arginine methyl ester (L NAME; 100 MUmol/l)/1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 MUmol/l) partially inhibited ACh-induced dilation. Furthermore, NOS activity (but not endothelial NOS expression) was increased in arteries from obese rats. L-NAME/ODQ alone or removal of the endothelium constricted arterioles from obese but not control rats. Expression of caveolin-1 and -2 oligomers (but not monomers or caveolin-3) was increased in arterioles from obese rats. The number of caveolae was reduced in the endothelium of arteries, and caveolae density was increased at the ends of smooth muscle cells from obese rats. Diet-induced obesity abolished the contribution of large-conductance Ca(2+)-activated K(+) channel to ACh mediated endothelium-dependent dilation of rat cremaster muscle arterioles, while increasing NOS activity and inducing an NO-dependent component. PMID- 22492719 TI - International harmonization of models for selecting less toxic chemical alternatives: Effect of regulatory disparities in the United States and Europe. AB - The desire to reduce human exposure to toxic chemicals associated with consumer products that are marketed globally demands the creation of comparative toxicity assessment tools that are based on uniform thresholds of acceptable risks and guidelines for materials use across international boundaries. The Toxic Potential Indicator (TPI) is a quantitative model based on European Union (EU) regulatory standards for toxicity and environmental quality. Here, we describe a version of TPI that we developed with US regulatory thresholds for environmental and human health impacts of toxic materials. The customized US-based TPI (USTPI) model integrates occupational permissible exposure limits (PELs), carcinogen categories based on the scheme of the International Agency for Research on Cancer (IARC), and median effect concentration for acute aquatic toxicity (EC50s). As a case study, we compare calculated scores for EU-based TPI (EUTPI) and USTPI for a large group of chemicals including 578 substances listed in the US Toxics Release Inventory (TRI). Statistical analyses show that the median difference between USTPI and EUTPI scores do not approximate to zero, implying a general discrepancy in TPI score results. Comparison of chemical ranking with Spearman's correlation coefficient suggests a positive but imperfect rank correlation. Although some discrepancies between EUTPI and USTPI may be explained by missing toxicity information in some regulatory categories, disparities between the 2 models are associated mostly with different input parameters, i.e., different regulatory thresholds and guidelines. These results demonstrate that regional differences in regulatory thresholds for material toxicity may compromise the ideals of international agreements, such as the Globally Harmonized System (GHS) of Classification and Labeling of Chemicals, and emphasis needs to be placed on eliminating inconsistencies in hazard assessment frameworks for substances. PMID- 22492720 TI - Birth weight in newborn infants with different diabetes-associated HLA genotypes in three neighbouring countries: Finland, Estonia and Russian Karelia. AB - BACKGROUND: Human leukocyte antigen (HLA) genotypes associated with increased risk for type 1 diabetes mellitus (T1D) have been reported to be associated with increased birth weight. We set out to investigate the association between HLA haplotypes conferring risk for T1D and birth weight and search for possible differences in the strength of these associations among populations with contrasting incidence of T1D. METHODS: As a part of the EU-funded DIABIMMUNE study, genotyping for the HLA haplotypes associated with T1D was performed in 8369 newborn infants from Estonia, Finland and Russian Karelia. Infants born before 35 gestational weeks, from mothers with diabetes, and multiple pregnancies were excluded. Relative birth weight, expressed in standard deviation scores, was estimated for each gestational week, sex and country. The standard deviation scores were calculated internally using the actual population studied. According to their HLA haplotypes, participants were divided into risk groups, and the distribution of birth weight between quartiles was analysed. RESULTS: We did not find any direct association between various HLA risk-associated genotypes (HLA DR3-DQ2/DR4-DQ8, DR3-DQ2/X or DR4-DQ8/X) and birth weight. We observed a significant relationship between increased relative birth weight and the protective HLA-DR2-DQ6 and DR13-DQ6 haplotypes. This association was significant only when these haplotypes were found together with the DR4-DQ8 haplotype. CONCLUSIONS: The previously reported association between HLA-risk haplotypes for T1D and an increased birth weight was not confirmed. This suggests that the mechanisms behind the association between high birth weight and risk for T1D may be not directly HLA related. PMID- 22492721 TI - Human RNF169 is a negative regulator of the ubiquitin-dependent response to DNA double-strand breaks. AB - Nonproteolytic ubiquitylation of chromatin surrounding deoxyribonucleic acid double-strand breaks (DSBs), mediated by the RNF8/RNF168 ubiquitin ligases, plays a key role in recruiting repair factors, including 53BP1 and BRCA1, to reestablish genome integrity. In this paper, we show that human RNF169, an uncharacterized E3 ubiquitin ligase paralogous to RNF168, accumulated in DSB repair foci through recognition of RNF168-catalyzed ubiquitylation products by its motif interacting with ubiquitin domain. Unexpectedly, RNF169 was dispensable for chromatin ubiquitylation and ubiquitin-dependent accumulation of repair factors at DSB sites. Instead, RNF169 functionally competed with 53BP1 and RAP80 BRCA1 for association with RNF168-modified chromatin independent of its catalytic activity, limiting the magnitude of their recruitment to DSB sites. By delaying accumulation of 53BP1 and RAP80 at damaged chromatin, RNF169 stimulated homologous recombination and restrained nonhomologous end joining, affecting cell survival after DSB infliction. Our results show that RNF169 functions in a noncanonical fashion to harness RNF168-mediated protein recruitment to DSB containing chromatin, thereby contributing to regulation of DSB repair pathway utilization. PMID- 22492722 TI - Dendritic position is a major determinant of presynaptic strength. AB - Different regulatory principles influence synaptic coupling between neurons, including positional principles. In dendrites of pyramidal neurons, postsynaptic sensitivity depends on synapse location, with distal synapses having the highest gain. In this paper, we investigate whether similar rules exist for presynaptic terminals in mixed networks of pyramidal and dentate gyrus (DG) neurons. Unexpectedly, distal synapses had the lowest staining intensities for vesicular proteins vGlut, vGAT, Synaptotagmin, and VAMP and for many nonvesicular proteins, including Bassoon, Munc18, and Syntaxin. Concomitantly, distal synapses displayed less vesicle release upon stimulation. This dependence of presynaptic strength on dendritic position persisted after chronically blocking action potential firing and postsynaptic receptors but was markedly reduced on DG dendrites compared with pyramidal dendrites. These data reveal a novel rule, independent of neuronal activity, which regulates presynaptic strength according to dendritic position, with the strongest terminals closest to the soma. This gradient is opposite to postsynaptic gradients observed in pyramidal dendrites, and different cell types apply this rule to a different extent. PMID- 22492723 TI - BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex. AB - MicroRNAs (miRNAs) are noncoding RNAs that function as key posttranscriptional regulators of gene expression. miRNA maturation is controlled by the DROSHA microprocessor complex. However, the detailed mechanism of miRNA biogenesis remains unclear. We show that the tumor suppressor breast cancer 1 (BRCA1) accelerates the processing of miRNA primary transcripts. BRCA1 increased the expressions of both precursor and mature forms of let-7a-1, miR-16-1, miR-145, and miR-34a. In addition, this tumor suppressor was shown to be directly associated with DROSHA and DDX5 of the DROSHA microprocessor complex, and it interacted with Smad3, p53, and DHX9 RNA helicase. We also found that BRCA1 recognizes the RNA secondary structure and directly binds with primary transcripts of miRNAs via a DNA-binding domain. Together, these results suggest that BRCA1 regulates miRNA biogenesis via the DROSHA microprocessor complex and Smad3/p53/DHX9. Our findings also indicate novel functions of BRCA1 in miRNA biogenesis, which may be linked to its tumor suppressor mechanism and maintenance of genomic stability. PMID- 22492724 TI - DDB2 promotes chromatin decondensation at UV-induced DNA damage. AB - Nucleotide excision repair (NER) is the principal pathway that removes helix distorting deoxyribonucleic acid (DNA) damage from the mammalian genome. Recognition of DNA lesions by xeroderma pigmentosum group C (XPC) protein in chromatin is stimulated by the damaged DNA-binding protein 2 (DDB2), which is part of a CUL4A-RING ubiquitin ligase (CRL4) complex. In this paper, we report a new function of DDB2 in modulating chromatin structure at DNA lesions. We show that DDB2 elicits unfolding of large-scale chromatin structure independently of the CRL4 ubiquitin ligase complex. Our data reveal a marked adenosine triphosphate (ATP)-dependent reduction in the density of core histones in chromatin containing UV-induced DNA lesions, which strictly required functional DDB2 and involved the activity of poly(adenosine diphosphate [ADP]-ribose) polymerase 1. Finally, we show that lesion recognition by XPC, but not DDB2, was strongly reduced in ATP-depleted cells and was regulated by the steady-state levels of poly(ADP-ribose) chains. PMID- 22492725 TI - MCAK activity at microtubule tips regulates spindle microtubule length to promote robust kinetochore attachment. AB - Mitotic centromere-associated kinesin (MCAK) is a microtubule-depolymerizing kinesin-13 member that can track with polymerizing microtubule tips (hereafter referred to as tip tracking) during both interphase and mitosis. MCAK tracks with microtubule tips by binding to end-binding proteins (EBs) through the microtubule tip localization signal SKIP, which lies N terminal to MCAK's neck and motor domain. The functional significance of MCAK's tip-tracking behavior during mitosis has never been explained. In this paper, we identify and define a mitotic function specific to the microtubule tip-associated population of MCAK: negative regulation of microtubule length within the assembling bipolar spindle. This function depends on MCAK's ability to bind EBs and track with polymerizing nonkinetochore microtubule tips. Although this activity antagonizes centrosome separation during bipolarization, it ultimately benefits the dividing cell by promoting robust kinetochore attachments to the spindle microtubules. PMID- 22492726 TI - The Arp2/3 complex is required for lamellipodia extension and directional fibroblast cell migration. AB - The Arp2/3 complex nucleates the formation of the dendritic actin network at the leading edge of motile cells, but it is still unclear if the Arp2/3 complex plays a critical role in lamellipodia protrusion and cell motility. Here, we differentiated motile fibroblast cells from isogenic mouse embryonic stem cells with or without disruption of the ARPC3 gene, which encodes the p21 subunit of the Arp2/3 complex. ARPC3(-/-) fibroblasts were unable to extend lamellipodia but generated dynamic leading edges composed primarily of filopodia-like protrusions, with formin proteins (mDia1 and mDia2) concentrated near their tips. The speed of cell migration, as well as the rates of leading edge protrusion and retraction, were comparable between genotypes; however, ARPC3(-/-) cells exhibited a strong defect in persistent directional migration. This deficiency correlated with a lack of coordination of the protrusive activities at the leading edge of ARPC3(-/ ) fibroblasts. These results provide insights into the Arp2/3 complex's critical role in lamellipodia extension and directional fibroblast migration. PMID- 22492727 TI - SNX17 protects integrins from degradation by sorting between lysosomal and recycling pathways. AB - The FERM-like domain-containing sorting nexins of the SNX17/SNX27/SNX31 family have been proposed to mediate retrieval of transmembrane proteins from the lysosomal pathway. In this paper, we describe a stable isotope labeling with amino acids in culture-based quantitative proteomic approach that allows an unbiased, global identification of transmembrane cargoes that are rescued from lysosomal degradation by SNX17. This screen revealed that several integrins required SNX17 for their stability, as depletion of SNX17 led to a loss of beta1 and beta5 integrins and associated a subunits from HeLa cells as a result of increased lysosomal degradation. SNX17 bound to the membrane distal NPXY motif in beta integrin cytoplasmic tails, thereby preventing lysosomal degradation of beta integrins and their associated a subunits. Furthermore, SNX17-dependent retrieval of integrins did not depend on the retromer complex. Consistent with an effect on integrin recycling, depletion of SNX17 also caused alterations in cell migration. Our data provide mechanistic insight into the retrieval of internalized integrins from the lysosomal degradation pathway, a prerequisite for subsequent recycling of these matrix receptors. PMID- 22492728 TI - Co-occurrence of 1,4-dioxane with trichloroethylene in chlorinated solvent groundwater plumes at US Air Force installations: Fact or fiction. AB - Increasing regulatory attention to 1,4-dioxane has prompted the United States Air Force (USAF) to evaluate potential environmental liabilities, primarily associated with legacy contamination, at an enterprise scale. Although accurately quantifying environmental liability is operationally difficult given limited historic environmental monitoring data, 1,4-dioxane is a known constituent (i.e., stabilizer) of chlorinated solvents, in particular 1,1,1-trichloroethane (TCA). Evidence regarding the co-occurrence of 1,4-dioxane and trichloroethylene (TCE), however, has been heavily debated. In fact, the prevailing opinion is that 1,4 dioxane was not a constituent of past TCE formulations and, therefore, these 2 contaminants would not likely co-occur in the same groundwater plume. Because historic handling, storage, and disposal practices of chlorinated solvents have resulted in widespread groundwater contamination at USAF installations, significant potential exists for unidentified 1,4-dioxane contamination. Therefore, the objective of this investigation is to determine the extent to which 1,4-dioxane co-occurs with TCE compared to TCA, and if these chemicals are co-contaminants, whether or not there is significant correlation using available monitoring data. To accomplish these objectives, the USAF Environmental Restoration Program Information Management System (ERPIMS) was queried for all relevant records for groundwater monitoring wells (GMWs) with 1,4-dioxane, TCA, and TCE, on which both categorical and quantitative analyses were carried out. Overall, ERPIMS contained 5788 GMWs from 49 installations with records for 1,4 dioxane, TCE, and TCA analytes. 1,4-Dioxane was observed in 17.4% of the GMWs with detections for TCE and/or TCA, which accounted for 93.7% of all 1,4-dioxane detections, verifying that 1,4-dioxane is seldom found independent of chlorinated solvent contamination. Surprisingly, 64.4% of all 1,4-dioxane detections were associated with TCE independently. Given the extensive data set, these results conclusively demonstrate for the first time that 1,4-dioxane is a relatively common groundwater co-contaminant with TCE. Trend analysis demonstrated a positive log-linear relationship where median 1,4-dioxane levels increased between approximately 6% and approximately 20% of the increase in TCE levels. In conclusion, this data mining exercise suggests that 1,4-dioxane has a probability of co-occurrence of approximately 17% with either TCE and/or TCA. Given the challenges imposed by remediation of 1,4-dioxane and the pending promulgation of a federal regulatory standard, environmental project managers should use the information presented in this article for prioritization of future characterization efforts to respond to the emerging issue. Importantly, site investigations should consider 1,4-dioxane a potential co-contaminant of TCE in groundwater plumes. PMID- 22492729 TI - Cardiovascular molecular imaging: the road ahead. AB - Despite significant advancements in medical and device-based therapies, cardiovascular disease remains the number one cause of death in the United States. Early detection of atherosclerosis, prevention of myocardial infarction and sudden cardiac death, and modulation of adverse ventricular remodeling still remain elusive goals. Molecular imaging focuses on identifying critical cellular and molecular targets and therefore plays an integral role in understanding these biologic processes in vivo. Because many imaging targets are upregulated before irreversible tissue damage occurs, early detection could ultimately lead to development of novel, preventive therapeutic strategies. This review addresses recent work on radionuclide imaging of cardiovascular inflammation, infection, and infarct healing. We further discuss opportunities provided by multimodality approaches such as PET/MRI and PET/optical imaging. PMID- 22492730 TI - In vivo dopamine transporter imaging in a unilateral 6-hydroxydopamine rat model of Parkinson disease using 11C-methylphenidate PET. AB - Dopamine transporter (DAT) function is altered by many neurodegenerative diseases. For instance, in Parkinson disease DAT density has been shown to decrease in early disease and to play a role in the occurrence of motor complications. DAT is thus an important imaging target with potential therapeutic relevance in humans and animal models of disease. The PET DAT marker (11)C methylphenidate is commonly used to quantify DAT function. Here we investigate the characteristics of the (11)C-methylphenidate-derived quantification of DAT in rodents using the 6-hydroxydopamine Parkinson disease rat model. METHODS: Seven unilaterally 6-hydroxydopamine-lesioned rats (dopaminergic denervation [DD] range, 36%-94%) were injected with 3.7 MBq/100 g of body weight and tracer masses ranging from 93.8 to 0.0041 MUg/100 g of body weight. We evaluated the maximum available transporter density and the in vivo (apparent) ligand-transporter dissociation constant (B(max) and K app d, respectively) with an in vivo Scatchard method using several modeling approaches and estimated the transporter occupancy as a function of the amount of tracer injected and tracer specific activity (SA). RESULTS: Strong evidence of different nonspecific binding in the striatal region, compared with the reference region, leading to bias in the estimate of DD severity was found. One percent transporter occupancy was reached with 0.14 MUg of tracer/100 g of body weight, corresponding to an SA of 5.7 kBq/pmol for the given radioactivity dose, and 10% occupancy was reached at 1.5 MUg of tracer/100 g of body weight, corresponding to an SA of 0.57 kBq/pmol. The 6-hydroxydopamine lesion affected B(max) (control, 402 +/- 94 pmol/mL; lesioned, 117 +/- 120 pmol/mL; P = 0.003) but not K app d (control, 331 +/- 63 pmol/mL; lesioned, 362 +/- 119 pmol/mL; P = 0.63). CONCLUSION: Although DAT imaging can be performed at a relatively high mass of (11)C-methylphenidate (low SA), the additional nonspecific binding found in the striatum can introduce a DD severity dependent bias in the estimate of tissue-derived binding potential and care must be taken in comparing (11)C-methylphenidate-derived assessment of DD with that obtained using other dopaminergic tracers. PMID- 22492731 TI - Transient ischemic dilation ratio in 82Rb PET myocardial perfusion imaging: normal values and significance as a diagnostic and prognostic marker. AB - In myocardial perfusion SPECT, transient ischemic dilation ratio (TID) is a well established marker of severe ischemia and adverse outcome. However, its role in the setting of (82)Rb PET is less well defined. METHODS: We analyzed 265 subjects who underwent clinical rest-dipyridamole (82)Rb PET/CT. Sixty-two subjects without a prior history of cardiac disease and with a normal myocardial perfusion study had either a low or a very low pretest likelihood of coronary artery disease or negative CT angiography. These subjects were used to establish a reference range of TID. In the remaining 203 patients with an intermediate or high pretest likelihood, subgroups with normal and abnormal TID were established and compared with respect to clinical variables, perfusion defect scores, left ventricular function, and absolute myocardial flow reserve. Follow-up was obtained for 969 +/- 328 d to determine mortality by review of the social security death index. RESULTS: In the reference group, TID ratio was 0.98 +/- 0.06. Accordingly, a threshold for abnormal TID was set at greater than 1.13 (0.98 + 2.5 SDs). In the study group, 19 of 203 patients (9%) had an elevated TID ratio. Significant differences between subgroups with normal and abnormal TID ratio were observed for ejection fraction reserve (5.0 +/- 6.4 vs. 1.8 +/- 7.9; P < 0.05), difference between end-systolic volume (ESV) at rest and stress (DeltaESV[stress-rest]; 1.8 +/- 7.4 vs. 12.3 +/- 13.0 mL; P < 0.0001), difference between end-diastolic volume (EDV) at rest and stress (DeltaEDV[stress-rest]; 10.8 +/- 11.5 vs. 23.8 +/- 14.6 mL; P < 0.0001), summed rest score (1.8 +/- 3.8 vs. 3.8 +/- 7.6; P < 0.05), summed stress score (3.0 +/- 5.4 vs. 7.5 +/- 9.8; P < 0.002), summed difference score (1.3 +/- 2.6 vs. 3.7 +/- 5.3; P < 0.02), and global myocardial flow reserve (2.1 +/- 0.8 vs. 1.7 +/- 0.6; P < 0.02). Additionally, TID-positive patients had a significantly lower overall survival probability (P < 0.05). In a subgroup analysis of patients without regional perfusion abnormalities, TID-positive patients' overall survival probability was significantly smaller (P < 0.03), and TID was an independent predictor (exponentiation of the B coefficients [Exp(b)] = 6.22; P < 0.009) together with an ejection fraction below 45% (Exp[b] = 6.16; P < 0.002). CONCLUSION: The present study suggests a reference range of TID for (82)Rb PET myocardial perfusion imaging that is in the range of previously established values for SPECT. Abnormal TID in (82)Rb PET is associated with more extensive left ventricular dysfunction, ischemic compromise, and reduced global flow reserve. Preliminary outcome analysis suggests that TID-positive subjects have a lower overall survival probability. PMID- 22492732 TI - 18F-FDG metabolic tumor volume and total glycolytic activity of oral cavity and oropharyngeal squamous cell cancer: adding value to clinical staging. AB - (18)F-FDG metabolic tumor volume (MTV) and total glycolytic activity (TGA) have been proposed as potential prognostic imaging markers for patient outcome in human solid tumors. The purpose of this study was to establish whether MTV and TGA add prognostic information to clinical staging in patients with oral and oropharyngeal squamous cell carcinomas (SCCs). METHODS: The Institutional Review Board approved this Health Insurance Portability and Accountability Act-compliant single-institution retrospective study. Forty-five patients with histologically proven oral or oropharyngeal SCC underwent PET/CT for initial cancer staging and were included in the study. MTV was measured using a gradient-based method (PET Edge) and fixed-threshold methods at 38%, 50%, and 60% of maximum standardized uptake value (SUV). The TGA is defined as MTV * mean SUV. Bland-Altman analysis was used to establish the reliability of the methods of segmentation. Outcome endpoints were overall survival (OS) and progression-free survival. Cox proportional hazards univariate and multivariate regression analyses were performed. RESULTS: In Cox regression models, MTV and TGA were the only factors significantly associated with survival outcome after adjusting for all other covariates including American Joint Committee on Cancer (AJCC) stage, with hazards ratio of 1.06 (95% confidence interval, 1.01-1.10; P = 0.006) and 1.00 (95% confidence interval, 1.00-1.01; P = 0.02). The model fit was significantly better when MTV was added to AJCC stage in model I (chi(2) value change, 1.16 6.71; P = 0.01) and when TGA was added to AJCC stage in model II (chi(2) value change, 1.16-4.37; P = 0.04). The median cutoff point of 7.7 mL for primary tumor MTV was predictive of time to OS (log rank P = 0.04). The median cutoff point of 55 g for PET Edge primary tumor TGA was predictive of time to OS (log rank P = 0.08), though the result was not statistically significant. CONCLUSION: Gradient based segmentations of primary tumor MTV and TGA are potential (18)F-FDG markers for time to survival in patients with oral and oropharyngeal SCC and may provide prognostic information in addition to AJCC stage. These exploratory imaging markers need validation in larger cohort studies. PMID- 22492733 TI - Oxygen breathing affects 3'-deoxy-3'-18F-fluorothymidine uptake in mouse models of arthritis and cancer. AB - Noninvasive in vivo imaging of biologic processes using PET is an important tool in preclinical studies. We observed significant differences in 3'-deoxy-3'-(18)F fluorothymidine ((18)F-FLT) uptake in arthritic ankles and carcinomas between dynamic and static PET measurements when mice breathed oxygen. Thus, we suspected that air or oxygen breathing and the anesthesia protocol might influence (18)F FLT tracer uptake. METHODS: We injected arthritic, healthy, and CT26 colon carcinoma-bearing mice with (18)F-FLT before static or dynamic small-animal PET measurements. The spontaneously oxygen- or air-breathing mice were kept conscious or anesthetized with ketamine and xylazine during (18)F-FLT uptake before the 10 min static PET measurements. For dynamic PET scans, mice were anesthetized during the entire measurement. (18)F-FLT uptake was reported in percentage injected dose per cubed centimeter by drawing regions of interest around ankles, carcinomas, and muscle tissue. Additionally, venous blood samples were collected before (18)F FLT injection and after PET measurement to analyze pH, carbon dioxide partial pressure (pCO(2)), and lactate values. RESULTS: A significantly reduced (18)F-FLT uptake was measured in arthritic ankles and in CT26 colon carcinomas when the mice breathed oxygen and were conscious during tracer uptake, compared with mice that were anesthetized during (18)F-FLT uptake. Breathing air completely abolished this phenomenon. Analysis of blood samples that were obtained from the mice before (18)F-FLT injection and after the PET scan implicated respiratory acidosis that was induced by oxygen breathing and consciousness during tracer uptake. Acidosis was found to be the primary factor responsible for the reduced (18)F-FLT uptake, as reflected by increased pCO(2) and reduced pH and lactate values. CONCLUSION: Oxygen-breathing conscious mice sustained respiratory acidosis and, consequently, reduced cell proliferation and (18)F-FLT uptake in arthritic ankles and CT26 colon carcinomas. Thus, we suggest the use of air instead of oxygen breathing for (18)F-FLT PET measurements. PMID- 22492735 TI - German battle casualties: the treatment of functional somatic disorders during World War I. AB - World War I witnessed the admission of large numbers of German soldiers with neurological symptoms for which there was no obvious organic cause. This posed a considerable challenge for the military and medical authorities and resulted in an active discussion on the etiology and treatment of these disorders. Current historiography is reliant on published physician accounts, and this represents the first study of treatment approaches based on original case notes. We analyzed patient records from two leading departments of academic psychiatry in Germany, those at Berlin and Jena, in conjunction with the contemporaneous medical literature. Treatment, which can be broadly classified into reward and punishment, suggestion, affective shock, cognitive learning, and physiological methods, was developed in the context of the emerging fields of animal learning and neurophysiology. A further innovative feature was the use of quantitative methods to assess outcomes. These measures showed good response rates, though most cured patients were not sent back to battle because of their presumed psychopathic constitution. While some treatments appear unnecessarily harsh from today's perspective and were also criticized by leading psychiatrists of the time, the concentration of effort and involvement of so many senior doctors led to the development of psychotherapeutic methods that were to influence the field of psychiatric therapy for decades to come. PMID- 22492734 TI - Dissociative changes in the Bmax and KD of dopamine D2/D3 receptors with aging observed in functional subdivisions of the striatum: a revisit with an improved data analysis method. AB - Separate measurements of B(max), the density of available receptors, and K(D), the equilibrium dissociation constant in the human brain, with PET have contributed to our understanding of neuropsychiatric disorders, especially with respect to the dopamine D(2)/D(3) receptor system. However, existing methods have limited applications to the whole striatum, putamen, or caudate nucleus. Improved methods are required to examine B(max) and K(D) in detailed functional striatal subdivisions that are becoming widely used. METHODS: In response, a new method (bolus-plus-infusion transformation [BPIT]) was developed. After completion of a validation study for (11)C-raclopride scans involving 81 subjects, age-associated changes in B(max) and K(D) were examined in 47 healthy subjects ranging in age from 18 to 77 y. RESULTS: The BPIT method was consistent with established reference tissue methods regarding regional binding potential. BPIT yielded time consistent estimates of B(max) and K(D) when scan and infusion lengths were set equal in the analysis. In addition, BPIT was shown to be robust against PET measurement errors when compared with a widely accepted transient equilibrium method. Altogether, BPIT was supported as a method for regional binding potential, B(max), and K(D). We demonstrated age-associated declines in B(max) in all 5 functional striatal subdivisions with BPIT when corrected for multiple comparisons. These age-related effects were not consistently attainable with the transient equilibrium method. Irrespective to methods, K(D) remained unchanged with age. CONCLUSION: The BPIT approach may be useful for understanding dopamine receptor abnormalities in neuropsychiatric disorders by enabling separate measurements of B(max) and K(D) in functional striatal subdivisions. PMID- 22492736 TI - Scientific strategy and ad hoc response: the problem of typhoid in America and England, C. 1910-50. AB - In the early twentieth century, death rates from typhoid in European cities reached an all time low. By contrast, death rates in America were six times as high, and the American public health community began a crusade against the disease in 1912. In the 1920s, hopes for greater control of the disease focused not just on sewers and drinking water supplies, but on the newly established scientific means of immunization, the supervision of food-related pathways of infection, and the management of healthy carriers. The management of carriers, which lay at the core of any typhoid control program, proved an intractable problem, and typhoid remained a public health concern. America and England both struggled with control of the disease during the interwar period. Coming from different starting points, however, their approaches to the problem differed. This paper compares and contrasts these different public health strategies, considers the variable quality of support provided by bacteriological laboratories, and demonstrates that "accidental" typhoid outbreaks continued to happen up to the outbreak of World War II. PMID- 22492737 TI - Kinderheilkunde and continental connections in child health: the "Glasgow school revisited"--again. AB - The last two hundred years or so have seen the transformation of medical practice from a clinical art to the application of science to the diagnosis and treatment of disease. There has been a historical debate about how the use of technology and discoveries of the laboratory have become integrated within medical practice. In trying to understand the evolution of "scientific medicine," this has generally focused on the tensions between the differing cultures, persons, and professions of the "laboratory" and "clinic" and sought to explain how they were resolved within specific institutions. This paper looks again at the "Glasgow School" (the subject of a number of seminal papers on this subject) and the forces that shaped it, by exploring the career of Leonard Findlay, whose training in Glasgow, and in Berlin (where he worked in a department in which science and medicine were integrated), defined a style of clinical medicine that formed the model for a new sort of university department of medicine in which clinicians and scientists worked side by side, albeit under the leadership of the former. As a clinician exposed in Berlin to the emerging new sciences of nutrition, microbiology, and immunology, which were particularly relevant to the care of sick children, Findlay created in Glasgow a department of medical pediatrics, which owed less to local factors, figures, and forces and more to his experience in Germany. PMID- 22492738 TI - Doctors in ancient Greek and Roman rhetorical education. AB - This article collects and examines all references to doctors in rhetorical exercises used in ancient Greek and Roman schools in the Roman Empire. While doctors are sometimes portrayed positively as philanthropic, expert practitioners of their divinely sanctioned art, they are more often depicted as facing charges for poisoning their patients. PMID- 22492739 TI - Olfactory ferric and ferrous iron absorption in iron-deficient rats. AB - The absorption of metals from the nasal cavity to the blood and the brain initiates an important route of occupational exposures leading to health risks. Divalent metal transporter-1 (DMT1) plays a significant role in the absorption of intranasally instilled manganese, but whether iron uptake would be mediated by the same pathway is unknown. In iron-deficient rats, blood (59)Fe levels after intranasal administration of the radioisotope in the ferrous form were significantly higher than those observed for iron-sufficient control rats. Similar results were obtained when ferric iron was instilled intranasally, and blood levels of (59)Fe were even greater in the iron-deficient rats compared with the amount of ferrous iron absorbed. Experiments with Belgrade (b/b) rats showed that DMT1 deficiency limited ferric iron uptake from the nasal cavity to the blood compared with +/b controls matched for iron deficiency. These results indicate that olfactory uptake of ferric iron by iron-deficient rats involves DMT1. Western blot experiments confirmed that DMT1 levels are significantly higher in iron-deficient rats compared with iron-sufficient controls in olfactory tissue. Thus the molecular mechanism of olfactory iron absorption is regulated by body iron status and involves DMT1. PMID- 22492740 TI - The CFTR and ENaC debate: how important is ENaC in CF lung disease? AB - Cystic fibrosis (CF) is caused by the loss of the cystic fibrosis transmembrane conductance regulator (CFTR) function and results in a respiratory phenotype that is characterized by dehydrated mucus and bacterial infections that affect CF patients throughout their lives. Much of the morbidity and mortality in CF results from a failure to clear bacteria from the lungs. What causes the defect in the bacterial clearance in the CF lung has been the subject of an ongoing debate. Here we discuss the arguments for and against the role of the epithelial sodium channel, ENaC, in the development of CF lung disease. PMID- 22492741 TI - Severe phenotype in MPS II patients associated with a large deletion including contiguous genes. AB - Hunter disease or mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disorder caused by the deficiency of iduronate-2-sulfatase, which is involved in the catabolism of the glycosaminoglycans (GAGs) heparan and dermatan sulphate. Our aim was to analyze three patients with severe Hunter syndrome that showed a total deletion of the iduronate-2-sulphatase (IDS) gene, after exon by exon PCR. DNA was used as a template for PCR synthesis of IDS, FRAXA, FRAXE, and DXS1113 specific amplicons. The DNA analysis for all three patients demonstrated a complete deletion of IDS, FRAXA, and FRAXE contiguous genes. We further performed SNP-array to delineate the deletion breakpoints and to characterize the deletion extension in the different patients. The results indicated a ~9.4 Mb deletion in Patient 1, a ~3.9 Mb deletion of the Xq27.3-Xq28 and a ~3.1 Mb duplication of the X q28 region in Patient 2 and a ~41.8 Kb deletion in Patient 3. SNP-array was shown to be important to map for deletion breakpoints. A comprehensive molecular analysis in patients with Hunter syndrome, especially in the ones presenting the severe form, is important to the understanding of the genetic determinants of the phenotype and for the genetic counseling to be provided to the families. PMID- 22492742 TI - Validation and field evaluation of a competitive enzyme-linked immunosorbent assay for diagnosis of Babesia bovis infections in Argentina. AB - Infections by Babesia bovis limit cattle production and cause important economic losses in tropical and subtropical areas around the world. Monitoring of calf sera can be used to detect unprotected cattle herds and to decide on strategic control measures, as well as for epidemiological studies. Merozoite surface antigen 2c (MSA-2c) is an immunodominant surface protein expressed in B. bovis merozoites and sporozoites and contains B-cell epitopes that are conserved among geographic isolates. A monoclonal antibody against recombinant MSA-2c (rMSA-2c) was previously shown to inhibit the binding of anti-B. bovis antibodies to a parasite B-cell epitope in a competitive enzyme-linked immunosorbent assay (cELISA) format. In the work at hand, the parameters of this cELISA were reevaluated and adjusted when necessary, and a cutoff value was determined by receiver operator characteristic (ROC) curve analysis of a total of 357 bovine sera of known reactivity, as assessed by indirect immunofluorescence assay (IFAT). The established rMSA-2c cELISA demonstrated a specificity of 98% and a sensitivity of 96.2%. An additional set of 303 field bovine sera from regions where ticks are endemic and tick-free regions of Argentina was tested by both rMSA-2c cELISA and IFAT, and the results were shown to be in very good agreement (kappa index, 0.8325). The performance shown by rMSA-2c cELISA in the detection of B. bovis-specific antibodies and its suitability for standardization and large scale production, as well as the possibility of its application in most veterinary diagnostic laboratories, make the assay a powerful tool for the surveillance of herd immunity as a strategic measure for the control of bovine babesiosis. PMID- 22492743 TI - Evaluation of influenza virus A/H3N2 and B vaccines on the basis of cross reactivity of postvaccination human serum antibodies against influenza viruses A/H3N2 and B isolated in MDCK cells and embryonated hen eggs. AB - The vaccine strains against influenza virus A/H3N2 for the 2010-2011 season and influenza virus B for the 2009-2010 and 2010-2011 seasons in Japan are a high growth reassortant A/Victoria/210/2009 (X-187) strain and an egg-adapted B/Brisbane/60/2008 (Victoria lineage) strain, respectively. Hemagglutination inhibition (HI) tests with postinfection ferret antisera indicated that the antisera raised against the X-187 and egg-adapted B/Brisbane/60/2008 vaccine production strains poorly inhibited recent epidemic isolates of MDCK-grown A/H3N2 and B/Victoria lineage viruses, respectively. The low reactivity of the ferret antisera may be attributable to changes in the hemagglutinin (HA) protein of production strains during egg adaptation. To evaluate the efficacy of A/H3N2 and B vaccines, the cross-reactivities of postvaccination human serum antibodies against A/H3N2 and B/Victoria lineage epidemic isolates were assessed by a comparison of the geometric mean titers (GMTs) of HI and neutralization (NT) tests. Serum antibodies elicited by the X-187 vaccine had low cross-reactivity to both MDCK- and egg-grown A/H3N2 isolates by HI test and narrow cross-reactivity by NT test in all age groups. On the other hand, the GMTs to B viruses detected by HI test were below the marginal level, so the cross-reactivity was assessed by NT test. The serum neutralizing antibodies elicited by the B/Brisbane/60/2008 vaccine reacted well with egg-grown B viruses but exhibited remarkably low reactivity to MDCK-grown B viruses. The results of these human serological studies suggest that the influenza A/H3N2 vaccine for the 2010-2011 season and B vaccine for the 2009-2010 and 2010-2011 seasons may possess insufficient efficacy and low efficacy, respectively. PMID- 22492744 TI - Strain-specific neutralizing antibody responses against human cytomegalovirus envelope glycoprotein N. AB - The human cytomegalovirus (HCMV) gM-gN complex is a major target of virus neutralizing activity, and gN subtypes induce strain-specific antibodies. However, the biological significance of HCMV gN polymorphisms is not known. Neutralizing antibody responses against HCMV gN recombinant viruses were investigated at study entry in 80 healthy HCMV-seropositive women who were monitored for the appearance of new antibody specificities against linear strain specific epitopes on glycoproteins gH and gB as evidence of HCMV reinfection. Neutralizing activity against all four gN recombinant viruses was seen in 74% of subjects, and 61% of subjects had strain-specific responses. Significantly fewer women (9/39 subjects [23%]) with serological evidence of reinfection had strain specific neutralizing responses than the women without reinfection (21/41 subjects [51%]). Women with antibodies against at least one of the four linear gB and gH antigens at study entry had higher neutralizing titers against gN-1 (P = 0.006) and gN-2 (P = 0.007). Neutralizing titers of >=400 against gN-3 (P = 0.043) and gN-4 (P = 0.049) at study entry were associated with longer times to serological evidence of reinfection. The findings demonstrate that HCMV gN elicits strain-specific neutralizing antibody responses and that broader anti-gN neutralizing activity may provide some protection from reinfection with a different virus strain. PMID- 22492746 TI - Metacognition: computation, biology and function. AB - Many complex systems maintain a self-referential check and balance. In animals, such reflective monitoring and control processes have been grouped under the rubric of metacognition. In this introductory article to a Theme Issue on metacognition, we review recent and rapidly progressing developments from neuroscience, cognitive psychology, computer science and philosophy of mind. While each of these areas is represented in detail by individual contributions to the volume, we take this opportunity to draw links between disciplines, and highlight areas where further integration is needed. Specifically, we cover the definition, measurement, neurobiology and possible functions of metacognition, and assess the relationship between metacognition and consciousness. We propose a framework in which level of representation, order of behaviour and access consciousness are orthogonal dimensions of the conceptual landscape. PMID- 22492745 TI - Live oral typhoid vaccine Ty21a induces cross-reactive humoral immune responses against Salmonella enterica serovar Paratyphi A and S. Paratyphi B in humans. AB - Enteric fever caused by Salmonella enterica serovar Paratyphi A infection has emerged as an important public health problem. Recognizing that in randomized controlled field trials oral immunization with attenuated S. enterica serovar Typhi live vaccine Ty21a conferred significant cross-protection against S. Paratyphi B but not S. Paratyphi A disease, we undertook a clinical study to ascertain whether humoral immune responses could explain the field trial results. Ty21a immunization of adult residents of Maryland elicited predominantly IgA antibody-secreting cells (ASC) that recognize S. Typhi lipopolysaccharide (LPS). Cross-reactivity to S. Paratyphi A LPS was significantly lower than that to S. Paratyphi B LPS. ASC producing IgG and IgA that bind LPS from each of these Salmonella serovars expressed CD27 and integrin alpha4beta7 (gut homing), with a significant proportion coexpressing CD62L (secondary lymphoid tissue homing). No significant differences were observed in serum antibody against LPS of the different serovars. Levels of IgA B memory (B(M)) cells to S. Typhi LPS were significantly higher than those against S. Paratyphi A or B LPS, with no differences observed between S. Paratyphi A and B. The response of IgA B(M) to outer membrane proteins (OMP) from S. Typhi was significantly stronger than that to OMP of S. Paratyphi A but similar to that to OMP of S. Paratyphi B. The percentages of IgG or IgA B(M) responders to LPS or OMP from these Salmonella strains were similar. Whereas cross-reactive humoral immune responses to S. Paratyphi A or B antigens are demonstrable following Ty21a immunization, they cannot explain the efficacy data gleaned from controlled field trials. PMID- 22492747 TI - Kinds of access: different methods for report reveal different kinds of metacognitive access. AB - In experimental investigations of consciousness, participants are asked to reflect upon their own experiences by issuing reports about them in different ways. For this reason, a participant needs some access to the content of her own conscious experience in order to report. In such experiments, the reports typically consist of some variety of ratings of confidence or direct descriptions of one's own experiences. Whereas different methods of reporting are typically used interchangeably, recent experiments indicate that different results are obtained with different kinds of reporting. We argue that there is not only a theoretical, but also an empirical difference between different methods of reporting. We hypothesize that differences in the sensitivity of different scales may reveal that different types of access are used to issue direct reports about experiences and metacognitive reports about the classification process. PMID- 22492748 TI - The highs and lows of theoretical interpretation in animal-metacognition research. AB - Humans feel uncertain. They know when they do not know. These feelings and the responses to them ground the research literature on metacognition. It is a natural question whether animals share this cognitive capacity, and thus animal metacognition has become an influential research area within comparative psychology. Researchers have explored this question by testing many species using perception and memory paradigms. There is an emerging consensus that animals share functional parallels with humans' conscious metacognition. Of course, this research area poses difficult issues of scientific inference. How firmly should we hold the line in insisting that animals' performances are low-level and associative? How high should we set the bar for concluding that animals share metacognitive capacities with humans? This area offers a constructive case study for considering theoretical problems that often confront comparative psychologists. The authors present this case study and address diverse issues of scientific judgement and interpretation within comparative psychology. PMID- 22492749 TI - Metacognition in human decision-making: confidence and error monitoring. AB - People are capable of robust evaluations of their decisions: they are often aware of their mistakes even without explicit feedback, and report levels of confidence in their decisions that correlate with objective performance. These metacognitive abilities help people to avoid making the same mistakes twice, and to avoid overcommitting time or resources to decisions that are based on unreliable evidence. In this review, we consider progress in characterizing the neural and mechanistic basis of these related aspects of metacognition-confidence judgements and error monitoring-and identify crucial points of convergence between methods and theories in the two fields. This convergence suggests that common principles govern metacognitive judgements of confidence and accuracy; in particular, a shared reliance on post-decisional processing within the systems responsible for the initial decision. However, research in both fields has focused rather narrowly on simple, discrete decisions-reflecting the correspondingly restricted focus of current models of the decision process itself-raising doubts about the degree to which discovered principles will scale up to explain metacognitive evaluation of real-world decisions and actions that are fluid, temporally extended, and embedded in the broader context of evolving behavioural goals. PMID- 22492750 TI - A computational framework for the study of confidence in humans and animals. AB - Confidence judgements, self-assessments about the quality of a subject's knowledge, are considered a central example of metacognition. Prima facie, introspection and self-report appear the only way to access the subjective sense of confidence or uncertainty. Contrary to this notion, overt behavioural measures can be used to study confidence judgements by animals trained in decision-making tasks with perceptual or mnemonic uncertainty. Here, we suggest that a computational approach can clarify the issues involved in interpreting these tasks and provide a much needed springboard for advancing the scientific understanding of confidence. We first review relevant theories of probabilistic inference and decision-making. We then critically discuss behavioural tasks employed to measure confidence in animals and show how quantitative models can help to constrain the computational strategies underlying confidence-reporting behaviours. In our view, post-decision wagering tasks with continuous measures of confidence appear to offer the best available metrics of confidence. Since behavioural reports alone provide a limited window into mechanism, we argue that progress calls for measuring the neural representations and identifying the computations underlying confidence reports. We present a case study using such a computational approach to study the neural correlates of decision confidence in rats. This work shows that confidence assessments may be considered higher order, but can be generated using elementary neural computations that are available to a wide range of species. Finally, we discuss the relationship of confidence judgements to the wider behavioural uses of confidence and uncertainty. PMID- 22492751 TI - The neural basis of metacognitive ability. AB - Ability in various cognitive domains is often assessed by measuring task performance, such as the accuracy of a perceptual categorization. A similar analysis can be applied to metacognitive reports about a task to quantify the degree to which an individual is aware of his or her success or failure. Here, we review the psychological and neural underpinnings of metacognitive accuracy, drawing on research in memory and decision-making. These data show that metacognitive accuracy is dissociable from task performance and varies across individuals. Convergent evidence indicates that the function of the rostral and dorsal aspect of the lateral prefrontal cortex (PFC) is important for the accuracy of retrospective judgements of performance. In contrast, prospective judgements of performance may depend upon medial PFC. We close with a discussion of how metacognitive processes relate to concepts of cognitive control, and propose a neural synthesis in which dorsolateral and anterior prefrontal cortical subregions interact with interoceptive cortices (cingulate and insula) to promote accurate judgements of performance. PMID- 22492752 TI - What failure in collective decision-making tells us about metacognition. AB - Condorcet (1785) proposed that a majority vote drawn from individual, independent and fallible (but not totally uninformed) opinions provides near-perfect accuracy if the number of voters is adequately large. Research in social psychology has since then repeatedly demonstrated that collectives can and do fail more often than expected by Condorcet. Since human collective decisions often follow from exchange of opinions, these failures provide an exquisite opportunity to understand human communication of metacognitive confidence. This question can be addressed by recasting collective decision-making as an information-integration problem similar to multisensory (cross-modal) perception. Previous research in systems neuroscience shows that one brain can integrate information from multiple senses nearly optimally. Inverting the question, we ask: under what conditions can two brains integrate information about one sensory modality optimally? We review recent work that has taken this approach and report discoveries about the quantitative limits of collective perceptual decision-making, and the role of the mode of communication and feedback in collective decision-making. We propose that shared metacognitive confidence conveys the strength of an individual's opinion and its reliability inseparably. We further suggest that a functional role of shared metacognition is to provide substitute signals in situations where outcome is necessary for learning but unavailable or impossible to establish. PMID- 22492753 TI - Metacognition and reasoning. AB - This article considers the cognitive architecture of human meta-reasoning: that is, metacognition concerning one's own reasoning and decision-making. The view we defend is that meta-reasoning is a cobbled-together skill comprising diverse self management strategies acquired through individual and cultural learning. These approximate the monitoring-and-control functions of a postulated adaptive system for metacognition by recruiting mechanisms that were designed for quite other purposes. PMID- 22492754 TI - Failures of metacognition and lack of insight in neuropsychiatric disorders. AB - Lack of insight or unawareness of illness are the hallmarks of many psychiatric disorders, especially schizophrenia (SCZ) and other psychoses and could be conceived of as a failure in metacognition. Research in this area in the mental health field h as burgeoned with the development and widespread use of standard assessment instruments and the mapping out of the clinical and neuropsychological correlates of insight and its loss. There has been a growing appreciation of the multi-faceted nature of the concept and of the different 'objects' of insight, such as the general awareness that one is ill, to more specific metacognitive awareness of individual symptoms, impairments and performance. This in turn has led to the notion that insight may show modularity and may fractionate across different domains and disorders, supported by work that directly compares metacognition of memory deficits and illness awareness in patients with SCZ, Alzheimer's disease and brain injury. The focus of this paper will be on the varieties of metacognitive failure in psychiatry, particularly the psychoses. We explore cognitive models based on self-reflectiveness and their possible social and neurological bases, including data from structural and functional MRI. The medial frontal cortex appears to play an important role in self-appraisal in health and disease. PMID- 22492755 TI - Judgements of agency in schizophrenia: an impairment in autonoetic metacognition. AB - We investigated judgements of agency in participants with schizophrenia and healthy controls. Participants engaged in a computer game in which they attempted to touch downward falling Xs and avoid touching Os. On some trials, participants were objectively in perfect control. On other trials, they were objectively not in complete control because the movement of the cursor on the screen was distorted with respect to the position of the mouse by random noise (turbulence), or it was lagged by 250 or 500 ms. Participants made metacognitive judgements of agency as well as judgements of performance. Control participants' judgements of agency were affected by the turbulence and lag variables-indicating that they knew they were objectively not in control in those conditions, and they were also influenced by their assessments of performance. The patients also used their assessments of performance but neither turbulence nor lag affected their judgements of agency. This indicated an impairment in agency monitoring. The patients, unlike the healthy controls, used only publically available external cues about performance in making judgements of 'agency' and did not rely on any additional access to internal self-relevant cues that were diagnostic in indicating whether or not they were, in fact, in control. PMID- 22492756 TI - A detection theoretic explanation of blindsight suggests a link between conscious perception and metacognition. AB - Blindsight refers to the rare ability of V1-damaged patients to perform visual tasks such as forced-choice discrimination, even though these patients claim not to consciously see the relevant stimuli. This striking phenomenon can be described in the formal terms of signal detection theory. (i) Blindsight patients use an unusually conservative criterion to detect targets. (ii) In discrimination tasks, their confidence ratings are low and (iii) such confidence ratings poorly predict task accuracy on a trial-by-trial basis. (iv) Their detection capacity (d') is lower than expected based on their performance in forced-choice tasks. We propose a unifying explanation that accounts for these features: that blindsight is due to a failure to represent and update the statistical information regarding the internal visual neural response, i.e. a failure in metacognition. We provide computational simulation data to demonstrate that this model can qualitatively account for the detection theoretic features of blindsight. Because such metacognitive mechanisms are likely to depend on the prefrontal cortex, this suggests that although blindsight is typically due to damage to the primary visual cortex, distal influence to the prefrontal cortex by such damage may be critical. Recent brain imaging evidence supports this view. PMID- 22492757 TI - Higher order thoughts in action: consciousness as an unconscious re-description process. AB - Metacognition is usually construed as a conscious, intentional process whereby people reflect upon their own mental activity. Here, we instead suggest that metacognition is but an instance of a larger class of representational re description processes that we assume occur unconsciously and automatically. From this perspective, the brain continuously and unconsciously learns to anticipate the consequences of action or activity on itself, on the world and on other people through three predictive loops: an inner loop, a perception-action loop and a self-other (social cognition) loop, which together form a tangled hierarchy. We ask what kinds of mechanisms may subtend this form of enactive metacognition. We extend previous neural network simulations and compare the model with signal detection theory, highlighting that while the latter approach assumes that both type I (objective) and type II (subjective, metacognition based) decisions tap into the same signal at different hierarchical levels, our approach is closer to dual-route models in which it is assumed that the re descriptions made possible by the emergence of meta-representations occur independently and outside of the first-order causal chain. We close by reviewing relevant neurological evidence for the idea that awareness, self-awareness and social cognition involve the same mechanisms. PMID- 22492758 TI - Higher-order awareness, misrepresentation and function. AB - Conscious mental states are states we are in some way aware of. I compare higher order theories of consciousness, which explain consciousness by appeal to such higher-order awareness (HOA), and first-order theories, which do not, and I argue that higher-order theories have substantial explanatory advantages. The higher order nature of our awareness of our conscious states suggests an analogy with the metacognition that figures in the regulation of psychological processes and behaviour. I argue that, although both consciousness and metacognition involve higher-order psychological states, they have little more in common. One thing they do share is the possibility of misrepresentation; just as metacognitive processing can misrepresent one's cognitive states and abilities, so the HOA in virtue of which one's mental states are conscious can, and sometimes does, misdescribe those states. A striking difference between the two, however, has to do with utility for psychological processing. Metacognition has considerable benefit for psychological processing; in contrast, it is unlikely that there is much, if any, utility to mental states' being conscious over and above the utility those states have when they are not conscious. PMID- 22492759 TI - Choosing wisely: helping physicians and patients make smart decisions about their care. PMID- 22492760 TI - Parental separation and pediatric cancer: a Danish cohort study. AB - OBJECTIVE: The purpose of this study was to determine the risk for separation (ending cohabitation) of the parents of a child with a diagnosis of cancer. METHODS: In a nationwide cohort, we compared the risk for ending cohabitation of the parents of 2450 children (aged 0-20 years) given a diagnosis of cancer with the risk of parents of 44 853 randomly selected, gender- and age-matched cancer free children. We adjusted for socioeconomic position and demographic factors. Rate ratios and 95% confidence intervals for separation were estimated in a Cox proportional hazards model. RESULTS: The parents of children with cancer did not have a higher risk for separation than the general population (rate ratio: 1.00 [95% confidence interval: 0.91-1.10]). Separate analyses according to type of cancer and survival of the child similarly yielded null results. CONCLUSIONS: Experiencing cancer in a child does not seem to be a risk factor for separation. Our study will allow clinicians to reassure parents and to support them in facing the trauma of cancer in their child. PMID- 22492761 TI - More codeine fatalities after tonsillectomy in North American children. AB - In 2009 we reported the fatal case of a toddler who had received codeine after adenotonsillectomy for obstructive sleep apnea syndrome. The child was an ultra rapid metabolizer of cytochrome P4502D6 (CYP2D6). We now report 3 additional fatal or life-threatening cases from North America. In the 2 fatal cases, functional gene duplications encoding for CYP2D6 caused a significantly greater production of potent morphine from its parent drug, codeine. A severe case of respiratory depression in an extensive metabolizer is also noted. These cases demonstrate that analgesia with codeine or other opioids that use the CYP2D6 pathway after adenotonsillectomy may not be safe in young children with obstructive sleep apnea syndrome. PMID- 22492762 TI - Level of NICU quality of developmental care and neurobehavioral performance in very preterm infants. AB - OBJECTIVE: To examine the relation between the neurobehavior of very preterm infants and the level of NICU quality of developmental care. METHODS: The neurobehavior of 178 very preterm infants (gestational age <=29 weeks and/or birth weight <=1500 g) from 25 NICUs participating in a large multicenter, longitudinal study (Neonatal Adequate Care for Quality of Life, NEO-ACQUA) was examined with a standardized neurobehavioral assessment, the NICU Network Neurobehavioral Scale (NNNS). A questionnaire, the NEO-ACQUA Quality of Care Checklist was used to evaluate the level of developmental care in each of the NICUs. A factor analyses applied to NEO-ACQUA Quality of Care Checklist produced 2 main factors: (1) the infant-centered care (ICC) index, which measures parents' involvement in the care of their infant and other developmentally oriented care interventions, and (2) the infant pain management (IPM) index, which measures the NICU approach to and the procedures used for reducing infant pain. The relations between NNNS neurobehavioral scores and the 2 indexes were evaluated. RESULTS: Infants from NICUs with high scores on the ICC evidenced higher attention and regulation, less excitability and hypotonicity, and lower stress/abstinence NNNS scores than infants from low-care units. Infants from NICUs with high scores on the IPM evidenced higher attention and arousal, lower lethargy and nonoptimal reflexes NNNS scores than preterm infants from low-scoring NICUs. CONCLUSIONS: Very preterm infant neurobehavior was associated with higher levels of developmental care both in ICC and in IPM, suggesting that these practices support better neurobehavioral stability. PMID- 22492763 TI - Complementary and alternative medicine use and adherence with pediatric asthma treatment. AB - BACKGROUND AND OBJECTIVE: Complementary and alternative medicine (CAM) use for pediatric asthma is increasing. The authors of previous studies linked CAM use with decreased adherence to conventional asthma medicines; however, these studies were limited by cross-sectional design. Our objective was to assess the effect of starting CAM on pediatric adherence with daily asthma medications. METHODS: We used a retrospective cohort study design. Telephone surveys were administered to caregivers of patients with asthma annually from 2004 to 2007. Dependent variables were percent missed doses per week and a previously validated "Medication Adherence Scale score." Independent variables included demographic factors, caregiver perception of asthma control, and initiation of CAM for asthma. We used multivariate linear regression to assess the relationship between medication adherence and previous initiation of CAM. RESULTS: From our longitudinal data set of 1322 patients, we focused on 187 children prescribed daily medications for all 3 years of our study. Patients had high rates of adherence. The mean percent missed asthma daily controller medication doses per week was 7.7% (SD = 14.2%). Medication Adherence Scale scores (range: 4-20, with lower scores reflecting higher adherence) had an overall mean of 7.5 (SD = 2.9). In multivariate analyses, controlling for demographic factors and asthma severity, initiation of CAM use was not associated with subsequent adherence (P > .05). CONCLUSIONS: The data from this study suggest that CAM use is not necessarily "competitive" with conventional asthma therapies; families may incorporate different health belief systems simultaneously in their asthma management. As CAM use becomes more prevalent, it is important for physicians to ask about CAM use in a nonjudgmental fashion. PMID- 22492764 TI - Randomized trial of probiotics and calcium on diarrhea and respiratory tract infections in Indonesian children. AB - OBJECTIVE: To investigate the effects of calcium and probiotics on the incidence and duration of acute diarrhea and acute respiratory tract infections (ARTIs) in low-socioeconomic communities of Jakarta, Indonesia. METHODS: We conducted a 6 month, double-blind, placebo-controlled study in 494 healthy children aged 1 to 6 years who received low-lactose milk with low calcium content (LC; ~50 mg/day; n = 124), regular calcium content (RC; ~440 mg/day; n = 126), RC with 5.10(8) colony forming units per day of Lactobacillus casei CRL431 (casei; n = 120), or RC with 5.10(8) colony-forming units per day of Lactobacillus reuteri DSM17938 (reuteri; n = 124). Number and duration of diarrhea and ARTIs episodes were primary and secondary outcomes, respectively. RESULTS: Incidence of World Health Organization defined diarrhea (>=3 loose/liquid stools in 24 hours) was not significantly different between RC and LC (relative risk [RR]: 0.99 [95% confidence interval (CI): 0.62-1.58]), between casei and RC (RR: 1.21 [95% CI: 0.76-1.92]), or between reuteri and RC (RR: 0.76 [95% CI: 0.46-1.25]) groups. Incidence of all reported diarrhea (>=2 loose/liquid stools in 24 hours) was significantly lower in the reuteri versus RC group (RR: 0.68 [95% CI: 0.46-0.99]). Irrespective of the definition used, reuteri significantly reduced diarrhea incidence in children with lower nutritional status (below-median height-and-weight-for-age z score). None of the interventions affected ARTIs. CONCLUSIONS: RC milk, alone or with L casei, did not reduce diarrhea or ARTIs in Indonesian children. L reuteri may prevent diarrhea, especially in children with lower nutritional status. PMID- 22492765 TI - Developing the 2011 Integrated Pediatric Guidelines for Cardiovascular Risk Reduction. AB - This article reviews aspects of development of the recently released "Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents" for pediatric care providers that remain in the area of human judgment. Discussed will be the context in which the guidelines were developed, the formal evidence review process, a consideration of how quality grades were established, key social/ethical issues that the panel confronted, and a critique of the final work with recommendations for future guideline development. Lessons learned are that both a formal evidence review process is essential to developing a credible document, and human judgment is critical to producing a meaningful result. Guideline development is a dynamic process that must be continuously self critical as new evidence is acquired and sociopolitical and environmental contexts evolve. PMID- 22492766 TI - Supplemental written information improves prenatal counseling: a randomized trial. AB - OBJECTIVE: To determine if maternal knowledge of prematurity is improved when verbal gestational age-specific counseling is supplemented with written gestational age-specific information. METHODS: Prospective, randomized study of 60 pregnant participants assessed to be at risk for premature delivery between 23 and 34 weeks' gestation. Counseling in the control group consisted of gestational age-specific verbal information, and counseling in the intervention group consisted of written gestational age-specific information 1 hour before the verbal gestational age-specific information. Both groups completed a Prematurity Knowledge Questionnaire after counseling and the State-Trait Anxiety Inventory before and after counseling. The Prematurity Knowledge Questionnaire consisted of questions regarding short-term problems (immature lungs, intraventricular hemorrhage, retinopathy, feeding problems, infection, apnea, and jaundice), long term problems (chronic lung disease, postdischarge respiratory infections, visual impairment, hearing impairment, brain damage, and learning and behavior problems), and numerical outcome data (probabilities of survival, survival without significant morbidity, severe intraventricular hemorrhage, severe retinopathy, and chronic lung disease). RESULTS: Knowledge of short-term problems was not statistically different between the intervention (82%) and control groups (67%). Knowledge of long-term problems was better in the intervention (71%) than the control group (45%). Knowledge of numerical data was better in the intervention (48%) than the control group (29%). State-Trait Anxiety Inventory scores decreased after counseling in the intervention group. CONCLUSIONS: Supplementation of face-to-face verbal counseling with written information improved knowledge of long-term problems and knowledge of numerical outcome data, and it also decreased anxiety in women expecting a premature delivery. PMID- 22492767 TI - Inpatient hospital care of children with trisomy 13 and trisomy 18 in the United States. AB - BACKGROUND AND OBJECTIVE: Trisomy 13 and trisomy 18 are generally considered fatal anomalies, with a majority of infants dying in the first year after birth. The inpatient hospital care that these patients receive has not been adequately described. This study characterized inpatient hospitalizations of children with trisomy 13 and trisomy 18 in the United States, including number and types of procedures performed. METHODS: Retrospective repeated cross-sectional assessment of hospitalization data from the nationally representative US Kids' Inpatient Database, for the years 1997, 2000, 2003, 2006, and 2009. Included hospitalizations were of patients aged 0 to 20 years with a diagnosis of trisomy 13 or trisomy 18. RESULTS: The number of hospitalizations for each trisomy type ranged from 846 to 907 per year for trisomy 13 (P = .77 for temporal trend) and 1036 to 1616 per year for trisomy 18 (P < .001 for temporal trend). Over one third (36%) of the hospitalizations were of patients older than 1 year of age. Patients underwent a total of 2765 major therapeutic procedures, including creation of esophageal sphincter (6% of hospitalizations; mean age 23 months), repair of atrial and ventricular septal defects (4%; mean age 9 months), and procedures on tendons (4%; mean age 8 years). CONCLUSIONS: Children with trisomy 13 and trisomy 18 receive significant inpatient hospital care. Despite the conventional understanding of these syndromes as lethal, a substantial number of children are living longer than 1 year and undergoing medical and surgical procedures as part of their treatment. PMID- 22492768 TI - Effects of description of options on parental perinatal decision-making. AB - OBJECTIVE: To examine whether parents' delivery room management decisions for extremely preterm infants are influenced by (1) the degree of detail with which options (comfort care [CC] or intensive care [IC]) are presented or (2) their order of presentation. METHODS: A total of 309 volunteers, 18 to 55 years old, were each randomized to 1 of 4 groups: (1) detailed descriptions, CC presented first; (2) detailed descriptions, IC presented first; (3) brief descriptions, CC presented first; or (4) brief descriptions, IC presented first. Each received the description of a hypothetical delivery of a 23-week gestation infant and chose either IC or CC. Open-ended and structured questions elicited reasoning. Data were analyzed by chi(2) and logistic regression analysis. RESULTS: Neither degree of detail, comparing groups 1+2 with 3+4 (37% vs 41%, odds ratio = 0.85, 95% confidence interval = 0.54-1.34, P = .48), nor order, comparing groups 1+3 with 2+4 (40% vs 37%, odds ratio = 0.88, 95% confidence interval = 0.56-1.39; P = .59), influenced the likelihood of choosing IC. Participants choosing IC were more likely to invoke sanctity of life and religiosity as personal values. Additional reasons for choosing IC were experiences with infants born at later gestational ages, giving the infant a chance, not watching their infant die, and equating CC with euthanasia. Some choosing CC wanted to avoid infant suffering. CONCLUSIONS: The degree of detail and order of presentation had no effect on treatment decisions, suggesting that individuals bring well-articulated preexisting preferences to such decisions. Understanding beliefs and attitudes motivating these preferences can assist physicians in helping parents make informed decisions consistent with their values. PMID- 22492769 TI - Effectiveness of antimicrobial guidelines for community-acquired pneumonia in children. AB - OBJECTIVE: To assess the effectiveness of guidelines and education on empirical therapy for community-acquired pneumonia. METHODS: Administrative records for children with a primary diagnosis of pneumonia from January 2007 to September 2009 were reviewed. Antimicrobial use was measured monthly over 3 periods: (1) before creation of an antimicrobial stewardship task force (ASTF), (2) after ASTF formation but before release of guidelines for antimicrobial use, and (3) after guideline release. Antimicrobial use over time was assessed by using quasi binomial logistic regression models that incorporated interrupted events, seasonality, and autocorrelation. Allowing calculation of immediate changes due to specific interventions and trends in use over each time period. The primary outcome was use of ampicillin as recommended in the guidelines versus ceftriaxone, the historical standard. Secondary outcomes included other antimicrobial use, length of stay, mortality, and readmission. RESULTS: One thousand two hundred forty-six children met study criteria. Ampicillin use increased from 2% at baseline to 6% after ASTF formation and 44% after guideline release. Ceftriaxone use increased slightly (from 56% to 59%) after ASTF formation but decreased to 28% after guideline release. An immediate change in prescription occurred in the month after guideline publication and remained stable over the following year. CONCLUSIONS: Guidelines and education can have an impact on antimicrobial use in the pediatric setting. Although the optimal strategies for pediatric antimicrobial stewardship programs still are being determined, we believe that our approach offers an inexpensive and low-risk step in the right direction. PMID- 22492771 TI - Severe pulmonary hypertension with therapeutic L-lysine ibuprofen in 2 preterm neonates. AB - Persistently patent ductus arteriosus (PDA), affecting approximately one-third of all very low birth weight infants, can lead to significant morbidity and mortality. Recently, ibuprofen has been recommended over indomethacin to close PDAs because of a reduction in risk of necrotizing enterocolitis. Pulmonary hypertension is a rare but potentially fatal complication of ibuprofen administration in preterm infants. We report 2 infants who developed this complication after receiving therapeutic L-lysine ibuprofen preparation for the PDA closure. The first infant, 1 of twins weighing 640 g, was born at 24 weeks' gestation. The second infant, born at 26 weeks' gestation, was small for gestational age, weighing 439 g. In both cases, ibuprofen was initiated after echocardiographic confirmation of a moderate-sized to large PDA and an otherwise normal intracardiac anatomy. Both infants had echocardiographic evidence of increased pulmonary vascular resistance but shunting across the PDA was left to right. The infants deteriorated within 48 to 72 hours, and repeat echocardiograms revealed evidence of severe pulmonary hypertension. Both infants died of refractory hypotension and hypoxemia. When considering the use of ibuprofen therapy for PDA closure, clinicians should keep in mind the potential serious complication of pulmonary hypertension, even if a shunt across the PDA is left to right. PMID- 22492770 TI - Early or delayed enteral feeding for preterm growth-restricted infants: a randomized trial. AB - BACKGROUND: Growth-restricted preterm infants are at increased risk of developing necrotizing enterocolitis (NEC) and initiation of enteral feeding is frequently delayed. There is no evidence that this delay is beneficial and it might further compromise nutrition and growth. METHODS: Infants with gestation below 35 weeks, birth weight below the 10th centile, and abnormal antenatal umbilical artery Doppler waveforms were randomly allocated to commence enteral feeds "early," on day 2 after birth, or "late," on day 6. Gradual increase in feeds was guided by a "feeding prescription" with rate of increase the same for both groups. Primary outcomes were time to achieve full enteral feeding sustained for 72 hours and NEC. RESULTS: Four hundred four infants were randomly assigned from 54 hospitals in the United Kingdom and Ireland (202 to each group). Median gestation was 31 weeks. Full, sustained, enteral feeding was achieved at an earlier age in the early group: median age was 18 days compared with 21 days (hazard ratio: 1.36 [95% confidence interval: 1.11-1.67]). There was no evidence of a difference in the incidence of NEC: 18% in the early group and 15% in the late group (relative risk: 1.2 [95% confidence interval: 0.77-1.87]). Early feeding resulted in shorter duration of parenteral nutrition and high-dependency care, lower incidence of cholestatic jaundice, and improved SD score for weight at discharge. CONCLUSIONS: Early introduction of enteral feeds in growth-restricted preterm infants results in earlier achievement of full enteral feeding and does not appear to increase the risk of NEC. PMID- 22492772 TI - Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. AB - OBJECTIVE: We examined whether metabolic conditions (MCs) during pregnancy (diabetes, hypertension, and obesity) are associated with autism spectrum disorder (ASD), developmental delays (DD), or impairments in specific domains of development in the offspring. METHODS: Children aged 2 to 5 years (517 ASD, 172 DD, and 315 controls) were enrolled in the CHARGE (Childhood Autism Risks from Genetics and the Environment) study, a population-based, case-control investigation between January 2003 and June 2010. Eligible children were born in California, had parents who spoke English or Spanish, and were living with a biological parent in selected regions of California. Children's diagnoses were confirmed by using standardized assessments. Information regarding maternal conditions was ascertained from medical records or structured interview with the mother. RESULTS: All MCs were more prevalent among case mothers compared with controls. Collectively, these conditions were associated with a higher likelihood of ASD and DD relative to controls (odds ratio: 1.61 [95% confidence interval: 1.10-2.37; odds ratio: 2.35 [95% confidence interval: 1.43-3.88], respectively). Among ASD cases, children of women with diabetes had Mullen Scales of Early Learning (MSEL) expressive language scores 0.4 SD lower than children of mothers without MCs (P < .01). Among children without ASD, those exposed to any MC scored lower on all MSEL and Vineland Adaptive Behavior Scales (VABS) subscales and composites by at least 0.4 SD (P < .01 for each subscale/composite). CONCLUSIONS: Maternal MCs may be broadly associated with neurodevelopmental problems in children. With obesity rising steadily, these results appear to raise serious public health concerns. PMID- 22492773 TI - The dance between attending physicians and senior residents as teachers and supervisors. AB - OBJECTIVE: To examine how attending physicians and senior residents negotiated shared responsibilities for teaching and supervising on clinical work rounds. METHODS: As part of a larger ethnographic field study, we observed clinical work rounds on a General Pediatrics ward over 8 months, and interviewed 14 of 18 attending physicians and 9 of 11 senior residents whom we observed. Struck by the frequency of 2 codes in that data set ("stand back" and "step up"), we used the metaphor of a dance as an analytic strategy for understanding the dynamic relationship between attending physicians and senior residents. RESULTS: Like a traditional dance with a priori choreography, and consistent with the traditional premise in graduate medical education, attending physicians frequently "stood back" and senior residents, accordingly, "stepped up" and took on teaching and supervising responsibilities. Less often, both attending physicians and senior residents assumed the lead, or attending physicians stepped up rather than entrust senior residents. The complex clinical context sometimes changed the choreography. Attending physicians and senior residents understood their mutual responsibilities but were not bound by them; they improvised to maintain high quality patient care. CONCLUSIONS: The metaphor of a dance enabled us to better understand not only how attending physicians and senior residents negotiate shared responsibilities for teaching and supervision on clinical work rounds, but also how the clinical context impacts this negotiation. A better understanding of this negotiated relationship may help to clarify assumptions and set realistic expectations for what it might take for senior residents to assume progressive responsibility for these responsibilities in today's clinical context. PMID- 22492774 TI - Intakes of alcohol and folate during adolescence and risk of proliferative benign breast disease. AB - OBJECTIVES: To examine the combined effect of alcohol and folate intake during adolescence on the risk of proliferative benign breast disease (BBD). METHODS: We used data from 29 117 women in the Nurses' Health Study II who completed both adolescent alcohol consumption questions in 1989 and an adolescent diet questionnaire in 1998. A total of 659 women with proliferative BBD diagnosed between 1991 and 2001 were confirmed by central pathology review. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CIs), adjusted for established risk factors of breast cancer. RESULTS: Adolescent alcohol consumption was dose-dependently associated with an increased risk of proliferative BBD (hazard ratio = 1.15 per 10 g/day consumption; 95% CI, 1.03-1.28). There was no significant association between adolescent folate intake and the risk of proliferative BBD. Stratified analyses showed that each 10-g/day alcohol intake during adolescence was associated with a 21% (95% CI, 1.01-1.45) increase in the risk of proliferative BBD among women with low folate intake during adolescence, which was not significantly different from the alcohol-associated risk among women with moderate and high folate intake during adolescence (P for interaction = 0.18). CONCLUSIONS: Adolescent alcohol consumption is associated with increased risk of proliferative BBD, which may not be reduced by increased folate intake during adolescence. PMID- 22492775 TI - AgRP and NPY expression in the human hypothalamic infundibular nucleus correlate with body mass index, whereas changes in alphaMSH are related to type 2 diabetes. AB - CONTEXT: Rodent data show that altered hypothalamic signaling contributes to the development of obesity and insulin resistance. OBJECTIVE: To determine differences in hypothalamic expression levels of neuropeptide Y (NPY), agouti related peptide (AgRP), and alphaMSH in the infundibular nucleus, the human equivalent of the arcuate nucleus, in relation to body mass index (BMI). In addition, the expression in the infundibular nucleus of eight subjects diagnosed with type 2 diabetes was measured to determine possible interference of type 2 diabetes with the association observed between neuropeptides and BMI. DESIGN: We studied AgRP, NPY, and alphaMSH expression by means of quantitative immunocytochemistry in postmortem hypothalami of 30 subjects with known BMI. In separate experiments, we compared neuropeptide expression in eight subjects with type 2 diabetes with eight matched controls. RESULTS: We found that AgRP immunoreactivity showed a U-shaped correlation with BMI. No evidence was found for possible influences of corticosteroid treatment. NPY immunoreactivity was significantly lower in overweight and obese subjects. alphaMSH did not correlate with BMI but was significantly lower in subjects with type 2 diabetes compared with controls. By contrast, NPY and AgRP expression was not affected in type 2 diabetes. CONCLUSION: Our results indicate that the expression of AgRP and NPY are correlated with body weight changes, rather than the presence of type 2 diabetes, whereas changes in alphaMSH immunoreactivity are related to the presence of type 2 diabetes, indicating separate hypothalamic mechanisms. PMID- 22492777 TI - Epithelial to mesenchymal transition is activated in metastatic pheochromocytomas and paragangliomas caused by SDHB gene mutations. AB - CONTEXT: Pheochromocytoma and paraganglioma are rare neural-crest-derived tumors. They are metastatic in 15% of cases, and the identification of a germline mutation in the SDHB gene is a predictive risk factor for malignancy and poor prognosis. To date, the link between SDHB mutations and malignancy is still missing. OBJECTIVE: Epithelial to mesenchymal transition (EMT) is a developmental event, reactivated in cancer cells to promote cell mobility and invasiveness. The aim of this study was to address the participation of EMT in the metastatic evolution of pheochromocytoma/paraganglioma. DESIGN AND PATIENTS: Transcriptomic profiling of EMT was performed on 188 tumor samples, using a set of 94 genes implicated in this pathway. Activation of EMT was further confirmed at protein level by immunohistochemistry in a second set of 93 tumors. RESULTS: Hierarchical unsupervised classification showed that most SDHB-metastatic samples clustered together, indicating that EMT is differently regulated in these tumors. Major actors of EMT, metalloproteases and components of cellular junctions, were either up-regulated (LOXL2, TWIST, TCF3, MMP2, and MMP1) or down-regulated (KRT19 and CDH2) in SDHB-metastatic tumors compared with nonmetastatic ones. Interestingly, within metastatic tumors, most of these genes (LOXL2, TWIST, TCF3, MMP2, and KRT19) also allowed us to discriminate SDHB-mutated from non-SDHB-related tumors. In the second set of tumors, we studied Snail1/2 expression by immunohistochemistry and observed its specific nuclear translocation in all SDHB metastatic tumors. CONCLUSION: We have identified the first pathway that distinguishes SDHB-metastatic from all other types of pheochromocytomas/paragangliomas and suggest that activation of the EMT process might play a critical role in the particularly invasive phenotype of this group of tumors. PMID- 22492778 TI - Mild maternal thyroid dysfunction at delivery of infants born <=34 weeks and neurodevelopmental outcome at 5.5 years. AB - CONTEXT: Mild maternal thyroid dysfunction during early pregnancy is associated with poor neurodevelopment in affected offspring. Most studies are population based or are smaller populations of term/late preterm infants. No studies were found that focused on more preterm infants. OBJECTIVE: Our objective was to describe the relationship between mild maternal thyroid dysfunction at delivery of infants born <=34 wk and neurodevelopment at 5.5 yr. DESIGN: The study design was follow-up of women and children recruited in Scotland between 1998 and 2001. MAIN OUTCOME: We evaluated delivery levels of maternal TSH, free T(4) (FT(4)), and T(4) and the association with McCarthy Scale scores adjusted for 26 confounders of neurodevelopment. RESULTS: Maternal serum levels and McCarthy scores were available for 143 women and 166 children. After adjustment for confounders, there were significant 3.2, 2.1, and 1.8 point decrements, respectively, in general cognitive index, verbal subscale, and the perceptual performance subscale for each milliunit per liter increment in maternal TSH. Maternal FT(4) levels were variably associated with neurodevelopment. After adjustment, significant associations were found for the general cognitive index, motor scale, and quantitative subscale; each picomole per liter decrease in FT(4) was associated with an increase of 1.5, 1.7, and 0.9 points, respectively. Maternal T(4) levels showed little relationship with neurodevelopment. None of the women in this analysis had overt hypothyroidism, but mild hypothyroidism was evident in 27%; thyroglobulin antibody (TgAb) was >= 40 U/ml in 28% of the women. CONCLUSIONS: Higher maternal levels of TSH at delivery of infants born preterm were associated with significantly lower scores on the general cognitive index at 5.5 yr. PMID- 22492776 TI - Detection of hypomethylation syndrome among patients with epigenetic alterations at the GNAS locus. AB - CONTEXT: Genomic imprinting is the modification of the genome so that genes from only one (rather than two) of the parental alleles are expressed. The mechanism underlying imprinting is epigenetic, occurring via changes in DNA methylation and histone modifications rather than through alterations in the DNA sequence. To date, nine different imprinting disorders have been clinically and genetically identified and a considerable research effort has been focused on determining the cause of the corresponding methylation defects. OBJECTIVE: Our objective was to identify multilocus imprinting defects and characterize any mutations in trans acting genes in patients with pseudohypoparathyroidism (PHP) caused by epigenetic alterations at GNAS locus. DESIGN: We have investigated multilocus imprinting defects in 22 PHP patients with aberrant methylation at the GNAS locus not due to previously described deletions or to paternal uniparental disomy (UPD) of chromosome 20. RESULTS: We found that, in contrast to what has been described in growth disorders, multilocus hypomethylation is an uncommon event in PHP patients. We were also unable to identify any genetic alteration causative of the epigenetic defects in the currently known methylation regulatory genes. CONCLUSION: Our work suggests that a trans-acting gene regulating the establishment or maintenance of imprinting at GNAS locus, if it exists, should be specific to PHP cases caused by epigenetic defects at GNAS. PMID- 22492779 TI - Seizure disorders in systemic lupus erythematosus results from an international, prospective, inception cohort study. AB - OBJECTIVE: The aim of this study was to describe the frequency, attribution, outcome and predictors of seizures in systemic lupus erythematosus (SLE). METHODS: The Systemic Lupus International Collaborating Clinics, or SLICC, performed a prospective inception cohort study. Demographic variables, global SLE disease activity (SLE Disease Activity Index 2000), cumulative organ damage (SLICC/American College of Rheumatology Damage Index (SDI)) and neuropsychiatric events were recorded at enrolment and annually. Lupus anticoagulant, anticardiolipin, anti-beta(2) glycoprotein-I, antiribosomal P and anti-NR2 glutamate receptor antibodies were measured at enrolment. Physician outcomes of seizures were recorded. Patient outcomes were derived from the SF-36 (36-Item Short Form Health Survey) mental component summary and physical component summary scores. Statistical analyses included Cox and linear regressions. RESULTS: The cohort was 89.4% female with a mean follow-up of 3.5+/-2.9 years. Of 1631 patients, 75 (4.6%) had >=1 seizure, the majority around the time of SLE diagnosis. Multivariate analysis indicated a higher risk of seizures with African race/ethnicity (HR (CI): 1.97 (1.07 to 3.63); p=0.03) and lower education status (1.97 (1.21 to 3.19); p<0.01). Higher damage scores (without neuropsychiatric variables) were associated with an increased risk of subsequent seizures (SDI=1:3.93 (1.46 to 10.55); SDI=2 or 3:1.57 (0.32 to 7.65); SDI>=4:7.86 (0.89 to 69.06); p=0.03). There was an association with disease activity but not with autoantibodies. Seizures attributed to SLE frequently resolved (59/78 (76%)) in the absence of antiseizure drugs. There was no significant impact on the mental component summary or physical component summary scores. Antimalarial drugs in the absence of immunosuppressive agents were associated with reduced seizure risk (0.07 (0.01 to 0.66); p=0.03). CONCLUSION: Seizures occurred close to SLE diagnosis, in patients with African race/ethnicity, lower educational status and cumulative organ damage. Most seizures resolved without a negative impact on health-related quality of life. Antimalarial drugs were associated with a protective effect. PMID- 22492780 TI - Increased type II deiodinase protein in OA-affected cartilage and allelic imbalance of OA risk polymorphism rs225014 at DIO2 in human OA joint tissues. AB - OBJECTIVE: Genetic variation at the type II deiodinase (D2) gene (DIO2) was previously identified as osteoarthritis (OA) risk factor. To investigate mechanisms possibly underlying this association, we assessed D2 protein in healthy and OA-affected cartilage and investigated allelic balance of the OA risk polymorphism rs225014 at DIO2 in human OA joints. METHODS: Immunohistochemical staining of healthy and OA-affected cartilage was performed for D2. We then assessed allelic balance of DIO2 mRNA within OA-affected cartilage both at and away from the lesion, ligaments and subchondral bone. Allelic balance was measured by the amount of alleles 'C' and 'T' of the intragenic OA risk polymorphism rs225014 in heterozygous carriers. RESULTS: A markedly higher amount of D2 positive cells and staining intensity was observed in OA cartilage. A significant, 1.3-fold higher presence was observed for the OA-associated rs225014 'C' allele relative to the 'T' allele of DIO2, which was significant in 28 of 31 donors. CONCLUSION: In OA cartilage, D2 protein presence is increased. The allelic imbalance of the DIO2 mRNA transcript, with the OA risk allele 'C' of rs225014 more abundant than the wild-type 'T' allele in heterozygote carriers provides a possible mechanism by which genetic variation at DIO2 confers OA risk. PMID- 22492781 TI - Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis. AB - BACKGROUND: Cannabinoids modulate fibrogenesis in scleroderma. Ajulemic acid (AjA) is a non-psychoactive synthetic analogue of tetrahydrocannabinol that can bind the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Recent evidence suggests a key role for PPAR-gamma in fibrogenesis. OBJECTIVE: To determine whether AjA can modulate fibrogenesis in murine models of scleroderma. MATERIAL AND METHODS: Bleomycin-induced experimental fibrosis was used to assess the antifibrotic effects of AjA in vivo. In addition, the efficacy of AjA in pre established fibrosis was analysed in a modified model of bleomycin-induced dermal fibrosis and in mice overexpressing a constitutively active transforming growth factor beta (TGFbeta) receptor I. Skin fibrosis was evaluated by quantification of skin thickness and hydroxyproline content. As a marker of fibroblast activation, alpha-smooth muscle actin was examined. To study the direct effect of AjA in collagen neosynthesis, skin fibroblasts from patients with scleroderma were treated with increasing concentrations of AjA. Protein expression of PPAR gamma, and its endogenous ligand 15d-PGJ2, and TGFbeta were assessed before and after AjA treatment. RESULTS: AjA significantly prevented experimental bleomycin induced dermal fibrosis and modestly reduced its progression when started 3 weeks into the disease. AjA strongly reduced collagen neosynthesis by scleroderma fibroblasts in vitro, an action which was reversed completely by co-treatment with a selective PPAR-gamma antagonist. CONCLUSIONS: AjA prevents progression of fibrosis in vivo and inhibits fibrogenesis in vitro by stimulating PPAR-gamma signalling. Since therapeutic doses of AjA are well tolerated in humans, it is suggested that AjA as an interesting molecule targeting fibrosis in patients with scleroderma. PMID- 22492782 TI - Defining discriminative pain trajectories in hip osteoarthritis over a 2-year time period. AB - BACKGROUND: Although pain due to osteoarthritis (OA) generally deteriorates over time, there is a large individual variation in the course of pain. This study examines the different longitudinal trajectories of patients with hip pain due to OA. METHODS: Data from a previously performed randomised controlled trial were used to investigate the course of pain over 2 years in 222 patients with clinically and radiographically determined hip OA. Pain was measured with a visual analogue scale (0-100). Latent class growth analysis was used to determine the number of trajectories of patients with hip pain due to OA. RESULTS: Analyses yielded five trajectories of pain due to hip OA. Trajectory 1 ('mild pain'; n=69) consists of patients with stable mild pain. Patients in trajectory 2 ('moderate pain'; n=31) fluctuated slightly between moderate and severe pain levels. Trajectory 3 ('always pain'; n=32) consists of patients with severe pain. Patients in trajectory 4 ('regularly progressing'; n=48) started with mild pain and progressed slowly to moderate pain. Trajectory 5 ('highly progressing'; n=42) patients also started with mild pain but quickly progressed to severe pain over 2 years. Compared with the 'mild pain' group, patients in the 'always pain' group had more severe radiographic hip OA, morning stiffness and decreased range of motion. The 'highly progressing' group had more severe radiographic hip OA and morning stiffness. CONCLUSIONS: Latent class growth analysis applied to longitudinal data of patients with hip OA identified five distinct trajectories of pain. More studies are needed to externally validate these findings. PMID- 22492783 TI - Exploring the cost-utility of stratified primary care management for low back pain compared with current best practice within risk-defined subgroups. AB - OBJECTIVES: Stratified management for low back pain according to patients' prognosis and matched care pathways has been shown to be an effective treatment approach in primary care. The aim of this within-trial study was to determine the economic implications of providing such an intervention, compared with non stratified current best practice, within specific risk-defined subgroups (low risk, medium-risk and high-risk). METHODS: Within a cost-utility framework, the base-case analysis estimated the incremental healthcare cost per additional quality-adjusted life year (QALY), using the EQ-5D to generate QALYs, for each risk-defined subgroup. Uncertainty was explored with cost-utility planes and acceptability curves. Sensitivity analyses were performed to consider alternative costing methodologies, including the assessment of societal loss relating to work absence and the incorporation of generic (ie, non-back pain) healthcare utilisation. RESULTS: The stratified management approach was a cost-effective treatment strategy compared with current best practice within each risk-defined subgroup, exhibiting dominance (greater benefit and lower costs) for medium-risk patients and acceptable incremental cost to utility ratios for low-risk and high risk patients. The likelihood that stratified care provides a cost-effective use of resources exceeds 90% at willingness-to-pay thresholds of L4000 (~ 4500; $6500) per additional QALY for the medium-risk and high-risk groups. Patients receiving stratified care also reported fewer back pain-related days off work in all three subgroups. CONCLUSIONS: Compared with current best practice, stratified primary care management for low back pain provides a highly cost-effective use of resources across all risk-defined subgroups. PMID- 22492784 TI - Preliminary evaluation of the first international reference preparation for anticitrullinated peptide antibodies. AB - BACKGROUND: A lyophilised reference serum from one patient with rheumatoid arthritis (RA) diluted with serum samples from healthy subjects was evaluated as a possible first international standard for anticitrullinated peptide antibodies (ACPAs). METHODS: The authors used 12 commercial ELISAs for ACPA detection in the reference serum and for testing the linearity of the assays by studying twofold serial dilutions. To test the effectiveness of the standardisation, sera from 20 RA patients with variable antibody concentrations were analysed, and the relative concentrations were calculated using both the kit's own curve and the six dilutions of the reference serum as a calibration curve. Fifty sera from normal healthy subjects were used to calculate cut-off values for the reference serum using each commercial kit. RESULTS: The calibration curve obtained for each of the 12 methods using the reference sample dilutions as calibrator allowed harmonisation of the ACPA concentration of the 20 RA serum samples, significantly reducing the dispersion of the values. The mean coefficient of variation (CV) was reduced from 76.4% to 27.9% (p=0.018) and from 85.9% to 33.5% (p=0.028) for the medium/high and negative samples, respectively. Low positive sera CV was also reduced, but to a smaller degree, from 82.5% to 55.5% (p=0.043). CONCLUSION: This first evaluation of the behaviour of the ACPA reference serum demonstrated that it tested positive in all the assays and that it may be used as a reference standard for establishing calibration curves, reducing the dispersion of antibody values and better comparing results obtained from different methods/laboratories. PMID- 22492785 TI - Low-sodium diet self-management intervention in heart failure: pilot study results. AB - BACKGROUND: Self-care management of a low-sodium diet is a critical component of comprehensive heart failure (HF) treatment. AIMS: The primary purpose of this study was to examine the effectiveness of an educational intervention on reducing the dietary sodium intake of patients with HF. Secondary purposes were to examine the effects of the intervention on attitudes, subjective norm, and perceived behavioural control towards following a low-sodium diet. METHODS: This was a randomized clinical trial of an educational intervention based on The Theory of Planned Behavior. Patients were randomized to either a usual care (n=25) or intervention group (n=27) with data collection at baseline, 6 weeks, and 6 months. The intervention group received low-sodium diet instructions and the usual care group received no dietary instructions. Nutrition Data Systems Research software was used to identify the sodium content of foods on food diaries. Attitudes, subjective norm, and perceived behavioural control were measured using the Dietary Sodium Restriction Questionnaire. RESULTS: Analysis of covariance (between-subjects effects) revealed that dietary sodium intake did not differ between usual care and intervention groups at 6 weeks; however, dietary sodium intake was lower in the intervention group (F=7.3, df=1,29, p=0.01) at 6 months. Attitudes subscale scores were higher in the intervention group at 6 weeks (F=7.6, df=1, 38, p<0.01). CONCLUSION: Carefully designed educational programmes have the potential to produce desired patient outcomes such as low sodium diet adherence in patients with heart failure. PMID- 22492786 TI - The MARVEL transmembrane motif of occludin mediates oligomerization and targeting to the basolateral surface in epithelia. AB - Occludin (Ocln), a MARVEL-motif-containing protein, is found in all tight junctions. MARVEL motifs are comprised of four transmembrane helices associated with the localization to or formation of diverse membrane subdomains by interacting with the proximal lipid environment. The functions of the Ocln MARVEL motif are unknown. Bioinformatics sequence- and structure-based analyses demonstrated that the MARVEL domain of Ocln family proteins has distinct evolutionarily conserved sequence features that are consistent with its basolateral membrane localization. Live-cell microscopy, fluorescence resonance energy transfer (FRET) and bimolecular fluorescence complementation (BiFC) were used to analyze the intracellular distribution and self-association of fluorescent-protein-tagged full-length human Ocln or the Ocln MARVEL motif excluding the cytosolic C- and N-termini (amino acids 60-269, FP-MARVEL-Ocln). FP MARVEL-Ocln efficiently arrived at the plasma membrane (PM) and was sorted to the basolateral PM in filter-grown polarized MDCK cells. A series of conserved aromatic amino acids within the MARVEL domain were found to be associated with Ocln dimerization using BiFC. FP-MARVEL-Ocln inhibited membrane pore growth during Triton-X-100-induced solubilization and was shown to increase the membrane ordered state using Laurdan, a lipid dye. These data demonstrate that the Ocln MARVEL domain mediates self-association and correct sorting to the basolateral membrane. PMID- 22492787 TI - MPs' concern about future of laboratory services in Wales. PMID- 22492788 TI - Soil Association calls for antibiotic use on farms to be halved in five years. PMID- 22492789 TI - US FDA told to stop certain antibiotics being used as growth promoters. PMID- 22492790 TI - Ombudsman criticises 'mishandled' withdrawal of pet insurance. PMID- 22492791 TI - FAO calls for urgent action to tackle FMD outbreak in Egypt. PMID- 22492792 TI - Developing veterinary education and animal health in China. PMID- 22492793 TI - Ticks and tickborne diseases: raising awareness of the risks. PMID- 22492796 TI - Paraprofessionals and modern large animal practice. PMID- 22492798 TI - Psoroptic mange in cattle and the Ghost of Christmas Yet to Come. PMID- 22492799 TI - Clarifying vets' role in food safety. PMID- 22492800 TI - Welsh decision to vaccinate badgers against bovine TB. PMID- 22492801 TI - Severe ocular dysplasia in British red deer (Cervus elaphus). PMID- 22492802 TI - George Gould. PMID- 22492810 TI - Oleic acid-dependent modulation of NITRIC OXIDE ASSOCIATED1 protein levels regulates nitric oxide-mediated defense signaling in Arabidopsis. AB - The conserved cellular metabolites nitric oxide (NO) and oleic acid (18:1) are well-known regulators of disease physiologies in diverse organism. We show that NO production in plants is regulated via 18:1. Reduction in 18:1 levels, via a genetic mutation in the 18:1-synthesizing gene SUPPRESSOR OF SA INSENSITIVITY OF npr1-5 (SSI2) or exogenous application of glycerol, induced NO accumulation. Furthermore, both NO application and reduction in 18:1 induced the expression of similar sets of nuclear genes. The altered defense signaling in the ssi2 mutant was partially restored by a mutation in NITRIC OXIDE ASSOCIATED1 (NOA1) and completely restored by double mutations in NOA1 and either of the nitrate reductases. Biochemical studies showed that 18:1 physically bound NOA1, in turn leading to its degradation in a protease-dependent manner. In concurrence, overexpression of NOA1 did not promote NO-derived defense signaling in wild-type plants unless 18:1 levels were lowered. Subcellular localization showed that NOA1 and the 18:1 synthesizing SSI2 proteins were present in close proximity within the nucleoids of chloroplasts. Indeed, pathogen-induced or low-18:1-induced accumulation of NO was primarily detected in the chloroplasts and their nucleoids. Together, these data suggest that 18:1 levels regulate NO synthesis, and, thereby, NO-mediated signaling, by regulating NOA1 levels. PMID- 22492811 TI - Requirement of the cytosolic interaction between PATHOGENESIS-RELATED PROTEIN10 and LEUCINE-RICH REPEAT PROTEIN1 for cell death and defense signaling in pepper. AB - Plants recruit innate immune receptors such as leucine-rich repeat (LRR) proteins to recognize pathogen attack and activate defense genes. Here, we identified the pepper (Capsicum annuum) pathogenesis-related protein10 (PR10) as a leucine-rich repeat protein1 (LRR1)-interacting partner. Bimolecular fluorescence complementation and coimmunoprecipitation assays confirmed the specific interaction between LRR1 and PR10 in planta. Avirulent Xanthomonas campestris pv vesicatoria infection induces PR10 expression associated with the hypersensitive cell death response. Transient expression of PR10 triggers hypersensitive cell death in pepper and Nicotiana benthamiana leaves, which is amplified by LRR1 coexpression as a positive regulator. LRR1 promotes the ribonuclease activity and phosphorylation of PR10, leading to enhanced cell death signaling. The LRR1-PR10 complex is formed in the cytoplasm, resulting in its secretion into the apoplastic space. Engineered nuclear confinement of both proteins revealed that the cytoplasmic localization of the PR10-LRR1 complex is essential for cell death mediated defense signaling. PR10/LRR1 silencing in pepper compromises resistance to avirulent X. campestris pv vesicatoria infection. By contrast, PR10/LRR1 overexpression in Arabidopsis thaliana confers enhanced resistance to Pseudomonas syringae pv tomato and Hyaloperonospora arabidopsidis. Together, these results suggest that the cytosolic LRR-PR10 complex is responsible for cell death mediated defense signaling. PMID- 22492813 TI - Concurrent aerobic exercise interferes with the satellite cell response to acute resistance exercise. AB - The addition of aerobic exercise (AE) to a resistance exercise (RE) program (concurrent exercise, CE) can interfere with maximum muscle fiber growth achieved with RE. Further, CE appears to markedly affect the growth of myosin heavy chain (MHC) I, but not MHC IIa fibers. The mechanism responsible for this "interference" is unclear. Satellite cell (SC) responsiveness to exercise appears to influence muscle adaptation but has not yet been examined following acute concurrent exercise. Thus, we assessed the fiber-type-specific SC response to RE, AE, and CE exercise. Eight college-aged males completed the following two exercise trials: the RE trial, which consisted of unilateral leg extensions and presses (4 sets >= 10 repetitions: 75% 1 repetition maximum, RM); and the AE/CE trial, which included an identical RE protocol with the opposite leg, immediately followed by subjects cycling for 90 min (60% W(max)). Muscle biopsies were obtained from the vastus lateralis before and 4 days after each session. Samples were cross-sectioned, stained with antibodies against NCAM, Ki-67, and MHC I, counterstained with DAPI, and analyzed for SC density (SC per fiber), SC activation, and fiber type. SC density increased to a greater extent following RE (38 +/- 10%), compared with CE (-6 +/- 8%). Similarly, MHC I muscle fiber SC density displayed a greater increase following RE (46 +/- 14%), compared with AE (-7 +/- 17%) and CE (-8 +/- 8%). Our data indicate that the SC response to RE is blunted when immediately followed by AE, at least in MHC I muscle fibers, and possibly MHC II fibers. This suggests that the physiological environment evoked by AE might attenuate the eventual addition of myonuclei important for maximum muscle fiber growth and consequent force-producing capacity. PMID- 22492812 TI - Patterns and evolution of nucleotide landscapes in seed plants. AB - Nucleotide landscapes, which are the way base composition is distributed along a genome, strongly vary among species. The underlying causes of these variations have been much debated. Though mutational bias and selection were initially invoked, GC-biased gene conversion (gBGC), a recombination-associated process favoring the G and C over A and T bases, is increasingly recognized as a major factor. As opposed to vertebrates, evolution of GC content is less well known in plants. Most studies have focused on the GC-poor and homogeneous Arabidopsis thaliana genome and the much more GC-rich and heterogeneous rice (Oryza sativa) genome and have often been generalized as a dicot/monocot dichotomy. This vision is clearly phylogenetically biased and does not allow understanding the mechanisms involved in GC content evolution in plants. To tackle these issues, we used EST data from more than 200 species and provided the most comprehensive description of gene GC content across the seed plant phylogeny so far available. As opposed to the classically assumed dicot/monocot dichotomy, we found continuous variations in GC content from the probably ancestral GC-poor and homogeneous genomes to the more derived GC-rich and highly heterogeneous ones, with several independent enrichment episodes. Our results suggest that gBGC could play a significant role in the evolution of GC content in plant genomes. PMID- 22492814 TI - Ghrelin modulates baroreflex-regulation of sympathetic vasomotor tone in healthy humans. AB - Ghrelin, a neuropeptide originally known for its growth hormone-releasing and orexigenic properties, exerts important pleiotropic effects on the cardiovascular system. Growing evidence suggests that these effects are mediated by the sympathetic nervous system. The present study aimed at elucidating the acute effect of ghrelin on sympathetic outflow to the muscle vascular bed (muscle sympathetic nerve activity, MSNA) and on baroreflex-mediated arterial blood pressure (BP) regulation in healthy humans. In a randomized double-blind cross over design, 12 lean young men were treated with a single dose of either ghrelin 2 MUg/kg iv or placebo (isotonic saline). MSNA, heart rate (HR), and BP were recorded continuously from 30 min before until 90 min after substance administration. Sensitivity of arterial baroreflex was repeatedly tested by injection of vasoactive substances based on the modified Oxford protocol. Early, i.e., during the initial 30 min after ghrelin injection, BP significantly decreased together with a transient increase of MSNA and HR. In the course of the experiment (>30 min), BP approached placebo level, while MSNA and HR were significantly lower compared with placebo. The sensitivity of vascular arterial baroreflex significantly increased at 30-60 min after intravenous ghrelin compared with placebo, while HR response to vasoactive drugs was unaltered. Our findings suggest two distinct phases of ghrelin action: In the immediate phase, BP is decreased presumably due to its vasodilating effects, which trigger baroreflex-mediated counter-regulation with increases of HR and MSNA. In the delayed phase, central nervous sympathetic activity is suppressed, accompanied by an increase of baroreflex sensitivity. PMID- 22492815 TI - Nitrite is a positive modulator of the Frank-Starling response in the vertebrate heart. AB - Evidence from both mammalian and nonmammalian vertebrates indicates that intracardiac nitric oxide (NO) facilitates myocardial relaxation, ventricular diastolic distensibility, and, consequently, the Frank-Starling response, i.e., the preload-induced increase of cardiac output. Since nitrite ion (NO(2)(-)), the major storage pool of bioactive NO, recently emerged as a cardioprotective endogenous modulator, we explored its influence on the Frank-Starling response in eel, frog, and rat hearts, used as paradigms of fish, amphibians, and mammals, respectively. We demonstrated that, like NO, exogenous nitrite improves the Frank Starling response in all species, as indicated by an increase of stroke volume and stroke work (eel and frog) and of left ventricular (LV) pressure and LVdP/dt max (rat), used as indexes of inotropism. Unlike in frog and rat, in eel, the positive influence of nitrite appeared to be dependent on NO synthase inhibition. In all species, the effect was sensitive to NO scavengers, independent on nitroxyl anion, and mediated by a cGMP/PKG-dependent pathway. Moreover, the nitrite treatment increased S-nitrosylation of lower-molecular-weight proteins in cytosolic and membrane fractions. These results suggest that nitrite acts as a physiological source of NO, modulating through different species-specific mechanisms, the stretch-induced intrinsic regulation of the vertebrate heart. PMID- 22492816 TI - Time-of-day modulation of homeostatic and allostatic sleep responses to chronic sleep restriction in rats. AB - To study sleep responses to chronic sleep restriction (CSR) and time-of-day influences on these responses, we developed a rat model of CSR that takes into account the polyphasic sleep patterns in rats. Adult male rats underwent cycles of 3 h of sleep deprivation (SD) and 1 h of sleep opportunity (SO) continuously for 4 days, beginning at the onset of the 12-h light phase ("3/1" protocol). Electroencephalogram (EEG) and electromyogram (EMG) recordings were made before, during, and after CSR. During CSR, total sleep time was reduced by ~60% from baseline levels. Both rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS) during SO periods increased initially relative to baseline and remained elevated for the rest of the CSR period. In contrast, NREMS EEG delta power (a measure of sleep intensity) increased initially, but then declined gradually, in parallel with increases in high-frequency power in the NREMS EEG. The amplitude of daily rhythms in NREMS and REMS amounts was maintained during SO periods, whereas that of NREMS delta power was reduced. Compensatory responses during the 2-day post-CSR recovery period were either modest or negative and gated by time of day. NREMS, REMS, and EEG delta power lost during CSR were not recovered by the end of the second recovery day. Thus the "3/1" CSR protocol triggered both homeostatic responses (increased sleep amounts and intensity during SOs) and allostatic responses (gradual decline in sleep intensity during SOs and muted or negative post-CSR sleep recovery), and both responses were modulated by time of day. PMID- 22492817 TI - The hibernating 13-lined ground squirrel as a model organism for potential cold storage of platelets. AB - Hibernating mammals have developed many physiological adaptations to extreme environments. During hibernation, 13-lined ground squirrels (Ictidomys tridecemlineatus) must suppress hemostasis to survive prolonged body temperatures of 4-8 degrees C and 3-5 heartbeats per minute without forming lethal clots. Upon arousal in the spring, these ground squirrels must be able to quickly restore normal clotting activity to avoid bleeding. Here we show that ground squirrel platelets stored in vivo at 4-8 degrees C were released back into the blood within 2 h of arousal in the spring with a body temperature of 37 degrees C but were not rapidly cleared from circulation. These released platelets were capable of forming stable clots and remained in circulation for at least 2 days before newly synthesized platelets were detected. Transfusion of autologous platelets stored at 4 degrees C or 37 degrees C showed the same clearance rates in ground squirrels, whereas rat platelets stored in the cold had a 140-fold increase in clearance rate. Our results demonstrate that ground squirrel platelets appear to be resistant to the platelet cold storage lesions observed in other mammals, allowing prolonged storage in cold stasis and preventing rapid clearance upon spring arousal. Elucidating these adaptations could lead to the development of methods to store human platelets in the cold, extending their shelf life. PMID- 22492819 TI - Radioactivity measurement of primordial radionuclides in and dose evaluation from marble and glazed tiles used as covering building materials in Turkey. AB - Measurements of the natural radioactivity arising from primordial radionuclides ((226)Ra, (232)Th and (40)K) in marble and glazed tile samples used covering building materials in Turkey were carried out by gamma-ray spectrometer with a high purity germanium detector. The mean activity concentrations of the (226)Ra, (232)Th and (40)K in marble and glazed tile samples were found as 8.2, 5.5 and 58.1 Bq kg(-1) and 81.2, 65.4 and 450.1 Bq kg(-1), respectively. The radiation doses received by occupants of buildings in which the sample marble and glazed tiles might be used are estimated using measured activity concentrations of constituent primordial radionuclides and dose conversion factors evaluated by the European Commission from models of tile use. Results obtained are presented for each radionuclide, analysed and compared with relevant national and international legislation, guidance and report, and with the results obtained from other studies. Results show that the use of such decorative building materials in the construction of domestic homes or workplaces in Turkey is unlikely to lead to any significant radiation exposure to the occupants. PMID- 22492820 TI - In situ occupational and general public exposure to VHF/UHF transmission for air traffic communication. AB - Occupational and general public exposure due to very high frequency (VHF)/ultra high frequency (UHF) transmission centres for verbal communication for air traffic control is investigated in situ for the first time. These systems are used for communication with aircraft, resulting in different human exposure from that of classical broadcasting. Measurement methods are proposed for the exposure assessment, and a measurement campaign is executed in three transmission centres. By investigating the temporal behaviour of the VHF signals for 6 d, a realistic worst-case duty cycle of 29 % is determined. Periods of high exposures corresponding with high aircraft traffic are from 7 a.m. to 1 p.m. and in the evening. All measured electric-field values satisfy the International Commission on Non-ionizing Radiation Protection guidelines. Fields vary from 0.2 to 21.1 V m(-1) for occupational exposure and from 0.007 to 8.0 V m(-1) for general public exposure. The average fields equal 5.2 V m(-1) for workers, and 0.7 V m(-1) for general public. PMID- 22492821 TI - Novel reference radiation fields for pulsed photon radiation installed at PTB. AB - Currently, ~70 % of the occupationally exposed persons in Germany are working in pulsed radiation fields, mainly in the medical sector. It has been known for a few years that active electronic dosemeters exhibit considerable deficits or can even fail completely in pulsed fields. Type test requirements for dosemeters exist only for continuous radiation. Owing to the need of a reference field for pulsed photon radiation and accordingly to the upcoming type test requirements for dosemeters in pulsed radiation, the Physikalisch-Technische Bundesanstalt has developed a novel X-ray reference field for pulsed photon radiation in cooperation with a manufacturer. This reference field, geared to the main applications in the field of medicine, has been well characterised and is now available for research and type testing of dosemeters in pulsed photon radiation. PMID- 22492818 TI - Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms. AB - Neural sites that interact with the suprachiasmatic nuclei (SCN) to generate rhythms of unrestricted feeding remain unknown. We used the targeted toxin, leptin conjugated to saporin (Lep-SAP), to examine the importance of leptin receptor-B (LepR-B)-expressing neurons in the arcuate nucleus (Arc) for generation of circadian feeding rhythms. Rats given Arc Lep-SAP injections were initially hyperphagic and rapidly became obese (the "dynamic phase" of weight gain). During this phase, Lep-SAP rats were arrhythmic under 12:12-h light-dark (LD) conditions, consuming 59% of their total daily intake during the daytime, compared with 36% in blank-SAP (B-SAP) controls. Lep-SAP rats were also arrhythmic in continuous dark (DD), while significant circadian feeding rhythms were detected in all B-SAP controls. Approximately 8 wk after injection, Lep-SAP rats remained obese but transitioned into a "static phase" of weight gain marked by attenuation of their hyperphagia and rate of weight gain. In this phase, Arc Lep-SAP rats exhibited circadian feeding rhythms under LD conditions, but were arrhythmic in continuous light (LL) and DD. Lep-SAP injections into the ventromedial hypothalamic nucleus did not cause hyperphagia, obesity, or arrhythmic feeding in either LD or DD. Electrolytic lesion of the SCN produced feeding arrhythmia in DD but not hyperphagia or obesity. Results suggest that both Arc Lep-SAP neurons and SCN are required for generation of feeding rhythms entrained to photic cues, while also revealing an essential role for the Arc in maintaining circadian rhythms of ad libitum feeding independent of light entrainment. PMID- 22492822 TI - Exposure to radiation from the natural radioactivity in Tunisian building materials. AB - Building materials can expose public and workers to radiation because of their content of radium, thorium and potassium isotopes. This is why it is very important from the radiological point of view to survey the natural radioactivity content of commonly used building materials in any country. This work consists of the measurement of (226)Ra, (232)Th and (40)K activity concentrations in a variety of commonly used building materials in Tunisia and on the estimation of their radiological hazard. The maximum value of radium equivalent for the studied materials was equal to 169 Bq kg(-1) and corresponds to the clay brick, which is lower than the recommended value of 370 Bq kg(-1). In this work, several radiological indexes were calculated and were found to be under their highest permitted limit. PMID- 22492823 TI - Removal of water-soluble and protein-bound solutes with reversed mid-dilution versus post-dilution haemodiafiltration. AB - BACKGROUND: Convective dialysis strategies are superior in the removal of protein bound uraemic retention solutes. Mid-dilution and mixed-dilution haemodiafiltration (HDF), both combining pre-dilution and post-dilution, are promising options to further improve removal capacity and have been shown of additional benefit for large middle molecules. In this study, we compared the removal of small water-soluble and protein-bound solutes in post-dilution versus mid-dilution HDF. METHODS: Fourteen chronic haemodialysis (HD) patients were included in this crossover study. Patients were kept for 4 weeks on high-flux HD. On the mid-week session of Weeks 3 and 4, either post-dilution or reversed mid dilution HDF were applied, in random order. Blood and dialysate flows were maintained at 300 and 800 mL/min, while the substitution flow was 75 mL/min in post-dilution and 150 mL/min in mid-dilution HDF. Based on the data collected during the sessions under study, extraction ratio (ER) and reduction ratio (RR) of small water-soluble and protein-bound solutes were calculated, as well as total solute removal (TSR) based on spent dialysate. RESULTS: No differences were observed for TSR, ER and RR for protein-bound solutes. For small water-soluble solutes, ER in post-dilution HDF was significantly higher than in mid-dilution HDF: 0.92 +/- 0.02 versus 0.87 +/- 0.04 for urea (P < 0.001), 0.92 +/- 0.02 versus 0.88 +/- 0.02 for creatinine (P < 0.001) and 0.84 +/- 0.02 versus 0.82 +/- 0.03 for uric acid (P = 0.009). TSR and RR were, however, not different due to the lower inlet concentrations with post-dilution HDF. CONCLUSIONS: TSR of mid dilution and post-dilution HDF was not different for both small water-soluble and protein-bound compounds. Both strategies in the setting as applied in this study are as adequate for the removal of these solutes. PMID- 22492824 TI - Tonsillectomy has beneficial effects on remission and progression of IgA nephropathy independent of steroid therapy. AB - BACKGROUND: Indication of tonsillectomy in IgA nephropathy is controversial. The purpose of this study was to examine the efficacy of tonsillectomy on remission and progression of IgA nephropathy. METHODS: We conducted a single-center 7-year historical cohort study in 200 patients with biopsy-proven IgA nephropathy. Study outcomes were clinical remission defined as disappearance of urine abnormalities at two consecutive visits, glomerular filtration rate (GFR) decline defined as 30% GFR decrease from baseline and GFR slope during the follow-up. RESULTS: Seventy of the 200 patients received tonsillectomy. Tonsillectomy was associated with increased incidence of clinical remission (P+0.01, log-rank test) and decreased incidence of GFR decline (P=0.01, log-rank test). After adjustment for age and gender, hazard ratios in tonsillectomy were 3.90 (95% confidence interval 2.46-6.18) for clinical remission and 0.14 (0.02-1.03) for GFR decline. After further adjustment for laboratory (baseline mean arterial pressure, GFR, 24-h proteinuria and hematuria score), histological (mesangial score, segmental sclerosis or adhesion, endocapillary proliferation and interstitial fibrosis) or treatment variables (steroid and renin-angiotensin system inhibitors), similar results were obtained in each model. Even after exclusion of 69 steroid-treated patients, results did not change. GFR slopes in tonsillectomy and non tonsillectomy groups were 0.60+/-3.65 and -1.64+/-2.59 mL/min/1.73 m2/year, respectively. In the multiple regression model, tonsillectomy prevented GFR decline during the follow-up period (regression coefficient 2.00, P=0.01). CONCLUSION: Tonsillectomy was associated with a favorable renal outcome of IgA nephropathy in terms of clinical remission and delayed renal deterioration even in non-steroid-treated patients. PMID- 22492825 TI - The cutting (w)edge--comparative evaluation of renal baseline biopsies obtained by two different methods. AB - BACKGROUND: The assessment of donor-derived damage of transplanted kidneys might be instrumental for estimating donor organ quality and for predicting short- and long-term organ outcome. In the present study, we report a new standardized method for obtaining pre-transplant kidney biopsy specimens. Instead of taking wedge biopsies (WBs), a skin punch biopsy (PB) tool was utilized to obtain standardized biopsy samples that also represented deeper cortical zones. METHODS: We compared 147 PB specimens and 114 WBs with respect to the number of glomeruli and arterial vessels they contained. The performance of the two biopsy methods in detecting glomerular damage, interstitial fibrosis/tubular atrophy (IF/TA) and arteriosclerosis was determined by evaluation of subsequent transplant core biopsies of the patients. Statistical comparison employed Kruskal-Wallis and kappa (kappa) tests. RESULTS: Significantly more PB samples (89%) than WBs (66%) were diagnostically adequate according to the Banff criteria. Despite a higher number of glomeruli in WBs (34.6 versus 21.7 in punch biopsies), arteries were present in only 68% of WBs but could be found in 93% of punch biopsies. The comparison of findings in pre-transplant biopsies with lesions in corresponding post-transplant core biopsies revealed a superior diagnostic concordance for IF/TA and arteriosclerosis for punch biopsies than for WBs, reaching kappa values of 0.823 versus 0.729 and 0.661 versus 0.516, respectively. CONCLUSION: The use of skin PB tools for obtaining baseline biopsies from transplanted kidneys is a safe and effective method for assessment of donor-derived damage of the organ. PMID- 22492826 TI - Classifying and predicting outcomes in ANCA-associated glomerulonephritis. PMID- 22492827 TI - Prevalence and risk factors of pre-diabetes after renal transplantation: a single centre cohort study in 200 consecutive patients. AB - BACKGROUND: After renal transplantation, patients are prone to develop impairments in glucose metabolism. In 2005, the American Diabetes Association published new guidelines on the diagnosis of pre-diabetes [plasma glucose levels from 100 to 125 mg/dL fasting or from 140 to 199 mg/dL 2 h after an oral glucose tolerance test (OGTT)]. This study sought to evaluate the prevalence and the potentially associated factors of pre-diabetes in a cohort of renal transplant patients on maintenance immunosuppressive medication. Furthermore, the diagnostic value of HbA1-c measurements in predicting pre-diabetes in transplant patients is undetermined. METHODS: Two hundred consecutive renal transplant patients of our outpatient transplant clinic were evaluated using a standard OGTT. On the day of testing, multiple factors presumably associated with pre-diabetes were assessed via a standardized questionnaire: daily steroid dosage, triglyceride levels, cholesterol levels, estimated glomerular filtration rate (eGFR) [abbreviated Modification of Diet in Renal Disease (MDRD) formula], systolic and diastolic blood pressure, pulse pressure, age, gender, body mass index (BMI), BMI <>30 and <>25, number of renal transplants, number of rejection episodes prior to testing, source of renal transplant, cause of renal failure and medications as related to the prescription of cyclosporine, tacrolimus, mycophenolate mophetil, angiotensin converting enzyme inhibitors, AT1-blockers, statins, beta-blockers and thiazide diuretics. Patients diagnosed with pre-diabetes were compared to subjects with normal test results. Fishers exact test and the Wilcoxon rank-sum test were applied to compare the two study populations, whereas multivariate logistic regression was used to seek potential risk factors as related to other covariates. Risk ratios (RRs) to develop pre-diabetes were calculated for significant variables. RESULTS: Ten patients had results indicative of post transplant diabetes whereas data sets of three other patients were incomplete and were thus not included in the analysis. From the remaining 187 patients, 130 (69.5%) displayed normal test results whereas 57 (30.5%) had results indicative of pre-diabetes. On multivariate regression analysis, patients with pre-diabetes were significantly older {55.3 +/- 12.1 versus 47.7 +/- 12.6 years, P = 0.0007, RRs per 5 years increase 1.28 [95% confidence interval (95% CI) 1.11-1.47]}, had more rejection episodes [0.26 +/- 0.48 versus 0.12 +/- 0.37, P = 0.0024, RRs per rejection episode 3.99 (95% CI 1.63-9.77)] and showed lower diastolic blood pressure readings [77 +/- 10 mmHg versus 81 +/- 10 mmHg, P = 0.0362, RR per 5 mmHg decrease 1.14 (95% CI 1.04-1.49)]. CONCLUSIONS: There is a high incidence of latent pre-diabetes among renal transplant recipients. Increasing age, rejection episodes and lower diastolic blood pressure proved to be associated with pre diabetes. In contrast to post-transplant diabetes, tacrolimus use and HbA1-c levels were not prognostic of pre-diabetes. PMID- 22492828 TI - Comparison of the MDRD Study and the CKD-EPI Study equations in evaluating trends of estimated kidney function at population level: findings from the National FINRISK Study. AB - BACKGROUND: There are no data comparing the Modification of Diet in Renal Disease (MDRD) Study and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Study equations in the evaluation of time-dependent trend of estimated glomerular filtration rate (eGFR) in the general population. METHODS: Changes in eGFR and in the association of eGFR with kidney disease and cardiovascular disease (CVD) risk factors across age groups were estimated in two independent cross-sectional population surveys in Finland in 2002 and 2007 with 11 277 study participants, aged 25-74 years, using both the MDRD and the CKD-EPI equations. RESULTS: A trend towards decreasing eGFRs between the study years was observed using both equations, but the trend was more substantial when using the MDRD equation. The MDRD equation yielded lower estimates of eGFR than the CKD-EPI equation, with small mean difference between the equations at low eGFR level but substantial at the level of only mildly decreased or near-normal to normal kidney function. Decrease of eGFR was associated with an increase in CKD and CVD risk factors. However, an increase of risk factors was not observed among those who had mildly decreased eGFR by only the MDRD equation but not by the CKD-EPI equation. CONCLUSION: In comparison with the CKD-EPI equation, the MDRD equation augmented the trend of increasing prevalence of CKD, showed a weaker association with risk factors and tended to assign impaired renal function to individuals without an excess of cardiovascular risk factors. PMID- 22492829 TI - Prospective study on clinical effects of renal replacement therapy in treatment resistant congestive heart failure. AB - BACKGROUND/AIMS: Clinical outcome in cardiorenal syndrome (CRS) Type 2 and treatment with dialysis. METHODS: Prospective observational non-randomized study. RESULTS: Twenty-three patients were included, mean age 66+/-21 years. Twelve (52%) patients were treated with peritoneal dialysis (PD) and 11 (48%) with intermittent haemodialysis (IHD). Median survival time after start of dialysis was 16 months. Hospitalizations for cardiovascular causes were reduced (1.4+/-0.6 pre-dialysis versus 0.4+/-0.6 days/patient/month post-dialysis, P=0.000), without significant changes in hospitalization for all causes (1.8+/-1.6 versus 2.1+/-2.9 days/patient/month). New York Heart Association (NYHA) class (3.8+/-0.4 at start versus 2.4+/-0.7 after 4 months, P=0.000, versus 2.7+/-0.9 after 8 months, P=0.001) and quality of life tended to improve (63+/-21 at start, versus 41+/-20 after 4 months, versus 51+/-25 after 8 months; P=0.056). Left ventricular ejection fraction did not change. The number of technical complications associated with dialysis therapy was relatively high in this population. CONCLUSIONS: After starting dialysis for CRS, hospitalizations for cardiovascular causes were reduced, but not hospitalizations for all causes. Functional NYHA class improved and quality of life tended to improve, without evidence for a change in cardiac function. In this small study, no differences between IHD and PD were observed. PMID- 22492830 TI - Renal failure in cirrhosis: prerenal azotemia, hepatorenal syndrome and acute tubular necrosis. PMID- 22492831 TI - Real-time monitoring of breath ammonia during haemodialysis: use of ion mobility spectrometry (IMS) and cavity ring-down spectroscopy (CRDS) techniques. AB - BACKGROUND: The diffusion of high-performance analytical technology has opened prospects for breath diagnosis as a non-invasive diagnostic tool. In this study, ion mobility spectrometry (IMS) and cavity ring-down spectroscopy (CRDS) techniques were used to analyse ammonia gas (NH3) in real-time in breath from patients undergoing haemodialysis (HD) treatment and any correlation with blood urea nitrogen (BUN) levels and Kt/V were investigated. METHODS: We studied 20 patients on intermittent HD treatment. The first breath samples were taken before the start of dialysis and further breath samples were taken every hour during the treatment and after the end of the session. An evaluation was also made of 20 healthy volunteers, acting as controls [healthy subjects (HS)]. RESULTS: Breath ammonia concentrations were higher in CRDS-HD (914.5+/-301.4 versus 280+/-120 parts per billion (p.p.b.), P<0.0001) and IMS-HD patients (964.4+/-402.4 versus 280+/-120 p.p.b., P<0.0001) than in HS. We assessed real-time variations in the levels of NH(3) and showed a continuous decrease in the levels of NH3. Expired NH3 correlated directly with BUN levels, both in the IMS-HD (P=0.002; r=0.84; P=0.009; r=0.76) and in the CRDS-HD group (P=0.005; r=0.80; P=0.008; r=0.77), respectively, both before and at the end of dialysis. A direct correlation with Kt/V was found in both groups studied (IMS-HD: P=0.003; r=0.82; CRDS-HD: P=0.006; r=0.79). CONCLUSIONS: Breath monitoring of NH3 with IMS and CRDS techniques could be useful to assess the real-time clinical status of patients during HD. By using pre-dialysis ammonia values, an approximate calculation of the Kt/Vurea ratio can be established. PMID- 22492832 TI - Body mass index and colon cancer screening: a systematic review and meta analysis. AB - BACKGROUND: Obesity is associated with increased colon cancer mortality and lower rates of mammography and Pap testing. METHODS: We conducted a systematic review to determine whether obesity is associated with lower rates of colon cancer screening. We searched the PubMed, CINAHL, and Cochrane Library databases. Two investigators reviewed citations, abstracts, and articles independently. Two investigators abstracted study information sequentially and evaluated quality independently using standardized forms. We included all studies in our qualitative syntheses. We used random effects meta-analyses to combine those studies providing screening results by the following body mass index (BMI) categories: Normal, 18.5-24.9 kg/m(2) (reference); overweight, 25-29.9 kg/m(2); class I obesity, 30-34.9 kg/m(2); class II obesity, 35-39.9 kg/m(2); and class III obesity, >= 40 kg/m(2). RESULTS: Of 5,543 citations, we included 23 articles. Almost all studies were cross-sectional and ascertained BMI and screening through self-report. BMI was not associated with colon cancer screening overall. The subgroup of obese white women reported lower rates of colon cancer screening compared with those with a normal BMI with combined ORs (95% CI) of 0.87 (0.82 0.93), 0.80 (0.65-0.99), and 0.73 (0.58-0.94) for class I, II, and III obesity, respectively. Results were similar among white men with class II obesity. CONCLUSIONS: Overall, BMI was not associated with colon cancer screening. Obese white men and women may be less likely to undergo colon cancer screening compared with those with a normal BMI. IMPACT: Further investigation of this disparity may reduce the risk of obesity-related colon cancer death. PMID- 22492833 TI - Dosing error with over-the-counter vitamin D supplement: a risk for vitamin D toxicity in infants. PMID- 22492834 TI - Psychotropic medication use in children with autism in the Kentucky Medicaid population. AB - This study reviewed Kentucky Medicaid claims data for children with autism spectrum disorders to determine psychotropic drug (PTD) use in this population. Children with autism spectrum disorders (ICD-9 code 299.XX) in 3 different age groups from 2005 to 2008 were identified; PTD use was defined as at least 1 prescription per year. PTD use in all age ranges was higher than in previously reported studies. High PTD use in children between 1 and 5 years is particularly of concern and may reflect perceived inadequacies of comprehensive educational/behavioral services for these children. PMID- 22492835 TI - The role of pulmonary follow-up in reducing health care utilization in infants with bronchopulmonary dysplasia. AB - OBJECTIVE: To determine whether pulmonary follow-up affects rates of rehospitalization and visitations to emergency departments (EDs) in preterm infants with bronchopulmonary dysplasia (BPD). METHODS: In this retrospective cohort study, the authors identified all preterm infants born at <= 32 weeks' gestation with at least one outpatient visit to a pulmonary follow-up clinic at Children's Hospital Boston or a high-risk primary neurodevelopmental follow-up clinic for preterm infants. ED visits and rehospitalizations were identified through electronic medical records. RESULTS: Infants with pulmonary follow-up compared with infants without pulmonary follow-up were, respectively, younger (mean gestational age 26.3 +/- 2.3 vs 28.3 +/- 2.3 weeks, P < .0001), smaller at birth (birth weight <1200 g, 87.6% vs 57.2%, P < .0001), and needed more supplemental oxygen (55.7% vs 2.6%, P < .0001) and diuretics (65.8% vs 4.7%, P < .001) at the time of discharge from the neonatal intensive care unit. Although rates of rehospitalization were higher in infants with pulmonary follow-up, rates of visits to an ED for respiratory causes were not statistically significant. After controlling for baseline differences in both groups, the rates of rehospitalization or ED visits were the same for both groups. CONCLUSIONS: Despite differences in lung disease status in infants with and without pulmonary follow-up, the rates of health care utilization were the same in both groups. Pulmonary follow-up may decrease the expected higher rates of ED visits and hospitalizations in preterm infants with more severe lung disease. PMID- 22492836 TI - Eat, play, love: adolescent and parent perceptions of the components of a multidisciplinary weight management program. AB - BACKGROUND: Participants' perceptions may be associated with the high attrition rates reported by weight management programs. OBJECTIVE: To explore participants' perceptions of a weight management program. METHODS: Semistructured interviews were performed (spring 2010) with past participants of the Michigan Pediatric Outpatient Weight Evaluation and Reduction program. Transcripts were reviewed and themes identified. RESULTS: Parents (38) and adolescents (25) were interviewed separately; similar themes emerged. Theme 1: Support/encouragement-Participants emphasized the importance of a supportive environment with a positive, compassionate approach from providers. Theme 2: Exercise-Fun, achievable activities were a valued means of making exercise enjoyable and building self efficacy. Theme 3: Nutrition-Hands on demonstrations and tangible suggestions were preferred over activities such as self-monitoring. Theme 4: Behavioral factors-Participants valued the opportunity to hear their peers' experiences. However, individual/family sessions addressing their personal concerns were also viewed as important. CONCLUSION: Beyond program content, participants valued a supportive environment emphasizing health over habitus. PMID- 22492837 TI - Assessment of patient dose and image quality for cardiac CT with breast shields. AB - Breast shielding can reduce dose to the female breast, a radiosensitive organ receiving significant radiation during computed tomography (CT) chest examinations, particularly in cardiac CT, where Electrocardiogram dose modulation currently precludes the use of radial dose modulation to reduce breast dose. However, breast shields may produce artefacts affecting interpretation of coronary arteries. This study explores the dose savings and the effect of breast shields on image quality with torso and CT dose index body phantoms and an organ dose calculator. Change in dose calculated: 53-63 % (female breast), 82-85 % (lung), 79-84 % (oesophagus) and 76-80 % (effective dose) with larger dose reductions at lower kVp. Image quality is preserved when breast shields are placed after the scout no closer than 10 mm from the skin. Therefore, breast shields can be used in cardiac CT to reduce breast dose without compromising image quality. Revised conversion factors for dose length product to effective dose are suggested for cardiac CT without and with breast shields. PMID- 22492838 TI - Perspectives and editorials: letter to the editor. PMID- 22492839 TI - Acute effects of sildenafil on uroflowmetric parameters in erectile dysfunction patients with and without lower urinary tract symptoms. AB - Using phosphodiesterase type 5 (PDE5) inhibitors in patients with lower urinary tract symptoms continues to draw attention. Despite clinical improvements in patients, it is still debatable whether urinary flow rates are increased or not. The aim of this study was to evaluate the acute effects of sildenafil, a PDE5 inhibitor, on uroflowmetry parameters. A total of 110 men who had applied to our outpatient clinics and who had had no history of alpha blocker and PDE5 inhibitor use were included in our study. Two uroflowmetries were performed within 24-72 hours without any treatment. Participants received 50 mg of sildenafil at their third visit, and uroflowmetry was repeated after 2 hours. A total of 102 men were included in the analysis, and baseline uroflowmetry values were compared with values obtained after sildenafil use. The mean age of the 102 participants who had attended all three visits (92.7%) was 52.1 +/- 12.2 years. Mean of baseline maximal flow rate values were 17.1 +/- 5.1 mL/s, mean of baseline maximal flow rate after sildenafil was 18.2 +/- 5.1 mL/s; average flow rate values at the baseline and after sildenafil were 9.5 +/- 3.5 and 9.9 +/- 3.5 mL/s, respectively. Means of postvoid residual urine volume for baseline and after sildenafil were 31.2 +/- 20.1 and 27.7 +/- 18.4 mL, respectively. Statistically significant difference is determined between baseline and postsildenafil values in terms of average flow rates at baseline and postvoid residual urine values. Results of this study suggest that sildenafil has an effect on uroflowmetric parameters during an acute period. PMID- 22492840 TI - Chronic oral administration of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) improves erectile function in aged rats. AB - Arginase expression and activity have been noted to be heightened in conditions associated with erectile dysfunction, including aging. Previously, arginase inhibition by chronic administration of the arginase inhibitor 2-(S)-amino-6 boronohexanoic acid (ABH) has been shown to improve endothelial dysfunction in aged rats. The objective of this study was to assess whether chronic oral ABH administration affects cavernosal erectile function. Rats were divided into 4 groups: young control, young treated with arginase inhibitor, aged control, and aged treated with arginase inhibitor. Arginase activity was measured and presented as a proportion of young untreated rats. In vivo erectile responses to cavernous nerve stimulation were measured in all cohorts. The cavernous nerve was stimulated with a graded electrical stimulus, and the intracavernosal/mean arterial pressure ratios and total intracavernosal pressure were recorded. Arginase activity was elevated in the aged rats compared with young controls; however, arginase activity was significantly decreased in aged rats treated with ABH. With the addition of ABH, erectile responses improved in the aged rats (P < .05). Oral inhibition of arginase with ABH results in improved erectile function in aged rats, resulting in erectile hemodynamics similar to young rats. This represents the first documentation of systemic arginase inhibition positively affecting corporal cavernosal function. PMID- 22492841 TI - Low amounts and high thiol oxidation of peroxiredoxins in spermatozoa from infertile men. AB - Seminal oxidative stress occurs when there is an increased production of reactive oxygen species (ROS) and/or a decrease of antioxidant activity, promoting impaired sperm function. Peroxiredoxins (PRDX) are abundant in human semen and are important antioxidant enzymes, which act as ROS scavengers and modulators in ROS-dependent signaling. Our aim was to determine whether the levels of PRDX1 and PRDX6 and their oxidation on thiol groups are associated with a decrease in sperm motility and DNA integrity. We evaluated the sperm and seminal PRDX level in men (13 healthy controls, 15 men with clinical varicocele, and 17 men with idiopathic infertility). We assessed conventional semen parameters, sperm DNA integrity (by the sperm chromatin structure assay), lipid peroxidation in seminal plasma and spermatozoa (by the thiobarbituric acid reactive substances assay), and the amount and thiol oxidation of PRDX1 and PRDX6 (by immunoblotting). PRDXs were affected in seminal plasma (lower amounts) and in sperm samples (lower amounts and higher levels of thiol oxidation) characterized by lower sperm motility, higher lipid peroxidation, and sperm DNA damage. The thioloxidation ratio of PRDXs (thiol-oxidized PRDX/total PRDX) correlated negatively with sperm motility (total and progressive) and positively with sperm DNA damage and sperm lipid peroxidation. In conclusion, because of the lower amount of total PRDX1 and PRDX6 and the high thiol oxidation of these PRDXs, very little (less than 20%) protection due to PRDXs remains, and this is associated with impaired sperm function and poor DNA integrity and suggests an important role of PRDXs in the protection of human spermatozoa against oxidative stress. PMID- 22492842 TI - The high frequency of sperm aneuploidy in klinefelter patients and in nonobstructive azoospermia is due to meiotic errors in euploid spermatocytes. AB - For nonobstructive azoospermic (NOA) patients with a normal karyotype or for Klinefelter syndrome (47,XXY) patients, intracytoplasmic sperm injection is associated with an increased aneuploidy risk in offspring. We examined testicular cells from patients with different azoospermia etiologies to determine the origin of the aneuploid spermatozoa. The incidence of chromosome abnormalities was investigated in all types of azoospermia. Four study subgroups were constituted: Klinefelter patients (group 1), NOA patients with spermatogenesis failure but a normal karyotype (group 2), obstructive azoospermic patients with normal spermatogenesis (group 3), and control patients with normal sperm (group 4). The pachytene stage (in the three azoospermic groups) and postmeiotic cells (in all groups) were analyzed with fluorescence in situ hybridization. No aneuploid pachytene spermatocytes were observed. Postmeiotic aneuploidy rates were higher in the two groups with spermatogenesis failure (5.3% and 4.0% for groups 1 and 2, respectively) than in patients with normal spermatogenesis (0.6% for group 3 and group 4). Whatever the etiology of the azoospermia, the spermatozoa originated from euploid pachytene spermatocytes. These results strengthen the hypothesis whereby sperm aneuploidy in both Klinefelter patients and NOA patients with a normal karyotype results from meiotic abnormalities and not from aneuploid spermatocytes. The fact that sperm aneuploidy was more frequent when spermatogenesis was altered suggests a deleterious testicular environment. The study results also provide arguments for offering preimplantation genetic diagnosis or prenatal diagnosis when a pregnancy occurs for fathers with NOA (whatever the karyotype). PMID- 22492843 TI - Luteinizing hormone (LH)-releasing hormone agonist reduces serum adrenal androgen levels in prostate cancer patients: implications for the effect of LH on the adrenal glands. AB - Recently, adrenal androgens have been targeted as key hormones for the development of castration-resistant prostate cancer therapeutics. Although circulating adrenal androgens originate mainly from the adrenal glands, the testes also supply about 10%. Although widely used in androgen deprivation medical castration therapy, the effect of luteinizing hormone-releasing hormone (LH-RH) agonist on adrenal androgens has not been fully studied. In this study, changes in testicular and adrenal androgen levels were measured and compared to adrenocorticotropic hormone levels. To assess the possible role of LH in the adrenal glands, immunohistochemical studies of the LH receptor in normal adrenal glands were performed. Forty-seven patients with localized or locally progressive prostate cancer were treated with LH-RH agonist with radiotherapy. Six months after initiation of treatment, testosterone, dihydrotestosterone, and estradiol levels were decreased by 90%-95%, and dehydroepiandrosterone-sulfate, dehydroepiandrosterone, and androstenedione levels were significantly decreased by 26%-40%. The suppressive effect of LH-RH agonist at 12 months was maintained. Adrenocorticotropic hormone levels showed an increasing trend at 6 months and a significant increase at 12 months. LH receptors were positively stained in the cortex cells of the reticular layer of the adrenal glands. The long-term LH-RH agonist treatment reduced adrenal-originated adrenal androgens. LH receptors in the adrenal cortex cells of the reticular layer might account for the underlying mechanism of reduced adrenal androgens. PMID- 22492844 TI - The tobacco BLADE-ON-PETIOLE2 gene mediates differentiation of the corolla abscission zone by controlling longitudinal cell expansion. AB - The BLADE-ON-PETIOLE (BOP) genes of Arabidopsis (Arabidopsis thaliana) have been shown to play an essential role in floral abscission by specializing the abscission zone (AZ) anatomy. However, the molecular and cellular mechanisms that underlie differentiation of the AZ are largely unknown. In this study, we identified a tobacco (Nicotiana tabacum) homolog of BOP (designated NtBOP2) and characterized its cellular function. In tobacco plants, the NtBOP2 gene is predominantly expressed at the base of the corolla in an ethylene-independent manner. Both antisense suppression of NtBOP genes and overexpression of NtBOP2 in tobacco plants caused a failure in corolla shedding. Histological analysis revealed that the differentiation of the corolla AZ was blocked in the transgenic flowers. This blockage was due to uncontrolled cell elongation at the region corresponding to wild-type AZ. The role of NtBOP2 in regulating cell elongation was further demonstrated in Bright Yellow 2 single cells: perturbation of NtBOP2 function by a dominant negative strategy led to the formation of abnormally elongated cells. Subcellular localization analysis showed that NtBOP2-green fluorescent protein fusion proteins were targeted to both the nucleus and cytoplasm. Yeast two-hybrid, firefly luciferase complementation imaging, and in vitro pull-down assays demonstrated that NtBOP2 proteins interacted with TGA transcription factors. Taken together, these results indicated that NtBOP2 mediated the differentiation of AZ architecture by controlling longitudinal cell growth. Furthermore, NtBOP2 may achieve this outcome through interaction with the TGA transcription factors and via an ethylene-independent signaling pathway. PMID- 22492845 TI - ATP-binding cassette B4, an auxin-efflux transporter, stably associates with the plasma membrane and shows distinctive intracellular trafficking from that of PIN FORMED proteins. AB - Intracellular trafficking of auxin transporters has been implicated in diverse developmental processes in plants. Although the dynamic trafficking pathways of PIN-FORMED auxin efflux proteins have been studied intensively, the trafficking of ATP-binding cassette protein subfamily B proteins (ABCBs; another group of auxin efflux carriers) still remains largely uncharacterized. In this study, we address the intracellular trafficking of ABCB4 in Arabidopsis (Arabidopsis thaliana) root epidermal cells. Pharmacological analysis showed that ABCB4 barely recycled between the plasma membrane and endosomes, although it slowly endocytosed via the lytic vacuolar pathway. Fluorescence recovery after photobleaching analysis revealed that ABCB4 is strongly retained in the plasma membrane, further supporting ABCB4's nonrecycling property. The endocytosis of ABCB4 was not dependent on the GNOM-LIKE1 function, and the sensitivity of ABCB4 to brefeldin A required guanine nucleotide exchange factors for adenosyl ribosylation factor other than GNOM. These characteristics of intracellular trafficking of ABCB4 are well contrasted with those of PIN-FORMED proteins, suggesting that ABCB4 may be a basic and constitutive auxin efflux transporter for cellular auxin homeostasis. PMID- 22492847 TI - Indian Ocean dipole and rainfall drive a Moran effect in East Africa malaria transmission. AB - BACKGROUND: Patterns of concerted fluctuation in populations-synchrony-can reveal impacts of climatic variability on disease dynamics. We examined whether malaria transmission has been synchronous in an area with a common rainfall regime and sensitive to the Indian Ocean Dipole (IOD), a global climatic phenomenon affecting weather patterns in East Africa. METHODS: We studied malaria synchrony in 5 15-year long (1984-1999) monthly time series that encompass an altitudinal gradient, approximately 1000 m to 2000 m, along Lake Victoria basin. We quantified the association patterns between rainfall and malaria time series at different altitudes and across the altitudinal gradient encompassed by the study locations. RESULTS: We found a positive seasonal association of rainfall with malaria, which decreased with altitude. By contrast, IOD and interannual rainfall impacts on interannual disease cycles increased with altitude. Our analysis revealed a nondecaying synchrony of similar magnitude in both malaria and rainfall, as expected under a Moran effect, supporting a role for climatic variability on malaria epidemic frequency, which might reflect rainfall-mediated changes in mosquito abundance. CONCLUSIONS: Synchronous malaria epidemics call for the integration of knowledge on the forcing of malaria transmission by environmental variability to develop robust malaria control and elimination programs. PMID- 22492846 TI - Auxin activates the plasma membrane H+-ATPase by phosphorylation during hypocotyl elongation in Arabidopsis. AB - The phytohormone auxin is a major regulator of diverse aspects of plant growth and development. The ubiquitin-ligase complex SCF(TIR1/AFB) (for Skp1-Cul1-F-box protein), which includes the TRANSPORT INHIBITOR RESPONSE1/AUXIN SIGNALING F-BOX (TIR1/AFB) auxin receptor family, has recently been demonstrated to be critical for auxin-mediated transcriptional regulation. Early-phase auxin-induced hypocotyl elongation, on the other hand, has long been explained by the acid growth theory, for which proton extrusion by the plasma membrane H(+)-ATPase is a functional prerequisite. However, the mechanism by which auxin mediates H(+) ATPase activation has yet to be elucidated. Here, we present direct evidence for H(+)-ATPase activation in etiolated hypocotyls of Arabidopsis (Arabidopsis thaliana) by auxin through phosphorylation of the penultimate threonine during early-phase hypocotyl elongation. Application of the natural auxin indole-3 acetic acid (IAA) to endogenous auxin-depleted hypocotyl sections induced phosphorylation of the penultimate threonine of the H(+)-ATPase and increased H(+)-ATPase activity without altering the amount of the enzyme. Changes in both the phosphorylation level of H(+)-ATPase and IAA-induced elongation were similarly concentration dependent. Furthermore, IAA-induced H(+)-ATPase phosphorylation occurred in a tir1-1 afb2-3 double mutant, which is severely defective in auxin-mediated transcriptional regulation. In addition, alpha (phenylethyl-2-one)-IAA, the auxin antagonist specific for the nuclear auxin receptor TIR1/AFBs, had no effect on IAA-induced H(+)-ATPase phosphorylation. These results suggest that the TIR1/AFB auxin receptor family is not involved in auxin-induced H(+)-ATPase phosphorylation. Our results define the activation mechanism of H(+)-ATPase by auxin during early-phase hypocotyl elongation; this is the long-sought-after mechanism that is central to the acid-growth theory. PMID- 22492848 TI - Stp1 and Stk1: the Yin and Yang of vancomycin sensitivity and virulence in vancomycin-intermediate Staphylococcus aureus strains. PMID- 22492849 TI - Myeloid dendritic cell dysfunction during primary HIV-1 infection is independent of interaction with gp120. PMID- 22492850 TI - Effects of short-course zidovudine on the selection of nevirapine-resistant HIV-1 in women taking single-dose nevirapine. AB - Single-dose nevirapine (sdNVP) given to prevent mother-to-child-transmission of HIV-1 selects NVP-resistance. Short-course zidovudine (ZDV) was hypothesized to lower rates of NVP-resistance. HIV-1 infected pregnant women administered sdNVP with or without short-course ZDV were assessed for HIV-1 mutations (K103N, Y181C, G190A, and V106M) prior to delivery and postpartum. Postpartum NVP-resistance was lower among 31 taking ZDV+sdNVP compared to 33 taking only sdNVP (35.5% vs. 72.7%; chi2 P = .003). NVP mutants decayed to <2% in 24/35 (68.6%) at a median 6 months postpartum, with no differences based on ZDV use (logrank P = .99). Short course ZDV was associated with reduced NVP-resistance mutations among women taking sdNVP. PMID- 22492851 TI - High prevalence of anelloviruses in vitreous fluid of children with seasonal hyperacute panuveitis. AB - Seasonal hyperacute panuveitis (SHAPU) is a potentially blinding ocular disease occurring in Nepal that principally affects young children. Random amplification of partially purified vitreous fluid (VF)-derived nucleic acid revealed the presence of human anelloviruses in VF of SHAPU patients. In a comparative study of patients with different ocular pathologies, SHAPU patients were at highest risk of harboring anelloviruses in their eyes. The majority of SHAPU patients had multiple anelloviruses in their VF. The ocular anellovirus load in SHAPU and non SHAPU patients did not differ and no SHAPU-specific anellovirus variant was detected. Analysis of paired serum and VF samples from SHAPU and non-SHAPU patients showed that the anellovirus detected in VF samples most likely originated from the systemic viral pool during viremia, potentially through breakdown of the blood-ocular barrier. The detection of anelloviruses in VF samples of uveitis patients, profoundly so in SHAPU patients, is imperative and warrants elucidation of its clinical significance. PMID- 22492852 TI - Interleukin 1 receptor-associated kinase m impairs host defense during pneumococcal pneumonia. AB - BACKGROUND: Streptococcus pneumoniae is the most common causative organism in community-acquired pneumonia. Pneumococci that try to invade the lower airways are recognized by innate immune cells through pattern recognition receptors, including Toll-like receptors 2, 4, and 9. Interleukin 1 (IL-1) receptor associated kinase (IRAK)-M is a proximal inhibitor of Toll-like receptor signaling. METHODS: To determine the role of IRAK-M in host defense during pneumococcal pneumonia, IRAK-M- deficient and wild-type mice were intranasally infected with S. pneumoniae. RESULTS: IRAK-M-deficient mice demonstrated a reduced lethality after infection with S. pneumoniae via the airways. Whereas bacterial burdens were similar in IRAK-M-deficient and wild-type mice early (3 hours) after infection, from 24 hours onward the number of pneumococci recovered from lungs and distant body sites were 10-100-fold lower in the former mouse strain. The diminished bacterial growth and dissemination in IRAK-M-deficient mice were preceded by an increased early influx of neutrophils into lung tissue and elevated pulmonary levels of IL-1beta and CXCL1. IRAK-M deficiency did not influence bacterial growth after intravenous administration of S. pneumoniae. CONCLUSIONS: These data suggest that IRAK-M impairs host defense during pneumococcal pneumonia at the primary site of infection at least in part by inhibiting the early immune response. PMID- 22492854 TI - Cytomegalovirus and immunological aging: the real driver of HIV and heart disease? PMID- 22492853 TI - Parvovirus 4 infection and clinical outcome in high-risk populations. AB - Parvovirus 4 (PARV4) is a DNA virus frequently associated with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, but its clinical significance is unknown. We studied the prevalence of PARV4 antibodies in 2 cohorts of HIV- and HCV-infected individuals (n = 469) and the correlations with disease status. We found that PARV4 infection frequently occurred in individuals exposed to bloodborne viruses (95% in HCV-HIV coinfected intravenous drug users [IDUs]). There were no correlations between PARV4 serostatus and HCV outcomes. There was, however, a significant association with early HIV-related symptoms, although because this was tightly linked to both HCV status and clinical group (IDU), the specific role of PARV4 is not yet clear. PMID- 22492855 TI - Serine/threonine phosphatase Stp1 contributes to reduced susceptibility to vancomycin and virulence in Staphylococcus aureus. AB - The genetic mechanisms that contribute to reduced susceptibility to vancomycin in Staphylococcus aureus are complex and heterogeneous. In addition, debate is emerging as to the true effect of reduced susceptibility to vancomycin on staphylococcal virulence. To investigate this, comparative genomics was performed on a collection of vancomycin-exposed isogenic S. aureus pairs (14 strains in total). Previously described mutations were observed in genes such as vraG, agrA, yvqF, and rpoB; however, a new mechanism was identified involving a serine/threonine phosphatase, Stp1. After constructing an stp1 deletion mutant, we showed that stp1 is important in vancomycin susceptibility and cell wall biosynthesis. Gene expression studies showed that stp1 also regulates virulence genes, including a hemolysin, superantigen-like protein, and phenol-soluble modulin, and that the deletion mutant is attenuated in virulence in vivo. Stp1 provides a new link between vancomycin susceptibility and virulence in S. aureus. PMID- 22492856 TI - Cytomegalovirus immunoglobulin G antibody is associated with subclinical carotid artery disease among HIV-infected women. AB - BACKGROUND: Cytomegalovirus (CMV) infection has been implicated in immune activation and accelerated progression of immunodeficiency from human immunodeficiency virus (HIV) coinfection. We hypothesized that CMV is associated with vascular disease in HIV-infected adults. METHODS: In the Women's Interagency HIV Study, we studied 601 HIV-infected and 90 HIV-uninfected participants. We assessed the association of CMV immunoglobulin G (IgG) level with carotid artery intima-media thickness, carotid artery distensibility, Young's elastic modulus, and blood pressures. Multivariable models adjusted for age, race/ethnicity, smoking, diabetes, and body mass index. RESULTS: Mean CMV IgG levels were higher in HIV-infected women compared with HIV-uninfected women (P < .01). Among HIV infected women, higher CMV IgG level was associated with decreased carotid artery distensibility (P < .01) and increased Young's modulus (P = .02). Higher CMV IgG antibody level was associated with increased prevalence of carotid artery lesions among HIV-infected women who achieved HIV suppression on antiretroviral therapy, but not among viremic or untreated HIV-infected women. Adjustment for Epstein Barr virus antibody levels and C-reactive protein levels had no effect on the associations between CMV IgG levels and vascular parameters. CONCLUSIONS: Cytomegalovirus antibody titers are increased in HIV-infected women and associated with subclinical cardiovascular disease. Host responses to CMV may be abnormal in HIV infection and associated with clinical disease. PMID- 22492857 TI - Illness severity in community-onset invasive Staphylococcus aureus infection and the presence of virulence genes. AB - BACKGROUND: It is uncertain whether particular clones causing invasive community onset methicillin-resistant and methicillin-sensitive Staphylococcus aureus (cMRSA/cMSSA) infection differ in virulence. METHODS: Invasive cMRSA and cMSSA cases were prospectively identified. Principal component analysis was used to derive an illness severity score (ISS) from clinical data, including 30-day mortality, requirement for intensive hospital support, the presence of bloodstream infection, and hospital length of stay. The mean ISS for each S. aureus clone (based on MLST) was compared with its DNA microarray-based genotype. RESULTS: Fifty-seven cMRSA and 50 cMSSA infections were analyzed. Ten clones caused 82 (77%) of these infections and had an ISS calculated. The enterotoxin gene cluster (egc) and the collagen adhesin (cna) gene were found in 4 of the 5 highest-ranked clones (ST47-MSSA, ST30-MRSA-IV[2B], ST45-MSSA, and ST22-MRSA IV[2B]) compared with none and 1 of the lowest 5 ranked clones, respectively. cMSSA clones caused more severe infection than cMRSA clones. The lukF/lukS Panton Valentine leukocidin (PVL) genes did not directly correlate with the ISS, being present in the second, fourth, and 10th most virulent clones. CONCLUSIONS: The clinical severity of invasive cMRSA and cMSSA infection is likely to be attributable to the isolates' entire genotype rather than a single putative virulence determinant such as PVL. PMID- 22492858 TI - Tryptophan catabolism during intracellular infection. PMID- 22492861 TI - Fluoroquinolone resistance in Neisseria gonorrhoeae: fitness cost or benefit? PMID- 22492860 TI - Impact of fluoroquinolone resistance mutations on gonococcal fitness and in vivo selection for compensatory mutations. AB - BACKGROUND: Quinolone-resistant Neisseria gonorrhoeae (QRNG) arise from mutations in gyrA (intermediate resistance) or gyrA and parC (resistance). Here we tested the consequence of commonly isolated gyrA(91/95) and parC86 mutations on gonococcal fitness. METHODS: Mutant gyrA(91/95) and parC86 alleles were introduced into wild-type gonococci or an isogenic mutant that is resistant to macrolides due to an mtrR(-79) mutation. Wild-type and mutant bacteria were compared for growth in vitro and in competitive murine infection. RESULTS: In vitro growth was reduced with increasing numbers of mutations. Interestingly, the gyrA(91/95) mutation conferred an in vivo fitness benefit to wild-type and mtrR( 79) mutant gonococci. The gyrA(91/95), parC86 mutant, in contrast, showed a slight fitness defect in vivo, and the gyrA(91/95), parC86, mtrR(-79) mutant was markedly less fit relative to the parent strains. A ciprofloxacin-resistant (Cip(R)) mutant was selected during infection with the gyrA(91/95), parC86, mtrR( 79) mutant in which the mtrR(-79) mutation was repaired and the gyrA(91) mutation was altered. This in vivo-selected mutant grew as well as the wild-type strain in vitro. CONCLUSIONS: gyrA(91/95) mutations may contribute to the spread of QRNG. Further acquisition of a parC86 mutation abrogates this fitness advantage; however, compensatory mutations can occur that restore in vivo fitness and maintain Cip(R). PMID- 22492862 TI - HLA-B signal peptide polymorphism influences the rate of HIV-1 acquisition but not viral load. AB - Human leukocyte antigen alleles influence the immune response to HIV-1. Signal peptides cleaved from those alleles bind to HLA-E and mediate natural killer cell function. Signal peptides of HLA-A and HLA-C proteins carry methionine (Met) at anchor position 2 (P2); those of HLA-B carry Met or threonine (Thr). Different P2 residues alter HLA-E binding to its cognate receptors and may impact HIV-1 acquisition. Among Zambian couples (N = 566) serodiscordant for HIV-1, P2-Met accelerated acquisition in the HIV-1-negative partner (relative hazard [RH], 1.79). Among seroconverting Zambian (n = 240) and Rwandan (n = 64) partners, P2 Met also accelerated acquisition (RH, 1.47 and RH, 1.83 respectively). HLA-B alleles displaying the reportedly protective Bw4 epitope carry P2-Thr. Bw4/P2-Thr and Bw6/P2-Thr showed similar protective effects compared with Bw6/P2-Met. Neither motif was associated with viral load. The influence of HLA-B alleles on HIV/AIDS may derive from multiple motifs in and beyond the mature proteins. PMID- 22492863 TI - Preexisting adenovirus seropositivity is not associated with increased HIV-1 acquisition in three HIV-1 vaccine efficacy trials. AB - The Step study of a recombinant adenovirus serotype 5 (Ad5)-based human immunodeficiency virus type 1 (HIV-1) vaccine revealed an increased risk of HIV-1 acquisition in vaccinees who were Ad5 seropositive at baseline. We therefore investigated whether preexisting Ad seropositivity to 7 different Ad serotypes was associated with increased risk of HIV-1 infection in 3 HIV-1 vaccine efficacy trials. In a case-control study involving 1570 adults enrolled in the VAX003 and VAX004 trials of a recombinant protein subunit HIV-1 vaccine and in the Step study, we observed that preexisting seropositivity to multiple Ad serotypes was not intrinsically associated with increased risk of HIV-1 acquisition. PMID- 22492864 TI - Tai Chi, arterial compliance, and muscle strength in older adults. AB - BACKGROUND: Aerobic exercise can alleviate the declines in arterial compliance common in older adults. However, when combined with strength training, aerobic exercise may not reduce arterial compliance. Tai Chi practice has been found to improve muscle strength and cardiopulmonary function in older subjects, but whether or not it improves arterial compliance is not known. The primary aim of this study was to investigate whether Tai Chi practitioners have better arterial compliance and muscle strength. DESIGN: Twenty-nine older Tai Chi practitioners (73.7 +/- 4.5 years) and 36 healthy control subjects (71.4 +/- 6.6 years) participated in this cross-sectional study. METHODS: The participants were independent in their daily living activities. They were screened for apparent cardiovascular disease and underwent arterial compliance testing and isokinetic knee muscle strength testing at 30 degrees /s. RESULTS: Tai Chi practitioners showed significantly better haemodynamic parameters than the controls as indexed by larger and small artery compliance. They also demonstrated greater eccentric muscle strength in both knee extensors and flexors. CONCLUSION: The findings of better muscle strength without jeopardizing arterial compliance suggests that Tai Chi could be a suitable exercise for older persons to improve both cardiovascular function and muscle strength. PMID- 22492865 TI - Rapidly upsloping ST-segment on exercise ECG: a marker of reduced coronary heart disease mortality risk. AB - BACKGROUND: The prognostic value of an isolated J-point depression, or rapidly upsloping ST-segment, on an exercise ECG has long been assumed to be a benign variant. However, little or no data supporting this assumption may be found in the literature. Our task was to examine if a rapidly upsloping ST-segment on an exercise ECG is associated with changes in risk of dying from CHD in 2014 healthy middle-aged men followed for 35 years. METHODS: A group of healthy middle-aged men (n = 2014) participated in a cardiovascular survey. They underwent an examination programme including a symptom-limited ECG bicycle exercise test. Exercise induced ST-segments were categorised in three groups: normal ST-segment (n = 1383), rapidly upsloping (n = 401), and ST-depression (n = 230). Survival analyses were adjusted for smoking status, total cholesterol, systolic blood pressure, maximal heart rate, and physical fitness. The mean follow-up time was 35 years. RESULTS: The rapidly upsloping group had a 30% decreased risk of CHD death (hazard ratio, HR, 0.70, 95% CI 0.51-0.95) compared to the normal ST segment group. The risk of CVD-death was numerically lower in the rapidly upsloping group (HR 0.82, 95% CI 0.65-1.04) compared to the normal ST-segment group. The ST-depression group had a 1.45-fold (HR 1.45, 95% CI 1.09-1.90) increased risk of CHD death compared to the normal ST-segment group. CONCLUSIONS: The rapidly upsloping ST-segment was a common finding (20%) on exercise ECG among healthy middle-aged men and was associated with a 30% reduced risk of dying from CHD compared to individuals with normal ST-segment. A rapidly upsloping ST segment on exercise ECG may represent the true healthy state. PMID- 22492866 TI - Chronotropic incompetence predicts impaired response to exercise training in heart failure patients with sinus rhythm. AB - BACKGROUND: In most patients with chronic heart failure (CHF), endurance training improves exercise capacity. However, some patients do not respond favourably. The purpose of this study was to explore the reasons of non-response and to determine their predictive value. METHODS: We studied a cohort of 120 consecutive CHF patients with sinus rhythm (mean age 57 +/- 12 years, ejection fraction 29.3 +/- 9.9%, peak VO2 17.3 +/- 5.1 ml/min/kg), participating in a 3-month outpatient cardiac rehabilitation programme. Responders were defined as subjects who improved peak VO2 by more than 5%, work load by more than 10%, or VE/VCO2 slope by more than 5%. Subjects who did not fulfil at least one of the above criteria were characterized as non-responders. Multivariate regression analyses were performed to identify parameters that were predictive for a response. Receiver operating characteristic (ROC) analyses were performed for predictive parameters to identify thresholds for response or non-response. RESULTS: Multivariate regression analyses revealed heart rate (HR) reserve, HR recovery at 1 min, and peak HR as significant predictors for a positive training response. ROC curves revealed the optimal thresholds separating responders from non-responders at less than 30 bpm for HR reserve, less than 6 bpm for HR recovery and less than 101 bpm for peak HR. CONCLUSIONS: The presence of impaired chronotropic competence is a major predictor of poor training response in CHF patients with sinus rhythm. PMID- 22492867 TI - The B gene of pea encodes a defective flavonoid 3',5'-hydroxylase, and confers pink flower color. AB - The inheritance of flower color in pea (Pisum sativum) has been studied for more than a century, but many of the genes corresponding to these classical loci remain unidentified. Anthocyanins are the main flower pigments in pea. These are generated via the flavonoid biosynthetic pathway, which has been studied in detail and is well conserved among higher plants. A previous proposal that the Clariroseus (B) gene of pea controls hydroxylation at the 5' position of the B ring of flavonoid precursors of the anthocyanins suggested to us that the gene encoding flavonoid 3',5'-hydroxylase (F3'5'H), the enzyme that hydroxylates the 5' position of the B ring, was a good candidate for B. In order to test this hypothesis, we examined mutants generated by fast neutron bombardment. We found allelic pink-flowered b mutant lines that carried a variety of lesions in an F3'5'H gene, including complete gene deletions. The b mutants lacked glycosylated delphinidin and petunidin, the major pigments present in the progenitor purple flowered wild-type pea. These results, combined with the finding that the F3'5'H gene cosegregates with b in a genetic mapping population, strongly support our hypothesis that the B gene of pea corresponds to a F3'5'H gene. The molecular characterization of genes involved in pigmentation in pea provides valuable anchor markers for comparative legume genomics and will help to identify differences in anthocyanin biosynthesis that lead to variation in pigmentation among legume species. PMID- 22492869 TI - A TSHR-LH/CGR chimera that measures functional thyroid-stimulating autoantibodies (TSAb) can predict remission or recurrence in Graves' patients undergoing antithyroid drug (ATD) treatment. AB - CONTEXT: A functional thyroid-stimulating autoantibodies (TSAb) assay using a thyroid-stimulating hormone receptor chimera (Mc4) appears to be clinically more useful than the commonly used assay, a binding assay that measures all the antibodies binding to the thyroid-stimulating hormone receptor without functional discrimination, in diagnosing patient with Graves' disease (GD). OBJECTIVE: The objective of the study was to investigate whether an Mc4 assay can predict relapse/remission of hyperthyroidism after antithyroid drug (ATD) treatment in patients with GD. DESIGN: An Mc4 assay was used to prospectively track TSAb activity in GD patients treated with ATD over a 5-yr period. SETTING AND PATIENTS: GD patients from the Chieti University participated in this study. INTERVENTIONS: Interventions included the assessment of patients' sera using the Mc4 assay, the Mc4-derivative assay (Thyretain), and a human monoclonal thyroid stimulating hormone receptor antibody, M22 assay. MAIN OUTCOME MEASURES: The Mc4 assay, a sensitive index of remission and recurrence, was used in this study. RESULTS: The TSAb levels significantly decreased only in the remitting group as evidenced by Mc4 assay values at the end of ATD (0.96 +/- 1.47, 10.9 +/- 26.6. and 24.7 +/- 37.5 arbitrary units for the remitting, relapsing, and unsuspended therapy groups, respectively). Additional prognostic help was obtained by thyroid volume measurements at the end of treatment. Although not statistically significant, the Mc4 assay has a trend toward improved positive predictive value (95.4 vs. 84.2 or 87.5%), specificity (96.4 vs. 86.4 and 90.9%), and accuracy (87.3 vs. 83.3 and 80.9%) comparing the Mc4, Thyretain, and M22 assays, respectively. Thyretain has a trend toward improved negative predictive value (82.6 vs. 81.8 and 76.9%) and sensitivity (80 vs. 77.8 and 70%) comparing Thyretain, Mc4, and M22 assays, respectively. CONCLUSION: The Mc4 assay is a clinically useful index of remission and relapse in patients with GD. Larger studies are required to confirm these findings. PMID- 22492868 TI - Relationship between adipose tissue lipolytic activity and skeletal muscle insulin resistance in nondiabetic women. AB - CONTEXT: Increased adipose tissue lipolytic activity is considered an important factor in the pathogenesis of skeletal muscle insulin resistance associated with obesity. OBJECTIVE: The objective of the study was to evaluate the relationship between the rate of release of free fatty acids (FFA) into plasma and skeletal muscle insulin sensitivity in human subjects. METHODS: We determined the palmitate rate of appearance (Ra) per kilogram fat-free mass (an index of FFA availability to lean tissues) during basal conditions and during insulin infusion (to simulate postprandial insulin concentrations) and skeletal muscle insulin sensitivity, defined as the percent increase in the glucose rate of disappearance, in 110 nondiabetic women (body mass index 20.6-46.4 kg/m(2)) by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotope tracer methods. RESULTS: Basal (r(s) = -0.379, P < 0.001) and insulin suppressed (r(s) = -0.631, P < 0.001) palmitate Ra correlated negatively with skeletal muscle insulin sensitivity. However, the strength of the correlation was greater for palmitate Ra during insulin infusion than palmitate Ra during basal conditions (P = 0.0007) when lipolytic rates and FFA availability were reduced to less than 20% of basal values. The relative suppression of palmitate Ra correlated directly with the relative stimulation of glucose rate of disappearance during insulin infusion (r(s) = 0.530, P < 0.001). CONCLUSION: These data suggest that the correlation between FFA kinetics and muscle glucose metabolism is due to multiorgan insulin resistance rather than a direct effect of FFA itself on skeletal muscle insulin action and challenge the view that increased adipose tissue lipolytic rate is an important cause of insulin resistance. PMID- 22492870 TI - Is biochemical screening for pheochromocytoma in adrenal incidentalomas expressing low unenhanced attenuation on computed tomography necessary? AB - OBJECTIVE: Pheochromocytomas are characterized by a high attenuation value on unenhanced computed tomography (CT). It is not known whether pheochromocytoma could be ruled out as a cause of adrenal incidentalomas on the basis of unenhanced attenuation values only. DESIGN: We retrospectively evaluated the outcome of routine biochemical screening for pheochromocytoma in a series of adrenal incidentalomas in relationship to the unenhanced attenuation values on CT. METHODS: An unenhanced CT was available in 174 of 184 patients with 214 adrenal incidentalomas. All patients were screened for pheochromocytoma with 24-h urinary metanephrines and normetanephrines and for hypercortisolism (1 mg dexamethasone test and ACTH). Hypertensive patients were screened for aldosterone overproduction (aldosterone to renin ratio and 24 h urinary aldosterone). The results were compared between incidentalomas with high [>=10 Hounsfield units (HU)] and low (<10 HU) unenhanced attenuation values. RESULTS: One hundred forty six incidentalomas in 115 patients had an unenhanced HU less than 10. None of these patients had elevated 24-h fractionated urinary metanephrines or normetanephrines suggesting pheochromocytoma. Sixty-eight incidentalomas in 59 patients had an unenhanced HU of 10 or greater, and nine (15.2%) of these patients had surgically and histologically verified pheochromocytoma. Incidentalomas with a HU of 10 or greater were significantly larger (2.6 +/- 1.5 vs. 2.3 +/- 1.2 cm; P < 0.001), more often functional (27.9 vs. 8.9%, P < 0.001), and more often operated (44.1 vs. 10.2%; P < 0.001) than those with a Hounsfield unit less than 10. CONCLUSION: The results of this study indicate that routine biochemical screening of pheochromocytoma in small homogenous adrenal incidentalomas characterized by an unenhanced Hounsfield unit value less than 10 HU may not be necessary. PMID- 22492871 TI - Endometrial miR-181a and miR-98 expression is altered during transition from normal into cancerous state and target PGR, PGRMC1, CYP19A1, DDX3X, and TIMP3. AB - CONTEXT: Evidence suggests that a number of microRNA (miRNA) are aberrantly expressed in endometrial disorders with potential posttranscriptional regulation of their specific target genes, including ovarian steroid receptors. OBJECTIVES: Our objective was to assess the endometrial expression of miR-98 and miR-181a and their respective target genes, progesterone (P4) receptor membrane component 1 (PGRMC1) and P4 receptor (PGR). DESIGN, SETTING, AND PATIENTS: We evaluated tissue expression and in vitro regulation at an academic university medical center in endometrial biopsies and endometrial tissues from follicular and luteal phases with and without exposure to hormonal therapies and grade I-III endometrial cancer (n = 52). INTERVENTIONS: INTERVENTIONS included endometrial biopsies and in vitro transfection. MAIN OUTCOME MEASURES: We evaluated expression and function of miR-98 and miR-181a. RESULTS: Aberrant expression of miR-98 and miR-181a is associated with endometrial transition from normal into cancerous states, which to some extent is influenced by hormonal milieu, and exhibited an inverse relationship with PGMRC1 and PGR expression, respectively. Treatments of Ishikawa cells with 17beta-estradiol, P4, or medroxyprogesterone acetate had limited effects on miR-98, miR-181a, and PGRMC1 expression, whereas 17beta-estradiol treatment increased PGR expression. In Ishikawa cells, gain of function of miR-98 repressed PGRMC1 and CYP19A1, and miR-181a repressed PGR, DDX3X, and TIMP3 at mRNA and protein levels through direct interactions with their respective 3'-untranslated regions and CCNE1 through miR-181a-induced DDX3X repression, with miR-98 reducing the rate of cell proliferation as compared with controls. CONCLUSION: miR-98 and miR-181a through their regulatory functions on PGRMC1, PGR, CYP19A1, TIMP3, and DDX3X expression may influence a wide range of endometrial cellular activities during normal menstrual cycle and transition into disease states, including endometrial cancer. PMID- 22492872 TI - Phospholipid transfer protein is differentially expressed in human arterial and venous placental endothelial cells and enhances cholesterol efflux to fetal HDL. AB - CONTEXT: Phospholipid (PL) transfer protein (PLTP) plays a crucial role in high density lipoprotein (HDL) metabolism. In the fetal circulation, HDL particles are the main cholesterol carriers and are involved in maternal-fetal cholesterol transfer across human placental endothelial cells (HPEC). OBJECTIVE: The aim was to investigate local function(s) of PLTP at the fetoplacental endothelium. Because HPEC display morphological and functional diversity when isolated from arteries or veins, we hypothesized that PLTP activity may differ between arterial and venous HPEC. DESIGN: We determined PLTP mRNA and activity levels from isolated HPEC and investigated PLTP-mediated remodeling of fetal HDL particles and their capacity in mediating cholesterol efflux from HPEC. RESULTS: Incubation of fetal HDL with active human plasma PLTP resulted in increased particle size (12.6 vs. 13.2 nm, P < 0.05), with a concomitant increase (3.5-fold) in pre-beta mobile HDL particles. Arterial HPEC showed higher Pltp expression levels and secreted PL transfer activity (1.8-fold, P < 0.001) than venous HPEC. In contrast to adult HDL(3), [(3)H]cholesterol efflux to fetal HDL was 21% higher (P < 0.05) from arterial than from venous HPEC. PLTP-facilitated particle conversion increased the cholesterol efflux capacity of fetal HDL to similar extents (55 and 48%, P < 0.001) from arterial and venous HPEC, respectively. CONCLUSION: PLTP mediates PL transfer and participates in reverse cholesterol transport pathways at the fetoplacental barrier. Enhanced cellular cholesterol efflux from HPEC to fetal HDL remodeled by PLTP supports the idea of a local atheroprotective role of PLTP in the placental vasculature. PMID- 22492873 TI - Melanocortin-4 receptor signaling is required for weight loss after gastric bypass surgery. AB - CONTEXT: Roux-en-Y gastric bypass (RYGB) is one of the most effective long-term therapies for the treatment of severe obesity. Recent evidence indicates that RYGB effects weight loss through multiple physiological mechanisms, including changes in energy expenditure, food intake, food preference, and reward pathways. OBJECTIVE: Because central melanocortin signaling plays an important role in the regulation of energy homeostasis, we investigated whether genetic disruption of the melanocortin-4 receptor (MC4R) in rodents and humans affects weight loss after RYGB. METHODS AND RESULTS: Here we report that MC4R(-/-) mice lost substantially less weight after surgery than wild-type animals, indicating that MC4R signaling is necessary for the weight loss effects of RYGB in this model. Mice heterozygous for MC4R remain fully responsive to gastric bypass. To determine whether mutations affect surgically induced weight loss in humans, we sequenced the MC4R gene in 972 patients undergoing RYGB. Patients heterozygous for MC4R mutations exhibited the same magnitude and distribution of postoperative weight loss as patients without such mutations, suggesting that although two normal copies of the MC4R gene are necessary for normal weight regulation, a single normal copy of the MC4R gene is sufficient to mediate the weight loss effects of RYGB. CONCLUSIONS: MC4R is the first gene identified that is required for the sustained effects of bariatric surgery. The need for MC4R signaling for the weight loss effects of RYGB in mice underscores the physiological mechanisms of action of this procedure and demonstrates that RYGB both influences and is dependent on the normal pathways that regulate energy balance. PMID- 22492874 TI - High rate of placental infarcts in type 2 compared with type 1 diabetes. AB - CONTEXT: Timing and cause of pregnancy loss differ between type 1 (T1DM) and type 2 diabetes mellitus (T2DM). OBJECTIVE: The objective of the study was to determine whether placental histology corresponds to differing causes of pregnancy loss in T1DM and T2DM. We hypothesized that placentas from mothers with T2DM would be more likely to demonstrate vascular pathology than those from mothers with T1DM. RESEARCH DESIGN/SETTING/PARTICIPANTS: We reviewed medical histories, pregnancy outcomes, and placental histology of women with pregestational T1DM and T2DM with singleton pregnancies between 2001 and 2009 at a single tertiary care medical center. MAIN OUTCOME MEASURES: Placental weight, placental dysmaturity, villous maturation, villitis of unclear etiology, and histological evidence of placental infarction were measured. RESULTS: Ninety eight placentas were available for review, 53 from T1DM mothers (56%) and 45 from T2DM mothers (46%). Mean age and glycemic control each trimester did not differ between diabetes types. T2DM placentas had a higher prevalence of placental infarcts (22 vs. 6%, P = 0.02) and a lower prevalence of placental dysmaturity (12 vs. 29%, P = 0.05) compared with T1DM; rates differed from those reported in the general population. There was no difference in placental weight, villous maturity, or villitis of unclear etiology between diabetes types. CONCLUSIONS: There were many similarities in placental histological findings between diabetes types. Still, one in five T2DM placentas displayed histological infarcts, consistent with a vascular, rather than glycemic, etiology of pregnancy complications, whereas T1DM placentas showed signs of abnormal development. PMID- 22492875 TI - The association of fasting insulin, glucose, and lipids with bone mass in adolescents: findings from a cross-sectional study. AB - CONTEXT: It is unclear whether variation in insulin resistance mediates the positive association of fat mass with bone mass in children/adolescents. OBJECTIVE: Our objective was to examine whether markers linked to insulin resistance [fasting insulin, glucose, triglycerides, and high-density lipoprotein cholesterol (HDLc)] are associated with bone mass in adolescents, and if they are, to examine whether they mediate the fat mass-bone mass association. DESIGN AND SETTING: We conducted a cross-sectional analysis in participants from the Avon Longitudinal Study of Parents and Children. PARTICIPANTS: Participants included 2305 (1100 male) individuals of mean age 15.5 yr. OUTCOME MEASURES: We evaluated total body less head bone mineral content (BMC) (grams), bone area (BA) (square centimeters), and bone mineral density (BMD) (grams per square centimeter) from a dual-energy x-ray absorptiometry scan. RESULTS: Fat mass, fasting insulin, and triglycerides were positively associated with BMD, BMC, and BA; HDLc was inversely associated with these outcomes. For example, the adjusted mean difference in BMC per 1 sd fasting insulin was 45 g (95% confidence interval = 17-73 g) in males and 50 g (95% confidence interval = 28-72 g) in females. When the associations of fat mass with outcomes were adjusted for markers of insulin resistance, they were largely unchanged. Associations of triglycerides and HDLc with outcomes were attenuated to the null when they were adjusted for fat mass, whereas those of insulin changed direction; i.e. with adjustment for fat mass, higher fasting insulin was associated with lower BMD, BMC, and BA. CONCLUSIONS: Fasting insulin, glucose, and lipids do not appear to mediate the positive association of fat mass with bone mass in children/adolescents. The inverse association of fasting insulin with BMD, BMC, and BA once fat mass has been controlled for needs further study. PMID- 22492876 TI - An infant with pseudohyperkalemia, hemolysis, and seizures: cation-leaky GLUT1 deficiency syndrome due to a SLC2A1 mutation. AB - CONTEXT: GLUT1 (glucose transporter 1) deficiency syndrome is a well-known presentation in pediatric practice. Very rare mutations not only disable carbohydrate transport but also cause the red cell membrane to be constitutively permeant to monovalent cations, namely sodium and potassium. OBJECTIVE: The aim of this study was to describe the pediatric presentation of a patient with GLUT1 deficiency with such a cation-leaky state. SUBJECT AND METHODS: The infant presented with erratic hyperkalemia, neonatal hyperbilirubinemia, anemia, hepatic dysfunction, and microcephaly. Later, seizures occurred and developmental milestones were delayed. Magnetic resonance imaging and computerized tomography scans of the brain showed multiple abnormalities including periventricular calcification. Visual impairment was present due to the presence of both cataracts and retinal dysfunction. RESULTS: Measurements of red cell cation content showed extremely leaky red cells (causing the hemolysis) and temperature dependent loss of potassium from red cells (explaining the hyperkalemia as pseudohyperkalemia). A trinucleotide deletion in SLC2A1, coding for the deletion of isoleucine 435 or 436 in GLUT1, was identified in the proband. CONCLUSION: This is the fourth pedigree to be described with this most unusual syndrome. The multisystem pathology probably reflects a combination of glucose transport deficiency at the blood-brain barrier (as in typical GLUT1 deficiency) and the deleterious osmotic effects of a cation-leaky membrane protein in the cells where GLUT1 is expressed, notably the red cell. We hope that this detailed description will facilitate rapid diagnosis of this disease entity. PMID- 22492877 TI - Investigation of unexpected serum CA19-9 elevation in Lewis-negative cancer patients. AB - BACKGROUND: Cancer patients with a Lewis (a-b-) phenotype have no carbohydrate antigen 19-9 (CA19-9) in their serum. However, we found a small but distinct elevation in the serum CA19-9 level in three cancer patients with the Lewis negative phenotype. Here, we investigated the reason of such phenomena. METHODS: Six cancer patients with a Lewis-negative phenotype were selected by very low CA19-9 concentrations: three showed a small elevation (Group A) and the other three showed no elevation (Group B) in the serum CA19-9. We investigated the difference by analyzing the Lewis/Secretor genotypes. RESULTS: All of the six patients with a Le (a-b-) phenotype were genuine Le-negative genotypes: four individuals were homozygous for le1 (le(59,508)), one patient was compound heterozygous for le1 (le(59,508)) and le2 (le(59,1067)) and one patient was compound heterozygous for le1 and le(202,314). As for the Secretor gene, the three patients in Group B were homozygous for Se2 (one patient) or compound heterozygous for Se2 and sej (two patients), while the patients in Group A were all homozygous for sej genotypes. CONCLUSIONS: Even genuinely Le-negative patients, who genetically lack the Le enzyme and theoretically never produce CA19 9, occasionally show a slight increase in serum CA19-9 level when they are homozygous for Se-negative genotypes and suffer from advanced cancer with overproduction of glycans as precursors of CA19-9. Although such cases are not frequent, we should be acquainted with the correlation between serum CA19-9 values and genotypes of Lewis and Secretor genes. PMID- 22492878 TI - Development of an automatic laboratory computer flagging system to identify urine albumin samples potentially affected by antigen excess ('hooking'). AB - BACKGROUND: Immunoassays for urinary albumin are often subject to the problem of antigen excess (the 'hook' effect) at high albumin concentrations. We developed an automated protocol to identify such samples based on urinary albumin to creatinine ratio (uACR) and urinary total protein (uTP) results. METHODS: An automated flagging system was designed and written into the laboratory computer system to alert technical staff to samples potentially affected by the 'hook effect'. This flag was activated when there was a combination of an uTP of >=2400 mg/L and an uACR of <30 mg/mmol. RESULTS: The potential rate of false-negative uACR results was approximately 0.17% in samples from primary care and diabetic clinic sources. CONCLUSIONS: Samples with falsely low uACR results were identified, allowing the vast majority of results to be authorized without intervention. The protocol prevented the reporting of false-negative uACR results which might impact on the management of patients. PMID- 22492879 TI - A high pressure liquid chromatography method for separation of prolactin forms. AB - BACKGROUND: Prolactin has multiple forms and macroprolactin, which is thought not to be bioavailable, can cause a raised serum prolactin concentration. Gel filtration chromatography (GFC) is currently the gold standard method for separating macroprolactin, but is labour-intensive. Polyethylene glycol (PEG) precipitation is suitable for routine use but may not always be accurate. We developed a high pressure liquid chromatography (HPLC) assay for macroprolactin measurement. METHODS: Chromatography was carried out using an Agilent Zorbax GF 250 (9.4 * 250 mm, 4 MUm) size exclusion column and 50 mmol/L Tris buffer with 0.15 mmol/L NaCl at pH 7.2 as mobile phase, with a flow rate of 1 mL/min. Serum or plasma was diluted 1:1 with mobile phase and filtered and 100 MUL injected. Fractions of 155 MUL were collected for prolactin measurement and elution profile plotted. The area under the curve of each prolactin peak was calculated to quantify each prolactin form, and compared with GFC. RESULTS: Clear separation of monomeric-, big- and macroprolactin forms was achieved. Quantification was comparable to GFC and precision was acceptable. Total time from injection to collection of the final fraction was 16 min. CONCLUSIONS: We have developed an HPLC method for quantification of macroprolactin, which is rapid and easy to perform and therefore can be used for routine measurement. PMID- 22492880 TI - 'Swinging for the fences' versus striking out on cancer. PMID- 22492881 TI - Passing the buck--or empowering states? Who will define essential health benefits. PMID- 22492882 TI - An analysis of whether higher health care spending in the United States versus Europe is 'worth it' in the case of cancer. AB - The United States spends more on health care than other developed countries, but some argue that US patients do not derive sufficient benefit from this extra spending. We studied whether higher US cancer care costs, compared with those of ten European countries, were "worth it" by looking at the survival differences for cancer patients in these countries compared to the relative costs of cancer care. We found that US cancer patients experienced greater survival gains than their European counterparts; even after considering higher US costs, this investment generated $598 billion of additional value for US patients who were diagnosed with cancer between 1983 and 1999. The value of that additional survival gain was highest for prostate cancer patients ($627 billion) and breast cancer patients ($173 billion). These findings do not appear to have been driven solely by earlier diagnosis. Our study suggests that the higher-cost US system of cancer care delivery may be worth it, although further research is required to determine what specific tools or treatments are driving improved cancer survival in the United States. PMID- 22492883 TI - How cancer patients value hope and the implications for cost-effectiveness assessments of high-cost cancer therapies. AB - Assessments of the medical and economic value of therapies in diseases such as cancer traditionally focus on average or median gains in patients' survival. This focus ignores the value that patients may place on a therapy with a wider "spread" of outcomes that offer the potential of a longer period of survival. We call such treatments "hopeful gambles" and contrast them with "safe bets" that offer similar average survival but less chance of a large gain. Real-world therapy options do not have these stylized forms, but they can differ in the spread of survival gains that patients face. We found that 77 percent of surveyed cancer patients with melanoma, breast cancer, or other kinds of solid tumors preferred hopeful gambles to safe bets. This suggests that current technology assessments, which often determine access to such cancer therapies, may be missing an important source of value to patients and should either incorporate hope into the value of therapies or set a higher threshold for an acceptable cost effectiveness ratio in the end-of-life context. PMID- 22492884 TI - Survey results show that adults are willing to pay higher insurance premiums for generous coverage of specialty drugs. AB - Generous coverage of specialty drugs for cancer and other diseases may be valuable not only for sick patients currently using these drugs, but also for healthy people who recognize the potential need for them in the future. This study estimated how healthy people value insurance coverage of specialty drugs, defined as high-cost drugs that treat cancer and other serious health conditions like multiple sclerosis, by quantifying willingness to pay via a survey. US adults were estimated to be willing to pay an extra $12.94 on average in insurance premiums per month for generous specialty-drug coverage--in effect, $2.58 for every dollar in out-of-pocket costs that they would expect to pay with a less generous insurance plan. Given the value that people assign to generous coverage of specialty drugs, having high cost sharing on these drugs seemingly runs contrary to what people value in their health insurance. PMID- 22492885 TI - Patients value metastatic cancer therapy more highly than is typically shown through traditional estimates. AB - There is a growing emphasis on promoting medical treatments that provide the most benefits relative to their costs. However, objective criteria for determining the value patients receive from treatment are lacking. This study used data on the treatment choices of terminally ill patients to estimate the value they associate with care. We found that patients place high valuations on metastatic cancer therapy--on average, twenty-three times higher than its cost--and that other traditional methods used to estimate the value of these treatments for patients significantly undervalues how patients view them. Our methods provide another framework for an evidence-based approach to assessing the value of treatments for terminal illness. PMID- 22492886 TI - Therapies for advanced cancers pose a special challenge for health technology assessment organizations in many countries. AB - Health technology assessment organizations evaluate medical therapies and technologies to help inform coverage and reimbursement decisions for payers around the globe. Even as they establish strict review processes, these organizations--and the reimbursement authorities that use their assessments--have sometimes handled cancer interventions with special care. We found that some countries have created separate health technology assessment pathways for cancer treatment, while others have eased access to cancer treatments through end-of life or disease-severity exceptions within health technology assessment policies. In the United States, although no separate evaluation pathways exist for cancer, cancer drugs receive special status by virtue of unique Medicare rules covering off-label indications. Worldwide, we demonstrate that health technology assessment organizations are struggling with cancer's "exceptionalism." PMID- 22492887 TI - In a survey, marked inconsistency in how oncologists judged value of high-cost cancer drugs in relation to gains in survival. AB - Amid calls for physicians to become better stewards of the nation's health care resources, it is important to gain insight into how physicians think about the cost-effectiveness of new treatments. Expensive new cancer treatments that can extend life raise questions about whether physicians are prepared to make "value for money" trade-offs when treating patients. We asked oncologists in the United States and Canada how much benefit, in additional months of life expectancy, a new drug would need to provide to justify its cost and warrant its use in an individual patient. The majority of oncologists agreed that a new cancer treatment that might add a year to a patient's life would be worthwhile if the cost was less than $100,000. But when given a hypothetical case of an individual patient to review, the oncologists also endorsed a hypothetical drug whose cost might be as high as $250,000 per life-year gained. The results show that oncologists are not consistent in deciding how many months an expensive new therapy should extend a person's life before the cost of therapy is justified. Moreover, the benefit that oncologists demand from new treatments in terms of length of survival does not necessarily increase according to the price of the treatment. The findings suggest that policy makers should find ways to improve how physicians are educated on the use of cost-effectiveness information and to influence physician decision making through clinical guidelines that incorporate cost-effectiveness information. PMID- 22492888 TI - Michigan oncology practices showed varying adherence rates to practice guidelines, but quality interventions improved care. AB - Despite improvements in care for patients with cancer, and in their survival rates, it is not clear that best practices are uniformly delivered to patients. We measured the quality of outpatient cancer care, using validated quality measures, in a consortium of thirty-six outpatient oncology practices in Michigan. We discovered that throughout the measurement period, for breast and colorectal cancer care, there was a more than 85 percent rate of adherence to quality care processes. For end-of-life care processes, the adherence rate was 73 percent, and for symptom and toxicity management care processes, adherence was 56 percent. In particular, we found variations in care around the fundamental oncologic task of management of cancer pain. To address quality gaps, we developed interventions to improve adherence to treatment guidelines, improve pain management, and incorporate palliative care into oncology practice. We concluded that statewide consortia that assume much of the cost burden of quality improvement activities can bring together oncology providers and payers to measure quality and design interventions to improve care. PMID- 22492889 TI - Michigan oncology practice applies quality measures to managing care. PMID- 22492890 TI - Appropriate and inappropriate imaging rates for prostate cancer go hand in hand by region, as if set by thermostat. AB - Policy makers interested in containing health care costs are targeting regional variation in utilization, including the use of advanced imaging. However, bluntly decreasing utilization among the highest-utilization regions may have negative consequences. In a cross-sectional study of prostate cancer patients from 2004 to 2005, we found that regions with lower rates of inappropriate imaging also had lower rates of appropriate imaging. Similarly, regions with higher overall imaging rates tended to have not only higher rates of inappropriate imaging, but also higher rates of appropriate imaging. In fact, men with high-risk prostate cancer were more likely to receive appropriate imaging if they resided in areas with higher rates of inappropriate imaging. This "thermostat model" of regional health care utilization suggests that poorly designed policies aimed at reducing inappropriate imaging could limit access to appropriate imaging for high-risk patients. Health care organizations need clearly defined quality metrics and supportive systems to encourage appropriate treatment for patients and to ensure that cost containment does not occur at the expense of quality. PMID- 22492891 TI - Urologists' self-referral for pathology of biopsy specimens linked to increased use and lower prostate cancer detection. AB - Federal law allows physicians in some circumstances to refer patients for additional services to a facility in which the physician has a financial interest. The practice of physician self-referral for imaging and pathology services has been criticized because it can lead to increased use and escalating health care expenditures, with little or no benefit to patients. This study examined Medicare claims for men in a set of geographically dispersed counties to determine how the "in-office ancillary services" exception affected the use of surgical pathology services and cancer detection rates associated with prostate biopsies. I found that self-referring urologists billed Medicare for 4.3 more specimens per prostate biopsy than the adjusted mean of 6 specimens per biopsy that non-self-referring urologists sent to independent pathology providers, a difference of almost 72 percent. Additionally, the regression-adjusted cancer detection rate in 2007 was twelve percentage points higher for men treated by urologists who did not self-refer. This suggests that financial incentives prompt self-referring urologists to perform prostate biopsies on men who are unlikely to have prostate cancer. These results support closing the loophole that permits self-referral to "in-office" pathology laboratories. PMID- 22492893 TI - Direct-to-consumer Internet promotion of robotic prostatectomy exhibits varying quality of information. AB - Robotic surgery to remove a cancerous prostate has become a popular treatment. Internet marketing of this surgery provides an intriguing case study of direct-to consumer promotions of medical devices, which are more loosely regulated than pharmaceutical promotions. We investigated whether the claims made in online promotions of robotic prostatectomy were consistent with evidence from comparative effectiveness studies. After performing a search and cross-sectional analysis of websites that mentioned the procedure, we found that many sites claimed benefits that were unsupported by evidence and that 42 percent of the sites failed to mention risks. Most sites were published by hospitals and physicians, which the public may regard as more objective than pages published by manufacturers. Unbalanced information may inappropriately raise patients' expectations. Increasing enforcement and regulation of online promotions may be beyond the capabilities of federal authorities. Thus, the most feasible solution may be for the government and medical societies to promote the production of balanced educational material. PMID- 22492892 TI - Growth of high-cost intensity-modulated radiotherapy for prostate cancer raises concerns about overuse. AB - To study the impact of new, expensive, and unproven therapies to treat prostate cancer, we investigated the dissemination of intensity-modulated radiotherapy (IMRT). IMRT is an innovative treatment for prostate cancer that delivers higher doses of radiation with improved precision compared to alternative radiotherapies. We observed rapid adoption of this new treatment among men diagnosed with prostate cancer from 2001 through 2007, despite uncertainty about its relative effectiveness. We compared patient and disease characteristics of those receiving IMRT and the previous radiation standard of care, three dimensional conformal therapy; assessed intermediate-term outcomes; and examined potential factors associated with the increased use of IMRT. We found that in the early period of IMRT adoption (2001-03) men with high-risk disease were more likely to receive IMRT, whereas after IMRT's initial dissemination (2004-07) men with low-risk disease had fairly similar likelihoods of receiving IMRT as men with high-risk disease. This raises concerns about overtreatment, as well as considerable health care costs, because treatment with IMRT costs $15,000-$20,000 more than other standard therapies. As health care delivery reforms gain traction, policy makers must balance the promotion of new, yet unproven, technology with the risk of overuse. PMID- 22492894 TI - An actuarial analysis shows that offering lung cancer screening as an insurance benefit would save lives at relatively low cost. AB - Lung cancer screening is not established as a public health practice, yet the results of a recent large randomized controlled trial showed that screening with low-dose spiral computed tomography reduces lung cancer mortality. Using actuarial models, this study estimated the costs and benefits of annual lung cancer screening offered as a commercial insurance benefit in the high-risk US population ages 50-64. Assuming current commercial reimbursement rates for treatment, we found that screening would cost about $1 per insured member per month in 2012 dollars. The cost per life-year saved would be below $19,000, an amount that compares favorably with screening for cervical, breast, and colorectal cancers. Our results suggest that commercial insurers should consider lung cancer screening of high-risk individuals to be high-value coverage and provide it as a benefit to people who are at least fifty years old and have a smoking history of thirty pack-years or more. We also believe that payers and patients should demand screening from high-quality, low-cost providers, thus helping set an example of efficient system innovation. PMID- 22492895 TI - Changing physician incentives for cancer care to reward better patient outcomes instead of use of more costly drugs. AB - More-sophisticated chemotherapy regimens have improved the outlook for cancer patients since the 1970s, but the payment system for cancer chemotherapy has not changed during that time span. The "buy and bill" approach for reimbursement provides incentives for medical oncologists to use expensive medications when less costly alternatives that deliver similar results are available. Furthermore, the system does nothing to assess how much value society derives from high-price drugs. This paper reviews the historical context of "buy and bill" reimbursement and considers the use of clinical pathways and bundled payments, two alternative strategies that are being tried to reward physicians for improving outcomes and reducing the total cost of cancer care. PMID- 22492897 TI - Medicare's flagship test of pay-for-performance did not spur more rapid quality improvement among low-performing hospitals. AB - Medicare's flagship hospital pay-for-performance program, the Premier Hospital Quality Incentive Demonstration, began in 2003 but changed its incentive design in late 2006. The goals were to encourage greater quality improvement, particularly among lower-performing hospitals. However, we found no evidence that the change achieved these goals. Although the program changes were intended to provide strong incentives for improvement to the lowest-performing hospitals, we found that in practice the new incentive design resulted in the strongest incentives for hospitals that had already achieved quality performance ratings just above the median for the entire group of participating hospitals. Yet during the course of the program, these hospitals improved no more than others. Our findings raise questions about whether pay-for-performance strategies that reward improvement can generate greater improvement among lower performing providers. They also cast some doubt on the extent to which hospitals respond to the specific structure of economic incentives in pay-for-performance programs. PMID- 22492896 TI - End-of-life care for Medicare beneficiaries with cancer is highly intensive overall and varies widely. AB - Studies have shown that cancer care near the end of life is more aggressive than many patients prefer. Using a cohort of deceased Medicare beneficiaries with poor prognosis cancer, meaning that they were likely to die within a year, we examined the association between hospital characteristics and eleven end-of-life care measures, such as hospice use and hospitalization. Our study revealed a relatively high intensity of care in the last weeks of life. At the same time, there was more than a twofold variation within hospital groups with common features, such as cancer center designation and for-profit status. We found that these hospital characteristics explained little of the observed variation in intensity of end-of-life cancer care and that none reliably predicted a specific pattern of care. These findings raise questions about what factors may be contributing to this variation. They also suggest that best practices in end-of life cancer care can be found in many settings and that efforts to improve the quality of end-of-life care should include every hospital category. PMID- 22492898 TI - Lower mortality rates at cardiac specialty hospitals traceable to healthier patients and to doctors' performing more procedures. AB - Physician-owned cardiac specialty hospitals advertise that they have outstanding physicians and results. To test this assertion, we examined who gets referred to these hospitals, as well as whether different results occur when specialty physicians split their caseloads among specialty and general hospitals in the same markets. Using data on 210,135 patients who underwent percutaneous coronary interventions in Texas during 2004-07, we found that the risk-adjusted in hospital mortality rate for patients treated at specialty hospitals was significantly below the rate for all hospitals in the state (0.68 percent versus 1.50 percent). However, the rate was significantly higher when physicians who owned cardiac specialty hospitals treated patients in general hospitals (2.27 percent versus 1.50 percent). In addition, several patient characteristics were associated with a lower likelihood of being admitted to a cardiac hospital for cardiac care, such as being African American or Hispanic and having Medicaid or no health insurance. After adjustment for patient severity and number of procedures performed, the overall outcomes for cardiologists who owned specialty hospitals were not significantly different from the "average outcomes" obtained at noncardiac hospitals. In contrast to previous studies, patient outcomes were found to be highly dependent on the type of hospital where the procedure was performed. To remove a potential source of bias and achieve a more balanced comparison, the quality statistics reported by physician-owned cardiac hospitals should be adjusted to incorporate the high rates of poor outcomes for the many procedures done by their cardiologists at nearby noncardiac hospitals. PMID- 22492899 TI - Multiple drug cost containment policies in Michigan's Medicaid program saved money overall, although some increased costs. AB - Michigan's Medicaid program implemented four cost containment policies--preferred drug lists, joint and multistate purchasing arrangements, and maximum allowable cost--during 2002-04. The goal was to control growth of drug spending for beneficiaries who were enrolled in both Medicaid and Medicare and taking antihypertensive or antihyperlipidemic prescription drugs. We analyzed the impact of each policy while holding the effect of all other policies constant. Preferred drug lists increased both preferred and generic drugs' market share and reduced daily cost--the cost per day for each prescription provided to a beneficiary. In contrast, the maximum allowable cost policy increased daily cost and was the only policy that did not generate cost savings. The joint and multistate arrangements did not affect daily cost. Despite these policy trade-offs, the cumulative effect was a 10 percent decrease in daily cost and a total cost savings of $46,195 per year. Our findings suggest that policy makers need to evaluate the impact of multiple policies aimed at restraining drug spending, and further evaluate the policy trade-offs, to ensure that scarce public dollars achieve the greatest return for money spent. PMID- 22492900 TI - Hospitals' geographic expansion in quest of well-insured patients: will the outcome be better care, more cost, or both? AB - The emphasis that hospitals place on cutting-edge technology and niche specialty services to attract physicians and patients has set the stage for health care's most recent competitive trend: an increased level of targeted, geographic service expansion to "capture" well-insured patients. We conducted interviews in twelve US communities in 2010 and found that many hospital systems--some with facilities in geographically undesirable areas--have expanded to compete for better-insured patients by building or buying facilities and physician practices in nearby, more affluent communities. Along with extending services to new markets, these hospital outposts often serve to pull well-insured patients to flagship facilities. The acceleration and expansion of such geographically competitive strategies by hospitals has implications for cost and access. Although payers and competitors contend such strategies will lead to higher costs, hospitals assert the expansions will increase efficiency, increase access, and improve the quality of care provided to patients. PMID- 22492901 TI - Living life in my own way--and dying that way as well. PMID- 22492904 TI - Preventing the exploitation and abuse of children. PMID- 22492906 TI - Aligning incentives for value-based health care. PMID- 22492907 TI - Trusting one's physician. PMID- 22492909 TI - Physicians with conflicts of interest. PMID- 22492911 TI - Involving clinicians in clinical research. PMID- 22492913 TI - Novel microRNAs encoded by duck enteritis virus. AB - Duck enteritis virus (DEV) is an important herpesvirus pathogen associated with acute, highly contagious lethal disease in waterfowls. Using a deep sequencing approach on RNA from infected chicken embryo fibroblast cultures, we identified several novel DEV-encoded micro (mi)RNAs. Unlike most mardivirus-encoded miRNAs, DEV-encoded miRNAs mapped mostly to the unique long region of the genome. The precursors of DEV miR-D18 and miR-D19 overlapped with each other, suggesting similarities to miRNA-offset RNAs, although only the DEV-miR-D18-3p was functional in reporter assays. Identification of these novel miRNAs will add to the growing list of virus-encoded miRNAs enabling the exploration of their roles in pathogenesis. PMID- 22492914 TI - Association of an indel polymorphism in the 3'UTR of the caprine SPRN gene with scrapie positivity in the central nervous system. AB - The aim of this study was to analyse the SPRN genes of goats from several scrapie outbreaks in order to detect polymorphisms and to look for association with scrapie occurrence, by an unmatched case-control study. A region of the caprine SPRN gene encompassing the entire ORF and a fragment of the 3'UTR revealed a total of 11 mutations: 10 single-nucleotide polymorphisms and one indel polymorphism. Only two non-synonymous mutations occurring at very low incidence were identified. A significant association with scrapie positivity in the central nervous system was found for an indel polymorphism (602_606insCTCCC) in the 3'UTR. Bioinformatics analyses suggest that this indel may modulate scrapie susceptibility via a microRNA-mediated post-transcriptional mechanism. This is the first study to demonstrate an association between the SPRN gene and goat scrapie. The identified indel may serve as a genetic target other than PRNP to predict disease risk in future genetics-based scrapie-control approaches in goats. PMID- 22492916 TI - Single amino acid mutations in the capsid switch the neutralization phenotype of porcine circovirus 2. AB - Porcine circovirus 2 (PCV2) is the causative agent of porcine circovirus associated diseases in pigs. Previously, it was demonstrated that mAbs 16G12, 38C1, 63H3 and 94H8 directed against the PCV2 capsid protein recognize PCV2 strains Stoon-1010 (PCV2a), 48285 (PCV2b), 1121 (PCV2a), 1147 (PCV2b) and II9F (PCV2b), but only neutralize Stoon-1010 and 48285. This points to the existence of two distinct PCV2 neutralization phenotypes: phenotype alpha (mAb recognition with neutralization; Stoon-1010 and 48285) and phenotype beta (mAb recognition without neutralization; 1121, 1147 and II9F). In the present study, amino acids that are important in determining the neutralization phenotype were identified in the capsid. Mutation of T at position 190 to A in strain 48285 (phenotype alpha) resulted in a capsid resembling that of strain 1147 (phenotype beta) and caused a loss of neutralization (switch from alpha to beta). Mutations of P at position 151 to T and A at position 190 to T in strain II9F (phenotype beta) resulted in a capsid resembling that of strain 48285 (phenotype alpha) and gave a gain of neutralization (switch from beta to alpha). Mutations of T at position 131 to P and of E at position 191 to R in Stoon-1010 (phenotype alpha) changed the capsid into that of 1121 (phenotype beta) and reduced neutralization (switch from alpha to beta). This study demonstrated that single amino acid changes in the capsid result in a phenotypic switch from alpha to beta or beta to alpha. PMID- 22492915 TI - Seamless replacement of Autographa californica multiple nucleopolyhedrovirus gp64 with each of five novel type II alphabaculovirus fusion sequences generates pseudotyped virus that fails to transduce mammalian cells. AB - Autographa californica multiple nucleopolyhedrovirus (AcMNPV), a member of the type I alphabaculoviruses, is able to transduce and deliver a functional gene to a range of non-host cells, including many mammalian lines and primary cells, a property mediated by the envelope fusion protein GP64. AcMNPV is non-cytopathic and inherently replication deficient in non-host cells. As such, AcMNPV represents a possible new class of gene therapy vector with potential future clinical utility. Whilst not a problem for in vitro gene delivery, the broad tropism displayed for non-host cells is less desirable in a gene therapy vector. The fusion protein F of type II alphabaculoviruses can substitute functionally for GP64, and such pseudotyped viruses display a severely impaired capacity for non-host-cell transduction. Thus, surface decoration of such an F-pseudotyped AcMNPV with cell-binding ligands may restore transduction competence and generate vectors with desirable cell-targeting characteristics. By seamlessly swapping the native gp64 coding sequence with each of five sequences encoding different F proteins, a set of F-pseudotyped AcMNPV was generated. This report details their relative abilities both to functionally replace GP64 in viral growth and to transduce human Saos-2 and HeLa cells. All five supported viable infections in insect cell cultures and one, the Mamestra configurata NPV (MacoNPV) F pseudotype, could be amplified to titres close to those of native AcMNPV. In contrast, none was able to transduce the Saos-2 and HeLa cell lines. The robust support provided by MacoNPV F in virus production makes the corresponding pseudotype a viable scaffold to display surface ligands to direct selective mammalian cell targeting. PMID- 22492917 TI - Naturally occurring substitutions of conserved residues in human immunodeficiency virus type 1 variants of different clades are involved in PG9 and PG16 resistance to neutralization. AB - The recently described anti-human immunodeficiency virus type 1 (HIV-1) human mAb PG9 and PG16 are cross-clade broadly neutralizing. Therefore, it can be postulated that the targeted epitope(s) are highly conserved among variants of the entire group M. We analysed the sensitivity to PG9 and PG16 of pseudotyped viruses carrying envelope glycoproteins from the viral quasispecies of three HIV 1 clade CRF01_AE-infected patients. The broad heterogeneity in sensitivity to PG9 and PG16, despite closely genetically related envelope glycoproteins issued from single individuals, allowed us to identify two gp120 cross-clade conserved residues, a lysine at position 168 in the V2 loop and an isoleucine at position 215 in the C2 region, whose substitutions were associated with resistance to PG9 and PG16. By site-directed mutagenesis, we confirmed both in clades B and CRF01_AE that the substitutions K168E and I215M have a major impact on PG9 and PG16 neutralization sensitivity of pseudotyped viruses. PMID- 22492918 TI - Immunization with recombinant macaque major histocompatibility complex class I and II and human immunodeficiency virus gp140 inhibits simian-human immunodeficiency virus infection in macaques. AB - Genetic, epidemiological and experimental evidence suggest that the major histocompatibility complex (MHC) is critical in controlling human immunodeficiency virus (HIV) infection. The objectives of this study were to determine whether novel recombinant Mamu MHC constructs would elicit protection against rectal challenge with heterologous simian-human immunodeficiency virus (SHIV) strain SF162.P4 in rhesus macaques. Mamu class I and II gene products were linked together with HIV gp140, simian immunodeficiency virus (SIV) p27 and heat shock protein 70 to dextran. The vaccine was administered to two groups, each consisting of nine macaques, either subcutaneously (SC), or rectally and boosted by SC immunization. The controls were untreated or adjuvant-treated animals. Repetitive rectal challenges with up to ten doses of SHIV SF162.P4 showed a significant decrease in the peak and sequential viral RNA concentrations, and three macaques remained uninfected, in the nine SC-immunized animals, compared with infection in all nine controls. Macaques immunized rectally followed by SC boosters showed a less significant decrease in both sequential and peak viral loads compared with the SC-immunized animals, and all were infected following rectal challenge with SHIV SF162.P4. Plasma and mucosal IgG and IgA antibodies to Mamu class I alleles and HIV gp120, as well as to RANTES (regulated upon activation, normal T-cell expressed, and secreted; CCR5) were increased, and showed significant inverse correlations with the peak viral load. These results suggested that allo-immunization with recombinant MHC constructs linked to HIV SIV antigens merits further investigation in preventing HIV-1 infection. PMID- 22492919 TI - A focus on antiarrhythmic properties of ranolazine. AB - Ranolazine is an antianginal drug that inhibits a number of ion currents that are important for the genesis of transmembrane cardiac action potential. It was initially developed as an antianginal agent but was found to additionally exert antiarrhythmic actions, due to its multichannel-blocking properties. In recent years, several studies about the antiarrhythmic properties of ranolazine were conducted, demonstrating the beneficial effects of this drug in both atrial and ventricular arrhythmias, such as atrial fibrillation, ventricular premature beats, ventricular tachycardia, torsades de pointes, and ventricular fibrillation. Our aim is to briefly review the main points of these studies, most more experimental than clinical. PMID- 22492920 TI - Curcumin attenuates cardiopulmonary bypass-induced lung oxidative damage in rats. AB - OBJECTIVE: Acute lung injury is a common complication after cardiopulmonary bypass (CPB). Oxidative damage greatly impacts CPB-induced lung ischemic pathogenesis and may represent a target for treatment. We aimed to investigate whether curcumin upregulates heme oxygenase 1 (HO-1) expression and ameliorates lung injury in a rat CPB model. METHODS: A total of 80 male Sprague-Dawley rats were divided into 2 sets of 5 groups (n = 8 per group): sham; control (CPB); vehicle; low-dose curcumin (L-Cur); and high-dose curcumin (H-Cur). Animals were pretreated with a single intraperitoneal injection of vehicle, L-Cur (50 mg/kg), or H-Cur (200 mg/kg) 2 hours prior to CPB. Lung tissue, serum, and bronchoalveolar lavage fluid was harvested 2 or 24 hours postoperatively. In the control group, CPB-induced lung injury was confirmed by histopathologic examination and a significantly increased wet-to-dry lung weight ratio and pulmonary permeability index value was observed (P < .05 vs sham group). Cardiopulmonary bypass was associated with a marked rise in the level of malondialdehyde and myeloperoxidase and a fall in superoxide dismutase 2 and 24 hours after surgery (P < .05 vs sham group). Administration of curcumin ameliorated lung damage and reversed the oxidative stress markers in a partially dose-dependent manner (P < .05 vs vehicle group). Furthermore, HO-1 gene transcription and protein expression were elevated to a greater extent in the lungs after curcumin pretreatment compared with the vehicle pretreatment. CONCLUSIONS: Curcumin has the potential to provide protection from CPB-induced lung damage reflected in the expression of oxidative stress markers. The antioxidant effect of curcumin may be partly related to upregulation of HO-1. PMID- 22492921 TI - Estimates of influenza vaccine effectiveness for 2007-2008 from Canada's sentinel surveillance system: cross-protection against major and minor variants. AB - OBJECTIVES: To estimate influenza vaccine effectiveness (VE) for the 2007-2008 season and assess the sentinel surveillance system in Canada for monitoring virus evolution and impact on VE. METHODS: Nasal/nasopharyngeal swabs and epidemiologic details were collected from patients presenting to a sentinel physician within 7 days of influenza-like illness onset. Cases tested positive for influenza A/B virus by real-time polymerase chain reaction; controls tested negative. Hemagglutination inhibition (HI) and gene sequencing explored virus relatedness to vaccine. VE was calculated as 1 minus the odds ratio for influenza in vaccinated versus nonvaccinated participants, with adjustment for confounders. RESULTS: Of 1425 participants, 21% were vaccinated. Influenza virus was detected in 689 (48%), of which isolates from 663 were typed/subtyped: 189 (29%) were A/H1, 210 (32%) were A/H3, and 264 (40%) were B. Of A/H1N1 isolates, 6% showed minor HI antigenic mismatch to vaccine, with greater variation based on genetic identity. All A/H3N2 isolates showed moderate antigenic mismatch, and 98% of influenza B virus isolates showed major lineage-level mismatch to vaccine. Adjusted VE for A/H1N1, A/H3N2, and B components was 69% (95% confidence interval [CI], 44%-83%), 57% (95% CI, 32%-73%), and 55% (95% CI, 32%-70%), respectively, with an overall VE of 60% (95% CI, 45%-71%). CONCLUSIONS: Detailed antigenic and genotypic analysis of influenza viruses was consistent with epidemiologic estimates of VE showing cross-protection. A routine sentinel surveillance system that combines detailed virus and VE monitoring annually, as modeled in Canada, may guide improved vaccine selection and protection. PMID- 22492922 TI - Effects of Functional Fascial Taping on pain and function in patients with non specific low back pain: a pilot randomized controlled trial. AB - OBJECTIVES: To compare the short-term and medium-term effect of Functional Fascial Taping to placebo taping on pain and function in people with non-specific low back pain. DESIGN: A pilot randomized controlled trial with a 2-week intervention, and 2-, 6- and 12-week follow-up. SETTING: Individuals with non specific low back pain recruited from local communities. PARTICIPANTS: Forty three participants with non-specific low back pain for more than 6 weeks were randomized into either Functional Fascial Taping group (n = 21) or placebo group (n = 22). INTERVENTIONS: The intervention group was treated with Functional Fascial Taping while the control group was treated with placebo taping. Both groups received four treatments over 2 weeks. MAIN OUTCOME MEASURES: Worst and average pain and function were assessed at baseline, after the 2-week intervention, and at 6 and 12 weeks follow-up. RESULTS: The Functional Fascial Taping group demonstrated significantly greater reduction in worst pain compared to placebo group after the 2-week intervention (P = 0.02, effect size = 0.74; 95% confidence interval 0.11-1.34). A higher proportion of participants in Functional Fascial Taping group attained the minimal clinically important difference in worst pain (P = 0.007) and function (P = 0.007) than those in placebo group after the 2-week intervention. There were no significant differences in either group's disability rating or clinically important difference in average pain at any time. CONCLUSIONS: Functional Fascial Taping reduced worst pain in patients with non acute non-specific low back pain during the treatment phase. No medium-term differences in pain or function were observed. PMID- 22492923 TI - Community-level impact of the reproductive health vouchers programme on service utilization in Kenya. AB - This paper examines community-level association between exposure to the reproductive health vouchers programme in Kenya and utilization of services. The data are from a household survey conducted among 2527 women (15-49 years) from voucher and comparable non-voucher sites. Analysis entails cross-tabulations with Chi-square tests and significant tests of proportions as well as estimation of multi-level logit models to predict service utilization by exposure to the programme. The results show that for births occurring after the voucher programme began, women from communities that had been exposed to the programme since 2006 were significantly more likely to have delivered at a health facility and to have received skilled care during delivery compared with those from communities that had not been exposed to the programme at all. There were, however, no significant differences in the timing of first trimester utilization of antenatal care (ANC) and making four or more ANC visits by exposure to the programme. In addition, poor women were significantly less likely to have used safe motherhood services (health facility delivery, skilled delivery care and postnatal care) compared with their non-poor counterparts regardless of exposure to the programme. Nonetheless, a significantly higher proportion of poor women from communities that had been exposed to the programme since 2006 used the services compared with their poor counterparts from communities that had not been exposed to the programme at all. The findings suggest that the programme is associated with increased health facility deliveries and skilled delivery care especially among poor women. However, it has had limited community-level impact on the first trimester timing of antenatal care use and making four or more visits, which remain a challenge despite the high proportion of women in the country that make at least one antenatal care visit during pregnancy. PMID- 22492924 TI - Complete genome sequence of a novel hantavirus variant of Rio Mamore virus, Maripa virus, from French Guiana. AB - We report the first complete genome sequence of Maripa virus identified in 2009 from a patient with hantavirus pulmonary syndrome in French Guiana. Maripa virus corresponds to a new variant of the Rio Mamore virus species in the Bunyaviridae family, genus Hantavirus. PMID- 22492925 TI - Complete genome of temperate phage ENT39118 from Cronobacter sakazakii. AB - Cronobacter sakazakii infection is particularly harmful to infants, and putative virulence factors of prophage origin have been identified in C. sakazakii. In this study, the phage ENT39118 was isolated from wild-type C. sakazakii; it belongs to the family Siphoviridae. The genomic sequence of phage ENT39118 was composed of circular double-stranded DNA with a length of 39,012 bp. The sequence of ENT39118 showed weak sequence similarity to some reported regions of the prophage sequences in the C. sakazakii BAA-894 genome. To our knowledge, this is the first study of the genomic sequencing and annotation of this temperate phage, which was obtained from a C. sakazakii isolate from powdered infant formula. PMID- 22492926 TI - Complete genome sequence of enterococcal bacteriophage SAP6. AB - Enterococcus faecalis is an important bacterium for use as a probiotic and is an opportunistic pathogen in human beings. The antibiotic resistance acquired by E. faecalis is restricted to antibiotics used in the clinical setting. While screening for alternative antibiotics for use against multidrug-resistant E. faecalis, we isolated a virulent enterococcal bacteriophage, SAP6, belonging to the family Siphoviridae. To our knowledge, this study is the first to report the complete genome sequence of bacteriophage SAP6, which might be used as a therapeutic agent in combination with alternative antibiotics for multidrug resistant E. faecalis. PMID- 22492927 TI - Complete genome sequence of an isolate of bluetongue virus serotype 2, demonstrating circulation of a Western topotype in southern India. AB - Bluetongue virus serotype 2 (IND2003/02) was isolated in Tiruneveli City, Tamil Nadu State, India, and is stored in the Orbivirus Reference Collection at the Institute for Animal Health, Pirbright, United Kingdom. The entire genome of this isolate was sequenced, showing that it is composed of a total of 19,203 bp (all 10 genome segments). This is the first report of the entire genome sequence of a western strain of BTV-2 isolated in India, indicating that this virus has been introduced and is circulating in the region. These data will aid in the development of diagnostics and molecular epidemiology studies of BTV-2 in the subcontinent. PMID- 22492928 TI - Genome of Klebsiella sp.-infecting bacteriophage vB_KleM_RaK2. AB - Despite the fact that multidrug-resistant Klebsiella sp. strains emerge rapidly (Xu J, et al., Adv. Mater. Res. 268-270:1954-1956, 2011) and bacteriophages have been reported to be useful in controlling these bacteria (Kumari S, Harjai K, Chhibber S, J. Med. Microbiol. 60:205-210, 2011), the complete genome sequences of only five Klebsiella phages (four siphoviruses and one myovirus) can be found in databases. In this paper, we report on the complete genome sequence of Klebsiella sp.-infecting bacteriophage vB_KleM_RaK2. With a genome size of 345,809 bp, this is the second largest myovirus and the largest Klebsiella phage sequenced to date. This phage differs substantially from other myoviruses since 411 out of 534 vB_KleM_RaK2 open reading frames have no known functions and lack any reliable database matches. Comparative analysis of the genome sequence of vB_KleM_RaK2 suggests that this phage forms a distinct phylogenetic branch within the family Myoviridae of tailed bacteriophages. PMID- 22492929 TI - Complete genomic sequence of an equine herpesvirus type 8 Wh strain isolated from China. AB - A new strain of equine herpesvirus type 8 (EHV-8), Wh, has been isolated from horses in China, and its complete genome has been sequenced and analyzed. The result indicates that the new strain has the same constitution and arrangement of open read frames as EHV-1 and EHV-9. This work is the first announced complete genome sequence of EHV-8. PMID- 22492930 TI - Bone graft from the distal medial tibia in foot and ankle surgery. AB - Autogenous bone graft is the ideal substrate for primary and revisional foot and ankle surgery. The distal medial tibia is an easily accessible site that provides both cancellous and corticocancellous autograft. Thirty cases of distal tibial bone graft with a minimum follow-up of 1 year are presented. There was an 86% union rate, and there were no stress fractures, persistent pain, or reported nerve injuries at the donor site. An efficient and versatile technique for harvesting both cancellous bone graft and corticocancellous graft is described. The use of distal tibial bone graft eliminates the need for a second surgeon and more lengthy harvest procedure and offers sufficient autograft material for foot and ankle applications with a low rate of complications. LEVELS OF EVIDENCE: Therapeutic, Level IV. PMID- 22492931 TI - Phase transitions in biogenic amorphous calcium carbonate. AB - Crystalline biominerals do not resemble faceted crystals. Current explanations for this property involve formation via amorphous phases. Using X-ray absorption near-edge structure (XANES) spectroscopy and photoelectron emission microscopy (PEEM), here we examine forming spicules in embryos of Strongylocentrotus purpuratus sea urchins, and observe a sequence of three mineral phases: hydrated amorphous calcium carbonate (ACC . H(2)O) -> dehydrated amorphous calcium carbonate (ACC) -> calcite. Unexpectedly, we find ACC . H(2)O-rich nanoparticles that persist after the surrounding mineral has dehydrated and crystallized. Protein matrix components occluded within the mineral must inhibit ACC . H(2)O dehydration. We devised an in vitro, also using XANES-PEEM, assay to identify spicule proteins that may play a role in stabilizing various mineral phases, and found that the most abundant occluded matrix protein in the sea urchin spicules, SM50, stabilizes ACC . H(2)O in vitro. PMID- 22492933 TI - Sacrificing economy to improve running performance--a reality in the ultramarathon? PMID- 22492932 TI - Natural variation in a polyamine transporter determines paraquat tolerance in Arabidopsis. AB - Polyamines (PAs) are ubiquitous, polycationic compounds that are essential for the growth and survival of all organisms. Although the PA-uptake system plays a key role in mammalian cancer and in plant survival, the underlying molecular mechanisms are not well understood. Here, we identified an Arabidopsis L-type amino acid transporter (LAT) family transporter, named RMV1 (resistant to methyl viologen 1), responsible for uptake of PA and its analog paraquat (PQ). The natural variation in PQ tolerance was determined in 22 Arabidopsis thaliana accessions based on the polymorphic variation of RMV1. An RMV1-GFP fusion protein localized to the plasma membrane in transformed cells. The Arabidopsis rmv1 mutant was highly resistant to PQ because of the reduction of PQ uptake activity. Uptake studies indicated that RMV1 mediates proton gradient-driven PQ transport. RMV1 overexpressing plants were hypersensitive to PA and PQ and showed elevated PA/PQ uptake activity, supporting the notion that PQ enters plant cells via a carrier system that inherently functions in PA transport. Furthermore, we demonstrated that polymorphic variation in RMV1 controls PA/PQ uptake activity. Our identification of a molecular entity for PA/PQ uptake and sensitivity provides an important clue for our understanding of the mechanism and biological significance of PA uptake. PMID- 22492935 TI - Prothrombolytic action of normobaric oxygen given alone or in combination with recombinant tissue-plasminogen activator in a rat model of thromboembolic stroke. AB - The potential benefit of 100 vol% normobaric oxygen (NBO) for the treatment of acute ischemic stroke patients is still a matter of debate. To advance this critical question, we studied the effects of intraischemic normobaric oxygen alone or in combination with recombinant tissue-plasminogen activator (rtPA) on cerebral blood flow and ischemic brain damage and swelling in a clinically relevant rat model of thromboembolic stroke. We show that NBO provides neuroprotection by achieving cerebral blood flow restoration equivalent to 0.9 mg/kg rtPA through probable direct interaction and facilitation of the fibrinolytic properties of endogenous tPA. In contrast, combined NBO and rtPA has no neuroprotective effect on ischemic brain damage despite producing cerebral blood flow restoration. These results 1) by providing a new mechanism of action of NBO highlight together with previous findings the way by which intraischemic NBO shows beneficial action; 2) suggest that NBO could be an efficient primary care therapeutic intervention for patients eligible for rtPA therapy; 3) indicate that NBO could be an interesting alternative for patients not eligible for rtPA therapy; and 4) caution the use of NBO in combination with rtPA in acute stroke patients. PMID- 22492936 TI - Vestibular-dependent spinal reflexes evoked by brief lateral accelerations of the heads of standing subjects. AB - An impulsive acceleration stimulus, previously shown to activate vestibular afferents, was applied to the mastoid. Evoked EMG responses from the soleus muscles in healthy subjects (n = 10) and patients with bilateral vestibular dysfunction (n = 3) were recorded and compared with the effects of galvanic stimulation (GVS). Subjects were stimulated while having their eyes closed, head rotated, and while tonically activating their soleus muscles. Rectified EMG responses were recorded from the leg contralateral to the direction of head rotation. Responses were characterized by triphasic potentials that consisted of short-latency (SL), medium-latency (ML), and long-latency (LL) components beginning at (mean +/- SD) 54.2 +/- 4.8, 88.4 +/- 4.7, and 121 +/- 7.1 ms, respectively. Mean amplitudes for the optimum stimulus rise times were 9.05 +/- 3.44% for the SL interval, 16.70 +/- 4.41% for the ML interval, and 9.75 +/- 4.89% for the LL interval compared with prestimulus values. Stimulus rise times of 14 and 20 ms evoked the largest ML amplitudes. GVS evoked biphasic responses (SL and ML) with similar latencies. Like GVS, the polarity of the initial interval was determined by the polarity of the stimulus and the evoked EMG response was attenuated when subjects were seated. There was no significant EMG response evoked when subjects were stimulated using 500-Hz vibration or in patients with bilateral vestibular dysfunction. Our study demonstrates that a brief lateral acceleration, likely to activate the utricle, can evoke spinal responses with properties similar to those previously shown for vestibular activation by GVS. The triphasic nature of the responses may allow the nervous system to respond differently to short compared with long-duration linear accelerations, consistent with their differing significance. PMID- 22492934 TI - Early apoptosis in different models of cardiac hypertrophy induced by high renin angiotensin system activity involves CaMKII. AB - The objective of this study was to establish whether 1) hyperactivity of renin angiotensin-aldosterone system (RAAS) produces apoptosis in early stages of cardiac disease; and 2) Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is involved in these apoptotic events. Two models of hypertrophy were used at an early stage of cardiac disease: spontaneously hypertensive rats (SHR) and isoproterenol-treated rats (Iso-rats). At 4 mo, SHR showed blood pressure, aldosterone serum levels, used as RAAS activity index, and left ventricular mass index, used as hypertrophy index, above control values by 84.2 +/- 2.6 mmHg, 211.2 +/- 25.8%, and 8.6 +/- 1.1 mg/mm, respectively. There was also an increase in apoptotis (Bax-to-Bcl-2 ratio and terminal deoxynucleotidyl transferase dUTP mediated nick-end labeling positive cells) associated with an enhancement of CaMKII activity with respect to age-matched controls (phosphorylated-CaMKII, 98.7 +/- 14.1 above control). Similar results were observed in 4-mo-old Iso-rats. Cardiac function studied by echocardiography remained unaltered in all groups. Enalapril treatment significantly prevented hypertrophy, apoptosis, and CaMKII activity. Moreover, intracellular Ca(2+) handling in isolated myocytes was similar between SHR, Iso-rats, and their aged-matched controls. However, SHR and Iso-rats showed a significant increase in superoxide anion generation (lucigenin) and lipid peroxidation (thiobarbituric acid reactive substance). In transgenic mice with targeted cardiomyocyte expression of a CaMKII inhibitory peptide (AC3 I) or a scrambled control peptide (AC3-C), Iso treatment increased thiobarbituric acid reactive substance in both strains, whereas it increased CaMKII activity and apoptosis only in AC3-C mice. Endogenous increases in RAAS activity induce ROS and CaMKII-dependent apoptosis in vivo. CaMKII activation could not be associated with intracellular Ca(2+) increments and was directly related to the increase in oxidative stress. PMID- 22492937 TI - Effects of beta2-agonists on force during and following anoxia in rat extensor digitorum longus muscle. AB - Electrical stimulation of isolated muscles may lead to membrane depolarization, gain of Na(+), loss of K(+) and fatigue. These effects can be counteracted with beta(2)-agonists possibly via activation of the Na(+)-K(+) pumps. Anoxia induces loss of force; however, it is not known whether beta(2)-agonists affect force and ion homeostasis in anoxic muscles. In the present study isolated rat extensor digitorum longus (EDL) muscles exposed to anoxia showed a considerable loss of force, which was markedly reduced by the beta(2)-agonists salbutamol (10(-6) M) and terbutaline (10(-6) M). Intermittent stimulation (15-30 min) clearly increased loss of force during anoxia and reduced force recovery during reoxygenation. The beta(2)-agonists salbutamol (10(-7)-10(-5) M) and salmeterol (10(-6) M) improved force development during anoxia (25%) and force recovery during reoxygenation (55-262%). The effects of salbutamol on force recovery were prevented by blocking the Na(+)-K(+) pumps with ouabain or by blocking glycolysis with 2-deoxyglucose. Dibutyryl cAMP (1 mM) or theophylline (1 mM) also improved force recovery remarkably. In anoxic muscles, salbutamol decreased intracellular Na(+) and increased (86)Rb uptake and K(+) content, indicating stimulation of the Na(+)-K(+) pumps. In fatigued muscles salbutamol induced recovery of excitability. Thus beta(2)-agonists reduce the anoxia-induced loss of force, leading to partial force recovery. These data strongly suggest that this effect is mediated by cAMP stimulation of the Na(+)-K(+) pumps and that it is not related to recovery of energy status (PCr, ATP, lactate). PMID- 22492938 TI - Volitional control of reflex cough. AB - Multiple studies suggest a role for the cerebral cortex in the generation of reflex cough in awake humans. Reflex cough is preceded by detection of an urge to cough; strokes specifically within the cerebral cortex can affect parameters of reflex cough, and reflex cough can be voluntarily suppressed. However, it is not known to what extent healthy, awake humans can volitionally modulate the cough reflex, aside from suppression. The aims of this study were to determine whether conscious humans can volitionally modify their reflexive cough and, if so, to determine what parameters of the cough waveform and corresponding muscle activity can be modified. Twenty adults (18-40 yr, 4 men) volunteered for study participation and gave verbal and written informed consent. Participants were seated and outfitted with a facemask and pneumotacograph, and two surface EMG electrodes were positioned over expiratory muscles. Capsaicin (200 MUM) was delivered via dosimeter and one-way (inspiratory) valve attached to a side port between the facemask and pneumotachograph. Cough airflow and surface EMG activity were recorded across tasks including 1) baseline, 2) small cough (cough smaller or softer than normal), 3) long cough (cough longer or louder than normal), and 4) not cough (alternative behavior). All participants coughed in response to 200 MUM capsaicin and were able to modify the cough. Variables exhibiting changes include those related to the peak airflow during the expiratory phase. Results demonstrate that it is possible to volitionally modify cough motor output characteristics. PMID- 22492939 TI - Concurrent resistance and aerobic exercise stimulates both myofibrillar and mitochondrial protein synthesis in sedentary middle-aged men. AB - We determined myofibrillar and mitochondrial protein fractional synthesis rates (FSR), intramuscular signaling protein phosphorylation, and mRNA expression responses after isolated bouts of resistance exercise (RE), aerobic exercise (AE), or in combination [termed concurrent exercise (CE)] in sedentary middle aged men. Eight subjects (age = 53.3 +/- 1.8 yr; body mass index = 29.4 +/- 1.4 kg.m(2)) randomly completed 8 * 8 leg extension repetitions at 70% of one repetition-maximum, 40 min of cycling at 55% peak aerobic power output (AE), or (consecutively) 50% of the RE and AE trials (CE). Biopsies were obtained (during a primed, constant infusion of l-[ring-(13)C(6)]phenylalanine) while fasted, and at 1 and 4 h following postexercise ingestion of 20 g of protein. All trials increased mitochondrial FSR above fasted rates (RE = 1.3-fold; AE = 1.5; CE = 1.4; P < 0.05), although only CE (2.2) and RE (1.8) increased myofibrillar FSR (P < 0.05). At 1 h postexercise, phosphorylation of Akt on Ser(473) (CE = 7.7; RE = 4.6) and Thr(308) (CE = 4.4; RE = 2.9), and PRAS40 on Thr(246) (CE = 3.8; AE = 2.5) increased (P < 0.05), with CE greater than AE for Akt Ser(473)-Thr(308) and greater than RE for PRAS40 (P < 0.05). Despite increased phosphorylation of Akt PRAS40, phosphorylation of mammalian target of rapamycin (Ser(2448)) remained unchanged (P > 0.05), while rpS6 (Ser(235/236)) increased only in RE (10.4) (P < 0.05). CE and AE both resulted in increased peroxisome proliferator receptor gamma coactivator 1-alpha (PGC1alpha) expression at 1 h (CE = 2.9; AE = 2.8; P < 0.05) and 4 h (CE = 2.6; AE = 2.4) and PGC1beta expression at 4 h (CE = 2.1; AE = 2.6; P < 0.05). These data suggest that CE-induced acute stimulation of myofibrillar and mitochondrial FSR, protein signaling, and mRNA expression are equivalent to either isolate mode (RE or AE). These results occurred without an interference effect on muscle protein subfractional synthesis rates, protein signaling, or mRNA expression. PMID- 22492940 TI - Monitoring urea transport in rat kidney in vivo using hyperpolarized 13C magnetic resonance imaging. AB - Urea functions as a key osmolyte in the urinary concentrating mechanism of the inner medulla. The urea transporter UT-A1 is upregulated by antidiuretic hormone, facilitating faster equilibration of urea between the lumen and interstitium of the inner medullary collecting duct, resulting in the formation of more highly concentrated urine. New methods in dynamic nuclear polarization, providing ~50,000-fold enhancement of nuclear magnetic resonance signals in the liquid state, offer a novel means to monitor this process in vivo using magnetic resonance imaging. In this study, we detected significant signal differences in the rat kidney between acute diuretic and antidiuretic states, using dynamic (13)C magnetic resonance imaging following a bolus infusion of hyperpolarized [(13)C]urea. More rapid medullary enhancement was observed under antidiuresis, consistent with known upregulation of UT-A1. PMID- 22492941 TI - Effects of the antioxidant drug tempol on renal oxygenation in mice with reduced renal mass. AB - We tested the hypothesis that reactive oxygen species (ROS) contributed to renal hypoxia in C57BL/6 mice with ⅚ surgical reduction of renal mass (RRM). ROS can activate the mitochondrial uncoupling protein 2 (UCP-2) and increase O(2) usage. However, UCP-2 can be inactivated by glutathionylation. Mice were fed normal (NS)- or high-salt (HS) diets, and HS mice received the antioxidant drug tempol or vehicle for 3 mo. Since salt intake did not affect the tubular Na(+) transport per O(2) consumed (T(Na/)Q(O2)), further studies were confined to HS mice. RRM mice had increased excretion of 8-isoprostane F(2alpha) and H(2)O(2), renal expression of UCP-2 and renal O(2) extraction, and reduced T(Na/)Q(O2) (sham: 20 +/- 2 vs. RRM: 10 +/- 1 MUmol/MUmol; P < 0.05) and cortical Po(2) (sham: 43 +/- 2, RRM: 29 +/- 2 mmHg; P < 0.02). Tempol normalized all these parameters while further increasing compensatory renal growth and glomerular volume. RRM mice had preserved blood pressure, glomeruli, and patchy tubulointerstitial fibrosis. The patterns of protein expression in the renal cortex suggested that RRM kidneys had increased ROS from upregulated p22(phox), NOX-2, and -4 and that ROS-dependent increases in UCP-2 led to hypoxia that activated transforming growth factor-beta whereas erythroid-related factor 2 (Nrf 2), glutathione peroxidase-1, and glutathione-S-transferase mu-1 were upregulated independently of ROS. We conclude that RRM activated distinct processes: a ROS dependent activation of UCP-2 leading to inefficient renal O(2) usage and cortical hypoxia that was offset by Nrf-2-dependent glutathionylation. Thus hypoxia in RRM may be the outcome of NADPH oxidase-initiated ROS generation, leading to mitochondrial uncoupling counteracted by defense pathways coordinated by Nrf-2. PMID- 22492942 TI - Angiotensin-(1-7) attenuates diabetic nephropathy in Zucker diabetic fatty rats. AB - Angiotensin (ANG)-(1-7) is known to attenuate diabetic nephropathy; however, its role in the modulation of renal inflammation and oxidative stress in type 2 diabetes is poorly understood. Thus in the present study we evaluated the renal effects of a chronic ANG-(1-7) treatment in Zucker diabetic fatty rats (ZDF), an animal model of type 2 diabetes and nephropathy. Sixteen-week-old male ZDF and their respective controls [lean Zucker rats (LZR)] were used for this study. The protocol involved three groups: 1) LZR + saline, 2) ZDF + saline, and 3) ZDF + ANG-(1-7). For 2 wk, animals were implanted with subcutaneous osmotic pumps that delivered either saline or ANG-(1-7) (100 ng.kg(-1).min(-1)) (n = 4). Renal fibrosis and tissue parameters of oxidative stress were determined. Also, renal levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), ED-1, hypoxia-inducible factor-1alpha (HIF-1alpha), and neutrophil gelatinase associated lipocalin (NGAL) were determined by immunohistochemistry and immunoblotting. ANG-(1-7) induced a reduction in triglyceridemia, proteinuria, and systolic blood pressure (SBP) together with a restoration of creatinine clearance in ZDF. Additionally, ANG-(1-7) reduced renal fibrosis, decreased thiobarbituric acid-reactive substances, and restored the activity of both renal superoxide dismutase and catalase in ZDF. This attenuation of renal oxidative stress proceeded with decreased renal immunostaining of IL-6, TNF-alpha, ED-1, HIF-1alpha, and NGAL to values similar to those displayed by LZR. Angiotensin converting enzyme type 2 (ACE2) and ANG II levels remained unchanged after treatment with ANG-(1-7). Chronic ANG-(1-7) treatment exerts a renoprotective effect in ZDF associated with a reduction of SBP, oxidative stress, and inflammatory markers. Thus ANG-(1-7) emerges as a novel target for treatment of diabetic nephropathy. PMID- 22492943 TI - Lack of protein kinase C-alpha leads to impaired urine concentrating ability and decreased aquaporin-2 in angiotensin II-induced hypertension. AB - Regulation of water and urea transport in the inner medullary collecting duct is essential for urine concentration. Aquaporin (AQP)2 water channels and urea transporter (UT)-A1 are inserted into the apical membrane upon phosphorylation of the channels to allow the transcellular movement of water and urea. Since ANG II activates PKC in many cell types, we tested the hypothesis that ANG II-induced regulation of water and urea transport is mediated by PKC. Osmotic minipumps delivered ANG II to wild-type (WT) or PKC-alpha(-/-) mice for 7 days. Inner medullas were harvested, and protein abundance was determined by immunoblot. ANG II increased systolic blood pressure to a similar degree in WT and PKC-alpha(-/-) mice. ANG II had no effect on the urine output of WT mice but increased that of PKC-alpha(-/-) mice. In accordance with observed differences in urine output, AQP2 abundance was unchanged in ANG II-treated WT animals but was decreased in PKC-alpha(-/-) mice. No change in membrane accumulation was seen. Phosphorylation of the cAMP-induced transcription factor CREB was decreased in PKC-alpha(-/-) mice in response to ANG II with no change in overall CREB abundance. ANG II did not alter the abundance of UT-A1 protein in WT or PKC-alpha(-/-) mice. Phosphorylation and overall abundance of tonicity-responsive enhancer-binding protein, a transcription factor that regulates UT-A1, were also unaltered by ANG II in either group. We conclude that PKC-alpha protects against ANG II-induced decreases in urine concentrating ability by maintaining AQP2 levels through CREB phosphorylation. PMID- 22492944 TI - Complement alternative pathway activation in the autologous phase of nephrotoxic serum nephritis. AB - The complement cascade is an important part of the innate immune system, but pathological activation of this system causes tissue injury in several autoimmune and inflammatory diseases, including immune complex glomerulonephritis. We examined whether mice with targeted deletion of the gene for factor B (fB(-/-) mice) and selective deficiency in the alternative pathway of complement are protected from injury in the nephrotoxic serum (NTS) nephritis model of antibody mediated glomerulonephritis. When the acute affects of the anti-glomerular basement membrane antibody were assessed, fB(-/-) mice developed a degree of injury similar to wild-type controls. If the mice were presensitized with sheep IgG or if the mice were followed for 5 mo postinjection, however, the fB(-/-) mice developed milder injury than wild-type mice. The immune response of fB(-/-) mice exposed to sheep IgG was similar to that of wild-type mice, but the fB(-/-) mice had less glomerular C3 deposition and lower levels of albuminuria. These results demonstrate that fB(-/-) mice are not significantly protected from acute heterologous injury in NTS nephritis but are protected from autologous injury in response to a planted glomerular antigen. Thus, although the glomerulus is resistant to antibody-initiated, alternative pathway-mediated injury, inhibition of this complement pathway may be beneficial in chronic immune complex-mediated diseases. PMID- 22492946 TI - Role of mitochondria in paricalcitol-mediated cytoprotection during obstructive nephropathy. AB - Vitamin D slows the progression of chronic kidney disease. Furthermore, activators of vitamin D receptors (VDR) have suppressant effects on the renin angiotensin system, as well as anti-inflammatory and antifibrotic actions. This study aimed to evaluate the cytoprotective effects of paricalcitol, a VDR activator, at the mitochondrial level using an obstructive nephropathy model [unilateral ureteral obstruction (UUO)]. Rats subjected to UUO and controls were treated daily with vehicle or paricalcitol. The control group underwent a sham surgery. The treatment was done for 15 days (30 ng/kg). The following were determined: biochemical parameters; fibrosis; apoptosis; mitochondrial morphology; VDR, AT(1) receptor, and NADPH oxidase 4 expression; and NADPH oxidase activity (in total and in mitochondrial fractions from the renal cortex). VDR activation prevented fibrosis (20 +/- 5 vs. 60 +/- 10%) and the number of TUNEL-positive apoptotic cells (10 +/- 3 vs. 25 +/- 4) in UUO. Biochemical, histological, and molecular studies suggest mitochondrial injury. Electron microscopy revealed in UUO electronically luminous material in the nucleus. Some mitochondria were increased in size and contained dilated crests and larger than normal spaces in their interiors. These changes were not present with paricalcitol treatment. Additionally, high AT(1)-receptor mRNA and NADPH activity was reverted in mitochondrial fractions from obstructed paricalcitol-treated animals (0.58 +/- 0.06 vs. 0.95 +/- 0.05 relative densitometry units and 9,000 +/ 800 vs. 15,000 +/- 1,000 relative fluorescence units.MUg protein(-1).min(-1), respectively). These changes were consistent with an improvement in VDR expression (0.75 +/- 0.05 vs. 0.35 +/- 0.04 relative densitometry units). These results suggest that paricalcitol confers a protective effect and reveal, as well, a possible AT(1) receptor-dependent protective effect that occurs at the mitochondrial level. PMID- 22492945 TI - Matrix metalloproteinases in kidney homeostasis and diseases. AB - Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that have been increasingly linked to both normal physiology and abnormal pathology in the kidney. Collectively able to degrade all components of the extracellular matrix, MMPs were originally thought to antagonize the development of fibrotic diseases solely through digestion of excessive matrix. However, increasing evidence has shown that MMPs play a wide variety of roles in regulating inflammation, epithelial-mesenchymal transition, cell proliferation, angiogenesis, and apoptosis. We now have robust evidence for MMP dysregulation in a multitude of renal diseases including acute kidney injury, diabetic nephropathy, glomerulonephritis, inherited kidney disease, and chronic allograft nephropathy. The goal of this review is to summarize current findings regarding the role of MMPs in kidney diseases as well as the mechanisms of action of this family of proteases. PMID- 22492948 TI - Percutaneous circulatory support in cardiogenic shock: interventional bridge to recovery. PMID- 22492949 TI - Giant congenital left atrial aneurysm in an 11-year-old boy. PMID- 22492950 TI - Cardiac amyloidosis mimicking hypertrophic cardiomyopathy with obstruction: treatment with disopyramide. PMID- 22492947 TI - Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease. PMID- 22492951 TI - Rivaroxaban to prevent pulmonary embolism after hip or knee replacement. PMID- 22492952 TI - Extrinsic compression of the left anterior descending coronary artery by rib in a patient with progressive left ventricular remodeling. PMID- 22492953 TI - Appreciating and mitigating bleeding risk. PMID- 22492955 TI - Letter by Nezami et al regarding article, "Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the gauging responsiveness with a VerifyNow P2Y12 assay: impact on thrombosis and safety (GRAVITAS) trial". PMID- 22492956 TI - Letter by De Miguel Castro et al regarding article, "Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time dependent analysis of the gauging responsiveness with a VerifyNow P2Y12 assay: impact on Thrombosis and Safety (GRAVITAS) trial". PMID- 22492957 TI - Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. AB - BRAF rearrangements and BRAF V600E point mutations are recurring events in pediatric low-grade gliomas. However, their clinical significance, including possible interactions between these markers and other glioma biomarkers, is unclear. In this study a retrospective cohort of 198 pediatric low-grade gliomas (including 40 treated with adjuvant therapy) was analyzed for BRAF rearrangements, BRAF V600E, p16/CDKN2A deletion, p53 expression, and MIB1 proliferation index. In tumors with BRAF rearrangement, homozygous p16 deletion correlated with shorter progression-free survival (P = .04). A high MIB1 proliferation index trended toward worse response to adjuvant radiotherapy compared to BRAF-rearranged, p16-intact tumors (P = .08). On multivariate analysis, the 2 most consistently powerful independent adverse prognostic markers were midline location (P = .0001) and p16 deletion (P = .03). Tumors with BRAF V600E had a strong trend toward an increased risk for progression (hazard ratio = 2.48, P = .07), whereas those with BRAF rearrangement had a milder trend toward reduced risk (hazard ratio = .54, P = .15). These data suggest that p16 deletion adversely impacts the outcomes of BRAF-driven gliomas, that high proliferation index may be a better marker of progression risk than BRAF, that BRAF rearrangement and BRAF V600E might not necessarily produce comparable outcomes, and that none of these markers is stronger than tumor location in determining prognosis in pediatric low-grade gliomas. PMID- 22492958 TI - Glioblastoma blood flow measured with stable xenon CT indicates tumor necrosis, vascularity, and brain invasion. AB - Tumor vasculature is a promising therapeutic target in glioblastoma. Imaging tumor blood flow may help assess the efficacy of anti-angiogenic treatments. We determined the clinical usefulness of stable xenon CT performed preoperatively in patients with glioblastoma. This is a prospective cohort study. We determined absolute tumor blood flow before surgery in 38 patients with glioblastoma using stable xenon CT. We also histologically examined tumor specimens obtained from surgery and quantified their vascularity (by CD31 and CD105 immunostain), necrosis (by hematoxylin and eosin stain), and the presence of neuronal processes (by neurofilament immunostain). According to the xenon CT blood flow map, there are 3 types of glioblastoma. Type I glioblastomas have unimodal high blood flow histograms; histologically there is little necrosis and vascular proliferation. Type II glioblastomas have unimodal low blood flow histograms; histologically there is prominent necrosis and vascular proliferation. We propose that in type II glioblastoma, the abnormal vessels induced by hypoxia are inefficient at promoting blood flow. Type III glioblastomas have multimodal blood flow histograms. Histologically there is significant neuronal tissue within the tumor. Patients with type III glioblastomas were more likely to develop a post-surgical deficit, consistent with the inclusion of normal tissue within the tumor. Preoperative measurement of absolute blood flow with stable xenon CT in patients with glioblastoma predicts key biological features of the tumor and may aid surgical planning. PMID- 22492959 TI - Insights into pediatric diffuse intrinsic pontine glioma through proteomic analysis of cerebrospinal fluid. AB - Diffuse intrinsic pontine glioma (DIPG) is a leading cause of brain tumor-related death in children. DIPG is not surgically resectable, resulting in a paucity of tissue available for molecular studies. As such, tumor biology is poorly understood, and, currently, there are no effective treatments. In the absence of frozen tumor specimens, body fluids--such as cerebrospinal fluid (CSF), serum, and urine--can serve as more readily accessible vehicles for detecting tumor secreted proteins. We analyzed a total of 76 specimens, including CSF, serum, urine, and normal and tumor brainstem tissue. Protein profiling of CSF from patients with DIPG was generated by mass spectrometry using an LTQ-Orbitrap-XL and database search using the Sequest algorithm. Quantitative and statistical analyses were performed with ProteoIQ and Partek Genomics Suite. A total of 528 unique proteins were identified, 71% of which are known secreted proteins. CSF proteomic analysis revealed selective upregulation of Cyclophillin A (CypA) and dimethylarginase 1 (DDAH1) in DIPG (n = 10), compared with controls (n = 4). Protein expression was further validated with Western blot analysis and immunohistochemical assays using CSF, brain tissue, serum, and urine from DIPG and control specimens. Immunohistochemical staining showed selective upregulation of secreted but not cytosolic CypA and DDAH1 in patients with DIPG. In this study, we present the first comprehensive protein profile of CSF specimens from patients with DIPG to demonstrate selective expression of tumor proteins potentially involved in brainstem gliomagenesis. Detection of secreted CypA and DDAH1 in serum and urine has potential clinical application, with implications for assessing treatment response and detecting tumor recurrence in patients with DIPG. PMID- 22492960 TI - Use of magnetic perfusion-weighted imaging to determine epidermal growth factor receptor variant III expression in glioblastoma. AB - Identification of the epidermal growth factor receptor variant III (EGFRvIII) mutation in glioblastoma has become increasingly relevant in the optimization of therapy. Traditionally, determination of tumor EGFRvIII-expression has relied on tissue-based diagnostics. Here, we assess the accuracy of magnetic resonance perfusion-weighted imaging (MR-PWI) in discriminating the EGFRvIII-expressing glioblastoma subtype. We analyzed RNA from 132 primary human glioblastoma tissue samples by reverse-transcription polymerase chain reaction (RT-PCR) for the EGFRvIII and EGFR wild-type mutations and by quantitative RT-PCR for expression of vascular endothelial growth factor (VEGF). Concurrently, 3 independent observers reviewed preoperative 1.5-Tesla (T)/SE or 3.0-Tesla (T)/GE MR perfusion images to determine the maximum relative tumor blood volume (rTBV) of each of these tumors. EGFRvIII-expressing glioblastomas showed significantly higher rTBV, compared with those tumors lacking EGFRvIII expression. This association was observed in both the 1.5T/SE (P = .000) and 3.0T/GE (P = .001) cohorts. By logistic regression analysis, combining the 2 MR system cohorts, rTBV was a very strong predictor of EGFRvIII mutation (odds ratio [rTBV] = 2.70; P = .000; McFadden's rho(2) = 0.23). Furthermore, by receiver-operating characteristic curve analysis, rTBV discriminated EGFRvIII with very high accuracy (A(z) = 0.81). In addition, we found that VEGF upregulation was associated, although without reaching statistical significance, with EGFRvIII expression (P = .16) and with increased rTBV (F-ratio = 2.71; P = .102). These trends suggest that VEGF mediated angiogenesis may be a potential mediator of angiogenesis to increase perfusion in EGFRvIII-expressing glioblastomas, but there are likely several other contributing factors. This study demonstrates the potential to use rTBV, a MR-PWI-derived parameter, as a noninvasive surrogate of the EGFRvIII mutation. PMID- 22492961 TI - Response assessment in recurrent glioblastoma treated with irinotecan bevacizumab: comparative analysis of the Macdonald, RECIST, RANO, and RECIST + F criteria. AB - Traditionally, the most widely used criteria for response assessment in glioblastoma have been Macdonald and the Response Evaluation Criteria In Solid Tumors (RECIST). Recently, new criteria addressing contrast enhancement and fluid attenuated inversion recovery (FLAIR)/T2 hyperintensity have been defined (the Response Assessment in Neuro-Oncology criteria) to better evaluate the effect of antiangiogenic therapy. Whether FLAIR/T2 imaging could also be helpful to refine RECIST criteria remains unresolved. This study proposed the RECIST + F criteria and compared the 4 methods (Macdonald, RECIST, RANO, and RECIST + F) to determine their agreement in identifying response and progression of recurrent glioblastomas to irinotecan-bevacizumab. Patients with recurrent glioblastoma treated with second-line irinotecan-bevacizumab were eligible. Clinical status, corticosteroid dose, and 1-dimensional and 2-dimensional measurements of tumor contrast enhancement and FLAIR hyperintensity were retrospectively assessed. Response and progression were determined according to each set of criteria. Seventy-eight patients were included. Response rates ranged from 34.2% with RECIST + F to 44.7% with Macdonald criteria. Agreement among the 4 methods in determining response and type of progression was high (kappa statistic > 0.75). One-third of patients exhibited nonenhancing progression with stable or improved contrast enhancement. Median progression-free survival was predicted by RECIST, at 13.6 weeks; RECIST + F, 12.3; Macdonald, 12.7; and RANO, 11.7 (P = .840). Intra- and interobserver correlations were high for both contrast enhancement and FLAIR hyperintensity measurements. There was a strong concordance among the different methods in determining response and progression to irinotecan bevacizumab. Criteria integrating FLAIR hyperintensity tended, however, to reduce response rates and progression-free survival compared with criteria considering only contrast enhancement. The 1-dimensional approach appeared to be as valid as the 2-dimensional approach. PMID- 22492962 TI - MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity. AB - An accurate, nonsurgical diagnostic test for brain tumors is currently unavailable, and the methods of monitoring disease progression are not fully reliable. MicroRNA profiling of biological fluids has recently emerged as a diagnostic tool for several pathologic conditions. Here we tested whether microRNA profiling of cerebrospinal fluid (CSF) enables detection of glioblastoma, discrimination between glioblastoma and metastatic brain tumors, and reflects disease activity. We determined CSF levels of several cancer associated microRNAs for 118 patients diagnosed with different types of brain cancers and nonneoplastic neuropathologies by quantitative reverse transcription PCR analysis. The levels of miR-10b and miR-21 are found significantly increased in the CSF of patients with glioblastoma and brain metastasis of breast and lung cancer, compared with tumors in remission and a variety of nonneoplastic conditions. Members of the miR-200 family are highly elevated in the CSF of patients with brain metastases but not with any other pathologic conditions, allowing discrimination between glioblastoma and metastatic brain tumors. Quantification of as few as 7 microRNAs in CSF enables differential recognition of glioblastoma and metastatic brain cancer using computational machine learning tools (Support Vector Machine) with high accuracy (91%-99%) on a test set of samples. Furthermore, we show that disease activity and treatment response can be monitored by longitudinal microRNA profiles in the CSF of glioblastoma and non small cell lung carcinoma patients. This study demonstrates that microRNA-based detection of brain malignancies can be reliably performed and that microRNAs in CSF can serve as biomarkers of treatment response in brain cancers. PMID- 22492963 TI - Simultaneous determination of aromatic acid metabolites of styrene and styrene oxide in rat urine by gas chromatography-flame ionization detection. AB - A convenient and reliable gas chromatographic method was developed for the simultaneous determination of six aromatic acid metabolites of styrene and styrene-oxide in rat urine; i.e., benzoic (BA), phenylacetic (PAA), mandelic (MA), phenylglyoxylic (PGA), hippuric (HA) and phenylaceturic (PAUA) acids. The method involves a one-pot esterification-extraction procedure, performed directly on urine without prior treatment. Analyses were performed on a RTX-1701 capillary column and the recovered isopropyl esters derivatives were detected by flame ionization detection. The analytical method was validated for selectivity, linearity, detection and quantification limits, recovery and intra-day and inter day precisions. Calibration curves showed linearity in the range of 8-800 mg/L, except for HA and PAUA (40-800 mg/L). Limits of detection were between 0.2 (PPA) and 7.0 (PAUA) mg/L. The intra-day precisions determined at three concentrations levels were less than 5% for BA, PAA, MA and PGA and 9% for HA and PAUA, respectively. The corresponding mean inter-day precisions for these two groups were 8 and 16%, respectively. The method was successfully applied to quantitatively analyze styrene, styrene-oxide, ethylbenzene and toluene metabolites in urine samples from rats exposed by inhalation to these compounds at levels close to the occupational threshold limit values. Provided that this method can be transposed to human urine, it could have applications as part of biological monitoring for workers exposed to styrene or related compounds. PMID- 22492964 TI - Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus. AB - Hepatitis C virus (HCV) infects ~2% of the world's population. It is estimated that there are more than 500,000 new infections annually in Egypt, the country with the highest HCV prevalence. An effective vaccine would help control this expanding global health burden. HCV is highly variable, and an effective vaccine should target conserved T- and B-cell epitopes of the virus. Conserved B-cell epitopes overlapping the CD81 receptor-binding site (CD81bs) on the E2 viral envelope glycoprotein have been reported previously and provide promising vaccine targets. In this study, we isolated 73 human mAbs recognizing five distinct antigenic regions on the virus envelope glycoprotein complex E1E2 from an HCV immune phage-display antibody library by using an exhaustive-panning strategy. Many of these mAbs were broadly neutralizing. In particular, the mAb AR4A, recognizing a discontinuous epitope outside the CD81bs on the E1E2 complex, has an exceptionally broad neutralizing activity toward diverse HCV genotypes and protects against heterologous HCV challenge in a small animal model. The mAb panel will be useful for the design and development of vaccine candidates to elicit broadly neutralizing antibodies to HCV. PMID- 22492965 TI - ErbB receptor tyrosine kinase/NF-kappaB signaling controls mammosphere formation in human breast cancer. AB - Breast cancer is one of the most common cancers in humans. However, our understanding of the cellular and molecular mechanisms underlying tumorigenesis in breast tissues is limited. Here, we identified a molecular mechanism that controls the ability of breast cancer cells to form multicellular spheroids (mammospheres). We found that heregulin (HRG), a ligand for ErbB3, induced mammosphere formation of a breast cancer stem cell (BCSC)-enriched population as well as in breast cancer cell lines. HRG-induced mammosphere formation was reduced by treatment with inhibitors for phosphatidyl inositol 3-kinase (PI3K) or NF-kappaB and by expression of IkappaBalpha-Super Repressor (IkappaBalphaSR), a dominant-negative inhibitor for NF-kappaB. Moreover, the overexpression of IkappaBalphaSR in breast cancer cells inhibited tumorigenesis in NOD/SCID mice. Furthermore, we found that the expression of IL8, a regulator of self-renewal in BCSC-enriched populations, was induced by HRG through the activation of the PI3K/NF-kappaB pathway. These findings illustrate that HRG/ErbB3 signaling appears to maintain mammosphere formation through a PI3K/NF-kappaB pathway in human breast cancer. PMID- 22492966 TI - Demyelination reduces brain parenchymal stiffness quantified in vivo by magnetic resonance elastography. AB - The detection of pathological tissue alterations by manual palpation is a simple but essential diagnostic tool, which has been applied by physicians since the beginnings of medicine. Recently, the virtual "palpation" of the brain has become feasible using magnetic resonance elastography, which quantifies biomechanical properties of the brain parenchyma by analyzing the propagation of externally elicited shear waves. However, the precise molecular and cellular patterns underlying changes of viscoelasticity measured by magnetic resonance elastography have not been investigated up to date. We assessed changes of viscoelasticity in a murine model of multiple sclerosis, inducing reversible demyelination by feeding the copper chelator cuprizone, and correlated our results with detailed histological analyses, comprising myelination, extracellular matrix alterations, immune cell infiltration and axonal damage. We show firstly that the magnitude of the complex shear modulus decreases with progressive demyelination and global extracellular matrix degradation, secondly that the loss modulus decreases faster than the dynamic modulus during the destruction of the corpus callosum, and finally that those processes are reversible after remyelination. PMID- 22492968 TI - Transcription factor 4 as an important determinant of gating function in schizophrenia. PMID- 22492970 TI - Protracted reproductive seasonality in the male giant panda (Ailuropoda melanoleuca) reflected by patterns in androgen profiles, ejaculate characteristics, and selected behaviors. AB - The female giant panda (Ailuropoda melanoleuca) experiences a brief (24-72 h) seasonal estrus, occurring once annually in spring (February-May). Our aim was to determine the existence and temporal profile of reproductive seasonality in the male of this species. The study was facilitated by 3 yr of access to eight giant panda males living in a large breeding center in China. Seasonal periods for the male were defined on the basis of female reproductive activity as prebreeding, breeding (early, peak, late), and nonbreeding seasons. Testes size, fecal androgen excretion, ejaculated sperm density, and frequency of reproductive behaviors (i.e., locomotion, scent marking, vocalizations) increased (P < 0.05) from the prebreeding period (October 1-January 31) to the early breeding season (February 1-March 21). Testes volume and sperm concentration were maximal from March 22 through April 15, a period coinciding with maximal female breeding activity. The occurrence of male reproductive behaviors and fecal androgen concentrations began declining during peak breeding and continued from April 16 through May 31 (late breeding period), returning to nadir throughout the nonbreeding interval (June 1-September 30). Reproductive quiescence throughout the latter period was associated with basal testes size/volume and aspermic ejaculates. Our results reveal that testes morphometry, fecal androgen excretion, seminal quality, and certain behaviors integrated together clearly demonstrate reproductive seasonality in the male giant panda. The coordinated increases in testes size, androgen production, sperm density, and sexual behaviors occur over a protracted interval, likely to prepare for and then accommodate a brief, unpredictable female estrus. PMID- 22492969 TI - Complex N-glycans are essential, but core 1 and 2 mucin O-glycans, O-fucose glycans, and NOTCH1 are dispensable, for mammalian spermatogenesis. AB - To identify roles in spermatogenesis for major subclasses of N- and O-glycans and Notch signaling, male mice carrying floxed C1galt1, Pofut1, Notch1 or Mgat1 alleles and a testis-specific Cre recombinase transgene were generated. T synthase (C1GALT1) transfers Gal to generate core 1 and core 2 mucin O-glycans; POFUT1 transfers O-fucose to particular epidermal growth factor-like repeats and is essential for canonical Notch signaling; and MGAT1 (GlcNAcT-I) transfers GlcNAc to initiate hybrid and complex N-glycan synthesis. Cre recombinase transgenes driven by various promoters were investigated, including Stra8-iCre expressed in spermatogonia, Sycp1-Cre expressed in spermatocytes, Prm1-Cre expressed in spermatids, and AMH-Cre expressed in Sertoli cells. All Cre transgenes deleted floxed alleles, but efficiencies varied widely. Stra8-iCre was the most effective, deleting floxed Notch1 and Mgat1 alleles with 100% efficiency and floxed C1galt1 and Pofut1 alleles with ~80% efficiency, based on transmission of deleted alleles. Removal of C1galt1, Pofut1, or Notch1 in spermatogonia had no effect on testicular weight, histology, or fertility. However, males in which the synthesis of complex N-glycans was blocked by deletion of Mgat1 in spermatogonia did not produce sperm. Spermatogonia, spermatocytes, and spermatids were generated, but most spermatids formed giant multinucleated cells or symplasts, and apoptosis was increased. Therefore, although core 1 and 2 mucin O-glycans, NOTCH1, POFUT1, O-fucose glycans, and Notch signaling are dispensable, MGAT1 and complex N-glycans are essential for spermatogenesis. PMID- 22492971 TI - Is the adult Sertoli cell terminally differentiated? AB - New data have challenged the convention that the adult Sertoli cell population is fixed and unmodifiable. The Sertoli cell has two distinct functions: 1) formation of the seminiferous cords and 2) provision of nutritional and structural support to developing germ cells. For these to occur successfully, Sertoli cells must undergo many maturational changes between fetal and adult life, the main switches occurring around puberty, including the loss of proliferative activity and the formation of the blood-testis barrier. Follicle-stimulating hormone plays a key role in promoting Sertoli cell proliferation, while thyroid hormone inhibits proliferative activity in early postnatal life. Together these regulate the Sertoli-germ cell complement and sperm output in adulthood. By puberty, the Sertoli cell population is considered to be stable and unmodifiable by hormones. But there is mounting evidence that the size of the adult Sertoli cell population and its maturational status is modifiable by hormones and that Sertoli cells can gain proliferative ability in the spermatogenically disrupted hamster and human model. This new information demonstrates that the adult Sertoli cell population, at least in the settings of testicular regression in the hamster and impaired fertility in humans in vivo and from mice and men in vitro, is not a terminally differentiated population. Data from the hamster now show that the adult Sertoli cell population size is regulated by hormones. This creates exciting prospects for basic and clinical research in testis biology. The potential to replenish an adult Sertoli-germ cell complement to normal in a setting of infertility may now be realized. PMID- 22492972 TI - Latrunculin A can improve the birth rate of cloned mice and simplify the nuclear transfer protocol by gently inhibiting actin polymerization. AB - Although animal cloning is becoming more practicable, there are many abnormalities in cloned embryos, and the success rate of producing live animals by cloning has been low. Here, we focused on the procedure for preventing pseudo second polar body extrusion from somatic cell nuclear transfer (SCNT)-derived oocytes. Typically, reconstructed oocytes are treated with cytochalasin B (CB), but here latrunculin A (LatA) was used instead of CB to prevent pseudo-second polar body extrusion by inhibiting actin polymerization. CB caps F-actin, LatA binds G-actin, and both drugs prevent their polymerization. When the localization of F-actin was examined using phalloidin staining, it was abnormally scattered in the cytoplasm of CB-treated 1-cell embryos, but this was not detected in LatA treated or in vitro fertilization-derived control embryos. The spindle was larger in CB-treated oocytes than in LatA-treated or untreated control oocytes. LatA treatment also doubled the rate of full-term development after embryo transfer. These results suggest that cloning efficiency in mice can be improved by optimizing each step of the SCNT procedure. Moreover, by using LatA, we could simplify the procedure with a higher birth rate of cloned mice compared with our original method. PMID- 22492973 TI - Equine luteal function regulation may depend on the interaction between cytokines and vascular endothelial growth factor: an in vitro study. AB - We hypothesized that cytokines influence luteal angiogenesis in mares, while angiogenic factors themselves can also regulate luteal secretory capacity. Therefore, the purpose of this study was to evaluate the role of cytokines--tumor necrosis factor alpha (TNF), interferon gamma (IFNG) and Fas ligand (FASL)--on in vitro modulation of angiogenic activity and mRNA level of vascular endothelial growth factor A (VEGF), its receptor VEGFR2, thrombospondin 1 (TSP1), and its receptor CD36 in equine corpus luteum (CL) throughout the luteal phase. After treatment, VEGF protein expression was determined in midluteal phase (mid) CL cells. The role of VEGF on regulation of luteal secretory capacity was assessed by progesterone (P(4)) and prostaglandin E(2) (PGE(2)) production and by mRNA levels for steroidogenic enzymes 3-beta-hydroxysteroid dehydrogenase (3betaHSD) and PGE synthase (PGES). In early CL cells, TNF increased angiogenic activity (bovine aortic endothelial cell viability) and VEGF and VEGFR2 mRNA levels and decreased CD36 (real-time PCR relative quantification). In mid-CL cells, TNF increased VEGF mRNA and protein expression (Western blot analysis) and reduced CD36 mRNA levels, while FASL and TNF+IFNG+FASL decreased VEGF protein expression. In late CL cells, TNF and TNF+IFNG+FASL reduced VEGFR2 mRNA, but TNF+IFNG+FASL increased TSP1 and CD36 mRNA. VEGF treatment increased mRNA levels of 3betaHSD and PGES and secretion of P(4) and PGE(2). In conclusion, these findings suggest a novel auto/paracrine action of cytokines, specifically TNF, on the up regulation of VEGF for angiogenesis stimulation in equine early CL, while at luteolysis, cytokines down-regulated angiogenesis. Additionally, VEGF stimulated P(4) and PGE(2) production, which may be crucial for CL establishment. PMID- 22492975 TI - Atom-by-atom nucleation and growth of graphene nanopores. AB - Graphene is an ideal thin membrane substrate for creating molecule-scale devices. Here we demonstrate a scalable method for creating extremely small structures in graphene with atomic precision. It consists of inducing defect nucleation centers with energetic ions, followed by edge-selective electron recoil sputtering. As a first application, we create graphene nanopores with radii as small as 3 A, which corresponds to 10 atoms removed. We observe carbon atom removal from the nanopore edge in situ using an aberration-corrected electron microscope, measure the cross section for the process, and obtain a mean edge atom displacement energy of 14.1 +/- 0.1 eV. This approach does not require focused beams and allows scalable production of single nanopores and arrays of monodisperse nanopores for atomic scale selectively permeable membranes. PMID- 22492974 TI - Simvastatin decreases invasiveness of human endometrial stromal cells. AB - Recently we reported that statins, the competitive inhibitors of the key enzyme regulating the mevalonate pathway, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), decrease proliferation of human endometrial stromal (HES) cells. Furthermore, we found that simvastatin treatment reduces the number and the size of endometrial implants in a nude mouse model of endometriosis. The present study was undertaken to investigate the effect of simvastatin on HES cell invasiveness and on expression of selected genes relevant to invasiveness: matrix metalloproteinase 2 (MMP2), MMP3, tissue inhibitor of matrix metalloproteinase 2 (TIMP2), and CD44. Because statin-induced inhibition of HMGCR reduces the production of substrates for isoprenylation-geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP)-the effects of GGPP and FPP were also evaluated. Simvastatin induced a concentration-dependent reduction of invasiveness of HES cells. This effect of simvastatin was abrogated by GGPP but not by FPP. Simvastatin also reduced the mRNA levels of MMP2, MMP3, and CD44, but increased TIMP2 mRNA; all these effects of simvastatin were partly or entirely reversed in the presence of GGPP. The present findings provide a novel mechanism of action of simvastatin on endometrial stroma that may explain reduction of endometriosis in animal models of this disease. Furthermore, the presently described effects of simvastatin are likely mediated, at least in part, by inhibition of geranylgeranylation. PMID- 22492976 TI - Superconductive sodalite-like clathrate calcium hydride at high pressures. AB - Hydrogen-rich compounds hold promise as high-temperature superconductors under high pressures. Recent theoretical hydride structures on achieving high-pressure superconductivity are composed mainly of H(2) fragments. Through a systematic investigation of Ca hydrides with different hydrogen contents using particle-swam optimization structural search, we show that in the stoichiometry CaH(6) a body centered cubic structure with hydrogen that forms unusual "sodalite" cages containing enclathrated Ca stabilizes above pressure 150 GPa. The stability of this structure is derived from the acceptance by two H(2) of electrons donated by Ca forming an "H(4)" unit as the building block in the construction of the three dimensional sodalite cage. This unique structure has a partial occupation of the degenerated orbitals at the zone center. The resultant dynamic Jahn-Teller effect helps to enhance electron-phonon coupling and leads to superconductivity of CaH(6). A superconducting critical temperature (T(c)) of 220-235 K at 150 GPa obtained from the solution of the Eliashberg equations is the highest among all hydrides studied thus far. PMID- 22492977 TI - The costimulatory immunogen LPS induces the B-Cell clones that infiltrate transplanted human kidneys. AB - The mechanism of chronic rejection of transplanted human kidneys is unknown. An understanding of this process is important because, chronic rejection ultimately leads to loss of the kidney allograft in most transplants. One feature of chronic rejection is the infiltration of ectopic B-cell clusters that are clonal into the transplanted kidney. We now show that the antibodies produced by these B-cells react strongly with the core carbohydrate region of LPS. Since LPS is a costimulatory immunogen that can react with both the B-cell receptor (BCR) and the Toll-like receptor 4 (TLR4), these results suggest a mechanism for the selective pressure that leads to clonality of these B-cell clusters and opens the possibility that infection and the attendant exposure to LPS plays a role in the chronic rejection of human kidney transplants. If confirmed by clinical studies, these results suggest that treating patients with signs of chronic rejection with antibiotics may improve kidney allograft survival. PMID- 22492978 TI - Quantifying internal friction in unfolded and intrinsically disordered proteins with single-molecule spectroscopy. AB - Internal friction, which reflects the "roughness" of the energy landscape, plays an important role for proteins by modulating the dynamics of their folding and other conformational changes. However, the experimental quantification of internal friction and its contribution to folding dynamics has remained challenging. Here we use the combination of single-molecule Forster resonance energy transfer, nanosecond fluorescence correlation spectroscopy, and microfluidic mixing to determine the reconfiguration times of unfolded proteins and investigate the mechanisms of internal friction contributing to their dynamics. Using concepts from polymer dynamics, we determine internal friction with three complementary, largely independent, and consistent approaches as an additive contribution to the reconfiguration time of the unfolded state. We find that the magnitude of internal friction correlates with the compactness of the unfolded protein: its contribution dominates the reconfiguration time of approximately 100 ns of the compact unfolded state of a small cold shock protein under native conditions, but decreases for more expanded chains, and approaches zero both at high denaturant concentrations and in intrinsically disordered proteins that are expanded due to intramolecular charge repulsion. Our results suggest that internal friction in the unfolded state will be particularly relevant for the kinetics of proteins that fold in the microsecond range or faster. The low internal friction in expanded intrinsically disordered proteins may have implications for the dynamics of their interactions with cellular binding partners. PMID- 22492979 TI - Cryo-EM structure of a transcribing cypovirus. AB - Double-stranded RNA viruses in the family Reoviridae are capable of transcribing and capping nascent mRNA within an icosahedral viral capsid that remains intact throughout repeated transcription cycles. However, how the highly coordinated mRNA transcription and capping process is facilitated by viral capsid proteins is still unknown. Cypovirus provides a good model system for studying the mRNA transcription and capping mechanism of viruses in the family Reoviridae. Here, we report a full backbone model of a transcribing cypovirus built from a near-atomic resolution density map by cryoelectron microscopy. Compared with the structure of a nontranscribing cypovirus, the major capsid proteins of transcribing cypovirus undergo a series of conformational changes, giving rise to structural changes in the capsid shell: (i) an enlarged capsid chamber, which provides genomic RNA with more flexibility to move within the densely packed capsid, and (ii) a widened peripentonal channel in the capsid shell, which we confirmed to be a pathway for nascent mRNA. A rod-like structure attributable to a partially resolved nascent mRNA was observed in this channel. In addition, conformational change in the turret protein results in a relatively open turret at each fivefold axis. A GMP moiety, which is transferred to 5'-diphosphorylated mRNA during the mRNA capping reaction, was identified in the pocket-like guanylyltransferase domain of the turret protein. PMID- 22492980 TI - Introducing endo-xylanase activity into an exo-acting arabinofuranosidase that targets side chains. AB - The degradation of the plant cell wall by glycoside hydrolases is central to environmentally sustainable industries. The major polysaccharides of the plant cell wall are cellulose and xylan, a highly decorated beta-1,4-xylopyranose polymer. Glycoside hydrolases displaying multiple catalytic functions may simplify the enzymes required to degrade plant cell walls, increasing the industrial potential of these composite structures. Here we test the hypothesis that glycoside hydrolase family 43 (GH43) provides a suitable scaffold for introducing additional catalytic functions into enzymes that target complex structures in the plant cell wall. We report the crystal structure of Humicola insolens AXHd3 (HiAXHd3), a GH43 arabinofuranosidase that hydrolyses O3-linked arabinose of doubly substituted xylans, a feature of the polysaccharide that is recalcitrant to degradation. HiAXHd3 displays an N-terminal five-bladed beta propeller domain and a C-terminal beta-sandwich domain. The interface between the domains comprises a xylan binding cleft that houses the active site pocket. Substrate specificity is conferred by a shallow arabinose binding pocket adjacent to the deep active site pocket, and through the orientation of the xylan backbone. Modification of the rim of the active site introduces endo-xylanase activity, whereas the resultant enzyme variant, Y166A, retains arabinofuranosidase activity. These data show that the active site of HiAXHd3 is tuned to hydrolyse arabinofuranosyl or xylosyl linkages, and it is the topology of the distal regions of the substrate binding surface that confers specificity. This report demonstrates that GH43 provides a platform for generating bespoke multifunctional enzymes that target industrially significant complex substrates, exemplified by the plant cell wall. PMID- 22492981 TI - Multidrug resistance-linked gene signature predicts overall survival of patients with primary ovarian serous carcinoma. AB - PURPOSE: This study assesses the ability of multidrug resistance (MDR)-associated gene expression patterns to predict survival in patients with newly diagnosed carcinoma of the ovary. The scope of this research differs substantially from that of previous reports, as a very large set of genes was evaluated whose expression has been shown to affect response to chemotherapy. EXPERIMENTAL DESIGN: We applied a customized TaqMan low density array, a highly sensitive and specific assay, to study the expression profiles of 380 MDR-linked genes in 80 tumor specimens collected at initial surgery to debulk primary serous carcinoma. The RNA expression profiles of these drug resistance genes were correlated with clinical outcomes. RESULTS: Leave-one-out cross-validation was used to estimate the ability of MDR gene expression to predict survival. Although gene expression alone does not predict overall survival (OS; P = 0.06), four covariates (age, stage, CA125 level, and surgical debulking) do (P = 0.03). When gene expression was added to the covariates, we found an 11-gene signature that provides a major improvement in OS prediction (log-rank statistic P < 0.003). The predictive power of this 11-gene signature was confirmed by dividing high- and low-risk patient groups, as defined by their clinical covariates, into four specific risk groups on the basis of expression levels. CONCLUSION: This study reveals an 11-gene signature that allows a more precise prognosis for patients with serous cancer of the ovary treated with carboplatin- and paclitaxel-based therapy. These 11 new targets offer opportunities for new therapies to improve clinical outcome in ovarian cancer. PMID- 22492982 TI - Evaluation of circulating tumor cells and circulating tumor DNA in non-small cell lung cancer: association with clinical endpoints in a phase II clinical trial of pertuzumab and erlotinib. AB - PURPOSE: Elevated levels or increases in circulating tumor cells (CTC) portend poor prognosis in patients with epithelial cancers. Less is known about CTCs as surrogate endpoints or their use for predictive biomarker evaluation. This study investigated the utility of CTC enumeration and characterization using the CellSearch platform, as well as mutation detection in circulating tumor DNA (ctDNA), in patients with advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Forty-one patients were enrolled in a single-arm phase II clinical trial of erlotinib and pertuzumab. Peripheral blood was analyzed for CTC enumeration, EGFR expression in CTCs, and detection of oncogenic mutations in CTCs and ctDNA. Changes in CTC levels were correlated with 2[18F]fluoro-2-deoxy-D glucose-positron emission tomographic (FDG-PET) and computed tomographic (CT) imaging and survival endpoints. RESULTS: CTCs were detected (>= 1 CTC) at baseline in 78% of patients. Greater sensitivity for mutation detection was observed in ctDNA than in CTCs and detected mutations were strongly concordant with mutation status in matched tumor. Higher baseline CTC counts were associated with response to treatment by Response Evaluation Criteria in Solid Tumors (RECIST, P = 0.009) and decreased CTC counts upon treatment were associated with FDG-PET and RECIST response (P = 0.014 and P = 0.019) and longer progression-free survival (P = 0.050). CONCLUSION: These data provide evidence of a correlation between decreases in CTC counts and radiographic response by either FDG-PET or RECIST in patients with advanced NSCLC. These findings require prospective validation but suggest a potential role for using CTC decreases as an early indication of response to therapy and ctDNA for real-time assessment of mutation status from blood. PMID- 22492983 TI - Actin-bundling proteins in cancer progression at a glance. PMID- 22492985 TI - The molecular chaperone Hsp47 is essential for cartilage and endochondral bone formation. AB - Heat shock protein 47 kDa (Hsp47) is considered as a molecular chaperone essential for the correct folding of type I and type IV procollagen in the ER. However, the function of Hsp47 for other types of procollagen and its importance for chondrogenesis have never been elucidated. To examine the function of Hsp47 in cartilage formation and endochondral ossification, we conditionally inactivated the Hsp47 gene in chondrocytes using Hsp47 floxed mice and mice carrying a chondrocyte-specific Col2a1-Cre transgene. Hsp47 conditional null mutant mice died just before or shortly after birth, and exhibited severe generalized chondrodysplasia and bone deformities with lower levels of type II and type XI collagen. Second-harmonic generation (SHG) analysis and electron microscopy revealed the accumulation of misaligned type I collagen molecules in the intervertebral discs and a substantial decrease in type II collagen fibers, respectively. Whole-mount skeletal staining showed no calcified region in the vertebral bodies of sacral vertebrae, and revealed that the endochondral bones were severely twisted and shortened. These results demonstrate that Hsp47 is indispensable for well-organized cartilage and normal endochondral bone formation. PMID- 22492984 TI - BH3-only proteins in apoptosis at a glance. PMID- 22492986 TI - LIMK2 is a crucial regulator and effector of Aurora-A-kinase-mediated malignancy. AB - Aurora A is overexpressed in majority of breast carcinomas. With the exception of BRCA1 and PHLDA1, no oncogenic Aurora A substrates are known in breast cancer. In this study, a chemical genetic approach was used to identify malignant targets of Aurora A, which revealed LIMK2 as a novel Aurora A substrate. Aurora A regulates LIMK2 kinase activity, subcellular localization and protein levels by direct phosphorylation at S283, T494 and T505. In response, LIMK2 also positively regulates the level of Aurora A, thereby engaging in a positive-feedback loop, promoting Aurora-A-mediated oncogenic pathways. Most importantly, LIMK2 ablation fully abrogates Aurora-A-mediated tumorigenesis in nude mice, suggesting that LIMK2 is a key oncogenic effector of Aurora A. Furthermore, LIMK2 ablation acts synergistically with inhibition of Aurora A in promoting cell death. Finally, Aurora-A-mediated upregulation of LIMK2 appears to be a common mechanism in many cancers. LIMK2 inhibition or ablation is therefore an alternative approach for modulating Aurora A deregulation in cancer. PMID- 22492987 TI - Low serum adiponectin predicts future risk for asthma in women. AB - RATIONALE: Our previous cross-sectional study showed that serum adiponectin is inversely associated with asthma among women. However, it is not known if serum adiponectin predicts future development of asthma or if asthma affects subsequent serum adiponectin concentrations among women. OBJECTIVES: To determine longitudinal association between serum adiponectin and incident asthma among women. METHODS: We used data from examinations at Years 10, 15, and 20 of the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. In our primary analysis, the association of CARDIA Year 15 serum adiponectin concentration with Year 20 incident asthma was evaluated. In our secondary analysis, the converse direction, that is, the association of CARDIA Year 10 prevalent asthma with Year 15 serum adiponectin, was evaluated, using logistic regression techniques. MEASUREMENTS AND MAIN RESULTS: Our primary analysis included 1,450 women, mostly premenopausal. Multivariable analyses demonstrated that the lowest tertile of Year 15 serum adiponectin concentration (<7 mg/L) predicted significantly higher risk for incident asthma at Year 20 among women (odds ratio, 2.07; 95% confidence interval, 1.05, 4.10), and particularly among current smokers (interaction P = 0.051). Further, low serum adiponectin was more important than body mass index in predicting the risk for incident asthma among women. We also showed that the converse relationship was not true; that is, Year 10 prevalent asthma did not predict Year 15 serum adiponectin concentrations in women. CONCLUSIONS: Serum adiponectin affects future risk for asthma in women and not vice versa. Measures that raise systemic adiponectin concentrations may lead to newer ways to prevent asthma among women, particularly among those who smoke. PMID- 22492988 TI - The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. AB - RATIONALE: Cognitive and psychiatric morbidity is common and potentially modifiable after acute lung injury (ALI). However, practical measures of neuropsychological function for use in multicenter trials are lacking. OBJECTIVES: To determine whether a validated telephone-based neuropsychological test battery is feasible in a multicenter trial. To determine the frequency and risk factors for long-term neuropsychological impairment. METHODS: As an adjunct study to the Acute Respiratory Distress Syndrome Clinical Trials Network Fluid and Catheter Treatment Trial, we assessed neuropsychological function at 2 and 12 months post-hospital discharge. MEASUREMENTS AND MAIN RESULTS: Of 406 eligible survivors, we approached 261 to participate and 213 consented. We tested 122 subjects at least once, including 102 subjects at 12 months. Memory, verbal fluency, and executive function were impaired in 13% (12 of 92), 16% (15 of 96), and 49% (37 of 76) of long-term survivors. Long-term cognitive impairment was present in 41 of the 75 (55%) survivors who completed cognitive testing. Depression, post-traumatic stress disorder, or anxiety was present in 36% (37 of 102), 39% (40 of 102), and 62% (63 of 102) of long-term survivors. Enrollment in a conservative fluid-management strategy (P = 0.005) was associated with cognitive impairment and lower partial pressure of arterial oxygen during the trial was associated with cognitive (P = 0.02) and psychiatric impairment (P = 0.02). CONCLUSIONS: Neuropsychological function can be assessed by telephone in a multicenter trial. Long-term neuropsychological impairment is common in survivors of ALI. Hypoxemia is a risk factor for long-term neuropsychological impairment. Fluid management strategy is a potential risk factor for long-term cognitive impairment; however, given the select population studied and an unclear mechanism, this finding requires confirmation. PMID- 22492989 TI - Occupational exposure to dusts, gases, and fumes and incidence of chronic obstructive pulmonary disease in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults. AB - RATIONALE: There is limited evidence from population-based studies demonstrating incidence of spirometric-defined chronic obstructive pulmonary disease (COPD) in association with occupational exposures. OBJECTIVES: We evaluated the association between occupational exposures and incidence of COPD in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA). MEASUREMENTS AND MAIN RESULTS: Prebronchodilator ratio of forced expiratory volume in 1 second over forced vital capacity (FEV(1)/FVC) was measured in 4,267 nonasthmatic SAPALDIA participants ages 18-62 at baseline in 1991 and at follow-up in 2001 2003. COPD was defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criterion (FEV(1)/FVC < 0.70) and Quanjer reference equation (FEV(1)/FVC < lower limit of normal [LLN]), and categorized by severity (>= 80% and <80% predicted FEV(1) for stage I and stage II+, respectively). Using a job exposure matrix, self-reported occupations at baseline were assigned exposures to biological dusts, mineral dusts, gases/fumes, and vapors, gases, dusts, or fumes (VGDF) (high, low, or unexposed as reference). Adjusted incident rate ratios (IRRs) of stage I and stage II+ COPD were estimated in mixed Poisson regression models. Statistically significant (P < 0.05) IRRs of stage II+ GOLD and LLN-COPD, indicating risks between two- and fivefold, were observed for all occupational exposures at high levels. Occupational exposure-associated risk of stage II+ COPD was observed mainly in males and ages >= 40 years, and remained elevated when restricted to nonsmokers. CONCLUSIONS: In a Swiss working adult population, occupational exposures to biological dusts, mineral dusts, gases/fumes, and VGDF were associated with incidence of COPD of at least moderate severity. PMID- 22492990 TI - Enriched rearing improves behavioral responses of an animal model for CNV-based autistic-like traits. AB - Potocki-Lupski syndrome (PTLS; MIM #610883), characterized by neurobehavioral abnormalities, intellectual disability and congenital anomalies, is caused by a 3.7-Mb duplication in 17p11.2. Neurobehavioral studies determined that ~70-90% of PTLS subjects tested positive for autism or autism spectrum disorder (ASD). We previously chromosomally engineered a mouse model for PTLS (Dp(11)17/+) with a duplication of a 2-Mb genomic interval syntenic to the PTLS region and identified consistent behavioral abnormalities in this mouse model. We now report extensive phenotyping with behavioral assays established to evaluate core and associated autistic-like traits, including tests for social abnormalities, ultrasonic vocalizations, perseverative and stereotypic behaviors, anxiety, learning and memory deficits and motor defects. Alterations were identified in both core and associated ASD-like traits. Rearing this animal model in an enriched environment mitigated some, and even rescued selected, neurobehavioral abnormalities, suggesting a role for gene-environment interactions in the determination of copy number variation-mediated autism severity. PMID- 22492991 TI - Gene identification in the congenital disorders of glycosylation type I by whole exome sequencing. AB - Congenital disorders of glycosylation type I (CDG-I) form a growing group of recessive neurometabolic diseases. Identification of disease genes is compromised by the enormous heterogeneity in clinical symptoms and the large number of potential genes involved. Until now, gene identification included the sequential application of biochemical methods in blood samples and fibroblasts. In genetically unsolved cases, homozygosity mapping has been applied in consanguineous families. Altogether, this time-consuming diagnostic strategy led to the identification of defects in 17 different CDG-I genes. Here, we applied whole-exome sequencing (WES) in combination with the knowledge of the protein N glycosylation pathway for gene identification in our remaining group of six unsolved CDG-I patients from unrelated non-consanguineous families. Exome variants were prioritized based on a list of 76 potential CDG-I candidate genes, leading to the rapid identification of one known and two novel CDG-I gene defects. These included the first X-linked CDG-I due to a de novo mutation in ALG13, and compound heterozygous mutations in DPAGT1, together the first two steps in dolichol-PP-glycan assembly, and mutations in PGM1 in two cases, involved in nucleotide sugar biosynthesis. The pathogenicity of the mutations was confirmed by showing the deficient activity of the corresponding enzymes in patient fibroblasts. Combined with these results, the gene defect has been identified in 98% of our CDG-I patients. Our results implicate the potential of WES to unravel disease genes in the CDG-I in newly diagnosed singleton families. PMID- 22492992 TI - Caffeine intake and CYP1A2 variants associated with high caffeine intake protect non-smokers from hypertension. AB - The 15q24.1 locus, including CYP1A2, is associated with blood pressure (BP). The CYP1A2 rs762551 C allele is associated with lower CYP1A2 enzyme activity. CYP1A2 metabolizes caffeine and is induced by smoking. The association of caffeine consumption with hypertension remains controversial. We explored the effects of CYP1A2 variants and CYP1A2 enzyme activity on BP, focusing on caffeine as the potential mediator of CYP1A2 effects. Four observational (n = 16 719) and one quasi-experimental studies (n = 106) including European adults were conducted. Outcome measures were BP, caffeine intake, CYP1A2 activity and polymorphisms rs762551, rs1133323 and rs1378942. CYP1A2 variants were associated with hypertension in non-smokers, but not in smokers (CYP1A2-smoking interaction P = 0.01). Odds ratios (95% CIs) for hypertension for rs762551 CC, CA and AA genotypes were 1 (reference), 0.78 (0.59-1.02) and 0.66 (0.50-0.86), respectively, P = 0.004. Results were similar for the other variants. Higher CYP1A2 activity was linearly associated with lower BP after quitting smoking (P = 0.049 and P = 0.02 for systolic and diastolic BP, respectively), but not while smoking. In non-smokers, the CYP1A2 variants were associated with higher reported caffeine intake, which in turn was associated with lower odds of hypertension and lower BP (P = 0.01). In Mendelian randomization analyses using rs1133323 as instrument, each cup of caffeinated beverage was negatively associated with systolic BP [-9.57 (-16.22, -2.91) mmHg]. The associations of CYP1A2 variants with BP were modified by reported caffeine intake. These observational and quasi experimental results strongly support a causal role of CYP1A2 in BP control via caffeine intake. PMID- 22492993 TI - C-reactive protein (CRP) promoter polymorphisms influence circulating CRP levels in a genome-wide association study of African Americans. AB - C-reactive protein (CRP) is an acute phase reactant protein produced primarily by the liver. Circulating CRP levels are influenced by genetic and non-genetic factors, including infection and obesity. Genome-wide association studies (GWAS) provide an unbiased approach towards identifying loci influencing CRP levels. None of the six GWAS for CRP levels has been conducted in an African ancestry population. The present study aims to: (i) identify genetic variants that influence serum CRP in African Americans (AA) using a genome-wide association approach and replicate these findings in West Africans (WA), (ii) assess transferability of major signals for CRP reported in European ancestry populations (EA) to AA and (iii) use the weak linkage disequilibrium (LD) structure characteristic of African ancestry populations to fine-map the previously reported CRP locus. The discovery cohort comprised 837 unrelated AA, with the replication of significant single-nucleotide polymorphisms (SNPs) assessed in 486 WA. The association analysis was conducted with 2 366 856 genotyped and imputed SNPs under an additive genetic model with adjustment for appropriate covariates. Genome-wide and replication significances were set at P < 5 * 10(-8) and P < 0.05, respectively. Ten SNPs in (CRP pseudogene-1) CRPP1 and CRP genes were associated with serum CRP (P = 2.4 * 10(-09) to 4.3 * 10(-11)). All but one of the top-scoring SNPs associated with CRP in AA were successfully replicated in WA. CRP signals previously identified in EA samples were transferable to AAs, and we were able to fine-map this signal, reducing the region of interest from the 25 kb of LD around the locus in the HapMap CEU sample to only 8 kb in our AA sample. PMID- 22492994 TI - Loss of HDAC6, a novel CHIP substrate, alleviates abnormal tau accumulation. AB - The abnormal accumulation of the microtubule-binding protein tau is associated with a number of neurodegenerative conditions, and correlates with cognitive decline in Alzheimer's disease. The ubiquitin ligase carboxy terminus of Hsp70 interacting protein (CHIP) and the molecular chaperone Hsp90 are implicated in protein triage decisions involving tau, and have consequently been targeted for therapeutic approaches aimed at decreasing tau burden. Here, we present evidence that CHIP binds, ubiquitinates and regulates expression of histone deacetylase 6 (HDAC6). As the deacetylase for Hsp90, HDAC6 modulates Hsp90 function and determines the favorability of refolding versus degradation of Hsp90 client proteins. Moreover, we demonstrate that HDAC6 levels positively correlate with tau burden, while a decrease in HDAC6 activity or expression promotes tau clearance. Consistent with previous research on Hsp90 clients in cancer, we provide evidence that a loss of HDAC6 activity augments the efficacy of an Hsp90 inhibitor and drives client degradation, in this case tau. Therefore, our current findings not only identify HDAC6 as a critical factor for the regulation of tau levels, but also indicate that a multi-faceted treatment approach could more effectively arrest tau accumulation in disease. PMID- 22492995 TI - Validated SNPs for eGFR and their associations with albuminuria. AB - Albuminuria and reduced glomerular filtration rate are manifestations of chronic kidney disease (CKD) that predict end-stage renal disease, acute kidney injury, cardiovascular disease and death. We hypothesized that SNPs identified in association with the estimated glomerular filtration rate (eGFR) would also be associated with albuminuria. Within the CKDGen Consortium cohort (n= 31 580, European ancestry), we tested 16 eGFR-associated SNPs for association with the urinary albumin-to-creatinine ratio (UACR) and albuminuria [UACR >25 mg/g (women); 17 mg/g (men)]. In parallel, within the CARe Renal Consortium (n= 5569, African ancestry), we tested seven eGFR-associated SNPs for association with the UACR. We used a Bonferroni-corrected P-value of 0.003 (0.05/16) in CKDGen and 0.007 (0.05/7) in CARe. We also assessed whether the 16 eGFR SNPs were associated with the UACR in aggregate using a beta-weighted genotype score. In the CKDGen Consortium, the minor A allele of rs17319721 in the SHROOM3 gene, known to be associated with a lower eGFR, was associated with lower ln(UACR) levels (beta = 0.034, P-value = 0.0002). No additional eGFR-associated SNPs met the Bonferroni corrected P-value threshold of 0.003 for either UACR or albuminuria. In the CARe Renal Consortium, there were no associations between SNPs and UACR with a P< 0.007. Although we found the genotype score to be associated with albuminuria (P= 0.0006), this result was driven almost entirely by the known SHROOM3 variant, rs17319721. Removal of rs17319721 resulted in a P-value 0.03, indicating a weak residual aggregate signal. No alleles, previously demonstrated to be associated with a lower eGFR, were associated with the UACR or albuminuria, suggesting that there may be distinct genetic components for these traits. PMID- 22492996 TI - Mitochondria-targeted catalase reduces abnormal APP processing, amyloid beta production and BACE1 in a mouse model of Alzheimer's disease: implications for neuroprotection and lifespan extension. AB - The purpose of this study was to investigate the protective effects of the mitochondria-targeted antioxidant catalase (MCAT) and lifespan extension in mice that express amyloid beta (Abeta). Using immunoblotting and immunostaining analyses, we measured the production of full-length amyloid precursor protein (APP), soluble APPalpha, C-terminal fragments CTF99 and CTF83, monomeric and oligomeric Abeta, Abeta deposits and beta site amyloid precursor protein cleaving enzyme 1 (BACE1), in different stages of disease progression in MCAT/AbetaPP and AbetaPP mice. Using quantitative reverse transcriptase polymerase chain reaction and immunostaining analyses, we studied the expression of catalase, BACE1, the Alzheimer's disease (AD) markers, synaptophysin, APP, neprilysin, insulin degrading enzyme and transthyretin in MCAT, AbetaPP, MCAT/AbetaPP and wild-type (WT) mice. Using the high pressure liquid chromatography analysis of 8-hydroxy-2 deoxyguanosine, we measured oxidative DNA damage in the cerebral cortical tissues from MCAT, AbetaPP, MCAT/AbetaPP and WT mice. We found that the AbetaPP transgenic mice that carried the human MCAT gene lived 5 months longer than did the AbetaPP mice. We also found that the overexpression of MCAT in the brain sections from the MCAT/AbetaPP transgenic mice significantly correlated with a reduction in the levels of full-length APP, CTF99, BACE1, Abeta levels (40 and 42), Abeta deposits and oxidative DNA damage relative to the brain sections from the AbetaPP mice. Interestingly, we found significantly increased levels of soluble APPalpha and CTF83 in the MCAT/AbetaPP mice, relative to the AbetaPP mice. These data provide direct evidence that oxidative stress plays a primary role in AD etiopathology and that in MCAT mice express Abeta, MCAT prevents abnormal APP processing, reduces Abeta levels and enhances Abeta-degrading enzymes in mice at different ages, corresponding to different stages of disease progression. These findings indicate that mitochondria-targeted molecules may be an effective therapeutic approach to treat patients with AD. PMID- 22492997 TI - DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway. AB - DJ-1, which is linked to recessively inherited Parkinson's disease when mutated, is a multi-functional protein with anti-oxidant and transcription regulatory activities. However, the mechanism(s) through which DJ-1 and the genes it regulates provide neuroprotection is not fully understood. Here, we show that wild-type DJ-1 induces the expression of thioredoxin 1 (Trx1), a protein disulfide oxidoreductase, whereas pathogenic mutant isoforms L166P and M26I cannot. Conversely, DJ-1 knockdown in SH-SY5Y cells and DJ-1 knockout in mice result in significant decrease in Trx1 protein and mRNA expression levels. The importance of Trx1 in the cytoprotective function of DJ-1 is confirmed using a pharmacological inhibitor of Trx reductase, 1-chloro-2,4-dinitrobenzene, and Trx1 siRNA. Both approaches result in partial loss of DJ-1-mediated protection. Additionally, knockdown of Trx1 significantly abrogates DJ-1-dependent, hydrogen peroxide-induced activation of the pro-survival factor AKT. Promoter analysis of the human Trx1 gene identified an antioxidant response element (ARE) that is required for DJ-1-dependent induction of Trx1 expression. The transcription factor Nuclear factor erythroid-2 related factor 2 (Nrf2), which is a critical inducer of ARE-mediated expression, is regulated by DJ-1. Overexpression of DJ-1 results in increased Nrf2 protein levels, promotes its translocation into the nucleus and enhances its recruitment onto the ARE site in the Trx1 promoter. Further, Nrf2 knockdown abolishes DJ-1-mediated Trx1 induction and cytoprotection against hydrogen peroxide, indicating the critical role of Nrf2 in carrying out the protective functions of DJ-1 against oxidative stress. These findings provide a new mechanism to support the antioxidant function of DJ-1 by increasing Trx1 expression via Nrf2-mediated transcriptional induction. PMID- 22492998 TI - Forkhead box protein p1 is a transcriptional repressor of immune signaling in the CNS: implications for transcriptional dysregulation in Huntington disease. AB - Forkhead box protein p1 (Foxp1), a transcription factor showing highly enriched expression in the striatum, has been implicated in central nervous system (CNS) development, but its role in the mature brain is unknown. In order to ascertain functional roles for Foxp1 in the CNS, we have identified gene targets for Foxp1 both in vitro and in vivo using genome-wide expression microarrays and chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) assays. We found that mouse Foxp1 overexpression in striatal cells elicited expression changes of genes related to immune signaling, transcriptional regulation and a manually curated Huntington's disease (HD)-signaling pathway. Similar results were found when the gene expression data set was integrated with Foxp1-binding data determined from ChIP-seq analysis. In vivo lentiviral-mediated overexpression of human FOXP1 in the context of mutant huntingtin (Htt) protein resulted in a robust downregulation of glial cell-associated, immune genes, including those encoding a variety of cytokines and chemokines. Furthermore, Foxp1-induced expression changes were significantly negatively correlated with those changes elicited by mutant Htt protein in several different HD mouse models, and most significantly in post-mortem caudate from human HD subjects. We finally show that Foxp1 interacts with mutant Htt protein in mouse brain and is present in nuclear Htt aggregates in the striatum of R6/1 transgenic mice. These findings implicate Foxp1 as a key repressor of immune signaling in the CNS and suggest that the loss of Foxp1-mediated gene regulation in HD contributes to the immune dysfunction in this disease. We further suggest that Foxp1-regulated pathways might be important mediators of neuronal-glial cell communication. PMID- 22492999 TI - Cigarette smoking behaviors and time since quitting are associated with differential DNA methylation across the human genome. AB - The impact of cigarette smoking can persist for extended periods following smoking cessation and may involve epigenetic reprogramming. Changes in DNA methylation associated with smoking may help to identify molecular pathways that contribute to the latency between exposure and disease onset. Cross-sectional cohort data from subjects in the International COPD Genetics Network (n = 1085) and the Boston Early-Onset COPD study (n = 369) were analyzed as the discovery and replication cohorts, respectively. Genome-wide methylation data on 27 578 CpG sites in 14 475 genes were obtained on DNA from peripheral blood leukocytes using the Illumina HumanMethylation27K Beadchip in both cohorts. We identified 15 sites significantly associated with current smoking, 2 sites associated with cumulative smoke exposure, and, within the subset of former smokers, 3 sites associated with time since quitting cigarettes. Two loci, factor II receptor-like 3 (F2RL3) and G protein-coupled receptor 15 (GPR15), were significantly associated in all three analyses and were validated by pyrosequencing. These findings (i) identify a novel locus (GPR15) associated with cigarette smoking and (ii) suggest the existence of dynamic, site-specific methylation changes in response to smoking which may contribute to the extended risks associated with cigarette smoking that persist after cessation. PMID- 22493000 TI - Chylomicronemia mutations yield new insights into interactions between lipoprotein lipase and GPIHBP1. AB - Lipoprotein lipase (LPL) is a 448-amino-acid head-to-tail dimeric enzyme that hydrolyzes triglycerides within capillaries. LPL is secreted by parenchymal cells into the interstitial spaces; it then binds to GPIHBP1 (glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1) on the basolateral face of endothelial cells and is transported to the capillary lumen. A pair of amino acid substitutions, C418Y and E421K, abolish LPL binding to GPIHBP1, suggesting that the C-terminal portion of LPL is important for GPIHBP1 binding. However, a role for LPL's N terminus has not been excluded, and published evidence has suggested that only full-length homodimers are capable of binding GPIHBP1. Here, we show that LPL's C-terminal domain is sufficient for GPIHBP1 binding. We found, serendipitously, that two LPL missense mutations, G409R and E410V, render LPL susceptible to cleavage at residue 297 (a known furin cleavage site). The C terminus of these mutants (residues 298-448), bound to GPIHBP1 avidly, independent of the N-terminal fragment. We also generated an LPL construct with an in-frame deletion of the N-terminal catalytic domain (residues 50-289); this mutant was secreted but also was cleaved at residue 297. Once again, the C-terminal domain (residues 298-448) bound GPIHBP1 avidly. The binding of the C-terminal fragment to GPIHBP1 was eliminated by C418Y or E421K mutations. After exposure to denaturing conditions, the C-terminal fragment of LPL refolds and binds GPIHBP1 avidly. Thus, the binding of LPL to GPIHBP1 requires only the C terminal portion of LPL and does not depend on full-length LPL homodimers. PMID- 22493001 TI - Neuronal and epithelial cell rescue resolves chronic systemic inflammation in the lipid storage disorder Niemann-Pick C. AB - Chronic systemic inflammation is thought to be a major contributor to metabolic and neurodegenerative diseases. Since inflammatory components are shared among different disorders, targeting inflammation is an attractive option for mitigating disease. To test the significance of inflammation in the lipid storage disorder (LSD) Niemann-Pick C (NPC), we deleted the macrophage inflammatory gene Mip1a/Ccl3 from NPC diseased mice. Deletion of Ccl3 had been reported to delay neuronal loss in Sandhoff LSD mice by inhibiting macrophage infiltration. For NPC mice, in contrast, deleting Ccl3 did not retard neurodegeneration and worsened the clinical outcome. Depletion of visceral tissue macrophages also did not alter central nervous system (CNS) pathology and instead increased liver injury, suggesting a limited macrophage infiltration response into the CNS and a beneficial role of macrophage activity in visceral tissue. Prevention of neuron loss or liver injury, even at late stages in the disease, was achieved through specific rescue of NPC disease in neurons or in liver epithelial cells, respectively. Local epithelial cell correction was also sufficient to reduce the macrophage-associated pathology in lung tissue. These results demonstrate that elevated inflammation and macrophage activity does not necessarily contribute to neurodegeneration and tissue injury, and LSD defects in immune cells may not preclude an appropriate inflammatory response. We conclude that inflammation remains secondary to neuronal and epithelial cell dysfunction and does not irreversibly contribute to the pathogenic cascade in NPC disease. Without further exploration of possible beneficial roles of inflammatory mediators, targeting inflammation may not be therapeutically effective at ameliorating disease severity. PMID- 22493002 TI - Ube3a-ATS is an atypical RNA polymerase II transcript that represses the paternal expression of Ube3a. AB - The Angelman syndrome gene, UBE3A, is subject to genomic imprinting controlled by mechanisms that are only partially understood. Its antisense transcript, UBE3A ATS, is also imprinted and hypothesized to suppress UBE3A in cis. In this research, we showed that the mouse antisense ortholog, Ube3a-ATS, was transcribed by RNA polymerase (RNAP) II. However, unlike typical protein-coding transcripts, Ube3a-ATS was not poly-adenylated and was localized exclusively in the nucleus. It was relatively unstable with a half-life of 4 h, shorter than most protein coding RNAs tested. To understand the role of Ube3a-ATS in vivo, a mouse model with a 0.9-kb genomic deletion over the paternal Snrpn major promoter was studied. The mice showed partial activation of paternal Ube3a, with decreased expression of Ube3a-ATS but not any imprinting defects in the Prader-Willi syndrome/Angelman syndrome region. A novel cell culture model was also generated with a transcriptional termination cassette inserted downstream of Ube3a on the paternal chromosome to reduce Ube3a-ATS transcription. In neuronally differentiated embryonic stem (ES) cells, paternal Ube3a was found to be expressed at a high level, comparable with that of the maternal allele. To further characterize the antisense RNA, a strand-specific microarray was performed. Ube3a-ATS was detectable across the entire locus of Ube3a and extended beyond the transcriptional start site of Ube3a. In summary, we conclude that Ube3a-ATS is an atypical RNAPII transcript that represses Ube3a on the paternal chromosome. These results suggest that the repression of human UBE3A-ATS may activate the expression of UBE3A from the paternal chromosome, providing a potential therapeutic strategy for patients with Angelman syndrome. PMID- 22493003 TI - Effects of androgens on cardiovascular remodeling. AB - Androgens, the male sex hormones, exert various biological effects on many target organs through the transcriptional effects of the nuclear androgen receptor (AR). ARs are expressed not only in classical target organs, such as the brain, genital organs, bone, and skeletal muscles, but also in the cardiovascular system. Because the female sex hormones estrogens are well-known to protect against cardiovascular disease, sex has been considered to have a significant clinical impact on cardiovascular mortality. However, the influence of androgens on the cardiovascular system has not been fully elucidated. To clarify this issue, we analyzed the effects of administration of angiotensin II and doxorubicin, an anticancer agent, in a loading model in male wild-type and AR-deficient mice. In this review, we focus on the actions of androgens as potential targets for the prevention of cardiovascular diseases in males. PMID- 22493004 TI - Dp71 gene disruption alters the composition of the dystrophin-associated protein complex and neuronal nitric oxide synthase expression in the hypothalamic supraoptic and paraventricular nuclei. AB - DP71 is the major cerebral dystrophin isoform and exerts its multiple functions via the dystrophin-associated protein complex (DAPC), also comprised of beta dystroglycan (beta-DG) and alpha1-syntrophin (alpha1-Syn). Since DP71 disruption leads to impairment in the central control of the osmoregulatory axis, we investigated: 1) the DAPC composition in the hypothalamic supraoptic nucleus (SON) and paraventricular nucleus (PVN) of Dp71-null mice; and 2) the expression and activity of neuronal nitric oxide synthase (nNOS), because it is a potential partner of the DAPC and a functional index of osmoregulatory axis activity. In wild-type mice, dystrophins and their autosomal homologs the utrophins, beta-DG, and alpha1-Syn were localized in astrocyte end feet. In Dp71-null mice, the levels of beta-DG and alpha1-Syn were lower and utrophin expression did not change. The location of the DAPC in astrocytic end feet suggests that it could be involved in hypothalamic osmosensitivity, which adapts the osmotic response. The altered composition of the DAPC in Dp71-null mice could thus explain why these mice manifest an hypo-osmolar status. In the SON and PVN neurons of Dp71-null mice, nNOS expression and activity were increased. Although we previously established that DP140 is expressed de novo in these neurons, the DAPC remained incomplete due to the low levels of beta-DG and alpha1-Syn produced in these cells. Our data reveal the importance of DP71 for the constitution of a functional DAPC in the hypothalamus. Such DAPC disorganization may lead to modification of the microenvironment of the SON and PVN neurons and thus may result in a perturbed osmoregulation. PMID- 22493006 TI - Different service delivery models for different communication disorders. PMID- 22493007 TI - Dialect-neutral indices of narrative cohesion and evaluation. AB - PURPOSE: This study compared the development of essential elements of narrative skill in children from African American English (AAE)- and general American English (GAE)-speaking communities using an innovative elicitation and evaluation protocol consisting of four key indices of narrative language: (a) reference contrasting, (b) temporal expressions, (c) mental state descriptions, and (d) understanding of behavior based on false belief. METHOD: Participants were 291 AAE speakers and 238 GAE speakers, 4 to 9 years of age. Approximately one-third of both dialect groups were identified as having language impairments. Children generated 2 stories based on short picture sequences. Their stories were coded for the 4 key indices of narrative language. Analyses of variance were performed with subsets of the measures and a composite index with all measures combined as outcomes; and with age, dialect group, and clinical status as predictors. RESULTS: Age and clinical status had statistically significant effects on the subset measures and the composite score. Variation between AAE and GAE dialect was not a significant factor. CONCLUSION: By focusing on dialect-neutral elements of narratives--creating links across sentences and providing mental state interpretations--this study adds to our knowledge of development and impairment in narrative production among both AAE- and GAE-background children. PMID- 22493008 TI - When larger visual distractors become less disruptive: behavioral evidence for lateral inhibition in saccade generation. AB - How neuronal activity is integrated over time may largely rely on excitatory and inhibitory mechanisms. Dynamic neural field models assume that local excitation and lateral inhibition (i.e., the "Mexican hat") shape the output of neural networks. Most models of saccade generation assume that such interactions in the superior colliculus play a key role in determining both the metrics and the latency of saccades. Here, we investigated the role of lateral inhibition in saccade metrics in humans. We used a saccade target task in which a visual distractor line was presented close to a peripheral visual target (i.e., a small circle). Models assuming lateral inhibition predict that beyond a critical size larger distractors induce less perturbation than smaller ones. To assess this prediction, we varied the length of the distractor. Results confirmed that a distractor presented along with the target deviated the saccade's landing position away from the target. This perturbation increased with distractor length but only up to a critical size as the effect reversed for larger distractors, leading to a reduced perturbation on saccade metrics. These results suggest that larger distractors induce a neuronal activity pattern wide enough to involve lateral inhibition, thereby decreasing the distractor's weight in the spatial integration of distractor and target locations. They are consistent with a critical role of lateral inhibition in the computation of saccade metrics. PMID- 22493009 TI - Site of mitochondrial reactive oxygen species production in skeletal muscle of chronic obstructive pulmonary disease and its relationship with exercise oxidative stress. AB - Exercise triggers skeletal muscle oxidative stress in patients with chronic obstructive pulmonary disease (COPD). The objective of this research was to study the specific sites of reactive oxygen species (ROS) production in mitochondria isolated from skeletal muscle of patients with COPD and its relationship with local oxidative stress induced by exercise. Vastus lateralis biopsies were obtained in 16 patients with COPD (66 +/- 10 yr; FEV(1), 54 +/- 12% ref) and in 14 control subjects with normal lung function who required surgery because of lung cancer (65 +/- 7 yr; FEV(1), 91 +/- 14% ref) at rest and after exercise. In these biopsies we isolated mitochondria and mitochondrial membrane fragments and determined in vitro mitochondrial oxygen consumption (Mit$$?stackrel{.}{?hbox{ V }}$$o(2)) and ROS production before and after inhibition of complex I (rotenone), complex II (stigmatellin), and complex III (antimycin-A). We related the in vitro ROS production during state 3 respiration), which mostly corresponds to the mitochondria respiratory state during exercise, with skeletal muscle oxidative stress after exercise, as measured by thiobarbituric acid reactive substances.State 3 Mit$$?stackrel{.}{?hbox{ V }}$$o(2) was similar in patients with COPD and control subjects (191 +/- 27 versus 229 +/- 46 nmol/min/mg; P = 0.058), whereas H(2)O(2) production was higher in the former (147 +/- 39 versus 51 +/- 8 pmol/mg/h; P < 0.001). The addition of complexI, II, and III inhibitors identify complex III as the main site of H(2)O(2) release by mitochondria in patients with COPD and in control subjects. The mitochondrial production of H(2)O(2) in state 3 respiration was related (r = 0.69; P < 0.001) to postexercise muscle thiobarbituric acid reactive substance levels. Our results show that complex III is the main site of the enhanced mitochondrial H(2)O(2) production that occurs in skeletal muscle of patients with COPD, and the latter appears to contribute to muscle oxidative damage. PMID- 22493010 TI - Rhinovirus-induced IL-1beta release from bronchial epithelial cells is independent of functional P2X7. AB - Airway epithelial cell defenses to viral infections are often compromised in disease or injury. Danger molecules, including ATP, are released during infection and contribute to nucleotide receptor-dependent inflammatory responses, largely through P2X(7). Although respiratory epithelium has been shown to express a variety of nucleotide receptors, the functional contribution of P2X(7) to the epithelial cell inflammatory response is unclear. We used human donor bronchial epithelial cells (BECs) and primary brushed epithelium to explore responses upon nucleotide and Toll-like receptor stimulation. P2X(7) messenger RNA and protein were observed in unprimed BECs, whereas inflammatory cytokine stimulation increased both messenger RNA and protein. Functional pore activity characteristic of P2X(7) was observed in BECs, and IL-1beta was rapidly released by BECs after Toll-like receptor 3 agonist, polyinosine-polycytidylic acid, priming followed by ATP administration, although no change was observed in IL-18 release. BECs produced more IL-1beta after stimulation with polyinosine-polycytidylic acid than LPS, showing a different preferential response than monocytes. In addition, blockade of nucleotide receptors with oxidized ATP significantly increased human rhinovirus (HRV) recovered 24 hours after infection in BECs, whereas 2'-3'-O-(4 benzoylbenzoyl) ATP treatment of brushed epithelial cells and respiratory cell lines nonsignificantly decreased HRV recovery. IL-1beta release was detected after HRV infection in both BECs and brushed cells, but BzATP did not significantly increase IL-1beta release further. BEC processing of pro-IL-1beta to the mature, cleaved, 17-kD form was confirmed by Western blotting. These results support the expression of functional P2X(7) in human lung epithelium, although its role in epithelial pathogen defense is likely independent of IL-1 family cytokine processing. PMID- 22493011 TI - Amphiregulin-dependent mucous cell metaplasia in a model of nonallergic lung injury. AB - Proliferation and differentiation of the pulmonary epithelium after injury is a critical process in the defense against the external environment. Defects in this response can result in airway remodeling, such as mucus cell metaplasia (MCM), commonly seen in patients with chronic lung disease. We have previously shown that amphiregulin (AREG), a ligand to the epidermal growth factor receptor (EGFR), is induced during the repair/differentiation process elicited by naphthalene-induced lung injury. Thus, we hypothesized that AREG signaling plays an important role in epithelial proliferation and differentiation of the repairing airway. Mice deficient in AREG and lung epithelial EGFR were used to define roles for AREG-dependent EGFR signaling in airway repair and remodeling. We show that AREG and epithelial EGFR expression is dispensable to pulmonary epithelial repair after naphthalene-induced lung injury, but regulates secretory cell differentiation to a mucus-producing phenotype. We show that the pulmonary epithelium is the source of AREG, suggesting that naphthalene-induced MCM is mediated through an autocrine signaling mechanism. However, induction of MCM resulting from allergen exposure was independent of AREG. Our data demonstrate that AREG-dependent EGFR signaling in airway epithelial cells contributes to MCM in naphthalene-induced lung injury. We conclude that AREG may represent a determinant of nonallergic chronic lung diseases complicated by MCM. PMID- 22493012 TI - Effect of insulin-like growth factor blockade on hyperoxia-induced lung injury. AB - Insulin-like growth factor (IGF)-1 is increased in different models of acute lung injury, and is an important determinant of survival and proliferation in many cells. We previously demonstrated that treatment of mice with IGF-1 receptor blocking antibody (A12) improved early survival in bleomycin-induced lung injury. We have now examined whether administration of A12 improved markers of lung injury in hyperoxia model of lung injury. C57BL/6 mice underwent intraperitoneal administration of A12 or control antibody (keyhole limpet hemocyanin [KLH]), then were exposed to 95% hyperoxia for 88-90 hours. Mice were killed and bronchoalveolar lavage (BAL) and lung tissue were obtained for analysis. Hyperoxia caused a significant increase in IGF levels in BAL and lung lysates. Peripheral blood neutrophils expressed IGF-1R at baseline and after hyperoxia. BAL neutrophils from hyperoxia-treated mice and patients with acute lung injury also expressed cell surface IGF-1R. A12-treated mice had significantly decreased polymorphonuclear cell (PMN) count in BAL compared with KLH control mice (P = 0.02). BAL from A12-treated mice demonstrated decreased PMN chemotactic activity compared with BAL from KLH-treated mice. Pretreatment of PMNs with A12 decreased their chemotactic response to BAL from hyperoxia-exposed mice. Furthermore, IGF-1 induced a dose-dependent chemotaxis of PMNs. There were no differences in other chemotactic cytokines in BAL, including CXCL1 and CXCL2. In summary, IGF blockade decreased PMN recruitment to the alveolar space in a mouse model of hyperoxia. Furthermore, the decrease in BAL PMNs was at least partially due to a direct effect of A12 on PMN chemotaxis. PMID- 22493013 TI - Factors associated with healthcare utilization among children with noncardiac chest pain and innocent heart murmurs. AB - OBJECTIVE: To examine differences in factors related to health care utilization (HCU) among children eventually diagnosed with noncardiac chest pain (NCCP) or an innocent heart murmur (IHM). METHODS: 67 pediatric patients with NCCP and 62 with IHM and their parent/guardian completed paper-and-pencil measures of psychological functioning and past HCU during an initial visit to the cardiologist's office. RESULTS: Children with NCCP utilized significantly more health care services compared to their IHM counterparts in the year prior to their cardiology visit. Children in the NCCP group had higher internalizing and somatic symptoms, and their parents experienced more anxious symptoms, than those in the IHM group. For the NCCP group only, child and parent psychological symptoms and parent HCU were positively related to child HCU. CONCLUSIONS: Results identify possible child and parent psychological factors that may be the focus of interventions to reduce high rates of HCU among children with NCCP. PMID- 22493014 TI - Myxococcus xanthus developmental cell fate production: heterogeneous accumulation of developmental regulatory proteins and reexamination of the role of MazF in developmental lysis. AB - Myxococcus xanthus undergoes a starvation-induced multicellular developmental program during which cells partition into three known fates: (i) aggregation into fruiting bodies followed by differentiation into spores, (ii) lysis, or (iii) differentiation into nonaggregating persister-like cells, termed peripheral rods. As a first step to characterize cell fate segregation, we enumerated total, aggregating, and nonaggregating cells throughout the developmental program. We demonstrate that both cell lysis and cell aggregation begin with similar timing at approximately 24 h after induction of development. Examination of several known regulatory proteins in the separated aggregated and nonaggregated cell fractions revealed previously unknown heterogeneity in the accumulation patterns of proteins involved in type IV pilus (T4P)-mediated motility (PilC and PilA) and regulation of development (MrpC, FruA, and C-signal). As part of our characterization of the cell lysis fate, we set out to investigate the unorthodox MazF-MrpC toxin-antitoxin system which was previously proposed to induce programmed cell death (PCD). We demonstrate that deletion of mazF in two different wild-type M. xanthus laboratory strains does not significantly reduce developmental cell lysis, suggesting that MazF's role in promoting PCD is an adaption to the mutant background strain used previously. PMID- 22493015 TI - Characterization of SSR42, a novel virulence factor regulatory RNA that contributes to the pathogenesis of a Staphylococcus aureus USA300 representative. AB - Staphylococcus aureus is a major human pathogen that is capable of producing an expansive repertoire of cell surface-associated and extracellular virulence factors. Herein we describe an S. aureus regulatory RNA, SSR42, which modulates the expression of approximately 80 mRNA species, including several virulence factors, in S. aureus strains UAMS-1 and USA300 (LAC) during stationary-phase growth. Mutagenesis studies revealed that SSR42 codes for an 891-nucleotide RNA molecule and that the molecule's regulatory effects are mediated by the full length transcript. Western blotting and functional assays indicated that the regulatory effects of SSR42 correlate with biologically significant changes in corresponding protein abundances. Further, in S. aureus strain LAC, SSR42 is required for wild-type levels of erythrocyte lysis, resistance to human polymorphonuclear leukocyte killing, and pathogenesis in a murine model of skin and soft tissue infection. Taken together, our results indicate that SSR42 is a novel S. aureus regulatory RNA molecule that contributes to the organism's ability to cause disease. PMID- 22493016 TI - The phosphodiesterase DipA (PA5017) is essential for Pseudomonas aeruginosa biofilm dispersion. AB - Although little is known regarding the mechanism of biofilm dispersion, it is becoming clear that this process coincides with alteration of cyclic di-GMP (c-di GMP) levels. Here, we demonstrate that dispersion by Pseudomonas aeruginosa in response to sudden changes in nutrient concentrations resulted in increased phosphodiesterase activity and reduction of c-di-GMP levels compared to biofilm and planktonic cells. By screening mutants inactivated in genes encoding EAL domains for nutrient-induced dispersion, we identified in addition to the previously reported DeltarbdA mutant a second mutant, the DeltadipA strain (PA5017 [dispersion-induced phosphodiesterase A]), to be dispersion deficient in response to glutamate, nitric oxide, ammonium chloride, and mercury chloride. Using biochemical and in vivo studies, we show that DipA associates with the membrane and exhibits phosphodiesterase activity but no detectable diguanylate cyclase activity. Consistent with these data, a DeltadipA mutant exhibited reduced swarming motility, increased initial attachment, and polysaccharide production but only somewhat increased biofilm formation and c-di-GMP levels. DipA harbors an N-terminal GAF (cGMP-specific phosphodiesterases, adenylyl cyclases, and FhlA) domain and two EAL motifs within or near the C-terminal EAL domain. Mutational analyses of the two EAL motifs of DipA suggest that both are important for the observed phosphodiesterase activity and dispersion, while the GAF domain modulated DipA function both in vivo and in vitro without being required for phosphodiesterase activity. Dispersion was found to require protein synthesis and resulted in increased dipA expression and reduction of c-di-GMP levels. We propose a role of DipA in enabling dispersion in P. aeruginosa biofilms. PMID- 22493017 TI - Identification of functionally important TonB-ExbD periplasmic domain interactions in vivo. AB - In gram-negative bacteria, the cytoplasmic membrane proton-motive force energizes the active transport of TonB-dependent ligands through outer membrane TonB-gated transporters. In Escherichia coli, cytoplasmic membrane proteins ExbB and ExbD couple the proton-motive force to conformational changes in TonB, which are hypothesized to form the basis of energy transduction through direct contact with the transporters. While the role of ExbB is not well understood, contact between periplasmic domains of TonB and ExbD is required, with the conformational response of TonB to presence or absence of proton motive force being modulated through ExbD. A region (residues 92 to 121) within the ExbD periplasmic domain was previously identified as being important for TonB interaction. Here, the specific sites of periplasmic domain interactions between that region and the TonB carboxy terminus were identified by examining 270 combinations of 45 TonB and 6 ExbD individual cysteine substitutions for disulfide-linked heterodimer formation. ExbD residues A92C, K97C, and T109C interacted with multiple TonB substitutions in four regions of the TonB carboxy terminus. Two regions were on each side of the TonB residues known to interact with the TonB box of TonB-gated transporters, suggesting that ExbD positions TonB for correct interaction at that site. A third region contained a functionally important glycine residue, and the fourth region involved a highly conserved predicted amphipathic helix. Three ExbD substitutions, F103C, L115C, and T121C, were nonreactive with any TonB cysteine substitutions. ExbD D25, a candidate to be on a proton translocation pathway, was important to support efficient TonB-ExbD heterodimerization at these specific regions. PMID- 22493018 TI - Germination protein levels and rates of germination of spores of Bacillus subtilis with overexpressed or deleted genes encoding germination proteins. AB - Deletion of Bacillus subtilis spores' GerA germinant receptor (GR) had no effect on spore germination via the GerB plus GerK GRs, and loss of GerB plus GerK did not affect germination via GerA. Loss of one or two GRs also did not affect levels of GRs that were not deleted. Overexpression of GRs 5- to 18-fold increased rates of germination via the overexpressed GR and slowed germination by other GRs up to 15-fold. However, overexpression of one or two GRs had no effect on levels of GRs that were not overexpressed. These results suggest that either interaction between different GRs reduces the activity of GRs in triggering spore germination or all GRs compete for interaction with a limiting amount of a downstream signaling molecule in the germination pathway. Overexpression or deletion of GRs also had no effect on spores' levels of the GerD protein needed for normal GR-dependent germination or of the SpoVAD protein likely involved in dipicolinic acid release early in germination. Loss of GerD also had no effect on levels of GRs or SpoVAD. Spores of a strain lacking the only B. subtilis prelipoprotein diacylglycerol transferase, GerF, also had no detectable GerD or the GerA's C subunit, both of which are most likely lipoproteins; GerA's A subunit was also absent. However, levels of GerB's C subunit, also almost certainly a lipoprotein, and GerK's A subunit were normal in gerF spores. These results with gerF spores were consistent with effects of loss of GerF on spore germination by different GRs. PMID- 22493019 TI - The ExbD periplasmic domain contains distinct functional regions for two stages in TonB energization. AB - The TonB system of gram-negative bacteria energizes the active transport of diverse nutrients through high-affinity TonB-gated outer membrane transporters using energy derived from the cytoplasmic membrane proton motive force. Cytoplasmic membrane proteins ExbB and ExbD harness the proton gradient to energize TonB, which directly contacts and transmits this energy to ligand-loaded transporters. In Escherichia coli, the periplasmic domain of ExbD appears to transition from proton motive force-independent to proton motive force-dependent interactions with TonB, catalyzing the conformational changes of TonB. A 10 residue deletion scanning analysis showed that while all regions except the extreme amino terminus of ExbD were indispensable for function, distinct roles for the amino- and carboxy-terminal regions of the ExbD periplasmic domain were evident. Like residue D25 in the ExbD transmembrane domain, periplasmic residues 42 to 61 facilitated the conformational response of ExbD to proton motive force. This region appears to be important for transmitting signals between the ExbD transmembrane domain and carboxy terminus. The carboxy terminus, encompassing periplasmic residues 62 to 141, was required for initial assembly with the periplasmic domain of TonB, a stage of interaction required for ExbD to transmit its conformational response to proton motive force to TonB. Residues 92 to 121 were important for all three interactions previously observed for formaldehyde cross-linked ExbD: ExbD homodimers, TonB-ExbD heterodimers, and ExbD-ExbB heterodimers. The distinct requirement of this ExbD region for interaction with ExbB raised the possibility of direct interaction with the few residues of ExbB known to occupy the periplasm. PMID- 22493020 TI - Oxalyl-coenzyme A reduction to glyoxylate is the preferred route of oxalate assimilation in Methylobacterium extorquens AM1. AB - Oxalate catabolism is conducted by phylogenetically diverse organisms, including Methylobacterium extorquens AM1. Here, we investigate the central metabolism of this alphaproteobacterium during growth on oxalate by using proteomics, mutant characterization, and (13)C-labeling experiments. Our results confirm that energy conservation proceeds as previously described for M. extorquens AM1 and other characterized oxalotrophic bacteria via oxalyl-coenzyme A (oxalyl-CoA) decarboxylase and formyl-CoA transferase and subsequent oxidation to carbon dioxide via formate dehydrogenase. However, in contrast to other oxalate degrading organisms, the assimilation of this carbon compound in M. extorquens AM1 occurs via the operation of a variant of the serine cycle as follows: oxalyl CoA reduction to glyoxylate and conversion to glycine and its condensation with methylene-tetrahydrofolate derived from formate, resulting in the formation of C3 units. The recently discovered ethylmalonyl-CoA pathway operates during growth on oxalate but is nevertheless dispensable, indicating that oxalyl-CoA reductase is sufficient to provide the glyoxylate required for biosynthesis. Analysis of an oxalyl-CoA synthetase- and oxalyl-CoA-reductase-deficient double mutant revealed an alternative, although less efficient, strategy for oxalate assimilation via one-carbon intermediates. The alternative process consists of formate assimilation via the tetrahydrofolate pathway to fuel the serine cycle, and the ethylmalonyl-CoA pathway is used for glyoxylate regeneration. Our results support the notion that M. extorquens AM1 has a plastic central metabolism featuring multiple assimilation routes for C1 and C2 substrates, which may contribute to the rapid adaptation of this organism to new substrates and the eventual coconsumption of substrates under environmental conditions. PMID- 22493021 TI - Biogenesis of outer membrane vesicles in Serratia marcescens is thermoregulated and can be induced by activation of the Rcs phosphorelay system. AB - Outer membrane vesicles (OMVs) have been identified in a wide range of bacteria, yet little is known of their biogenesis. It has been proposed that OMVs can act as long-range toxin delivery vectors and as a novel stress response. We have found that the formation of OMVs in the gram-negative opportunistic pathogen Serratia marcescens is thermoregulated, with a significant amount of OMVs produced at 22 or 30 degrees C and negligible quantities formed at 37 degrees C under laboratory conditions. Inactivation of the synthesis of the enterobacterial common antigen (ECA) resulted in a hypervesiculation phenotype, supporting the hypothesis that OMVs are produced in response to stress. We demonstrate that the phenotype can be reversed to wild-type (WT) levels upon the loss of the Rcs phosphorelay response regulator RcsB, but not RcsA, suggesting a role for the Rcs phosphorelay in the production of OMVs. MS fingerprinting of the OMVs provided evidence of cargo selection within wild-type cells, suggesting a possible role for Serratia OMVs in toxin delivery. In addition, OMV-associated cargo proved toxic upon injection into the haemocoel of Galleria mellonella larvae. These experiments demonstrate that OMVs are the result of a regulated process in Serratia and suggest that OMVs could play a role in virulence. PMID- 22493022 TI - Fructose degradation in the haloarchaeon Haloferax volcanii involves a bacterial type phosphoenolpyruvate-dependent phosphotransferase system, fructose-1 phosphate kinase, and class II fructose-1,6-bisphosphate aldolase. AB - The halophilic archaeon Haloferax volcanii utilizes fructose as a sole carbon and energy source. Genes and enzymes involved in fructose uptake and degradation were identified by transcriptional analyses, deletion mutant experiments, and enzyme characterization. During growth on fructose, the gene cluster HVO_1495 to HVO_1499, encoding homologs of the five bacterial phosphotransferase system (PTS) components enzyme IIB (EIIB), enzyme I (EI), histidine protein (HPr), EIIA, and EIIC, was highly upregulated as a cotranscript. The in-frame deletion of HVO_1499, designated ptfC (ptf stands for phosphotransferase system for fructose) and encoding the putative fructose-specific membrane component EIIC, resulted in a loss of growth on fructose, which could be recovered by complementation in trans. Transcripts of HVO_1500 (pfkB) and HVO_1494 (fba), encoding putative fructose-1-phosphate kinase (1-PFK) and fructose-1,6-bisphosphate aldolase (FBA), respectively, as well as 1-PFK and FBA activities were specifically upregulated in fructose-grown cells. pfkB and fba knockout mutants did not grow on fructose, whereas growth on glucose was not inhibited, indicating the functional involvement of both enzymes in fructose catabolism. Recombinant 1-PFK and FBA obtained after homologous overexpression were characterized as having kinetic properties indicative of functional 1-PFK and a class II type FBA. From these data, we conclude that fructose uptake in H. volcanii involves a fructose specific PTS generating fructose-1-phosphate, which is further converted via fructose-1,6-bisphosphate to triose phosphates by 1-PFK and FBA. This is the first report of the functional involvement of a bacterial-like PTS and of class II FBA in the sugar metabolism of archaea. PMID- 22493023 TI - Integrating functional measures with treatment: a tactic for enhancing personally significant change in the treatment of adults and adolescents who stutter. AB - PURPOSE: It is proposed that stuttering treatment, particularly for adults and adolescents who stutter, may benefit from more inventive and extensive use of functional measurement-measures that are also treatment agents. Such measures can be tailored to produce more personally significant and evidence-based treatment benefits. They may be especially useful when employed in conjunction with partial self-management and performance-contingent procedures. METHOD: Previous approaches to the definition of stuttering treatment goals and the measurement of stuttering treatment outcomes are critically reviewed. Suggestions for improvements are presented within the framework of an evidence-based and relatively standardized stuttering treatment. RESULTS AND CONCLUSION: Results from a review of existing literature and from 2 case studies show that 2 specific personally significant problems, saying one's name and addressing large audiences, were improved by implementing these strategies in treatment. Functional measures directly connected to treatment, and partially self-managed performance-contingent schedules, merit further research as methodologies that are suitable for conducting personally significant and evidence-based treatments with adults and adolescents who stutter. PMID- 22493024 TI - Relations between anxiety sensitivity, somatization, and health-related quality of life in children with chronic pain. AB - OBJECTIVE: To further understand the influence of psychological variables on pain and functioning in children with chronic pain by examining the relations between pain, anxiety sensitivity (AS), somatization, and health-related quality of life (HRQOL), and whether they vary as a function of age and gender. METHODS: 66 children (8-12 years) and adolescents (13-18 years) with chronic pain completed measures assessing pain intensity, AS (childhood anxiety sensitivity index), somatization (child somatization inventory), and HRQOL (pediatric quality of life inventory 4.0). RESULTS: Somatization was significantly related to higher pain intensity. Somatization significantly predicted HRQOL over and above pain. AS was a significant predictor of impaired HRQOL for children and females in the sample, but not for adolescents or males. CONCLUSION: Somatization and AS may be better predictors of HRQOL impairment than pain intensity in children with chronic pain. This may differ as a function of age and gender. PMID- 22493025 TI - Psychological parameters in the reproductive phenotypes of polycystic ovary syndrome. AB - BACKGROUND: The aim of this study was to assess the psychological features in women with different polycystic ovary syndrome (PCOS) phenotypes [National Institute of Health (NIH) and non-NIH diagnostic criteria] and women without PCOS. METHODS: An observational, cross-sectional study compared overweight (BMI >= 25 kg/m(2)) premenopausal women with PCOS (n = 29 NIH and n = 25 non-NIH) and controls (n = 27). Anxiety and depression were compared between women with NIH or non-NIH PCOS and women without PCOS. Health-related quality of life (HRQoL) domains related to emotions, body hair, weight, infertility and menstrual problems were compared between women with NIH and non-NIH PCOS. RESULTS: Overall, women with PCOS had worse anxiety (P = 0.007) and depression (P = 0.048) compared with women without PCOS. Both women with NIH PCOS and non-NIH PCOS presented more often with moderate anxiety (P = 0.005 and P = 0.01, respectively) compared with women without PCOS. Women with NIH PCOS had worse HRQoL related to infertility (P = 0.012), emotions (P = 0.02) and weight (P = 0.016). No significant differences were observed between the two PCOS phenotypes for HRQoL domains related to body hair or menstrual problems. Both NIH (beta = 0.30, P = 0.024) and non-NIH (beta = 0.32, P = 0.016) PCOS status predicted anxiety, whereas age (beta = 0.35, P = 0.008) and free androgen index (beta = 0.31, P = 0.027) predicted depression. CONCLUSIONS: PCOS is associated with anxiety and depression. Non-NIH phenotypes present with similar psychological profiles to NIH PCOS, indicating increased psychological dysfunction in PCOS, even in milder reproductive phenotypes. However, women with NIH PCOS appear to have worse HRQoL in some areas than women with non-NIH PCOS. Psychological function and HRQoL should be considered in all women with PCOS. PMID- 22493026 TI - New surgical approaches for the treatment of deep infiltrating endometriosis of the rectum. PMID- 22493027 TI - Assisted oocyte activation is not beneficial for all patients with a suspected oocyte-related activation deficiency. AB - BACKGROUND: Despite the success of ICSI, total fertilization failure (TFF) still occurs in 1-3% of all ICSI cycles. ICSI followed by assisted oocyte activation (ICSI-AOA) can restore fertilization, most efficiently in cases of sperm-related fertilization deficiency. The indication for ICSI-AOA is less obvious when the capacity of the sperm to activate oocytes is considered normal, as proved by a heterologous ICSI model, such as the mouse oocyte activation test (MOAT). In this study, we verified whether ICSI-AOA is beneficial for patients in whom an oocyte related activation deficiency is suspected. METHODS: A prospective study was conducted including patients presenting with a history of TFF or low fertilization (LF) following conventional ICSI in our centre (in-house cases, n= 2) or elsewhere (out-house cases, n= 12). In all cases a sperm deficiency was refuted by the MOAT. In a next treatment cycle, ICSI-AOA was performed on half of the sibling metaphase II oocytes and conventional ICSI on the rest ('split ICSI AOA cycle'). The main outcome parameters were fertilization, pregnancy and live birth rates. RESULTS: Overall, ICSI-AOA was able to improve fertilization rates in couples with a suspected oocyte-related fertilization problem, with a mean fertilization rate of 74.2% following ICSI-AOA compared with 43.5% following conventional ICSI (P< 0.001). Cumulative pregnancy rate and live birth rate per cycle were 35.7 and 14.3%, respectively. Considering the out-house patients only, fertilization rates with ICSI-AOA were higher in couples with previous TFF than with conventional ICSI (P< 0.001). Interestingly, for out-house patients who had experienced low, but not zero, fertilization elsewhere, ICSI-AOA could not enhance the fertilization rate. For the two in-house patients, both suffering from previous LF following conventional ICSI, the ICSI-AOA procedure enhanced the mean fertilization rate (25 versus 75%, respectively). CONCLUSIONS: For patients with a suspected oocyte-related activation deficiency, as diagnosed by a heterologuous ICSI model, the indication for ICSI-AOA still remains debatable. Our data show that ICSI-AOA is very efficient in patients with a suspected oocyte related activation deficiency and previous TFF after conventional ICSI. In contrast, when there was a history of LF in another centre, one should be careful and test the efficiency of ICSI-AOA on half of the sibling oocytes, because ICSI AOA is not always beneficial for patients with previous LF and a suspected oocyte related activation deficiency. For these patients, a split ICSI-AOA cycle using sibling oocytes can help to distinguish between a molecular oocyte-related activation deficiency and a previous technical or other biological failure. Moreover, this split ICSI-AOA strategy enables us to set the appropriate strategy for future treatment cycles. Further research with larger groups of patients is now required. PMID- 22493028 TI - Guidelines for infertility counselling in different countries: is there an emerging trend? AB - BACKGROUND: It is widely accepted that infertility and involuntary childlessness, and the decision to engage with assisted reproduction technology (ART) services as a patient, donor or surrogate can entail wide-ranging psychosocial issues. Psychosocial counselling has, therefore, become valued as an integral element of ART services. The objective of this study was to begin to map out what exists globally by the way of guidelines for infertility counselling. METHODS: Data were analysed from formal guidelines produced by seven national infertility counselling bodies, onetransnational infertility counselling organization, reports of the American Society for Reproductive Medicine Ethics Committee and Practice Committee and the ESHRE Task Force on Ethics and Law. Additional sources of data were the International Infertility Counseling Organization and counselling colleagues internationally. RESULTS: Four broad areas concerning contemporary practice in infertility counselling are identified: (i) the legal mandate for counselling; (ii) eligibility credentials for individuals carrying out professional counselling activities; (iii) different forms of counselling and (iv) counselling practice in relation to specific elements of assisted reproduction treatment. CONCLUSIONS: Internationally, the development of infertility guidelines is best described as a 'work in progress', although key trends are evident. PMID- 22493029 TI - Testicular sperm aneuploidy in non-obstructive azoospermic patients. AB - BACKGROUND: Non-obstructive azoospermic (NOA) men can father children after testicular sperm extraction (TESE). Previous studies suggest that they may be at risk of producing chromosomally abnormal spermatozoa, but the number of sperm analysed per patient was usually very low. METHODS: Multicolour fluorescence in situ hybridization was used for detection of chromosome 13, 15, 16, 18, 21, 22, X and Y disomy and diploidy in sperm obtained from NOA men (n = 17) and control donors (n = 10). At least 500 testicular sperm were scored in each patient to increase the precision of our study. RESULTS: The mean frequency of overall disomy (2.32%) and diploidy (0.80%) found in 13 689 testicular spermatozoa of NOA patients was significantly higher than in the ejaculated sperm of normospermic control donors, disomy (0.62%) and diploidy (0.29%). A highly significant increase in frequencies of chromosome 15, Y and overall disomy (P < 0.001), and a significant increase in disomy of chromosome 13 (P = 0.002), 16 (P = 0.031) and 21 (P = 0.018), overall diploidy (P = 0.031) and diploidy caused by errors in meiosis I (P = 0.011) were observed in the NOA group. CONCLUSIONS: Testicular sperm samples of NOA patients show a higher incidence of numerical chromosomal abnormalities compared with ejaculated sperm of control donors. Appropriate genetic counselling is necessary in NOA men undergoing TESE. PMID- 22493030 TI - Pseudomonas biofilms, cystic fibrosis, and phage: a silver lining? AB - In contrast to usual laboratory conditions, most bacteria in the human body grow in biofilms. Encased in a structured matrix, many pathogens display heightened resistance to antibiotics. Pseudomonas aeruginosa lung infections in cystic fibrosis patients represent a prime example of the clinical challenges that antibiotic resistance in biofilms can represent. In the March 6, 2012 issue of mBio, Colin Hill and his colleagues report on experiments that add to the evidence that Pseudomonas phages are a potential treatment option for these infections. PMID- 22493031 TI - Mammalian-transmissible highly pathogenic H5N1 influenza: epidemiological context. PMID- 22493032 TI - Characterization of cleavage events in the multifunctional cilium adhesin Mhp684 (P146) reveals a mechanism by which Mycoplasma hyopneumoniae regulates surface topography. AB - Mycoplasma hyopneumoniae causes enormous economic losses to swine production worldwide by colonizing the ciliated epithelium in the porcine respiratory tract, resulting in widespread damage to the mucociliary escalator, prolonged inflammation, reduced weight gain, and secondary infections. Protein Mhp684 (P146) comprises 1,317 amino acids, and while the N-terminal 400 residues display significant sequence identity to the archetype cilium adhesin P97, the remainder of the molecule is novel and displays unusual motifs. Proteome analysis shows that P146 preprotein is endogenously cleaved into three major fragments identified here as P50(P146), P40(P146), and P85(P146) that reside on the cell surface. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) identified a semitryptic peptide that delineated a major cleavage site in Mhp684. Cleavage occurred at the phenylalanine residue within sequence (672)ATEF?QQ(677), consistent with a cleavage motif resembling S/T-X-F?X-D/E recently identified in Mhp683 and other P97/P102 family members. Biotinylated surface proteins recovered by avidin chromatography and separated by two-dimensional gel electrophoresis (2 D GE) showed that more-extensive endoproteolytic cleavage of P146 occurs. Recombinant fragments F1(P146)-F3(P146) that mimic P50(P146), P40(P146), and P85(P146) were constructed and shown to bind porcine epithelial cilia and biotinylated heparin with physiologically relevant affinity. Recombinant versions of F3(P146) generated from M. hyopneumoniae strain J and 232 sequences strongly bind porcine plasminogen, and the removal of their respective C-terminal lysine and arginine residues significantly reduces this interaction. These data reveal that P146 is an extensively processed, multifunctional adhesin of M. hyopneumoniae. Extensive cleavage coupled with variable cleavage efficiency provides a mechanism by which M. hyopneumoniae regulates protein topography. IMPORTANCE: Vaccines used to control Mycoplasma hyopneumoniae infection provide only partial protection. Proteins of the P97/P102 families are highly expressed, functionally redundant molecules that are substrates of endoproteases that generate multifunctional adhesin fragments on the cell surface. We show that P146 displays a chimeric structure consisting of an N terminus, which shares sequence identity with P97, and novel central and C-terminal regions. P146 is endoproteolytically processed at multiple sites, generating at least nine fragments on the surface of M. hyopneumoniae. Dominant cleavage events occurred at S/T-X-F?X-D/E-like sites generating P50(P146), P40(P146), and P85(P146). Recombinant proteins designed to mimic the major cleavage fragments bind porcine cilia, heparin, and plasminogen. P146 undergoes endoproteolytic processing events at multiple sites and with differential processing efficiency, generating combinatorial diversity on the surface of M. hyopneumoniae. PMID- 22493034 TI - Enhancing the ICD system in recording alcohol's involvement in disease and injury. AB - Among the tasks facing those who code alcohol-related disorders in an international classification of disease are an examination of the multiple places in which the involvement of alcohol and other psychoactive substances (and their associated disorders) are captured and finding out how this can be optimized for clinical and epidemiological purposes. It is important to adjust the current coding system so that the involvement of alcohol in injuries is routinely recorded. The suggestions by Touquet and Harris (2012) for enhancing the International Classification of Diseases (ICD) system are valuable input for this process, pointing to the importance of codes that can be used in the emergency department environment both for capturing alcohol's involvement and to point to the necessary therapeutic response. PMID- 22493035 TI - Review of endophthalmitis following Boston keratoprosthesis type 1. AB - Endophthalmitis remains one of the most damaging and challenging complications following Boston keratoprosthesis type 1 (KPro) surgery. The authors reviewed the literature from 2001 onward to identify cases of endophthalmitis following KPro surgery and present an additional case of endophthalmitis in a patient with Stevens Johnson syndrome. The prevalence of endophthalmitis between 2001 and 2011 was 5.4%. Gram-positive bacteria are the most common agents responsible for endophthalmitis in this patient population while gram-negative bacteria and fungi are emerging pathogens. Risk factors for endophthalmitis include preoperative diagnosis of cicatricial disease and postoperative infectious keratitis, glaucoma drainage device erosion and non-compliance with antibiotic prophylaxis. Additional studies on the prevention and treatment of endophthalmitis are required to improve the overall prognosis of these patients. PMID- 22493033 TI - A new family of membrane electron transporters and its substrates, including a new cell envelope peroxiredoxin, reveal a broadened reductive capacity of the oxidative bacterial cell envelope. AB - The Escherichia coli membrane protein DsbD functions as an electron hub that dispatches electrons received from the cytoplasmic thioredoxin system to periplasmic oxidoreductases involved in protein disulfide isomerization, cytochrome c biogenesis, and sulfenic acid reduction. Here, we describe a new class of DsbD proteins, named ScsB, whose members are found in proteobacteria and Chlamydia. ScsB has a domain organization similar to that of DsbD, but its amino terminal domain differs significantly. In DsbD, this domain directly interacts with substrates to reduce them, which suggests that ScsB acts on a different array of substrates. Using Caulobacter crescentus as a model organism, we searched for the substrates of ScsB. We discovered that ScsB provides electrons to the first peroxide reduction pathway identified in the bacterial cell envelope. The reduction pathway comprises a thioredoxin-like protein, TlpA, and a peroxiredoxin, PprX. We show that PprX is a thiol-dependent peroxidase that efficiently reduces both hydrogen peroxide and organic peroxides. Moreover, we identified two additional proteins that depend on ScsB for reduction, a peroxiredoxin-like protein, PrxL, and a novel protein disulfide isomerase, ScsC. Altogether, our results reveal that the array of proteins involved in reductive pathways in the oxidative cell envelope is significantly broader than was previously thought. Moreover, the identification of a new periplasmic peroxiredoxin indicates that in some bacteria, it is important to directly scavenge peroxides in the cell envelope even before they reach the cytoplasm. IMPORTANCE: Peroxides are reactive oxygen species (ROS) that damage cellular components such as lipids, proteins, and nucleic acids. The presence of protection mechanisms against ROS is essential for cell survival. Bacteria express cytoplasmic catalases and thiol-dependent peroxidases to directly scavenge harmful peroxides. We report the identification of a peroxide reduction pathway active in the periplasm of Caulobacter crescentus, which reveals that, in some bacteria, it is important to directly scavenge peroxides in the cell envelope even before they reach the cytoplasm. The electrons required for peroxide reduction are delivered to this pathway by ScsB, a new type of membrane electron transporter. We also identified two additional likely ScsB substrates, including a novel protein disulfide isomerase. Our results reveal that the array of proteins involved in reductive pathways in the oxidative environment of the cell envelope is significantly broader than was previously thought. PMID- 22493036 TI - Primary bilateral silicone frontalis suspension for good levator function ptosis in oculopharyngeal muscular dystrophy. AB - AIM: To evaluate outcomes of patients with oculopharyngeal muscular dystrophy (OPMD) with levator function (LF) >= 10mm who underwent primary bilateral silicone frontalis suspension. METHODS: 31 patients with OPMD satisfied the following inclusion criteria: LF >= 10 mm; no previous eyelid surgery; and pre operative measurements, silcone frontalis suspension and post-operative measurements performed by a single individual. The following data were collected: age; gender; pre-operative margin reflex distance (MRD), palpebral fissure height (PF), and LF; post-operative MRD, PF and lagophthalmos; follow-up; and complications. RESULTS: Mean age at surgery was 61.5 +/- 5.8 years. Pre-operative measurements for MRD, PF and LF were -0.05 +/- 0.82 mm (OD), -0.13 +/- 0.91 mm (OS); 5.2 +/- 1.2 mm (OD), 5.2 +/- 1.3 mm (OS); 11.6 +/- 1.3 mm (OD), and 11.7 +/ 1.3 mm (OS), respectively. Post-operative measurements for MRD and PF were 2.23 +/- 0.97 mm (OD), 2.10 +/- 1.09 mm (OS), 7.9 +/- 1.4 mm (OD), and 7.7 +/- 1.6 mm (OS), respectively (all p < 0.0001). The mean follow-up period was 22.8 +/- 22.4 months. There was no sling (infection or extrusion) or ophthalmic (significant corneal compromise) complication after the surgery. Six patients (19%) underwent early (within 3 months) tightening of their slings for under correction. Three patients (10%) underwent late (> 39 months) tightening of their frontalis slings for recurrent ptosis after their initial surgery. CONCLUSIONS: Primary bilateral silicone frontalis suspension for good LF ptosis secondary to OPMD appears to be an effective, safe treatment which gives symmetrical upper lid elevation. Early sling adjustment may be required to attain optimal eyelid height and late tightening for expectant loosening of the sling is safe and effective. PMID- 22493037 TI - Avoidable sight loss from glaucoma: is it unavoidable? AB - AIMS: To review the characteristics of patients attending a tertiary ophthalmic referral centre certified as sight impaired (SI) or severely sight impaired (SSI) from glaucoma. METHODS: One hundred consecutive patients certified SI/SSI from the Glaucoma Service at Moorfields Eye Hospital, London, from January 2007 were identified from the England and Wales certification of visual impairment database. Clinical and demographic data were collected from hospital case records. RESULTS: The median (IQR) age of patients at presentation was 66.3 (55.6 to 75.3) years; median (IQR) interval to certification was 62.2 (22.5 to 129.3) months. Fifty-seven patients presented with bilateral SSI (median (IQR) age 70.4 (59.0 to 76.9) years); interval to certification was 35.4 (5.6 to 78.1) months. Seventeen patients presented with a bilateral SI (median (IQR) age 62.1 (58.7 to 68.4) years; median (IQR) interval to certification: 137.4 (64.4 to 190.4) months). Twenty-eight patients showed disease progression while under National Health Service hospital eye service care, five of whom had no certifiable visual impairment in either eye at presentation. This was attributed to inadequate intraocular pressure control; five of these patients (18%) were deemed poorly compliant to topical hypotensive medication. CONCLUSIONS: Over 80% patients on the certification of visual impairment register from Moorfields Eye Hospital with glaucoma as the primary cause had a significant visual disability at presentation, with almost two-thirds of patients presenting bilaterally 'blind'. There appear to be delays to certification. Despite being under the hospital eye service, a number of glaucoma patients still progress to certifiable visual impairment. PMID- 22493038 TI - Epithelial ingrowth cells after LASIK/ALTK (automated lamellar therapeutic keratoplasty): are they corneal epithelial stem cells? PMID- 22493039 TI - Risk of selected eye diseases in people admitted to hospital for hypertension or diabetes mellitus: record linkage studies. AB - AIMS: Associations among hypertension, diabetes mellitus and some ophthalmic diseases are well established; associations with others are more equivocal. The aim was to quantify associations accurately using large epidemiological datasets. METHODS: Analysis of the Oxford Record Linkage Study (ORLS), 1963-1998, and English linked hospital episode statistics (LHES), 1999-2010; calculation of rate ratios of eye disease in a hypertension cohort and a diabetes cohort, compared with a reference cohort as control. RESULTS: Risk of cataract following hypertension was marginally elevated (rate ratio ORLS 1.15, 95% CI 1.00 to 1.31; LHES 1.06, 1.01 to 1.10), as was risk of glaucoma (LHES 1.07, 1.00 to 1.14) and age-related macular degeneration (AMD) (LHES 1.14, 1.02 to 1.27). Risk of retinal vein or artery occlusion was elevated three- to fivefold in both populations. Risk of retinal detachment was elevated in LHES at 1.52 (1.43 to 1.73). Risk of cataract in diabetes was high in ORLS and LHES at, respectively, 2.95 (2.75 to 3.16) and 2.30 (2.24 to 2.35), as was risk of glaucoma: 2.47 (2.14 to 2.84) and 2.23 (2.15 to 2.30). Risks were high for AMD (10.3, 8.1 to 13.1, and 3.46, 3.35 to 3.58) and retinal detachment (3.41, 2.71 to 4.25, and 7.96, 7.63 to 8.30), and very high for retinal vein and artery occlusion. CONCLUSIONS: With the exception of retinal vascular occlusion, elevations of risk of the ophthalmic diseases studied in hypertension were modest. By contrast, there were significant and substantial increases of risk for each eye disease in people with diabetes. PMID- 22493040 TI - Keratopigmentation: techniques and results. PMID- 22493041 TI - The dipeptidyl peptidase-4 inhibitor linagliptin attenuates inflammation and accelerates epithelialization in wounds of diabetic ob/ob mice. AB - In recent years, new and effective therapeutic agents for blood glucose control have been added to standard diabetes therapies: dipeptidyl peptidase-4 (DPP-4) inhibitors, which prolong the bioavailability of the endogenously secreted incretin hormone glucagon-like peptide-1 (GLP-1). Full-thickness excisional wounding was performed in wild-type (C57BL/6J) and diabetic [C57BL/6J-obese/obese (ob/ob)] mice. DPP-4 activity was inhibited by oral administration of linagliptin during healing. Wound tissue was analyzed by using histological, molecular, and biochemical techniques. In healthy mice, DPP-4 was constitutively expressed in the keratinocytes of nonwounded skin. After skin injury, DPP-4 expression declined and was lowest during the most active phase of tissue reassembly. In contrast, in ob/ob mice, we observed increasing levels of DPP-4 at late time points, when delayed tissue repair still occurs. Oral administration of the DPP-4 inhibitor linagliptin strongly reduced DPP-4 activity, stabilized active GLP-1 in chronic wounds, and improved healing in ob/ob mice. At day 10 postwounding, linagliptin-treated ob/ob mice showed largely epithelialized wounds characterized by the absence of neutrophils. In addition, DPP-4 inhibition reduced the expression of the proinflammatory markers cyclooxygenase-2 and macrophage inflammatory protein-2, but enhanced the formation of myofibroblasts in healing wounds from ob/ob mice. Our data suggest a potentially beneficial role of DPP-4 inhibition in diabetes-affected wound healing. PMID- 22493043 TI - To know or not to know? Dilemmas for women receiving unknown oocyte donation. AB - BACKGROUND: This study aims to provide insight into the reasons for choosing an unknown oocyte donor and to explore recipients' feelings and wishes regarding donor information. METHODS: In-depth interviews were carried out with 11 women at different stages of treatment. Seven were on a waiting list and four have given birth to donor oocyte babies. The interviews were analysed using interpretative phenomenological analysis. RESULTS: The choice of unknown donor route was motivated by a wish to feel secure in the role of mother as well as to avoid possible intrusions into family relationships. The information that is available about unknown donors is often very limited. In the preconception phase of treatment, some participants wanted more information about the donor but others adopted a not-knowing stance that protected them from the emotional impact of needing a donor. In the absence of information that might normalize her, there was a tendency to imagine the donor in polarised simplistic terms, so she may be idealized or feared. Curiosity about the donor intensified once a real baby existed, and the task of telling a child was more daunting when very little was known about the donor. A strong wish for same-donor siblings was expressed by all of the participants who had given birth. CONCLUSIONS: This qualitative study throws light on the factors that influence the choice of unknown donation. It also highlights the scope for attitudes to donor information to undergo change over the course of treatment and after giving birth. The findings have implications for pretreatment counselling and raise a number of issues that merit further exploration. PMID- 22493042 TI - Resveratrol inhibits paraquat-induced oxidative stress and fibrogenic response by activating the nuclear factor erythroid 2-related factor 2 pathway. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is an antioxidant-activated transcription factor that recently emerged as a critical regulator of cellular defense against oxidative and inflammatory lesions. Resveratrol (Res) is a natural phytoalexin that exhibits multiple therapeutic potentials, including antioxidative and anti-inflammatory effects in animals. Paraquat (PQ) is the second most widely used herbicide worldwide, but it selectively accumulates in human lungs to cause oxidative injury and fibrosis with high mortality. Here, we analyzed the molecular mechanism of the fibrogenic response to PQ and its inhibition by Res and Nrf2. PQ dose-dependently caused toxicity in normal human bronchial epithelial cells (BEAS-2B), resulting in mitochondrial damage, oxidative stress, and cell death. Res at 10 MUM markedly inhibited PQ toxicity. PQ at 10 MUM stimulated production of inflammatory and profibrogenic factors (tumor necrosis factor alpha, interleukin 6, and transforming growth factor beta1) and induced the transformation of normal human lung fibroblasts (WI38 VA13) to myofibroblasts; both effects were inhibited by Res. Res strongly activated the Nrf2 signaling pathway and induced antioxidant response element dependent cytoprotective genes. On the other hand, knockout or knockdown of Nrf2 markedly increased PQ-induced cytotoxicity, cytokine production, and myofibroblast transformation and abolished protection by Res. The findings demonstrate that Res attenuates PQ-induced reactive oxygen species production, inflammation, and fibrotic reactions by activating Nrf2 signaling. The study reveals a new pathway for molecular intervention against pulmonary oxidative injury and fibrosis. PMID- 22493044 TI - Trisomic pregnancy and intermediate CGG repeat length at the FMR1 locus. AB - BACKGROUND: We hypothesized that trisomy arises as a function of the size of the oocyte pool, with risk increased among women with diminished pools. Diminished pools may cause primary ovarian failure, which has been associated with premutation and intermediate CGG repeat length at the Fragile X mental retardation (FMR1) locus. Thus, we hypothesized that the risk of trisomic pregnancy is increased among women with intermediate CGG repeat length on the FMR1 gene. METHODS: The analysis drew on data from two hospital-based case control studies. We compared 207 women with trisomic spontaneous abortions (SAs) to three comparison groups: 82 women with other chromosomally abnormal SAs, 99 women with chromosomally normal SAs and 537 women with live births (LBs), age matched to women with SAs. We defined the length of the CGG repeat in four ways: the biallelic mean, the genotypic mean, the length on allele 2 and the length on allele 1. We analyzed CGG repeat length as a categorical variable. All analyses were adjusted for site, age and ethnicity. RESULTS: CGG repeat length did not differ significantly between women with trisomic SAs and any of the three comparison groups. For the biallelic mean, the adjusted odds ratio relating trisomy (versus LB controls) to the highest category (35.5-59.5 repeats) versus the modal category (26.5-30.0 repeats) was 1.5 (95% confidence interval (CI): 0.7, 3.1). Comparisons with the two SA control groups also showed increased odds of more repeats among trisomy cases. Results were similar when repeat length was defined by the genotypic mean or by the repeat length on allele 2. For allele 1, the odds of short (9-19) repeat length were lower, but not significantly so, for trisomy cases compared with LB controls. Excluding women with premutations (n= 2) from the analysis yielded an adjusted odds ratio of 1.4 (95% CI: 0.7, 2.9) for the biallelic mean. CONCLUSIONS: Our data are equivocal. The direction of associations is consistent with the hypothesis that repeat length in the intermediate range is associated with trisomy. However, differences between the trisomy cases and the comparison groups are neither large nor statistically significant. Our data rule out odds ratios larger than about 3. PMID- 22493045 TI - Alcohol dependence, consumption of alcoholic energy drinks and associated work characteristics in the Taiwan working population. AB - AIMS: To examine the association between work characteristics and the risk of alcohol dependence across different employment types and occupations, including the pattern of alcohol consumption in the form of energy drinks and its association with alcohol dependence. METHODS: A total of 13,501 men and 8584 women participated in a national survey in Taiwan. Alcohol dependence was defined as >=2 points in the CAGE questionnaire. A self-administered questionnaire recorded drinking behaviors, consumption of alcoholic energy drinks, employment type, occupation and a number of psychosocial work stressors, namely job demands, job control, employment security and workplace justice. RESULTS: Of the total, 9.4% of men and 0.8% of women were CAGE-positive, and 6.0% of men and 0.7% of women regularly consumed alcoholic energy drinks. In male and female regular consumers of alcoholic energy drinks, 38.7 and 23.3%, respectively, were alcohol dependent. Multivariate regression analyses showed that male employees in manual skilled occupations, with lower workplace justice, having weekly working hours <40 h and on piece-rated or time-based pay systems were at higher risks of alcohol dependence. CONCLUSION: Certain occupational groups and workers with adverse psychosocial work characteristics should be targets for prevention of alcohol dependence. Alcoholic energy drink consumption should be taken into consideration while studying alcohol dependence in the work population in Taiwan. PMID- 22493046 TI - Factors predicting change in frequency of heavy drinking days among alcohol dependent participants in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). AB - AIMS: To discover the predictors of change in the frequency of heavy drinking (HD) over a 4-year period in alcohol dependent (AD)-individuals identified in the general population, namely, among participants of the US National Epidemiologic Survey on Alcohol and Related Conditions interviewed at Wave 1 (2001-2002) and at Wave 2 (2004-2005). METHODS: The study cohort included subjects meeting DSM-IV criteria for AD in the past year at Wave 1 (n = 1484), who were present at Wave 2 (n = 1172) and had complete data on factors of interest (n = 1123). Frequency of HD was defined as the number of HD days (HDD) (>=5 drinks per day for men and >=4 for women). Change in frequency of HDD from baseline (Wave 1) to ~3 years later (Wave 2) was determined. An analysis of covariance model (ANCOVA), adjusting for baseline HDD, was used to examine individual factors associated with change in frequency of HDD, while a multivariable regression model was employed to assess factors associated with change in frequency of HDD simultaneously. RESULTS: Overall, there was a decrease in mean (SE) HDD [from 119.4 (1.8) at Wave 1 to 82.5 (2.1) at Wave 2, P < 0.0001]. Compared with smokers, non-smokers had a mean (SE) HDD reduction of 13.4 (6.7), P < 0.05. AD criteria of tolerance was significantly associated (P < 0.05) with less reduction in HDD. Change in depression/dysthymia status was associated with greater reduction in HDD in the ANCOVA model, but not the fully adjusted multivariable model. CONCLUSION: Findings from this study suggest that smoking and AD criteria of tolerance are important factors for long-term follow-up of AD patients and they should influence the selection of the kinds of interventions required for AD patients to achieve maximal therapeutic benefit. PMID- 22493047 TI - The epidemiology of alcohol consumption and misuse among Chinese college students. AB - AIMS: To understand alcohol-related risk behaviours among Chinese college students. METHODS: As part of the first China National Youth Risk Behaviour Survey, undertaken in 2009, 52,150 students at 119 colleges were randomly sampled. Information was obtained from self-administered questionnaires. RESULTS: Prevalences were: lifetime drinkers 80.8%, current drinkers 49.3% (drank alcohol in past 30 days) and binge drinkers 23.5% ('binge drinkers' reporting at least five alcoholic drinks on a single occasion at least six times during the past 30 days). Multinomial logistic analysis revealed the contribution of sociodemographic factors to three high-risk drinking behaviours: odds ratio (95% confidence interval) = 3.64 (2.69-4.60) with frequent drinking; 3.27 (1.82-4.72) with binge drinking; and 5.48 (3.20-7.77) with heavy binge drinking. These three rates were greater among males than females, in the Western more than the Eastern region, among students living off-campus and among those whose mothers had higher education. Heavy drinking was linked to lower academic self-rating. CONCLUSION: There is a trend towards risky drinking among Chinese college students. Measures such as a minimum drinking age, advertisement restrictions, taxation, drunk driving penalties and campaigns to heighten public awareness of alcohol-related health risks should be instituted in order to improve the situation on college campuses where alcohol abuse is particularly prevalent. PMID- 22493048 TI - Emergency department visits due to alcohol intoxication: characteristics of patients and impact on the emergency room. AB - AIMS: The aim of the study was to describe the epidemiology, management and cost of emergency department (ED) visits due to alcohol intoxication. METHODS: A retrospective review of medical records of all episodes of alcohol intoxication was made, excepting those where another diagnosis such as trauma or psychiatric illness was primary, in patients older than 16 years, who presented to the ED of a large university hospital in Belgium over a 12-month period from 1 January 2009. RESULTS: A total of 635 such patients accounted for 1.2% of all ED visits; 429 were males and 48.3% were aged between 41 and 60 years; 63.8% of the patients had a history of alcohol use disorder and 60.3% had a history of psychiatric disorder; 74.3% of the patients received some form of medical treatment and 62% were seen by a psychiatrist. Of the total, 57.5% of the patients were admitted to the ED observation ward, with a mean length of stay of 8.4 h. The estimated total cost was ?318 838.25, with an average of ?541.32 per patient. CONCLUSION: Alcohol intoxication leads to a financial burden on the community. In addition to imposing physical, social and psychological stress on the community, the often agitated or aggressive patient imposes stress on ED staff. Close surveillance of trends in alcohol abuse is warranted, and the ED should consider implementing a questionnaire method of screening for alcohol abuse. PMID- 22493049 TI - A patient-driven adaptive prediction technique to improve personalized risk estimation for clinical decision support. AB - OBJECTIVE: Competing tools are available online to assess the risk of developing certain conditions of interest, such as cardiovascular disease. While predictive models have been developed and validated on data from cohort studies, little attention has been paid to ensure the reliability of such predictions for individuals, which is critical for care decisions. The goal was to develop a patient-driven adaptive prediction technique to improve personalized risk estimation for clinical decision support. MATERIAL AND METHODS: A data-driven approach was proposed that utilizes individualized confidence intervals (CIs) to select the most 'appropriate' model from a pool of candidates to assess the individual patient's clinical condition. The method does not require access to the training dataset. This approach was compared with other strategies: the BEST model (the ideal model, which can only be achieved by access to data or knowledge of which population is most similar to the individual), CROSS model, and RANDOM model selection. RESULTS: When evaluated on clinical datasets, the approach significantly outperformed the CROSS model selection strategy in terms of discrimination (p<1e-14) and calibration (p<0.006). The method outperformed the RANDOM model selection strategy in terms of discrimination (p<1e-12), but the improvement did not achieve significance for calibration (p=0.1375). LIMITATIONS: The CI may not always offer enough information to rank the reliability of predictions, and this evaluation was done using aggregation. If a particular individual is very different from those represented in a training set of existing models, the CI may be somewhat misleading. CONCLUSION: This approach has the potential to offer more reliable predictions than those offered by other heuristics for disease risk estimation of individual patients. PMID- 22493050 TI - Unified Medical Language System term occurrences in clinical notes: a large-scale corpus analysis. AB - OBJECTIVE: To characterise empirical instances of Unified Medical Language System (UMLS) Metathesaurus term strings in a large clinical corpus, and to illustrate what types of term characteristics are generalisable across data sources. DESIGN: Based on the occurrences of UMLS terms in a 51 million document corpus of Mayo Clinic clinical notes, this study computes statistics about the terms' string attributes, source terminologies, semantic types and syntactic categories. Term occurrences in 2010 i2b2/VA text were also mapped; eight example filters were designed from the Mayo-based statistics and applied to i2b2/VA data. RESULTS: For the corpus analysis, negligible numbers of mapped terms in the Mayo corpus had over six words or 55 characters. Of source terminologies in the UMLS, the Consumer Health Vocabulary and Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT) had the best coverage in Mayo clinical notes at 106426 and 94788 unique terms, respectively. Of 15 semantic groups in the UMLS, seven groups accounted for 92.08% of term occurrences in Mayo data. Syntactically, over 90% of matched terms were in noun phrases. For the cross-institutional analysis, using five example filters on i2b2/VA data reduces the actual lexicon to 19.13% of the size of the UMLS and only sees a 2% reduction in matched terms. CONCLUSION: The corpus statistics presented here are instructive for building lexicons from the UMLS. Features intrinsic to Metathesaurus terms (well formedness, length and language) generalise easily across clinical institutions, but term frequencies should be adapted with caution. The semantic groups of mapped terms may differ slightly from institution to institution, but they differ greatly when moving to the biomedical literature domain. PMID- 22493057 TI - Proton beam therapy for inoperable recurrence of bronchial high-grade mucoepidermoid carcinoma. AB - We report the case of a 17-year-old patient who received four courses of proton beam therapy for inoperable recurrent high-grade bronchial mucoepidermoid carcinoma of the chest wall and lymph nodes. The equivalent doses in conventional fractionation of 79.2-80.6 Gy were applied to the tumor from the first to third courses of proton beam therapy; the hemi-chest wall was also irradiated prophylactically in the third course. The irradiated tumor recurred marginally and liver metastasis developed, but tumor size within the irradiated field was suppressed. Proton beam therapy was also applied to the marginally recurrent tumor in the fourth course. The patient died of cancer about 5 years after the first course of proton beam therapy-about 9 years after the initial diagnosis and surgery. Repeated irradiation of the mediastinum and chest wall with photon radiotherapy is often limited by side-effects in the heart, esophagus and spinal cord. However, no severe late complications in critical organs were detected in this case. Only a Grade 2 skin reaction and lymphatic edema were observed. Therefore, high-dose proton beam therapy may be an option as a salvage therapy with less toxicity to normal tissues compared with photon radiotherapy and provide an alternative to repeated surgery. PMID- 22493058 TI - Clinical features and survival analysis of T1mic, a, bN0M0 breast cancer. AB - OBJECTIVE: To analyze the clinicopathological features and prognosis of T1mic, a, bN0M0 breast cancer. METHODS: The clinical data and survival status of 4487 cases of operable breast cancer treated in our hospital from 2002 to 2005 were collected, including 372 cases with T1mic, a, bN0M0 breast cancers. These patients were divided into four subtypes: Luminal A, Luminal B, triple-negative and human epidermal growth factor receptor 2-positive. Disease-free survival and risk factors for recurrence were identified. RESULTS: We identified 372 eligible patients. The median follow-up was 78 months (range: 5-106 months). Univariate analysis showed age, adjuvant endocrine therapy, hormonal receptor and human epidermal growth factor receptor 2 were prognostic factors. Multivariate analysis showed that hormonal receptor and human epidermal growth factor receptor 2 were prognostic factors. In the hormonal receptor-positive group, human epidermal growth factor receptor 2-positive patients (Luminal B) had a four times higher recurrence risk than human epidermal growth factor receptor 2 negative (Luminal A) patients. However, there was no statistically significant difference between hormonal receptor-negative groups (triple-negative and human epidermal growth factor receptor 2-positive). CONCLUSIONS: Hormonal receptor and human epidermal growth factor receptor 2 were independent factors of 5-year disease-free survival for patients with T1mic, a, bN0M0 breast cancer. The Luminal B group had a worse prognosis than the Luminal A group, but there was no statistically significant difference between triple-negative and human epidermal growth factor receptor 2 positive groups. PMID- 22493059 TI - LST8 regulates cell growth via target-of-rapamycin complex 2 (TORC2). AB - The evolutionarily conserved serine/threonine protein kinase target-of-rapamycin (TOR) controls cell growth as a core component of TOR complexes 1 (TORC1) and 2 (TORC2). Although TORC1 is the more central growth regulator, TORC2 has also been shown to affect cell growth. Here, we demonstrate that Drosophila LST8, the only conserved TOR-binding protein present in both TORC1 and TORC2, functions exclusively in TORC2 and is not required for TORC1 activity. In mutants lacking LST8, expression of TOR and RAPTOR, together with their upstream activator Rheb, was sufficient to provide TORC1 activity and stimulate cell and organ growth. Furthermore, using an lst8 knockout mutation, we show that TORC2 regulates cell growth cell autonomously. Surprisingly, however, TORC2 does not regulate cell growth via its best-characterized target, AKT. Our findings support the possible application of TORC2-specific drugs in cancer therapy. PMID- 22493060 TI - Trm112 is required for Bud23-mediated methylation of the 18S rRNA at position G1575. AB - Posttranscriptional and posttranslational modification of macromolecules is known to fine-tune their functions. Trm112 is unique, acting as an activator of both tRNA and protein methyltransferases. Here we report that in Saccharomyces cerevisiae, Trm112 is required for efficient ribosome synthesis and progression through mitosis. Trm112 copurifies with pre-rRNAs and with multiple ribosome synthesis trans-acting factors, including the 18S rRNA methyltransferase Bud23. Consistent with the known mechanisms of activation of methyltransferases by Trm112, we found that Trm112 interacts directly with Bud23 in vitro and that it is required for its stability in vivo. Consequently, trm112Delta cells are deficient for Bud23-mediated 18S rRNA methylation at position G1575 and for small ribosome subunit formation. Bud23 failure to bind nascent preribosomes activates a nucleolar surveillance pathway involving the TRAMP complexes, leading to preribosome degradation. Trm112 is thus active in rRNA, tRNA, and translation factor modification, ideally placing it at the interface between ribosome synthesis and function. PMID- 22493061 TI - hnRNP Q regulates Cdc42-mediated neuronal morphogenesis. AB - The RNA-binding protein hnRNP Q has been implicated in neuronal mRNA metabolism. Here, we show that knockdown of hnRNP Q increased neurite complexity in cultured rat cortical neurons and induced filopodium formation in mouse neuroblastoma cells. Reexpression of hnRNP Q1 in hnRNP Q-depleted cells abrogated the morphological changes of neurites, indicating a specific role for hnRNP Q1 in neuronal morphogenesis. A search for mRNA targets of hnRNP Q1 identified functionally coherent sets of mRNAs encoding factors involved in cellular signaling or cytoskeletal regulation and determined its preferred binding sequences. We demonstrated that hnRNP Q1 bound to a set of identified mRNAs encoding the components of the actin nucleation-promoting Cdc42/N-WASP/Arp2/3 complex and was in part colocalized with Cdc42 mRNA in granules. Using subcellular fractionation and immunofluorescence, we showed that knockdown of hnRNP Q reduced the level of some of those mRNAs in neurites and redistributed their encoded proteins from neurite tips to soma to different extents. Overexpression of dominant negative mutants of Cdc42 or N-WASP compromised hnRNP Q depletion-induced neurite complexity. Together, our results suggest that hnRNP Q1 may participate in localization of mRNAs encoding Cdc42 signaling factors in neurites, and thereby may regulate actin dynamics and control neuronal morphogenesis. PMID- 22493062 TI - UG4 enhancer-driven GATA-2 and bone morphogenetic protein 4 complementation remedies the CAKUT phenotype in Gata2 hypomorphic mutant mice. AB - During renal development, the proper emergence of the ureteric bud (UB) from the Wolffian duct is essential for formation of the urinary system. Previously, we showed that expression of transcription factor GATA-2 in the urogenital primordium was demarcated anteroposteriorly into two domains that were regulated by separate enhancers. While GATA-2 expression in the caudal urogenital mesenchyme is controlled by the UG4 enhancer, its more-rostral expression is regulated by UG2. We found that anteriorly displaced budding led to obstructed megaureters in Gata2 hypomorphic mutant mice, possibly due to reduced expression of the downstream effector bone morphogenetic protein 4 (BMP4). Here, we report that UG4-driven, but not UG2-driven, GATA-2 expression in the urogenital mesenchyme significantly reverts the uropathy observed in the Gata2 hypomorphic mutant mice. Furthermore, the data show that transgenic rescue by GATA-2 reverses the rostral outgrowth of the UB. We also provide evidence for a GATA-2-BMP4 epistatic relationship by demonstrating that reporter gene expression from a Bmp4 bacterial artificial chromosome (BAC) transgene is altered in Gata2 hypomorphs; furthermore, UG4-directed BMP4 expression in the mutants leads to reduced incidence of megaureters. These results demonstrate that GATA-2 expression in the caudal urogenital mesenchyme as directed by the UG4 enhancer is crucial for proper development of the urinary tract and that its regulation of BMP4 expression is a critical aspect of this function. PMID- 22493063 TI - Protection from bacterial-toxin-induced apoptosis in macrophages requires the lipogenic transcription factor sterol regulatory element binding protein 1a. AB - Sterol regulatory element binding protein (SREBP) transcription factors activate genes of lipid metabolism, but recent studies indicate they also activate genes involved in other physiologic processes, suggesting that SREPBs have evolved to connect lipid metabolism with diverse physiologic responses. There are three major mammalian SREBPs, and the 1a isoform is specifically expressed at very high levels in macrophages, where a recent study showed that it couples lipid synthesis to the proinflammatory phase of the innate immune response. In the present study, we show that loss of SREBP-1a also results in an increase in apoptosis after exposure to bacterial pore-forming toxins and we show this is a result of a selective reduction in the expression of the gene coding for the antiapoptotic factor apoptosis inhibitor 6 (Api6). Additional studies demonstrate that SREBP-1a specifically activates the Api6 gene through a binding site in its proximal promoter, thus establishing the Api6 gene as a newly identified SREBP-1a target gene. PMID- 22493064 TI - Protein landscape at Drosophila melanogaster telomere-associated sequence repeats. AB - The specific set of proteins bound at each genomic locus contributes decisively to regulatory processes and to the identity of a cell. Understanding of the function of a particular locus requires the knowledge of what factors interact with that locus and how the protein composition changes in different cell types or during the response to internal and external signals. Proteomic analysis of isolated chromatin segments (PICh) was developed as a tool to target, purify, and identify proteins associated with a defined locus and was shown to allow the purification of human telomeric chromatin. Here we have developed this method to identify proteins that interact with the Drosophila telomere-associated sequence (TAS) repeats. Several of the purified factors were validated as novel TAS-bound proteins by chromatin immunoprecipitation, and the Brahma complex was confirmed as a dominant modifier of telomeric position effect through the use of a genetic test. These results offer information on the efficacy of applying the PICh protocol to loci with sequence more complex than that found at human telomeres and identify proteins that bind to the TAS repeats, which might contribute to TAS biology and chromatin silencing. PMID- 22493065 TI - Histone demethylase UTX and chromatin remodeler BRM bind directly to CBP and modulate acetylation of histone H3 lysine 27. AB - Trithorax group (TrxG) proteins antagonize Polycomb silencing and are required for maintenance of transcriptionally active states. We previously showed that the Drosophila melanogaster acetyltransferase CREB-binding protein (CBP) acetylates histone H3 lysine 27 (H3K27ac), thereby directly blocking its trimethylation (H3K27me3) by Polycomb repressive complex 2 (PRC2) in Polycomb target genes. Here, we show that H3K27ac levels also depend on other TrxG proteins, including the histone H3K27-specific demethylase UTX and the chromatin-remodeling ATPase Brahma (BRM). We show that UTX and BRM are physically associated with CBP in vivo and that UTX, BRM, and CBP colocalize genome-wide on Polycomb response elements (PREs) and on many active Polycomb target genes marked by H3K27ac. UTX and BRM bind directly to conserved zinc fingers of CBP, suggesting that their individual activities are functionally coupled in vivo. The bromodomain-containing C terminus of BRM binds to the CBP PHD finger, enhances PHD binding to histone H3, and enhances in vitro acetylation of H3K27 by recombinant CBP. brm mutations and knockdown of UTX by RNA interference (RNAi) reduce H3K27ac levels and increase H3K27me3 levels. We propose that direct binding of UTX and BRM to CBP and their modulation of H3K27ac play an important role in antagonizing Polycomb silencing. PMID- 22493066 TI - Constitutive Notch activation upregulates Pax7 and promotes the self-renewal of skeletal muscle satellite cells. AB - Notch signaling is a conserved cell fate regulator during development and postnatal tissue regeneration. Using skeletal muscle satellite cells as a model and through myogenic cell lineage-specific NICD(OE) (overexpression of constitutively activated Notch 1 intracellular domain), here we investigate how Notch signaling regulates the cell fate choice of muscle stem cells. We show that in addition to inhibiting MyoD and myogenic differentiation, NICD(OE) upregulates Pax7 and promotes the self-renewal of satellite cell-derived primary myoblasts in culture. Using MyoD(-/-) myoblasts, we further show that NICD(OE) upregulates Pax7 independently of MyoD inhibition. In striking contrast to previous observations, NICD(OE) also inhibits S-phase entry and Ki67 expression and thus reduces the proliferation of primary myoblasts. Overexpression of canonical Notch target genes mimics the inhibitory effects of NICD(OE) on MyoD and Ki67 but not the stimulatory effect on Pax7. Instead, NICD regulates Pax7 through interaction with RBP-Jkappa, which binds to two consensus sites upstream of the Pax7 gene. Importantly, satellite cell-specific NICD(OE) results in impaired regeneration of skeletal muscles along with increased Pax7(+) mononuclear cells. Our results establish a role of Notch signaling in actively promoting the self-renewal of muscle stem cells through direct regulation of Pax7. PMID- 22493067 TI - PERK utilizes intrinsic lipid kinase activity to generate phosphatidic acid, mediate Akt activation, and promote adipocyte differentiation. AB - The endoplasmic reticulum (ER) resident PKR-like kinase (PERK) is necessary for Akt activation in response to ER stress. We demonstrate that PERK harbors intrinsic lipid kinase, favoring diacylglycerol (DAG) as a substrate and generating phosphatidic acid (PA). This activity of PERK correlates with activation of mTOR and phosphorylation of Akt on Ser473. PERK lipid kinase activity is regulated in a phosphatidylinositol 3-kinase (PI3K) p85alpha dependent manner. Moreover, PERK activity is essential during adipocyte differentiation. Because PA and Akt regulate many cellular functions, including cellular survival, proliferation, migratory responses, and metabolic adaptation, our findings suggest that PERK has a more extensive role in insulin signaling, insulin resistance, obesity, and tumorigenesis than previously thought. PMID- 22493068 TI - Two different replication factor C proteins, Ctf18 and RFC1, separately control PCNA-CRL4Cdt2-mediated Cdt1 proteolysis during S phase and following UV irradiation. AB - Recent work identified the E3 ubiquitin ligase CRL4(Cdt2) as mediating the timely degradation of Cdt1 during DNA replication and following DNA damage. In both cases, proliferating cell nuclear antigen (PCNA) loaded on chromatin mediates the CRL4(Cdt2)-dependent proteolysis of Cdt1. Here, we demonstrate that while replication factor C subunit 1 (RFC1)-RFC is required for Cdt1 degradation after UV irradiation during the nucleotide excision repair process, another RFC complex, Ctf18-RFC, which is known to be involved in the establishment of cohesion, has a key role in Cdt1 degradation in S phase. Cdt1 segments having only the degron, a specific sequence element in target protein for ubiquitination, for CRL4(Cdt2) were stabilized during S phase in Ctf18-depleted cells. Additionally, endogenous Cdt1 was stabilized when both Skp2 and Ctf18 were depleted. Since a substantial amount of PCNA was detected on chromatin in Ctf18 depleted cells, Ctf18 is required in addition to loaded PCNA for Cdt1 degradation in S phase. Our data suggest that Ctf18 is involved in recruiting CRL4(Cdt2) to PCNA foci during S phase. Ctf18-mediated Cdt1 proteolysis occurs independent of cohesion establishment, and depletion of Ctf18 potentiates rereplication. Our findings indicate that individual RFC complexes differentially control CRL4(Cdt2) dependent proteolysis of Cdt1 during DNA replication and repair. PMID- 22493069 TI - Central actions of the chemokine stromal cell-derived factor 1 contribute to neurohumoral excitation in heart failure rats. AB - The ample expression of chemokines and their receptors by neurons in the brain suggests that they play a functional role beyond the coordination of inflammatory and immune responses. Growing evidence implicates brain chemokines in the regulation of neuronal activity and neurohormonal release. This study examined the potential role of brain chemokines in regulating hemodynamic, sympathetic, and neuroendocrine mechanisms in rats with ischemia-induced heart failure (HF). Immunohistochemical analysis revealed that the chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12 was highly expressed in the hypothalamic paraventricular nucleus and subfornical organ and that SDF-1 expression was significantly increased in HF rats compared with sham-operated (SHAM) control rats. ICV injection of SDF-1 induced substantial and long-lasting increases in blood pressure, heart rate, and renal sympathetic nerve activity in both SHAM and HF rats, but responses were exaggerated in HF rats. Bilateral microinjection of SDF 1 into the paraventricular nucleus also elicited exaggerated increases in blood pressure, heart rate, and renal sympathetic nerve activity in the HF rats. A 4 hour ICV infusion of SDF-1 increased plasma levels of arginine vasopressin, adrenocorticotropic hormone, and norepinephrine in normal rats, responses that were prevented by pretreatment with ICV SDF-1 short-hairpin RNA (shRNA). ICV administration of SDF-1 shRNA also reduced plasma arginine vasopressin, adrenocorticotropic hormone, and norepinephrine levels in HF rats. These data suggest that the chemokine SDF-1, acting within the brain, plays an important role in regulating sympathetic drive, neuroendocrine release, and hemodynamic function in normal and pathophysiological conditions and so may contribute to the neural and humoral activation in HF. PMID- 22493070 TI - Adipocytes produce aldosterone through calcineurin-dependent signaling pathways: implications in diabetes mellitus-associated obesity and vascular dysfunction. AB - We reported aldosterone as a novel adipocyte-derived factor that regulates vascular function. We aimed to investigate molecular mechanisms, signaling pathways, and functional significance of adipocyte-derived aldosterone and to test whether adipocyte-derived aldosterone is increased in diabetes mellitus associated obesity, which contributes to vascular dysfunction. Studies were performed in the 3T3-L1 adipocyte cell line and mature adipocytes isolated from human and mouse (C57BL/6J) adipose tissue. Mesenteric arteries with and without perivascular fat and mature adipocytes were obtained from obese diabetic db/db and control db/+ mice. Aldosterone synthase (CYP11B2; mRNA and protein) was detected in 3T3-L1 and mature adipocytes, which secrete aldosterone basally and in response to angiotensin II (Ang II). In 3T3-L1 adipocytes, Ang II stimulation increased aldosterone secretion and CYP11B2 expression. Ang II effects were blunted by an Ang II type 1 receptor antagonist (candesartan) and inhibitors of calcineurin (cyclosporine A and FK506) and nuclear factor of activated T-cells (VIVIT). FAD286 (aldosterone synthase inhibitor) blunted adipocyte differentiation. In candesartan-treated db/db mice (1 mg/kg per day, 4 weeks) increased plasma aldosterone, CYP11B2 expression, and aldosterone secretion were reduced. Acetylcholine-induced relaxation in db/db mesenteric arteries containing perivascular fat was improved by eplerenone (mineralocorticoid receptor antagonist) without effect in db/+ mice. Adipocytes possess aldosterone synthase and produce aldosterone in an Ang II/Ang II type 1 receptor/calcineurin/nuclear factor of activated T-cells-dependent manner. Functionally adipocyte-derived aldosterone regulates adipocyte differentiation and vascular function in an autocrine and paracrine manner, respectively. These novel findings identify adipocytes as a putative link between aldosterone and vascular dysfunction in diabetes mellitus-associated obesity. PMID- 22493071 TI - Role of heart rate reduction in the prevention of experimental heart failure: comparison between If-channel blockade and beta-receptor blockade. AB - To investigate whether heart rate reduction via I(f)-channel blockade and beta receptor blockade prevents left ventricular (LV) dysfunction, we studied ivabradine and metoprolol in angiotensin II-induced heart failure. Cardiac dysfunction in C57BL/6J mice was induced by implantation of osmotic pumps for continuous subcutaneous dosing of angiotensin II (1.8 mg/kg per day SC) over a period of 3 weeks. Ivabradine (10 mg/kg per day) and metoprolol (90 mg/kg per day), which resulted in similar heart rate reduction, or placebo treatments were simultaneously started with infusion of angiotensin II. After 3 weeks, LV function was estimated by conductance catheter technique, cardiac remodeling assessed by estimation of cardiac hypertrophy, fibrosis, and inflammatory stress response by immunohistochemistry or PCR, respectively. Compared with controls, angiotensin II infusion resulted in hypertension in impaired systolic (LV contractility, stroke volume, end systolic elastance, afterload, index of arterial-ventricular coupling, and cardiac output; P<0.05) and diastolic (LV relaxation, LV end diastolic pressure, tau, and stiffness constant beta; P<0.05) LV function. This was associated with a significant increase in cardiac hypertrophy and fibrosis. Increased cardiac stress was also indicated by an increase in cardiac inflammation and apoptosis. Both ivabradine and metoprolol led to a similar reduction in heart rate. Metoprolol also reduced systolic blood pressure. Ivabradine led to a significant improvement in systolic and diastolic LV function (P<0.05). This was associated with less cardiac hypertrophy, fibrosis, inflammation, and cardiac apoptosis (P<0.05). Metoprolol treatment did not prevent the reduction in cardiac function and adverse remodeling, despite a reduction of the inflammatory stress response. Behind heart rate reduction, additional beneficial cardiac effects contribute to heart failure prevention with I(f)-channel inhibition. PMID- 22493072 TI - Reduced methylation of the thromboxane synthase gene is correlated with its increased vascular expression in preeclampsia. AB - Preeclampsia is characterized by increased thromboxane and decreased prostacyclin levels, which predate symptoms, and can explain some of the clinical manifestations of preeclampsia, including hypertension and thrombosis. In this study, we examined DNA methylation of the promoter region of the thromboxane synthase gene (TBXAS1) and the expression of thromboxane synthase in systemic blood vessels of normal pregnant and preeclamptic women. Thromboxane synthase is responsible for the synthesis of thromboxane A(2), a potent vasoconstrictor and activator of platelets. We also examined the effect of experimentally induced DNA hypomethylation on the expression of thromboxane synthase in a neutrophil-like cell line (HL-60 cells) and in cultured vascular smooth muscle and endothelial cells. We found that DNA methylation of the TBXAS1 promoter was decreased and thromboxane synthase expression was increased in omental arteries of preeclamptic women as compared with normal pregnant women. Increased thromboxane synthase expression was observed in vascular smooth muscles cells, endothelial cells, and infiltrating neutrophils. Experimentally induced DNA hypomethylation only increased expression of thromboxane synthase in the neutrophil-like cell line, whereas tumor necrosis factor-alpha, a neutrophil product, increased its expression in cultured vascular smooth muscle cells. Our study suggests that epigenetic mechanisms and release of tumor necrosis factor-alpha by infiltrating neutrophils could contribute to the increased expression of thromboxane synthase in maternal systemic blood vessels, contributing to the hypertension and coagulation abnormalities associated with preeclampsia. PMID- 22493073 TI - A double-blind, placebo-controlled, crossover trial comparing the effects of amiloride and hydrochlorothiazide on glucose tolerance in patients with essential hypertension. AB - Hypertension guidelines advise limiting the dose of thiazide diuretics and avoiding combination with beta-blockade, because of increased risk of diabetes mellitus. We tested whether changes in the 2-hour oral glucose tolerance test could be detected after 4 weeks of treatment with a thiazide and could be avoided by switching to amiloride. Two double-blind, placebo-controlled, crossover studies were performed. In study 1 (41 patients), we found that changes in glucose during a 2-hour oral glucose tolerance test could be detected after 4 weeks of treatment with bendroflumethiazide. In study 2, 37 patients with essential hypertension received, in random order, 4 weeks of once-daily treatment with hydrochlorothiazide (HCTZ) 25 to 50 mg, nebivolol 5 to 10 mg, combination (HCTZ 25-50 mg+nebivolol 5-10 mg), amiloride (10-20 mg), and placebo. Each drug was force titrated at 2 weeks and separated by a 4-week placebo washout. At each visit, we recorded blood pressure and performed a 75-g oral glucose tolerance test. Primary outcome was the difference in glucose (over the 2 hours of the oral glucose tolerance test) between 0 and 4 weeks, when HCTZ and amiloride were compared by repeated-measures analysis. For similar blood pressure reductions, there were opposite changes in glucose between the 2 diuretics (P<0.0001). Nebivolol did not impair glucose tolerance, either alone or in combination. There was a negative correlation between Deltapotassium and Delta2-hour glucose (r= 0.28; P<0.0001). In 2 crossover studies, 4 weeks of treatment with a thiazide diuretic impaired glucose tolerance. No impairment was seen with K(+)-sparing diuretic or beta(1)-selective blockade. Substitution or addition of amiloride may be the solution to preventing thiazide-induced diabetes mellitus. PMID- 22493075 TI - Influence of high glycemic index and glycemic load diets on blood pressure during adolescence. AB - We aimed to prospectively examine the association between the glycemic index and glycemic load of foods consumed and the dietary intakes of carbohydrates, sugars, fiber, and principal carbohydrate-containing food groups (eg, breads, cereals, and sugary drinks) with changes in blood pressure during adolescence. A total of 858 students aged 12 years at baseline (422 girls and 436 boys) were examined from 2004-2005 to 2009-2011. Dietary data were assessed from validated semiquantitative food frequency questionnaires. Blood pressure was measured using a standard protocol. In girls, after adjusting for age, ethnicity, parental education, parental history of hypertension, baseline height, baseline blood pressure, change in body mass index, and time spent in physical and sedentary activities, each 1-SD (1-SD = 7.10 g/d) increase in baseline dietary intake of total fiber was associated with a 0.96-, 0.62-, and 0.75-mmHg decrease in mean systolic (P = 0.02), diastolic (P = 0.01), and arterial blood pressures (P = 0.002), respectively, 5 years later. In girls, each 1-SD increase in dietary glycemic index, glycemic load, carbohydrate, and fructose was concurrently related to increases of 1.81 (P = 0.001), 4.02 (P = 0.01), 4.74 (P = 0.01), and 1.80 mm Hg (P = 0.03) in systolic blood pressure, respectively, >5 years. Significant associations between carbohydrate nutrition variables and blood pressure were not observed among boys. Excessive dietary intake of carbohydrates, specifically from high glycemic index/glycemic load foods, could adversely influence blood pressure, particularly in girls, whereas fiber-rich diets may be protective against elevated blood pressure during adolescence. PMID- 22493074 TI - Adipose and height growth through childhood and blood pressure status in a large prospective cohort study. AB - Raised blood pressure (BP) is the world's leading mortality risk factor. Childhood BP substantially predicts adult levels, and although both prenatal and postnatal growth influence it, their relative importance is debated. In a longitudinal study (Avon Longitudinal Study of Parents and Children) of 12 962 healthy children, we aimed to assess the relative contribution of different growth periods and of standardized measures of height versus weight-for-height (an adiposity marker) to BP at age 10 years. Conditional growth modeling was used in the 3230 boys and 3346 girls with BP measurements. Systolic BP was inversely associated with birth weight and weight-for-height but not length (-0.33, -0.27, and -0.12 mm Hg . SD(-1); P=0.003, 0.035, and 0.35, respectively). In infancy, weight, weight-for-height, and height gains were all positively associated with systolic BP (0.90, 0.41, and 0.82 mm Hg . SD(-1), respectively; all P<0.001). After infancy, all of the growth modalities were positively associated with systolic BP (weight, 1.91; weight-for-height, 1.56; height, 1.20 mm Hg . SD(-1); all P<0.001). Similar but weaker associations were found with diastolic BP. Although BP at 10 years was associated with both prenatal and early postnatal growth, their influence was small compared with that of later growth. Because BP ranking relative to the population is substantially determined in the first decade of life, a focus on strategies to reduce the development of adiposity from infancy onward, rather than an emphasis on the nutrition and weight of mothers and infants, should bring greater reductions in population BP. PMID- 22493076 TI - Effects of potassium-sparing versus thiazide diuretics on glucose tolerance: new data on an old topic. PMID- 22493077 TI - Oxidative stress promotes hypertension and albuminuria during the autoimmune disease systemic lupus erythematosus. PMID- 22493078 TI - Heart rate reduction: an old and novel candidate heart failure therapy. PMID- 22493079 TI - TASK-3 channel deletion in mice recapitulates low-renin essential hypertension. AB - Idiopathic primary hyperaldosteronism (IHA) and low-renin essential hypertension (LREH) are common forms of hypertension, characterized by an elevated aldosterone renin ratio and hypersensitivity to angiotensin II. They are suggested to be 2 states within a disease spectrum that progresses from LREH to IHA as the control of aldosterone production by the renin-angiotensin system is weakened. The mechanism(s) that drives this progression remains unknown. Deletion of Twik related acid-sensitive K(+) channels (TASK) subunits, TASK-1 and TASK-3, in mice (T1T3KO) produces a model of human IHA. Here, we determine the effect of deleting only TASK-3 (T3KO) on the control of aldosterone production and blood pressure. We find that T3KO mice recapitulate key characteristics of human LREH, salt sensitive hypertension, mild overproduction of aldosterone, decreased plasma renin concentration with elevated aldosterone:renin ratio, hypersensitivity to endogenous and exogenous angiotensin II, and failure to suppress aldosterone production with dietary sodium loading. The relative differences in levels of aldosterone output and aldosterone:renin ratio and in autonomy of aldosterone production between T1T3KO and T3KO mice are reminiscent of differences in human hypertensive patients with LREH and IHA. Our studies establish a model of LREH and suggest that loss of TASK channel activity may be one mechanism that advances the syndrome of low renin hypertension. PMID- 22493080 TI - Stromal-derived IL-6 alters the balance of myeloerythroid progenitors during Toxoplasma gondii infection. AB - Inflammation alters hematopoiesis, often by decreasing erythropoiesis and enhancing myeloid output. The mechanisms behind these changes and how the BM stroma contributes to this process are active areas of research. In this study, we examine these questions in the setting of murine Toxoplasma gondii infection. Our data reveal that infection alters early myeloerythroid differentiation, blocking erythroid development beyond the Pre MegE stage, while expanding the GMP population. IL-6 was found to be a critical mediator of these differences, independent of hepcidin-induced iron restriction. Comparing the BM with the spleen showed that the hematopoietic response was driven by the local microenvironment, and BM chimeras demonstrated that radioresistant cells were the relevant source of IL-6 in vivo. Finally, direct ex vivo sorting revealed that VCAM(+)CD146(lo) BM stromal fibroblasts significantly increase IL-6 secretion after infection. These data suggest that BMSCs regulate the hematopoietic changes during inflammation via IL-6. PMID- 22493082 TI - Annexin A1 modulates natural and glucocorticoid-induced resolution of inflammation by enhancing neutrophil apoptosis. AB - This study aimed at assessing whether AnxA1, a downstream mediator for the anti inflammatory effects of GCs, could affect the fate of immune cells in tissue exudates, using LPS-induced pleurisy in BALB/c mice. AnxA1 protein expression in exudates was increased during natural resolution, as seen at 48-72 h post-LPS, an effect augmented by treatment with GC and associated with marked presence of apoptotic neutrophils in the pleural exudates. The functional relevance of AnxA1 was determined using a neutralizing antibody or a nonspecific antagonist at FPR/ALXRs: either treatment inhibited both spontaneous and GC-induced resolution of inflammation. Injection of Ac2-26 (100 MUg, given 4 h into the LPS response), an AnxA1-active N-terminal peptide, promoted active resolution and augmented the extent of neutrophil apoptosis. Such an effect was prevented by the pan-caspase inhibitor zVAD-fmk. Mechanistically, resolution of neutrophilic inflammation was linked to cell apoptosis with activation of Bax and caspase-3 and inhibition of survival pathways Mcl-1, ERK1/2, and NF-kappaB. These novel in vivo data, using a dynamic model of acute inflammation, provide evidence that AnxA1 is a mediator of natural and GC-induced resolution of inflammation with profound effects on neutrophil apoptosis. PMID- 22493081 TI - FcgammaRI mediates serum amyloid P inhibition of fibrocyte differentiation. AB - Fibrotic diseases, such as cardiac and pulmonary fibrosis, have a poor prognosis with no FDA approved therapies. Monocyte-derived, fibroblast-like cells, called fibrocytes, participate in the formation of fibrotic lesions. The conserved pentraxin protein SAP inhibits fibrocyte differentiation in cell culture, and injections of SAP significantly reduce fibrosis in several animal models. SAP binds to the receptors for the Fc portion of IgG (FcgammaR) and has been crystallized bound to FcgammaRIIa (CD32a). The in vivo activity of SAP appears to be dependent on the FcRgamma. We find that mutagenesis of the residues critical for SAP binding to FcgammaRIIa only moderately decreases the ability of SAP to inhibit fibrocyte differentiation. In murine cells, deletion of FcRgamma or FcgammaRI (CD64) significantly reduced sensitivity to SAP. Deletion of the combination of FcgammaRIIb, FcgammaRIIIa, and FcgammaRIV did not significantly affect sensitivity to SAP, whereas deletion of just the inhibitory receptor FcgammaRIIb (CD32b) increased sensitivity to SAP. In human cells, siRNA-mediated reduction of FcRgamma or FcgammaRI levels significantly decreased sensitivity to SAP, whereas reduction of FcgammaRIIb levels increased sensitivity to SAP. These observations suggest that SAP, at least in part, uses FcgammaRI and FcRgamma to inhibit fibrocyte differentiation. PMID- 22493083 TI - Perforin- and granzyme-mediated cytotoxic effector functions are essential for protection against Francisella tularensis following vaccination by the defined F. tularensis subsp. novicida DeltafopC vaccine strain. AB - A licensed vaccine against Francisella tularensis is currently not available. Two Francisella tularensis subsp. novicida (herein referred to by its earlier name, Francisella novicida) attenuated strains, the DeltaiglB and DeltafopC strains, have previously been evaluated as potential vaccine candidates against pneumonic tularemia in experimental animals. F. novicida DeltaiglB, a Francisella pathogenicity island (FPI) mutant, is deficient in phagosomal escape and intracellular growth, whereas F. novicida DeltafopC, lacking the outer membrane lipoprotein FopC, which is required for evasion of gamma interferon (IFN-gamma) mediated signaling, is able to escape and replicate in the cytosol. To dissect the difference in protective immune mechanisms conferred by these two vaccine strains, we examined the efficacy of the F. novicida DeltaiglB and DeltafopC mutants against pulmonary live-vaccine-strain (LVS) challenge and found that both strains provided comparable protection in wild-type, major histocompatibility complex class I (MHC I) knockout, and MHC II knockout mice. However, F. novicida DeltafopC-vaccinated but not F. novicida DeltaiglB-vaccinated perforin-deficient mice were more susceptible and exhibited greater bacterial burdens than similarly vaccinated wild-type mice. Moreover, perforin produced by natural killer (NK) cells and release of granzyme contributed to inhibition of LVS replication within macrophages. This NK cell-mediated LVS inhibition was enhanced with anti-F. novicida DeltafopC immune serum, suggesting antibody-dependent cell-mediated cytotoxicity (ADCC) in F. novicida DeltafopC-mediated protection. Overall, this study provides additional immunological insight into the basis for protection conferred by live attenuated F. novicida strains with different phenotypes and supports further investigation of this organism as a vaccine platform for tularemia. PMID- 22493084 TI - Salmonella enterica induces joint inflammation and expression of interleukin-17 in draining lymph nodes early after onset of enterocolitis in mice. AB - In developing countries, one-third of reactive arthritis (ReA) cases are associated with Salmonella enterocolitis; nevertheless, there is no animal model for studying this pathology. Here we induced a self-limiting Salmonella enterica serovar Enteritidis enterocolitis in mice to analyze the onset of ReA. BALB/c mice received orally 20 MUg of streptomycin 24 h before intragastric inoculation of a low dose (3 * 10(3) to 4 * 10(3) CFU) of S. Enteritidis. In response to Salmonella infection, a 30-fold increase in the expression of interleukin-17 (IL 17), measured by quantitative PCR, was observed in mesenteric lymph nodes 5 days postinfection. At this time synovitis was already evident, and concomitantly, a significant increase in joint tumor necrosis factor alpha (TNF-alpha) was detected by enzyme-linked immunosorbent assay (ELISA). The early development of joint lesions was accompanied by an increased expression of IL-17 in inguinal and popliteal lymph nodes. Infection with 10(7) CFU of an isogenic DeltainvG mutant bearing a defective type III secretion system of Salmonella encoded in the pathogenicity island 1 apparatus (TTSS-1) induced enterocolitis histologically similar to that triggered by the wild-type strain. Interestingly, despite the higher infective dose used, the mutant did not trigger intestinal IL-17. Moreover, no synovitis was observed in mice suffering DeltainvG enterocolitis. Neutralization of IL-17 in mice infected with S. Enteritidis prevented both synovitis and the increment of TNF-alpha in the joints, suggesting that IL-17 participates in the generation of Salmonella-induced ReA through the induction of TNF-alpha in the joints. PMID- 22493085 TI - Alterations in the porcine colon microbiota induced by the gastrointestinal nematode Trichuris suis. AB - Helminth parasites ensure their survival by regulating host immunity through mechanisms that dampen inflammation. These properties have recently been exploited therapeutically to treat human diseases. The biocomplexity of the intestinal lumen suggests that interactions between the parasite and the intestinal microbiota would also influence inflammation. In this study, we characterized the microbiota in the porcine proximal colon in response to Trichuris suis (whipworm) infection using 16S rRNA gene-based and whole-genome shotgun (WGS) sequencing. A 21-day T. suis infection in four pigs induced a significant change in the composition of the proximal colon microbiota compared to that of three parasite-naive pigs. Among the 15 phyla identified, the abundances of Proteobacteria and Deferribacteres were changed in infected pigs. The abundances of approximately 13% of genera were significantly altered by infection. Changes in relative abundances of Succinivibrio and Mucispirillum, for example, may relate to alterations in carbohydrate metabolism and niche disruptions in mucosal interfaces induced by parasitic infection, respectively. Of note, infection by T. suis led to a significant shift in the metabolic potential of the proximal colon microbiota, where 26% of all metabolic pathways identified were affected. Besides carbohydrate metabolism, lysine biosynthesis was repressed as well. A metabolomic analysis of volatile organic compounds (VOCs) in the luminal contents showed a relative absence in infected pigs of cofactors for carbohydrate and lysine biosynthesis, as well as an accumulation of oleic acid, suggesting altered fatty acid absorption contributing to local inflammation. Our findings should facilitate development of strategies for parasitic control in pigs and humans. PMID- 22493086 TI - Type VI secretion system-associated gene clusters contribute to pathogenesis of Salmonella enterica serovar Typhimurium. AB - The enteropathogen Salmonella enterica serovar Typhimurium employs a suite of tightly regulated virulence factors within the intracellular compartment of phagocytic host cells resulting in systemic dissemination in mice. A type VI secretion system (T6SS) within Salmonella pathogenicity island 6 (SPI-6) has been implicated in this process; however, the regulatory inputs and the roles of noncore genes in this system are not well understood. Here we describe four clusters of noncore T6SS genes in SPI-6 based on a comparative relationship with the T6SS-3 of Burkholderia mallei and report that the disruption of these genes results in defects in intracellular replication and systemic dissemination in mice. In addition, we show that the expression of the SPI-6-encoded Hcp and VgrG orthologs is enhanced during late stages of macrophage infection. We identify six regions that are transcriptionally active during cell infections and that have regulatory contributions from the regulators of virulence SsrB, PhoP, and SlyA. We show that levels of protein expression are very weak under in vitro conditions and that expression is not enhanced upon the deletion of ssrB, phoP, slyA, qseC, ompR, or hfq, suggesting an unknown activating factor. These data suggest that the SPI-6 T6SS has been integrated into the Salmonella Typhimurium virulence network and customized for host-pathogen interactions through the action of noncore genes. PMID- 22493087 TI - Activation of JNK/c-Jun is required for the proliferation, survival, and angiogenesis induced by EET in pulmonary artery endothelial cells. AB - Pulmonary artery endothelial plexiform lesion is responsible for pulmonary vascular remodeling (PVR), a basic pathological change of pulmonary arterial hypertension (PAH). Recent evidence suggests that epoxyeicosatrienoic acid (EET), which is derived from arachidonic acid by cytochrome p450 (CYP) epoxygenase, has an essential role in PAH. However, until now, most research has focused on pulmonary vasoconstriction; it is unclear whether EET produces mitogenic and angiogenic effects in pulmonary artery endothelial cells (PAEC). Here we found that 500 nM/l 8,9-EET, 11,12-EET, and 14,15-EET markedly augmented JNK and c-Jun activation in PAECs and that the activation of c-Jun was mediated by JNK, but not the ERK or p38 MPAK pathway. Moreover, treatment with 8,9-EET, 11,12-EET, and 14,15-EET promoted cell proliferation and cell-cycle transition from the G0/G1 phase to S phase and stimulated tube formation in vitro. All these effects were reversed after blocking JNK with Sp600125 (a JNK inhibitor) or JNK1/2 siRNA. In addition, the apoptotic process was alleviated by three EET region isomers through the JNK/c-Jun pathway. These observations suggest that 8,9-EET, 11,12 EET, and 14,15-EET stimulate PAEC proliferation and angiogenesis, as well as protect the cells from apoptosis, via the JNK/c-Jun pathway, an important underlying mechanism that may promote PAEC growth and angiogenesis during PAH. PMID- 22493089 TI - Intense exercise and airway hyper-responsiveness/asthma: importance of environmental factors. PMID- 22493088 TI - The use of stable isotope-labeled glycerol and oleic acid to differentiate the hepatic functions of DGAT1 and -2. AB - Diacylglycerol acyltransferase (DGAT) catalyzes the final step in triglyceride (TG) synthesis. There are two isoforms, DGAT1 and DGAT2, with distinct protein sequences and potentially different physiological functions. To date, the ability to determine clear functional differences between DGAT1 and DGAT2, especially with respect to hepatic TG synthesis, has been elusive. To dissect the roles of these two key enzymes, we pretreated HepG2 hepatoma cells with (13)C(3)-D(5) glycerol or (13)C(18)-oleic acid, and profiled the major isotope-labeled TG species by liquid chromatography tandem mass spectrometry. Selective DGAT1 and DGAT2 inhibitors demonstrated that (13)C(3)-D(5)-glycerol-incorporated TG synthesis was mediated by DGAT2, not DGAT1. Conversely, (13)C(18)-oleoyl incorporated TG synthesis was predominantly mediated by DGAT1. To trace hepatic TG synthesis and VLDL triglyceride (VLDL-TG) secretion in vivo, we administered D(5)-glycerol to mice and measured plasma levels of D(5)-glycerol-incorporated TG. Treatment with an antisense oligonucleotide (ASO) to DGAT2 led to a significant reduction in D(5)-glycerol incorporation into VLDL-TG. In contrast, the DGAT2 ASO had no effect on the incorporation of exogenously administered (13)C(18)-oleic acid into VLDL-TG. Thus, our results indicate that DGAT1 and DGAT2 mediate distinct hepatic functions: DGAT2 is primarily responsible for incorporating endogenously synthesized FAs into TG, whereas DGAT1 plays a greater role in esterifying exogenous FAs to glycerol. PMID- 22493090 TI - Economic analysis of physical activity interventions. PMID- 22493091 TI - A to Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance: part 32. PMID- 22493092 TI - The absence of ABCD2 sensitizes mice to disruptions in lipid metabolism by dietary erucic acid. AB - ABCD2 (D2) is a peroxisomal transporter that is highly abundant in adipose tissue and promotes the oxidation of long-chain MUFA. Erucic acid (EA, 22:1omega9) reduces very long chain saturated fatty acids in patients with X-linked adrenoleukodystrophy but promotes dyslipidemia and dilated cardiomyopathy in rats. To determine the role of D2 in the metabolism of EA, we challenged wild type and D2 deficient mice (D2 KO) with an enriched EA diet. In D2 KO mice, dietary EA resulted in the rapid expansion of adipose tissue, adipocyte hypertrophy, hepatic steatosis, and the loss of glycemic control. However, D2 had no impact on the development of obesity phenotypes in two models of diet-induced obesity. Although there was a significant increase in EA in liver of D2 KO mice, it constituted less than 2% of all fatty acids. Metabolites of EA (20:1, 18:1, and 16:1) were elevated, particularly 18:1, which accounted for 50% of all fatty acids. These data indicate that the failure to metabolize EA in adipose results in hepatic metabolism of EA, disruption of the fatty acid profile, and the development of obesity and reveal an essential role for D2 in the protection from dietary EA. PMID- 22493093 TI - Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. AB - The manner in which insulin resistance impinges on hepatic mitochondrial function is complex. Although liver insulin resistance is associated with respiratory dysfunction, the effect on fat oxidation remains controversial, and biosynthetic pathways that traverse mitochondria are actually increased. The tricarboxylic acid (TCA) cycle is the site of terminal fat oxidation, chief source of electrons for respiration, and a metabolic progenitor of gluconeogenesis. Therefore, we tested whether insulin resistance promotes hepatic TCA cycle flux in mice progressing to insulin resistance and fatty liver on a high-fat diet (HFD) for 32 weeks using standard biomolecular and in vivo (2)H/(13)C tracer methods. Relative mitochondrial content increased, but respiratory efficiency declined by 32 weeks of HFD. Fasting ketogenesis became unresponsive to feeding or insulin clamp, indicating blunted but constitutively active mitochondrial beta-oxidation. Impaired insulin signaling was marked by elevated in vivo gluconeogenesis and anaplerotic and oxidative TCA cycle flux. The induction of TCA cycle function corresponded to the development of mitochondrial respiratory dysfunction, hepatic oxidative stress, and inflammation. Thus, the hepatic TCA cycle appears to enable mitochondrial dysfunction during insulin resistance by increasing electron deposition into an inefficient respiratory chain prone to reactive oxygen species production and by providing mitochondria-derived substrate for elevated gluconeogenesis. PMID- 22493094 TI - AMPK activation with glabridin ameliorates adiposity and lipid dysregulation in obesity. AB - In this study, we demonstrate that activation of AMP-activated protein kinase (AMPK) with glabridin alleviates adiposity and hyperlipidemia in obesity. In several obese rodent models, glabridin decreased body weight and adiposity with a concomitant reduction in fat cell size. Further, glabridin ameliorated fatty liver and plasma levels of triglyceride and cholesterol. In accordance with these findings, glabridin suppressed the expression of lipogenic genes such as sterol regulatory element binding transcription factor (SREBP)-1c, fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase (SCD)-1 in white adipose tissues and liver, whereas it elevated the expression of fatty acid oxidation genes such as carnitine palmitoyl transferase (CPT)1, acyl-CoA oxidase (ACO), and peroxisome proliferator-activated receptor (PPAR)alpha in muscle. Moreover, glabridin enhanced phosphorylation of AMPK in muscle and liver and promoted fatty acid oxidation by modulating mitochondrial activity. Together, these data suggest that glabridin is a novel AMPK activator that would exert therapeutic effects in obesity-related metabolic disorders. PMID- 22493095 TI - Dynamically regulated sumoylation of HDAC2 controls p53 deacetylation and restricts apoptosis following genotoxic stress. AB - Histone deacetylase 2 (HDAC2) is relevant for homeostasis and plays a critical role in gastrointestinal cancers. Here, we report that post-translational modification of endogenous HDAC2 with small ubiquitin-related modifier 1 (SUMO1) is a new regulatory switch for the tumor suppressor p53. Sumoylation of HDAC2 at lysine 462 allows binding of HDAC2 to p53. Moreover, sumoylated HDAC2 is a previously not recognized biologically relevant site-specific deacetylase for p53. Deacetylation of p53 at lysine 320 by sumoylated HDAC2 blocks recruitment of p53 into promoter-associated complexes and p53-dependent expression of genes for cell cycle control and apoptosis. Thereby, catalytically active sumoylated HDAC2 restricts p53 functions and attenuates DNA damage-induced apoptosis. Genotoxic stress evokes desumoylation of HDAC2, enabling p53-dependent gene expression. Our data show a new molecular mechanism involving a dynamically controlled HDAC2 sumoylation/p53-acetylation switch that regulates cell fate decisions following genotoxic stress. PMID- 22493096 TI - Isolated gonococcal ascending aorta aneurysm. AB - We present a very rare case of an acute septic infection and vegetative mycotic aneurysm caused by Neisseria gonorrhoeae in a 52-year old male. The aortic valve was bicuspid and calcified. He was successfully treated by the resection of the ascending aorta and the aortic valve with a replacement by separate prostheses, followed by 2 weeks of intravenous antibiotic therapy. The patient was followed up 18 months postoperatively with no signs of reinfection. PMID- 22493097 TI - Optimal thromboprophylaxis following bioprosthetic aortic valve replacement: still a matter of debate? AB - Optimal thromboprophylaxis following bioprosthetic aortic valve replacement (AVR) remains controversial. The main objective, which is the effective prevention of central nervous or peripheral embolic events, especially in the early postoperative period, will have to be weighed against the haemorrhagic risk that is associated with the utilization of different antithrombotic regimes. Most governing bodies in cardiovascular medicine have issued recommendations on thromboprophylaxis after the surgical implantation of aortic bioprostheses. However, the level of evidence to support these recommendations remains low, largely due to the inherent limitations of conducting appropriately randomized and adequately powered clinical research in this area. It is apparent from the recent surveys and large registries that there is a great variability in antithrombotic practice at an institutional or individual-clinician level reflecting this controversy and the lack of robust evidence. While organizational, financial or conceptual limitations could hinder the conduct and availability of conclusive research on optimal thromboprophylaxis after aortic bioprosthesis, it is imperative that all evidence is presented in a systematic way in order to assist the decision-making for the modern clinician. In this review, we provide an outline of the current recommendations for thromboprophylaxis, followed by a comprehensive and analytical presentation of all comparative studies examining anticoagulation vs. antiplatelet therapy after bioprosthetic AVR. PMID- 22493098 TI - Effects of vascular photodynamic therapy in a newly adapted experimental rat aortic aneurysm model. AB - The hypothesis driving this study was that photodynamic therapy (PDT) may limit abdominal aortic aneurysm growth due to matrix changes. The aortas of 12 rats were incubated with elastase using a newly modified experimental aneurysm model (3.5 mg/ml). Rats were allocated to an elastase-only group (n = 6) to study the elastase-induced aneurysm growth and an elastase +/- PDT group to evaluate if PDT limited aneurysm growth (n = 6). PDT was performed with the photosensitizer methylene blue, and thermoneutral laser light (660 nm) was applied (120 J/cm(2), 100 mW/cm(2)) using a diode laser. Four untreated rats served as controls. The arteries were analysed after 4 weeks based on histology, immunohistochemistry and morphometry. This modified rat elastase model led to reproducible aneurysm development with no elastase-induced mortality compared with control animals (circumference, controls: 2.9 +/- 0.2 vs. elastase: 5.5 +/- 0.9 mm; P < 0.01). PDT after elastase incubation did not inhibit inflammatory cell infiltration. No significant change in the circumference was observed between elastase incubation and PDT treatment after elastase incubation (circumference, elastase: 5.5 +/- 0.9 vs. elastase and PDT: 6.1 +/- 0.8 mm; P < 0.01). Despite a PDT-induced resistance to protease digestion, PDT did not reduce aortic dilatation in the elastase treated rat aorta. These findings suggest that PDT may not be a useful modality to prevent aneurysm growth. PMID- 22493099 TI - Outcomes following redo sternotomy for aortic surgery. AB - Proximal thoracic aortic reconstruction performed with or without hypothermic circulatory arrest (HCA) is an effective surgical strategy for aortic pathology. In this study, the clinical outcomes of patients undergoing reoperative proximal thoracic aortic surgery were evaluated. A retrospective review was performed for reoperative proximal aortic surgery from 2004 to date. Patient data were abstracted from the society of thoracic surgeons (STS) institutional database and patient charts. Univariate analysis was conducted on the HCA group in order to determine the impact of variables on in-hospital mortality. Kaplan-Meier survival estimates were calculated for long-term survival analysis. One hundred and twenty two patients were included in the analysis. Twenty-seven (22.1%) were female, and the mean age was 53.8 years. Seventy-seven (63.1%) patients had an aortic root replacement, and 93 (76.2%) patients underwent aortic arch replacement. Circulatory arrest was performed in 92 (75.4%) patients. Operative mortality occurred in 14 patients (11.5%). Complications included re-exploration for haemorrhage (nine patients, 7.4%), stroke (four, 3.3%), renal failure (13, 10.7%) and major adverse events (18, 14.8%). Univariate and multivariate analyses of HCA patients showed cardiopulmonary bypass (CPB) time, preoperative renal failure and prior coronary revascularization as independent predictors of mortality. Reoperative proximal aortic surgery can be performed with acceptable morbidity and mortality. These data also suggest that HCA represents a safe operative strategy for this patient population. PMID- 22493100 TI - Early graft failure after heart transplant: risk factors and implications for improved donor-recipient matching. AB - Early graft failure (EGF) is a dreaded complication after heart transplantation (HT). Despite several improvements, no effective therapy has been developed and the prognosis is poor. We evaluated the risk factors and clinical impact of EGF. In a consecutive series of 317 HTs performed at a single institution between January 1999 and December 2008, variables associated significantly with EGF were sought in bivariate and multivariable discriminant analyses. The deriving propensity score was used to stratify the study sample in to three groups (low, intermediate and high risk for EGF). Comparisons were performed between the higher-risk group and the remaining population in terms of preoperative features and outcomes. EGF occurred in 10.1% of the overall population (2.9, 3.8 and 23.6%, respectively, in the three groups). Overall, EGF-related mortality was 56.3% (100, 75 and 48%, respectively, in the three groups). Determinants of EGF in the highest-risk group were: redo procedure, valvular cardiomyopathy, status one at transplant, recipient male sex, donor-recipient (D/R) weight mismatch, high inotropic donor support, ischaemic time and first day troponin I release. In conclusion, several donor and recipient features predicted EGF. Since such characteristics are not readily modifiable but synergistically determine the occurrence of EGF, optimization of D/R matching is crucial to prevent it. PMID- 22493101 TI - Remote ischaemic preconditioning does not protect the heart in patients undergoing coronary artery bypass grafting. AB - Remote ischaemic preconditioning (RIPC) gained attention as a possibility to reduce myocardial injury after a subsequent sustained episode of myocardial ischaemia. This prospective randomized study was carried out to assess whether RIPC reduces myocardial injury in coronary artery bypass grafting patients. Eighty patients were assigned to remote preconditioning or control treatment. Ischaemic preconditioning was induced by three 5-min cycles of upper limb ischaemia and reperfusion after anaesthesia induction. Haemodynamic and markers of myocardial damage were analysed preoperatively and over 48 h postoperatively. The cardiac index was higher immediately after remote preconditioning in the main group. There were no differences in other haemodynamic, troponin I and creatine kinase-MB concentrations at any time point between groups. Thus, short-term remote preconditioning improves haemodynamics and does not reduce myocardial injury after coronary artery bypass surgery. Further study of high-risk patients may be needed to fully evaluate the clinical effect of RIPC. PMID- 22493102 TI - The role of wild mammals in the maintenance of Rift Valley fever virus. AB - Rift Valley fever virus (RVFV) is a zoonotic arbovirus affecting primarily domestic ruminants and humans. Numerous vector species are known or implicated in the transmission of RVFV. The role of mammals in the maintenance of RVFV, and the existence of a wild mammal reservoir in the epidemiologic cycle of RVFV, remain largely unknown. Our objective is to present a detailed review of studies undertaken on RVFV, often associated with wild mammals, with the aim of focusing future research on potential reservoirs of the virus. Natural and experimental infections related to RVFV in several mammalian orders, including Artiodactyla, Chiroptera, Rodentia, Primata (nonhuman), Perissodactyla, Carnivora, Proboscidea, Erinaceomorpha, and Lagomorpha, are reviewed; the first four orders have received the greatest attention. The possible role of wild ruminants, especially African buffalo (Syncerus caffer), is also discussed. Conflicting results have been published concerning rodents but, based on the literature, the likely candidate species include the African genera Arvicanthis and Micaelamys and the widely introduced roof rat (Rattus rattus). Members of the orders Chiroptera and Rodentia should receive greater attention associated with new research programs. For the other orders mentioned above, few data are available. We are unaware of any investigation concerning the orders Afrosoricida and Soricomorpha, which are represented in the geographic area of RVFV and can be abundant. As a first step to resolve the question of wild mammals as a reservoir of RVFV, serologic and virologic surveys should be promoted during epizootic periods to document infected wild animals and, in the case of positive results, extended to interepidemic periods to explore the role of wild animals as possible reservoirs. PMID- 22493103 TI - Ecology of rodent-associated hantaviruses in the Southern Cone of South America: Argentina, Chile, Paraguay, and Uruguay. AB - Thirteen hantavirus genotypes, associated with at least 12 sigmodontine reservoir rodents, have been recognized in the four countries that represent the Southern Cone of South America. Host-virus relationships are not as well defined as in North America; several Southern Cone hantaviruses appear to share a common host and some viruses do not occur throughout the range of their host. Although hantavirus-host relationships in the Southern Cone are less strictly concordant with the single-host-single-virus pattern reported elsewhere, recent studies suggest that much of the ambiguity may result from an incomplete understanding of host and hantavirus systematics. Although some Southern Cone host species are habitat generalists, some sympatric species are habitat specialists, helping to explain how some strict host-virus pairings may be maintained. In some cases, host population densities were higher in peridomestic habitats and prevalence of hantavirus infection was higher in host populations in peridomestic habitats. Seasonal and multiyear patterns in climate and human disturbance affect host population densities, prevalence of infection, and disease risk to humans. Unusually high hantavirus antibody prevalence in indigenous human populations may be associated with frequent and close contact with host rodents. Ongoing studies are improving our understanding of hantavirus-host ecology and providing tools that may predict human risk. PMID- 22493104 TI - Factors affecting hematology and plasma biochemistry in the southwest carpet python (Morelia spilota imbricata). AB - Despite increased worldwide popularity of keeping reptiles as pets, we know little about hematologic and biochemical parameters of most reptile species, or how these measures may be influenced by intrinsic and extrinsic factors. Blood samples from 43 wild-caught pythons (Morelia spilota imbricata) were collected at various stages of a 3-yr ecological study in Western Australia. Reference intervals are reported for 35 individuals sampled at the commencement of the study. As pythons were radiotracked for varying lengths of time (radiotransmitters were surgically implanted), repeated sampling was undertaken from some individuals. However, because of our ad hoc sampling design we cannot be definitive about temporal factors that were most important or that exclusively influenced blood parameters. There was no significant effect of sex or the presence of a hemogregarine parasite on blood parameters. Erythrocyte measures were highest for pythons captured in the jarrah forest and at the stage of radiotransmitter implantation, which was also linked with shorter time in captivity. Basophil count, the only leukocyte influenced by the factors tested, was highest when the python was anesthetized, as was globulin concentration. Albumin and the albumin:globulin ratio were more concentrated in summer (as was phosphorous) and at the initial stage of radiotransmitter placement (as was calcium). No intrinsic or extrinsic factors influenced creatinine kinase, aspartate aminotransferase, uric acid, or total protein. This study demonstrates that factors including season, location, surgical radiotransmitter placement, and anesthetic state can influence blood parameters of M. s. imbricata. For accurate diagnosis, veterinarians should be aware that the current reference intervals used to identify the health status of individuals for this species are outdated and the interpretation and an understanding of the influence of intrinsic and extrinsic factors are limited. PMID- 22493105 TI - Baseline health parameters and species comparisons among free-ranging Atlantic sharpnose (Rhizoprionodon terraenovae), bonnethead (Sphyrna tiburo), and spiny dogfish (Squalus acanthias) sharks in Georgia, Florida, and Washington, USA. AB - Sharks are of commercial, research, conservation, and exhibition importance but we know little regarding health parameters and population status for many species. Here we present health indicators and species comparisons for adults of three common wild-caught species: 30 Atlantic sharpnose sharks (Rhizoprionodon terraenovae) and 31 bonnethead sharks (Sphyrna tiburo) from the western Atlantic, and 30 spiny dogfish sharks (Squalus acanthias) from the eastern Pacific. All animals were captured during June-July 2009 and 2010. Median values and preliminary reference intervals were calculated for hematology, plasma biochemistry, trace nutrients, and vitamin A, E, and D concentrations. Significant differences, attributable to physiologic differences among the species, were found in the basic hematologic and plasma biochemistry variables. Significant species differences in arsenic and selenium plasma concentrations were found and appear to coincide with diet and habitat variability among these three species. Vitamin E was significantly higher in the bonnethead shark, again related to the foraging ecology and ingestion of plant material by this species. The Atlantic sharpnose had significantly higher vitamin A concentrations, supported by the higher proportion of teleosts in the diet. Vitamin D was below the limit of quantification in all three species. These preliminary reference intervals for health variables can be used to assess and monitor the population health and serve as indicators of nutritional status in these populations of wild elasmobranchs. PMID- 22493106 TI - Hematology and plasma biochemistry values for the giant garter snake (Thamnophis gigas) and valley garter snake (Thamnophis sirtalis fitchi) in the Central Valley of California. AB - Hematology and plasma biochemistry parameters are useful in the assessment and management of threatened and endangered species. Although reference ranges are readily available for many mammalian species, reference ranges for snakes are lacking for most species. We determined hematology and plasma biochemistry reference ranges for giant garter snakes (Thamnophis gigas) and valley garter snakes (Thamnophis sirtalis fitchi) living in four management areas in the Central Valley of California. White blood cell, heterophil, lymphocyte, and azurophil counts in giant garter snakes were approximately twice the values of valley garter snakes. Statistically significant differences in aspartate aminotransferase, globulin, and potassium between the two species did not appear clinically significant. No significant differences were found in the measured parameters between male and female giant garter snakes. Some differences were found among collection sites. These reference ranges provide baseline data for comparisons over time and between collection sites. PMID- 22493107 TI - Hematologic and serum biochemical values of gravid freshwater Australian Chelonians. AB - Hematologic and serum biochemical analyses were performed on 30 wild-caught, gravid, Australian freshwater chelonians. Species sampled were western long necked turtles (Chelodina oblonga; n = 13), common long-necked turtles (Chelodina longicollis; n = 8), and Murray River turtles (Emydura macquarii; n = 9). Turtles were obtained from Lake Goolellal in Perth, Western Australia (C. oblonga), and Lake Coranderrk in Healesville, Victoria (C. longicollis and E. macquarii). All turtles were considered healthy at the time of sample collection. Blood results were similar to those reported in other freshwater chelonians, with the exception of elevated calcium levels in all species. Hypercalcemia was attributed to egg development and maturation. A hemoparasite morphologically resembling Haemogregarina clelandi was found in all C. oblonga samples and in four C. longicollis samples. Infection with H. clelandi appeared to have no physiological effects on blood parameters or morphometrics of infected turtles. Blood parameters were also considered poor indicators of female chelonian morphometrics and fecundity. PMID- 22493108 TI - Avian influenza virus infection dynamics in shorebird hosts. AB - To gain insight into avian influenza virus (AIV) transmission, exposure, and maintenance patterns in shorebirds at Delaware Bay during spring migration, we examined temporal AIV prevalence trends in four Charadriiformes species with the use of serial cross-sectional data from 2000 through 2008 and generalized linear and additive models. Prevalence of AIV in Ruddy Turnstones (Arenaria interpres morinella) increased after arrival, peaked in mid-late May, and decreased prior to departure. Antibody prevalence also increased over this period; together, these results suggested local infection and recovery prior to departure. Red Knots (Calidris canutus rufa), Sanderlings (Calidris alba), and Laughing Gulls (Leucophaeus atricilla) were rarely infected, but dynamic changes in antibody prevalence differed among species. In Red Knots, declining antibody prevalence over the stopover period suggested AIV exposure prior to arrival at Delaware Bay with limited infection at this site. Antibody prevalence was consistently high in Laughing Gulls and low in Sanderlings. Both viral prevalence and antibody prevalence in Sanderlings varied directly with those in turnstones, suggesting virus spillover to Sanderlings. Results indicate that, although hundreds of thousands of birds concentrate at Delaware Bay during spring, dynamics of AIV infection differ among species, perhaps due to differences in susceptibility, potential for contact with AIV at this site, or prior exposure. Additionally, Ruddy Turnstones possibly act as a local AIV amplifying host rather than a reservoir. PMID- 22493109 TI - Ecology and geography of human monkeypox case occurrences across Africa. AB - As ecologic niche modeling (ENM) evolves as a tool in spatial epidemiology and public health, selection of the most appropriate and informative environmental data sets becomes increasingly important. Here, we build on a previous ENM analysis of the potential distribution of human monkeypox in Africa by refining georeferencing criteria and using more-diverse environmental data to identify environmental parameters contributing to monkeypox distributional ecology. Significant environmental variables include annual precipitation, several temperature-related variables, primary productivity, evapotranspiration, soil moisture, and pH. The potential distribution identified with this set of variables was broader than that identified in previous analyses but does not include areas recently found to hold monkeypox in southern Sudan. Our results emphasize the importance of selecting the most appropriate and informative environmental data sets for ENM analyses in pathogen transmission mapping. PMID- 22493111 TI - Effects of chronic wasting disease on reproduction and fawn harvest vulnerability in Wisconsin white-tailed deer. AB - Chronic wasting disease (CWD) is a fatal, transmissible spongiform encephalopathy that affects free-ranging and captive North American cervids. Although the impacts of CWD on cervid survival have been documented, little is known about the disease impacts on reproduction and recruitment. We used genetic methods and harvest data (2002-04) to reconstruct parentage for a cohort of white-tailed deer (Odocoileus virginianus) fawns born in spring 2002 and evaluate the effects of CWD infection on reproduction and fawn harvest vulnerability. There was no difference between CWD-positive and CWD-negative male deer in the probability of being a parent. However, CWD-positive females were more likely to be parents than CWD-negative females. Because our results are based on harvested animals, we evaluated the hypothesis that higher parentage rates occurred because fawns with CWD-positive mothers were more vulnerable to harvest. Male fawns with CWD positive mothers were harvested earlier (>1 mo relative to their mother's date of harvest) and farther away from their mothers than male fawns with CWD-negative mothers. Male fawns with CWD-positive mothers were also harvested much earlier and farther away than female fawns from CWD-positive mothers. Most female fawns (86%) with CWD-positive mothers were harvested from the same section as their mothers, while almost half of male and female fawns with CWD-negative mothers were farther away. We conclude that preclinical stages of CWD infection do not prohibit white-tailed deer from successfully reproducing. However, apparently higher harvest vulnerability of male fawns with CWD-positive mothers suggests that CWD infection may make females less capable of providing adequate parental care to ensure the survival and recruitment of their fawns. PMID- 22493110 TI - Prediction of Peromyscus maniculatus (deer mouse) population dynamics in Montana, USA, using satellite-driven vegetation productivity and weather data. AB - Deer mice (Peromyscus maniculatus) are the main reservoir host for Sin Nombre virus, the primary etiologic agent of hantavirus pulmonary syndrome in North America. Sequential changes in weather and plant productivity (trophic cascades) have been noted as likely catalysts of deer mouse population irruptions, and monitoring and modeling of these phenomena may allow for development of early warning systems for disease risk. Relationships among weather variables, satellite-derived vegetation productivity, and deer mouse populations were examined for a grassland site east of the Continental Divide and a sage-steppe site west of the Continental Divide in Montana, USA. We acquired monthly deer mouse population data for mid-1994 through 2007 from long-term study sites maintained for monitoring changes in hantavirus reservoir populations, and we compared these with monthly bioclimatology data from the same period and gross primary productivity data from the Moderate Resolution Imaging Spectroradiometer sensor for 2000-06. We used the Random Forests statistical learning technique to fit a series of predictive models based on temperature, precipitation, and vegetation productivity variables. Although we attempted several iterations of models, including incorporating lag effects and classifying rodent density by seasonal thresholds, our results showed no ability to predict rodent populations using vegetation productivity or weather data. We concluded that trophic cascade connections to rodent population levels may be weaker than originally supposed, may be specific to only certain climatic regions, or may not be detectable using remotely sensed vegetation productivity measures, although weather patterns and vegetation dynamics were positively correlated. PMID- 22493112 TI - Black-backed jackal exposure to rabies virus, canine distemper virus, and Bacillus anthracis in Etosha National Park, Namibia. AB - Canine distemper virus (CDV) and rabies virus (RABV) occur worldwide in wild carnivore and domestic dog populations and pose threats to wildlife conservation and public health. In Etosha National Park (ENP), Namibia, anthrax is endemic and generates carcasses frequently fed on by an unusually dense population of black backed jackals (Canis mesomelas). Using serology, phylogenetic analyses (on samples obtained from February 2009-July 2010), and historical mortality records (1975-2011), we assessed jackal exposure to Bacillus anthracis (BA; the causal bacterial agent of anthrax), CDV, and RABV. Prevalence of antibodies against BA (95%, n = 86) and CDV (71%, n = 80) was relatively high, while that of antibodies against RABV was low (9%, n = 81). Exposure to BA increased significantly with age, and all animals >6 mo old were antibody-positive. As with BA, prevalence of antibodies against CDV increased significantly with age, with similar age specific trends during both years of the study. No significant effect of age was found on the prevalence of antibodies against RABV. Three of the seven animals with antibodies against RABV were monitored for more than 1 yr after sampling and showed no signs of active infection. Mortality records revealed that rabid animals are destroyed nearly every year inside the ENP tourist camps. Phylogenetic analyses demonstrated that jackal RABV in ENP is part of the same transmission cycle as other dog-jackal RABV cycles in Namibia. PMID- 22493114 TI - Temporal association between land-based runoff events and California sea otter (Enhydra lutris nereis) protozoal mortalities. AB - Toxoplasma gondii and Sarcocystis neurona have caused significant morbidity and mortality in threatened Southern sea otters (Enhydra lutris nereis) along the central California coast. Because only terrestrial animals are known to serve as definitive hosts for T. gondii and S. neurona, infections in otters suggest a land to sea flow of these protozoan pathogens. To better characterize the role of overland runoff in delivery of terrestrially derived fecal pathogens to the near shore, we assessed the temporal association between indicators of runoff and the timing of sea otter deaths due to T. gondii and S. neurona. Sea otter stranding records 1998-2004, from Monterey and Estero bays were reviewed and cases identified for which T. gondii or S. neurona were determined to be a primary or contributing cause of death. Precipitation and stream flow data from both study sites were used as indicators of land-based runoff. Logistic regression was applied to determine if a temporal association could be detected between protozoal mortalities and runoff indicators that occur in the 2 mo preceding mortality events. A significant association was found between S. neurona otter deaths at Estero Bay and increased stream flow that occurred 30-60 days prior to mortality events. At this site, the cause of otter mortality following increased river flows was 12 times more likely to be S. neurona infection compared with nonprotozoal causes of death. There were no significant associations between the timing of T. gondii otter deaths and indicators of overland runoff. Our results indicate that the association between overland runoff and otter mortalities is affected by geography as well as parasite type, and highlight the complex mechanisms that influence transmission of terrestrially derived pathogens to marine wildlife. Policy and management practices that aim to mitigate discharges of contaminated overland runoff can aid conservation efforts by reducing pathogen pollution of coastal waters, which impacts the health of threatened marine wildlife and humans. PMID- 22493113 TI - Detection of avian influenza viruses from shorebirds: evaluation of surveillance and testing approaches. AB - Although influenza A viruses have been isolated from numerous shorebird species (Family: Scolopacidae) worldwide, our understanding of natural history of these viruses in this diverse group is incomplete. Gaining this information can be complicated by sampling difficulties related to live capture, the need for large sample sizes related to a potentially low prevalence of infection, and the need to maintain flexibility in diagnostic approaches related to varied capabilities and resources. To provide information relevant to improving sampling and testing of shorebirds for influenza A viruses, we retrospectively evaluated a combined data set from Delaware Bay, USA, collected from 2000 to 2009. Our results indicate that prevalence trends and subtype diversity can be effectively determined by either direct sampling of birds or indirect sampling of feces; however, the extent of detected subtype diversity is a function of the number of viruses recovered during that year. Even in cases where a large number of viruses are identified, an underestimate of true subtype diversity is likely. Influenza A virus isolation from Ruddy Turnstones can be enhanced by testing both cloacal and tracheal samples, and matrix real-time PCR can be used as an effective screening tool. Serologic testing to target species of interest also has application to shorebird surveillance. Overall, all of the sampling and diagnostic approaches have utility as applied to shorebird surveillance, but all are associated with inherent biases that need to be considered when comparing results from independent studies. PMID- 22493115 TI - Heterogeneity in levels of serum neutralizing antibodies against viral hemorrhagic septicemia virus genotype IVB among fish species in Lake St. Clair, Michigan, USA. AB - The presence of neutralizing antibodies against viral hemorrhagic septicemia virus (VHSV-IVb) was investigated in sera of 13 fish species collected from Lake St. Clair, Michigan, USA, a VHSV-endemic water body. We tested 297 sera collected May 2004-June of 2010, using a complement-dependent 50% plaque neutralization test (50% PNT). Neutralizing antibodies were detected in 23% (67/297) of the samples. The highest overall antibody prevalence (85%, 34/40) and mean positive antibody titer (12,113 +/- 11,699 SD) were detected in muskellunge (Esox masquinongy). Antibodies were also detected in 50% (15/30) of sampled northern pike (E. lucius), 25% (15/61) of freshwater drum (Aplodinotus grunniens), and 7% (3/41) of smallmouth bass (Micropterus dolomieu). All sera from channel catfish (Ictalurus punctatus), lake sturgeon (Acipenser fulvescens), quillback (Carpiodes cyprinus), rock bass (Ambloplites rupestris), shorthead redhorse (Moxostoma macrolepidotum), silver redhorse (M. anisurum), walleye (Sander vitreus), white perch (Morone americana), and yellow perch (Perca flavescens) were negative. Antibodies in one or more fish species were detected in all sampling years (2004, 2006, 2007, 2009, and 2010), whereas in parallel sampling periods, VHS virus was detected only in 2006 and 2009. Our results suggest the continued presence of VHSV-IVb in the Lake St. Clair ecosystem, and underscore the importance of assessing immune responses of fish populations to determine prior virus exposure. PMID- 22493116 TI - Antibody prevalence and molecular identification of Babesia spp. In roe deer in France. AB - In a region-wide serologic study carried out in 2004 on free-ranging hunted roe deer in various landscapes, we found that 58% of the animals (237 out of 406) were antibody positive for Babesia divergens antigen. Serologic and infection status was also analyzed for 327 roe deer live-trapped in two fenced forest areas over 5 yr (2004-08). For two consecutive years during this period, 92 and 94% of the deer in these closed populations were antibody-positive for B. divergens. Babesia spp. were isolated in autologous red blood cell culture for 131 of the trapped animals (40%). Molecular typing was done on 76 isolates with polymerase chain reaction (PCR)-restriction fragment length polymorphism methods targeted at the 18S ribosomal subunit gene (18 isolates) and the Bd37 gene coding for a merozoite surface antigen implicated in a protective response (60 isolates). Results indicated continuous cocirculation of B. capreoli and B. venatorum in both forests and possible coinfection of animals with both species. No infection with B. divergens was detected. Fifteen isolates were confirmed to be B. capreoli by sequencing part of the 18S rRNA gene. Using PCR detection of the Bd37 gene, all nine isolates of B. venatorum in this study were negative, whereas the 15 confirmed and 50 putative B. capreoli isolates showed very variable restriction profiles, distinct from those known for Bd37 in B. divergens. Two isolates showed conflicting results, suggestive of mixed infection. PMID- 22493117 TI - Detection of PrPCWD in feces from naturally exposed Rocky Mountain elk (Cervus elaphus nelsoni) using protein misfolding cyclic amplification. AB - Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy affecting captive and free-ranging cervids. Currently, tests for CWD in live animals involve relatively invasive procedures to collect lymphoid tissue biopsies and examine them for CWD-associated, protease-resistant cervid prion protein (PrP(CWD)) detected by immunohistochemistry (IHC). We adapted an ultrasensitive prion detection system, protein misfolding cyclic amplification (PMCA), to detect PrP(CWD) in Rocky Mountain elk (Cervus elaphus nelsoni) feces. Our PMCA reproducibly detected a 1.2 * 10(7) dilution of PrP(CWD) (a 10% infected brain homogenate diluted 1.2 * 10(6)-fold into 10% fecal homogenates), equivalent to approximately 100 pg of PrP(CWD)/g of feces. We developed a semiquantitative scoring system based on the first PMCA round at which PrP(CWD) was detected and fit a nonlinear regression curve to our serial dilutions to correlate PMCA scores with known PrP(CWD) concentrations. We used this PMCA scoring system to detect PrP(CWD) and estimate its concentration in feces from free-ranging elk from Rocky Mountain National Park, Colorado. We compared our results to PrP(CWD) IHC of rectoanal mucosa-associated lymphoid tissue and obex from the same animals. The PMCA successfully detected PrP(CWD) in feces from elk that were positive by IHC, with estimated prion loads from 100 to 5,000 pg PrP(CWD)/g of feces. These data show for the first time PrP(CWD) in feces from naturally exposed free-ranging elk and demonstrate the potential of PMCA as a new, noninvasive CWD diagnostic tool to complement IHC. PMID- 22493118 TI - Field immobilization of feral 'Judas' donkeys (Equus asinus) by remote injection of medetomidine and ketamine and antagonism with atipamezole. AB - The Judas technique is a method used for landscape control of feral donkeys (Equus asinus) in northern Australia. Central to the success of any Judas program is the safe, efficient, and humane attachment of the telemetry device. For feral donkeys, this involves the use of field immobilization. We examine the replacement of the current chemical capture agent, succinylcholine, with contemporary immobilization agents to achieve positive animal welfare outcomes. A combination of medetomidine and ketamine delivered by remote injection from a helicopter was used to capture 14 free-ranging feral donkeys for the fitting of telemetry collars in Western Australia in November 2010. Dose rates of 0.14 mg/kg medetomidine and 4.1 mg/kg ketamine were appropriate to immobilize animals in 9 min (+/- SD = 3). Mean recovery time (total time in recumbency) was 21 min (+/- 14). All animals recovered uneventfully after being administered atipamezole, a specific antagonist of medetomidine, intramuscularly at 0.35 mg/kg. Physiologic parameters were recorded during recumbency, with environment-related hyperthermia being the only abnormality recognized. No significant complications were encountered, and this drug combination represents an efficient approach to capturing wild donkeys. This new method allows a rapid, safe, cost-effective approach to the immobilization of feral donkeys for use as Judas animals. This drug combination will replace the relatively inhumane succinylcholine for the field immobilization of feral donkeys. PMID- 22493119 TI - Bait trapping linked to higher avian influenza virus detection in wild ducks. AB - In 2007, we assessed whether trapping method influenced apparent prevalence of low pathogenic avian influenza viruses (AIV) in wild ducks sampled during Canada's Inter-agency Wild Bird Influenza Survey. Combined cloacal and oropharyngeal swabs were collected from 514 ducks captured by bait trapping (356) and netting from airboats (158), and tested by real-time reverse transcriptase polymerase chain reaction for influenza type A viruses. When controlling for species and capture site, ducks caught in bait traps were 2.6 times more likely to test positive for AIV compared with those netted from airboats (95% CI=1.2 6.0). If bait trapping increases AIV transmission among artificially aggregated ducks, this could have important implications for interpretation of disease surveillance results and waterfowl management programs. PMID- 22493120 TI - Detection of Mycoplasma ovipneumoniae and M. arginini in bighorn sheep using enrichment culture coupled with genus- and species-specific polymerase chain reaction. AB - Mycoplasma species are of interest as possible primary pathogens in the pneumonia complex of bighorn sheep (Ovis canadensis). Previous investigations have not commonly detected low frequencies of Mycoplasma spp. from free-ranging bighorn sheep, possibly due to the fastidious and slow growth of these organisms. We developed a culture protocol that employed an average initial 3-day enrichment culture in liquid Hayflick broth in a CO(2)-enhanced atmosphere. The broth was plated to solid Hayflick medium and the cultures observed for growth for up to 30 days. Polymerase chain reaction (PCR) was performed on DNA isolated from the enrichment broth and on isolates obtained from culture using Mycoplasma genus specific PCR assays and species-specific PCR assays for M. arginini and M. ovipneumoniae. Some cultures that grew on Hayflick plates were picked as single colonies but were mixed because two organisms may grow together and appear as a single colony. Culture and PCR tests produced similar results for M. arginini, but for M. ovipneumoniae, culture alone was less accurate than PCR. Use of genus specific primers also may allow detection of other species in samples negative for M. arginini and M. ovipneumoniae. Two methods of transport from field to laboratory (Port-a-CulTM tubes, cryoprotectant in liquid N(2) and Fisher Transport System) gave similar results under our study conditions. PMID- 22493121 TI - Acute fatal toxoplasmosis in three Eurasian red squirrels (Sciurus vulgaris) caused by genotype II of Toxoplasma gondii. AB - Toxoplasma gondii parasites belonging to endemic genotype II caused fatal infection in three (16%) of 19 Eurasian red squirrels (Sciurus vulgaris) sent for necropsy in Finland between May 2006 and April 2009. The liver, spleen, and lungs were the organs most affected in all three cases, and high numbers of T. gondii parasites were visualized immunohistochemically in all the tissue samples available from them. The genotyping of the parasite strains was based on the results of analysis of length polymorphism at six microsatellite markers (B18, TUB2, TgM-A, W35, B17, and M33). The length of the PCR product at the additional seventh marker (M48) was 233 base pairs from the first two cases that were found dead together, suggesting a common infection source, and 215 base pairs from the third. Eurasian red squirrels may be exceptionally susceptible to T. gondii infection. PMID- 22493122 TI - A comparison of oxygen saturation in white-tailed deer estimated by pulse oximetry and from arterial blood gases. AB - Physiologic monitoring is important when chemically immobilizing wildlife. Blood oxygenation is usually monitored by pulse oximetry in the field; however, there is some question whether this technique accurately reflects oxygen saturation in wild white-tailed deer (Odocoileus virginianus). We evaluated different doses of medetomidine (125, 150, 175, or 200 MUg/kg) mixed with ketamine (1.5 mg/kg), and tiletamine-zolazepam (1.0 mg/kg) in 22 female white-tailed deer at the University of Georgia Whitehall Deer Research Facility in Athens, Georgia on 14-15 and 21 May 2009. Deer were hand-injected intramuscularly while physically restrained in a squeeze chute, and then they were released into a pen for monitoring. Hemoglobin saturation estimated using pulse oximetry (SpO(2)) was compared with hemoglobin saturation value from arterial blood gases (SaO(2)) at 0, 10, and 20 min postimmobilization with deer in a sternal position. We made 56 simultaneous comparisons of oxygen saturation using SpO(2) (range, 54-95%) and SaO(2) (range, 60-95%). We used a Bland-Altman analysis for determining agreement between the two methods. Hemoglobin saturation estimated using SpO(2) was generally greater than SaO(2) when the mean of the two measurements was >80%. At mean values <80% oxygen saturation, there is not sufficient agreement between the techniques. Multiple readings over time may help recognition of outliers. PMID- 22493123 TI - A serosurvey for Brucella suis, classical swine fever virus, porcine circovirus type 2, and pseudorabies virus in feral swine (Sus scrofa) of eastern North Carolina. AB - As feral swine (Sus scrofa) populations expand their range and the opportunity for feral swine hunting increases, there is increased potential for disease transmission that may impact humans, domestic swine, and wildlife. From September 2007 to March 2010, in 13 North Carolina, USA, counties and at Howell Woods Environmental Learning Center, we conducted a serosurvey of feral swine for Brucella suis, pseudorabies virus (PRV), and classical swine fever virus (CSFV); the samples obtained at Howell Woods also were tested for porcine circovirus type 2 (PCV-2). Feral swine serum was collected from trapped and hunter-harvested swine. For the first time since 2004 when screening began, we detected B. suis antibodies in 9% (9/98) of feral swine at Howell Woods and <1% (1/415) in the North Carolina counties. Also, at Howell Woods, we detected PCV-2 antibodies in 59% (53/90) of feral swine. We did not detect antibodies to PRV (n=512) or CSFV (n=307) at Howell Woods or the 13 North Carolina counties, respectively. The detection of feral swine with antibodies to B. suis for the first time in North Carolina warrants increased surveillance of the feral swine population to evaluate speed of disease spread and to establish the potential risk to commercial swine and humans. PMID- 22493125 TI - Use of real-time PCR to detect canine parvovirus in feces of free-ranging wolves. AB - Using real-time PCR, we tested 15 wolf (Canis lupus) feces from the Superior National Forest (SNF), Minnesota, USA, and 191 from Yellowstone National Park (YNP), USA, collected during summer and 13 during winter for canine parvovirus (CPV)-2 DNA. We also tested 20 dog feces for CPV-2 DNA. The PCR assay was 100% sensitive and specific with a minimum detection threshold of 10(4) 50% tissue culture infective dose. Virus was detected in two winter specimens but none of the summer specimens. We suggest applying the technique more broadly especially with winter feces. PMID- 22493124 TI - Pathogen and rodenticide exposure in American badgers (Taxidea taxus) in California. AB - Urban and agricultural land use may increase the risk of disease transmission among wildlife, domestic animals, and humans as we share ever-shrinking and fragmented habitat. American badgers (Taxidae taxus), a species of special concern in California, USA, live in proximity to urban development and often share habitat with livestock and small peridomestic mammals. As such, they may be susceptible to pathogens commonly transmitted at this interface and to anticoagulant rodenticides used to control nuisance wildlife on agricultural lands. We evaluated free-ranging badgers in California for exposure to pathogens and anticoagulant rodenticides that pose a risk to wildlife, domestic animals, or public health. We found serologic evidence of badger exposure to Francisella tularensis, Toxoplasma gondii, Anaplasma phagocytophilum, canine distemper virus, and three Bartonella species: B. henselae, B. clarridgeiae, and B. vinsonii subsp. berkhoffii. Badger tissues contained anticoagulant rodenticides brodifacoum and bromadiolone, commonly used to control periurban rodent pests. These data provide a preliminary investigation of pathogen and toxicant exposure in the wild badger population. PMID- 22493126 TI - Optimal medetomidine dose when combined with ketamine and tiletamine-zolazepam to immobilize white-tailed deer. AB - Chemical immobilization is often needed for safe and effective capture and handling of wildlife. We evaluated medetomidine (125, 150, 175, or 200 MUg/kg; for synergistic effects and relaxation) mixed with ketamine (1.5 mg/kg; for relatively shorter recovery) and tiletamine-zolazepam (1.0 mg/kg; for rapid induction) in 22 female white-tailed deer (Odocoileus virginianus) at the University of Georgia Whitehall Deer Research Facility in Athens, Georgia, USA, on 14-15 and 21 May 2009. Deer were weighed before treatment, hand-injected intramuscularly (IM) while restrained in a squeeze chute, and released into a pen for monitoring. We measured rectal temperature, respiration rate, heart rate, hemoglobin saturation (using pulse oximetry), and arterial blood gases at 0, 10, and 20 min postimmobilization. We found no differences in induction time with different doses of medetomidine. Deer became laterally recumbent for all treatments combined at a median of 4.2 (2.6-21.3) min and were approachable by a median of 4.8 (3.5-21.8) min. Twelve of the 22 deer had rectal temperatures >40 C at time 0 and were treated with a cold-water enema. Hemoglobin saturation, estimated using pulse oximetry, was 79.5, 82.0, and 82.3% at times 0, 10, and 20, respectively. We injected atipamezole (0.35 mg/kg, IM) for reversal. Recovery occurred sooner and was more consistent for 125 and 150 MUg/kg medetomidine whereby deer stood with minimal sedation to moderate ataxia within 60-90 min after atipamezole administration. We recommend using 150 MUg of medetomidine with ketamine (1.5 mg/kg) and tiletamine-zolazepam (1.0 mg/kg) to provide effective and safe chemical immobilization of white-tailed deer. PMID- 22493127 TI - Sarcomas in three free-ranging northern sea otters (Enhydra lutris kenyoni) in Alaska. AB - Three sarcomas were diagnosed in wild northern sea otters (Enhydra lutris kenyoni) during the mid- to late 1990s. Histologically, the tumors were a chondrosarcoma and two low-grade fibrosarcomas with myofibroblastic cell differentiation. The three sea otters were surviving in the wild and were killed by hunters. PMID- 22493128 TI - Chlamydiosis: seroepidemiologic survey in a red deer (Cervus elaphus) population in Italy. AB - Chlamydiae are obligate, intracellular, gram-negative bacteria that are responsible for important diseases in humans, other mammals, and birds. Studies have shown that chlamydiae could be present in wild ruminants, but the serodiagnostic method most commonly used did not allow identification of chlamydial species. We determined the prevalence of antibodies to Chlamydia pecorum, Chlamydia suis, Chlamydia abortus, and Chlamydia psittaci in 271 red deer (Cervus elaphus) of a central Italian population, by using the microimmunofluorescence test that shows antibody response against genus-specific and species-specific antigens. No sera had detectable antibodies to C. pecorum and C. abortus. Antibodies were detected against C. psittaci (9.6%) and C. suis (3.3%). Antibody response could be related to contact of the red deer with birds and wild boars (Sus scrofa), respectively, and confirm an extended host range of individual Chlamydia species. In view of the potential zoonotic risk related to exposition of C. psittaci, our findings suggest surveillance of wild ruminants as potential reservoirs for chlamydiae. PMID- 22493129 TI - Prevalence of antibody to six Leptospira servovars in Swedish wild boars. AB - Zoonotic Leptospira bacteria are pathogens that may increase in importance with climate change. We investigated the prevalence of antibody to six Leptospira serovars (sv) in the Swedish wild boar (Sus scrofa) population, which is increasing in number and geographic distribution. The serovars we selected cause disease in pigs or may be of use as sentinel serovars to measure the potential spread in Swedish fauna. In total, 386 serum samples from wild boars collected between 2005 and 2007 were investigated using a microscopic agglutination test for Leptospira interrogans sv Bratislava strain Jez Bratislava, sv Icterohaemorrhagiae strain Kantorowicz, sv Pomona strain Pomona, Leptospira kirschneri sv Grippotyphosa strain Duyster, and Leptospira borgpetersenii sv Tarassovi strain Perepelitsin, and a domestic strain closely related to sv Sejroe. Twelve (3.1%) of the analyzed samples were antibody-positive. Of those, nine (2.3%) were positive for sv Bratislava and 0.8% for sv Icterohaemorrhagiae. All antibody-positive samples originated from areas where wild boars are reported to be common. We conclude that Leptospira infection is less common in Swedish wild boar than in continental Europe. However, we recommend continuous surveillance to follow the effects of climate change and an increasing wild boar population. PMID- 22493130 TI - High prevalence of Aleutian mink disease virus in free-ranging mink on a remote Danish island. AB - Aleutian mink disease virus (AMDV) causes severe disease in farmed mink (Neovison vison) worldwide. In Denmark, AMDV in farmed mink has been confined to the northern part of the mainland since 2002. From 1998 to 2009, samples from 396 free-ranging mink were collected from mainland Denmark, and a low AMDV antibody prevalence (3% of 296) was found using countercurrent immune electrophoresis. However, on the island of Bornholm in the Baltic Sea, a high prevalence (45% of 142 mink) was detected in the free-ranging mink. Aleutian mink disease virus was detected by polymerase chain reaction in 32 of 49 antibody-positive free-ranging mink on Bornholm, but not in mink collected from other parts of Denmark. Sequence analysis of 370 base pairs of the nonstructural gene of the AMDV of 17 samples revealed two clusters with closest similarity to Swedish AMDV strains. PMID- 22493131 TI - Prevalence of Baylisascaris procyonis in habitat associated with Allegheny woodrat (Neotoma magister) populations in Indiana. AB - Allegheny woodrat (Neotoma magister) populations have been in decline across their range since the late 1970s. Hypotheses proposed to explain these declines include habitat fragmentation and loss, decreased food availability, and increased mortality from infection with Baylisascaris procyonis. We investigated the prevalence of B. procyonis at raccoon (Procyon lotor) latrines in woodrat cliff habitats (n = 18) along the Ohio River in southern Indiana in 1995. We located 275 latrines (mean = 15.3/site; range, 6-34) and found B. procyonis in 13 (4.7%) latrines across all sites. When present at a site, B. procyonis occurred, on average, at 11.1%of latrines (range, 3-36%). Woodrat abundance, determined through a concurrent live-trapping program, was significantly higher (chi(2) = 5.12, df = 1, P = 0.024) at sites where B. procyonis was not found (9.5 +/- 2.52) than at sites with B. procyonis (3.7 +/- 2.2). Our analyses support the hypothesis that this parasite could contribute to declines in woodrat abundance. Because woodrats cache nonfood items, including raccoon feces, and are highly susceptible to the parasite, they are at increased risk for B. procyonis infection, which could be deleterious, especially to small populations. PMID- 22493132 TI - Extended incubation period of rabies virus in a captive big brown bat (Eptesicus fuscus). AB - Rabies virus incubation in bats is typically less than 180 days, yet longer incubation periods have been described. We report a 267-day incubation in a big brown bat (Eptesicus fuscus) exposed to rabies virus before entering our captive colony. PMID- 22493133 TI - Squirrel monkey cytomegalovirus antibodies in free-ranging black howler monkeys (Alouatta caraya), Misiones, Argentina. AB - Serum from four black howler monkeys (Alouatta caraya) was screened for antibodies to seven viruses by dot immunoassay. Cytomegalovirus antibodies were detected in three of four individuals and provide the first evidence of exposure by black howler monkeys to this virus. PMID- 22493134 TI - Exertional myopathy in pileated woodpeckers (Dryocopus pileatus) subsequent to capture. AB - Out of 33 Pileated Woodpeckers (Dryocopus pileatus) captured and fitted with radio-transmitters, 12 were later found dead. Three carcasses were recovered and submitted for necropsy. One bird had large pale foci in multiple muscles. Microscopically, skeletal muscle in all three had evidence of severe coagulative necrosis, consistent with capture myopathy. PMID- 22493135 TI - Granulomatous peritonitis in a European brown bear caused by Baylisascaris transfuga. AB - We report a case of granulomatous peritonitis due to Baylisascaris transfuga in a young male European brown bear (Ursus arctus). At necropsy, there were extensive abdominal adhesions and extensive granulomatous tissue on the peritoneum and liver capsule. In the gastrointestinal tract, there were 58 nematodes that were identified as Baylisascaris transfuga using light and scanning electron microscopy. PMID- 22493136 TI - First occurrence of Paramphistomum microbothrium (Fischoeder 1901) in roe deer (Capreolus capreolus) in Serbia. AB - Paramphistomum parasites identified by histology as Paramphistomum microbothrium were found in 18 of 34 roe deer (Capreolus capreolus) intestines from central Serbia, examined between 1998 and 2004. This represents the first record of P. microbothrium in roe deer in Serbia. PMID- 22493137 TI - Disseminated pulmonary adiaspiromycosis in a crested porcupine (Hystrix cristata Linnaeus, 1758). AB - Adiaspiromycosis is primarily a necrotizing granulomatous pneumonia caused by a dimorphic fungus of the genus Emmonsia. A young crested porcupine (Hystrix cristata) found dead showed multiple fractures, chronic pleuritis, and granulomatous pneumonia. Microscopically, cystic structures were consistent with adiaspiromycosis by Emmonsia crescens. The diagnosis was confirmed using molecular methods. PMID- 22493138 TI - Survival patterns in white-tailed and mule deer after oral inoculation with a standardized, conspecific prion dose. AB - We orally inoculated white-tailed deer (Odocoileus virginianus) and mule deer (Odocoileus hemionus) with a standardized, conspecific prion dose and collected biologic samples throughout the disease course. Mule deer (PRNP genotype 225SS) and PRNP genotype 96GG white-tailed deer succumbed along similar trajectories, but 96GS- and 96SS-genotype individuals tended to survive longer. PMID- 22493139 TI - Assessment of prospective preventive therapies for chronic wasting disease in mule deer. AB - We compared prion infection rates among mule deer (Odocoileus hemionus) receiving pentosan polysulfate, tannic acid, tetracycline HCl, or no treatment 14 days before to 14 days after (dpi) oral inoculation with tonsil tissue homogenate. All deer were infected, but the rapid disease course (230-603 dpi) suggested our challenge was overwhelming. PMID- 22493142 TI - Ormeloxifene inhibits osteoclast differentiation in parallel to downregulating RANKL-induced ROS generation and suppressing the activation of ERK and JNK in murine RAW264.7 cells. AB - Ormeloxifene (Orm), a triphenylethylene compound, has been established as a selective estrogen receptor modulator (SERM) that suppresses the ovariectomy induced bone resorption in rats. However, the precise mechanism underlying the bone-preserving action of Orm remains unclear. In this study, we evaluated the effect of Orm on osteoclast formation induced by receptor activator of nuclear factor kappaB ligand (RANKL) in the murine macrophage cell line RAW264.7. We also explored the mechanism of action of Orm by studying the RANKL-induced signaling pathways required for osteoclast differentiation. We found that Orm inhibited osteoclast formation from murine macrophage RAW264.7 cells induced by RANKL in a dose-dependent manner. Orm was able to abolish RANKL-induced reactive oxygen species (ROS) elevation and inhibited the transcriptional activation of two key RANKL-induced transcription factors namely activator protein-1 (AP-1) and NF kappaB through mechanisms involving MAPKs. Activation of two MAPKs, i.e. ERK (MAPK1) and JNK (MAPK8), was alleviated by Orm effectively, which subsequently affected the activation of c-Jun and c-Fos, which are the essential components of the AP-1 transcription complex. Taken together, our results demonstrate that Orm potentially inhibits osteoclastogenesis by inhibiting ROS generation and thereby suppressing the activation of ERK1/2 (MAPK3/MAPK1) and JNK (MAPK8) and transcription factors (NF-kappaB and AP-1), which subsequently affect the regulation of osteoclastogenesis. These results provide a possible mechanism of action of Orm in regulating osteoclastogenesis, thereby supporting the beneficial bone-protective effects of this compound. PMID- 22493143 TI - Synergistic effect of p53 on TSA-induced stanniocalcin 1 expression in human nasopharyngeal carcinoma cells, CNE2. AB - Human stanniocalcin 1 (STC1) has recently been identified as a putative protein factor involved in cellular apoptosis. The use of histone deacetylase inhibitor (i.e. trichostatin A (TSA)) and doxorubicin (Dox) is one of the common treatment methods to induce apoptosis in human cancer cells. A study on TSA and Dox mediated apoptosis may shed light on the regulation and function of STC1 in cancer treatment. In this study, TSA and Dox cotreatment in human nasopharyngeal carcinoma cells (CNE2) elicited synergistic effects on STC1 gene expression and cellular apoptosis. An activation of p53 (TP53) transcriptional activity in Dox- or Dox+TSA-treated cells was revealed by the increased expression levels of p53 mRNA/protein as well as p53-driven luciferase activities. To elucidate the possible involvement of p53 in STC1 gene transcription, a vector expressing wild type or dominant negative (DN) p53 was transiently transfected into the cells. Both STC1 promoter luciferase constructs and chromatin immunoprecipitation assays did not support the direct role of p53 in STC1 gene transactivation. However, the synergistic effects of p53 on the induction of NF-kappaB phosphorylation and the recruitment of acetylated histone H3 in STC1 promoter were observed in TSA cotreated cells. The overexpression of exogenous STC1 sensitized apoptosis in Dox treated cells. Taken together, this study provides data to show the cross talk of NF-kappaB, p53, and histone protein in the regulation of STC1 expression and function. PMID- 22493144 TI - Tissue-specific selection of stable reference genes for real-time PCR normalization in an obese rat model. AB - Obesity is a complex pathology with interacting and confounding causes due to the environment, hormonal signaling patterns, and genetic predisposition. At present, the Zucker rat is an eligible genetic model for research on obesity and metabolic syndrome, allowing scrutiny of gene expression profiles. Real-time PCR is the benchmark method for measuring mRNA expressions, but the accuracy and reproducibility of its data greatly depend on appropriate normalization strategies. In the Zucker rat model, no specific reference genes have been identified in myocardium, kidney, and lung, the main organs involved in this syndrome. The aim of this study was to select among ten candidates (Actb, Gapdh, Polr2a, Ywhag, Rpl13a, Sdha, Ppia, Tbp, Hprt1 and Tfrc) a set of reference genes that can be used for the normalization of mRNA expression data obtained by real time PCR in obese and lean Zucker rats both at fasting and during acute hyperglycemia. The most stable genes in the heart were Sdha, Tbp, and Hprt1; in kidney, Tbp, Actb, and Gapdh were chosen, while Actb, Ywhag, and Sdha were selected as the most stably expressed set for pulmonary tissue. The normalization strategy was used to analyze mRNA expression of tumor necrosis factor alpha, the main inflammatory mediator in obesity, whose variations were more significant when normalized with the appropriately selected reference genes. The findings obtained in this study underline the importance of having three stably expressed reference gene sets for use in the cardiac, renal, and pulmonary tissues of an experimental model of obese and hyperglycemic Zucker rats. PMID- 22493145 TI - [Health related quality of life and disease burden of patients with schizophrenia in Hungary]. AB - INTRODUCTION: According to the international literature disease burden of schizophrenia is substantial, however data from Eastern Central Europe is scarce. Our aim was to assess the quality of life and costs of patients with schizophrenia in Hungary. METHODS: A cross sectional questionnaire survey was performed in 3 hospital based psychiatry centres involving patients with schizophrenia. Demographics, disease severity (Clinical Global Impression, CGI), functional ability (Global Assessment of Functioning, GAF) and general health status (EQ-5D) was assessed. Health care utilisation and aids were surveyed for the past 12 months. Costing was performed from the societal perspective and human capital approach was applied. RESULTS: Altogether 78 patients (female 43.6%) were involved with a mean age of 44.2 (SD=13.1) years, disease duration was >10 years at 49 (62.8%) cases, 66 (84.6%) patients were disability pensioners. Distribution between CGI 3-4-5-6 levels were 12 (16%), 33 (43%), 21 (28%), 10 (13%) patients, respectively, mean GAF was 52.6 (SD=13.9). The average EQ-5D score was 0.64 (SD=0.3) and it was significantly worse than the age-matched general population's score in Hungary (p < 0.01). Mean yearly cost was 13 878 Euros/patient (conversion 1 Euro=280.6 HUF), the rate of direct medical,direct non-medical and indirect costs was 28.5%, 5.4% and 66.1%, respectively. Among direct costs hospitalisation and drug costs were dominant. Total cost correlates with disease severity (CGI). CONCLUSION: Schizophrenia leads to notable deterioration in health related quality of life and induce high costs to society, mainly due to the productivity loss of the patients. Nevertheless disease related costs in Hungary are lower than in economically more developed European countries. Our study offers basic data about disease burden of schizophrenia in Hungary to support clinical and health policy decision making. PMID- 22493146 TI - [Traditional and modern views of dissociation]. AB - Dissociation is a failure to integrate aspects of identity, memory, perception, and consciousness. Dissociation is conceptualized as a dimensional process existing along a continuum from normal and relatively common dissociative experiences to severe and clinically relevant forms. There is a growing body of clinical and empirical evidence that dissociation may occur especially as a defense during trauma. In case of traumatic events dissociation considered as an attempt to maintain mental control just as physical control is lost. Dissociation can be either a symptom of some complex mental disorder or a distinct clinical entity categorized among dissociative and somatoform disorders in DSM-IV. The article describes the conceptual issues of dissociation and presents a new classification by Nijenhuis where the so-called somatoform dissociative symptoms are included as well in the list of dissociative symptoms. Finally, this paper summarizes the measures of dissociative phenomena and the cognitive-behavioral approaches of dissociation, and highlights the main features of the new structural dissociation model. PMID- 22493147 TI - [The phenomenon of drug change in the interviews with injecting drug users]. AB - INTRODUCTION: Important part of the studies on drug use deals with drug use transitions because of their public health consequences. Narrating of drug use change states the active decision making in the centre of the process with adding mental states of the participants to the change process. The transitional narratives can be embedded in the social context of "risk environment". METHODS: In the micro-segregation of the Middle-Jozsefvaros (8th district, Budapest) the Blue Point Foundation runs a needle-exchange service in its "Contact Programme". Here the number of registered clients was 2066 in 2010. The study participants were recruited from the clients of this needle-exchange service (from December 2010 to February 2011). The criterion of entering the study sample was injecting mephedrone in the past 30 days. 17 participants were interviewed. The life story interviews had been coded thematically; it had been done until new codes did not carry new meanings. RESULTS: Study participants speak about rapid tolerance and more intensive use of mephedrone after changing their usual drug. This use is more risky because of more frequent injecting. The effect of mephedrone was described like 3,4- Methylenedioxymethamphetamine (MDMA) and cocaine. In the interviews the usual pattern was narrating the positive effects of mephedrone and after this text the narrating of the negative effects. The "risk narrative" and the "enjoyment narrative" were presented separately in the interviews. CONCLUSIONS: Not the expansion of the drug market, but the drug change was observed: earlier drugs to mephedrone or parallel use of mephedrone with earlier drugs (amphetamine and heroin). The purity and availability of heroin and the increase availability of mephedrone may take a role in this process. The absent of drug market expansion was explained by the closeness of the micro-segregation. Results raise attention of the public health consequences of drug change and the proper training of professionals for this change. PMID- 22493148 TI - [The effect of prostitution on the stability of romantic relationships. Empirical testing of an evolutionary model]. AB - OBJECTIVES: Until now prostitution has only been explained from two evolutionary points of view. According to the short-term mate choice strategy approach motives for seeking prostitutes are to be found in the nature of male sexuality. Another theory - the evolutionary interpretation of female promiscuity's motivational base - indirectly completes the understanding of prostitution. This theory emphasizes the adaptive benefits of female promiscuity under certain circumstances. The aim of our study was to test a third idea (Adaptive Support Theory), according to which women in long-term relationships support their partners' (husbands') sexual relations with prostitutes. METHODS: University female students (n=208, age mean+/-SD=23.55+/-7.13, min=18, max=50) completed our questionnaire. RESULTS: Female participants are presumed to recognize the advantages and threats of their partners' sexual relations with prostitutes compared to other possible forms of betrayal. Hence it is hypothesized that women overtly support the possibility of their partners' relations with prostitutes. Our results show that women are able to assess the favorable and unfavorable effects of their partners' relations with prostitutes. At the same time they do not directly support this form of betrayal over other possibilities. However, female participants were more approving of their partners' relations with prostitutes (in a thought- experiment), than they guessed their partner would demand such services. CONCLUSIONS: According to our model women living in long term relationship are adaptively interested in their partner's cheating on them with a prostitute (rather than engaging in other kinds of sexual relations), because this finance based external sexual liaison is the least threatening for the stability of the long-term relationship. PMID- 22493150 TI - Traumatic false aneurysms of the left ventricle after an attempt at video thoracoscopic surgery. AB - OBJECTIVES Video-thoracoscopic surgery (VTS) has been accepted as a safe and credible technique since 1990. Lung injury is one of the main perioperative complications. Few data are available about cardiac trauma and VTS-related false aneurysm of the left ventricular (LV) wall has not yet been reported. METHODS A 62-year old woman presented with a left thoracic empyema. Video-thoracoscopy was attempted for bacterial sampling and surgical drain of the pleura. A rapid conversion to open thoracotomy was necessary to control massive bleeding after the first thoracic port intrusion. An apical systolic murmur was found 2 weeks later during a systematic clinical examination. The patient was asymptomatic and had no personal history of cardiac disease. RESULTS Colour Doppler imaging showed two spurious aneurysms on the LV wall without any haemopericardium. Pericardial enhancement around the left ventricle was observed on the chest computerized tomography scan with the injection of contrast. After the careful excision of the two false aneurysms, a surgical repair was strengthened with a suture under a cardiopulmonary bypass. The postoperative course was uneventful and the patient was safe at 3 years. CONCLUSIONS This is the first report of LV traumatic false aneurysms secondary to an attempt of a video-thoracoscopic procedure. This is a rare but life-threatening complication because of the risk of spontaneous rupture. Left persistent thoracic empyemas associated with the ipsilateral mediastinum deviation carry a high risk of myocardial damage related to the trocar port intrusion. PMID- 22493151 TI - Cardiac denervation procedure to treat refractory angina in a patient with Churg Strauss syndrome and non-obstructive coronary lesions. AB - Cardiac involvement in Churg-Strauss syndrome is common and represents the main cause of mortality. We report the case of a patient with Churg-Strauss vasculitis, mitral regurgitation with left ventricular dysfunction, paroxysmal atrial fibrillation and refractory angina with non-significant coronary lesions. Cardiac denervation was proposed as an associated procedure to treat angina. The total removal of peri-adventitial and adventitial tissue around the superior vena cava, ascending aorta and main pulmonary trunk was performed. After 3 months of follow-up, the patient was angina-free and could resume his normal lifestyle. PMID- 22493152 TI - Shorter telomere length is associated with increased ovarian cancer risk in both familial and sporadic cases. AB - BACKGROUND: Alterations in telomere maintenance mechanisms leading to short telomeres underlie different genetic disorders of ageing and cancer predisposition syndromes. It is known that short telomeres and subsequent genomic instability contribute to malignant transformation, and it is therefore likely that people with shorter telomeres are at higher risk for different types of cancer. Recently, the authors demonstrated that the genes BRCA1 and BRCA2 are modifiers of telomere length (TL) in familial breast cancer. The present study analysed TL in peripheral blood leucocytes of hereditary and sporadic ovarian cancer cases, as well as in female controls, to evaluate whether TL contributes to ovarian cancer risk. METHODS: TL was measured by quantitative PCR in 178 sporadic and 168 hereditary ovarian cases (46 BRCA1, 12 BRCA2, and 110 BRCAX) and compared to TL in 267 controls. RESULTS: Both sporadic and hereditary cases showed significantly shorter age adjusted TLs than controls. Unconditional logistic regression analysis revealed an association between TL and ovarian cancer risk with a significant interaction with age (p<0.001). Risk was higher in younger women and progressively decreased with age, with the highest OR observed in women under 30 years of age (OR 1.56, 95% CI 1.34 to 1.81; p=1.0*10(-18)). CONCLUSION: These findings indicate that TL could be a risk factor for early onset ovarian cancer. PMID- 22493153 TI - Oxidative stability of fermented meat products. AB - Meat and meat products, which form a major part of our diet, are very susceptible to quality changes resulting from oxidative processes. Quality of fermented food products depends on the course of various physicochemical and biochemical processes. Oxidation of meat components in raw ripening products may be the result of enzymatic changes occurring as a result of activity of enzymes originating in tissues and microorganisms, as well as lipid peroxidation by free radicals. Primary and secondary products of lipid oxidation are extremely reactive and react with other components of meat, changing their physical and chemical properties. Oxidised proteins take on a yellowish, red through brown hue. Products of lipid and protein degradation create a specific flavour and aroma ; furthermore, toxic substances (such as biogenic amines or new substances) are formed as a result of interactions between meat components, e.g. protein lipid or protein-protein combinations, as well as transverse bonds in protein structures. Oxidation of meat components in raw ripening products is a particularly difficult process. On the one hand it is essential, since the enzymatic and non-enzymatic lipid oxidation creates flavour and aroma compounds characteristic for ripening products; on the other hand excessive amounts or transformations of those compounds may cause the fermented meat product to become a risk to health. PMID- 22493154 TI - Flow cytometric analysis of microbial contamination in food industry technological lines--initial study. AB - BACKGROUND: Flow cytometry constitutes an alternative for traditional methods of microorganisms identification and analysis, including methods requiring cultivation step. It enables the detection of pathogens and other microorganisms contaminants without the need to culture microbial cells meaning that the sample (water, waste or food e.g. milk, wine, beer) may be analysed directly. This leads to a significant reduction of time required for analysis allowing monitoring of production processes and immediate reaction in case of contamination or any disruption occurs. Apart from the analysis of raw materials or products on different stages of manufacturing process, the flow cytometry seems to constitute an ideal tool for the assessment of microbial contamination on the surface of technological lines. MATERIAL AND METHODS: In the present work samples comprising smears from 3 different surfaces of technological lines from fruit and vegetable processing company from Greater Poland were analysed directly with flow cytometer. The measured parameters were forward and side scatter of laser light signals allowing the estimation of microbial cell contents in each sample. RESULTS: Flow cytometric analysis of the surface of food industry production lines enable the preliminary evaluation of microbial contamination within few minutes from the moment of sample arrival without the need of sample pretreatment. CONCLUSIONS: The presented method of fl ow cytometric initial evaluation of microbial state of food industry technological lines demonstrated its potential for developing a robust, routine method for the rapid and labor saving detection of microbial contamination in food industry. PMID- 22493155 TI - Effect of homogenization on the properties and microstructure of Mozzarella cheese from buffalo milk. AB - BACKGROUND: The name pasta filata refers to a unique plasticizing and texturing treatments of the fresh curd in hot water that imparts to the finished cheese its characteristic fibrous structure and melting properties. Mozzarella cheese made from standardized homogenized and non-homogenized buffalo milk with 3 and 1.5%fat. The effect of homogenization on rheological, microstructure and sensory evaluation was carried out. MATERIAL AND METHODS: Fresh raw buffalo milk and starter cultures of Streptococcus thermophilus and Lactobacillus delbrueckii ssp. bulgaricus were used. The coagulants were calf rennet powder (HA-LA). Standardized buffalo milk was homogenized at 25 kg/cm2 pressure after heating to 60 degrees C using homogenizer. Milk and cheese were analysed. Microstructure of the cheese samples was investigated either with an application of transmission or scanning electron microscope. Statistical analyses were applied on the obtained data. RESULTS: Soluble nitrogen total volatile free fatty acids, soluble tyrosine and tryptophan increased with using homogenized milk and also, increased with relatively decrease in case of homogenized Mozzarella cheese. Meltability of Mozzarella cheese increased with increasing the fat content and storage period and decrease with homogenization. Mozzarella cheese firmness increased with homogenization and also, increased with progressing of storage period. Flavour score, appearance and total score of Mozzarella cheese increased with homogenization and storage period progress, while body and texture score decreased with homogenization and increased with storage period progress. Microstructure of Mozzarella cheese showed the low fat cheese tends to be harder, more crumbly and less smooth than normal. Curd granule junctions were prominent in non-homogenized milk cheese. CONCLUSION: Homogenization of milk cheese caused changes in the microstructure of the Mozzarella cheese. Microstructure studies of cheese revealed that cheese made from homogenized milk is smoother and has a finer texture than non-homogenized but is also, firmer and more elastic. PMID- 22493156 TI - Modelling moisture diffusivity of pomegranate seed cultivars under fixed, semi fluidized and fluidized bed using mathematical and neural network methods. AB - BACKGROUND: Modelling moisture diffusivity of pomegranate cultivars is considered to be a major aspect of the drying process optimization. Its goal is mainly to apply the optimum drying method and conditions in which the final product meets the required standards. Temperature is the major parameter which affects the moisture diffusivity. This parameter is not equal for different cultivars of pomegranate. So modelling of moisture diffusivity is important in designing, optimizing and adjusting the dryer system. MATERIAL AND METHODS: This research studied thin layer drying of three cultivars of pomegranate seeds (Alak, Siah and Malas) under fixed, semi fluidized and fluidized bed conditions. Drying process of samples was implemented at 50, 60, 70 and 80 degrees C air temperature levels. Second law of Fick in diffusion was utilized to compute the effective moisture diffusivity (D(eff)) of the seeds. Linear and artificial neural networks (ANNs) also were used to model D(eff) of seeds. RESULTS: Maximum and minimum values of the D(eff) were related to Malas and Alak cultivars, respectively. Three linear models were found to fit the experimental data with average R2 = 0.9350, 0.9320 and 0.9400 for Alak, Siah and Malas cultivars, respectively. The best results for neural network were related to feed forward neural network with training algorithm of Levenberg-Marquardt was appertained to the topology of 3-4-3-1 and threshold function of LOGSIG. By the use of this structure, R2 = 0.9972 was determined. CONCLUSION: A direct relationship was found between D(eff) and thickness of fleshy section of the seeds. The Siah cultivar has the highest value of D(eff). This is due to higher volume of fleshy section of the Siah cultivar. Cultivar type and air velocity have the highest and the least effect on D(eff), respectively. PMID- 22493157 TI - Comparison between the amino acid, fatty acid, mineral and nutritional quality of raw, germinated and fermented African locust bean (Parkia biglobosa) flour. AB - BACKGROUND: The most popular form of utilization of African locust bean (ALB) is in its traditional fermentation food condiment (iru/dawadawa), which adds protein to a protein-poor diet and also as medicine. In view of the nutritive values of ALB, the present study therefore aimed at investigating the effect of germination and fermentation on the nutritional quality of ALB flour. MATERIAL AND METHODS: The ALB was obtained from a local market in Akure, Nigeria. The seeds were divided into three portions, and treated as raw African locust bean (RALB), germinated African locust bean (GALB) and fermented African locust bean (FALB) respectively. Each of the samples was milled, sieved and analysed for chemical, functional properties and nutritional qualities using standard methods. RESULTS: Some most important results of the chemical analysis were as follows: protein content range between 33.64 +/-0.41 - 41.49 +/-1.89 g/100 g, while the energy value was between 442.79 +/-2.32 - 457.20 +/-2.15 kcal. The P/Ca and Na/K ratio of the RALB were higher than other fl our samples respectively. Total essential amino acid was between 29.960-27.514 mg/100 g. Protein efficiency ratio (PER) was between 1.78-1.87; essential amino acid index 31.43-34.75%; while biological values were 22.56-26.18%. The dominant fatty acid (FA) composition of the samples was linoleic with 33.687%, 31.578% and 28.7% for RALB, GALB and FALB respectively; while the least was lauric acid. The polyunsaturated/saturated FA ratio ranges between 0.589-0.718. The antinutrient concentration of fermented flour sample was significantly reduced than other food samples. CONCLUSION: The present study investigated the effect of germination and fermentation on the nutritional quality of ALB flour. The finding showed that fermentation technique significantly reduced antinutrient concentration and also improved the nutrient composition, particularly amino acid profile of ALB flour. PMID- 22493158 TI - Antioxidant properties of extracts from buckwheat by-products. AB - BACKGROUND: In the course of production of buckwheat groats by-products are produced, such as bran and hull, which apart from high content of dietary fiber, may also constitute valuable sources of antioxidants. The aim of these investigations was to determine the antioxidant activity of extracts from by products produced during processing of buckwheat for groats. MATERIAL AND METHOD: Analyses were conducted on bran and hull of buckwheat cv. Kora. Extraction was run using acetone, methanol and water at room temperature for 24 h. The level of phenolics was determined spectrophotometrically with the Folin-Ciocalteau reagent, using (+) catechin as a standard. Antioxidant activity of extracts was analysed in relation to linoleic acid, running incubation for 19 h, by scavenging of stable radicals of DPPH (2,2-diphenyl-1-picrylhydrazyl) and on the basis of metal chelating ability. Recorded results were compared with the activity of BHT (butylated hydroxytoluene). RESULTS: The highest content of polyphenols was found in the methanol extract of hull (168.5 mg/g d.m.), which was also characterised by the best antiradical properties. The lowest content of total phenols was found for water extracts of bran after grinding and final bran, at 20.3 mg/g d.m. and 10.2 mg/g d.m. In the emulsion system the highest activity was found for methanol extracts of hull and bran after grinding (Wo = 0.89), as well as the extract of final bran (Wo = 0.85). A higher chelating ability in relation to Fe (II) ions was observed for bran extracts (after grinding - 76.1%, final bran - 62.2%) than for hull extracts (26%). CONCLUSIONS: Extracts obtained from by-products of buckwheat were characterised by high antioxidant activity in the applied model systems. PMID- 22493159 TI - Antioxidant activity of potato juice. AB - BACKGROUND: The interest in potato juice as a therapeutic agent goes back to the 19th century but its application was not supported by any knowledge about biological activity of this raw material. Factors restricting the medical application of potato juice include its inattractive sensory and functional properties. The aim of the presented investigations was preliminary evaluation of the biological activity of potato juice and the impact on it of some technological operations such as: cryoconcentration and hydrolysis in a membrane reactor. MATERIAL AND METHODS: Experiments comprised investigations of antioxidative potentials of fresh potato juice, products of its processing as well as fractions separated because of the size of their molecules using, for this purpose, Folin-Ciocalteu methods and reactions with the ABTS cation radical. RESULTS: The value of the antioxidative potential of fresh potato juice determined by means of the ABTS reagent corresponded to approximately 330 MUmol/100 g which is in keeping with literature data. As a result of the cryoconcentration process, the value determined by the Folin-Ciocalteu method was found to increase only slightly whereas the value determined by means of the ABTS reagent almost tripled. The antioxidative potential was found to grow even more strongly in the case of the application of both methods when the process of enzymatic hydrolysis was employed. The total of 5 protein fractions of molecular masses ranging from 11 000 Da to over 600 000 Da, as well as an organic non protein fraction of the molecular mass of 600 Da, were obtained as a result of the performed separation. All the examined fractions exhibited antioxidative activities. The highest values determined by the Folin-Ciocalteu method were recorded for the protein fraction of 80 000 Da mean molecular mass, while using the ABTS reagent--for the organic, non-protein fraction. CONCLUSIONS: Potato juice possesses antioxidative activity which can be enhanced by means of processing, especially, in the course of enzymatic hydrolysis. In addition, it was demonstrated that the organic nonprotein fraction of 600 Da mean molecular mass was characterised by the highest antioxidative activity. PMID- 22493160 TI - New actions for old nutrients. AB - The purpose of this review is to present information regarding new effects for certain nutrients other than those traditionally known. Zinc has been found to prevent and reduce the duration of common colds. In developing countries, zinc has been shown to reduce the duration and severity of diarrhea and even decrease relapses. Iron supplementation in iron deficient children, has been shown to improve several aspects of brain function. In studies where iron was given to the mother, 3 of 5 randomized, controlled trials showed a beneficial effect of iron supplementation on the Psychomotor Development Index at some time points, whereas 2 did not. The chances for infants supplemented with docosahexaenoic acid in the fi rst year of life of having at least 1 event of allergic manifestation or upper respiratory infection or at least 1 event of wheezing/asthma, wheezing/asthma/atopic dermatitis, any allergy, or an upper respiratory tract infection during the fi rst 3 years of life were significantly lower than in the non supplemented group. Epidemiological studies have established a relationship between low levels of serum vitamin D and reduced lung function in healthy adults and asthma onset and severity in children. There was a trend for an independent association between higher levels of maternal circulating 25(OH)D3 levels in pregnancy and decreased odds of lower respiratory tract infections in offspring. PMID- 22493161 TI - Effect of microwave field on trypsin inhibitors activity and protein quality of broad bean seeds (Vicia faba var. major). AB - BACKGROUND: In human nutrition legume seeds are usually subjected to soaking and thermal processes, mainly by using traditional cooking method. This method which has been used for decades, does not allow to control and adjust the parameters of this process. Therefore it does not seem to be the optimal method. Undoubtedly, microwave field is an alternative thermal process to conventional technique. The aim of this study was to assess the impact of microwave field on the activity of trypsin inhibitors and protein quality of three varieties of broad bean seeds. MATERIAL AND METHODS: The study was performed on dry seeds of broad bean varieties Windsor White, Bachus and Basta. The seeds were soaked and heated in a microwave. The seeds absorbed different energy doses from 500 J/g, through 750, 1000, 1250, 1500, 1750 to 2000 J/g. The study material prepared in this way was tested for trypsin inhibitor activity, protein solubility and in vitro protein digestibility. The results were analysed by the one-way analysis of variance. RESULTS: Microwave heating resulted in decreased activity of trypsin inhibitors and protein solubility and increased digestibility of protein in all tested varieties of broad bean seeds. With increasing doses of the microwave field energy a decrease in protein solubility was observed. Satisfactory reduction in trypsin inhibitors at the level of 70-75% and highest protein digestibility were obtained by using a microwave field with energy dose of 1000 J/g of seeds. CONCLUSION: It can be concluded that the optimal dose of microwave energy field which will produce a relatively low activity of trypsin inhibitors and the highest protein digestibility together with maintaining solubility of broad been seeds was 1000 J/g seed. PMID- 22493162 TI - Content of nutritive components, dietary fibre and energy value of artichoke depending on the variety. AB - BACKGROUND: The artichoke (Cynara scolymus L.) is a perennial plant belonging to Asteraceae family. It is less popular vegetable in Poland but very valuable from nutritive and medicinal points of view plant. MATERIAL AND METHODS: The experiments were conducted in 2008 and 2009 on fi ve artichoke varieties: 'Deutscher Hybrid', 'Emerald F1', Green Globe', 'Gros Camus de Bretague' and 'Kerlouan', grew in Poland, France and Austria. The experimental material was assessed for: dry mass, protein, ash, vitamin C and dietary fiber contents and some mineral components (calcium, magnesium, phosphorus, potassium, sodium, iron, zinc) levels. Also the energy value and total carbohydrates content were calculated in the vegetable. RESULTS: Among assessed varieties, the highest contents of such components as: dry mass (total solids), carbohydrates, ash, vitamin C, sodium, potassium, magnesium, iron were found in 'Gros Camus de Bretague'. The hearts of that artichoke had also higher energy value than others, whereas the lowest ash, phosphorus, sodium, potassium and magnesium were noticed in 'Kerlouan' variety. But the highest values of dietary fiber was observed in that variety. CONCLUSIONS: Basing on performed assessments the differences in nutritive components and dietary fiber, between analysed vegetable varieties were found. PMID- 22493163 TI - The impact of vegan diet on B-12 status in healthy omnivores: five-year prospective study. AB - BACKGROUND: There are no long-term prospective studies assessing the impact of the vegan diet on vitamin B-12 (B-12) status. Many vegans take B-12 supplements irregularly or refuse to adopt them at all, considering them to be "unnatural" products. The use of B-12 fortified food may be an alternative. Therefore, we aimed to estimate the long-term effect of a vegan diet on serum B-12 concentrations in healthy omnivore adults, comparing the influence of natural products consumption and B-12 fortified food. MATERIAL AND METHODS: A five year prospective study was carried out comprising 20 omnivore healthy adult subjects, who moved to strict vegan diet for 5 years. Ten volunteers followed vegan diet based entirely on natural products, while the remaining ten subjects consumed food fortified in B-12. In all subjects serum vitamin B-12 concentration was determined before and 6, 12, 24 and 60 months after the implementation of the diet. RESULTS: A significant decrease (p < 0.0002) of serum B-12 concentrations in the whole studied group was noted after 60 months of vegan diet. However, observed changes were in fact limited to the subgroup consuming exclusively natural products (p < 0.0001). CONCLUSIONS: Transition from omnivore to vegan diet is associated with the risk of vitamin B-12 deficiency. B-12 fortified products might constitute a valuable alternative in vegans refusing to take vitamin supplements. PMID- 22493164 TI - Systematic analysis of dimeric E3-RING interactions reveals increased combinatorial complexity in human ubiquitination networks. AB - Ubiquitination controls the stability or function of many human proteins, thereby regulating a wide range of physiological processes. In most cases the combinatorial pattern of protein interactions that facilitate substrate recognition or modification remain unclear. Moreover, the efficiency of ubiquitination reactions can be altered by the formation of homo- and heterotypic E3-RING complexes. To establish the prevalence and nature of binary E3-RING/E3 RING interactions systematic yeast two-hybrid screens were performed to test 7269 potential interactions between 124 human E3-RING proteins. These studies identified 228 dimeric interactions between 100 E3-RINGs, of which 205 were novel. Complementary co-immunoprecipitation studies were performed to test predicted network interactions, showing a high correlation (64%) with primary yeast two-hybrid data. This data was integrated with known E3-RING interactions, tissue expression profiles and proteomic ubiquitination datasets to facilitate identification of subnetworks in which E3-RING dimerization events have the potential to alter network structure. These results reveal a widespread yet selective pattern of E3-RING dimerization events, which have the potential to confer further combinatorial complexity within human ubiquitination cascades. PMID- 22493165 TI - Bioethics, cultural differences and the problem of moral disagreements in end-of life care: a terror management theory. AB - Cultural differences in end-of-life care and the moral disagreements these sometimes give rise to have been well documented. Even so, cultural considerations relevant to end-of-life care remain poorly understood, poorly guided, and poorly resourced in health care domains. Although there has been a strong emphasis in recent years on making policy commitments to patient-centred care and respecting patient choices, persons whose minority cultural worldviews do not fit with the worldviews supported by the conventional principles of western bioethics face a perpetual struggle in getting their care needs met in a meaningful, safe, and healing way. In this essay, attention is given to exploring why cultural differences exist, why they matter, and how health care providers should treat them in order to reduce the incidence and impact of otherwise preventable harmful moral outcomes in end-of-life care. In addressing these questions, a novel application of the renowned terror management theory will be made. PMID- 22493166 TI - Polyhedral oligomeric silsesquioxane (POSS)-poly(ethylene glycol) (PEG) hybrids as injectable biomaterials. AB - One of the major issues with the currently available injectable biomaterials for hard tissue replacement is the mismatch between their mechanical properties and those of the surrounding bone. Hybrid bone cements that combine the benefits of tough polymeric and bioactive ceramic materials could become a good alternative. In this work, polyhedral oligomeric silsesquioxane (POSS) was copolymerized with poly(ethylene glycol) (PEG) to form injectable in situ cross-linkable hybrid cements. The hybrids were characterized in terms of their mechanical, rheological, handling and in vitro bioactive properties. The results indicated that hybridization improves the mechanical and bioactive properties of POSS and PEG. The Young moduli of the hybrids were lower than those of commercial cements and more similar to those of cancellous bone. Furthermore, the strength of the hybrids was similar to that of commercial cements. Calcium deficient hydroxyapatite grew on the surface of the hybrids after 28 days in PBS, indicating bioactivity. The study showed that PEG-POSS-based hybrid materials are a promising alternative to commercial bone cements. PMID- 22493167 TI - Synthesis and characterization of thermo- and pH-sensitive poly(vinyl alcohol)/poly(N, N-diethylacrylamide-co-itaconic acid) semi-IPN hydrogels. AB - In this paper, a series of thermo- and pH-sensitive poly(vinyl alcohol)/poly(N, N diethylacrylamide-co-itaconic acid) (PVA/P(DEA-co-IA)) semi-interpenetrating polymer network (semi-IPN) hydrogels were synthesized by radical polymerization and semi-IPN technology. The influence of PVA on the property of resulting PVA/P(DEA-co-IA) (PVA/PDI) semi-IPN hydrogels was investigated and characterized. The interior morphology observed by scanning electron microscopy (SEM) revealed that freeze-dried semi-IPN hydrogels had small pore size and interconnected porous network structures. X-ray diffraction (XRD) studies showed that a sharp characteristic peak of PVA in semi-IPN hydrogel could be observed at about 2theta = 20 degrees . The incorporation of PVA decreased the equilibrium swelling ratio of modified hydrogels when compared with a usual PDI hydrogel. The semi-IPN hydrogels exhibited unconventional thermosensitive characteristics, such as faster deswelling rates and slower swelling rates in response to temperature change, and excellent mutative values in response to an alternation of the pH value, the changing degree of which depended on the PVA content. The release behaviors of the model drug, aminophylline, were found to be dependent on hydrogel compositions and the environmental temperature. Compared with the usual PDI hydrogel, the drug release rate of the semi-IPN hydrogel is slower, which could be expected to be useful in the biomedical and biotechnology fields. PMID- 22493169 TI - Reconstruction of applicator positions from multiple-view images for accurate superficial hyperthermia treatment planning. AB - In the current clinical practice, prior to superficial hyperthermia treatments (HT), temperature probes are placed in tissue to document a thermal dose. To investigate whether the painful procedure of catheter placement can be replaced by superficial HT planning, we study if the specific absorption rate (SAR) coverage is predictive for treatment outcome. An absolute requirement for such a study is the accurate reconstruction of the applicator setup. The purpose of this study was to investigate the feasibility of the applicator setup reconstruction from multiple-view images. The accuracy of the multiple-view reconstruction method has been assessed for two experimental setups using six lucite cone applicators (LCAs) representing the largest array applied at our clinic and also the most difficult scenario for the reconstruction. For the two experimental setups and 112 distances, the mean difference between photogrametry reconstructed and manually measured distances was 0.25 +/- 0.79 mm (mean+/-1 standard deviation). By a parameter study of translation T (mm) and rotation R ( degrees ) of LCAs, we showed that these inaccuracies are clinically acceptable, i.e. they are either from +/-1.02 mm error in translation or +/-0.48 degrees in rotation, or combinations expressed by 4.35R(2) + 0.97T(2) = 1. We anticipate that such small errors will not have a relevant influence on the SAR distribution in the treated region. The clinical applicability of the procedure is shown on a patient with a breast cancer recurrence treated with reirradiation plus superficial hyperthermia using the six-LCA array. The total reconstruction procedure of six LCAs from a set of ten photos currently takes around 1.5 h. We conclude that the reconstruction of superficial HT setup from multiple-view images is feasible and only minor errors are found that will have a negligible influence on treatment planning quality. PMID- 22493170 TI - Geobacter luticola sp. nov., an Fe(III)-reducing bacterium isolated from lotus field mud. AB - A novel species of Fe(III)-reducing bacterium, designated strain OSK6(T), belonging to the genus Geobacter, was isolated from lotus field mud in Japan. Strain OSK6(T) was isolated using a solid medium containing acetate, Fe(III) nitrilotriacetate (NTA) and gellan gum. The isolate is a strictly anaerobic, gram negative, motile, straight rod-shaped bacterium, 0.6-1.9 um long and 0.2-0.4 um wide. The growth of the isolate occurred at 20-40 degrees C with optima of 30-37 degrees C and pH 6.5-7.5 in the presence of up to 0.5 g NaCl l(-1). The G+C content of the genomic DNA was determined by HPLC to be 59.7 mol%. The major respiratory quinone was MK-8. The major fatty acids were 16 : 1omega7c and 16 : 0. Strain OSK6(T) was able to grow with Fe(III)-NTA, ferric citrate, amorphous iron (III) hydroxide and nitrate, but not with fumarate, malate or sulfate as electron acceptors. Among examined substrates grown with Fe(III)-NTA, the isolate grew on acetate, lactate, pyruvate and succinate. Analysis of the near full length 16S rRNA gene sequence revealed that strain OSK6(T) is closely related to Geobacter daltonii and Geobacter toluenoxydans with 95.6 % similarity to the type strains of these species. On the basis of phylogenetic analysis and physiological tests, strain OSK6(T) is described as a representative of a novel species, Geobacter luticola sp. nov.; the type strain is OSK6(T) ( = DSM 24905(T) = JCM 17780(T)). PMID- 22493171 TI - Fretibacterium fastidiosum gen. nov., sp. nov., isolated from the human oral cavity. AB - SGP1(T), a strain belonging to a lineage of the phylum Synergistetes with no previously cultivated representatives was subjected to a comprehensive range of phenotypic and genotypic tests. For good growth the strain was dependent on co culture with, or extracts from, selected other oral bacteria. Cells of strain SGP1(T) were asaccharolytic and major amounts of acetic acid and moderate amounts of propionic acid were produced as end products of metabolism in peptone-yeast extract-glucose broth supplemented with a filtered cell sonicate of Fusobacterium nucleatum subsp. nucleatum ATCC 25586(T) (25 %, v/v). Hydrogen sulphide was produced and gelatin was weakly hydrolysed. The major cellular fatty acids were C(14 : 0), C(18 : 0) and C(16 : 0). The DNA G+C content of strain SGP1(T) was 63 mol%. Phylogenetic analysis of the full-length 16S rRNA gene showed that strain SGP1(T) represented a novel group within the phylum Synergistetes. A novel species in a new genus, Fretibacterium fastidiosum gen. nov., sp. nov., is proposed. The type strain of Fretibacterium fastidiosum is SGP1(T) ( = DSM 25557(T) = JCM 16858(T)). PMID- 22493172 TI - Description of Gemmobacter fontiphilus sp. nov., isolated from a freshwater spring, reclassification of Catellibacterium nectariphilum as Gemmobacter nectariphilus comb. nov., Catellibacterium changlense as Gemmobacter changlensis comb. nov., Catellibacterium aquatile as Gemmobacter aquaticus nom. nov., Catellibacterium caeni as Gemmobacter caeni comb. nov., Catellibacterium nanjingense as Gemmobacter nanjingensis comb. nov., and emended description of the genus Gemmobacter and of Gemmobacter aquatilis. AB - A light-yellow-pigmented bacterial strain designated JS43(T) was isolated from a freshwater spring in Taiwan and was characterized using a polyphasic taxonomic approach. Cells of strain JS43(T) were Gram-negative-staining, facultatively anaerobic, rod-shaped, non-motile and non-spore-forming. Growth occurred at 10-30 degrees C (optimum, 25 degrees C), at pH 7.0-10.0 (optimum, pH 7.0-8.0) and with 0-0.5 % (w/v) NaCl (optimum, 0 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain JS43(T) was a member of the family Rhodobacteraceae of the class Alphaproteobacteria. Sequence similarities to type strains of the genera Gemmobacter and Catellibacterium were between 94.6 and 98.1 %. The highest sequence similarity was found with Gemmobacter aquatilis DSM 3857(T). Strain JS43(T) contained C(18 : 1)omega7c as the predominant fatty acid (74.4 %). The major isoprenoid quinone was Q-10 and the DNA G+C content was 69.3 mol%. The polar lipid profile consisted of a mixture of phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, two uncharacterized aminolipids and three uncharacterized phospholipids. The DNA-DNA relatedness values of strain JS43(T) with respect to the phylogenetically related Gemmobacter aquatilis DSM 3857(T), Catellibacterium aquatile A1-9(T) and Catellibacterium caeni DCA-1(T) were less than 70 %. The taxonomic relationship between members of the genera Gemmobacter and Catellibacterium was clarified by means of a direct experimental comparison. Based on phylogenetic, chemotaxonomic and phenotypic data, we propose that all species currently classified in the genus Catellibacterium should be transferred to the genusGemmobacter. The following new combinations are proposed: Catellibacterium nectariphilum is reclassified as Gemmobacter nectariphilus comb. nov. (type strain, AST4(T) = DSM 15620(T) = JCM 11959(T) = NBRC 100046(T)), Catellibacterium changlense as Gemmobacter changlensis comb. nov. (type strain, JA139(T) = CCUG 53722(T) = DSM 18774(T) = JCM 14338(T)), Catellibacterium aquatile as Gemmobacter aquaticus nom. nov. (type strain, A1-9(T) = CGMCC 1.7029(T) = NBRC 104254(T)), Catellibacterium caeni as Gemmobacter caeni comb. nov. (type strain, DCA-1(T) = CGMCC 1.7745(T) = DSM 21823(T)) and Catellibacterium nanjingense as Gemmobacter nanjingensis comb. nov. (type strain, Y12(T) = CCTCC AB 2010218(T) = KCTC 23298(T)). Emended descriptions of the genus Gemmobacter and of Gemmobacter aquatilis are also presented. Strain JS43(T) could be distinguished from recognized species of the genera Gemmobacter and Catellibacterium. It is suggested, on the basis of genotypic and phenotypic characteristics, that strain JS43(T) ( = BCRC 80082(T) = LMG 25376(T)) represents a novel species for which the name Gemmobacter fontiphilus is proposed. PMID- 22493173 TI - Amphibacillus indicireducens sp. nov., an alkaliphile that reduces an indigo dye. AB - Two indigo-reducing alkaliphilic strains, designated strain C40(T) and strain N214, were isolated from a fermented Polygonum Indigo (Polygonum tinctorium Lour.) liquor sample aged for 10 months and obtained from Date City, Hokkaido, Japan. 16S rRNA gene sequence phylogeny suggested that strains C40(T) and N214 were members of the genus Amphibacillus with the closest relative being Amphibacillus xylanus JCM 7361(T) (97.5 % 16S rRNA gene sequence similarity with strain C40(T)), which is the only strain having a 16S rRNA gene sequence similarity higher than 97 % with strain C40(T). Cells of strain C40(T) were Gram stain-positive, facultatively anaerobic, straight rods that were motile by means of peritrichous flagella. The strains grew between 17 and 39 degrees C (optimum, 35 degrees C) and in the pH range of 9.0-12.0. No isoprenoid quinone was detected and the DNA G+C content was 37.5-37.7 mol%. The whole-cell fatty acid profile mainly consisted of iso-C(15 : 0) and anteiso-C(15 : 0). DNA-DNA hybridization of strain C40(T) with Amphibacillus xylanus JCM 7361(T) revealed a DNA-DNA relatedness value of 10+/-3 %. Owing to the differences in phenotypic characteristics and phylogenetic analyses based on 16S rRNA gene sequences, as well as DNA-DNA relatedness data from reported species of the genus Amphibacillus, the isolates merit classification as a novel species in the genus Amphibacillus, for which the name Amphibacillus indicireducens sp. nov. is proposed. The type strain is C40(T) ( = JCM 17250(T) = NCIMB 14686(T)). An additional strain of the species is N214. An emended description of the genus Amphibacillus is provided. PMID- 22493174 TI - Brockia lithotrophica gen. nov., sp. nov., an anaerobic thermophilic bacterium from a terrestrial hot spring. AB - A novel thermophilic bacterium, strain Kam1851(T), was isolated from a terrestrial hot spring of the Uzon Caldera, Kamchatka Peninsula, Russia. Cells of strain Kam1851(T) were spore-forming rods with a gram-positive type of cell wall. Growth was observed between 46 and 78 degrees C, and pH 5.5-8.5. The optimal growth (doubling time, 6.0 h) was at 60-65 degrees C and pH 6.5. The isolate was an obligate anaerobe growing in pre-reduced medium only. It grew on mineral medium with molecular hydrogen or formate as electron donors, and elemental sulfur, thiosulfate or polysulfide as electron acceptors. The main cellular fatty acids were C(16 : 0) (34.2 %), iso-C(16 : 0) (18 %), C(18 : 0) (12.8 %) and iso C(17 : 0) (11.1 %). The G+C content of the genomic DNA of strain Kam1851(T) was 63 mol%. 16S rRNA gene sequence analysis showed that strain Kam1851(T) belonged to the order Thermoanaerobacterales, but it was not closely related to representatives of any genera with validly published names. The most closely related strains, which had no more than 89.2 % sequence similarity, were members of the genera Ammonifex and Caldanaerobacter. On the basis of its phylogenetic position and novel phenotypic features, isolate Kam1851(T) is proposed to represent a novel species in a new genus, Brockia lithotrophica gen. nov., sp. nov.; the type strain of Brockia lithotrophica is Kam1851(T) ( = DSM 22653(T) = VKM B-2685(T)). PMID- 22493175 TI - Arenimonas daechungensis sp. nov., isolated from the sediment of a eutrophic reservoir. AB - A gram-negative, non-motile, non-spore-forming and rod-shaped bacterial strain, CH15-1(T), was isolated from a sediment sample taken from Daechung Reservoir, South Korea, during the late-blooming period of cyanobacteria. Strain CH15-1(T) grew optimally at pH 7.0 and 30 degrees C. A phylogenetic analysis based on 16S rRNA gene sequences confirmed that strain CH15-1(T) belongs to the genus Arenimonas with the similarity range from 92.6-97.4 % and is closely related to Arenimonas oryziterrae YC6267(T) (97.4 %), Arenimonas composti TR7-09(T) (95.4 %), Arenimonas metalli CF5-1(T) (94.7 %), Arenimonas malthae CC-JY-1(T) (94.6 %) and Arenimonas donghaensis HO3-R19(T) (92.6 %). However, the DNA-DNA hybridization between strain CH15-1(T) and the closest strain, Arenimonas oryziterrae YC6267(T), was 8.9-12.9 %. The DNA G+C content was 63.9 mol% compared to A. oryziterrae YC626(T), 65.8 mol%. Strain CH15-1(T) included Q-8 as the major ubiquinone and phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and phosphatidylmonomethylethanolamine as the major polar lipids. The major fatty acids (>5 %) were iso-C(15 : 0), iso-C(16 : 0), iso-C(14 : 0), iso-C(11 : 0) 3-OH, iso-C(17 : 0) and summed feature 9 (iso-C(17 : 1)omega9c and/or C(16 : 0) 10-methyl). On the basis of phylogenetic, phenotypic and genetic data, strain CH15-1(T) was classified in the genus Arenimonas as a member of a novel species, for which the name Arenimonas daechungensis sp. nov. is proposed. The type strain is CH15-1(T) ( = KCTC 23553(T) = DSM 24763(T)). PMID- 22493176 TI - Protein turnover quantification in a multilabeling approach: from data calculation to evaluation. AB - Liquid chromatography coupled to tandem mass spectrometry in combination with stable-isotope labeling is an established and widely spread method to measure gene expression on the protein level. However, it is often not considered that two opposing processes are responsible for the amount of a protein in a cell--the synthesis as well as the degradation. With this work, we provide an integrative, high-throughput method--from the experimental setup to the bioinformatics analysis--to measure synthesis and degradation rates of an organism's proteome. Applicability of the approach is demonstrated with an investigation of heat shock response, a well-understood regulatory mechanism in bacteria, on the biotechnologically relevant Corynebacterium glutamicum. Utilizing a multilabeling approach using both heavy stable nitrogen as well as carbon isotopes cells are metabolically labeled in a pulse-chase experiment to trace the labels' incorporation in newly synthesized proteins and its loss during protein degradation. Our work aims not only at the calculation of protein turnover rates but also at their statistical evaluation, including variance and hierarchical cluster analysis using the rich internet application QuPE. PMID- 22493177 TI - Enhanced peptide identification by electron transfer dissociation using an improved Mascot Percolator. AB - Peptide identification using tandem mass spectrometry is a core technology in proteomics. Latest generations of mass spectrometry instruments enable the use of electron transfer dissociation (ETD) to complement collision induced dissociation (CID) for peptide fragmentation. However, a critical limitation to the use of ETD has been optimal database search software. Percolator is a post-search algorithm, which uses semi-supervised machine learning to improve the rate of peptide spectrum identifications (PSMs) together with providing reliable significance measures. We have previously interfaced the Mascot search engine with Percolator and demonstrated sensitivity and specificity benefits with CID data. Here, we report recent developments in the Mascot Percolator V2.0 software including an improved feature calculator and support for a wider range of ion series. The updated software is applied to the analysis of several CID and ETD fragmented peptide data sets. This version of Mascot Percolator increases the number of CID PSMs by up to 80% and ETD PSMs by up to 60% at a 0.01 q-value (1% false discovery rate) threshold over a standard Mascot search, notably recovering PSMs from high charge state precursor ions. The greatly increased number of PSMs and peptide coverage afforded by Mascot Percolator has enabled a fuller assessment of CID/ETD complementarity to be performed. Using a data set of CID and ETcaD spectral pairs, we find that at a 1% false discovery rate, the overlap in peptide identifications by CID and ETD is 83%, which is significantly higher than that obtained using either stand-alone Mascot (69%) or OMSSA (39%). We conclude that Mascot Percolator is a highly sensitive and accurate post-search algorithm for peptide identification and allows direct comparison of peptide identifications using multiple alternative fragmentation techniques. PMID- 22493180 TI - Energy response of optically stimulated luminescent dosimeters for non-reference measurement locations in a 6 MV photon beam. AB - Optically stimulated luminescent dosimeters (OSLDs) are becoming increasingly popular for measuring an absorbed dose in clinical radiotherapy. OSLDs have known energy dependence, and this is accounted for by either calibrating the OSLD with a specific nominal energy, or using a standard energy correction factor to account for differences between the experimental beam photon energy and the photon energy used to establish the OSLD's sensitivity (e.g., (60)Co). This work is typically done under reference conditions (e.g., at d(max)). The impact of variations in photon spectra on the OSLD response is typically ignored for measurement positions that are different than the reference position. We determined that it is generally necessary to apply an additional non-reference energy correction factor to OSLD measurements made at locations that do not correspond to the reference position, particularly for OSLD measurements made out of-field, where the photon spectra are softer. We determined this energy correction factor for a range of 6 MV photon spectra using two independent methods: Burlin cavity theory and measurements. The non-reference energy correction factor was found to range from 0.97 to 1.00 for in-field measurement locations and from 0.69 to 0.95 for out-of-field measurement locations. The use of a non-reference energy correction factor can improve the accuracy of OSLDs, especially when used out-of-field. PMID- 22493178 TI - A cell surfaceome map for immunophenotyping and sorting pluripotent stem cells. AB - Induction of a pluripotent state in somatic cells through nuclear reprogramming has ushered in a new era of regenerative medicine. Heterogeneity and varied differentiation potentials among induced pluripotent stem cell (iPSC) lines are, however, complicating factors that limit their usefulness for disease modeling, drug discovery, and patient therapies. Thus, there is an urgent need to develop nonmutagenic rapid throughput methods capable of distinguishing among putative iPSC lines of variable quality. To address this issue, we have applied a highly specific chemoproteomic targeting strategy for de novo discovery of cell surface N-glycoproteins to increase the knowledge-base of surface exposed proteins and accessible epitopes of pluripotent stem cells. We report the identification of 500 cell surface proteins on four embryonic stem cell and iPSCs lines and demonstrate the biological significance of this resource on mouse fibroblasts containing an oct4-GFP expression cassette that is active in reprogrammed cells. These results together with immunophenotyping, cell sorting, and functional analyses demonstrate that these newly identified surface marker panels are useful for isolating iPSCs from heterogeneous reprogrammed cultures and for isolating functionally distinct stem cell subpopulations. PMID- 22493179 TI - Overcoming species boundaries in peptide identification with Bayesian information criterion-driven error-tolerant peptide search (BICEPS). AB - Currently, the reliable identification of peptides and proteins is only feasible when thoroughly annotated sequence databases are available. Although sequencing capacities continue to grow, many organisms remain without reliable, fully annotated reference genomes required for proteomic analyses. Standard database search algorithms fail to identify peptides that are not exactly contained in a protein database. De novo searches are generally hindered by their restricted reliability, and current error-tolerant search strategies are limited by global, heuristic tradeoffs between database and spectral information. We propose a Bayesian information criterion-driven error-tolerant peptide search (BICEPS) and offer an open source implementation based on this statistical criterion to automatically balance the information of each single spectrum and the database, while limiting the run time. We show that BICEPS performs as well as current database search algorithms when such algorithms are applied to sequenced organisms, whereas BICEPS only uses a remotely related organism database. For instance, we use a chicken instead of a human database corresponding to an evolutionary distance of more than 300 million years (International Chicken Genome Sequencing Consortium (2004) Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432, 695-716). We demonstrate the successful application to cross-species proteomics with a 33% increase in the number of identified proteins for a filarial nematode sample of Litomosoides sigmodontis. PMID- 22493181 TI - The association between jockey experience and race-day falls in flat racing in Australia. AB - OBJECTIVES: Apprentice thoroughbred racing jockeys have a higher fall rate than their more experienced counterparts. The authors describe rates of occurrence and investigate risk factors for falls among less-experienced thoroughbred flat racing jockeys in Australia who commenced their race riding career between August 2002 and July 2009. METHODS: Data on race-day falls were extracted from stewards' reports. Denominator data were provided by Racing Information Services Australia on races conducted in Australia. HRs were estimated using time-to-event (survival analysis) methods. RESULTS: Factors found to be associated with falls by less experienced jockeys (as indicated by number of career rides or career stage) were older jockey age at commencement of career (p=0.001), fewer previous rides this meeting (p<0.001), fewer previous starts by the horse (p<0.001), younger horse age (p<0.001), lower race grade (p<0.001), lower prize money (p<0.001), shorter race distance (p<0.001) and drier track rating (p<0.001). Apprentice experience was inversely and strongly associated with increased rates of falls (p<0.001). Three indicators of less accomplished horses (lower race grade, fewer previous starts by the horse and less prize money at stake) and two race conditions (drier tracks and shorter race distance) were found to be associated with a progressively higher hazard of falls for less-experienced jockeys. CONCLUSIONS: This study identified factors that preferentially contribute to falls by inexperienced jockeys. The authors suggest that consideration be given to restricting apprentice jockeys with little race-riding experience from riding horses that have not yet won a race (maiden) or that have had few previous race starts. PMID- 22493182 TI - Proteomics identification of annexin A2 as a key mediator in the metastasis and proangiogenesis of endometrial cells in human adenomyosis. AB - Adenomyosis is a common estrogen-dependent disorder of females characterized by a downward extension of the endometrium into the uterine myometrium and neovascularization in ectopic lesions. It accounts for chronic pelvic pain, dysmenorrhea, menorrhagia, and infertility in 8.8-61.5% women worldwide. However, the molecular mechanisms for adenomyosis development remain poorly elucidated. Here, we utilized a two-dimensional polyacrylamide gel electrophoresis/MS-based proteomics analysis to compare and identify differentially expressed proteins in matched ectopic and eutopic endometrium of adenomyosis patients. A total of 93 significantly altered proteins were identified by tandem MS analysis. Further cluster analysis revealed a group of estrogen-responsive proteins as dysregulated in adenomyosis, among which annexin A2, a member of annexin family proteins, was found up-regulated most significantly in the ectopic endometrium of adenomyosis compared with its eutopic counterpart. Overexpression of ANXA2 was validated in ectopic lesions of human adenomyosis and was found to be tightly correlated with markers of epithelial to mesenchymal transition and dysmenorrhea severity of adenomyosis patients. Functional analysis demonstrated that estrogen could remarkably up-regulate ANXA2 and induce epithelial to mesenchymal transition in an in vitro adenomyosis model. Enforced expression of ANXA2 could mediate phenotypic mesenchymal-like cellular changes, with structural and functional alterations in a beta-catenin/T-cell factor (Tcf) signaling-associated manner, which could be reversed by inhibition of ANXA2 expression. We also proved that enforced expression of ANXA2 enhanced the proangiogenic capacity of adenomyotic endometrial cells through HIF-1alpha/VEGF-A pathway. In vivo, we demonstrated that ANXA2 inhibition abrogated endometrial tissue growth, metastasis, and angiogenesis in an adenomyosis nude mice model and significantly alleviated hyperalgesia. Taken together, our data unraveled a dual role for ANXA2 in the pathogenesis of human adenomyosis through conferring endometrial cells both metastatic potential and proangiogenic capacity, which could serve as a potential therapeutic target for the treatment of adenomyosis patients. PMID- 22493184 TI - An analysis of US fertility centre educational materials suggests that informed consent for preimplantation genetic diagnosis may be inadequate. AB - The use of preimplantation genetic diagnosis (PGD) has expanded both in number and scope over the past 2 decades. Initially carried out to avoid the birth of children with severe genetic disease, PGD is now used for a variety of medical and non-medical purposes. While some human studies have concluded that PGD is safe, animal studies and a recent human study suggest that the embryo biopsy procedure may result in neurological problems for the offspring. Given that the long-term safety of PGD has not been clearly established in humans, this study sought to determine how PGD safety is presented to prospective patients by means of a detailed website analysis. The websites of 262 US fertility centres performing PGD were analysed and comments about safety and risk were catalogued. Results of the analysis demonstrated that 78.2% of centre websites did not mention safety or risk of PGD at all. Of the 21.8% of centres that did contain safety or risk information about PGD, 28.1% included statements highlighting the potential risks, 38.6% presented information touting the procedure as safe and 33.3% included statements highlighting potential risks and the overall safety of the procedure. Thus, 86.6% of PGD-performing centres state that PGD is safe and/or fail to disclose any risks on their websites despite the fact that the impact of the procedure on the long-term health of offspring is unproven. This lack of disclosure suggests that informed consent is inadequate; this study examines numerous factors that are likely to inhibit comprehensive discussions of safety. PMID- 22493183 TI - Proteomic study and marker protein identification of Caenorhabditis elegans lipid droplets. AB - Lipid droplets (LDs) are a neutral lipid storage organelle that is conserved across almost all species. Many metabolic syndromes are directly linked to the over-storage of neutral lipids in LDs. The study of LDs in Caenorhabditis elegans (C. elegans) has been difficult because of the lack of specific LD marker proteins. Here we report the purification and proteomic analysis of C. elegans lipid droplets for the first time. We identified 306 proteins, 63% of these proteins were previously known to be LD-proteins, suggesting a similarity between mammalian and C. elegans LDs. Using morphological and biochemical analyses, we show that short-chain dehydrogenase, DHS-3 is almost exclusively localized on C. elegans LDs, indicating that it can be used as a LD marker protein in C. elegans. These results will facilitate further mechanistic studies of LDs in this powerful genetic system, C. elegans. PMID- 22493185 TI - It is the lifetime that matters: public preferences over maximising health and reducing inequalities in health. AB - Scarce healthcare resources can be allocated in many ways. The National Institute for Health and Clinical Excellence in the UK focuses on the size of the benefit relative to costs, yet we know that there is support among clinicians and the general public for reducing inequalities in health. This paper shows how the UK general public trade-off these sometimes competing objectives, and the data we gather allow us to show the weight given to different population groups, for example, 1 extra year of life in full health to someone who would otherwise die at the age of 60 years is worth more than twice as much as an additional year of life to someone who would otherwise die at the age of 70 years. Such data can help inform the rationing decisions faced by all healthcare systems around the world. PMID- 22493186 TI - Ethical issues raised by the introduction of payment for performance in France. AB - CONTEXT: In France, a new payment for performance (P4P) scheme for primary care physicians was introduced in 2009 through the 'Contract for Improving Individual Practice' programme. Its objective was to reduce healthcare expenditures while enhancing improvement in guidelines' observance. Nevertheless, in all countries where the scheme was implemented, it raised several concerns in the domain of professional ethics. OBJECTIVE: To draw out in France the ethical tensions arising in the general practitioner's (GP) profession linked to the introduction of P4P. METHOD: Qualitative research using two focus groups: first one with a sample of GPs who joined P4P and second one with those who did not. All collective interviews were recorded and fully transcribed. An inductive analysis of thematic content with construction of categories was conducted. All the data were triangulated. RESULTS: All participants agreed that conflicts of interest were a real issue, leading to the resurgence of doctor's dirigisme, which could be detrimental for patient's autonomy. GPs who did not join P4P believed that the scheme would lead to patient's selection while those who joined P4P did not. The level of the maximal bonus of the P4P was considered low by all GPs. This was considered as an offense by non-participating GPs, whereas for participating ones, this low level minimised the risk of patient's selection. CONCLUSION: This work identified several areas of ethical tension, some being different from those previously described in other countries. The authors discuss the potential impact of institutional contexts and variability of implementation processes on shaping these differences. PMID- 22493187 TI - Genomic sovereignty and the African promise: mining the African genome for the benefit of Africa. AB - Scientific interest in genomics in Africa is on the rise with a number of funding initiatives aimed specifically at supporting research in this area. Genomics research on material of African origin raises a number of important ethical issues. A prominent concern relates to sample export, which is increasingly seen by researchers and ethics committees across the continent as being problematic. The concept of genomic sovereignty proposes that unique patterns of genomic variation can be found in human populations, and that these are commercially, scientifically or symbolically valuable and in need of protection against exploitation. Although it is appealing as a response to increasing concerns regarding sample export, there are a number of important conceptual problems relating to the term. It is not clear, for instance, whether it is appropriate that ownership over human genomic samples should rest with national governments. Furthermore, ethnic groups in Africa are frequently spread across multiple nation states, and protection offered in one state may not prevent researchers from accessing the same group elsewhere. Lastly, scientific evidence suggests that the assumption that genomic data is unique for population groups is false. Although the frequency with which particular variants are found can differ between groups, such genes or variants per se are not unique to any population group. In this paper, the authors describe these concerns in detail and argue that the concept of genomic sovereignty alone may not be adequate to protect the genetic resources of people of African descent. PMID- 22493188 TI - Realising new health technologies: problems of regulating human stem cells in the USA. AB - Stem cell technology holds the promise of radically changing medicine through the provision of better disease models; the creation of tissue, cells, and organs for therapeutic uses; and the increased personalisation of healthcare. However, the degree to which any of these developments can be realised in the USA rests upon how effective the regulatory environment is in nurturing the technology to market. This article assesses the regulation in terms of its ability to minimise factors which erode the public interest in developing medical innovations (abuse) and promoting them to the market. This requires an overarching review of patent law (and how it fits with anti-trust and contract law); as well as the general regulation of innovation through ethical review, clinical trials, market authorisation, post-market oversight; government lead regulation of stem cells; and finally incorporating the impact of self-regulation by industry. From this assessment, it becomes possible to appreciate that the optimal system of regulation is reliant upon the gentle tweaking of many factors, rather than the wholesale revision of only a few. It also becomes possible to identify that individual tools of regulation have varying impacts. For example, the patent system may be the most open to abuse by individual companies, but as a regulatory framework it has the most mechanisms for dealing with such abuses. However, the biggest impact upon curtailing abuse derives from the self-regulation of the industry. Conversely, government led regulation is open to abuse from political agendas, but it has the greatest capacity to nurture innovation productively. PMID- 22493189 TI - Complete genome sequence of Klebsiella oxytoca KCTC 1686, used in production of 2,3-butanediol. AB - Here we report the full genome sequence of Klebsiella oxytoca KCTC 1686, which is used in production of 2,3-butanediol. The KCTC 1686 strain contains 5,974,109 bp with G+C content of 56.05 mol% and contains 5,488 protein-coding genes and 110 structural RNAs. PMID- 22493190 TI - Complete genome sequence of Enterobacter aerogenes KCTC 2190. AB - This is the first complete genome sequence of the Enterobacter aerogenes species. Here we present the genome sequence of E. aerogenes KCTC 2190, which contains 5,280,350 bp with a G + C content of 54.8 mol%, 4,912 protein-coding genes, and 109 structural RNAs. PMID- 22493191 TI - Genome sequence of the model hyperthermophilic archaeon Thermococcus litoralis NS C. AB - The hyperthermophilic archaeon Thermococcus litoralis strain NS-C, first isolated in 1985, has been a foundational organism for archaeal research in biocatalysis, DNA replication, metabolism, and the discovery of inteins. Here, we present the genome sequence of T. litoralis with a focus on the replication machinery and inteins. PMID- 22493192 TI - Sequence and annotation of Rickettsia sibirica sibirica genome. AB - Rickettsia sibirica sibirica is the causative agent of Siberian or North Asian tick typhus, a tick-borne rickettsiosis known to exist in Siberia and eastern China. Here we present the draft genome of Rickettsia sibirica sibirica strain BJ 90 isolated from Dermacentor sinicus ticks collected in Beijing, China. PMID- 22493193 TI - Whole-genome sequences of Bacillus subtilis and close relatives. AB - We sequenced four strains of Bacillus subtilis and the type strains for two closely related species, Bacillus vallismortis and Bacillus mojavensis. We report the high-quality Sanger genome sequences of B. subtilis subspecies subtilis RO-NN 1 and AUSI98, B. subtilis subspecies spizizenii TU-B-10(T) and DV1-B-1, Bacillus mojavensis RO-H-1(T), and Bacillus vallismortis DV1-F-3(T). PMID- 22493194 TI - Shotgun genome sequence of the large purple photosynthetic bacterium Rhodospirillum photometricum DSM122. AB - Here, we present the shotgun genome sequence of the purple photosynthetic bacterium Rhodospirillum photometricum DSM122. The photosynthetic apparatus of this bacterium has been particularly well studied by microscopy. The knowledge of the genome of this oversize bacterium will allow us to compare it with the other purple bacterial organisms to follow the evolution of the photosynthetic apparatus. PMID- 22493195 TI - Genome sequence of the polyhydroxybutyrate producer Pseudomonas extremaustralis, a highly stress-resistant Antarctic bacterium. AB - Pseudomonas extremaustralis 14-3b presents genes involved in the synthesis of different polyhydroxyalkanoates, in tolerance and degradation of pollutants, and in microaerobic metabolism. Several genomic islands were detected. Genetic machinery could contribute to the adaptability to stressful conditions. This is the first genome sequence reported from a Pseudomonas isolated from cold environments. PMID- 22493196 TI - Draft genome sequence of Rhizobium sp. strain PDO1-076, a bacterium isolated from Populus deltoides. AB - Rhizobium sp. strain PDO1-076 is a plant-associated bacterium isolated from Populus deltoides, and its draft genome sequence is reported. PMID- 22493197 TI - Genome sequence of the persistent Salmonella enterica subsp. enterica serotype Senftenberg strain SS209. AB - Salmonella enterica subsp. enterica serotype Senftenberg is an emerging serotype in poultry production which has been found to persist in animals and the farm environment. We report the genome sequence and annotation of the SS209 strain of S. Senftenberg, isolated from a hatchery, which was identified as persistent in broiler chickens. PMID- 22493198 TI - Genome sequence of the invasive Salmonella enterica subsp. enterica serotype enteritidis strain LA5. AB - Salmonella enterica subsp. enterica serotype Enteritidis is one of the major causes of gastroenteritis in humans due to consumption of poultry derivatives. Here we report the whole-genome sequence and annotation, including the virulence plasmid, of S. Enteritidis LA5, which is a chicken isolate used by numerous laboratories in virulence studies. PMID- 22493199 TI - Genome sequence of "Rickettsia sibirica subsp. mongolitimonae". AB - "Rickettsia sibirica subsp. mongolitimonae" is the agent of lymphangitis associated rickettsiosis, an emerging human disease that has been diagnosed in Europe and Africa. The present study reports the draft genome of Rickettsia sibirica subsp. mongolitimonae strain HA-91. PMID- 22493200 TI - Genome sequence of the naturally plasmid-free Lactobacillus plantarum strain NC8 (CCUG 61730). AB - Lactobacillus plantarum is a highly versatile lactic acid bacterium found in various ecological niches, such as fermented vegetable, meat, and dairy products and the gastrointestinal tract. We sequenced the genome of L. plantarum NC8, a naturally plasmid-free strain, which has been used as a model strain in many laboratories worldwide. PMID- 22493201 TI - Genome sequence of strain HIMB55, a novel marine gammaproteobacterium of the OM60/NOR5 clade. AB - Strain HIMB55 is a phylogenetically unique member of the OM60/NOR5 clade of the Gammaproteobacteria isolated from coastal seawater of Kaneohe Bay on the northeastern shore of Oahu, Hawaii, by extinction culturing in seawater-based oligotrophic medium. Here we present the genome sequence of strain HIMB55, including genes for bacteriochlorophyll-based phototrophy. PMID- 22493202 TI - Genome sequence of Xanthomonas axonopodis pv. punicae strain LMG 859. AB - We report the 4.94-Mb genome sequence of Xanthomonas axonopodis pv. punicae strain LMG 859, the causal agent of bacterial leaf blight disease in pomegranate. The draft genome will aid in comparative genomics, epidemiological studies, and quarantine of this devastating phytopathogen. PMID- 22493203 TI - Genome sequence of Amycolatopsis sp. strain ATCC 39116, a plant biomass-degrading actinomycete. AB - We announce the availability of a high-quality draft of the genome sequence of Amycolatopsis sp. strain 39116, one of few bacterial species that are known to consume the lignin component of plant biomass. This genome sequence will further ongoing efforts to use microorganisms for the conversion of plant biomass into fuels and high-value chemicals. PMID- 22493204 TI - Complete genome sequence of a thermophilic methanogen, Methanocella conradii HZ254, isolated from Chinese rice field soil. AB - Members of the order Methanocellales play a key role in methane emissions in paddy fields. Because of their slow growth and fastidious culture conditions, pure cultures are difficult to isolate and have been unavailable until recently. Here we report the complete genome sequence of a novel isolate in this group, Methanocella conradii strain HZ254. PMID- 22493205 TI - Draft genome sequence of the anaerobic, nitrate-dependent, Fe(II)-oxidizing bacterium Pseudogulbenkiania ferrooxidans strain 2002. AB - Pseudogulbenkiania ferrooxidans strain 2002 was isolated as a lithoautotrophic, Fe(II)-oxidizing, nitrate-reducing bacterium. Phylogenetically, it is in a clade within the family Neisseriaceae in the order Nessieriales of the class Betaproteobacteria. It is anticipated that comparative genomic analysis of this strain with other nitrate-dependent, Fe(II)-oxidizing bacteria will aid in the elucidation of the genetics and biochemistry underlying this critically important geochemical metabolism. PMID- 22493206 TI - Draft genome sequences of Helicobacter pylori strains 17874 and P79. AB - Helicobacter pylori is a human pathogen that colonizes the human gastric mucosa, causing gastritis, duodenal and gastric ulcers, and gastric carcinoma. Here we announce the draft genomes of H. pylori strain 17874, commonly used for studying motility, and P79, a strain for which plasmid vectors have been developed. PMID- 22493207 TI - Genome sequence of a novel member of the genus Psychrobacter isolated from Antarctic soil. AB - Psychrobacter spp. have shown characteristics indicating remarkable capabilities at subzero temperatures that identify them as potential model organisms for the study of low-temperature adaptations. Here we present the draft genome sequence of Psychrobacter sp. PAMC 21119, which was isolated from permafrost soil of Antarctica; this information could provide insight into adaptation and evolution strategies under extreme environmental conditions. PMID- 22493208 TI - Genome sequence of a Salinibacterium sp. isolated from Antarctic soil. AB - The draft genome of Salinibacterium sp. PAMC 21357, isolated from permafrost soil of Antarctica, was determined. Here we present a 3.1-Mb draft genome sequence of Salinibacterium sp. that could provide further insight into the genetic determination of its cold-adaptive properties. PMID- 22493209 TI - Genome sequence of Peptoniphilus rhinitidis 1-13T, an anaerobic coccus strain isolated from clinical specimens. AB - A new Peptoniphilus species has been isolated from samples from a patient who was scheduled for endoscopic sinus surgery for chronic rhinosinusitis. The isolate, Peptoniphilus rhinitidis 1-13(T) (KCTC 5985(T)), can use peptone as a sole carbon source and produce butyrate as a metabolic end product. This is the first report of the draft genome sequence of a novel species in the genus Peptoniphilus within the group of Gram-positive anaerobic cocci. PMID- 22493210 TI - A new chelator in the house. AB - In this issue of Blood, Neufeld and colleagues present promising results on the safety and efficacy of a novel iron chelator for the treatment of transfusional iron overload. PMID- 22493211 TI - Evidence over hope for pregnancy complications. AB - Low molecular weight heparins are widely used to try to prevent pregnancy complications.In this issue of Blood, Martinelli and colleagues report a critical randomized trial that demonstrates no efficacy from such treatment PMID- 22493212 TI - BRAF mutation: supporting diversity in HCL. AB - In this issue of Blood, Xi and colleagues report on v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in hairy cell leukemia (HCL) subsets, demonstrating that BRAF V600E mutations are absent in variant HCL forms and in a subset of classic HCL (HCLc). PMID- 22493213 TI - Does "more" necessarily mean "better"? AB - In this issue of Blood, Leon and colleagues describe the effects of romiplostim, athrombopoietin (Tpo) mimetic peptide, in the mouse model of inherited platelet dysfunction because of mutation of the myosin 9 gene.1 PMID- 22493214 TI - Abeta and C(lot), but not D(egradation). AB - In this issue of Blood, Zamolodchikov and Strickland examine the association of beta-amyloid (Abeta) peptide with fibrin(ogen). These findings shed new light on the relationship between Alzheimer disease and cardiovascular disease, as well as on a novel biochemical mechanism regulating clot stability and dissolution. PMID- 22493215 TI - JAMming the signals. AB - In this issue of Blood, Naik and colleagues have identified a new mechanism used by platelets to inhibit the signals that drive their activation through integrin alphaIIbbeta3,which serves to prevent inappropriate or premature thrombus formation. PMID- 22493216 TI - Azacitidine after allo-SCT: the good without the bad? PMID- 22493217 TI - ESR spectroscopy identifies inhibitory Cu2+ sites in a DNA-modifying enzyme to reveal determinants of catalytic specificity. AB - The relationship between DNA sequence recognition and catalytic specificity in a DNA-modifying enzyme was explored using paramagnetic Cu(2+) ions as probes for ESR spectroscopic and biochemical studies. Electron spin echo envelope modulation spectroscopy establishes that Cu(2+) coordinates to histidine residues in the EcoRI endonuclease homodimer bound to its specific DNA recognition site. The coordinated His residues were identified by a unique use of Cu(2+)-ion based long range distance constraints. Double electron-electron resonance data yield Cu(2+) Cu(2+) and Cu(2+)-nitroxide distances that are uniquely consistent with one Cu(2+) bound to His114 in each subunit. Isothermal titration calorimetry confirms that two Cu(2+) ions bind per complex. Unexpectedly, Mg(2+)-catalyzed DNA cleavage by EcoRI is profoundly inhibited by Cu(2+) binding at these hitherto unknown sites, 13 A away from the Mg(2+) positions in the catalytic centers. Molecular dynamics simulations suggest a model for inhibition of catalysis, whereby the Cu(2+) ions alter critical protein-DNA interactions and water molecule positions in the catalytic sites. In the absence of Cu(2+), the Mg(2+) dependence of EcoRI catalysis shows positive cooperativity, which would enhance EcoRI inactivation of foreign DNA by irreparable double-strand cuts, in preference to readily repaired single-strand nicks. Nonlinear Poisson-Boltzmann calculations suggest that this cooperativity arises because the binding of Mg(2+) in one catalytic site makes the surface electrostatic potential in the distal catalytic site more negative, thus enhancing binding of the second Mg(2+). Taken together, our results shed light on the structural and electrostatic factors that affect site-specific catalysis by this class of endonucleases. PMID- 22493218 TI - Tuning DNA-amphiphile condensate architecture with strongly binding counterions. AB - Electrostatic self-assembly of colloidal and nanoparticles has attracted a lot of attention in recent years, since it offers the possibility of producing novel crystalline structures that have the potential to be used as advanced materials for photonic and other applications. The stoichiometry of these crystals is not constrained by charge neutrality of the two types of particles due to the presence of counterions, and hence a variety of three-dimensional structures have been observed depending on the relative sizes of the particles and their charge. Here we report structural polymorphism of two-dimensional crystals of oppositely charged linear macroions, namely DNA and self-assembled cylindrical micelles of cationic amphiphiles. Our system differs from those studied earlier in terms of the presence of a strongly binding counterion that competes with DNA to bind to the micelle. The presence of these counterions leads to novel structures of these crystals, such as a square lattice and a ?3 x ?3 superlattice of an underlying hexagonal lattice, determined from a detailed analysis of the small-angle diffraction data. These lower-dimensional equilibrium systems can play an important role in developing a deeper theoretical understanding of the stability of crystals of oppositely charged particles. Further, it should be possible to use the same design principles to fabricate structures on a longer length-scale by an appropriate choice of the two macroions. PMID- 22493219 TI - Coupling actin flow, adhesion, and morphology in a computational cell motility model. AB - Cell migration is a pervasive process in many biology systems and involves protrusive forces generated by actin polymerization, myosin dependent contractile forces, and force transmission between the cell and the substrate through adhesion sites. Here we develop a computational model for cell motion that uses the phase-field method to solve for the moving boundary with physical membrane properties. It includes a reaction-diffusion model for the actin-myosin machinery and discrete adhesion sites which can be in a "gripping" or "slipping" mode and integrates the adhesion dynamics with the dynamics of the actin filaments, modeled as a viscous network. To test this model, we apply it to fish keratocytes, fast moving cells that maintain their morphology, and show that we are able to reproduce recent experimental results on actin flow and stress patterns. Furthermore, we explore the phase diagram of cell motility by varying myosin II activity and adhesion strength. Our model suggests that the pattern of the actin flow inside the cell, the cell velocity, and the cell morphology are determined by the integration of actin polymerization, myosin contraction, adhesion forces, and membrane forces. PMID- 22493220 TI - Active contractility in actomyosin networks. AB - Contractile forces are essential for many developmental processes involving cell shape change and tissue deformation. Recent experiments on reconstituted actomyosin networks, the major component of the contractile machinery, have shown that active contractility occurs above a threshold motor concentration and within a window of cross-link concentration. We present a microscopic dynamic model that incorporates two essential aspects of actomyosin self-organization: the asymmetric load response of individual actin filaments and the correlated motor driven events mimicking myosin-induced filament sliding. Using computer simulations, we examine how the concentration and susceptibility of motors contribute to their collective behavior and interplay with the network connectivity to regulate macroscopic contractility. Our model is shown to capture the formation and dynamics of contractile structures and agree with the observed dependence of active contractility on microscopic parameters, including the contractility onset. Cooperative action of load-resisting motors in a force percolating structure integrates local contraction/buckling events into a global contractile state via an active coarsening process, in contrast to the flow transition driven by uncorrelated kicks of susceptible motors. PMID- 22493221 TI - Single-wavelength two-photon excitation-stimulated emission depletion (SW2PE STED) superresolution imaging. AB - We developed a new class of two-photon excitation-stimulated emission depletion (2PE-STED) optical microscope. In this work, we show the opportunity to perform superresolved fluorescence imaging, exciting and stimulating the emission of a fluorophore by means of a single wavelength. We show that a widely used red emitting fluorophore, ATTO647N, can be two-photon excited at a wavelength allowing both 2PE and STED using the very same laser source. This fact opens the possibility to perform 2PE microscopy at four to five times STED-improved resolution, while exploiting the intrinsic advantages of nonlinear excitation. PMID- 22493222 TI - Mechanistic insight into the blocking of CO diffusion in [NiFe]-hydrogenase mutants through multiscale simulation. AB - [NiFe]-hydrogenases are fascinating biological catalysts with potential application in biofuel cells. However, a severe problem in practical application is the strong sensitivity of hydrogenase to gaseous inhibitor molecules such as CO and O(2). Recently, a number of successful protein engineering studies have been reported that aimed at lowering the access of diatomic inhibitors to the active site pocket, but the molecular mechanism conferring increased resistance remained unclear. Here we use a multiscale simulation approach combining molecular dynamics with a master equation formalism to explain the steady drop in CO diffusion rate observed for the mutants V74M L122A, V74M L122M, and V74M of Desulfovibrio fructosovorans [NiFe]-hydrogenase. We find that diffusion in these variants is controlled by two gates, one between residues 74 and 476 and the other between residues 74 and 122. The existence of two control points in different locations explains why the reduction in the experimental diffusion rate does not simply correlate with the width of the main gas channel. We also find that in the more effective mutation (V74M) CO molecules are still able to reach the active site through transitions that are gated by the microsecond dihedral motions of the side chain of R476 and the thermal fluctuations of the width of the gas channel defined by M74 and L122. Reflecting on the molecular information gained from simulation, we discuss future mutation experiments that could further lower the diffusion rates of small ligands inhibiting [NiFe]-hydrogenase. PMID- 22493223 TI - Structure of human Mad1 C-terminal domain reveals its involvement in kinetochore targeting. AB - The spindle checkpoint prevents aneuploidy by delaying anaphase onset until all sister chromatids achieve proper microtubule attachment. The kinetochore-bound checkpoint protein complex Mad1-Mad2 promotes the conformational activation of Mad2 and serves as a catalytic engine of checkpoint signaling. How Mad1 is targeted to kinetochores is not understood. Here, we report the crystal structure of the conserved C-terminal domain (CTD) of human Mad1. Mad1 CTD forms a homodimer and, unexpectedly, has a fold similar to those of the kinetochore binding domains of Spc25 and Csm1. Nonoverlapping Mad1 fragments retain detectable kinetochore targeting. Deletion of the CTD diminishes, does not abolish, Mad1 kinetochore localization. Mutagenesis studies further map the functional interface of Mad1 CTD in kinetochore targeting and implicate Bub1 as its receptor. Our results indicate that CTD is a part of an extensive kinetochore binding interface of Mad1, and rationalize graded kinetochore targeting of Mad1 during checkpoint signaling. PMID- 22493224 TI - Interfacial electronic effects in functional biolayers integrated into organic field-effect transistors. AB - Biosystems integration into an organic field-effect transistor (OFET) structure is achieved by spin coating phospholipid or protein layers between the gate dielectric and the organic semiconductor. An architecture directly interfacing supported biological layers to the OFET channel is proposed and, strikingly, both the electronic properties and the biointerlayer functionality are fully retained. The platform bench tests involved OFETs integrating phospholipids and bacteriorhodopsin exposed to 1-5% anesthetic doses that reveal drug-induced changes in the lipid membrane. This result challenges the current anesthetic action model relying on the so far provided evidence that doses much higher than clinically relevant ones (2.4%) do not alter lipid bilayers' structure significantly. Furthermore, a streptavidin embedding OFET shows label-free biotin electronic detection at 10 parts-per-trillion concentration level, reaching state of-the-art fluorescent assay performances. These examples show how the proposed bioelectronic platform, besides resulting in extremely performing biosensors, can open insights into biologically relevant phenomena involving membrane weak interfacial modifications. PMID- 22493225 TI - Role of the Bering Strait on the hysteresis of the ocean conveyor belt circulation and glacial climate stability. AB - Abrupt climate transitions, known as Dansgaard-Oeschger and Heinrich events, occurred frequently during the last glacial period, specifically from 80-11 thousand years before present, but were nearly absent during interglacial periods and the early stages of glacial periods, when major ice-sheets were still forming. Here we show, with a fully coupled state-of-the-art climate model, that closing the Bering Strait and preventing its throughflow between the Pacific and Arctic Oceans during the glacial period can lead to the emergence of stronger hysteresis behavior of the ocean conveyor belt circulation to create conditions that are conducive to triggering abrupt climate transitions. Hence, it is argued that even for greenhouse warming, abrupt climate transitions similar to those in the last glacial time are unlikely to occur as the Bering Strait remains open. PMID- 22493226 TI - Greater focus needed on methane leakage from natural gas infrastructure. AB - Natural gas is seen by many as the future of American energy: a fuel that can provide energy independence and reduce greenhouse gas emissions in the process. However, there has also been confusion about the climate implications of increased use of natural gas for electric power and transportation. We propose and illustrate the use of technology warming potentials as a robust and transparent way to compare the cumulative radiative forcing created by alternative technologies fueled by natural gas and oil or coal by using the best available estimates of greenhouse gas emissions from each fuel cycle (i.e., production, transportation and use). We find that a shift to compressed natural gas vehicles from gasoline or diesel vehicles leads to greater radiative forcing of the climate for 80 or 280 yr, respectively, before beginning to produce benefits. Compressed natural gas vehicles could produce climate benefits on all time frames if the well-to-wheels CH(4) leakage were capped at a level 45-70% below current estimates. By contrast, using natural gas instead of coal for electric power plants can reduce radiative forcing immediately, and reducing CH(4) losses from the production and transportation of natural gas would produce even greater benefits. There is a need for the natural gas industry and science community to help obtain better emissions data and for increased efforts to reduce methane leakage in order to minimize the climate footprint of natural gas. PMID- 22493227 TI - Transition states of native and drug-resistant HIV-1 protease are the same. AB - HIV-1 protease is an important target for the treatment of HIV/AIDS. However, drug resistance is a persistent problem and new inhibitors are needed. An approach toward understanding enzyme chemistry, the basis of drug resistance, and the design of powerful inhibitors is to establish the structure of enzymatic transition states. Enzymatic transition structures can be established by matching experimental kinetic isotope effects (KIEs) with theoretical predictions. However, the HIV-1 protease transition state has not been previously resolved using these methods. We have measured primary (14)C and (15)N KIEs and secondary (3)H and (18)O KIEs for native and multidrug-resistant HIV-1 protease (I84V). We observed (14)C KIEs ((14)V/K) of 1.029 +/- 0.003 and 1.025 +/- 0.005, (15)N KIEs ((15)V/K) of 0.987 +/- 0.004 and 0.989 +/- 0.003, (18)O KIEs ((18)V/K) of 0.999 +/- 0.003 and 0.993 +/- 0.003, and (3)H KIEs ((3)V/K) KIEs of 0.968 +/- 0.001 and 0.976 +/- 0.001 for the native and I84V enzyme, respectively. The chemical reaction involves nucleophilic water attack at the carbonyl carbon, proton transfer to the amide nitrogen leaving group, and C-N bond cleavage. A transition structure consistent with the KIE values involves proton transfer from the active site Asp-125 (1.32 A) with partial hydrogen bond formation to the accepting nitrogen (1.20 A) and partial bond loss from the carbonyl carbon to the amide leaving group (1.52 A). The KIEs measured for the native and I84V enzyme indicate nearly identical transition states, implying that a true transition-state analogue should be effective against both enzymes. PMID- 22493228 TI - Dynamical quantum Hall effect in the parameter space. AB - Geometric phases in quantum mechanics play an extraordinary role in broadening our understanding of fundamental significance of geometry in nature. One of the best known examples is the Berry phase [M.V. Berry (1984), Proc. Royal. Soc. London A, 392:45], which naturally emerges in quantum adiabatic evolution. So far the applicability and measurements of the Berry phase were mostly limited to systems of weakly interacting quasi-particles, where interference experiments are feasible. Here we show how one can go beyond this limitation and observe the Berry curvature, and hence the Berry phase, in generic systems as a nonadiabatic response of physical observables to the rate of change of an external parameter. These results can be interpreted as a dynamical quantum Hall effect in a parameter space. The conventional quantum Hall effect is a particular example of the general relation if one views the electric field as a rate of change of the vector potential. We illustrate our findings by analyzing the response of interacting spin chains to a rotating magnetic field. We observe the quantization of this response, which we term the rotational quantum Hall effect. PMID- 22493229 TI - Thermodynamic glass transition in a spin glass without time-reversal symmetry. AB - Spin glasses are a longstanding model for the sluggish dynamics that appear at the glass transition. However, spin glasses differ from structural glasses in a crucial feature: they enjoy a time reversal symmetry. This symmetry can be broken by applying an external magnetic field, but embarrassingly little is known about the critical behavior of a spin glass in a field. In this context, the space dimension is crucial. Simulations are easier to interpret in a large number of dimensions, but one must work below the upper critical dimension (i.e., in d < 6) in order for results to have relevance for experiments. Here we show conclusive evidence for the presence of a phase transition in a four-dimensional spin glass in a field. Two ingredients were crucial for this achievement: massive numerical simulations were carried out on the Janus special-purpose computer, and a new and powerful finite-size scaling method. PMID- 22493231 TI - Contributions of local knowledge to the physical limnology of Lake Como, Italy. AB - This article shows how local knowledge may be valuably integrated into a scientific approach in the study of large and complex hydrological systems where data collection at high resolution is a challenge. This claim is supported through a study of the hydrodynamics of a large lake where qualitative data collected from professional fishers was combined with theory to develop a hypothesis that was then verified by numerical modeling. First the fishermen's narratives were found to describe with accuracy internal wave motions that were evident in water column temperature records, which revealed their practical knowledge of the lake's hydrodynamics. Second, local knowledge accounts emphasized the recurrent formation of mesoscale gyres and return flows in certain zones of the lake in stratified conditions, which did not appear in the physical data because of limitations of sampling resolution. We hypothesized that these features developed predominantly because of the interaction of wind-driven internal motions with the lake's bathymetry, and the Earth's rotation in the widest areas of the basin. Numerical simulation results corroborated the fishers' descriptions of the flow paths and supported the hypothesis about their formation. We conclude that the collaboration between scientific and local knowledge groups, although an unusual approach for a physical discipline of the geosciences, is worth exploring in the pursuit of a more comprehensive understanding of complex geophysical systems such as large lakes. PMID- 22493230 TI - Trigger loop dynamics mediate the balance between the transcriptional fidelity and speed of RNA polymerase II. AB - During transcription, RNA polymerase II (RNAPII) must select the correct nucleotide, catalyze its addition to the growing RNA transcript, and move stepwise along the DNA until a gene is fully transcribed. In all kingdoms of life, transcription must be finely tuned to ensure an appropriate balance between fidelity and speed. Here, we used an optical-trapping assay with high spatiotemporal resolution to probe directly the motion of individual RNAPII molecules as they pass through each of the enzymatic steps of transcript elongation. We report direct evidence that the RNAPII trigger loop, an evolutionarily conserved protein subdomain, serves as a master regulator of transcription, affecting each of the three main phases of elongation, namely: substrate selection, translocation, and catalysis. Global fits to the force velocity relationships of RNAPII and its trigger loop mutants support a Brownian ratchet model for elongation, where the incoming NTP is able to bind in either the pre- or posttranslocated state, and movement between these two states is governed by the trigger loop. Comparison of the kinetics of pausing by WT and mutant RNAPII under conditions that promote base misincorporation indicate that the trigger loop governs fidelity in substrate selection and mismatch recognition, and thereby controls aspects of both transcriptional accuracy and rate. PMID- 22493232 TI - Robust self-replication of combinatorial information via crystal growth and scission. AB - Understanding how a simple chemical system can accurately replicate combinatorial information, such as a sequence, is an important question for both the study of life in the universe and for the development of evolutionary molecular design techniques. During biological sequence replication, a nucleic acid polymer serves as a template for the enzyme-catalyzed assembly of a complementary sequence. Enzymes then separate the template and complement before the next round of replication. Attempts to understand how replication could occur more simply, such as without enzymes, have largely focused on developing minimal versions of this replication process. Here we describe how a different mechanism, crystal growth and scission, can accurately replicate chemical sequences without enzymes. Crystal growth propagates a sequence of bits while mechanically-induced scission creates new growth fronts. Together, these processes exponentially increase the number of crystal sequences. In the system we describe, sequences are arrangements of DNA tile monomers within ribbon-shaped crystals. 99.98% of bits are copied correctly and 78% of 4-bit sequences are correct after two generations; roughly 40 sequence copies are made per growth front per generation. In principle, this process is accurate enough for 1,000-fold replication of 4-bit sequences with 50% yield, replication of longer sequences, and darwinian evolution. We thus demonstrate that neither enzymes nor covalent bond formation are required for robust chemical sequence replication. The form of the replicated information is also compatible with the replication and evolution of a wide class of materials with precise nanoscale geometry such as plasmonic nanostructures or heterogeneous protein assemblies. PMID- 22493233 TI - Structure of the Plasmodium 6-cysteine s48/45 domain. AB - The s48/45 domain was first noted in Plasmodium proteins more than 15 y ago. Previously believed to be unique to Plasmodium, the s48/45 domain is present in other aconoidasidans. In Plasmodium, members of the s48/45 family of proteins are localized on the surface of the parasite in different stages, mostly by glycosylphosphatydylinositol-anchoring. Members such as P52 and P36 seem to play a role in invasion of hepatocytes, and Pfs230 and Pfs48/45 are involved in fertilization in the sexual stages and have been consistently studied as targets of transmission-blocking vaccines for years. In this report, we present the molecular structure for the s48/45 domain corresponding to the C-terminal domain of the blood-stage protein Pf12 from Plasmodium falciparum, obtained by NMR. Our results indicate that this domain is a beta-sandwich formed by two sheets with a mixture of parallel and antiparallel strands. Of the six conserved cysteines, two pairs link the beta-sheets by two disulfide bonds, and the third pair forms a bond outside the core. The structure of the s48/45 domain conforms well to the previously defined surface antigen 1 (SAG1)-related-sequence (SRS) fold observed in the SAG family of surface antigens found in Toxoplasma gondii. Despite extreme sequence divergence, remarkable spatial conservation of one of the disulfide bonds is observed, supporting the hypothesis that the domains have evolved from a common ancestor. Furthermore, a homologous domain is present in ephrins, raising the possibility that the precursor of the s48/45 and SRS domains emerged from an ancient transfer to Apicomplexa from metazoan hosts. PMID- 22493234 TI - Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice. AB - Obesity triggers a low-grade systemic inflammation, which plays an important role in the development of obesity-associated metabolic diseases. In searching for links between lipid accumulation and chronic inflammation, we examined invariant natural killer T (iNKT) cells, a subset of T lymphocytes that react with lipids and regulate inflammatory responses. We show that iNKT cells respond to dietary lipid excess and become activated before or at the time of tissue recruitment of inflammatory leukocytes, and that these cells progressively increase proinflammatory cytokine production in obese mice. Such iNKT cells skew other leukocytes toward proinflammatory cytokine production and induce an imbalanced proinflammatory cytokine environment in multiple tissues. Further, iNKT cell deficiency ameliorates tissue inflammation and provides protection against obesity-induced insulin resistance and hepatic steatosis. Conversely, chronic iNKT cell stimulation using a canonical iNKT cell agonist exacerbates tissue inflammation and obesity-associated metabolic disease. These findings place iNKT cells into the complex network linking lipid excess to inflammation in obesity and suggest new therapeutic avenues for obesity-associated metabolic disorders. PMID- 22493235 TI - Spinal 12-lipoxygenase-derived hepoxilin A3 contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors. AB - Peripheral inflammation initiates changes in spinal nociceptive processing leading to hyperalgesia. Previously, we demonstrated that among 102 lipid species detected by LC-MS/MS analysis in rat spinal cord, the most notable increases that occur after intraplantar carrageenan are metabolites of 12-lipoxygenases (12 LOX), particularly hepoxilins (HXA(3) and HXB(3)). Thus, we examined involvement of spinal LOX enzymes in inflammatory hyperalgesia. In the current work, we found that intrathecal (IT) delivery of the LOX inhibitor nordihydroguaiaretic acid prevented the carrageenan-evoked increase in spinal HXB(3) at doses that attenuated the associated hyperalgesia. Furthermore, IT delivery of inhibitors targeting 12-LOX (CDC, Baicalein), but not 5-LOX (Zileuton) dose-dependently attenuated tactile allodynia. Similarly, IT delivery of 12-LOX metabolites of arachidonic acid 12(S)-HpETE, 12(S)-HETE, HXA(3), or HXB(3) evoked profound, persistent tactile allodynia, but 12(S)-HpETE and HXA(3) produced relatively modest, transient heat hyperalgesia. The pronociceptive effect of HXA(3) correlated with enhanced release of Substance P from primary sensory afferents. Importantly, HXA(3) triggered sustained mobilization of calcium in cells stably overexpressing TRPV1 or TRPA1 receptors and in acutely dissociated rodent sensory neurons. Constitutive deletion or antagonists of TRPV1 (AMG9810) or TRPA1 (HC030031) attenuated this action. Furthermore, pretreatment with antihyperalgesic doses of AMG9810 or HC030031 reduced spinal HXA(3)-evoked allodynia. These data indicate that spinal HXA(3) is increased by peripheral inflammation and promotes initiation of facilitated nociceptive processing through direct activation of TRPV1 and TRPA1 at central terminals. PMID- 22493236 TI - Engagement of beta-arrestin by transactivated insulin-like growth factor receptor is needed for V2 vasopressin receptor-stimulated ERK1/2 activation. AB - G protein-coupled receptors (GPCRs) have been shown to activate the mitogen activated protein kinases, ERK1/2, through both G protein-dependent and independent mechanisms. Here, we describe a G protein-independent mechanism that unravels an unanticipated role for beta-arrestins. Stimulation of the V2 vasopressin receptor (V2R) in cultured cells or in vivo in rat kidney medullar collecting ducts led to the activation of ERK1/2 through the metalloproteinase mediated shedding of a factor activating the insulin-like growth factor receptor (IGFR). This process was found to be both Src- and beta-arrestin-dependent. Whereas Src was found to act upstream of the metalloproteinase activation and be required for the release of the IGFR-activating factor, beta-arrestins were found to act downstream of the IGFR transactivation. Unexpectedly, the engagement of beta-arrestins by the IGFR but not by the V2R was needed to promote the vasopressin-stimulated ERK1/2 activation, indicating that a pool of beta arrestins distinct from those beta-arrestins recruited to the V2R acts downstream of the receptor tyrosine kinase to activate ERK1/2. Such a dual site of action for beta-arrestins helps explain the pleiotropic actions of this scaffolding protein. Given the role that V2R-stimulated ERK1/2 plays in kidney cell proliferation, this transactivation mechanism may have important implications for renal pathophysiology. Still, the role of beta-arrestins downstream of a transactivation event is not limited to the V2R, because we observed a similar involvement for an unrelated GPCR (the platelet-activating factor receptor), indicating that it may be a general mechanism shared among GPCRs. PMID- 22493237 TI - Inoculation of bats with European Geomyces destructans supports the novel pathogen hypothesis for the origin of white-nose syndrome. AB - White-nose syndrome (WNS) is an emerging disease of hibernating bats associated with cutaneous infection by the fungus Geomyces destructans (Gd), and responsible for devastating declines of bat populations in eastern North America. Affected bats appear emaciated and one hypothesis is that they spend too much time out of torpor during hibernation, depleting vital fat reserves required to survive the winter. The fungus has also been found at low levels on bats throughout Europe but without mass mortality. This finding suggests that Gd is either native to both continents but has been rendered more pathogenic in North America by mutation or environmental change, or that it recently arrived in North America as an invader from Europe. Thus, a causal link between Gd and mortality has not been established and the reason for its high pathogenicity in North America is unknown. Here we show that experimental inoculation with either North American or European isolates of Gd causes WNS and mortality in the North American bat, Myotis lucifugus. In contrast to control bats, individuals inoculated with either isolate of Gd developed cutaneous infections diagnostic of WNS, exhibited a progressive increase in the frequency of arousals from torpor during hibernation, and were emaciated after 3-4 mo. Our results demonstrate that altered torpor arousal cycles underlie mortality from WNS and provide direct evidence that Gd is a novel pathogen to North America from Europe. PMID- 22493238 TI - Entropy-driven binding of opioid peptides induces a large domain motion in human dipeptidyl peptidase III. AB - Opioid peptides are involved in various essential physiological processes, most notably nociception. Dipeptidyl peptidase III (DPP III) is one of the most important enkephalin-degrading enzymes associated with the mammalian pain modulatory system. Here we describe the X-ray structures of human DPP III and its complex with the opioid peptide tynorphin, which rationalize the enzyme's substrate specificity and reveal an exceptionally large domain motion upon ligand binding. Microcalorimetric analyses point at an entropy-dominated process, with the release of water molecules from the binding cleft ("entropy reservoir") as the major thermodynamic driving force. Our results provide the basis for the design of specific inhibitors that enable the elucidation of the exact role of DPP III and the exploration of its potential as a target of pain intervention strategies. PMID- 22493239 TI - Cotranslational cis-phosphorylation of the COOH-terminal tail is a key priming step in the maturation of cAMP-dependent protein kinase. AB - cAMP-dependent protein kinase A (PKA), ubiquitously expressed in mammalian cells, regulates a plethora of cellular processes through its ability to phosphorylate many protein substrates, including transcription factors, ion channels, apoptotic proteins, transporters, and metabolic enzymes. The PKA catalytic subunit has two phosphorylation sites, a well-studied site in the activation loop (Thr(197)) and another site in the C-terminal tail (Ser(338)) for which the role of phosphorylation is unknown. We show here, using in vitro studies and experiments with S49 lymphoma cells, that cis-autophosphorylation of Ser(338) occurs cotranslationally, when PKA is associated with ribosomes and precedes posttranslational phosphorylation of the activation loop Thr(197). Ser(338) phoshorylation is not required for PKA activity or formation of the holoenzyme complex; however, it is critical for processing and maturation of PKA, and it is a prerequisite for phosphorylation of Thr(197). After Thr(197) and Ser(338) are phosphorylated, both sites are remarkably resistant to phosphatases. Phosphatase resistance of the activation loop, a unique feature of both PKA and PKG, reflects the distinct way that signal transduction dynamics are controlled by cyclic nucleotide-dependent PKs. PMID- 22493240 TI - Mast cells orchestrate type 2 immunity to helminths through regulation of tissue derived cytokines. AB - Mast cells (MCs) are potent inflammatory cells that are distributed throughout mucosal barrier tissues and respond rapidly to pathogenic stimuli. During helminth infections, MCs play an important role as late-stage effectors. However, it is currently unknown whether MCs contribute to the early innate events that determine the priming of adaptive immunity. MC-deficient mouse strains and mice treated with the MC stabilizing agent cromolyn sodium had dramatically reduced Th2 priming and type 2 cytokine production and harbored increased parasite burdens following infection with gastrointestinal helminths (Heligmosomoides polygyrus bakeri and Trichuris muris). In addition, early production of the tissue-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) was significantly diminished in MC-deficient mice and resulted in decreased numbers of infection-elicited IL-25-dependent (Lin(-)CD45(-))CD34(+)Sca-1(+) progenitors, which produced type 2 cytokines and could be differentiated into mast cells ex vivo. Finally, repair of MC deficiency increased production of IL 25, IL-33, and TSLP, restored progenitor cell numbers and Th2 priming, and reduced parasite burden. Our data reveal an innate IgE-independent role for MCs in orchestrating type 2 immune responses via the regulation of IL-25, IL-33, and TSLP. PMID- 22493241 TI - Single-molecule imaging of DNA curtains reveals mechanisms of KOPS sequence targeting by the DNA translocase FtsK. AB - FtsK is a hexameric DNA translocase that participates in the final stages of bacterial chromosome segregation. Here we investigate the DNA-binding and translocation activities of FtsK in real time by imaging fluorescently tagged proteins on nanofabricated curtains of DNA. We show that FtsK preferentially loads at 8-bp KOPS (FtsK Orienting Polar Sequences) sites and that loading is enhanced in the presence of ADP. We also demonstrate that FtsK locates KOPS through a mechanism that does not involve extensive 1D diffusion at the scale of our resolution. Upon addition of ATP, KOPS-bound FtsK translocates in the direction dictated by KOPS polarity, and once FtsK has begun translocating it does not rerecognize KOPS from either direction. However, FtsK can abruptly change directions while translocating along DNA independent of KOPS, suggesting that the ability to reorient on DNA does not arise from DNA sequence-specific effects. Taken together, our data support a model in which FtsK locates KOPS through random collisions, preferentially engages KOPS in the ADP-bound state, translocates in the direction dictated by the polar orientation of KOPS, and is incapable of recognizing KOPS while translocating along DNA. PMID- 22493242 TI - Plant-activated bacterial receptor adenylate cyclases modulate epidermal infection in the Sinorhizobium meliloti-Medicago symbiosis. AB - Legumes and soil bacteria called rhizobia have coevolved a facultative nitrogen fixing symbiosis. Establishment of the symbiosis requires bacterial entry via root hair infection threads and, in parallel, organogenesis of nodules that subsequently are invaded by bacteria. Tight control of nodulation and infection is required to maintain the mutualistic character of the interaction. Available evidence supports a passive bacterial role in nodulation and infection after the microsymbiont has triggered the symbiotic plant developmental program. Here we identify in Sinorhizobium meliloti, the Medicago symbiont, a cAMP-signaling regulatory cascade consisting of three receptor-like adenylate cyclases, a Crp like regulator, and a target gene of unknown function. The cascade is activated specifically by a plant signal during nodule organogenesis. Cascade inactivation results in a hyperinfection phenotype consisting of abortive epidermal infection events uncoupled from nodulation. These findings show that, in response to a plant signal, rhizobia play an active role in the control of infection. We suggest that rhizobia may modulate the plant's susceptibility to infection. This regulatory loop likely aims at optimizing legume infection. PMID- 22493243 TI - Disruption of the 5-lipoxygenase pathway attenuates atherogenesis consequent to COX-2 deletion in mice. AB - Suppression of cyclooxygenase 2 (COX-2)-derived prostacyclin (PGI(2)) is sufficient to explain most elements of the cardiovascular hazard from nonsteroidal antinflammatory drugs (NSAIDs). However, randomized trials are consistent with the emergence of cardiovascular risk during chronic dosing with NSAIDs. Although deletion of the PGI(2) receptor fosters atherogenesis, the importance of COX-2 during development has constrained the use of conventional knockout (KO) mice to address this question. We developed mice in which COX-2 was deleted postnatally, bypassing cardiorenal defects exhibited by conventional KOs. When crossed into ApoE-deficient hyperlipidemic mice, COX-2 deletion accelerated atherogenesis in both genders, with lesions exhibiting leukocyte infiltration and phenotypic modulation of vascular smooth muscle cells, as reflected by loss of alpha-smooth muscle cell actin and up-regulation of vascular cell adhesion molecule-1. Stimulated peritoneal macrophages revealed suppression of COX-2 derived prostanoids and augmented 5-lipoxygenase product formation, consistent with COX-2 substrate rediversion. Although deletion of the 5-lipoxygenase activating protein (FLAP) did not influence atherogenesis, it attenuated the proatherogeneic impact of COX-2 deletion in hyperlipidemic mice. Chronic administration of NSAIDs may increasingly confer a cardiovascular hazard on patients at low initial risk. Promotion of atherogenesis by postnatal COX-2 deletion affords a mechanistic explanation for this observation. Coincident inhibition of FLAP may offer an approach to attenuating such a risk from NSAIDs. PMID- 22493244 TI - Drosophila Golgi membrane protein Ema promotes autophagosomal growth and function. AB - Autophagy is a self-degradative process in which cellular material is enclosed within autophagosomes and trafficked to lysosomes for degradation. Autophagosomal biogenesis is well described; however mechanisms controlling the growth and ultimate size of autophagosomes are unclear. Here we demonstrate that the Drosophila membrane protein Ema is required for the growth of autophagosomes. In an ema mutant, autophagosomes form in response to starvation and developmental cues, and these autophagosomes can mature into autolysosomes; however the autophagosomes are very small, and autophagy is impaired. In fat body cells, Ema localizes to the Golgi complex and is recruited to the membrane of autophagosomes in response to starvation. The Drosophila Golgi protein Lva also is recruited to the periphery of autophagosomes in response to starvation, and this recruitment requires ema. Therefore, we propose that Golgi is a membrane source for autophagosomal growth and that Ema facilitates this process. Clec16A, the human ortholog of Ema, is a candidate autoimmune susceptibility locus. Expression of Clec16A can rescue the autophagosome size defect in the ema mutant, suggesting that regulation of autophagosome morphogenesis may be a fundamental function of this gene family. PMID- 22493245 TI - Transcription from the second heavy-strand promoter of human mtDNA is repressed by transcription factor A in vitro. AB - Cell-based studies support the existence of two promoters on the heavy strand of mtDNA: heavy-strand promoter 1 (HSP1) and HSP2. However, transcription from HSP2 has been reported only once in a cell-free system, and never when recombinant proteins have been used. Here, we document transcription from HSP2 using an in vitro system of defined composition. An oligonucleotide template representing positions 596-685 of mtDNA was sufficient to observe transcription by the human mtRNA polymerase (POLRMT) that was absolutely dependent on mitochondrial transcription factor B2 (TFB2M). POLRMT/TFB2M-dependent transcription was inhibited by concentrations of mitochondrial transcription factor A (TFAM) stoichiometric with the transcription template, a condition that activates transcription from the light-strand promoter (LSP) in vitro. Domains of TFAM required for LSP activation were also required for HSP2 repression, whereas other mtDNA binding proteins failed to alter transcriptional output. Binding sites for TFAM were located on both sides of the start site of transcription from HSP2, suggesting that TFAM binding interferes with POLRMT and/or TFB2M binding. Consistent with a competitive binding model for TFAM repression of HSP2, the impact of TFAM concentration on HSP2 transcription was diminished by elevating the POLRMT and TFB2M concentrations. In the context of our previous studies of LSP and HSP1, it is now clear that three promoters exist in human mtDNA. Each promoter has a unique requirement for and/or response to the level of TFAM present, thus implying far greater complexity in the regulation of mammalian mitochondrial transcription than recognized to date. PMID- 22493246 TI - The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis. AB - Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive human malignancies, is thought to be initiated by KRAS activation. Here we find that transcriptional activation mediated by the Gli family of transcription factors, although dispensable for pancreatic development, is required for Kras-induced proliferation and survival in primary pancreatic epithelial cells in culture and for Kras-driven pancreatic intraepithelial neoplasia and PDAC formation in vivo. Further, ectopic Gli1 activation in the mouse pancreas accelerates Kras-driven tumor formation, underscoring the importance of Gli transcription factors in pancreatic tumorigenesis. Interestingly, we demonstrate Gli-regulated I-kappa-B kinase epsilon (IKBKE) and NF-kappaB activity in pancreatic cancer cells and show that this activity is a critical downstream mediator for Gli-dependent PDAC cell transformation and survival. Together, these studies demonstrate the requirement for Gli in Kras-dependent pancreatic epithelial transformation, suggest a mechanism of Gli-NF-kappaB oncogenic activation, and provide genetic evidence supporting the therapeutic targeting of Gli activity in pancreatic cancer. PMID- 22493248 TI - Fire-free land use in pre-1492 Amazonian savannas. AB - The nature and scale of pre-Columbian land use and the consequences of the 1492 "Columbian Encounter" (CE) on Amazonia are among the more debated topics in New World archaeology and paleoecology. However, pre-Columbian human impact in Amazonian savannas remains poorly understood. Most paleoecological studies have been conducted in neotropical forest contexts. Of studies done in Amazonian savannas, none has the temporal resolution needed to detect changes induced by either climate or humans before and after A.D. 1492, and only a few closely integrate paleoecological and archaeological data. We report a high-resolution 2,150-y paleoecological record from a French Guianan coastal savanna that forces reconsideration of how pre-Columbian savanna peoples practiced raised-field agriculture and how the CE impacted these societies and environments. Our combined pollen, phytolith, and charcoal analyses reveal unexpectedly low levels of biomass burning associated with pre-A.D. 1492 savanna raised-field agriculture and a sharp increase in fires following the arrival of Europeans. We show that pre-Columbian raised-field farmers limited burning to improve agricultural production, contrasting with extensive use of fire in pre-Columbian tropical forest and Central American savanna environments, as well as in present-day savannas. The charcoal record indicates that extensive fires in the seasonally flooded savannas of French Guiana are a post-Columbian phenomenon, postdating the collapse of indigenous populations. The discovery that pre-Columbian farmers practiced fire-free savanna management calls into question the widely held assumption that pre-Columbian Amazonian farmers pervasively used fire to manage and alter ecosystems and offers fresh perspectives on an emerging alternative approach to savanna land use and conservation that can help reduce carbon emissions. PMID- 22493247 TI - Staphylococcal biofilm-forming protein has a contiguous rod-like structure. AB - Staphylococcus aureus and Staphylococcus epidermidis form communities (called biofilms) on inserted medical devices, leading to infections that affect many millions of patients worldwide and cause substantial morbidity and mortality. As biofilms are resistant to antibiotics, device removal is often required to resolve the infection. Thus, there is a need for new therapeutic strategies and molecular data that might assist their development. Surface proteins S. aureus surface protein G (SasG) and accumulation-associated protein (S. epidermidis) promote biofilm formation through their "B" regions. B regions contain tandemly arrayed G5 domains interspersed with approximately 50 residue sequences (herein called E) and have been proposed to mediate intercellular accumulation through Zn(2+)-mediated homodimerization. Although E regions are predicted to be unstructured, SasG and accumulation-associated protein form extended fibrils on the bacterial surface. Here we report structures of E-G5 and G5-E-G5 from SasG and biophysical characteristics of single and multidomain fragments. E sequences fold cooperatively and form interlocking interfaces with G5 domains in a head-to tail fashion, resulting in a contiguous, elongated, monomeric structure. E and G5 domains lack a compact hydrophobic core, and yet G5 domain and multidomain constructs have thermodynamic stabilities only slightly lower than globular proteins of similar size. Zn(2+) does not cause SasG domains to form dimers. The work reveals a paradigm for formation of fibrils on the 100-nm scale and suggests that biofilm accumulation occurs through a mechanism distinct from the "zinc zipper." Finally, formation of two domains by each repeat (as in SasG) might reduce misfolding in proteins when the tandem arrangement of highly similar sequences is advantageous. PMID- 22493249 TI - Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current. AB - Infusion of the chemotherapeutic agent oxaliplatin leads to an acute and a chronic form of peripheral neuropathy. Acute oxaliplatin neuropathy is characterized by sensory paresthesias and muscle cramps that are notably exacerbated by cooling. Painful dysesthesias are rarely reported for acute oxaliplatin neuropathy, whereas a common symptom of chronic oxaliplatin neuropathy is pain. Here we examine the role of the sodium channel isoform Na(V)1.6 in mediating the symptoms of acute oxaliplatin neuropathy. Compound and single-action potential recordings from human and mouse peripheral axons showed that cooling in the presence of oxaliplatin (30-100 MUM; 90 min) induced bursts of action potentials in myelinated A, but not unmyelinated C-fibers. Whole-cell patch-clamp recordings from dissociated dorsal root ganglion (DRG) neurons revealed enhanced tetrodotoxin-sensitive resurgent and persistent current amplitudes in large, but not small, diameter DRG neurons when cooled (22 degrees C) in the presence of oxaliplatin. In DRG neurons and peripheral myelinated axons from Scn8a(med/med) mice, which lack functional Na(V)1.6, no effect of oxaliplatin and cooling was observed. Oxaliplatin significantly slows the rate of fast inactivation at negative potentials in heterologously expressed mNa(V)1.6r in ND7 cells, an effect consistent with prolonged Na(V) open times and increased resurgent and persistent current in native DRG neurons. This finding suggests that Na(V)1.6 plays a central role in mediating acute cooling-exacerbated symptoms following oxaliplatin, and that enhanced resurgent and persistent sodium currents may provide a general mechanistic basis for cold-aggravated symptoms of neuropathy. PMID- 22493250 TI - Effects of self-motion on auditory scene analysis. AB - Auditory scene analysis requires the listener to parse the incoming flow of acoustic information into perceptual "streams," such as sentences from a single talker in the midst of background noise. Behavioral and neural data show that the formation of streams is not instantaneous; rather, streaming builds up over time and can be reset by sudden changes in the acoustics of the scene. Here, we investigated the effect of changes induced by voluntary head motion on streaming. We used a telepresence robot in a virtual reality setup to disentangle all potential consequences of head motion: changes in acoustic cues at the ears, changes in apparent source location, and changes in motor or attentional processes. The results showed that self-motion influenced streaming in at least two ways. Right after the onset of movement, self-motion always induced some resetting of perceptual organization to one stream, even when the acoustic scene itself had not changed. Then, after the motion, the prevalent organization was rapidly biased by the binaural cues discovered through motion. Auditory scene analysis thus appears to be a dynamic process that is affected by the active sensing of the environment. PMID- 22493251 TI - Social environment is associated with gene regulatory variation in the rhesus macaque immune system. AB - Variation in the social environment is a fundamental component of many vertebrate societies. In humans and other primates, adverse social environments often translate into lasting physiological costs. The biological mechanisms associated with these effects are therefore of great interest, both for understanding the evolutionary impacts of social behavior and in the context of human health. However, large gaps remain in our understanding of the mechanisms that mediate these effects at the molecular level. Here we addressed these questions by leveraging the power of an experimental system that consisted of 10 social groups of female macaques, in which each individual's social status (i.e., dominance rank) could be experimentally controlled. Using this paradigm, we show that dominance rank results in a widespread, yet plastic, imprint on gene regulation, such that peripheral blood mononuclear cell gene expression data alone predict social status with 80% accuracy. We investigated the mechanistic basis of these effects using cell type-specific gene expression profiling and glucocorticoid resistance assays, which together contributed to rank effects on gene expression levels for 694 (70%) of the 987 rank-related genes. We also explored the possible contribution of DNA methylation levels to these effects, and identified global associations between dominance rank and methylation profiles that suggest epigenetic flexibility in response to status-related behavioral cues. Together, these results illuminate the importance of the molecular response to social conditions, particularly in the immune system, and demonstrate a key role for gene regulation in linking the social environment to individual physiology. PMID- 22493252 TI - Transcranial direct-current stimulation modulates synaptic mechanisms involved in associative learning in behaving rabbits. AB - Transcranial direct-current stimulation (tDCS) is a noninvasive brain stimulation technique that has been successfully applied for modulation of cortical excitability. tDCS is capable of inducing changes in neuronal membrane potentials in a polarity-dependent manner. When tDCS is of sufficient length, synaptically driven after-effects are induced. The mechanisms underlying these after-effects are largely unknown, and there is a compelling need for animal models to test the immediate effects and after-effects induced by tDCS in different cortical areas and evaluate the implications in complex cerebral processes. Here we show in behaving rabbits that tDCS applied over the somatosensory cortex modulates cortical processes consequent to localized stimulation of the whisker pad or of the corresponding area of the ventroposterior medial (VPM) thalamic nucleus. With longer stimulation periods, poststimulation effects were observed in the somatosensory cortex only after cathodal tDCS. Consistent with the polarity specific effects, the acquisition of classical eyeblink conditioning was potentiated or depressed by the simultaneous application of anodal or cathodal tDCS, respectively, when stimulation of the whisker pad was used as conditioned stimulus, suggesting that tDCS modulates the sensory perception process necessary for associative learning. We also studied the putative mechanisms underlying immediate effects and after-effects of tDCS observed in the somatosensory cortex. Results when pairs of pulses applied to the thalamic VPM nucleus (mediating sensory input) during anodal and cathodal tDCS suggest that tDCS modifies thalamocortical synapses at presynaptic sites. Finally, we show that blocking the activation of adenosine A1 receptors prevents the long-term depression (LTD) evoked in the somatosensory cortex after cathodal tDCS. PMID- 22493253 TI - Footprints of positive selection associated with a mutation (N1575Y) in the voltage-gated sodium channel of Anopheles gambiae. AB - Insecticide resistance is an ideal model to study the emergence and spread of adaptative variants. In the African malaria mosquito, Anopheles gambiae, this is complemented by a strong public health rationale. In this insect, resistance to pyrethroid and DDT insecticides is strongly associated with the mutations L1014F and L1014S within the para voltage-gated sodium channel (VGSC). Across much of West Africa, 1014F frequency approaches fixation. Here, we document the emergence of a mutation, N1575Y, within the linker between domains III-IV of the VGSC. In data extending over 40 kbp of the VGSC 1575Y occurs on only a single long-range haplotype, also bearing 1014F. The 1014F-1575Y haplotype was found in both M and S molecular forms of An. gambiae in West/Central African sample sites separated by up to 2,000 km. In Burkina Faso M form, 1575Y allele frequency rose significantly from 0.053 to 0.172 between 2008 and 2010. Extended haplotype homozygosity analysis of the wild-type 1575N allele showed rapid decay of linkage disequilibrium (LD), in sharp contrast to the extended LD exhibited by 1575Y. A haplotype with long-range LD and high/increasing frequency is a classical sign of strong positive selection acting on a recent mutant. 1575Y occurs ubiquitously on a 1014F haplotypic background, suggesting that the N1575Y mutation compensates for deleterious fitness effects of 1014F and/or confers additional resistance to insecticides. Haplotypic tests of association suggest the latter: The 1014F-1575Y haplotype confers a significant additive benefit above 1014F-1575N for survival to DDT (M form P = 0.03) and permethrin (S form P = 0.003). PMID- 22493254 TI - Bax regulates primary necrosis through mitochondrial dynamics. AB - The defining event in apoptosis is mitochondrial outer membrane permeabilization (MOMP), allowing apoptogen release. In contrast, the triggering event in primary necrosis is early opening of the inner membrane mitochondrial permeability transition pore (mPTP), precipitating mitochondrial dysfunction and cessation of ATP synthesis. Bcl-2 proteins Bax and Bak are the principal activators of MOMP and apoptosis. Unexpectedly, we find that deletion of Bax and Bak dramatically reduces necrotic injury during myocardial infarction in vivo. Triple knockout mice lacking Bax/Bak and cyclophilin D, a key regulator of necrosis, fail to show further reduction in infarct size over those deficient in Bax/Bak. Absence of Bax/Bak renders cells resistant to mPTP opening and necrosis, effects confirmed in isolated mitochondria. Reconstitution of these cells or mitochondria with wild type Bax, or an oligomerization-deficient mutant that cannot support MOMP and apoptosis, restores mPTP opening and necrosis, implicating distinct mechanisms for Bax-regulated necrosis and apoptosis. Both forms of Bax restore mitochondrial fusion in Bax/Bak-null cells, which otherwise exhibit fragmented mitochondria. Cells lacking mitofusin 2 (Mfn2), which exhibit similar fusion defects, are protected to the same extent as Bax/Bak-null cells. Conversely, restoration of fused mitochondria through inhibition of fission potentiates mPTP opening in the absence of Bax/Bak or Mfn2, indicating that the fused state itself is critical. These data demonstrate that Bax-driven fusion lowers the threshold for mPTP opening and necrosis. Thus, Bax and Bak play wider roles in cell death than previously appreciated and may be optimal therapeutic targets for diseases that involve both forms of cell death. PMID- 22493255 TI - Using translational enhancers to increase transgene expression in Drosophila. AB - The ability to specify the expression levels of exogenous genes inserted in the genomes of transgenic animals is critical for the success of a wide variety of experimental manipulations. Protein production can be regulated at the level of transcription, mRNA transport, mRNA half-life, or translation efficiency. In this report, we show that several well-characterized sequence elements derived from plant and insect viruses are able to function in Drosophila to increase the apparent translational efficiency of mRNAs by as much as 20-fold. These increases render expression levels sufficient for genetic constructs previously requiring multiple copies to be effective in single copy, including constructs expressing the temperature-sensitive inactivator of neuronal function Shibire(ts1), and for the use of cytoplasmic GFP to image the fine processes of neurons. PMID- 22493256 TI - Clathrin-mediated endocytosis is inhibited during mitosis. AB - A long-standing paradigm in cell biology is the shutdown of endocytosis during mitosis. There is consensus that transferrin uptake is inhibited after entry into prophase and that it resumes in telophase. A recent study proposed that endocytosis is continuous throughout the cell cycle and that the observed inhibition of transferrin uptake is due to a decrease in available transferrin receptor at the cell surface, and not to a shutdown of endocytosis. This challenge to the established view is gradually becoming accepted. Because of this controversy, we revisited the question of endocytic activity during mitosis. Using an antibody uptake assay and controlling for potential changes in surface receptor density, we demonstrate the strong inhibition of endocytosis in mitosis of CD8 chimeras containing any of the three major internalization motifs for clathrin-mediated endocytosis (YXXPhi, [DE]XXXL[LI], or FXNPXY) or a CD8 protein with the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor. The shutdown is not gradual: We describe a binary switch from endocytosis being "on" in interphase to "off" in mitosis as cells traverse the G(2)/M checkpoint. In addition, we show that the inhibition of transferrin uptake in mitosis occurs despite abundant transferrin receptor at the surface of HeLa cells. Our study finds no support for the recent idea that endocytosis continues during mitosis, and we conclude that endocytosis is temporarily shutdown during early mitosis. PMID- 22493257 TI - Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation. AB - The ability of skeletal muscle to enhance lipid utilization during exercise is a form of metabolic plasticity essential for survival. Conversely, metabolic inflexibility in muscle can cause organ dysfunction and disease. Although the transcription factor Kruppel-like factor 15 (KLF15) is an important regulator of glucose and amino acid metabolism, its endogenous role in lipid homeostasis and muscle physiology is unknown. Here we demonstrate that KLF15 is essential for skeletal muscle lipid utilization and physiologic performance. KLF15 directly regulates a broad transcriptional program spanning all major segments of the lipid-flux pathway in muscle. Consequently, Klf15-deficient mice have abnormal lipid and energy flux, excessive reliance on carbohydrate fuels, exaggerated muscle fatigue, and impaired endurance exercise capacity. Elucidation of this heretofore unrecognized role for KLF15 now implicates this factor as a central component of the transcriptional circuitry that coordinates physiologic flux of all three basic cellular nutrients: glucose, amino acids, and lipids. PMID- 22493258 TI - Y265C DNA polymerase beta knockin mice survive past birth and accumulate base excision repair intermediate substrates. AB - DNA is susceptible to damage by a wide variety of chemical agents that are generated either as byproducts of cellular metabolism or exposure to man-made and harmful environments. Therefore, to maintain genomic integrity, having reliable DNA repair systems is important. DNA polymerase beta is known to be a key player in the base excision repair pathway, and mice devoid of DNA polymerase beta do not live beyond a few hours after birth. In this study, we characterized mice harboring an impaired pol beta variant. This Y265C pol beta variant exhibits slow DNA polymerase activity but WT lyase activity and has been shown to be a mutator polymerase. Mice expressing Y265C pol beta are born at normal Mendelian ratios. However, they are small, and 60% die within a few hours after birth. Slow proliferation and significantly increased levels of cell death are observed in many organs of the E14 homozygous embryos compared with WT littermates. Mouse embryo fibroblasts prepared from the Y265C pol beta embryos proliferate at a rate slower than WT cells and exhibit a gap-filling deficiency during base excision repair. As a result of this, chromosomal aberrations and single- and double strand breaks are present at significantly higher levels in the homozygous mutant versus WT mouse embryo fibroblasts. This is study in mice is unique in that two enzymatic activities of pol beta have been separated; the data clearly demonstrate that the DNA polymerase activity of pol beta is essential for survival and genome stability. PMID- 22493259 TI - Summer temperature variability and long-term survival among elderly people with chronic disease. AB - Time series studies show that hot temperatures are associated with increased death rates in the short term. In light of evidence of adaptation to usual temperature but higher deaths at unusual temperatures, a long-term exposure relevant to mortality might be summertime temperature variability, which is expected to increase with climate change. We investigated whether the standard deviation (SD) of summer (June-August) temperatures was associated with survival in four cohorts of persons over age 65 y with predisposing diseases in 135 US cities. Using Medicare data (1985-2006), we constructed cohorts of persons hospitalized with chronic obstructive pulmonary disease, diabetes, congestive heart failure, and myocardial infarction. City-specific yearly summer temperature variance was linked to the individuals during follow-up in each city and was treated as a time-varying exposure. We applied a Cox proportional hazard model for each cohort within each city, adjusting for individual risk factors, wintertime temperature variance, yearly ozone levels, and long-term trends, to estimate the chronic effects on mortality of long-term exposure to summer temperature SD, and then pooled results across cities. Mortality hazard ratios ranged from 1.028 (95% confidence interval, 1.013- 1.042) per 1 degrees C increase in summer temperature SD for persons with congestive heart failure to 1.040 (95% confidence interval, 1.022-1.059) per 1 degrees C increase for those with diabetes. Associations were higher in elderly persons and lower in cities with a higher percentage of land with green surface. Our data suggest that long term increases in temperature variability may increase the risk of mortality in different subgroups of susceptible older populations. PMID- 22493260 TI - Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. AB - Autophagy is a cellular catabolic pathway by which long-lived proteins and damaged organelles are targeted for degradation. Activation of autophagy enhances cellular tolerance to various stresses. Recent studies indicate that a class of anticancer agents, histone deacetylase (HDAC) inhibitors, can induce autophagy. One of the HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA), is currently being used for treating cutaneous T-cell lymphoma and under clinical trials for multiple other cancer types, including glioblastoma. Here, we show that SAHA increases the expression of the autophagic factor LC3, and inhibits the nutrient sensing kinase mammalian target of rapamycin (mTOR). The inactivation of mTOR results in the dephosphorylation, and thus activation, of the autophagic protein kinase ULK1, which is essential for autophagy activation during SAHA treatment. Furthermore, we show that the inhibition of autophagy by RNAi in glioblastoma cells results in an increase in SAHA-induced apoptosis. Importantly, when apoptosis is pharmacologically blocked, SAHA-induced nonapoptotic cell death can also be potentiated by autophagy inhibition. Overall, our findings indicate that SAHA activates autophagy via inhibiting mTOR and up-regulating LC3 expression; autophagy functions as a prosurvival mechanism to mitigate SAHA-induced apoptotic and nonapoptotic cell death, suggesting that targeting autophagy might improve the therapeutic effects of SAHA. PMID- 22493261 TI - Phosphodiesterases coordinate cAMP propagation induced by two stimulatory G protein-coupled receptors in hearts. AB - Inflammation is a significant player in the progression of heart failure and has detrimental effects on cardiac function. Prostaglandin (PG)E2, a major proinflammatory prostanoid in the cardiovascular system, is a potent stimulus in inducing intracellular cAMP but minimally affects cardiac contractile function. Here, we show that the PGE2 stimulation attenuates the adrenergic-induced cardiac contractile response in animal hearts. Stimulation with PGE2 leads to stimulatory G protein (Gs)-dependent production of cAMP. However, the induced cAMP is spatially restricted because of its degradation by phosphodiesterase (PDE)4 and cannot access the intracellular sarcoplasmic reticulum (SR) for increasing calcium signaling and myocyte contraction. Moreover, pretreatment with PGE2 significantly inhibits PKA activities at the SR induced by a beta-adrenergic agonist, isoproterenol, and subsequently blocks isoproterenol-induced PKA phosphorylation of phospholamban and contractile responses in myocytes. Further analysis reveals that the PGE2-induced cAMP/PKA is sufficient to phosphorylate and activate PDE4D isoforms, which, in turn, spatially inhibits the diffusion of adrenergic-induced cAMP from the plasma membrane to the SR. Inhibition of PDE4 rescues the adrenergic-induced increase in cAMP/PKA activities at the SR, PKA phosphorylation of phospholamban, and contractile responses in PGE2-pretreated myocytes. Thus, this offers an example that one Gs-coupled receptor is able to inhibit the intracellular signaling transduction initiated by another Gs-coupled receptor via controlling the diffusion of cAMP, presenting a paradigm for G protein-coupled receptor (GPCR) signal transduction. It also provides a mechanism for the integration of signaling initiated by different neurohormonal stimuli, as well as long-term effects of chronically circulating proinflammatory factors in myocardium. PMID- 22493262 TI - Aristolochic acid-associated urothelial cancer in Taiwan. AB - Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL) DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53 mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of (5')AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health. PMID- 22493263 TI - QnAs with W. E. Moerner. Interview by Prashant Nair. PMID- 22493264 TI - Neural basis of egalitarian behavior. AB - Individuals are willing to sacrifice their own resources to promote equality in groups. These costly choices promote equality and are associated with behavior that supports cooperation in humans, but little is known about the brain processes involved. We use functional MRI to study egalitarian preferences based on behavior observed in the "random income game." In this game, subjects decide whether to pay a cost to alter group members' randomly allocated incomes. We specifically examine whether egalitarian behavior is associated with neural activity in the ventromedial prefrontal cortex and the insular cortex, two regions that have been shown to be related to social preferences. Consistent with previous studies, we find significant activation in both regions; however, only the insular cortex activations are significantly associated with measures of revealed and expressed egalitarian preferences elicited outside the scanner. These results are consistent with the notion that brain mechanisms involved in experiencing the emotional states of others underlie egalitarian behavior in humans. PMID- 22493265 TI - Heterosis of Arabidopsis hybrids between C24 and Col is associated with increased photosynthesis capacity. AB - Arabidopsis thaliana shows hybrid vigor (heterosis) in progeny of crosses between Columbia-0 and C24 accessions. Hybrid vigor was evident as early as mature seeds and in seedlings 3 d after sowing (DAS). At 3 DAS, genes encoding chloroplast located proteins were significantly overrepresented (187) among the 724 genes that have greater than midparent values of expression in the hybrid. Many of these genes are involved in chlorophyll biosynthesis and photosynthesis. The rate of photosynthesis was constant per unit leaf area in parents and hybrids. Larger cell sizes in the hybrids were associated with more chloroplasts per cell, more total chlorophyll, and more photosynthesis. The increased transcription of the chloroplast-targeted genes was restricted to the 3-7 DAS period. At 10 DAS, only 118 genes had expression levels different from the expected midparent value in the hybrid, and only 12 of these genes were differentially expressed at 3 DAS. The early increase in activity of genes involved in photosynthesis and the associated phenomena of increases in cell size and number through development, leading to larger leaf areas of all leaves in the hybrid, suggest a central role for increased photosynthesis in the production of the heterotic biomass. In support of this correlation, we found that an inhibitor of photosynthesis eliminated heterosis and that higher light intensities enhanced both photosynthesis and heterosis. In hybrids with low-level heterosis (Landsberg erecta x Columbia-0), chloroplast-targeted genes were not up-regulated and leaf areas were only marginally increased. PMID- 22493266 TI - The E. coli CsgB nucleator of curli assembles to beta-sheet oligomers that alter the CsgA fibrillization mechanism. AB - Curli are extracellular proteinaceous functional amyloid aggregates produced by Escherichia coli, Salmonella spp., and other enteric bacteria. Curli mediate host cell adhesion and invasion and play a critical role in biofilm formation. Curli filaments consist of CsgA, the major subunit, and CsgB, the minor subunit. In vitro, purified CsgA and CsgB exhibit intrinsically disordered properties, and both are capable of forming amyloid fibers similar in morphology to those formed in vivo. However, in vivo, CsgA alone cannot form curli fibers, and CsgB is required for filament growth. Thus, we studied the aggregation of CsgA and CsgB both alone and together in vitro to investigate the different roles of CsgA and CsgB in curli formation. We found that though CsgA and CsgB individually are able to self-associate to form aggregates/fibrils, they do so using different mechanisms and with different kinetic behavior. CsgB rapidly forms structured oligomers, whereas CsgA aggregation is slower and appears to proceed through large amorphous aggregates before forming filaments. Substoichiometric concentrations of CsgB induce a change in the mechanism of CsgA aggregation from that of forming amorphous aggregates to that of structured intermediates similar to those of CsgB alone. Oligomeric CsgB accelerated the aggregation of CsgA, in contrast to monomeric CsgB, which had no effect. The structured beta-strand oligomers formed by CsgB serve as nucleators for CsgA aggregation. These results provide insights into the formation of curli in vivo, especially the nucleator function of CsgB. PMID- 22493267 TI - Heritable polymorphism predisposes to high BAALC expression in acute myeloid leukemia. AB - Overexpression of the brain and acute leukemia, cytoplasmic (BAALC) gene is implicated in myeloid leukemogenesis and associated with poor outcome in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients. Additionally, high BAALC expression occurs in glioblastoma, melanoma, and childhood gastrointestinal stroma tumors, suggesting an oncogenic role for BAALC. However, the mechanisms underlying the deregulated expression are unknown. We hypothesized that a common heritable genetic feature located in cis might account for overexpression of BAALC in an allele-specific manner. By sequencing the genomic region of BAALC we identified nine informative single nucleotide polymorphisms (SNPs) and tested them for a possible association with BAALC expression levels. We show that BAALC overexpression occurs in the presence of the T allele of SNP rs62527607[GT], which creates a binding site for the activating RUNX1 transcription factor in the BAALC promoter region. The mechanism is demonstrated experimentally in vitro using luciferase reporter assays and electrophoretic mobility shift assay (EMSA) analysis. The association of high BAALC expression with the T allele and its correlations with RUNX1 expresser status are shown in vivo in a test set (n = 253) and validation set (n = 105) of samples from cytogenetically normal AML patients from different populations. Thus, we identify a heritable genomic feature predisposing to overexpression of an oncogene, thereby possibly leading to enhanced AML leukemogenesis. Our findings further suggest that genomic variants might become useful tools in the practice of personalized medicine. PMID- 22493268 TI - Differential effects of poly(ADP-ribose) polymerase inhibition on DNA break repair in human cells are revealed with Epstein-Barr virus. AB - Poly(ADP-ribose) polymerase (PARP) inhibitors can generate synthetic lethality in cancer cells defective in homologous recombination. However, the mechanism(s) by which they affect DNA repair has not been established. Here we directly determined the effects of PARP inhibition and PARP1 depletion on the repair of ionizing radiation-induced single- and double-strand breaks (SSBs and DSBs) in human lymphoid cell lines. To do this, we developed an in vivo repair assay based on large endogenous Epstein-Barr virus (EBV) circular episomes. The EBV break assay provides the opportunity to assess quantitatively and simultaneously the induction and repair of SSBs and DSBs in human cells. Repair was efficient in G1 and G2 cells and was not dependent on functional p53. shRNA-mediated knockdown of PARP1 demonstrated that the PARP1 protein was not essential for SSB repair. Among 10 widely used PARP inhibitors, none affected DSB repair, although an inhibitor of DNA-dependent protein kinase was highly effective at reducing DSB repair. Only Olaparib and Iniparib, which are in clinical cancer therapy trials, as well as 4 AN inhibited SSB repair. However, a decrease in PARP1 expression reversed the ability of Iniparib to reduce SSB repair. Because Iniparib disrupts PARP1-DNA binding, the mechanism of inhibition does not appear to involve trapping PARP at SSBs. PMID- 22493269 TI - H2O2 activates G protein, alpha 12 to disrupt the junctional complex and enhance ischemia reperfusion injury. AB - The epithelial cell tight junction separates apical and basolateral domains and is essential for barrier function. Disruption of the tight junction is a hallmark of epithelial cell damage and can lead to end organ damage including renal failure. Herein, we identify Galpha12 activation by H(2)O(2) leading to tight junction disruption and demonstrate a critical role for Galpha12 activation during bilateral renal ischemia/reperfusion injury. Madin-Darby canine kidney (MDCK) cells with inducible Galpha12 (Galpha12-MDCK) and silenced Galpha12 (shGalpha12-MDCK) were subjected to ATP depletion/repletion and H(2)O(2)/catalase as models of tight junction disruption and recovery by monitoring transepithelial resistance. In ATP depleted cells, barrier disruption and recovery was not affected by Galpha12, but reassembly was accelerated by Galpha12 depletion. In contrast, silencing of Galpha12 completely protected cells from H(2)O(2) stimulated barrier disruption, a response that rapidly occurred in control cells. H(2)O(2) activated Src and Rho, and Src inhibition (by PP2), but not Rho (by Y27632), protected cells from H(2)O(2)-mediated barrier disruption. Immunofluorescent and biochemical analysis showed that H(2)O(2) led to increased tyrosine phosphorylation of numerous proteins and altered membrane localization of tight junction proteins through Galpha12/Src signaling pathway. Galpha12 and Src were activated in vivo during ischemia/reperfusion injury, and transgenic mice with renal tubular QLalpha12 (activated mutant) expression were delayed in recovery and showed more extensive injury. Conversely, Galpha12 knockout mice were nearly completely protected from ischemia/reperfusion injury. Taken together, these studies reveal that ROS stimulates Galpha12 to activate injury pathways and identifies a therapeutic target for ameliorating ROS mediated injury. PMID- 22493270 TI - Crystal structure of Staphylococcus aureus transglycosylase in complex with a lipid II analog and elucidation of peptidoglycan synthesis mechanism. AB - Bacterial transpeptidase and transglycosylase on the surface are essential for cell wall synthesis, and many antibiotics have been developed to target the transpeptidase; however, the problem of antibiotic resistance has arisen and caused a major threat in bacterial infection. The transglycosylase has been considered to be another excellent target, but no antibiotics have been developed to target this enzyme. Here, we determined the crystal structure of the Staphylococcus aureus membrane-bound transglycosylase, monofunctional glycosyltransferase, in complex with a lipid II analog to 2.3 A resolution. Our results showed that the lipid II-contacting residues are not only conserved in WT and drug-resistant bacteria but also significant in enzymatic activity. Mechanistically, we proposed that K140 and R148 in the donor site, instead of the previously proposed E156, are used to stabilize the pyrophosphate-leaving group of lipid II, and E100 in the acceptor site acts as general base for the 4-OH of GlcNAc to facilitate the transglycosylation reaction. This mechanism, further supported by mutagenesis study and the structure of monofunctional glycosyltransferase in complex with moenomycin in the donor site, provides a direction for antibacterial drugs design. PMID- 22493271 TI - Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy. AB - G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate most cellular responses to hormones and neurotransmitters, representing the largest group of therapeutic targets. Recent studies show that some GPCRs signal through both G protein and arrestin pathways in a ligand-specific manner. Ligands that direct signaling through a specific pathway are known as biased ligands. The arginine-vasopressin type 2 receptor (V2R), a prototypical peptide-activated GPCR, is an ideal model system to investigate the structural basis of biased signaling. Although the native hormone arginine-vasopressin leads to activation of both the stimulatory G protein (Gs) for the adenylyl cyclase and arrestin pathways, synthetic ligands exhibit highly biased signaling through either Gs alone or arrestin alone. We used purified V2R stabilized in neutral amphipols and developed fluorescence-based assays to investigate the structural basis of biased signaling for the V2R. Our studies demonstrate that the Gs-biased agonist stabilizes a conformation that is distinct from that stabilized by the arrestin biased agonists. This study provides unique insights into the structural mechanisms of GPCR activation by biased ligands that may be relevant to the design of pathway-biased drugs. PMID- 22493272 TI - Redox signal-mediated sensitization of transient receptor potential melastatin 2 (TRPM2) to temperature affects macrophage functions. AB - The ability to sense temperature is essential for organism survival and efficient metabolism. Body temperatures profoundly affect many physiological functions, including immunity. Transient receptor potential melastatin 2 (TRPM2) is a thermosensitive, Ca(2+)-permeable cation channel expressed in a wide range of immunocytes. TRPM2 is activated by adenosine diphosphate ribose and hydrogen peroxide (H(2)O(2)), although the activation mechanism by H(2)O(2) is not well understood. Here we report a unique activation mechanism in which H(2)O(2) lowers the temperature threshold for TRPM2 activation, termed "sensitization," through Met oxidation and adenosine diphosphate ribose production. This sensitization is completely abolished by a single mutation at Met-214, indicating that the temperature threshold of TRPM2 activation is regulated by redox signals that enable channel activity at physiological body temperatures. Loss of TRPM2 attenuates zymosan-evoked macrophage functions, including cytokine release and fever-enhanced phagocytic activity. These findings suggest that redox signals sensitize TRPM2 downstream of NADPH oxidase activity and make TRPM2 active at physiological body temperature, leading to increased cytosolic Ca(2+) concentrations. Our results suggest that TRPM2 sensitization plays important roles in macrophage functions. PMID- 22493274 TI - The impacts of molecular motor traffic jams. PMID- 22493273 TI - Neurofibromatosis-like phenotype in Drosophila caused by lack of glucosylceramide extension. AB - Glycosphingolipids (GSLs) are of fundamental importance in the nervous system. However, the molecular details associated with GSL function are largely unknown, in part because of the complexity of GSL biosynthesis in vertebrates. In Drosophila, only one major GSL biosynthetic pathway exists, controlled by the glycosyltransferase Egghead (Egh). Here we discovered that loss of Egh causes overgrowth of peripheral nerves and attraction of immune cells to the nerves. This phenotype is reminiscent of the human disorder neurofibromatosis type 1, which is characterized by disfiguring nerve sheath tumors with mast cell infiltration, increased cancer risk, and learning deficits. Neurofibromatosis type 1 is due to a reduction of the tumor suppressor neurofibromin, a negative regulator of the small GTPase Ras. Enhanced Ras signaling promotes glial growth through activation of phosphatidylinositol 3-kinase (PI3K) and its downstream kinase Akt. We find that overgrowth of peripheral nerves in egh mutants is suppressed by down-regulation of the PI3K signaling pathway by expression of either dominant-negative PI3K, the tumor suppressor PTEN, or the transcription factor FOXO in the subperineurial glia. These results show that loss of the glycosyltransferase Egh affects membrane signaling and activation of PI3K signaling in glia of the peripheral nervous system, and suggest that glycosyltransferases may suppress proliferation. PMID- 22493275 TI - Universal conditions for exact path integration in neural systems. AB - Animals are capable of navigation even in the absence of prominent landmark cues. This behavioral demonstration of path integration is supported by the discovery of place cells and other neurons that show path-invariant response properties even in the dark. That is, under suitable conditions, the activity of these neurons depends primarily on the spatial location of the animal regardless of which trajectory it followed to reach that position. Although many models of path integration have been proposed, no known single theoretical framework can formally accommodate their diverse computational mechanisms. Here we derive a set of necessary and sufficient conditions for a general class of systems that performs exact path integration. These conditions include multiplicative modulation by velocity inputs and a path-invariance condition that limits the structure of connections in the underlying neural network. In particular, for a linear system to satisfy the path-invariance condition, the effective synaptic weight matrices under different velocities must commute. Our theory subsumes several existing exact path integration models as special cases. We use entorhinal grid cells as an example to demonstrate that our framework can provide useful guidance for finding unexpected solutions to the path integration problem. This framework may help constrain future experimental and modeling studies pertaining to a broad class of neural integration systems. PMID- 22493276 TI - Members of the NODE (Nanog and Oct4-associated deacetylase) complex and SOX-2 promote the initiation of a natural cellular reprogramming event in vivo. AB - Differentiated cells can be forced to change identity, either to directly adopt another differentiated identity or to revert to a pluripotent state. Direct reprogramming events can also occur naturally. We recently characterized such an event in Caenorhabditis elegans, in which a rectal cell switches to a neuronal cell. Here we have used this single-cell paradigm to investigate the molecular requirements of direct cell-type conversion, with a focus on the early steps. Our genetic analyses revealed the requirement of sem-4/Sall, egl-27/Mta, and ceh 6/Oct, members of the NODE complex recently identified in embryonic stem (ES) cells, and of the OCT4 partner sox-2, for the initiation of this natural direct reprogramming event. These four factors have been shown to individually impact on ES cell pluripotency; however, whether they act together to control cellular potential during development remained an open question. We further found that, in addition to acting at the same time, these factors physically associate, suggesting that they could act together as a NODE-like complex during this in vivo process. Finally, we have elucidated the functional domains in EGL-27/MTA that mediate its reprogramming activity in this system and have found that modulation of the posterior HOX protein EGL-5 is a downstream event to allow the initiation of Y identity change. Our data reveal unique in vivo functions in a natural direct reprogramming event for these genes that impact on ES cells pluripotency and suggest that conserved nuclear events could be shared between different cell plasticity phenomena across phyla. PMID- 22493277 TI - Prevalence, distribution and antifungal susceptibility profiles of Candida parapsilosis, Candida orthopsilosis and Candida metapsilosis bloodstream isolates. AB - The Candida parapsilosis group encompasses three species: C. parapsilosis, Candida orthopsilosis and Candida metapsilosis. These species are phenotypically indistinguishable, and molecular methods are needed for their detection. We analysed 152 unique blood culture isolates of the C. parapsilosis group obtained during 1997-2011. The isolates were screened by PCR amplification of the gene encoding secondary alcohol dehydrogenase, followed by digestion with the restriction enzyme BanI. Isolates with RFLP patterns distinct from those of the C. parapsilosis group were characterized as C. parapsilosis sensu stricto (90.8 %), C. orthopsilosis (8.6 %) and C. metapsilosis (0.6 %). Antifungal susceptibility tests indicated that all isolates were susceptible to itraconazole, amphotericin B and caspofungin. Although C. orthopsilosis and C. metapsilosis isolates were susceptible to fluconazole, higher MICs (>=2 mg l(-1)) were observed for C. orthopsilosis. Three isolates (2.0 %) of C. parapsilosis sensu stricto were resistant to voriconazole. Five C. parapsilosis isolates (3.3 %) were intermediate, and a single isolate (0.7 %) was resistant (MIC 16 mg l( 1)) to fluconazole. These data were confirmed using reference strains. It was observed that C. parapsilosis isolates were less susceptible to all triazoles, and this finding deserves further attention to assess the appearance of cross resistance phenomena. In conclusion, C. metapsilosis and C. orthopsilosis are involved in a small but significant number of invasive infections in Brazil. PMID- 22493278 TI - Genetic diversity of locus of enterocyte effacement genes of enteropathogenic Escherichia coli isolated from Peruvian children. AB - The aim of this study was to determine the frequency and allele associations of locus of enterocyte effacement encoded esp and tir genes among 181 enteropathogenic Escherichia coli (EPEC) strains (90 diarrhoea-associated and 91 controls) isolated from Peruvian children under 18 months of age. We analysed espA, espB, espD and tir alleles by PCR-RFLP. EPEC strains were isolated with higher frequency from healthy controls (91/424, 21.7%) than from diarrhoeal samples (90/936, 9.6%) (P<0.001); 28.9% of diarrhoeal and 17.6% of control samples were typical EPEC (tEPEC). The distribution of espA alleles (alpha, beta, beta2 and gamma) and espD alleles (alpha, beta, gamma and a new variant, espD-N1) between tEPEC and atypical EPEC (aEPEC) was significantly different (P<0.05). espD-alpha was more common among acute episodes (P<0.05). espB typing resulted in five alleles (alpha, beta, gamma and two new sub-alleles, espB-alpha2 and espB alpha3), while tir-beta and tir-gamma2 were the most common intimin receptor subtypes. Seventy-two combinations of espA, espB, espD and tir alleles were found; the most prevalent combination was espA-beta, espB-beta, espD-beta, tir beta (34/181 strains), which was more frequent among tEPEC strains (P<0.05). Our findings indicate that there is a high degree of heterogeneity among EPEC strains isolated from Peruvian children and that aEPEC and tEPEC variants cluster. PMID- 22493279 TI - Globally dispersed mobile drug-resistance genes in gram-negative bacterial isolates from patients with bloodstream infections in a US urban general hospital. AB - Mobile drug-resistance genes with identical nucleic acid sequences carried by multidrug-resistant Escherichia coli strains that cause community-acquired infections are becomingly increasingly dispersed worldwide. Over a 2-year period, we analysed gram-negative bacterial (GNB) pathogens from the blood of inpatients at an urban public hospital to determine what proportion of these isolates carried such globally dispersed drug-resistance genes. Of 376 GNB isolates, 167 (44 %) were Escherichia coli, 50 (13 %) were Klebsiella pneumoniae, 25 (7 %) were Pseudomonas aeruginosa, 25 (7 %) were Proteus mirabilis and 20 (5 %) were Enterobacter cloacae; the remainder (24 %) comprised 26 different GNB species. Among E. coli isolates, class 1 integrons were detected in 64 (38 %). The most common integron gene cassette configuration was dfrA17-aadA5, found in 30 (25 %) of 119 drug-resistant E. coli isolates and in one isolate of Moraxella morganii. Extended-spectrum beta-lactamase (ESBL) genes were found in 16 E. coli isolates (10 %). These genes with identical sequences were found in nearly 40 % of bloodstream E. coli isolates in the study hospital, as well as in a variety of bacterial species from clinical and non-clinical sources worldwide. Thus, a substantial proportion of bloodstream infections among hospitalized patients were caused by E. coli strains carrying drug-resistance genes that are dispersed globally in a wide variety of bacterial species. PMID- 22493280 TI - Bullous impetigo associated with Abiotrophia defectiva in an immunocompetent adult. AB - Infection of humans by Abiotrophia defectiva, a nutritionally variant streptococcus, most commonly takes the form of endocarditis, though a variety of other manifestations ranging from central nervous system abscesses to orthopaedic infections have been seen. We report here what we believe is the first case of bullous impetigo associated with this organism. PMID- 22493281 TI - Identification of non-tuberculous mycobacteria by real-time PCR coupled with a high-resolution melting system. AB - Non-tuberculous mycobacteria (NTM) are increasingly important opportunistic pathogens responsible for a variety of clinical diseases. The aim of this study was to evaluate a novel technique, real-time PCR coupled with high-resolution melting analysis (real-time PCR-HRMA), for NTM identification. Two pairs of unique primers targeted to the 16S rRNA gene and the 16S-23S internal transcribed spacer region were selected for further evaluation. A total of 149 mycobacterial clinical isolates were subjected to analysis using the real-time PCR-HRMA system. Overall, 134 NTM identified by the 16S rRNA full-gene sequencing method were categorized into four major groups: Mycobacterium avium complex, Mycobacterium chelonae group, Mycobacterium gordonae and Mycobacterium fortuitum group. Of the 134 prevalent mycobacterial isolates, 101 mycobacteria (75.4 %) could be identified correctly by the real-time PCR-HRMA system. The individual sensitivities for the M. avium complex, M. chelonae group, M. gordonae and M. fortuitum groups were 90.9, 89.1, 100 and 36.8 %, respectively. The specificity of identifying these groups varied from 96.4 to 100 %. When identification failed, mostly it was attributable to various species in the M. fortuitum group. The real-time PCR-HRMA system is therefore a rapid and sensitive method for identifying prevalent NTM in a clinical laboratory. PMID- 22493282 TI - Limited detectability of linezolid-resistant Staphylococcus aureus by the Etest method and its improvement using enriched media. AB - The aim of this study was to evaluate Etest for detectability of linezolid resistant meticillin-resistant Staphylococcus aureus (MRSA). The MIC of linezolid obtained by the Etest method in 18 linezolid-resistant strains of MRSA was compared with that obtained using standard agar and broth dilution methods according to Clinical and Laboratory Standards Institute guidelines. The mean linezolid MIC obtained by Etest in 18 linezolid-resistant strains of MRSA using Mueller-Hinton (MH) agar was 12.6-fold lower than that obtained by the agar dilution method, with the result that 78 % of the linezolid-resistant strains were incorrectly classified as linezolid-susceptible. The MIC of linezolid by Etest on brain-heart infusion (BHI) agar had a mean value 2.5-fold lower than that obtained by the agar dilution method, suggesting that replacing MH agar with BHI agar considerably improved the detectability of linezolid-resistant MRSA. Use of blood agar (MH agar supplemented with 5 % sheep blood) and 48 h of incubation resulted in 100 % agreement with the agar and broth dilution methods. Thus, this study revealed that the Etest on MH agar and BHI agar yielded false-negative results in a significant fraction of the linezolid-resistant MRSA. Hence, the use of blood agar and prolonged incubation is highly recommended for the accurate detection of linezolid-resistant MRSA using Etest. PMID- 22493283 TI - Osmotic stress regulates mammalian target of rapamycin (mTOR) complex 1 via c-Jun N-terminal Kinase (JNK)-mediated Raptor protein phosphorylation. AB - mTOR complex 1 (mTORC1) is a multiprotein complex that integrates diverse signals including growth factors, nutrients, and stress to control cell growth. Raptor is an essential component of mTORC1 that functions to recruit specific substrates. Recently, Raptor was suggested to be a key target of regulation of mTORC1. Here, we show that Raptor is phosphorylated by JNK upon osmotic stress. We identified that osmotic stress induces the phosphorylation of Raptor at Ser-696, Thr-706, and Ser-863 using liquid chromatography-tandem mass spectrometry. We found that JNK is responsible for the phosphorylation. The inhibition of JNK abolishes the phosphorylation of Raptor induced by osmotic stress in cells. Furthermore, JNK physically associates with Raptor and phosphorylates Raptor in vitro, implying that JNK is responsible for the phosphorylation of Raptor. Finally, we found that osmotic stress activates mTORC1 kinase activity in a JNK-dependent manner. Our findings suggest that the molecular link between JNK and Raptor is a potential mechanism by which stress regulates the mTORC1 signaling pathway. PMID- 22493285 TI - In vitro targeting of strand transfer by the Ty3 retroelement integrase. AB - The Saccharomyces cerevisiae long terminal repeat retrotransposon Ty3 integrates within one or two nucleotides of the transcription initiation sites of genes transcribed by RNA polymerase III. In this study the minimal components required to re-constitute position-specific strand transfer by Ty3 integrase are defined. Ty3 integrase targeted by a synthetic fusion of RNA polymerase III transcription factor IIIB subunits, Brf1 and TBP, mediated position-specific strand transfer of duplex oligonucleotides representing the ends of the Ty3 cDNA. These results further delimit the TFIIIB domains targeted by the Ty3 element and show that IN is the Ty3 component sufficient in vitro to target integration. These results underscore the commonality of protein interactions that mediate transcription and retrotransposon targeting. Surprisingly, in the presence of MnCl(2), strand transfer was TFIIIB-independent and targeted sequences resembling the Ty3 terminal inverted repeat. PMID- 22493284 TI - Ataxia-Telangiectasia, Mutated (ATM)/Nuclear Factor kappa light chain enhancer of activated B cells (NFkappaB) signaling controls basal and DNA damage-induced transglutaminase 2 expression. AB - Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme that cross-links proteins and its overexpression, linked to a drug resistant phenotype, is commonly observed in cancer cells. Further, up-regulation of TG2 expression occurs during response to various forms of cell stress; however, the molecular mechanisms that drive inducible expression of the TG2 gene (TGM2) require elucidation. Here we show that genotoxic stress induces TG2 expression through the Ataxia-Telangiectasia, Mutated (ATM)/Nuclear Factor kappa light chain enhancer of activated B cells (NFkappaB) signaling pathway. We further document that NFkappaB is both necessary and sufficient to drive constitutive TG2 expression in cultured cell lines. Additionally, shRNA-mediated knockdown or pharmacological inhibition of the ATM kinase results in reduced constitutive TG2 expression and NFkappaB transcriptional activity. We document that the NFkappaB subunit p65 (RelA) interacts with two independent consensus NFkappaB binding sites within the TGM2 promoter, that mutation of either site or pharmacological inhibition of NFkappaB reduces TGM2 promoter activity, and genotoxic stress drives heightened association of p65 with the TGM2 promoter. Finally, we observed that knockdown of either p65 or ATM in MDA-MB-468 breast cancer cells expressing recombinant TG2 partially reduces resistance to doxorubicin, indicating that the drug resistance linked to overexpression of TG2 functions, in part, through p65 and ATM. This work establishes a novel ATM-dependent signaling loop where TG2 and NFkappaB activate each other resulting in sustained activation of NFkappaB and acquisition of a drug-resistant phenotype. PMID- 22493286 TI - Translation initiation on mRNAs bound by nuclear cap-binding protein complex CBP80/20 requires interaction between CBP80/20-dependent translation initiation factor and eukaryotic translation initiation factor 3g. AB - In the cytoplasm of mammalian cells, either cap-binding proteins 80 and 20 (CBP80/20) or eukaryotic translation initiation factor (eIF) 4E can direct the initiation of translation. Although the recruitment of ribosomes to mRNAs during eIF4E-dependent translation (ET) is well characterized, the molecular mechanism for CBP80/20-dependent translation (CT) remains obscure. Here, we show that CBP80/20-dependent translation initiation factor (CTIF), which has been shown to be preferentially involved in CT but not ET, specifically interacts with eIF3g, a component of the eIF3 complex involved in ribosome recruitment. By interacting with eIF3g, CTIF serves as an adaptor protein to bridge the CBP80/20 and the eIF3 complex, leading to efficient ribosome recruitment during CT. Accordingly, down regulation of CTIF using a small interfering RNA causes a redistribution of CBP80 from polysome fractions to subpolysome fractions, without significant consequence to eIF4E distribution. In addition, down-regulation of eIF3g inhibits the efficiency of nonsense-mediated mRNA decay, which is tightly coupled to CT but not to ET. Moreover, the artificial tethering of CTIF to an intercistronic region of dicistronic mRNA results in translation of the downstream cistron in an eIF3 dependent manner. These findings support the idea that CT mechanistically differs from ET. PMID- 22493287 TI - HoxA10 protein regulates transcription of gene encoding fibroblast growth factor 2 (FGF2) in myeloid cells. AB - HoxA10 is a member of a highly conserved family of homeodomain transcription factors that are involved in definitive hematopoiesis and implicated in the pathogenesis of acute myeloid leukemia (AML). During normal hematopoiesis, HoxA10 facilitates myeloid progenitor expansion and impedes myeloid differentiation. To better understand the molecular mechanisms that control these events, we have been identifying and characterizing HoxA10 target genes. In this study, we identified the gene encoding fibroblast growth factor 2 (Fgf2 or basic fibroblast growth factor) as a target gene that is relevant to the biological effects of HoxA10. We identified two cis elements in the proximal FGF2 promoter that are activated by HoxA10 in myeloid progenitor cells and differentiating phagocytes. We determined that Fgf2 expression and secretion are regulated in a HoxA10 dependent manner in these cells. We found that increased Fgf2 production by HoxA10-overexpressing myeloid progenitor cells induced a phosphoinositol 3-kinase dependent increase in beta-catenin protein. This resulted in autocrine stimulation of proliferation in HoxA10-overexpressing cells and hypersensitivity to other cytokines that share this pathway. Therefore, these studies identified expression of Fgf2 as a mechanism by which HoxA10 controls the size of the myeloid progenitor population. These studies also suggested that aberrant production of Fgf2 may contribute to leukemogenesis in the subset of AML with dysregulated Hox expression. Therapeutic targeting of Fgf2-stimulated signaling pathways might be a rational approach to this poor prognosis subset of AML. PMID- 22493288 TI - Atypical membrane-embedded phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) binding site on p47(phox) Phox homology (PX) domain revealed by NMR. AB - The Phox homology (PX) domain is a functional module that targets membranes through specific interactions with phosphoinositides. The p47(phox) PX domain preferably binds phosphatidylinositol 3,4-bisphosphate (PI(3,4)P(2)) and plays a pivotal role in the assembly of phagocyte NADPH oxidase. We describe the PI(3,4)P(2) binding mode of the p47(phox) PX domain as identified by a transferred cross-saturation experiment. The identified PI(3,4)P(2)-binding site, which includes the residues of helices alpha1 and alpha1' and the following loop up to the distorted left-handed PP(II) helix, is located at a unique position, as compared with the phosphoinositide-binding sites of all other PX domains characterized thus far. Mutational analyses corroborated the results of the transferred cross-saturation experiments. Moreover, experiments with intact cells demonstrated the importance of this unique binding site for the function of the NADPH oxidase. The low affinity and selectivity of the atypical phosphoinositide binding site on the p47(phox) PX domain suggest that different types of phosphoinositides sequentially bind to the p47(phox) PX domain, allowing the regulation of the multiple events that characterize the assembly and activation of phagocyte NADPH oxidase. PMID- 22493289 TI - Low NO concentration dependence of reductive nitrosylation reaction of hemoglobin. AB - The reductive nitrosylation of ferric (met)hemoglobin is of considerable interest and remains incompletely explained. We have previously observed that at low NO concentrations the reaction with tetrameric hemoglobin occurs with an observed rate constant that is at least 5 times faster than that observed at higher concentrations. This was ascribed to a faster reaction of NO with a methemoglobin nitrite complex. We now report detailed studies of this reaction of low NO with methemoglobin. Nitric oxide paradoxically reacts with ferric hemoglobin with faster observed rate constants at the lower NO concentration in a manner that is not affected by changes in nitrite concentration, suggesting that it is not a competition between NO and nitrite, as we previously hypothesized. By evaluation of the fast reaction in the presence of allosteric effectors and isolated beta- and alpha-chains of hemoglobin, it appears that NO reacts with a subpopulation of beta-subunit ferric hemes whose population is influenced by quaternary state, redox potential, and hemoglobin dimerization. To further characterize the role of nitrite, we developed a system that oxidizes nitrite to nitrate to eliminate nitrite contamination. Removal of nitrite does not alter reaction kinetics, but modulates reaction products, with a decrease in the formation of S-nitrosothiols. These results are consistent with the formation of NO(2)/N(2)O(3) in the presence of nitrite. The observed fast reductive nitrosylation observed at low NO concentrations may function to preserve NO bioactivity via primary oxidation of NO to form nitrite or in the presence of nitrite to form N(2)O(3) and S nitrosothiols. PMID- 22493290 TI - Impaired manganese metabolism causes mitotic misregulation. AB - Manganese is an essential trace element, whose intracellular levels need to be carefully regulated. Mn(2+) acts as a cofactor for many enzymes and excess of Mn(2+) is toxic. Alterations in Mn(2+) homeostasis affect metabolic functions and mutations in the human Mn(2+)/Ca(2+) transporter ATP2C1 have been linked to Hailey-Hailey disease. By deletion of the yeast orthologue PMR1 we have studied the impact of Mn(2+) on cell cycle progression and show that an excess of cytosolic Mn(2+) alters S-phase transit, induces transcriptional up-regulation of cell cycle regulators, bypasses the need for S-phase cell cycle checkpoints and predisposes to genomic instability. On the other hand, we find that depletion of the Golgi Mn(2+) pool requires a functional morphology checkpoint to avoid the formation of polyploid cells. PMID- 22493291 TI - Neuromedin U type 1 receptor stimulation of A-type K+ current requires the betagamma subunits of Go protein, protein kinase A, and extracellular signal regulated kinase 1/2 (ERK1/2) in sensory neurons. AB - Although neuromedin U (NMU) has been implicated in analgesia, the detailed mechanisms still remain unclear. In this study, we identify a novel functional role of NMU type 1 receptor (NMUR1) in regulating the transient outward K(+) currents (I(A)) in small dorsal root ganglion (DRG) neurons. We found that NMU reversibly increased I(A) in a dose-dependent manner, instead the sustained delayed rectifier K(+) current (I(DR)) was not affected. This NMU-induced I(A) increase was pertussis toxin-sensitive and was totally reversed by NMUR1 knockdown. Intracellular application of GDPbetaS (guanosine 5'-O-(2 thiodiphosphate)), QEHA peptide, or a selective antibody raised against the Galpha(o) or Gbeta blocked the stimulatory effects of NMU. Pretreatment of the cells with the protein kinase A (PKA) inhibitor or ERK inhibitor abolished the NMU-induced I(A) response, whereas inhibition of phosphatidylinositol 3-kinase or PKC had no such effects. Exposure of DRG neurons to NMU markedly induced the phosphorylation of ERK (p-ERK), whereas p-JNK or p-p38 was not affected. Moreover, the NMU-induced p-ERK increase was attenuated by PKA inhibition and activation of PKA by foskolin would mimic the NMU-induced I(A) increase. Functionally, we observed a significant decrease of the firing rate of neuronal action potential induced by NMU and pretreatment of DRG neurons with 4-AP could abolish this effect. In summary, these results suggested that NMU increases I(A) via activation of NMUR1 that couples sequentially to the downstream activities of Gbetagamma of the G(o) protein, PKA, and ERK, which could contribute to its physiological functions including neuronal hypoexcitability in DRG neurons. PMID- 22493293 TI - Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. AB - Despite improvements in first-line therapies, published results on the treatment of relapsed adult acute lymphoblastic leukemia (ALL) show that prognosis is still poor. The aim of the present retrospective analysis of the German Multicenter Study Group for Adult ALL was to identify prognostic factors and options for improvement. A total of 547 patients with a median age of 33 years (range, 15-55) experiencing their first relapse (406 vs 141 shorter or longer than 18 months from diagnosis) were evaluated. The aim of salvage therapy was to achieve a complete remission (CR) with subsequent a stem cell transplantation (SCT). The CR rate (assessed in Philadelphia chromosome- and BCR-ABL-negative ALL without CNS involvement) after the first salvage in relapse after chemotherapy (n = 224) was 42%. After failure of first salvage (n = 82), the CR rate after second salvage was 33%. In relapse after SCT (n = 48) the CR rate after first salvage was 23%. The median overall survival after relapse was 8.4 months and survival was 24% at 3 years. Prognostic factors for survival were relapse localization, response to salvage, performance of SCT, and age. Overall survival appeared superior compared with previously published studies, likely because of the high rate of SCT in the present study (75%). Further improvement may be achieved with earlier relapse detection and experimental approaches in early relapse. PMID- 22493292 TI - Conserved asparagine residue located in binding pocket controls cation selectivity and substrate interactions in neuronal glutamate transporter. AB - Transporters of the major excitatory neurotransmitter glutamate play a crucial role in glutamatergic neurotransmission by removing their substrate from the synaptic cleft. The transport mechanism involves co-transport of glutamic acid with three Na(+) ions followed by countertransport of one K(+) ion. Structural work on the archeal homologue Glt(Ph) indicates a role of a conserved asparagine in substrate binding. According to a recent proposal, this residue may also participate in a novel Na(+) binding site. In this study, we characterize mutants of this residue from the neuronal transporter EAAC1, Asn-451. None of the mutants, except for N451S, were able to exhibit transport. However, the K(m) of this mutant for l-aspartate was increased ~30-fold. Remarkably, the increase for d-aspartate and l-glutamate was 250- and 400-fold, respectively. Moreover, the cation specificity of N451S was altered because sodium but not lithium could support transport. A similar change in cation specificity was observed with a mutant of a conserved threonine residue, T370S, also implicated to participate in the novel Na(+) site together with the bound substrate. In further contrast to the wild type transporter, only l-aspartate was able to activate the uncoupled anion conductance by N451S, but with an almost 1000-fold reduction in apparent affinity. Our results not only provide experimental support for the Na(+) site but also suggest a distinct orientation of the substrate in the binding pocket during the activation of the anion conductance. PMID- 22493294 TI - Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis. AB - Gaucher disease (GD), an inherited macrophage glycosphingolipidosis, manifests with an extraordinary variety of phenotypes that show imperfect correlation with mutations in the GBA gene. In addition to the classic manifestations, patients suffer from increased susceptibility to hematologic and nonhematologic malignancies. The mechanism(s) underlying malignancy in GD is not known, but is postulated to be secondary to macrophage dysfunction and immune dysregulation arising from lysosomal accumulation of glucocerebroside. However, there is weak correlation between GD/cancer phenotype and the systemic burden of glucocerebroside-laden macrophages. Therefore, we hypothesized that genetic modifier(s) may underlie the GD/cancer phenotype. In the present study, the genetic basis of GD/T-cell acute lymphoblastic lymphoma in 2 affected siblings was deciphered through genomic analysis. GBA gene sequencing revealed homozygosity for a novel mutation, D137N. Whole-exome capture and massively parallel sequencing combined with homozygosity mapping identified a homozygous novel mutation in the MSH6 gene that leads to constitutional mismatch repair deficiency syndrome and increased cancer risk. Enzyme studies demonstrated that the D137N mutation in GBA is a pathogenic mutation, and immunohistochemistry confirmed the absence of the MSH6 protein. Therefore, precise phenotype annotation followed by individual genome analysis has the potential to identify genetic modifiers of GD, facilitate personalized management, and provide novel insights into disease pathophysiology. PMID- 22493295 TI - Runx1 regulates embryonic myeloid fate choice in zebrafish through a negative feedback loop inhibiting Pu.1 expression. AB - Proper cell fate choice in myelopoiesis is essential for generating correct numbers of distinct myeloid subsets manifesting a wide spectrum of subset specific activities during development and adulthood. Studies have suggested that myeloid fate choice is primarily regulated by transcription factors; however, new intrinsic regulators and their underlying mechanisms remain to be elucidated. Zebrafish embryonic myelopoiesis gives rise to neutrophils and macrophages and represents a promising system to derive new regulatory mechanisms for myeloid fate decision in vertebrates. Here we present an in vivo study of cell fate specification during zebrafish embryonic myelopoiesis through characterization of the embryos with altered Pu.1, Runx1 activity alone, or their combinations. Genetic analysis shows that low and high Pu.1 activities determine embryonic neutrophilic granulocyte and macrophage fate, respectively. Inactivation and overexpression of Runx1 in zebrafish uncover Runx1 as a key embryonic myeloid fate determinant that favors neutrophil over macrophage fate. Runx1 is induced by high Pu.1 level and in turn transrepresses pu.1 expression, thus constituting a negative feedback loop that fashions a favorable Pu.1 level required for balanced fate commitment to neutrophils versus macrophages. Our findings define a Pu.1 Runx1 regulatory loop that governs the equilibrium between distinct myeloid fates by assuring an appropriate Pu.1 dosage. PMID- 22493296 TI - Targeting recombinant thrombomodulin fusion protein to red blood cells provides multifaceted thromboprophylaxis. AB - Thrombin generates fibrin and activates platelets and endothelium, causing thrombosis and inflammation. Endothelial thrombomodulin (TM) changes thrombin's substrate specificity toward cleavage of plasma protein C into activated protein C (APC), which opposes its thrombotic and inflammatory activities. Endogenous TM activity is suppressed in pathologic conditions, and antithrombotic interventions involving soluble TM are limited by rapid blood clearance. To overcome this problem, we fused TM with a single chain fragment (scFv) of an antibody targeted to red blood cells. scFv/TM catalyzes thrombin-mediated generation of activated protein C and binds to circulating RBCs without apparent damage, thereby prolonging its circulation time and bioavailability orders of magnitude compared with soluble TM. In animal models, a single dose of scFv/TM, but not soluble TM, prevents platelet activation and vascular occlusion by clots. Thus, scFv/TM serves as a prodrug and provides thromboprophylaxis at low doses (0.15 mg/kg) via multifaceted mechanisms inhibiting platelets and coagulation. PMID- 22493297 TI - MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia. AB - Although microRNAs (miRNAs) are increasingly linked to various physiologic processes, including hematopoiesis, their function in the myeloid development is poorly understood. We detected up-regulation of miR-29a and miR-142-3p during myeloid differentiation in leukemia cell lines and CD34(+) hematopoietic stem/progenitor cells. By gain-of-function and loss-of-function experiments, we demonstrated that both miRNAs promote the phorbol 12-myristate 13-acetate-induced monocytic and all-trans-retinoic acid-induced granulocytic differentiation of HL 60, THP-1, or NB4 cells. Both the miRNAs directly inhibited cyclin T2 gene, preventing the release of hypophosphorylated retinoblastoma and resulting in induction of monocytic differentiation. In addition, a target of miR-29a, cyclin dependent kinase 6 gene, and a target of miR-142-3p, TGF-beta-activated kinase 1/MAP3K7 binding protein 2 gene, are involved in the regulation of both monocytic and granulocytic differentiation. A significant decrease of miR-29a and 142-3p levels and an obvious increase in their target protein levels were also observed in blasts from acute myeloid leukemia. By lentivirus-mediated gene transfer, we demonstrated that enforced expression of either miR-29a or miR-142-3p in hematopoietic stem/progenitor cells from healthy controls and acute myeloid leukemia patients down-regulated expression of their targets and promoted myeloid differentiation. These findings confirm that miR-29a and miR-142-3p are key regulators of normal myeloid differentiation and their reduced expression is involved in acute myeloid leukemia development. PMID- 22493300 TI - Legless pathogens: how bacterial physiology provides the key to understanding pathogenicity. AB - This review argues that knowledge of microbial physiology and metabolism is a prerequisite to understanding mechanisms of pathogenicity. The ability of Neisseria gonorrhoeae to cope with stresses such as those found during infection requires a sialyltransferase to sialylate its lipopolysaccharide using host derived CMP-NANA in the human bloodstream, the ability to oxidize lactate that is abundant in the human body, outer-membrane lipoproteins that provide the first line of protection against oxidative and nitrosative stress, regulation of NO reduction independently from the nitrite reductase that forms NO, an extra haem group on the C-terminal extension of a cytochrome oxidase subunit, and a respiratory capacity far in excess of metabolic requirements. These properties are all normal components of neisserial physiology; they would all fail rigid definitions of a pathogenicity determinant. In anaerobic cultures of enteric bacteria, duplicate pathways for nitrate reduction to ammonia provide a selective advantage when nitrate is either abundant or scarce. Selection of these alternative pathways is in part regulated by two parallel two-component regulatory systems. NarX-NarL primarily ensures that nitrate is reduced in preference to thermodynamically less favourable terminal electron acceptors, but NarQ-NarP facilitates reduction of limited quantities of nitrate or other, less favourable, terminal electron acceptors in preference to fermentative growth. How enteric bacteria repair damage caused by nitrosative and oxidative damage inflicted by host defences is less well understood. In both N. gonorrhoeae and Escherichia coli, parallel pathways that duplicate particular biochemical functions are far from redundant, but fulfil specific physiological roles. PMID- 22493299 TI - Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. AB - Immunoglobulin light-chain (AL) amyloidosis is a rare, incurable plasma cell disorder. Its therapy has benefited immensely from the expanding drug armamentarium available for multiple myeloma. Pomalidomide in combination with weekly dexamethasone (Pom/dex) is active among patients with relapsed myeloma. In the present study, we explored the Pom/dex combination in patients with previously treated AL. Patients were eligible for this prospective phase 2 trial if they had had at least one prior regimen and if they had reasonably preserved organ function. Patients were treated with oral Pom/dex. Thirty-three patients were enrolled. The median age was 66 years. Median time from diagnosis to on study was 37 months. Eighty-two percent had cardiac involvement. The confirmed hematologic response rate was 48%, with a median time to response of 1.9 months. Organ improvement was documented in 5 patients. The median overall and progression-free survival rates were 28 and 14 months, respectively; the 1-year overall and progression-free survival rates were 76% and 59%, respectively. There was a discordance between the hematologic response and the N-terminal pro-brain natriuretic peptide response. The most common grade 3-5 adverse events, regardless of attribution, were neutropenia and fatigue. We conclude that pomalidomide appears to be a valuable drug covering an unmet clinical need in patients with previously treated AL. The trial is registered at www.clinicaltrials.gov as NCT00558896. PMID- 22493298 TI - Chronic myelogenous leukemia stem and progenitor cells demonstrate chromosomal instability related to repeated breakage-fusion-bridge cycles mediated by increased nonhomologous end joining. AB - Chromosomal aberrations are an important consequence of genotoxic exposure and contribute to pathogenesis and progression of several malignancies. We investigated the susceptibility to chromosomal aberrations in chronic myelogenous leukemia (CML) progenitors after exposure to ionizing radiation. In normal progenitors, ionizing radiation induced both stable and unstable chromosomal lesions, but only stable aberrations persisted after multiple divisions. In contrast, radiation of chronic phase CML progenitors resulted in enhanced generation of unstable lesions that persisted after multiple divisions. CML progenitors demonstrated active cell cycle checkpoints and increased nonhomologous end joining DNA repair, suggesting that persistence of unstable aberrations was the result of continued generation of these lesions. CML progenitors demonstrated enhanced susceptibility to repeated cycles of chromosome damage, repair, and damage through a breakage-fusion-bridge mechanism. Perpetuation of breakage-fusion-bridge cycles in CML progenitors was mediated by classic nonhomologous end joining repair. These studies reveal a previously unrecognized mechanism of chromosomal instability in leukemia progenitors because of continued generation of unstable chromosomal lesions through repeated cycles of breakage and repair of such lesions. PMID- 22493301 TI - A low-molecular-mass aspartic protease inhibitor from a novel Penicillium sp.: implications in combating fungal infections. AB - A low-molecular-mass aspartic protease inhibitor was isolated from a novel Penicillium sp. The inhibitor was purified to homogeneity, as shown by reversed phase HPLC and SDS-PAGE. The M(r) of the inhibitor was 1585 and the amino acid composition showed the presence of D, D, D, E, A, K, L, Y, H, I and W residues. The steady-state kinetic interactions of Aspergillus saitoi aspartic protease with the inhibitor revealed the reversible, competitive, time-dependent tight binding nature of the inhibitor, with IC(50) and K(i) values of 1.8 and 0.85 uM, respectively. Fluorescence spectroscopy and circular dichroism analysis showed that inactivation of the enzyme was due to binding of the inhibitor to the active site. The inhibitor was found to inhibit mycelial growth and spore germination of Aspergillus fumigatus and Aspergillus niger in vitro with MIC values of 1.65 and 0.30 ug ml(-1), respectively. This study will potentially open the way towards the development of a tight-binding peptidic inhibitor against fungal aspartic proteases to combat human fungal infections. PMID- 22493302 TI - Cyclopropanation of alpha-mycolic acids is not required for cording in Mycobacterium brumae and Mycobacterium fallax. AB - The capacity to form microscopic cords (cording) of Mycobacterium species has been related to their virulence. The compounds responsible for cording are unknown, but a recent study has shown that cording could be related to the fine structure of alpha-mycolic acids. This investigation attributes the need for a proximal cyclopropane in alpha-mycolic acids for cording in Mycobacterium tuberculosis and Mycobacterium bovis BCG and proposes cyclopropanases as good targets for new chemotherapeutic agents. As other Mycobacterium species in addition to M. tuberculosis and M. bovis form microscopic cords, it would be of major interest to know whether the relationship between proximal cyclopropanation of alpha-mycolic acids and cording could be extended to non-tuberculous mycobacteria. In this study, we have examined the correlation between the cording and cyclopropanation of alpha-mycolic acids in two species, Mycobacterium brumae and Mycobacterium fallax. Scanning electron microscopy images showed, for the first time to our knowledge, the fine structure of microscopic cords of M. brumae and M. fallax, confirming that these two species form true cords. Furthermore, NMR analysis performed on the same cording cultures corroborates the absence of cyclopropane rings in their alpha-mycolic acids. Therefore, we can conclude that the correlation between cording and cyclopropanation of alpha-mycolic acids cannot be extended to all mycobacteria. As M. brumae and M. fallax grow rapidly and have a simple pattern of mycolic acids (only alpha-unsaturated mycolic acids), we propose these two species as suitable models for the study of the role of mycolic acids in cording. PMID- 22493303 TI - Outer-membrane cytochrome-independent reduction of extracellular electron acceptors in Shewanella oneidensis. AB - Dissimilatory metal reduction under pH-neutral conditions is dependent on an extended respiratory chain to the cell surface. The final reduction is catalysed by outer-membrane cytochromes that transfer respiratory electrons either directly to mineral surfaces and metal ions bound in larger organic complexes such as Fe(III) citrate, or indirectly using endogenous or exogenous electron shuttles such as humic acids and flavins. Consequently, a Shewanella oneidensis deletion mutant devoid of outer-membrane cytochromes is unable to reduce Fe(III) citrate or manganese oxide minerals and reduces humic acids at lower rates. Surprisingly, the phenotype of this quintuple deletion mutant can be rescued by a suppressor mutation, which enables metal or humic acid reduction without any outer-membrane cytochrome. Furthermore, the type II secretion system, essential for metal reduction in wild-type S. oneidensis, is not necessary for the suppressor strain. Using genome sequencing we identified two point mutations in key genes for metal reduction: mtrA and mtrB. These mutations are necessary and sufficient to account for the observed phenotype. This study is the first evidence for a catabolic, outer-membrane cytochrome-independent electron transport chain to ferric iron, manganese oxides and humic acid analogues operating in a mesophilic organism. Available bioinformatic data allow the hypothesis that outer-membrane cytochrome independent electron transfer might resemble an evolutionary intermediate between ferrous iron-oxidizing and ferric iron-reducing micro-organisms. PMID- 22493305 TI - Transcriptional regulation of nitrate assimilation in Pseudomonas aeruginosa occurs via transcriptional antitermination within the nirBD-PA1779-cobA operon. AB - Bioinformatic approaches employed to analyse intergenic regions of Pseudomonas aeruginosa O1 (PAO1) for small RNAs (sRNAs) revealed a putative RNA gene encoded upstream of the nitrate assimilation operon nirBD-PA1779-cobA. Here, we show that this RNA, termed nitrogen assimilation leader A (NalA), represents the leader RNA of the nirBD-PA1779-cobA operon, and that nalA transcription is sigma(54)- and NtrC-dependent. A PAO1 nalA deletion strain and a strain bearing a deletion in ORF PA1785 failed to grow on nitrate. PA1785 was identified as a homologue of the Azotobacter vinelandii nasT gene, the product of which is required for transcription of the A. vinelandii nitrite/nitrate reductase operon. Collectively, these studies reveal that transcriptional antitermination of the leader RNA NalA is required for expression of the PAO1 nitrate assimilation operon, and that this process is governed by conserved functions in PAO1 and A. vinelandii. PMID- 22493304 TI - Autoinducer-2 influences interactions amongst pioneer colonizing streptococci in oral biofilms. AB - Streptococcus gordonii and Streptococcus oralis are among the first bacterial species to colonize clean tooth surfaces. Both produce autoinducer-2 (AI-2): a family of inter-convertible cell-cell signal molecules synthesized by the LuxS enzyme. The overall aim of this work was to determine whether AI-2 alters interspecies interactions between S. gordonii DL1 and S. oralis 34 within dual species biofilms in flowing human saliva. Based upon AI-2 bioluminescence assays, S. gordonii DL1 produced more AI-2 activity than S. oralis 34 in batch culture, and both were able to remove AI-2 activity from solution. In single-species, saliva-fed flowcell systems, S. oralis 34 formed scant biofilms that were similar to the luxS mutant. Conversely, S. gordonii DL1 formed confluent biofilms while the luxS mutant formed architecturally distinct biofilms that possessed twofold greater biovolume than the wild-type. Supplementing saliva with 0.1-10 nM chemically synthesized AI-2 (csAI-2) restored the S. gordonii DL1 luxS biofilm phenotype to that which was similar to the wild-type; above or below this concentration range, biofilms were architecturally similar to that formed by the luxS mutant. In dual-species biofilms, S. gordonii DL1 was always more abundant than S. oralis 34. Compared with dual-species, wild-type biofilms, the biovolume occupied by S. oralis 34 was reduced by greater than sevenfold when neither species produced AI-2. The addition of 1 nM csAI-2 to the dual-species luxS-luxS mutant biofilms re-established the biofilm phenotype to resemble that of the wild type pair. Thus, this work demonstrates that AI-2 can alter the biofilm structure and composition of pioneering oral streptococcal biofilms. This may influence the subsequent succession of other species into oral biofilms and the ecology of dental plaque. PMID- 22493306 TI - Molecular analysis of the bacteriocin-encoding plasmid pDGL1 from Enterococcus durans and genetic characterization of the durancin GL locus. AB - Enterococci constitute a significant component of the lactic acid bacteria normally present in the intestinal microflora and include strains that produce bacteriocins. The genetic determinants for durancin GL in Enterococcus durans 41D were identified on the 8347 bp plasmid pDGL1 by plasmid curing experiments. pDGL1 contained nine putative ORFs, with ORF1 and ORF2 encoding plasmid replication proteins, and ORF3 and ORF6 showing high similarity to genes encoding mobilization proteins. The predicted protein encoded by ORF4 showed 74 % identity to BacA, a bacteriocin produced by Enterococcus faecalis. The deduced DurA protein contained the conserved motif YYGNG, suggesting that durancin GL is a typical subclass IIa bacteriocin. ORF5 was shown to share 85 % identity to the immunity protein BacB of Enterococcus faecalis. ORF9 displayed 87 % sequence identity to a conserved hypothetical protein of unknown function. To further clarify the minimum requirement for durancin GL production, a 547 bp fragment containing the durAB gene was fitted with the Streptococcus thermophilus P(2201) promoter and then subcloned and heterologously expressed in S. thermophilus ST128. The result demonstrated that the cloned fragment contained all the genetic components required for durancin GL production. PMID- 22493307 TI - Management of papillary microcarcinoma: primum non nocere? PMID- 22493308 TI - Incretin hormones and the up-regulation of insulin secretion in insulin resistance. PMID- 22493309 TI - Following the bone density trail: a clinical perspective. PMID- 22493315 TI - Radioactive iodine treatment for hyperthyroidism. PMID- 22493317 TI - CSAP localizes to polyglutamylated microtubules and promotes proper cilia function and zebrafish development. AB - The diverse populations of microtubule polymers in cells are functionally distinguished by different posttranslational modifications, including polyglutamylation. Polyglutamylation is enriched on subsets of microtubules including those found in the centrioles, mitotic spindle, and cilia. However, whether this modification alters intrinsic microtubule dynamics or affects extrinsic associations with specific interacting partners remains to be determined. Here we identify the microtubule-binding protein centriole and spindle-associated protein (CSAP), which colocalizes with polyglutamylated tubulin to centrioles, spindle microtubules, and cilia in human tissue culture cells. Reducing tubulin polyglutamylation prevents CSAP localization to both spindle and cilia microtubules. In zebrafish, CSAP is required for normal brain development and proper left-right asymmetry, defects that are qualitatively similar to those reported previously for depletion of polyglutamylation conjugating enzymes. We also find that CSAP is required for proper cilia beating. Our work supports a model in which polyglutamylation can target selected microtubule-associated proteins, such as CSAP, to microtubule subpopulations, providing specific functional capabilities to these populations. PMID- 22493318 TI - A dual role for K63-linked ubiquitin chains in multivesicular body biogenesis and cargo sorting. AB - In yeast, the sorting of transmembrane proteins into the multivesicular body (MVB) internal vesicles requires their ubiquitylation by the ubiquitin ligase Rsp5. This allows their recognition by the ubiquitin-binding domains (UBDs) of several endosomal sorting complex required for transport (ESCRT) subunits. K63 linked ubiquitin (K63Ub) chains decorate several MVB cargoes, and accordingly we show that they localize prominently to the class E compartment, which accumulates ubiquitylated cargoes in cells lacking ESCRT components. Conversely, yeast cells unable to generate K63Ub chains displayed MVB sorting defects. These properties are conserved among eukaryotes, as the mammalian melanosomal MVB cargo MART-1 is modified by K63Ub chains and partly missorted when the genesis of these chains is inhibited. We show that all yeast UBD-containing ESCRT proteins undergo ubiquitylation and deubiquitylation, some being modified through the opposing activities of Rsp5 and the ubiquitin isopeptidase Ubp2, which are known to assemble and disassemble preferentially K63Ub chains, respectively. A failure to generate K63Ub chains in yeast leads to an MVB ultrastructure alteration. Our work thus unravels a double function of K63Ub chains in cargo sorting and MVB biogenesis. PMID- 22493319 TI - FOXO3/FKHRL1 is activated by 5-aza-2-deoxycytidine and induces silenced caspase-8 in neuroblastoma. AB - Forkhead box O (FOXO) transcription factors control diverse cellular functions, such as cell death, metabolism, and longevity. We analyzed FOXO3/FKHRL1 expression and subcellular localization in tumor sections of neuroblastoma patients and observed a correlation between nuclear FOXO3 and high caspase-8 expression. In neuroblastoma caspase-8 is frequently silenced by DNA methylation. Conditional FOXO3 activated caspase-8 gene expression but did not change the DNA methylation pattern of regulatory sequences in the caspase-8 gene. Instead, FOXO3 induced phosphorylation of its binding partner ATM and of the ATM downstream target cAMP-responsive element binding protein (CREB), which was critical for FOXO3-mediated caspase-8 expression. Caspase-8 levels above a critical threshold sensitized neuroblastoma cells to tumor necrosis factor-related apoptosis inducing ligand-induced cell death. The DNA-demethylating drug 5-Aza-2 deoxycytidine (5-azadC) induced rapid nuclear accumulation of FOXO3, ATM dependent CREB phosphorylation, and caspase-8 expression in a FOXO3-dependent manner. This indicates that 5-azadC activates the FOXO3-ATM-CREB signaling pathway, which contributes to caspase-8 expression. The combined data suggest that FOXO3 is activated by 5-azadC treatment and triggers expression of caspase-8 in caspase-8-negative neuroblastoma, which may have important implication for metastasis, therapy, and death resistance of this childhood malignancy. PMID- 22493321 TI - The education corner: updates on new and established core concepts and methods in epidemiology. PMID- 22493320 TI - Structure of Shroom domain 2 reveals a three-segmented coiled-coil required for dimerization, Rock binding, and apical constriction. AB - Shroom (Shrm) proteins are essential regulators of cell shape and tissue morpho logy during animal development that function by interacting directly with the coiled-coil region of Rho kinase (Rock). The Shrm-Rock interaction is sufficient to direct Rock subcellular localization and the subsequent assembly of contractile actomyosin networks in defined subcellular locales. However, it is unclear how the Shrm-Rock interaction is regulated at the molecular level. To begin investigating this issue, we present the structure of Shrm domain 2 (SD2), which mediates the interaction with Rock and is required for Shrm function. SD2 is a unique three-segmented dimer with internal symmetry, and we identify conserved residues on the surface and within the dimerization interface that are required for the Rock-Shrm interaction and Shrm activity in vivo. We further show that these residues are critical in both vertebrate and invertebrate Shroom proteins, indicating that the Shrm-Rock signaling module has been functionally and molecularly conserved. The structure and biochemical analysis of Shrm SD2 indicate that it is distinct from other Rock activators such as RhoA and establishes a new paradigm for the Rock-mediated assembly of contractile actomyosin networks. PMID- 22493322 TI - The Hertfordshire Cohort Study: from historical to high-tech studies of musculoskeletal ageing in men and women entering their ninth decade. PMID- 22493323 TI - Classification of epidemiological study designs. PMID- 22493324 TI - Social origin, schooling and individual change in intelligence during childhood influence long-term mortality: a 68-year follow-up study. AB - BACKGROUND: Intelligence at a single time-point has been linked to health outcomes. An individual's IQ increases with longer schooling, but the validity of such increase is unclear. In this study, we assess the hypothesis that individual change in the performance on IQ tests between ages 10 and 20 years is associated with mortality later in life. METHODS: The analyses are based on a cohort of Swedish boys born in 1928 (n = 610) for whom social background data were collected in 1937, IQ tests were carried out in 1938 and 1948 and own education and mortality were recorded up to 2006. Structural equation models were used to estimate the extent to which two latent intelligence scores, at ages 10 and 20 years, manifested by results on the IQ tests, are related to paternal and own education, and how all these variables are linked to all-cause mortality. RESULTS: Intelligence at the age of 20 years was associated with lower mortality in adulthood, after controlling for intelligence at the age of 10 years. The increases in intelligence partly mediated the link between longer schooling and lower mortality. Social background differences in adult intelligence (and consequently in mortality) were partly explained by the tendency for sons of more educated fathers to receive longer schooling, even when initial intelligence levels had been accounted for. CONCLUSIONS: The results are consistent with a causal link from change in intelligence to mortality, and further, that schooling induced changes in IQ scores are true and bring about lasting changes in intelligence. In addition, if both these interpretations are correct, social differences in access to longer schooling have consequences for social differences in both adult intelligence and adult health. PMID- 22493327 TI - Commentary: the past, present and future of affordable antiretroviral therapy in Africa. PMID- 22493326 TI - Effectiveness of generic and proprietary first-line anti-retroviral regimens in a primary health care setting in Lusaka, Zambia: a cohort study. AB - BACKGROUND: Although generic anti-retroviral drugs are in common use throughout the developing world, studies comparing their clinical effectiveness with that of proprietary formulations are lacking. METHODS: We analysed observational data from a large cohort of adults on anti-retroviral therapy (ART) to assess potential differences between generic and proprietary zidovudine (ZDV) formulations in post-90-day mortality, 'programme failure' (a composite of death, follow-up losses and withdrawals) and other clinical outcomes. We accounted for drug exposure in three ways: an 'initial dispensation' approach that categorized patients according to the first prescription; 'time-varying' approach that attributed an outcome to the formulation taken at the time of event; and 'predominant exposure' approach that considered only those with >75% exposure to either brand or generic ZDV. Proprietary formulations were used as the reference group in all adjusted Cox proportional hazard regressions. RESULTS: Among 14 736 patients eligible for analysis, 7277 (49%) initiated a generic formulation of ZDV and 7459 (51%) initiated a proprietary formulation. When categorized according to initial dispensation, no difference in post-90-day mortality was observed between the two groups [adjusted hazard ratio (AHR): 0.93, 95% confidence interval (CI): 0.77-1.12]. Similar findings were noted when drug formulation was treated as a time-varying exposure (AHR: 1.15, 95% CI: 0.89-1.48) when analysis was limited to those with a predominant exposure to one formulation or the other (AHR: 0.59, 95% CI: 0.24-1.49). Results were consistent across all approaches when programme failure was considered as an outcome. No longitudinal differences were detected between formulations for CD4 response, weight change and haemoglobin concentration. Generic ZDV formulations were associated with slight decreases in single-drug substitution. CONCLUSIONS: In this large programmatic cohort of adults starting ZDV-based first-line therapy, clinical outcomes appeared similar among patients on generic or proprietary formulations. These findings support continued use of generic anti-retroviral drug formulations in resource constrained settings. PMID- 22493325 TI - All-cause mortality in treated HIV-infected adults with CD4 >=500/mm3 compared with the general population: evidence from a large European observational cohort collaboration. AB - BACKGROUND: Using data from a large European collaborative study, we aimed to identify the circumstances in which treated HIV-infected individuals will experience similar mortality rates to those of the general population. METHODS: Adults were eligible if they initiated combination anti-retroviral treatment (cART) between 1998 and 2008 and had one prior CD4 measurement within 6 months. Standardized mortality ratios (SMRs) and excess mortality rates compared with the general population were estimated using Poisson regression. Periods of follow-up were classified according to the current CD4 count. RESULTS: Of the 80 642 individuals, 70% were men, 16% were injecting drug users (IDUs), the median age was 37 years, median CD4 count 225/mm(3) at cART initiation and median follow-up was 3.5 years. The overall mortality rate was 1.2/100 person-years (PY) (men: 1.3, women: 0.9), 4.2 times as high as that in the general population (SMR for men: 3.8, for women: 7.4). Among 35 316 individuals with a CD4 count >=500/mm(3), the mortality rate was 0.37/100 PY (SMR 1.5); mortality rates were similar to those of the general population in non-IDU men [SMR 0.9, 95% confidence interval (95% CI) 0.7-1.3] and, after 3 years, in women (SMR 1.1, 95% CI 0.7-1.7). Mortality rates in IDUs remained elevated, though a trend to decrease with longer durations with high CD4 count was seen. A prior AIDS diagnosis was associated with higher mortality. CONCLUSIONS: Mortality patterns in most non-IDU HIV infected individuals with high CD4 counts on cART are similar to those in the general population. The persistent role of a prior AIDS diagnosis underlines the importance of early diagnosis of HIV infection. PMID- 22493328 TI - Rapid detection of the top six non-O157 Shiga toxin-producing Escherichia coli O groups in ground beef by flow cytometry. AB - Rapid, sensitive, and highly specific flow-cytometric assays were developed for the detection of the top six non-O157 Shiga toxin-producing Escherichia coli (STEC) O groups in ground beef. The analytical sensitivity of the assays was 2 * 10(3) target cells in a bacterial mixture of 10(5) CFU/ml, and the limit of detection in ground beef was 1 to 10 CFU following 8 h of enrichment. The assays may be utilized for rapid detection of STEC O groups in meat. PMID- 22493329 TI - Detection of OmpK36 porin loss in Klebsiella spp. by matrix-assisted laser desorption ionization-time of flight mass spectrometry. PMID- 22493330 TI - Analysis of the excretion dynamics and genotypic characteristics of rotavirus A during the lives of pigs raised on farms for meat production. AB - To determine the excretion dynamics and genotypic characteristics of rotavirus A (RVA), a longitudinal observational study was performed in 10 pigs from 3 litters at a farrow-to-finish farm. A total of 400 fecal samples were directly collected from the rectums of individual pigs (aged 7 to 217 days) at 3- to 14-day intervals. Seventy-one samples (17.5%) were positive for RVA by reverse transcription-PCR designed to detect the VP7 and VP4 genes. At least 13 combinations of 5 G (G2, G4, G5, G9, and G11) and 6 P (P[6], P[7], P[13], P[23], P[27], and P[34]) genotypes were identified by direct sequencing of the PCR products. We were able to detect RVA VP7 sequences from each pig 4 to 6 times with intervals of 7 to 52 days (from 7 to 119 days of age). Each pig harbored RVAs with at least 3 to 6 different combinations of G and P genotypes, while repeated excretions of RVAs carrying the same combinations of G and P genotypes were also observed. Virus shedding and changes in G and P genotypes appeared to be associated with movement of the pigs into weaning, growing, and finishing barns. These results indicated that, over their lifetimes, pigs raised for meat frequently and intermittently excrete genetically diverse RVAs. PMID- 22493331 TI - Quantification by real-time PCR assay of Staphylococcus aureus load: a useful tool for rapidly identifying persistent nasal carriers. AB - The Cepheid Xpert MRSA/SA nasal PCR assay was compared to culture for quantifying Staphylococcus aureus load from 104 nasal samples (r = 0.91, P < 0.0001). Using a bacterial load-based algorithm, the test was found able to predict the carrier state in 32 of 35 healthy volunteers (22 persistent and 13 nonpersistent carriers). PMID- 22493332 TI - Growth detection failures by the nonradiometric Bactec MGIT 960 mycobacterial culture system. AB - Mycobacterial growth in liquid culture can go undetected by automated, nonradiometric growth detection systems. In our laboratory, instrument-negative tubes from the Bactec MGIT 960 system are inspected visually for clumps suggestive of mycobacterial growth, which (if present) are examined by acid-fast smear analysis. A 3-year review demonstrated that ~1% of instrument-negative MGIT cultures contained mycobacterial growth and that 10% of all cultures yielding mycobacteria were instrument negative. Isolates from instrument-negative MGIT cultures included both tuberculous and nontuberculous mycobacteria. PMID- 22493333 TI - Use of urine with nested PCR targeting the flagellin gene (fliC) for diagnosis of typhoid fever. AB - This study was planned to evaluate the efficacy of the use of nested PCR with a large volume of easily available urine as an effort to devise a test that can meet the levels necessary to be considered a gold standard for the diagnosis of typhoid fever. A total of 60 subjects with suspected cases of typhoid fever and 20 apparently healthy control subjects were included in the study. The study period extended from March 2010 to June 2011. Blood, urine, and stool specimens were collected from the participating individuals. Nested PCR was done targeting the flagellin gene (fliC) of Salmonella enterica subspecies enterica serotype Typhi. Specimens in all three categories could be collected from 22 of the subjects with suspected cases of typhoid fever; 21 of the 22 urine samples (95.4%) yielded a desired amplicon of 343 bp, whereas none of the urine samples collected from the 20 control subjects (0%) yielded the amplicon. The analyses of blood and stool samples were found to be inferior to urine sample analysis in sensitivity, with detection rates of 90.9% and 68.1%, respectively. Culture isolation was observed to display very poor sensitivity (31.8%). A large volume of urine may be the ideal specimen for PCR-based detection of typhoid fever. PMID- 22493334 TI - Multiplex PCR for rapid and improved diagnosis of bloodstream infections in liver transplant recipients. AB - This prospective study evaluated the utility of the SeptiFast (SF) test in detecting 25 clinically important pathogens in 225 blood samples from 170 intensive care unit (ICU) patients with suspected sepsis after liver transplantation (LTX) or after other major abdominal surgery (non-LTX). SF yielded a significantly higher positivity rate in the LTX group (52.3%) than in the non-LTX group (30.5%; P = 0.0009). SF may be a powerful tool for the early diagnosis of bloodstream infections in LTX patients. PMID- 22493335 TI - Impact of results of a rapid Staphylococcus aureus diagnostic test on prescribing of antibiotics for patients with clustered gram-positive cocci in blood cultures. AB - In tropical northern Australia, approximately 20% of Staphylococcus aureus bacteremia is caused by methicillin-resistant Staphylococcus aureus (MRSA). We prospectively evaluated the impact on clinician antibiotic prescribing of the results obtained from performing the GeneXpert MRSA/SA test on 151 positive blood cultures with clustered gram-positive cocci. The GeneXpert result led to earlier appropriate prescription of vancomycin for 54% of patients with MRSA; 25% of patients avoided vancomycin, and 16% of patients had all antibiotics ceased. PMID- 22493336 TI - Multicenter evaluation of the Staphylococcus QuickFISH method for simultaneous identification of Staphylococcus aureus and coagulase-negative staphylococci directly from blood culture bottles in less than 30 minutes. AB - A novel rapid peptide nucleic acid fluorescence in situ hybridization (FISH) method, Staphylococcus QuickFISH, for the direct detection of Staphylococcus species from positive blood culture bottles was evaluated in a multicenter clinical study. The method utilizes a microscope slide with predeposited positive and negative-control organisms and a self-reporting 15-min hybridization step, which eliminates the need for a wash step. Five clinical laboratories tested 722 positive blood culture bottles containing gram-positive cocci in clusters. The sensitivities for detection of Staphylococcus aureus and coagulase-negative staphylococci (CoNS) were 99.5% (217/218) and 98.8% (487/493), respectively, and the combined specificity of the assay was 89.5% (17/19). The combined positive and negative predictive values of the assay were 99.7% (696/698) and 70.8% (17/24), respectively. Studies were also performed on spiked cultures to establish the specificity and performance sensitivity of the method. Staphylococcus QuickFISH has a turnaround time (TAT) of <30 min and a hands-on time (HOT) of <5 min. The ease and speed of the method have the potential to improve the accuracy of therapeutic intervention by providing S. aureus/CoNS identification simultaneously with Gram stain results. PMID- 22493337 TI - Bloodstream infection caused by nontoxigenic Corynebacterium diphtheriae in an immunocompromised host in the United States. AB - Corynebacterium species are well-known causes of catheter-related bloodstream infections. Toxigenic strains of Corynebacterium diphtheriae cause respiratory diphtheria. We report a bloodstream infection caused by a nontoxigenic strain of C. diphtheriae and discuss the epidemiology, possible sources of the infection, and the implications of rapid species identification of corynebacteria. PMID- 22493338 TI - Use of nucleic acid amplification testing for diagnosis of anorectal sexually transmitted infections. AB - Nucleic acid amplification testing (NAAT) has become the preferred method to detect Chlamydia trachomatis and Neisseria gonorrhoeae, but no commercial tests are cleared by the U.S. Food and Drug Administration for use with rectal swab samples. This study evaluated the performance of strand displacement amplification (SDA) and transcription-mediated amplification (TMA) to detect C. trachomatis and N. gonorrhoeae and to determine if TMA could also detect Mycoplasma genitalium and Trichomonas vaginalis in men and women reporting a history of receptive anal intercourse. Discordant results between the NAATs were reevaluated using the Aptima CT or Aptima GC assay, each of which targets primers other than those targeted by the Aptima Combo 2 (AC2) assay, as the confirmatory test. Of 497 evaluable participants, 41 (8.2%) were positive for C. trachomatis, 21 (4.2%) were positive for N. gonorrhoeae, 26 (5.2%) were positive for T. vaginalis, and 47 (9.5%) were positive for M. genitalium. The sensitivity and specificity of the C. trachomatis test were 100% and 99.8% for AC2 and 56.1% and 100% for SDA, respectively. The sensitivity and specificity of the N. gonorrhoeae test were 100% and 100% for AC2 and 76.2% and 100% for SDA, respectively, while culture was only 23.8% sensitive. Of the 114 participants who had a positive result for any of the four infectious agents, 16 were positive for two pathogens and 3 were positive for three pathogens. These data suggest that rectal infection is common and that the AC2 is superior to SDA for the detection of C. trachomatis and N. gonorrhoeae from rectal swab samples. PMID- 22493339 TI - New real-time PCR assay using allelic discrimination for detection and differentiation of equine herpesvirus-1 strains with A2254 and G2254 polymorphisms. AB - A single-nucleotide polymorphism (A(2254) or G(2254)) in open reading frame 30 (ORF30) has been linked to the neuropathogenic phenotype of equine herpesvirus-1 (EHV-1). Identification of this polymorphism led to the development of a real time PCR (rPCR) assay using allelic discrimination (E(2)) to distinguish between potentially neuropathogenic and nonneuropathogenic EHV-1 strains (G. P. Allen, J. Vet. Diagn. Invest. 19:69-72, 2007). Although this rPCR assay can detect and genotype EHV-1 strains, subsequent studies demonstrated that it lacks the sensitivity for the routine detection of viral nucleic acid in clinical specimens. Therefore, a new allelic discrimination EHV-1 rPCR assay (E(1)) was developed by redesigning primers and probes specific to ORF30. The E(1) and E(2) rPCR assays were evaluated using 76 archived EHV isolates and 433 clinical specimens from cases of suspected EHV-1 infection. Nucleotide sequence analysis of ORF30 was used to confirm the presence of EHV-1 and characterize the genotype (A(2254) or G(2254)) in all archived isolates plus 168 of the clinical samples. The E(1) assay was 10 times more sensitive than E(2), with a lower detection limit of 10 infectious virus particles. Furthermore, all A(2254) and G(2254) genotypes along with samples from three cases of dual infection (A(2254)+G(2254)) were correctly identified by E(1), whereas E(2) produced 20 false dual positive results with only one actual mixed A(2254)+G(2254) genotype confirmed. Based on these findings, E(1) offers greater sensitivity and accuracy for the detection and A/G(2254) genotyping of EHV-1, making this improved rPCR assay a valuable diagnostic tool for investigating outbreaks of EHV-1 infection. PMID- 22493340 TI - American Society of Clinical Oncology identifies five key opportunities to improve care and reduce costs: the top five list for oncology. PMID- 22493342 TI - Varicella zoster virus infection of malignant glioma cell cultures: a new candidate for oncolytic virotherapy? AB - BACKGROUND: Glioblastoma multiforme is a highly aggressive tumor with a median survival of 14 months despite all standard therapies. Focusing on alternative treatment strategies, we evaluated the oncolytic potential of varicella zoster virus (VZV) in malignant glioma cell cultures. MATERIALS AND METHODS: Replication of wildtype and mutant VZV was comparatively analyzed in glioma cell lines (U87, U251 and U373) and in primary malignant glioma cells (n=10) in vitro by infectious foci assay, immunofluorescence microscopy and western blot analysis. Additionally, the tumor-targeting potential of VZV-infected human mesenchymal stem cells was evaluated. RESULTS: VZV replicated efficiently in all the glioma cells studied here followed by rapid oncolysis in vitro. The attenuated vaccine VZV mutant rOKA/ORF63rev[T171] exhibited most efficient replication. Human mesenchymal stem cells were found suitable for targeting VZV to sites of tumor growth. CONCLUSION: VZV exhibits an intrinsic oncolytic potential in malignant glioma cell cultures and might be a novel candidate for virotherapy in glioblastoma multiforme. PMID- 22493343 TI - Correlation between adenovirus-neutralizing antibody titer and adenovirus vector mediated transduction efficiency following intratumoral injection. AB - Pre-existing anti-adenovirus neutralizing antibodies (AdNAbs) are a major barrier in clinical gene therapy using adenovirus vectors; however, the transduction profile of adenovirus vectors in the presence of AdNAbs following intratumoral injection has not been fully examined, although such vectors are often intratumorally injected in clinical studies. In this study, we evaluated the correlation between the titer of AdNAbs in the serum and the transduction profiles in the tumor and the liver following intratumoral administration into mice possessing various titers of AdNAbs. Adenovirus vector-mediated transduction in the tumor was inhibited by AdNAbs; however, when the titer of AdNAbs was less than 200, the levels of inhibition in the transduction efficiencies within the tumor ranged from approximately 2- to 100-fold. A more than 2500-fold reduction of adenovirus vector-mediated transduction was found in most of the mice when the titers of AdNAbs were >200. On the other hand, the transduction efficiencies in the liver were largely reduced almost to the levels of the mock-transduced mice even at the low titers of AdNAbs. These results provide crucial information for the clinical use of adenovirus vectors. PMID- 22493344 TI - Reduction of tumorigenicity by placental extracts. AB - The influence of adult stem cells on tumor growth is paradoxical. On one hand, angiogenic factors secreted by stem cells are known to be essential for tumor vascularization. On the other hand, stem cell-derived factors can reportedly induce tumor differentiation or direct death of tumor cells. Both the placenta and umbilical cord are rich sources of stem cells with immune modulatory and tissue-healing properties; however, the effects of placental components on cancer cells have not been fully defined. Here we demonstrate that extracts of placental lysates reduce the malignancy of a variety of human tumor cell lines in a species unrestricted manner. Using a standard model of leukemia cell differentiation, we demonstrated that addition of placental extracts to tumor cells, or co-culture of tumor cells with the CD34(+) cells from umbilical cord blood, induced tumor cell differentiation. Inhibition of tumor growth and metastasis in vivo was also observed following administration of placental extracts. These data support the concept of non-toxic biological therapy of cancer using stem cell derivatives, possibly through the induction of tumor cell differentiation. PMID- 22493345 TI - Stem cell markers as predictors of oral cancer invasion. AB - We previously showed that within primary tumors there exist subpopulations of cells expressing stem cell markers. Using immunofluorescence and western blotting, we examined the expression of stem cell markers tumor-rejection antigen 1-60 (TRA1-60) and octamer-binding transcription factor 3/ 4 (OCT3/4) to determine their relationship with cell invasiveness. Six human oral cancer cell lines were examined and a direct correlation was found between expression of these stem cell markers and invasion. Poor expression of E-cadherin and increased expression of N-cadherin was also found in TRA1-60- and OCT3/4- expressing cells. Phosphorylation of the major signaling molecule mitogen activated protein kinase (MAPK) was greatest in the TRA1-60- and OCT3/4- expressing cells. These results suggest that expression of specific stem cell markers in tumors may help guide a clinician's choice of treatment. PMID- 22493341 TI - Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. AB - BACKGROUND: Many recent studies suggest the immune system plays a significant role in the pathogenesis of autoimmune diseases, chronic inflammatory diseases, and cancer. MATERIALS AND METHODS: Literature published between 2001 and 2011 was reviewed for risk of cancer development in patients with autoimmune and chronic inflammatory diseases. Mode of risk assessment employed did not limit inclusion of studies. Autoimmune conditions developing after diagnosis of a pre-existing cancer were also considered. RESULTS: We report a pervasive, largely positive association between 23 autoimmune and inflammatory diseases and subsequent cancer development. We discuss associations for celiac disease, inflammatory bowel disease rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis in detail. We also address the less frequently reported development of some autoimmune conditions within the course of some malignancies, such as vitiligo developing in the course of melanoma. CONCLUSION: Evidence demonstrates that chronic inflammation and autoimmunity are associated with the development of malignancy. Additionally, patients with a primary malignancy may develop autoimmune like disease. These relationships imply a need for surveillance of patients on immunomodulatory therapies for potential secondary disease processes. PMID- 22493346 TI - Sarcoma cells induce alteration in adipogenic differentiation. AB - BACKGROUND: Sarcomas consist of both tumor and stromal cells, and the interaction between these compartments is critical for tumor progression and metastasis. Tumor-derived factors may alter the differentiation capacity of the adjacent stromal cells. The aim of this study was to elucidate the paracrine impact of liposarcoma cells on pre-adipocytes, their adipogenic differentiation process and miRNA expression profile. MATERIALS AND METHODS: 3T3-L1 pre-adipocytes were exposed to sarcoma pre-conditioned media. Following induction of adipogenic differentiation morphometrical changes were assessed. Differences in miRNA expression of conditioned and non-conditioned 3T3-L1 cells were analyzed. RESULTS: Exposure to sarcoma pre-conditioned media substantially altered the differentiation capability of 3T3-L1 pre-adipocytes. Significant changes in the miRNA expression profile between conditioned and non-conditioned pre-adipocytes were observed. CONCLUSION: Sarcoma cells directly modulate pre-adipocyte differentiation. This study demonstrates that sarcoma cells influence differentiation of pre-adipocytes via paracrine factors and alter their miRNA expression. PMID- 22493347 TI - Imageable fluorescent metastasis resulting in transgenic GFP mice orthotopically implanted with human-patient primary pancreatic cancer specimens. AB - Tumors from pancreatic cancer patients were established in NOD/SCID mice immediately after surgery and subsequently passaged orthotopically in transgenic nude mice ubiquitously expressing green fluorescent protein (GFP). The primary patient tumors acquired GFP-expressing stroma. Subsequent liver metastases, and disseminated peritoneal metastases maintained the stroma from the primary tumor, and possibly recruited additional GFP-expressing stroma, resulting in their very bright fluorescence. The GFP-expressing stroma included cancer-associated fibroblasts and tumor-associated macrophages in both the primary and metastatic tumors. This imageable model of metastasis from a patient-tumor is an important advance over patient "tumorgraft" models currently in use, which are implanted subcutaneously, do not metastasize and are not imageable. The new imageable model of patient pancreatic cancer metastasis provides unique opportunities to identify current and novel antimetastatic therapeutics for individual patients. PMID- 22493348 TI - Physiological concentrations of genistein and 17beta-estradiol inhibit MDA-MB-231 breast cancer cell growth by increasing BAX/BCL-2 and reducing pERK1/2. AB - AIM: The aim of the present study was to identify the mechanism by which genistein and 17beta-estradiol inhibit proliferation of MDA-MB-231 breast cancer cells. MATERIALS AND METHODS: The expression of cell signaling proteins involved in cell apoptosis, proliferation, and survival (BCL-2 associated X protein, BAX; B-cell lymphoma 2, BCL-2; extracellular signal regulated kinase, pERK1/2; and protein kinase B, pAKT) were examined by western blotting, and tested whether these effects correlated with cell proliferation and apoptosis. RESULTS: Compared to the control, 1 MUM genistein plus 1 nM 17beta-estradiol significantly increased apoptosis, and the BAX/BCL-2 ratio, with a concomitant decrease in ERK1/2 phosphorylation. High concentrations of genistein (100 MUM) both in the presence and absence of 17beta-estradiol also increased apoptosis; however, these changes were not correlated with the BAX/BCL-2 ratio or with phosphorylation of ERK1/2. CONCLUSION: These results suggest that different concentrations of genistein elicit cell responses through different signaling mechanisms. These results are especially relevant in premenopausal women with breast cancer who are on a soy diet. PMID- 22493349 TI - 5-aminosalicylic acid mediates expression of cyclooxygenase-2 and 15 hydroxyprostaglandin dehydrogenase to suppress colorectal tumorigenesis. AB - BACKGROUND: Cyclooxygenase-2 (COX-2) is a key enzyme that produces prostaglandin E2 (PGE2) and plays an important role in colorectal tumor growth. In addition, recent researches focused on 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which degrades PGE2. Here we determined the effect of 5-aminosalicylic acid (5 ASA) on COX-2 and 15-PGDH expression and investigated its preventive effect for colorectal cancer (CRC). MATERIALS AND METHODS: HT-29 cells were used in the in vitro experiments. c-Ha-ras transgenic mice were employed in order to explore the chemopreventive effects. Western blotting analysis was performed and the protein expression of COX-2 and 15-PGDH was quantified. RESULTS: 5-ASA significantly suppressed COX-2 expression and induced 15-PGDH expression in HT-29 cells. In the transgenic mice, oral 5-ASA intake reduced the incidence of colorectal tumor formation and the tumor size. Furthermore, we observed a down-regulation of COX-2 and an up-regulation of 15-PGDH in the tissue from colons of these mice. CONCLUSION: 5-ASA exerts a preventive effect against colorectal tumor development through mediation of COX-2 and 15-PGDH expression. PMID- 22493350 TI - Effective targeting of the tumor microenvironment for cancer therapy. AB - BACKGROUND: The tumor microenvironment is an emerging source of novel therapeutic targets in cancer. The glycosaminoglycan hyaluronan (HA) accumulates in 20-30% of tumors and is often associated with poor prognosis. MATERIALS AND METHODS: We developed a digitized, semiquantitative scoring system for tumor-associated HA content, then grouped tumors (from animal models or patients) according to the degree of HA accumulation (HA+1,2,3). The antitumor response to HA-depletion by pegylated PH20 hyaluronidase (PEGPH20) was then characterized as a function of HA accumulation. RESULTS: Semiquantitative grouping of tumors demonstrated that HA accumulation predicts the response of tumors in animal models to PEGPH20. Prospective analysis of HA content was used to predict response to PEGPH20 of squamous cell-type explants from patients with non-small cell lung cancer in nude mice. CONCLUSION: Measurement of HA is a viable biomarker approach for predicting antitumor response in animal models to the HA-depleting agent, PEGPH20. PMID- 22493351 TI - Efficacy of the Chinese traditional medicinal herb Celastrus orbiculatus Thunb on human hepatocellular carcinoma in an orthothopic fluorescent nude mouse model. AB - This study aimed to explore the inhibitory effect of Celastrus orbiculatus Thunb. (COT) on tumor growth, metastasis and antiogenesis of hepatocelluar carcinoma (HCC) in an orthotopic nude mouse model using fluorescence imaging technology. Human HCC Hep-G2 cells expressing red fluorescent protein (RFP) were orthotopically implanted onto the liver of nude mice. One group of mice was treated with ethyl acetate extract of COT p.o. at a dose of 20 mg/kg starting on day 3 post-tumor implantation (early treatment). All other mice were randomized into four groups from day 20 post-tumor implantation and received either no treatment, oxaliplatin (25 mg/kg), or low-dose (20 mg/kg) or high-dose (40 mg/kg) COT. Real-time whole-body fluorescence imaging was performed to measure tumor growth and monitor metastasis development during the study. Vascular endothelial growth factor(VEGF) expression in the tumors collected at autopsy was analyzed by immunohistochemical staining and reverse transcription-polymerase chain reaction(RT-PCR). High-dose treatments, early treatment with COT, demonstrated significant efficacy on controlling tumor volume and tumor weight in the human HCC Hep-G2 orthotopic tumor model. No significant differences were found for metastasis incidence among the different study groups. VEGF expression in the tumors was significantly reduced by oxaliplatin and COT treatment. This study demonstrates the inhibitory efficacy of COT on the growth of HCC tumor. VEGF inhibition may contribute in part to the inhibition of HCC tumor growth. The results of the present report suggest COT has potential to treat HCC. PMID- 22493352 TI - CK20 expression enhances the invasiveness of tamoxifen-resistant MCF-7 cells. AB - Cytokeratin 20 (CK20) is an intermediate filament that is known to be a prognostic marker in several types of cancer. However, little is known about CK20 expression and tumor metastasis in tamoxifen-resistant MCF-7 (TRM-7) breast cancer cells. TRM-7 cells overexpress CK20, resulting in enhanced invasiveness in vitro. CK20 silencing reduced the invasiveness of TRM-7 cells. Moreover, CK20 expression in MCF-7 cells was regulated by peroxisome proliferator-activated receptor gamma (PPARgamma). Our findings suggest that PPARgamma-dependent CK20 expression enhances the metastatic potential of MCF-7 breast cancer cells and may be a potential therapeutic target in tamoxifen-resistant breast cancer. PMID- 22493353 TI - COM-1/p8 acts as a tumour growth enhancer in colorectal cancer cell lines. AB - BACKGROUND: Candidate of metastasis-1 (COM-1) is a molecule which is stress induced and cell growth-related. The current study investigated the impact of COM 1 and role of Peroxisome Proliferating Activator Receptor-gamma (PPARgamma) agonists on COM-1 knock down in colorectal cancer cells. MATERIALS AND METHODS: Expression of COM-1 was knocked out in the colorectal cancer cell lines RKO and CaCO2 by transfection with ribozyme transgenes which specifically targeted COM-1. Cell growth, cell migration and apoptosis were measured in wild-type, control and COM-1 knock down cells. The impact or treatment with the PPARgamma agonists on the function of COM-1 knock down cells was monitored. RESULTS: COM-1 knock-down cells grew slower than wild-type and control cells. When treated with the PPARgamma agonist ciglitazone and bisphenol A diglycidyl ether (BADGE) at several different concentrations, all types of cells grew slower to some extent. Cells with COM-1 knock-down had the same mobility as wild-type and control cells. More apoptotic and dead cells were detected when cells were treated with ciglitazone at 3 MUM, especially of COM-1 knock down cells. CONCLUSION: COM-1 is an anti apoptotic gene and a cell growth promoter. Furthermore, the PPARgamma agonist could increase the inhibitory effect seen in COM-1 knock-down cell growth and to promote apoptosis. In regards to metastasis, COM-1 appears to play no role in cell motility. PMID- 22493354 TI - Radiosensitization of p53-deficient lung cancer cells by pre-treatment with cytostatic compounds. AB - BACKGROUND/AIM: This study specifies a strategy to improve radiotherapy by partial synchronization of p53-deficient cancer cells (FaDu and H1299) in mitosis using taxol, with protecting p53 wild-type cells (A549) by the prior administration of cytostatic compounds. Cytotoxic and cytostatic effects of ionizing radiation, cisplatin, doxorubicin and taxol, administrated alone or in combination were investigated in vitro by flow cytometry. RESULTS: A protective effect of doxorubicin but not cisplatin was found after administration of triple sequence with ionizing radiation and taxol. It was found that preliminary administration of doxorubicin induced growth arrest and protected A549 cells from the taxol/radiation treatment, while simultaneously killing FaDu and H1299 cells. CONCLUSION: The proposed therapeutic strategy allows protection of p53 wild-type cells and selectively increases radiosensitivity of p53-deficient cancer cells. PMID- 22493355 TI - Molecular characterization of human cutaneous melanoma-derived cell lines. AB - BACKGROUND: Several studies have demonstrated that different genetic profiles contribute to melanoma development and progression. MATERIALS AND METHODS: To evaluate the existence of different molecular aberration patterns in melanoma associated with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) or 9p21 locus alterations, eleven patient-derived melanoma cell lines were characterized. Multiplex ligation probe amplification (MLPA) was used to detect chromosomal alterations. Single- strand conformation analysis and sequencing were performed to study BRAF, neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (c-KIT), melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor) (MC1R), cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4) genes. RESULTS: BRAFV600E mutation was detected in 54% of cell lines. NRAS was mutated in one cell line also carrying multiple copies of NRAS. All cell lines with MC1R variants harboured BRAFV600E. Concurrent loss of MUTYH (1p33), gains of c-MYC (8q24) and of CDK6 (7q21) were found to be significantly associated in cell lines (45%) that harboured biallelic 9p21 deletions including CDKN2B-CDKN2A-MTAP. CONCLUSION: These data suggest the existence of a specific pattern of somatic alterations in genes that are involved in DNA repair (MUTYH) and in cell cycle regulation (c-MYC, CDK6, CDKN2A and CDKN2B). Interestingly, all MC1R variants were associated with BRAFV600E and all cell lines from visceral metastases harboured BRAFV600E. PMID- 22493356 TI - Human papillomavirus molecular testing in women with low grade cervical lesions: experience from an Italian hospital. AB - BACKGROUND: In recent years, efforts have been made to identify molecular markers as potential screening tools in the early detection of cervical cancer precursors. PATIENTS AND METHODS: One-hundred-eighty-two women admitted to the Colposcopy Unit of Tor Vergata University Hospital were enrolled in this study. The inclusion criteria were: i) Pap test with atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL); ii) normal cytology but human papillomavirus (HPV) DNA test positive for at least one of the most frequently detected five high-risk HPV types (16, 18, 31, 33 and 45). HPV DNA was detected with the HPV Sign kit and the type was assigned by pyrosequencing using the PyroMark ID System. E6/E7 transcripts of the high-risk HPV types 16, 18, 31, 33 and 45 were detected by the NucliSense EasyQ HPV kit. RESULTS: Overall, 90 (49.5%) patients were HPV-DNA negative, whereas 92 (50.5%) were HPV-DNA positive. Single infections were detected in 55 women: HPV 16 ranked first (56.4%), followed by HPV 18 (21.8%), HPV 31 (9%), HPV 33 (7.3%), and HPV 45 (5.5%). Co-infections were detected in 37/92 (40.2%) positive cases; HPV 16 was detected most frequently (27/37), followed by HPV 18 and 31. All patients underwent HPV RNA testing: 47/182 (25.8%) tested positively while 135/182 (74.2%) were negative. HPV 16 E6/E7 transcripts was the most frequently detected. CONCLUSION: Detection of HPV E6/E7 oncogenic transcripts may be used as a molecular biomarker in women with ASCUS or LSIL to help identify women at risk of disease progression. PMID- 22493357 TI - Comparison of genomic signatures of non-small cell lung cancer recurrence between two microarray platforms. AB - BACKGROUND: Cancer genomic signatures may vary using different platforms. We compared the differential gene expression in non-small cell lung cancer (NSCLC) between two platforms in order to find the most relevant genomic signatures of tumor recurrence. MATERIALS AND METHODS: We analyzed gene expression in frozen lung cancer tissue from 59 selected patients who had undergone surgical resection of NSCLC. These patients were divided into two groups: group R, patients who had a tumor recurrence within four years, n=37; group NR, patients who remained disease-free four years following initial surgery, n=22. Each RNA sample was assayed twice using both Affymetrix and Illumina GeneChip. Data were analyzed by principal component analysis and leave-one-out cross-validation. RESULTS: Using the same filtering criteria, 13 genes that were differentially expressed between R and NR were identified by Affymetrix, while 21 genes were identified by Illumina GeneChip. In common, a total of six genes were detected by both systems. Using univariate analysis, four (lipocalin 2, LCN2; parathyroid hormone-like hormone, PTHLH; ras-related protein Rab-38, RAB38; and four jointed box 1, FJX1) of these six genes were associated with survival. A risk score of survival was calculated according to the four-gene expression. There was a significant difference in overall survival between low- and high-risk groups. CONCLUSION: A four-gene signature is associated with survival among patients with early-stage NSCLC. Further validation of these findings is warranted. PMID- 22493358 TI - Enhanced siRNA delivery using oleic acid derivative of polyethylenimine. AB - BACKGROUND: RNA interference has promising therapeutic potential. However, safe and efficacious delivery systems are necessary for its application in the clinic. MATERIALS AND METHODS: An oleic acid (OA) derivative of branched polyethylenimine (PEI, M.W. 2000 Da), PEI-OA, was synthesized and evaluated for small interfering RNA (siRNA) delivery in SK-HEP-1 liver cancer cells stably transfected with luciferase. The physiochemical properties of PEI-OA/siRNA complexes, their cellular uptake, gene silencing activity based on luciferase reporter gene down regulation, and cytotoxicity were investigated. RESULTS: PEI-OA complexes effectively delivered siRNA into SK-HEP-1 cells and efficiently induced down regulation of luciferase reporter gene expression. Compared with free siRNA and PEI/siRNA, PEI-OA/siRNA was significantly more effective, reducing luciferase activity by ~50%. CONCLUSION: PEI-OA warrants further evaluation for therapeutic delivery of siRNA. PMID- 22493359 TI - Immunohistochemical study of the epithelial-mesenchymal transition phenotype in cancer of unknown primary: incidence, correlations and prognostic utility. AB - BACKGROUND: The epithelial to mesenchymal transition (EMT) has been associated with metastatic dissemination and poor outcome in several solid tumour types. Our aim was to study its incidence and its prognostic significance in cancer of unknown primary (CUP). PATIENTS AND METHODS: One hundred tumour samples of CUP were loaded in tissue microarrays and were studied for immunohistochemical (IHC) expression of E-cadherin, N-cadherin, vimentin, the EMT transcription factor (SNAIL) and the stem cell marker octamer-binding transcription marker 4(OCT4). An EMT phenotype was defined as low expression of E-cadherin, expression of N cadherin with/without vimentin with concomitant expression of SNAIL, as assessed by percentage of tumour cell staining. RESULTS: Among 100 CUP cases, the histological diagnosis was adenocarcinoma in 55, squamous carcinoma in 20 and undifferentiated carcinoma in 15, with a high grade seen in 46. Therapy consisted of palliative chemotherapy, mostly platinum based. The median progression-free survival and overall survival (OS) were 7 and 12 months respectively. Distributional studies resulted in selection of IHC cut-offs for E-cadherin (negative when expressed in <60% of tumour cells), N-cadherin, vimentin (positive when expressed in >=40% of tumour cells), SNAIL (positive when stained in >=80% of tumour cells). An EMT phenotype was observed in 8 cases (8.1%) and was strongly associated with poor OS (median OS EMT(-)=13 months vs. median OS EMT(+)=8 months, p=0.023). When we used staining intensity (H-Score), an EMT phenotype was observed in 16 patients and carried borderline adverse prognostic utility for outcome (median OS 9 vs. 14 months, p=0.07). The presence of the EMT phenotype correlated significantly with male gender, high grade and presence of visceral metastases (chi(2) p<0.05), while EMT mediator expression was correlated to high NOTCH 2/3 expression. Other factors, prognostic for poor survival, were male gender, PS>=2, non-platinum therapy (chi(2) p<0.05). CONCLUSION: EMT is infrequently seen in tumours of CUP. However, an adverse prognostic significance for patient outcome has been identified and may warrant studies of therapeutic targeting. PMID- 22493360 TI - EPLIN-alpha expression in human oesophageal cancer and its impact on cellular aggressiveness and clinical outcome. AB - BACKGROUND: Epithelial protein lost in neoplasm-alpha (EPLIN-alpha) is a cytoskeletal protein whose expression is often lost or is aberrant in cancerous cells and tissues and whose loss is believed to be involved in aggressive phenotype. Our current study examined this molecule in human oesophageal tissues and investigated the cellular impact of EPLIN-alpha on oesophageal cancer cells. MATERIALS AND METHODS: Expression of the EPLIN-alpha transcript in human oesophageal tissues (tumour, paratumour and normal) was determined using the Quantitative Polymerase Chain Reaction (Q-PCR) method. In vitro models, including invasion, cellular migration (Electrical Cell substrate Impedance Sensing based method), cell growth and matrix adhesion assays were employed in order to assess the biological influence of EPLIN-alpha expression on KYSE150 oesophageal cancer cells. RESULTS: EPLIN-alpha expression was lower in tumour tissues compared to normal tissue. Grade 3-5 tumours had slightly lower levels of EPLIN-alpha compared with those of grade 2. Patients who died of oesophageal cancer had significantly lower levels of EPLIN-alpha compared to those who remained disease free (p=0.022). Lower levels of EPLIN-alpha transcript were seen in advanced oesophageal cancer, including TNM stages 2 to 4. Reduced EPLIN-alpha expression was associated with lymphatic metastasis and local advanced T-stage cancer, including T2-T4. Forced expression of EPLIN-alpha in oesophageal cancer cells rendered cells less invasive and reduced their cell growth rate in vitro. CONCLUSION: Our study suggests that EPLIN-alpha is expressed at lower levels in oesophageal cancer tissues. This down-regulation has a prognostic value. Together with the findings that EPLIN-alpha inhibits cellular growth and invasion, we conclude that EPLIN-alpha is a tumour suppressor of oesophageal cancer. PMID- 22493361 TI - Rapid, laser-induced conversion of 20-hydroxyecdysone and its diacetonide -- experimental set-up of a system for photochemical transformation of bioactive substances. AB - BACKGROUND: Photochemical transformation of certain bioactive compounds for the purpose of obtaining derivatives with increased bioactivity is a prospective area of synthetic chemistry. Ecdysteroids, analogs of the insect molting hormone, which can also exert several beneficial effects in mammals including humans, contain an enone moiety in their B ring, and, as such, are good candidates for photochemical transformations. MATERIALS AND METHODS: 20-hydroxyecdysone (20E), the most common ecdysteroid in Nature, and the easily obtained derivative 20 hydroxyecdysone 2,3;20,22-diacetonide (20ED), at different concentrations, were exposed to a 266 nm laser beam at an energy level of 6.5 mJ for different periods of time and evaluated for fluorescence emission during the process of irradiation. The products of irradiation were scanned from 200 to 1500 nm and then subjected to one-dimensional and two-dimensional thin layer chromatography. RESULTS: During irradiation, progressive significant changes in the fluorescence emission spectra were noted for both compounds with time that were accompanied by changes in their UV-Vis spectra. Full conversion of both compounds was reached within 14 minutes, and both compounds yielded several major products and several minor ones representing a wide polarity range. CONCLUSION: The photo transformation system described here was proven to be a useful and flexibly adjustable tool for the laser-catalyzed conversion of bioactive compounds. Due to the multi-drug resistance reversal activity of the less polar ecdysteroids, several new products are promising for being tested against various cancer cell lines. Fractionation, isolation and characterization of the irradiated products are currently in process. PMID- 22493362 TI - The relationship between secretory leukocyte protease inhibitor expression and Epstein-Barr virus status among patients with nasopharyngeal carcinoma. AB - AIM: The aim was to study the expression of Secretory Leukocyte Protease Inhibitor (SLPI) and to explore its correlation with the presence of Epstein-Barr Virus (EBV) among patients with nasopharyngeal carcinoma. MATERIALS AND METHODS: The expression levels of SLPI mRNA in NPC cell lines and in ten matched-pairs of NPC and adjacent normal tissue were examined by quantitative real-time Polymerase Chain Reaction (PCR). Furthermore, protein expression of SLPI in 71 paraffin embedded NPC biopsies was assessed by immunohistochemistry. Finally, the serum level of SLPI in 177 NPC patients and 103 healthy controls was evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: The expression of SLPI mRNA in NPC cells was significantly lower than in the adjacent normal epithelium (p<0.001). When the expression of SLPI in EBV-positive and -negative NPC cell lines was compared, we found that both mRNA and protein expressions of SLPI were significantly higher in EBV-negative cells. Furthermore, the results of immunohistochemical analysis demonstrated that the frequency of reduced SLPI expression in EBV-positive biopsies was significantly higher than that in EBV negative biopsies. CONCLUSION: In this study, we have confirmed that SLPI is significantly down-regulated in NPC tissues. In addition, based on our preliminary results, we propose that the reduction of SLPI in NPC cells is associated with the presence of the EBV genome and/or the expression of EBV encoded genes. SLPI may play an important role in EBV-mediated NPC tumorigenesis. PMID- 22493363 TI - Treatment of breast cancer cells by IGF1R tyrosine kinase inhibitor combined with conventional systemic drugs. AB - AIM: Insulin-like growth factor-1 receptor (IGF1R) is a tyrosine kinase receptor mediating cell growth and survival of cancer cells. We studied responses to IGF1R tyrosine kinase inhibitor NVP-AEW541 combined with conventional systemic drugs in breast cancer cell lines of different clinical subtype. MATERIALS AND METHODS: Sensitivity to NVP-AEW541, single treatment and combinations with tamoxifen, trastuzumab, doxorubicin or paclitaxel, was tested in MCF7, SKBR3 and T47D cells. Cells were assayed for proliferation, cell death, cell cycle distribution and phosphorylation of proteins downstream of IGF1R. RESULTS: Treatment of NVP-AEW541 resulted in reduced proliferation, G-1 cell cycle arrest and reduced phosphorylation of protein kinase B (AKT) and extracellular-signal-regulated protein kinase (ERK). Sensitivity to IGF1R tyrosine kinase inhibition was low in T47D cells, despite their high IGF1R expression. NVP-AEW541 combined with trastuzumab had synergistic cytotoxic effects in T47D cells, and additive effects were shown in MCF7 and SKBR3 cells. Also, combination with doxorubicin had antagonistic effects in T47D cells. Doxorubicin caused up-regulation of phosphorylated ERK in T47D cells, which was not inhibited by NVP-AEW541. CONCLUSION: Antagonistic effects should be anticipated when IGF1R inhibitors are combined with conventional systemic drugs in a subset of breast tumors. Development of functional biomarkers predicting tumor response to tailored IGF1R therapy is warranted. PMID- 22493364 TI - Methylation of the DFNA5 gene is frequently detected in colorectal cancer. AB - BACKGROUND: Recently, the human deafness, autosomal dominant 5 gene, DFNA5, has frequently been detected in cancer tissues. The methylation status of the DFNA5 gene in colorectal cancer was examined and was compared to the clinocopathological findings. MATERIALS AND METHODS: Eighty-five tumor samples and corresponding normal tissues were obtained from patients with colorectal cancer who underwent surgery at our hospital. The methylation status of the DFNA5 gene in these samples was examined by quantitative methylation-specific PCR (qMSP). Subsequently, the clinicopathological findings were correlated with the methylation status of the DFNA5 gene. RESULTS: DFNA5 gene methylation was found in 29 (34%) out of the 85 colorectal carcinomas, suggesting that it was frequently observed in colorectal cancer. A significant correlation with methylation was observed for lymphatic vessel invasion and TNM stage (p=0.0268 and p=0.0189, respectively). CONCLUSION: DFNA5 might act as a tumor suppressor gene and DFNA5 gene methylation might play an important role in the development of colorectal cancer. Our data implicate DFNA5 gene methylation as a novel molecular biomarker in colorectal cancer. PMID- 22493365 TI - Oncogramme responses of breast tumour cells treated with herceptin correlate with HER2/C-ERB B2 pathological status. AB - BACKGROUND: Among targeted therapies, Herceptin is a monoclonal antibody successfully used on patients with breast cancer expressing Human Epidermal Growth Factor Receptor-2 (HER2 receptors). Oncogramme is a method developed to predict anticancer activity of molecules and thus individualize chemotherapeutic strategies. Before this ex vivo test enters clinical validation, it was desirable to correlate breast cancer cell responses to Herceptin observed through Oncogramme with HER2 expression by these cells. MATERIALS AND METHODS: Breast tumour fragments were dissociated and obtained cells were cultured in defined medium. After Herceptin treatment, cytotoxicity was detected by cell death analysis, and responses compared to tumour HER2 status were determined by pathologists. RESULTS: Cell responses to increasing doses of Herceptin obtained with Oncogramme were in correlation with HER2 expression. CONCLUSION: Comparison between Herceptin responses obtained with Oncogramme and HER2 status of breast tumour cells confirmed that Oncogramme is a reliable method for prediction of patient cell sensitivity to anticancer drugs. PMID- 22493366 TI - A pilot study of letrozole for one year in women at enhanced risk of developing breast cancer: effects on mammographic density. AB - BACKGROUND: Tamoxifen or raloxifen for 5 years reduces the risk of developing invasive breast cancer by 40%. To address safety concerns and seek enhanced efficacy, studies of new chemopreventive agents using mammographic density as a surrogate end point are attractive. PATIENTS AND METHODS: Postmenopausal women with risk factors for developing breast cancer were given letrozole 2.5 mg daily for one year, and mammographic density was the biomarker of breast cancer risk modification. It was assessed (blinded to the reader) at baseline, 6, and 12 months in 16 evaluable women among 20 enrolled. RESULTS: Eight patients exhibited decreased mammographic density at six months, and eleven at 12 months. Toxicities included joint aches not precluding continued treatment. CONCLUSION: This pilot study supports the use of letrozole for reducing breast cancer risk. In addition, it encourages prospective studies of serial changes in mammographic density as a biomarker of risk modification within a selected high-risk population. PMID- 22493367 TI - A prospective clinical trial of cholecalciferol 2000 IU/day in colorectal cancer patients: evidence of a chemotherapy-response interaction. AB - BACKGROUND: We have previously reported a negative correlation between the effect of chemotherapy and 25-hydroxy vitamin D(3) (25-D(3)) levels in patients with colorectal cancer. Based on this finding, we hypothesized that the response to vitamin D(3) supplementation may be attenuated in patients with colorectal cancer. AIM: To determine 25-D(3) response to 2000 IU/day vitamin D(3) supplementation in patients with colorectal cancer. MATERIALS AND METHODS: Fifty evaluable colorectal cancer patients were treated with vitamin D(3) at 2000 IU/day for 6 months. Serum 25-D(3) levels were measured at baseline, 3, and 6 months of supplementation. RESULTS: The mean 25-D(3) level was 17.5 ng/ml at baseline, 31.6 ng/ml at 3 months, and 33.8 ng/ml at 6 months. The most important factor in determining 25-D(3) response was chemotherapy status. A rise in 25-D(3) of >=10 ng/ml at the 3-month interval was observed in 92% of chemotherapy-free patients vs. 39% of chemotherapy patients. Similar differences in response were noted at the 6-month interval. CONCLUSION: Depressed 25-D(3) levels are common in patients with colorectal cancer. Active chemotherapy is associated with an attenuated response to 2000 IU of D(3) supplementation in this patient population. Alternative vitamin D(3) dosing schedules need further investigation in colorectal cancer patients undergoing chemotherapy. PMID- 22493368 TI - The value of induction chemotherapy for survival in patients with non-small cell lung cancer treated with radiotherapy. AB - AIM: The aim of the present study was to retrospectively investigate the impact of induction chemotherapy on treatment outcome in patients treated with curatively intended radiotherapy for non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with a diagnosed NSCLC that have been subjected to curatively intended irradiation (>=50 Gy) and treated in an oncology department in Sweden during the years 1990-2000 were included in the study. Operated patients and patients having received concomitant chemotherapy were excluded. The included patients were localised by a manual search of all the oncology departments' medical records and radiation charts. RESULTS: Patients treated with induction chemotherapy (n=79) had a significantly better overall survival compared with patients treated with radiotherapy alone (p=0.0097) in a univariate Cox regression analysis. A platinum/taxane combination produced the greatest survival benefit; hazard ratio=0.49 (95% confidence interval=0.31 to 0.75). CONCLUSION: We found that patients treated with induction chemotherapy in addition to radiotherapy for NSCLC have a better overall survival than patients treated with radiotherapy alone and that the best results are achieved using a platinum/taxane combination. PMID- 22493369 TI - Low-dose cytarabine plus aclarubicin for patients with previously untreated acute myeloid leukemia or high-risk myelodysplastic syndrome ineligible for standard dose cytarabine plus anthracycline. AB - BACKGROUND: In order to assess the role of the combination of low-dose cytarabine (Ara-C) plus aclarubicin (CA) in remission induction for patients with untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), we retrospectively analyzed the efficacy and safety of CA. PATIENTS AND METHODS: Data of twenty patients with untreated AML or high-risk MDS who were ineligible for standard-dose Ara-C plus anthracycline and received CA as remission-induction therapy were analyzed. CA consisted of low-dose Ara-C (10 mg/m(2), subcutaneous injection every 12 hours, for 14 days) and aclarubicin (14 mg/m(2) for patients <70 years old and 10 mg/m(2) for patients >=70 years old in a one-hour infusion for 4 days). Granulocyte colony-stimulating factor (G-CSF) was used from day 1 of CA to white blood cell count (WBC) recovery, except for patients with initial WBC of more than 20.0*10(3)/mm(3). RESULTS: Eleven patients (55%) achieved complete remission. All four patients whose WBC were >=20.0*10(3)/mm(3) and did not receive G-CSF were refractory to CA. The predicted 2-year overall survival rate and median survival duration of all 20 patients were 37.9% and 363 days, respectively. The predicted 1-year relapse-free survival (RFS) rate and median duration of RFS of 11 patients who achieved complete remission were 30.3% and 332 days, respectively. Only one patient died due to transfusion-related acute lung injury. No patients died due to severe infections. CONCLUSION: CA combination with G-CSF as remission-induction therapy is promising and well-tolerated in patients with previously untreated AML or high-risk MDS who are ineligible for standard-dose Ara-C plus anthracycline without leukocytosis. In order to improve RFS, intensive postremission chemotherapy or allogeneic hematopoietic stem cell transplantation should be introduced. PMID- 22493370 TI - Sarcoidosis in a patient with metastatic melanoma sequentially treated with anti CTLA-4 monoclonal antibody and selective BRAF inhibitor. AB - A female patient with stage IV-M1c (distant lymph node and breast metastases), chemotherapy-refractory melanoma was treated with the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-inhibitory monoclonal antibody ipilimumab. At first evaluation following induction treatment, there was marked increase in the volume of the lymphadenopathies (including new adenopathies) and strong uptake of (18)Fluorodeoxy-D-glucose ((18)FDG); marked enlargement of the spleen and interstitial lung infiltrates were also observed. Non-necrotising granulomas were discovered on transbronchial mucosal biopsy and cytology on bronchoalveolar lavage established the diagnosis of sarcoidosis. There was a marked clinical and (18)FDG-positron emission tomography/computed tomography ((18)FDG-PET/CT) documented response following six weeks of corticotherapy. At follow-up, progression of subdiaphragmatic melanoma lymph node metastases was documented. Regression of these metastatic sites was observed during treatment with the selective v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor vemurafenib. The patient died due to progressive disease after three months of vemurafenib treatment. Our case report illustrates the need to take into consideration exacerbation of sarcoidosis as a potential confounder in the assessment of tumor response in a melanoma patient treated with the anti-CTLA-4 mononclonal antibody ipilimumab. PMID- 22493371 TI - Expression of serotonin receptors 5-HT1A, 5-HT1B, 5-HT2B and 5-HT4 in ovary and in ovarian tumours. AB - BACKGROUND: Recently we have shown that serotonin receptors may be involved in prostate cancer development. In ovarian carcinogenesis, oestrogen may play a role. As oestrogen seems to mediate at least some of its biological effects through serotonin, we decided to evaluate if serotonin receptors are expressed in ovary and in ovarian tumours and if the expression is correlated to ovarian tumour development. MATERIALS AND METHODS: An immunohistochemical study of the serotonin (5-HT) receptors 5-HTR1A, 5-HTR1B, 5-HTR2B and 5-HTR4 in frozen samples of ovary, and benign, borderline and invasive ovarian tumours was performed. RESULTS: Expression of all four serotonin receptors was strong to intermediate in the ovarian epithelium. In benign and non-invasive cancer cells, strong staining was seen, while in invasive cancer cells, decreased expression was observed. For 5-HTR2B, the decrease was correlated to dissemination of the disease. For none of the serotonin receptors was the expression correlated to survival. In the stromal part, a variable immunoreactivity was observed that was strongest for 5-HTR2B in both ovary and tumours. Staining of blood vessels was observed in ovary and all tumour groups for 5-HTR2B, but only occasionally was a weak expression seen for 5 HTR1A, 5-HTR1B and 5-HTR4. CONCLUSION: The staining pattern of serotonin receptors in ovary indicates their functional role in ovarian physiology. In ovarian tumours, the expression is in harmony with a tumour suppressor role in ovarian carcinogenesis, which is supported by observations in the literature. Further studies are necessary to resolve the connection between serotonin and ovarian tumour development. PMID- 22493372 TI - Expression and function of FRA2/JUND in cutaneous T-cell lymphomas. AB - Adult T-cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphomas (CTCLs) are known to frequently express CC chemokine receptor 4 (CCR4). Previously, we investigated the transcriptional control of CCR4 expression in ATLL and have found that an activating protein 1 (AP1) family member, FBJ murine osteosarcoma viral oncogene homolog (FOS)-related antigen 2 (FRA2), is consistently expressed at high levels in ATLL and, together with v-JUN avian sarcoma virus 17 oncogene homolog D (JUND), up-regulates the expression of CCR4 as well as that of several proto-oncogenes such as v-MYB myeloblastosis viral oncogene homolog (MYB), murine double minute 2 homolog (MDM2), and B-cell lymphoma 6 (BCL6). Here, we examined the expression of these genes in clinical samples of CTCLs. We detected the transcripts of FRA2, JUND, CCR4, MYB, MDM2, and BCL6 at high levels in CTCL skin lesions. Except for BCL6, we confirmed protein expression of FRA2, JUND, CCR4, MYB, and MDM2 in CTCL skin lesions. Furthermore, siRNA-mediated knockdown of FRA2 or JUND suppressed cell growth and the expression of CCR4, MYB, MDM2, and BCL6 in CTCL cell lines. Our results, thus, demonstrate the presence of a common oncogenic cascade initiated by FRA2/JUND in CCR4-expressing mature T-cell malignancies such as ATLL and CTCLs. PMID- 22493373 TI - Retinal neovascularization and hemorrhage associated with the use of imatinib (Gleevec((r))) in a patient being treated for gastrointestinal stromal tumor (GIST). AB - BACKGROUND: Gastrointestinal stromal tumor (GIST) is a mesenchymal malignancy of the gastrointestinal tract. Imatinib mesylate (Gleevec((r)), ST1571, Novartis Pharmaceuticals, Basel, Switzerland) is a selective inhibitor of break point cluster-Ableson (BCR-ABL), c-Kit, and platelet-derived growth factor receptor alpha (PDGFRalpha) tyrosine kinases. Imatinib has been approved in the U.S. for the treatment of Philadelphia-chromosome positive chronic myeloid leukemia, KIT (CD117)-positive unresectable and metastatic malignant GIST and adjuvant treatment of adult patients following resection. Ocular side effects are commonly reported with Gleevec((r)), the most common being periorbital edema and epiphora. CASE REPORT: Here we present the case of a 62-year-old male with a history of GIST in the jejunum who was started with imatinib mesylate at 400 milligrams daily. Seven months into his therapy, he reported blurry vision. He was evaluated by an ophthalmologist, and was ultimately found to have retinal hemorrhage and neovascularization. His dose was reduced by 50% to 200 milligrams daily with an almost complete resolution of symptoms within several weeks. No recurrence of symptoms or signs was noticed at 6 months follow-up. DISCUSSION: This patient's Naranjo scale was calculated to be 7, indicating a probable adverse drug reaction. Our patient's symptoms significantly improved with a dose reduction of imatinib, and this hints that there was a dose-dependent effect. The World Health Organization has categorized retinal hemorrhage as an unlikely side-effect of therapy, and to our knowledge this has never been reported before in a patient receiving imatinib mesylate for GIST treatment. Neovascularization also has not been previously reported in patients receiving this medication. It is important to identify less common ocular toxicity in patients receiving imatinib. PMID- 22493374 TI - Improved chemotherapy for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer and it is the third leading cause of cancer-related deaths worldwide. Once diagnosed with the disease, only 30-40% of patients are deemed eligible for curative intention with treatment modalities including surgical resection, liver transplantation, and chemoembolization. Eventually, most patients will receive some forms of chemotherapy in hope of prolonging life. Sorafenib is the first molecular inhibitor to be approved by the FDA for the treatment of advanced HCC. It is a tyrosine kinase inhibitor, targeting multiple molecular pathways. Prior to the arrival of sorafenib, doxorubicin was routinely used as a single drug for advanced HCC, but has shown inefficacy, with a response rate of about 15-20%. Other chemotherapy agents, such as epirubicin, cisplatin, 5-fluorouracil, etoposide and their combinations, demonstrate even lower efficacy. While being considered an advance over conventional chemotherapy, sorafenib only improves life expectancy approximately by 3 months over placebo. With that in mind, continuous efforts have been put into finding new targets and molecular pathways for possible new drug development. In this article, we summarize the current literature over the past year on chemotherapy treatment of advanced HCC. PMID- 22493375 TI - Intra-arterial infusion of irinotecan-loaded drug-eluting beads (DEBIRI) versus intravenous therapy (FOLFIRI) for hepatic metastases from colorectal cancer: final results of a phase III study. AB - BACKGROUND: Metastases to the liver receive most of their blood supply from the arterial route, therefore for patients with hepatic metastases from large bowel cancer, hepatic arterial infusion adopting drug-eluting beads preloaded with irinotecan (DEBIRI) may offer a chance of cure. PATIENTS AND METHODS: In a multi institutional study, 74 patients were randomly assigned to receive DEBIRI (36) versus systemic irinotecan, fluorouracil and leucovorin (FOLFIRI, 38). The primary end-point was survival; secondary end points were response, recurrence, toxicity, quality of life, cost and influence of molecular markers. RESULTS: At 50 months, overall survival was significantly longer for patients treated with DEBIRI than for those treated with FOLFIRI (p=0.031, log-rank). Median survival was 22 (95% Confidence Interval CI=21-23) months, for DEBIRI and 15 (95% CI=12 18) months for FOLFIRI. Progression-free survival was 7 (95% CI=3-11) months in the DEBIRI group compared to 4 (95% CI=3-5) months in the FOLFIRI group and the difference between groups was statistically significant (p=0.006, log-rank). Extrahepatic progression had occurred in all patients by the end of the study, at a median time of 13 (95% CI=10-16) months in the DEBIRI group compared to 9 (95% CI 5-13) months in the FOLFIRI group. A statistically significant difference between groups was not observed (p=0.064, log-rank).The median time for duration of improvement to quality of life was 8 (95% CI=3-13) months in the DEBIRI group and 3 (95% CI=2-4) months in the FOLFIRI group. The difference in duration of improvement was statistically significant (p=0.00002, log-rank). CONCLUSION: This study showed a statistically significant difference between DEBIRI and FOLFIRI for overall survival (7 months), progression-free survival (3 months) and quality of life (5 months). In addition, a clinically significant improvement in time to extrahepatic progression (4 months) was observed for DEBIRI, a reversal of the expectation for a regional treatment. This suggests a benefit of DEBIRI treatment over standard chemotherapy and serves to establish the expected difference between these two treatment options for planning future large randomized studies. PMID- 22493376 TI - Adjuvant chemoradiation with 5-fluorouracil or capecitabine in patients with gastric cancer after D2 nodal dissection. AB - AIM: To evaluate outcome and prognostic factors in patients with locally advanced gastric cancer. PATIENTS AND METHODS: From 2007 to 2011, 55 patients underwent adjuvant radiotherapy and concurrent chemotherapy with 5-fluorouracil (64%) or capecitabine (36%). D2 node resection was performed in all patients. The pathological stage was as follows: 13% IB; 29% II; 24% IIIA; 9% IIIB and 25% stage IV. RESULTS: The median follow up was 21 months. Five-years overall and disease-free survival were 44.5% and 48%, respectively. Eighteen patients experienced disease relapse after combined treatment; in five of these patients, relapse was both locoregional and systemic. The most common toxicity was grade 1 2 leukopenia, reported in 32% of cases. Six patients developed grade 3 toxicity. Nodal ratio >=0.4 and N3 stage were significant prognostic factors for survival and relapse. CONCLUSION: Adjuvant conformal radiotherapy and concurrent chemotherapy is a feasible and well-tolerated treatment for patients with locally advanced gastric cancer. PMID- 22493377 TI - Phase II study of docetaxel, cisplatin and 5-fluorouracil (DCF) for metastatic esophageal cancer (OGSG 0403). AB - BACKGROUND: The aims of this multiple-institution phase II study were to evaluate the efficacy and tolerability of docetaxel, cisplatin and 5-fluorouracil (DCF) for the therapy of patients with metastatic squamous cell carcinoma of the esophagus (SCCE). PATIENTS AND METHODS: Eligible patients included those with previously untreated SCCE, score of ECOG 0-2 and adequate organ function. Patients received 60 mg/m(2) docetaxel and 70 mg/m(2) cisplatin on day 1, and 600 mg/m(2) 5-fluorouracil on days 1-5 every four weeks. RESULTS: Twenty-nine (22 male, 7 female) patients with metastatic SCCE (M1a: 20, M1b: 9) were enrolled. Three cases achieved complete response and seven a partial response. In addition to these patients, three patients achieved good response and underwent surgical resection, giving an overall response rate of 34.5% (95% Confidene Interval=17.9 54.3) in confirmed cases and 44.8% (95% CI=26.4-64.3) in unconfirmed cases. Grade 3 or 4 hematological toxicities were as follows: leukopenia in 15 patients (52%), neutropenia in 22 patients (76%) and febrile neutropenia in 6 patients (21%), while grade 3 or 4 non-hematological toxicities were relatively rare. CONCLUSION: This DCF regimen was well tolerated; the results of this study provide information on the potential of DCF for treatment of patients with metastatic SCCE. PMID- 22493378 TI - C-reactive protein is associated with distant metastasis of T3 colorectal cancer. AB - Few studies have examined the relationship between systemic inflammatory response (SIR) and distant metastasis in patients with T3 colorectal cancer (T3 CRC). Uni- and multivariate analyses were performed in order to evaluate the influence of SIR on distant metastasis in patients with T3 CRC using collected clinical data. Between January 2000 and August 2009, 335 patients with pathologically diagnosed T3CRC were enrolled. Univariate analysis revealed that tumor differentiation, lymphatic invasion, venous invasion, lymph node metastasis, serum carcinoembryonic antigen (CEA) level, carbohydrate antigen 19-9 (CA 19-9) level, C-reactive protein (CRP) level and the Glasgow Prognostic Score (GPS) were associated with distant metastasis. Multivariate analysis using these selected characteristics disclosed that the CRP level was associated with distant metastasis of T3 CRC, as well as with lymph node metastasis, and CEA and CA19-9 levels. The level of CRP is one of the important clinical characteristics associated with distant metastasis of T3 CRC. PMID- 22493379 TI - Factors resulting in 5-year disease-free survival after resection of hepatocellular carcinoma. AB - BACKGROUND/AIM: Hepatectomy without recurrence for more than five years may be considered as being a sufficient resection of primary hepatocellular carcinoma (HCC). The purpose of the present study was to clarify the predictive factors for sufficient resection for HCC patients. PATIENTS AND METHODS: In our Department, 77 patients with HCC survived without recurrence for more than five years following hepatectomy (curative group) and 187 patients underwent hepatectomy but developed recurrence within five years (recurrence group). We compared the clinicopathology between these two groups and evaluated the favorable factors for HCC without recurrence using logistic regression analysis. RESULTS: The curative group was associated with three independent factors by multivariate logistic regression analyses: tumor size, serum indocyanine green retention rate (ICG15) and anatomic wide hepatectomy (all p<0.05). CONCLUSION: Sufficient resection is closely related to patient, tumor, and treatment factors. Anatomic wide hepatectomy for small (<29 mm) HCC in patients with sufficient liver function (ICG15 <16.5%) can achieve sufficient resection. PMID- 22493380 TI - Long-term amrubicin chemotherapy for small-cell lung cancer. AB - BACKGROUND: Amrubicin is an active agent for the treatment of small-cell lung cancer (SCLC). However, there have been no reports of long-term amrubicin use. PATIENTS AND METHODS: Twelve patients with SCLC who were treated with eight or more cycles of amrubicin chemotherapy were retrospectively reviewed. RESULTS: The median number of cycles of amrubicin chemotherapy received by the patients was 12 (range=8-20), and the median cumulative dose of amrubicin was 2076 mg (range=1200 2856 mg). The median survival time of the study patients was 1104 days (range=459 1997 days). The main adverse events observed during amrubicin chemotherapy were leukopenia and neutropenia. The cardiothoracic ratio (CTR), expressed as the mean (standard deviation) of the values measured at the initiation and termination of amrubicin chemotherapy was 46.2 (4.0), and 46.1 (5.1), respectively. The change in CTR did not reach statistical significance (p=0.92). CONCLUSION: Long-term amrubicin chemotherapy is a safe and effective treatment that is associated with a good survival prognosis in properly selected patients. PMID- 22493381 TI - Elevated HER2 extracellular domain level in primary breast cancer with HER2 overexpression predicts early failure of adjuvant trastuzumab. AB - AIM: To investigate in a prospective study the prognostic value of serum HER2 extracellular domain (ECD) level in patients with primary breast cancer overexpressing HER2 treated with adjuvant chemotherapy and trastuzumab. PATIENTS AND METHODS: All the patients treated for primary breast cancer with chemotherapy and adjuvant trastuzumab from April 1, 2005 to December 31, 2006 at the Centre de Lutte Contre le Cancer de Haute Normandie were enrolled in this prospective study. HER2 ECD was measured in frozen serum by a commercial kit with a cut-off value of 15 ng/ml. RESULTS: Sixty-five patients were enrolled. Seven patients (11%) had an elevated serum HER2 ECD level (mean=25.1 ng/ml, range 15.1-38.9 ng/ml). During follow-up, 13 patients (20%) developed metastases and seven patients (11%) died. Death was related to breast cancer metastases in six patients (9%). Out of the seven patient with elevated serum HER2 ECD level, five (71%) developed metastases and three (43%) died of metastases during follow-up. Multivariate analysis showed that elevated serum HER2 ECD level was the unique factor for both disease-free survival (p<0.0006) and overall survival (p=0.008) in this series. CONCLUSION: Elevated serum HER2 ECD level is a strong prognostic factor in primary breast cancer overexpressing HER2 treated with adjuvant therapy of trastuzumab. In addition, our results suggest that it could predict failure of adjuvant therapy of trastuzumab. PMID- 22493382 TI - Lymphoepithelioma-like carcinoma of the breast: a case report with a special analysis of an association with human papilloma virus. AB - Lymphoepithelioma-like carcinoma (LELC) of the breast is a very rare tumor, and fewer than 20 cases have been reported. A recent report suggested the implication of human papilloma virus (HPV) in the pathogenesis of breast LELC. We report a case of LELC of the breast with a review of its relevance to an association with HPV. A 45-year-old female patient presented with a solid mass in the outer-upper part of her left breast, which was diagnosed as malignant (ductal carcinoma) by fine-needle aspiration cytology. The patient underwent a quadrantectomy of the breast and axillary sentinel node biopsy. Pathological examination revealed cohesive sheets or nests of malignant epithelial cells, with unclear circumscription in a background of diffuse lymphoid infiltration; the postsurgical clinical stage was pT1pN0M0, stage 1. Immunohistochemistry demonstrated that the tumor was triple negative and basal-like breast cancer. In the present case in situ hybridization demonstrated positive HPV signals in a few tumor cells; however, polymerase chain reaction study failed to detect HPV in tumor cells. CONCLUSION: To the best of our knowledge, this is the second report on HPV infection associated with breast LELC. PMID- 22493383 TI - Histopathological classification of pseudomyxoma peritonei and the prognostic importance of PINCH protein. AB - AIM: The aims of this study were i) to assess a new and more detailed histopathological classification and to analyze concordance between pathologists in the histopathological classification of pseudomyxoma peritonei (PMP); ii) to analyze the expression in the stroma of the particularly interesting new cysteine histidine (PINCH) protein and its prognostic importance in PMP. MATERIALS AND METHODS: Surgical specimens from 81 patients, classified according to the Ronnett et al histopathological classification were compared to a new system with four groups ranging from indolent to aggressive growth patterns. PINCH protein expression was analyzed and was related to clinical variables. RESULTS: The new four-group classification provided better prognostic information than the classification according to Ronnett et al. (p=0.04). Expression of the PINCH protein in the stroma was found in 83% of the cases and was associated with high tumor burden (p=0.002) and a poor prognosis (p=0.04). CONCLUSION: The proposed new PMP classification system may provide additional prognostic information. PINCH protein is expressed in PMP and has prognostic information. PMID- 22493384 TI - Secondary tumors of the pancreas: a case series. AB - Metastatic carcinoma of the pancreas from another primary site is uncommon and it accounts for 2-5% of all pancreatic cancer cases. We reported the case of one patient with pancreatic metastasis from colon carcinoma in the past and would like to add another six cases of pancreatic metastases from different types of cancer. The diagnosis of cancer metastatic to the pancreas should be suspected when patients have a history of malignancy, especially of kidney, skin, lung, colon and breast cancer. Besides imaging studies, such as computed tomography (CT) scan, bone scan and positron emission tomography (PET)/CT scan, endoscopic ultrasound (EUS)-guided biopsy has most value in ruling out second primary pancreatic cancer. The prognosis of pancreatic metastases is essentially determined by the underlying primary cancer and the potential treatment options. PMID- 22493385 TI - Nedaplatin and irinotecan in patients with large-cell neuroendocrine carcinoma of the lung. AB - BACKGROUND: No standard chemotherapy has been established for patients with large cell neuroendocrine carcinoma (LCNEC). PATIENTS AND METHODS: Patients with LCNEC of the lung were treated with nedaplatin (NP) at 50 mg/m(2) and irinotecan at 50 mg/m(2) on days 1 and 8 every four weeks for four cycles. RESULTS: Data for 18 of the LCNEC patients were retrospectively analyzed. All patients were male, with a performance status 0 or 1, and the median age was 68 (range 58-80) years. Nine patients received adjuvant chemotherapy after undergoing complete surgical resection. Fourteen patients were able to receive four cycles of nedaplatin and irinotecan. Grade 4 leukopenia and neutropenia occurred in 5.6% and 16.7%, respectively. Four patients experienced grade 3 non-hematologic toxicities, such as diarrhea, enterocolitis, duodenal perforation and myocardial infarction. There were no treatment-related deaths. Two patients achieved complete response and four achieved partial response, and the median survival time was 12.3 months for the nine patients with advanced disease. CONCLUSION: Nedaplatin plus irinotecan is effective and safe for patients with LCNEC of the lung. PMID- 22493386 TI - Comparison of the chemosensitivity of the primary lesion and a pancreatic metastasis of colon cancer: a case report. AB - Pancreatic metastasis from colorectal cancer is rare, and accounts for less than 2% of all pancreatic metastases. There have been no studies that have reported the differences in the sensitivity to chemotherapy between the primary lesion and the pancreatic metastasis in colorectal cancer. We experienced a rare example of pancreatic metastasis from colorectal cancer, and report here the difference in the sensitivity to the antitumor drug. A 68-year-old female underwent colectomy for rectal carcinoma with a mass in the pancreatic tail and the liver. The patient also underwent a distal pancreatectomy and a segmental liver resection at the same time. v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and tumor protein 53 (TP53) gene mutation analyses, in addition to the histopathological examinations, revealed tumors of the liver and the pancreatic tail as being metastases from the primary carcinoma. We employed a collagen gel droplet-embedded culture drug sensitivity test for both the primary lesion and the pancreatic metastasis. The sensitivity to oxaliplatin and FOLFOX (5 flurouracil, folinic acid and oxaliplatin) were lower in the pancreatic metastasis compared to the primary lesion. In conclusion, pancreatic metastasis from colorectal malignancy is rare, and the present results suggest that there are potential differences in the sensitivity to chemotherapy between the primary colorectal tumor and its pancreatic metastasis. PMID- 22493387 TI - A modified vimentin histological score helps recognize pulmonary sarcomatoid carcinoma in small biopsy samples. AB - BACKGROUND: As pulmonary sarcomatoid carcinomas (PSCs) are life-threatening tumors, an improvement in their recognition in small-sized tumor samples is clinically warranted. MATERIALS AND METHODS: Preoperative biopsy samples and paired surgical specimens from 20 pleomorphic carcinomas, two pulmonary blastomas and one carcinosarcoma (training set) were studied for vimentin immunohistochemistry. A modified vimentin histologic score (M-VHS) was devised by multiplying three independently assessed parameters, i.e. the percentage of positive cells (from 0 to 5+, by quintiles), the intensity of immunostaining (low=1 vs. strong=2) and the distribution pattern within the cytoplasm (partial=1 vs. diffuse=2), so ranging from 0 to 20. Forty-eight consecutive and independent cases of non-small cell lung carcinoma (NSCLC), including two additional cases of PSC, were used as control groups (validation set). RESULTS: No differences in M VHS were found between biopsies and surgical specimens of PSC, thus confirming the occurrence of stable epithelial mesenchymal transition (EMT) and hence the specific diagnosis of PSC. All types of PSC shared the same M-VHS. The M-VHS of 46 conventional NSCLC was by far lower (p<0.0001), whereas two additional cases of PSC showed the same results as the training set. Poorly differentiated NSCLC with marked pleomorphism but not stable EMT did not exhibit significantly increased M-VHS values. CONCLUSION: M-VHS helped in morphological analysis to render more definite diagnoses on small biopsies of PSC. PMID- 22493388 TI - Concurrent chemoradiotherapy with paclitaxel and cisplatin for adenocarcinoma of the cervix. AB - BACKGROUND: It is unclear whether cisplatin-based concurrent chemoradiotherapy (CCRT) has the same effect on adenocarcinoma as on squamous cell carcinoma. PATIENTS AND METHODS: We retrospectively analyzed data for 32 patients with stage IIB-IVA cervical adenocarcinoma who were treated with radiotherapy (RT) or CCRT. Fourteen patients were treated with RT, 8 with CCRT using cisplatin alone (CCRT P), and 10 with CCRT using cisplatin plus paclitaxel (CCRT-TP). RESULTS: Complete response was achieved in 7/14 patients in the RT group, 4/8 patients in the CCRT P group, and 9/10 patients in the CCRT-TP group. Ten out of the 14 patients in the RT, 7/8 patients in the CCRT-P, and 2/10 patients in the CCRT-TP groups experienced locoregional recurrence. The 5-year overall survival rate in the RT, CCRT-P, and CCRT-TP groups was 7.1%, 25.0%, and 74.1%, respectively (p=0.0094). CONCLUSION: The present study demonstrated that CCRT-TP achieved much better local control for adenocarcinoma of the cervix, leading to a decrease in locoregional recurrence. PMID- 22493389 TI - Extravasation of liposomal doxorubicin induces irritant reaction without vesicant injury. AB - Anthracycline extravasation is an uncommon but very serious complication. Very few data are available in the literature concerning the consequences and the management of extravasation of liposomal doxorubicin. This report describes the cases of two patients with liposomal doxorubicin extravasation who developed irritant reaction without vesicant or necrotic lesions. It is concordant with other cases described in the literature and suggests that extravasation of liposomal doxorubicin can be relatively well tolerated. The process applied to extravasations of irritant and non-vesicant agents could be used to manage extravasations of liposomal doxorubicin. PMID- 22493390 TI - Complete response and long-term survival in malignant pleural mesothelioma: case report. AB - Malignant pleural mesothelioma is a rare tumour. A three-modal strategy, comprising of surgery, radiotherapy and chemotherapy has been shown to be essential for appropriate management. Current literature evidences the importance of radiation therapy in the adjuvant setting for local control of the disease, as part of a multidisciplinary treatment, with increment of progression-free survival rate, but also of disease-free survival. CASE REPORT: At the beginning of 2007, a 26-year-old Peruvian woman was admitted to the hospital referring breathlessness and other non-specific symptoms such as fever and weight loss. After the diagnosis of pleural mesothelioma by thoracoscopic talc insufflation, combined with pleural biopsy, and total body computed tomographic scan, the patient underwent two cycles of neoadjuvant chemotherapy with pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)), followed by an extra-pleural pneumonectomy. After 6 months, the patient was treated with three-dimensional external beam radiation therapy to the left hemithorax. Computed tomographic scans, performed after the ending of the radiotherapy, integrated with positron-emission tomography, were all negative for neoplastic pathology. The patient remains in good health and free from recurrence at four years. CONCLUSION: This clinical case shows a disease-free survival interval of 4 years for malignant pleural mesothelioma. A good staging system and a combined treatment, involving surgery, neoadjuvant chemotherapy and adjuvant radiation therapy, represent a useful strategy not only to contain local disease progression, but even to increase disease-free survival in pleural mesothelioma. PMID- 22493391 TI - Study of AP endonuclease (APEX1/REF1), a DNA repair enzyme, in gallbladder carcinoma. AB - AIM: This study investigated the levels of Apurinic/Apyrimidinic Endonuclease (APEX1) in gallbladder carcinoma (CaGB) tissue and co-related these levels with various clinicopathological parameters. PATIENTS AND METHODS: Twenty cases of CaGB and cholelithiasis were included in the study. Western blot analysis of APEX1 protein was performed using actin as the reference point. Densitometric analysis and the integrated density value (IDV) of APEX1 protein samples were determined. The ratio of IDV of APEX1/actin was determined. RESULTS: The mean IDV ratio of APEX1 in CaGB was 0.63+/-0.33 and 0.45+/-0.19 in cholelithiasis. The mean IDV ratio of a variant of APEX1 (DeltaAPEX1) in CaGB was 0.50+/-0.09, whereas it was 0.40+/-0.16 in cholelithiasis. Calculating the mean IDV ratio of total APEX (APEX1+DeltaAPEX1) in CaGB was 1.13+/-0.31 whereas in cholelithiasis, 0.85+/-0.23. The differences were statistically significant (p<0.05). CONCLUSION: A significant correlation was found between the relative expressions of APEX1 in cancer as compared to that in cholelithiasis patients. There was significant association between APEX1 expression and perineural invasion. A variant of APEX1 correlated with tumor infiltration. Hence APEX1 may be of use as a prognostic marker in patients with CaGB. PMID- 22493392 TI - Adjuvant intravesical instillation for primary T1G3 bladder cancer: BCG versus MMC in Korea. AB - AIM: To compare the efficacy of bacillus Calmette-Guerin (BCG) and mitomycin-C (MMC) intravesical instillation for primary T1G3 bladder cancer (BC). PATIENTS AND METHODS: This retrospective study included 107 patients with newly diagnosed primary T1G3 BC who were treated by transurethral resection (TUR) plus intravesical instillation. The BCG group was administered BCG-RIVM (2*10(8) colony forming unit) instilled once weekly for 6 weeks, or the same regimen as induction therapy followed by three once-weekly instillations at 3, 6, 12 and 18 months after initiation of the induction therapy. The MMC group was administered MMC (30 mg) in six weekly instillations, or the same regimen with subsequent monthly instillations for one year. We evaluated differences between these agents in disease recurrence-free survival and disease progression rate at the time of recurrence. RESULTS: The mean observation period was 24.3+/-28.6 months. The BCG and MMC groups comprised 53 patients (49.5%) and 54 patients (50.5%), respectively. During the observation period, recurrences developed in 61 patients (57.0%). The median time to recurrence for the BCG and MMC arm were 24.0 and 26.0 months, respectively. There were no significant differences for recurrence-free survival between the two groups (log-rank p=0.616). At the time of recurrence, 9.4% (5 out of 53) of patients in the BCG arm and 7.4% (4 out of 54) patients in the MMC arm also experienced by disease progression (p=1.000). CONCLUSION: There were no statistically significant differences regarding recurrence and disease progression rate at the time of recurrence between the two adjuvant treatments in primary T1G3 BC. Thus, large prospective studies in Asian population are required. PMID- 22493393 TI - Investigative clinical study on prostate cancer part VIII: prolactin hormone and the pituitary-testicular-prostate axis at the time of initial diagnosis and subsequent cluster selection of the patient population after radical prostatectomy. AB - AIM: To evaluate the prolactin hormone (PRL) physiopathology along the pituitary testicular prostate axis at the time of initial diagnosis of prostate cancer and the subsequent cluster selection of the patient population after radical prostatectomy in relation to clinical and pathological variables. PATIENTS AND METHODS: Ninety-two operated prostate cancer patients were retrospectively reviewed. No patient had previously received hormonal treatment. The investigated variables included PRL, follicle stimulating hormone (FSH), luteinizing hormone (LH), total testosterone (TT), free testosterone (FT), total prostate specific antigen (PSA), percentage of positive cores at transrectal ultrasound scan biopsy (TRUSB) (P+), biopsy Gleason score (bGS), pathology Gleason score (pGS), estimated tumor volume in relation to percentage of prostate volume (V+), overall prostate weight (Wi) and age. Empirical PRL correlations and multiple linear predictions were investigated along the pituitary testis prostate axis in the different groups of the prostate cancer population and clustered according to pT (2a/b, 3a, 3b/4) status. The patient population was classified according to the log(10) PRL/V+ ratio and clustered as follows: group A (log(10) PRL/V+ <=1.5), B (1.5< log(10)PRL/V+ <=2.0) and C (log(10) PRL/V+ >2.0). Simple linear regression analysis of V+ predicting PRL was computed for assessing the clustered model and analysis of variance was performed for assessing significant differences between the groups. RESULTS: PRL was independently predicted by FSH (p=0.01), LH (p=0.008) and P+ (p=0.06) in low-stage prostate cancer (pT2a/b). Interestingly, PRL was independently predicted by LH (p=0.03) and FSH, TT, FT, PSA, bGS, pGS, V+, Wi and age (all at p=0.01) in advanced stage-disease (pT3b/4). V+ was also significantly correlated (r=0.47) and predicted by P+ (p<0.0001) in the prostate cancer population. PRL was significantly correlated and predicted by V+ when the patient population was clustered according to the log(10)PRL/V+ ratio in group A (p=0.008), B (p<0.0001) and C (p<0.0001). Moreover, the three groups had significantly different mean values of PRL (p<0.0001), PSA (p=0.007), P+ (p=0.0001), V+ (p<0.0001), Wi (p=0.03), bGS (p=0.008), pGS (p=0.003); also, groups A, B and C had significant different pGS (p=0.03), pT (p=0.0008) and pR (p=0.01) frequency distributions. CONCLUSION: At diagnosis, in an operated prostate cancer population, PRL was significantly correlated and independently predicted along the pituitary testis prostate axis in high-stage disease; V+ was also significantly correlated and predicted by P+. Because of the high correlation and prediction of PRL by both V+ and P+, the prostate cancer population at diagnosis was clustered according to the log(10)PRL/V+ ratio into groups A, B and C that, in theory, might be models with prognostic potential and clinical applications in the prostate cancer population. However, confirmatory studies are needed. PMID- 22493394 TI - PKCeta is a novel prognostic marker in non-small cell lung cancer. AB - BACKGROUND: Novel biomarkers which may serve as therapeutic targets are essential for lung cancer treatment. Here we investigated the prognostic significance of protein kinase Ceta (PKCeta), a cell cycle regulator involved in tumorigenesis and chemotherapy resistance, in patients diagnosed with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Sixty-three chemotherapy-naive patients were examined for PKCeta by immunohistochemistry and divided into PKCeta H-Score tertiles (low, intermediate and high). Time until event (relapse or mortality) within one year was determined using Cochran-Armitage test and Cox proportional hazards regression model. RESULTS: The distribution of patients according to clinical stage 1-4 was: 27%, 5%, 26% and 42%, respectively. PKCeta overexpression was associated with advanced stage (p=0.03) and the risk for an event (p=0.045). Patients of the lowest tertile were less likely to experience an event. CONCLUSION: PKCeta is a novel prognostic marker in NSCLC that may predict poor prognosis. The use of PKCeta-specific inhibitors in NSCLC may prove valuable. PMID- 22493395 TI - Ameloblastic carcinoma, primary type: case report, immunohistochemical analysis and literature review. AB - Ameloblastic carcinoma (AC) is a rare malignant odontogenic neoplasm with scarce reported cases in the literature and it can be confused with benign ameloblastoma (AM). This study reports a case of AC, and presents a literature review of AC classified into primary type (ACPt) or secondary type (ACSt) by the World Health Organization (WHO). The review addressed 31 cases published in the English literature between the years 2005 and 2011. The majority of cases were ACSt. The mandible was the most common site of occurrence for both AC types. All patients who died of their disease had ACSt. Tumors with plexiform pattern, hyperchromatism, mitosis and necrosis were associated with a higher ratio of histories of recurrence and death by disease, as well as the tumors with clear cells, especially in the ACSt. ACSt appeared to correlate with recurrence and mortality. The histological features may have different prognostic importance depending on the AC type. PMID- 22493396 TI - Correlation of MACC1 and MET expression in rectal cancer after neoadjuvant chemoradiotherapy. AB - BACKGROUND: Metastasis associated in colon cancer 1 (MACC1) is a recently identified gene that plays a key role in regulating hepatocyte growth factor-MET signaling. In this study, we demonstrated the correlation and the clinical significance of MACC1 and MET expression in rectal cancer patients treated with chemoradiotherapy (CRT) followed by surgery. MATERIALS AND METHODS: The expression of MACC1 and MET mRNA in residual cancer cells from 52 patients after CRT was determined by quantitative real-time polymerase chain reaction. Protein expression was also investigated by immunohistochemical staining. RESULTS: MACC1 and MET expressions were positively correlated. Furthermore, these proteins were also co-expressed in immunohistochemical analyses. High expression of MACC1 or MET was associated with reduced relapse-free survival and the prognosis was worse when both genes were highly expressed. CONCLUSION: Evaluation of MACC1 and MET expression may be useful for predicting prognosis in patients with rectal cancer treated with CRT followed by surgery. PMID- 22493397 TI - A two-step selection of breast cancer patients candidates for exclusive IORT with electrons: a mono-institutional experience. AB - AIM: To assess the impact of a two-step multiparameter selection on the actual enrollment of women with breast cancer into a prospective intraoperative radiotherapy (IORT) trial. PATIENTS AND METHODS: From September 2009, a prospective clinical trial was started in order to deliver adjuvant exclusive single -fraction IORT to patients with early breast cancer. To select patients meeting suitable eligibility criteria for the clinical trial, a two-step decision process was developed: at pre-surgical examination (first step) and during surgery (second step). RESULTS: A series of 464 patients with breast cancer was analysed: at the first step, out of 464 patients, 333 (71%) were considered eligible for the IORT protocol; at the second step, out of 333 patients, 199 (60%) met the eligibility criteria and received the IORT fraction according to the criteria of the controlled trial. CONCLUSION: In our experience, the ultimate rate of patients who enrolled in the IORT clinical trial after the two-step decision process was 43%. PMID- 22493398 TI - Impact of epidural analgesia on survival in patients undergoing complete cytoreductive surgery for ovarian cancer. AB - BACKGROUND: Potential benefits of regional analgesia in reduction of cancer recurrence have been reported for breast and prostate cancer. The aim of this study was to evaluate the influence of regional analgesia on recurrence-free survival and overall survival in patients with advanced-stage ovarian cancer (ASOC) following complete cytoreduction. PATIENTS AND METHODS: This is a retrospective study of 104 patients who had undergone complete cytoreduction for ASOC between 01/2007 and 12/2009: 51 with patient controlled epidural analgesia (PCEA) and 53 without PCEA. RESULTS: No significant difference was found between the two groups in terms of overall survival, while there was a trend in favour of PCEA for disease free survival. CONCLUSION: In our study, regional analgesia had no clear impact on cancer recurrence. More studies on this subject are warranted in order to determine the possible impact of regional analgesia on ASOC. PMID- 22493399 TI - Lip cancer: a 10-year retrospective epidemiological study. AB - BACKGROUND: Lip cancer is the most frequent tumor of the oral-maxillary region. A high incidence of lip cancer has been reported among the Italian population over the past decade. MATERIALS AND METHODS: This retrospective study analyzes epidemiological data and risk factors for lip cancer among patients who presented to our department between 2000-2010. Statistical analysis for this study was calculated employing Student T and chi-square tests. RESULTS: Of 540 cases, most were found among men (82%), and those aged over 45 years (84.8%). The dominant cancer type was squamous cell carcinoma of the external lower lip (predominantly in men). We recorded high rates of chronic solar exposure, and tobacco and alcohol drinking habits in patients with squamous cell carcinoma. CONCLUSION: Individuals aged over 45 years are at higher risk for lip cancer. The high association of the examined risk factors with the rate of squamous cell carcinoma confirms their role in the development of this type of tumor. PMID- 22493400 TI - The prognostic significance of HER2 positivity for advanced gastric cancer patients undergoing first-line modified FOLFOX-6 regimen. AB - AIM: We aimed to clarify the prognostic significance of HER2 positivity in advanced gastric cancer. PATIENTS AND METHODS: The cohort included patients with initially metastatic or recurrent gastric cancer treated with first-line modified FOLFOX-6. The HER2 status was analyzed according to modified scoring criteria specific for gastric cancer. RESULTS: HER2 positivity was shown in 10 out of 114 patients (9.0%). The median time-to-progression (TTP) (4.3 months, 95% confidence interval (CI)=3.6-4.9) and the overall survival (OS) (7.5 months, 95% CI=6.1-8.8) of patients with HER2-positive gastric cancer tended to be shorter than the median TTP (5.9 months, 95% CI=4.5-7.2) and OS (10.8 months, 95% CI=9.2-12.3) of those with HER2-negative gastric cancer (TTP, p=0.177; OS, p=0.068). Particularly in the subgroup of patients without diffuse-type histology, HER2-positive gastric cancer had a worse TTP than those with HER2-negative gastric cancer (p=0.024). In multivariate analysis of this subgroup, HER2 positivity and ECOG performance status of 2 were associated with shorter TTP (hazard ratio (HR)=2.926, p=0.014; HR=2.489, p=0.035, respectively). CONCLUSION: HER2-positive gastric cancer seems to confer poorer prognosis, particularly in patients without diffuse-type tumor, treated with modified FOLFOX-6. PMID- 22493401 TI - Pretreatment neutrophil:lymphocyte ratio as a prognostic factor in cervical carcinoma. AB - AIM: This study was designed to investigate the prognostic value of the neutrophil:lymphocyte ratio (NLR) in cervical cancer. PATIENTS AND METHODS: Patients with clinically staged cervical carcinoma (IB to IVA) at Samsung Medical Center, Seoul, Korea, from 1996 to 2007 were retrospectively enrolled. RESULTS: We enrolled 1061 patients with cervical cancer. The median NLR was 1.9, with a range of 0.3-27.0. When the cohort was divided according to the median NLR, poorer survival outcomes were observed in the group with higher NLR (>=1.9) than in the lower NLR group (<1.9). Patients of the higher NLR group (>=1.9) were younger in age and had more advanced staged disease when compared with those of the lower NLR group (<1.9). In multivariable analysis, higher pretreatment NLR was identified as being an independent poor prognostic factor for survival. CONCLUSION: Pretreatment NLR may be a cost-effective biomarker to stratify risk of recurrence and death in patients with cervical cancer. PMID- 22493404 TI - Measles in a mother and her newborn baby. PMID- 22493405 TI - The epidemiology of hypernatraemia in hospitalised children in Lothian: a 10-year study showing differences between dehydration, osmoregulatory dysfunction and salt poisoning. AB - INTRODUCTION: The relative frequencies of the causes of hypernatraemia in children after the neonatal period are unknown. Salt poisoning and osmoregulatory dysfunction are extremely rare and potentially fatal. In this retrospective 10 year study, the incidence, causes and differential biochemistry of hypernatraemia in children is examined. METHODS: Children with hypernatraemia (sodium >= 150 mmol/litre) aged >2 weeks to 17 years were identified from laboratory data of two paediatric departments serving the Lothian region of Scotland. A review of patient notes established time of onset and cause. Denominator data were available from the Scottish Health Service. RESULTS: On admission to hospital, 1 in 2288 children (1:1535 admitted as an emergency) had hypernatraemia. This is 1 in 30 563 Lothian children <17 years. Overall 0.04% hospital stays had an episode of hypernatraemia. In 45 children admitted with 64 separate episodes (11 from a case of salt poisoning), the commonest cause was dehydration secondary to either gastroenteritis or systemic infection; 31% had an underlying chronic neurological disorder. A total of 177 further cases developed hypernatraemia after admission. The commonest causes were dehydration secondary to severe systemic infection and postoperative cardiac surgery. Urine sodium:creatinine ratio and fractional excretion of sodium were both much higher in the salt poisoning case than in a child with osmoregulatory dysfunction or children with simple dehydration. CONCLUSIONS: Hypernatraemia after 2 weeks of age is uncommon, and on admission is usually associated with dehydration. Salt poisoning and osmoregulatory dysfunction are rare but should be considered in cases of repeated hypernatraemia without obvious cause. Routine measurement of urea, creatinine and electrolytes on paired urine and plasma on admission will differentiate these rare causes. PMID- 22493406 TI - Chest mass in a 13-year-old boy. PMID- 22493407 TI - Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. AB - BACKGROUND: Although previous randomized, double-blind, placebo-controlled trials reported the efficacy of omega-3 fatty acid supplements in the secondary prevention of cardiovascular disease (CVD), the evidence remains inconclusive. Using a meta-analysis, we investigated the efficacy of eicosapentaenoic acid and docosahexaenoic acid in the secondary prevention of CVD. METHODS: We searched PubMed, EMBASE, and the Cochrane Library in April 2011. Two of us independently reviewed and selected eligible randomized controlled trials. RESULTS: Of 1007 articles retrieved, 14 randomized, double-blind, placebo-controlled trials (involving 20 485 patients with a history of CVD) were included in the final analyses. Supplementation with omega-3 fatty acids did not reduce the risk of overall cardiovascular events (relative risk, 0.99; 95% CI, 0.89-1.09), all-cause mortality, sudden cardiac death, myocardial infarction, congestive heart failure, or transient ischemic attack and stroke. There was a small reduction in cardiovascular death (relative risk, 0.91; 95% CI, 0.84-0.99), which disappeared when we excluded a study with major methodological problems. Furthermore, no significant preventive effect was observed in subgroup analyses by the following: country location, inland or coastal geographic area, history of CVD, concomitant medication use, type of placebo material in the trial, methodological quality of the trial, duration of treatment, dosage of eicosapentaenoic acid or docosahexaenoic acid, or use of fish oil supplementation only as treatment. CONCLUSION: Our meta-analysis showed insufficient evidence of a secondary preventive effect of omega-3 fatty acid supplements against overall cardiovascular events among patients with a history of cardiovascular disease. PMID- 22493408 TI - Evidence of pharmaceutical innovation and therapeutic enthusiasm: strategies for patent extension. PMID- 22493409 TI - Avoidance of generic competition by Abbott Laboratories' fenofibrate franchise. AB - The ongoing debate concerning the efficacy of fenofibrate has overshadowed an important aspect of the drug's history: Abbott Laboratories, the maker of branded fenofibrate, has produced several bioequivalent reformulations that dominate the market, although generic fenofibrate has been available for almost a decade. This continued use of branded formulations, which cost twice as much as generic versions of fenofibrate, imposes an annual cost of approximately $700 million on the US health care system. Abbott Laboratories maintained its dominance of the fenofibrate market in part through a complex switching strategy involving the sequential launch of branded reformulations that had not been shown to be superior to the first-generation product and patent litigation that delayed the approval of generic formulations. The small differences in dose of the newer branded formulations prevented their substitution with generics of older generation products. As soon as direct generic competition seemed likely at the new dose level, where substitution would be allowed, Abbott would launch another reformulation, and the cycle would repeat. Based on the fenofibrate example, our objective is to describe how current policy can allow pharmaceutical companies to maintain market share using reformulations of branded medications, without demonstrating the superiority of next-generation products. PMID- 22493410 TI - Omega-3 fatty acids and secondary prevention of cardiovascular disease-is it just a fish tale?: comment on "Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease". PMID- 22493411 TI - Long-term dynamics of bone mineral density during intermittent androgen deprivation for men with nonmetastatic, hormone-sensitive prostate cancer. AB - PURPOSE: To investigate changes in bone mineral density (BMD) and fracture risk in men who received intermittent androgen deprivation (IAD) for nonmetastatic, hormone-sensitive prostate cancer. PATIENTS AND METHODS: Men with prostate cancer who lacked radiographically detectable metastases were treated in a prospective trial of IAD. After 9 months of treatment with leuprolide and flutamide, androgen deprivation therapy (ADT) was stopped until prostate-specific antigen reached a threshold (1 ng/mL for radical prostatectomy; 4 ng/mL for radiation or primary ADT) for a new cycle. Dual-energy x-ray absorptiometry (DXA) scans were performed before starting ADT and subsequently with each change in therapy. At least two consecutive DXA scans were required for this analysis. Computed tomography, bone scintigraphy, and lumbar spine x-rays were performed at the beginning and end of each treatment period. RESULTS: Fifty-six of 100 patients met criteria for this analysis. The median age at study entry was 64.5 years (range, 49.8 to 80.9 years). The average percentage change in BMD during the first on-treatment period was -3.4% (P < .001) for the spine and -1.2% (P = .001) for the left hip. During the first off-treatment period (median, 37.4 weeks; range, 13.4 weeks to 8.7+ years), BMD recovery at the spine was significant, with an average percentage change of +1.4% (P = .002). Subsequent periods had heterogeneous changes of BMD without significant average changes. After a median of 5.5 years (range, 1.1 to 13.8+) years on trial, one patient (1.8%) had a compression fracture associated with trauma. CONCLUSION: Patients experienced the greatest average change in BMD during early treatment periods of IAD with a smaller average change thereafter. Fractures were rare. PMID- 22493412 TI - Is colon cancer survival influenced by tumor location? PMID- 22493413 TI - Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial. AB - PURPOSE: In chronic lymphocytic leukemia (CLL), TP53 deletion/mutation is strongly associated with an adverse outcome and resistance to chemotherapy-based treatment. In contrast, TP53 defects are not associated with resistance to the anti-CD52 monoclonal antibody alemtuzumab or methylprednisolone. In an attempt to improve the treatment of TP53-defective CLL, a multicenter phase II study was developed to evaluate alemtuzumab and methylprednisolone in combination. PATIENTS AND METHODS: Thirty-nine patients with TP53-deleted CLL (17 untreated and 22 previously treated) received up to 16 weeks of treatment with alemtuzumab 30 mg three times a week and methylprednisolone 1.0 g/m(2) for five consecutive days every 4 weeks. Antimicrobial prophylaxis consisted of cotrimoxazole, itraconazole, and aciclovir (or valganciclovir for asymptomatic cytomegalovirus viremia). The primary end point was response as assigned by an end-point review committee. Secondary end points were safety, progression-free survival (PFS) and overall survival (OS). RESULTS: The overall response rate, complete response rate (including with incomplete marrow recovery), median PFS, and median OS were 85%, 36%, 11.8 months, and 23.5 months, respectively, in the entire cohort and 88%, 65%, 18.3 months, and 38.9 months, respectively, in previously untreated patients. Grade 3 to 4 hematologic and glucocorticoid-associated toxicity occurred in 67% and 23% of patients, respectively. Grade 3 to 4 infection occurred in 51% of the overall cohort and in 29% of patients less than 60 years of age. Treatment-related mortality was 5%. CONCLUSION: Alemtuzumab plus methypredisolone is the most effective induction regimen hitherto reported in TP53-deleted CLL. The risk of infection is age related and, in younger patients, seems only marginally higher than that associated with rituximab, fludarabine, and cyclophosphamide. PMID- 22493414 TI - Neoadjuvant trials of human epidermal growth factor receptor 2 targeting: how many drugs do we need? PMID- 22493415 TI - Low-stage ovarian clear cell carcinoma: population-based outcomes in British Columbia, Canada, with evidence for a survival benefit as a result of irradiation. AB - PURPOSE: To evaluate the population-based outcomes of stage I and II ovarian clear cell carcinoma (OCCC) in a North American population treated with carboplatin/paclitaxel and abdominopelvic irradiation. PATIENTS AND METHODS: Retrospective analysis was performed of 241 patients referred in the carboplatin/paclitaxel era. Irradiation was to be used with a few defined exceptions. However, because of differing beliefs as to its effectiveness, its use was consistently avoided by specific oncologists, allowing the opportunity to study its possible effect on disease-free survival (DFS) in these concurrent cohorts. RESULTS: Five- and 10-year DFS rates were 84% and 70% for stage IA/B; 67% and 57% for stage IC; and 49% and 44% for stage II, respectively. Five- and 10-year DFS rates for those with stage IC disease based purely on rupture were similar to rates for patients with stage IA/B, at 92% and 71%, respectively. The remaining patients with stage IC had 48% 5- and 10-year DFS. Multivariate analysis using a decision tree identified positive cytology as the most important factor (72% relapse rate if positive and 27% if negative or unknown). If, in addition, the capsule surface was involved, then the relapse rate was 93%. Irradiation had no discernible survival benefit for patients with stage IA and IC (rupture alone), whereas for the remainder of patients with stage IC and stage II, it improved DFS by 20% at 5 years (relative risk, 0.5); the benefit was most evident in the cytologically negative/unknown group. CONCLUSION: DFS is similar in this North American population with early OCCC to the DFS reported in Asia. A potential benefit from irradiation was evident in a subset. PMID- 22493416 TI - [18F]Fluorodeoxyglucose positron emission tomography/computed tomography-positive gastric adenocarcinoma in a 12-year-old girl with Peutz-Jeghers syndrome. PMID- 22493417 TI - Quality of breast cancer care: perception versus practice. AB - PURPOSE: Because insurers use performance and quality metrics to inform reimbursement, identifying remediable causes of poor-quality cancer care is imperative. We undertook this descriptive cohort study to assess key predictors of women's perceived quality of their breast cancer care and actual guideline concordant quality of care received. PATIENTS AND METHODS: We surveyed inner-city women with newly diagnosed and surgically treated early-stage breast cancer requiring adjuvant treatment who were enrolled onto a randomized controlled trial (RCT) of patient assistance to reduce disparities in care. We assessed women's perceived quality of care and perceived quality of the process of getting care, such as getting referrals, test results, and treatments; we abstracted records to determine the actual quality of care. RESULTS: Of the 374 new patients with early stage breast cancer enrolled onto the RCT, only a slight majority of women (55%) perceived their quality of care as excellent; 88% actually received good-quality, guideline-concordant care. Excellent perceived quality (P < .001) was significantly associated with patients' perception of the quality of the process of getting care (adjusted relative risk [RR], 1.78; 95% CI, 1.65 to 1.87). Also associated with perceived quality-and mediated by race-were trust in one's physician (adjusted RR, 1.43; 95% CI, 1.16 to 1.64) and perceived racism, which affected black women more than women of other races/ethnicities (black race adjusted RR for perceived racism, 0.33 [95% CI, 0.10 to 0.87]; black race adjusted RR for trust, 1.61 [95% CI, 0.97 to 1.90]; c = 0.82 for the model; P < .001). Actual quality of care provided did not affect perceived quality of care received. CONCLUSION: Patients' perceived quality of care differs from their receipt of high-quality care. Mutable targets to improve perceived quality of care include the processes of getting care and trusting their physician. PMID- 22493418 TI - Insulin therapy and cancer-specific mortality in patients with colorectal cancer and diabetes. PMID- 22493420 TI - Concordance between human epidermal growth factor receptor 2 testing by reverse transcriptase polymerase chain reaction and fluorescent in situ hybridization. PMID- 22493419 TI - Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study. AB - PURPOSE: This is a noncomparative, randomized, phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 (HER2) -positive, stage II to IIIA operable breast cancer. The primary aim was to estimate the percentage of pathologic complete response (pCR; no invasive tumor in breast and axillary nodes). PATIENTS AND METHODS: In the three arms, chemotherapy consisted of weekly paclitaxel (80 mg/m(2)) for 12 weeks followed by fluorouracil, epirubicin, and cyclophosphamide for four courses every 3 weeks. The patients randomly assigned to arm A received a 4-mg loading dose of trastuzumab followed by 2 mg weekly; in arm B patients received lapatinib 1,500 mg orally (PO) daily; and in arm C, patients received trastuzumab and lapatinib 1,000 mg PO daily. RESULTS: A total of 121 patients were randomly assigned. Diarrhea and dermatologic and hepatic toxicities were observed more frequently in patients receiving lapatinib. No episodes of congestive heart failure were observed. The rates of breast-conserving surgery were 66.7%, 57.9%, and 68.9% in arms A, B and C, respectively. The pCR rates were 25% (90% CI, 13.1% to 36.9%) in arm A, 26.3% (90% CI, 14.5% to 38.1%) in arm B, and 46.7% (90% CI, 34.4% to 58.9%) in arm C (exploratory P = .019). CONCLUSION: The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib. These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer. PMID- 22493421 TI - Establishing a framework for improving the quality of clinical and translational research. PMID- 22493422 TI - Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma. AB - PURPOSE: The antitumor activity and safety of tivozanib, which is a potent and selective vascular endothelial growth factor receptor-1, -2, and -3 inhibitor, was assessed in patients with advanced/metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: In this phase II, randomized discontinuation trial, 272 patients received open-label tivozanib 1.5 mg/d (one cycle equaled three treatment weeks followed by a 1-week break) orally for 16 weeks. Thereafter, 78 patients who demonstrated >= 25% tumor shrinkage continued to take tivozanib, and 118 patients with less than 25% tumor change were randomly assigned to receive tivozanib or a placebo in a double-blind manner; patients with >= 25% tumor growth were discontinued. Primary end points included safety, the objective response rate (ORR) at 16 weeks, and the percentage of randomly assigned patients who remained progression free after 12 weeks of double-blind treatment; secondary end points included progression-free survival (PFS). RESULTS: Of 272 patients enrolled onto the study, 83% of patients had clear-cell histology, 73% of patients had undergone nephrectomy, and 54% of patients were treatment naive. The ORR after 16 weeks of tivozanib treatment was 18% (95% CI, 14% to 23%). Of the 118 randomized patients, significantly more patients who were randomly assigned to receive double-blind tivozanib remained progression free after 12 weeks versus patients who received the placebo (49% v 21%; P = .001). Throughout the study, the ORR was 24% (95% CI, 19% to 30%), and the median PFS was 11.7 months (95% CI, 8.3 to 14.3 months) in the overall study population. The most common grade 3 and 4 treatment-related adverse event was hypertension (12%). CONCLUSION: Tivozanib was active and well tolerated in patients with advanced RCC. These data support additional development of tivozanib in advanced RCC. PMID- 22493423 TI - Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. AB - PURPOSE: Neoadjuvant chemoradiotherapy for rectal cancer is associated with improved local control and may result in complete tumor response. Associations between tumor response and disease control following radical resection should be established before tumor response is used to evaluate treatment strategies. The purpose of this study was to assess and compare oncologic outcomes associated with the degree of pathologic response after chemoradiotherapy. PATIENTS AND METHODS: All patients with locally advanced (cT3-4 or cN+ by endorectal ultrasonography, computed tomography, or magnetic resonance imaging) rectal carcinoma diagnosed from 1993 to 2008 at our institution and treated with preoperative chemoradiotherapy and radical resection were identified, and their records were retrospectively reviewed. The median radiation dose was 50.4 Gy with concurrent chemotherapy. Recurrence-free survival (RFS), distant metastasis (DM), and local recurrence (LR) rates were compared among patients with complete (ypT0N0), intermediate (ypT1-2N0), or poor (ypT3-4 or N+) response by using Kaplan-Meier survival analysis and multivariate Cox proportional hazards regression. RESULTS: In all, 725 patients were classified by tumor response: complete (131; 18.1%), intermediate (210; 29.0%), and poor (384; 53.0%). Age, sex, cN stage, and tumor location were not related to tumor response. Tumor response (complete v intermediate v poor) was associated with 5-year RFS (90.5% v 78.7% v 58.5%; P < .001), 5-year DM rates (7.0% v 10.1% v 26.5%; P < .001), and 5 year LR only rates (0% v 1.4% v 4.4%; P = .002). CONCLUSION: Treatment response to neoadjuvant chemoradiotherapy among patients with locally advanced rectal cancer undergoing radical resection is an early surrogate marker and correlate to oncologic outcomes. These data provide guidance with response-stratified oncologic benchmarks for comparisons of novel treatment strategies. PMID- 22493424 TI - Accurate assessment of human epidermal growth factor receptor 2. PMID- 22493425 TI - Directed evolution of lectins with sugar-binding specificity for 6-sulfo galactose. AB - 6-sulfo-galactose (6S-Gal) is a prevalent motif observed in highly sulfated keratan sulfate, which is closely associated with the glioblastoma malignancy while acting as a critical determinant for endogenous lectins. However, facile detection of this unique glycoepitope is greatly hampered because of a lack of appropriate probes. We have previously reported tailoring an alpha2-6-linked sialic acid-binding lectin from a ricin-B chain-like galactose-binding protein, EW29Ch, by a reinforced ribosome display system following an error-prone PCR. In this study, we challenged the creation of novel lectins to recognize 6S-Gal terminated glycans by incorporating a high-throughput screening system with a glycoconjugate microarray. After two rounds of selection procedures, 20 mutants were obtained and 12 were then successfully expressed in Escherichia coli, 8 of which showed a significant affinity for 6'-Sulfo-LN (6-O-sulfo-Galbeta1-4GlcNAc), which the parental EW29Ch lacked. Analysis of two representative mutants by frontal affinity chromatography revealed a substantial affinity (K(d) ~3 MUm) for a 6S-Gal-terminated glycan. On the basis of the observation that all eight mutants have a common mutation at Glu-20 to Lys, site-directed mutagenesis experiments were performed focusing on this aspect. The results clearly indicated that the E20K mutation is necessary and sufficient to acquire the specificity for 6S-Gal. We also confirmed a difference in binding between E20K and EW29Ch to CHO cells, in which enzymes to catalyze the synthesis of 6S-Gal were overexpressed. The results clearly demonstrate that these mutants have potential to distinguish between cells containing different amounts of 6S-Gal-terminated glycans. This new technology will be used to provide novel tools essential for sulfoglycomics. PMID- 22493427 TI - Structural adaptation of a thermostable biotin-binding protein in a psychrophilic environment. AB - Shwanavidin is an avidin-like protein from the marine proteobactrium Shewanella denitrificans, which exhibits an innate dimeric structure while maintaining high affinity toward biotin. A unique residue (Phe-43) from the L3,4 loop and a distinctive disulfide bridge were shown to account for the high affinity toward biotin. Phe-43 emulates the function and position of the critical intermonomeric Trp that characterizes the tetrameric avidins but is lacking in shwanavidin. The 18 copies of the apo-monomer revealed distinctive snapshots of L3,4 and Phe-43, providing rare insight into loop flexibility, binding site accessibility, and psychrophilic adaptation. Nevertheless, as in all avidins, shwanavidin also displays high thermostability properties. The unique features of shwanavidin may provide a platform for the design of a long sought after monovalent form of avidin, which would be ideal for novel types of biotechnological application. PMID- 22493426 TI - IQGAP proteins reveal an atypical phosphoinositide (aPI) binding domain with a pseudo C2 domain fold. AB - Class I phosphoinositide (PI) 3-kinases act through effector proteins whose 3-PI selectivity is mediated by a limited repertoire of structurally defined, lipid recognition domains. We describe here the lipid preferences and crystal structure of a new class of PI binding modules exemplified by select IQGAPs (IQ motif containing GTPase-activating proteins) known to coordinate cellular signaling events and cytoskeletal dynamics. This module is defined by a C-terminal 105-107 amino acid region of which IQGAP1 and -2, but not IQGAP3, binds preferentially to phosphatidylinositol 3,4,5-trisphosphate (PtdInsP(3)). The binding affinity for PtdInsP(3), together with other, secondary target-recognition characteristics, are comparable with those of the pleckstrin homology domain of cytohesin-3 (general receptor for phosphoinositides 1), an established PtdInsP(3) effector protein. Importantly, the IQGAP1 C-terminal domain and the cytohesin-3 pleckstrin homology domain, each tagged with enhanced green fluorescent protein, were both re-localized from the cytosol to the cell periphery following the activation of PI 3-kinase in Swiss 3T3 fibroblasts, consistent with their common, selective recognition of endogenous 3-PI(s). The crystal structure of the C-terminal IQGAP2 PI binding module reveals unexpected topological similarity to an integral fold of C2 domains, including a putative basic binding pocket. We propose that this module integrates select IQGAP proteins with PI 3-kinase signaling and constitutes a novel, atypical phosphoinositide binding domain that may represent the first of a larger group, each perhaps structurally unique but collectively dissimilar from the known PI recognition modules. PMID- 22493428 TI - Nanog increases focal adhesion kinase (FAK) promoter activity and expression and directly binds to FAK protein to be phosphorylated. AB - Nanog and FAK were shown to be overexpressed in cancer cells. In this report, the Nanog overexpression increased FAK expression in 293, SW480, and SW620 cancer cells. Nanog binds the FAK promoter and up-regulates its activity, whereas Nanog siRNA decreases FAK promoter activity and FAK mRNA. The FAK promoter contains four Nanog-binding sites. The site-directed mutagenesis of these sites significantly decreased up-regulation of FAK promoter activity by Nanog. EMSA showed the specific binding of Nanog to each of the four sites, and binding was confirmed by ChIP assay. Nanog directly binds the FAK protein by pulldown and immunoprecipitation assays, and proteins co-localize by confocal microscopy. Nanog binds the N-terminal domain of FAK. In addition, FAK directly phosphorylates Nanog in a dose-dependent manner by in vitro kinase assay and in cancer cells in vivo. The site-directed mutagenesis of Nanog tyrosines, Y35F and Y174F, blocked phosphorylation and binding by FAK. Moreover, overexpression of wild type Nanog increased filopodia/lamellipodia formation, whereas mutant Y35F and Y174F Nanog did not. The wild type Nanog increased cell invasion that was inhibited by the FAK inhibitor and increased by FAK more significantly than with the mutants Y35F and Y174F Nanog. Down-regulation of Nanog with siRNA decreased cell growth reversed by FAK overexpression. Thus, these data demonstrate the regulation of the FAK promoter by Nanog, the direct binding of the proteins, the phosphorylation of Nanog by FAK, and the effect of FAK and Nanog cross-regulation on cancer cell morphology, invasion, and growth that plays a significant role in carcinogenesis. PMID- 22493429 TI - Small ubiquitin-like modifier (SUMO) modification mediates function of the inhibitory domains of developmental regulators FOXC1 and FOXC2. AB - FOXC1 and FOXC2 are forkhead transcription factors that play essential roles during development and physiology. Despite their critical role, the mechanisms that regulate the function of these factors remain poorly understood. We have identified conserved motifs within a previously defined N-terminal negative regulatory region of FOXC1/C2 that conforms to the definition of synergy control or SC motifs. Because such motifs inhibit the activity of transcription factors by serving as sites of post-translational modification by small ubiquitin-like modifier (SUMO), we have examined whether FOXC1/C2 are targets of SUMOylation and probed the functional significance of this modification. We find that endogenous FOXC1 forms modified by SUMO2/3 can be detected. Moreover, in cell culture, all three SUMO isoforms are readily conjugated to FOXC1 and FOXC2. The modification can be reconstituted in vitro with purified components and can be reversed in vitro by treatment with the SUMO protease SENP2. SUMOylation of FOXC1 and FOXC2 occurs primarily on one consensus synergy control motif with minor contributions of a second, more degenerate site. Notably, although FOXC1 is also phosphorylated at multiple sites, disruption of sites immediately downstream of the SC motifs does not influence SUMOylation. Consistent with a negative functional role, SUMOylation-deficient mutants displayed higher transcriptional activity when compared with wild type forms despite comparable protein levels and subcellular localization. Thus, the findings demonstrate that SC motifs mediate the inhibitory function of this region by serving as sites for SUMOylation and reveal a novel mechanism for acute and reversible regulation of FOXC1/C2 function. PMID- 22493430 TI - Characterization of member of DUF1888 protein family, self-cleaving and self assembling endopeptidase. AB - The crystal structure of SO1698 protein from Shewanella oneidensis was determined by a SAD method and refined to 1.57 A. The structure is a beta sandwich that unexpectedly consists of two polypeptides; the N-terminal fragment includes residues 1-116, and the C-terminal one includes residues 117-125. Electron density also displayed the Lys-98 side chain covalently linked to Asp-116. The putative active site residues involved in self-cleavage were identified; point mutants were produced and characterized structurally and in a biochemical assay. Numerical simulations utilizing molecular dynamics and hybrid quantum/classical calculations suggest a mechanism involving activation of a water molecule coordinated by a catalytic aspartic acid. PMID- 22493431 TI - N-glycosylation of TRPM8 ion channels modulates temperature sensitivity of cold thermoreceptor neurons. AB - TRPM8 is a member of the transient receptor potential ion channel superfamily, which is expressed in sensory neurons and is activated by cold and cooling compounds, such as menthol. Activation of TRPM8 by agonists takes place through shifts in its voltage activation curve, allowing channel opening at physiological membrane potentials. Here, we studied the role of the N-glycosylation occurring at the pore loop of TRPM8 on the function of the channel. Using heterologous expression of recombinant channels in HEK293 cells we found that the unglycosylated TRPM8 mutant (N934Q) displays marked functional differences compared with the wild type channel. These differences include a shift in the threshold of temperature activation and a reduced response to menthol and cold stimuli. Biophysical analysis indicated that these modifications are due to a shift in the voltage dependence of TRPM8 activation toward more positive potentials. By using tunicamycin, a drug that prevents N-glycosylation of proteins, we also evaluated the effect of the N-glycosylation on the responses of trigeminal sensory neurons expressing TRPM8. These experiments showed that the lack of N-glycosylation affects the function of native TRPM8 ion channels in a similar way to heterologously expressed ones, causing an important shift of the temperature threshold of cold-sensitive thermoreceptor neurons. Altogether, these results indicate that post-translational modification of TRPM8 is an important mechanism modulating cold thermoreceptor function, explaining the marked differences in temperature sensitivity observed between recombinant and native TRPM8 ion channels. PMID- 22493432 TI - Diphenylarsinic acid promotes degradation of glutaminase C by mitochondrial Lon protease. AB - Glutaminase C (GAC), a splicing variant of the kidney-type glutaminase (KGA) gene, is a vital mitochondrial enzyme protein that catalyzes glutamine to glutamate. Earlier studies have shown that GAC proteins in the human hepatocarcinoma cell line, HepG2, were down-regulated by diphenylarsinic acid (DPAA), but the mechanism by which DPAA induced GAC protein down-regulation remained poorly understood. Here, we showed that DPAA promoted GAC protein degradation without affecting GAC transcription and translation. Moreover, DPAA induced GAC proteolysis was mediated by mitochondrial Lon protease. DPAA insolubilized 0.5% Triton X-100-soluble GAC protein and promoted the accumulation of insoluble GAC in Lon protease knockdown cells. DPAA destroyed the native tetrameric GAC conformation and promoted an increase in the unassembled form of GAC when DPAA was incubated with cell extracts. Decreases in the tetrameric form of GAC were observed in cells exposed to DPAA, and decreases occurred prior to a decrease in total GAC protein levels. In addition, decreases in the tetrameric form of GAC were observed independently with Lon protease. Mitochondrial heat shock protein 70 is known to be an indispensable protein that can bind to misfolded proteins, thereby supporting degradation of proteins sensitive to Lon protease. When cells were incubated with DPAA, GAC proteins that can bind with mtHsp70 increased. Interestingly, the association of mtHsp70 with GAC protein increased when the tetrameric form of GAC was reduced. These results suggest that degradation of native tetrameric GAC by DPAA may be a trigger in GAC protein degradation by Lon protease. PMID- 22493433 TI - Characterization of a novel Agrobacterium tumefaciens galactarolactone cycloisomerase enzyme for direct conversion of D-galactarolactone to 3-deoxy-2 keto-L-threo-hexarate. AB - Microorganisms use different pathways for D-galacturonate catabolism. In the known microbial oxidative pathway, D-galacturonate is oxidized to D galactarolactone, the lactone hydrolyzed to galactarate, which is further converted to 3-deoxy-2-keto-hexarate and alpha-ketoglutarate. We have shown recently that Agrobacterium tumefaciens strain C58 contains an uronate dehydrogenase (At Udh) that oxidizes D-galacturonic acid to D-galactarolactone. Here we report identification of a novel enzyme from the same A. tumefaciens strain, which we named Galactarolactone cycloisomerase (At Gci) (E.C. 5.5.1.-), for the direct conversion of the D-galactarolactone to 3-deoxy-2-keto-hexarate. The At Gci enzyme is 378 amino acids long and belongs to the mandelate racemase subgroup in the enolase superfamily. At Gci was heterologously expressed in Escherichia coli, and the purified enzyme was found to exist as an octameric form. It is active both on D-galactarolactone and D-glucarolactone, but does not work on the corresponding linear hexaric acid forms. The details of the reaction mechanism were further studied by NMR and optical rotation demonstrating that the reaction product of At Gci from D-galactaro-1,4-lactone and D-glucaro-1,4-lactone conversion is in both cases the L-threo form of 3-deoxy-2-keto-hexarate. PMID- 22493434 TI - Models for the binary complex of bacteriophage T4 gp59 helicase loading protein: gp32 single-stranded DNA-BINDING protein and ternary complex with pseudo-Y junction DNA. AB - Bacteriophage T4 gp59 helicase assembly protein (gp59) is required for loading of gp41 replicative helicase onto DNA protected by gp32 single-stranded DNA-binding protein. The gp59 protein recognizes branched DNA structures found at replication and recombination sites. Binding of gp32 protein (full-length and deletion constructs) to gp59 protein measured by isothermal titration calorimetry demonstrates that the gp32 protein C-terminal A-domain is essential for protein protein interaction in the absence of DNA. Sedimentation velocity experiments with gp59 protein and gp32DeltaB protein (an N-terminal B-domain deletion) show that these proteins are monomers but form a 1:1 complex with a dissociation constant comparable with that determined by isothermal titration calorimetry. Small angle x-ray scattering (SAXS) studies indicate that the gp59 protein is a prolate monomer, consistent with the crystal structure and hydrodynamic properties determined from sedimentation velocity experiments. SAXS experiments also demonstrate that gp32DeltaB protein is a prolate monomer with an elongated A domain protruding from the core. Fitting structures of gp59 protein and the gp32 core into the SAXS-derived molecular envelope supports a model for the gp59 protein-gp32DeltaB protein complex. Our earlier work demonstrated that gp59 protein attracts full-length gp32 protein to pseudo-Y junctions. A model of the gp59 protein-DNA complex, modified to accommodate new SAXS data for the binary complex together with mutational analysis of gp59 protein, is presented in the accompanying article (Dolezal, D., Jones, C. E., Lai, X., Brister, J. R., Mueser, T. C., Nossal, N. G., and Hinton, D. M. (2012) J. Biol. Chem. 287, 18596-18607). PMID- 22493435 TI - B-cell translocation gene 2 (BTG2) stimulates cellular antioxidant defenses through the antioxidant transcription factor NFE2L2 in human mammary epithelial cells. AB - The B-cell translocation gene 2, BTG2, a member of the BTG/TOB (B-cell translocation gene/transducers of ErbB2) gene family, has been implicated in cell cycle regulation, normal development, and possibly tumor suppression. Previously, it was shown that BTG2 expression is lost or down-regulated in human breast cancers. We now report that BTG2 protects human mammary epithelial cells from oxidative stress due to hydrogen peroxide and other oxidants. BTG2 protection against oxidative stress is BRCA1-independent but requires the antioxidant transcription factor NFE2L2 and is associated with up-regulation of the expression of antioxidant enzymes, including catalase and superoxide dismutases 1 and 2. BTG2 stimulation of antioxidant gene expression is also NFE2L2-dependent. We further demonstrate that BTG2 is a binding partner for NFE2L2 and increases its transcriptional activity. In addition, BTG2 is detectable at the antioxidant response element (ARE) of several NFE2L2-responsive genes. Finally, we show that the ability of BTG2 to associate with NFE2L2, to protect cells against oxidative stress, and to stimulate antioxidant gene expression requires box B, a short highly conserved amino acid motif characteristic of BTG2/TOB family proteins, but does not require boxes A or C. These findings suggest a novel role for BTG2 as a co-activator for NFE2L2 in up-regulating cellular antioxidant defenses. PMID- 22493436 TI - Nigericin-induced impairment of autophagic flux in neuronal cells is inhibited by overexpression of Bak. AB - Bak is a prototypic pro-apoptotic Bcl-2 family protein expressed in a wide variety of tissues and cells. Recent studies have revealed that Bcl-2 family proteins regulate apoptosis as well as autophagy. To investigate whether and how Bak exerts a regulatory role on autophagy-related events, we treated independent cell lines, including MN9D neuronal cells, with nigericin, a K(+)/H(+) ionophore. Treatment of MN9D cells with nigericin led to an increase of LC3-II and p62 levels with concomitant activation of caspase. Ultrastructural examination revealed accumulation of autophagic vacuoles and swollen vacuoles in nigericin treated cells. We further found that the LC3-II accumulated as a consequence of impaired autophagic flux and the disrupted degradation of LC3-II in nigericin treated cells. In this cell death paradigm, both transient and stable overexpression of various forms of Bak exerted a protective role, whereas it did not inhibit the extent of nigericin-mediated activation of caspase-3. Subsequent biochemical and electron microscopic studies revealed that overexpressed Bak maintained autophagic flux and reduced the area occupied by swollen vacuoles in nigericin-treated cells. Similar results were obtained in nigericin-treated non neuronal cells and another proton ionophore-induced cell death paradigm. Taken together, our study indicates that a protective role for Bak during ionophore induced cell death may be closely associated with its regulatory effect on maintenance of autophagic flux and vacuole homeostasis. PMID- 22493437 TI - Functional asymmetries of proteasome translocase pore. AB - Degradation by proteasomes involves coupled translocation and unfolding of its protein substrates. Six distinct but paralogous proteasome ATPase proteins, Rpt1 to -6, form a heterohexameric ring that acts on substrates. An axially positioned loop (Ar-Phi loop) moves in concert with ATP hydrolysis, engages substrate, and propels it into a proteolytic chamber. The aromatic (Ar) residue of the Ar-Phi loop in all six Rpts of S. cerevisiae is tyrosine; this amino acid is thought to have important functional contacts with substrate. Six yeast strains were constructed and characterized in which Tyr was individually mutated to Ala. The mutant cells were viable and had distinct phenotypes. rpt3, rpt4, and rpt5 Tyr/Ala mutants, which cluster on one side of the ATPase hexamer, were substantially impaired in their capacity to degrade substrates. In contrast, rpt1, rpt2, and rpt6 mutants equaled or exceeded wild type in degradation activity. However, rpt1 and rpt6 mutants had defects that limited cell growth or viability under conditions that stressed the ubiquitin proteasome system. In contrast, the rpt3 mutant grew faster than wild type and to a smaller size, a defect that has previously been associated with misregulation of G1 cyclins. This rpt3 phenotype probably results from altered degradation of cell cycle regulatory proteins. Finally, mutation of five of the Rpt subunits increased proteasome ATPase activity, implying bidirectional coupling between the Ar-Phi loop and the ATP hydrolysis site. The present observations assign specific functions to individual Rpt proteins and provide insights into the diverse roles of the axial loops of individual proteasome ATPases. PMID- 22493438 TI - Evidence for cooperative and domain-specific binding of the signal transducing adaptor molecule 2 (STAM2) to Lys63-linked diubiquitin. AB - As the upstream component of the ESCRT (endosomal sorting complexes required for transport) machinery, the ESCRT-0 complex is responsible for directing ubiquitinated membrane proteins to the multivesicular body pathway. ESCRT-0 is formed by two subunits known as Hrs (hepatocyte growth factor-regulated substrate) and STAM (signal transducing adaptor molecule), both of which harbor multiple ubiquitin-binding domains (UBDs). In particular, STAM2 possesses two UBDs, the VHS (Vps27/Hrs/Stam) and UIM (ubiquitin interacting motif) domains, connected by a 20-amino acid flexible linker. In the present study, we report the interactions of the UIM domain and VHS-UIM construct of STAM2 with monoubiquitin (Ub), Lys(48)- and Lys(63)-linked diubiquitins. Our results demonstrate that the UIM domain alone binds monoubiquitin, Lys(48)- and Lys(63)-linked diubiquitins with the same affinity and in the same binding mode. Interestingly, binding of VHS-UIM to Lys(63)-linked diubiquitin is not only avid, but also cooperative. We also show that the distal domain of Lys(63)-linked diubiquitin stabilizes the helical structure of the UIM domain and that the corresponding complex adopts a specific structural organization responsible for its greater affinity. In contrast, binding of VHS-UIM to Lys(48)-linked diubiquitin and monoubiquitin is not cooperative and does not show any avidity. These results may explain the better sorting efficiency of some cargoes polyubiquitinated with Lys(63)-linked chains over monoubiquitinated cargoes or those tagged with Lys(48)-linked chains. PMID- 22493439 TI - Influenza virus partially counteracts restriction imposed by tetherin/BST-2. AB - Influenza virus infections lead to a burst of type I interferon (IFN) in the human respiratory tract, which most probably accounts for a rapid control of the virus. Although in mice, IFN-induced Mx1 factor mediates a major part of this response, the situation is less clear in humans. Interestingly, a recently identified IFN-induced cellular protein, tetherin (also known as CD317, BST-2, or HM1.24), exerts potent antiviral activity against a broad range of retroviruses, as well as several other enveloped viruses, by impeding the release of newly generated viral particles from the cell surface. Here we show that influenza virus belongs to the targets of this potent antiviral factor. Ectopic expression of tetherin strongly inhibited fully replicative influenza virus. In addition, depleting endogenous tetherin increased viral production of influenza virions, both in cells constitutively expressing tetherin and upon its induction by IFN. We further demonstrate, by biochemical and morphological means, that tetherin exerts its antiviral action by tethering newly budded viral particles, a mechanism similar to the one that operates against HIV-1. In addition, we determined that the magnitude of tetherin antiviral activity is comparable with or higher than the one of several previously identified anti-influenza cellular factors, such as MxA, ADAR1, ISG15, and viperin. Finally, we demonstrate that influenza virus reduces the impact of tetherin-mediated restriction on its replication by several mechanisms. First, the influenza virus NS1 protein impedes IFN-mediated tetherin induction. Second, influenza infection leads to a decrease of tetherin steady state levels, and the neuraminidase surface protein partly counteracts its activity. Overall, our study helps to delineate the intricate molecular battle taking place between influenza virus and its host cells. PMID- 22493440 TI - alpha6beta4 integrin, a master regulator of expression of integrins in human keratinocytes. AB - Three major laminin and collagen-binding integrins in skin (alpha6beta4, alpha3beta1, and alpha2beta1) are involved in keratinocyte adhesion to the dermis and dissemination of skin cells during wound healing and/or tumorigenesis. Knockdown of alpha6 integrin in keratinocytes not only results in motility defects but also leads to decreased surface expression of the alpha2, alpha3, and beta4 integrin subunits. Whereas alpha2 integrin mRNA levels are decreased in alpha6 integrin knockdown cells, alpha3 and beta4 integrin mRNAs levels are unaffected. Expression of either alpha6 or alpha3 integrin in alpha6 integrin knockdown cells restores alpha2 integrin mRNA levels. Moreover, re-expression of alpha6 integrin increases beta4 integrin protein at the cell surface, which results in an increase in alpha3 integrin expression via activation of initiation factor 4E-binding protein 1. Our data indicate that the alpha6beta4 integrin is a master regulator of transcription and translation of other integrin subunits and underscore its pivotal role in wound healing and cancer. PMID- 22493441 TI - Mechanism of beta-catenin-mediated transcriptional regulation of epidermal growth factor receptor expression in glycogen synthase kinase 3 beta-inactivated prostate cancer cells. AB - Wnt/beta-catenin and EGFR pathways are important in cancer development and often aberrantly activated in human cancer. However, it is very important to understand the mechanism responsible for this activation and the relation between them. Here, we report the mechanism of EGFR expression by transcriptionally active beta catenin in GSK3beta-inactivated prostate cancer cells that eventually leads to its enhanced proliferation and survival. Expressions of beta-catenin and EGFR are elevated in various cancers specifically in prostate cancer cells, DU145. When GSK3beta is inactivated in these cells, beta-catenin gets stabilized, phosphorylated at Ser-552 by protein kinase A, accumulates in the nucleus, and regulates the expression of its target genes that include EGFR. Chromatin immunoprecipitation (ChIP) and promoter analysis revealed that the EGFR promoter gets occupied by transcriptionally active beta-catenin when elevated in GSK3beta inactivated cells. This phenomenon not only leads to increased expression of EGFR but also initiates the activation of its downstream molecules such as ERK1/2 and Stat3, ultimately resulting in up-regulation of multiple genes involved in cell proliferation and survival. PMID- 22493442 TI - Melanocortin 1 receptor regulates melanoma cell migration by controlling syndecan 2 expression. AB - The melanocortin 1 receptor (MC1R), a key regulator of melanogenesis, is known to control inflammation, acting in concert with the MC1R ligand alpha-melanocyte stimulating hormone. Although cell migration is a key event in inflammation, few studies have addressed the function of MC1R in this context. Using highly motile melanoma cells, we found that the expression level of MC1R was associated with the extent of migration of mouse melanoma cells, suggesting that MC1R plays a functional role in controlling this migration. Overexpression of MC1R enhanced melanoma cell migration, whereas the opposite was true when MC1R levels were knocked down using small inhibitory RNAs. Interestingly, MC1R expression enhanced the synthesis of syndecan-2, a cell surface heparan sulfate proteoglycan known to be involved in melanoma cell migration. Knockdown of syndecan-2 expression decreased MC1R-mediated cell migration. Further, MC1R inhibited the activation of p38 MAPK, subsequently enhancing expression of sydnecan-2, in parallel with an increase in the extent of cell migration. Consistently, activation of p38 by H(2)O(2) inhibited syndecan-2 expression and cell migration, whereas inhibition of p38 activation enhanced syndecan-2 expression and cell migration. Finally, we found that alpha-melanocyte-stimulating hormone inhibited MC1R-mediated cell migration via activation of p38 and inhibition of syndecan-2 expression. Together, the data strongly suggest that MC1R regulates melanoma cell migration via inhibition of syndecan-2 expression. PMID- 22493443 TI - Orphan nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) protein negatively regulates bone morphogenetic protein 2-induced osteoblast differentiation through suppressing runt-related gene 2 (Runx2) activity. AB - Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) is an orphan nuclear receptor of the steroid-thyroid hormone receptor superfamily. COUP TFII is widely expressed in multiple tissues and organs throughout embryonic development and has been shown to regulate cellular growth, differentiation, and organ development. However, the role of COUP-TFII in osteoblast differentiation has not been systematically evaluated. In the present study, COUP-TFII was strongly expressed in multipotential mesenchymal cells, and the endogenous expression level decreased during osteoblast differentiation. Overexpression of COUP-TFII inhibited bone morphogenetic protein 2 (BMP2)-induced osteoblastic gene expression. The results of alkaline phosphatase, Alizarin Red staining, and osteocalcin production assay showed that COUP-TFII overexpression blocks BMP2 induced osteoblast differentiation. In contrast, the down-regulation of COUP-TFII synergistically induced the expression of BMP2-induced osteoblastic genes and osteoblast differentiation. Furthermore, the immunoprecipitation assay showed that COUP-TFII and Runx2 physically interacted and COUP-TFII significantly impaired the Runx2-dependent activation of the osteocalcin promoter. From the ChIP assay, we found that COUP-TFII repressed DNA binding of Runx2 to the osteocalcin gene, whereas Runx2 inhibited COUP-TFII expression via direct binding to the COUP-TFII promoter. Taken together, these findings demonstrate that COUP TFII negatively regulates osteoblast differentiation via interaction with Runx2, and during the differentiation state, BMP2-induced Runx2 represses COUP-TFII expression and promotes osteoblast differentiation. PMID- 22493444 TI - Involvement of phosphoinositide 3-kinase and PTEN protein in mechanism of activation of TRPC6 protein in vascular smooth muscle cells. AB - TRPC6 is a cation channel in the plasma membrane that plays a role in Ca(2+) entry after the stimulation of a G(q)-protein-coupled or tyrosine-kinase receptor. TRPC6 translocates to the plasma membrane upon stimulation and remains there as long as the stimulus is present. However, the mechanism that regulates the trafficking and activation of TRPC6 are unclear. In this study we showed phosphoinositide 3-kinase and its antagonistic phosphatase, PTEN, are involved in the activation of TRPC6. The inhibition of PI3K by PIK-93, LY294002, or wortmannin decreased carbachol-induced translocation of TRPC6 to the plasma membrane and carbachol-induced net Ca(2+) entry into T6.11 cells. Conversely, a reduction of PTEN expression did not affect carbachol-induced externalization of TRPC6 but increased Ca(2+) entry through TRPC6 in T6.11 cells. We also showed that the PI3K/PTEN pathway regulates vasopressin-induced translocation of TRPC6 to the plasma membrane and vasopressin-induced Ca(2+) entry into A7r5 cells, which endogenously express TRPC6. In summary, we provided evidence that the PI3K/PTEN pathway plays an important role in the translocation of TRPC6 to the plasma membrane and may thus have a significant impact on Ca(2+) signaling in cells that endogenously express TRPC6. PMID- 22493445 TI - Anti-human activin receptor-like kinase 1 (ALK1) antibody attenuates bone morphogenetic protein 9 (BMP9)-induced ALK1 signaling and interferes with endothelial cell sprouting. AB - Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1), a transforming growth factor beta (TGF-beta) type I receptor, and endoglin, a TGF beta co-receptor, play an essential role in vascular development and pathological angiogenesis. Several agents that interfere with ALK1 and endoglin function are currently in clinical trials for antiangiogenic activity in cancer therapy. One of these agents, PF-03446962 (anti-hALK1 antibody), shows promising results in the clinic. However, its effects on endothelial cell function and mechanism of action are unclear. Here we demonstrate that anti-hALK1 antibody selectively recognizes human ALK1. The anti-hALK1 antibody interfered with bone morphogenetic protein 9 (BMP9)-induced signaling in endothelial cells. Consistent with this notion, anti-hALK1 antibody was found to compete highly efficiently with the binding of the ALK1 ligand BMP9 and TGF-beta to ALK1. Moreover, it prevented BMP9 dependent recruitment of co-receptor endoglin into this angiogenesis-mediating signaling complex. In addition, we demonstrated that anti-hALK1 antibody inhibited endothelial cell sprouting but did not directly interfere with vascular endothelial growth factor (VEGF) signaling, VEGF-induced proliferation, and migration of endothelial cells. Finally, we demonstrated that BMP9 in serum is essential for endothelial sprouting and that anti-hALK1 antibody inhibits this potently. Our data suggest that both the VEGF/VEGF receptor and the BMP9/ALK1 pathways are essential for stimulating angiogenesis, and targeting both pathways simultaneously may be an attractive strategy to overcome resistance to antiangiogenesis therapy. PMID- 22493446 TI - Structural and functional insights into (S)-ureidoglycine aminohydrolase, key enzyme of purine catabolism in Arabidopsis thaliana. AB - The ureide pathway has recently been identified as the metabolic route of purine catabolism in plants and some bacteria. In this pathway, uric acid, which is a major product of the early stage of purine catabolism, is degraded into glyoxylate and ammonia via stepwise reactions of seven different enzymes. Therefore, the pathway has a possible physiological role in mobilization of purine ring nitrogen for further assimilation. (S)-Ureidoglycine aminohydrolase enzyme converts (S)-ureidoglycine into (S)-ureidoglycolate and ammonia, providing the final substrate to the pathway. Here, we report a structural and functional analysis of this enzyme from Arabidopsis thaliana (AtUGlyAH). The crystal structure of AtUGlyAH in the ligand-free form shows a monomer structure in the bicupin fold of the beta-barrel and an octameric functional unit as well as a Mn(2+) ion binding site. The structure of AtUGlyAH in complex with (S) ureidoglycine revealed that the Mn(2+) ion acts as a molecular anchor to bind (S) ureidoglycine, and its binding mode dictates the enantioselectivity of the reaction. Further kinetic analysis characterized the functional roles of the active site residues, including the Mn(2+) ion binding site and residues in the vicinity of (S)-ureidoglycine. These analyses provide molecular insights into the structure of the enzyme and its possible catalytic mechanism. PMID- 22493447 TI - Cdc6 protein obstructs apoptosome assembly and consequent cell death by forming stable complexes with activated Apaf-1 molecules. AB - Cdc6 is the bifunctional AAA+ ATPase that assembles prereplicative complexes on origins of replication and activates p21(CIP1)- or p27(KIP1)-bound Cdk2. During the G(1)-S transition, the Cdc6 gene essential for chromosomal replication is activated by the E2F transcriptional factor. Paradoxically, Apaf-1 encoding the central component of the apoptosome is also activated at the same time and by E2F. Consequently, genes for antipodal life and death are regulated in the same manner by the same transcriptional factor. Here we report a striking solution to this paradox. Besides performing prereplicative complex assembly and Cdk2 activation, Cdc6 obstructed apoptosome assembly by forming stable complexes very likely with a monomer of cytochrome c-activated Apaf-1 molecules. This function depended on its own ATPase domain but not on the cyclin-binding motif. In proliferating rodent fibroblasts, Cdc6 continued to block apoptosome assembly induced by a non-cytochrome c or some other mechanism, suppressing seemingly unintended apoptosis when promoting cell proliferation. Thus, Cdc6 is an AAA+ ATPase with three functions, all working for life. PMID- 22493448 TI - AMP-activated protein kinase phosphorylates cardiac troponin I at Ser-150 to increase myofilament calcium sensitivity and blunt PKA-dependent function. AB - AMP-activated protein kinase (AMPK) is an energy-sensing enzyme central to the regulation of metabolic homeostasis. In the heart AMPK is activated during cardiac stress-induced ATP depletion and functions to stimulate metabolic pathways that restore the AMP/ATP balance. Recently it was demonstrated that AMPK phosphorylates cardiac troponin I (cTnI) at Ser-150 in vitro. We sought to determine if the metabolic regulatory kinase AMPK phosphorylates cTnI at Ser-150 in vivo to alter cardiac contractile function directly at the level of the myofilament. Rabbit cardiac myofibrils separated by two-dimensional isoelectric focusing subjected to a Western blot with a cTnI phosphorylation-specific antibody demonstrates that cTnI is endogenously phosphorylated at Ser-150 in the heart. Treatment of myofibrils with the AMPK holoenzyme increased cTnI Ser-150 phosphorylation within the constraints of the muscle lattice. Compared with controls, cardiac fiber bundles exchanged with troponin containing cTnI pseudo phosphorylated at Ser-150 demonstrate increased sensitivity of calcium-dependent force development, blunting of both PKA-dependent calcium desensitization, and PKA-dependent increases in length dependent activation. Thus, in addition to the defined role of AMPK as a cardiac metabolic energy gauge, these data demonstrate AMPK Ser-150 phosphorylation of cTnI directly links the regulation of cardiac metabolic demand to myofilament contractile energetics. Furthermore, the blunting effect of cTnI Ser-150 phosphorylation cross-talk can uncouple the effects of myofilament PKA-dependent phosphorylation from beta-adrenergic signaling as a novel thin filament contractile regulatory signaling mechanism. PMID- 22493449 TI - Autoantigen conformation influences both B- and T-cell responses and encephalitogenicity. AB - It has become increasingly clear that only antibodies recognizing conformation dependent epitopes of myelin oligodendrocyte glycoprotein (MOG) have a demyelinating potential in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Nevertheless, for the induction of EAE, most studies to date have used MOG peptides or bacterially expressed MOG, neither of which contain the tertiary structure of the native antigen. Non-refolded recombinant human MOG does not induce EAE in DA rats. Therefore, we refolded this protein in order to assess the influence of MOG conformation on its pathogenicity in DA rats. DA rats immunized with refolded human MOG developed severe acute EAE. As expected, rats immunized with the refolded protein had a higher amount of conformational MOG antibodies present in serum. But in addition, a striking effect of MOG refolding on the generation of T-cell responses was found. Indeed, T-cell responses against the encephalitogenic MOG 91-108 epitope were greatly enhanced after refolding. Therefore, we conclude that refolding of MOG increases its pathogenicity both by generating conformation-dependent MOG antibodies and by enhancing its processing or/and presentation on MHC molecules. These data are important in regard to investigations of the pathogenic potential of many (auto)antigens. PMID- 22493450 TI - Molecular recognition of Candida albicans (1->2)-beta-mannan oligosaccharides by a protective monoclonal antibody reveals the immunodominance of internal saccharide residues. AB - A self-consistent model of beta-mannan oligosaccharides bound to a monoclonal antibody, C3.1, that protects mice against Candida albicans has been developed through chemical mapping, NMR spectroscopic, and computational studies. This antibody optimally binds di- and trisaccharide epitopes, whereas larger oligomers bind with affinities that markedly decrease with increasing chain length. The (1 >2)-beta-linked di-, tri-, and tetramannosides bind in helical conformations similar to the solution global minimum. Antibody recognition of the di- and trisaccharide is primarily dependent on the mannose unit at the reducing end, with the hydrophobic face of this sugar being tightly bound. Recognition of a tetrasaccharide involves a frameshift in the ligand interaction, shown by strong binding of the sugar adjacent to the reducing end. We show that frameshifting may also be deliberately induced by chemical modifications. Molecular recognition patterns similar to that of mAb C3.1, determined by saturation transfer difference-NMR, were also observed in polyclonal sera from rabbits immunized with a trisaccharide glycoconjugate. The latter observation points to the importance of internal residues as immunodominant epitopes in (1->2)-beta-mannans and to the viability of a glycoconjugate vaccine composed of a minimal length oligosaccharide hapten. PMID- 22493451 TI - Plant leucine aminopeptidases moonlight as molecular chaperones to alleviate stress-induced damage. AB - Leucine aminopeptidases (LAPs) are present in animals, plants, and microbes. In plants, there are two classes of LAPs. The neutral LAPs (LAP-N and its orthologs) are constitutively expressed and detected in all plants, whereas the stress induced acidic LAPs (LAP-A) are expressed only in a subset of the Solanaceae. LAPs have a role in insect defense and act as a regulator of the late branch of wound signaling in Solanum lycopersicum (tomato). Although the mechanism of LAP-A action is unknown, it has been presumed that LAP peptidase activity is essential for regulating wound signaling. Here we show that plant LAPs are bifunctional. Using three assays to monitor protein protection from heat-induced damage, it was shown that the tomato LAP-A and LAP-N and the Arabidopsis thaliana LAP1 and LAP2 are molecular chaperones. Assays using LAP-A catalytic site mutants demonstrated that LAP-A chaperone activity was independent of its peptidase activity. Furthermore, disruption of the LAP-A hexameric structure increased chaperone activity. Together, these data identify a new class of molecular chaperones and a new function for the plant LAPs as well as suggesting new mechanisms for LAP action in the defense of solanaceous plants against stress. PMID- 22493453 TI - STE20-related kinase adaptor protein alpha (STRADalpha) regulates cell polarity and invasion through PAK1 signaling in LKB1-null cells. AB - LKB1 is a Ser/Thr kinase, and its activity is regulated by the pseudokinase, STE20-related adaptor alpha (STRADalpha). The STRADalpha-LKB1 pathway plays critical roles in epithelial cell polarity, neuronal polarity, and cancer metastasis. Though much attention is given to the STRADalpha-LKB1 pathway, the function of STRADalpha itself, including a role outside of the LKB1 pathway, has not been well-studied. Data in Caenorhabditis elegans suggest that STRADalpha has an LKB1-independent role in regulating cell polarity, and therefore we tested the hypothesis that STRADalpha regulates cancer cell polarity and motility when wild type LKB1 is absent. These results show that STRADalpha protein is reduced in LKB1-null cell lines (mutation or homozygous deletion) and this partial degradation occurs through the Hsp90-dependent proteasome pathway. The remaining STRADalpha participates in cell polarity and invasion, such that STRADalpha depletion results in misaligned lamellipodia, improper Golgi positioning, and reduced invasion. To probe the molecular basis of this defect, we show that STRADalpha associates in a complex with PAK1, and STRADalpha loss disrupts PAK1 activity via Thr(423) PAK1 phosphorylation. When STRADalpha is depleted, PAK1 induced invasion could not occur, suggesting that STRADalpha is necessary for PAK1 to drive motility. Furthermore, STRADalpha overexpression caused increased activity of the PAK1-activating protein, rac1, and a constitutively active rac1 mutant (Q61L) rescued pPAK(Thr423) and STRADalpha invasion defects. Taken together, these results show that a STRADalpha-rac1-PAK1 pathway regulates cell polarity and invasion in LKB1-null cells. It also suggests that while the function of LKB1 and STRADalpha undoubtedly overlap, they may also have mutually exclusive roles. PMID- 22493452 TI - Polythiophenes inhibit prion propagation by stabilizing prion protein (PrP) aggregates. AB - Luminescent conjugated polymers (LCPs) interact with ordered protein aggregates and sensitively detect amyloids of many different proteins, suggesting that they may possess antiprion properties. Here, we show that a variety of anionic, cationic, and zwitterionic LCPs reduced the infectivity of prion-containing brain homogenates and of prion-infected cerebellar organotypic cultured slices and decreased the amount of scrapie isoform of PrP(C) (PrP(Sc)) oligomers that could be captured in an avidity assay. Paradoxically, treatment enhanced the resistance of PrP(Sc) to proteolysis, triggered the compaction, and enhanced the resistance to proteolysis of recombinant mouse PrP(23-231) fibers. These results suggest that LCPs act as antiprion agents by transitioning PrP aggregates into structures with reduced frangibility. Moreover, ELISA on cerebellar organotypic cultured slices and in vitro conversion assays with mouse PrP(23-231) indicated that poly(thiophene-3-acetic acid) may additionally interfere with the generation of PrP(Sc) by stabilizing the conformation of PrP(C) or of a transition intermediate. Therefore, LCPs represent a novel class of antiprion agents whose mode of action appears to rely on hyperstabilization, rather than destabilization, of PrP(Sc) deposits. PMID- 22493454 TI - Plastocyanin controls the stabilization of the thylakoid Cu-transporting P-type ATPase PAA2/HMA8 in response to low copper in Arabidopsis. AB - PAA2/HMA8 (P-type ATPase of Arabidopsis/Heavy-metal-associated 8) is a thylakoid located copper (Cu)-transporter in Arabidopsis thaliana. In tandem with PAA1/HMA6, which is located in the inner chloroplast envelope, it supplies Cu to plastocyanin (PC), an essential cuproenzyme of the photosynthetic machinery. We investigated whether the chloroplast Cu transporters are affected by Cu addition to the growth media. Immunoblots showed that PAA2 protein abundance decreased significantly and specifically when Cu in the media was increased, while PAA1 remained unaffected. The function of SPL7, the transcriptional regulator of Cu homeostasis, was not required for this regulation of PAA2 protein abundance and Cu addition did not affect PAA2 transcript levels, as determined by qRT-PCR. We used the translational inhibitor cycloheximide to analyze turnover and observed that the stability of the PAA2 protein was decreased in plants grown with elevated Cu. Interestingly, PAA2 protein abundance was significantly increased in paa1 mutants, in which the Cu content in the chloroplast is half of that of the wild-type, due to impaired Cu import into the organelle. In contrast in a pc2 insertion mutant, which has strongly reduced plastocyanin expression, the PAA2 protein levels were low regardless of Cu addition to the growth media. Together, these data indicate that plastid Cu levels control PAA2 stability and that plastocyanin, which is the target of PAA2 mediated Cu delivery in thylakoids, is a major determinant of this regulatory mechanism. PMID- 22493455 TI - Significance of calcium binding, tyrosine phosphorylation, and lysine trimethylation for the essential function of calmodulin in vertebrate cells analyzed in a novel gene replacement system. AB - Calmodulin (CaM) was shown to be essential for survival of lower eukaryotes by gene deletion experiments. So far, no CaM gene deletion was reported in higher eukaryotes. In vertebrates, CaM is expressed from several genes, which encode an identical protein, making it difficult to generate a model system to study the effect of CaM gene deletion. Here, we present a novel genetic system based on the chicken DT40 cell line, in which the two functional CaM genes were deleted and one allele replaced with a CaM transgene that can be artificially regulated. We show that CaM is essential for survival of vertebrate cells as they die in the absence of CaM expression. Reversal of CaM repression or ectopic expression of HA tagged CaM rescued the cells. Cells exclusively expressing HA-CaM with impaired individual calcium binding domains as well as HA-CaM lacking the ability to be phosphorylated at residues Tyr(99)/Tyr(138) or trimethylated at Lys(115) survived and grew well. CaM mutated at both Ca(2+) binding sites 3 and 4 as well as at both sites 1 and 2, but to a lesser degree, showed decreased ability to support cell growth. Cells expressing CaM with all calcium binding sites impaired died with kinetics similar to that of cells expressing no CaM. This system offers a unique opportunity to analyze CaM structure-function relationships in vivo without the use of pharmacological inhibitors and to analyze the function of wild type and mutated CaM in modulating the activity of different target systems without interference of endogenous CaM. PMID- 22493456 TI - Tumors with nonfunctional retinoblastoma protein are killed by reduced gamma tubulin levels. AB - In various tumors inactivation of growth control is achieved by interfering with the RB1 signaling pathway. Here, we describe that RB1 and gamma-tubulin proteins moderate each other's expression by binding to their respective gene promoters. Simultaneous reduction of RB1 and gamma-tubulin protein levels results in an E2F1 dependent up-regulation of apoptotic genes such as caspase 3. We report that in various tumors types, there is an inverse correlation between the expression levels of gamma-tubulin and RB1 and that in tumor cell lines with a nonfunctioning RB1, reduction of gamma-tubulin protein levels leads to induction of apoptosis. Thus, the RB1/gamma-tubulin signal network can be considered as a new target for cancer treatment. PMID- 22493457 TI - Agonist- and Ca2+-dependent desensitization of TRPV1 channel targets the receptor to lysosomes for degradation. AB - TRPV1 receptor agonists such as the vanilloid capsaicin and the potent analog resiniferatoxin are well known potent analgesics. Depending on the vanilloid, dose, and administration site, nociceptor refractoriness may last from minutes up to months, suggesting the contribution of different cellular mechanisms ranging from channel receptor desensitization to Ca(2+) cytotoxicity of TRPV1-expressing neurons. The molecular mechanisms underlying agonist-induced TRPV1 desensitization and/or tachyphylaxis are still incompletely understood. Here, we report that prolonged exposure of TRPV1 to agonists induces rapid receptor endocytosis and lysosomal degradation in both sensory neurons and recombinant systems. Agonist-induced receptor internalization followed a clathrin- and dynamin-independent endocytic route, triggered by TRPV1 channel activation and Ca(2+) influx through the receptor. This process appears strongly modulated by PKA-dependent phosphorylation. Taken together, these findings indicate that TRPV1 agonists induce long-term receptor down-regulation by modulating the expression level of the channel through a mechanism that promotes receptor endocytosis and degradation and lend support to the notion that cAMP signaling sensitizes nociceptors through several mechanisms. PMID- 22493458 TI - The cytoskeletal protein alpha-catenin unfurls upon binding to vinculin. AB - Adherens junctions (AJs) are essential for cell-cell contacts, morphogenesis, and the development of all higher eukaryotes. AJs are formed by calcium-dependent homotypic interactions of the ectodomains of single membrane-pass cadherin family receptors. These homotypic interactions in turn promote binding of the intracellular cytoplasmic tail domains of cadherin receptors with beta-catenin, a multifunctional protein that plays roles in both transcription and AJs. The cadherin receptor-beta-catenin complex binds to the cytoskeletal protein alpha catenin, which is essential for both the formation and the stabilization of these junctions. Precisely how alpha-catenin contributes to the formation and stabilization of AJs is hotly debated, although the latter is thought to involve its interactions with the cytoskeletal protein vinculin. Here we report the crystal structure of the vinculin binding domain (VBD) of alpha-catenin in complex with the vinculin head domain (Vh1). This structure reveals that alpha catenin is in a unique unfurled mode allowing dimer formation when bound to vinculin. Finally, binding studies suggest that vinculin must be in an activated state to bind to alpha-catenin and that this interaction is stabilized by the formation of a ternary alpha-catenin-vinculin-F-actin complex, which can be formed via the F-actin binding domain of either protein. We propose a feed forward model whereby alpha-catenin-vinculin interactions promote their binding to the actin cytoskeleton to stabilize AJs. PMID- 22493459 TI - Interpersonal trauma exposure and cognitive development in children to age 8 years: a longitudinal study. AB - BACKGROUND: Childhood trauma exposure has been associated with deficits in cognitive functioning. The influence of timing of exposure on the magnitude and persistence of deficits is not well understood. The impact of exposure in early development has been especially under-investigated. This study examined the impact of interpersonal trauma exposure (IPT) in the first years of life on childhood cognitive functioning. METHODS: Children (N=206) participating in a longitudinal birth cohort study were assessed prospectively for exposure to IPT (physical or emotional abuse or neglect, sexual abuse, witnessing maternal partner violence) between birth and 64 months. Child intelligent quotient (IQ) scores were assessed at 24, 64 and 96 months of age. Race/ethnicity, gender, socioeconomic status, maternal IQ, birth complications, birth weight and cognitive stimulation in the home were also assessed. RESULTS: IPT was significantly associated with decreased cognitive scores at all time points, even after controlling for socio-demographic factors, maternal IQ, birth complications, birth weight and cognitive stimulation in the home. IPT in the first 2 years appeared to be especially detrimental. On average, compared with children not exposed to IPT in the first 2 years, exposed children scored one half SD lower across cognitive assessments. CONCLUSION: IPT in early life may have adverse effects on cognitive development. IPT during the first 2 years may have particular impact, with effects persisting at least into later childhood. PMID- 22493460 TI - Wide QRS Tachycardia in a young patient. PMID- 22493462 TI - Influenza vaccine effectiveness in patients on hemodialysis: an analysis of a natural experiment. AB - BACKGROUND: Although the influenza vaccine is recommended for patients with end stage renal disease, little is known about its effectiveness. Observational studies of vaccine effectiveness (VE) are challenging because vaccinated subjects may be healthier than unvaccinated subjects. METHODS: Using US Renal Data System data, we estimated VE for influenza-like illness, influenza/pneumonia hospitalization, and mortality in adult patients undergoing hemodialysis by using a natural experiment created by the year-to-year variation in the match of the influenza vaccine to the circulating virus. We compared vaccinated patients in matched years (1998, 1999, and 2001) with a mismatched year (1997) using Cox proportional hazards models. Ratios of hazard ratios compared vaccinated patients between 2 years and unvaccinated patients between 2 years. We calculated VE as 1 effect measure. RESULTS: Vaccination rates were less than 50% each year. Conventional analysis comparing vaccinated with unvaccinated patients produced average VE estimates of 13%, 16%, and 30% for influenza-like illness, influenza/pneumonia hospitalization, and mortality, respectively. When restricted to the preinfluenza period, results were even stronger, indicating bias. The pooled ratio of hazard ratios comparing matched seasons with a placebo season resulted in a VE of 0% (95% CI, -3% to 2%) for influenza-like illness, 2% (-2% to 5%) for hospitalization, and 0% (-3% to 3%) for death. CONCLUSIONS: Relative to a mismatched year, we found little evidence of increased VE in subsequent well matched years, suggesting that the current influenza vaccine strategy may have a smaller effect on morbidity and mortality in the end-stage renal disease population than previously thought. Alternate strategies (eg, high-dose vaccine, adjuvanted vaccine, and multiple doses) should be investigated. PMID- 22493463 TI - Adherence to colorectal cancer screening: a randomized clinical trial of competing strategies. AB - BACKGROUND: Despite evidence that several colorectal cancer (CRC) screening strategies can reduce CRC mortality, screening rates remain low. This study aimed to determine whether the approach by which screening is recommended influences adherence. METHODS: We used a cluster randomization design with clinic time block as the unit of randomization. Persons at average risk for development of CRC in a racially/ethnically diverse urban setting were randomized to receive recommendation for screening by fecal occult blood testing (FOBT), colonoscopy, or their choice of FOBT or colonoscopy. The primary outcome was completion of CRC screening within 12 months after enrollment, defined as performance of colonoscopy, or 3 FOBT cards plus colonoscopy for any positive FOBT result. Secondary analyses evaluated sociodemographic factors associated with completion of screening. RESULTS: A total of 997 participants were enrolled; 58% completed the CRC screening strategy they were assigned or chose. However, participants who were recommended colonoscopy completed screening at a significantly lower rate (38%) than participants who were recommended FOBT (67%) (P < .001) or given a choice between FOBT or colonoscopy (69%) (P < .001). Latinos and Asians (primarily Chinese) completed screening more often than African Americans. Moreover, nonwhite participants adhered more often to FOBT, while white participants adhered more often to colonoscopy. CONCLUSIONS: The common practice of universally recommending colonoscopy may reduce adherence to CRC screening, especially among racial/ethnic minorities. Significant variation in overall and strategy-specific adherence exists between racial/ethnic groups; however, this may be a proxy for health beliefs and/or language. These results suggest that patient preferences should be considered when making CRC screening recommendations. Trial Registration clinicaltrials.gov Identifier: NCT00705731. PMID- 22493464 TI - The importance of choosing colorectal cancer screening tests: comment on "Adherence to colorectal cancer screening". PMID- 22493465 TI - "Lost to follow-up": the public health goals of accountable care. AB - The Affordable Care Act made admirable strides toward the "triple aim" of reducing health care costs, increasing health care quality, and improving the health of the community at large. A key element of reform is the accountable care organization (ACO), which restructures health care delivery such that networks of providers are held responsible for a group of patients they serve. The recently announced Medicare ACO program lays the foundation for 2 of its 3 major goals by allowing ACOs to share in any cost savings, provided they meet quality criteria. Yet it seems that the public health goals of accountable care-arguably the most important of the 3-have been left behind. To better address public health goals, we propose a novel method for quality reporting within ACOs: introducing an "expanded denominator" that attributes patients to a health system if they have ever been seen within the system. An expanded denominator would ensure that ACOs are held accountable not only for patients already engaged in primary care but also for patients with fragmented care and high-risk community members not receiving adequate care. Ultimately, payment reform in Medicare, and potentially Medicaid, must support this new approach to quality measurement for it to have lasting ramifications. PMID- 22493466 TI - Continuous mortality risk among peritoneal dialysis patients. PMID- 22493467 TI - Mentholated cigarettes and cardiovascular and pulmonary diseases: a population based study. PMID- 22493468 TI - Use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and cardiovascular outcomes in chronic dialysis patients: a population-based cohort study. PMID- 22493469 TI - Do the benefits of medications outweigh the burdens for hemodialysis patients?: comment on "Use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and cardiovascular outcomes in chronic dialysis patients". PMID- 22493470 TI - A multidimensional prognostic index in common conditions leading to death in older patients. PMID- 22493471 TI - Coffee or camaraderie? PMID- 22493472 TI - Association between glycemic control and adverse outcomes in diabetic patients with CKD. PMID- 22493473 TI - Management of erectile dysfunction: do not forget hypertension. PMID- 22493474 TI - Levels and predictors of exercise referral scheme uptake and adherence: a systematic review. AB - BACKGROUND: The effectiveness of exercise referral schemes (ERS) is influenced by uptake and adherence to the scheme. The identification of factors influencing low uptake and adherence could lead to the refinement of schemes to optimise investment. OBJECTIVES: To quantify the levels of ERS uptake and adherence and to identify factors predictive of uptake and adherence. METHODS: A systematic review and meta-analysis was undertaken. MEDLINE, EMBASE, PsycINFO, Cochrane Library, ISI WOS, SPORTDiscus and ongoing trial registries were searched (to October 2009) and included study references were checked. Included studies were required to report at least one of the following: (1) a numerical measure of ERS uptake or adherence and (2) an estimate of the statistical association between participant demographic or psychosocial factors (eg, level of motivation, self-efficacy) or programme factors and uptake or adherence to ERS. RESULTS: Twenty studies met the inclusion criteria, six randomised controlled trials (RCTs) and 14 observational studies. The pooled level of uptake in ERS was 66% (95% CI 57% to 75%) across the observational studies and 81% (95% CI 68% to 94%) across the RCTs. The pooled level of ERS adherence was 49% (95% CI 40% to 59%) across the observational studies and 43% (95% CI 32% to 54%) across the RCTs. Few studies considered anything other than gender and age. Women were more likely to begin an ERS but were less likely to adhere to it than men. Older people were more likely to begin and adhere to an ERS. LIMITATIONS: Substantial heterogeneity was evident across the ERS studies. Without standardised definitions, the heterogeneity may have been reflective of differences in methods of defining uptake and adherence across studies. CONCLUSIONS: To enhance our understanding of the variation in uptake and adherence across ERS and how these variations might affect physical activity outcomes, future trials need to use quantitative and qualitative methods. PMID- 22493475 TI - Towards the next generation of public health research in India: a call for a health equity lens. AB - BACKGROUND: Public health research is at a cross road in India. Despite a high level of health needs and new public health challenges arising in the context of rapid economic growth and social change, public health research is not keeping up with the needs of Indian society. There are, however, new initiatives creating opportunities to increase public health research, thereby raising debates about public health research priorities. OBJECTIVE: In this paper, the authors offer their own view on an agenda for the next generation of public health research in India. FINDINGS: The authors first outline the main reasons why they believe that public health research has been sidelined in India. Then, the authors argue that health equity should be the overarching principle guiding a public health research agenda. The authors suggest how to integrate equity-oriented strategies into the public health research agenda and propose some key research questions that require urgent attention from their respective disciplines. PMID- 22493476 TI - Risk of invasive pneumococcal disease in people admitted to hospital with selected immune-mediated diseases: record linkage cohort analyses. AB - BACKGROUND: Invasive pneumococcal disease is a serious infection, and it is an important cause of morbidity and mortality in certain groups of 'at-risk' people. Those considered 'at-risk' in the UK include very young children, people aged 65 years and older and people with certain serious chronic diseases, asplenia or immunosuppression. There is little evidence about whether people with immune mediated diseases are at increased risk of pneumococcal disease and therefore may benefit from pneumococcal vaccination. METHODS: Retrospective cohort studies, using linked hospital data, from the longstanding Oxford Record Linkage Study (1963-2008) and from recent English national linked Hospital Episode Statistics (1999-2008); analysis of whether people with immune-mediated diseases are more likely than others to be admitted to hospital for pneumococcal disease; calculation of rate ratio for pneumococcal disease in cohorts with immune mediated disease compared with control cohorts. RESULTS: There were elevated rate ratios for many of the immune-mediated diseases, for example, Addison's disease in England 3.8 (95% CI 3.4 to 4.2), autoimmune haemolytic anaemia 4.9 (4.4 to 5.3), Crohn's disease 2.2 (2.1 to 2.3), diabetes mellitus 3.7 (3.4 to 4.1), multiple sclerosis 3.7 (3.5 to 3.8), myxoedema 1.60 (1.58 to 1.63), pernicious anaemia 1.74 (1.66 to 1.83), primary biliary cirrhosis 3.3 (2.9 to 3.7), polyarteritis nodosa 5.0 (4.0 to 6.0), rheumatoid arthritis 2.47 (2.41 to 2.52), scleroderma 4.2 (3.8 to 4.7), Sjogren's syndrome 3.2 (2.9 to 3.5) and systemic lupus erythematosus 5.0 (4.6 to 5.4). Findings in the Oxford and all England data sets were similar. CONCLUSIONS: People admitted to hospital with immune-mediated diseases are at higher risk than those with invasive pneumococcal disease. Vaccination should be considered in this group of patients. PMID- 22493477 TI - Clean cord care practices and neonatal mortality: evidence from rural Uttar Pradesh, India. AB - BACKGROUND: About a million newborns die each year in India, accounting for about a fourth of total global neonatal deaths. Infections are among the leading causes of neonatal mortality. Care practices immediately following delivery contribute to newborns' risk of infection and mortality. OBJECTIVES: This study examined the association between clean cord care practices and neonatal mortality in rural Uttar Pradesh, India. METHODS: The study used data from a household survey conducted to evaluate a community-based intervention program in two districts of Uttar Pradesh, India. Analysis included data from 5741 singleton live births delivered at home during 2005. The association between clean cord care (clean instrument used to cut cord, clean thread used to tie cord and antiseptics or nothing applied to the cord) and neonatal mortality was estimated using multivariate logistic regression models. RESULTS: Thirty per cent of the study mothers practiced clean cord care. Neonatal mortality rate was significantly lower among newborns exposed to clean cord care (36.5/1000 live births, 95% CI 28.0 to 46.8) than those who did not practice (53.0/1000 live births, 95% CI 46.1 to 60.6). Clean cord care was associated with 37% lower neonatal mortality (OR=0.63; 95% CI 0.46 to 0.87) after adjusting for mother's age, education, caste/tribe, religion, household wealth, newborn thermal care practice and care seeking during the first week after birth and study arms. CONCLUSIONS: Promoting clean cord care practice among neonates in community-based maternal and newborn care programs has the potential to improve neonatal survival in rural India and similar other settings. PMID- 22493478 TI - Mobilising community collectivisation among female sex workers to promote STI service utilisation from the government healthcare system in Andhra Pradesh, India. AB - BACKGROUND: To assess the association between female sex workers' (FSWs) degree of community collectivisation and self-efficacy, utilisation of sexually transmitted infection (STI) services from government-run health centres in Andhra Pradesh, India. METHODS: Cross-sectional analyses of 1986 FSWs recruited using a probability-based sampling from five districts of Andhra Pradesh during 2010 2011. Multiple logistic regression models were constructed to assess associations. The independent variables included-collective efficacy, collective agency and collective action-measured using a series of items that assessed the grouping of the community on issues that concern most sex workers. An additional independent variable included FSWs belonging to an area where there was a project partnership with government health centres to provide STI treatment services to FSWs. The outcome indicators included self-efficacy for service utilisation from government health facilities and the treatment for STIs from government health facilities at least once in the past year experience of STI symptoms. RESULTS: Of the 1986 FSWs, nearly two-fifths (39.5%) reported a high level of overall collectivisation (collective efficacy: 89%, collective agency: 50.7%; collective action: 12.7%). Sex workers with a high degree compared with low degree of overall collectivisation were significantly more likely to report high self efficacy to use government health facilities (75.0% vs 57.3%, adjusted OR 2.5, 95% CI 2.0 to 3.1) and to use government health centres for STI treatment in past 1 year (78.1% vs 63.2%, adjusted OR 2.1, 95% CI 1.6 to 2.8), irrespective of project partnership with government centres. CONCLUSION: The current research findings reinforce the need for stronger community mobilisation for better utilisation of government health facilities for STI and HIV prevention interventions. PMID- 22493479 TI - The association between lung function and fatal stroke in a community followed for 4 decades. AB - BACKGROUND: Previous studies, all of <20 years of follow-up, have suggested an association between lung function and the risk of fatal stroke. This study investigates the stability of this association in a cohort followed for 4 decades. METHODS: The Bergen Clinical Blood Pressure Survey was conducted in Norway in 1964-1971. The risk of fatal stroke associated with forced expiratory volume after one second (FEV(1)) was estimated with Cox proportional hazards regression, making progressive adjustment for potential confounders. RESULTS: Of 5617 (84%) participants with recorded baseline FEV(1), 462 died from stroke over 152 786 subsequent person-years of follow-up according to mortality statistics of 2005; mean (SD) follow-up was 27 (12) years. An association between baseline FEV(1) (L) and fatal stroke was observed; HR=1.38 (95% CI 1.11 to 1.71) and HR=1.62 (95% CI 1.22 to 2.15) for men and women, respectively (adjusted for age and height). The findings were not explained by smoking, hypertension, diabetes, atherosclerosis, socioeconomic status, obstructive lung disease, physical inactivity, cholesterol or body mass index and persisted in subgroups of never smokers, subgroups without respiratory symptoms and survivors of the first 20 years of follow-up. For male survivors with a valid FEV(1) at follow-up (1988 1990) (n=953), baseline FEV(1) (L) indicated a possible strong and independent association to the risk of fatal stroke after adjustments for individual changes in FEV(1) (ml/year) (HR 1.95 (95% CI 0.98 to 3.86)). CONCLUSION: There is a consistent, independent and long-lasting association between lung function and fatal stroke, probably irrespective of changes during adult life. PMID- 22493480 TI - POZ-, AT-hook-, and zinc finger-containing protein (PATZ) interacts with human oncogene B cell lymphoma 6 (BCL6) and is required for its negative autoregulation. AB - The PATZ1 gene encoding a POZ/AT-hook/Kruppel zinc finger (PATZ) transcription factor, is considered a cancer-related gene because of its loss or misexpression in human neoplasias. As for other POZ/domain and Kruppel zinc finger (POK) family members, the transcriptional activity of PATZ is due to the POZ-mediated oligomer formation, suggesting that it might be not a typical transactivator but an architectural transcription factor, thus functioning either as activator or as repressor depending on the presence of proteins able to interact with it. Therefore, to better elucidate PATZ function, we searched for its molecular partners. By yeast two-hybrid screenings, we found a specific interaction between PATZ and BCL6, a human oncogene that plays a key role in germinal center (GC) derived neoplasias. We demonstrate that PATZ and BCL6 interact in germinal center derived B lymphoma cells, through the POZ domain of PATZ. Moreover, we show that PATZ is able to bind the BCL6 regulatory region, where BCL6 itself acts as a negative regulator, and to contribute to negatively modulate its activity. Consistently, disruption of one or both Patz1 alleles in mice causes focal expansion of thymus B cells, in which BCL6 is up-regulated. This phenotype was almost completely rescued by crossing Patz1(+/-) with Bcl6(+/-) mice, indicating a key role for Bcl6 expression in its development. Finally, a significant number of Patz1 knock-out mice (both heterozygous and homozygous) also develop BCL6 expressing lymphomas. Therefore, the disruption of one or both Patz1 alleles may favor lymphomagenesis by activating the BCL6 pathway. PMID- 22493481 TI - Characterization of chromoshadow domain-mediated binding of heterochromatin protein 1alpha (HP1alpha) to histone H3. AB - The chromoshadow domain (CSD) of heterochromatin protein 1 (HP1) was recently shown to contribute to chromatin binding and transcriptional regulation through interaction with histone H3. Here, we demonstrate the structural basis of this interaction for the CSD of HP1alpha. This mode of H3 binding is dependent on dimerization of the CSD and recognition of a PxVxL-like motif, as for other CSD partners. NMR chemical shift mapping showed that the H3 residues that mediate the CSD interaction occur in and adjacent to the alphaN helix just within the nucleosome core. Access to the binding region would require some degree of unwrapping of the DNA near the nucleosomal DNA entry/exit site. PMID- 22493482 TI - Gli1 protein participates in Hedgehog-mediated specification of osteoblast lineage during endochondral ossification. AB - With regard to Hedgehog signaling in mammalian development, the majority of research has focused on Gli2 and Gli3 rather than Gli1. This is because Gli1(-/-) mice do not show any gross abnormalities in adulthood, and no detailed analyses of fetal Gli1(-/-) mice are available. In this study, we investigated the physiological role of Gli1 in osteogenesis. Histological analyses revealed that bone formation was impaired in Gli1(-/-) fetuses compared with WT fetuses. Gli1( /-) perichondrial cells expressed neither runt-related transcription factor 2 (Runx2) nor osterix, master regulators of osteogenesis, in contrast to WT cells. In vitro analyses showed that overexpression of Gli1 up-regulated early osteogenesis-related genes in both WT and Runx2(-/-) perichondrial cells, and Gli1 activated transcription of those genes via its association with their 5' regulatory regions, underlying the function of Gli1 in the perichondrium. Moreover, Gli1(-/-);Gli2(-/-) mice showed more severe phenotypes of impaired bone formation than either Gli1(-/-) or Gli2(-/-) mice, and osteoblast differentiation was impaired in Gli1(-/-);Gli3(-/-) perichondrial cells compared with Gli3(-/-) cells in vitro. These data suggest that Gli1 itself can induce early osteoblast differentiation, at least to some extent, in a Runx2-independent manner. It also plays a redundant role with Gli2 and is involved in the repressor function of Gli3 in osteogenesis. On the basis of these findings, we propose that upon Hedgehog input, Gli1 functions collectively with Gli2 and Gli3 in osteogenesis. PMID- 22493483 TI - Kruppel-like factor 15 (KLF15) is a key regulator of podocyte differentiation. AB - Podocyte injury resulting from a loss of differentiation is the hallmark of many glomerular diseases. We previously showed that retinoic acid (RA) induces podocyte differentiation via stimulation of the cAMP pathway. However, many podocyte maturity markers lack binding sites for RA-response element or cAMP response element (CREB) in their promoter regions. We hypothesized that transcription factors induced by RA and downstream of CREB mediate podocyte differentiation. We performed microarray gene expression studies in human podocytes treated with and without RA to identify differentially regulated genes. In comparison with known CREB target genes, we identified Kruppel-like factor 15 (KLF15), a kidney-enriched nuclear transcription factor, that has been previously shown to mediate cell differentiation. We confirmed that RA increased KLF15 expression in both murine and human podocytes. Overexpression of KLF15 stimulated expression of differentiation markers in both wild-type and HIV-1-infected podocytes. Also, KLF15 binding to the promoter regions of nephrin and podocin was increased in RA-treated podocytes. Although KLF15(-/-) mice at base line had minimal phenotype, lipopolysaccharide- or adriamycin-treated KLF15(-/-) mice had a significant increase in proteinuria and podocyte foot process effacement with a reduction in the expression of podocyte differentiation markers as compared with the wild-type treated mice. Finally, KLF15 expression was reduced in glomeruli isolated from HIV transgenic mice as well as in kidney biopsies from patients with HIV-associated nephropathy and idiopathic focal segmental glomerulosclerosis. These results indicate a critical role of KLF15 in mediating podocyte differentiation and in protecting podocytes against injury. PMID- 22493484 TI - Endoplasmic reticulum stress-associated cone photoreceptor degeneration in cyclic nucleotide-gated channel deficiency. AB - Cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 account for >70% of all known cases of achromatopsia. Cones degenerate in achromatopsia patients and in CNGA3(-/-) and CNGB3(-/-) mice. This work investigates the molecular basis of cone degeneration in CNG channel deficiency. As cones comprise only 2-3% of the total photoreceptor population in the wild-type mouse retina, we generated mouse lines with CNG channel deficiency on a cone-dominant background, i.e. CNGA3(-/ )/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) mice. The retinal phenotype and potential cell death pathways were examined by functional, biochemical, and immunohistochemical approaches. CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) mice showed impaired cone function, opsin mislocalization, and cone degeneration similar to that in the single knock-out mice. The endoplasmic reticulum stress marker proteins, including Grp78/Bip, phospho-eIF2alpha, phospho-IP(3)R, and CCAAT/enhancer binding protein homologous protein, were elevated significantly in CNGA3(-/ )/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) retinas, compared with the age-matched (postnatal 30 days) Nrl(-/-) controls. Along with these, up-regulation of the cysteine protease calpains and cleavage of caspase-12 and caspase-7 were found in the channel-deficient retinas, suggesting an endoplasmic reticulum stress associated apoptosis. In addition, we observed a nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G in CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) retinas, implying a mitochondrial insult in the endoplasmic reticulum stress-activated cell death process. Taken together, our findings suggest a crucial role of endoplasmic reticulum stress in cone degeneration associated with CNG channel deficiency. PMID- 22493485 TI - Nicotinamide-induced mitophagy: event mediated by high NAD+/NADH ratio and SIRT1 protein activation. AB - Active autophagy coupled with rapid mitochondrial fusion and fission constitutes an important mitochondrial quality control mechanism and is critical to cellular health. In our previous studies, we found that exposure of cells to nicotinamide causes a decrease in mitochondrial content and an increase in mitochondrial membrane potential (MMP) by activating autophagy and inducing mitochondrial fragmentation. Here, we present evidence to show that the effect of nicotinamide is mediated through an increase of the [NAD(+)]/[NADH] ratio and the activation of SIRT1, an NAD(+)-dependent deacetylase that plays a role in autophagy flux. The [NAD(+)]/[NADH] ratio was inversely correlated with the mitochondrial content, and an increase in the ratio by the mobilization of the malate-aspartate shuttle resulted in autophagy activation and mitochondrial transformation from lengthy filaments to short dots. Furthermore, treatment of cells with SIRT1 activators, fisetin or SRT1720, induced similar changes in the mitochondrial content. Importantly, the activators induced mitochondrial fragmentation only when SIRT1 expression was intact. Meanwhile, MMP did not increase when the cells were treated with the activators, suggesting that the change in MMP is not induced by the mitochondrial turnover per se and that elevation of the [NAD(+)]/[NADH] ratio may activate additional mechanisms that cause MMP augmentation. Together, our results indicate that a metabolic state resulting in an elevated [NAD(+)]/[NADH] ratio can modulate mitochondrial quantity and quality via pathways that may include SIRT1-mediated mitochondrial autophagy. PMID- 22493486 TI - GPR41 gene expression is mediated by internal ribosome entry site (IRES) dependent translation of bicistronic mRNA encoding GPR40 and GPR41 proteins. AB - GPR41 is a G protein-coupled receptor activated by short chain fatty acids. The gene encoding GPR41 is located immediately downstream of a related gene encoding GPR40, a receptor for long chain fatty acids. Expression of GPR41 has been reported in a small number of cell types, including gut enteroendocrine cells and sympathetic ganglia, where it may play a role in the maintenance of metabolic homeostasis. We now demonstrate that GPR41, like GPR40, is expressed in pancreatic beta cells. Surprisingly, we found no evidence for transcriptional control elements or transcriptional initiation in the intergenic GPR40-GPR41 region. Rather, using 5'-rapid amplification of cDNA ends analysis, we demonstrated that GPR41 is transcribed from the promoter of the GPR40 gene. We confirmed this finding by generating bicistronic luciferase reporter plasmids, and we were able to map a potential internal ribosome entry site-containing region to a 2474-nucleotide region of the intergenic sequence. Consistent with this, we observed m(7)G cap-independent reporter gene expression upon transfection of RNA containing this region. Thus, GPR41 expression is mediated via an internal ribosome entry site located in the intergenic region of a bicistronic mRNA. This novel sequence organization may be utilized to permit coordinated regulation of the fatty acid receptors GPR40 and GPR41. PMID- 22493487 TI - Novel role of ADAMTS-5 protein in proteoglycan turnover and lipoprotein retention in atherosclerosis. AB - Atherosclerosis is initiated by the retention of lipoproteins on proteoglycans in the arterial intima. However, the mechanisms leading to proteoglycan accumulation and lipoprotein retention are poorly understood. In this study, we set out to investigate the role of ADAMTS-5 (a disintegrin and metalloprotease with thrombospondin motifs-5) in the vasculature. ADAMTS-5 was markedly reduced in atherosclerotic aortas of apolipoprotein E-null (apoE(-/-)) mice. The reduction of ADAMTS-5 was accompanied by accumulation of biglycan and versican, the major lipoprotein-binding proteoglycans, in atherosclerosis. ADAMTS-5 activity induced the release of ADAMTS-specific versican (DPEAAE(441)) and aggrecan ((374)ALGS) fragments as well as biglycan and link protein from the aortic wall. Fibroblast growth factor 2 (FGF-2) inhibited ADAMTS-5 expression in isolated aortic smooth muscle cells and blocked the spontaneous release of ADAMTS-generated versican and aggrecan fragments from aortic explants. In aortas of ADAMTS-5-deficient mice, DPEAAE(441) versican neoepitopes were not detectable. Instead, biglycan levels were increased, highlighting the role of ADAMTS-5 in the catabolism of vascular proteoglycans. Importantly, ADAMTS-5 proteolytic activity reduced the LDL binding ability of biglycan and released LDL from human aortic lesions. This study provides the first evidence implicating ADAMTS-5 in the regulation of proteoglycan turnover and lipoprotein retention in atherosclerosis. PMID- 22493488 TI - Pre-steady-state kinetics for hydrolysis of insoluble cellulose by cellobiohydrolase Cel7A. AB - The transient kinetic behavior of enzyme reactions prior to the establishment of steady state is a major source of mechanistic information, yet this approach has not been utilized for cellulases acting on their natural substrate, insoluble cellulose. Here, we elucidate the pre-steady-state regime for the exo-acting cellulase Cel7A using amperometric biosensors and an explicit model for processive hydrolysis of cellulose. This analysis allows the identification of a pseudo-steady-state period and quantification of a processivity number as well as rate constants for the formation of a threaded enzyme complex, processive hydrolysis, and dissociation, respectively. These kinetic parameters elucidate limiting factors in the cellulolytic process. We concluded, for example, that Cel7A cleaves about four glycosidic bonds/s during processive hydrolysis. However, the results suggest that stalling the processive movement and low off rates result in a specific activity at pseudo-steady state that is 10-25-fold lower. It follows that the dissociation of the enzyme-substrate complex (half time of ~30 s) is rate-limiting for the investigated system. We suggest that this approach can be useful in attempts to unveil fundamental reasons for the distinctive variability in hydrolytic activity found in different cellulase substrate systems. PMID- 22493489 TI - Eps8 protein facilitates phagocytosis by increasing TLR4-MyD88 protein interaction in lipopolysaccharide-stimulated macrophages. AB - Toll-like receptors (TLRs) are crucial in macrophage phagocytosis, which is pivotal in host innate immune response. However, the detailed mechanism is not fully defined. Here, we demonstrated that the induction of Src and Eps8 in LPS treated macrophages was TLR4- and MyD88-dependent, and their attenuation reduced LPS-promoted phagocytosis. Confocal microscopy indicated the colocalization of Eps8 and TLR4 in the cytosol and at the phagosome. Consistently, both Eps8 and TLR4 were present in the same immunocomplex regardless of LPS stimulation. Inhibition of this complex formation by eps8 siRNA or overexpression of pleckstrin homology domain-truncated Eps8 (i.e. 261-p97(Eps8)) decreased LPS induced TLR4-MyD88 interaction and the following activation of Src, focal adhesion kinase, and p38 MAPK. Importantly, attenuation of Eps8 impaired the bacterium-killing ability of macrophages. Thus, Eps8 is a key regulator of the LPS-stimulated TLR4-MyD88 interaction and contributes to macrophage phagocytosis. PMID- 22493490 TI - Ectopic expression of human MutS homologue 2 on renal carcinoma cells is induced by oxidative stress with interleukin-18 promotion via p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) signaling pathways. AB - Human MutS homologue 2 (hMSH2), a crucial element of the highly conserved DNA mismatch repair system, maintains genetic stability in the nucleus of normal cells. Our previous studies indicate that hMSH2 is ectopically expressed on the surface of epithelial tumor cells and recognized by both T cell receptor gammadelta (TCRgammadelta) and natural killer group 2 member D (NKG2D) on Vdelta2 T cells. Ectopically expressed hMSH2 could trigger a gammadelta T cell-mediated cytolysis. In this study, we showed that oxidative stress induced ectopic expression of hMSH2 on human renal carcinoma cells. Under oxidative stress, both p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) pathways have been confirmed to mediate the ectopic expression of hMSH2 through the apoptosis-signaling kinase 1 (ASK1) upstream and activating transcription factor 3 (ATF3) downstream of both pathways. Moreover, renal carcinoma cell derived interleukin (IL)-18 in oxidative stress was a prominent stimulator for ectopically induced expression of hMSH2, which was promoted by interferon (IFN) gamma as well. Finally, oxidative stress or pretreatment with IL-18 and IFN-gamma enhanced gammadelta T cell-mediated cytolysis of renal carcinoma cells. Our results not only establish a mechanism of ectopic hMSH2 expression in tumor cells but also find a biological linkage between ectopic expression of hMSH2 and activation of gammadelta T cells in stressful conditions. Because gammadelta T cells play an important role in the early stage of innate anti-tumor response, gammadelta T cell activation triggered by ectopically expressed hMSH2 may be an important event in immunosurveillance for carcinogenesis. PMID- 22493492 TI - Purification and identification of naringenin 7-O-methyltransferase, a key enzyme in biosynthesis of flavonoid phytoalexin sakuranetin in rice. AB - Sakuranetin, the major flavonoid phytoalexin in rice, is induced by ultraviolet (UV) irradiation, CuCl(2) treatment, jasmonic acid treatment, and infection by phytopathogens. It was recently demonstrated that sakuranetin has anti inflammatory activity, anti-mutagenic activity, anti-pathogenic activities against Helicobacter pylori, Leishmania, and Trypanosoma and contributes to the maintenance of glucose homeostasis in animals. Thus, sakuranetin is a useful compound as a plant antibiotic and a potential pharmaceutical agent. Sakuranetin is biosynthesized from naringenin by naringenin 7-O-methyltransferase (NOMT). In previous research, rice NOMT (OsNOMT) was purified to apparent homogeneity from UV-treated wild-type rice leaves, but the purified protein, named OsCOMT1, exhibited caffeic acid O-methyltransferase (COMT) activity and not NOMT activity. In this study, we found that OsCOMT1 does not contribute to sakuranetin production in rice in vivo, and we purified OsNOMT using the oscomt1 mutant. A crude protein preparation from UV-treated oscomt1 leaves was subjected to three sequential purification steps, resulting in a 400-fold purification from the crude enzyme preparation. Using SDS-PAGE, the purest enzyme preparation showed a minor band at an apparent molecular mass of 40 kDa. Two O-methyltransferase-like proteins, encoded by Os04g0175900 and Os12g0240900, were identified from the 40 kDa band by MALDI-TOF/TOF analysis. Recombinant Os12g0240900 protein showed NOMT activity, but the recombinant Os04g0175900 protein did not. Os12g0240900 expression was induced by jasmonic acid treatment in rice leaves prior to sakuranetin accumulation, and the Os12g0240900 protein showed reasonable kinetic properties to OsNOMT. On the basis of these results, we conclude that Os12g0240900 encodes an OsNOMT. PMID- 22493491 TI - Protein-tyrosine phosphatases are involved in interferon resistance associated with insulin resistance in HepG2 cells and obese mice. AB - Insulin resistance is a risk factor for non-response to interferon/ribavirin therapy in patients with chronic hepatitis C. The aim of this study was to determine the role played by protein-tyrosine phosphatases (PTPs) in the absence of interferon-alpha (IFNalpha) response associated with insulin resistance. We induced insulin resistance by silencing IRS-2 or by treating HepG2 cells with tumor necrosis factor-alpha (TNFalpha) and analyzed insulin response by evaluating Akt phosphorylation and IFNalpha response by measuring Stat-1 tyrosine phosphorylation and 2',5'-oligoadenylate synthase and myxovirus resistance gene expression. The response to IFNalpha was also measured in insulin-resistant obese mice (high fat diet and ob/ob mice) untreated and treated with metformin. Silencing IRS-2 mRNA induces insulin resistance and inhibits IFNalpha response. Likewise, TNFalpha suppresses insulin and IFNalpha response. Treatment of cells with pervanadate and knocking down PTP-1B restores insulin and IFNalpha response. Both silencing IRS-2 and TNFalpha treatment increase PTP and PTP-1B activity. Metformin inhibits PTP and improves IFNalpha response in insulin-resistant cells. Insulin-resistant ob/ob mice have increased PTP-1B gene expression and activity in the liver and do not respond to IFNalpha administration. Treatment with metformin improves this response. In HepG2 cells, insulin resistance provokes IFNalpha resistance, which is associated with an increased PTP-1B activity in the liver. Inhibition of PTP-1B activity with pervanadate and metformin or knocking down PTP-1B reestablishes IFNalpha response. Likewise, metformin decreases PTP-1B activity and improves response to IFNalpha in insulin-resistant obese mice. The use of PTP-1B inhibitors may improve the response to IFNalpha/ribavirin therapy. PMID- 22493494 TI - Assessing actual contribution of IF1, inhibitor of mitochondrial FoF1, to ATP homeostasis, cell growth, mitochondrial morphology, and cell viability. AB - F(o)F(1)-ATP synthase (F(o)F(1)) synthesizes ATP in mitochondria coupled with proton flow driven by the proton motive force (pmf) across membranes. It has been known that isolated IF1, an evolutionarily well conserved mitochondrial protein, can inhibit the ATP hydrolysis activity of F(o)F(1). Here, we generated HeLa cells with permanent IF1 knockdown (IF1-KD cells) and compared their energy metabolism with control cells. Under optimum growth conditions, IF1-KD cells have lower cellular ATP levels and generate a higher pmf and more reactive oxygen species. Nonetheless, IF1-KD cells and control cells show the same rates of cell growth, glucose consumption, and mitochondrial ATP synthesis. Furthermore, contrary to previous reports, the morphology of mitochondria in IF1-KD cells appears to be normal. When cells encounter sudden dissipation of pmf, the cytoplasmic ATP level in IF1-KD cells drops immediately (~1 min), whereas it remains unchanged in the control cells, indicating occurrence of futile ATP hydrolysis by F(o)F(1) in the absence of IF1. The lowered ATP level in IF1-KD cells then recovers gradually (~10 min) to the original level by consuming more glucose than control cells. The viability of IF1-KD cells and control cells is the same in the absence of pmf. Thus, IF1 contributes to ATP homeostasis, but its deficiency does not affect the growth and survival of HeLa cells. Only when cells are exposed to chemical ischemia (no glycolysis and no respiration) or high concentrations of reactive oxygen species does IF1 exhibit its ability to alleviate cell injury. PMID- 22493493 TI - Cisplatin-induced ototoxicity is mediated by nitroxidative modification of cochlear proteins characterized by nitration of Lmo4. AB - Tyrosine nitration is an important sequel of cellular signaling induced by reactive oxygen species. Cisplatin is an anti-neoplastic agent that damages the inner ear through reactive oxygen species and by the formation of DNA adducts. This study reveals a correlation between cisplatin-mediated hearing loss and nitroxidative modification of cochlear proteins and is the first to report nitration of Lmo4. Cisplatin induced a dose-dependent increase in hearing loss in Wistar rats. A 10-15-dB decrease in distortion product amplitude and massive loss of outer hair cells at the basal turn of the cochlea was observed 3 days post treatment after a 16 mg/kg dose. Cisplatin induced nitration of cellular proteins within the organ of Corti, spiral ganglion, and stria vascularis, which are known targets of cisplatin ototoxicity. Nitration of a 76-kDa cochlear protein correlated with cisplatin dose. The nitrated protein was identified as Lmo4 (LIM domain only 4) by MALDI-TOF (matrix-assisted laser desorption/ionization time of flight) mass spectrometry and confirmed by reciprocal immunoprecipitation and immunoblotting. Co-localization of nitrotyrosine and Lmo4 was particularly high in outer hair cell nuclei after cisplatin treatment. Cochlear levels of Lmo4 were decreased in rats treated with cisplatin. In vitro studies supported the repression of Lmo4 in nitroxidative conditions and the induction of apoptosis upon repression of Lmo4. Inhibition of cochlear protein nitration prevented cisplatin-induced hearing loss. As Lmo4 is a transcriptional regulator that controls the choice between cell survival and cell death, these results support the hypothesis that nitration of Lmo4 influences cisplatin-induced ototoxicity. PMID- 22493495 TI - Liver-specific p70 S6 kinase depletion protects against hepatic steatosis and systemic insulin resistance. AB - Obesity-associated hepatic steatosis is a manifestation of selective insulin resistance whereby lipogenesis remains sensitive to insulin but the ability of insulin to suppress glucose production is impaired. We created a mouse model of liver-specific knockdown of p70 S6 kinase (S6K) (L-S6K-KD) by systemic delivery of an adeno-associated virus carrying a shRNA for S6K and examined the effects on steatosis and insulin resistance. High fat diet (HFD) fed L-S6K-KD mice showed improved glucose tolerance and systemic insulin sensitivity compared with controls, with no changes in food intake or body weight. The induction of lipogenic gene expression was attenuated in the L-S6K-KD mice with decreased sterol regulatory element-binding protein (SREBP)-1c expression and mature SREBP 1c protein, as well as decreased steatosis on HFD. Our results demonstrate the importance of S6K: 1) as a modulator of the hepatic response to fasting/refeeding, 2) in the development of steatosis, and 3) as a key node in selective hepatic insulin resistance in obese mice. PMID- 22493496 TI - Roles for peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgamma coactivators 1alpha and 1beta in regulating response of white and brown adipocytes to hypoxia. AB - Obese white adipose tissue is hypoxic but is incapable of inducing compensatory angiogenesis. Brown adipose tissue is highly vascularized, facilitating delivery of nutrients to brown adipocytes for heat production. In this study, we investigated the mechanisms by which white and brown adipocytes respond to hypoxia. Brown adipocytes produced lower amounts of hypoxia-inducible factor 1alpha (HIF-1alpha) than white adipocytes in response to low O(2) but induced higher levels of hypoxia-associated genes. The response of white adipocytes to hypoxia required HIF-1alpha, but its presence alone was incapable of inducing target gene expression under normoxic conditions. In addition to the HIF-1alpha targets, hypoxia also induced many inflammatory genes. Exposure of white adipocytes to a peroxisome proliferator-activated receptor gamma (PPARgamma) ligand (troglitazone) attenuated induction of these genes but enhanced expression of the HIF-1alpha targets. Knockdown of PPARgamma in mature white adipocytes prevented the usual robust induction of HIF-1alpha targets in response to hypoxia. Similarly, knockdown of PPARgamma coactivator (PGC) 1beta in PGC-1alpha deficient brown adipocytes eliminated their response to hypoxia. These data demonstrate that the response of white adipocytes requires HIF-1alpha but also depends on PPARgamma in white cells and the PPARgamma cofactors PGC-1alpha and PGC-1beta in brown cells. PMID- 22493498 TI - Metabolic flux of extracellular heme uptake in Pseudomonas aeruginosa is driven by the iron-regulated heme oxygenase (HemO). AB - Heme utilization by Pseudomonas aeruginosa involves several proteins required for internalization and degradation of heme. In the following report we provide the first direct in vivo evidence for the specific degradation of extracellular heme to biliverdin (BV) by the iron-regulated HemO. Moreover, through isotopic labeling ((13)C-heme) and electrospray ionization-MS analysis we have confirmed the regioselectivity and ratio of (13)C-delta and beta-BV IX (70:30) is identical in vivo to that previously observed for the purified protein. Furthermore, the (13)C-BV IXdelta and BV IXbeta products are effluxed from the cell by an as yet unidentified transporter. Conversion of extracellular heme to BV is dependent solely on the iron-regulated HemO as evidenced by the lack of BV production in the P. aeruginosa hemO deletion strain. Complementation of P. aeruginosa DeltahemO with a plasmid expressing either the wild type HemO or alpha regioselective HemO mutant restored extracellular heme uptake and degradation. In contrast deletion of the gene encoding the cytoplasmic heme-binding protein, PhuS, homologs of which have been proposed to be heme oxygenases, did not eliminate (13)C-BV IXdelta and IXbeta production. In conclusion the metabolic flux of extracellular heme as a source of iron is driven by the catalytic action of HemO. PMID- 22493497 TI - Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9). AB - The epithelial Na(+) channel (ENaC) is critical for Na(+) homeostasis and blood pressure control. Defects in its regulation cause inherited forms of hypertension and hypotension. Previous work found that ENaC gating is regulated by proteases through cleavage of the extracellular domains of the alpha and gamma subunits. Here we tested the hypothesis that ENaC is regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9), a protease that modulates the risk of cardiovascular disease. PCSK9 reduced ENaC current in Xenopus oocytes and in epithelia. This occurred through a decrease in ENaC protein at the cell surface and in the total cellular pool, an effect that did not require the catalytic activity of PCSK9. PCSK9 interacted with all three ENaC subunits and decreased their trafficking to the cell surface by increasing proteasomal degradation. In contrast to its previously reported effects on the LDL receptor, PCSK9 did not alter ENaC endocytosis or degradation of the pool of ENaC at the cell surface. These results support a role for PCSK9 in the regulation of ENaC trafficking in the biosynthetic pathway, likely by increasing endoplasmic reticulum-associated degradation. By reducing ENaC channel number, PCSK9 could modulate epithelial Na(+) absorption, a major contributor to blood pressure control. PMID- 22493499 TI - Receptor signaling lymphocyte-activation molecule family 1 (Slamf1) regulates membrane fusion and NADPH oxidase 2 (NOX2) activity by recruiting a Beclin 1/Vps34/ultraviolet radiation resistance-associated gene (UVRAG) complex. AB - Phagocytosis is a pivotal process by which macrophages eliminate microorganisms upon recognition by pathogen sensors. Surprisingly, the self-ligand cell surface receptor Slamf1 functions not only as a co-stimulatory molecule but also as a microbial sensor of several Gram-negative bacteria. Upon entering the phagosome of macrophages Slamf1 induces production of phosphatidylinositol 3-phosphate, which positively regulates the activity of the NOX2 enzyme and phagolysosomal maturation. Here, we report that in Escherichia coli-containing phagosomes of mouse macrophages, Slamf1 interacts with the class III PI3K Vps34 in a complex with Beclin-1 and UVRAG. Upon phagocytosis of bacteria the NOX2 activity was reduced in macrophages isolated from Beclin-1(+/-) mice compared with wild-type mice. This Slamf1/Beclin-1/Vps34/UVRAG protein complex is formed in intracellular membrane compartments as it is found without inducing phagocytosis in macrophages, human chronic lymphocytic leukemia cells, and transfectant HEK293 cells. Elimination of its cytoplasmic tail abolished the interaction of Slamf1 with the complex, but deletion or mutation of the two ITAM motifs did not. Both the BD and CCD domains of Beclin-1 were required for efficient binding to Slamf1. Because Slamf1 did not interact with Atg14L or Rubicon, which can also form a complex with Vps34 and Beclin-1, we conclude that Slamf1 recruits a subset of Vps34-associated proteins, which is involved in membrane fusion and NOX2 regulation. PMID- 22493500 TI - Structural evidence that colicin A protein binds to a novel binding site of TolA protein in Escherichia coli periplasm. AB - The Tol assembly of proteins is an interacting network of proteins located in the Escherichia coli cell envelope that transduces energy and contributes to cell integrity. TolA is central to this network linking the inner and outer membranes by interactions with TolQ, TolR, TolB, and Pal. Group A colicins, such as ColA, parasitize the Tol network through interactions with TolA and/or TolB to facilitate translocation through the cell envelope to reach their cytotoxic site of action. We have determined the first structure of the C-terminal domain of TolA (TolAIII) bound to an N-terminal ColA polypeptide (TA(53-107)). The interface region of the TA(53-107)-TolAIII complex consists of polar contacts linking residues Arg-92 to Arg-96 of ColA with residues Leu-375-Pro-380 of TolA, which constitutes a beta-strand addition commonly seen in more promiscuous protein-protein contacts. The interface region also includes three cation-pi interactions (Tyr-58-Lys-368, Tyr-90-Lys-379, Phe-94-Lys-396), which have not been observed in any other colicin-Tol protein complex. Mutagenesis of the interface residues of ColA or TolA revealed that the effect on the interaction was cumulative; single mutations of either partner had no effect on ColA activity, whereas mutations of three or more residues significantly reduced ColA activity. Mutagenesis of the aromatic ring component of the cation-pi interacting residues showed Tyr-58 of ColA to be essential for the stability of complex formation. TA(53-107) binds on the opposite side of TolAIII to that used by g3p, ColN, or TolB, illustrating the flexible nature of TolA as a periplasmic hub protein. PMID- 22493501 TI - Stretch-induced fetal type II cell differentiation is mediated via ErbB1-ErbB4 interactions. AB - Stretch-induced differentiation of lung fetal type II epithelial cells is mediated through EGFR (ErbB1) via release of HB-EGF and TGF-alpha ligands. Employing an EGFR knock-out mice model, we further investigated the role of the ErbB family of receptors in mechanotranduction during lung development. Deletion of EGFR prevented endogenous and mechanical stretch-induced type II cell differentiation via the ERK pathway, which was rescued by overexpression of a constitutively active MEK. Interestingly, the expression of ErbB4, the only ErbB receptor that EGFR co-precipitates in wild-type cells, was decreased in EGFR deficient type II cells. Similar to EGFR, ErbB4 was activated by stretch and participated in ERK phosphorylation and type II cell differentiation. However, neuregulin (NRG) or stretch-induced ErbB4 activation were blunted in EGFR deficient cells and not rescued after ErbB4 overexpression, suggesting that induction of ErbB4 phosphorylation is EGFR-dependent. Finally, we addressed how shedding of ligands is regulated by EGFR. In knock-out cells, TGF-alpha, a ligand for EGFR, was not released by stretch, while HB-EGF, a ligand for EGFR and ErbB4, was shed by stretch although to a lower magnitude than in normal cells. Release of these ligands was inhibited by blocking EGFR and ERK pathway. In conclusion, our studies show that EGFR and ErbB4 regulate stretch-induced type II cell differentiation via ERK pathway. Interactions between these two receptors are important for mechanical signals in lung fetal type II cells. These studies provide novel insights into the cell signaling mechanisms regulating ErbB family receptors in lung cell differentiation. PMID- 22493502 TI - Carrier subunit of plasma membrane transporter is required for oxidative folding of its helper subunit. AB - We study the amino acid transport system b(0,+) as a model for folding, assembly, and early traffic of membrane protein complexes. System b(0,+) is made of two disulfide-linked membrane subunits: the carrier, b(0,+) amino acid transporter (b(0,+)AT), a polytopic protein, and the helper, related to b(0,+) amino acid transporter (rBAT), a type II glycoprotein. rBAT ectodomain mutants display folding/trafficking defects that lead to type I cystinuria. Here we show that, in the presence of b(0,+)AT, three disulfides were formed in the rBAT ectodomain. Disulfides Cys-242-Cys-273 and Cys-571-Cys-666 were essential for biogenesis. Cys 673-Cys-685 was dispensable, but the single mutants C673S, and C685S showed compromised stability and trafficking. Cys-242-Cys-273 likely was the first disulfide to form, and unpaired Cys-242 or Cys-273 disrupted oxidative folding. Strikingly, unassembled rBAT was found as an ensemble of different redox species, mainly monomeric. The ensemble did not change upon inhibition of rBAT degradation. Overall, these results indicated a b(0,+)AT-dependent oxidative folding of the rBAT ectodomain, with the initial and probably cotranslational formation of Cys-242-Cys-273, followed by the oxidation of Cys-571-Cys-666 and Cys-673-Cys-685, that was completed posttranslationally. PMID- 22493503 TI - Estradiol protects dermal hyaluronan/versican matrix during photoaging by release of epidermal growth factor from keratinocytes. AB - Hyaluronan (HA) and versican are key components of the dermis and are responsive to ultraviolet (UV)B-induced remodeling. The aim of this study was to explore the molecular mechanisms mediating the effects of estrogen (E(2)) on HA-rich extracellular matrix during photoaging. Hairless skh-1 mice were irradiated with UVB (three times, 1 minimal erythema dose (80 mJ/cm(2)), weekly) for 10 weeks, and endogenous sex hormone production was abrogated by ovariectomy. Subcutaneous substitution of E(2) by means of controlled-release pellets caused a strong increase in the dermal HA content in both irradiated and nonirradiated skin. The increase in dermal HA correlated with induction of HA synthase HAS3 by E(2). Expression of splice variant 2 of the HA-binding proteoglycan versican was also increased by E(2). In search of candidate mediators of these effects, it was found that E(2) strongly induced the expression of epidermal growth factor (EGF) in UVB-irradiated epidermis in vivo and in keratinocytes in vitro. EGF in turn up regulated the expression of HAS3 and versican V2 in dermal fibroblasts. HAS3 knockdown by shRNA caused inhibition of fibroblast proliferation. Furthermore, HAS3 and versican V2 induction by E(2) correlated positively with proliferation in vivo. In addition, the accumulation of inflammatory macrophages, expression of inducible cyclooxygenase 2, as well as proinflammatory monocyte chemotactic protein 1 were decreased in response to E(2) in the dermis. Collectively, these data suggest that E(2) treatment increases the amount of dermal HA and versican V2 via paracrine release of EGF, which may be implicated in the pro-proliferative and anti-inflammatory effects of E(2) during photoaging. PMID- 22493504 TI - The epidermal basement membrane is a composite of separate laminin- or collagen IV-containing networks connected by aggregated perlecan, but not by nidogens. AB - The basement membrane between the epidermis and the dermis is indispensable for normal skin functions. It connects, and functionally separates, the epidermis and the dermis. To understand the suprastructural and functional basis of these connections, heterotypic supramolecular aggregates were isolated from the dermal epidermal junction zone of human skin. Individual suprastructures were separated and purified by immunomagnetic beads, each recognizing a specific, molecular component of the aggregates. The molecular compositions of the suprastructures were determined by immunogold electron microscopy and immunoblotting. A composite of two networks was obtained from fibril-free suspensions by immunobeads recognizing either laminin 332 or collagen IV. After removal of perlecan containing suprastructures or after enzyme digestion of heparan sulfate chains, a distinct network with a diffuse electron-optical appearance was isolated with magnetic beads coated with antibodies to collagen IV. The second network was more finely grained and comprised laminin 332 and laminins with alpha5-chains. The core protein of perlecan was an exclusive component of this network whereas its heparan sulfate chains were integrated into the collagen IV-containing network. Nidogens 1 and 2 occurred in both networks but did not form strong molecular cross-bridges. Their incorporation into one network appeared to be masked after their incorporation into the other one. We conclude that the epidermal basement membrane is a composite of two structurally independent networks that are tightly connected in a spot-welding-like manner by perlecan-containing aggregates. PMID- 22493505 TI - N-methyl-D-aspartate (NMDA) receptor composition modulates dendritic spine morphology in striatal medium spiny neurons. AB - Dendritic spines of medium spiny neurons represent an essential site of information processing between NMDA and dopamine receptors in striatum. Even if activation of NMDA receptors in the striatum has important implications for synaptic plasticity and disease states, the contribution of specific NMDA receptor subunits still remains to be elucidated. Here, we show that treatment of corticostriatal slices with NR2A antagonist NVP-AAM077 or with NR2A blocking peptide induces a significant increase of spine head width. Sustained treatment with D1 receptor agonist (SKF38393) leads to a significant decrease of NR2A containing NMDA receptors and to a concomitant increase of spine head width. Interestingly, co-treatment of corticostriatal slices with NR2A antagonist (NVP AAM077) and D1 receptor agonist augmented the increase of dendritic spine head width as obtained with SKF38393. Conversely, NR2B antagonist (ifenprodil) blocked any morphological effect induced by D1 activation. These results indicate that alteration of NMDA receptor composition at the corticostriatal synapse contributes not only to the clinical features of disease states such as experimental parkinsonism but leads also to a functional and morphological outcome in dendritic spines of medium spiny neurons. PMID- 22493506 TI - Cardiomyocyte specific deficiency of serine palmitoyltransferase subunit 2 reduces ceramide but leads to cardiac dysfunction. AB - The role of serine palmitoyltransferase (SPT) and de novo ceramide biosynthesis in cardiac ceramide and sphingomyelin metabolism is unclear. To determine whether the de novo synthetic pathways, rather than ceramide uptake from circulating lipoproteins, is important for heart ceramide levels, we created cardiomyocyte specific deficiency of Sptlc2, a subunit of SPT. Heart-specific Sptlc2-deficient (hSptlc2 KO) mice had a >35% reduction in ceramide, which was limited to C18:0 and very long chain ceramides. Sphingomyelinase expression, and levels of sphingomyelin and diacylglycerol were unchanged. But surprisingly phospholipids and acyl CoAs contained increased saturated long chain fatty acids. hSptlc2 KO mice had decreased fractional shortening and thinning of the cardiac wall. While the genes regulating glucose and fatty acid metabolism were not changed, expression of cardiac failure markers and the genes involved in the formation of extracellular matrices were up-regulated in hSptlc2 KO hearts. In addition, ER stress markers were up-regulated leading to increased apoptosis. These results suggest that Sptlc2-mediated de novo ceramide synthesis is an essential source of C18:0 and very long chain, but not of shorter chain, ceramides in the heart. Changes in heart lipids other than ceramide levels lead to cardiac toxicity. PMID- 22493507 TI - Peroxisomal fatty acid uptake mechanism in Saccharomyces cerevisiae. AB - Peroxisomes play a major role in human cellular lipid metabolism, including fatty acid beta-oxidation. The most frequent peroxisomal disorder is X-linked adrenoleukodystrophy, which is caused by mutations in ABCD1. The biochemical hallmark of X-linked adrenoleukodystrophy is the accumulation of very long chain fatty acids (VLCFAs) due to impaired peroxisomal beta-oxidation. Although this suggests a role of ABCD1 in VLCFA import into peroxisomes, no direct experimental evidence is available to substantiate this. To unravel the mechanism of peroxisomal VLCFA transport, we use Saccharomyces cerevisiae as a model organism. Here we provide evidence that in this organism very long chain acyl-CoA esters are hydrolyzed by the Pxa1p-Pxa2p complex prior to the actual transport of their fatty acid moiety into the peroxisomes with the CoA presumably being released into the cytoplasm. The Pxa1p-Pxa2p complex functionally interacts with the acyl CoA synthetases Faa2p and/or Fat1p on the inner surface of the peroxisomal membrane for subsequent re-esterification of the VLCFAs. Importantly, the Pxa1p Pxa2p complex shares this molecular mechanism with HsABCD1 and HsABCD2. PMID- 22493508 TI - Tudor staphylococcal nuclease (Tudor-SN) participates in small ribonucleoprotein (snRNP) assembly via interacting with symmetrically dimethylated Sm proteins. AB - Human Tudor staphylococcal nuclease (Tudor-SN) is composed of four tandem repeats of staphylococcal nuclease (SN)-like domains, followed by a tudor and SN-like domain (TSN) consisting of a central tudor flanked by two partial SN-like sequences. The crystal structure of the tudor domain displays a conserved aromatic cage, which is predicted to hook methyl groups. Here, we demonstrated that the TSN domain of Tudor-SN binds to symmetrically dimethylarginine (sDMA) modified SmB/B' and SmD1/D3 core proteins of the spliceosome. We demonstrated that this interaction ability is reduced by the methyltransferase inhibitor 5 deoxy-5-(methylthio)adenosine. Mutagenesis experiments indicated that the conserved amino acids (Phe-715, Tyr-721, Tyr-738, and Tyr-741) in the methyl binding cage of the TSN domain are required for Tudor-SN-SmB interaction. Furthermore, depletion of Tudor-SN affects the association of Sm protein with snRNAs and, as a result, inhibits the assembly of uridine-rich small ribonucleoprotein mediated by the Sm core complex in vivo. Our results reveal the molecular basis for the involvement of Tudor-SN in regulating small nuclear ribonucleoprotein biogenesis, which provides novel insight related to the biological activity of Tudor-SN. PMID- 22493509 TI - Circadian autodephosphorylation of cyanobacterial clock protein KaiC occurs via formation of ATP as intermediate. AB - The cyanobacterial circadian oscillator can be reconstituted in vitro; mixing three clock proteins (KaiA, KaiB, and KaiC) with ATP results in an oscillation of KaiC phosphorylation with a periodicity of ~24 h. The hexameric ATPase KaiC hydrolyzes ATP bound at subunit interfaces. KaiC also exhibits autokinase and autophosphatase activities, the latter of which is particularly noteworthy because KaiC is phylogenetically distinct from typical protein phosphatases. To examine this activity, we performed autodephosphorylation assays using (32)P labeled KaiC. The residual radioactive ATP bound to subunit interfaces was removed using a newly established method, which included the dissociation of KaiC hexamers into monomers and the reconstitution of KaiC hexamers with nonradioactive ATP. This approach ensured that only the signals derived from (32)P-labeled KaiC were examined. We detected the transient formation of [(32)P]ATP preceding the accumulation of (32)P(i). Together with kinetic analyses, our data demonstrate that KaiC undergoes dephosphorylation via a mechanism that differs from those of conventional protein phosphatases. A phosphate group at a phosphorylation site is first transferred to KaiC-bound ADP to form ATP as an intermediate, which can be regarded as a reversal of the autophosphorylation reaction. Subsequently, the ATP molecule is hydrolyzed to form P(i). We propose that the ATPase active site mediates not only ATP hydrolysis but also the bidirectional transfer of the phosphate between phosphorylation sites and the KaiC-bound nucleotide. On the basis of these findings, we can now dissect the dynamics of the KaiC phosphorylation cycle relative to ATPase activity. PMID- 22493510 TI - Receptor for advanced glycation end products (RAGE) functions as receptor for specific sulfated glycosaminoglycans, and anti-RAGE antibody or sulfated glycosaminoglycans delivered in vivo inhibit pulmonary metastasis of tumor cells. AB - Altered expression of chondroitin sulfate (CS) and heparan sulfate (HS) at the surfaces of tumor cells plays a key role in malignant transformation and tumor metastasis. Previously we demonstrated that a Lewis lung carcinoma (LLC)-derived tumor cell line with high metastatic potential had a higher proportion of E disaccharide units, GlcUA-GalNAc(4,6-O-disulfate), in CS chains than low metastatic LLC cells and that such CS chains are involved in the metastatic process. The metastasis was markedly inhibited by the pre-administration of CS-E from squid cartilage rich in E units or by preincubation with a phage display antibody specific for CS-E. However, the molecular mechanism of the inhibition remains to be investigated. In this study the receptor molecule for CS chains containing E-disaccharides expressed on LLC cells was revealed to be receptor for advanced glycation end products (RAGE), which is a member of the immunoglobulin superfamily predominantly expressed in the lung. Interestingly, RAGE bound strongly to not only E-disaccharide, but also HS-expressing LLC cells. Furthermore, the colonization of the lungs by LLC cells was effectively inhibited by the blocking of CS or HS chains at the tumor cell surface with an anti-RAGE antibody through intravenous injections in a dose-dependent manner. These results provide the clear evidence that RAGE is at least one of the critical receptors for CS and HS chains expressed at the tumor cell surface and involved in experimental lung metastasis and that CS/HS and RAGE are potential molecular targets in the treatment of pulmonary metastasis. PMID- 22493511 TI - Quantitative proteomic analysis of eight cartilaginous tissues reveals characteristic differences as well as similarities between subgroups. AB - Human synovial joints display a characteristic anatomic distribution of arthritis, e.g. rheumatoid arthritis primarily affects the metacarpophalangeal and proximal finger joints, but rarely the distal finger joints, whereas osteoarthritis occurs in the distal and proximal finger joints. Pelvospondylitis has a selective localization to the spine and sacroiliac joints. Is this tropism due to differences between the cartilages at the molecular level? To substantiate this concept the present study provides a background detailed compositional analysis by relative quantification of extracellular matrix proteins in articular cartilages, meniscus, intervertebral disc, rib, and tracheal cartilages on samples from 5-6 different individuals using an optimized approach for proteomics. Tissue extraction followed by trypsin digestion and two-dimensional LC separations coupled to tandem mass spectrometry, relative quantification with isobaric labeling, iTRAQ(TM), was used to compare the relative abundance of about 150 proteins. There were clear differences in protein patterns between different kinds of cartilages. Matrilin-1 and epiphycan were specific for rib and trachea, whereas asporin was particularly abundant in the meniscus. Interestingly, lubricin was prominent in the intervertebral disc, especially in the nucleus pulposus. Fibromodulin and lumican showed distributions that were mirror images of one other. Analyses of the insoluble residues from guanidine extraction revealed that a fraction of several proteins remained unextracted, e.g. asporin, CILP, and COMP, indicating cross-linking. Distinct differences in protein patterns may relate to different tissue mechanical properties, and to the intriguing tropism in different patterns of joint pathology. PMID- 22493512 TI - Serglycin proteoglycan promotes apoptotic versus necrotic cell death in mast cells. AB - The mechanisms that govern whether a cell dies by apoptosis or necrosis are not fully understood. Here we show that serglycin, a secretory granule proteoglycan of hematopoietic cells, can have a major impact on this decision. Wild type and serglycin(-/-) mast cells were equally sensitive to a range of cell death inducing regimens. However, whereas wild type mast cells underwent apoptotic cell death, serglycin(-/-) cells died predominantly by necrosis. Investigations of the underlying mechanism revealed that cell death was accompanied by leakage of secretory granule compounds into the cytosol and that the necrotic phenotype of serglycin(-/-) mast cells was linked to defective degradation of poly(ADP-ribose) polymerase-1. Cells lacking mouse mast cell protease 6, a major serglycin associated protease, exhibited similar defects in apoptosis as observed in serglycin(-/-) cells, indicating that the pro-apoptotic function of serglycin is due to downstream effects of proteases that are complex-bound to serglycin. Together, these findings implicate serglycin in promoting apoptotic versus necrotic cell death. PMID- 22493513 TI - Association of serum 25-hydroxyvitamin D3 and D2 with academic performance in childhood: findings from a prospective birth cohort. AB - BACKGROUND: Higher total serum 25-hydroxyvitamin D (25(OH)D) concentrations have been associated with better cognitive function mainly in cross-sectional studies in adults. It is unknown if the associations of different forms of 25(OH)D (25(OH)D(3) and 25(OH)D(2)) are similar. METHODS: Prospective cohort study (n=3171) with serum 25(OH)D(3) and 25(OH)D(2) concentrations measured at mean age of 9.8 years and academic performance at age 13-14 years (total scores in English, mathematics and science) and 15-16 years (performance in General Certificates of Education examinations). RESULTS: Serum 25(OH)D(3) concentrations were not associated with any educational outcomes. Higher 25(OH)D(2) concentrations were associated with worse performance in English at age 13-14 years (adjusted SD change per doubling in 25(OH)D(2) (95% CI) -0.05 (-0.08 to 0.01)) and with worse academic performance at age 15-16 years (adjusted OR for obtaining >=5 A*-C grades (95% CI) 0.91 (0.82 to 1.00)). CONCLUSION: The null findings with 25(OH)D(3) are in line with two previous cross-sectional studies in children. It is possible that the positive association of 25(OH)D with cognitive function seen in adults does not emerge until later in life or that the results from previous cross-sectional adult studies are due to reverse causality. The unexpected inverse association of 25(OH)D(2) with academic performance requires replication in further studies. Taken together, our findings do not support suggestions that children should have controlled exposure to sunlight, or vitamin D supplements, in order to increase academic performance. PMID- 22493514 TI - Dioxin silences gonadotropin expression in perinatal pups by inducing histone deacetylases: a new insight into the mechanism for the imprinting of sexual immaturity by dioxin. AB - Maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes the impairment of reproduction and development in the pups. Our previous studies have revealed that maternal treatment with TCDD attenuates the fetal production of pituitary gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone) at gestational day (GD) 20, leading to the impairment of sexual behavior in adulthood. However, the mechanism underlying such a reduction has remained unknown until now. When pregnant rats at GD15 were given an oral dose of TCDD (1 MUg/kg), the testicular expression of steroidogenic proteins was reduced between GD20 and postnatal days (PND) 2. In accordance with this, the pituitary expression of gonadotropin beta-subunit and serum gonadotropin were also attenuated from GD20 to PND0 in a pup-specific fashion. To identify the target genes linked to a fetal reduction in gonadotropin beta-subunit, we performed a DNA microarray analysis using the fetal pituitary and its regulatory organ, the hypothalamus. The results obtained showed that TCDD induced histone deacetylases (HDACs) in the fetal pituitary. In support with this, TCDD markedly deacetylated histones H3 and H4 twined around the promoter of the fetal LHbeta gene. This effect was fetus- and LHbeta-specific, and this was not observed in the maternal pituitary or for other pituitary hormone genes. Finally, an LHbeta reduction caused by TCDD was completely restored by maternal co-treatment with valproic acid, an HDAC inhibitor. These results strongly suggest that the increased deacetylation of histone owing to HDAC induction plays a critical role in the TCDD-induced reduction in LHbeta in the fetal pituitary. PMID- 22493515 TI - A conserved function for the H2A.Z C terminus. AB - Histone H2A variants generate diversity in chromatin structure and functions, as nucleosomes containing variant H2A histones have altered physical, chemical, and biological properties. H2A.Z is an evolutionarily ancient and highly conserved H2A variant that regulates processes ranging from gene expression to the DNA damage response. Here we find that the unstructured portion of the C-terminal tail of H2A.Z is required for the normal functions of this histone variant in budding yeast. We have also identified a novel splice isoform of the human H2A.Z 2 gene that encodes a C-terminally truncated H2A.Z protein that is similar to the truncation mutants we identified in yeast. The short forms of H2A.Z in both yeast and human cells are more loosely associated with chromatin than the full-length proteins, indicating a conserved function for the H2A.Z C-terminal tail in regulating the association of H2A.Z with nucleosomes. PMID- 22493516 TI - Proinflammatory cytokine signaling required for the generation of natural killer cell memory. AB - Although natural killer (NK) cells are classified as innate immune cells, recent studies demonstrate that NK cells can become long-lived memory cells and contribute to secondary immune responses. The precise signals that promote generation of long-lived memory NK cells are unknown. Using cytokine receptor deficient mice, we show that interleukin-12 (IL-12) is indispensible for mouse cytomegalovirus (MCMV)-specific NK cell expansion and generation of memory NK cells. In contrast to wild-type NK cells that proliferated robustly and resided in lymphoid and nonlymphoid tissues for months after MCMV infection, IL-12 receptor-deficient NK cells failed to expand and were unable to mediate protection after MCMV challenge. We further demonstrate that a STAT4-dependent IFN-gamma-independent mechanism contributes toward the generation of memory NK cells during MCMV infection. Understanding the full contribution of inflammatory cytokine signaling to the NK cell response against viral infection will be of interest for the development of vaccines and therapeutics. PMID- 22493517 TI - Expansion of somatically reverted memory CD8+ T cells in patients with X-linked lymphoproliferative disease caused by selective pressure from Epstein-Barr virus. AB - Patients with the primary immunodeficiency X-linked lymphoproliferative disease (XLP), which is caused by mutations in SH2D1A, are highly susceptible to Epstein Barr virus (EBV) infection. Nonetheless, some XLP patients demonstrate less severe clinical manifestations after primary infection. SH2D1A encodes the adaptor molecule SLAM-associated protein (SAP), which is expressed in T and natural killer cells and is required for cytotoxicity against B cells, the reservoir for EBV. It is not known why the clinical presentation of XLP is so variable. In this study, we report for the first time the occurrence of somatic reversion in XLP. Reverted SAP-expressing cells resided exclusively within the CD8(+) T cell subset, displayed a CD45RA(-)CCR7(-) effector memory phenotype, and were maintained at a stable level over time. Importantly, revertant CD8(+) SAP(+) T cells, but not SAP(-) cells, proliferated in response to EBV and killed EBV infected B cells. As somatic reversion correlated with EBV infection, we propose that the virus exerts a selective pressure on the reverted cells, resulting in their expansion in vivo and host protection against ongoing infection. PMID- 22493518 TI - Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis. AB - Rheumatoid arthritis is a destructive arthropathy characterized by chronic synovial inflammation that imposes a substantial socioeconomic burden. Under the influence of the proinflammatory milieu, synovial fibroblasts (SFs), the main effector cells in disease pathogenesis, become activated and hyperplastic, releasing proinflammatory factors and tissue-remodeling enzymes. This study shows that activated arthritic SFs from human patients and animal models express significant quantities of autotaxin (ATX; ENPP2), a lysophospholipase D that catalyzes the conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA). ATX expression from SFs was induced by TNF, and LPA induced SF activation and effector functions in synergy with TNF. Conditional genetic ablation of ATX in mesenchymal cells, including SFs, resulted in disease attenuation in animal models of arthritis, establishing the ATX/LPA axis as a novel player in chronic inflammation and the pathogenesis of arthritis and a promising therapeutic target. PMID- 22493519 TI - Xenobiotic sensing and signalling in higher plants. AB - Anthropogenic changes and chemical pollution confront plant communities with various xenobiotic compounds or combinations of xenobiotics, involving chemical structures that are at least partially novel for plant species. Plant responses to chemical challenges and stimuli are usually characterized by the approaches of toxicology, ecotoxicology, and stress physiology. Development of transcriptomics and proteomics analysis has demonstrated the importance of modifications to gene expression in plant responses to xenobiotics. It has emerged that xenobiotic effects could involve not only biochemical and physiological disruption, but also the disruption of signalling pathways. Moreover, mutations affecting sensing and signalling pathways result in modifications of responses to xenobiotics, thus confirming interference or crosstalk between xenobiotic effects and signalling pathways. Some of these changes at gene expression, regulation and signalling levels suggest various mechanisms of xenobiotic sensing in higher plants, in accordance with xenobiotic-sensing mechanisms that have been characterized in other phyla (yeast, invertebrates, vertebrates). In higher plants, such sensing systems are difficult to identify, even though different lines of evidence, involving mutant studies, transcription factor analysis, or comparative studies, point to their existence. It remains difficult to distinguish between the hypothesis of direct xenobiotic sensing and indirect sensing of xenobiotic related modifications. However, future characterization of xenobiotic sensing and signalling in higher plants is likely to be a key element for determining the tolerance and remediation capacities of plant species. This characterization will also be of interest for understanding evolutionary dynamics of stress adaptation and mechanisms of adaptation to novel stressors. PMID- 22493520 TI - Sleep Disturbance in Bipolar Disorder Across the Lifespan. AB - The aim of this article is to highlight the importance of the sleep-wake cycle in children, adolescents, and adults with bipolar disorder. After reviewing the evidence that has accrued to date on the nature and severity of the sleep disturbance experienced, we document the importance of sleep for quality of life, risk for relapse, affective functioning, cognitive functioning, health (sleep disturbance is implicated in obesity, poor diet, and inadequate exercise), impulsivity, and risk taking. We argue that sleep may be critically important in the complex multifactorial cause of interepisode dysfunction, adverse health outcomes, and relapse. An agenda for future research is presented that includes improving the quality of sleep measures and controlling for the impact of bipolar medications. PMID- 22493521 TI - Prediction of the three-dimensional structure of serine/threonine protein kinase pto of Solanum lycopersicum by homology modelling. AB - The resistant gene Pto of Solanum lycopersicum interacts with the avr Pto gene product of the bacterial pathogen Pseudomonas syringae pv tomato to launch a cascade of molecular events that triggers the hypersensitive disease-resistance response in tamato. The paper describes attempts to predict the structure of Pto encoding a serine/threonine protein kinase to understand the mechanism and function. A three-dimensional model based on the crystal structure of effect protein Avr ptob complexed with Kinase Pto and bacterial effector protein Avrpto was generated using Modeller9v7. We adopted different modelling approaches for our study, Intialy, we generated a model based on a single template protein and then a model based on multiple templates. The models generated through these approaches were further assessed with ANOLEA energy assessment, Ram Page server and PROCHECK for stereochemistry and geometry check. Comparative analysis suggested that the model generated was better than the templates. This study paves the way for generating computer molecular models for proteins whose crystal structures are not available and which would aid in studying protein-protein interactions. PMID- 22493522 TI - Molecular docking studies of banana flower flavonoids as insulin receptor tyrosine kinase activators as a cure for diabetes mellitus. AB - Diabetes mellitus is a metabolic disorder caused due to insulin deficiency. Banana flower is a rich source of flavonoids that exhibit anti diabetic activity. Insulin receptor is a tetramer that belongs to a family of receptor tyrosine kinases. It contains two alpha subunits that form the extracellular domain and two beta subunits that constitute the intracellular tyrosine kinase domain. Insulin binds to the extracellular region of the receptor and causes conformational changes that lead to the activation of the tyrosine kinase. This leads to autophosphorylation, a step that is crucial in insulin signaling pathway. Hence, compounds that augment insulin receptor tyrosine kinase activity would be useful in the treatment of diabetes mellitus. The 3D structure of IR tyrosine kinase was obtained from PDB database. The list of flavonoids found in banana flower was obtained from USDA database. The structures of the flavonoids were obtained from NCBI Pubchem. Docking analysis of the flavonoids was performed using Autodock 4.0 and Autodock Vina. The results indicate that few of the flavonoids may be potential activators of IR tyrosine kinase. PMID- 22493523 TI - Abberent expression analysis of LMNA gene in hutchinson-gilford progeria syndrome. AB - Hutchinson-Gilford progeria syndrome (HGPS) is caused by de novo dominant point mutations of the genes encoding nuclear lamina proteins, leading towards premature aging. A protein sequence is subjected to mutations in nature which can affect the function and folding pattern of the protein by different ways. Mutations involved in HGPS were identified and were substituted in the seed sequence retrieved from the UniProt database to get the mutated versions. Tertiary structure of the Lamin A protein was previously unpredicted so was performed for all the mutated as well as for the seed protein to analyze the effects of mutations on the protein structure, folding and interactions. All the predicted models were refined and validated through multiple servers for multiple parameters. The validated 3D structure of seed protein was then successfully submitted to the Protein Model Database and was assigned with the PMDB ID PM0077829. All the predicted structures were superimposed with a root mean square deviation value of 7.0 A and a high Dali Z-score of 1.9. It was observed that mutations affected physiochemical properties as well as instability index and thus is affecting the domains in specific and the whole structure in general. It was further analyzed that HGPS is the result of affected Lamin a protein interactions with other integral and binding proteins in the inner nuclear membrane affecting the link in between the nuclear membrane and the network of the lamina. PMID- 22493524 TI - Optimization of DNA extraction from seeds and leaf tissues of Chrysanthemum (Chrysanthemum indicum) for polymerase chain reaction. AB - Chrysanthemums constitute approximately 30 species of perennial flowering plants, belonging to the family Asteraceae, native to Asia and Northeastern Europe. Chrysanthemum is a natural cosmetic additive extracted from Chinese herb by modern biochemical technology. It has the properties of anti-bacterial, anti viral, reducing (detoxification) and anti-inflammation. It possesses antioxidant characteristics, which could assist in minimizing free-radical induced damage. Therefore, it is widely used in skin and hair care products. Chemical composition of this herbal remedy includes kikkanols, sesquiterpenes, flavonoids, various essential oils containing camphor, cineole, sabinol, borneole and other elements that interfere with DNA, causing erroneous or no PCR products. In the present study, testing and modification of various standard protocols for isolation of high-quality DNA from leaf tissues and seeds of C. indicum was done. It was observed that the DNA obtained from seeds and leaf tissues with a modified cetyltrimethylammonium bromide buffer protocol was of good quality, with no colored pigments and contaminants. Also, DNA could be extracted from leaf tissues without using liquid nitrogen. Quality of DNA extracted from seeds was much better as compared to that extracted from leaf tissues. The extracted DNA was successfully amplified by PCR using arbitrary RAPD primers. The same protocol will probably be useful for extraction of high-molecular weight DNA from other plant materials containing large amounts of secondary metabolites and essential oils. PMID- 22493525 TI - Atherogenic effect of Arecoline: A computational study. AB - There are over 600 million people worldwide covering Asian and Oceanic countries including India have the habit of chewing areca nut as masticator in different forms. Arecoline (C(8)H(13)NO(2)) has been reported as one of the abundant constituents of areca nut. A good number of scientific publications have made Arecoline responsible for oral cancer. Based on observation from clinical situation in North East India, one of the most betel quid chewing region of the country, we suspected a link between consumption of areca nut and Cerebro Vascular Disease like stroke. Therefore, we considered Low Density Lipoprotein (LDL) receptor as target and Arecoline as ligand and studied ligand -target interaction using computational tools. Also we considered High Density Lipoprotein (HDL) receptor as another target to see if Arecoline has any binding potential with it over and above LDL receptor. Docking result indicated that Arecoline and Cholesterol both, have affinity towards extracellular domain of Human LDL receptor but affinity of Arecoline is much higher (-12.3560.) than that of Cholesterol(-0.1810). Docking of Arecoline and 1, 2-Hexyl-1- cyclopentanone thiosemicarbazone (thiosemicarbazone) with Bovine HDL receptor showed that Arecoline also has the potential (Score, -6.2690Kcal/Mol) to block HDL receptor though its potential is less than that (score, -10.0509 Kcal/Mol) of control (thiosemicarbazone). We, therefore, suggest that by inhibiting endocytosis of LDL cholesterol because of blocking LDL receptor function and also by preventing LDL cholesterol uptake by liver from blood because of interference with HDL receptor, Arecoline may contribute to atherosclerosis. The study therefore, indicates a positive correlation between chewing of betel quid and Cerebro Vascular Disease. PMID- 22493526 TI - IntDb: A comprehensive database for classified introns of saccharomyces & human. AB - Introns (intra-genic) are non-coding regions of several eukaryotic genes. However, their role in regulation of transcription, embryonic development, stimulate gene (HEG) is apparent in recent years. Thus current research focuses on mutation in introns and their influence in causing various diseases. Though many available intron databases like YIDB, IDB, ExInt, GISSD, FUGOID, etc. discusses on various aspects of introns but none of them have classified the introns where identification of start intron is found to be important which mainly regulates the various activities of protein at gene level. This lead to an idea for development of "Intdb"; a database meant for classifying introns as start, middle and stop on the basis of position of specific consensus site. Information provided in IntDb is useful for gene prediction, determination of splicing sites and identification of diseases. In addition, the main focus is on violation of consensus rule and frequency of other deviations observed in classified introns. Further, GC content, length variations according to the biased residues and occurrence of consensus pattern to discover potential role of introns is also emphasized in IntDb. AVAILABILITY: The database is available for free at http://introndb.bicpu.edu.in/ PMID- 22493527 TI - Cell-culture Database: Literature-based reference tool for human and mammalian experimentallybased cell culture applications. AB - Cultivation of primary cells is essential for biotechnological research and viral vaccine production. Significant advances in cell and tissue culture, more specifically, advances in the transfection and transduction of human and mammalian cells, has directly led to giant leaps forward in fields such as cancer research, genetics, and public health. At the same time, a corresponding increase has been seen in available cell culture related literature. Often times, due to the sheer number and degree of variability of available literature, it is a challenge to find specific, yet practical cell culture related information.To respond to this rising tide of information, a practical, user-friendly database containing cell-lines, plasmids, vectors, selection agents, concentrations and media was created. The database currently consists of over 3,900 cell lines (Human and Mammalian) and 1,900 plasmids/vectors collected from 2,700 pieces of published literature. The database is continually being expanded and it is hoped that through the continual addition of unique data, the database can further serve and enrich the work of cell and molecular biologists, life-science professionals, and the worldwide scientific community at large. AVAILABILITY: The database is available for free at http://cell-lines.toku-e.com/ PMID- 22493528 TI - Distribution of biological databases over lowbandwidth networks. AB - Databases are integral part of bioinformatics and need to be accessed most frequently, thus downloading and updating them on a regular basis is very critical. The establishment of bioinformatics research facility is a challenge for developing countries as they suffer from inherent low-bandwidth and unreliable internet connections. Therefore, the identification of techniques supporting download and automatic synchronization of large biological database at low bandwidth is of utmost importance. In current study, two protocols (FTP and Bit Torrent) were evaluated and the utility of a BitTorren based peer-to-peer (btP2P) file distribution model for automatic synchronization and distribution of large dataset at our facility in Pakistan have been discussed. PMID- 22493529 TI - Gene Locater: Genetic linkage analysis software using three-point testcross. AB - Locating genes on a chromosome is important for understanding the gene function and its linkage and recombination. Knowledge of gene positions on chromosomes is necessary for annotation. The study is essential for disease genetics and genomics, among other aspects. Currently available software's for calculating recombination frequency is mostly limited to the range and flexibility of this type of analysis. GENE LOCATER is a fully customizable program for calculating recombination frequency, written in JAVA. Through an easy-to-use interface, GENE LOCATOR allows users a high degree of flexibility in calculating genetic linkage and displaying linkage group. Among other features, this software enables user to identify linkage groups with output visualized graphically. The program calculates interference and coefficient of coincidence with elevated accuracy in sample datasets. AVAILABILITY: The database is available for free at http://www.moperandib.com. PMID- 22493530 TI - Comparative modeling of DszC, an enzyme in biodesulfurization, and performing in silico point mutation for increasing tendency to oil. AB - Desulfurization protein named DszC from Rhodococcus erythropolis is the key enzyme for biodesulforization of dibenzothiophene (DBT) in 4S pathway, which is a pathway with four enzymes. DszC enzyme biodesulfurizes DBT and its derivatives in oil components and biphasic systems. It functions well at the oil- water interface. In this study point mutation performed in DszC enzyme regarding to increase protein hydrophobicity and stability for application in immobilized form. 3D model of DszC predicted using Phyre2, SAM-T08 and M4t servers. I-Mutant 2 server used to determine potential spots for point mutation, and Molegro Virtual Docker (MVD) used for performing point mutation on 3D model. Hydrophobicity plots generated by Bioedit version 7.0.8.0 in Kyte-Doolittle scale indicated that protein hydrophobicity is increased after mutation. Also protein stability increased 26.11 units in scale of DDC2. PMID- 22493531 TI - Binding Energy calculation of GSK-3 protein of Human against some anti-diabetic compounds of Momordica charantia linn (Bitter melon). AB - Diabetes is one of the major life threatening diseases worldwide. It creates major health problems in urban India. Glycogen Synthase Kinase-3 (GSK-3) protein of human is known for phosphorylating and inactivating glycogen synthase which also acts as a negative regulator in the hormonal control of glucose homeostasis. In traditional medicine, Momordica charantia is used as antidiabetic plant because of its hypoglycemic effect. Hence to block the active site of the GSK-3 protein three anti-diabetic compounds namely, charantin, momordenol & momordicilin were taken from Momordica charantia for docking study and calculation of binding energy. The aim of present investigation is to find the binding energy of three major insulin-like active compounds against glycogen synthase kinase-3 (GSK-3), one of the key proteins involved in carbohydrate metabolism, with the help of molecular docking using ExomeTM Horizon suite. The study recorded minimum binding energy by momordicilin in comparison to the others. PMID- 22493532 TI - Microsatellite analysis in organelle genomes of Chlorophyta. AB - Simple Sequence Repeats (SSRs) or microsatellites constitute a significant portion of genomes however; their significance in organellar genomes has not been completely understood. The availability of organelle genome sequences allows us to understand the organization of SSRs in their genic and intergenic regions. In the present work, SSRs were identified and categorized in 14 mitochondrial and 22 chloroplast genomes of algal species belonging to Chlorophyta. Based on the study, it was observed that number of SSRs in non-coding region were more as compared to coding region and frequency of mononucleotides repeats were highest followed by dinucleotides in both mitochondrial and chloroplast genomes. It was also observed that maximum number of SSRs was found in genes encoding for beta subunit of RNA polymerase in chloroplast genomes and NADH dehydrogenase in mitochondrial genomes. This is the first and original report on whole genomes sequence analysis of organellar genomes of green algae. PMID- 22493533 TI - Mining for SSRs and FDMs from expressed sequence tags of Camellia sinensis. AB - Simple Sequence Repeats (SSRs) developed from Expressed Sequence Tags (ESTs), known as EST-SSRs are most widely used and potentially valuable source of gene based markers for their high levels of crosstaxon portability, rapid and less expensive development. The EST sequence information in the publicly available databases is increasing in a faster rate. The emerging computational approach provides a better alternative process of development of SSR markers from the ESTs than the conventional methods. In the present study, 12,851 EST sequences of Camellia sinensis, downloaded from National Center for Biotechnology Information (NCBI) were mined for the development of Microsatellites. 6148 (4779 singletons and 1369 contigs) non redundant EST sequences were found after preprocessing and assembly of these sequences using various computational tools. Out of total 3822.68 kb sequence examined, 1636 (26.61%) EST sequences containing 2371 SSRs were detected with a density of 1 SSR/1.61 kb leading to development of 245 primer pairs. These mined EST-SSR markers will help further in the study of variability, mapping, evolutionary relationship in Camellia sinensis. In addition, these developed SSRs can also be applied for various studies across species. PMID- 22493534 TI - Ty1-copia group retrotransposons and the evolution of retroelements in several angiosperm plants: evidence of horizontal transmission. AB - The phylogenetic relationships among thirty-seven new Ty1-copia group retrotransposons in seven angiosperm plants were examined by reverse transcriptase and ribonuclease H sequence analysis. Distribution pattern of the retrotransposons of closely related plant species generally reflects a close phylogenetic relationship. In contrast, we found that several retrotransposon sequences from the same genome exhibited a high degree of divergence and had a relatively high degree of identity versus retrotransposon sequences from widely divergent species, including an ancestral phytopathogen fungus. This finding supports the hypothesis that the horizontal transmission from phytopatogen organism to the host flowering plants could have played a role in the evolutionary dynamics of Ty1-copia group retrotransposons. PMID- 22493535 TI - Immunoinformatic evaluation of multiple epitope ensembles as vaccine candidates: E coli 536. AB - Epitope prediction is becoming a key tool for vaccine discovery. Prospective analysis of bacterial and viral genomes can identify antigenic epitopes encoded within individual genes that may act as effective vaccines against specific pathogens. Since B-cell epitope prediction remains unreliable, we concentrate on T-cell epitopes, peptides which bind with high affinity to Major Histacompatibility Complexes (MHC). In this report, we evaluate the veracity of identified T-cell epitope ensembles, as generated by a cascade of predictive algorithms (SignalP, Vaxijen, MHCPred, IDEB, EpiJen), as a candidate vaccine against the model pathogen uropathogenic gram negative bacteria Escherichia coli (E-coli) strain 536 (O6:K15:H31). An immunoinformatic approach was used to identify 23 epitopes within the E-coli proteome. These epitopes constitute the most promiscuous antigenic sequences that bind across more than one HLA allele with high affinity (IC50 < 50nM). The reliability of software programmes used, polymorphic nature of genes encoding MHC and what this means for population coverage of this potential vaccine are discussed. PMID- 22493536 TI - Exploring the role of BCHE in the onset of Diabetes, Obesity and Neurological Disorders. AB - Diabetes, Obesity and Neurological disturbances, most often show co-occurrence. There has been an extensive research in this domain, but the exact mechanism underlying the co-occurrence of the three conditions is still an enigma. The current paper is an approach to establish the role of Butyryl cholinesterase (BCHE) in Diabetes, Obesity and Neurological disorders by performing a comparative analysis with Neuroligin (NLGN2) a protein belonging to the same family. BCHE has its role in glucose regulation, Lipid metabolism and nerve signaling. Emphasis is laid on BCHE's diverse functions whose impediment affects the above mentioned metabolic pathways. Insilco techniques were employed to analyze the sequence, structural and functional similarities of the two proteins. A point mutation is focused which is common to both BCHE and Neuroligin. The mutation occurs at the homologous position in both the proteins making them deficient. This affects the three metabolic pathways leading to the respective disorders. The work describes the pathway that describes the role of BCHE in the onset of obesity mediated diabetes. The pathway further explains the association between Diabetes, Obesity and neurological disturbances. PMID- 22493537 TI - BacterialLectinDb: An integrated bacterial lectin database. AB - Studies of various diversified bacterial lectins/ lectin data may serve as a tool with enormous promise to help biotechnologists/ geneticists in their innovative technology to explore a deeper understanding in proteomics/ genomics research for finding the molecular basis of infectious diseases and also to new approaches for their prevention and in development of new bacterial vaccines. Hence we developed a bacterial lectin database named 'BacterialLectinDb'. An organized database schema for BacterialLectinDb was designed to collate all the available information about all bacterial lectins as a central repository. The database was designed using HTML, XML. AVAILABILITY: The database is available for free at http://www.research-bioinformatics.in. PMID- 22493538 TI - Ssa miRNAs DB: Online repository of in silico predicted miRNAs in Salmo salar. AB - The Atlantic salmon (Salmo salar) is a very valuable commercial salmonid species. As with other aquaculture species, intensive aquaculture of Atlantic salmon often faces disease problems especially in early life stages which can limit stable production of the species. 'Ssa miRNAs DB', a bioinformatics and manually curated database, aims at providing a comprehensive resource of microRNA in Altantic salmon, with a user friendly interface for a convenient retrieval of each entry by microRNA ID or target gene. The current version of Ssa miRNAs DB involved the prediction of 41 and 266 homologous and novel microRNAs, respectively. AVAILABILITY: The database is available for free at http://www.molgenv.com/ssa_mirnas_db_home.php. PMID- 22493539 TI - MAPT and PAICE: Tools for time series and single time point transcriptionist visualization and knowledge discovery. AB - With the advent of next-generation sequencing, -omics fields such as transcriptomics have experienced increases in data throughput on the order of magnitudes. In terms of analyzing and visually representing these huge datasets, an intuitive and computationally tractable approach is to map quantified transcript expression onto biochemical pathways while employing datamining and visualization principles to accelerate knowledge discovery. We present two cross platform tools: MAPT (Mapping and Analysis of Pathways through Time) and PAICE (Pathway Analysis and Integrated Coloring of Experiments), an easy to use analysis suite to facilitate time series and single time point transcriptomics analysis. In unison, MAPT and PAICE serve as a visual workbench for transcriptomics knowledge discovery, data-mining and functional annotation. Both PAICE and MAPT are two distinct but yet inextricably linked tools. The former is specifically designed to map EC accessions onto KEGG pathways while handling multiple gene copies, detection-call analysis, as well as UN/annotated EC accessions lacking quantifiable expression. The latter tool integrates PAICE datasets to drive visualization, annotation, and data-mining. AVAILABILITY: The database is available for free at http://sourceforge.net/projects/paice/http://sourceforge.net/projects/mapt/ PMID- 22493540 TI - Model requirements for Biobank Software Systems. AB - Biobanks are essential tools in diagnostics and therapeutics research and development related to personalized medicine. Several international recommendations, standards and guidelines exist that discuss the legal, ethical, technological, and management requirements of biobanks. Today's biobanks are much more than just collections of biospecimens. They also store a huge amount of data related to biological samples which can be either clinical data or data coming from biochemical experiments. A well-designed biobank software system also provides the possibility of finding associations between stored elements. Modern research biobanks are able to manage multicenter sample collections while fulfilling all requirements of data protection and security. While developing several biobanks and analyzing the data stored in them, our research group recognized the need for a well-organized, easy-to-check requirements guideline that can be used to develop biobank software systems. International best practices along with relevant ICT standards were integrated into a comprehensive guideline: The Model Requirements for the Management of Biological Repositories (BioReq), which covers the full range of activities related to biobank development. The guideline is freely available on the Internet for the research community. AVAILABILITY: The database is available for free at http://bioreq.astridbio.com/bioreq_v2.0.pdf. PMID- 22493541 TI - Risk for gastric neoplasias in patients with chronic atrophic gastritis: a critical reappraisal. AB - Chronic atrophic gastritis (CAG) is an inflammatory condition characterized by the loss of gastric glandular structures which are replaced by connective tissue (non-metaplastic atrophy) or by glandular structures inappropriate for location (metaplastic atrophy). Epidemiological data suggest that CAG is associated with two different types of tumors: Intestinal-type gastric cancer (GC) and type I gastric carcinoid (TIGC). The pathophysiological mechanisms which lead to the development of these gastric tumors are different. It is accepted that a multistep process initiating from Helicobacter pylori-related chronic inflammation of the gastric mucosa progresses to CAG, intestinal metaplasia, dysplasia and, finally, leads to the development of GC. The TIGC is a gastrin dependent tumor and the chronic elevation of gastrin, which is associated with CAG, stimulates the growth of enterochromaffin-like cells with their hyperplasia leading to the development of TIGC. Thus, several events occur in the gastric mucosa before the development of intestinal-type GC and/or TIGC and these take several years. Knowledge of CAG incidence from superficial gastritis, its prevalence in different clinical settings and possible risk factors associated with the progression of this condition to gastric neoplasias are important issues. This editorial intends to provide a brief review of the main studies regarding incidence and prevalence of CAG and risk factors for the development of gastric neoplasias. PMID- 22493542 TI - Mouse models of pancreatic cancer. AB - Pancreatic cancer is one of the most lethal of human malignancies ranking 4th among cancer-related death in the western world and in the United States, and potent therapeutic options are lacking. Although during the last few years there have been important advances in the understanding of the molecular events responsible for the development of pancreatic cancer, currently specific mechanisms of treatment resistance remain poorly understood and new effective systemic drugs need to be developed and probed. In vivo models to study pancreatic cancer and approach this issue remain limited and present different molecular features that must be considered in the studies depending on the purpose to fit special research themes. In the last few years, several genetically engineered mouse models of pancreatic exocrine neoplasia have been developed. These models mimic the disease as they reproduce genetic alterations implicated in the progression of pancreatic cancer. Genetic alterations such as activating mutations in KRas, or TGFb and/or inactivation of tumoral suppressors such as p53, INK4A/ARF BRCA2 and Smad4 are the most common drivers to pancreatic carcinogenesis and have been used to create transgenic mice. These mouse models have a spectrum of pathologic changes, from pancreatic intraepithelial neoplasia to lesions that progress histologically culminating in fully invasive and metastatic disease and represent the most useful preclinical model system. These models can characterize the cellular and molecular pathology of pancreatic neoplasia and cancer and constitute the best tool to investigate new therapeutic approaches, chemopreventive and/or anticancer treatments. Here, we review and update the current mouse models that reproduce different stages of human pancreatic ductal adenocarcinoma and will have clinical relevance in future pancreatic cancer developments. PMID- 22493543 TI - Magnifying endoscopy in upper gastroenterology for assessing lesions before completing endoscopic removal. AB - Any prognosis of gastrointestinal (GI) cancer is closely related to the stage of the disease at diagnosis. Endoscopic submucosal dissection (ESD) and en bloc endoscopic mucosal resection (EMR) have been performed as curative treatments for many early-stage GI lesions in recent years. The technologies have been widely accepted in many Asian countries because they are minimally invasive and supply thorough histopathologic evaluation of the specimens. However, before engaging in endoscopic therapy, an accurate diagnosis is a precondition to effecting the complete cure of the underlying malignancy or carcinoma in situ. For the past few years, many new types of endoscopic techniques, including magnifying endoscopy with narrow-band imaging (ME-NBI), have emerged in many countries because these methods provide a strong indication of early lesions and are very useful in determining treatment options before ESD or EMR. However, to date, there is no comparable classification equivalent to "Kudo's Pit Pattern Classification in the colon", for the upper GI, there is still no clear internationally accepted classification system of magnifying endoscopy. Therefore, in order to help unify some viewpoints, here we will review the defining optical imaging characteristics and the current representative classifications of microvascular and microsurface patterns in the upper GI tract under ME-NBI, describe the accurate relationship between them and the pathological diagnosis, and their clinical applications prior to ESD or en bloc EMR. We will also discuss assessing the differentiation and depth of invasion, defying the lateral spread of involvement and targeting biopsy in real time. PMID- 22493544 TI - Probiotic modulation of dendritic cells co-cultured with intestinal epithelial cells. AB - AIM: To investigate cytokine production and cell surface phenotypes of dendritic cells (DC) in the presence of epithelial cells stimulated by probiotics. METHODS: Mouse DC were cultured alone or together with mouse epithelial cell monolayers in normal or inverted systems and were stimulated with heat-killed probiotic bacteria, Bifidobacterium lactis AD011 (BL), Bifidobacterium bifidum BGN4 (BB), Lactobacillus casei IBS041 (LC), and Lactobacillus acidophilus AD031 (LA), for 12 h. Cytokine levels in the culture supernatants were determined by enzyme-linked immunosorbent assay and phenotypic analysis of DC was investigated by flow cytometry. RESULTS: BB and LC in single-cultured DC increased the expression of I Ad, CD86 and CD40 (I-Ad, 18.51 vs 30.88, 46.11; CD86, 62.74 vs 92.7, 104.12; CD40, 0.67 vs 6.39, 3.37, P < 0.05). All of the experimental probiotics increased the production of inflammatory cytokines, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha. However, in the normal co-culture systems, LC and LA decreased the expression of I-A(d) (39.46 vs 30.32, 33.26, P < 0.05), and none of the experimental probiotics increased the levels of IL-6 or TNF-alpha. In the inverted co-culture systems, LC decreased the expression of CD40 (1.36 vs -2.27, P < 0.05), and all of the experimental probiotics decreased the levels of IL-6. In addition, BL increased the production of IL-10 (103.8 vs 166.0, P < 0.05) and LC and LA increased transforming growth factor-beta secretion (235.9 vs 618.9, 607.6, P < 0.05). CONCLUSION: These results suggest that specific probiotic strains exert differential immune modulation mediated by the interaction of dendritic cells and epithelial cells in the homeostasis of gastrointestinal tract. PMID- 22493545 TI - Enhancement of CTLs induced by DCs loaded with ubiquitinated hepatitis B virus core antigen. AB - AIM: To investigate whether hepatitis B virus (HBV) could induce a hepatitis B virus core antigen (HBcAg)-specific cytotoxic T lymphocyte (CTL) response in vitro by dendritic cells (DCs) transduced with lentiviral vector-encoding ubiquitinated hepatitis B virus core antigen (LV-Ub-HBcAg). METHODS: Recombinant LV-Ub-HBcAg were transfected into highly susceptible 293 T cells to obtain high virus titres. Bone marrow-derived DCs isolated from BALB/c mice were cultured with recombinant granulocyte-macrophage colony-stimulating factor and recombinant interleukin (IL)-4. LV-Ub-HBcAg, lentiviral vector-encoding hepatitis B virus core antigen (LV-HBcAg), lentiviral vector (LV) or lipopolysaccharide were added to induce DC maturation, and the DC phenotypes were analyzed by flow cytometry. The level of IL-12 in the supernatant was detected by enzyme-linked immunosorbent assay (ELISA). T lymphocytes were proliferated using Cell Counting Kit-8. DCs were cultured and induced to mature using different LVs, and co-cultured with allogeneic T cells to detect the secretion levels of IL-2, IL-4, IL-10 and interferon-gamma in the supernatants of T cells by ELISA. Intracellular cytokines of proliferative T cells were analyzed by flow cytometry, and specific CTL activity was measured by a lactate dehydrogenase release assay. RESULTS: LV-Ub HBcAg-induced DCs secreted more IL-12 and upregulated the expression of CD80, CD86 and major histocompatibility class II. DCs sensitised by different LVs effectively promoted cytokine secretion; the levels of IL-2 and interferon-gamma induced by LV-Ub-HBcAg were higher than those induced by LV-HBcAg. Compared with LV-HBcAg-transduced DCs, LV-Ub-HBcAg-transduced DCs more efficiently stimulated the proliferation of T lymphocytes and generated HBcAg-specific cytotoxic T lymphocytes. CONCLUSION: LV-Ub-HBcAg effectively induced DC maturation. The mature DCs efficiently induced T cell polarisation to Th1 and generated HBcAg specific CTLs. PMID- 22493546 TI - Loss of Wnt5a and Ror2 protein in hepatocellular carcinoma associated with poor prognosis. AB - AIM: To investigate the expression and clinical significance of Wnt member 5a (Wnt5a) and receptor tyrosine kinase-like orphan receptor 2 (Ror2) in hepatocellular carcinoma (HCC). METHODS: In HCC tissues obtained from 85 patients, the protein expressions of Wnt5a, Ror2, beta-catenin, and Ki-67 via immunohistochemical staining using the Envision Plus System. The antibody binding was visualized with 3, 3'-diaminobenzidine tetrahydrochloride (DAB) before brief counterstaining with Mayer's hematoxylin. The degree of immunohistochemical staining was recorded using a semiquantitative and subjective grading system. The mRNA expression of Ror2 was examined by real-time reverse transcription polymerase chain reaction, including nineteen of the 85 HCC and three normal liver tissues. The ratios of Ror2 to the housekeeping gene GAPDH represented the normalized relative levels of Ror2 expression. To determine the prognostic factor, the outcome of the 82 patients was determined by reviewing their medical charts. The overall and disease-free survival rates were estimated using the Kaplan-Meier method and compared with the log-rank test. The prognostic analysis was carried out with univariate and multivariate Cox regressions models. RESULTS: Compared to nontumorous (hepatitis or cirrhotic) tissues, Ror2 mRNA expression was clearly decreased in HCC. Ror2 and Wnt5a protein expressions in the majority of HCC patients (63% and 77%, respectively) was significantly less in tumor tissues, as compared to adjacent nontumorous tissues, and this reduction was correlated with increasing serum alpha-fetoprotein and tumor stage. In 68% (58/85) of the HCC cases, the expression of beta-catenin in tumor tissues was either downregulated in the cellular membrane, upregulated in the cytoplasm, or both. Survival analysis indicated that Wnt5a and Ror2 protein expressions could be regarded as independent prognostic factors for HCC; HCC patients with decreased Wnt5a or Ror2 protein expression had a poorer prognosis than those with elevated Wnt5a and Ror2 expression (P = 0.016, P = 0.007, respectively). CONCLUSION: Wnt5a and Ror2 may serve as tumor suppressor genes in the development of HCC, and may serve as clinicopathologic biomarkers for prognosis in HCC patients. PMID- 22493547 TI - Chronic hepatitis C: treat or wait? Medical decision making in clinical practice. AB - AIM: To analyzes the decision whether patients with chronic hepatitis C virus (HCV) infection are treated or not. METHODS: This prospective cohort study included 7658 untreated patients and 6341 patients receiving pegylated interferon alpha 2a/ribavirin, involving 434 physicians/institutions throughout Germany (377 in private practice and 57 in hospital settings). A structured questionnaire had to be answered prior to the treatment decision, which included demographic data, information about the personal life situation of the patients, anamnesis and symptomatology of hepatitis C, virological data, laboratory data and data on concomitant diseases. A second part of the study analyzes patients treated with pegylated interferon alpha2a. All questionnaires included reasons against treatment mentioned by the physician. RESULTS: Overall treatment uptake was 45%. By multivariate analysis, genotype 1/4/5/6, HCV-RNA <= 520,000 IU/mL, normal alanine aminotransferase (ALT), platelets <= 142,500/MUL, age > 56 years, female gender, infection length > 12.5 years, concomitant diseases, human immunodeficiency virus co-infection, liver biopsy not performed, care in private practice, asymptomatic disease, and unemployment were factors associated with reduced treatment rate. Treatment and sustained viral response rates in migrants (1/3 of cohort) were higher than in German natives although 1/3 of migrants had language problems. Treatment rate and liver biopsy were higher in clinical settings when compared to private practice and were low when ALT and HCV-RNA were low. CONCLUSION: Some reasons against treatment were medically based whereas others were related to fears, socio-economical problems, and information deficits both on the side of physicians and patients. PMID- 22493548 TI - Celiac disease: management of persistent symptoms in patients on a gluten-free diet. AB - AIM: To investigate all patients referred to our center with non-responsive celiac disease (NRCD), to establish a cause for their continued symptoms. METHODS: We assessed all patients referred to our center with non-responsive celiac disease over an 18-mo period. These individuals were investigated to establish the eitiology of their continued symptoms. The patients were first seen in clinic where a thorough history and examination were performed with routine blood work including tissue transglutaminase antibody measurement. They were also referred to a specialist gastroenterology dietician to try to identift any lapses in the diet and sources of hidden gluten ingestion. A repeat small intestinal biopsy was also performed and compared to biopsies from the referring hospital where possible. Colonoscopy, lactulose hydrogen breath testing, pancreolauryl testing and computed tomography scan of the abdomen were undertaken if the symptoms persisted. Their clinical progress was followed over a minimum of 2 years. RESULTS: One hundred and twelve consecutive patients were referred with NRCD. Twelve were found not to have celiac disease (CD). Of the remaining 100 patients, 45% were not adequately adhering to a strict gluten-free diet, with 24 (53%) found to be inadvertently ingesting gluten, and 21 (47%) admitting non compliance. Microscopic colitis was diagnosed in 12% and small bowel bacterial overgrowth in 9%. Refractory CD was diagnosed in 9%. Three of these were diagnosed with intestinal lymphoma. After 2 years, 78 patients remained well, eight had continuing symptoms, and four had died. CONCLUSION: In individuals with NRCD, a remediable cause can be found in 90%: with continued gluten ingestion as the leading cause. We propose an algorithm for investigation. PMID- 22493549 TI - Second-line therapy for gemcitabine-pretreated advanced or metastatic pancreatic cancer. AB - AIM: To investigate second-line chemotherapy in gemcitabine-pretreated patients with advanced or metastatic pancreatic cancer [(frequency, response, outcome, course of carbohydrate antigen 19-9 (CA 19-9)]. METHODS: This retrospective study included all patients with advanced or metastatic pancreatic cancer (adenocarcinoma or carcinoma) treated with second-line chemotherapy in our center between 2000 and 2008. All patients received first-line chemotherapy with gemcitabine, and prior surgery or radiotherapy was permitted. We analyzed each chemotherapy protocol for second-line treatment, the number of cycles and the type of combination used. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, response rate, grade 3-4 toxicity, dosage modifications and CA 19-9 course. RESULTS: A total of eighty patients (38%) underwent a second-line therapy among 206 patients who had initially received first-line treatment with a gemcitabine-based regimen. Median number of cycles was 4 (range: 1-12) and the median duration of treatment was 2.6 mo (range: 0.3-7.4). The overall disease control rate was 40.0%. The median overall survival and progression-free survival from the start of second-line therapy were 5.8 (95% CI: 4.1-6.6) and 3.4 mo (95% CI: 2.4-4.2), respectively. Toxicity was generally acceptable. Median overall survival of patients with a CA 19-9 level declining by more than 20% was 10.3 mo (95% CI: 4.5-11.6) vs 5.2 mo (95% CI: 4.0 6.4) for others (P = 0.008). CONCLUSION: A large proportion of patients could benefit from second-line therapy, and CA 19-9 allows efficient treatment monitoring both in first and second-line chemotherapy. PMID- 22493550 TI - Post-cholecystectomy symptoms were caused by persistence of a functional gastrointestinal disorder. AB - AIM: To classify gallstone disease as a basis for assessment of post cholecystectomy symptoms. METHODS: One hundred and fifty three patients with a clinical and ultrasonographic diagnosis of gallstones filled out a structured questionnaire on abdominal pain symptoms and functional gastrointestinal disorder (FGID) before and at six months after cholecystectomy. Symptom frequency groups (SFG) were categorized according to frequency of pain attacks. According to certain pain characteristics in gallstone patients, a gallstone symptom score was accorded on a scale from one to ten. A visual analogue scale was used to quantify pain. Operative specimens were examined for size and magnitude of stone contents as well as presence of bacteria. Follow-up took place after six months with either a consultation or via a mailed questionnaire. Results were compared with those obtained pre-operatively to describe and analyze symptomatic outcome. RESULTS: SFG groups were categorized as severe (24.2%), moderate (38.6%), and mild (22.2%) attack frequency, and a chronic pain condition (15%). Pain was cured or improved in about 90% of patients and two-thirds of patients obtained complete symptom relief. Patients with the most frequent pain episodes were less likely to obtain symptom relief. FGID was present in 88% of patients pre-operatively and in 57% post-operatively (P = 0.244). Those that became asymptomatic or improved with regard to pain also had most relief from FGID (P = 0.001). No pre-operative FGID meant almost complete cure. CONCLUSION: Only one third of patients with FGID experienced postoperative relief, indicating that FGID was a dominant cause of post-cholecystectomy symptoms. PMID- 22493551 TI - Three benefits of microcatheters for retrograde transvenous obliteration of gastric varices. AB - AIM: To evaluate the usefulness of the microcatheter techniques in balloon occluded retrograde transvenous obliteration (BRTO) of gastric varices. METHODS: Fifty-six patients with gastric varices underwent BRTOs using microcatheters. A balloon catheter was inserted into gastrorenal or gastrocaval shunts. A microcatheter was navigated close to the varices, and sclerosant was injected into the varices through the microcatheter during balloon occlusion. The next morning, thrombosis of the varices was evaluated by contrast enhanced computed tomography (CE-CT). In patients with incomplete thrombosis of the varices, a second BRTO was performed the following day. Patients were followed up with CE-CT and endoscopy. RESULTS: In all 56 patients, sclerosant was selectively injected through the microcatheter close to the varices. In 9 patients, microcoil embolization of collateral veins was performed using a microcatheter. In 12 patients with incomplete thrombosis of the varices, additional injection of sclerosant was performed through the microcatheter that remained inserted overnight. Complete thrombosis of the varices was achieved in 51 of 56 patients, and the remaining 5 patients showed incomplete thrombosis of the varices. No recurrence of the varices was found in the successful 51 patients after a median follow up time of 10.5 mo. We experienced one case of liver necrosis, and the other complications were transient. CONCLUSION: The microcatheter techniques are very effective methods for achieving a higher success rate of BRTO procedures. PMID- 22493552 TI - Branched-chain amino acid treatment before transcatheter arterial chemoembolization for hepatocellular carcinoma. AB - AIM: To examine the significance of branched-chain amino acid (BCAA) treatment before transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). METHODS: This study included 99 patients who underwent TACE therapy for HCC at our hospital and were followed up without treatment for at least 6 mo between January 2004 and January 2010. They were divided into 2 groups: those receiving BCAA granules (n = 40) or regular diet (n = 59, control). Data obtained were retrospectively analyzed (prior to TACE, and 1 wk, 1, 3, and 6 mo after TACE) in terms of nutritional condition and clinical laboratory parameters (serum albumin level and Child-Pugh score), both of which are determinants of hepatic functional reserve. RESULTS: The BCAA group comprised 27 males and 13 females with a mean age of 69.9 +/- 8.8 years. The patients of the BCAA group were classified as follows: Child-Pugh A/B/C in 22/15/3 patients, and Stage II/III/IVA HCC in 12/23/5 patients, respectively. The control group comprised 32 males and 27 females with a mean age of 73.2 +/- 10.1 years. In the control group, 9 patients had chronic hepatitis, Child-Pugh A/B/C in 39/10/1 patients, and StageI/II/III/IVA HCC in 1/11/35/12 patients, respectively. Overall, both serum albumin level and Child-Pugh score improved significantly in the BCAA group as compared with the control 3 and 6 mo after TACE (P < 0.05). Further analysis was performed by the following categorization: (1) child-Pugh classification; (2) liver cirrhosis subgroup with a serum albumin level > 3.5 g/dL; and (3) epirubicin dose. A similar trend indicating a significant improvement of all variables in the BCAA group was noted (P < 0.05). CONCLUSION: Treatment with BCAA granules in patients who have undergone TACE for HCC is considered useful to maintain their hepatic functional reserve. PMID- 22493553 TI - Assessment of disease progression in patients with transfusion-associated chronic hepatitis C using transient elastography. AB - AIM: To evaluate the relationship between liver stiffness and duration of infection in blood transfusion-associated hepatitis C virus (HCV) patients with or without hepatocellular carcinoma (HCC). METHODS: Between December 2006 and June 2008, a total of 524 transfusion-associated HCV-RNA positive patients with or without HCC were enrolled. Liver stiffness was obtained noninvasively by using Fibroscan (Echosens, Paris, France). The date of blood transfusion was obtained by interview. Duration of infection was derived from the interval between the date of blood transfusion and the date of liver stiffness measurement (LSM). Patients were stratified into four groups based on the duration of infection (17 29 years; 30-39 years; 40-49 years; and 50-70 years). The difference in liver stiffness between patients with and without HCC was assessed in each group. Multiple linear regression analysis was used to determine the factors associated with liver stiffness. RESULTS: A total of 524 patients underwent LSM. Eight patients were excluded because of unsuccessful measurements. Thus 516 patients were included in the current analysis (225 with HCC and 291 without). The patients were 244 men and 272 women, with a mean age of 67.8 +/- 9.5 years. The median liver stiffness was 14.3 kPa (25.8 in HCC group and 7.6 in non-HCC group). The patients who developed HCC in short duration of infection were male dominant, having lower platelet count, with a history of heavier alcohol consumption, showing higher liver stiffness, and receiving blood transfusion at an old age. Liver stiffness was positively correlated with duration of infection in patients without HCC (r = 0.132, P = 0.024) but not in patients with HCC (r = -0.103, P = 0.123). Liver stiffness was significantly higher in patients with HCC than in those without in each duration group (P < 0.0001). The factors significantly associated with high liver stiffness in multiple regression were age at blood transfusion (P < 0.0001), duration of infection (P = 0.0015), and heavy alcohol consumption (P = 0.043). CONCLUSION: Although liver stiffness gradually increases over time, HCC develops in patients with high stiffness value regardless of the duration of infection. PMID- 22493554 TI - Opiate-induced constipation related to activation of small intestine opioid MU2 receptors. AB - AIM: To investigate the role of opioid MU-receptor subtype in opiate-induced constipation (OIC). METHODS: The effect of loperamide on intestinal transit was investigated in mice. Ileum strips were isolated from 12-wk-old male BALB/c mice for identification of isometric tension. The ileum strips were precontracted with 1 MUmol/L acetylcholine (ACh). Then, decrease in muscle tone (relaxation) was characterized after cumulative administration of 0.1-10 MUmol/L loperamide into the organ bath, for a concentration-dependent study. Specific blockers or antagonists were used for pretreatment to compare the changes in loperamide induced relaxation. RESULTS: In addition to the delay in intestinal transit, loperamide produced a marked relaxation in isolated ileum precontracted with ACh, in a dose-dependent manner. This relaxation was abolished by cyprodime, a selective opioid MU-receptor antagonist, but not modified by naloxonazine at a dose sufficient to block opioid MU-1 receptors. Also, treatment with opioid MU-1 receptor agonist failed to modify the muscle tone. Moreover, the relaxation by loperamide was attenuated by glibenclamide at a dose sufficient to block ATP sensitive K+ (K(ATP)) channels, and by protein kinase A (PKA) inhibitor, but was enhanced by an inhibitor of phosphodiesterase for cyclic adenosine monophosphate (cAMP). CONCLUSION: Loperamide induces intestinal relaxation by activation of opioid MU-2 receptors via the cAMP-PKA pathway to open K(ATP) channels, relates to OIC. PMID- 22493555 TI - Notch3 regulates the activation of hepatic stellate cells. AB - AIM: To investigate whether Notch signaling is involved in liver fibrosis by regulating the activation of hepatic stellate cells (HSCs). METHODS: Immunohistochemistry was used to detect the expression of Notch3 in fibrotic liver tissues of patients with chronic active hepatitis. The expression of Notch3 in HSC-T6 cells treated or not with transforming growth factor (TGF)-beta1 was analyzed by immunofluorescence staining. The expression of Notch3 and myofibroblastic marker alpha-smooth muscle actin (alpha-SMA) and collagen I in HSC-T6 cells transfected with pcDNA3.1-N3ICD or control vector were detected by Western blotting and immunofluorescence staining. Moreover, effects of Notch3 knockdown in HSC-T6 by Notch3 siRNA were investigated by Western blotting and immunofluorescence staining. RESULTS: The expression of Notch3 was significantly up-regulated in fibrotic liver tissues of patients with chronic active hepatitis, but not detected in normal liver tissues. Active Notch signaling was found in HSC T6 cells. TGF-beta1 treatment led to up-regulation of Notch3 expression in HSC-T6 cells, and over-expression of Notch3 increased the expression of alpha-SMA and collagen I in HSC-T6 without TGF-beta1 treatment. Interestingly, transient knockdown of Notch3 decreased the expression of myofibroblastic marker and antagonized TGF-beta1-induced expression of alpha-SMA and collagen I in HSC-T6. CONCLUSION: Notch3 may regulate the activation of HSCs, and the selective interruption of Notch3 may provide an anti-fibrotic strategy in hepatic fibrosis. PMID- 22493556 TI - Endoscopic stenting and concurrent chemoradiotherapy for advanced esophageal cancer: a case-control study. AB - AIM: To evaluate the role of endoscopic stenting with or without concurrent 3 dimensional conformal chemoradiotherapy (3D-CRT) in patients with inoperable esophageal cancer. METHODS: Advanced esophageal cancer patients indicated for esophagectomy received esophageal stents. A part of patients completed 3D-CRT after stenting. Efficacy was assessed by endoscopy and computed tomographic scan before and 4 wk after completion of the treatment. The median survival, 3D-CRT toxicity and complications were compared between 3D-CRT and control groups. RESULTS: From 1999 to 2008, 99 consecutive patients with T3/T4 disease and unsuitable for esophagectomy were placed with esophageal stents. Sixty-seven patients received 3D-CRT, while 36 patients treated with endoscopic stents alone were recruited as controls. After 3D-CRT treatment, the median tumor volume of 3D CRT patients were reduced significantly from 43.7 +/- 10.2 cm3 to 28.8 +/- 8.5 cm3 (P < 0.05). The complete and partial response rate was 85.1%, and no response was 14.9%. After 3D-CRT, the incidence rate of T2 and T3 disease evident on CT scan increased to 78.4% while T4 decreased from 66.7% to 21.6% (P < 0.05). 3D-CRT Karnofsky Performance Status improved in 3D-CRT patients compared with the control group (P = 0.031). 3D-CRT patients had a longer survival than the control group (251.7 d vs 91.1 d, P < 0.05). And the median half-year survival rate in 3D CRT group (91%) was higher than in the control group (50%, P < 0.05). The most common toxicity was leukocytopenia in the 3D-CRT group (46.7% vs 18.8%, P = 0.008). The control group had a higher rate of restenosis than the 3D-CRT group (81.3% vs 9.0%, P < 0.05). The rate of nephrotoxicity was increased in 3D-CRT as compared with the control group (31.3% vs 15.6%, P < 0.05). CONCLUSION: 3D-CRT can improve dysphagia in patients with inoperable esophageal carcinoma. 3D-CRT combined with stenting results in better survival as compared with endoscopic stents used alone. PMID- 22493557 TI - A rare case of langerhans cell histiocytosis of the gastrointestinal tract. AB - Langerhans cell histiocytosis (LCH) is a group of idiopathic disorders characterized by the proliferation of specialized, bone marrow-derived langerhans cells and mature eosinophils. The clinical spectrum ranges from an acute, fulminant, disseminated disease called Letterer-Siwe disease to solitary or few, indolent and chronic lesions of the bone or other organs called eosinophilic granuloma. Involvement of the gastrointestinal tract is very rare in LCH. We present the case of a 53-year-old woman referred by her primary care physician for a screening colonoscopy. A single sessile polyp, measuring 4 mm in size, was found in the rectum. Histopathological examination revealed that the lesion was relatively well circumscribed and comprised mainly a mixture of polygonal cells with moderate-to-abundant pink slightly granular cytoplasm. The nuclei within these cells had frequent grooves and were occasionally folded. Immunohistochemical staining was positive for CD-1a which confirmed the diagnosis of LCH. On further workup, there was no evidence of involvement of any other organ. On follow up colonoscopy one year later, there was no evidence of disease recurrence. Review of the published literature revealed that LCH presenting as solitary colonic polyp is rare. However, with the increasing rates of screening colonoscopy, more colonic polyps may be identified as LCH on histopathology. This underscores the importance of recognizing this rare condition and ensuring proper follow-up to rule out systemic disease. PMID- 22493559 TI - Nonmethane Hydrocarbons in Ambient Air of Hazy and Normal Days in Foshan, South China. AB - A first study of nonmethane hydrocarbons (NMHCs) on hazy and normal days was performed in Foshan for providing deep insight into the local deteriorating air quality. Ethane, propane, i-pentane, ethene, propene, ethyne, benzene, and toluene were eight most abundant compounds, accounting for 71%-85% of total NMHCs. Most hydrocarbons showed much higher levels on hazy days than normal days together with hydrocarbon/ethyne ratios and diurnal variations, indicating hazy days are more dominated by vehicular emission. Correlation coefficients (R(2)) of ethane, propane, ethane, propene, benzene, and total NMHCs with ethyne were 0.62 0.83, indicating these compounds are mainly related to vehicular emission. R(2) analysis indicated that solvent usage is responsible for toluene and other aromatic hydrocarbons (e.g., ethylbezene). Benzene/toluene (B/T) ratio was 0.44+/ 0.23 during whole sampling periods, again indicating vehicular emission is the dominant source. Lower B/T ratio (0.30+/-0.14) on hazy days than that (0.58+/ 0.21) on normal days suggested that solvent usage emitted toluene. PMID- 22493558 TI - Pseudomelanosis duodeni associated with chronic renal failure. AB - Pseudomelanosis duodeni (PD) is a rare dark speckled appearance of the duodenum associated with gastrointestinal bleeding, hypertension, chronic heart failure, chronic renal failure and consumption of different drugs. We report four cases of PD associated with chronic renal failure admitted to the gastroenterology outpatient unit due to epigastric pain, nausea, melena and progressive reduction of hemoglobin index. Gastroduodenal endoscopy revealed erosions in the esophagus and stomach, with no active bleeding at the moment. In addition, the duodenal mucosa presented marked signs of melanosis; later confirmed by histopathological study. Even though PD is usually regarded as a benign condition, its pathogenesis and clinical significance is yet to be defined. PMID- 22493560 TI - Increased Levels of Circulating and Tissue mRNAs of Oct-4, Sox-2, Bmi-1 and Nanog is ESCC Patients: Potential Tool for Minimally Invasive Cancer Diagnosis. AB - BACKGROUND: Early stages of esophageal cancer lack a specific symptom, a reliable biomarker and accurate non-invasive diagnostic modalities prompting the pressing need for identification of a marker for early diagnosis of this disease. METHODS: In the present study we investigated the levels of circulating and tissue mRNAs of Oct-3/4, Sox-2, Nanog and Bmi-1 in esophageal cancer patients using Reverse Transcription Polymerase Chain Reaction (RT-PCR) with the aim of evaluating their potential as minimally invasive diagnostic markers. RESULT: Increased transcript levels of Oct-4, Sox-2, Bmi-1 and Nanog were detected in (92%), (95%), (75%) and (67%) of the esophageal cancer tissues, respectively as compared with the matched distant normals. CONCLUSION: Interestingly, most of the preneoplastic tissues exhibited increased transcript levels of these stemness markers suggesting their role in early stages of esophageal tumorigenesis. Furthermore, the detection of elevated levels of circulating mRNAs of Oct-4 and Nanog in sera of esophageal cancer patients emphasizes their potential as minimally invasive diagnostic markers for esophageal cancer. PMID- 22493561 TI - Holistic Control of Herbal Teas and Tinctures Based on Sage (Salvia officinalis L.) for Compounds with Beneficial and Adverse Effects using NMR Spectroscopy. AB - A methodology that utilizes (1)H-NMR spectroscopy has been developed to simultaneously analyze toxic terpenes (thujone and camphor), major polyphenolic compounds, the total antioxidant capacity (ORAC) and the Folin-Ciocalteu (FC) index in foods and medicines containing sage. The quantitative determination of rosmarinic acid (limit of detection (LOD) = 10 mg/L) and total thujone (LOD = 0.35 mg/L) was possible using direct integration of the signals. For other parameters (derivatives of rosmarinic acid, carnosol and flavone glycosides, ORAC and FC index), chemometric regression models obtained separately for alcohol based tinctures (R(2) = 0.94-0.98) and aqueous tea infusions (R(2) = 0.79-0.99) were suitable for screening analysis. The relative standard deviations for authentic samples were below 10%. The developed methodology was applied for the analysis of a wide variety of sage products (n = 108). The total thujone content in aqueous tea infusions was found to be in the range of not detectable (nd) to 37.5 mg/L (average 9.2 mg/L), while tinctures contained higher levels (range nd 409 mg/L, average 107 mg/L). The camphor content varied from 2.1 to 43.7 mg/L in aqueous infusions and from not detectable to 748 mg/L in tinctures (averages were 14.1 and 206 mg/L, respectively). Phenolic compounds were also detected in the majority of the investigated products. (1)H-NMR spectroscopy was proven to have the ability to holistically control all important adverse and beneficial compounds in sage products in a single experiment, considerably saving time, resources and costs as NMR replaces four separate methodologies that were previously needed to analyze the same parameters. PMID- 22493562 TI - Molecular Modelling of Oligomeric States of DmOR83b, an Olfactory Receptor in D. Melanogaster. AB - After the discovery of the complete repertoire of D. melanogaster Olfactory Receptors (ORs), candidate ORs have been identified from at least 12 insect species from four orders (Coleoptera, Lepidoptera, Diptera, and Hymenoptera), including species of economic or medical importance. Although all ORs share the same G-protein coupled receptor structure with seven transmembrane domains, they share poor sequence identity within and between species, and have been identified mainly through genomic data analyses. To date, D. melanogaster remains the only insect species where ORs have been extensively studied, from expression pattern establishment to functional investigations. These studies have confirmed several observations made in vertebrates: one OR type is selectively expressed in a subtype of olfactory receptor neurons, and one olfactory neuron expresses only one type of OR. The olfactory mechanism, further, appears to be conserved between insects and vertebrates. Understanding the function of insect ORs will greatly contribute to the understanding of insect chemical communication mechanisms, particularly with agricultural pests and disease vectors, and could result in future strategies to reduce their negative effects. In this study, we propose molecular models for insect olfactory receptor co-receptor OR83b and its possible functional oligomeric states. The functional similarity of OR83b to GPCRs and ion channels has been exploited for understanding the structure of OR83b. We could observe that C-terminal region (TM4-7) of OR83b is involved in homodimer amd heterodimer formation (with OR22a) which suggests why C-terminus of insect ORs are highly conserved across different species. We also propose two possible ion channel pathways in OR83b: one formed by TM4-5 region with intracellular pore forming domain and the other formed by TM5-6 with extracellular pore forming domain using analysis of the electrostatics distribution of the pore forming domain. PMID- 22493563 TI - Triad of iron deficiency anemia, severe thrombocytopenia and menorrhagia-a case report and literature review. AB - INTRODUCTION: Thrombocytosis is a common disorder in patients diagnosed with iron deficiency anemia. The decreased platelet counts commonly found iron deficiency anemia is rarely reported in clinical practice. The exact mechanism of the occurrence of thrombocytopenia in iron deficiency anemia remains unclear. In this case report we discuss a triad of symptoms seen in the African American population: Iron deficiency anemia, menorrhagia and thrombocytopenia. CASE PRESENTATION: A 40 year old multiparous African-American woman presented with heavy vaginal bleed, severe anemia (3.5 g/dL) and thrombocytopenia (30,000/mm(3)). The peripheral blood smear showed marked microcytic hypochromic cells with decreased platelets counts. After excluding other causes of thrombocytopenia and anemia, increased red cell distribution width and low iron saturation confirmed the diagnosis of iron deficiency anemia. Treatment for iron deficiency anemia was initiated with intravenous and oral iron supplements. Two months following treatment of iron deficiency anemia, the triad of manifestations resolved and patient remained stable. CONCLUSION: Profound degree of iron deficiency anemia can present with thrombocytopenia and severe menorrhagia. Iron replacement should be the main treatment goal in these patients. This case report further supports the 2 compartment model of the role of iron in maintaining platelet counts. PMID- 22493564 TI - Vertebral bone mineral measures and psychological wellbeing among individuals with modic changes. AB - PURPOSE: This case-control pilot study examined whether vertebral bone mineral measures were associated with the presence of chronic low back pain (CLBP) and Modic changes (MCs), and to compare psychological wellbeing and inflammation among individuals with CLBP and MCs, compared to individuals with no history of low back pain and without MCs. METHODS: Eleven individuals with MRI-defined MCs in the lumbar spine and CLBP (cases) and 10 individuals with no history of CLBP or MCs (controls) responded to standard questionnaires regarding pain characteristics and psychological health. Bone mineral density (BMD) was measured with postero-anterior and lateral-projection dual energy X-ray absorptiometry (DXA) to estimate areal BMD (aBMD) and apparent volumetric BMD (ap.vBMD). High sensitivity serum C-reactive protein (hsCRP) was measured as an index of inflammation. RESULTS: While there was no difference between the groups in measures of depression, anxiety and stress, cases reported significantly greater pain catastrophizing attitudes (P < 0.01). hsCRP concentrations did not differ between groups (P = 0.54). Among the 7 cases where MCs were identified between L3 4, significantly higher mean aBMD was observed at the affected vertebral level, compared to the adjacent, unaffected, cephalad level (P = 0.01-0.04), but not when ap.vBMD was calculated (P = 0.36). CONCLUSIONS: Vertebral BMD is not reduced among individuals with CLBP and MCs compared to a control group, although pain catastrophizing attitudes are increased among individuals with CLBP and MCs. PMID- 22493565 TI - Steroid-induced sigmoid diverticular perforation in a patient with temporal arteritis: a rare clinical pathology. AB - Corticosteroids are used in the treatment of many rheumatological diseases including temporal arteritis. The gastrointestinal perforation during corticosteroid treatment is a serious complication. Colon perforation after steroid use was first reported by Beck et al in 1950.1 Although the pathophysiological mechanism is not understood clearly, it is claimed that steroids probably by disturbing the intestinal mucosal barrier, facilitate the intestinal perforation. The long term treatment with corticosteroids increases the risk of colon perforation. We are presenting a patient who was taking corticosteroid due to temporal arteritis for two years and operated with sigmoid diverticular perforation. PMID- 22493566 TI - Carotid stents to prevent stroke: a nonsurgical option. AB - Angioplasty and stent placement have become accepted alternatives to surgery in many vascular territories. The most recent application of percutaneous intervention has been to explore its clinical utility and safety for stroke prevention in carotid arteries. Over the past 8 years, from January 1994 until Nov 2002, we performed 449 elective carotid stent procedures in 426 patients and in 481 vessels. Informed consent was obtained from each patient. Success was achieved in 97.3% of the patients treated. After one month of follow-up, 12 (2.8%) patients experienced stroke or death. After an average of 2.8 +/- 1.7 years (range 1 month to 8.8 years) of follow-up, restenosis was found in 11 (2.6%) patients and was treated with balloon angioplasty. Our results, in a predominantly high-risk surgery group of patients, suggest that carotid stent placement is a viable treatment alternative to conventional surgery. It is likely that as the technology continues to evolve, the procedural risks of stroke and death will be minimized by embolic protection devices, making carotid stenting an option for low-risk surgical patients. PMID- 22493567 TI - Cellular imaging and emerging technologies for adult neurogenesis research. PMID- 22493568 TI - The Impact of Deliberative Strategy Dissociates ERP Components Related to Conflict Processing vs. Reinforcement Learning. AB - We applied the event-related brain potential (ERP) technique to investigate the involvement of two neuromodulatory systems in learning and decision making: The locus coeruleus-norepinephrine system (NE system) and the mesencephalic dopamine system (DA system). We have previously presented evidence that the N2, a negative deflection in the ERP elicited by task-relevant events that begins approximately 200 ms after onset of the eliciting stimulus and that is sensitive to low probability events, is a manifestation of cortex-wide noradrenergic modulation recruited to facilitate the processing of unexpected stimuli. Further, we hold that the impact of DA reinforcement learning signals on the anterior cingulate cortex (ACC) produces a component of the ERP called the feedback-related negativity (FRN). The N2 and the FRN share a similar time range, a similar topography, and similar antecedent conditions. We varied factors related to the degree of cognitive deliberation across a series of experiments to dissociate these two ERP components. Across four experiments we varied the demand for a deliberative strategy, from passively watching feedback, to more complex/challenging decision tasks. Consistent with our predictions, the FRN was largest in the experiment involving active learning and smallest in the experiment involving passive learning whereas the N2 exhibited the opposite effect. Within each experiment, when subjects attended to color, the N2 was maximal at frontal-central sites, and when they attended to gender it was maximal over lateral-occipital areas, whereas the topology of the FRN was frontal-central in both task conditions. We conclude that both the DA system and the NE system act in concert when learning from rewards that vary in expectedness, but that the DA system is relatively more exercised when subjects are relatively more engaged by the learning task. PMID- 22493570 TI - Changes of oscillatory activity in pitch processing network and related tinnitus relief induced by acoustic CR neuromodulation. AB - Chronic subjective tinnitus is characterized by abnormal neuronal synchronization in the central auditory system. As shown in a controlled clinical trial, acoustic coordinated reset (CR) neuromodulation causes a significant relief of tinnitus symptoms along with a significant decrease of pathological oscillatory activity in a network comprising auditory and non-auditory brain areas, which is often accompanied with a significant tinnitus pitch change. Here we studied if the tinnitus pitch change correlates with a reduction of tinnitus loudness and/or annoyance as assessed by visual analog scale (VAS) scores. Furthermore, we studied if the changes of the pattern of brain synchrony in tinnitus patients induced by 12 weeks of CR therapy depend on whether or not the patients undergo a pronounced tinnitus pitch change. Therefore, we applied standardized low resolution brain electromagnetic tomography (sLORETA) to EEG recordings from two groups of patients with a sustained CR-induced relief of tinnitus symptoms with and without tinnitus pitch change. We found that absolute changes of VAS loudness and VAS annoyance scores significantly correlate with the modulus, i.e., the absolute value, of the tinnitus pitch change. Moreover, as opposed to patients with small or no pitch change we found a significantly stronger decrease in gamma power in patients with pronounced tinnitus pitch change in right parietal cortex (Brodmann area, BA 40), right frontal cortex (BA 9, 46), left temporal cortex (BA 22, 42), and left frontal cortex (BA 4, 6), combined with a significantly stronger increase of alpha (10-12 Hz) activity in the right and left anterior cingulate cortex (ACC; BA 32, 24). In addition, we revealed a significantly lower functional connectivity in the gamma band between the right dorsolateral prefrontal cortex (BA 46) and the right ACC (BA 32) after 12 weeks of CR therapy in patients with pronounced pitch change. Our results indicate a substantial, CR induced reduction of tinnitus-related auditory binding in a pitch processing network. PMID- 22493569 TI - Pattern formation during development of the embryonic cerebellum. AB - The patterning of the embryonic cerebellum is vital to establish the elaborate zone and stripe architecture of the adult. This review considers early stages in cerebellar Purkinje cell patterning, from the organization of the ventricular zone to the development of Purkinje cell clusters-the precursors of the adult stripes. PMID- 22493572 TI - How a cerebral hemorrhage altered my art. AB - "How a Cerebral Hemorrhage Altered My Art" examines how a massive stroke affected my art practice. The paralysis that ensued forced me to switch hands and become a left-handed painter. It was postulated by several neuroscientists that the "interpreter" in my brain was severely damaged during my CVA. This has had a profoundly liberating effect on my work. Whereas my pre-stroke period had the tendency to be over-intellectualized and forced, my post-stroke art is less self conscious, more urgent and expressive. The primary subject matter of both periods is the brain. In my practice as an artist, my stroke is a challenge and an opportunity rather than a loss. PMID- 22493571 TI - Cortico-limbic morphology separates tinnitus from tinnitus distress. AB - Tinnitus is a common auditory disorder characterized by a chronic ringing or buzzing "in the ear."Despite the auditory-perceptual nature of this disorder, a growing number of studies have reported neuroanatomical differences in tinnitus patients outside the auditory-perceptual system. Some have used this evidence to characterize chronic tinnitus as dysregulation of the auditory system, either resulting from inefficient inhibitory control or through the formation of aversive associations with tinnitus. It remains unclear, however, whether these "non-auditory" anatomical markers of tinnitus are related to the tinnitus signal itself, or merely to negative emotional reactions to tinnitus (i.e., tinnitus distress). In the current study, we used anatomical MRI to identify neural markers of tinnitus, and measured their relationship to a variety of tinnitus characteristics and other factors often linked to tinnitus, such as hearing loss, depression, anxiety, and noise sensitivity. In a new cohort of participants, we confirmed that people with chronic tinnitus exhibit reduced gray matter in ventromedial prefrontal cortex (vmPFC) compared to controls matched for age and hearing loss. This effect was driven by reduced cortical surface area, and was not related to tinnitus distress, symptoms of depression or anxiety, noise sensitivity, or other factors. Instead, tinnitus distress was positively correlated with cortical thickness in the anterior insula in tinnitus patients, while symptoms of anxiety and depression were negatively correlated with cortical thickness in subcallosal anterior cingulate cortex (scACC) across all groups. Tinnitus patients also exhibited increased gyrification of dorsomedial prefrontal cortex (dmPFC), which was more severe in those patients with constant (vs. intermittent) tinnitus awareness. Our data suggest that the neural systems associated with chronic tinnitus are different from those involved in aversive or distressed reactions to tinnitus. PMID- 22493574 TI - Decoupling the scholarly journal. AB - Although many observers have advocated the reform of the scholarly publishing system, improvements to functions like peer review have been adopted sluggishly. We argue that this is due to the tight coupling of the journal system: the system's essential functions of archiving, registration, dissemination, and certification are bundled together and siloed into tens of thousands of individual journals. This tight coupling makes it difficult to change any one aspect of the system, choking out innovation. We suggest that the solution is the "decoupled journal (DcJ)." In this system, the functions are unbundled and performed as services, able to compete for patronage and evolve in response to the market. For instance, a scholar might deposit an article in her institutional repository, have it copyedited and typeset by one company, indexed for search by several others, self-marketed over her own social networks, and peer reviewed by one or more stamping agencies that connect her paper to external reviewers. The DcJ brings publishing out of its current seventeenth-century paradigm, and creates a Web-like environment of loosely joined pieces-a marketplace of tools that, like the Web, evolves quickly in response to new technologies and users' needs. Importantly, this system is able to evolve from the current one, requiring only the continued development of bolt-on services external to the journal, particularly for peer review. PMID- 22493573 TI - The hippocampus and the flexible use and processing of language. AB - Fundamental to all human languages is an unlimited expressive capacity and creative flexibility that allow speakers to rapidly generate novel and complex utterances. In turn, listeners interpret language "on-line," incrementally integrating multiple sources of information as words unfold over time. A challenge for theories of language processing has been to understand how speakers and listeners generate, gather, integrate, and maintain representations in service of language processing. We propose that many of the processes by which we use language place high demands on and receive contributions from the hippocampal declarative memory system. The hippocampal declarative memory system is long known to support relational binding and representational flexibility. Recent findings demonstrate that these same functions are engaged during the real-time processes that support behavior in-the-moment. Such findings point to the hippocampus as a potentially key contributor to cognitive functions that require on-line integration of multiple sources of information, such as on-line language processing. Evidence supporting this view comes from findings that individuals with hippocampal amnesia show deficits in the use of language flexibly and on line. We conclude that the relational binding and representational flexibility afforded by the hippocampal declarative memory system positions the hippocampus as a key contributor to language use and processing. PMID- 22493575 TI - The pipeline system for Octave and Matlab (PSOM): a lightweight scripting framework and execution engine for scientific workflows. AB - The analysis of neuroimaging databases typically involves a large number of inter connected steps called a pipeline. The pipeline system for Octave and Matlab (PSOM) is a flexible framework for the implementation of pipelines in the form of Octave or Matlab scripts. PSOM does not introduce new language constructs to specify the steps and structure of the workflow. All steps of analysis are instead described by a regular Matlab data structure, documenting their associated command and options, as well as their input, output, and cleaned-up files. The PSOM execution engine provides a number of automated services: (1) it executes jobs in parallel on a local computing facility as long as the dependencies between jobs allow for it and sufficient resources are available; (2) it generates a comprehensive record of the pipeline stages and the history of execution, which is detailed enough to fully reproduce the analysis; (3) if an analysis is started multiple times, it executes only the parts of the pipeline that need to be reprocessed. PSOM is distributed under an open-source MIT license and can be used without restriction for academic or commercial projects. The package has no external dependencies besides Matlab or Octave, is straightforward to install and supports of variety of operating systems (Linux, Windows, Mac). We ran several benchmark experiments on a public database including 200 subjects, using a pipeline for the preprocessing of functional magnetic resonance images (fMRI). The benchmark results showed that PSOM is a powerful solution for the analysis of large databases using local or distributed computing resources. PMID- 22493576 TI - Data sharing in neuroimaging research. AB - Significant resources around the world have been invested in neuroimaging studies of brain function and disease. Easier access to this large body of work should have profound impact on research in cognitive neuroscience and psychiatry, leading to advances in the diagnosis and treatment of psychiatric and neurological disease. A trend toward increased sharing of neuroimaging data has emerged in recent years. Nevertheless, a number of barriers continue to impede momentum. Many researchers and institutions remain uncertain about how to share data or lack the tools and expertise to participate in data sharing. The use of electronic data capture (EDC) methods for neuroimaging greatly simplifies the task of data collection and has the potential to help standardize many aspects of data sharing. We review here the motivations for sharing neuroimaging data, the current data sharing landscape, and the sociological or technical barriers that still need to be addressed. The INCF Task Force on Neuroimaging Datasharing, in conjunction with several collaborative groups around the world, has started work on several tools to ease and eventually automate the practice of data sharing. It is hoped that such tools will allow researchers to easily share raw, processed, and derived neuroimaging data, with appropriate metadata and provenance records, and will improve the reproducibility of neuroimaging studies. By providing seamless integration of data sharing and analysis tools within a commodity research environment, the Task Force seeks to identify and minimize barriers to data sharing in the field of neuroimaging. PMID- 22493577 TI - Dorsal premotor cortex is involved in switching motor plans. AB - Previous studies have shown that neural activity in primate dorsal premotor cortex (PMd) can simultaneously represent multiple potential movement plans, and that activity related to these movement options is modulated by their relative subjective desirability. These findings support the hypothesis that decisions about actions are made through a competition within the same circuits that guide the actions themselves. This hypothesis further predicts that the very same cells that guide initial decisions will continue to update their activities if an animal changes its mind. For example, if a previously selected movement option suddenly becomes unavailable, the correction will be performed by the same cells that selected the initial movement, as opposed to some different group of cells responsible for online guidance. We tested this prediction by recording neural activity in the PMd of a monkey performing an instructed-delay reach selection task. In the task, two targets were simultaneously presented and their border styles indicated whether each would be worth 1, 2, or 3 juice drops. In a random subset of trials (FREE), the monkey was allowed a choice while in the remaining trials (FORCED) one of the targets disappeared at the time of the GO signal. In FORCED-LOW trials the monkey was forced to move to the less valuable target and started moving either toward the new target (Direct) or toward the target that vanished and then curved to reach the remaining one (Curved). Prior to the GO signal, PMd activity clearly reflected the monkey's subjective preference, predicting his choices in FREE trials even with equally valued options. In FORCED LOW trials, PMd activity reflected the switch of the monkey's plan as early as 100 ms after the GO signal, well before movement onset (MO). This confirms that the activity is not related to feedback from the movement itself, and suggests that PMd continues to participate in action selection even when the animal changes its mind on-line. These findings were reproduced by a computational model suggesting that switches between action plans can be explained by the same competition process responsible for initial decisions. PMID- 22493578 TI - Imaging granulomatous lesions with optical coherence tomography. AB - AIM: To investigate and compare the presentation of granulomatous lesions in optical coherence tomography (OCT) images and compare this to previous studies of nonmelanoma skin tumors. METHODS: Two patients with granulomas, tophi and granuloma annulare (GA), respectively, were photographed digitally, OCT-scanned and biopsied in the said order. Normal skin was OCT-scanned for comparison, but not biopsied. The OCT images from each lesion were compared with their histologic images as well as with OCT images with similar characteristics obtained from nonmelanoma skin tumors. RESULTS: The OCT images of the tophi showed hyperreflective, rounded cloud-like structures in dermis, their upper part sharply delineated by a hyporeflective fringe. The deeper areas appeared blurred. The crystalline structures were delineated by a hyporeflective fringe. OCT images of GA showed two different structures in dermis: a hyporeflective rounded one, and one that was lobulated and wing-like. CONCLUSION: Granulomatous tissue surrounding urate deposits appeared as a clear hyporeflective fringe surrounding a light, hyperreflective area. The urate crystals appeared as hyperreflective areas, shielding the deeper part of dermis, meaning OCT could only visualize the upper part of the lesions. The lobulated, wing-like structure in GA may resemble diffuse GA or a dense lymphocytic infiltrate as seen on histology. The rounded structure in GA may represent an actual granuloma or either diffuse GA or a dense lymphocytic infiltrate as described above. This case suggests that OCT images granulomatous tissue as absorbent, hyporeflective areas, and urate crystals appear as reflective areas, obscuring the underlying tissue. In GA a new image shape looking like a wing has been found. The frequency, specificity and sensitivity of this new pattern in OCT imaging will require further studies. PMID- 22493579 TI - Omalizumab for chronic urticaria: a case series and overview of the literature. AB - Omalizumab is a recombinant humanized monoclonal antibody that blocks the high affinity Fc receptor of IgE. Omalizumab has been approved for the treatment of moderate to severe asthma; however, there is currently more and more data showing promising results in the management also of chronic urticaria. We present a case series of 19 patients with chronic urticaria treated in a university department with omalizumab and give an overview of the existing literature comprising an additional 59 cases as well as a total of 139 patients enrolled in two randomized controlled trials comparing omalizumab with placebo. The collective evidence points to omalizumab as a safe and effective treatment option for patients with chronic urticaria who do not sufficiently respond to standard therapy as recommended by existing guidelines. PMID- 22493580 TI - Pseudolymphomatous folliculitis on the nose. AB - Pseudolymphomatous folliculitis (PLF), which sometimes mimicks cutaneous lymphoma, is a rare manifestation of cutaneous pseudolymphoma and cutaneous lymphoid hyperplasia. We describe a 57-year-old Japanese woman with PLF on the nose that resembled cutaneous lymphoma clinically. The biopsy specimen revealed dense lymphocytes, especially CD1a+ cells, infiltrated around the hair follicles. Without any additional treatment, her nodule rapidly decreased before we performed a second biopsy for analysis of the clonal gene rearrangement. Though PLF typically behaves as benign lymphohyperplasia, differentiation from cutaneous lymphoma is necessary. PMID- 22493581 TI - The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. AB - Bilirubin belongs to a phylogenetically old superfamily of tetrapyrrolic compounds, which have multiple biological functions. Although for decades bilirubin was believed to be only a waste product of the heme catabolic pathway at best, and a potentially toxic compound at worst; recent data has convincingly demonstrated that mildly elevated serum bilirubin levels are strongly associated with a lower prevalence of oxidative stress-mediated diseases. Indeed, serum bilirubin has been consistently shown to be negatively correlated to cardiovascular diseases (CVD), as well as to CVD-related diseases and risk factors such as arterial hypertension, diabetes mellitus, metabolic syndrome, and obesity. In addition, the clinical data are strongly supported by evidence arising from both in vitro and in vivo experimental studies. This data not only shows the protective effects of bilirubin per se; but additionally, of other products of the heme catabolic pathway such as biliverdin and carbon monoxide, as well as its key enzymes (heme oxygenase and biliverdin reductase); thus, further underlining the biological impacts of this pathway. In this review, detailed information on the experimental and clinical evidence between the heme catabolic pathway and CVD, and those related diseases such as diabetes, metabolic syndrome, and obesity is provided. All of these pathological conditions represent an important threat to human civilization, being the major killers in developed countries, with a steadily increasing prevalence. Thus, it is extremely important to search for novel markers of these diseases, as well as for novel therapeutic modalities to reverse this unfavorable situation. The heme catabolic pathway seems to fulfill the criteria for both diagnostic purposes as well as for potential therapeutical interventions. PMID- 22493582 TI - Cytokines and STATs in Liver Fibrosis. AB - Liver fibrosis, or cirrhosis, is a common end-stage condition of many chronic liver diseases after incomplete recovery from hepatocyte damage. During fibrosis progression, hepatocellular damage and inflammation trigger complex cellular events that result in collagen deposition and the disruption of the normal liver architecture. Hepatic stellate cell activation and transdifferentiation into myofibroblasts are key events in liver fibrogenesis. Research findings from cell culture and animal models have revealed that the Janus kinase-signal transducer and activator of transcription (Jak-STAT) signaling pathway, which can be activated by many cytokines, growth factors, and hormones, plays a critical role in hepatic fibrogenesis. This review summarizes the biological significance of diverse cytokines and their downstream signaling protein STATs in hepatic fibrogenesis. PMID- 22493585 TI - Implicit self-esteem in borderline personality and depersonalization disorder. AB - Self-perception is disrupted in people with borderline personality disorder (BPD) and depersonalization disorder (DPD), fluctuating with sudden shifts in affect in BPD and experienced as detached in DPD. Measures of implicit self-esteem (ISE), free from conscious control and presentation biases, may highlight how such disruptions of self-concept differentially affect these two populations on an unconscious level. We examined ISE using the Implicit Association Test, along with measures of emotion, behavior, and temperament, in BPD (n = 18), DPD (n = 18), and healthy control (n = 35) participants. DPD participants had significantly higher ISE and were more harm avoidant than BPD and control participants, while BPD participants had more "frontal" behaviors and impulsivity and less self-directedness and cooperativeness than DPD and control participants. Thus, while BPD and DPD commonly overlap in terms of dissociative symptoms and emotional irregularities, differences in self-esteem, behavior, and temperament can help identify where they diverge in terms of their cognition, behavior, and ultimately underlying neurobiology. PMID- 22493584 TI - Tropomyosin flexural rigidity and single ca(2+) regulatory unit dynamics: implications for cooperative regulation of cardiac muscle contraction and cardiomyocyte hypertrophy. AB - Striated muscle contraction is regulated by dynamic and cooperative interactions among Ca(2+), troponin, and tropomyosin on the thin filament. While Ca(2+) regulation has been extensively studied, little is known about the dynamics of individual regulatory units and structural changes of individual tropomyosin molecules in relation to their mechanical properties, and how these factors are altered by cardiomyopathy mutations in the Ca(2+) regulatory proteins. In this hypothesis paper, we explore how various experimental and analytical approaches could broaden our understanding of the cooperative regulation of cardiac contraction in health and disease. PMID- 22493583 TI - Neuroprotective effects of 17beta-estradiol rely on estrogen receptor membrane initiated signals. AB - Besides its crucial role in many physiological events, 17beta-estradiol (E2) exerts protective effects in the central nervous system. The E2 effects are not restricted to the brain areas related with the control of reproductive function, but rather are widespread throughout the developing and the adult brain. E2 actions are mediated through estrogen receptors (i.e., ERalpha and ERbeta) belonging to the nuclear receptor super-family. As members of the ligand regulated transcription factor family, classically, the actions of ERs in the brain were thought to mediate only the E2 long-term transcriptional effects. However, a growing body of evidence highlighted rapid, membrane initiated E2 effects in the brain that are independent of ER transcriptional activities and are involved in E2-induced neuroprotection. The aim of this review is to focus on the rapid effects of E2 in the brain highlighting the specific role of the signaling pathway(s) of the ERbeta subtype in the neuroprotective actions of E2. PMID- 22493586 TI - Response errors explain the failure of independent-channels models of perception of temporal order. AB - Independent-channels models of perception of temporal order (also referred to as threshold models or perceptual latency models) have been ruled out because two formal properties of these models (monotonicity and parallelism) are not borne out by data from ternary tasks in which observers must judge whether stimulus A was presented before, after, or simultaneously with stimulus B. These models generally assume that observed responses are authentic indicators of unobservable judgments, but blinks, lapses of attention, or errors in pressing the response keys (maybe, but not only, motivated by time pressure when reaction times are being recorded) may make observers misreport their judgments or simply guess a response. We present an extension of independent-channels models that considers response errors and we show that the model produces psychometric functions that do not satisfy monotonicity and parallelism. The model is illustrated by fitting it to data from a published study in which the ternary task was used. The fitted functions describe very accurately the absence of monotonicity and parallelism shown by the data. These characteristics of empirical data are thus consistent with independent-channels models when response errors are taken into consideration. The implications of these results for the analysis and interpretation of temporal order judgment data are discussed. PMID- 22493587 TI - A comparison of facial emotion processing in neurological and psychiatric conditions. AB - Patients suffering from various neurological and psychiatric disorders show different levels of facial emotion recognition (FER) impairment, sometimes from the early phases of the disease. Investigating the relative severity of deficits in FER across different clinical and high-risk populations has potential implications for the diagnosis and treatment of these diseases, and could also allow us to understand the neurobiological mechanisms of emotion perception itself. To investigate the role of the dopaminergic system and of the frontotemporal network in FER, we reanalyzed and compared data from four of our previous studies investigating FER performance in patients with frontotemporal dysfunctions and/or dopaminergic system abnormalities at different stages. The performance of patients was compared to the performance obtained by a specific group of matched healthy controls using Cohen's d effect size. We thus compared emotion and gender recognition in patients with frontotemporal dementia (FTD), amnestic mild cognitive impairment (aMCI), Alzheimer's disease (AD) at the mild dementia stage, major depressive disorder, Parkinson's disease treated by l-DOPA (PD-ON) or not (PD-OFF), remitted schizophrenia (SCZ-rem), first-episode schizophrenia treated by antipsychotic medication (SCZ-ON), and drug-naive first episode schizophrenia (SCZ-OFF), as well as in unaffected siblings of patients with schizophrenia (SIB). The analyses revealed a pattern of differential impairment of emotion (but not gender) recognition across pathological conditions. On the one hand, dopaminergic medication seems not to modify the moderate deficits observed in SCZ and PD groups (ON vs. OFF), suggesting that the deficit is independent from the dopaminergic system. On the other hand, the observed increase in effect size of the deficit among the aMCI, AD, and FTD groups (and also among the SIB and SCZ-rem groups) suggests that the deficit is dependent on neurodegeneration of the frontotemporal neural networks. Our transnosographic approach combining clinical and high-risk populations with the impact of medication provides new information on the trajectory of impaired emotion perception in neuropsychiatric conditions, and on the role of the dopaminergic system and the frontotemporal network in emotion perception. PMID- 22493588 TI - 15-month-old infants fast map words but not representational gestures of multimodal labels. AB - This study investigated whether 15-month-old infants fast map multimodal labels, and, when given the choice of two modalities, whether they preferentially fast map one better than the other. Sixty 15-month-old infants watched films where an actress repeatedly and ostensively labeled two novel objects using a spoken word along with a representational gesture. In the test phase, infants were assigned to one of three conditions: Word, Word + Gesture, or Gesture. The objects appeared in a shelf next to the experimenter and, depending on the condition, infants were prompted with either a word, a gesture, or a multimodal word-gesture combination. Using an infant eye tracker, we determined whether infants made the correct mappings. Results revealed that only infants in the Word condition had learned the novel object labels. When the representational gesture was presented alone or when the verbal label was accompanied by a representational gesture, infants did not succeed in making the correct mappings. Results reveal that 15 month-old infants do not benefit from multimodal labeling and that they prefer words over representational gestures as object labels in multimodal utterances. Findings put into question the role of multimodal labeling in early language development. PMID- 22493589 TI - The Fate of Incoming Stimuli during NREM Sleep is Determined by Spindles and the Phase of the Slow Oscillation. AB - The present study aimed at identifying the neurophysiological responses associated with auditory stimulation during non-rapid eye movement (NREM) sleep using simultaneous electroencephalography (EEG)/functional magnetic resonance imaging (fMRI) recordings. It was reported earlier that auditory stimuli produce bilateral activation in auditory cortex, thalamus, and caudate during both wakefulness and NREM sleep. However, due to the spontaneous membrane potential fluctuations cortical responses may be highly variable during NREM. Here we now examine the modulation of cerebral responses to tones depending on the presence or absence of sleep spindles and the phase of the slow oscillation. Thirteen healthy young subjects were scanned successfully during stage 2-4 NREM sleep in the first half of the night in a 3 T scanner. Subjects were not sleep-deprived and sounds were post hoc classified according to (i) the presence of sleep spindles or (ii) the phase of the slow oscillation during (+/-300 ms) tone delivery. These detected sounds were then entered as regressors of interest in fMRI analyses. Interestingly wake-like responses - although somewhat altered in size and location - persisted during NREM sleep, except during present spindles (as previously published in Dang-Vu et al., 2011) and the negative going phase of the slow oscillation during which responses became less consistent or even absent. While the phase of the slow oscillation did not alter brain responses in primary sensory cortex, it did modulate responses at higher cortical levels. In addition EEG analyses show a distinct N550 response to tones during the presence of light sleep spindles and suggest that in deep NREM sleep the brain is more responsive during the positive going slope of the slow oscillation. The presence of short temporal windows during which the brain is open to external stimuli is consistent with the fact that even during deep sleep meaningful events can be detected. Altogether, our results emphasize the notion that spontaneous fluctuations of brain activity profoundly modify brain responses to external information across all behavioral states, including deep NREM sleep. PMID- 22493590 TI - Age-Related Influences of Prior Sleep on Brain Activation during Verbal Encoding. AB - Disrupted sleep is more common in older adults (OLD) than younger adults (YOUNG), often co-morbid with other conditions. How these sleep disturbances affect cognitive performance is an area of active study. We examined whether brain activation during verbal encoding correlates with sleep quantity and quality the night before testing in a group of healthy OLD and YOUNG. Twenty-seven OLD (ages 59-82) and 27 YOUNG (ages 19-36) underwent one night of standard polysomnography. Twelve hours post-awakening, subjects performed a verbal encoding task while undergoing functional magnetic resonance imaging. Analyses examined the group (OLD vs. YOUNG) by prior sleep quantity (total sleep time, TST) or quality (sleep efficiency, SE) interaction on cerebral activation, controlling for performance. Longer TST promoted higher levels of activation in the bilateral anterior parahippocampal in OLD and lower activation levels in the left anterior parahippocampus in YOUNG. Greater SE promoted higher activation levels in the left posterior parahippocampus and right inferior frontal gyrus in YOUNG, but not in OLD. The roles of these brain regions in verbal encoding suggest, in OLD, longer sleep duration may be linked to the ability to engage in functional compensation during cognitive challenges. By contrast, in YOUNG, shorter sleep duration may necessitate functional compensation to maintain cognitive performance, similar to what is seen following acute sleep deprivation. Additionally, in YOUNG, better sleep quality may improve semantic retrieval processes, thereby aiding encoding. PMID- 22493591 TI - Diversity and activity of denitrifiers of chilean arid soil ecosystems. AB - The Chilean sclerophyllous matorral is a Mediterranean semiarid ecosystem affected by erosion, with low soil fertility, and limited by nitrogen. However, limitation of resources is even more severe for desert soils such as from the Atacama Desert, one of the most extreme arid deserts on Earth. Topsoil organic matter, nitrogen and moisture content were significantly higher in the semiarid soil compared to the desert soil. Although the most significant loss of biologically preferred nitrogen from terrestrial ecosystems occurs via denitrification, virtually nothing is known on the activity and composition of denitrifier communities thriving in arid soils. In this study we explored denitrifier communities from two soils with profoundly distinct edaphic factors. While denitrification activity in the desert soil was below detection limit, the semiarid soil sustained denitrification activity. To elucidate the genetic potential of the soils to sustain denitrification processes we performed community analysis of denitrifiers based on nitrite reductase (nirK and nirS) genes as functional marker genes for this physiological group. Presence of nirK type denitrifiers in both soils was demonstrated but failure to amplify nirS from the desert soil suggests very low abundance of nirS-type denitrifiers shedding light on the lack of denitrification activity. Phylogenetic analysis showed a very low diversity of nirK with only three distinct genotypes in the desert soil which conditions presumably exert a high selection pressure. While nirK diversity was also limited to only few, albeit distinct genotypes, the semiarid matorral soil showed a surprisingly broad genetic variability of the nirS gene. The Chilean matorral is a shrub land plant community which form vegetational patches stabilizing the soil and increasing its nitrogen and carbon content. These islands of fertility may sustain the development and activity of the overall microbial community and of denitrifiers in particular. PMID- 22493592 TI - Organic Acid Excretion in Penicillium ochrochloron Increases with Ambient pH. AB - Despite being of high biotechnological relevance, many aspects of organic acid excretion in filamentous fungi like the influence of ambient pH are still insufficiently understood. While the excretion of an individual organic acid may peak at a certain pH value, the few available studies investigating a broader range of organic acids indicate that total organic acid excretion rises with increasing external pH. We hypothesized that this phenomenon might be a general response of filamentous fungi to increased ambient pH. If this is the case, the observation should be widely independent of the organism, growth conditions, or experimental design and might therefore be a crucial key point in understanding the function and mechanisms of organic acid excretion in filamentous fungi. In this study we explored this hypothesis using ammonium-limited chemostat cultivations (pH 2-7), and ammonium or phosphate-limited bioreactor batch cultivations (pH 5 and 7). Two strains of Penicillium ochrochloron were investigated differing in the spectrum of excreted organic acids. Confirming our hypothesis, the main result demonstrated that organic acid excretion in P. ochrochloron was enhanced at high external pH levels compared to low pH levels independent of the tested strain, nutrient limitation, and cultivation method. We discuss these findings against the background of three hypotheses explaining organic acid excretion in filamentous fungi, i.e., overflow metabolism, charge balance, and aggressive acidification hypothesis. PMID- 22493593 TI - The phn Island: A New Genomic Island Encoding Catabolism of Polynuclear Aromatic Hydrocarbons. AB - Bacteria are key in the biodegradation of polycyclic aromatic hydrocarbons (PAH), which are widespread environmental pollutants. At least six genotypes of PAH degraders are distinguishable via phylogenies of the ring-hydroxylating dioxygenase (RHD) that initiates bacterial PAH metabolism. A given RHD genotype can be possessed by a variety of bacterial genera, suggesting horizontal gene transfer (HGT) is an important process for dissemination of PAH-degrading genes. But, mechanisms of HGT for most RHD genotypes are unknown. Here, we report in silico and functional analyses of the phenanthrene-degrading bacterium Delftia sp. Cs1-4, a representative of the phn(AFK2) RHD group. The phn(AFK2) genotype predominates PAH degrader communities in some soils and sediments, but, until now, their genomic biology has not been explored. In the present study, genes for the entire phenanthrene catabolic pathway were discovered on a novel ca. 232 kb genomic island (GEI), now termed the phn island. This GEI had characteristics of an integrative and conjugative element with a mobilization/stabilization system similar to that of SXT/R391-type GEI. But, it could not be grouped with any known GEI, and was the first member of a new GEI class. The island also carried genes predicted to encode: synthesis of quorum sensing signal molecules, fatty acid/polyhydroxyalkanoate biosynthesis, a type IV secretory system, a PRTRC system, DNA mobilization functions and >50 hypothetical proteins. The 50% G + C content of the phn gene cluster differed significantly from the 66.7% G + C level of the island as a whole and the strain Cs1-4 chromosome, indicating a divergent phylogenetic origin for the phn genes. Collectively, these studies added new insights into the genetic elements affecting the PAH biodegradation capacity of microbial communities specifically, and the potential vehicles of HGT in general. PMID- 22493594 TI - Tropism of Pandemic 2009 H1N1 Influenza a Virus. AB - Substitutions at the receptor-binding site of the pandemic H1N1 2009 influenza A virus (H1N1pdm) hemagglutinin (HA) gene may be critical in determining whether a virus binds to human or avian receptors. Previous reports suggest that HA Gly(222) and/or Arg(223) allow viruses to bind preferentially to the alpha2,3 linked sialic acid found in avian species. We also demonstrated that serial passaging of influenza A virus in embryonated chicken eggs increased viral growth 32- to 64-fold, coincident with the increased prevalence of Gly(222) or Arg(223) in HA protein (Yasugi et al., 2012). In this study, we showed that the minor genotype of alpha2,3-linkage-tropic viruses in upper airways became dominant after passaging through chicken eggs. Viruses possessing HA containing N125D Q223R, N125D-D187E-Q223R, K119N-D222G, and K119N-N129S-D222G, were detected in both clinical specimens and egg-passaged samples. These results might suggest that egg-adapted viruses, likely represented by alpha2,3-linkage-tropic virus, were also present in human upper airways as a minor population and transmitted in humans during the outbreak of H1N1pdm. PMID- 22493595 TI - Dysregulation of ion homeostasis by antifungal agents. AB - Ion-signaling and transduction networks are central to fungal development and virulence because they regulate gene expression, filamentation, host association, and invasion, pathogen stress response and survival. Dysregulation of ion homeostasis rapidly mediates cell death, forming the mechanistic basis by which a growing number of amphipathic but structurally unrelated compounds elicit antifungal activity. Included in this group is carvacrol, a terpenoid phenol that is a prominent component of oregano and other plant essential oils. Carvacrol triggers an early dose-dependent Ca(2+) burst and long lasting pH changes in the model yeast Saccharomyces cerevisiae. The distinct phases of ionic transients and a robust transcriptional response that overlaps with Ca(2+) stress and nutrient starvation point to specific signaling events elicited by plant terpenoid phenols, rather than a non-specific lesion of the membrane, as was previously considered. We discuss the potential use of plant essential oils and other agents that disrupt ion-signaling pathways as chemosensitizers to augment conventional antifungal therapy, and to convert fungistatic drugs with strong safety profiles into fungicides. PMID- 22493596 TI - Isolation of phyllosilicate-iron redox cycling microorganisms from an illite smectite rich hydromorphic soil. AB - The biogeochemistry of phyllosilicate-Fe redox cycling was studied in a Phalaris arundinacea (reed canary grass) dominated redoximorphic soil from Shovelers Sink, a small glacial depression near Madison, WI. The clay size fraction of Shovelers Sink soil accounts for 16% of the dry weight of the soil, yet contributes 74% of total Fe. The dominant mineral in the clay size fraction is mixed layer illite smectite, and in contrast to many other soils and sediments, Fe(III) oxides are present in low abundance. We examined the Fe biogeochemistry of Shovelers Sink soils, estimated the abundance of Fe redox cycling microorganisms, and isolated in pure culture representative phyllosilicate-Fe oxidizing and reducing organisms. The abundance of phyllosilicate-Fe reducing and oxidizing organisms was low compared to culturable aerobic heterotrophs. Both direct isolation and dilution-to-extinction approaches using structural Fe(II) in Bancroft biotite as a Fe(II) source, and O(2) as the electron acceptor, resulted in recovery of common rhizosphere organisms including Bradyrhizobium spp. and strains of Cupriavidus necator and Ralstonia solanacearum. In addition to oxidizing biotite and soluble Fe(II) with O(2), each of these isolates was able to oxidize Fe(II) in reduced NAu-2 smectite with [Formula: see text] as the electron acceptor. Oxidized NAu-2 smectite or amorphous Fe(III) oxide served as electron acceptors for enrichment and isolation of Fe(III)-reducing microorganisms, resulting in recovery of a strain related to Geobacter toluenoxydans. The ability of the recovered microorganisms to cycle phyllosilicate-Fe was verified in an experiment with native Shovelers Sink clay. This study confirms that Fe in the native Shovelers Sink clay is readily available for microbial redox transformation and can be cycled by the Fe(III)-reducing and Fe(II)-oxidizing microorganisms recovered from the soil. PMID- 22493597 TI - Renal Dysfunction in the Presence of Normoalbuminuria in Type 2 Diabetes: Results from the DEMAND Study. AB - BACKGROUND/AIMS: Microalbuminuria is associated with diabetes and is an independent risk factor for developing diabetic nephropathy. We have previously reported the overall prevalence of normoalbuminuria, microalbuminuria, and macroalbuminuria to be 51, 39, and 9.8%, respectively, in an unselected population of patients with type 2 diabetes. Renal dysfunction was present in a large proportion of these patients without proteinuria, assessed by a single random albumin-to-creatinine ratio (ACR). We therefore undertook to characterize the nature of this association of non-proteinuric renal dysfunction in type 2 diabetes. METHODS: In the DEMAND (Developing Education on Microalbuminuria for Awareness of Renal and Cardiovascular Risk in Diabetes) study, a global, cross sectional study which described the prevalence and risk factors for albuminuria in a clinic-based cohort, kidney function was assessed in 11,573 patients; ACR was measured using the Bayer reagent strip Multistix(r) 10SG. Normoalbuminuria was defined as ACR <30 mg/g, microalbuminuria as 30-299 mg/g, and macroalbuminuria as >300 mg/g. RESULTS: Among the patients with estimated kidney function determined, chronic kidney disease was noted in 17% of those with normoalbuminuria (stage 3-5), and significant kidney dysfunction was found in 27% of those with microalbuminuria and 31% of those with overt proteinuria. CrCl was <60 ml/min in 20.5% of normoalbuminurics, 30.7% of microalbuminurics, and 35.0% of macroalbuminurics (p < 0.0001). CONCLUSION: A large proportion of diabetic patients with completely normal urinary albumin excretion or microalbuminuria presented with significant kidney dysfunction. Therefore, further investigation is warranted. PMID- 22493599 TI - Low-Dose Treatment with Erythropoiesis-Stimulating Agents and Cardiovascular Geometry in Chronic Kidney Disease: Is Darbepoetin-alpha More Effective than Expected? AB - INTRODUCTION: Chronic kidney disease (CKD) is a widespread invalidating condition, leading to erythropoietin deficiency and decreased cardiovascular performance. Darbepoetin-alpha and epoetin-alpha are extensively used to correct renal anemia. The aim of this study was to evaluate cardiological outcomes in two groups of CKD patients treated with erythropoiesis-stimulating agents (ESA: 20 MUg darbepoetin-alpha weekly vs. 2,000 IU epoetin-alpha thrice weekly) with an unconventional 1:300 conversion ratio. METHODS: The study was designed as a single center, retrospective, observational study. One hundred stage IV CKD patients were selected. Hemoglobin (Hb), hematocrit, C-reactive protein, pro brain natriuretic peptide (BNP) and basal echocardiograms were monitored every 3 months. RESULTS: Darbepoetin-alpha was significantly more effective in increasing Hb levels after 3 (p < 0.0001), 6 (p < 0.0001), 9 (p < 0.01) and 12 months (p < 0.01) compared to epoetin-alpha. The optimal Hb target level (11 g/dl < Hb < 12 g/dl) was completely reached after 1 year of treatment with darbepoetin alpha and in 70% of the patients treated with epoetin-alpha (p < 0.01). Cardiovascular performance (left ventricular end-diastolic volume, ejection fraction and pro-BNP) was significantly improved after darbepoetin-alpha treatment at the 6- and 12-month follow-ups compared to epoetin-alpha. Discussion: Despite the limitations of a retrospective observational study, these results encourage nephrologists to test the 1:300 darbepoetin/epoetin conversion ratio in 'easy' patients, and aggressive protocols for the treatment of anemia in CKD patients are avoided. Darbepoetin-alpha appeared effective in anemia correction, improving cardiovascular performance in a significantly higher proportion than epoetin. At low doses, on the other hand, it has to be borne in mind that a treatment regimen with only one submaximal administration per week may increase patient compliance and adherence to therapy, explaining in part the observed results. PMID- 22493598 TI - Ultrasonography: Ariadne's Thread in the Diagnosis of the Cardiorenal Syndrome. AB - The term cardiorenal syndrome (CRS) describes a broad spectrum of clinical conditions with four combinations of acute and chronic heart and kidney failure. Based on the pathophysiological primum movens, the actual classification recognizes five CRS types: in type I and II CRS, the initiating event is heart failure (acute or chronic), while it is kidney failure in type III and IV CRS; type V is linked to systemic diseases. Ultrasound techniques (echocardiography and ultrasonography of the kidney, inferior vena cava and chest) can be extremely helpful in establishing a prompt diagnosis and a correct CRS classification. Basic echocardiography allows evaluation of ventricular diastolic and systolic functions, investigates pulmonary congestion and pericardial effusion, and describes volume overload. On the other hand, renal ultrasound helps clinicians to distinguish between acute and chronic renal failure, excludes urinary tract dilation or pathological bladder repletion, and provides crucial information regarding kidney volume or echogenicity. Applying basic knowledge of echocardiography and renal ultrasound, nephrologists may be in a better position for patient treatment and management, bearing in mind that doctors can properly use a stethoscope although not being a cardiologist. PMID- 22493600 TI - Adjusting for Urinary Creatinine Overestimates Arsenic Concentrations in Diabetics. AB - BACKGROUND/AIMS: Arsenic (As) is linked to insulin resistance in animal studies, but the effect of low-level As exposure on the prevalence of diabetes in humans is uncertain. An optimal method to report inorganic As in humans has not been established. Measurements of As in spot urine are usually adjusted to creatinine (Cr). However, urinary Cr is an independent variable in diabetes. Our aims are to optimize reporting of urinary As in the setting of diabetes and insulin resistance. METHODS: Urinary inorganic As was measured in 24-hour or first-void spot urine from diabetic (n = 31) and non-diabetic (n = 12) subjects and normalized to Cr or specific gravity (SG). The relation of normalized urinary inorganic As to glycemia and surrogate measures of insulin resistance was investigated. Blood pressure, waist circumference, and glycated hemoglobin were also assessed. Homeostasis model assessment was used to determine insulin resistance. RESULTS: A strong correlation was found between spot urinary As adjusted to Cr (R(2) = 0.82) or SG (R(2) = 0.61) to 24-hour urinary As (p < 0.001), while non-adjusted urinary As did not correlate well (R(2) = 0.03, p = 0.46). Adjusting for Cr revealed significant differences in total 24-hour urinary As when comparing diabetic to normal subjects. In contrast, no differences were found when As was adjusted to SG using either 24-hour or spot urine. Moreover, adjusted urinary spot or 24-hour As measures did not correlate with measures of glycemia or insulin resistance. Conclusions: Urinary Cr is an independent variable in diabetes, therefore adjusting spot As for SG is preferred. PMID- 22493601 TI - Cardiorenal Syndrome Type 1 May Be Immunologically Mediated: A Pilot Evaluation of Monocyte Apoptosis. AB - BACKGROUND: Cardiorenal syndrome (CRS) type 1 is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). An immune mediated damage and alteration of immune response have been postulated as potential mechanisms involved in CRS type 1. In this pilot study, we examined the possible role of the immune-mediated mechanisms in the pathogenesis of this syndrome. The main objective was to analyze in vitro that plasma of CRS type 1 patients was able to trigger a response in monocytes resulting in apoptosis. The secondary aim was to evaluate TNF-alpha and IL-6 plasma levels of CRS type 1 patients. METHODS: Fifteen patients with acute heart failure (AHF) and CRS type 1 were enrolled and 20 healthy volunteers without AHF or AKI were recruited as control group. Plasma from these two groups was incubated with monocytes and, subsequently, cell apoptosis was evaluated. In addition, the activity of caspase 8 was assessed after 24 h incubation. Quantitative determination of TNF-alpha and IL-6 levels was performed. RESULTS: Plasma-induced apoptosis was significantly higher in CRS type 1 patients compared with healthy controls at 72 h (78 vs. 11%) and 96 h (81 vs. 11%). At 24 h, the activity of caspase-8 was significantly higher in monocytes incubated with plasma from the CRS type 1 group. TNF-alpha (2.39 vs. 28.49 pg/ml) and IL-6 (4.8 vs. 16.5 pg/ml) levels were significantly elevated in the CRS type 1 group (p < 0.01). CONCLUSIONS: In conclusion, there is a defective regulation of monocyte apoptosis in CRS type 1 patients, and inflammatory pathways may have a central role in the pathogenesis of CRS type 1 and may be fundamental in damage to distant organs. PMID- 22493602 TI - The Relationship between Epicardial Adipose Tissue and Coronary Artery Calcification in Peritoneal Dialysis Patients. AB - BACKGROUND: Atherosclerosis, endothelial dysfunction, coronary artery calcification (CAC), and left ventricular hypertrophy are the most commonly encountered risk factors in the pathogenesis of cardiovascular disease in end stage renal disease patients. Epicardial adipose tissue (EAT) is the true visceral fat depot of the heart. The relationship between coronary artery disease and EAT has been shown in healthy subjects and patients with a high risk of coronary artery disease. In the present study, we aimed to investigate the relationship between EAT and CAC in peritoneal dialysis (PD) patients. Patients and Methods: Forty-five PD patients (18 females, 27 males, with a mean age of 50.6 +/- 15 years) and 25 healthy subjects (12 females, 13 males, with a mean age of 52.4 +/- 10.7 years) were enrolled in the study. EAT and CAC score (CACS) measurements were performed by a multidetector computed tomography scanner. RESULTS: EAT of the PD patients was significantly higher than that of the healthy subjects (p = 0.02). When patients were divided into two subgroups (group 1: CACS <=10, n = 20; group 2: CACS >10, n = 25), EAT was also significantly higher in group 2 patients than in group 1 patients and healthy subjects. Age and EAT were also found to be correlated with CACS >=10. CONCLUSION: There is a relationship between the anatomic assessment of coronary artery lesions by multidetector computed tomography and EAT in PD patients. This relationship might be attributed to increased inflammation and proinflammatory cytokines in uremic patients. PMID- 22493603 TI - A Case of Carcinoid Tumor-Associated Hypercalcemia. AB - Hypercalcemia as a complication of carcinoid tumors is extremely rare. Accordingly, we report the case of a 55-year-old male with metastatic carcinoid tumor and hypercalcemia, which corrected when the patient was treated with octreotide for symptomatic relief of watery diarrhea. The etiology of the hypercalcemia is presumed to be a neoplastic expression of fibroblast growth factor-23, which was found to be inappropriately high-to-normal when other factors such as parathyroid hormone, calcitonin and vitamin D were appropriately low or low-to-normal. PMID- 22493604 TI - Very Low Density Lipoprotein Metabolism in Patients with Chronic Kidney Disease. AB - BACKGROUND: Hypertriglyceridemia is a common metabolic complication of chronic kidney disease (CKD) and an important risk factor for coronary heart disease in this patient population. The mechanisms responsible for the development of hypertriglyceridemia in subjects with CKD are not clear. METHODS: We studied very low density lipoprotein triglyceride (VLDL-TG) and VLDL-apolipoprotein B-100 (VLDL-apoB-100) kinetics in vivo in 6 subjects with non-dialysis-dependent CKD (CKD-ND), 6 subjects with CKD treated with peritoneal dialysis (CKD-PD) and 24 sex-, age- and body mass index-matched control subjects with normal renal function (12 control subjects each matched with the CKD-ND and CKD-PD group, respectively). RESULTS: The secretion rates of VLDL-TG and VLDL-apoB-100 into plasma were not different between CKD-ND or CKD-PD and their respective control groups. The mean residence times of VLDL-TG and VLDL-apoB-100 in plasma, which represents the time VLDL-TG and VLDL-apoB-100 spend in the circulation after secretion by the liver, tended to be greater in subjects with CKD-ND than in control subjects (222 +/- 38 vs. 143 +/- 21 min, p = 0.07, and 352 +/- 102 vs. 200 +/- 20 min, p = 0.06, respectively) and were about two-fold greater in subjects with CKD-PD compared with their control group (248 +/- 51 vs. 143 +/- 21 min and 526 +/- 116 vs. 182 +/- 16 min, respectively; both p <= 0.01). CONCLUSION: Impaired plasma clearance of VLDL-TG and VLDL-apoB-100 is the major abnormality associated with hypertriglyceridemia in patients with either CKD-ND or CKD-PD. PMID- 22493605 TI - Ultrastructure Study of Transgenic Ren2 Rat Aorta - Part 1: Endothelium and Intima. AB - BACKGROUND: The renin-angiotensin-aldosterone system plays an important role in the development and progression of hypertension and accelerated atherosclerosis (atheroscleropathy) associated with the cardiorenal metabolic syndrome and type 2 diabetes mellitus. Additionally, the renin-angiotensin-aldosterone system plays an important role in vascular-endothelial-intimal cellular and extracellular remodeling. METHODS: Thoracic aortas of young male transgenic heterozygous (mRen2)27 (Ren2) rats were utilized for this ultrastructural study. This lean model of hypertension, insulin resistance and oxidative stress harbors the mouse renin gene with increased local tissue (aortic) levels of angiotensin II and angiotensin type 1 receptors and elevated plasma aldosterone levels. RESULTS: The ultrastructural observations included marked endothelial cell retraction, separation, terminal nuclear lifting, adjacent duplication, apoptosis and a suggestion of endothelial progenitor cell attachment. The endothelium demonstrated increased caveolae, microparticles, depletion of Weibel-Palade bodies, loss of cell-cell and basal adhesion hemidesmosome-like structures, platelet adhesion and genesis of subendothelial neointima. CONCLUSION: These observational ultrastructural studies of the transgenic Ren2 vasculature provide an in-depth evaluation of early abnormal remodeling changes within conduit elastic arteries under conditions of increased local levels of angiotensin II, oxidative stress, insulin resistance and hypertension. PMID- 22493606 TI - Meta-Analysis of Global Transcriptomics Suggests that Conserved Genetic Pathways are Responsible for Quercetin and Tannic Acid Mediated Longevity in C. elegans. AB - Recent research has highlighted that the polyphenols Quercetin and Tannic acid are capable of extending the lifespan of Caenorhabditis elegans. To gain a deep understanding of the underlying molecular genetics, we analyzed the global transcriptional patterns of nematodes exposed to three concentrations of Quercetin or Tannic acid, respectively. By means of an intricate meta-analysis it was possible to compare the transcriptomes of polyphenol exposure to recently published datasets derived from (i) longevity mutants or (ii) infection. This detailed comparative in silico analysis facilitated the identification of compound specific and overlapping transcriptional profiles and allowed the prediction of putative mechanistic models of Quercetin and Tannic acid mediated longevity. Lifespan extension due to Quercetin was predominantly driven by the metabolome, TGF-beta signaling, Insulin-like signaling, and the p38 MAPK pathway and Tannic acid's impact involved, in part, the amino acid metabolism and was modulated by the TGF-beta and the p38 MAPK pathways. DAF-12, which integrates TGF beta and Insulin-like downstream signaling, and genetic players of the p38 MAPK pathway therefore seem to be crucial regulators for both polyphenols. Taken together, this study underlines how meta-analyses can provide an insight of molecular events that go beyond the traditional categorization into gene ontology terms and Kyoto encyclopedia of genes and genomes-pathways. It also supports the call to expand the generation of comparative and integrative databases, an effort that is currently still in its infancy. PMID- 22493607 TI - Influence of Nitrate and Nitrite on Thyroid Hormone Responsive and Stress Associated Gene Expression in Cultured Rana catesbeiana Tadpole Tail Fin Tissue. AB - Nitrate and nitrite are common aqueous pollutants that are known to disrupt the thyroid axis. In amphibians, thyroid hormone (TH)-dependent metamorphosis is affected, although whether the effect is acceleration or deceleration of this developmental process varies from study to study. One mechanism of action of these nitrogenous compounds is through alteration of TH synthesis. However, direct target tissue effects on TH signaling are hypothesized. The present study uses the recently developed cultured tail fin biopsy (C-fin) assay to study possible direct tissue effects of nitrate and nitrite. Tail biopsies obtained from premetamorphic Rana catesbeiana tadpoles were exposed to 5 and 50 mg/L nitrate (NO(3)-N) and 0.5 and 5 mg/L nitrite (NO(2)-N) in the absence and presence of 10 nM T(3). Thyroid hormone receptor beta (TRbeta) and Rana larval keratin type I (RLKI), both of which are TH-responsive gene transcripts, were measured using quantitative real time polymerase chain reaction. To assess cellular stress which could affect TH signaling and metamorphosis, heat shock protein 30, and catalase (CAT) transcript levels were also measured. We found that nitrate and nitrite did not significantly change the level of any of the four transcripts tested. However, nitrate exposure significantly increased the heteroscedasticity in response of TRbeta and RLKI transcripts to T(3). Alteration in population variation in such a way could contribute to the previously observed alterations of metamorphosis in frog tadpoles, but may not represent a major mechanism of action. PMID- 22493609 TI - The role and clinical significance of high-sensitivity C-reactive protein in cardiovascular disease. PMID- 22493608 TI - Constrictive Pericarditis as a Never Ending Story: What's New? AB - Nowadays, we have a better understanding of the natural history of constrictive pericarditis such as transient constriction. In addition, we have acquired the correct understanding of hemodynamic features that are unique to constrictive pericarditis. This understanding has allowed us to diagnose constrictive pericarditis reliably with Doppler echocardiography and differentiation between constrictive pericarditis and restrictive cardiomyopathy is no longer a clinical challenge. The advent of imaging modalities such as CT or MR is another advance in the diagnosis of constrictive pericarditis. We can accurately measure pericardial thickness and additional information such as the status of coronary artery and the presence of myocardial fibrosis can be obtained. We no longer perform cardiac catheterization for the diagnosis of constrictive pericarditis. However, these advances are useless unless we suspect and undergo work-up for constrictive pericarditis. In constrictive pericarditis, the most important diagnostic tool is clinical suspicion. In a patient with signs and symptoms of increased systemic venous pressure i.e. right sided heart failure, that are disproportionate to pulmonary or left sided heart disease, possibility of constrictive pericarditis should always be included in the differential diagnosis. PMID- 22493610 TI - A comparative study on mechanical and biochemical properties of bovine pericardium after single or double crosslinking treatment. AB - BACKGROUND AND OBJECTIVES: Glutaraldehyde (GA) has been used as a representative method of tissue preservation in cardiovascular surgery. However, GA has showed limited durability including calcification, mechanical failure and toxicity. To overcome those unsolved problems, we analyzed the crosslinking differences of primary amines, GA and genipin in their mechanical and biochemical properties with a single or double crosslinking agent for clinical application. MATERIALS AND METHODS: Samples were divided into 3 groups; control, single crosslinking fixation and double crosslinking fixation after decellurarization using bovine pericardium. For analysis of the biochemical and mechanical properties of each crosslinking method, tensile strength, percentage strain, thermal stability, resistance to pronase, nynhydrin and cytotoxicity test were studied. RESULTS: Combined hexamethylene diamine and suberic acid in the carbodiimide hydrochloride/N-hydroxysucinimide solution (EDC/NHS) after decellurarization, tensile strength and strain percentage were not statistically significant compared to the single crosslinking treated groups (p>0.05). Tissue crosslinking stability was weak in single treatment of diphenylphosphoryl azide, suberic acid, low concentration of EDC, hexamethylene diamine and procyanidin groups, but thermal stability and resistance to the pronase and ninhydrin were markedly increased in concentrated EDC/NHS or after combined double treatment with low concentration of GA or genipin (p<0.001). CONCLUSION: Single or double crosslinking with low concentration of carbodiimide, diphenylphosphonyl azide, procyanidin, suberic acid and hexane diamine were not as effective in mechanical, biochemical, cytotoxic and crosslinking properties compared to GA or genipin fixation, but their mechanical and chemical properties were much improved when combined with low concentrations of GA or genipin in the double crosslinking process. PMID- 22493611 TI - Prognostic impact of baseline high-sensitivity C-reactive protein in patients with acute myocardial infarction undergoing percutaneous coronary intervention based on body mass index. AB - BACKGROUND AND OBJECTIVES: Serum high sensitivity C-reactive protein (hs-CRP) is a marker of inflammation and may lead to the development of atherosclerosis, adversely affecting mortality. The aim of this study was to evaluate the relationship between baseline hs-CRP level and 12-month clinical outcomes in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) according to their body mass index (BMI) status. SUBJECTS AND METHODS: Using data from the Korea Acute Myocardial Infarction Registry from November 2005 to September 2008, a total of 8174 consecutive AMI patients were studied. Cox proportional hazard model revealed that higher baseline levels of hs CRP was associated with 12-month all-cause mortality (p=0.045). To further understand this association, patients were divided into 3 groups based on their body mass index: 1) overweight/obese, 2) normal weight, and 3) underweight patients. Then each group was stratified into quartiles based on their hs-CRP. RESULTS: In overweight/obese patients, Cox model showed significant association of hs-CRP with 12-month mortality when adjusted for age and gender (p<0.001), however, after adjustment with multiple covariates, mortality was highest in the 4th quartile {HR 2.382, (1.079-5.259), p=0.032} though statistically insignificant (p=0.172). We observed no significant association of serum hs-CRP with 12-month mortality in normal weight (p=0.681) and underweight (p=0.760) patients. CONCLUSION: Higher baseline hs-CRP level (>=4.08 mg/dL) in overweight/obese AMI patients showed significant association with 12-month all cause mortality independent of other prognostic markers. PMID- 22493612 TI - The relevance of the primary prevention criteria for implantable cardioverter defibrillator implantation in korean symptomatic severe heart failure patients. AB - BACKGROUND AND OBJECTIVES: Implantable cardioverter defibrillator (ICD) therapy is recommended as the primary tool for prevention of sudden cardiac death (SCD) in symptomatic patients with severe left ventricular dysfunction. There is a paucity of information on whether this recommendation is appropriate for the Korean population with severe heart failure. SUBJECTS AND METHODS: The study group consisted of 275 consecutive patients (mean age 65 years, 71% male) who met the ICD implantation criteria for primary prevention (left ventricular ejection fraction <=30% and New York Heart Association functional class II or III). We analyzed the clinical characteristics and outcomes of an ischemic cardiomyopathy (ICMP) group (n=131) and a non-ischemic cardiomyopathy (NICMP) group (n=144). The outcomes of these 2 groups were compared with the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) conventional and Defibrillators in the Non-ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) standard therapy groups, respectively. RESULTS: Eighty patients (29%) died during a follow-up period of 40+/-17 months. The NICMP group had better all-cause mortality rates than the ICMP group (19% vs. 40%, p<0.001), however both groups had a similar incidence of SCD (7% vs. 10%, p=0.272). The 2-year all-cause mortality and SCD for the ICMP group were similar to those of the MADIT-II conventional therapy group (20% vs. 20%, 7% vs. 10%, respectively, all p>0.05). All-cause mortality and the incidence of SCD in the NICMP group were comparable to those of the DEFINITE standard therapy group (13% vs. 17%, 6% vs. 6%, respectively, all p>0.05). CONCLUSION: Korean patients with severe heart failure in both the ICMP and NICMP groups had all-caused mortality and risk of SCD comparable to patients in the MADIT-II and DEFINITE standard therapy groups. Therefore, the primary prevention criteria for ICD implantation would be appropriate in both Korean ICMP and NICMP patients. PMID- 22493613 TI - The effect of enalapril and carvedilol on left ventricular dysfunction in middle childhood and adolescent patients with muscular dystrophy. AB - BACKGROUND AND OBJECTIVES: In Duchenne and Becker muscular dystrophies, cardiac function deteriorates with time resulting in heart failure which is often fatal. We prospectively evaluated the effect of enalapril and carvedilol on left ventricular (LV) dysfunction in middle childhood and adolescent patients with muscular dystrophy. SUBJECTS AND METHODS: Twenty-three patients with LV dysfunction (22 with Duchenne muscular dystrophy, 1 with Becker muscular dystrophy) were enrolled. We prescribed enalapril (13 patients) or carvedilol (10 patients) randomly from July 2008 to August 2010 and followed up the patients until September 2011. The changes in LV function parameters before and after the treatment were evaluated by echocardiography. RESULTS: The mean age at the start of treatment with enalapril or carvedilol was 12.6+/-3.7 years (median 13 years), and mean follow-up duration was 20.1+/-8.9 months. In the enalapril group, LV fractional shortening (FS) increased from 25.8+/-2.1 to 26.6+/-3.0 (p=0.241). In the carvedilol group, LV FS increased from 26.4+/-1.1 to 28.6+/-4.2 (p=0.110). In all 23 patients, LV FS significantly increased from 26.1+/-1.7 (before) to 27.6+/ 3.7 (after treatment) (p<0.046). Indexed LV dimension at end diastole and LV end diastolic volume decreased slightly, but without statistical significance by tri plane volumetry. LV diastolic functional parameters were maintained during follow up period. CONCLUSION: Enalapril or carvedilol could improve LV systolic function in middle childhood and adolescent patients with muscular dystrophy without significant adverse effects. PMID- 22493614 TI - B-type natriuretic Peptide assay for the diagnosis and prognosis of patent ductus arteriosus in preterm infants. AB - BACKGROUND AND OBJECTIVES: Patent ductus arteriosus (PDA) is a significant cause of morbidity and mortality in preterm infants. Measurement of plasma B-type natriuretic peptide (BNP) has been reported to be a useful bedside screening tool for the presence of hemodynamically significant PDA (hsPDA) in neonates. This study was conducted to investigate the usefulness of a BNP assay as a biochemical marker for the diagnosis of hsPDA and predictive biomarker of the response to indomethacin in preterm infants. SUBJECTS AND METHODS: Preterm infants born at <37 weeks' gestational age were prospectively enrolled within 24 hours of birth. Plasma BNP levels were measured on days 1, 4, and 7. Significant PDA was diagnosed by large ductal flow with left to right shunt on color Doppler echocardiography, along with clinical features of PDA. Following that, hsPDA was treated with indomethacin. RESULTS: A total of 28 preterm infants were prospectively enrolled in this study. Seven infants with PDA had higher on day 4 plasma BNP values (median 654.68 pg/mL; range 428.29-1280.00) compared to the control group (median 124.52 pg/mL; range 37.21-290.49). The area under the receiver operator characteristic curve for the detection of hsPDA was high: 0.998 (95% confidence interval: 0.995-1.002). The cutoff of BNP concentration for the diagnosis of hsPDA was determined to be 412 pg/mL (sensitivity: 100%; specificity: 95%). CONCLUSION: B-type natriuretic peptide can be a useful biomarker for the screening and diagnosis of PDA in preterm infants. Serial BNP measurements are valuable for assessing the clinical course and indomethacin responsiveness of PDA. PMID- 22493615 TI - Subarachnoid hemorrhage mimicking leakage of contrast media after coronary angiography. AB - We report a patient who developed subarachnoid hemorrhage (SAH) just after coronary angiography (CAG) with non-ionic contrast media (CM) and minimal dose of heparin. The 55-year-old man had a history of acute ST elevation myocardial infarction that had been treated with primary percutaneous coronary intervention and was admitted for a follow-up CAG. The CAG was performed by the transradial approach, using 1000 U of unfractionated heparin for the luminal coating and 70 mL of iodixanol. At the end of CAG, he complained of nausea and rapidly became stuporous. Brain CT showed a diffusely increased Hounsfield unit (HU) in the cisternal space, similar to leakage of CM. The maximal HU was 65 in the cisternal space. No vascular malformations were detected on cerebral angiography. The patient partially recovered his mental status and motor weakness after 2 days. Two weeks later, subacute SAH was evident on magnetic resonance imaging. The patient was discharged after 28 days. PMID- 22493616 TI - Successful retrieval of a fractured and entrapped 0.035-inch terumo wire in the femoral artery using biopsy forceps. AB - A 0.035-inch guide wire fracture and entrapment in a peripheral artery is a very rare complication, but when it does occur it may lead to life-threatening complications, such as perforation, thrombus formation, embolization, and subsequent limb ischemia. We describe our experience of successfully retrieving a fractured 0.035-inch Terumo guide wire in the external iliac artery using a biopsy forcep. PMID- 22493617 TI - Contrast echo-a simple diagnostic tool for a coronary artery fistula. AB - Coronary artery fistulas have been diagnosed with aortography, coronary angiography, and coronary computed tomography (CT). A large fistula can be occasionally found as a mass lesion on echocardiography but cannot be easily confirmed. Here, we report a new diagnostic approach to coronary artery fistulas using a contrast agent and transthoracic echocardiography. Transthoracic echocardiography of a 46-year-old female suffering from dyspnea revealed suspicious small turbulent flow in the main pulmonary artery. Following infusion of a contrast agent, we found whitish flow in the main pulmonary artery during the diastolic phase, and aortic CT revealed two huge right coronary artery fistulas in the main pulmonary artery. A simple diagnostic approach to a coronary artery fistula using contrast agent helped us confirm the diagnosis because of the typical diastolic whitish flow in the pulmonary artery. PMID- 22493618 TI - A rare coronary anomaly: atypical double right coronary artery with an acute inferior myocardial infarction. AB - Coronary artery anomalies are uncommon and often asymptomatic. A double right coronary artery (RCA) is an extremely rare coronary artery anomaly, and only a few cases of double RCA have been reported. We report on an atherosclerotic double RCA that appeared after primary percutaneous intervention in a patient with an acute inferior myocardial infarction. This is the second case in the literature in which coronary arteries can be accepted as a double RCA, which were hidden by a total atherosclerotic occlusion in the proximal part of the RCA. PMID- 22493619 TI - A case of swallow syncope associated with cold beverage ingestion. AB - Swallow syncope (also known as deglutition syncope) is a relatively rare type of syncope that is treatable if diagnosed correctly. We report a case of a 39-year old man with recurrent swallow syncope. The patient did not have structural heart disease. He developed a complete atrioventricular block upon drinking a cold beverage (Chilsung cider) while undergoing a repeated head-up tilt test. The patient was advised to avoid cold beverages and has been symptom free for 5 months. PMID- 22493620 TI - Subarachnoid Hemorrhage Misdiagnosed as an Acute ST Elevation Myocardial Infarction. AB - Without significant coronary artery stenosis, ischemic electrocardiographic change including ST segment elevation, segmental wall motion abnormality and elevated serum cardiac-specific markers (creatine kinase-MB, Troponin-T) may develop after central nervous system injuries such as subarachnoid, intracranial or subdural hemorrhage. Misdiagnosing these patients as acute myocardial infarction may result in catastrophic outcomes. By reporting a case of a 55-year old female with subarachnoid hemorrhage mimicking acute ST elevation myocardial infarction, we hope to underline that careful attention of neurologic abnormality is critical in making better prognosis. PMID- 22493621 TI - Pressure tracings in hypertrophic cardiomyopathy with dynamic midventricular obstruction. PMID- 22493622 TI - Surgical techniques for personalized oncoplastic surgery in breast cancer patients with small- to moderate-sized breasts (part 1): volume displacement. AB - Despite the popularity of breast-conserving surgery (BCS), which constitutes 50 60% of all breast cancer surgeries, discussions regarding cosmetic results after BCS are not specifically conducted. The simple conservation of breast tissue is no longer adequate to qualify for BCS completion. The incorporation of oncological and plastic surgery techniques allows for the complete resection of local disease while achieving superior cosmetic outcome. Oncoplastic BCS can be performed in one of the following two ways: 1) volume displacement techniques and 2) volume replacement techniques. This study reports volume displacement surgical techniques, which allow the use of remaining breast tissue after BCS by glandular reshaping or reduction techniques for better cosmetic results. Thorough understanding of these procedures and careful consideration of the patient's breast size, tumor location, excised volume, and volume of the remaining breast tissue during the surgery in choosing appropriate patient and surgical techniques will result in good cosmetic results. Surgery of the contralateral breast may be requested to improve symmetry and may take the form of a reduction mammoplasty or mastopexy. The timing of such surgery and the merits of synchronous versus delayed approaches should be discussed in full with the patients. Because Korean women have relatively small breast sizes compared to Western women, it is not very easy to apply the oncoplastic volume displacement technique to cover defects. However, we have performed various types of oncoplastic volume displacement techniques on Korean women, and based on our experience, we report a number of oncoplastic volume displacement techniques that are applicable to Korean women with small- to moderate-sized breasts. PMID- 22493623 TI - Surgical techniques for personalized oncoplastic surgery in breast cancer patients with small- to moderate-sized breasts (part 2): volume replacement. AB - Oncoplastic breast surgery has become a popular choice of treatment for breast reconstruction after mastectomy. There are two different techniques in oncoplastic surgery depending on the volume of the excised breast tissue. One is the volume displacement procedure, which combines resection with a variety of different breast-reshaping and breast-reduction techniques; the other is the volume replacement procedure in which the volume of excised breast tissue is replaced with autologous tissue. In this study, current authors performed various volume replacement techniques based on the weight of the excised tumor and its margin of resection. We used a latissimus dorsi myocutaneous flap for cases in which the resection mass was greater than 150 g, and for cases in which the resection mass was less than 150 g, we used a regional flap, such as a lateral thoracodorsal flap, a thoracoepigastric flap, or perforator flaps, such as an intercostal artery perforator flap or a thoracodorsal artery perforator flap. In the patients with small to moderate-sized breasts, when a postoperative deformity is expected due to a large-volume tumor resection, the replacement of non-breast tissue is required. Many of whom have small breasts, oncoplastic volume replacement techniques in breast-conserving surgery allow an extensive tumor excision without concern of compromising the cosmetic outcome and can be reliable and useful techniques with satisfactory aesthetic results. PMID- 22493624 TI - Aberrant Expression of Cancer Stem Cells Marker Prominin-1 in Low-Grade Tubulolobular Breast Carcinoma: A Correlative Study between qRT-PCR, Flow Cytometric and Immunohistochemistry Analysis [corrected]. AB - PURPOSE: Prominin1/CD133 has become the ideal marker for cancer stem cells (CSCs) detection in human tumors. In this study we examined the expression of this marker in several breast cancer specimens to associate CSCs percentage with risk factor for this neoplasia. METHODS: We examined specimens from 12 patients using CD133 and CD44 antibodies for CSCs immunohistochemistry detection and for flow cytometry analysis. For each patient, we also performed the immunohistochemical staining to evaluate the expression of estrogen receptor, progesterone receptor, c-erbB-2, Ki67, and E-cadherin markers. A Taqman probe for CD133 was used for mRNA quantification by real-time polymerase chain reaction. RESULTS: Prominin-1 expression was heterogeneous in different carcinomas but was strikingly hyperexpressed in a tubulolobular variant of breast cancer. The results were confirmed by all three methods. CONCLUSION: Our data, although produced on a limited number of samples, showed an particularly high expression of stem cell marker CD133 in a breast cancer variant, generally with a good prognosis. Since CSCs detection by CD133 has been described as an important prognostic factor for several human cancers, we suggest the importance of detecting stem cell compartiments in all histotypes of breast carcinomas. PMID- 22493625 TI - Multiplication of Chromosome 17 Centromere Is Associated with Prognosis in Patients with Invasive Breast Cancers Exhibiting Normal HER2 and TOP2A Status. AB - PURPOSE: This study aimed to investigate the clinical significance of chromosome 17 centromere (CEP17) multiplication (increased copy number of CEP17) related to human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) status in patients with invasive breast cancer. METHODS: We constructed tissue microarrays using 594 invasive breast cancer samples and performed single color silver-enhanced in situ hybridization (SISH) assay for HER2, TOP2A, and CEP17 to assess for copy number aberrations. The association of CEP17 multiplication with patient survival was analyzed according to HER2 and TOP2A status. RESULTS: Among 567 informative cases, HER2 amplification was noted in 22.8%, TOP2A amplification in 8.3% and TOP2A deletion in 11.1%. CEP17 multiplication was identified in 33.2% and was significantly associated with worse overall survival (OS) (p=0.02) and disease-free survival (DFS) (p=0.02). CEP17 multiplication correlated with patient survival in patients with normal TOP2A or non-amplified HER2 status, but the prognostic significance was lost in those with altered TOP2A or amplified HER2. On multivariate analyses, CEP17 multiplication was an independent prognostic factor for poorer OS (p=0.02) and DFS (p=0.01) in patients with normal TOP2A and non-amplified HER2. CONCLUSION: CEP17 multiplication was identified as a promising prognostic marker in patients with invasive breast cancer exhibiting either non-amplified HER2 or normal TOP2A status. PMID- 22493626 TI - Circulating Tumor Cells Detected by RT-PCR for CK-20 before Surgery Indicate Worse Prognostic Impact in Triple-Negative and HER2 Subtype Breast Cancer. AB - PURPOSE: Circulating tumor cells (CTC) clearly correlate with unfavorable outcomes for patients with metastatic breast cancer, but the long-term prognostic implications of CTC for molecular subtypes of operable breast cancer are not yet known. We explored the relationships between previously established prognostic factors and CTC in operable breast cancer, and the significance of CTC by breast cancer molecular subtype. METHODS: We retrospectively evaluated 166 patients with operable breast cancer (stage I-IIIA) diagnosed from April 1997 to May 2003. CTC were detected using cytokeratin-20 (CK-20) mRNA expression in peripheral blood samples that were collected just prior to surgery under general anesthesia. Clinicopathological characteristics of the cancer were analyzed according to CTC status. Metastasis-free survival (MFS) and overall survival (OS) were analyzed according to CTC status and breast cancer molecular subtype. RESULTS: CK-20 mRNA positive CTC was detected in 37 of 166 patients (22.3%) and was not correlated with any previous clinical factors in univariate analysis (p>0.05). After a median follow-up of 100 months, the patients with CK-20 mRNA-positive CTC had less favorable outcomes in terms of MFS and OS than those without detectable CTC (log-rank p<0.05). Among molecular subtypes of operable breast cancer, the patients with CK-20 mRNA-positive CTC had shorter MFS and OS in triple negative and human epidermal growth factor 2 (HER2) breast cancer subtype (log-rank, p<0.05). CONCLUSION: CK-20 mRNA-positive CTC may lend insight into tumor progression as a prognostic indicator especially in the triple negative and HER2 subtypes of operable breast cancer. PMID- 22493627 TI - Use of the international classification of functioning, disability and health as a functional assessment tool for breast cancer survivors. AB - PURPOSE: To develop a patient self-completed questionnaire from the items of the Brief Core Set Questionnaire for Breast Cancer (BCSQ-BC) and to investigate the prevalence of specific dysfunctions throughout the course of cancer and treatments. METHODS: From January 2010 to February 2011, 96 breast cancer patients were evaluated with BCSQ-BC developed for clinical application of International Classification of Functioning, Disability and Health (ICF). Quality of life and upper limb dysfunction using disabilities of arm, shoulder and hand (DASH) were assessed. Content validity was evaluated using correlations between BCSQ-BC and European Organization for Research and Treatment of Cancer (EORTC) QLQ and DASH scores. Construct validity was computed using exploratory factor analysis. Kappa statistics were computed for agreement between test-retest ICF data. The level of significance and odds ratios were reported for individuals with early post-acute and long-term context and with total mastectomy and breast conservative surgery. RESULTS: There was consistently good test-retest agreement in patient-completed questionnaires (kappa value, 0.76). Body function, activity and participation subscales are significantly related with EORTC QLQ and DASH. Problems with activity and participation were strongly associated with physical functional domains of EORTC QLQ (r=-0.708, p<0.001) and DASH (r=0.761, p<0.001). The prevalence of dysfunctions varied with type of surgery and time after cancer. Immobility of joint (15% vs. 7%) and lymphatic dysfunction (17% vs. 3%) were indexed more frequently in extensive surgery cases than in conservative surgery. Muscle power (16% vs. 8%), exercise tolerance functions (12% vs. 4%) and looking after one's health (10% vs. 2%) were impaired within 1 year after surgery, while sleep dysfunction (8% vs. 14%) was a major problem over 1 year after surgery. CONCLUSION: The BCSQ-BC identifies the problems comprehensively in functioning of patients with breast cancer. We revealed the interaction with the ICF framework adopting a multifactor understanding of function and disability. PMID- 22493628 TI - Estimating the risks and benefits of tamoxifen for prophylactic breast cancer chemoprevention in Korea. AB - PURPOSE: According to the National Surgical Adjuvant Breast and Bowel Project P1 (NSABP-P1) study, tamoxifen can prevent 49% of invasive breast cancers in patients who have a 5-year risk of 1.67% or more. Because tamoxifen is associated with both adverse effects (endometrial cancer, stroke, pulmonary embolism) and protective effect (fracture prevention), it is necessary to weigh the risks and benefits of using tamoxifen for prevention in Korean women. This study weighed those risks and benefits. METHODS: Data were reviewed on the incidences of breast cancer, hip fracture, endometrial cancer and stroke in the absence of tamoxifen treatment in Korean women. We also reviewed NSABP-P1 data on the effects of tamoxifen on these outcomes. A risk-benefit index was calculated according to age and specific risk of breast cancer. Sensitivity analyses were performed with assumptions regarding the effects of tamoxifen. RESULTS: Compared to U.S. women, the numbers of hip fractures and endometrial cancers were lower, but the number of strokes was much higher. The net benefit of tamoxifen was reduced with increasing age because of a high risk of stroke in older women. Older Korean women had more risk than benefit from tamoxifen chemoprevention. Only women younger than age 40 had a positive risk-benefit index with an average 5-year risk of breast cancer in Korea. Sensitivity analysis showed that this result was robust. CONCLUSION: Women under the age 40 had more benefit than risk from tamoxifen chemoprevention. Tamoxifen chemoprevention should be limited to Korean women younger than age 40. PMID- 22493629 TI - Imaging findings of invasive micropapillary carcinoma of the breast. AB - PURPOSE: The purpose of this study is to evaluate imaging and histopathologic findings including the immunohistochemical characteristics of invasive micropapillary carcinoma (IMPC) of the breast. METHODS: Twenty-nine patients diagnosed with IMPC were included in the present study. Mammographic, sonographic, and magnetic resonance imaging (MRI) findings were analyzed retrospectively according to the American College of Radiology Breast Imaging Reporting and Data System lexicon. (18)F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) findings were also evaluated. Microscopic slides of surgical specimens were reviewed in consensus by two pathologists with a specialty in breast pathology. RESULTS: Most IMPCs presented as a high density irregular mass with a non-circumscribed margin associated with microcalcifications on mammography, as an irregular hypoechoic mass with a spiculated margin on ultrasound, and as irregular spiculated masses with washout patterns on MRI. PET-CT showed a high maximum standardized uptake value (SUVmax) (mean, 11.2). Axillary nodal metastases were identified in 65.5% of the patients. Immunohistochemical studies showed high positivities for estrogen receptor and c erbB-2 (93.1% and 51.7u, respectively). CONCLUSION: Even though the imaging characteristics of IMPCs are not distinguishable from typical invasive ductal carcinomas, this tumor type frequently results in nodal metastases and high positivities for both estrogen receptor and c-erbB-2. The high SUVmax value that is apparent on PET-CT might be helpful in the diagnosis of IMPC. PMID- 22493630 TI - Classification of Metastatic versus Non-Metastatic Axillary Nodes in Breast Cancer Patients: Value of Cortex-Hilum Area Ratio with Ultrasound. AB - PURPOSE: To investigate the significance of the cortex-hilum (CH) area ratio and longitudinal-transverse (LT) axis ratio and the blood flow pattern for diagnosis of metastatic axillary lymph nodes by ultrasound in breast cancer patients. METHODS: From October 2005 to July 2006, we prospectively evaluated axillary nodes with ultrasound in 205 consecutive patients who had category 4B, 4C or 5 breast lesions according to the Breast Imaging Reporting and Data System Ultrasound (BI-RADS-Ultrasound(r)). Among the 205, there were 24 patients who had pathologic verification of breast cancer and axillary lymph node status. For a total of 80 axillary nodes we measured the areas of the cortex and hilum of lymph nodes and calculated the area ratio. We also measured the length of the longitudinal and transverse axis of the lymph nodes and calculated the length ratio. We evaluated the blood flow pattern on power Doppler imaging and classified each lymph node into a central or peripheral pattern. Diagnostic performance was analyzed according to positive criteria for lymph node metastasis (CH area ratio >2, LT axis ratio <2, peripheral type on power Doppler imaging). RESULTS: The sensitivity of the CH area ratio was superior to that of the LT axis ratio (94.1% vs. 82.3%, p=0.031) and to that of the blood flow pattern (94.1% vs. 29.4%, p=0.009). For specificity, all three evaluating parameters had high values (89.1-95.6%) and no significant differences were found (p=0.121). The CH area ratio had a better positive predictive value than the LT axis ratio (94.1% vs. 80.0%, p=0.030) and power Doppler imaging (94.1% vs. 66.6%, p=0.028). For the negative predictive value, the CH area ratio was superior to the LT axis ratio (95.6% vs. 86.6%, p=0.035) and the blood flow pattern (95.6% vs. 63.0%, p=0.027). CONCLUSION: We recommend the CH area ratio of an axillary lymph node on ultrasound as a quantitative indicator for the classification of lymph nodes. The CH area ratio can improve diagnostic performance when compared with the LT axis ratio or blood flow pattern. PMID- 22493631 TI - Impact of Serum HER2 Levels on Survival and Its Correlation with Clinicopathological Parameters in Women with Breast Cancer. AB - PURPOSE: The aims of our study were to assess the correlation between serum HER2 and clinicopathologic factors, the effect of serum HER2 on survival rate, and the effect of changes in serum HER2 levels between pre- and post-adjuvant chemotherapy on survival rate. METHODS: The study subjects, 200 women with breast cancer, were a subset of patients operated on between January 2005 and December 2006. We evaluated changes in serum HER2 levels between pre- and post-adjuvant chemotherapy. RESULTS: Being estrogen receptor (ER) negative was also correlated with high serum HER2 (p=0.017). The number of patients with changes in serum HER2 (>20% increased level during the follow-up period) was correlated with advanced T stage (p=0.010), advanced American Joint Committee on Cancer (AJCC) stage (p=0.015) and poor histologic grade (p=0.001). Univariate analysis for prognostic factors associated with disease-free survival (DFS) revealed that the difference in DFS between those with serum HER2 level <15 ng/mL and those with levels >=15 ng/mL was statistically significant (p=0.0129) and the changes in serum HER2 levels were also statistically significant (p=0.001). Prognostic factors associated with overall survival revealed that the changes in serum HER2 levels between pre- and post-adjuvant chemotherapy were statistically significant (p=0.0012). CONCLUSION: Serum HER2 level is associated with a more advanced degree of axillary lymph node involvement and associated with ER negativity. And Changes in serum HER2 levels are associated with more advanced AJCC staging and histologic tumor grade. There are significant associations between serum HER2 level, changes in serum HER2 levels and 5-year DFS. PMID- 22493632 TI - Prognostic Significance of High Expression of ER-beta in Surgically Treated ER Positive Breast Cancer Following Endocrine Therapy. AB - PURPOSE: This study evaluated estrogen receptor (ER)-beta mRNA and ER-beta protein expression and its prognostic implications in hormone receptor-positive breast cancer. METHODS: Paraffin sections from 139 hormone receptor-positive breast cancer cases were prepared. The expression of ER-beta mRNA and protein were analyzed by branched-chain assay and immunohistochemistry (IHC), respectively. RESULTS: The Allred score of ER-beta IHC was correlated with smaller tumor size (p=0.043), the Allred score of ER-alpha IHC (p<0.001), and the Allred score of progesterone receptor (PR) IHC (p=0.022) but not with the HER2 IHC score. ER-beta mRNA level was correlated with PR mRNA levels (p<0.001) but not with the Allred score of ER-beta IHC, ER-alpha IHC, and PR IHC, nor with the HER2 IHC score and ER-alpha mRNA level. In survival analysis, high expression of ER-beta mRNA was associated with worse disease-free survival along with poor differentiation, lymph node metastasis and absence of PR protein expression in univariate analysis (p=0.040, p=0.002, p=0.018, and p=0.007, respectively) and multivariate analysis (p=0.044, p=0.002, p=0.035, and p=0.007, respectively). CONCLUSION: High expression of ER-beta mRNA is an independent predictor of disease recurrence in hormone-receptor-positive breast cancer. PMID- 22493633 TI - Value of sentinel lymph node biopsy in breast cancer patients with previous excisional biopsy. AB - PURPOSE: Sentinel lymph node biopsy (SLNB) in breast cancer patients with clinically negative axilla will ensure axillary dissection only for cases with lymph node metastasis and provide information about pathologic staging as accurate as the axillary dissection. It was shown that SLNB could be successfully performed regardless of the type of biopsy. The aim of this study was to investigate the feasibility of SLNB after excisional biopsy. METHODS: One hundred patients diagnosed with excisional biopsy or guide wire-localization and operated on with SLNB between February 2007 and March 2009 were retrospectively analyzed. SLNB was performed with 10 cc of 1% methylene blue alone or both methylene blue and 1 mCi of Tc-99m nanocolloid combination. Age, tumor localization and size, length of the biopsy incision, size of the biopsy specimen, multifocality, lymphovascular invasion, tumor grade, staining with methylene blue, localization, number and metastatic status of the lymph nodes stained, and success rate with a gamma probe were evaluated. RESULTS: Sentinel lymph node (SLN) could not be identified in 9 (16.9%) of patients in the methylene blue group (n=53). In the combination group (n=47), SLN could not be identified in one patient. Of 32 patients with negative SLNB, metastatic involvement was found to be present in 5 patients after axillary lymph node dissection (false negatives). The average numbers of SLNs found in the methylene blue group and combination group were 1.4 and 1.6, respectively. SLN detection and false negative rates in the methylene blue group were 83% and 15.7%, respectively. The rates for the combination group were 98% and 6.4%, respectively. None of the parameters related to patient, tumor or process were found to affect detection rates of SLN. CONCLUSION: Only SLNB using a combination method is a safe and reliable technique for breast cancer patients diagnosed with excisional biopsy. PMID- 22493634 TI - The efficacy of arm node preserving surgery using axillary reverse mapping for preventing lymphedema in patients with breast cancer. AB - PURPOSE: The axillary reverse mapping (ARM) technique to identify and preserve arm nodes during sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) was developed to prevent lymphedema. The purpose of this study was to investigate the location and metastatic rate of the arm node, and to evaluate the short term incidence of lymphedema after arm node preserving surgery. METHODS: From January 2009 to October 2010, 97 breast cancer patients who underwent ARM were included. Blue-dye (2.5 mL) was injected into the ipsilateral upper-inner arm. At least 20 minutes after injection, SLNB or ALND was performed and blue-stained arm nodes and/or lymphatics were identified. Patients were divided into two groups, an arm node preserved group (70 patients had ALND, 10 patients had SLNB) and an unpreserved group (13 patients had ALND, 4 patients had SLNB). The difference in arm circumference between preoperative and postoperative time points was checked in both groups. RESULTS: The mean number of identified blue stained arm nodes was 1.4+/-0.6. In the majority of patients (92%), arm nodes were located between the lower level of the axillary vein and just below the second intercostobrachial nerve. In the arm node unpreserved group, 2 patients had metastasis in their arm node. Among ALND patients, in the arm node preserved group, the difference in arm circumference between preoperative and postoperative time points in ipsilateral and contralateral arms was 0.27 cm and 0.07 cm, respectively, whereas it was 0.47 cm and -0.03 cm in the unpreserved group; one case of lymphedema was found after 6 months. No difference was found between arm node preserved and unpreserved group among SLNB patients. CONCLUSION: Arm node preserving was possible in all breast cancer patients with identifiable arm nodes, during ALND or SLNB, except for those with high surgical N stage, and lymphedema did not develop in patients with arm node preserving surgery. PMID- 22493635 TI - Long-term outcome of internal mammary lymph node detected by lymphoscintigraphy in early breast cancer. AB - PURPOSE: Internal mammary lymph node (IMLN) metastasis is an important prognostic indicator in breast cancer. However, the necessity of internal mammary sentinel lymph node biopsy for accurate staging, for choosing adjuvant treatment, and as a prognostic indicator, has remained controversial. METHODS: From January 2001 to December 2006, 525 female breast cancer patients underwent radical surgery after preoperative lymphatic scintigraphy. We retrospectively analyzed the follow-up results, recurrences, and deaths of all patients. RESULTS: There was no significant difference in the clinicopathological characteristics between the axilla and the IMLN groups. The median follow-up period was 118.8 months (range, 7-122 months) in the axilla group and 107.7 months (range, 14-108 months) in the IMLN group. During the median follow-up period, the breast cancer-related death rate in the axilla group was 3.6%, which was not significantly different from that of the IMLN group (1.3%) (p=0.484). The five-year survival rates did not differ between the two groups (p=0.306). The overall recurrence rate and the locoregional recurrence rate also did not differ between the two groups (p=0.835 and p=0.582, respectively). The recurrence rate of IMLN (both ipsilateral and contralateral) metastasis was very low, accounting for 0.5% in the axilla group and 1.3% in the IMLN group (p=0.416). CONCLUSION: The long-term follow-up results showed that there was no significant difference in both overall outcome and regional recurrence between the two groups. Therefore, the requirement for identification of nodal basins outside the axilla or IMLN sentinel biopsy should be reconsidered. PMID- 22493636 TI - Dose-Volume Analysis of Lung and Heart according to Respiration in Breast Cancer Patients Treated with Breast Conserving Surgery. AB - PURPOSE: Adjuvant radiotherapy of breast cancer using a photon tangential field incurs a risk of late heart and lung toxicity. The use of free breathing (FB), expiration breath hold (EBH), and deep inspiration breath hold (DIBH) during tangential breast radiotherapy as a means of reducing irradiated lung and heart volume was evaluated. METHODS: In 10 women with left-sided breast cancer (mean age, 44 years) post-operative computed tomography (CT) scanning was done under different respiratory conditions using FB, EBH, and DIBH in 3 CT scans. For each scan, an optimized radiotherapy plan was designed with 6 MV photon tangential fields encompassing the clinical target volume after breast-conserving surgery. RESULTS: The results of dose-volume histograms were compared using three breathing pattern techniques for the irradiated volume and dose to the heart. A significant reduction dose to the irradiated heart volume for the DIBH breathing technique was compared to FB and EBH breathing techniques (p<0.05). CONCLUSION: This study demonstrated that the irradiated heart volume can be significantly reduced in patients with left-sided breast cancer using the DIBH breathing technique for tangential radiotherapy. PMID- 22493637 TI - Differential diagnosis in idiopathic granulomatous mastitis and tuberculous mastitis. AB - PURPOSE: Idiopathic granulomatous mastitis (IGM) is a rare chronic inflammatory disease of unknown etiology. The diagnosis of IGM requires that other granulomatous lesions in the breast be excluded. Tuberculous mastitis (TM) is also an uncommon disease that is often difficult to differentiate from IGM. The purpose of this study is to develop a new algorithm for the differential diagnosis and treatment of IGM and TM. METHODS: Medical records of 68 patients (58 with IGM and 10 with TM) between July 1999 and February 2009 were retrospectively reviewed. RESULTS: The mean age of the patients was 33.5 (IGM) and 40 (TM) years (p=0.018). The median follow-up was 84 months. Of the total 10 patients with TM, 5 patients had a history of pulmonary tuberculosis. The most common symptoms of the diseases were breast lump and pain. However, axillary lymphadenopathy was more seen in TM (50%) compared to IGM (20.6%) (p=0.048). TM showed more cancer-mimicking findings on radiologic study (p=0.028). In IGM, 48 patients (82.7%) underwent surgical wide excision and 21 patients (36.2%) were managed with corticosteroid therapy and antibiotics. All of the TM patients received anti-tuberculosis medications and 9 patients (90%) underwent wide excision. The mean treatment duration was 2.8 months in IGM and 8.4 months in TM. Recurrence developed in 5 patients (8.6%) in IGM and 1 patient (10%) in TM. CONCLUSION: This study shows different characteristics between IGM and TM. The IGM patients were younger and had more mastalgia symptoms than the TM patients. Axillary lymphadenopathy was seen more often in TM patients. Half of the TM patients had pulmonary tuberculosis or tuberculosis lymphadenitis. Surgical wide excision might be both therapeutic and useful for providing an exact diagnosis. PMID- 22493638 TI - Medical and surgical treatment of idiopathic granulomatous lobular mastitis: a benign inflammatory disease mimicking invasive carcinoma. AB - PURPOSE: Idiopathic granulomatous lobular mastitis (IGLM) is a rare chronic inflammatory disease of the breast with obscure etiology that mimics invasive carcinoma both clinically and radiologically. The treatment of IGLM remains controversial. The aim of proper management is to use a combination of medical and surgical treatment of this benign condition to achieve a good cosmetic result and low recurrence rate. METHODS: A retrospective analysis of 19 patients with IGLM is performed based on the findings of clinical, radiological, and pathological examinations. The results of two treatments are presented: medical treatment with oral corticosteroids, and consecutive surgical excision after a follow-up period of 20 months (range, 6-75 months). RESULTS: The majority of patients treated in this paper were young (mean, 34 years) parous women with a history of hormonal medication use. The main clinical finding is large, irregular, and painful mass. Hypoechoic lobulated, irregular tubular or oval shaped masses had been imaged by ultrasound. Mammographic findings were an ill defined mass, enlarged axillary lymph nodes, asymmetric density, and architectural distortion. Diagnoses of IGLM had been established by cytological or histological examination. Symptoms subside and inflammatory changes regressed with medical treatment. The remaining lesions were excised by consecutive breast conserving surgery. The disease recurred in one patient during the follow-up period. CONCLUSION: IGLM is an inflammatory breast disease found in young women who present with a large painful irregular mass, which mimics carcinoma, as a physical change. Breast imaging modalities are not helpful to differentiate IGLM from invasive cancer. The correct diagnosis is established by cytological or histological examination. Medical treatment with corticosteroids provides significant regression of the inflammatory disease, allowing more conservative surgery. Consecutive surgical excision of the remaining lesions with good cosmetic results provides definitive treatment and reduces the risk of recurrence. PMID- 22493639 TI - Primary leiomyosarcoma of the breast: a case report. AB - Primary leiomyosarcoma of the breast is an extremely rare tumor, accounting for less than 1% of all breast tumors and only 24 cases have been reported in the English medical journals. It is quite difficult to diagnose leiomyosarcoma preoperatively. Establishing an accurate diagnosis is very important in planning treatment. When preoperative diagnosis can be achieved before or during the operation, wide resection should be performed. There is no need for axillary lymph node dissection. In this case report, we present a case involving primary leiomysarcoma of the breast in a 48-year-old woman and we discuss optimal treatment options. PMID- 22493640 TI - A case report of breast cancer with extensive pulmonary lymphovascular tumor emboli. AB - We describe a patient with breast cancer who relapsed with an extensive pulmonary lymphovascular tumor embolism. A 38-year-old female, who previously received neoadjuvant chemotherapy and curative resection of breast cancer, underwent adjuvant chemotherapy and was referred to the emergency room because of sudden onset pleuritic chest pain lasting for 10 days. Despite a trial of empirical antibiotics, the chest pain and the extent of consolidative lung lesion on chest radiographs rapidly aggravated. We performed an open lung biopsy to confirm the etiology. The histopathological review revealed a hemorrhagic infarction caused by lymphovascular tumor emboli from a metastatic breast carcinoma. Palliative first-line chemotherapy was administered, consisting of ixabepilone and capecitabine, and the lung lesion improved markedly. PMID- 22493641 TI - Chylous leakage: a rare complication after axillary lymph node dissection in breast cancer and surgical management. AB - Chylous leakage is an extremely rare complication of surgery for breast cancer. We experienced a case of chylous leakage after axillary lymph node dissection. A 38-year-old woman with invasive ductal carcinoma in the left breast underwent a modified radical mastectomy after four cycles of neoadjuvant chemotherapy. The postoperative serosanguinous drainage fluid became "milky" on the fourth postoperative day. After trying conservative management, we re-explored the axilla and ligated the lymphatic trunk. Although the success of many cases supports conservative management, timely surgical intervention represents an alternative in cases where leakage persists or where the output is high. PMID- 22493642 TI - Intraductal lipid-rich carcinoma of the breast with a component of glycogen-rich carcinoma. AB - We report a rare case of intraductal lipid-rich carcinoma of the breast with a component of glycogen-rich carcinoma. An impalpable tumor that was revealed by mammography and magnetic resonance imaging was excised. Histologic examination showed vacuolated neoplastic cells in the mammary ducts, and electron microscopy confirmed lipid droplets in the cytoplasm. The coexistence of glycogen-rich carcinoma was shown. Lipid-rich carcinoma that is coexistent with glycogen-rich carcinoma is rare, and most lipid-rich carcinomas are invasive. Intraductal lipid rich carcinoma is difficult to detect without echography or mammography. PMID- 22493645 TI - Alcohol and breast cancer: the mechanisms explained. AB - Breast cancer is a leading cause of death amongst women, several studies have shown significant association between alcohol consumption and breast cancer. The aim of this overview is to highlight some of the mechanisms by which alcohol consumption could increase the risk of developing breast cancer. Using online Medline search engine, article containing details about mechanisms which explain the link between alcohol and breast cancer were examined. A number of mechanisms were found by which alcohol could increase the risk of breast cancer, alcohol's interaction and effect on oestrogen secretion; number of oestrogen receptors; the generation of acetaldehyde and hydroxyl free radicals; cells migration and metastasis; secretion of IGF1 and interaction with HRT and folate metabolism. In conclusion, it is essential for clinicians to understand these mechanisms and inform patients of the link between alcohol and breast cancer. KEYWORDS: Breast cancer; Alcohol; Mechanisms. PMID- 22493646 TI - Ethical and Scientific Perspectives of Placebo-controlled Trials in Schizophrenia. AB - Clinical trials for development of new medications are essential in all fields of medicine. The requirement for a placebo arm in pharmaceutical trials presents ethical and clinical dilemmas that are especially complicated with regard to mentally ill persons whose free choice and ability to provide informed consent may be questionable. On the other hand, we do not believe that this predicament justifies unconditional rejection of placebo use in psychiatry, when the investigational drug may ultimately provide substantial benefit for some patients. At the same time it is the psychiatrist's responsibility to insure that investigators are adequately trained to conduct clinical trials and that stringent regulatory committees supervise the scientific, clinical and ethical aspects of the trials. KEYWORDS: Placebo-control; Schizophrenia; Medical ethics; Clinical trials. PMID- 22493647 TI - Tissue factor expression in the symptomatic carotid plaque. AB - BACKGROUND: The aims of this study were to identify that the differences in the natural history of patients with symptomatic and asymptomatic carotid stenosis may be reflected in differences in the expression of procoagulant protein factors. METHODS: Carotid artery plaques were obtained from 33 symptomatic and 4 asymptomatic patients with internal carotid artery stenosis of greater than 70%. These plaques were stained with monoclonal antibody against human tissue factor. Areas of staining for the cap and core were analysed using the analySIS computer programme. RESULTS: There were 37 patients, of whom 27 were male with a mean age 69.3 years and a range of 53 to 83 years. Statistical analysis using non parametric tests revealed a significant increase in the area of positive staining for tissue factor in plaques taken from symptomatic patients when compared to those who were asymptomatic (P = 0001). Within the symptomatic patients group there was significantly increased tissue factor in the plaque core of those who were the most recently symptomatic (P = 0.003). CONCLUSIONS: The unstable carotid artery plaque is associated with significantly increased tissue factor expression in the cap and core. Plaques from the most recently symptomatic patients have significantly more tissue factor in the core and this may represent part of the mechanism responsible for plaque destabilisation. More research is needed in this important area. KEYWORDS: Tissue Factor; Carotid stenosis; Stroke; Plaque stability. PMID- 22493648 TI - In vitro sensitivity of leukemia cells to propranolol. AB - BACKGROUND: Propranolol, as a beta-adrenergic blocker is used for treatment of a large number of cardiovascular diseases such as hypertension and arrhythmias. The inhibitory effects of propranolol on tumor cells growth and also its cytotoxicity on cancerous cells have been revealed by several studies. In this study the sensitivity of a number of human leukemic cell lines to propranolol was evaluated in vitro. METHODS: Two human leukemic T cells (Molt-4 and Jurkat) and a monocyte (U937) cell line were used in this study. The cells were cultured in complete RPMI medium and then incubated with different concentrations of propranolol (0.0004 -0.4 mM) in the presence or absence of phytoheamagglutinin (20 MUg/ml) for 12, 24 and 48 hours. The cytotoxic effect of the drug was then assessed by trypan blue dye exclusion and also 3-(4,5-dimethyl thiazol-2,5 diphenyltetrazoliumbromide) (MTT) reduction methods. RESULTS: Propranolol induced a significant dose dependent cytotoxic effect at >= 0.2 mM concentration on all three human cell lines (Molt-4, Jurkat and U937) used in this study, after 12 hours incubation onwards, compared to untreated control cells. CONCLUSIONS: Our results demonstrated that leukemic cell lines used in this study were sensitive to propranolol at >= 0.2 mM concentration of the drug. These results suggest that propranolol may have potential implication in chemoprevention of lymphoproliferative disorders along with its chronic long-term usage in cardiac problems. KEYWORDS: Propranolol; Leukemia; Cell lines; Sensitivity. PMID- 22493649 TI - Malondialdehyde and Antioxidant Enzymes in Maternal and Cord Blood, and their Correlation in Normotensive and Preeclamptic Women. AB - BACKGROUND: An increased oxidative level and decreased antioxidant activities in the blood of preeclamptic women have been reported by us and other workers. The present study was aimed to evaluate oxidative stress in infants born to preeclamptic mothers, and to examine whether cord blood with oxygen radical disease had different total enzymatic antioxidant status than those without preeclampsia. METHODS: The present study consisted of 23 normotensive (served as control) and 23 preeclamptic mothers. We compared their oxidative and anti oxidative system in maternal and cord blood of pair-matched mother and neonate. Their blood malondialdehyde (MDA), antioxidant enzymes were determined and compared to evaluate if pro-oxidative status of preeclampsia differs from the status in cord blood of pair-matched neonate. RESULTS: The MDA content in preeclamptic maternal plasma was significantly high (p < 0.001) compared to that of control. Interestingly, its content in preeclamptic cord blood was significantly low (p < 0.001) compared to their pair-matched maternal blood. Superoxide dismutase (SOD) activity was 8.7% higher in cord as compared to pair matched normotensive maternal blood which was significant (p = 0.01) whereas in preeclamptic cord the level decreased significantly (p = 0.011) in comparison to pair-matched preeclamptic maternal. Glutathione peroxidase (GPx) was 16.4% higher in normotensive cord compared to maternal blood, and 7% low in preeclamptic cord compared to pair-matched maternal blood. The increase was significant (P = 0.011) in normotensive cord whereas in preeclamptic cord the decrease was insignificant (p = 0.06). Contrary to earlier reports on catalase activity, our results showed 20.97% elevation in normotensive and 16.12% increase in the preeclamptic cord blood compared to their pair-matched maternal blood. This change was significant with p = 0.01 and p = 0.017 in control and preeclamptic group respectively. CONCLUSIONS: Our results showed the significantly low MDA contents in the pair matched cord blood and the activities of SOD, GPx and Catalase mentioned above, we conclude that the oxidative stress status is low in the blood of neonates born to preeclamptic mothers. Further studies are needed to explore strategies so that the normal levels of antioxidant vitamins are maintained to combat preeclampsia in women at high risk. KEYWORDS: Maternal; Cord blood; Malondialdehyde; Antioxidant enzymes; Glutathione peroxidase; Glutathione reductase; Superoxide dismutase; Catalase. PMID- 22493650 TI - Prevalence of temporomandibular joint disorders among students of the university of jordan. AB - BACKGROUND: This study aimed to investigate the prevalence of temporomandibular disorder (TMD) among students of the University of Jordan. METHODS: Information about the symptoms of TMD and the possible risk factors were collected using specifically designed questionnaires. The collected data sets were treated statistically using the SPSS release 14 package. RESULTS: The results of the present investigation showed that pain in or about the ears or cheeks was the most prevalent symptom whereas locking of the temporomandibular joint (TMJ) was the least prevalent. Nearly one-third of the investigated sample (31.4%, 346/1103) had no symptoms of TMD whereas 68.6% (757/1103) had at least one symptom. Students of health science studies had significantly the highest risk in developing TMJ clicking compared to students studying pure science or humanitarian studies. CONCLUSIONS: TMD is of a high prevalence among students of the University of Jordan, particularly among students of health and science studies, which signify the role of stress in the development and/or progression of TMD. The findings of this study are alarming and entailing further investigations to identify risk factors associated with TMD in order to establish measures for prevention and treatment. KEYWORDS: TMD; Clicking; Health sciences; Humanitarian studies. PMID- 22493651 TI - Adult Spinal Cord Injury without Radiographic Abnormalities (SCIWORA): Clinical and Radiological Correlations. AB - BACKGROUND: This study is aimed to determine the clinical and radiological corellations of adult patients with Spinal Cord Injury Without Radiographic Abnormalities (SCIWORA). METHODS: The study population consisted of all adult patients with suspected cervical spine injury. SCIWORA was defined as the presence of either no injury or a neural injury on Magnetic Resonance Imaging (MRI) in the absence of radiographic or Computed Tomographic (CT) Scan findings suggestive of trauma in patients with neurological deficit. Purely extra neural compressive lesions were excluded from the study. RESULTS: Twelve of ninety seven (12.4%) patients had a neural injury on MRI with normal radiographs and CT scan. These included cord contusion in five cases, cord edema in five cases and cord hemorrhage in two cases. Ten patients were managed conservatively and two patients with disc prolapse were managed surgically. All patients showed at least one ASIA Impairment Scale (AIS) grade improvement and three patients (25%) recovered completely. CONCLUSIONS: Parenchymal spinal cord injury is the single most important determinant in the long term outcome of adult SCIWORA patients. Cord hemorrhage has the worst prognosis and cord edema has the best. Longitudinal signal extension and associated extra neural injuries are also associated with poorer outcomes. Cases with purely neural injuries can be managed conservatively, but associated extra neural injuries, especially disc prolapse and ligamentous instability, warrant surgical management. KEYWORDS: Post Traumatic Myelopathy; Spinal Cord Trauma; Computed tomography; Magnetic resonance imaging; SCIWORA. PMID- 22493652 TI - Septic arthritis in rheumatology: review of five cases. AB - This report illustrates five cases of patients admitted to medical ward in HUKM, diagnosed and treated as septic arthritis over the course of two months. Their age ranged from 32 to 67 years old with one patient had history of monoarticular pain and the other four had polyarticular pain. Two of these patients had pre existing joint disease, namely gouty arthritis and rheumatoid arthritis, and another patient with background history of mixed connective tissue disease on long term steroid therapy. The diagnosis of septic arthritis was made mainly from clinical assessment, supported by synovial fluid assessment and blood investigations. All patients received minimum of two weeks intravenous antibiotic followed by one month course of antibiotic. All of them had arthrocentesis for diagnostic and therapeutic purposes and two had laparoscopic arthroscopy with wash out done. KEYWORDS: Septic arthritis; Arthrocentesis; Arthroscopy. PMID- 22493653 TI - Subclavian Vein Thrombosis Extending into the Internal Jugular Vein: Paget-von Schroetter Syndrome. AB - Paget-von Schroetter syndrome refers to spontaneous thrombosis of the subclavian vein and constitutes 0.5-1% of all venous thromboses. It is prevalent among young and healthy adult males who engage in sports. Early diagnosis and treatment is essential to avoid long-term sequelae. Herein, we report a 42-year-old male weightlifter who presented with swelling of the left arm, pain and a feeling of tightness in the anterior chest wall. At Doppler US and MR angiography, subclavian vein thrombosis extending into the internal jugular vein was detected. Thrombolytic treatment ensured continuous venous flow and the patient's complaints decreased. KEYWORDS: Veins; Thrombosis; Thorombolytic therapy. PMID- 22493654 TI - Direct intracranial extension of malignant eccrine spiradenoma of the face. AB - Malignant eccrine spiradenomas are exceedingly rare tumours. They are aggressive tumours normally arising in long-standing benign eccrine spiradenomas. We present a case of malignant eccrine spiradenoma of the right side of the face with direct intracranial extension without distant metastasis. A 48 years old woman presented with a large exophytic tumour on the right side of her face. Radiological imaging of the head and neck region revealed extensive invasion of the facial tissues around right orbit, maxilla and extension into the middle cranial fossa involving the right temporal lobe. She underwent craniotomy and debulking of the right temporal lobe and biopsy of the facial tumour. Histopathological findings were consistent with malignant eccrine spiradenoma. This is a rare case of facial malignant eccrine spiradenoma with direct intracranial extension with no distant metastasis. A literature search revealed that it is first case to be reported of this kind. KEYWORDS: Eccrine carcinoma; Spiradenoma; Adnexal carcinoma; Malignant eccrine spiradenoma. PMID- 22493655 TI - Lymphoma of the base of the tongue: an incidental finding on the preoperative workup for a spine surgery. AB - Lymphoma of the tongue is very rare and accounts for 1% of all malignant tumors of the oral cavity. We present a patient who presented with weakness and difficulties with ambulation who was a known cervical spine spondylosis and stenosis patient. During the preoperative workup for cervical spine surgery a tumor at the base of the tongue was discovered which was confirmed by pathology to be a lymphoma. KEYWORDS: Lymphoma; Tongue; Spine surgery; Preoperative workup. PMID- 22493656 TI - Laparoscopic anterograde cholecystectomy in acute cholecystitis. AB - In the laparoscopic surgery of acute cholecystitis, no identification of anatomic structures in Calot triangle prevents the retrograde disection. Therefore, the anterograde disection of gall bladder, which we often use in open cholecystectomy, was applied as an alternative method in laparoscopic cholecystectomy in our 2 cases. Through this method, the safety of the attempt was increased and the patients were not deprived of the comfort of laparoscopic cholecystectomy. KEYWORDS: Laparoscopic anterograde cholecystectomy; Acute cholecystitis; Gall bladder. PMID- 22493657 TI - Event timing in associative learning: from biochemical reaction dynamics to behavioural observations. AB - Associative learning relies on event timing. Fruit flies for example, once trained with an odour that precedes electric shock, subsequently avoid this odour (punishment learning); if, on the other hand the odour follows the shock during training, it is approached later on (relief learning). During training, an odour induced Ca(++) signal and a shock-induced dopaminergic signal converge in the Kenyon cells, synergistically activating a Ca(++)-calmodulin-sensitive adenylate cyclase, which likely leads to the synaptic plasticity underlying the conditioned avoidance of the odour. In Aplysia, the effect of serotonin on the corresponding adenylate cyclase is bi-directionally modulated by Ca(++), depending on the relative timing of the two inputs. Using a computational approach, we quantitatively explore this biochemical property of the adenylate cyclase and show that it can generate the effect of event timing on associative learning. We overcome the shortage of behavioural data in Aplysia and biochemical data in Drosophila by combining findings from both systems. PMID- 22493658 TI - Uptake and accumulation of oxidized low-density lipoprotein during Mycobacterium tuberculosis infection in guinea pigs. AB - The typical host response to infection of humans and some animals by M. tuberculosis is the accumulation of reactive oxygen species generating inflammatory cells into discrete granulomas, which frequently develop central caseous necrosis. In previous studies we showed that infection of immunologically naive guinea pigs with M. tuberculosis leads to localized and systemic oxidative stress that results in a significant depletion of serum total antioxidant capacity and the accumulation of malondialdehyde, a bi-product of lipid peroxidation. Here we show that in addition, the generation of excessive reactive oxygen species in vivo resulted in the accumulation of oxidized low density lipoproteins (OxLDL) in pulmonary and extrapulmonary granulomas, serum and lung macrophages collected by bronchoalveolar lavage. Macrophages from immunologically naive guinea pigs infected with M. tuberculosis also had increased surface expression of the type 1 scavenger receptors CD36 and LOX1, which facilitate the uptake of oxidized host macromolecules including OxLDL. Vaccination of guinea pigs with Bacillus Calmette Guerin (BCG) prior to aerosol challenge reduced the bacterial burden as well as the intracellular accumulation of OxLDL and the expression of macrophage CD36 and LOX1. In vitro loading of guinea pig lung macrophages with OxLDL resulted in enhanced replication of bacilli compared to macrophages loaded with non-oxidized LDL. Overall, this study provides additional evidence of oxidative stress in M. tuberculosis infected guinea pigs and the potential role OxLDL laden macrophages have in supporting intracellular bacilli survival and persistence. PMID- 22493659 TI - Icariside II induces apoptosis in U937 acute myeloid leukemia cells: role of inactivation of STAT3-related signaling. AB - BACKGROUND: The aim of this study is to determine anti-cancer effect of Icariside II purified from the root of Epimedium koreanum Nakai on human acute myeloid leukemia (AML) cell line U937. METHODOLOGY/PRINCIPAL FINDINGS: Icariside II blocked the growth U937 cells in a dose- and time-dependent manner. In this anti proliferation process, this herb compound rendered the cells susceptible to apoptosis, manifested by enhanced accumulation of sub-G1 cell population and increased the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. Icariside II was able to activate caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP) in a time-dependent manner. Concurrently, the anti-apoptotic proteins, such as bcl-x(L) and survivin in U937 cells, were downregulated by Icariside II. In addition, Icariside II could inhibit STAT3 phosphorylation and function and subsequently suppress the activation of Janus activated kinase 2 (JAK2), the upstream activators of STAT3, in a dose- and time dependent manner. Icariside II also enhanced the expression of protein tyrosine phosphatase (PTP) SH2 domain-containing phosphatase (SHP)-1, and the addition of sodium pervanadate (a PTP inhibitor) prevented Icariside II-induced apoptosis as well as STAT3 inactivation in STAT3 positive U937 cells. Furthermore, silencing SHP-1 using its specific siRNA significantly blocked STAT3 inactivation and apoptosis induced by Icariside II in U937 cells. CONCLUSIONS/SIGNIFICANCE: Our results demonstrated that via targeting STAT3-related signaling, Icariside II sensitizes U937 cells to apoptosis and perhaps serves as a potent chemotherapeutic agent for AML. PMID- 22493660 TI - Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the Abl tyrosine kinase domain. AB - Chronic myeloid leukemia (CML) is caused by the kinase activity of the BCR-Abl fusion protein. The Abl inhibitors imatinib, nilotinib and dasatinib are currently used to treat CML, but resistance to these inhibitors is a significant clinical problem. The kinase inhibitor bosutinib has shown efficacy in clinical trials for imatinib-resistant CML, but its binding mode is unknown. We present the 2.4 A structure of bosutinib bound to the kinase domain of Abl, which explains the inhibitor's activity against several imatinib-resistant mutants, and reveals that similar inhibitors that lack a nitrile moiety could be effective against the common T315I mutant. We also report that two distinct chemical compounds are currently being sold under the name "bosutinib", and report spectroscopic and structural characterizations of both. We show that the fluorescence properties of these compounds allow inhibitor binding to be measured quantitatively, and that the infrared absorption of the nitrile group reveals a different electrostatic environment in the conserved ATP-binding sites of Abl and Src kinases. Exploiting such differences could lead to inhibitors with improved selectivity. PMID- 22493661 TI - Performance analysis of orthogonal pairs designed for an expanded eukaryotic genetic code. AB - BACKGROUND: The suppression of amber stop codons with non-canonical amino acids (ncAAs) is used for the site-specific introduction of many unusual functions into proteins. Specific orthogonal aminoacyl-tRNA synthetase (o-aaRS)/amber suppressor tRNA(CUA) pairs (o-pairs) for the incorporation of ncAAs in S. cerevisiae were previously selected from an E. coli tyrosyl-tRNA synthetase/tRNA(CUA) mutant library. Incorporation fidelity relies on the specificity of the o-aaRSs for their ncAAs and the ability to effectively discriminate against their natural substrate Tyr or any other canonical amino acid. METHODOLOGY/PRINCIPAL FINDINGS: We used o-pairs previously developed for ncAAs carrying reactive alkyne-, azido-, or photocrosslinker side chains to suppress an amber mutant of human superoxide dismutase 1 in S. cerevisiae. We found worse incorporation efficiencies of the alkyne- and the photocrosslinker ncAAs than reported earlier. In our hands, amber suppression with the ncAA containing the azido group did not occur at all. In addition to the incorporation experiments in S. cerevisiae, we analyzed the catalytic properties of the o-aaRSs in vitro. Surprisingly, all o-aaRSs showed much higher preference for their natural substrate Tyr than for any of the tested ncAAs. While it is unclear why efficiently recognized Tyr is not inserted at amber codons, we speculate that metabolically inert ncAAs accumulate in the cell, and for this reason they are incorporated despite being weak substrates for the o aaRSs. CONCLUSIONS/SIGNIFICANCE: O-pairs have been developed for a whole plethora of ncAAs. However, a systematic and detailed analysis of their catalytic properties is still missing. Our study provides a comprehensive scrutiny of o pairs developed for the site-specific incorporation of reactive ncAAs in S. cerevisiae. It suggests that future development of o-pairs as efficient biotechnological tools will greatly benefit from sound characterization in vivo and in vitro in parallel to monitoring intracellular ncAA levels. PMID- 22493662 TI - Evaluation of MCM-2 expression in TMA cervical specimens. AB - BACKGROUND: Minichromosome maintenance proteins (MCM) are highly expressed in actively replicating cells. The need for biological markers for cervical carcinoma and its precursor lesions is emerging. Our main aim was to determine the immunohistochemical expression of MCM-2 in HIV-positive and -negative dysplastic cervical specimens. METHODS: Immunohistochemical analysis of MCM-2 was performed in a total of 352 cervical TMA specimens of normal control, low-grade CIN, high-grade CIN and invasive tumor. 38 specimens were from HIV-positive women. A receiver operating characteristic (ROC) curve was constructed to determine the best cutoff to diagnose high-grade CIN and invasive cervical cancer. RESULTS: In the progression from normal epithelium to high-grade CIN and invasive tumor we found significant differences in the MCM-2 expression (p<0.05). Based on the ROC curve of 80% with an area under the curve (AUC) of 0.78, expression of MCM-2 to diagnose high-grade CIN and invasive tumor resulted in sensitivity of 81%, specificity of 66%, a positive predictive value (PPV) of 86% and a negative predictive value (NPV) of 57%. HIV-positive cervices revealed a decreasing expression of MCM-2 in both LGCIN and HGCIN compared with HIV-negative specimens (p<0.0001). CONCLUSIONS: The present study suggests that immunohistochemical MCM-2 may not be a promising biomarker for diagnosing high grade CIN and invasive cancer. PMID- 22493663 TI - Summer diatom blooms in the North Pacific subtropical gyre: 2008-2009. AB - The summertime North Pacific subtropical gyre has widespread phytoplankton blooms between Hawaii and the subtropical front (~30 degrees N) that appear as chlorophyll (chl) increases in satellite ocean color data. Nitrogen-fixing diatom symbioses (diatom-diazotroph associations: DDAs) often increase 10(2)-10(3) fold in these blooms and contribute to elevated export flux. In 2008 and 2009, two cruises targeted satellite chlorophyll blooms to examine DDA species abundance, chlorophyll concentration, biogenic silica concentration, and hydrography. Generalized observations that DDA blooms occur when the mixed layer depth is < 70 m are supported, but there is no consistent relationship between mixed layer depth, bloom intensity, or composition; regional blooms between 22-34 degrees N occur within a broader temperature range (21-26 degrees C) than previously reported. In both years, the Hemiaulus-Richelia and Rhizosolenia-Richelia DDAs increased 10(2)-10(3) over background concentrations within satellite-defined bloom features. The two years share a common trend of Hemiaulus dominance of the DDAs and substantial increases in the >10 um chl a fraction (~40-90+% of total chl a). Integrated diatom abundance varied 10-fold over <10 km. Biogenic silica concentration tracked diatom abundance, was dominated by the >10 um size fraction, and increased up to 5-fold in the blooms. The two years differed in the magnitude of the surface chl a increase (2009>2008), the abundance of pennate diatoms within the bloom (2009>2008), and the substantially greater mixed layer depth in 2009. Only the 2009 bloom had sufficient chl a in the >10 um fraction to produce the observed ocean color chl increase. Blooms had high spatial variability; ocean color images likely average over numerous small events over time and space scales that exceed the individual event scale. Summertime DDA export flux noted at the Hawaii time-series Sta. ALOHA is probably a generalized feature of the eastern N. Pacific north to the subtropical front. PMID- 22493664 TI - Epidemiology of malaria, schistosomiasis, geohelminths, anemia and malnutrition in the context of a demographic surveillance system in northern Angola. AB - BACKGROUND: Malaria, schistosomiasis and geohelminth infection are linked to maternal and child morbidity and mortality in sub-Saharan Africa. Knowing the prevalence levels of these infections is vital to guide governments towards the implementation of successful and cost-effective disease control initiatives. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study of 1,237 preschool children (0-5 year olds), 1,142 school-aged children (6-15 year olds) and 960 women (>15 year olds) was conducted to understand the distribution of malnutrition, anemia, malaria, schistosomiasis (intestinal and urinary) and geohelminths in a north-western province of Angola. We used a recent demographic surveillance system (DSS) database to select and recruit suitable households. Malnutrition was common among children (23.3% under-weight, 9.9% wasting and 32.2% stunting), and anemia was found to be a severe public health problem (i.e., >40%). Malaria prevalence was highest among preschool children reaching 20.2%. Micro-hematuria prevalence levels reached 10.0% of preschool children, 16.6% of school-aged children and 21.7% of mothers. Geohelminth infections were common, affecting 22.3% of preschool children, 31.6% of school-aged children and 28.0% of mothers. CONCLUSIONS: Here we report prevalence levels of malaria, schistosomiasis and geohelminths; all endemic in this poorly described area where a DSS has been recently established. Furthermore we found evidence that the studied infections are associated with the observed levels of anemia and malnutrition, which can justify the implementation of integrated interventions for the control of these diseases and morbidities. PMID- 22493665 TI - Adaptive evolution in the glucose transporter 4 gene Slc2a4 in Old World fruit bats (family: Pteropodidae). AB - Frugivorous and nectarivorous bats are able to ingest large quantities of sugar in a short time span while avoiding the potentially adverse side-effects of elevated blood glucose. The glucose transporter 4 protein (GLUT4) encoded by the Slc2a4 gene plays a critical role in transmembrane skeletal muscle glucose uptake and thus glucose homeostasis. To test whether the Slc2a4 gene has undergone adaptive evolution in bats with carbohydrate-rich diets in relation to their insect-eating sister taxa, we sequenced the coding region of the Slc2a4 gene in a number of bat species, including four Old World fruit bats (Pteropodidae) and three New World fruit bats (Phyllostomidae). Our molecular evolutionary analyses revealed evidence that Slc2a4 has undergone a change in selection pressure in Old World fruit bats with 11 amino acid substitutions detected on the ancestral branch, whereas, no positive selection was detected in the New World fruit bats. We noted that in the former group, amino acid replacements were biased towards either Serine or Isoleucine, and, of the 11 changes, six were specific to Old World fruit bats (A133S, A164S, V377F, V386I, V441I and G459S). Our study presents preliminary evidence that the Slc2a4 gene has undergone adaptive changes in Old World fruit bats in relation to their ability to meet the demands of a high sugar diet. PMID- 22493666 TI - Whole body screening using high-temperature superconducting MR volume resonators: mice studies. AB - High temperature superconducting (HTS) surface resonators have been used as a low loss RF receiver resonator for improving magnetic resonance imaging image quality. However, the application of HTS surface resonators is significantly limited by their filling factor. To maximize the filling factor, it is desirable to have the RF resonator wrapped around the sample so that more nuclear magnetic dipoles can contribute to the signal. In this study, a whole new Bi(2)Sr(2)Ca(2)Cu(2)O(3) (Bi-2223) superconducting saddle resonator (width of 5 cm and length of 8 cm) was designed for the magnetic resonance image of a mouse's whole body in Bruker 3 T MRI system. The experiment was conducted with a professionally-made copper saddle resonator and a Bi-2223 saddle resonator to show the difference. Signal-to-noise ratio (SNR) with the HTS saddle resonator at 77 K was 2.1 and 2 folds higher than that of the copper saddle resonator at 300 K for a phantom and an in-vivo mice whole body imaging. Testing results were in accordance with predicted ones, and the difference between the predicted SNR gains and measured SNR gains were 2.4%~2.7%. In summary, with this HTS saddle system, a mouse's whole body can be imaged in one scan and could reach a high SNR due to a 2 folds SNR gain over the professionally-made prototype of copper saddle resonator at 300 K. The use of HTS saddle resonator not only improves SNR but also enables a mouse's whole body screen in one scan. PMID- 22493667 TI - Toolbox for non-intrusive structural and functional analysis of recombinant VLP based vaccines: a case study with hepatitis B vaccine. AB - BACKGROUND: Fundamental to vaccine development, manufacturing consistency, and product stability is an understanding of the vaccine structure-activity relationship. With the virus-like particle (VLP) approach for recombinant vaccines gaining popularity, there is growing demand for tools that define their key characteristics. We assessed a suite of non-intrusive VLP epitope structure and function characterization tools by application to the Hepatitis B surface antigen (rHBsAg) VLP-based vaccine. METHODOLOGY: The epitope-specific immune reactivity of rHBsAg epitopes to a given monoclonal antibody was monitored by surface plasmon resonance (SPR) and quantitatively analyzed on rHBsAg VLPs in solution or bound to adjuvant with a competitive enzyme-linked immunosorbent assay (ELISA). The structure of recombinant rHBsAg particles was examined by cryo transmission electron microscopy (cryoTEM) and in-solution atomic force microscopy (AFM). PRINCIPAL FINDINGS: SPR and competitive ELISA determined relative antigenicity in solution, in real time, with rapid turn-around, and without the need of dissolving the particulate aluminum based adjuvant. These methods demonstrated the nature of the clinically relevant epitopes of HBsAg as being responsive to heat and/or redox treatment. In-solution AFM and cryoTEM determined vaccine particle size distribution, shape, and morphology. Redox treated rHBsAg enabled 3D reconstruction from CryoTEM images--confirming the previously proposed octahedral structure and the established lipid-to-protein ratio of HBsAg particles. Results from these non-intrusive biophysical and immunochemical analyses coalesced into a comprehensive understanding of rHBsAg vaccine epitope structure and function that was important for assuring the desired epitope formation, determinants for vaccine potency, and particle stability during vaccine design, development, and manufacturing. SIGNIFICANCE: Together, the methods presented here comprise a novel suite of non-intrusive VLP structural and functional characterization tools for recombinant vaccines. Key VLP structural features were defined and epitope-specific antigenicity was quantified while preserving epitope integrity and particle morphology. These tools should facilitate the development of other VLP-based vaccines. PMID- 22493668 TI - Inferring phylogenies from RAD sequence data. AB - Reduced-representation genome sequencing represents a new source of data for systematics, and its potential utility in interspecific phylogeny reconstruction has not yet been explored. One approach that seems especially promising is the use of inexpensive short-read technologies (e.g., Illumina, SOLiD) to sequence restriction-site associated DNA (RAD)--the regions of the genome that flank the recognition sites of restriction enzymes. In this study, we simulated the collection of RAD sequences from sequenced genomes of different taxa (Drosophila, mammals, and yeasts) and developed a proof-of-concept workflow to test whether informative data could be extracted and used to accurately reconstruct "known" phylogenies of species within each group. The workflow consists of three basic steps: first, sequences are clustered by similarity to estimate orthology; second, clusters are filtered by taxonomic coverage; and third, they are aligned and concatenated for "total evidence" phylogenetic analysis. We evaluated the performance of clustering and filtering parameters by comparing the resulting topologies with well-supported reference trees and we were able to identify conditions under which the reference tree was inferred with high support. For Drosophila, whole genome alignments allowed us to directly evaluate which parameters most consistently recovered orthologous sequences. For the parameter ranges explored, we recovered the best results at the low ends of sequence similarity and taxonomic representation of loci; these generated the largest supermatrices with the highest proportion of missing data. Applications of the method to mammals and yeasts were less successful, which we suggest may be due partly to their much deeper evolutionary divergence times compared to Drosophila (crown ages of approximately 100 and 300 versus 60 Mya, respectively). RAD sequences thus appear to hold promise for reconstructing phylogenetic relationships in younger clades in which sufficient numbers of orthologous restriction sites are retained across species. PMID- 22493669 TI - Sensitivity and bias in decision-making under risk: evaluating the perception of reward, its probability and value. AB - BACKGROUND: There are few clinical tools that assess decision-making under risk. Tests that characterize sensitivity and bias in decisions between prospects varying in magnitude and probability of gain may provide insights in conditions with anomalous reward-related behaviour. OBJECTIVE: We designed a simple test of how subjects integrate information about the magnitude and the probability of reward, which can determine discriminative thresholds and choice bias in decisions under risk. DESIGN/METHODS: Twenty subjects were required to choose between two explicitly described prospects, one with higher probability but lower magnitude of reward than the other, with the difference in expected value between the two prospects varying from 3 to 23%. RESULTS: Subjects showed a mean threshold sensitivity of 43% difference in expected value. Regarding choice bias, there was a 'risk premium' of 38%, indicating a tendency to choose higher probability over higher reward. An analysis using prospect theory showed that this risk premium is the predicted outcome of hypothesized non-linearities in the subjective perception of reward value and probability. CONCLUSIONS: This simple test provides a robust measure of discriminative value thresholds and biases in decisions under risk. Prospect theory can also make predictions about decisions when subjective perception of reward or probability is anomalous, as may occur in populations with dopaminergic or striatal dysfunction, such as Parkinson's disease and schizophrenia. PMID- 22493670 TI - Conductive polymer combined silk fiber bundle for bioelectrical signal recording. AB - Electrode materials for recording biomedical signals, such as electrocardiography (ECG), electroencephalography (EEG) and evoked potentials data, are expected to be soft, hydrophilic and electroconductive to minimize the stress imposed on living tissue, especially during long-term monitoring. We have developed and characterized string-shaped electrodes made from conductive polymer with silk fiber bundles (thread), which offer a new biocompatible stress free interface with living tissue in both wet and dry conditions.An electroconductive polyelectrolyte, poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT PSS) was electrochemically combined with silk thread made from natural Bombyx mori. The polymer composite 280 um thread exhibited a conductivity of 0.00117 S/cm (which corresponds to a DC resistance of 2.62 Mohm/cm). The addition of glycerol to the PEDOT-PSS silk thread improved the conductivity to 0.102 S/cm (20.6 kohm/cm). The wettability of PEDOT-PSS was controlled with glycerol, which improved its durability in water and washing cycles. The glycerol treated PEDOT PSS silk thread showed a tensile strength of 1000 cN in both wet and dry states. Without using any electrolytes, pastes or solutions, the thread directly collects electrical signals from living tissue and transmits them through metal cables. ECG, EEG, and sensory evoked potential (SEP) signals were recorded from experimental animals by using this thread placed on the skin. PEDOT-PSS silk glycerol composite thread offers a new class of biocompatible electrodes in the field of biomedical and health promotion that does not induce stress in the subjects. PMID- 22493671 TI - Identification and characterization of microRNAs in Asiatic cotton (Gossypium arboreum L.). AB - To date, no miRNAs have been identified in the important diploid cotton species although there are several reports on miRNAs in upland cotton. In this study, we identified 73 miRNAs, belonging to 49 families, from Asiatic cotton using a well developed comparative genome-based homologue search. Several of the predicted miRNAs were validated using quantitative real time PCR (qRT-PCR). The length of miRNAs varied from 18 to 22 nt with an average of 20 nt. The length of miRNA precursors also varied from 46 to 684 nt with an average of 138 +/-120 nt. For a majority of Asiatic cotton miRNAs, there is only one member per family; however, multiple members were identified for miRNA 156, 414, 837, 838, 1044, 1533, 2902, 2868, 5021 and 5142 families. Nucleotides A and U were dominant, accounted for 62.95%, in the Asiatic cotton pre-miRNAs. The Asiatic cotton pre-miRNAs had high negative minimal folding free energy (MFE) and adjusted MFE (AMFE) and high MFE index (MFEI). Many miRNAs identified in Asiatic cotton suggest that miRNAs also play a similar regulatory mechanism in diploid cotton. PMID- 22493672 TI - Insulation for daydreams: a role for tonic norepinephrine in the facilitation of internally guided thought. AB - Although consciousness can be brought to bear on both perceptual and internally generated information, little is known about how these different cognitive modes are coordinated. Here we show that between-participant variance in thoughts unrelated to the task being performed (known as task unrelated thought, TUT) is associated with longer response times (RT) when target presentation occurs during periods when baseline Pupil Diameter (PD) is increased. As behavioral interference due to high baseline PD can reflect increased tonic activity in the norepinephrine system (NE), these results might implicate high tonic NE activity in the facilitation of TUTs. Based on these findings, it is hypothesised that high tonic mode NE leads to a generalised de-amplification of task relevant information that prioritses internally generated thought and insulates it from the potentially disruptive events taking place in the external environment. PMID- 22493673 TI - The predicted secretome of the plant pathogenic fungus Fusarium graminearum: a refined comparative analysis. AB - The fungus Fusarium graminearum forms an intimate association with the host species wheat whilst infecting the floral tissues at anthesis. During the prolonged latent period of infection, extracellular communication between live pathogen and host cells must occur, implying a role for secreted fungal proteins. The wheat cells in contact with fungal hyphae subsequently die and intracellular hyphal colonisation results in the development of visible disease symptoms. Since the original genome annotation analysis was done in 2007, which predicted the secretome using TargetP, the F. graminearum gene call has changed considerably through the combined efforts of the BROAD and MIPS institutes. As a result of the modifications to the genome and the recent findings that suggested a role for secreted proteins in virulence, the F. graminearum secretome was revisited. In the current study, a refined F. graminearum secretome was predicted by combining several bioinformatic approaches. This strategy increased the probability of identifying truly secreted proteins. A secretome of 574 proteins was predicted of which 99% was supported by transcriptional evidence. The function of the annotated and unannotated secreted proteins was explored. The potential role(s) of the annotated proteins including, putative enzymes, phytotoxins and antifungals are discussed. Characterisation of the unannotated proteins included the analysis of Pfam domains and features associated with known fungal effectors, for example, small size, cysteine-rich and containing internal amino acid repeats. A comprehensive comparative genomic analysis involving 57 fungal and oomycete genomes revealed that only a small number of the predicted F. graminearum secreted proteins can be considered to be either species or sequenced strain specific. PMID- 22493674 TI - Rapid release of tissue enzymes into blood after blast exposure: potential use as biological dosimeters. AB - Explosive blast results in multiple organ injury and polytrauma, the intensity of which varies with the nature of the exposure, orientation, environment and individual resilience. Blast overpressure alone may not precisely indicate the level of body or brain injury after blast exposure. Assessment of the extent of body injury after blast exposure is important, since polytrauma and systemic factors significantly contribute to blast-induced traumatic brain injury. We evaluated the activity of plasma enzymes including aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and creatine kinase (CK) at different time points after blast exposure using a mouse model of single and repeated blast exposures to assess the severity of injury. Our data show that activities of all the enzymes in the plasma were significantly increased as early as 1 h after blast exposure. The elevated enzyme activity remained up to 6 h in an overpressure dose-dependent manner and returned close to normal levels at 24 h. Head-only blast exposure with body protection showed no increase in the enzyme activities suggesting that brain injury alone does not contribute to the systemic increase. In contrast to plasma increase, AST, ALT and LDH activity in the liver and CK in the skeletal muscle showed drastic decrease at 6 h after blast exposures. Histopathology showed mild necrosis at 6 h and severe necrosis at 24 h after blast exposures in liver and no changes in the skeletal muscle suggesting that the enzyme release from the tissue to plasma is probably triggered by transient cell membrane disruption from shockwave and not due to necrosis. Overpressure dependent transient release of tissue enzymes and elevation in the plasma after blast exposure suggest that elevated enzyme activities in the blood can be potentially used as a biological dosimeter to assess the severity of blast injury. PMID- 22493675 TI - Activation of glial FGFRs is essential in glial migration, proliferation, and survival and in glia-neuron signaling during olfactory system development. AB - Development of the adult olfactory system of the moth Manduca sexta depends on reciprocal interactions between olfactory receptor neuron (ORN) axons growing in from the periphery and centrally-derived glial cells. Early-arriving ORN axons induce a subset of glial cells to proliferate and migrate to form an axon-sorting zone, in which later-arriving ORN axons will change their axonal neighbors and change their direction of outgrowth in order to travel with like axons to their target areas in the olfactory (antennal) lobe. These newly fasciculated axon bundles will terminate in protoglomeruli, the formation of which induces other glial cells to migrate to surround them. Glial cells do not migrate unless ORN axons are present, axons fail to fasciculate and target correctly without sufficient glial cells, and protoglomeruli are not maintained without a glial surround. We have shown previously that Epidermal Growth Factor receptors and the IgCAMs Neuroglian and Fasciclin II play a role in the ORN responses to glial cells. In the present work, we present evidence for the importance of glial Fibroblast Growth Factor receptors in glial migration, proliferation, and survival in this developing pathway. We also report changes in growth patterns of ORN axons and of the dendrites of olfactory (antennal lobe) neurons following blockade of glial FGFR activation that suggest that glial FGFR activation is important in reciprocal communication between neurons and glial cells. PMID- 22493676 TI - Measuring the quality of observational study data in an international HIV research network. AB - Observational studies of health conditions and outcomes often combine clinical care data from many sites without explicitly assessing the accuracy and completeness of these data. In order to improve the quality of data in an international multi-site observational cohort of HIV-infected patients, the authors conducted on-site, Good Clinical Practice-based audits of the clinical care datasets submitted by participating HIV clinics. Discrepancies between data submitted for research and data in the clinical records were categorized using the audit codes published by the European Organization for the Research and Treatment of Cancer. Five of seven sites had error rates >10% in key study variables, notably laboratory data, weight measurements, and antiretroviral medications. All sites had significant discrepancies in medication start and stop dates. Clinical care data, particularly antiretroviral regimens and associated dates, are prone to substantial error. Verifying data against source documents through audits will improve the quality of databases and research and can be a technique for retraining staff responsible for clinical data collection. The authors recommend that all participants in observational cohorts use data audits to assess and improve the quality of data and to guide future data collection and abstraction efforts at the point of care. PMID- 22493677 TI - Phylogenetic incongruence in E. coli O104: understanding the evolutionary relationships of emerging pathogens in the face of homologous recombination. AB - Escherichia coli O104:H4 was identified as an emerging pathogen during the spring and summer of 2011 and was responsible for a widespread outbreak that resulted in the deaths of 50 people and sickened over 4075. Traditional phenotypic and genotypic assays, such as serotyping, pulsed field gel electrophoresis (PFGE), and multilocus sequence typing (MLST), permit identification and classification of bacterial pathogens, but cannot accurately resolve relationships among genotypically similar but pathotypically different isolates. To understand the evolutionary origins of E. coli O104:H4, we sequenced two strains isolated in Ontario, Canada. One was epidemiologically linked to the 2011 outbreak, and the second, unrelated isolate, was obtained in 2010. MLST analysis indicated that both isolates are of the same sequence type (ST678), but whole-genome sequencing revealed differences in chromosomal and plasmid content. Through comprehensive phylogenetic analysis of five O104:H4 ST678 genomes, we identified 167 genes in three gene clusters that have undergone homologous recombination with distantly related E. coli strains. These recombination events have resulted in unexpectedly high sequence diversity within the same sequence type. Failure to recognize or adjust for homologous recombination can result in phylogenetic incongruence. Understanding the extent of homologous recombination among different strains of the same sequence type may explain the pathotypic differences between the ON2010 and ON2011 strains and help shed new light on the emergence of this new pathogen. PMID- 22493678 TI - Host plant adaptation in Drosophila mettleri populations. AB - The process of local adaptation creates diversity among allopatric populations, and may eventually lead to speciation. Plant-feeding insect populations that specialize on different host species provide an excellent opportunity to evaluate the causes of ecological specialization and the subsequent consequences for diversity. In this study, we used geographically separated Drosophila mettleri populations that specialize on different host cacti to examine oviposition preference for and larval performance on an array of natural and non-natural hosts (eight total). We found evidence of local adaptation in performance on saguaro cactus (Carnegiea gigantea) for populations that are typically associated with this host, and to chemically divergent prickly pear species (Opuntia spp.) in a genetically isolated population on Santa Catalina Island. Moreover, each population exhibited reduced performance on the alternative host. This finding is consistent with trade-offs associated with adaptation to these chemically divergent hosts, although we also discuss alternative explanations for this pattern. For oviposition preference, Santa Catalina Island flies were more likely to oviposit on some prickly pear species, but all populations readily laid eggs on saguaro. Experiments with non-natural hosts suggest that factors such as ecological opportunity may play a more important role than host plant chemistry in explaining the lack of natural associations with some hosts. PMID- 22493679 TI - MicroRNA-22 can reduce parathymosin expression in transdifferentiated hepatocytes. AB - Pancreatic acinar cells AR42J-B13 can transdifferentiate into hepatocyte-like cells permissive for efficient hepatitis B virus (HBV) replication. Here, we profiled miRNAs differentially expressed in AR42J-B13 cells before and after transdifferentiation to hepatocytes, using chip-based microarray. Significant increase of miRNA expression, including miR-21, miR-22, and miR-122a, was confirmed by stem-loop real-time PCR and Northern blot analyses. In contrast, miR 93, miR-130b, and a number of other miRNAs, were significantly reduced after transdifferentiation. To investigate the potential significance of miR-22 in hepatocytes, we generated cell lines stably expressing miR-22. By 2D-DIGE, LC MS/MS, and Western blot analyses, we identified several potential target genes of miR-22, including parathymosin. In transdifferentiated hepatocytes, miR-22 can inhibit both mRNA and protein expression of parathymosin, probably through a direct and an indirect mechanism. We tested two computer predicted miR-22 target sites at the 3' UTR of parathymosin, by the 3' UTR reporter gene assay. Treatment with anti-miR-22 resulted in significant elevation of the reporter activity. In addition, we observed an in vivo inverse correlation between miR-22 and parathymosin mRNA in their tissue distribution in a rat model. The phenomenon that miR-22 can reduce parathymosin protein was also observed in human hepatoma cell lines Huh7 and HepG2. So far, we detected no major effect on several transdifferentiation markers when AR42J-B13 cells were transfected with miR-22, or anti-miR-22, or a parathymosin expression vector, with or without dexamethasone treatment. Therefore, miR-22 appears to be neither necessary nor sufficient for transdifferentiation. We discussed the possibility that altered expression of some other microRNAs could induce cell cycle arrest leading to transdifferentiation. PMID- 22493680 TI - Mutation accumulation may be a minor force in shaping life history traits. AB - Is senescence the adaptive result of tradeoffs between younger and older ages or the nonadaptive burden of deleterious mutations that act at older ages? To shed new light on this unresolved question we combine adaptive and nonadaptive processes in a single model. Our model uses Penna's bit-strings to capture different age-specific mutational patterns. Each pattern represents a genotype and for each genotype we find the life history strategy that maximizes fitness. Genotypes compete with each other and are subject to selection and to new mutations over generations until equilibrium in gene-frequencies is reached. The mutation-selection equilibrium provides information about mutational load and the differential effects of mutations on a life history trait--the optimal age at maturity. We find that mutations accumulate only at ages with negligible impact on fitness and that mutation accumulation has very little effect on the optimal age at maturity. These results suggest that life histories are largely determined by adaptive processes. The non-adaptive process of mutation accumulation seems to be unimportant at evolutionarily relevant ages. PMID- 22493681 TI - Metabonomic profiles delineate the effect of traditional Chinese medicine sini decoction on myocardial infarction in rats. AB - BACKGROUND: In spite of great advances in target-oriented Western medicine for treating myocardial infarction (MI), it is still a leading cause of death in a worldwide epidemic. In contrast to Western medicine, Traditional Chinese medicine (TCM) uses a holistic and synergistic approach to restore the balance of Yin-Yang of body energy so the body's normal function can be restored. Sini decoction (SND) is a well-known formula of TCM which has been used to treat MI for many years. However, its holistic activity evaluation and mechanistic understanding are still lacking due to its complex components. METHODOLOGY/PRINCIPAL FINDINGS: A urinary metabonomic method based on nuclear magnetic resonance and ultra high performance liquid chromatography coupled to mass spectrometry was developed to characterize MI-related metabolic profiles and delineate the effect of SND on MI. With Elastic Net for classification and selection of biomarkers, nineteen potential biomarkers in rat urine were screened out, primarily related to myocardial energy metabolism, including the glycolysis, citrate cycle, amino acid metabolism, purine metabolism and pyrimidine metabolism. With the altered metabolism pathways as possible drug targets, we systematically analyze the therapeutic effect of SND, which demonstrated that SND administration could provide satisfactory effect on MI through partially regulating the perturbed myocardial energy metabolism. CONCLUSIONS/SIGNIFICANCE: Our results showed that metabonomic approach offers a useful tool to identify MI-related biomarkers and provides a new methodological cue for systematically dissecting the underlying efficacies and mechanisms of TCM in treating MI. PMID- 22493682 TI - Universal sequence replication, reversible polymerization and early functional biopolymers: a model for the initiation of prebiotic sequence evolution. AB - Many models for the origin of life have focused on understanding how evolution can drive the refinement of a preexisting enzyme, such as the evolution of efficient replicase activity. Here we present a model for what was, arguably, an even earlier stage of chemical evolution, when polymer sequence diversity was generated and sustained before, and during, the onset of functional selection. The model includes regular environmental cycles (e.g. hydration-dehydration cycles) that drive polymers between times of replication and functional activity, which coincide with times of different monomer and polymer diffusivity. Template directed replication of informational polymers, which takes place during the dehydration stage of each cycle, is considered to be sequence-independent. New sequences are generated by spontaneous polymer formation, and all sequences compete for a finite monomer resource that is recycled via reversible polymerization. Kinetic Monte Carlo simulations demonstrate that this proposed prebiotic scenario provides a robust mechanism for the exploration of sequence space. Introduction of a polymer sequence with monomer synthetase activity illustrates that functional sequences can become established in a preexisting pool of otherwise non-functional sequences. Functional selection does not dominate system dynamics and sequence diversity remains high, permitting the emergence and spread of more than one functional sequence. It is also observed that polymers spontaneously form clusters in simulations where polymers diffuse more slowly than monomers, a feature that is reminiscent of a previous proposal that the earliest stages of life could have been defined by the collective evolution of a system-wide cooperation of polymer aggregates. Overall, the results presented demonstrate the merits of considering plausible prebiotic polymer chemistries and environments that would have allowed for the rapid turnover of monomer resources and for regularly varying monomer/polymer diffusivities. PMID- 22493683 TI - Neighborhood influences on perceived social support among parents: findings from the project on human development in Chicago neighborhoods. AB - BACKGROUND: Social support is frequently linked to positive parenting behavior. Similarly, studies increasingly show a link between neighborhood residential environment and positive parenting behavior. However, less is known about how the residential environment influences parental social support. To address this gap, we examine the relationship between neighborhood concentrated disadvantage and collective efficacy and the level and change in parental caregiver perceptions of non-familial social support. METHODOLOGY/PRINCIPAL FINDINGS: The data for this study came from three data sources, the Project on Human Development in Chicago Neighborhoods (PHDCN) Study's Longitudinal Cohort Survey of caregivers and their offspring, a Community Survey of adult residents in these same neighborhoods and the 1990 Census. Social support is measured at Wave 1 and Wave 3 and neighborhood characteristics are measured at Wave 1. Multilevel linear regression models are fit. The results show that neighborhood collective efficacy is a significant (beta = .04; SE = .02; p = .03), predictor of the positive change in perceived social support over a 7 year period, however, not of the level of social support, adjusting for key compositional variables and neighborhood concentrated disadvantage. In contrast concentrated neighborhood disadvantage is not a significant predictor of either the level or change in social support. CONCLUSION: Our finding suggests that neighborhood collective efficacy may be important for inducing the perception of support from friends in parental caregivers over time. PMID- 22493684 TI - Genetic association studies of copy-number variation: should assignment of copy number states precede testing? AB - Recently, structural variation in the genome has been implicated in many complex diseases. Using genomewide single nucleotide polymorphism (SNP) arrays, researchers are able to investigate the impact not only of SNP variation, but also of copy-number variants (CNVs) on the phenotype. The most common analytic approach involves estimating, at the level of the individual genome, the underlying number of copies present at each location. Once this is completed, tests are performed to determine the association between copy number state and phenotype. An alternative approach is to carry out association testing first, between phenotype and raw intensities from the SNP array at the level of the individual marker, and then aggregate neighboring test results to identify CNVs associated with the phenotype. Here, we explore the strengths and weaknesses of these two approaches using both simulations and real data from a pharmacogenomic study of the chemotherapeutic agent gemcitabine. Our results indicate that pooled marker-level testing is capable of offering a dramatic increase in power (> 12 fold) over CNV-level testing, particularly for small CNVs. However, CNV-level testing is superior when CNVs are large and rare; understanding these tradeoffs is an important consideration in conducting association studies of structural variation. PMID- 22493685 TI - Pigments, parasites and personalitiy: towards a unifying role for steroid hormones? AB - A surging interest in the evolution of consistent trait correlations has inspired research on pigment patterns as a correlate of behavioural syndromes, or "animal personalities". Associations between pigmentation, physiology and health status are less investigated as potentially conserved trait clusters. In the current study, lice counts performed on farmed Atlantic salmon Salmo salar naturally infected with ectoparasitic sea lice Lepeophtheirus salmonis showed that individual fish with high incidence of black melanin-based skin spots harboured fewer female sea lice carrying egg sacs, compared to less pigmented fish. There was no significant association between pigmentation and lice at other developmental stages, suggesting that host factors associated with melanin-based pigmentation may modify ectoparasite development to a larger degree than settlement. In a subsequent laboratory experiment a strong negative correlation between skin spots and post-stress cortisol levels was revealed, with less pigmented individuals showing a more pronounced cortisol response to acute stress. The observation that lice prevalence was strongly increased on a fraction of sexually mature male salmon which occurred among the farmed fish further supports a role for steroid hormones as mediators of reduced parasite resistance. The data presented here propose steroid hormones as a proximate cause for the association between melanin-based pigmentation and parasites. Possible fundamental and applied implications are discussed. PMID- 22493686 TI - Fisher information as a metric of locally optimal processing and stochastic resonance. AB - The origins of Fisher information are in its use as a performance measure for parametric estimation. We augment this and show that the Fisher information can characterize the performance in several other significant signal processing operations. For processing of a weak signal in additive white noise, we demonstrate that the Fisher information determines (i) the maximum output signal to-noise ratio for a periodic signal; (ii) the optimum asymptotic efficacy for signal detection; (iii) the best cross-correlation coefficient for signal transmission; and (iv) the minimum mean square error of an unbiased estimator. This unifying picture, via inequalities on the Fisher information, is used to establish conditions where improvement by noise through stochastic resonance is feasible or not. PMID- 22493687 TI - Radiating on oceanic islands: patterns and processes of speciation in the land snail genus Theba (Risso 1826). AB - Island radiations have played a major role in shaping our current understanding of allopatric, sympatric and parapatric speciation. However, the fact that species divergence correlates with island size emphasizes the importance of geographic isolation (allopatry) in speciation. Based on molecular and morphological data, we investigated the diversification of the land snail genus Theba on the two Canary Islands of Lanzarote and Fuerteventura. Due to the geological history of both islands, this study system provides ideal conditions to investigate the interplay of biogeography, dispersal ability and differentiation in generating species diversity. Our analyses demonstrated extensive cryptic diversification of Theba on these islands, probably driven mainly by non-adaptive allopatric differentiation and secondary gene flow. In a few cases, we observed a complete absence of gene flow among sympatrically distributed forms suggesting an advanced stage of speciation. On the Jandia peninsula genome scans suggested genotype-environment associations and potentially adaptive diversification of two closely related Theba species to different ecological environments. We found support for the idea that genetic differentiation was enhanced by divergent selection in different environments. The diversification of Theba on both islands is therefore best explained by a mixture of non-adaptive and adaptive speciation, promoted by ecological and geomorphological factors. PMID- 22493688 TI - A rapid, cost-effective method of assembly and purification of synthetic DNA probes >100 bp. AB - Here we introduce a rapid, cost-effective method of generating molecular DNA probes in just under 15 minutes without the need for expensive, time-consuming gel-extraction steps. As an example, we enzymatically concatenated six variable strands (50 bp) with a common strand sequence (51 bp) in a single pool using Fast Link DNA ligase to produce 101 bp targets (10 min). Unincorporated species were then filtered out by passing the crude reaction through a size-exclusion column (<5 min). We then compared full-length product yield of crude and purified samples using HPLC analysis; the results of which clearly show our method yields three-quarters that of the crude sample (50% higher than by gel-extraction). And while we substantially reduced the amount of unligated product with our filtration process, higher purity and yield, with an increase in number of stands per reaction (>12) could be achieved with further optimization. Moreover, for large-scale assays, we envision this method to be fully automated with the use of robotics such as the Biomek FX; here, potentially thousands of samples could be pooled, ligated and purified in either a 96, 384 or 1536-well platform in just minutes. PMID- 22493689 TI - Reduced exercise tolerance and pulmonary capillary recruitment with remote secondhand smoke exposure. AB - RATIONALE: Flight attendants who worked on commercial aircraft before the smoking ban in flights (pre-ban FAs) were exposed to high levels of secondhand smoke (SHS). We previously showed never-smoking pre-ban FAs to have reduced diffusing capacity (Dco) at rest. METHODS: To determine whether pre-ban FAs increase their Dco and pulmonary blood flow (Qc) during exercise, we administered a symptom limited supine-posture progressively increasing cycle exercise test to determine the maximum work (watts) and oxygen uptake (VO2) achieved by FAs. After 30 min rest, we then measured Dco and Qc at 20, 40, 60, and 80 percent of maximum observed work. RESULTS: The FAs with abnormal resting Dco achieved a lower level of maximum predicted work and VO2 compared to those with normal resting Dco (mean+/-SEM; 88.7+/-2.9 vs. 102.5+/-3.1%predicted VO2; p = 0.001). Exercise limitation was associated with the FAs' FEV(1) (r = 0.33; p = 0.003). The Dco increased less with exercise in those with abnormal resting Dco (mean+/-SEM: 1.36+/-0.16 vs. 1.90+/-0.16 ml/min/mmHg per 20% increase in predicted watts; p = 0.020), and amongst all FAs, the increase with exercise seemed to be incrementally lower in those with lower resting Dco. Exercise-induced increase in Qc was not different in the two groups. However, the FAs with abnormal resting Dco had less augmentation of their Dco with increase in Qc during exercise (mean+/-SEM: 0.93+/-0.06 vs. 1.47+/-0.09 ml/min/mmHg per L/min; p<0.0001). The Dco during exercise was inversely associated with years of exposure to SHS in those FAs with >=10 years of pre-ban experience (r = -0.32; p = 0.032). CONCLUSIONS: This cohort of never-smoking FAs with SHS exposure showed exercise limitation based on their resting Dco. Those with lower resting Dco had reduced pulmonary capillary recruitment. Exposure to SHS in the aircraft cabin seemed to be a predictor for lower Dco during exercise. PMID- 22493690 TI - Effects of vagus nerve stimulation and vagotomy on systemic and pulmonary inflammation in a two-hit model in rats. AB - Pulmonary inflammation contributes to ventilator-induced lung injury. Sepsis induced pulmonary inflammation (first hit) may be potentiated by mechanical ventilation (MV, second hit). Electrical stimulation of the vagus nerve has been shown to attenuate inflammation in various animal models through the cholinergic anti-inflammatory pathway. We determined the effects of vagotomy (VGX) and vagus nerve stimulation (VNS) on systemic and pulmonary inflammation in a two-hit model. Male Sprague-Dawley rats were i.v. administered lipopolysaccharide (LPS) and subsequently underwent VGX, VNS or a sham operation. 1 hour following LPS, MV with low (8 mL/kg) or moderate (15 mL/kg) tidal volumes was initiated, or animals were left breathing spontaneously (SP). After 4 hours of MV or SP, rats were sacrificed. Cytokine and blood gas analysis was performed. MV with 15, but not 8 mL/kg, potentiated the LPS-induced pulmonary pro-inflammatory cytokine response (TNF-alpha, IL-6, KC: p<0.05 compared to LPS-SP), but did not affect systemic inflammation or impair oxygenation. VGX enhanced the LPS-induced pulmonary, but not systemic pro-inflammatory cytokine response in spontaneously breathing, but not in MV animals (TNF-alpha, IL-6, KC: p<0.05 compared to SHAM), and resulted in decreased pO(2) (p<0.05 compared to sham-operated animals). VNS did not affect any of the studied parameters in both SP and MV animals. In conclusion, MV with moderate tidal volumes potentiates the pulmonary inflammatory response elicited by systemic LPS administration. No beneficial effects of vagus nerve stimulation performed following LPS administration were found. These results questions the clinical applicability of stimulation of the cholinergic anti-inflammatory pathway in systemically inflamed patients admitted to the ICU where MV is initiated. PMID- 22493691 TI - Novel associations for hypothyroidism include known autoimmune risk loci. AB - Hypothyroidism is the most common thyroid disorder, affecting about 5% of the general population. Here we present the current largest genome-wide association study of hypothyroidism, in 3,736 cases and 35,546 controls. Hypothyroidism was assessed via web-based questionnaires. We identify five genome-wide significant associations, three of which are well known to be involved in a large spectrum of autoimmune diseases: rs6679677 near PTPN22, rs3184504 in SH2B3, and rs2517532 in the HLA class I region (p-values 2.8.10(-13), 2.6.10(-12), and 1.3.10(-8), respectively). We also report associations with rs4915077 near VAV3 (p-value 7.5.10(-10)) and rs925489 near FOXE1 (p value 2.4.10(-19)). VAV3 is involved in immune function, and FOXE1 and PTPN22 have previously been associated with hypothyroidism. Although the HLA class I region and SH2B3 have previously been linked with a number of autoimmune diseases, this is the first report of their association with thyroid disease. The VAV3 association is also novel. We also show suggestive evidence of association for hypothyroidism with a SNP in the HLA class II region (independent of the other HLA association) as well as SNPs in CAPZB, PDE8B, and CTLA4. CAPZB and PDE8B have been linked to TSH levels and CTLA4 to a variety of autoimmune diseases. These results suggest heterogeneity in the genetic etiology of hypothyroidism, implicating genes involved in both autoimmune disorders and thyroid function. Using a genetic risk profile score based on the top association from each of the five genome-wide significant regions in our study, the relative risk between the highest and lowest deciles of genetic risk is 2.0. PMID- 22493693 TI - Recycling attitudes and behavior among a clinic-based sample of low-income Hispanic women in southeast Texas. AB - We examined attitudes and behavior surrounding voluntary recycling in a population of low-income Hispanic women. Participants (N = 1,512) 18-55 years of age completed a self-report survey and responded to questions regarding household recycling behavior, recycling knowledge, recycling beliefs, potential barriers to recycling (transportation mode, time), acculturation, demographic characteristics (age, income, employment, marital status, education, number of children, birth country), and social desirability. Forty-six percent of participants (n = 810) indicated that they or someone else in their household recycled. In a logistic regression model controlling for social desirability, recycling behavior was related to increased age (P<0.05), lower acculturation (P<0.01), knowing what to recycle (P<0.01), knowing that recycling saves landfill space (P<0.05), and disagreeing that recycling takes too much time (P<0.001). A Sobel test revealed that acculturation mediated the relationship between recycling knowledge and recycling behavior (P<0.05). We offer new information on recycling behavior among Hispanic women and highlight the need for educational outreach and intervention strategies to increase recycling behavior within this understudied population. PMID- 22493692 TI - Hepatitis C virus network based classification of hepatocellular cirrhosis and carcinoma. AB - Hepatitis C virus (HCV) is a main risk factor for liver cirrhosis and hepatocellular carcinoma, particularly to those patients with chronic liver disease or injury. The similar etiology leads to a high correlation of the patients suffering from the disease of liver cirrhosis with those suffering from the disease of hepatocellular carcinoma. However, the biological mechanism for the relationship between these two kinds of diseases is not clear. The present study was initiated in an attempt to investigate into the HCV infection protein network, in hopes to find good biomarkers for diagnosing the two diseases as well as gain insights into their progression mechanisms. To realize this, two potential biomarker pools were defined: (i) the target genes of HCV, and (ii) the between genes on the shortest paths among the target genes of HCV. Meanwhile, a predictor was developed for identifying the liver tissue samples among the following three categories: (i) normal, (ii) cirrhosis, and (iii) hepatocellular carcinoma. Interestingly, it was observed that the identification accuracy was higher with the tissue samples defined by extracting the features from the second biomarker pool than that with the samples defined based on the first biomarker pool. The identification accuracy by the jackknife validation for the between genes approach was 0.960, indicating that the novel approach holds a quite promising potential in helping find effective biomarkers for diagnosing the liver cirrhosis disease and the hepatocellular carcinoma disease. It may also provide useful insights for in-depth study of the biological mechanisms of HCV-induced cirrhosis and hepatocellular carcinoma. PMID- 22493694 TI - Context-specific protein network miner--an online system for exploring context specific protein interaction networks from the literature. AB - BACKGROUND: Protein interaction networks (PINs) specific within a particular context contain crucial information regarding many cellular biological processes. For example, PINs may include information on the type and directionality of interaction (e.g. phosphorylation), location of interaction (i.e. tissues, cells), and related diseases. Currently, very few tools are capable of deriving context-specific PINs for conducting exploratory analysis. RESULTS: We developed a literature-based online system, Context-specific Protein Network Miner (CPNM), which derives context-specific PINs in real-time from the PubMed database based on a set of user-input keywords and enhanced PubMed query system. CPNM reports enriched information on protein interactions (with type and directionality), their network topology with summary statistics (e.g. most densely connected proteins in the network; most densely connected protein-pairs; and proteins connected by most inbound/outbound links) that can be explored via a user friendly interface. Some of the novel features of the CPNM system include PIN generation, ontology-based PubMed query enhancement, real-time, user-queried, up to-date PubMed document processing, and prediction of PIN directionality. CONCLUSIONS: CPNM provides a tool for biologists to explore PINs. It is freely accessible at http://www.biotextminer.com/CPNM/. PMID- 22493695 TI - The Digital Fish Library: using MRI to digitize, database, and document the morphological diversity of fish. AB - Museum fish collections possess a wealth of anatomical and morphological data that are essential for documenting and understanding biodiversity. Obtaining access to specimens for research, however, is not always practical and frequently conflicts with the need to maintain the physical integrity of specimens and the collection as a whole. Non-invasive three-dimensional (3D) digital imaging therefore serves a critical role in facilitating the digitization of these specimens for anatomical and morphological analysis as well as facilitating an efficient method for online storage and sharing of this imaging data. Here we describe the development of the Digital Fish Library (DFL, http://www.digitalfishlibrary.org), an online digital archive of high-resolution, high-contrast, magnetic resonance imaging (MRI) scans of the soft tissue anatomy of an array of fishes preserved in the Marine Vertebrate Collection of Scripps Institution of Oceanography. We have imaged and uploaded MRI data for over 300 marine and freshwater species, developed a data archival and retrieval system with a web-based image analysis and visualization tool, and integrated these into the public DFL website to disseminate data and associated metadata freely over the web. We show that MRI is a rapid and powerful method for accurately depicting the in-situ soft-tissue anatomy of preserved fishes in sufficient detail for large-scale comparative digital morphology. However these 3D volumetric data require a sophisticated computational and archival infrastructure in order to be broadly accessible to researchers and educators. PMID- 22493696 TI - DNA methylation analysis of bone marrow cells at diagnosis of acute lymphoblastic leukemia and at remission. AB - To detect genes with CpG sites that display methylation patterns that are characteristic of acute lymphoblastic leukemia (ALL) cells, we compared the methylation patterns of cells taken at diagnosis from 20 patients with pediatric ALL to the methylation patterns in mononuclear cells from bone marrow of the same patients during remission and in non-leukemic control cells from bone marrow or blood. Using a custom-designed assay, we measured the methylation levels of 1,320 CpG sites in regulatory regions of 413 genes that were analyzed because they display allele-specific gene expression (ASE) in ALL cells. The rationale for our selection of CpG sites was that ASE could be the result of allele-specific methylation in the promoter regions of the genes. We found that the ALL cells had methylation profiles that allowed distinction between ALL cells and control cells. Using stringent criteria for calling differential methylation, we identified 28 CpG sites in 24 genes with recurrent differences in their methylation levels between ALL cells and control cells. Twenty of the differentially methylated genes were hypermethylated in the ALL cells, and as many as nine of them (AMICA1, CPNE7, CR1, DBC1, EYA4, LGALS8, RYR3, UQCRFS1, WDR35) have functions in cell signaling and/or apoptosis. The methylation levels of a subset of the genes were consistent with an inverse relationship with the mRNA expression levels in a large number of ALL cells from published data sets, supporting a potential biological effect of the methylation signatures and their application for diagnostic purposes. PMID- 22493698 TI - Not all kinds of revegetation are created equal: revegetation type influences bird assemblages in threatened Australian woodland ecosystems. AB - The value for biodiversity of large intact areas of native vegetation is well established. The biodiversity value of regrowth vegetation is also increasingly recognised worldwide. However, there can be different kinds of revegetation that have different origins. Are there differences in the richness and composition of biotic communities in different kinds of revegetation? The answer remains unknown or poorly known in many ecosystems. We examined the conservation value of different kinds of revegetation through a comparative study of birds in 193 sites surveyed over ten years in four growth types located in semi-cleared agricultural areas of south-eastern Australia. These growth types were resprout regrowth, seedling regrowth, plantings, and old growth. Our investigation produced several key findings: (1) Marked differences in the bird assemblages of plantings, resprout regrowth, seedling regrowth, and old growth. (2) Differences in the number of species detected significantly more often in the different growth types; 29 species for plantings, 25 for seedling regrowth, 20 for resprout regrowth, and 15 for old growth. (3) Many bird species of conservation concern were significantly more often recorded in resprout regrowth, seedling regrowth or plantings but no species of conservation concern were recorded most often in old growth. We suggest that differences in bird occurrence among different growth types are likely to be strongly associated with growth-type differences in stand structural complexity.Our findings suggest a range of vegetation growth types are likely to be required in a given farmland area to support the diverse array of bird species that have the potential to occur in Australian temperate woodland ecosystems. Our results also highlight the inherent conservation value of regrowth woodland and suggest that current policies which allow it to be cleared or thinned need to be carefully re-examined. PMID- 22493697 TI - Cholesterol depletion in adipocytes causes caveolae collapse concomitant with proteosomal degradation of cavin-2 in a switch-like fashion. AB - Caveolae, little caves of cell surfaces, are enriched in cholesterol, a certain level of which is required for their structural integrity. Here we show in adipocytes that cavin-2, a peripheral membrane protein and one of 3 cavin isoforms present in caveolae from non-muscle tissue, is degraded upon cholesterol depletion in a rapid fashion resulting in collapse of caveolae. We exposed 3T3-L1 adipocytes to the cholesterol depleting agent methyl-beta-cyclodextrin, which results in a sudden and extensive degradation of cavin-2 by the proteasome and a concomitant movement of cavin-1 from the plasma membrane to the cytosol along with loss of caveolae. The recovery of cavin-2 at the plasma membrane is cholesterol-dependent and is required for the return of cavin-1 from the cytosol to the cell surface and caveolae restoration. Expression of shRNA directed against cavin-2 also results in a cytosolic distribution of cavin-1 and loss of caveolae. Taken together, these data demonstrate that cavin-2 functions as a cholesterol responsive component of caveolae that is required for cavin-1 localization to the plasma membrane, and caveolae structural integrity. PMID- 22493699 TI - Learning temporal patterns of risk in a predator-diverse environment. AB - Predation plays a major role in shaping prey behaviour. Temporal patterns of predation risk have been shown to drive daily activity and foraging patterns in prey. Yet the ability to respond to temporal patterns of predation risk in environments inhabited by highly diverse predator communities, such as rainforests and coral reefs, has received surprisingly little attention. In this study, we investigated whether juvenile marine fish, Pomacentrus moluccensis (lemon damselfish), have the ability to learn to adjust the intensity of their antipredator response to match the daily temporal patterns of predation risk they experience. Groups of lemon damselfish were exposed to one of two predictable temporal risk patterns for six days. "Morning risk" treatment prey were exposed to the odour of Cephalopholis cyanostigma (rockcod) paired with conspecific chemical alarm cues (simulating a rockcod present and feeding) during the morning, and rockcod odour only in the evening (simulating a rockcod present but not feeding). "Evening risk" treatment prey had the two stimuli presented to them in the opposite order. When tested individually for their response to rockcod odour alone, lemon damselfish from the morning risk treatment responded with a greater antipredator response intensity in the morning than in the evening. In contrast, those lemon damselfish previously exposed to the evening risk treatment subsequently responded with a greater antipredator response when tested in the evening. The results of this experiment demonstrate that P. moluccensis have the ability to learn temporal patterns of predation risk and can adjust their foraging patterns to match the threat posed by predators at a given time of day. Our results provide the first experimental demonstration of a mechanism by which prey in a complex, multi-predator environment can learn and respond to daily patterns of predation risk. PMID- 22493701 TI - Bioturbation in a declining oxygen environment, in situ observations from Wormcam. AB - Bioturbation, the displacement and mixing of sediment particles by fauna or flora, facilitates life supporting processes by increasing the quality of marine sediments. In the marine environment bioturbation is primarily mediated by infaunal organisms, which are susceptible to perturbations in their surrounding environment due to their sedentary life history traits. Of particular concern is hypoxia, dissolved oxygen (DO) concentrations <=2.8 mg l(-1), a prevalent and persistent problem that affects both pelagic and benthic fauna. A benthic observing system (Wormcam) consisting of a buoy, telemetering electronics, sediment profile camera, and water quality datasonde was developed and deployed in the Rappahannock River, VA, USA, in an area known to experience seasonal hypoxia from early spring to late fall. Wormcam transmitted a time series of in situ images and water quality data, to a website via wireless internet modem, for 5 months spanning normoxic and hypoxic periods. Hypoxia was found to significantly reduce bioturbation through reductions in burrow lengths, burrow production, and burrowing depth. Although infaunal activity was greatly reduced during hypoxic and near anoxic conditions, some individuals remained active. Low concentrations of DO in the water column limited bioturbation by infaunal burrowers and likely reduced redox cycling between aerobic and anaerobic states. This study emphasizes the importance of in situ observations for understanding how components of an ecosystem respond to hypoxia. PMID- 22493700 TI - Contribution of efflux to the emergence of isoniazid and multidrug resistance in Mycobacterium tuberculosis. AB - Multidrug resistant (MDR) tuberculosis is caused by Mycobacterium tuberculosis resistant to isoniazid and rifampicin, the two most effective drugs used in tuberculosis therapy. Here, we investigated the mechanism by which resistance towards isoniazid develops and how overexpression of efflux pumps favors accumulation of mutations in isoniazid targets, thus establishing a MDR phenotype. The study was based on the in vitro induction of an isoniazid resistant phenotype by prolonged serial exposure of M. tuberculosis strains to the critical concentration of isoniazid employed for determination of drug susceptibility testing in clinical isolates. Results show that susceptible and rifampicin monoresistant strains exposed to this concentration become resistant to isoniazid after three weeks; and that resistance observed for the majority of these strains could be reduced by means of efflux pumps inhibitors. RT-qPCR assessment of efflux pump genes expression showed overexpression of all tested genes. Enhanced real-time efflux of ethidium bromide, a common efflux pump substrate, was also observed, showing a clear relation between overexpression of the genes and increased efflux pump function. Further exposure to isoniazid resulted in the selection and stabilization of spontaneous mutations and deletions in the katG gene along with sustained increased efflux activity. Together, results demonstrate the relevance of efflux pumps as one of the factors of isoniazid resistance in M. tuberculosis. These results support the hypothesis that activity of efflux pumps allows the maintenance of an isoniazid resistant population in a sub-optimally treated patient from which isoniazid genetically resistant mutants emerge. Therefore, the use of inhibitors of efflux should be considered in the development of new therapeutic strategies for preventing the emergence of MDR-TB during treatment. PMID- 22493702 TI - Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia. AB - Heterozygous glucokinase (GCK) mutations cause a subtype of maturity-onset diabetes of the young (GCK-MODY). Over 600 GCK mutations have been reported of which ~65% are missense. In many cases co-segregation has not been established and despite the importance of functional studies in ascribing pathogenicity for missense variants these have only been performed for <10% of mutations. The aim of this study was to determine the minimum prevalence of GCK-MODY amongst diabetic subjects in Slovakia by sequencing GCK in 100 Slovakian probands with a phenotype consistent with GCK-MODY and to explore the pathogenicity of identified variants through family and functional studies. Twenty-two mutations were identified in 36 families (17 missense) of which 7 (I110N, V200A, N204D, G258R, F419S, c.580-2A>C, c.1113-1114delGC) were novel. Parental DNA was available for 22 probands (covering 14/22 mutations) and co-segregation established in all cases. Bioinformatic analysis predicted all missense mutations to be damaging. Nine (I110N, V200A, N204D, G223S, G258R, F419S, V244G, L315H, I436N) mutations were functionally evaluated. Basic kinetic analysis explained pathogenicity for 7 mutants which showed reduced glucokinase activity with relative activity indices (RAI) between 0.6 to <0.001 compared to wild-type GCK (1.0). For the remaining 2 mutants additional molecular mechanisms were investigated. Differences in glucokinase regulatory protein (GKRP) -mediated-inhibition of GCK were observed for both L315H & I436N when compared to wild type (IC(50) 14.6+/-0.1 mM & 20.3+/ 1.6 mM vs.13.3+/-0.1 mM respectively [p<0.03]). Protein instability as assessed by thermal lability studies demonstrated that both L315H and I436N show marked thermal instability compared to wild-type GCK (RAI at 55 degrees C 8.8+/-0.8% & 3.1+/-0.4% vs. 42.5+/-3.9% respectively [p<0.001]). The minimum prevalence of GCK MODY amongst Slovakian patients with diabetes was 0.03%. In conclusion, we have identified 22 GCK mutations in 36 Slovakian probands and demonstrate that combining family, bioinformatic and functional studies can aid the interpretation of variants identified by molecular diagnostic screening. PMID- 22493703 TI - Do native parasitic plants cause more damage to exotic invasive hosts than native non-invasive hosts? An implication for biocontrol. AB - Field studies have shown that native, parasitic plants grow vigorously on invasive plants and can cause more damage to invasive plants than native plants. However, no empirical test has been conducted and the mechanism is still unknown. We conducted a completely randomized greenhouse experiment using 3 congeneric pairs of exotic, invasive and native, non-invasive herbaceous plant species to quantify the damage caused by parasitic plants to hosts and its correlation with the hosts' growth rate and resource use efficiency. The biomass of the parasitic plants on exotic, invasive hosts was significantly higher than on congeneric native, non-invasive hosts. Parasites caused more damage to exotic, invasive hosts than to congeneric, native, non-invasive hosts. The damage caused by parasites to hosts was significantly positively correlated with the biomass of parasitic plants. The damage of parasites to hosts was significantly positively correlated with the relative growth rate and the resource use efficiency of its host plants. It may be the mechanism by which parasitic plants grow more vigorously on invasive hosts and cause more damage to exotic, invasive hosts than to native, non-invasive hosts. These results suggest a potential biological control effect of native, parasitic plants on invasive species by reducing the dominance of invasive species in the invaded community. PMID- 22493704 TI - Suppressive effects on the immune response and protective immunity to a JEV DNA vaccine by co-administration of a GM-CSF-expressing plasmid in mice. AB - As a potential cytokine adjuvant of DNA vaccines, granulocyte-macrophage colony stimulating factor (GM-CSF) has received considerable attention due to its essential role in the recruitment of antigen-presenting cells, differentiation and maturation of dendritic cells. However, in our recent study of a Japanese encephalitis virus (JEV) DNA vaccine, co-inoculation of a GM-CSF plasmid dramatically suppressed the specific IgG response and resulted in decreased protection against JEV challenge. It is known that GM-CSF has been used in clinic to treat neutropenia for repopulating myeloid cells, and as an adjuvant in vaccine studies; it has shown various effects on the immune response. Therefore, in this study, we characterized the suppressive effects on the immune response to a JEV DNA vaccine by the co-administration of the GM-CSF-expressing plasmid and clarified the underlying mechanisms of the suppression in mice. Our results demonstrated that co-immunization with GM-CSF caused a substantial dampening of the vaccine-induced antibody responses. The suppressive effect was dose- and timing-dependent and likely related to the immunogenicity of the antigen. The suppression was associated with the induction of immature dendritic cells and the expansion of regulatory T cells but not myeloid-derived suppressor cells. Collectively, our findings not only provide valuable information for the application of GM-CSF in clinic and using as a vaccine adjuvant but also offer further insight into the understanding of the complex roles of GM-CSF. PMID- 22493705 TI - Salvianolic acid B prevents bone loss in prednisone-treated rats through stimulation of osteogenesis and bone marrow angiogenesis. AB - Glucocorticoid (GC) induced osteoporosis (GIO) is caused by the long-term use of GC for treatment of autoimmune and inflammatory diseases. The GC related disruption of bone marrow microcirculation and increased adipogenesis contribute to GIO development. However, neither currently available anti-osteoporosis agent is completely addressed to microcirculation and bone marrow adipogenesis. Salvianolic acid B (Sal B) is a polyphenolic compound from a Chinese herbal medicine, Salvia miltiorrhiza Bunge. The aim of this study was to determine the effects of Sal B on osteoblast bone formation, angiogenesis and adipogenesis associated GIO by performing marrow adipogenesis and microcirculation dilation and bone histomorphometry analyses. (1) In vivo study: Bone loss in GC treated rats was confirmed by significantly decreased BMD, bone strength, cancellous bone mass and architecture, osteoblast distribution, bone formation, marrow microvessel density and diameter along with down-regulation of marrow BMPs expression and increased adipogenesis. Daily treatment with Sal B (40 mg/kg/d) for 12 weeks in GC male rats prevented GC-induced cancellous bone loss and increased adipogenesis while increasing cancellous bone formation rate with improved local microcirculation by capillary dilation. Treatment with Sal B at a higher dose (80 mg/kg/d) not only prevented GC-induced osteopenia, but also increased cancellous bone mass and thickness, associated with increase of marrow BMPs expression, inhibited adipogenesis and further increased microvessel diameters. (2) In vitro study: In concentration from 10(-6) mol/L to 10(-7) mol/L, Sal B stimulated bone marrow stromal cell (MSC) differentiation to osteoblast and increased osteoblast activities, decreased GC associated adipogenic differentiation by down-regulation of PPARgamma mRNA expression, increased Runx2 mRNA expression without osteoblast inducement, and, furthermore, Sal B decreased Dickkopf-1 and increased beta-catenin mRNA expression with or without adipocyte inducement in MSC. We conclude that Sal B prevented bone loss in GC-treated rats through stimulation of osteogenesis, bone marrow angiogenesis and inhibition of adipogenesis. PMID- 22493706 TI - Emergent functional properties of neuronal networks with controlled topology. AB - The interplay between anatomical connectivity and dynamics in neural networks plays a key role in the functional properties of the brain and in the associated connectivity changes induced by neural diseases. However, a detailed experimental investigation of this interplay at both cellular and population scales in the living brain is limited by accessibility. Alternatively, to investigate the basic operational principles with morphological, electrophysiological and computational methods, the activity emerging from large in vitro networks of primary neurons organized with imposed topologies can be studied. Here, we validated the use of a new bio-printing approach, which effectively maintains the topology of hippocampal cultures in vitro and investigated, by patch-clamp and MEA electrophysiology, the emerging functional properties of these grid-confined networks. In spite of differences in the organization of physical connectivity, our bio-patterned grid networks retained the key properties of synaptic transmission, short-term plasticity and overall network activity with respect to random networks. Interestingly, the imposed grid topology resulted in a reinforcement of functional connections along orthogonal directions, shorter connectivity links and a greatly increased spiking probability in response to focal stimulation. These results clearly demonstrate that reliable functional studies can nowadays be performed on large neuronal networks in the presence of sustained changes in the physical network connectivity. PMID- 22493707 TI - Hand asymmetry does not relate to key life history traits in post-menopausal contemporary Finnish women. AB - Associations between fluctuating asymmetry (FA, a putative marker of developmental instability, DI) and life history traits have received a great deal of attention in the non-human literature. However, the patterns found are very heterogeneous and generalizations are difficult to make. In humans, only a few studies have related FA to life histories and fitness. In this paper we study such relationships using hand FA and several key life history traits in 209 post menopausal Finnish women born between 1946 and 1958. Asymmetry measurements were based on scans of the hands and the life histories of these women were collected using questionnaires. No significant associations were detected and trends were opposite to expectations. We did find evidence for directional asymmetry, as traits in the right hand were larger on average. This may be due to handedness, questioning the usefulness of hand FA as a measure of DI. We conclude that future studies in humans should carefully examine the usefulness of traits as measures of DI. PMID- 22493708 TI - Opt-out of voluntary HIV testing: a Singapore hospital's experience. AB - INTRODUCTION: Since 2008, the Singapore Ministry of Health (MOH) has expanded HIV testing by increasing anonymous HIV test sites, as well as issuing a directive to hospitals to offer routine voluntary opt out inpatient HIV testing. We reviewed this program implemented at the end of 2008 at Tan Tock Seng Hospital (TTSH), the second largest acute care general hospital in Singapore. METHODS AND FINDINGS: From January 2009 to December 2010, all inpatients aged greater or equal than 21 years were screened for HIV unless they declined or were not eligible for screening. We reviewed the implementation of the Opt Out testing policy. There were a total of 93,211 admissions; 41,543 patients were included based on HIV screening program eligibility criteria. Among those included, 79% (n = 32,675) opted out of HIV screening. The overall acceptance rate was 21%. Majority of eligible patients who were tested (63%) were men. The mean age of tested patients was 52 years. The opt out rate was significantly higher among females (OR: 1.5, 95%CI: 1.4-1.6), aged >60 years (OR: 2.3, 95%CI: 2.2-2.4) and Chinese ethnicity (OR: 1.7, 95%CI:1.6-1.8). The false positive rate of the HIV screening test is 0.56%. The proportion of patients with HIV infection among those who underwent HIV screening is 0.18%. All 16 confirmed HIV patients were linked to care. CONCLUSION: The default opt-in rate of inpatient HIV testing was low at Tan Tock Seng Hospital, Singapore. Efforts to address individual HIV risk perception and campaigns against HIV stigma are needed to encourage more individuals to be tested for HIV. PMID- 22493709 TI - Red is not a proxy signal for female genitalia in humans. AB - Red is a colour that induces physiological and psychological effects in humans, affecting competitive and sporting success, signalling and enhancing male social dominance. The colour is also associated with increased sexual attractiveness, such that women associated with red objects or contexts are regarded as more desirable. It has been proposed that human males have a biological predisposition towards the colour red such that it is 'sexually salient'. This hypothesis argues that women use the colour red to announce impending ovulation and sexual proceptivity, with this functioning as a proxy signal for genital colour, and that men show increased attraction in consequence. In the first test of this hypothesis, we show that contrary to the hypothesis, heterosexual men did not prefer redder female genitalia and, by extension, that red is not a proxy signal for genital colour. We found a relative preference for pinker genital images with redder genitalia rated significantly less sexually attractive. This effect was independent of raters' prior sexual experience and variation in female genital morphology. Our results refute the hypothesis that men's attraction to red is linked to an implied relationship to genital colour and women's signalling of fertility and sexual proceptivity. PMID- 22493710 TI - A GFP-lacZ bicistronic reporter system for promoter analysis in environmental gram-negative bacteria. AB - Here, we describe a bicistronic reporter system for the analysis of promoter activity in a variety of gram-negative bacteria at both the population and single cell levels. This synthetic genetic tool utilizes an artificial operon comprising the gfp and lacZ genes that are assembled in a suicide vector, which is integrated at specific sites within the chromosome of the target bacterium, thereby creating a monocopy reporter system. This tool was instrumental for the complete in vivo characterization of two promoters, Pb and Pc, that drive the expression of the benzoate and catechol degradation pathways, respectively, of the soil bacterium Pseudomonas putida KT2440. The parameterization of these promoters in a population (using beta-galactosidase assays) and in single cells (using flow cytometry) was necessary to examine the basic numerical features of these systems, such as the basal and maximal levels and the induction kinetics in response to an inducer (benzoate). Remarkably, GFP afforded a view of the process at a much higher resolution compared with standard lacZ tests; changes in fluorescence faithfully reflected variations in the transcriptional regimes of individual bacteria. The broad host range of the vector/reporter platform is an asset for the characterization of promoters in different bacteria, thereby expanding the diversity of genomic chasses amenable to Synthetic Biology methods. PMID- 22493711 TI - A multi-cancer mesenchymal transition gene expression signature is associated with prolonged time to recurrence in glioblastoma. AB - A stage-associated gene expression signature of coordinately expressed genes, including the transcription factor Slug (SNAI2) and other epithelial-mesenchymal transition (EMT) markers has been found present in samples from publicly available gene expression datasets in multiple cancer types, including nonepithelial cancers. The expression levels of the co-expressed genes vary in a continuous and coordinate manner across the samples, ranging from absence of expression to strong co-expression of all genes. These data suggest that tumor cells may pass through an EMT-like process of mesenchymal transition to varying degrees. Here we show that, in glioblastoma multiforme (GBM), this signature is associated with time to recurrence following initial treatment. By analyzing data from The Cancer Genome Atlas (TCGA), we found that GBM patients who responded to therapy and had long time to recurrence had low levels of the signature in their tumor samples (P = 3*10(-7)). We also found that the signature is strongly correlated in gliomas with the putative stem cell marker CD44, and is highly enriched among the differentially expressed genes in glioblastomas vs. lower grade gliomas. Our results suggest that long delay before tumor recurrence is associated with absence of the mesenchymal transition signature, raising the possibility that inhibiting this transition might improve the durability of therapy in glioma patients. PMID- 22493712 TI - Dispersal strategies, few dominating or many coexisting: the effect of environmental spatial structure and multiple sources of mortality. AB - Interspecific competition, life history traits, environmental heterogeneity and spatial structure as well as disturbance are known to impact the successful dispersal strategies in metacommunities. However, studies on the direction of impact of those factors on dispersal have yielded contradictory results and often considered only few competing dispersal strategies at the same time. We used a unifying modeling approach to contrast the combined effects of species traits (adult survival, specialization), environmental heterogeneity and structure (spatial autocorrelation, habitat availability) and disturbance on the selected, maintained and coexisting dispersal strategies in heterogeneous metacommunities. Using a negative exponential dispersal kernel, we allowed for variation of both species dispersal distance and dispersal rate. We showed that strong disturbance promotes species with high dispersal abilities, while low local adult survival and habitat availability select against them. Spatial autocorrelation favors species with higher dispersal ability when adult survival and disturbance rate are low, and selects against them in the opposite situation. Interestingly, several dispersal strategies coexist when disturbance and adult survival act in opposition, as for example when strong disturbance regime favors species with high dispersal abilities while low adult survival selects species with low dispersal. Our results unify apparently contradictory previous results and demonstrate that spatial structure, disturbance and adult survival determine the success and diversity of coexisting dispersal strategies in competing metacommunities. PMID- 22493713 TI - One plus one makes three (for social networks). AB - Members of social network platforms often choose to reveal private information, and thus sacrifice some of their privacy, in exchange for the manifold opportunities and amenities offered by such platforms. In this article, we show that the seemingly innocuous combination of knowledge of confirmed contacts between members on the one hand and their email contacts to non-members on the other hand provides enough information to deduce a substantial proportion of relationships between non-members. Using machine learning we achieve an area under the (receiver operating characteristic) curve (AUC) of at least 0.85 for predicting whether two non-members known by the same member are connected or not, even for conservative estimates of the overall proportion of members, and the proportion of members disclosing their contacts. PMID- 22493714 TI - The structure of the mitotic spindle and nucleolus during mitosis in the amebo flagellate Naegleria. AB - Mitosis in the amebo-flagellate Naegleria pringsheimi is acentrosomal and closed (the nuclear membrane does not break down). The large central nucleolus, which occupies about 20% of the nuclear volume, persists throughout the cell cycle. At mitosis, the nucleolus divides and moves to the poles in association with the chromosomes. The structure of the mitotic spindle and its relationship to the nucleolus are unknown. To identify the origin and structure of the mitotic spindle, its relationship to the nucleolus and to further understand the influence of persistent nucleoli on cellular division in acentriolar organisms like Naegleria, three-dimensional reconstructions of the mitotic spindle and nucleolus were carried out using confocal microscopy. Monoclonal antibodies against three different nucleolar regions and alpha-tubulin were used to image the nucleolus and mitotic spindle. Microtubules were restricted to the nucleolus beginning with the earliest prophase spindle microtubules. Early spindle microtubules were seen as short rods on the surface of the nucleolus. Elongation of the spindle microtubules resulted in a rough cage of microtubules surrounding the nucleolus. At metaphase, the mitotic spindle formed a broad band completely embedded within the nucleolus. The nucleolus separated into two discreet masses connected by a dense band of microtubules as the spindle elongated. At telophase, the distal ends of the mitotic spindle were still completely embedded within the daughter nucleoli. Pixel by pixel comparison of tubulin and nucleolar protein fluorescence showed 70% or more of tubulin co-localized with nucleolar proteins by early prophase. These observations suggest a model in which specific nucleolar binding sites for microtubules allow mitotic spindle formation and attachment. The fact that a significant mass of nucleolar material precedes the chromosomes as the mitotic spindle elongates suggests that spindle elongation drives nucleolar division. PMID- 22493715 TI - Discovery of potential piRNAs from next generation sequences of the sexually mature porcine testes. AB - Piwi-interacting RNAs (piRNAs), a new class of small RNAs discovered from mammalian testes, are involved in transcriptional silencing of retrotransposons and other genetic elements in germ line cells. In order to identify a full transcriptome set of piRNAs expressed in the sexually mature porcine testes, small RNA fractions were extracted and were subjected to a Solexa deep sequencing. We cloned 6,913,561 clean reads of Sus Scrofa small RNAs (18-30 nt) and performed functional characterization. Sus Scrofa small RNAs showed a bimodal length distribution with two peaks at 21 nt and 29 nt. Then from 938,328 deep sequenced small RNAs (26-30 nt), 375,195 piRNAs were identified by a k-mer scheme and 326 piRNAs were identified by homology searches. All piRNAs predicted by the k-mer scheme were then mapped to swine genome by Short Oligonucleotide Analysis Package (SOAP), and 81.61% of all uniquely mapping piRNAs (197,673) were located to 1124 defined genomic regions (5.85 Mb). Within these regions, 536 and 501 piRNA clusters generally distributed across only minus or plus genomic strand, 48 piRNA clusters distributed on two strands but in a divergent manner, and 39 piRNA clusters distributed on two strands in an overlapping manner. Furthermore, expression pattern of 7 piRNAs identified by homology searches showed 5 piRNAs displayed a ubiquitous expression pattern, although 2 piRNAs were specifically expressed in the testes. Overall, our results provide new information of porcine piRNAs and their specific expression pattern in porcine testes suggests that piRNAs have a role in regulating spermatogenesis. PMID- 22493716 TI - Genome-wide identification and mapping of NBS-encoding resistance genes in Solanum tuberosum group phureja. AB - The majority of disease resistance (R) genes identified to date in plants encode a nucleotide-binding site (NBS) and leucine-rich repeat (LRR) domain containing protein. Additional domains such as coiled-coil (CC) and TOLL/interleukin-1 receptor (TIR) domains can also be present. In the recently sequenced Solanum tuberosum group phureja genome we used HMM models and manual curation to annotate 435 NBS-encoding R gene homologs and 142 NBS-derived genes that lack the NBS domain. Highly similar homologs for most previously documented Solanaceae R genes were identified. A surprising ~41% (179) of the 435 NBS-encoding genes are pseudogenes primarily caused by premature stop codons or frameshift mutations. Alignment of 81.80% of the 577 homologs to S. tuberosum group phureja pseudomolecules revealed non-random distribution of the R-genes; 362 of 470 genes were found in high density clusters on 11 chromosomes. PMID- 22493717 TI - Growth hormone improves growth retardation induced by rapamycin without blocking its antiproliferative and antiangiogenic effects on rat growth plate. AB - Rapamycin, an immunosuppressant agent used in renal transplantation with antitumoral properties, has been reported to impair longitudinal growth in young individuals. As growth hormone (GH) can be used to treat growth retardation in transplanted children, we aimed this study to find out the effect of GH therapy in a model of young rat with growth retardation induced by rapamycin administration. Three groups of 4-week-old rats treated with vehicle (C), daily injections of rapamycin alone (RAPA) or in combination with GH (RGH) at pharmacological doses for 1 week were compared. GH treatment caused a 20% increase in both growth velocity and body length in RGH animals when compared with RAPA group. GH treatment did not increase circulating levels of insulin-like growth factor I, a systemic mediator of GH actions. Instead, GH promoted the maturation and hypertrophy of growth plate chondrocytes, an effect likely related to AKT and ERK1/2 mediated inactivation of GSK3beta, increase of glycogen deposits and stabilization of beta-catenin. Interestingly, GH did not interfere with the antiproliferative and antiangiogenic activities of rapamycin in the growth plate and did not cause changes in chondrocyte autophagy markers. In summary, these findings indicate that GH administration improves longitudinal growth in rapamycin-treated rats by specifically acting on the process of growth plate chondrocyte hypertrophy but not by counteracting the effects of rapamycin on proliferation and angiogenesis. PMID- 22493718 TI - Salmonella transiently reside in luminal neutrophils in the inflamed gut. AB - BACKGROUND: Enteric pathogens need to grow efficiently in the gut lumen in order to cause disease and ensure transmission. The interior of the gut forms a complex environment comprising the mucosal surface area and the inner gut lumen with epithelial cell debris and food particles. Recruitment of neutrophils to the intestinal lumen is a hallmark of non-typhoidal Salmonella enterica infections in humans. Here, we analyzed the interaction of gut luminal neutrophils with S. enterica serovar Typhimurium (S. Tm) in a mouse colitis model. RESULTS: Upon S. Tm(wt) infection, neutrophils transmigrate across the mucosa into the intestinal lumen. We detected a majority of pathogens associated with luminal neutrophils 20 hours after infection. Neutrophils are viable and actively engulf S. Tm, as demonstrated by live microscopy. Using S. Tm mutant strains defective in tissue invasion we show that pathogens are mostly taken up in the gut lumen at the epithelial barrier by luminal neutrophils. In these luminal neutrophils, S. Tm induces expression of genes typically required for its intracellular lifestyle such as siderophore production iroBCDE and the Salmonella pathogenicity island 2 encoded type three secretion system (TTSS-2). This shows that S. Tm at least transiently survives and responds to engulfment by gut luminal neutrophils. Gentamicin protection experiments suggest that the life-span of luminal neutrophils is limited and that S. Tm is subsequently released into the gut lumen. This "fast cycling" through the intracellular compartment of gut luminal neutrophils would explain the high fraction of TTSS-2 and iroBCDE expressing intra- and extracellular bacteria in the lumen of the infected gut. CONCLUSION: In conclusion, live neutrophils recruited during acute S. Tm colitis engulf pathogens in the gut lumen and may thus actively engage in shaping the environment of pathogens and commensals in the inflamed gut. PMID- 22493719 TI - Genomic clustering and homology between HET-S and the NWD2 STAND protein in various fungal genomes. AB - BACKGROUND: Prions are infectious proteins propagating as self-perpetuating amyloid polymers. The [Het-s] prion of Podospora anserina is involved in a cell death process associated with non-self recognition. The prion forming domain (PFD) of HET-s adopts a beta-solenoid amyloid structure characterized by the two fold repetition of an elementary triangular motif. [Het-s] induces cell death when interacting with HET-S, an allelic variant of HET-s. When templated by [Het s], HET-S undergoes a trans-conformation, relocates to the cell membrane and induces toxicity. METHODOLOGY/PRINCIPAL FINDINGS: Here, comparing HET-s homologs from different species, we devise a consensus for the HET-s elementary triangular motif. We use this motif to screen genomic databases and find a match to the N terminus of NWD2, a STAND protein, encoded by the gene immediately adjacent to het-S. STAND proteins are signal transducing ATPases which undergo ligand-induced oligomerisation. Homology modelling predicts that the NWD2 N-terminal region adopts a HET-s-like fold. We propose that upon NWD2 oligomerisation, these N terminal extensions adopt the beta-solenoid fold and template HET-S to adopt the amyloid fold and trigger toxicity. We extend this model to a putative prion, the sigma infectious element in Nectria haematococca, because the s locus controlling propagation of sigma also encodes a STAND protein and displays analogous features. Comparative genomic analyses indicate evolutionary conservation of these STAND/prion-like gene pairs, identify a number of novel prion candidates and define, in addition to the HET-s PFD motif, two distinct, novel putative PFD like motifs. CONCLUSIONS/SIGNIFICANCE: We suggest the existence, in the fungal kingdom, of a widespread and evolutionarily conserved mode of signal transduction based on the transmission of an amyloid-fold from a NOD-like STAND receptor protein to an effector protein. PMID- 22493720 TI - Spontaneous eyeblinks are correlated with responses during the Stroop task. AB - The timing and frequency of spontaneous eyeblinking is thought to be influenced by ongoing internal cognitive or neurophysiological processes, but how precisely these processes influence the dynamics of eyeblinking is still unclear. This study aimed to better understand the functional role of eyeblinking during cognitive processes by investigating the temporal pattern of eyeblinks during the performance of attentional tasks. The timing of spontaneous eyeblinks was recorded from 28 healthy subjects during the performance of both visual and auditory versions of the Stroop task, and the temporal distributions of eyeblinks were estimated in relation to the timing of stimulus presentation and vocal response during the tasks. We found that the spontaneous eyeblink rate increased during Stroop task performance compared with the resting rate. Importantly, the subjects (17/28 during the visual Stroop, 20/28 during the auditory Stroop) were more likely to blink before a vocal response in both tasks (150-250 msec) and the remaining subjects were more likely to blink soon after the vocal response (200 300 msec), regardless of the stimulus type (congruent or incongruent) or task difficulty. These findings show that spontaneous eyeblinks are closely associated with responses during the performance of the Stroop task on a short time scale and suggest that spontaneous eyeblinks likely signal a shift in the internal cognitive or attentional state of the subjects. PMID- 22493721 TI - Averaged differential expression for the discovery of biomarkers in the blood of patients with prostate cancer. AB - BACKGROUND: The identification of a blood-based diagnostic marker is a goal in many areas of medicine, including the early diagnosis of prostate cancer. We describe the use of averaged differential display as an efficient mechanism for biomarker discovery in whole blood RNA. The process of averaging reduces the problem of clinical heterogeneity while simultaneously minimizing sample handling. METHODOLOGY/PRINCIPAL FINDINGS: RNA was isolated from the blood of prostate cancer patients and healthy controls. Samples were pooled and subjected to the averaged differential display process. Transcripts present at different levels between patients and controls were purified and sequenced for identification. Transcript levels in the blood of prostate cancer patients and controls were verified by quantitative RT-PCR. Means were compared using a t-test and a receiver-operating curve was generated. The Ring finger protein 19A (RNF19A) transcript was identified as having higher levels in prostate cancer patients compared to healthy men through the averaged differential display process. Quantitative RT-PCR analysis confirmed a more than 2-fold higher level of RNF19A mRNA levels in the blood of patients with prostate cancer than in healthy controls (p = 0.0066). The accuracy of distinguishing cancer patients from healthy men using RNF19A mRNA levels in blood as determined by the area under the receiving operator curve was 0.727. CONCLUSIONS/SIGNIFICANCE: Averaged differential display offers a simplified approach for the comprehensive screening of body fluids, such as blood, to identify biomarkers in patients with prostate cancer. Furthermore, this proof-of-concept study warrants further analysis of RNF19A as a clinically relevant biomarker for prostate cancer detection. PMID- 22493722 TI - Reactive oxygen species facilitate translocation of hormone sensitive lipase to the lipid droplet during lipolysis in human differentiated adipocytes. AB - In obesity, there is an increase in reactive oxygen species (ROS) within adipose tissue caused by increases in inflammation and overnutrition. Hormone sensitive lipase (HSL) is part of the canonical lipolytic pathway and critical for complete lipolysis. This study hypothesizes that ROS is a signal that integrates regulation of lipolysis by targeting HSL. Experiments were performed with human differentiated adipocytes from the subcutaneous depot. Antioxidants were employed as a tool to decrease ROS, and it was found that scavenging ROS with diphenyliodonium, N-acetyl cysteine, or resveratrol decreased lipolysis in adipocytes. HSL phosphorylation of a key serine residue, Ser552, as well as translocation of this enzyme from the cytosol to the lipid droplet upon lipolytic stimulation were both abrogated by scavenging ROS. The phosphorylation status of other serine residues on HSL were not affected. These findings are significant because they document that ROS contributes to the physiological regulation of lipolysis via an effect on translocation. Such regulation could be useful in developing new obesity therapies. PMID- 22493723 TI - Potassium dependent regulation of astrocyte water permeability is mediated by cAMP signaling. AB - Astrocytes express potassium and water channels to support dynamic regulation of potassium homeostasis. Potassium kinetics can be modulated by aquaporin-4 (AQP4), the essential water channel for astrocyte water permeability regulation. We investigated whether extracellular potassium ([K(+)](o)) can regulate astrocyte water permeability and the mechanisms of such an effect. Studies were performed on rat primary astrocytes and a rat astrocyte cell line transfected with AQP4. We found that 10 mM [K(+)](o) caused an immediate, more than 40%, increase in astrocyte water permeability which was sustained in 5 min. The water channel AQP4 was a target for this regulation. Potassium induced a significant increase in intracellular cAMP as measured with a FRET based method and with enzyme immunoassay. We found that protein kinase A (PKA) could phosphorylate AQP4 in vitro. Further elevation of [K(+)](o) to 35 mM induced a global intracellular calcium response and a transient water permeability increase that was abolished in 5 min. When inwardly rectifying potassium (Kir)-channels were blocked, 10 mM [K(+)](o) also induced a calcium increase and the water permeability increase no longer persisted. In conclusion, we find that elevation of extracellular potassium regulates AQP4 and astrocyte water permeability via intracellular signaling involving cAMP. A prolonged increase of astrocyte water permeability is Kir-channel dependent and this response can be impeded by intracellular calcium signaling. Our results support the concept of coupling between AQP4 and potassium handling in astrocytes. PMID- 22493724 TI - Transcriptome responses of insect fat body cells to tissue culture environment. AB - Tissue culture is performed to maintain isolated portions of multicellular organisms in an artificial milieu that is outside the individual organism and for considerable periods of time; cells derived from cultured explants are, in general, different from cells of the corresponding tissue in a living organism. The changes in cultured tissues that precede and often explain the subsequent cell proliferation of explant-derived cells have been partially studied, but little is known about the molecular and genomic basis of these changes. Comparative transcriptomics of intact and cultured (90 hours in MGM-450 insect medium) Bombyx mori tissues revealed that fewer genes represented a larger portion of the transcriptome of intact fat body tissues than of cultured fat body tissues. This analysis also indicated that expression of genes encoding sugar transporters and immune response proteins increased during culture and that expression of genes encoding lipoproteins and cuticle proteins decreased during culture. These results provide support for hypotheses that cultured tissues respond immunologically to surgery, adapt to the medium by accelerating sugar uptake, and terminate their identity as part of an intact organism by becoming independent of that organism. PMID- 22493725 TI - Aconitase B is required for optimal growth of Xanthomonas campestris pv. vesicatoria in pepper plants. AB - The aerobic plant pathogenic bacterium Xanthomonas campestris pv. vesicatoria (Xcv) colonizes the intercellular spaces of pepper and tomato. One enzyme that might contribute to the successful proliferation of Xcv in the host is the iron sulfur protein aconitase, which catalyzes the conversion of citrate to isocitrate in the tricarboxylic acid (TCA) cycle and might also sense reactive oxygen species (ROS) and changes in cellular iron levels. Xcv contains three putative aconitases, two of which, acnA and acnB, are encoded by a single chromosomal locus. The focus of this study is aconitase B (AcnB). acnB is co-transcribed with two genes, XCV1925 and XCV1926, encoding putative nucleic acid-binding proteins. In vitro growth of acnB mutants was like wild type, whereas in planta growth and symptom formation in pepper plants were impaired. While acnA, XCV1925 or XCV1926 mutants showed a wild-type phenotype with respect to bacterial growth and in planta symptom formation, proliferation of the acnB mutant in susceptible pepper plants was significantly impaired. Furthermore, the deletion of acnB led to reduced HR induction in resistant pepper plants and an increased susceptibility to the superoxide-generating compound menadione. As AcnB complemented the growth deficiency of an Escherichia coli aconitase mutant, it is likely to be an active aconitase. We therefore propose that optimal growth and survival of Xcv in pepper plants depends on AcnB, which might be required for the utilization of citrate as carbon source and could also help protect the bacterium against oxidative stress. PMID- 22493726 TI - Leukocyte telomere length in the Finnish Diabetes Prevention Study. AB - Leukocyte telomere length (TL) is considered a biomarker for biological aging. Shortened TL has been observed in many complex diseases, including type 2 diabetes (T2DM). Lifestyle intervention studies, e.g. the Diabetes Prevention Study (DPS), have shown a decrease in the incidence of T2DM by promoting healthy lifestyles in individuals with impaired glucose tolerance (IGT). Our aim was to study in the DPS the influence of the lifestyle intervention on TL. TL was measured by quantitative PCR-based method at two time points (N = 334 and 343) on average 4.5 years apart during the active intervention and post-intervention follow-up. TL inversely correlated with age. Our main finding was that TL increased in about two thirds of the individuals both in the intervention and in the control groups during follow-up; TL increased most in individuals with the shortest TL at the first measurement. TL was not associated with development of T2DM, nor did lifestyle intervention have an effect on TL. No association between insulin secretion or insulin resistance indices and TL was observed. We did not detect an association between TL and development of T2DM in the DPS participants. It could be due to all participants being overweight and having IGT at baseline, both of which have been found to be independently associated with shorter leukocyte TL in some earlier studies. TL had no substantial role in worsening of glucose tolerance in people with IGT. Our study confirms that leukocyte TL can increase with time even in obese people with impaired glucose metabolism. PMID- 22493727 TI - Effect of a dipeptidyl peptidase-IV inhibitor, des-fluoro-sitagliptin, on neointimal formation after balloon injury in rats. AB - BACKGROUND: Recently, it has been suggested that enhancement of incretin effect improves cardiac function. We investigated the effect of a DPP-IV inhibitor, des fluoro-sitagliptin, in reducing occurrence of restenosis in carotid artery in response to balloon injury and the related mechanisms. METHODS AND FINDINGS: Otsuka Long-Evans Tokushima Fatty rats were grouped into four: control (normal saline) and sitagliptin 100, 250 and 500 mg/kg per day (n = 10 per group). Sitagliptin or normal saline were given orally from 1 week before to 2 weeks after carotid injury. After 3 weeks of treatment, sitagliptin treatment caused a significant and dose-dependent reduction in intima-media ratio (IMR) in obese diabetic rats. This effect was accompanied by improved glucose homeostasis, decreased circulating levels of high-sensitivity C-reactive protein (hsCRP) and increased adiponectin level. Moreover, decreased IMR was correlated significantly with reduced hsCRP, tumor necrosis factor-alpha and monocyte chemoattractant protein-1 levels and plasminogen activator inhibitor-1 activity. In vitro evidence with vascular smooth muscle cells (VSMCs) demonstrated that proliferation and migration were decreased significantly after sitagliptin treatment. In addition, sitagliptin increased caspase-3 activity and decreased monocyte adhesion and NFkappaB activation in VSMCs. CONCLUSIONS: Sitagliptin has protective properties against restenosis after carotid injury and therapeutic implications for treating macrovascular complications of diabetes. PMID- 22493728 TI - Aberrant localization of FUS and TDP43 is associated with misfolding of SOD1 in amyotrophic lateral sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is incurable and characterized by progressive paralysis of the muscles of the limbs, speech and swallowing, and respiration due to the progressive degeneration of voluntary motor neurons. Clinically indistinguishable ALS can be caused by genetic mutations of Cu/Zn superoxide dismutase (SOD1), TAR-DNA binding protein 43 (TDP43), or fused in sarcoma/translocated in liposarcoma (FUS/TLS), or can occur in the absence of known mutation as sporadic disease. In this study, we tested the hypothesis that FUS/TLS and TDP43 gain new pathogenic functions upon aberrant accumulation in the cytosol that directly or indirectly include misfolding of SOD1. METHODOLOGY/PRINCIPAL FINDINGS: Patient spinal cord necropsy immunohistochemistry with SOD1 misfolding-specific antibodies revealed misfolded SOD1 in perikarya and motor axons of SOD1-familial ALS (SOD1-FALS), and in motor axons of R521C-FUS FALS and sporadic ALS (SALS) with cytoplasmic TDP43 inclusions. SOD1 misfolding and oxidation was also detected using immunocytochemistry and quantitative immunoprecipitation of human neuroblastoma SH-SY5Y cells as well as cultured murine spinal neural cells transgenic for human wtSOD1, which were transiently transfected with human cytosolic mutant FUS or TDP43, or wtTDP43. CONCLUSION/SIGNIFICANCE: We conclude that cytosolic mislocalization of FUS or TDP43 in vitro and ALS in vivo may kindle wtSOD1 misfolding in non-SOD1 FALS and SALS. The lack of immunohistochemical compartmental co-localization of misfolded SOD1 with cytosolic TDP43 or FUS suggests an indirect induction of SOD1 misfolding followed by propagation through template directed misfolding beyond its site of inception. The identification of a final common pathway in the molecular pathogenesis of ALS provides a treatment target for this devastating disease. PMID- 22493729 TI - Over-expression of LSD1 promotes proliferation, migration and invasion in non small cell lung cancer. AB - BACKGROUND: Lysine specific demethylase 1 (LSD1) has been identified and biochemically characterized in epigenetics, but the pathological roles of its dysfunction in lung cancer remain to be elucidated. The aim of this study was to evaluate the prognostic significance of LSD1 expression in patients with non small cell lung cancer (NSCLC) and to define its exact role in lung cancer proliferation, migration and invasion. METHODS: The protein levels of LSD1 in surgically resected samples from NSCLC patients were detected by immunohistochemistry or Western blotting. The mRNA levels of LSD1 were detected by qRT-PCR. The correlation of LSD1 expression with clinical characteristics and prognosis was determined by statistical analysis. Cell proliferation rate was assessed by MTS assay and immunofluorescence. Cell migration and invasion were detected by scratch test, matrigel assay and transwell invasion assay. RESULTS: LSD1 expression was higher in lung cancer tissue more than in normal lung tissue. Our results showed that over-expression of LSD1 protein were associated with shorter overall survival of NSCLC patients. LSD1 was localized mainly to the cancer cell nucleus. Interruption of LSD1 using siRNA or a chemical inhibitor, pargyline, suppressed proliferation, migration and invasion of A549, H460 and 293T cells. Meanwhile, over-expression of LSD1 enhanced cell growth. Finally, LSD1 was shown to regulate epithelial-to-mesenchymal transition in lung cancer cells. CONCLUSIONS: Over-expression of LSD1 was associated with poor prognosis in NSCLC, and promoted tumor cell proliferation, migration and invasion. These results suggest that LSD1 is a tumor-promoting factor with promising therapeutic potential for NSCLC. PMID- 22493730 TI - Apilimod inhibits the production of IL-12 and IL-23 and reduces dendritic cell infiltration in psoriasis. AB - Psoriasis is characterized by hyperplasia of the epidermis and infiltration of leukocytes into both the dermis and epidermis. IL-23, a key cytokine that induces T(H)17 cells, has been found to play a critical role in the pathogenesis of psoriasis. Apilimod is a small-molecule compound that selectively suppresses synthesis of IL-12 and IL-23. An open-label clinical study of oral administration of apilimod was conducted in patients with psoriasis. Substantial improvements in histology and clinical measurements were observed in patients receiving 70 mg QD. The expression of IL-23p19 and IL-12/IL-23p40 in skin lesions was significantly reduced in this dose group, with a simultaneous increase in IL-10 observed. A decrease in the levels of T(H)1 and T(H)17 cytokines/chemokines in skin lesions followed these p19 and p40 changes. In parallel, a reduction in skin-infiltrating CD11c(+) dendritic cells and CD3(+) T cells was seen, with a greater decrease in the CD11c(+) population. This was accompanied by increases in T and B cells, and decreases in neutrophils and eosinophils in the periphery. This study demonstrates the immunomodulatory activity of apilimod and provides clinical evidence supporting the inhibition of IL-12/IL-23 synthesis for the treatment of T(H)1- and T(H)17-mediated inflammatory diseases. PMID- 22493731 TI - Monocytes contribute to differential immune pressure on R5 versus X4 HIV through the adipocytokine visfatin/NAMPT. AB - BACKGROUND: The immune system exerts a diversifying selection pressure on HIV through cellular, humoral and innate mechanisms. This pressure drives viral evolution throughout infection. A better understanding of the natural immune pressure on the virus during infection is warranted, given the clinical interest in eliciting and sustaining an immune response to HIV which can help to control the infection. We undertook to evaluate the potential of the novel HIV-induced, monocyte-derived factor visfatin to modulate viral infection, as part of the innate immune pressure on viral populations. RESULTS: We show that visfatin is capable of selectively inhibiting infection by R5 HIV strains in macrophages and resting PBMC in vitro, while at the same time remaining indifferent to or even favouring infection by X4 strains. Furthermore, visfatin exerts a direct effect on the relative fitness of R5 versus X4 infections in a viral competition setup. Direct interaction of visfatin with the CCR5 receptor is proposed as a putative mechanism for this differential effect. Possible in vivo relevance of visfatin induction is illustrated by its association with the dominance of CXCR4-using HIV in the plasma. CONCLUSIONS: As an innate factor produced by monocytes, visfatin is capable of inhibiting infections by R5 but not X4 strains, reflecting a potential selective pressure against R5 viruses. PMID- 22493732 TI - Needle-age related variability in nitrogen, mobile carbohydrates, and delta13C within Pinus koraiensis tree crowns. AB - For both ecologists and physiologists, foliar physioecology as a function of spatially and temporally variable environmental factors such as sunlight exposure within a tree crown is important for understanding whole tree physiology and for predicting ecosystem carbon balance and productivity. Hence, we studied concentrations of nitrogen (N), non-structural carbohydrates (NSC = soluble sugars + starch), and delta(13)C in different-aged needles within Pinus koraiensis tree crowns, to understand the needle age- and crown position-related physiology, in order to test the hypothesis that concentrations of N, NSC, and delta(13)C are needle-age and crown position dependent (more light, more photosynthesis affecting N, NSC, and delta(13)C), and to develop an accurate sampling strategy. The present study indicated that the 1-yr-old needles had significantly higher concentration levels of mobile carbohydrates (both on a mass and an area basis) and N(area) (on an area basis), as well as NSC-N ratios, but significantly lower levels of N(mass) (on a mass basis) concentration and specific leaf area (SLA), compared to the current-year needles. Azimuthal (south facing vs. north-facing crown side) effects were found to be significant on starch [both on a mass (ST(mass)) and an area basis (ST(area))], delta(13)C values, and N(area), with higher levels in needles on the S-facing crown side than the N-facing crown side. Needle N(mass) concentrations significantly decreased but needle ST(mass), ST(area), and delta(13)C values significantly increased with increasing vertical crown levels. Our results suggest that the sun exposed crown position related to photosynthetic activity and water availability affects starch accumulation and carbon isotope discrimination. Needle age associated with physiological activity plays an important role in determining carbon and nitrogen physiology. The present study indicates that across-scale sampling needs to carefully select tissue samples with equal age from a comparable crown position. PMID- 22493733 TI - Quality of data entry using single entry, double entry and automated forms processing--an example based on a study of patient-reported outcomes. AB - BACKGROUND: The clinical and scientific usage of patient-reported outcome measures is increasing in the health services. Often paper forms are used. Manual double entry of data is defined as the definitive gold standard for transferring data to an electronic format, but the process is laborious. Automated forms processing may be an alternative, but further validation is warranted. METHODS: 200 patients were randomly selected from a cohort of 5777 patients who had previously answered two different questionnaires. The questionnaires were scanned using an automated forms processing technique, as well as processed by single and double manual data entry, using the EpiData Entry data entry program. The main outcome measure was the proportion of correctly entered numbers at question, form and study level. RESULTS: Manual double-key data entry (error proportion per 1000 fields = 0.046 (95% CI: 0.001-0.258)) performed better than single-key data entry (error proportion per 1000 fields = 0.370 (95% CI: 0.160-0.729), (p = 0.020)). There was no statistical difference between Optical Mark Recognition (error proportion per 1000 fields = 0.046 (95% CI: 0.001-0.258)) and double-key data entry (p = 1.000). With the Intelligent Character Recognition method, there was no statistical difference compared to single-key data entry (error proportion per 1000 fields = 6.734 (95% CI: 0.817-24.113), (p = 0.656)), as well as double-key data entry (error proportion per 1000 fields = 3.367 (95% CI: 0.085-18.616)), (p = 0.319)). CONCLUSIONS: Automated forms processing is a valid alternative to double manual data entry for highly structured forms containing only check boxes, numerical codes and no dates. Automated forms processing can be superior to single manual data entry through a data entry program, depending on the method chosen. PMID- 22493734 TI - Interactions between multiple recruitment drivers: post-settlement predation mortality and flow-mediated recruitment. AB - BACKGROUND: Dispersal is a primary driver in shaping the future distribution of species in both terrestrial and marine systems. Physical transport by advection can regulate the distance travelled and rate of propagule supply to a habitat but post-settlement processes such as predation can decouple supply from recruitment. The effect of flow-mediated recruitment and predation on the recruitment success of an intertidal species, the eastern oyster Crassostrea virginica was evaluated in two-replicated field experiments. Two key crab species were manipulated to test predator identity effects on oyster mortality. FINDINGS: Recruitment was ~58% higher in high flow compared to low flow, but predation masked those differences. Predation mortality was primarily attributed to the blue crab Callinectes sapidus, whilst the mud crab Panopeus herbstii had no effect on recruit mortality. Recruit mortality from predation was high when recruit densities were high, but when recruit density was low, predation effects were not seen. Under high recruitment (supply), predation determined maximum population size and in low flow environments, recruitment success is likely determined by a combination of recruitment and resource limitation but not predation. CONCLUSIONS: Four processes are demonstrated: (1) Increases in flow rate positively affect recruitment success; (2) In high flow (recruitment) environments, resource availability is less important than predation; (3) predation is an important source of recruit mortality, but is dependent upon recruit density; and (4) recruitment and/or resource limitation is likely a major driver of population structure and functioning, modifying the interaction between predators and prey. Simultaneous testing of flow-mediated recruitment and predation was required to differentiate between the role of each process in determining population size. Our results reinforce the importance of propagule pressure, predation and post-settlement mortality as important determinants of population growth and persistence, but demonstrate that they should not be considered mutually exclusive. PMID- 22493735 TI - Sirt1 inhibits resistin expression in aortic stenosis. AB - The development of human calcified aortic stenosis (AS) includes age-dependent processes that have been involved in atherosclerosis, such as infiltration of macrophages in aortic valves, which then promote production of many pro inflammatory cytokines, including resistin. However, the molecular mechanisms contributing to these processes are not established. Since Sirt1 has been shown to modulate macrophage biology and inflammation, we examined its levels in human AS and tested its impact on resistin expression. Sirt1 mRNA (p = 0.01) and protein (p<0.05) levels were reduced in explanted valves from AS patients (n = 51) compared to those from control (n = 11) patients. Sirt1 mRNA levels were negatively associated with resistin mRNA levels quantified in AS valves (p = 0.02). Stimulation of Sirt1 by resveratrol or virus-driven overexpression robustly diminished resistin mRNA and protein expression in macrophages, whereas down-regulation of Sirt1 triggered a large increase in resistin expression. These effects were direct, as chromatin immunoprecipitation assays showed that Sirt1 physically interacted with the resistin promoter region at an AP-1 response element. Moreover, Sirt1 blocked c-jun-induced resistin transactivation in gene reporter assays. These findings demonstrate that, in calcified AS, levels of Sirt1 are reduced whereas those of resistin are increased within aortic valve leaflets. Our results also suggest that this loss of Sirt1 expression alleviates its inhibition of resistin transcription in macrophages. Although the overall contribution of this process to the underlying mechanisms for AS disease development remains unresolved, these observations suggest that modification of Sirt1 expression and/or activity could represent a novel approach against inflammation in AS. PMID- 22493736 TI - An alternating GluN1-2-1-2 subunit arrangement in mature NMDA receptors. AB - NMDA receptors (NMDARs) form glutamate-gated ion channels that play a critical role in CNS physiology and pathology. Together with AMPA and kainate receptors, NMDARs are known to operate as tetrameric complexes with four membrane-embedded subunits associating to form a single central ion-conducting pore. While AMPA and some kainate receptors can function as homomers, NMDARs are obligatory heteromers composed of homologous but distinct subunits, most usually of the GluN1 and GluN2 types. A fundamental structural feature of NMDARs, that of the subunit arrangement around the ion pore, is still controversial. Thus, in a typical NMDAR associating two GluN1 and two GluN2 subunits, there is evidence for both alternating 1/2/1/2 and non-alternating 1/1/2/2 arrangements. Here, using a combination of electrophysiological and cross-linking experiments, we provide evidence that functional GluN1/GluN2A receptors adopt the 1/2/1/2 arrangement in which like subunits are diagonal to one another. Moreover, based on the recent crystal structure of an AMPA receptor, we show that in the agonist-binding and pore regions, the GluN1 subunits occupy a "proximal" position, closer to the central axis of the channel pore than that of GluN2 subunits. Finally, results obtained with reducing agents that differ in their membrane permeability indicate that immature (intracellular) and functional (plasma-membrane inserted) pools of NMDARs can adopt different subunit arrangements, thus stressing the importance of discriminating between the two receptor pools in assembly studies. Elucidating the quaternary arrangement of NMDARs helps to define the interface between the subunits and to understand the mechanism and pharmacology of these key signaling receptors. PMID- 22493737 TI - Retinol metabolism in the mollusk Osilinus lineatus indicates an ancient origin for retinyl ester storage capacity. AB - Although retinoids have been reported to be present and active in vertebrates and invertebrates, the presence of mechanisms for retinoid storage in the form of retinyl esters, a key feature to maintain whole-organism retinoid homeostasis, have been considered to date a vertebrate innovation. Here we demonstrate for the first time the presence of retinol and retinyl esters in an invertebrate lophotrochozoan species, the gastropod mollusk Osilinus lineatus. Furthermore, through a pharmacological approach consisting of intramuscular injections of different retinoid precursors, we also demonstrate that the retinol esterification pathway is active in vivo in this species. Interestingly, retinol and retinyl esters were only detected in males, suggesting a gender-specific role for these compounds in the testis. Females, although lacking detectable levels of retinol or retinyl esters, also have the biochemical capacity to esterify retinol, but at a lower rate than males. The occurrence of retinyl ester storage capacity, together with the presence in males and females of active retinoids, i.e., retinoic acid isomers, indicates that O. lineatus has a well developed retinoid system. Hence, the present data strongly suggest that the capacity to maintain retinoid homeostasis has arisen earlier in Bilateria evolution than previously thought. PMID- 22493738 TI - A genetic variant in long non-coding RNA HULC contributes to risk of HBV-related hepatocellular carcinoma in a Chinese population. AB - BACKGROUND: Recently, several studies have demonstrated that two long non-coding RNAs (lncRNAs), HULC and MALAT1, may participate in hepatocellular carcinoma (HCC) development and progression. However, genetic variations in the two lncRNAs and their associations with HCC susceptibility have not been reported. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) in HULC and MALAT1 may contribute to HCC risk. METHODS: We conducted a case-control study and genotyped two SNPs, rs7763881 in HULC and rs619586 in MALAT1, in 1300 HBV positive HCC patients, 1344 HBV persistent carriers and 1344 subjects with HBV natural clearance to test the associations between the two SNPs and susceptibility to HCC and HBV chronic infection. RESULTS: The variant genotypes of rs7763881 were significantly associated with decreased HCC risk in a dominant genetic model [AC/CC vs. AA: adjusted odds ration (OR) = 0.81, 95% confidence intervals (CIs) = 0.68-0.97, P = 0.022]. Furthermore, the variant genotypes of rs619586 was associated with decreased HCC risk with a borderline significance (AG/GG vs. AA: adjusted OR = 0.81, 95% CIs = 0.65-1.01, P = 0.057). However, no significant association was found between the two SNPs and HBV clearance. CONCLUSIONS: The variant genotypes of rs7763881 in HULC may contribute to decreased susceptibility to HCC in HBV persistent carriers. PMID- 22493739 TI - Applicability of age-based hunting regulations for African leopards. AB - In species in which juvenile survival depends strongly on male tenure, excessive trophy hunting can artificially elevate male turnover and increase infanticide, potentially to unsustainable levels. Simulation models show that the likelihood of safe harvests can be improved by restricting offtakes to males old enough to have reared their first cohort of offspring to independence; in the case of African leopards, males were >=7 years old. Here, we explore the applicability of an age-based approach for regulating trophy hunting of leopards. We conducted a structured survey comprising photographs of known-age leopards to assess the ability of wildlife practitioners to sex and age leopards. We also evaluated the utility of four phenotypic traits for use by trophy hunters to age male leopards in the field. Our logistic regression models showed that male leopard age affected the likelihood of survey respondents identifying the correct sex; notably, males <2 years were typically misidentified as females, while mature males (>=4 years) were sexed correctly. Mature male leopards were also more likely to be aged correctly, as were portrait photographs. Aging proficiency was also influenced by the profession of respondents, with hunters recording the lowest scores. A discriminant model including dewlap size, the condition of the ears, and the extent of facial scarring accurately discriminated among male leopard age classes. Model classification rates were considerably higher than the respective scores attained by survey respondents, implying that the aging ability of hunters could theoretically improve with appropriate training. Dewlap size was a particularly reliable indicator of males >=7 years and a review of online trophy galleries suggested its wider utility as an aging criterion. Our study demonstrated that an age-based hunting approach is practically applicable for leopards. However, implementation would require major reform within the regulatory framework and the hunting industry. PMID- 22493740 TI - Pre-diagnostic plasma 25-hydroxyvitamin D levels and risk of non-melanoma skin cancer in women. AB - BACKGROUND: Recent reports have shown that vitamin D status was inversely associated with the risk of various cancers. However, few studies examined the association between vitamin D levels and risk of skin cancer. METHODS: We prospectively evaluated the association between baseline plasma 25(OH)D levels and the risk of incident squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) among 4,641 women from the Nurses' Health Study (NHS) and the NHS II with 510 incident BCC cases and 75 incident SCC cases. We used multivariate logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Plasma 25(OH)D levels were positively associated with risk of BCC after adjusting for age at blood draw, season of blood draw, lab batch, hair color, burning tendency, the number of sunburns, and ultra-violet B flux of residence at blood collection. Women in the highest quartile of 25(OH)D had more than 2-fold increased risk of BCC compared with women in the lowest quartile (OR = 2.07, 95% CI = 1.52-2.80, P for trend <0.0001). We also found a significantly positive association between plasma 25(OH)D levels and SCC risk after adjusting for the same covariates (OR, highest vs. lowest quartile = 3.77, 95% CI = 1.70 8.36, P for trend= 0.0002). CONCLUSION: In this prospective study of women, plasma vitamin D levels were positively associated with non-melanoma skin cancer risk. Considering that most circulating vitamin D is due to sun exposure, the positive association between plasma vitamin D and non-melanoma skin cancer is confounded by sun exposure. Our data suggest that one-time measurement of plasma vitamin D levels may reasonably reflect long-term sun exposure and predict the risk of non-melanoma skin cancer. PMID- 22493741 TI - Structural olfactory nerve changes in patients suffering from idiopathic intracranial hypertension. AB - BACKGROUND: Complications of idiopathic intracranial hypertension (IIH) are usually caused by elevated intracranial pressure (ICP). In a similar way as in the optic nerve, elevated ICP could also compromise the olfactory nerve system. On the other side, there is growing evidence that an extensive lymphatic network system around the olfactory nerves could be disturbed in cerebrospinal fluid disorders like IIH. The hypothesis that patients with IIH suffer from hyposmia has been suggested in the past. However, this has not been proven in clinical studies yet. This pilot study investigates whether structural changes of the olfactory nerve system can be detected in patients with IIH. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-three patients with IIH and 23 matched controls were included. Olfactory bulb volume (OBV) and sulcus olfactorius (OS) depth were calculated by magnetic resonance techniques. While mean values of total OBV (128.7+/-38.4 vs. 130.0+/-32.6 mm(3), p=0.90) and mean OS depth (8.5+/ 1.2 vs. 8.6+/-1.1 mm, p=0.91) were similar in both groups, Pearson correlation showed that patients with a shorter medical history IIH revealed a smaller OBV (r=0.53, p<0.01). In untreated symptomatic patients (n=7), the effect was greater (r=0.76, p<0.05). Patients who suffered from IIH for less than one year (n=8), total OBV was significantly smaller than in matched controls (116.6+/-24.3 vs. 149.3+/-22.2 mm(3), p=0.01). IIH patients with visual disturbances (n=21) revealed a lower OS depth than patients without (8.3+/-0.9 vs. 10.8+/-1.0 mm, p<0.01). CONCLUSIONS/SIGNIFICANCE: The results suggest that morphological changes of the olfactory nerve system could be present in IIH patients at an early stage of disease. PMID- 22493742 TI - Repertoire enhancement with adoptively transferred female lymphocytes controls the growth of pre-implanted murine prostate cancer. AB - BACKGROUND: In prostate cancer, genes encoding androgen-regulated, Y-chromosome encoded, and tissue-specific antigens may all be overexpressed. In the adult male host, however, most high affinity T cells targeting these potential tumor rejection antigens will be removed during negative selection. In contrast, the female mature T-cell repertoire should contain abundant precursors capable of recognizing these classes of prostate cancer antigens and mediating effective anti-tumor immune responses. METHODOLOGY/PRINCIPAL FINDINGS: We find that syngeneic TRAMP-C2 prostatic adenocarcinoma cells are spontaneously rejected in female hosts. Adoptive transfer of naive female lymphocytes to irradiated male hosts bearing pre-implanted TRAMP-C2 tumor cells slows tumor growth and mediates tumor rejection in some animals. The success of this adoptive transfer was dependent on the transfer of female CD4 T cells and independent of the presence of CD25-expressing regulatory T cells in the transferred lymphocytes. We identify in female CD4 T cells stimulated with TRAMP-C2 a dominant MHC II-restricted response to the Y-chromosome antigen DBY. Furthermore, CD8 T cell responses in female lymphocytes to the immunodominant MHC I-restricted antigen SPAS-1 are markedly increased compared to male mice. Finally, we find no exacerbation of graft-versus-host disease in either syngeneic or minor-antigen mismatched allogeneic lymphocyte adoptive transfer models by using female into male versus male into male cells. CONCLUSIONS/SIGNIFICANCE: This study shows that adoptively transferred female lymphocytes, particularly CD4 T cells, can control the outgrowth of pre-implanted prostatic adenocarcinoma cells. This approach does not significantly worsen graft-versus-host responses suggesting it may be viable in the clinic. Further, enhancing the available immune repertoire with female derived T cells may provide an excellent pool of prostate cancer reactive T cells for further augmentation by combination with either vaccination or immune regulatory blockade strategies. PMID- 22493743 TI - Structural and functional analysis of the symmetrical Type I restriction endonuclease R.EcoR124I(NT). AB - Type I restriction-modification (RM) systems are comprised of two multi-subunit enzymes, the methyltransferase (~160 kDa), responsible for methylation of DNA, and the restriction endonuclease (~400 kDa), responsible for DNA cleavage. Both enzymes share a number of subunits. An engineered RM system, EcoR124I(NT), based on the N-terminal domain of the specificity subunit of EcoR124I was constructed that recognises the symmetrical sequence GAAN(7)TTC and is active as a methyltransferase. Here, we investigate the restriction endonuclease activity of R. EcoR124I(NT)in vitro and the subunit assembly of the multi-subunit enzyme. Finally, using small-angle neutron scattering and selective deuteration, we present a low-resolution structural model of the endonuclease and locate the motor subunits within the multi-subunit enzyme. We show that the covalent linkage between the two target recognition domains of the specificity subunit is not required for subunit assembly or enzyme activity, and discuss the implications for the evolution of Type I enzymes. PMID- 22493744 TI - Growth hormone secretagogues protect mouse cardiomyocytes from in vitro ischemia/reperfusion injury through regulation of intracellular calcium. AB - BACKGROUND: Ischemic heart disease is a leading cause of mortality. To study this disease, ischemia/reperfusion (I/R) models are widely used to mimic the process of transient blockage and subsequent recovery of cardiac coronary blood supply. We aimed to determine whether the presence of the growth hormone secretagogues, ghrelin and hexarelin, would protect/improve the function of heart from I/R injury and to examine the underlying mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: Isolated hearts from adult male mice underwent 20 min global ischemia and 30 min reperfusion using a Langendorff apparatus. Ghrelin (10 nM) or hexarelin (1 nM) was introduced into the perfusion system either 10 min before or after ischemia, termed pre- and post-treatments. In freshly isolated cardiomyocytes from these hearts, single cell shortening, intracellular calcium ([Ca(2+)](i)) transients and caffeine-releasable sarcoplasmic reticulum (SR) Ca(2+) were measured. In addition, RT-PCR and Western blots were used to examine the expression level of GHS receptor type 1a (GHS-R1a), and phosphorylated phospholamban (p-PLB), respectively. Ghrelin and hexarelin pre- or post-treatments prevented the significant reduction in the cell shortening, [Ca(2+)](i) transient amplitude and caffeine-releasable SR Ca(2+) content after I/R through recovery of p-PLB. GHS R1a antagonists, [D-Lys3]-GHRP-6 (200 nM) and BIM28163 (100 nM), completely blocked the effects of GHS on both cell shortening and [Ca(2+)](i) transients. CONCLUSION/SIGNIFICANCE: Through activation of GHS-R1a, ghrelin and hexarelin produced a positive inotropic effect on ischemic cardiomyocytes and protected them from I/R injury probably by protecting or recovering p-PLB (and therefore SR Ca(2+) content) to allow the maintenance or recovery of normal cardiac contractility. These observations provide supporting evidence for the potential therapeutic application of ghrelin and hexarelin in patients with cardiac I/R injury. PMID- 22493745 TI - CagI is an essential component of the Helicobacter pylori Cag type IV secretion system and forms a complex with CagL. AB - Helicobacter pylori, the causative agent of type B gastritis, peptic ulcers, gastric adenocarcinoma and MALT lymphoma, uses the Cag type IV secretion system to induce a strong proinflammatory response in the gastric mucosa and to inject its effector protein CagA into gastric cells. CagA translocation results in altered host cell gene expression profiles and cytoskeletal rearrangements, and it is considered as a major bacterial virulence trait. Recently, it has been shown that binding of the type IV secretion apparatus to integrin receptors on target cells is a crucial step in the translocation process. Several bacterial proteins, including the Cag-specific components CagL and CagI, have been involved in this interaction. Here, we have examined the localization and interactions of CagI in the bacterial cell. Since the cagI gene overlaps and is co-transcribed with the cagL gene, the role of CagI for type IV secretion system function has been difficult to assess, and conflicting results have been reported regarding its involvement in the proinflammatory response. Using a marker-free gene deletion approach and genetic complementation, we show now that CagI is an essential component of the Cag type IV secretion apparatus for both CagA translocation and interleukin-8 induction. CagI is distributed over soluble and membrane-associated pools and seems to be partly surface-exposed. Deletion of several genes encoding essential Cag components has an impact on protein levels of CagI and CagL, suggesting that both proteins require partial assembly of the secretion apparatus. Finally, we show by co-immunoprecipitation that CagI and CagL interact with each other. Taken together, our results indicate that CagI and CagL form a functional complex which is formed at a late stage of secretion apparatus assembly. PMID- 22493746 TI - Caprin controls follicle stem cell fate in the Drosophila ovary. AB - Adult stem cells must balance self-renewal and differentiation for tissue homeostasis. The Drosophila ovary has provided a wealth of information about the extrinsic niche signals and intrinsic molecular processes required to ensure appropriate germline stem cell renewal and differentiation. The factors controlling behavior of the more recently identified follicle stem cells of the ovary are less well-understood but equally important for fertility. Here we report that translational regulators play a critical role in controlling these cells. Specifically, the translational regulator Caprin (Capr) is required in the follicle stem cell lineage to ensure maintenance of this stem cell population and proper encapsulation of developing germ cells by follicle stem cell progeny. In addition, reduction of one copy of the gene fmr1, encoding the translational regulator Fragile X Mental Retardation Protein, exacerbates the Capr encapsulation phenotype, suggesting Capr and fmr1 are regulating a common process. Caprin was previously characterized in vertebrates as Cytoplasmic Activation/Proliferation-Associated Protein. Significantly, we find that loss of Caprin alters the dynamics of the cell cycle, and we present evidence that misregulation of CycB contributes to the disruption in behavior of follicle stem cell progeny. Our findings support the idea that translational regulators may provide a conserved mechanism for oversight of developmentally critical cell cycles such as those in stem cell populations. PMID- 22493748 TI - Correlations of urinary phytoestrogen excretion with lifestyle factors and dietary intakes among middle-aged and elderly Chinese women. AB - Isoflavones and lignans, two major groups of phytoestrogens, have been postulated to have multiple health benefits, including anti-estrogenic, anti-cancer, pro cardiovascular health, and ameliorating menopausal symptoms. Urinary excretion of isoflavonoids, including daidzein, genistein, glycitein, O-desmethylangolensin (O DMA), dihydro-daidzein, dihydrogenistein, and equol, and lignans, including enterodiol and enterolactone, have been used as biomarkers of phytoestrogen exposure in epidemiologic studies. We evaluated the urinary excretion of phytoestrogens and their correlations with lifestyle and dietary factors among 2,165 women who participated in the Shanghai Women's Health Study (SWHS), a population-based prospective cohort study of 74,942 urban Chinese women aged 40 70 years at study enrollment (1996-2000). The medians (in nmol/mg creatinine) were: isoflavonoids, 17.13; daidzein, 5.57; genistein, 2.41; glycitein, 0.94; O DMA, 1.52; dihydrodaidzein, 0.81; dihydrogenistein, 0.19; equol, 0.11; enterodiol, 0.30; and enterolactone, 1.18. These levels are 2- (enterodiol) to 126- (O-DMA) fold higher than levels among US women similar in age range with the exception of enterolactone, for which a similar level was observed for both populations. Urinary isoflavonoid excretion was higher among older women and women who engaged in regular exercise and significantly associated with soy food intake, but was inversely related to fruit intake. Urinary excretions of dihydrodaidzein, dihydrogenistein, equol, enterodiol, and enterolactone were inversely associated with body mass index (BMI). Urinary excretion of isoflavones correlated with soy food intake and healthy lifestyle but was inversely associated with fruit intake among middle-aged and elderly Chinese women. Our study adds important information to the rapidly growing body of research on the potential health benefits of phytoestrogens. PMID- 22493747 TI - Germ line variation in nucleotide excision repair genes and lung cancer risk in smokers. AB - Since nucleotide excision repair (NER) is primarily responsible for detecting and removing bulky DNA lesions induced by tobacco smoke in the respiratory tract, single nucleotide polymorphisms (SNPs) in NER protein-encoding genes may influence lung cancer risk, particularly in smokers. Studies testing this hypothesis have produced inconsistent results, with most analyzing a few SNPs in relatively small population samples. In a study nested in the Beta- Carotene and Retinol Efficacy Trial, we examined 79 tag and previously reported risk associated SNPs in the ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, LIG1, POLE, XPA, and XPC genes in 744 lung cancer cases and 1,477 controls, all of whom were non Hispanic white smokers. Using logistic regression, odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to estimate lung cancer risk associated with SNP genotypes and haplotypes, adjusting for case-control matching factors. Lung cancer risk was modestly associated with LIG1 rs156640 (OR per G allele, 1.23; 95% CI, 1.08-1.40), rs156641 (OR per A allele, 1.23; 95% CI, 1.08 1.40), and rs8100261 (OR per A allele, 0.83; 95% CI, 0.76-0.98); XPA rs3176658 (OR per A allele, 0.83; 95% CI, 0.69-1.00); and ERCC2 rs50871 (OR per C allele, 1.15; 95% CI: 1.01-1.30). Associations with LIG1 and XPA, but not ERCC2, haplotypes were found. The results of this study and others suggest that inherited variants in LIG1 and possibly other NER genes may predispose to smoking related lung cancer. Given that chance likely accounts for one or more of the associations observed, replication of our findings is needed. PMID- 22493749 TI - Genetic variation in MME in relation to neprilysin protein and enzyme activity, Abeta levels, and Alzheimer's disease risk. AB - Neprilysin (NEP), also known as membrane metalloendopeptidase (MME), is considered amongst the most important beta-amyloid (Abeta)-degrading enzymes with regard to prevention of Alzheimer's disease (AD) pathology. Variation in the NEP gene (MME) has been suggested as a risk factor for AD. We conducted a genetic association study of 7MME SNPs - rs1836914, rs989692, rs9827586, rs6797911, rs61760379, rs3736187, rs701109 - with respect to AD risk in a cohort of 1057 probable and confirmed AD cases and 424 age-matched non-demented controls from the United Kingdom, Italy and Sweden. We also examined the association of these MME SNPs with NEP protein level and enzyme activity, and on biochemical measures of Abeta accumulation in frontal cortex - levels of total soluble Abeta, oligomeric Abeta(1-42), and guanidine-extractable (insoluble) Abeta - in a sub group of AD and control cases with post-mortem brain tissue. On multivariate logistic regression analysis one of the MME variants (rs6797911) was associated with AD risk (P = 0.00052, Odds Ratio (O.R. = 1.40, 95% confidence interval (1.16 1.70)). None of the SNPs had any association with Abeta levels; however, rs9827586 was significantly associated with NEP protein level (p=0.014) and enzyme activity (p=0.006). Association was also found between rs701109 and NEP protein level (p=0.026) and a marginally non-significant association was found for rs989692 (p=0.055). These data suggest that MME variation may be associated with AD risk but we have not found evidence that this is mediated through modification of NEP protein level or activity. PMID- 22493750 TI - Interactions between PPAR-alpha and inflammation-related cytokine genes on the development of Alzheimer's disease, observed by the Epistasis Project. AB - OBJECTIVE: Neuroinflammation contributes to the pathogenesis of sporadic Alzheimer's disease (AD). Variations in genes relevant to inflammation may be candidate genes for AD risk. Whole-genome association studies have identified relevant new and known genes. Their combined effects do not explain 100% of the risk, genetic interactions may contribute. We investigated whether genes involved in inflammation, i.e. PPAR-alpha, interleukins (IL) IL- 1alpha, IL-1beta, IL-6, and IL-10 may interact to increase AD risk. METHODS: The Epistasis Project identifies interactions that affect the risk of AD. Genotyping of single nucleotide polymorphisms (SNPs) in PPARA, IL1A, IL1B, IL6 and IL10 was performed. Possible associations were analyzed by fitting logistic regression models with AD as outcome, controlling for centre, age, sex and presence of apolipoprotein epsilon4 allele (APOEepsilon4). Adjusted synergy factors were derived from interaction terms (p<0.05 two-sided). RESULTS: We observed four significant interactions between different SNPs in PPARA and in interleukins IL1A, IL1B, IL10 that may affect AD risk. There were no significant interactions between PPARA and IL6. CONCLUSIONS: In addition to an association of the PPARA L162V polymorphism with the AD risk, we observed four significant interactions between SNPs in PPARA and SNPs in IL1A, IL1B and IL10 affecting AD risk. We prove that gene-gene interactions explain part of the heritability of AD and are to be considered when assessing the genetic risk. Necessary replications will require between 1450 and 2950 of both cases and controls, depending on the prevalence of the SNP, to have 80% power to detect the observed synergy factors. PMID- 22493751 TI - Patients with Panton-Valentine leukocidin positive Staphylococcus aureus infections run an increased risk of longer hospitalisation. AB - Staphylococcus aureus is a major cause of purulent infections. The spectrum of staphylococcal infections varies from mild superficial to invasive life threatening diseases due to S. aureus ability to produce a wide range of virulence factors, including toxins. A prospective observational study was conducted in the Children Clinical University Hospital in Riga, Latvia. During a period of sixteen months from November 2006 to March 2008 224 S. aureus isolates were collected. Our study revealed that Panton-Valentine leukocidine (PVL) genes are carried by a high number (75%) of S. aureus isolates recovered from children hospitalised in the Children Clinical University hospital. Most of these isolates were associated with abscesses and other skin and soft tissue infections. Patients with PVL positive invasive infections stayed significantly longer in hospital than patients with PVL negative invasive infections. Clonal distribution of PVL positive S. aureus isolates were closely related, which provides evidence for the wide spread of PVL producing spa type t435 and ST121 staphylococci in community. PMID- 22493752 TI - Comparison of HIV-1 resistance profiles in plasma RNA versus PBMC DNA in heavily treated patients in Honduras, a resource-limited country. AB - The World Health Organization currently does not recommend the use of dried blood spot specimens for drug resistance testing in patients undergoing antiretroviral therapy (ART). Therefore, HIV-1 resistance testing using peripheral blood mononuclear cells (PBMCs) may be of value in resource-limited settings. We compared genotypic resistance profiles in plasma and PBMCs from patients failing ART in two cities of Honduras (Tegucigalpa and San Pedro Sula), a resource limited country. One hundred patients failing ART were randomly selected from a longitudinal patient monitoring cohort. Plasma and PBMC samples without patient identifier were used for genotypic resistance testing. Sequence data were analyzed, resistance profiles were determined and compared using Stanford HIV Drug Resistance Database algorithm. Specimens with concordant resistance profiles between the two compartments were 88% (95% CI: 80.3% - 94.5 %). Nine specimens (12%, 95% CI: 6.5% - 21.3%) had discordant resistance profiles of clinical significance. Logistic regression analyses indicated that patients on triple therapy were 17.24 times more likely to have concordant drug resistance profile than those on non-triple therapies (OR=17.24, 95% CI: 3.48, 83.33), while patients with increasing number of regimens and years on ART have a decreased rate of concordance (OR = 0.59, 95% CI: 0.32, 1.09 and OR = 0.62, 95% CI: 0.43, 0.88), respectively, than those with less number of regimens and years on ART. Our results show high level of concordance between plasma and PBMC resistance profiles, indicating the possibility of using PBMCs for drug resistance testing in resources-limited settings. PMID- 22493753 TI - Biomarker-based score to predict mortality in persons aged 50 years and older: a new approach in the Swedish AMORIS study. AB - BACKGROUND: Management of frailty is the cornerstone of geriatric medicine, but there remains a need to identify biomarkers that can predict early death, and thereby lead to effective clinical interventions. We aimed to study the combination of C-reactive protein (CRP), albumin, gamma-glutamyl transferase (GGT), and HDL to predict mortality. METHODS: A total of 44,457 persons aged 50+ whose levels of CRP, albumin, GGT, and HDL were measured at baseline were selected from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study. A mortality score, ranging from 0 to 4, was created by adding the number of markers with abnormal values according to the clinical cut-off (CRP > 10 mg/L, albumin < 35 mg/L, GGT > 36 kU/L, HDL < 1.04 mmol/L). Mortality was studied with multivariate Cox proportional hazards models. RESULTS: 2,245 persons died from cancer, 3,276 from circulatory disease, and 1,860 from other causes. There was a positive trend between mortality score and all-cause mortality as well as cancer and circulatory disease-specific death (e.g. HR for all-cause mortality: 1.39 (95%CI: 1.32-1.46), 2.04 (1.89-2.21), and 3.36 (2.87-3.93), for score=1, 2, and 3+, compared to score=0). Among cancer patients with no other co-morbidities (n=1,955), there was a positive trend between the score and mortality (HR: 1.24 (95%CI: 1.0.-1.49), 2.38 (95%CI: 1.76-3.22), and 5.47 (95%CI: 2.98-10.03) for score=1, 2, and 3+ compared to score=0). CONCLUSIONS: By combining biomarkers of different mechanisms contributing to patient frailty, we found a strong marker for mortality in persons aged 50+. Elevated risks among cancer patients with no other co-morbidities prior to biomarker assessment call for validation in other cohorts and testing of different combinations and cut-offs than those used here, in order to aid decision-making in treatment of older cancer patients. PMID- 22493754 TI - Classification of exon 18 linked variants of VWF gene in von Willebrand disease. AB - Defects in von Willebrand factor, a crucial protein in haemostasis, lead to the most common inherited coagulopathy in man, von Willebrand disease. To date, over 350 mutations and 170 single nucleotide polymorphisms of VWF gene have been reported. In the present study, the distribution of two linked VWF gene variants, rs1063856 and rs1063857 have been assessed. The proportional frequency of rs1063856 (2365A/G) and rs1063857 (2385T/C) in healthy individuals were 0.70/0.30. Frequency of polymorphisms was in agreement with predicted geographical distribution. von Willebrand disease was more common in subjects with 2365A and 2385T alleles (odds ratio=1.35), although the difference was not statistically significant (p-values>0.05). The perfect correlation between these two single nucleotide polymorphisms supports their joint contribution in von Willebrand factor biology. PMID- 22493755 TI - Fluconazole susceptibility and ERG11 gene expression in vaginal candida species isolated from Lagos Nigeria. AB - Fluconazole resistance is an important type of resistance in Candida because in most countries, fluconazole is the drug of choice for vulvovaginal candidiasis. Candida species resist fluconazole by various mechanisms but there is paucity of data on these in our environment. Such mechanisms include among others, over expression of the ERG11 gene, which codes for synthesis of the target enzymes in the fungus. The aim of this study was to screen Candida spp. resistant to fluconazole for the expression of ERG11 gene. Fluconazole susceptibility test was performed on 28 clinical strains of Candida species previously obtained from students of a School of Nursing in Lagos, Nigeria. They were identified by API Candida, CHROMagar candida and germ tube test. Using 25 mcg discs, fluconazole susceptibility was determined by the disc diffusion method and results were interpreted in accordance with the Clinical Laboratory Standard Institute (CLSI) criteria; sensitive (S), resistant (R) and susceptible dose dependent (SDD). The R and SDD isolates were subsequently evaluated for the presence of ERG11 gene. Of the 28 clinical isolates, 14 were identified as C. albicans and six as C. tropicalis. The remaining isolates were identified as C. glabrata (2), C. famata (2) C. kefyr (2) one each of C. parapsilosis and C. guilliermondii respectively. In this study, 18 were susceptible (S) to fluconazole, eight were SDD and two were resistant to the antifungal agent. Out of the 14 C. albicans isolates, 12 were susceptible, one showed high level resistance and similar number showed susceptible dose dependence. ERG11 was detected in three susceptible dose dependent Candida species. This analysis demonstrates that susceptible dose dependence should not be overlooked as it may be associated with the presence of ERG11 gene and resistance to fluconazole. There is a need to consider routine antifungal susceptibility testing for Candida species causing vulvovaginitis. PMID- 22493756 TI - An examination of TOR1A variants in recurrent major depression. AB - BACKGROUND: Observations of comorbid depression in subjects with primary dystonia have suggested a dual role for the TOR1A gene in mood disorders and movement disorders. We conducted a systematic search for carriers of the DeltaGAG deletion and for other variants in TOR1A exon 5 among 414 Caucasian subjects with recurrent major depression from the Upper Palatinate. FINDINGS: Allele frequencies were determined for 27 TOR1A diallelic markers, including two novel synonymous substitutions (L262L and E310E) in the region encoding the torsinA C terminus, plus four novel variants in the gene's 3'UTR. No carriers of the DeltaGAG deletion were observed. When data were compared to previously examined control populations, no significant allelic associations were noted after corrections for multiple testing. CONCLUSIONS: The present study adds to the spectrum of TOR1A mutations but provides no evidence of a common genetic predisposition to DYT1 dystonia and recurrent major depression. PMID- 22493757 TI - Single cell genome analysis supports a link between phagotrophy and primary plastid endosymbiosis. AB - Two cases of primary plastid endosymbiosis are known. The first occurred ca. 1.6 billion years ago and putatively gave rise to the canonical plastid in algae and plants. The second is restricted to a genus of rhizarian amoebae that includes Paulinella chromatophora. Photosynthetic Paulinella species gained their plastid from an alpha-cyanobacterial source and are sister to plastid-lacking phagotrophs such as Paulinella ovalis that ingest cyanobacteria. To study the role of feeding behavior in plastid origin, we analyzed single-cell genome assemblies from six P. ovalis-like cells isolated from Chesapeake Bay, USA. Dozens of contigs in these cell assemblies were derived from prey DNA of alpha-cyanobacterial origin and associated cyanophages. We found two examples of horizontal gene transfer (HGT) in P. ovalis-like nuclear DNA from cyanobacterial sources. This work suggests the first evidence of a link between feeding behavior in wild-caught cells, HGT, and plastid primary endosymbiosis in the monophyletic Paulinella lineage. PMID- 22493758 TI - The Role of the Habenula in Nicotine Addiction. AB - To thrive in any given environment, mobile creatures must be able to learn from the outcomes of both successful and disappointing events. To learn from success, the brain relies on signals originating in the ventral tegmental area and substantia nigra that result in increased release of dopamine in the striatum. Recently, it was shown that to learn from disappointment the brain relies on signals originating in the lateral habenula, which indirectly inhibit dopaminergic activity. The habenula is a small brain region that has been shown in mice to be critical for the appearance of nicotine withdrawal symptoms. The nicotinic acetylcholine receptor subunits expressed in the medial habenula are necessary to observe withdrawal symptoms in mice, and blocking nicotinic activity in the medial habenula only is sufficient to precipitate withdrawal in dependent mice. In addition, recent genome wide association studies have shown that in humans, genetic variants in the same nicotinic receptor subunits are at least partially responsible for the genetic predisposition to become a smoker. The habenula is linked not only to nicotine, but also to the effects of several other drugs. We postulate that the continuous use of drugs of abuse results in habenular hyperactivity as a compensatory mechanism for artificially elevated dopamine release. Drug withdrawal would then result in non-compensated habenular hyperactivity, and could be thought of as a state of continuous disappointment (or a negative emotional state), driving repeated drug use. We believe that drugs that alter habenular activity may be effective therapies against tobacco smoke and drug addiction in general. PMID- 22485199 TI - Recrudescent wave of pandemic A/H1N1 influenza in Mexico, winter 2011-2012: Age shift and severity. AB - BACKGROUND: A substantial recrudescent wave of pandemic influenza A/H1N1 that began in December 2011 is ongoing and has not yet peaked in Mexico, following a 2 year period of sporadic transmission. Mexico previously experienced three pandemic waves of A/H1N1 in 2009, associated with higher excess mortality rates than those reported in other countries, and prompting a large influenza vaccination campaign. Here we describe changes in the epidemiological patterns of the ongoing 4th pandemic wave in 2011-12, relative to the earlier waves in 2009. The analysis is intended to guide public health intervention strategies in near real time. METHODS: We analyzed demographic and geographic data on all hospitalizations with acute respiratory infection (ARI) and laboratory-confirmed A/H1N1 influenza, and inpatient deaths, from a large prospective surveillance system maintained by the Mexican Social Security medical system during 01-April 2009 to 10-Feb 2012. We characterized the age and regional patterns of A/H1N1 positive hospitalizations and inpatient-deaths relative to the 2009 A/H1N1 influenza pandemic. We also estimated the reproduction number (R) based on the growth rate of the daily case incidence by date of symptoms onset. RESULTS: A total of 5,795 ARI hospitalizations and 186 inpatient-deaths (3.2%) were reported between 01-December 2011 and 10-February 2012 (685 A/H1N1-positive inpatients and 75 A/H1N1-positive deaths). The nationwide peak of daily ARI hospitalizations in early 2012 has already exceeded the peak of ARI hospitalizations observed during the major fall pandemic wave in 2009. The mean age was 34.3 y (SD=21.3) among A/H1N1 inpatients and 43.5 y (SD=21) among A/H1N1 deaths in 2011-12. The proportion of laboratory-confirmed A/H1N1 hospitalizations and deaths was higher among seniors >=60 years of age (Chi-square test P<0.001) and lower among younger age groups (Chi-square test, P<0.03) for the 2011-2012 pandemic wave, compared to the earlier waves in 2009. The reproduction number of the winter 2011-12 wave in central Mexico was estimated at 1.2-1.3, similar to that reported for the fall 2009 wave, but lower than that of spring 2009. CONCLUSIONS: We have documented a substantial and ongoing increase in the number of ARI hospitalizations during the period December 2011-February 2012 and an older age distribution of laboratory confirmed A/H1N1 influenza hospitalizations and deaths, relative to 2009 A/H1N1 pandemic patterns. The gradual change in the age distribution of A/H1N1 infections in the post-pandemic period is reminiscent of historical pandemics and indicates either a gradual drift in the A/H1N1 virus, and/or a build-up of immunity among younger populations. PMID- 22493760 TI - Oncologic manifestations of neurofibromatosis type 1 in Korea. AB - PURPOSE: The aim of this study was to investigate the incidence and spectrum of malignant tumors in Korean neurofibromatosis type 1 (NF1) patients. METHODS: We retrospectively reviewed 125 patients who were diagnosed with NF1 at a single institution from 1995 to 2010. The incidence, location, histologic type, and radiologic findings of malignant tumors as well as development of multiple primary tumors were analyzed. RESULTS: Eighteen malignant tumors occurred in 16 patients (12.8%) among 125 Korean NF1 patients; 9 carcinomas, 8 sarcomas and 1 central nervous system (CNS) tumor. Five tumors were of nervous system origin and 13 were non-nervous system tumors. The locations of the tumors were as follow: 1 CNS, 2 lung, 3 breast, 3 stomach, 3 small bowel, 1 colon, 1 liver, 1 uterus, 1 neck, and 2 in extremities. Three malignant peripheral nerve sheath tumors (MPNSTs) occurred at the neck and extremity, and one in the liver. All three gastrointestinal stromal tumors (GISTs) had multiple tumors in the jejunum, and one MPNST and one pheochromocytoma were accompanied in two GISTs. Multiple primary tumors, benign or malignant were reported in 4 patients (25.0%), synchronously or metachronously. CONCLUSION: Korean NF1 patients had a high risk of developing malignant tumors. The common malignant tumors in Koreans such as breast, lung and stomach cancers developed frequently in addition to the NF1 related tumors such as MPNST or GIST. PMID- 22493761 TI - Impact of chronologic age in the elderly with gastric cancer. AB - PURPOSE: Although the incidence of gastric cancer has declined in the general population, it is the second most frequent cause of death due to malignancy in the world with its incidence in the elderly increasing as a result of increased life expectancy. This present study tried to find the optimal treatment for patients aged 75 years or older with gastric cancer through comparison of the clinicopathological characteristics, surgical outcomes, and identifying prognostic factors of survival. METHODS: Elderly patients who underwent gastric resection for gastric cancer from January, 1999 to February, 2009 (n = 470) were divided into two groups: very elderly patients, 75 years or older (n = 95), and younger elderly patients, between 65 and 74 years old (n = 365). RESULTS: Distinct characteristics of very elderly patients included more frequent underlying disease, deeper invasion, and more frequent lymph node metastasis. There were significant differences in overall survival between the two groups at stages III-B and IV. However, postoperative hospital stays, postoperative morbidity, mortality and early stage did not differ between curatively resected patients in the two groups. CONCLUSION: Due to improved postoperative care, gastrectomy of gastric cancer is the treatment of choice in very elderly patients. Therefore, early diagnosis through regular medical screening and curative gastrectomy with lymph node dissection should be performed in very elderly gastric cancer patients. PMID- 22493762 TI - Prognostic significance of computed tomography defined ascites in advanced gastric cancer. AB - PURPOSE: The aim of this study was to investigate the clinicopathologic features and prognosis in patients with computed tomography (CT) findings of ascites, with a focus on the correlation with peritoneal carcinomatosis. METHODS: This study included a total of 157 patients who underwent surgery for advanced gastric cancer from 2003 to 2008 at the Department of Surgery, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea, which were analyzed retrospectively. RESULTS: Fourteen patients (8.9%) presented ascites on their CT scan. Among them, 10 patients had peritoneal carcinomatosis, and showed significant difference with CT ascites positive group in the incidence of peritoneal carcinomatosis. The presence of CT ascites was significantly correlated with pathologic T stage, tumor size, histologic type, CT T and N stages, CT peritoneal nodularity and curability of surgery, statistically. The prognosis of CT ascites positive group was much poorer in the total advanced gastric cancer patients (P < 0.001), as well as in patients with pathologic T4 (P = 0.002). Also in patients without peritoneal carcinomatosis, CT ascites positive subgroup tended to have a worse prognosis than CT ascites negative subgroup (P = 0.086). Tumor size, CT T and N stages and the presence of CT peritoneal nodularity and ascites influenced the prognosis significantly; among which, if a tumor size larger than 5 cm, CT T4 stage and the presence of CT ascites were identified as independent prognostic factors. CONCLUSION: The presence of ascites was closely associated with peritoneal metastasis, and was the most significant independent prognostic factor in advanced gastric cancer in the present study. PMID- 22493763 TI - Postoperative pneumoperitoneum: guilty or not guilty? AB - PURPOSE: The aim of this study was to determine the incidence and duration of postoperative pneumoperitoneum on plain radiographs and to identify the radiologic findings associated with anastomotic leakage. METHODS: A retrospective analysis was conducted on plain radiographs of 384 patients who underwent intra abdominal anastomoses between March 2005 and December 2008. RESULTS: Of the 384 patients, 93 patients (24.2%) had postoperative pneumoperitoneums. Of the 93 patients, 86 patients (92.5%) had physiologic pneumoperitoneums and 7 patients (7.5%) had pneumoperitoneums associated with anastomotic leakage. The initial air height was significantly greater in the leakage group than the physiologic air group (12.16 +/- 7.65 mm vs. 7.71 +/- 5.08 mm, P = 0.04). The area under the receiver operating characteristic curve of the initial height of free air for anastomotic leakage was 0.69 (95% confidence interval, 0.59 to 0.78). The best cut-off point was 11.7 mm. The height of the pneumoperitoneum increased with time in the leakage group. Ileus was significantly more prevalent in the leakage group than the physiologic air group (P < 0.01). CONCLUSION: Postoperative pneumoperitoneum is a common phenomenon after abdominal surgery. An initial air height >11.7 mm, increasing air height over time, and the presence of ileus on plain radiographs suggest a high likelihood of anastomotic leakage. PMID- 22493765 TI - Splenectomy affects the balance between hepatic growth factor and transforming growth factor-beta and its effect on liver regeneration is dependent on the amount of liver resection in rats. AB - PURPOSE: Small-for-size syndrome (SFSS) is a major problem in liver surgery, and splenectomy has been used to prevent SFSS. However, it is unknown whether splenectomy has the same effect on liver regeneration in both standard and marginal hepatectomy. The aim of this study is to see a difference in effect of splenectomy on liver regeneration according to the amount of liver resection. METHODS: Thirty male Sprague-Dawley rats (220 to 260 g) were divided into the following five groups: control (n = 6), 70% hepatectomy (n = 6), 70% hepatectomy with splenectomy (n = 6), 90% hepatectomy (n = 6), and 90% hepatectomy with splenectomy (n = 6). The animals were euthanized 24 hours after surgery and liver specimens were obtained. To assess liver regeneration, we performed immunohistochemistry of liver tissue using 5-bromo-2-deoxyuridine (BrdU) labeling and Western blot analysis of hepatic growth factor (HGF) and transforming growth factor-beta (TGF-beta) in the liver tissue. RESULTS: The splenectomized subgroup had a higher BrdU-positive cell count in the 90% hepatectomy group, but not in the 70% hepatectomy group (P < 0.001). Splenectomy significantly decreased TGF beta expression (P = 0.005) and increased the HGF to TGF-beta ratio (P = 0.002) in the 90% hepatectomy group, but not in the 70% hepatectomy group. CONCLUSION: The positive effect of splenectomy on liver regeneration was greater in the group with the larger liver resection. This phenomenon may be related to the relative balance between HGF and TGF-beta in the liver. PMID- 22493764 TI - Clinical and radiologic preoperative predicting factors for GB cholesterol polyp. AB - PURPOSE: To use the clinical and radiological data to differentiate non cholesterol versus cholesterol gall bladder (GB) polyps, which can be useful in deciding the treatment of the patient. METHODS: One hundred and eighty-seven patients underwent cholecystectomy for GB polyps of around 10 mm for 10 years, and were divided into two groups, cholesterol polyps (146 patients) and non cholesterol polyps (41 patients) based on the postoperative pathological findings. Gender, age, body weight, height, body mass index (BMI), symptoms, laboratory findings, size, number of polyps, presence of GB stone and maximum diameter measured by preoperative ultrasonography (USG), computed tomography (CT), and pathological diameter were subjected to comparative analysis. RESULTS: Patients diagnosed with cholesterol polyps were younger in age and had higher BMI, and the total cholesterol levels and white blood cell levels were higher, but were not statistically significant. It was notable to see that 28.6% of the cholesterol polyps were not found in the preoperative CT yet the percentage of the undetectable rate was significantly lower (8%) in the non-cholesterol polyp group. There was a discrepancy in maximum diameters between the two radiological methods in both groups but the discrepancy was significantly larger in the cholesterol polyp group. CONCLUSION: The clinical signs that can be helpful to diagnose whether it is a cholesterol polyp or not are younger patients who have high BMI, polyps which are detectable only on the USG and large maximum diameters between the USG and CT. And if the discrepancy of the maximum diameter is lesser than 1mm the polyp may be considered as a non-cholesterol polyp. PMID- 22493767 TI - A case report of primary breast angiosarcoma with fatal pulmonary hemorrhage due to thrombocytopenia. AB - Primary angiosarcomas of the breast are rare malignancy that account for fewer than 0.04% of all malignant breast tumors. The prognosis is poor. Surgery is the first line of treatment for angiosarcoma. Adjuvant chemotherapy and radiotherapy have been tried, but their efficacy remains controversial. Here we present the case of a 47-year-old woman with a palpable left breast mass that was diagnosed as a primary angiosarcoma. The patient underwent modified radical mastectomy with adjuvant chemotherapy and radiotherapy. Postoperatively, eighteen months later, the angiosarcoma recurred. The patient returned complaining of dyspnea and hemoptysis and was found to have a large pleural effusion. She developed a gradual onset of thrombocytopenia that persisted despite platelet transfusions. Finally, the patient died of respiratory failure secondary to pulmonary hemorrhage. PMID- 22493766 TI - Adrenocortical tumors in children 18 years old and younger. AB - PURPOSE: Pediatric adrenocortical tumors (ACTs) are rare. We reviewed findings in 8 children, 18 years of age or younger, diagnosed with ACT in our institution over the past 15 years. METHODS: We retrospectively reviewed 8 children with ACTs treated between 1996 and 2010. RESULTS: Three girls and 5 boys were treated for ACTs; their median age at presentation was 144 months (range, 28 months to 18 years). Seven patients showed signs of endocrine dysfunction, 4 with Cushing syndrome, 2 with virilization, and 1 with hyperaldosteronism. One patient, with symptoms of hematuria, underwent a computed tomography scan, which showed an adrenal mass. The median duration of symptoms prior to resection was 6 months (range, 1 to 24 months). Five patients had adenomas and 3 had carcinomas. All underwent complete resection of the tumor, with laparoscopic adrenalectomy performed on 3 patients with adenoma and 1 with carcinoma. The median tumor weight was 12.5 g (range, 1 to 130 g) and the median tumor volume was 18.3 cm(3) (range, 2.2 to 299.2 cm(3)). At a median follow-up of 5.1 years (range, 4 months to 15 years), all 8 patients remain alive with no recurrence of disease. CONCLUSION: The characteristics of pediatric ACTs vary considerably. Laboratory findings, clinical hormonal features, and tumor size could not distinguish adenomas from carcinomas before surgery. Complete tumor resection was successful, with no tumor recurrence. However, the small number of patients and short follow up period limit assessments of prognosis. PMID- 22493768 TI - Laparoscopic reversal of Hartmann's procedure. AB - Reversal of Hartmann's procedure is a major surgical procedure associated with significant morbidity and mortality. Because of the difficulty of the procedure, laparoscopic reversal of Hartmann's procedure is not well established. We describe our experience with this laparoscopic procedure to assess its difficulty and safety. Five patients (4 men and 1 woman) underwent laparoscopic reversal of Hartmann's procedure (LRHP). The initial surgeries were performed to manage obstructive colorectal cancer for 4 patients, and rectovesical fistula for one patient. The procedure was laparoscopically completed for 4 patients. Conversion to open laparotomy was required for one patient, secondary to massive adhesion in lower abdomen. Transient ileostomies were made in 2 cases. Operative time ranged from 240 to 545 minutes. There was no operative mortality. LRHP can be performed safely by an experienced surgeon. However, it is still technically challenging and time consuming. PMID- 22493769 TI - Spontaneous aortic rupture in a patient with neurofibromatosis type 1. AB - Neurofibromatosis type I (NF-1) is a rare autosomal dominant genetic disorder occurring in 1 in 3,000 individuals. Vasculopathy is a rarely reported finding in patients with NF-1. Here, we report a case of recurrent aortic pseudoaneurysm after endovascular aneurysm repair in a 49-year-old male patient with NF-1. On the sixth postoperative day following a successful open surgical repair of an aortic pseudoaneurysm, he developed hemoperitoneum due to a delayed rupture of the mesenteric artery branch. This was treated with endovascular coil embolization. We report the clinical features and histologic findings of this rare vascular disorder with a review of the relevant literature. PMID- 22493770 TI - Primary tuberculosis appendicitis with mesenteric mass. AB - Tuberculosis primarily affecting the appendix is extremely rare and the diagnosis is difficult. Here, we report the case of a 14-year-old healthy boy presenting with right lower quadrant abdominal pain. On computed tomography, the distended appendix with 3.3 * 2.7 cm mass located at the right side of the right iliac artery was detected. There was neither bowel wall thickening nor active lung lesion. After laparoscopic appendectomy with mass excision, histopathological examination revealed chronic granulomatous inflammation, with caseous necrosis of the appendix. We made a diagnosis of primary tuberculosis of appendix and administrated anti-tuberculosis medication. PMID- 22493771 TI - "Turn on" electron-transfer-based selective detection of ascorbic acid via copper complexes immobilized on glass. AB - "Turn-on" optical detection of parts-per-million (ppm) levels of ascorbic acid (AA) in water has been determined using a redox-active monolayer on glass. PMID- 22493772 TI - Fast measurement of binding kinetics with dual slope SPR microchips. AB - We demonstrate a new dual slope SPR technique that is ten-fold faster than the conventional step-response method. The new scheme utilizes rapid slope-based measurements followed by rapid reset, and it separates association and dissociation half reaction measurements at two separate sites inside a dual chamber PDMS microfluidic chip. For a model CAII-ABS test system, the association and dissociation slopes were measured in 30 seconds compared to 5 minutes for step-response. The values of k(a) and k(d) calculated from the slope method are 3.66 +/- 0.19 * 10(3) M(-1) s(-1) and 4.83 +/- 0.17 * 10(-2) s(-1), respectively, matching well with step-response values while facilitating ~10 to 15 fold faster detection and quantification. PMID- 22493773 TI - Interactive hyperspectral approach for exploring and interpreting DESI-MS images of cancerous and normal tissue sections. AB - Desorption electrospray ionization (DESI) is an ambient mass spectrometry (MS) technique that can be operated in an imaging mode. It is known to provide valuable information on disease state and grade based on lipid profiles in tissue sections. Comprehensive exploration of the spatial and chemical information contained in 2D MS images requires further development of methods for data treatment and interpretation in conjunction with multivariate analysis. In this study, we employ an interactive approach based on principal component analysis (PCA) to interpret the chemical and spatial information obtained from MS imaging of human bladder, kidney, germ cell and prostate cancer and adjacent normal tissues. This multivariate strategy facilitated distinction between tumor and normal tissue by correlating the lipid information with pathological evaluation of the same samples. Some common lipid ions, such as those of m/z 885.5 and m/z 788.5, nominally PI(18 : 0/20 : 4) and PS(18 : 0/18 : 1), as well as ions of free fatty acids and their dimers, appeared to be highly characterizing for different types of human cancers, while other ions, such as those of m/z 465.5 (cholesterol sulfate) for prostate cancer tissue and m/z 795.5 (seminolipid 16 : 0/16 : 0) for germ tissue, appeared to be extremely selective for the type of tissue analyzed. These data confirm that lipid profiles can reflect not only the disease/health state of tissue but also are characteristic of tissue type. The manual interactive strategy presented here is particularly useful to visualize the information contained in hyperspectral MS images by automatically connecting regions of PCA score space to pixels of the 2D physical object. The procedures developed in this study consider all the spectral variables and their inter correlations, and guide subsequent investigations of the mass spectra and single ion images to allow one to maximize characterization between different regions of any DESI-MS image. PMID- 22493774 TI - Selective recognition of xylene isomers using ZnO-SWNTs hybrid gas sensors. AB - We demonstrate a hybrid ZnO nanoparticle decorated SWNT network device that can conductometrically differentiate between xylene isomers at room temperature with minimal interference from background VOCs. Field effect transistor measurements are conducted to identify the sensing mechanism which is attributed to enhanced SWNT transduction of chemical interaction with ZnO surfaces. PMID- 22493775 TI - Proton-induced switching of the single molecule magnetic properties of a porphyrin based Tb(III) double-decker complex. AB - A tetraphenylporphyrin based Tb(III) double-decker complex has been synthesized and the crystal structure of both protonated and deprotonated forms has been determined. The ac magnetic susceptibility measurements revealed that the SMM properties of the double-decker complex can be reversibly switched by only a single proton. PMID- 22493777 TI - The significance of serial histopathology in a residual mass for outcome of intermediate risk stage 3 neuroblastoma. AB - BACKGROUND: To describe the serial histopathology of intermediate risk stage 3 neuroblastoma after chemotherapy, and correlate with residual mass at therapy completion and outcome. PROCEDURE: A retrospective review of intermediate risk stage 3 neuroblastoma patients treated 1989-2005 at Children's Hospital Los Angeles according to CCG 3881 or CCG 3961 protocols was performed, with central review of histopathology, radiology, and surgery. RESULTS: Eighteen patients treated per CCG 3881 (n = 9) or CCG 3961 (n = 9), with including 1 (n = 5), 2 (n = 9), >= 3 (n = 3), or unknown number (n = 1) of surgical procedures were included. At therapy completion, 10 patients had residual tumor: <10% original size (n = 3), >10% original size (n = 6) (5 MIBG avid; 4 with elevated catecholamines), and CT non-measurable MIBG avid tumor (n = 1). Post-chemotherapy histology showed tumor regression (n = 4); or maturation with (n = 6) or without (n = 2) Schwannian development. Histologic changes correlated with median tumor shrinkage of 80% (regressing tumors) and <25% (maturing tumors). Tumor size increased in one patient with maturing tumor and Schwannian development. Overall survival was 100%. CONCLUSION: Post-chemotherapy histopathology of intermediate risk stage 3 neuroblastoma was characterized by regression or maturation. Persisting residual and maturing tumors were not associated with tumor progression, despite MIBG uptake and/or elevated catecholamines, supporting observation only. Histopathology should be obtained in future studies to confirm these findings, and guide length of chemotherapy. PMID- 22493776 TI - Metal ion redox potential plays an important role in high-yield synthesis of monodisperse silver nanoparticles. AB - A facile method is developed to prepare monodisperse silver nanoparticles in a much enhanced yield by adding a trace amount of Fe(3+) ions into the reaction of AgNO(3) with oleic acid and oleylamine. We propose that Fe(2+) ions speed up the nucleation and growth of silver nanoparticles due to the electron-transfer between Ag(+) and Fe(2+), in which Fe(2+) is from Fe(3+) reduced by oleylamine. PMID- 22493778 TI - Crystal structure of the Kar3-like kinesin motor domain from the filamentous fungus Ashbya gossypii. AB - Kar3 kinesins are microtubule (MT) minus-end-directed motors with pleiotropic functions in mitotic spindle formation and nuclear movement in budding and fission yeasts. A Kar3-like kinesin is also expressed by the filamentous fungus Ashbya gossypi, which exhibits different nuclear movement challenges from its yeast relatives. Presented here is a 2.35 A crystal structure and enzymatic analysis of the AgKar3 motor domain (AgKar3MD). Compared to the previously published Saccharomyces cerevisiae Kar3MD structure (ScKar3MD), AgKar3MD displays differences in the conformation of some of its nucleotide-binding motifs and peripheral elements. Unlike ScKar3MD, the salt bridge between Switch I and Switch II in AgKar3MD is broken. Most of the Switch I, and the adjoining region of helix alpha3, are also disordered instead of bending into the active site cleft as is observed in ScKar3MD. These aspects of AgKar3MD are highly reminiscent of the ScKar3 R598A mutant that disrupts the Switch I-Switch II salt bridge and impairs MT-stimulated ATPase activity of the motor. Subtle differences in the disposition of secondary structure elements in the small lobe (beta1a, beta1b, and beta1c) at the edge of the MD are also apparent even though it contains approximately the same number of residues as ScKar3. These differences may reflect the unique enzymatic properties we measured for this motor, which include a lower MT stimulated ATPase rate relative to ScKar3, or they could relate to its interactions with different regulatory companion proteins than its budding yeast counterpart. PMID- 22493780 TI - External electric fields trigger drug release from new hydrogel formulation. PMID- 22493779 TI - Injectable scaffolds achieve sustained siRNA release for tissue repair. PMID- 22493781 TI - Abstracts of the 15th WFSA (World Federation of Societies of Anesthesiologists) World Congress of Anaesthesiologists. March 25-30, 2012. La Rural, Predio Ferial de Buenos Aires, Argentina. PMID- 22493782 TI - Abstracts of the 22nd European Congress of Clinical Microbiology and Infectious Diseases. London, United Kingdom. March 31-April 3, 2012. PMID- 22493783 TI - Combining imaging and pathway profiling: an alternative approach to cancer drug discovery. AB - Conventional drug discovery strategies are typically 'target centric' based on the selection of lead compounds with optimised 'on-target' potency and selectivity profiles. However, high-attrition rates are often the result of compensatory or redundant cancer mechanisms and the fact that tumours do not find it difficult to escape inhibition of a single pathway. In this article, we highlight two emerging and complimentary technologies; namely phenotypic imaging and post-translational pathway profiling, which when combined with relevant disease models can provide pharmacodiagnostic and drug combination strategies that predict and counteract inherent and adaptive drug resistance. The implementation of such approaches at early stages of the drug discovery process enables more informed decisions on candidate drug selection and how to maximise and predict efficacy before clinical development. PMID- 22493784 TI - Predictive in vivo animal models and translation to clinical trials. AB - Vast resources are expended during the development of new cancer therapeutics, and selection of optimal in vivo models should improve this process. Genetically engineered mouse models (GEMM) of cancer have progressively improved in technical sophistication and, accurately recapitulating the human cognate condition, have had a measureable impact on our knowledge of tumourigenesis. However, the application of GEMMs to facilitate the development of innovative therapeutic and diagnostic approaches has lagged behind. GEMMs that recapitulate human cancer offer an additional opportunity to accelerate drug development, and should complement the role of the widely used engraftment tumour models. PMID- 22493786 TI - Abstracts of the 13th Annual International Meeting of the Institute of Human Virology. October 30-November 2, 2011. Baltimore, Maryland, USA. PMID- 22493785 TI - Stratified medicine for cancer therapy. AB - As knowledge of the biological processes underlying malignant transformation becomes increasingly sophisticated, apparently similar diseases can be redefined according to the critical disrupted biological pathways and networks. The key genetic changes in most cancers can be mapped to one of a relatively few pathways, making it possible to classify tumours by their abnormal pathways and to identify potentially treatable--'druggable'--targets within these. The aim of the stratified approach to cancer therapy is to improve the effectiveness, tolerability and affordability of novel therapeutic agents. PMID- 22493787 TI - Abstracts of the 38th Annual Meeting of the European Group for Blood and Marrow Transplantation. April 1-4, 2012. Geneva, Switzerland. PMID- 22493788 TI - A validated enantioselective HPLC assay of dexibuprofen in dexibuprofen tablet formulations. AB - A high-performance liquid chromatography-diode array detector (HPLC-DAD) method was developed and validated for the quantitation of dexibuprofen in dexibuprofen tablets using ovomucoid chiral stationary phase (Ultron ES-OVM). The mobile phasewas composed of 0.025 M potassium phosphate dibasic (pH 4.5)-methanol ethanol (85:10:5 v/v/v). The method was validated for specificity, linearity, range, accuracy, precision and robustness. The method was enantiomerspecific for the determination of dexibuprofen [S-(+)-isomer ibuprofen] in the presence of R-( )-isomer ibuprofen in bulk drug, pharmaceutical dosage form and under stress degradation. The method was linear over the range 15-35 mg/mL with r2 = 0.9995; accuracy and precision were acceptable with %RSD < 2.0%. The method was found to be specific, precise, accurate, robust and stability-indicating, and can be successfully applied for the routine analysis of dexibuprofen in bulk drug and pharmaceutical dosage form. PMID- 22493790 TI - Abstracts of the Annual Scientific Meeting of the American Geriatrics Society. May 2-5, 2012. Seattle, Washington, USA. PMID- 22493789 TI - Determination of imidol hydrochloride in human plasma and urine by high performance liquid chromatography-tandem mass spectrometry and its application to clinical pharmacokinetic study. AB - Imidol hydrochloride is a novel drug for the treatment of hepatitis B virus infection. A simple, special and sensitive solid-phase extraction liquid chromatography-tandem mass spectrometry method for determination of imidol in human plasma and urine was developed for the first time and applied to a pharmacokinetic study. The chromatographic separation was achieved on a C18 column (50 x 2.1 mm, 3.5 MUm) using gradient elution with acetonitrile and water both containing 0.1% acetic acid at a flow rate of 0.25 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode via a positive eletrospray ionization source. The mass transition pairs of m/z 517.8 --> 325 and m/z 298 --> 174 were used to detect imidol and the (-)-clausenamide (internal standard), respectively. The retention times of imidol and (-)-clausenamide were 2.5 and 2.7 min, respectively. Linearity, accuracy, precision, recovery, matrix effect, dilution test and stability were evaluated during method validation over the range of 0.2-500 ng/mL in human plasma and 0.5 500 ng/mL in urine. The method was successfully applied to a clinical pharmacokinetic study of imidol in healthy volunteers following oral administration. PMID- 22493791 TI - Abstracts of the Annual Meeting of the AUA (American Urological Association).May 19-23, 2012. Atlanta, Georgia, USA. PMID- 22493792 TI - Colorectal complications of end-stage renal failure and renal transplantation: a review. AB - AIM: End-stage renal failure (ESRF) and renal transplant recipients are thought to be associated with an increased risk of colorectal complications. METHOD: A review of the literature was performed to assess the prevalence and outcome in both benign and malignant colorectal disease. RESULTS: No prospective randomized studies assessing colorectal complications in ESRF or renal transplant were identified. Case series and case reports have described the incidence and management of benign colorectal complications. Complications included diverticulitis,infective colitis, colonic bleeding and colonic perforation. There was insufficient evidence to associated iverticular disease with adult polycystic kidney disease.Three population-based studies have shown up to a twofold increased incidence of colonic cancer but not rectal cancer for renal transplant recipients. Bowel cancer screening (as per the general population) by faecal occult blood testing appears justified for renal transplant patients; however, evidence suggests that consideration of starting screening at a younger age may be worthwhile because of an increased risk of developing colonic cancer.Two population-based studies have shown a threefold and 10-fold increased incidence of anal cancer for renal transplant recipients. A single case-control study demonstrated significant increased prevalence of anal human papilloma virus (HPV) and intraepithelial neoplasia (AIN)in patients with established renal transplants. CONCLUSIONS: Despite the lack of high-level evidence,ESRF and renal transplantation were associated with colorectal complications that could result in major morbidity and mortality. Bowel cancer screening in this patient group appears justified. The effectiveness of screening for HPV, AIN and anal cancer in renal transplant recipients remains unclear. PMID- 22493793 TI - Nonsurgical treatment for pelvic organ prolapse: calling on nurses for pessary fittings. PMID- 22493794 TI - Access to quality healthcare--beyond the headlines. PMID- 22493796 TI - The influence of silkworm species on cellular interactions with novel PVA/silk sericin hydrogels. AB - Sericin peptides and PVA are chemically modified with methacrylate groups to produce a covalent PVA/sericin hydrogel. Preservation of the sericin bioactivity following methacrylation is confirmed, and PVA/sericin hydrogels are fabricated for both B. mori and A. mylitta sericin. Cell adhesion studies confirm the preservation of sericin bioactivity post incorporation in PVA gels. PVA/A. mylitta gels are observed to facilitate cell adhesion to a significantly greater degree than PVA/B. mori gels. Overall, the incorporation of sericin does not alter the physical properties of the PVA hydrogels but does result in significantly improved cellular interaction, particularly from A. mylitta gels. PMID- 22493798 TI - [Role of stress in depression insomnia and sleep characteristics of commonly used animal stress models]. AB - Depression and insomnia are intimately related. Depressed patients usually manifest sleep discontinuity and early awakening, reduced or no slow wave sleep (SWS) and shortened latency of rapid eye movement (REM) sleep. These sleep abnormalities are very similar to those caused by over activated hypothalamic pituitary-adrenal (HPA) axis with stress. Therefore, the animal models developed by post-traumatic stress disorder or chronic unpredictable mild stress could be used to evaluate drugs which have effects of both anti-depression and improvement of sleep quality, and to provide a more reliable platform for further studis on the mechanisms of depression and accompanied insomnia. This review mainly focuses on the typical features of sleep disturbance of depression, possible pathophysiological mechanisms, establishment of animal stress models and analysis of their abnormal sleep characteristics. PMID- 22493797 TI - Prostate-cancer-targeted N-(2-hydroxypropyl)methacrylamide copolymer/docetaxel conjugates. AB - Biodistribution, pharmacokinetics, and efficacy of prostate-cancer-targeted HPMA copolymer/DTX conjugates are evaluated in nude mice bearing prostate cancer C4-2 xenografts. PSMA-specific monoclonal antibodies 3F/11 are used as the targeting moiety. Control conjugates tumor accumulation to total background organs (heart, lung, kidney, liver, spleen and blood) accumulation increase substantially with time for the targeted conjugate, and the ratio at 48 h is 7-fold higher than that at 6 h. Preliminary evaluation of the efficacy of the conjugates in vivo show tumor growth inhibition for all HPMA copolymer/DTX conjugates. PMID- 22493799 TI - [Research progress of the selective sphingosine-1-phosphate receptor 1 agonists]. AB - Sphingosine-1-phosphate (S1P) is a lysophospholipid signaling molecule that regulates important biological functions in both intracellular and extracellular compartments. It interacts with five G protein-coupled receptors subtypes (S1PR(1 5)) to generate multiple downstream signaling. Activation of S1PR1 has been validated to be involved in the process of immune modulation. Fingolimod (FTY720), the novel S1PR1 agonist, has been approved for the treatment of multiple sclerosis in clinical trials. The study towards discovery of selective S1PR1 agonists has become hot spot for immunological diseases. This article summarized the research progress of S1PR1 agonists, emphasizing their structure types, structure-activity relationship and direction of development. PMID- 22493800 TI - [Progress in study of the structure, catalytic mechanism and inhibitors of aromatase]. AB - Aromatase is a key enzyme responsible for in vivo estrogen biosynthesis. Inhibition of the activity of the aromatase has become an alterative way for treatment of breast cancer. In this review, the structure and catalytic mechanism of the aromatase is briefly introduced followed by thorough review of the progress in the study of the steroidal and non-steroidal aromatase inhibitors. This review is focused on the natural compounds that exhibit the aromatase inhibition, which include flavonoids, xanthones, coumarins, and sesquiterpenes. The structure-activity relationship of these compounds is also discussed. PMID- 22493801 TI - [The progress of nanomedicine inspired by bacteriophage]. AB - Nanomedicine offers great promise for early diagnosis and treatment of formidable diseases. The unique morphology and biology characteristics of bacteriophage provide unprecedented opportunity for such endeavor. The paper summarizes the application of bacteriophage in nanobiomaterials, nanomedicine, nanomedicine delivery and nanodiagnosis, especially the nano-imaging reagents and future direction concerning nanomedicine based on bacteriophage. PMID- 22493802 TI - [Anthocyanidin inhibits immunoglobulin E-mediated allergic response in mast cells]. AB - This study is to investigate the anti-allergic effect of anthocyanidin and to explore its possible mechanism. The experiments of passive cutaneous anaphylaxis reaction (PCA) and colorimetry were used to determine the effect of anthocyanidin on degranulation of mast cells in vivo. For in vitro study, various concentrations of anthocyanidin (100, 50 and 25 micromol x L(-1)) were added to the culture medium of mast cells cultured with 100 microg x L(-1) of dinitrophenyl (DNP) specific IgE overnight. The azelastine (100 micromol x L(-1)) was selected as the positive control. The antigen (DNP-human serum albumin, DNP HAS)-induced release of degranulation was measured by enzymatic assay, histamine was determined by EIA, and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured by Western blotting, separately. In addition, the effects of anthocyanidin on phosphorylation of NF-kappaB, p38MAPK and Akt were observed by Western blotting. The results showed that treatments with anthocyanidin (100 and 50 mg x kg(-1)) were followed by a decrease in PCA of rats. Anthocyanidin (100 and 50 micromol x L(-1)) obviously suppressed the degranulation from mast cells, whereas results from anthocyanidin (100 and 50 micromol x L(-1)) group indicated significant inhibitory effect on histamine, the calcium uptake, TNF-alpha, IL-6, phosphorylation of NF-kappaB, p38MAPK and Akt of mast cells induced by antigen. Anthocyanidin may suppress the anaphylactic reaction by inhibiting the action of mast cells. NF-kappaB, p38MAPK and Akt at least in part contribute to this event. PMID- 22493803 TI - [Leucine zippers improves protein splicing-mediated coagulation factor VIII gene delivery by dual-vector system]. AB - In our recent study by exploring an intein-based dual-vector to deliver a B domain-deleted FVIII (BDD-FVIII) gene, it showed that covalently ligated intact BDD-FVIII molecules with a specific coagulant activity could be produced from expressed heavy and light chains by protein trans-splicing. Here, we assessed the hypothesis that the efficiency of trans-splicing may be increased by adding to the intein sequences a pair of leucine zippers that are known to bring about specific and strong protein binding. The intein-fused heavy and light chain genes were co-transferred into cultured COS-7 cells using a dual-vector system. After transient expression, the intracellular BDD-FVIII splicing was observed and the spliced BDD-FVIII and bioactivity secreted to culture media were quantitatively analyzed. An enhanced splicing of BDD-FVIII with decreased protein precursors from gene co-transfected cells was observed by Western blotting. The amount of spliced BDD-FVIII and bioactivity secreted to the culture media were 106 +/- 12 ng x mL(-1) and 0.89 +/- 0.11 U x mL(-1) analyzed by ELISA and Coatest method respectively, which was greater than leucine zipper free intein-fused heavy and light chain genes co-transfected cells (72 +/- 10 ng x mL(-1) and 0.62 +/- 0.07 U x mL(-1)). The activity of cellular mechanism-independent protein splicing was also improved, as showed by the increasing of spliced BDD-FVIII and bioactivity in culture media from combined cells separately transfected with heavy and light chain genes which was 36 +/- 11 ng x mL(-1) and 0.28 +/- 0.09 U x mL(-1). It demonstrated that the leucine zippers could be used to increase the efficiency of protein trans-splicing to improve the efficacy of a dual-vector mediated BDD FVIII gene delivery by strengthening the interaction between the two intein pieces fused to heavy and light chains. It provided evidence for further study in animal model using a dual-adeno-associated virus vector to deliver FVIII gene in vivo. PMID- 22493804 TI - [Indirubin inhibits ATP-induced phagocytosis attenuation, ROS production and cell death of macrophages]. AB - This study is to investigate the effects of indirubin on ATP-induced immune responses of macrophages. For this, neutral red dye uptake method was used to test phagocytosis, MTT assay was used for measuring cell death, and reactive oxygen species (ROS) was tested with fluorescent probe DHE. The data showed that extracellular ATP attenuated phagocytosis, induced cell death and increased ROS production, and these effects were restored by pre-treating with indirubin. This result suggested that indirubin blockade the effects of ATP on macrophages, because extracellular ATP-induced effects are dependent on P2 receptors, in particular P2X7 receptors. Furthermore, the effects of indirubin on the activation of P2 receptors were tested, in particular P2X7 receptors. The data showed that indirubin significantly decreased ATP-induced, P2 receptors mediated intracellular Ca2+ concentration ([Ca2+]i) rise and inhibited P2X7 receptor-based ethidium bromide (EB) dye uptake. These results suggested the inhibitory effects of indirubin on the activation of P2X7 receptors, which may underlying the effects on ATP induced ROS production, phagocytosis attenuation and cell death of macrophages. PMID- 22493805 TI - [A preliminary study of anti-aging and wound healing of recombination cytoglobin]. AB - In this paper, the preliminary study on antioxidant, enhancement of antioxidant enzymes activity, reducing the content of oxygen free radicals, delaying skin aging of the recombination cytoglobin (rCygb) purified by our lab were investigated through human keratinocyte cell line (HaCAT) H2O2 oxidative stress model, mouse skin aging model caused by continuous subcutaneous injection D-gal, rat acute liver injury model induced by CCl4 and rat skin wound healing model. The results showed that rCygb improved the activities of total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), reduced the activities of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) as well as decreased the content of malondialdehyde (MDA). Skin biopsy showed that rCygb promoted angiogenesis, increased expression of collagen and improved the anti-inflammatory ability. All results displayed that rCygb improved the oxygen free radical scavenging ability, delayed skin aging and promoted wound healing. PMID- 22493806 TI - [Anti-lipotoxic action of sesamin on renovascular hypertensive rats fed with a high-fat, high-sucrose diet]. AB - This study is to observe anti-lipotoxic effect of sesamin on renovascular hypertensive rats fed with a high-fat, high-sucrose diet. Thirty-four complex model rats were induced by two-kidney, one-clip method and on high-fat and refined-carbohydrate diet for thirteen weeks. From the fifth week, intragastric administration of sesamin (120, 60 and 30 mg x kg(-1) x d(-1)) lasted for eight weeks. Blood pressure (BP), blood fat (BF), blood glucose (BG), free fatty acids (FFA), insulin (Ins), tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were determined. Pathological changes of pancreas, perirenal fat and liver were semiquantitatively analyzed. In sesamin (120 and 60 mg x kg(-1) x d(-1)) group, it was found that there were decrease of levels of BP, BF, BG, TNF-alpha, IL-6 and FFA, improvement of insulin resistance and glucose tolerance, alleviation of body weight, humid weight of fat, liver and pancreas and their organ index, and reduction of islet cell hyperplasia and amount of lipid droplet vacuoles in lipocyte and hepatocyte. It is implied that sesamin had anti-lipotoxic effect and its mechanism may be closely associated with the amelioration of insulin resistance via reducing lipidoses in hepatocyte and inflammatory adipokines such as TNF-alpha and IL-6. PMID- 22493807 TI - [Part IV. Synthesis and antitumor evaluation of s-triazolothiadiazines and pyrazolo s-triazoles derived from ciproxacin]. AB - An efficient modified route based on the targeting mechanism of antibacterial fluoroquinolones for the shift from the antibacterial activity to the antitumor one was further developed. Using a fused heterocyclic ring, s-triazolothiadiazine as a carboxyl bioisostere of ciprofloxacin, the title compounds, 1-cyclopropyl-6 fluoro-7-piperazin-1-yl-3-(6-substituted-phenyl-7H-[1, 2, 4]triazolo[3, 4-b][1, 3, 4]thiadiazin-3-yl)-quinolin-4(1H)-ones (5a-5e) and their corresponding N acetyl products (6a-6e), were designed and synthesized, separately. Meaningfully, a ring-contraction of fused six-membered thiadiazine occurred by a sulfur extrusion reaction gave new tri-acetylated fused heterocycles related to pyrazolo[5, 1-c][1, 2, 4] triazoles (7a-7e). The in vitro antitumor activity against L1210, CHO and HL60 cell lines was also evaluated for the synthesized fifteen heterocycles compared to parent ciprofloxacin by methylthiazole trazolium (MTT) assay. Interestingly, the results displayed that fifteen fused heterocyclic compounds showed more significant growth inhibitory activity (IC50 < 25.0 micromo x L(-1)) than that of parent ciprofloxacin (IC50 > 150.0 micromol x L(-1)), and the active order decreased from 7a-7e to 5a-5e to 6a-6e, respective. PMID- 22493808 TI - [Synthesis and anti-tumor activity of paeonol and its derivatives]. AB - A series of paeonol derivatives have been synthesized by simple acylation and etherification of the paeonol. Anti-tumor activities of the synthesized compounds were evaluated against HeLa and MCF-7 cells lines in vitro by the standard MTT assay. It was found that the derivatives were more active against HeLa than MCF 7. The results also indicated that 4-methoxy group is the synergistic group of paeonol's anti-tumor activity and ketone carbonyl side chain is essential functional group of paeonol's anti-tumor activity. Compound 2d had stronger antiproliferative activities than paeonol against HeLa and MCF-7 cell lines with IC50 values of 2.67 and 4.74 micromol x L(-1) respectively. The results showed that paeonol derivatives were worth to be intensively studied further. PMID- 22493809 TI - Triterpenes from Callicarpa integerrima Champ. AB - A new triterpenoid saponin and fourteen known triterpenoids were isolated from the methanol extract of the stems and leaves of Callicarpa integerrima Champ, which is used in Chinese folk medicine for stopping bleeding, expelling the wind, dissipating stagnation, and treating scrofula, by using various chromatographies, such as silica gel, Sephadex LH-20 and RP-C18 column chromatography. Their structures were identified as a new compound 2alpha, 3beta, 19alpha, 23 tetrahydroxy-olean-12-en-28-oic acid-28-O-beta-D-glucopyranosyl-(1 --> 4)-beta-D glucopyranoside (1), together with fourteen known compounds: oleanolic acid (2), 3-acetyl oleanolic acid (3), 3beta-O-acetyl ursolic acid (4), 2alpha-hydroxy ursolic acid (5), 2alpha, 3beta, 19alpha, 23-tetrahydroxy-urs-12-en-28-oic acid (6), alpha-amyrin-3-O-beta-D-glucopyranoside (7), pomolic acid (8), betulinic acid (9), ursolic acid (10), 2alpha, 3beta, 19alpha, 23-tetrahydroxy-olean-12-en 28-oic acid (arjungenin) (11), 2alpha-hydroxy-oleanolic acid (12), hederagenin (13), 2alpha, 19alpha-dihydroxy-ursolic acid (14) and pruvuloside A (15), by the spectroscopic techniques of NMR, HMBC, IR and MS, separately. All these compounds were obtained from this plant for the first time, and compounds 3, 4 and 15 were isolated from genus Callicarpa L. for the first time. PMID- 22493810 TI - [Simultaneous determination of five main index components and specific chromatograms analysis in Xiaochaihu granules]. AB - Reversed phase high performance liquid chromatography with diode array detector was employed for simultaneous determination of five main index components and specific chromatograms analysis in Xiaochaihu granules with a linear gradient elution of acetonitrile-water (containing 0.1% phosphoric acid) as mobile phase. The results showed that five main index components (baicalin, baicalein, wogonoside, wogonin, enoxolone) were separated well under the analytical condition. The linear ranges of five components were 0.518 - 16.576, 0.069 - 2.197, 0.167 - 5.333, 0.009 - 0.297 and 0.006 - 0.270 mg x g(-1), respectively. The correlation coefficients were 0.999 9, and the average recoveries ranged from 95% to 105%. Twelve common peaks were selected as the specific chromatograms of Xiaochaihu granules with baicalin as the reference peak. There were good similarities between the reference and the ten batches of samples. The similarity coefficients were no less than 0.9. The analytical method established is highly sensitive with strong specificity and it can be used efficiently in the quality control of Xiaochaihu granules. PMID- 22493811 TI - Pharmacokinetics of ibuprofen enantiomers in rats after intravenous and oral administration of ibuprofen arginate. AB - The pharmacokinetics of ibuprofen enantiomers were studied in rats after intravenous and oral administration of ibuprofen arginate by means of a chiral HPLC method. The pharmacokinetics of ibuprofen was stereoselective after intravenous and oral administration of ibuprofen arginate. The pharmacokinetic stereoselectivity was higher after oral administration than that after intravenous administration. The systematic (R)-(-)-to-(S)-(+) inversion might be more important than the presystematic one in the stereoselective pharmacokinetics after oral administration. Oral administration of ibuprofen arginate resulted in a very rapid absorption of (S)-(+)-ibuprofen (eutomer), and the absolute bioavailabilities of (S)-(+)-ibuprofen and (R)-(-)-ibuprofen were about 100% and 80%, respectively. Based on the systemic exposure of (S)-(+)-ibuprofen, it could be concluded that the pharmacological actions might be similar when ibuprofen arginate was given orally and intravenously, except some differences in the onset of action. PMID- 22493812 TI - Pharmacokinetic analysis of alpha and beta epimers of glycyrrhetinic acid in rat plasma: differences in singly and combined administrations. AB - An HPLC method for the determination of 18alpha-glycyrrhetinic acid and 18beta glycyrrhetinic acid in rat plasma was established, which was used subsequently to determine the pharmacokinetic profiles of both epimers of glycyrrhetinic acid in rats. alpha-glycyrrhetinic acid, beta-glycyrrhetinic acid, and a mixture of alpha glycyrrhetinic and beta-glycyrrhetinic acids were administered to rats via gastric infusion. Blood samples were collected at different time intervals and extracted by liquid-liquid extraction. Separation was achieved by using a Kromasil C18 column (150 mm x 4.6 mm, 5 microm) with the mobile phase composed of acetonitrile--4 mmol x L(-1) ammonium acetate solution (46 : 54, v/v) at a flow rate of 1.0 mL x min(-1), and the detection wavelength was set at 250 nm. The pharmacokinetic parameters were calculated using the software DAS 2.0. In a combined administration, the main pharmacokinetic parameters of beta glycyrrhetinic acid are significantly different from that of alpha-glycyrrhetinic acid (P < 0.05), while no significant difference was obtained when administrated individually. Compared to the single administration, significant differences (P < 0.05) on the values of AUC(0-t) and AUC(0-infinity) of beta-glycyrrhetinic acid were observed when this chemical was administrated together with alpha glycyrrhetinic acid. In contrast, the pharmacokinetic parameters of alpha glycyrrhetinic acid were not affected even under the co-administration. Here, a sensitive, specific, rapid and reproducible HPLC method was developed for the pharmacokinetic studies of alpha-glycyrrhetinic acid and beta-glycyrrhetinic acid in rat plasma. PMID- 22493813 TI - [Pharmacokinetics--pharmacodynamics of modafinil in mice]. AB - To guide the reasonable clinical application of modafinil (MOD), pharmacokinetics and pharmacodynamics of MOD in mice and the correlation between them were investigated. Male mice (Kunming strain) were given a single oral dose of MOD (120 mg x kg(-1)). The plasma concentration of MOD was measured by HPLC and the pharmacokinetic parameters were calculated with DAS 3.0 software. For another batch of male Kunming strain mice, their locomotor activities were recorded by an infrared ray passive sensor after a same oral dose of MOD, and the synchronization and correlation between the changes of MOD plasma concentration and the locomotor activity induced by MOD were compared and analyzed. The results showed that the plasma concentration-time curve of MOD was fitted to two compartment open model with a first order absorption. The main pharmacokinetic parameters t1/2alpha, t1/2beta, t(max), C(max) and AUC(0-inifinity) were 0.42 h, 3.10 h, 1.00 h, 41.34 mg x L(-1) and 142.22 mg x L(-1) x h, respectively. MOD significantly increased locomotor activity and the effect lasted for about 4 h. The changes of MOD plasma concentration and the locomotor activity induced by MOD were synchronous. In conclusion, there is a significant correlation between the effect of MOD and its plasma concentration after administration of 120 mg x kg( 1) in mice. PMID- 22493814 TI - [Enantioselective determinination of R-warfarin/S-warfarin in human plasma using liquid chromatography-tandem mass spectrometry and its application in a drug-drug interaction study]. AB - To study the drug-drug interaction of morinidazole and warfarin and its application, a sensitive and rapid liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for the determination of R warfarin/S-warfarin in human plasma. In a random, two-period crossover study, 12 healthy volunteers received a single oral dose of 5 mg racemic warfarin in the absence and presence of morinidazole. Blood samples were collected according to a pre-designed time schedule. R-warfarin, S-warfarin and methyclothiazide were extracted with ethylether : methylenechloride (3 : 2), then separated on a Astec Chirobiotic V (150 mm x 4.6 mm ID, 5 microm) column using 5 mmol x L(-1) ammonium acetate (pH 4.0) - acetonitrile as mobile phase at a flow-rate of 1.5 mL x min( 1). The mobile phase was splitted and 0.5 mL x min(-1) was introduced into MS. A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the negative ion mode. Quantification was performed using multiple reaction monitoring (MRM). The resolution of warfarin enantiomers is 1.56. The linear calibration curves for R-warfarin and S-warfarin both were obtained in the concentration range of 5 - 1 000 ng x mL(-1). Intra- and inter day relative standard deviation (RSD) for R-warfarin and S-warfarin over the entire concentration range across three validation runs was both less than 10%, and relative error (RE) ranged from -4.9% to 0.7%, separately. The method herein described is effective and convenient, and suitable for the study of metabolic interaction between morinidazole and warfarin. The results showed that coadministration of warfarin with morinidazole did not affect the pharmacokinetics of either R-warfarin or S-warfarin. PMID- 22493815 TI - [Degradation of earthworm extracts prepared by wet superfine grinding in simulated gastrointestinal environment]. AB - This is to report the study of degradation of earthworm extracts prepared by wet superfine grinding in simulated gastrointestinal environment. Enzymatic reactions were terminated by adjusting the solution pH or using membrane bioreactor principle. Earthworm protein concentration change was detected by Bradford method, the degraded state of protein was described with SDS-PAGE technology, and the degraded state of small molecule substances was detected by HPLC. The results showed that earthworm protein degraded completely in artificial gastric juice. High molecular weight protein degraded greatly in artificial intestinal fluid, while low molecular weight protein was not significantly degraded. Small molecular substances degradation did not degrade in artificial gastric juice, while they degraded obviously in artificial intestinal fluid, there is even new small molecule substance appeared. Finally it is concluded that the substance that having therapeutic effects in vivo may be some degraded peptide, amino acid and stable small molecules existed in artificial intestinal fluid. PMID- 22493816 TI - [The complexes of adenovirus and anionic liposomes: preparation and in vitro characterization]. AB - This study is to report the preparation of complexes of Ad5 and anionic liposomes (AL-Ad5), the amplification of adenoviruses with enhanced green fluorescent protein (eGFP) reporter gene performed by HEK 293 cells, the adenoviral vectors purified by cesium chloride gradient centrifugation, and the titer of adenovirus determined by cytopathic effect (CPE) method, hexon capsid immunoassay and quantitative-PCR (Q-PCR), separately. The prescription and experiment conditions were optimized by central composite design (CCD). The complexes of Ad5 and AL-Ad5 were formulated by the calcium-induced phase change method. The morpholopy, particle size and zeta potential were detected by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. Additionally, the bicolourable fluoresce-labeled complexes (F(labeled)-AL-Ad5) were prepared and their intracellular location in MDCK cells was detected by confocal laser scanning microscopy (CLSM). The results indicate that the complexes of AL-Ad5 exhibited a uniform distribution with a particle size of 211 +/- 10 nm and a zeta potential of -41.2 +/- 2.2 mV. The result of CLSM demonstrates that the intracellular location of red fluoresce-labeled adenovirus was consistent with that of green fluoresce-labeled liposomes suggesting that the naked adenovirus was well encapsulated by the anionic liposomes in complexes of AL-Ad5. PMID- 22493817 TI - [High-throughput pyrosequencing of the complete chloroplast genome of Magnolia officinalis and its application in species identification]. AB - Chloroplast genome sequences have comprehensive application prospects in DNA barcoding and chloroplast engineering in traditional Chinese medicine. The complete chloroplast genome of Magnolia officinalis sequenced by high-throughput pyrosequencing and a sequencing procedure was established. Fourteen contigs were obtained after de nove assembly. The sequencing percent of coverage was 99.99%. The chloroplast genome is 160 183 bp in size, and has a typical quadripartite structure with the large (LSC, 88 210 bp) and small copy (SSC, 18 843 bp) regions separated by two copies of an inverted repeat (IRs, 26 565 bp each). chloroplast genes were successfully annotated, of which 17 genes located in each IR region. The chloroplast genome features in Magnolia officinalis are nearly identical to those from other Magnoliid chloroplast genomes. Phylogenetic analyses were performed based on 81 shared coding-genes for a total of 9 Magnolia samples of 5 closely related species. Results showed that distinguishing among species was generally straightforward at the species and population level. This study confirmed the effectiveness of our chloroplast genome sequencing procedure. The chloroplast genome can provide distinguishing differences to help identify Magnolia officinalis and its closely related plants. PMID- 22493818 TI - [Wheat germ agglutinin anchored chitosan nanoparticles and its conjugation with N acetylglucosamine]. AB - This study is undertaken to modify the chitosan nanoparticles (CS-NPs) with wheat germ agglutinin (WGA), and investigate the conjugation between WGA-CS-NPs and N acetylglucosamine (NAG). CS-NPs were prepared by ionotropic gelation process and then conjugated with WGA under the activation of glutaricdialdehyde. The mean diameter of the CS-NPs was approximately 113.5 nm and the poly-dispersity index (PDI) was 0.18. The binding yield of WGA to CS-NPs was comprised between 27.8% and 87.9% depending mostly on the addition of 0.3% (w/v) glutaraldehyde solution. A competitive inhibition experiment of WGA-CS-NPs to bovine submaxillary gland mucin (BSM) was taken to illuminate the binding activity of WGA-CS-NPs to the sugar of N-acetylglucosamine. After the addition of NAG, the binding rates between CS-NPs and BSM almost didn't change, while the binding rates between WGA CS-NPs and BSM dropped down significantly, which confirmed the specific binding characteristics of WGA to NAG. PMID- 22493819 TI - Breast reconstruction improves well-being and quality of life. Advanced techniques prove safe and effective for older women. PMID- 22493820 TI - TIAs: 'transient' in name only. PMID- 22493821 TI - Are all hip implants created equal? An FDA analysis takes on the question and finds that newer doesn't mean better. PMID- 22493822 TI - Nuts may benefit those with metabolic syndrome. PMID- 22493823 TI - Daily low-dose aspirin: beware of GI bleeding. PMID- 22493824 TI - Why does my doctor insist I undergo a standard colonoscopy when a virtual colonoscopy sounds easier? PMID- 22493825 TI - What are the warning signs of Alzheimer's disease? My husband has been unusually forgetful lately. PMID- 22493826 TI - [The clinical application of infrared imaging technology in teenagers with cervicodynia]. AB - OBJECTIVE: To compare the temperature distribution of both sides of shoulder, provide objective reference for the application thermoview in the diagnosis of cervicodynia in teenagers. METHODS: Forty-five adolescents with cervicodynias from March 2009 to December 2009 were collected. There were 23 males and 22 females, with an average age of 21 years (ranged from 19 to 22 years). The course of disease ranged from 2 to 20 weeks (averaged 13 weeks). C7 horizontal line were used to divide the back into the neck area and shoulders area, and the midline to subdivide the chosen area into left and right area. Thermal infrared imaging was used to observe the temperature both sides of neck and shoulders, the data was analyzed by the computer. RESULTS: The temperature of shoulder was higher than neck. There were significant differences in the highest and average temperature both of the left and right side of neck and shoulder (P < 0.05), but no difference in the lowest temperature both of left and right side of neck. CONCLUSION: The thermal infrared imaging is important for diagnosing cervical imbalance syndrome, finding the sign of abnormal muscle metabolism of shoulder and providing the basis for prevention. PMID- 22493827 TI - 20 years later, not much has changed. PMID- 22493828 TI - Inhaler use: tell patients to purse their lips. PMID- 22493829 TI - Hormone replacement therapy and breast cancer: causation and epidemiology. PMID- 22493830 TI - European Archives of Paediatric Dentistry. PMID- 22493831 TI - Strong capital purchasing process calls for partnership, transparency. PMID- 22493832 TI - BMP use up sharply, but outcomes not improved. PMID- 22493833 TI - Streamlining preoperative care: role of software. PMID- 22493834 TI - Electronic tool aids in navigating preop process. PMID- 22493835 TI - Duke protocol ensures right level of screening. PMID- 22493836 TI - Sterile reprocessing: rely on the experts to aid OR. PMID- 22493837 TI - New study benchmarks performance of ASCs. PMID- 22493838 TI - Tracking TASS: registry eyes an elusive target. PMID- 22493839 TI - Borrelia burgdorferi. PMID- 22493840 TI - Description of two new sand fly species related to Nyssomyia antunesi (Diptera, Psychodidae, Phlebotominae). AB - Both sexes of two new Brazilian phlebotomine sand flies of the genus Nyssomyia Barretto 1962 [= Lutzomyia (Nyssomyia) sensu Barretto], Nyssomyia delsionatali n. sp. and Nyssomyia urbinattii n. sp., presenting close affinity with Nyssomyia antunesi (Coutinho), are described and illustrated. N. delsionatali n. sp was captured on the edge of a riparian Amazonian forest on the Juruena river in the northwest of Mato Grosso state and N. urbinattii n. sp in a riparian Amazonian forest on the Teles Pires river between Mato Grosso and Para states. Some measurements of both sexes of N. antunesi and illustration of the male genitalia and the female spermathecae as well as an identification key for males and females of the genus Nyssomyia are provided. PMID- 22493841 TI - Dispersion and sampling of adult Dermacentor andersoni in rangeland in Western North America. AB - A fixed precision sampling plan was developed for off-host populations of adult Rocky Mountain wood tick, Dermacentor andersoni (Stiles) based on data collected by dragging at 13 locations in Alberta, Canada; Washington; and Oregon. In total, 222 site-date combinations were sampled. Each site-date combination was considered a sample, and each sample ranged in size from 86 to 250 10 m2 quadrats. Analysis of simulated quadrats ranging in size from 10 to 50 m2 indicated that the most precise sample unit was the 10 m2 quadrat. Samples taken when abundance < 0.04 ticks per 10 m2 were more likely to not depart significantly from statistical randomness than samples taken when abundance was greater. Data were grouped into ten abundance classes and assessed for fit to the Poisson and negative binomial distributions. The Poisson distribution fit only data in abundance classes < 0.02 ticks per 10 m2, while the negative binomial distribution fit data from all abundance classes. A negative binomial distribution with common k = 0.3742 fit data in eight of the 10 abundance classes. Both the Taylor and Iwao mean-variance relationships were fit and used to predict sample sizes for a fixed level of precision. Sample sizes predicted using the Taylor model tended to underestimate actual sample sizes, while sample sizes estimated using the Iwao model tended to overestimate actual sample sizes. Using a negative binomial with common k provided estimates of required sample sizes closest to empirically calculated sample sizes. PMID- 22493842 TI - A study on distribution and seasonal abundance of Aedes albopictus (Diptera: Culicidae) population in Athens, Greece. AB - In September 2008, Aedes (Stegomyia) albopictus (Skuse 1894), a mosquito of great medical importance, was reported for the first time in a district of Athens, Greece. The following year, its distribution and population abundance over time around its first detection site was investigated. A network of 50 ovitraps was established in a surrounding area of 25 km2 and monitored for 17 mo from 17 August 2009 through 31 December 2010. Weekly servicing of the ovitraps and subsequent laboratory treatment of the collected mosquito eggs, revealed that Ae. albopictus is the dominant container breeding Aedes species and is widespread in the entire study area. The seasonal monitoring showed that this mosquito is continuously active from mid spring until the end of December with a considerably high oviposition activity recorded during summer and fall. Moreover, comparison of its activity during late August and end of December, between the two consecutive surveillance years, indicated a significant increase of population abundance the second year. The current study suggests the necessity of setting up in the city of Athens an integrated surveillance program in a greater scale for Asian tiger mosquito's effective control. PMID- 22493843 TI - Weather variability affects abundance of larval Culex (Diptera: Culicidae) in storm water catch basins in suburban Chicago. AB - Culex pipiens L. (Diptera: Culicidae) and Culex restuans Theobald are the primary enzootic and bridge vectors of West Nile virus in the eastern United States north of 36 degrees latitude. Recent studies of the natural history of these species have implicated catch basins and underground storm drain systems as important larval development sites in urban and suburban locales. Although the presence of larvae in these habitats is well-documented, the influence of abiotic factors on the ecology of Culex larvae developing in them remains poorly understood. Therefore, we examined the effects of multiple abiotic factors and their interactions on abundance of Culex larvae in catch basins in the Chicago, IL, metropolitan area. Low precipitation and high mean daily temperature were associated with high larval abundance, whereas there was no correlation between catch basin depth or water depth and larval abundance. Rainfall was an especially strong predictor of presence or absence of larvae in the summer of 2010, a season with an unusually high precipitation. Regression tree methods were used to build a schematic decision tree model of the interactions among these factors. This practical, visual representation of key predictors of high larval production may be used by local mosquito abatement districts to target limited resources to treat catch basins when they are particularly likely to produce West Nile virus vectors. PMID- 22493844 TI - Weak larval competition between the invasive mosquito Aedes japonicus japonicus (Diptera: Culicidae) and three resident container-inhabiting mosquitoes in the laboratory. AB - The spread of exotic mosquito species into new environments can introduce shifts in mosquito populations and potentially alter public health risks to mosquito borne diseases. The successful establishment of exotic species may occur due to their competitive advantage over other cohabitating species. We hypothesized that the recently introduced exotic mosquito Aedes japonicus japonicus (Theobald) would be a more effective competitor than Aedes atropalpus (Coquillett) and Aedes triseriatus (Say), and an equal competitor to Culex pipiens (L.) based on larval abundance data within tire habitats. Impacts of competition were measured using the larval developmental rate and survival of larvae, adult mortality, wing length, and sex ratio. We found that intraspecific competition acted strongest against Ae. japonicus versus the other three resident mosquito species by delaying larval development and increasing adult mortality. Interspecific competition was generally weak and significant main effects were only detected for species and density. Overall, our results show that larval competition between Ae. japonicus and the three resident species was weak when present, indicating that other ecological or behavioral factors may be influencing the invasion success for Ae. japonicus in North America. PMID- 22493845 TI - Dewatered sewage biosolids provide a productive larval habitat for stable flies and house flies (Diptera: Muscidae). AB - Species diversity and seasonal abundance of muscoid flies (Diptera: Muscidae) developing in biosolid cake (dewatered biosolids) stored at a wastewater treatment facility in northeastern Kansas were evaluated. Emergence traps were deployed 19 May through 20 October 2009 (22 wk) and 27 May through 18 November 2010 (25 wk). In total, 11,349 muscoid flies were collected emerging from the biosolid cake. Stable flies (Stomoxys calcitrans (L.)) and house flies (Musca domestica (L.)), represented 80 and 18% of the muscoid flies, respectively. An estimated 550 stable flies and 220 house flies per square-meter of surface area developed in the biosolid cake annually producing 450,000 stable flies and 175,000 house flies. Stable fly emergence was seasonally bimodal with a primary peak in mid-July and a secondary peak in late August. House fly emergence peaked with the first stable fly emergence peak and then declined gradually for the remainder of the year. House flies tended to emerge from the biosolid cake sooner after its deposition than did stable flies. In addition, house fly emergence was concentrated around midsummer whereas stable fly emergence began earlier in the spring and continued later into the fall. Biosolid age and temperature were the most important parameters affecting emergence for house flies and stable flies, whereas precipitation was not important for either species. This study highlights the importance of biosolid cake as a larval developmental habitat for stable flies and house flies. PMID- 22493846 TI - Evaluation of artificial larval rearing media waste as oviposition attractant for New World screwworms (Diptera: Calliphoridae). AB - The waste artificial larval rearing media of New World screwworms, Cochliomyia hominivorax (Coquerel) were evaluated to determine their effectiveness as oviposition attractants. Various concentrations of waste larval media resulting from rearing screwworm larvae in gel and cellulose fiber-based artificial diets tested over a 4-wk period attracted varying number of gravid screwworm flies to oviposit. Three-day-old waste medium with concentrations of 10 and 25% were most attractive to gravid female flies for oviposition and resulted in the most oviposition. One and 7-d-old wastes at all concentrations were less attractive for oviposition than the 3d-old media. The fresh (0-d-old), 14-d- and 28-d-old waste media were the least attractive substrates for oviposition. The waste from the cellulose fiber-based diet resulted in significantly more oviposition compared with waste from the gel-based diet. Microorganisms growing in the waste media probably produce metabolites that attract gravid screwworm flies to oviposit. Use of the waste products of appropriate age and dilution as oviposition substrates would enhance oviposition in mass production colony cages. PMID- 22493847 TI - High degree of single nucleotide polymorphisms in California Culex pipiens (Diptera: Culicidae) sensu lato. AB - Resolution of systematic relationships among members of the Culex pipiens (L.) complex has important implications for public health as well as for studies on the evolution of sibling species. Currently held views contend that in California considerable genetic introgression occurs between Cx. pipiens and Cx. quinquefasciatus Say, and as such, these taxa behave as if they are a single species. Development of high throughput SNP genotyping tools for the analysis of Cx. pipiens complex population structure is therefore desirable. As a first step toward this goal, we sequenced 12 gene fragments from specimens collected in Marin and Fresno counties. On average, we found a higher single nucleotide polymorphism (SNP) density than any other mosquito species reported thus far. Coding regions contained significantly higher GC content (median 54.7%) than noncoding regions (42.4%; Wilcoxon rank sum test, P = 5.29 x 10(-5)). Differences in SNP allele frequencies observed between mosquitoes from Marin and Fresno counties indicated significant genetic divergence and suggest that SNP markers will be useful for future detailed population genetic studies of this group. The high density of SNPs highlights the difficulty in identifying species within the complex and may be associated with the large degree of phenotypic variation observed in this group of mosquitoes. PMID- 22493848 TI - Single-nucleotide polymorphisms for high-throughput genotyping of Anopheles arabiensis in East and southern Africa. AB - Anopheles arabiensis Patton is one of the principal vectors of malaria in sub Saharan Africa, occupying a wide variety of ecological zones. This species is increasingly responsible for malaria transmission in Africa and is becoming the dominant vector species in some localities. Despite its growing importance, little is known about genetic polymorphisms in this species. Multiple sequences of various gene fragments from An. arabiensis isolates from Cameroon were obtained from GenBank. In total, 20 gene fragments containing single-nucleotide polymorphisms (SNPs) at moderate density were selected for direct sequencing from field collected specimens from Tanzania and Zambia. We obtained 301 SNPs in total from the 20 gene fragments, 60 of which were suitable for Illumina GoldenGate SNP genotyping. A greater number of SNPs (n = 185) was suitable for analysis using Sequenom iPLEX, an alternative high-throughput genotyping technology using mass spectrometry. An SNP was present every 59 (+/- 44.5) bases on average. Overall, An. arabiensis from Tanzania and Zambia are genetically closer (mean F(ST) = 0.075) than either is to populations in Cameroon (F(ST, TZ-CM) = 0.250, F(ST,ZA CM) = 0.372). A fixed polymorphism between East/southern and Central Africa was identified on AGAP000574, a gene on the X chromosome. We have identified SNPs in natural populations of An. arabiensis. SNP densities in An. arabiensis were higher than Anopheles gambiae s.s., suggesting a greater challenge in the development of high-throughput SNP analysis for this species. The SNP markers provided in this study are suitable for a high-throughput genotyping analysis and can be used for population genetic studies and association mapping efforts. PMID- 22493849 TI - Transcription profiling associated with life cycle of Anopheles gambiae. AB - Complex biological events occur during the developmental process of the mosquito Anopheles gambiae (Giles). Using cDNA expression microarrays, the expression patterns of 13,440 clones representing 8,664 unique transcripts were revealed from six different developmental stages: early larvae (late third instar/early fourth instar), late larvae (late fourth instar), early pupae (< 30 min after pupation), late pupae (after tanning), and adult female and male mosquitoes (24 h postemergence). After microarray analysis, 560 unique transcripts were identified to show at least a fourfold up- or down-regulation in at least one developmental stage. Based on the expression patterns, these gene products were clustered into 13 groups. In total, eight genes were analyzed by quantitative real-time polymerase chain reaction to validate microarray results. Among 560 unique transcripts, 446 contigs were assigned to respective genes from the An. gambiae genome. The expression patterns and annotations of the genes in the 13 groups are discussed in the context of development including metabolism, transport, protein synthesis and degradation, cellular processes, cellular communication, intra- or extra-cellular architecture maintenance, response to stress or immune-related defense, and spermatogenesis. PMID- 22493850 TI - Lethal and sublethal effects of avermectin/milbemycin parasiticides on the African malaria vector, Anopheles arabiensis. AB - Four cattle parasiticides of the avermectin/milbemycin class were examined for lethal and sublethal effects on the zoophilic, African malaria vector Anopheles arabiensis. Ivermectin, moxidectin, doramectin, and eprinomectin were mixed with bovine blood and provided to laboratory-reared An. arabiensis in a membrane feeder. Ivermectin and eprinomectin were lethal to An. arabiensis at low concentrations (LC50s of 7.9 ppb and 8.5 ppb, respectively). While the lethality of doramectin (LC50 of 23.9 ppb), was less than that of ivermectin and eprinomectin, it markedly reduced egg development. The concentration of moxidectin required to reduce survivorship and egg production in An. arabiensis was > 100 fold greater than for ivermectin or eprinomectin. Moxidectin was weak in its actions against An. arabiensis relative to the other three chemicals. These results suggest that cattle treated with ivermectin or eprinomectin in the prescribed range of low dosages as parasiticides have blood toxic to zoophilic malaria vectors. Regionally coordinated, seasonal treatment of cattle could suppress An. arabiensis populations, thereby reducing malaria transmission. Doramectin (although less toxic) would have population level effects on egg production if used in this manner. PMID- 22493851 TI - Insecticidal activity of individual and mixed monoterpenoids of geranium essential oil against Pediculus humanus capitis (Phthiraptera: Pediculidae). AB - The major components of geranium (Geranium maculatum L.) oil and their mixtures were tested against female Pediculus humanus capitis De Geer (Phthiraptera: Pediculidae). Chemical analysis by gas chromatography coupled to mass spectrometry revealed four major constituents: citronellol (38%), geraniol (16%), citronellyl formate (10.4%), and linalool (6.45%) (concentration expressed as percentage of total). Topical application demonstrated that the most potent component was citronellol and geraniol, with LD50 values 9.7 and 12.7 microg/insect, respectively. Linalool and Citronellyl formate were less toxic with LD50 values 24.7 and 38.5 microg/insect, respectively. Toxicity of these four major constituents in the same proportion as the natural oil, was greater than whole oil and each individual component. Removal of any four constituents produced a decreased in effectiveness. The absence of citronellol caused the greatest decrease in toxicity (DL50 from 2.2 to 10.9 microg/insect), leading us to conclude that this constituent is the major contributor to oil toxicity. The knowledge of the role of each constituent in the toxicity of the whole oil gives the possibility to create artificial blends of different constituents for the development of more effective control agents. PMID- 22493852 TI - Ovicidal response of NYDA formulations on the human head louse (Anoplura: Pediculidae) using a hair tuft bioassay. AB - Using the in vitro rearing system in conjunction with the hair tuft bioassay, NYDA and NYDA without fragrances formulations (92% wt:wt dimeticones) were 100% ovicidal (0% of treated eggs hatched) after an 8-h exposure of the eggs of the human head louse (Pediculus humanus capitis De Geer) following the manufacturer's instructions. Comparatively, 78 and 66% of eggs similarly exposed hatched after distilled deionized water or Nix (1% permethrin) treatments, respectively. NYDA and NYDA without fragrances formulations were also statistically and substantially more ovicidal than either distilled deionized water or Nix treatments after 10, 30 min, and 1 h exposures. Only the 10 min exposure of eggs to NYDA and NYDA without fragrances formulations resulted in hatched lice that survived to adulthood (5-8% survival). Of the lice that hatched from eggs exposed to NYDA formulations for 10 min, there were no significant differences in the time it took them to become adults, female fecundity or the viability of eggs laid by surviving females. The longevity of adults, however, was reduced after the 10 min treatments of eggs with NYDA and NYDA without fragrances formulations compared with either the distilled deionized water or Nix treatments. PMID- 22493853 TI - Ability of newly emerged adult Culex quinquefasciatus (Diptera: Culicidae) mosquitoes to exit belowground stormwater treatment systems via lateral conveyance pipes. AB - Culex quinquefasciatus Say mosquitoes flourish in belowground stormwater systems in the southern United States. Recent evidence suggests that oviposition-site seeking females may have difficulties locating, entering, and ovipositing inside permanent water chambers when surface entry through pickholes in manhole covers are sealed. It remains unknown, however, if newly emerged adults are able to detect cues necessary to exit these partly sealed systems via lateral conveyance pipes or if they perish belowground. Fourth instar Cx. quinquefasciatus were placed within proprietary belowground stormwater treatment systems to determine the percentage of newly emerged adults able to escape treatment chambers via a single lateral conveyance pipe. Overall, 56% of deployed mosquitoes were captured in adult exit traps with an 1:1 male:female ratio. The percentage of adults captured varied significantly among chambers, but was not associated with structural site characteristics such as the chamber depth or the length and course of conveyance pipe to the exit trap. Empirical observations suggested that longbodied cellar spiders, Pholcus phalangioides (Fuesslin), ubiquitous in these structures, may have reduced adult trap capture. Findings demonstrate that newly emerged Cx. quinquefasciatus can exit subterranean chambers under potentially difficult structural conditions but suggest that a portion may perish in the absence of surface exit points in manhole shafts. PMID- 22493854 TI - Mosquitocidal properties of natural product compounds isolated from Chinese herbs and synthetic analogs of curcumin. AB - Because of resistance to current insecticides and to environmental, health, and regulatory concerns, naturally occurring compounds and their derivatives are of increasing interest for the development of new insecticidal compounds against vectors of disease-causing pathogens. Fifty-eight compounds, either extracted and purified from plants native to China or synthetic analogs of curcumin, were evaluated for both their larvicidal activity against Aedes aegypti (L.) and their ability to inhibit binding of cholesterol to Ae. aegypti sterol carrier protein-2 in vitro. Of the compounds tested, curcumin analogs seem especially promising in that of 24 compounds tested five were inhibitors of Ae. aegypti sterol carrier protein-2 with EC50 values ranging from 0.65 to 62.87 microM, and three curcumin analogs exhibited larvicidal activity against fourth instar Ae. aegypti larvae with LC50 values ranging from 17.29 to 27.90 microM. Adding to the attractiveness of synthetic curcumin analogs is the relative ease of synthesizing a large diversity of compounds; only a small fraction of such diversity has been sampled in this study. PMID- 22493856 TI - Gene expression analysis of Xenopsylla cheopis (Siphonaptera: Pulicidae) suggests a role for reactive oxygen species in response to Yersinia pestis infection. AB - Fleas are vectors for a number of pathogens including Yersinia pestis, yet factors that govern interactions between fleas and Y. pestis are not well understood. Examining gene expression changes in infected fleas could reveal pathways that affect Y. pestis survival in fleas and subsequent transmission. We used suppression subtractive hybridization to identify genes that are induced in Xenopsylla cheopis (Rothschild) (Siphonaptera: Pulicidae) in response to oral or hemocoel infection with Y. pestis. Overall, the transcriptional changes we detected were very limited. We identified several genes that are likely involved in the production or removal of reactive oxygen species (ROS). Midgut ROS levels were higher in infected fleas and antioxidant treatment before infection reduced ROS levels and resulted in higher bacterial loads. An ROS-sensitive mutant strain of Y. pestis lacking the OxyR transcriptional regulator showed reduced growth early after infection. Our results indicate that ROS may limit Y. pestis early colonization of fleas and that bacterial strategies to overcome ROS may enhance transmission. PMID- 22493855 TI - The effect of ivermectin in seven strains of Aedes aegypti (Diptera: Culicidae) including a genetically diverse laboratory strain and three permethrin resistant strains. AB - Seven different strains of Aedes aegypti (L.), including a genetically diverse laboratory strain, three laboratory-selected permethrin-resistant strains, a standard reference strain, and two recently colonized strains were fed on human blood containing various concentrations of ivermectin. Ivermectin reduced adult survival, fecundity, and hatch rate of eggs laid by ivermectin-treated adults in all seven strains. The LC50 of ivermectin for adults and the concentration that prevented 50% of eggs from hatching was calculated for all strains. Considerable variation in adult survival after an ivermectin-bloodmeal occurred among strains, and all three permethrin-resistant strains were significantly less susceptible to ivermectin than the standard reference strain. The hatch rate after an ivermectin bloodmeal was less variable among strains, and only one of the permethrin resistant strains differed significantly from the standard reference strain. Our studies suggest that ivermectin induces adult mortality and decreases the hatch rate of eggs through different mechanisms. A correlation analysis of log transformed LC50 among strains suggests that permethrin and ivermectin cross resistance may occur. PMID- 22493857 TI - Culex annulirostris (Diptera: Culicidae) host feeding patterns and Japanese encephalitis virus ecology in northern Australia. AB - Japanese encephalitis virus (JEV) transmission in northern Australia has, in the past, been facilitated by Culex annulirostris Skuse feeding on domestic pigs, the primary amplifying hosts of the virus. To further characterize mosquito feeding behavior in northern Australia, 1,128 bloodmeals from Cx. annulirostris were analyzed using a double-antibody enzyme-linked immunosorbent assay. Overall, Cx. annulirostris obtained > 94% of blood meals from mammals, comprising marsupials (37%), pigs (20%), dogs (16%), and cows (11%), although the proportion feeding on each of these host types varied between study locations. Where JEV activity was detected, feeding rates on pigs were relatively high. At the location that yielded the first Australian mainland isolate of JEV from mosquitoes, feral pigs (in the absence of domestic pigs) accounted for 82% of bloodmeals identified, representing the first occasion that feeding on feral pigs has been associated with JEV transmission in Australia. Interestingly, < 3% of Cx. annulirostris had fed on pigs at locations on Badu Island where JEV was detected in multiple pools of mosquitoes in a concurrent study. This suggests that either alternative hosts, such as birds, which comprised 21% of blood meals identified, or infected mosquitoes immigrating from areas where domestic pigs are housed, may have contributed to transmission at this location. Because Cx. annulirostris is both an opportunistic feeder and the primary JEV vector in the region, environmental characteristics and host presence can determine JEV transmission dynamics in northern Australia. PMID- 22493858 TI - Developing models for the forage ratios of Culiseta melanura and Culex erraticus using species characteristics for avian hosts. AB - Studies of mosquito preferences for avian hosts have found that some bird species are at greater risk than others of being fed upon by mosquitoes. The ecological factors that determine this interspecific variation in avian host use by mosquitoes have been little studied, despite the possibility that such variation may influence spatial and temporal patterns of the occurrence of mosquito-borne pathogens. Our objective was to identify ecological variables associated with the avian host forage ratios estimated from a previous study of mosquito feeding patterns in Tuskegee National Forest, AL. We used species' characteristics derived from the literature to develop multiple linear regression models for the forage ratios of Culiseta melanura (Coquillett) and Culex erraticus (Dyar & Knab) for avian hosts. We found that habitat-edge association and body mass of avian host species were the best predictors of forage ratios of Cx. erraticus for avian hosts. Although no avian host traits were inferred to be strong predictors of forage ratios of Cs. melanura, body mass had the greatest importance weight among those considered. Our results suggest that characteristics of avian hosts may predict their levels of use by some mosquito species. PMID- 22493859 TI - Aedes albopictus (Diptera: Culicidae) population size survey in the 2007 chikungunya outbreak area in Italy. II: Estimating epidemic thresholds. AB - Our study compared different estimates of adult mosquito abundance (Pupal Demographic Survey [PDS], Human Landing Collection [HLC], Number of Bites declared by Citizens during interviews [NBC]) to the mean number of eggs laid in ovitraps. We then calculated a disease risk threshold in terms of number of eggs per ovitrap above which an arbovirus epidemic may occur. The study was conducted during the summers of 2007 and 2008 in the Emilia-Romagna region of Italy where a chikungunya epidemic occurred in 2007. Ovitrap monitoring lasted from May to September, while adult sampling by means of PDS, HLC, and NBC was repeated three times each summer. Based on calculated rate of increase of the disease (R(0)) and the number of bites per human per day measured during the outbreak, we estimated that only 10.1% of the females transmitted the chikungunya virus in the principal focus. Under our conditions, we demonstrated that a positive correlation can be found between the females' density estimated by means of PDS, HLC, and NBC and the mean number of eggs in the ovitraps. We tested our hypothesis during the 2007 secondary outbreak of CHIKV in Cervia, and found that R(0) calculated based on the number of biting females estimated from the egg density was comparable to the R(0) calculated based on the progression of the human cases. The identification of an epidemic threshold based on the mean egg density may define the high risk areas and focus control programs. PMID- 22493860 TI - Passive surveillance for I. scapularis ticks: enhanced analysis for early detection of emerging Lyme disease risk. AB - Lyme disease (LD) is emerging in Canada because of the northward expansion of the geographic range of the tick vector Ixodes scapularis (Say). Early detection of emerging areas of LD risk is critical to public health responses, but the methods to do so on a local scale are lacking. Passive tick surveillance has operated in Canada since 1990 but this method lacks specificity for identifying areas where tick populations are established because of dispersion of ticks from established LD risk areas by migratory birds. Using data from 70 field sites in Quebec visited previously, we developed a logistic regression model for estimating the risk of I. scapularis population establishment based on the number of ticks submitted in passive surveillance and a model-derived environmental suitability index. Sensitivity-specificity plots were used to select an optimal threshold value of the linear predictor from the model as the signal for tick population establishment. This value was used to produce an "Alert Map" identifying areas where the passive surveillance data suggested ticks were establishing in Quebec. Alert Map predictions were validated by field surveillance at 76 sites: the prevalence of established I. scapularis populations was significantly greater in areas predicted as high-risk by the Alert map (29 out of 48) than in areas predicted as moderate-risk (4 out of 30) (P < 0.001). This study suggests that Alert Maps created using this approach can provide a usefully rapid and accurate tool for early identification of emerging areas of LD risk at a geographic scale appropriate for local disease control and prevention activities. PMID- 22493861 TI - Facilitative ecological interactions between invasive species: Arundo donax stands as favorable habitat for cattle ticks (Acari: Ixodidae) along the U.S. Mexico border. AB - The cattle tick, Rhipicephalus (Boophilus) spp. is a key vector of protozoa that cause bovine babesiosis. Largely eradicated from most of the United States, the cattle tick continues to infest south Texas, and recent outbreaks in this area may signal a resurgence of cattle tick populations despite current management efforts. An improved understanding of the dynamic ecology of cattle fever ticks along the U.S.-Mexico border is required to devise strategies for sustainable eradication efforts. Management areas of the cattle tick overlap considerably with dense, wide infestations of the non-native, invasive grass known as giant reed (Arundo donax L.). Here we show that stands of giant reed are associated with abiotic and biotic conditions that are favorable to tick survival, especially when compared with other nearby habitats (open pastures of buffelgrass (Pennisetum ciliare) and closed canopy native forests). Overhead canopies in giant reed stands and native riparian forests reduce daily high temperature, which was the best abiotic predictor of oviposition by engorged females. In sites where temperatures were extreme, specifically open grasslands, fewer females laid eggs and the resulting egg masses were smaller. Pitfall trap collections of ground dwelling arthropods suggest a low potential for natural suppression of tick populations in giant reed stands. The finding that A. donax infestations present environmental conditions that facilitate the survival and persistence of cattle ticks, as well or better than native riparian habitats and open grasslands, represents an alarming complication for cattle fever tick management in the United States. PMID- 22493862 TI - Sindbis virus infection alters blood feeding responses and DEET repellency in Aedes aegypti (Diptera: Culicidae). AB - Aedes aegypti (L.) (Diptera: Culicidae) female mosquitoes infected systemically with Sindbis virus (SINV) took longer than uninfected mosquitoes to locate and fully engorge on blood. On days 7 and 14 postexposure, blood feeding took 1.3 and 1.5 times longer in mosquitoes with a disseminated SINV infection, respectively. SINV dissemination did not affect the average weight of unfed Ae. aegypti, but did result in a 10 and 12% increase in blood imbibed compared with mosquitoes without a positive SINV dissemination and non-SINV-exposed mosquitoes, respectively. Ae. aegypti mosquitoes with a disseminated SINV infection fed an average of 4 h sooner than uninfected mosquitoes when offered a bloodmeal contained inside a DEET (N,N-diethyl-3-methylbenzamide) saturated (30%) bovine sausage casing. Together, these results indicate that behavioral changes in mosquito host-seeking, blood feeding and sensitivity to DEET occurred in mosquitoes after SINV infection and dissemination. PMID- 22493863 TI - Oviposition preferences of two forensically important blow fly species, Chrysomya megacephala and C. rufifacies (Diptera: Calliphoridae), and implications for postmortem interval estimation. AB - Necrophagous blow fly species (Diptera: Calliphoridae) are the most important agents for estimating the postmortem interval (PMI) in forensic entomology. Nevertheless, the oviposition preferences of blow flies may cause a bias of PMI estimations because of a delay or acceleration of egg laying. Chrysomya megacephala (F.) and C. rufifacies (Macquart) are two predominant necrophagous blow fly species in Taiwan. Their larvae undergo rather intense competition, and the latter one can prey on the former under natural conditions. To understand the oviposition preferences of these two species, a dual-choice device was used to test the choice of oviposition sites by females. Results showed when pork liver with and without larvae of C. rufifacies was provided, C. megacephala preferred to lay eggs on the liver without larvae. However, C. megacephala showed no preference when pork liver with and without conspecific larvae or larvae of Hemipyrellia ligurriens (Wiedemann) was provided. These results indicate that females of C. megacephala try to avoid laying eggs around larvae of facultatively predaceous species of C. rufifacies. However, C. rufifacies showed significant oviposition preference for pork liver with larvae of C. megacephala or conspecific ones when compared with pork liver with no larvae. These results probably imply that conspecific larvae or larvae of C. megacephala may potentially be alternative food resources for C. rufifacies, so that its females prefer to lay eggs in their presence. When considering the size of the oviposition media, pork livers of a relatively small size were obviously unfavorable to both species. This may be because females need to find sufficient resources to meet the food demands of their larvae. In another experiment, neither blow fly species showed an oviposition preference for pork livers of different stages of decay. In addition, the oviposition preferences of both species to those media with larvae were greatly disturbed in a dark environment. If we removed the larvae that had previously fed on the pork liver and let the females choose, no oviposition preference was observed; but both species still showed a preference for the larger media in the dark. This suggests that female blow flies can use visual cues to recognize larvae on the media and decide on their oviposition site. Our studies point out the effects of some biotic and abiotic factors which were previously overlooked, and remind us to reevaluate these effects on oviposition, especially when using insect developmental data to estimate PMIs. PMID- 22493864 TI - Serological evidence of tick-borne encephalitis virus infection in rodents captured at four sites in Switzerland. AB - In a previous study, the presence of tick-borne encephalitis virus (TBEV) in questing Ixodes ricinus L. ticks and in field derived ticks that engorged on small mammals (n = 9,986) was investigated at four sites located in a TBE area in Switzerland. Two of these sites were already recognized as TBE foci (Thun and Belp) and the screening of ticks revealed the presence of TBEV in ticks at a third site, Kiesen, but not at the fourth one, Trimstein. The aim here was to test another approach to detect TBE endemic areas. Sera from 333 small mammals (Apodemus flavicollis, A. sylvaticus, Myodes glareolus) captured in 2006 and 2007 at the four sites were examined for the presence of antibodies against TBEV using immunofluorescence and avidity tests. Overall the prevalence of antibodies against TBEV in rodents reached 3.6% (12/333). At two sites known as TBE foci, Thun and Belp, anti-TBEV antibodies were detected in 9.9% (9/91) and 1.6% (1/63) of rodent sera, respectively. At the third site, Kiesen, recently identified as a TBE focus by the detection of TBEV in ticks, anti-TBEV antibodies were detected in 1.8% (2/113) of rodent sera. Finally, at Trimstein, none of the examined rodent sera had antibodies against TBEV (0/66). This study shows another approach to detect TBE foci by testing antibodies in small mammal sera that is less time consuming and less expensive than molecular tools. PMID- 22493865 TI - Education, education, education! PMID- 22493866 TI - To educate or not to educate? That is the question! PMID- 22493867 TI - Modernising the Professional Qualifications Directive will make it easier for professionals to find skilled jobs across Europe. PMID- 22493868 TI - Legal, ethical and professional concepts within the operating department. AB - There are a number of desirable healthcare practices, such as the requirement for consent and confidentiality, and a respect for the patient, that are ethically sound and legally required (Staunton & Chiarella 2008). The purpose of the law is to provide a deterrent to malpractice, and compensation when things go wrong. All health professionals should be actively aware of the law and its various key concepts. These are primarily negligence, consent, accountability, confidentiality and advocacy (Watson & Tilley 2004). This article is designed to identify the concepts that are important within the operating department. Legal, ethical and professional perspectives that underpin these concepts will be discussed along with relevant case law, ethical theory and the Health Professions Council's (HPC) code of conduct. PMID- 22493870 TI - Effective procurement. PMID- 22493869 TI - Inadvertent perioperative hypothermia: a literature review. AB - Up to 70% of surgical patients develop hypothermia perioperatively. Inadvertent hypothermia can be caused by a cold operating theatre, anaesthetic effects, exposure to the environment and administration of cold intravenous or irrigation fluids. The adverse effects of unplanned hypothermia include increased blood loss, morbid cardiac events, impaired wound healing and increased mortality. Preventing unplanned hypothermia increases patient comfort and prevents associated complications. It can be achieved by simple preventative measures (Burger & Fitzpatrick 2009, Lynch et al 2010). PMID- 22493871 TI - Commercial procurement collaborative explained. PMID- 22493872 TI - The safety of medical devices. PMID- 22493873 TI - How the MHRA regulate devices. PMID- 22493874 TI - The medical device driving licence. PMID- 22493875 TI - The smoke factor: things you should know. AB - Surgical smoke is a regular hazard that the majority of perioperative personnel are exposed to. Many staff are unaware of the risks of surgical smoke and many more may take it for granted that a surgical facemask provides enough protection. This article provides detail on the composition of surgical smoke and highlights the potential dangers that theatre staff face and what could be done to protect them. It will demonstrate the potential harm for the patient with particular reference to laparoscopic procedures as these are becoming more favourable in general and gynaecological specialities and are of particular interest to the author. PMID- 22493876 TI - A critical review of the literature regarding the use of povidone iodine chlorhexidine gluconate for preoperative surgical skin preparation. AB - This paper presents a critical analysis of studies regarding the effectiveness of preoperative skin preparation solutions. The aim was to allow evidence based practice at a local level. PMID- 22493877 TI - Is the commonly told story of Lister's antisepsis a whiggish one? AB - Joseph Lister is often seen as a hero of surgery, but his famous method of antisepsis was not solely his work alone. The commonly told account of the development of antisepsis displays several characteristics of whig history. This investigation will highlight these whiggish features, showing that Lister's original antiseptic technique was not without its failures and that there were other important figures who contributed to its development. PMID- 22493878 TI - The early days of surgery for cancer of the rectum. AB - Long before being aware of tumours elsewhere along the alimentary canal, surgeons from the earliest days of the profession were all too familiar with cancer of the rectum. The vivid local symptoms of rectal bleeding and mucous discharge, bowel disturbance and then intractable local pain, and the ready detection of the growth by a finger inserted into the fundament made diagnosis all too easy and with it, of course, a hopeless outlook for the poor sufferer. Until quite recent times, treatment was entirely palliative, with the use of hot baths, emollient enemas and dilatations of the constricting growth with bougies. Opium and laudanum, (opium dissolved in alcohol), would be prescribed in advanced cases. Some bold surgeons would use the cautery--an iron heated to red heat--to burn down a fungating growth presenting at the anal margin. PMID- 22493879 TI - Understanding nurse staffing beyond the numbers. PMID- 22493880 TI - Tracking influenza in Nebraska. PMID- 22493881 TI - [Effects of different altitudes on cardiac hemodynamics and electrocardiogram of healthy male adults]. AB - OBJECTIVE: To detect the changes of cardiovascular system at different altitudes, so as to prevent and predict the susceptibility to acute mountain sickness. METHODS: The test was performed with noninvasive cardiovascular monitor and electrocardiogram in healthy male Chinese members of the 25th and 26th expeditions to the antarctic kunlun station at different altitudes (40 m, 3 650 m and 4 300 m). RESULTS: Compared with 40 m, from 3 650 m to 4 300 m, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), systemic vascular resistance (SVR), systemic vascular resistance index (SVRI) significantly increased (P < 0.05); cardiac output (CO), cardiac index (CI), stroke volume (SV), stroke index (SI), velocity index (VI), acceleration index (ACI), left ventricular ejection time (LVET) significantly decreased (P < 0.05) and pre-ejection period(PEP) decreased with no significance (P > 0.05). CONCLUSION: SVR significantly increased but contractile and blood pumping function of left ventricular decreased inversely associated with the Q-Tc interval, as the altitude is increasing. PMID- 22493882 TI - [Effect of swimming exercise on the expression of apelin and its receptor in pulmonary tissues of rats with hypoxic pulmonary hypertension]. AB - OBJECTIVE: To study the effects of swimming exercise on the expression of apelin and its receptor (APJ) system in pulmonary tissues of rats with pulmonary hypertension induced by hypoxia. METHODS: Forty-five male SD rats were randomly divided into control group, hypoxia group (seven-week) and swimming group (four week swimming group after three-week hypoxia). The animal model of hypoxic pulmonary hypertension was established by exposing the rats to isobaric hypoxic chamber (8 h/d, 6 d/w). The rats of swimming group swam 60 min/day, 7 d/week for 4 weeks after three-week hypoxia. The mean pulmonary arterial pressure (mPAP) and the mean carotid arterial pressure (mCAP) were measured by either right or left cardiac catheterization, and the weight ratio of right ventricule/left ventricle plus septum [RV/(LV + S)] were calculated. The Masson's trichrome stained lung specimens were used by light microscope to examine the vessel wall area/total area (WA/TA), vessel cavity area/total area (CA/TA) and media thickness of pulmonary arterioles (PAMT). Meanwhile, apelin/ APJ expressions were determined by Western blot and immunohistochemistry. RESULTS: (1) mPAP and RV/(LV + S) of hypoxia group were higher than those of control group by 73.6% and 31.2% (P < 0.01), and mPAP and RV/(LV + S) of swimming group were lower than those of hypoxia group by 21.1%and 8.9 % (P < 0.05), respectively. (2) Masson's trichrome staining revealed that WA/TA and PAMT of hypoxia group were higher than those of control group by 70.8% and 102%. However, WA/TA and PAMT of swimming group were lower than those of hypoxia group by 24.8% and 40.1% (all P < 0.01), respectively. CA/TA of hypoxia group was lower than that of control group by 15.1%, and CA/TA of swimming group was lower than that of hypoxia group by 10.3% (all P < 0.01). (3) Compared with control group, hypoxia group showed up regulated apelin expression and down-regulated APJ expression in pulmonary tissues (all P < 0.01). Compared with hypoxia group, swimming group showed decreased apelin expression and elevated APJ expression in pulmonary tissues (all P < 0.01). (4) Apelin localized mainly in intracytoplasm of inflammatory cell and tunica adventitia of vessel, and APJ were in vascular intima and tunica externa and plasmalemma of inflammatory cell. CONCLUSION: The improving effect of swimming exercise on hypoxic pulmonary hypertension in rats could be mediated by regulating the pulmonary apelin/APJ system. PMID- 22493883 TI - [The role of nitric oxide in ethanol postconditioning induced cardioprotection]. AB - OBJECTIVE: To investigate whether the release of nitric oxide (NO) was involved in the cardioprotection of ethanol postconditioning in isolated rat hearts. METHODS: Hearts isolated from male SD rats were subjected to 30 min of regional ischemia (occlusion of left anterior descending artery) followed by 120 min of reperfusion. Ethanol postconditioning was fulfilled through perfusion of 50 mmol/L ethanol for 15 min (at the end of cardiac ischemia for 5 min and at the beginning of reperfusion for 10 min). The rats were divided into five groups: normal, ischemia and reperfusion, ethanol postconditioning, ethanol postconditioning + L-nitro-arginine-methylester (L-NAME) and ethanol postconditioning + atractyloside. The ventricular hemodynamic parameters and lactate dehydrogenase (LDH) release during reperfusion were measured. The infarct size was measured by TTC staining method and NO content was measured by nitric acid reductase method. The expressions of Bcl-2 and Bax mRNA were detected by RT PCR analysis. RESULTS: In contrast to ischemia and reperfusion, ethanol postconditioning improved left ventricular developed pressure, rate pressure product during reperfusion, reduced LDH release and infarct size. NO content was decreased. The ratio of Bcl-2/Bax was increased. Administration of nitric oxide synthase inhibitor L-NAME or mitochondrial permeability transition pore opener atractyloside both attenuated the role of ethanol postconditioning, which inhibited the recovery of hemodynamic parameters, the decreases of LDH and infarct size. NO content was decreased further. The ratio of Bcl-2/Bax was decreased. CONCLUSION: The cardioprotection of ethanol postconditioning may be associated with reducing nitric oxide release, inhibiting the opening of mitochondrial permeability transition pore and decreasing the happening of apoptosis. PMID- 22493884 TI - [Effect of alcohol exposure during pregnancy on learning and memory and expression of cdk5 in the hippocampus of infant rats]. PMID- 22493885 TI - [Cis-CA1P inhibits tumor cell proliferation and prevents blood vessel formation]. AB - OBJECTIVE: To investigate the effects of cis-combretastatin-A1 phosphate (cis CA1P) on tumor cell proliferation, and its effects on the blood vessel formations. METHODS: MTT and IC50 values were used to assess the inhibitory effects of cis-CA1P on tumor cell proliferation. Chicken embryo chorioallantoic membrane and thoracic aorta annulations isolated from rats were used to investigate the effects of cis-CAIP on the blood vessel formation. RESULTS: Cis CA1P concentration-dependently inhibited the proliferations of several cancer cell lines, including human gastric carcinoma cell line MGC-803, human leukemic monocyte lymphoma cell line U937, human melanoma cell line A375, human colon cancer cell line HCT116, human breast carcinoma cell line MDA-MB-231, and human leukemia cell line K562. Cis-CAIP significantly decreased the formation of blood vessels in chicken embryo chorioallantoic membrane and in thoracic aorta annulations. CONCLUSION: Cis-CA1P inhibits cancer cell proliferation and prevents blood vessel formation. PMID- 22493887 TI - [The effect of the magnesium supplementation on vascular calcification in rats]. AB - OBJECTIVE: To observe the role of magnesium sulfate in vascular calcification, to explore the role and the mechanism of magnesium sulfate in vascular calcification. METHODS: The vascular calcification model was established by administration of vitamin D3 plus nicotine (VDN) in SD rats. To estimate the extent of calcification by Von Kossa staining, calcium content and alkaline phosphatase activity, osteopontin (OPN) mRNA were determined by using semi quantitative reverse-transcription polymerase chain reaction.The malondialdehyde (MDA) and nitric oxide (NO) content and activities of superoxide dismutase(SOD) were measured by biochemistry. RESULTS: A strong positive staining of black/brown areas among the elastic fibers of the medial layer in calcified aorta by Von Kossa staining, calcium content and ALP activity in calcified arteries increased by 3.9-and 3.4-fold as compared with the controls. The expression of OPN mRNA was up-regulated by 40% (P < 0.01). The lipid peroxidation products MDA in vascular were increased 2.0-fold (P < 0.01). The NO content and SOD activity were greatly decreased by 64% and 72% (P < 0.01), respectively, compared with controls. However, calcium content and ALP activity in VDN plus magnesium sulfate group were lower than those in VDN group. Low and high dosage magnesium sulfate obviously relieved degree of calcification in the cardiovascular tissues in a dosage-dependent manner (P < 0.01). CONCLUSION: Magnesium sulfate plays a role in the pathogenesis of vascular calcification by reducing vascular calcification and decreasing vascular injury. PMID- 22493886 TI - [Effect of butylphthalide on levels of glutamate and expression of NR2B in the hippocampus of rats with alcohol addiction]. PMID- 22493888 TI - [Nicotine regulates large conductance ca2+ activated K+ channels in rat coronary arterial smooth muscle cells]. AB - OBJECTIVE: The present study was to explore signaling mechanisms underlying nicotine-induced inhibition of large-conductance calcium-activated potassium channels (BK(Ca)). METHODS: 8 week male Wistar rats were divided randomly into saline group and nicotine group and received respectively injection with saline or nicotine (Sigma, Shanghai, China) at 2 mg/(kg x d) for 21 days. Coronary vascular smooth muscle cells were dissociated enzymatically. Dissociated smooth muscle cells were interfered with CPT-cAMP (100 micromol/L) or forskolin (10 micromol/L). The signal channel open dwell-time (To), close dwell-time (Tc) and open probability (Po) were recorded. RESULTS: CPT-cAMP or forskolin significantly prolonged To, shorten Tc and increased Po in saline group (P < 0.01). But in nicotine group To, Tc and Po did not been changed. CONCLUSION: This phenomenon may serve as a physiological mechanism that nicotine inhibits BK(Ca) channel activity to increase via cAMP/PKA-dependent pathway. PMID- 22493889 TI - [Cardioprotective effects of limb ischemic postconditioning by different strength and time in rabbits]. AB - OBJECTIVE: In this study, we try to find the better protocol of limb ischemia postconditioning by observing different protective effects of limb ischemic postconditioning (different strength and time windows in rabbits). METHODS: 42 healthy New Zealand rabbits were randomly divided into 7 groups (n = 6): Sham; Control (CON); Skeletal muscle postconditioning (SP); 6 min-delayed skeletal muscle postconditioning (6M-DSP); 1 min-delayed skeletal muscle postconditioning (1M-DSP); Strengthen skeletal muscle postconditioning (SSP); Weakened skeletal muscle postconditioning (WSP). Acute ischemia/reperfusion (I/R) model was induced by 45 minutes occlusion on left circumflex coronary artery (LCX) and 2 hours reperfusion in all anesthetized open-chest rabbits except the Sham. Limb ischemia was induced by external iliac arteries occlusion and reperfusion through artery clamps. The extent of myocardial infarction was assessed by triphenyltetrazolium (TTC) staining. Blood serum creatine kinase (CK) activity and lactate dehydrogenase (LDH) activity were measured at baseline,the end of ischemia, after 1 hour and 2 hours of reperfusion respectively. RESULTS: Compared with the CON, the weight ratio and area ratio of myocardial infarction size were significantly decreased by 49.97% and 43.78% in SP, by 42.32% and 42.68% in 1M-DSP, by 48.36% and 48.86% in SSP (P < 0.05). But there was no significant difference between SP and 1M-DSP and SSP (P > 0.05). Otherwise, compared with the CON, myocardial infarct size was not significantly reduced in 6M-DSP or WSP (P > 0.05). The change of CK was similar to the trend of myocardial infarct size. CONCLUSION: The limb ischemia strength of 5 mini/1 minR x 1 cycle could significantly reduce the myocardial ischemia/ reperfusion injury in rabbits, if it was achieved before myocardial reperfusion. PMID- 22493890 TI - [Study of DiBAC4(3) for dynamic measurement of embryo membrane potentials]. PMID- 22493891 TI - [Experimental study on the glutamine's intervention effect on the opening of permeability transition pore in myocardial mitochondrial membrane]. AB - OBJECTIVE: To explore the intervention effect and the possibly mechanism of the glutamine (Gln) on the opening change of the permeability transition pore (PTP) in the myocardial mitochondrial membrane under the overtraining state. METHODS: 30 SD rats were randomly divided into 3 groups (n = 10): control group (CG group), overtraining group (OG group) and supplementary (Gln) + overtraining group group). Spectrophotometry was used to test the openness of the permeability transition pore in the myocardial mitochondrial membrane. Electrochemistry was used to test the malondialdehyde (MDA) and the glutathione (GSH) content and the phospholipase A2 (PLA2) activity. RESULTS: OG group compared with the GOG group, the absorbance (A0) and the absorbance change (Delta A) were decreased significantly (P < 0.05). Rh123 fluorescence (F0) intensity was significantly increased (P < 0.05). Rhodamine123 (Rh123) fluorescence change (delta F) was significantly decreased (P < 0.05). Compared with the GOG, the mitochondrial GSH was significantly decreased (P < 0.05), the PLA2 activity and the content of MDA were significantly increased (P <0.05). CONCLUSION: Overtraining could lead to opening increase of permeability transition pore in the myocardial mitochondrial membrane, after overtraining, the production of the reactive oxygen species (ROS) and PLA2 activity were increased, GSH content was decreased. But added exogenous Gln had a significant intervention effect for these changes. PMID- 22493892 TI - [Effect of hyperbaric oxygen on the expression of nitric oxide synthase mRNA in cortex after acute traumatic cerebral injury]. AB - OBJECTIVE: To investigate the effect of hyperbaric oxygen (HBO) treatment on the expression of nitric oxide synthase (NOS) mRNA in cortex after acute traumatic cerebral injury, and to study the mechanism of HBO on brain injury. METHODS: Acute traumatic brain injury model was established with rest received free fall injury method in SD rats. 0.25 MPa HBO treatment was used 1 h or 12 h after brain injury and the cortex was isolated 6 h or 24 h after brain injury respectively. The expression of mRNA coding for nNOS, eNOS or iNOS were assayed using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The expression of nNOS, eNOS and iNOS mRNA were significantly decreased in 0.25 MPa HBO treatment groups than those in acute cerebral injury groups (P < 0.01). The amount of nNOS, eNOS and iNOS mRNA was significantly lower in HBOT 24 h group than those in HBOT 6 h group (P < 0.05, P < 0.01). There was no significantly difference among nNOS, eNOS and iNOS mRNA in 0.25 MPa normoxic hyperbaric nitrogen groups and acute cerebral injury groups (P > 0.05). CONCLUSION: HBO may exert significant effects on the expression of nNOS mRNA/iNOS mRNA and protect cortical neuronal from traumatic cerebral injury. PMID- 22493893 TI - [Therapeutic efficacy of hyperbaric oxygen on traumatic brain injury in the rat and the underlying mechanisms]. AB - OBJECTIVE: To investigate the effects of hyperbaric oxygen (HBO) treatment on the activation of astrocytes and the expression of glia-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) in the brain after traumatic brain injury (TBI). METHODS: 54 male SD rats were randomly divided into three groups (n = 18): sham-operated, TBI and HBO treatment groups. TBI was induced with Feeney's method, bone window was opened without strike on the brain tissue in the sham operated group. HBO group rats received HBO treatment for 60 min in the hyperbaric chamber containing O2 100% at 3 ATA. When neurological functions were measured 48 h after TBI, rats were decapitated, the brain water content of 18 rats was measured, 18 brains were sliced for the morphological observation after Nissl staining and for the immunohistochemistry staining of astrocyte markers glial fibrillary acidic protein (GFAP), vimentin and S100, and the other 18 brains of injured side were used for Western blot analysis of GDNF and NGF. RESULTS: HBO treatment reduced the neurological deficit, brain water content and hippocampal neuronal loss. In the observed cortex and hippocampal area astrocytes were activated, the cell number of positive expression of astrocyte markers GFAP, vimentin and S100 was increased, and the expression of GDNF and NGF was elevated after TBI. However, these indices were all enhanced further after the HBO treatment. CONCLUSION: It is suggested that HBO may be an effective therapy for TBI and upregulation of the expression of GDNF and NGF may underly the effect of HBO. PMID- 22493894 TI - [Effect of electrical stimulation of the entopeduncular nucleus on the neuronal activities of pedunculopontine nucleus in rats]. PMID- 22493895 TI - [The role of the spinal cord inducible nitric oxide synthase in morphine dependence and naloxone-precipitated withdrawal rats]. AB - OBJECTIVE: To explore if induced nitric oxide in the spinal cord mediates withdrawal syndrome in morphine-dependent rats. METHODS: Male SD rats weighing 200-250 g were employed in the present study. To set up morphine dependence model, rats were subcutaneously injected with morphine (twice a day, for 5 d). The dose of morphine was 10 mg/kg in the first day and was increased by 10 mg/kg each day. On day 6, 4 h after the injection of morphine (50 mg/kg), morphine withdrawal syndrome was precipitated by an injection of naloxone (4 mg/kg, ip). Inducible nitric oxide synthase (iNOS) inhibitors aminoguanidine (AG) was intrathecally injected 30 min before the administration of naloxone. All the rats were divided into four groups: control group, dependence group, withdrawal group, AG group. Morphine withdrawal score, touch evoked agitation scores (TEA scores), immunohistochemical and Western blot technique were used to evaluate morphine withdrawal response and the expression of iNOS in the spinal cord. RESULTS: Intrathecal injection of iNOS inhibitors AG could alleviate morphine withdrawal symptoms. Morphine withdrawal scores and touch evoked agitation scores in AG group were significantly lower than that of withdrawal group (P < 0.05). iNOS positive neurons in dorsal horn of AG group were significantly lower than that of withdrawal group (P < 0.05). Level of iNOS protein in spinal cord of AG group was significantly lower than that of withdrawal group (P < 0.05). CONCLUSION: Induced nitric oxide in the spinal cord may mediate withdrawal syndrome in morphine dependent rats. PMID- 22493896 TI - [Influence of salidroside from Rhodiola Sachalinensis A. Bor on some related indexes of free radical and energy metabolism after exercise in mice]. AB - OBJECTIVE: To study the anti-fatigue mechanism of salidroside from Rhodiola SachalinensisA.Bor (SRS)in anti-oxidation and energy metabolic systems in mice , some related indexes of free radical and energy metabolism after exercise were measured. METHODS: Forty male mice were divided into four groups (n = 10): SRS sport group(SS), SRS quiet group(SQ),sport control group(SC), quiet control group (QC). The mice of SS and SQ groups received SRS solution of 150 ml/kg body weight per day for two weeks, while the mice of SC and QC groups received the same volume of distilled water. 30 min after the last treatment, the mice of SS and SC groups were forced to swim for 120 min without loads. then the biochemical parameters related to fatigue were determined. RESULT: SRS could increase liver superoxide dismutase (SOD) , glutathione peroxidase (GSH-Px) activity of antioxidant enzymes and reduce the malondialdehyde (MDA) content, which might increase the body activity of antioxidant enzymes to play the role of anti oxidation; SRS had some effect of stabilizing blood sugar, increasing liver glycogen and muscle glycogen reserves, preventing blood sugar, liver glycogen and muscle glycogen levels from reducing in long time exercise on mice; SRS could increase plasma total cholesterol (TC), triglyceride (TG) and free fatty acid (FFA) levels in exercise mice, and it had some effect on metabolism of fat under different conditions, and promoted the use of the role of fat. CONCLUSION: Influence of SRS on some related indexes of free radical and energy metabolism is one of the mechanisms of anti-exercise-induced fatigue of SRS. PMID- 22493897 TI - [Reactivity to substance P of isolated lymphatics in hemorrhagic shock rat]. AB - OBJECTIVE: To observe the change of lymphatic reactivity to substance P (SP) during the process of hemorrhagic shock (HS) with a technique of lymphatic perfusion in vitro in this study. METHODS: Male Wistar rats were randomly divided into control group (surgical procedure only) and HS group (the rats in this group were further divided into five subgroups: shock 0 h, 0.5 h, 1 h, 2 h and 3 h groups after duplicating the HS model with method of bloodletting to mean arterial blood pressure was 40 mmHg through the femoral venous). Thoracic ducts were separated from HS rats at the corresponding time points in each group. A segment of thoracic duct was pressed and perfused in vitro at transmural pressure of 3 cm H2O, and then stimulated with gradient SP respectively. The end systolic diameter, end diastolic diameter, contraction frequency (CF) and passive diameter of isolated lymphatics were measured, while the contraction amplitude (CA), tonic index (TI) and fractional pump flow (FPF) were calculated, and the different values between pre- and post- administration of SP of CF, CA, TI and FPF were calculated and expressed as Delta CF, Delta TI, Delta CA and Delta FPF to further assess the reactivity of lymphatics. RESULTS: After SP incubation, the Delta CF, Delta TI, Delta CA and Delta FPF of 0 h- and 0.5 h shocked lymphatics were significantly increased when compared with that of control group on one or several concentrations. The Delta CF (at 3 x 10(-7) mol/L of SP) and Delta TI (1 x 10(-7) mol/L) of 2 h- shocked lymphatics and the Delta CF (1 x 10(-7) mol/L, 3 x 10(-7) mol/L), Delta TI (1 x 10(-7) mol/L) and Delta CA (1 x 10(-7) mol/L) of 3 h- shocked lymphatics were all significantly reduced when compared with control group. CONCLUSION: The reactivity of lymphatics to SP presented a biphasic change during the process of HS: increase in early phase and decline in later stage. PMID- 22493898 TI - [Effects of aerobic exercise training on the changes of endothelium-dependent relaxations in rat thoracic aorta rings and its mechanisms]. PMID- 22493899 TI - [Effects of alpha-linolenic acid on inflammation and oxidative stress in the diabetic rats]. AB - OBJECTIVE: To investigate the effects of alpha-linolenic acid (ALA) on inflammation and oxidative stress in the diabetic rats. METHODS: An experimental type 2 diabetes mellitus model was induced by feeding male SD rats with diet of high fat for 4 weeks and then injected them intraperitoneally with streptozocin (STZ) at 30 mg/kg. Then the animals were randomly divided into three groups (n = 10): control group, diabetic group and ALA group. Four weeks later, tumor necrosis factor (TNF)-a, soluble P-selectin (sP-selectin), soluble intercellular adhesion molecule-1 (sICAM-1), nitric oxide (NO) production, malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) in the serum were determined. RESULTS: Inflammatory agents including TNF-alpha, sP-selectin and sICAM-1 increased in diabetic rats to compare with control group. Treatment with ALA significantly decreased TNF-alpha, sP-selectin and slCAM-1 to compare with diabetic group. Furthermore, compared with control group, serum MDA production increased whereas NO production, SOD and CAT activities decreased in diabetic rats. Treatment with ALA reduced MDA production, increased NO production, promoted SOD and CAT activities compared with diabetic group. CONCLUSION: These results indicate that diet rich in ALA exerted the anti-inflammatory and anti oxidative effects in diabetic rats, which may be beneficial to the prevention and treatment of diabetes. PMID- 22493900 TI - [Effect of irbesartan on the proliferation, apoptosis and VEGF mRNA expression of human umbilical vein cell line ea. hy926 in vitro]. AB - OBJECTIVE: To evaluate the effect of irbesartan on the proliferation, apoptosis, and VEGF mRNA expression of human umbilical vein cell line EA.hy926 in vitro. METHODS: The human umbilical vein cell line EA.hyY926 were treated with various concentrations of irbesartan for 24 h. The cell proliferation after the treatment was detected by CCK8 assay, flow cytometry and FITC Annexin V/PI kit were used to detect changes in the cell apoptosis. RT-PCR was used to evaluate the expression of VEGF mRNA. RESULTS: There were no changes in cell shape with various concentration of irbesartan. CCK-8 assay showed a greater rate of the cell proliferation in irbesartan group than that in control group with a dose independent manner after 24 h treatment. After incubation with irbesartan, cell proliferation rate was significant (P < 0.05). FCM analysis showed no significantly changes in the cell apoptosis. Irbesartan increased the proliferation of EA.hy926 cells. At concentration of 1 x 10(-4), 1 x 10(-5), 1 x 10(-6) mol/L, VEGF mRNA expression enhanced either (P < 0.05). CONCLUSION: Irbesartan could promote the proliferation and up-regulated VEGFmRNA expression in EA.hy926 cell line. This result suggested that in addition to antihypertensive effect, angiotensin receptor antagonist might be a novel therapeutic approach to chronic ischemic heart disease as heart failure. PMID- 22493901 TI - [The change of immunoreactivity in glia cells and its sense by using early Parkinson's disease rat model]. PMID- 22493902 TI - [Role of endotoxin translocation on mesenteric lymph reperfusion aggravating multiple organ injury in SMAO shock rats]. AB - OBJECTIVE: To investigate the role of mesenteric lymph reperfusion (MLR) aggravates multiple organs injury in superior mesenteric artery occlusion (SMAO) shock and its mechanism. METHODS: Twenty four Wistar rats were randomly divided into 4 groups (n = 6): Sham group (only anesthetized and operated), MLR group rats performed 1 h occlusion of mesenteric lymph duct (MLD), then followed by 2 h of reperfusion, SMAO group (rats performed 1 h occlusion of superior mesenteric artery (SMA) and then followed by 2 h of reperfusion), SMAO + MLR group (rats performed 1 h occlusion of SMA and MLD and then followed by 2 h of reperfusion). The blood sample was taken out from abdominal aortic for plasma and the liver, kidney, myocardium, lung tissues in fixed position were prepared for making homogenate after reperfusion of 2 h respectively. And the levels of endotoxin (ET) in plasma and homogenates were determined with kinetic turbidimetric technique of tachypleus amebocyte lysate, the contents of lipopolysaccharide binding protein (LBP), lipopolysaccharide receptor (CD14) and tumor necrosis factor-alpha (TNF-alpha) in homogenates were determined with enzyme-linked immunosorbent assay method. RESULTS: The indices have no statistics difference between sham group and MLR group. The ET levels of the plasma and hepatic, renal, myocardial, pulmonary homogenates in SMAO and SMAO + MLR groups were significant higher than that of sham and MLR groups, and these indices in SMAO + MLR were increased significantly than those in SMAO group. The CD14, LBP and TNF-alpha contents of the hepatic, renal, myocardial and pulmonary homogenates in SMAO and SMAO + MLR groups were significant higher than those in sham and MLR groups, and these indices in SMAO+ MLR were higher than SMAO group significantly. CONCLUSION: The mechanism of MLR aggravates multiple organs injury in SMAO shock may be associated with enterogenous ET through intestinal lymphatic pathway to translocate, activate the LBP/CD14 as endotoxin sensitizing system and promote inflammatory response. PMID- 22493903 TI - [Role of P38-MAPK signal transduction pathway and effect of panax notoginoside in rats with hypoxic hypercapnia pulmonary hypertension]. AB - OBJECTIVE: To investigate the role and significance of P38-MAPK in the pathological process of hypoxic hypercapnia pulmonary hypertension in rats, and the protection of panax notoginoside (PNS). METHODS: (1) To set up rat pathological model of hypoxic hypercapnia pulmonary hypertension: seventy two male SD rats (200 280 g) were randomly divided into six groups (n = 12), which were normal group (N group), hypoxic hypercapnia for 3-day group (H3d), hypoxic hypercapnia for 1-week group(H1w), hypoxic hypercapnia for 2-week group (H2w), hypoxic hypercapnia for 4-week group (H4w) and PNS-injected group (Hp). The rats of PNS -injected group were injected PNS before being placed in the chamber (50 mg/(kg x d), ip), and other groups were injected normal sodium (2 ml/kg, ip). (2) The shapes of pulmonary artery were detected by HE staining. (3) Western blot was used to study the protein expression of p38-MAPK. The expression of p38-MAPK in lung tissue and pulmonary blood vessel was investigated by immunohistochemistry. RESULTS: (1) The ratio of vessel wall area/total area (WA/ TA) in H1w, H2w, H4w and Hp group was higher than that of N group (P < 0.05), but that of H3d group did not change obviously (P > 0. 05 vs N group). The ratio of WA/TA in Hp group was obviously lower than that of H4w, group (P < 0.05). (2) The levels of P-p38 protein was markedly ascended in H3d group (0.225 +/- 0.071) compared with N group (0.012 +/- 0.006), and expression of P-p38 protein was significantly positive in H1w, H2w, H4w groups. (P < 0.05). (3) As P-p38 protein in pulmonary arterial tunica intima and tunica media, sterile expression in N group (0.099 +/- 0.015) and H3d group (0.107 +/- 0.013) contrasted to H4w group (0.124 +/- 0.025, P < 0.05), then tended to rise in H2w, H4w group (P < 0.05). (4) In pulmonary tissue, the levels of P-p38 protein in PNS-injected group were lower 53.02% (P < 0.05) than those in H4w group. In pulmonary arterial tunica intima and tunica media the levels of P-p38 protein in PNS-injected group were lower 87.33% (P < 0.05) than those in H4w group. CONCLUSION: p38-MAPK as a signal transduction may play an important role in the development of hypoxia induced pulmonary hypertension. The effect of PNS on reducing pulmonary hypertension and improving pulmonary vascular wall remodeling may be related to its inhibiting expression of p38 MAPK. PMID- 22493904 TI - [Zinc supplementation effects on alcoholic liver disease and the molecular mechanism]. AB - OBJECTIVE: To examine dietary zinc supplementation could alleviate the damage of alcoholic liver disease and the relationship with the expression of hepatocyte nuclear factor 4alpha (HNF-4alpha). METHODS: 40 adult C57 BL/6 mice were randomly divided into four groups (n = 10): control, zinc, ethanol and zinc plus ethanol, which were sacrificed after fed four different diets for 6 months. Zinc sulfate was added in the drinking water of the Zinc and Zinc Plus Ethanol group and the content was 75 mg/L. Liver regeneration was assessed by immunohistochemical staining of proliferating cell nuclear antigen (PCNA), and the expression of HNF 4alpha was determined by RT-PCR and Western blot. And as to assess the status of oxidative stress of the mice, malondialdehyde (MDA) and superoxide dismutase (SOD) were detected. RESULTS: Compared with the control group, the expression level of HNF-4alpha decreased significantly in the ethanol group (P < 0.05), and the content of MDA increased significantly in this group, while the content of SOD declined significantly (P < 0.05). Compared with the ethanol group, the number of PCNA-positive hepatocytes increased significantly, and the expression level of HNF-4alpha also increased in the zinc plus ethanol group (P < 0.05), and the content of SOD increased in this group, while MDA decreased significantly (P < 0.05). CONCLUSION: Long term ethanol exposure can lead to oxidoreduction imbalances which can be reversed by zinc supplementation. We suppose that zinc enhanced liver regeneration is associated with an increase in HNF-4alpha, suggesting that dietary zinc supplementation may have beneficial effects in alcoholic liver disease. PMID- 22493905 TI - [The metabolism characteristics of blood lipids and the correlation analysis of blood lipids and related factors such as age in the middle-aged and elderly men]. AB - OBJECTIVE: To investigate the relationship between the blood lipids and risk factors such as age in middle-aged and elderly men. METHODS: 1603 men aged over 50 years old who took health examinations in June 2006 in the Chinese PLA General hospital were taken into the study. The total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), fasting serum glucose (FBG), serum creatinine (Cr) and blood uric acid (UA) were detected, and the clinical data such as age, body height, body weight and blood pressure were recorded. RESULTS: (1) The detection rates of hyperlipidemia, abnormal TC, abnormal TG, abnormal HDL-c and abnormal LDL-c were 56.27%, 36.74%, 28.20%, 10.79% and 6.92% respectively, and the TC and/or TG abnormality were the majority. (2) Compared with the 50 59 years old group, the elderly men aged over 80 years old had lower detection rates of abnormal TC and abnormal HDL-c, lower levels of TC and TG and higher levels of HDL-c (P < 0.05). After adjusting for BMI, SBP, DBP, UA, FBG and CCr, the multiple regression analysis showed that the levels of TC and TG decreased by 0.097 mmol/L and 0.087 mmol/L respectively every 10 years older, while the level of HDL-c increased by 0.113 mmol/L. CONCLUSION: The study showed that the majority types of hyperlipidemia in middle-aged and elderly men were abnormal TC and abnormal TG. The levels of TC, TG were correlated with age positively and the HDL-c was negatively correlated with age. The blood lipids metabolism characteristics of elderly men aged over 80 years old should be considered before the treatment of hyperlipidemia. PMID- 22493906 TI - [Deconstruction of the clinical research model for acupuncture effects]. AB - To explore the many links that impact acupuncture-moxibustion effect and to analyze the questions existed in the clinical research methodology in terms of the research direction and characteristics of acupuncture and moxibustion, so as to propose the features of multi-factor complex in the research on the clinical effects of acupuncture and moxibustion. Eventually, a set of perfect methodology can be established for the clinical research of acupuncture and moxibustion on the basis of multivariate statistical analysis. PMID- 22493907 TI - [Moxa stick on garlic for treatment of plantar warts]. PMID- 22493908 TI - [Double-center randomized controlled trial on post-stroke shoulder pain treated by electroacupuncture combined with Tuina]. AB - OBJECTIVE: To evaluate clinical therapeutic effect of post-stroke shoulder pain treated by acupuncture combined with Tuina. METHODS: Three hundred cases of post stroke shoulder pain were randomly divided into an acupuncture and Tuina group and a rehabilitation group by double-center randomized controlled clinical trial method. In acupuncture and Tuina group, normalized electroacupuncture and Tuina therapy were applied, that was electroacupuncture at main points, such as Chize (LU 5), Quze (PC 3), Shaohai (HT 3), Jianyu (LI 15), Jianliao (TE 14) and Jianjing (GB 21),etc., combined with traditional Tuina manipulations; in rehabilitation group, the rehabilitation methods such as the electrostimulation through nervus cutaneus and the squeezing and stabilizing manipulations of Proprioceptive Neuromuscular Facilitation (PNF), etc. were applied. The treatment courses of both groups were 6 weeks. The main therapeutic effect indices were the Assessment Face Scale (AFS) for pain when shoulder was in passive motion and the Fugl-Meyer Motor Assessment for upper limbs active function; the secondary indices were the moditied Rankin Scale (mRS) and the clinical incidences of shoulder-hand syndrome of hemiplegia and shoulder joint subluxation of hemiplegia. RESULTS: After 6 weeks treatment and 12 weeks follow-up, AFS score, Fugl-Meyer motor assessment of upper limbs active function and mRS evaluation in acupuncture and Tuina group were more obviously improved than those in rehabilitation group (P < 0.05, P < 0.01). Although the clinical incidences of shoulder-hand syndrome of hemiplegia and shoulder joint subluxation of hemiplegia in acupuncture and Tuina group was equal to those in rehabilitation group [3.55% (5/141) vs 8.45% (12/142), 1.42% (2/141) vs 5.63% (8/142), both P > 0.05], the data indicated that there was a superiority tendency in acupuncture and Tuina group. CONCLUSION: The combined therapy of electroacupuncture and Tuina is a normative manipulation, and the therapeutic effect is satisfying for post-stroke shoulder pain, superior to that of comprehensive rehabilitation treatment. PMID- 22493909 TI - [Thirty-two cases of insomnia treated with acupuncture]. PMID- 22493910 TI - [Trigeminal neuralgia of hyperactive of liver yang type treated with acupuncture at Xiaguan (ST 7) at different depth: a randomized controlled trial]. AB - OBJECTIVE: To observe the differences of therapeutic effect in primary trigeminal neuralgia (PTN) of hyperactive of liver yang type treated by deep and shallow puncturing at Xiaguan (ST 7). METHODS: Sixty-three cases of PTN of hyperactive of liver yang type were randomly divided into a deep puncturing group (32 cases) and a shallow puncturing group (31 cases). Xiaguan (ST 7) of affected region, Hegu (LI 4) and Taichong (LV 3) of bilateral sides, Cuanzhu (BL 2), Sibai (ST 2) and Jiachengjiang (Extra) relevant to the affected branch of nerve stem were selected in both groups. In deep puncturing group, Xiaguan (ST 7) was punctured to the depth of spheno-palatine ganglion (SPG); Cuanzhu (BL 2), Sibai (ST 2) and Jiachengjiang (Extra) were respectively punctured to the depth of supraorbital foramen, infraorbital foramen and mental foramen. In shallow group, routine puncturing was applied; the needles were connected with G6805 electric acupuncture apparatus, and switched on for 30 min every time; the treatment was applied every other day. Pain index, traditional Chinese medicine symptoms index and clinical therapeutic effect were observed after 2 courses of treatment. RESULTS: In deep puncturing group, the VAS scores and the traditional Chinese medicine symptoms scores (pain degree, pain frequency, upsetting, conjunctival congestion, bitter mouth and hypochondriac pain) after treatment were much more lower than those before treatment (all P < 0.01); in shallow puncturing group, except hypochondriac pain (P > 0.05), other indices above after treatment were obviously lower than those before treatment (P < 0.01, P < 0.05). Compared with the indices in both groups after treatment, the VAS scores, the pain degree, conjunctival congestion and total scores of traditional Chinese medicine symptoms in deep puncturing group were more significant (all P < 0.05). The total effective rate was 93.8% (30/32) in deep puncturing group, superior to that of 87.1% (27/31) in shallow puncturing group (P < 0.05). No any adverse reaction was observed in both groups. CONCLUSION: The therapeutic effect of trigeminal neuralgia of hyperactive of liver yang type treated with electroacupuncture is remarkable, and deep puncturing at Xiaguan(ST 7) to SPG is more effective than routine puncturing. PMID- 22493911 TI - [Fifty-six cases of Hunt facial paralysis treated by syndrome differentiation acupuncture combined with buccal mucosal bleeding]. PMID- 22493912 TI - [Effects of electroacupuncture on embryo implanted potential for patients with infertility of different symptom complex]. AB - OBJECTIVE: To explore the impacts of electroacupuncture on embryo implanted potential and its molecular mechanism in the patients with infertility of different symptom complex. METHODS: Among the patients with infertility treated with electroacupuncture and in vitro fertilization and embryo transplantation (IVF-ET), 82 cases of kidney deficiency (group A), 74 cases of liver qi stagnation (group B) and 54 cases of phlegm dampness (group C) were selected. All of the patients in three groups received long-program ovarian hyper-stimulation. Additionally, electroacupuncturecan was applied before controlled ovarian hyper stimulation (COH) and in the process of ovarian hyper-stimulation. The levels of human leukocyte antigen-G (HLA-G) in the serum were determined on the 2nd day of the menstruation (M2), on the day of human Chorionic Gonadotropin (hCG) injection and on the day of embryo transplantation in the culture solution in three groups separately. The fertilization rate, implantation rate and clinical pregnancy rate were observed for the patients in three groups. RESULTS: The levels of HLA-G in the serum on hCG injection day and in the culture solution on embryo transplantation day in group A and B were significantly higher than those in group C (all P < 0.05). But, there was no significant difference in serum HLA-G levels on M2 day among three groups. The high-quality embryo rate in either group A (73.6%, 352/478) or group B (70.6%, 379/537) was higher significantly than that in group C (54.2%, 208/384) separately, presenting statistical significant difference (all P < 0.01). But there were no significant differences in clinical pregnancy rate, fertilization rate and cleavage rate among three groups. CONCLUSION: Electroacupuncture can increase the contents of HLA-G in the body and the level of HLA-G secreted in embryos for the patients in the process of IVF-ET. Eventually, the pregnancy outcome and the pregnancy rate are improved. The clinical effects of electroacupuncture for the patients of kidney deficiency and liver qi stagnation are better than those for the patients of phlegm dampness. PMID- 22493913 TI - [Observation of the therapeutic effect on COPD of cold phlegm blocking the lung type at stable stage treated with acupoint sticking therapy in different season]. AB - OBJECTIVE: To systematically observe the clinical effect on chronic obstructive pulmonary disease (COPD) at the stable stage, differentiated as cold phlegm blocking the lung type, treated with acupoint sticking therapy during the dog days and the three nine-day periods after the winter solstice so as to propose the latest clinical idea and theoretic evidence for the treatment of COPD. METHODS: One hundred and fifty cases of COPD at stable stage, which were in accordance with the inclusive standard were randomly divided into three groups, named group A (treatment in dog days and the three nine-day periods after the winter solstice), group B (treatment in dog days) and group C (treatment in the three nine-day periods after the winter solstice), 50 cases in each group. The ingredients (Semen Brassicae, Euphoribia Kansui, Asarum, Rhizome Corydalis, Cinnamon, ginger juice) and doses of herbal medicine plaster were same in each group. The herbal plaster was applied to Feishu (BL 13), Shenshu (BL 23), Dazhui (GV 14), Tiantu (CV 22), Danzhong (CV 17) and Zhongfu (LU 1). In group B, the treatment was given once on the 1st day of each dog-day period, totally 3 treatments were included. In group C, the treatment was given once on the 1st day of each nine-day periods after the winter solstice, totally, 3 treatments were involved. In group A, the treatment was given once on the 1st day of each dog-day period and each nine-day periods after the winter solstice separately, totally 6 treatments were required. The therapeutic effect was evaluated in 4 aspects, named comprehensive clinical efficacy, survival quality (the scores for symptoms, activity limitation and influence on daily life), the attach frequency and pulmonary function. RESULTS: The total effective rate was 88.0% (46/50) in group A, which was superior to 76.0% (38/50) in group B and 70.0% (35/50) in group C separately (P < 0.01, P < 0.001). The results of the attack frequency, clinical symptom score and pulmonary function indices after treatment were all improved apparently as compared with those before treatment in each group (all P < 0.01). All the above indices in group A were improved much apparently as compared with the other two groups (P < 0.01, P < 0.001). Except for the level of forced vital capacity (FVC), the results of clinical symptom score and the other pulmonary function indices in group B were all improved significantly as compared with group C (P < 0.05, P < 0.001). CONCLUSION: Acupoint sticking therapy during different season of the year achieves a superior clinical efficacy for the patients with COPD at stable stage. This therapy can reduce the attack frequency and improve the survival quality and pulmonary function for the patients. It is concluded that the efficacy of the treatment in dog days and the three nine-day periods after the winter solstice is superior to simple dog-day treatment and the treatment in the three nine-day periods after the winter solstice, and the efficacy of dog days treatment is better than that in the three nine-day periods after the winter solstice. PMID- 22493914 TI - [Effect of aconite cake-separated moxibustion at Guanyuan (CV 4) and Mingmen (GV 4) on thyroid function in patients of Hashimoto's thyroiditis]. AB - OBJECTIVE: To explore the effects on thyroid function in patients of Hashimoto's thyroiditis treated with aconite cake-separated moxibustion and option the better therapeutic program. METHODS: Eighty-five cases were randomly divided into a moxibustion group (42 cases) and a western medication group (43 cases). The moxibustion group was treated by aconite cake-separated moxibustion therapy with acupoints of two groups [(1) Danzhong (CV 17), Zhongwan (CV 12), Guanyuan (CV 4); (2) Dazhui (GV 14), Shenshu (BL 23), Mingmen (GV 4)] alternatively and oral administration of 25 microg Euthyrox everyday. The western medication group was oral administration of 25 microg Euthyrox everyday. Indices of thyroid function before and after treatment and clinical effect were compared between two groups. RESULTS: The clinical total effective rate and effective rate of thyroid function were 25.0% (10/40), 87.5% (35/40) in moxibustion group respectively, 7.53% (3/40) and 57.5% (23/40) in western medication group, with significant differences between two groups (both P < 0.05). Content of serum free thyroxine index (FT4) increased significantly in the moxibustion group after treatment (P < 0.01); content of serum supersensitive thyrotropin (S-TSH) in the moxibustion group was lower than that of western medication group, and contents of serum FT4 and free triiodothyronine (FT3) were higher than those of western medication group, but with no significant differences (all P > 0.05). CONCLUSION: Aconite cake separated moxibustion at Guanyuan (CV 4) and Mingmen (GV 4) combined with oral administration of Euthyrox can improve clinical symptoms and thyroid function in patients of Hashimoto's thyroiditis, which is better than simple oral administration of Euthyrox. PMID- 22493915 TI - [Acupuncture at digital end combined with opposing needling for pain of head and face]. PMID- 22493917 TI - [Conversion method between local time and Beijing time]. PMID- 22493916 TI - [Analysis of therapeuttic effect of lower limb sensation disorder after lumbar disc herniation operation treated with plum-blossom needle along meridians]. AB - OBJECTIVE: To compare the differences of therapeutic effect in lower limb sensation disorder after lumbar disc herniation operation treated with plum blossom needle along meridians and Methylcobalamin with oral administration, and explore the best time for plum-blossom needle intervention. METHODS: Eighty cases of lower limb sensation disorder caused by nucleus pulposus discectomy of lumbar disc herniation were randomly divided into a plum-blossom needle group (40 cases) and a western medication group (40 cases). In plum-blossom needle group, tapping with plum-blossom needle along meridians was received, the meridians located at sensation areas which were dominated by relevant segmental nerve root in operation were selected: the lower limb section of the Spleen Meridian of Foot Taiyin was selected for operation at L3/L4; the lower limb section of the Gall Bladder Meridian of Foot-Shaoyang was selected for operation at L4 /L5; the lower limb section of the Bladder Meridian of Foot-Taiyang was selected for operation at L5/S1; once treatment was applied every 3 days, and 20 times treatments were applied totally. In western medication group, Methylcobalamin was orally taken for 500 microg, 3 times a day. The recovery of lower limb sensation disorder was evaluated and compared by the comprehensive evaluation method of sensory function of body nerve after 2 months in both groups. RESULTS: The total effective rate was 90.0% (36/40) in plum-blossom needle group, superior to that of 60.0% (24/40) in western medication group (P < 0.05). In plum-blossom needle group, the effect for the cases which received treatment within one month after operation was superior to that received treatment during 1-3 months after operation (P < 0.05); and there was no significant differences between the cases which received the treatment during 1-3 months after operation and more than 3 months after operation (P > 0.05). CONCLUSION: The therapeutic effect of lower limb sensation disorder after lumbar disc herniation operation treated with plum-blossom needle along meridians is superior to that of Methylcobalamin with oral administration; the plum-blossom needle intervention within one month after operation can receive the best effect. PMID- 22493918 TI - [Regular pattern of pain reaction by pressing along the Governor Vessel on the back in patients with digestive system disease]. AB - OBJECTIVE: To find out the regular pattern of pain reaction by pressing along the Governor Vessel at the levels of T3 to L4 on the back in patients with digestive system disease, so as to provide references for diagnosis of the disease. METHODS: Thirty patients diagnosed with digestive system disease by gastroscopy and colonoscopy as well as 16 patients with digestive symptoms without accurate diagnosis by endoscopy checks were observed. Pressing was applied from Zhiyang (GV 9) to Yaoyangguan (GV 3), including non-acupoints along the Governor Vessel. Positive reaction was recognized since pain, soreness or distension sensation appeared in the space between the spinous process. RESULTS: The positive ratios of 30 patients with endoscopy checks and 16 without the check accounted for 100.0%. The tender spots, usually 5 to 9 in number, were mainly focused on the relative acupoints and non-acupoints along the Governor Vessel from T6 to T10. CONCLUSION: The pain reaction from Lingtai (GV 10) to Zhongshu (GV 7), which are at the level of T6 to T10, along the Governor Vessel is closely related with digestive system disease. And it can be regarded as function criterion of the digestive system and important reference of auxiliary diagnosis. PMID- 22493919 TI - [Characteristics of anatomical structures and clinical significance of lumbar Jiaji (EX-B 2) points]. AB - OBJECTIVE: To observe the anatomical structure of Jiaji (EX-B 2) points at the level of lower lumbar region so as to provide evidence for the insertion angle and depth. METHODS: Thirty spine samples of male adults were adopted, and perpendicular insertion of the needle was applied at 3 locations including 1 cun, 0.5 cun and 0.3 cun lateral to the lower border of the spinous process of the lumbar vertebra. The needles were fixed at the local region. Structures and the adjacent major blood vessels and nerves were observed during the anatomy. RESULTS: When the needle was inserted perpendicularly at the point 1 cun lateral to the lower border of the spinous process of the lumber vertebra with the insertion depth of (35.77 +/- 5.86) mm, the zygapophyseal joints, the adjacent osteo-fibrous canal and osteo-fibrous aperture were touched by the tip of the needle, and the medial ramus of dorsal primary ramus of spinal nerve and concomitant vessels were stimulated. Then, needles were inserted perpendicularly 0.5 cun and 0.3 cun lateral to the lower border of the spinous process of the lumber vertebra with the insertion depth of (32.89 +/- 4.79)mm for both. When needle was inserted 0.5 cun lateral, the medial ramus of dorsal primary ramus of spinal nerve and the concomitant vessels were touched by the tip of the needle at where they across the lamina periosteum and erector spinae. When needle was inserted 0.3 cun lateral, the body of the needle reached the terminal branches of the medial ramus of dorsal primary ramus of spinal nerve and the concomitant vessels through the deep paraspinal muscles and the thoracolumbar fascia. CONCLUSION: The medial ramus of dorsal primary ramus of lumbar spinal nerve and concomitant vessels distributed at the region 1 cun, 0.5 cun and 0.3 cun beside the lower border of each lumbar spinous process. Therefore, the location of Jiaji (EX-B 2) points can be considered in the region from 0.3 cun to 1 cun beside the lower border of each spinous process. PMID- 22493920 TI - [Acupuncture combined with core stability training for 35 cases of knee osteoarthritis]. PMID- 22493921 TI - [Study on point location of Lieque (LU 7) based on anatomy]. PMID- 22493922 TI - [Effects of electroacupuncture at "Neiguan" (PC 6) on p38 MAPK signaling pathway in rats with cardiac hypertrophy]. AB - OBJECTIVE: To discuss the mechanisms of electroacupuncture at "Neiguan" (PC 6) on p38 MAPK signaling pathway in rats with cardiac hypertrophy. METHODS: Forty SD rats were randomly divided into four groups: a normal group, a model group, a model plus p38 MAPK inhibitor group, a model plus electroacupuncture group, ten rats in each group. The model rats were established by subcutaneous injection 3 mg/(kg x d) of Isoprenaline Hydrochloride; model plus p38 MAPK inhibitor group were injected 0.3 mg/(kg x d) of specific inhibitor SB 203580; model plus electroacupuncture group was treated by electroacupuncture at "Neiguan"(PC 6) with continuous-wave, 2 Hz and 1 mA for 20 minutes, once a day for 14 days. There was no treatment in other two groups. The contents of TNF-alpha and IL-1beta in heart tissue were detected by radioimmunoassay and the p38 MAPK, p-p38 MAPK by western blot. RESULTS: Compared with normal group, the contents of TNF-alpha, IL 1beta, p38 MAPK, p-p38 MAPK were significantly increased in model group (all P < 0.01). The contents of TNFalpha, IL-1beta, p38 MAPK, p-p38 MAPK were significantly decreased in model plus p38 MAPK inhibitor group and model plus electroacupuncture group, compared with model group, all P < 0.05; compared with normal group, P < 0.05, P < 0.01; but no significant difference between model plus p38 MAPK inhibitor group and model plus electroacupuncture group (P > 0.05). CONCLUSION: Electroacupuncture at "Neiguan" (PC 6) can prevent the phosphorylation of p38 MAPK of myocardial hypertrophy, and the mechanism maybe adjust p38 MAPK signaling pathway by inhibiting the expression of TNF-alpha and IL-1beta. PMID- 22493923 TI - [Antipyretic effect of moxibustion at different temperatures and its relationship with the activity of temperature sensitive neurons in thermotaxic center]. AB - OBJECTIVE: To discover the central mechanisms of antipyretic effect of moxibustion and its relationship with the acupoint sensor so as to provide the scientific evidence for "the treatment of heat syndrome with moxibustion". METHODS: Eighteen New Zealand Rabbits were randomly assigned into three groups, named group A (modeling with intravenous injection of Endotoxin), group B (moxibustion at 40 degrees C after Endotoxin injection) and group C (moxibustion at 48 degrees C after Endotoxin injection), 6 rabbits in each one. The experiment was undergoing in the condition of muscular relaxation and artificial respiration for the animals. The spotlight moxibustion at constant temperature was applied to "Zhiyang" (GV 9). The discharge of heat sensitive neurons (HSNs) at the preoptic region and anterior hypothalamus (POAH) was taken as the index. The impacts of the treatment on HSNs were observed in each group. RESULTS AND CONCLUSION: Moxibustion had significant antagonism to the pyrogen on its inhibition to the activity of HSNs in the thermotaxic center. As a result, the antipyretic effect was obtained. It is concluded that the effective result of moxibustion is achieved by stimulating polymodal receptors of acupoints. PMID- 22493924 TI - [Experience and discussion on the national standard Standardized Manipulation of Acupuncture and Moxibustion. Part 8: Intradermal Needle]. AB - Standardized Manipulation of Acupuncture and Moxibustion Part 8: Intradermal Needle was compiled with the following principles. The compiling standard, technical features and clinic manipulations of intradermal needle were taken as the basic principle for compiling. Literature research, expert survey and clinic practice verification were applied as the drafting methods. The key issues were focused on the relationship between standardization and individualization, normalization and effectiveness, qualification and quantification. And the postural selection, reinforcing and reducing manipulations, fixing materials and embedding duration involved in intradermal needling were emphasized particularly. At the same time, details and the future way of thinking of intradermal needle were expounded in this article as well. PMID- 22493925 TI - [Effect of Tuina at breast on postpartum lactation]. AB - OBJECTIVE: To explore the efficacy of Tuina for postpartum lactation and work out a optimal protocol involved. METHODS: With a randomized, controlled and clinical method, 84 primiparas were divided into a Tuina group and a control group. While patients in the control group received rooming-in conventional managements, those in the Tuina group were additionally treated with Tuina, including local manipulations on breasts combined with acupoint manipulations. The colostrum time, lactation quantity and prolactin were observed to make the comparisons between two groups. RESULTS: The scores of lactation quantity after 1th, 2nd, 3rd of the treatment were 1.660 +/- 0.785, 2.530 +/- 1.030, 2.880 +/- 1.171 in Tuina group and 1.270 +/- 0.533, 1.460 +/- 0.811, 1.500 +/- 0.583 in control group respectively, where there were significant differences in each time stage between two groups (all P < 0.001). The time of colostrum was (21.6 6 +/- 10.508) h in the Tuina group and (22.5 +/- 9.762) h in the control group, in which the difference was not statistically significant (P > 0.05). The levels of prolactin (314.35 +/- 110.37) ng/mL and (321.56 +/- 109.61) ng/mL in Tuina group, (385.78 +/- 85.19) ng/mL and (340.12 +/- 103.10) ng/mL in control group before and after treatment, there were no significant differences (both P > 0.05). CONCLUSION: Postpartum Tuina on breasts could increase the quantity of lactation and delay the decreasing of the levels of prolactin, which contributes primiparas to lactate more and sooner. PMID- 22493926 TI - [Observations and countermeasures on adverse reaction of acupoint sticking used treating winter disease in summer]. PMID- 22493927 TI - [Treatment of infantile asthma in remission stage with Chinese medicine and new moxibustion-massage apparatus]. AB - OBJECTIVE: To compare differences of effects between new moxibustion-massage apparatus and suspended moxibustion for infantile asthma. METHODS: Sixty patients were divided into 2 groups randomly, observation group and control group, 30 cases in each. Tiaoyuan Yuping Decoction, a decoction made by the hospital, was applied for both groups. New moxibustion-massage apparatus was applied for the observation group, and suspended moxibustion was adopted for the control group. Moxibustion was applied on acupoints of Fengmen (BL 12), Feishu (BL 13), Geshu (BL 17), Pishu (BL 20), Juque (CV 14) and Zhongwan (CV 12) for 3 months, and therapeutic effect was observed. RESULTS: The remarkably effective rate of the observe group is 66.7% (20/30) and the total effective rate is 90.0% (27/30), which are better than 40.0% (12/30) and 83.3% (25/30) of the control group. The asthma of attack of both groups after the treatment obviously decreased (both P < 0.05). The asthma of attack of the observation group is obviously lower than that of the control group (P < 0.05). And the effect is approved without side-effects such as dermal infection. CONCLUSION: It is held that the combination of new moxibustion-massage apparatus and Chinese medicine for infantile asthma in remission stage has obvious therapeutic effect, which can reduce the attack of asthma and alleviate symptoms. The result is better than suspended moxibustion. PMID- 22493928 TI - [Acupuncture and massage therapy for 23 cases of pharyngitis caused by cervical vertebra disease]. PMID- 22493929 TI - [Analysis on meridian view of professor CHENG Dan-an]. AB - To collect and arrange the explanations of meridian theory of professor CHENG Dan an at different stages, and analyze the point, value and connotation of views of meridian theory of professor CHENG Dan-an. Affected by western medicine, professor CHENG Dan-an once expounded the views of meridian theory from blood vessel and nerves, and eventually returned the study to tradition. Moreover, he held on that meridian theory was the key point of acupuncture foundation and clinic was the important perspective for meridian theory understanding and researching. PMID- 22493930 TI - [ Current situation of the development of acupuncture and moxibustion in Madagascar]. AB - The development of acupuncture and moxibustion therapy in Madagascar is introduced briefly in this paper. Acupuncture and moxibustion therapy was introduced to Madagascar in 1975 by China Medical Aid Team. China Medical Aid Team had established acupuncture and moxibustion department in four hospitals, with 10 to 20 treatment beds. Taking Vatomandry Hospital and Sambava Hospital as the examples to introduce the general situation and the current questions in acupuncture-moxibustion department of comprehensive hospitals in Madagascar, so as to explore the future development potential of acupuncture-moxibustion therapy in the country. PMID- 22493931 TI - [Review and reflection on 2010' Hwato Cup National University Students' Acupuncture Manipulation Skills Competition]. AB - The questionnaire and the result of 2010' Hwato Cup National University Students' Acupuncture Manipulation Skills Competition were analyzed in this paper. It was showed that the competition achieved the significant effects of enhancing acupuncture manipulation skills for the university students and promoting the standardization on teaching acupuncture manipulation skills. The teachers and students were not very satisfied with the current acupuncture manipulation skill education. In the competition, only the item of reciting the classics achieved more than 90 scores, which just displayed the memory ability. The results of the manipulation competition were generally not very high. It is suggested that concerning to teaching acupuncture and moxibustion in the future, the ratio of class time for improving the practice ability on the human body should be increased and the practice on some manipulation techniques such as inserting the needle by holding the needle tip with the pressing hand, reinforcing-reducing technique by twirling and rotating the needle and warming needle technique should be intensified. It is necessary to enhance the interpretation, emphasis and supplementation on the keys and details of some manipulations of acupuncture and moxibustion. PMID- 22493932 TI - [Discussion on knowledge structural system of modern acupuncture professionals]. AB - To explore the knowledge structural system that the modern acupuncture professionals should have. The current situation of personnel training for modern acupuncture professionals was multi-dimensionally and comprehensively analyzed from course offering of higher education, laws of famous physicians growth, and discipline development features of the acupuncture and moxibustion subject, and suggestions were made to the shortages. The reasonable knowledge structural system that the modern acupuncture professionals should have included establishment of good Chinese medicine thoughts, mastery of complete Chinese medicine therapy, and ability of followup of dynamic development of subject. The reformation of course design is imperative in order to promote the reasonable knowledge structural system formation of modern acupuncture professionals. PMID- 22493933 TI - [Modern medical explanation on Ashi points]. AB - According to the comparison between Ashi points and trigger points, a modern medical explanation that trigger points could be considered as a special Ashi points was put forward, and a further investigation on the enlightenment of theory and practice of trigger points to the pathological specificity, positioning and the intervention methods of trigger points was as follows: Ashi points could be central trigger points, whose pathology is degeneration and contracture of sarcomere; it is not always in the area of pain, while the signs of pain may be helpful for its stereotaxic positioning; the intervention methods of Ashi and trigger points can be learned from each other. This is a new angle of view on Ashi points, which has contributed to the exploration and improvement of its theory and practice. PMID- 22493934 TI - [Oxygen metabolism and meridian qi]. AB - The relationship between the state of oxygen metabolism in modern physiology and the concept of meridian qi in Chinese medicine was investigated with the theory of Chinese medicine, biomedicine and experimental medicine for exploring the essence of meridians and meridian qi. The hypothesis concerning the relationship between meridian qi in Chinese medicine and oxygen metabolism in modern medicine proposed by the author was expounded and proved by a series of experiment results and theoretical analysis. According to the knowledge of oxygen metabolism and the theory of meridians and meridian qi, it is held that both qi and oxygen have extreme high similarity in both physiological functions and pathological reactions since both of them have material, functional and informational features. And the experiment results indicated that meridian qi in Chinese medicine have very close relationship with oxygen metabolism in modern medicine. Therefore, conclusions were made on the base of the above mentioned results: (1) The essence of meridian qi in Chinese medicine is closely related to oxygen and the metabolism of oxygen; (2) The specific distribution of oxygen metabolism related substance and its function may be one of the essence of the meridians and meridian qi; (3) Oxygen and vertebrate globin are probably the main contents of the "qi-blood" in Chinese medicine; (4) The mechanism of qi regulation with acupuncture-moxibustion may be fulfilled by the regulation of general and local state of oxygen metabolism. PMID- 22493935 TI - [Survey on the evaluation indices of acupuncture clinical trials for primary dysmenorrhea in recent 10 years]. AB - Based on the retrieval of literatures at home and abroad from 2000 to 2011, the evaluation indices of acupuncture clinical trials for primary dysmenorrhea (PD) were analyzed. The results indicated that in domestic area the reports were more concerned with the improvement of clinical symptoms and signs while paid less attention on the objective evaluation methodology, on the other hand, the studies abroad generally took many kinds of scales as their evaluation indices and focused on the patients' quality and activity of daily life. The authors suggeste that our clinical research, according to the designed intentions, should combine the general indicators with the specific indicators of diseases to have a more comprehensive evaluation on the effects of acupuncture for PD in clinical practice. PMID- 22493936 TI - A membrane-based ELISA assay and electrochemical immunosensor for microcystin-LR in water samples. AB - We describe within this paper the development of an affinity sensor for the detection of the cyanobacterial toxin microcystin-LR. The first stage of the work included acquiring and testing of the antibodies to this target. Following the investigation, a heterogeneous direct competitive enzyme-linked immunosorbent assay (ELISA) format for microcystin-LR detection was developed, achieving a detection limit, LLD(80) = 0.022 MUg L(-1). The system was then transferred to an affinity membrane sorbent-based ELISA. This was an amenable format for immunoassay incorporation into a disposable amperometric immunosensor device. This membrane-based ELISA achieved a detection limit, LLD(80) = 0.06 MUg L(-1). A three-electrode immunosensor system was fabricated using thick-film screen printing technology. Amperometric horseradish peroxidase transduction of hydrogen peroxide catalysis, at low reducing potentials, versus Ag/AgCl reference and carbon counter electrodes, was facilitated by hydroquinone-mediated electron transfer. A detection limit of 0.5 MUg L(-1) for microcystin-LR was achieved. Similar levels of detection could be obtained using direct electrochemical sensing of the dye produced using the membrane-based ELISA. These techniques proved to be simple, cost-effective, and suitable for the detection of microcystin-LR in buffer and spiked tap and river water samples. PMID- 22493937 TI - Polarity assignment in ZnTe, GaAs, ZnO, and GaN-AlN nanowires from direct dumbbell analysis. AB - Aberration corrected scanning transmission electron microscopy (STEM) with high angle annular dark field (HAADF) imaging and the newly developed annular bright field (ABF) imaging are used to define a new guideline for the polarity determination of semiconductor nanowires (NWs) from binary compounds in two extreme cases: (i) when the dumbbell is formed with atoms of similar mass (GaAs) and (ii) in the case where one of the atoms is extremely light (N or O: ZnO and GaN/AlN). The theoretical fundaments of these procedures allow us to overcome the main challenge in the identification of dumbbell polarity. It resides in the separation and identification of the constituent atoms in the dumbbells. The proposed experimental via opens new routes for the fine characterization of nanostructures, e.g., in electronic and optoelectronic fields, where the polarity is crucial for the understanding of their physical properties (optical and electronic) as well as their growth mechanisms. PMID- 22493938 TI - Boosting the efficiency of quantum dot sensitized solar cells through modulation of interfacial charge transfer. AB - The demand for clean energy will require the design of nanostructure-based light harvesting assemblies for the conversion of solar energy into chemical energy (solar fuels) and electrical energy (solar cells). Semiconductor nanocrystals serve as the building blocks for designing next generation solar cells, and metal chalcogenides (e.g., CdS, CdSe, PbS, and PbSe) are particularly useful for harnessing size-dependent optical and electronic properties in these nanostructures. This Account focuses on photoinduced electron transfer processes in quantum dot sensitized solar cells (QDSCs) and discusses strategies to overcome the limitations of various interfacial electron transfer processes. The heterojunction of two semiconductor nanocrystals with matched band energies (e.g., TiO(2) and CdSe) facilitates charge separation. The rate at which these separated charge carriers are driven toward opposing electrodes is a major factor that dictates the overall photocurrent generation efficiency. The hole transfer at the semiconductor remains a major bottleneck in QDSCs. For example, the rate constant for hole transfer is 2-3 orders of magnitude lower than the electron injection from excited CdSe into oxide (e.g., TiO(2)) semiconductor. Disparity between the electron and hole scavenging rate leads to further accumulation of holes within the CdSe QD and increases the rate of electron-hole recombination. To overcome the losses due to charge recombination processes at the interface, researchers need to accelerate electron and hole transport. The power conversion efficiency for liquid junction and solid state quantum dot solar cells, which is in the range of 5-6%, represents a significant advance toward effective utilization of nanomaterials for solar cells. The design of new semiconductor architectures could address many of the issues related to modulation of various charge transfer steps. With the resolution of those problems, the efficiencies of QDSCs could approach those of dye sensitized solar cells (DSSC) and organic photovoltaics. PMID- 22493939 TI - Oxidation of low-density lipoprotein by iron at lysosomal pH: implications for atherosclerosis. AB - Low-density lipoprotein (LDL) has recently been shown to be oxidized by iron within the lysosomes of macrophages, and this is a novel potential mechanism for LDL oxidation in atherosclerosis. Our aim was to characterize the chemical and physical changes induced in LDL by iron at lysosomal pH and to investigate the effects of iron chelators and alpha-tocopherol on this process. LDL was oxidized by iron at pH 4.5 and 37 degrees C and its oxidation monitored by spectrophotometry and high-performance liquid chromatography. LDL was oxidized effectively by FeSO(4) (5-50 MUM) and became highly aggregated at pH 4.5, but not at pH 7.4. The level of cholesteryl esters decreased, and after a pronounced lag, the level of 7-ketocholesterol increased greatly. The total level of hydroperoxides (measured by the triiodide assay) increased up to 24 h and then decreased only slowly. The lipid composition after 12 h at pH 4.5 and 37 degrees C was similar to that of LDL oxidized by copper at pH 7.4 and 4 degrees C, i.e., rich in hydroperoxides but low in oxysterols. Previously oxidized LDL aggregated rapidly and spontaneously at pH 4.5, but not at pH 7.4. Ferrous iron was much more effective than ferric iron at oxidizing LDL when added after the oxidation was already underway. The iron chelators diethylenetriaminepentaacetic acid and, to a lesser extent, desferrioxamine inhibited LDL oxidation when added during its initial stages but were unable to prevent aggregation of LDL after it had been partially oxidized. Surprisingly, desferrioxamine increased the rate of LDL modification when added late in the oxidation process. alpha-Tocopherol enrichment of LDL initially increased the rate of oxidation of LDL but decreased it later. The presence of oxidized and highly aggregated lipid within lysosomes has the potential to perturb the function of these organelles and to promote atherosclerosis. PMID- 22493940 TI - C2 hydroxyl group governs the difference in hydrolysis rates of methyl-alpha-D glycero-D-guloseptanoside and methyl-beta-D-glycero-D-guloseptanoside. AB - A computational investigation into the hydrolysis of two methyl septanosides, methyl-alpha-D-glycero-D-guloseptanoside and methyl-beta-D-glycero-D guloseptanoside was undertaken. These septanosides were chosen as model compounds for comparison to methyl pyranosides and allowed direct comparison of alpha versus beta hydrolysis rates for a specific septanoside isomer. Results suggest that hydrolysis takes place without proceeding through a transition state, an observation that was suggested in previous computational studies on exocyclic bond cleavage of carbohydrates. A conformational analysis of alpha- and beta anomers 1 and 2 and their corresponding oxocarbenium 3, coupled with relaxed potential energy surface (PES) scans (M06-2X/6-311+G**, implicit methanol), indicated that hydrolysis of the alpha-anomer is favored by 1-2 kcal/mol over the beta-anomer, consistent with experiment. Model systems revealed that the lowest energy conformations of the septanoside ring system destabilize the beta-anomer by 2-3 kcal/mol relative to the alpha-anomer, and the addition of a single hydroxyl group at the C2-position on a minimal oxepane acetal can reproduce the PES for the septanoside 1. These results suggest that the C2 hydroxyl plays a unique role in the hydrolysis mechanism, destabilizing the septanoside via its proximity to the anomeric carbon and also through its interaction with the departing methanol from the alpha-anomer via hydrogen-bonding interactions. PMID- 22493941 TI - New insights into the mechanism of amine/nitroxide cycling during the hindered amine light stabilizer inhibited oxidative degradation of polymers. AB - High-level ab initio molecular orbital theory calculations are used to identify the origin of the remarkably high inhibition stoichiometric factors exhibited by dialkylamine-based radical-trapping antioxidants. We have calculated the free energy barriers and reaction energies at 25, 80, and 260 degrees C in the gas phase and in aqueous solution for a broad range of reactions that might, potentially, be involved in amine/nitroxide cycling, as well as several novel pathways proposed as part of the present work, including that of N-alkyl hindered amine light stabilizer activation. We find that most of the literature nitroxide regeneration cycles should be discarded on either kinetic or thermodynamic grounds; some are even inconsistent with existing experimental observations. We therefore propose a new mechanistic cycle that relies on abstraction of a beta hydrogen atom from an alkoxyamine (R(1)R(2)NOCHR(3)R(4)). Our results suggest that this cycle is energetically feasible for a range of substrates and provides an explanation for previously misinterpreted or unexplained experimental results. We also explore alternative mechanisms for amine/nitroxide cycling for cases where the alkoxyamines do not possess an abstractable beta-hydrogen. PMID- 22493942 TI - Colour and spatial cueing in low-prevalence visual search. AB - In visual search, 30-40% of targets with a prevalence rate of 2% are missed, compared to 7% of targets with a prevalence rate of 50% (Wolfe, Horowitz, & Kenner, 2005). This "low-prevalence" (LP) effect is thought to occur as participants are making motor errors, changing their response criteria, and/or quitting their search too soon. We investigate whether colour and spatial cues, known to improve visual search when the target has a high prevalence (HP), benefit search when the target is rare. Experiments 1 and 2 showed that although knowledge of the target's colour reduces miss errors overall, it does not eliminate the LP effect as more targets were missed at LP than at HP. Furthermore, detection of a rare target is significantly impaired if it appears in an unexpected colour-more so than if the prevalence of the target is high (Experiment 2). Experiment 3 showed that, if a rare target is exogenously cued, target detection is improved but still impaired relative to high-prevalence conditions. Furthermore, if the cue is absent or invalid, the percentage of missed targets increases. Participants were given the option to correct motor errors in all three experiments, which reduced but did not eliminate the LP effect. The results suggest that although valid colour and spatial cues improve target detection, participants still miss more targets at LP than at HP. Furthermore, invalid cues at LP are very costly in terms of miss errors. We discuss our findings in relation to current theories and applications of LP search. PMID- 22493943 TI - Plasma leptin concentration in donkeys. AB - BACKGROUND: Donkeys appear to be more predisposed than large breed horses to suffer from hyperlipemia. The reason for that predisposition is unknown but anorexia is a consistent feature of the disease. Leptin, a protein synthesized in fat tissue, is one of the major inhibitors of appetite in mammals. OBJECTIVE: We hypothesized that donkeys could have elevated plasma leptin concentrations compared to horses. ANIMALS AND METHODS: Blood samples were obtained from 50 donkeys for measurement of leptin, triglycerides (TGs), glucose, and insulin. Glucose/insulin ratio, modified insulin to glucose ratio, and reciprocal of the square root of insulin were calculated. Based on their body condition score (BCS), donkeys were classified as lean (n = 18), normal (n = 16), or overweight (n = 16). The results were compared with reference values from our laboratory and with a group of horses (n = 25) used as an internal control. RESULTS: Values of both leptin and TGs in donkeys were above the horse reference range and also significantly higher than those of the control horses: leptin (11.2 +/- 1.7 versus 5.8 +/- 0.5 ug/L, p < 0.05) and TGs (0.93 +/- 0.1 versus 0.54 +/- 0.1 mmol/L, p < 0.01). Overweight donkeys had leptin (19.3 +/- 2.9 ug/L) and TG (1.3 +/- 0.2 mmol/L) concentrations that were significantly (p < 0.01) higher than normal (9.4 +/- 3.3 ug/L and 0.85 +/- 0.1 mmol/L, respectively) and lean (5.5 +/- 1.0 ug/L and 0.66 +/- 0.1 mmol/L, respectively) donkeys. A significant positive correlation (p < 0.01) was found between BCS and leptin (r = 0.43), TGs (r = 0.46), glucose (r = 0.41), and insulin (r = 0.40). CONCLUSION: Donkeys have higher plasma leptin concentrations than horses and leptin is correlated with BCS. PMID- 22493944 TI - Photoinduced reactivity of doxorubicin: catalysis and degradation. AB - Doxorubicin exhibits unusual photoreactivity in aqueous solutions. Our data show that there are two distinct photoreactive pathways for doxorubicin. One is a two step process that leads to the formation of 3-methoxysalicylic acid, a stable degradation product. The other pathway is a photoreduction of doxorubicin to form the corresponding dihydroquinone, which undergoes spontaneous oxidation mediated by dissolved oxygen to recover doxorubicin with the formation of hydrogen peroxide. Our data account for the known nonlinear dependence of doxorubicin fluorescence intensity on concentration. PMID- 22493945 TI - Molecular characterization and antifungal susceptibility of the Candida parapsilosis species complex of clinical isolates from Monterrey, Mexico. AB - Recently, it was proposed that the opportunistic yeast pathogen Candida parapsilosis was a complex composed of the following three species: Candida parapsilosis sensu stricto, Candida orthopsilosis, and Candida metapsilosis. A set of 344 clinical isolates of Candida parapsilosis from Monterrey, Mexico was re-identified by RFLP. Their antifungal susceptibility to fluconazole, caspofungin, anidulafungin and micafungin was determined using the Clinical and Laboratory Standards Institute M27-A3 protocol. Candida parapsilosis sensu stricto was the most frequent species, and was the only one which showed resistance to antifungals. PMID- 22493947 TI - Description of Riouxgolvania kapapkamui Sp. N. (Nematoda: Muspiceoidea: Muspiceidae), a peculiar intradermal parasite of bats in Hokkaido, Japan. AB - Riouxgolvania kapapkamui sp. n. (Nematoda: Muspiceoidea: Muspiceidae), a peculiar intradermal parasite, is described based on gravid adults, eggs, and first-, second-, and third-stage larvae collected from dermal nodules formed in Myotis macrodactylus and Myotis ikonnikovi bats from Hokkaido, Japan. The nematode is readily distinguished from 3 previously described congeners in having a globular body with brown, transverse striae in the anterior region of fully grown females. The third-stage larva is also distinguished from other congeners by having a round tail end. Nucleotide sequences of the analyzed partial SSU rDNA-ITS1 region and partial cytochrome c oxidase subunit 1 of mtDNA showed greater similarity to chromadoreans rather than to enopleans. This is the first report of muspiceoid nematodes from Asia. PMID- 22493946 TI - Morphological heterogeneity of Paracoccidioides brasiliensis: relevance of the Rho-like GTPase PbCDC42. AB - Paracoccidioides brasiliensis budding pattern and polymorphic growth were previously shown to be closely linked to the expression of PbCDC42 and to influence the pathogenesis of the fungus. In this work we conducted a detailed morphogenetic evaluation of the yeast-forms of 11 different clinical and environmental P. brasiliensis isolates comprising four phylogenetic lineages (S1, PS2, PS3 and Pb01-like), as well as a PbCDC42 knock-down strain. High variations in the shape and size of mother and bud cells of each isolate were observed but we did not find a characteristic morphologic profile for any of the phylogenetic groups. In all isolates studied, the bud size and shape were demonstrated to be highly dependent on the mother cell. Importantly, we found strong correlations between PbCDC42 expression and both the shape of mother and bud cells and the size of the buds in all isolates and the knock-down strain. Our results suggested that PbCDC42 expression can explain approximately 80% of mother and bud cell shape and 19% of bud cell size. This data support PbCDC42 expression level as being a relevant predictor of P. brasiliensis morphology. Altogether, these findings quantitatively describe the polymorphic nature of the P. brasiliensis yeast form and provide additional support for the key role of PbCDC42 expression on yeast cell morphology. PMID- 22493948 TI - Thrombus at ostium of coronary sinus discovered during evaluation for cardiac resynchronization therapy. AB - A 50-year-old male patient with dilated cardiomyopathy was evaluated for cardiac resynchronization therapy. A transthoracic echocardiogram revealed a mass in close proximity to the coronary sinus ostium.The mass was considered to be a thrombus and found to have disappeared at the repeat echocardiogram performed following a month of anticoagulation therapy with warfarin. In this case report, we aim to emphasize the importance of coronary sinus imaging, especially during echocardiographic evaluation for cardiac asynchrony. PMID- 22493949 TI - Tripolar spinal cord stimulation for the treatment of abdominal pain associated with irritable bowel syndrome. AB - OBJECTIVES: The objective of this case report is to describe the use of transverse tripolar dorsal column stimulation in a patient with a history of irritable bowel syndrome (IBS) associated with abdominal pain resistant to conservative treatments. METHOD: We report a 36-year-old man who presented to the pain clinic with an eight-year history of IBS (constipation predominant with occasional diarrheal episodes), with "crampy and sharp" abdominal pain. He also had nonradicular thoracic spine pain due to thoracic scoliosis. Both pains were affecting his ability to function as an attorney. Prior conservative therapy, including psychologic treatment, antidepressants, and opioids, was without any benefits. RESULTS: The use of a spinal cord stimulator (SCS) was discussed with the patient. The procedure was performed after Institutional Review Board approval. A tripolar SCS was implanted at the T8 level using one-eight contact and two-four contact percutaneous leads based on paresthesia reproduction of patient's areas of discomfort. This tripolar spinal cord stimulation provided relief of abdominal and thoracic pain, and better management of gastrointestinal symptoms. The patient was followed-up for one year, and his quality of life also was improved via the IBS-Severity Scoring System quality of life tool. CONCLUSIONS: The use of the tripolar SCS in this patient provided relief of abdominal and thoracic spine pain, regulated bowel habits, and improved the patient's quality of life. We believe that the use of SCS should be considered as a treatment option in patients with IBS when all conservative treatments failed. PMID- 22493951 TI - Electrical storm in short-QT syndrome successfully treated with Isoproterenol. AB - Short-QT Syndrome. A 28-year-old man was admitted after aborted sudden cardiac death while sleeping. QTc was 320 ms, suggesting short-QT syndrome (SQTS). The patient then presented with electrical storm with 8 successive episodes of ventricular fibrillation while on deep sedation and hypothermia. Isoproterenol infusion was introduced, leading to rapid cessation of any arrhythmic event. Isoproterenol can be effective in managing electrical storm in patients with SQTS. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1028-1030, September 2012). PMID- 22493950 TI - The Cys-loop pentameric ligand-gated ion channel receptors: 50 years on. AB - This year, 2011, the Department of Pharmacology at the University of Alberta celebrated its 50th anniversary. This timeframe covers nearly the entire history of Cys-loop pentameric ligand-gated ion channel (pLGIC) research. In this review we consider how major technological advancements affected our current understanding of pLGICs, and highlight the contributions made by members of our department. The individual at the center of our story is Susan Dunn; her passing earlier this year has robbed the Department of Pharmacology and the research community of a most insightful colleague. Her dissection of ligand interactions with the nAChR, together with their interpretation, was the hallmark of her extensive collaborations with Michael Raftery. Here, we highlight some electrophysiological studies from her laboratory over the last few years, using the technique that she introduced to the department in Edmonton, the 2-electrode voltage-clamp of Xenopus oocytes. Finally, we discuss some single-channel studies of the anionic GlyR and GABA(A)R that prefaced the introduction of this technique to her laboratory. PMID- 22493952 TI - New triterpenoids from the stem bark of Hypodaphnis zenkeri. AB - A new pentacyclic triterpenoid and three new derivatives based on the taraxer-14 ene skeleton with a C-28 attached a carboxylic acid group have been isolated from the stem bark of Hypodaphnis zenkeri, together with six known compounds. The new product was identified as 2alpha,3alpha-dihydroxytaraxer-14-en-28-oic acid (1). Its derivatives, 2alpha,3alpha-diacetyltaraxer-14-en-28-oic acid (2), 2alpha,3alpha-di-O-carbonyl-2alpha,3alpha-dihydroxytaraxer-14-en-28-oic acid (3) and 2alpha,3alpha-dipropionyltaraxer-14-en-28-oic acid (4) were obtained by semisynthesis. The known compounds were identified as 3beta-hydroxytaraxer-14-en 28-oic acid or aleuritolic acid (5) (McPhail, A.T., McPhail, D.R., Wani, M.C., Wall, M.E. & A.W., Nicholas, A.W. (1989). Identity of maprounic acid with aleuritolic acid. Revision of the structure of maprounic acid: X-ray crystal structure of p-bromobenzyl acetylmaprounate. Journal Natural Products, 52, 212), 3alpha-hydroxytaraxer-14-en-28-oic acid or isoaleuritolic acid (6), 3alpha acetyltaraxer-14-en-28-oic acid acetate or aleuritolic acid acetate (7) (Chaudhuri, S.K., Fullas, F., Brown, D.M., Wani, M.C., Wall, M.E., Cai, L., ... Kinghorn, A.D. (1995). Isolation and structural elucidation of pentacyclic triterpenoids from Maprounea africana. Journal of Natural Products, 58, 1-9), 3 oxo-taraxer-14-ene or taraxerone (8) beta-sitosterol (9) and stigmasterol (10) (Kamboj & Saluja, 2011), together with fatty acids. Their structures were established on the basis of spectroscopic studies and chemical transformations. PMID- 22493953 TI - The tariff -- traps for the unwary. PMID- 22493954 TI - 'The future ain't what it used to be'-- reflections on the evolution of anaesthesia. PMID- 22493956 TI - The effect of temperature on di(2-ethylhexyl) phthalate leaching from PVC infusion sets exposed to lipid emulsions. AB - Poly vinyl chloride (PVC) infusion equipment contains substantial amounts of the plasticiser di(2-ethylhexyl) phthalate (DEHP). We determined the amount of DEHP leached from Mediplus Dual TIVA((r)) Infusion sets, into lipid and non-lipid infusates. Two propofol admixtures (Diprivan((r)) 1%, Propoven((r)) 1%), Intralipid((r)) 10% and 0.9% saline were evaluated as infusates. Solutions were infused through TIVA sets at 12 ml.h(-1) for 6 h at 24, 32 and 37 degrees C. In addition, TIVA sets were filled with 2 ml infusates, sealed and incubated at 24 and 37 degrees C for 6 h. Di(2-ethylhexyl) phthalate was detected in all lipid infusates after dynamic infusion and static contact, and in 0.9% saline after dynamic infusion at 37 degrees C. At 32 and 37 degrees C, the quantity of di(2 ethylhexyl) phthalate leaching into the lipid infusates may exceed the recommended maximum exposure amount set by the European Union for DEHP of 20-48 MUg.kg(-1) day(-1) if lipid based infusates are used for sedation or intravenous feeding of infants or neonates. PMID- 22493955 TI - Incidence and estimated annual cost of emergency laparotomy in England: is there a major funding shortfall?. AB - Significant recent interest has focussed on improving outcomes after emergency laparotomy. This retrospective database analysis estimated the annual incidence and associated inpatient costs of emergency laparotomy in England. Demographic, process and outcome data were collected for all patients undergoing emergency laparotomy in Brighton for two calendar years (2009-2010). Cost analysis assumed L16 per minute theatre time, and L282 per day ward bed and L1382 per day critical care bed costs. National incidence was confirmed from Hospital Episode Statistics and Office of National Statistics mid-year population data. In total, 768 patients underwent 850 emergency laparotomies. The incidence of emergency laparotomy was estimated as ~1:1100 population. Thirty-six percent (276 patients) were admitted for a median (IQR [range]) of 5 (3-11 [1-76]) days of critical care. Postoperative median (IQR [range]) length of stay was 13 (8-24 [1-176]) days. Our estimated annual inpatient cost of emergency laparotomy for Brighton was ~L5 million, equivalent to ~L13 000 per patient, and for England, an annual estimated cost of ~L650 million. However, 'Payment by Results' reimbursement amounted to a mean (SD) hospital income of just L6905 (2639) per patient, a net financial loss of ~L6100 per patient, equivalent to a reimbursement shortfall nationally of ~L300 million. We also found that patients > 70 years (46%) had significantly higher 30-day postoperative mortality (18% vs 6%, p < 0.0001), significantly prolonged median (IQR [range]) length of stay (15 (10-26 [1-123]) days vs 12 (7-22 [1-176]) days, p < 0.001) and incurred higher costs (median (IQR [range]) L9667 (6620-15 732 [1920-103 624]) vs L7467 (4975-14 251 [1178-118 060]), p < 0.001). Emergency laparotomy is a common procedure associated with considerable cost, particularly among elderly patients. A National Emergency Laparotomy Database will help provide an evidence base on which to improve clinical outcome and cost efficiency. PMID- 22493957 TI - The UK needs more critical care investment in order to improve peri-operative outcomes. PMID- 22493958 TI - Don't forget cardioprotective strategies in high-risk surgical patients! PMID- 22493959 TI - Confirming extravasation from a peripheral venous catheter: another role for ultrasonography. PMID- 22493960 TI - Difficult mask ventilation and the use of sugammadex. PMID- 22493961 TI - Prevention of damage to teeth and gums: an often neglected advantage of indirect laryngoscopy with the Airtraq. PMID- 22493962 TI - Placement of a gastric tube using a flexible intubating fibrescope. PMID- 22493963 TI - Mandibular nerve blocks. PMID- 22493964 TI - Internal diameter marking on tracheal tube connectors. PMID- 22493965 TI - It is time to establish an international manufacturing standard for paediatric tracheal tubes? PMID- 22493966 TI - Evaluation of the association between quality of handover and length of stay in the post anaesthesia care unit: a pilot study. PMID- 22493967 TI - Freezing blood samples to reduce costs and improve patient safety. PMID- 22493968 TI - Conversion from regional to general anaesthesia for caesarean section: are we meeting the standards? PMID- 22493970 TI - iPhone for measuring 15 degrees tilt during caesarean section. PMID- 22493971 TI - iPhone for monitoring neuromuscular function. PMID- 22493972 TI - Misconceptions about coercion and undue influence: reflections on the views of IRB members. AB - Payment to recruit research subjects is a common practice but raises ethical concerns relating to the potential for coercion or undue influence. We conducted the first national study of IRB members and human subjects protection professionals to explore attitudes as to whether and why payment of research participants constitutes coercion or undue influence. Upon critical evaluation of the cogency of ethical concerns regarding payment, as reflected in our survey results, we found expansive or inconsistent views about coercion and undue influence that may interfere with valuable research. In particular, respondents appear to believe that coercion and undue influence lie on a continuum; by contrast, we argue that they are wholly distinct: whereas undue influence is a cognitive distortion relating to assessment of risks and benefits, coercion is a threat of harm. Because payment is an offer, rather than a threat, payment is never coercive. PMID- 22493973 TI - Brood mixing and reduced polyandry in a maternally mouthbrooding cichlid with elevated among-breeder relatedness. AB - Uniparental maternal brood care often coincides with multiple paternity and single maternity of broods, possibly reflecting benefits of polyandry and costs of uniparental care. Genetic data from the maternally mouthbrooding cichlid fish Simochromis pleurospilus revealed the opposite pattern--low polyandry and allomaternal care. More than 70% of the investigated females had mated with a single male, and 14% of the females had unrelated fry in their broods. Broods with foreign fry were in the late stage of brood care, in which females guard free-swimming fry and recall the broods into their mouths for protection. With one exception, fostering females were related to their adopted fry at the level of first cousins (R(QG) > 0.12), but relatedness between fosters and adopted fry was not significantly higher than between fosters and fry tended by other females. Relatedness among breeders extended to the level of first-order relatives. Mean relatedness among contemporaneously breeding dams (R(QG) = 0.08) was significantly higher than among dams breeding in different seasons (R(QG) = 0.04), which suggests a temporal or spatial concentration of mouthbrooding relatives. Indeed, females sometimes brood in small groups. This behaviour may reduce brood predation but will increase the risk of brood mixing, which is possibly mitigated by low costs of brood care and indirect benefits accrued by relatedness among the breeders in the group. Remarkably, the apparent inbreeding potential did not give rise to bet-hedging polyandry or active avoidance of relatives, as half of the mated individuals were related at R(QG) > 0.13 and polyandry did not coincide with high within-pair relatedness. PMID- 22493974 TI - Effect of silicon and sodium on thermoelectric properties of thallium-doped lead telluride-based materials. AB - Thallium (Tl)-doped lead telluride (Tl(0.02)Pb(0.98)Te) thermoelectric materials fabricated by ball milling and hot pressing have decent thermoelectric properties but weak mechanical strength. Addition of silicon (Si) nanoparticles strengthened the mechanical property by reducing the grain size and defect density but resulted in low electrical conductivity that was not desired for any thermoelectric materials. Fortunately, doping of sodium (Na) into the Si added Tl(0.02)Pb(0.98)Te brings back the high electrical conductivity and yields higher figure-of-merit ZT values of ~1.7 at 770 K. The ZT improvement by Si addition and Na doping in Tl(0.02)Pb(0.98)Te sample is the direct result of concurrent electron and phonon engineering by improving the power factor and lowering the thermal conductivity, respectively. PMID- 22493975 TI - A unique form of light-load training improves steadiness and performance on some functional tasks in older adults. AB - Beginning Movement Load (BML) training is a unique form of light-load training that comprises a lengthening-shortening sequence of muscle actions about multiple degrees of freedom. The purpose of the study was to determine the effectiveness of BML training at improving the performance of old adults on four functional tasks and to identify some of the neuromuscular adaptations that contributed to these gains. Healthy old adults (67.5 +/- 5.23 years) were randomly assigned to either a BML training group (n = 17) or a control group (n = 7). The training group exercised with a 30% of the one repetition-maximum (1-RM) load and performed five to seven sets of 15 repetitions, three times per week for 8 weeks. BML training increased maximal voluntary contraction (MVC) force significantly for the knee extensors (31.6%), but not the elbow flexors (9.8%), and improved the steadiness of isometric contractions (10%, 30%, and 65% MVC forces). Training associated changes in times for ascending and descending stairs and one-legged balance, but not the chair rise, were predicted by changes in selected combinations of MVC force and steadiness. The attributes of BML training that enabled it to elicit functionally meaningful adaptations in the neuromuscular system of older adults should be explored with more mechanistic studies. PMID- 22493977 TI - Recent advances on structural modifications of benzothiazoles and their conjugate systems as potential chemotherapeutics. AB - INTRODUCTION: Benzothiazole scaffold comprises a bicyclic ring system and is known to exhibit a wide range of biological properties including antimicrobial and anticancer activities. Benzothiazole derivatives have long been therapeutically used for the treatment of various diseases. However, in recent years, 2-arylbenzothiazoles have emerged as an important pharmacophore in the development of antitumor agents. The promising biological profile and synthetic accessibility have been attractive in the design and development of new benzothiazoles and their conjugate systems as potential chemotherapeutics. AREAS COVERED: This review mainly focuses on the structural modifications of benzothiazole scaffold, development of various series of benzothiazoles and their conjugates as new antitumor agents. Furthermore, heterocyclic derivatives bearing benzothiazole moiety and their in vitro as well as in vivo screening, structure activity relationships (SAR), mechanism, pharmacokinetics, clinical use and their future therapeutic applications are discussed here. EXPERT OPINION: A large number of benzothiazole derivatives discussed here possess potent anticancer activity and can be further developed as drug candidates. Benzothiazole conjugates could also display synergistic effect and still there is a need to use the drug combinations permitting lower dose and development of new generation of drugs. Despite encouraging results that have been observed for their response to tumor in clinical studies, full characterization of their toxicity is further required for their clinical usage as safe drugs for the treatment of cancer. We believe that this review gives a better understanding and scope for future drug design and development of benzothiazole-based compounds to implicate their use in cancer chemotherapy. PMID- 22493978 TI - JAK2 inhibition for the treatment of hematologic and solid malignancies. AB - INTRODUCTION: Mutations in Janus kinase 2 (JAK2), and in particular JAK2 V617F, are common in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). In the past several years, JAK2 inhibitors have been rapidly developed as targeted therapies for MPNs. AREAS COVERED: JAK2 mutations, including JAK2 V617F and unique fusion proteins, are critical for oncogenesis of some hematologic malignancies. Although JAK2 mutations are extremely rare in solid cancers, pathophysiological JAK2/STAT signaling can still promote tumor cell growth, proliferation, migration, invasion and angiogenesis. JAK2 inhibition can curtail malignant cellular behaviors and thus may be a promising therapeutic strategy. EXPERT OPINION: The involvement of oncogenic JAK2 mutations in hematologic malignancies indicates that JAK2 inhibition has the potential to be a highly successful treatment option. The exact role of JAK2 signaling in solid cancers is unclear, but JAK2 inhibition may prevent disease progression by restricting malignant cell phenotypes. JAK2 inhibitors in development for the treatment of MPNs have demonstrated clinical activity with minimal toxicity. This class of agents should be investigated more rigorously for the treatment of other malignancies with aberrant JAK2 signaling with or without JAK2 mutations. PMID- 22493979 TI - Investigational ABC transporter inhibitors. AB - INTRODUCTION: Multidrug resistance (MDR) is the main cause of failure in cancer therapy. One mechanism responsible for MDR is the active efflux of drugs by ATP binding cassette (ABC) transporters. Several agents have been developed to block transporter-mediated drug efflux and some of these compounds have entered Phase II/III clinical testing. Evidence is also emerging of the role played by ABC transporters in cancer cell signalling that is likely to be important in disease progression and which is distinct from MDR. AREAS COVERED: This article reviews current literature to analyse the rationale for targeting ABC transporters in cancer. Preclinical and clinical results of ABC transporter inhibitors in early clinical trials, as single agents or in combination with other drugs, are described. The development of new strategies to target MDR and the emerging roles of ABC transporters in cancer signalling are discussed. EXPERT OPINION: The intense active search for safe and effective inhibitors of ABC transporters has led to some success in MDR reversal in preclinical studies. However, there has been little impact on clinical outcome. The discovery of novel, potent and nontoxic inhibitors as well as new treatment strategies is therefore needed. PMID- 22493980 TI - Inhibition of pro-protein convertase subtilisin kexin 9 [corrected] (PCSK-9) as a treatment for hyperlipidaemia. AB - INTRODUCTION: Pro-protein [corrected] convertase subtilisin kexin (PCSK)-9 is a newly discovered protein involved in intracellular and extracellular regulation of low-density lipoprotein receptor (LDLR) expression. Autosomal dominant activating mutations in PCSK-9 cause familial hypercholesterolaemia whereas inactivating mutations in man reduce LDL cholesterol (LDL-C) and are associated with a decreased lifetime risk of cardiovascular events. AREAS COVERED: As PCSK-9 binds to the LDLR, a number of approaches involving small molecule or peptide inhibition of binding, antibody-mediated inactivation of binding and the use of antisense oligonucleotides are being investigated as therapeutic approaches to lower LDL-C in man. This article reviews the biochemistry and physiology of PCSK 9 and details the efforts made to design novel molecules with the ability to inhibit PCSK-9 activity. Work in animal models has confirmed that reducing PCSK-9 expression can reduce atherosclerosis in mice, rats and primates. Monoclonal antibodies such as REGN-727 and AMG-145 have been shown to reduce LDL-C in patients with familial hypercholesterolaemia already treated with statins or healthy normocholesterolaemic controls. EXPERT OPINION: PCSK-9 inhibition is a potentially interesting novel addition to the armamentarium of LDL-C reducing drugs. Its effects in reducing LDL-C will need to be confirmed to reduce CVD events in large-scale clinical trials. PMID- 22493981 TI - New frontiers in female contraception (and male condoms): 2012. AB - INTRODUCTION: Contraception made profound contributions to women's health in the twentieth century and has the potential to help achieve each of the eight millennium development goals in the twenty-first. However, contraception has not met its full potential, in large part due to inconsistent use. Choice is uniquely important to contraceptive success, so continued innovation in all aspects of birth control is needed. AREAS COVERED: First, we will review recent advances in the introduction of new methods of birth control. Then we will report recent developments in areas that strongly influence contraceptive use, including non contraceptive benefits, ways to minimize side effects and practice protocols designed to encourage ready access to various methods. In the second half of the paper we will discuss methods that are in development, but not yet available, as well as new research into non-contraceptive benefits, new approaches to reduce side effects and new ways to provide contraceptives so that users can be more successful. EXPERT OPINION: The goal of being planned and prepared for pregnancies is still only an abstract concept. Significant barriers to success from traditional sources (ambivalence, cultural and societal beliefs, the status of women, poverty) persist and are now joined by many other emerging structural problems. The consolidation of pharmaceutical companies reduces competition. The loss of profitability for contraceptives due to short-lasting patents, growing demand for generics and growing challenges from product liability reduce incentives for innovation. Healthcare reform in the US may further discourage new product development. However, new advances may still be possible from small start up companies, philanthropic foundations and governmental research efforts. Other advances may be made by providing contraception in innovative ways and in the techniques we use to motivate patients to be more successful contraceptors. PMID- 22493982 TI - Transforming the journey for newly licensed registered nurses. AB - Newly licensed nurses entering into practice experience stressors related to daily challenges. This evidence-based practice project implemented a nurse residency program designed to ease the transition during the first year of practice. Newly licensed nurses at a Midwestern health care organization were enrolled in a yearlong nurse residency program and were required to attend one 4 hour session monthly. Program outcomes included a decrease in turnover and improved confidence. PMID- 22493983 TI - The use of an advanced medical-surgical course for the retention and professional development of medical-surgical nurses in an acute care hospital. AB - The retention and professional development of the medical-surgical nurse is a challenging endeavor. Voluntary nurse turnover affects the collective costs of direct and indirect recruiting, productivity and training, and termination. These costs are estimated to be 0.75 to 1.30 times a nurse's average departing salary. The multifactorial dimensions of nursing retention remain a challenge for leaders at the organizational level. This article describes an educational strategy in the form of an advanced medical-surgical course used by a multicampus academic community Magnet(r) hospital to increase the retention and professional development of medical-surgical nurses. The authors report the goals, content, and outcomes of this advanced medical-surgical course. PMID- 22493985 TI - Is the autophagy induced by thiopurines beneficial or deleterious? AB - Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine), are drugs useful in the treatment of leukemia, autoimmune diseases, as well as in organ transplantation. After many years of use is still not well understood their mode of action. Recently, several groups have found that thiopurines can activate autophagy by different mechanisms. Autophagy is a process of auto-digestion. After an infection, radiation, injury, oxidative stress, or after drug treatment, the cellular organelles may be damaged. In those cases the damaged structures are recognized by the cell, isolated in a double-membrane vacuole and finally degraded in autolysosomes. The digestion gives rise to biosynthetic precursors needed to regenerate partially destroyed structures, so as to produce the energy essential in the anabolic process. During fasting, the protein aggregates, lipid droplets and glycogen deposits are degraded by this pathway for releasing nutrients to the blood. Therefore this process is of vital importance in the maintaining of cellular functions and in the systemic homeostasis of whole organism. The therapy with thiopurines leads to adverse effects such as myelosuppression and hepatotoxicity whose mechanism is not well understood today. Autophagy is also involved in liver degeneration induced by drugs, alcohol or viruses. Therefore, seems to be very attractive know whether the autophagy induced by thiopurines is the cause of the hepatotoxicity associated with these drugs, or rather, autophagy is a compensatory response that protects the liver against the deleterious effects of the thiopurines. Our results and previous data suggest that autophagy is beneficial for the liver because protects it against the deleterious effects of thiopurines. PMID- 22493984 TI - Aspirin as a chemoprevention agent for colorectal cancer. AB - Colorectal cancer (CRC) is one of the leading causes of mortality in the western world. It is widely accepted that neoplasms such as colonic polyps are precursors to CRC formation; with the polyp-adenoma-carcinoma sequences well described in medical literature [1, 2]. It has been shown that Aspirin and other non-steroid anti-inflammatory drugs (NSAID) have a negative effect on polyp and cancer formation. This review aims to describe some of the mechanism behind the chemoprotective properties of aspirin; COX 2 inhibition, regulation of proliferation and apoptosis and effects on the immune system and also the current evidence that supports its use as a chemoprevention agent against CRC. We will also aim to explore the side effects with the use of aspirin and the pitfalls of using aspirin routinely for primary prophylaxis against CRC. PMID- 22493986 TI - The influence of CYP2C19 genetic polymorphism on the pharmacokinetics/- pharmacodynamics of proton pump inhibitor-containing Helicobacter pylori treatments. AB - Proton pump inhibitors (PPIs) are the most potent acid suppressants available. PPIs undergo hepatic metabolism via the CYP2C system for the isoforms CYP2C19 and CYP3A4 in particular. Genetic polymorphisms in CYP2C19 may affect the metabolism of individual PPIs to different extents. Although PPIs are highly effective as a class, differences in their pharmacokinetics, such as bioavailability and metabolism, may translate into differences in clinical outcomes. In Helicobacter pylori infection, a significantly lower eradication rate was seen in extensive metabolizers with omeprazole but no with rabeprazole. PMID- 22493987 TI - Drug treatment of eosinophilic oesophagitis. AB - Eosinophilic oesophagitis is a clinicopathological disease characterized by oesophageal eosinophilia and gastrointestinal symptoms. Currently, the optimal treatment regimens remain unclear. The pathogenesis of eosinophilic oesophagitis appears to involve immune dysregulation, while acid reflux may have a secondary role; the mainstays in treatment are aimed principally at these dual processes. While a trial of a PPI is worthwhile it is likely that PPI therapy is treating concurrent acid reflux rather than true eosinophilic oesophagitis. Dietary elimination with elemental feed is safe but poorly tolerated. Swallowed topical steroids are the mainstay of commercially available therapies. Both fluticasone and budesonide have been proven to be beneficial both symptomatically and in reducing oesophageal eosinophil counts in the short and medium term. Basic studies have determined a role for IL-5 in oesophageal remodelling in eosinophilic esophagitis. Initial clinical studies have shown single or multiple infusions of monoclonal antibody to IL-5 to be well tolerated and to cause a long term decrease in both peripheral and sputum eosinophil count in these eosinophil driven conditions. At present, swallowed corticosteroids are the mainstay of treatment for patients with eosinophilic oesophagitis in patients failing PPI therapy. Studies have been heterogenous in their diagnostic criteria for eosinophilic oesophagitis and in the definition of response to therapy, making comparison of results difficult. PMID- 22493988 TI - Utility of assessing thiopurine S-methyltransferase polymorphisms before azathioprine therapy. AB - Thiopurine S-methyltransferase (TPMT) catalyzes the methylation of thiopurine drugs, such as azathioprine and mercaptopurine, which are used in a variety of diseases. Several mutations in the TPMT gene correlate with low enzyme activity and subsequent adverse effects, mainly myelotoxicity. Hence, genotyping TPMT makes it possible to identify patients at high risk of drug toxicity and adjust dosage accordingly. However, further research about the availability of a reliable and universal screening method and more costeffectiveness studies are necessary. PMID- 22493989 TI - Vitamin D: new roles and therapeutic potential in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) encompasses 2 independent but related entities: ulcerative colitis (UC) and Crohn's disease. Crohn's disease is characterised by transmural patchy inflammation which can involve any portion of the gastrointestinal tract. UC is characterised by superficial inflammation that begins in the rectum and extends proximally along the colon. In Europe, approximately 2.2 million people have a diagnosis of IBD. The aetiology of IBD is unknown, however, immune, environmental and genetic factors are thought to be involved. Individuals with IBD are at risk of developing osteoporosis. In line with this, there are clear guidelines that recommend vitamin D supplementation for IBD patients to prevent bone disease, especially when undergoing steroid treatment. Despite an established role for vitamin D in IBD, deficiency is common. More novel effects of vitamin D beyond bone are emerging. It is now well established that vitamin D is an important regulator of the immune system which may have implications for the development, severity and management of immune related disorders such as IBD. The efficacy of vitamin D as an immune modulator in IBD remains to be proven. This review aims to evaluate the evidence implicating vitamin D deficiency in IBD pathogenesis, to examine vitamin D's anti inflammatory mechanisms and to explore its therapeutic potential, optimal serum levels and dietary intakes which may support immune function in this disease. PMID- 22493990 TI - Bound context features are integrated at encoding. AB - In the present research, we tested the predictions of different accounts of context binding in "remember" judgements. Context binding, defined as the stochastically dependent retrieval of two different context features, has previously been suggested to be due to mechanisms operating at retrieval either by cueing among context features (Meiser & Broder, 2002) or by cueing between item and context features (Starns & Hicks, 2008). These accounts, however, do not make specific assumptions regarding the underlying memory representation supporting context binding. By contrast, here we propose that a binding process at encoding integrates item and context information into a coherent memory representation. Varying the presentation of the context features during encoding either with both context features presented simultaneously or with features spread over two encoding episodes, data from two experiments corroborate the notion that binding is produced at encoding. This result suggests that a binding process integrating the context features at encoding is necessary for stochastically dependent retrieval of context features. PMID- 22493991 TI - Assembly of naturally occurring glycosides, evolved tactics, and glycosylation methods. AB - Glycosylation of proteins and lipids is critical to many life processes. Secondary metabolites (or natural products), such as flavonoids, steroids, triterpenes, and antibiotics, are also frequently modified with saccharides. The resulting glycosides include diverse structures and functions, and some of them have pharmacological significance. The saccharide portions of the glycosides often have specific structural characteristics that depend on the aglycones. These molecules also form heterogeneous "glycoform" mixtures where molecules have similar glycosidic linkages but the saccharides vary in the length and type of monosaccharide unit. Thus, it is difficult to purify homogeneous glycosides in appreciable amounts from natural sources. Chemical synthesis provides a feasible access to the homogeneous glycosides and their congeners. Synthesis of a glycoside involves the synthesis of the aglycone, the saccharide, the connection of these two parts, and the overall manipulation of protecting groups. However, most synthetic efforts to date have focused on the aglycones, treating the attachment of saccharides onto the aglycones as a dispensable topic. The synthesis of the aglycone and the synthesis of the saccharide belong to two independent categories of chemistry, and different types of the aglycones and saccharides pose as specific synthetic subjects in their own disciplines. The only reaction that integrates the broad chemistry of glycoside synthesis is the glycosidic bond formation between the saccharide and the aglycone. Focusing on this glycosylation reaction in this Account, we string together our experience with the synthesis of the naturally occurring glycosides. We briefly describe the synthesis of 18 glycosides, including glycolipids, phenolic glycosides, steroid glycosides, and triterpene glycosides. Each molecule represents a prototypical structure of a family of the natural glycosides with interesting biological activities, and we emphasize the general tactics for the synthesis of these diverse structures. We provide a rationale for four tactics for the synthesis of glycosides, based on the stage at which the glycosidic bond is formed between the saccharide and the aglycone. This choice of tactic determines the success or failure of a synthesis, and the flexibility and the overall efficiency of the synthesis as well. Toward the synthesis of heterogeneous glycoform mixtures, we discuss successive and random glycosylation reactions. Finally, we have developed two new glycosylation protocols that address the challenges in the glycosylation of aglycones that are poorly nucleophilic, extremely acid labile, or extremely electrophilic. One of these new protocols takes advantage of glycosyl trifluoroacetimidate donors, and a second protocol uses gold(I)-catalyzed glycosylation with glycosyl ortho-alkynylbenzoate donors. PMID- 22493992 TI - Pleiotropic effects of membrane cholesterol upon translocation of protein across the endoplasmic reticulum membrane. AB - Various proteins are translocated through and inserted into the endoplasmic reticulum membrane via translocon channels. The hydrophobic segments of signal sequences initiate translocation, and those on translocating polypeptides interrupt translocation to be inserted into the membrane. Positive charges suppress translocation to regulate the orientation of the signal sequences. Here, we investigated the effect of membrane cholesterol on the translocational behavior of nascent chains in a cell-free system. We found that the three distinct translocation processes were sensitive to membrane cholesterol. Cholesterol inhibited the initiation of translocation by the signal sequence, and the extent of inhibition depended on the signal sequence. Even when initiation was not inhibited, cholesterol impeded the movement of the positively charged residues of the translocating polypeptide chain. In surprising contrast, cholesterol enhanced the translocation of hydrophobic sequences through the translocon. On the basis of these findings, we propose that membrane cholesterol greatly affects partitioning of hydrophobic segments into the membrane and impedes the movement of positive charges. PMID- 22493993 TI - Successful use of a gonadotropin-releasing hormone (GnRH) analog for the treatment of tertiary hypogonadism (GnRH deficiency) in a 5-year-old Belgian Blue bull. AB - A bull was referred for a progressive oligoasthenotheratozoospermia that resulted in a unsuitable seminal quality for the cryopreservation. Breeding soundness evaluation results suggested gonadal dysfunction. Because of the lack of normal ranges for these hormones in the bull, in this study, the hypogonadism and the site of the dysfunction (hypothalamus) were diagnosed by the gonadotropin releasing hormone (GnRH) stimulation test. The evaluation of pituitary and testicular responsiveness by a GnRH stimulating test revealed a responsiveness of the pituitary and testis, thus a secondary hypogonadism (hypothalamic hypogonadism) was postulated and a therapeutic approach based on the subcutaneous administration of GnRH analog was attempted. An increase in semen volume, concentration and sperm characteristics were detected 9 weeks after the start of the treatment, corroborating the hypothalamic origin of the disease and the useful of the GnRH therapy. PMID- 22493994 TI - Recent overview of ocular patents. AB - Ocular drug therapy has always been considered as a major challenge in the field of drug delivery. The presence of blood ocular barriers and efflux pumps has imposed a great concern as well. Various vision threatening disorders require a long term therapy of drug molecules, especially for the diseases that affect the posterior segment. Pharmaceutical companies and other research institutes have adopted a multidisciplinary approach to meet the current challenges which is evidenced by the trends seen in the published and filed U.S. patents. Various strategies have been employed to achieve long term sustained and targeted delivery for both the anterior and the posterior segments of the ocular diseases. These strategies include formulating drugs into implant, micro or nanoparticulate systems and hydrogel-based systems. Transporter targeted approach has also allowed scientists to deliver drugs to both the segments of the eye. Recent developments such as delivery of drugs utilizing ultrasound, iontophoresis and microneedle based devices have been promising. Genebased therapeutics has opened a new avenue for vision threatening disorders. In all, the current developments in the entire field have been very exciting for finding out new strategies to treat vision threatening disorders. PMID- 22493995 TI - Enhancing atmospheric mercury research in China to improve the current understanding of the global mercury cycle: the need for urgent and closely coordinated efforts. AB - The current understanding of the global mercury (Hg) cycle remains uncertain because Hg behavior in the environment is very complicated. The special property of Hg causes the atmosphere to be the most important medium for worldwide dispersion and transformation. The source and fate of atmospheric Hg and its interaction with the surface environment are the essential topics in the global Hg cycle. Recent declining measurement trends of Hg in the atmosphere are in apparent conflict with the increasing trends in global anthropogenic Hg emissions. As the single largest country contributor of anthropogenic Hg emission, China's role in the global Hg cycle will become more and more important in the context of the decreasing man-made Hg emission from developed regions. However, much less Hg information in China is available. As a global pollutant which undergoes long-range transport and is persistence in the environment, increasing Hg knowledge in China could not only promote the Hg regulation in this country but also improve the understanding of the fundamental of the global Hg cycle and further push the abatement of this toxin on a global scale. Then the atmospheric Hg research in China may be a breakthrough for improving the current understanding of the global Hg cycle. However, due to the complex behavior of Hg in the atmosphere, a deeper understanding of the atmospheric Hg cycle in China needs greater cooperation across fields. PMID- 22493996 TI - Photoswitchable oligonucleotide-modified gold nanoparticles: controlling hybridization stringency with photon dose. AB - We describe a new class of stimulus-responsive DNA-functionalized gold nanoparticles that incorporate azobenzene-modified oligonucleotides. Beyond the classic directed assembly and sensing behaviors associated with oligonucleotide modified nanoparticles, these particles also exhibit reversible photoswitching of their assembly behavior. Exposure to UV light induces a trans-cis isomerization of the azobenzene which destabilizes the DNA duplex, resulting in dissociation of the nanoparticle assemblies. The isomerization is reversible upon exposure to blue light, resulting in rehybridization and reassembly of the DNA-linked nanoparticle clusters. We show that perfectly complementary and partially mismatched strands exhibit clearly distinguishable photoinduced melting properties, and we demonstrate that photon dose can thus be used in place of temperature or ionic strength to control hybridization stringency with the ability to discriminate single-base mismatches. PMID- 22493997 TI - Beyond the distinction between biomedical and social dimensions of HIV prevention through the lens of a social public health. AB - Developing effective HIV prevention requires that we move beyond the historical but problematic distinction between biomedical and social dimensions of HIV. The current claim that prevention has failed has led to a strong interest in the role of treatment as HIV prevention; however, the turn to "biomedical prevention," "test and treat," and "combination prevention" instances pervasive confusions about prevention. These confusions arise from a failure to realize that all HIV prevention interventions must engage with the everyday lives of people and be integrated into their social relations and social practices. We challenge the claim that prevention has failed (illustrating this with discussion of prevention in Australia, Uganda, and Zimbabwe). We explain the enduring appeal of misguided approaches to prevention by examining how 1996 can be seen as a pivotal moment in the history of the global response to HIV, a moment marked by the rise and fall of distinct biomedical and social narratives of HIV. PMID- 22493998 TI - Race/ethnicity and all-cause mortality in US adults: revisiting the Hispanic paradox. AB - OBJECTIVES: We examined the association between race/ethnicity and all-cause mortality risk in US adults and whether this association differs by nativity status. METHODS: We used Cox proportional hazards regression to estimate all cause mortality rates in 1997 through 2004 National Health Interview Survey respondents, relating the risk for Hispanic subgroup, non-Hispanic Black, and other non-Hispanic to non-Hispanic White adults before and after controlling for selected characteristics stratified by age and gender. RESULTS: We observed a Hispanic mortality advantage over non-Hispanic Whites among women that depended on nativity status: US-born Mexican Americans aged 25 to 44 years had a 90% (95% confidence interval [CI] = 0.03, 0.31) lower death rate; island- or foreign-born Cubans and other Hispanics aged 45 to 64 years were more than two times less likely to die than were their non-Hispanic White counterparts. Island- or foreign born Puerto Rican and US-born Mexican American women aged 65 years and older exhibited at least a 25% lower rate of dying than did their non-Hispanics White counterparts. CONCLUSIONS: The "Hispanic paradox" may not be a static process and may change with this population growth and its increasing diversity over time. PMID- 22493999 TI - Longitudinal associations between adolescent alcohol use and adulthood sexual risk behavior and sexually transmitted infection in the United States: assessment of differences by race. AB - OBJECTIVES: We examined race differences in the longitudinal associations between adolescent alcohol use and adulthood sexually transmitted infection (STI) risk in the United States. METHODS: We estimated multivariable logistic regression models using Waves I (1994-1995: adolescence) and III (2001-2002: young adulthood) of the National Longitudinal Study of Adolescent Health (n = 10 783) to estimate associations and assess differences between Whites and African Americans. RESULTS: In adjusted analyses, adolescent alcohol indicators predicted adulthood inconsistent condom use for both races but were significantly stronger, more consistent predictors of elevated partnership levels for African Americans than Whites. Among African Americans but not Whites, self-reported STI was predicted by adolescent report of any prior use (adjusted odds ratio [AOR] = 1.47; 95% confidence interval [CI] = 1.00, 2.17) and past-year history of getting drunk (AOR = 1.53; 95% CI = 1.01, 2.32). Among Whites but not African Americans, biologically confirmed STI was predicted by adolescent report of past-year history of getting drunk (AOR = 1.68; 95% CI = 1.07, 2.63) and consistent drinking (AOR = 1.65; 95% CI = 1.03, 2.65). CONCLUSIONS: African American and White adolescent drinkers are priority populations for STI prevention. Prevention of adolescent alcohol use may contribute to reductions in adulthood STI risk. PMID- 22494000 TI - A Smoke-Free Paso del Norte: impact over 10 years on smoking prevalence using the Behavioral Risk Factor Surveillance System. AB - OBJECTIVES: We assessed the impact of a tobacco control initiative over 10 years on cessation and prevention. METHODS: We examined 2000-2009 Behavioral Risk Factor Surveillance System cases of a metropolitan statistical area (MSA) with systematic tobacco control efforts throughout the decade (El Paso, TX) and 2 comparison MSAs similar in size and population with less coordinated tobacco control efforts (Austin-Round Rock, TX and San Antonio, TX). RESULTS: Yearly, El Paso exhibited a 6% increase in the prevalence of former smokers, a 6% decrease in prevalence of daily smokers, and a 7% decrease in the prevalence of established smoking (>= 100 cigarettes per lifetime and currently smoking); we did not observe similar trends in the comparison MSAs. There was no change in the prevalence of nondaily smokers in any of the MSAs. CONCLUSIONS: The coordinated tobacco control activities in El Paso are related to cessation among daily smokers and prevention of established smoking at the population level but have not stimulated cessation among nondaily smokers. Comprehensive tobacco control should focus more on not only daily smokers but also nondaily smokers. PMID- 22494001 TI - Research on race/ethnicity and health care discrimination: where we are and where we need to go. PMID- 22494005 TI - Destigmatizing alcohol dependence: the requirement for an ethical (not only medical) remedy. AB - The disease model of alcohol dependence or "alcoholism" is often presented as the linchpin in addressing the condition successfully. It has been argued, for example, that adopting a medical approach will reduce the stigma that impedes the provision and acceptance of treatment. However, the medical paradigm has existed for many years without significantly affecting the negative social attitudes that surround dependence. I argue that a reductive scientific approach is not equipped to address the socioethical tensions that dependence creates. To lessen the stigmatization of dependence, it is important to integrate ethical analysis into policy debates on the condition. PMID- 22494006 TI - A retrospective view on the viability of water fluoridation in South Africa to prevent dental caries. AB - OBJECTIVES: Despite a Commission of Inquiry into water fluoridation recommending the fluoridation of public water supplies to the optimal fluoride concentration of 0.7 ppm, as well as regulations for the introduction of water fluoridation which compel water providers to fluoridate public water supplies, no artificially fluoridated water scheme exists in South Africa. In view of concerns expressed by South African local authorities about cost and reports urging further investigation into the effectiveness of water fluoridation, the aim of this study was to determine whether water fluoridation is still a viable option to reduce dental caries in South Africa. METHODS: A model based on a cost evaluation of 44 communities in Florida, United States, and applied to South Africa was used as the basis for this study. Twenty-three input variables were used to create a computerized model which was populated with 2006 and 2011 data. Per capita cost, cost-effectiveness ratio and cost-benefit ratio were calculated as economic outputs to facilitate decision making for projected caries reductions of 15%, 30% and 50%. RESULTS: The average per capita cost of water fluoridation for all category water providers combined is US$0.28 in 2006 and US$0.35 in 2011, an increase of 23.2% over this period. The average cost-effectiveness for all water providers combined varies from US$3.32 for a 50% to US$11.08 for a 15% caries reduction. Despite higher cost-effective values for some cities and towns, the cost per person per year to save one Decayed, Missing or Filled Tooth (DMFT) at a projected caries reduction of at least 15% as a result of the introduction of water fluoridation, is at least 48.4% less than the cost of a two surface restoration. The average cost-benefit for all water providers combined varies from 0.1 at a 50% to 0.34 at a 15% caries reduction. For both cost-effectiveness and cost-benefit ratio better results are achieved when the projected caries reduction increases. CONCLUSIONS: The results of this study show that water fluoridation is still a viable option to prevent dental caries in communities in South Africa along with the reduction in the prevalence of dental caries and increases in economically driven variables. PMID- 22494002 TI - The state of research on racial/ethnic discrimination in the receipt of health care. AB - OBJECTIVES: We conducted a review to examine current literature on the effects of interpersonal and institutional racism and discrimination occurring within health care settings on the health care received by racial/ethnic minority patients. METHODS: We searched the PsychNet, PubMed, and Scopus databases for articles on US populations published between January 1, 2008 and November 1, 2011. We used various combinations of the following search terms: discrimination, perceived discrimination, race, ethnicity, racism, institutional racism, stereotype, prejudice or bias, and health or health care. Fifty-eight articles were reviewed. RESULTS: Patient perception of discriminatory treatment and implicit provider biases were the most frequently examined topics in health care settings. Few studies examined the overall prevalence of racial/ethnic discrimination and none examined temporal trends. In general, measures used were insufficient for examining the impact of interpersonal discrimination or institutional racism within health care settings on racial/ethnic disparities in health care. CONCLUSIONS: Better instrumentation, innovative methodology, and strategies are needed for identifying and tracking racial/ethnic discrimination in health care settings. PMID- 22494007 TI - High kinetic stability of HXeBr upon interaction with carbon dioxide: HXeBr...CO2 complex in a xenon matrix and HXeBr in a carbon dioxide matrix. AB - We investigate the conditions when noble-gas hydrides can be found in real environments and report on the preparation and identification of the HXeBr...CO(2) complex in a xenon matrix and HXeBr in a carbon dioxide matrix. The H-Xe stretching mode of the HXeBr...CO(2) complex in a xenon matrix is observed at 1557 cm(-1), showing a spectral shift of +53 cm(-1) from the HXeBr monomer. The calculations at the CCSD(T)/aug-cc-pVTZ-PP(Xe,Br) level of theory give two stable structures for the HXeBr...CO(2) complex with frequency shifts of +55 and +103 cm(-1), respectively. On the basis of the calculations, the experimentally observed band is assigned to the more stable structure with a "parallel" geometry. The HXeBr molecule was prepared in a carbon dioxide matrix and has the H-Xe stretching frequency of 1646 cm(-1), meaning a strong matrix shift and stabilization of the H-Xe bond. The deuterated species DXeBr in a carbon dioxide matrix absorbs at 1200 cm(-1). This is the first case where a noble-gas hydride is prepared in a molecular solid. The thermal stabilities of HXeBr and HXeBr...CO(2) complex in a xenon matrix and HXeBr in a carbon dioxide matrix were examined. We have found a high thermal stability of HXeBr in carbon dioxide ice (at least up to 100 K), i.e., under conditions that may occur in nature. PMID- 22494008 TI - Comparison of matrix proteins in different types of urinary stone by proteomic analysis using liquid chromatography-tandem mass spectrometry. AB - OBJECTIVES: To analyze the crystal components and matrix proteins of urinary stones by proteomic analysis using liquid chromatography-tandem mass spectrometry. METHODS: Urinary stones were obtained from patients with gout and hyperuricemia. The outside and inside of the stones were measured non destructively with a micro area X-ray diffractometer. After stones were powdered, extracted proteins were analyzed by proteomic analysis. RESULTS: Of 17 investigated stones, seven were composed of calcium oxalate monohydrate or calcium oxalate dihydrate, seven were of uric acid, and three were a mixture of calcium oxalate monohydrate and uric acid. In calcium oxalate monohydrate or calcium oxalate dihydrate stones, osteopontin, uromodulin, albumin, protein Z, prothrombin, protein S, hemoglobin and histone H4 were identified. In uric acid stones, uromodulin, albumin, hemoglobin, calgranulins and immunoglobin G fragments were detected. Mixed stones of calcium oxalate monohydrate and uric acid contained both Ca-binding proteins and abundant proteins. Matrix proteins were different when the crystal components of the stone were different, even when from the same patient. CONCLUSIONS: Proteins, such as uromodulin and albumin, are often detected in stones, regardless of crystal components. However, osteopontin, prothrombin, protein S and protein Z are identified specifically in calcium oxalate stones. Furthermore, immunoglobin G fragments are detected in uric acid stones. The role of these specific proteins in the different types of stones can be of particular interest. PMID- 22494009 TI - Ureteroscopic holmium laser ablation of a knotted ureteral stent. AB - Ureteral stents are commonly used in urologic practice and have a number of well recognized complications. A rare complication is knotting with associated difficult removal having been reported in only 15 previous cases. Various methods of removal have been described. We report an additional case in which a ureteroscopic holmium laser was successfully used to remove a knotted ureteral stent. A literature review of all previous cases of this rare complication is also presented. PMID- 22494011 TI - The AJOB Experiment. PMID- 22494010 TI - Molecular phylogenies reveal host-specific divergence of Ophiocordyceps unilateralis sensu lato following its host ants. AB - Ophiocordyceps unilateralis (Hypocreales, Ascomycetes) is an entomopathogenic fungus specific to formicine ants (Formicinae, Hymenoptera). Previous works have shown that the carpenter ant Camponotus leonardi acts as the principal host with occasional infections of ants from the genus Polyrhachis (sister genus of Camponotus). Observations were made on the permanent plots of Mo Singto, Khao Yai National Park of Thailand according to which O. unilateralis was found to occur predominantly on three host species: C. leonardi, C. saundersi and P. furcata. Molecular phylogenies of the elongation factor 1-alpha and beta-Tubulin genes indicate a separation of O. unilateralis samples into three clades, reflecting specificity to each of the three different ant species. Samples collected from P. furcata and from C. leonardi were found to form sister groups with samples from C. saundersi forming an outgroup to the latter. Additional samples collected from unidentified ant species of Camponotus and Polyrhachis were positioned as outgroups to those samples on identified species. These results demonstrate that O. unilateralis is clearly not a single phylogenetic species and comprises at least three species that are specific to different host ant species. These cryptic species may arise through recent events of speciation driven by their specificity to host ant species. PMID- 22494012 TI - Direct peptide bioconjugation/PEGylation at tyrosine with linear and branched polymeric diazonium salts. AB - Direct polymer conjugation at peptide tyrosine residues is described. In this study Tyr residues of both leucine enkephalin and salmon calcitonin (sCT) were targeted using appropriate diazonium salt-terminated linear monomethoxy poly(ethylene glycol)s (mPEGs) and poly(mPEG) methacrylate prepared by atom transfer radical polymerization. Judicious choice of the reaction conditions-pH, stoichiometry, and chemical structure of diazonium salt-led to a high degree of site-specificity in the conjugation reaction, even in the presence of competitive peptide amino acid targets such as histidine, lysines, and N-terminal amine. In vitro studies showed that conjugation of mPEG(2000) to sCT did not affect the peptide's ability to increase intracellular cAMP induced in T47D human breast cancer cells bearing sCT receptors. Preliminary in vivo investigation showed preserved ability to reduce [Ca(2+)] plasma levels by mPEG(2000)-sCT conjugate in rat animal models. PMID- 22494013 TI - Spinal cord stimulation therapy for patients with refractory angina who are not candidates for revascularization. AB - OBJECTIVES: The aim of this study was to evaluate the safety and efficacy of spinal cord stimulation (SCS) for refractory angina. MATERIALS AND METHODS: This multicenter, randomized, single-blind, controlled trial evaluated SCS in two patient groups: high stimulation (HS) (treatment) and low stimulation (LS) (control). The HS group controlled SCS with a programmer for a minimum of two hours four times daily. The LS group received SCS therapy above the paresthesia threshold for one min once daily. The primary efficacy endpoint was number of angina attacks recorded by patients at six months. The primary safety endpoint was the major adverse cardiac event (MACE) rate at six months. RESULTS: Due to slow enrollment, a futility analysis was performed, resulting in early termination of the study. Sixty-eight patients were randomized after implantation. Mean change in angina attacks per day from baseline to six months was -1.19 +/- 2.13 (HS) and -1.29 +/- 1.66 (LS). The difference from baseline was significant within each group (both p < 0.001) but not between groups (p = 0.45). Total exercise time and time to angina onset increased significantly from baseline to six months within each group (both p = 0.02 and 0.002) but not between groups (p = 0.52 and 0.51). MACE was similar between groups. CONCLUSION: Although this study was terminated early, the results obtained at six months suggest that SCS (HS) is not more effective than the control (LS) in patients with refractory angina. PMID- 22494014 TI - DDX39 acts as a suppressor of invasion for bladder cancer. AB - The object of the present study was to identify markers for predicting urinary bladder cancer progression by comparative proteome analysis of bladder cancers and paired normal mucosas. We found that DDX39 was overexpressed in four of six bladder cancers examined compared with respective control tissues. Immunohistochemical analysis using 303 bladder cancer specimens revealed that DDX39 was inversely correlated to pT stage and histological grade progression. The incidence of DDX39(high) tumors (positive cells >=50%) was 68.6%, 43.5%, 20.0%, and 5.3% in pTa, pT1, pTis, and >=pT2 tumors, respectively, and 65.2%, 60.7%, and 19.6% in G1, G2, and G3 tumors, respectively. The incidence of DDX39(high) tumors was significantly lower in pT1 and >=pT2 compared to pTa tumors, and also significantly lower in G3 compared to G1 and G2 tumors. Follow up analysis (n = 105) revealed that DDX39(low) tumors (positive cells <50%) were associated with disease progression (hazard ratio 7.485; P = 0.0083). Furthermore, DDX39-knockdown bladder cancer cells increased their invasion ability compared to negative control cells. These results suggest that DDX39 is a suppressor of invasion and loss of its function predicts disease progression in bladder cancers. PMID- 22494015 TI - Water-soluble iron oxide nanocubes with high values of specific absorption rate for cancer cell hyperthermia treatment. AB - Iron oxide nanocrystals (IONCs) are appealing heat mediator nanoprobes in magnetic-mediated hyperthermia for cancer treatment. Here, specific absorption rate (SAR) values are reported for cube-shaped water-soluble IONCs prepared by a one-pot synthesis approach in a size range between 13 and 40 nm. The SAR values were determined as a function of frequency and magnetic field applied, also spanning technical conditions which are considered biomedically safe for patients. Among the different sizes tested, IONCs with an average diameter of 19 +/- 3 nm had significant SAR values in clinical conditions and reached SAR values up to 2452 W/g(Fe) at 520 kHz and 29 kAm(-1), which is one of the highest values so far reported for IONCs. In vitro trials carried out on KB cancer cells treated with IONCs of 19 nm have shown efficient hyperthermia performance, with cell mortality of about 50% recorded when an equilibrium temperature of 43 degrees C was reached after 1 h of treatment. PMID- 22494016 TI - A pilot study of systolic dyssynchrony index by real time three-dimensional echocardiography and Doppler tissue imaging parameters predicting the hemodynamic response to biventricular pacing in the early postoperative period after cardiac surgery. AB - OBJECTIVE: To evaluate systolic dyssynchrony index (SDI) measured by real time three-dimensional echocardiography (RT3DE) and Doppler tissue imaging (DTI) dyssynchrony parameters in predicting the hemodynamic response to biventricular (BIV) pacing in the early postoperative period after cardiac surgery. To compare right ventricular (RV) and BIV pacing using invasively measured hemodynamic values. METHODS: A prospective randomized clinical study enrolling 11 patients with ischemic heart disease, concomitant valvular heart disease, and left ventricular ejection fraction (LVEF) <= 35% comparing preoperative SDI by RT3DE and DTI LV dyssynchrony parameters to hemodynamic values obtained during RV or BIV sequential (DDD) epicardial pacing in the first 72 hours after cardiac surgery. RESULTS: BIV pacing produced a statistically significant higher cardiac output (CO) (6.27 +/- 1.55 L/min) and cardiac index (CI) (3.44 +/- 0.93 L/min per m(2) ) than RV pacing (CO 5.44 +/- 0.97 L/min, CI 3.03 +/- 0.83 L/min per m(2) , P < 0.05). We found a statistically moderate correlation between preoperative SDI by RT3DE and CO (r = 0.596, P < 0.05) and a nonsignificant correlation to CI (r = 0.535, P < 0.10) during BIV pacing. No correlation was observed between DTI dyssynchrony parameters and measured hemodynamic values. BIV pacing reduced the ICU stay and inotropic support requirements of patients after heart surgery. CONCLUSIONS: SDI measured preoperatively using RT3DE can predict CO during BIV pacing in the early postoperative period after cardiac surgery. BIV pacing is more hemodynamically effective than RV pacing in patients with LV dysfunction after coronary artery bypass grafting with or without a valve procedure. PMID- 22494017 TI - Molecular and immunological characterization of a novel 32-kDa secreted protein of Babesia microti. AB - A cDNA encoding the Babesia microti 32-kDa protein was identified by serological immunoscreening of a cDNA expression library and designated as BmP32. The full length of BmP32 contains an open reading frame of 918 base pairs consisting of 306 amino acids having a significant homology with B. microti secreted antigen 1. Antiserum raised against recombinant protein (rBmP32) specifically reacted with a 32-kDa native protein of the parasite lysate using western blot analysis. The indirect immunofluorescent antibody test showed a preferable localization of BmP32 in the cytoplasm of the intra- and extracellular parasites. Moreover, BmP32 was secreted in the cytosol of infected erythrocytes, especially during the peak parasitemia and the recovery phase of the infection. Next, the antigenicity of rBmP32 was examined by an enzyme-linked immunosorbent assay (ELISA) and sera from mice experimentally infected with either B. microti or closely related parasites. ELISA was highly specific and sensitive when used for the detection of B. microti antibody in a mouse model. Furthermore, mice immunized with rBmP32 emulsified with Freund's adjuvant were not significantly protected against challenge infection with B. microt i. However, high antibody titer was detected just before the challenge infection. Our data suggest that rBmP32 may be a specific diagnostic antigen but not a subunit vaccine. PMID- 22494018 TI - Glycemic effectiveness and medication adherence with fixed-dose combination or coadministered dual therapy of antihyperglycemic regimens: a meta-analysis. AB - OBJECTIVES: To compare effects of fixed-dosed combinations (FDCs) and coadministered dual therapy (CDT) of antihyperglycemic agents on glycemic control (i.e., HbA(1c)) and medication adherence. METHODS: A systematic literature review and meta-analysis were performed to compare the HbA(1c) response and medication adherence between the two drug regimens. Selected articles were limited to studies that compared equivalent drug components within FDC and CDT. Searches used PubMed, Embase, Web of Knowledge, and Cochrane databases. The search results were independently screened and reviewed by two authors (SH, KI). Of the 1246 identified abstracts, 152 articles were reviewed, and ten met the inclusion criteria. Results were extracted and pooled in a meta-analysis, using a random effects model. Cohort comparisons were described as mean differences (MDs) with 95% confidence intervals (CIs). RESULTS: The ten articles that met the inclusion criteria had a total study size of 70,573 patients. Four articles reported HbA(1c) results, which had a total of five cohort comparisons of FDC and CDT use. The meta-analysis revealed a significantly greater HbA(1c) reduction with FDC (MD = -0.53% [95% CI: -0.78, -0.28]; p < 0.0001). Eight studies evaluated medication adherence (measured as medication possession ratio [MPR]). Of the eight studies reporting MPR results, a total of 12 cohort comparisons were made and were further divided into three subgroups based on comparison types. Five comparisons described MPR for FDC versus CDT cohorts, with significantly higher MPR with FDC (MD = 8.6% [95% CI: 1.6, 15.6]; p = 0.0162]). Four comparisons examined patients who switched from monotherapy to FDC or CDT, with higher MPR for patients who switched to FDC (MD = 7.7% [95% CI: 5.7, 9.6]; p < 0.0001). Three comparisons described results for patients who switched from CDT to FDC or stayed on CDT, with higher MPR for patients who switched to FDC (MD = 5.0% [95% CI: 3.1, 6.8]; p < 0.0001). LIMITATIONS: A limited number of published studies were available for this meta-analysis and all of those included were observational studies. There was heterogeneity between studies in the statistical methods used to control for confounding variables and differing population characteristics. CONCLUSIONS: In a meta-analysis, use of FDCs with antihyperglycemic agents was associated with lower HbA(1c) and higher MPR values compared to CDT use in patients with type 2 diabetes. PMID- 22494019 TI - A novel approach to the evaluation of bleeding-related episodes in patients with chronic immune thrombocytopenia. AB - OBJECTIVE: In clinical studies of patients with severe thrombocytopenia, rescue treatments are used to prevent or stop bleeding. Estimating risk reductions of bleeding for clinical study medications can be challenging. This study evaluated a new and possibly more accurate way of assessing the effects of a treatment intervention on bleeding-related outcomes. We developed a composite endpoint, termed bleeding-related episodes (BRE). RESEARCH DESIGN AND METHODS: BREs were assessed in a post-hoc analysis of patients with chronic immune thrombocytopenia (ITP) who participated in two romiplostim, phase 3, placebo-controlled studies. Patients received romiplostim or placebo once weekly for 24 weeks. A BRE was defined as an actual bleeding event and/or the use of rescue medication. In total, 125 patients (41 placebo, 84 romiplostim) with platelet counts <30 K were enrolled. CLINICAL TRIAL REGISTRATION: NCT00102323/NCT00102336. RESULTS: The rate of all BREs across all studies was reduced by 56% in patients receiving romiplostim compared with placebo. The rate of BREs using immunoglobulin (IVIg or anti-D Ig) was reduced by 89% in patients receiving romiplostim compared with placebo. BREs were more frequent in both groups at platelet counts <50 * 10(9)/L. Results were similar between splenectomized and nonsplenectomized patients. We believe that prior to the development of this tool, bleeding events were underdiagnosed. The BRE tool allowed the identification of multiple interventions within bleeding episodes, which may have required separate interventions and were therefore considered to be additional BREs. CONCLUSIONS: In this study, the composite endpoint of a bleeding event and the use of rescue medication within close proximity of the bleeding event appears to be feasible and informative. The BRE tool allows for more precise understanding of the effect of rescue therapies in ITP and has broader applications to future clinical trials where assessment of bleeding risk can be complicated or masked by rescue interventions. LIMITATIONS: This was a post hoc analysis. The assignment of platelet counts to a BRE was based on the platelet count on the first day of a BRE, which may not reflect the platelet count during the entire episode, and the assignment of platelet counts was based on the estimation required for events that occurred between weekly measurements. PMID- 22494021 TI - Time-resolved photoinduced thermoelectric and transport currents in GaAs nanowires. AB - In order to clarify the temporal interplay of the different photocurrent mechanisms occurring in single GaAs nanowire based circuits, we introduce an on chip photocurrent pump-probe spectroscopy with a picosecond time resolution. We identify photoinduced thermoelectric, displacement, and carrier lifetime limited currents as well as the transport of photogenerated holes to the electrodes. Moreover, we show that the time-resolved photocurrent spectroscopy can be used to investigate the drift velocity of photogenerated carriers in semiconducting nanowires. Hereby, our results are relevant for nanowire-based optoelectronic and photovoltaic applications. PMID- 22494020 TI - Characterizing and understanding body weight patterns in patients treated with pregabalin. AB - OBJECTIVE: We examined patterns of weight change among patients treated with pregabalin for up to 1 year. METHODS: Patients with >=1 pre-treatment weight measurement, >=2 measurements in Period 1 (day 2-56), and >=2 during Period 2 (day 57-356) were identified from pooled data of 106 studies including 43,525 patients. Seven patterns were developed and used for exploratory 'change point' analyses (day on-treatment when weight-change trend changed from initial trajectory) and to assess patterns of weight change by baseline weight/body mass index (BMI). RESULTS: A total of 3187 patients (from 41 studies) were eligible. 98.9% of patients were described by three of the seven patterns. The majority of patients (2607/3187 [81.8%]) remained within +/-7% of baseline weight ('Pattern 4'). Fewer patients (463/3187 [14.5%]) were 'delayed weight gainers' (exceeded 7% weight gain in Period 2 but not Period 1 ['Pattern 6']), fewer still (82/3187 [2.6%]) were 'early weight gainers' (exceeded >=7% baseline weight in Period 1 and remained above 7% or continued to gain weight in Period 2 ['Pattern 7']). Overall weight gainers (Patterns 6, 7) experienced 1-year weight gain (median [% change]) of +6.20 kg [+9.12%] and 5.46 kg [+13.9%] vs. 2.22 kg [+2.10%] for non weight gainers (Pattern 4). Average baseline weight/BMI was lower for weight gainers (Patterns 6, 7) versus other patterns. Early weight gainers (Pattern 7) had change point day at day 40 versus day 54 for Pattern 4 and day 69 for Pattern 6. Use of concomitant medications and influence of comorbid conditions on weight should be considered as inherent variables when interpreting the study. CONCLUSIONS: The majority of patients treated with pregabalin (150-600 mg/day) for 1 year maintained weight within +/-7% baseline weight. One in six patients gained >=7% weight from baseline, and generally exceeded 7%, 2-12 months after treatment onset. PMID- 22494022 TI - Laughter-induced left bundle branch block. AB - We present the case of a patient with ischemic heart disease and intermittent left bundle branch block, reproducibly induced by laughter. Following treatment of ischemia with successful deployment of a drug-eluting stent, no further episodes of inducible LBBB were seen. Transient ischemia, exacerbated by elevated intrathoracic pressure during laughter, may have contributed to onset of this phenomenon. PMID- 22494023 TI - Sol-flame synthesis: a general strategy to decorate nanowires with metal oxide/noble metal nanoparticles. AB - The hybrid structure of nanoparticle-decorated nanowires (NP@NW) combines the merits of large specific surface areas for NPs and anisotropic properties for NWs and is a desirable structure for applications including batteries, dye-sensitized solar cells, photoelectrochemical water splitting, and catalysis. Here, we report a novel sol-flame method to synthesize the NP@NW hybrid structure with two unique characteristics: (1) large loading of NPs per NW with the morphology of NP chains fanning radially from the NW core and (2) intimate contact between NPs and NWs. Both features are advantageous for the above applications that involve both surface reactions and charge transport processes. Moreover, the sol-flame method is simple and general, with which we have successfully decorated various NWs with binary/ternary metal oxide and even noble metal NPs. The unique aspects of the sol-flame method arise from the ultrafast heating rate and the high temperature of flame, which enables rapid solvent evaporation and combustion, and the combustion gaseous products blow out NPs as they nucleate, forming the NP chains around NWs. PMID- 22494024 TI - Locally resolved membrane binding affinity of the N-terminus of alpha-synuclein. AB - alpha-Synuclein is abundantly present in Lewy bodies, characteristic of Parkinson's disease. Its exact physiological role has yet to be determined, but mitochondrial membrane binding is suspected to be a key aspect of its function. Electron paramagnetic resonance spectroscopy in combination with site-directed spin labeling allowed for a locally resolved analysis of the protein-membrane binding affinity for artificial phospholipid membranes, supported by a study of binding to isolated mitochondria. The data reveal that the binding affinity of the N-terminus is nonuniform. PMID- 22494025 TI - Vitamin D levels in pregnant women booking for antenatal care in Far North Queensland. AB - Serum concentrations of vitamin D were measured in pregnant women booking for antenatal care in Cairns Base Hospital, Queensland. Of 116 women, none was found to be vitamin D deficient. With a threshold of 50 nmol/L, no woman demonstrated vitamin D insufficiency; with a threshold of 75 nmol/L, 6.9% would have mild insufficiency. Further investigation into vitamin D concentrations of women living in northern Australia is required before recommendations are made for universal vitamin D screening of all pregnant women in Australia. PMID- 22494026 TI - A new flavonol from Oxytropis ochrocephala Bunge. AB - A new acylated flavonoid, 3-O-rhamnocitrin-6-O-benzoyl-beta-D-glucopyranoside (1), together with five known flavonoids, rhamnocitrin (2), pratensein (3), (3R) 7,3'-dihydroxy-2',4'-dimethoxyisoflavan (4), (3R)-7,2'-dihydroxy-3',4' dimethoxyisoflavan (5) and isoliquiritigenin (6), was isolated from Oxytropis ochrocephala Bunge. The structural elucidation of the isolated compounds was primarily based on HRESIMS, IR and 1-D- and 2-D-NMR analyses. PMID- 22494027 TI - Repair of dilated aortic root and sinotubular junction using a stabilizer ring. AB - Aortic root aneurysm and dissection are potentially life-threatening conditions that involve a structural weakness of the aortic wall. Management of aortic root aneurysm (with or without aortic insufficiency) has recently been the subject of much scholarly discussion which resulted in some modifications. The current trend is a valve-sparing root repair or replacement as well as preserving or restoring the diameter of the aortic annulus and sinutubular junction. This manuscript reviews the etiology and diagnosis of aortic root aneurysm or dilated aortic annulus as well as a novel treatment approach. A newly patented apparatus that restores and repairs the aortic annulus and sinotubular junction is reviewed. PMID- 22494028 TI - Prospective comparison of outcomes of percutaneous nephrolithotomy in elderly patients versus younger patients. AB - PURPOSE: The purpose of the study was to prospectively compare operative and postoperative characteristics and outcomes in elderly patients undergoing percutaneous nephrolithotomy (PCNL) compared with younger patients. PATIENTS AND METHODS: Prospectively collected data from the Clinical Research Office of the Endourological Society (CROES) Global PCNL Study database were used. Elderly patients were defined as those aged 70 years and above, while younger patients were those between 18 and 70 years of age. Matched and unmatched group comparisons were performed based on imaging modality used for assessing stone free status. Patient characteristics, operative data, and postoperative outcomes were compared. RESULTS: The median age of the elderly group vs the young group was 74 years (range 70-93 years) vs 49 years. In the unmatched analysis, staghorn stones were seen at higher rates in the elderly group (27.8% vs 21.8%, P=0.014); however, the mean stone size was not significantly different (465.0 vs 422.8, P=0.063). The length of hospitalization was significantly longer in the elderly group compared with the young group in the unmatched analysis (5 days vs 4.1 days, P<0.001). The same difference was not apparent in the matched analysis (5.0 days vs 4.4 days, P=0.288). Overall complication rates were not significantly different in the unmatched analysis. In the matched analysis, however, a statistically significant higher rate of overall complications was seen. Stone free rates were similar among all groups. CONCLUSION: PCNL in elderly patients over the age of 70 years produces results comparable to those seen in younger patients. With only a slightly higher-be it statistically significant complication rate, the stone-free rate in older patients was the same as in the younger group. PMID- 22494029 TI - Post-translational modification of human heat shock factors and their functions: a recent update by proteomic approach. AB - Heat shock factors (HSFs) are vital for modulating stress and heat shock-related gene expression in cells. The activity of HSFs is controlled largely by post translational modifications (PTMs). For example, basal phosphorylation of HSF1 on three serine sites suppresses the heat shock response, and hyperphosphorylation of HSF1 on several other serine and threonine sites by stress-activated kinases results in its activation, while acetylation on K80 inhibits its DNA-binding ability. Sumoylation of HSF2 on K82 regulates its DNA-binding ability, whereas sumoylation of HSF4B on K293 represses its transcriptional activity. With the advancement of proteomic technology, novel PTM sites on various HSFs have been identified with the use of tandem mass spectrometry (MS/MS), but the functions of many of these PTMs are still unclear. Yet, it should be noted that the discovery of these novel PTM sites provided the necessary evidence for the existence of these PTM marks in vivo. Followed by subsequent functional analysis, this would ultimately lead to a better understanding of these PTM marks. MS/MS-based proteomic approach is becoming a gold standard in PTM validation in the field of life science. Here, the recent literature of all known PTMs reported on human HSFs and the resulting functions will be discussed. PMID- 22494030 TI - Weekend catch-up sleep is associated with decreased risk of being overweight among fifth-grade students with short sleep duration. AB - Previous studies have reported a relationship between short sleep duration and childhood overweight. Although school-aged children tend to compensate for weekday sleep deficit by increasing weekend sleep duration, the association between weekend catch-up sleep and childhood overweight remains unclear. This study aimed to examine the relationship between weekend catch-up sleep and being overweight in children. A total of 936 school children (48.2% boys) aged 10 or 11 years participated in this school-based cohort study. Anthropometric measurements including height and body weight were carried out. We obtained data on sleep patterns, lifestyle and parent characteristics using questionnaires. The main outcome measure was childhood overweight. After adjusting for the relevant confounding variables (age, sex, breakfast eating, screen time and parental obesity), longer sleep on weekdays and weekends was associated with decreased odds of childhood overweight (OR: 0.68; 95% CI: 0.54-0.86; OR: 0.64; 95% CI: 0.53 0.77, respectively). Participants with increased catch-up sleep duration during weekends also had decreased odds of being overweight (OR: 0.67; 95% CI: 0.53 0.85). There was an interaction between weekday sleep duration and weekend catch up sleep in relation to childhood overweight, and this effect of weekend catch-up sleep on being overweight was stronger as the participants slept less on weekdays (P = 0.024). These results indicate that weekend catch-up sleep is independently associated with decreased risk of being overweight in fifth-grade students, and this effect can be varied by the weekday sleep duration. A prospective study is required to confirm this observation. PMID- 22494031 TI - Self-reported ability to concentrate in patients with painful temporomandibular disorders compared to the general population. AB - OBJECTIVES: This study explored whether patients with painful temporomandibular disorders (TMD) differ from the general population in the frequency of self reported disability to concentrate, because altered processing of sensory information had been reported previously. Additionally, the correlation of the frequency of concentration problems with the dysfunctional grade of TMD pain shall be evaluated. METHODS: Subjects were 286 consecutive German patients with painful TMD diagnosed using the Research Diagnostic Criteria (RDC/TMD) and 2026 members of a representative German community sample. Concentration was measured using two questions, one from the 'Oral Health Impact Profile (OHIP-49 G)' and one from the German version of 'Center for Epidemiologic Studies - Depression Scale (CES-D)'. The dysfunctional grade of TMD pain was measured using the Graded Chronic Pain Scale. RESULTS: Responses between the two individual questions concerning the ability to concentrate (OHIP item and CES-D item) correlated moderately (r(Spearman) = 0.58, P < 0.001). A two-sample test of proportions revealed that patients with TMD pain reported a significantly greater frequency of 'fairly often' or 'very often' occurring concentration problems, 24.0%, than did the general population subjects, 1.2% (P < 0.001). Moreover, the frequency of concentration problems correlated with an increase in dysfunctional pain grade in the patients with TMD pain (tetrachoric correlation coefficient of 0.52, P < 0.001). CONCLUSIONS: Self-reported frequency of concentration problems is greater in patients with TMD pain than in the general population and is reported at a higher frequency in patients with more severe dysfunctional pain grades. These findings are consistent with the concept that TMD pain is associated with changes in the central processing. PMID- 22494032 TI - The genus Guerrerostrongylus (Nematoda: Heligmonellidae) in cricetid rodents from the Atlantic rain forest of Misiones, Argentina: emended description of Guerrerostrongylus zetta (Travassos, 1937) and description of a new species. AB - Two species of Guerrerostrongylus Sutton and Durette-Desset, 1991, are reported in cricetid rodents from the Atlantic rain forest of Misiones, Argentina. Guerrerostrongylus zetta (Travassos, 1937) is redescribed on the basis of material collected from Oligoryzomys nigripes from Argentina and material loaned by CHIOC from Brazil. It is characterized by a synlophe with about 40-45 (35-48) well-developed cuticular ridges, caudal bursa with long rays 6 and dorsal ray divided at mid-length, and well-sclerotized spicules with marked twisting. It was found with a prevalence of 100% in O. nigripes (14 hosts examined); however, it was not found in its type host Nectomys squamipes (4 hosts examined). Guerrerostrongylus ulysi n. sp., which is described from Sooretamys angouya , differs from the remaining species in the genus mainly by a synlophe with a strong reduction of the cuticular ridges and struts on the right side, and by a heart-shaped caudal bursa, with short rays 6 and a dorsal ray divided distally. It was found with a prevalence of 100% in 5 hosts examined. PMID- 22494033 TI - Characterisation and applications of microcapsules obtained by interfacial polycondensation. AB - This review highlights the materials, mechanisms and applications of microencapsulation by interfacial polycondensation in different areas. This technology entraps active ingredients inside microcapsules/microspheres, having an average diameter ranging from nanosize to several 100 u. Polycondensation reactions take place at the boundary of two phases to form the shells of microcapsules or matrix microspheres. The emulsion can be classified into three types: water-in-oil, oil-in-water and oil-in-oil. According to the hydrophilic lipophilic property of core phase, different active substances, such as proteins, enzymes, insecticides, herbicides, vitamins, catalysts, drugs, essential oils, dyes and phase change materials, have been successfully incorporated into different microcapsules/microspheres. Based on the shell-forming materials, this technology is capable of preparing polyamine, polyurea, polyurethane, polythiourea, polyester, polyepoxide, polyacrylamide and polysiloxane microcapsules. Over the past two decades, microcapsules prepared by interfacial polycondensation have been widely used in carbonless paper, cosmetics, pharmacy, agriculture, energy storage/transfer, thermal insulation/regulation and information and magnetic recording. PMID- 22494034 TI - Cardiac involvement in hereditary-transthyretin related amyloidosis. AB - Hereditary transthyretin-related amyloidosis remains a widely underdiagnosed condition, owing to its extreme phenotypic variability: the clinical spectrum of the disease ranges from an almost exclusive neurologic involvement to strictly cardiac manifestations. This heterogeneity is linked to several factors including specific transthyretin mutations, geographic distribution and endemic vs. non endemic aggregation type. The existence of exclusively or predominantly cardiac phenotypes makes the recognition of the disease very challenging since it can mimic other more common causes of left ventricular "hypertrophy". Assessment of such patients should include an active search for possible red flags that can indicate the correct final diagnosis. PMID- 22494035 TI - Two-dimensional color Doppler echocardiography for left ventricular stroke volume assessment: a comparison study with three-dimensional echocardiography. AB - AIM: Whether measurement of left ventricular outflow tract diameter (LVOTd) using color Doppler (CD) in order to more accurately define LVOTd is more accurate for determination of stroke volume (SV) than gray scale and compare it with direct measurement of LVOT area (a) using three-dimensional echocardiography (3DE) for SV determination. METHODS AND RESULTS: Twenty-one volunteers were examined. LVOTa was calculated by two-dimensional echocardiography (2DE) using the following formula: pi* (d/2)(2) , d = LVOT diameter by gray scale and CD, respectively. Planimetry of LVOTa was performed in parasternal long axis using 3DE. Eccentricity Index was calculated using the lateral and anterior-posterior LVOTd. SV was obtained by four different methods: (1) 2D gray scale, (2) 2D color, (3) LVOTa * LVOT velocity time integral, and (4) SV by Simpson's biplane method. Gray scale LVOTd was significantly smaller compared to LVOTd obtained with CD (P < 0.05). Significant differences occurred between LVOTa gray scale and CD (3.29 +/- 0.74 cm(2) vs 3.67 +/- 0.70 cm(2) , P < 0.05) and between LVOTa calculated by gray scale in comparison to 3DE planimetry; (3.29 +/- 0.74 cm(2) vs 3.61 +/- 0.89 cm(2) , P = 0.011). Half of the subjects had at least 17% difference between the lateral and anterior-posterior LVOTd. There were significant differences between SV by 2D gray scale and 2D CD (82.8 +/- 17.1 mL vs 92.4 +/- 16.8 mL, P < 0.05) and between 2D gray scale and 3DE planimetry (82.8 +/- 17.1 mL vs 90.7 +/- 19.8 mL, P = 0.025). CONCLUSION: Our study demonstrates LVOT being frequently elliptical. SV and LVOTa were found to be similar when comparing 2DE CD and 3DE planimetry and showed higher values in comparison to 2DE gray scale, which suggests 2DE CD to be an alternative approach for SV assessment. PMID- 22494037 TI - A modest proposal. PMID- 22494036 TI - Theoretical study on the mechanism and kinetics for the self-reaction of C2H5O2 radicals. AB - Oxygen-to-oxygen coupling, direct H-abstraction and oxygen-to-(alpha)carbon nucleophilic substitution processes have been investigated for both the singlet and triplet self-reaction of C(2)H(5)O(2) radicals at the CCSD(T)/cc pVDZ//B3LYP/6-311G(2d,2p) level to evaluate the reaction mechanisms, possible products and rate constants. The calculated results show that the title reaction mainly occurs through the singlet oxygen-to-oxygen coupling mechanism with the formation of entrance tetroxide intermediates, and the most dominant product is C(2)H(5)O + HO(2) + CH(3)CHO (P5) generated in channel R5. Beginning from the radical products of P5 (C(2)H(5)O, HO(2)) and reactant (C(2)H(5)O(2)), five secondary reactions HO(2) + HO(2) (a), HO(2) + C(2)H(5)O (b), C(2)H(5)O + C(2)H(5)O (c), HO(2) + C(2)H(5)O(2) (d), and C(2)H(5)O + C(2)H(5)O(2) (e) mainly proceed on the triplet potential energy surface. Among these reactions, (a), (b), and (d) are kinetically favorable because of lower barrier heights. The calculated rate constants of channel R5 between 200 and 295 K are almost independent of the temperature, which is in agreement with the experimental report. With regard to the final products distribution, CH(3)CHO, C(2)H(5)OH, C(2)H(5)OOH, H(2)O(2), and (3)O(2) are predicted to be major, whereas C(2)H(5)OOC(2)H(5) should be in minor amount. PMID- 22494038 TI - Stem Cells and the Metaphysics of Choice: A Rationale--or Ruse--for Genetic Research? PMID- 22494039 TI - Review of Cynthia R. Daniels, At Women's Expense: State Power and the Politics of Fetal Rights. PMID- 22494040 TI - Review of jerry menikoff, law and bioethics: an introduction. PMID- 22494041 TI - Liquid chromatography-atmospheric pressure electron capture dissociation mass spectrometry for the structural analysis of peptides and proteins. AB - Atmospheric pressure electron capture dissociation (AP-ECD) is an emerging technique with the potential to be a more accessible alternative to conventional ECD/electron transfer dissociation (ETD) methods because it can be implemented using a stand-alone ion source device suitable for use with any existing or future electrospray ionization mass spectrometer. With AP-ECD, no modification of the main instrument is required, so it may easily be retrofitted to instruments not originally equipped with ECD/ETD capabilities. Here, we present our first purpose-built AP-ECD source and demonstrate its use in conjunction with capillary LC for the analysis of substance P, a tryptic digest of bovine serum albumin, and a phosphopeptide mixture. Quality ECD spectra were obtained for all the samples at the low femtomole level, proving that LC-AP-ECD-MS is suitable for the structural analysis of peptides and protein digests, in this case using an unmodified quadrupole time-of-flight mass spectrometer built ca. 2002. PMID- 22494042 TI - Signatures of cooperative effects and transport mechanisms in conductance histograms. AB - We present a computational investigation into the line shapes of peaks in conductance histograms, finding that they possess high information content. In particular, the histogram peak associated with conduction through a single molecule elucidates the electron transport mechanism and is generally well described by beta distributions. A statistical analysis of the peak corresponding to conduction through two molecules reveals the presence of cooperative effects between the molecules and also provides insight into the underlying conduction channels. This work describes tools for extracting additional interpretations from experimental statistical data, helping us better understand electron transport processes. PMID- 22494043 TI - Impact of ablation catheter irrigation design on silent cerebral embolism after radiofrequency catheter ablation of atrial fibrillation: results from a pilot study. AB - INTRODUCTION: Silent cerebral lesions (SCL) are a sensitive tool to evaluate thromboembolic risk of catheter ablation. Recent data showed the possibility to reduce thrombus formation when the electrode-tissue interface cooling is optimized by a homogeneous flushing of saline along the entire surface of the distal electrode through a larger number of irrigation holes. The study aim is to compare procedural parameters and safety of pulmonary vein isolation (PVI) performed by using open-irrigated catheters with different irrigation design. METHODS AND RESULTS: Eighty patients (74% males; age 57 +/- 12 years) with paroxysmal AF randomly underwent PVI performed with a new irrigation design catheter (group A, 40 patients) versus a standard irrigated catheter (group B, 40 patients). A cerebral magnetic resonance imaging (MRI) was performed before and after the procedure. Postprocedural brain MRI unveiled SCL in 2 patients in group A and in 3 in group B (5% vs 7.5%, P = 0.500). Intraprocedural ACT was the only independent factor associated with the occurrence of SCL (OR = 0.996; 95% CI 0.994-0.998, P < 0.001). Among procedural parameters, we observed a reduction of irrigation saline volume of 662 mL in group A versus group B (P < 0.001). CONCLUSION: PVI performed with a new irrigated catheter did not reduce significantly the SCL risk when compared to a standard irrigated catheter. Intraprocedural ACT reduces the SCL risk of 0.4% for each point of ACT increase. For ACT > 320 seconds no SCL occurred. Finally, compared to a standard irrigated catheter, PVI performed with a new irrigation design catheter reduces significantly saline volume infusion. PMID- 22494044 TI - Anterograde revision of cervical spinal cord stimulator paddle electrode: a case report. AB - OBJECTIVES: To illustrate a new surgical revision strategy for malfunctioning spinal cord stimulation (SCS) paddle electrodes. BACKGROUND: SCS is a treatment for chronic neuropathic pain that delivers therapeutic doses of electric current to the dorsal columns resulting in dermatomal paresthesia and pain reduction. Reasons for SCS failure include hardware malfunction or breakage and medical complications. CASE REPORT: A 34-year-old woman presented with a two-year history of intractable pain in the left upper extremity and thoracic region which was previously controlled by SCS. Imaging demonstrated breakage of the cervical electrode wire that had been advanced in the caudal direction from the C1 spinal level. Revision of the broken electrode was performed by hemilaminectomy of C3-C4 and the replacement electrode was advanced in the cephalad direction. RESULTS: Ideal and exact paresthesia pattern was confirmed intraoperatively and the patient maintained successful pain reduction at five-year follow-up. CONCLUSION: Advancing SCS electrodes into the upper cervical spine in the cephalad direction, using the previously formed scar capsule, offers an alternate strategy for revision of malfunctioning SCS paddle electrodes. PMID- 22494045 TI - A display module implemented by the fast high-temperatue response of carbon nanotube thin yarns. AB - Suspending superaligned multiwalled carbon nanotube (MWCNT) films were processed into CNT thin yarns, about 1 MUm in diameter, by laser cutting and an ethanol atomization bath treatment. The fast high-temperature response under a vacuum was revealed by monitoring the incandescent light with a photo diode. The thin yarns can be electrically heated up to 2170 K in 0.79 mS, and the succeeding cool-down time is 0.36 mS. The fast response is attributed to the ultrasmall mass of the independent single yarn, large radiation coefficient, and improved thermal conductance through the two cool ends. The millisecond response time makes it possible to use the visible hot thin yarns as light-emitting elements of an incandescent display. A fully sealed display with 16 * 16 matrix was successfully fabricated using screen-printed thick electrodes and CNT thin yarns. It can display rolling characters with a low power consumption. More applications can be further developed based on the addressable CNT thermal arrays. PMID- 22494046 TI - Targeting nuclear factor-kappaB suppresses the negative effect of toll-like receptor 4 signaling on antimetastasis therapy based on targeting alphavbeta3. AB - The targeting of alphavbeta3 is a promising therapeutic strategy for suppressing tumor metastasis. However, it is unclear whether the therapeutic efficacy could be influenced by metastasis-promoting factor(s) in vivo. Here we report that Toll like receptor 4 (TLR4) ligand released from damaged tumor cells or bacteria had a negative effect on the therapeutic effect of a recombinant CBD-HepII polypeptide of fibronectin (CH50) that suppresses tumor metastasis by targeting alphavbeta3. The TLR4 ligand could antagonize the inhibitory effect of CH50 on tumor cell adhesion and invasion by promoting the expression and activity of alphavbeta3 in tumor cells. The TLR4 ligand also reduced the antimetastasis effect of CH50 by promoting tumor cell survival in circulation. Moreover, TLR4 ligands released by tumor cells in circulation could increase the survival and proliferation capacity of tumor cells after extravasation, resulting in the formation of more metastatic nodules. The effect of TLR4 signaling was mainly mediated by nuclear factor kappaB (NF-kappaB). Inhibiting NF-kappaB could abrogate the negative effect of TLR4 ligand, and augment the inhibitory effect of CH50 on tumor metastasis. Consistently, the combination of NF-kappaB inhibitor and CH50 significantly inhibited metastasis of tumor cells in vivo and prolonged the survival of mice. The findings in this study suggest that the combination of NF-kappaB inhibitor and alphavbeta3 antagonist would be a novel therapeutic option for the prevention of tumor metastasis. PMID- 22494047 TI - Aeromedical transfer of women at risk of preterm delivery in remote and rural Western Australia: why are there no births in flight? AB - OBJECTIVE: For more than three decades, women at imminent risk of preterm birth (PTB) in Western Australia have been transferred by small aircraft over long distances to the single tertiary level perinatal centre in Perth, with no known case of birth during the flight. We aimed to review recent experience to understand how aircraft travel may delay PTB. DESIGN AND SETTING: Retrospective observational study of 500 consecutive Royal Flying Doctor Service (RFDS) transfers of women at risk of preterm labour to the tertiary referral centre, from September 2007 to December 31, 2009. MAIN OUTCOME MEASURES: In-flight delivery, complications associated with transfer and factors associated with delay in preterm delivery. RESULTS: There were no in-flight deliveries or serious complications associated with the aeromedical transfer of these patients. In a multivariable Cox proportional hazards regression analysis, clinical factors in the presentation that were associated with a shorter time from landing to subsequent delivery included cervical dilatation >= 4 cm, ruptured membranes, gestational age > 32 weeks and nulliparity. The aircraft reaching an ambient altitude > 14,000 feet, or cabin altitude above zero (sea level), was associated with a delay in time from landing to delivery for women who were not in spontaneous preterm labour. CONCLUSIONS: Our findings add to a 30-year experience that women at risk of preterm labour do not deliver during aeromedical transfer. Ambient and cabin altitude of the aircraft were associated with an extension in the time to delivery after arrival. The mechanisms underpinning this effect warrant further investigation. PMID- 22494048 TI - Bax and Bcl-xL exert their regulation on different sites of the ceramide channel. AB - The present study demonstrates the important structural features of ceramide required for proper regulation, binding and identification by both pro-apoptotic and anti-apoptotic Bcl-2 family proteins. The C-4=C-5 trans-double bond has little influence on the ability of Bax and Bcl-xL to identify and bind to these channels. The stereochemistry of the headgroup and access to the amide group of ceramide is indispensible for Bax binding, indicating that Bax may interact with the polar portion of the ceramide channel facing the bulk phase. In contrast, Bcl xL binding to ceramide channels is tolerant of stereochemical changes in the headgroup. The present study also revealed that Bcl-xL has an optimal interaction with long-chain ceramides that are elevated early in apoptosis, whereas short chain ceramides are not well regulated. Inhibitors specific for the hydrophobic groove of Bcl-xL, including 2-methoxyantimycin A3, ABT-737 and ABT-263 provide insights into the region of Bcl-xL involved in binding to ceramide channels. Molecular docking simulations of the lowest-energy binding poses of ceramides and Bcl-xL inhibitors to Bcl-xL were consistent with the results of our functional studies and propose potential binding modes. PMID- 22494049 TI - Regional differences and similarities of familial amyloidotic polyneuropathy (FAP) presentation in Brazil. AB - Familial amyloidotic polyneuropathy (FAP) is a worldwide disease with various clinical presentations according to geographical origin of the cases. Brazil is a country of Portuguese colonization and Portuguese descendants are estimated to be more than 25 millions. The Brazilian FAP population was characterized in this text as having basically the same diseases characteristics as the most common Portuguese FAP type I patients. PMID- 22494050 TI - Antibacterial activity of xanthones from Garcinia mangostana (L.) and their structure-activity relationship studies. AB - Antibacterial activities of prenylated xanthones from Garcinia mangostana and their synthetic analogues were investigated, and their structure-activity relationships have been studied. gamma-Mangostin has shown antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), methicillin sensitive Staphylococcus aureus (MSSA), vancomycin-resistant Enterococcus (VRE) and vancomycin-sensitive Enterococcus (VSE) strains at MICs 3.13, 6.25, 6.25 and 6.25 ug mL(-1), respectively. In these experiments, gentamicin was used as the positive control. Further, some analogues of gamma-mangostin and alpha-mangostin were synthesised and their activity was tested against MRSA and VRE strains. The analysis of the bioassay results above indicated that, the combination of C-6 and C-3 hydroxyl groups along with the prenyl side chain at C-2 in the 1,3,6,7 tetraoxygenated xanthones from G. mangostana is essential to have a high antibacterial activity. PMID- 22494051 TI - Quantitative evaluation of right ventricle function by transthoracic echocardiography in childhood congenital heart disease patients with pulmonary hypertension. AB - INTRODUCTION AND OBJECTIVE: The present study aims to quantitatively evaluate the right ventricle (RV) function by means of transthoracic echocardiography in normal children and childhood congenital heart disease patients with pulmonary hypertension. PATIENTS AND METHODS: This study was conducted in a cohort including 40 healthy children and 30 pediatric patients with pulmonary hypertension who were diagnosed under close surveillance at the study center between October 2009 and November 2010. RESULTS: Statistically significant differences were found between the patient and control groups for the right ventricle myocardial performance index (RVMPI), the left ventricle myocardial performance index (LVMPI), the tricuspid valve systolic flow velocity (Ts), the ratio of systolic pulmonary artery pressure to the right ventricle outflow tract systolic flow velocity time integral (sPAP/RVOT VTI), and the ratio of systolic pulmonary artery pressure to right ventricle outflow tract systolic flow velocity time integral * heart rate (sPAP/[RVOT VTI*HR]). When the children were divided into three groups based on their pulmonary vascular resistance significant differences emerged that predicted an increasing severity of RV dysfunction. Significant differences were also observed for the RVMPI, the LVMPI, and the Ts as well as for echocardiographic pulmonary flow (Qp) and systemic flow (Qs). DISCUSSION: The present study demonstrates that echocardiographic parameters can be used for the quantitative detection of RV dysfunction in childhood congenital heart disease patients with high pulmonary artery pressure (systolic, diastolic, and mean) or pulmonary vascular resistance. PMID- 22494052 TI - Cost comparison of robot-assisted and laparoscopic pyeloplasty. AB - BACKGROUND AND PURPOSE: Laparoscopic repair of ureteropelvic junction obstruction is now the standard of care at many institutions. The objective of this study is to compare costs associated with robot-assisted pyeloplasty (RP) vs laparoscopic pyeloplasty (LP). MATERIALS AND METHODS: A decision analysis model was developed to compare costs of each procedure based on hospital-related cost centers. A literature search was performed to identify nonoverlapping studies with outcomes for RP and LP. Weighted means were calculated for operative time and length of stay. Cost data were obtained from our institution. One- and two-way sensitivity analyses were performed to evaluate the effect of changing variables on the cost effectiveness of RP. RESULTS: Eight studies were identified with 181 and 145 patients undergoing RP or LP, respectively. Operative times were 211 minutes for RP and 224 minutes for LP. Hospital stays were shorter for RP at 1.54 days compared with 1.98 days for LP. Mean direct costs were higher for RP at $10,635 vs $9,065 for LP. The largest difference was in fixed surgical supply costs per case at $1357 for RP and $406 for LP. One-way sensitivity analysis showed that RP would be cost effective if performed in less than 96 minutes. Even if RP was performed on an outpatient basis or more than 1000 cases/year, however, LP would still be cost superior. Two-way analyses showed areas where RP could be more cost effective than LP. CONCLUSIONS: RP is associated with higher cost compared with LP, predominately because of the cost of the robot and surgical supply costs. Decreasing operative time and equipment costs may result in RP being more cost effective than LP. Shorter hospital stay alone, however, is insufficient to allow RP to be cost-effective. One would need to demonstrate tangible advantages to the robot to justify the added costs. PMID- 22494054 TI - Prognostic significance of implantable defibrillator shock: are all shocks created equal? PMID- 22494056 TI - New subsections for JPC A/B/C and JPC letters. PMID- 22494053 TI - Intravenous immunoglobulin protects neurons against amyloid beta-peptide toxicity and ischemic stroke by attenuating multiple cell death pathways. AB - Intravenous immunoglobulin (IVIg) preparations obtained by fractionating blood plasma, are increasingly being used increasingly as an effective therapeutic agent in treatment of several inflammatory diseases. Its use as a potential therapeutic agent for treatment of stroke and Alzheimer's disease has been proposed, but little is known about the neuroprotective mechanisms of IVIg. In this study, we investigated the effect of IVIg on downstream signaling pathways that are involved in neuronal cell death in experimental models of stroke and Alzheimer's disease. Treatment of cultured neurons with IVIg reduced simulated ischemia- and amyloid betapeptide (Abeta)-induced caspase 3 cleavage, and phosphorylation of the cell death-associated kinases p38MAPK, c-Jun NH2 -terminal kinase and p65, in vitro. Additionally, Abeta-induced accumulation of the lipid peroxidation product 4-hydroxynonenal was attenuated in neurons treated with IVIg. IVIg treatment also up-regulated the anti-apoptotic protein, Bcl2 in cortical neurons under ischemia-like conditions and exposure to Abeta. Treatment of mice with IVIg reduced neuronal cell loss, apoptosis and infarct size, and improved functional outcome in a model of focal ischemic stroke. Together, these results indicate that IVIg acts directly on neurons to protect them against ischemic stroke and Abeta-induced neuronal apoptosis by inhibiting cell death pathways and by elevating levels of the anti-apoptotic protein Bcl2. PMID- 22494057 TI - Dimethylsulfoxide exposure modulates HL-60 cell rolling interactions. AB - Human leukaemic HL-60 cells are widely used for studying interactions involving adhesion molecules [e.g. P-selectin and PSGL-1 (P-selectin glycoprotein ligand 1)] since their rolling behaviour has been shown to mimic the dynamics of leucocyte rolling in vitro. HL-60 cells are neutrophilic promyelocytes that can undergo granulocytic differentiation upon exposure to compounds such as DMSO (dimethylsulfoxide). Using a parallel plate flow chamber functionalized with recombinant P-selectin-Fc chimaera, undifferentiated and DMSO-induced (48, 72 and 96 h) HL-60 cells were assayed for rolling behaviour. We found that depending on P-selectin incubation concentration, undifferentiated cells incurred up to a 6 fold increase in rolling velocity while subjected to an approximately 10-fold increase in biologically relevant shear stress. HL-60 cells exposed to DMSO for up to 72 h incurred up to a 3-fold increase in rolling velocity over the same shear stress range. Significantly, cells exposed for up to 96 h incurred up to a 9-fold decrease in rolling velocity, compared with undifferentiated HL-60 cells. Although cell surface and nuclear morphological changes were evident upon exposure to DMSO, flow cytometric analysis revealed that PSGL-1 expression was unchanged, irrespective of treatment duration. The results suggest that DMSO treated HL-60 cells may be problematic as a substitute for neutrophils for trafficking studies during advanced stages of the LAC (leucocyte adhesion cascade). We suggest that remodelling of the cell surface during differentiation may affect rolling behaviour and that DMSO-treated HL-60 cells would behave differently from the normal leucocytes during inflammatory response in vivo. PMID- 22494058 TI - ALEX1 suppresses colony formation ability of human colorectal carcinoma cell lines. AB - Arm protein lost in epithelial cancers, on chromosome X (ALEX; also known as armadillo repeat containing, X-linked [ARMCX]) is a novel subgroup within the armadillo (ARM) family, which has several ARM repeat domains. The biological function of classical ARM family members such as beta-catenin is well understood, but that of the ALEX/ARMCX family members is largely unknown. Here we evaluate the effects of ALEX1 overexpression on in vitro colony formation ability and expression of ALEX1 mRNA in human colorectal tumor. Overexpression of ALEX1 suppressed the anchorage-dependent and -independent colony formation of human colorectal carcinoma cell lines by the study of stable clones of HCT116 cells expressing ALEX1 protein. Bisulfite genomic sequencing revealed that the promoter region of ALEX1 gene was highly methylated in both HCT116 and SW480 cells in comparison with PANC-1 and MCF-7 cells, which express endogenous ALEX1 mRNA, indicating the capability of promoter methylation to silence ALEX1 gene in HCT116 and SW480 cells. Our current findings suggest that overexpression of ALEX1 play a negative role in human colorectal tumorigenesis. PMID- 22494059 TI - Development of a secondary antibody thio-functionalized microcantilever immunosensor and an ELISA for measuring ginsenoside Re content in the herb ginseng. AB - Ginsenoside Re (GRe) is a major active component of the Chinese medicinal herb ginseng, Panax ginseng . A sensitive and specific monoclonal antibody (mAb), designated as mAb3D6, was generated with a GRe-bovine serum albumin conjugate as an immunogen. Microcantilever immunosensors (MCS), one modified with thiolated anti-GRe antibody and one modified with thiolated goat antimouse immunoglobulin G (IgG), were developed to detect the content of ginsenoside. The MCS immobilized with thiolated goat antimouse IgG had a better sensitivity than the MCS modified with thiolated anti-GRe antibody. The advantage of a secondary antibody thio functionalized MCS was verified with the anti-paclitaxel mAb. An indirect competitive enzyme-linked immunosorbent assay (icELISA) was also established with mAb3D6. The concentration of analyte producing 50% inhibition and the working range of icELISA were 1.20 and 0.15-16.1 ng/mL, respectively. The icELISA had a cross-reactivity of 89% with ginsenoside Rg1 and less than 3% with other ginsenosides. The icELISA and MCS with thiolated secondary antibody were applied for the determination of GRe in ginseng samples, and the results agreed well with those determined by high-performance liquid chromatography. PMID- 22494060 TI - An in vitro method for detecting chemical sensitization using human reconstructed skin models and its applicability to cosmetic, pharmaceutical, and medical device safety testing. AB - Chemical sensitization is a serious condition caused by small reactive molecules and is characterized by a delayed type hypersensitivity known as allergic contact dermatitis (ACD). Contact with these molecules via dermal exposure represent a significant concern for chemical manufacturers. Recent legislation in the EU has created the need to develop non-animal alternative methods for many routine safety studies including sensitization. Although most of the alternative research has focused on pure chemicals that possess reasonable solubility properties, it is important for any successful in vitro method to have the ability to test compounds with low aqueous solubility. This is especially true for the medical device industry where device extracts must be prepared in both polar and non polar vehicles in order to evaluate chemical sensitization. The aim of this research was to demonstrate the functionality and applicability of the human reconstituted skin models (MatTek Epiderm((r)) and SkinEthic RHE) as a test system for the evaluation of chemical sensitization and its potential use for medical device testing. In addition, the development of the human 3D skin model should allow the in vitro sensitization assay to be used for finished product testing in the personal care, cosmetics, and pharmaceutical industries. This approach combines solubility, chemical reactivity, cytotoxicity, and activation of the Nrf2/ARE expression pathway to identify and categorize chemical sensitizers. Known chemical sensitizers representing extreme/strong-, moderate-, weak-, and non-sensitizing potency categories were first evaluated in the skin models at six exposure concentrations ranging from 0.1 to 2500 uM for 24 h. The expression of eight Nrf2/ARE, one AhR/XRE and two Nrf1/MRE controlled gene were measured by qRT-PCR. The fold-induction at each exposure concentration was combined with reactivity and cytotoxicity data to determine the sensitization potential. The results demonstrated that both the MatTek and SkinEthic models performed in a manner consistent with data previously reported with the human keratinocyte (HaCaT) cell line. The system was tested further by evaluating chemicals known to be associated with the manufacture of medical devices. In all cases, the human skin models performed as well or better than the HaCaT cell model previously evaluated. In addition, this study identifies a clear unifying trigger that controls both the Nrf2/ARE pathway and essential biochemical events required for the development of ACD. Finally, this study has demonstrated that by utilizing human reconstructed skin models, it is possible to evaluate non-polar extracts from medical devices and low solubility finished products. PMID- 22494061 TI - Self-care after traumatic injury and the use of the therapeutic self care scale in trauma populations. AB - AIMS: To report a correlational study of the relationship between gender, age, severity of injury, length of hospital stay and self-care behaviour in patients with traumatic injuries. BACKGROUND: This study may provide a foundation for targeted nursing intervention and education programmes to help patients better recover from their injury, which is a fundamental aspect of nursing. DESIGN: A longitudinal cohort study. METHOD: This study of patients hospitalized for traumatic injury was conducted from May 2006-November 2007. The Therapeutic Self Care Scale along with demographic and clinical data, were completed at 3 and 6 months after hospital discharge. Using data from the 3-month survey, the validity and reliability of the scale was calculated. Multiple regression was used to identify predictors of self-care at 3 and 6 months. FINDING: Participants (n = 125) completed the questionnaire at 3 months and 103 participants completed it at 6 months. Self-care was high on both occasions and high self-care at 3 months was related to high self-care at 6 months. Older participants reported higher self care at 3 months compared with younger patients. Factor analysis of the scale revealed three clear components; taking medication, recognition and managing symptoms and managing changes in health conditions, which explained a total of 59.8% of the variance. The 10-item revised scale was reliable. CONCLUSION: The findings indicate that self-care remains fairly high and stable in the first 6 months after trauma. The revised Therapeutic Self Care Scale was valid and reliable in the trauma population. PMID- 22494062 TI - The effect of I-gel TM airway on intraocular pressure in pediatric patients who received sevoflurane or desflurane during strabismus surgery. AB - OBJECTIVES: The aim of this study was to investigate the effect of I-gel(TM) laryngeal mask airway on intraocular pressure (IOP) in children with strabismus undergoing balanced anesthesia with sevoflurane or desflurane. METHODS: Forty seven children, ASA physical status I, were scheduled for elective strabismus surgery. Patients were randomly assigned to one of the two inhalation anesthetic groups. Sevoflurane group comprised of 27 children, and desflurane group comprised of 20 children. Anesthesia was induced and maintained with sevoflurane or desflurane. No muscle relaxant was used. IOPs were measured before anesthesia, at 2 and 5 min after insertion of I-gel(TM) and after removal of I-gel(TM) . IOP measurements were obtained by Tonopen((r)). RESULTS: Intraocular pressure significantly decreased 2 min after insertion of I-gel(TM) in both sevoflurane and desflurane groups (P < 0.001). Measurements 5 min after I-gel(TM) insertion were also significantly lower than those of before insertion in both groups (P < 0.01). However, no significant differences were found between the preoperative measurement and the measurement after removal of I-gel(TM) within two groups (P = 0.072 and P = 0.547, respectively). No significant differences were found in all IOP measurements between sevoflurane and desflurane groups. CONCLUSION: Insertion of I-gel(TM) laryngeal mask airway with giving sevoflurane or desflurane inhalation anesthetics seemed not to cause any increase in IOPs in pediatric ophthalmic surgery. PMID- 22494063 TI - Determination of lucidin-specific DNA adducts by liquid chromatography with tandem mass spectrometry in the livers and kidneys of rats given lucidin-3-O primeveroside. AB - Lucidin-3-O-primeveroside (LuP) is a component of madder color (MC), a compound which is carcinogenic in the kidney and liver of rats. Since LuP is metabolized to generate genotoxic compounds such as lucidin (Luc) and rubiadin, it is likely that these play key roles in MC carcinogenesis. In fact, after incubation of Luc with calf thymus DNA, Luc-N(2)-dG and N(6)-dA adducts were reportedly formed, possibly via the sulfotransferase metabolic pathway. However, the precise extent of formation in vivo remains uncertain. In the present study, to quantitatively determine Luc-specific DNA adducts in in vivo samples, we developed an online sample purification method using column-switching and an isotope dilution LC-ESI MS/MS technique. The limits of quantification were 0.2 and 0.04 fmol on column for Luc-N(2)-dG and N(6)-dA adducts, respectively. Using the new analytical method, we attempted to measure adduct levels in the kidneys and livers of rats treated with 0.06, 0.3, and 1.5% LuP in the diet for one week. Luc-N(2)-dG and N(6)-dA adducts in these organs were detected at ranges from 7.97 to 51.67/10(9) dG and from1.83 to 37.10/10(9) dA, respectively. Dose-dependent increases of each adduct were observed in both organs. These quantitative data obtained with our newly developed analytical method might help to improve our understanding of MC carcinogenesis. PMID- 22494064 TI - In vitro transdermal and biological evaluation of ALA-loaded poly(N isopropylacrylamide) and poly(N-isopropylacrylamide-co-acrylic acid) microgels for photodynamic therapy. AB - Poly(N-isopropylacrylamide) (PNIPA) and Poly(N-isopropylacrylamide-co-acrylic acid) (P(NIPA-co-AA)) microgels loaded with 5-aminolevulinic acid (ALA) were prepared by the spray-drying method. The amount of drug loaded was 290 ug ALA/mg microgel for PNIPA and 244 ug ALA/mg microgel for P(NIPA-co-AA) microgels. Maximum in vitro drug release took place within 15-30 min for PNIPA and 1-1.5 h for P(NIPA-co-AA) microgels as a function of pH, at 37 degrees C. Transdermal delivery from microgels showed permeation fluxes 10 times higher than the passive diffusion flux. The cytotoxicity of microgels synthesized in HeLa cells after the application of photodynamic therapy (PDT) was superior compared with the administration of ALA in solution alone. Finally, the use of these microgels as a delivery vehicle for ALA constitutes a system capable of enhancing its topical administration and PDT effectiveness. PMID- 22494065 TI - Substrate dependent self-organization of mesoporous cobalt oxide nanowires with remarkable pseudocapacitance. AB - A scheme of current collector dependent self-organization of mesoporous cobalt oxide nanowires has been used to create unique supercapacitor electrodes, with each nanowire making direct contact with the current collector. The fabricated electrodes offer the desired properties of macroporosity to allow facile electrolyte flow, thereby reducing device resistance and nanoporosity with large surface area to allow faster reaction kinetics. Co(3)O(4) nanowires grown on carbon fiber paper collectors self-organize into a brush-like morphology with the nanowires completely surrounding the carbon microfiber cores. In comparison, Co(3)O(4) nanowires grown on planar graphitized carbon paper collectors self organize into a flower-like morphology. In three electrode configuration, brush like and flower-like morphologies exhibited specific capacitance values of 1525 and 1199 F/g, respectively, at a constant current density of 1 A/g. In two electrode configuration, the brush-like nanowire morphology resulted in a superior supercapacitor performance with high specific capacitances of 911 F/g at 0.25 A/g and 784 F/g at 40 A/g. In comparison, the flower-like morphology exhibited lower specific capacitance values of 620 F/g at 0.25 A/g and 423 F/g at 40 A/g. The Co(3)O(4) nanowires with brush-like morphology exhibited high values of specific power (71 kW/kg) and specific energy (81 Wh/kg). Maximum energy and power densities calculated for Co(3)O(4) nanowires with flower-like morphology were 55 Wh/kg and 37 kW/kg respectively. Both electrode designs exhibited excellent cycling stability by retaining ~91-94% of their maximum capacitance after 5000 cycles of continuous charge-discharge. PMID- 22494066 TI - Clinical development of an antisense therapy for the treatment of transthyretin associated polyneuropathy. AB - Transthyretin (TTR)-associated amyloidosis is a late-onset autosomal-dominant genetic disease. Over 100 amyloidogenic mutations have been identified in TTR which destabilize the TTR tetramer thereby inducing the formation of amyloid fibrils in tissues such as the heart and peripheral nerves. This disease mainly affects peripheral nerves, causing familial amyloid polyneuropathy (FAP) or heart, causing familial amyloid cardiomyopathy (FAC). Circulating TTR is predominantly produced by liver, and the only widely available clinical treatment for FAP is orthotopic liver transplantation (OLT), whereas no treatment currently exists for FAC. Using second-generation antisense technology, we identified an antisense oligonucleotide (ASO) targeting TTR, ISIS-TTR(Rx), for the treatment of TTR-associated amyloidosis. When tested in a human TTR transgenic mouse model (hTTR Ile84Ser), ISIS-TTR(Rx) showed a dose-dependent reduction of human TTR (up to >80%) at both the mRNA and protein levels. In cynomolgus monkeys, ISIS-TTR(Rx) treatment produced a time-dependent reduction in plasma TTR levels. After 12 weeks of treatment in monkey, liver TTR mRNA and plasma TTR protein levels were reduced by ~80%. As expected, treatment with ISIS-TTR(Rx) also produced a significant decrease in plasma RBP4 levels that correlated with reductions in TTR levels. ISIS-TTR(Rx) treatment was well tolerated in both rodents and monkeys and produced a PK/PD profile consistent with prior experiences using this chemistry platform. ISIS-TTR(Rx) is currently under evaluation in a Phase 1 clinical trial in normal healthy volunteers, and interim results of this trial will be presented. PMID- 22494067 TI - Value of conventional and tissue Doppler echocardiography in the noninvasive measurement of right atrial pressure. AB - BACKGROUND: Evaluation of right atrial pressure (RAP) provides useful diagnostic, therapeutic, and prognostic information. AIM: To assess the utility of several conventional and tissue Doppler parameters in the estimation of RAP. METHODS: Among 50 consecutive patients (median age: 50 years; all in sinus rhythm), invasively measured RAP was simultaneously correlated with pulsed Doppler of tricuspid inflow (peak E and A velocities, E-wave deceleration time) and pulsed tissue Doppler of lateral tricuspid annulus (peak E' and A' velocities, isovolumic relaxation time [IVRT], acceleration time and rate of E'-wave, deceleration time and rate of E'-wave). These ratios were calculated: E/A, E'/A', E/E', and E/IVRT. RESULTS: The median RAP was 14 mmHg (range 1-27 mmHg) with 29 patients (58%) having an elevated RAP (>10 mmHg). Among all studied Doppler variables, E/E' ratio showed the strongest correlation with RAP (r = 0.84, P < 0.001) with the following regression equations: RAP = 1.24 + (1.69 * E/E'). The mean difference between Doppler and invasively measured RAP was 0.21 +/- 2.6 mmHg. E/ E' ratio >= 4.5 provides 89% sensitivity and 100% specificity for detection of elevated RAP (receiver operating characteristic area 0.95; P < 0.001). CONCLUSION: Of all echocardiographic variables investigated, tricuspid annular E/E' ratio is identified as the best index for noninvasive determination of RAP. PMID- 22494068 TI - Evaluation of root surface microtopography following the use of four instrumentation systems by confocal microscopy and scanning electron microscopy: an in vitro study. AB - BACKGROUND AND OBJECTIVE: The ideal instrument for initial periodontal therapy should enable the removal of all extraneous substances from the root surfaces without any iatrogenic effects. Because of that the objective of this study is to analyse and to compare the root surface roughness after using Gracey curettes, termination diamond burs (40 MUm), a piezo-ceramic ultrasonic scaler and a piezosurgery ultrasonic scaler using confocal microscopy and scanning electron microscopy. MATERIAL AND METHODS: A 2 mm * 2 mm interproximal root area of 20 teeth (n = 40 surfaces) was evaluated by confocal microscopy (*20 magnification) and scanning electron microscopy (*50 to *1000 magnification). Teeth were randomly assigned to the following four groups: Gracey curettes with 15 vertical strokes; termination diamond burs (40 MUm) at 3000 r.p.m.; a piezo-ceramic ultrasonic scaler with a power of 11; and a piezosurgery ultrasonic scaler in mode ROOT with a power of two. RESULTS: Confocal microscopy revealed that curettes [mean changes in the value of surface roughness average reduced by 0.11 +/- 0.3], piezo-ceramic ultrasonic scaler (roughness average reduced by 0.47 +/- 0.93) and piezosurgery ultrasonic scaler (roughness average reduced by 0.62 +/- 0.93) left a smoother surface than termination diamond burs (roughness average increased by 0.39 +/- 0.18). Statistically significant differences were observed in roughness (p = 0.005) between piezosurgery and termination diamond burs (p = 0.005). No statistically significant differences were between piezosurgery and Gracey curettes (p = 0.140) and between piezosurgery and piezo-ceramic ultrasonic scalers (p = 0.745). Confocal microscopy and scanning electron microscopy showed that piezosurgery seems to leave the smoothest surface. Surfaces treated with termination burs appear to show more scratches and pits. CONCLUSION: Three of the four instruments tested for root planing reduced surface roughness; however, the piezosurgery ultrasonic scaler produced the smoothest surface. The termination diamond burs (40 MUm) produced a rougher surface than the ultrasonic instruments and the hand curettes. Further clinical studies are needed. PMID- 22494069 TI - Transition interval of atrial tachycardia. PMID- 22494070 TI - Na+/H+ exchanger 1 inhibition contributes to K562 leukaemic cell differentiation. AB - The effect of hypoxia on the differentiation of chronic myeloid leukaemic K562 cells were studied, as was the role of the NHE1 (Na+/H+ exchanger 1). Hypoxia induced differentiation of K562 cells as seen by modifications in their morphological features, up-regulation of C/EBPalpha (CCAAT/enhancer-binding protein alpha), and marked IL-8 (interleukin-8) release. Inhibition of NHE1 under hypoxia additionally enhanced the level of C/EBPalpha and further promoted leukaemic cells differentiation. Pharmacological inhibition of p38 MAPK (mitogen activated protein kinase) also significantly suppressed C/EBPalpha expression under hypoxia conditions after NHE1 inhibition. These results indicate the enhancement of hypoxia-induced K562 differentiation by NHE1 inhibition, which may be due to up-regulation of C/EBPalpha via p38 MAPK signalling pathway, which suggests a possible therapeutic target of NHE1 under hypoxia microenvironment in the treatment of leukaemic diseases. PMID- 22494071 TI - Asymmetrical dimethylarginine levels on the implantation success of in vitro fertilization and embryo transfer. AB - The aim of this study was to evaluate the level of asymmetrical dimethylarginine (ADMA) levels before gonadotrophine treatment and on the day of oocytes retrieval in order to determine whether ADMA can be used as a predictive marker for implantation success in in vitro fertilization (IVF) cycles. Forty-four unexplained infertile patients were included in the study. Controlled ovarian hyperstimulation was performed using the recombinant follicle-stimulating hormone (FSH) with the standard long protocol for all patients. ADMA and E2 were measured at the beginning of the ovulation induction and on oocyte retrieval day. The primary outcome was the difference in ADMA levels in implantation positive and implantation negative women. At the beginning of the ovulation induction, the mean ADMA levels were 1553 MUmol/L and 1.464 MUmol/L in the implantation positive and negative groups, respectively. There was no statistically significant difference between groups (p: 0.90). On the day of oocyte retrieval, the mean ADMA levels were 1173 MUmol/L and 1170 MUmol/L in the implantation positive and negative groups, respectively. There was no statistically significant difference between groups (p: 0.97). In conclusion, ADMA levels before gonadotrophine treatment and the day of oocytes retrieval cannot be used as a predictive marker for implantation success in IVF cycles. PMID- 22494072 TI - Insulin-like growth factor binding protein-3 suppresses vascular endothelial growth factor expression and tumor angiogenesis in head and neck squamous cell carcinoma. AB - Angiogenesis, the process by which new blood vessels are recruited to existing ones, is essential for tumor development. Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3), which modulates bioavailability of IGF, has been studied for its potential role in angiogenesis during tissue regeneration and cancer development. In this study, we assessed the role of IGFBP-3 in tumor angiogenesis in head and neck squamous cell carcinoma (HNSCC) and human umbilical vein endothelial cells (HUVECs) using adenoviral (Ad-BP3) and recombinant (rBP3) IGFBP-3. Using an in vivo orthotopic tongue tumor model, we confirmed that both Ad-BP3 and rBP3 suppress the growth of UMSCC38 HNSCC cells in vivo. Ad-BP3 inhibited vascularization in tongue tumors and chorio-allantoic membrane, and suppressed angiogenesis-stimulating activities in UMSCC38 cells. In HUVECs, Ad BP3 decreased migration, invasion, and tube formation. rBP3 also suppressed production of vascular endothelial growth factor (VEGF) in HUVECs and UMSCC38 cells. IGFBP-3-GGG, a mutant IGFBP-3 with loss of IGF binding capacity, suppressed VEGF production. In addition, we found that IGFBP-3 suppressed VEGF expression, even in mouse embryonic fibroblasts from an IGF-1R-null mouse. Finally, we demonstrated that IGFBP-3-GGG inhibits tumor angiogenesis and growth to the same degree as wild-type IGFBP-3. Taken together, these results support the hypothesis that IGFBP-3 has anti-angiogenic activity in HNSCC, at least in part due to IGF-independent suppression of VEGF production from vascular endothelial cells and cancer cells. PMID- 22494073 TI - Oxygen tension modifies the 'stemness' of human cord blood-derived stem cells. AB - BACKGROUND AIMS: Amongst different stem cell populations derived from human cord blood (CB), unrestricted somatic stem cells (USSC) are distinguished from CB mesenchymal stromal cells (CB MSC) by expression patterns of homeobox (HOX) genes, delta-like1 homolog (DLK1) expression and adipogenic differentiation potential. In this study we investigated the effects of oxygen tension on the generation, proliferation and expression of stem cell marker genes, which could be critical during large-scale cell culture for clinical applications. METHODS: We cultured CB-derived stem cells at 5% and 20% O(2). Telomere length shortening was analyzed and we investigated gene expression using reverse-transcription (RT) polymerase chain reaction (PCR) and real-time PCR. Additionally we performed adipogenic and osteogenic in vitro differentiation. Results. Altering the cultivation conditions of USSC or CB MSC from 20% to 5% O(2) had no significant impact. In contrast, cell populations derived from primary cultures prepared at 5% O(2) qualified as neither USSC nor as CB MSC. When converted to 20%, their proliferation was diminished, telomere shortening was accelerated, and two of six cell lines ceased expression of HOX genes. The HOX code of the other cell populations was not been affected by culture conditions. CONCLUSIONS: Altering culture conditions during generation can impact cell characteristics such as the HOX code. These effects need to be considered when dealing with cell cultures for clinical applications. PMID- 22494074 TI - Characteristic differences among osteogenic cell populations of rat bone marrow stromal cells isolated from untreated, hemolyzed or Ficoll-treated marrow. AB - BACKGROUND AIMS: Although bone marrow (BM) stromal cells (SC; BMSC) isolated from adherent cultures of untreated BM are known to contain both committed and uncommitted osteogenic cells, it remains unknown whether BMSC isolated either by hemolysis or Ficoll centrifugation also contain both of these populations. METHODS: Differences in the osteogenic cell populations of rat BMSC isolated from untreated, hemolyzed or Ficoll-treated BM were analyzed by in vivo transplantation, flow cytometry, alkaline phosphatase (ALP) assay, real-time polymerase chain reaction (PCR) and alizarin red staining. RESULTS: Transplantation of non-cultured samples indicated that the Ficolled BMSC contained the lowest number of committed osteogenic cells. Flow cytometric analysis of cultured, non-induced samples showed that the percentage of ALP positive cells was significantly lower in Ficolled BMSC. Quantitative ALP assays confirmed that the lowest ALP activity was in the Ficolled BMSC. Hemolyzed BMSC also contained lower numbers of committed osteogenic cells than untreated BMSC, but still more than Ficolled BMSC. Interestingly, the Ficolled BMSC showed the greatest levels of osteogenic ability when cultured in osteogenic induction medium. CONCLUSIONS: These findings suggest that, although Ficolled BMSC rarely contain committed osteogenic cells, they are able to show comparable or even greater levels of osteogenic ability after induction, possibly because they contain a greater proportion of uncommitted stem cells. In contrast, induction is optional but recommended for both untreated and hemolyzed BMSC before use, because both these groups contain both committed and uncommitted osteogenic cells. These findings are of significant importance when isolating BMSC for use in bone tissue engineering. PMID- 22494076 TI - Next-generation sequencing for mitochondrial diseases: a wide diagnostic spectrum. AB - BACKGROUND: The current diagnostic approach for mitochondrial disorders requires invasive procedures such as muscle biopsy and multiple biochemical testing but the results are often inconclusive. Clinical sequencing tests are available only for a limited number of genes. Recently, massively parallel sequencing has become a powerful tool for testing genetically heterogeneous conditions such as mitochondrial disorders. METHODS: Targeted next-generation sequencing was performed on 26 patients with known or suspected mitochondrial disorders using in solution capture for the exons of 908 known and candidate nuclear genes and an Illumina genome analyzer. RESULTS: None of the 18 patients with various abnormal respiratory chain complex (RCC) activities had molecular defects in either subunits or assembly factors of mitochondrial RCC enzymes except a reference control sample with known mutations in SURF1. Instead, several variants in known pathogenic genes including CPT2, POLG, PDSS1, UBE3A, SDHD, and a few potentially pathogenic variants in candidate genes such as MTO1 or SCL7A13 were identified. CONCLUSIONS: Sequencing only nuclear genes for RCC subunits and assembly factors may not provide the diagnostic answers for suspected patients with mitochondrial disorders. The present findings indicate that the diagnostic spectrum of mitochondrial disorders is much broader than previously thought, which could potentially lead to misdiagnosis and/or inappropriate treatment. Overall analytic sensitivity and precision appear acceptable for clinical testing. Despite the limitations in finding mutations in all patients, the present findings underscore the considerable clinical benefits of targeted next-generation sequencing and serve as a prototype for extending the clinical evaluation in this clinically heterogeneous patient group. PMID- 22494075 TI - Microchip device with 64-site electrode array for multiplexed immunoassay of cell surface antigens based on electrochemiluminescence resonance energy transfer. AB - This paper describes a novel on-chip microarray platform based on an electrochemiluminescence resonance energy transfer (ECL-RET) strategy for rapid assay of cancer cell surface biomarkers. This platform consists of 64 antigen decorated CdS nanorod spots with the diameter of 1.0 cm uniformly distributed on 16 indium tin oxide (ITO) strips, which is coated with a multichannel decorated polydimethylsiloxane (PDMS) slice to realize multiplexed determination of antigens. To shorten the immune reaction time in the microchannels and simplify the device, magnetic stirring and four-channel universal serial bus (USB) ports for plug-and-play were used. When Ru(bpy)(3)(2+) labeled antibodies were selectively captured by the corresponding antigens on the CdS nanorod spot array, ECL-RET from the CdS nanorod (donor) by cathodic emission in the presence of K(2)S(2)O(8) to Ru(bpy)(3)(2+) (acceptor) occurred. With signal amplification of Ru(bpy)(3)(2+) and competitive immunoassay, carcinoembryonic antigen (CEA), alpha fetoprotein (AFP), and prostate specific antigen (PSA) as models were detected on this microfluidic device via recording the increased ECL-RET signals on electrode surfaces. Furthermore, this multiplexed competitive immunoassay was successfully used for detecting cancer cell surface antigens via the specific antibody-cell interactions and cell counting via cell surface receptors and antigens on the CdS nanorod surface. This platform provides a rapid and simple but sensitive approach with microliter-level sample volume and holds great promise for multiplexed detection of antigens and antigen-specific cells. PMID- 22494077 TI - What is evidence? Reflections on the AMEE symposium, Vienna, August 2011. AB - In this article, we present a summary of the discussion from the symposium on 'what is evidence', which took place at the AMEE conference in 2011. A panel of five academics and clinicians, plus the chair, considered the nature of evidence, in particular in relation to the 'evidence' in the best evidence medical education reviews. Evidence has multiple meanings depending on context and use, and this reflects the complex and often chaotic world in which we work and research. PMID- 22494078 TI - Online professionalism and Facebook--falling through the generation gap. AB - BACKGROUND: Facebook is the most popular social networking site (SNS) worldwide. The growing popularity of SNSs brings 'e-professionalism' to the forefront. AIMS: To assess Facebook use, publicly accessible material and awareness of privacy guidelines and online professionalism by students, foundation year doctors (FYDs) and senior staff grades (SSGs). METHODS: It was an ethical risk to access publicly available information online as many users do not appreciate the lack of privacy involved, therefore a cross-sectional survey was undertaken. Participants included 42 students, 20 FYDs and 20 SSGs from the Severn Deanery (UK). RESULTS: All 42 students and 20 FYDs had Facebook compared with 6 (30%) SSGs. Of these, 17 students (41%), 15 FYDs (75%) and 3 SSGs (50%) had public 'info pages'. 37 students (88%) reported colleagues behaving unprofessionally online with 16 FYDs (80%) but no SSGs. 32 students (76%) felt their professionalism was threatened online, alongside 18 FYDs (90%) and 2 SSGs (33%). Only 11 students (26%), 10 trainees (50%) and no SSGs were aware of guidelines. CONCLUSIONS: Professionals lack awareness of their professional vulnerability online. They are not careful in restricting access to their posted information and are not mindful that the principles of professionalism apply to SNSs. PMID- 22494079 TI - A comparison of self-perceived competencies of traditional and reformed curriculum graduates 6 years after graduation. AB - BACKGROUND: In 1996, the University of Liverpool reformed its medical course from a traditional lecture-based programme to an integrated, community based PBL curriculum based on the recommendations in Tomorrow's Doctors (General Medical Council, 1993). AIM: A project has been underway since 2000 to evaluate this change. METHODS: This article will summarize questionnaires which were distributed to the final two cohorts to graduate from the traditional curriculum with the first two cohorts to graduate from the reformed curriculum 6 years after graduation. The questionnaires asked the graduates about their preparation for the key skills required to work as doctors. RESULTS: There were significant differences between reformed and traditional curriculum graduates on nearly all the questionnaire variables. Reformed curriculum graduates felt significantly better prepared for undertaking practical procedures, working in a team, understanding evidence-based medicine. The traditional graduates felt better prepared in variables relating to basic sciences such as understanding disease processes. CONCLUSION: Reforming the curriculum can change the way graduates from the same medical school view their undergraduate education. PMID- 22494080 TI - Do GP trainers use feedback in drawing up their Personal Development Plans (PDPs)? Results from a quantitative study. AB - BACKGROUND: General practice (GP) trainers play a key role GP trainees' education. To stimulate development of trainer competencies a Personal Development Plan (PDP) can be helpful, especially when feedback is incorporated. AIMS: To investigate to what extent GP trainers use feedback in PDPs. METHODS: GP trainers were provided with three feedback sources: trainees' rating scores, trainees' narrative comments, and self-assessment scores. Trainers were instructed to use these while drawing up PDP goals. With quantitative analyses the extent to feedback sources were used was determined. RESULTS: Of the trainers 93% submitted a PDP. More than 75% of goals were based on provided feedback. Multiple sources addressing the same issue increased feedback use. If two sources pointed in the same direction, feedback was used more often if one of them concerned "narrative comments". Ratings were lowest for GP-related Expertise and Teaching Skills. Most goals defined concerned these domains. Fewer goals regarded Personal Functioning. Proportion of feedback used concerning Personal functioning was lowest. CONCLUSIONS: GP trainers use most feedback and address issues most commented upon. Narrative comments deserve a profound place when eliciting feedback. Research into the quality with which feedback is used in PDP goals should complement these results. PMID- 22494081 TI - SMART, SMARTER, SMARTEST: the influence of peer groups compared to practice visits on the quality of action plans. AB - BACKGROUND: It has been reported that appraisal by peers can be effective. AIM: To investigate whether feedback from a peer group (PG) compared to that by a staff member during a practice visit (PV) is as effective in improving the quality of action plans. METHODS: Seventy-three general practitioner (GP) trainers randomized into either a PG or PV were instructed to draw up action plans using the SMART criteria to realize the goals set in their personal development plans (PDPs). To improve action plans, feedback was given in either PG or PV. Quality of baseline and follow-up action plans, operationalized as the SMARTness with which plans were formulated, was assessed using a study-specific instrument. RESULTS: Response rate for submitting both baseline and follow-up action plans was 89% in the PG versus 79% in the PV. It was feasible to determine scores on all SMART criteria, except for the criterion 'Acceptability'. Significant improvement was made on the remaining four criteria irrespective of the feedback setting. CONCLUSIONS: PGs cost less and seem equally effective in improving the SMARTness of the action plans. Moreover, they also seem to stimulate GP trainers more to write a PDP. Therefore, they may be favoured over PVs. PMID- 22494082 TI - Functional analysis and functional communication training in individuals with Angelman syndrome. AB - OBJECTIVE: To assess the functions of challenging behaviour in four children with Angelman syndrome (AS) and to study the effects of functional communication training (FCT) with precursor-based prompting. This study builds on and extends the study of Allen et al. METHOD: Experimental functional analysis assessed behavioural functions. FCT was implemented within an ABAB design and effect sizes were calculated. Burst analyses depict tendencies in (precursor) behaviours surrounding target behaviours. RESULTS: Results show challenging behaviour to be aimed at receiving attention, tangibles or escape. Burst analysis designated physical and eye contact and reaching for tangibles as precursors. Effects of FCT ranged from small to large. CONCLUSION: Behavioural functions for challenging behaviour were found and FCT was effective in reducing its frequency, when precursors were used as the onset of prompting. Functional equivalence between challenging and communicative behaviour was found. Implementing treatment for challenging behaviour based on precursors is advised. PMID- 22494083 TI - Plantarflexor muscle and spatiotemporal gait characteristics of children with hemiplegic cerebral palsy: an observational study. AB - OBJECTIVE: The study investigated associations between the active and passive mechanical properties of the calf muscle in children with cerebral palsy and the spatiotemporal features of their gait on both level ground and over stairs. METHODS: 26 children with hemiplegic cerebral palsy (age 4 - 10 years) walked barefoot across a level ten metre pathway and a staircase. Walking speed, stride length and cadence were calculated and spasticity, maximum isometric strength, stiffness and hysteresis of the affected side calf muscle measured. Multiple linear regression was used to determine the associations among variables. RESULTS: Walking speed and stride length were significantly associated with dorsiflexor muscle strength and the stiffness of the calf muscle, while stair ascent and descent speeds were significantly and inversely related to the amount of hysteresis displayed by the calf muscle. CONCLUSION: Passive mechanical properties of the calf muscle are influential in gait performance in these children. PMID- 22494084 TI - Computer-based interventions to improve social and emotional skills in individuals with autism spectrum disorders: a systematic review. AB - OBJECTIVE: To review studies involving the use of computer-based interventions (CBI) to improve the social and emotional skills (e.g. emotional recognition) of individuals with autism spectrum disorders (ASD). METHODS: The use of computer based intervention (CBI) in the treatment of autism spectrum disorders (ASD) may offer some advantages to traditional one-to-one or group instruction including easier differentiation of instruction, decreased distractions and the incorporation of an individual's relative visual learning strengths. However, the results of past research suggest varying outcomes for CBI with individuals with ASD. This review provides a systematic analysis of studies investigating CBI to improve social and emotional skills (e.g. emotion recognition) of individuals with ASD. Electronic database searches and ancestral searches were used to identify studies that met pre-determined inclusion criteria. The included studies were then summarized in terms of: (a) participant characteristics, (b) social and emotional skills targeted, (c) details of the CBI, (d) results, and (e) certainty of evidence. RESULTS: The results of these studies indicated that CBI's effect on social and emotional skills was mixed, with the majority of studies reporting unacceptable outcomes following intervention. CONCLUSIONS: Overall, this review suggests that the use of CBI to improve the social and emotional skills of individuals with ASD is a promising practice. A comparison of CBI plus tutoring and face-to-face social skills training suggests that CBI can be as effective as face-to-face instruction. Practitioners should carefully consider the preferences and existing abilities of individuals with ASD and the customizability of the software when deciding to use CBI and selecting a software program. PMID- 22494085 TI - Functional analysis of insistence on sameness in an 11-year old boy with Asperger syndrome. AB - OBJECTIVE: To identify the functional properties of insistence on sameness associated with autism spectrum disorders. METHOD: An 11-year-old boy with Asperger syndrome was observed during play where scenarios (mistakes, misplaced items, interrupted activity) were created to correspond with parent-reported scenarios where the child would insist on sameness. The extent of problem behaviour was observed under four functional assessment conditions (restore environment, tangible, attention, escape), according to a multi-element design. RESULTS: The results showed an interaction between the scenario type and type of functional assessment condition. Problem behaviour appeared to have a restorative function related to correcting a mistake, an attention function related to attempting to recruit help in finding a missing item and a tangible function suggesting an attempt to regain access to the materials and activity. CONCLUSION: Problem behaviours related to insistence on sameness may be motivated by different consequences depending on the scenario created. PMID- 22494086 TI - Expressive writing in early breast cancer survivors. AB - AIMS: This article is the report of a study aimed at determining whether or not expressive writing improves the quality-of-life of early breast cancer survivors. An additional aim is the investigation of whether or not the type of writing prompt makes a difference in results. BACKGROUND: The risk of distress can extend well beyond the time of a breast cancer diagnosis. Emotional expression may assist in dealing with this. DESIGN: Randomized controlled study. METHODS: Participants (n = 120) were randomized into one of four groups: a control group (no writing) or one of three expressive writing groups: breast cancer trauma, any self-selected trauma and facts related to breast cancer. Participants wrote 20 minutes a day for 4 consecutive days. Their quality-of-life was measured, using the 'Functional Assessment of Cancer Therapy-Breast Cancer Version', at baseline and at 1 month and 6 months after writing. Paired t-tests, multivariate analysis of variance and multiple regression were used to analyse the data of the 97 participants who completed the journaling assignment and at least the first assessment, collected in 2006. Intention-to-treat analysis was used. RESULTS/FINDINGS: Expressive writing about one's breast cancer, breast cancer trauma and facts related to breast cancer, significantly improved the quality-of life outcome. CONCLUSION: Expressive writing, focusing the instructions on writing about one's living and dealing with a diagnosis of breast cancer, is recommended for early breast cancer survivors as a feasible and easily implemented treatment approach to improve quality-of-life. PMID- 22494087 TI - Does childhood nutrition influence adult cardiovascular disease risk?--insights from the Young Finns Study. AB - There is a paucity of detailed information about the role of childhood food patterns or on the impact of individual nutrients on adulthood cardiovascular disease (CVD). We review here the reports that have investigated these questions in the Young Finns Study with its 3596 subjects at baseline, aged 3 to 18 years. All the participants filled in a food habit questionnaire, and half of them provided a 48-hour dietary recall interview. In adulthood, cardiovascular risk factors as well as structural and functional markers of subclinical atherosclerosis were measured, i.e. carotid artery intima media thickness (IMT), and measurements of arterial elasticity and brachial artery endothelial function. Our data demonstrate that dietary patterns can already be identified in childhood. These patterns remain relatively stable over the life-course and associate with cardiovascular risk factors and vascular markers of subclinical atherosclerosis. For example, a traditional dietary pattern characterized by low intakes of fruits and vegetables was associated with elevated increased adulthood IMT especially in men, whereas a diet with a high intake of vegetables was independently associated with increased arterial elasticity in both genders. Our findings and the current literature suggest that childhood nutrition has a significant role in the progression of CVD. PMID- 22494088 TI - Fractionation of mouse bone-marrow cells limits functional efficacy in non reperfused mouse model of acute myocardial infarction. AB - BACKGROUND AND OBJECTIVES: Clinical trials of bone-marrow (BM)-derived cells for therapy after acute myocardial infarct (MI) have been controversial. The most commonly used cells for these trials have been mononuclear cells (MNC), obtained by fractionation of BM cells (BMCs) via different protocols. In this study, we performed a head-to-head comparison of: 1) whole BMC; 2) fractionated BM (fBM) using the commonly used Ficoll protocol; 3) the extract derived from the fBM (fBM extract) versus 4) saline (HBSS) control for treatment of acute MI. METHODS: In total, 155 male C57BL/6J (10-12-week old) mice were included. Echocardiography was performed at baseline and 2 days after permanent ligation of the left anterior descending artery to induce MI. Echocardiography and histology were employed to measure outcome at 28 days post-MI. RESULTS: Whole BMC therapy improved left ventricular ejection fraction (LVEF) post-MI, but fBM or fBM extract was not beneficial compared to control (change of LVEF of 4.9% +/-4.6% (P = 0.02), -0.4% +/-5.8% (P = 0.86), -2.0% +/-6.2% (P = 0.97) versus -1.4% +/-5.3%, respectively). The histological infarct size or numbers of arterioles or capillaries at infarct or border zone did not differ between the groups. CONCLUSIONS: Clinical studies should be performed to test whether whole BMC therapy translates into better outcome also after human MI. PMID- 22494089 TI - Large physisorption strain in chemical vapor deposition of graphene on copper substrates. AB - Graphene single layers grown by chemical vapor deposition on single crystal Cu substrates are subject to nonuniform physisorption strains that depend on the orientation of the Cu surface. The strains are revealed in Raman spectra and quantitatively interpreted by molecular dynamics (MD) simulations. An average compressive strain on the order of 0.5% is determined in graphene on Cu(111). In graphene on Cu (100), MD simulations interpret the observed highly nonuniform strains. PMID- 22494090 TI - Association and diffusion of nutrition and physical activity policies on the state and district level. AB - BACKGROUND: School district wellness policies designed to reduce obesity and promote student health and well-being often lack specific requirements or any mandate that schools comply with the policy. Researchers, educators, and policymakers have called for states to take an active role in shaping district policies. The objective of this study was to determine if states with strong school-based nutrition and physical activity (PA)-related policies have stronger district wellness policies, and explore the direction of policy diffusion between states and districts. METHODS: State policies and nationally representative samples of district policies for the 2006-2007 and 2008-2009 school years were obtained across 5 domains-competitive foods, school meals, nutrition education, physical education (PE), and PA-and were classified as "strong" or "weak," based on policy language, in each grade level (elementary, middle, high). Linear models estimated the cross-sectional and longitudinal associations between state and district policies. RESULTS: In 2006-2007 and 2008-2009, district elementary school competitive food policies were stronger in states with strong policies. For policies governing competitive foods in high schools and school meals at all grade levels, mean district policy strength increased from 2006-2007 to 2008-2009 in states with strong 2006-2007 policies. States that strengthened their PE policies from 2006-2007 to 2008-2009 saw an increase in mean district PE policy strength. Across all domains, states that had weak 2006-2007 policies and made no changes saw little increase in district policy strength. CONCLUSION: District competitive food, school meal, and PE policies are stronger in states that have developed strong policies in these domains. PMID- 22494091 TI - Are farm-to-school programs more common in states with farm-to-school-related laws? AB - BACKGROUND: Farm-to-School programs (FTSPs) connect schools with locally grown food. This article examines whether FTSPs are more common in public elementary schools (ESs) in states with a formal, FTSP law or with a related, locally grown procurement law. METHODS: A pooled, cross-sectional analysis linked nationally representative samples of 1872 public ESs (across 47 states) for the 2006-2007, 2007-2008, and 2008-2009 school years with state laws effective as of the beginning of September of each year that were collected and analyzed for all states. Multivariate logistic regression models examined the impact of state law on school FTSP participation, controlling for year and school-level race/ethnicity, region, locale, free-reduced lunch participation, and school size. RESULTS: The percentage of schools located in a state with a FTSP-specific law increased from 7.3% to 20.4% over the 3-year period, while the percentage of schools located in a state with a locally grown procurement law was approximately 30% across all years. The percentage of schools with FTSPs has more than tripled over the last 3 years (from 4.9% to 17.7%). After adjusting for all covariates except year, FTSPs were significantly more likely in states with a FTSP-specific law (OR = 2.45, 95% CI = 1.28-4.67); once adjusting for year, the results were marginally significant (OR = 1.72, 95% CI = .91-3.25). School-level FTSPs were not related to state locally grown procurement laws. CONCLUSION: Although the percentage of schools with FTSPs is relatively small, these programs are becoming more common, particularly in states with FTSP-specific laws. PMID- 22494092 TI - Surveying teens in school to assess the prevalence of problematic drug use. AB - BACKGROUND: Illicit drug use by school-aged teens can adversely affect their health and academic achievement. This study used a survey administered in schools to assess the prevalence of problematic drug use among teenagers in a Midwestern community. METHODS: Self-report data were collected from 11th- and 12th-grade students (N = 3974) in 16 school districts in the Dayton, Ohio, area. Students responded to a drug use survey that also included CRAFFT, a brief substance abuse screening instrument. Binomial and zero-inflated Poisson regressions were used to examine the association between CRAFFT scores and drug use practices, including abstinence. RESULTS: More than one third of students had CRAFFT scores suggestive of problematic use. Of these, 14.1% had scores suggesting drug dependence. Although alcohol, marijuana, and tobacco were the drugs most commonly used, an array of other drugs including opioids, benzodiazepines, stimulants, hallucinogens, and dextromethorphan were also commonly used. Higher CRAFFT scores were associated with a greater number of drugs used (p < .0001). Proportionately more 12th graders than 11th graders had CRAFFT scores indicating problems (p < .0001). Among 12th graders, boys were more likely than girls to have CRAFFT scores indicating dependence (p = .01). CONCLUSIONS: The results suggest that problematic drug use among high school students is more prevalent than has been recognized previously. CRAFFT can be used easily to assess the prevalence of problematic drug use among teenagers in school settings. CRAFFT results can also inform prevention and intervention activities, particularly if the CRAFFT instrument is paired with a drug use survey. PMID- 22494093 TI - Physical activity energy expenditure in Dutch adolescents: contribution of active transport to school, physical education, and leisure time activities. AB - BACKGROUND: Detailed knowledge about physical activity energy expenditure (PAEE) can guide the development of school interventions aimed at reducing overweight in adolescents. However, relevant components of PAEE have never been objectively quantified in this population. This study investigated the contribution of active transport to and from school, physical education (PE), and leisure time activities to total PAEE during a regular school week in adolescents. METHODS: Seventy-three adolescents (mean age: 15.7 years) wore an individually calibrated combined heart rate-acceleration monitor and kept an activity diary during a regular school week. Branched equation modeling was used to calculate PAEE of the specific activity categories, and their relative contribution to total PAEE was determined. RESULTS: Active transport and PE contributed 30.0% and 17.4%, respectively, to school-related PAEE. Active transport to and from school contributed 15% to total PAEE. Youth with a high physical activity level (PAL) spent 4 hours less in sedentary behavior than subjects with a medium or low PAL (F = 77.415 (2.70), p < .001) and had higher PAEE during leisure time sports (F = 9.135 (2.70), p < .001) and work-related activities (F = 10.583 (2.70), p < .001) than youth with medium or low PAL values. CONCLUSIONS: Active transport and PE contribute significantly to PAEE during school hours in adolescents. To achieve an increase in total PAEE in the least active group of adolescents, promising strategies might be to reduce inactive behavior, increase participation in leisure time sports, and possibly to replace inactive for active jobs. PMID- 22494094 TI - Educating coaches about concussion in sports: evaluation of the CDC's "Heads Up: concussion in youth sports" initiative. AB - BACKGROUND: Concussions remain a serious public health concern. It is important that persons involved in youth sports, particularly coaches, be made aware and educated on the signs and symptoms of concussion. This study assessed the perceptions of youth sport coaches who have received the Centers for Disease Control and Prevention's (CDC's) "Heads Up: Concussion in Youth Sports" materials in preventing, recognizing, and responding to concussions. METHODS: A 22-item survey was developed with questions pertaining to demographics, awareness of sports-related concussion, and the usefulness of the CDC's "Heads Up: Concussion in Youth Sports" initiative and materials. A total of 340 youth sport coaches completed the survey, for a response rate of 34.0%. RESULTS: All youth sport coaches reported having the "Heads Up" materials for approximately 6 months before completing the survey. Seventy-seven percent of youth sports coaches reported being better able to identify athletes who may have a concussion, with 50% reported having learned something new about concussion after reviewing the materials. Sixty-three percent of youth sport coaches viewed concussions as being more serious, while 72% of coaches reporting that they are now educating others on concussion. CONCLUSION: The "Heads Up" materials demonstrated that youth sports coaches' were able to appropriately prevent, recognize, and respond to sports-related concussions after reviewing the materials. Future studies should concentrate on evaluating the impact of concussion policies, laws and media coverage on coaches' awareness and prevention, recognition, and response to concussions using a rigorous design including a control group. PMID- 22494095 TI - The relationship among state laws, district policies, and elementary school-based measurement of children's body mass index. AB - BACKGROUND: School-based measurement of children's body mass index (BMI) is a useful tool for tracking childhood obesity rates, and may be an effective intervention strategy for reducing the increasing trends in obesity. This article examines the relationship between state law, district policy, and school-level BMI measurement practices. METHODS: Data were collected during 3 school years (2006-2007, 2007-2008, 2008-2009) as part of an annual study on health policies and practices in a nationally representative sample of US public elementary schools. Data collected included school-level data via a mailed questionnaire, and district-level policies and state laws from publicly available sources. We examined whether state laws and district policies were linked to school-level BMI measurement, either directly, or via a mediation effect. RESULTS: Schools were most likely to measure student BMI if there was a state law in place (65.0% of schools) than where there was not a state law regarding BMI measurement (38.4% of schools; chi(2) = 120.91, p < .001). However, school-level BMI measurement did not differ by whether the district had a relevant policy or not (49.8% vs. 49.2%, ns). These effects held up in multivariate logistic regression models controlling for relevant school-level covariates (region, race/ethnicity, location, school size, and socioeconomic status). Schools in the south and those with a majority of White students were most likely to measure students' BMI. CONCLUSION: State laws are associated with school-level BMI measurement, and therefore may be a helpful tool in monitoring and addressing childhood obesity. PMID- 22494096 TI - Environmental justice at school: understanding research, policy, and practice to improve our children's health. AB - BACKGROUND: No overarching federal agencies or policies are responsible for ensuring environmental health at schools in the United States, potentially allowing many inequities for low-income and minority communities to persist. This article examines emergent research, policy, and practice-based efforts that may be used to identify and address environmental justice at school. METHODS: A brief literature review was conducted to understand (1) major mental, behavioral, and physical outcomes associated with environmental risk for school-aged children and (2) current research methods for assessing these relationships. Documents prepared by government agencies, school districts, and advocacy groups were also collected and synthesized to improve understanding of the state of planning and policies for maintaining or improving school environments. RESULTS: Environmental risk can manifest in diverse ways such as mold, poor air quality, poor community design, or contaminated playgrounds. Deeply rooted in national and state structures of school funding and planning, such risks can lead to outcomes including respiratory illness, poor performance in school, and reduced levels of physical activity. With growing attention to these concerns, methods for measuring environmental risks and underlying disparities have advanced tremendously in the last few decades, yet development of innovative research approaches may be necessary to further advance and evaluate appropriate interventions. CONCLUSIONS: Environmental injustice is generally unacknowledged during decision-making in US school districts. Continued dialogue reflective of translatable science is necessary to support school districts with limited funding in ensuring safe, healthy environments for learning. PMID- 22494097 TI - Long-term prognostic value of the right ventricular myocardial performance index compared to other indexes of right ventricular function in patients with moderate chronic heart failure. AB - BACKGROUND: The ventricular myocardial performance index (MPI) is a feasible echocardiographic parameter for the evaluation of patients with chronic heart failure (CHF). The long-term prognostic role of right ventricular MPI (RV MPI) has been already assessed in patients with more advanced CHF but data are lacking in moderate CHF. The aim of the study is to evaluate the possible prognostic role of RV MPI in moderate CHF patients compared to others traditional RV parameters. METHODS: From 2003 to 2004 we enrolled 95 consecutive NYHA class II CHF patients (65 males and 30 females), with the mean age of 66 +/- 11 years with left ventricular ejection fraction (LVEF) <40%, on optimal medical treatment. All patients were evaluated clinically and by echocardiography with a follow-up of 5 years (combined end point: cardiovascular mortality and hospitalization for HF). RESULTS: RV MPI was 0.45 +/- 0.36, tricuspid annular plane systolic excursion was 21 +/- 8 mm, RV fractional area change was 42 +/- 12%, systolic pulmonary artery pressure was 33 +/- 9 mmHg, and acceleration time of pulmonic flow was 115.5 + 22.62 msec. After the 5 year follow-up the total mortality was 24.2% and HF hospitalization rate was 33%. At Cox multivariate analysis only an RV MPI superior to median value (>0.38) and tricuspid annular plane systolic excursion inferior to median value (<18 mm) had shown a significant prognostic role. CONCLUSION: The RV MPI in a population of moderate CHF showed to have a more long term powerful prognostic value than other conventional and traditional echocardiographic right ventricular functional parameters. PMID- 22494098 TI - Dabigatran and dabigatran ethyl ester: potent inhibitors of ribosyldihydronicotinamide dehydrogenase (NQO2). AB - Recent studies have revealed that compounds believed to be highly selective frequently address multiple target proteins. We investigated the protein interaction profile of the widely prescribed thrombin inhibitor dabigatran (1), resulting in the identification and subsequent characterization of an additional target enzyme. Our findings are based on an unbiased functional proteomics approach called capture compound mass spectrometry (CCMS) and were confirmed by independent biological assays. 1 was shown to specifically bind ribosyldihydronicotinamide dehydrogenase (NQO2), a detoxification oxidoreductase. Molecular dockings predicted and biological experiments confirmed that dabigatran ethyl ester (2) inhibits NQO2 even more effectively than the parent 1 itself. Our data show that 1 and 2 are inhibitors of NQO2, thereby revealing a possible new aspect in the mode of action of 1. We present a workflow employing chemical proteomics, molecular modeling, and functional assays by which a compound's protein-interaction profile can be determined and used to tune the binding affinity. PMID- 22494099 TI - Recruitment of circulating dendritic cell precursors into the infarcted myocardium and pro-inflammatory response in acute myocardial infarction. AB - DC (dendritic cells) play an important role in the immune system. They invade peripheral tissues to detect harmful antigens, inducing a local immune response. Studies suggest that DCPs (dendritic cell precursors) might be reduced in AMI (acute myocardial infarction); however, the reason for their reduction is unknown yet. In the present study, circulating mDCPs (myeloid DCPs), pDCPs (plasmacytoid DCPs), tDCPs (total DCPs) and serum levels of TNFalpha (tumour necrosis factor alpha), IL (interleukin)-2, -4, -5, -6, -10 and -12 were analysed by flow cytometry in blood of patients with NSTEMI [non-STEMI (ST-segment elevation myocardial infarction)] (n=44) and STEMI (n=34) compared with controls with excluded CAD (coronary artery disease) (n=45). Post-mortem myocardial specimens of patients with AMI (n=12) and healthy myocardium of accident victims (n=10) were immunostained for mDCs (myeloid dendritic cells) T-cells and macrophages. Compared with controls, in patients with AMI a significant decrease in circulating mDCPs, pDCPs and tDCPs was observed (each P<0.0001). The extent of the decrease was higher in STEMI than NSTEMI patients. Serum levels were significantly higher in patients with AMI compared with controls for IL-6, -10, 12 and TNFalpha (each P<0.03). Immunostaining revealed significantly higher number of DCs, T-cells and macrophages (each P<0.002) in infarcted than control myocardium. We show that circulating DCPs are significantly reduced in AMI, with a pronounced reduction in STEMI patients. This was accompanied by a significant increase of inflammatory serum cytokines in patients with AMI. Immunohistochemical analysis unravelled that the reduction of circulating DCPs might be due to recruitment into the infarcted myocardium. PMID- 22494100 TI - Solventless dry powder coating for sustained drug release using mechanochemical treatment based on the tri-component system of acetaminophen, carnauba wax and glidant. AB - OBJECTIVE: Solventless dry powder coating methods have many advantages compared to solvent-based methods: they are more economical, simpler, safer, more environmentally friendly and easier to scale up. The purpose of this study was to investigate a highly effective dry powder coating method using the mechanofusion system, a mechanochemical treatment equipped with high compressive and shearing force. MATERIALS AND METHODS: Acetaminophen (AAP) and carnauba wax (CW) were selected as core particles of the model drug and coating material, respectively. Mixtures of AAP and CW with and without talc were processed using the mechanofusion system. RESULTS: Sustained AAP release was observed by selecting appropriate processing conditions for the rotation speed and the slit size. The dissolution rate of AAP processed with CW substantially decreased with an increase in talc content up to 40% of the amount of CW loaded. Increasing the coating amount by two-step addition of CW led to more effective coating and extended drug release. Scanning electron micrographs indicated that CW adhered and showed satisfactory coverage of the surface of AAP particles. CONCLUSION: Effective CW coating onto the AAP surface was successfully achieved by strictly controlling the processing conditions and the composition of core particles, coating material and glidant. Our mechanochemical dry powder coating method using the mechanofusion system is a simple and promising means of solventless pharmaceutical coating. PMID- 22494102 TI - Probing colloid-substratum contact stiffness by acoustic sensing in a liquid phase. AB - In a quartz crystal microbalance, particles adhering to a sensor crystal are perturbed around their equilibrium positions via thickness-shear vibrations at the crystal's fundamental frequency and overtones. The amount of adsorbed molecular mass is measured as a shift in resonance frequency. In inertial loading, frequency shifts are negative and proportional to the adsorbed mass, in contrast with "elastic loading", where particles adhere via small contact points. Elastic loading in air yields positive frequency shifts according to a coupled resonance model. We explore here the novel application of a coupled resonance model for colloidal particle adhesion in a liquid phase theoretically and demonstrate its applicability experimentally. Particles with different radii and in the absence and presence of ligand-receptor binding showed evidence of coupled resonance. By plotting the frequency shifts versus the quartz crystal microbalance with dissipation overtone number, frequencies of zero-crossing could be inferred, indicative of adhesive bond stiffness. As a novelty of the model, it points to a circular relation between bandwidth versus frequency shift, with radii indicative of bond stiffness. The model indicates that bond stiffness for bare silica particles adhering on a crystal surface is determined by attractive Lifshitz-van der Waals and ionic-strength-dependent, repulsive electrostatic forces. In the presence of ligand-receptor interactions, softer interfaces develop that yield stiffer bonds due to increased contact areas. In analogy with molecular vibrations, the radii of adhering particles strongly affect the resonance frequencies, while bond stiffness depends on environmental parameters to a larger degree than for molecular adsorption. PMID- 22494101 TI - Nomegestrol acetate sequentially or continuously combined to estradiol did not negatively affect membrane-receptor associated progestogenic effects in human breast cancer cells. AB - OBJECTIVES: Recently the first monophasic contraceptive pill containing estradiol has been developed which is thought to be a milestone in contraception. Nomegestrol acetate (NOM) is the progestogenic component. Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in the tissue of breast cancer patients, and can predict a progestogen dependent risk of breast cancer. METHODS: MCF-7 cells were transfected with PGRMC1 expression plasmid, and were stimulated with estradiol (E2, 10(-12) and 10(-10) M). NOM, progesterone (P), medroxyprogesterone acetate (MPA) and norethisterone (NET) (each 10(-7) M) were added sequentially or continuously. RESULTS: E2 at 10(-10) M elicited a significant increase of cell proliferation from 150 to 200%. No effect was seen at 10(-12) M. Addition of the progestogens to E2 at 10(-10) M had no significant effect. However, at an E2 10(-12) M, NET significantly stimulated cell proliferation more pronounced in the continuous combined model. No effect was seen for NOM, P and MPA. The E2/NET combined effect could be abrogated by the addition of an estrogen receptor (ER) antagonist. CONCLUSION: Since NOM did not increase proliferation it may be concluded that it will be neutral in terms of breast cancer risk when combined with E2 at least in women overexpressing PGRMC1. PMID- 22494103 TI - Dysadherin expression promotes the motility and survival of human breast cancer cells by AKT activation. AB - High dysadherin expression has been recognized as a biological predictor of metastasis and poor prognosis for many different cancer types; however, the molecular mechanisms of how dysadherin affects cancer progression are still poorly understood. In this study, we examined whether AKT signaling could link dysadherin expression with downstream events that promote the metastatic potential of human breast cancer cells. Immunohistochemical analysis of breast cancer tissues showed that dysadherin expression was highly associated with elevated expression of phospho-AKT. The introduction of dysadherin cDNA into BT 474, MCF-7 and T-47D breast cancer cell lines enhanced their levels of AKT phosphorylation, while knockdown of dysadherin in MDA-MB-231 and Hs578T breast cancer cell lines suppressed AKT phosphorylation. Treatment with the AKT inhibitor triciribine suppressed dysadherin-mediated pro-metastatic effects, including epithelial-mesenchymal transition, cell motility and drug resistance. These findings suggest that dysadherin might contribute to breast cancer progression through AKT activation. PMID- 22494104 TI - Regular atrial tachyarrhythmia with double coronary sinus potentials: what is the diagnosis? PMID- 22494105 TI - Evidence supporting an independent association between childhood physical abuse and lifetime suicidal ideation. AB - A regionally representative Canadian sample was used to investigate the gender specific relationship between childhood physical abuse and lifetime suicidal ideation. The prevalence of suicidal ideation was about five times higher in abused men and women compared with their nonabused counterparts. After controlling for five clusters of potentially confounding factors (adverse childhood conditions, socioeconomic factors, health behaviors, psychosocial stressors/chronic illnesses, and mental health), childhood physical abuse was significantly associated with suicidal ideation (OR(adjusted) women = 4.48, 95% CI = 3.32-6.04; men = 3.57, 95% CI = 2.08-6.14). These findings suggest childhood physical abuse is independently associated with suicidal ideation and highlight the importance of providing preventative treatment to childhood abuse survivors. PMID- 22494106 TI - The effects of high-intensity resistance exercise on the blood lipid profile and liver function in hypercholesterolemic hamsters. AB - It is well established that atherogenic dyslipidemia, characterized by high levels of triglycerides (TG), total cholesterol (TC), and low-density lipoprotein (LDL) cholesterol and low levels of high-density lipoprotein (HDL) cholesterol, constitutes important risk factors for cardiovascular disease. Regular exercise has been associated with a reduced risk for metabolic diseases. However, studies supporting the concept that resistance exercise is a modifier of blood lipid parameters are often contradictory. The aim of this study was to investigate the effects of high-intensity resistance exercise on the serum levels of TG, TC, HDL and non-HDL cholesterol, glucose, and the liver function enzymes alanine aminotransferase (ALT, EC 2.6.1.2) and aspartate aminotransferase (AST, EC 2.6.1.1) in golden Syrian hamsters (Mesocricetus auratus (Waterhouse, 1839)) fed a hypercholesterolemic diet. Sedentary groups (S) and exercise groups (E) were fed a standard diet (SS and ES) or a cholesterol-enriched diet (standard plus 1% cholesterol, SC and EC). Resistance exercise was performed by jumps in the water, carrying a load strapped to the chest, representing 10 maximum repetitions (10 RM, 30 s rest, five days per week for five weeks). Mean blood sample comparisons were made by ANOVA + Tukey or ANOVA + Kruskal-Wallis tests (p < 0.05) to compare parametric and nonparametric samples, respectively. There were no differences in blood lipids between the standard diet groups (SS and ES) (p > 0.05). However, the EC group increased the glucose, non-HDL, and TC levels in comparison with the ES group. Moreover, the EC group increased the TG levels versus the SC group (p < 0.05). In addition, the ALT levels were increased only by diet treatment. These findings indicated that high-intensity resistance exercise contributed to dyslipidemia in hamsters fed a hypercholesterolemic diet, whereas liver function enzymes did not differ in regards to the exercise protocol. PMID- 22494107 TI - Electron-beam-induced elastic-plastic transition in Si nanowires. AB - It is generally accepted that silicon nanowires (Si NWs) exhibit linear elastic behavior until fracture without any appreciable plastic deformation. However, the plasticity of Si NWs can be triggered under low strain rate inside the transmission electron microscope (TEM). In this report, two in situ TEM experiments were conducted to investigate the electron-beam (e-beam) effect on the plasticity of Si NWs. An e-beam illuminating with a low current intensity would result in the bond re-forming processes, achieving the plastic deformation with a bent strain over 40% in Si NWs near the room temperature. In addition, an effective method was proposed to shape the Si NWs, where an e-beam-induced elastic-plastic (E-P) transition took place. PMID- 22494108 TI - Factors associated with ambulance use among patients with low-acuity conditions. AB - BACKGROUND: The use of ambulances for low-acuity medical complaints depletes emergency medical services (EMS) resources that could be used for higher-acuity conditions and contributes to emergency department (ED) overcrowding and ambulance diversion. Objective. We sought to understand the characteristics of patients who use ambulances for low-acuity conditions. We hypothesized that patients who arrive to the ED by ambulance for low-acuity conditions are more likely to be members of vulnerable populations. METHODS: A secondary analysis was performed on the National Hospital Ambulatory Medical Care Survey (NHAMCS). We included only patients aged 18 years or older who were triaged to the "nonurgent" category upon presentation to the ED. To compare patients who arrived by ambulance with those who arrived by all other modes, multivariate logistic regression was performed using a generalized linear model, and adjusted relative risks (ARRs) were calculated. RESULTS: A total of 16,109 records from 1997 to 2008 (excluding 2001-2002) were included in the analysis. Significantly higher rates of ambulance use for low-acuity conditions were associated with: 1) older age (ARR 1.30, 95% confidence interval [CI]: 1.18-1.43; per 10 years); 2) Medicare or Medicaid insurance (ARR 1.81, 95% CI: 1.36-2.41, and ARR 1.46, 95% CI: 1.12-1.91, respectively); 3) homelessness (ARR 3.30, 95% CI: 1.61-6.78); 4) arrival between 11 pm and 6:59 am (ARR 1.80, 95% CI: 1.43-2.27); and 5) certain chief complaint categories: psychiatric (ARR 1.78, 95% CI: 1.03-3.07), toxicologic/poisoning (ARR 3.26, 95% CI: 1.85-5.76), and neurologic/psychological (ARR 1.71, 95% CI: 1.34-2.18). Patients who arrived by ambulance were more likely than nonambulance patients to receive laboratory diagnostic tests (ARR 3.50, 95% CI: 2.80-4.39), radiographic imaging (ARR 2.26, 95% CI: 1.91-2.68), and admission to the hospital (ARR 3.99, 95% CI: 3.03-5.27). CONCLUSION: Our study builds on a body of work highlighting the factors associated with ambulance transport to EDs, confirms that certain vulnerable populations disproportionately use ambulances, and may inform interventions aimed at increasing access to nonambulance transportation and urgent care for these patients. PMID- 22494109 TI - Know thy nano neighbor. Plasmonic versus electron charging effects of metal nanoparticles in dye-sensitized solar cells. AB - Neighboring metal nanoparticles influence photovoltaic and photocatalytic behavior of semiconductor nanostructures either through Fermi level equilibration by accepting electrons or inducing localized surface plasmon effects. By employing SiO(2)- and TiO(2)-capped Au nanoparticles we have identified the mechanism with which the performance of dye-sensitized solar cells (DSSC) is influenced by the neighboring metal nanoparticles. The efficiency of an N719 dye sensitized solar cell (9.3%) increased to 10.2% upon incorporation of 0.7% Au@SiO(2) and to 9.8% upon loading of 0.7% Au@TiO(2) nanoparticles. The plasmonic effect as monitored by introducing Au@SiO(2) in DSSC produces higher photocurrent. However, Au nanoparticles undergo charge equilibration with TiO(2) nanoparticles and shift the apparent Fermi level of the composite to more negative potentials. As a result, Au@TiO(2) nanoparticle-embedded DSSC exhibit higher photovoltage. A better understanding of these two effects is crucial in exploiting the beneficial aspects of metal nanoparticles in photovoltaics. PMID- 22494110 TI - Method to study the effect of blend flowability on the homogeneity of acetaminophen. AB - CONTEXT: Excipient selection is key to product development because it affects their processability and physical properties, which ultimately affect the quality attributes of the pharmaceutical product. OBJECTIVE: To study how the flowability of lubricated formulations affects acetaminophen (APAP) homogeneity. MATERIALS AND METHODS: The formulations studied here contain one of two types of cellulose (Avicel 102 or Ceollus KG-802), one of three grades of Mallinckrodt APAP (fine, semi-fine, or micronized), lactose (Fast-Flo) and magnesium stearate. These components are mixed in a 300-liter bin blender. Blend flowability is assessed with the Gravitational Displacement Rheometer. APAP homogeneity is assessed with off-line NIR. RESULTS: Excluding blends dominated by segregation, there is a trend between APAP homogeneity and blend flow index. Blend flowability is affected by the type of microcrystalline cellulose and by the APAP grade. CONCLUSION: The preliminary results suggest that the methodology used in this paper is adequate to study of the effect of blend flow index on APAP homogeneity. PMID- 22494111 TI - Controlling health care spending--the Massachusetts experiment. PMID- 22494112 TI - Involvement of CaM kinase II in the impairment of endothelial function and eNOS activity in aortas of Type 2 diabetic rats. AB - In the present sutdy, we have examined the relationship between the CaMKII (Ca(2+)/calmodulin-dependent protein kinase II) pathway and endothelial dysfunction in aortas from GK (Goto-Kakizaki) Type 2 diabetic rats. The ACh (acetylcholine)-induced relaxation and NO production were each attenuated in diabetic aortas (compared with those from age-matched control rats). ACh stimulated Ser(1177)-eNOS (endothelial NO synthase) phosphorylation was significantly decreased in diabetic aortas (compared with their controls). ACh markedly increased the CaMKII phosphorylation level within endothelial cells only in control aortas (as assessed by immunohistochemistry and Western blotting). ACh stimulated Thr(286)-CaMKII phosphorylation within endothelial cells was significantly decreased in diabetic aortas (compared with their controls). The ACh-induced relaxations, NO production, eNOS phosphorylation, and CaMKII phosphorylation were inhibited by KN93 and/or by lavendustin C (inhibitors of CaMKII) in control aortas, but not in diabetic ones. Pre-incubation of aortic strips with a PP (protein phosphatase)-1 inhibitor, PPI2 (protein phosphatase inhibitor 2), or with a PP2A inhibitor, CA (cantharidic acid), corrected the above abnormalities in diabetic aortas. The expression of PP2A type A subunit was increased in diabetic aortas. The ACh-stimulated Thr(320)-phosphorylation level of PP1alpha was lower in diabetic aortas than in their controls, but the total PP1alpha protein level was not different. These results suggest that the aortic relaxation responses, NO production, and eNOS activity mediated by CaMKII phosphorylation are decreased in this Type 2 diabetic model, and that these impairments of CaMKII signalling may be, at least in part, due to enhancements of PP1alpha activity and PP2A expression. PMID- 22494113 TI - Two strawberry miR159 family members display developmental-specific expression patterns in the fruit receptacle and cooperatively regulate Fa-GAMYB. AB - * We have reported previously that the gibberellin (GA) content in strawberry receptacle is high, peaking at specific stages, pointing to a role of this hormone in fruit development. In Arabidopsis, miR159 levels are dependent on GA concentration. This prompted us to investigate the role of two members of the miR159 family and their putative strawberry target gene, GAMYB, in relation to changes in GA content during the course of fruit development. * The highest expression level of the two Fa-MIR159 genes was in the fruit's receptacle tissue, with dramatic changes observed throughout development. The lowest levels of total mature miR159 (a and b) were observed during the white stage of receptacle development, which was concurrent with the highest expression of Fa-GAMYB. A functional interaction between miR159 and Fa-GAMYB has been demonstrated in receptacle tissue. * The application of bioactive GA (i.e. GA(3) ) to strawberry plants caused the down-regulated expression of Fa-MIR159a, but the expression of Fa-MIR159b was not affected significantly. Clear discrepancies between Fa-MIR159b and mature Fa-miR159b levels were indicative of post-transcriptional regulation of Fa-MIR159b gene expression. * We propose that Fa-miR159a and Fa-miR159b interact with Fa-GAMYB during the course of strawberry receptacle development, and that they act in a cooperative fashion to respond, in part, to changes in GA endogenous levels. PMID- 22494114 TI - Ultra-low flow electrospray ionization-mass spectrometry for improved ionization efficiency in phosphoproteomics. AB - The potential benefits of ultra-low flow electrospray ionization (ESI) for the analysis of phosphopeptides in proteomics was investigated. First, the relative flow dependent ionization efficiency of nonphosphorylated vs multiplyphosphorylated peptides was characterized by infusion of a five synthetic peptide mix with zero to four phophorylation sites at flow rates ranging from 4.5 to 500 nL/min. Most importantly, similar to what was found earlier by Schmidt et al., it has been verified that at flow rates below 20 nL/min the relative peak intensities for the various peptides show a trend toward an equimolar response, which would be highly beneficial in phosphoproteomic analysis. As the technology to achieve liquid chromatography separation at flow rates below 20 nL/min is not readily available, a sheathless capillary electrophoresis-electrospray ionization mass spectrometry (CE-ESI-MS) strategy based on the use of a neutrally coated separation capillary was used to develop an analytical strategy at flow rates as low as 6.6 nL/min. An in-line preconcentration technique, namely, transient isotachophoresis (t-ITP), to achieve efficient separation while using larger volume injections (37% of capillary thus 250 nL) was incorporated to achieve even greater sample concentration sensitivities. The developed t-ITP-ESI-MS strategy was then used in a direct comparison with nano-LC-MS for the detection of phosphopeptides. The comparison showed significantly improved phosphopeptide sensitivity in equal sample load and equal sample concentration conditions for CE MS while providing complementary data to LC-MS, demonstrating the potential of ultra-low flow ESI for the analysis of phosphopeptides in liquid based separation techniques. PMID- 22494115 TI - Ecotropic viral integration site 1, stem cell self-renewal and leukemogenesis. AB - It has become evident that acute myeloid leukemia (AML) is organized as a cellular hierarchy initiated and maintained by a subset of self-renewing leukemia stem cells. Recent gene expression profile analysis of human leukemia stem cells and hematopoietic stem cell (HSC) populations identified a key transcriptional program shared by leukemia stem cells and HSC, which is associated with adverse outcomes in AML patients. One molecule that has been established as a pivotal regulator in fine-tuning of stem cell properties as well as a potent oncogenic determinant is ecotropic viral integration site 1 (EVI1). EVI1 is a transcription factor that has stem cell-specific expression pattern and is essential for the regulation of HSC self-renewal. This gene is notorious for its involvement in AML, as its activation confers extremely poor prognosis in patients with AML. Molecular analysis has identified a variety of gene products that are involved in HSC regulation as downstream targets or interacting proteins of EVI1. Thus, exploration of the molecular pathogenesis underlying EVI1-related leukemogenesis provides insight into how shared stemness transcriptional programs contribute to leukemia progression and therapeutic resistance in AML. Here, we review the current knowledge regarding the role of EVI1 in HSC self-renewal and leukemogenesis and highlight the relationship between stem cell self-renewal properties and adverse outcome in myeloid malignancies. PMID- 22494116 TI - Use of intracardiac echocardiography for early detection of phrenic nerve injury during cryoballoon pulmonary vein isolation. AB - Cryoballoon catheter ablation has recently emerged as an effective tool to achieve pulmonary vein isolation (PVI). Right-sided PVI with cryoballoon ablation has been associated with a significant incidence of phrenic nerve palsy. Multiple modalities are currently utilized to monitor phrenic nerve function during ablation. We describe a novel approach toward monitoring and diagnosing phrenic nerve palsy using intracardiac echocardiography (ICE) during cryoballoon ablation of the right pulmonary veins. This technique of monitoring has the advantage of continuous direct diaphragmatic visualization without the use of fluoroscopy, hence significantly minimizing radiation to both the patient and the operator. In addition, this technique does not require extra personnel to monitor the diaphragm using manual palpation. Further prospective studies of our and other methods for prevention of phrenic nerve palsy are required. PMID- 22494117 TI - Testing reciprocal longitudinal relations between peer victimization and depressive symptoms in young adolescents. AB - A 2-wave longitudinal study of young adolescents was used to test whether peer victimization predicts depressive symptoms, depressive symptoms predict peer victimization, or the 2 constructs show reciprocal relations. Participants were 598 youths in Grades 3 through 6, ages 8 to 14 (M = 10.9, SD = 1.2) at Wave 1. The sample was 50.7% female and 90.3% Caucasian. Participants completed self reports of depressive symptoms, and self-reports and peer nomination measures of physical and relational peer victimization at 2 time points separated by 1 year. The results were as follows: (a) depressive symptoms predicted change in both physical and relational victimization, but neither type of peer victimization predicted change in depressive symptoms; (b) depressive symptoms were more predictive of physical victimization for boys than for girls; and (c) boys experienced more physical victimization, and girls experienced more relational victimization. Expression of some depressive symptoms may represent signs of vulnerability. For boys, they may also represent a violation of gender stereotypes. Both factors could be responsible for these effects. Implications for intervention include the possibility that treatment of depression in young adolescents may reduce the likelihood of peer victimization. PMID- 22494118 TI - Preventing suicide through improved training in suicide risk assessment and care: an American Association of Suicidology Task Force report addressing serious gaps in U.S. mental health training. AB - There are twice as many suicides as homicides in the United States, and the suicide rate is rising. Suicides increased 12% between 1999 and 2009. Mental health professionals often treat suicidal patients, and suicide occurs even among patients who are seeking treatment or are currently in treatment. Despite these facts, training of most mental health professionals in the assessment and management of suicidal patients is surprisingly limited. The extant literature regarding the frequency with which mental health professionals encounter suicidal patients is reviewed, as is the prevalence of training in suicide risk assessment and management. Most importantly, six recommendations are made to address the longstanding insufficient training within the mental health professions regarding the assessment and management of suicidal patients. PMID- 22494119 TI - Addressing refractive error visual impairment: volunteer organisations' alignment with Vision 2020 and public health principles. AB - BACKGROUND: Eye care professionals have been making short visits to developing countries for decades in an effort to reduce visual impairment caused by refractive error. A 2006 survey revealed that volunteer organisations were not working within the Vision 2020 framework. Recommendations were made for volunteer organisations that would better align their work with accepted Vision 2020 and public health principles. METHODS: This study re-evaluates the alignment of volunteer organisations with Vision 2020 and public health principles. To determine their philosophies and methods, a web-based survey was sent to 89 volunteer organisations identified from an internet search. RESULTS: The response rate was 48 per cent. Many (70.7 per cent) organisations exclusively mention direct service provision in their statement of purpose, often provided by student volunteers (75.6 per cent). A few (19.5 per cent) provide short training in refraction, not necessarily following best principles. The majority (82.1 per cent) dispenses recycled spectacles and many use medications not on national essential drug lists. Few attempt to follow aid effectiveness principles with only 26.8 per cent stating they follow Vision 2020 country plans. Overall, as in 2006, the work of these organisations is largely not in alignment with Vision 2020 and public health principles. CONCLUSION: Organisations interested in decreasing visual impairment due to refractive error in the developing world are encouraged to transition to organisations that not only recognise but also implement public health principles. This should include reprioritisation of their work to developing human resources and infrastructure, determining the burden and causes of disease, assisting in the training of mid-level personnel and providing professional and community education, collaborating via partnerships, discontinuing the use of recycled spectacles and inappropriate medications, and evaluating their outcomes. Following these recommendations as well as creating a better alignment with public health principles in general will increase the likelihood that their programs will be effective in decreasing visual impairment due to refractive error in the developing world. PMID- 22494120 TI - Outcomes after induction failure in childhood acute lymphoblastic leukemia. AB - BACKGROUND: Failure of remission-induction therapy is a rare but highly adverse event in children and adolescents with acute lymphoblastic leukemia (ALL). METHODS: We identified induction failure, defined by the persistence of leukemic blasts in blood, bone marrow, or any extramedullary site after 4 to 6 weeks of remission-induction therapy, in 1041 of 44,017 patients (2.4%) 0 to 18 years of age with newly diagnosed ALL who were treated by a total of 14 cooperative study groups between 1985 and 2000. We analyzed the relationships among disease characteristics, treatments administered, and outcomes in these patients. RESULTS: Patients with induction failure frequently presented with high-risk features, including older age, high leukocyte count, leukemia with a T-cell phenotype, the Philadelphia chromosome, and 11q23 rearrangement. With a median follow-up period of 8.3 years (range, 1.5 to 22.1), the 10-year survival rate (+/ SE) was estimated at only 32+/-1%. An age of 10 years or older, T-cell leukemia, the presence of an 11q23 rearrangement, and 25% or more blasts in the bone marrow at the end of induction therapy were associated with a particularly poor outcome. High hyperdiploidy (a modal chromosome number >50) and an age of 1 to 5 years were associated with a favorable outcome in patients with precursor B-cell leukemia. Allogeneic stem-cell transplantation from matched, related donors was associated with improved outcomes in T-cell leukemia. Children younger than 6 years of age with precursor B-cell leukemia and no adverse genetic features had a 10-year survival rate of 72+/-5% when treated with chemotherapy only. CONCLUSIONS: Pediatric ALL with induction failure is highly heterogeneous. Patients who have T-cell leukemia appear to have a better outcome with allogeneic stem-cell transplantation than with chemotherapy, whereas patients who have precursor B-cell leukemia without other adverse features appear to have a better outcome with chemotherapy. (Funded by Deutsche Krebshilfe and others.). PMID- 22494122 TI - Dengue. PMID- 22494121 TI - A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. AB - BACKGROUND: Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). METHODS: In this multicenter, randomized, placebo-controlled, double-blind clinical trial, we assigned patients at elevated risk for post-ERCP pancreatitis to receive a single dose of rectal indomethacin or placebo immediately after ERCP. Patients were determined to be at high risk on the basis of validated patient- and procedure-related risk factors. The primary outcome was post-ERCP pancreatitis, which was defined as new upper abdominal pain, an elevation in pancreatic enzymes to at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least 2 nights. RESULTS: A total of 602 patients were enrolled and completed follow-up. The majority of patients (82%) had a clinical suspicion of sphincter of Oddi dysfunction. Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P=0.005). Moderate-to-severe pancreatitis developed in 13 patients (4.4%) in the indomethacin group and in 27 patients (8.8%) in the placebo group (P=0.03). CONCLUSIONS: Among patients at high risk for post-ERCP pancreatitis, rectal indomethacin significantly reduced the incidence of the condition. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00820612.). PMID- 22494123 TI - Images in clinical medicine. Leonine facies: lepromatous leprosy. PMID- 22494124 TI - Case records of the Massachusetts General Hospital. Case 11-2012. A 60-year-old man with weakness, rash, and renal failure. PMID- 22494125 TI - Attacking remaining challenges in childhood leukemia. PMID- 22494127 TI - Rifapentine and isoniazid for latent tuberculosis. PMID- 22494128 TI - Rifapentine and isoniazid for latent tuberculosis. PMID- 22494130 TI - Fitness memberships and favorable selection in Medicare Advantage plans. PMID- 22494131 TI - Fitness memberships and favorable selection in Medicare Advantage plans. PMID- 22494133 TI - Case 1-2012: a man with persistent ulcers on the hands. PMID- 22494134 TI - Clinical phenotype and mutant TRalpha1. PMID- 22494136 TI - Generic atorvastatin and health care costs. PMID- 22494139 TI - Images in clinical medicine. Achalasia. PMID- 22494140 TI - Interactive medical case. Whistling in the dark. PMID- 22494141 TI - The Mediator subunit SFR6/MED16 controls defence gene expression mediated by salicylic acid and jasmonate responsive pathways. AB - * Arabidopsis SENSITIVE TO FREEZING6 (SFR6) controls cold- and drought-inducible gene expression and freezing- and osmotic-stress tolerance. Its identification as a component of the MEDIATOR transcriptional co-activator complex led us to address its involvement in other transcriptional responses. * Gene expression responses to Pseudomonas syringae, ultraviolet-C (UV-C) irradiation, salicylic acid (SA) and jasmonic acid (JA) were investigated in three sfr6 mutant alleles by quantitative real-time PCR and susceptibility to UV-C irradiation and Pseudomonas infection were assessed. * sfr6 mutants were more susceptible to both Pseudomonas syringae infection and UV-C irradiation. They exhibited correspondingly weaker PR (pathogenesis-related) gene expression than wild-type Arabidopsis following these treatments or after direct application of SA, involved in response to both UV-C and Pseudomonas infection. Other genes, however, were induced normally in the mutants by these treatments. sfr6 mutants were severely defective in expression of plant defensin genes in response to JA; ectopic expression of defensin genes was provoked in wild-type but not sfr6 by overexpression of ERF5. * SFR6/MED16 controls both SA- and JA-mediated defence gene expression and is necessary for tolerance of Pseudomonas syringae infection and UV-C irradiation. It is not, however, a universal regulator of stress gene transcription and is likely to mediate transcriptional activation of specific regulons only. PMID- 22494142 TI - Ligand-assisted extraction for separation and preconcentration of gold nanoparticles from waters. AB - A new two-step extraction procedure is proposed for separation and preconcentration of gold nanoparticles (Au-NPs) from aqueous samples. First, Au NPs are loaded onto a reversed phase C-18 (RP-C18) column, and then ligand assisted extraction into chloroform is performed. 1-Dodecanethiol (1-DDT, 5 mM) was used as selective ligand for quantitative extraction under ultrasonic condition. Parameters of the extraction procedure, such as sample volume, organic solvent, concentration and nature of the ligand, ultrasonication time, pH of the sample, and different coating as well as sizes of Au-NPs were investigated in regard to the extraction efficiency of Au-NPs. The optimized procedure allows separation and preconcentration of the Au-NPs with an enrichment factor of up to 250 assuring no changes in size and/or shape of the NPs. This was proved by investigation of the particles by UV-vis spectrometry and transmission electron microscopy (TEM). Furthermore, the presence of potentially interfering other metal nanoparticles (M-NPs) and dissolved organic matter (DOM) was studied. Observed minor recoveries of Au-NPs in DOM model solutions were overcome by hydrogen peroxide pretreatment up to a DOM concentration of about 4 mg/L. Feasibility of the proposed method was proved by application of the optimized procedure to 5 real water samples. Recoveries of Au-NPs in the real waters spiked in a concentration range from 0.15 to 5100 MUg/L obtained by this method varied from 68.4% to 99.4%. Consequently, the proposed approach has great potential for the analysis of M-NPs in environmental waters. PMID- 22494143 TI - Catheter ablation of atrial fibrillation in octogenarians: the right "medicine?". PMID- 22494144 TI - The use of mechanical restraint in mental health: a catalyst for change? AB - The Care Quality Commission recently acknowledged the use of mechanical restraint/s as an intervention for the management of self-harm. I implemented the use of mechanical restraint for a female patient in life-threatening circumstances. This involved an exploration of the defining characteristics as well as the history and ethics of mechanical restraint. Informed consent and examining the legal, ethical and organizational frameworks supporting the use of this intervention in the clinical setting were critical to implementation. Ultimately the outcome not only proved to be life saving, but also a 'catalyst for change'. PMID- 22494145 TI - Behavioral control in at-risk toddlers: the influence of the family check-up. AB - This study examines the role of one component of emotion regulation, behavioral control, in the growth of children's early behavior problems by examining whether increases in parental positive behavior support brought about by a family centered intervention were associated with greater child behavioral control, and whether greater behavioral control at age 3 mediated the association between improvements in aspects of positive behavior support from ages 2 to 3 and decreases in growth of behavior problems from ages 2 to 4. The sample included 713 at-risk children (50% female) and their primary caregivers (50% European American, 28% African American, 13% biracial, 9% other) who were randomly assigned to the intervention or control group. Children had a mean age of 29.91 months at the initial assessment. Data were collected through home visits at child ages 2 to 4, which involved questionnaires for primary caregivers and structured and unstructured play activities for children with primary and alternative caregivers and siblings. Results indicated that the intervention improved parental positive behavior support and reduced growth of child behavior problems. One dimension of positive behavior support, proactive parenting, was modestly associated with behavioral control at age 3, which in turn was significantly associated with growth in behavior problems from ages 2 to 4, with greater behavioral control related to lower levels of growth in behavior problems. Results provide support for the notion that proactive parenting is an important factor in the development of children's behavioral control and that behavioral control plays an important role in the growth of behavior problems. PMID- 22494146 TI - Comparison between magnetic resonance imaging and histological findings in the navicular bone of horses with foot pain. AB - REASONS FOR PERFORMING STUDY: There is limited knowledge about both histological features in early navicular disease and what histological features are represented by increased signal intensity in fat-suppressed magnetic resonance (MR) images of the navicular bone. OBJECTIVE: To characterise increased signal intensity in the spongiosa of the navicular bone in fat-suppressed MR images and to compare this with histopathology; and to compare objective grading of all aspects of the navicular bone on MR images with histological findings. METHODS: One or both front feet of 22 horses with foot pain and a median lameness duration of 3 months were examined using high-field MR imaging (MRI) and histopathology. The dorsal, palmar, proximal and distal borders of the navicular bone and the spongiosa were assigned an MRI grade (0-3) and a histological grade and compared statistically. RESULTS: Increased signal intensity in the spongiosa of the navicular bone was associated with a variety of abnormalities, including fat atrophy, with lipocytes showing loss of definition of cytoplasmic borders, a proliferation of capillaries within the altered marrow fat, perivascular or interstitial oedema, enlarged intertrabecular bone spaces, fibroplasia and thinned trabeculae showing loss of bone with irregularly spiculated edges of moth eaten appearance. There were significant associations among histological lesions of the fibrocartilage, calcified cartilage and subchondral bone. There were also significant associations between MRI grading of the spongiosa and both histological marrow fat grade and the combined maximum of the MRI grades for the fibrocartilage. CONCLUSIONS AND POTENTIAL RELEVANCE: Increased signal intensity in the spongiosa of the navicular bone in fat-suppressed MR images may occur in association with lesions of the fibrocartilage with or without subchondral bone or may represent a separate disease entity, particularly if diffuse, reflecting a variety of alterations of trabecular bone and marrow fat architecture. PMID- 22494147 TI - Impact of treated wastewater irrigation on antibiotic resistance in agricultural soils. AB - Antibiotic resistance (AR) is a global phenomenon with severe epidemiological ramifications. Anthropogenically impacted natural aquatic and terrestrial environments can serve as reservoirs of antibiotic resistance genes (ARG), which can be horizontally transferred to human-associated bacteria through water and food webs, and thus contribute to AR proliferation. Treated-wastewater (TWW) irrigation is becoming increasingly prevalent in arid regions of the world, due to growing demand and decline in freshwater supplies. The release of residual antibiotic compounds, AR bacteria, and ARGs from wastewater effluent may result in proliferation of AR in irrigated soil microcosms. The aim of this study was to assess the impact of TWW-irrigation on soil AR bacterial and ARG reservoirs. Tetracycline, erythromycin, sulfonamide, and ciprofloxacin resistance in soil was assessed using standard culture-based isolation methods and culture-independent molecular analysis using quantitative real-time PCR (qPCR). High levels of bacterial antibiotic resistance were detected in both freshwater- and TWW irrigated soils. Nonetheless, in most of the soils analyzed, AR bacteria and ARG levels in TWW-irrigated soils were on the whole identical (or sometimes even lower) than in the freshwater-irrigated soils, indicating that the high number of resistant bacteria that enter the soils from the TWW are not able to compete or survive in the soil environment and that they do not significantly contribute ARG to soil bacteria. This strongly suggests that the impact of the TWW-associated bacteria on the soil microbiome is on the whole negligible, and that the high levels of AR bacteria and ARGs in both the freshwater- and the TWW-irrigated soils are indicative of native AR associated with the natural soil microbiome. PMID- 22494148 TI - Transposed-letter priming effect in Hebrew in the same-different task. AB - We investigated the interaction between morphological structure and transposed letter priming using the same-different task with Hebrew, a Semitic language in which morphology has been shown to play a key role in visual word recognition. In contrast to the results observed with lexical decision (e.g., Velan & Frost, 2009, 2011), a transposed-letter priming effect was observed irrespective of the morphological structure of the words. We take these results to suggest that morphological decomposition occurs only in the service of lexical access. We discuss further a unique feature of written Arabic, another Semitic language, to explain the apparent conflict between our findings and those reported by Perea, Abu Mallouh, Garcia-Orza, and Carreiras (2010). PMID- 22494149 TI - Abstracts of the Australian Rheumatology Association in conjunction with Rheumatology Health Professionals 53rd Annual Scientific Meeting, 12-15 May 2012, Canberra, Australia. PMID- 22494150 TI - Drowning after falling from a medium-height bridge: multiple trauma victims. AB - INTRODUCTION: Drowning following a fall from a bridge can lead to cardiac arrest caused by hypoxia, hypothermia, or severe traumatic injury. Every year patients are brought to our hospital who have nearly drowned in the local river after a jump from a bridge (approximate height 16-22 meters). We report traumatic injuries in patients admitted to our hospital for out-of-hospital cardiac arrest due to drowning. METHODS: We retrospectively reviewed the charts of all patients admitted to the intensive care units of our hospital for out-of-hospital cardiac arrest due to drowning after a jump from a bridge in the Seine River between 2002 and 2010. All clinical or radiologic evidence of trauma was recorded. RESULTS: A total of 37 patients where admitted to our hospital for out-of-hospital cardiac arrest due to drowning. Fourteen patients had radiologic examinations. Five of these examinations showed evidence of severe trauma. In one case, clinical examination showed evidence of severe peripheral neurologic trauma. Seven of these patients (19%) were discharged from the hospital alive. CONCLUSIONS: Patients found nearly drowned in a river spanned by a medium-height bridge should undergo spinal immobilization and complete radiologic examination as soon as possible. PMID- 22494152 TI - Alternating hemiplegia of childhood in chinese following long-term treatment with flunarizine or topiramate. AB - OBJECTIVE: Alternating hemiplegia of childhood (AHC) is a rare and intractable disorder. The etiology and standard therapy of AHC remain unknown. The long-term effects of flunarizine or topiramate on patients with AHC are still not clear. METHODS: Fifteen patients were investigated in this study. Their neurological disturbance and mental retardation after drug therapy were evaluated. RESULTS: Nine patients treated with flunarizine therapy and three children with topimarate treatment presented with shorter duration or less frequency of the hemiplegic attacks. These drug responsive patients also showed improvements on neurological disturbance including eye movement disorder, choreoathetotic movements, dystonia, and ataxia. However, seizure episodes and cognitive impairments were not alleviated in AHC with long-term drug therapy. CONCLUSIONS: The findings from the present study support flunarizine or topitamate as the rational treatment for AHC. PMID- 22494153 TI - Hg(II) ion detection using thermally reduced graphene oxide decorated with functionalized gold nanoparticles. AB - Fast and accurate detection of aqueous contaminants is of significant importance as these contaminants raise serious risks for human health and the environment. Mercury and its compounds are highly toxic and can cause various illnesses; however, current mercury detectors suffer from several disadvantages, such as slow response, high cost, and lack of portability. Here, we report field-effect transistor (FET) sensors based on thermally reduced graphene oxide (rGO) with thioglycolic acid (TGA) functionalized gold nanoparticles (Au NPs) (or rGO/TGA AuNP hybrid structures) for detecting mercury(II) ions in aqueous solutions. The lowest mercury(II) ion concentration detected by the sensor is 2.5 * 10(-8) M. The drain current shows rapid response within less than 10 s after the solution containing Hg(2+) ions was added to the active area of the rGO/TGA-AuNP hybrid sensors. Our work suggests that rGO/TGA-AuNP hybrid structures are promising for low-cost, portable, real-time, heavy metal ion detectors. PMID- 22494151 TI - Environmental heme-based sensor proteins: implications for understanding bacterial pathogenesis. AB - SIGNIFICANCE: Heme is an important prosthetic group required in a wide array of functions, including respiration, photosynthesis, metabolism, O(2) transport, xenobiotic detoxification, and peroxide production and destruction, and is an essential cofactor in proteins such as catalases, peroxidases, and members of the cytochrome P450 superfamily. Importantly, bacterial heme-based sensor proteins exploit the redox chemistry of heme to sense environmental gases and the intracellular redox state of the cell. RECENT ADVANCES: The bacterial proteins FixL (Rhizobium ssp.), CooA (Rhodospirillum rubrum), EcDos (Escherichia. coli), RcoM (Burkholderia xenovorans), and particularly Mycobacterium tuberculosis (Mtb) DosS and DosT have emerged as model paradigms of environmental heme-based sensors capable of detecting multiple gases including NO, CO, and O(2). CRITICAL ISSUES: How the diatomic gases NO, CO, or O(2) bind to heme iron to generate Fe-NO, Fe CO, and Fe-O(2) bonds, respectively, and how the oxidation of heme iron by O(2) serves as a sensing mechanism that controls the activity of key proteins is complex and largely unclear. This is particularly important as many bacterial pathogens, including Mtb, encounters three overlapping host gases (NO, CO, and O(2)) during human infection. FUTURE DIRECTIONS: Heme is an important prosthetic group that monitors the microbe's internal and external surroundings to alter signal transduction or enzymatic activation. Modern expression, metabolomic and biochemical technologies combined with in vivo pathogenesis studies should provide fresh insights into the mechanism of action of heme-based redox sensors. PMID- 22494154 TI - Generation of transgenic mice with antithetical KEL1 and KEL2 human blood group antigens on red blood cells. AB - BACKGROUND: KEL1, also known as "K", is one of the most immunogenic red blood cell (RBC) antigens. KEL2, also known as "k," differs from KEL1 by a single amino acid. Anti-Kell system antibodies can lead to significant adverse clinical outcomes in humans, including hemolytic complications in alloimmunized transfusion recipients or in infants of alloimmunized mothers. To provide a platform for in-depth immunologic studies of alloimmunization and subsequent sequelae, we generated transgenic mice expressing the human KEL1 or KEL2 antigens. STUDY DESIGN AND METHODS: Vectors were created in which cDNAs encoding either KEL1 or KEL2 were regulated by an erythroid specific beta-globin promoter and enhancer. Pronuclear microinjections were carried out into a C57BL6 background, and founder pups were identified by polymerase chain reaction and screened for expression by flow cytometry. RBC life span and antigen stability were assessed by dye labeling RBCs, transfusing into agammaglobulinemic (uMT) recipients, and tracking by flow cytometry. RESULTS: The expression of either KEL1 or KEL2 is RBC specific and first occurs on early RBC precursors. Both KEL1 and KEL2 RBCs have a normal circulatory life span and stable antigen expression. Expression of KEL1 or KEL2 does not result in altered levels of murine Kell, and resulting RBCs have normal hematologic variables. CONCLUSION: The KEL1 and KEL2 mice represent the first murine system of RBC immunity with antithetical antigens, allowing a more precise modeling of human RBC immunology in general and also a platform for development of novel therapeutics to prevent or minimize the dangers of RBC alloimmunization to the KEL1 and KEL2 antigens in particular. PMID- 22494155 TI - Malnutrition is high and underestimated during chemotherapy in gastrointestinal cancer: an AGEO prospective cross-sectional multicenter study. AB - Although malnutrition is known to be frequent in cancer patients, it has not been described in a selected population of patients with gastrointestinal malignancies under chemotherapy only. Physician judgment about malnutrition and risk factors for malnutrition were also evaluated. All consecutive in- and outpatients of 11 centers were prospectively enrolled in a cross-sectional 14-day period study and classified according to the French health recommendations [Haute Autorite de Sante (HAS)]. Among 313 patients enrolled in 11 centers (mean age = 63 yr; range = 21-93; 67% male) mainly with colorectal (58%), pancreatic (15%), gastric (11%), and hepatobiliary (10%) primary tumors, the prevalence of malnutrition was 52%. Moderate and severe malnutrition was present in 27% and 25% of cases, respectively. Physicians considered it in 36% and 6% of cases, respectively, thereby misclassifying 134 patients (43%). The agreement between the HAS definition and the physicians' judgment was very low (kappa = 0.30). Most of the patients who were identified as severely malnourished received no nutritional support. Performance status and pancreatic and gastric cancers were independently associated with malnutrition. Malnutrition levels are high, around 50%, unequally distributed according to the primitive tumor. It is still underestimated by physicians. Weight loss remains a clinically relevant, simple, and reliable marker of malnutrition. PMID- 22494156 TI - Characterization of glucose homeostasis and lipid profile in adult, seizure-free, epileptic patients in Asian population. AB - BACKGROUND AND PURPOSE: The most common prescribed antiepileptic drugs (AEDs), phenytoin and valproate, are potent enzyme inducers and inhibitors of the cytochrome P450 system, which interfere with lipid profile and glucose homeostasis. Studies on this topic have suffered from inadequate assessment of confounders and have rarely included glucose homeostasis and lipid profile as well as both enzyme inducers and inhibitors in the same study. We sought to determine whether these drugs had an effect on lipid profile and glucose homeostasis in Thai epileptic patients. METHODS: We recruited 98 patients with epilepsy (45 taking phenytoin, 27 taking valproate, and 26 not taking any AED). Fasting blood samples were obtained to measure serum lipid, and glucose homeostasis was evaluated via the oral glucose tolerance test. We calculated the homeostasis model assessment index for each patient. RESULTS: Our study revealed that CYP450 was induced by AEDs, and that patients on phenytoin had an increased mean value of serum total cholesterol, serum total triglycerides, and serum LDL cholesterol when compared with patients with epilepsy taking valproate and those taking no AEDs. No statistical significant difference was observed between patients taking valproate and patients taking no AEDs. In addition, patients with epilepsy taking phenytoin had higher fasting plasma glucose levels at fasting state than both those taking valproate and those taking no AEDs. Thirty percent of the patients taking phenytoin exhibited insulin resistance. We have found a negative correlation between log insulin sensitivity and log TG, but not high density lipoprotein (HDL). CONCLUSION: CYP450-induced phenytoin produces significant amelioration in several serologic markers of atherosclerosis. These findings suggest that phenytoin may substantially increase the risk of vascular events. PMID- 22494157 TI - Local airborne particulate concentration is associated with visible tracheal mucus in Thoroughbred racehorses. AB - REASON FOR PERFORMING STUDY: Accumulations of tracheal mucus assessed by endoscopic examination are associated with poor performance in racehorses. The air quality in horses' stalls may contribute to this visible tracheal mucus. OBJECTIVES: To determine whether the concentration and number of airborne particulates in stalls are associated with visible accumulations of tracheal mucus and with the number of inflammatory cells in tracheal aspirates. METHODS: We studied 107 racehorses from 3 stables, in 3 different months, and measured airborne particulate matter 3 times daily in each of the stalls. On each monthly visit, horse airways were examined endoscopically and assigned a mucus score, and tracheal lavage was performed. Bivariate procedures, general estimating equations and linear mixed models were applied to estimate the association between PM and the presence of accumulations of mucus and number of inflammatory cells. RESULTS: Stable, stall, month and PM were all significantly associated with the presence of accumulations of tracheal mucus, which had an overall prevalence of 67%. The odds of horses having visible accumulation of mucus were increased when horses occupied enclosed stables or stalls with higher particulate concentrations, and when concentrations of larger particles (<= 10 um in diameter) were elevated. Sixty-eight percent of tracheal wash samples contained more than 20% neutrophils. Increased numbers of neutrophils were associated with the concentration of smaller particles (<= 2.5 um in diameter). POTENTIAL RELEVANCE: Careful consideration of stable construction and management practices focused on maintaining the lowest possible dust concentrations throughout the day should reduce the prevalence of visible accumulations of tracheal mucus, potentially improving racing performance. PMID- 22494158 TI - A retrospective study: form-deprivation myopia in unilateral congenital ptosis. AB - BACKGROUND: The aim of this retrospective study was to investigate the relationship between unilateral congenital ptosis in patients older than eight years and their refractive state and spherical equivalent refraction (SER). METHODS: The study involved a review of the clinical records of 85 patients admitted to the First Affiliated Hospital, Sun Yat-sen University between 1998 and 2010 with unilateral congenital ptosis. The average age was 16.83 years (nine to 27 years). The patients were classified into mild (27 cases), moderate (37 cases) or severe (21 cases) ptosis according to the degree of the droopy eyelid covering the cornea. The fellow eyes served as controls. RESULTS: In 85 eyes with unilateral ptosis, the frequency of myopia (SER of -0.50 D or more myopia) was significantly higher than in the fellow eye (47 versus 32, p = 0.031). The frequency of myopia in eyes with severe unilateral ptosis was significantly higher than in the fellow eyes (16 versus 7, p = 0.012), whereas there were no significant differences in patients with mild (15/27 versus 13/27, p = 0.79) or moderate (16/37 versus 12/37, p = 0.47) unilateral ptosis. Similarly, the SER was significantly more myopic in eyes with severe ptosis compared with the fellow eye (-1.37 D versus -0.85 D, p = 0.01), whereas no significant differences were found in patients with mild or moderate unilateral ptosis. CONCLUSIONS: The results showed a higher frequency of myopia and more myopic SER in eyes with severe unilateral ptosis compared with the fellow eye. The myopia found in eyes with unilateral ptosis might be caused by a mechanism similar to that resulting in myopia among animals subjected to form deprivation. It is important to pay attention to possible refractive error in patients with unilateral ptosis. Surgical correction of unilateral ptosis at an early age is recommended. PMID- 22494159 TI - (Pro)renin and its receptors: pathophysiological implications. AB - Tissue angiotensin generation depends on the uptake of circulating (kidney derived) renin and/or its precursor prorenin [together denoted as (pro)renin]. Since tissue renin levels are usually somewhat higher than expected based upon the amount of (renin-containing) blood in tissue, an active uptake mechanism has been proposed. Several candidates have been evaluated in the past three decades, including a renin-binding protein, the mannose 6-phosphate/insulin-like growth factor II receptor and the (pro)renin receptor. Although the latter seemed the most promising, its nanomolar affinity for renin and prorenin is several orders of magnitude above their actual (picomolar) levels in blood, raising doubt on whether (pro)renin-(pro)renin receptor interaction will ever occur in vivo. A wide range of in vitro studies have now demonstrated (pro)renin-receptor-induced effects at nanomolar renin and prorenin concentrations, resulting in a profibrotic phenotype. In addition, beneficial in vivo effects of the putative (pro)renin receptor blocker HRP (handle region peptide) have been observed, particularly in diabetic animal models. Despite these encouraging results, many other studies have reported either no or even contrasting effects of HRP, and (pro)renin-receptor-knockout studies revealed lethal consequences that are (pro)renin-independent, most probably due to the fact that the (pro)renin receptor co-localizes with vacuolar H+-ATPase and possibly determines the stability of this vital enzyme. The present review summarizes all of the recent findings on the (pro)renin receptor and its blockade, and critically compares it with the other candidates that have been proposed to mediate (pro)renin uptake from blood. It ends with the conclusion that the (pro)renin-(pro)renin receptor interaction, if it occurs in vivo, is limited to (pro)renin-synthesizing organs such as the kidney. PMID- 22494160 TI - Systems biology of antioxidants. AB - Understanding the role of oxidative injury will allow for therapy with agents that scavenge ROS (reactive oxygen species) and antioxidants in the management of several diseases related to free radical damage. The majority of free radicals are generated by mitochondria as a consequence of the mitochondrial cycle, whereas free radical accumulation is limited by the action of a variety of antioxidant processes that reside in every cell. In the present review, we provide an overview of the mitochondrial generation of ROS and discuss the role of ROS in the regulation of endothelial and adipocyte function. Moreover, we also discuss recent findings on the role of ROS in sepsis, cerebral ataxia and stroke. These results provide avenues for the therapeutic potential of antioxidants in a variety of diseases. PMID- 22494161 TI - Temporal coincidence of environmental stress events modulates predation rates. AB - Climate warming experiments generally test the ecological effects of constant treatments while neglecting the influence of more realistic patterns of environmental fluctuations. Thus, little is known regarding how the temporal interaction between multiple episodes of thermal stress influences biotic interactions. We measured the sensitivity of predation rate in an intertidal sea star to changing levels of temporal coincidence of underwater and aerial thermal stress events. In laboratory trials, we controlled for intensity, variance and temporal patterning of both underwater and aerial body temperature. Predation rate decreased as underwater and aerial thermal stress episodes became temporally non-coincident, despite a similar intensity and variance among treatments. Experiments under constant conditions were a poor predictor of more complex environmental scenarios because of these strong temporal interactions. Such temporal interactions may be widespread in various ecosystems, suggesting a strong need for empirical studies and models that link environmental complexity, physiology, behaviour and species interactions. PMID- 22494162 TI - Analytical and biological characterization of halogenated gemfibrozil produced through chlorination of wastewater. AB - The cholesterol-lowering pharmaceutical gemfibrozil is a relevant environmental contaminant because of its frequency of detection in U.S. wastewaters at concentrations which have been shown to disrupt endocrine function in aquatic species. The treatment of gemfibrozil solutions with sodium hypochlorite yielded a 4'-chlorinated gemfibrozil analog (chlorogemfibrozil). In the presence of bromide ion, as is often encountered in municipal wastewater, hypobromous acid generated through a halogen exchange reaction produced an additional 4' brominated gemfibrozil product (bromogemfibrozil). Standards of chloro- and bromogemfibrozil were synthesized, isolated and characterized using mass spectrometry and NMR spectroscopy. Mass spectrometry was used to follow the in situ halogenation reaction of gemfibrozil in deionized water and wastewater matrices, and to measure levels of gemfibrozil (254 +/- 20 ng/L), chlorogemfibrozil (166 +/- 121 ng/L), and bromogemfibrozil (50 +/- 11 ng/L) in advanced primary wastewater treatment effluent treated by chlorination. Chlorogemfibrozil demonstrated a significant (p < 0.05) reduction in the levels of 11-ketotestosterone at 55.1 MUg/L and bromogemfibrozil demonstrated a significant (p < 0.05) reduction in the levels of testosterone at 58.8 MUg/L in vivo in Japanese medaka in a 21 day exposure. These results indicated that aqueous exposure to halogenated degradates of gemfibrozil enhanced the antiandrogenicity of the parent compound in a model fish species, demonstrating that chlorination may increase the toxicity of pharmaceutically active compounds in surface water. PMID- 22494163 TI - Is the penoscrotal approach inferior to the perineal approach for artificial sphincter implantation in male urinary incontinence? A preliminary experience. AB - Artificial urinary sphincter is the gold standard of treatment for urinary incontinence as a result of sphincter incompetence. The perineal incision for cuff placement, and low abdominal incision for the placement of a pressure regulating balloon and pump is the original design. Wilson et al. presented a modified method by a single penoscrotal (transscrotal) incision for implantation of all pieces. However, some experts believe there are important differences between the two methods, and the traditional perineal incision is better than the modified penoscrotal incision. The objective of our study was to show the characteristics of penoscrotal incision and determine whether the penoscrotal approach is inferior to the perineal approach in clinical outcome and complications. From May 1994 to July 2011, a total of 21 male patients underwent 27 artificial urinary sphincter implantations. Twelve cuffs were placed with the perineal approach and 15 with the penoscrotal approach. The patients in the penoscrotal group had a shorter operative time (86.0 +/- 21.1 vs 115.4 +/- 32.0 min, P = 0.018) and hospital stay (5.4 +/- 2.2 vs 9.3 +/- 2.5 days, P = 0.002) compared with the perineal group. There was no statistical significance in long term completely dry rate (penoscrotal vs perineal: 66.7% vs 50%, P = 0.767), infection rate (20% vs 33.3%, P = 0.617) and subsequent tandem cuff-added rate (6.7% vs 16.7%, P = 0.675) between the two approaches. Hence, penoscrotal incision is not inferior to traditional perineal incision for artificial urinary sphincter implantation in male urinary incontinence. PMID- 22494164 TI - Cellular response on Auger- and Beta-emitting nuclides: human embryonic stem cells (hESC) vs. keratinocytes. AB - PURPOSE: We studied the response of human embryonic stem cells (hESC) to the beta emitter (131)I, which affects the entire cell and to the Auger electron emitter (125)I-deoxyuridine ((125)I-dU), primarily affecting the deoxyribonuleic acid (DNA). The effects were also studied in keratinocytes as a prototype for somatic cells. METHODS: HESC (H1) and human keratinocytes (HaCaT, human) were exposed to (125)I-dU (5 * 10(-5) - 5 MBq/ml) and (131)I-iodide (5 * 10(-5) - 12.5 MBq/ml) and apoptosis was measured by DNA-fragmentation. Cell morphology was studied by light microscopy and electron microscopy. Transcriptional profiling was done on the Agilent oligonucleotide microarray platform. RESULTS: Auger-process induced no apoptosis but a strong transcriptional response in hESC. In contrast, HaCaT cells showed a pronounced induction of apoptosis but only a moderate transcriptional response. Transcriptional response of hESC was similar after (125)I-dU and (131)I treatments, whereas HaCaT cells expressed a much more pronounced response to (125)I-dU than to (131)I. A striking radiation-induced down-regulation of pluripotency genes was observed in hESC whereas in keratinocytes the enriched gene annotations were related primarily to apoptosis, cell division and proliferation. CONCLUSIONS: Human embryonic stem cells respond to ionizing radiation by (125)I-dU and (131)I in a different way compared to keratinocytes. Transcriptional response and gene expression appear to facilitate an escape from programmed cell death by striking a new path which probably leads to cell differentiation. PMID- 22494165 TI - Reliability of presynaptic inhibition in patients with diabetic peripheral neuropathy. AB - There has been rising interest in evaluating spinal reflex activity within the clinical population, however no study has yet investigated the reliability of presynaptic inhibition (PI) on patients with diabetic peripheral neuropathy (DPN). Because neuropathy is closely related to central nervous system modification, it is important to understand the mechanism of spinal reflex activity in the DPN population. Therefore, the purpose of the study was to evaluate the reliability of PI in patients with DPN. Eight participants (58.24 +/ 6.38 yrs.) diagnosed with either type I or type II diabetes and peripheral neuropathy were recruited for the study. Each subject's H-reflex was measured using an EMG to elicit and record a series of 10 paired reflex depression trials. Reliability was measured by calculating Intra Class Correlation Coefficients (ICCs) with a 95% confidence interval. The results showed excellent reliability in both intraday (0.94) and interday (0.88) reliability. Therefore, analyzing PI in the central nervous system allows for an accurate evaluation of spinal cord circuitry in a non-invasive manner. PMID- 22494176 TI - Abstracts of the International Brain Injury Association's Ninth World Congress on Brain Injury, March 21-25, 2012, Edinburgh, Scotland. PMID- 22494178 TI - Editorial comment to novel posterior reconstruction technique during robot assisted laparoscopic prostatectomy: description and comparative outcomes. PMID- 22494177 TI - Direct observation of cooperative protein structural dynamics of homodimeric hemoglobin from 100 ps to 10 ms with pump-probe X-ray solution scattering. AB - Proteins serve as molecular machines in performing their biological functions, but the detailed structural transitions are difficult to observe in their native aqueous environments in real time. For example, despite extensive studies, the solution-phase structures of the intermediates along the allosteric pathways for the transitions between the relaxed (R) and tense (T) forms have been elusive. In this work, we employed picosecond X-ray solution scattering and novel structural analysis to track the details of the structural dynamics of wild-type homodimeric hemoglobin (HbI) from the clam Scapharca inaequivalvis and its F97Y mutant over a wide time range from 100 ps to 56.2 ms. From kinetic analysis of the measured time-resolved X-ray solution scattering data, we identified three structurally distinct intermediates (I(1), I(2), and I(3)) and their kinetic pathways common for both the wild type and the mutant. The data revealed that the singly liganded and unliganded forms of each intermediate share the same structure, providing direct evidence that the ligand photolysis of only a single subunit induces the same structural change as the complete photolysis of both subunits does. In addition, by applying novel structural analysis to the scattering data, we elucidated the detailed structural changes in the protein, including changes in the heme-heme distance, the quaternary rotation angle of subunits, and interfacial water gain/loss. The earliest, R-like I(1) intermediate is generated within 100 ps and transforms to the R-like I(2) intermediate with a time constant of 3.2 +/- 0.2 ns. Subsequently, the late, T-like I(3) intermediate is formed via subunit rotation, a decrease in the heme-heme distance, and substantial gain of interfacial water and exhibits ligation-dependent formation kinetics with time constants of 730 +/- 120 ns for the fully photolyzed form and 5.6 +/- 0.8 MUs for the partially photolyzed form. For the mutant, the overall kinetics are accelerated, and the formation of the T-like I(3) intermediate involves interfacial water loss (instead of water entry) and lacks the contraction of the heme-heme distance, thus underscoring the dramatic effect of the F97Y mutation. The ability to keep track of the detailed movements of the protein in aqueous solution in real time provides new insights into the protein structural dynamics. PMID- 22494179 TI - Influence of MHC class I and II haplotypes on the experimental infection of Mauritian cynomolgus macaques with SHIVSF162P4cy. AB - Mauritian cynomolgus macaques (MCM) are widely used in human immunodeficiency virus research because of their restricted major histocompatibility complex (MHC) diversity which provides the opportunity to address the influence of host factors on vaccine studies. We herein report the impact of MHC haplotype on the outcome of 21 MCM infections with the CCR5-tropic simian/human immunodeficiency virus (SHIV)(SF162P4cy). MCM were susceptible to SHIV(SF162P4cy) infection as shown by viremia and loss of CD4+ T cells. A significant association between haplotype M7 (class IA, IB, II) and persistent viremia was observed in chronic phase, whereas recombinant class IA haplotype was associated with a reduction of viral RNA during acute infection. Class IB M4 haplotype displayed significantly lower acute phase provirus copy numbers. In addition, statistical analysis indicated a detrimental effect of haplotype M4 (class IA, IB) on the course of infection as indicated by lower CD4+ T-cell levels during chronic infection. A decrease in post-acute phase CD4+ T-cell numbers was also observed in haplotype M2 animals. This is the first report that documents the effects of host MHC class I and II molecules on the SHIV(SF162P4cy) infection in MCM, particularly with regard to the association between recombinant class IA, M4, and M7 haplotypes and the dynamic of viral replication and level of CD4+ T cells. PMID- 22494180 TI - Improvement of both dystonia and tics with 60 Hz pallidal deep brain stimulation. AB - Deep brain stimulation has been utilized in both dystonia and in medication refractory Tourette syndrome. We present an interesting case of a patient with a mixture of disabling dystonia and Tourette syndrome whose coexistent dystonia and tics were successfully treated with 60 Hz-stimulation of the globus pallidus region. PMID- 22494181 TI - Implications of acute left ventricular remodeling during squatting stress echocardiography. AB - BACKGROUND: We previously demonstrated that squatting induces left ventricular (LV) wall motion abnormalities (WMA) in areas subtended by stenotic coronary arteries. In addition, it was observed that some subjects developed acute changes in LV shape (acute left ventricular remodeling [ALVRM]) during squatting. OBJECTIVE: This study tested the hypothesis that patients with ALVRM during squatting echocardiography have higher incidences of severe coronary artery disease (CAD). METHODS: Echocardiography was performed in all standard views during standing and squatting. End-systolic frames in the apical four-chamber view were analyzed. RESULTS: The subjects were divided into three groups. Group 1 consisted of 12 subjects who developed squatting-induced ALVRM with apical and distal posterior septal akinesis, dilation of the apex and marked LV shape change at end-systole. Group 2 consisted of 20 subjects with distal posterior septal and apical akinesis without ALVRM, during squatting. Group 3 consisted of 64 subjects who developed WMA in areas other than the apex (n = 49), or normal wall motion (n = 15) during squatting. Coronary angiography in group 1 revealed that 6 subjects had left main coronary artery stenosis (LMCAS >= 50%), two had severe three vessel disease (>= 90% stenosis), and one had 100% left anterior descending coronary artery occlusion. Severe CAD was defined for purpose of this study as the presence of LMCAS, or severe three vessel disease (>= 90% stenosis). Six subjects in group 2 had LMCAS and none had severe three vessel disease (P < 0.05 vs. group 1 for LMCAS and/or three vessel disease). In group 3, eight had LMCAS and none had severe three vessel disease (P < 0.0001 vs. group 1). CONCLUSION: Patients with ALVRM have severe CAD. Therefore, patients who develop ALVRM during squatting require urgent evaluation for revascularization therapy. PMID- 22494182 TI - Adolescent performance enhancing substance use: regional differences across the US. AB - Performance enhancing substances (PES) constitute a multi-billion dollar industry, fueling public health concerns regarding use in adolescents hoping to enhance athletic performance and body appearance, or fight obesity. Adverse effects may include violent behavior, suicide attempts, and premature deaths. Prevalence of use is difficult to ascertain due to secrecy issues and misinterpretation of survey questions. Healthcare providers are less familiar with PES than other types of substance use. A correlational secondary analysis of 2007 National Youth Risk Behavior Survey (YRBS) data was conducted (n =14,041) to better understand predictors of PES use (methamphetamines, steroid pills/injections, and diet pill/powder/liquids). Bandura's Social Cognitive Theory served as the organizing framework guiding the analysis. SPSS version 17.0 Complex Samples was used to examine relationships among variables; bi-variate and logistic regression analyses were performed. Feeling sad/ hopeless, considering suicide, perceiving being overweight, being offered drugs at school, geographic location, being sexually active, cigarette smoking, and alcohol use were significantly associated (p <.05) with PES use. Rates of being offered/sold/given illegal drugs at school ranged from 17-39%; PES use ranged from 5-17% across the US. Multiple factors predicted PES use; those contributing to morbidity and mortality may be preventable. Though policies are designed to ensure safe school settings, high rates of obtaining drugs at school were reported. The South US region reported the highest rates of PES use. Regional differences have implications for health professionals and policy makers who must address physical, psychological, and social issues related to adolescent PES use. PMID- 22494183 TI - Incidence and survival of symptomatic lacunar infarction in a Beijing population: a 6-year prospective study. AB - BACKGROUND AND PURPOSE: The incidence of ischaemic stroke has increased or remained high in China; however, little population-based evidence is available on the incidence and survival of lacunar infarction (LAC). We examined the incidence of LAC in a northern Chinese (Beijing) population and monitored survival. METHODS: A prospective registry population-based study was conducted over a 6 year period in a general, unselected, and representative community in Beijing with approximately 100,000 long-term permanent residents. All first-ever stroke cases were registered. RESULTS: A total of 1184 patients with ischaemic stroke were identified; 36.9% (437 cases) were classified as LAC. Age-standardized incidence rates of LAC ranged from 24.0 to 51.3/100,000 with an average rate of 35.3/100,000 during study period. The incidence of LAC increased with age before 70 years. The incidence of non-LAC increased with age. There were no significant differences in crude incidence of LAC between men and women (78.4/100,000 vs. 75.4/100,000). The incidence of non-LAC was significantly higher in men than in women (155/100,000 vs. 107/100,000, P < 0.001). The 28-day case fatality proportions were significantly lower in patients with LAC (0.5%) versus non-LAC (14.9%). One year after acute stroke onset, the survival rates between LAC and non-LAC were similar. CONCLUSION: LAC is a common stroke subtype in Northern China. Men or the elderly are more likely to have non-LAC. Long-term survival following LAC is similar to non-LAC patients. PMID- 22494184 TI - Weak organic ligands enhance zinc uptake in marine phytoplankton. AB - A recent study of the effect of pH on Zn and Cd bioavailability shows that binding to weak organic ligands can increase the pool of metals available to phytoplankton in the presence of strong chelating agents. We explore the underlying mechanism in laboratory experiments with the model species Emiliania huxleyi and Thalassiosira weissflogii. Additions of L- and D- isomers of cysteine (Cys) result in similar increases in Zn uptake rates in the presence of the strong chelator ethylenediaminetetraacetic acid (EDTA) but decrease it in the absence of EDTA, ruling out uptake by a specific Zn-Cys transporter. The effect of Cys does not result from alleviating diffusion limitation of inorganic Zn. The enhancement of Zn uptake kinetics by weak ligands is consistent with a mechanism involving formation of a transient ternary complex with uptake molecules: (1) the enhancement is most dramatic in Zn limited cells whose high affinity transporters should be most effective at extracting Zn from weak ligands; (2) the enhancement occurs with a variety of weak ligands, demonstrating that the underlying mechanism has little chemical specificity; and (3) no enhancement of uptake is seen when Zn is bound in complexes that would make formation of multiligand complexes with uptake molecules difficult. Weak complexing agents which have received heretofore little attention may play a key role in the bioavailability of metals in natural waters. PMID- 22494185 TI - Robotic repair of vesicovaginal fistula (VVF). PMID- 22494186 TI - Development of male genital lichen sclerosus in penile reconstruction skin grafts after cancer surgery: an unreported complication. PMID- 22494188 TI - Greenlight HPSTM 120-w laser vaporization vs transurethral resection of the prostate (<60 ml): a 2-year randomized double-blind prospective urodynamic investigation. PMID- 22494190 TI - Integrative analysis of N-linked human glycoproteomic data sets reveals PTPRF ectodomain as a novel plasma biomarker candidate for prostate cancer. AB - In an attempt to identify prostate cancer biomarkers with greater diagnostic and prognostic capabilities, we have developed an integrative proteomic discovery workflow focused on N-linked glycoproteins that refines the target selection process. In this work, hydrazide-based chemistry was used to identify N-linked glycopeptides from 22Rv1 prostate cancer cells cultured in vitro, which were compared with glycopeptides identified from explanted 22Rv1 murine tumor xenografts. One hundred and four human glycoproteins were identified in the former analysis and 75 in the latter, with 40 proteins overlapping between data sets. Of the 40 overlapping proteins, 80% have multiple literature references to the neoplastic process and ~40% to prostatic neoplasms. These include a number of well-known prostate cancer-associated biomarkers, such as prostate-specific membrane antigen (PSMA). By integrating gene expression data and available literature, we identified members of the overlap data set that deserve consideration as potential prostate cancer biomarkers. Specifically, the identification of the extracellular domain of protein tyrosine phosphatase receptor type F (PTPRF) was of particular interest due to the direct involvement of PTPRF in the control of beta-catenin signaling, as well as dramatically elevated gene expression levels in the prostate compared to other tissues. In this investigation, we demonstrate that the PTPRF E-subunit is more abundant in human prostate tumor tissue compared to normal control and also detectable in murine plasma by immunoblot and ELISA. Specifically, PTPRF distinguishes between animals xenografted with the 22Rv1 cells and control animals as early as 14 days after implantation. This result suggests that the ectodomain of PTPRF has the potential to function as a novel plasma or tissue-based biomarker for prostate cancer. The workflow described adds to the literature of potential biomarker candidates for prostate cancer and demonstrates a pathway to developing new diagnostic assays. PMID- 22494191 TI - Ultimate bending strength of Si nanowires. AB - Test platforms for the ideal strength of materials are provided by almost defect free nanostructures (nanowires, nanotubes, nanoparticles, for example). In this work, the ultimate bending strengths of Si nanowires with radii in the 20-60 nm range were investigated by using a new bending protocol. Nanowires simply held by adhesion on flat substrates were bent through sequential atomic force microscopy manipulations. The bending states prior to failure were analyzed in great detail to measure the bending dynamics and the ultimate fracture strength of the investigated nanowires. An increase in the fracture strengths from 12 to 18 GPa was observed as the radius of nanowires was decreased from 60 to 20 nm. The large values of the fracture strength of these nanowires, although comparable with the ideal strength of Si, are explained in terms of the surface morphology of the nanowires. PMID- 22494192 TI - On being a bioethicist: a review of john h. Evans playing god?: human genetic engineering and the rationalization of public bioethical debate. PMID- 22494193 TI - Review of ward ethics: dilemmas for medical students and doctors in training. PMID- 22494194 TI - When access to chronic dialysis is limited: one center's approach to emergent hemodialysis. AB - Emergent hemodialysis is the practice of dialyzing a patient only when there is a life-threatening need for this treatment. Undocumented immigrants in many cities depend on this practice, as they are not entitled to the regularly scheduled hemodialysis treatments available to US citizens. There are several medical and ethical challenges to emergent hemodialysis. One example is defining the criteria that determine the need for an emergent treatment. Although it is lifesaving, emergent dialysis is inadequate dialysis; it results in unnecessary patient complications, is medically burdensome for the treating physician, and expensive to the providing facility. This article describes how undocumented immigrants are cared for in one county hospital system in a large city. PMID- 22494195 TI - Hypolipidemic effects of a new piperine derivative GB-N from Piper longum in high fat diet-fed rats. AB - CONTEXT: Long pepper, Piper longum Linn. (Piperaceae), is widely used in traditional Mongolian medicine for treating hyperlipidemia and coronary heart disease. OBJECTIVE: To investigate the hypolipidemic effects of a new piperine derivative GB-N isolated from long pepper in high-fat diet-fed rats. METHODS: The levels of serum total cholesterol, triacylglycerols (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were determined by enzymatic colorimetric method. The levels of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA), CYP7A1, lecithin cholesterol acyltransferase (LCAT) and LDL receptor (LDLR) mRNA and protein expression were detected by real time polymerase chain reaction and western blot analysis. RESULTS AND DISCUSSION: Compared with model rats, oral administration of GB-N at doses of 2.5-10 mg/kg to hyperlipidemic rats could significantly decrease the levels of serum TG from 1.54 mmol/L in hyperlipidemic rats to 0.94-1.02 mmol/L, with an increase in serum HDL C levels from 0.40 mmol/L in hyperlipidemic rats to 1.21-2.26 mmol/L. Treatment with GB-N (10 mg/kg) could also significantly upregulate levels of hepatic HMG CoA reductase, CYP7A1, LCAT and LDLR mRNA and protein expression. CONCLUSION: GB N had hypolipidemic activity via regulating lipid metabolism pathways in liver of hyperlipidemic rats and could be explored as a potential agent for the prevention of hyperlipidemia diseases. PMID- 22494196 TI - Monitoring complex secundum atrial septal defects percutaneous closure with real time three-dimensional echocardiography. AB - BACKGROUND: Atrial septal defect (ASD) is one of the most common congenital heart diseases. Nowadays, percutaneous closure is considered the treatment of choice in most of secundum ASDs. Assessment of the defect and procedure monitoring have been usually performed by angiographic balloon-sizing and/or two-dimensional (2D) transesophageal echocardiography. However, in complex ASDs these techniques might be inaccurate. METHODS: From January 2009 to January 2011 all adult patients with complex ASDs submitted for percutaneous closure were selected. Those defects, where shunts were present through a device previously implanted on the atrial septum or through multiperforated septums, were considered complex ASDs. Two dimensional transesophageal echocardiography and real time three-dimensional (3D) echocardiography were performed simultaneously during the percutaneous closure procedure. Number of orifices, relationships between the defect, catheter, and device, as well as residual shunt were assessed. RESULTS: Seven patients were included. Five patients had a multiperforated septum and in two cases the defect in the septum was through a previously implanted device. In all cases, 3D echocardiography was superior to 2D echocardiography in relation to the assessment of the relationship between the defect and the catheter or the device. Mechanisms responsible for residual shunts through a device were also better assessed by 3D echocardiography. CONCLUSION: Three-dimensional echocardiography is a safe and useful technique when monitoring percutaneous closure of ASDs, showing relevant advantages over 2D echocardiography. PMID- 22494197 TI - Anarchic hand syndrome following resection of a frontal lobe tumor. AB - Anarchic hand syndrome (AHS) is a rare disorder characterized by unwilled, but seemingly purposeful movements of the affected upper limb which are perceived by the patients not to be under their control. It often interferes with goal directed movements and bimanual tasks. At present there is no effective method of treatment of AHS. We report here a case of AHS following resection of a frontal lobe tumor and describe its effects on the patient's functional activities. The patient used avoidance behavior and mental concentration to overcome the disabling effect of AHS. These strategies appear to be useful in the management of AHS. PMID- 22494198 TI - Using trichloroacetic acid in the treatment of acanthosis nigricans: a pilot study. AB - BACKGROUND: Despite several therapeutic modalities, acanthosis nigricans (AN) remains a difficult dermatosis to treat. OBJECTIVE: This study aims to test the safety and efficacy of trichloroacetic acid (TCA) as a chemical peel in the treatment of AN in a random sample of Egyptian female patients. METHOD: Six females with AN lesions were included in this pilot study. All patients received chemical peeling sessions using TCA over the affected skin lesions. Sessions were carried out to all patients once per week. Treatment was continued for 1 month. Treatment efficacy was evaluated by determining the average rate of response of the lesions to the treatment on a weekly basis. RESULTS: All patients showed improvement as regard hyperpigmentation, thickening, and the overall appearance. The physician assessment was excellent in three lesions, moderate in five, and was mild in two. No side effects had been reported. CONCLUSION: The study may present TCA as a safe, easy, and an effective method for the treatment of AN. PMID- 22494199 TI - Recirculation usually precedes malignant edema in middle cerebral artery infarcts. AB - OBJECTIVES: In patients with large middle cerebral artery (MCA) infarcts, maximum brain swelling leading to cerebral herniation and death usually occurs 2-5 days after onset of stroke. The study aimed at exploring the pattern of compounds related to cerebral energy metabolism in infarcted brain tissue. METHODS: Forty four patients with malignant MCA infarcts were included after decision to perform decompressive hemicraniectomy (DHC). Cerebral energy metabolism was in all patients monitored bedside by 1-3 microdialysis catheters inserted into the infarcted hemisphere during DHC. In 29 of the patients, one microdialysis catheter was also placed in the non-infarcted hemisphere. MCA blood-flow velocity was monitored bilaterally by transcranial Doppler ultrasound. RESULTS: The interstitial glucose levels were in both sides within normal limits throughout the monitoring period. Mean lactate/pyruvate (LP) ratio was very high in infarcted tissue immediately after DHC. The ratio slowly decreased but did not reach normal level during the study period. In the infarcted hemisphere, MCA blood-flow velocities increased from approximately 42 cm/s 1 day prior to DHC (nine of nine patients) to approximately 60 cm/s at day 4. CONCLUSIONS: Normal interstitial glucose level in the infarcted hemisphere in combination with substantial MCA blood-flow velocities bilaterally even before DHC was performed indicates that malignant brain swelling usually commences when the embolus/thrombosis has been largely resolved and recirculation of the infarcted area has started. The protracted increase of the LP ratio in infarcted tissue might indicate mitochondrial dysfunction. PMID- 22494200 TI - In vitro protein degradation of 38 sainfoin accessions and its relationship to tannin content by different assays. AB - This study compared 38 sainfoin and 2 Lotus accessions to their respective tannin contents, N buffer solubility, and in vitro protein degradation. Tannin contents were measured by a protein precipitation method using either bovine serum albumin or Rubisco and by the colorimetric HCl/butanol method. Precipitation of bovine serum albumin and Rubisco was highly correlated (R(2) = 0.939). Correlations between the protein precipitation variants and the HCl/butanol method were relatively low (R(2) < 0.6). Protein degradation was measured at 4 h of incubation in an inhibited in vitro system and could not be explained by any of the tannin assays (R(2) < 0.03) and only partially by N buffer solubility (R(2) <= 0.433). Decisive factors other than the quantity of tannins or their ability to precipitate proteins must be considered. Resistance of soluble protein toward degradation can possibly be caused by tannin protein binding. PMID- 22494201 TI - Adolescents and sexual ambiguity. PMID- 22494202 TI - Re-evaluating the recipient criteria for organ transplants. PMID- 22494203 TI - A 14-year-old girl with leg length discrepancy. PMID- 22494204 TI - Families that refuse to vaccinate their infants. PMID- 22494205 TI - Adolescent development. PMID- 22494207 TI - Health issues in the homeless youth population. PMID- 22494208 TI - Monitoring psychiatric medications in children. PMID- 22494209 TI - 40 Years of pediatric innovations: congenital heart disease. PMID- 22494210 TI - A conversation with Ari A. Brown, MD, FAAP. Interviewed by Stanford T. Shulman. PMID- 22494211 TI - Growth and growth disorders in children and adolescents. AB - Evaluation of a child's growth is one of the most important aspects of the general pediatric visit. Concerns about abnormal growth are the leading reasons general pediatricians refer patients to a pediatric endocrinologist. There is wide variation in normal growth patterns and an even greater variety of conditions that manifest with growth abnormalities. Here, we review patterns of normal growth in the pediatric and adolescent populations. We then review abnormal patterns of growth that require further evaluation and possible treatment. PMID- 22494212 TI - The physiology of puberty and its disorders. AB - Puberty is a complex process of developmental change regulated by multiple genetic and endocrine controls. Abnormal pubertal development (both precocious and delayed puberty) can cause significant distress to the patient and may in some instances be a sign of life-threatening pathology. Delayed puberty is often due to constitutional delay of growth and puberty, but will also occur in cases of primary gonadal failure and in patients with disorders leading to diminished gonadotropin levels (ie, central nervous system [CNS] tumors). Precocious puberty may occur due to CNS disorders, certain genetic disorders, ectopic gonadotropin secretion or autonomous sex steroid secretion. Treatment is directed toward the underlying pathology, and may include agents to either stimulate or block pubertal development. Health care providers require knowledge of the normal onset of timing and rate of progression of puberty, and must be able to identify patients with abnormal pubertal development, as well as initiate the appropriate laboratory workup. PMID- 22494213 TI - Guidelines for evaluating and managing children born with disorders of sexual development. AB - Children born with disorders of sexual differentiation (DSD) pose numerous challenges for the parents, family, and treating physicians. The pediatrician is usually the first medical contact for newborns with DSD or for toddlers and children who present with DSD at a later time. Several years ago, we formed a Gender Medicine Team (GMT) at Baylor College of Medicine and Texas Children's Hospital (TCH) to explore and evaluate the most appropriate management strategies, which had long been a matter of concern and contention. Subsequently, the GMT, composed of experts in the fields of endocrinology, ethics, genetics, gynecology, psychology, pediatric surgery, and urology, formed a Task Force to evaluate the information available from our own experiences and from reviews of the literature. Utilizing the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system to assess the evidence and recommendations, the Task Force developed a consensus statement for clinical management of DSD and for making appropriate sex assignments. PMID- 22494214 TI - Two teenage males with hypocalcemia and elevated parathyroid hormone levels. AB - Vitamin D deficiency is not a rare disorder, particularly in minority groups. The Institute of Medicine recommends serum 25-hydroxyvitamin (OH)D levels >20 ng/mL and The Endocrine Society recommends levels >30 ng/mL for good health. In contrast, the 2003-2006 National Health and Nutrition Examination Survey reported average total 25-(OH)D concentrations of 25.6 +/- 0.4 ng/mL in whites, 19.5 +/- 0.5 ng/mL in Mexican Americans, and 14.8 +/- 0.4 ng/mL in blacks. Pediatric patients with vitamin D deficiency may be asymptomatic or may present either with rickets, hypocalcemia, or seizures. Pseudohypoparathyroidism (PHP) is a rare disorder characterized by parathyroid hormone (PTH) resistance with (type 1a) or without (type 1b) the Albright Hereditary Os-teodystrophy (AHO) phenotype of short stature, brachydactyly, and mental retardation. Patients with PHP have elevated PTH levels and may have hyperphosphatemia and hypocalcemia. However, the same laboratory values can be seen in children with vitamin D deficiency, and diagnostic confusion is common. We report two cases of vitamin D deficiency with presentations suggestive of PHP. PMID- 22494215 TI - Screening for PBT chemicals among the "existing" and "new" chemicals of the EU. AB - Under the European chemicals legislation, REACH, industrial chemicals that are imported or manufactured at more than 10 t/yr need to be evaluated with respect to their persistence (P), bioaccumulation potential (B), and toxicity (T). This assessment has to be conducted for several 10,000 of chemicals but, at the same time, empirical data on degradability, bioaccumulation potential and toxicity of industrial chemicals are still scarce. Therefore, the identification of PBT chemicals among all chemicals on the market remains a challenge. We present a PBT screening of approximately 95,000 chemicals based on a comparison of estimated P, B, and T properties of each chemical with the P, B, and T thresholds defined under REACH. We also apply this screening procedure to a set of 2576 high production volume chemicals and a set of 2781 chemicals from the EU's former list of "new chemicals" (ELINCS). In the set of 95,000 chemicals, the fraction of potential PBT chemicals is around 3%, but in the ELINCS chemicals it reaches 5%. We identify the most common structural elements among the potential PBT chemicals. Analysis of the P, B, and T data for all chemicals considered here shows that the uncertainty in persistence data contributes most to the uncertainty in the number of potential PBT chemicals. PMID- 22494216 TI - Early endoscopic detection and subsequent removal of sphincter penetrating anastomotic sutures may prevent irreversible urinary incontinence after radical prostatectomy. AB - BACKGROUND AND PURPOSE: Iatrogenic sphincter lesions are possible reasons for sphincteric incompetence and postprostatectomy urinary incontinence. The aim of this study was to identify early possible sphincter injuries as causes for urinary incontinence after radical prostatectomy by endoscopic evaluation of the anastomotic region. PATIENTS AND METHODS: Among 374 patients who had undergone radical prostatectomy from 2005 to 2009 at our institution, we investigated patients with early postoperative urinary incontinence. Nineteen incontinent patients were identified with the symptomatic triad of early incontinence, reduced urinary flow, and post-void residual (PVR) volume after catheter removal. Patients were examined endoscopically, and the clinical effect of early suture removal in patients with sphincter penetration was evaluated. RESULTS: Urethrocystoscopic evaluation revealed an isolated sphincter penetration as reason for early postoperative incontinence in 15/19 cases. The suture penetration was observed predominantly in the 3-degree (7/19) and 9-degree (8/19) positions and less frequently in the 12-degree (2/19) and 6-degree (2/19) positions. Four of (21%) 19 patients did show an additional sphincter transection. The penetrating sutures of the urethrovesical anastomosis were removed during the endoscopic procedure, and initial urinary incontinence could be corrected in all cases of isolated sphincter penetration. CONCLUSION: Early severe urinary incontinence, reduced urinary flow, and PVR volume after radical prostatectomy may indicate sphincter penetration by anastomosis sutures. In our patients, early transurethral punctual removal of the penetrating sutures could decrease the early postoperative incontinence rate. PMID- 22494217 TI - Is there a need for the Fournier's gangrene severity index? Comparison of scoring systems for outcome prediction in patients with Fournier's gangrene. AB - Study Type - Prognosis (prospective cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Fournier's gangrene (FG) is a rare but life-threatening disease challenging the treating medical staff. Despite the fact that antibiotic therapy combined with surgery and intensive care surveillance are performed as standard treatment, mortality rates remain high. There have been efforts to develop a reliable tool to predict severity of the disease, not only to identify patients at highest risk of major complications or death but also to provide a target for medical teams and researchers aiming to improve outcome and to gather information for counselling patients. Laor et al. published the FG severity index (FGSI) in 1995 presenting a complex prediction score solely for patients with FG. Fifteen years later, Yilmazlar et al. suggested a new and supposedly more powerful scoring system, the Uludag FGSI (UFGSI), adding an age score and an extent of disease score to the FGSI. In the present study population we applied two scoring systems for outcome prediction that are solitarily applicable in patients with FG (FGSI, UFGSI), as well as two general scoring systems such as the established age-adjusted Charlson Comorbidity Index (ACCI) and the recently introduced surgical Apgar Score (sAPGAR) to compare them and to test whether one system might be superior to the other. In addition, we identified potential prognostic factors in the study population. By contrast to many earlier studies, we performed a combined prospective and retrospective analysis and provided a 30-day follow up. In the cohort of the present study, older patients with comorbidities as well as a need for mechanical ventilation and blood transfusion are at higher risk of lethal outcome. All scores are useful to predict mortality. Despite including more variables, the UFGSI does not seem to be more powerful than the FGSI. In daily routine we suggest applying ACCI and sAPGAR, as they are more easily calculated, generally applicable and well validated. OBJECTIVE: * To compare four published scoring systems for outcome prediction (Fournier's gangrene severity index [FGSI], Uludag FGSI [UFGSI], age adjusted Charlson Comorbidity Index [ACCI] and surgical Apgar Score [sAPGAR]) and evaluate risk factors in patients with Fournier's gangrene (FG). PATIENTS AND METHODS: * In all, 44 patients were analysed. The scores were applied. * A Mann Whitney U-test, Fisher's exact test, receiver operator characteristic (ROC) analysis and Pearson correlation analysis were performed. RESULTS: * The results of the present study show a significant association among FGSI (P= 0.002), UFGSI (P= 0.002), ACCI (P= 0.004), sAPGAR (P= 0.018) and death. * The differences between the area under the receiver operating characteristic curve of the scores were not significant. * Non-survivors were older (P= 0.046), had a greater incidence of acute renal failure (P < 0.001) and coagulopathy (P= 0.041), were treated more often with mechanical ventilation (P= 0.001) and received more packed red blood cells (RBCs; P= 0.001). CONCLUSION: * Older patients with comorbidities and need for mechanical ventilation and RBCs are at higher risk for death. * In the present cohort, scores calculated easily at the bedside, such as ACCI and sAPGAR, seemed to be as good at predicting outcome in patients with FG as FGSI and UFGSI. PMID- 22494218 TI - Selective adsorption to particular crystal faces of ZnO. AB - We examine the hypothesis that selective adsorption to a particular face of ZnO is responsible for the ability of small organic molecules to control the aspect ratio of ZnO crystals during hydrothermal synthesis. Large, single crystals of ZnO were prepared such that the vast majority of a surface consisted of a single crystal plane, as shown by atomic force microscopy, and the adsorption to a single crystal plane was determined by attenuated total reflectance spectroscopy. The results show that citrate strongly and selectively adsorbs to the (0001) face. Similarly, results show that ethylenediamine selectively adsorbs to the (1010) face. Each of these results separately shows a correlation between selective adsorption to and growth of large areas of a particular face, and thus, each result is consistent with the proposed hypothesis. PMID- 22494219 TI - New-type planar field emission display with superaligned carbon nanotube yarn emitter. AB - With the superaligned carbon nanotube yarn as emitter, we have fabricated a 16 * 16 pixel field emission display prototype by adopting screen printing and laser cutting technologies. A planar diode field emission structure has been adopted. A very sharp carbon nanotube yarn tip emitter can be formed by laser cutting. Low voltage phosphor was coated on the anode electrodes also by screen printing. With a specially designed circuit, we have demonstrated the dynamic character display with the field emission display prototype. The emitter material and fabrication technologies in this paper are both easy to scale up to large areas. PMID- 22494221 TI - Acceptance of naltrexone by pregnant women enrolled in comprehensive drug addiction treatment: an initial survey. AB - This paper reports the results of an initial survey regarding the potential interest in naltrexone treatment by pregnant women enrolled in comprehensive treatment for substance use disorders. Pregnant women (N = 112) were asked about their interest in taking either an oral or long-acting injectable medication that would stop heroin and/or alcohol use, leave them "clear-headed," and without neonatal withdrawal. Results indicate strong interest among pregnant women in antagonist treatment, in either form, with clear interest in learning more about naltrexone. Findings lend support for patients' acceptance of a clinical trial of antagonist treatment in this population. PMID- 22494220 TI - TGI Monday?: drug-dependent outpatients report lower stress and more happiness at work than elsewhere. AB - In the general population, experience-sampling studies show that work is the aspect of daily life most associated with momentary unhappiness and a desire to be elsewhere. We assessed whether this holds true for urban outpatients in treatment for heroin and cocaine dependence. In a 25-week natural-history study, 79 employed methadone-maintained misusers of heroin and cocaine carried electronic diaries on which mood and behavior were assessed up to five times per day. Being at work was associated with lower stress, greater happiness, and lower drug craving. Work accounted for 14% of the variance in stress, 30% of the variance in happiness, and 50% of the variance in cocaine craving. Participants with skilled jobs reported more positive and less negative mood states (and lower cocaine craving) at all times compared to participants with semi/unskilled jobs, although the latter reported greater mood improvement at work. In all participants, mood improvements occurred specifically in the presence of coworkers (not other companions). Our seemingly unusual findings might be specific to substance-disorder patients (for whom work may be a respite from drug using companions), but might also hold for other urban dwellers of similar socioeconomic backgrounds (for whom work may be a respite from environmental stressors). PMID- 22494222 TI - An examination of pathways from childhood maltreatment to adolescent binge drinking. AB - Considerable clinical and empirical evidence has accumulated over the past decades indicating that there is a strong association between childhood maltreatment and heavy episodic drinking in adolescence, but there is a paucity of empirically based knowledge about the processes linking the association. The aim of this paper is to examine mechanisms that might account for the association between childhood maltreatment and heavy episodic drinking in adolescence. Using a nationally representative sample of adolescents (ages ranging 12-21; N = 6,337), this study examined the role of individual self-regulatory processes in the associations, controlling for age, gender, race/ethnicity, peer substance use, parental alcoholism, and parent-child conflict. Factor analyses were used to test the measurement structure of self-regulatory processes. Findings confirmed the association between childhood maltreatment and heavy episodic drinking in adolescence. Structural modeling analyses indicated indirect effects for childhood maltreatment primarily through poor self-regulatory processes and peer substance use. Implications for future research are discussed. PMID- 22494223 TI - Gender differences in craving and cue reactivity to smoking and negative affect/stress cues. AB - There is evidence that women may be less successful when attempting to quit smoking than men. One potential contributory cause of this gender difference is differential craving and stress reactivity to smoking- and negative affect/stress related cues. The present human laboratory study investigated the effects of gender on reactivity to smoking and negative affect/stress cues by exposing nicotine dependent women (n = 37) and men (n = 53) smokers to two active cue types, each with an associated control cue: (1) in vivo smoking cues and in vivo neutral control cues, and (2) imagery-based negative affect/stress script and a neutral/relaxing control script. Both before and after each cue/script, participants provided subjective reports of smoking-related craving and affective reactions. Heart rate (HR) and skin conductance (SC) responses were also measured. Results indicated that participants reported greater craving and SC in response to smoking versus neutral cues and greater subjective stress in response to the negative affect/stress versus neutral/relaxing script. With respect to gender differences, women evidenced greater craving, stress and arousal ratings and lower valence ratings (greater negative emotion) in response to the negative affect/stressful script. While there were no gender differences in responses to smoking cues, women trended towards higher arousal ratings. Implications of the findings for treatment and tobacco-related morbidity and mortality are discussed. PMID- 22494225 TI - Drinking correlates of DSM-IV alcohol use disorder diagnostic orphans in college students. AB - One major limitation of the DSM-IV criteria for alcohol abuse and dependence is that a cluster of individuals who endorse a subthreshold number of dependence criteria and no abuse criteria do not receive a formal diagnosis; despite elevated risk for alcohol-related problems relative to those with an abuse diagnosis. These individuals have been referred to as diagnostic orphans. The primary aim of this study was to examine alcohol use correlates of a group of diagnostic orphans in a sample of 396 nontreatment seeking college students who reported drinking on at least one occasion in the last 90 days. DSM-IV criteria were assessed using a modified version of the Composite International Diagnostic Interview-Substance Abuse Module (CIDI-SAM). Diagnostic orphans represented 34.1% (n = 135) of the original sample who did not receive a formal diagnosis; with the most frequently endorsed dependence criteria being tolerance and drinking larger/longer amounts than intended. Diagnostic orphans reported a range of alcohol-related negative consequences and reported greater frequencies of social and enhancement drinking motives in comparison to coping motives. They were similar to alcohol abusers and dissimilar to those with dependence or those without a diagnosis on alcohol consumption, alcohol problem severity, drinking motives and restraint variables. The present findings indicate that diagnostic orphans in college students represent a distinct group of drinkers who may be at risk for the development of alcohol use disorders and may be in need of intervention, given their similarity to those with an abuse diagnosis. Prevention and intervention efforts across college campuses should target this group to prevent escalation of alcohol problem severity. PMID- 22494224 TI - Delay discounting, locus of control, and cognitive impulsiveness independently predict tobacco dependence treatment outcomes in a highly dependent, lower socioeconomic group of smokers. AB - Tobacco use disproportionately affects lower socioeconomic status (SES) groups. Current explanations as to why lower SES groups respond less robustly to tobacco control efforts and tobacco dependence treatment do not fully account for this disparity. The identification of factors that predict relapse in this population might help to clarify these differences. Good candidates for novel prognostic factors include the constellation of behaviors associated with executive function including self-control/impulsiveness, the propensity to delay reward, and consideration and planning of future events. This study examined the ability of several measures of executive function and other key clinical, psychological, and cognitive factors to predict abstinence for highly dependent lower SES participants enrolled in intensive cognitive-behavioral treatment for tobacco dependence. Consistent with predictions, increased discounting and impulsiveness, an external locus of control as well as greater levels of nicotine dependence, stress, and smoking for negative affect reduction predicted relapse. These findings suggest that these novel factors are clinically relevant in predicting treatment outcomes and suggest new targets for therapeutic assessment and treatment approaches. PMID- 22494226 TI - Characteristics of homeless youth who use cocaine and methamphetamine. AB - This cross-sectional hepatitis health promotion study (N = 156) was designed to identify correlates of cocaine and methamphetamine use among young, homeless persons living in Los Angeles County. Structured questionnaires were administered at baseline to assess sociodemographic characteristics, drug history, and social support. Unadjusted analysis showed that older age, having a history of incarceration, injection drug use (IDU), 10 or more sexual partners, and sex for money were associated with both cocaine and methamphetamine use. Logistic regression results showed that injection drug users had over seven times greater odds of using each stimulant compared with nonusers of injection drugs; those reporting at least 10 sexual partners and alcohol use in the past 6 months were more likely to use cocaine than their respective counterparts. African Americans were also less likely than Whites to report cocaine use. Understanding of these relationships can guide interventions targeting the multiple challenges faced by this population. PMID- 22494227 TI - Desire to dissociate: implications for problematic drinking in college students with childhood or adolescent sexual abuse exposure. AB - Alcohol use to replace inadequate dissociative capabilities, or chemical dissociation, has been linked to college students with childhood or adolescent sexual abuse (CASA). Insofar as CASA-exposed persons experience a restricted range of dissociative capabilities, what remains relatively unclear is whether some desire to achieve greater dissociative experiences. Nonclinical levels of dissociative tendencies have positively predicted alcohol-related blackouts in CASA-exposed students, and dissociation mediated the relations between CASA and intoxication frequency. Although alcohol (similar to dissociation) can reduce physiological and psychological responses to stress, alcohol consumption may be prompted by a desire to dissociate rather than inadequate dissociative tendencies alone. To investigate this interpretation of the chemical dissociation phenomenon, researchers examined the mediating potential of dissociative tendencies using the Dissociative Experiences Scale-II (DES-II) as well as the desire to dissociate concept (ie, a modified version of the DES-II) on the relations between CASA exposure and problematic alcohol use in college students (N = 298). Results indicated that dissociation scores did not replicate previous mediation findings whereas desire to dissociate scores fully mediated CASA exposure and problematic alcohol use. Implications of the results are discussed including possible reasons why prior mediation results were not replicated as well as links to experiential avoidance. PMID- 22494228 TI - The Short Inventory of Problems-Modified for Drug Use (SIP-DU): validity in a primary care sample. AB - Primary care physicians can help drug-dependent patients mitigate adverse drug use consequences; instruments validated in primary care to measure these consequences would aid in this effort. This study evaluated the validity of the Short Inventory of Problems-Alcohol and Drugs modified for Drug Use (SIP-DU) among subjects recruited from a primary care clinic (n= 106). SIP-DU internal consistency was evaluated using Cronbach's alphas, convergent validity by correlating the total SIP-DU score with the DAST-10, and construct validity by analyzing the factor structure. The SIP-DU demonstrated high internal consistency (Cronbach's alpha for overall scale .95, subscales .72-.90) comparable with other SIP versions and correlated well with the DAST-10 (r= .70). Confirmatory factor analysis suggested an unacceptable fit of previously proposed factors; exploratory factor analyses suggested a single factor of drug use consequences. The SIP-DU offers primary care clinicians a valid and practical assessment tool for drug use consequences. PMID- 22494229 TI - Decision making, impulsivity, and personality traits in alcohol-dependent subjects. AB - The aim of the study was to assess the relationship among decision-making (DM) ability (as measured by the Iowa Gambling Task [IGT]), impulsivity, and temperament and character traits in a long-term abstinent alcohol-dependent sample. Twenty-six abstinent alcohol-dependent subjects, referred to a Drug Addiction Unit of the National Health Service of L'Aquila, were evaluated using the IGT, the Barratt Impulsiveness Scale, version 11 (BIS-11), and the Temperament and Character Inventory 125-item (TCI-125) version. Twenty-four control subjects were recruited and assessed with IGT only. The clinical and control samples were significantly different in their IGT performance, the former sample making disadvantageous choices leading to lower scores. Significant negative correlations between IGT total score and BIS Non-Planning Impulsivity and a trend toward significance with TCI Novelty Seeking dimension were reported. Our data confirm the results of other studies suggesting DM impairment related to impulsive dimension as an important feature in subjects with alcohol dependence: the finding suggests a role of DM impairment in increasing proneness to a chronic relapsing course. PMID- 22494230 TI - Impact of an 18-month, NHS-based, treatment exposure for heroin dependence: results from the London Area Treat 2000 Study. AB - We set out to examine the impact of treatment for heroin dependence on drug use, injecting behavior, health problems, criminality, and physical and mental health over 18 months among heroin-dependent Londoners. A total of 100 heroin users were recruited for this longitudinal prospective cohort study with repeated measures (T0 as baseline, T1 after 9 months, and T2 after 18 months). The psychiatric evaluation and assessment of drug abuse levels were determined by the CIDI and the EuropASI. Additional evaluations included the WHO-DAS II for disability assessment and the UCLA-SSI for social support. The number of days of heroin use in the 30 days previous to each single assessment significantly reduced over time (p < .001). Similar reduction levels were observed for cocaine (p < .05), benzodiazepines (p < .001), and polydrug abuse (p < .001), but not for cannabis and alcohol. The number of injecting occasions reduced in parallel, with increase in days in work and reduction of money spent for drug acquisition activities and money obtained from criminal/illegal activities. The number of subjects experiencing suicidal ideation reduced over time (p < .05). In line with previous suggestions, significant reductions in drug use, criminality, psychopathology, and injecting behavior following treatment exposure for heroin dependence were observed. It is, however, of concern that alcohol and cannabis misuse levels remained unchanged. PMID- 22494231 TI - Reflections on treating addictive disorders: a psychodynamic perspective. PMID- 22494232 TI - Proposed DSM-5 substance use disorders for adolescents: if you build it, will they come? PMID- 22494234 TI - Treatment of opioid dependence and cancer pain with sublingual buprenorphine: a case report. PMID- 22494235 TI - A case of diagnosing a long-standing psychotic disorder during medical withdrawal. PMID- 22494236 TI - Synthetic cannabinoid induced psychosis in a previously nonpsychotic patient. PMID- 22494237 TI - Case report: adverse reaction to synthetic marijuana. PMID- 22494238 TI - Coma after single dose of zopiclone. PMID- 22494240 TI - Review of twice dead: organ transplants and the reinvention of death. PMID- 22494241 TI - Dehydrative C-H alkylation and alkenylation of phenols with alcohols: expedient synthesis for substituted phenols and benzofurans. AB - A well-defined cationic Ru-H complex catalyzes the dehydrative C-H alkylation reaction of phenols with alcohols to form ortho-substituted phenol products. Benzofuran derivatives are efficiently synthesized from the dehydrative C-H alkenylation and annulation reaction of phenols with 1,2-diols. The catalytic C-H coupling method employs cheaply available phenols and alcohols, exhibits a broad substrate scope, tolerates carbonyl and amine functional groups, and liberates water as the only byproduct. PMID- 22494243 TI - Should medical directors assume responsibility for facility-specific outcomes? PMID- 22494239 TI - Multiple cellular mechanisms prevent chromosomal rearrangements involving repetitive DNA. AB - Repetitive DNA is present in the eukaryotic genome in the form of segmental duplications, tandem and interspersed repeats, and satellites. Repetitive sequences can be beneficial by serving specific cellular functions (e.g. centromeric and telomeric DNA) and by providing a rapid means for adaptive evolution. However, such elements are also substrates for deleterious chromosomal rearrangements that affect fitness and promote human disease. Recent studies analyzing the role of nuclear organization in DNA repair and factors that suppress non-allelic homologous recombination (NAHR) have provided insights into how genome stability is maintained in eukaryotes. In this review, we outline the types of repetitive sequences seen in eukaryotic genomes and how recombination mechanisms are regulated at the DNA sequence, cell organization, chromatin structure, and cell cycle control levels to prevent chromosomal rearrangements involving these sequences. PMID- 22494242 TI - Structural intermediates in a model of the substrate translocation path of the bacterial glutamate transporter homologue GltPh. AB - Excitatory amino acid transporters (EAATs) are membrane proteins responsible for reuptake of glutamate from the synaptic cleft to terminate neurotransmission and help prevent neurotoxically high, extracellular glutamate concentrations. Important structural information about these proteins emerged from crystal structures of GltPh, a bacterial homologue of EAATs, in conformations facing outward and inward. These remarkably different conformations are considered to be end points of the substrate translocation path (STP), suggesting that the transport mechanism involves major conformational rearrangements that remain uncharted. To investigate possible steps in the structural transitions of the STP between the two end-point conformations, we applied a combination of computational modeling methods (motion planning, molecular dynamics simulations, and mixed elastic network models). We found that the conformational changes in the transition involve mainly the repositioning the "transport domain" and the "trimerization domain" identified previously in the crystal structures. The two domains move in opposite directions along the membrane normal, and the transport domain also tilts by ~17 degrees with respect to this axis. Moreover, the TM3-4 loop undergoes a flexible, "restraining bar"-like conformational change with respect to the transport domain. As a consequence of these conformational rearrangements along the transition path we calculated a significant decrease of nearly 20% in the area of the transport-to-trimerization domain interface (TTDI). Water penetrates parts of the TTDI in the modeled intermediates but very much less in the end-point conformations. We show that these characteristics of the modeled intermediate states agree with experimental results from residue accessibility studies in individual monomers and identify specific residues that can be used to test the proposed STP. Moreover, MD simulations of complete GltPh trimers constructed from initially identical monomer intermediates suggest that asymmetry can appear in the trimer, consonant with available experimental data showing independent transport kinetics by individual monomers in the trimers. PMID- 22494244 TI - Evaluation of right ventricular regional volume and systolic function in patients with pulmonary arterial hypertension using three-dimensional echocardiography. AB - OBJECTIVE: To evaluate right ventricular (RV) regional volume and systolic function in patients with pulmonary arterial hypertension (PAH) using real time three-dimensional echocardiography (RT3DE), and to explore the relationship between parameters measured by RT3DE and right heart catheterization (RHC). METHODS: RT3DE images were acquired from 24 patients with PAH and 27 normal controls for evaluation and analysis to obtain RV regional end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF) in three compartments (inflow, body, and outflow). Conventional echocardiographic parameters were calculated and recorded. RHC was performed in 17 patients to obtain pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR). RESULTS: RV regional EDV and ESV were significantly higher while regional EF was significantly lower in the PAH patients when compared with controls (P < 0.001). In the PAH group, EDV was similar in the inflow and body compartment, both higher than that in the outflow compartment (P < 0.05); EF was the highest in the inflow compartment and the lowest in the body compartment (P < 0.05). RV regional EF in the inflow compartment and global EF were negatively correlated with PASP (r = 0.766, -0.816, P < 0.001) and PVR (r =-0.529, -0.656, P < 0.05). CONCLUSIONS: In patients with PAH, RV regional volume was enlarged and systolic function was impaired with distinct characteristics; regional EF in the inflow compartment and global EF were inversely correlated with PASP and PVR. Evaluation of RV regional systolic function using RT3DE may play a potential role in the noninvasive assessment of the severity of PAH. PMID- 22494245 TI - Human exposure to perfluorinated compounds in Catalonia, Spain: contribution of drinking water and fish and shellfish. AB - In this study, the concentrations of 15 perfluorinated compounds (PFCs) were analyzed in 30 water samples collected in Catalonia (Spain) at three stages of the drinking water treatment process in several water purification plants. In addition, the concentrations of 13 PFCs were determined in samples of fish and shellfish collected from coastal areas of Catalonia. The intake of PFCs through both pathways, drinking water intake and fish and shellfish consumption, was also estimated. In water samples, the highest mean concentrations corresponded to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) (1.81 and 2.40 ng/L, respectively), whereas perfluorodecanosulfonate (PFDS) and perfluorotetradecanoic acid (PFTDA) were under their respective limits of detection in all analyzed samples. The results show that although the current treatment processes caused slight reductions in PFC concentrations, these processes did not mean significant changes in the amounts of PFCs already contained in the raw water. Among the analyzed PFCs in fish and shellfish, only seven compounds could be detected in at least one composite sample. PFOS showed the highest mean concentration (2.70 ng/g fw), being detected in all species with the exception of mussels. With regard to PFOA (mean, 0.074 ng/g fw), the highest concentrations were detected in prawn and hake (0.098 and 0.091 ng/g fw, respectively). The current exposure to PFCs through consumption of fish and shellfish indicates that it should not be of concern for the consumers. The amounts ingested are well below the recommended tolerable daily intakes, at least for those PFCs for which information is available. PMID- 22494246 TI - Gliadin antibodies in older population and neurological and psychiatric disorders. AB - OBJECTIVES: A variety of neurological and psychiatric disorders have recently been linked to coeliac disease and gluten sensitivity. We here explored whether persistently positive gliadin antibodies (AGA) and coeliac-type HLA increase the risk of gluten sensitivity-related neurological and psychiatric manifestations. The study was carried out in an older population who had consumed gluten for decades but who had no previous coeliac disease diagnosis. MATERIALS AND METHODS: The original study population comprised 4272 randomly selected older individuals, of whom 2089 had AGA and transglutaminase 2 antibodies (antiTG2) measured twice within a 3-year interval. Forty-nine persistently AGA-positive but antiTG2 negative subjects with coeliac-type HLA and 52 randomly selected persistently AGA and antiTG2-negative age- and sex-matched controls were clinically examined for neurological disorders. The Psychological General Well-Being (PGWB) questionnaire, the SF-36 health survey questionnaire and the Depression Scale (DEPS) were employed to evaluate psychological well-being. The medical files of all the study subjects were analysed for previous illnesses. RESULTS: Persistently AGA-positive but antiTG2-negative older subjects carrying coeliac disease-type HLA did not evince significantly more neurological symptoms or diseases than AGA-negative control subjects (P = 0.682, P = 0.233). There were no statistically significant differences between AGA-positive and AGA-negative groups in psychological well-being and quality of life when measured by PGWB (P = 0.426), SF-36 questionnaires (P = 0.120) and DEPS (P = 0.683). CONCLUSIONS: At population level, persistent AGA positivity did not indicate gluten sensitivity related neurological and psychiatric disorders. PMID- 22494247 TI - Novel necrotrophic effectors from Stagonospora nodorum and corresponding host sensitivities in winter wheat germplasm in the southeastern United States. AB - Stagonospora nodorum blotch (SNB), caused by the necrotrophic fungus Stagonospora nodorum (teleomorph: Phaeosphaeria nodorum), is among the most common diseases of winter wheat in the United States. New opportunities in resistance breeding have arisen from the recent discovery of several necrotrophic effectors (NEs, also known as host-selective toxins) produced by S. nodorum, along with their corresponding host sensitivity (Snn) genes. Thirty-nine isolates of S. nodorum collected from wheat debris or grain from seven states in the southeastern United States were used to investigate the production of NEs in the region. Twenty-nine cultivars with varying levels of resistance to SNB, representing 10 eastern-U.S. breeding programs, were infiltrated with culture filtrates from the S. nodorum isolates in a randomized complete block design. Three single-NE Pichia pastoris controls, two S. nodorum isolate controls, and six Snn-differential wheat controls were also used. Cultivar-isolate interactions were visually evaluated for sensitivity at 7 days after infiltration. Production of NEs was detected in isolates originating in each sampled state except Maryland. Of the 39 isolates, 17 produced NEs different from those previously characterized in the upper Great Plains region. These novel NEs likely correspond to unidentified Snn genes in Southeastern wheat cultivars, because NEs are thought to arise under selection pressure from genes for resistance to biotrophic pathogens of wheat cultivars that differ by geographic region. Only 3, 0, and 23% of the 39 isolates produced SnToxA, SnTox1, and SnTox3, respectively, by the culture-filtrate test. A Southern dot-blot test showed that 15, 74, and 39% of the isolates carried the genes for those NEs, respectively; those percentages were lower than those found previously in larger international samples. Only two cultivars appeared to contain known Snn genes, although half of the cultivars displayed sensitivity to culture filtrates containing unknown NEs. Effector sensitivity was more frequent in SNB-susceptible cultivars than in moderately resistant (MR) cultivars (P = 0.008), although some susceptible cultivars did not exhibit sensitivity to NEs produced by isolates in this study and some MR cultivars were sensitive to NEs of multiple isolates. Our results suggest that NE sensitivities influence but may not be the only determinant of cultivar resistance to S. nodorum. Specific knowledge of NE and Snn gene frequencies in this region can be used by wheat breeding programs to improve SNB resistance. PMID- 22494248 TI - Evidence for morphological, vegetative, genetic, and mating-type diversity in Sclerotinia homoeocarpa. AB - Morphology, vegetative compatibility groups, and molecular characteristics were compared among 47 isolates of the dollar spot pathogen Sclerotinia homoeocarpa. Isolates were collected from cool- and warm-season turfgrasses in Florida and the northern United States. Mycelial pigment accumulation, substratal stromata formation, and symptom development were used to separate the collection into two distinct morphological types: a common-type (C-type) and a Floridian-type (F type). Phylogenetic relationships estimated from ITS sequences supported the morphological typing. Identification and characterization of the S. homoeocarpa mating-type locus revealed an idiomorphic organization for both C- and F-types with nearly equal frequencies of each mating types present in both groups. These findings suggest heterothallic control of mating and indicate potential for outcrossing in both groups. Dollar spot disease of turfgrass in Florida is caused by two distinct morphological types of S. homoeocarpa which may be cryptic species. These findings could have implications for disease management. PMID- 22494249 TI - Manipulating inoculum densities of Verticillium dahliae and Pratylenchus penetrans with green manure amendments and solarization influence potato yield. AB - We used cover crops with demonstrated efficacy against Verticillium dahliae and Pratylenchus penetrans in combination with the biocidal practice of solarization to determine the importance of targeting both organisms for managing potato early dying, an issue relevant to the search for alternatives to soil fumigation. Two experiments were conducted in commercial fields using a split-plot design with cover crop treatments of rapeseed, marigold, forage pearl millet, sorghum sudangrass, and corn as the main plot factor and solarization as the subplot factor. Cover crops were grown and solarization applied in year one, followed by potato in year two. The main effect of solarization was significant for reduced inoculum levels of both organisms in year two and increased tuber yields. The main effect of cover crop was also significant with lower population densities of P. penetrans following the marigold and millet treatments and of V. dahliae following rape and sorghum-sudangrass. The cover crop treatments influenced yield in only one of the experiments in the absence of solarization. The combinatorial effect of cover crops and solarization resulted in a wide range of pathogen population densities. Mean soil inoculum levels were negatively related to yield for V. dahliae in experiment 1, and for P. penetrans and the P. penetrans * V. dahliae interaction in both experiments. PMID- 22494250 TI - Distinguishing Galactomyces citri-aurantii from G. geotrichum and characterizing population structure of the two postharvest sour rot pathogens of fruit crops in California. AB - A growth assay in lemon juice and polymerase chain reaction amplifications using newly designed species-specific primers from endopolygalacturonase and beta tubulin genes rapidly differentiated isolates of the morphologically similar fruit sour rot pathogens Galactomyces citriaurantii and G. geotrichum. Isolates of both species were collected from agricultural soils and decaying fruit at locations within and outside California, including worldwide locations, and were used in population genetic studies based on amplified fragment length polymorphic (AFLP) DNA markers. For all four geographically defined subpopulations (three counties of California and locations outside California) among 97 isolates of G. citri-aurantii and for the two subpopulations (origin within or outside California) among 35 isolates of G. geotrichum, the proportion of polymorphic loci and haplotypic diversity was high. In total, 82 unique haplotypes were identified for G. citri-aurantii for the four subpopulations and, of these, 80 haplotypes were unique among subpopulations. For G. geotrichum, 25 unique haplotypes were identified among the two subpopulations and no haplotype was shared. Indices of genetic differences (F(ST)) between subpopulations within each species were all low (e.g., 0.038 for G. geotrichum and 0.085 to 0.226 for G. citriaurantii), indicating a low level of genetic differentiation. Following clone correction, mating type segregation ratios for G. citri-aurantii did not significantly (P > 0.1) deviate from a 1:1 ratio for all four subpopulations or the entire population. Tests of the index of association (I(A)) and parsimony tree-length permutation tests (PTLPT) supported a random mating structure for clone-corrected data for the Kern, Tulare, and Ventura County subpopulations and the null hypothesis of random mating could not be rejected. Additionally, PTLPT also supported random mating for the "outside of California" population. For G. geotrichum, random mating was only tested using I(A) and PTLPT and the null hypothesis of random mating was not rejected (P > 0.05) using clone-corrected data. Further evidence that sexual recombination likely occurs in both species of Galactomyces was the lack of grouping consistency in the unweighted pair-group method with arithmetic mean clustering of AFLP data. A high confidence based on bootstrap values was obtained for only a few of the nodes in each of the two trees. A mixed reproduction system with an out-crossing sexual mating system and a prolific asexual phase is proposed for both species. PMID- 22494251 TI - Virulence profile and genetic structure of a North Dakota population of Pyrenophora teres f. teres, the causal agent of net form net blotch of barley. AB - A Pyrenophora teres f. teres population in North Dakota was analyzed for virulence variation and genetic diversity using 75 monospore isolates that were collected across a 4-year period (2004 to 2007) from two North Dakota State University agricultural experiment stations at Fargo and Langdon. Pathogenicity tests by inoculation onto 22 barley differential lines at seedling stage revealed 49 pathotypes, indicating a wide range of pathogenic diversity. Two-way analysis of variance of disease ratings revealed a significant difference in the virulence among isolates and in the resistance among barley lines, as well as in the interactions between the two. 'CI5791', 'Algerian', and 'Heartland' were three barley lines showing a high level of seedling resistance to all North Dakota isolates tested; however, many previously reported resistance genes have been overcome. Forty multilocus genotypes were identified from this set of isolates by genotyping at 13 simple-sequence repeat loci. High percentages of clonal cultures were detected in the samplings from 2005 and 2007 in Fargo and 2005 in Langdon. Using a clone-corrected sample set, the mean gene diversity (h) was estimated to be 0.58, approximately the same for both locations. The calculated Wright's F(ST) value is small (0.11) but was significantly >0, indicating a significant differentiation between the Fargo and Langdon populations. In the gametic disequilibrium test, only 3 of 78 possible pairwise comparisons over all isolates showed significant (P < 0.05) nonrandom association, suggesting a random mating mode. Our results suggest that the populations from the two locations are derived from a common source and undergo frequent recombination. This research provides important information for barley breeders regarding development and deployment of cultivars with resistance to net form net blotch in this region. PMID- 22494252 TI - Design and application of new imidazolylsulfonate-based benzyne precursor: an efficient triflate alternative. AB - Several o-(trimethylsilyl)aryl imidazolylsulfonates were synthesized in a simple process and successfully applied in cycloadditions involving benzyne intermediates. The precursor offers an efficient alternative for generating benzynes compared to widely used ortho TMS triflates under similar reaction conditions. With the utilization of this new precursor, the formation of potentially genotoxic trifluoromethanesulfonate side product is eliminated. The applicability of the new benzyne precursor was demonstrated in different types of cycloaddition reactions to prepare heterocyclic molecules. PMID- 22494253 TI - Review of Jean-Pierre Changeux and Paul Ricoeur. 2000. What Makes Us Think? A Neuroscientist and Philosopher Argue about Ethics, Human Nature, and the Brain. PMID- 22494254 TI - Review of donald R. Griffin. 2001. Animal minds: beyond cognition to consciousness. PMID- 22494255 TI - Kudos to the ADEA and to Dr. Lily T. Garcia. PMID- 22494256 TI - Letter to the editor. Re: The effect of recasting on bond strength between porcelain and base-metal alloys. PMID- 22494257 TI - Accident in implant dentistry: involuntary screwdriver ingestion during surgical procedure. A clinical report. AB - Although unusual, foreign body ingestion occurs in dentistry and may result in serious complications, such as intestinal perforation. The presence of the foreign body should be confirmed with the use of radiographs. The exam will allow the correct diagnosis and the treatment to be conducted according to the specific situation of the object in the gastrointestinal (GI) tract. The orientation of the patient as well as the awareness of the patient's medical history are key factors in preventing serious complications. Generally, instruments that enter the GI tract pass asymptomatically and atraumatically within 4 days to 2 weeks. Sometimes, a surgical approach is necessary to remove the instrument when there is bleeding, obstruction, or impaction in the GI tract. Thus, a correct diagnosis is vital to avoid unnecessary surgical interventions. The aim of this article is to report an accidental ingestion of a screwdriver by a patient who had previously undergone a hemi-mandibulectomy and its medical resolution. PMID- 22494260 TI - Gerstmann-Straussler-Scheinker syndrome with the P102L pathogenic mutation presenting as familial Creutzfeldt-Jakob disease: a case report and review of the literature. AB - Gerstmann-Straussler-Scheinker syndrome is a rare autosomal dominant disease caused by a mutation in the prion gene, usually manifesting as progressive ataxia with late cognitive decline. A 44-year-old woman with a positive family history developed early personality and behavior changes, followed by paresthesias and ataxia, later associated with memory problems, pyramidal signs, anosognosia and very late myoclonus, spasticity, and severe dysexecutive impairment. Magnetic resonance showed caudate, mesio-frontal, and insular hyper-intensities, electroencephalography revealed generalized triphasic periodic complexes. A pathogenic P102L mutation in the prion gene was detected. Our case differed from classical Gerstmann-Straussler-Scheinker syndrome by rapid progression, severe dementia, abnormal electroencephalography and magnetic resonance findings, which were highly suggestive of familial Creutzfeldt-Jakob disease. PMID- 22494261 TI - Electrochemical and spectroscopic study of the self-assembling mechanism of normal and chelating alkanethiols on copper. AB - The self-assembly of aliphatic thiol (RSH), dithiol (R(SH)(2)), and dithiocarboxylic acid (RS(2)H) onto mildly oxidized and highly oxidized copper was studied in real time by in situ electrochemical impedance spectroscopy (EIS). Ex situ characterization of the films was carried out using linear sweep voltammetry (LSV), polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS), and X-ray photoelectron spectroscopy (XPS). In situ EIS studies found a very fast adsorption of RSH, R(SH)(2), and RS(2)H (within 10-15 s). This fast adsorption step is followed by the long-term additional adsorption and consolidation of SAM. However, the self-assembly of RS(2)H passes through an intermediate step of molecule rearrangement for around 10 to 30 min after around 2 to 7 min of self-assembly. The binding of both sulfur moieties of R(SH)(2) with Cu happens simultaneous. The oxide reduction capacity of RSH, R(SH)(2), and RS(2)H was good. However, the XPS studies showed the decomposition of RS(2)H based SAMs to Cu(2)S. Monolayers prepared on both mildly oxidized and heavily oxidized Cu with R(SH)(2) had the highest stability. Monolayers of RS(2)H showed the least stability on both mildly oxidized and heavily oxidized Cu. Although RSH based SAMs had good organization on both mildly oxidized and highly oxidized Cu, R(SH)(2)-based SAMs did not show good organization in either case. The RS(2)H monolayer had good organization only on mildly oxidized Cu. PMID- 22494263 TI - Synthesis of oligo(thiophene)-coated star-shaped ROMP polymers: unique emission properties by the precise integration of functionality. AB - A facile synthesis of oligo(thiophene)-modified (coated) "soluble" star (ball) shaped polymers has been achieved via sequential living ring-opening metathesis polymerization (ROMP) of norbornene and a cross-linking reagent using Mo(CHCMe(2)Ph)(N-2,6-(i)Pr(2)C(6)H(3))(O(t)Bu)(2) as the initiator and oligo(thiophene) carboxaldehydes for termination. The resultant star-shaped ROMP polymers containing ter- and tetrathiophene moieties exhibit unique emission properties due to an integration of the ROMP polymers (arranged functionalities): the blue emission was tuned to the white emission upon addition of 2-[2-[(E)-4 (dimethylamino)styryl]-6-methyl-4H-pyran-4-ylidene]malononitrile. PMID- 22494262 TI - A comparison of multiscale methods for the analysis of molecular dynamics simulations. AB - Molecular dynamics (MD) is the only technique available for obtaining dynamic protein data at atomic spatial resolution and picosecond or finer temporal resolution. In recent years, the cost of computational resources has decreased exponentially while the number of known protein structures, many of which are not characterized biochemically, has increased rapidly. These events have led to an increase in the use of MD in biological research, both to examine phenomena that cannot be resolved experimentally and to generate hypotheses that direct further experimental research. In fact, several databases of MD simulations have arisen in recent years. MD simulations, and especially MD simulation databases, contain massive amounts of data, yet interesting phenomena often occur over very short time periods and on the scale of only a few atoms. Analysis of such data must balance these fine-detail events with the global picture they create. Here, we address the multiscale nature of the problem by comparing several MD analysis methods to show their strengths and weaknesses at various scales using the wild type and R282W mutant forms of the DNA-binding domain of protein p53. By leveraging these techniques together, we are able to pinpoint fine-detail and big picture differences between the protein's variants. Our analyses indicate that the R282W mutation of p53 destabilizes the L1 loop and loosens the H2 helix conformation, but the loosened L1 loop can be rescued by residue H115, preventing the R282W mutation from completely destabilizing the protein or abolishing activity. PMID- 22494264 TI - New P2 compound with brucite-like layers: potassium lithiostannate. AB - A new compound with brucite-like layers, K(0.72)Li(0.24)Sn(0.76)O(2), has been obtained two ways, via solid-state reactions: with a big excess of KOH and in a controllable atmosphere without water and carbon dioxide. It has P2 structure (in Hagenmuller's definition) as previously described for K(0.70)Zn(0.35)Sn(0.65)O(2). The latter compound has been repeatedly prepared using the new technique presented here. The structure was refined using powder X ray profile analysis. Lithium cations are disordered with tin (+4) in the rigid part and introduce "acid" properties. Both types of potassium positions are split. The metastable P3 phase also appears in the K(2)O-Li(2)O-SnO(2) system. The sodium analogue Na(0.72)Li(0.24)Sn(0.76)O(2) with P2 structure has been prepared using an ion-exchange technique. PMID- 22494265 TI - Can better understanding and use of treatment center performance feedback improve hemodialysis care? A role for the medical director. PMID- 22494266 TI - Economic evaluation of anti-epileptic drug therapies with specific focus on teratogenic outcomes. AB - BACKGROUND: Anti-epileptic drugs are known to be teratogenic, yet many women do need to continue the anti-epileptic drug use during pregnancy. OBJECTIVES: To perform an economic evaluation of the anti-epileptic drug choice in young women who potentially wish to become pregnant. In particular, to estimate the impact of teratogenicity on the costs per quality adjusted life year (QALY). METHODS: A decision-tree model is used to calculate the costs per QALY, taking into account the malformation risk in offspring due to the exposure to carbamazepine, lamotrigine or valproic acid, based on the European birth cohort of 2007. Probabilistic sensitivity analyses were performed using Monte Carlo simulation. RESULTS: Valproic acid is dominated by carbamazepine after rank ordering on costs. The incremental cost-effectiveness of lamotrigine vs carbamazepine was estimated at ?175,534 per QALY. Although valproic acid was dominated by carbamazepine in terms of costs and related effects, it is clinically relevant to compare lamotrigine with valproic acid. In particular, treatment options are dependent on several individual and clinical characteristics and these agents are therefore not always considered as interchangeable for all specified populations. The incremental cost-effectiveness for lamotrigine vs valproic acid was estimated at ?13,370 per QALY. With assuming a willingness to pay threshold of ?50,000 per QALY, results from the probabilistic analysis resulted in an acceptance level for lamotrigine vs carbamazepine and lamotrigine vs valproic acid of 4% and 99%, respectively. CONCLUSION: Based on epidemiological data it is advised to whenever possible avoid valproic acid during pregnancy. Both carbamazepine and lamotrigine are estimated to be cost-effective treatment options vs valproic acid if focused on teratogenicity. PMID- 22494267 TI - Cost-effectiveness of rivaroxaban in the prevention of venous thromboembolism: A Canadian analysis using the Ontario Ministry of Health Perspective. AB - OBJECTIVES: A cost-effectiveness model for rivaroxaban evaluated the cost effectiveness of prophylaxis with rivaroxaban (a once-daily, orally administered Factor Xa inhibitor) vs enoxaparin in the prevention of venous thromboembolism (VTE) after total hip replacement (THR) and total knee replacement (TKR). This Canadian analysis was conducted using the Ontario Ministry of Health perspective over a 5-year time horizon. The model combined clinical data and builds upon existing economic models. METHODS: The model included both acute VTE (represented as a decision tree) and long-term complications (represented as a Markov process with 1-year cycles) phases. The model allowed VTE event rates, quality-adjusted life expectancy and direct medical costs to be estimated over a 5-year time horizon, based on current approved practice patterns in Canada. A number of one way sensitivity analyses were performed on the baseline assumptions, including a comparison of rivaroxaban with dalteparin, and probabilistic sensitivity analyses were performed to address any uncertainty concerning model inputs. RESULTS: When comparing equal durations of therapy, rivaroxaban dominated enoxaparin in the prevention of VTE events in patients undergoing THR and TKR, providing more benefit at a lower cost. Rivaroxaban was cost-effective when comparing 35 days' prophylaxis with 14 days' prophylaxis with enoxaparin following THR. One-way and probabilistic sensitivity analyses demonstrated that the results of the economic analysis were robust to variations in key inputs. Rivaroxaban remained dominant during one-way sensitivity analyses comparing rivaroxaban with dalteparin after THR or TKR. LIMITATIONS: Although clinical trial data were used in the prophylaxis module, assumptions and values used in the post-prophylaxis and long term complication (LTC) modules were based on several different literature sources; it was not always possible to source Canadian data. CONCLUSIONS: This economic analysis suggests that the use of rivaroxaban for the prophylaxis of VTE after THR or TKR in Canada was cost-effective. PMID- 22494268 TI - Pseudo-pulmonic stenosis in non-hodgkin's large B-cell lymphoma. AB - There have only been a few cases reported of right ventricular outflow tract obstruction secondary to diffuse large B-cell lymphomas. Mediastinal masses rarely cause extrinsic compression of the heart resulting in hemodynamically significant obstruction. We report a rare case of right ventricular outflow tract obstruction secondary to diffuse large B-cell lymphomas. Echocardiography has been found to be a useful modality in the prompt identification of mediastinal masses and their effects on the otherwise healthy heart. PMID- 22494269 TI - Different enantioselective degradation of pyraclofos in soils. AB - This study investigated the enantioselective degradation behavior of pyraclofos in three soils (NC, HZ, and ZZ) under native and sterilized conditions. The absolute configuration of pyraclofos enantiomers has been determined by the combination of experimental and calculated electronic circular dichroism spectra. S-(+)- and R-(-)-Pyraclofos were separated and determined on a cellulose tri-(4 chloro-3-methylphenylcarbamate) (Lux Cellulose-4) chiral column by reversed-phase high-performance liquid chromatography-tandem mass spectrometry. Pyraclofos enantiomers were configurationally stable in three soils and no interconversion was observed during the incubation of enantiopure S-(+)- or R-(-)-pyraclofos under native conditions. The enantioselective degradation behavior of chiral pyraclofos was dramatically different in three soils under native conditions, with half-lives (t(1/2)) of pyraclofos in NC, HZ, and ZZ soils of 2.6, 13.4, and 7.8 days for S-(+)-pyraclofos and 9.2, 9.3, and 8.2 days for R-(-)-pyraclofos. Compared to the half-lives (t(1/2)) of rac-pyraclofos of 21.5, 55.9, and 14.4 days in sterilized NC, HZ and ZZ soils, the degradation velocity was greatly improved in native soils, indicating that degradation was greatly attributed to microbially mediated processes in agricultural cultivating soils. PMID- 22494270 TI - Being prepared for acculturation: on the importance of the first months after immigrants enter a new culture. AB - We hypothesized that perceived communication effectiveness at arrival and initial friendships with members of the receiving society during the first months after arrival in a new country have a long-term effect on the development of acculturation orientations and that this effect is pronounced for individuals with a high need for cognitive closure (NCC). We examined the hypotheses in a study with Spanish-speaking immigrants in Switzerland (n = 146) and in Italy (n = 147). We asked participants to indicate their current attitude to contact with the receiving society and cultural maintenance and report retrospectively their perceived communication effectiveness at arrival and initial friendships. In line with the predictions, the perceptions of high communication effectiveness at arrival and friendships with members of the receiving society during the initial phase in the new culture were positively correlated with the current attitude to contact with the receiving society assessed 7 years after arrival on average. Also, initial friendships with members of the receiving society were negatively correlated with present cultural maintenance. Moreover, with an increase in NCC, these correlations increased. PMID- 22494271 TI - Effect of low-frequency rTMS on motor neuron excitability after stroke. AB - OBJECTIVES: The purpose of this study was to test the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) over the non-lesional hemisphere on motor neuron excitability of the paretic upper limb in post-stroke patients by electrophysiological examination. MATERIALS AND METHODS: Thirteen post-stroke patients with spastic upper limb hemiparesis were studied (age, 57.5 +/- 11.1 years; time after stroke, 55.2 +/- 51.4 months). Low-frequency rTMS of 1 Hz was applied for 20 min to the motor cortex of the non-lesional hemisphere. The M-response amplitude and F-wave parameters were recorded in the abductor pollicis brevis muscle following stimulation of the median nerve in both the affected and unaffected upper limbs. The F-wave frequency, F-max/M ratio (ratio of maximum F wave amplitude to M-response amplitude), and F-mean/M ratio (the ratio of mean F wave amplitude to the M-response amplitude) were measured before and after the 20 min rTMS, analyzed for both limbs. RESULTS: Application of low-frequency rTMS did not result in significant changes in the frequency of F-wave and F-max/M ratio in both upper limbs, but significantly decreased F-mean/M ratio in the affected upper limb (P < 0.005), but not in the unaffected limb. CONCLUSIONS: Low frequency rTMS applied to the non-lesional hemisphere might be potentially useful therapeutically for post-stroke patients with spastic upper limb hemiparesis. PMID- 22494272 TI - Well-defined ruthenium(II) carboxylate as catalyst for direct C-H/C-O bond arylations with phenols in water. AB - The ruthenium(II) carboxylate complex [Ru(O(2)CMes)(2)(p-cymene)] enabled efficient direct arylations of unactivated C-H bonds with easily available, inexpensive phenols. Extraordinary chemoselectivity of the well-defined ruthenium catalyst set the stage for challenging C-H/C-O bond functionalizations to occur under solvent-free conditions as well as in water, and allowed first direct C-H bond arylations with user-friendly diaryl sulfates as electrophiles. PMID- 22494273 TI - Noninvasive and invasive neuromodulation for the treatment of tinnitus: an overview. AB - OBJECTIVE: Nonpulsatile tinnitus is an auditory phantom percept characterized as a tone, or a noise-like sound such as a hissing or buzzing sound or polyphonic, in the absence of any objective physical sound source. Although advances have been made in symptomatic pharmacologic and nonpharmacologic treatments, these treatments are unable to eliminate the tinnitus sensation in most patients. A novel approach using noninvasive and invasive neuromodulation has emerged as an interesting and promising modality for tinnitus relief. METHODOLOGY: We review noninvasive neuromodulation techniques including transcranial magnetic stimulation, transcranial direct current stimulation, transcutaneous electrical nerve stimulation, and cortical neurofeedback, as well as invasive neuromodulation techniques including auditory cortex stimulation, dorsolateral prefrontal cortex stimulation, subcutaneous occipital nerve stimulation, and deep brain stimulation, as potential treatments of tinnitus. CONCLUSION: Although the different techniques introduced revealed promising results, further research is needed to better understand how these techniques work and how the brain responds to neuromodulation. More sophisticated stimulation regimens and parameters should be developed to dynamically stimulate various regions at different frequencies and intensities, physiologically tailored to the patient's brain state in an attempt to maximize efficacy. PMID- 22494274 TI - When solving 22-7 is much more difficult than 99-12. AB - We describe the case of a 69-year-old professor of mathematics (GV) who was examined 2 years after left-hemispheric capsular-thalamic haemorrhage. GV showed disproportionate impairment in subtractions requiring borrowing (22 - 7). For large subtraction problems without borrowing (99 - 12) performance was almost flawless. Subtractions with borrowing mostly relied on inadequate attempts to invert subtractions into the corresponding additions (22 - 7 = x as 7 + x = 22). The hypothesis is advanced that difficulty in the inhibitory components of attention tasks (Stroop test, go-no-go task) might be the responsible factor of his calculation impairment. A deficit in subtractions with borrowing might be related to left-hemispheric damage involving thalamo-cortical connections. PMID- 22494275 TI - Slow magnetic relaxation induced by a large transverse zero-field splitting in a Mn(II)Re(IV)(CN)2 single-chain magnet. AB - The model compounds (NBu(4))(2)[ReCl(4)(CN)(2)] (1), (DMF)(4)ZnReCl(4)(CN)(2) (2), and [(PY5Me(2))(2)Mn(2)ReCl(4)(CN)(2)](PF(6))(2) (3) have been synthesized to probe the origin of the magnetic anisotropy barrier in the one-dimensional coordination solid (DMF)(4)MnReCl(4)(CN)(2) (4). High-field electron paramagnetic resonance spectroscopy reveals the presence of an easy-plane anisotropy (D > 0) with a significant transverse component, E, in compounds 1-3. These findings indicate that the onset of one-dimensional spin correlations within the chain compound 4 leads to a suppression of quantum tunneling of the magnetization within the easy plane, resulting in magnetic bistability and slow relaxation behavior. Within this picture, it is the transverse E term associated with the Re(IV) centers that determines the easy axis and the anisotropy energy scale associated with the relaxation barrier. The results demonstrate for the first time that slow magnetic relaxation can be achieved through optimization of the transverse anisotropy associated with magnetic ions that possess easy-plane anisotropy, thus providing a new direction in the design of single-molecule and single-chain magnets. PMID- 22494276 TI - Left atrial dissection after left ventricular aneurysm repair. AB - Left atrial (LA) dissection is an uncommon entity that occurs most often after mitral valve surgery. We present a case of a 52-year-old man who developed an LA dissection after repair of a postinfarction left ventricular (LV) aneurysm. Transesophageal echocardiography was used to establish the diagnosis of an LA dissection that almost completely occluded the LA, limiting LV filling and causing hemodynamic instability. PMID- 22494277 TI - Effects of long-term feeding of chitosan on postprandial lipid responses and lipid metabolism in a high-sucrose-diet-impaired glucose-tolerant rat model. AB - This study was designed to investigate the effects of long-term feeding of chitosan on postprandial lipid response and lipid metabolism in a high-sucrose (HS)-diet-impaired glucose-tolerant rat model. As the results, HS-diet-fed rats supplemented with 5 and 7% chitosan in diets for 9 weeks had lower postprandial plasma total cholesterol (TC) levels, but 7% chitosan in the diet had higher postprandial plasma triglyceride (TG) and TG-rich lipoprotein TG levels. Supplementation of chitosan significantly decreased the postprandial ratio of apolipoprotein B (apoB)48/apoB100 in TG-rich lipoprotein fractions of HS-diet-fed rats. Long-term supplementation of 5 and 7% chitosan in diets for 16 weeks had lower plasma TC, low-density lipoprotein cholesterol (LDL-C) + very low density lipoprotein cholesterol (VLDL-C), TC/high-density lipoprotein (HDL-C) ratio, leptin, and tumor necrosis factor-alpha (TNF-alpha) levels in HS-diet-fed rats. Moreover, it was noticed that the VLDL receptor (VLDLR) protein expression in skeletal muscles of HS-diet-fed rats was significantly decreased, which could be significantly reversed by supplementation of 5 and 7% chitosan. Rats supplemented with 7% chitosan in the diet significantly elevated the lipolysis rate and decreased the accumulation of TG in epididymal fat pads of HS-diet-fed rats. The plasma angiopoietin-like 4 (ANGPTL4) protein expression was not affected in HS diet-fed rats, but it was significantly increased in 7% chitosan-supplemented HS diet-fed rats. Taken together, these results indicate that supplementation of chitosan in the diet can improve the impairment of lipid metabolism in a HS-diet fed rat model, but long-term high-dose chitosan feeding may enhance postprandial plasma TG and TG-rich lipoprotein TG levels in HS-diet-fed rats through an ANGPTL4-regulated pathway. PMID- 22494278 TI - Formation of GM1 ganglioside clusters on the lipid membrane containing sphingomyeline and cholesterol. AB - GM1 gangliosides form a microdomain with sphingomyeline (SM) and cholesterol (Chol) and are deeply involved in the aggregation of amyloid beta (Abeta) peptides on neural membranes. We performed molecular dynamics simulations on two kinds of lipid bilayers containing GM1 ganglioside: GM1/SM/Chol and GM1/POPC. Both 10 and 100 ns simulations and another set of 10 ns simulations with different initial lipid arrangement essentially showed the same computational results. GM1 molecules in the GM1/SM/Chol membrane were condensed, whereas those in GM1/POPC membrane scattered. That is, the formation of GM1 cluster was observed only on the GM1/SM/Chol mixed membrane. There appeared numerous hydrogen bonds among glycan portions of the GM1 clusters due to the condensation. A comparison in distribution of lipid molecules between the two kinds of membranes suggested that cholesterol had important roles to prevent the membrane from interdigitation and to stabilize other lipids for interacting with each other. This property of cholesterol promotes the formation of GM1 clusters. PMID- 22494285 TI - The medical director's role in improving outcomes: a nursing perspective. PMID- 22494286 TI - Revealing correlation of valence state with nanoporous structure in cobalt catalyst nanoparticles by in situ environmental TEM. AB - Simultaneously probing the electronic structure and morphology of materials at the nanometer or atomic scale while a chemical reaction proceeds is significant for understanding the underlying reaction mechanisms and optimizing a materials design. This is especially important in the study of nanoparticle catalysts, yet such experiments have rarely been achieved. Utilizing an environmental transmission electron microscope equipped with a differentially pumped gas cell, we are able to conduct nanoscopic imaging and electron energy loss spectroscopy in situ for cobalt catalysts under reaction conditions. Studies reveal quantitative correlation of the cobalt valence states with the particles' nanoporous structures. The in situ experiments were performed on nanoporous cobalt particles coated with silica, while a 15 mTorr hydrogen environment was maintained at various temperatures (300-600 degrees C). When the nanoporous particles were reduced, the valence state changed from cobalt oxide to metallic cobalt and concurrent structural coarsening was observed. In situ mapping of the valence state and the corresponding nanoporous structures allows quantitative analysis necessary for understanding and improving the mass activity and lifetime of cobalt-based catalysts, for example, for Fischer-Tropsch synthesis that converts carbon monoxide and hydrogen into fuels, and uncovering the catalyst optimization mechanisms. PMID- 22494287 TI - The limits of life. PMID- 22494288 TI - New-onset hypothyroidism in a 102-year-old assisted living resident. PMID- 22494289 TI - Solitary nail dystrophy in an elderly adult: what lies beneath? PMID- 22494290 TI - Relationship between sleep apnea and respiratory infections in bedridden elderly individuals on tube feeding. PMID- 22494291 TI - Serum fibroblast growth factor 21 is associated with renal function and chronic kidney disease in community-dwelling adults. PMID- 22494292 TI - Cognitive effects of vitamin D supplementation in older outpatients visiting a memory clinic: a pre-post study. PMID- 22494293 TI - Outcome of surgical treatment for complicated humeral shaft fractures in elderly adults with osteoporosis. PMID- 22494294 TI - Determinants of quality of life in older adults after lower limb amputation and rehabilitation in skilled nursing facilities. PMID- 22494295 TI - Comparison of a hospital-wide antibiogram with that of an associated long-term care facility. PMID- 22494296 TI - Social determinants of frailty in elderly Mexican community-dwelling adults. PMID- 22494297 TI - Association between geriatric function and subjective economy in elderly adults living in a rural community in Japan. PMID- 22494298 TI - Outcomes of emergency reduction of tube feeding in hospitalized elderly adults during the aftermath of the Great East Japan Earthquake. PMID- 22494299 TI - Caution when prescribing cholinesterase inhibitors. PMID- 22494300 TI - Are the antipsychotic medications truly dangerous? The role of the geriatrician. PMID- 22494303 TI - Framing the ultimatum game: gender differences and autonomic responses. AB - The present study aimed at investigating whether the way offers are framed in the Ultimatum Game (UG) affects behavioral and autonomic responses in men and women. The "I give you" and "I take" expressions were used as gain and loss frames, respectively. Skin conductance and heart rate were recorded as indices of autonomic activation in response to unfair, mid-value, and fair offers. Acceptance rates were higher in men than in women under the gain frame. Moreover, men showed higher acceptance rates under the gain than under the loss frame with mid-value offers, whereas women's choices were not affected by frame. On the physiological level, men produced differential autonomic response patterns during decision-making when offers were presented under gain and loss framing. The "I take" frame, by acting as a loss frame, elicited in men the characteristic defensive response pattern that is evoked by aversive stimulation, in which increases in skin conductance are coupled with increases in heart rate. On the other hand, the "I give you" frame, by acting as a gain frame, elicited in men increases in skin conductance associated with prevailing heart rate deceleratory responses, reflecting a state of enhanced attention and orienting. In contrast, women's autonomic reactivity was not affected by frame, consistent with behavioral results. Phasic changes in heart rate were crucial in revealing differential functional significance of skin conductance responses under different frames in men, thus questioning the assumption that this autonomic measure can be used as an index of negative emotional arousal in the UG. PMID- 22494304 TI - DREEM on, dentists! Students' perceptions of the educational environment in a German dental school as measured by the Dundee Ready Education Environment Measure. AB - OBJECTIVES: The educational climate in which future doctors are trained is an important aspect of medical education. In contrast to human medicine, it has been rather neglected in dental educational research. The aim of the study was to supplement this lack by applying and validating the Dundee Ready Education Environment Measure (DREEM) for the first time in a German-speaking sample of dental students. METHODS: All dental students at the Medical Faculty of Heinrich Heine-University Dusseldorf were asked to complete a German adaptation of the DREEM and the Dusseldorf Mission Statement Questionnaire (DMSQ) in a paper-pencil survey. Data from 205 participants were analysed. Psychometric validation included analysis of item homogeneity and discrimination, test reliability, criterion and construct validity (convergent, factorial). RESULTS: DREEM item parameters were satisfactory, reliability (alpha = 0.87) and convergent validity (r = 0.66 with DMSQ) were also high. Factor analyses, however, yielded dimensions which did not fully correspond to the original DREEM subscales. Overall perception of the educational environment was positive (DREEM total score = 122.95 +/- 15.52). Students in the clinical part of course rated the atmosphere more negatively, but their academic self-perception more positively than preclinical students. CONCLUSIONS: Showing satisfactory psychometric properties, DREEM proved suitable for assessing educational environments among dental students. Given the right circumstances, e.g., small and early clinically oriented classes, traditional curricula can generate positive environments. PMID- 22494305 TI - Appraisal of the Dundee Ready Educational Environment Measure in the New Zealand dental educational environment. AB - AIMS: To examine the reliability and validity of the Dundee Ready Educational Environment Measure (DREEM) amongst New Zealand students in the first professional year of the Bachelor of Dental Surgery (BDS) and Bachelor of Oral Health (BOH) programmes. METHOD: In 2009 and 2010, students' perceptions of the educational environment were evaluated using a modified version of the 50-item DREEM, completed on the first and last day of their first professional year. Individual DREEM items' strengths and weaknesses were identified. The difference or dissonance between students' expectations and actual experience was determined by subtracting the Actual DREEM score (for each item or subscale) from the Expected DREEM score. Effect-size statistics were calculated, and internal consistency was tested using Cronbach's alpha. RESULTS: Overall, 82% of 2009 and 2010 BDS and BOH students in their first professional year completed the Expected and Actual DREEM (N = 176). Both groups identified the 'overemphasis of factual learning' as an Expected and Actual aspect and 'memorising all I need to know' as an Actual aspect of the educational environment. Internal consistency was high for the overall DREEM and the BDS and BOH Expected DREEM (0.89 and 0.88, respectively) and excellent for both the BDS and BOH Actual DREEM (0.92 and 0.90, respectively). CONCLUSION: Overall, students entering the courses anticipated a number of strengths and weaknesses and those expectations were relatively similar in the different programmes (BDS and BOH). The DREEM showed excellent internal consistency for the overall scores, and that for the subscale scores was generally acceptable. The study confirms the DREEM's utility for the NZ dental education environment. PMID- 22494306 TI - Students' perception of the prognosis for a single-surface amalgam restoration. AB - The aim of the study was to assess the self-rated skill, clinical judgement and competency of final-year pre-doctoral dental students. The study was also designed to determine whether the students' estimated durability of their single surface restorations was determined by their confidence. Students were given a questionnaire and completed it anonymously. One hundred and ninety-six forms were returned from the 238 students (82% return rate). Complete analysis was possible on 169 questionnaires. The students' self-assessed skill and judgement were a significant factor in predicting how long they would tell a patient that their restoration would last. Those ranking themselves below average were more likely to state that their amalgam restorations would have a shorter life (odds increased by 2.82 for those ranking themselves lower than most others). There was a significant association between the students' self-assessed skill and judgement and their confidence in dealing with both the initial management of patients' medical emergencies (rho = 0.244, P = 0.001, n = 191) and their general confidence in dealing with medical emergencies (rho = 0.187, P = 0.01, n = 188). Given a conversational scenario with a patient, the treatment prognosis given by final-year pre-doctoral students for a single-surface amalgam restoration was dependent on their self-assessed competence, skill and judgement. PMID- 22494307 TI - The use of video-clips as a teaching aide. AB - INTRODUCTION: Video-clips of tooth preparations recorded with a digital head mounted camera replaced live demonstrations midway in a preclinical operative dentistry course. DVDs of the video-clips were made available to the students for home use. AIMS: The aim of this study was to determine whether the use of these video-clips had any impact on students' practical examination results and to analyse students' opinions of this new technology and the perceived impact on their learning. METHODS: A questionnaire was administered to all students (n = 26) who completed the course, asking their opinions on the video-clips. The results of student practical examinations before the introduction of the camera were compared with those after the video-clips were available and also to the examination outcomes of the previous year's students (ANOVA, P < 0.05). RESULTS: Twenty-one students completed the questionnaire. Sixteen students (76%) preferred the video-clips to the live demonstrations, and 12 students (57%) made and reviewed the DVDs at home. They expressed a preference for the videos to be made available online or as podcasts. Twelve students (57%) felt that one-to-one supervision was more effective developing their competence in tooth preparations when compared to their viewing of the video-clips. There were no statistically significant differences between the practical examination results. CONCLUSION: In this group of students, video-clips were the preferred method of demonstration of tooth preparations in the preclinical environment. However, students perceived their learning to be facilitated more by one-to-one supervision. The students preferred to have the video-clips made available to them online instead of in the form of a DVD. The introduction of this educational aide did not make a difference in practical examination results. PMID- 22494308 TI - Restructuring an undergraduate dental curriculum to global standards--a case study in an Indian dental school. AB - Globalisation has affected all aspects of life and dentistry is no exception. In the context of today's dentist being a global citizen, undergraduate training in dentistry is set to ensure converging standards so that international recognition of dental qualifications can move forward. The decision of the Dental Council of India to expand the undergraduate dental program to five years provides an opportunity to be part of the endeavor of the Global Dental Congress to achieve converging standards which was initially for the European Union, and now spreading out globally. Economic emergence in Indian subcontinent has resulted in growing oral health care needs both in quality and quantity. To address this issue, the graduating dentist needs to be trained following a competency based curricular model. Access to Internet facilitated the goal of achieving converging standards of dental schools to be feasible because of the instant communication and capacity to share information about training strategies via technology across the globe. Upgrading the undergraduate training to global standards by dental schools in India could be a wise and strategic move both for attracting students to study in India, as well as retaining the graduates after their training. The following is a case study of an Indian dental school set to restructure the undergraduate curriculum to global standards using the 8 steps of Kotter's transformational change. Change in curriculum and the subsequent accreditation of the school in global platform not only attracts prospective students but also results in producing competent dentists. Dental education provided by the institution can result in quality assurance, benchmarking the assessment system to achieve international recognition. This paper highlights the need and importance of facilitation of international convergence with long term aspirations for mutual recognition of international degrees. PMID- 22494309 TI - Academic environment in a newly established dental school with an enquiry-based curriculum: perceptions of students from the inaugural cohorts. AB - INTRODUCTION: Established in 2007, Peninsula Dental School offers a highly innovative, enquiry-based, student-led, patient-centred curriculum. It is one of the first dental schools in UK to be based exclusively in a primary care setting. This study was carried out to evaluate the academic environment at Peninsula Dental School and to identify differences between expectations of new entrants and perceptions of senior cohorts. METHODS: This was a cross-sectional survey utilising an online questionnaire based on Dundee Ready Educational Environment Measure (DREEM). The subjects were 234 dental students from all years in this enquiry-based Bachelor of Dental Surgery programme. RESULTS: The response rate to the questionnaire was 56.42% with an equal gender distribution of the participants. The overall mean DREEM score of the four cohorts was 143.58 (SD +/- 20.84), and the mean score for individual items was 2.87 (SD +/- 0.41). The reliability of the DREEM data as a whole was strong (alpha = 0.93). The difference in questionnaire means for the new entrants and the senior cohorts was not significant (P > 0.05). The ANOVA results showed that there were no significant effects of age, gender or ethnicity on the mean DREEM scores. The MANOVA results showed a significant effect of ethnicity with regard to perceptions of teachers and atmosphere. CONCLUSIONS: An enquiry-based, student centred curriculum at the Peninsula Dental School provides a positive academic environment for the students. PMID- 22494310 TI - Doing qualitative research in dentistry and dental education. AB - The purpose of this paper is to assist dental researchers to develop their expertise in qualitative research. It sketches the key characteristics of qualitative research; summarises theoretical perspectives; outlines the core skills of qualitative data collection and the procedures which underlie three methods of qualitative research: interviewing, focus groups and concept maps. The paper offers some guidance on writing qualitative research and provides examples of qualitative research drawn from dentistry and dental education. PMID- 22494312 TI - Human technologies in rehabilitation: 'Who' and 'How' we are with our clients. AB - PURPOSE: It is often observed that different rehabilitation practitioners carrying out the same intervention can have a quite different impact on outcome. The relationship or connection between the practitioner and patient, referred to here as the therapeutic alliance (TA), is receiving growing attention as potentially contributing to the disparate response to treatment observed. In this paper, we discuss what we currently know about the TA in rehabilitation and its impact on engagement (and what do we not know) and consider the ramifications of not knowing. KEY MESSAGES: The TA is increasingly identified as an important determinant of engagement in, and health outcome following, rehabilitation. However, research identifying its core components is limited, with very little exploring howpractitioners might develop a more positive TA with patients. Further, what we do know/understand is limited by inadequate measurement tools. Research aiming to better understand the key ingredients of the TA that contribute to outcome and its role in rehabilitation is urgently required. CONCLUSIONS: Arguably, if we fail to advance knowledge in this field and seek answers to some of the questions we have raised, we may fail to tap into the true potential of the TA as a covariate of rehabilitation outcome. PMID- 22494313 TI - A self-immolative spacer that enables tunable controlled release of phenols under neutral conditions. AB - A current challenge in the area of responsive materials is the design of reagents and polymers that provide controlled release of phenols in environments that are less polar than water. In these contexts, a molecular strategy that enables release of nearly any phenol with predictable and tunable rates and without complication from background hydrolysis would substantially increase the precision with which materials can be designed to respond to a particular signal. This Article addresses this problem at the fundamental level by describing the design, synthesis, and physical-organic characterization of two small molecule self-immolative spacers that are capable of releasing phenols in organic and mixed organic-aqueous solutions. The rate of release from these small molecule model systems is predictable and tunable, such that nearly any type of phenol, regardless of pK(a) value, can be released in neutral solutions without complications from nonspecific background release due to hydrolysis. Furthermore, the release properties of the spacers can be predicted from bond length and conformation data (obtained from crystal structures). On the basis of these results, it should now be possible to incorporate these design elements into materials to enable precise response properties in environments that are not 100% aqueous. PMID- 22494314 TI - A new "turn-on" naphthalenedimide-based chemosensor for mercury ions with high selectivity: successful utilization of the mechanism of twisted intramolecular charge transfer, near-IR fluorescence, and cell images. AB - For the first time, a new near-IR "turn-on" fluorescent chemosensor with high selectivity for Hg(2+) ions was designed according to the twisted intramolecular charge transfer (TICT) mechanism. The selective fluorescence enhancement effect can be optimized by modulating the solvent systems. And this naphthalenedimide based sensor with long wavelength absorption and emission can be used to image intracellular Hg(2+) ions in living Hela cells. PMID- 22494315 TI - Spinal cord stimulation in pregnancy: a literature review. AB - OBJECTIVE: Currently, the use of spinal cord stimulation (SCS) therapy is not recommended in pregnancy because the effects of SCS on the pregnancy and developing fetus are unknown. However, many SCS recipients are women of childbearing age who may later become pregnant. The purpose of the present report is to review and summarize the existing literature on the use of SCS therapy during the prenatal period. METHODS: We first present the case of a 38-year-old woman from our center who became pregnant after receiving an SCS implantation. We then provide a synopsis of previous reports that were identified in a literature search. We highlight the key findings from these cases as they relate to the course of pregnancy, fetal development, labor and delivery management, fertility, and technical complications. RESULTS: In our literature review, we identified 12 cases of pregnancy in 8 women. To these we add the present case. CONCLUSIONS: Women of childbearing age who are candidates for SCS implantation should be tested for pregnancy prior to implantation surgery. They also should be informed about the limited state of our scientific knowledge regarding the impact of this technology on reproductive health. For patients already implanted with SCS, decisions about ongoing use in the event of pregnancy should be made on an individual basis after a careful consideration of potential risks and benefits. PMID- 22494316 TI - Schizophrenia-like psychosis associated with right lacunar thalamic infarct. AB - Thalamic dysfunction has been associated with schizophrenia and other psychotic disorders. We describe an adult patient with a lacunar infarct in the posterior region of the right thalamus exhibiting a paranoid schizophrenia-like psychosis as the only clinical manifestation. Neuropsychological assessment showed alterations in visuospatial memory and executive functions at follow up. This case highlights the role of information processing by the thalamus in the development of delusions. We suggest that dysfunction of the right mediodorsal and pulvinar thalamic nuclei disrupts both thalamic sensory processing and thalamo-prefrontal circuits mediating belief evaluation, leading to delusional beliefs. PMID- 22494317 TI - Effect of wheat-based dried distillers' grains with solubles inclusion on barley based feed chemical profile, energy values, rumen degradation kinetics, and protein supply. AB - The objectives of this study were to determine the effect of replacing the barley grain portion of the diet by wheat-based dried distillers' grains with solubles (wDDGS) at graded levels on feeding value for beef cattle. Two cultivars of barley were mixed with two sources of wDDGS in ratios of 100:0, 75:25, 50:50, and 25:75% (weight DM basis; denoted B0, B25, B50, and B75, respectively). This study revealed that increasing wDDGS inclusion level increased most of the nutritional composition linearly except for starch, which linearly decreased (from 609 to 320 g/kg of DM). Soluble, slowly degradable, and undegradable Cornel Net Carbohydrate and Protein System (CNCPS) protein and carbohydrate fractions linearly increased with increasing wDDGS inclusion level, whereas their rapidly and intermediately degradable fractions decreased. With increasing wDDGS inclusion, the rumen degradation rate of all measured parameters decreased linearly, the extent of degradability of organic matter was not affected, and the extent of CP degradability (g/kg DM) as well as the predicted protein supply in the small intestine and degraded protein balance in the rumen was increased. The inclusion of wDDGS in barley-based diets up to 50% did not alter energy values of the diet. Furthermore, optimum N to energy balance of the feed mixture for microbial growth in the rumen was reached by replacing 25% of barley by wDDGS. Thus, the nutritive value of the barley-based diets is manipulated by including wDDGS, which can be used to overcome the shortcomings of barley-dominated diets for beef cattle. PMID- 22494318 TI - What really drives chemical reactions on contact charged surfaces? AB - Although it is known that contact-electrified polymers can drive chemical reactions, the origin of this phenomenon remains poorly understood. To date, it has been accepted that this effect is due to excess electrons developed on negatively charged surfaces and to the subsequent transfer of these electrons to the reactants in solution. The present study demonstrates that this view is incorrect and, in reality, the reactions are driven by mechanoradicals created during polymer-polymer contact. PMID- 22494319 TI - Electronic transport with dielectric confinement in degenerate InN nanowires. AB - In this Letter, we present the size effects on charge conduction in InN nanowires by comprehensive transport studies supported by theoretical analysis. A consistent model for highly degenerate narrow gap semiconductor nanowires is developed. In contrast to common knowledge of InN, there is no evidence of an enhanced surface conduction, however, high intrinsic doping exists. Furthermore, the room-temperature resistivity exhibits a strong increase when the lateral size becomes smaller than 80 nm and the temperature dependence changes from metallic to semiconductor-like. This effect is modeled by donor deactivation due to dielectric confinement, yielding a shift of the donor band to higher ionization energies as the size shrinks. PMID- 22494320 TI - Mechanistic insight into the photosensory versatility of DXCF cyanobacteriochromes. AB - Cyanobacteriochromes (CBCRs) are photosensory proteins related to the red/far-red phytochromes. Like phytochromes, CBCRs use linear tetrapyrrole (bilin) chromophores covalently attached via a thioether linkage to a conserved Cys residue also found in plant and cyanobacterial phytochromes. Unlike almost all phytochromes, CBCRs require only an isolated GAF domain to undergo efficient, reversible photocycles that are responsible for their broad light sensing range, spanning the visible to the near ultraviolet (UV). Sensing of blue, violet, and near-UV light by CBCRs requires another Cys residue proposed to form a second linkage to the bilin precursor. Light triggers 15,16-double bond isomerization as in phytochromes. After photoisomerization, elimination of the second linkage frequently occurs, thus yielding a large red shift of the stable photoproducts. Here we examine this process for representative DXCF CBCRs, a large subfamily named for the conserved Asp-Xaa-Cys-Phe motif that contains their second Cys residue. DXCF CBCRs with such dual-Cys photocycles yield a wide diversity of photoproducts absorbing teal, green, or orange light. Using a combination of CD spectroscopy, chemical modification, and bilin substitution experiments with recombinant CBCRs from Thermosynechococcus elongatus and Nostoc punctiforme expressed in Escherichia coli, we establish that second-linkage elimination is required for all of these photocycles. We also identify deconjugation of the D ring as the mechanism for specific detection of teal light, at approximately 500 nm. Our studies thus provide new mechanistic insight into the photosensory versatility of this important family of photosensory proteins. PMID- 22494321 TI - Ion binding sites and their representations by reduced models. AB - The binding of small metal ions to complex macromolecular structures is typically dominated by strong local interactions of the ion with its nearest ligands. Progress in understanding the molecular determinants of ion selectivity can often be achieved by considering simplified reduced models comprised of only the most important ion-coordinating ligands. Although the main ingredients underlying simplified reduced models are intuitively clear, a formal statistical mechanical treatment is nonetheless necessary in order to draw meaningful conclusions about complex macromolecular systems. By construction, reduced models only treat the ion and the nearest coordinating ligands explicitly. The influence of the missing atoms from the protein or the solvent is incorporated indirectly. Quasi-chemical theory offers one example of how to carry out such a separation in the case of ion solvation in bulk liquids, and in several ways, a statistical mechanical formulation of reduced binding site models for macromolecules is expected to follow a similar route. However, there are also important differences when the ion-coordinating moieties are not solvent molecules from a bulk phase but are molecular ligands covalently bonded to a macromolecular structure. Here, a statistical mechanical formulation of reduced binding site models is elaborated to address these issues. The formulation provides a useful framework to construct reduced binding site models, and define the average effect from the surroundings on the ion and the nearest coordinating ligands. PMID- 22494322 TI - Role of free radicals and antioxidant defences in oral cavity-related pathologies. AB - Free radicals play a key role in the development of several pathological conditions. Therefore, several methods have been developed to measure oxidative stress from bodily fluids including blood, urine and, more recently, saliva. Free radical and antioxidant defences within the oral cavity may play a key role in odontostomatological pathologies. This review provides an update of the literature concerning the association of oxidative stress with pathological conditions associated with the oral cavity. It focuses on the diagnostic and therapeutic importance of the tests based on saliva specimens in a preventive perspective. PMID- 22494323 TI - Enterococcus gallinarum causing native valve endocarditis and aorto-atrial fistula: a case report and literature review. PMID- 22494324 TI - False positives observed on the Seratec(r) PSA SemiQuant Cassette Test with condom lubricants. AB - In the course of the validation of a new component of the prostate-specific antigen (PSA) SemiQuant Cassette Test marketed by Seratec((r)) , a false-positive reaction was observed when testing samples collected from the surface of unused, lubricated condoms. A variety of personal lubricants and condoms were tested to determine the frequency of the false positive, as well as its potential source. Samples were extracted in both water and the manufacturer-provided buffer, and the test was performed according to the manufacturer's suggested protocol. The false positive was observed intermittently, but occurred consistently with samples containing nonoxynol-9, a strong detergent utilized as a spermicide. The reaction may be attributable to the combination of latex and nonoxynol-9. Because of the unreliability of the test to confirm the presence of PSA in samples collected from condoms, the PSA cassette is an unsuitable method for confirming the presence of seminal fluid in condoms. PMID- 22494325 TI - The effect of metformin on mean platelet volume in diabetic patients. AB - Diabetes mellitus (DM) is an independent risk factor for cardiovascular diseases. Metformin, the most commonly used antidiabetic, also has an antiatherogenic effect. Mean platelet volume (MPV) is increased in patients with high thrombogenic activation and also at risk for atherosclerosis. The purpose of this study was to examine the effects of metformin on MPV values in newly diagnosed type II DM patients on metformin monotherapy. In this study, 60 newly diagnosed type II DM patients (45 females, 15 males), who had applied to the Kocaeli University School of Medicine Endocrinology outpatient clinic, and 47 healthy individuals (35 females, 12 males) were included. The two groups have similarity for age, sex and body mass index. The patients with additional disease, nephropathy, smoking and using drugs that may affect the MPV were excluded. At baseline and 6 months after metformin treatment, patient demographics and laboratory values were compared. MPV was higher among type II DM patients than the control group (p < 0.001). After 6 months of metformin treatment, MPV values were significantly decreased (p < 0.001). HbA1c and mean platelet mass were also significantly decreased (p = 0.022 and 0.001, respectively). There was no correlation between MPV and HbA1c values (r = -0.13, p = 0.926). Metformin, which has been shown to exhibit antiatherogenic effect through positive effects on cholesterol levels, inflammatory markers and vascular adhesion molecules, decreased MPV values that appear to play a crucial role at the beginning of atherosclerosis development. We conclude that our result may contribute to the explanation for antiatherogenic effect of metformin. PMID- 22494326 TI - Metabolomics and first-trimester prediction of early-onset preeclampsia. AB - OBJECTIVE: To evaluate the use of metabolomics for the first-trimester detection of maternal metabolic dysfunction and prediction of subsequent development of early-onset preeclampsia (PE). STUDY DESIGN: This was a case-control study of maternal plasma samples collected at 11-13 weeks' gestation from 30 women who had subsequently developed PE requiring delivery before 34 weeks and 60 unaffected controls. Nuclear magnetic Resonance (NMR) spectroscopy was used to identify and quantify metabolomic changes in cases versus controls. Both genetic computing and standard statistical analyses were performed to predict the development of PE from the metabolite concentrations alone as well as the combination of metabolite concentrations with maternal characteristics and first-trimester uterine artery Doppler pulsatility index (PI). RESULTS: Significant differences between cases and controls were found for 20 metabolites. A combination of four of these metabolites (citrate, glycerol, hydroxyisovalerate, and methionine) appeared highly predictive of PE with an estimated detection rate of 75.9%, at a false positive rate (FPR) of 4.9%. The predictive performance was improved by the addition of uterine artery Doppler PI and fetal crown-rump length (CRL) and with an estimated detection rate of 82.6%, at a FPR of 1.6%. CONCLUSION: A profound change in the first-trimester metabolite profile was noted in women who had subsequently developed early-onset PE. Preliminary algorithms appeared highly sensitive for first trimester prediction of early onset PE. PMID- 22494330 TI - Characterization of carbon nanotube fiber compressive properties using tensile recoil measurement. AB - The tensile properties of carbon nanotube (CNT) fibers have been widely studied. However, the knowledge of their compressive properties is still lacking. In this work, the compressive properties of both pure CNT fibers and epoxy infiltrated CNT fibers were studied using the tensile recoil measurement. The compressive strengths were obtained as 416 and 573 MPa for pure CNT fibers and CNT-epoxy composite fibers, respectively. In addition, microscopic analysis of the fiber surface morphologies revealed that the principal recoil compressive failure mode of pure CNT fiber was kinking, while the CNT-epoxy composite fibers exhibited a failure mode in bending with combined tensile and compressive failure morphologies. The effect of resin infiltration on CNT fiber compressive properties, including the compressive strength and the deformation mode, is discussed. This work expands the knowledge base of the overall mechanical properties of CNT fibers, which are essential for their application in multifunctional composites. PMID- 22494331 TI - Behcet's Disease (Syndrome) with Myalgia and Its Response to 3% Amino Acids and 3% Glycerin. PMID- 22494333 TI - Copper(II)-catalyzed silyl conjugate addition to alpha,beta-unsaturated conjugated compounds: Bronsted base-assisted activation of Si-B bond in water. AB - A mild method for the installation of the dimethylphenylsilyl group on the beta carbon of electron-deficient olefins is reported. In the presence of a catalytic amount of copper(II) (1 mol %) and amine base (5 mol %) at rt, the transformation proceeds efficiently in water within 1.5-5 h to afford beta-silylated products in yields of up to 90%. PMID- 22494332 TI - Polyanalgesic Consensus Conference--2012: consensus on diagnosis, detection, and treatment of catheter-tip granulomas (inflammatory masses). AB - INTRODUCTION: Continuous intrathecal infusion of drugs to treat chronic pain and spasticity has become a standard part of the algorithm of care. The use of opioids has been associated with noninfectious inflammatory masses at the tip of the intrathecal catheter, which can result in neurologic complications. METHODS: The Polyanalgesic Consensus Conference is a meeting of a group of well-published and experienced practitioners; the purpose of the meeting is to update the standard of care for intrathecal therapies to reflect current knowledge gleaned from literature and clinical experience. An exhaustive literature search was performed, and information from this search was provided to panel members. Analysis of the published literature was coupled with the clinical experience of panel participants to form recommendations regarding intrathecal inflammatory masses or granulomas. RESULTS: The panel has made recommendations for the prevention, diagnosis, and management of intrathecal granulomas. CONCLUSION: The use of chronic infusions of intrathecal opioids is associated with the formation of inflammatory masses at the intrathecal catheter tip in a small minority of treated patients. Nonetheless, the appearance of these space-occupying lesions can lead to devastating neurologic sequelae. The prevention, early detection, and successful treatment of intraspinal granulomas are important considerations when offering intrathecal drug therapy to patients with chronic intractable pain. PMID- 22494334 TI - Microwave-assisted one-pot synthesis of isoquinolines, furopyridines, and thienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminal acetylenes and ammonium acetate. AB - A palladium-catalyzed microwave-assisted one-pot reaction for the synthesis of isoquinolines is developed. The reaction is carried out by sequential coupling imination-annulation reactions of ortho-bromoarylaldehydes and terminal alkynes with ammonium acetate, and a variety of substituted isoquinolines, furopyridines, and thienopyridines is prepared in moderate to excellent yields (up to 86%). PMID- 22494335 TI - The perceived benefits and barriers of sport in spinal cord injured individuals: a qualitative study. AB - PURPOSE: This study explores what individuals with spinal cord injury (SCI) perceive to be the benefits of becoming involved in organized sport and identifies the barriers to participation. METHOD: Seven SCI athletes from a variety of sports were interviewed in a semi-structured format. RESULTS: 20 benefits and 18 individual barriers were identified and categorized into sub themes: benefits were categorized into sub-themes of "socialization," "self worth," "physical challenge" and "emotional." Barriers were grouped into "organization," "medical," "emotional," "a lack of available information" and "views held by others." CONCLUSION: A variety of benefits from participating in sport were identified, including socialization, the acquisition of knowledge from others, the development of greater awareness of health and well-being issues, weight maintenance, functional development and independence. Barriers identified included financial constraints, the lack of information regarding medical complications and sporting opportunities, and the need for able-bodied support. The findings have implications for the rehabilitation of individuals with SCI. PMID- 22494336 TI - Formation of metallic glass nanowires by gas atomization. AB - Gas atomization which is a conventional technique in powder metallurgy is adapted for the formation of metallic glass nanowires. This approach is able to produce a large quantity of nanowires with diameters in the 50-2000 nm range. Experiments performed with different conditions and alloy compositions confirm that the key mechanism of the nanowire formation is the spinnability which increases exponentially when the melt stream is supercooled from the liquid state. PMID- 22494337 TI - Implant-guided Volumetric Analysis of Edentulous Maxillary Bone With Cone Beam CT Scan. Maxillary Sinus Pneumatization Classification. AB - Abstract Purpose: The primary goal of this anatomic study was to measure the average bone volume of the edentulous maxilla with a CBCT scan and determine its suitability for implant treatment without additional bone grafting. The secondary goal of the study was to estimate the degree of sinus pneumatization in reviewed CBCT scans, assess the maxillary sinus-to-maxillary bone inter-relationship in edentulism, and attempt to classify maxillary sinuses based on the degree of their pneumatization.Patients and Methods: This retrospective radiographic quantitative study consisted of the analysis of CBCT scans of randomly selected 30 maxillary edentulous patients who presented in 2008-2010 to the University of the Pacific, School of Dentistry for evaluation and treatment of their edentulism. A volume of edentulous maxillary bone mesial to the maxillary sinuses (inter-sinal region) that can be used for a full-arch implant treatment was evaluated based on specifically selected and clinically relevant measurement criteria.Results: There were 30 CBCT scans of maxillary edentulous patients reviewed (9 males, 21 females) with a mean age of 67.3 years old (range from 41 to 92 years old). The total mean maxillary bone volume (MMBV) suitable for implantation was 4,408.1 mm3 and ranged from 1,489.7 to 7,263.1 mm3.Conclusion: Although many other clinical criteria are important (bone quality, alveolar crest anatomy, etc.), the results of this CBCT radiographic study indicate that in many maxillary edentulous cases the existing bone quantity (volume) can be sufficient for a full-arch maxillary implant treatment with at least 4 implants without the additional trauma or expense of bone grafts and sinus lifts. A variety of implant treatment options can be proposed based on maxillary bone availability and bone to sinus inter-relationship. It appears that with age and edentulism, the amount of available maxillary bone is steadily decreasing. PMID- 22494338 TI - Proteome profiling of seed storage proteins reveals the nutritional potential of Salicornia brachiata Roxb., an extreme halophyte. AB - Salicornia brachiata is an extreme halophyte that grows in salty marshes and is considered to be a potential alternative crop for seawater agriculture. Salicornia seeds are rich in protein, and its tender shoots are eaten as salad greens. Seed storage proteins were fractionated by sequential extraction using different solvents, including distilled water for albumins, NaCl (1.0 M) for globulins, NaOH (0.1 N) for glutelins, and ethanol (70% v/v) for prolamins. Globulins accounted for 54.75% of the total seed storage proteins followed by albumins (34.30%) and glutelins (8.70%). The fractionated proteins were characterized using 2D-diagonal SDS-PAGE and matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. The globulin fraction, composed of seven intermolecular disulfide-linked polypeptide pairs of molecular mass 63.5, 62.5, 54.7, 53.0, 43.2, 38.5, and 35.1 kDa, encompassed a basic and an acidic subunit. Two-dimensional gels revealed approximately 32 spots, with isoelectric points and molecular masses ranging from 4.93 to 11.6 and from ~5.2 to ~109.4 kDa, respectively. Protein spots were identified by MALDI-TOF MS peptide mass fingerprint analysis and further classified. Homology analysis demonstrated that 19% of the proteins were involved in metabolism, 16% were involved in signaling, and 15% were regulatory proteins. Peptide mass fingerprint analysis confirmed the presence of inter- and intramolecular disulfide linkages in the globulin fraction. Sulfur-rich proteins are of high nutritional value, and disulfides make S. brachiata a potential source of dietary supplementation. PMID- 22494340 TI - Physical components of soft-tissue ballistic wounding and their involvement in the generation of blood backspatter. AB - Gunshot backspatter comprises biological material expelled backward through bullet entry holes. Crime scene investigators analyze backspatter patterns to infer wounding circumstances. An understanding of the mechanism of backspatter generation, and the relationship between spatter patterns and bullet and tissue characteristics, would enhance the predictive value of such analysis. We examined soft-tissue ballistic wounding responses to determine the underlying components and how these might be relevant to the generation of backspatter. We identified five mechanistic components to ballistic wounding (elastic, viscous, crushing, cutting, and thermal), each related to mechanical disciplines (respectively, solid mechanics, fluid mechanics, fracture mechanics, rheology, and thermodynamics). We identified potential roles for these five components in backspatter formation and provide a scenario whereby a sequence of events incorporating these components could lead to backspatter generation and expulsion. This research provides a framework for the mathematical representation, and subsequent computational predictive modeling, of backspatter generation and pattern formation. PMID- 22494339 TI - Solution structure of a complex of the histidine autokinase CheA with its substrate CheY. AB - In the bacterial chemotaxis two-component signaling system, the histidine containing phosphotransfer domain (the "P1" domain) of CheA receives a phosphoryl group from the catalytic domain (P4) of CheA and transfers it to the cognate response regulator (RR) CheY, which is docked by the P2 domain of CheA. Phosphorylated CheY then diffuses into the cytoplasm and interacts with the FliM moiety of the flagellar motors, thereby modulating the direction of flagellar rotation. Structures of various histidine phosphotransfer domains (HPt) complexed with their cognate RR domains have been reported. Unlike the Escherichia coli chemotaxis system, however, these systems lack the additional domains dedicated to binding to the response regulators, and the interaction of an HPt domain with an RR domain in the presence of such a domain has not been examined on a structural basis. In this study, we used modern nuclear magnetic resonance techniques to construct a model for the interaction of the E. coli CheA P1 domain (HPt) and CheY (RR) in the presence of the CheY-binding domain, P2. Our results indicate that the presence of P2 may lead to a slightly different relative orientation of the HPt and RR domains versus those seen in such complex structures previously reported. PMID- 22494341 TI - Loss of DRAK2 signaling enhances allogeneic transplant survival by limiting effector and memory T cell responses. AB - Here, we demonstrate that loss of DRAK2 signaling significantly promotes the acceptance of allogeneic engraftment in two separate transplant models without promoting generalized immunosuppression. Drak2-/- T cells failed to reject allogeneic tumors, and were defective in rejecting Balb/C allogeneic skin grafts on C57BL6/J recipients. A significant fraction of alloreactive Drak2-/- T cells underwent apoptosis following activation, whereas enforced expression of Bcl-xL in Drak2-/- T cells restored allograft rejection. Formation of allogeneic memory was also greatly hampered in T cells lacking the Drak2 gene. Adoptive transfer of memory T cells from Drak2-/- mice failed to promote the rejection of allogeneic tumors, and such cells led to significantly delayed rejection of skin allografts in the Balb/C->C57BL/6J model. Costimulatory blockade by in vivo administration of Cytotoxic T-Lymphocyte Antigen 4 fusion protein (CTLA4-Ig) synergized with the DRAK2 deficiency and led to long-term allogeneic skin graft acceptance. Overall, these results demonstrate that DRAK2 plays an important role in primary and memory T cell responsiveness to allografts. Because previous studies have demonstrated that a loss of DRAK2 does not negatively impact antiviral immunity, the studies here underscore the potential utility of pharmacological blockade of DRAK2 to achieve transplant maintenance without the imposition of generalized immunosuppression. PMID- 22494343 TI - Review of invasive cervical cancers and uptake of disclosure of results: an audit of procedures and response. AB - OBJECTIVE: To audit the process and outcome of case reviews performed for invasive cervical cancers diagnosed between 2003 and 2007, and the timely disclosure of results to the respective patients. METHODS: Invasive cervical cancer reviews were performed on all cases of cervical cancer diagnosed between 2003 and 2007. Following the review, women were classified into two categories: a group who developed invasive cancer despite adherence to the screening programme or in whom a management or diagnostic decision was determined to have been a principal factor in the development of their disease (Group A), and a second group who either had never undergone a cervical smear or had been established defaulters from the screening programme (Group B). RESULTS: Ninety-seven of the 98 cases of invasive cervical cancer diagnosed in the 4-year study period were reviewed. Sixty of the 61 women in Group A were sent an invitation to discuss the results of their case review. Thirty-six (37%) were classified as Group B, and it was deemed neither appropriate nor possible to invite the patients for a review consultation. Of the women sent an invitation, only 24 (40%) chose to attend. CONCLUSION: A policy of selective invitation for the disclosure of invasive review results is feasible. Less than one-half of patients diagnosed with cervical cancer appear to want to know how they developed cervical cancer despite previously participating in a screening programme. PMID- 22494344 TI - The effect of explanation in simple binary decision tasks. AB - Many studies of explanation have focused on higher level tasks and on how explanations draw upon relevant prior knowledge, which then helps in understanding some event or observation. However, explanations may also affect performance in simple tasks even when they include no task-relevant information. In three experiments, we show that explanations adding no task-relevant information alter performance in a sequential binary decision task. Whereas people with no explanation for why two events occurred at different rates tended to predict each outcome in proportion to their probability of occurrence (to "probability match"), people with an explanation tended to predict the more likely event more often (to "overmatch," a better strategy). These results suggest a broader view of explanation, which includes a role in shaping simple tasks outside of higher level reasoning. PMID- 22494345 TI - Does time of day or physician experience affect outcome of acute ischemic stroke patients treated with thrombolysis? A study from Finland. AB - BACKGROUND: Maintaining a steady thrombolysis service for treatment of acute ischemic stroke 24 h/7 days is challenging. Diurnal and seasonal variability of stroke onset affects the clinical outcome of these patients. HYPOTHESIS: We state that a 24 h/7 days availability of stroke-trained physicians ameliorates weekend effects and other seasonal, weekday, or non-office-hour-related influences on outcome of ischemic stroke patients treated with intravenous thrombolysis. METHODS: All consecutive ischemic stroke patients treated with thrombolysis at the Helsinki University Central Hospital were prospectively registered (n = 1581). Patients with basilar artery occlusion (n = 154) were excluded. Door-to needle time, three-month clinical outcome as measured by the modified Rankin Scale dichotomized at 0 to 2 vs. 3 to 6, and symptomatic intracerebral hemorrhage were analyzed with logistic regression models adjusting for baseline variables. The treating physician was defined as experienced after 18 decisions made to give thrombolysis treatment. RESULTS: Door-to-needle time or clinical outcome did not differ with regard to time of day or season of presentation. Higher rates of symptomatic intracerebral hemorrhage occurred in spring (odds ratio 2.06, 95% confidence interval 1.03-4.11) and fall (odds ratio 2.08, 95% confidence interval 1.03-4.18). Physician experience reduced the door-to-needle time (odds ratio 0.40, 95% confidence interval 0.32-0.50) but was not associated with patient outcome (modified Rankin scale 3 to 6, odds ratio 1.22, 95% confidence interval 0.95-1.59) or symptomatic intracerebral hemorrhage (odds ratio 0.80, 95% confidence interval 0.51-1.27) rates. CONCLUSIONS: Thrombolytic therapy can be delivered at a steady service level at all times. With proper training, less experienced physicians can provide high quality thrombolysis, but experience translates into faster treatment. PMID- 22494347 TI - Percutaneous mechanical disc decompression using Dekompressor device: an appraisal of the current literature. AB - OBJECTIVES: The objective of this study was to determine if the available literature answers the following questions: does percutaneous disc decompression using Dekompressor device relieve radicular pain caused by a small disc herniation? Is the duration of response stable and clinically worthwhile? Is relief of pain corroborated by improvements in physical and social function? Does relief of pain result in reduction in the use of other health care? Is there a risk of serious side effects or complications? DESIGN/SETTINGS: The study was designed as a narrative review and description of the available evidence, drawn from the databases of PubMed, EMBASE, and the Cochrane Library. Innovatively, the concept of the "context of the patient" was introduced in the assessment. It required the assessors to consider the alternatives the patients and their treating practitioners faced. RESULTS: The literature search identified three nonrandomized clinical trials, and a single case series. All studies were reasonably rigorous in reporting relief of pain and the use of analgesics. Evidence with respect to physical functioning was scarce. Although investigators reported on the relief of pain, they lacked rigor when reporting associated outcome measures such as use of other health care and physical functioning. CONCLUSIONS: Unfortunately, the context of a patient with persistent radicular pain caused by a small disc herniation is the lack of good alternatives to Dekompressor procedure. The moral question is whether Dekompressor is any less valid an option than perpetual opioids or discectomy. This question would be much easier to answer if the literature on Dekompressor was more rigorous and more compelling in its evidence. PMID- 22494346 TI - The relationship of newborn adiposity to fetal growth outcome based on birth weight or the modified neonatal growth assessment score. AB - OBJECTIVES: (1) Develop reference ranges of neonatal adiposity using air displacement plethysmography. (2) Use new reference ranges for neonatal adiposity to compare two different methods of evaluating neonatal nutritional status. METHODS: Three hundred and twenty-four normal neonates (35-41 weeks post menstrual age) had body fat (%BF) and total fat mass (FM, g) measured using air displacement plethysmography shortly after delivery. Results were stratified for 92 of these neonates with corresponding fetal biometry using two methods for classifying nutritional status: (1) population-based weight percentiles; and (2) a modified neonatal growth assessment score (m(3)NGAS(51)). RESULTS: At the 50th percentile, %BF varied from 7.7% (35 weeks) to 11.8% (41 weeks), while the corresponding 50th percentiles for total FM were 186-436 g. Among the subset of 92 neonates, no significant differences in adiposity were found between small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA) groups using population-based weight standards. Classification of the same neonates using m(3)NGAS(51) showed significant differences in mean %BF between corresponding groups. CONCLUSIONS: Population based weight criteria for neonatal nutritional status can lead to misclassifications on the basis of adiposity. A neonatal growth assessment score, that considers the growth potential of several anatomic parameters, appears to more effectively classify under- and over-nourished newborns. PMID- 22494353 TI - Iron-catalyzed cyclopropanation with glycine ethyl ester hydrochloride in water. AB - An iron-catalyzed cyclopropanation reaction of styrenes in aqueous media is disclosed that employs glycine ethyl ester hydrochloride in a tandem diazotization/cyclopropanation reaction. The products are accessed in good yields and good diastereoselectivity using readily available and inexpensive starting materials. Moreover, a wide range of transition metals may be used under these conditions, thus opening new opportunities for efficient carbene-transfer reactions under user-friendly conditions. PMID- 22494354 TI - Aligned growth of gold nanorods in PMMA channels: parallel preparation of nanogaps. AB - We demonstrate alignment and positional control of gold nanorods grown in situ on substrates using a seed-mediated synthetic approach. Alignment control is obtained by directing the growth of spherical nanoparticle seeds into nanorods in well-defined poly(methyl methacrylate) nanochannels. Substrates with prepatterned metallic electrodes provide an additional handle for the position of the gold nanorods and yield nanometer-sized gaps between the electrode and nanorod. The presented approach is a novel demonstration of bottom-up device fabrication of multiple nanogap junctions on a single chip mediated viain situ growth of gold nanorods acting as nanoelectrodes. PMID- 22494355 TI - A copper-catalyzed Petasis reaction for the synthesis of tertiary amines and amino esters. AB - We have developed a copper-catalyzed process for the coupling of aldehydes, amines, and boronic acids. This allows greater reactivity with simple aryl boronic acids and allows coupling reactions to proceed that previously failed. Initial mechanistic studies support a process involving transmetalation from boron to copper. PMID- 22494356 TI - Asymmetric allylic alkylation of pyrroles and 4,7-dihydroindoles with alkene phosphine ligands. AB - A palladium-catalyzed highly enantioselective allylic alkylation of pyrroles and 4,7-dihydroindoles has been successfully developed with the use of chiral alkene phosphine hybrid ligands to furnish the desired products in high yields with excellent ee's. It is noteworthy that alkene-phosphine ligands are much more effective than some other types of chiral ligands in this catalytic system. PMID- 22494357 TI - Polyanalgesic Consensus Conference--2012: recommendations on trialing for intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. AB - INTRODUCTION: Trialing for intrathecal pump placement is an essential part of the decision-making process in placing a permanent device. In both the United States and the international community, the proper method for trialing is ill defined. METHODS: The Polyanalgesic Consensus Conference (PACC) is a group of well published experienced practitioners who meet to update the state of care for intrathecal therapies on the basis of current knowledge in the literature and clinical experience. Anexhaustive search is performed to create a base of information that the panel considers when making recommendations for best clinical practices. This literature, coupled with clinical experience, is the basis for recommendations and for identification of gaps in the base of knowledge regarding trialing for intrathecal pump placement. RESULTS: The panel has made recommendations for the proper methods of trialing for long-term intrathecal drug delivery. CONCLUSION: The use of intrathecal drug delivery is an important part of the treatment algorithm for moderate to severe chronic pain. It has become common practice to perform a temporary neuroaxial infusion before permanent device implantation. On the basis of current knowledge, the PACC has developed recommendations to improve care. The need to update these recommendations will be very important as new literature is published. PMID- 22494358 TI - Utilization of antenatal ultrasound scan and implications for caesarean section: a cross-sectional study in rural Eastern China. AB - BACKGROUND: Antenatal ultrasound scan is a widely accepted component of antenatal care. Studies have looked at the relationship between ultrasound scanning and caesarean section (CS) in certain groups of women in China. However, there are limited data on the utilization of antenatal ultrasound scanning in the general population, including its association with CS. The purpose of this study is to describe the utilization of antenatal ultrasound screening in rural Eastern China and to explore the association between antenatal ultrasound scan and uptake of CS. METHODS: Based on a cluster randomized sample, a total of 2326 women with childbirth participated in the study. A household survey was conducted to collect socio-economic information, obstetric history and utilization of maternal health services. RESULTS: Coverage of antenatal care was 96.8% (2251/2326). During antenatal care, 96.1% (2164/2251) women received ultrasound screening and the reported average number was 2.55. 46.8% women received at least 3 ultrasound scans and the maximum number reached 11. The CS rate was found to be 54.8% (1275/2326). After adjusting for socio-demographic and clinical variables, it showed a statistically significant association between antenatal ultrasound scans and uptake of CS by multivariate logistic regression model. High husband education level, high maternal age, having previous adverse pregnant outcome and pregnancy complications during the index pregnancy were also found to be risk factors of choosing a CS. CONCLUSIONS: A high use of antenatal ultrasound scan in rural Eastern China is found and is influenced by socio-demographic and clinical factors. Evidence-based guidelines for antenatal ultrasound scans need to be developed and disseminated to clinicians including physicians, nurses and sonographers. Guidance about the appropriate use of ultrasound scans should also be shared with women in order to discourage unreasonable expectations and demands. It is important to monitor the use of antenatal ultrasound scan as well as the indications for caesarean section in rural China. PMID- 22494359 TI - Dopamine transporter polymorphisms affect social approach-avoidance tendencies. AB - There is increasing interest in the role of striatal dopaminergic activity in social approach-avoidance motivation. The 9-repeat allele of the dopamine transporter (DAT) gene, associated with increased striatal dopamine levels, has been found to be related to increased sensitivity to reward. However, it remains unexplored whether this polymorphism influences automatic action tendencies in the social domain. We set out to test experimentally whether human carriers of the 9-repeat allele show increased approach-avoidance tendencies compared to non 9-repeat carriers. One hundred and one healthy adults, genotyped for the DAT gene, performed the social Approach-Avoidance Task, a reaction time task requiring participants to approach or avoid visually presented emotional (happy and angry) faces, by pulling a joystick towards them or pushing the joystick away from themselves, respectively. In accordance with expectations, 9-repeat carriers showed stronger approach-avoidance effects compared to non-9-repeat carriers. These results suggest a role for striatal dopaminergic polymorphisms in motivational responses to social-emotional cues. Our findings may be relevant in the selection of candidate genes in future studies involving social behavior. PMID- 22494360 TI - Basophils and antigen presentation: of mice and not men? PMID- 22494361 TI - Anaphylaxis to pork kidney is related to IgE antibodies specific for galactose alpha-1,3-galactose. AB - BACKGROUND: Carbohydrate-specific IgE antibodies present on nonprimate mammalian proteins were incriminated recently in delayed meat anaphylaxis. The aim of this study was to explore whether anaphylaxis to mammalian kidney is also associated with galactose-alpha-1,3-galactose (alphaGal)-specific IgE. METHODS: Fourteen patients with anaphylaxis to pork or beef kidney underwent prick tests to meat and kidney. Some patients also underwent skin tests to Erbitux((r)) (cetuximab). IgE antibodies to alphaGal, swine urine proteins, beef and pork meat, serum albumin proteins, cat, and rFel d 1 were measured by ImmunoCAP((r)). The alphaGal levels were estimated in meats and kidney by ELISA inhibition assay. Cross reactivity between alphaGal and pork kidney was studied with the ImmunoCAP((r)) inhibition assay. RESULTS: Among the 14 patients, 12 presented with anaphylactic shock. Reactions occurred within 2 h from exposure in 67% of patients. Associated risk factors were observed in 10 cases, and alcohol was the main cofactor. Three patients underwent an oral challenge to pork kidney, and anaphylaxis occurred after ingestion of small quantities (1-2 g). Prick tests to kidney were positive in 54% of patients. All tested patients showed positive skin tests to Erbitux((r)). All patients tested positive for IgE to alphaGal, with levels ranging from 0.4 to 294 kU/l. IgE binding to alphaGal was inhibited by raw pork kidney extract (mean, 77%; range, 55-87%), which showed a high amount of alphaGal determinants. CONCLUSIONS: Pork or beef kidney anaphylaxis is related to alphaGal IgE. Its peculiar severity could be due to an elevated content of alphaGal epitopes in kidney. PMID- 22494362 TI - Scheduling observational and physical practice: influence on the coding of simple motor sequences. AB - The main purpose of the present experiment was to determine the coordinate system used in the development of movement codes when observational and physical practice are scheduled across practice sessions. The task was to reproduce a 1,300-ms spatial-temporal pattern of elbow flexions and extensions. An intermanual transfer paradigm with a retention test and two effector (contralateral limb) transfer tests was used. The mirror effector transfer test required the same pattern of homologous muscle activation and sequence of limb joint angles as that performed or observed during practice, and the non-mirror effector transfer test required the same spatial pattern movements as that performed or observed. The test results following the first acquisition session replicated the findings of Gruetzmacher, Panzer, Blandin, and Shea (2011) . The results following the second acquisition session indicated a strong advantage for participants who received physical practice in both practice sessions or received observational practice followed by physical practice. This advantage was found on both the retention and the mirror transfer tests compared to the non-mirror transfer test. These results demonstrate that codes based in motor coordinates can be developed relatively quickly and effectively for a simple spatial-temporal movement sequence when participants are provided with physical practice or observation followed by physical practice, but physical practice followed by observational practice or observational practice alone limits the development of codes based in motor coordinates. PMID- 22494363 TI - Stress-related temporary hearing loss--evaluation of bio-humoral parameters: forensic and criminological applications. AB - The body-alarm reaction results from the activation of hypothalamic-pituitary adrenal axis, which can lead to physio-psychological phenomena such as an exclusion/occlusion of the sense of hearing. One hypothesis to explain this alteration consists in a hydromechanical dysfunction of the internal ear attributable to antidiuretic hormone. In this study, we evaluated the perception of acoustic stimuli administered in stressful conditions in 14 phobic patients and in 20 healthy subjects, in order to assess the influence of stress on perceiving capabilities. We also measured the concentration of salivary cortisol and IL-1beta and neurovegetative parameters to objectivise and quantify the physiological reactions. Our results show a worse perception of the frequencies of the human voice under stress; these findings could have a dual value: in the legal field, concerning criminal liability, and on the operative context, regarding the efficiency of verbal communication among law enforcement officers in situations inducing intense emotional stress. PMID- 22494364 TI - Ultra-subwavelength two-dimensional plasmonic circuits. AB - We report electronics regime (GHz) two-dimensional (2D) plasmonic circuits, which locally and nonresonantly interface with electronics, and thus offer to electronics the benefits of their ultrasubwavelength confinement, with up to 440,000-fold mode-area reduction. By shaping the geometry of 2D plasmonic media 80 nm beneath an unpatterned metallic gate, plasmons are routed freely into various types of reflections and interferences, leading to a range of plasmonic circuits, e.g., plasmonic crystals and plasmonic-electromagnetic interferometers, offering new avenues for electronics. PMID- 22494365 TI - QRS pattern and improvement in right and left ventricular function after cardiac resynchronization therapy: a radionuclide study. AB - BACKGROUND: Predicting response to cardiac resynchronization therapy (CRT) remains a challenge. We evaluated the role of baseline QRS pattern to predict response in terms of improvement in biventricular ejection fraction (EF). METHODS: Consecutive patients (pts) undergoing CRT implantation underwent radionuclide angiography at baseline and at mid-term follow-up. The relationship between baseline QRS pattern and mechanical dyssynchrony using phase analysis was evaluated. Changes in left and right ventricular EF (LVEF and RVEF) were analyzed with regard to baseline QRS pattern. RESULTS: We enrolled 56 pts, 32 with left bundle branch block (LBBB), 4 with right bundle branch block (RBBB) and 20 with non-specific intraventricular conduction disturbance (IVCD). A total of 48 pts completed follow-up. LBBB pts had significantly greater improvement in LVEF compared to RBBB or non-specific IVCD pts (+9.6 +/- 10.9% vs. +2.6 +/- 7.6%, p = 0.003). Response (defined as >= 5% increase in LVEF) was observed in 68% of LBBB vs. 24% of non-specific IVCD pts (p = 0.006). None of the RBBB pts were responders. RVEF was significantly improved in LBBB (+5.0 +/- 9.0%, p = 0.007), but not in non-specific IVCD and RBBB pts (+0.4 +/- 5.8%, p = 0.76). At multivariate analysis, LBBB was the only predictor of LVEF response (OR, 7.45; 95% CI 1.80-30.94; p = 0.006), but not QRS duration or extent of mechanical dyssynchrony. CONCLUSIONS: Presence of a LBBB is a marker of a positive response to CRT in terms of biventricular improvement. Pts with non-LBBB pattern show significantly less benefit from CRT than those with LBBB. PMID- 22494366 TI - Risk factors for nonspecific low-back pain in Chinese adolescents: a case-control study. AB - OBJECTIVES: The objective of this study was to gain a basic understanding of the influential factors for nonspecific low-back pain (LBP) among adolescents of southern China. DESIGN: The study was designed as a school-based case control study. SETTING: Nonspecific LBP is a common health problem in adolescence. Although some behaviors and socio-demographic factors are believed to contribute to the disorder, influential factors of LBP remain undefined. Moreover, until now there is no available information of influential factors for LBP in Chinese adolescents. SUBJECTS: A total of 1,214 adolescents were involved in the study, including 607 cases with nonspecific LBP and 607 controls without history of nonspecific LBP. OUTCOME MEASURES: A self-administered questionnaire was designed for epidemiological survey to investigate the risk factors for nonspecific LBP. All cases and controls were investigated for their family histories of nonspecific LBP, physical activities, sedentary activities, schoolbag weights, school performances, living conditions, and etc. METHOD: A 1:1 matched case control study was conducted on 1,214 adolescents from an elementary school and a secondary school in Guangzhou City, southern China. RESULTS: Family history (odds ratio [OR] 2.57, 95% confidence interval [CI] 1.85-3.58), long duration of carrying schoolbag (OR 1.38, 95% CI 1.11-1.72) and rest position between classes (OR 1.18, 95% CI 1.01-1.39) were positively correlated with self-reported nonspecific LBP. Students regularly playing basketball (OR 1.58, 95% CI 1.09 2.30) was found to be significantly more likely to have LBP. Also, students who feel schoolbag uncomfortable (OR 1.38, 95% CI 1.11-1.72) was found to experience more LBP. CONCLUSIONS: Family history, feeling schoolbag uncomfortable, duration of schoolbag carrying, basketball playing and rest position between classes are the major risk factors for nonspecific LBP in adolescents. PMID- 22494367 TI - Developing consensus on important factors associated with lower limb prosthetic prescription and use. AB - PURPOSE: There is an ongoing concern in lower limb prosthetic rehabilitation with underuse and nonuse of prosthetic technology. The aim of this study was to gather expert opinion on the most important outcomes, predictors and facilitators of lower limb prosthetic prescription and use, with a long-term goal of improving satisfaction with prosthetic technology. METHOD: An electronic Delphi study was conducted using an expert panel of 21 service providers and users and was undertaken over three iterations. RESULTS: The process resulted in the identification of 13 outcomes, 19 predictor and 34 facilitator factors. CONCLUSIONS: Psychosocial factors related to service provision and prosthetic use have not been widely recognized or incorporated into clinical practice. We highlight the need for creating standardized measures tha[Box: see text]. PMID- 22494368 TI - Parental stress as a predictor of early childhood caries among preschool children in India. AB - BACKGROUND. The health and well-being of children are linked to their parents' physical, emotional and social health in addition to child-rearing practices. OBJECTIVES. To investigate the association of parental stress as a risk indicator to early childhood caries (ECC) prevalence among preschool children of Moradabad, India. METHODS. A case-control study was conducted among 800 preschool children [400 cases (caries active) and 400 controls (caries free)] aged 4-5 years along with their parents. Using the Parental Stress Index-Short Form (PSI/SF), we determined the stress of primary caregivers of young children. These children were clinically examined for dental caries using Dentition Status and Treatment needs. Student's t-test, Pearson's correlation and linear regression were used for statistical analysis. RESULTS. An overall mean parenting stress index was found to be 193.48 +/- 59.63. Significantly higher mean stress scores were obtained among cases than among controls. Parental stress was significantly correlated with dmft scores and it was found to be one of the best predictors of ECC. CONCLUSION. This study provides data to suggest that parental stress has a pervasive impact on the children's oral health. The practitioners should be aware of this possible relationship and be prepared to provide appropriate intervention. PMID- 22494369 TI - Risks of exposure to ionizing and millimeter-wave radiation from airport whole body scanners. AB - Considerable public concern has been expressed around the world about the radiation risks posed by the backscatter (ionizing radiation) and millimeter-wave (nonionizing radiation) whole-body scanners that have been deployed at many airports. The backscatter and millimeter-wave scanners currently deployed in the U.S. almost certainly pose negligible radiation risks if used as intended, but their safety is difficult-to-impossible to prove using publicly accessible data. The scanners are widely disliked and often feared, which is a problem made worse by what appears to be a veil of secrecy that covers their specifications and dosimetry. Therefore, for these and future similar technologies to gain wide acceptance, more openness is needed, as is independent review and regulation. Publicly accessible, and preferably peer-reviewed evidence is needed that the deployed units (not just the prototypes) meet widely-accepted safety standards. It is also critical that risk-perception issues be handled more competently. PMID- 22494370 TI - Phenolic compound profiles and antioxidant capacity of Persea americana Mill. peels and seeds of two varieties. AB - Avocado processing by the food and cosmetic industries yields a considerable amount of phenolic-rich byproduct such as peels and seeds. Utilization of these byproducts would be favorable from an economic point of view. Methanolic (80%) extracts obtained from lyophilized ground peels and seeds of avocado (Persea americana Mill.) of the Hass and Shepard varieties were characterized for their phenolic compound profiles using the HPLC-PAD technique. The structures of the identified compounds were subsequently unambiguously confirmed by ESI-MS. Compositional analysis revealed that the extracts contained four polyphenolic classes: flavanol monomers, proanthocyanidins, hydroxycinnamic acids, and flavonol glycosides. The presence of 3-O-caffeoylquinic acid, 3-O-p coumaroylquinic acid, and procyanidin A trimers was identified in seeds of both varieties. Intervarietal differences were apparent in the phenolic compound profiles of peels. Peels of the Shepard variety were devoid of (+)-catechin and procyanidin dimers, which were present in the peels of the Hass variety. Peels of both varieties contained 5-O-caffeoylquinic acid and quercetin derivatives. The differences in the phenolic profiles between varietals were also apparent in the different antioxidant activity of the extracts. The peel extracts had a higher total phenolic compound content and antioxidant activity when compared to the seed extracts. The highest TEAC and ORAC values were apparent in peels of the Haas variety in which they amounted to 0.16 and 0.47 mmol Trolox/g DW, respectively. No significant (p > 0.05) differences were apparent between the TEAC values of seeds of the two varieties but the ORAC values differed significantly (p < 0.05). Overall these findings indicate that both the seeds and peel of avocado can be utilized as a functional food ingredient or as an antioxidant additive. PMID- 22494371 TI - Effects of the organic matter from swine wastewater on the adsorption and desorption of alachlor in soil. AB - The application of swine wastewater to the soil for agricultural purposes results in the addition of total and dissolved organic matter to the soil, which may interfere with the dynamics of pesticides in the soil. The objective of this study was to evaluate the effects of the application of total and dissolved organic matter from a biodigester and a treatment lagoon of swine wastewater in the adsorption and desorption of alachlor [2-chloro-2,6-diethyl-N(methoxymethyl acetamide)]. The assay was performed by the batch equilibrium method, and the results were fitted to the Freundlich model. The curve comparison test revealed a greater adsorption of alachlor in the soil treated with swine wastewater from the biodigester. The adsorption and desorption of alachlor increased in the soils where swine wastewater was added, and hysteresis was observed in all of the treatments. PMID- 22494372 TI - Solid beef cattle manure application impacts on soil properties and 17beta estradiol fate in a clay loam soil. AB - Livestock manure applied to agricultural land is one of the ways natural steroid estrogens enter soils. To examine the impact of long-term solid beef cattle (Bos Taurus) manure on soil properties and 17beta-estradiol sorption and mineralization, this study utilized a soil that had received beef cattle manure over 35 years. The 17beta-estradiol was strongly sorbed and sorption significantly increased (P < 0.05) with increasing soil organic carbon content (SOC) and with an increasing annual rate of beef cattle manure. The 17beta estradiol mineralization half-life was significantly negatively correlated, and the total amount of 17beta-estradiol mineralized at 90 days (MAX) was significantly positively correlated with 17beta-estradiol sorption. The long-term rate of manure application had no significant effect on MAX, but the addition of fresh beef cattle manure in the laboratory resulted in significantly (P < 0.05) smaller MAX values. None of the treatments showed MAX values exceeding one-third of the 17beta-estradiol applied. PMID- 22494373 TI - Distribution of the herbicide atrazine in a microcosm with riparian forest plants. AB - Pesticides applied on sugarcane reach the subsoil of riparian forests and probably contaminate the river water. This work was conducted to learn about the phytoremediation of atrazine and subsoil contamination using the common riparian forest species of Cecropia hololeuca Miq. and Trema micranta (L.) Blum. These plants were grown in soil microcosms where (14)C-atrazine at 1/10 of the field recommended dose was applied at the bottom of the microcosm simulating the movement from contaminated ground water to the upper soil layers and into plants. Residues of (14)C-atrazine were detected in all parts of the microcosm including soil, rhizosphere and the roots in different layers of the microcosm, stem and leaves. Atrazine mineralization was higher (10.2%) in the microcosms with plants than the control microcosms without plants (1.2%). The upward movement of this pesticide from deeper to more superficial soil layers occurred in all the microcosms with plants, powered by evapotranspiration process. From the atrazine applied in this study about 45% was taken up by C. hololeuca and 35% by T. micrantha. The highest amount of radioactivity (%) was found in the fine roots and the specific radioactivity (% g(-1)) showed that thick, fine roots and leaves bioaccumulate atrazine. The enhanced mineralization of atrazine as well the phytostabilization effect of the tree biomass will reduce the bioavailability of these residues and consequently decrease the hazardous effects on the environment. PMID- 22494374 TI - Cholinesterase characterization in Corbicula fluminea and effects of relevant environmental contaminants: a pesticide (chlorfenvinphos) and a detergent (SDS). AB - This study characterizes the cholinesterasic forms present in the bivalve Corbicula fluminea, through the analysis of differential affinity towards various substrates and inhibitors. This approach also permitted the validation of cholinesterase inhibition in the mentioned species for monitoring purposes by evaluating the inhibitory activity of a detergent (SDS) and a pesticide (chlorfenvinphos), both in vitro and in vivo. The cholinesterasic form present in the tissues of C. fluminea showed intermediate properties in terms of its relation with substrates and inhibitors. Furthermore, it was not inhibited by the detergent SDS under any of the test conditions, but was clearly inhibited by the selected organophosphate. The data show clearly that the main cholinesterasic form in C. fluminea is responsive to the organophosphate chlorfenvinphos, thus supporting the use of this biomarker for the environmental monitoring of specific contaminants such as anticholinesterasic pesticides. Despite not being commonly attained in the wild, the levels of chlorfenvinphos required to elicit a significant ChE inhibition were only one order of magnitude above actual values of aquatic contamination by this pesticide. PMID- 22494375 TI - Bioefficacy evaluation of controlled release formulations based on amphiphilic nano-polymer of carbofuran against Meloidogyne incognita infecting tomato. AB - In the present investigation, the bioefficacy of developed carbofuran formulations, with PEG-600 (7a, CP1) & PEG-900 (7b, CP2) @ 5, 10 and 20 ppm, along with commercial formulation of carbofuran 3G (CP0) were evaluated against the root-knot nematode, Meloidogyne incognita infecting tomato (cv. Pusa Ruby) in pot and field conditions. The bioefficacy data indicated that the formulations developed by utilizing polymers having PEG - 900 (7b) as hydrophilic segment were effective even at 14 days post inoculation (dpi) as evident from shoot and root length. Also, the reduction in penetration was found to be maximum with CP2 (3.6 4.6 J2s) at all concentrations compared to CP1 (6.6-16.4 J2s) and CP0 (29.3-32.6 J2s). Overall, CP2 was more effective in reducing the number of nematodes up to 14 days, compared to CP1 and CP0. Both the CR formulations (CP1 and CP2) in general significantly reduced the number of galls, when compared to CP0. However, under field conditions, lower concentrations (5, and 10 ppm) of CP2, were less effective in controlling the gall formation whereas, CP2 at 20 ppm, was most effective than other treatments. The study revealed that the developed CR formulations of carbofuran have the potential for effective management of M. incognita in tomato under field conditions. PMID- 22494376 TI - Fatty acid profile and elemental content of avocado (Persea americana Mill.) oil- effect of extraction methods. AB - Interest in vegetable oil extracted from idioblast cells of avocado fruit is growing. In this study, five extraction methods to produce avocado oil have been compared: traditional solvent extraction using a Soxhlet or ultrasound, Soxhlet extraction combined with microwave or ultra-turrax treatment and supercritical fluid extraction (SFE). Traditional Soxhlet extraction produced the most reproducible results, 64.76 +/- 0.24 g oil/100 g dry weight (DW) and 63.67 +/- 0.20 g oil/100 g DW for Hass and Fuerte varieties, respectively. Microwave extraction gave the highest yield of oil (69.94%) from the Hass variety. Oils from microwave extraction had the highest fatty acid content; oils from SFE had wider range of fatty acids. Oils from Fuerte variety had a higher monounsaturated: saturated FA ratio (3.45-3.70). SFE and microwave extraction produced the best quality oil, better than traditional Soxhlet extraction, with the least amount of oxidizing metals present. PMID- 22494377 TI - Evaluation of bendiocarb cytotoxicity in mammalian and insect cell cultures. AB - There is an increasing need for rapid and easily interpreted in vitro assays to screen for possible cytotoxicity of pesticides. The objective of this study was to investigate the effect of the carbamate insecticide bendiocarb on mammalian and insect cell cultures. The cytotoxicity of this insecticide was evaluated by cell proliferation and cellular damage was assessed by evaluation of the cytopathic effect and lactate dehydrogenase (LDH) leakage. Cells of insect origin (Sf21) were the most sensitive to bendiocarb with significant (P < 0.01) suppression of their proliferative activity ranging from 10(-1)-10(-5) M. However, significant suppression of proliferative activity was also recorded in rat liver cells (WBF344; 10(-1)-10(-3) M; P < 0.01-0.05) and rabbit kidney cells (RK13; 10(-1) M; P < 0.01). In contrast with the proliferation activity of cells, a cytopathic effect based on cellular damage and LDH leakage into the medium was observed only at the highest concentration (10(-1) M) in RK 13 and WBF344 cells, but not in the Sf21 insect cell line. Our results indicate that bendiocarb exposure caused a cell-type dependent decrease in cell proliferation; however, cell damage and LDH leakage into the medium were not present or were strongly limited, dependent on the cell phenotype. Cell proliferation was shown as a sensitive indicator for evaluation of the cytotoxic effect of bendiocarb in vitro; on the other hand, microscopic signs of cellular damage and LDH leakage were insufficient in vitro markers. PMID- 22494378 TI - Catalytic ozonation of 2,4-dichlorophenoxyacetic acid using alumina in the presence of a radical scavenger. AB - Using a laboratory-scale mixed reactor, the performance of alumina in degrading 2,4-Dichlorophenoxyacetic acid with ozone in the presence of tert-butyl alcohol radical scavenger was studied. The operating variables investigated were the dose of alumina catalyst and solution pH. Results showed that using ozone and alumina leads to a significant increase in 2,4-D removal in comparison to non-catalytic ozonation and adsorption processes. The observed reaction rate constants (k(obs)) for 2,4-D during ozonation were found to increase linearly with increasing catalyst dose. At pH 5, the k(obs) value increased from 19.3 to 26 M(-1) s(-1) and 67 M(-1) s(-1) when varying the alumina dose from 1 to 2 and 4 g L(-1), respectively. As pH was increased, higher reaction rates were observed for both non-catalytic ozonation and catalytic ozonation processes. Thus, at pH 3 and using a catalyst dose of 8 g L(-1), the k(obs) values for non-catalytic ozonation and catalytic ozonation processes were 3.4 and 58.9 M(-1) s(-1), respectively, whereas at pH 5 reaction rate constants of 6.5 and 128.5 M(-1) s(-1) were observed, respectively. Analysis of total organic carbon suggested that catalytic ozonation with alumina achieved a considerable level of mineralization of 2,4-D. Adsorption of 2,4-D on alumina was found to play an important role in the catalytic ozonation process. PMID- 22494379 TI - Optimization of photo-Fenton process parameters on carbofuran degradation using central composite design. AB - Carbofuran, one of the most toxic and biorefractory carbamate compounds, is widely used in insecticides in Taiwan (9-18% of total insecticides production per year). In the present study, a central composite design experiment was used to study the effect of photo-Fenton treatment on carbofuran solution and to optimize the process variables such as carbofuran concentration (1-100 mg L(-1)), H(2)O(2) dosage rate (0.25-6 mg L(-1) min(-1)) and Fe(3+) dosage (1-50 mg L(-1)), which influenced the efficiency of carbofuran degradation and mineralization. The results indicated that all the variables investigated in this study had significant roles in the degradation and mineralization of carbofuran in solution. The carbofuran degradation and mineralization efficiencies were increased with increase in H(2)O(2) dosage rate and Fe(3+) dosage, and with decrease in carbofuran concentration. Furthermore, optimum values of both H(2)O(2) dosage rate and Fe(3+) dosage were found to shift to higher values as carbofuran concentration increased. Based on the model obtained in this study, optimum H(2)O(2) dosage rate and Fe(3+) dosage were found to be 4 mg L(-1) min( 1) and 20 mg L(-1), respectively, for 51 mg L(-1) of carbofuran concentration. Under these conditions, carbofuran was completely removed within 30 min and coupled with 78% mineralization at the end of experiment. PMID- 22494380 TI - Estimation of K(OA) values of 209 polychlorinated trans-azobenzenes by PM6 and DFT methods. AB - The octanol-air partition coefficients (K(OA)) of all 209 PCt-ABs were determined computationally to fill gaps on their environmentally relevant physical and chemical properties. These properties have been determined using two computational approaches: the semi-empirical quantum chemistry method for property parameterization (PM6) of the molecular orbital package (MOPAC) and density functional theory (DFT) method using B3LYP functional and 6-311++G** basis set in Gaussian 03 software and artificial neural network (ANN) predicting abilities. Both computational methods enabled estimation of log K(OA) partition coefficients of PCt-ABs with a similar accuracy and precision. The PM6 method compared to DFT was highly superior because it requires much less time, manpower and cost of hardware. The determined log K(OA) values of the investigated PCt-ABs for standard condition (25 degrees C) varied between 8.30 and 8.75 for Mono-; 8.71 and 9.92 for Di-; 9.58 and 10.72 for Tri-; 10.11 and 11.34 for Tetra-, 10.83 and 11.85 for Penta-; 11.24 and 12.36 for Hexa-; 11.87 and 12.66 for Hepta-; 12.31 and 12.97 for Octa-; 12.89 and 13.21 for Nona-Ct-ABs; and 13.17- and 13.49 for Deca-Ct-AB. PCt-ABs, in view of these log K(OA) values, can be classified as compounds of relatively low (Mono-, Di- and some of Tri- Ct-ABs with values of log K(OA) around 8 to 10) environmental mobility (most of Tri- to Nona-Ct-ABs and Deca-Ct-AB homologues with values of log K(OA) >10), and with a potential to be adsorbed by soil particles. PMID- 22494381 TI - Determination of wine microbiota using classical method, polymerase chain method and Step One Real-Time PCR during fermentation process. AB - The aim of our study was the identification of grape, must and wine microbiota during the fermentation process using a classical microbiological method and Real Time PCR. The changes in different groups of microorganisms were monitored in total counts of bacteria, lactobacilli and yeasts. Microbiological parameters were observed during the current collection and processing of grapes in 2009. Samples were taken during the fermentation process in wine enterprises and a private vineyard. During this period 30 samples of wine among Muller Thurgau, Cabernet Sauvignon, Chardonnay, Tramin and Red Bio-wine were examined. Samples were collected from stages of grape-must unfiltered, grape-must filtered, the beginning of fermentation, fermentation, late fermentation and young wine. The highest total counts of bacteria ranged from 0.00 to 176 +/- 15 CFU.mL(-1) in the wine of Muller Thurgau, the highest number of yeast ranged from 0.00 to 150 +/- 9 CFU.mL(-1) in the wine of Muller Thurgau and the number of Lactobacillus spp. ranged from 0.00 to 92 +/- 5 CFU.mL(-1) in the sample of Cabernet Sauvignon wine. The presence and sensitivity of Gram-positive and Gram-negative bacterial species Enterococcus faecium, Lactobacillus acidophilus, Lactobacillus crispatus and Lactobacillus salivarius were detected using Real-Time PCR (RTQ PCR). Susceptibility of Enterococcus faecium varied in different isolates from 1 to 10(6) CFU.mL(-1), the sensitivity of the species Lactobacillus acidophilus in different isolates of the wine samples ranged from 1 to 10(5) CFU.mL(-1). We also monitored representation of species Lactobacillus crispatus, which were captured by RTQ PCR sensitivity and ranged from 1 to 10(5) CFU.mL(-1). Identification of the species Lactobacillus salivarius in each of isolates by RTQ PCR method showed the presence of these bacteria in the range of 1 to 10(4) CFU.mL(-1). PMID- 22494382 TI - Photocatalytic mineralization of glyphosate in a small-scale plug flow simulation reactor by UV/TiO2. AB - The present work involves the photocatalytic mineralization of glyphosate on a plug flow reactor by UV/TiO(2). The effect of catalyst loading shows an optimal value (0.4 g L(-1)) which is necessary to mineralize glyphosate. The kinetic rate of glyphosate mineralization decreases with the increasing initial concentration of glyphosate, and the data can be described using the first-order model. An alkaline environment is conducive to glyphosate mineralization. The mineralization efficiency increases with elevated flow rate to 114 mL min(-1), which is followed by a decrease with a further increase in flow rate due to the reduction of the residence time. The presence of external oxidants (K(2)S(2)O(8), H(2)O(2) and KBrO(3)) and photosencitizer (humic acid) can significantly enhance glyphosate mineralization. Photocatalysis oxidation ability of the three studied oxidants decrease in the order of: S(2)O(8)(2-) > BrO(3)(-) > H(2)O(2). Finally, the Langmuir-Hinshelwood (L-H) model was used to rationalize the mechanisms of reactions occurring on TiO(2) surfaces and L-H model constants were also determined. PMID- 22494383 TI - Key parameters and practices controlling pesticide degradation efficiency of biobed substrates. AB - We studied the contribution of each of the components of a compost-based biomixture (BX), commonly used in Europe, on pesticide degradation. The impact of other key parameters including pesticide dose, temperature and repeated applications on the degradation of eight pesticides, applied as a mixture, in a BX and a peat-based biomixture (OBX) was compared and contrasted to their degradation in soil. Incubation studies showed that straw was essential in maintaining a high pesticide degradation capacity of the biomixture, whereas compost, when mixed with soil, retarded pesticide degradation. The highest rates of degradation were shown in the biomixture composed of soil/compost/straw suggesting that all three components are essential for maximum biobed performance. Increasing doses prolonged the persistence of most pesticides with biomixtures showing a higher tolerance to high pesticide dose levels compared to soil. Increasing the incubation temperature from 15 degrees C to 25 degrees C resulted in lower t(1/2) values, with biomixtures performing better than soil at the lower temperature. Repeated applications led to a decrease in the degradation rates of most pesticides in all the substrates, with the exception of iprodione and metalaxyl. Overall, our results stress the ability of biomixtures to perform better than soil under unfavorable conditions and extreme pesticide dose levels. PMID- 22494384 TI - Emergency health risk communication during the 2007 San Diego wildfires: comprehension, compliance, and recall. AB - In October 2007, wildfires burned nearly 300,000 acres in San Diego County, California. Emergency risk communication messages were broadcast to reduce community exposure to air pollution caused by the fires. The objective of this investigation was to determine residents' exposure to, understanding of, and compliance with these messages. From March to June 2008, the authors surveyed San Diego County residents using a 40-question instrument and random digit dialing. The 1,802 respondents sampled were predominantly 35-64 years old (65.9%), White (65.5%), and educated past high school (79.0%). Most (82.5%) lived more than 1 mile away from the fires, although many were exposed to smoky air for 5-7 days (60.7%) inside and outside their homes. Most persons surveyed reported hearing fire-related health messages (87.9%) and nearly all (97.9%) understood the messages they heard. Respondents complied with most to all of the nontechnical health messages, including staying inside the home (58.7%), avoiding outdoor exercise (88.4%), keeping windows and doors closed (75.8%), and wetting ash before cleanup (75.6%). In contrast, few (<5%) recalled hearing technical messages to place air conditioners on recirculate, use High-Efficiency Particulate Air filters, or use N-95 respirators during ash cleanup, and less than 10% of all respondents followed these specific recommendations. The authors found that nontechnical message recall, understanding, and compliance were high during the wildfires, and reported recall and compliance with technical messages were much lower. Future disaster health communication should further explore barriers to recall and compliance with technical recommendations. PMID- 22494385 TI - The course of physical functional limitations and occupational conditions in a middle-aged working population in France. AB - BACKGROUND: Physical functional limitations (PFL) have mainly been studied in older populations. The aim of this study was to better understand the course of PFL and associations with occupational factors by gender in a middle-aged working population. METHODS: The data came from 16,950 workers in the ESTEV (Enquete Sante Travail et Vieillissement) cohort in France. PFL were assessed using the physical abilities section of the Nottingham Health Profile. Occupational conditions were measured with a self-administered questionnaire covering physical and psychosocial factors in 1990 and 1995. Multivariate analyses were used to assess the associations. RESULTS: The PFL appearance rate in 1995 was the same by gender (6.3%); the rate of PFL recovery was higher in men (23.9% versus 20.9%). Age was an independent factor of PFL at age 47 years or older in both genders after adjusting for confounding factors. The PFL appearance rate in 1995 was higher with physical occupational exposure in 1990, such as awkward work with a dose relation in both genders, while the PFL recovery rate decreased significantly only for men. Exposure to psychosocial occupational conditions, such as having the means to produce quality work in 1990, was significantly associated with a decreased PFL appearance rate in 1995 in both genders, and having high decision latitude in 1990 was associated with a decreased PFL appearance rate in 1995 only in men. Changes in exposure to occupational factors between 1990 and 1995 were associated with the PFL appearance and recovery rates in 1995 in both genders. CONCLUSIONS: After five years, the course of PFL in this working population changed and was associated with physical and psychosocial occupational factors. Relationships were stronger for the PFL appearance rate in both genders and were weaker for recovery from PFL, mainly among women. PMID- 22494387 TI - Driving forces of conformational changes in single-layer graphene oxide. AB - The extensive oxygen-group functionality of single-layer graphene oxide proffers useful anchor sites for chemical functionalization in the controlled formation of graphene architecture and composites. However, the physicochemical environment of graphene oxide and its single-atom thickness facilitate its ability to undergo conformational changes due to responses to its environment, whether pH, salinity, or temperature. Here, we report experimental and molecular simulations confirming the conformational changes of single-layer graphene oxide sheets from the wet or dry state. MD, PM6, and ab initio simulations of dry SLG and dry and wetted SLGO and electron microscopy imaging show marked differences in the properties of the materials that can explain variations in previously observed results for the pH dependent behavior of SLGO and electrical conductivity of chemically modified graphene-polymer composites. Understanding the physicochemical responses of graphene and graphene oxide architecture and performing selected chemistry will ultimately facilitate greater tunability of their performance. PMID- 22494388 TI - Falls after stroke. AB - Falls are common at all stages after stroke, occurring in the acute, rehabilitative, and chronic phases. Consequences of falls include death or serious injury, minor injuries, functional limitations, reduced mobility and activity, and fear of falling. These consequences can have implications for independence and quality of life after stroke. The high frequency of falls may be due to a combination of existing falls risk factors prior to the stroke as well as impairments from the stroke, such as decreased strength and balance, hemineglect, perceptual problems, and visual problems. This paper reviews the magnitude of the problem of falls in people with stroke, highlights risk factors, and summarizes the limited randomized controlled trial evidence on falls prevention in this population. There is a need for further high quality research investigating the effectiveness of interventions to reduce falls and injury in people with stroke from onset through to the chronic stage. PMID- 22494389 TI - Stereoselective synthesis of fluoro-homoneplanocin A as a potential antiviral agent. AB - Fluoro-homoneplanocin A (4) was synthesized from d-ribose, via the enyne ring closing metathesis of 9, the stereoselective opening of epoxide 23a with fluoride, and a simultaneous oxidation-elimination reaction. The key intermediate 8 is expected to serve as a versatile intermediate for the synthesis of carbanucleosides. PMID- 22494386 TI - Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer's disease. AB - Mutations in both the amyloid precursor protein (APP) and the presenilin (PSEN) genes cause familial Alzheimer's disease (FAD) with autosomal dominant inheritance and early onset of disease. The clinical course and neuropathology of FAD and sporadic Alzheimer's disease are highly similar, and patients with FAD constitute a unique population in which to conduct treatment and, in particular, prevention trials with novel pharmaceutical entities. It is critical, therefore, to exactly defi ne the molecular consequences of APP and PSEN FAD mutations. Both APP and PSEN mutations drive amyloidosis in FAD patients through changes in the brain metabolism of amyloid-beta (Abeta) peptides that promote the formation of pathogenic aggregates. APP mutations do not seem to impair the physiological functions of APP. In contrast, it has been proposed that PSEN mutations compromise gamma-secretase-dependent and -independent functions of PSEN. However, PSEN mutations have mostly been studied in model systems that do not accurately refl ect the genetic background in FAD patients. In this review, we discuss the reported cellular phenotypes of APP and PSEN mutations, the current understanding of their molecular mechanisms, the need to generate faithful models of PSEN mutations, and the potential bias of APP and PSEN mutations on therapeutic strategies that target Abeta. PMID- 22494390 TI - Systems and genome-wide approaches unite to provide a route to personalized medicine. AB - A report on the Keystone Symposium 'Complex Traits: Genomics and Computational approaches', Breckenridge, Colorado, USA, 20-25 February 2012. PMID- 22494391 TI - Concise enantioselective synthesis of duloxetine via direct catalytic asymmetric aldol reaction of thioamide. AB - Direct catalytic asymmetric aldol reaction of thioamide offers a new entry to the concise enantioselective synthesis of duloxetine. The direct aldol protocol was scalable (>20 g) to afford the aldol product in 92% ee after LiAlH(4) reduction, and 84% of the chiral ligand was recovered after recrystallization. The following four steps of transformation delivered duloxetine. PMID- 22494392 TI - Current status of near-total laryngectomy: review. AB - Concurrent chemoradiation is currently the accepted 'standard of care' for locally advanced laryngeal and hypopharyngeal cancers. However, there is a subset of patients not suitable for chemoradiation, in whom primary surgery is the best option. Speech preservation is of prime importance in these patients. Near-total laryngectomy is a voice-preserving procedure which can be considered as an alternative to total laryngectomy for selected patients with lateralised, locally advanced cancers of the larynx and hypopharynx. Although these patients are left with a permanent tracheostomy, lung-powered speech is maintained by way of a dynamic shunt created from the uninvolved tissues of the larynx. Since its first description in the early 1980s, the procedure has been shown by various authors to be oncologically sound, with high success rates. Unfortunately, the procedure has not gained wide acceptance due to perceived fears of surgical complexity. In this review, we discuss the various issues related to the procedure and we review the relevant literature. PMID- 22494393 TI - A direct and quantitative image of the internal nanostructure of nonordered porous monolithic carbon using FIB nanotomography. AB - A direct study of the shape, size and connectivity of nonordered pores in carbon materials is particularly challenging. A new method that allows direct three dimensional (3D) investigations of mesopores in monolithic carbon materials and quantitative characterization of their physical properties (surface area and pore size distribution) is reported. Focused ion beam (FIB) nanotomography technique is performed by combination of focused ion beam and scanning electron microscope. Porous monolithic carbon is produced by carbonization of a resorcinol formaldehyde gel in the presence of a cationic polyelectrolyte as a pore stabilizer. PMID- 22494395 TI - InterStoreDB: a generic integration resource for genetic and genomic data. AB - Associating phenotypic traits and quantitative trait loci (QTL) to causative regions of the underlying genome is a key goal in agricultural research. InterStoreDB is a suite of integrated databases designed to assist in this process. The individual databases are species independent and generic in design, providing access to curated datasets relating to plant populations, phenotypic traits, genetic maps, marker loci and QTL, with links to functional gene annotation and genomic sequence data. Each component database provides access to associated metadata, including data provenance and parameters used in analyses, thus providing users with information to evaluate the relative worth of any associations identified. The databases include CropStoreDB, for management of population, genetic map, QTL and trait measurement data, SeqStoreDB for sequence related data and AlignStoreDB, which stores sequence alignment information, and allows navigation between genetic and genomic datasets. Genetic maps are visualized and compared using the CMAP tool, and functional annotation from sequenced genomes is provided via an EnsEMBL-based genome browser. This framework facilitates navigation of the multiple biological domains involved in genetics and genomics research in a transparent manner within a single portal. We demonstrate the value of InterStoreDB as a tool for Brassica research. InterStoreDB is available from: http://www.interstoredb.org. PMID- 22494394 TI - Association between commercial and traditional sugar-sweetened beverages and measures of adiposity in Costa Rica. AB - OBJECTIVE: Increasing trends in the consumption of commercial sugar-sweetened beverages (SSB) have occurred in parallel with rising levels of obesity in Latin America, but data showing the relationship between these SSB and obesity are limited. The current study examined the association between commercial and traditional SSB and measures of adiposity in Costa Rica. DESIGN: A cross sectional analysis was conducted in which the exposure, SSB intake, was defined as frequency of daily servings of 'fresco' (a traditional home-made beverage), fruit drink (commercially available SSB), soda and fruit juice (made from fruits at home). Multivariate linear regression was used to estimate associations between SSB intake and BMI, waist-to-hip ratio and skinfold thickness. SETTING: Central Valley, Costa Rica. SUBJECTS: Controls (n 2045) of a case-control study on diet and heart disease in Costa Rica. RESULTS: Fresco, fruit drink, soda and fruit juice were consumed >=1 time/d by 47 %, 14 %, 4 % and 14 % of the population, respectively. One serving/d of soda, fruit drink and fresco was associated with 0.89, 0.49 and 0.21 kg/m2 higher BMI, respectively (all P < 0.05). Fruit drink (>=1 serving/d) was associated with higher waist-to-hip ratio (P = 0.004), while soda and fresco were associated with higher skinfold thickness (P = 0.02 and 0.01, respectively). Associations with fruit juice intake were modest and not statistically significant. Other factors associated with higher BMI were higher income and less education, smoking and physical inactivity (all P < 0.05). CONCLUSIONS: Increasing intake of commercially available SSB could be in part responsible for the high prevalence of obesity among Hispanic adults. PMID- 22494396 TI - Polymorphism of two-dimensional boron. AB - The structural stability and diversity of elemental boron layers are evaluated by treating them as pseudoalloy B(1-x)[hexagon](x), where [hexagon] is a vacancy in the close-packed triangular B lattice. This approach allows for an elegant use of the cluster expansion method in combination with first-principles density functional theory calculations, leading to a thorough exploration of the configurational space. A finite range of compositions x is found where the ground state energy is essentially independent of x, uncovering a variety of stable B layer phases (all metallic) and suggesting polymorphism, in stark contrast to graphene or hexagonal BN. PMID- 22494397 TI - Engaging rehabilitation technologies: making things happen. AB - For some people, the word "technology" in rehabilitation brings to mind equipment and assistive devices. For others - it is a brave new frontier where robotic advance means many of the functional consequences of impairment are/will be alleviated, and many roles health professionals and carers currently perform will disappear. Like most things in life, a simplistic interpretation in complexity rarely capture what is truly going on. This is certainly true for rehabilitation technologies where devices are clearly important for our clients and for our professions but, it is not just about gadgets - it is far more than that. Of the numerous definitions available, most have in common a notion of tools to apply knowledge to practical issues or, as noted in the Britannica Concise Encyclopaedia [ 1 ]: "Whereas science is concerned with how and why things happen, technology focuses on making things happen". PMID- 22494398 TI - Novel natural alleles at FLC and LVR loci account for enhanced vernalization responses in Arabidopsis thaliana. AB - Vernalization, the induction of flowering by low winter temperatures, is likely to be involved in plant climatic adaptation. However, the genetic, molecular and ecological bases underlying the quantitative variation that tunes vernalization sensitivity to natural environments are largely unknown. To address these questions, we have studied the enhanced vernalization response shown by the Ll-0 accession of Arabidopsis thaliana. Quantitative trait locus (QTL) mapping for several flowering initiation traits in relation to vernalization, in a new Ler * Ll-0 recombinant inbred line (RIL) population, identified large effect alleles at FRI, FLC and HUA2, together with two small effect loci named as Llagostera vernalization response (LVR) 1 and 2. Phenotypic analyses of near isogenic lines validated LVR1 effect on flowering vernalization responses. To further characterize the FLC allele from Ll-0, we carried out genetic association analyses using a regional collection of wild genotypes. FLC-Ll-0 appeared as a low-frequency allele that is distinguished by polymorphism Del(-57), a 50-bp deletion in the 5'-UTR. Del(-57) was significantly associated with enhanced vernalization responses and FLC RNA expression, as well as with altitude and minimum temperatures. These results are consistent with Del(-57) acting as a novel cis-regulatory FLC polymorphism that may confer climatic adaptation by increasing vernalization sensitivity. PMID- 22494399 TI - The influence of exercise-induced fatigue on cognitive function. AB - Although anecdotal reports suggest that information processing and decision making is impaired immediately following prolonged periods of physical activity, results obtained from laboratory studies of exercise-induced fatigue have been inconsistent. Fatigue effects may be task specific and related to the time of post-exercise testing. The present study examined the effects on adults' performance of two cognitive tasks that differed in processing demands over an 80 min period of fatigue. Thirty young adult men and women were randomly assigned to either an exercise group and completed a 60-min bout of cycle ergometry at 90% ventilatory threshold or a control group and rested for 60 min. Following interventions, each participant completed a simple and complex version of a visual perceptual discrimination test, a 40-min memory-based vigilance test and a repetition of the visual perceptual discrimination tests. Those who exercised evidenced significant decrements in performance on complex perceptual discrimination tasks compared to participants who rested. The response time of exercisers during a memory-demanding vigilance test were significantly slower than those of participants who rested; however, detection performance did not differ between groups neither was there a decrease in target detection across the vigil. The effects of exercise-induced fatigue may be task specific, with greater effects on perceptual tasks, which involve relatively automatic processing, compared to effortful memory-based tasks. PMID- 22494400 TI - Is it time to consider palliative care? PMID- 22494401 TI - Pain management of chronic lateral epicondylitis: emerging new therapeutic options. PMID- 22494402 TI - Evidence-based practice standards for the use of topical pressurised oxygen therapy. AB - Whenever a new therapy enters the wound care arena it is mandatory to deliver the best evidence to clinicians, healthcare administrators and policy makers to support integration of the technology into clinical practice. While this can often be problematic when novel therapies lack a large body of supporting evidence, methods that incorporate the use of expert opinion do exist to evaluate existing evidence and create consensus statements that can help guide decisions. Topical pressurised oxygen therapy is a method of delivering pressurised and humidified oxygen directly to the wound bed to support the healing of chronic and hypoxic wounds. This article will present the process by which the evidence was identified and evaluated as well as present standards based on the evidence related to topical pressurised oxygen therapy. We will show, through the use of the evidence, how this therapy can be a non invasive safe approach for wound management for selected patients in all clinical care settings. PMID- 22494404 TI - Kinetic resolution of chiral cyclohex-2-enones by rhodium(I)/binap-catalyzed 1,2- and 1,4-additions. AB - The feasibility of kinetic resolutions of racemic monosubstituted cyclohex-2 enones by Rh/binap-catalyzed reactions was investigated. 1,2-Addition of AlMe(3) to the 5-substituted derivatives furnished allylic alcohols in the matched case, while the less reactive enantiomers were either left over or transformed into trans-3,5-disubstituted cyclohexanones in parallel or sequential 1,4-additions. Altogether, these represent regiodivergent reactions on racemic mixtures. In contrast, 1,4-addition of aryl groups led to inferior results since either catalyst or substrate control dominated. PMID- 22494403 TI - Synthesis and biological response of size-specific, monodisperse drug-silica nanoconjugates. AB - Drug-containing nanoparticles (NPs) with monodisperse, controlled particle sizes are highly desirable for drug delivery. Accumulating evidence suggests that NPs with sizes less than 50 nm demonstrate superior performance in vitro and in vivo. However, it is difficult to fabricate monodisperse, drug-containing NPs with discrete sizes required for studying and characterizing existing relationships among particle size, biologic processing, and therapeutic functionality. Here, we report a scalable process of fabricating drug-silica conjugated nanoparticles, termed drug-silica nanoconjugates (drug-NCs), which possess monodisperse size distributions and desirable particle sizes as small as 20 nm. We find that 20 nm NCs are superior to their 50 and 200 nm NC analogues by 2-5- and 10-20-fold, respectively, with regard to tumor accumulation and penetration and cellular internalization. These fundamental findings underscore the importance and necessity of further miniaturizing nanomedicine size for optimized drug delivery applications. PMID- 22494405 TI - Lead exposures from varnished floor refinishing. AB - We evaluated the presence of lead in varnish and factors predicting lead exposure from floor refinishing and inexpensive dust suppression control methods. Lead in varnish, settled dust, and air were measured using XRF, laboratory analysis of scrape and wipe samples, and National Institute for Occupational Safety and Health (NIOSH) Method 7300, respectively, during refinishing (n = 35 homes). Data were analyzed using step-wise logistic regression. Compared with federal standards, no lead in varnish samples exceeded 1.0 mg/cm(2), but 52% exceeded 5000 ppm and 70% of settled dust samples after refinishing exceeded 40 MUg/ft(2). Refinishing pre-1930 dwellings or stairs predicted high lead dust on floors. Laboratory analysis of lead in varnish was significantly correlated with airborne lead (r = 0.23, p = 0.014). Adding dust collection bags into drum sanders and HEPA vacuums to edgers and buffers reduced mean floor lead dust by 8293 MUg Pb/ft(2) (p<0.05) on floors and reduced most airborne lead exposures to less than 50 MUg/m(3). Refinishing varnished surfaces in older housing produces high but controllable lead exposures. PMID- 22494406 TI - Transperitoneal laparoscopic excision of seminal vesicle cyst: a single-center experience. AB - BACKGROUND AND PURPOSE: Seminal vesicle cyst (SVC) is a rare disease and its treatment is still controversial. This article contains the largest series of transperitoneal laparoscopic excision of SVC to date, summarizing our surgical techniques and clinical experience with this disease. PATIENTS AND METHODS: From December 2003 to May 2010, seven patients received transperitoneal laparoscopic excision of SVC using a five-port transperitoneal approach. Nearly the total cyst was removed by only leaving a narrow strip of the cyst wall with the bilateral vas deferens and SV preserved completely. Pelvic CT or MRI was performed 3 and 6 months after surgery, and thereafter annually for at least 3 years. RESULTS: Transperitoneal laparoscopic excision of SVC was completed successfully in all seven patients without conversion to open surgery. The mean operative time was 73 minutes (range 60-100 min) with negligible blood loss (less than 20 mL). The mean postoperative hospital stay was 4.3 days (range 3-5 days). No intraoperative or postoperative complication occurred. The patients were followed up for a mean of 45 months (range 18-84 mos), during which they all remained symptom free with normal erectile and ejaculatory function without evidence of recurrence. CONCLUSION: Our study has demonstrated that transperitoneal laparoscopic excision of SVC is a safe, feasible, and efficacious procedure, and offers an excellent option for minimally invasive treatment of patients with SVC. PMID- 22494407 TI - Endophytic fungi from pigeon pea [Cajanus cajan (L.) Millsp.] produce antioxidant Cajaninstilbene acid. AB - In this study, novel endophytic fungi producing cajaninstilbene acid (CSA) from pigeon pea [ Cajanus cajan (L.) Millsp.] were investigated and screened. CSA has prominent pharmacological activities. A total of 110 endophytic fungi isolates were grouped into 8 genera on the basis of morphological characteristics, and CSA producing fungi were screened by liquid chromatography-tandem mass spectrometry (LC-MS/MS). According to ITS-rDNA sequences analysis, the CSA-producing fungi were identified as Fusarium solani (ERP-07), Fusarium oxysporum (ERP-10), and Fusarium proliferatum (ERP-13), respectively. The amount of CSA produced by the ERP-13 reached 504.8 +/- 20.1 MUg/L or 100.5 +/- 9.4 MUg/g dry weight of mycelium. In a DPPH radical-scavenging assay, when the concentration of fungal CSA was 500 MUg/mL, inhibition percentage could reach 80%, which was almost the same as that of standard CSA. This study first reported the natural antioxidant CSA from endophytic fungi F. solani and F. proliferatum isolated from pigeon pea. PMID- 22494408 TI - Adolescent migration and the 1990s nuptiality transition in Mali. AB - Attempts to explain the rise in women's age at marriage across Africa have focused mainly on determinants in the urban environment, notably women's education and the economic recession. In our study, we examined the migration of adolescent girls as a factor in the transition to a later age of marriage in rural Mali, using an analysis of data from a longitudinal survey conducted over 20 years. The findings show a close correlation between the rise in labour migration and the onset of this nuptiality transition. Continuing changes in marriage patterns include not only its postponement but also a breakdown in the marriage formalization process. Two main mechanisms are documented: a direct one, as migration enables young women to choose the timing of their marriage and is a source of empowerment; and an indirect one, as migration challenges family marriage conventions and contributes to elders disengaging from control over marriage and young people. PMID- 22494409 TI - Comment on "Pretreatment of lignocellulosic material with fungi capable of higher lignin degradation and lower carbohydrate degradation improves substrate acid hydrolysis and the eventual conversion to ethanol". PMID- 22494410 TI - Soft drink consumption in Sri Lankan adolescents. AB - OBJECTIVE: To determine the factors associated with sugar-sweetened soft drink consumption in adolescents from Sri Lanka. DESIGN: A cross-sectional study where the data were collected by means of a self-administered questionnaire. SETTING: Government, private and international schools in the Colombo district of Sri Lanka. SUBJECTS: Adolescents aged 17 years attending sixty-five schools. RESULTS: Overall 82 % consumed sugar-sweetened soft drinks once weekly or more often, while 77 % and 48 % consumed sugar-sweetened carbonated drinks and sugar sweetened fruit drinks once weekly or more often. Being a boy (OR = 1.44; 95 % CI 1.02, 2.03), attending a private/international school (OR = 4.12; 95 % CI 1.94, 8.75), mother's level of education (OR = 1.53; 95 % CI 1.03, 2.28) and father's occupation (middle level: OR = 2.39; 95 % CI 1.63, 3.52; upper level: OR = 2.48; 95 % CI 1.35, 4.56) were independently associated with the consumption of sugar sweetened soft drinks. CONCLUSIONS: The majority of adolescents in this sample consumed sugar-sweetened beverages once weekly or more often. It was evident that some sociodemographic factors were associated with the consumption of these drinks. PMID- 22494411 TI - Modulation of chlorophyll biosynthesis by water stress in rice seedlings during chloroplast biogenesis. AB - To understand the impact of water stress on the greening process, water stress was applied to 6-day-old etiolated seedlings of a drought-sensitive cultivar of rice (Oryza sativa), Pusa Basmati-1 by immersing their roots in 40 mm polyethylene glycol (PEG) 6000 (-0.69 MPa) or 50 mm PEG 6000 (-1.03 MPa) dissolved in half-strength Murashige and Skoog (MS)-nutrient-solution, 16 h prior to transfer to cool-white-fluorescent + incandescent light. Chlorophyll (Chl) accumulation substantially declined in developing water-stressed seedlings. Reduced Chl synthesis was due to decreased accumulation of chlorophyll biosynthetic intermediates, that is, glutamate-1-semialdehyde (GSA), 5 aminolevulinic acid, Mg-protoporphyrin IX monomethylester and protochlorophyllide. Although 5-aminolevulinic acid synthesis decreased, the gene expression and protein abundance of the enzyme responsible for its synthesis, GSA aminotransferase, increased, suggesting its crucial role in the greening process in stressful environment. The biochemical activities of Chl biosynthetic enzymes, that is, 5-aminolevulinic acid dehydratase, porphobilinogen deaminase, coproporphyrinogen III oxidase, porphyrinogen IX oxidase, Mg-chelatase and protochlorophyllide oxidoreductase, were down-regulated due to their reduced protein abundance/gene expression in water-stressed seedlings. Down-regulation of protochlorophyllide oxidoreductase resulted in impaired Shibata shift. Our results demonstrate that reduced synthesis of early intermediates, that is, GSA and 5-aminolevulinic acid, could modulate the gene expression of later enzymes of Chl biosynthesis pathway. PMID- 22494412 TI - Assessment of reporting quality of conference abstracts in sports injury prevention according to CONSORT and STROBE criteria and their subsequent publication rate as full papers. AB - BACKGROUND: The preliminary results of a study are usually presented as an abstract in conference meetings. The reporting quality of those abstracts and the relationship between their study designs and full paper publication rate is unknown. We hypothesized that randomized controlled trials are more likely to be published as full papers than observational studies. METHODS: 154 oral abstracts presented at the World Congress of Sports Injury Prevention 2005 Oslo and the corresponding full paper publication were identified and analysed. The main outcome measures were frequency of publication, time to publication, impact factor, CONSORT (for Consolidated Standards of Reporting Trials) score, STROBE (for Strengthening the Reporting of Observational Studies in Epidemiology) score, and minor and major inconsistencies between the abstract and the full paper publication. RESULTS: Overall, 76 of the 154 (49%) presented abstracts were published as full papers in a peer-reviewed journal with an impact factor of 1.946 +/- 0.812. No significant difference existed between the impact factor for randomized controlled trials (2.122 +/- 1.015) and observational studies (1.913 +/- 0.765, p = 0.469). The full papers for the randomized controlled trials were published after an average (SD) of 17 months (+/- 13 months); for observational studies, the average (SD) was 12 months (+/- 14 months) (p = 0.323). A trend was observed in this study that a higher percentage of randomized controlled trial abstracts were published as full papers (71% vs. 47%, p = 0.078) than observational trials. The reporting quality of abstracts, published as full papers, significantly increased compared to conference abstracts both in randomized control studies ( CONSORT: 5.7 +/- 0.7 to 7.2 +/- 1.3; p = 0.018, CI 2.7 to -0.32) and in observational studies (STROBE: 8.2 +/- 1.3 to 8.6 +/- 1.4; p = 0.007, CI -0.63 to -0.10). All of the published abstracts had at least one minor inconsistency (title, authors, research center, outcome presentation, conclusion), while 65% had at least major inconsistencies (study objective, hypothesis, study design, primary outcome measures, sample size, statistical analysis, results, SD/CI). Comparing the results of conference and full paper; results changed in 90% vs. 68% (randomized, controlled studies versus observational studies); data were added (full paper reported more result data) in 60% vs. 30%, and deleted (full paper reported fewer result data) in 40% vs. 30%. CONCLUSIONS: No significant differences with respect to type of study (randomized controlled versus observational), impact factor, and time to publication existed for the likelihood that a World Congress of Sports Injury conference abstract could be published as a full paper. PMID- 22494413 TI - Normal nasal patency: problems in obtaining standard reference values for the surgeon. AB - This review examines why there is no normal range of nasal patency available to the surgeon when assessing nasal obstruction, and discusses the factors that influence nasal patency. Current normal ranges are examined and criticised because of the variability of normal values and the poor sampling methods used. Instability of physiological nasal patency is related to factors such as the nasal cycle and the nose's direct exposure to the external environment. Decongestion of the nose is proposed as a way of stabilising anatomical nasal patency, and measurements of patency in this state may be more useful to the surgeon. Population studies are needed to establish a normal range, but these studies must control for factors such as age, height, sex, and nasal shape and size related to climatic adaptation. Rather than classify populations according to unscientific categories such as race, anthropometric measures such as the nasal index are proposed. PMID- 22494414 TI - Rainbow radiating single-crystal Ag nanowire nanoantenna. AB - Optical antennas interface an object with optical radiation and boost the absorption and emission of light by the objects through the antenna modes. It has been much desired to enhance both excitation and emission processes of the quantum emitters as well as to interface multiwavelength channels for many nano optical applications. Here we report the experimental implementation of an optical antenna operating in the full visible range via surface plasmon currents induced in a defect-free single-crystalline Ag nanowire (NW). With its atomically flat surface, the long Ag NW reliably establishes multiple plasmonic resonances and produces a unique rainbow antenna radiation in the Fresnel region. Detailed antenna radiation properties, such as radiating near-field patterns and polarization states, were experimentally examined and precisely analyzed by numerical simulations and antenna theory. The multiresonant Ag NW nanoantenna will find superb applications in nano-optical spectroscopy, high-resolution nanoimaging, photovoltaics, and nonlinear signal conversion. PMID- 22494415 TI - IDH2 mutations are frequent in Chinese patients with acute myeloid leukemia and associated with NPM1 mutations and FAB-M2 subtype. AB - INTRODUCTION: Gene mutations play an important role in acute myeloid leukemia (AML) pathogenesis. Several genes have been identified in AML, such as FLT3, KIT, NPM1, and JAK2. This study investigated the frequency of novel mutations in IDH1 (amino acid R132) and IDH2 (R140 and R172) and analyzed their impact on disease biology and interaction with other mutations in Chinese patients with de novo AML. METHODS: A total of 195 patients were screened for mutations in the IDH1, IDH2, JAK2 V617F, NPM1, FLT3, and KIT genes, using polymerase chain reaction (PCR)-based and direct sequencing assays. RESULTS: IDH mutations occurred at a considerable frequency of 15.89% in Chinese AML cases; IDH2 R140Q was the most frequent genetic alteration and was associated with older age, normal karyotype, and French-American-British classification M2 at diagnosis. There was a strong association of IDH2 mutation with NPM1 mutations and a trend with FLT3-internal tandem duplication. CONCLUSION: IDH mutations may be a novel genetic marker in cytogenetically normal AML and may cooperate in leukemogenesis. PMID- 22494416 TI - Molecular network profiling of U373MG human glioblastoma cells following induction of apoptosis by novel marine-derived anti-cancer 1,2,3,4 tetrahydroisoquinoline alkaloids. AB - BACKGROUND: Glioblastoma is the most aggressive form of brain tumors showing resistance to treatment with various chemotherapeutic agents. The most effective way to eradicate glioblastoma requires the concurrent inhibition of multiple signaling pathways and target molecules involved in the progression of glioblastoma. Recently, we obtained a series of 1,2,3,4-tetrahydroisoquinoline alkaloids with potent anti-cancer activities, including ecteinascidin-770 (ET 770; the compound 1a) and renieramycin M (RM; the compound 2a) from Thai marine invertebrates, together with a 2'-N-4"-pyridinecarbonyl derivative of ET-770 (the compound 3). We attempted to characterize the molecular pathways responsible for cytotoxic effects of these compounds on a human glioblastoma cell line U373MG. METHODS: We studied the genome-wide gene expression profile on microarrays and molecular networks by using pathway analysis tools of bioinformatics. RESULTS: All of these compounds induced apoptosis of U373MG cells at nanomolar concentrations. The compound 3 reduced the expression of 417 genes and elevated the levels of 84 genes, while ET-770 downregulated 426 genes and upregulated 45 genes. RM decreased the expression of 274 genes and increased the expression of 9 genes. The set of 196 downregulated genes and 6 upregulated genes showed an overlap among all the compounds, suggesting an existence of the common pathways involved in induction of apoptosis. We identified the ErbB (EGFR) signaling pathway as one of the common pathways enriched in the set of downregulated genes, composed of PTK2, AKT3, and GSK3B serving as key molecules that regulate cell movement and the nervous system development. Furthermore, a GSK3B-specific inhibitor induced apoptosis of U373MG cells, supporting an anti-apoptotic role of GSK3B. CONCLUSION: Molecular network analysis is a useful approach not only to characterize the glioma-relevant pathways but also to identify the network-based effective drug targets. PMID- 22494417 TI - The relationship between functional disability and health-related quality of life in patients with a rotator cuff tear. AB - PURPOSE: To determine the relationship between functional disability and health related quality of life (HRQoL) in rotator cuff tear (RCT) patients. METHOD: In 67 RCT patients (mean age, 54 years; 57% males), functional disability was self reported with the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), HRQoL with the Short-Form 36 Health Survey (SF-36), and pain by visual analogue scale. ASES results were divided into tertiles (12-38, 39 51, and 52-82). RESULTS: Mean ASES score was 48 (range, 12-82). Patients with the highest functional disability and highest pain level had the lowest HRQoL. For the highest, middle, and lowest ASES categories, respectively, mean SF-36 Physical Component Summary (PCS) scores were 35 SD 5, 36 SD 8, and 41 SD 6 (p< 0.001) (r = 0.47 for ASES vs. PCS; p< 0.001), and Mental Component Summary (MCS) scores were 50 SD 13, 56 SD 10, and 58 SD 8 (p = 0.011) (r = 0.37 for ASES vs. MCS; p= 0.003). CONCLUSIONS: Patients with higher functional disability had lower HRQoL. RCT extensively affects patients' lives; therefore, capturing both generic and shoulder-specific measures of RCT problems is recommended. PMID- 22494418 TI - Photoselective vaporization versus transurethral resection of the prostate for benign prostatic hyperplasia: a meta-analysis. AB - PURPOSE: To determine whether photoselective vaporization has advantages over transurethral resection of the prostate (TURP) in terms of effectiveness and safety for treatment of patients with benign prostatic hyperplasia. MATERIALS AND METHODS: MEDLINE, EMBASE, and the Cochrane Controlled Trial Register were searched for randomized controlled trials. The risk ratio, mean difference, and their corresponding 95% confidence intervals were calculated for dichotomous and continuous outcomes, respectively. Risk of bias of enrolled trials was assessed according to Cochrane Handbook. RESULTS: A total of five trials were enrolled. There was no significant difference in the International Prostate Symptom Score and maximum flow rate between photoselective vaporization and TURP at 6-, 12-, and 24-month follow-up. Photoselective vaporization was associated with significantly lower risk of capsule perforation, transurethral resection syndrome, and clot retention, significantly lower transfusion requirements, a shorter catheterization time, and a shorter length of hospital stay. TURP was associated with a shorter operative time and a lower risk of reoperation. In addition, there was no difference in risk of acute urinary retention and urethral/bladder neck sclerosis between photoselective vaporization and TURP. CONCLUSIONS: Photoselective vaporization and TURP provide comparable improvements in functional results, including International Prostate Symptom Score and maximum flow rate at 6-, 12-, and 24-month follow-up. Photoselective vaporization offers advantages over TURP in terms of intraoperative safety; however, TURP is found to have a shorter operative time and lower reoperative risk. PMID- 22494419 TI - Autologous bone marrow-derived cells with placental extract for healing excisional cutaneous wounds in animal model. AB - Topical wound-healing potential of autologous bone marrow-derived nucleated cells along with placental extract was evaluated in comparison with buffy coat of autologous blood on full-thickness cutaneous wounds in the thoracolumbar region of 15 clinically healthy New Zealand rabbits. Three wounds of 2 * 2 cm, one on the right side of the body and two on the left side of the midline were created on the dorsal lumbar region of each rabbit under xylazine-ketamine anaesthesia. The wounds of each animal were randomly assigned to one of the three treatments: topical application of autologous bone marrow-derived cells with placental extract (group I), application of buffy coat in the autologous plasma with placental extract (group II) and autologous plasma with placental extract as control (group III). Wounds were observed for 30 days macroscopically and for granulation tissue formation, histomorphological and histochemical evaluation. Time of appearance of granulation tissues and filling of wound beds were faster in group I followed by group II and group III animals, respectively. Histomorphological findings exhibited an earlier disappearance of inflammatory reaction, better epithelialisation, significantly maximum neovascularisation, fibroplasias and collagenation in group I followed by group II and group III animals, respectively. Histochemical findings also depicted maximum number of robust, thick, interwoven type of collagen fibres, stout, highly tortuous and interwoven network of elastin fibres and numerous mesh war form of reticulin fibres within the dermal component were present in group I when compared with group II and III animals. Experiment conclude that single application of autologous bone marrow-nucleated cells with placental extract topically could be a novel option for faster healing in complicated non healing wounds both in human beings and animals. PMID- 22494420 TI - Editorial: Nursing alumni building a strong voice for the future. PMID- 22494421 TI - Administrative stressors and nursing job outcomes in Australian public and non profit health care organisations. AB - AIMS AND OBJECTIVES: The main aim of this study is to develop a path model to examine the effect of administrative stressors on nursing work outcomes in a sample of Australian public and non-profit nurses. BACKGROUND: The implementation of managerial reform initiatives has negative consequences on work outcomes. However, less is known about the effects of these stressors in public and non profit health care organisations. DESIGN: An online, self-completion questionnaire was sent to a random sample of nurses, employed in nursing-related occupations. PARTICIPANTS: Useable surveys were received from 251 nurses. METHODS: The path model was analysed using SmartPLS software (SmartPLS, Hamburg, Germany). RESULTS: Public and non-profit nurses experienced time and resource administrative-related stressors (such as resource shortage and pay not as good as other people doing similar work). They relied on work-related social support to reduce the negative consequences. Resource stressors led to job dissatisfaction while time stressors led to psychological strain. Nursing staff who reported better psychological health reported higher job satisfaction and higher level of commitment towards their organisations. CONCLUSIONS: Context specific administrative stressors have a negative impact on the work outcomes of public and non-profit nurses. Work-related social support mechanisms were found to mediate the negative consequences of administrative resourcing stressors on nursing job satisfaction. RELEVANCE TO CLINICAL PRACTICE: Nursing managers have to be sympathetic and care for the negative experiences of nursing staff, especially when there is an increasing level of administrative expectations during organisational change. Senior management should take note of the stressors caused by the lack of resources such as information, staffing and resources, as these were found to lead to an increase in nurses seeking work-related social support from their peers and supervisors. Effective implementation of these strategies would lead to a nursing workforce, which has higher level of psychological health, job satisfaction and organisational commitment. PMID- 22494422 TI - Psychometric testing of compliance with universal precautions scale in clinical nursing. PMID- 22494423 TI - Commentary on Van Bogaert P Commentary on Kowalski C, Ommen O, Driller E, Ernstmann N, Wirtz M, Koehler T & Pfaff H (2010) Burnout in nurses - the relationship between social capital in hospitals and emotional exhaustion. Journal of Clinical Nursing 19, 1654-1663. Journal of Clinical Nursing20, 913 914. PMID- 22494424 TI - Commentary on Bailey C, Murphy R & Porock D (2011) Professional tears: developing emotional intelligence around death and dying in emergency work. Journal of Clinical Nursing 20, 3364-3372. PMID- 22494425 TI - Response to Watson R (2011) Commentary on Aselage MB (2010) Measuring mealtime difficulties: eating, feeding, and meal behaviours in older adults with dementia. Journal of Clinical Nursing19, 621-631. Journal of Clinical Nursing 20, 297-298. PMID- 22494426 TI - Hypovitaminosis D and pain in cystic fibrosis. PMID- 22494429 TI - MicroRNAs in rheumatoid arthritis: potential role in diagnosis and therapy. AB - Rheumatoid arthritis (RA) is a systemic, inflammatory, autoimmune disorder with progressive articular damage that may result in lifelong disability. Although major strides in understanding the disease have been made, the pathogenesis of RA has not yet been fully elucidated. Early treatment can prevent severe disability and lead to remarkable patient benefits, although a lack of therapeutic efficiency in a considerable number of patients remains problematic. MicroRNAs (miRNAs) are small, non-coding RNAs that, depending upon base pairing to messenger RNA (mRNA), mediate mRNA cleavage, translational repression or mRNA destabilization. As fine tuning regulators of gene expression, miRNAs are involved in crucial cellular processes and their dysregulation has been described in many cell types in different diseases. In body fluids, miRNAs are present in microvesicles or incorporated into complexes with Argonaute 2 (Ago2) or high density lipoproteins and show high stability. Therefore, they are of interest as potential biomarkers of disease in daily diagnostic applications. Targeting miRNAs by gain or loss of function approaches have brought therapeutic effects in various animal models. Over the past several years it has become clear that alterations exist in the expression of miRNAs in patients with RA. Increasing numbers of studies have shown that dysregulation of miRNAs in peripheral blood mononuclear cells or isolated T lymphocytes, in synovial tissue and synovial fibroblasts that are considered key effector cells in joint destruction, contributes to inflammation, degradation of extracellular matrix and invasive behaviour of resident cells. Thereby, miRNAs maintain the pathophysiological process typical of RA. The aim of the current review is to discuss the available evidence linking the expression of miRNAs to inflammatory and immune response in RA and their potential as biomarkers and the novel targets for treatment in patients with RA. PMID- 22494428 TI - Implementation outcomes of evidence-based quality improvement for depression in VA community based outpatient clinics. AB - BACKGROUND: Collaborative-care management is an evidence-based practice for improving depression outcomes in primary care. The Department of Veterans Affairs (VA) has mandated the implementation of collaborative-care management in its satellite clinics, known as Community Based Outpatient Clinics (CBOCs). However, the organizational characteristics of CBOCs present added challenges to implementation. The objective of this study was to evaluate the effectiveness of evidence-based quality improvement (EBQI) as a strategy to facilitate the adoption of collaborative-care management in CBOCs. METHODS: This nonrandomized, small-scale, multisite evaluation of EBQI was conducted at three VA Medical Centers and 11 of their affiliated CBOCs. The Plan phase of the EBQI process involved the localized tailoring of the collaborative-care management program to each CBOC. Researchers ensured that the adaptations were evidence based. Clinical and administrative staff were responsible for adapting the collaborative-care management program for local needs, priorities, preferences and resources. Plan Do-Study-Act cycles were used to refine the program over time. The evaluation was based on the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) Framework and used data from multiple sources: administrative records, web-based decision-support systems, surveys, and key-informant interviews. RESULTS: Adoption: 69.0% (58/84) of primary care providers referred patients to the program. Reach: 9.0% (298/3,296) of primary care patients diagnosed with depression who were not already receiving specialty care were enrolled in the program. Fidelity: During baseline care manager encounters, education/activation was provided to 100% (298/298) of patients, barriers were assessed and addressed for 100% (298/298) of patients, and depression severity was monitored for 100% (298/298) of patients. Less than half (42.5%, 681/1603) of follow-up encounters during the acute stage were completed within the timeframe specified. During the acute phase of treatment for all trials, the Patient Health Questionnaire (PHQ9) symptom-monitoring tool was used at 100% (681/681) of completed follow-up encounters, and self-management goals were discussed during 15.3% (104/681) of completed follow-up encounters. During the acute phase of treatment for pharmacotherapy and combination trials, medication adherence was assessed at 99.1% (575/580) of completed follow-up encounters, and side effects were assessed at 92.4% (536/580) of completed follow-up encounters. During the acute phase of treatment for psychotherapy and combination trials, counseling session adherence was assessed at 83.3% (239/287) of completed follow-up encounters. Effectiveness: 18.8% (56/298) of enrolled patients remitted (symptom free) and another 22.1% (66/298) responded to treatment (50% reduction in symptom severity). Maintenance: 91.9% (10/11) of the CBOCs chose to sustain the program after research funds were withdrawn. CONCLUSIONS: Provider adoption was good, although reach into the target population was relatively low. Fidelity and maintenance were excellent, and clinical outcomes were comparable to those in randomized controlled trials. Despite the organizational barriers, these findings suggest that EBQI is an effective facilitation strategy for CBOCs. TRIAL REGISTRATION: Clinical trial # NCT00317018. PMID- 22494430 TI - Meryl Streep and the problems of clinical trials. PMID- 22494431 TI - Controlled switching within an organic molecule deliberately pinned to a semiconductor surface. AB - Bistable organic molecules were deposited on a weakly binding III-V semiconductor surface and then pinned into place using individual native adatoms. These pinning atoms, positioned by atomically precise manipulation techniques in a cryogenic scanning tunneling microscope (STM) at 5 K, stabilize the pi-conjugated molecule against rotation excited by the tunneling electrons. The pinning allows triggering of the molecule's intrinsic switching mechanism (a hydrogen transfer reaction) by the STM tunnel current. Density-functional theory calculations reveal that the energetics of the switching process is virtually unaffected by both the surface and the pinning atoms. Hence, we have demonstrated that individual molecules with predictable, predefined functions can be stabilized and assembled on semiconductor templates. PMID- 22494432 TI - A ferromagnetic methoxido-bridged Mn(III) dimer and a spin-canted metamagnetic MU(1,3)-azido-bridged chain. AB - Two new Mn(III) complexes of formulas [MnL(1)(N(3))(OMe)](2) (1) and [MnL(2)(N(3))(2)](n) (2) have been synthesized by using two tridentate NNO-donor Schiff base ligands HL(1){(2-[(3-methylaminoethylimino)-methyl]-phenol)} and HL(2) {(2-[1-(2-dimethylaminoethylimino)methyl]phenol)}, respectively. Substitution of the H atom on the secondary amine group of the N-methyldiamine fragment of the Schiff base by a methyl group leads to a drastic structural change from a methoxido-bridged dimer (1) to a single MU(1,3)-azido-bridged 1D helical polymer (2). Both complexes were characterized by single-crystal X-ray structural analyses and variable-temperature magnetic susceptibility measurements. The magnetic properties of compound 1 show the presence of weak ferromagnetic exchange interactions mediated by double methoxido bridges (J = 0.95 cm(-1)). Compound 2 shows the existence of a weak antiferromangetic coupling along the chain (J = -8.5 cm(-1)) through the single MU(1,3)-N(3) bridge with a spin canting that leads to a long-range antiferromagnetic order at T(c) ~ 9.3 K and a canting leading to a weak ferromagnetic long-range order at T(c) ~ 8.5 K. It also exibits metamagnetic behavior at low temperatures with a critical field of ca.1.2 T due to the weak antiferromagnetic interchain interactions that appear in the canted ordered phase. PMID- 22494433 TI - Implants in reconstructed bone: a comparative study on the outcome of Straumann(r) tissue level and bone level implants placed in vertically deficient alveolar ridges treated by means of autogenous onlay bone grafts. AB - PURPOSE: To evaluate: (1) the survival rate of Straumann(r) Tissue Level and Bone Level implants placed in atrophic edentulous jaws previously reconstructed by means of autogenous onlay bone grafts; (2) to compare peri-implant bone resorption values over time. MATERIALS AND METHODS: From 2005 to 2010, 50 patients presenting with vertical or tridimensional defects of the edentulous ridges were treated with autogenous bone grafts. Three to 7 months afterward, 192 implants were placed (Group A: 97 Tissue Level implants; Group B: 95 Bone Level implants) in the reconstructed areas. After a further waiting period of 2 to 3 months, patients were rehabilitated with implant-supported fixed prostheses. The follow-up ranged from 12 to 68 months after the start of prosthetic loading (mean: 33 months). RESULTS: No implants were removed (survival rate: 100%), but in Group B 13 implants (8 placed in iliac grafts, 2 placed in ramus grafts, and 3 placed in calvarial grafts) presented peri-implant bone resorption values higher than those proposed by Albrektsson and colleagues. for successful implants: the overall implant success rate was then 100% for Group A and 86.8% for Group B. No prosthetic failures were recorded, thus leading to a 100% prostheses success rate. CONCLUSION: No significant differences were found between the two types of implants as far as implant survival rate is concerned, but results from this study seem to demonstrate that Tissue Level implants may present better long-term results in terms of peri-implant bone maintenance, as compared with Bone Level implants, when placed in reconstructed areas. PMID- 22494435 TI - Mesenchymal stem cell therapy prevents interstitial fibrosis and tubular atrophy in a rat kidney allograft model. AB - In solid organ transplantation, mesenchymal stem cell (MSC) therapy is strongly emerging among other cell therapies due to the positive results obtained in vitro and in vivo as an immunomodulatory agent and their potential regenerative role. We aimed at testing whether a single dose of MSCs, injected at 11 weeks after kidney transplantation for the prevention of chronic mechanisms, enhanced regeneration and provided protection against the inflammatory and fibrotic processes that finally lead to the characteristic features of chronic allograft nephropathy (CAN). Either bone marrow mononuclear cells (BMCs) injection or no therapy (NT) were used as control treatments. A rat kidney transplantation model of CAN with 2.5 h of cold ischemia was used, and functional, histological, and molecular parameters were assessed at 12 and 24 weeks after transplantation. MSC and BMC cell therapy preserves renal function at 24 weeks and abrogates proteinuria, which is typical of this model (NT24w: 68.9 +/- 26.5 mg/24 h, MSC24w: 16.6 +/- 2.3 mg/24 h, BMC24w: 24.1 +/- 5.3 mg/24 h, P<0.03). Only MSC treated animals showed a reduction in interstitial fibrosis and tubular atrophy (NT24w: 2.3 +/- 0.29, MSC24w: 0.4 +/- 0.2, P<0.03), less T cells (NT: 39.6 +/- 9.5, MSC: 8.1 +/- 0.9, P<0.03) and macrophages (NT: 20.9 +/- 4.7, MSC: 5.9 +/- 1.7, P<0.05) infiltrating the parenchyma and lowered expression of inflammatory cytokines while increasing the expression of anti-inflammatory factors. MSCs appear to serve as a protection from injury development rather than regenerate the damaged tissue, as no differences were observed in Ki67 expression, and kidney injury molecule-1, Clusterin, NGAL, and hepatocyte growth factor expression were only up-regulated in nontreated animals. Considering the results, a single delayed MSC injection is effective for the long-term protection of kidney allografts. PMID- 22494436 TI - Chronic wounds - is cellular 'reception' at fault? Examining integrins and intracellular signalling. AB - As with all physiologic processes, chronic wounds are associated with unique intracellular and cellular/extracellular matrix (ECM) receptor types and signalling messages. These cellular receptors mediate responses of the epidermis to provisional wound matrix and change in form and number in cases of impaired wound healing. Integrins are the major cell-surface receptors for cell adhesion and migration and epidermal keratinocytes express several integrins that bind ECM ligands in provisional wound ECM. Integrin receptors and more particularly integrin clusters and focal adhesion points appear to influence epidermal and dermal cell matrix interactions, cell motility, cell phenotype and ultimate healing trajectory. In chronic wounds, a variety of changes in receptors have been identified: decreased integrin alpha5beta1 receptors affect the integration of fibronectin and subsequent keratinocyte migration; integrin alphavbeta6 stimulate transforming growth factor (TGF)-beta and may increase the susceptibility to ulceration and fibrosis; however, TGF-beta signal receptors have been found to be dysfunctional in many chronic wounds; additionally receptor interactions result in increased senescent cells including fibroblasts, myofibroblasts and even keratinocytes - this produces a degradative ECM and wound bed and corrosive chronic wound fluid. The activation or inhibition of integrin receptors by various agents may provide an excellent means of influencing wound healing. This process offers an earlier intervention into the wound healing cascade promoting intrinsic healing and elaboration of growth factors and ECM proteins, which may be more cost effective than the traditional attempts at extrinsic addition of these agents. PMID- 22494437 TI - Designing informed game-based rehabilitation tasks leveraging advances in virtual reality. AB - PURPOSE: This paper details a brief history and rationale for the use of virtual reality (VR) technology for clinical research and intervention, and then focuses on game-based VR applications in the area of rehabilitation. An analysis of the match between rehabilitation task requirements and the assets available with VR technology is presented. KEY MESSAGES AND IMPLICATIONS: Low-cost camera-based systems capable of tracking user behavior at sufficient levels for game-based virtual rehabilitation activities are currently available for in-home use. Authoring software is now being developed that aims to provide clinicians with a usable toolkit for leveraging this technology. This will facilitate informed professional input on software design, development and application to ensure safe and effective use in the rehabilitation context. CONCLUSION: The field of rehabilitation generally stands to benefit from the continual advances in VR technology, concomitant system cost reductions and an expanding clinical research literature and knowledge base. Home-based activity within VR systems that are low cost, easy to deploy and maintain, and meet the requirements for "good" interactive rehabilitation tasks could radically improve users' access to care, adherence to prescribed training and subsequently enhance functional activity in everyday life in clinical populations. PMID- 22494438 TI - Reliability of Hoechst 33342 staining under wide-field microscopy for evaluation of the nuclear status of living dog oocytes. AB - Due to the marked cytoplasmic opacity of canine oocytes, the diagnosis of their nuclear status is difficult. The objective of the present study was to evaluate the accuracy of Hoechst staining observed under epifluorescence wide-field microscopy [living oocyte observation (LivOO)] by comparison to a reference technique [DNA staining with ethidium homodimer-2 under confocal microscopy; fixed oocyte observation (FixOO)]. Four Hoechst 33342 concentrations (200 ng, 500 ng, 1 MUg, 2 MUg/mL) were tested and 1 MUg/mL was the lowest one with the lowest proportion of oocytes in which DNA was missed. At this concentration, LivOO procedure did not affect the degeneration rate. On 379 oocytes observed individually with the two techniques successively, diagnosis of meiosis resumption by LivOO was exact in 87.3% of the cases, but the meiosis resumption rate was underestimated (23.5% versus 34.3% with FixOO; p < 0.001). Diagnosis for metaphase II was exact in 80% of the cases, but LivOO detected only 72.7% of the metaphase II oocytes present. Metaphase rates did not differ between LivOO and FixOO. This study contributes to a better interpretation of in vitro maturation results. The developmental potential of metaphase II canine oocytes sorted after Hoechst staining is to be evaluated. PMID- 22494439 TI - 3D-QSAR studies on UDP-glucuronosyltransferase 2B7 substrates using the pharmacophore and VolSurf approaches. AB - UDP-glucuronosyltransferase 2B7 (UGT2B7) is an important enzyme responsible for clearance of many drugs. Here, we report two 3D quantitative structure-activity relationship (QSAR) models for UGT2B7 using the pharmacophore and VolSurf approach, respectively. The dataset included 53 structurally diverse UGT2B7 substrates, 36 of which were used for the training set and 17 of which for the external test set. Pharmacophore-based 3D-QSAR model (or hypothesis) was developed using the Discovery Studio program. A user-defined "glucuronidation site" feature was forcefully included in a pharmacophore hypothesis. VolSurf based 3D-QSAR model was generated using the VolSurf program. This involves calculation of VolSurf descriptors, variable selection with the FFD algorithm, and partial least squares (PLS) analyses. The best pharmacophore model (r(2) = 0.736) consists of one glucuronidation site, one hydrogen bond acceptor, and three hydrophobic regions. Using this model, K(m) values for 14 of 17 test substrates were predicted within one log unit. The yielded VolSurf (PLS) model with two components shows statistical significance in both fitting and internal predicting (r(2) = 0.866, q(2) = 0.728). Further, the K(m) values for all test substrates were predicted within one log unit. In addition, the VolSurf model reveals an overlay of chemical features influencing the enzyme-substrate binding. Those include molecular size and shape, integy moments, capacity factors, best volumes of DRY probe, H-bonding, and log P. In conclusion, the pharmacophore and VolSurf approaches are successfully utilized to establish predictive models for UGT2B7. The derived models should be an efficient tool for high throughput prediction of UGT2B7 metabolism. PMID- 22494440 TI - Gastroesophageal reflux disease and tympanoplasty surgical outcome: is there a relationship? AB - OBJECTIVE: To investigate the possible clinical relationship between gastroesophageal reflux disease and the type one tympanoplasty surgical outcomes of adults with chronic otitis media, by using a simple, cost-effective, reliable questionnaire and physical findings. METHODS: Fifty-two of 147 patients undergoing type one tympanoplasty were studied. Gastroesophageal reflux disease symptoms were evaluated using the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease questionnaire. Laryngoscopic physical findings of laryngopharyngeal reflux were evaluated using the Reflux Finding Score. A successful outcome was defined as an intact tympanic membrane. Correlations between the two assessment tool results and the patient's surgical success were calculated. RESULTS: The gastroesophageal reflux disease questionnaire score was significantly higher in patients with unsuccessful tympanic membrane closure (group one) than in patients with successful closure (group two) (p < 0.05). The Reflux Finding Score was also significantly higher in group one than group two (p < 0.05). There was a significant positive relationship between the gastroesophageal reflux disease questionnaire score and the Reflux Finding Score (p < 0.01). CONCLUSION: Gastroesophageal reflux disease may be a significant prognostic factor for tympanoplasty failure. Therefore, reflux investigation may be important during the treatment of chronic otitis media, and positive cases may need reflux treatment as well as ear disease treatment. PMID- 22494441 TI - Anticonvulsant and analgesic activities of crude extract and its fractions of the defensive secretion from the Mediterranean sponge, Spongia officinalis. AB - This study progresses in the direction of identifying component(s) from the Mediterranean sponge, Spongia officinalis with anticonvulsant and analgesic activities. We investigated the efficacy of crude extract and its semi-purified fractions (F1-F3) of the defensive secretion from Spongia officinalis for their in vivo anticonvulsant activity using the pentylenetetrazole (PTZ) seizure model and analgesic activity using the writhing test in mice. Among the series the crude extract exhibited interesting analgesic activity in a dose dependent manner. Similarly the fraction F2 showed a partial protection of mice from PTZ induced seizure and interesting analgesic activity in a dose dependent manner. The purification and the determination of chemical structure(s) of compound(s) of this active fraction are under investigation. PMID- 22494442 TI - Re: Ureteral stent encrustation, incrustation, and coloring: morbidity related to indwelling times. PMID- 22494443 TI - Biological degradation of anthroquinone and azo dyes by a novel laccase from Lentinus sp. AB - This study identifies a new fungal strain, Lentinus sp., that can produce extracellular forms of laccases with an activity of approximately 58 300 U/L. A purified laccase (designated lcc3) was identified by LC-ESI MS/MS as an N-linkage glycosylated protein. The isolated lcc3 cDNA is composed of 1563 bp encoding for a polypeptide of 521 amino acid residues with 4 putative Cu binding regions. Kinetic analyses revealed that the specific activity, k(cat), K(m), and k(cat)/K(m) of lcc3 at pH 2.5 and 70 degrees C with 2,2'-azino-bis-(3 ethylbenzthiazoline-6-sulfonic acid) used as a substrate was 2047 U mg(-1), 2017 s(-1), 8.4 MUM, and 240 s(-1) MUM(-1), respectively. Lcc3 is stable at pH 6.0 10.0 and has a midpoint temperature (T(m)) of 77.1 degrees C. We observed 97% decolorization efficiency on Acid Blue 80, 88% on RBBR, and 61% on Acid Red 37 by lcc3. Structural modeling analysis showed that five, four, and three hydrogen bonds can be formed between Acid Blue 80 and Arg(178), Arg(182), or Asn(358); between RBBR and His(132), Ser(134), or Asp(482); and between Acid Red 37 and Arg(178), respectively. Notably, Lentinus lcc3 efficiently reversed the toxicity of anthraquinone and azo dyes on rice seed germination and decolorized industrial textile effluent, suggesting the enzyme may be valuable for bioremediation. PMID- 22494446 TI - Macroscopic assembly of indefinitely long and parallel nanowires into large area photodetection circuitry. AB - Integration of nanowires into functional devices with high yields and good reliability turned out to be a lot more challenging and proved to be a critical issue obstructing the wide application of nanowire-based devices and exploitation of their technical promises. Here we demonstrate a relatively easy macrofabrication of a nanowire-based imaging circuitry using a recently developed nanofabrication technique. Extremely long and polymer encapsulated semiconducting nanowire arrays, mass-produced using the iterative thermal drawing, facilitate the integration process; we manually aligned the fibers containing selenium nanowires over a lithographically defined circuitry. Controlled etching of the encapsulating polymer revealed a monolayer of nanowires aligned over an area of 1 cm(2) containing a 10 * 10 pixel array. Each light-sensitive pixel is formed by the contacting hundreds of parallel photoconductive nanowires between two electrodes. Using the pixel array, alphabetic characters were identified by the circuitry to demonstrate its imaging capacity. This new approach makes it possible to devise extremely large nanowire devices on planar, flexible, or curved substrates with diverse functionalities such as thermal sensors, phase change memory, and artificial skin. PMID- 22494445 TI - The high comorbidity burden of the hepatitis C virus infected population in the United States. AB - BACKGROUND: Chronic hepatitis C (HCV) disease can be complicated with comorbid conditions that may impact treatment eligibility and outcomes. The aim of the study was to systematically review comorbidities and symptoms in an HCV infected population, specifically assessing comorbidities associated with HCV anti-viral treatment and disease, as well as comparing comorbidities between an HCV infected and uninfected control population. METHODS: This was a retrospective cohort study within a United States medical claims database among patients with chronic HCV designed to estimate the two-year period prevalence of comorbidities. Patients with two HCV diagnosis codes, 24 months of continuous health insurance coverage, and full medical and pharmacy benefits were included. RESULTS: Among a chronic HCV cohort of 7411 patients, at least one comorbid condition was seen in almost all patients (> 99%) during the study period. HCV-infected patients reported almost double the number of comorbidities compared to uninfected controls. Of the 25 most common comorbidities, the majority of the comorbidities (n = 22) were known to be associated with either HCV antiviral treatment or disease. The five most frequent comorbidities were liver disease [other] (37.5%), connective tissue disease (37.5%), abdominal pain (36.1%), upper respiratory infections (35.6%), and lower respiratory disease (33.7%). Three notable comorbidities not known to be associated with antiviral treatment or disease were benign neoplasms (24.3%), genitourinary symptoms & ill-defined conditions (14.8%), and viral infections (13.8%). CONCLUSIONS: This US medically insured HCV population is highly comorbid. Effective strategies to manage these comorbidities are necessary to allow wider access to HCV treatment and reduce the future burden of HCV disease and its manifestations. PMID- 22494444 TI - Prodrug strategy for PSMA-targeted delivery of TGX-221 to prostate cancer cells. AB - TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110beta catalytic subunit. Recent studies showed that TGX-221 has antiproliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles was significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than that of the naked drug, and the drug clearance rate was 6.16-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment. PMID- 22494447 TI - Hb Haaglanden: a new nonsickling beta7Glu>Val variant. Consequences for basic diagnostics, screening, and risk assessment when dealing with HbS-like variants. AB - INTRODUCTION: To report a new hemoglobin variant undistinguishable from the common HbS on HPLC. To show the efficiency of the simplest confirmation method for HbS and to discuss the implications that may occur if HbS-like variants are wrongly reported as HbS. METHODS: Basic hematology, separation and measurement of the Hb fractions, 'sickle test,' and molecular analysis. RESULTS: The abnormal Hb fractions were eluting in the HbS window on HPLC, sickle test was however negative, and DNA sequencing of the beta globin gene revealed an unclassified variant HBBc.23A>T, p.Glu8Val in heterozygous form. CONCLUSIONS: Although the amino acid substitution of this new variant is identical to that of HbS and shifted of a single amino acid position, no polymerization occurs in vitro. The sickle test is a valid method to confirm or exclude HbS trait in individual cases. Whenever the case is part of a possible couple at risk, then one has to use full DNA analysis in both partners not to miss hidden concomitant defects important for genetic risk predictions. PMID- 22494448 TI - Long-acting injectable antipsychotics for the maintenance treatment of bipolar disorder. AB - Depot antipsychotics have been used as a strategy to reduce non-adherence to medications in schizophrenia and bipolar disorder (BD). This article reviews the literature on the efficacy and safety of first- and second-generation depot antipsychotics (FGDA and SGDA, respectively) for the maintenance treatment of BD. Although FGDA have been studied in BD, they have not been approved for use in this disease. Among the SGDA, only depot risperidone has been studied and approved for the maintenance treatment of BD. We found eight studies on FGDA (three on flupenthixol, two on depot haloperidol, one on fluphenazine and flupenthixol, two on a mix of diverse antipsychotics) and ten studies on SGDA (all on depot risperidone). Differences in efficacy and safety were found between the two classes of depot antipsychotics. Although FGDA may be effective in reducing manic relapses, they possibly increase the risk of worsening depression. Depot risperidone is effective as a maintenance treatment in BD with effect noted predominantly for preventing mania. However, no worsening in depression was observed. Depot risperidone also is better tolerated than FGDA, mainly in relation to extrapyramidal symptoms. Studies with the new depot antipsychotics, olanzapine pamoate and paliperidone palmitate, are needed in BD patients. Further, there is currently little information on the metabolic changes (apart from bodyweight gain) that may occur with the use of depot risperidone in patients with bipolar disorder, and this issue needs further investigation. PMID- 22494449 TI - Multicentre prospective observational study on professional wound care using honey (MedihoneyTM). AB - In recent years, the treatment of wounds with honey has received an increasing amount of attention from healthcare professionals in Germany and Austria. We conducted a prospective observational multicentre study using MedihoneyTM dressings in 10 hospitals - nine in Germany and one in Austria. Wound-associated parameters were monitored systematically at least three times in all patients. Data derived from the treatment of 121 wounds of various aetiologies over a period of 2 years were analysed. Almost half of the patients were younger than 18 years old, and 32% of the study population was oncology patients. Overall, wound size decreased significantly during the study period and many wounds healed after relatively short time periods. Similarly, perceived pain levels decreased significantly, and the wounds showed noticeably less slough/necrosis. In general, our findings show honey to be an effective and feasible treatment option for professional wound care. In addition, our study showed a relationship between pain and slough/necrosis at the time of recruitment and during wound healing. Future comparative trials are still needed to evaluate the extent to which the positive observations made in this and other studies can definitely be attributed to the effects of honey in wound care. PMID- 22494450 TI - What is the future of CCR5 antagonists in rheumatoid arthritis? PMID- 22494451 TI - Improved electrogram attenuation during ablation of paroxysmal atrial fibrillation with the Hansen robotic system. AB - BACKGROUND: Robotic catheter ablation aims to improve outcomes after ablation of atrial fibrillation (AF) through improved lesion quality. This study examined electrogram attenuation as a measure of efficacy in response to robotic (ROB) and manual (MAN) ablation. METHODS: Patients with paroxysmal AF undergoing ablation as part of an ongoing randomized controlled trial were studied (Clinical Trials Registration NCT01037296). Patients underwent pulmonary vein isolation using NavX (St. Jude Medical, St. Paul, MN, USA). Patients were randomized to MAN or ROB catheter ablation using a 3.5-mm irrigated-tip catheter with standardized ablation settings. Bipolar electrogram voltage was measured at 0, 5, 10, 20, and 30 seconds after ablation onset. Distance from ablation lesion to the left atrial surface on NavX were calculated. RESULTS: Similar ablation energy was delivered in ROB and MAN groups, achieving comparable rates of PV isolation (100% vs 98%). The bipolar voltages of 4,434 electrograms from 303 ablation lesions (146 ROB, 157 MAN) were measured. At 30 seconds, signal attenuation was greater in the ROB group than MAN (mean 65 +/- 4% vs 55 +/- 4% of baseline voltage, P < 0.01). A total of 2,064 NavX ablation lesions were assessed (906 ROB and 1,158 MAN). ROB lesions were on average 0.52 mm further inside the geometry than MAN (P < 0.0001). CONCLUSIONS: Robotic ablation results in greater signal attenuation in man. This is achieved despite manual lesions being closer to the left atrial surface. Catheter stability and constant energy delivery may be key to achieving signal attenuation, rather than increased contact force. PMID- 22494452 TI - Mortality and hospitalisation costs of rheumatic fever and rheumatic heart disease in New Zealand. AB - AIMS: To estimate the annual mortality and the cost of hospital admissions for acute rheumatic fever (ARF) and rheumatic heart disease (RHD) for New Zealand residents. METHODS: Hospital admissions in 2000-2009 with a principal diagnosis of ARF or RHD (ICD9_AM 390-398; ICD10-AM I00-I099) and deaths in 2000-2007 with RHD as the underlying cause were obtained from routine statistics. The cost of each admission was estimated by multiplying its diagnosis-related group (DRG) cost weight by the national price for financial year 2009/2010. RESULTS: There were on average 159 RHD deaths each year with a mean annual mortality rate of 4.4 per 100, 000 (95% confidence limit 4.2, 4.7). Age-adjusted mortality was five- to 10-fold higher for Maori and Pacific peoples than for non-Maori/Pacific. The mean age at RHD death (male/female) was 56.4/58.4 for Maori, 50.9/59.8 for Pacific and 78.2/80.6 for non-Maori, non-Pacific men and women. The average annual DRG-based cost of hospital admissions in 2000-2009 for ARF and RHD across all age groups was $12.0 million (95% confidence limit $11.1 million, $12.8 million). Heart valve surgery accounted for 28% of admissions and 71% of the cost. For children 5 14 years of age, valve surgery accounted for 7% of admissions and 27% of the cost. Two-thirds of the cost occurs after the age of 30. CONCLUSIONS: ARF and RHD comprise a burden of mortality and hospital cost concentrated largely in middle age. Maori and Pacific RHD mortality rates are substantially higher than those of non-Maori/Pacific. PMID- 22494454 TI - The importance of a percutaneous trial of a spinal cord stimulator in a patient with extreme scoliosis. PMID- 22494455 TI - Sensitivity of silver(I) complexes of a pyrimidine-hydrazone ligand to solvent, counteranion, and metal-to-ligand ratio changes. AB - Metal complexation studies were performed with AgSO(3)CF(3) and AgBF(4) and the ditopic pyrimidine-hydrazone ligand 6-(hydroxymethyl)pyridine-2-carboxaldehyde (2 methylpyrimidine-4,6-diyl)bis(1-methylhydrazone) (1) in both CH(3)CN and CH(3)NO(2) in a variety of metal-to-ligand ratios. The resulting complexes were studied in solution by NMR spectroscopy and in the solid state by X-ray crystallography. Reacting either AgSO(3)CF(3) or AgBF(4) with 1 in either CH(3)CN or CH(3)NO(2) in a 1:1 metal-to-ligand ratio produced a double helicate in solution. This double helicate could be converted into a linear complex by increasing the metal-to-ligand ratio; however, the degree of conversion depended on the solvent and counteranion used. Attempts to crystallize the linear AgSO(3)CF(3) complex resulted in crystals with the dimeric structure [Ag(2)1(CH(3)CN)(2)](2)(SO(3)CF(3))(4) (2), while attempts to crystallize the AgSO(3)CF(3) double helicate from CH(3)CN resulted in crystals of another dimeric complex, [Ag(2)1(SO(3)CF(3))(CH(3)CN)(2)](2)(SO(3)CF(3))(2).H(2)O (3). The AgSO(3)CF(3) double helicate was successfully crystallized from a mixture of CH(3)CN and CH(3)NO(2) and had the structure [Ag(2)1(2)](SO(3)CF(3))(2).3CH(3)NO(2) (4). The linear AgBF(4) complex could not be isolated from the double helicate in solution; however, crystals grown from a solution containing both the AgBF(4) double helicate and linear complexes in CH(3)CN had the structure [Ag(2)1(CH(3)CN)(2)](BF(4))(2) (5). The AgBF(4) double helicate could only be crystallized from CH(3)NO(2) and had the structure [Ag(2)1(2)](BF(4))(2).2CH(3)NO(2) (6). PMID- 22494456 TI - Emergency total thyroidectomy due to non traumatic disease. Experience of a surgical unit and literature review. AB - BACKGROUND: Acute respiratory failure due to thyroid compression or invasion of the tracheal lumen is a surgical emergency requiring urgent management. The aim of this paper is to describe a series of six patients treated successfully in the emergency setting with total thyroidectomy due to ingravescent dyspnoea and asphyxia, as well as review related data reported in literature. METHODS: During 2005-2010, of 919 patients treated by total thyroidectomy at our Academic Hospital, 6 (0.7%; 4 females and 2 men, mean age: 68.7 years, range 42-81 years) were treated in emergency. All the emergency operations were performed for life threatening respiratory distress. The clinical picture at admission, clinical features, type of surgery, outcomes and complications are described. Mean duration of surgery was 146 minutes (range: 53-260). RESULTS: In 3/6 (50%) a manubriotomy was necessary due to the extension of the mass into the upper mediastinum. In all cases total thyroidectomy was performed. In one case (16.7%) a parathyroid gland transplantation and in another one (16.7%) a tracheotomy was necessary due to a condition of tracheomalacia. Mean post-operative hospital stay was 6.5 days (range: 2-10 days). Histology revealed malignancy in 4/6 cases (66.7%), showing 3 primitive, and 1 secondary tumors. Morbidity consisted of 1 transient recurrent laryngeal palsy, 3 transient postoperative hypoparathyroidism, and 4 pleural effusions, treated by medical therapy in 3 and by drains in one. There was no mortality. CONCLUSION: On the basis of our experience and of literature review, we strongly advocate elective surgery for patients with thyroid disease at the first signs of tracheal compression. When an acute airway distress appears, an emergency life-threatening total thyroidectomy is recommended in a high-volume centre. PMID- 22494457 TI - New directions in the treatment of autism spectrum disorders from animal model research. AB - INTRODUCTION: Currently, there is not an effective pharmacotherapy for the core symptoms of the autism spectrum disorders (ASD), which include aberrant social behavior, delayed communication and repetitive behavior and/or restricted interests. There are several drugs that treat the symptoms associated with autism including irritability, aggressiveness and hyperactivity. Current drug research is based on the ongoing genetic, animal model and neuropathologic research. Two areas in particular, the glutamate and oxytocin systems, provide exciting new avenues for drug discovery. AREAS COVERED: This review examines what approaches have been used for the drugs that are currently being used to treat people with ASD. For the most part, drugs that treat other neuropsychiatric disorders have been examined to treat the people with ASD, unfortunately with little effect on the core symptoms. EXPERT OPINION: Until recently, there was not a plethora of knowledge about the neurobiological substrates of social behavior, pragmatic language usage and repetitive and/or restricted behaviors. Therefore, drug discovery has used the tools available for other neuropsychiatric disorders. Now that more biological information is available, there are many avenues for research for drug targets for ASD. PMID- 22494458 TI - Abundance and composition dynamics of soil ammonia-oxidizing archaea in an alpine fir forest on the eastern Tibetan Plateau of China. AB - Real-time qPCR and clone library sequencing targeting amoA genes were used to investigate the seasonal dynamics of an ammonia-oxidizing archaea (AOA) community in an alpine fir forest in western China. AOA were detected at all sampling dates, and there were significant variations in archaeal amoA gene copy numbers (7.63 * 10(5) to 8.35 * 10(8) per gram of dry soil) throughout the nongrowing season. Compared with ammonia-oxidizing bacteria (AOB), the AOA displayed a higher abundance on the majority of sampling dates during the freeze-thaw period. All of the AOA sequences fell within soil and sediment lineages and were affiliated with 7 clusters. Compared with the other clusters, cluster 1 was more sensitive to low temperature and was the dominant group in August. In contrast, cluster 3 dominated the AOA community in winter and probably represents a group of cold-adapted archaea. Redundancy analysis (RDA) revealed that the seasonality of the AOA community was mainly attributed to changes in soil temperature and nutrient availability (e.g., dissolved organic nitrogen and carbon). Our results indicate that AOA exist in frozen soils in the alpine coniferous forest ecosystem of the eastern Tibetan Plateau. Moreover, soil temperature may directly and (or) indirectly affect AOA abundance and composition and may further influence the soil N cycle during the winter. PMID- 22494459 TI - Interpretation of urine drug testing in pain patients. AB - BACKGROUND: Traditionally, urine drug screens have only been concerned with positive or negative results. Those results provide physicians treating patients for pain with chronic opioid therapy with information about medication compliance, use of nonprescribed medications, and use of illicit drugs. However, the analysis of urine for drugs offers additional information that, when compiled and accurately interpreted, may also be of great value to these doctors. PURPOSE: The aim of this article was to discuss the interpretation of urine drug tests and their application to pain physician practices. METHOD: We utilized a selection of recent articles on urine drug screening applicable to the pain patient population. RESULTS AND CONCLUSIONS: The article provides pertinent information about interpretation of urine drug testing, which is separated into six categories: which drugs and metabolites to test for; which analytical cutoffs to use; pain medication metabolism; identification of alcohol use; determination of patient compliance; and which patient groups to consider for more frequent testing. PMID- 22494460 TI - X-ray diffraction study of K- and Ca-exchanged montmorillonites in CO2 atmospheres. AB - Powder X-ray diffraction shows that K- and Ca-exchanged montmorillonites swell upon interacting with CO(2) at ambient temperatures, depending on their initial hydration state. K-exchanged montmorillonite swells rapidly to a maximum d(001) of ~12.2 A. In contrast, Ca-exchanged montmorillonite swells more slowly, but reaches a maximum d(001) of ~15.1 A. Reaction kinetics differ significantly between the K- and Ca-exchanged montmorillonite complexes. Expansion of K exchanged montmorillonite samples was rapid, occurring on time scales of tens of minutes or less. The Ca-exchanged montmorillonite samples continued to expand over periods up to 42 h. Aging of both K- and Ca-exchanged montmorillonite complexes at elevated CO(2) pressure for 1-2 days resulted in greater stability when CO(2) pressure was released. The observed intercalation reactions have important consequences for carbon sequestration: (1) CO(2) absorption by swelling clays may represent a significant pathway for storage of CO(2). (2) The swelling of smectites under CO(2) pressure may have a significant impact on the permeability of caprock formations. PMID- 22494461 TI - The role of myelin oligodendrocyte glycoprotein in autoimmune demyelination: a target for multiple sclerosis therapy? AB - INTRODUCTION: Myelin oligodendrocyte glycoprotein (MOG) is a myelin antigen at the outer surface of the central nervous system (CNS) myelin sheath, which may trigger T-cell as well as B-cell responses. It therefore constitutes a pivotal target for autoimmune responses, which result in inflammation and also demyelination in the CNS. In particular, it is a major target for auto-antibodies in experimental autoimmune encephalomyelitis (EAE), which mimics many aspects of multiple sclerosis (MS). B-cell responses toward MOG and anti-MOG antibodies have also been demonstrated in patients with demyelinating diseases, such as MS and acute disseminating encephalomyelitis (ADEM). Co-transfer of such anti-MOG antibodies in experimental models results in a distinct lesion pattern with antibody and complement-mediated demyelination, which is also hallmark of some lesion subtypes in MS. AREAS COVERED: A comprehensive literature search on MOG, B cells, MS, and ADEM was performed to outline the role of MOG in autoimmune demyelination in animal models and its relevance for human disease. EXPERT OPINION: Although the definite role of MOG in the pathogenesis of MS still remains to be clarified, innovative therapeutic strategies targeting B cells may reduce pathogenic immune responses against myelin auto-antigens including anti myelin auto-antibodies. PMID- 22494453 TI - Large-scale species delimitation method for hyperdiverse groups. AB - Accelerating the description of biodiversity is a major challenge as extinction rates increase. Integrative taxonomy combining molecular, morphological, ecological and geographical data is seen as the best route to reliably identify species. Classic molluscan taxonomic methodology proposes primary species hypotheses (PSHs) based on shell morphology. However, in hyperdiverse groups, such as the molluscan family Turridae, where most of the species remain unknown and for which homoplasy and plasticity of morphological characters is common, shell-based PSHs can be arduous. A four-pronged approach was employed to generate robust species hypotheses of a 1000 specimen South-West Pacific Turridae data set in which: (i) analysis of COI DNA Barcode gene is coupled with (ii) species delimitation tools GMYC (General Mixed Yule Coalescence Method) and ABGD (Automatic Barcode Gap Discovery) to propose PSHs that are then (iii) visualized using Klee diagrams and (iv) evaluated with additional evidence, such as nuclear gene rRNA 28S, morphological characters, geographical and bathymetrical distribution to determine conclusive secondary species hypotheses (SSHs). The integrative taxonomy approach applied identified 87 Turridae species, more than doubling the amount previously known in the Gemmula genus. In contrast to a predominantly shell-based morphological approach, which over the last 30 years proposed only 13 new species names for the Turridae genus Gemmula, the integrative approach described here identified 27 novel species hypotheses not linked to available species names in the literature. The formalized strategy applied here outlines an effective and reproducible protocol for large-scale species delimitation of hyperdiverse groups. PMID- 22494462 TI - Attitudes towards euthanasia and assisted suicide: a comparison between psychiatrists and other physicians. AB - Euthanasia and physician assisted-suicide are terms used to describe the process in which a doctor of a sick or disabled individual engages in an activity which directly or indirectly leads to their death. This behavior is engaged by the healthcare provider based on their humanistic desire to end suffering and pain. The psychiatrist's involvement may be requested in several distinct situations including evaluation of patient capacity when an appeal for euthanasia is requested on grounds of terminal somatic illness or when the patient is requesting euthanasia due to mental suffering. We compare attitudes of 49 psychiatrists towards euthanasia and assisted suicide with a group of 54 other physicians by means of a questionnaire describing different patients, who either requested physician-assisted suicide or in whom euthanasia as a treatment option was considered, followed by a set of questions relating to euthanasia implementation. When controlled for religious practice, psychiatrists expressed more conservative views regarding euthanasia than did physicians from other medical specialties. Similarly female physicians and orthodox physicians indicated more conservative views. Differences may be due to factors inherent in subspecialty education. We suggest that in light of the unique complexity and context of patient euthanasia requests, based on their training and professional expertise psychiatrists are well suited to take a prominent role in evaluating such requests to die and making a decision as to the relative importance of competing variables. PMID- 22494464 TI - Improvement of depth resolution of ADF-SCEM by deconvolution: effects of electron energy loss and chromatic aberration on depth resolution. AB - Scanning confocal electron microscopy (SCEM) is a new imaging technique that is capable of depth sectioning with nanometer-scale depth resolution. However, the depth resolution in the optical axis direction (Z) is worse than might be expected on the basis of the vertical electron probe size calculated with the existence of spherical aberration. To investigate the origin of the degradation, the effects of electron energy loss and chromatic aberration on the depth resolution of annular dark-field SCEM were studied through both experiments and computational simulations. The simulation results obtained by taking these two factors into consideration coincided well with those obtained by experiments, which proved that electron energy loss and chromatic aberration cause blurs at the overfocus sides of the Z-direction intensity profiles rather than degrade the depth resolution much. In addition, a deconvolution method using a simulated point spread function, which combined two Gaussian functions, was adopted to process the XZ-slice images obtained both from experiments and simulations. As a result, the blurs induced by energy loss and chromatic aberration were successfully removed, and there was also about 30% improvement in the depth resolution in deconvoluting the experimental XZ-slice image. PMID- 22494463 TI - Imported malaria in pregnancy in Madrid. AB - BACKGROUND: Malaria in pregnancy is associated with maternal and foetal morbidity and mortality in endemic areas, but information on imported cases to non-endemic areas is scarce.The aim of this study was to describe the clinical and epidemiological characteristics of malaria in pregnancy in two general hospitals in Madrid, Spain. METHODS: Retrospective descriptive study of laboratory confirmed malaria in pregnant women at the Fuenlabrada University Hospital and the Principe de Asturias University Hospital, in Madrid, over a six- and 11-year period, respectively. Relevant epidemiological, clinical and laboratory data was obtained from medical records. RESULTS: There were 19 pregnant women among 346 malaria cases (5.4%). The average age was 27 years. The gestational age (trimester) was: 53% 3rd, 31% 1st, 16% 2nd. All but one were multigravidae. Three were HIV positive. All were sub-Saharan immigrants: two were recently arrived immigrants and seventeen (89%) had visited friends and relatives. None had taken prophylaxis nor seeked pre-travel advice. PRESENTATION: 16 symptomatic patients (fever in fourteen, asthenia in two), three asymptomatic. Median delay in diagnosis: 7.5 days. Laboratory tests: anaemia (cut off Hb level 11 g/dl) 78.9% (mild 31.6%, moderate 31.6%, severe 15.8%) thrombocytopaenia 73.7%, hypoglycaemia 10.5%. All cases were due to Plasmodium falciparum, one case of hyperparasitaemia. Quinine + clindamycin prescribed in 84%. OUTCOMES: no severe maternal complications or deaths, two abortions, fifteen term pregnancies, no low birth-weight newborns, two patients were lost to follow-up. CONCLUSIONS: Though cases of malaria in pregnancy are uncommon, a most at risk group is clearly defined: young sub-Saharan mothers visiting friends and relatives without pre travel counselling and recently-arrived immigrants. The most common adverse maternal and foetal effects were anaemia and stillbirth. Given that presentation can be asymptomatic, malaria should always be considered in patients with unexplained anaemia arriving from endemic areas. These findings could help Maternal Health programme planners and implementers to target preventive interventions in the immigrant population and should create awareness among clinicians. PMID- 22494465 TI - Heparan sulfate proteoglycan-mediated entry pathway for charged tri-platinum compounds: differential cellular accumulation mechanisms for platinum. AB - We examined the mechanism of accumulation of charged polynuclear platinum complexes (PPCs) based on analogy of polyarginine interactions with the cell surface heparan sulfate proteoglycan (HSPG) family of protein-linked glycosoaminoglycan polysaccharides (GAGs). GAGS such as heparan sulfate (HS) and chondroitin sulfate (CS) mediate the cellular entry of many charged molecules. Fluorescence microscopy and flow cytometry showed that PPCs, but not the neutral cisplatin or oxaliplatin, blocked the cellular entry of TAMRA-R(9) (a nonarginine peptide, R(9)) coupled to the TAMRA fluorescent label 5-(and 6 )carboxytetramethylrhodamine) in Chinese hamster ovary (CHO), human colon carcinoma (HCT116), and osteosarcoma (SAOS-2) cells. Furthermore, detection of platinum accumulation in wt CHO, mutant CHO-pgsD-677 (lacking HS), and CHO-pgsA (lacking HS/CS) cells confirms that HSPG-mediated interactions are an important mechanism for PPC internalization but not so for uncharged cisplatin and oxaliplatin. Endocytosis inhibitor studies show that macropinocytosis, a mechanism of cell entry for heparan sulfate GAGs and arginine-rich peptides, is important in the cellular accumulation of noncovalent TriplatinNC and, to a lesser degree, the covalently binding BBR3464. Clathrin-mediated endocytosis, however, was not involved in either case. Overall, the results suggest a new proteoglycan-mediated mechanism for cellular accumulation of PPCs not shared by cisplatin or oxaliplatin. The results have significant implications for the rational design of platinum antitumor drugs with distinct biological profiles in comparison to those of the clinically used agents as well as expanding the chemotypes for HS proteoglycan-dependent receptors. PMID- 22494466 TI - Designing prodrugs for the treatment of Parkinson's disease. AB - INTRODUCTION: Current Parkinson's disease (PD) therapy is essentially symptomatic, and l-Dopa (LD), is the treatment of choice in more advanced stages of the disease. However, motor complications often develop after long-term treatment, and at this point physicians usually prescribe adjuvant therapy with other classes of antiparkinsonian drugs, including dopamine (DA) agonists, catechol-O-methyl transferase (COMT) or monoamine oxidase (MAO)-B inhibitors. In order to improve bioavailability, the prodrug approach appeared to be the most promising, and some antiparkinsonian prodrugs have been prepared in an effort to solve these problems. AREAS COVERED: This review discusses the evidence of progress in PD therapy, mainly focused on prodrug approach for treatment of this neurological disorder. Several derivatives were studied with the aim of enhancing its chemical stability, water or lipid solubility, as well as diminishing the susceptibility to enzymatic degradation. Chemical structures mainly related to LD, DA and dopaminergic agonists are also reviewed in this paper. EXPERT OPINION: In order to strengthen the pharmacological activity of antiparkinsonian drugs, enhancing their penetration of the blood-brain barrier (BBB), different approaches are possible. Among these, the prodrug approach appeared to be the most promising, and many prodrugs have been prepared in an effort to optimize physicochemical characteristics. In addition, novel therapeutic strategies based on formulations linking dopaminergic drugs with neuroprotective agents, increasing LD striatal levels and offering sustained release of the drug without any fluctuation of brain concentration, offer promising avenues for development of other effective new treatments for PD. PMID- 22494467 TI - Branchial cleft anomalies: accuracy of pre-operative diagnosis, clinical presentation and management. AB - OBJECTIVE: To examine the accuracy of the pre-operative diagnosis of branchial cleft anomalies, and also to describe their occurrence, clinical presentation and management. METHODS: Retrospective review of the records of patients diagnosed with a branchial cleft anomaly between 1997 and 2006. RESULTS: One hundred and twenty-six patients were included. Pre-operative diagnosis had a positive predictive value of 0.856 (95 per cent confidence interval, 0.771-0.918) and a sensitivity of 0.944 (95 per cent confidence interval, 0.869-0.979). These patients' demographic data, investigations, findings and management are presented, along with a possible strategy for dealing with solitary cystic masses in the neck. CONCLUSION: As pre-operative diagnosis has a positive predictive value of 86 per cent, cystic lesions in the neck should be presumed to be carcinomatous until proven otherwise. Branchial fistulae and sinuses seem to be a disease of childhood, while branchial cysts occur mainly in adults. Branchial cleft anomalies are equally frequent in men and women, and equally distributed on the left and right side of the neck. PMID- 22494468 TI - Non-replication study of a genome-wide association study for hypertension and blood pressure in African Americans. AB - BACKGROUND: A recent genome wide association study in 1017 African Americans identified several single nucleotide polymorphisms that reached genome-wide significance for systolic blood pressure. We attempted to replicate these findings in an independent sample of 2474 unrelated African Americans in the Milwaukee metropolitan area; 53% were women and 47% were hypertensives. METHODS: We evaluated sixteen top associated SNPs from the above genome wide association study for hypertension as a binary trait or blood pressure as a continuous trait. In addition, we evaluated eight single nucleotide polymorphisms located in two genes (STK-39 and CDH-13) found to be associated with systolic and diastolic blood pressures by other genome wide association studies in European and Amish populations. TaqMan MGB-based chemistry with fluorescent probes was used for genotyping. We had an adequate sample size (80% power) to detect an effect size of 1.2-2.0 for all the single nucleotide polymorphisms for hypertension as a binary trait, and 1% variance in blood pressure as a continuous trait. Quantitative trait analyses were performed both by excluding and also by including subjects on anti-hypertensive therapy (after adjustments were made for anti-hypertensive medications). RESULTS: For all 24 SNPs, no statistically significant differences were noted in the minor allele frequencies between cases and controls. One SNP (rs2146204) showed borderline association (p = 0.006) with hypertension status using recessive model and systolic blood pressure (p = 0.02), but was not significant after adjusting for multiple comparisons. In quantitative trait analyses, among normotensives only, rs12748299 was associated with SBP (p = 0.002). In addition, several nominally significant associations were noted with SBP and DBP among normotensives but none were statistically significant. CONCLUSIONS: This study highlights the importance of replication to confirm the validity of genome wide association study results. PMID- 22494469 TI - The influence of the HLA-DRB, HLA-DQB and polymorphic positions of the HLA DRbeta1 and HLA-DQbeta1 molecules on risk of Iranian type 1 diabetes mellitus patients. AB - Type 1 Diabetes mellitus (T1D) is an autoimmune and multifactorial disease. HLA DRB1 and DQB1 loci have the strongest association with T1D. This study aimed at investigating (i) susceptibility or protection of alleles, genotypes and haplotypes of HLA-DRB1 and DQB1 loci; and (ii) highly polymorphic amino acid residues of HLA-DRbeta1 and DQbeta1 in 105 Iranian T1D patients and 100 controls. The results indicated that DRB1*04:01, 03:01, DQB1*03:02, 02:01 alleles, DRB1*03:01/04:01, 03:01/13:03, DQB1*02:01/03:02 genotypes, DRB1*04:01-DQB1*03:02, DRB1*03:01-DQB1*02:01, DRB1*07:01-DQB1*03:03 haplotypes had positive association with T1D. In contrast, HLA-DRB1*15:01, 13:01, DQB1*03:01, 06:01 alleles, DRB1*11:01/15:01, DQB1*03:01/06:01, 03:01/05:01 genotypes and DRB1*15:01 DQB1*06:01, DRB1*11:01-DQB1*03:01 haplotypes had negative association with T1D. Analysis of amino acid sequence of HLA-DRbeta1 and DQbeta1 revealed that DRbeta1(Lys71+) and DQbeta1(Asp57-) were significantly more frequent in patients than in controls and had a positive effect in the development of T1D. Haplotype analysis demonstrated that HLA-DRB1(Lys71+) allele provided major susceptibility for T1D, and DQbeta1(Asp57-) had an additive effect. We designed an allele-specific primer to develop an easy, quick and cost-benefit method to detect the DRbeta1(Lys71+) . This method can identify all 114 DRB1 alleles encoding DRbeta1(Lys71+) by three PCR reactions. The PcPPV and PcNPV were also calculated to determine the impact of HLA genotype testing at amino acid positions. It showed that the DRbeta1(Lys71+/+) genotype carrier had 1% absolute risk of developing T1D. PMID- 22494470 TI - Reducing the pain: a systematic review of postdischarge analgesia following elective orthopedic surgery. AB - OBJECTIVE: This study aimed to determine which analgesic modalities used following discharge have the greatest efficacy in reducing postoperative pain after elective non-axial orthopedic surgery. DESIGN AND SETTING: A systematic review was conducted using the databases CENTRAL, MEDLINE, and EMBASE, as well as clinical practice guidelines databases and trial registries. Titles and abstracts were perused by two reviewers for randomized clinical trials in English fulfilling inclusion and exclusion criteria. Quality assessments, including the Oxford Quality Score, selective reporting, and sources of funding, were also performed. OUTCOME MEASURES: Pain intensity/relief, global patient evaluation, and use of rescue analgesia, as well as adverse events and withdrawals. RESULTS: 2,167 articles were retrieved and 23 articles were eligible for inclusion. They investigated analgesic modalities including alternative therapies (5); cyclooxygenase-2 inhibitors (3); nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) (12); opioids (2); and other pharmaceutical classes (1). Cycooxygenase-2 inhibitors and opioids demonstrated significant efficacy with minimal side effects. Most nonselective NSAIDs were effective analgesics but had a poorer side-effect profile. Alternative therapies demonstrated no significant efficacy. CONCLUSIONS: Opioids and cyclooxygenase-2 inhibitors are effective in providing analgesia in the extended postoperative period following orthopedic surgery with a minimal side-effect profile, while nonselective NSAIDs need to be treated with caution. Homeopathy is not an effective analgesic, while acupuncture has varied evidence and effectiveness. Treatment of postoperative fatigue may also improve analgesia control. This study provides orthopedic surgeons with a basis for evidence-based prescribing of postdischarge analgesia. However, further studies to validate these results against modern reporting standards are needed. PMID- 22494471 TI - Effect of an elastic wall on the dynamics of an encapsulated microbubble: A simulation study. AB - The purpose of the present simulation study is to reveal how confining surfaces with different mechanical properties affect the acoustic response of a contrast agent microbubble. To this end, numerical simulations are carried out for three types of walls: a plastic (OptiCell) wall, an aluminium wall, and a biological tissue. For each wall, the behaviour of contrast microbubbles of three sizes is investigated. The spectral characteristics of the scattered pressure produced by the microbubbles are compared for two cases: the bubble oscillates far away from the wall and the same bubble oscillates in the immediate vicinity of the wall. The results of the simulations allow one to make the following main conclusions. The effect of the OptiCell wall on the acoustic bubble response is stronger than that of the aluminium and tissue walls. Changes in the bubble response near the wall are stronger when bubbles are excited above their resonance frequency. Considering changes in the fundamental and the 2nd harmonic with respect to the peak values of these components at different bubble radii, it is found that the changes are stronger for smaller bubbles and that the changes in the 2nd harmonic are stronger than those in the fundamental. These results allow one to gain an insight into conditions under which the effect of an elastic wall on the acoustic response of a contrast agent microbubble is easier to be detected. PMID- 22494472 TI - A phylogeographic investigation of the hybrid origin of a species of swordtail fish from Mexico. AB - Hybrid speciation may contribute significantly to generating biodiversity, but only a few well-documented examples for it exist so far that do not involve polyploidization as a mechanism. The swordtail fish, Xiphophorus clemenciae, shows common hallmarks of a hybrid origin and still overlaps in its current geographic distribution with its putative ancestral species (Xiphophorus hellerii and Xiphophorus maculatus). Xiphophorus clemenciae provides an ideal system for investigating the possible continued genetic interactions between a hybrid and its parental species. Here, we use microsatellite and mitochondrial markers to investigate the population structure of these species of swordtails and search for signs of recent hybridization. Individuals were sampled from 21 localities across the known range of X. clemenciae- the Isthmus of Tehuantepec (IT) Mexico, and several environmental parameters that might represent barriers to dispersal were recorded. The hybridization event that gave rise to X. clemenciae appears to be rather ancient, and a single origin is likely. We find negligible evidence for ongoing hybridization and introgression between the putative ancestral species, because they now occupy distinct ecological niches, and a common haplotype is shared by most populations of X. clemenciae. The population structure within these species shows an isolation-by-distance (IBD) pattern and genetic differentiation between most populations is significant and high. We infer that tectonic evolution in the Isthmus has greatly restricted gene flow between the southern and central IT populations of X. clemenciae and X. helleriii and provide preliminary information to aid in conservation management of this geographically restricted hybrid species, X. clemenciae. PMID- 22494473 TI - PMN-PT nanowires with a very high piezoelectric constant. AB - A profound way to increase the output voltage (or power) of the piezoelectric nanogenerators is to utilize a material with higher piezoelectric constants. Here we report the synthesis of novel piezoelectric 0.72Pb(Mg(1/3)Nb(2/3))O(3) 0.28PbTiO(3) (PMN-PT) nanowires using a hydrothermal process. The unpoled single crystal PMN-PT nanowires show a piezoelectric constant (d(33)) up to 381 pm/V, with an average value of 373 +/- 5 pm/V. This is about 15 times higher than the maximum reported value of 1-D ZnO nanostructures and 3 times higher than the largest reported value of 1-D PZT nanostructures. These PMN-PT nanostructures are of good potential being used as the fundamental building block for higher power nanogenerators, high sensitivity nanosensors, and large strain nanoactuators. PMID- 22494474 TI - Direct and indirect photolysis of the phytoestrogens genistein and daidzein. AB - Genistein and daidzein are two estrogenic compounds derived from plants, especially legumes. This research begins to explore their environmental fate, focusing on direct and indirect photolysis. UV-visible spectra for both compounds at varying pH values were taken, the pK(a) values for both compounds were measured, and UV-visible spectra for each protonation state were determined. The loss of both compounds in deionized water was observed upon exposure to natural sunlight, and the quantum yields were determined for each protonation state. In Mississippi River water, direct photolysis does not account for all of the loss of genistein and daidzein. The mechanism of indirect photolysis was probed using quenchers and sensitizers, and results suggest that daidzein is transformed mainly via direct photolysis and singlet oxygenation, while genistein is transformed mainly via reaction with triplet-state natural organic matter. The parameters determined in this study will allow for estimation of the concentration of genistein and daidzein in sunlit surface waters, which will allow for assessment of any risks posed to aquatic wildlife. PMID- 22494475 TI - Ruthenium(II) thiol and H2S complexes: synthesis, characterization, and thermodynamic properties. AB - The known, green, five-coordinate species trans-RuCl(2)(P-N)(PPh(3)) react with R'SH thiols to give yellow cis-RuCl(2)(P-N)(PPh(3))(R'SH) products (P-N = o diphenylphosphino-N,N'-dimethylaniline; R' = alkyl). The MeSH and EtSH compounds are structurally characterized, with the former being the first reported for a transition metal-MeSH complex, while the thiol complexes with R' = (n)Pr, (i)Pr, (n)Pn (pentyl), (n)Hx (hexyl), and Bn (benzyl) are synthesized in situ. Other trans-RuX(2)(P-N)(PR(3)) complexes (X = Br, I; R = Ph, p-tolyl) are synthesized, and their H(2)S adducts, of a type reported earlier by our group, are also prepared. Thermodynamic data are presented for the reversible formation of the MeSH and EtSH complexes and the H(2)S analogues. The Ru(II)Cl(2)(P-N)(PPh(3)) complex in solution decomposes under O(2) to form [Ru(III)Cl(P-N)](2)(MU-O)(MU Cl)(2). PMID- 22494476 TI - Dermatologic presentations of orthopedic pathologies: a review of diagnosis and treatment. AB - Dermatologic presentations of orthopedic diseases are commonly encountered in the dermatology clinic. These disorders often necessitate prompt recognition in order to properly refer for definitive treatment as well as to avoid unnecessary diagnostic procedures. As such, the presentations of these diseases as well as the treatments available deserve special attention. This review aims to identify orthopedic diseases with dermatologic presentations and discuss the diagnosis and treatment of these pathologies. In conducting this review, a comprehensive literature search was conducted. Our inquiry was limited to conditions with a unitary orthopedic etiology. By excluding syndromic dysfunctions with both orthopedic and dermatologic manifestations, we were able to create a consistent approach to the review. At the same time, such exclusions created an omission of many important disease processes that require the cooperation of orthopedists and dermatologists. In all, 19 orthopedic disorders and disorder classes with dermatologic findings were identified and carefully examined. The orthopedic pathologies identified require varying diagnostic and therapeutic approaches. While some do not warrant further work-up or referral, the disease course of certain pathologies is drastically altered by timely recognition, cautious diagnostic interrogation, and prompt referral. PMID- 22494477 TI - Cicatricial (scarring) alopecias: an overview of pathogenesis, classification, diagnosis, and treatment. AB - Cicatricial (scarring) alopecia forms a group of disorders in which the common final pathway is the destruction of the hair follicle unit that is replaced by fibrous tissue. Hair loss may occur as a primary event when the follicle is the main target of the disease process (primary cicatricial alopecias) or as a secondary event when the follicle act as an 'innocent bystander' in the course of a disease occurring outside of the follicular unit (secondary cicatricial alopecias). Permanent hair loss may also occur in the late phases of some nonscarring alopecias that are called 'biphasic alopecias.' Primary cicatricial alopecia accounts for 5% of all trichologic consultations at the Section of Dermatology, University of Genoa, Genoa, Italy. Considering that hair loss has a strong impact on patients' psychology and quality of life, and that cicatricial alopecias can be associated with underlying systemic implications, it is extremely important that every clinician is familiar with the diagnosis and treatment of the different types of cicatricial alopecia. An accurate clinical assessment integrated with (video) dermatoscopy and histopathologic studies permits a high standard performance of correct diagnoses. A brief review of our current knowledge of disease pathogenesis and the hypothetical disease mechanisms is presented. Some practical considerations for improving the 2001 North American Hair Research Society working classification of the primary cicatricial alopecias are suggested. The aim of treatment is to slow or stop the progression of the inflammatory waves and the scarring process at the earliest phase of involvement. Recommendations for therapy are based upon a literature review, personal experience, expected adverse effects, and some pragmatic considerations such as the cost and patient compliance. PMID- 22494478 TI - Accumulation of 20 elements in great cormorant (Phalacrocorax carbo) and its main prey, common carp (Cyprinus carpio) and Prussian carp (Carassius gibelio). AB - In this study, 20 heavy metals and trace elements (Al, As, B, Ba, Cd, Co, Cr, Cu, Fe, Hg, Li, Mg, Mn, Mo, Ni, Pb, Si, Se, Sr and Zn) were analyzed in different tissues (muscle, liver, intestine, feather and bone) of the great cormorant (Phalacrocorax carbo) and in different tissues (muscle, liver, gills, kidney and gonad) of their main prey (common carp-Cyprinus carpio and Prussian carp Carassius gibelio) during the nesting season. Cormorant and fish specimens were collected at the Ecka Fishing Farm (Serbia) and from the nearby river. Principal components analysis (PCA) showed that cormorant livers were differentiated from other four tissues by higher concentrations of Hg, Fe, Cu and Mo, feathers by higher concentrations of Al and Si, and bones by higher concentrations of Sr and Mg. Differentiation among the three age classes of cormorants was observed only with regard to elemental concentrations in their feathers: subadult cormorants were differentiated by higher Hg and Zn concentrations, while the adults were separated by higher concentrations of Fe. In comparison with their prey (common carp and Prussian carp) cormorants were differentiated by higher concentrations of Fe, Hg and Cu in the muscle. Toxic mercury concentrations above 4MUgg(-1)dw were determined in the liver of juvenile cormorants, as well as in the liver and feathers of subadults. Hg concentrations were significantly correlated among all studied tissues. Cormorant had significantly higher concentrations of Fe and Hg in muscle and liver than two studied fish species. PMID- 22494479 TI - Environmental exposure to organophosphate pesticides: assessment of endocrine disruption and hepatotoxicity in pregnant women. AB - In utero exposure is the first point of contact with environmental xenobiotics that may affect the maternal-placental-fetal balance. Considering that maternal pathophysiological changes affect intrauterine development, this pilot study was conducted to address how environmental exposure to organophosphate pesticides (OPs) during pregnancy may contribute to maternal endocrine disruption and disturbed hepatic function. A prospective study was carried out with pregnant women (n=97) living in a rural area of the Rio Negro province where OPs are intensively applied throughout 6 months of the year. Blood samples were obtained and biomarkers of OPs exposure (cholinesterases and beta-glucuronidase), cortisol (CT) and progesterone (PG) levels, as well as glycemia, were determined. Parameters of liver injury were assayed by measuring aspartate aminotransferase (AST) and alanine aminotransferase (ALT); liver function was assayed by measuring albumin. Biomonitoring carried out during the pre-spraying period (PreS) and spraying period (SP) showed that the population studied was exposed to OPs, proven by the fact that plasma (PCh) and erythrocyte cholinesterase (AChE) decreased very significantly (p<0.01) during SP. CT values increased very significantly (p<0.01) in the first trimester of pregnancy during SP with respect to PreS. Individual values above the upper limit of the CT and PG reference range were found both in PreS and SP. This finding could be associated with changes in hormone metabolism pathways produced by OPs exposure. During the second trimester of pregnancy there were increases in ALT values and the AST/ALT ratio in SP, suggesting subclinical hepatotoxicity. In SP, glycemia was unchanged while albuminemia increased. Although anthropometric newborn parameters and pregnancy alterations were within normal values for the general population, the increase in CT in the maternal compartment may lead to impaired newborn health later in life. PMID- 22494480 TI - Ultrasound appearance of forearm muscles in 18 patients with complex regional pain syndrome 1 of the upper extremity. AB - OBJECTIVE: To explore the potential diagnostic utility of musculoskeletal ultrasonography (USG) changes in complex regional pain syndrome type 1 (CRPS-1) of the upper extremity. METHODS: With informed consent, 18 consecutive patients referred to our institution with CRPS-1 of the upper limb were examined with ultrasound scanning of both upper limbs. Qualitative comparison of the scan of the forearm muscles of the affected side with the unaffected side was made. RESULTS: The muscles affected by CRPS-1 demonstrated increased echogenecity. The outlines of the muscles were either indistinct or completely obliterated. A group of several muscles appeared like one homogenous, hyperechoic mass, with loss of normal architecture. Compared with the unaffected side, the muscle thickness on the CRPS-1 side measured by calipers on ultrasound was reduced irrespective of the duration of disability or disuse of the hand. The flexors and extensor muscles of the forearm were maximally affected. CONCLUSION: Ultrasonography provides useful anatomical information, regarding structure, kinesiology, and gross pathological changes of muscle, that may prove useful in understanding the motor impairment associated with CRPS-1. USG shows promise as a cost-effective bedside tool for the diagnosis of CRPS-1 and in guiding physical therapy. PMID- 22494481 TI - Oxygen absorption by skin exposed to oxygen supersaturated water. AB - The present study tests the hypothesis that skin on the plantar surface of the foot absorbs oxygen (O(2)) when immersed in water that has a high dissolved O(2) content. Healthy male and female subjects (24.2 +/- 1.4 years) soaked each foot in tap water (1.7 +/- 0.1 mg O(2).L(-1); 30.7 +/- 0.3 degrees C) or O(2)-infused water (50.2 +/- 1.7 mg O(2).L(-1); 32.1 +/- 0.5 degrees C) for up to 30 min in 50 different experiments. Transcutaneous oximetry and near infrared spectroscopy were used to evaluate changes in skin PO(2), oxygenated haemoglobin, and cytochrome oxidase aa(3) that resulted from treatment. Compared with the tap water condition, tissue oxygenation index was 3.5% +/- 1.3% higher in feet treated for 30 min with O(2)-infused water. This effect persisted after treatment, as skin PO(2) was higher in feet treated with O(2)-infused water at 2 min (237 +/- 9 vs. 112 +/- 5 mm HG) and 15 min (131 +/- 1 vs. 87 +/- 4 mm HG) post-treatment. When blood flow to the foot was occluded for 5 min, feet resting in O(2)-infused water maintained a 3-fold higher O(2) consumption rate than feet treated with tap water (9.1 +/- 1.4 vs. 3.0 +/- 1.0 uL.100 g(-1).min(-1)). We estimate that skin absorbs 4.5 mL of O(2).m(-2).min(-1) from O(2)-infused water. Thus, skin absorbs appreciable amounts of O(2) from O(2)-infused water. This finding may prove useful and assist development of treatments targeting skin diseases with ischemic origin. PMID- 22494483 TI - Incidence of acute rheumatic fever in New Zealand children and youth. AB - AIM: To estimate acute rheumatic fever (ARF) incidence rates for New Zealand children and youth by ethnicity, socioeconomic deprivation and region. METHODS: National hospital admissions with a principal diagnosis of ARF (ICD9_AM 390-392; ICD10-AM I00-I02) were obtained from routine statistics and stratified by age, ethnicity, socioeconomic deprivation index (NZDep2006) and District Health Board (DHB). RESULTS: The mean incidence rate for ARF in 2000-2009 peaked at 9 to 12 years of age. Incidence rates for children 5 to 14 years of age for Maori were 40.2 (95% confidence interval 36.8, 43.8), Pacific 81.2 (73.4, 89.6), non Maori/Pacific 2.1 (1.6, 2.6) and all children 17.2 (16.1, 18.3) per 100 000. Maori and Pacific incidence rates increased by 79% and 73% in 1993-2009, while non-Maori/Pacific rates declined by 71%. Overall rates increased by 59%. In 2000 2009, Maori and Pacific children comprised 30% of children 5-14 years of age but accounted for 95% of new cases. Almost 90% of index cases of ARF were in the highest five deciles of socioeconomic deprivation and 70% were in the most deprived quintile. A child living in the most deprived decile has about one in 150 risk of being admitted to the hospital for ARF by 15 years of age. Ten DHBs containing 76% of the population 5 to 14 years of age accounted for 94% of index cases of ARF. CONCLUSIONS: ARF with its attendant rheumatic heart disease is an increasing public health issue for disadvantaged North Island communities with high concentrations of Maori and/or Pacific families. PMID- 22494482 TI - Placebo analgesia: cognitive influences on therapeutic outcome. AB - The therapeutic response to a drug treatment is a mixture of direct pharmacological action and placebo effect. Therefore, harnessing the positive aspects of the placebo effect and reducing the negative ones could potentially benefit the patient. This article is aimed at providing an overview for clinicians of the importance of contextual psychosocial variables in determining treatment response, and the specific focus is on determinants of the placebo response. A better understanding of the physiological, psychological, and social mechanisms of placebo may aid in predicting which contexts have the greatest potential for inducing positive treatment responses. We examine the evidence for the role of psychological traits, including optimism, pessimism, and the effect of patient expectations on therapeutic outcome. We discuss the importance of the patient-practitioner relationship and how this can be used to enhance the placebo effect, and we consider the ethical challenges of using placebos in clinical practice. PMID- 22494484 TI - Characterization of the bioactive motif of neuregulin-1, a fibroblast-derived paracrine factor that regulates the constitutive color and the function of melanocytes in human skin. AB - Interactions between melanocytes and neighboring cells in the skin (keratinocytes and fibroblasts) play important roles in regulating human skin color. We recently reported that neuregulin-1 (NRG1) is highly expressed in fibroblasts from Fitzpatrick type VI skin (the darkest) and at least in part determines the constitutive color of human skin. We have now characterized the bioactive motif of NRG1 that is involved in modulating melanin production in human melanocytes. We found that 8-mer motifs (PSRYLCKC and LCKCPNEF) increased melanin production but did not increase the proliferation of melanocytes; the minimum fragment that could elicit that effect was the tetrapeptide LCKC. This smaller bioactive peptide might have an advantage in clinical applications in which it modulates only pigmentation and does not stimulate melanocyte proliferation. PMID- 22494485 TI - Why are thoracic operations postponed? AB - AIM: To investigate and present the reasons that cause the postponement of thoracic surgical operations. METHODS: We retrospectively included in the study all patients submitted to elective thoracic surgery in our department during the 4-year period 2007-2010 and noted all cases of postponement after official inclusion in the operating schedule. RESULTS: 81 out of a total of 542 patients (14.9%) scheduled for elective thoracic operation had their procedure postponed. The reasons were mainly organisatory (in 42 cases, 51.85%), which in order of significance were: shortage in matching erythrocyte units, shortage in anaesthetic/nursing staff and unavailability in operating rooms. The rest of the cases (39, 48.1%) were postponed due to medical reasons, which in descending order of significance were: respiratory infections and exacerbations of COPD, cardiological problems, misregulation of antiplatelet/antithrombotic drugs and infections from other systems (gastrointestinal, urinary, etc.). Elderly male patients planned for major/oncologic surgery were most possible to have their operation postponed for medical reasons. DISCUSSION-CONCLUSIONS: Thoracic operations are postponed owed to organisatory as well as medical reasons, the latter mainly affecting elderly, morbid patients awaiting for major/oncologic surgery. PMID- 22494486 TI - Acellular bone colonization and aggregate culture conditions diversely influence murine periosteum mesenchymal stem cell differentiation potential in long-term in vitro osteoinductive conditions. AB - Periosteum contains mesenchymal stem cells (Pe-MSCs) that contribute to normal bone growth, healing, and turnover; understanding Pe-MSC capabilities may shed light over the treatment of bone defects using tissue engineering. Bone tissue regeneration needs in vitro bone precursors or stem cell coculture onto specific scaffolds but, despite extensive research in the field, very little is known about the matrix structure of the tissue-engineered tissues and the scaffold's effects on cell differentiation. To this purpose we have selected a clonal population (murine Pe-MSCs) that was seeded and differentiated onto an acellular bone scaffold. Cell differentiation was assessed after 3 months and 1 year by molecular, histological, biochemical, and biophysical analyses and results were compared with the same osteoinduced clonal cells cultured as cellular aggregates. Our data show that Pe-MSCs cultured onto acellular bone scaffold develop a complex three-dimensional matrix and an osteoblastic phenotype but do not produce hydroxyapatite (HA); moreover, they seem able to reabsorb the colonized bone scaffold. On the contrary, cells cultured as three-dimensional aggregates differentiate and produce osteoblastic markers and HA nanocrystals. PMID- 22494487 TI - Heroin addiction and voluntary choice: the case of informed consent. AB - Does addiction to heroin undermine the voluntariness of heroin addicts' consent to take part in research which involves giving them free and legal heroin? This question has been raised in connection with research into the effectiveness of heroin prescription as a way of treating dependent heroin users. Participants in such research are required to give their informed consent to take part. Louis C. Charland has argued that we should not presume that heroin addicts are competent to do this since heroin addiction by nature involves a loss of ability to resist the desire for heroin. In this article, I argue that Charland is right that we should not presume that heroin addicts are competent to consent, but not for the reason he thinks. In fact, as Charland's critics correctly point out, there is plenty of evidence showing that heroin addicts can resist their desire for heroin. These critics are wrong, however, to conclude from this that we should presume that heroin addicts are competent to give their voluntary consent. There are, I shall argue, other conditions associated with heroin addiction that might constrain heroin addicts' choice in ways likely to undermine the voluntariness of their consent. In order to see this, we need to move beyond the focus on the addicts' desires for heroin and instead consider the wider social and psychological circumstances of heroin addiction, as well as the effects these circumstances may have on the addicts' beliefs about the nature of their options. PMID- 22494488 TI - Bean and rice meals reduce postprandial glycemic response in adults with type 2 diabetes: a cross-over study. AB - BACKGROUND: Around the world, beans and rice are commonly consumed together as a meal. With type 2 diabetes increasing, the effect of this traditional diet pattern on glycemic response has not been studied fully. METHODS: We evaluated the glycemic response of bean and rice traditional meals compared to rice alone in adults with type 2 diabetes. Seventeen men and women with type 2 diabetes controlled by metformin (n = 14) or diet/exercise (n = 3) aged 35-70 years participated in the randomized 4 * 4 crossover trial. The white long grain rice control, pinto beans/rice, black beans/rice, red kidney beans/rice test meals, matched for 50 grams of available carbohydrate, were consumed at breakfast after a 12 hour fast. Capillary blood glucose concentrations at baseline and at 30 minute intervals up to 180 minutes postprandial were collected. MANOVA for repeated measures established glucose differences between treatments. Paired t tests identified differences between bean types and the rice control following a significant MANOVA. RESULTS: Postprandial net glucose values were significantly lower for the three bean/rice treatments in contrast to the rice control at 90, 120 and 150 minutes. Incremental area under the curve values were significantly lower for the pinto and black bean/rice meals compared to rice alone, but not for kidney beans. CONCLUSIONS: Pinto, dark red kidney and black beans with rice attenuate the glycemic response compared to rice alone. Promotion of traditional foods may provide non-pharmaceutical management of type 2 diabetes and improve dietary adherence with cultural groups. PMID- 22494489 TI - Sleep deprivation impairs Ca2+ expression in the hippocampus: ionic imaging analysis for cognitive deficiency with TOF-SIMS. AB - Sleep deprivation causes cognitive dysfunction in which impaired neuronal plasticity in hippocampus may underlie the molecular mechanisms of this deficiency. Considering calcium-mediated NMDA receptor subunit 1 (NMDAR1) and neuronal nitric oxide synthase (nNOS) activation plays an important role in the regulation of neuronal plasticity, the present study is aimed to determine whether total sleep deprivation (TSD) would impair calcium expression, together with injury of the neuronal plasticity in hippocampus. Adult rats subjected to TSD were processed for time-of-flight secondary ion mass spectrometry, NMDAR1 immunohistochemistry, nNOS biochemical assay, cytochrome oxidase histochemistry, and the Morris water maze learning test to detect ionic, neurochemical, bioenergetic as well as behavioral changes of neuronal plasticity, respectively. Results indicated that in normal rats, strong calcium signaling along with intense NMDAR1/nNOS expression were observed in hippocampal regions. Enhanced calcium imaging and neurochemical expressions corresponded well with strong bioenergetic activity and good performance of behavioral testing. However, following TSD, both calcium intensity and NMDAR1/nNOS expressions were significantly decreased. Behavioral testing also showed poor responses after TSD. As proper calcium expression is essential for maintaining hippocampal neuronal plasticity, impaired calcium expression would depress downstream NMDAR1-mediated nNOS activation, which might contribute to the initiation or development of TSD related cognitive deficiency. PMID- 22494490 TI - An overview of the mTOR pathway as a target in cancer therapy. AB - INTRODUCTION: The mammalian target of rapamycin (mTOR) signaling cascade is a key regulatory pathway controlling initiation of mRNA translation in mammalian cells. The mTOR inhibitor rapamycin and its derivatives have shown potent antineoplastic activities in many preclinical models and clinical trials. First-generation mTOR inhibitors are now FDA-approved for the treatment of renal cell carcinoma. AREAS COVERED: This article reviews the components of the mTOR pathway and their normal functions, highlighting the most common alterations in the pathway, seen in various human malignancies. It also discusses elements and effectors of this signaling cascade and reviews the therapeutic relevance of pharmacological inhibitors of the pathway in several malignancies, including lymphomas, leukemias, sarcomas, renal cell carcinoma, and breast cancer. EXPERT OPINION: mTOR targeting is a highly promising therapeutic approach. First-generation mTOR inhibitors have already shown substantial activity in the treatment of certain tumors, while the emergence of second-generation catalytic mTOR inhibitors provides a better approach to target the pathway in malignant cells and has raised the potential for better clinical outcomes in the future. PMID- 22494492 TI - Microbial transformations of arsenic: mobilization from glauconitic sediments to water. AB - In the Inner Coastal Plain of New Jersey, arsenic (As) is released from glauconitic sediment to carbon- and nutrient-rich shallow groundwater. This As rich groundwater discharges to a major area stream. We hypothesize that microbes play an active role in the mobilization of As from glauconitic subsurface sediments into groundwater in the Inner Coastal Plain of New Jersey. We have examined the potential impact of microbial activity on the mobilization of arsenic from subsurface sediments into the groundwater at a site on Crosswicks Creek in southern New Jersey. The As contents of sediments 33-90 cm below the streambed were found to range from 15 to 26.4 mg/kg, with siderite forming at depth. Groundwater beneath the streambed contains As at concentrations up to 89 MUg/L. Microcosms developed from site sediments released 23 MUg/L of As, and active microbial reduction of As(V) was observed in microcosms developed from site groundwater. DNA extracted from site sediments was amplified with primers for the 16S rRNA gene and the arsenate respiratory reductase gene, arrA, and indicated the presence of a diverse anaerobic microbial community, as well as the presence of potential arsenic-reducing bacteria. In addition, high iron (Fe) concentrations in groundwater and the presence of iron-reducing microbial genera suggests that Fe reduction in minerals may provide an additional mechanism for release of associated As, while arsenic-reducing microorganisms may serve to enhance the mobility of As in groundwater at this site. PMID- 22494491 TI - Impact of smoking cessation on incidence of diabetes mellitus among overweight or normal-weight Japanese men. AB - AIMS: To assess the impact of smoking cessation on incidence of diabetes among overweight or normal-weight Japanese men. METHODS: This 9.2-year cohort study included 2070 men aged 40-69 years without diabetes. We classified them according to smoking status as non-smokers, past smokers (>9, 6-9, 3-5 and <3 years) and current smokers. Participants were followed up until diabetes developed or the end of 2006. The incidence of diabetes was determined from fasting and random plasma glucose levels, HbA(1c) levels or being under medical treatment for diabetes. RESULTS: During 18,963 person-years of follow-up, 246 of the participants developed diabetes. The risk for diabetes peaked within 3 years of quitting (HR: 2.98, 95% CI: 1.38-6.27) and persisted at 5 years after quitting smoking (HR, 2.49; 95% CI, 1.18-5.26) among overweight individuals. Moreover, this study identified a high risk for diabetes among past smokers who had quit >9 years in both normal weight and overweight. CONCLUSIONS: Cigarette smoking predicts incidence of diabetes, but smoking cessation leads to higher short-term risk in overweight and long-term risk in both. Preventing smoking is superior to smoking cessation, and is very important for avoiding diabetes. PMID- 22494493 TI - The effect of thermal hydrolysis pretreatment on the anaerobic degradation of nonylphenol and short-chain nonylphenol ethoxylates in digested biosolids. AB - The presence of micropollutants can be a concern for land application of biosolids. Of particular interest are nonylphenol diethoxylate (NP(2)EO), nonylphenol monoethoxylate (NP(1)EO), and nonylphenol (NP), collectively referred to as NPE, which accumulate in anaerobically digested biosolids and are subject to regulation based on the environmental risks associated with them. Because biosolids are a valuable nutrient resource, it is essential that we understand how various treatment processes impact the fate of NPE in biosolids. Thermal hydrolysis (TH) coupled with mesophilic anaerobic digestion (MAD) is an advanced digestion process that destroys pathogens in biosolids and increases methane yields and volatile solids destruction. We investigated the impact of thermal hydrolysis pretreatment on the subsequent biodegradation of NPE in digested biosolids. Biosolids were treated with TH, anaerobic digestion, and aerobic digestion in laboratory-scale reactors, and NPE were analyzed in the influent and effluent of the digesters. NP(2)EO and NP(1)EO have been observed to degrade to the more estrogenic NP under anaerobic conditions; therefore, changes in the ratio of NP:NPE were of interest. The increase in NP:NPE following MAD was 56%; the average increase of this ratio in four sets of TH-MAD samples, however, was only 24.6 +/- 3.1%. In addition, TH experiments performed in pure water verified that, during TH, the high temperature and pressure alone did not directly destroy NPE; TH experiments with NP added to sludge also showed that NP was not destroyed by the high temperature and pressure of TH when in a more complex sludge matrix. The post-aerobic digestion phases removed NPE, regardless of whether TH pretreatment occurred. This research indicates that changes in biosolids processing can have impacts beyond just gas production and solids destruction. PMID- 22494494 TI - Photodegradation of selected beta-blockers in aqueous fulvic acid solutions: kinetics, mechanism, and product analysis. AB - The photodegradation of the widely used beta-blockers atenolol and metoprolol were investigated in the presence of fulvic acid (FA) under simulated sunlight. Both atenolol and metoprolol undergo indirect photodegradation in the FA solutions. The triplet excited state of FA ((3)FA(*)) was verified to be main reactive species responsible for the photosensitized degradation of beta blockers. An electron transfer mechanism for the interaction between beta blockers and (3)FA(*) was proposed on the basis of a series of experiments. Magnetic property of metal ions exhibited significant impact on photosensitized degradation. Diamagnetic metal ions such as Mg(2+), Ca(2+), Zn(2+), and Al(3+) negligibly affected the degradation. In contrast, paramagnetic metal ions including Mn(2+), Cu(2+), Fe(3+), and Cr(3+) markedly inhibited the reactions in the order of Cr(3+) < Fe(3+) < Cu(2+) < Mn(2+). The inhibition was related to the complexation ability with FA. By LC-ESI-MS/MS analysis, deisopropyl-atenolol (metoprolol) was identified as the main photosensitized product. The degradation pathways of beta-blockers involving electron transfer processes were proposed. This finding strongly suggests that (3)FA(*) was important reactive species for the degradation of beta-blockers in natural waters. PMID- 22494495 TI - A retrospective case review of isolated sinonasal amyloidosis. AB - OBJECTIVE: We report an extremely rare case of isolated primary sinonasal amyloidosis. METHOD: A case report and comprehensive literature review are presented. Common symptoms, signs and treatment options are examined, and used to derive an algorithm with which the practising otolaryngologist can diagnose and manage this condition. RESULTS: Only 15 cases of true primary idiopathic amyloid restricted to the sinonasal tract have previously been reported. Isolated sinonasal amyloid presents with common rhinological symptoms which mimic chronic rhinosinusitis, i.e. nasal obstruction, nasal discharge, epistaxis, 'glue ear' and post-nasal drip. The lesion itself can appear as a simple inflammatory polyp. In children, the symptoms are easily attributed to enlarged adenoids. Although there is a concern that surgically induced trauma to the paranasal mucosa might incite reactive amyloid deposition, this seems not to be the case, and surgery provides symptomatic relief in the majority of patients. CONCLUSION: This article is the first to report the characteristic features of isolated primary sinonasal amyloidosis. The evidence suggests that meticulous surgery can produce substantial symptomatic improvement in these patients. PMID- 22494496 TI - Design of PID controllers in double feedback loops for SISO systems with set point filters. AB - A PID controller is widely used to control industrial processes that are mostly open loop stable or unstable. Selection of proper feedback structure and controller tuning helps to improve the performance of the loop. In this paper a double-feedback loop/method is used to achieve stability and better performance of the process. The internal feedback is used for stabilizing the process and the outer loop is used for good setpoint tracking. An internal model controller (IMC) based PID method is used for tuning the outer loop controller. Autotuning based on relay feedback or the Ziegler-Nichols method can be used for tuning an inner loop controller. A tuning parameter (lambda) that is used to tune IMC-PID is used as a time constant of a setpoint filter that is used for reducing the peak overshoot. The method has been tested successfully on many low order processes. PMID- 22494497 TI - Lipid-conjugated 27-nucleotide double-stranded RNAs with dicer-substrate potency enhance RNAi-mediated gene silencing. AB - Short interfering RNAs (siRNAs), used in RNA interference (RNAi) technology, are powerful tools for target-gene silencing in a sequence-specific manner. In this study, Dicer-substrate 27-nucleotide (nt) double-stranded RNAs (dsRNAs), which are known to have a highly potent RNAi effect, were conjugated with palmitic acid at the 5'-end of the sense strand to enhance intracellular delivery and RNAi efficacy. The palmitic acid-conjugated 27-nt dsRNAs (C16-ds27RNAs) were prepared by our simple synthesis strategy in good yield. The C16-ds27RNAs were cleaved by a Dicer enzyme, leading to the release of 21-nt siRNAs. The high level of stability in serum using C16-ds27RNAs was also confirmed. The C16-ds27RNAs showed enhanced RNAi potency targeted to both an exogenous luciferase and an endogenous vascular endothelial growth factor (VEGF) gene in the presence or absence of a transfection reagent, such as Lipofectamine 2000. In addition, the C16-ds27RNAs had a more potent gene-silencing activity than the other lipid-conjugated 21-nt siRNAs and 27-nt dsRNAs. The C16-ds27RNAs also exhibited significant membrane permeability. These results suggested that the C16-ds27RNAs will be useful for next-generation RNAi molecules that can address the problems of RNAi technology. PMID- 22494498 TI - Dexmedetomidine is neuroprotective in an in vitro model for traumatic brain injury. AB - BACKGROUND: The alpha2-adrenoreceptor agonist dexmedetomidine is known to provide neuroprotection under ischemic conditions. In this study we investigated whether dexmedetomidine has a protective effect in an in vitro model for traumatic brain injury. METHODS: Organotypic hippocampal slice cultures were subjected to a focal mechanical trauma and then exposed to varying concentrations of dexmedetomidine. After 72 h cell injury was assessed using propidium iodide. In addition, the effects of delayed dexmedetomidine application, of hypothermia and canonical signalling pathway inhibitors were examined. RESULTS: Dexmedetomidine showed a protective effect on traumatically injured hippocampal cells with a maximum effect at a dosage of 1 MUM. This effect was partially reversed by the simultaneous administration of the ERK inhibitor PD98059. CONCLUSION: In this TBI model dexmedetomidine had a significant neuroprotective effect. Our results indicate that activation of ERK might be involved in mediating this effect. PMID- 22494499 TI - Pulse oximetry screening in Wisconsin. AB - INTRODUCTION: Pulse oximetry can be used as a screening tool to detect critical congenital heart disease (CCHD) in neonates prior to hospital discharge and the development of symptoms. Newborns suspected of having CCHD based on pulse oximetry screening should have the diagnosis excluded or confirmed with echocardiography. However, echocardiography is not immediately available in all settings in which newborns are delivered and the best course of action in these settings remains to be determined. The purpose of this study was to evaluate the resources available to diagnose and treat newborns with CCHD born in the state of Wisconsin. METHODS: We surveyed the nurse managers or administrators of the 99 Wisconsin hospitals in which babies are routinely delivered in the state of Wisconsin. A telephone survey was performed in February and March 2011. The number of births per facility was estimated from the most recent available data (2010). RESULTS: There were 66 179 total births occurring in 106 hospitals in the state of Wisconsin in 2010, with 99 hospitals routinely delivering newborns. Surveys were completed in 88/99 (88.9%), representing 95% of the state's in hospital births. All responding hospitals had pulse oximetry available in the nursery. Twenty-five of 88 (28.4%) of responding hospitals routinely use pulse oximetry to screen for CCHD, representing 35.2% of surveyed hospital births. Same day neonatal echocardiography was available at 33/88 (37.5%) of the responding hospitals, representing 74.4% of surveyed hospital births. The average distance to the higher-level care facility of choice from the hospitals without neonatal echocardiography is 53.1 miles. CONCLUSION: Pulse oximetry is universally available in Wisconsin newborn nurseries, and pulse oximetry screening for CCHD is currently being performed for many of Wisconsin's newborns. The majority of births in Wisconsin occur in hospitals where same-day neonatal echocardiography is available for confirmatory diagnosis of CCHD when necessary. PMID- 22494500 TI - Understanding of basic concepts of orofacial pain among dental students and a cohort of general dentists. AB - OBJECTIVES: Temporomandibular disorders and orofacial pain are common presenting conditions to dentists. There has been a call for improvement in teaching about these conditions in the international literature since the 1970s. DESIGN: This study evaluates the current state of knowledge about basic pain mechanisms and management in dental students and dentists in Victoria, Australia, using a pain knowledge test adapted for dentists. RESULTS: The results show that overall 47% of fourth year dental students and 58% of final year dental students scored correctly on the pain knowledge test compared with 48% of a convenience sample of practicing dentists on the same test. CONCLUSIONS: This pilot study indicates that levels of knowledge about pain are consistently low among dental students. There does appear to be improvement in knowledge after exposure to teaching in advanced training years in this dental school. There is some evidence that graduate dentists as a group may also have low levels of knowledge about basic pain mechanisms and evidenced-based treatment principles. This study highlights the need for improved training of dentists and dental students with regard to pain and orofacial pain. PMID- 22494501 TI - Brightening of the lowest exciton in carbon nanotubes via chemical functionalization. AB - Using time-dependent density functional theory, we found that chemical functionalization at low concentrations of single-walled carbon nanotubes (SWNTs) locally alters the pi-conjugated network of the nanotube surface and leads to a spatial confinement of the electronically excited wave functions. Depending on the adsorbant positions, the chemisorption significantly modifies the optical selection rules. Our modeling suggests that photoluminescent efficiency of semiconducting SWNT materials can be controlled by selective chemical functionalization. PMID- 22494502 TI - Solid-state ligand-driven light-induced spin change at ambient temperatures in bis(dipyrazolylstyrylpyridine)iron(II) complexes. AB - We previously reported that an Fe(II) complex ligated by two (Z)-2,6-di(1H pyrazol-1-yl)-4-styrylpyridine ligands (Z-H) presented a solid state ligand driven light-induced spin change (LD-LISC) upon one-way Z-to-E photoisomerization, although modulation of the magnetism was trivial at ambient temperatures (Chem. Commun.2011, 47, 6846). Here, we report the synthesis of new derivatives of Z-H, Z-CN and Z-NO(2), in which electron-withdrawing cyano and nitro substituents are introduced at the 4-position of the styryl group to attain a more profound photomagnetism at ambient temperatures. Z-CN and Z-NO(2) undergo quantitative one-way Z-to-E photochromism upon excitation of the charge transfer band both in acetonitrile and in the solid state, similar to the behavior observed for Z-H. In solution, these substituents stabilized the low-spin (LS) states of Z-CN and Z-NO(2), and the behavior was quantitatively analyzed according to the Evans equation. The photomagnetic properties in the solid state, on the other hand, cannot be explained in terms of the substituent effect alone. Z-CN displayed photomagnetic properties almost identical to those of Z-H. Z-CN preferred the high-spin (HS) state at all temperatures tested, whereas photoirradiated Z-CN yielded a lower chi(M)T at ambient temperatures. The behavior of Z-NO(2) was counterintuitive, and the material displayed surprising photomagnetic properties in the solid state. Z-NO(2) occupied the LS state at low temperatures and underwent thermal spin crossover (SCO) with a T(1/2) of about 270 K. The photoirradiated Z-NO(2) displayed a higher value of chi(M)T and the modulation of chi(M)T exceeded that of Z-H or Z-CN. Z-NO(2).acetone, in which acetone molecules were incorporated into the crystal lattice, further stabilized the LS state (T(1/2) > 300 K), thereby promoting large modulations of the chi(M)T values (87% at 273 K and 64% at 300 K) upon Z-to-E photoisomerization. Single crystal X-ray structure analysis revealed that structural factors played a vital role in the photomagnetic properties in the solid state. Z-H and Z-CN favored intermolecular pi-pi stacking among the ligand molecules. The coordination sphere around the Fe(II) nucleus was distorted, which stabilized the HS state. In contrast, Z-NO(2).acetone was liberated from such intermolecular pi-pi stacking and coordination distortion, resulting in the stabilization of the LS state. PMID- 22494503 TI - Persistent genetic signatures of historic climatic events in an Antarctic octopus. AB - Repeated cycles of glaciation have had major impacts on the distribution of genetic diversity of the Antarctic marine fauna. During glacial periods, ice cover limited the amount of benthic habitat on the continental shelf. Conversely, more habitat and possibly altered seaways were available during interglacials when the ice receded and the sea level was higher. We used microsatellites and partial sequences of the mitochondrial cytochrome oxidase 1 gene to examine genetic structure in the direct-developing, endemic Southern Ocean octopod Pareledone turqueti sampled from a broad range of areas that circumvent Antarctica. We find that, unusually for a species with poor dispersal potential, P. turqueti has a circumpolar distribution and is also found off the islands of South Georgia and Shag Rocks. The overriding pattern of spatial genetic structure can be explained by hydrographic (with ocean currents both facilitating and hindering gene flow) and bathymetric features. The Antarctic Peninsula region displays a complex population structure, consistent with its varied topographic and oceanographic influences. Genetic similarities between the Ross and Weddell Seas, however, are interpreted as a persistent historic genetic signature of connectivity during the hypothesized Pleistocene West Antarctic Ice Sheet collapses. A calibrated molecular clock indicates two major lineages within P. turqueti, a continental lineage and a sub-Antarctic lineage, that diverged in the mid-Pliocene with no subsequent gene flow. Both lineages survived subsequent major glacial cycles. Our data are indicative of potential refugia at Shag Rocks and South Georgia and also around the Antarctic continent within the Ross Sea, Weddell Sea and off Adelie Land. The mean age of mtDNA diversity within these main continental lineages coincides with Pleistocene glacial cycles. PMID- 22494504 TI - Restoring sinus rhythm results in blood pressure reduction in patients with persistent atrial fibrillation and a history of hypertension. AB - INTRODUCTION: The long-term effects of atrial fibrillation (AF) on blood pressure (BP) in patients with hypertension (HTN) remain unclear. We hypothesized that restoration of normal sinus rhythm (NSR) results in a decrease in BP despite the expected increase in cardiac output. METHODS AND RESULTS: Twenty-four-hour BP measurements were obtained during AF, and on Day 1 and Day 30 post-successful cardioversion in 18 patients with AF and HTN (cardioversion group), and another 22 patients with AF and HTN with no immediate plans for cardioversion (control group). Except for the duration of AF, the clinical characteristics and use of medications were similar between the groups. In the cardioversion group, a significant decrease in diastolic blood pressure (DBP) and mean blood pressure (MBP) were noted on Day 1 post-cardioversion with no significant change in systolic blood pressure (SBP): 117/74/88 +/- 13/9/9 mmHg during AF and 116/70/85 +/- 13/9/10 mmHg during Day 1 post-cardioversion (P = 0.68; <0.01 and 0.04 for SBP, DBP, and MBP, respectively). In the 13 subjects who remained in NSR at Day 30, DBP and MBP decreased further on Day 30 when compared to Day 1 with no significant change in SBP: 118/76/90 +/- 13/7/8 mmHg during AF; 119/72/88 +/- 12/8/9 mmHg during Day 1; and 118/69/86 +/- 10/8/7 mmHg during Day 30 post cardioversion (P = 0.97; <0.001 and 0.03 for SBP, DBP, and MBP, respectively). In the control group, no significant changes in BP were noted. CONCLUSION: Restoring NSR in patients with AF and HTN resulted in a sustained decrease in DBP and MBP. To our knowledge, this is the first study to show that maintenance of NSR improves BP control in patients with AF and HTN. PMID- 22494506 TI - The 'warrior gene' and the Maori people: the responsibility of the geneticists. AB - The 'gene of' is a teleosemantic expression that conveys a simplistic and linear relationship between a gene and a phenotype. Throughout the 20th century, geneticists studied these genes of traits. The studies were often polemical when they concerned human traits: the 'crime gene', 'poverty gene', 'IQ gene', 'gay gene' or 'gene of alcoholism'. Quite recently, a controversy occurred in 2006 in New Zealand that started with the claim that a 'warrior gene' exists in the Maori community. This claim came from a geneticist working on the MAOA gene. This article is interested in the responsibility of that researcher regarding the origin of the controversy. Several errors were made: overestimation of results, abusive use of the 'gene of' kind of expression, poor communication with the media and a lack of scientific culture. The issues of the debate were not taken into account sufficiently, either from the political, social, ethical or even the genetic points of view. After more than 100 years of debates around 'genes of' all kinds (here, the 'warrior gene'), geneticists may not hide themselves behind the media when a controversy occurs. Responsibilities have to be assumed. PMID- 22494507 TI - Coronectomy of the lower third molar is safe within the first 3 years. AB - PURPOSE: There is no long-term evaluation on the safety of coronectomy of the lower third molar. The aim of this study was to investigate the 3-year morbidity of coronectomy of the lower third molars and to monitor the behavior and migration pattern of the retained roots after coronectomy. MATERIALS AND METHODS: This was a prospective cohort study. Patients with lower third molars with specific radiographic sign(s) showing proximity of the roots to the inferior alveolar nerve who underwent coronectomy in a previous randomized clinical trial were reviewed postoperatively in the first week and the third, sixth, 12th, 24th, and 36th months. The morbidities of infection, pain, root eruption, reoperation to remove the root, and the development of any pathology were recorded. The pattern of any root migration was analyzed. RESULTS: Ninety-eight patients (35 men and 63 women; mean age, 25.7 yrs; standard deviation, 7.9 yrs) with 135 coronectomies completed the 36-month review. None presented with infection or pain from the postoperative third month onward. Root eruption causing sensitivity occurred in 3% (4/135) of the sample and the erupted roots were removed. None of the reoperated cases presented with a postoperative inferior alveolar nerve deficit. No pathology developed in any of the retained roots after coronectomy. Root migration was noted in most cases in the first 12 months, and all roots stopped migrating from the 24th month onward. The mean root migration at 36 months was 2.8 mm (standard deviation, 1.4 mm). CONCLUSIONS: This study confirms that retained roots after coronectomy in the lower third molars produce no complications in terms of infection, pain, or the development of pathologies within the first 3 years. Root eruption can occur in a very small percentage of patients and may require reoperation to remove the root. PMID- 22494505 TI - Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression: an association study with mechanistic implications. AB - BACKGROUND: Glutathione S-transferase omega-1 and 2 genes (GSTO1, GSTO2), residing within an Alzheimer and Parkinson disease (AD and PD) linkage region, have diverse functions including mitigation of oxidative stress and may underlie the pathophysiology of both diseases. GSTO polymorphisms were previously reported to associate with risk and age-at-onset of these diseases, although inconsistent follow-up study designs make interpretation of results difficult. We assessed two previously reported SNPs, GSTO1 rs4925 and GSTO2 rs156697, in AD (3,493 ADs vs. 4,617 controls) and PD (678 PDs vs. 712 controls) for association with disease risk (case-controls), age-at-diagnosis (cases) and brain gene expression levels (autopsied subjects). RESULTS: We found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, p = 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of GSTO1 rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, p = 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both GSTO SNPs associate with lower brain levels of GSTO2 (p = 4.7 * 10-11-1.9 * 10-27), but not GSTO1. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (p = 0.003). CONCLUSION: These results suggest that GSTO locus variants may lower brain GSTO2 levels and consequently confer AD risk in older age. Other glutathione metabolism genes should be assessed for their effects on AD and other chronic, neurologic diseases. PMID- 22494508 TI - Extranodal non-hodgkin lymphomas of the oral cavity and maxillofacial region: a clinical study of 58 cases and review of the literature. AB - PURPOSE: Approximately one third of non-Hodgkin lymphomas (NHLs) arise in tissues other than the lymph nodes. The purposes of this study are to evaluate the clinical outcome of NHLs of the oral cavity and maxillofacial region in a group of 58 patients who were diagnosed in our clinic and to discuss the clinical, histologic, and immunohistochemical features of these malignant neoplasms, as well as the prognosis. MATERIALS AND METHODS: The study included 58 patients with extranodal NHLs of the oral cavity and maxillofacial region. There were 32 male and 26 female patients. The patients' ages ranged from 7 to 81 years. The most frequent sites of occurrence were the salivary glands (24 patients) and intraoral mucosa (21 patients). Other sites were the paranasal sinus (3 patients), Waldeyer ring (4 patients), bone of the jaws (3 patients), and orbit (3 patients). The histologic subtype was extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT) in 21 patients, diffuse large B-cell lymphoma (DLBCL) in 19, chronic lymphocytic leukemia in 10, mantle cell lymphoma in 4, follicular lymphoma in 2, Burkitt lymphoma/leukemia in 1, and B-cell acute lymphocytic leukemia (B-ALL) in 1. Of the DLBCL cases, 13 were stage IIE and 6 were stage IE. All the MALT lymphomas were stage IE. RESULTS: The mean follow-up was 5 years after the initial diagnosis. A better prognosis was found in patients with MALT lymphomas (19 of 21 patients are alive) compared with those with DLBCLs (10 of 19 patients are alive). CONCLUSIONS: MALT lymphomas have a more favorable outcome (about 90%) in comparison with DLBCLs. Careful examination of the oral cavity and neck by the maxillofacial surgeon is essential for the diagnosis and staging of lymphomas. PMID- 22494509 TI - Maxillary third molar: patterns of impaction and their relation to oroantral perforation. AB - PURPOSE: The objectives of this study were to examine 1) the patterns of the impacted maxillary wisdom tooth and 2) the proximity of the impacted maxillary wisdom tooth to the maxillary sinus in relation to oroantral perforation during the removal of a maxillary wisdom tooth. MATERIALS AND METHODS: This retrospective study reviewed the clinical records and dental pantomograms of patients who underwent the removal of maxillary wisdom teeth under general anesthesia over a 6-month period. Using a modified version of the Archer classification of impacted maxillary wisdom teeth, types of impaction were classified according to depth, angulation of impaction, and proximity to the floor of the sinus. Clinical records showed the occurrence of oroantral perforation. RESULTS: In total, 845 maxillary wisdom teeth were removed; 66.8% were by routine extraction and 33.2% were removed surgically. The most common type of impaction was vertical followed by mesioangular. Most impacted teeth were at the level between the occlusal and cervical level of the adjacent second molar. Only 7 of the 278 excised wisdom teeth produced an oroantral perforation. Only 0.9% of all cases with a close sinus approximation showed an oroantral perforation. Statistical analysis with the Fisher exact test showed statistically significant associations of depth of impaction (P < .001), eruption status (P = .001), and long-axis position (P < .001) to the occurrence of an oroantral perforation. Sinus approximation showed no association with the occurrence of an oroantral perforation (P = 1.000). CONCLUSION: The depth of impaction of the maxillary wisdom tooth is a possible predictor of the possibility of oro-antral perforation if removal of the tooth is required. Due to the limitation of the radiograph, it is not a reliable to use radiographic close proximity of the sinus to predict the occurrence of oro-antral perforation when the maxillary wisdom tooth is removed. PMID- 22494510 TI - Atypical fibroxanthoma--a retrospective immunohistochemical study of 42 cases. AB - PURPOSE: Atypical fibroxanthoma is a cutaneous dermal malignancy that presents on the sun-damaged skin of elderly people. It requires a definitive diagnosis, from a high-grade sarcoma to a nonmesenchymal neoplasm. The recommended treatment protocol differs from similar histologically related tumors; thus, a diagnosis of atypical fibroxanthoma should fulfill strict histologic and immunohistochemical stain criteria. The use of these standards will exclude other skin malignancies, including malignant fibrous histiocytoma, angiosarcoma, malignant melanoma, and squamous cell carcinoma. This study was performed with the aim of identifying key immunostains to develop diagnostic criteria. MATERIALS AND METHODS: Forty-two cases were studied retrospectively over a 10-year period using a panel of immunostains. RESULTS: The average age at presentation was 78 years, with a male predominance. The scalp was found to be the most common site of occurrence, although other investigators have found the forehead, cheeks, nose, and ears as the prevailing sites of presentation. CONCLUSIONS: An extensive panel of immunohistochemical stains can be used to prove a diagnosis of atypical fibroxanthoma. PMID- 22494511 TI - Dental extraction in a hemophilia patient without factor replacement therapy: a case report. PMID- 22494512 TI - Submental liposuction versus formal cervicoplasty: which one to choose? AB - PURPOSE: Esthetic rejuvenation of the submental area is a fairly common concern of patients seeking cosmetic surgery. There are several techniques used to obtain esthetic results. A common dilemma is the proper determination as to which procedure, liposuction versus formal cervicoplasty, is more appropriate. This manuscript describes the factors involved in the aging process of the submental area, as well as the inherent advantages of formal cervicoplasty over liposuction. MATERIALS AND METHODS: A comprehensive review of the intrinsic and extrinsic aging process is described, and advantages and disadvantages of liposuction as well as cervicoplasty are detailed. RESULTS: On the basis of the specific factors leading to the fullness of the anterior neck/submental area, proper rejuvenation technique must include platysmaplasty, in addition to liposuction. Isolated liposuction is only beneficial in an isolated group of cosmetic patients. CONCLUSIONS: Formal cervicoplasty, including open liposuction and platysmaplasty, is a superior operation compared with isolated liposuction of the submental area. Whereas liposuction does have a role in cosmetic surgery of the submental area, it is not a comprehensive procedure and does not address all of the anatomic components leading to submental fullness. PMID- 22494513 TI - Computer-aided design/computer-aided manufacturing implant guide used in flapless surgery for auricular prosthesis. PMID- 22494515 TI - Analysis of fumonisin contamination and the presence of Fusarium in wheat with kernel black point disease in the United States. AB - The ability of the fungus Fusarium proliferatum to cause kernel black point disease in wheat was previously established, but natural contamination of black point wheat with both F. proliferatum and fumonisin mycotoxins has not been studied in the United States. Low levels of fumonisins were detected in nine of 43 wheat samples with kernel black point disease that were obtained from across the United States. A subset of samples was contaminated with F. proliferatum as well as with F. fujikuroi, F. nygamai, F. thapsinum and F. verticillioides, species closely related to F. proliferatum and morphologically similar to it in that they produce chains of asexual spores, or conidia. Nevertheless, of conidial chain-forming fusaria isolated from symptomatic wheat, F. proliferatum dominated. In greenhouse tests, isolates of F. proliferatum and the other species recovered from wheat samples were able to cause symptoms of kernel black point and, in some cases, low levels of fumonisin contamination of wheat. These data add to the understanding of the risk of fumonisin contamination of wheat and the potential for Fusarium species to cause kernel black point disease and fumonisin contamination of wheat. Further, the results of this study indicate that while US grown wheat can sporadically be contaminated by fumonisins, the natural contamination levels seem to be low. The observations made provide evidence that fumonisins are not likely to be a factor contributing to the ability of Fusarium to cause kernel black point disease. PMID- 22494514 TI - Intimal lining layer macrophages but not synovial sublining macrophages display an IL-10 polarized-like phenotype in chronic synovitis. AB - INTRODUCTION: Synovial tissue macrophages play a key role in chronic inflammatory arthritis, but the contribution of different macrophage subsets in this process remains largely unknown. The main in vitro polarized macrophage subsets are classically (M1) and alternatively (M2) activated macrophages, the latter comprising interleukin (IL)-4 and IL-10 polarized cells. Here, we aimed to evaluate the polarization status of synovial macrophages in spondyloarthritis (SpA) and rheumatoid arthritis (RA). METHODS: Expression of polarization markers on synovial macrophages, peripheral blood monocytes, and in vitro polarized monocyte-derived macrophages from SpA versus RA patients was assessed by immunohistochemistry and flow cytometry, respectively. The polarization status of the intimal lining layer and the synovial sublining macrophages was assessed by double immunofluorescence staining. RESULTS: The expression of the IL-10 polarization marker cluster of differentiation 163 (CD163) was increased in SpA compared with RA intimal lining layer, but no differences were found in other M1 and M2 markers between the diseases. Furthermore, no significant phenotypic differences in monocytes and in vitro polarized monocyte-derived macrophages were seen between SpA, RA, and healthy controls, indicating that the differential CD163 expression does not reflect a preferential M2 polarization in SpA. More detailed analysis of intimal lining layer macrophages revealed a strong co expression of the IL-10 polarization markers CD163 and cluster of differentiation 32 (CD32) but not any of the other markers in both SpA and RA. In contrast, synovial sublining macrophages had a more heterogeneous phenotype, with a majority of cells co-expressing M1 and M2 markers. CONCLUSIONS: The intimal lining layer but not synovial sublining macrophages display an IL-10 polarized like phenotype, with increased CD163 expression in SpA versus RA synovitis. These differences in the distribution of the polarized macrophage subset may contribute to the outcome of chronic synovitis. PMID- 22494516 TI - Simultaneous quantification of coumarins, flavonoids and limonoids in Fructus Citri Sarcodactylis by high performance liquid chromatography coupled with diode array detector. AB - A high performance liquid chromatography coupled with diode array detector (HPLC DAD) method was developed for simultaneous quantification of eleven major bioactive components including six coumarins, three flavonoids and two limonoids in Fructus Citri Sarcodactylis. The analysis was performed on a Cosmosil 5 C(18) MS-II column (4.6 mm * 250 mm, 5 MUm) with water-acetonitrile gradient elution. The method was validated in terms of linearity, sensitivity, precision, stability and accuracy. It was found that the calibration curves for all analytes showed good linearity (R(2)>0.9993) within the test ranges. The overall limit of detection (LOD) and limit of quantification (LOQ) were less than 3.0 and 10.2 ng. The relative standard deviations (RSDs) for intra- and inter-day repeatability were not more than 4.99% and 4.92%, respectively. The sample was stable for at least 48 h. The spike recoveries of eleven components were 95.1-104.9%. The established method was successfully applied to determine eleven components in three samples from different locations. The results showed that the newly developed HPLC-DAD method was linear, sensitive, precise and accurate, and could be used for quality control of Fructus Citri Sarcodactylis. PMID- 22494517 TI - HPTLC methods to assay active ingredients in pharmaceutical formulations: a review of the method development and validation steps. AB - High-performance thin-layer chromatography (HPTLC) is still increasingly finding its way in pharmaceutical analysis in some parts of the world. With the advancements in the stationary phases and the introduction of densitometers as detection equipment, the technique achieves for given applications a precision and trueness comparable to high-performance liquid chromatography (HPLC). In this review, the literature is surveyed for developed and validated HPTLC methods to assay active ingredients in pharmaceutical formulations published in the period 2005-2011. Procedures and approaches for method development, validation and quantitative assays are compared with the standard ways of conducting them. Applications of HPTLC in some other areas are also briefly highlighted. PMID- 22494518 TI - Analysis of counterfeit Cialis(r) tablets using Raman microscopy and multivariate curve resolution. AB - Counterfeit medicines have become a serious global problem. Consequently, analytical and pharmaceutical scientists have been active in developing and applying new methodologies to detect and analyze counterfeit medicines. Vibrational spectroscopy combined with chemometric methods is becoming a popular choice in this area of research. In this study, Raman microscopy was used to collect chemical images of counterfeit tadalafil tablets and multivariate curve resolution (MCR) was used to analyze the Raman spectra and reveal the identities of the excipients and active pharmaceutical ingredients (API) in each tablet. Resolved counterfeit tablet spectra were compared to the resolved genuine tablet spectra. Both similarities and dissimilarities were revealed by the analysis in terms of the identity of the excipients, the quantity of the API, and the distribution of the components. It was concluded that Raman microscopy combined with MCR is a powerful method to detect and analyze counterfeit tablets. PMID- 22494519 TI - Simultaneous determination of adenine nucleotides, creatine phosphate and creatine in rat liver by high performance liquid chromatography-electrospray ionization-tandem mass spectrometry. AB - A high performance liquid chromatography-electrospray ionization-tandem mass spectrometric method (HPLC-ESI-MS/MS) was developed for simultaneous determination of adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP), creatine phosphate (CP), and creatine in rat liver. After extraction with pre-cooled (4 degrees C) methanol/water (1:1, v/v), the analytes were separated on a porous graphitic carbon (Hypercarb) column (2.1 mm * 150 mm, 5 MUm) using a programmed gradient elution with a mobile phase consisting of 2 mmol/L ammonium acetate in water and 2 mmol/L ammonium acetate in acetonitrile (pH=10.0). The analytes were detected in a way of multiple reaction monitoring (MRM) under negative scan mode by a triple quadrupole mass spectrometer with electrospray ionization (ESI). An external calibration method with linear ranges from 10 to 5000 ng/mL for the five target compounds was used for quantification with a correlation coefficients>=0.9973. The limits of detection and limits of quantification for all analytes were in ranges from 0.50 to 1.5 ng/mL and 1.6 to 0.5 ng/mL, respectively. The average recoveries spiked in three levels were from 77.2% to 102% and precisions expressed in RSDs were from 0.2% to 4.8%. The established method was successfully applied to determination of ATP, ADP, AMP, CP and creatine in liver tissue. PMID- 22494520 TI - Dispersive liquid-liquid microextraction combined with capillary electrophoresis and time-of-flight mass spectrometry for urine analysis. AB - The combination of dispersive liquid-liquid microextraction (DLLME) with capillary electrophoresis (CE) and a time-of-flight mass spectrometer (TOF-MS) was evaluated for the toxicological screening in urine samples. A methodology based on design of experiments (DOE) was implemented to increase the extraction efficiency. Dichloromethane and isopropanol were selected as the extraction and dispersing solvents, respectively. Seven factors for DLLME were screened with the help of a Plackett-Burmann DOE using two model compounds before fine investigation of the important parameters to maximise the compound extraction. These experiments were performed in the CE-UV configuration to overcome potential MS matrix effects. The performance of the entire procedure was then evaluated using CE-ESI-TOF-MS. With a preconcentration factor of more than 130, the highly sensitive DLLME-CE-ESI-TOF-MS method allowed for the detection of 30 toxicological compounds (i.e., amphetamines and their derivatives, opiates, cocaine and its metabolites and pharmaceuticals) in urine with limits of detection in the sub-ng/mL level and was used to analyse real toxicological samples. The combination of DLLME and CE was particularly attractive because of the small amount of organic solvents required. PMID- 22494521 TI - Asenapine: a clinical review of a second-generation antipsychotic. AB - BACKGROUND: Schizophrenia and bipolar disorder are both prevalent types of psychiatric illness in the United States. As second-generation antipsychotics have become a more viable first-line treatment option, their use has been associated with a new era of adverse events (AEs), most notably metabolic and cardiovascular concerns. Although treatment options for schizophrenia and bipolar disorder have arguably improved, there continues to be a need for medications that achieve and maintain desired efficacy with minimal AEs. OBJECTIVES: This article serves as a comprehensive review of the pharmacologic profile of the second-generation antipsychotic asenapine, as well as a review of its efficacy and safety profiles based on the findings from clinical trials in schizophrenia and bipolar disorder. METHODS: Searches of Ovid MEDLINE, EMBASE, and IDIS were conducted (January 1996 to November 2011) to identify clinical studies and other primary literature sources with the following search terms: asenapine, bipolar disorder, antipsychotic, psychosis, dopamine, and schizophrenia. Only studies of asenapine and placebo and/or active-comparator arms were included. RESULTS: The literature search yielded 67 unique articles, including review articles, which were excluded. The efficacy of asenapine was reported in 3 clinical studies in patients with schizophrenia, 1 each in acute and long-term settings, measured as significant changes in Positive and Negative Syndrome Scale scores over 6 and 52 weeks. Asenapine also had reported efficacy in the prevention of relapse in schizophrenia during a 26-week extension study. In addition, efficacy of asenapine was reported in 2 studies in acute mania as well as extension phases of both 9 and 40 weeks, as determined by significant changes in Young Mania Rating Scale scores. The most commonly reported AEs in these studies were somnolence (13%-24%), extrapyramidal symptoms (EPS) (7%-12%), and dizziness (11%). CONCLUSIONS: The findings from multiple studies have suggested that asenapine is efficacious in the acute treatment of schizophrenia. Asenapine has reported long term efficacy for this indication and the potential to reduce the incidence of relapse. Asenapine efficacy was also reported in the treatment of acute manic or mixed states associated with bipolar I disorder. Asenapine had an acceptable safety profile across the different disease states studied, although it was not devoid of metabolic and EPS-related AEs. PMID- 22494522 TI - The role of melatonin in patients with chronic kidney disease undergoing haemodialysis. AB - Patients with chronic kidney disease including those undergoing haemodialysis have deranged sleep-wake pattern. In large part this is due to an abnormal circadian cycle of melatonin, a hormone secreted by the pineal gland in the evening and induces sleep. Subjects undergoing automated peritoneal dialysis or nocturnal haemodialysis have better sleep profile compared to those on daytime dialysis. Studies have shown that exogenous melatonin improves sleep-wake cycle in daytime haemodialysis patients. However, large randomised controlled trials are needed in order to establish its role in this patient population. PMID- 22494523 TI - Impact of psychological problems in chemical warfare survivors with severe ophthalmologic complication, a cross sectional study. AB - BACKGROUND: Sulfur mustard (SM) has been used as a chemical warfare agent since the early twentieth century. Despite the large number of studies that have investigated SM induced ocular injuries, few of those studies have also focused on the psychological health status of victims. This study has evaluated the most prominent influences on the psychological health status of patients with severe SM induced ocular injuries. METHODS: This descriptive study was conducted on 149 Iranian war veterans with severe SM induced eye injuries. The psychological health status of all patients was assessed using the Iranian standardized Symptom Check List 90-Revised (SCL90-R) questionnaire. The results of patients' Global Severity Index (GSI) were compared with the optimal cut-off point of 0.4 that has previously been calculated for GSI in Iranian community. The Mann-Whitney U test, T tests and effect sizes (using Cohen's d) were employed as statistical methods. Data were analyzed using SPSS software. RESULTS: The mean age of patients was 44.86 (SD=8.7) and mean duration of disease was 21.58 (SD=1.20) years. Rate of exposure was once in 99 (66.4%) cases. The mean GSI (1.46) of the study group was higher compared to standardized cut off point (0.4) of the Iranian community. The results of this study showed that the mean of total GSI score was higher in participants with lower educational levels (effect size=0.507), unemployment (effect size=0.464) and having more than 3 children (effect size=0.62). Among the participants, 87 (58.4%) cases had a positive psychological history for hospitalization or receiving outpatient cares previously and 62 (41.6%) cases had a negative psychological history. In addition, the mean of GSI in participants with negative psychological history was lower than those with positive psychological history (Mean Change Difference=-0.621 with SD=0.120). There was a significant difference between positive and negative psychological history with respect to GSI (P<0.001). CONCLUSION: The study showed that severe ophthalmologic complications in chemical survivors are accompanied with destructive effects on psychological health status. Appropriate management may improve psychological health status in these patients. PMID- 22494524 TI - Targeting IL-8 in colorectal cancer. AB - INTRODUCTION: Colorectal cancer is the leading cause of death from gastrointestinal malignancy in the US. Chemokines and their receptors are being recognized as key regulators of cancers and increasingly as therapeutic targets for metastatic cancers, including colorectal cancer. Several studies have demonstrated that IL-8 and its receptor CXCR2 are two of the most significantly upregulated chemokines in colorectal cancer. IL-8 through binding to its receptors can act not only on inflammatory responses and infectious diseases, but also on cancer cells via their receptors to promote migration, invasion and proliferation, and in vivo angiogenesis. Therefore, IL-8 and CXCR2 may be important therapeutic targets against colorectal cancer. AREAS COVERED: This review provides an update on the roles of IL-8 and its receptors in colorectal cancer preclinical models and translational relevance: i) Increased expression of IL-8 and/or its receptors has been characterized in colon cancer cells; ii) IL-8 signaling pathway in colorectal cancer cells; iii) targeting IL-8 expression, or receptor-targeted strategies in colorectal cancer, eliminates the redundant function of IL-8 signaling and determines the effects of suppressing IL-8 signaling on tumor progression and development. EXPERT OPINION: IL-8 and its receptor CXCR2 may function as significant regulatory factors within the tumor microenvironment and be important therapeutic targets in colorectal cancers. Not only may they lead to antitumor properties, but also they may chemosensitize the tumor toward the current chemotherapy. PMID- 22494525 TI - The human factor: re-organisations in public health policy. AB - INTRODUCTION: Public health policy-making activities are currently split between local authority and NHS organisations. Despite an increasing body of research on evidence-based policy (EBP), few studies explore the process of policy-making. Little is known about how policies are made in a local context, or how (scientific) evidence is used. Previous research has ignored the 'human element' in EBP. Social network analysis (SNA) techniques are becoming increasingly important in health policy. This paper describes an innovative study giving a fresh perspective on policy-making processes in public health. METHODS: A social network analysis of public health policy making networks in Greater Manchester based on publicly available data (documents, websites and meeting papers) and an electronic survey, asking actors to nominate those who influenced their own views, those who were powerful, and those who were a source of evidence or information. RESULTS AND CONCLUSIONS: Policy-making networks are described. Formal executive roles are loosely related to perceived influence and power. Evidence-seeking networks are less coherent, with key organisations not represented. These data indicate the importance of collaboration and good relationships between researchers and policy-makers, but few academic researchers with a direct impact on health policy were identified within the networks. PMID- 22494526 TI - Spanish health care cuts: penny wise and pound foolish? AB - The purpose of this paper is to convey the specific health care actions and policies undertaken by the Spanish government, as well as by regional governments, as a result of the economic crisis. Throughout the last two years we have witnessed a number of actions in areas such as human capital, activity and processes, outsourcing and investment that, poorly coordinated, have shaped the nature of financial cuts on public services. This paper discloses the size and magnitude of these actions, the main actors involved and the major consequences for the health sector, citizens and patients. We further argue that there are a number of factors which have been neglected in the discourse and in the actions undertaken. First, the crisis situation is not being used as an opportunity for major reforms in the health care system. Further, the lay public and professionals have remained as observers in the process, with little to no participation at any point. Moreover, there is a general perception that the solution to the Spanish situation is either the proposed health care cuts or an increase in cost sharing for services which neglects alternative and/or complementary measures. Finally, there is a complete absence of any scientific component in the discourse and in the policies proposed. PMID- 22494527 TI - Skull base meningiomas mimicking otitis media. AB - INTRODUCTION: Meningiomas are slow-growing, benign tumours originating from the arachnoid villi of the meninges. They account for 13 to 26 per cent of all intracranial neoplasms. Less than 1 per cent of all meningiomas are primary extracranial tumours of the ear and temporal bone. Intracranial meningiomas extending to the middle-ear cleft are uncommon, with fewer than 100 cases reported to date. Presenting symptoms of the latter condition may include hearing loss, tinnitus, dizziness, vertigo and facial palsy. Otitis media with effusion secondary to eustachian tube dysfunction has also been reported. AIM: To describe three patients in whom chronic otitis media was the presenting sign of skull base meningioma. METHOD: Case presentations. RESULTS: Presentation of clinical and imaging findings as well as management considerations. CONCLUSION: Meningioma involving the middle ear is an extremely rare condition, and is diagnosed by computed tomography in conjunction with magnetic resonance imaging. When biopsy is performed, the histological features, characteristic immunophenotype and ultrastructural analysis are valuable aids to definitive diagnosis. In patients with no neurological symptoms, 'wait and scan' is often the best management option. PMID- 22494528 TI - Occurrence of pharmaceuticals in a municipal wastewater treatment plant: mass balance and removal processes. AB - Occurrence and removal efficiencies of fifteen pharmaceuticals were investigated in a conventional municipal wastewater treatment plant in Michigan. Concentrations of these pharmaceuticals were determined in both wastewater and sludge phases by a high-performance liquid chromatograph coupled to a tandem mass spectrometer. Detailed mass balance analysis was conducted during the whole treatment process to evaluate the contributing processes for pharmaceutical removal. Among the pharmaceuticals studied, demeclocycline, sulfamerazine, erythromycin and tylosin were not detected in the wastewater treatment plant influent. Other target pharmaceuticals detected in wastewater were also found in the corresponding sludge phase. The removal efficiencies of chlortetracycline, tetracycline, sulfamerazine, acetaminophen and caffeine were >99%, while doxycycline, oxytetracycline, sulfadiazine and lincomycin exhibited relatively lower removal efficiencies (e.g., <50%). For sulfamethoxazole, the removal efficiency was approximately 90%. Carbamazepine manifested a net increase of mass, i.e. 41% more than the input from the influent. Based on the mass balance analysis, biotransformation is believed to be the predominant process responsible for the removal of pharmaceuticals (22% to 99%), whereas contribution of sorption to sludge was relatively insignificant (7%) for the investigated pharmaceuticals. PMID- 22494529 TI - Blood serum concentrations of perfluorinated compounds in men from Greenlandic Inuit and European populations. AB - Perfluorinated compounds (PFCs), such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), are used in large quantities. They are persistent and found in measurable levels in human serum around the world. They have been associated with developmental, hepatic, and carcinogenic effects in animal studies. The aim of the present study was to describe levels of PFCs in serum among Inuits from Greenland and inhabitants from Warsaw, Poland and Kharkiv, Ukraine. Furthermore, the aim was to define social- and lifestyle related determinants of exposure for these compounds. Serum levels of seven PFCs were analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS). The concentrations of PFOS and PFOA were the highest of all PFCs in all three populations with a total amount of almost 90% of the PFCs. The mean levels of PFOS and PFOA were in the Greenlandic Inuits 52 and 4.8 ng mL(-1), in Poland 19 and 5.2 ng mL(-1), and in Ukraine 8.1 and 1.9 ng mL(-1), respectively. Thus, levels of PFCs in the serum of Inuits on Greenland were among the highest described in a general population whereas the levels in Poland were similar to other industrialized countries. The exposure in Ukraine was rather low. In the Greenlandic Inuit population, intake of seafood, tea, age and area of living were significant determinants of PFOS concentrations and explained about 22% of the variation. For the other populations no strong determinants were found. PMID- 22494530 TI - Oxidation of acid-volatile sulfide in surface sediments increases the release and toxicity of copper to the benthic amphipod Melita plumulosa. AB - Acid-volatile sulfides (AVS) are an important metal-binding phase in sediments. For sediments that contain an excess of AVS over simultaneously extracted metal (SEM) concentrations, acute or chronic effects should not result from the metals Cd, Cu, Ni, Pb and Zn. While AVS phases may exist in surface sediments, the exposure to dissolved oxygen may oxidize the AVS and release metals to more bioavailable forms. We investigated the role of oxidation of AVS, and specifically copper sulfide phases, in surface sediments, in the toxicity to juveniles of the epibenthic amphipod, Melita plumulosa. Sediments containing known amounts of copper sulfide were prepared either in situ by reacting dissolved copper with AVS that had formed in field sediments or created in sediments within the laboratory, or by addition of synthesised CuS to sediments. Regardless of the form of the copper sulfide, considerable oxidation of AVS occurred during the 10-d tests. Sediments that had a molar excess of AVS compared to SEM at the start of the tests, did not always have an excess at the end of the tests. Consistent with the AVS-SEM model, no toxicity was observed for sediments with an excess of AVS throughout the tests. However, the study highlights the need to carefully consider the changes in AVS concentrations during tests, and that measurements of AVS and SEM concentrations should carefully target the materials to which the organisms are being exposed throughout tests, which in the case of juvenile M. plumulosa is the top few mm of the sediments. PMID- 22494531 TI - Removal of SO2 with a Mg-Al oxide slurry via reconstruction of a Mg-Al layered double hydroxide. AB - Although effective treatments of SO(x) are essential for preventing air pollution, current methods pose other environmental problems such as increased amounts of desulfurized gypsum and reduced landfill lifetimes. We report a process for removing SO(2) from waste streams using a Mg-Al oxide slurry. The ability of the mixed oxide to remove SO(2) increased with slurry quantity and temperature but decreased with time. SO(2) was removed through the reconstruction of a Mg-Al layered double hydroxide (Mg-Al LDH) intercalated with SO(3)(2-), which was derived from the dissociation of H(2)SO(3) upon dissolution of SO(2) in the slurry. SO(2) was not adsorbed onto the surface of the Mg-Al oxide. These results suggest that SO(2) removal using a Mg-Al oxide slurry may be possible without the concomitant problems of conventional treatment methods. PMID- 22494532 TI - The effects of music on the sleep quality of adults with chronic insomnia using evidence from polysomnographic and self-reported analysis: a randomized control trial. AB - BACKGROUND: Research-based evidence supports the therapeutic use of music to improve the sleep quality measured by self-reported questionnaires. However, scientific knowledge of the effects of music measured using standard polysomnography in chronic insomnia adults is currently insufficient. OBJECTIVES: The objective of this study was to evaluate the effect of soothing music on objective and subjective sleep quality in adults with chronic insomnia. METHODS: Fifty participants were enrolled in a randomized controlled trial conducted in the sleep laboratory of a hospital, with 25 participants allocated to the music group and 25 to the control group. For four days, the experimental group was exposed to soothing music selected by the participants or researchers for 45 min at nocturnal sleep time, whereas the control group was not exposed to music. Sleep was measured using polysomnography (PSG) and self-reported questionnaires. A general estimating equation was applied to analyze the data. RESULTS: After controlling for baseline data, the music group had significantly better scores for rested rating (p=0.01), shortened stage 2 sleep (p=0.03), and prolonged REM sleep (p=0.04) compared to the control group, shown by the generalized estimating equations. However, there was no evidence of the effectiveness of music on other sleep parameters as measured by PSG. Additional findings indicate no difference in sleep quality between those who listened to their own preferred music (n=10) and those who listened to music selected by the researchers (n=15). CONCLUSION: The results contribute to knowledge of the effectiveness of music as a therapy to improve sleep quality in adults experiencing insomnia. Listening to soothing music at nocturnal sleep time improved the rested rating scores, shortened stage 2 sleep, and prolonged REM sleep, but has little effect on sleep quality as measured by polysomnography and self-reported questionnaires. PMID- 22494533 TI - Linking microstructure and nanochemistry in human dental tissues. AB - Mineralized dental tissues and dental pulp were characterized using advanced analytical transmission electron microscopy (TEM) methods. Quantitative X-ray energy dispersive spectroscopy was employed to determine the Ca/P and Mg/P concentration ratios. Significantly lower Ca/P concentration ratios were measured in peritubular dentine compared to intertubular dentine, which is accompanied by higher and variable Mg/P concentration ratios. There is strong evidence that magnesium is partially substituting calcium in the hydroxyapatite structure. Electron energy-loss near-edge structures (ELNES) of C-K and O-K from enamel and dentine are noticeably different. We observe a strong influence of beam damage on mineralized dental tissues and dental pulp, causing changes of the composition and consequently also differences in the ELNES. In this article, the importance of TEM sample preparation and specimen damage through electron irradiation is demonstrated. PMID- 22494534 TI - Clustering of depression and inflammation in adolescents previously exposed to childhood adversity. AB - BACKGROUND: There is mounting interest in the hypothesis that inflammation contributes to the pathogenesis of depression and underlies depressed patients' vulnerability to comorbid medical conditions. However, research on depression and inflammation has yielded conflicting findings, fostering speculation that these conditions associate only in certain subgroups, such as patients exposed to childhood adversity. METHODS: We studied 147 female adolescents. All were in good health at baseline but at high risk for depression because of family history or cognitive vulnerability. Subjects were assessed every 6 months for 2.5 years, undergoing diagnostic interviews and venipuncture for measurement of two inflammatory biomarkers, C-reactive protein (CRP) and interleukin-6 (IL-6). Childhood adversity was indexed by parental separation, low socioeconomic status, and familial psychopathology. RESULTS: Multilevel models indicated that childhood adversity promotes clustering of depression and inflammation. Among subjects exposed to high childhood adversity, the transition to depression was accompanied by increases in both CRP and IL-6. Higher CRP remained evident 6 months later, even after depressive symptoms had abated. These lingering effects were bidirectional, such that among subjects with childhood adversity, high IL-6 forecasted depression 6 months later, even after concurrent inflammation was considered. This coupling of depression and inflammation was not apparent in subjects without childhood adversity. CONCLUSIONS: These findings suggest that childhood adversity promotes the formation of a neuroimmune pipeline in which inflammatory signaling between the brain and periphery is amplified. Once established, this pipeline leads to a coupling of depression and inflammation, which may contribute to later affective difficulties and biomedical complications. PMID- 22494535 TI - Mechanisms of drug resistance reversal in Dox-resistant MCF-7 cells by pH responsive amphiphilic polyphosphazene containing diisopropylamino side groups. AB - pH-responsive drug carriers derived from polymers containing weak base groups have been shown to improve the antitumor effect of chemotherapeutics. The common interpretation is that a "proton sponge effect" caused by pH-responsive polymers facilitates endosomal membrane destruction and accelerates cytoplasmic drug release in tumor cells. However, the mechanisms by which pH-responsive weak base polymers disrupt membranes have not been expatiated clearly. Herein, we synthesized a series of pH-responsive amphiphilic polyphosphazenes containing diisopropylamino (DPA) side groups with various contents and investigated the effect of DPA content on the actions of polymers with cell membranes. In a certain pH range, the polymers with elevated DPA content showed enhanced membrane disruptive activity. Electrical interactions between the protonated DPA groups of polymers and the cell lipid bilayer are critical for pH-dependent membrane disruption, which can be competitively prevented by serum proteins. On the other hand, the hydrophobic unprotonated DPA moieties can insert into lipophilic regions of cell membrane. These synergic actions caused the alteration of biomembrane permeability consequently. More interestingly, it was also found that DPA-rich polymers exhibit higher P-glycoprotein (P-gp) inhibition activity as compared with the polymer containing only low levels of DPA by efficiently blocking the internal epitope of P-gp. These findings strongly provide rational support for pH-responsive amphiphilic polyphosphazenes containing DPA side groups to be quite promising drug carriers for intracellular drug delivery applications, especially the treatment of P-gp overexpressing, drug-resistant tumors. PMID- 22494536 TI - Clinicopathological characteristics, hormone receptor status and matrix metallo proteinase-9 (MMP-9) immunohistochemical expression in spinal meningiomas. AB - Meningiomas involving the spinal meninges show a reduced tendency to recur compared to those of the intracranial compartment. Nonetheless, due to the few reports with a significant number of patients, their biological characteristics largely remain to be investigated. With the aim of clarifying the biology of these tumors, we examined in the present paper the clinicopathological features, the estrogen receptor (ER) and progesterone receptor (PR) status, as well as the Ki-67 labeling index (LI) and matrix metallo-proteinase-9 (MMP-9) expression of 58 spinal meningiomas. Ki-67 LI ranged between 1% and 5% (median: 1%); no expression of ER was found in all the cases, whereas PR immunoexpression was found in 86% of the tumors. High MMP-9 expression was encountered in 46% of meningiomas, and it was significantly correlated with the percentage of PR expression. The recurrence rate was 1.7%. The only recurred case showed high MMP 9 expression, absence of PR and low Ki-67 LI. Our findings confirm that spinal meningiomas are indolent tumors with low growth fraction and recurrence rate. In these neoplasms, high MMP-9 expression seems to be associated with the development of recurrences only in the absence of PR expression. Thus, the evaluation of both MMP-9 and PR expression might be of use in the identification of spinal meningiomas at higher risk of relapse. PMID- 22494538 TI - Simultaneous papillary fibroelastomas of the pulmonary and aortic valves. AB - Cardiac papillary fibroelastomas (PFEs) are uncommon valve tumors. Multiple PFEs at the same or different locations in the heart account for less than 10% of patients with PFE. We herein describe a case of an asymptomatic PFE of both pulmonary and aortic valves which was incidentally diagnosed by echocardiography in a 60-year-old woman. Both PFEs were removed surgically without valve replacement. To our knowledge, this combination of lesions has not been previously reported. Even though PFEs are classified as benign cardiac tumors, they can present serious complications, such as embolic episodes, mechanical obstruction or valvular dysfunction. Valve-sparing shave excision of the lesions can be readily accomplished in most instances with good long-term results. All surgically removed valvular lesions should be histopathologically examined to confirm the echocardiographic diagnosis. PMID- 22494537 TI - Plexiform hybrid granular cell tumor/perineurioma: a novel variant of benign peripheral nerve sheath tumor with divergent differentiation. AB - The descriptive term hybrid peripheral nerve sheath tumor refers to any neoplasm of the neurilemmal apparatus composed of more than one pathologically defined tumoral equivalent derived from its constituent cells. Within this uncommon nosological category, participation of granular cell tumor - a neoplasm of modified Schwann cells - has been reported only exceptionally. We describe a hitherto not documented variant composed of an organoid mixture of granular cell tumor and perineurioma with plexiform growth. A solitary subcutaneous nodule of 1.5 cm diameter was excised from the right ring finger of a 19-year-old female with no antecedents of neurofibromatosis or relevant trauma. Histology revealed a monotonous, yet cytologically dimorphic proliferation of classical granular cells intermingled with flattened, inconspicuous perineurial cells. Immunohistochemical double labeling detected expression of S100 protein in the former and of EMA and GLUT-1 in the latter. While the respective staining patterns for S100 protein and EMA or GLUT-1 tended to be mutually exclusive, a minority of cells exhibited transitional granular cell/perineurial immunophenotype. Electron microscopy permitted direct visualization of a plethora of lysosomes in the granular cell moiety, and of pinocytotic vesicles and tight junctions in perineurial cells. Intratumoral axons were not detected. Expanding intraneurally, the lesion showed discrete encapsulation by the local perineurium, and resulted in plexiform growth. The MIB-1 labeling index averaged 1%. We interpret our findings as supporting evidence for the dual cell lineage to have arisen through metaplasia, with the tumor's dynamics probably having been driven by the granular cell component. PMID- 22494539 TI - Altered central aortic elastic properties in Kawasaki disease are related to changes in left ventricular geometry and coronary artery aneurysm formation. AB - BACKGROUND: Recent evidence has suggested that patients display altered arterial elasticity after Kawasaki disease (KD). However, changes in the elastic properties of the central aorta and their relevance to left ventricular geometry have not been studied in patients after KD with and without coronary artery aneurysms (CAAs). METHODS: Clinical and laboratory characteristics of 75 patients with KD were compared with those of 57 controls. The patients with KD included 17 patients with CAAs and 58 patients without CAAs. Values for aortic stiffness index, aortic distensibility, aortic strain, and left ventricular mass index (LVMI) were retrospectively obtained from echocardiographic measurements of the ascending aorta and left ventricle with noninvasive blood pressure evaluation. RESULTS: Systolic blood pressure, pulse pressure, LVMI, and aortic stiffness index were significantly higher and aortic distensibility and aortic strain significantly lower in patients with KD than in the controls. In patients with KD, age at the time of study, interval between the onset of KD and the initiation of this study, CAAs, and LVMI were significantly associated with aortic stiffness index, aortic distensibility, and aortic strain. Multivariate analysis revealed that CAAs and LVMI were independently relevant to aortic stiffness index and aortic distensibility. CONCLUSIONS: The central aortas of patients after KD have altered elastic properties. CAAs and LVMI are independently correlated with central aortic elasticity. PMID- 22494540 TI - Feasibility and acceptability of a midwife-led intervention programme called 'Eat Well Keep Active' to encourage a healthy lifestyle in pregnancy. AB - BACKGROUND: Eating a diet that is high in fat and sugar and having a sedentary lifestyle during pregnancy is understood to increase the risk of excessive gestational weight gain and obesity following the birth of the baby. However, there are no clinical guidelines in the UK on what is considered to be appropriate gestational weight gain. Indeed, clinical recommendations discourage the routine re-weighing of pregnant women, stating instead that women should be advised regarding their diet and activity levels, in order to prevent excessive weight gain. Pregnancy is seen as a time when many women may have an increased motivation to improve their lifestyle behaviours for the benefit of the fetus. However, it is evident that many women have difficulty in both maintaining a healthy balanced diet and remaining active through pregnancy. It would seem that midwives may be ideally placed to assist women to make and maintain healthier lifestyle choices during pregnancy. METHODS/DESIGN: This study will look at the feasibility and acceptability of a newly devised intervention programme called 'Eat Well Keep Active'. Participants will complete a questionnaire prior to the programme to obtain baseline data on food frequency, physical activity and to gauge their perception of personal ability to improve/maintain healthy lifestyle. The programme comprises client centred techniques; motivational interviewing and goal setting delivered early in pregnancy (12-16 weeks) with the aim of supporting a healthy well balanced diet and either continuing or commencing appropriate levels of physical activity. Participants will then be followed up six weeks following the intervention with a one-to-one interview, and a further brief questionnaire. The interview will provide preliminary data regarding perceived effectiveness and acceptability of the 'Eat Well Keep Active' programme whilst the questionnaire will provide data regarding changes in the confidence of participants to lead a healthy lifestyle. DISCUSSION: There is an identified need for effective interventions that assist pregnant women in managing their diet and activity levels. Results from this study will demonstrate whether women find this programme of intervention, designed to elicit healthy behaviours in pregnancy, acceptable and whether they perceive it to be effective. PMID- 22494541 TI - Highly selective trapping of enteropathogenic E. coli on Fabry-Perot sensor mirrors. AB - Untreated recycled water, such as sewage and graywater, will almost always contain a wide range of agents that are likely to present risks to human health, including chemicals and pathogenic microorganisms. The microbial hazards, such as large numbers of enteric pathogens that can cause gastroenteric illness if ingested, are the main cause of concern for human health. The presence of the enteropathogenic Escherichia coli (EPEC) serotype is of particular concern, as this group of bacteria is responsible for causing severe infant and travelers' diarrhea, gastroenteritis and hemolytic uremic syndrome. A biosensing system based on an optical Fabry-Perot (FP) cavity, capable of directly detecting the presence of EPEC within 5 min, has been developed using a simple micro-thin double-sided adhesive tape and two semi-transparent FP mirror plates. The system utilizes a poly(methyl methacrylate) (PMMA) or glass substrates sputtered by 40 nm-thick gold thin films serving as FP mirrors. Mirrors have been activated using 0.1M mercaptopropionic acid, influencing an immobilization density of the translocated intimin receptor (TIR) of 100 ng/cm(2). The specificity of recognition was confirmed by exposing TIR functionalized surfaces to four taxonomically related and/or distantly related bacterial strains. It was found that the TIR-functionalized surfaces did not show any bacterial capture for these other bacterial strains within a 15 min incubation period. PMID- 22494544 TI - WITHDRAWN: Respiratory Muscle Assessment in Predicting Extubation Outcome in Patients With Stroke. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.arbr.2012.06.007. The duplicate article has therefore been withdrawn. PMID- 22494542 TI - Fabrication of stratified nanoporous gold for enhanced biosensing. AB - By a dealloying/annealing/redealloying strategy, nanoporous gold (NPG) with hierarchical microstructure is fabricated for electrochemical biosensing application. The first dealloying and annealing would produce NPG/AuAg alloy composite with a large-pore NPG layer and the second dealloying would further etch the AuAg alloy part in the composite, generating a small-pore NPG layer. By using the large-pore (~ 100 nm) layer as the glucose oxidase (GOx) container, and the small-pore (~ 12 nm) layer as a signal producer, this novel hierarchical NPG is demonstrated to be a good support for enzyme immobilization and fabricating enzyme-based biosensors. The immobilized GOx retains ~ 92% of the initial activity after 7 repeated use. The GOx-loaded stratified NPG biosensor can detect glucose more sensitively with a wider linear range (up to 22 mM) than normal NPG with a uniform pore size of 30-40 nm (linear range: up to 17 mM). PMID- 22494545 TI - Targeted array CGH as a valuable molecular diagnostic approach: experience in the diagnosis of mitochondrial and metabolic disorders. AB - Oligonucleotide array-based comparative genomic hybridization (aCGH) targeted to coding exons of genes of interest has been proven to be a valuable diagnostic tool to complement with Sanger sequencing for the detection of large deletions/duplications. We have developed a custom designed oligonucleotide aCGH platform for this purpose. This array platform provides tiled coverage of the entire mitochondrial genome and high-density coverage of a set of nuclear genes involving mitochondrial and metabolic disorders and can be used to evaluate large deletions in targeted genes. A total of 1280 DNA samples from patients suspected of having mitochondrial or metabolic disorders were evaluated using this targeted aCGH. We detected 40 (3%) pathogenic large deletions in unrelated individuals, including 6 in genes responsible for mitochondrial DNA (mtDNA) depletion syndromes, 23 in urea cycle genes, 11 in metabolic and related genes. Deletion breakpoints have been confirmed in 31 cases by PCR and sequencing. The possible deletion mechanism has been discussed. These results illustrate the successful utilization of targeted aCGH to detect large deletions in nuclear and mitochondrial genomes. This technology is particularly useful as a complementary diagnostic test in the context of a recessive disease when only one mutant allele is found by sequencing. For female carriers of X-linked disorders, if sequencing analysis does not detect point mutations, targeted aCGH should be considered for the detection of large heterozygous deletions. PMID- 22494546 TI - 30-year follow-up of a patient with classic citrullinemia. AB - Citrullinemia is a urea cycle defect requiring long-term care with nutritional and pharmacological management. Despite treatment, morbidity and mortality of this disease remain high, and long-term complications include mild to profound mental retardation, seizures, and growth deficiency. We report a 31-year old woman with classic, neonatal-onset citrullinemia who developed progressive hypertrophic cardiomyopathy and cataracts, neither of which has been recognized previously as a complication of the disease or a consequence of long-term drug treatment. PMID- 22494547 TI - Mapping the T helper cell response to acid alpha-glucosidase in Pompe mice. AB - Pompe disease is a neuromuscular disease caused by an inherited deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). The resulting accumulation of glycogen causes muscle weakness with the severe form of the disease resulting in death by cardiorespiratory failure in the first year of life. The only available treatment, enzyme replacement therapy (ERT) with recombinant GAA (rhGAA), is severely hampered by antibody responses that reduce efficacy and cause immunotoxicities. Currently, Pompe mice represent the only pre-clinical model for development of new treatments and for immunological studies. While antibody formation following ERT in this model has been described, the underlying T cell response has not been studied. In order to define the T helper response to rhGAA in Pompe mice, immunodominant CD4(+) T cell epitopes were mapped in GAA(-/-) 129SVE mice using ELISpot. Additionally, cytokine responses and antibody formation against rhGAA during ERT were measured. Among the three CD4(+) T cell epitopes identified, only epitope IFLGPEPKSVVQ, predicted to be the strongest MHC II binder, consistently contributed to IL-4 production. Frequencies of IL-4 producing T cells were considerably higher than those of IL-17 or IFN-gamma producing cells, suggesting a predominantly Th2 cell mediated response. This is further supported by IgG1 being the prevalent antibody subclass against rhGAA during ERT and consistent with prior reports on IgE formation and anaphylaxis in this model. These results will facilitate mechanistic studies of the immune response to rhGAA in Pompe mice during development of new therapies and tolerance protocols. PMID- 22494548 TI - Left atrial ablation of atrial fibrillation: is the fly in the ointment a silent stroke? PMID- 22494549 TI - Contemporary management of tooth replacement in the traumatized dentition. AB - Dental trauma can result in tooth loss despite best efforts at retaining and maintaining compromised teeth (Dent Traumatol, 24, 2008, 379). Upper anterior teeth are more likely to suffer from trauma, and their loss can result in significant aesthetic and functional problems that can be difficult to manage (Endod Dent Traumatol, 9, 1993, 61; Int Dent J 59, 2009, 127). Indeed, teeth of poor prognosis may not only present with compromised structure but trauma may also result in damage to the support tissues. Injury to the periodontium and alveolus can have repercussions on subsequent restorative procedures (Fig. 19). Where teeth are identified as having a hopeless prognosis either soon after the incident or at delayed presentation; planning for eventual tooth loss and replacement can begin at the early stages. With advances in both adhesive and osseointegration technologies, there are now a variety of options for the restoration of edentate spaces subsequent to dental trauma. This review aims to identify key challenges in the provision of tooth replacement in the traumatized dentition and outline contemporary methods in treatment delivery. PMID- 22494550 TI - Mechanism of atmospheric CO2 fixation in the cavities of a dinuclear cryptate. AB - Using density functional theory (DFT) methods, we have investigated two possible mechanisms for atmospheric CO(2) fixation in the cavity of the dinuclear zinc(II) octa-azacryptate, and the subsequent reaction with methanol whereby this latter reaction transforms the (essentially) chemically inert CO(2) into useful products. The first mechanism (I) was proposed by Chen et al. [Chem.-Asian J. 2007, 2, 710], and involves the attachment of one CO(2) molecule onto the hydroxyl-cryptate form, resulting in the formation of a bicarbonate-cryptate species and subsequent reaction with one methanol molecule. In addition, we suggest another mechanism that is initiated via the attachment of a methanol molecule onto one of the Zn-centers, yielding a methoxy-cryptate species. The product is used to activate a CO(2) molecule and generate a methoxycarbonate cryptate. The energy profiles of both mechanisms were determined, and we conclude that, while both mechanisms are energetically feasible, free energy profiles suggest that the scheme proposed by Chen et al. is most likely. PMID- 22494551 TI - Finding the "PR-fect" solution: what is the best tool to measure fetal cardiac PR intervals for the detection and possible treatment of early conduction disease? AB - In the absence of structural heart disease, the great majority of cases with complete congenital heart block will be associated with the maternal autoantibodies directed to components of the SSA/Ro-SSB/La ribonucleoprotein complex. Usually presenting in fetal life before 26 weeks' gestation, once third degree (complete) heart block develops, it is irreversible. Therefore, investigators over the past several years have attempted to predict which fetuses will be at risk for advanced conduction abnormalities by identifying a biomarker for less severe or incomplete disease, in this case, PR interval prolongation or first-degree atrioventricular block. In this state-of-the-art review, we critically analyze the various approaches to defining PR interval prolongation in the fetus, and then analyze several clinical trials that have attempted to address the question of whether complete heart block can be predicted and/or prevented. We find that, first and foremost, definitions of first-degree atrioventricular block vary but that the techniques themselves are all similarly valid and reliable. Nevertheless, the task of predicting those fetuses at risk, and who are therefore candidates for treatment, remains challenging. Of concern, despite anecdotal evidence, there is currently no conclusive proof that a prolonged PR interval predicts complete heart block. PMID- 22494552 TI - The development of agoraphobia is associated with the symptoms and location of a patient's first panic attack. AB - BACKGROUND: The place where a patient experiences his/her first panic attack (FPA) may be related to their agoraphobia later in life. However, no investigations have been done into the clinical features according to the place where the FPA was experienced. In particular, there is an absence of detailed research examining patients who experienced their FPA at home. In this study, patients were classified by the location of their FPA and the differences in their clinical features were explored (e.g., symptoms of FPA, frequency of agoraphobia, and severity of FPA). METHODS: The subjects comprised 830 panic disorder patients who were classified into 5 groups based on the place of their FPA (home, school/office, driving a car, in a public transportation vehicle, outside of home), The clinical features of these patients were investigated. Additionally, for panic disorder patients with agoraphobia at their initial clinic visit, the clinical features of patients who experienced their FPA at home were compared to those who experienced their attack elsewhere. RESULTS: In comparison of the FPAs of the 5 groups, significant differences were seen among the 7 descriptors (sex ratio, drinking status, smoking status, severity of the panic attack, depression score, ratio of agoraphobia, and degree of avoidance behavior) and 4 symptoms (sweating, chest pain, feeling dizzy, and fear of dying). The driving and public transportation group patients showed a higher incidence of co-morbid agoraphobia than did the other groups. Additionally, for panic disorder patients with co-morbid agoraphobia, the at-home group had a higher frequency of fear of dying compared to the patients in the outside-of-home group and felt more severe distress elicited by their FPA. CONCLUSION: The results of this study suggest that the clinical features of panic disorder patients vary according to the place of their FPA. The at-home group patients experienced "fear of dying" more frequently and felt more distress during their FPA than did the subjects in the other groups. These results indicate that patients experiencing their FPA at home should be treated with a focus on the fear and distress elicited by the attack. PMID- 22494553 TI - Influence of agronomic and climatic factors on Fusarium infestation and mycotoxin contamination of cereals in Norway. AB - A total of 602 samples of organically and conventionally grown barley, oats and wheat was collected at grain harvest during 2002-2004 in Norway. Organic and conventional samples were comparable pairs regarding cereal species, growing site and harvest time, and were analysed for Fusarium mould and mycotoxins. Agronomic and climatic factors explained 10-30% of the variation in Fusarium species and mycotoxins. Significantly lower Fusarium infestation and concentrations of important mycotoxins were found in the organic cereals. The mycotoxins deoxynivalenol (DON) and HT-2 toxin (HT-2) constitute the main risk for human and animal health in Norwegian cereals. The impacts of various agronomic and climatic factors on DON and HT-2 as well as on their main producers F. graminearum and F. langsethiae and on total Fusarium were tested by multivariate statistics. Crop rotation with non-cereals was found to reduce all investigated characteristics significantly--mycotoxin concentrations as well as various Fusarium infestations. No use of mineral fertilisers and herbicides was also found to decrease F. graminearum, whereas lodged fields increased the occurrence of this species. No use of herbicides was also found to decrease F. langsethiae, but for this species the occurrence was lower in lodged fields. Total Fusarium infestation was decreased with no use of fungicides or mineral fertilisers, and with crop rotation, as well as by using herbicides and increased by lodged fields. Clay and to some extent silty soils seemed to reduce F. graminearum in comparison with sandy soils. Concerning climate factors, low temperature before grain harvest was found to increase DON; and high air humidity before harvest to increase HT-2. F. graminearum was negatively correlated with precipitation in July but correlated with air humidity before harvest. F. langsethiae was correlated with temperature in July. Total Fusarium increased with increasing precipitation in July. Organic cereal farmers have fewer cereal intense rotations than conventional farmers. Further, organic farmers do not apply mineral fertiliser or pesticides (fungicides, herbicides or insecticides), and have less problem with lodged fields. The study showed that these agronomic factors were related to the infestation of Fusarium species and the concentration of mycotoxins. Hence, it is reasonable to conclude that farming system (organic versus conventional) impacts Fusarium infestation, and that organic management tends to reduce Fusarium and mycotoxins. However, Fusarium infestation and mycotoxin concentrations may be influenced by a range of factors not studied here, such as local topography and more local climate, as well as cereal species and variety. PMID- 22494554 TI - Direct inoculation method using BacT/ALERT 3D and BD Phoenix System allows rapid and accurate identification and susceptibility testing for both Gram-positive cocci and Gram-negative rods in aerobic blood cultures. AB - This study describes a direct inoculation method using the automated BacT/ALERT 3D and the BD Phoenix System in combination for identification and susceptibility testing of isolates from positive blood cultures. Organism identification and susceptibility results were compared with the conventional method for 211 positive aerobic blood cultures. Of 110 Gram-positive cocci (GPCs), 98 (89.1%) isolates were correctly identified to the species level. Of 101 Gram-negative rods (GNRs), 98 (97.0%) isolates were correctly identified to the species level. The overall categorical agreement in antimicrobial susceptibility testing among the 110 GPCs was 92.7%, with 0.04% very major and 0.7% major error rates. The overall categorical agreement among 78 isolates of enterobacteria and 23 isolates of nonfermenters in GNRs was 99.5% and 91.1%, respectively, with no major errors identified. We conclude that, compared with previously reported direct inoculation methods, our method is superior in identification and susceptibility testing of GPCs. PMID- 22494555 TI - The utility of cerebrospinal fluid parameters in the early microbiological assessment of meningitis. AB - The measurement of cerebrospinal fluid (CSF) protein, glucose, and white cell count (WCC) is an essential part of the initial examination of CSF. The aim of this study was to determine the utility of CSF parameters in assessing the likely aetiological agent. A total of 2290 CSF samples from a 13-year period were retrospectively reviewed. The initial parameters were compared between bacterial, viral, and cryptococcal meningitis and cases where no pathogen was found. A protein concentration of <600 mg/L and a WCC <90 * 10(6)/L were found to be optimal cut-offs for excluding bacterial meningitis. A WCC of <25 * 10(6)/L was found to be optimal for excluding cryptococcal meningitis and a WCC of <10 * 10(6) for excluding viral meningitis. Decreased glucose concentration was found to be a poor indicator of the aetiological agent. PMID- 22494556 TI - Human rhinovirus and human respiratory enterovirus (EV68 and EV104) infections in hospitalized patients in Italy, 2008-2009. AB - The epidemiology of picornavirus infections along with associated risk factors for lower respiratory tract infections (LRTI) and duration of virus shedding were investigated in 985 hospitalized patients in the period October 2008-September 2009. One-third of patients were human rhinovirus (HRV)-positive. Of 336 HRV associated episodes, 153 (45.5%) were sustained by HRV-A, 31 (9.2%) by HRV-B, and 93 (27.7%) by HRV-C, while 7 episodes showed multiple HRV types and 52 were sustained by undefined HRV species. Independent risk factors for LRTI included high viral load and age less than 5 years. Twenty (2.1%) patients were enterovirus (EV)-positive (12 had EV-68, 7 EV-104, and 1 E-13 infection). Half of the EV-positive patients had a LRTI and were younger with respect to patients with upper RTI (median 18 months versus 37 years; P < 0.001). HRVs are often the cause of LRTI in children less than 5 years, frequently in association with a high viral load. PMID- 22494557 TI - Epidemiologic cutoff values for triazole drugs in Cryptococcus gattii: correlation of molecular type and in vitro susceptibility. AB - Cryptococcus gattii causes infection in tropical and subtropical regions worldwide but has garnered increased attention since its 1999 emergence in North America. C. gattii can be divided into 4 molecular types that may represent cryptic species. Recent evidence has shown that azole antifungal MIC values differ among these molecular types. We tested a large collection of C. gattii isolates for susceptibility to 4 azole drugs. We found that isolates of molecular type VGII have the highest geometric mean (GM) fluconazole MIC values (8.6 MUg/mL), while isolates of molecular type VGI have the lowest (1.7 MUg/mL). For fluconazole, itraconazole, and voriconazole GM MIC values, VGI < VGIII < VGIV < VGII. The GM MIC values for posaconazole were similarly represented across molecular types, with the exception that VGII < VGIII and VGIV. We used the MIC values to establish preliminary epidemiologic cutoff values for each azole and molecular type of C. gattii. PMID- 22494558 TI - Clinical comparison of the Bactec Mycosis IC/F, BacT/Alert FA, and BacT/Alert FN blood culture vials for the detection of candidemia. AB - The present study analyzed the performance of Bactec Mycosis IC/F, BacT/Alert FA, and BacT/Alert FN vials in detection and time to detection (TTD) of Candida spp. in 179 simultaneous blood cultures. The Mycosis IC/F, BacT/Alert FA, and BacT/Alert FN vials could detect Candida spp. in 144 (80.45%) of 179, 149 (83.24%) of 179, and 8 (4.47%) of 179 samples, respectively. With the presence of antifungal therapy, the numbers of positive vials were higher in BacT/Alert FA compared to Mycosis IC/F, 87/99 versus 73/99, respectively (P < 0.05). TTD (SD) for C. albicans was shorter in Mycosis IC/F than in BacT/Alert FA vials without antifungal therapy, 20.89 (9.33) versus 28.26 (9.77), respectively (P < 0.01). The detection of Candida spp., with concomitant bacteremia, was higher in Mycosis IC/F than in BacT/Alert FA vials, 28/30 and 19/30, respectively (P = 0.01). The present data show that the use of Bactec Mycosis IC/F together with BacT/Alert FA vials might improve the detection of Candida spp. PMID- 22494559 TI - Identification and molecular discrimination of toxigenic and nontoxigenic diphtheria Corynebacterium strains by combined real-time polymerase chain reaction assays. AB - With the recognition of several diphtheria outbreaks and the emergence of nontoxigenic corynebacteria strains, there has been renewed interest in the development of laboratory diagnostic methods. Previously reported polymerase chain reaction (PCR) assays can have low diagnostic sensitivity or give species misidentifications among clinical isolates. The aim of the present study was the development of combined real-time PCR assays, based on the tox and rpoB genes, for the detection and differentiation of toxigenic and nontoxigenic corynebacteria. By the PCR tox assay, it was possible to perform the direct identification of DT tox gene of Corynebacterium diphtheriae and Corynebacterium ulcerans, while the PCR rpoB assay differentiated C. diphtheriae from C. ulcerans, irrespective of their toxigenic status. In addition, we detected the DT toxin of Corynebacterium pseudotuberculosis for the first time. These assays revealed high sensitivity, specificity, and reproducibility, and the availability of plasmid controls will facilitate further research into the diagnostics of diphtheria corynebacteria. PMID- 22494560 TI - Evaluation of molecular methods for detection of Borrelia burgdorferi senso lato in ticks. AB - Borrelia burgdorferi sensu lato (s. l.), the agent of Lyme disease, is distributed widely worldwide. A large number of polymerase chain reaction (PCR) methods have been developed and used for detection of B. burgdorferi s. l. However, there is a lack of a reference standard because of the genetic diversity of the B. burgdorferi s. l. complex. In this study, 4 PCR methods, based on the OspA, flagellin, rrs, and P66 genes, for detection of B. burgdorferi s. l. were evaluated by detection of genomic DNA from 3 reference genospecies and tick samples. The sensitivity of the PCR methods was analyzed using serially diluted gDNA from B. afzelii (Bo23), B. burgdorferi sensu stricto (B31), and B. garinii (PBi). The performance of the PCRs was evaluated by detection of the gDNA of 543 ticks. The results showed that the PCRs targeting the OspA gene, fla gene, rrs gene, and P66 gene detected 37 (6.8%), 74 (13.6%), 16 (2.9%), and 14 (2.6%) tick samples, respectively. The PCR targeting the fla gene was the most sensitive method for the detection of B. burgdorferi s. l. PMID- 22494561 TI - Haemophilus parasuis serovars isolated from pathological samples in Northern Italy. AB - From January 2007 to December 2011, a total of 106 Haemophilus parasuis strains isolated from pigs were serotyped by agar gel diffusion test (DG). Serovar 4 was the most prevalent (24.5%), followed by serovar 13 (19.8%) and serovar 5 (11.3%). Twenty-nine strains were non-typeable (27.3%). The strains were divided into two groups, depending on whether they were isolated from specific pathological lesions of systemic disease such as polyserositis, arthritis or meningitis (73 cases of 106) or from the lower respiratory tract of pigs suffering from bronchopneumonia (33 cases of 106). Serovars 4 and 13 had a higher prevalence in systemic infection (polyserositis) than in respiratory disease only. Pasteurella multocida (14/106), Streptococcus suis (7/106), Actinobacillus pleuropneumoniae (4/106), Bordetella bronchiseptica (3/106) and Arcanobacterium pyogenes (3/106) were isolated in association with H. parasuis. PMID- 22494562 TI - Endoscopic resection of skull base tumours utilising the ultrasonic dissector. AB - OBJECTIVE: We report the use and benefits of the ultrasonic dissector in the resection of difficult skull base lesions. METHOD: Five case reports are presented, and the utilisation of ultrasonic dissectors in otorhinolaryngology is reviewed. RESULTS: The ultrasonic dissector was found to be a useful tool during the endoscopic resection of poorly accessible skull base tumours. Safe dissection and complete removal of all five lesions were achieved without any vascular injury. To our knowledge, this is the first report of the use of the ultrasonic dissector for the resection of sinonasal and skull base tumours. CONCLUSION: The ultrasonic dissector was found to be particularly useful during the endoscopic transnasal approach to the petrous apex. During minimally invasive endonasal surgery, benefits include the length of the instrument, speed and precision of dissection, and low risk of vascular injury. PMID- 22494563 TI - Small bowel involvement is a prognostic factor in colorectal carcinomatosis treated with complete cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising treatment for patients with peritoneal carcinomatosis (PC). Our objective was to identify new prognostic factors in patients with PC from colorectal cancer treated with this procedure. METHODS: All patients with PC from colorectal cancer treated by HIPEC from January 2000 to December 2007 were prospectively included. The tumor extension was assessed by the Peritoneal Cancer Index (PCI) and the residual disease was recorded using the completeness cytoreductive score (CCs). All clinical and treatment data were computed in univariate and multivariable analyses using survival as primary end point. RESULTS: We carried out 51 complete procedures in 49 consecutive patients. The mean PCI was 10. The allocation of CCs was: CC-0 = 37, CC-1 = 14. The five-year overall and progression-free survival rate were 40% and 20%, respectively. Several prognostic factors for survival were identified by univariate analysis: PCI < 9 (P < 0.001), CC-0 vs. CC-1 (P < 0.01) and involvement of area 4 (P = 0.06), area 5 (P = 0.031), area 7 (P = 0.014), area 8 (P = 0.022), area 10 (P < 0.0001), and area 11 (P = 0.02). Only the involvement of the distal jejunum (area 10) was significant in the multivariable analysis (P = 0.027). CONCLUSIONS: We demonstrated that the involvement of area 10 (distal jejunum of the PCI score) was an independent factor associated with poor prognosis. PMID- 22494564 TI - Cervical epidural depth: correlation between needle angle, cervical anatomy, and body surface area. AB - OBJECTIVES: Prior to performing a cervical interlaminar epidural steroid injection (CIESI), knowledge of the depth from lamina to epidural space may assist in preventing cord injury. METHODS: This is a prospective analysis of data including gender, age, weight, height, previous surgery, neck circumference, distances from tip of chin to sternal notch, occiput to C7 vertebral prominence, and ear lobe to tip of shoulder, pain score, angle from C7 vertebral prominence to the back, depth at which the Tuohy needle contacted T1 vertebral lamina and depth at which the epidural space was entered was conducted with 92 subjects, average age (+/- standard deviation [SD]) 41.3 +/- 13.2 years underwent fluoroscopically guided C7-T1 intralaminar epidural steroid injections. RESULTS: Depth to lamina was the best individual predictor with an r value of 0.86. Weight, neck circumference, and body mass index (BMI) positively correlated with depth to epidural space with r values of 0.66, 0.62, and 0.61, respectively. A linear regression model of depth to lamina for predicting depth to epidural space was accurate to within +/- 0.5 cm of the actual depth in 69% of subjects. However, when comparing predicted with actual depth to epidural space for individual subjects, the prediction was inaccurate by as much as 1.6 cm deep or 1.7 cm shallow. CONCLUSIONS: While statistically significant correlations do exist between both quantitative external body characteristics and depth to cervical epidural space and T1vertebral lamina to depth of cervical epidural space for fluoroscopically guided interlaminar epidural steroid injections at C7 T1, even the most optimal regression models do not permit clinical confidence in predicted depth to epidural space. PMID- 22494565 TI - No increased rate of acute myocardial infarction or stroke among patients with ankylosing spondylitis-a retrospective cohort study using routine data. AB - OBJECTIVES: To examine if people with ankylosing spondylitis (AS) are at higher risk of acute myocardial infarction (MI) or stroke compared to those without AS. METHODS: Primary care records were linked with all hospital admissions and deaths caused by MI or stroke in Wales for the years 1999-2010. The linked data were then stratified by AS diagnosis and survival analysis was used to obtain the incidence rate of MI and separately cerebrovascular disease (CVD)/stroke. Cox regression was used to adjust for gender and age. Logistic regression was used to examine prevalence of diabetes, hypertension, or hyperlipidemia for those with AS compared to those without. RESULTS: There were 1686 AS patients (75.9% male, average age 46.1 years) compared to 1,206,621 controls (48.9% male, average age 35.9 years). Age- and gender-adjusted hazard ratios for MI were 1.28 (95% CI: 0.93 to 1.74) P = 0.12, and for CVD/stroke 1.0 (95% CI: 0.73 to 1.39) P = 0.9, in AS compared to controls. The prevalence of diabetes and hypertension, but not hyperlipidemia/hypercholesterolemia, was higher in AS. CONCLUSIONS: There is no increase in the MI or CVD/stroke rates in patients with AS compared to those without AS, despite higher rates of hypertension, which may be related to nonsteroidal anti-inflammatory drug use. PMID- 22494566 TI - Detection of EML4-ALK fusion genes in a few cancer cells from transbronchial cytological specimens utilizing immediate cytology during bronchoscopy. AB - The presence of fusion genes between the anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) genes is useful for determining appropriate molecular-targeted therapies in patients with non-small cell lung cancer (NSCLC). The diagnosis of NSCLC is often judged from transbronchial cytological specimens. The efficacy of RT-PCR for detection of EML4-ALK fusion genes in transbronchial cytological specimens has not been studied. Here, we evaluated the detection rate of EML4-ALK fusion genes in transbronchial cytological specimens positive for NSCLC by immediate cytology during bronchoscopic examination. Various numbers of H2228 cells carrying EML4 ALK variant 3 were combined with 1*10(6) wild-type WBCs. The RNA was extracted and the sensitivity of detection of the EML4-ALK fusion gene was determined using a nested RT-PCR. A total of 161 cell samples, from cases without available tissue samples, obtained by bronchoscopic examinations utilized for immediate cytology in patients with NSCLC were subsequently analyzed for EML4-ALK fusion genes using a nested multiplex RT-PCR. EML4-ALK variant 3 was detected in a small number of H2228 cells (10 cells), even in the presence of 1*10(6) WBCs (sensitivity: 0.001%). In the patient cytological samples, EML4-ALK fusion genes were detected in five of 161 NSCLCs (3.1%) and four of 88 adenocarcinomas (4.5%). Sequencing confirmed that these samples included three variant 1 genes, one variant 2 gene and one variant 3 gene. Using the same cytological samples, EGFR mutations were detected in 39 of 161 NSCLCs (24.2%) and 36 of 88 adenocarcinomas (40.9%). There was no case in which both EML4-ALK fusion and EGFR mutation were simultaneously detected. Rapid diagnosis during bronchoscopy utilizing immediate cytology contributed to the selection of the best samples for genetic analysis. EML4-ALK fusion genes as well as EGFR mutations were successfully detected in a small number of cancer cells from transbronchial cytological specimens using a nested multiplex RT-PCR. Our present strategy can be integrated into the clinical process without additional invasive examination of patients. In the era of molecular-targeted treatments for NSCLC, the combination of rapid diagnosis during bronchoscopic examination and stocking samples as cDNA could further correspond to genetic analyses of accumulating driver genes in NSCLC. PMID- 22494567 TI - Efficacy and safety of maintenance erlotinib in Asian patients with advanced non small-cell lung cancer: a subanalysis of the phase III, randomized SATURN study. AB - Maintenance therapy, commenced immediately after the completion of first-line chemotherapy, is a promising strategy for improving treatment outcomes in patients with non-small-cell lung cancer (NSCLC). The global phase III SequentiAl Tarceva in UnResectable NSCLC (SATURN) study evaluated the efficacy and safety of the epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib as maintenance treatment in NSCLC patients without progression after first-line chemotherapy. We report a retrospective subanalysis of Asian patients enrolled in SATURN. Patients with advanced NSCLC with no evidence of progression after four cycles of chemotherapy were randomized to receive erlotinib 150 mg/day or placebo, until progressive disease or limiting toxicity. The co-primary endpoints of SATURN were progression-free survival (PFS) in all patients and in those with positive EGFR immunohistochemistry (IHC) status. Secondary endpoints included overall survival (OS), disease control rate, safety, quality of life (QoL) and biomarker analyses. In total, 126 patients from East and South-East Asian centers were randomized (14% of the intent-to-treat population): 88 from Korea, 28 from China and 10 from Malaysia; one patient was excluded from this analysis due to Indian ethnicity. PFS was significantly prolonged in the erlotinib treatment arm, both overall (hazard ratio [HR]: 0.57; p=0.0067) and in patients with EGFR IHC positive disease (HR=0.50; p=0.0057). There was a trend towards an increase in OS, which reached statistical significance in the EGFR IHC-positive subgroup (p=0.0233). The overall response rate was significantly higher with erlotinib compared with placebo (24% versus 5%; p=0.0025). Erlotinib was generally well tolerated and had no negative impact on QoL in this subpopulation. The most common treatment-related adverse events were rash, diarrhea and pruritus. Erlotinib was effective and well tolerated in Asian patients, producing benefits consistent with those observed in the overall SATURN population. Maintenance treatment with erlotinib appears to be a useful option for the management of Asian patients with advanced NSCLC without progression after first-line chemotherapy. PMID- 22494568 TI - Pharmacological and genetic interventions in serotonin (5-HT)(2C) receptors to alter drug abuse and dependence processes. AB - The present review provides an overview on serotonin (5-hydroxytryptamine; 5 HT)(2C) receptors and their relationship to drug dependence. We have focused our discussion on the impact of 5-HT(2C) receptors on the effects of different classes of addictive drugs, illustrated by reference to data using pharmacological and genetic tools. The neurochemical mechanism of the interaction between 5-HT(2C) receptors, with focus on the mesocorticolimbic dopaminergic system, and drugs of abuse (using cocaine as an example) is discussed. Finally, we integrate recent nonclinical and clinical research and information with marketed products possessing 5-HT(2C) receptor binding affinities. Accordingly, available nonclinical data and some clinical observations targeting 5-HT(2C) receptors may offer innovative translational strategies for combating drug dependence.This article is part of a Special Issue entitled: Brain Integration. PMID- 22494570 TI - Experimental parameter estimation method for nonlinear viscoelastic composite material models: an application on arterial tissue. AB - This study is aimed at setting a method of experimental parameter estimation for large-deforming nonlinear viscoelastic continuous fibre-reinforced composite material model. Specifically, arterial tissue was investigated during experimental research and parameter estimation studies, due to medical, scientific and socio-economic importance of soft tissue research. Using analytical formulations for specimens under combined inflation/extension/torsion on thick-walled cylindrical tubes, in vitro experiments were carried out with fresh sheep arterial segments, and parameter estimation procedures were carried out on experimental data. Model restrictions were pointed out using outcomes from parameter estimation. Needs for further studies that can be developed are discussed. PMID- 22494569 TI - BRCA1 as tumor suppressor: lord without its RING? AB - BRCA1 is a tumor suppressor with critical roles in the maintenance of genomic stability. It encodes a large protein with an amino-terminal RING domain that possesses ubiquitin-ligase activity. Given the occurrence of numerous cancer causing mutations within its RING domain, investigators have long suspected that BRCA1's ubiquitin ligase is important for its tumor suppression and DNA repair activities. Using genetically engineered mouse models, two recent studies shed light on this age-old hypothesis. PMID- 22494571 TI - A novel method to harvest microalgae via co-culture of filamentous fungi to form cell pellets. AB - While current approaches have limitations for efficient and cost-effective microalgal biofuel production, new processes, which are financially economic, environmentally sustainable, and ecologically stable, are needed. Typically, microalgae cells are small and grow individually. Harvest of these cells is technically difficult and it contributes to 20-30% of the total cost of biomass production. A new process of pelletized cell cultivation is described in this study to co-culture a filamentous fungal species with microalgae so that microalgae cells can be co-pelletized into fungal pellets for easier harvest. This new process can be applied to microalgae cultures in both autotrophic and heterotrophic conditions to allow microalgae cells attach to each other. The cell pellets, due to their large size, can be harvested through sieve, much easier than individual cells. This method has the potential to significantly decrease the processing cost for generating microagal biofuel or other products. PMID- 22494572 TI - Syngas fermentation to biofuel: evaluation of carbon monoxide mass transfer and analytical modeling using a composite hollow fiber (CHF) membrane bioreactor. AB - In this study, the volumetric mass transfer coefficients (Ka) for CO were examined in a composite hollow fiber (CHF) membrane bioreactor. The mass transfer experiments were conducted at various inlet gas pressures (from 5 to 30 psig (34.5-206.8 kPa(g))) and recirculation flow rates (300, 600, 900, 1200 and 1500 mL/min) through CHF module. The highest Ka value of 946.6 1/h was observed at a recirculation rate of 1500 mL/min and at an inlet gas pressure of 30 psig(206.8 kPa(g)). The findings of this study confirm that the use of CHF membranes is effective and improves the efficiency CO mass transfer into the aqueous phase. PMID- 22494573 TI - Assessment of the metabolic capacity and adaptability of aromatic hydrocarbon degrading strain Pseudomonas putida CSV86 in aerobic chemostat culture. AB - Pseudomonas putida CSV86 utilizes aromatic compounds preferentially over sugars and co-metabolizes aromatics along with organic acids. In the present study, the metabolic capacity and adaptability of strain CSV86 were assessed in a chemostat at benzyl alcohol concentrations ranging from 1 g l(-1) to 3 g l(-1) and in the presence of glucose and succinate by systematically varying the dilution rate. Complete removal of benzyl alcohol was achieved for loadings up to 640 mg l(-1) h(-1) in presence of benzyl alcohol alone. The strain responded within 1 min towards step changes in substrate loading as indicated by an increase in the oxygen uptake rate, presumably as a result of excess metabolic capacity. These results suggest that CSV86 exhibits considerable metabolic elasticity upon increase in substrate load. Metabolic elasticity of the microorganism is an important parameter in wastewater treatment plants due to the changing substrate loads. PMID- 22494574 TI - A facile whole-cell biocatalytic approach to regioselective synthesis of monoacylated 1-beta-D-arabinofuranosylcytosine: influence of organic solvents. AB - The lyophilized Pseudomonas fluorescens cell was an efficient alternative catalyst to enzymes for highly regioselective acylation of a polar nucleoside, 1 beta-D-arabinofuranosylcytosine (ara-C). The cells showed an evident solvent dependence in the reaction. Among the tested solvents except for acetonitrile pyridine, catalytic activity of the cells clearly increased with increasing the polarity of the organic solvents used. Among all the tested solvents both pure and binary, the best results were observed in isopropyl ether-pyridine system, in which the catalyst also showed good thermal and operational stabilities. For the biocataylsis in isopropyl ether-pyridine, the optimal isopropyl ether concentration, water content, acyl donor/ara-C ratio, biocatalyst dosage and reaction temperature were 30% (v/v), 4%, 45, 50mg/mL and 30 degrees C, respectively, under which the initial rate, yield and 5'-regioselectivity were 2.93 mM/h, 77.1% and 97.3%, respectively. The bacterial cells exhibited comparable 5'-regioselectivity to the expensive immobilized enzyme, which could also have environmental and cost advantages. PMID- 22494575 TI - Modeling of the separation of inhibitory components from pretreated rice straw hydrolysate by nanofiltration membranes. AB - The main objective of this work was to remove inhibitors and concentrate sugars in hydrolysates obtained from dilute acid-treated rice straw. The Donnan steric pore flow model (DSPM) was applied for membrane characterization and it captured the membrane transport adequately. The polyamide and polyethylene sulfate nanofiltration membranes of 150 Da molecular weight cut-off showed a separation factor of 3 for acetic acid over glucose and xylose and 7 over cellobiose for a simulated mixture at the optimum pH of 3. A separation factor of 3 was also found for the inhibitors hydroxymethyl furfural, ferulic and vanilic acids over sugars. The concentration of rice straw acid hydrolysate by a volume concentration ratio of 4 increased the concentrations of xylose, glucose, arabinose, cellobiose and inhibitor by 100%, 104%, 93%, 151% and 3%, respectively which indicates the membrane can be used for separating the inhibitors from acid-pretreated rice straw hydrolysate while simultaneously concentrating sugars. PMID- 22494576 TI - Husbands' involvement in delivery care utilization in rural Bangladesh: A qualitative study. AB - BACKGROUND: A primary cause of high maternal mortality in Bangladesh is lack of access to professional delivery care. Examining the role of the family, particularly the husband, during pregnancy and childbirth is important to understanding women's access to and utilization of professional maternal health services that can prevent maternal mortality. This qualitative study examines husbands' involvement during childbirth and professional delivery care utilization in a rural sub-district of Netrokona district, Bangladesh. METHODS: Using purposive sampling, ten households utilizing a skilled attendant during the birth of the youngest child were selected and matched with ten households utilizing an untrained traditional birth attendant, or dhatri. Households were selected based on a set of inclusion criteria, such as approximate household income, ethnicity, and distance to the nearest hospital. Twenty semi-structured interviews were conducted in Bangla with husbands in these households in June 2010. Interviews were transcribed, translated into English, and analyzed using NVivo 9.0. RESULTS: By purposefully selecting households that differed on the type of provider utilized during delivery, common themes--high costs, poor transportation, and long distances to health facilities--were eliminated as sufficient barriers to the utilization of professional delivery care. Divergent themes, namely husbands' social support and perceived social norms, were identified as underlying factors associated with delivery care utilization. We found that husbands whose wives utilized professional delivery care provided emotional, instrumental and informational support to their wives during delivery and believed that medical intervention was necessary. By contrast, husbands whose wives utilized an untrained dhatri at home were uninvolved during delivery and believed childbirth should take place at home according to local traditions. CONCLUSIONS: This study provides novel evidence about male involvement during childbirth in rural Bangladesh. These findings have important implications for program planners, who should pursue culturally sensitive ways to involve husbands in maternal health interventions and assess the effectiveness of education strategies targeted at husbands. PMID- 22494577 TI - Nifekalant enlarged the transmural activation-recovery interval difference as well as the peak-to-end interval on surface ECG in a patient with short-QT syndrome. AB - A 38-year-old woman with type 1 short-QT syndrome (SQTS) was referred to our hospital. Her ECG showed short QT/QTc interval and peaked T wave. Activation recovery intervals (ARIs) were calculated from the intracardiac endocardial and epicardial electrode catheters placed in the left ventricle (LV). Intravenous administration of nifekalant prolonged effective refractory period at multiple ventricular sites as well as the QT/QTc interval (from 260/300 to 364/419 ms) on the surface ECG. Nifekalant also enlarged the transmural ARI dispersion of the ventricular repolarization, which was measured by the difference between the longest endocardial ARI and the shortest epicardial ARI during atrial pacing at 90 bpm, from 73 to 103-105 ms. These values corresponded to the intervals between the peak and end of the T wave on the surface ECG. Nifekalant-induced QT interval prolongation on the surface ECG may not indicate attenuation of the arrhythmogenic potential in the heart of SQTS patients. PMID- 22494578 TI - Optimization of literature searching. PMID- 22494580 TI - Relationship between environmental factors, dry matter loss and mycotoxin levels in stored wheat and maize infected with Fusarium species. AB - This study examined the relationship between storage environmental factors (water activity (a(w)) (0.89-0.97) and temperature (15 degrees C-30 degrees C)), colonisation of wheat and maize by Fusarium graminearum and F. verticillioides respectively and the dry matter losses (DMLs) caused and quantified by contamination with deoxynivalenol (DON), zearalenone (ZEA) and fumonisins (FUMs) during storage. Fungal growth was assessed by the amount of CO(2) produced under different interacting conditions of a(w) and temperature. DMLs were quantified using the cumulative CO(2) data, and these were shown to increase as temperature and a(w) increased. The amount of DON, ZEA (wheat for human consumption) and FUMs (feed maize) produced was significantly affected by the storage conditions. The three toxins however showed different patterns of production. Optimum for DON was at the wettest conditions (0.97a(w)) and the highest temperature assessed (30 degrees C), whereas for ZEA this shifted to 25 degrees C. FUMs were produced in higher amounts in maize at 30 degrees C and 0.97a(w); however, at intermediate a(w) levels (0.955a(w)), the highest production occurred at 25 degrees C followed by 20 degrees C. Polynomial models were developed for the effect of the storage factors on DMLs and toxin production. DMLs under different environmental conditions were significantly correlated with DON and FUMs. DON contamination was above the EU limits in at least 80% of the wheat samples with DMLs >1%, whereas at least 70% of the same samples contained ZEA above the respective EU legislative limits. Similarly, at least 75% of the maize samples with DMLs >= 0.9% exceeded the EU limits for the sum of FUMs in feed. These results show that it may be possible to use temporal CO(2) production during storage of grains as an indicator of the level of contamination of the grain with mycotoxins. PMID- 22494579 TI - The importance of measuring strength-of-preference scores for health care options in preference-sensitive care. AB - OBJECTIVE: The objective was to determine whether a paired-comparison/Leaning Scale (LS) method: 1) could feasibly be used to elicit strength-of-preference scores for elective health care options in large community-based survey settings and 2) could reveal preferential subgroups that would have been overlooked if only a categorical-response format had been used. STUDY DESIGN: Medicare beneficiaries in four different regions of the United States were interviewed in person. Participants considered eight clinical scenarios, each with two to three different health care options. For each scenario, participants categorically selected their favored option, then indicated how strongly they favored that option relative to the alternative on a paired-comparison bidirectional LS. RESULTS: Two hundred two participants were interviewed. For seven of the eight scenarios, a clear majority (>50%) indicated that, overall, they categorically favored one option over the alternative(s). However, the bidirectional strength of-preference LS scores revealed that, in four scenarios, for half of those participants, their preference for the favored option was actually "weak" or "neutral." CONCLUSION: Investigators aiming to assess population-wide preferential attitudes toward different elective health care scenarios should consider gathering ordinal-level strength-of-preference scores and could feasibly use the paired-comparison/bidirectional LS to do so. PMID- 22494581 TI - Tumor bed dynamics after surgical resection of brain metastases: implications for postoperative radiosurgery. AB - PURPOSE: To analyze 2 factors that influence timing of radiosurgery after surgical resection of brain metastases: target volume dynamics and intracranial tumor progression in the interval between surgery and cavity stereotactic radiosurgery (SRS). METHODS AND MATERIALS: Three diagnostic magnetic resonance imaging (MRI) scans were retrospectively analyzed for 41 patients with a total of 43 resected brain metastases: preoperative MRI scan (MRI-1), MRI scan within 24 hours after surgery (MRI-2), and MRI scan for radiosurgery planning, which is generally performed <=1 week before SRS (MRI-3). Tumors were contoured on MRI-1 scans, and resection cavities were contoured on MRI-2 and MRI-3 scans. RESULTS: The mean tumor volume before surgery was 14.23 cm3, and the mean cavity volume was 8.53 cm3 immediately after surgery and 8.77 cm3 before SRS. In the interval between surgery and SRS, 20 cavities (46.5%) were stable in size, defined as a change of <=2 cm3; 10 cavities (23.3%) collapsed by >2 cm3; and 13 cavities (30.2%) increased by >2 cm3. The unexpected increase in cavity size was a result of local progression (2 cavities), accumulation of cyst-like fluid or blood (9 cavities), and nonspecific postsurgical changes (2 cavities). Finally, in the interval between surgery and SRS, 5 cavities showed definite local tumor progression, 4 patients had progression elsewhere in the brain, 1 patient had both local progression and progression elsewhere, and 33 patients had stable intracranial disease. CONCLUSIONS: In the interval between surgical resection and delivery of SRS, surgical cavities are dynamic in size; however, most cavities do not collapse, and nearly one-third are larger at the time of SRS. These observations support obtaining imaging for radiosurgery planning as close to SRS delivery as possible and suggest that delaying SRS after surgery does not offer the benefit of cavity collapse in most patients. A prospective, multi institutional trial will provide more guidance to the optimal timing of cavity SRS. PMID- 22494582 TI - Volumetric image guidance using carina vs spine as registration landmarks for conventionally fractionated lung radiotherapy. AB - PURPOSE: To compare the relative accuracy of 2 image guided radiation therapy methods using carina vs spine as landmarks and then to identify which landmark is superior relative to tumor coverage. METHODS AND MATERIALS: For 98 lung patients, 2596 daily image-guidance cone-beam computed tomography scans were analyzed. Tattoos were used for initial patient alignment; then, spine and carina registrations were performed independently. A separate analysis assessed the adequacy of gross tumor volume, internal target volume, and planning target volume coverage on cone-beam computed tomography using the initial, middle, and final fractions of radiation therapy. Coverage was recorded for primary tumor (T), nodes (N), and combined target (T+N). Three scenarios were compared: tattoos alignment, spine registration, and carina registration. RESULTS: Spine and carina registrations identified setup errors >= 5 mm in 35% and 46% of fractions, respectively. The mean vector difference between spine and carina matching had a magnitude of 3.3 mm. Spine and carina improved combined target coverage, compared with tattoos, in 50% and 34% (spine) to 54% and 46% (carina) of the first and final fractions, respectively. Carina matching showed greater combined target coverage in 17% and 23% of fractions for the first and final fractions, respectively; with spine matching, this was only observed in 4% (first) and 6% (final) of fractions. Carina matching provided superior nodes coverage at the end of radiation compared with spine matching (P=.0006), without compromising primary tumor coverage. CONCLUSION: Frequent patient setup errors occur in locally advanced lung cancer patients. Spine and carina registrations improved combined target coverage throughout the treatment course, but carina matching provided superior combined target coverage. PMID- 22494583 TI - DNA-PKcs expression predicts response to radiotherapy in prostate cancer. AB - PURPOSE: Double-strand breaks, the most lethal DNA lesions induced by ionizing radiation, are mainly repaired by the nonhomologous end-joining system. The expression of the nonhomologous end-joining pathway has never been studied in prostate cancer, and its prognostic value for patients undergoing radiotherapy remains unknown. METHODS: Pretreatment biopsies from 238 patients treated with exclusive external beam radiotherapy for localized prostate cancer with >= 2 years of follow-up were reviewed to reassess the Gleason score. Of these 238 cases, 179 were suitable for in situ analysis and were included in the tissue microarrays. Expression of the nonhomologous end-joining proteins Ku70, Ku80, DNA dependent protein kinase, catalytic subunits (DNA-PKcs), and X-ray repair cross complementing 4-like factor was studied by immunohistochemistry, together with the proliferation marker Ki67. RESULTS: The predictive value of the Gleason score for biochemical relapse (using the Phoenix criteria) was markedly improved after review (P<.0001) compared with the initial score (P=.003). The clinical stage, pretreatment prostate-specific antigen level, and perineural invasion status were also associated with progression-free survival (P=.005, P<.0001, and P=.03, respectively). High proliferation (>4%) tends to be associated with biochemical recurrence; however, the difference did not reach statistical significance (P=.06). Although the expression of Ku70, Ku80, and X-ray repair cross complementing 4-like factor was not predictive of relapse, positive DNA-PKcs nuclear staining was closely associated with biochemical recurrence (P=.0002). On multivariate analysis, only the Gleason score, prostate-specific antigen level, and DNA-PKcs status remained predictive of recurrence (P=.003, P=.002, and P=.01, respectively). CONCLUSIONS: The results of the present study highly suggest that DNA-PKcs could be a predictive marker of recurrence after radiotherapy, independently of the classic prognostic markers, including the Gleason score modified after review. PMID- 22494584 TI - Twelve-month prostate-specific antigen values and perineural invasion as strong independent prognostic variables of long-term biochemical outcome after prostate seed brachytherapy. AB - PURPOSE: To determine whether post-treatment prostate-specific antigen (ptPSA) values at 12 months and other clinical parameters predict long-term PSA relapse free survival (PRFS) following prostate seed brachytherapy. METHODS AND MATERIALS: Records of 204 hormone-naive patients with localized adenocarcinoma of the prostate treated at St. Mary's Regional Medical Center in Reno, NV, and at Carson Tahoe Regional Medical Center in Carson City, NV, between 1998 and 2003, using I-125 or Pd-103 seed brachytherapy, were retrospectively analyzed. Treatment planning was done using a preplanned, modified peripheral loading technique. A total of 185 of 204 patients had PSA records at 12 months after implant. Variables included were age, initial pretreatment PSA, Gleason score, T stage, National Comprehensive Cancer Network (NCCN) risk group (RG), perineural invasion (PNI), external beam boost, dose, and ptPSA levels at 12 months with cutpoints at <=1, 1.01 to 2.00, 2.01 to 3.00, and >3.00 ng/ml. RESULTS: Median follow-up was 80 months, and median age was 69 years. The numbers of patients stratified by NCCN low, intermediate, and high RG were 110:65:10, respectively. Monotherapy and boost prescription doses were 145 Gy and 110 Gy for I-125, and 125 Gy and 100 Gy for Pd-103 seeds, respectively. The median dose (D90) was 95.4% of the prescribed dose. The 5-year PRFS at the 12-months ptPSA levels of <=1, 1.01 to 2.00, 2.01 to 3.00, and >3.00 ng/ml were 98.5%, 85.7%, 61.5%, and 22.2%, respectively. The 10-year PRFS at the 12-months ptPSA levels of <=1 and 1.01 to 2.00 ng/ml were 90.5% and 85.7%, respectively. In multivariate analysis, both ptPSA and PNI were significant independent predictors of PRFS. Hazard ratios (HR) for ptPSA levels at <=1, 1.01 to 2.00, 2.01 to 3.00, and >3.00 ng/ml at 12 months were 1, 4.96, 27.57, and 65.10, respectively. PNI had an HR of 6.1 (p=0.009). CONCLUSIONS: Presence of PNI and ptPSA values at 12 months are strong prognostic variables for long-term PRFS after definitive prostate brachytherapy seed implantation. PMID- 22494585 TI - The impact of new technologies on radiation oncology events and trends in the past decade: an institutional experience. AB - PURPOSE: To review the type and frequency of patient events from external-beam radiotherapy over a time period sufficiently long to encompass significant technology changes. METHODS AND MATERIALS: Ten years of quality assurance records from January 2001 through December 2010 were retrospectively reviewed to determine the frequency of events affecting patient treatment from four radiation oncology process steps: simulation, treatment planning, data entry/transfer, and treatment delivery. Patient events were obtained from manual records and, from May 2007 onward, from an institution-wide database and reporting system. Events were classified according to process step of origination and segregated according to the most frequently observed event types. Events from the institution-wide database were evaluated to determine time trends. RESULTS: The overall event rate was 0.93% per course of treatment, with a downward trend over time led by a decrease in treatment delivery events. The frequency of certain event types, particularly in planning and treatment delivery, changed significantly over the course of the study, reflecting technologic and process changes. Treatments involving some form of manual intervention carried an event risk four times higher than those relying heavily on computer-aided design and delivery. CONCLUSIONS: Although the overall event rate was low, areas for improvement were identified, including manual calculations and data entry, late-day treatments, and staff overreliance on computer systems. Reducing the incidence of pretreatment events is of particular importance because these were more likely to occur several times before detection and were associated with larger dosimetric impact. Further improvements in quality assurance systems and reporting are imperative, given the advent of electronic charting, increasing reliance on computer systems, and the potentially severe consequences that can arise from mistakes involving complex intensity-modulated or image-guided treatments. PMID- 22494586 TI - Reproducibility of tumor motion probability distribution function in stereotactic body radiation therapy of lung cancer. AB - PURPOSE: To evaluate the reproducibility of tumor motion probability distribution function (PDF) in stereotactic body radiation therapy (SBRT) of lung cancer using cine megavoltage (MV) images. METHODS AND MATERIALS: Cine MV images of 20 patients acquired during three-dimensional conformal (6-11 beams) SBRT treatments were retrospectively analyzed to extract tumor motion trajectories. For each patient, tumor motion PDFs were generated per fraction (PDF(n)) using three selected "usable" beams. Patients without at least three usable beams were excluded from the study. Fractional PDF reproducibility (R(n)) was calculated as the Dice similarity coefficient between PDF(n) to a "ground-truth" PDF (PDF(g)), which was generated using the selected beams of all fractions. The mean of R(n), labeled as R(m), was calculated for each patient and correlated to the patient's mean tumor motion rang (A(m)). Change of R(m) during the course of SBRT treatments was also evaluated. Intra- and intersubject coefficient of variation (CV) of R(m) and A(m) were determined. RESULTS: Thirteen patients had at least three usable beams and were analyzed. The mean of R(m) was 0.87 (range, 0.84 0.95). The mean of A(m) was 3.18 mm (range, 0.46-7.80 mm). R(m) was found to decrease as A(m) increases following an equation of R(m) = 0.17e(-0.9Am) + 0.84. R(m) also decreased slightly throughout the course of treatments. Intersubject CV of R(m) (0.05) was comparable to intrasubject CV of R(m) (range, 0.02-0.09); intersubject CV of A(m) (0.73) was significantly greater than intrasubject CV of A(m) (range, 0.09-0.24). CONCLUSIONS: Tumor motion PDF can be determined using cine MV images acquired during the treatments. The reproducibility of lung tumor motion PDF decreased exponentially as the tumor motion range increased and decreased slightly throughout the course of the treatments. PMID- 22494587 TI - The risk factors of symptomatic communicating hydrocephalus after stereotactic radiosurgery for unilateral vestibular schwannoma: the implication of brain atrophy. AB - PURPOSE: To identify the effect of brain atrophy on the development of symptomatic communicating hydrocephalus (SCHCP) after stereotactic radiosurgery (SRS) for sporadic unilateral vestibular schwannomas (VS). METHODS AND MATERIALS: A total of 444 patients with VS were treated with SRS as a primary treatment. One hundred eighty-one patients (40.8%) were male, and the mean age of the patients was 53+/-13 years (range, 11-81 years). The mean follow-up duration was 56.8+/ 35.8 months (range, 12-160 months). The mean tumor volume was 2.78+/-3.33 cm3 (range, 0.03-23.30 cm3). The cross-sectional area of the lateral ventricles (CALV), defined as the combined area of the lateral ventricles at the level of the mammillary body, was measured on coronal T1-weighted magnetic resonance images as an indicator of brain atrophy. RESULTS: At distant follow-up, a total of 25 (5.6%) patients had SCHCP. The median time to symptom development was 7 months (range, 1-48 months). The mean CALV was 334.0+/-194.0 mm2 (range, 44.70 1170 mm2). The intraclass correlation coefficient was 0.988 (95% confidence interval [CI], 0.976-0.994; p<0.001). In multivariate analysis, the CALV had a significant relationship with the development of SCHCP (p<0.001; odds ration [OR]=1.005; 95% CI, 1.002-1.007). Tumor volume and female sex also had a significant association (p<0.001; OR=1.246; 95% CI, 1.103-1.409; p<0.009; OR=7.256; 95% CI, 1.656-31.797, respectively). However, age failed to show any relationship with the development of SCHCP (p=0.364). CONCLUSION: Brain atrophy may be related to de novo SCHCP after SRS, especially in female patients with a large VS. Follow-up surveillance should be individualized, considering the risk factors involved for each patient, for prompt diagnosis of SCHCP. PMID- 22494588 TI - Fluorodeoxyglucose positron emission tomography response and normal tissue regeneration after stereotactic body radiotherapy to liver metastases. AB - PURPOSE: To characterize changes in standardized uptake value (SUV) in positron emission tomography (PET) scans and determine the pace of normal tissue regeneration after stereotactic body radiation therapy (SBRT) for solid tumor liver metastases. METHODS AND MATERIALS: We reviewed records of patients with liver metastases treated with SBRT to >=40 Gy in 3-5 fractions. Evaluable patients had pretreatment PET and >=1 post-treatment PET. Each PET/CT scan was fused to the planning computed tomography (CT) scan. The maximum SUV (SUV(max)) for each lesion and the total liver volume were measured on each PET/CT scan. Maximum SUV levels before and after SBRT were recorded. RESULTS: Twenty-seven patients with 35 treated liver lesions were studied. The median follow-up was 15.7 months (range, 1.5-38.4 mo), with 5 PET scans per patient (range, 2-14). Exponential decay curve fitting (r=0.97) showed that SUV(max) declined to a plateau of 3.1 for controlled lesions at 5 months after SBRT. The estimated SUV(max) decay half-time was 2.0 months. The SUV(max) in controlled lesions fluctuated up to 4.2 during follow-up and later declined; this level is close to 2 standard deviations above the mean normal liver SUV(max) (4.01). A failure cutoff of SUV(max) >=6 is twice the calculated plateau SUV(max) of controlled lesions. Parenchymal liver volume decreased by 20% at 3-6 months and regenerated to a new baseline level approximately 10% below the pretreatment level at 12 months. CONCLUSIONS: Maximum SUV decreases over the first months after SBRT to plateau at 3.1, similar to the median SUV(max) of normal livers. Transient moderate increases in SUV(max) may be observed after SBRT. We propose a cutoff SUV(max) >=6, twice the baseline normal liver SUV(max), to score local failure by PET criteria. Post-SBRT values between 4 and 6 would be suspicious for local tumor persistence or recurrence. The volume of normal liver reached nadir 3-6 months after SBRT and regenerated within the next 6 months. PMID- 22494589 TI - Prone accelerated partial breast irradiation after breast-conserving surgery: five-year results of 100 patients. AB - PURPOSE: To report the 5-year results of a prospective trial of three-dimensional conformal external beam radiotherapy (3D-CRT) to deliver accelerated partial breast irradiation in the prone position. METHODS AND MATERIALS: Postmenopausal patients with Stage I breast cancer with nonpalpable tumors <2 cm, negative margins and negative nodes, positive hormone receptors, and no extensive intraductal component were eligible. The trial was offered only after eligible patients had refused to undergo standard whole-breast radiotherapy. Patients were simulated and treated on a dedicated table for prone setup. 3D-CRT was delivered at a dose of 30 Gy in five 6-Gy/day fractions over 10 days with port film verification at each treatment. Rates of ipsilateral breast failure, ipsilateral nodal failure, contralateral breast failure, and distant failure were estimated using the cumulative incidence method. Rates of disease-free, overall, and cancer specific survival were recorded. RESULTS: One hundred patients were enrolled in this institutional review board-approved prospective trial, one with bilateral breast cancer. One patient withdrew consent after simulation, and another patient elected to interrupt radiotherapy after receiving two treatments. Ninety-eight patients were evaluable for toxicity, and, in 1 case, both breasts were treated with partial breast irradiation. Median patient age was 68 years (range, 53-88 years); in 55% of patients the tumor size was <1 cm. All patients had hormone receptor-positive cancers: 87% of patients underwent adjuvant antihormone therapy. At a median follow-up of 64 months (range, 2-125 months), there was one local recurrence (1% ipsilateral breast failure) and one contralateral breast cancer (1% contralateral breast failure). There were no deaths due to breast cancer by 5 years. Grade 3 late toxicities occurred in 2 patients (one breast edema, one transient breast pain). Cosmesis was rated good/excellent in 89% of patients with at least 36 months follow-up. CONCLUSIONS: Five-year efficacy and toxicity of 3D-CRT delivered in prone partial breast irradiation are comparable to other experiences with similar follow-up. PMID- 22494590 TI - Prospective assessment of optimal individual position (prone versus supine) for breast radiotherapy: volumetric and dosimetric correlations in 100 patients. AB - PURPOSE: Damage to heart and lung from breast radiotherapy is associated with increased cardiovascular mortality and lung cancer development. We conducted a prospective study to evaluate which position is best to spare lung and heart from radiotherapy exposure. METHODS AND MATERIALS: One hundred consecutive Stage 0-IIA breast cancer patients consented to participate in a research trial that required two computed tomography simulation scans for planning both supine and prone positions. The optimal position was defined as that which best covered the contoured breast and tumor bed while it minimized critical organ irradiation, as quantified by the in-field heart and lung volume. The trial was designed to plan the first 100 patients in each position to study correlations between in-field volumes of organs at risk and dose. RESULTS: Fifty-three left and 47 right breast cancer patients were consecutively accrued to the trial. In all patients, the prone position was optimal for sparing lung volume compared to the supine setup (mean lung volume reduction was 93.5 cc for right and 103.6 cc for left breast cancer patients). In 46/53 (87%) left breast cancer patients best treated prone, in-field heart volume was reduced by a mean of 12 cc and by 1.8 cc for the other 7/53 (13%) patients best treated supine. As predicted, supine-prone differences in in-field volume and mean dose of heart and lung were highly correlated (Spearman's correlation coefficient for left breast cancer patients was 0.90 for heart and 0.94 for lung and 0.92 for right breast cancer patients for lung). CONCLUSIONS: Prone setup reduced the amount of irradiated lung in all patients and reduced the amount of heart volume irradiated in 87% of left breast cancer patients. In-field organ volume is a valid surrogate for predicting dose; the trial continued to the planned target of 400. PMID- 22494591 TI - Analysis of dose response for circulatory disease after radiotherapy for benign disease. AB - PURPOSE: To assess the shape of the dose-response for various circulatory disease endpoints, and modifiers by age and time since exposure. METHODS AND MATERIALS: This was an analysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by circulatory disease endpoint (ischemic heart, cerebrovascular, other circulatory disease). RESULTS: There were significant excess risks for all circulatory disease, with an excess relative risk Gy(-1) of 0.082 (95% CI 0.031 0.140), and ischemic heart disease, with an excess relative risk Gy(-1) of 0.102 (95% CI 0.039-0.174) (both p = 0.01), and indications of excess risk for stroke. There were no statistically significant (p > 0.2) differences between risks by endpoint, and few indications of curvature in the dose-response. There were significant (p < 0.001) modifications of relative risk by time since exposure, the magnitude of which did not vary between endpoints (p > 0.2). Risk modifications were similar if analysis was restricted to patients receiving radiation, although the relative risks were slightly larger and the risk of stroke failed to be significant. The slopes of the dose-response were generally consistent with those observed in the Japanese atomic bomb survivors and in occupationally and medically exposed groups. CONCLUSIONS: There were excess risks for a variety of circulatory diseases in this dataset, with significant modification of risk by time since exposure. The consistency of the dose-response slopes with those observed in radiotherapeutically treated groups at much higher dose, as well as in lower dose-exposed cohorts such as the Japanese atomic bomb survivors and nuclear workers, implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure. PMID- 22494592 TI - Simultaneous integrated boost irradiation after breast-conserving surgery: physician-rated toxicity and cosmetic outcome at 30 months' follow-up. AB - PURPOSE: To evaluate toxicity and cosmetic outcome (CO) in breast cancer survivors treated with three-dimensional conformal radiotherapy with a hypofractionated, simultaneous integrated boost (3D-CRT-SIB) and to identify risk factors for toxicity, with special focus on the impact of age. METHODS AND MATERIALS: Included were 940 consecutive disease-free patients treated for breast cancer (Stage 0-III) with 3D-CRT-SIB, after breast-conserving surgery, from 2005 to 2010. Physician-rated toxicity (Common Terminology Criteria for Adverse Events version 3.0) and CO were prospectively assessed during yearly follow-up, up to 5 years after radiotherapy. Multivariate logistic regression analyses using a bootstrapping method were performed. RESULTS: At 3 years, toxicity scores of 436 patients were available. Grade >= 2 fibrosis in the boost area was observed in 8.5%, non-boost fibrosis in 49.4%, pain to the chest wall in 6.7%, and fair/poor CO in 39.7% of cases. Radiotherapy before chemotherapy was significantly associated with grade >= 2 boost fibrosis at 3 years (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.3-6.0). Non-boost fibrosis was associated with re resection (OR 2.2, 95% CI 1.2-4.0) and larger tumors (OR 1.1, 95% CI 1.0-1.1). At 1 year, chest wall pain was significantly associated with high boost dosage (OR 2.1, 95% CI 1.2-3.7) and younger age (OR 0.4, 95% CI 0.2-0.7). A fair/poor CO was observed more often after re-resection (OR 4.5, 95% CI 2.4-8.5), after regional radiotherapy (OR 2.9, 95% CI 1.2-7.1), and in larger tumors (OR 1.1, 95% CI 1.0 1.1). CONCLUSIONS: Toxicity and CO are not impaired after 3D-CRT-SIB. Fibrosis was not significantly associated with radiotherapy parameters. Independent risk factors for fibrosis were chemotherapy after radiotherapy, re-resection, and larger tumor size. Re-resection was most predictive for worse CO. Age had an impact on chest wall pain occurrence. PMID- 22494593 TI - Comparison of Alpha 200 and CoughAssist as intermittent positive pressure breathing devices: a bench study. AB - BACKGROUND: Intermittent positive pressure breathing (IPPB) is used in non intubated patients to increase lung volume and to enhance coughing. Alpha 200 (Salvia Lifetec, Kronberg, Germany) is a specific IPPB device. CoughAssist (Respironics France, Carquefou, France) is a mechanical insufflator-exsufflator used to remove secretions in patients with inefficient cough. Both can also be used for intubated or tracheotomized patients. We assessed the impact of various artificial airways on the ability of the Alpha 200 and CoughAssist to generate insufflated volume. METHODS: We measured the insufflated volume and pressure at the airway opening in a lung model under 2 conditions of compliance (30 or 60 mL/cm H(2)O) at single resistance of 5 cm H(2)O/L/s. The devices were used at 2 set pressures: 30 and 40 cm H(2)O. The Alpha 200 was set at 2 inflation flows: 0.5 and 1 L/s, whereas CoughAssist was set at its highest value of 10 L/s. Measurements were done without (control) and with different size endotracheal tubes and tracheostomy cannulae. The relationships between insufflated volume and measured pressure were analyzed using linear regressions. RESULTS: The slopes and intercepts of the control relationship between insufflated volume and pressure were significantly greater with Alpha 200 at each set flow than with CoughAssist. As artificial airways were used, the insufflated volume did not differ from the control with CoughAssist, while with Alpha 200 it increased at each flow setting and for all mechanical conditions. The largest differences in insufflated volume between the 2 devices were observed for the largest endotracheal tubes and tracheostomy cannulas and for the lowest inflation flow setting in Alpha 200. These results can be explained in terms of how the devices function, as CoughAssist adapts by increasing flow, while Alpha 200 adapts by increasing inspiratory time. CONCLUSIONS: This bench study has shown that in the presence of artificial airways the value of the insufflated volume generated by the CoughAssist device was significantly lower than that generated by the Alpha 200 device. PMID- 22494594 TI - Ultrasound-assisted coating of polyester fiber with silver bromide nanoparticles. AB - The growth of silver bromide nanoparticles on polyester fiber was achieved by sequential dipping steps in alternating bath of potassium bromide and silver nitrate under ultrasound irradiation. The effects of ultrasound irradiation, concentration and sequential dipping steps in growth of the AgBr nanoparticles have been studied. Particle sizes and morphology of nanoparticle are depending on power of ultrasound irradiation, sequential dipping steps and concentration. These systems depicted a decrease in the particles size accompanying an increase in the sonication power. Results suggest that an increasing of sequential dipping steps and concentration led to an increasing of particle size. The physicochemical properties of the nanoparticles were determined by powder X-ray diffraction (XRD) and scanning electron microscopy (SEM). PMID- 22494595 TI - Remarkable influence of microwave heating on Morita-baylis-Hillman reaction in PEG-200. AB - BACKGROUND: Morita Baylis Hillman (MBH) reaction is used to introduce carbon carbon or carbon-heteroatom bond in a molecule. The major drawback of this reaction is the relatively low product yield and long reaction time. Though notable changes have been made to improve the reaction rate and yield of MBH adduct by various groups, a reliable synthetic procedure under ambient temperature in presence moisture and air is remain unsolved. Continuing the effort to improve the rate and yield, we report here an eco-friendly and cost effective method to generate MBH adducts. Non-volatile polyethylene glycol-200 is used as reusable solvents and the reaction was carried out under the influence of microwave energy. RESULTS: Microwave irradiation have a remarkable influence on PEG suspended 4-Diazabicyclo [2.2.2] octane (DABCO) catalysed MBH reaction between aldehydes and ethyl acrylate. Molecular weight of the PEG is found to have a significant influence on the reaction yield. PEG-200 was the most efficient solvent and in combination with DABCO, the medium can be recycled upto three more runs. This reaction condition is successfully applied to obtain MBH adduct of five different aldehydes in very short time with excellent yield and the required catalyst concentration was very low compared to standard MBH reaction. Since the MBH adduct is an important reactive intermediates for many complex organic syntheses, this approach can be successfully utilised as an alternative to existing reaction conditions. CONCLUSION: A new method was developed to improve the reaction rate and yield of MBH reaction The PEG 200 DABCO combination provides a sustainable, non-volatile, recyclable and environment friendly solvent medium to produce MBH adducts. This medium in combination with microwave energy proved to be very effective to introduce a new carbon-carbon or a carbon-heteroatom bond in a molecule. PMID- 22494596 TI - Ultrasound-guided fascia iliaca compartment block for hip fractures in the emergency department. AB - BACKGROUND: Hip fracture (HFx) is a painful injury that is commonly seen in the emergency department (ED). Patients who experience pain from HFx are often treated with intravenous opiates, which may cause deleterious side effects, particularly in elderly patients. An alternative to systemic opioid analgesia involves peripheral nerve blockade. This approach may be ideally suited for the ED environment, where one injection could control pain for many hours. OBJECTIVES: We hypothesized that an ultrasound-guided fascia iliaca compartment block (UFIB) would provide analgesia for patients presenting to the ED with pain from HFx and that this procedure could be performed safely by emergency physicians (EP) after a brief training. METHODS: In this prospective, observational, feasibility study, a convenience sample of 20 cognitively intact patients with isolated HFx had a UFIB performed. Numerical pain scores, vital signs, and side effects were recorded before and after administration of the UFIB at pre-determined time points for 8h. RESULTS: All patients reported decreased pain after the nerve block, with a 76% reduction in mean pain score at 120 min. There were no procedural complications. CONCLUSION: In this small group of ED patients, UFIB provided excellent analgesia without complications and may be a useful adjunct to systemic pain control for HFx. PMID- 22494597 TI - Uvula necrosis, an atypical presentation of sore throat. PMID- 22494598 TI - A melioidosis patient presenting with brainstem signs in the emergency department. AB - BACKGROUND: Neurological abnormalities in melioidosis are rare but may manifest as an acute stroke, and in the emergency department (ED), an inappropriate stroke treatment may threaten a patient's life. OBJECTIVES: A case of cerebral melioidosis is reported in a patient presenting with brainstem signs to increase awareness of the uncommon presentations of melioidosis that may cause a delayed diagnosis in the ED. CASE REPORT: A 45-year-old man who worked as a construction worker, with diabetes mellitus and alcoholic liver cirrhosis, presented to the ED after a 10-day period of fever and cough. He was initially diagnosed and treated as a case of community-acquired pneumonia. However, a sudden change in consciousness with 6th and 7th cranial nerve palsy and flaccid paralysis were noted while he was in the ED, and acute brainstem stroke was suspected. Brain magnetic resonance imaging disclosed brainstem lesions, slightly hypointense on T1-weighted images and hyperintense on T2-weighted images. Blood and urine cultures subsequently yielded Burkholderia pseudomallei. Abdominal computed tomography revealed multiple small consolidated patches, ground-glass opacities, small nodules in the lower lungs bilaterally, and a pancreatic tail abscess. Systemic melioidosis with lung, pancreas, urogenic tract, and brainstem involvement was diagnosed. Three weeks after admission, the patient died from a sudden onset of apnea and asystole. CONCLUSIONS: In light of this case, patients with identifiable risk factors, especially underlying diabetes, a history of positive soil contact, and those who lived in an endemic area or ever traveled to an endemic area, and who present themselves with fever and neurologic deficit or multi-organ involvement, should have melioidosis considered in the differential diagnosis. PMID- 22494599 TI - MRSA rates and antibiotic susceptibilities from skin and soft tissue cultures in a suburban ED. AB - BACKGROUND: Prior studies suggest that more than half of all skin and soft tissue infections (SSTIs) are caused by methicillin-resistant Staphylococcus aureus (MRSA). These data mainly represent inner-city urban centers. OBJECTIVE: We determined the bacteriologic etiologies and antibiotic susceptibilities from wound cultures in the emergency department (ED). We hypothesized that in a suburban ED, MRSA would not represent the major pathogen. METHODS: The study design was a retrospective, electronic medical record review in a suburban tertiary care ED with 80,000 annual visits. Subjects included ED patients of all ages who had skin or soft tissue cultures obtained in 2005-2008. Demographics and clinical data, including type of SSTI (MRSA or methicillin-sensitive S. aureus [MSSA]), culture results, and antibiotic susceptibility, were analyzed using descriptive statistics. RESULTS: From the 1246 cultures obtained during the study period, 252 (20.2%) were MSSA and 270 (21.6%) were MRSA. The rates of MRSA infections over time increased from 13.5% to 25.7% during 2005-2008. The rates of MRSA in males and females were comparable at 23.3% and 19.6%, respectively. In 2008, MRSA was 97-100% susceptible to vancomycin, linezolid, rifampin, nitrofurantoin, chloramphenicol, gentamycin, tetracycline, and trimethoprim sulfamethoxazole (TMP-SMZ). To a lesser extent it was susceptible to clindamycin (75%), erythromycin (62%), and levofloxacin (50%). CONCLUSIONS: There has been a significant increase in the rates of MRSA SSTIs in a suburban ED, yet only 1 in 4 SSTIs are caused by MRSA. Both MRSA and MSSA are completely susceptible to vancomycin, linezolid, rifampin, nitrofurantoin, and chloramphenicol. Gentamicin, tetracycline, and TMP-SMZ cover > 97% of both isolates. PMID- 22494600 TI - Does the emergency medical treatment and labor act affect emergency department use? AB - BACKGROUND: Emergency departments (EDs) face increasing patient volumes and economic pressures. These problems have been attributed to the Emergency Medical Treatment and Labor Act (EMTALA). STUDY OBJECTIVE: To determine whether modifying EMTALA might reduce ED use. METHODS: We surveyed ED patients to assess their knowledge of hospitals' obligations to treat all patients regardless of insurance and to determine whether knowledge is associated with ED use. RESULTS: Among 4136 study subjects, 72% reported awareness of the law. Sixty-one percent of subjects were moderate ED users (>= 1 additional ED visit in 12 months). Moderate users more often knew the law (74% vs. 70%, p=0.005). Multivariate regression showed that factors associated with moderate use were: awareness of EMTALA (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.24-1.67), adult patient (OR 1.94; 95% CI 1.69-2.22), and government insurance (OR 2.67; 95% CI 2.30-3.08) or uninsured (OR 1.72; 95% CI 1.42-2.08). Only 8% of subjects were high-frequency users (>=5 visits). High-frequency users were more often aware of EMTALA (78% vs. 72%, p=0.02). Covariates associated with high frequency were EMTALA awareness (OR 1.69; 95% CI 1.28-2.24), adult patient (OR 2.59; 95% CI 2.00-3.36), and government insurance (OR 3.73; 95% CI 2.76-5.06) or uninsured (OR 3.77; 95% CI 2.65-5.35). CONCLUSION: Many patients know that the law requires hospitals to provide care. This knowledge is associated with more frequent ED use. EMTALA changes might reduce ED use, but broader policy implications should be considered. PMID- 22494601 TI - Cough and hemoptysis in athletes of an ice hockey team. PMID- 22494602 TI - Factors influencing perceived effectiveness in dealing with self-harming patients in a sample of emergency department staff. AB - BACKGROUND: Past self-harming behavior is one of the most significant predictors of future suicide. Each year in Ireland there are approximately 11,000 presentations of self-harm to emergency departments (EDs) across the country. STUDY OBJECTIVES: This study examines predictors of perceived personal effectiveness in dealing with self-harming patients as reported by ED staff. The predictors are derived from past research and are influenced by Bandura's Social Cognitive Theory. METHOD: One hundred twenty-five ED medical staff (28 doctors and 97 nurses) from five EDs in the West and South of Ireland completed a questionnaire. Predictor variables included in the design, and informed by past research, included knowledge of self-harm and suicidal behavior and confidence in dealing with incidents of self-harm. RESULTS: Standard multiple regression suggested a statistically significant model fit between the two predictors and the criterion variable, accounting for 24% of total variance. Knowledge and Confidence were significant contributors to perceived personal effectiveness in dealing with self-harming patients. CONCLUSIONS: Little is known regarding specific factors that influence perceived effectiveness in dealing with self harming patients in the ED setting. These findings have implications for psycho education and training content for staff. The findings suggest that increasing knowledge of self-harm and confidence in dealing with self-harming patients can lead to more positive perceived personal effectiveness in responding to clients' needs. PMID- 22494603 TI - Acute atraumatic quadriplegia. PMID- 22494604 TI - Cardiac injury due to accidental discharge of nail gun. AB - BACKGROUND: Since 1991, the incidence of injuries associated with pneumatic and explosive powered nail guns has steadily been rising due to increasing use of these devices by the untrained consumer. The vast majority of injuries involve the extremities, but injuries have been reported to occur in virtually every area of the body. OBJECTIVE: Discuss the epidemiology, pathophysiology, and management of penetrating cardiac nail gun injuries. CASE REPORT: A 33-year-old man sustained a penetrating cardiac injury from accidental discharge of a nail gun. The patient had successful repair of a laceration to his right ventricle. CONCLUSIONS: Penetrating cardiac injuries from pneumatic nail guns are rare and have mortality similar to stab wounds. Improved safety mechanisms and training are the keys to prevention. Consideration also should be given to implementing legislation restricting the sale of nail guns. PMID- 22494605 TI - A case of Bell's palsy associated with blepharospasm. AB - BACKGROUND: Bell's palsy is the most common acute mononeuropathy, with an incidence of 20 to 30 cases per 100,000 people per year. OBJECTIVES: Blepharospasm associated with Bell's palsy has been rarely reported. We describe an unusual presentation of Bell's palsy associated with blepharospasm. CASE REPORT: A 44-year-old man presented to the Emergency Department with a few hours' history of right eye blepharospasm. His cornea and conjunctiva were normal on slit lamp examination, including fluorescein staining. His cranial nerves were intact except for a complete right facial nerve weakness, with the patient unable to raise his right eyebrow, and his mouth deviated towards the left. The patient was diagnosed with Bell's palsy associated with blepharospasm and discharged home on prednisone and famciclovir. By the eighth week he was back to baseline with no sequelae. CONCLUSION: Although very rare, physicians should be aware of the existence of Bell's palsy associated with blepharospasm, as it may be under reported. PMID- 22494606 TI - Oxygen reservoir bags simulating chest pathology: a case series. AB - BACKGROUND: We present a series of plain chest radiographs taken in acute settings, with artifactual projections from oxygen reservoir bags. These artifacts are shown to simulate chest pathology in each case. OBJECTIVES: The identification of artifacts on imaging prevents misdiagnosis and potential mistreatment of patients in acute settings. We highlight patterns of findings caused by the projection of oxygen reservoir bags in radiographs taken in the emergency setting. CASE REPORTS: We present plain chest films in 4 patients taken in the acute setting, either in the emergency department or acute admissions unit. In this case series, oxygen reservoir bags simulate pneumothoraces, lung edges, and bullous disease. CONCLUSION: Artifacts on chest radiographs are potential causes of misdiagnosis and subsequent inappropriate treatment. By highlighting the patterns created by the projection of oxygen reservoir bags, emergency physicians, radiologists, and reporting radiographers will be aware of the potential problems. PMID- 22494607 TI - Multidetector-row computed tomography evaluation of bilateral bronchial narrowing associated with increased pulmonary blood flow in children with congenital heart disease. AB - BACKGROUND: Quantitative assessment of bilateral bronchial narrowing in children with congenital heart disease (CHD) with a left-to-right shunt has not yet been reported. OBJECTIVE: In the present study, main bronchial size was evaluated bilaterally in normal subjects using multidetector-row computed tomography (MDCT), and the feasibility for diagnosis of bronchial narrowing in children with CHD associated with increased pulmonary blood flow was investigated. MATERIAL AND METHODS: The short-axis diameter, long-axis diameter, and the cross-sectional area of the bilateral bronchi were measured immediately proximal to the origin of the superior lobar branch in 86 children aged 1-52 months. Subjects were divided into three groups as follows: group 1 (normal subjects; n = 52), group 2 (asymptomatic left-to-right shunt group; n = 25), and group 3 (symptomatic left to-right shunt group with respiratory insufficiency; n = 9). RESULTS: Age, height, weight, and body surface area were significantly correlated with short- and long-axis bronchial diameters, and bronchial cross-sectional area in group 1. In group 2, the left bronchial cross-sectional area was significantly lower than group 1 (P < .001), whereas the right bronchial area was not significantly different. In group 3, the right bronchial area was significantly lower than that in groups 1 and 2 (P < .05). Although the left bronchial area in group 3 was significantly lower than in group 1 (P < .001), it was not significantly different from that in group 2. CONCLUSION: Our study suggests that MDCT can be used to quantify bilateral bronchial narrowing. Left main bronchial obstruction develops during the early stage of heart failure, followed by the development of right bronchial narrowing. PMID- 22494608 TI - Tracheal resection for thyroid cancer. AB - INTRODUCTION: Thyroid cancers infiltrating the upper aerodigestive tract are not uncommon. The management of these cases can be demanding, with a high level of surgical skill required to achieve adequate primary resection and reconstruction. MATERIALS AND METHODS: This study was a single institution series of seven patients, managed over two years, who underwent tracheal resection for advanced thyroid cancer. All patients were older than 45 years (range, 45-65 years) and were predominantly male (six of seven). All patients presented to us with a swelling in the neck. Fine needle aspiration cytology detected thyroid cancer in all patients. None of the patients required a tracheostomy prior to surgery; however, they all had varying levels of airway compromise. One patient had lung metastasis at presentation. In all patients, the airway was successfully secured with fibre-optic assisted intubation prior to surgery. All patients underwent a total thyroidectomy with tracheal resection and anastomosis. Montgomery's suprahyoid release was utilised to achieve adequate laryngeal drop. None of the patients required a tracheostomy in the post-operative period. All patients received adjuvant therapy with either radioiodine ablation and/or radiotherapy. CONCLUSION: Tracheal resection and primary reconstruction is a feasible surgical procedure for patients with thyroid cancer infiltrating the upper aerodigestive tract, with good clinical outcomes. However, the morbidity of the procedure mandates careful case selection, airway management and meticulous surgical technique. PMID- 22494609 TI - Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. AB - The seemingly inexorable decline in insulin independence after islet transplant alone (ITA) has raised concern about its clinical utility. We hypothesized that induction immunosuppression therapy determines durability of insulin independence. We analyzed the proportion of insulin-independent patients following final islet infusion in four groups of ITA recipients according to induction immunotherapy: University of Minnesota recipients given FcR nonbinding anti-CD3 antibody alone or T cell depleting antibodies (TCDAb) and TNF-alpha inhibition (TNF-alpha-i) (group 1; n = 29); recipients reported to the Collaborative Islet Transplant Registry (CITR) given TCDAb+TNF-alpha-i (group 2; n = 20); CITR recipients given TCDAb without TNF-alpha-i (group 3; n = 43); and CITR recipients given IL-2 receptor antibodies (IL-2RAb) alone (group 4; n = 177). Results were compared with outcomes in pancreas transplant alone (PTA) recipients reported to the Scientific Registry of Transplant Recipients (group 5; n = 677). The 5-year insulin independence rates in group 1 (50%) and group 2 (50%) were comparable to outcomes in PTA (group 5: 52%; p>>0.05) but significantly higher than in group 3 (0%; p = 0.001) and group 4 (20%; p = 0.02). Induction immunosuppression was significantly associated with 5-year insulin independence (p = 0.03), regardless of maintenance immunosuppression or other factors. These findings support potential for long-term insulin independence after ITA using potent induction therapy, with anti-CD3 Ab or TCDAb+TNF-alpha-i. PMID- 22494610 TI - From Jack the Ripper to epidemiology and ecology. PMID- 22494611 TI - Type I error hinders recycling: a response to Rohr and Martin. PMID- 22494612 TI - Analysis of transferred keratinocyte-like cells derived from mouse embryonic stem cells on experimental surgical skin wounds of mouse. AB - Autologous/allogenic skin grafts constituted from differentiated adult or embryonic stem cells can be used in treatment of skin disorders. In our study we aimed to differentiate keratinocytes from mouse embryonic stem cells and the transfer of viable keratinocyte-like cells to a model of surgical skin wound of mouse. Embryoid bodies, derived from mouse embryonic stem cells, were cultured on basement membrane matrix with added BMP-4 for 10 days. The identification of differentiated keratinocyte-like cells was done by detection of cytokeratin-8 and cytokeratin-14 localization using an indirect immunoperoxidase technique and transmission electron microscopy evaluation. Distribution of BrdU, cytokeratin-8 and cytokeratin-14 were evaluated using an indirect immunoperoxidase technique from the experimental (dressing including BrdU labelled cells applied after the surgical wound was created on mouse), control (only the surgical wound was created on mouse) and sham (only the dressing applied after the surgical wound was created on mouse) in groups after 3, 5 and 7 days. Immunohistochemically and ultrastructurally, cells derived from mouse embryonic stem cells were similar to differentiated keratinocyte-like cells. Differentiated keratinocyte-like cells were demonstrated by positive BrdU, cytokeratin-8 and cytokeratin-14 staining after transfer to the wound area. In the experimental group wound healing was better after transferring differentiated keratinocytes when compared to the sham and control groups. In vivo continuity and usability of derived cells are very important issues. In wound repair mechanisms, keratinocyte-like cells could provide positive effects during the wound healing and could be used in clinical treatments of wound repair process. PMID- 22494613 TI - Collagen and elastin histochemistry of the teleost bulbus arteriosus: false positives. AB - This report analyzes the localization of collagen and elastin in the teleost bulbus arteriosus by histochemistry and by transmission electron microscopy. Martin's trichrome staining shows widespread distribution of collagen in the wall of the bulbus. However, Sirius red indicates that collagen is mostly restricted to the valves and to the subepicardial layer. This is confirmed by transmission electron microscopy. Trichrome staining gives false positives that may be related to the chemical characteristics of both matrix components and dyes. By contrast, Sirius red constitutes a highly reliable method to detect collagen distribution. On the other hand, orcein heavily stains the bulbus of all teleosts examined. This includes the bulbus of the Antarctic teleosts, which do not show structurally discernable elastin fibers. In these cases, orcein may be staining non-elastin components, or basic elastin components not assembled into larger units. In the teleost bulbus, accurate identification of collagen and elastin cannot be based solely on histochemistry, but should be accompanied by structural identification of the components under study. PMID- 22494614 TI - 3D registration of MR and X-ray spine images using an articulated model. AB - This paper presents a magnetic resonance image (MRI)/X-ray spine registration method that compensates for the change in the curvature of the spine between standing and prone positions for scoliotic patients. MRIs in prone position and X rays in standing position are acquired for 14 patients with scoliosis. The 3D reconstructions of the spine are then aligned using an articulated model which calculates intervertebral transformations. Results show significant decrease in registration error when the proposed articulated model is compared with rigid registration. The method can be used as a basis for full body MRI/X-ray registration incorporating soft tissues for surgical simulation. PMID- 22494615 TI - Preparation, antibacterial evaluation and preliminary structure-activity relationship (SAR) study of benzothiazol- and benzoxazol-2-amine derivatives. AB - In this study, a novel benzothiazol- and benzooxazol-2-amine scaffold with antibacterial activity was designed and synthesized. Preliminary structure activity relationship analysis displayed that compound 8t with a 5,6 difluorosubstituted benzothiazole was found to be a potent inhibitor of Gram positive pathogens, and exhibited some potential against drug-resistant bacteria and without cytotoxicity in therapeutic concentrations. In addition, molecular docking studies indicated that Staphylococcus aureus methionyl-tRNA synthetase might be the possible target of these compounds. Taken together, the present study provides an effective entry to the synthesis of a good lead for subsequent optimization and a new small molecule candidate drug for antibacterial therapeutics. PMID- 22494616 TI - Design, synthesis, and biological evaluation of chalcone oxime derivatives as potential immunosuppressive agents. AB - A series of deoxybenzoin oximes were recently reported as potent immunosuppressive agents by our group. In order to continue the original research for potential immunosuppressive agents with high efficacy and low toxicity, we synthesized a series of new chalcone oximes and evaluated them for their cytotoxicities and immunosuppressive activities. Among the synthesized compounds, chalcone oximes 25 and 27 exhibited lower cytotoxicities and higher inhibitory activities on anti-CD3/anti-CD28 co-stimulated lymph node cells than other compounds. Specially, compound 27 displayed 200-fold lower cytotoxicity (CC(50)=2174.39 MUM) than cyclosporin A (CC(50)=10.10 MUM) and showed SI value (SI=176.69) close to cyclosporin A (SI=154.13). Besides, the preliminary mechanism of inhibition effect of compounds 25 and 27 was also detected by flow cytometry, and the compounds exerted immunosuppressive activities via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Also, the deep mechanism of apoptosis was detected by Western blot analysis. PMID- 22494617 TI - Glucose-aspirin: Synthesis and in vitro anti-cancer activity studies. AB - Glucose-aspirin (GA) was synthesized by conjugating aspirin (ASA) to glucose. The water solubility and biological activity of GA was studied in comparison to aspirin. The human serum protease activity on the ester showed a slower hydrolysis rate, compared to ASA. Glucose-aspirin was sevenfold more water soluble than aspirin and it was about 8- to 9-fold more active in inhibiting cell growth than aspirin in their anti-cancer cell culture activity on breast (SKBR3), pancreatic (PANC-1), and prostate (PC3) cell lines, whereas the activity was similar on a benign non-cancerous cell line (WI 38). In conclusion, GA is a highly water soluble derivative of aspirin. Although the serum hydrolysis for GA was slower, there was significant anti-cancer activity at the doses studied under the experimental conditions. PMID- 22494619 TI - Carbohydrate-based synthetic ion transporters. AB - In this work, carbohydrate-based systems designed as artificial ion transporters have been surveyed. Despite the large structural diversity and ease of manipulations of carbohydrates, in principle endowed with a variety of desirable properties for ionophoric activity, only few examples of sugar-containing compounds have been reported in the literature for these purposes. The most remarkable example is the family of modified beta-cyclodextrins, resulting in active cation and/or anion transporters when long, flexible n-alkyl or oligo ethylene or butylene glycol chains are appended at the lower rim of the macrocycle. Interesting features have been also found in amphiphilic CyPLOS (Cyclic Phosphate-Linked Oligosaccharide) dimers, that is macrocycles with two phenyl-beta-D-glucopyranoside residues, 4,6-linked through phosphodiester bonds, derivatized with tetraethylene glycol tentacles. A wider repertoire of available carbohydrate-based scaffolds is expected to largely stimulate the discovery of novel, efficient artificial ionophores, of great interest for both technological and biomedical applications. PMID- 22494621 TI - Removal of 10-nm contaminant particles from Si wafers using CO2 bullet particles. AB - Removal of nanometer-sized contaminant particles (CPs) from substrates is essential in successful fabrication of nanoscale devices. The particle beam technique that uses nanometer-sized bullet particles (BPs) moving at supersonic velocity was improved by operating it at room temperature to achieve higher velocity and size uniformity of BPs and was successfully used to remove CPs as small as 10 nm. CO2 BPs were generated by gas-phase nucleation and growth in a supersonic nozzle; appropriate size and velocity of the BPs were obtained by optimizing the nozzle contours and CO2/He mixture fraction. Cleaning efficiency greater than 95% was attained. BP velocity was the most important parameter affecting removal of CPs in the 10-nm size range. Compared to cryogenic Ar or N2 particles, CO2 BPs were more uniform in size and had higher velocity and, therefore, cleaned CPs more effectively. PMID- 22494620 TI - RAC1 GTPase plays an important role in gamma-irradiation induced G2/M checkpoint activation. AB - INTRODUCTION: In response to gamma-irradiation (IR)-induced double-strand DNA breaks, cells undergo cell-cycle arrest, allowing time for DNA repair before reentering the cell cycle. G2/M checkpoint activation involves activation of ataxia telangiectasia mutated (ATM)/ATM- and rad3-related (ATR) kinases and inhibition of Cdc25 phosphatases, resulting in inhibition of Cdc2 kinase and subsequent G2/M cell-cycle arrest. Previous studies from our laboratory showed that the G2/M checkpoint activation after IR exposure of MCF-7 breast cancer cells is dependent on the activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signaling. In the present studies, we investigated the role of Ras-related C3 botulinum toxin substrate 1 (Rac1) guanosine triphosphatase (GTPase) in IR-induced G2/M checkpoint response and ERK1/2 activation, as well as in cell survival after IR. METHODS: With Rac1-specific inhibitor, dominant negative mutant Rac1 (N17Rac1) and specific small interfering RNA, the effect of Rac1 on IR-induced G2/M checkpoint response and ERK1/2 activation was examined in human breast cancer cells. In addition, the effect of Rac1 on cell survival after irradiation was assessed by using Rac1-specific inhibitor. RESULTS: IR exposure of MCF-7 breast cancer cells was associated with a marked activation of Rac1 GTPase. Furthermore, inhibition of Rac1 by using specific inhibitor, dominant-negative Rac1 mutant, or specific siRNA resulted in attenuation of IR-induced G2/M arrest and concomitant diminution of IR-induced activation of ATM, ATR, Chk1, and Chk2 kinases, as well as phosphorylation of Cdc2-Tyr15. Moreover, Rac1 inhibition or decreased Rac1 expression also abrogated IR-induced phosphorylation of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) and ERK1/2. Ultimately, inhibition of Rac1 markedly increased cellular sensitivity to IR exposure, which involves induction of apoptosis. CONCLUSION: Studies in this report suggest that Rac1 GTPase plays an essential role in the activation of IR-induced ERK1/2 signaling and subsequent G2/M checkpoint response. Furthermore, results also support a role for Rac1 in promoting cell survival after irradiation treatment. PMID- 22494622 TI - Intractable neuropathic pain in spinal intramedullary cavernoma treated successfully with a novel combination cream. PMID- 22494623 TI - LICC: L-BLP25 in patients with colorectal carcinoma after curative resection of hepatic metastases: a randomized, placebo-controlled, multicenter, multinational, double-blinded phase II trial. AB - BACKGROUND: 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC. METHODS/DESIGN: This is a multinational, phase II, multicenter, randomized, double-blind, placebo controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 MUg once weekly for 8 weeks, followed by s.c. L-BLP25 930 MUg maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned. DISCUSSION: The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion. TRIAL REGISTRATION: EudraCT Number 2011-000218-20. PMID- 22494624 TI - Advances in cell-based therapy for peripheral vascular disease. AB - Evidence is accumulating to support cell-based therapies as a new approach for chronic diseases. Perhaps the area of greatest impact, in terms of patient numbers, is cardiovascular disorders. This review considers cell transplantation as a potential treatment for peripheral vascular disease, including ischemic stroke and erectile dysfunction. Bone marrow derived cells are required for endogenous repair in adult individuals affected by angiopathies. Clinical trials using progenitor cells generated from monocytic or non-monocytic cells indicate that both are effective, suggesting that angiogenesis is the result of cross talk between different cells and pathways. Currently, there are 14 registered clinical trials (ClinicalTrials.gov) examining different approaches to stem cell therapy to cure peripheral artery disease, of which 6 have completed enrollment. Here, we will review published clinical studies that used cell transplantation for peripheral vascular ischemic disorders. PMID- 22494625 TI - Inhibition of hepatic scavenger receptor-class B type I by RNA interference decreases atherosclerosis in rabbits. AB - OBJECTIVE: Scavenger receptor-class B type I (SR-BI), the receptor for HDL cholesterol, plays a key role in HDL metabolism, whole body cholesterol homeostasis, and reverse cholesterol transport. We investigated the in vivo impact of hepatic SR-BI inhibition on lipoprotein metabolism and the development of atherosclerosis employing RNA interference. METHODS: Small hairpin RNA plasmid specific for rabbit SR-BI was complexed with galactosylated poly-l-lysine, allowing an organ-selective, receptor-mediated gene transfer. Rabbits were fed a cholesterol-rich diet, and were injected with plasmid-complexes once a week. RESULTS: After 2 weeks of treatment hepatic SR-BI mRNA levels were reduced by 80% accompanied by reduced SR-BI protein levels and a modulation of the lipoprotein profile. Rabbits treated with SR-BI-specific plasmid-complexes displayed higher cholesteryl ester transfer from HDL to apoB-containing lipoproteins, lower HDL cholesterol, and higher VLDL-cholesterol levels, when compared to controls. In a long-term study, this gene therapeutic intervention led to a similar modulation of the lipoprotein profile, to lower total cholesterol levels, and most importantly to a 50% reduction of the relative atherosclerotic lesion area. CONCLUSION: Our results are another indication that the role of SR-BI in lipoprotein metabolism and atherogenesis in rabbits--a CETP-expressing animal model displaying a manlike lipoprotein profile may be different from the one found in rodents. PMID- 22494626 TI - Human group X secreted phospholipase A2 induces dendritic cell maturation through lipoprotein-dependent and -independent mechanisms. AB - OBJECTIVE: Increased secreted phospholipase A(2) (sPLA(2)) activity has been documented in several inflammatory disorders. Among sPLA(2)s, the human group X (hGX)-sPLA(2) has the highest catalytic activity towards phosphatidylcholine (PC), the major phospholipid of cell membranes and blood lipoproteins. hGX sPLA(2) has been detected in human atherosclerotic lesions, indicating that sPLA(2)s are an important link between lipids and inflammation, both involved in atherosclerosis. The presence of dendritic cells (DC), the most potent antigen presenting cells, in atherosclerotic lesions has raised the question about their role in disease progression. METHODS AND RESULTS: In this study, we show that hGX sPLA(2)-treated LDL induces human monocyte-derived DC maturation, resulting in a characteristic mature DC phenotype and enhanced DC ability to activate IFNgamma secretion from T cells. hGX-sPLA(2) phospholipolysis of LDL produces high levels of lipid mediators, such as lysophosphatidylcholine (LPC) and free fatty acids (FFAs), which also modulate DC maturation. The major molecular species of LPC containing a palmitic or stearic acid esterified in the sn-1 position induce DC maturation, whereas the FFAs can positively or negatively modulate DC maturation depending on their nature. hGX-sPLA(2) added alone can also activate DC in vitro through the hydrolysis of the DC membrane phospholipids leading, however, to a different cytokine profile secretion pattern than the one observed with hGX sPLA(2)-phospholipolysed LDL. CONCLUSION: hGX-sPLA(2) secreted in inflamed tissues can contribute to local DC maturation, resulting in pro-Th1 cells, through the production of various lipid mediators from hydrolysis of either LDL and/or cell plasma membrane. PMID- 22494627 TI - Infection of chickens caused by avian influenza virus A/H5N1 delivered by aerosol and other routes. AB - This study presents results of the study of infectivity of avian influenza virus (AIV) A subtype H5N1 strains isolated from agricultural birds across the territory of the Russian Federation and CIS countries. The results of the susceptibility of chickens to the AIV isolates delivered by the aerosol route and the dissemination of the virus in the organs of infected birds are presented. As was observed, the sensitivity of birds to AIV by the aerosol route of infection is 30 times higher than by intranasal route, 500 times higher than by the oral route and 10000 times higher than by the intragastric route of infection, which is indicative of higher permissivity of respiratory organs to AIV. The highest titres of AIV A subtype H5N1(A/Chicken/Kurgan/05/2005 strain) in aerosol-infected chickens were found in nasal cavity mucosa, lungs, cloaca, serum and kidney, where viable virus accumulation was detected by 18h post-infection (p.i.). The highest virus titres were observed 54h p.i. in lungs, serum and kidney, reaching the value of 8.16 lg EID50 /g(ml) in the lungs. The results showed that birds infected by the aerosol route developed higher titres of virus than those infected by other routes. PMID- 22494628 TI - Catheter ablation of atrial fibrillation in octogenarians: safety and outcomes. AB - INTRODUCTION: Radiofrequency catheter ablation (RFCA) is an effective treatment for atrial fibrillation (AF), although studies evaluating the role of RFCA have largely excluded elderly patients. We report the safety and outcomes of RFCA of AF in octogenarians. METHODS AND RESULTS: From 2008 to 2011, out of 2,754 consecutive patients undergoing RFCA of AF, 103 (3.7%) had >=80 years (age 85 +/- 3 years, 4 with >90 years). Pulmonary vein (PV) antrum isolation was performed in paroxysmal AF. In nonparoxysmal AF, ablation was extended to the entire left atrial posterior wall and to complex fractionated electrograms. Non-PV triggers were disclosed by isoproterenol challenge at the end of the procedure and targeted for ablation. Octogenarians presented a high rate of non-PV triggers (84% vs 69%, P = 0.001), especially in patients with paroxysmal AF (62% vs 19%, P < 0.001); non-PV triggers were most commonly mapped in the coronary sinus (54%), left atrial appendage (32%), interatrial septum and superior vena cava (14%). After a mean follow-up of 18 +/- 6 months, 71 (69%) octogenarians remained free from AF recurrence off antiarrhythmic drugs after a single procedure (vs 71% in patients <80 years, P = 0.65). The success rate reached 87% after 2 procedures. Total periprocedural complication rates also did not differ between the 2 age groups. CONCLUSIONS: RFCA of AF is safe and effective in octogenarians. A high rate of non-PV triggers is present in these patients, and targeting multiple structures other than the pulmonary veins is often necessary to achieve long-term success. PMID- 22494629 TI - Development of a method for quantifying the midsole reaction model parameters. AB - Midsole force-deformation pattern has important implications in determining the kinematics and kinetics of foot during locomotion. Furthermore, the midsole stiffness and viscosity determine the midsole's force-deformation behaviour. Despite the importance of stiffness and damping components of the midsole reaction, which determines the shoe-specific ground reaction forces during locomotion, there is still a lack of methodology to quantify them separately. The purpose of this study was to develop a method of extracting the shoe-specific midsole stiffness and damping components during uniaxial compression testing. For this purpose, the force-deformation behaviour of the sole was modelled as a system consisting of a nonlinear spring and a nonlinear damper. Based on the fact that the stiffness and damping component of the midsole reaction force acts in favour during loading, and work against each other during unloading, the stiffness and damping components were separated. Utilising a curve-fitting technique, a parametric curve represented by the stiffness and damping components of the midsole reaction force model was fitted to each components of force deformation data to extract the parameters. Statistical tests indicated that the proposed method is reliable for extracting the midsole reaction model parameters with the stiffness and damping components producing favorable results (R2 0.998 +/- 0.000 and 0.984 +/- 0.018/root mean squared error of 5.550 +/- 0.954 and 3.286 +/- 2.504, respectively). PMID- 22494630 TI - A chiral quadruple-stranded helicate cage for enantioselective recognition and separation. AB - The self-assembly of enantiopure pyridyl-functionalized metallosalan units affords a homochiral helicate cage, [Zn(8)L(4)Cl(8)], in which the optical rotation of each ligand is increased by a factor of 10 upon coordination. The octanuclear cage featuring a chiral amphiphilic cavity exhibits enantioselective luminescence enhancement by amino acids in solution. The cage exists in two different crystalline polymorphic forms that possess porous structures built of helicate cages interconnected by 1D channels or pentahedral cages and have the ability to separate small racemic molecules by adsorption but with different enantioselectivities. PMID- 22494631 TI - Prevalence of and racial differences in pterygium: a multiethnic population study in Asians. AB - PURPOSE: To describe the prevalence and risk factors of pterygium in a multiethnic Asian population and to examine racial differences. DESIGN: Population-based study in Singapore, located 1 degrees north of the equator. PARTICIPANTS: Data were analyzed from 8906 participants from 3 population-based studies of Malays, Indians, and Chinese persons 40 years of age and older conducted between 2004 and 2011. METHODS: Standardized slit-lamp examinations were performed by trained study ophthalmologists to examine the anterior segment for evidence of pterygium. Every subject underwent standardized systemic and ocular examinations, interviewer-administered questionnaires, and blood investigations for risk factor assessment. Regression and principle component analysis models were constructed to study the relationship of race and other factors to pterygium. MAIN OUTCOME MEASURES: Any pterygium and severe (grade 3 or opaque) pterygium. RESULTS: The overall prevalence of any pterygium was 10.1% (n = 900), of which severe pterygium was seen in 1.6% (n = 142). The prevalence of any pterygium was more common in Malays (15.5%) than Chinese (7.0%; P<0.001) or Indians (7.0%; P<0.001). Multivariate analysis revealed increasing age (P<0.001), male gender (P<0.001), Malay race (P<0.001), and having a poorer education level (P<0.001) as significant factors for any pterygium. Race contributed significantly to presence of any pterygium (41%; P<0.001) or presence in both eyes (33%; P<0.001) compared with other risk factors. Severe pterygium was associated with outdoor occupation (P = 0.02), but race was not a significant risk factor in multivariate analysis. CONCLUSIONS: This population-based study in Asian persons of different races living in the same geographical location at the equator indicated that race is a significant risk factor for pterygium, with Malays having higher prevalence than Indians and Chinese, while controlling for other risk factors. PMID- 22494632 TI - Acquired optic nerve and peripapillary pits in pathologic myopia. AB - PURPOSE: To examine the incidence and characteristics of pit-like structures around the optic disc and myopic conus in eyes with high myopia. DESIGN: Prospective, observational case series. PARTICIPANTS: We evaluated 198 eyes of 119 patients with pathologic myopia (spherical equivalent >-8 diopters [D]). We also evaluated 32 eyes of 32 subjects with emmetropia (refractive error <=+/-3 D) as controls. METHODS: The papillary and peripapillary areas were examined with a prototype swept-source optical coherence tomography (OCT) system with a center wavelength of 1050 nm. We studied the structural characteristics of pit-like changes. MAIN OUTCOME MEASURES: The incidence and characteristics of the optic nerve (ON) pits in eyes with high myopia. RESULTS: Pit-like clefts were found at the outer border of the ON or within the adjacent scleral crescent in 32 of 198 highly myopic eyes (16.2%) but in none of the emmetropic eyes. The eyes with these pits were more myopic, had significantly longer axial lengths, and had significantly larger optic discs than the highly myopic eyes without pits. The pits were located in the optic disc area (optic disc pits) in 11 of 32 eyes and in the area of the conus outside the optic disc (conus pits) in 22 of 32 eyes. One eye had both optic disc pits and conus pits. The optic disc pits existed in the superior or inferior border of the optic disc. All but 1 eye with conus pits had a type IX staphyloma, and the location of the conus pits were present nasal to the scleral ridge or outside the ridge temporal to the nerve. The optic disc pits were associated with discontinuities of the lamina cribrosa, whereas the conus pits appeared to develop from a scleral stretch-associated schisis or to emissary openings for the short posterior ciliary arteries in the sclera. The nerve fiber tissue overlying the pits was discontinuous at the site of the pits. CONCLUSIONS: Optic nerve pits are common in highly myopic eyes. The ON pits are barely visible ophthalmoscopically but can be demonstrated by using swept-source OCT. PMID- 22494633 TI - Inhibitory effects of luteolin on transendothelial migration of monocytes and formation of lipid-laden macrophages. AB - OBJECTIVE: Because of an initial activation of proinflammatory cytokines that facilitates leukocyte transmigration, atherosclerosis is a chronic inflammatory disease and its severity is accelerated by the occurrence of complex interactions of oxidatively modified low-density lipoprotein (LDL) with monocyte-derived macrophages. METHODS: The present study investigated whether luteolin suppresses adheren junction-associated monocyte transmigration and platelet-derived growth factor-BB-mediated foam cell formation. The involvement of monocyte integrins and macrophage scavenger receptors (SRs) also was determined. RESULTS: Luteolin, non toxic at 1 to 20 MUmol/L, blocked the monocyte-endothelium interactions by inhibiting the cytokine-associated monocyte induction of integrin-beta2. Luteolin retarded the transendothelial migration of monocytes by firmly localizing the occludin present in paracellular endothelial junctions and by blunting the monocyte activity of matrix-degrading matrix metalloproteinase-9. Treatment with luteolin showed inhibitory effects on oxidized LDL-triggered foam cell formation by decreasing SR-A and SR-B1 induction in THP-1 cell-derived macrophages, which was confirmed by Oil red O and 1,1'-dioctadecyl-3,3,3',3' tetramethylindocarbocyanine perchlorate staining. Furthermore, luteolin attenuated the oxidized LDL-induced macrophage secretion of platelet-derived growth factor-BB, entailing the induction of SR-A and SR-B1. These results demonstrate that luteolin encumbered monocyte cytokine-instigated endothelial transmigration and oxidized LDL-elicited macrophage foam cell formation. CONCLUSION: Luteolin may qualify as an antiatherogenic agent in LDL systems, which may have implications for strategies attenuating monocyte/macrophage dysfunction-related atherosclerosis. PMID- 22494634 TI - Is extravascular lung water index useful for the diagnostic accuracy of lung injury in patients with shock? We need more evidence. PMID- 22494635 TI - Kinetics and thermochemistry of 2,5-dimethyltetrahydrofuran and related oxolanes: next next-generation biofuels. AB - The enthalpies of formation, entropies, specific heats at constant pressure, enthalpy functions, and all carbon-hydrogen and carbon-methyl bond dissociation energies have been computed using high-level methods for the cyclic ethers (oxolanes) tetrahydrofuran, 2-methyltetrahydrofuran, and 2,5 dimethyltetrahydrofuran. Barrier heights for hydrogen-abstraction reactions by hydrogen atoms and the methyl radical are also computed and shown to correlate with reaction energy change. The results show a pleasing consistency and considerably expands the available data for these important compounds. Abstraction by OH is accompanied by formation of both pre- and postreaction weakly bound complexes. The resulting radicals formed after abstraction undergo ring-opening reactions leading to readily recognizable intermediates, while competitive H-elimination reactions result in formation of dihydrofurans. Formation enthalpies of all 2,3- and 2,5-dihydrofurans and associated radicals are also reported. It is probable that the compounds at the center of this study will be relatively clean-burning biofuels, although formation of intermediate aldehydes might be problematic. PMID- 22494636 TI - Posterior reversible encephalopathy syndrome in liver transplant patients: clinical presentation, risk factors and initial management. AB - Posterior reversible encephalopathy syndrome (PRES) is an uncommon but well-known complication after transplantation diagnosed by characteristic radiological features. As limited data on this complex syndrome exist we sought to better define the incidence, clinical presentation and risk factors for PRES in liver transplant (LTx) patients. We conducted a retrospective analysis of 1923 adult LTx recipients transplanted between 2000 and 2010. PRES was diagnosed radiologically in 19 patients (1%), with 84% of cases occurring within 3 months post-LTX. We compared this cohort of PRES patients to 316 other LTx recipients also requiring radiographic imaging within 3 months after LTx for neurological symptoms. Seizure was the most common clinical manifestation in the PRES group (88% vs. 16%, p< 0.001) and 31% had an intracranial hemorrhage. Those with hemorrhage on imaging were more likely to be coagulopathic. PRES patients were significantly more likely to have had alcoholic liver disease and infection/sepsis. These factors may be related to a common pathway of vascular dysregulation/damage that appears to characterize this complex syndrome. Intracranial bleeding and seizures may be the end result of these phenomena. The relationship of these associated factors to the hypothesized pathophysiology of PRES is discussed. PMID- 22494637 TI - Can cost-effectiveness analysis integrate concerns for equity? Systematic review. AB - OBJECTIVES: The aim of this study was to promote approaches to health technology assessment (HTA) that are both evidence-based and values-based. We conducted a systematic review of published studies describing formal methods to consider equity in the context of cost-effectiveness analysis (CEA). METHODS: Candidate studies were identified through an unrestricted search of the Pub Med and EMBASE databases. The search closed on January 20, 2011. We identified additional studies by consulting experts and checking article bibliographies. Two authors independently reviewed each candidate study to determine inclusion and extracted data from studies retained for review. In addition to documenting methods, data extraction identified implicit and explicit notions of fairness. Data were synthesized in narrative form. Study quality was not assessed. RESULTS: Of the 695 candidate articles, 51 were retained for review. We identified three broad methods to facilitate quantitative consideration of equity concerns in economic evaluation: integration of distributional concerns through equity weights and social welfare functions, exploration of the opportunity costs of alternative policy options through mathematical programming, and multi-criteria decision analysis. CONCLUSIONS: Several viable techniques to integrate equity concerns within CEA now exist, ranging from descriptive approaches to the quantitative methods studied in this review. Two obstacles at the normative level have impeded their use in decision making to date: the multiplicity of concepts and values discussed under the rubric of equity, and the lack of a widely accepted normative source on which to ground controversial value choices. Clarification of equity concepts and attention to procedural fairness may strengthen use of these techniques in HTA decision making. PMID- 22494638 TI - Repair of near-atretic coarctation of the aorta in children with a new low profile covered stent. AB - This article, which shows a technically very challenging angioplasty of a near atretic coarctation of the aorta, underlines the importance of an anticipated procedure planning and of the right selection of available technology. Additionally, the performance and clinical setting of utilization of a new small premounted stent--the Advanta Atrium stent--is highlighted. PMID- 22494639 TI - Development of analysis of volatile polyfluorinated alkyl substances in indoor air using thermal desorption-gas chromatography-mass spectrometry. AB - The study attempts to utilize thermal desorption (TD) coupled with gas chromatography-mass spectrometry (GC-MS) for determination of indoor airborne volatile polyfluorinated alkyl substances (PFASs), including four fluorinated alcohols (FTOHs), two fluorooctane sulfonamides (FOSAs), and two fluorooctane sulfonamidoethanols (FOSEs). Standard stainless steel tubes of Tenax/Carbograph 1 TD were employed for low-volume sampling and exhibited minimal breakthrough of target analytes in sample collection. The method recoveries were in the range of 88-119% for FTOHs, 86-138% for FOSAs, exhibiting significant improvement compared with other existing air sampling methods. However, the widely reported high method recoveries of FOSEs were also observed (139-210%), which was probably due to the structural differences between FOSEs and internal standards. Method detection limit, repeatability, linearity, and accuracy were reported as well. The approach has been successfully applied to routine quantification of targeted PFASs in indoor environment of Singapore. The significantly shorter sampling time enabled the observation of variations of concentrations of targeted PFASs within different periods of a day, with higher concentration levels at night while ventilation systems were shut off. This indicated the existence of indoor sources and the importance of building ventilation and air conditioning system. PMID- 22494640 TI - Simultaneous analysis of 10 trihalomethanes at nanogram per liter levels in water using solid-phase microextraction and gas chromatography mass-spectrometry. AB - Trihalomethanes are predominantly formed during disinfection of water via reactions of the oxidant with natural organic matter. Even though chlorinated and brominated trihalomethanes are the most widespread organic contaminants in drinking water, when iodide is present in raw water iodinated trihalomethanes can also be formed. The formation of iodinated trihalomethanes can lead to taste and odor problems and is a potential health concern since they have been reported to be more toxic than their brominated or chlorinated analogs. Currently, there is no published standard analytical method for I-THMs in water. The analysis of 10 trihalomethanes in water samples in a single run is challenging because the iodinated trihalomethanes are found at very low concentrations (ng/L range), while the regulated chlorinated and brominated trihalomethanes are present at much higher concentrations (above MUg/L). An automated headspace solid-phase microextraction technique, with a programmed temperature vaporizer inlet coupled with gas chromatography-mass spectrometry, was developed for routine analysis of 10 trihalomethanes i.e. bromo-, chloro- and iodo-trihalomethanes in water samples. The carboxen/polydimethylsiloxane/divinylbenzene fiber was found to be the most suitable. The optimization, linearity range, accuracy and precision of the method are discussed. The limits of detection range from 1 ng/L to 20 ng/L for iodoform and chloroform, respectively. Matrix effects in treated groundwater, surfacewater, seawater, and secondary wastewater were investigated and it was shown that the method is suitable for the analysis of trace levels of iodinated trihalomethanes in a wide range of waters. The method developed in the present study has the advantage of being rapid, simple and sensitive. A survey conducted throughout various process stages in an advanced water recycling plant showed the presence of iodinated trihalomethanes at ng/L levels. PMID- 22494641 TI - Computer assisted optimization of liquid chromatographic separations of small molecules using mixed-mode stationary phases. AB - Mixed-mode stationary phases are gaining adepts in liquid chromatography (LC) as more and more applications are published and new commercial columns appear in the market ought to their ability to retain and separate analytes with multiple functionalities. The increased number of adjustable variables gives these columns an enhanced value for the chromatographer, but, on the other hand, it complicates the process of developing satisfactory separations when complex samples must be analyzed. Thus, the availability of computer assisted methods development (CAMD) tools is highly desirable in this field. Therefore, the first specific tool for the CAMD of LC separations in mixed-mode columns is presented. The tool consists in two processes. The first one develops a retention model for peaks in a predefined experimental domain of pH and buffer concentration. In this domain, the retention as a function of the proportion of organic modifier is modeled using a two-stage re-calibration process departing from isocratic retention data and then, from gradient elutions. With this two-stage approach, reliability is gained. In the second process, the model is finally interpolated and used for the unattended optimization of the different possible elution modes available in these columns. This optimization process is driven by an evolutionary algorithm. The development and application of this new chemometrics tool is demonstrated by the optimization of a mixture of neutral and ionizable compounds. Hence, several different types of gradients were generated, showing a good agreement between simulated and experimental data, with retention time errors lower than 5% in most cases. On the other hand, classical CAMD tools, such as design of experiments, were unable to efficiently deal with mixed-mode optimizations, rendering errors above 30% for several compounds. PMID- 22494642 TI - Aqueous two-phase systems for protein separation: phase separation and applications. AB - Aqueous two-phase systems (ATPS) that are formed by mixing a polymer (usually polyethylene glycol, PEG) and a salt (e.g. phosphate, sulphate or citrate) or two polymers, and water can be effectively used for the separation and purification of proteins. The partitioning between both phases is dependent on the surface properties of the proteins and on the composition of the two phase system as has been recently reviewed by Asenjo and Andrews [1]. This paper analyses and reviews some elements that are important for implementation of these processes which are related to phase separation and continuous processing of ATPS. Phase separation for ATPS formed by PEG and salts has been studied and has been found to depend on which of the phases is continuous. Profiles of dispersion heights can be represented as a fraction of the initial height and are independent of the dimensions of the separator. This is important for the design of large scale aqueous two-phase separations. The kinetics of phase separation has been investigated as a function of the physical properties of the system. The settling rate is a crucial parameter for equipment design and it has been studied as a function of viscosity and density of the phases as well as the interfacial tension between them. Correlations that describe the rate of phase separation have been developed. Working in a continuous bottom-phase region is advantageous to ensure fast separation. A mathematical model to describe the continuous, study state operation of these systems has been investigated. Two simulations to show the effect of phase ratio on purification have been carried out which clearly show the effectivity of using such models. The practical application of ATPS has been demonstrated in many cases including a number of industrial applications with excellent levels of purity and yield. Examples include the purification of alpha-amylase and the large scale "in situ" purification of IGF-1 carried out by Genentech. The production scale purification of chymosin from recombinant Aspergillus supernatant is the most successful industrial application of this technology. Other applications include the separation and purification of human alpha-antitrypsin from transgenic sheep milk, the purification of monoclonal antibodies, tPA from CHO supernatant and recombinant VLPs (virus like particles) from yeast cells. PMID- 22494643 TI - Placing supercritical fluid chromatography one step ahead of reversed-phase high performance liquid chromatography in the achiral purification arena: a hydrophilic interaction chromatography cross-linked diol chemistry as a new generic stationary phase. AB - A major driving force hindering the application of supercritical fluid chromatography (SFC) to achiral medium-throughput (MT) and/or high-throughput (HT) purification in the pharmaceutical industry is the absence of a widely applicable column for the analysis and purification of structurally diverse research compounds. As a result, method development is more time-consuming compared to reversed-phase high-performance liquid chromatography (RP-HPLC) where 2 stationary phases, each one used at a different pH, can successfully resolve the majority of mixtures, and SFC is considered a step behind this traditional tool. In early 2010, our group identified a hydrophilic interaction chromatography (HILIC) cross-linked diol chemistry as the most generic column tested so far for achiral SFC application. Analytical and semi-preparative pilot studies using internal research mixtures exceeded our best expectations and allowed for the reduction of our initial 5 column screen on diol, 2-ethyl pyridine, benzenesulfonamide, diethylaminopropyl and dinitrophenyl to a one column (HILIC cross-linked diol) or two column (HILIC cross-linked diol and 2 ethyl pyridine) screen for MT and HT purification. This very high-efficiency and cost-effective approach was immediately implemented as our routine process. Since then, scope, generality and robustness have been validated: 85-90% of samples received in our labs can be purified by SFC, 98% of them using the new 1-2 column simplified screening strategy and in a single pass. In addition, the compound of interest (COI) is isolated at greater than 95% purity and with 85-90% recovery. The success of the new approach has enabled the group to shift from RP-HPLC/MS to SFC/MS as the primary technique for purification within the achiral area. PMID- 22494644 TI - Chromatographic analysis of age-related changes in mucosal serotonin transmission in the murine distal ileum. AB - BACKGROUND: In the upper bowel, alterations in motility and absorption of key nutrients have been observed as part of the normal ageing process. Serotonin (5 HT) is a key signalling molecule in the gastrointestinal tract and is known to influence motility, however little is known of how the ageing process alters 5-HT signalling processes in the bowel. RESULTS: An isocratic chromatographic method was able to detect all 5-HT precursors and metabolites. Using extracellular and intracellular sampling approaches, we were able to monitor all key parameters associated with the transmission process. There was no alteration in the levels of tryptophan and 5-HTP between 3 and 18 month old animals. There was a significant increase in the ratio of 5-HT:5-HTP and an increase in intracellular 5-HT between 3 and 18 month old animals suggesting an increase in 5-HT synthesis. There was also a significant increase in extracellular 5-HT with age, suggesting increased 5-HT release. There was an age-related decrease in the ratio of intracellular 5-HIAA:extracellular 5-HT, whilst the amount of 5-HIAA did not change with age. In the presence of an increase in extracellular 5-HT, the lack of an age-related change in 5-HIAA is suggestive of a decrease in re-uptake via the serotonin transporter (SERT). CONCLUSIONS: We have used intracellular and extracellular sampling to provide more insight into alterations in the neurotransmission process of 5-HT during normal ageing. We observed elevated 5-HT synthesis and release and a possible decrease in the activity of SERT. Taken together these changes lead to increased 5-HT availability and may alter motility function and could lead to the changes in adsorption observed in the elderly. PMID- 22494645 TI - The impact of peripheral nerve techniques on hospital stay following major orthopedic surgery. AB - OBJECTIVE: To determine the impact of regional anesthesia on hospital stay for selected orthopedic procedures compared with traditional pain control modalities. DESIGN: In an era of an increasing volume of orthopedic surgeries, pain modalities that can optimize patient care while minimizing hospital length of stay can have an impact on reducing hospital costs as well as increasing patient satisfaction and improving patient outcomes. Previous studies have shown the potential benefits of regional anesthesia over traditional intravenous (IV) narcotics in meeting these goals in selected orthopedic procedures. METHODS: We retrospectively analyzed the medical records of 494 patients who underwent major orthopedic procedures performed with traditional postoperative pain management alone (IV patient-controlled analgesia and oral narcotics), single injection peripheral nerve block (PNB), and continuous peripheral nerve block (CPNB) in order to determine the impact that different pain modalities might have on hospital length of stay. RESULTS: When compared with traditional pain control modalities, single PNB and CPNB were associated with decreased length of hospital stay, though results for specific surgeries varied. The hazard ratios for hospital discharge from a Current Procedural Terminology code-stratified, covariate (age, gender, and ASA status) adjusted Cox proportional hazards model for single PNB vs no PNB and for CPNB vs no PNB were 1.35 (95% confidence interval: 1.02-1.79) and 1.91 (95% confidence interval: 1.42-2.57), respectively, pointing toward earlier hospital discharge when PNBs were used. CONCLUSIONS Our retrospective case review showed that, overall, hospital lengths of stay tended to be shorter for orthopedic surgery patients receiving single PNB and CPNB than for those receiving no block and traditional pain management. PMID- 22494646 TI - Effect of non-random mating on genomic and BLUP selection schemes. AB - BACKGROUND: The risk of long-term unequal contribution of mating pairs to the gene pool is that deleterious recessive genes can be expressed. Such consequences could be alleviated by appropriately designing and optimizing breeding schemes i.e. by improving selection and mating procedures. METHODS: We studied the effect of mating designs, random, minimum coancestry and minimum covariance of ancestral contributions on rate of inbreeding and genetic gain for schemes with different information sources, i.e. sib test or own performance records, different genetic evaluation methods, i.e. BLUP or genomic selection, and different family structures, i.e. factorial or pair-wise. RESULTS: Results showed that substantial differences in rates of inbreeding due to mating design were present under schemes with a pair-wise family structure, for which minimum coancestry turned out to be more effective to generate lower rates of inbreeding. Specifically, substantial reductions in rates of inbreeding were observed in schemes using sib test records and BLUP evaluation. However, with a factorial family structure, differences in rates of inbreeding due mating designs were minor. Moreover, non random mating had only a small effect in breeding schemes that used genomic evaluation, regardless of the information source. CONCLUSIONS: It was concluded that minimum coancestry remains an efficient mating design when BLUP is used for genetic evaluation or when the size of the population is small, whereas the effect of non-random mating is smaller in schemes using genomic evaluation. PMID- 22494647 TI - [Human, economics and social sciences: rebounds of ideas on genomics and clinical trials]. PMID- 22494648 TI - [Clinical research and human and social sciences at Canceropole PACA]. PMID- 22494649 TI - [Clinical research and human and social sciences at Institut National du Cancer (INCa)]. PMID- 22494650 TI - [The emergence and development of gene expression profiling: a key component of the 3B (bench, bedside, bytes) in translational research]. AB - This paper examines the emergence and development of one of the key components of genomics, namely gene expression profiling. It does so by resorting to computer based methods to analyze and visualize networks of scientific publications. Our results show the central role played by oncology in this domain, insofar as the initial proof-of-principle articles based on a plant model organism have quickly led to the demonstration of the value of these techniques in blood cancers and to applications in the field of solid tumors, and in particular breast cancer. The article also outlines the essential role played by novel bioinformatics and biostatistical tools in the development of the domain. These computational disciplines thus qualify as one of the three corners (in addition to the laboratory and the clinic) of the translational research triangle. PMID- 22494651 TI - [Genomics and clinical research for breast cancer]. AB - Genomics of breast cancer is paving the way towards more and more tailored treatments. The number of molecularly targeted therapies under development is increasing. In parallel, the high-throughput analyses revealed the molecular heterogeneity of disease, and identified several very different molecular subtypes, numerous and sometimes very scarce molecular alterations, and multigenic signatures predictive for clinical outcome, some of which are being tested in prospective clinical trials. This molecular segmentation of breast cancer and the multitude of new drugs to be tested (alone and in combination) lead to develop clinical trials based on the molecular profile of tumors to guide the patient towards the most suitable drug. PMID- 22494652 TI - [Health care expenditures linked to the use of targeted therapies and diagnostic tests for cancer patients]. AB - Recent advances in cancer research have led to the development of very expensive new drugs for cancer treatment: the targeted therapies. However, the introduction of these new therapeutic agents which costs are increasing could threaten the diffusion of these innovations. It is thus necessary to determine whether the use of targeted therapies yields clinical benefits that justify their increasing cost. The development of companion diagnosis tests to target drugs and thus to select those patients most likely to benefit from the treatment may provide a useful means of containing the progress of health care expenditures and improve the cost/benefit ratio. In this paper, we present current estimates of health care expenditures linked to the use of targeted therapies for cancer care. We also discuss some of the issues related to the regulatory decisions (pricing and reimbursement) concerning the test/drug couple. PMID- 22494653 TI - [Targeted chemotherapy for breast cancer: patients perception of the use of tumor gene profiling approaches to better adapt treatments]. AB - The purpose of this review of the literature is to document how breast cancer patients perceive the use of tumor gene profiling approaches to better adapt treatments, and to identify the features of these approaches that may impact their clinical application. In general, the use of tumor genomic analysis was perceived by patients as an approach facilitating personalized medicine and received considerable support. Nevertheless, a number of confusions and worries about these practices were also identified. Improving the quality of provider/patient communications should enable patients to play a more active part in the decision-making about their treatment. This will ensure that those who agree to their tumor gene analysis have realistic expectations and sound deductions of the final result disclosure process. PMID- 22494654 TI - [Perception by cancer patients of biomedical research in the era of large-scale biobanking]. AB - In French hospitals, patients are increasingly asked to participate in research, particularly in oncology where the development of research is stimulated at a national level (plan Cancer). This article express our thoughts based on the literature about the perception by cancer patients of research activities developed in the care centre where they are treated. We focus mainly on the consent for biobanking in a context in which cancer patients are routinely requested to donate tumour samples for research. This article presents the results of a survey among patients treated in a comprehensive cancer centre. The available literature shows that patients have an overall positive image of medical research and of the existence of research activities intertwined with medical care. Patients are globally expressing a wish for more proposals to participate in research in collaboration with scientific teams. PMID- 22494655 TI - [How to share results of clinical trials with study participants?]. AB - Informing research participants of the results of clinical trials in which they were enrolled is in agreement with patients' rights and human dignity; such feedback is considered an ethical standard applied to clinical research. Cancer patients who participate in a clinical trial usually want to know the results. Here we analysed the literature about the different ways of disclosure of clinical trial results to participants, questioning their expectations and the meanings they give to the results. We describe some of the dilemma and intertwining between clinical care and clinical research. We highlight how the standardisation of sharing such results to participants could raise difficulties particularly for the relationship between doctor and patients. PMID- 22494656 TI - [The patient partner of research and care: paradox or necessity?]. PMID- 22494657 TI - Dynamic CT angiography after abdominal aortic endovascular aneurysm repair: differences in contrast agent dynamics in the aorta and endoleaks--preliminary results. AB - PURPOSE: To assess differences in aortic and endoleak enhancement in patients after endovascular aneurysm repair (EVAR) with dynamic computed tomography (CT) angiography. MATERIALS AND METHODS: Twenty-one consecutive patients (mean age, 74.5 y +/- 6; range, 61-88 y) with endoleaks after EVAR of the abdominal aorta were examined on a second-generation dual-source CT unit with 10 unidirectional scan phases (temporal resolution, 5 s; 80 kV; 120 reference-mAs; z-axis field of view, 283 mm), followed by a venous scan phase. Enhancement was assessed in aorta and endoleaks for all phases by density measurements. The diagnostic reliability of endoleak detection was assessed on a five-point confidence scale. RESULTS: In total, 26 endoleaks (type I, n = 1; type II, n = 25) were detected. The highest detection rate was found in phase 5 (22 s after threshold; P < .01 vs other dynamic phases). Mean peak aortic enhancement (560 HU +/- 96) was present in an early arterial phase (phase 3, 12 s after threshold), whereas the mean peak endoleak enhancement (398 HU +/- 174) for type II endoleaks was present later, in phase 4 (17 s after threshold). Despite perceived high diagnostic confidence in phases 1 and 2 (ie, typical arterial phase of biphasic CT protocol), only 23% and 62% of endoleaks were detected, respectively, whereas peak diagnostic confidence (phases 4 and 5) corresponded well with the maximum endoleak detection rate but decreased significantly in later phases (ie, 6-10). CONCLUSIONS: Preliminary dynamic CT angiography results in post-EVAR follow-up revealed notably different peaks of endoleak and aortic enhancement, which are not covered sufficiently by conventional biphasic CT protocols. Phase 5 demonstrated the highest type II endoleak detection rate, with high diagnostic confidence. PMID- 22494658 TI - Cone-beam computed tomography fusion and navigation for real-time positron emission tomography-guided biopsies and ablations: a feasibility study. AB - PURPOSE: To describe a novel technique for multimodality positron emission tomography (PET) fusion-guided interventions that combines cone-beam computed tomography (CT) with PET/CT before the procedure. MATERIALS AND METHODS: Subjects were selected among patients scheduled for a biopsy or ablation procedure. The lesions were not visible with conventional imaging methods or did not have uniform uptake on PET. Clinical success was defined by adequate histopathologic specimens for molecular profiling or diagnosis and by lack of enhancement on follow-up imaging for ablation procedures. Time to target (time elapsed between the completion of the initial cone-beam CT scan and first tissue sample or treatment), total procedure time (time from the moment the patient was on the table until the patient was off the table), and number of times the needle was repositioned were recorded. RESULTS: Seven patients underwent eight procedures (two ablations and six biopsies). Registration and procedures were completed successfully in all cases. Clinical success was achieved in all biopsy procedures and in one of the two ablation procedures. The needle was repositioned once in one biopsy procedure only. On average, the time to target was 38 minutes (range 13-54 min). Total procedure time was 95 minutes (range 51-240 min, which includes composite ablation). On average, fluoroscopy time was 2.5 minutes (range 1.3-6.2 min). CONCLUSIONS: An integrated cone-beam CT software platform can enable PET guided biopsies and ablation procedures without the need for additional specialized hardware. PMID- 22494659 TI - The stress of sleep in patients prone to atrial tachyarrhythmias. PMID- 22494660 TI - Genistein cooperates with the histone deacetylase inhibitor vorinostat to induce cell death in prostate cancer cells. AB - BACKGROUND: Among American men, prostate cancer is the most common, non-cutaneous malignancy that accounted for an estimated 241,000 new cases and 34,000 deaths in 2011. Previous studies have suggested that Wnt pathway inhibitory genes are silenced by CpG hypermethylation, and other studies have suggested that genistein can demethylate hypermethylated DNA. Genistein is a soy isoflavone with diverse effects on cellular proliferation, survival, and gene expression that suggest it could be a potential therapeutic agent for prostate cancer. We undertook the present study to investigate the effects of genistein on the epigenome of prostate cancer cells and to discover novel combination approaches of other compounds with genistein that might be of translational utility. Here, we have investigated the effects of genistein on several prostate cancer cell lines, including the ARCaP-E/ARCaP-M model of the epithelial to mesenchymal transition (EMT), to analyze effects on their epigenetic state. In addition, we investigated the effects of combined treatment of genistein with the histone deacetylase inhibitor vorinostat on survival in prostate cancer cells. METHODS: Using whole genome expression profiling and whole genome methylation profiling, we have determined the genome-wide differences in genetic and epigenetic responses to genistein in prostate cancer cells before and after undergoing the EMT. Also, cells were treated with genistein, vorinostat, and combination treatment, where cell death and cell proliferation was determined. RESULTS: Contrary to earlier reports, genistein did not have an effect on CpG methylation at 20 MUM, but it did affect histone H3K9 acetylation and induced increased expression of histone acetyltransferase 1 (HAT1). In addition, genistein also had differential effects on survival and cooperated with the histone deacteylase inhibitor vorinostat to induce cell death and inhibit proliferation. CONCLUSION: Our results suggest that there are a number of pathways that are affected with genistein and vorinostat treatment such as Wnt, TNF, G2/M DNA damage checkpoint, and androgen signaling pathways. In addition, genistein cooperates with vorinostat to induce cell death in prostate cancer cell lines with a greater effect on early stage prostate cancer. PMID- 22494661 TI - Older participants are frequently excluded from Parkinson's disease research. AB - BACKGROUND: The exclusion of older participants from clinical research is common and limits the generalisation of research findings. We aimed to assess the current potential for older patients to participate in Parkinson's disease (PD) research. METHOD: We performed a systematic analysis of data extracted from the World Health Organization Clinical Trials Registry Platform regarding 206 actively recruiting PD research studies. Data regarding study variables and exclusion on the grounds of an upper age limit was extracted from each registry entry and subsequently used for statistical analysis. RESULTS: Exclusion by arbitrary upper age limit is common, with 101 (49%) of studies excluding participants by age and with a mean upper age limit for exclusion of 79.3 years (range 64-95 years). Exclusion by age was significantly more common in studies with an estimated enrollment of fewer than 100 participants; OR 1.92 (95%CI 1.13 3.42) P = 0.018. Rates of exclusion by age were not significantly influenced by study subject, study location, source of funding, study duration or number of centres. CONCLUSION: Exclusion of participants from PD research on the basis of an upper age limit is common and particularly problematic in smaller studies. The exclusion of older participants seriously compromises the generalisation of findings from PD research to the large numbers of elderly PD patients seen in clinical practice. PMID- 22494662 TI - Cortical myoclonus in childhood and juvenile onset Huntington's disease. AB - OBJECTIVE: Huntington's disease (HD) appearing before the age of 20 years gives rise to a distinct phenotype with respect to the classical adult-onset disease. Here we describe three patients with childhood or juvenile HD onset presenting with action myoclonus. METHODS: We performed jerk-locked back-averaging (JLBA), EEG-EMG coherence and phase analysis, long-loop reflexes (LLRs) and somatosensory evoked potentials (SSEPs). In one patient, we also performed transcranial magnetic stimulation (TMS) using single and paired pulses. RESULTS: In all patients, the EMG features revealed movement activated quasi-rhythmic repetitive jerks; the JLBA and EEG-EMG spectral and coherence profiles indicated a cortical generator of the myoclonus. All patients had enhanced LLRs during muscle contraction, while none showed giant SSEPs. The evaluation of intracortical inhibition by means of TMS revealed reduced inhibition at short and long interstimulus intervals. CONCLUSIONS: The rhythmic course of the action myoclonus and the characteristics of the LLRs suggest that myoclonus is due to a reverberant circuit involving the motor cortex, possibly because of an imbalance between excitatory and inhibitory cortical neuronal systems. SIGNIFICANCE: Our findings suggest a similar cortical dysfunction in childhood and juvenile onset HD, which probably results from a specific circuitry impairment. PMID- 22494663 TI - A biomechanical model to assess the contribution of pelvic musculature weakness to the development of stress urinary incontinence. AB - A biomechanical model of the female pelvic support system was developed to explore the contribution of pelvic floor muscle defect to the development of stress urinary incontinence (SUI). From a pool of 135 patients, clinical data of 26 patients with pelvic muscular defect were used in modelling. The model was employed to estimate the parameters that describe the stiffness properties of the vaginal wall and ligament tissues for individual patients. The parameters were then implemented into the model to evaluate for each patient the impact of pelvic muscular defect on the vaginal apex support and the bladder neck support, a factor that relates to the onset of SUI. For the modelling analysis, the compromise of pelvic muscular support was demonstrated to contribute to vaginal apex prolapse and bladder neck prolapse, a condition commonly seen in SUI patients, while simulated conditions of restored muscular support were shown to help re-establish both vaginal apex and bladder neck supports. The findings illustrate the significance of pelvic muscle strength to vaginal support and urinary continence; therefore, the clinical recommendation of pelvic muscle strengthening, such as Kegel exercises, has been shown to be an effective treatment for patients with SUI symptoms. PMID- 22494665 TI - Quantifying the number of lymph nodes identified in one-stage versus two-stage axillary dissection in breast cancer. AB - PURPOSE: To establish whether a different number of lymph nodes is identified in a delayed versus an immediate axillary lymph node dissection (ALND) in breast cancer patients. METHODS: Using data from the Danish National Patient Register and the Danish Breast Cancer Cooperative Group Database we identified 864 breast cancer patients with sentinel lymph node dissection (SLND) and delayed ALND and 7393 breast cancer patients with SLND and immediate ALND operated between 2002 and 2010. We compared the number of lymph nodes identified in the two groups by a student's t-test. RESULTS: The mean number of lymph nodes identified in patients with immediate and delayed ALND was 16.55 and 15.59, respectively. This difference was statistically significant (P < 0.0001). CONCLUSION: The number of lymph nodes identified in breast cancer patients is slightly reduced if delayed ALND is performed. However, the difference is small and considered to be without clinical significance. PMID- 22494666 TI - Secretory carcinoma of the breast: results from the survival, epidemiology and end results database. AB - BACKGROUND: Secretory carcinoma of the breast is a rare breast cancer that is associated with incidence at a young age and an indolent course. The role for breast conservation and adjuvant radiation is unknown. METHODS: The SEER database was reviewed and 83 patients were identified with secretory carcinoma of the breast between the years 1983 and 2007. Baseline characteristics were compared with chi(2) or Fisher's exact test. Overall survival (OS) and cause-specific survival (CSS) were estimated using the Kaplan-Meier method. Analyses were performed using PASW Statistics, version 18. RESULTS: Median follow-up was 70 months. Median patient age was 53 years (range 11-86 years). 29 patients (34.9%) had involved regional lymph nodes. 39 patients (47.0%) underwent lumpectomy and 44 patients (53.0%) underwent mastectomy. 35 patients (42.2%) received radiation. Patients receiving radiation were more likely to have undergone lumpectomy, and the use of radiation increased over time. 5-year OS was 87.2%; 10-year OS was 76.5%. 5-year CSS was 94.4%; 10-year CSS was 91.4%. Among the lumpectomy patients, 25 patients (64.1%) received radiation. For lumpectomy patients, those who did not receive radiation had a 5-year OS of 92.9% and 10-year OS of 72.2% while patients who did receive radiation had a 5-year OS of 95.5% and 10-year OS of 85.9%. Only 1 patient treated with lumpectomy only died of cancer (92.9% CSS) and no patients treated with lumpectomy and radiation died of cancer (100% CSS). CONCLUSIONS: Secretory carcinoma of the breast commonly occurs at a later age than previously recognized, and is associated with good long-term survival. PMID- 22494667 TI - Lest we forget the endothelial glycocalyx in sepsis. AB - Sepsis is the third largest cause of death in industrialised countries, but treatment remains largely supportive and effective therapeutic interventions are urgently needed. Disruption and dysfunction of the microvascular endothelium leading directly or indirectly to multiple organ failure are now recognised to underpin the pathophysiology of sepsis. Biomarkers of endothelial activation may therefore assume an important role in guiding future research efforts. We suggest that integral to this approach is the investigation and evaluation of endothelial glycocalyx biomarkers, not only as indicators of the pathogenic process but also to inform the development of pharmacological and other therapies. PMID- 22494668 TI - Hydrothermal synthesis of GSH-TGA co-capped CdTe quantum dots and their application in labeling colorectal cancer cells. AB - We have successfully synthesized GSH and TGA co-capped CdTe quantum dots (QDs) with good biological compatibility and high fluorescence intensity. The effects of different reaction time, temperature, pH value, ligand concentration and the molar ratio of GSH/TGA were carefully investigated to optimize the synthesis condition. The optical properties of as-prepared CdTe QDs were studied by UV visible absorption spectrum and fluorescence spectrum, meanwhile their structure and morphology were characterized using transmission electron microscope (TEM), Fourier transform infrared spectra (FT-IR) and X-ray powder diffraction (XRD). Compared with the CdTe QDs that are single-capped with either GSH or TGA, the GSH TGA co-capped CdTe QDs demonstrated significantly improved fluorescence intensity and optical stability. In addition, GSH-TGA co-capped CdTe QDs were conjugated to amonoclonal antibody ND-1. The GSH-TGA co-capped CdTe QDs-antibody probe was successfully used to label colorectal cancer cells, CCL187, in vitro. PMID- 22494669 TI - Collagen coated tantalum substrate for cell proliferation. AB - The extracellular matrix (ECM) plays a key role in cell culture in various physiological and pathological processes in the field of tissue engineering. Recently, the type I collagen ECM has been widely utilized in vitro model systems for the attachment of many different cell lines since it has multi-functions in human tissues. For example it accounts for 6% of the weight of strong, tendinous muscles. In this paper, we reported a new material by coating tantalum (Ta), one highly biocompatible metal, with type I collagen fibrils. The morphology of the new material was studied by high resolution atomic force microscope. It was shown that the adhesion force between type I collagen fibrils network and Ta was strong enough to overcome surface defects. A possible way to explain the phenomenon is that the longitudinal periodicity of collagen fibrils matches the grain size of the Ta domains, which results in increase of the physical adsorption contact area, thereby inducing the dramatic adhesion enhancement between collagen fibrils and Ta. The obtained material was then employed as a template for cell proliferation. Although the surface of this template is more hydrophobic by comparison with the bare Ta surface, the cells on this material were successfully incubated, indicating that the collagen coated Ta might be used as the buffer layer for proliferating cells in hydrophobic biomaterials. PMID- 22494670 TI - Mesoporous silica nanoparticles with manipulated microstructures for drug delivery. AB - A range of mesoporous silica nanoparticles (MSNs) with controlled microstructural characteristics were successfully prepared via the binary surfactant templated synthesis approach with varied concentration of triblock copolymer Pluronic F127. The relationship between the MSNs structural evolution and the surfactant concentration was extensively discussed. Ibuprofen (IBU) was loaded as drug model to uncover the in vitro drug releasing kinetics. It was found that the quantity of the drug loaded mainly depended on the specific surface area, while the drug releasing rate was dominantly determined by the length and curvature of the mesopores. This study has uncovered the core influential factors of MSNs system on its drug releasing properties, and thus demonstrated a facile approach to prepare MSNs with manipulated structural characteristics for drug delivery applications. PMID- 22494671 TI - A randomized, controlled study to assess the conversion from calcineurin inhibitors to everolimus after liver transplantation--PROTECT. AB - Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal-sparing alternative. In this randomized 1-year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post-LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft-Gault formula (-2.9 mL/min in favor of EVR, 95%-CI: [-10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (-7.8 mL/min, 95%-CI: [-14.366; -1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy-proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI-based to EVR-based immunosuppression proved to be a safe alternative post-LTx that deserves further investigation in terms of nephroprotection. PMID- 22494672 TI - The integrity of sperm chromatin in young tropical composite bulls. AB - Sperm chromatin fragmentation is associated with subfertility, but its relationship with age progression in young bulls is poorly understood. The objective was to assess sperm chromatin fragmentation during the early post pubertal development of 20 tropical composite bulls, using a sperm chromatin structure assay (SCSA) and sperm-bos-halomax (SBH). Bulls were subjected to bull breeding soundness evaluation (BBSE) at mean ages of 13, 18, and 24 mo. Traits measured included liveweight (WT), body condition score (BCS) and scrotal circumference (SC). Semen samples were collected by electroejaculation and assessed for mass activity (MA), motility (Mot), concentration (conc), sperm morphology and chromatin fragmentation. Concentration (r=0.34, P=0.0076), Mot (r=0.36, P=0.0041) and percentage of morphologic normal sperm (percent normal sperm (PNS); r=0.31, P=0.0132) were positively correlated with age. The percentage of sperm with proximal droplets (PD) was negatively correlated with age (r=-0.28, P=0.0348), whereas neither SCSA nor SBH results were significantly correlated with age. The percentage of sperm with chromatin fragmentation using SCSA was correlated with PNS (r=-0.53, P<0.0001), the percentage of sperm with head abnormalities (r=0.68, P<0.0001) and the percentage of intact sperm (Int) with SBH (r=-0.26, P=0.0456). In summary, for assessment of sperm chromatin fragmentation, samples could be equally collected at 13, 18 or 24 mo of age, as results did not vary with age. PMID- 22494673 TI - Sperm quality analysis in XX, XY and YY males of the Nile tilapia (Oreochromis niloticus). AB - In Nile tilapia (Oreochromis niloticus), individuals with atypical sexual genotype are commonly used in farming (use of YY males to produce all-male offspring), but they also constitute major tools to study sex determinism mechanisms. In other species, sexual genotype and sex reversal procedures affect different aspects of biology, such as growth, behavior and reproductive success. The aim of this study was to assess the influence of sexual genotype on sperm quality in Nile tilapia. Milt characteristics were compared in XX (sex-reversed), XY and YY males in terms of gonadosomatic index, sperm count, sperm motility and duration of sperm motility. Sperm motility was measured by computer-assisted sperm analysis (CASA) quantifying several parameters: total motility, progressive motility, curvilinear velocity, straight line velocity, average path velocity and linearity. None of the sperm traits measured significantly differed between the three genotypes. Mean values of gonadosomatic index, sperm concentration and sperm motility duration of XX, XY and YY males, respectively ranged from 0.92 to 1.33%, from 1.69 to 2.22 *10(9) cells mL(-1) and from 18'04" to 27'32". Mean values of total motility and curvilinear velocity 1 min after sperm activation, respectively ranged from 53 to 58% and from 71 to 76 MUm s(-1) for the three genotypes. After 3 min of activity, all the sperm motility and velocity parameters dropped by half and continued to slowly decrease thereafter. Seven min after activation, only 9 to 13% of spermatozoa were still progressive. Our results prove that neither sexual genotype nor hormonal sex reversal treatments affect sperm quality in male Nile tilapias with atypical sexual genotype. PMID- 22494674 TI - Lengthening the superstimulatory treatment protocol increases ovarian response and number of transferable embryos in beef cows. AB - This study determined if lengthening the superstimulation protocol from 4 to 7 days would result in an increase in the superovulatory response with no adverse effects on oocyte/embryo competence in beef cows. Follicular ablation was performed, a progesterone-releasing intravaginal device (PRID) was inserted, and cows were assigned to one of two treatment groups 5 to 8 days after ovulation: Control (4 days of follicle stimulating hormone (FSH)) or Long (7 days of FSH; n=12 per group). The FSH treatments were initiated 1.5 days later (Day 0). A dose of 400 mg NIH-FSH-P1 (Folltropin-V) was distributed equally over 8 (Control) or 14 (Long) im injections at 12-h intervals. Prostaglandin F2alpha (PGF) was administered twice, 12 h apart, on Day 2 (Control) or Day 5 (Long), and PRID were removed 12 h after the second PGF. Both groups were given 25 mg pLH (lutropin-V) im 24 h after PRID removal and AI was done 12 and 24 h later. Ova/embryos were collected 7 days after the pLH injection. The mean (+/-SEM) number of >=9 mm follicles at the time of first AI did not differ (P=0.24) between groups, but more ovulations (30.9+/-3.9 vs. 18.3+/-2.9, P=0.01) and CL (27.2+/-2.1 vs. 20.8+/ 2.2, P=0.04) occurred in the Long group. A higher proportion of the >=9 mm follicles ovulated between 12 and 36 h after pLH in the Long group (93 vs. 69%; P=0.001). Although numerically higher in the Long group, mean numbers of total ova/embryos, fertilized ova, transferable or freezable embryos did not differ. In conclusion, a lengthened superstimulatory treatment protocol resulted in more follicles acquiring the capacity to ovulate with an increased number of ovulations, and without a decrease in oocyte/embryo competence. PMID- 22494675 TI - Fertilization rates and in vitro embryo production using sexed or non-sexed semen selected with a silane-coated silica colloid or Percoll. AB - The aim of this study was to evaluate sperm fertilization rates and in vitro embryo development rates for sexed and non-sexed semen selected using a silane coated silica colloid method (Isolate) or Percoll. Frozen/thawed, sexed and unsexed semen samples from four Holstein bulls were randomly allocated to one of two different density gradient selection methods. Sperm quality (motility, concentration, morphology and membrane integrity) were evaluated and compared before and after sperm selection. Sperm motility and morphology improved (P < 0.005) after the sperm selection process with no differences between the two methods. For non-sexed semen, Percoll gradient increased the mean (+/- SEM) percentage of sperm recovered (57.3 +/- 2.8) compared to Isolate (46.0 +/- 1.8; P < 0.01). However, membrane integrity was higher after Isolate than Percoll (sexed semen: 41.0 +/- 0.6 vs. 38.8 +/- 0.8 and non-sexed semen 60.8 +/- 1.6 vs. 58.8 +/ 0.5; P < 0.05). The percentage of blastocysts produced was higher when either sexed or non-sexed semen was selected by Isolate (14.0 +/- 1.0; 22.0 +/- 1.1) than by Percoll (10.5 +/- 1.5; 17.0 +/- 2.1, respectively; P < 0.05). In summary, Isolate was a more effective method for the recovery of high quality sperm for in vitro fertilization embryo production. PMID- 22494676 TI - Restoration of seminal plasma to stallion spermatozoa selected by colloid centrifugation increases sperm progressive motility but is detrimental to chromatin integrity. AB - There is controversy about whether the presence of some seminal plasma (SP) in an equine insemination dose is necessary for promoting fertility. A new technique for improving stallion sperm quality, single layer centrifugation (SLC) using a species-specific colloid, Androcoll-E, selects a sperm subpopulation that is highly motile with normal morphology, intact membranes and good chromatin integrity from the rest of the ejaculate and removes SP. The present study was designed to investigate the effect of restoring homologous SP (5% and 10%) on the progressive motility, velocity, and chromatin integrity of SLC-selected stallion spermatozoa in 44 semen samples over time. Sperm progressive motility (P<0.01) and the proportion with class A velocity (>50 MUm/sec) were increased in samples where SP was restored, whereas the proportion with class B velocity (10 to 50 MUm/sec) was decreased compared with SLC samples. However, after 24 h cold storage of treated samples, progressive motility was not different for the SP treated groups compared with SLC, whereas chromatin damage DNA fragmentation index (%DFI) was higher. In contrast, adding SP to untreated 24 h-stored SLC samples did not affect progressive motility although it did increase the proportion of spermatozoa with class A velocity. There was individual variation between stallions whether 5% or 10% SP produced a greater increase in progressive motility. In conclusion, 5% to 10% SP can be added back to SLC-selected samples if considered necessary to optimize fertility. However, it should be added immediately before insemination rather than before storage of the sperm dose, to benefit from the transient increase in sperm progressive motility and avoid increased chromatin damage. PMID- 22494677 TI - Humoral immune response in lactating dairy cows after repeated exposure to human chorionic gonadotropin. AB - Our objective was to determine if repeated exposure of lactating dairy cows to human chorionic gonadotropin (hCG) would induce an antibody (Ab) response against hCG. Cows either received an hCG injection (hCG; n = 24, each given 2000 IU im) or no treatment (CON; n = 22) 18 days after a timed AI (TAI) and 7 days before initiation of Ovsynch for resynchronization of ovulation and TAI. A subgroup of cows continued in the experiment to receive a second hCG injection (n = 17) 35 days after the first exposure to hCG, whereas another subgroup served as controls (n = 9). Another subgroup of cows continued in the experiment to receive a third hCG injection (n = 11) 35 days after the second exposure to hCG, whereas cows not receiving hCG served as controls (n = 8). A binding radioimmunoassay was used to detect hCG antibodies in serum samples collected 0, 7, 14, 21, and 28 days after treatment. A positive Ab response (>6.2% bound) was defined as three standard deviations above CON binding. No cows had hCG antibodies at Day 0 before the first exposure to hCG. After the first hCG treatment, there was no difference (P = 0.52) between Ab positive cows in CON (0%) and hCG (4%) treatments. At the second hCG treatment, on Day 0 there was no difference (P = 0.65) between CON (0%) and hCG (6%) cows, whereas, more (P = 0.02) hCG cows (47%) were positive than CON cows (0%) within 28 days of the hCG injection. At the third hCG injection, hCG cows tended (P = 0.09) to have a greater percentage of Ab positive (36%) than CON cows (0%), whereas after the injection, a greater (P < 0.01) percentage of hCG cows were positive (hCG = 73% vs. CON = 0%). After the second and third exposure to hCG, 8 of 17 and 8 of 11 cows within the hCG group had greater percent Ab bound at 7, 14, 21, and 28 days after hCG than cows in CON and those with no Ab response. The greatest percent Ab binding occurred at 14 days after the second and third hCG exposure. We concluded that some but not all lactating dairy cows developed an Ab response after repeated exposure to hCG and that maximum response occurred within 14 days after hCG exposure. PMID- 22494678 TI - A novel SNP of the PNRC1 gene and its association with reproductive traits in Tsaiya ducks. AB - Proline-rich nuclear receptor coactivator (PNRC)1 is a member of a new family of nuclear receptor coactivators capable of potentiating the transcriptional activity of nuclear receptors. The objective was to investigate the relationship between PNRC1 genotypes of single nucleotide polymorphism (SNP) and reproductive traits in ducks. Brown Tsaiya ducks (N = 305) from two lines, a control line with no selection and the selected line, were used. Polymerase chain reaction-single strand polymorphism and DNA sequencing were done to screen polymorphisms of the PNRC1 gene. A novel SNP (G98T) in 3'-untranslated region of the PNRC1 gene was identified and resulted in two genotypes, GG and GT. The frequencies of genotype GG and allele G were higher in both lines investigated. Regarding egg weight at first egg (EWFE), based on SNP trait association analysis, ducks with the GG genotype had a 4.48 g per egg greater egg weight at first egg when compared with ducks of the GT genotype in the control line (P < 0.05). In addition, this SNP was associated with the hatchability rate (HR) in the selected line; ducks with the GT genotype had a 6.70% higher hatchability rate than those with the GG genotype (P < 0.05). Therefore, we inferred that the PNRC1 gene could be a candidate locus or linked to a major gene that influenced egg weight-related and hatchability traits in Tsaiya ducks. Further investigations on additional duck populations with larger sample sizes are needed to confirm these results. PMID- 22494679 TI - Production of IVF transgene-expressing bovine embryos using a novel strategy based on cell cycle inhibitors. AB - The objective was to evaluate the effects of cell cycle inhibitors (6 dimethylaminopurine [DMAP], and dehydroleukodine [DhL]) on transgene expression efficiency and on mosaic expression patterns of IVF bovine zygotes cytoplasmically injected with oolema vesicles coincubated with transgene. The DNA damage induced by the transgene or cell cycle inhibitors was measured by detection of phosphorylated histone H2AX foci presence (marker of DNA double stranded breaks). Cloning of egfp blastomeres was included to determine continuity of expression after additional rounds of cellular division. The pCX EGFP [enhanced green fluorescent protein gene (EGFP) under the chimeric cytomegalovirus IE-chicken-beta-actin enhancer promoter control] gene plasmid (50 ng/MUL) was injected alone (linear or circular exogenous DNA, leDNA and ceDNA, respectively) or associated with ooplasmic vesicles (leDNA-v or ceDNA-v). The effects of 2 mm DMAP or 1 MUm DhL for 6 h (from 15 to 21 h post IVF) was evaluated for groups injected with vesicles. The DMAP increased (P < 0.05) egfp homogenous expression relative to transgene alone (21%, 18%, and 11% for leDNA-v + DMAP, leDNA-v, and leDNA, respectively) and also increased (P < 0.05) the phosphorylated histone H2AX foci area. Expression of egfp was higher (P < 0.05) for linear than for circular pCX-EGFP, and egfp blastocyst rates were higher (P < 0.05) for groups injected with linear transgene coincubated with vesicles than for linear transgene alone (95%, 77%, 84%, and 52% for leDNA-v + DMAP, leDNA-v + DhL, leDNA-v, and leDNA, respectively). Moreover, DMAP tended to improve egfp blastocysts rates for both circular and linear transgenes. Based on fluorescent in situ hybridization (FISH) analysis, there was evidence of integration in egfp embryos. Finally, clones derived from leDNA-v + DMAP had the highest egfp expression rates (96%, 65%, and 65% for leDNA-v + DMAP, leDNA-v, and leDNA, respectively). Transgenesis by cytoplasmic injection of leDNA-v + DMAP is a promising alternative for transgenic animal production. PMID- 22494680 TI - Microfluidic mixing for sperm activation and motility analysis of pearl Danio zebrafish. AB - Sperm viability in aquatic species is increasingly being evaluated by motility analysis via computer-assisted sperm analysis (CASA) following activation of sperm with manual dilution and mixing by hand. User variation can limit the speed and control over the activation process, preventing consistent motility analysis. This is further complicated by the short interval (i.e., less than 15 s) of burst motility in these species. The objectives of this study were to develop a staggered herringbone microfluidic mixer to: 1) activate small volumes of Danio pearl zebrafish (Danio albolineatus) sperm by rapid mixing with diluent, and 2) position sperm in a viewing chamber for motility evaluation using a standard CASA system. A herringbone micromixer was fabricated in polydimethylsiloxane (PDMS) to yield high quality smooth surfaces. Based on fluorescence microscopy, mixing efficiency exceeding 90% was achieved within 5 s for a range of flow rates (from 50 to 250 MUL/h), with a correlation of mixing distances and mixing efficiency. For example, at the nominal flow rate of 100 MUL/h, there was a significant difference in mixing efficiency between 3.5 mm (75+/-4%; mean+/-SD) and 7 mm (92+/-2%; P=0.002). The PDMS micromixer, integrated with standard volumetric slides, demonstrated activation of fresh zebrafish sperm with reduced user variation, greater control, and without morphologic damage to sperm. Analysis of zebrafish sperm viability by CASA revealed a statistically higher motility rate for activation by micromixing (56+/-4%) than manual activation (45+/-7%; n=5, P=0.011). This micromixer represented a first step in streamlining methods for consistent, rapid assessment of sperm quality for zebrafish and other aquatic species. The capability to rapidly activate sperm and consistently measure motility with CASA using the PDMS micromixer described herein will improve studies of germplasm physiology and cryopreservation. PMID- 22494681 TI - Susceptibility to persistent breeding-induced endometritis in the mare: relationship to endometrial biopsy score and age, and variations between seasons. AB - The objectives were to: (1) investigate the associations of age and endometrial biopsy score with uterine fluid retention after insemination; and (2) determine if a strict classification of susceptibility to persistent breeding-induced endometritis (PBIE) based on biopsy score, endometrial cytology, and fluid retention after inseminations, is consistent over subsequent breeding seasons. In Experiment 1, 57 mares were inseminated with 10(9) freeze-killed sperm during estrus and evaluated for uterine fluid retention 48 h and 96 h after insemination. Comparisons were made between fluid retention and biopsy score or age. In Experiment 2, a subset of 14 mares was classified for susceptibility to persistent breeding-induced endometritis in two subsequent breeding seasons. Biopsy score and age were associated with fluid retention (P < 0.001). In addition, age was related to biopsy score (P < 0.001). Of the mares examined for susceptibility, 36% (5 of 14) changed status during subsequent seasons. Three mares changed to a more severe classification (intermediate to susceptible, or resistant to intermediate), whereas two mares changed to a less severe classification (susceptible to intermediate). PMID- 22494682 TI - Detection of aromatase, androgen, and estrogen receptors in bank vole spermatozoa. AB - Spermatozoa are highly specialized cells which transport a single-copy haploid genome to the site of fertilization. Before this, spermatozoa undergo a series of biochemical and functional modifications. In recent years, the crucial role of androgens and estrogens in proper germ cell differentiation during spermatogenesis has been demonstrated. However, their implication in the biology of mature male gametes is still to be defined. Our study provides evidence for the first time that aromatase, the androgen receptor (AR), as well as the estrogen receptors alpha and beta (ERalpha and ERbeta), are present in bank vole spermatozoa. We demonstrated the region-specific localization of these proteins in bank vole spermatozoa using confocal microscopy. Immunoreactive aromatase was observed in the proximal head region and in both the proximal and distal tail regions, whereas steroid hormone receptors were found only in the proximal region of the sperm head. Protein expression in sperm lysates was detected by Western blot analysis. Immunohistochemical results were analyzed quantitatively. Our results show that bank vole spermatozoa are both a source of estrogens and a target for steroid hormone action. Moreover, the presence of aromatase and steroid hormone receptors in the bank vole spermatozoa indicates a potential function of these proteins during capacitation and/or the acrosome reaction. PMID- 22494683 TI - A serologic study of canine herpes virus-1 infection in the Norwegian adult dog population. AB - Canine herpes virus-1 (CHV1) causes a fatal hemorrhagic disease in neonatal puppies and is associated with reproductive problems in female dogs. This serologic study was conducted to assess the seroprevalence of CHV1 infection in Norway. Blood samples were collected from clinically healthy dogs (n = 436) one yr of age and older of both genders, supplied by four small animal clinics (A, B, C and D) in different parts of the country. The immunoperoxidase monolayer assay was used for testing of CHV1 antibodies. Serum titers were recorded as the reciprocal value of the highest dilution producing specific cell staining. Titers equal to or above 80 were considered positive for exposure to CHV1. In total, 80.0% of the dogs had titers >=80 and were classified as positive. Mean age for seronegative dogs was 4.7 yrs (95% CI 4.1-5.4) and for seropositive dogs 5.0 yrs (95% CI 4.7-5.4). Of the dogs, 32.8% displayed a weakly positive titer of 80, whereas 41.5 and 5.7% fell into the moderately (titer 160 and 320) and strongly (titer >=640) positive categories, respectively. No association was demonstrated when comparing CHV1 antibody titers to gender or reproductive parameters like previous matings, pregnancies, births or number of puppies born. Age, visit in foreign countries and clinic explained together 78% of the variation in antibody titer categories. The percentage of positive samples differed significantly between the four clinics (A 98%, B 58.5%, C 74.6%, D 89.5%). A reasonable explanation for this finding has not been established. No information about an ongoing outbreak of CHV1 infection was available. In conclusion, this study strongly indicates that CHV1 infection is endemic in the dog population of Norway. There are significant differences in seroprevalence between geographic regions in the country. PMID- 22494684 TI - Contribution of oocyte source and culture conditions to phenotypic and transcriptomic variation in commercially produced bovine blastocysts. AB - Bovine embryo production is practiced worldwide for commercial purposes. A major concern of embryo suppliers is the impact of in vitro production systems on embryo quality. In the present study, we compared Buffalo Rat Liver cell coculture with semidefined, medium-based culture, oocytes recovered postmortem with those obtained from live animals, and in vitro with in vivo embryo development. Gene expression levels in expanded blastocysts were measured using microarray and quantitative RT-PCR. The systems were similar in terms of blastocyst yield and rate of development, whereas embryo productivity was greater for immature oocytes collected in vivo. Although immature oocytes collected in vivo had greater developmental competence, they yielded blastocysts that were indistinguishable (in terms of level of gene expression) from embryos derived from immature oocytes recovered postmortem. Culture conditions had a significant impact on gene expression, particularly among genes involved in lipid metabolism. Numerous uncharacterized novel transcript regions were also influenced by in vitro treatments. In conclusion, ovum pick-up combined with in vitro culture in semidefined medium provided a high blastocyst yield, without the deleterious effects associated with coculture. PMID- 22494685 TI - Surface-associated metal catalyst enhances the sorption of perfluorooctanoic acid to multi-walled carbon nanotubes. AB - The perfluorooctanoic acid (PFOA) sorption behavior of two commercial multi walled carbon nanotubes (MWCNTs) (C 150 P from Bayer MaterialScience: BA and C MWNTs from NanoTechLabs Inc.: CP) was investigated from aqueous solution. The BA nanotubes contained Co/Mn/Mg/Al catalysts both on their outer surface and in the inner bore while CP contained Fe-based catalyst typically within the tubes. The adsorption isotherms of (14)C-radiolabeled PFOA were measured by batch experiments and fitted to the Freundlich model (r(2)>0.92). The adsorption affinity and capacity on BA were significantly higher than on CP. Increasing the pH reduced the adsorption of PFOA due to the electrostatic interaction between the pH-sensitive surface and the adsorbate. Increasing the NaCl concentration led to the aggregation of the MWCNTs reducing the available surface and thus the adsorption capacity. Removal of the catalyst from the outer surface of BA changed the electrophoretic mobility from a positive to a negative value and also decreased the adsorbed amount of PFOA. The surface charge of the surface associated metal catalyst favors the electrostatic sorption of PFOA. Such surface modifications may be a promising way to improve the sorption capacity of MWCNTs for pollutants such as PFOA and to broaden their potential application in water purification. PMID- 22494686 TI - Competitive sorption of carbonate and arsenic to hematite: combined ATR-FTIR and batch experiments. AB - The competitive sorption of carbonate and arsenic to hematite was investigated in closed-system batch experiments. The experimental conditions covered a pH range of 3-7, arsenate concentrations of 3-300 MUM, and arsenite concentrations of 3 200 MUM. Dissolved carbonate concentrations were varied by fixing the CO(2) partial pressure at 0.39 (atmospheric), 10, or 100 hPa. Sorption data were modeled with a one-site three plane model considering carbonate and arsenate surface complexes derived from ATR-FTIR spectroscopy analyses. Macroscopic sorption data revealed that in the pH range 3-7, carbonate was a weak competitor for both arsenite and arsenate. The competitive effect of carbonate increased with increasing CO(2) partial pressure and decreasing arsenic concentrations. For arsenate, sorption was reduced by carbonate only at slightly acidic to neutral pH values, whereas arsenite sorption was decreased across the entire pH range. ATR FTIR spectra indicated the predominant formation of bidentate binuclear inner sphere surface complexes for both sorbed arsenate and sorbed carbonate. Surface complexation modeling based on the dominant arsenate and carbonate surface complexes indicated by ATR-FTIR and assuming inner-sphere complexation of arsenite successfully described the macroscopic sorption data. Our results imply that in natural arsenic-contaminated systems where iron oxide minerals are important sorbents, dissolved carbonate may increase aqueous arsenite concentrations, but will affect dissolved arsenate concentrations only at neutral to alkaline pH and at very high CO(2) partial pressures. PMID- 22494687 TI - Surface modification of silver nanofilms for improved perchlorate detection by surface-enhanced Raman scattering. AB - Surface-enhanced Raman scattering (SERS), as one of the most sensitive spectroscopic analysis methods, has been investigated extensively for the detection of environmental contaminants in recent years. In this work, we reported the new development of robust SERS substrates for rapid and sensitive sensing of aqueous perchlorate, a widespread environmental contaminant. The fabrication of the substrates consisted of two simple steps: (a) formation of Ag nanofilms on Cu and surface-roughened Cu foils (Ag/Cu and Ag/rCu nanofilms) using a controllable and inexpensive one-step electroless plating process, and (b) surface modification of the Ag nanofilms with cysteamine (Cys) self-assembly monolayer (SAM) (Cys-Ag/Cu and Cys-Ag/rCu substrates). Due to the strong affinity of -NH(3)(+) groups of the Cys molecules for perchlorate ions, the rapid SERS detection of perchlorate has been realized with a limit of detection (LOD) down to 5 MUg L(-1) (ppb) for aqueous samples without need for drying. Various calibration curves with good linear relationships were obtained, indicating the quantification potential of SERS analysis of perchlorate using these new substrates. It was found that the neutral pH yielded the maximum SERS signals, and 85% of original sensitivity was remained in 5 days of storage time in the air, indicating the substrates are fairly stable. Within 10 regeneration-reuse cycles, the SERS signals of perchlorate kept in the range of 85-105% of the original value, verifying its reusability. PMID- 22494688 TI - Interactive effects of pore size control and carbonization temperatures on supercapacitive behaviors of porous carbon/carbon nanotube composites. AB - Porous carbon-based electrodes were prepared by carbonization with poly(vinylidene fluoride) (PVDF)/carbon nanotube (CNT) composites to further increase the specific capacitance for supercapacitors. The specific capacitance, pore size distribution, and surface area of the PVDF/CNT composites were measured, and the effect of the carbonization temperatures was examined. The electrochemical properties were examined by cyclic voltammetry, impedance spectroscopy, and galvanostatic charge-discharge performance using a two electrode system in TEABF(4) (tetraethylammonium tetrafluoroborate)/acetonitrile as a non-aqueous electrolyte. The highest specific capacitance of ~101 Fg(-1) was obtained for the samples carbonized at 600 degrees C. The pore size of the samples could be controlled to below 7 nm through the carbonization process. This suggests that micropores make a significant contribution to the specific capacitance due to improved charge transfer between the pores of the electrode materials and the electrolyte. PMID- 22494689 TI - Effect of pH value on the microstructure and deNO(x) catalytic performance of titanate nanotubes loaded CeO2. AB - The relationship between catalytic performance and pH value of post-treatment of the catalyst supports-titanate materials was investigated and discussed. Three types of titanate nanotubes (TNTs) that are acidic TNTs (TNTs-1.6, pH value at 1.6), neutral TNTs (TNTs-7), and alkaline TNTs (TNTs-12) were synthesized by hydrothermal method with the controlled washing pH value and then were used as the catalyst supports for ceria. These titanate-supported ceria catalysts showed extremely different performance for the selective catalytic reduction in NO. The pH value had a notable effect on the structure and composition of titanate nanotubes and further affected the state and redox property of cerium oxides. The structure of TNTs-1.6, TNTs-7, and TNTs-12 were identified as anatase-like structure, protonated titanate (H(2)Ti(3)O(7)), and Na-containing titanate, respectively. Indeed, the residual sodium (TNTs-12) was harmful to ceria, but the presence of water in the interlayer (TNTs-7) was beneficial to the stability of nanotube structure. Therefore, TNTs-7 doped ceria showed the best SCR activity among these tested samples. PMID- 22494690 TI - The impact of selective visceral perfusion on intestinal macrohemodynamics and microhemodynamics in a porcine model of thoracic aortic cross-clamping. AB - INTRODUCTION: Despite its presumed effectiveness and clinical use, the physiology of selective visceral perfusion combined with distal aortic perfusion during open thoracoabdominal aortic surgery has not been characterized. Thus, the aim of this study was to establish a translatable model of thoracic aortic-clamping to assess the effect of selective visceral perfusion with added distal aortic perfusion on local intestinal macrohemodynamics and microhemodynamics, intestinal histopathology, and markers of inflammation and intestinal damage. METHODS: A thoracolaparotomy was performed in 15 pigs, and the aorta was exposed, including the origins of celiac trunk and superior mesenteric artery. The animals were divided into three cohorts: control (I), thoracic aortic cross-clamping (II), and thoracic aortic cross-clamping with selective visceral perfusion plus distal aortic perfusion using extracorporeal circulation (III). Macrocirculatory and microcirculatory blood flow was assessed by transit time ultrasound volume flow measurements and fluorescent microspheres. Intestinal ischemia-reperfusion injury was determined by the analysis of perioperative intestinal fatty acid-binding protein (IFABP) and interleukin-8 (IL-8) levels and correlated with histopathologic changes. RESULTS: Severe intestinal tissue injury and an inflammatory response were observed in cohort II compared with cohort III for IL 8 (38.2 vs 3.56 pg/mL; P = .04). The procedure in cohort III resulted in a flow and pressure-associated intestinal hypoperfusion compared with cohort I in the superior mesenteric artery (mean blood pressure, 24.1 +/- 10.4 vs 67.2 +/- 7.4 mm Hg; P < .0001; mean flow rates: 353.3 +/- 133.8 vs 961.7 +/- 310.8 mL/min; P < .0001). This was paralleled in cohort III vs cohort I by a significant mucosal injury (IFABP, 713 +/- 307.1 vs 170 +/- 115.4 pg/mL; P = .014) despite a profound recruitment of intestinal microcirculation (338% +/- 206.7% vs 135% +/- 123.7%; P = .05). CONCLUSIONS: This study reports a novel large-animal model of thoracic aortic cross-clamping that allows the study of visceral perfusion strategies. However, we demonstrated with IL-8 and IFABP measurements that thoracoabdominal aortic aneurysm surgery with selective visceral perfusion and distal aortic perfusion is superior to the clamp-and-sew technique, even though small intestinal tissue damage cannot be completely avoided by selective visceral perfusion and distal aortic perfusion. In any case, this model seems to be a platform to evaluate and optimize measures for gut wall protection. PMID- 22494691 TI - Aortic banding and endovascular aneurysm repair in a case of juxtarenal aortic aneurysm with unsuitable infrarenal neck. AB - The proximal aortic neck is one of the limiting factors for endovascular aneurysm repair (EVAR) and represents a crucial factor for success or failure of the procedure. In contrast to open surgery, where a clamp can be placed suprarenally but the repair performed infrarenally, EVAR requires a good infrarenal neck for durable fixation and seal. In a high-risk surgical 79-year-old patient with juxtarenal aortic aneurysm with unsuitable infrarenal neck, a hybrid procedure was chosen: juxtarenal aortic banding and EVAR. The banding allowed a successful EVAR by reshaping the juxtarenal aneurysmal aortic segment, hence converting a previously untreatable anatomy into a treatable one. PMID- 22494692 TI - Left common iliac artery to inferior vena cava abdominal wall arteriovenous graft for hemodialysis access. AB - We describe a novel arteriovenous graft configuration in the abdominal wall for hemodialysis in a 51-year-old woman with sickle cell disease. Upper extremity access sites were exhausted, and intrathoracic central veins occluded. Because of diminished quality of the left groin due to scar tissue from previous infected access, inadequate vasculature, and the presence of functional femoral catheter in the right groin with common iliac vein stenosis, we decided to create an arteriovenous graft from the left common iliac artery to the inferior vena cava. Adequate thrill and uneventful postoperative recovery was observed. At 4 months, the patient has been successfully using her graft. PMID- 22494693 TI - Buildup and decay of the optical absorption in the ultrafast photo-generation and reaction of benzhydryl cations in solution. AB - The identification of the transition state or a short-lived intermediate of a chemical reaction is essential for the understanding of the mechanism. For a direct identification typically transient optical spectroscopy is used, preferentially with high temporal resolution. We combine broad-band femtosecond transient absorption measurements and on-the-fly molecular dynamics calculations to decipher the microscopic evolution of the geometry and solvation of photogenerated benzhydryl cations (Ar(2)CH(+), Ar = phenyl, p-tolyl, m fluorophenyl, or m,m'-difluorophenyl) in bulk solution. From the high level quantum chemical calculations on the microsolvated cation we can deduce a narrowing and blue shift of the cation absorption that is nearly quantitatively equal to the experimental finding. The roughly 300 fs initial increase in the absorption signal found for all investigated combinations of benzhydryl chlorides or phosphonium salts as benzhydryl cation precursors and solvents is therefore assigned to the planarization and solvation of the nascent fragment of the bond cleavage. The actual cleavage time cannot directly be deduced from the rise of the spectroscopic signal. For alcohols as solvent, the cation combines on the picosecond time scale either with one of the solvent molecules to the ether or to a lesser degree geminately with the leaving group. The study shows that the absorption signal attributable to a species like the benzhydryl cation does not mirror the concentration during the first instances of the process. Rather, the signal is determined by the geometrical relaxation of the photoproduct and the response of the solvent. PMID- 22494695 TI - Consider context and stakeholders. PMID- 22494694 TI - Two structurally discrete GH7-cellobiohydrolases compete for the same cellulosic substrate fiber. AB - BACKGROUND: Cellulose consisting of arrays of linear beta-1,4 linked glucans, is the most abundant carbon-containing polymer present in biomass. Recalcitrance of crystalline cellulose towards enzymatic degradation is widely reported and is the result of intra- and inter-molecular hydrogen bonds within and among the linear glucans. Cellobiohydrolases are enzymes that attack crystalline cellulose. Here we report on two forms of glycosyl hydrolase family 7 cellobiohydrolases common to all Aspergillii that attack Avicel, cotton cellulose and other forms of crystalline cellulose. RESULTS: Cellobiohydrolases Cbh1 and CelD have similar catalytic domains but only Cbh1 contains a carbohydrate-binding domain (CBD) that binds to cellulose. Structural superpositioning of Cbh1 and CelD on the Talaromyces emersonii Cel7A 3-dimensional structure, identifies the typical tunnel-like catalytic active site while Cbh1 shows an additional loop that partially obstructs the substrate-fitting channel. CelD does not have a CBD and shows a four amino acid residue deletion on the tunnel-obstructing loop providing a continuous opening in the absence of a CBD. Cbh1 and CelD are catalytically functional and while specific activity against Avicel is 7.7 and 0.5 U.mg prot-1, respectively specific activity on pNPC is virtually identical. Cbh1 is slightly more stable to thermal inactivation compared to CelD and is much less sensitive to glucose inhibition suggesting that an open tunnel configuration, or absence of a CBD, alters the way the catalytic domain interacts with the substrate. Cbh1 and CelD enzyme mixtures on crystalline cellulosic substrates show a strong combinatorial effort response for mixtures where Cbh1 is present in 2:1 or 4:1 molar excess. When CelD was overrepresented the combinatorial effort could only be partially overcome. CelD appears to bind and hydrolyze only loose cellulosic chains while Cbh1 is capable of opening new cellulosic substrate molecules away from the cellulosic fiber. CONCLUSION: Cellobiohydrolases both with and without a CBD occur in most fungal genomes where both enzymes are secreted, and likely participate in cellulose degradation. The fact that only Cbh1 binds to the substrate and in combination with CelD exhibits strong synergy only when Cbh1 is present in excess, suggests that Cbh1 unties enough chains from cellulose fibers, thus enabling processive access of CelD. PMID- 22494696 TI - Shikonin enhances efficacy of a gene-based cancer vaccine via induction of RANTES. AB - BACKGROUND: Shikonin, a phytochemical purified from Lithospermum erythrorhizon, has been shown to confer diverse pharmacological activities, including accelerating granuloma formation, wound healing, anti-inflammation and others, and is explored for immune-modifier activities for vaccination in this study. Transdermal gene-based vaccine is an attractive approach for delivery of DNA transgenes encoding specific tumor antigens to host skin tissues. Skin dendritic cells (DCs), a potent antigen-presenting cell type, is known to play a critical role in transmitting and orchestrating tumor antigen-specific immunities against cancers. The present study hence employs these various components for experimentation. METHOD: The mRNA and protein expression of RANTES were detected by RT-PCR and ELISA, respectively. The regional expression of RANTES and tissue damage in test skin were evaluated via immunohistochemistry assay. Fluorescein isothiocyanate sensitization assay was performed to trace the trafficking of DCs from the skin vaccination site to draining lymph nodes. Adjuvantic effect of shikonin on gene gun-delivered human gp100 (hgp100) DNA cancer vaccine was studied in a human gp100-transfected B16 (B16/hgp100) tumor model. RESULTS: Among various phytochemicals tested, shikonin induced the highest level of expression of RANTES in normal skin tissues. In comparison, mouse RANTES cDNA gene transfection induced a higher level of mRANTES expression for a longer period, but caused more extensive skin damage. Topical application of shikonin onto the immunization site before gene gun-mediated vaccination augmented the population of skin DCs migrating into the draining lymph nodes. A hgp100 cDNA gene vaccination regimen with shikonin pretreatment as an adjuvant in a B16/hgp100 tumor model increased cytotoxic T lymphocyte activities in splenocytes and lymph node cells on target tumor cells. CONCLUSION: Together, our findings suggest that shikonin can effectively enhance anti-tumor potency of a gene-based cancer vaccine via the induction of RANTES expression at the skin immunization site. PMID- 22494697 TI - Limbic encephalopathy and central vestibulopathy caused by mefloquine: a case report. AB - Mefloquine is a 4-methanolquinoline anti-malarial that in recent years has fallen out of favor for use as chemoprophylaxis against infection with chloroquine resistant Plasmodium falciparum malaria owing in part to growing concerns of side effects and potential neurotoxicity. Despite over 20 years of licensed use, the pathophysiological mechanisms underlying mefloquine's neuropsychiatric and physical side effects and the clinical significance of the drug's neurotoxicity have remained poorly understood. In this report, an adverse reaction to mefloquine chemoprophylaxis is described characterized by prodromal symptoms of anxiety with subsequent development of psychosis, short-term memory impairment, confusion and personality change accompanied by complaints of disequilibrium and vertigo, with objective findings of central vestibulopathy. It is posited that these effects represent an idiosyncratic neurotoxic syndrome of progressive limbic encephalopathy and multifocal brainstem injury caused by the drug. This case provides insights into the clinical significance of mefloquine neuronal gap junction blockade and neurotoxicity demonstrated in animal models, points to recommendations for the management of affected patients including diagnostic considerations and appropriate referrals, and highlights critical implications for the continued safe use of the medication. PMID- 22494698 TI - Suppression of movement disorders by jaw realignment. PMID- 22494699 TI - Systolic right ventricular function in children and young adults with pulmonary artery hypertension secondary to congenital heart disease and tetralogy of Fallot: tricuspid annular plane systolic excursion (TAPSE) and magnetic resonance imaging data. AB - OBJECTIVE: The tricuspid annular plane systolic excursion (TAPSE), as echocardiographic index to assess right ventricular (RV) systolic function, has not been investigated thoroughly in children and young adults with tetralogy of Fallot (TOF) and pulmonary artery hypertension secondary to congenital heart disease (PAH-CHD). PATIENTS: TAPSE values of 49 patients with PAH-CHD and 156 patients with TOF were compared with age-matched normal subjects. TAPSE values were also compared with RV ejection fraction (RVEF) and RV indexed end-diastolic volume (RVEDVi) determined by magnetic resonance imaging in PAH-CHD and TOF patients. RESULTS: Patients with a PAH-CHD showed a positive correlation between TAPSE with RVEF (r= 0.81; P < 0.001) and a negative correlation between TAPSE with RVEDVi (r=-0.67; P < 0.001). Similarly, in our TOF patients, a positive correlation between TAPSE with RVEF (r= 0.65; P < 0.001) and a negative correlation between TAPSE with RVEDVi (r=-0.42; P < 0.001) was seen. CONCLUSIONS: Significant pressure overload in PAH-CHD patients and volume overload in TOF patients lead to a decreased systolic RV function, determined by TAPSE and magnetic resonance imaging and to increased RVEDVi values, determined by MRI, with time. PMID- 22494700 TI - Infant difficult behaviors in the context of perinatal biomedical conditions and early child environment. AB - BACKGROUND: Problems experienced within the first year of an infant's life can be precursors of later mental health conditions. The purpose of this study was to examine the frequency and continuity of difficult behaviors in infants at 3 and 6 months of age and the associations of these difficulties with biomedical and psychosocial factors. METHODS: This study was a part of an ongoing prospective birth-cohort study. Study participants were 189 uniparous mothers and their full term newborns. The index of infant difficult behavior was constructed. This index was then associated with the following factors: delivery mode, newborn function after birth, maternal emotional well-being, risk behavior, subjective evaluation of the quality of the relationship of the couple, and attitudes toward infant rearing. RESULTS: Common difficult behaviors, including crying, sleeping and eating problems, were characteristic for 30.2% of 3 month old and for 22.2% of 6 month old full-term infants. The expression of infant difficult behaviors at the age of 3 months increased the likelihood of the expression of these difficulties at 6 months by more than 5 times. Factors including younger maternal age, poor prenatal and postnatal emotional well-being, prenatal alcohol consumption, low satisfaction with the couple's relationship before pregnancy, and deficiency of infant-centered maternal attitudes towards infant-rearing increased the likelihood of difficult behaviors in infants at the age of 3 months. Low maternal satisfaction with the relationship of the couple before pregnancy, negative emotional reactions of both parents toward pregnancy (as reported by the mother) and the deficiency of an infant-centered maternal attitude towards infant-rearing increased the likelihood of infant difficult behaviors continuing between the ages of 3 to 6 months. Perinatal biomedical conditions were not related to the difficult behaviors in infants. CONCLUSIONS: Our study suggests that early onset of difficult behavior highly increases the risk for the continuation of difficult behavior during infancy. In general, the impact of prenatal psychosocial environment on infant behavior decreases from the ages of 3 to 6 months; however, some prenatal and preconceptional psychosocial factors have direct associations with the continuity of difficult behaviors through the first half-year of an infant's life. PMID- 22494701 TI - Antihypertensives are administered selectively in emergency department patients with subarachnoid hemorrhage. AB - Elevated blood pressure is common in patients with acute subarachnoid hemorrhage (SAH). American Heart Association guidelines do not specify a blood pressure target, but limited data suggest that systolic blood pressure (SBP)>=160 mmHg is associated with increased risk of rebleeding and neurologic decline. In a population-based study, we determined the frequency of antihypertensive therapy in emergency department (ED) patients with SAH and the proportion of those patients with SBP>=160 mmHg who received this therapy. In 2005, nontraumatic SAH cases were retrospectively ascertained at 16 hospitals in our region by screening for International Classification of Diseases Ninth Revision diagnostic codes 430 436. Blood pressure was recorded at ED presentation and also before and after any treatment with antihypertensives. Hypotension was defined as SBP<100 mmHg. The Mann-Whitney U test and chi2 test were used for comparisons. Our cohort comprised 82 patients with SAH presenting to an ED; 4 patients were excluded. The median age of the included patients was 54 years, 74.4% were female, 29.5% were black, and 31 (39.7%) had SBP>=160 mmHg. Antihypertensive therapy was given to 22 of 31 patients (70.9%) with SBP>=160 mmHg and to 4 of 47 patients (8.5%) with SBP<160 mmHg. No patients became hypotensive after receiving treatment. Age, sex, Glascow Coma Scale score, and National Institutes of Health Stroke Scale score were similar between treated and untreated patients. In the absence of definitive evidence, current blood pressure management in local EDs appears reasonable. Further studies of blood pressure management in acute SAH are warranted. PMID- 22494702 TI - Neurotrophic factors in obsessive-compulsive disorder. AB - In this cross-sectional study, we assessed the levels of neurotrophins (NF) of patients with obsessive-compulsive disorder (OCD) in different stages of treatment and their relationship with OCD clinical features. Forty patients with OCD and 40 healthy controls had Brain-Derived Neurotrophic Factor (BDNF), Nerve Growth Factor (NGF), and Glial Cell-Derived Neurotrophic Factor (GNDF) plasma levels measured by enzyme-linked immunosorbent assay (ELISA). Patients with OCD were further examined with the Obsessive-Compulsive Inventory-Revised, the Beck Depression Inventory, the Beck Anxiety Inventory, and the Sheehan Disability Scale (SDS). Patients with OCD exhibited significantly lower levels of BDNF and significantly increased levels of NGF as compared to healthy controls. In OCD, statistically significant negative correlations between BDNF levels and number of working days lost per week were found. Additional analyses revealed a statistically significant positive correlation between both NGF and GDNF and severity of washing symptoms. Plasma levels of NF were not affected by age, age at OCD onset, gender, major depressive disorder, the relative dose of serotonin reuptake inhibitors being prescribed, or the use of antipsychotics. Our findings suggest that patients with OCD may exhibit a particular NF profile, with functional impairment correlating with BDNF levels and severity of washing symptoms correlating with NGF and GDNF levels. PMID- 22494703 TI - Why the factorial structure of the SCL-90-R is unstable: comparing patient groups with different levels of psychological distress using Mokken Scale Analysis. AB - Since its introduction, there has been a debate about the validity of the factorial structure of the SCL-90-R. In this study we investigate whether the lack of agreement with respect to the dimensionality can be partly explained by important variables that might differ between samples such as level of psychological distress, the variance of the SCL-90-R scores and sex. Three samples were included: a sample of severely psychiatrically disturbed patients (n=3078), a sample of persons with Gender Incongruence (GI; n=410) and a sample of depressed patients (n=223). A unidimensional pattern of findings were found for the GI sample. For the severely disturbed and depressed sample, a multidimensional pattern was found. In the depressed sample sex differences were found in dimensionality: we found a unidimensional pattern for the females, and a multidimensional one for the males. Our analyses suggest that previously reported conflicting findings with regard to the dimensional structure of the SCL-90-R may be due to at least two factors: (a) level of self-reported distress, and (b) sex. Subscale scores should be used with care in patient groups with low self-reported level of distress. PMID- 22494704 TI - Delusionality of body image beliefs in eating disorders. AB - Preoccupation with body shape and weight is characteristic of both anorexia nervosa and bulimia nervosa. Despite their diagnostic and clinical significance, evidence on the nature of the underlying beliefs is relatively scarce. We used the Brown Assessment of Beliefs Scale (BABS) to assess the degree of delusionality of body image beliefs in seventy-two participants: 39 with anorexia and 33 with bulimia nervosa. We also investigated the relationship between body image delusionality and other clinical characteristics in eating disorders. Only patients with anorexia nervosa (28.8%) had delusional body image beliefs, whereas overvalued ideas appeared to be frequent in both anorexia and bulimia nervosa. Body image delusionality in anorexia nervosa was associated with restrictive eating pathology, early onset of the disorder and body dissatisfaction, whereas in the bulimia group it was linked to shorter duration of the illness, more intense dieting behaviors and specific psychological factors: ineffectiveness and maturity fears. Results suggest that a delusional variant of anorexia nervosa represents the one end of a continuum of insight among patients with eating disorders. Categorization of patients with eating disorders based on the level of delusionality of body image beliefs could facilitate further research on the role of insight deficits in these disorders. PMID- 22494705 TI - Relationship of self-mutilative behaviours with severity of borderline personality, childhood trauma and impulsivity in male substance-dependent inpatients. AB - The aim of this study was to investigate the relationship of self-mutilation (SM) with the severity of borderline personality features (BPF), childhood trauma and impulsivity in male substance-dependent inpatients. Participants were consecutively admitted comprising 200 male substance-dependent inpatients. Patients were investigated with the Self-mutilative Behaviour Questionnaire (SMBQ), the Childhood Trauma Questionnaire (CTQ-28), the Barratt Impulsiveness Scale (BIS-11) and the Borderline Personality Inventory (BPI). Among 200 subjects, 62.0% (n=124) were considered as the group with SM. Mean scores of CTQ 28 total and subscales (other than emotional abuse), BIS-11 total and attentional impulsiveness subscale and BPI were higher in the SM group. In the regression model, emotional neglect, attentional impulsiveness and drug dependency were the predictors of SM, whereas in the new model in which the severity of BPF was included emotional neglect and the severity of BPF predicted SM. Among those with SMB, physical neglect and the severity of BPF predicted the number of SM episodes. Thus, to better understand SMB among substance-dependent patients, clinicians must carefully evaluate BPF and history of childhood trauma among substance-dependent inpatients. In addition, results suggest that the relationship between SMB and BPF is more prominent in drug-dependent inpatients than alcohol-dependent inpatients. PMID- 22494706 TI - Dynamics of neurological soft signs and its relationship to clinical course in patients with first-episode schizophrenia. AB - The aim of the study was to assess the dynamics of neurological soft signs (NSS) over four years from the clinical onset of schizophrenia, depending on the clinical course of the disease, and to evaluate the relationship of NSS to symptomatic dimensions in patients with first-episode schizophrenia. Sixty-eight patients with first-episode schizophrenia were included in the trial. The clinical status was assessed using Positive and Negative Syndrome Scale (PANSS) at the same time as the neurological examination, at admission to the hospital for first-episode schizophrenia and at a check-up examination four years later. The assessment of NSS using the Neurological Evaluation Scale (NES) coincided with the assessment of the clinical condition of the patients. According to the Andreasen remission criterion of schizophrenia, after four years we found that 57% of patients' were remitters and 43% were non-remitters. During the monitoring period, in remitters total NES score and sensory integration/sequencing of motor acts items of the NES decreased. In non-remitters, increase in the total NES score and the 'others' item of the NES was observed. A connection between the dynamics of NSS and the clinical course of schizophrenia, over the period of four years, and a relationship between NSS and negative schizophrenia symptoms was found. PMID- 22494708 TI - Can data provenance go the full monty? PMID- 22494707 TI - Disability associated with mental disorders in metropolitan China: an application of the quantile regression approach. AB - Recently active mental disorders are associated with substantial disability, but there is little research on residual disability once symptoms have subsided. The aim of this study is to estimate the degree to which recent disability might be due to recent or past history of mental disorders using a quantile regressions (QR) model that makes it possible to study the full range of disability. Data were from cross-sectional surveys of Chinese living in Beijing and Shanghai, China (n=1628). The World Health Organization Disability Assessment Schedule and the WHO Composite International Diagnostic Interview were used to assess recent disability and common mental disorders, respectively. Recently active mental disorders are found to be associated with elevated levels of disability, especially for current substance use disorder. Anxiety disorders stand out with high levels of disability. Individuals at the higher disability levels show large variations in their disability levels. These epidemiological estimates from China add to the evidence based on the global burden of neuropsychiatric disorders, quantifying the hypothesized influence of recently active and past disorders with the novel QR approach. In future studies, we hope to complete more detailed studies of the causal role of mental disorders in the development of disability. PMID- 22494709 TI - Characterization of alien chromosomes in backcross derivatives of Triticum aestivum * Elymus rectisetus hybrids by using molecular markers and sequential multicolor FISH/GISH. AB - Wild Triticeae grasses serve as important gene pools for forage and cereal crops. Based on DNA sequences of genome-specific RAPD markers, sequence-tagged site (STS) markers specific for W and Y genomes have been obtained. Coupling with the use of genomic in situ hybridization, these STS markers enabled the identification of the W- and Y-genome chromosomes in backcross derivatives from hybrids of bread wheat Triticum aestivum L. (2n=42; AABBDD) and Elymus rectisetus (Nees in Lehm.) A. Love & Connor (2n=42; StStWWYY). The detection of six different alien chromosomes in five of these derivatives was ascertained by quantitative PCR of STS markers, simple sequence repeat markers, rDNA genes, and (or) multicolor florescence in situ hybridization. Disomic addition line 4687 (2n=44) has the full complement of 42 wheat chromosomes and a pair of 1Y chromosomes that carry genes for resistance to tan spot (caused by Pyrenophora tritici-repentis (Died.) Drechs.) and Stagonospora nodorum blotch (caused by Stagonospora nodorum (Berk.) Castellani and Germano). The disomic addition line 4162 has a pair of 1St chromosomes and 21 pairs of wheat chromosomes. Lines 4319 and 5899 are two triple substitution lines (2n=42) having the same chromosome composition, with 2A, 4B, and 6D of wheat substituted by one pair of W- and two pairs of St-genome chromosomes. Line 4434 is a substitution-addition line (2n=44) that has the same W- and St-genome chromosomes substituting 2A, 4B, and 6D of wheat as in lines 4319 and 5899 but differs by having an additional pair of Y genome chromosome, which is not the 1Y as in line 4687. The production and identification of these alien cytogenetic stocks may help locate and isolate genes for useful agronomic traits. PMID- 22494710 TI - [Mechanical behaviour of three types of surgical knots using 4/0 monofilament]. AB - OBJECTIVE: To experimentally study the behaviour of 4 types of monofilament with 3 knotting techniques, very often used in surgery, employing mechanical tests. MATERIAL AND METHODS: Four 4/0 monofilaments were chosen, two of nylon, and the other two of polypropylene. Three types of knot designs were made with each thread. The first design (D-S-S) consisted of a double half-knot (D) followed by one single (S) in the opposite direction, a third S in turn in the opposite direction. The configuration of the second design was D-S-D, and the third, S-S D. A mechanical fracture test was performed by stretching the thread at a rate of 4N/s, the force and deformation being recorded at intervals of 100 ms. RESULTS: There was a decrease in the force and deformation in the tests on threads with knots compared to threads without knots. In all cases the rupture of the thread occurred in the knot area, presumably due to damage caused to the thread during the knotting process. The D-S-D knot had the greatest resistance with polypropylene threads, and S-S-D provided the greatest resistance with nylon threads CONCLUSIONS: Polypropylene threads, with D-S-D knots, should be more indicated to suture tissues that have to support great forces and with little deformation of the suture (e.g., tendons). Nylon threads, with S-S-D knots, would be better indicated for tissues that have to support smaller forces and that require greater elasticity (e.g., skin). PMID- 22494711 TI - [Evaluation of the sentinel lymph node in T1-T2 papillary thyroid cancer: a preliminary study]. AB - OBJECTIVE: Sentinel lymph node biopsy in differentiated thyroid cancer may benefit patients with no clinically affected lymph nodes and can avoid a prophylactic or staging lymphadenectomy. METHODS: A prospective study was conducted on 23 consecutive patients with papillary thyroid carcinoma with no clinical or radiological suspicion of lymph involvement. After injecting methylene blue around the tumour during the biopsy of the identified sentinel lymph node, a total thyroidectomy and a via-b ipsilateral lymphadenectomy was performed for the later study with cytokeratin. If the sentinel lymph node was positive, a modified ipsilateral radical lymphadenectomy was perfumed (groups ii to v). RESULTS: The sentinel lymph node was clearly identified in 21 of the 23 patients (91.3%). Seven (33%) of the 21 lymph nodes identified were positive in the intra-operative study, of which 3 (42.8%) demonstrated involvement with the lateral compartment. All together, 9 patients (39.1%) showed lymph node involvement group vi, with two more patients being identified with micro metastases in the later study. Biopsy of the sentinel lymph node had a sensitivity of 87.5%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 93.7%, with 7.1% false negatives. Five patients (21.7%) had transient hypocalcaemia. CONCLUSIONS: The identification of the sentinel lymph node in patients with T1-T2 tumours with no suspicion of lymph node involvement helps in the selection of patients who should be treated with selective lymphadenectomies. PMID- 22494712 TI - Re: inadequacy of biopsy for diagnosis of upper tract urothelial carcinoma: implications for conservative management. PMID- 22494713 TI - Re: ureteral and multifocal tumours have worse prognosis than renal pelvic tumours in urothelial carcinoma of the upper urinary tract treated by nephroureterectomy. PMID- 22494715 TI - Re: the role of haematuria in bladder cancer screening among men with former occupational exposure to aromatic amines. PMID- 22494714 TI - Re: randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC Study 30986. PMID- 22494716 TI - Re: urinary cytology has a poor performance for predicting invasive or high-grade upper-tract urothelial carcinoma. PMID- 22494717 TI - Re: defecation disturbances after cystectomy for urinary bladder cancer. PMID- 22494718 TI - Re: EPCA-2: a highly specific serum marker for prostate cancer. PMID- 22494719 TI - Re: impact of meat consumption, preparation, and mutagens on aggressive prostate cancer. PMID- 22494720 TI - Re: vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). PMID- 22494722 TI - Re: antibiotics and observation have a similar impact on asymptomatic patients with a raised PSA. PMID- 22494721 TI - Re: outcomes in patients with Gleason score 8-10 prostate cancer: relation to preoperative PSA level. PMID- 22494723 TI - Re: long-term fluoroquinolone use before the prostate biopsy may increase the risk of sepsis caused by resistant microorganisms. PMID- 22494724 TI - Re: towards the definition of the best management and prognostic factors of teratoma with malignant transformation: a single-institution case series and new proposal. PMID- 22494725 TI - Re: minimally invasive methods for bulbar urethral strictures: a survey of members of the American Urological Association. PMID- 22494726 TI - Re: residual heat of laparoscopic energy devices: how long must the surgeon wait to touch additional tissue? PMID- 22494727 TI - Re: patient-reported body image and cosmesis outcomes following kidney surgery: comparison of laparoendoscopic single-site, laparoscopic, and open surgery. PMID- 22494728 TI - Re: failure after laparoscopic pyeloplasty: prevention and management. PMID- 22494729 TI - Re: promise of urinary nerve growth factor for assessment of overactive bladder syndrome. PMID- 22494730 TI - Re: rectal distension: the effect on bladder function. PMID- 22494731 TI - Re: contemporary management of postprostatectomy incontinence. PMID- 22494732 TI - Re: the role of invasive and non-invasive urodynamics in male voiding lower urinary tract symptoms. PMID- 22494733 TI - Re: silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double blind, placebo- and active-controlled clinical trial performed in Europe. PMID- 22494734 TI - Re: clinical significance of postvoid residual volume in older ambulatory women. PMID- 22494735 TI - Re: is well-being associated with lower urinary tract symptoms in patients with stroke? PMID- 22494736 TI - Re: MRI evaluation of urethral diverticula and differential diagnosis in symptomatic women. PMID- 22494737 TI - Re: urologist compliance with AUA best practice guidelines for benign prostatic hyperplasia in Medicare population. PMID- 22494738 TI - Re: CD4+ and CD8+ T-lymphocyte scores cannot reliably predict progression in patients with benign prostatic hyperplasia. PMID- 22494739 TI - Re: phase 1 and 2 studies demonstrate the safety and efficacy of intraprostatic injection of PRX302 for the targeted treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. PMID- 22494740 TI - Re: desensitization in HLA-incompatible kidney recipients and survival. PMID- 22494741 TI - Re: donor kidney adapts to body dimensions of recipient: no influence of donor gender on renal function after transplantation. PMID- 22494742 TI - Re: the prognostic value of renal resistance during hypothermic machine perfusion of deceased donor kidneys. PMID- 22494743 TI - Re: the natural progression and regression of erectile dysfunction: follow-up results from the MMAS and MALES studies. PMID- 22494744 TI - Re: time to onset of action of vardenafil: a retrospective analysis of the pivotal trials for the orodispersible and film-coated tablet formulations. PMID- 22494745 TI - Re: addition of metformin to sildenafil treatment for erectile dysfunction in eugonadal non-diabetic men with insulin resistance. A prospective, randomized, double blind pilot study. PMID- 22494746 TI - Re: correlates of PDE5i use among subjects with erectile dysfunction in two population-based surveys. PMID- 22494747 TI - Re: low-intensity extracorporeal shock wave therapy--a novel effective treatment for erectile dysfunction in severe ED patients who respond poorly to PDE5 inhibitor therapy. PMID- 22494748 TI - Re: sexual satisfaction in the elderly female population: a special focus on women with gynecologic pathology. PMID- 22494749 TI - Re: association between higher levels of sexual function, activity, and satisfaction and self-rated successful aging in older postmenopausal women. PMID- 22494750 TI - Re: XX males SRY negative: a confirmed cause of infertility. PMID- 22494751 TI - Re: fecundity and sex ratio of offspring in an infertile cohort. PMID- 22494752 TI - Re: semen washing procedures do not eliminate human papilloma virus sperm infection in infertile patients. PMID- 22494753 TI - Re: effects of advanced selection methods on sperm quality and ART outcome: a systematic review. PMID- 22494754 TI - Re: delivering affordable cancer care in high-income countries. PMID- 22494755 TI - Re: large variations in Medicare payments for surgery highlight savings potential from bundled payment programs. PMID- 22494757 TI - Re: prospective randomized trial comparing dissection with Plastibell(r) circumcision. PMID- 22494756 TI - Re: the many different prices paid to providers and the flawed theory of cost shifting: is it time for a more rational all-payer system? PMID- 22494758 TI - Re: congenital megalourethra: prenatal diagnosis and postnatal/autopsy findings in 10 cases. PMID- 22494759 TI - Re: the challenge of early surgery for cryptorchidism. PMID- 22494760 TI - Re: are stone protocol computed tomography scans mandatory for children with suspected urinary calculi? PMID- 22494761 TI - Re: nephrocalcinosis and urolithiasis in children. PMID- 22494762 TI - Re: DMRT1 prevents female reprogramming in the postnatal mammalian testis. PMID- 22494763 TI - Re: prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies. PMID- 22494765 TI - Re: net intestinal transport of oxalate reflects passive absorption and SLC26A6 mediated secretion. PMID- 22494764 TI - Re: the E3 ubiquitin ligase Cullin 4A regulates meiotic progression in mouse spermatogenesis. PMID- 22494766 TI - Re: hydroxyproline metabolism in mouse models of primary hyperoxaluria. PMID- 22494767 TI - Re: hypercalciuria associated with high dietary protein intake is not due to acid load. PMID- 22494768 TI - Re: improvements in human sperm quality by long-term in vitro co-culture with isolated porcine Sertoli cells. PMID- 22494769 TI - Renal transplantation under prophylactic eculizumab in atypical hemolytic uremic syndrome with CFH/CFHR1 hybrid protein. AB - We report the first observation of successful kidney transplantation under pre emptive eculizumab treatment in a 7-year-old boy with atypical hemolytic uremic syndrome (aHUS) and a known hybrid CFH/CFHR1 gene, who was dependent on plasma therapy during the 3-year dialysis period. The hybrid CFH/CFHR1 protein has an altered C3b/C3d binding, is incapable to protect cells from complement attack and is directly implicated in aHUS pathogenesis. There was no evidence of recurrence during the first 16-month follow-up period. We conclude that eculizumab alone, without plasma therapy (plasma infusion and/or plasma exchange), is sufficient to prevent recurrence of aHUS and to maintain long-term graft function. PMID- 22494770 TI - Early perfusion changes in patients with recurrent high-grade brain tumor treated with Bevacizumab: preliminary results by a quantitative evaluation. AB - BACKGROUND: To determine whether early monitoring of the effects of bevacizumab in patients with recurrent high-grade gliomas, by a Perfusion Computed Tomography (PCT), may be a predictor of the response to treatment assessed through conventional MRI follow-up. METHODS: Sixteen patients were enrolled in the present study. For each patient, two PCT examinations, before and after the first dose of bevacizumab, were acquired. Areas of abnormal Cerebral Blood Volume (CBV) were manually defined on the CBV maps, using co-registered T1- weighted images, acquired before treatment, as a guide to the tumor location. Different perfusion metrics were derived from the histogram analysis of the normalized CBV (nCBV) maps; both hyper and hypo-perfused sub-volumes were quantified in the lesion, including tumor necrosis. A two-tailed Wilcoxon test was used to establish the significance of changes in the different perfusion metrics, observed at baseline and during treatment. The relationships between changes in perfusion and morphological MRI modifications at first follow-up were investigated. RESULTS: Significant reductions in mean and median nCBV were detected throughout the entire patient population, after only a single dose of bevacizumab. The nCBV histogram modifications indicated the normalization effect of bevacizumab on the tumor abnormal vasculature. An improvement in hypoxia after a single dose of bevacizumab was predictive of a greater reduction in T1-weighted contrast enhanced volumes at first follow-up. CONCLUSIONS: These preliminary results show that a quantification of changes in necrotic intra-tumoral regions could be proposed as a potential imaging biomarker of tumor response to anti-VEGF therapies. PMID- 22494771 TI - A forced-attention dichotic listening fMRI study on 113 subjects. AB - We report fMRI and behavioral data from 113 subjects on attention and cognitive control using a variant of the classic dichotic listening paradigm with pairwise presentations of consonant-vowel syllables. The syllable stimuli were presented in a block-design while subjects were in the MR scanner. The subjects were instructed to pay attention to and report either the left or right ear stimulus. The hypothesis was that paying attention to the left ear stimulus (FL condition) induces a cognitive conflict, requiring cognitive control processes, not seen when paying attention to the right ear stimulus (FR condition), due to the perceptual salience of the right ear stimulus in a dichotic situation. The FL condition resulted in distinct activations in the left inferior prefrontal gyrus and caudate nucleus, while the right inferior frontal gyrus and caudate were activated in both the FL and FR conditions, and in a non-instructed (NF) baseline condition. PMID- 22494773 TI - Hepatorenal syndrome: one size does not fit all. PMID- 22494772 TI - Ubiquitination is involved in secondary growth, not initial formation of polyglutamine protein aggregates in C. elegans. AB - BACKGROUND: Protein misfolding and subsequent aggregation are hallmarks of several human diseases. The cell has a variety of mechanisms for coping with misfolded protein stress, including ubiquitin-mediated protein degradation. In fact, the presence of ubiquitin at protein aggregates is a common feature of protein misfolding diseases. Ubiquitin conjugating enzymes (UBCs) are part of the cascade of enzymes responsible for the regulated attachment of ubiquitin to protein substrates. The specific UBC used during ubiquitination can determine the type of polyubiquitin chain linkage, which in turn plays an important role in determining the fate of the ubiquitinated protein. Thus, UBCs may serve an important role in the cellular response to misfolded proteins and the fate of protein aggregates. RESULTS: The Q82 strain of C. elegans harbors a transgene encoding an aggregation prone tract of 82 glutamine residues fused to green fluorescent protein (Q82::GFP) that is expressed in the body wall muscle. When measured with time-lapse microscopy in young larvae, the initial formation of individual Q82::GFP aggregates occurs in approximately 58 minutes. This process is largely unaffected by a mutation in the C. elegans E1 ubiquitin activating enzyme. RNAi of ubc-22, a nematode homolog of E2-25K, resulted in higher pre aggregation levels of Q82::GFP and a faster initial aggregation rate relative to control. Knockdown of ubc-1 (RAD6 homolog), ubc-13, and uev-1 did not affect the kinetics of initial aggregation. However, RNAi of ubc-13 decreases the rate of secondary growth of the aggregate. This result is consistent with previous findings that aggregates in young adult worms are smaller after ubc-13 RNAi. mCherry::ubiquitin becomes localized to Q82::GFP aggregates during the fourth larval (L4) stage of life, a time point long after most aggregates have formed. FLIP and FRAP analysis indicate that mCherry::ubiquitin is considerably more mobile than Q82::GFP within aggregates. CONCLUSIONS: These data indicate that initial formation of Q82::GFP aggregates in C. elegans is not directly dependent on ubiquitination, but is more likely a spontaneous process driven by biophysical properties in the cytosol such as the concentration of the aggregating species. The effect of ubiquitination appears to be most significant in later, secondary aggregate growth. PMID- 22494774 TI - Prognostic significance of tumor extension into venous system in patients undergoing surgical treatment for renal cell carcinoma with venous tumor thrombus. AB - AIMS: The objective of this study was to evaluate the prognostic significance of the extent of a tumor thrombus in renal cell carcinoma (RCC) involving the venous system. METHODS: This study included 135 consecutive RCC patients with a venous tumor thrombus undergoing radical nephrectomy and tumor thrombectomy between 1985 and 2009. These patients were classified based on the maximal level of the tumor thrombus extending into the venous system, as follows: group 1, renal vein; group 2, infradiaphragmatic; and group 3, supradiaphragmatic. RESULTS: Of the 135 patients, 65, 49 and 21 were classified into groups 1, 2 and 3, respectively. The 1, 3 and 5-year cancer-specific survival (CSS) rates in these 135 patients were 89.2, 56.9 and 49.2%, respectively. Among several factors examined, tumor size, tumor grade, perirenal fat invasion and presence of metastasis, but not extent of tumor thrombus, were significantly associated with CSS on univariate analysis. Of these significant factors, only tumor size and presence of metastasis appeared to be independently related to CSS on multivariate analysis. When the patients without metastasis were analyzed separately, CSS in groups 2 and 3 was significantly poorer than that in group 1. CONCLUSIONS: These findings suggest the absence of a significant prognostic impact of the level of the tumor thrombus in a complete cohort of RCC patients with a venous tumor thrombus; however, it is warranted to determine whether the level of the tumor thrombus has different effects on the prognosis according to the presence of metastatic diseases. PMID- 22494775 TI - Differential estrogenic actions of endocrine-disrupting chemicals bisphenol A, bisphenol AF, and zearalenone through estrogen receptor alpha and beta in vitro. AB - BACKGROUND: Endocrine-disrupting chemicals (EDCs) are widely found in the environment. Estrogen-like activity is attributed to EDCs, such as bisphenol A (BPA), bisphenol AF (BPAF), and zearalenone (Zea), but mechanisms of action and diversity of effects are poorly understood. OBJECTIVES: We used in vitro models to evaluate the mechanistic actions of BPA, BPAF, and Zea on estrogen receptor (ER) alpha and ERbeta. METHODS: We used three human cell lines (Ishikawa, HeLa, and HepG2) representing three cell types to evaluate the estrogen promoter activity of BPA, BPAF, and Zea on ERalpha and ERbeta. Ishikawa/ERalpha stable cells were used to determine changes in estrogen response element (ERE)-mediated target gene expression or rapid action-mediated effects. RESULTS: The three EDCs showed strong estrogenic activity as agonists for ERalpha in a dose-dependent manner. At lower concentrations, BPA acted as an antagonist for ERalpha in Ishikawa cells and BPAF acted as an antagonist for ERbeta in HeLa cells, whereas Zea was only a partial antagonist for ERalpha. ERE-mediated activation by BPA and BPAF was via the AF-2 function of ERalpha, but Zea activated via both the AF-1 and AF-2 functions. Endogenous ERalpha target genes and rapid signaling via the p44/42 MAPK pathway were activated by BPA, BPAF, and Zea. CONCLUSION: BPA and BPAF can function as EDCs by acting as cell type-specific agonists (>= 10 nM) or antagonists (<= 10 nM) for ERalpha and ERbeta. Zea had strong estrogenic activity and activated both the AF-1 and AF-2 functions of ERalpha. In addition, all three compounds induced the rapid action-mediated response for ERalpha. PMID- 22494777 TI - Exchanging views on HTA. PMID- 22494776 TI - Efficacy of movement control exercises versus general exercises on recurrent sub acute nonspecific low back pain in a sub-group of patients with movement control dysfunction. Protocol of a randomized controlled trial. AB - BACKGROUND: Practice guidelines recommend various types of exercise for chronic back pain but there have been few head-to-head comparisons of these interventions. General exercise seems to be an effective option for management of chronic low back pain (LBP) but very little is known about the management of a sub-acute LBP within sub-groups. Recent research has developed clinical tests to identify a subgroup of patients with chronic non-specific LBP who have movement control dysfunction (MD). METHOD/DESIGN: We are conducting a randomized controlled trial (RCT) to compare the effects of general exercise and specific movement control exercise (SMCE) on disability and function in patients with MD within recurrent sub-acute LBP. The main outcome measure is the Roland Morris Disability Questionnaire. DISCUSSION: European clinical guideline for management of chronic LBP recommends that more research is required to develop tools to improve the classification and identification of specific clinical sub-groups of chronic LBP patients. Good quality RCTs are then needed to determine the effectiveness of specific interventions aimed at these specific target groups. This RCT aims to test the hypothesis whether patients within a sub-group of MD benefit more through a specific individually tailored movement control exercise program than through general exercises. PMID- 22494778 TI - Risk of recurrent stroke before carotid endarterectomy: the ANSYSCAP study. AB - BACKGROUND: Carotid endarterectomy yields greater risk reduction for ipsilateral ischemic stroke when performed within two-weeks of the last cerebrovascular symptom than when performed two-weeks or more after the last symptom. However, additional benefit might be gained if carotid endarterectomy is performed earlier than within two-weeks. AIMS: To investigate the 90-day risk of ipsilateral ischemic stroke recurrence after amaurosis fugax, retinal artery occlusion, transient ischemic attack, or minor ischemic stroke in patients with 50-99% carotid stenosis before carotid endarterectomy, with emphasis on the first 14 days. METHODS: Prospective cohort study. 230 consecutive patients with symptomatic 50-99% carotid stenosis (North American Symptomatic Carotid Endarterectomy Trial grading method) who underwent evaluation before carotid endarterectomy. Of these, 183 underwent carotid endarterectomy; the median delay to carotid endarterectomy was 29 days. Blood pressure lowering medication was used by 93% and lipid-lowering medication by 90%. RESULTS: The risk of ipsilateral ischemic stroke recurrence before carotid endarterectomy was 5.2% (n = 12) within two-days, 7.9% (n = 18) within seven-days, 11.2% (n = 25) within 14 days, and 18.6% (n = 33) within 90 days of the presenting event. The risk of ipsilateral ischemic stroke recurrence was higher if the presenting event was a stroke (adjusted hazard ratio 12.4, P = 0.015) or transient ischemic attack (adjusted hazard ratio 10.2, P = 0.026) compared with an amaurosis fugax. DISCUSSION: The risk of recurrent ipsilateral ischemic stroke was high within the first days of the presenting event. Many recurrences would likely have been avoided if carotid endarterectomy had been performed within the first days of the presenting event. PMID- 22494779 TI - Anterior cruciate ligament tears in children. AB - Anterior cruciate ligament (ACL) injuries have become common in children and adolescents who practice competitive sports, accounting for 0.5-3% of all ACL injuries. Magnetic resonance imaging (MRI) is useful for diagnosis and treatment planning, but is no better than clinical examination, especially when the MRI is interpreted by less experienced health care professionals. Management of ACL deficiency in children is still controversial, but the present trend is towards early reconstruction, because repeated instability episodes may lead to secondary lesions of the knee, and induce meniscal tears and early degenerative alterations of the joint. Postoperatively, complications are rare, and most of the documented growth complications are secondary to avoidable technical errors such as placement of a fixation device across a growth plate. We recommend to reconstruct the ACL paying attention to avoid irreversible damage to the epiphyseal growth plates of the lower femur and upper tibia. PMID- 22494780 TI - Accurate ab-initio-based single-sheeted DMBE potential-energy surface for ground state N2O. AB - A global accurate double-many-body expansion potential-energy surface is reported for the electronic ground state of N(2)O. The new form is shown to accurately mimic the ab-initio points calculated at the multireference configuration interaction level using the aug-cc-pVTZ basis set and the full-valence-complete active-space wave function as reference. To improve the calculated raw energies, they have been extrapolated to the completed basis set limit and most importantly to the full configuration-interaction limit by correcting semiempirically the calculated dynamical correlation with the double-many-body expansion-scaled external correlation method. The topographical features of the novel potential energy surface were examined in detail and compared with those of other potential functions available in the literature. Good agreement with the experimental data is observed. PMID- 22494781 TI - Efforts to change transfusion practice and reduce transfusion rates are effective in coronary artery bypass surgery. AB - OBJECTIVES: Efforts to decrease allogeneic blood transfusion and avoid unnecessary transfusions in cardiac surgery are important because transfusions are associated with increased postoperative morbidity and mortality. The purpose of the present study was to evaluate the long-term effects of multidisciplinary efforts to reduce allogeneic blood transfusion rates and avoid unnecessary red blood cell (RBC) transfusions in primary elective coronary artery bypass graft (CABG) surgery. DESIGN: A retrospective observational study. SETTING: A single center study in a university-affiliated hospital. PARTICIPANTS: A total of 450 patients undergoing primary elective CABG surgery during 2004, 2008, or 2010. INTERVENTIONS: The application of systematic multimodal perioperative blood sparing techniques and interventions directed to change transfusion behaviors. MEASUREMENTS AND MAIN RESULTS: The results from an audit on transfusion practices in 2004 were compared with similar audits performed in 2008 and 2010 using a before-and-after study design. The patient populations were comparable throughout the years. The median postoperative chest tube bleeding was decreased from 950 mL in 2004 to 750 mL in 2010. The proportion of patients transfused with allogeneic blood products was decreased from 64% to 47%. Overtransfusion with allogeneic RBCs defined as the proportion of patients transfused with RBCs discharged with hemoglobin >7 mmol/L (11.3 g/dL) was reduced from 36% to 16%. CONCLUSIONS: Multimodal efforts to change transfusion behaviors and decrease transfusion rates in CABG surgery have persistent effects for several years. PMID- 22494782 TI - Carotid endarterectomy plus medical therapy or medical therapy alone for carotid artery stenosis in symptomatic or asymptomatic patients: a meta-analysis. AB - OBJECTIVE: The purpose of this study was to compare carotid endarterectomy (CEA) plus medical therapy (MT) with MT alone for symptomatic and asymptomatic patients suffering from carotid artery stenosis in terms of long-term stroke/death rate. DESIGN: A meta-analysis of parallel randomized, controlled trials (RCTs) (blind or open) published in English. SETTING: A university-based electronic search. PARTICIPANTS: Patients suffering from carotid artery stenosis symptomatic or not. INTERVENTIONS: Patients were subjected to CEA plus MT or MT alone. MEASUREMENTS AND MAIN RESULTS: For asymptomatic patients, 6 RCTs comprising 5,733 patients (CEA = 2,853 and MT = 2,880) were included. CEA did not affect the stroke/death risk for asymptomatic patients (risk ratio [RR] = 0.93; 95% confidence interval [CI], 0.84 to 1.02; I(2) = 0%; p = 0.14). For symptomatic patients, 2 RCTs were included. They had 5,627 patients (CEA = 3,069 and MT = 2,558) of whom 2,295 patients (CEA = 1,213; MT = 1,082) had severe stenosis (North American Symptomatic Carotid Endarterectomy Trial [NASCET] technique >=50% and European Carotid Surgery Trial technique >=70%). CEA decreased the stroke/death risk only for patients with severe stenosis (RR = 0.69; 95% CI, 0.59-0.81; p < 0.001 [random effects model]; I(2) = 0% on the odds ratio and 17% on the RR [benefit or harm side]; number needed to treat = 11 [95% CI, 8-17]). CONCLUSIONS: CEA is helpful for recently symptomatic patients with carotid artery stenosis >=50% (NASCET technique) but adds no benefit in terms of stroke/death for asymptomatic patients. PMID- 22494783 TI - Mechanisms and consequences of acquired brain injury during development. AB - The brain of the infant and young child is a developing, dynamic, structure subject to functional remodelling under the influence of factors responsible for optimal neuronal development and synaptogenesis. It exhibits age dependent variation in metabolic rate, blood flow, and ability to tolerate oxidative stress. It is also characterized by an exuberance of neurotransmitter activity, particularly in the first few years of life. The dynamic evolution and adaptability of early brain function permits the organization of neuronal networks to be influenced by environmental stimulation, and, to reduce the functional impact of injury. However, these same processes may also exacerbate the harm sustained by the brain following an acquired brain injury (ABI). The developing neurons are susceptible to excitotoxicity, oxidative stress, and, inflammation, often leading to cellular necrosis and apoptosis. Despite being immunologically privileged via the blood brain barrier, the developing brain is susceptible to injury from systemic inflammation through alteration of normally protective cerebrovascular endothelial cell function. Finally, many of the therapeutic agents currently employed in post-ABI hospital care may also compromise ABI outcome via non-intended pharmacological effects. These agents include analgesic, sedative and anti-convulsant medications. This review emphasizes those physiological considerations in the developing brain which may impact the outcome after ABI, including, the cellular mechanisms of neuronal and cerebrovascular endothelial cell injury, ABI outcome and future therapeutic directions. PMID- 22494784 TI - Primary graft dysfunction after living donor liver transplantation is characterized by delayed functional hyperbilirubinemia. AB - The purpose of this study is to propose a new concept of primary graft dysfunction (PGD) after living donor liver transplantation (LDLT), characterized by delayed functional hyperbilirubinemia (DFH) and a high early graft mortality rate. A total of 210 adult-to-adult LDLT grafts without anatomical, immunological or hepatitis-related issues were included. All of the grafts with early mortality (n = 13) caused by PGD in LDLT had maximum total bilirubin levels >20 mg/dL after postoperative day 7 (p < 0.001). No other factors, including prothrombin time, ammonia level or ascites output after surgery were associated with early mortality. Thus, DFH of >20 mg/dL for >seven consecutive days occurring after postoperative day 7 (DFH-20) was used to characterize PGD. DFH-20 showed high sensitivity (100%) and specificity (95.4%) for PGD with early mortality. Among the grafts with DFH-20 (n = 22), those with early mortality (n = 13) showed coagulopathy (PT-INR > 2), compared with those without mortality (p = 0.002). Pathological findings in the grafts with DFH-20 included hepatocyte ballooning and cholestasis, which were particularly prominent in the centrilobular zone. PGD after LDLT is associated with DFH-20 caused by graft, recipient and surgical factors, and increases the risk of early graft mortality. PMID- 22494785 TI - Emergency department length of stay for patients requiring mechanical ventilation: a prospective observational study. AB - BACKGROUND: Recommendations for acceptable emergency department (ED) length of stay (LOS) vary internationally with <= 8 h generally considered acceptable. Protracted ED LOS may place critically ill patients requiring mechanical ventilation at increased risk of adverse events as most EDs are not resourced for longitudinal delivery of critical care. Our objective was to quantify the ED LOS for mechanically ventilated patients (invasive and/or non-invasive ventilation [NIV]) and to explore patient and system level predictors of prolonged ED LOS. Additionally, we aimed to describe delivery and monitoring of ventilation in the ED. METHODS: Prospective observational study of ED LOS for all patients receiving mechanical ventilation at four metropolitan EDs in Toronto, Canada over two six month periods in 2009 and 2010. RESULTS: We identified 618 mechanically ventilated patients which represented 0.5% (95% CI 0.4%-0.5%) of all ED visits. Of these, 484 (78.3%) received invasive ventilation, 118 (19.1%) received NIV; 16 received both during the ED stay. Median Kaplan-Meier estimated duration of ED stay for all patients was 6.4 h (IQR 2.8-14.6). Patients with trauma diagnoses had a shorter median (IQR) LOS, 2.5 h (1.3-5.1), compared to ventilated patients with non-trauma diagnoses, 8.5 h (3.3-14.0) (p <0.001). Patients requiring NIV had a longer ED stay (16.6 h, 8.2-27.9) compared to those receiving invasive ventilation exclusively (4.6 h, 2.2-11.1) and patients receiving both (15.4 h, 6.4-32.6) (p <0.001). Longer ED LOS was associated with ED site and lower priority triage scores. Shorter ED LOS was associated with intubation at another ED prior to transfer. CONCLUSIONS: While patients requiring mechanical ventilation represent a small proportion of overall ED visits these critically ill patients frequently experienced prolonged ED stay especially those treated with NIV, assigned lower priority triage scores at ED presentation, and non trauma patients. PMID- 22494786 TI - Effect of vitamin E and C supplements on lipid peroxidation and GSH-dependent antioxidant enzyme status in the blood of women consuming oral contraceptives. AB - BACKGROUND: Oral contraceptives (OCs) may affect oxidative stress status. We aimed to assess whether supplementation with vitamins E and C reduced this OC effect. STUDY DESIGN: One hundred twenty healthy female individuals were divided into three groups: A, control; B, untreated OCU (OC users); and C, treated OCU (OC users with vitamin E and C supplementation). In all cases, plasma glutathione peroxidase (GPx) and glutathione reductase (GR) activities and malondialdehyde (MDA) level were determined. RESULTS: Significant increases were found in the plasma MDA level, and activities of GPx and GR in plasma were decreased in Group B compared to the control group. Supplementation with vitamin C and E significantly increased the activity of GPx and GR activity, and reduced plasma MDA levels in Group C (p<.05). CONCLUSIONS: These data suggest that low-dose OCs, by enhancing the stress oxidative and lipid peroxidation, may represent a potential cardiovascular risk factor, and the use of vitamins E and C may be beneficial in ameliorating this side effect of OCs. PMID- 22494787 TI - Protocol-directed care in the ICU: making a future generation of intensivists less knowledgeable? AB - CITATION: Prasad M, Holmboe ES, Lipner RS, Hess BJ, Christie JD, Bellamy SL, Rubenfeld GD, Kahn JM. Clinical Protocols and Trainee Knowledge About Mechanical Ventilation. JAMA. 2011; 306(9):935-941. PubMed PMID: 21900133 This is available on http://www.pubmed.gov BACKGROUND: Clinical protocols are associated with improved patient outcomes; however, they may negatively affect medical education by removing trainees from clinical decision making. METHODS: OBJECTIVE: To study the relationship between critical care training with mechanical ventilation protocols and subsequent knowledge about ventilator management. DESIGN: A retrospective cohort equivalence study linking a national survey of mechanical ventilation protocol availability with knowledge about mechanical ventilation. Exposure to protocols was defined as high intensity if an intensive care unit had 2 or more protocols for at least 3 years and as low intensity if 0 or 1 protocol. SETTING: Accredited US pulmonary and critical care fellowship programs. SUBJECTS: First-time examinees of the American Board of Internal Medicine (ABIM) Critical Care Medicine Certification Examination in 2008 and 2009. INTERVENTION: N/AOutcomes: Knowledge, measured by performance on examination questions specific to mechanical ventilation management, calculated as a mechanical ventilation score using item response theory. The score is standardized to a mean (SD) of 500 (100), and a clinically important difference is defined as 25. Variables included in adjusted analyses were birth country, residency training country, and overall first-attempt score on the ABIM Internal Medicine Certification Examination. RESULTS: The 90 of 129 programs (70%) responded to the survey. Seventy seven programs (86%) had protocols for ventilation liberation, 66 (73%) for sedation management, and 54 (60%) for lung-protective ventilation at the time of the survey. Eighty eight (98%) of these programs had trainees who completed the ABIM Critical Care Medicine Certification Examination, totaling 553 examinees. Of these 88 programs, 27 (31%) had 0 protocols, 19 (22%) had 1 protocol, 24 (27%) had 2 protocols, and 18 (20%) had 3 protocols for at least 3 years. 42 programs (48%) were classified as high intensity and 46 (52%) as low intensity, with 304 trainees (55%) and 249 trainees (45%), respectively. In bi-variable analysis, no difference in mean scores was observed in high-intensity (497; 95% CI, 486-507) vs low-intensity programs (497; 95% CI, 485-509). Mean difference was 0 (95% CI, 16 to 16), with a positive value indicating a higher score in the high-intensity group. In multivariable analyses, no association of training was observed in a high-intensity program with mechanical ventilation score (adjusted mean difference, -5.36; 95% CI, -20.7 to 10.0). CONCLUSIONS: Among first-time ABIM Critical Care Medicine Certification Examination examinees, training in a high intensity ventilator protocol environment compared with a low-intensity environment was not associated with worse performance on examination questions about mechanical ventilation management. PMID- 22494788 TI - Postoperative morbidity in head and neck cancer ablative surgery followed by microsurgical free tissue transfer in the elderly. AB - OBJECTIVE: To identify the risk factors for postoperative morbidities in elderly patients (?65 years old) who underwent head and neck tumor ablation followed by immediate free tissue transfer. METHODS: We performed a retrospective analysis of 1012 patients who underwent free tissue transfer after head and neck cancer ablation between 2007 and 2010. A total of 167 patients aged 65 and older were identified. These patients were divided into two age-related subgroups: patients aged between 65 and 70 years in one cohort and patients older than 70 years in the second cohort. The demographic and operative variables as well as postoperative medical and surgical morbidities were analyzed. RESULTS: The older group had significantly prolonged ICU stay (p = 0.014) and hospital stay (p = 0.039). The same group also had higher rates of intraoperative blood transfusion ?2 units (p = 0.019), unplanned reintubation (p < 0.001), medical (p = 0.004), and surgical (p < 0.001) complications. The intraoperative blood loss of >220 mL was a significant predictive factor for postoperative medical morbidities (odds ratio [OR] 2.25; 95% confidence interval [CI], 1.01-5.03; p = 0.048). The age of >70 years was an independent risk factor for postoperative medical and surgical morbidity (OR [95% CI]: 4.08 [1.67-9.99] and 3.48 [1.56-7.78], p = 0.002, respectively). CONCLUSIONS: Age over 70 years and intraoperative blood loss of >220 mL are significant risk factors for predicting postoperative morbidity, and a thorough pre-treatment evaluation and care for elderly patients are required. PMID- 22494790 TI - Experience talks. PMID- 22494789 TI - Using ontology-based annotation to profile disease research. AB - BACKGROUND: Profiling the allocation and trend of research activity is of interest to funding agencies, administrators, and researchers. However, the lack of a common classification system hinders the comprehensive and systematic profiling of research activities. This study introduces ontology-based annotation as a method to overcome this difficulty. Analyzing over a decade of funding data and publication data, the trends of disease research are profiled across topics, across institutions, and over time. RESULTS: This study introduces and explores the notions of research sponsorship and allocation and shows that leaders of research activity can be identified within specific disease areas of interest, such as those with high mortality or high sponsorship. The funding profiles of disease topics readily cluster themselves in agreement with the ontology hierarchy and closely mirror the funding agency priorities. Finally, four temporal trends are identified among research topics. CONCLUSIONS: This work utilizes disease ontology (DO)-based annotation to profile effectively the landscape of biomedical research activity. By using DO in this manner a use-case driven mechanism is also proposed to evaluate the utility of classification hierarchies. PMID- 22494791 TI - A review of epinephrine administration in pediatric anaphylaxis. PMID- 22494792 TI - EggLib: processing, analysis and simulation tools for population genetics and genomics. AB - BACKGROUND: With the considerable growth of available nucleotide sequence data over the last decade, integrated and flexible analytical tools have become a necessity. In particular, in the field of population genetics, there is a strong need for automated and reliable procedures to conduct repeatable and rapid polymorphism analyses, coalescent simulations, data manipulation and estimation of demographic parameters under a variety of scenarios. RESULTS: In this context, we present EggLib (Evolutionary Genetics and Genomics Library), a flexible and powerful C++/Python software package providing efficient and easy to use computational tools for sequence data management and extensive population genetic analyses on nucleotide sequence data. EggLib is a multifaceted project involving several integrated modules: an underlying computationally efficient C++ library (which can be used independently in pure C++ applications); two C++ programs; a Python package providing, among other features, a high level Python interface to the C++ library; and the egglib script which provides direct access to pre programmed Python applications. CONCLUSIONS: EggLib has been designed aiming to be both efficient and easy to use. A wide array of methods are implemented, including file format conversion, sequence alignment edition, coalescent simulations, neutrality tests and estimation of demographic parameters by Approximate Bayesian Computation (ABC). Classes implementing different demographic scenarios for ABC analyses can easily be developed by the user and included to the package. EggLib source code is distributed freely under the GNU General Public License (GPL) from its website http://egglib.sourceforge.net/ where a full documentation and a manual can also be found and downloaded. PMID- 22494793 TI - Innate immunity gene single nucleotide polymorphisms and otitis media. AB - OBJECTIVE: Toll-like receptors (TLR) activate the innate immune system. Single nucleotide polymorphisms (SNPs) in TLR genes are linked to increased susceptibility to infections. TLR4-deficient mice have increased incidence and duration of otitis media. We hypothesize that SNPs in TLR genes are more common in otitis-prone children than in children without a history of otitis media. METHODS: Cases (n=70) included children undergoing surgery for otitis media. Control subjects (n=70) included children undergoing surgery for non-otologic indication. Genomic DNA was extracted from blood samples. RT-PCR genotyping was performed for TLR2 (rs5743708), TLR4 (rs4986790 and rs4986791), TLR9 (rs5743836 & rs187084), and CD14 (rs2569190). RESULTS: There were no significant differences between the groups in family history, day care, smoke exposure, allergies or prevalence of the SNPs. The most common pre-op diagnosis in control subjects was obstructive sleep apnea (OSA). CONCLUSIONS: TLR2, TLR4, TLR9 and CD14 gene SNPs were not more prevalent in otitis-prone children. PMID- 22494794 TI - Metal ion levels in large-diameter total hip and resurfacing hip arthroplasty- preliminary results of a prospective five year study after two years of follow up. AB - BACKGROUND: Metal-on-metal hip resurfacing is an alternative to metal-on-metal total hip arthroplasty, especially for young and physically active patients. However, wear which might be detected by increased serum ion levels is a matter of concern. METHODS: The aims of this preliminary study were to determine the raise of metal ion levels at 2-years follow-up in a prospective setting and to evaluate differences between patients with either resurfacing or total hip arthroplasty. Furthermore we investigated if the inclination of the acetabular component and the arc of cover would influence these findings. Therefore, 36 patients were followed prospectively. RESULTS: The results showed increments for Co and Cr in both implant groups. Patients treated with large-diameter total hip arthroplasty showed fourfold and threefold, respectively, higher levels for Co and Cr compared to the resurfacing group (Co: p < 0,001 and Cr: p = 0,005). Nevertheless, we observed no significant correlation between serum ion levels, inclination and arc of cover. DISCUSSION: In order to clarify the biologic effects of ion dissemination and to identify risks concerning long-term toxicity of metals, the exposure should be monitored carefully. Therefore, long-term studies have to be done to determine adverse effects of Co and Cr following metal on-metal hip replacement. PMID- 22494795 TI - Eruptive vellus hair cysts in association with syringomas. PMID- 22494796 TI - The effect of levetiracetam on focal nocturnal epileptiform activity during sleep -a placebo-controlled double-blind cross-over study. AB - Electric Status Epilepticus during Sleep (ESES) occurs in children with and without epilepsy. It may be related to disturbances as autism spectrum disorder, attention-deficit hyperactivity disorder and acquired aphasia (Landau-Kleffner syndrome). Antiepileptic drug (AED) treatment has been reported in small studies without placebo control. This study was designed to assess AED effect in a placebo-controlled double-blind cross-over study. Levetiracetam (LEV) was chosen based on clinical evidence. Eighteen patients fulfilled the inclusion criteria. The mean spike index at baseline was 56, falling to a mean of 37 at the end of the LEV treatment period. Assessed with a 2-way ANOVA, there is a significant treatment effect (p<0.0002). To the best of our knowledge, this is the first placebo-controlled double-blind cross-over study for any AED in patients with ESES. The effect of LEV is comparable with its effect in treatment of epileptic seizures. PMID- 22494797 TI - Developing a method to identify medicines non-adherence in a community sample of adults with epilepsy. AB - The aim is to propose a simple way of identifying patients at risk of antiepileptic drug (AED) non-adherence during epilepsy review (a scheduled consultation to review the patient and their condition). The use of a multi-modal approach to the problem of non-adherence is necessary because of the limitations of existing methods. A mixed methodology was developed in a nested study using a case record review to calculate the medicine possession ratio (MPR) from the AED medication records of a community sample, a literature review and a consensus panel to develop a questionnaire to address how people manage their epilepsy, particularly medicine management, and how to collect information about non adherence through stated findings in keeping with non-adherent behavior. Results show that a medicine record can be used to estimate the MPR (<80% indicates non adherence) and that an open and non-confrontational consultation style can be fostered by using key questions within the consultation to identify those at risk of non-adherence. PMID- 22494798 TI - Thalidomide for improving cutaneous and pulmonary sarcoidosis in patients resistant or with contraindications to corticosteroids. AB - BACKGROUND: Limited data report thalidomide improves cutaneous sarcoidosis; no benefit has been reported for pulmonary localization. OBJECTIVES: To evaluate feasibility and efficacy of prolonged treatment with thalidomide for cutaneous sarcoidosis associated to pulmonary involvement in patients with resistance or contraindications to steroids. METHODS: Nineteen patients were treated with thalidomide for 24 months starting with 200 mg/d for first 2 weeks, followed by 100 mg/d for 11 weeks and a maintenance dose of 100mg on alternate days for 35 weeks, and a gradual scaling down until therapy interruption. Criteria of efficacy were: skin score, serum ACE levels (s-ACE), chest X-ray (CXR), lung function tests (LFTs), and diffusing lung capacity for CO (DLCO). The skin score was computed as arithmetic sum of seven score parameters (min: 0, max: 28). RESULTS: Skin score significantly decreased (P<0.001). Lower skin scores occurred after 3 and 6 months (P<0.05). s-ACE levels decreased over time at the third month (P<0.001). CXR assessed by radiological stage significantly improved during the first 6 months (P<0.001). DLCO showed a continuous trend of improvement. Minor side effects that have forced the suspension of the drug were drowsiness/sedation (74%), constipation (68%), and weight gain (53%). Deep vein thrombosis of the lower limbs occurred in one patient (who did not drop out the study). Eight patients (42%) abandoned thalidomide for axonal sensitive peripheral neuropathy (PN) between the ninth and the 24th month of treatment. CONCLUSIONS: Thalidomide, long-term at mid-low doses, can be considered as an effective therapeutic alternative in chronic sarcoidosis with resistance or contraindications to steroids. PMID- 22494799 TI - Chemokine receptor CXCR3 is involved in the acute pancreatitis-associated lung injury. AB - Acute pancreatitis is a common disease, which is divided into mild pancreatitis and severe pancreatitis. For the latter, a systemic inflammatory response may occur and lead to distant organ damage and the development of multiple organ dysfunction syndrome (MODS), which accounts for significant morbidity and mortality in humans. Chemokines and their receptors are being believed to play a pivotal role in the pathogenesis of acute pancreatitis. Chemokine receptor CXCR3 is reported to be involved in acute tissue injury, for example acute lung injury induced by cigarette smoking, but its role in acute pancreatitis is not yet known. In this study, two animal models of acute pancreatitis (cerulein- and arginine-induced pancreatitis) were applied in CXCR3-/- mice and wild-type mice, in order to explore the role of CXCR3 in acute pancreatitis. Serum amylase, lipase and histological observations revealed that CXCR3 knockout did not affect the severity of acute pancreatitis. However, edema and inflammatory cell infiltrate in the lung tissue were attenuated in CXCR3-/- mice when acute pancreatitis was induced. In conclusion, chemokine receptor CXCR3 is not involved in acute pancreatic injury, but has a connection with acute pancreatitis associated lung injury. Acute pulmonary injury is attenuated in CXCR3 knockout mice in experimental acute pancreatitis. PMID- 22494800 TI - Cognitive behaviour therapy for adolescents with body dysmorphic disorder: a case series. AB - BACKGROUND: Body dysmorphic disorder (BDD) is relatively common in adolescents and can have serious negative consequences. However, the treatment of BDD in young people has received virtually no empirical attention to date, and the evidence-base for cognitive behaviour therapy (CBT) in this population is limited to a small number of single case reports. AIMS: This study aimed to investigate treatment outcomes associated with CBT, primarily consisting of exposure and response prevention, in a group of young people with BDD. METHOD: Six adolescents with a diagnosis of BDD received a course of developmentally appropriate CBT for BDD with parental involvement. BDD and depressive symptoms were evaluated at pre treatment, post-treatment and at 3- or 6-month follow-up, using the Yale-Brown Obsessive Compulsive Scale for BDD (BDD-YBOCS) and the Beck Depression Inventory Youth, respectively. RESULTS: Scores on the BDD-YBOCS indicated a 44% improvement in BDD symptoms at post-treatment and a 57% improvement at follow-up for the group. Considering response as a >= 30% reduction in BDD-YBOCS score, four of the six adolescents were classified as treatment responders. Improvements in depressive symptoms were observed among the treatment responders, but not the non responders. CONCLUSIONS: These findings indicate the potential efficacy of CBT, including exposure and response prevention for adolescents with BDD, and highlight the need for further controlled trials. PMID- 22494801 TI - Importance of local interactions for the stability of inhibitory helix 1 in apo Ets-1. AB - Inhibitory helix 1 (HI-1) of the Ets-1 human transcription factor unfolds upon binding the target DNA sequence. To identify the interactions that stabilize HI-1 in the apo state, we performed replica exchange and molecular dynamics simulations of various apo Ets-1 constructs. The simulations indicate the importance of local interactions for the stability of HI-1. The HI-2 and H4 helices stabilize the helical state of HI-1 through specific residue-residue contacts and macrodipolar interactions. The amount of stabilization in small length HI-1+H2 and HI-1+H4 constructs was similar to that in the protein. The studies suggest that the partial unfolding of Ets-1 upon DNA binding can be achieved by the removal of just a few specific local contacts. PMID- 22494802 TI - Staphylococcus aureus determinants for nasal colonization. AB - Approximately 20% of the healthy human population is persistently colonized in the nasal cavity with Staphylococcus aureus, which constitutes a major risk for infection. S. aureus seems to predominantly colonize the anterior part of the nasal cavity by adhering to nasal surface structures and escaping the host innate and adaptive immune responses. Several bacterial and host factors that play a role in these processes have been identified in the past few years and were in part functionally evaluated in appropriate colonization models. However, the dynamics of host-pathogen crosstalk is only partially understood. PMID- 22494803 TI - Exploitation of evolutionarily conserved amoeba and mammalian processes by Legionella. AB - Legionella pneumophila proliferates within various protists and metazoan cells, where a cadre of ~300 effectors is injected into the host cell by the defect in organelle trafficking/intracellular multiplication (Dot/Icm) type IVB translocation system. Interkingdom horizontal gene transfer of genes of protists and their subsequent convergent evolution to become translocated effectors has probably enabled L. pneumophila to adapt to the intracellular life within various protists and metazoan cells through exploitation of evolutionarily eukaryotic processes, such as endoplasmic reticulum-to-Golgi vesicle traffic, phosphoinositol metabolism, AMPylation, deAMPylation, prenylation, polyubiquitination, proteasomal degradation and cytosolic amino- and oligo peptidases. This is highlighted by the ankyrin B (AnkB) F-box effector that exploits multiple conserved eukaryotic machineries to generate high levels of free amino acids as sources of carbon and energy essential for intracellular proliferation in protists and metazoan cells and for manifestation of pulmonary disease in mammals. PMID- 22494804 TI - Pertussis control: time for something new? AB - Childhood acellular pertussis vaccines were licensed and implemented in the US in the 1990s following an effort to improve on the safety profile of whole-cell vaccines. However, waning of immunity from acellular vaccines may be driving the recent resurgence of pertussis, raising the need to consider new prevention strategies. PMID- 22494805 TI - Stroke management in northern Lombardy: organization of an emergency-urgency network and development of a connection between prehospital and in-hospital settings. AB - Stroke is the leading cause of disability in adulthood, and the principal aim of care in cerebrovascular disease is the reduction of this negative outcome and mortality. Several studies demonstrated the efficacy of thrombolytic therapy in ischemic stroke, but up to 80% of cases could not be treated because the diagnostic workup exceeds the time limit. In this article, we described the design of a study conducted in the northern Lombardy, within the district of Sondrio, Lecco, Como, and Varese. The awaited results of this study are reduction of avoidable delay, organization of an operative stroke emergency network, and identification of highly specialized structures. The study schedules education and data registration with implementation and training of acute stroke management algorithms. The use of standardized protocols during prehospital and in-hospital phase can optimize acute stroke pathways. The results of this study could contribute to the assessment of an effective and homogeneous health system to manage acute stroke. PMID- 22494806 TI - A Pilot study of the Sharing Risk Information Tool (ShaRIT) for Families with Hereditary Breast and Ovarian Cancer Syndrome. AB - BACKGROUND: Individuals who carry deleterious BRCA mutations face significantly elevated risks of breast, ovarian, and other cancers. These individuals are also responsible for informing relatives of their increased risk for carrying the family BRCA mutation. Few interventions have been developed to facilitate this family communication process. METHODS: We developed the Sharing Risk Information Tool (ShaRIT), a personalized educational intervention, to support BRCA carriers as they discuss BRCA positive results and their implications with relatives. We conducted a pilot study of 19 BRCA carriers identified through the University of California San Francisco Cancer Risk Program. Our study had two aims: 1) to assess the feasibility and acceptability of ShaRIT, and 2) describe characteristics associated with increased family communication and BRCA testing. Participants in our study were divided into two groups: those who had not received ShaRIT as part of their genetic counseling protocol (control group, n = 10) and those who received ShaRIT (n = 9). RESULTS: All 9 women who received ShaRIT reported that it was a useful resource. Characteristics associated with increased sharing and testing included: female gender, degree of relationship, and frequency of communication. Increased pedigree knowledge showed a trend toward higher rates of sharing. CONCLUSIONS: Both participants and genetic counselors considered ShaRIT a well-received, comprehensive tool for disseminating individual risk information and clinical care guidelines to Hereditary Breast and Ovarian Cancer Syndrome families. Because of this, ShaRIT has been incorporated as standard of care at our institution. In the future we hope to evaluate the effects of ShaRIT on family communication and family testing in larger populations of BRCA positive families. PMID- 22494807 TI - Low vitamin D levels, prediabetes and prehypertension in healthy African American adults. AB - AIMS: To determine if customary lower serum vitamin D concentrations in healthy African American (AA) adults are associated with modest elevations in fasting plasma glucose (FPG) and/or resting blood pressure (BP). Numerous health disparities between African American (AA) and Caucasian American (CA) adults, especially those which increase cardiovascular morbidity and mortality, have been attributed to lower serum vitamin D concentrations in the AA. Prediabetes (PreDM) and prehypertension (PreHTN) are significantly more prevalent in healthy disease free CA adults with serum vitamin D concentrations below the 75th percentile for the Caucasian cohort. We hypothesized that despite overall lower serum vitamin D concentrations in AA, an increase in the prevalence for PreDM and PreHTN would be seen in those with low vitamin D levels. METHODS AND RESULTS: Disease free AA adults in the National Health and Nutrition Examination Survey 2001-2006 were assessed. PreDM and PreHTN were diagnosed using the ADA and JNC 7 criteria: (FPG) 100-125 mg/dL and resting systolic (SBP) 120-139 and/or diastolic (DBP) 80-89 mm Hg, respectively. Logistic regression was employed to assess effects of low vitamin D concentrations on the odds for PreDM and PreHTN (n = 621). Age, gender and BMI adjusted odds ratio for co-morbid PreDM and PreHTN in AA men (n = 343) and women (n = 278) with vitamin D levels <=45.4 versus >45.4 nmol/L was 2.02 (1.11, 3.68), (p < 0.021). CONCLUSIONS: Evaluating serum vitamin D levels, with consideration for supplementation in seemingly healthy AA adults with prediabetes, prehypertension, or co-existing prediabetes and prehypertension, has merit. PMID- 22494808 TI - Absence of an independent association between serum uric acid and left ventricular mass in Caucasian hypertensive women and men. AB - BACKGROUND AND AIM: Experimentally uric acid may induce cardiomyocyte growth and interstitial fibrosis of the heart. However, clinical studies exploring the relationship between serum uric acid (SUA) and left ventricular (LV) mass yielded conflicting results. The aim of our study was to evaluate the relationships between SUA and LV mass in a large group of Caucasian essential hypertensive subjects. METHODS AND RESULTS: We enrolled 534 hypertensive patients free of cardiovascular complications and without severe renal insufficiency. In all subjects routine blood chemistry, including SUA determination, echocardiographic examination and 24 h ambulatory blood pressure (BP) monitoring were obtained. In the overall population we observed no significant correlation of SUA with LV mass indexed for height(2.7) (LVMH(2.7)) (r = 0.074). When the same relationship was analysed separately in men and women, we found a statistically significant correlation in female gender (r = 0.27; p < 0.001), but not in males (r = -0.042; p = NS). When we grouped the study population in sex-specific tertiles of SUA, an increase in LVMH(2.7) was observed in the highest tertiles in women (44.5 +/- 15.6 vs 47.5 +/- 16 vs 55.9 +/- 22.2 g/m(2.7); p < 0.001), but not in men. The association between SUA and LVMH(2.7) in women lost statistical significance in multiple regression analyses, after adjustment for age, 24 h systolic BP, body mass index, serum creatinine and other potential confounders. CONCLUSIONS: Our findings do not support an independent association between SUA and LV mass in Caucasian men and women with arterial hypertension. PMID- 22494809 TI - Low beta-carotene concentrations increase the risk of cardiovascular disease mortality among Finnish men with risk factors. AB - BACKGROUND & AIMS: Healthy diet rich in fruits and vegetables is an important factor in prevention of cardiovascular diseases (CVD). Some previous epidemiological studies have suggested that dietary and serum carotenoids are associated with decreased CVD mortality, but the results have been inconsistent. We assessed relations between the concentrations of serum carotenoids and CVD mortality among Eastern Finnish men. METHODS & RESULTS: The study population consisted of 1031 Eastern Finnish men aged 46-65 years in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) cohort. Subjects were classified quartiles according to concentrations of carotenoids and subgroups according to risk factors. Hazard ratios of serum lycopene, alpha-carotene and beta-carotene were estimated by the Cox proportional hazard model after adjusting for potential confounding factors. During the median 15.9-year follow-up, 122 deaths from CVDs, were identified among the cohort subjects. Low serum concentrations of beta carotene were strongly related to an increased CVD mortality risk after adjustment for confounders. For beta-carotene, the hazard ratio (95% confidence interval) for the lowest versus highest quartile was 2.23 (1.26-3.93; P=0.006). However, the strongest risk of CVD mortality was observed among smokers with lowest levels of beta-carotene (HR=3.15, 95%, CI: 1.19-8.33; P=0.020). Other carotenoids and the sum of carotenoids were not significantly related to increased risk of CVD mortality. CONCLUSIONS: Low concentrations of serum beta carotene concentrations may increase the risk for CVD mortality among Eastern Finnish men; thus elevated serum concentrations of beta-carotene may have clinical and public health relevance. PMID- 22494810 TI - Correlation between high blood IL-6 level, hyperglycemia, and glucose control in septic patients. AB - INTRODUCTION: The aim of the present study was to investigate the relationship between the blood IL-6 level, the blood glucose level, and glucose control in septic patients. METHODS: This retrospective observational study in a general ICU of a university hospital included a total of 153 patients with sepsis, severe sepsis, or septic shock who were admitted to the ICU between 2005 and 2010, stayed in the ICU for 7 days or longer, and did not receive steroid therapy prior to or after ICU admission. The severity of stress hyperglycemia, status of glucose control, and correlation between those two factors in these patients were investigated using the blood IL-6 level as an index of hypercytokinemia. RESULTS: A significant positive correlation between blood IL-6 level and blood glucose level on ICU admission was observed in the overall study population (n = 153; r = 0.24, P = 0.01), and was stronger in the nondiabetic subgroup (n = 112; r = 0.42, P < 0.01). The rate of successful glucose control (blood glucose level < 150 mg/dl maintained for 6 days or longer) decreased with increase in blood IL-6 level on ICU admission (P < 0.01). The blood IL-6 level after ICU admission remained significantly higher and the 60-day survival rate was significantly lower in the failed glucose control group than in the successful glucose control group (P < 0.01 and P < 0.01, respectively). CONCLUSIONS: High blood IL-6 level was correlated with hyperglycemia and with difficulties in glucose control in septic patients. These results suggest the possibility that hypercytokinemia might be involved in the development of hyperglycemia in sepsis, and thereby might affect the success of glucose control. PMID- 22494811 TI - The value "social responsibility" as a motivating factor for adolescents' readiness to participate in different types of political actions, and its socialization in parent and peer contexts. AB - Based on a sample of tetrads (N = 839), including 16 year-old adolescents, their mothers, fathers, and same-sex friends, it was analyzed in which way the value social responsibility is related to adolescents' readiness for different types of political participation. Results showed that social responsibility was positively linked to readiness for participation in legal protest actions. No relationships with readiness for participation in federal elections or with readiness for participation in illegal protest actions occurred, and a negative relationship with readiness for participation in political violent actions was found. In a second step, the socialization of the value social responsibility in the parents and peer context was the focus. Value similarities between adolescents, their parents and friends, as well as other contextual factors were considered. Multiple regression analyses revealed differential effects for male and female adolescents. In male adolescents, authoritative parenting and political discussions with parents were positively linked to social responsibility. Furthermore, peer-group membership had a negative impact. For female adolescents, significant value similarities with their parents, especially with their mothers, occurred. Value similarities with their friend were found in both gender groups, but appeared to be higher in the female group. Also, in both gender groups, a positive parent-child relationship quality was linked to higher social responsibility. In sum, findings show that parents as well as peer contextual factors were contributing to the adolescents' value acquisition. PMID- 22494812 TI - Anti-CD45RB/anti-TIM-1-induced tolerance requires regulatory B cells. AB - The role of B cells in transplant tolerance remains unclear. Although B-cell depletion often prolongs graft survival, sometimes it results in more rapid rejection, suggesting that B cells may have regulatory activity. We previously demonstrated that tolerance induction by anti-CD45RB antibody requires recipient B cells. Here, we show that anti-CD45RB in combination with anti-TIM-1 antibody has a synergistic effect, inducing tolerance in all recipients in a mouse islet allograft model. This effect depends on the presence of recipient B cells, requires B-cell IL-10 activity, and is antigen-specific. These data suggest the existence of a regulatory B-cell population that promotes tolerance via an IL-10 dependent pathway. PMID- 22494813 TI - Preserved stimulus-reward and reversal learning after selective neonatal orbital frontal areas 11/13 or amygdala lesions in monkeys. AB - Neither lesions of orbital frontal (OFC) areas 11/13 nor selective amygdala lesions alter the ability to learn stimulus-reinforcer association and reversal discriminations in adult monkeys. Here, we investigated whether the same conclusion will hold true when the same lesions occur in infancy. Infant rhesus monkeys received sham-operations, neurotoxic amygdala lesions, or aspiration OFC 11/13 lesions at 8-15 days of age and were trained on object discrimination reversal (ODR) tasks. Performance on a single pair (1-Pair) ODR was assessed at the age of 3 months and 3 years, and then animals were tested in a 5-Pair ODR task in which they had to concurrently learn and reverse five discrimination problems. The results indicated that the ability to solve a single-pair discrimination problem followed by six reversals appears to be late maturing in monkeys but is spared following selective lesions of either OFC areas 11/13 or amygdala, even with the use of the more challenging 5-object ODR task. Finally, performance in the 1 and 5-Pair ODR at 3 years was comparable to that following adult-onset lesions, indicating that neither OFC areas 11/13 nor amygdala are critical for the development of reversal learning. PMID- 22494814 TI - De novo assembly and characterization of the root transcriptome of Aegilops variabilis during an interaction with the cereal cyst nematode. AB - BACKGROUND: Aegilops variabilis No.1 is highly resistant to cereal cyst nematode (CCN). However, a lack of genomic information has restricted studies on CCN resistance genes in Ae. variabilis and has limited genetic applications in wheat breeding. RESULTS: Using RNA-Seq technology, we generated a root transcriptome at a sequencing depth of 4.69 gigabases of Ae. variabilis No. 1 from a pooled RNA sample. The sample contained equal amounts of RNA extracted from CCN-infected and untreated control plants at three time-points. Using the Trinity method, nearly 52,081,238 high-quality trimmed reads were assembled into a non-redundant set of 118,064 unigenes with an average length of 500 bp and an N50 of 599 bp. The total assembly was 59.09 Mb of unique transcriptome sequences with average read-depth coverage of 33.25*. In BLAST searches of our database against public databases, 66.46% (78,467) of the unigenes were annotated with gene descriptions, conserved protein domains, or gene ontology terms. Functional categorization further revealed 7,408 individual unigenes and three pathways related to plant stress resistance. CONCLUSIONS: We conducted high-resolution transcriptome profiling related to root development and the response to CCN infection in Ae. variabilis No.1. This research facilitates further studies on gene discovery and on the molecular mechanisms related to CCN resistance. PMID- 22494815 TI - Cardiac Outcomes Through Digital Evaluation (CODE) STEMI project: prehospital digitally-assisted reperfusion strategies. AB - BACKGROUND: Guidelines for reperfusion in ST-elevation myocardial infarction (STEMI) were recently adopted by the Canadian Cardiovascular Society. We have developed a blended model of prehospital thrombolytic (PHL) therapy or primary percutaneous coronary intervention (PPCI) activation, in order to achieve guideline times. METHODS: In our urban centre of 658,700 people, emergency medical services (EMS) were trained to perform and screen electrocardiograms (ECGs) for suspected STEMI. Suspected ECGs were transmitted to a physician's hand held device. If the physician confirmed the diagnosis they coordinated initiation of either PHL or PPCI. In cases where physicians found the prehospital ECG negative for STEMI (PHENST), patients were transported to the closest emergency room. RESULTS: From July 21, 2008 to July 21, 2010, the Cardiac Outcomes Through Digital Evaluation (CODE) STEMI project received 380 transmitted calls. There were 226 confirmed STEMI by the on-call physician, 158 (70%) received PPCI, 48 (21%) received PHL, and 20 (9%) had angiography but no revascularization. The PPCI, median time from first medical contact to reperfusion was 76 minutes (interquartile range [IQR], 64-93). For PHL, median time from first medical contact to needle was 32 minutes (IQR, 29-39). The overall mortality rate for the STEMI patients was 8% (PHL = 4 [8.3%], PPCI = 8 [5%], medical therapy = 7 [35%]). There were 154 PHENST patients, 44% later diagnosed with acute coronary syndrome. The mortality rate for PHENST was 14%. CONCLUSIONS: Through a model of EMS prehospital ECG interpretation, digital transmission, direct communication with a physician, and rapid coordinated service, we demonstrate that benchmark reperfusion times in STEMI can be achieved. PMID- 22494816 TI - Hypovitaminosis D as a risk factor of subsequent vertebral fractures after kyphoplasty. AB - BACKGROUND CONTEXT: Over the past 20 years, methods of minimally invasive surgery have been developed for the treatment of vertebral compression fractures. Balloon kyphoplasty and vertebroplasty are associated with a recurrent fracture risk in the adjacent levels after the surgical procedure. In certain patient categories with impaired bone metabolism, the risk of subsequent fractures after kyphoplasty is increased. PURPOSE: To determine the incidence of recurrent fractures after kyphoplasty and explore whether the status of bone metabolism and 25 hydroxyvitamin D (25(OH)D) levels affect the occurrence of these fractures. STUDY DESIGN: Prospective longitudinal clinical study. PATIENT SAMPLE: Forty female postmenopausal women with primary osteoporosis and acute symptomatic vertebral compression fractures. OUTCOME MEASURES: Identification of new vertebral fractures and documentation of indicators of bone metabolism. METHODS: A total of ninety-eight kyphoplasties were performed in 40 female patients. Balloon kyphoplasty was performed on all symptomatic acute vertebral compression fractures. Age, body mass index, history of tobacco use, number of initial vertebral fractures, intradiscal cement leakage, history of nonspinal fractures, use of antiosteoporotic medications, bone mineral density, bone turnover markers, and 25(OH)D levels were assessed. All participants were evaluated clinically and/or radiographically. Follow-up period was 18 months. RESULTS: The mean population age was 70.6 years (range, 40-83 years). After initial kyphoplasty procedure, nine patients (11 levels) (22.5% of patients; 11.2% of levels) developed a postkyphoplasty vertebral compression fracture. Cement leakage was identified in seven patients (17.5%). The patients without recurrent fractures after kyphoplasty demonstrated higher levels of 25(OH)D (22.6+/-5.51 vs. 14.39+/ 7.47; p=.001) and lower N-terminal cross-linked telopeptide values (17.11+/-10.20 vs. 12.90+/-4.05; p=.067) compared with the patients with recurrent fractures. CONCLUSIONS: Bone metabolism and 25(OH)D levels seem to play a role in the occurrence of postkyphoplasty recurrent vertebral compression fractures. PMID- 22494817 TI - Making (good) use of Wolbachia: what the models say. AB - Wolbachia, probably the most common animal endosymbiont, infects a wide range of arthropods as well as filarial nematodes. Generally vertically transmitted from mothers to offspring, it has evolved various strategies, ranging from brutal male killing to mutualism, which facilitate invasion and persistence of the infections within host populations. Current interest in Wolbachia as a potential control agent against harmful nematodes and arthropods makes it important to be able to predict Wolbachia epidemiology and evolutionary trajectory. Here we highlight recent theoretical developments and suggest future modelling and empirical directions for basic and applied research in this domain. PMID- 22494818 TI - The effect of saponins from Ampelozizyphus amazonicus Ducke on the renal Na+ pumps' activities and urinary excretion of natriuretic peptides. AB - BACKGROUND: In a previous study, we showed that a saponin mixture isolated from the roots of Ampelozizyphus amazonicus Ducke (SAPAaD) reduces urine excretion in rats that were given an oral loading of 0.9 % NaCl (4 ml/100 g body weight). In the present study, we investigated whether atrial natriuretic peptides (ANP) and renal ATPases play a role in the SAPAaD- induced antidiuresis in rats. METHODS: To evaluate the effect of SAPAaD on furosemide-induced diuresis, Wistar rats (250 300 g) were given an oral loading of physiological solution (0.9 % NaCl, 4 ml/100 g body weight) to impose a uniform water and salt state. The solution containing furosemide (Furo, 13 mg/kg) was given 30 min after rats were orally treated with 50 mg/kg SAPAaD (SAPAaD + Furo) or 0.5 ml of 0.9 % NaCl (NaCl + Furo). In the SAPAaD + NaCl group, rats were pretreated with SAPAaD and 30 min later they received the oral loading of physiological solution. Animals were individually housed in metabolic cages, and urine volume was measured every 30 min throughout the experiment (3 h). To investigate the role of ANP and renal Na(+) pumps on antidiuretic effects promoted by SAPAaD, rats were given the physiological solution (as above) containing SAPAaD (50 mg/kg). After 90 min, samples of urine and blood from the last 30 min were collected. Kidneys and atria were also removed after previous anesthesia. ANP was measured by radioimmunoassay (RIA) and renal cortical activities of Na(+)- and (Na(+),K(+))-ATPases were calculated from the difference between the [32P] Pi released in the absence and presence of 1 mM furosemide/2 mM ouabain and in the absence and presence of 1 mM ouabain, respectively. RESULTS: It was observed that SAPAaD inhibited furosemide-induced diuresis (at 90 min: from 10.0 +/- 1.0 mL, NaCl + Furo group, n = 5, to 5.9 +/- 1.0 mL, SAPAaD + Furo group n = 5, p < 0.05), increased both Na(+)-ATPase (from 25.0 +/- 5.9 nmol Pi.mg(-1).min(-1), control, to 52.7 +/- 8.9 nmol Pi.mg(-1).min( 1), p < 0.05) and (Na(+),K(+))-ATPase (from 47.8 +/- 13.3 nmol Pi.mg(-1).min(-1), control, to 79.8 +/- 6.9 nmol Pi .mg(-1).min(-1), p < 0.05) activities in the renal cortex. SAPAaD also lowered urine ANP (from 792 +/- 132 pg/mL, control, to 299 +/- 88 pg/mL, p < 0.01) and had no effect on plasma or atrial ANP. CONCLUSION: We concluded that the SAPAaD antidiuretic effect may be due to an increase in the renal activities of Na(+)- and (Na(+),K(+))-ATPases and/or a decrease in the renal ANP. PMID- 22494819 TI - Medium term results of per-operative knee arthroscopy in confirming suitability for unicompartmental arthroplasty. AB - INTRODUCTION: The status of the lateral compartment of the knee is a determining factor in the long-term outcome of medial unicompartmental arthroplasty (UKA). Various methods of assessing the lateral compartment have been used including stress radiography, radioisotope bone scanning, magnetic resonance imaging and visualisation at the time of surgery. Arthroscopy is another means of directly assessing the integrity of the articular cartilage and the meniscus in the lateral compartment. PURPOSE: This study aims to show that per-operative arthroscopy is a safe and effective means of deciding whether to proceed with UKA or convert to total knee arthroplasty (TKA). METHOD: We have used arthroscopy of the lateral compartment to assess suitability for UKA in 151 knees over 8 years. RESULTS: At time of arthroscopy 34 knees underwent a change of surgical plan from UKA to TKA (22.5%). There has been one revision to TKA and 2 bearing exchanges for dislocation. CONCLUSION: Immediate per-operative arthroscopy is a reliable method for assessing the suitability of a knee for UKA, in particular the lateral compartment. PMID- 22494820 TI - Sun products: products which have particular formulation requirements. PMID- 22494821 TI - Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer. AB - BACKGROUND: Cancers often arise within an area of cells (e.g. an epithelial patch) that is predisposed to the development of cancer, i.e. a "field of cancerization" or "field defect." Sporadic colon cancer is characterized by an elevated mutation rate and genomic instability. If a field defect were deficient in DNA repair, DNA damages would tend to escape repair and give rise to carcinogenic mutations. PURPOSE: To determine whether reduced expression of DNA repair proteins Pms2, Ercc1 and Xpf (pairing partner of Ercc1) are early steps in progression to colon cancer. RESULTS: Tissue biopsies were taken during colonoscopies of 77 patients at 4 different risk levels for colon cancer, including 19 patients who had never had colonic neoplasia (who served as controls). In addition, 158 tissue samples were taken from tissues near or within colon cancers removed by resection and 16 tissue samples were taken near tubulovillous adenomas (TVAs) removed by resection. 568 triplicate tissue sections (a total of 1,704 tissue sections) from these tissue samples were evaluated by immunohistochemistry for 4 DNA repair proteins. Substantially reduced protein expression of Pms2, Ercc1 and Xpf occurred in field defects of up to 10 cm longitudinally distant from colon cancers or TVAs and within colon cancers. Expression of another DNA repair protein, Ku86, was infrequently reduced in these areas. When Pms2, Ercc1 or Xpf were reduced in protein expression, then either one or both of the other two proteins most often had reduced protein expression as well. The mean inner colon circumferences, from 32 resections, of the ascending, transverse and descending/sigmoid areas were measured as 6.6 cm, 5.8 cm and 6.3 cm, respectively. When combined with other measurements in the literature, this indicates the approximate mean number of colonic crypts in humans is 10 million. CONCLUSIONS: The substantial deficiencies in protein expression of DNA repair proteins Pms2, Ercc1 and Xpf in about 1 million crypts near cancers and TVAs suggests that the tumors arose in field defects that were deficient in DNA repair and that deficiencies in Pms2, Ercc1 and Xpf are early steps, often occurring together, in progression to colon cancer. PMID- 22494822 TI - Anthracene decomposition in soils by conventional ozonation. AB - Anthracene decomposition in solid phase by conventional ozonation was investigated employing model and real soil samples. Reaction in a two-phase system (soil-ozone) and a three-phase system (soil-water-ozone) was studied. The total anthracene decomposition in the two studied systems (sand-ozone and burned soil-ozone) was obtained at 15 and 30 min of treatment by ozone, respectively, and the efficiency of ozonation was depended on the water content in treated soil samples. The anthracene degradation in an agricultural soil (free water) was carried up slower (only 30% after 90 min of ozonation), because the real solid samples content organic matter that provokes the additionally ozone consuming. The pre-ozonation of free anthracene agricultural soil depicts the content of the organic matter fraction, which have the ozone reactivity orders as aromatic>aliphatic>polar. In all cases, the ozonation by-products were identified partiality; the majority of by-products formatted react with ozone. Actually some of them were decomposed totally, while others were accumulated. Some products identified in all systems such as anthrone, 9,10-anthraquinone and phthalic acid, are less toxic than the anthracene. PMID- 22494823 TI - Apocalypse now? PMID- 22494824 TI - Shoot excision has no effect on net flux of protons, ammonium or nitrate in seedling roots of a conifer and three crop species. AB - A high-flux region, 5mm from the root tips of seedlings of coastal Douglas-fir (Pseudotsuga menziesii), soybean (Glycine max), zucchini (Cucurbita pepo) and pea (Pisum sativum), was monitored using a microelectrode ion flux measurement system, for changes in the net fluxes of H(+), NH(4)(+) and NO(3)(-) in response to shoot removal. In all species, careful excision of the seedling shoot had no significant effect on the net fluxes of H(+), NH(4)(+) or NO(3)(-) measured 5mm from the root tip. Experiments were carried out for up to 80min after shoot removal, and no temporal interactions were noted. PMID- 22494825 TI - Bolus-dose vitamin D and prevention of childhood pneumonia. PMID- 22494826 TI - Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial. AB - BACKGROUND: Vitamin D has a role in regulating immune function, and its deficiency is a suggested risk factor for childhood pneumonia. Our aim was to assess whether oral supplementation of vitamin D(3) (cholecalciferol) will reduce the incidence and severity of pneumonia in a high-risk infant population. METHODS: We did a randomised placebo-controlled trial to compare oral 100,000 IU (2.5 mg) vitamin D(3) with placebo given to children aged 1-11 months in Kabul, Afghanistan. Randomisation was by use of a computer-generated list. Vitamin D or placebo was given by fieldworkers once every 3 months for 18 months. Children presenting at the study hospital with signs of pneumonia had their diagnosis confirmed radiographically. Our primary outcome was the first or only episode of radiologically confirmed pneumonia. Our analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00548379. FINDINGS: 1524 children were assigned to receive vitamin D(3) and 1522 placebo. There was no significant difference between the incidence of first or only pneumonia between the vitamin D (0.145 per child per year, 95% CI 0.129-0.164) and the placebo group (0.137, 0.121-0.155); the incidence rate ratio was 1.06 (95% CI 0.89-1.27). From 652 children during five separate periods of testing serum calcifediol, only one child in each of two testing periods had results greater than 375 nmol/L in the intervention group--a toxic level. INTERPRETATIONS: Quarterly bolus doses of oral vitamin D(3) supplementation to infants are not an effective intervention to reduce the incidence of pneumonia in infants in this setting. FUNDING: Wellcome Trust and British Council. PMID- 22494827 TI - Pulmonary embolism and deep vein thrombosis. AB - Pulmonary embolism is the third most common cause of death from cardiovascular disease after heart attack and stroke. Sequelae occurring after venous thromboembolism include chronic thromboembolic pulmonary hypertension and post thrombotic syndrome. Venous thromboembolism and atherothrombosis share common risk factors and the common pathophysiological characteristics of inflammation, hypercoagulability, and endothelial injury. Clinical probability assessment helps to identify patients with low clinical probability for whom the diagnosis of venous thromboembolism can be excluded solely with a negative result from a plasma D-dimer test. The diagnosis is usually confirmed with compression ultrasound showing deep vein thrombosis or with chest CT showing pulmonary embolism. Most patients with venous thromboembolism will respond to anticoagulation, which is the foundation of treatment. Patients with pulmonary embolism should undergo risk stratification to establish whether they will benefit from the addition of advanced treatment, such as thrombolysis or embolectomy. Several novel oral anticoagulant drugs are in development. These drugs, which could replace vitamin K antagonists and heparins in many patients, are prescribed in fixed doses and do not need any coagulation monitoring in the laboratory. Although rigorous clinical trials have reported the effectiveness and safety of pharmacological prevention with low, fixed doses of anticoagulant drugs, prophylaxis remains underused in patients admitted to hospital at moderate risk and high risk for venous thromboembolism. In this Seminar, we discuss pulmonary embolism and deep vein thrombosis of the legs. PMID- 22494828 TI - Dance and emotion in posterior parietal cortex: a low-frequency rTMS study. AB - BACKGROUND: The neural bases of emotion are most often studied using short non natural stimuli and assessed using correlational methods. Here we use a brain perturbation approach to make causal inferences between brain activity and emotional reaction to a long segment of dance. OBJECTIVE/HYPOTHESIS: We aimed to apply offline rTMS over the brain regions involved in subjective emotional ratings to explore whether this could change the appreciation of a dance performance. METHODS: We first used functional magnetic resonance imaging (fMRI) to identify regions correlated with fluctuating emotional rating during a 4-min dance performance, looking at both positive and negative correlation. Identified regions were further characterized using meta-data interrogation. Low-frequency repetitive TMS was applied over the most important node in a different group of participants prior to them rating the same dance performance as in the fMRI session. RESULTS: FMRI revealed a negative correlation between subjective emotional judgement and activity in the right posterior parietal cortex. This region is commonly involved in cognitive tasks and not in emotional task. Parietal rTMS had no effect on the general affective response, but it significantly (P<0.05 using exact t-statistics) enhanced the rating of the moments eliciting the highest positive judgements. CONCLUSION: These results establish a direct link between posterior parietal cortex activity and emotional reaction to dance. They can be interpreted in the framework of competition between resources allocated to emotion and resources allocated to cognitive functions. They highlight potential use of brain stimulation in neuro-aesthetic investigations. PMID- 22494830 TI - Brain stimulation and inhibitory control. AB - Inhibitory control mechanisms are important in a range of behaviours to prevent execution of motor acts which, having been planned, are no longer necessary or appropriate. Examples of this can be seen in a range of sports, such as cricket and baseball, where the choice between execution and inhibition of a bat swing must be made in a very brief time window. Deficits in inhibitory control have been associated with problems in behavioural regulation in impulsive violence as well as a range of clinical disorders. The roles of various areas, including the frontal eye fields (FEF), the pre-supplementary motor area (pre-SMA) and the inferior frontal gyrus, in inhibitory control have been investigated using an inhibitory control task and both transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Typically effects on response inhibition but no effects on response generation have been seen. The contributions of these areas to performance seem to differ with, for example, pre SMA being involved when the task is relatively novel whereas this is not the case for FEF. The findings from brain stimulation studies offer both insight into which areas are necessary for effective inhibitory control and recent extension of findings for the role of the inferior frontal gyrus illustrate how the specific functions by which these areas contribute may be further clarified. Future work, including making use of the temporal specificity of TMS and combination of TMS/tDCS with other neuroimaging techniques, may further clarify the nature and functions played by the network of areas involved in inhibitory control. PMID- 22494829 TI - Effect of continuous theta burst stimulation of the right dorsolateral prefrontal cortex on cerebral blood flow changes during decision making. AB - Decision making is a cognitive function relaying on a complex neural network. In particular, the right dorsolateral prefrontal cortex (DLPFC) plays a key role within this network. We used positron emission tomography (PET) combined with continuous theta burst transcranial magnetic stimulation (cTBS) to investigate neuronal and behavioral changes in normal volunteers while performing a delay discounting (DD) task. We aimed to test whether stimulation of right DLPFC would modify the activation pattern of the neural circuit underlying decision making during the DD task and influence discounting behavior. We found that cTBS of the right DLPFC influenced decision making by reducing impulsivity and inducing participants to favor large but delayed rewards instead of immediate but small rewards. Stimulation also affected activation in several prefrontal areas associated with DD. In particular, we observed a reduced regional cerebral blood flow (rCBF) in the ipsilateral DLPFC (BA 46) extending into the rostral part of the prefrontal cortex (BA 10) as well as a disrupted relationship between impulsivity (k-value) and rCBF in these and other prefrontal areas. These findings suggest that transcranial magnetic stimulation of the DLPFC influences the neural network underlying impulsive decision making behavior. PMID- 22494831 TI - Brain activity underlying visual perception and attention as inferred from TMS EEG: a review. AB - Probing brain functions by brain stimulation while simultaneously recording brain activity allows addressing major issues in cognitive neuroscience. We review recent studies where electroencephalography (EEG) has been combined with transcranial magnetic stimulation (TMS) in order to investigate possible neuronal substrates of visual perception and attention. TMS-EEG has been used to study both pre-stimulus brain activity patterns that affect upcoming perception, and also the stimulus-evoked and task-related inter-regional interactions within the extended visual-attentional network from which attention and perception emerge. Local processes in visual areas have been probed by directly stimulating occipital cortex while monitoring EEG activity and perception. Interactions within the attention network have been probed by concurrently stimulating frontal or parietal areas. The use of tasks manipulating implicit and explicit memory has revealed in addition a role for attentional processes in memory. Taken together, these studies helped to reveal that visual selection relies on spontaneous intrinsic activity in visual cortex prior to the incoming stimulus, their control by attention, and post-stimulus processes incorporating a re-entrant bias from frontal and parietal areas that depends on the task. PMID- 22494832 TI - Task-specific facilitation of cognition by cathodal transcranial direct current stimulation of the cerebellum. AB - A role for the cerebellum in cognition is controversial, but it is a view that is becoming increasingly popular. The aim of the current study was to investigate this issue using transcranial Direct Current Stimulation (tDCS) during two cognitive tasks that require comparable motor skills, but different levels of working memory and attention. Three groups of twenty-two participants each performed the Paced Auditory Serial Addition Task (PASAT) and a novel variant of this task called the Paced Auditory Serial Subtraction Task (PASST), together with a verb generation task and its two controls, before and after the modulation of cortico-cerebellar connectivity using anodal or cathodal tDCS over the cerebellum. Participants' performance in the difficult PASST task significantly improved after cathodal stimulation compared to sham or anodal stimulation. Improvement in the easier PASAT was equal across all three stimulation conditions. Improvement in verbal response latencies were also greatest during the PASST task after cathodal stimulation, compared to sham and anodal stimulation, and became less variable. Results for the verb generation task complimented those for the PASST, such that the rate and consistency of participants' verbal responses were facilitated by cathodal stimulation, compared to sham and anodal stimulation. These findings suggest that DC stimulation over the right cerebellum affects working memory and attention differently depending on task difficulty. They support a role for the cerebellum in cognitive aspects of behaviour, whereby activity in the prefrontal cortex is likely dis-inhibited by cathodal tDCS stimulation over the right cerebellar cortex, which normally exerts an overall inhibitory tone on the cerebral cortex. We speculate that the cerebellum is capable of releasing cognitive resources by dis-inhibition of prefrontal regions of cerebral cortex, enhancing performance when tasks become demanding. PMID- 22494834 TI - The levels of soluble ST2 in sera and bullous fluid from patients with bullous pemphigoid. AB - Soluble ST2 (sST2) is a soluble form of the transmembrane receptor for interleukin (IL)-33, ST2L, and is a member of the IL-1 receptor family. sST2 antagonizes IL-33-ST2L signaling by competing with ST2L as a decoy receptor for IL-33. We investigated the sST2 and IL-33 levels in the sera and bullous fluid of bullous pemphigoid patients and compared these with the corresponding levels in normal healthy controls. As controls, we used the bullous fluid of burn patients and that from suction blisters induced in normal healthy volunteers. The serum sST2 concentrations of bullous pemphigoid patients were higher than those of healthy controls. Serum sST2 levels correlated with the area of skin involvement and serum lactate dehydrogenase levels, suggesting that serum sST2 levels reflect disease severity. The sST2 concentrations in bullous fluid from bullous pemphigoid patients were higher than those from controls. The concentration of IL 33 ligand was below the detectable limits in all enzyme-linked immunosorbent assay samples. Thus, our study suggested that the serum sST2 level may be a useful marker of disease severity and that sST2 functions as a negative regulator in the pathophysiology of bullous pemphigoid. PMID- 22494835 TI - [Aortic arch geometry after aortic coarctation repair: systematic magnetic resonance study in a consecutive series of patients]. PMID- 22494833 TI - Gene expression analysis of Drosophilaa Manf mutants reveals perturbations in membrane traffic and major metabolic changes. AB - BACKGROUND: MANF and CDNF are evolutionarily conserved neurotrophic factors that specifically support dopaminergic neurons. To date, the receptors and signalling pathways of this novel MANF/CDNF family have remained unknown. Independent studies have showed upregulation of MANF by unfolded protein response (UPR). To enlighten the role of MANF in multicellular organism development we carried out a microarray-based analysis of the transcriptional changes induced by the loss and overexpression of Drosophila Manf. RESULTS: The most dramatic change of expression was observed with genes coding membrane transport proteins and genes related to metabolism. When evaluating in parallel the ultrastructural data and transcriptome changes of maternal/zygotic and only zygotic Manf mutants, the endoplasmic reticulum (ER) stress and membrane traffic alterations were evident. In Drosophila Manf mutants the expression of several genes involved in Parkinson's disease (PD) was altered as well. CONCLUSIONS: We conclude that besides a neurotrophic factor, Manf is an important cellular survival factor needed to overcome the UPR especially in tissues with high secretory function. In the absence of Manf, the expression of genes involved in membrane transport, particularly exocytosis and endosomal recycling pathway was altered. In neurodegenerative diseases, such as PD, correct protein folding and proteasome function as well as neurotransmitter synthesis and uptake are crucial for the survival of neurons. The degeneration of dopaminergic neurons is the hallmark for PD and our work provides a clue on the mechanisms by which the novel neurotrophic factor MANF protects these neurons. PMID- 22494836 TI - Angiotensin-converting enzyme gene single polymorphism as a genetic biomarker of diabetic peripheral neuropathy: longitudinal prospective study. AB - BACKGROUND: Identifying patients at risk of developing diabetic peripheral neuropathy (DPN) is of paramount importance in those with type 2 diabetes mellitus (T2DM) to provide and anticipate secondary prevention measures as well as intensify action on risk factors, particularly so in primary care. Noteworthy, the incidence of DPN remains unknown in our environment. AIMS: (i) To analyze a single angiotensin-converting enzyme (ACE) gene polymorphism (D/I) as a genetic marker of risk of developing DPN, and (ii) to determine the incidence of DPN in our environment. RESEARCH DESIGN AND METHODS: Longitudinal study with annual follow-up for 3years involving a group of T2DM (N=283) randomly selected. ACE gene polymorphism distribution (I=insertion; D=deletion) was determined. DPN was diagnosed using clinical and neurophysiology evaluation. RESULTS: Baseline DPN prevalence was 28.97% (95% CI, 23.65-34.20). ACE polymorphism heterozygous genotype D/I presence was 60.77% (95% CI, 55.05-66.5) and was independently associated with a decreased risk of DPN (RR, 0.51; 95% CI, 0.30-0.86). DPN correlated with age (P<0.001) but not with gender (P=0.466) or time of evolution of T2DM (P=0.555). Regarding end point, DPN prevalence was 36.4% (95% CI, 30.76 42.04), and accumulated incidence was 10.4% 3years thereafter. In the final Poisson regression analysis, the presence of heterozygous genotype remained independently associated with a decreased risk of DPN (RR, 0.71; (95% CI, 0.53 0.96). DPN presence remained correlated with age (P=0.002), but not with gender (P=0.490) or time of evolution (P=0.630). CONCLUSIONS: In our series, heterozygous ACE polymorphism (D/I) stands as a protective factor for DPN development. Accumulated incidence of DPN was relevant. Further prospective studies are warranted. PMID- 22494837 TI - Predictive value of admission blood glucose level on short-term mortality in acute cerebral ischemia. AB - BACKGROUND: Admission hyperglycemia increases the risk of death in patients with acute stroke. However, the most appropriate cut-off of glucose level indicating an increased risk of short-term mortality remains unknown. PURPOSE AND METHODS: We aimed at establishing the optimum cut-offs of several variables (including admission blood glucose levels) predicting case-fatality (72hours, 7days) and unfavorable outcome [modified Rankin Scale (mRS) score 5-6 at 7 days] in consecutive first-ever acute ischemic stroke. Receiver operating characteristic (ROC) curves were constructed. RESULTS: Eight hundred eleven consecutive patients were included [median age of 77 (69-83) years; 418 (52%) male; 239 (30%) diabetics; median admission National Institutes of Health Stroke Scale (NIHSS) 7 (4-12), 32 (4%) dead within 72hours; 64 (8%) dead within day 7; 155 (19%) with unfavorable outcome]. Median admission glucose levels were 113 (97-155)mg/dL. Diabetics had significantly higher median glucose levels than non-diabetics [163 (133-214) vs. 107 (92-123) mg/dL, p<0.001]. According to ROC analysis, the only significant predictive value of glycemia was >=143mg/dL for 72-hour fatality (sensitivity 88% and specificity 70%) especially in non-diabetics (sensitivity 88% and sensitivity 62%). This cut-off point was an independent predictor for 72 hour fatality (overall: OR=4.0, CI=1.6-9.9, p=0.003; non-diabetics: OR=4.9, CI=1.7-14.5, p=0.004). The cut-offs of fasting total cholesterol levels and admission leukocytes had poor predictive values for each outcome, while those of admission NIHSS had good discrimination in predicting short-term outcome measures. CONCLUSIONS: Admission hyperglycemia (>=143mg/dL) is a strong and an independent predictor for 72-hour fatality, especially in patients with no prior history of diabetes mellitus. PMID- 22494839 TI - Cigarette smoking among adolescents with type 1 diabetes: strategies for behavioral prevention and intervention. AB - Smoking is the leading preventable cause of death in the U.S. and preventing smoking initiation among adolescents is a public health priority and a central element of comprehensive tobacco control. While cigarette smoking is harmful to all youths, those with special healthcare needs are particularly vulnerable to the negative health consequences of smoking, and adolescents with type 1 diabetes (T1D) urgently stand out as a high-risk group. Available literature suggests the prevalence and risk factors for smoking among adolescents with T1D are strikingly similar to the general population. Moreover, smoking negatively affects T1D management and increases risk for and progression of adverse health outcomes related to T1D. Adolescents with T1D are also influenced by disease-related social and behavioral factors that affect decisions about smoking. Pediatric health care providers (HCPs) are optimally-positioned to screen and counsel adolescents with T1D to avoid smoking, as they have well-established relationships with young patients and regularly scheduled visits surrounding T1D management. However, several barriers inhibit HCPs from screening/counseling adolescents with T1D for smoking on a regular basis. Well-established strategies for behavioral counseling for smoking in the healthcare setting may be effective to prevent and reduce smoking among adolescents with T1D. HCPs who care for these young patients can tailor proven counseling approaches to the context of T1D to address smoking alongside other behavioral factors that are central to disease management. Empirical research is also needed to inform the development and deployment of healthcare-based interventions and maximize their impact within this population. PMID- 22494840 TI - AdVance sling in postprostatectomy urinary incontinence: more data available and some questions still open. PMID- 22494841 TI - New saccharin derivatives as tyrosinase inhibitors. AB - A newly series of 6-(phenylurenyl/thiourenyl) saccharin (6a-y) derivatives were synthesized and their inhibitory effects on the diphenolase activity of banana tyrosinase were evaluated. A 70-fold purification of the enzyme with 6.85% yield was achieved by using a Sepharose 4B-l-tyrosine-p-amino benzoic acid affinity column. The result showed that all the synthesized compounds inhibited the tyrosinase enzyme activity. Among the compounds synthesized, 6-(3 iodophenylthiourenyl) saccharin (6s) was found to be most active one (K(i)=3.95 MUM) and the inhibition kinetics analyzed by Lineweaver-Burk double reciprocal plots revealed that compound 6s was a competitive inhibitor. Structure-activity relationships study showed that generally, most of the 6-(phenylthiourenyl) saccharin derivatives (6m-y) exhibited higher inhibitory activity than 6 (phenylurenyl) saccharin derivatives (6a-l). An electron-withdrawing group at 3 position of phenylurenyl-ring increased in activity and the halogen series at 3 position of phenylthiourenyl-ring showed a qualitative relationship for higher inhibitory activity with increasing size and polarizability. We also calculated HOMO-LUMO energy levels and dipole moments of some selected the synthesized compounds (6a, 6h, 6m and 6s) using Gaussian software. PMID- 22494842 TI - The design and synthesis of potent, selective benzodiazepine sulfonamide bombesin receptor subtype 3 (BRS-3) agonists with an increased barrier of atropisomerization. AB - Bombesin receptor subtype 3 (BRS-3) is an orphan G-protein coupled receptor expressed primarily in the hypothalamus which plays a role in the onset of both diabetes and obesity. We report herein our progress made towards identifying a potent, selective bombesin receptor subtype-3 (BRS-3) agonist related to the previously described MK-7725(1) Chobanian et al. (2012) that would prevent atropisomerization through the increase of steric bulk at the C-2 position. This would thereby make clinical development of this class of compounds more cost effective by inhibiting racemization which can occur over long periods of time at room/elevated temperature. PMID- 22494843 TI - Synthesis and fungicidal activity of tubulin polymerisation promoters. Part 2: pyridazines. AB - Special tetrasubstituted pyridazines are potent fungicides by promoting the tubulin polymerisation, hereby disrupting the microtubule dynamics in the fungus. They are monocyclic analogs of similar substituted triazolopyrimidines and pyridopyrazines with the same mode of action. The fungicidal activity of these pyridazines was evaluated against the plant pathogens Botrytis cinerea (grey mould), Mycosphaerella graminicola (wheat leaf blotch) and Alternaria solani (potato and tomato early blight). Structure-activity relationship studies revealed the importance of a methyl and a chlorine substituent next to both ring nitrogen atoms and two aryl or heteroaryl groups in the other two pyridazine positions. PMID- 22494844 TI - Design and synthesis of 4-O-methylhonokiol analogs as inhibitors of cyclooxygenase-2 (COX-2) and PGF1 production. AB - A series of novel 4-O-methylhonokiol analogs were synthesized in light of revealing structure-activity relationship for inhibitory effect of COX-2 enzyme. The key strategy of the molecular design was oriented towards modification of the potential metabolic soft spots (e.g., phenol and olefin) or by altering the polar surface area via incorporating heterocycles such as isoxazole and triazole. Most of all exhibited the inhibitory effects on COX-2 and PGF(1) production but not macrophage NO production. Especially, aryl carbamates 10 and 11 exhibited more potent inhibitory activity against COX-2 and PGF(1) production. PMID- 22494845 TI - Antidepressant-like effects of methanol extract of Hibiscus tiliaceus flowers in mice. AB - BACKGROUND: Hibiscus tiliaceus L. (Malvaceae) is used in postpartum disorders. Our purpose was to examine the antidepressant, anxiolytic and sedative actions of the methanol extract of H. tiliaceus flowers using animal models. METHODS: Adult male Swiss albino mice were treated with saline, standard drugs or methanol extract of H. tiliaceus and then subjected to behavioral tests. The forced swimming and tail suspension tests were used as predictive animal models of antidepressant activity, where the time of immobility was considered. The animals were submitted to the elevated plus-maze and ketamine-induced sleeping time to assess anxiolytic and sedative activities, respectively. RESULTS: Methanol extract of H. tiliaceus significantly decreased the duration of immobility in both animal models of antidepressant activity, forced swimming and tail suspension tests. This extract did not potentiate the effect of ketamine-induced hypnosis, as determined by the time to onset and duration of sleeping time. CONCLUSION: Our results indicate an antidepressant-like profile of action for the extract of Hibiscus tiliaceus without sedative side effect. PMID- 22494846 TI - In vitro effects of fetal rat cerebrospinal fluid on viability and neuronal differentiation of PC12 cells. AB - BACKGROUND: Fetal cerebrospinal fluid (CSF) contains many neurotrophic and growth factors and has been shown to be capable of supporting viability, proliferation and differentiation of primary cortical progenitor cells. Rat pheochromocytoma PC12 cells have been widely used as an in vitro model of neuronal differentiation since they differentiate into sympathetic neuron-like cells in response to growth factors. This study aimed to establish whether PC12 cells were responsive to fetal CSF and therefore whether they might be used to investigate CSF physiology in a stable cell line lacking the time-specific response patterns of primary cells previously described. METHODS: In vitro assays of viability, proliferation and differentiation were carried out after incubation of PC12 cells in media with and without addition of fetal rat CSF. An MTT tetrazolium assay was used to assess cell viability and/or cell proliferation. Expression of neural differentiation markers (MAP-2 and beta-III tubulin) was determined by immunocytochemistry. Formation and growth of neurites was measured by image analysis. RESULTS: PC12 cells differentiate into neuronal cell types when exposed to bFGF. Viability and cell proliferation of PC12 cells cultured in CSF supplemented medium from E18 rat fetuses were significantly elevated relative to the control group. Neuronal-like outgrowths from cells appeared following the application of bFGF or CSF from E17 and E19 fetuses but not E18 or E20 CSF. Beta III tubulin was expressed in PC12 cells cultured in any media except that supplemented with E18 CSF. MAP-2 expression was found in control cultures and in those with E17 and E19 CSF. MAP2 was located in neurites except in E17 CSF when the whole cell was positive. CONCLUSIONS: Fetal rat CSF supports viability and stimulates proliferation and neurogenic differentiation of PC12 cells in an age dependent way, suggesting that CSF composition changes with age. This feature may be important in vivo for the promotion of normal brain development. There were significant differences in the effects on PC12 cells compared to primary cortical cells. This suggests there is an interaction in vivo between developmental stage of cells and the composition of CSF. The data presented here support an important, perhaps driving role for CSF composition, specifically neurotrophic factors, in neuronal survival, proliferation and differentiation. The effects of CSF on PC12 cells can thus be used to further investigate the role of CSF in driving development without the confounding issues of using primary cells. PMID- 22494848 TI - Vapor phase mediated cellular uptake of sub 5 nm nanoparticles. AB - Nanoparticles became an important and wide-used tool for cell imaging because of their unique optical properties. Although the potential of nanoparticles (NPs) in biology is promising, a number of questions concerning the safety of nanomaterials and the risk/benefit ratio of their usage are open. Here, we have shown that nanoparticles produced from silicon carbide (NPs) dispersed in colloidal suspensions are able to penetrate into surrounding air environment during the natural evaporation of the colloids and label biological cells via vapor phase. Natural gradual size-tuning of NPs in dependence to the distance from the NP liquid source allows progressive shift of the fluorescence color of labeled cells in the blue region according to the increase of the distance from the NP suspension. This effect may be used for the soft vapor labeling of biological cells with the possibility of controlling the color of fluorescence. However, scientists dealing with the colloidal NPs have to seriously consider such a NP's natural transfer in order to protect their own health as well as to avoid any contamination of the control samples. PMID- 22494847 TI - DNA methylation signatures for breast cancer classification and prognosis. AB - Changes in gene expression that reset a cell program from a normal to a diseased state involve multiple genetic circuitries, creating a characteristic signature of gene expression that defines the cell's unique identity. Such signatures have been demonstrated to classify subtypes of breast cancers. Because DNA methylation is critical in programming gene expression, a change in methylation from a normal to diseased state should be similarly reflected in a signature of DNA methylation that involves multiple gene pathways. Whole-genome approaches have recently been used with different levels of success to delineate breast-cancer-specific DNA methylation signatures, and to test whether they can classify breast cancer and whether they could be associated with specific clinical outcomes. Recent work suggests that DNA methylation signatures will extend our ability to classify breast cancer and predict outcome beyond what is currently possible. DNA methylation is a robust biomarker, vastly more stable than RNA or proteins, and is therefore a promising target for the development of new approaches for diagnosis and prognosis of breast cancer and other diseases. Here, I review the scientific basis for using DNA methylation signatures in breast cancer classification and prognosis. I discuss the role of DNA methylation in normal gene regulation, the aberrations in DNA methylation in cancer, and candidate-gene and whole-genome approaches to classify breast cancer subtypes using DNA methylation markers. PMID- 22494849 TI - Sequence of busulfan-induced neural progenitor cell damage in the fetal rat brain. AB - The sequence of neural progenitor cell (NPC) damage induced in fetal rat brain by transplacental exposure to busulfan, an antineoplastic bifunctional-alkylating agent, on gestational day 13 was examined by immunohistochemical and real-time RT PCR analyses. Following busulfan treatment, pyknotic NPCs first appeared in the medial layer and then extended to the dorsal layer of the ventricular zone (VZ) of the telencephalon. Pyknotic NPCs that were immunohistochemically positive for cleaved caspase-3, i.e. apoptotic NPCs, began to increase at 24 h after treatment, peaked at 48 h, and returned to the control levels at 96 h. On the other hand, the index (%) of phospho-histone H3-positive NPCs, i.e. mitotic NPCs, and that of BrdU-positive NPCs, i.e. S-phase cells, decreased in accordance with the increase in the index of apoptotic NPCs. Prior to the peak time of apoptotic NPCs, the indices of p53- and p21-positive NPCs peaked at 36 h. In addition, the expression levels of p21 and Puma (p53-target genes) mRNAs were elevated in real time RT-PCR analysis. These findings indicated that busulfan not only induced apoptosis through the p53-mediated intrinsic pathway but also inhibited cell proliferation in NPCs, resulting in a reduction of the width of the telencephalon. On the other hand, in spite of up-regulation of p21 expression, the expression of cyclin D1, part of the cell cycle machinery of the G1/S transition, and the expression levels of Cdc20 and cyclin B1 which are involved in G2/M transition, showed no changes, giving no possible information of busulfan induced cell cycle arrest in NPCs. PMID- 22494850 TI - A national interactive web-based physical activity intervention in women, evaluation of the american heart association choose to move program 2006-2007. AB - Increased physical activity (PA) is associated with improvement of cardiac risk factors and prevention of cardiovascular disease, yet many women remain sedentary. With rising Internet use, Web-based interventions provide an alternative to improve PA, but their effectiveness for change in PA and quality of life (QOL) in a real-world setting is unknown. Participants were United States women >=18 years old who received 12 weekly PA modules and completed surveys on PA, QOL, and readiness for PA at registration (registration cohort, n = 3,796) or registration and 12 weeks (evaluation cohort, n = 892). QOL was assessed with a modified Short Form-36 with subscores for energy and well-being. Participants showed significant (p <0.001) favorable changes in PA (baseline, median 240 kcal/week, interquartile range 62 to 667; 12 weeks, 343 kcal/week, 131 to 828), stage of readiness for PA, and body mass index (baseline, 29.3 kg/m(2), 24.9 to 34.7; 12 weeks, 28.9 kg/m(2), 24.6 to 34.2). Significant improvements (p <0.0001) were also found in composite scores for energy and well-being. Compliance with PA guideline recommendations increased from 15.8% to 21.4%. Program weeks completed (p = 0.03), energy (p = 0.04), and well-being (p = 0.002) were significantly associated with achieving guideline compliance. In women reporting no PA at baseline (n = 88), program participation resulted in 54.6% achieving some PA and another 9.1% achieving total compliance with recommendations. In conclusion, in this national cohort of women, a 12-week Web-based intervention improved PA and QOL measurements, resulting in higher short-term PA guideline compliance and better QOL. Increasing use of this simple Web-based tool could improve PA and promote disease prevention. PMID- 22494851 TI - Bloodstream infections caused by Stenotrophomonas maltophilia: a seven-year review. AB - BACKGROUND: Stenotrophomonas maltophilia is a significant nosocomial pathogen, responsible for an increasing number of infections, particularly in immunocompromised patients. AIM: This study describes the clinical and microbiological characteristics of patients with Stenotrophomonas maltophilia bacteraemia. METHODS: We reviewed the charts of 102 patients with Stenotrophomonas maltophilia bacteraemia over a seven-year period from 2001 to 2007 in two tertiary care centres in New York, USA. FINDINGS: There were 79 episodes (77.5%) related to nosocomial acquisition, 21 (20.6%) were healthcare associated and two episodes (2%) were community-acquired. The most common source of bacteraemia was an infected central catheter in 44 patients (43.1%); 17 (16.6%) were related to neutropenic sepsis; nine (8.8%) were from an abdominal source; six (5.9%) were from a respiratory source, and the source of the bacteraemia was unclear in 26 cases (25.5%). The majority (94.1%) of the patients had central venous access devices. Intensive care unit stay, intubation, septic shock, neutropenia at the time of bacteraemia or carbapenem antibiotic use within 30 days of the episode were associated with mortality according to univariate analysis. By multivariate analysis, hypotensive shock and carbapenem use within 30 days of the episode were factors significantly correlated with mortality. The 102 isolates were mostly susceptible in vitro to trimethoprim-sulfamethoxazole (97.1%), levofloxacin (92.9%), ceftazidime (53.0%) and ticarcillin-clavulanic acid (49.2%). CONCLUSION: Our data describe the characteristics of patients with Stenotrophomonas maltophilia bacteraemia and emphasize the importance of careful evaluation of vascular access devices in those patients. PMID- 22494852 TI - Mental retrieval of treatment context in dental phobia. AB - BACKGROUND: The effect of mental retrieval of an exposure session was investigated during a follow-up examination in dental phobia patients. METHOD: The exposure session took place at the psychology unit and the follow-up a week later at the dental clinic prior to dental treatment while patients were seated in the dental chair. During exposure, individuals with dental phobia (N = 72) were shown a video of a dental appointment, after which they were instructed to imagine themselves receiving dental treatment. During follow-up half of the participants received instructions to mentally retrieve the exposure session and the other half were asked to recall everyday activities. Before and after exposure treatment, and after mental retrieval, participants were shown three dental instruments while heart rate (HR) and avoidance and subjective units of discomfort (SUD) were recorded. RESULTS: Questionnaires of phobic anxiety administered before and after treatment indicated significant improvement. Mental retrieval of treatment was moderately superior to the control condition with regard to avoidance. Over 80% of patients underwent the subsequent dental treatment session. Those not adhering showed initially more dysfunctional cognitions and more desire for control. CONCLUSION: There is some evidence that retrieval of treatment context may have a moderately beneficial effect on avoidance. PMID- 22494853 TI - The role of large marine vertebrates in the assessment of the quality of pelagic marine ecosystems. AB - The Marine Strategy Framework Directive (MSFD) establishing a framework for community action in the field of marine environmental policy has been developed and is being implemented, with the objective to deliver "Good Environmental Status" by 2020. A pragmatic way forward has been achieved through the development of 11 "qualitative descriptors". In an attempt to identify gaps in MSFD, regarding the data on large marine vertebrates, the SETAC--Italian Branch organised a workshop in Siena (IT). Particular attention was paid to the qualitative descriptors 8 (contaminants and pollution effects) and 10 (marine litter). The specific remit was to discuss the potential use of large marine vertebrates (from large pelagic fish, sea turtles, sea birds and cetaceans) in determining the environmental status of pelagic marine ecosystems. During the workshop it emerged that large pelagic fish may be especially useful for monitoring short- to medium-term changes in pelagic ecosystems, while cetaceans provided a more integrated view over the long-term. A theme that strongly emerged was the broad recognition that biomarkers offer real potential for the determination of good ecological status detecting the "undesirable biological effects" (indicator for descriptor 8). PMID- 22494854 TI - Cortical rigidity of round cells in mitotic phase and suspended state. AB - This paper describes the results of the analysis of cortical rigidity in two round cell states: mitotic round cells and detached round cells after trypsinization using atomic force microscopy (AFM). These two states are primary cell events with dynamic morphological alterations in vitro. The trypsinized detached cells were fixed on the substrate of membrane anchoring oleyl surface. Fluorescent images taken by confocal laser scanning microscopy revealed diverse cell surface protrusions and cortical actin development in the round cells under different conditions. Although the cortical actin of these cells seemed to develop similarly, cortical rigidity of the trypsinized round cells showed greater stiffness than that of mitotic round cells. The elasticity measurements by AFM may detect invisible information about the maturation or strength of F actin structures and such measurements may indicate that the strength of the actomyosin cortex would be higher in trypsinized round cells compared to mitotic cells. The mechanical properties can help provide better insights into the characteristics of the actin cytoskeleton network in vicinity of cell surface during dynamic morphological alterations. PMID- 22494855 TI - Guided ordering: clinician interactions with complex order-sets. AB - BACKGROUND: Electronic order-sets increasingly ask clinicians to answer questions or follow algorithms. Cooperation with such requests has not been studied. SETTING: Internal Medicine service of an academic medical center. OBJECTIVE: We studied the accuracy of clinician responses to questions embedded in electronic admission and discharge order-sets. Embedded questions asked whether any of three "core" diagnoses was present; a response was required to submit orders. Endorsement of any diagnosis made available best-practice ordering screens for that diagnosis. DESIGN: Three reviewers examined 180 electronic records (8% of discharges), drawn equally (for each core diagnosis) from possible combinations of Yes/No responses on admission and discharge. In addition to noting responses, we identified whether the core diagnosis was coded, determined from notes whether the admitting clinician believed that diagnosis present, and sought clinical evidence of disease on admission. We also surveyed participating clinicians anonymously about practices in answering embedded questions. MEASUREMENTS: We measured occurrence of six admission and five discharge scenarios relating medical record evidence of disease to clinician responses about its presence. RESULTS: The commonest discordant pattern between response and evidence was a negative response to disease presence on admission despite both early clinical evidence and documentation. Survey of study clinicians found that 75% endorsed some intentional inaccuracy; the commonest reason given was that questions were sometimes irrelevant to the clinical situation at the point asked. CONCLUSION: Through faults in order-set design, limitations of software, and/or because of an inherent tendency to resist directed behavior, clinicians may often ignore questions embedded in order-sets. PMID- 22494856 TI - Recurrence rates and patient assessed outcomes of 0.5% 5-fluorouracil in combination with salicylic acid treating actinic keratoses. AB - BACKGROUND: Actinic keratoses (AK) have been classified as early in situ squamous cell carcinomas and should be treated. OBJECTIVES: To evaluate the clinical benefit of 5-fluorouracil 0.5%/salicylic acid 10.0% (5-FU/SA) versus 3% diclofenac/hyaluronic acid (HA) for the treatment of AK and report patients' assessments of efficacy, tolerability and practicability. METHODS: Randomised, placebo-controlled, double-blind, parallel-group, multicentre trial. Patients received topical 0.5% 5-FU/SA once daily, its vehicle or diclofenac/HA twice daily for maximum of 12 weeks. Lesion recurrence rates were evaluated at 6 and 12 months after end of treatment (EOT). Patients' assessments were evaluated at 6 weeks, EOT, post-treatment (PT) visit, 6 and 12 months. RESULTS: At 12 months 85.8% of lesions did not recur in the 5-FU/SA group compared to 79.8% (p=0.04419) in the vehicle and 81.0% (p=0.02476) in the diclofenac/HA groups. At PT visit 93.2% patients (n=163/175) in the 5-FU/SA group rated clinical improvement as "very good" or "good" compared to vehicle (66.7%, n=62/93, p<0.0001) and diclofenac/HA (81.6%, n=142/174, p<0.0001). Local side effects (inflammation and burning) were more common with 0.5% FU/SA but in general did not lead to discontinuation of therapy. Overall, patients were satisfied with the therapy. At 12 months, there were no differences in practicability and handling between treatments. CONCLUSIONS: Topical 0.5% 5-FU/SA demonstrated superior sustained clinical efficacy versus diclofenac/HA with acceptable tolerability. Patient satisfaction was high. PMID- 22494858 TI - Ethnic/racial differences in circulating markers of angiogenesis and their association with cardiovascular risk factors and cardiovascular disease. AB - OBJECTIVE: To determine (a) whether ethnic/racial differences exist in circulating markers of angiogenesis (Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang 2), soluble Tie-2 receptor (sTie-2) and Angiogenin) between South Asian (SA; from India, Pakistan and Bangladesh); Black African-Caribbean and White (W) ethnic groups, and (b) associations between these markers in stable cardiovascular disease (CVD) and its risk factors. PATIENTS AND METHODS: We recruited 243 subjects (82 SA, 84 Black and 77 W) with symptomatic and clinically confirmed CVD (n=108), risk factor controls (with >= 1 cardiovascular risk factor, e.g. smoking, diabetes mellitus, dyslipidaemia, hypertension) and with ankle brachial pressure index >1) (n=64) and healthy controls free of CVD and risk factors (n=56). Angiogenic markers were measured by enzyme linked immunoassay. RESULTS: In healthy controls, angiogenin was higher in SA and Black subjects, compared to Whites (p<0.05). sTie-2 correlated inversely with angiogenin (p=0.001), was higher in women (p=0.029) and was lower in smokers (p=0.007). Overall, age (p=0.001) was the only independent factor associated with angiopoietin-1. Angiogenin (p=0.01) and SBP (p=0.014) were both independently higher in the Black group compared to the White group. CONCLUSIONS: Ethnic, racial, and demographic differences are evident in certain circulating markers of angiogenesis. With the exception of an effect of smoking on sTie-2, these differences are not influenced by the presence of other risk factors, nor the presence of stable cardiovascular disease. PMID- 22494859 TI - Residual aortic regurgitation is a major determinant of late mortality after transcatheter aortic valve implantation. PMID- 22494857 TI - Drug repositioning for personalized medicine. AB - Human diseases can be caused by complex mechanisms involving aberrations in numerous proteins and pathways. With recent advances in genomics, elucidating the molecular basis of disease on a personalized level has become an attainable goal. In many cases, relevant molecular targets will be identified for which approved drugs already exist, and the potential repositioning of these drugs to a new indication can be investigated. Repositioning is an accelerated route for drug discovery because existing drugs have established clinical and pharmacokinetic data. Personalized medicine and repositioning both aim to improve the productivity of current drug discovery pipelines, which expend enormous time and cost to develop new drugs, only to have them fail in clinical trials because of lack of efficacy or toxicity. Here, we discuss the current state of research in these two fields, focusing on recent large-scale efforts to systematically find repositioning candidates and elucidate individual disease mechanisms in cancer. We also discuss scenarios in which personalized drug repositioning could be particularly rewarding, such as for diseases that are rare or have specific mutations, as well as current challenges in this field. With an increasing number of drugs being approved for rare cancer subtypes, personalized medicine and repositioning approaches are poised to significantly alter the way we diagnose diseases, infer treatments and develop new drugs. PMID- 22494860 TI - Adequacy of antithrombotic therapy and gender differences in hypertensive patients with atrial fibrillation. PMID- 22494861 TI - Periprocedural myocardial infarction is not associated with an increased risk of long-term cardiac mortality after coronary bifurcation stenting. AB - BACKGROUND: Debate continues over the importance of periprocedural myocardial infarction (PMI) after percutaneous coronary intervention (PCI). We evaluated the prognostic significance of PMI in patients undergoing PCI for bifurcation lesions. METHODS: Between January 2004 and June 2006, patients from 16 centers who received non-left main bifurcation lesion PCIs were enrolled. PMI was defined as a peak creatine kinase-myocardial band (CK-MB) >= 3 times the upper limit of normal after PCI. We compared long-term cardiac mortality between patients with and without PMI. RESULTS: Among the 1188 patients, PMI occurred in 119 (10.0%). Left ventricular ejection fraction<50% (adjusted hazard ratio [HR]: 2.08, 95% confidence interval [CI]: 1.13-3.82, p=0.018), multi-vessel coronary artery disease (adjusted HR: 2.28, 95% CI: 1.36-3.81, p=0.002), and PCI-related acute closure in a side branch (adjusted HR: 3.34, 95% CI: 1.23-9.02, p=0.018) were the significant risk factors for PMI. During the median follow-up of 22.7 months, the unadjusted rate of long-term cardiac mortality was significantly higher in patients with PMI than in those without PMI (2.5% vs. 0.7%, p=0.026). After multivariable adjustment, the relationship between PMI and short-term (<= 30 day) cardiac mortality was significant (adjusted HR: 12.32, 95% CI: 1.07-141.37, p=0.044). However, PMI was not an independent prognostic factor of long-term cardiac mortality (adjusted HR: 2.59, 95% CI: 0.62-10.85, p=0.20). CONCLUSIONS: PMI occurs in patients with a higher prevalence of adverse cardiac risks and predicts short-term but not long-term cardiac mortality in patients undergoing bifurcation lesion PCI. PMID- 22494862 TI - Stress-induced takotsubo cardiomyopathy complicated with wall rupture and thrombus formation. PMID- 22494863 TI - Novel oral anticoagulants versus warfarin in non-valvular atrial fibrillation: a meta-analysis of 50,578 patients. AB - BACKGROUND: Warfarin, despite its known limitations, is the reference standard treatment for patients with AF and risk factors for stroke. We performed a meta analysis of phase III trials that compare novel oral anticoagulants (NOACs) with warfarin to determine whether they improve clinical outcomes of patients with non valvular atrial fibrillation (AF). METHODS: Three randomized trials that compared NOACs with warfarin in AF were selected. The primary efficacy endpoint was the incidence of stroke or systemic embolism. The primary safety endpoint was the incidence of major bleeding. RESULTS: A total of 50578 patients were included. NOACs significantly decreased stroke or systemic embolism (2.8% vs 3.5%, odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74-0.91, P<0.001), death (6.0% vs 6.3%, OR 0.88, 95% CI 0.82-0.95, P=0.001) and stroke (2.4% vs 3.0%, OR 0.79, 95% CI 0.71-0.88, P<0.001). The reduction in stroke was mainly driven by fewer hemorrhagic strokes (0.3% vs 0.8%, OR 0.79, 95% CI 0.71-0.88, P<0.001). Major bleeding occurred in 5.0% and 5.6% of patients in the NOACs and warfarin groups (OR 0.85, 95% CI 0.69-1.05, P=0.14 in the random-effects model). NOACs were associated with lower rates of intracranial bleeding (0.6% vs 1.3%, P<0.001) and higher rates of gastrointestinal bleeding (2.3% vs 1.3%, P=0.036). CONCLUSIONS: In patients with non-valvular AF, NOACs decrease stroke or systemic embolism, hemorrhagic stroke and mortality, with similar risk of major bleeding compared to warfarin. PMID- 22494864 TI - Moderate dietary weight loss reduces myocardial steatosis in obese and overweight women. AB - BACKGROUND: Excessive myocardial triglyceride (MTG) content in obesity and type 2 diabetes is associated with impaired cardiac function. Previous studies suggest that MTG could be mobilized through lifestyle interventions. We assessed influences of moderate dietary weight loss in non diabetic obese and overweight women on MTG content and cardiac function. METHODS: We selected a subgroup of 38 women from the B-SMART study population. The B-SMART study compared weight loss and associated metabolic and cardiovascular markers with reduced-carbohydrate and reduced-fat hypocaloric diets. Selected subjects had completed a cardiac magnetic resonance (MR) scan including imaging and proton spectroscopy to assess cardiac structure and function as well as MTG content. RESULTS: An average weight reduction of 5.4 +/- 4.3 kg at six months was associated with a relative decrease of MTG of 25% (from 0.72 +/- 0.29% at baseline to 0.54 +/- 0.23% at follow-up, p<0.001). The response was similar with carbohydrate and fat restriction. Diastolic function expressed as ratio of peak filling rate in E- and A-Phase (PFRE/PFRA) was unchanged. Reductions of left atrial size (from 21.9 +/- 4.0 cm(2) to 20.0 +/- 3.7 cm(2), p=0.002), the normalized ratio of PFRE and early diastolic lengthening velocity PLV (from 8.2 +/- 2.6 to 7.5 +/- 2.5, p<0.001) and fat free mass (from 55.1 +/- 6.9 kg to 52.7 +/- 6.5 kg, p=0.007) reflected altered cardiac volume loading after diet, but did not correlate to MTG content. CONCLUSIONS: Moderate dietary weight loss significantly reduced MTG content in women with uncomplicated overweight or obesity. Macronutrient composition of the diet did not significantly affect the extent of MTG reduction. PMID- 22494865 TI - Comparable effects of pioglitazone and perindopril on circulating endothelial progenitor cells, inflammatory process and oxidative stress in patients with diabetes mellitus. PMID- 22494866 TI - Postconditioning during coronary angioplasty in acute myocardial infarction: the POST-AMI trial. AB - BACKGROUND: Postconditioning (PC) has been suggested to reduce myocardial damage during primary percutaneous coronary intervention (PPCI), nevertheless clinical experience is limited. We aimed to explore the cardioprotective effect of PC using cardiac magnetic resonance (CMR) in ST-elevation myocardial infarction (STEMI) patients treated by PPCI. METHODS: A total of 78 patients with first STEMI (aged 59+/-12 years) referred for PPCI, were stratified for STEMI location and randomly assigned to conventional PPCI or PPCI with PC. All patients, with occluded infarct related artery and no collateral circulation, received abciximab intravenously before PPCI. After reperfusion by effective direct stenting, control subjects underwent no further intervention, while in treated patients PC was performed within 1 min of reflow by 4 cycles of 1-minute inflation and 1 minute deflation of the angioplasty balloon. Primary end-point was infarct size (IS) reduction, expressed as percentage of left ventricle mass assessed by delayed enhancement on CMR at 30+/-10 days after index PPCI. RESULTS: All baseline characteristics but diabetes (p=0.06) were balanced between groups. Postconditioning patients trended toward a larger IS compared to those treated by standard PPCI (20+/-12% vs 14+/-10%, p=0.054). After exclusion of diabetics, PC group still showed a trend to larger IS (p=0.116). Major adverse events seem to be more frequent in PC group irrespective to diabetic status (p=0.053 and p=0.080, respectively). CONCLUSIONS: This prospective, randomized trial suggests that PC did not have the expected cardioprotective effect and on the contrary it might harm STEMI patients treated by PPCI plus abciximab. (Clinical Trial Registration-unique identifier: NCT01004289). PMID- 22494867 TI - Plasma active matrix metalloproteinase 9 and indices of diastolic function in patients with preserved systolic function. AB - BACKGROUND: This study aimed to investigate whether the endogenous active levels of MMP-9 or tissue inhibitor of metalloproteinases-1 (TIMP-1) were related to indices of diastolic dysfunction (DD) in the setting of contemporary treatment of coronary artery disease (CAD). METHODS AND RESULTS: We prospectively studied 116 patients with CAD and preserved left ventricular LV systolic function (ejection fraction >= 45%). All patients were free of heart failure symptoms at recruitment and underwent percutaneous intervention (PCI) of culprit lesions. Demographic and angiographic characteristics were collected. Plasma samples were analysed for the active form of MMP-9 and TIMP-1 using enzyme-linked immunosorbent assay-based isoform sensitive assays. Conventional and tissue Doppler-echocardiographic assessment of diastolic filling was undertaken with measurements of maximal early (E) and late (A) transmitral velocities in diastole, E/A ratio, E-wave deceleration time, isovolumic relaxation time, peak systolic (S), diastolic (D) and atrial reversal velocities of pulmonary venous flow, S/D fraction, time difference between A and duration of atrial reversal flow, early diastolic peak velocities of the lateral mitral annulus (E') and E/E'. Active MMP-9 level was higher in patients with more severe phases of DD (normal [n=22]: median 0.57 ng/ml; mild [n=19] 0.83 ng/ml; mild-moderate [n=41] 0.64 ng/ml; moderate or severe [n=34] 1.63 ng/ml; p<0.0001 for trend). Three month post-PCI elevated levels of active MMP-9 had an adjusted odds ratio of 11.2 (2.3-56.0, p<0.004) for association with moderate or severe DD. CONCLUSION: Elevated active MMP-9 level is associated with more severe DD in patients with CAD and preserved systolic function, which may indicate abnormal extracellular matrix metabolism in myocardial ischaemia. PMID- 22494868 TI - Incremental prognostic value of cardiopulmonary exercise testing and resting haemodynamics in pulmonary arterial hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal disease despite recent treatment advances. Individual risk stratification is important. Exercise capacity and invasive haemodynamic data are both relevant, but data on the combined prognostic power are lacking. METHODS: 226 consecutive patients with idiopathic or familial PAH were included at seven specialised tertiary centres. All patients underwent right heart catheterization and cardiopulmonary exercise testing (CPET). RESULTS: During follow-up (1508 +/- 1070 days) 72 patients died and 30 underwent transplantation. On multivariate analysis percentage of predicted peak oxygen uptake (%predicted peak VO2 [risk ratio 0.95]), pulmonary vascular resistance (PVR [1.105,]) and increase in heart rate during exercise (DeltaHR [0.974]) were independent prognostic predictors (all p<0.0001). Peak VO2 allowed for risk stratification with a survival of 100, 92.9, 87.4 and 69.6% at 1 year and 97.7, 63.2, 41 and 23% at 5 years for the 4th, 3rd, 2nd and 1st quartiles, respectively. Dichotomizing by median peak VO2 and intra-group median PVR showed a worse 1-year survival for patients with low peak VO2/higher PVR compared to patients with low peak VO2/low PVR, high peak VO2/high PVR and high peak VO2/low PVR (65 vs. 93, 93, 100%, p<0.001). At 10 years survival was different for all 4 subgroups (19 vs. 25 vs. 48 vs. 75%, adjusted p<0.05). CONCLUSIONS: Peak VO2, PVR and DeltaHR independently predict prognosis in patients with PAH. Low peak VO2, high PVR and low DeltaHR refer to poor prognosis. Combined use of peak VO2 and PVR provides accurate risk stratification underlining the complementary prognostic information from cardiopulmonary exercise testing and resting invasive haemodynamic data. PMID- 22494869 TI - Efficacy and safety profile of dronedarone in clinical practice. Preliminary results of the Magdeburg Dronedarone Registry. PMID- 22494870 TI - Parasympathetic alteration during sub-clinical seizures. AB - INTRODUCTION: Autonomic instability is considered a contributing factor in sudden unexpected death in epilepsy (SUDEP). The aim of this pilot study was to measure parasympathetic activity in sub-clinical seizures to investigate autonomic instability. MATERIALS AND METHODS: A prospective study based on Video electroencephalography (EEG)/electrocardiography (ECG)/oxygen saturation (SAO2) recordings was selected from patients having sub-clinical seizures during stage 3 or 4 sleep. We analysed R-R intervals in the ECG from 1-min prior to the electrographic onset to the end of sub-clinical seizures. Matched non-ictal R-R baseline measurements were selected from stages 3 or 4 sleep. R-R interval data were analysed using NeuroScope software providing a cardiac index of parasympathetic activity (CIPA). BioSignal short-term heart rate variability (HRV) software was used to analyse the same R-R interval data previously analysed using NeuroScope except that sub-clinical seizure data was embedded within 5-min epochs and compared to 5-min epochs of non-ictal measurements. RESULTS: A total of 33 sub-clinical seizures were recorded from 11 patients comprising 19 generalised sub-clinical seizures (2 patients), 9 right temporal lobe sub clinical seizures (5 patients) and 5 left temporal lobe sub-clinical seizures (4 patients) were compared to matched non-ictal measurements. Parasympathetic activity was clearly altered during total sub-clinical seizures in terms of the CIPA (p<0.001) and 5-min HRV high frequency (HF) % (p=0.026) measures. Generalised sub-clinical seizures resulted in increased cardiac parasympathetic activity whereas temporal lobe seizures were associated with a decrease in parasympathetic activity. CONCLUSION: This pilot study indicates that parasympathetic changes occur during sub-clinical seizures. Generalised sub clinical seizures may be associated with more autonomic instability compared to temporal lobe sub-clinical seizures. PMID- 22494871 TI - Asking the right questions to ascertain early childhood secondhand smoke exposures. AB - Secondhand smoke is associated with a myriad of adverse health outcomes. Therefore, it is essential for clinicians to ask precise questions about exposures, particularly for children. We present 4 questions that incorporate several locations of exposure and provide a more comprehensive account of children's smoke exposures than maternal smoking alone. PMID- 22494872 TI - Quantitative neonatal glucose-6-phosphate dehydrogenase screening: distribution, reference values, and classification by phenotype. AB - OBJECTIVE: To determine enzyme assay reference values for newborns in a Sephardic Jewish population at high risk for glucose-6-phosphate dehydrogenase (G6PD) deficiency. STUDY DESIGN: Quantitative G6PD testing was performed on umbilical cord blood. The reduction of nicotinamide adenine dinucleotide phosphate to nicotinamide adenine dinucleotide phosphate-oxidase, reflecting G6PD activity, was measured spectrophotometrically. Hemoglobin (Hb) was measured on the same sample. G6PD activity was recorded as U/g Hb. RESULTS: Males (N = 1502) were separated into 2 distinct groups: those <7 U/g Hb (n = 243 [16.2%], median 0.28 U/g Hb), designated G6PD deficient, presumably hemizygotes; and those >= 9 U/g Hb (n = 1256 [83.8%], 18.76 U/g Hb), designated G6PD normal, presumably hemizygotes. Female (n = 1298) values were a continuum and were categorized based on the male distribution: those <7 U/g Hb (n = 81 [6.2%], 4.84 U/g Hb), G6PD deficient, probably homozogytes; those >= 9.5 U/g Hb, equivalent to 50% of the male normal value, (n = 1153 (88.8%), 18.36 U/g Hb), G6PD normal, probably homozygotes; and those with intermediate values (n = 64 [4.9%], 8.61 U/g Hb), probable heterozygotes. CONCLUSIONS: Accurate identification of the male G6PD-deficient state was possible despite high normal neonatal G6PD values. Female values were presented as a continuum preventing accurate classification but were classified based on male phenotype for practical use. PMID- 22494874 TI - Born with a balloon. PMID- 22494873 TI - Anemia, apnea of prematurity, and blood transfusions. AB - OBJECTIVE: To compare the frequency and severity of apneic events in very low birth weight (VLBW) infants before and after blood transfusions using continuous electronic waveform analysis. STUDY DESIGN: We continuously collected waveform, heart rate, and oxygen saturation data from patients in all 45 neonatal intensive care unit beds at the University of Virginia for 120 weeks. Central apneas were detected using continuous computer processing of chest impedance, electrocardiographic, and oximetry signals. Apnea was defined as respiratory pauses of >10, >20, and >30 seconds when accompanied by bradycardia (<100 beats per minute) and hypoxemia (<80% oxyhemoglobin saturation as detected by pulse oximetry). Times of packed red blood cell transfusions were determined from bedside charts. Two cohorts were analyzed. In the transfusion cohort, waveforms were analyzed for 3 days before and after the transfusion for all VLBW infants who received a blood transfusion while also breathing spontaneously. Mean apnea rates for the previous 12 hours were quantified and differences for 12 hours before and after transfusion were compared. In the hematocrit cohort, 1453 hematocrit values from all VLBW infants admitted and breathing spontaneously during the time period were retrieved, and the association of hematocrit and apnea in the next 12 hours was tested using logistic regression. RESULTS: Sixty seven infants had 110 blood transfusions during times when complete monitoring data were available. Transfusion was associated with fewer computer-detected apneic events (P < .01). Probability of future apnea occurring within 12 hours increased with decreasing hematocrit values (P < .001). CONCLUSIONS: Blood transfusions are associated with decreased apnea in VLBW infants, and apneas are less frequent at higher hematocrits. PMID- 22494875 TI - Identification of facilitators and barriers to physical activity in children and adolescents with cerebral palsy. AB - OBJECTIVE: To explore facilitators and barriers to participation in physical activity and sport in youth with cerebral palsy (CP). STUDY DESIGN: This was a qualitative study involving in-depth focus group interviews with 33 ambulatory youth with CP and their parents. The interviews were conducted until informational redundancy was achieved. RESULTS: Youth with CP and their parents reported personal and environmental facilitators and barriers to participation in physical activity. Seven major themes related to personal and environmental factors were identified. CONCLUSIONS: This study suggests that various personal and environmental factors play a key role in determining the extent to which youth with CP participate in physical activity. The facilitators and barriers identified provide important theoretical insights into how and why youth with CP and their parents might change their physical activity behavior. PMID- 22494877 TI - Health and quality of life in adults with Noonan syndrome. AB - OBJECTIVE: To obtain information on health and quality of life in adults with Noonan syndrome. STUDY DESIGN: From a cohort of 144 children with the diagnosis of Noonan syndrome whose height data had been published 23 years ago, 103 pediatric files providing adequate data were identified. Participants were sent questionnaires and asked to provide saliva for DNA analysis and to return for physical examination. RESULTS: Ten of 103 individuals had died, 3 of them suddenly (standardized mortality ratio, 3.00; 95% CI, 1.44-5.52). Eighty-one individuals could be contacted by mail, with a positive response from 45. Genotyping in 36 of 45 participants revealed characteristic mutations in 61%. Median age at follow-up was 42.8 years. Mean adult heights were 169.2 cm (men) and 154.4 cm (women). In comparison with the general population, participants had lower educational status and lived more frequently without any partner. According to the response to the Short Form-36 questionnaire, quality of life was not impaired. CONCLUSIONS: Individuals with Noonan syndrome have higher mortality, lower education, and rarely partnership. Quality of life according to self reported Short Form-36 was good. Men grew taller than previously reported from this cohort. PMID- 22494876 TI - Fatal and near-fatal asthma in children: the critical care perspective. AB - OBJECTIVE: To characterize the clinical course, therapies, and outcomes of children with fatal and near-fatal asthma admitted to pediatric intensive care units (PICUs). STUDY DESIGN: This was a retrospective chart abstraction across the 8 tertiary care PICUs of the Collaborative Pediatric Critical Care Research Network (CPCCRN). Inclusion criteria were children (aged 1-18 years) admitted between 2005 and 2009 (inclusive) for asthma who received ventilation (near fatal) or died (fatal). Data collected included medications, ventilator strategies, concomitant therapies, demographic information, and risk variables. RESULTS: Of the 261 eligible children, 33 (13%) had no previous history of asthma, 218 (84%) survived with no known complications, and 32 (12%) had complications. Eleven (4%) died, 10 of whom had experienced cardiac arrest before admission. Patients intubated outside the PICU had a shorter duration of ventilation (median, 25 hours vs 84 hours; P < .001). African-Americans were disproportionately represented among the intubated children and had a shorter duration of intubation. Barotrauma occurred in 15 children (6%) before admission. Pharmacologic therapy was highly variable, with similar outcomes. CONCLUSION: Of the children ventilated in the CPCCRN PICUs, 96% survived to hospital discharge. Most of the children who died experienced cardiac arrest before admission. Intubation outside the PICU was correlated with shorter duration of ventilation. Complications of barotrauma and neuromyopathy were uncommon. Practice patterns varied widely among the CPCCRN sites. PMID- 22494878 TI - Biomarkers of brain injury in neonatal encephalopathy treated with hypothermia. AB - OBJECTIVE: To determine if early serum S100B and neuron-specific enolase (NSE) levels are associated with neuroradiographic and clinical evidence of brain injury in newborns with encephalopathy. STUDY DESIGN: Patients who received therapeutic whole-body hypothermia were prospectively enrolled in this observational study. Serum specimens were collected at 0, 12, 24, and 72 hours of cooling. S100B and NSE levels were measured by enzyme linked immunosorbent assay. Magnetic resonance imaging was performed in surviving infants at 7-10 days of life. Standardized neurologic examination was performed by a child neurologist at 14 days of life. Multiple linear regression analyses were performed to evaluate the association between S100B and NSE levels and unfavorable outcome (death or severe magnetic resonance imaging injury/significant neurologic deficit). Cutoff values were determined by receiver operating curve analysis. RESULTS: Newborns with moderate to severe encephalopathy were enrolled (n = 75). Median pH at presentation was 6.9 (range, 6.5-7.35), and median Apgar scores of 1 at 1 minute, 3 at 5 minutes, and 5 at 10 minutes. NSE and S100B levels were higher in patients with unfavorable outcomes across all time points. These results remained statistically significant after controlling for covariables, including encephalopathy grade at presentation, Apgar score at 5 minutes of life, initial pH, and clinical seizures. CONCLUSION: Elevated serum S100B and NSE levels measured during hypothermia were associated with neuroradiographic and clinical evidence of brain injury in encephalopathic newborns. These brain-specific proteins may be useful immediate biomarkers of cerebral injury severity. PMID- 22494879 TI - Effects of acute nicotine and alcohol on the rating of attractiveness in social smokers and alcohol drinkers. AB - BACKGROUND: Nicotine and alcohol are often consumed together. Previous research suggests that both can independently increase the perceived attractiveness of social stimuli, which may be a mechanism that drives continued use. This study examined whether there was an additive effect of nicotine and alcohol on perceived attractiveness of social and environmental stimuli. METHODS: Male and female (n=96) social alcohol consumers and light cigarette smokers (no more than 14 cigarettes per week) were randomized to smoke either a nicotinized or denicotinized cigarette and drink either an alcoholic or non-alcoholic (placebo) beverage. The primary outcome was attractiveness ratings of facial and landscape stimuli. Secondary outcomes were self-report mood and craving. RESULTS: There was a main effect of drink (p=.031) and a trend toward a main effect of cigarette (p=.057) with higher ratings of attractiveness after alcohol compared to placebo and after a nicotinized cigarette compared to a denicotinized cigarette. Nicotine and alcohol appeared to work additively on ratings of attractiveness, with the highest ratings in the nicotine/alcohol group. There were no interactions between drink, cigarette and stimulus type. CONCLUSIONS: When co-administered, nicotine and alcohol consumption resulted in the highest perceptions of attractiveness across all stimulus types. This additive effect may be a mechanism by which administration of one drug reinforces use of the other, and which leads to an increased likelihood of habitual consumption and relapse. PMID- 22494880 TI - Commentary on "The role of the breast cancer surgeon in personalized cancer care: clinical utility of the 21-gene assay". PMID- 22494881 TI - Running sutures anchored with square knots are unreliable. AB - BACKGROUND: A previous study showed that running polypropylene sutures anchored with square knots retain only 75% of their strength compared with half hitches. The aim of this study was to investigate whether anchor knot geometry similarly affects the tensile strength of other types of sutures used in continuous closures. METHODS: Monofilament and multifilament sutures (all 3-0) were anchored with either square knots or half hitches to 1 tensionometer post, and the running ends were secured to the other. The force required to break the running suture and the site of suture failure were recorded. RESULTS: The running sutures anchored with square knots retained only 50% to 84% of the strength of the identical sutures secured with half hitches (P < .001). CONCLUSIONS: A running suture anchored with half hitches is stronger and safer in comparison with the same suture anchored with square knots. This study provokes a fundamental reconsideration of the use of square knots to anchor running sutures. PMID- 22494882 TI - Breakfast consumption and CVD risk factors in European adolescents: the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) Study. AB - OBJECTIVE: To examine the association between breakfast consumption and CVD risk factors in European adolescents. DESIGN: Cross-sectional. Breakfast consumption was assessed by the statement 'I often skip breakfast' and categorized into 'consumer', 'occasional consumer' and 'skipper'. Blood pressure, weight, height, waist circumference, skinfold thickness, total cholesterol (TC), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), TAG, insulin and glucose were measured and BMI, TC:HDL-C, LDL-C:HDL-C and homeostasis model assessment-insulin resistance index (HOMA-IR) were calculated. SETTING: The European Union-funded HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) Study. SUBJECTS: European adolescents, aged 12?50-17?49 years, from ten cities within the HELENA study (n 2929, n 925 with blood sample, 53% females). RESULTS: In males, significant differences across breakfast consumption category ('consumer', 'occasional consumer' and 'skipper') were seen for age, BMI, skinfold thickness, waist circumference, cardiorespiratory fitness, systolic and diastolic blood pressures, TC:HDL-C, LDL-C:HDL-C, glucose, insulin, HOMA-IR and LDL-C; in females, for cardiorespiratory fitness, skinfold thickness, BMI, insulin and HOMA-IR. In overweight/obese males significant differences were also seen for TC and LDL-C, whereas no differences were observed in non-overweight males or in females regardless of weight status. CONCLUSIONS: Our findings among European adolescents confirm previous data indicating that adolescents who regularly consume breakfast have lower body fat content. The results also show that regular breakfast consumption is associated with higher cardiorespiratory fitness in adolescents, and with a healthier cardiovascular profile, especially in males. Eating breakfast regularly may also negate somewhat the effect of excess adiposity on TC and LDL-C, especially in male adolescents. PMID- 22494883 TI - Reprogramming of somatic cells via TAT-mediated protein transduction of recombinant factors. AB - Generation of induced pluripotent stem cells (iPSCs) holds great promise to regenerative medicine. However, before this technology can be applied for clinical purpose, the issues of iPSC efficiency and safety need to be addressed. In this study, we have compared a simple TAT- and 11 arginine (R)-protein transduction domain (PTD) for somatic cell reprogramming and explored the optimal conditions for the PTD to transduce reprogramming factors (RFs). We show that all recombinant TAT- and 11R-fused RFs are transcriptionally active as they activate their corresponding reporter genes in reporter assays. The TAT-RFs are in general transcriptionally more active than the corresponding 11R-RFs, but less active than the corresponding retroviral transduced RFs. Furthermore, each of TAT-RFs can substitute for their corresponding retrovirus in reprogramming. Finally, using five TAT-RFs together with an HDAC inhibitor, we can generate iPSC-like colonies from human fibroblast cells with high efficiency approximately 2 weeks after the first protein transduction. These colonies exhibit unique features of pluripotent stem cells including the morphology and the expression of pluripotency-associated markers. This characterization of recombinant RFs in reprogramming should facilitate the generation of clinically useful and genetic material-free human iPSCs. PMID- 22494884 TI - The cytotoxic effects of polymer-coated quantum dots and restrictions for live cell applications. AB - The interest in the biomedical use of highly fluorescent and photostable nanoparticles such as quantum dots (QDots) is vastly increasing. One major hurdle that impedes QDot use in live cells and animals is their potential toxicity. Here, we employ a recently described multiparametric setup to determine the concentration at which common polymer-coated QDots become non-cytotoxic. We found that toxic effects are strongly related to the intracellular QDot amount that can be controlled by their specific surface coating. Using lysosomal buffer systems and proliferation-restricted cells, intracellular QDots were found to localize in endosomes, where they generate reactive oxygen species, interfere with cell cytoskeleton and leach free Cd(2+) ions due to QDot dissolution, resulting in increased toxicity and impeded QDot fluorescence. Furthermore, we find that asymmetric partitioning of QDots upon recurrent cell division results in the sacrifice of heavily-loaded cells and a rapid loss of particles in live cells, limiting the use of currently available QDots for long-term imaging and defining the non-cytotoxic concentration as 10-fold lower than commonly used concentrations. PMID- 22494885 TI - Development and in-vivo characterization of supramolecular hydrogels for intrarenal drug delivery. AB - Intrarenal drug delivery from a hydrogel carrier implanted under the kidney capsule is an innovative way to induce kidney tissue regeneration and/or prevent kidney inflammation or fibrosis. We report here on the development of supramolecular hydrogels for this application. We have synthesized two types of supramolecular hydrogelators by connecting the hydrogen bonding moieties to poly(ethylene glycols) in two different ways in order to obtain hydrogels with different physico-chemical properties. Chain-extended hydrogelators containing hydrogen bonding units in the main chain, and bifunctional hydrogelators end functionalized with hydrogen bonding moieties, were made. The influence of these hydrogels on the renal cortex when implanted under the kidney capsule was studied. The overall tissue response to these hydrogels was found to be mild, and minimal damage to the cortex was observed, using the infiltration of macrophages, formation of myofibroblasts, and the deposition of collagen III as relevant read out parameters. Differences in tissue response to these hydrogels could be related to the different physico-chemical properties of the three hydrogels. The strong, flexible and slow eroding chain-extended hydrogels are proposed to be suitable for long-term intrarenal delivery of organic drugs, while the weaker, soft and fast eroding bifunctional hydrogel is eminently suitable for short-term, fast delivery of protein drugs to the kidney cortex. The favourable biological behaviour of the supramolecular hydrogels makes them exquisite candidates for subcapsular drug delivery, and paves the way to various opportunities for intrarenal therapy. PMID- 22494886 TI - An (125)I-labeled octavalent peptide fluorescent nanoprobe for tumor-homing imaging in vivo. AB - Targeting radiopeptides are promising agents for radio-theranostics. However, in vivo evaluation of their targeting specificity is often obscured by their short biologic half-lives and low binding affinities. Here, we report an approach to efficiently examine targeting radiopeptides with a new class of octavalent peptide fluorescent nanoprobe (Octa-FNP) platform, which is composed of candidate targeting peptides and a tetrameric far-red fluorescent protein (tfRFP) scaffold. To shed light on this process, (125)I-Octa-FNP, (125)I-tfRFP and (125)I-peptide were synthesized, and their targeting functionalities were compared. Both fluorescence imaging and radioactive quantification results confirmed that (125)I Octa-FNP had a significantly higher cellular binding capability than (125)I tfRFP. In vivo biodistribution studies show that at 6 h post-injection, (125)I Octa-FNP had 2-fold and 30-fold higher tumor uptake than that of (125)I-tfRFP and (125)I-peptide, respectively. Moreover, gamma-imaging at 24 h post-injection revealed a remarkable accumulation of (125)I-Octa-FNP in the tumor while maintaining an extremely low background contrast, which was further confirmed by immunofluorescence analysis. These data suggested that, as an engineered and multivalent platform, Octa-FNP could enhance the tumor targeting of a designed peptide and provide excellent contrast radioimaging, making it a valuable tool for the evaluation of the targeting ability of specifically designed radiopeptides for cancer theranostics. PMID- 22494887 TI - The biocompatibility and antibacterial properties of collagen-stabilized, photochemically prepared silver nanoparticles. AB - Spherical 3.5 nm diameter silver nanoparticles (AgNP) stabilized in type I collagen (AgNP@collagen) were prepared in minutes (5-15 min) at room temperature by a photochemical method initiated by UVA irradiation of a water-soluble non toxic benzoin. This biocomposite was examined to evaluate its biocompatibility and its anti-bacterial properties and showed remarkable properties. Thus, while keratinocytes and fibroblasts were not affected by AgNP@collagen, it was bactericidal against Bacillus megaterium and E. coli but only bacteriostatic against S. epidermidis. In particular, the bactericidal properties displayed by AgNP@collagen were proven to be due to AgNP in AgNP@collagen, rather than to released silver ions, since equimolar concentrations of Ag are about four times less active than AgNP@collagen based on total Ag content. This new biocomposite was stable over a remarkable range of NaCl, phosphate, and 2-(N morpholino)ethanesulfonic acid concentrations and for over one month at 4 degrees C. Circular dichroism studies show that the conformation of collagen in AgNP@collagen remains intact. Finally, we have compared the properties of AgNP@collagen with a similar biocomposite prepared using alpha-poly-L-Lysine and also with citrate stabilized AgNP; neither of these materials showed comparable biocompatibility, stability, or anti-bacterial activity. PMID- 22494888 TI - CD44 antibody-targeted liposomal nanoparticles for molecular imaging and therapy of hepatocellular carcinoma. AB - Most hepatocellular carcinoma (HCC) therapies fail to target cancer stem cells (CSCs) and monitor cancer progression or regression. The purpose of this study was to evaluate the possibility of cancer imaging and simultaneously monitoring targeted therapy in a single animal by anti-CD44 antibody-mediated liposomal nanoparticle. In this study, an in situ liver tumor model was applied for therapy by injecting 1.0 * 10(6) HepG2 cells carrying a reporter system encoding a double fusion (DF) reporter gene consisting of firefly luciferase (Fluc) and green fluorescent protein (GFP) into the liver of NOD/SCID mice. A strategy was developed which specifically targeted HCC via anti-CD44 antibody-mediated liposomal nanoparticle delivery, loaded of either doxorubicin (Dox) or a triple fusion (TF) gene containing the herpes simplex virus truncated thymidine kinase (HSV-ttk) and renilla luciferase (Rluc) and red fluorescent protein (RFP). The NOD/SCID mice were subsequently treated with ganciclovir (GCV) and the growth status of tumor was monitored by optical bioluminescence imaging (BLI) of Fluc and specific targeting of the liposomal nanoparticle was tracked by Rluc imaging. CD44 antibody-mediated liposomal nanoparticle, loaded of TF plasmids, were shown to be useful for monitoring and evaluating targeting efficacy and gene therapy by non-invasive molecular imaging. Here, we demonstrate the time intensive preclinical steps involved in molecular target identification, validation, and characterization by dual molecular imaging. This targeted and traceable therapeutic strategy has potential advantages to overcome the problems of conventional tumor therapy and may open a new application for the treatment of HCC by targeting CSCs. PMID- 22494889 TI - Stem cell membrane engineering for cell rolling using peptide conjugation and tuning of cell-selectin interaction kinetics. AB - Dynamic cell-microenvironment interactions regulate many biological events and play a critical role in tissue regeneration. Cell homing to targeted tissues requires well balanced interactions between cells and adhesion molecules on blood vessel walls. However, many stem cells lack affinity with adhesion molecules. It is challenging and clinically important to engineer these stem cells to modulate their dynamic interactions with blood vessels. In this study, a new chemical strategy was developed to engineer cell-microenvironment interactions. This method allowed the conjugation of peptides onto stem cell membranes without affecting cell viability, proliferation or multipotency. Mesenchymal stem cells (MSCs) engineered in this manner showed controlled firm adhesion and rolling on E selectin under physiological shear stresses. For the first time, these biomechanical responses were achieved by tuning the binding kinetics of the peptide-selectin interaction. Rolling of engineered MSCs on E-selectin is mediated by a Ca(2+) independent interaction, a mechanism that differs from the Ca(2+) dependent physiological process. This further illustrates the ability of this approach to manipulate cell-microenvironment interactions, in particular for the application of delivering cells to targeted tissues. It also provides a new platform to engineer cells with multiple functionalities. PMID- 22494890 TI - Engineered phage-based therapeutic materials inhibit Chlamydia trachomatis intracellular infection. AB - Developing materials that are effective against sexually transmitted pathogens such as Chlamydia trachomatis (Ct) and HIV-1 is challenging both in terms of material selection and improving bio-membrane and cellular permeability at desired mucosal sites. Here, we engineered the prokaryotic bacterial virus (M13 phage) carrying two functional peptides, integrin binding peptide (RGD) and a segment of the polymorphic membrane protein D (PmpD) from Ct, as a phage-based material that can ameliorate Ct infection. Ct is a globally prevalent human pathogen for which there are no effective vaccines or microbicides. We show that engineered phage stably express both RGD motifs and Ct peptides and traffic intracellularly and into the lumen of the inclusion in which the organism resides within the host cell. Engineered phage were able to significantly reduce Ct infection in both HeLa and primary endocervical cells compared with Ct infection alone. Polyclonal antibodies raised against PmpD and co-incubated with constructs prior to infection did not alter the course of infection, indicating that PmpD is responsible for the observed decrease in Ct infection. Our results suggest that phage-based design approaches to vector delivery that overcome mucosal cellular barriers may be effective in preventing Ct and other sexually transmitted pathogens. PMID- 22494891 TI - Mechanical properties and biomineralization of multifunctional nanodiamond-PLLA composites for bone tissue engineering. AB - Multifunctional bone scaffold materials have been produced from a biodegradable polymer, poly(L-lactic acid) (PLLA), and 1-10% wt of octadecylamine functionalized nanodiamond (ND-ODA) via solution casting followed by compression molding. By comparison to pure PLLA, the addition of 10% wt of ND-ODA resulted in a significant improvement of the mechanical properties of the composite matrix, including a 280% increase in the strain at failure and a 310% increase in fracture energy in tensile tests. The biomimetic process of bonelike apatite growth on the ND-ODA/PLLA scaffolds was studied using microscopic and spectroscopic techniques. The enhanced mechanical properties and the increased mineralization capability with higher ND-ODA concentration suggest that these biodegradable composites may potentially be useful for a variety of biomedical applications, including scaffolds for orthopedic regenerative engineering. PMID- 22494892 TI - Hyperbaric oxygen preconditioning attenuates hyperglycemia enhanced hemorrhagic transformation after transient MCAO in rats. AB - BACKGROUND: Hemorrhagic transformation (HT) can be a devastating complication of ischemic stroke. Hyperbaric oxygen preconditioning (HBO-PC) has been shown to improve blood-brain barrier (BBB) permeability in stroke models. The purpose of this study is to examine whether HBO-PC attenuates HT after focal cerebral ischemia, and to investigate whether the mechanism of HBO-PC against HT includes up-regulation of antioxidants in hyperglycemic rats. METHODS: Male Sprague-Dawley rats (280-320 g) were divided into the following groups: sham, middle cerebral artery occlusion (MCAO) for 2 h, and MCAO treated with HBO-PC. HBO-PC was conducted giving 100% oxygen at 2.5 atm absolute (ATA), for 1 h at every 24 h interval for 5 days. At 24 h after the last session of HBO-PC, rats received an injection of 50% glucose (6 ml/kg intraperitoneally) and were subjected to MCAO 15 min later. At 24 h after MCAO, neurological behavior tests, infarct volume, blood-brain barrier permeability, and hemoglobin content were measured to evaluate the effect of HBO-PC. Western blot analysis of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was evaluated at multiple time-points before and after MCAO. RESULTS: HBO-PC improved neurological behavior test, and reduced infarction volume, HT and Evans blue extravasation in the ipsilateral hemisphere at 24 h after MCAO. Western blot analysis failed to demonstrate up-regulation of Nrf2 in HBO-PC group before and after MCAO. Paradoxically, HBO-PC decreased HO-1 expression at 24 h after MCAO, as compared with htMCAO group. CONCLUSIONS: HBO-PC improved neurological deficits, infarction volume, BBB disruption, and HT after focal cerebral ischemia. However, its mechanism against focal cerebral ischemia and HT may not include activation of Nrf2 and subsequent HO-1 expression. PMID- 22494893 TI - Letter to the editor. PMID- 22494894 TI - Neutron and photon spectra in LINACs. AB - A Monte Carlo calculation, using the MCNPX code, was carried out in order to estimate the photon and neutron spectra in two locations of two linacs operating at 15 and 18 MV. Detailed models of both linac heads were used in the calculations. Spectra were estimated below the flattening filter and at the isocenter. Neutron spectra show two components due to evaporation and knock-on neutrons. Lethargy spectra under the filter were compared to the spectra calculated from the function quoted by Tosi et al. that describes reasonably well neutron spectra beyond 1 MeV, though tends to underestimate the energy region between 10(-6) and 1 MeV. Neutron and the Bremsstrahlung spectra show the same features regardless of the linac voltage. PMID- 22494896 TI - A novel anticancer and antifungus phenazine derivative from a marine actinomycete BM-17. AB - A marine actinomycete, designated strain BM-17, was isolated from a sediment sample collected in the Arctic Ocean. The strain was identified as Nocardia dassonvillei based on morphological, cultural, physiological, biochemical characteristics, along with the cell wall analysis and 16S rDNA gene sequence analysis. A new secondary metabolite (1), N-(2-hydroxyphenyl)-2-phenazinamine (NHP), and six known antibiotics (2-7) have been isolated from the saline culture broth of the stain by sequentially purification over macroporous resin D101, silica gel, Sephadex LH-20 column chromatography and preparative HPLC after the stain was incubated in soy bean media at 28 degrees C for 7 days. The chemical structures of the compounds were elucidated on the basis of spectroscopic analysis, including two-dimensional (2D) NMR and HR-ESI-MS data. The new compound showed significant antifungal activity against Candida albicans, with a MIC of 64 MUg/ml and high cancer cell cytotoxicity against HepG2, A549, HCT-116 and COC1 cells. PMID- 22494895 TI - Very high specific activity 66/68Ga from zinc targets for PET. AB - This work describes the production of very high specific activity (66/68)Ga from (nat)Zn(p,n) and (66)Zn(p,n) using proton irradiations between 7 and 16 MeV, with emphasis on (66)Ga for use with common bifunctional chelates. Principal radiometallic impurities are (65)Zn from (p,x) and (67)Ga from (p,n). Separation of radiogallium from target material is accomplished with cation exchange chromatography in hydrochloric acid solution. Efficient recycling of Zn target material is possible using electrodeposition of Zn from its chloride form, but these measures are not necessary to achieve high specific activity or near quantitative radiolabeling yields from natural targets. Inductively coupled plasma mass spectroscopy (ICP-MS) measures less than 2 ppb non-radioactive gallium in the final product, and the reactivity of (66)Ga with common bifunctional chelates, decay corrected to the end of irradiation, is 740 GBq/MUmol (20 Ci/MUmol) using natural zinc as a target material. Recycling enriched (66)Zn targets increased the reactivity of (66)Ga with common bifunctional chelates. PMID- 22494897 TI - L-Phenylalanine catabolism and L-phenyllactic acid production by a phototrophic bacterium, Rubrivivax benzoatilyticus JA2. AB - A phototrophic bacterium (Rubrivivax benzoatilyticus JA2) grows at the expense of L-phenylalanine as sole source of nitrogen but not as carbon source. Near stoichiometric yields of L-phenylpyruvic acid (0.4 mM) and L-phenyllactate (0.4 mM) were observed from L-phenylalanine (0.9 mM consumed). Aminotransfarase and dehydrogenase activities involved in the formation of L-phenylpyruvic acid and L phenyllactate were demonstrated unequivocally in Rubrivivax benzoatilyticus JA2. Growth conditions and carbon sources had an influence on L-phenyllactate production. The process yielded a maximum of 0.92 mM L-phenyllactate from L phenylalanine (1 mM) when fructose served as carbon source for R. benzoatilyticus JA2. PMID- 22494898 TI - Cell wall proteome of Clostridium thermocellum and detection of glycoproteins. AB - Clostridium thermocellum, a thermophilic anaerobe, has the unusual capacity to convert cellulosic biomass into ethanol and hydrogen. In this work, the cell wall proteome of C. thermocellum was investigated. The proteins in the cell wall fraction of C. thermocellum prepared by the boiling SDS method were released by mutanolysin digestion and resolved on two-dimensional (2D) gel. One hundred and thirty-two proteins were identified by mass spectrometry, among which the extracellular solute-binding protein (CbpB/cthe_1020), enolase, glyceraldehyde-3 phosphate dehydrogenase and translation elongation factor EF-Tu were detected as highly abundant proteins. Besides the known surface localized proteins, including FtsZ, MinD, GroEL, DnaK, many enzymes involved in bioenergetics, such as alcohol dehydrogenases and hydrogenases were also detected. By glycan stain and MS analysis of glycopeptides, we identified CbpB as a glycoprotein, which is the second glycoprotein from C. thermocellum characterized. The fact that CbpB was highly abundant in the cell wall region and glycosylated, reflects its importance in substrate assimilation. Our results indicate cell wall proteins constitute a significant portion of cellular proteins and may play important physiological roles (i.e. bioenergetics) in this bacterium. The insights described are relevant for the development of C. thermocellum as a biofuel producer. PMID- 22494899 TI - Evaluation of a BK virus viral load assay using the QIAGEN Artus BK Virus RG PCR test. AB - BACKGROUND: Viral load testing for BK Virus (BKV) has become the standard of care for the diagnosis of infection and monitoring of therapy of kidney transplant patients infected with BKV. However, there are currently no FDA-approved BKV quantification assays and no standardization among available tests. OBJECTIVE AND STUDY DESIGN: This study evaluated the performance of the Artus BK Virus RG PCR (RUO) assay (QIAGEN) for accuracy, linearity, precision, analytical sensitivity, specificity, and correlation with a referral laboratory test in patient samples. RESULTS: Linear regression analysis of the quantitative results demonstrated a linear range of quantification from 192 to 194 million (2.28 to 8.29 log(10)) DNA copies/mL and a coefficient of determination (R(2)) of 0.994. A dilution series demonstrated a limit of detection and a limit of quantification of 2.00 log(10), and 2.30 log(10) copies/mL (>95% positivity rate), respectively. The precision of the assay was highly reproducible among runs with coefficients of variance (CV) ranging from 0.2% to 7.0%. A comparison of 34 matched samples showed a good agreement (R(2)=0.983) between the Artus BK test and the referral laboratory results, with an average positive bias (0.39 log(10) copies/mL). Genotyping analysis using large-T antigen sequences demonstrated that 90% of the positive samples were BKV type I, and that there was no significant difference in quantification between the referral laboratory and Artus BK Virus tests. CONCLUSIONS: The Artus BK Virus RG PCR test is a reliable and sensitive assay for BKV DNA quantification as compared to the referral laboratory test. PMID- 22494900 TI - Wet air oxidation of pretreatment of pharmaceutical wastewater by Cu2+ and [PxWmOy]q- co-catalyst system. AB - This study concentrates on the pretreatment of real wastewater using catalytic wet air oxidation (CWAO). WO(3-) and PO(4)(3-) contained in fosfomycin pharmaceutical wastewater (FPW) and Cu(2+) contained in berberine pharmaceutical wastewater (BPW) were studied as CWAO influent. Mixture of this two streams were reused to form Cu(2+) and [P(x)W(m)O(y)](q-), namely polyoxometalates (POMs) as co-catalyst system to treat themselves. Experiments were conducted to investigate the effects of the initial oxygen pressure and temperature on the COD (chemical oxygen demand), TOC (total organic carbon) removal and biodegradable enhancement, it was discovered that over 40% of COD and TOC removal can be easily realized in an hour of WAO oxidation at 523 K, 1.4 MPa. The BOD(5)/COD (BOD(5), biochemical oxygen demand in 5 days) of this two pharmaceutical mixture ascended from nonexistent to maximum 0.41 depends on the optimal FPW:BPW volume ratio 4:1, to compose POM co-catalyst system. Organic pollutants were incompletely oxidized to propionic acid and other intermediates. Some properties (e.g., TGA, IR, XRF) of POM catalyst separated from effluent, were obtained to provide additional information. PMID- 22494901 TI - Superparamagnetic high-surface-area Fe3O4 nanoparticles as adsorbents for arsenic removal. AB - Superparamagnetic ascorbic acid-coated Fe(3)O(4) nanoparticles with a high specific surface area were successfully synthesized via an environmentally friendly hydrothermal route in the absence of any templates. The as-synthesized ascorbic acid-coated Fe(3)O(4) nanoparticles have a diameter of less than 10 nm, thus leading to a high specific surface area of about 179 m(2)/g, which is even larger than those of well-defined mesoporous structures. The only used capped agent is ascorbic acid, which serves as a functionalized molecule to make sure the high dispersibility and stability of the ascorbic acid-coated Fe(3)O(4) nanoparticles in aqueous solution. The ascorbic acid-coated Fe(3)O(4) nanoparticles exhibit superparamagnetic properties at room temperature and saturation magnetization approaches 40 emu g(-1). The ascorbic acid-coated Fe(3)O(4) nanoparticles were evaluated as an absorbent to remove heavy metal arsenic from wastewater. The adsorption data obeyed the Langmuir equation with a maximum adsorption capacity of 16.56 mg/g for arsenic (V), and 46.06 mg/g for arsenic (III). PMID- 22494902 TI - Evaluation of three reagent dosing strategies in a photo-Fenton process for the decolorization of azo dye mixtures. AB - Three reagent dosing strategies used in the solar photo-assisted decolorization of a mixture of sulfonated dyes consisting of acid blue 113, acid orange 7 and acid red 151 were evaluated. Results demonstrated that the dosing strategy influenced both reagent consumption and the biodegradability and toxicity of the effluent. In one strategy (E(1)), the Fenton's reactants were dosed in a punctual mode, while in the other two strategies (E(2) an E(3)), the reactants were dosed continuously. In the E(2) strategy the reactants were dosed by varying the duration of the injection time. In the E(3) strategy, the reactants were dosed during 60 min at a constant rate, but with different concentrations. All cases showed that feeding the reactor between 40% and 60% of the maximal dose was sufficient to decolorize more than 90% of the mixture of azo dyes. The E(1) strategy was less effective for aromatic content reduction. Conversely, the continuous addition of the reagents (E(2) and E(3) strategies) improved the aromatic content removal. E(3) strategy was substantially more appropriate than E(1) strategy due to improved the effluent quality in two key areas: toxicity and biodegradability. PMID- 22494903 TI - Spatial distribution of diuron sorption affinity as affected by soil, terrain and management practices in an intensively managed apple orchard. AB - We investigated how the sorption affinity of diuron (3'-(3,4-dichlorophenyl)-1,1 dimenthyl-urea), a moderately hydrophobic herbicide, is affected by soil properties, topography and management practices in an intensively managed orchard system. Soil-landscape analysis was carried out in an apple orchard which had a strong texture contrast soil and a landform with relief difference of 50 m. Diuron sorption (K(d)) affinity was successfully predicted (R(2)=0.79; p<0.001) using a mid-infrared - partial least squares model and calibrated against measured data using a conventional batch sorption technique. Soil and terrain properties explained 75% of the variance of diuron K(d) with TOC, pH(w), slope and WI as key variables. Mean diuron K(d) values were also significantly different (p<0.05) between alley and tree line and between the different management zones. Soil in the tree line generally had lower sorption capacity for diuron than soil in the alleys. Younger stands, which were found to have lower TOC than in the older stands, also had lower diuron K(d) values. In intensively managed orchards, sorption affinity of pesticides to soils was not only affected by soil properties and terrain attributes but also by management regime. PMID- 22494904 TI - Differential pulse voltammetric determination of methyl parathion based on multiwalled carbon nanotubes-poly(acrylamide) nanocomposite film modified electrode. AB - A sensitive electrochemical differential pulse voltammetry method was developed for detecting methyl parathion based on multiwalled carbon nanotubes poly(acrylamide) (MWCNTs-PAAM) nanocomposite film modified glassy carbon electrode. The novel MWCNTs-PAAM nanocomposite, containing high content of amide groups, was synthesized by PAAM polymerizing at the vinyl group functionalized MWCNTs surface using free radical polymerization. The MWCNTs-PAAM nanocomposite was characterized by Fourier transform infrared spectroscopy, thermal gravimetric analysis and scanning electron microscopy. Electrochemical behavior and interference studies of MWCNTs-PAAM/GCE for methyl parathion were investigated. The experimental results demonstrated that the MWCNTs-PAAM/GCE exhibited a high adsorption and strong affinity toward methyl parathion compared with some metal ions and nitroaromatic compounds, which exist in environmental samples. The adsorbed amount of methyl parathion on the MWCNTs-PAAM/GCE approached the equilibrium value upon 5 min adsorption time. A linear calibration curve for methyl parathion was obtained in the concentration range from 5.0*10(-9) to 1.0*10(-5) mol L(-1), with a detection limit of 2.0*10(-9) mol L(-1). The MWCNTs PAAM/GCE was proved to be a suitable sensing tool for the fast, sensitive and selective determination of methyl parathion in environmental water samples. PMID- 22494905 TI - Prophylactic and metaphylactic antimicrobial use in Belgian fattening pig herds. AB - The monitoring of antimicrobial use is an essential step to control the selection and spread of antimicrobial resistance. Between January and October 2010 data on prophylactic and metaphylactic antimicrobial use were collected retrospectively on 50 closed or semi-closed pig herds. Ninety-three percent of the group treatments were prophylactic whereas only 7% were methaphylactic. The most frequently used antimicrobials orally applied at group level were colistin (30.7%), amoxicillin (30.0%), trimethoprim-sulfonamides (13.1%), doxycycline (9.9%) and tylosin (8.1%). The most frequently applied injectable antimicrobials were tulathromycin (45.0%), long acting ceftiofur (40.1%) and long acting amoxicillin (8.4%). The treatment incidences (TI) based on the used daily dose pig (UDD(pig) or the actually administered dose per day per kg pig of a drug) for all oral and injectable antimicrobial drugs was on average 200.7 per 1000 pigs at risk per day (min=0, max=699.0), while the TI based on the animal daily dose pig (ADD(pig) or the national defined average maintenance dose per day per kg pig of a drug used for its main indication) was slightly higher (average=235.8, min=0, max=1322.1). This indicates that in reality fewer pigs were treated with the same amount of antimicrobials than theoretically possible. Injectable products were generally overdosed (79.5%), whereas oral treatments were often underdosed (47.3%). In conclusion, this study shows that prophylactic group treatment was applied in 98% of the visited herds and often includes the use of critically important and broad-spectrum antimicrobials. In Belgium, the guidelines for prudent use of antimicrobials are not yet implemented. PMID- 22494906 TI - The association between submission counts to a veterinary diagnostic laboratory and the economic and disease challenges of the Ontario swine industry from 1998 to 2009. AB - An intuitive assumption is to believe that the number of submissions made to a veterinary diagnostic laboratory is dictated by the financial state of the industries using the laboratory. However, no research is available to document how the economics of a food animal industry affects laboratory submissions and therefore disease monitoring and surveillance efforts. The objective of this study was to determine if economic indices associated with the Ontario swine industry can account for the variability seen in these submissions. Retrospective swine submissions made to the Animal Health Laboratory at the University of Guelph, Guelph, Ontario from January 1998 to July 2009 were compiled. The following economic, demographic, and health variables impacting Ontario swine production were selected for analysis: auction price, lean-hog futures, currency exchange rate, price of corn, an outbreak of porcine circovirus type-2 associated diseases (PCVAD), government incentive program, number of farms in province, and average farm size. All independent variables identified by unconditional associations to have a significance of P<=0.2 with the outcome of monthly submission count were included in a multivariable negative binomial model. A final model was identified by a backwards elimination procedure. A total of 30,432 swine submissions were recorded. The mean frequency of monthly submissions over 139 months was 212.9 (SD=56.0). After controlling for farm size, the number of pigs in Ontario, higher submission counts were associated with a weaker CAD$ versus US$, higher auction prices, and a PCVAD outbreak (P<0.001). The results suggest that both economic volatility and disease outbreaks in the Ontario swine industry drive submissions to the laboratory. In conclusion, lab submissions are a useful source of animal health data for disease surveillance; however, surveillance activities should also monitor the economics of the industry. PMID- 22494907 TI - Comparative floral development in Lithospermum (Boraginaceae) and implications for the evolution and development of heterostyly. AB - PREMISE OF THE STUDY: The evolution and development of floral developmental patterns were investigated in three heterostylous and three homostylous species of Lithospermum to determine whether species that independently acquired the same floral form follow the same pattern of development or different patterns. METHODS: Using light and scanning electron microscopy, we observed developmental patterns in flowers at different stages of maturity. These patterns were compared within individual species, between heterostylous morphs, and among heterostylous and homostylous species. KEY RESULTS: Although heterostyly has been determined by phylogenetic analysis to have originated independently in each of the heterostylous species, flowers of the long-style morph of each species follow similar patterns of gross development, as do those of the short-style morph. In addition, the flowers of each morph develop in a manner similar to those of their respective homostylous, herkogamous relatives. However, the developmental patterns of the stylar epidermal cells differ among these species and between heterostylous and homostylous species. CONCLUSIONS: Floral developmental patterns in homostylous species provide evidence that modification of specific traits, such as patterns of stylar growth, can lead to the evolution of heterostyly. The developmental changes that affect the positions of the stigmas and anthers in each morph likely involve either temporal or spatial modifications of gene function. The floral developmental patterns described here and the occurrence of multiple types of herkogamy within some species of Lithospermum provide evidence that heterostylous species in the genus have originated via distinct evolutionary developmental pathways. PMID- 22494908 TI - Roles of climate and functional traits in controlling toothed vs. untoothed leaf margins. AB - PREMISE OF THE STUDY: Leaf-margin state (toothed vs. untoothed) forms the basis of several popular methods for reconstructing temperature. Some potential confounding factors have not been investigated with large data sets, limiting our understanding of the adaptive significance of leaf teeth and their reliability to reconstruct paleoclimate. Here we test the strength of correlations between leaf margin state and deciduousness, leaf thickness, wood type (ring-porous vs. diffuse-porous), height within community, and several leaf economic variables. METHODS: We assembled a trait database for 3549 species from six continents based on published and original data. The strength of associations between traits was quantified using correlational and principal axes approaches. KEY RESULTS: Toothed species, independent of temperature, are more likely to be deciduous and to have thin leaves, a high leaf nitrogen concentration, a low leaf mass per area, and ring-porous wood. Canopy trees display the highest sensitivity between leaf-margin state and temperature; subcanopy plants, especially herbs, are less sensitive. CONCLUSIONS: Our data support hypotheses linking the adaptive significance of teeth to leaf thickness and deciduousness (in addition to temperature). Toothed species associate with the "fast-return" end of the leaf economic spectrum, providing another functional link to thin leaves and the deciduous habit. Accounting for these confounding factors should improve climate estimates from tooth-based methods. PMID- 22494909 TI - The ease of breathing test tracks clinical changes in cystic fibrosis. AB - INTRODUCTION: The EOB is a measure of dyspnea that correlates with CF pulmonary function and exercise tolerance, but has not been shown to track clinical changes. METHODS: The EOB was administered before and after treatment for twelve episodes of exacerbations in eleven pediatric CF subjects. Each subject performed the EOB Sustained Phonation and Single Breath Counting measures before and after treatment both at rest and after exercise. RESULTS: Phonation was significantly better pre-exercise after treatment than initially (Z=-2.20, p=0.028). Phonation post-exercise was longer at follow-up than pre- antibiotics (Z=-1.91, p=0.056). Changes in post-exercise Phonation correlated significantly with changes in FEV1 before and after treatment (R=0.66, p=0.020). CONCLUSIONS: The EOB Sustained Phonation is a validated tool for tracking improvement of pediatric CF patients after antibiotic therapy and has potential as a research tool to gauge efficacy of new therapies. PMID- 22494910 TI - Intraocular and orbital metastasis as a rare form of clinical presentation of insular thyroid cancer. AB - Insular carcinoma of thyroid is a rare tumor, which accounts for 4 to 6% of thyroid malignancies. Clinically and morphologically it is considered to be in an intermediate position between well-differentiated carcinoma of the thyroid (papillary or follicular) and undifferentiated or anaplastic carcinoma of the thyroid. Capsular and blood vessel invasion is seen frequently, and metastases to regional lymph nodes, lungs and bones are common. The initial presentation of distant metastasis in patients with thyroid cancer is rare. Thus metastatic thyroid carcinoma rarely involves the orbit. We report a rare case of choroidal metastasis from insular thyroid carcinoma. PMID- 22494911 TI - Role of high mobility group box chromosomal protein 1 in ischemia-reperfusion injury in the rat small intestine. AB - BACKGROUND: High mobility group box chromosomal protein 1 (HMGB1) has recently been shown to be an important late mediator of endotoxic shock and sepsis. The purpose of the present study was to investigate the role of HMGB1 in response to ischemia-reperfusion injury. METHODS: Ischemia-reperfusion injury was induced in male Wistar rats by clamping the superior mesenteric artery for 60 min. Using this model, the serum concentrations and localization of HMGB1 were investigated. The histologic findings from reperfused intestines and the survival rates were compared between the anti-HMGB1 antibody treatment groups (group A treated with 6.0 mg/kg antibody and group B with 0.6 mg/kg antibody) and the control antibody treatment group (control group). RESULTS: Serum HMGB1 concentrations increased early after reperfusion and peaked at 3 h. Immunohistochemistry for HMGB1 revealed a high degree of positive staining in the epithelial cells of the damaged villi. Anti-HMGB1 antibody treatment significantly reduced this damage (P < 0.05) and improved the 48-h survival rate (90% in group A versus 50% in the controls; P < 0.05). CONCLUSIONS: These results suggest that HMGB1 plays a key role in small intestinal ischemia-reperfusion injury. PMID- 22494912 TI - A novel mouse model of isolated limb perfusion for extremity melanoma. AB - BACKGROUND: Isolated limb perfusion (ILP) for extremity melanoma has been used clinically for over half a century. Mouse modeling of ILP may offer significant experimental advantages compared with existing models. We propose a novel mouse model and report our initial experience. METHODS: We injected female C57BL/6 mice (22-25 g) with 1 * 10(6) B16 melanoma cells subcutaneously in the distal right thigh. After 7 d of tumor establishment, we cannulated the superficial femoral artery (inflow) and vein (outflow) of anesthetized mice and placed a proximal tourniquet. Non-oxygenated perfusate included low-dose or high-dose melphalan and saline (control). We analyzed endpoints of cannulation time, procedural complications, morbidity, toxicity, and tumor response. RESULTS: We performed 11 superficial femoral vessel cannulations. Median cannulation time was 19 min (range, 15-32 min). Intact perfusion models were obtained in 10 of 11 cases (91%); one case failed owing to superficial femoral vein dissection. Morbidity rate was 20% (one wound dehiscence and one hematoma). Both high- and low-dose melphalan perfusion groups (4 mice/group) trended to growth delay and regression compared with saline-perfused groups. Toxicity was greater in the high-dose melphalan-treated mice. CONCLUSIONS: We have established the first reproducible mouse model of ILP for melanoma. Future experiments will take advantage of the large number of established mouse knockout models and reagents to dissect the precise mechanisms of tumor control after ILP, and examine to novel agents. PMID- 22494913 TI - Liver hypertrophy and accelerated growth of implanted tumors in nonembolized liver of rabbit after left portal vein embolization. AB - BACKGROUND: Portal vein embolization (PVE) has become a standard preoperative procedure to promote hypertrophy of the future remnant liver to reduce postoperative liver failure. Whether PVE accelerates tumor growth is still controversial. We developed a left PVE procedure and investigated its effect on liver hypertrophy and tumor growth in a rabbit liver tumor model. MATERIALS AND METHODS: VX2 tumors were implanted in both the external left and right middle lobe (the bilateral group) or in the external left lobe only (the unilateral group) of rabbit liver. Both groups were further divided into a PVE or a sham/control group. Tumor volume and tumor growth rate as volume relative increase were determined by ultrasound. Liver volume-to-body weight index, an index for liver volume, was compared. Serum HGF was measured by ELISA. RESULTS: In the bilateral PVE group, tumor volume and relative increase value in the nonembolized lobe were significantly (71% and 65%, respectively) greater than those in the control group at 5 d post-PVE. In the unilateral PVE group, liver volume-to-body weight index of the nonembolized lobes was significantly increased by 17%. Increase of serum HGF level after PVE was correlated well with both tumor growth and liver hypertrophy. CONCLUSIONS: Left PVE promoted both the growth of implanted tumors and liver hypertrophy in the nonembolized liver, in which serum HGF might play an important role. PMID- 22494914 TI - Mesenteric ischemia-reperfusion injury: clearly improved hemodynamics but only minor protection of the rat small intestine by (sub)therapeutic heparin sodium and enoxaparin doses. AB - BACKGROUND: Tissue protection against ischemia (I)/reperfusion (R) injury by heparins can be due to their anticoagulant and/or non-anticoagulant properties. Here we studied the protective potential of the anticoagulant and the non anticoagulant features of heparin sodium (HepSo) and enoxaparin (Enox) against mesenteric I/R injury in a rat model. MATERIALS AND METHODS: Mesenteric I/R was induced in rats (n = 6 per group) by superior mesenteric artery occlusion (SMAO; 90 min) and reopening (120 min). Therapeutic/clinical and subtherapeutic/non anticoagulant doses of HepSo (0.25 mg/kg bolus + 0.25 mg/kg * h; 0.05 mg/kg bolus + 0.1 mg/kg * h) or Enox (0.5 mg/kg bolus + 0.5 mg/kg * h; 0.05 mg/kg bolus + 0.1 mg/kg * h) were administered intravenously starting 30 min before SMAO to the end of reperfusion. Systemic/vital and intestinal microcirculatory parameters were measured during the whole experimental procedure, those of small intestine injury at the end. RESULTS: During intestinal reperfusion, mean arterial blood pressure and heart rates were significantly increased by HepSo and, less effectively, by Enox, in a dose-dependent manner. Intestinal microcirculation was only affected by the therapeutic HepSo dose, which decreased the microvascular flow and S(O2) during reperfusion. The subtherapeutic Enox treatment, as opposed to any HepSo dose, most effectively diminished I/R-induced intestinal hemorrhages, myeloperoxidase activity (as a measure of neutrophil invasion), and histopathological changes. CONCLUSION: Therapeutic but, to a lesser extent, also the subtherapeutic doses of both HepSo and Enox clearly improve hemodynamics during mesenteric reperfusion, while intestinal protection is exclusively provided by Enox, especially at its subtherapeutic dose. Alterations in intestinal microcirculation are not responsible for these effects. Thus, non anticoagulant Enox doses and, preferably, heparin(oid)s unable to affect coagulation, could diminish clinical risks of I/R-induced gastrointestinal complications. PMID- 22494915 TI - Commentary on "Interaction between Kupffer cells and platelets in the early period of hepatic ischemia-reperfusion injury". PMID- 22494916 TI - The challenge behind brain death organ transplantation in liver ischemia and reperfusion injury. PMID- 22494917 TI - Maternal dietary patterns and associated nutrient intakes during each trimester of pregnancy. AB - OBJECTIVE: To determine the main dietary patterns of pregnant women during each of the three trimesters of pregnancy and to examine associated nutrient intakes. DESIGN: Participants completed a 3 d food diary during each trimester of pregnancy. Thirty-six food groups were created and dietary patterns were derived using k-means cluster analysis. SETTING: National Maternity Hospital, Dublin, Ireland. SUBJECTS: Two hundred and eighty-five healthy pregnant women aged between 20 and 41 years. RESULTS: Two dietary patterns were identified at each time point. They were labelled 'Unhealthy' (n =143, 150 and 155 at trimester 1, 2 and 3, respectively) and 'Health Conscious' (n 142, 135 and 130 at trimester 1, 2 and 3, respectively). Women in the 'Health Conscious' cluster were significantly older, had lower BMI and were higher educated than those in the 'Unhealthy' cluster. Of those in the 'Unhealthy' cluster in the first trimester (n =143), 103 (72.0 %) continued in this dietary pattern into trimester 2 and eighty-one (56.6 %) continued into trimester 3. Of those in the 'Health Conscious' cluster in trimester 1 (n =142), ninety-five (66.9 %) continued in this dietary pattern into trimester 2 and sixty-nine (48.6 %) continued into trimester 3. CONCLUSIONS: Cluster analysis produced two clearly defined dietary patterns at each stage of pregnancy. Knowledge of maternal dietary patterns is important for the development of pregnancy-specific dietary guidelines. Identifying women with an 'Unhealthy' dietary pattern in early pregnancy affords the opportunity for a dietary intervention which may positively impact both maternal and infant health. PMID- 22494918 TI - Effects of pulsed infra-red low level-laser irradiation on open skin wound healing of healthy and streptozotocin-induced diabetic rats by biomechanical evaluation. AB - Diabetes is one of the most common causes of delayed wound healing. Low-level laser therapy (LLLT) are one of the therapeutic modalities used for the treatment of wounds. The aim of present study is to evaluate the effect of LLLT in experimentally-induced diabetic rats. Two full thickness skin incisions were made on dorsal regions of each rat. The wounds were randomly divided into laser treated and placebo. Laser-treated wounds of the healthy (non-diabetic) animals were submitted to a pulsed-infrared 890nm laser with an 80Hz frequency and 0.03J/cm(2) for each wound point in the first healthy group and 0.2J/cm(2) in the second healthy group. Laser-treated wounds of the diabetic animals received the same pulsed-infrared laser treatments as the second group for each wound point. On day 15, a sample from each wound was extracted and submitted for tensile strength evaluation. Laser irradiation with 0.03J/cm(2) significantly decreased the maximum load for wound repair in healthy rats (p=0.015). Laser irradiation with 0.2J/cm(2) significantly increased the maximum load in wounds from the healthy control (p=0.021) and diabetic (p<001) groups. Laser treatments with a pulsed infrared laser at 0.2J/cm(2) significantly accelerated wound healing in both healthy and diabetic rats. PMID- 22494919 TI - Absence of C-C motif chemokine ligand 5 in mice leads to decreased local macrophage recruitment and behavioral hypersensitivity in a murine neuropathic pain model. AB - Accumulated evidence suggests that the C-C motif chemokine ligand 5 (CCL5) modulates migration of inflammatory cells in several pathological conditions. This study tested the hypothesis that lack of CCL5 would modulate the recruitment of inflammatory cells to painful, inflamed sites and could attenuate pain in a murine chronic neuropathic pain model. Nociceptive sensitization, immune cell infiltration, multiple cytokine expression, and opioid peptide expression in damaged nerves were studied in wild-type (CCL5 +/+) and CCL5-deficient (CCL5 -/-) mice after partial sciatic nerve ligation (PSNL). Results indicated that CCL5 -/- mice had less behavioral hypersensitivity after PSNL. Macrophage infiltration and proinflammatory cytokines (tumor necrosis factor-alpha, interleukin [IL]-1beta, IL-6, and interferon-gamma) in damaged nerves following PSNL were significantly decreased in CCL5 -/- mice. Conversely, several antiinflammatory cytokine (IL-4 and IL-10) proteins were significantly increased in CCL5 -/- animals and the expression of enkephalin, beta-endorphin, and dynorphin mRNA was significantly lower than in wild-type control mice. These results represent the first evidence that CCL5 is capable of regulating the pathway that controls hyperalgesia at the level of the peripheral injured site in a murine chronic neuropathic pain model. We demonstrated that lack of CCL5 modulated cell infiltration and the proinflammatory milieu within the injured nerve. Attenuated behavioral hypersensitivity in CCL5 -/- mice observed in the current study could be a result of decreased macrophage infiltration, mobilization, and functional ability at injured sites. Collectively, the present study results suggest that CCL5 receptor antagonists may ultimately provide a novel class of analgesics for therapeutic intervention in chronic neuropathic pain. PMID- 22494920 TI - Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations. AB - A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo ("assay sensitivity"). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence-based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety. PMID- 22494921 TI - How does the lidocaine patch (5%) relieve pain? PMID- 22494922 TI - Age-related differences in predictive response timing in children: evidence from regularly relative to irregularly paced reaction time performance. AB - Predictive timing refers to the anticipation and precise timing of planned motor responses. This study was performed to investigate children's predictive response timing abilities while accounting for confounding age-related effects of motor speed. Indices of predictive timing were evaluated for their contributions in motor skill proficiency as well. Eighty typically developing children in 4 age groups (5-6, 7-8, 9-10 and 11-12 years) performed a visuomotor reaction time (RT) test. Differences in speed and anticipatory responding at regularly relative to irregularly paced stimuli were evaluated as indices of predictive timing. Also, explicit timing and motor tests (M-ABC-2, VMI tracing, and KTK jumping) were administered. Significant faster responding for regularly versus irregularly paced stimuli was found from the ages of 9-10 years on. Better anticipatory responding behavior for regular in contrast with irregular stimuli was found to be present already at 7-8 years. Overall, predictive timing abilities increased across the 4 age groups. Also, inter-individual differences in the speed indices of predictive timing contributed to predicting VMI tracing and KTK jumping outcomes when controlling for age and overall motor response speed. In conclusion, predictive motor timing abilities increase during age 5 to 12 and correlate with motor skill performance. PMID- 22494923 TI - Recording and sorting live human sperm undergoing acrosome reaction. AB - OBJECTIVE: To develop and evaluate a method to detect acrosome reaction (AR) in live human sperm. DESIGN: Prospective study. SETTING: Basic research laboratory. PATIENT(S): Human semen samples with normal parameters obtained from healthy donors. INTERVENTION(S): Acrosome reaction assays. MAIN OUTCOME MEASURE(S): Fluorescence assessment of AR. RESULT(S): Evaluating acrosomal exocytosis in live human sperm is challenging. In this study, we report that in reacting sperm, Pisum sativum agglutinin conjugated to fluorescein isothiocyanate rapidly permeates into the acrosome when fusion pores open and stabilizes the acrosomal matrix, preventing the dispersal of the granule contents. CONCLUSION(S): Fluorescent Pisum sativum agglutinin can be used to visualize AR in real time, to determine the percentage of sperm undergoing exocytosis upon stimulation, and to separate the population of reacting sperm by flow cytometry. PMID- 22494924 TI - Serum progesterone level effects on the outcome of in vitro fertilization in patients with different ovarian response: an analysis of more than 10,000 cycles. AB - OBJECTIVE: To investigate the relationship between serum P levels on the day of hCG administration and pregnancy outcomes in different responders undergoing IVF. DESIGN: Retrospective study. SETTING: Teaching hospital. PATIENT(S): A total of 11,055 women who underwent their first IVF/intracytoplasmic sperm injection cycles and a subgroup of 4,021 women undergoing frozen-embryo transfer (FET) cycles. INTERVENTION(S): Patients underwent IVF-ET with the long GnRH agonist protocol. The ovarian response was classified as high (>= 20 oocytes; n = 2,023), poor (<= 4 oocytes; n = 827), or intermediate (remaining cases; n = 8,205) according to the number of oocytes retrieved. Clinical outcomes of IVF-ET and FET cycles were analyzed according to plasma P levels. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rates (PRs). RESULT(S): Ongoing PRs in fresh cycle were inversely associated with serum P levels on the day of hCG administration for all patients. Different P threshold concentrations were determined according to different ovarian response: We proposed a serum P level of 1.5 ng/mL as the threshold for poor responders, 1.75 ng/mL for intermediate responders, and 2.25 ng/mL for high responders. Our study does not show negative results for elevated P levels on oocyte performance in terms of fertilization, cleavage rate, or PR of FET cycles within different ovarian responses, offering no evidence for a detrimental effect of high P on oocyte quality. CONCLUSION(S): Elevated P levels on the day of hCG administration negatively influence PR regardless of different ovarian responses, although increased P threshold concentration is associated with better ovarian responses. The detrimental effect of P elevation on PR seems to be unrelated to oocyte quality in all responders. PMID- 22494925 TI - Circulating vitamin D correlates with serum antimullerian hormone levels in late reproductive-aged women: Women's Interagency HIV Study. AB - OBJECTIVE: To study the correlation between circulating 25-hydroxyvitamin D (25OH D) levels and serum antimullerian hormone (AMH) in women enrolled in the Women's Interagency HIV Study. DESIGN: Cross-sectional study. SETTING: None. PATIENT(S): All premenopausal women (n = 388) with regular menstrual cycles were included and subdivided into three groups: group 1 with age <35 years (n = 128), group 2 with age 35-39 years (n = 119), and group 3 with age >=40 years (n = 141). INTERVENTION(S): Serum for 25OH-D, AMH, fasting glucose and insulin, and creatinine levels. MAIN OUTCOME MEASURE(S): Correlation between 25OH-D and AMH before and after adjusting for HIV status, body mass index, race, smoking, illicit drug use, glucose and insulin levels, estimated glomerular filtration rate, and geographic site of participation. RESULT(S): After adjusting for all covariates, the regression slope in all participants for total 25OH-D predicting log(10)AMH for 25-year-olds (youngest participant) was -0.001 (SE = 0.008); and for 45-year-olds (oldest participant) the corresponding slope was +0.011 (SE = 0.005). Fasting insulin level was negatively correlated with serum AMH. The regression slope for the correlation between 25OH-D and AMH in group 1 was +0.002 (SE = 0.006); in group 2 was +0.006 (SE = 0.005); and in group 3 was +0.011 (SE = 0.005). There was no association between HIV and AMH. CONCLUSION(S): A novel relationship is reported between circulating 25OH-D and AMH in women aged >=40 years, suggesting that 25OH-D deficiency might be associated with lower ovarian reserve in late-reproductive-aged women. PMID- 22494926 TI - Peak serum estradiol level during controlled ovarian hyperstimulation is associated with increased risk of small for gestational age and preeclampsia in singleton pregnancies after in vitro fertilization. AB - OBJECTIVE: To assess the impact of elevated peak serum E(2) levels (EPE(2); defined as levels >90th percentile) on the day of hCG administration during controlled ovarian hyperstimulation (COH) for IVF on the likelihood for small for gestational age (SGA), preeclampsia (PreE), and preterm delivery (PTD) in singleton pregnancies. DESIGN: Retrospective cohort study. SETTING: Tertiary-care academic medical center. PATIENT(S): Singleton live-birth pregnancies conceived after fresh IVF-ET. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The delivery rate of SGA infants and the development of PreE and PTD in patients with and without EPE(2). RESULT(S): Patients with EPE(2) during COH were more likely to deliver SGA infants (7 [26.9%] vs. 10 [3.8%]; odds ratio [OR], 95% confidence interval [CI] {9.40, 3.22-27.46}) and develop PreE (5 [18.5%] vs. 12 [4.5%]; adjusted OR, 95% CI {4.79, 1.55-14.84}). No association was found between EPE(2) and the likelihood for delivery before 37 weeks, 35 weeks, or 32 weeks of gestation. Receiver operating characteristic analysis revealed that EPE(2) level predicted adverse obstetrical outcome (SGA + PreE) with 38.5% and 91.7% sensitivity and specificity, respectively. Using a serum peak E(2) cutoff value of 3,450 pg/mL (>90th percentile level), the positive predictive value was 37%, while the negative predictive value was 92%. CONCLUSION(S): EPE(2) level (>3,450 pg/mL) on the day of hCG administration during COH is associated with greater odds of developing PreE and delivery of an SGA infant in singleton pregnancies resulting from IVF cycles. PMID- 22494928 TI - Rapid and sensitive measurement of PET radioligands in plasma by fast liquid chromatography/radiometric detection. AB - A fast and sensitive liquid chromatographic (fast-LC) method with radiometric detection was developed and validated to analyze positron emission tomography (PET) radioligands in plasma during PET studies. The plasma samples were deproteinized with acetonitrile and the extracts were injected into the fast-LC system coupled to an on-line radioactivity detector. Under the optimum conditions, complete separation of target PET radioligands from their radioactive metabolites was achieved within the short run time of only 3.5-min. The limits of detection were 1.0-1.2 Becquerel (Bq) for (11)C and (18)F-labeled compounds. This method can successfully be applied to study the metabolism of a wide variety of PET radioligands in human and monkey plasma with higher numbers of samples to be analyzed compared to the traditional LC method. PMID- 22494929 TI - Meta-analysis of two genome-wide association studies identifies four genetic loci associated with thyroid function. AB - Thyroid hormones play key roles in cellular growth, development and metabolism. Although there is a strong genetic influence on thyroid hormone levels, the genes involved are widely unknown. The levels of circulating thyroid hormones are tightly regulated by thyrotropin (TSH), which also represents the most important diagnostic marker for thyroid function. Therefore, in order to identify genetic loci associated with TSH levels, we performed a discovery meta-analysis of two genome-wide association studies including two cohorts from Germany, KORA (n = 1287) and SHIP (n = 2449), resulting in a total sample size of 3736. Four genetic loci at 5q13.3, 1p36, 16q23 and 4q31 were associated with serum TSH levels. The lead single-nucleotide polymorphisms of these four loci were located within PDE8B encoding phosphodiesterase 8B, upstream of CAPZB that encodes the beta-subunit of the barbed-end F-actin-binding protein, in a former 'gene desert' that was recently demonstrated to encode a functional gene (LOC440389) associated with thyroid volume, and upstream of NR3C2 encoding the mineralocorticoid receptor. The latter association for the first time suggests the modulation of thyroid function by mineral corticoids. All four loci were replicated in three additional cohorts: the HUNT study from Norway (n = 1487) and the two German studies CARLA (CARLA, n = 1357) and SHIP-TREND (n = 883). Together, these four quantitative trait loci accounted for ~3.3% of the variance in TSH serum levels. These results contribute to our understanding of genetic factors and physiological mechanisms mediating thyroid function. PMID- 22494930 TI - Surgical therapy of an asymptomatic primary popliteal venous aneurysm. AB - Primary popliteal venous aneurysm is a rare condition. To date, approximately 150 cases have been reported. In the present article, we report a 59-year-old man who presented with a swelling of the left popliteal fossa. Duplex ultrasound scan revealed a saccular aneurysm of the popliteal vein, with a diameter of 2.5 * 2.5 cm. The distal part of the popliteal vein was dilated in a fusiform configuration up to 2.0 cm on both sides. The diagnosis was confirmed using magnetic resonance imaging and ascending phlebography. There was no sign of venous thrombosis. Our patient presented without any previous clinical evidence of pulmonary emboli. Surgery was deemed indicated. A traditional tangential aneurysmectomy and lateral venorrhaphy of the distal fusiform part of the popliteal lesion was performed as well as resection of the saccular part using a dorsal approach. Surgery and recovery were uneventful. The patient presented for follow-up after 6 and 12 weeks without any complaints. Duplex ultrasound scanning and ascending phlebography (only once after 12 weeks) were performed, which confirmed patency. PMID- 22494931 TI - Eversion carotid endarterectomy--our experience after 20 years of carotid surgery and 9897 carotid endarterectomy procedures. AB - BACKGROUND: The aim of this article is to review our experience in surgical treatment of carotid atherosclerosis using eversion carotid endarterectomy (eCEA) in 9,897 patients performed in the last 20 years, with particular attention to diagnostic approach, surgical technique, medical therapy, and final outcome. METHODS: From January 1991 to December 2010, 9,897 primary eCEAs were performed for high-grade carotid stenosis. Patients treated for restenosis after previous carotid surgery were excluded from the analysis. Follow-up included routine clinical evaluation and noninvasive surveillance, with duplex scanning, 1 and 6 months after surgery, and annually afterward. RESULTS: The majority of the patients were symptomatic (stroke, 42.8%; transient ischemic attack, 55.1% [focal cerebral and retinal ischemia]), whereas only 2.1% of the patients were asymptomatic. For the final diagnosis, duplex scanning was performed in 83.4% of patients and angiography in only 16.3% (P < 0.001). Average carotid artery clamping time was 11.9 +/- 3.2 minutes, and the majority of the patients were operated under general anesthesia (99.4%). Intraoperative shunting and local anesthesia were rarely performed; 0.6% of the patients were operated under local anesthesia, and in 0.5% of the patients, intraluminal shunt was used. Neurological and total morbidity showed a steady decline over time, with rate of neurological morbidity of 1.1% and total morbidity of 3.9% at the end of 2010. Neurological mortality and total mortality also showed a steady decline over time, with rate of neurological mortality of 0.3% and total mortality of 0.8% at the end of 2010. There was a low rate of both, nonsignificant restenosis (<50%), which was verified in 2.1% of the patients, and significant restenosis (>50%), which was observed in 4.3% of the patients. CONCLUSION: Our data show that eCEA is a reliable surgical technique for the treatment of atherosclerotic carotid disease, with low morbidity and mortality. The specificity of our experience is the significant number of patients with preoperative stroke, but despite this fact, results are comparable with previously published series. It also highlights the importance of comprehensive surgical training in reducing complications. PMID- 22494932 TI - Expression, prognostic and predictive impact of VEGF and bFGF in non-small cell lung cancer. AB - Despite major advances in cancer therapeutics, the prognosis for lung cancer patients is still poor and the median survival for patients presenting with advanced non-small cell lung cancer (NSCLC) is only 8-10 months. Angiogenesis is an important biological process and a relatively early event during lung cancer pathogenesis. Anti-angiogenic agents are used in treating patients with NSCLC, and their molecular biomarkers are also being assessed to predict response. A better understanding of the biology of angiogenesis in NSCLC may reveal new targets for treating this malignancy. In this article, we review the expression and prognostic impact of the angiogenic growth factors, vascular endothelial growth factor and basic fibroblast growth factor, in NSCLC. PMID- 22494933 TI - Targeted agents to reverse resistance to endocrine therapy in metastatic breast cancer: where are we now and where are we going? AB - Endocrine therapy is the most important systemic therapy for hormone receptor positive breast cancer; however, some patients with ER+ breast cancer show intrinsic resistance to endocrine therapy, whereas others develop acquired resistance. Preclinical models have shown that endocrine resistance is associated with enhanced expression of membrane growth factor pathways or activation of various intracellular pathways involved in signal transduction and cell survival. Despite encouraging preclinical data, clinical trials investigating the combination of endocrine therapy with trastuzumab or the TKIs gefitinib, erlotinib and lapatinib have yielded varied results. This may be related to some limitations in the studies conducted so far: lack of appropriate patient selection and stratification based on previous endocrine exposure and/or sensitivity; lack of identification of a molecular biomarker; lack of appropriate clinical endpoints in the trial design. More promising results come from clinical studies which have focused on novel agents such as the mTOR inhibitor everolimus. The two randomized trials (BOLERO-2 and TAMRAD) evaluating everolimus+/-endocrine therapy in a selected subgroup of HR-positive metastatic breast cancer patients have demonstrated a significant improvement in progression free survival for the combination compared to the endocrine therapy alone. The data reported so far show that the combination of target agents with endocrine therapy is effective in overcoming acquired resistance in patients with hormone receptor positive metastatic breast cancer. However, this therapeutic strategy is not yet a standard treatment for this patients. Application of more rigorous trial design, tumor and patient selection criteria will be important to better understand the complexity of endocrine resistance. PMID- 22494934 TI - Methylmercury and elemental mercury differentially associate with blood pressure among dental professionals. AB - Methylmercury-associated effects on the cardiovascular system have been documented though discrepancies exist, and most studied populations experience elevated methylmercury exposures. No paper has investigated the impact of low level elemental (inorganic) mercury exposure on cardiovascular risk in humans. The purpose of this study was to increase understanding of the association between mercury exposure (methylmercury and elemental mercury) and blood pressure measures in a cohort of dental professionals that experience background exposures to both mercury forms. Dental professionals were recruited during the 2010 Michigan Dental Association Annual Convention. Mercury levels in hair and urine samples were analyzed as biomarkers of methylmercury and elemental mercury exposure, respectively. Blood pressure (systolic, diastolic) was measured using an automated device. Distribution of mercury in hair (mean, range: 0.45, 0.02 5.18 MUg/g) and urine (0.94, 0.03-5.54 MUg/L) correspond well with the US National Health and Nutrition Examination Survey. Linear regression models revealed significant associations between diastolic blood pressure (adjusted for blood pressure medication use) and hair mercury (n=262, p=0.02). Urine mercury results opposed hair mercury in many ways. Notably, elemental mercury exposure was associated with a significant systolic blood pressure decrease (n=262, p=0.04) that was driven by the male population. Associations between blood pressure and two forms of mercury were found at exposure levels relevant to the general population, and associations varied according to type of mercury exposure and gender. PMID- 22494935 TI - Reference ranges for key biomarkers of chemical exposure within the UK population. AB - Human biomonitoring (HBM) is a widely accepted tool to aid assessment of chemical uptake in risk assessment. However, our understanding of the biological relevance of the results of HBM can be restricted, due in some part to the limited information on background environmental exposures and biomarker concentrations in the general population. The study described here specifically addresses the question of what constitutes normal background levels in the UK population of a number of biomarkers (the chemical itself or one of its stable metabolites) for a variety of environmental chemicals that are frequently encountered because of their widespread use. The environmental chemicals selected for this study were benzene, chlorinated hydrocarbons, dithiocarbamates, cadmium, mercury, naphthalene, diethylhexyl phthalate, synthetic pyrethroids and xylene. Volunteers (n=436) were randomly sought by a postal survey based on the UK Electoral Register. Participants were asked to complete a questionnaire and provide a urine sample. The overall response rate was 7.5%, with volunteers being recruited from all areas of the UK including, England, Scotland, Wales and Northern Ireland. Study participants were adults and comprised 45% male and 55% females. We have conducted a simple, postal-based, cost-effective study and generated similar reference values to very large surveys such as NHANES. This demonstrates that large investigations may not be necessary to get a reasonable idea of environmental exposures, especially in initial 'screening-type' investigations to identify particular exposures of concern or to demonstrate that exposures are reassuring low and that no further survey data needs to be gathered. PMID- 22494936 TI - Umbilical cord blood levels of perfluoroalkyl acids and polybrominated flame retardants. AB - Perfluoroalkyl acids (PFAAs) and polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants representing two classes of environmental contaminants of toxicological concern, especially for infants. Canadian biomonitoring data on these chemicals are limited. The objectives of this study were to measure PFAAs and PBDEs in umbilical cord blood from approximately 100 hospital deliveries in Ottawa (Ontario, Canada) and examine associations with characteristics of the mother and infant. Geometric means were 1.469 ng/mL for perfluorooctanoate (PFOA) (95% confidence interval of 1.292-1.671 ng/mL), 4.443 ng/mL for perfluorooctane sulfonate (PFOS) (95% CI of 3.735-5.285 ng/mL), 0.359 ng/mL for perfluorononanoic acid (PFNA) (95% CI of 0.318-0.404 ng/mL), and 0.579 ng/mL for perfluorohexanesulfonate (PFHxS) (95% CI of 0.473-0.709 ng/mL). The final multiple regression models indicated that lower gravida, term gestational age, smoking during pregnancy and vaginal delivery were significantly associated with higher levels of PFOS. Similarly, a vaginal delivery was significantly associated with higher PFOA, while weak associations were found with lower gravida and birth weight less than 2500 g. Furthermore, higher PFNA concentrations were significantly associated with older mothers, and vaginal delivery, while weakly associated with term gestational age. Elevated PFHxS concentrations were significantly associated with smoking during pregnancy and lower gravida. Similar to reports from other countries, the preponderant PBDE congener measured in the cord blood was PBDE-47. Questions remain on why various studies have reported conflicting results on the association between PFAAs and birth weight. PMID- 22494937 TI - Eimeria tenella heat shock protein 70 enhances protection of recombinant microneme protein MIC2 subunit antigen vaccination against E. tenella challenge. AB - Heat shock proteins have been reported to stimulate the immune system via innate receptors. Our study found that the novel immunopotentiator, Eimeria tenella (E. tenella) heat shock protein 70 (HSP70), enhanced protective immunity elicited by E. tenella antigen microneme protein 2 (EtMIC2) against avian coccidiosis. It demonstrated that the expression of TLR2 and TLR4 were strongly upregulated in EtHSP70 and EtMIC2 plus EtHSP70 stimulated chicken embryo fibroblasts (CEF) compared with untreated controls and EtMIC2 alone. In addition, the same treatment induced high levels of interleukin (IL)-12 and interferon (IFN)-gamma that are critical cytokines of innate immunity. In vivo experiments involved using broiler chickens subcutaneously immunized with EtMIC2 alone or EtMIC2 plus EtHSP70 at 7 and 14 days post-hatch, which were then orally challenged with live E. tenella at 7 days following secondary immunization. Body weight gains, cecal lesion scores, fecal oocyst shedding, serum antibody responses against MIC2, and intestinal cytokine transcript levels were assessed as measures of protective immunity. Chickens immunized with EtMIC2 plus EtHSP70 showed increased body weight gains, decreased oocyst shedding, increased serum antibody responses, and high levels of IL-12, IFN-gamma, and IL-17 compared with the EtMIC2 only or control groups. Moreover, chickens immunized with EtHSP70 alone showed significantly protective effect against E. tenella infection. In summary, this study provides the first evidence of the immunoenhancing activities of EtHSP70 in poultry. PMID- 22494938 TI - Genetic analysis of Trichuris suis and Trichuris trichiura recovered from humans and pigs in a sympatric setting in Uganda. AB - The whipworms Trichuris trichiura and Trichuris suis in humans and pigs, respectively, are believed to be two different species yet closely related. Morphologically, adult worms, eggs and larvae of the two species are indistinguishable. The aim of this study was to examine the genetic variation of Trichuris sp. mainly recovered from natural infected pigs and humans. Worm material isolated from humans and pigs living in the same geographical region in Uganda were analyzed by PCR, cloning and sequencing. Measurements of morphometric characters were also performed. The analysis of the ITS-2 (internal transcribed spacer) region showed a high genetic variation in the human-derived worms with two sequence types, designated type 1 and type 2, differing with up to 45%, the type 2 being identical to the sequence found in pig-derived worms. A single human derived worm showed exclusively the type 2-genotype (T. suis-type) and three cases of 'heterozygote' worms in humans were identified. However, the analysis showed that sympatric Trichuris primarily assorted with host origin. Sequence analysis of a part of the genetically conserved beta-tubulin gene confirmed two separate populations/species but also showed that the 'heterozygote' worms had a T. suis-like beta-tubulin gene. A PCR-RFLP on the ITS-2 region was developed, that could distinguish between worms of the pig, human and 'heterozygote' type. The data suggest that Trichuris in pigs and humans belong to two different populations (i.e. are two different species). However, the data presented also suggest that cross-infections of humans with T. suis takes place. Further studies on sympatric Trichuris populations are highly warranted in order to explore transmission dynamics and unravel the zoonotic potential of T. suis. PMID- 22494939 TI - Evaluation of dicyclanil (CLiKZiN(r)) treatment for the early-season protection of ewes against blowfly strike. AB - Protecting sheep against early season myiasis (strike) is a significant problem in northern temperate farming systems, where fully-fleeced ewes and early-season lambs approaching market weight, are at high initial risk. Here, the prevention of early-season blowfly strike in ewes was examined on matched commercial sheep farms in south west England, using a new formulation of dicyclanil (CLiKZiN((r)) pour on) with a short withdrawal period of 7 days. The ewes on seven farms received a prophylactic treatment with dicyclanil (CLiKZiN 1.25% pour-on suspension) in April 2011; ewes on three control farms received no treatment. The lambs at all farms remained untreated. No adverse reactions to treatment were recorded. On the treatment farms no ewe strikes were recorded between April and June (10 weeks). On control farms, there were 16 strike cases in ewes over the same period, giving a cumulative incidence of 31 cases per 1000 ewes. On the treatment farms only one lamb was struck whereas at the control farms 10 lamb strikes were recorded. The data demonstrate that CLiKZiN was highly effective at protecting ewes against early season strike-challenge. PMID- 22494940 TI - Prevalence of Parascaris equorum infection in foals on French stud farms and first report of ivermectin-resistant P. equorum populations in France. PMID- 22494941 TI - Climate and the epidemiology of gastrointestinal nematode infections of sheep in Europe. AB - The free-living stages of gastrointestinal nematode parasites of sheep are strongly affected by climate. Thus, extreme heat and cold are detrimental to development and survival, while, within tolerable limits, increasing temperatures generally accelerate development but increase mortality. Moisture is needed for development and translation of larvae from faeces to pasture, and so rainfall is a limiting factor for transmission. Together, these factors underpin seasonal patterns of infection in sheep, as well as geographic variation in the epidemiology and relative importance of different species within Europe. Local knowledge and experience enable treatment to be targeted appropriately to prevent dangerous levels of infection. This traditional know-how can be supplemented by predictive epidemiological models, built on thorough understanding of the influence of climate on larval availability. However, management also has a dominant role in determining patterns of infection, and is itself influenced by climate. Current geographic variation in nematode epidemiology across Europe, and knowledge of systems from outside Europe, can provide only limited perspectives on the likely effects of climate change on disease in future. This is because disease arises from complex interaction between host and parasite factors, and the implementation of optimal control strategies to meet new challenges will be slowed by the inertia of current systems. Approaches to nematode control must therefore take account not only of parasite biology, but also the forces that shape sheep farming systems and management decisions. PMID- 22494942 TI - Caligus sclerotinosus (Copepoda: Caligidae), a serious pest of cultured red seabream Pagrus major (Sparidae) in Korea. AB - Caligid copepods (Crustacea) known as sea lice are pests of cultured fish, causing serious diseases and economic losses in fish aquaculture worldwide. One species, Caligus sclerotinosus Roubal, Armitage & Rohde, 1983 (Caligidae), is considered a serious pest of the highly prized red seabream Pagrus major (Temminck and Schlegel, 1843) (Sparidae) cultured in Japan. Recently, in neighboring Korea, red seabream culture has intensified and almost replaced yellow tail culture. However, until now, there have been no reports on infection of this sea louse from red seabream in Korea. We surveyed 120 (20 fish per month) P. major from a sea ranched Tongyeong Marine Research Center aquaculture facility, Gyeongsangnamdo, Korea for six months in 2011 (June to November). We recorded severe infection by the sea louse C. sclerotinosus on the skin of P. major. Prevalence was 100%, mean intensity 7.06, maximum intensity 49, and minimum intensity 2. Adult females (624), males (219) and few chalimi (5) were observed and identified by their morphology. As an average of all our collections, less than 0.6% of individuals were chalimi. We suggest, therefore, that adults of C. sclerotinosus undergo ontogenetic host switching after their final moult. No infection of C. sclerotinosus was found on wild P. major collected from Tongyeong and Yeosu fish markets on the southern coast of Korea. Severe infection by this sea louse may cause secondary infections of the host. This copepod is already reported from Australia and Japan and hence, this is the first report from Korea. We expect this pest to have an impact on Korean red seabream fisheries equally serious to that being experienced in Japan. PMID- 22494943 TI - Echinococcus multilocularis in dogs from two French endemic areas: no evidence of infection but hazardous deworming practices. AB - The life cycle of the zoonotic parasite Echinococcus multilocularis is predominantly sylvatic, involving foxes as definitive hosts infected by predation of rodents, the intermediate hosts. The North-Eastern French departments of Meuse and Haute-Saone are highly endemic, with an estimated fox prevalence of 41% and 36% respectively. Although most of the parasites' biomass occurs in foxes, domestic dogs can also be infected, leading to a major risk of human infection due to the close proximity of dogs and owners. In the present study, dog faeces were collected after praziquantel treatment provided by veterinarians. In all, 860 faecal samples were collected throughout Meuse (n=493) and Haute-Saone (n=367). Intestinal helminth eggs were isolated from the faeces using a flotation technique and observed by microscopy. Parasite species were identified in samples positive for taeniid eggs by sequence analysis after PCR amplification. To study the factors associated with infestation, each sample was linked to a questionnaire filled in by the dog owners. Taeniid eggs were observed in seven faecal samples (0.8%) but none of them were positive for E. multilocularis. Thus, the apparent prevalence of E. multilocularis in dog populations is lower than 1.00% for Haute-Saone and lower than 0.75% for Meuse. In Haute-Saone, a high proportion of dogs observed suspected preying on rodents were not dewormed monthly. In endemic areas, these dogs must be considered at risk of transmitting E. multilocularis to humans. PMID- 22494944 TI - [Metabolic changes in prepuberty children with extrauterine growth restriction]. AB - INTRODUCTION: Extrauterine growth restriction (EUGR) is associated with severe nutritional deficit during the first weeks of life, which, as intrauterine growth restriction, may lead to metabolic anomalies in later stages of life. PATIENTS AND METHODS: A group of 38 prepuberty children with a history of EUGR were selected, along with a control group of 123 children with similar age and gender. Perinatal stage was assessed in the EUGR group. Anthropometric parameters, blood pressure, serum biochemical markers of carbohydrate metabolism, and lipid profile were measured in both groups. RESULTS: The EUGR group had height and body mass index values significantly lower than in the control group (P<.001) and higher systolic and diastolic blood pressure (P<.001). The majority (70%) of EUGR children were below the 50th percentile for weight and height, and 55% were below the 25th percentile for body mass index (P<.001), as well as 46% and 37% above the 95% percentile for systolic and diastolic blood pressure, respectively (P<.001). The EUGR group had higher glucose levels (P<.001) and lower high density lipoprotein cholesterol (HDLc) (P<.001) than the control group, although without clinical relevance. CONCLUSIONS: Children with a history of EUGR have anthropometric, blood pressure and metabolic alterations in the prepuberty stage. It would be desirable to control the nutrition they receive in the perinatal period, and follow them up in childhood as alterations may occur in the future. PMID- 22494945 TI - PPARgamma as a therapeutic target in cystic fibrosis. AB - Cystic fibrosis (CF) is characterized by a proinflammatory pulmonary condition that may result from increased infections and altered intracellular metabolism in CFTR-deficient cells. The lipid-activated transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma) has well-established roles in immune cell function and inflammatory modulation and has been demonstrated to play an important role in the heightened inflammatory response in CF cells. Here, we summarize current literature describing PPARgamma-dependent alterations of CF cells and discuss the potential of PPARgamma ligands for treating CF. PMID- 22494946 TI - Efficacy and retention of the French-Canadian version of the wheelchair skills training program for manual wheelchair users: a randomized controlled trial. AB - OBJECTIVES: To test the hypotheses that, in comparison with a control group that received standard care, users of manual wheelchairs who also received the French Canadian version of the Wheelchair Skills Training Program (WSTP) would significantly improve their wheelchair-skills capacity and that these improvements would be retained at 3 months. DESIGN: Multicenter, single-blind, randomized controlled trial. SETTING: Three rehabilitation centers in Montreal, Quebec, Canada. PARTICIPANTS: Manual wheelchair users (N=39), a sample of convenience. INTERVENTION: Participants were randomly allocated to the WSTP or control groups. Participants in both groups received standard care. Participants in the WSTP group also received a mean of 5.9 training sessions (a mean total duration of 5h and 36min). MAIN OUTCOME MEASURES: The French-Canadian version of the Wheelchair Skills Test (WST) (Version 3.2) was administered at evaluation at first time period (baseline) (t1), evaluation at second time period (posttraining) (t2) (a mean of 47d after t1), and at evaluation at third time period (follow-up) (t3) (a mean of 101d after t2). RESULTS: At t2, the mean +/- SD total percentage WST capacity scores were 77.4%+/-13.8% for the WSTP group and 69.8%+/-18.4% for the control group (P=.030). Most of this difference was due to the community-level skills (P=.002). The total and subtotal Wheelchair Skills Test scores at t3 decreased by <=0.5% from the t2 values, but differences between groups at t3, adjusting for t1, did not reach statistical significance (P>=.017 at a Bonferroni-adjusted alpha level of .005). CONCLUSION: WSTP training improves wheelchair skills immediately after training, particularly at the community skills level, but this study did not show statistically significant differences between the groups at 3 months. PMID- 22494947 TI - Physiotherapy exercise after fast-track total hip and knee arthroplasty: time for reconsideration? AB - Major surgery, including total hip arthroplasty (THA) and total knee arthroplasty (TKA), is followed by a convalescence period, during which the loss of muscle strength and function is considerable, especially early after surgery. In recent years, a combination of unimodal evidence-based perioperative care components has been demonstrated to enhance recovery, with decreased need for hospitalization, convalescence, and risk of medical complications after major surgery-the fast track methodology or enhanced recovery programs. It is the nature of this methodology to systematically and scientifically optimize all perioperative care components, with the overall goal of enhancing recovery. This is also the case for the care component "physiotherapy exercise" after THA and TKA. The 2 latest meta-analyses on the effectiveness of physiotherapy exercise after THA and TKA generally conclude that physiotherapy exercise after THA and TKA either does not work or is not very effective. The reason for this may be that the "pill" of physiotherapy exercise typically offered after THA and TKA does not contain the right active ingredients (too little intensity) or is offered at the wrong time (too late after surgery). We propose changing the focus to earlier initiated and more intensive physiotherapy exercise after THA and TKA (fast-track physiotherapy exercise), to reduce the early loss of muscle strength and function after surgery. Ideally, the physiotherapy exercise interventions after THA and TKA should be simple, using few and well-chosen exercises that are described in detail, adhering to basic exercise physiology principles, if possible. PMID- 22494948 TI - Association of race, socioeconomic status, and health care access with pressure ulcers after spinal cord injury. AB - OBJECTIVE: To assess the associations of race and socioeconomic status (SES) with pressure ulcers (PUs) after accounting for health care access among persons with spinal cord injury (SCI). DESIGN: Cross-sectional. SETTING: Large specialty hospital in the southeastern United States. PARTICIPANTS: Persons with traumatic SCI who (1) had residual effects from their injury, (2) were 18 years or older at the time of the survey, and (3) were a year or more postinjury at the time of survey (N=2549). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Outcomes were measured by a mail-in survey: having a current PU (yes vs no), having a PU in the past year with or without reduced sitting time (no PU, no reduced sitting time, month or less, >=5wk), and having at least 1 PU surgery since SCI onset (yes vs no). RESULTS: Of participants, 39.3% reported a PU in the past year, 19.9% had a current PU, and 21.9% reported having had surgery for a PU since their SCI onset. While race was preliminarily associated with each PU outcome, it became nonsignificant after controlling for SES and health care access. In each analysis, household income was significantly associated with PU outcomes after controlling for demographic and injury factors and remained significant after accounting for the health care access factors. Persons with lower income had higher odds of each PU outcome. Health care access was not consistently related to PU outcomes. CONCLUSIONS: Even after accounting for health care access, household income, a measure of SES, remained significantly associated with PU outcomes after SCI; however, race became nonsignificant. PMID- 22494949 TI - Multifocal osteonecrosis associated with human immunodeficiency virus infection. AB - The osteonecrosis has emerged in the last years as a potentially disabling osteoarticular complication in HIV-infected patients. There is a high prevalence of traditional risk factors for osteonecrosis development in these patients, but they also have factors associated to HIV infection in itself and the high activity antiretroviral therapy. The HIV-associated osteonecrosis often affects the hips, with a trend to bilaterally, but concomitant affection of 3 or more locations (multifocal osteonecrosis) has been infrequently reported. We present the case of a 49-years-old male patient, with long duration HIV infection and antiretroviral therapy, who developed osteonecrosis with concomitant affection of hips, knees, heels and tarsus. PMID- 22494950 TI - Epidemiology of fungal infection in burns: therapeutic implications. PMID- 22494951 TI - Body mass index, exercise, and other lifestyle factors in relation to age at natural menopause: analyses from the breakthrough generations study. AB - The authors examined the effect of women's lifestyles on the timing of natural menopause using data from a cross-sectional questionnaire used in the United Kingdom-based Breakthrough Generations Study in 2003-2011. The analyses included 50,678 women (21,511 who had experienced a natural menopause) who were 40-98 years of age at study entry and did not have a history of breast cancer. Cox competing risks proportional hazards models were fitted to examine the relation of age at natural menopause to lifestyle and anthropometric factors. Results were adjusted for age at reporting, smoking status at menopause, parity, and body mass index at age 40 years, as appropriate. All P values were 2-sided. High adult weight (P(trend) < 0.001), high body mass index (P(trend) < 0.001), weight gain between the ages of 20 and 40 years (P(trend) = 0.01), not smoking (P < 0.001), increased alcohol consumption (P(trend) < 0.001), regular strenuous exercise (P < 0.01), and not being a vegetarian (P < 0.001) were associated with older age at menopause. Neither height nor history of an eating disorder was associated with menopausal age. These findings show the importance of lifestyle factors in determining menopausal age. PMID- 22494952 TI - Growth hormone receptor polymorphism and growth hormone therapy response in children: a Bayesian meta-analysis. AB - Recombinant human growth hormone (rhGH) therapy is used in the long-term treatment of children with growth disorders, but there is considerable treatment response variability. The exon 3-deleted growth hormone receptor polymorphism (GHR(d3)) may account for some of this variability. The authors performed a systematic review (to April 2011), including investigator-only data, to quantify the effects of the GHR(fl-d3) and GHR(d3-d3) genotypes on rhGH therapy response and used a recently established Bayesian inheritance model-free approach to meta analyze the data. The primary outcome was the 1-year change-in-height standard deviation score for the 2 genotypes. Eighteen data sets from 12 studies (1,527 children) were included. After several prior assumptions were tested, the most appropriate inheritance model was codominant (posterior probability = 0.93). Compared with noncarriers, carriers had median differences in 1-year change-in height standard-deviation score of 0.09 (95% credible interval (CrI): 0.01, 0.17) for GHR(fl-d3) and of 0.14 (95% CrI: 0.02, 0.26) for GHR(d3-d3). However, the between-study standard deviation of 0.18 (95% CrI: 0.10, 0.33) was considerable. The authors tested by meta-regression for potential modifiers and found no substantial influence. They conclude that 1) the GHR(d3) polymorphism inheritance is codominant, contrasting with previous reports; 2) GHR(d3) genotypes account for modest increases in rhGH effects in children; and 3) considerable unexplained variability in responsiveness remains. PMID- 22494953 TI - Aerosolized MMR vaccine: evaluating potential transmission of components to vaccine administrators and contacts of vaccinees. AB - Although numerous operative and immunological advantages accompany aerosol immunization, potential vaccine virus transmission from the aerosol device to vaccine administrators or from aerosol vaccinees to their contacts requires further study. We conducted a clinical and serological follow-up study of vaccine administrators and matched classroom or household contacts of young adults who received the MMR vaccines by aerosol or injection. Differences in incidence of clinical adverse events between vaccinees and contacts were not statistically significant. No seroresponses to any components of MMR vaccine were noted among 25 matched contacts of persons receiving injected vaccines, and only one equivocal seroresponse was noted among 25 matched contacts of aerosol recipients. No seroresponses were observed in 3 persons who administered aerosol vaccine. The composite findings of this study provide additional evidence of the safety of this approach. PMID- 22494954 TI - MS clinical trials: what can subgroup analyses teach us? PMID- 22494955 TI - Prediction of potential for organ donation after cardiac death in patients in neurocritical state: a prospective observational study. AB - BACKGROUND: Successful donation of organs after cardiac death (DCD) requires identification of patients who will die within 60 min of withdrawal of life sustaining treatment (WLST). We aimed to validate a straightforward model to predict the likelihood of death within 60 min of WLST in patients with irreversible brain injury. METHODS: In this multicentre, observational study, we prospectively enrolled consecutive comatose patients with irreversible brain injury undergoing WLST at six medical centres in the USA and the Netherlands. We assessed four clinical characteristics (corneal reflex, cough reflex, best motor response, and oxygenation index) as predictor variables, which were selected on the basis of previous findings. We excluded patients who had brain death or were not intubated. The primary endpoint was death within 60 min of WLST. We used univariate and multivariable logistic regression analyses to assess associations with predictor variables. Points attributed to each variable were summed to create a predictive score for cardiac death in patients in neurocritical state (the DCD-N score). We assessed performance of the score using area under the curve analysis. FINDINGS: We included 178 patients, 82 (46%) of whom died within 60 min of WLST. Absent corneal reflexes (odds ratio [OR] 2.67, 95% CI 1.19-6.01; p=0.0173; 1 point), absent cough reflex (4.16, 1.79-9.70; p=0.0009; 2 points), extensor or absent motor responses (2.99, 1.22-7.34; p=0.0168; 1 point), and an oxygenation index score of more than 3.0 (2.31, 1.10-4.88; p=0.0276; 1 point) were predictive of death within 60 min of WLST. 59 of 82 patients who died within 60 min of WLST had DCD-N scores of 3 or more (72% sensitivity), and 75 of 96 of those who did not die within this interval had scores of 0-2 (78% specificity); taking into account the prevalence of death within 60 min in this population, a score of 3 or more was translated into a 74% chance of death within 60 min (positive predictive value) and a score of 0-2 translated into a 77% chance of survival beyond 60 min (negative predictive value). INTERPRETATION: The DCD-N score can be used to predict potential candidates for DCD in patients with non survivable brain injury. However, this score needs to be tested specifically in a cohort of potential donors participating in DCD protocols. FUNDING: None. PMID- 22494957 TI - Donation after cardiac death: enter the neurologist. PMID- 22494958 TI - Drive for muscularity and disordered eating among French adolescent boys: a sociocultural model. AB - The pursuit of muscularity is an important body image concern among boys which has been described within sociocultural models of risk for eating disorders. This study explored a sociocultural model of disordered eating in which drive for thinness and pursuit of muscularity were both pathways to disordered eating among French adolescent boys. A sample of 146 adolescents completed a questionnaire assessing drive for thinness, drive for muscularity, media-ideal internalization, appearance comparison, and sociocultural pressure. The model was a good fit to the data and both drive for thinness and the pursuit of muscularity were related to disordered eating. Furthermore, internalization and appearance comparison mediated the relationships between pressure to increase muscle and both drive for muscularity and drive for thinness. Longitudinal research could help clarify the role of the pursuit of muscularity in the development of disordered eating and extreme body shape changing behaviors. PMID- 22494959 TI - Wanting a body that's better than average: the effect of manipulated body norms on ideal body size perception. AB - We examined the effect of body norms on ideal and current body size perception. In Study One, female participants were randomly assigned to one of three experimental conditions: (1) a thinner body norm, (2) a heavier body norm, or (3) no body norm. Body norms were manipulated by indicating a bogus "population average," and current and ideal body size perception were subsequently measured using a body silhouettes measure. Women had a thinner ideal body size in the thinner norm condition than in the heavier norm condition. Study Two replicated these results, but in a sample of young men and with regards to muscularity rather than thinness. Men had a more muscular ideal body size in the more muscular norm condition than in the less muscular norm condition. Current body size perception was also influenced by body norms, but only for women and after controlling for BMI. PMID- 22494960 TI - Explaining African-Americans' depressive symptoms: a stress-distress and coping perspective. AB - Findings from five community surveys suggest that the depressive symptom scores of African-Americans are the same as, or lower than, those of Whites. This seems at odds with the minority status hypothesis that predicts higher rates of mental disorders for African-Americans. However, little is known about the role of African-American coping capacity during the life stress process which may shed light on the seeming contradiction. This cross-sectional survey examined the role of spirituality-coping, sense of control, and stress in predicting depressive symptoms among 3570 African-Americans. The findings showed that sense of control mediates the relationship between spirituality, life stressors, and depressive symptoms. PMID- 22494956 TI - Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study. AB - BACKGROUND: Fingolimod 0.5 mg once daily is approved for treatment of relapsing multiple sclerosis (MS). In the phase 3, 2-year FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in MS) study, fingolimod significantly reduced annualised relapse rates (ARRs) and the risk of confirmed disability progression compared with placebo. We aimed to investigate whether the beneficial treatment effect reported for the overall population is consistent in subgroups of patients with different baseline characteristics. METHODS: We did subgroup analyses of ARRs (primary outcome) and confirmed disability progression (a secondary outcome) over 24 months in the FREEDOMS study, a randomised, double blind study that included 1272 patients with relapsing-remitting MS who were assigned 1:1:1 to fingolimod (0.5 mg or 1.25 mg) or placebo once daily for 24 months. Subgroups were predefined, predefined and slightly modified, or defined post hoc, by demographic factors (including sex and age), disease characteristics (including baseline disability scores, relapse rates, and lesion parameters), and response to previous therapy (including analyses in patients eligible for fingolimod treatment according to the European label). Data were analysed by intention to treat. The FREEDOMS study is registered with ClinicalTrials.gov, number NCT00289978. FINDINGS: Treatment with fingolimod 0.5 mg was associated with significantly lower ARRs versus placebo across all subgroups except for patients aged over 40 years. ARR ratios ranged from 0.76 (95% CI 0.54-1.09; p=0.13) in patients aged over 40 years to 0.29 (0.16-0.52; p<0.0001) in patients who had relapse activity despite receiving interferon beta during the year before study enrolment. Hazard ratios for confirmed disability progression over 24 months with fingolimod 0.5 mg versus placebo ranged from 0.85 (95% CI 0.53-1.36; p=0.50) in patients with a T2 lesion volume of 3300 mm(3) or less to 0.32 (0.14 0.73; p=0.0066) in patients with an EDSS over 3.5. In patients who relapsed and had lesion activity despite treatment with interferon beta in the previous year, the ARR ratio for fingolimod 0.5 mg versus placebo was 0.38 (95% CI 0.21-0.68, p=0.0011), and for treatment-naive patients with rapidly evolving severe disease it was 0.33 (0.18-0.62, p=0.0006). Hazard ratios for confirmed disability progression over 24 months were 0.68 (0.29-1.62; p=0.39) and 0.73 (0.25-2.07; p=0.55), respectively, in these groups. INTERPRETATION: Patients with relapsing remitting MS with a wide spectrum of clinical and MRI features including subgroups specified by the European label can potentially benefit from treatment with 0.5 mg fingolimod. FUNDING: Novartis. PMID- 22494961 TI - The potential of TiO2 nanoparticles as carriers for cadmium uptake in Lumbriculus variegatus and Daphnia magna. AB - The use of engineered nanoparticles (e.g. in industrial applications and consumer products) is increasing. Consequently, these particles will be released into the aquatic environment. Through aggregation/agglomeration and sedimentation, sediments are expected ultimately to be sinks for nanoparticles. Both in the water phase and in the sediments engineered nanoparticles will mix and interact with other environmental pollutants, including metals. In this study the toxicity of cadmium to two freshwater organisms, water column crustacean Daphnia magna and sediment oligochaete Lumbriculus variegatus, was investigated both in the absence and presence of titanium dioxide (TiO(2)) nanoparticles (P25 Evonic Degussa, d: 30 nm). The uptake of cadmium in sub-lethal concentrations was also studied in the absence and presence of 2 mg/L TiO(2) nanoparticles. Formation of larger nanoparticles aggregates/agglomerates was observed and sizes varied depending on media composition (358+/-13 nm in US EPA moderately hard synthetic freshwater and 1218+/-7 nm in Elendt M7). TiO(2) nanoparticles are potential carriers for cadmium and it was found that 25% and 6% of the total cadmium mass in the test system for L. variegatus and D. magna tests were associated to suspended TiO(2) particles, respectively. MUXRF (micro X-ray fluorescence) analysis confirmed the uptake of TiO(2) in the gut of D. magna. For L. variegatus MUXRF analysis indicated attachment of TiO(2) nanoparticles to the organism surface as well as a discrete distribution within the organisms. Though exact localisation in this organism was more difficult to assess, the uptake seems to be within the coelomic cavity. Results show that the overall body burden and toxicity of cadmium to L. variegatus was unchanged by addition of TiO(2) nanoparticles, showing that cadmium adsorption to TiO(2) nanoparticles did not affect overall bioavailability. Despite facilitated uptake of cadmium by TiO(2) nanoparticles in D. magna, resulting in increased total cadmium body burden, no change in toxicity was observed. PMID- 22494962 TI - Effects of uranium on the metabolism of zebrafish, Danio rerio. AB - The increasing demand for nuclear energy results in heightened levels of uranium (U) in aquatic systems which present a potential health hazard to resident organisms. The aim of this study was to mechanistically assess how chronic exposure to environmentally relevant concentrations of U perturbs the complex interplay between feeding, growth, maintenance, maturation and reproduction throughout the life-cycle of an individual. To this end we analysed literature based and original zebrafish toxicity data within a same mass and energy balancing conceptual framework. U was found to increase somatic maintenance leading to inhibition of spawning as well as increase hazard rate and costs for growth during the early life stages. The fish's initial conditions and elimination through reproduction greatly affected toxico-kinetics and effects. We demonstrate that growth and reproduction should be measured on specific individuals since mean values were hardly interpretable. The mean food level differed between experiments, conditions and individuals. This last 'detail' contributed substantially to the observed variability by its combined effect on metabolism, toxic effects and toxico-kinetics. The significance of this work is that we address exactly how these issues are related and derive conclusions which are independent of experimental protocol and coherent with a very large body of literature on zebrafish eco-physiology. PMID- 22494963 TI - Behavioral assessment of Japanese children with epilepsy using SDQ (strengths and difficulties questionnaire). AB - The aim of this study was to elucidate the availability of the strengths and difficulties questionnaire (SDQ) as a screening tool for identifying behavioral problems in Japanese children with epilepsy. METHODS: Eighty-three 4-16 year-old epileptic patients, followed at Tanabe-Kadobayashi Children's Clinic, were studied. Children with severe mental or physical disability were excluded. The Japanese version of the SDQ was used, and scores were compared to the Japanese standard. RESULTS: 'Hyperactivity' was the SDQ category with the most striking differences from normal: a significant numbers of children had scores above the clinically normal range and only a small proportion were within the normal range (p<0.0001). The rates of epilepsy patients with scores above normal range were also significantly higher for 'peer problems' and 'conduct problems' (p<0.0001 and p<0.01). The rates of epilepsy patients with scores within the normal range was significantly lower for 'emotional symptoms' than in normal controls (p<0.001). On the other hand, the 'pro-social behavior' score did not differ significantly from the Japanese standard. As for clinical factors, patients with symptomatic localization-related epilepsy and focal electroencephalographic abnormalities had significantly higher scores for some SDQ items. Age at epilepsy onset correlated negatively with scores for 'total difficulties' and 'hyperactivity', suggesting early onset to be a risk factor for poor SDQ scores. CONCLUSIONS: These findings confirm that higher rates of psychiatric comorbidity in Japanese children with epilepsy may be diagnosed using SDQ in Japanese children with epilepsy. These problems should be addressed in the early phase of epilepsy management in order to preserve health-related quality of life for affected patients. PMID- 22494964 TI - Comparison of pneumatic and laser lithotripsy in the treatment of pediatric ureteral stones. AB - OBJECTIVE: To compare the effectiveness and safety of pneumatic and holmium:YAG laser lithotripters in the treatment of pediatric ureterolithiasis. PATIENTS AND METHODS: Medical records of patients treated using pneumatic (PL) (n = 29) or laser (LL) (n = 35) lithotripter between 2009 and 2011 were retrospectively analysed. The patients were evaluated with respect to age, gender, stone size, complications, and stone-free rates 1 month after the operation. RESULTS: For the PL and LL groups, mean ages (8.8 +/- 3.4 and 8.3 +/- 3.5 years), male/female ratios (19:10 and 22:13) and stone locations were similar (p > 0.05). Mean stone sizes were 55.6 mm2 and 47.6 mm2 in the PL and LL group, respectively, with no statistically significant difference (p = 0.850). Mean operative times were 20.5 min in the PL group and 25.2 min in the LL group, with a statistically significant difference (p = 0.020). Stone-free rates 1 month after intervention were 79% in the PL group and 97% in the LL group (p = 0.022). Stone migration was detected in the PL group (n = 6) and in the LL group (n = 1). No major complication was found in either group. CONCLUSION: In the ureteroscopic treatment of pediatric ureterolithiasis, both pneumatic and laser lithotripters are effective and successful. However, laser lithotripsy has a higher stone-free rate and lower complication rate. PMID- 22494965 TI - Therapeutic approaches to myeloma bone disease: an evolving story. AB - Bone disease is a major morbidity factor in patients with multiple myeloma and significantly affects their overall survival. A complex interplay between malignant plasma cells and other marrow cells results in the generation of a microenvironment capable of enhancing both tumor growth and bone destruction. Bisphosphonates have consistently reduced the incidence of skeletal-related events in patients with multiple myeloma and other osteotropic tumors as well. However, their use is burdened with side-effects, including the risks of osteonecrosis of the jaw and kidney failure, suggesting that they should be discontinued after prolonged administration. New molecular targets of cell cross talk in myeloma bone marrow are therefore under intensive investigation and new drugs are being explored in preclinical and clinical studies of myeloma bone disease. Compounds targeting osteoclast activation pathways, such as receptor activator of nuclear factor-kappaB/receptor activator of nuclear factor-kappaB ligand/osteoprotegerin, B-cell activating factor, mitogen-activated protein kinase and macrophage inflammatory protein-1alpha/chemokine receptor for macrophage inflammatory protein-1alpha axes, or soluble agents that improve osteoblast differentiation by modulating specific inhibitors such as Dickkopf-1 and transforming growth factor-beta, as well as novel approaches of cytotherapy represent a new generation of promising drugs for the treatment of myeloma bone disease. PMID- 22494966 TI - Mesenchymal stem cell signaling in cancer progression. AB - Mesenchymal (multipotent) stem/stromal cells (MSCs) may affect cancer progression through a number of secreted factors triggering activation of various cell signaling pathways. Depending on receptor status, phosphatase and tensin homolog (PTEN) status, or Wnt activation in the cancer cells, the signals may either result in increased growth and metastasis or lead to inhibition of growth with increased cell death. Thus, MSCs can play a dual role in cancer progression depending on the cellular context wherein they reside. The phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway has a central role in regulating tumor growth, and several MSC secreted factors stimulate activation of this pathway. A comprehensive understanding of the signals regulating MSC-tumor cross-talk is highly important for the development of MSCs as potential therapeutic vehicles. Thus, the presented review focuses on factors released by MSCs and on the dual role they may have on various stages of tumorigenesis. PMID- 22494967 TI - Bending effects of ZnO nanorod metal-semiconductor-metal photodetectors on flexible polyimide substrate. AB - The authors report the fabrication and I-V characteristics of ZnO nanorod metal semiconductor-metal photodetectors on flexible polyimide substrate. From field emission scanning electron microscopy and X-ray diffraction spectrum, ZnO nanorods had a (0002) crystal orientation and a wurtzite hexagonal structure. During the I-V and response measurement, the flexible substrates were measured with (i.e., the radius of curvatures was 0.2 cm) and without bending. From I-V results, the dark current decreased, and the UV-to-visible rejection ratio increased slightly in bending situation. The decreasing tendency of the dark current under bending condition may be attributed to the increase of the Schottky barrier height. PMID- 22494968 TI - Epidermal growth factor in the treatment of diabetic foot ulcers: an update. AB - Management of diabetic foot ulcers remains a rather challenging task. Epidermal growth factor (EGF) plays a central role in wound healing. It acts on epithelial cells and fibroblasts promoting restoration of damaged epithelium. However, its bioavailability is impaired in chronic diabetic foot ulcers. Current evidence suggests that application of human recombinant EGF in addition to standard treatment is able to achieve both partial and complete healing and to prevent foot amputations. Its efficacy has been tested at various concentrations and by various administration routes (topical application and intralesional injection). Intralesional injection has better availability on the deep wound layers, but pain at the injection site is a common complaint. Generally, adverse events have been minor to mild. Finally, numerous issues need to be further clarified before widespread use of EGF becomes possible in everyday practice. Such issues include optimal dosage and administration route, characteristics of the ulcers most likely to heal (severity and ischemic/neuropathic or both), and cost effectiveness. PMID- 22494969 TI - Wnt/beta-catenin and MAPK signaling: allies and enemies in different battlefields. AB - Two papers published in Science Signaling reveal extensive crosstalk between Wnt/beta-catenin and mitogen-activated protein kinase (MAPK) signaling in cancer. Although both studies describe previously unknown links between these two signaling pathways, the relationship between Wnt/beta-catenin and MAPK signaling depends on the specific cellular context. Indeed, in melanoma, hyperactivated MAPK signaling down-regulates the Wnt/beta-catenin signal transduction cascade, thereby establishing a negative crosstalk between the two signaling pathways. In contrast, in colorectal cancer, stimulation of the Wnt/beta-catenin pathway leads to activation of the MAPK pathway through Ras stabilization, representing an example of positive crosstalk. Moreover, activation of Wnt/beta-catenin signaling has context-dependent functions that trigger opposing effects on tumor growth. In melanoma, aberrant activation of Wnt/beta-catenin signaling may have anti oncogenic functions by promoting programmed cell death; by contrast, in the intestine, Wnt/beta-catenin signaling drives malignant transformation. Thus, there is no single correct way to target the Wnt/beta-catenin pathway for all cancers. PMID- 22494970 TI - Direct binding between Orai1 and AC8 mediates dynamic interplay between Ca2+ and cAMP signaling. AB - The interplay between calcium ion (Ca(2+)) and cyclic adenosine monophosphate (cAMP) signaling underlies crucial aspects of cell homeostasis. The membrane bound Ca(2+)-regulated adenylyl cyclases (ACs) are pivotal points of this integration. These enzymes display high selectivity for Ca(2+) entry arising from the activation of store-operated Ca(2+) (SOC) channels, and they have been proposed to functionally colocalize with SOC channels to reinforce crosstalk between the two signaling pathways. Using a multidisciplinary approach, we have identified a direct interaction between the amino termini of Ca(2+)-stimulated AC8 and Orai1, the pore component of SOC channels. High-resolution biosensors targeted to the AC8 and Orai1 microdomains revealed that this protein-protein interaction is responsible for coordinating subcellular changes in both Ca(2+) and cAMP. The demonstration that Orai1 functions as an integral component of a highly organized signaling complex to coordinate Ca(2+) and cAMP signals underscores how SOC channels can be recruited to maximize the efficiency of the interplay between these two ubiquitous signaling pathways. PMID- 22494971 TI - Ras stabilization through aberrant activation of Wnt/beta-catenin signaling promotes intestinal tumorigenesis. AB - Although the guanosine triphosphate/guanosine diphosphate loading switch is a major regulatory mechanism that controls the activity of the guanosine triphosphatase Ras, we report a distinct mechanism for regulating Ras activity through phosphorylation-mediated degradation and describe the role of this second regulatory mechanism in the suppression of cellular transformation and tumors induced by Ras mutations. We found that negative regulators of Wnt/beta-catenin signaling contributed to the polyubiquitin-dependent degradation of Ras after its phosphorylation by glycogen synthase kinase 3beta (GSK3beta) and the subsequent recruitment of beta-TrCP-E3 ligase. We found a positive association between tumorigenesis and Ras stabilization resulting from the aberrant activation of Wnt/beta-catenin signaling in adenomas from two mouse models of colon cancer, human colonic tumors from various stages, and colon polyps of patients with familial adenomatous polyposis. Our results indicated that GSK3beta plays an essential role in Ras degradation and that inhibition of this degradation pathway by aberrant Wnt/beta-catenin signaling may contribute to Ras-induced transformation in colorectal tumorigenesis. PMID- 22494972 TI - The publication of ethically uncertain research: attitudes and practices of journal editors. AB - BACKGROUND: Publication of ethically uncertain research occurs despite well published guidelines set forth in documents such as the Declaration of Helsinki. Such guidelines exist to aide editorial staff in making decisions regarding ethical acceptability of manuscripts submitted for publication, yet examples of ethically suspect and uncertain publication exist. Our objective was to survey journal editors regarding practices and attitudes surrounding such dilemmas. METHODS: The Editor-in-chief of each of the 103 English-language journals from the 2005 Abridged Index Medicus list publishing original research were asked to complete a survey sent to them by email between September-December 2007. RESULTS: A response rate of 33% (n = 34) was obtained from the survey. 18% (n = 6) of respondents had published ethically uncertain or suspect research within the last 10 years. 85% (n = 29) of respondents stated they would always reject ethically uncertain articles submitted for publication on ethical grounds alone. 12% (n = 4) of respondents stated they would approach each submission on a case-by-case basis. 3% (n = 1) stated they would be likely to publish such research, but only with accompanying editorial. Only 38% (n = 13) give reviewers explicit instruction to reject submissions on ethical grounds if found wanting. CONCLUSIONS: Editorial compliance with the Declaration of Helsinki in rejecting research that is conducted unethically was difficult to ascertain because of a poor response rate despite multiple attempts using different modalities. Of those who did respond, the majority do reject ethically suspect research but few explicitly advise reviewers to do so. In this study editors did not take advantage of the opportunity to describe their support for the rejection of the publication of unethical research. PMID- 22494973 TI - Nitrous oxide emissions from Phragmites australis-dominated zones in a shallow lake. AB - Nitrous oxide (N(2)O) emissions from Phragmites australis (reed)--dominated zones in Baiyangdian Lake, the largest shallow lake of Northern China, were investigated under different hydrological conditions with mesocosm experiments during the growing season of reeds. The daily and monthly N(2)O emissions were positively correlated with air temperature and the variation of aboveground biomass of reeds (p < 0.05), respectively. The N(2)O emissions from reeds were about 45.8-52.8% of that from the sediments. In terms of the effect of hydrological conditions, N(2)O emissions from the aquatic-terrestrial ecotone were 9.4-26.1% higher than the submerged zone, inferring that the variation of water level would increase N(2)O emissions. The annual N(2)O emission from Baiyangdian Lake was estimated to be about 114.2 t. This study suggested that N(2)O emissions from shallow lakes might be accelerated by the climate change as it has increased air temperature and changed precipitation, causing the variation of water level. PMID- 22494974 TI - Public awareness of military sexual trauma, which is experienced by men and women, has led to VA interventions. PMID- 22494975 TI - Are there gender differences in quality of life and symptomatology between fibromyalgia patients? AB - The purpose of this study is to examine gender differences in quality of life (QoL) and symptomatology in fibromyalgia (FM) patients. A total of 20 men (48.0 +/- 8.0 years) and 78 women (49.8 +/- 7.2 years) with FM participated in the study (age range 31-63 years). Health-related QoL and FM impact were assessed by means of the Spanish versions of the Short-Form-36 Health Survey (SF36) and the Fibromyalgia Impact Questionnaire (FIQ), respectively. Comparisons in QoL were performed using one-way analysis of covariance adjusted by age and body mass index (BMI), and comparisons in FIQ dimensions were performed using Mann-Whitney test. Overall FM impact, as measured by FIQ-total score (p = .01) and FIQ physical impairment (p = .02) was higher in men, whereas women presented higher values of FIQ-fatigue and FIQ-morning tiredness (p = .04) and less SF36-vitality (p = .02). Therefore, women appear to feel more fatigue, whereas men present higher FM overall impact. Due to the small number of men included in this study and the consequent small statistical power, these results should be taken as preliminary. Higher powered studies are warranted to further address gender differences in FM in order to design more successful treatments. PMID- 22494976 TI - Pro- and anti-angiogenic agents. AB - The vascular endothelium has been characterized in every organ system, and is described as a selective permeable barrier and as a dynamic and disseminated organ with endocrine function. These activities have been shown to result from the interactions of ligands with membrane-bound receptors as well as through specific junctional proteins and receptors that govern cell-cell interactions. The endothelial cells' movement (e.g., angiogenesis) has been hypothesized to occur following the release of stimuli that could promote the formation of new blood vessels. Angiogenesis has also been reported to be the continued expansion of the vascular tree in avascular regions, as a result of the sprouting of endothelial cells from existing vessels. Most commonly, angiogenesis has been characterized during wound healing and tumour growth. Herein we summarize and discuss the latest results from fundamental laboratory research aimed at proving a link between the proliferation of cancer and angiogenesis, as well as the new rationale around novel pro- and anti-angiogenic molecules. PMID- 22494977 TI - Reproductive history and nest environment are correlated with circulating androgen and glucocorticoid concentrations in a parental care-providing teleost fish. AB - Using a long-term study population of wild smallmouth bass Micropterus dolomieu in a connected river-lake system, we investigated whether circulating glucocorticoid (cortisol) and androgen (testosterone) concentrations are influenced by reproductive investment and nesting environment in fish providing nest-guarding paternal care. For all individuals, we collected measures of reproductive history and the value of current parental care. We assessed nest environment and monitored individuals to quantify seasonal reproductive success. Finally, we measured circulating cortisol concentrations following a standardized stressor and circulating testosterone concentrations. Using general linear models, we found that poststress circulating cortisol concentrations were positively related to water temperature and were higher in fish nesting in the river than in the lake. Circulating testosterone concentrations were negatively related to water temperature and were higher in reproductively experienced fish. When considering the factors that influence reproductive success, we found that only parental size was positively related to current nest success. In summary, the results demonstrate that nesting environment is correlated with parental stress responses during parental care, while reproductive history and nesting environment are correlated with circulating androgen concentrations. Collectively, these results offer insight into the roles of both glucocorticoid and androgen steroid hormones during parental care in teleost fish. PMID- 22494978 TI - Temporal and spatial complexity of maternal thermoregulation in tropical pythons. AB - Parental care is a widespread adaptation that evolved independently in a broad range of taxa. Although the dynamics by which two parents meet the developmental needs of offspring are well studied in birds, we lack understanding about the temporal and spatial complexity of parental care in taxa exhibiting female-only care, the predominant mode of parental care. Thus, we examined the behavioral and physiological mechanisms by which female water pythons Liasis fuscus meet a widespread developmental need (thermoregulation) in a natural setting. Although female L. fuscus were not facultatively thermogenic, they did use behaviors on multiple spatial scales (e.g., shifts in egg-brooding postures and surface activity patterns) to balance the thermal needs of their offspring throughout reproduction (gravidity and egg brooding). Maternal behaviors in L. fuscus varied by stage within reproduction and were mediated by interindividual variation in body size and fecundity. Female pythons with relatively larger clutch sizes were cooler during egg brooding, suggesting a trade-off between reproductive quantity (size of clutch) and quality (developmental temperature). In nature, caregiving parents of all taxa must navigate both extrinsic factors (temporal and spatial complexity) and intrinsic factors (body size and fecundity) to meet the needs of their offspring. Our study used a comprehensive approach that can be used as a general template for future research examining the dynamics by which parents meet other developmental needs (e.g., predation risk or energy balance). PMID- 22494979 TI - Do gravid females become selfish? Female allocation of energy during gestation. AB - Net energy availability depends on plasma corticosterone concentrations, food availability, and their interaction. Limited net energy availability requires energy trade-offs between self-maintenance and reproduction. This is important in matrotrophic viviparous animals because they provide large amounts of energy for embryos, as well as self-maintenance, for the extended period of time during gestation. In addition, gravid females may transmit environmental information to the embryos in order to adjust offspring phenotype. We investigated effects of variation in maternal plasma corticosterone concentration and maternal food availability (2 * 2 factorial design) during gestation on offspring phenotype in a matrotrophic viviparous lizard (Pseudemoia entrecasteauxii). Subsequently, we tested preadaptation of offspring phenotype to their postnatal environment by measuring risk-averse behavior and growth rate using reciprocal transplant experiments. We found that maternal net energy availability affected postpartum maternal body condition, offspring snout-vent length, offspring mass, offspring performance ability, and offspring fat reserves. Females treated with corticosterone allocated large amounts of energy to their own body condition, and their embryos allocated more energy to energy reserves than somatic growth. Further, offspring from females in high plasma corticosterone concentration showed compensatory growth. These findings suggest that while females may be selfish when gestation conditions are stressful, the embryos may adjust their phenotype to cope with the postnatal environment. PMID- 22494980 TI - Dynamic influence of maternal and pup traits on maternal care during lactation in an income breeder, the antarctic fur seal. AB - Life-history theory predicts that selection will favor optimal levels of parental effort that balance benefits of current reproduction with costs to survival and future reproduction. The optimal level of effort depends on parental traits, offspring traits, and provisioning strategy. Additionally, how these factors influence effort may differ depending on the stage of reproduction. The relative importance of maternal and offspring traits on energy allocation to offspring was investigated in known-age Antarctic fur seals Arctocephalus gazella across four stages of reproduction, using birth mass and milk-consumption measurements. Maternal traits were important during three of the four stages investigated, with larger females giving birth to larger pups and investing more in pups during perinatal and molt stages. Pup mass influenced maternal effort during the premolt stage, and provisioning strategy influenced postnatal maternal effort at all stages. Energy provided to the offspring during an attendance visit was positively related to the duration of the foraging-trip/visit cycle; however, when investment was controlled for trip/visit cycle duration, the overall rate of energy transfer was similar across trip durations. In addition to strong effects of maternal mass, pup traits affected energy allocation, suggesting that pup demand is important in determining maternal care. These findings emphasize the importance of considering state variables in life-history studies and suggest that timing of measurements of effort in species with long provisioning periods may influence conclusions and our ability to make comparisons of reproductive effort among species. PMID- 22494981 TI - Innate immunity in free-ranging African buffalo (Syncerus caffer): associations with parasite infection and white blood cell counts. AB - Mammalian immunology has been studied in great detail in laboratory animals, but few of the tools and less of the insight derived from these studies have been placed in the context of natural, outbred wildlife populations subject to variable environments. We investigated patterns of innate immunity in free ranging African buffalo in relation to host traits (age, reproductive status, body condition, white blood cell counts) and disease status (bovine tuberculosis [BTB], gastrointestinal nematodes, coccidia, ticks). We evaluated and used an in vitro assay measuring bactericidal competence of blood to assess a component of innate immunity in 200 female buffalo captured at Kruger National Park, South Africa, in June/July and October 2008. Animals with BTB had higher bactericidal competence of blood. Animals with higher neutrophil counts had higher bactericidal competence, whereas animals with lower lymphocyte counts had higher bactericidal competence. This pattern was driven by animals captured at the end of the dry season (October) and may be evidence of immune polarization, whereby individuals are unable to upregulate multiple components of immunity simultaneously. Bactericidal competence did not vary with host pregnancy status, body condition, age, lactation, tick infestation, nematode egg count, or coccidia oocyst count. Overall, we demonstrate that the bactericidal competence assay is practical and informative for field-based studies in wild bovids. Our results also show a correlation between bactericidal competence and bovine tuberculosis infection and reveal possible functional polarizations between different types of immune response in a free-ranging mammal. PMID- 22494982 TI - Optimal body size with respect to maximal speed for the yellow-spotted monitor lizard (Varanus panoptes; Varanidae). AB - Studies of locomotor performance often link variation in morphology with ecology. While maximum sprint speed is a commonly used performance variable, the absolute limits for this performance trait are not completely understood. Absolute maximal speed has often been shown to increase linearly with body size, but several comparative studies covering a large range of body sizes suggest that maximal speed does not increase indefinitely with body mass but rather reaches an optimum after which speed declines. Because of the comparative nature of these studies, it is difficult to determine whether this decrease is due to biomechanical constraints on maximal speed or is a consequence of phylogenetic inertia or perhaps relaxed selection for lower maximal speed at large body size. To explore this issue, we have examined intraspecific variations in morphology, maximal sprint speed, and kinematics for the yellow-spotted monitor lizard Varanus panoptes, which varied in body mass from 0.09 to 5.75 kg. We show a curvilinear relationship between body size and absolute maximal sprint speed with an optimal body mass with respect to speed of 1.245 kg. This excludes the phylogenetic inertia hypothesis, because this effect should be absent intraspecifically, while supporting the biomechanical constraints hypothesis. The relaxed selection hypothesis cannot be excluded if there is a size-based behavioral shift intraspecifically, but the biomechanical constraints hypothesis is better supported from kinematic analyses. Kinematic measurements of hind limb movement suggest that the distance moved by the body during the stance phase may limit maximum speed. This limit is thought to be imposed by a decreased ability of the bones and muscles to support body mass for larger lizards. PMID- 22494983 TI - Quantitative assessment of hemolymph metabolites in two physiological states and two populations of the land snail Helix pomatia. AB - Hemolymph metabolite composition in ectothermic species is mainly constrained by trophic and climatic habitat conditions. In temperate regions, ectothermic species have to face subzero temperatures in winter, to which they typically respond with a state of inactivity. With use of ultra-performance liquid chromatography and gas chromatography-mass spectrometry techniques, we investigated the hemolymph metabolite composition of the land snail Helix pomatia with respect to physiological states (activity and hibernation) in a mountain population (800 m above sea level) and a valley population (150 m above sea level) in Germany. The dry masses of active snails as well as the saccharide and amino acid concentrations in active snails were higher in the mountain population than in the valley population. These differences between populations might reflect differences in microhabitat conditions, such as climate and vegetal food, and consequent differences in metabolic activity. Galactose was the most abundant component in hemolymph besides glucose. Both saccharides might indicate glycolytic activity, which could provide energy for locomotion and foraging. In hibernation, glutamate, alpha-alanine, glycine, aspartate, serine, homoserine, hydroxyproline, glycerol, and triglycerides were accumulated in both populations. The concentrations were correlated with a decrease in body supercooling point. Therefore, these metabolites might have a role in the cold hardiness of H. pomatia that should be further investigated in a functional study. PMID- 22494984 TI - A role for oxygen delivery and extracellular magnesium in limiting cold tolerance of the sub-antarctic stone crab Paralomis granulosa? AB - A low capacity for regulation of extracellular Mg(2+) has been proposed to exclude reptant marine decapod crustaceans from temperatures below 0 degrees C and thus to exclude them from the high Antarctic. To test this hypothesis and to elaborate the underlying mechanisms in the most cold-tolerant reptant decapod family of the sub-Antarctic, the Lithodidae, thermal tolerance was determined in the crab Paralomis granulosa (Decapoda, Anomura, Lithodidae) using an acute stepwise temperature protocol (-1 degrees , 1 degrees , 4 degrees , 7 degrees , 10 degrees , and 13 degrees C). Arterial and venous oxygen partial pressures (Po(2)) in hemolymph, heartbeat and ventilation beat frequencies, and hemolymph cation composition were measured at rest and after a forced activity (righting) trial. Scopes for heartbeat and ventilation beat frequencies and intermittent heartbeat and scaphognathite beat rates at rest were evaluated. Hemolymph [Mg(2+)] was experimentally reduced from 30 mmol L(-1) to a level naturally observed in Antarctic caridean shrimps (12 mmol L(-1)) to investigate whether the animals remain more active and tolerant to cold (-1 degrees , 1 degrees , and 4 degrees C). In natural seawater, righting speed was significantly slower at -1 degrees and 13 degrees C, compared with acclimation temperature (4 degrees C). Arterial and venous hemolymph Po(2) increased in response to cooling even though heartbeat and ventilation beat frequencies as well as scopes decreased. At rest, ionic composition of the hemolymph was not affected by temperature. Activity induced a significant increase in hemolymph [K(+)] at -1 degrees and 1 degrees C. Reduction of hemolymph [Mg(2+)] did not result in an increase in activity, an increase in heartbeat and ventilation beat frequencies, or a shift in thermal tolerance to lower temperatures. In conclusion, oxygen delivery in this cold water crustacean was not acutely limiting cold tolerance, and animals may have been constrained more by their functional capacity and motility. In contrast to earlier findings in temperate and subpolar brachyuran crabs, these constraints remained insensitive to changing Mg(2+) levels. PMID- 22494985 TI - Individual consistency and covariation of measures of oxidative status in greenfinches. AB - Oxidative stress results from a mismatch between production of reactive oxygen species (ROS) and the organism's capacity to mitigate their damaging effects by building up sufficient antioxidant protection and/or repair mechanisms. Because ROS production is a universal consequence of cellular metabolism and immune responses, evolutionary animal ecologists have become increasingly interested in involvement of oxidative stress as a proximate mechanism responsible for the emergence of trade-offs related to the evolution of life-history and signal traits. Among the most practical problems pertinent to ecological research on oxidative stress is finding a combination of biomarkers of oxidative status that can be applied to typical wild animal models such as small birds, mammals, and reptiles. This study describes covariation and individual consistency of eight parameters of oxidative status in a small passerine bird, wild-caught captive greenfinch (Carduelis chloris). We measured two markers of plasma antioxidant potential--total antioxidant capacity (TAC) and oxygen radical absorbance (OXY)- and concentrations of one lipophilic (carotenoids) and two hydrophilic (uric acid and ascorbate) antioxidants in plasma. We also measured total glutathione (GSH) concentration and superoxide dismutase (SOD) activity in erythrocytes. Oxidative damage was assessed on the basis of plasma malondialdehyde (MDA) levels, measured by high-performance liquid chromatography. Plasma carotenoids, TAC, and erythrocyte GSH showed significant individual consistency over an 8-d period, indicating that those variables reflected more persistent differences between individuals than plasma OXY, MDA, and uric acid. We did not detect any strong or moderate correlations between the studied parameters, which suggests that all of these biomarkers contain potentially unique information. Injection of a synthetic mimetic of SOD and catalase--EUK-134--did not affect any of the parameters of oxidative status. Capability of phagocytes to produce oxidative burst was not associated with MDA, indicating that under our experimental conditions, ROS production by phagocytes was not a strong determinant of oxidative damage. Altogether these findings suggest that attempts to characterize oxidative balance should use a wide range of biomarkers, and further studies of oxidative status in wild animals may benefit from the experimental induction of oxidative stress. PMID- 22494987 TI - Role of corticotropin-releasing hormone family peptides in androgen receptor and vitamin D receptor expression and translocation in human breast cancer MCF-7 cells. AB - The presence of corticotropin-releasing hormone (CRH) in breast cancer biopsies suggests that it may play a role in the development of breast cancer. Here, the role of CRH in apoptosis and the relevant mechanisms were investigated. The CRH homologues, Urocortins, which have equal affinity for both corticotropin releasing hormone receptor types 1 and 2, were secreted in MCF-7 breast cancer cells. CRH (receptor type 1 agonist) and Urocortin2 (receptor type 2 agonist) were used to substitute Urocortin to identify the differences between the two receptors. The results showed that both CRH and Urocortin2 promoted apoptosis of MCF-7 cells by regulating expressions and distributions of androgen receptor and vitamin D receptor. CRH down-regulated androgen receptor mRNA through inducing its decay while up-regulating androgen receptor protein expression and promoting nuclear transportation. Urocortin2 repressed the mRNA production of androgen receptor but had no significant impact on its protein expression. Both CRH and Urocortin2 time-dependently increased the protein expression of vitamin D receptor which translocated into the nuclei to realize its genic activity thereafter. The activity of CRH and Urocortin2 could be inhibited by Antalarmin and Antisauvagine-30, respectively. Additional analyses showed that CRH and Urocortin2 both phosphorylated heat shock protein 27, and this phosphorylation was associated with the nuclear transportation of vitamin D receptor. In conclusion, the results firstly revealed that CRH and Urocortin2 could induce breast cancer cell apoptosis via the two different receptors. The mechanisms involve phosphorylation of heat shock protein 27, the increment of androgen receptor and vitamin D receptor protein expression and their nuclear translocation. PMID- 22494988 TI - Challenges in global improvement of oral cancer outcomes: findings from rural Northern India. AB - BACKGROUND: In India, 72% of the population resides in rural areas and 30-40% of cancers are found in the oral cavity. The majority of Haryana residents live in villages where inadequate medical facilities, no proper primary care infrastructure or cancer screening tools and high levels of illiteracy all contribute to poor oral cancer (OC) outcomes. In this challenging environment, the objective of this study was to assess the association between various risk factors for OC among referrals for suscipious lesions and to design and pilot test a collaborative community-based effort to identify suspicious lesions for OC. METHODS: SETTING: Community-based cross sectional OC screening. PARTICIPANTS: With help from the Department of Health (DOH), Haryana and the local communities, we visited three villages and recruited 761 participants of ages 45-95 years. PARTICIPANTS received a visual oral cancer examination and were interviewed about their dental/medical history and personal habits. Pregnant women, children and males/females below 45 years old with history of OC were excluded. MAIN OUTCOME: Presence of a suspicious oral lesion. RESULTS: Out of 761 participants, 42 (5.5%) were referred to a local dentist for follow-up of suspicious lesions. Males were referred more than females. The referral group had more bidi and hookah smokers than non smokers as compared to non referral group. The logistic regression analysis revealed that smoking bidi and hookah (OR = 3.06 and 4.42) were statistically significant predictors for suspicious lesions. CONCLUSIONS: Tobacco use of various forms in rural, northern India was found to be quite high and a main risk factor for suspicious lesions. The influence of both the DOH and community participation was crucial in motivating people to seek care for OC. PMID- 22494989 TI - Predicting current memory with the modified telephone interview for cognitive status. AB - The modified Telephone Interview for Cognitive Status (mTICS) is a commonly used screening tool for categorizing mental status of older adults. Recently, prediction equations have been developed to estimate performance on an in-person memory composite based on the mTICS; however, these equations need validation. The current study compared predicted memory functioning based on these equations with observed memory functioning in 101 community-dwelling older adults. Observed and predicted memory composites were comparable for 2 of 6 equations (mTICS total score and immediate recall item), indicating that these equations adequately predict observed memory scores. The predicted memory composite based on the total score was also most highly correlated with the observed memory composite. These results further validate the mTICS, as well as some of the prediction equations, and continue to point out this measure as an efficient tool for screening of cognitive functioning in later life. PMID- 22494991 TI - Decision time and perseveration of adolescent rats in the T-maze are affected differentially by buspirone and independent of 5-HT-1A expression. AB - Disruption of spontaneous alternation behavior (SAB) by the serotonin 1A (5-HT 1A) receptor agonist, 8-hydroxy-dipropylaminotetraline (8-OH-DPAT), results in repetitive behaviors that have been used to model the perseveration and indecisiveness of human obsessive-compulsive disorder (OCD). In the present study, we compared the effects of buspirone to those of 8-OH-DPAT in two strains of adolescent rats and analyzed repetitive choices of arms of the maze and prolonged apparent decision time due to induction of vicarious trial and error (VTE) behavior. In adolescent Sprague-Dawley (SD) rats, 8-OH-DPAT induced repetitive choices of arms of the maze (perseveration) and increased the apparent decision time. Buspirone induced VTE behavior and increased apparent decision time without perseveration. This distinct effect of buspirone was seen in SD adolescents but not in Long-Evans (LE) adolescents which appeared to be insensitive to buspirone. Lack of responsiveness to buspirone was dependent on the developmental stage because buspirone induced VTE behavior and prolonged decision time in LE adults. Western blotting of brain 5-HT-1A receptors showed expression of receptor protein in adolescent LE brain was comparable to that of adolescent SD and adult LE. The 5-HT-1A antagonist WAY 100365 blocked the effect 8-OH-DPAT on repetitive choice of arms but not the effect of buspirone on VTE behavior. We conclude that the adolescent LE rat has normal levels of 5-HT-1A receptor and that the effect of buspirone on VTE behavior is not mediated by the 5-HT-1A receptor. The LE strain may provide a useful system for further study of the adolescent brain and potential genetic differences in induction of repetitive behaviors. PMID- 22494990 TI - Progress on stem cell research towards the treatment of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of Lewy body inclusions along with selective destruction of dopaminergic (DA) neurons in the nigrostriatal tract of the brain. Genetic studies have revealed much about the pathophysiology of PD, enabling the identification of both biomarkers for diagnosis and genetic targets for therapeutic treatment, which are evolved in tandem with the development of stem cell technologies. The discovery of induced pluripotent stem (iPS) cells facilitates the derivation of stem cells from adult somatic cells for personalized treatment and thus overcomes not only the limited availability of human embryonic stem cells but also ethical concerns surrounding their use. Non viral, non-integration, or non-DNA-mediated reprogramming technologies are being developed. Protocols for generating midbrain DA neurons are undergoing constant refinement. The iPS cell-derived DA neurons provide cellular models for investigating disease progression in vitro and for screening molecules of novel therapeutic potential and have beneficial effects on improving the behavior of parkinsonian animals. Further progress in the development of safer non-viral/non biased reprogramming strategies and the subsequent generation of homogenous midbrain DA neurons shall pave the way for clinical trials. A combined approach of drugs, cell replacement, and gene therapy to stop disease progression and to improve treatment may soon be within our reach. PMID- 22494992 TI - Influence of ABCC2, SLCO1B1, and ABCG2 polymorphisms on the pharmacokinetics of olmesartan. AB - This study was designed to determine whether genetic polymorphisms of multidrug resistant protein 2 (ABCC2), organic anion transporting polypeptide 1B1 (SLCO1B1), and breast cancer resistance protein (ABCG2) have an effect on olmesartan pharmacokinetics in Korean subjects. Sixty-eight healthy male volunteers who participated in previous pharmacokinetics studies of olmesartan medoxomil (single dose, 20 mg or 40 mg) were enrolled. All subjects were analyzed and grouped according to the genotypes of ABCC2, SLCO1B1, and ABCG2. The dose normalized peak plasma concentration (C(max)) and area under the plasma concentration-time curve (AUCt) values were analyzed. The dose-normalized mean C(max) and AUC(t) in the ABCC2 -24CT genotype group were higher than those in the -24CC genotype group [C(max,dn): CT 26.1 +/- 6.5 (ng/mL)/mg versus CC 22.1 +/- 6.7 (ng/mL)/mg, P = 0.010, AUC(t,dn): CT 178.7 +/- 45.6 (hr.ng(-1).mL(-1))/mg versus CC 149.9 +/- 39.8 (hr.ng(-1).mL(-1))/mg, P = 0.010]. The difference in AUC(t,dn) between the ABCC2 -1549GG and -1549GA genotype groups was statistically significant [GG 149.0 +/- 41.0 (hr.ng(-1).mL(-1))/mg versus GA 174.1 +/- 43.3 (hr.ng(-1).mL(-1))/mg, P = 0.019]. No significant differences were observed for any other single nucleotide polymorphism in ABCC2, SLCO1B1, or ABCG2. The ABCC2 24CC genotype group exhibited lower systemic exposure of olmesartan than the 24CT genotype group, whereas no significant differences were observed in the other transporter genotype groups. PMID- 22494993 TI - Different effects of AT1 receptor antagonist and ET(A) receptor antagonist on ischemia-induced norepinephrine release in rat hearts. AB - Angiotensin type 1 receptor (AT1R) antagonist and endothelin type A receptor (ET(A)R) antagonist were compared as regards their effects on ischemia-induced exocytotic or carrier-mediated norepinephrine (NE) release from cardiac sympathetic nerve endings. According to the Langendorff technique, isolated rat hearts were subjected to 20-minute or 40-minute global ischemia followed by 30 minute reperfusion. Candesartan (selective AT1R antagonist) and ABT-627 (selective ET(A)R antagonist) were perfused, beginning 15 minutes before ischemia. Candesartan (10 and 100 nM) and ABT-627 (3 MUM) suppressed excessive NE overflow (exocytotic release) in the coronary effluent from the heart exposed to 20-minute ischemia. In addition, these agents improved postischemic cardiac dysfunction. On the other hand, the beneficial effects of ABT-627 (1 and 3 MUM) on NE overflow (carrier-mediated release) and cardiac dysfunction were also observed in 40-minute ischemia, whereas those were not improved by treatment with candesartan (10 and 100 nM and 1 MUM). These findings suggest that both AT1R antagonist and ET(A)R antagonist have ability to inhibit the exocytotic NE release, but the carrier-mediated NE release induced by prolonged ischemia cannot be avoided by AT1R antagonist. Thus, ET(A)R antagonist may be more useful than AT1R antagonist in the clinical settings of ischemic heart disease. PMID- 22494994 TI - Suppression of vascular inflammation by kinin B1 receptor antagonism in a rat model of insulin resistance. AB - BACKGROUND: Kinin B1 receptor (B1R) intervenes in a positive feedback loop to amplify and perpetuate the vascular oxidative stress in glucose-fed rats, a model of insulin resistance. This study aims at determining whether B1R blockade could reverse vascular inflammation in this model. METHODS/RESULTS: Young male Sprague Dawley rats were fed with 10% D-glucose or tap water (controls) for 8 weeks, and during the last week, rats were administered the B1R antagonist SSR240612 (10 mg/kg/day, gavage) or the vehicle. The outcome was determined on glycemia, insulinemia, insulin resistance (homeostasis model assessment index), and on protein or mRNA expression of the following target genes in the aorta (by Western blot and real-time quantitative polymerase chain reaction): B1R, endothelial nitric oxide synthase, inducible nitric oxide synthase, macrophage CD68, macrophage/monocyte CD11b, interleukin (IL) -1beta, tumor necrosis factor-alpha, IL-6, macrophage migration inhibitory factor, intercellular adhesion molecule-1, and E-selectin (endothelial adhesion molecule). Data showed increased expression of all these markers in the aorta of glucose-fed rats except endothelial nitric oxide synthase and tumor necrosis factor-alpha, which were not affected. SSR240612 reversed hyperglycemia, hyperinsulinemia, insulin resistance, and the upregulation of B1R, inducible nitric oxide synthase, macrophage CD68, and CD11b, IL-1beta, inter-cellular adhesion molecule-1, macrophage migration inhibitory factor, and E-selectin in glucose-fed rats, yet it had no significant effect on IL-6 and in control rats. CONCLUSIONS: Kinin B1R antagonism reversed the upregulation of its own receptor and several pro-inflammatory markers in the aorta of glucose-fed rats. These data provide the first evidence that B1R may contribute to the low-grade vascular inflammation in insulin resistance, an early event in the development of type-2 diabetes. PMID- 22494995 TI - Cribriform-morular variant of papillary thyroid carcinoma in an 8-year-old girl: a case report with immunohistochemical and molecular testing. AB - The description of the histological features and the immunohistochemical and molecular analyses of a case of cribriform-morular variant of papillary thyroid carcinoma in an 8-year-old girl with a family history of adenomatous polyposis is presented. The neoplasm was multifocal and bilateral, with a mixed pattern of solid, trabecular, and morular areas. The neoplasm showed angioinvasive behavior, extracapsular infiltration with extension to the perythyroidal muscles, and lymph node metastases. Tumor cells were positive for CAM 5.2, cytokeratins 5/6, TTF-1, HBME-1, galectin-3, and beta-catenin. In addition, the molecular tests did not reveal BRAF mutations, RET/PTC rearrangement, APC mutation, or KRAS mutation. PMID- 22494996 TI - Giant cell tumor of uterus resembling osseous giant cell tumor: case report and review of literature. AB - Osteoclast-like giant cells (OLGCs) are multinucleated cells of histiocytic lineage and have been identified in a wide array of neoplasms. In the uterus, they have most frequently been reported in association with leiomyosarcomas. This article describes a case of an osteoclast-like giant cell-rich uterine tumor that was essentially indistinguishable at the morphologic and immunophenotypic levels, from typical giant cell tumor of bone. This is the first example of such a case that has been reported in the uterus to the authors' knowledge. PMID- 22494997 TI - Age-related guanine nucleotide exchange factor, mouse Zizimin2, induces filopodia in bone marrow-derived dendritic cells. AB - BACKGROUND: We recently isolated and identified Zizimin2 as a functional factor that is highly expressed in murine splenic germinal center B cells after immunization with T-cell-dependent antigen. Zizimin2 was revealed to be a new family member of Dock (dedicator of cytokinesis), Dock11, which is the guanine nucleotide exchange factor for Cdc42, a low-molecular-weight GTPase. However, the molecular function of Zizimin2 in acquired immunity has not been elucidated. RESULTS: In this study, we show that the protein expression of Zizimin2, which is also restricted to lymphoid tissues and lymphocytes, is reduced in aged mice. Over-expression of full-length Zizimin2 induced filopodial formation in 293T cells, whereas expression of CZH2 domain inhibited it. Stimulation of Fcgamma receptor and Toll-like receptor 4 triggered Zizimin2 up-regulation and Cdc42 activation in bone marrow-derived dendritic cells. CONCLUSIONS: These data suggest that Zizimin2 is an immune-related and age-regulated guanine nucleotide exchange factor, which facilitates filopodial formation through activation of Cdc42, which results in activation of cell migration. PMID- 22494998 TI - Upregulated expression of voltage-gated sodium channel Nav1.3 in cortical lesions of patients with focal cortical dysplasia type IIb. AB - Focal cortical dysplasia (FCD) is one of the causes of intractable epilepsy in humans. Cytomegalic neurons, not balloon cells, are considered to be the putative generators of epileptic activity in FCD type IIb (FCDIIb). Voltage-gated sodium channel III alpha-isoforms (Nav1.3) play crucial roles in the initiation and propagation of action potentials and are important regulators of neuronal excitability. Here, we examined 12 FCDIIb surgical specimens from patients undergoing surgery for epilepsy and used age-matched normal control cortical tissue (CTX) from 10 autopsy samples as controls. Using reverse transcription-PCR and western blot techniques, we found that the mRNA and protein levels of Nav1.3 were clearly upregulated in FCDIIb surgical specimens compared with the controls (CTX). Results of immunohistochemistry analyses demonstrated that Nav1.3 immunoreactivity was widely present in FCDIIb lesion tissue; specifically, high levels of Nav1.3 immunoreactive proteins were located mainly in cytomegalic neurons of different sizes and shapes, not in balloon cells. Double-labeling studies showed most cytomegalic neurons expressing Nav1.3 colabeled with neuronal markers and glutamate receptors-1. Taken together, our results show an upregulation of Nav1.3 protein and a specific cellular distribution of Nav1.3 proteins in FCDIIb lesion tissue samples, suggesting that Nav1.3 may be involved in the generation of epileptic activity in FCDIIb. PMID- 22494999 TI - Threat interferes with response inhibition. AB - A potential threat, such as a spider, captures attention and engages executive functions to adjust ongoing behavior and avoid danger. We and many others have reported slowed responses to neutral targets in the context of emotional distractors. This behavioral slowing has been explained in the framework of attentional competition for limited resources with emotional stimuli prioritized. Alternatively, slowed performance could reflect the activation of avoidance/freezing-type motor behaviors associated with threat. Although the interaction of attention and emotion has been widely studied, little is known on the interaction between emotion and executive functions. We studied how threat related stimuli (spiders) interact with executive performance and whether the interaction profile fits with a resource competition model or avoidance/freezing type motor behaviors. Twenty-one young healthy individuals performed a Go-NoGo visual discrimination reaction time (RT) task engaging several executive functions with threat-related and emotionally neutral distractors. The threat related distractors had no effect on the RT or the error rate in the Go trials. The NoGo error rate, reflecting failure in response inhibition, increased significantly because of threat-related distractors in contrast to neutral distractors, P less than 0.05. Thus, threat-related distractors temporarily impaired response inhibition. Threat-related distractors associated with increased commission errors and no effect on RT does not suggest engagement of avoidance/freezing-type motor behaviors. The results fit in the framework of the resource competition model. A potential threat calls for evaluation of affective significance as well as inhibition of undue emotional reactivity. We suggest that these functions tax executive resources and may render other executive functions, such as response inhibition, temporarily compromised when the demands for resources exceed availability. PMID- 22495000 TI - Glutamate microinjection in the medial septum of rats decreases paradoxical sleep and increases slow wave sleep. AB - The role of the medial septum in suppressing paradoxical sleep and promoting slow wave sleep was suggested on the basis of neurotoxic lesion studies. However, these conclusions need to be substantiated with further experiments, including chemical stimulation studies. In this report, the medial septum was stimulated in adult male rats by microinjection of L-glutamate. Sleep-wakefulness was electrophysiologically recorded, through chronically implanted electrodes, for 2 h before the injection and 4 h after the injection. There was a decrease in paradoxical sleep during the first hour and an increase in slow wave sleep during the second hour after the injection. The present findings not only supported the lesion studies but also showed that the major role of the medial septum is to suppress paradoxical sleep. PMID- 22495001 TI - Normal learning ability of mice with a surgically exposed hippocampus. AB - In rats and mice, the hippocampus lies beneath higher than 1 mm of the neocortex. This anatomical feature makes it difficult to experimentally access the hippocampus from the surface of the brain in vivo. This problem may be solved by surgical removal of the cortical tissue above the hippocampus; however, it has not been examined whether this 'hippocampal window' surgery preserves the normal hippocampal function. We bilaterally aspirated the posterior parietal cortex above the dorsal hippocampus of adult male mice. These mice still exhibited normal local field potentials of the hippocampus, normal motor activity, and normal cognitive ability in the water-maze test and contextual fear conditioning, compared with intact or sham-operated controls. Thus, exposed hippocampal preparations provide a useful experimental model to study the physiology of the hippocampus. PMID- 22495002 TI - Factors affecting caregivers' perceptions of residents' oral health in long-term care facilities in Taiwan. AB - The purpose of this study was to investigate the differences between resident oral care policies provided by 2 types of long-term care (LTC) institutions. The study also investigated factors affecting LTC institutional caregivers' perceptions of the residents' oral health. Overall, 103 completed questionnaires were returned. Of these, 44 were from senior citizen welfare institutions, and 59 were from nursing homes. The variables affecting these perceptions included institution type and whether the residents attended hospital dental clinics or consulted a hospital doctor regarding oral health problems. The research results showed that institution type and whether an oral care-related professional was available in an institution were correlated with an increase in institutional caregivers' perceptions of oral care. PMID- 22495004 TI - [A boy with a painful upper leg]. AB - A 13-year-old boy came to the Emergency Department with a Salter Harris type 1 epiphysiolysis of the distal femur. These fractures can be treated with a closed reduction and possible fixation. They cause a growth disturbance in 65 % of dislocated cases and therefore should be clinically evaluated until skeletal maturity. PMID- 22495003 TI - Association of ADIPOR1 polymorphisms with bone mineral density in postmenopausal Korean women. AB - Adiponectin may affect bone through interactions with two known receptors, adiponectin receptors (ADIPOR) 1 and 2. We examined the association between polymorphisms of ADIPOR1 and ADIPOR2 and bone mineral density (BMD) in postmenopausal Korean women. Six polymorphisms in ADIPOR1 and four polymorphisms in ADIPOR2 were selected and genotyped in all study participants (n = 1,329). BMD at the lumbar spine and femur neck were measured using dual-energy X-ray absorptiometry. Lateral thoracolumbar (T4-L4) radiographs were obtained for vertebral fracture assessment and the occurrence of non-vertebral fractures examined using self-reported data. P values were adjusted for multiple testing using Bonferroni correction (P(corr)). ADIPOR1 rs16850799 and rs34010966 polymorphisms were significantly associated with femur neck BMD (P(corr) = 0.036 in the dominant model; P(corr) = 0.024 and P(corr) = 0.006 in the additive and dominant models, respectively). Subjects with the rare allele of each polymorphism had lower BMD, and association of rs34010966 with BMD showed a gene dosage effect. However, ADIPOR2 single nucleotide polymorphisms and haplotypes were not associated with BMD at any site. Our results suggest that ADIPOR1 polymorphisms present a useful genetic marker for BMD in postmenopausal Korean women. PMID- 22495006 TI - [Recognition of nasopharyngeal carcinoma]. AB - In two patients the presenting symptoms of nasopharyngeal carcinoma were non specific: a woman aged 35 years born in Hong-Kong with unilateral hearing loss, and a man aged 59 years with acute otitis media who later developed cranial nerve palsy. The woman was successfully treated with chemotherapy and radiotherapy, the man was in a poor general condition and refused treatment; he died within 9 weeks. Nasopharyngeal carcinoma is rare and can occur at any age. Symptoms of the disease are not specific and sometimes subtle resulting in a late diagnosis and a reduced chance of cure. In South-East Asia its incidence is much higher and recognition and prognosis are better. If a malignant tumour in the nasopharynx is suspected, endoscopy may not be adequate as the tumour can grow submucosally, necessitating radiological examination with MRI or CT. MRI is the most sensitive radiological examination for the detection of this tumour and the assessment of the extent of its local and perineural spread. PMID- 22495007 TI - [Immunotherapy for type 1 diabetes mellitus (DM1)]. AB - Treatment of type 1 diabetes mellitus (DM1) has greatly improved but remains limited to combating the consequences of the disease. Target values for glucose regulation are achieved in only 20% of patients. Immunosuppression can slow disease progression, but does not cure DM1. Immunotherapy attempts to protect remaining insulin-producing beta cells and beta cell function. Promising results of immunotherapy in phase 2 studies in patients with DM1 could not be reproduced in phase 3 studies. These studies showed heterogeneity played a role in patient populations and between ethnic groups. In future studies better endpoints of efficacy, biomarkers of disease progression and response to therapy are essential. Vaccination with beta-cell specific antigens to stimulate tolerance and vaccination combined with immunotherapy (biologicals) are options for future therapy. Discussion on the acceptability of the side effects of immunotherapy is desirable. PMID- 22495008 TI - ['Malignant peritoneal mesothelioma': a condition difficult to diagnose]. AB - BACKGROUND: Malignant mesothelioma is an aggressive neoplasm, which arises from serous membranes, such as the pleura and the peritoneum. Malignant peritoneal mesothelioma is relatively rare, but the incidence is increasing worldwide because of intensive asbestos use during the 20th century. CASE DESCRIPTION: A 60 year-old man complained of malaise, night sweating and weight loss and was seen by a specialist in internal medicine. Additional investigation included a CT scan, 2 PET-CT scans, 2 diagnostic laparoscopies and histological examination of peritoneum biopsies. After 7 months the diagnosis of malignant peritoneal mesothelioma was made. CONCLUSION: Histological investigation is of great importance when there is indication of malignant peritoneal mesothelioma. There is not yet a consensus concerning the optimal treatment, but a small increase in survival can be achieved by systemic chemotherapy or intraperitoneal therapy consisting of hyperthermic intraperitoneal chemotherapy after cytoreductive surgery. PMID- 22495009 TI - [Thomas Hodgkin and his disease]. AB - Thomas Hodgkin (1798-1866), born into a family of Quakers, would remain faithful all his life to the principles and rules of the 'Society of Friends'. He studied pharmacy and medicine in London, Edinburgh and Paris. As curator for the museum of pathological anatomy of Guy's Hospital (1825-1837) he introduced modern, organ based, medicine in England, together with the clinicians Richard Bright and Thomas Addison. In 1832 Hodgkin reported autopsy findings of seven patients who had shown swollen lymph glands and an enlarged spleen, without evidence of tuberculosis, purulent inflammation or cancer. Later the diagnosis 'Hodgkin's disease' would be restricted to lymphomas with giant, multinucleated Reed Sternberg cells on microscopic examination. Especially in his later years, Hodgkin devoted much time and effort to the emancipation of oppressed or destitute minorities, especially abroad. He died of dysentery on a journey to Palestine and lies buried in Jaffa. PMID- 22495010 TI - [Manual therapy for neck pain: increasing evidence for effectiveness]. AB - Most patients with acute neck pain (< 2 weeks) recover quickly and respond well to a wait-and-see approach. If the neck pain persists for more than 2 weeks there are various treatment options available. A new RCT from the USA has shown that spinal manipulation, or even a programme of home exercise, was more effective than medication (including analgesia) for patients with neck pain with a duration of 2-12 weeks. The magnitude of the difference in effectiveness of treatment was quite low. However, since the results are largely in line with a previous RCT from the Netherlands in which manual therapy showed the best clinical and cost effective results compared to physiotherapy and usual care by the general practitioner, the evidence in favour of manual therapy is now accumulating. Manual therapy is a rational treatment option for patients with neck pain persisting longer than 2 weeks. PMID- 22495011 TI - Perceptions of cardiac specialists and rehabilitation programs regarding patient access to cardiac rehabilitation and referral strategies. AB - BACKGROUND: Access to cardiac rehabilitation (CR) remains at approximately 30%, despite a national target of 70%. This study evaluated cardiac specialist and CR program perceptions of CR access and referral strategies. METHODS: Postal and online surveys of Canadian CR specialists and CR programs were administered. Responses were received from 71 of 765 CR specialists (9.3%) and 92 of 149 CR programs (61.7%). Respondents rated perceptions on 5-point Likert scales. RESULTS: Specialists rated patient access to CR as moderate (2.9 +/- 1.4). While they reported that they refer 65.9% of their patients, they most frequently do not refer because their patients report disinterest (23.4%) or geographic barriers to access (23.4%). Cardiac rehabilitation programs reported having capacity to serve a median of 275 patients annually, yet reportedly serving up to 350. The most commonly used methods of referral included discharge order sets (over 60%) and allied health care provider support. Electronic referral was perceived to be highly effective (4.1 +/- 1.0) yet the least frequently used. Cardiac rehabilitation programs perceived more patients are accessing CR because of these referral strategies, but increased patients strain program resources. CONCLUSIONS: Some of the least frequently used referral strategies were perceived as, and are also empirically demonstrated to be, most effective. Broader implementation of these strategies, while better-resourcing CR programs, may improve the continuum of care for cardiac patients. PMID- 22495012 TI - Partially irreversible paresis of the deep peroneal nerve caused by osteocartilaginous exostosis of the fibula without affecting the tibialis anterior muscle. AB - Dysfunction of the lower limb's muscles can cause severe impairment and immobilisation of the patient. As one of the leg's major motor and sensory nerves, the deep peroneal nerve (synonym: deep fibular nerve) plays a very important role in muscle innervation in the lower extremities. We report the case of a 19-year-old female patient, who suffered from a brace-like exostosis 6-cm underneath her left fibular head causing a partially irreversible paresis of her deep peroneal nerve. This nerve damage resulted in complete atrophy of her extensor digitorum longus and extensor hallucis longus muscle, and in painful sensory disturbance at her left shin and first web space. The tibialis anterior muscle stayed intact because its motor branch left the deep peroneal nerve proximal to the nerve lesion. Diagnosis was first verified 6 years after the onset of symptoms by a magnetic resonance imaging (MRI) scan of her complete left lower leg. Subsequently, the patient was operated on in our clinic, where a neurolysis was performed and the 4-cm-long osteocartilaginous exostosis was removed. Paralysis was already irreversible but sensibility returned completely after neurolysis. The presented case shows that an osteocartilaginous exostosis can be the cause for partial deep peroneal nerve paresis. If this disorder is diagnosed at an early stage, nerve damage is reversible. Typical for an exostosis is its first appearance during the juvenile growth phase. PMID- 22495013 TI - Lateral facial contouring via a single preauricular incision. AB - Many Asians have faces with prominent zygomas, and therefore reduction malarplasty is one of the most frequently undergone surgeries in Asia, including South Korea. It is performed using various surgical approaches (external, intraoral, bicoronal or their combination). The reduction technique that is the most effective, safest and with the lowest morbidity needs to be determined. From December 2005 to January 2010, 1652 patients who wanted to undergo zygoma reduction for purely aesthetic reasons were operated on using a novel technique that we have developed (the 3S technique), which is a simple and safe surgical technique that results in only a short scar. First, under local anaesthesia, a 13 to 15-mm-long skin incision is made at each sideburn. The subperiosteal dissection is continued anteriorly all the way to the body of the zygoma. Zygoma reduction is then performed in three steps: (1) malar shaving (lateral area of the zygoma body), (2) lateral corticotomy (zygomatic arch) and (3) full-thickness osteotomy (pretubercular area of the temporomandibular joint). Next, the zygomatic arch is displaced medially with digital pressure (infracture). Finally, a Silastic drain is inserted through the incision site, skin repair is completed and a gentle compressive dressing is applied. Most of the patients were satisfied with the results of the operation. This technique provides the following advantages: (1) it is simple and safe because it is performed under only local anaesthesia; (2) only one scar is created at the sideburn; (3) no foreign bodies, such as wires or miniplates, are used; and (4) it is minimally invasive, and as such there are fewer potential complications (e.g., no cheek drooping due to a wide muscle incision or dissection, less oedema and bleeding and a short hospitalisation time). The presented technique is simpler and more effective than previously described surgical techniques for reduction malarplasty. PMID- 22495014 TI - Ultrasound as a basic and auxiliary process for dye remediation: a review. AB - Ultrasonic treatment of recalcitrant contaminants has been of utmost interest recently due to the advantages of the cavitation phenomenon, which enhances the efficiency of Advanced Oxidation Processes (AOPs). The current review summarizes the use of ultrasound with biochemical, electrochemical, ozonation, photolysis, photocatalysis and Fenton processes for the degradation of mostly textile dyes and dyebath. There is a few studies about ultrasonic degradation of textile effluents or wastewater due to highly variable contents. It was found that the most common use of ultrasonic irradiation for dye degradation is the combined with the heterogeneous catalysts/adsorbents. The reaction mechanism of the ultrasonic irradiation in heterogeneous media was well investigated and understood. However, there is still lack of information about the reaction mechanism of ultrasonic irradiation in the homogeneous solutions, especially containing ferrous ions. Fenton reaction is already fast itself and gives effective degradation during the oxidation. Therefore, addition of ultrasonic irradiation to Fenton oxidation was less effective compared to other auxiliary processes. It should also be noted that ultrasonic irradiation had a negative effect on dye degradation during combined with electro-oxidation process. PMID- 22495015 TI - Triggering change: towards a conceptualisation of major change processes in farm decision-making. AB - In this paper, we present a broad conceptualisation of major change in farm level trajectories. We argue that as a result of path dependency, major changes in farming practice primarily occur in response to 'trigger events', after which farm managers intensify their consideration of the options open to them, and may set a new course of action. In undertaking new actions, the farm system enters a period of instability, while new practices become established. Over time these new practices, if successfully achieving anticipated aims, lead to a further period of path dependency. Recognising and capitalising upon this pattern of events is important for the development of policies oriented towards incentivising major change in farming practices, and may explain why similar projects and/or policies influence some 'types' of farmers differently, and at different times. To illustrate our arguments, examples of this process are described in relation to empirical examples of major on-farm change processes, drawn from qualitative interviews with organic and conventional farmers in two English case study areas. PMID- 22495016 TI - Using electronic conductivity and hardness data for rapid assessment of stream water quality. AB - A graphical screening method was previously developed by Kney and Brandes (2007) for assessing stream water quality data using electronic conductivity (EC) and alkalinity data. The method was aimed at providing citizen scientists involved in stream monitoring programs with a relatively simple way to interpret EC data. The method utilizes a plot of EC against concurrent alkalinity data, and is used to distinguish EC values for impacted or degraded streams from those that can be considered background values in a particular geologic setting. The method performs well in areas underlain by carbonate bedrock, as streams in those areas characteristically have EC values that are strongly correlated with alkalinity. However, in areas of low stream alkalinity (less than approximately 50 mg/L as CaCO(3)), the Kney and Brandes (2007) method was found to be much less effective in identifying impacted streams. This paper extends the graphical screening approach to streams with low alkalinity, specifically regions underlain by clastic sedimentary or crystalline bedrock, by using the strong correlation between EC and total hardness (TH). A baseline relationship of EC vs. TH is developed using surface water chemistry data from Hydrologic Benchmark Network streams (deemed as having minimal anthropogenic impacts) and regional groundwater quality data. The usefulness of the method is demonstrated by application to publicly available stream chemistry data and to field data collected from streams of eastern Pennsylvania under baseflow conditions. Results demonstrate that for streams with alkalinity <75 mg/L as CaCO(3), the TH-based graphical screening method should be used rather than the alkalinity-based method of Kney and Brandes (2007). PMID- 22495017 TI - Carbon storage and fluxes in existing and newly created urban soils. AB - Carbon storage (carbon density; kg C m(2)), concentrations of dissolved organic carbon (DOC) in soil pore water and soil respiration (g C m(2) yr(-1)) were measured in a 35 year old urban lawn soil amended with a surface mulch application of green waste compost and compared to those in two newly created urban soils, manufactured by mixing different volumes of green waste compost with existing soils or soil forming materials. The aim was to determine C storage and calculate annual fluxes in two newly created urban soils compared to an existing urban soil, to establish the potential for maintaining and building carbon storage. In the lawn soil, organic carbon storage was largely limited to the upper 15 cm of the soil, with material below 30 cm consisting of substantial amounts of alkaline building debris augmenting sandstone parent material. Leaching of DOC directly from the surface applied compost mulch amendment was readily mobile within the upper 15 cm of soil beneath, but not to 30 cm depth, indicating limited vertical redistribution of the soluble organic C fraction to the deeper, technic horizons. Only a very small proportion of annual C losses were attributable to DOC export (<= 0.5%) whilst a much greater amount was accounted for by soil respiration (~20%). In the two newly created urban soils, <= 30% additions of compost mixed with existing soil forming materials trebled C densities from <2 to 6 kg total carbon (TC) m(2), surpassing those of the existing lawn soil (<= 5 kg TC m(2)). Adding 45% compost served only to reduce bulk density so that C densities did not increase further until >50% compost was applied. Combined increases in soil respiration losses and DOC leaching associated with higher compost application rates suggested that volumes of ~30% compost were altogether optimal for sustainable C storage whilst minimising annual losses. Thus repeated applications of small amounts, rather than single applications of large amounts of green waste compost could be most effective at maintaining and building C storage in urban soils. PMID- 22495018 TI - Transepidermal elimination of sarcoidal granuloma in a patient with sarcoidosis and systemic sclerosis overlap. PMID- 22495020 TI - Residents' corner March 2012. sQUIZ your knowledge! Darier disease. PMID- 22495021 TI - Residents' corner March 2012. (Carpe)DIEM--dermatological indications for electron microscopy: orf infection. PMID- 22495024 TI - Processing peptidases in mitochondria and chloroplasts. AB - Most of the mitochondrial and chloroplastic proteins are nuclear encoded and synthesized in the cytosol as precursor proteins with N-terminal extensions called targeting peptides. Targeting peptides function as organellar import signals, they are recognized by the import receptors and route precursors through the protein translocons across the organellar membranes. After the fulfilled function, targeting peptides are proteolytically cleaved off inside the organelles by different processing peptidases. The processing of mitochondrial precursors is catalyzed in the matrix by the Mitochondrial Processing Peptidase, MPP, the Mitochondrial Intermediate Peptidase, MIP (recently called Octapeptidyl aminopeptidase 1, Oct1) and the Intermediate cleaving peptidase of 55kDa, Icp55. Furthermore, different inner membrane peptidases (Inner Membrane Proteases, IMPs, Atp23, rhomboids and AAA proteases) catalyze additional processing functions, resulting in intra-mitochondrial sorting of proteins, the targeting to the intermembrane space or in the assembly of proteins into inner membrane complexes. Chloroplast targeting peptides are cleaved off in the stroma by the Stromal Processing Peptidase, SPP. If the protein is further translocated to the thylakoid lumen, an additional thylakoid-transfer sequence is removed by the Thylakoidal Processing Peptidase, TPP. Proper function of the D1 protein of Photosystem II reaction center requires its C-terminal processing by Carboxy terminal processing protease, CtpA. Both in mitochondria and in chloroplasts, the cleaved targeting peptides are finally degraded by the Presequence Protease, PreP. The organellar proteases involved in precursor processing and targeting peptide degradation constitute themselves a quality control system ensuring the correct maturation and localization of proteins as well as assembly of protein complexes, contributing to sustenance of organelle functions. Dysfunctions of several mitochondrial processing proteases have been shown to be associated with human diseases. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids. PMID- 22495025 TI - Phototherapeutic keratectomy in diffuse stromal haze in granular corneal dystrophy type 2. AB - PURPOSE: To determine the minimum depth of phototherapeutic keratectomy (PTK) required for diffuse haze removal in granular corneal dystrophy type 2 and to determine whether Fourier domain optical coherence tomography (FD-OCT) can be an effective technique for predicting the exact required depth of ablation. METHODS: The depth of ablation used for diffuse stromal haze removal was evaluated with the slit lamp and serially taken photographs during the PTK procedure. The depth of diffuse haze was measured preoperatively using FD-OCT. RESULTS: Forty-three eyes of 30 patients were included in this study. The mean age of the patients was 62.0 +/- 8.4 years. The mean depth of PTK required was 43.7 +/- 6.2 MUm (range, 31-59 MUm). The mean follow-up period for 29 eyes of 22 patients, who had follow up periods of more than 6 months, was 21.0 +/- 12.0 months. The mean best spectacle-corrected visual acuity of these 29 eyes was 0.43 +/- 0.15 preoperatively and 0.71 +/- 0.16 (P = 0.022) 1 month postoperatively. Of the 43 eyes of 30 patients, FD-OCT was evaluated in 29 eyes of 22 patients. The mean preoperative depth of diffuse haze using FD-OCT was 44.3 +/- 6.4 MUm. The mean depth of ablation required to remove diffuse stromal haze was 44.5 +/- 5.9 MUm. The actual ablated depths correlated well with the depth of haze detected by FD OCT preoperatively (intraclass correlation coefficient = 0.719). CONCLUSIONS: FD OCT is an accurate method of predicting the depth of PTK required to remove visually significant diffuse haze in patients with granular corneal dystrophy type 2. We advocate the use of slit-lamp biomicroscopy after the initial 30-MUm ablation to determine the necessity for any further ablation. PMID- 22495026 TI - Thygeson superficial punctate keratitis and scarring. AB - PURPOSE: Thygeson superficial punctate keratitis (TSPK), a chronic, inflammatory disease, has traditionally been taught to resolve spontaneously and without scarring. We present 4 cases with TSPK who developed sight-altering scarring after a prolonged disease course. METHODS: Retrospective chart review of cases seen at the Proctor Medical Group. RESULTS: Patients age ranged from 31 to 68 years. All patients were male and had been symptomatic from 2 to 53 years. Follow up period ranged from 1 month to 35 years. All 3 patients developed significant corneal scarring. Case 1 had bilateral corneal thickening and a Salzmann nodule with vascularization. Case 2 had bilateral stromal opacification. Case 3 developed corneal scarring to the point of needing an anterior lamellar corneal transplant. Pathological evaluation of this tissue showed disruption of the Bowman layer with band keratopathy, thickening of the basement membrane, and subepithelial fibrosis. The diagnosis of TSPK in these cases was never in doubt, 2 of the cases having been diagnosed by Dr Thygeson. CONCLUSIONS: Prolonged corneal inflammation associated with TSPK can cause visually significant scarring of the anterior corneal stroma. In those patients with chronic disease, the use of a topical corticosteroid may be needed not just for comfort but to reduce the risk of corneal scarring. PMID- 22495027 TI - Comparative study of central corneal thickness using Fourier-domain optical coherence tomography versus ultrasound pachymetry in primary open-angle glaucoma. AB - PURPOSE: To compare central corneal thickness (CCT) results measured by Fourier domain optical coherence tomography (FD-OCT) and ultrasound pachymetry (USP) in glaucomatous eyes. METHODS: In this prospective, observational cross-sectional study, 80 eyes of 80 patients with primary open-angle glaucoma (POAG) and no other ocular abnormality were selected: 28 were treated with 1 drug (subgroup 1), 32 with 2 drugs (subgroup 2), and 20 with 3 drugs (subgroup 3). CCT was measured by FD-OCT (RTVue OCT) and USP (Pachymeter Reichert IOPac). Bland-Altman plots were used to assess the agreement between both instruments. The differences between CCTs measured by USP and FD-OCT were compared among the 3 subgroups. RESULTS: The mean CCT was 537.76 +/- 32.24 MUm and 520.53 +/- 30.44 MUm for USP and FD-OCT, respectively. A significant difference was found between the mean values obtained by FD-OCT and USP (17.22 +/- 7.96 MUm, P < 0.001, paired Student t test). A high correlation was obtained for CCT measured by both methods (Pearson correlation coefficient = 0.969; P < 0.001), and there was good agreement between the 2 pachymetry methods. Similar differences in CCT using USP and FD-OCT were found among the 3 treatment subgroups (P > 0.05 in all pairwise comparisons, analysis of variance). CONCLUSIONS: FD-OCT underestimates CCT compared with CCT measured by USP in POAG. Although highly correlated, the difference between these 2 devices can be clinically significant in the context of refractive surgeries in POAG patients but not in intraocular pressure estimation. This difference also seems to be independent of the number of antiglaucoma treatments used. PMID- 22495028 TI - The use of fibrin glue to seal Descemet membrane microperforations occurring during deep anterior lamellar keratoplasty. AB - PURPOSE: To report the use of fibrin glue to seal microperforations in Descemet membrane (DM) during deep anterior lamellar keratoplasty (DALK). METHODS: Two patients with keratoconus underwent DALK complicated by DM microperforation. Fibrin glue was successfully used to seal the microperforation in both cases. RESULTS: DM remained attached postoperatively in both cases, with no opacification, increased inflammation, or vascularization of the corneal stroma. CONCLUSIONS: The use of fibrin glue for managing microperforations in DALK may be a viable option. PMID- 22495029 TI - Outcomes of deep anterior lamellar keratoplasty for keratoconus: learning curve and advantages of the big bubble technique. AB - PURPOSE: To evaluate retrospectively the outcomes of a case series of deep anterior lamellar keratoplasties by air dissection (DALK-AD) using the big bubble (BB) technique, in the surgical treatment of keratoconus (KC). METHODS: Forty four consecutive keratoplasties of 42 patients for KC were performed at the French National Reference Center for KC from January 2008 to June 2010 by the same surgeon with the aim of systematically performing DALK-AD with the BB technique. The outcomes of the DALK-AD not converted to penetrating keratoplasty were analyzed, and a learning curve was established to successfully achieve the DALK-AD using the BB technique. RESULTS: Thirty-two DALK-AD procedures were successfully performed among 44 consecutively operated keratoplasties, with 12 being converted to penetrating keratoplasty during the surgical procedure. At 12 months, the mean best-corrected logarithm of the minimum angle of resolution visual acuity was 0.88 +/- 0.14 with 93.3% seeing best-corrected visual acuity >= 20/30 and 100% seeing best-corrected visual acuity >= 20/40. The mean gain of visual acuity in logarithm of the minimum angle of resolution lines at 6 and 12 months was 6.12 +/- 3.97 (P < 0.0001) and 6.94 +/- 4.18 (P < 0.005), respectively. The rate for intraoperative and postoperative complications was 31.8% and 4.5%, respectively. CONCLUSION: Despite a learning period needed to successfully perform deep lamellar anterior keratoplasty with the BB technique, this approach is safe and provides very good visual outcomes when adequate baring of Descemet membrane is achieved. The learning curve showed that complications related to this technique decrease significantly after the first 10 cases. PMID- 22495030 TI - The change in ocular higher-order aberrations after pterygium excision with conjunctival autograft: a 1-year prospective clinical trial. AB - PURPOSE: To investigate the effects of pterygium excision with conjunctival autograft plus corneal polishing on ocular higher-order aberrations (HOAs) and to monitor the changes throughout the first postoperative year. METHODS: A total of 18 eyes of 16 patients with primary pterygium who had an indication for surgical excision were included in the study. All patients underwent a detailed ophthalmologic examination preoperatively and at the third and twelfth postoperative months. Pterygium excision with conjunctival autograft plus corneal polishing was performed by the same surgeon (K.G.). Corneal topography and ocular HOAs were measured by NIDEK optical path difference scanning system ARK-10000 refractive power/corneal analyzer. RESULTS: Root mean square values of total aberrations and total HOAs were found to be significantly decreased both at 3 and 12 months after an uneventful pterygium surgery. Although solely root mean square values of coma and trefoil revealed a statistically significant reduction in the third postoperative month (P=0.043 and P=0.018, respectively), after 1 year, all parameters (total coma: P<0.001; total trefoil: P=0.004; total quatrefoil: P=0.010; and total high astigmatism: P=0.016) except for total spherical aberration (P=0.236) were found to be lower when compared with the preoperative values. CONCLUSION: Uneventful pterygium excision with conjunctival autograft plus corneal polishing can significantly reduce most of the pterygium-induced HOAs. Moreover, the reduced postoperative aberrations continue to change beyond the early postoperative period even into the 1-year postoperative period. Therefore, any refractive procedures should be postponed at least 1 year after the pterygium surgery until corneal stability occurs. PMID- 22495031 TI - Changes of corneal biomechanics with keratoconus. AB - PURPOSE: To perform advanced analysis of the corneal deformation response to air pressure in keratoconics compared with age- and sex-matched controls. METHODS: The ocular response analyzer was used to measure the air pressure-corneal deformation relationship of 37 patients with keratoconus and 37 age (mean 36 +/- 10 years)- and sex-matched controls with healthy corneas. Four repeat air pressure-corneal deformation profiles were averaged, and 42 separate parameters relating to each element of the profiles were extracted. Corneal topography and pachymetry were performed with the Orbscan II. The severity of the keratoconus was graded based on a single metric derived from anterior corneal curvatures, difference in astigmatism in each meridian, anterior best-fit sphere, and posterior best-fit sphere. RESULTS: Most of the biomechanical characteristics of keratoconic eyes were significantly different from normal eyes (P < 0.001), especially during the initial corneal applanation. With increasing keratoconus severity, the cornea was thinner (r = -0.407, P < 0.001), the speed of corneal concave deformation past applanation was quicker (dive; r2 = -0.314, P = 0.01), and the tear film index was lower (r = -0.319, P = 0.01). The variance in keratoconus severity could be accounted for by the corneal curvature and central corneal thickness (r = 0.80) with biomechanical characteristics contributing an additional 4% (total r = 0.84). The area under the receiver operating characteristic curve was 0.919 +/- 0.025 for keratometry alone, 0.965 +/- 0.014 with the addition of pachymetry, and 0.972 +/- 0.012 combined with ocular response analyzer biomechanical parameters. CONCLUSIONS: Characteristics of the air pressure-corneal deformation profile are more affected by keratoconus than the traditionally extracted corneal hysteresis and corneal resistance factors. These biomechanical metrics slightly improved the detection and severity prediction of keratoconus above traditional keratometric and pachymetric assessment of corneal shape. PMID- 22495032 TI - Prevalence of sleep apnea syndrome and high-risk characteristics among keratoconus patients. AB - PURPOSE: To determine the prevalence and risk factors for sleep apnea in a keratoconus population. METHODS: Ninety-two keratoconus patients and 92 controls were classified as high risk or low risk for sleep apnea, using the Berlin Questionnaire (BQ) or individual history of sleep apnea. Logistic regression was used to investigate the risk factors associated with high risk of sleep apnea in keratoconus patients and controls. RESULTS: Of the 92 keratoconus patients, 18 (19.6%) had a positive known history for sleep apnea, and 49 (53.3%) were categorized to be at high risk by the BQ. Of the 92 control patients, 6 (6.5%) had a positive known history for sleep apnea, and 25 (27.2%) were categorized to be at high risk by the BQ. In keratoconus patients, body mass index was the only risk factor for sleep apnea, whereas in control patients, age, body mass index, and family history of sleep apnea were the risk factors for sleep apnea. CONCLUSIONS: Keratoconus patients are at increased risk for sleep apnea, and different risk factors are associated with sleep apnea in keratoconus patients and controls. Ophthalmologists should consider screening keratoconus patients for obstructive sleep apnea, if appropriate. PMID- 22495033 TI - Oculopalpebral borreliosis as an unusual manifestation of Lyme disease. AB - PURPOSE: To report the case of acrodermatitis chronica atrophicans as an ocularpalpebral manifestation of Lyme borreliosis, with peripheral keratopathy and associated vasculitis. METHODS: Case report. RESULTS: A 16-year-old girl, with a 4-year history of recurrent left eye photophobia, intense redness, and superior eyelid edema, presented with lid erythema, ptosis, superficial venous tortuosity, conjunctival hyperemia, corneal thinning with precipitates, and vascularization. Borrelia burgdorferi was confirmed by immunoblotting. Treatments with doxycycline followed by ceftriaxone were only partially effective. Eyelid biopsy revealed spirochetes and vasculitis with deposition of immunoglobulin G. Oral cefuroxime for 28 days was ineffective. Due to the vasculitis, immunosuppression with azathioprine and topical cyclosporine were given for 4 months. Since then she has been free of flare-ups. CONCLUSIONS: Lyme borreliosis should be considered in patients with recurrent chronic lid edema and associated keratopathy. PMID- 22495034 TI - Confocal microscopy of corneal crystals in a patient with hereditary tyrosinemia type I, treated with NTBC. AB - PURPOSE: To describe the confocal microscopic findings in a patient with hereditary tyrosinemia type I (HT-I) treated with 2-(2-nitro-4 trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) who developed corneal crystals. METHODS: In this case study, we describe the confocal microscopic findings in a boy, who was diagnosed with HT-I at the age of 4 months. At 16 years of age, he developed painful corneal lesions in both eyes. On slit-lamp examination, whorl-like branching epithelial corneal lesions were found, staining faintly with fluorescein. His NTBC treatment was stopped and reintroduced at a lower dose after 1 month. The lesions clearly regressed, leaving only mild residual epithelial scarring, without fluorescein staining and without pain. Confocal microscopy was performed in the acute painful stage and in the asymptomatic convalescent stage 5 months later. RESULTS: Confocal microscopy confirmed the presence of slender birefringent spiky crystals in the very superficial corneal epithelium. In the asymptomatic convalescent phase, the crystals clearly persisted on confocal microscopy, although they were barely visible on slit-lamp examination. CONCLUSIONS: This is the first in vivo demonstration by confocal microscopy of corneal crystals present in a patient with proven type I tyrosinemia, under NTBC treatment. PMID- 22495035 TI - Ocular surface deficits contributing to persistent epithelial defect after penetrating keratoplasty. AB - PURPOSE: To determine the ocular surface deficits contributing to persistent epithelial defect (PED) after penetrating keratoplasty (PKP). METHODS: Four ocular surface deficits that contribute to PED and their corrective measures were reviewed in 11 eyes of 11 patients with PED after PKP. RESULTS: Among these 11 eyes, PED developed early in 8 eyes and late in 3 eyes after PKP. They all had more than 2 ocular surface deficits, with infrequent blinking (11 eyes) and lagophthalmos (9 eyes) being more common. Proper corrective measures resulted in rapid epithelialization in 1 week (1 eye), 2 weeks (9 eyes), and 3 weeks (1 eye) via insertion of a bandage contact lens to maintain tear film for treating infrequent blinking (4 eyes), tarsorrhaphy to correct nocturnal lagophthalmos (2 eyes), and fornix reconstruction to eliminate pathogenic symblepharon (4 eyes). During the follow-up of 22.1 +/- 7.6 months after healing of PED, 8 eyes retained a stable and clear graft, whereas 3 eyes with more ocular surface deficits had recurrent PED and graft failure develop. Two of the latter were corrected by a repeat PKP combined with oral mucosal graft to correct the remaining cicatricial eyelids. CONCLUSIONS: Besides the neurotrophic state and aqueous tear deficiency dry eye common in this cohort, infrequent blinking, lagophthalmos, and pathogenic symblepharon also contribute to PED after PKP. Proper corrective measures and vigilant follow-up are crucial for maintaining PKP graft survival in these severe cicatricial ocular surface diseases. PMID- 22495036 TI - Clinicomicrobiological characteristics and treatment outcome of sclerocorneal tunnel infection. AB - PURPOSE: To analyze the clinical presentation, microbiological evaluation, and management of post-cataract surgery sclerocorneal tunnel infection. METHODS: This is a retrospective chart review of 11 patients with sclerocorneal tunnel infection after cataract surgery, managed between November 2006 and October 2009. The clinical characteristics and treatment outcomes were analyzed. RESULTS: All patients presented within 1 to 10 weeks of primary surgery. The presenting visual acuity ranged from hand motions to 20/50. Ten of 11 patients had sclerocorneal involvement, and 4 patients had associated endophthalmitis. The causative organisms were fungus (n = 6), bacteria (n = 4), or both (n = 1). Deroofing of the tunnel and sclerocorneal patch graft was done in 4 patients. Intensive medication was administered to all patients. The final visual acuity ranged from light perception to 20/50 at a mean follow-up of 119 days (median, 66 days; range, 2-357 days). Five patients had >=20/100 vision. The mean interval between presentation to resolution of infiltrate and formation of peripheral scarring was 20 days (median, 11 days; range, 2-66 days). CONCLUSIONS: Sclerocorneal tunnel infection must be microbiologically evaluated. Intensive medical management, wound revision and repair may lead to a favorable outcome. PMID- 22495037 TI - Experience-dependent plasticity in pitch encoding: from brainstem to auditory cortex. AB - Linguistic and musical pitch provide an analytic window to evaluate how neural representations of important pitch attributes of a sound undergo transformation from early sensory to later cognitive stages of processing in the human brain, and how pitch-relevant experience shapes these representations. These pitch attributes are shaped differentially depending on their functional relevance to a listener. Neural encoding of pitch-relevant information is shaped by the perceptual salience of domain-specific features at subcortical (auditory brainstem) and cortical stages of processing. The emergence of a functional ear asymmetry in the neural encoding of pitch-relevant information at a lower sensory processing level supports the view that local and feedforward and feedback mechanisms are involved in pitch-relevant processing. A theoretical framework for a neural network is proposed involving coordination between local, feedforward, and feedback components that can account for experience-induced enhancement of pitch representations at multiple levels of the auditory pathway. PMID- 22495038 TI - Perceptual-cognitive training improves biological motion perception: evidence for transferability of training in healthy aging. AB - In our everyday life, processing complex dynamic scenes such as crowds and traffic is of critical importance. Further, it is well documented that there is an age-related decline in complex perceptual-cognitive processing, which can be reversed with training. It has been suggested that a specific dynamic scene perceptual-cognitive training procedure [the three-dimensional multiple object tracking speed task (3D-MOT)] helps observers manage socially relevant stimuli such as human body movements as seen in crowds or during sports activities. Here, we test this assertion by assessing whether training older observers on 3D-MOT can improve biological motion (BM) perception. Research has shown that healthy older adults require more distance in virtual space between themselves and a point-light walker to integrate BM information than younger adults. Their performances decreased markedly at a distance as far away as 4 m (critical for collision avoidance), whereas performance in young adults remained constant up to 1 m. We trained observers between 64 and 73 years of age on the 3D-MOT speed task and looked at BM perception at 4 and 16 m distances in virtual space. We also had a control group trained on a visual task and a third group without training. The perceptual-cognitive training eliminated the difference in BM perception between 4 and 16 m after only a few weeks, whereas the two control groups showed no transfer. This demonstrates that 3D-MOT training could be a good generic process for helping certain observers deal with socially relevant dynamic scenes. PMID- 22495039 TI - Premature birth is associated with not fully differentiated contractile smooth muscle cells in human umbilical artery. AB - Smooth muscle cells (SMCs) participate to the regulation of peripheral arterial resistance and blood pressure. To assume their function, SMCs differentiate throughout the normal vascular development from a synthetic phenotype towards a fully differentiated contractile phenotype by acquiring a repertoire of proteins involved in contraction. In human fetal muscular arteries and umbilical arteries (UAs), no data are available regarding the differentiation of SMCs during the last trimester of gestation. The objective of this study was to characterize the phenotype of SMCs during this gestation period in human UAs. We investigated the phenotype of SMCs in human UAs from very preterm (28-31 weeks of gestation), late preterm (32-35 weeks) and term (37-41 weeks) newborns using biochemical and immunohistochemical detection of alpha-actin, smooth muscle myosin heavy chain, smoothelin, and non-muscle myosin heavy chain. We found that the number of SMCs positive for smoothelin in UAs increased with gestational age. Western blot analysis revealed a higher content of smoothelin in term compared to very preterm UAs. These results show that SMCs in human UAs gradually acquire a fully differentiated contractile phenotype during the last trimester of gestation and thus that premature birth is associated with not fully differentiated contractile SMCs in human UAs. PMID- 22495040 TI - Occurrence and distribution of pepper veinal mottle virus and cucumber mosaic virus in pepper in Ibadan, Nigeria. AB - Viral diseases constitute obstacles to pepper production in the world. In Nigeria, pepper plants are primarily affected by pepper veinal mottle virus (PVMV), Cucumber mosaic virus (CMV), Pepper leaf curl Virus (TLCV), Tobacco mosaic virus (TMV), Pepper mottle virus (PMV) and a host of other viruses. The experiment was carried out with a diagnostic survey on the experimental field of the National Horticultural Research Institute, Ibadan, Nigeria and on pepper farms in six local government areas within Ibadan Oyo State, Nigeria, forty samples were collected from each of the farms. Diseased samples were obtained from the field and taken to the laboratory for indexing. In ELISA test some of the samples from the pepper farms showed positive reaction to single infection with PVMV (36.79%), CMV (22.14%) while some others showed positive reaction to mixed infection of the two viruses (10%) but some also negative reaction to PVMV and CMV antisera (31.07). PMID- 22495041 TI - [Clinical effectiveness of measurement of serum total human chorionic gonadotropin for diagnosis and management of testicular seminomatous germ cell tumor]. AB - Serum free-beta human chorionic gonadotropin (fbhCG) has been used for the diagnosis and management of testicular tumors for many years in Japan, while the measurement of serum hCG is widely used in the world. There have been reports of false-positive cases with serum fbhCG and due care must be taken in order not to take the wrong treatment strategy. Serum hCG is said to be more useful in the diagnosis and management of non-seminoma than serum fbhGC. Because of the false positive issue with serum fbhCG, however, we consider it appropriate to use serum hCG for measurement even in seminoma. We simultaneously measured serum hCG and serum fbhCG in 25 cases of seminoma in order to evaluate the usefulness of hCG assay in the diagnosis and management of seminoma. In the measurements, we found 5 false-positive cases (20%) with serum fbhCG. The diagnostic sensitivity of the 20 cases with the exception of the 5 false-positive cases was 16 cases (80%) and 14 cases (70%) with serum hCG and serum fbhCG, respectively. We conclude that serum hCG is more reliable and is a useful assay in the diagnosis and management of seminoma, but serum fbhCG is not useful in the diagnosis and management of testicular tumor and its independent measurement should not be used to avoid misleading results. PMID- 22495042 TI - [The clinical value of 3 tesla diffusion-weighted magnetic resonance imaging in the diagnosis of prostate cancer]. AB - Diffusion-weighted imaging (DWI) is a magnetic resonance imaging (MRI) method and is considered potentially useful for detecting prostate cancer. We evaluated the clinical value of DWI with apparent diffusion coefficient (ADC) maps in addition to T2-weighted imaging (T2WI) using 3 tesla (3 T) MRI. Thirty-three patients with elevated prostate specific antigen were evaluated by MRI with T2WI and DWI prior to transperineal template-guided mapping biopsy. The MRI findings were compared with the pathology of biopsy specimens in six parts of prostate : both sides of outer peripheral zones, inner peripheral zones, and transition zones. The sensitivities, specificities and accuracies were 42.1, 84.4 and 76.3% in T2WI, 57.1, 84.7 and 80.8% in T2WI/DWI, and 87.5, 85.2 and 85.4% in DWI/ADC using 0.951*10 -3 mm2/s as cutoff ADC value. The hazard ratio of patients whose ADC values were under the cutoff was 25.86 by multivariate analysis. Mean ADC values were significantly different between cancer positive and negative cores (p<0.001). The ADC value showed a negative correlation with increasing tumor length (p=0.0047). Although further study with a large number of patients is necessary, DWI/ADC using 3 T MRI is a useful tool for detecting prostate cancer. PMID- 22495043 TI - [Adrenocortical carcinoma detected by retroperitoneal hemorrhage : a case report]. AB - Spontaneous massive retroperitoneal hemorrhage from an adrenal tumor is rare and is usually fatal if unrecognized. We report a case of spontaneous rupture of a primary adrenocortical carcinoma that occurred in a 79-year-old man. He visited our hospital with left abdominal pain. Computed tomography (CT) showed a left retroperitoneal hemorrhage. We could not find the origin of this hemorrhage. Two months later, CT showed the left adrenal tumor, and left adrenalectomy and nephrectomy were performed successfully. The histological diagnosis was adrenocortical carcinoma. He rejected adjuvant therapy. Local recurrence of the tumor was found, and right adrenal gland, brain, and mediastinal lymph node metastases were recognized 6 months after the operation. He died 11 months after the operation. PMID- 22495044 TI - [Renal actinomycosis with pneumonia]. AB - A 55-year-old man was hospitalized for pneumonia. His fever did not subside despite administration of antibiotics ; therefore, he was referred to our hospital. A chest radiograph and thoracic computed tomography showed multiple tubercles ; abdominal computed tomography (CT) showed left renal abscess. The patient's temperature fell after antibiotic administration, but inflammation reaction exacerbated. Abdominal CT showed inflammation spreading to the subcutaneous tissues. We considered renal resection, but the patient could not be administered general anesthesia because of low breathing function caused by pneumonia. We attempted open drainage and wedge resection of the left renal under local anesthesia ; but we were not able to identify the infectious bacteria. Four days later, the patient had blood poisoning and died because of deterioration of breathing function. Actinomyces was detected in the lungs and the kidneys by pathological examination. PMID- 22495045 TI - [Successful gemcitabine-nedaplatin therapy in a hemodialysis patient with ureteral carcinoma after bilateral nephroureterectomy]. AB - A 79-year-old male, who received hemodialysis due to bilateral nephroureterectomy and cysto-prostateurethrectomy. Five months later, an enlarged lymph node was found in the left of inguinal area. Abdominal computed tomography revealed a low density mass from the para-aortic lymph node to the left of inguinal area, suggesting lymph node metastasis of ureteral carcinoma. After 3 cycles of gemcitabinenedaplatin therapy, the size of lymph node metastasis decreased. This is a report of successful treatment of ureteral carcinoma with hemodialysis. PMID- 22495046 TI - [Primary small cell carcinoma of the bladder in which the bladder preservation was achieved by chemotherapy and transurethral resection]. AB - A 78-year-old man was referred to our hospital for asymptomatic gross hematuria on April 16, 2007. Cystoscopy and abdominal computed tomography revealed a nonpapillary tumor at the upper area of the bladder. Abdominal and thoracic computed tomography showed no lymph nodes and no metastasis to other organs. Transurethral resection of bladder tumor (TURBT) was performed, and a pathological diagnosis of small cell carcinoma of the bladder at stage pT2N0M0 was made. Considering the patient's age and the location of the tumor, we administered chemotherapy using carboplatin and etoposide after resection of the tumor. After 2 courses of chemotherapy, a second-look TURBT was performed, and pathological examination showed no viable tumor cells. Cystoscopy performed after 3 months revealed recurrence of a nonpapillary tumor at a different area of the bladder. We performed TURBT and made a pathological diagnosis of small cell carcinoma of the bladder at stage pT1N0M0. The patient was free from disease in January 2011. PMID- 22495047 TI - [Tubercular prostatic abscess following intravesical Bacillus Calmette-Guerin therapy]. AB - We report a case of tubercular prostatic abscess in a male patient who had undergone intravesical Bacillus Calmette-Guerin therapy for bladder carcinoma in situ. The abscess was successfully treated with transurethral resection of the prostate for drainage and subsequent antituberculous regime of chemotherapy. PMID- 22495048 TI - [Retention cyst of the prostate in a patient with urinary difficulty]. AB - A 54-year-old man visited our clinic for dysuria. Transabdominal ultrasonography revealed a multilocular cyst at the neck of the bladder, and a cystoscopy revealed obstruction of the neck of the bladder. Dysuria improved after tamsulosin treatment was initiated, and abdominal magnetic resonance imaging (MRI) showed disappearance of the cyst. The patient had urinary difficulty again after 2 years. An MRI and cystoscopy revealed recurrence of the cyst. Tamsulosin administration was reinitiated, but his urinary difficulty did not improve. Transurethral resection of the cystic wall was performed. Histopathological examination indicated a retention cyst. PMID- 22495049 TI - [A case of malignant peritoneal mesothelioma presenting with bilateral swelling of spermatic cord]. AB - A 67-year-old man had pain and swelling in the bilateral inguinal region. His past medical history included non-alcoholic steatohepatitis and liver cirrhosis. A clinical examination revealed a solid mass that was palpable along with the bilateral spermatic cord from the external inguinal ring to the root of the scrotum. Other than a hydrocele in the right testis, the epididymis and testes were intact. Abdominal computed tomography showed ascites and a solid tumor of the bilateral spermatic cord. Magnetic resonance imaging findings did not suggest malignancy, while antibiotics showed no effects. The patient wanted relief from the inguinal pain and a bilateral high orchiectomy was performed, during which time the spermatic cord was found firmly adhered to the surrounding tissue, and could not be completely resected. A histopathological examination showed epithelial mesothelioma. For additional examination of the ascites, the patient underwent paracentesis, which revealed an extremely high level of hyaluronic acid. Our working diagnosis was peritoneal malignant mesothelioma that had infiltrated the bilateral spermatic cord. We began systemic chemotherapy treatment with pemetrexed and cisplatin, but, the patient died 3 months after the operation. PMID- 22495050 TI - Routine vaccination against chickenpox? AB - Varicella-zoster virus (VZV) causes both varicella and herpes zoster. In 1995 a varicella vaccine was licensed in the USA and was incorporated into the routine vaccination programme for children; a decline of varicella among children and adults, and a reduction in associated hospitalisation, complications and mortality, has resulted. In the UK, a policy of targeted vaccination of at-risk groups has been in place since the vaccine was introduced. Here we review the evidence for the different approaches to VZV vaccination policy. PMID- 22495051 TI - Management of simple insect bites: where's the evidence? AB - Many insects bite in order to obtain a blood meal and, in the process, inject the victim with saliva that may contain a number of substances, some of which can be immunogenic. The consequences of insect bites include local reactions, immune (allergic) reactions including anaphylaxis, and secondary bacterial infections (e.g. impetigo, cellulitis). Although insect bites are perceived to be common in the UK, the exact incidence is difficult to estimate since most are likely to go unreported: only those causing the more serious reactions are seen in primary care settings. Simple insect bites are those that are not accompanied or followed by anaphylactic shock or systemic infection. Many preparations for the treatment of insect bites, including antihistamines and topical corticosteroids, are available for purchase over the counter (OTC) in the UK. However, there is a lack of evidence for the efficacy of these treatments and, in general, recommendations for treatment are based on expert opinion and clinical experience. This article reviews the evidence for the management of simple bites by insects commonly encountered in the UK, but excludes ticks, mites and lice. PMID- 22495052 TI - Cognitive decline in Parkinson's disease is associated with slowing of resting state brain activity: a longitudinal study. AB - The pathophysiological mechanisms of Parkinson's disease (PD)-related dementia (PDD) are still poorly understood. Previous studies using electroencephalography (EEG) and magnetoencephalography (MEG) have demonstrated widespread slowing of oscillatory brain activity as a neurophysiological characteristic of PD-related dementia. Here, we use MEG to longitudinally study early changes in oscillatory brain activity in initially nondemented PD patients that may be associated with cognitive decline. Using a longitudinal design, resting-state MEG recordings were performed twice at an approximate 4-year interval in 14 healthy controls and 49 PD patients. Changes in peak frequency and in relative spectral power for 10 brain regions were analyzed in relation to clinical measures of cognitive and motor function. In contrast to healthy controls, PD patients showed a slowing of the dominant peak frequency. Furthermore, analysis per frequency band revealed an increase in theta power over time, along with decreases in alpha1 and alpha2 power. In PD patients, decreasing cognitive performance was associated with increases in delta and theta power, as well as decreases in alpha1, alpha2, and gamma power, whereas increasing motor impairment was associated with a theta power increase only. The present longitudinal study revealed widespread progressive slowing of oscillatory brain activity in initially nondemented PD patients, independent of aging effects. The slowing of oscillatory brain activity strongly correlated with cognitive decline and therefore holds promise as an early marker for the development of dementia in PD. PMID- 22495053 TI - Thoracoscopic epicardial ablation of the left and right atrium. Beating heart procedure in patients with atrial fibrillation. AB - INTRODUCTION: Atrial fibrillation (AF) is a common arrhythmia affecting approximately 1% to 2% of the general population. OBJECTIVES: The aim of the study was to evaluate the efficacy and safety of thoracoscopic ablation in patients with AF. PATIENTS AND METHODS: A total of 25 patients aged from 42 to 77 years (mean 56.4 years) with persistent or long-standing persistent AF were scheduled for the procedure. Thoracoscopic epicardial ablation of the right atrium, pulmonary veins, and left atrium was performed on the beating heart using the Cox MAZE III-based diagram, via 3 ports and 2 cm incision below the xiphoid. Exit block was always assessed. Patients were prospectively followed for 12 months after the procedure. 24-hour electrocardiography (Holter monitoring) was used to confirm the results. RESULTS: Conduction block across ablation lines was achieved in 21 patients (84%). At 1 month of follow-up, the sinus rhythm (SR) was observed in 18 of 20 patients. At 3 months, the SR was observed in 19 patients (76%). Two patients had atrial flutter, while 3 still experienced AF. At 6 months, the SR was observed in 21 patients (84%); 2 patients still had AF, 1 patient atrial flutter, and 1 patient had a pacemaker implanted. Results of follow-up at 1 year did not differ from those at 6 months. No changes in the size of the left atrium and left ventricular ejection fraction, no deaths, stroke, transient ischemic attack, or infectious complications were observed. CONCLUSIONS: The efficacy of epicardial thoracoscopic ablation of the left and right atrium was high, reaching 84% during 1-year follow-up. No serious complications were observed in the postoperative period (except for the need for pacemaker implantation in 1 patient). PMID- 22495054 TI - A pilot study using children's books to understand caregiver perceptions of parenting practices. AB - OBJECTIVE: To conduct a pilot study to test the feasibility and acceptability of using children's books to understand caregiver perceptions of parenting practices around common behavior challenges. METHODS: A prospective 1-month pilot study was conducted in 3 community-based pediatric clinics serving lower income families living in central Indianapolis. One hundred caregivers of 4- to 7-year-old children presenting for a well-child visit chose 1 of 3 available children's books that dealt with a behavioral concern the caregiver reported having with the child. The book was read aloud to the child in the caregiver's presence by a trained research assistant and given to the families to take home. Outcomes measured were caregiver intent to change their interaction with their child after the book reading, as well as caregiver reports of changes in caregiver-child interactions at 1 month. RESULTS: Reading the book took an average of 3 minutes. Most (71%) caregivers reported intent to change after the book reading; two thirds (47/71) were able to identify a specific technique or example illustrated in the story. One month later, all caregivers remembered receiving the book, and 91% reported reading the book to their child and/or sharing it with someone else. Three-fourths of caregivers (60/80) reported a change in caregiver-child interactions. CONCLUSIONS: The distribution of children's books with positive parenting content is a feasible and promising tool, and further study is warranted to see whether these books can serve as an effective brief intervention in pediatric primary care practice. PMID- 22495055 TI - Thoracic radiotherapy for limited stage small cell lung carcinoma. PMID- 22495057 TI - Using the Surveillance, Epidemiology, and End Results database to investigate rare cancers, second malignancies, and trends in epidemiology, treatment, and outcomes. PMID- 22495058 TI - Role of surgery for small cell lung cancer. PMID- 22495056 TI - Novel therapeutic approaches for small cell lung cancer: the future has arrived. PMID- 22495059 TI - Psychosocial pressure and menarche: a review of historic evidence for social amenorrhea. AB - OBJECTIVE: The age of menarche is usually considered to be affected by nutritional, health-related, social, and economic factors and has significantly decreased since the mid-19th century. The present study was performed to investigate whether the timing of menarche paralleled the general acceleration of physical development, or whether this pattern differed. STUDY DESIGN: In all, 30 German studies on menarcheal age (n = >200) since 1848 were collected. Frequency distributions were analyzed. RESULTS: During the second half of the 19th and the early 20th century, mean menarcheal age decreased from 18 to 12-13 years in Europe. Yet, the data fail to support the conventional hypothesis that menarcheal age mainly depends on nutritional, health, and economic factors. CONCLUSIONS: We suggest that later than usual menarche may not necessarily be regarded as a physical illness, but in view of the apparently physiological delay of menarche in the 19th century, may be viewed as "collective social amenorrhea." TARGET AUDIENCE: Obstetricians & Gynecologists and Family Physicians. LEARNING OBJECTIVES: After participating in this CME activity, physicians should be better able to evaluate menarche as an indicator of developmental tempo in both historical and modern settings, compare menarche in healthy mid-19th century girls with menarche in average modern girls, and assess the marked sensitivity of full pubertal development to environmental circumstances. PMID- 22495060 TI - Visual disturbances in (pre)eclampsia. AB - This review aims to summarize existing information concerning visual disturbances in (pre) eclampsia that have been described in the literature. Preeclampsia is one of the leading causes of maternal and fetal morbidity and mortality worldwide. Visual disturbances in (pre)eclampsia seem to be frequent phenomena. Therefore, the obstetrician/gynecologist may encounter women with serious, and sometimes debilitating, pathology of the visual pathways. Established ophthalmic entities associated with (pre)eclampsia are cortical blindness, serous retinal detachment, Purtscher-like retinopathy, central retinal vein occlusions, and retinal or vitreous hemorrhages. Ensuing visual symptoms include blurry vision, diplopia, amaurosis fugax, photopsia, and scotomata, including homonymous hemianopsia. In general, aside from lowering the blood pressure and preventing (further) seizures with magnesium sulfate, no specific therapy seems indicated for (pre)eclamptic women who experience visual changes. Although in most cases visual acuity returns to normal within weeks to months after the onset of symptoms, rarely permanent visual impairment can occur. Health care providers such as emergency room physicians, obstetricians, family physicians, neurologists, and ophthalmologists should be aware that acute onset of visual symptoms in pregnant women can be the first sign of (pre)eclampsia. Given that visual changes are a diagnostic criterion for severe preeclampsia, obstetricians should appreciate the significance of these changes and discuss appropriate diagnostic options with the ophthalmologist. Affected women can be reassured that most cases are transient. TARGET AUDIENCE: Obstetricians and gynecologists, ophthalmologists, neurologists, family physicians, emergency room physicians LEARNING OBJECTIVES: After completing this CME activity, obstetricians and gynecologists should be better able to classify visual disturbances at an early stage during pregnancy, interpret acute onset of visual disturbances as the first sign of preeclampsia, and evaluate possible residual visual symptoms during follow-up. PMID- 22495061 TI - Influenza and tetanus, diphtheria, and acellular pertussis vaccinations during pregnancy. AB - Vaccinations in pregnancy are an important aspect of prenatal care and of improving not only maternal health but also neonatal outcomes. Only 2 vaccines are specifically recommended during pregnancy: influenza and tetanus, diphtheria, and acellular pertussis (Tdap). Because influenza illness disproportionately affects pregnant women compared with other populations, annual prevention of influenza illness is recommended for all women who will be pregnant during influenza season (October to May). Influenza vaccination has been recently reported to also result in decreased febrile respiratory illnesses in the newborn, likely through passive antibody transfer. Pertussis infection rates are rising in the United States as vaccine-induced immunity wanes, with the mortality burden primarily seen in infants aged <6 months. Pertussis immunization with Tdap is now recommended for all pregnant women during the late second (>20 weeks) or third trimester with the intent to both protect the pregnant woman and provide passive antibody to the infant before vaccination at 2 months of age. Provider support for these recommendations regarding both annual influenza vaccination and postpartum Tdap vaccination during pregnancy is critical to ensuring vaccine delivery and improving both maternal and fetal health. The article reviews the epidemiology and clinical aspects of influenza and pertussis infection with particular attention to pregnancy and recommendations for vaccination in these women. TARGET AUDIENCE: Obstetricians and gynecologists, ophthalmologists, neurologists, family physicians, emergency room physicians LEARNING OBJECTIVES: After completing this CME activity, obstetricians and gynecologists should be better able to analyze how influenza infection disproportionally affects pregnant women. Assess how influenza vaccination improves maternal and likely neonatal outcomes. Evaluate pertussis infection and immunity in adults, and counsel pregnant women as to the benefits of Tdap vaccination, particularly for the infant. PMID- 22495062 TI - On the epigenetic origin of cancer stem cells. AB - Epigenetic mechanisms are the key component of the dynamic transcriptional programming that occurs along the process of differentiation from normal stem cells to more specialized cells. In the development of cancer and according to the cancer stem cell model, aberrant epigenetic changes may ensure the property of cancer cells to switch cancer stem cell markers on and off in order to generate a heterogeneous population of cells. The tumour will then be composed of tumourigenic (cancer stem cells) and non-tumourigenic (the side population that constitutes the bulk of the tumour) cells. Characterizing epigenetic landscapes may thus help discriminate aberrant marks (good candidates for tumour detection) from cancer stem cell specific profiles. In this review, we will give some insights about what epigenetics can teach us about the origin of cancer stem cells. We will also discuss how identification of epigenetic reprogramming may help designing new drugs that will specifically target cancer stem cells. PMID- 22495063 TI - Does dietary inulin affect biological activity of a grapefruit flavonoid-rich extract? AB - BACKGROUND: The aim of the study was to verify that the concomitant presence of grapefruit flavonoid extract with inulin in a Western-type diet may provide synergistic effects to the hindgut metabolism, as well as blood lipid and mineral profiles. METHODS: Forty male Wistar rats were distributed into 4 groups and fed for 28 days with diets rich in fat, cholesterol and protein. A two-way repeated measures ANOVA was applied to assess the effects of inulin (v. sucrose, 5% of the diet), the addition of dietary grapefruit flavonoid extract (diets without or with 0.3% of an extract from hard parts of grapefruit) and the interaction between these two dietary factors. RESULTS: When compared to the control sucrose containing diet, the diet enriched with inulin led to typical changes within the caecum, the main part of hindgut fermentation in rats, such as acidification of the digesta, support of bifidobacteria growth and increase of propionate and butyrate production. The dietary grapefruit flavonoid extract without inulin increased the bulk and pH value of caecal digesta, whereas short-chain fatty acid concentration and the bifidobacteria population were lowered compared to the extract-free diets. Simultaneous dietary addition of both tested components decreased slightly the pH value and increased somewhat the bifidobacteria number and the propionate concentration, however to the level observed with the control sucrose-containing diet. With regard to blood lipids, dietary grapefruit flavonoid extract decreased the triglyceride concentration regardless of the dietary carbohydrate type. CONCLUSION: Inulin does not provide any additional benefit to the blood lipid profile caused by the dietary application of grapefruit flavonoid extract and it does not counteract clearly detrimental effects of the extract in the hindgut. Adding grapefruit extract to the diet must be performed with caution due to possible adverse hindgut responses with overdoses. PMID- 22495064 TI - A cost-effectiveness analysis of early vs late reconstruction of iatrogenic bile duct injuries. AB - BACKGROUND: Controversy exists regarding the optimal timing of repair after iatrogenic bile duct injuries (BDI). Several studies advocate late repair (>=6 weeks after injury) with mandatory drainage and resolution of inflammation. Others indicate that early repair (<6 weeks after injury) produces comparable or superior clinical outcomes. Additionally, although most studies have reported inferior outcomes with primary surgeon repair, this practice continues. With disparate published recommendations and rising health care costs, decision analysis was used to examine the cost-effectiveness of BDI repair. STUDY DESIGN: A Markov model was developed to evaluate primary surgeon repair (PSR), late repair by a hepatobiliary surgeon (LHBS), and early repair by a hepatobiliary surgeon (EHBS). Baseline values and ranges were collected from the literature. Sensitivity analsyses were conducted to test the strength of the model and variability of parameters. RESULTS: The model demonstrated that EHBS was associated with lower costs, earlier return to normal activity, and better quality of life. Specifically, 1 year after repair, PSR yielded 0.53 quality adjusted life years (QALYs) ($120,000/QALY) and LHBS yielded 0.74 QALYs ($74,000/QALY); EHBS yielded 0.82 QALYs ($48,000/QALY). Sensitivity analyses supported these findings at clinically meaningful probabilities. CONCLUSIONS: This cost-effectiveness model demonstrates that early repair by a hepatobiliary surgeon is the superior strategy for the treatment of BDI in properly selected patients. Although there is little clinical difference between early and late repair, there is a great difference in cost and quality of life. Ideally, costs and quality of life should be considered in decisions regarding strategies of repair of injured bile ducts. PMID- 22495065 TI - Changes in rat n-3 and n-6 fatty acid composition during pregnancy are associated with progesterone concentrations and hepatic FADS2 expression. AB - The mechanisms responsible for changes to long-chain polyunsaturated fatty acid (LC PUFA) status during pregnancy have not been fully elucidated. Tissue samples were collected from virgin and pregnant (day 12 and 20) female rats. LC PUFA status, sex hormone concentrations and hepatic mRNA expression of FADS1, FADS2 and elongase were assessed. Day 20 gestation females had higher plasma and liver docosahexaenoic acid and lower arachidonic acid content than virgin females (P<0.05). There was higher FADS2 mRNA expression during pregnancy (P=0.051). Progesterone and oestradiol concentrations positively correlated with hepatic FADS2 mRNA expression (P=0.043, P=0.004). Progesterone concentration positively correlated with hepatic n-6 docosapentaenoic acid content (P=0.006), and inversely correlated with intermediates in LC PUFA synthesis including n-3 docosapentaenoic acid, gamma-linolenic acid and 20:2n-6 (P<0.05). Changes in progesterone and oestradiol during pregnancy may promote the synthesis of LC PUFA via increased FADS2 expression. PMID- 22495066 TI - Polyethylene glycol-modified pigment epithelial-derived factor: new prospects for treatment of retinal neovascularization. AB - Pathological retinal neovascularization and choroidal neovascularization are major causes of vision loss in a variety of clinical conditions, such as retinopathy of prematurity, age-related macular degeneration, and diabetic retinopathy. Pigment epithelial-derived factor (PEDF) has been found to be the most potent natural, endogenous inhibitor of neovascularization, but its application is restricted because of its instability and short half-life. Polyethylene glycol (PEG) has been used as a drug carrier to slow clearance rate for decades. The present study investigated PEGylated-PEDF for the first time and evaluated its long-term effects on preventing angiogenesis in vitro and in vivo. PEG showed lower cytotoxicity to human umbilical vein endothelial cells (HUVECs). In vitro, PEGylated-PEDF inhibited HUVEC proliferation, migration, tube formation, and vascular endothelium growth factor secretion and induced HUVEC apoptosis in a dose-dependent manner, and it showed a statistically significant difference compared with the PEDF treatment group. In vivo, PEGylated-PEDF had a long-lasting effect in both plasma and retinal concentrations. In an oxygen induced retinopathy model, one intravitreous injection of PEGylated-PEDF after mouse pups were moved into room air resulted in a significant difference in the inhibition of retinal neovascularization, which decreased the nonperfusion area, compared with the PEDF-treated group. Our present study demonstrated for the first time the long-term inhibitory effects of PEGylated-PEDF on the prevention of neovascularization in vitro and in vivo. These data suggest that PEGylated PEDF could offer an innovative therapeutic strategy for preventing retinal neovascularization. PMID- 22495067 TI - Nonsteroidal anti-inflammatory drug-activated gene-1 plays a role in the impairing effects of cyclooxygenase inhibitors on gastric ulcer healing. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) can impair gastric ulcer healing. This study investigates the involvement of NSAID-activated gene-1 (NAG-1) in ulcer repair impairment by cyclooxygenase (COX) inhibitors. Gastric ulcers were induced in rats by acetic acid. Four days later, animals received daily intragastric indomethacin (nonselective COX-1/COX-2 inhibitor; 1 mg/kg), 5-(4 chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (selective COX-1 inhibitor; 2.5 mg/kg), (5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl) phenyl-2(5H)-furanone (DFU) (selective COX-2 inhibitor; 5 mg/kg), celecoxib (selective COX-2 inhibitor; 1 mg/kg), and valdecoxib (selective COX-2 inhibitor; 1 mg/kg), for 1, 3, or 7 days. Ulcerated tissues were processed to assess: 1) COX 1, COX-2, NAG-1, proliferating cell nuclear antigen (PCNA), and activated caspase 3 expression; 2) ulcer area; and 3) prostaglandin E(2) (PGE(2)) levels. COX-1 expression in ulcerated tissues was decreased, whereas COX-2 expression was enhanced. Ulcer healing was delayed by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. Ulcer PGE(2) levels were decreased by SC-560, DFU, celecoxib, valdecoxib, and indomethacin. NAG-1 was overexpressed in ulcerated tissues and further enhanced by indomethacin, DFU, and SC-560, but not by celecoxib or valdecoxib. PCNA expression in ulcerated areas was reduced by indomethacin, but not by the other test drugs. The expression of activated caspase-3 in ulcers was increased and enhanced further by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. These findings indicate that: 1) COX inhibitors exert differential impairing effects on gastric ulcer healing, through mechanisms unrelated to the inhibition of COX isoforms and prostaglandin production; and 2) NAG-1 induction, followed by activation of proapoptotic pathways, can contribute to the impairing effects of COX inhibitors on ulcer healing. PMID- 22495068 TI - Structural resilience of the gut microbiota in adult mice under high-fat dietary perturbations. AB - Disruption of the gut microbiota by high-fat diet (HFD) has been implicated in the development of obesity. It remains to be elucidated whether the HFD-induced shifts occur at the phylum level or whether they can be attributed to specific phylotypes; additionally, it is unclear to what extent the changes are reversible under normal chow (NC) feeding. One group (diet-induced obesity, DIO) of adult C57BL/6J mice was fed a HFD for 12 weeks until significant obesity and insulin resistance were observed, and then these mice were switched to NC feeding for 10 weeks. Upon switching to NC feeding, the metabolic deteriorations observed during HFD consumption were significantly alleviated. The second group (control, CHO) remained healthy under continuous NC feeding. UniFrac analysis of bar-coded pyrosequencing data showed continued structural segregation of DIO from CHO on HFD. At 4 weeks after switching back to NC, the gut microbiota in the DIO group had already moved back to the CHO space, and continued to progress along the same age trajectory and completely converged with CHO after 10 weeks. Redundancy analysis identified 77 key phylotypes responding to the dietary perturbations. HFD-induced shifts of these phylotypes all reverted to CHO levels over time. Some of these phylotypes exhibited robust age-related changes despite the dramatic abundance variations in response to dietary alternations. These findings suggest that HFD-induced structural changes of the gut microbiota can be attributed to reversible elevation or diminution of specific phylotypes, indicating the significant structural resilience of the gut microbiota of adult mice to dietary perturbations. PMID- 22495070 TI - Regarding "diurnal pattern of intraocular pressure is affected by microgravity when measured in space with the pressure phosphene tonometer". PMID- 22495071 TI - Intraocular pressure elevation during space flight. PMID- 22495069 TI - Vertical segregation and phylogenetic characterization of ammonia-oxidizing Archaea in a deep oligotrophic lake. AB - Freshwater habitats have been identified as one of the largest reservoirs of archaeal genetic diversity, with specific lineages of ammonia-oxidizing archaea (AOA) populations different from soils and seas. The ecology and biology of lacustrine AOA is, however, poorly known. In the present study, vertical changes in archaeal abundance by CARD-FISH, quantitative PCR (qPCR) analyses and identity by clone libraries were correlated with environmental parameters in the deep glacial high-altitude Lake Redon. The lake is located in the central Spanish Pyrenees where atmospheric depositions are the main source of reactive nitrogen. Strong correlations were found between abundance of thaumarchaeotal 16S rRNA gene, archaeal amoA gene and nitrite concentrations, indicating an ammonium oxidation potential by these microorganisms. The bacterial amoA gene was not detected. Three depths with potential ammonia-oxidation activity were unveiled along the vertical gradient, (i) on the top of the lake in winter-spring (that is, the 0 (o)C slush layers above the ice-covered sheet), (ii) at the thermocline and (iii) the bottom waters in summer-autumn. Overall, up to 90% of the 16S rRNA gene sequences matched Thaumarchaeota, mostly from both the Marine Group (MG) 1.1a (Nitrosoarchaeum-like) and the sister clade SAGMGC-1 (Nitrosotalea-like). Clone-libraries analysis showed the two clades changed their relative abundances with water depth being higher in surface and lower in depth for SAGMGC-1 than for MG 1.1a, reflecting a vertical phylogenetic segregation. Overall, the relative abundance and recurrent appearance of SAGMGC-1 suggests a significant environmental role of this clade in alpine lakes. These results expand the set of ecological and thermal conditions where Thaumarchaeota are distributed, unveiling vertical positioning in the water column as a key factor to understand the ecology of different thaumarchaeotal clades in lacustrine environments. PMID- 22495072 TI - Elevated levels of RhoA in the optic nerve head of human eyes with glaucoma. AB - PURPOSE: To determine changes in the expression profile of RhoA and Rho kinase (ROCK-1 and ROCK-2) in the aqueous humor outflow pathway and optic nerve head (ONH) of human eyes with or without glaucoma to explore their potential involvement in glaucoma pathophysiology. METHODS: Age-matched paraffin-embedded postmortem eyes from patients with or without glaucoma were stained immunohistochemically using polyclonal antibodies raised against RhoA, ROCK-1, and ROCK-2. The intensity of the immunostaining in the aqueous humor outflow pathway and the ONH was graded by 4 individuals who were masked concerning whether the eyes were from normal individuals or those with glaucoma. RESULTS: Both normal eyes and those with glaucoma showed a positive staining for RhoA, ROCK-1, and ROCK-2 in the trabecular meshwork, ciliary muscle, and ONH. There was a significant increase in the RhoA protein levels in the glaucomatous ONH compared with the age-matched controls. CONCLUSIONS: Elevated levels of RhoA in the ONH of glaucomatous eyes suggest possible involvement of RhoA in the pathophysiology of glaucoma. PMID- 22495073 TI - Impact of an antimicrobial stewardship intervention on shortening the duration of therapy for community-acquired pneumonia. AB - BACKGROUND: Initial management of community-acquired pneumonia (CAP) has been a Centers for Medicare and Medicaid Services performance measure for a decade. We hypothesized that an intervention directed at management of CAP that assesses areas not covered by the performance measures-treatment duration and antimicrobial selection after additional microbiology data are available--would further improve CAP management. METHODS: We performed a single-center, prospective study to compare management of adult inpatients with presumed CAP before (from 1 January 2008 through 31 March 2008) and after (from 1 February 2010 through 10 May 2010) an intervention consisting of education and prospective feedback to teams regarding antibiotic choice and duration. The primary outcome measure was duration of antibiotic therapy in the 2 periods. RESULTS: There were 62 patients in the preintervention period and 65 patients in the intervention period. The duration of antibiotic therapy decreased from a median of 10 to 7 days (P < .001), with 148 fewer days of antibiotic therapy. The median lengths of stay were similar in the 2 groups (4 vs 5 days). A causative pathogen was identified less frequently during the intervention period (14% vs 34%); however, antibiotics were more frequently narrowed or modified on the basis of susceptibility results during the intervention period (67% vs 19%). Fewer patients received duplicate therapy within 24 hours in the intervention period (90% vs 55%). CONCLUSIONS: The duration of therapy for CAP was excessive at our institution and was decreased with a stewardship intervention. Confirmatory studies at other institutions are needed; efforts to assess and reduce duration of therapy for CAP should be strongly considered. PMID- 22495075 TI - Miconazole mucoadhesive tablets: a novel delivery system. AB - Oropharyngeal candidiasis (OPC) is among the most common opportunistic infections observed in persons infected with human immunodeficiency virus. A once-daily miconazole 50 mg mucoadhesive buccal tablet (MBT) is a novel delivery system with potent in vitro activity against many Candida species, including some that may be resistant to other azoles. MBT, although more expensive, offers an effective, safe, and well-tolerated topical treatment option for OPC that is administered as a convenient once-daily dose. PMID- 22495077 TI - Panton-Valentine leukocidin-positive Staphylococcus aureus skin infections. PMID- 22495074 TI - Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected patients receiving tesamorelin. AB - BACKGROUND: Tesamorelin, a growth hormone-releasing hormone analogue, decreases visceral adipose tissue (VAT) by 15%-20% over 6-12 months in individuals with human immunodeficiency virus (HIV)-associated abdominal adiposity, but it is unknown whether VAT reduction is directly associated with endocrine and metabolic changes. METHODS: In 2 phase III, randomized, double-blind studies, men and women with HIV-associated abdominal fat accumulation were randomly assigned (ratio, 2:1) to receive tesamorelin or placebo for 26 weeks. At week 26, patients initially receiving tesamorelin were randomly assigned to continue receiving tesamorelin or to receive placebo for an additional 26 weeks. In per-protocol analysis of 402 subjects initially randomly assigned to receive tesamorelin, those with >=8% reduction in VAT were defined a priori as responders per the statistical analysis plan. Post hoc analyses were performed to assess differences between responders and nonresponders. RESULTS: Compared with tesamorelin nonresponders, responders experienced greater mean (+/-SD) reduction in triglyceride levels (26 weeks: -0.6 +/- 1.7 mmol/L vs -0.1 +/- 1.2 mmol/L [P = .005]; 52 weeks: -0.8 +/- 1.8 mmol/L vs 0.0 +/- 1.1 mmol/L [P = .003]) and attenuated changes in fasting glucose levels (26 weeks: 1 +/- 16 mg/dL vs 5 +/- 14 mg/dL [P = .01]; 52 weeks: -1 +/- 14 mg/dL vs 8 +/- 17 mg/dL [P < .001]), hemoglobin A1c levels (26 weeks: 0.1 +/- 0.3% vs 0.3 +/- 0.4% [P < .001]; 52 weeks: 0.0 +/- 0.3% vs 0.2 +/- 0.5% [P = .003]), and other parameters of glucose homeostasis. Similar patterns were seen for adiponectin levels, with significant improvement in responders vs nonresponders. Changes in lipid levels and glucose homeostasis were significantly associated with percentage change in VAT. CONCLUSIONS: In contrast to nonresponders, HIV-infected patients receiving tesamorelin with >=8% reduction in VAT have significantly improved triglyceride levels, adiponectin levels, and preservation of glucose homeostasis over 52 weeks of treatment. CLINICALTRIALS.GOV REGISTRATION: NCT00123253, NCT00435136, NCT00608023. PMID- 22495078 TI - Pregnancy and fetal outcomes after exposure to mefloquine in the pre- and periconception period and during pregnancy. AB - BACKGROUND: Pregnant women who travel to malarious areas and their clinicians need data on the safety of malaria chemoprophylaxis. METHODS: The effect of exposure to mefloquine on pregnancy and offspring outcomes was evaluated using the F. Hoffmann-La Roche global drug safety database for the time frame 31 January 1986 through 26 October 2010. We investigated pregnancy and fetal outcomes in maternal, paternal, and both-parent exposure cases with a focus on congenital malformations and fetal loss. The main outcome measures were birth defect prevalence and types of malformations. RESULTS: A total of 2506 cases of mefloquine exposure during pregnancy or in the pre- and periconception period were evaluated. Most cases were maternal prospective (outcome of the pregnancy unknown at the time of reporting; n = 2246 [89.6%]) followed by maternal retrospective cases (outcome of the pregnancy known at the time of reporting; n = 227 [9.0%]), with small numbers of paternal and both-parent exposure cases. Of the total 2246 mefloquine maternal prospective exposures (95.2%), 2139 occurred before conception and/or during the first trimester. Of 1383 maternal prospective cases with known outcome, 978 (70.7%) resulted in delivery, 405 (29.3%) resulted in abortion (112 spontaneous, 293 therapeutic), and 43 resulted in birth defects, corresponding to a birth defect prevalence of 4.39% (43 of 978). Prospective cases overall showed no specific pattern of birth malformations. CONCLUSIONS: The drug safety database analysis of mefloquine exposure in pregnancy showed that the birth defect prevalence and fetal loss in maternal, prospectively monitored cases were comparable to background rates. PMID- 22495079 TI - Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993-2008. AB - BACKGROUND: Age-specific comparisons of influenza and respiratory syncytial virus (RSV) hospitalization rates can inform prevention efforts, including vaccine development plans. Previous US studies have not estimated jointly the burden of these viruses using similar data sources and over many seasons. METHODS: We estimated influenza and RSV hospitalizations in 5 age categories (<1, 1-4, 5-49, 50-64, and >=65 years) with data for 13 states from 1993-1994 through 2007-2008. For each state and age group, we estimated the contribution of influenza and RSV to hospitalizations for respiratory and circulatory disease by using negative binomial regression models that incorporated weekly influenza and RSV surveillance data as covariates. RESULTS: Mean rates of influenza and RSV hospitalizations were 63.5 (95% confidence interval [CI], 37.5-237) and 55.3 (95% CI, 44.4-107) per 100000 person-years, respectively. The highest hospitalization rates for influenza were among persons aged >=65 years (309/100000; 95% CI, 186 1100) and those aged <1 year (151/100000; 95% CI, 151-660). For RSV, children aged <1 year had the highest hospitalization rate (2350/100000; 95% CI, 2220 2520) followed by those aged 1-4 years (178/100000; 95% CI, 155-230). Age standardized annual rates per 100000 person-years varied substantially for influenza (33-100) but less for RSV (42-77). CONCLUSIONS: Overall US hospitalization rates for influenza and RSV are similar; however, their age specific burdens differ dramatically. Our estimates are consistent with those from previous studies focusing either on influenza or RSV. Our approach provides robust national comparisons of hospitalizations associated with these 2 viral respiratory pathogens by age group and over time. PMID- 22495080 TI - Peripheral lymphovenous communication in lymphoedema. AB - AIM: To investigate whether in lower extremity lymphoedema, lymph proteins enter blood before they do the thoracic duct. METHODS: Retrospective analysis of routine lymphoscintigraphy in 69 adults imaged at 5, 45 and 150 min following bilateral subcutaneous web space injection of Tc-nanocolloid was carried out. Regions of interest were placed over the liver and ilioinguinal lymph nodes bilaterally on the anterior images at 45 and 150 min. Individual minor (0.5 point for each) and major (1 point for each) criteria of abnormal scintigraphy were applied to each limb and summed to give a lymphoscintigraphic abnormality score. An abnormal limb had a score >=1. RESULTS: The ratio of hepatic counts per pixel to total bilateral ilioinguinal counts (L/N ratio) was higher in patients with abnormal results on lymphoscintigraphy (median 6.2; interquartile range 4.0-15.6 pixels*10; n=48) compared with that in patients with normal lymphoscintigraphic results (2.5 [1.5-5.0] pixels*10; n=21; P<0.0002). In the abnormal group, the lymphoscintigraphic score (two limbs summed) correlated with the 150-min L/N ratio (r s=0.42; P<0.005). L/N ratios at 45 and 150 min correlated in the abnormal group (r s=0.44; P<0.005) but not in the normal group (r s=0.3; P>0.05). The 45-min activity, as a percentage of the 150-min activity, was higher in lymph nodes than in the liver in both the abnormal (35.0 [8.2-50.0] vs. 10.6 [5.8 30.0]%; P<0.0001]) and normal groups (38.3 [18.4-63.5] vs. 23.3 [12.4-33.1]%; P<0.05), and, with respect to the liver, was higher in the normal group (P<0.01). CONCLUSION: In lymphoedema, more lymph proteins enter blood proximal to the thoracic duct. The time courses of nodal and hepatic activities suggest that access may occur within nodes themselves. PMID- 22495081 TI - Brain perfusion SPECT imaging and acetazolamide challenge in vascular cognitive impairment. AB - Cerebrovascular disease is recognized as a common cause of cognitive impairment and dementia, alone or coexisting with other neurodegenerative diseases, mostly Alzheimer's disease. Vascular cognitive impairment (VCI) is a part of the heterogenous disorders group related to cerebral vessel disease. Although age is one of the most important risk factors for VCI, other common cardiovascular risk factors are also involved. By investigating these risk factors, a high proportion of these cognitive disorders can be prevented and/or delayed. Until now, only treatment of midlife arterial hypertension has been recognized as a preventing factor of vascular dementia. Brain MRI is becoming the method of choice to investigate cerebral vascular pathologies. However, this form of morphological imaging remains inadequate and does not provide useful functional information during VCI exploration, despite which functional imaging such as brain perfusion single-photon computed tomography, performed in baseline conditions and/or after an acetazolamide challenge, is underutilized in VCI exploration. The common strategies for VCI screening have not been standardized until now, and therefore further long-term imaging studies are needed to establish early diagnostic protocols. The present review summarizes the potential benefits of brain perfusion single-photon computed tomography imaging and possible scintigraphic quantification of cerebral hemodynamic reserves in investigation of VCI. PMID- 22495082 TI - Do induced hypertension and hypotension affect stroke volume variation in man? AB - STUDY OBJECTIVE: To investigate changes in stroke volume variation (SVV) by both induced hypertension (pressor test) and hypotension (depressor test), and also by induced hypotensive anesthesia in patients with good cardiac function. DESIGN: Prospective, controlled clinical study. SETTING: University hospital. PATIENTS: 31 ASA physical status 1 and 2 patients, aged 39-62 years, who were scheduled for elective surgery. INTERVENTIONS: We conducted three studies: a pressor test study, a depressor test study, and an induced hypotensive anesthesia study. In the pressor test, patients received a bolus of phenylephrine 0.001 mg/kg to increase systolic arterial pressure (SAP) by 30% to 40% compared with baseline. In the depressor test, patients received a bolus of nitroglycerine 0.005 mg/kg to decrease SAP by 30% to 40% compared with baseline. In the induced hypotensive anesthesia test, patients received intravenous (IV) nitroglycerine continuously until mean arterial pressure (MAP) was reduced to 60-70 mmHg. MEASUREMENTS: When arterial pressure reached the target pressure for each study type, SVV and other parameters were recorded. MAIN RESULTS: Induced hypertension (pressor test) decreased SVV, while induced hypotension (depressor test) and induced hypotensive anesthesia increased SVV. CONCLUSIONS: SVV does not misinterpret preload dependency assessment of patients receiving medications to increase or to lower blood pressure. PMID- 22495083 TI - Anosmia and hypogeusia as a complication of general anesthesia. AB - A 57 year old woman with no previous history of any sensory deficits developed anosmia and hypogeusia after general anesthesia for laparoscopic cholecystectomy, with complete recovery over 6 months. There were no other identifiable factors that may have contributed to her anosmia and hypogeusia after general anesthesia. As anosmia and hypogeusia related to anesthesia and surgery are not frequently reported, the incidence of these events related to anesthesia may be higher than expected. PMID- 22495084 TI - An adult patient with Klippel-Feil syndrome presenting for repeat operation: a cautionary tale of the GlideScope. AB - The introduction of video laryngoscopes has increased the success of intubating the difficult airway. However, failures have been reported in the literature that are associated with certain patient characteristics. Klippel-Feil Syndrome is a condition that typically presents with decreased cervical spine motion, a characteristic that has been associated with GlideScope failure. After an uneventful first anesthetic, a case of a near impossible-to-intubate occurred in a patient with Klippel-Feil Syndrome. PMID- 22495085 TI - A method of securing the Xomed endotracheal tube for accurate monitoring of the recurrent laryngeal nerve. PMID- 22495086 TI - Airway management for rigid bronchoscopy via a freshly performed tracheostomy in a child with Goldenhar syndrome. AB - A case of tooth aspiration in a 6 year old boy with Goldenhar syndrome and known difficult intubation is presented. A fresh tracheostomy was performed after a failed fiberoptic intubation and dental aspiration. The patient was transferred to our tertiary-care children's hospital for emergency bronchoscopy through the fresh tracheostomy for removal of an aspirated tooth. Rigid bronchoscopy performed via a fresh tracheostomy presents several challenges. The major complications associated with bronchoscopy performed via a fresh tracheostomy, as well as management of airway emergencies are discussed. PMID- 22495087 TI - A potentially hazardous complication during central venous catheterization: lost guidewire retained in the patient. AB - Guidewires are routinely used in the Seldinger technique during central venous catheter placement. A case in which a guidewire was unsuspectingly released and retained in a patient during the catheterization of the internal jugular vein is presented. Physicians from multiple services subsequently failed to detect the retained guidewire on several chest radiographs; however, the guidewire was incidentally discovered after a computed tomographic scan was obtained. PMID- 22495088 TI - Knotting of an orogastric tube around an endotracheal tube. PMID- 22495089 TI - Calculating the burden of disease of suicide, attempted suicide, and suicide ideation by estimating disability weights. PMID- 22495091 TI - A new protolimonoid from Capuronianthus mahafalensis. AB - From stem barks of Capuronianthus mahafalensis (Meliaceae) endemic to Madagascar, a new protolimonoid named capulin containing a four membered ring in its side chain was isolated by repeated silica gel column chromatography. Its structure was determined by 1D and 2D NMR spectroscopy and high-resolution MS. To the best of our knowledge, this is the first time that a four-membered ring occurs in the side chain of protolimonoids. PMID- 22495092 TI - Utility of stress echocardiography in selecting the optimal mitral valve procedure in patients with severe ischemic mitral regurgitation undergoing coronary artery bypass grafting. AB - INTRODUCTION: Severe functional ischemic mitral regurgitation (FIMR) considerably worsens the prognosis of patients after myocardial infarction. The complex pathomechanism of FIMR and its dynamic nature make it difficult to develop effective therapeutic methods. OBJECTIVES: The aim of the study was to prospectively assess a diagnostic strategy based on stress echocardiography in referring patients with severe FIMR for appropriate surgical procedure: coronary artery bypass grafting alone (CABGa) or CABG with mitral annuloplasty (CABGma) or replacement (CABGmr). PATIENTS AND METHODS: A prospective analysis included 42 patients (23 women, 19 men) aged 67 +/-12 years with severe FIMR after myocardial infarction, scheduled for CABG. In each patient, mitral valve morphology, left ventricular function, FIMR degree as assessed by the effective regurgitation orifice area (severe >= 20 mm2), myocardial viability, and mitral deformation indexes were assessed prior to surgery. Based on clinical assessment and rest and stress echocardiography parameters, patients were referred for CABGa (group 1; n = 6), CABGma (group 2; n = 27), or CABGmr (group 3; n = 9). RESULTS: In all study groups, no differences in clinical and echocardiographic results were observed during a 12-month follow-up. A significant improvement was reported in the majority of patients regardless of the surgical procedure. Early (30-day) mortality in the whole study population was 11.9% (n = 5). Survival at 12 months was 100%, 81.5%, and 77.8% for groups 1, 2, and 3, respectively (P = 0.3). In all study groups, a statistically significant FIMR reduction was observed in a 12 month follow-up: small, moderate, and severe FIMR was observed in 29 (83%), 5 (14%), and 1 (3%) surviving patient, respectively. Reverse left ventricular remodeling was observed in 83% of the patients in group 1, 63.7% in group 2, and 100% in group 3 (statistically nonsignificant difference). CONCLUSIONS: The presented diagnostic strategy, based on stress echocardiography, may facilitate the process of choosing a suitable cardiac surgical procedure for patients with severe FIMR. PMID- 22495094 TI - Black widow spider envenomation, a rare cause of Horner's syndrome. AB - Horner's syndrome involves a triad of eyelid ptosis, miosis, and facial anhidrosis that results from disruption of the oculosympathetic pathway. Acquired Horner's syndrome is associated with a variety of medical conditions including Pancoast tumor and carotid dissection. We report the unique case of a 47-year-old man presenting with Horner's syndrome 4 weeks after black widow spider envenomation. Workup did not reveal any alternative explanatory etiology. We hypothesize that late sequelae of black widow spider envenomation secondary to autonomic nerve injury or retrograde axonal transport after mechanical inoculation may have led to an acquired defect in the oculosympathetic pathway resulting in a Horner's syndrome. This case introduces a rare cause of Horner's syndrome and highlights the importance of environmental exposures in the evaluation of these patients. PMID- 22495093 TI - Effectiveness of Physio Acoustic Sound (PAS) therapy in demented nursing home residents with nocturnal restlessness: study protocol for a randomized controlled trial. AB - BACKGROUND: Many older people with neuropsychiatric disorders such as Alzheimer's disease and frontotemporal dementia suffer from sleeping problems and often show nocturnal restlessness. Professionals and informal carers face considerable problems in solving these problems. Attempts to diminish these problems with medication in a safe and responsible manner have proven hardly effective or not effective at all. Therefore, nowadays the focus lies more on non-pharmacological solutions, for example by influencing environmental factors. There are indications that treatment with low-frequency acoustic vibrations, that is Physio Acoustic Sound (PAS) therapy, has a positive effect on sleeping problems. Therefore we study the effectiveness of PAS therapy in demented patients with nocturnal restlessness. METHODS: In a randomized clinical trial, 66 nursing home patients will be divided into two groups: an intervention group and a control group. For both groups nocturnal restlessness will be measured with actiwatches during a period of six weeks. In addition, a sleep diary will be filled in.For the intervention group the baseline will be assessed, in the first two weeks, reflecting the existing situation regarding nocturnal restlessness. In the next two weeks, this group will sleep on a bed identical to their own, but with a mattress containing an in-built PAS device. As soon as the patient is lying in bed, the computer programme inducing the vibrations will be switched on for the duration of 30 min. In the last two weeks, the wash-out period, the measurements of the intervention group are continued, without the PAS intervention.During the total study period, other relevant data of all the implied patients will be recorded systematically and continuously, for example patient characteristics (data from patient files), the type and seriousness of the dementia, occurrence of neuropsychiatric symptoms during the research period, and the occurrence of intermittent co-morbidity. DISCUSSION: If PAS therapy turns out to be effective, it can be of added value to the treatment of nocturnal restlessness in demented patients. Non-pharmacological PAS therapy is not only safe and patient-friendly, but it can also be widely used in a simple and relatively inexpensive way, both in institutions such as nursing homes and residential homes for the elderly, and at home. Ultimately, this may lead to a decrease in the frequent and still common use of psychotropic drugs. In addition, care needs of demented patients also may decrease as well as the number of preventable admissions to care institutions. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR3242. PMID- 22495095 TI - Primary care intervention programme to improve early detection of hearing loss in the elderly. AB - OBJECTIVE: To improve audiology screening in general practice, using an intervention programme aiming to empower older adults and their general practitioners. METHODS: We conducted a quasi-experimental community study comparing 206 patients and two control groups (the first being 101 people registered with the same general practitioner, and the second 87 people registered with another general practitioner). Outcome measures were: rates of hearing tests in the six months before interview, and screening recommendation by the general practitioner. RESULTS: Amongst patients, there was a significant increase in numbers undergoing a hearing test, from 19 per cent before the intervention to 49 per cent two years later, while in the two control groups there was little change. Twenty-two per cent of patients and 19 per cent of the first control group reported that their physicians suggested undergoing a hearing test; the second control group subjects (whose general practitioners received no specific educational intervention) showed no change. CONCLUSION: The two crucial factors for improving hearing screening uptake in the elderly are general practitioner education and patient empowerment. PMID- 22495096 TI - Cyclosporin A promotes crosstalk between human cytotrophoblast and decidual stromal cell through up-regulating CXCL12/CXCR4 interaction. AB - BACKGROUND: Our previous studies have demonstrated that cyclosporin A (CsA) can increase the cell number in and invasion by human first-trimester trophoblasts and induce maternal-fetal tolerance. C-X-C chemokine receptor type 4 (CXCR4) and C-X-C chemokine ligand 12 (CXCL12) are important mediators at the maternal-fetal interface during early pregnancy. In this study, we further investigate the molecular mechanisms underlying modulation by CsA of the crosstalk between human cytotrophoblast and decidual stromal cell (DSC). METHODS: Human first-trimester cytotropoblast and DSC were treated with CsA in the absence or presence of U0126 pretreatment, and then the mRNA and protein levels of CXCL12 and CXCR4 were measured by RT-PCR, qPCR, in-cell western blots and enzyme-linked immunosorbent assay (ELISA), respectively. 3-(4,5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide and Matrigel invasion assays were used to determine the invasiveness of cytotrophoblast, respectively. The activity of matrix metalloproteinase (MMP)-9 and MMP-2 was detected by gelatin zymography. A co culture with direct contact between cytotrophoblast and DSC was established and used to investigate the interaction between these two cells. RESULTS: CsA up regulated CXCL12 and CXCR4 expression in human first-trimester cytotrophoblast cells, but not in DSCs. Blocking the mitogen-activated proteinkinase/extracellular signal-regulated kinase (MAPK/ERK1/2) signaling by U0126 abrogated the CsA-induced increase in CXCL12 and CXCR4 expression and neutralizing antibodies to CXCL12 or CXCR4 completely inhibited the CsA-induced increase in cell number, invasion and MMP-9 and MMP-2 activity of cytotrophoblast. CsA also significantly promoted the activity of MMP-9 and MMP-2 in DSCs, but this was unaffected by CXCL12 or CXCR4 neutralizing antibody. Furthermore, the CsA-induced MMP-9 and MMP-2 activity and the invasiveness of cytotrophoblast in the cytotrophoblast and DSC co-culture were significantly increased compared with CsA-treated trophoblast cultured alone, and CXCR4 blocking antibody effectively abolished the increased MMP activity and invasion of cytotrophoblasts in the cytotrophoblast-DSC co-culture stimulated by CsA. CONCLUSIONS: CsA can promote the crosstalk between cytotrophoblast and DSC through up-regulating CXCL12/CXCR4 interaction via MAPK signaling, resulting in the increased numbers of and invasion by human cytotrophoblast cells. PMID- 22495098 TI - Comparing two safety culture surveys: safety attitudes questionnaire and hospital survey on patient safety. AB - OBJECTIVE: To examine the reliability and predictive validity of two patient safety culture surveys-Safety Attitudes Questionnaire (SAQ) and Hospital Survey on Patient Safety Culture (HSOPS)-when administered to the same participants. Also to determine the ability to convert HSOPS scores to SAQ scores. METHOD: Employees working in intensive care units in 12 hospitals within a large hospital system in the southern United States were invited to anonymously complete both safety culture surveys electronically. RESULTS: All safety culture dimensions from both surveys (with the exception of HSOPS's Staffing) had adequate levels of reliability. Three of HSOPS's outcomes-frequency of event reporting, overall perceptions of patient safety, and overall patient safety grade-were significantly correlated with SAQ and HSOPS dimensions of culture at the individual level, with correlations ranging from r=0.41 to 0.65 for the SAQ dimensions and from r=0.22 to 0.72 for the HSOPS dimensions. Neither the SAQ dimensions nor the HSOPS dimensions predicted the fourth HSOPS outcome-number of events reported within the last 12 months. Regression analyses indicated that HSOPS safety culture dimensions were the best predictors of frequency of event reporting and overall perceptions of patient safety while SAQ and HSOPS dimensions both predicted patient safety grade. Unit-level analyses were not conducted because indices did not indicate that aggregation was appropriate. Scores were converted between the surveys, although much variance remained unexplained. CONCLUSIONS: Given that the SAQ and HSOPS had similar reliability and predictive validity, investigators and quality and safety leaders should consider survey length, content, sensitivity to change and the ability to benchmark when selecting a patient safety culture survey. PMID- 22495097 TI - Prognostic value of the biomarkers procalcitonin, interleukin-6 and C-reactive protein in severe sepsis. AB - AIM: To determine the prognostic value of the biomarkers procalcitonin, interlukin-6 and C-reactive protein in septic patients. DESIGN: A cohort of 81 septic patients. SETTING: Critical Care Unit. Dr. Peset Hospital. Valencia (Spain). PATIENTS: Divided according to sepsis classification (sepsis, severe sepsis and septic shock), source and two different groups (medical and postsurgical). VARIABLES ANALYZED: Quantitative (procalcitonin, interleukin-6, C reactive protein, lactate, age, Apache II and SOFA scores upon admission and after 3 and 7 days). Qualitative (ICU mortality, multiorgan failure development and sex). STATISTICAL ANALYSIS: Mann-Whitney U-test for the comparison of quantitative variables, chi2 test for qualitative variables. Multivariate analysis with mortality and multiorgan failure as dependent variables and the described quantitative parameters as independent variables. ROC curves of the variables found to be significant in the multivariate analysis. RESULTS: Septic shock patients showed greater mortality and more frequent multiorgan failure. Comparison of survivors versus deceased patients showed significant differences in Apache II score, interleukin-6 and lactate (p<0.001) upon admission and after 3 and 7 days. Similar findings applied to the comparison of patients with and without multiorgan failure, and on the same days. Procalcitonin only showed differences on days 3 and 7 (p=0.001). In the multivariate analysis with mortality as dependent variable, interleukin-6 proved significant on day 3 (OR 2.6). With multiorgan failure as dependent variable, only the SOFA score showed significance (OR 2.3). The Apache II and interleukin-6 ROC curves corresponding to day 3 showed areas of 0.80 and 0.86, respectively. CONCLUSIONS: 1) Interleukin 6 is an inflammatory biomarker with mortality prognostic value. 2) None of the biomarkers proved predictive of multiorgan failure. PMID- 22495099 TI - How reliable are clinical systems in the UK NHS? A study of seven NHS organisations. AB - BACKGROUND: It is well known that many healthcare systems have poor reliability; however, the size and pervasiveness of this problem and its impact has not been systematically established in the UK. The authors studied four clinical systems: clinical information in surgical outpatient clinics, prescribing for hospital inpatients, equipment in theatres, and insertion of peripheral intravenous lines. The aim was to describe the nature, extent and variation in reliability of these four systems in a sample of UK hospitals, and to explore the reasons for poor reliability. METHODS: Seven UK hospital organisations were involved; each system was studied in three of these. The authors took delivery of the systems' intended outputs to be a proxy for the reliability of the system as a whole. For example, for clinical information, 100% reliability was defined as all patients having an agreed list of clinical information available when needed during their appointment. Systems factors were explored using semi-structured interviews with key informants. Common themes across the systems were identified. RESULTS: Overall reliability was found to be between 81% and 87% for the systems studied, with significant variation between organisations for some systems: clinical information in outpatient clinics ranged from 73% to 96%; prescribing for hospital inpatients 82-88%; equipment availability in theatres 63-88%; and availability of equipment for insertion of peripheral intravenous lines 80-88%. One in five reliability failures were associated with perceived threats to patient safety. Common factors causing poor reliability included lack of feedback, lack of standardisation, and issues such as access to information out of working hours. CONCLUSIONS: Reported reliability was low for the four systems studied, with some common factors behind each. However, this hides significant variation between organisations for some processes, suggesting that some organisations have managed to create more reliable systems. Standardisation of processes would be expected to have significant benefit. PMID- 22495100 TI - Impact of the operative delay and the degree of neurologic sequelae on recurrence of excised heterotopic ossification in patients with traumatic brain injury. AB - The timing of surgery with regard to recurrence risk after neurologic heterotopic ossification (HO) excision is still debated. This study investigated the association between recurrence risk after HO excision in traumatic brain injury (TBI) patients and (1) the operative delay and (2) the degree of neurologic sequelae (Garland status). A case-control study was performed. Patients who developed troublesome HO requiring surgery after TBI with (case, n = 16) or without recurrence (control, n = 64) were retrospectively included. Other matching criteria were sex and age at the time of surgery (+/- 4 years). The median delay for first HO surgery was 13.7 months (interquartile range: 9.0-37.1) for the case group and 13.2 months (interquartile range: 7.8-30.0) for the control group. No significant link was found between recurrence and operative delay (P = .54), even after inclusion of all matching factors (P = .53), or Garland status (P = .81). The inclusion of Garland status into the model did not change this result (P = .64). After TBI, no link was found between HO operative delay and recurrence. In spite of a common notion of a relationship between initial severity of TBI and HO development, no link was found between HO recurrence risk and the severity of sequelae. PMID- 22495101 TI - Factors associated with strain in carers of people with traumatic brain injury. AB - OBJECTIVE: To explore factors associated with strain in carers of patients with traumatic brain injury. DESIGN: Cross-sectional cohort study. PARTICIPANTS: Forty eight carers of patients with traumatic brain injury admitted to a neurosurgical unit over a 9-year period were assessed an average of 9.3 years after injury. MEASURES: Caregiver Strain Index (CSI), Neurobehavioral Functioning Inventory (NFI), Glasgow Outcome Scale (GOS), Virginia Prediction Tree Score, and carer and patient demographics. PROCEDURE: Carers were assessed via postal survey for levels of strain using the CSI and for their perception of the patients' disabilities using the NFI. RESULTS: Elevated levels of strain were found in 42% of carers. Using logistic regression, outcome as rated by the patients' general practitioner on the GOS and all subscales of the NFI (except Somatic) explained 41% to 57% of the variance in strain and predicted group membership correctly in 72.9% of cases. No individual variable contributed significantly to the explained variance in the model. CONCLUSION: A number of factors appear to combine to result in feelings of strain, but the GOS could be used as a crude screening tool. Interventions for cognitive, behavioral, and emotional difficulties may be most useful for carers. PMID- 22495102 TI - Altered integrated locomotor and cognitive function in elite athletes 30 days postconcussion: a preliminary study. AB - OBJECTIVE: To begin to understand changes in locomotor navigation in elite athletes following concussion. METHODS: Clinical measures and gait analysis were undertaken on average 37.33 days (SD = 4.8) postconcussion for 6 athletes as well as for a control group of athletes matched for age, sex, and team. The locomotor task consisted of walking at a self-selected speed along an unobstructed or obstructed path with and without a visual interference task. The trends for 4 dependent variables were described (2 for gait behavior and 2 for cognitive behavior). A principal component analysis was used to reduce data to root sources of variance among these variables. General group differences were tested with Wilcoxon matched-pairs tests on factorial scores. RESULTS: Athletes with concussion were symptom free at the time of testing and their neuropsychological test results were not different from those of athletes in the control group. However, when the laboratory data between paired groups were compared, descriptive analyses suggested potential group differences in navigating the obstacle. The simultaneous Stroop task appeared to present difficulty for both groups. A significant group effect was found on the component of the factorial analysis that was highly loaded with both gait and cognitive variables (minimum clearance, Stroop task errors, and cognitive dual-task costs), generally supporting the descriptive analyses by suggesting that athletes with concussion do not navigate the targeted complex environments like the control group. CONCLUSIONS: Athletes with concussion appear to still show navigational deficits in environments well after being considered fully recovered according to current return-to-play protocols. Although still preliminary and requiring further study, the present findings suggest that functional assessment within complex environment contexts could be considered before sending athletes back to play following a concussion, even in the absence of postconcussion symptoms or with normal clinical outcomes. PMID- 22495103 TI - Alexithymia and avoidance coping following traumatic brain injury. AB - BACKGROUND: Individuals who develop maladaptive coping styles after traumatic brain injury (TBI) usually experience difficulty expressing their emotional state, increasing the risk of psychological distress. Difficulties expressing emotion and identifying feelings are features of alexithymia, which is prevalent following TBI. OBJECTIVE: To examine the relations among coping styles, alexithymia, and psychological distress following TBI. PARTICIPANTS: Seventy-one patients with TBI drawn from a head injury clinic population and 54 demographically matched healthy controls. MAIN MEASURES: Toronto Alexithymia Scale-20, Estonian COPE-D Inventory, Beck Depression Inventory-II, and Beck Anxiety Inventory. RESULTS: The participants with TBI exhibited significantly higher rates of alexithymia and psychological distress and lower levels of task oriented coping than healthy controls. Levels of avoidance coping and psychological distress were significantly higher in a subgroup of TBI patients with alexithymia than in a non-alexithymic TBI subsample. There were significant relations among alexithymia, avoidance coping, and levels of psychological distress. Regression analysis revealed that difficulty identifying feelings was a significant predictor for psychological distress. CONCLUSION: Early screening for alexithymia following TBI might identify those most at risk of developing maladaptive coping mechanisms. This could assist in developing early rehabilitation interventions to reduce vulnerability to later psychological distress. PMID- 22495104 TI - The relations among cognitive impairment, coping style, and emotional adjustment following traumatic brain injury. AB - OBJECTIVE: To examine the direct, mediated, and moderated associations among cognition, coping, and emotional adjustment following traumatic brain injury (TBI). DESIGN: Cross-sectional, single-group design. PARTICIPANTS: Ninety-seven participants with mild to severe TBI recruited from their rehabilitation hospital and assessed on average 19 months postinjury. MEASURES: The BIRT Memory and Information Processing Battery, Doors Test from the Doors and People Test, Hayling Sentence Completion Test, Controlled Oral Word Association Test, Trail Making Test, Digit Span, Symbol Digit Modalities Test-Oral Version, Hospital Anxiety and Depression Scale, and the Coping Scale for Adults. RESULTS: Poorer performance on measures of memory, executive functions, and attention and information processing was associated with greater levels of self-reported depression and anxiety. No mediated relation was found between cognition and emotional adjustment. However, the use of adaptive coping strategies was found to moderate the relation between the Hayling A-a measure of information processing speed-and self-reported depression. CONCLUSIONS: Greater impairments in cognition directly predicted higher levels of anxiety and depression following TBI. In addition, the results suggest that the use of adaptive coping strategies has a greater effect on levels of depression for individuals with poor information processing speed. PMID- 22495105 TI - Assisted reproductive technology and pregnancy-related hypertensive complications: a systematic review. AB - Hypertensive complications in pregnancy are the leading cause of maternal morbidity, at least in the developed countries. In recent years, infertility issues are managed with ever growing therapeutic options namely assisted reproductive technologies (ART), which improve the ratio of successful induction of pregnancy. It is still debated whether various ART modalities are associated with adverse pregnancy outcomes, including hypertensive complications, particularly with higher incidence of preeclampsia. The main source of controversy stems from the diversity of effect modifiers modulating the association between ART-oriented pregnancy and hypertensive disorders. Indeed, women undergoing an ART procedure are affected by diverse causes of infertility, are frequently characterized by different genetic patterns with respect to their artificially conceived embryo and experienced multiple gestations. In order to investigate whether ART modalities are associated with increased incidence of hypertensive complications in pregnancy, we reviewed all published studies carried out before the end of 2010 and identified in the PubMed database. Among the 47 studies finally selected and by acknowledging the potential of shortcomings related to the different study design and populations, the overall evidence suggests that ART-oriented pregnancies-especially the in-vitro fertilization techniques-are accompanied by increased risk for gestational hypertension and preeclampsia as compared with non-ART pregnancies, even after adjustment for confounders. Multiple gestations, advanced age and underlying polycystic ovary syndrome resulted in constant confounders of the questioned association. Reducing multiple gestations by implementing single embryo techniques might be the therapeutic limiting step to lower the rate of hypertensive complications in assisted pregnancies. PMID- 22495106 TI - Inflammatory markers and blood pressure: sex differences and the effect of fat mass in the CoLaus Study. AB - Several studies have reported high levels of inflammatory biomarkers in hypertension, but data coming from the general population are sparse, and sex differences have been little explored. The CoLaus Study is a cross-sectional examination survey in a random sample of 6067 Caucasians aged 35-75 years in Lausanne, Switzerland. Blood pressure (BP) was assessed using a validated oscillometric device. Anthropometric parameters were also measured, including body composition, using electrical bioimpedance. Crude serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and ultrasensitive C-reactive protein (hsCRP) were positively and IL-1beta (IL-1beta) negatively (P<0.001 for all values), associated with BP. For IL-6, IL-1beta and TNF-alpha, the association disappeared in multivariable analysis, largely explained by differences in age and body mass index, in particular fat mass. On the contrary, hsCRP remained independently and positively associated with systolic (beta (95% confidence interval): 1.15 (0.64; 1.65); P<0.001) and diastolic (0.75 (0.42; 1.08); P<0.001) BP. Relationships of hsCRP, IL-6 and TNF-alpha with BP tended to be stronger in women than in men, partly related to the difference in fat mass, yet the interaction between sex and IL-6 persisted after correction for all tested confounders. In the general population, the associations between inflammatory biomarkers and rising levels of BP are mainly driven by age and fat mass. The stronger associations in women suggest that sex differences might exist in the complex interplay between BP and inflammation. PMID- 22495107 TI - Alu insertion profiling: array-based methods to detect Alu insertions in the human genome. AB - The analysis of the genetic variability associated to Alu sequences was hampered by the absence of genome-wide methodologies able to efficiently detect new polymorphisms/mutations among these repetitive elements. Here we describe two Alu insertion profiling (AIP) methods based on the hybridization of Alu-flanking genomic fragments on tiling microarrays. Protocols are designed to preferentially detect active Alu subfamilies. We tested AIP methods by analyzing chromosomes 1 and 6 in two genomic samples. In genomic regions covered by array-features, with a sensitivity of 2% (AIP1) -4% (AIP2) and 5% (AIP1) -8% (AIP2) for the old J and S Alu lineages respectively, we obtained a sensitivity of 67% (AIP1) -90% (AIP2) for the young Ya subfamily. Among the loci showing sample-to-sample differences, 5 (AIP1) -8 (AIP2) were associated to known Alu polymorphisms. Moreover, we were able to confirm by PCR and DNA sequencing 4 new intragenic Alu elements, polymorphic in 10 additional individuals. PMID- 22495108 TI - Obsessive-compulsive disorder and comorbid depression: the role of OCD-related and non-specific factors. AB - Although comorbid depression is a predictor of poor treatment response in obsessive-compulsive disorder (OCD), there is limited understanding of factors that contribute to depression severity in OCD. The current study examines the influence of OCD-related factors (autogenous obsessions and obsessional beliefs) and non-specific factors (avoidance and anxiety) on depression severity in a sample of OCD patients. There were 56 participants with only OCD and 46 with OCD and comorbid depression. Self-report questionnaires measuring depression, OCD related factors, and non-specific factors were completed. Although there were no significant differences between the two groups on these variables, depression severity was positively correlated with anxiety, avoidance, obsessional beliefs, and autogenous obsessions in the whole sample. When entered into a multiple regression model to predict depression severity, these factors accounted for 51% of the variance. While OCD-related factors remained significant predictors after controlling for non-specific factors, the non-specific factors made the most significant contributions to the model. Our findings suggest that in addition to dealing with autogenous obsessions, addressing anxiety and avoidance might lead to improvements in the treatment of OCD with comorbid depression. PMID- 22495109 TI - Association between asthma medications and suicidal ideation in adult asthmatics. AB - BACKGROUND: Asthma has been associated with suicidal ideation (SI), though the mechanisms remain poorly understood. Some asthma medications (e.g., theophylline and beta-2 adrenergic agonists) have been shown to provoke feelings of anxiety, fear, and irritability, but their link to SI among asthmatics has not been examined, which was the purpose of the present study. METHODS: 664 adult asthma outpatient (39% male, M age = 49 +/- 14.3) underwent a sociodemographic, psychiatric, and medical history interview. Patients reported asthma medication use, which was verified by chart review. All patients underwent spirometry and completed questionnaires including the beck depression inventory-II (BDI-II) which includes an item that assesses SI in the past two weeks. RESULTS: 11.5% of patients reported having SI in the past two weeks. After adjusting for age, sex, smoking, asthma severity, and depressive disorders, analyses indicated that theophylline use was associated with an increased likelihood of SI (OR = 2.67, 95% CI = 1.07-6.65). Sensitivity analyses including asthma control levels and benzodiazepine use as additional covariates did not alter this association (respectively: OR = 2.54, 95% CI = 1.04-6.37; OR = 2.71, 95% CI = 1.09-6.78), though adding cohabitation rendered it no longer statistically significant (OR = 2.34, 95% CI = 0.90-6.09). There were no associations between SI and LABA use. CONCLUSIONS: Findings suggest that theophylline but not LABA use may be associated with an increased risk of SI among adult asthmatics independent of depressive disorders, asthma control levels, and asthma severity, but not cohabitation, suggesting that cohabitation may be important for SI in this population. Physicians should be cautious when prescribing theophylline or similar agents to asthmatics, and ensure adequate follow-up. PMID- 22495110 TI - The treatment of pulmonary sarcoidosis. AB - This manuscript offers an approach to the treatment of pulmonary sarcoidosis based on current available information. The treatment of pulmonary sarcoidosis is not mandatory as the disease may be self-limiting and therapy is often associated with significant drug side effects. The decision to treat rests predominantly on the presence of significant symptoms or functional limitation. Corticosteroids are the drug of choice. Alternative agents to corticosteroids may be useful primarily as corticosteroid sparing agents. PMID- 22495111 TI - Detection and treatment of hypercholesterolemia in primary health care. Results of the POLKARD program of the Ministry of Health of the Republic of Poland. AB - INTRODUCTION: About 90% of Polish adults with hypercholesterolemia are not aware of their disease or are not treated. OBJECTIVES: The aim of the study was to evaluate hypercholesterolemia control in general practice and to assess the implications of introducing the nationwide Program of Cardiovascular Disease Prevention (PCVDP). PATIENTS AND METHODS: Sixty-six primary care clinics were scheduled to participate in the study. In half of them, PCVDP was implemented (active clinics), the remaining 33 constituted the control group. Study participants were selected from a group of persons aged 35-55 years with medical records established before January 1, 2005. Patients with coronary heart disease, stroke, or peripheral atherosclerosis were excluded. In a random sample of patients scheduled for the study, medical records were reviewed followed by an interview, physical examination, and blood lipid tests. RESULTS: The availability of data on total cholesterol (TC) levels increased from 19.2% to 40.5% in patients from the active clinics and did not change in the control group. Hypercholesterolemia treatment was reported more often in the active clinics than in the control group (4.4% and 3.3%, respectively, P <0.01). Patients from the active clinics more often reported that a physician informed them about increased TC levels compared with the control group (29.1% and 24.1%, respectively, P <0.01). However, the percentage of patients with increased TC or low-density lipoprotein cholesterol levels and those using statins did not differ between the study groups. CONCLUSIONS: PCVDP is an effective tool to identify subjects with hypercholesterolemia but has no effect on the rate of achieving the recommended treatment targets. PMID- 22495112 TI - Antibody response to Streptococcus pneumoniae proteins PhtD, LytB, PcpA, PhtE and Ply after nasopharyngeal colonization and acute otitis media in children. AB - We prospectively compared serum antibody levels of 5 Streptococcus pneumoniae (Spn) proteins: PcpA PhtD, PhtE Ply and LytB associated with nasopharyngeal (NP) colonization and acute otitis media (AOM) infection in a cohort of 6-30 mo old children. Antigen-specific antibody titers were determined by ELISA. A total of 731 visits among 168 children were studied. There were 301 Spn NP colonization episodes documented in 109 (65%) children and 42 Spn AOM episodes in 34 (20%) children. IgG antibody titers to the 5 proteins were significantly different among children over time (p < 0.001), with a rank order as follows: PcpA > PhtE = PhtD > Ply > LytB Characterization of IgG and IgM acute and convalescent serum antibody levels of Spn AOM infection showed the kinetics of the response differed among children, with the same rank order of antibody levels over time. Individual data showed that some children responded to AOM with an antibody increase to one or more of these Spn proteins but some children failed to respond. We conclude that antibody levels to Spn proteins PcpA PhtD, PhtE, Ply and LytB, all rise over time in children age 6 to 30 mo following natural exposure to Spn after NP colonization and AOM; however, there were significant differences in quantity of antibody elicited among these potential vaccine antigens. PMID- 22495113 TI - The burden of hospitalizations for head and neck neoplasm in Spain (1997-2008): an epidemiologic study. AB - BACKGROUND: Cancers of the head and neck currently figure as the 6th most important cause of cancer globally. They are strongly associated with tobacco and alcohol consumption, but recent studies showed the presence of HPV in patients with these types of cancer. The incidence of cancers of the head and neck potentially attributable to HPV has increased in the last years. This study aims to provide population-based estimates of the burden of hospitalisation for head & neck neoplasm in Spain that may be useful when cost-effectiveness models are developed to evaluate the impact of HPV vaccination in Spain. METHODS: Epidemiological retrospective survey to assess the burden of hospitalisation for head and neck neoplasm in the general population in Spain during the 1997-2008 period. Differences in proportions were assessed by the Chi-square test. ANOVA was used for multiple comparisons. The post hoc Bonferroni correction was used to adjust statistical significance for multiple comparisons. Poisson regression was used to assess differences in the hospitalisation rate during the study period in all the age groups. RESULTS: A total of 199,304 hospital discharges for head and neck malignant neoplasm were recorded during the 12-years of study: 55,475 (46,560 males and 8,915 females) corresponded to oral cavity; 46,699 (45,020 males and 1,679 females) to pharynx and 97,139 (93,374 males and 3,765 females) to larynx malignant neoplasms. Hospitalization rates increased significantly with age. Overall hospitalization rates in men were more than 10-fold higher than in women. Rates decreased significantly in men during the study period but increased significantly in women in all locations. CONCLUSIONS: Although a slight decrease has been observed in hospitalization rates due to head and neck neoplasm in the last years in men, they still generate a substantial morbidity and mortality, especially in adults over 50 years of age. PMID- 22495114 TI - Evaluating the health impact of a public-private partnership: to reduce rotavirus disease in Nicaragua. AB - The purpose of this article is to describe the RotaTeq((r)) Nicaragua Partnership and the evaluation of the public health impact of the vaccine conducted by the partners, including the creation of a rotavirus surveillance program and a vaccine effectiveness assessment. The three main objectives of the partnership were to demonstrate that a new rotavirus vaccine could (1) be introduced rapidly in a developing country, (2) be successfully integrated into the existing vaccine delivery infrastructure, and (3) have a significant and measurable public health impact at the end of the 3-y program. The vaccine impact assessment required collaboration among partners with different areas of expertise, including the Nicaraguan Ministry of Health, Merck, local hospitals, government health clinics, laboratories, and a Technical Advisory Group. Through the partnership, RotaTeq((r)) became available in a GAVI-eligible developing country, Nicaragua, in the same year it was approved in the United States. Vaccine coverage rapidly reached over > 90% of eligible Nicaraguan children. The impact assessment evaluated over 10,000 subjects and leveraged and enhanced the existing diarrheal surveillance infrastructure, ultimately providing the scientific community with some of the first real-world rotavirus vaccine effectiveness data from a developing country. The successful public-private partnership (PPP) was internationally recognized as a model for the rapid adoption of a new vaccine in a developing world setting. The model could be adapted to benefit other PPPs interested in demonstrating the impact of their own programs. PMID- 22495115 TI - Advances in vaccines against neglected tropical diseases: enhancing physical stability of a recombinant hookworm vaccine through biophysical and formulation studies. AB - A bivalent recombinant vaccine for human hookworm disease is under development. One of the lead candidate antigens in the vaccine is a glutathione S-transferase cloned from the hookworm Necator americanus (Na-GST-1) which is expressed in the yeast Pichia pastoris. Based on preliminary studies demonstrating that the recombinant protein was not stable in an acetate buffer at pH 6, we undertook an extensive stability analysis of the molecule. To improve and optimize stability we complemented traditional methods employed for macromolecule and vaccine stabilization with biophysical techniques that were incorporated into a systematic process based on an eigenvector approach. Large data sets, obtained from a variety of experimental methods were used to establish a color map ("empirical phase diagram") of the physical stability of the vaccine antigen over a wide range of temperature and pH. The resulting map defined "apparent phase boundaries" that were used to develop high throughput screening assays. These assays were then employed to identify excipients that stabilized the antigen against physical degradation that could otherwise result in losses of physicochemical integrity, immunogenicity, and potency of the vaccine. Based on these evaluations, the recombinant Na-GST-1 antigen was reformulated and ultimately produced under Good Manufacturing Practices and with an acceptable stability profile. PMID- 22495116 TI - Filterable forms and L-forms of Mycobacterium bovis BCG: impact for live vaccine features. AB - Bacterial L-form conversion, or existence without cell walls, is assumed a universal phenomenon in nature. An interesting aspect of this phenomenon is occurrence of L-forms in vaccine strains. Since BCG is currently a widely used and extensively studied live vaccine for tuberculosis, understanding L-form conversion of M. bovis BCG bacilli can provide new insight into behavior of BCG vaccine. In this respect, specific features, concerning the ability of BCG vaccine to produce viable filterable forms and L-forms, were studied by filtration and starvation stress experiments in vitro. The filterable forms obtained after filtration of BCG suspension, grew on Middlebrook 7H9 semisolid agar and formed typical "fried eggs" L-form colonies. Electron microscopy clearly demonstrated presence of L-form elements with size smaller than the size of bacterial filter pores of 0.2 um in M. bovis BCG strains. Development of L-form subpopulation with typical morphological appearance of self-replicating cell wall defective forms was observed after filtration, as well as after starvation stress. Specific DNA detection of pncA gene in derived L-form cultures from filterable and stressed BCG strains verified their identity as M. bovis BCG. In conclusion, the results confirm existence of filterable forms in commercial BCG vaccine, which are able to develop L-form population under appropriate conditions. L-form transformation of BCG bacilli displays a new intriguing aspect concerning exhibition of unusual features and atypical behavior of live BCG vaccine. Further research is requested to explore the influence of L-form phenomenon on BCG vaccine effects in vivo. PMID- 22495117 TI - Safety and persistence of immunological response 6 months after intramuscular vaccination with an AS03-adjuvanted H1N1 2009 influenza vaccine: an open-label, randomized trial in Japanese children aged 6 months to 17 years. AB - This study evaluated the long-term persistence of immune response and safety of two doses of an A/California/7/2009 H1N1 pandemic influenza vaccine adjuvanted with AS03 (an alpha-tocopherol oil-in-water emulsion-based Adjuvant System) in Japanese children (NCT01001169). Sixty healthy subjects aged 6 mo-17 y were enrolled (1:1) into two study groups to receive 21 d apart, two doses of 1.9 ug haemagglutinin [HA]+AS03B (5.93 mg alpha-tocopherol) vaccine (6 mo-9 y) and 3.75 ug HA+AS03A (11.86 mg alpha-tocopherol) vaccine (10-17 y), respectively. Immunogenicity data (by haemagglutination inhibition [HI] and microneutralisation assays) to six months after the first vaccine dose are reported here. It was observed that following Dose 2, the HI immune response against the vaccine homologous strain induced by the two different dosages of the AS03-adjuvanted vaccine met and exceeded the US and European regulatory guidance criteria for pandemic influenza vaccines (seroprotection rate[SPR]/seroconversion rate[SCR]: 100%/100%; geometric mean fold rise GMFR: 146.8/57.1). Further, the immune response persisted for at least six months after the first vaccine dose wherein these regulatory criteria were still met (SPR: 100%/100%; SCR: 96.4%/89.7%; GMFR: 25.3/23.5). The neutralising antibody response was comparable to the HI immune response at Day 42 (vaccine response rate [VRR]: 100%/100%) and at Day 182 (VRR: 96.4%/82.8%). Overall, both vaccine dosages had a clinically acceptable safety profile. Thus, two doses of a 1.9 ug or 3.75 ug HA AS03-adjuvanted H1N1 2009 pandemic influenza vaccine in children aged 6 mo-17 y induced strong immune responses against the vaccine homologous strain that persisted for at least six months after the first vaccine dose. PMID- 22495118 TI - Insulin-specific vaccination for type 1 diabetes: a step closer? AB - Vaccination against self-antigens to avert pathological immunity to self- 'negative vaccination'--is the Holy Grail of autoimmune disease therapy. This approach depends on deletion or inactivation of pathogenic T cells, or induction of protective, 'regulatory' T cells. While effective in inbred rodent models, it is yet to be translated to humans. Reasons for this include its application only in end-stage disease, ignorance about antigen form, route of delivery and dose schedule required for a bio-response, lack of meaningful and measurable bio response markers, co-activation of pathogenic immunity and genetic heterogeneity. PMID- 22495119 TI - Development of a group A meningococcal conjugate vaccine, MenAfriVac(TM). AB - Group A meningococcal disease has been an important public health problem in sub Saharan Africa for over a century. Outbreaks occur there annually, and large epidemics occur at intervals ranging between 8 and 12 y. The Meningitis Vaccine Project was established in 2001 with funding from the Gates Foundation with the goal of developing, testing, licensing, and introducing an affordable group A meningococcal conjugate vaccine into Africa. From 2003 to 2009 a monovalent group A conjugate vaccine, MenAfriVac(TM) , was developed at the Serum Institute of India, Ltd through an innovative public/private partnership. Preclinical studies of the new conjugate vaccine were completed in 2004 and a Phase 1 study began in India in 2005. Phase 2/3 studies in African 1-29 y olds were completed in 2009 showing the new meningococcal A conjugate vaccine to be as safe as currently licensed meningococcal polysaccharide vaccines, but much more immunogenic. After Indian market authorization (December 2009) and WHO prequalification (June 2010), MenAfriVac(TM) was introduced at public health scale using a single 10 ug dose in individuals 1-29 y of age in Burkina Faso, Mali, and Niger in December 2010. We summarize the laboratory and clinical studies leading to prequalification of MenAfriVac(TM). The 2011 epidemic season ended with no reported case of group A meningitis in vaccinated individuals. PMID- 22495120 TI - Rubella vaccine: new horizon in prevention of congenital rubella syndrome in the India. AB - Rubella is a contagious viral disease, which mainly affects the fetus, if the mother is infected in the 1st trimester of her pregnancy. All adolescent girls (aged 11 to 19 y) and women of childbearing age are at risk of developing rubella. This disease is mild and self-limiting, and incubation period is 2-3 weeks. Humans are the only hosts for rubella. Rubella infection during pregnancy may lead to abortions, stillbirth or congenital deformities (birth defects). Moreover it is surprising to know that over 200,000 babies are born with birth defects because of Rubella infection during pregnancy in the Indian sub continent. The risk of fetal infection is highest in first trimester; the infection rate declines between 12-28 weeks, suggesting that the placenta may prevent transfer of virus but not completely. The incidence of defects is inversely related to the time of maternal infection. Rubella outbreaks have been reported from many countries in South East Asian region with congenital rubella syndrome (CRS) due to maternal rubella being on the increase in many countries. In India, although the endemicity of rubella is established, the majority of cases remain undiagnosed, being subclinical or clinically mild. Consequently, in spite of evidence of CRS in all States of India, no distinct policy has been envisaged for assessing the burden of rubella, and no control measures against this silent crippling disease are in place. The European Regional Committee of the World Health Organization has adopted the goals of "Elimination of CRS" in the Health for All programs. There is no treatment for rubella. Vaccination is the only way to prevent all these complications. PMID- 22495121 TI - The mucosal vaccine quandary: intranasal vs. sublingual immunization against influenza. AB - Intranasal vaccination can effectively induce both local and systemic immune responses and protect against influenza, but poses a risk of antigen or adjuvant delivery into the central nervous system (CNS). Sublingual vaccine delivery has recently received increased attention as a safer alternative to the intranasal route. Studies comparing the two routes have found that higher immune responses may be induced by intranasal than sublingual administration, possibly as a consequence of the differences in mucosal tissues between the two routes. Here we examine evidence of antigen transport into the CNS following intranasal immunisation and discuss possible reasons for the superiority of the intranasal as compared with the sublingual route in terms of vaccine immunogenicity. We encourage generation of more information on the safety of mucosal adjuvants and propose that the next generation of vaccines and adjuvants may be designed specifically for administration via the different mucosal routes. PMID- 22495122 TI - Dynamics of the antibodies in cohorts of cured cases of visceral leishmaniasis: its implication on the validity of serological test, value in prognosis and in post therapeutic assessment. AB - The major disadvantage of a Serological test like Direct Agglutination Test (DAT) for Visceral Leishmaniasis (also called Kala-azar) is its inability to distinguish between recent and past infection. The objective of our study was to look at rate of decline of antibodies in fully cured cases of Kala-azar and length of time it takes for DAT to become negative. Cohort Study involving completely treated Kala-azar cases from Government Hospital during one calendar year of study. Cases were selected on the basis of treatment cohorts 0, 3, 6, 9 & 12 mo after completion of treatment.. Phase I--The cases were traced and after obtaining the informed consent they were subjected to Direct Agglutination Test (DAT). Phase II--The five treatment cohorts, constituting 82 cured cases (average of 15 cured cases per each treatment cohort) were tested again with DAT three months after the first test. The titers of Phase-I and phase-II tests were analyzed for the dynamics of the antibodies for the period. Cutoff-Values of DAT below 1:800 are considered negative. Values of 1:800, 1:1200, 1:1600 and so on are considered positive. The mean titer [Geometric Mean Titer (GMT)] at the start of treatment was 1:1120, which showed steady decline up to six months, plummeting below the cutoff titer for the DAT (1:800) at the ninth month. Antibodies continue to linger for about one year in cured Kala-azar cases even after correct and complete treatment. Single DAT results may be misleading due to high false positivity up to one year after the cure. Paired test defined as two tests 3 mo apart on the same subject. Paired test is highly recommended for diagnosis and prognosis. DAT is still a very useful tool for diagnosis if used along with clinical correlation. PMID- 22495123 TI - Microscopic and nuclear morphometric findings of chromophobe renal cell carcinoma, renal oncocytoma, and tumor with overlapping histology. AB - We compared the microscopic and nuclear morphometric characteristics of classical chromophobe renal cell carcinoma (C-ChRC) and renal oncocytoma (RO) and applied meaningful characteristics to differentiate eosinophilic chromophobe renal cell carcinoma (E-ChRC) from RO that has overlapping histology (RO-OH) with E-ChRC to know the usefulness of nuclear morphometry. Microscopic and morphometric characteristics were evaluated in 24 C-ChRCs, 6 E-ChRCs, 5 RO-OHs, and 25 classical ROs (C-ROs). The microscopic findings favoring C-ChRC were rasinoid nuclei, perinuclear halo, and distinct cytoplasmic membrane. Characteristic for C RO was either stromal edema or hyalinization. The morphometric values of nearest nuclear distance, shortest nuclear diameter, and nuclear diameter ratio were significantly different between C-ChRC and C-RO. However, it was impossible to distinguish E-ChRC from RO-OH by histology and nuclear morphometry. The results of our study show that nuclear morphometry and histomorphology can distinguish between C-ChRC and C-RO but not between E-ChRC and RO-OH. PMID- 22495124 TI - [Microalbuminuria and renal insufficiency in chronic hepatitis C virus infection]. AB - INTRODUCTION: Chronic hepatitis C virus (HCV) infection is associated with glomerular disease, which is manifested by proteinuria with or without renal dysfunction. METHOD: To determine the prevalence of HCV-associated renal injury and associated risk factors, we performed an observational, analytic, cross sectional study of 120 HCV-positive patients and 145 HCV-negative controls. Data were gathered from medical records and history-taking and at least three blood and urine analyses were performed over a 1-year period. Renal insufficiency was defined as an estimated glomerular filtration rate of less than 60ml/min/1.73 m2 and/or microalbuminuria of more than 20mg/l or a microalbumin/creatinine ratio higher than 30 mcg/mg. RESULTS: The prevalence of microalbuminuria and renal insufficiency was 19.3% and 11.7% in HCV-positive patients versus 10.5% and 0.7% in HCV-negative controls (p 0.04), respectively. A total of 26.1% of HCV-positive patients had signs of renal injury compared with 11.8% of HCV-negative controls (p 0.003). HCV infection was independently and significantly associated with the probability of worsening of renal function. The prevalence of microalbuminuria and renal insufficiency progressively increased with greater age. CONCLUSION: HCV positive patients show a high prevalence of microalbuminuria and renal insufficiency compared with HCV-negative individuals. The risk of HCV-associated renal insufficiency is independent of the presence of other predisposing factors such hypertension and diabetes. PMID- 22495125 TI - Salivary duct carcinoma: what is already known, and can we improve survival? AB - Salivary duct carcinoma is an aggressive malignancy with a high mortality rate, which phenotypically resembles high-grade breast ductal carcinoma. The parotid gland is the most common location. Standard treatment is surgery to the primary tumour together with post-operative radiotherapy. Despite this, there is a high rate of local recurrence, cervical nodal involvement and distant metastasis. Chemotherapy is currently considered only for end-stage, disseminated disease; however, current evidence indicates that chemotherapy used with radiotherapy may result in improved disease control and survival.Human epidermal growth factor receptor-2 is a proto-oncogene which is over-expressed in both breast ductal carcinoma and salivary duct carcinoma. Clinical studies of patients with metastatic breast cancer, using trastuzumab, a monoclonal antibody directed against human epidermal growth factor receptor-2, have shown significant efficacy in tumour response, resulting in improved survival. Such advances in immunohistochemistry, and in targeted immunotherapy for breast ductal carcinoma, should be applied to the treatment of salivary duct carcinoma. PMID- 22495126 TI - Device-guided breathing exercises in the control of human blood pressure: systematic review and meta-analysis. AB - OBJECTIVE: To evaluate whether device-guided breathing (DGB) lowers blood pressure (BP) in adults. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched Medline (1950-2010), Embase (1980-2010), the Cochrane Library including the Cochrane Central register of Controlled Trials (CENTRAL), AMED (1985-2010), CINAHL (1980-2010) and the Current Controlled Trials registry (as of October 2010). OUTCOME MEASURES: Primary outcomes included the mean change in SBP and DBP. Secondary outcomes included change in heart rate, quality of life, compliance with the device and any side effects of the device. RESULTS: We included eight trials of the Resperate device (InterCure Ltd, Lod, Israel), consisting of 494 adult patients. Use of this device resulted in significantly reduced SBP by 3.67 mmHg [95% confidence interval (CI) = -5.99 to -1.39; P = 0.002] and decreased DBP by 2.51 mmHg (95% CI = -4.15 to -0.87; P = 0.003). However, sensitivity analysis was carried out excluding the five trials sponsored by or involving the manufacturers of the device, which revealed no overall effect on BP using the device. The maximum trial duration was 9 weeks and no overall effect was seen on heart rate or quality of life using the device. CONCLUSION: There is evidence that short-term use of DGB may reduce both DBP and DBP. However, five of the eight trials were sponsored by or involved the manufactures of the device. When these trials were excluded we found no overall effect. We conclude that longer term, independent trials are required to validate this intervention. PMID- 22495127 TI - Genomic epidemiology of blood pressure salt sensitivity. AB - High blood pressure (BP) is a complex trait determined by genetic and environmental factors, as well as their interactions. Over the past few decades, there has been substantial progress elucidating the genetic determinants underlying BP response to sodium intake, or BP salt sensitivity. Research of monogenic BP disorders has highlighted the importance of renal salt handling in BP regulation, implicating genes and biological pathways subsequently identified in candidate gene studies of salt sensitivity. Despite these advancements, certain candidate gene findings await replication evidence, and some biological pathways warrant further investigation. Furthermore, results from genome-wide association studies (GWASs) and sequencing work have yet to be reported. GWAS will be valuable for uncovering novel mechanisms underlying salt sensitivity, whereas future sequencing efforts promise the discovery of functional variants related to this complex trait. Delineating the genetic architecture of salt sensitivity will be critical to understanding how genes and dietary sodium interact to influence BP. PMID- 22495128 TI - Should ambulatory blood pressure monitoring be mandatory for future studies in resistant hypertension: a perspective. AB - Recent technologic advances rekindled interventional management of resistant hypertension, either by carotid baroreceptor activation or renal sympathetic denervation. Interventional techniques result in impressive falls in office blood pressure (BP); however, ambulatory BP reductions are rather modest. This disparity between office and ambulatory BP reductions is observed with antihypertensive drugs, but at a much lower degree. Available explanations are not convincing, therefore, we propose that sympathetic overactivity may partially explain this divergence. Further studies are needed to prove or disprove our hypothesis. PMID- 22495129 TI - Genetics, genomics and other molecular approaches: example of salt-sensitive hypertension. PMID- 22495130 TI - Resistant hypertension and obstructive sleep apnea in end-stage renal disease. PMID- 22495131 TI - Hypertensive crisis: forget the numbers. PMID- 22495132 TI - Electrocardiographic diagnosis of left-ventricular hypertrophy: good news for the clinician? PMID- 22495133 TI - Prediction and prevention of atrial fibrillation in patients with high blood pressure or history of hypertension. PMID- 22495134 TI - B-type natriuretic peptide-guided hypertension management? PMID- 22495135 TI - Factors associated with carotid intima-media thickness and carotid plaques in type 2 diabetic patients. AB - OBJECTIVE: Factors associated with carotid atherosclerosis are unclear in type 2 diabetic patients. The aim was to investigate the independent correlates of carotid intima-media thickness (IMT) and plaques in these individuals. METHODS: In a cross-sectional study, we measured carotid IMT at three sites (common carotid, bifurcation and internal carotid artery) and the severity of extracranial carotid artery (ECCA) atherosclerosis by plaque score in 441 type 2 diabetic patients. Nontraditional cardiovascular risk factors [ambulatory blood pressures (BPs), aortic stiffness, C-reactive protein and ankle-brachial index) were obtained. Multivariate linear and logistic regressions assessed the independent correlates of carotid IMT and ECCA plaque score. RESULTS: Patients with greater carotid IMT or plaque scores had worse clinical and laboratory profile than those with lower IMT and plaque scores, including higher BPs, aortic stiffness and prevalences of diabetic complications. On multivariate analysis, carotid IMT and plaques were mainly associated with older age, male sex, current past smoking and ambulatory BPs, but not with clinic BPs. Night-time pulse pressure was the most important modifiable determinant of increased carotid IMT. No microvascular complication was independently associated with carotid atherosclerosis, except retinopathy for plaque score. Additionally, internal carotid IMT and plaque score were associated with ankle-brachial index in the subgroup of patients without macrovascular diseases. CONCLUSION: In type 2 diabetic patients, older age, male sex, smoking status and ambulatory BPs, particularly night-time pulse pressure, were the main independent correlates of ultrasonographic carotid atherosclerosis. This finding reinforces the importance of ambulatory BP monitoring in type 2 diabetes management. PMID- 22495136 TI - Lack of impact of pulse pressure on outcomes in patients with malignant phase hypertension: the West Birmingham Malignant Hypertension study. AB - OBJECTIVE: To investigate the impact of pulse pressure at presentation on the primary outcome (death or dialysis) in patients with malignant phase hypertension (MPH). METHODS: Three hundred and sixty-five patients [overall mean (SD) age 48 (13) years; 66% male; 63% white European; 23% African-Caribbean, 14% south Asian] from the West Birmingham MPH study were included. Baseline pulse pressure was divided into quartiles. Two hundred and forty-two primary outcomes (death or dialysis) occurred during a median (interquartile range) follow-up of 7 (1.5 14.8) years. RESULTS: Significantly higher pulse pressure was evident among older patients and white Europeans. Baseline BMI (P = 0.49), retinopathy (P = 0.56), proteinuria (P = 0.61), haematuria (P = 0.56) and left ventricular hypertrophy (P = 0.43) were not related to pulse pressure. Multivariate analyses found that baseline age [hazard ratio (95% confidence intervals] [1.05 (1.04-1.06); P < 0.0001], smoking [1.60 (1.16-2.21); P = 0.004], proteinuria [1.33 (1.10-1.61); P = 0.003] and creatinine level [1.002 (1.001-1.002); P < 0.0001] were independent predictors of the primary outcome of 'death or dialysis'. A multivariate analysis also revealed that independent predictors of future dialysis alone were as follows: baseline age [0.92 (0.89-0.95); P < 0.001) and haematuria [2.74 (1.17 6.42); P = 0.02), with a trend seen for baseline creatinine levels [1.001 (1.000 1.002); P = 0.052)]. Pulse pressure at baseline did not predict death or dialysis. CONCLUSION: Age, smoking status and severity of renal failure at presentation with MPH (represented by proteinuria and creatinine levels) are independent predictors of the risk of death or dialysis. Pulse pressure at presentation does not predict death or dialysis in patients with MPH. Careful monitoring of renal functioning and effective management of blood pressure is mandatory in patients with MPH to prevent/slow future complications. PMID- 22495137 TI - Normal values of left-ventricular mass: echocardiographic findings from the PAMELA study. AB - BACKGROUND AND AIM: Upper reference values of echocardiographic left-ventricular mass in the European population are based on scanty data mostly derived from northern European population-based samples. Furthermore, data in apparently healthy populations have included individuals with conditions affecting left ventricular mass such as obesity, diabetes and masked hypertension. Thus, from 1051 individuals with normal office blood pressure (BP) belonging to the PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni) study population, we selected a group of 675 sustained normotensive individuals in order to provide reliable echocardiographic reference values for defining the criteria of left ventricular hypertrophy (LVH). METHODS: The study group (women 58%, mean age 42 +/- 11 years) was identified after excluding individuals with isolated home or ambulatory hypertension, obesity, diabetes, cardiovascular diseases and echocardiographic examinations of insufficient quality to evaluate left ventricular mass. RESULTS: Sex-specific upper limits of normality [mean + 1.96 standard deviation (SD)] for left-ventricular mass, left-ventricular mass indexed to body surface area, heightand height were the following: 213 g, 114 g/m, 51 g/h, 123 g/h in men and 161 g, 99 g/m, 47 g/h, 101 g/h in women. In multivariate analyses, body size measures and ambulatory BP levels were the most important correlates of left-ventricular mass. CONCLUSIONS: Our investigation by providing upper reference limits of left-ventricular mass in a southern European population sample, carefully selected after exclusion of a large number of conditions affecting left-ventricular mass, may offer a contribution for revising diagnostic criteria of echocardiographic LVH currently recommended by European hypertension guidelines. PMID- 22495138 TI - Blood pressure and other determinants of new-onset atrial fibrillation in patients at high cardiovascular risk in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease studies. AB - BACKGROUND: Evidence on new-onset atrial fibrillation in high-risk vascular patients without heart failure is limited. New-onset atrial fibrillation was a prespecified secondary objective of the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) studies. METHODS: We studied 30 424 ONTARGET/TRANSCEND patients (mean age +/- SD, 66.4 +/- 7.0) with vascular disease or complicated diabetes who were in sinus rhythm at entry. A copy of ECG was sent to central office every time new atrial fibrillation was detected by investigators. RESULTS: During a median follow-up period of 4.7 years, new atrial fibrillation occurred in 2092 patients (15.1 per 1000 patient-years). Risk of atrial fibrillation increased with age, SBP and pulse pressure, left ventricular hypertrophy, BMI, serum creatinine and history of hypertension, coronary artery disease and cerebrovascular disease (all P < 0.01). After adjustment for BMI and other variables, atrial fibrillation risk increased with hip circumference. History of hypertension was associated with a 34% higher risk of new atrial fibrillation. New atrial fibrillation portended an increased risk of congestive heart failure [hazard ratio 2.89, 95% confidence interval (CI) 2.45-3.40, P < 0.01] and cardiovascular death (hazard ratio 1.22, 95% CI 1.05-1.41, P < 0.01). Risk of stroke was unaffected (hazard ratio 1.14, 95% CI 0.93-1.40), whereas that of myocardial infarction was reduced (hazard ratio 0.64, 95% CI 0.50-0.82). Patients with new atrial fibrillation were more likely to receive vitamin K antagonists (P < 0.01), statins (P < 0.05) and beta blockers (P < 0.01) than those in sinus rhythm. CONCLUSION: New atrial fibrillation is common in high-risk vascular patients and is associated with several risk factors including history of hypertension. Hip circumference was the strongest anthropometric predictor. Despite extensive use of modern therapies, new atrial fibrillation carries a high risk of congestive heart failure and death over a relatively short term. PMID- 22495139 TI - An unusual case of systolic hypertension associated with ticlopidine treatment. PMID- 22495140 TI - Why adjustment for current weight can bias the estimate of the effect of birth weight on blood pressure: shedding light using causal graphs. PMID- 22495141 TI - Clarifying the role of preoperative alpha-blockade in pheochromocytoma? PMID- 22495144 TI - Comparison of the acute inflammatory response of two commercial platelet-rich plasma systems in healthy rabbit tendons. AB - BACKGROUND: Numerous studies have shown platelet-rich plasma (PRP) preparations differ with respect to the inclusion of certain blood components, which may affect the host's cellular response. HYPOTHESIS: This study evaluated the inflammatory effect of Biomet GPS III leukocyte-rich PRP (LR-PRP) versus MTF Cascade leukocyte-poor PRP (LP-PRP) after intratendinous injection in an animal model. The authors anticipated that LR-PRP would incite a greater acute inflammatory response than LP-PRP. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 17 skeletally mature New Zealand White rabbits were tested. In all cases, healthy patellar tendons were treated. In the control animals, one patellar tendon was injected with 2 mL autologous whole blood, and the other was injected with 2 mL sterile saline. Seven total tendons were injected with whole blood, and 7 tendons were injected with saline. In the experimental animals, one patellar tendon was injected with 2 mL LR-PRP, and the other was injected with 2 mL LP-PRP. Ten tendons were injected with LR-PRP, and 10 tendons were injected with LP-PRP. Animals were euthanized at 5 or 14 days after injection. Tendons were harvested and stained using hematoxylin and eosin and scored semi quantitatively for total white blood cells (WBCs), mononuclear cells (macrophages and lymphocytes), polymorphonuclear cells (PMNs), vascularity, fiber structure, and fibrosis. RESULTS: At 5 days after injection, tendons treated with LR-PRP had significantly greater overall tendon scores (6.3 +/- 1.79 vs 1.8 +/- 1.64, P = .012), as well as mean scores for fiber structure (1.4 +/- 0.22 vs 0.50 +/- 0.50, P = .012), denoting disrupted composition, total WBCs (1.1 +/- 0.89 vs 0.10 +/- 0.22, P = .014), mononuclear cells (macrophages and lymphocytes) (0.80 +/- 0.45 vs 0.10 +/- 0.22, P = .014), vascularity (1.7 +/- 0.27 vs 0.80 +/- 0.16, P = .008), and fibrosis (1.0 +/- 0.35 vs 0.3 +/- 0.45, P = .037) compared with tendons treated with LP-PRP. Otherwise, there were no significant differences in mononuclear cells (P = .590), PMN cells (P = 1.00), total WBCs (P = .811), vascularity (P = .650), or total tendon score (P = .596) in any of the treatment groups at 14 days. CONCLUSION: Compared with leukocyte-poor Cascade PRP, leukocyte-rich GPS III PRP causes a significantly greater acute inflammatory response at 5 days after injection. There is no significant difference in the inflammatory response or cellularity regardless of the injection type at 14 days after intratendinous injection. CLINICAL RELEVANCE: Platelet-rich plasma injections are frequently prepared using commercial systems and are administered for clinical treatment of chronic tendinopathy. It is important to characterize the cellular responses elucidated by different injection preparations to further understand their effect on tissue healing and aid clinical decision making. Future investigations are necessary to apply these findings to the clinical setting. PMID- 22495145 TI - Complications of arthroscopic meniscectomy in the older population. AB - BACKGROUND: Complications of arthroscopic meniscectomy in the older population have not been established. PURPOSE: To determine the risk and relative risk of developing pyogenic arthritis (PA), a deep vein thrombosis (DVT), and pulmonary embolism (PE) in an older population of patients who have undergone arthroscopic meniscectomy. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Men and women >=65 years old who underwent procedures coded as CPT-29880 (medial and lateral meniscectomy) and CPT-29881 (medial or lateral meniscectomy) were identified in the Medicare Standard Analytic Files database from 2005 to 2008. Identified patients were analyzed for gender and postoperative complications, including PA, DVT, and PE, occurring within 90 days of the index operation. RESULTS: Overall, 314,578 patients (119,814 men and 194,764 women) were identified. With respect to the Current Procedural Terminology codes, 131,420 patients were coded 29880 and 183,158 patients were coded 29881. In the study population, 0.4% (1107 patients) developed PA, 0.8% (2507 patients) developed a DVT, and 0.3% (982 patients) developed a PE. Among male patients, 0.4% developed PA, 0.7% developed a DVT, and 0.2% developed a PE. Among female patients, 0.3% developed PA, 0.8% developed a DVT, and 0.3% developed a PE. Overall, men had a statistically significant higher relative risk of PA and women had a statistically significant higher relative risk of DVT and PE. CONCLUSION: Postoperative complications, including PA, DVTs, and PEs, are rare in patients >=65 years old. However, gender-specific differences in the rate and type of postoperative complications may exist. Further studies in this population are warranted. PMID- 22495143 TI - Pharmacologic magnetic resonance imaging (phMRI): imaging drug action in the brain. AB - The technique of functional magnetic resonance (fMRI), using various cognitive, motor and sensory stimuli has led to a revolution in the ability to map brain function. Drugs can also be used as stimuli to elicit an hemodynamic change. Stimulation with a pharmaceutical has a number of very different consequences compared to user controllable stimuli, most importantly in the time course of stimulus and response that is not, in general, controllable by the experimenter. Therefore, this type of experiment has been termed pharmacologic MRI (phMRI). The use of a drug stimulus leads to a number of interesting possibilities compared to conventional fMRI. Using receptor specific ligands one can characterize brain circuitry specific to neurotransmitter systems. The possibility exists to measure parameters reflecting neurotransmitter release and binding associated with the pharmacokinetics and/or the pharmacodynamics of drugs. There is also the ability to measure up- and down-regulation of receptors in specific disease states. phMRI can be characterized as a molecular imaging technique using the natural hemodynamic transduction related to neuro-receptor stimulus. This provides a coupling mechanism with very high sensitivity that can rival positron emission tomography (PET) in some circumstances. The large numbers of molecules available, that do not require a radio-label, means that phMRI becomes a very useful tool for performing drug discovery. Data and arguments will be presented to show that phMRI can provide information on neuro-receptor signaling and function that complements the static picture generated by PET studies of receptor numbers and occupancies. PMID- 22495146 TI - The effect of platelet-rich fibrin matrix on rotator cuff tendon healing: a prospective, randomized clinical study. AB - BACKGROUND: There is a strong need for methods to improve the biological potential of rotator cuff tendon healing. Platelet-rich fibrin matrix (PRFM) allows delivery of autologous cytokines to healing tissue, and limited evidence suggests a positive effect of platelet-rich plasma on tendon biology. PURPOSE: To evaluate the effect of platelet-rich fibrin matrix on rotator cuff tendon healing. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: Seventy-nine patients undergoing arthroscopic rotator cuff tendon repair were randomized intraoperatively to either receive PRFM at the tendon-bone interface (n = 40) or standard repair with no PRFM (n = 39). Standardized repair techniques were used for all patients. The postoperative rehabilitation protocol was the same in both groups. The primary outcome was tendon healing evaluated by ultrasound (intact vs defect at repair site) at 6 and 12 weeks. Power Doppler ultrasound was also used to evaluate vascularity in the peribursal, peritendinous, and musculotendinous and insertion site areas of the tendon and bone anchor site. Secondary outcomes included standardized shoulder outcome scales (American Shoulder and Elbow Surgeons [ASES] and L'Insalata) and strength measurements using a handheld dynamometer. Patients and the evaluator were blinded to treatment group. All patients were evaluated at minimum 1-year follow up. A logistic regression model was used to predict outcome (healed vs defect) based on tear severity, repair type, treatment type (PRFM or control), and platelet count. RESULTS: Overall, there were no differences in tendon-to-bone healing between the PRFM and control groups. Complete tendon-to-bone healing (intact repair) was found in 24 of 36 (67%) in the PRFM group and 25 of 31 (81%) in the control group (P = .20). There were no significant differences in healing by ultrasound between 6 and 12 weeks. There were gradual increases in ASES and L'Insalata scores over time in both groups, but there were no differences in scores between the groups. We also found no difference in vascularity in the peribursal, peritendinous, and musculotendinous areas of the tendon between groups. There were no differences in strength between groups. Platelet count had no effect on healing. Logistic regression analysis demonstrated that PRFM was a significant predictor (P = .037) for a tendon defect at 12 weeks, with an odds ratio of 5.8. CONCLUSION: Platelet-rich fibrin matrix applied to the tendon-bone interface at the time of rotator cuff repair had no demonstrable effect on tendon healing, tendon vascularity, manual muscle strength, or clinical rating scales. In fact, the regression analysis suggests that PRFM may have a negative effect on healing. Further study is required to evaluate the role of PRFM in rotator cuff repair. PMID- 22495160 TI - Expression patterns of Ca(V)1.3 channels in the rat cochlea. AB - Although Ca(V)1.3 channels are known to be essential for neuronal excitation and signal transduction in the auditory system, their expression patterns in the cochlea are still not fully understood, particularly in the regions where non sensory cells are located. We performed immunohistochemistry, western blotting and reverse transcription-polymerase chain reaction (RT-PCR) to identify the expression and distribution of Ca(V)1.3 channels in the rat cochlea. Immunohistochemistry revealed that Ca(V)1.3 channels were localized in the outer hair cells (OHCs), inner hair cells (IHCs), limbus laminae spiralis, spiral ganglion cell, spiral ligament (SL), and stria vascularis (STV). The results of RT-PCR and western blotting demonstrated Ca(V)1.3 channels had a tissue-specific expression pattern. Ca(V)1.3 mRNA and protein were intensively expressed in the basilar membrane and spiral ganglion while moderate level of Ca(V)1.3 channels was observed in SL and STV. Our study preliminarily revealed the expression patterns of Ca(V)1.3 channels in the rat cochlea, providing a theoretical basis for further research on the role of Ca(V)1.3 channels in the periphery auditory system. PMID- 22495161 TI - Sclerotherapy of varicose veins: my method (HCS). AB - AIM: The aim of my study has been to evaluate the efficacy of a new method of compression sclerotherapy of great saphenous vein (GSV) and small saphenous vein (SSV). METHODS: Two hundred fifty-five lower extremities with primary varicose veins, with a long reflux of the GSV (C2-6, Ep, As2 +/- p, Pr), have been submitted to sclerotherapy applying the following method: injection of the trunk of the GSV, according to Sigg's technique; echoguided compression of sapheno femoral junction (done by an inflatable balloon called Safeguard(r)); immediate eccentric positive compression on the trunk of the GSV; and short elastic bandage. RESULTS: The results have shown that applying this method of sclerotherapy the failure rate decreases. CONCLUSION: The use of Safeguard(r) interrupts reflux to the lower veins, and these can so be well sclerosed and compressed with short elastic bandage. PMID- 22495162 TI - Dual source CT: state of the art in the depiction of coronary arteries anatomy, anatomical variants and myocardial segments. AB - Cardiovascular disease is the leading cause of death in adults in western countries. Coronary angiography remains the gold standard for the diagnosis of coronary artery disease, a procedure that carries risks. Nowadays, a significant number of the coronary angiographies performed every year are only diagnostic. Multidetector computed tomography (MDCT) allows non-invasive evaluation of coronary arteries. It is a continuously developing technique, and actually the top technology is represented by Dual Source CT. This scanner of new conception permits an improvement in image quality, and visualization of distal vessels and small collateral branches. The aim of our work is to illustrate the actual state of the art in non-invasive coronary arteries evaluation represented by Dual Source CT, presenting images of coronary arteries normal anatomy, anatomical variants and myocardial segment. PMID- 22495163 TI - Statins and coronary artery disease: clinical evidence and future perspective. AB - Many clinical trials have demonstrated the beneficial effects of statins on cardiovascular risk, both in patients with history of coronary heart disease and in healthy subjects with risk factors, because of a significant reduction in acute coronary events. The introduction of more powerful statins in the market offered the opportunity to study whether an intensive lipid lowering treatment could yields even better cardiovascular outcomes than a moderate statin therapy and several clinical trial confirmed this hypothesis. Statins have also pleiotropic effect behind their lipid lowering function: they reduce inflammation, which plays an important role in the atherosclerotic process. PMID- 22495164 TI - Saphenous vein graft interventions: strategies and devices to minimize distal embolization. AB - Percutaneous coronary intervention of degenerated saphenous vein grafts remains relatively high risk when compared to native vessel interventions, despite advances in pharmacotherapy and embolic protection. This article discusses the phenomenon of distal embolization that seems to plague saphenous vein graft interventions, reviews device-based strategies for embolic protection, and offers a perspective on the utility of percutaneous saphenous vein graft intervention in both elective and acute settings. PMID- 22495165 TI - Cardiogenic shock: management of right ventricular infarction shock. AB - Right ventricular infarction is a not uncommon cause of cardiogenic shock, whose frecuency is variable and could be underestimated. Although left ventricular myocardial management is well defined in the right ventricular infarction are few studies with low level of evidence, to establish definitive guidelines. It is assumed that the treatment is similar to that of the left ventricle, although there are some differences. The axis of the therapeutic management, as well as the left ventricle infarction, is based on early myocardial reperfusion, particularly through percutaneous coronary interventionism. Throm-bolysis is an option, especially after an increase in systemic blood pressure using vasoactive drugs such as norepinephrine. The preload optimization by volume administration during resuscitation of shock is useful, but it must be with caution. The use of levosimendan could be potentially beneficial option. On the neurohormonal modulation of systemic inflammatory response produced after the cardiogenic shock (CS), the use of ACE inhibitors and beta-blockers is controversial. PMID- 22495166 TI - The role of B-type natriuretic peptide testing in patients with acute coronary syndromes. AB - B-type (brain) natriuretic peptide (BNP) is a cardiac hormone whose measurement can be helpful in a variety of clinical settings, but has been most extensively studied in patients with heart failure and acute coronary syndrome (ACS). The value of both BNP and its N-terminal fragment, NT-proBNP, as independent prognostic biomarkers in ACS is supported by data from a number of clinical trials. BNP/NT-proBNP levels can predict death and subsequent development of heart failure, but not recurrent ischemic events. BNP may also be helpful as an aid in establishing the diagnosis of ACS in patients presenting with chest pain. The role of BNP in determining treatment has not yet been defined, though patients with high levels may derive more benefit from invasive management and from treatment with ranolazine. The National Academy of Clinical Biochemists (NACB) guidelines state that measurement of BNP/NT-proBNP may be useful in prognosis for ACS patients, but do not yet recommend its routine use, naming a number of other issues that need to be resolved in the use of this marker. Age- and gender-related decision limits should be determined, and cutoff levels of BNP/NT-proBNP corresponding to low, intermediate, and high risk patients should be ascertained. Additional evidence regarding the impact of BNP/NT-proBNP levels on treatment strategy in ACS patients will be helpful in further defining the role of B-type natriuretic peptide testing in the acute coronary syndromes. PMID- 22495167 TI - Clinical impact of BNP and other emerging biomarkers in heart failure evaluation and management. AB - Hospitalization for decompensated heart failure (HF) is associated with extraordinarily high rates of morbidity and mortality. Despite its high prevalence its pathophysiologic mechanisms and future risk stratification remain poorly defined and understudied. Several clinical Risk Scores to recognize high risk patients, has been purposed in the past but they are not able to completely identify future adverse events. In this sense, laboratory biomarkers play an important role in heart failure, but there remain unanswered questions regarding optimization of their use. One of the biggest hopes for utilizing biomarker testing is to determine the level of disease severity in a manner to triage medical decisions as well as to monitor their responses. Early diagnosis is very important for a better therapy optimization and outcome improving. Indeed, identification is often difficult because of symptoms unspecificity and the lack of gold standard protocol to make diagnosis. B-type natriuretic peptide is a useful tool to confirm or rule out heart failure. Therefore, BNP is one of the most best prognostic indicator in all stages of heart failure predicting outcome in both hospitalized and outpatients. Other neurohormonal, inflammatory and metabolic markers may add complementary information to that provided by currently available B-type natriuretic peptide assays. However all specific and general laboratory parameters cannot substitute to traditional clinical evaluation but could be used in adjunction for more precise evaluation and assessment. We reviewed traditional and some of emerging biomarkers of potential clinical application in HF setting. PMID- 22495168 TI - Multivessel disease in primary percutaneous coronary intervention. AB - Primary percutaneous coronary intervention (PCI) is currently the preferred revascularization strategy in acute trasmural myocardial infarction (AMI). In this setting, about one half of patients will be diagnosed with concomitant multivessel (MV) coronary artery disease, associated with a multitude of negative prognostic factors but also still an independent predictor of adverse cardiac events and increased long-term mortality. Since additional "angiographic" lesions found at primary PCI are not directly responsile for the acute presentation, their treatment represents a difficult decision-making problem in cardiology. The article summarizes available clinical data on treatment in this setting and also review our current understanding of short-term progression of atherosclerosis after AMI. PMID- 22495169 TI - An approach to echocardiography in hypertrophic cardiomyopathy and other causes of LVH. AB - Hypertrophic cardiomyopathy (HCM) is the most prevalent genetic cardiovascular disease with a prevalence of 1:500 in the general population. Its identification is of critical importance as it is a common cause of sudden death in the young and can lead to considerable morbidity, including heart failure and atrial fibrillation. There are several conditions that can mimic the phenotypic appearance of HCM on echocardiography. Echocardiography remains an invaluable tool in both initial diagnosis and regular surveillance of patients with this condition. Although no single echocardiographic parameter is ideal, a structured and comprehensive assessment of cardiac structure and function will provide invaluable clues to the diagnosis and often hint towards an alternate diagnosis. The purpose of this review is to reassess the typical echocardiographic features of HCM and to highlight echocardiographic features that may help to distinguish other causes of left ventricular hypertrophy (LVH). PMID- 22495170 TI - Biomarkers in heart failure. AB - The meaning of the term biomarker has been standardized by a working group of the National Institutes of Health as "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention". The ability of a biomarker to enhance the quality and efficacy of clinical care depends on several factors, including pretest probability, sensitivity and specificity, costs, benefits, risks, and even patient preference and alternatives. With the aim to better diagnose the multifactorial and complex syndrome of heart failure, research has led to discover many categories of potential pathophysiologic biomarkers for this debilitating disease. Such categories have been mainly designed by matching different molecules levels to different pathophysiological stages of chronic heart failure, and comprise biomarkers of inflammation, oxidative stress, extracellular-matrix remodeling, neurohormones, myocte injury and stress, with an additional group of new biomarkers not yet fully characterized. The quest for an ideal biomarker in heart failure is still underway, and several newly discovered, but also old and overlooked markers might prove their relevance. Since at present we cannot apply the application of the perfect marker, maybe combining different molecules will provide information compensating for the shortcoming of individual tests. The accumulated basic and clinical research experience, and the continuing exploration of the genome, coupled with the evolving disciplines of proteomics and metabolomics, ensure that there will be no shortage of newly discovered candidate biomarker molecules for the future. PMID- 22495171 TI - Cardiovascular adverse reactions after the administration of recombinant human erythropoietin: light and shade. AB - From the trials published till now, it is clear that the most important and frequent adverse reactions related to the treatment with recombinant human erythropoietin (rHuEpo) are thrombovascular accidents and systemic hypertension. Only on very rare occasions cephalea and epileptic fits may occur. Even if these adverse reactions are so precisely defined, there is no evident interpretation of the biological and pathophysiological mechanisms that sustain these events. This work intends to describe the state of the art in the international literature in order to enable the reader to understand the real risks of rHuEpo administration. PMID- 22495172 TI - Technological devices in peripheral percutaneous interventions. AB - New innovations and novel approaches to peripheral arterial occlusive disease have brought enormous benefits to the vascular patient. Diseases that were once manageable only by surgical intervention are now easily and successfully treated by minimally invasive procedures. While the early days of percutaneous intervention were filled with inventions of new devices, today the focus centers on using modern technology and manufacturing to further improve upon these devices. Advances in guidewires and catheters have allowed us to visualize and treat lesions in nearly any vessel, and technology is guiding us towards specialized applications for specific lesions in specific vessels. However, one of the big hurdles remaining in treating arterial occlusive diseases is the rate of restenosis and the need for reinterventions. The location and architecture of these vessels make them uniquely difficult to treat, and call for new technology to address these challenges. Current developments of drug-eluting and bioabsorbable stents are at the forefront of new advancements specifically directed at improving current patency and restenosis rates; perhaps the next step in percutaneous intervention will rely on nanotechnology and the molecular surface engineering that may achieve a new era of devices that are able to target specific cell ligands or proteins to prevent the inflammatory and proliferative response from vessels. The present review will focus on the current literature regarding technological devices in peripheral percutaneous interventions and clinical applications. Future advancements in materials engineering and biotechnology will continue to improve the current standard of percutaneous intervention for peripheral arterial occlusive diseases. PMID- 22495173 TI - Predicting cavity formation free energy: how far is the Gaussian approximation valid? AB - We examine the range of validity of the Gaussian model for various water-like liquids whose intermolecular potentials differ from SPC/E water, to provide insight into the temperature dependence of the hydrophobic effect for small hard sphere solutes. We find that low compressibility liquids that have more close packed network structures show much larger deviations from Gaussian fluctuations for low or zero occupancies relative to more compressible fluids with more open networks. Water appears to be a unique molecular fluid in possessing equilibrium density fluctuations that are faithfully described by the Gaussian theory. We ascribe this success to the fact, shown here, that the orientational correlations near a small hard sphere solute involve remarkably little reorganization from the bulk, which is a consequence of water's low solvent reorganization enthalpy and entropy. PMID- 22495174 TI - DRD1 associations with smoking abstinence across slow and normal nicotine metabolizers. AB - Nicotine metabolism and genetic variation have an impact on nicotine addiction and smoking abstinence; however, further research is required. The nicotine metabolite ratio (NMR) is a robust biomarker of nicotine metabolism used to categorize slow and normal nicotine metabolizers (lower 25th quartile cut off). In two randomized clinical trials of smoking abstinence treatments, we conducted NMR-stratified analyses on smoking abstinence across 13 regions coding for nicotinic acetylcholine receptors and proteins involved in the dopamine reward system. Gene*NMR interaction P-values were adjusted for multiple correlated tests, and we used a Bonferroni-corrected alpha-level of 0.004 to determine system-wide significance. Three single-nucleotide polymorphisms in DRD1 (rs11746641, rs2168631, and rs11749035) had significant interactions (0.001 <= adjusted P-values <= 0.004) with increased odds of abstinence within slow metabolizers (odds ratios=3.1-3.5, 95% confidence interval 1.7-6.7). Our findings support the role of DRD1 in nicotine dependence, and identify genetic and nicotine metabolism profiles that may interact to impact nicotine dependence. PMID- 22495175 TI - Characterization of the human hair keratin-associated protein 2 (KRTAP2) gene family. AB - Hair keratin-associated proteins (KRTAPs) are one of the major structural components of the hair shaft. Approximately 100 KRTAP genes have been identified in humans to date, with each of the genes classified into a number of families based on their sequence homology and the nature of the repeat structures. The biophysical features of KRTAPs, however, have remained largely unknown. In this study, we investigated the characteristics of the human KRTAP2 family members at the DNA, RNA, and protein levels. We initially found that these genes had various size polymorphisms that were mainly due to differences in the length of the 3' noncoding sequences. Reverse transcriptase-PCR experiments further detected the presence of KRTAP2 transcripts in plucked human hairs. Using indirect immunofluorescence with an anti-KRTAP2 antibody, we found that there was a predominant expression of the KRTAP2 proteins in the keratinizing zone of the human hair shaft cortex. In addition, we showed that the KRTAP2 proteins interacted with each other and preferentially bound to hair keratins, but not to epithelial keratins. Finally, we determined that the head domain of the hair keratins was essential for the affinity to KRTAP2 proteins. Our results further enhance the crucial roles of KRTAPs in hair shaft keratinization in humans. PMID- 22495176 TI - MYD88 somatic mutation is a genetic feature of primary cutaneous diffuse large B cell lymphoma, leg type. PMID- 22495177 TI - Vitamin D receptor mediates DNA repair and is UV inducible in intact epidermis but not in cultured keratinocytes. PMID- 22495179 TI - Spliceosome-mediated trans-splicing: the therapeutic cut and paste. AB - Spliceosome-mediated RNA trans-splicing (SMaRT) is an RNA-based technology to reprogram genes for diagnostic and therapeutic purposes. For the correction of genetic diseases, SMaRT offers several advantages over traditional gene replacement strategies. SMaRT protocols have recently been used for in vitro phenotypic correction of a variety of genetic disorders, ranging from epidermolysis bullosa to neurodegenerative diseases. In vivo studies are currently bringing trans-splicing RNA therapy toward clinical application. In this review, we summarize the progress made toward the medical use of SMaRT and provide an outlook on its upcoming applications. PMID- 22495178 TI - beta2AR antagonists and beta2AR gene deletion both promote skin wound repair processes. AB - Skin wound healing is a complex process requiring the coordinated, temporal orchestration of numerous cell types and biological processes to regenerate damaged tissue. Previous work has demonstrated that a functional beta-adrenergic receptor autocrine/paracrine network exists in skin, but the role of beta2 adrenergic receptor (beta2AR) in wound healing is unknown. A range of in vitro (single-cell migration, immunoblotting, ELISA, enzyme immunoassay), ex vivo (rat aortic ring assay), and in vivo (chick chorioallantoic membrane assay, zebrafish, murine wild-type, and beta2AR knockout excisional skin wound models) models were used to demonstrate that blockade or loss of beta2AR gene deletion promoted wound repair, a finding that is, to our knowledge, previously unreported. Compared with vehicle-only controls, beta2AR antagonism increased angiogenesis, dermal fibroblast function, and re-epithelialization, but had no effect on wound inflammation in vivo. Skin wounds in beta2AR knockout mice contracted and re epithelialized faster in the first few days of wound repair in vivo. beta2AR antagonism enhanced cell motility through distinct intracellular signalling mechanisms and increased vascular endothelial growth factor secretion from keratinocytes. beta2AR antagonism promoted wound repair processes in the early stages of wound repair, revealing a possible new avenue for therapeutic intervention. PMID- 22495180 TI - Ascorbic acid deficiency leads to epidermal atrophy and UVB-induced skin pigmentation in SMP30/GNL knockout hairless mice. PMID- 22495181 TI - BBF2H7-mediated Sec23A pathway is required for endoplasmic reticulum-to-Golgi trafficking in dermal fibroblasts to promote collagen synthesis. AB - Collagen fibers, structural elements responsible for mechanical strength in skin, are synthesized constitutively in response to cytokines such as IGF-I. However, little is known about their intracellular trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus during synthesis. We demonstrate herein that the BBF2 human homolog on chromosome 7 (BBF2H7)-mediated Sec23A pathway is involved in regulation of intracellular procollagen trafficking. The mRNA and protein expression of BBF2H7, Sec23A, and type I and III collagen (COL1 and COL3) was induced by IGF-I stimulation. In addition, the cleaved form of BBF2H7 was detected in IGF-I-treated cultures, indicating that activation occurs concurrently with its expression. Knockdown with small interfering RNAs targeting BBF2H7 caused a significant reduction in the expression of COL1 and COL3, regardless of IGF-I treatment. Both mitogen-activated protein kinase and phosphatidylinositol-3 kinase pathways via IGF-I receptor activation were required for BBF2H7 induction. Using immunofluorescence microscopy, we showed that Golgi apparatus dysmorphology is due to coat protein complex II vehicle hypoplasia caused by the absence of BBF2H7 and Sec23A. The BBF2H7-mediated Sec23A pathway was required for ER-to-Golgi procollagen trafficking to promote collagen synthesis. This role of growth factors such as IGF-I, which to our knowledge is previously unreported, suggests antiaging strategies. PMID- 22495182 TI - Regulation of T-plastin expression by promoter hypomethylation in primary cutaneous T-cell lymphoma. AB - T-plastin (PLS3) is an actin-bundling protein normally expressed in epithelial cells but absent in cells of hematopoietic origin. Aberrant PLS3 expression has been demonstrated in lymphocytes from Sezary syndrome (SS) patients and has been proposed as a biomarker for SS; however, the mechanism underlying dysregulation of PLS3 has not been determined. In this study, PLS3 mRNA expression was demonstrated in 21/35 (60%) SS patients and in 3/8 (38%) mycosis fungoides patients, all of whom had clonal blood involvement. No evidence for PLS3 mutations within coding or promoter regions was found, but significant hypomethylation of CpG dinucleotides 95-99 within the PLS3 CpG island was observed and this was restricted to the PLS3+ population. A polyclonal antibody specific to PLS3 was raised to examine coexpression of PLS3 with a panel of T cell differentiation markers. All PLS3+ cells were CD3+CD4+ and CD26-, suggesting that loss of CD26 is consistently associated with gain of PLS3, whereas all other markers were distributed heterogeneously. However, a patient-specific TCR copy number assay also demonstrated heterogeneity in PLS3 expression in tumor cell populations. Importantly, our findings demonstrate PLS3 expression in the majority of SS patients and provide insight into the molecular regulation of PLS3 expression in CTCL. PMID- 22495183 TI - Effects of repeated oxycodone administration on its analgesic and subjective effects in normal, healthy volunteers. AB - Tolerance to the analgesic effects of opioids has been demonstrated in laboratory animals after repeated drug administration; yet, this effect has been studied less frequently under controlled laboratory conditions in humans. This within subject, double-blind, placebo-controlled study was designed to determine whether tolerance developed to the analgesic, subjective, and physiological effects of the commonly prescribed opioid oxycodone when it was administered daily for 5 days. The effects of oxycodone (0, 5, and 20 mg/70 kg, orally) were compared, using a within-session cumulative dosing procedure, on the first and fifth days of the 'daily' dosing phase to assess for tolerance; active oxycodone was administered on the second and fourth days of the daily dosing phase. Changes in the effects of oxycodone were also compared when the medication was only administered on the first and the fifth day of a 5-day 'intermittent' dosing phase; placebo medication was administered on the second and fourth days of the intermittent dosing phase. A 9-day 'washout' period occurred between phases during which no medication was administered. Healthy volunteers (N=10) with no history of drug dependence or current drug use participated in this outpatient study. Analgesia was assessed using the cold pressor test, pain and drug effects were measured using a variety of questionnaires, and pupil diameter was monitored as an index of physiological effects. When administered daily, no differences were observed in oxycodone-induced analgesia between the first and the fifth days, but tolerance did develop to some of the positive subjective effects of oxycodone. In contrast, oxycodone-induced analgesia and participant ratings of some positive subjective drug effects were greater on the fifth compared with the first day of the intermittent dosing phase. No differences in the miotic effects of oxycodone between the first and the fifth days of either dosing phase were detected. Although obtained under limited experimental conditions, these findings suggest that tolerance may not develop to the analgesic effects of therapeutic doses of oxycodone under short-term daily dosing conditions, even though some of its subjective effects may decrease. These data also suggest that intermittent administration may enhance the analgesic effects of oxycodone, while also increasing some of the drug's positive subjective effects related to abuse liability. PMID- 22495184 TI - Potential involvement of tyrosine phosphatase and calpain-related pathways in opioid withdrawal syndrome in mice. AB - The present study was designed to determine the effect of N'-[6,7-dichloro-4-(4 methoxy-phenyl)-3-oxo-3,4-dihydroquinoxalin-2-yl] hydrazide (SJA 7019), a selective nonpeptide inhibitor of calpain, and sodium orthovanadate, a selective inhibitor of tyrosine phosphatase, on the development of physiological dependence, as assessed by precipitated morphine withdrawal behavior in mice. Subchronic morphine administration (5 mg/kg, intraperitoneally, twice daily for 5 days), followed by a single injection of naloxone was used to precipitate the opioid withdrawal syndrome in mice. Behavioral observations were made immediately after naloxone treatment. Withdrawal syndrome was assessed quantitatively in terms of the withdrawal severity score and the frequency of jumping, rearing, forepaw licking, and circling. Daily single administration of SJA 7019 (1.5, 3, and 6 mg/kg, intraperitoneally) or sodium orthovanadate (5, 10, and 20 mg/kg, intraperitoneally) was continued during the morphine treatment procedure. Administration of SJA 7019 as well as the sodium orthovanadate dose-dependently attenuated the naloxone-induced morphine withdrawal syndrome. Neither SJA 7019 nor sodium orthovanadate significantly affected locomotor activity or morphine induced antinociception. Therefore, it may be concluded that treatment with SJA 7019 or sodium orthovanadate during the morphine exposure period attenuated the development of physiological dependence on morphine, possibly through mechanisms linked to activation of tyrosine phosphatase and calpain. PMID- 22495185 TI - The phosphodiesterase inhibitor isobutylmethylxanthine attenuates behavioral sensitization to cocaine. AB - The factors influencing sensitization to cocaine are complex and likely include both cellular and neural systems factors. Upregulation of the striatal dopamine cAMP-signaling pathway and enhanced accumbens adenosine tone are two mechanisms that have been proposed to underlie the development of cocaine sensitization. Isobutylmethylxanthine (IBMX) is a nonspecific inhibitor of phosphodiesterase (PDE) that may enhance the intracellular cAMP levels. However, IBMX may inhibit the PDE-mediated production of adenosine. In this study, intracerebroventricular IBMX did not affect the acute hyperlocomotor response to cocaine, but when coadministered with cocaine for 7 consecutive days, attenuated development of behavioral sensitization. These results suggest that IBMX inhibition of PDE mediated adenosine production is a stronger influence on cocaine sensitization than inhibition of intracellular PDE-mediated cAMP metabolism. PMID- 22495186 TI - Coadministration of cannabinoid CB1-receptor and adenosine A1-receptor antagonists improves the acquisition of spatial memory in mice: participation of glutamatergic neurotransmission. AB - The aim of this study was to characterize the interaction of adenosine A1 receptor and cannabinoid CB1-receptor antagonists in the water maze and object location tasks, and to evaluate the participation of glutamatergic neurotransmission in the hippocampus in the learning enhancement induced by the coadministration of both antagonists. Our results show that coadministration of ineffective doses of DPCPX (8-cyclopentyl-1,3-dipropylxanthine) (an A1-receptor antagonist) and AM251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl) 4-methyl-1H-pyrazole-3-carboxamide) (a CB1-receptor antagonist) in different proportions enhanced the acquisition of spatial learning. N-methyl-D-aspartate receptor blockade disrupted the effects of the selected drug combination [AM251 0.25 mg/kg intraperitoneally (i.p.)+DPCPX 0.30 mg/kg i.p.] either in the water maze or in the object-location task. Moreover, this drug combination induced a significant ex-vivo enhancement in glutamate release into hippocampal slices. In addition, the blockade of N-methyl-D-aspartate receptors with MK-801 (0.25 ug/site) infused into the hippocampal CA1 area reversed the effects of coadministration, as evaluated in the object-location task. In conclusion, this is the first study to show that A1-receptor and CB1-receptor antagonists might interact on hippocampal neurons to enhance spatial memory in mice. PMID- 22495187 TI - Acute kidney injury in children. AB - Acute kidney injury (AKI) affects 5% of critically ill hospitalized children and is a risk factor for increased morbidity and mortality. The current review focuses on new definitions of acute kidney injury, standardized to reflect the entire spectrum of the disease, as well as on ongoing research to identify early biomarkers of kidney injury. Its also provides an overview of current practice and available therapies, with emphasis on new strategies for the prevention and pharmacological treatment of diarrhea-associated hemolytic uremic syndrome. Furthermore, a decision-making algorithm is presented for the use of renal replacement therapies in critically ill children with AKI. PMID- 22495188 TI - New treatment strategies in idiopathic nephrotic syndrome. AB - Idiopathic nephrotic syndrome (INS) is probably due to a plasma factor of immunologic origin. This circulating factor probably interacts with the glomerular filtration barrier and is responsible for massive proteinuria. Most patients respond to steroids. However, a considerable proportion of children run a steroid dependent course. Cyclosporine A (CyA) and cyclophosphamide (CyP) have been classical treatment strategies for such cases, but specific toxicity limits the use of these drugs. Mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase and thus de novo purine synthesis. Clinical trials have demonstrated the efficacy of MMF in steroid dependent NS and in children with nephrotoxicity due to prolonged CyA treatment. While MMF is a well established strategy against steroid dependency, rituximab (RTX) has emerged as a new treatment option in case of calcineurin inhibitor dependency. Non-compliance to steroid therapy can be responsible for multiple relapses and may be misinterpreted as steroid dependency and may therefore lead to unjustified increase of the immunosuppressive treatment. Triamcinolone acetonide, a long acting steroid for intramuscular injection, can replace the usual oral prednisone treatment if non-compliance is suspected. Whereas the treatment of the primary course of INS is well established, steroid dependent and steroid resistant forms are still a challenge for pediatric nephrologists. Both under-treatment with multiple relapses with disease or steroid associated morbidity on the one hand and over-treatment with specific side effects of immunosuppressive drugs may have severe consequences for the patients. The narrow path between steroid side effects and potential nephrotoxicity emphasizes the need for individualized management in severe form of INS. PMID- 22495189 TI - Urinary tract infections in children: a review. AB - Febrile urinary tract infection is the most common serious bacterial infection in childhood, but the most appropriate evaluation of children with this condition is still unclear, overall regarding the best long-term management of children after a first UTI. Here we review current recommendations for the diagnosis, treatment, imaging evaluation and use of antibiotic prophylaxis in children with the first febrile urinary tract infection. Nevertheless, the development of a universally accepted diagnostic protocol remains elusive. PMID- 22495190 TI - Chronic hemodialysis in pediatric patients: technical and practical aspects of use. AB - Chronic kidney disease (CKD) is a continuum of progressive reduction in kidney function lasting for more than three months, due to either structural and/or functional renal abnormalities that may lead to irreversible kidney damage. The term "renal supportive therapy" (RST) generally characterizes the spectrum of dialysis therapies available to support existing renal function in patients with CKD during progression to end-stage renal disease (ESRD) and/or renal transplantation. Chronic RST modalities include conventional hemodialysis, peritoneal dialysis and home hemodialysis therapies. The modality chosen to deliver RST in the pediatric patient is often guided by a variety of factors including institutional resources, local expertise, patient characteristics, treatment goals, and physician preference. Chronic RST in a pediatric population requires the flexible utilization of multiple delivery modalities for effective care across infancy into adulthood and is not typically initiated until GFR declines to between 15-30 mL/min per 1.73 m2, although thresholds for initiation of RST will vary between patients. This review will provide an overview of current approaches to management and technical approaches to pediatric patients requiring chronic hemodialysis. PMID- 22495191 TI - Arterial hypertension and proteinuria in pediatric chronic kidney disease. AB - A variety of chronic kidney diseases tend to progress towards end-stage kidney disease. Progression is largely due to factors unrelated to the initial disease, including arterial hypertension and proteinuria. Intensive treatment of these two factors is potentially able to slow the progression of kidney disease. Blockers of the renin-angiotensin-aldosterone system, either converting enzyme inhibitors or angiotensin II receptor antagonists, reduce both blood pressure and proteinuria and appear superior to a conventional antihypertensive treatment regimen in preventing progression to end-stage kidney disease. The most recent recommendations state that in children with chronic kidney disease without proteinuria the blood pressure goal is the corresponding 75th centile for body length, age and gender; whereas the 50th centile should be aimed in children with chronic kidney disease and pathologically increased proteinuria. PMID- 22495192 TI - Vesico-ureteral reflux: a critical appraisal. AB - It has been nearly fifty years since J.M. Smellie published a seminal work that changed the landscape of vesicoureteral reflux when he reported the outcomes of 116 children with chronic pyelonephritis and the benefits of chemoprophylaxis. Even then, he conceded "the effectiveness of any form of treatment will be known only after prolonged follow-up". Forty-six years later, the answers to many questions remain elusive. The surfeit of available information continues to provoke controversy - from the presentation of reflux to the management thereof. We endeavor to survey the rocky landscape of vesicoureteral reflux and provide a critical appraisal of the available evidence and challenges for the future. PMID- 22495193 TI - Minimal change (steroid sensitive) nephrotic syndrome in children: new aspects on pathogenesis and treatment. AB - Steroid sensitive (minimal change) nephrotic syndrome (MCNS) has been regarded as immunological disorder because of clinical and experimental evidence as well as the response to immunosuppressive treatment. Recent work increased dramatically the understanding of podocyte biology which may be the key structure involved in MCNS, Interestingly many treatment options which were thought to work via an immunosuppressive pathway are now known to have a direct -non immunological- impact on the glomerular filtration barrier, i.e. the podocyte. Aim of this review is the presentation of recent research regarding the podocyte biology but also concerning the treatment of this disorder. PMID- 22495194 TI - State of pediatric kidney transplantation in 2011. AB - Fifty years ago children with renal failure died due to the lack of adequate therapy. Today, the implementation of dialysis procedures, such as peritoneal dialysis and hemodialysis as well as kidney transplantation, has become almost standard care for pediatric patients. Even infants can now be dialyzed or receive transplants. A kidney transplant allows for a 20-year patient survival in >90% of patients and almost age-appropriate mental and physical development. A better transplant survival is achieved with a living organ donation than with a post mortem donation. It has been shown that kidneys from deceased juvenile and young adult donors should be allocated primarily to children as they obtain significantly better transplant function in the short and medium term than adults. Unfortunately, the problem of a long waiting period for a postmortem donated kidneys for children in the Eurotransplant area remains. Although, the allocation system for children was amended in December 2010, it remains to be seen whether this change will positively influence waiting times. New immunosuppressive regimens have resulted in significantly improved long-term transplant function and transplant survival. The main challenge, however, concerns chronic humoral transplant rejection, therapy for recurrence of the underlying disease, and the execution of AB0 incompatible transplantations. PMID- 22495195 TI - [Etiological, clinical and neuroradiological investigation of deaf children with additional neuropsychiatric disabilities]. AB - AIM: Sensorineural hearing loss (SNHL) is complicated by additional disabilities in about 30% of cases, but the epidemiology of associated disorders, in terms of type, frequency and aetiology is still not clearly defined. Additional disabilities in a deaf child have important consequences in assessing and choosing a therapeutic treatment, in particular when considering cochlear implantation (CI) or hearing aids (HA). The aim of this paper was to evaluate frequency, type and severity of additional neurodevelopmental disabilities in children with profound bilateral sensorineural hearing loss and to investigate the relationship between disability and the etiology of deafness. METHODS: Eighty children with profound bilateral sensorineural hearing loss (mean age 5.4 years) were investigated by means of a diagnostic protocol including clinical, neurodevelopmental, and audiological procedures together with genetic and neurometabolic tests and neuroradiological investigation by brain MRI. RESULTS: Fifty-five percent of the sample exhibited one or more disabilities in addition to deafness, with cognitive, behavioural-emotional and motor disorders being the most frequent. The risk of additional disabilities varied according to aetiology, with a higher incidence in hereditary syndromic deafness, in cases due to pre perinatal pathology (in comparison to unknown and hereditary non syndromic forms) and in the presence of major brain abnormalities at MRI. CONCLUSION: Our results suggest that the aetiology of deafness may be a significant risk indicator for the presence of neuropsychiatric disorders. A multidimensional evaluation, including aetiological, neurodevelopmental and MRI investigation is needed for formulating prognosis and for planning therapeutic intervention, especially in those children candidated to cochlear implant. PMID- 22495196 TI - [Proper antibiotic therapy. From penicillin to pharmacogenomic]. AB - Antibiotics have always been considered one of the wonder discoveries of the 20th century. The use of penicillin by Flaming, opened up the golden era of antibiotics and now is hard to imagine the practice of medicine without antibiotics. Life-threatening infections, such as meningitis, endocarditis, bacteremic pneumonia sepsis, would again prove fatal. Also aggressive chemotherapy and transplant procedures would prove impossible. Another real wonder has been the rise of antibiotic resistance soon after the clinical use of penicillin in hospitals and communities. Several study demonstrated an excessive amount of antibiotic prescribing for communities patients and inpatients and in some hospital up to 50% of antibiotic usage is inappropriate: the benefits of antibiotic treatment come with the risk of antibiotic resistance development. In hospitals, infections caused by antibiotic-resistant bacteria are associated with higher mortality, morbidity and prolonged hospital stay compared with infections caused by antibiotic-susceptible bacteria. A variety of strategies has been proposed to reduce the cost and improve the quality of medication use. Education, guidelines and evidence based recommendations are considered to be essential elements of any program designed to influence prescribing behavior and can provide a foundation of knowledge that will enhance and increase the acceptance of stewardship strategies. Evidence-based recommendations, an approach to clinical practice helping to make decisions based on clinical expertise and on intimate knowledge of the individual patient's situations, beliefs, and priorities, enhance antimicrobial stewardship, that include appropriate selection, dosing, route, and duration of antimicrobial therapy can maximize clinical cure or prevention of infection while limiting the unintended consequences, such as the emergence of resistance, adverse drug events, and cost. These evidence-based guidelines are not a substitute for clinical judgment, and clinical discretion is always required in their application. Genome studies have identified hundreds of genetic polymorphism important determinants of the efficacy of therapy and several trial demonstrated the successful use of pharmacogenomic testing to reduce the incidence of hypersensitivity reactions in patients. Knowing the phenotype of a patient prior to therapy, optimal dose and type drugs can be prescribed to achieve better management of patients. PMID- 22495197 TI - Appendiceal abscess and right ovarian teratoma: a rare association. AB - Many pediatric patients presenting to the Emergency Department with acute abdomen are subject to one or even more than one imaging modalities in order to determine the reason for the patient's symptoms. Most of the times, imaging can render an accurate diagnosis and help clinicians and surgeons for the decision making plan and further management. In some circumstances, image findings are equivocal, non specific or simply misinterpreted and a correct diagnosis cannot been made preoperatively. Authors present a unique case of an unexpected acute appendicitis found during surgical exploration performed in order to remove an ovarian tumor in an eight-year-old girl. PMID- 22495198 TI - [An unusual pneumomediastinum case in a child caused by spontaneous bronchial rupture]. AB - We report a case of spontaneous pneumomediastinum (SPM) in a 3 year-old child, admitted to the emergency department because he presented dyspnea for a few hours, after a paroxysm of cough. The SPM is rare in children; the term "spontaneous" is reserved for cases of pneumomediastinum that haven't a traumatic cause. SPM is seen most commonly in asthmatics and in any patient who induces a Valsalva maneuver. The clinical diagnosis is confirmed by chest radiograph. When the diagnosis is uncertain, the chest CT scan is considered the gold standard of imaging tests, capable of detecting pneumomediastinum even in patients with small amounts of mediastinal air. In this case CT images showed the cause: spontaneous bronchial rupture. The direct sign of bronchial injury is the contiguity of the luminal air with that in the mediastinum. In the literature SPM cases are very rare, at least in health patients without tracheobronchial anomalies. The SPM is generally a benign entity that requires supportive care, and resolution occurs spontaneously, such as in our patient. In this article we want to explain the main clinical, diagnostic and therapeutic aspects of SPM, because, even if it's rare in children, it must be considered in the differential diagnosis of dyspnea; then we want to demonstrate as, in this case, a TC scan was important to identifying the SPM cause: a bronchial rupture. PMID- 22495199 TI - [A case of neonatal lupus syndrome and congenital atrioventricular block associated with maternal antibodies antiRo/SS-A]. AB - The neonatal lupus erythematosus syndrome (LEN) is a disease due to the transplacental passage of maternal antiextractable nuclear antigens (ENA) antibodies, particularly anti-Ro/SS-A and anti-La/SS-B. The disease affects neonates born from mothers with autoimmune diseases. It is characterized by erythematous annular polycylic skin lesions, slightly scaling with prevalent face localization, hematologic and liver diseases and only in 2% of cases with extracutaneous lesions including complete atrioventricular block. The Authors describe a case of LEN characterized by isolated atrioventricular block at birth and endocardial fibroelastosis without skin lesions in a preterm infant female. She was born from asymptomatic, ANA (Anti-Nuclear Antibodies) and ENA (anti Extractable Nuclear Antigen) positive mother, with a previous miscarriage at the 5th week of gestation. PMID- 22495200 TI - A comparative study on the sensitivity of Cyprinus carpio muscle and liver FBPase toward AMP and calcium. AB - The activity of fructose-1,6-bisphosphatase (FBPase; EC 3.1.3.11) isozymes is influenced by AMP, Ca2+ and by reversible interactions with subcellular structures. In contrast to mammalian and avian isozymes, the kinetic properties of FBPases from ectothermal vertebrates are not fully described. To get some insight into mechanism of glycogen resynthesis in ectothermal vertebrates we examined the features of FBPases isolated from Cyprinus carpio skeletal muscle and liver. To investigate the evolutionary origin of the sensitivity of FBPase to effectors, we performed a phylogenetic analysis of known animal amino acids sequences of the enzyme. Based on our findings, we hypothesize that the high, mammalian-like, sensitivity of FBPase to Ca2+ is not essential for controlling the stability of glyconeogenic complex in striated muscles, instead it ensures the precise regulation of mitochondrial metabolism during prolonged Ca2+ elevation in contracting muscle fibers. Comparison of the kinetic properties of vertebrate and insect FBPases suggests that the high sensitivity of muscle isozyme to inhibitors has arisen as an adaptation enabling coordination of energy metabolism in warm-blooded animals. PMID- 22495201 TI - The effect of hydrogen bonding on the excited-state proton transfer in 2-(2' hydroxyphenyl)benzothiazole: a TDDFT molecular dynamics study. AB - The dynamics of the excited-state proton transfer (ESPT) in a cluster of 2-(2' hydroxyphenyl)benzothiazole (HBT) and hydrogen-bonded water molecules was investigated by means of quantum chemical simulations. Two different enol ground state structures of HBT interacting with the water cluster were chosen as initial structures for the excited-state dynamics: (i) an intramolecular hydrogen-bonded structure of HBT and (ii) a cluster where the intramolecular hydrogen bond in HBT is broken by intermolecular interactions with water molecules. On-the-fly dynamics simulations using time-dependent density functional theory show that after photoexcitation to the S(1) state the ESPT pathway leading to the keto form strongly depends on the initial ground state structure of the HBT-water cluster. In the intramolecular hydrogen-bonded structures direct excited-state proton transfer is observed within 18 fs, which is a factor two faster than proton transfer in HBT computed for the gas phase. Intermolecular bonded HBT complexes show a complex pattern of excited-state proton transfer involving several distinct mechanisms. In the main process the tautomerization proceeds via a triple proton transfer through the water network with an average proton transfer time of approximately 120 fs. Due to the lack of the stabilizing hydrogen bond, intermolecular hydrogen-bonded structures have a significant degree of interring twisting already in the ground state. During the excited state dynamics, the twist tends to quickly increase indicating that internal conversion to the electronic ground state should take place at the sub-picosecond scale. PMID- 22495203 TI - Is a lateral view essential in management of hip fracture? AB - INTRODUCTION: Neck of femur accounts to about 86,000 cases per annum in UK. AP and lateral radiographs form an essential investigation in planning the management of these fractures. Recently it has been suggested that lateral view does not provide any additional information in majority of the cases. MATERIALS AND METHODS: We looked retrospectively at 25 consecutive radiographs with intracapsular and extracapsular fracture neck of femur each presenting to our department between May 2010 and January 2011. These radiographs were put on the CD in 2 folders as AP and lateral. It was reviewed by 2 observers who suggested their preferred treatment. The results were compared for the intra observer agreement to assess the necessity of the lateral view of the radiographs. We also compared the treatment options with the gold standard. RESULTS: Our results showed that lateral view did not make any difference in the management in majority of the cases with excellent agreement based on kappa statistics. CONCLUSION: We feel that the lateral view does not make any difference in most of the cases as shown by a good intraobserver agreement. PMID- 22495202 TI - Prognostic value of perfusion defect volume at dual energy CTA in patients with pulmonary embolism: correlation with CTA obstruction scores, CT parameters of right ventricular dysfunction and adverse clinical outcome. AB - PURPOSE: To investigate the prognostic value of perfusion defect volume (PDvol) at dual-energy-CT-angiography (DE-CTA) in patients with acute pulmonary embolism (PE) by correlating PDvol with CTA-obstruction-scores (OS), CT parameters of right-ventricular-dysfunction (RVD), and adverse-clinical-outcome. MATERIALS AND METHODS: DE-CTA of 60 patients (mean age: 65+/-14.4 years) with PE were analyzed. Iodine maps were generated, and normalized PDvol--defined as volume of perfusion defects/total lung volume--was quantified. Furthermore, established prognostic parameters (Qanadli and Mastora-OS, and CT parameters of RVD) were obtained. CT parameters of RVD--namely the right ventricle/left ventricle (RV/LV) diameter ratio measured on transverse sections (RV/LVtrans), four-chamber views (RV/LV4ch), and RV/LV volume ratios (RV/LVvol)--were assessed. PDvol was correlated with OS, CT parameters of RVD and adverse clinical outcome (defined as the need for intensive care treatment or death). RESULTS: 10 of 60 patients with PE experienced adverse clinical outcome. Patients with adverse clinical outcome showed significantly higher PDvol (35+/-11% vs. 23+/-10%, p=0.002), RV/LV ratios (RV/LV4ch 1.46+/-0.32 vs. 1.18+/-0.26, p=0.005; RV/LVvol 2.25+/-1.33 vs. 1.19+/ 0.56, p=0.002) and higher Mastora global scores (52 vs. 13, p=0.02) compared to those without adverse clinical outcome. A weak correlation was observed between PDvol and the Mastora global score (r=0.5; p=0.0003), as well as between PDvol and RV/LV4Ch (r=0.432, p=0.0006). No correlation was found between PDvol and the Qanadli score or the remainder of the RVD-CT parameters. CONCLUSION: The extent of perfusion defects as assessed by DE-CTA correlates with adverse clinical outcome in patients with PE. Therefore, volumetric quantification of perfusion defects at DE-CTA allows the identification of low-risk patients who do not require intensified monitoring and treatment. PMID- 22495204 TI - Resident selection protocols in plastic surgery: a national survey of plastic surgery independent program directors. AB - BACKGROUND: Plastic surgery training programs draw applicants directly from medical school (the "integrated path"), and they may also draw applicants who have completed other categorical training (the "independent path"). Much of the literature on applicant selection focuses on the integrated path. The authors sought to characterize the selection process of independent path programs and how they compare with the integrated path programs. METHODS: An anonymous, 42 question, multiple-choice, online survey was designed for program directors of the independent training path; it was mirrored to the previously designed survey of the integrated training path. Surveys were sent to all independent path program directors in the United States. RESULTS: Fifty of the 51 qualifying program directors (98 percent) completed the survey. Fewer exclusively independent programs (30 percent) used a United States Medical Licensing Examination step-1 cutoff for interviews than did programs using both training pathways (71 percent; p=0.015). Letters of recommendation were deemed the most important academic criteria. The attrition rate for independent residents was 3 percent. The combined rate of the adverse outcomes of probation and attrition was statistically lower for independent programs (30 percent) than for integrated programs (43 percent; p=0.033). CONCLUSIONS: These results may answer some questions regarding what programs are looking for. The low rates of probation, dismissal, and attrition compared with those of the integrated path would support maintaining the independent path as a viable option for those who meet selection protocols, as these candidates may have already been preselected for success through their previous training programs. PMID- 22495205 TI - Body contouring in the male weight loss population: assessing gender as a factor in outcomes. AB - BACKGROUND: Growing numbers of men are presenting for consultation and potential postbariatric body contouring surgery. Due to concerns about whether men might have increased rates of complications or dissatisfaction with aesthetic surgery, the authors assessed their clinical experience with male patients. METHODS: The authors examined male patients in their prospective database who had undergone body-contouring surgery. Chi-square analysis, regression analysis, and a binary logistic regression model were used to study categorical variables, surgical outcomes, continuous variables, and significant factors. Odds ratios were calculated. RESULTS: Of 481 patients, 48 (10 percent) were male. There were no significant differences in baseline comorbidities between the genders, except that women had a higher incidence of anxiety/depression. Men had a greater weight loss before body-contouring surgery, but this did not correlate with greater operative time or estimated blood loss. Male gender, however, was associated with a 14.6 percent incidence of postoperative hematoma and a 25 percent incidence of seroma, in contrast to female gender, with 3.5 and 13 percent, respectively. Logistic regression showed that male gender was associated with an increased incidence of hematoma, seroma, and postoperative complications. It was an independent risk factor for hematoma and seroma formation, with odds ratios of 3.76 and 2.65, respectively. Gender was not an independent predictor of wound dehiscence, flap loss, transfusion, or surgical-site infection. CONCLUSIONS: Men who are considering body-contouring surgery should be advised that they are at an increased risk of postoperative hematoma and seroma formation. The causal relationship between gender and postoperative complications is an area for further study. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 22495206 TI - Patterns of use and patient satisfaction with breast reconstruction among obese patients: results from a population-based study. AB - BACKGROUND: The national obesity epidemic is contributing to an increased proportion of overweight and obese breast cancer patients. The authors' purpose was to determine whether patterns of use and outcomes of reconstruction differed among obese and nonobese patients. METHODS: The authors performed a 5-year follow up survey of mastectomy-treated breast cancer patients from the Los Angeles and Detroit Surveillance, Epidemiology and End Results Cancer Registries (response rate, 59 percent). Patients were divided into three body mass index categories: normal weight (body mass index<25 kg/m), overweight (25 to 30 kg/m), and obese (>30 kg/m). Outcomes of interest were receipt of reconstruction, type and timing of reconstruction, access barriers, and satisfaction. Chi-square and t tests were used for analysis. Logistic regression was used to identify predictors of autologous reconstruction. RESULTS: Of 374 mastectomy-treated patients, receipt of reconstruction did not vary by body mass index (53 percent normal weight, 48 percent overweight, and 45 percent obese; p=0.43). Receipt did vary by type of reconstruction: significantly more obese patients received transverse rectus abdominis musculocutaneous flaps compared with normal weight patients (53 percent versus 26 percent; p=0.01). No specific access barriers to reconstruction were identified. Patient satisfaction with surgical decision-making and surgical outcomes was similar across body mass index categories. CONCLUSIONS: Obese compared with normal weight breast cancer patients have similar use of breast reconstruction, are more likely to receive an autologous procedure, and report similar satisfaction with surgical outcomes. Future efforts should be directed at decreasing the surgical risk in this challenging patient population. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 22495207 TI - The distally based adipofascial sural artery flap: faster, safer, and easier? A long-term comparison of the fasciocutaneous and adipofascial method in a multimorbid patient population. AB - BACKGROUND: Complex wounds of the distal third of the leg are challenging to treat. Despite free tissue transfer, local pedicled flaps such as the distally pedicled sural artery flap remain a valuable option. METHODS: The authors conducted a retrospective comparison of the classical harvesting technique of the sural artery flap with a simplified method without a skin island. RESULTS: We report on 148 patients who were treated with 104 adipofascial flaps and 44 fasciocutaneus flaps from 1997 to 2010. The adipofascial group showed a shorter operative time and a better aesthetic outcome. Complications did not differ in this multimorbid patient group. CONCLUSIONS: With a simple modification, the distally based sural artery flap is easier and faster to perform. The study shows that the adipofascial flap is as safe as the classic version, with the advantage of an improved donor-site appearance. Therefore, the described technique is a valuable tool in cases where free tissue transfer is not suitable. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 22495208 TI - Aesthetic improvement of the female breast in funnel chest deformity by surgical repair of the thoracic wall: indication or lifestyle surgery? AB - BACKGROUND: Adults are increasingly seeking surgical correction of pectus excavatum deformity, and the alternative custom-made silicone implant is not always desired or suitable. The paramount concern of female patients is the apparent strabism of their breasts. In some cases, the standard minimally invasive reconstruction of pectus excavatum procedure or a modified approach with a semiopen technique can help remodel the anterior thoracic wall and simultaneously reposition the female breasts to a desired and aesthetically acceptable position. METHODS: Between November of 2000 and March of 2011, 35 female adolescent and adult patients underwent surgical funnel chest repair with different approaches. In seven of these patients, a pectus bar was implanted using minimally invasive reconstruction of pectus excavatum, whereas 15 underwent a combined semiopen approach. The pectus bar was removed after a period of 14 to 39 months (mean, 31 months) in the minimally invasive reconstruction group and 12 to 25 months (mean, 13.5 months) in the other group. Preoperative and postoperative photographs were examined, and the results were assessed by independent surgeons. RESULTS: During the follow-up period of 1 month to 3.9 years (mean, 12 months), no major complications occurred. The aesthetic appearance of the anterior thoracic wall was distinctly improved, and breast strabism and breast tissue projection were eliminated. CONCLUSIONS: Pectus bar implantation appears to be an excellent method for the correction of breast malposition in female adults with a funnel chest deformity. Although invasive, it allows permanent remodeling of the anterior thoracic wall and the decollete, and a repositioning of the female breast to achieve a natural appearance. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 22495209 TI - A position paper in support of face transplantation in the blind. AB - Facially disfigured blind patients have historically been considered for face transplantation with skepticism. Although no formal position paper regarding their exclusion has been published to date, functional, social, rehabilitative, and ethical concerns related to blind patients' candidacy for face transplantation may be inferred. The authors provide a summary of these reservations and a counterargument to their assumptions, drawing on outcomes measures reported for face transplant procedures performed to date, and their own institutional experience in performing face transplants on blind patients. The authors therefore provide a rationale for the inclusion of facially disfigured blind patients in face transplantation protocols in the future. PMID- 22495210 TI - Endogenous stem cell therapy enhances fat graft survival. AB - BACKGROUND: Lipoaspirate centrifugation creates graded density of adipose tissue. High-density fat contains more vasculogenic cytokines and progenitor cells and has greater graft survival than low-density fat. The authors hypothesize that accelerating the bone marrow-derived progenitor cell response to injected low density fat will improve its graft survival. METHODS: Male 8-week-old FVB mice (n=60) were grafted with either high-density (n=20) or low-density (n=40) human lipoaspirate. Half of the mice receiving low-density fat (n=20) were treated with a stem cell mobilizer for 14 days. Grafted fat was harvested at 2 and 10 weeks for analysis. RESULTS: Low-density fat, low-density fat plus daily AMD3100, and high-density fat had 26+/-3.0, 61.2+/-7.5, and 49.6+/-3.5 percent graft survival, respectively, at 2 weeks (low-density fat versus low-density fat plus daily AMD3100 and low-density fat versus high-density fat, both p<0.01). Similar results were observed 10 weeks after grafting. Mice receiving low-density fat plus daily AMD3100 had significantly more vasculogenic progenitor cells per cubic centimeter of peripheral blood (p<0.01) and more new blood vessels (p<0.01). Both low-density fat plus daily AMD3100 and high-density fat contained more stromal derived factor-1alpha and vascular endothelial growth factor mRNA/protein. CONCLUSION: Endogenous progenitor cell mobilization enhances low-density fat neovascularization, increases vasculogenic cytokine expression, and improves graft survival to a level equal to that of high-density fat grafts. PMID- 22495211 TI - Overcoming the learning curve: a curriculum-based model for teaching zone II flexor tendon repairs. AB - BACKGROUND: Repairs of zone II flexor tendons have benefited in recent years from modifications involving suture technique and configuration. These advances, however, present new obstacles in resident training. A focused tutorial incorporating a practical, hands-on exercise and standardization of technique may offer an effective low-risk, low-cost strategy for overcoming these challenges. METHODS: Plastic surgery residents (n=14) were asked to perform their preferred zone II flexor tendon repair using a tabletop exercise before and after a focused tutorial. The tutorial reviewed primary literature and presented a standardized technique. Repairs were photographed, tested for load strength, and analyzed to determine effectiveness of this teaching approach. Participants were retested at 6 months to evaluate for persistence of findings. RESULTS: Posttutorial repairs required higher loads to generate a 2-mm gap (p<0.001) and ultimate breakage (p<0.001). Tendon purchase and resident confidence increased significantly. Subgroup analysis demonstrated significant improvements for both junior and senior residents. Retesting at 6 months revealed that gains were maintained over time. CONCLUSIONS: The authors created a practical educational model to teach zone II flexor tendon repair outside of the time- and error-sensitive confines of the operating room. Analysis of resident pretutorial repairs revealed common misconceptions in suture technique, strand count, and purchase. This may in part be attributable to the multitude of suggested repair techniques, difficulty in comparing data across multiple studies, and steep learning curve. Training programs can use this hands-on teaching exercise as part of a hand surgery simulation curriculum. PMID- 22495212 TI - A 10-year review of frontal sinus fractures: clinical outcomes of conservative management of posterior table fractures. AB - BACKGROUND: Frontal sinus cranialization is commonly indicated for posterior table fractures with significant comminution, displacement, or cerebrospinal fluid leaks. This study assessed the clinical outcomes of conservative management. METHODS: A 10-year retrospective review of all frontal sinus fractures treated at a level 1 trauma center was performed using medical records and radiographic images. RESULTS: A total of 875 patients with frontal sinus fractures were identified, and 68 had posterior table involvement. Nine died within the first 48 hours from other injuries. The remaining 59 patients constituted the study population. Average follow-up approached 1 year (342 days). The more common mechanisms of injury were blunt interpersonal violence (29 percent) and motor vehicle accidents (27 percent). Concurrent central nervous system injury was common (73 percent), and the average Glasgow Coma Scale score was 12.7. Posterior wall fracture pattern was nondisplaced and noncomminuted in 33 patients (54 percent) and comminuted and/or displaced in 27 (46 percent). Cerebrospinal fluid leak was recorded in 11 patients (19 percent). Conservative management was the more common strategy (78 percent), followed by open reduction and internal fixation with sinus preservation (12 percent), obliteration (8 percent), and cranialization (2 percent). Of the 27 patients with comminuted and/or displaced fractures, 16 (59 percent) underwent conservative management, and 11 (41 percent) underwent surgical management, but only one patient (2 percent) underwent cranialization. There was no incidence of intracranial infection, except for one patient who died from encephalitis secondary to a gunshot wound to the head. CONCLUSION: The vast majority of frontal sinus fractures involving the posterior table, including those with comminution, displacement, or cerebrospinal fluid leaks, can be safely managed without cranialization. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 22495214 TI - The evolution of critical concepts in aesthetic craniofacial microsurgical reconstruction. AB - BACKGROUND: Over the last several decades, there have been numerous advances in the fields of aesthetic, craniofacial, and microsurgery. Aesthetic units are no longer "skin deep" but are recognized as being composed of both soft and hard tissue. Indeed, hard tissue must complement the soft tissue to recreate the unit. In addition, revisionary procedures have become necessary to achieve the desired result. Here, the authors integrate seven critical concepts and provide a patient series illustrating their success. METHODS: The authors assembled a two-center, retrospective cohort review of patients who underwent free-tissue transfer of craniofacial defects at the R Adams Cowley Shock Trauma Center and the Johns Hopkins Hospital from 2003 to 2011. Patients were categorized by anatomic location, complications recorded, and illustrative cases selected. RESULTS: A total of 184 patients with craniofacial defects were identified: 79 female and 105 male patients, with a mean age of 44 years. Etiologies included cancer (51.6 percent), trauma (39.1 percent), congenital defects (6.5 percent), and infection (2.7 percent). Free-tissue transfers included 67 fibula, 42 anterolateral thigh, 41 ulnar, 18 groin, 14 iliac, three radius, and one vastus lateralis flaps. The success rate was 97.3 percent and complication rate was 10.8 percent. Secondary procedures included suction lipectomy, dermabrasion, tissue resuspension, and cutaneous flap excision followed by full-thickness skin grafting or tissue rearrangement. CONCLUSIONS: To achieve aesthetically pleasing results in free flap facial reconstruction, the authors define seven critical concepts to guide the reconstruction: aesthetic-unit appearance, defect boundaries, tissue requirements, vascularized skeletal buttress framework, ample soft-tissue volume, early reconstruction, and local revisional procedures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 22495215 TI - Assessment of postoperative venous thromboembolism risk in plastic surgery patients using the 2005 and 2010 Caprini Risk score. AB - BACKGROUND: Venous thromboembolism is an important patient safety issue. The authors sought to compare the predictive capacity of the 2005 and 2010 Caprini Risk Assessment Models for perioperative venous thromboembolism risk. METHODS: The authors performed a retrospective, observational, crossover study using an established surgical outcomes database. A total of 3334 adult plastic surgery patients were identified. Patients were risk-stratified using both the 2005 and 2010 Caprini Risk Assessment Models. Each patient served as his or her own control, resulting in precise matching for identified and unidentified confounders. The outcome of interest was 60-day, symptomatic venous thromboembolism. The predictive capacities of the 2005 and 2010 Caprini risk scores were compared. RESULTS: Use of the 2010 Caprini Risk Assessment Model resulted in a systematic increase in the aggregate risk score. The median 2010 Caprini score was significantly higher than the median 2005 Caprini score (6 versus 5, p<0.001). When compared with the 2010 model, the 2005 Caprini Risk Assessment Model was able to better separate the lowest and highest risk patients from one another. Patients classified as "super-high" risk (Caprini score>8) using the 2005 Caprini Risk Assessment Model were significantly more likely to have a 60-day venous thromboembolism event when compared with patients classified as super-high risk using the 2010 guidelines (5.85 percent versus 2.52 percent, p=0.021). CONCLUSIONS: When compared with the 2010 Caprini Risk Assessment Model, the 2005 Caprini Risk Assessment Model provides superior risk stratification. The 2005 Caprini Risk Assessment Model is the more appropriate method to risk stratify plastic surgery patients for perioperative venous thromboembolism risk. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 22495216 TI - Late seromas after breast implants: theory and practice. AB - BACKGROUND: Late seromas surrounding breast implants are becoming an increasingly important issue in breast surgery. The authors report their experience with late seromas and describe their previous management options. METHODS: A multicenter retrospective review of patients who developed late seromas (clinically presenting seromas without evidence of overt or documented infection more than 1 year after implant operation) was performed. Management, surgical technique, outcomes, complications, culture findings, and cytology results were recorded. RESULTS: Between 2005 and 2010, 28 late seromas were identified in 25 patients. The average interval from the patient's last surgery to seroma onset was 4.7 years; 27 of 28 breasts (96 percent) had a Biocell textured device in place at the time of seroma development. The late seromas in the series were managed as follows: 15 (53.6 percent) by complete capsulectomy, seroma drainage, and new implant placement; three (10.7 percent) by seroma drainage and new implant placement but without capsulectomy; two (7.1 percent) by complete capsulectomy and seroma drainage but without implant replacement; five (17.9 percent) by only ultrasound-guided seroma drainage without the need for surgical intervention; and three (10.7 percent) by antibiotic therapy alone. All cultures and cytology studies were negative for malignancy or infection; 27 of 28 seromas (96 percent) were treated successfully by one of the described approaches. CONCLUSIONS: Biocell textured implants were more likely to be associated with late seromas than were smooth shell implants. The overwhelming majority of late seromas appear to be idiopathic, without clear evidence of infection or malignancy. A graduated approach, including several different management strategies, was used to successfully manage these patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 22495217 TI - Wet and dry techniques for structural fat graft harvesting: histomorphometric and cell viability assessments of lipoaspirated samples. AB - BACKGROUND: Autologous fat transplantation is among the surgical procedures performed most commonly by plastic surgeons for cosmetic and/or reconstructive purposes. In the procedure, autologous fat is harvested and infiltrated during the same operation, and the success of this procedure relies on harvesting and transferring viable adipocytes. This study was designed to assess the histomorphometric characteristics and viability of the lipoaspirated cells that were harvested through different techniques. METHODS: This study enrolled 65 patients undergoing lipofilling for reconstructive purposes. Subcutaneous fat samples were collected manually through the wet and dry techniques using a two hole Coleman blunt cannula attached to a 10-cc Luer-Lok syringe. Fat tissue preservation was assessed through conventional histomorphometry and a cell viability assessment, evaluating the mitochondrial function through the MTS CellTiter 96 Aqueous One Solution Assay (Promega Corp., Madison, Wis.). RESULTS: No differences were observed between adipocyte samples harvested with or without tumescent solution. The morphometric analysis and adipocyte viability assessment confirmed the visual findings: the mean surface area and shape (circularity index) of the adipocytes were not significantly different in the lipoaspirate collected through the different techniques. CONCLUSION: The results from the present study provide the first histologic evidence and cell viability assessment to demonstrate that there are no substantial differences in the adipose tissue specimens harvested with the wet and dry techniques. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 22495218 TI - Hydroxylation mechanism of methane and its derivatives over designed methane monooxygenase model with peroxo dizinc core. AB - The peroxo dizinc Zn(2)O(2) complex Q coordinated by imidazole and carboxylate groups for each Zn center has been designed to model the hydroxylase component of methane monooxygenase (MMO) enzyme, on the basis of the experimentally available structure information of enzyme with divalent zinc ion and the MMO with Fe(2)O(2) core. The reaction mechanism for the hydroxylation of methane and its derivatives catalyzed by Q has been investigated at the B3LYP*/cc-pVTZ, Lanl2tz level in protein solution environment. These hydroxylation reactions proceed via a radical rebound mechanism, with the rate-determining step of the C-H bond cleavage. This radical-rebound reaction mechanism is analogous to the experimentally available MMOs with diamond Fe(2)O(2) core accompanied by a coordinate number of six for the hydroxylation of methane. The rate constants for the hydroxylation of substrates catalyzed by Q increase along CH(4) < CH(3)F < CH(3)CN ~ CH(3)NO(2) < CH(3)CH(3). Both the activation strain DeltaE(?)(strain) and the stabilizing interaction DeltaE(?)(int) jointly affect the activation energy DeltaE(?). For the C-H cleavage of substrate CH(3)X, with the decrease of steric shielding for the substituted CH(3)X (X = F > H > CH(3) > NO(2) > CN) attacking the O center in Q, the activation strain DeltaE(?)(strain) decreases, whereas the stabilizing interaction DeltaE(?)(int) increases. It is predicted that the MMO with peroxo dizinc Zn(2)O(2) core should be a promising catalyst for the hydroxylation of methane and its derivatives. PMID- 22495219 TI - Experimental and DFT theoretical studies of surface enhanced Raman scattering effect on the silver nano arrays modified electrode. AB - Well-ordered silver nano arrays, prepared using anodic aluminum oxide (AAO) template by laser molecular beam epitaxy (L-MBE) method, were adhered to the work electrode using conductive adhesive to be a Surface-enhanced Raman scattering (SERS) substrate. Variable SERS signals of paranitrobenzoic acid (PNA) on the electrode modified with silver nano arrays were recorded with electric potential ranging from 0.1 to -0.5 V. The SERS spectra of PNA using DFT-B3PW91 with lanl2dz based on two models were calculated. It indicate that the adsorption orientation of probe molecules on the silver nano arrays with potential change of the electrode. PMID- 22495220 TI - Electronic spectrum of 17 electronic states of BN molecule: a theoretical study. AB - The potential energy curves (PECs) of the X(3)Pi, a(1)Sigma(+), b(1)Pi, A(3)Sigma(+), B(3)Sigma(-), c(1)Delta, D(3)Pi, 1(5)Pi, 3(1)Sigma(+), 3(3)Pi, 2(1)Pi, 2(3)Sigma(+), 1(3)Delta, 1(5)Sigma(+), 4(3)Pi, 2(3)Sigma(-) and 1(5)Sigma(-) electronic states of the BN molecule are calculated using an ab initio quantum chemical method. The PEC calculations have been made for internuclear separations from 0.06 to 1.20 nm using the complete active space self-consistent field (CASSCF) method, which is followed by the valence internally contracted multireference configuration interaction (MRCI) approach in combination with a correlation-consistent aug-cc-pV5Z basis set. To improve the quality of PECs, core-valence correlation and relativistic corrections are included. Relativistic correction calculations are carried out using the third order Douglas-Kroll Hamiltonian (DKH3) approximation. Core-valence correlation corrections are included using a cc-pCVQZ basis set. Relativistic corrections are calculated at the level of a cc-pVQZ basis set. To obtain more reliable results, the PECs determined by the MRCI calculations are corrected for size-extensivity errors by means of the Davidson modification (MRCI+Q). These PECs are extrapolated to the complete basis set limit by the total-energy extrapolation scheme. The spectroscopic parameters are determined by fitting the vibrational levels, which are calculated in a direct forward manner from the analytic potential by solving the ro-vibrational Schrodinger equation using Numerov's method. The spectroscopic results have been compared in detail with those reported in the literature. Excellent agreement has been found between the present spectroscopic results and the experimental ones. Using the Breit-Pauli operator, the spin-orbit coupling effect on the spectroscopic parameters is included in the X(3)Pi and D(3)Pi electronic states. The vibrational level, inertial rotation and centrifugal distortion constants are calculated for each vibrational state of each electronic state. And those of the first 20 vibrational states of each electronic state are reported when the rotational quantum number equals zero. Comparison with the measurements shows that the present results are accurate. The spectroscopic parameters of the c(1)Delta, 1(5)Pi, 3(1)Sigma(+), 3(3)Pi, 2(1)Pi, 2(3)Sigma(+), 1(3)Delta, 1(5)Sigma(+), 4(3)Pi and 1(5)Sigma(-) electronic states and the vibrational manifolds of all the electronic states obtained here are expected to be reliable predicted results. PMID- 22495221 TI - Synthesis and photophysical properties of metallophthalocyanines substituted with a benzofuran based fluoroprobe. AB - The synthesis, characterization and photophysical properties of the tetra- {6-( benzofuran-2-carboxylate)-hexylthio} substituted copper(II), cobalt(II), manganese(III) and zinc (II) phthalocyanines, {M[Pc(beta-S(CH(2))(6)OCOBz Furan)(4)], which were derived from 6-(3,4-dicyanophenylthio)-hexyl-2 benzofuranate (BzF) (1-4) are reported for the first time. The new compounds have been synthesized and fully characterized by elemental analysis, FTIR, UV-vis, (1)H- and (13)C NMR, MS (Maldi-TOF). In this work, we also report the effects of peripherally bound BzF substituent on the photophysical properties of metallo phthalocyanine derivatives. The effects of changing the central metal ions on quantum yield are discussed. It was found that the substitution of BzF groups on the framework of phthalocyanines diminished the fluorescence quantum yield of these complexes depending on paramagnetic behavior of central metal atoms. In addition, central metal atoms like Co and Cu also caused to decrease in quantum yield of phthalocyanine backbone. PMID- 22495222 TI - Decomposition of methylamine on nitrogen atom modified Mo(100): a density functional theory study. AB - Three possible pathways for C-N bond breaking in methylamine have been investigated over clean Mo(100) and nitrogen atom-modified Mo(100) surfaces with a nitrogen coverage of 0.25 monolayer (ML) (N-Mo(100)) firstly, and the C-N bond breaking following the intramolecular hydrogen transfer from the CH3 to NH2 is excluded owing to the high barriers. Then methylamine decomposition starting with C-H, N-H, and C-N scission over the nitrogen atom-modified Mo(100) surface with a nitrogen coverage of 0.5 ML (2N-Mo(100)) has been systematically investigated, and the decomposition network has been mapped out. The thermochemistry and energy barriers for all the elementary steps, starting with C-H, N-H, and C-N scission, and sequential reactions from the resulting intermediates, are presented here. The most likely decomposition path is H3CNH2-> H2CNH2 + H -> HCNH2 + H + H -> CNH2 + H + H + H -> C + NH2 + H + H + H -> C + NH3 + H2-> C + NH3(g) + H2(g). For the decomposition reactions involved in the likely decomposition path, there is a linear relationship between the energy of transition state and the energy of final state. For the reverse processes of the dehydrogenation of CH, NH, NH2, it is found that there is a linear relationship between the barrier and the valency of A (A[double bond, length as m-dash]C, N, and NH). PMID- 22495224 TI - Diastolic dysfunction following HIV infection. PMID- 22495223 TI - Selective transmigration of monocyte-associated HIV-1 across a human cervical monolayer and its modulation by seminal plasma. AB - OBJECTIVE: To analyse the transmigration of immune cells infected by HIV-1 across the epithelial monolayer using the endometrial human endometrial carcinoma (HEC) 1A cell line and to study the influence of seminal plasma in this process. DESIGN: After sexual intercourse involving a male partner infected by HIV-1, a selection process has been shown to lead to a predominant transmission of the R5 phenotype despite the presence of X4 and R5 strains in semen. Transmigration of HIV-infected monocytes present in semen may represent a pertinent mechanism that could explain this tropism selection. METHODS: Epithelial monolayer crossing was studied by using HEC-1A epithelial cells cultured on permeable support and monocyte-enriched or lymphocyte-enriched populations of cells infected or not by HIV R5 or X4 strains. Transmigrating cells were quantified and analysed for their ability to transmit HIV infection to immune target cells. The effect of HIV negative seminal plasma on cell transmigration was analysed. RESULTS: A preferential passage of the R5 strain associated with monocyte-enriched populations was observed together with the ability of this strain to transmit infection. Seminal plasma was found able to decrease the epithelial crossing of immune cells by enhancing transepithelial resistance and by increasing the adherence of immune cells to the monolayer. CONCLUSION: The preferential transmigration of HIV R5 strains associated with monocytes across the endocervical monolayer may explain the predominant transmission of the R5 strains after sexual intercourse. By its capacity to modulate the tightness of the epithelial structure, seminal plasma reinforces this selection process. PMID- 22495225 TI - Cerebral abscess caused by Rhizobium radiobacter: first case report. PMID- 22495226 TI - Antibodies cross-reactive to influenza A (H3N2) variant virus and impact of 2010 11 seasonal influenza vaccine on cross-reactive antibodies - United States. AB - Since August 2011, a total of 12 human infections with influenza A (H3N2) variant viruses with genes from avian, swine, and human viruses (i.e., A [H3N2]v) that had acquired the M gene from influenza A (H1N1)pdm09 virus have been reported to CDC. Eleven of the cases occurred in children aged <10 years. In six cases, no history of recent exposure to swine was noted, suggesting that human-to-human transmission had occurred. This new gene constellation for A (H3N2)v viruses and its temporal association with an increase in human cases of A (H3N2)v highlight the need to better understand the risk for human infection with these viruses and the extent to which current seasonal vaccines might elicit cross-reactive antibodies to them. CDC conducted a preliminary analysis to evaluate the age specific presence of serum cross-reactive antibody in U.S. populations vaccinated or not vaccinated with the 2010-11 seasonal trivalent influenza vaccine (TIV). The results indicated that 1) little or no cross-reactive antibody to A (H3N2)v exists among children aged <10 years, 2) immunization with the 2010-11 TIV had no impact on cross-reactive antibody levels in those aged <3 years, 3) cross reactive antibody was detected in 20%-30% of those aged >=10 years, and 4) among adults, vaccination with TIV provided a modest boost to the level of cross reactive A (H3N2)v antibodies. Receipt of seasonal influenza vaccine continues to be recommended to protect against circulating human influenza viruses for all age groups and might provide limited protection against A (H3N2)v infection in the adult population. A vaccine virus specific for A (H3N2)v has been developed and could be used to produce an H3N2v vaccine, if needed. PMID- 22495227 TI - Rabies risk assessment of exposures to a bat on a commercial airliner - United States, August 2011. AB - On August 5, 2011, a bat flew through the cabin of a commercial airliner minutes after takeoff during an early morning flight from Wisconsin to Georgia, potentially exposing the passengers and flight crew to rabies virus. Three days later, the Wisconsin Division of Public Health (WDPH) requested assistance from CDC to conduct a rabies risk assessment for the passengers, flight crew, and ground crew members associated with the flight. No one was determined to have been exposed to rabies virus based on Advisory Committee on Immunization Practices guidelines for rabies prevention. An environmental assessment of the Wisconsin airport found a rigorous animal control and incident documentation program and no evidence of bat infestation. Although none of the persons assessed required postexposure rabies prophylaxis in this incident, bats active in daylight or found in areas where they are not normally found (e.g., aboard an aircraft) can pose risks for rabies transmission, and public health officials should be prepared to respond to such occurrences. PMID- 22495228 TI - Human Orf virus infection from household exposures - United States, 2009-2011. AB - Orf, also known as contagious ecthyma, is a zoonotic infection caused by a dermatotropic parapoxvirus that commonly infects sheep and goats; it is transmitted to humans through contact with an infected animal or fomites. In humans, orf manifests as an ulcerative skin lesion sometimes resembling bacterial infection or neoplasm. Human infection typically is associated with occupational animal contact and has been reported in children after visiting petting zoos and livestock fairs. Cases lacking these exposure histories might be misdiagnosed, leading to unnecessary treatment of orf lesions, which do not usually require any specific treatment. This report describes four cases of human orf associated with household meat processing or animal slaughter, highlighting the importance of nontraditional risk factors. Orf should be included in the differential diagnosis of patients with clinically compatible skin lesions and a history of household meat processing or animal slaughter. Persons and communities with these exposure risks also should receive counseling regarding the use of nonpermeable gloves and hand hygiene to prevent infection. PMID- 22495229 TI - HMGB1 in vascular diseases: Its role in vascular inflammation and atherosclerosis. AB - The nuclear protein high mobility group box 1 (HMGB1) has been suggested to be involved in the pathogenesis of several vascular diseases such as systemic vasculitis and atherosclerosis. In systemic vasculitides including ANCA associated vasculitis and Kawasaki disease, serum HMGB1 levels are higher in patients with active disease compared to healthy controls. In atherosclerotic disease, HMGB1 displays increased expression in nuclei and cytoplasm of macrophages and smooth muscle cells in the atherosclerotic lesions, and is implicated in the progression of the atherosclerotic plaque. Experimental models of acute coronary syndromes and cerebrovascular accidents show that HMGB1 is not only involved in the amplification of the inflammatory response during acute ischemic injury, but also in the recovery and remodeling process after ischemia. Patients with acute coronary syndromes or stroke present significantly higher serum levels of HMGB1 than healthy controls and levels are associated with disease severity and mortality. Here we review clinical and experimental studies dealing with the role of HMGB1 in vascular diseases. PMID- 22495230 TI - Hybrids of amino acids and acetylenic DNA-photocleavers: optimising efficiency and selectivity for cancer phototherapy. AB - Hybrid agents which combine potent DNA-photocleavers with tunable amino acids or small peptides were designed to improve selectivity of Nature's most potent class of antibiotics towards cancer cells. The ability of these compounds to photocleave DNA is controlled by their incorporation into hybrid architectures with functional elements derived from natural amino acids. These conjugates are highly effective at inducing double-strand DNA cleavage and, in some cases, rival or even surpass both naturally occurring DNA cleavers and anticancer agents that are currently in clinical use. The possibility of triggering their activity in a photochemical and pH-sensitive fashion allows for a high degree of selectivity over activation. The conjugates were shown to penetrate cell membranes and induce efficient intracellular DNA cleavage. Initial in vitro tests against a variety of cancer cell lines confirm the potential of these compounds as anticancer agents at low nanomolar concentrations. PMID- 22495231 TI - Morning surge, pulse wave velocity, and autonomic function tests in elderly adults. AB - OBJECTIVE: To assess the complex interplay between morning surge (MS), the autonomic reflex response at the cardiovascular level, and target organ damage (arterial stiffening, left ventricle hypertrophy). METHODS: Fifty-nine consecutive elder patients (>65 years old) underwent a 24-h ambulatory blood pressure monitoring. Pulse wave velocity (PWV) was measured as an indicator of arterial stiffness. Autonomic status was assessed by scoring five conventional tests [handgrip, orthostatic pressor response, Valsalva maneuver, heart rate variation during deep breathing ('I:E'), and immediate heart rate response to standing ('30 : 15')]. RESULTS: (a) MS was correlated to left ventricle mass (P<0.005), the orthostatic pressor response (P<0.02), and blood pressure variability (BPVar) (P<0.0001) (n=59). (b) PWV explained 61.4% of MS variation for MS values 40 mmHg or less (84% of patients) (P<0.03, n=49) and 38% of MS variation in nondippers (P<0.04, n=25). (c) There were sex-related differences. PWV was associated with the orthostatic pressor response (P<0.02), 'I:E' values (P<0.04) and the '30 : 15' test (P<0.04) in men (n=14). In women (n=41), the 'I:E' values were associated with MS and BPVar (P<0.003). CONCLUSION: MS was closely related to PWV (arterial stiffening) and BPVar in a small urban sample of cardiovascular patients. MS was also associated with dysautonomia (orthostatic blood pressure/heart rate response to challenges), mostly with impaired parasympathetic modulation. MS and high BPVar cause left ventricular hypertrophy, whereas arterial stiffness alters baroreceptor sensitivity, which in turn affects BPVar, perpetuating a vicious cycle. These findings, although obtained in a small number of participants, provide relevant information not yet available in the local databases. PMID- 22495232 TI - Chronic wasting disease and atypical forms of bovine spongiform encephalopathy and scrapie are not transmissible to mice expressing wild-type levels of human prion protein. AB - The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several novel TSEs in sheep, cattle and deer have been described and the risk posed to humans by these agents is currently unknown. In this study, we inoculated two forms of atypical BSE (BASE and H-type BSE), a chronic wasting disease (CWD) isolate and seven isolates of atypical scrapie into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP). Upon challenge with these ruminant TSEs, gene-targeted Tg mice expressing human PrP did not show any signs of disease pathology. These data strongly suggest the presence of a substantial transmission barrier between these recently identified ruminant TSEs and humans. PMID- 22495233 TI - Identification and characterization of bocaviruses in cats and dogs reveals a novel feline bocavirus and a novel genetic group of canine bocavirus. AB - We report the identification and genome characterization of a novel bocavirus, feline bocavirus (FBoV), and novel bocaviruses closely related to canine bocavirus (CBoV) strain Con-161 in stray cats and dogs in Hong Kong, respectively. FBoV was detected by PCR in 7.2, 0.3, 1.6, 2.0 and 0.8% of faecal, nasal, urine, kidney and blood samples, respectively, from 364 cats, while CBoV was detected in 4.6, 5.1, 6.3 and 0.3% of faecal, nasal, urine and blood samples, respectively, from 351 dogs. Three FBoV genomes sequenced revealed the presence of three ORFs characteristic of bocaviruses. Phylogenetic analysis showed that FBoVs were related only distantly to other bocaviruses, forming a distinct cluster within the genus, with <= 5.7% nucleotide identities to the genome of minute virus of canines. The four CBoV genomes sequenced shared 87.4-89.2% nucleotide identities with that of CBoV strain Con-161. In addition to the three bocavirus ORFs, they encoded an additional ORF, ORF4, immediately downstream of the ORF for non-structural protein 1 (NS1), which was not found in other bocaviruses including CBoV strain Con-161. They also possessed a putative second exon encoding the C-terminal region of NS1 and conserved RNA-splicing signals, previously described in human bocaviruses. Partial VP1/VP2 sequence analysis of 23 FBoV and 25 CBoV strains demonstrated inter-host genetic diversity, with two potential genetic groups of FBoV and a novel CBoV group, CBoV-HK, distinct from the three groups, CBoV-A to -C, found in the USA. Although the pathogenicity of FBoV and CBoV remains to be determined, their presence in different host tissues suggested wide tissue tropism. PMID- 22495234 TI - Protective effect of the maternally derived porcine circovirus type 2 (PCV2) specific cellular immune response in piglets by dam vaccination against PCV2 challenge. AB - The objective of the present study was to evaluate (i) the passive transfer of maternally derived functional porcine circovirus type 2 (PCV2)-specific lymphocytes of seronegative sows immunized with the PCV2 vaccine to newborn piglets and (ii) the functional role of the maternally derived PCV2-specific cellular immune response in protecting newborn piglets from challenge with PCV2. After ingesting colostrums, piglets from vaccinated sows (PT01 and PT02) have significantly higher numbers of PCV2-specific gamma interferon-secreting cells, an increased PCV2-specific delayed type hypersensitivity response, and a stronger proliferative response of peripheral blood mononuclear cells compared with piglets from non-vaccinated seronegative sows (PT03 and PT04). In the PCV2 challenge study, the number of serum genomic PCV2 copies was significantly less in piglets from vaccinated sows (PT02) compared with piglets from non-vaccinated sows (PT04) at 7-28 days post-inoculation (P<0.05 and P<0.001). The histopathological lesions and immunohistochemical scores were significantly lower in piglets of vaccinated sows compared with those of non-vaccinated sows. To our knowledge, this is the first report of transferring a maternally derived PCV2 specific cellular immune response from vaccinated dams to their offspring. Maternally derived adaptive cellular immune responses play a critical role in protecting newborn piglets challenged with PCV2 at 3 weeks of age. PMID- 22495236 TI - Coronary artery stent mimicking intracardiac thrombus on cardiac magnetic resonance imaging due to signal loss: case report. AB - Since the introduction of percutaneous coronary intervention for coronary artery disease, thousands of patients have been treated with the implantation of coronary stents. Moreover, several of the patients with coronary stent undergo cardiac magnetic resonance (CMR) imaging every year. This case report is of a 77 year-old man who was previously treated with the implantation of a coronary stent in the left circumflex artery. He underwent CMR imaging, which revealed a process 14*21 mm in the left atrium. Cardiac contrast computed tomography did not demonstrate any cardiac pathology. While the signal loss on MRI associated with implanted metallic devices is known, we report a case where an implanted coronary stent in the left circumflex artery led to an intracardiac signal loss mimicking intracardiac thrombus/tumor. PMID- 22495235 TI - Development of a reverse-genetics system for murine norovirus 3: long-term persistence occurs in the caecum and colon. AB - Human noroviruses (HuNoV) are a major cause of viral gastroenteritis worldwide, yet, due to the inability to propagate HuNoV in cell culture, murine norovirus (MNV) is typically used as a surrogate to study norovirus biology. MNV-3 represents an attractive strain to study norovirus infections in vivo because it establishes persistence in wild-type mice, yet causes symptoms resembling gastroenteritis in immune-compromised STAT1(-/-) mice. The lack of reverse genetics approaches to recover genetically defined MNV-3 has limited further studies on the identification of viral sequences that contribute to persistence. Here we report the establishment of a combined DNA-based reverse-genetics and mouse-model system to study persistent MNV-3 infections in wild-type (C57BL/6) mice. Viral RNA and infectious virus were detected in faeces for at least 56 days after inoculation. Strikingly, the highest concentrations of viral RNA during persistence were detected in the caecum and colon, suggesting that viral persistence is maintained in these tissues. Possible adaptive changes arising during persistence in vivo appeared to accumulate in the minor capsid protein (VP2) and the viral polymerase (NS7), in contrast with adaptive mutations selected during cell-culture passages in RAW264.7 cells that appeared in the major capsid protein (VP1) and non-structural protein NS4. This system provides an attractive model that can be readily used to identify viral sequences that contribute to persistence in an immunocompetent host and to more acute infection in an immunocompromised host, providing new insights into the biology of norovirus infections. PMID- 22495237 TI - Transient and sustained components of the sensorimotor BOLD response in fMRI. AB - Blood oxygenation level-dependent (BOLD) signal time courses in functional magnetic resonance imaging are estimated within the framework of general linear modeling by convolving an input function, that represents neural activity, with a canonical hemodynamic response function (HRF). Here we investigate the performance of different neural input functions and latency-optimized HRFs for modeling BOLD signals in response to vibrotactile somatosensory stimuli of variable durations (0.5, 1, 4, 7 s) in 14 young, healthy adults who were required to make button press responses at each stimulus cessation. Informed by electrophysiology and the behavioral task, three nested models with an increasing number of parameters were considered: a boxcar; boxcar and offset transient; and onset transient, boxcar and offset transient (TBT). The TBT model provided the best fit of the group-averaged BOLD time courses based on chi(2) and F statistics. Only the TBT model was capable of fitting the bimodal shape of the BOLD response to the 7-s stimulus and the relative peak amplitudes for all stimulus lengths in key somatosensory and motor areas. This suggests that the TBT model provides a more comprehensive description of brain sensorimotor responses in this experiment than provided by the simple boxcar model. Work comparing the activation maps obtained with the TBT model with magnetoencephalography data is under way. PMID- 22495238 TI - Magnetic resonance differentiation between T2 and T1 gallbladder carcinoma: significance of subserosal enhancement on the delayed phase dynamic study. AB - PURPOSE: The aim of this study is to investigate whether subserosal enhancement on the delayed-phase dynamic magnetic resonance (MR) study (SED) can differentiate T2 from T1 gallbladder carcinoma (GBC). METHODS: The institutional research board approved this retrospective study. Between 1997 and 2006, there were surgically proven 11 T1 and 21 T2 GBC in 30 patients, all of whom had undergone preoperative contrast enhanced dynamic MR study, either with a 2D sequence (n=17) or 3D sequences (n=15). All images were reviewed by two radiologists for the presence of SED, and receiver operating characteristic (ROC) curve analysis was performed. Sensitivity, specificity, positive and negative predictive values were calculated by consensus. RESULTS: The areas under the ROC curves of the two readers were 0.91 and 0.86, and the kappa value was 0.78. Of the 21 T2 GBC, 18 and 3 showed positive and negative SED, respectively. Of the 11 T1 GBC, 1 and 10 showed positive and negative SED, respectively. The sensitivity, specificity, positive and negative predictive values of SED for diagnosing T2 lesions were 86%, 88%, 91% and 77%, respectively. CONCLUSIONS: In conclusion, SED may be a useful sign to differentiate T2 from T1 GBC, which would affect the preoperative surgical planning of the patients. PMID- 22495239 TI - Imaging features of small (<= 3 cm) pancreatic solid tumors on gadoxetic-acid enhanced MR imaging and diffusion-weighted imaging: an initial experience. AB - OBJECTIVE: The objective was to determine imaging features that distinguish small (<=3cm) solid pancreatic adenocarcinoma, neuroendocrine tumor (NET) and solid pseudopapillary tumor (SPT) on gadoxetic-acid-enhanced magnetic resonance imaging (MRI) and diffusion-weighed imaging (DWI). MATERIALS AND METHODS: Twenty-four adenocarcinomas, 10 NETs and 8 SPTs were retrospectively included. Two radiologists analyzed morphologic features, signal intensity of the tumors on MR images including DWI (b=800) and dynamic enhancement pattern with consensus. Tumor-to-parenchyma ratio and tumor apparent diffusion coefficients (ADCs) were quantitatively assessed. RESULTS: All adenocarcinomas had an ill-defined margin and irregular shape, and more frequently had pancreatic duct dilatation compared with other tumors (P<.05). All SPTs and all but one of the adenocarcinomas (95.8%) had no arterial enhancement with progressively increased enhancement, whereas seven NETs (70%) had arterial enhancement with progressively decreased enhancement (P<.01). The mean value of tumor-to-parenchyma ratio on arterial and portal phases was significantly higher for NETs, and the mean value of tumor ADCs was significantly lower for SPTs than for other tumors (P<.05). CONCLUSIONS: Gadoxetic-acid-enhanced MRI may aid in differentiation between small adenocarcinomas, NETs and SPTs based on morphologic features with dynamic enhancement pattern in adenocarcinomas, dynamic enhancement pattern with tumor-to parenchyma ration on arterial and portal phases in NETs, and dynamic enhancement pattern with lower ADC value in SPTs. PMID- 22495240 TI - Manifestation and post hoc correction of gradient cross-term artifacts in DTI. AB - Cross-terms between imaging and diffusion gradients, unaccounted for during tensor calculations, can lead to erroneous estimation of diffusivity and fractional anisotropy (FA) in regions of isotropic and anisotropic diffusion. Cross-term of magnitude 136.8+/-1.6 s/mm(2), artificially introduced in the slice encode direction, caused an increase in FA in isotropic phantom from 0.0546+/ 0.0001 to 0.0996+/-0.0001, while the change in chimpanzee brain depended on the orientation of the white matter (WM). Mean diffusivity (MD) remained unchanged in isotropic phantom, but increased by ~20% in the WM due to cross-terms. A bias was observed in the principal eigenvectors in both phantom and chimpanzee brain, resulting in significant increase in midline crossing fibers along the bias than perpendicular to it in tractography in chimpanzee brain. Post hoc correction of these artifacts was achieved by estimating the cross-term factors using calibration scans on an isotropic phantom and modifying the b-matrix before tensor calculation. Upon correction, the FA and MD values closely resembled the values obtained from sequence without cross-terms, and the bias in principal eigenvectors was eliminated. Customized sequences involving large b-values, high resolution imaging, or long diffusion or echo times should therefore be evaluated and any residual cross-terms corrected before implementation. PMID- 22495241 TI - Dynamic properties of water in silicalite-1 powder. AB - Self-diffusion of D(2)O in partially filled silicalite-1 crystals was studied at 25 degrees C by (2)H nuclear magnetic resonance (NMR) with bipolar field gradient pulses and longitudinal Eddy-current-delay. For the first time, reliable experimental diffusion data for this system were obtained. Analysis of NMR diffusion decays revealed the presence of a continuous distribution of apparent self-diffusion coefficients (SDCs) of water, ranging from 10(-7) to ~10(-10) m(2)/s, which include values much higher and lower than that of bulk water (~10( 9) m(2)/s) in liquid phase. The observed distribution of SDC changes with variation of the diffusion time in the range of 10-200 ms. A two-site Karger exchange model was successfully fitted to the data. Finally, the water distribution and exchange in silicalite-1 pores were described by taking into account (a) a gas-like phase in the zeolite pores, a gas-like phase in mesopores and an intercrystalline gas-like phase and (b) intercrystalline liquid droplets with intermediate exchange rate with the other phases. The other phases experience fast exchange on the NMR diffusion time scale. Diffusion coefficients and mean residence times of water in some of these states were estimated. PMID- 22495242 TI - Use of fat suppression in R2 relaxometry with MRI for the quantification of tissue iron overload in beta-thalassemic patients. AB - PURPOSE: To assess the performance and results of R(2) relaxometry using a fat suppressed (FS) multiecho sequence and compare these to conventional R(2) relaxometry in estimating tissue iron overload. MATERIALS AND METHODS: Relaxation rate values (R(2)=1/T2) of the liver, spleen, pancreas and vertebral bone marrow (VBM) were estimated in 21 patients with beta-thalassemia major, using a respiratory-triggered 16-echo Carr-Purcell-Meiboom-Gill (CPMG) spin-echo sequence before (R(2)) and after (R(2) FS) the application of chemically selective fat suppression. RESULTS: Hepatic and splenic R(2) FS values correlated with respective R(2) values (r=0.98 and r=0.96, P<.001), whereas correlations between R(2) FS and R(2) values for pancreas and VBM were not statistically significant. Bland-Altman plots show disagreement between R(2) and R(2) FS values, particularly for pancreas and VBM. Hepatic, pancreatic and VBM R(2) FS values correlated with serum ferritin (r=0.88, P<.001; r=0.51, P<.003; and r=0.75, P<.002, respectively). Hepatic R(2) FS values correlated with splenic R(2) FS (r=0.77, P<.03), pancreatic R(2) FS (r=0.61, P<.006) and VBM R(2) FS values (r=0.70, P<.001), whereas pancreatic R(2) FS values correlated also with VMB R(2) FS values. On the contrary, among the R(2) values of the above tissues, obtained without fat suppression, only hepatic R(2) values correlated with serum ferritin, whereas no correlation was documented between hepatic and pancreatic or VBM R(2) values. The application of fat suppression did not improve breathing or flow artifacts. CONCLUSION: Application of fat suppression in the standard CPMG sequence improved the capability of MRI in noninvasive quantification of iron, particularly in lipid-rich tissues, such as vertebral bone marrow (VBM) and pancreas. PMID- 22495243 TI - Effect of cerebrovascular changes on brain DTI quantitation: a hypercapnia study. AB - Quantitative diffusion tensor imaging (DTI) offers a valuable tool to probe the microstructural changes in neural tissues in vivo, where absolute quantitation accuracy and reproducibility are essential. It has been long recognized that measurement of apparent diffusion coefficient (ADC) using DTI could be influenced by the presence of water molecules in cerebrovasculature. However, little is known about to what extent such blood signal affects DTI quantitation. In this study, we quantitatively examined the effect of cerebral hemodynamic change on DTI indices by using a standard multislice echo planar imaging (EPI) spin echo (SE) DTI acquisition protocol and a rat model of hypercapnia. In response to 5% CO(2) challenge, mean, radial and axial diffusivities measured with diffusion factor (b-value) of b=1.0 ms/MUm(2) were found to increase in whole brain (1.52%+/-0.22%, 1.66%+/-0.16% and 1.35%+/-0.37%, respectively), gray matter (1.56%+/-0.23%, 1.63%+/-0.14% and 1.47%+/-0.45%, respectively) and white matter regions (1.45%+/-0.28%, 1.88%+/-0.33% and 1.10%+/-0.26%, respectively). Fractional anisotropy (FA) was found to decrease by 1.67%+/-0.38%, 1.91%+/-0.59% and 1.46%+/-0.30% in whole brain, gray matter and white matter regions, respectively. In addition, these diffusivity increases and FA decreases became more pronounced at a lower b-value (b=0.3 ms/MUm(2)). The results indicated that in vivo DTI quantitation in brain can be contaminated by vascular factors on the order of few percentages. Consequently, alterations in cerebrovasculature and hemodynamics can affect the DTI quantitation and its efficacy in characterizing the neural tissue microstructures in normal and diseased states. Caution should be taken in designing and interpreting quantitative DTI studies as all DTI indices can be potentially confounded by physiologic conditions and by cerebrovascular and hemodynamic characteristics. PMID- 22495244 TI - Single-incision laparoscopic splenectomy versus conventional multiport laparoscopic splenectomy: a retrospective comparison of outcomes. AB - BACKGROUND: The authors report their experience with single-incision laparoscopic splenectomy (SLS) and compare postoperative outcomes of conventional multiport laparoscopic splenectomy (MLS) with SLS in patients with spleen sizes <=15 cm. METHODS: Demographic, intraoperative, and postoperative data were analyzed retrospectively and compared between patients who underwent MLS from June 20, 2006, to July 9, 2009 (MLS group, 18 patients) and those who underwent SLS from July 28, 2009, to November 2, 2010 (SLS group, 16 patients). RESULTS: Blood loss was significantly greater in the SLS group than in the MLS group (206.25 +/- 142.45 vs 111.11 +/- 99.58 mL, respectively; P = .047). The Numeric Pain Rating Scale in the SLS group was significantly lower than in the MLS group (3.81 +/- 0.91 vs 4.56 +/- 1.29, respectively; P = .041). There were no significant differences between the groups for other variables. CONCLUSIONS: SLS is a feasible method with good cosmetic benefit and equivalent clinical outcomes as compared with MLS. PMID- 22495245 TI - Benefits and drawbacks of SILS cholecystectomy: a report of 60 SILS cholecystectomies with conventional instrumentation from an academic center. AB - BACKGROUND: Single-incision laparoscopic surgery is a rapidly emerging approach to gallbladder disease. METHODS: From February 2009 to September 2010, 60 patients were subjected to single-incision laparoscopic cholecystectomy. In all the patients, a 12-mm incision was made in the umbilicus and a 2-trocar technique was applied. Gallbladder was suspended with 2 sutures and the procedure was accomplished with standard partly reusable laparoscopic instruments. RESULTS: In all, 41 women (68.3%) and 19 men (31.7%) were enrolled in this study. Mean age was 50.7 years (range = 17-72 years), mean body mass index was 26.2 kg/m(2) (range = 18.3-37.7 kg/m(2)) and mean operative time was 52.6 minutes (range = 30 120 minutes). No mortality or morbidity was recorded and hospital stay was less than 24 hours. At follow-up visits, no complications were recorded and cosmesis was excellent. CONCLUSION: Single-incision laparoscopic cholecystectomy can be safely performed with conventional instrumentation with minimal cost. PMID- 22495246 TI - Oxygen reduction activity of Pd-Mn3O4 nanoparticles and performance enhancement by voltammetrically accelerated degradation. AB - Electrochemical properties of Pd-Mn3O4 nanoparticles toward oxygen reduction reaction (ORR) in acidic media were investigated. The catalysts were prepared by polyol reduction of Pd(acac)2 and thermal decomposition of Mn2(CO)10. Surface composition and structure of the particles vary depending on the injection temperature of Mn2(CO)10 and are closely related to the electrochemical properties. The presence of Mn3O4 promotes the performance towards ORR by facilitating oxygen transfer to the active sites of Pd. Through an accelerated degradation test (ADT), nanoparticles with a Pd-rich shell are obtained by dissolution of surface exposed Mn3O4 and at 0.57 V (vs. Ag/AgCl) this catalyst shows the highest activity towards ORR, 149% in mass activity and 142% in specific activity compared to that of Pd/C. PMID- 22495247 TI - No association of polymorphisms in human endogenous retrovirus K18 and CD48 with schizophrenia. AB - The human endogenous retrovirus HERV-K18 is located within intron 1 of CD48 on chromosome 1q and is still active in the human genome. Genetic variation in HERV K18 single-nucleotide polymorphisms (SNPs) has previously been associated with an increased risk of schizophrenia (SZ) and with type 2 diabetes (T2D) among individuals with SZ. Here, we present a replication study of association of two SNPs in HERV-K18 and 19 tagSNPs in CD48 with (a) SZ and (b) T2D in patients with SZ in two Danish samples (total number of cases=750 and controls=1214). No association was found with SZ or with T2D among individuals with SZ for any of the investigated SNPs. However, one HERV-K18 SNP showed a tendency toward an association with T2D in younger SZ patients, in agreement with previous findings, but due to a very low sample size, this result needs to be further investigated. PMID- 22495248 TI - Enantioselective synthesis of bio-relevant 3,5-diaryl pyrazolines. AB - The straightforward asymmetric construction of bio-relevant Delta(2)-pyrazolines having either N-(thio)amide or N-acetyl functional groups and flanked by aryl substituents such as phenol at C3 and C5 has been achieved through an enantioselective phase transfer organocatalytic addition of N-Boc hydrazine to chalcones followed by a transprotection sequence allowing N-Boc transformation into N-CXNHR (X = S, O) or N-Ac functional groups. This approach was applied to a straightforward elaboration of chiral monoamine oxidase inhibitor derivatives. PMID- 22495249 TI - Overtime work and blood pressure in normotensive Japanese male workers. AB - BACKGROUND: Epidemiological studies have observed conflicting patterns as to whether overtime work increases blood pressure (BP), probably as a consequence of methodological issues. METHODS: We conducted a prospective cohort study to investigate the relationship between overtime work hours and 1-year changes in BP in 1,235 normotensive Japanese male workers who carried out a variety of jobs in a manufacturing factory. Casual BP measurements were repeated at annual health examinations in 2004-2005, using an automatic manometer. An analysis of covariance that incorporated potential confounding factors including baseline age, body mass index (BMI), and lifestyle factors was used to calculate and compare the means of the 1-year change in systolic (SBP) and diastolic BP (DBP). The participants were grouped according to their average monthly overtime work hours obtained from timecard data between April and September 2004. RESULTS: The multivariate-adjusted mean for 1-year change in DBP in 611 male assembly-line workers was 1.5 mm Hg (95% confidence interval (CI) 0.8-2.2) for <40.0 h/month, 2.3 mm Hg (95% CI 1.3-3.2) for 40.0-79.9 h/month, and 5.3 mm Hg (95% CI 2.7-7.9) for >= 80.0 h/month (P for heterogeneity = 0.02). A broadly similar pattern was observed for SBP. In contrast, there was no significant difference in means 1 year change for both SBP and DBP in 315 clerks and 309 engineers/special technicians, grouped according to overtime work hours. CONCLUSIONS: Extensive overtime work was associated with increased BP in normotensive male assembly-line workers, but not in clerks and engineers/special technicians. PMID- 22495250 TI - Is location associated with high risk of hypertension? Shimane COHRE Study. AB - BACKGROUND: There is growing evidence that residential environment is associated with hypertension. Recently, interest has also turned toward examining the possible influence of remoteness on hypertension. The aim of this study is to explore the effect of remoteness, the shortest path between the subject location and the population center, on hypertension prevalence in a rural region in Japan. METHODS: We analyzed data from the Shimane COHRE Study conducted from 2006 to 2009 in rural mountainous regions of Japan. After excluding the missing data, we conducted a logistic regression analysis of the data for 1,348 individuals. Geographic information systems (GIS) were used in the network analysis. Network analysis determined the distance between subject's location and population center on road networks, and the distance was divided into tertiles: 0-26,685.8 m = close distance, 26,685.9 m-38,350.6 m = moderate distance, 38,350.7 m-68,070.1 m = far distance. RESULTS: According to self-reported hypertension, the odds ratios for hypertension (taking antihypertensive medication or under treatment for hypertension without medication) were 1.44 (95% confidence interval (CI): 1.04 1.99) and 1.78 (95% CI: 1.29-2.46) in moderate and far distances, respectively, after adjustment for potential confounders. The odds ratios no longer remained significant after considering the measurement of blood pressure (BP) to define hypertension (taking antihypertensive medication or under treatment for hypertension without medication or BP >= 140/90 mm Hg for systolic BP (SBP)/diastolic BP (DBP)). CONCLUSIONS: Our findings show that residential remoteness might be associated with a higher risk of hypertension in a rural region in Japan. PMID- 22495251 TI - Identification of montgomeryite mineral [Ca4MgAl4(PO4)6.(OH)4.12H2O] found in the Jenolan Caves-Australia. AB - In this paper, we report on many phosphate containing natural minerals found in the Jenolan Caves - Australia. Such minerals are formed by the reaction of bat guano and clays from the caves. Among these cave minerals is the montgomeryite mineral [Ca(4)MgAl(4)(PO(4))(6).(OH)(4).12H(2)O]. The presence of montgomeryite in deposits of the Jenolan Caves - Australia has been identified by X-ray diffraction (XRD). Raman spectroscopy complimented with infrared spectroscopy has been used to characterise the crystal structure of montgomeryite. The Raman spectrum of a standard montgomeryite mineral is identical to that of the Jenolan Caves sample. Bands are assigned to H(2)PO(4)(-), OH and NH stretching vibrations. By using a combination of XRD and Raman spectroscopy, the existence of montgomeryite in the Jenolan Caves - Australia has been proven. A mechanism for the formation of montgomeryite is proposed. PMID- 22495252 TI - Portable Biomarker Detection with Magnetic Nanotags. AB - This paper presents a hand-held, portable biosensor platform for quantitative biomarker measurement. By combining magnetic nanoparticle (MNP) tags with giant magnetoresistive (GMR) spin-valve sensors, the hand-held platform achieves highly sensitive (picomolar) and specific biomarker detection in less than 20 minutes. The rapid analysis and potential low cost make this technology ideal for point-of care (POC) diagnostics. Furthermore, this platform is able to detect multiple biomarkers simultaneously in a single assay, creating a promising diagnostic tool for a vast number of applications. PMID- 22495253 TI - Neighborhood deprivation and mortality in individuals with cancer: a multilevel analysis from Sweden. AB - Little information is available on the effect of neighborhood deprivation on mortality in individuals with cancer. The aim of this study was to investigate the effect of level of neighborhood deprivation on mortality after a wide range of cancer diagnoses. This 1990-2004 follow-up study included all individuals in Sweden aged 25-74 years and used multilevel logistic regression with individual level variables at the first level and the level of neighborhood deprivation at the second level. There was a relationship between the level of neighborhood deprivation and mortality for both men and women with cancer. The model accounted for age and socioeconomic factors. For individuals with cancer, the overall risk of mortality was 24% higher for men and 20% higher for women living in the most deprived neighborhoods than in those living in the least deprived neighborhoods. In men and women with kidney, urinary bladder, and endocrine gland cancers, squamous cell carcinoma of the skin, and non-Hodgkin's lymphoma, mortality differed according to the level of neighborhood deprivation. In men with cancer of the prostate, testes, upper aerodigestive tract, colon, rectum, and lung, mortality differed according to the level of neighborhood deprivation. Mortality differences were also found in women with cancer of the breast, cervix, endometrium, and small intestine, and leukemia. In conclusion, neighborhood deprivation predicts the risk of mortality among adults with certain cancers. PMID- 22495254 TI - Prediagnosis lifestyle exposures and survival of patients with gastric cancer: systematic review and meta-analysis. AB - The relation between lifestyles and gastric cancer has been investigated thoroughly; however few studies have addressed the impact of these exposures on prognosis. Therefore, we quantified the association between prediagnosis smoking, alcohol intake and other dietary exposures and the survival of gastric cancer patients through a systematic review and meta-analysis. We searched Pubmed and EMBASE up to April 2011 and computed summary hazard ratio estimates and respective 95% confidence intervals (95% CIs) through a random-effects meta analysis (DerSimonian and Laird). Heterogeneity was quantified using the I2 statistic. Seven articles, providing data from 6856 cases evaluated in seven countries (Canada, Japan, Italy, USA, Korea, Iran and Sweden), were eligible for meta-analysis. The summary hazard ratio was 1.08 (95% CI: 0.90-1.30) for smoking (current vs. never smokers, seven studies; I2=56.2%) and 1.13 (95% CI: 1.00-1.28) for alcohol consumption (drinkers vs. nondrinkers, five studies; I2=13.2%). Only two studies assessed the effect of other dietary factors. This study summarizes the best evidence available on the relation between prediagnosis lifestyles and the survival of gastric cancer patients. Alcohol drinkers have lower survival, but results on the effect of smoking lack consistency and there is almost no information on the effects of dietary factors. PMID- 22495255 TI - Review of epidemiologic studies of dietary acrylamide intake and the risk of cancer. AB - Conjectured associations between dietary acrylamide intake and cancer have been evaluated in more than 15 epidemiologic studies examining almost every major cancer site. We have critically reviewed the epidemiologic studies of estimated dietary acrylamide exposure and cancer. As substantially greater acrylamide exposure occurs through tobacco smoke than dietary exposure, we present the results separately for never smokers or adjusted statistically for smoking status, where possible. After an extensive examination of the published literature, we found no consistent or credible evidence that dietary acrylamide increases the risk of any type of cancer in humans, either overall or among nonsmokers. In particular, the collective evidence suggests that a high level of dietary acrylamide intake is not a risk factor for breast, endometrial, or ovarian cancers, which have generated particular interest because of a conjectured hormonal mechanism of acrylamide. Moreover, the absence of a positive association between smoking and ovarian and endometrial cancers suggests that any association of these cancers with the much lower, more sporadic dietary acrylamide intake is unlikely. In conclusion, epidemiologic studies of dietary acrylamide intake have failed to demonstrate an increased risk of cancer. In fact, the sporadically and slightly increased and decreased risk ratios reported in more than two dozen papers examined in this review strongly suggest the pattern one would expect to find for a true null association over the course of a series of trials. Therefore, continued epidemiologic investigation of acrylamide and cancer risk appears to be a misguided research priority. PMID- 22495256 TI - Serum myeloperoxidase is independent of the risk factors of atherosclerosis. AB - OBJECTIVES: The main hypothesis of the study was that as serum myeloperoxidase (MPO) concentration is known to indicate the progression of the atherosclerotic process, MPO may be associated with common risk factors of atherosclerosis. Therefore, the presence of these risk factors (especially elevated glucose and lipid concentrations) should predict an increased MPO level during the subsequent months. We also hypothesized an association of MPO with markers of other chronic diseases involving inflammation. METHODS: Fifty-three patients with ischemic heart disease were followed for 24 weeks by biweekly visits, during which the basic MPO level was measured (500 measurements in total, 2-12 per patient). The association of the patients' typical MPO with the risk factors of atherosclerosis and other personal determinants was examined by trend analysis and analysis of variance. RESULTS: MPO was statistically significantly associated with blood leukocyte, neutrophil, and lymphocyte concentrations of the patients (P=0.001 0.003). MPO was also associated with high-sensitivity C-reactive protein (P=0.02). MPO was not associated with markers of lipid and glucose metabolism, of atherosclerosis, or of other chronic diseases. CONCLUSION: Contradictory to our hypotheses, the results indicate that the serum MPO level is independent of the commonly measured risk factors of atherosclerosis and markers of other chronic diseases. Consequently, the findings suggest that MPO-related acute pathologic events (such as plaque destabilization) are not associated with the preceding glucose or lipid values. However, the results support the third hypothesis and previously reported view that MPO is a marker of inflammation in patients of ischemic heart disease. PMID- 22495257 TI - In situ identification of the adsorption of 4,4'-thiobisbenzenethiol on silver nanoparticles surface: a combined investigation of surface-enhanced Raman scattering and density functional theory study. AB - We investigated the configuration characteristic and adsorption behavior of 4,4' thiobisbenzenethiol (TBBT) on the surface of silver nanoparticles (NPs). Under different conditions and preparation processes, several possible surface species were produced including single-end adsorption on a silicon wafer, double-end adsorption and bridge-like adsorption. Although consisting of the same molecule and nano material, different adsorption systems exhibited different spectral characteristics in the surface-enhanced Raman spectroscopy (SERS). A density functional theory (DFT) study further verified the corresponding adsorption states. The combined SERS-DFT study provided a framework towards investigating and designing adsorption systems at a molecular level, indicating the potential use in applications such as nano-sensors. PMID- 22495259 TI - The vascular endothelial growth factor family in adverse pregnancy outcomes. AB - BACKGROUND: Pre-eclampsia, small-for-gestational-age infants, preterm birth and recurrent miscarriage complicate a significant number of pregnancies. The vascular endothelial growth factor (VEGF) family of angiogenic growth factors is implicated in the pathophysiology of these complications. We aimed to elucidate the role of these angiogenic factors in placentation and to evaluate the predictive value of their protein concentrations and genetic variations in pregnancy complications. METHODS: We performed a systematic search of PubMed, and retrieved original articles. The search included a combination of terms such as VEGF-A, placental growth factor (PlGF), kinase insert domain receptor, fms-like tyrosine-kinase receptor 1, soluble fms-like-tyrosine-kinase receptor 1, pre eclampsia, small-for-gestational-age infants, preterm birth, recurrent miscarriage, placenta, prediction and polymorphisms. RESULTS: This review summarizes the current knowledge of the roles of the VEGF family in early placentation and of the abnormalities in maternal plasma and placental expression of angiogenic proteins in adverse pregnancy outcomes compared with normal pregnancy. PlGF and sFLT-1 in combination with other clinical and biochemical markers in late first or second trimester appear to predict early-onset pre eclampsia with a high sensitivity and specificity. However, VEGF family proteins do not have sufficient power to accurately predict late-onset pre-eclampsia, small-for-gestational age pregnancies or preterm birth. Functional polymorphisms in these angiogenic genes are implicated in pregnancy complications, but their contribution appears to be minor. CONCLUSIONS: Although the VEGF family has important roles in normal and complicated pregnancy, the current predictive value of the VEGF family as biomarkers appears to be limited to early-onset pre eclampsia. PMID- 22495260 TI - Intrarater reliability of assessing strength of the shoulder and scapular muscles. AB - CONTEXT: Handheld dynamometry (HHD) is considered an objective method of measuring strength, but the reliability of the procedure can be compromised by inadequate tester strength and insufficient stabilization of the dynamometer especially, for the scapular muscles. OBJECTIVE: Primarily, to determine the intrarater reliability of HHD when testing shoulder and scapular muscle strength, and secondarily, to report reliability when corrected for body-mass index (BMI). DESIGN: Technical report. SETTING: University physiotherapy department. PARTICIPANTS: 57 adults (17 men, 40 women; mean age = 35.05 +/- 13.5 y), both healthy individuals and patients with shoulder impingement. INTERVENTION: HHD. MAIN OUTCOME VARIABLES: Muscle strength of the upper, middle, and lower trapezius; anterior deltoid; serratus anterior; supraspinatus; and latissimus dorsi determined by HHD. Each muscle was assessed 3 times, and the mean value was calculated. The subjects were divided into 3 groups according to BMI. Group 1: BMI <= 20 kg/m(2) (n = 22); Group 2: BMI <= 24.9 kg/m(2) (n = 54); and Group 3: BMI <= 29.9 kg/m(2) (n = 38). RESULTS: Correlations were calculated for each pair of strength scores. Intraclass correlation coefficients (ICCs) ranged from .77 to .99 in healthy subjects and from .75 to .99 in patients, for all muscle groups except the upper trapezius (P < .05). Reliability values ranged from good to high in healthy subjects but were less consistent for the upper trapezius (ICC .45 .65). The relationship with BMI and muscle strength illustrates that as BMI increases, there is a decrease in reliability values of the lower trapezius (ICC = .35-.65). CONCLUSION: The study demonstrates that evaluating the strength of scapular and shoulder muscles using HHD presents reliable results for both patients with impingement syndrome and healthy subjects. Reliability values were compressed when testing the trapezius in subjects with higher BMI. This is likely a result of the examiner's difficulty in overcoming the patients with this maneuver. PMID- 22495261 TI - A new organic-inorganic hybrid based on the crescent-shaped polyoxoanion [H6SiNb18O54]8- and copper-organic cations. AB - A new organic-inorganic hybrid, [Cu(en)(2)](3){[Cu(en)(2)][H(6)SiNb(18)O(54)]}.22H(2)O (1, en = ethylenediamine) containing the crescent-shaped polyoxoanion [H(6)SiNb(18)O(54)](8-) and copper organic cations has been successfully synthesized, and elemental analyses, IR spectra, thermogravimetric analyses and single-crystal X-ray diffraction were investigated. PMID- 22495262 TI - Intraoperative use of a chest physiotherapy system during whole lung lavage for pulmonary alveolar proteinosis. AB - Pulmonary alveolar proteinosis (PAP) is a rare condition caused by the excessive alveolar accumulation of surfactant proteins. The current standard of care for removing these secretions is through therapeutic whole lung lavage (WLL). We describe two successful cases of bilateral WLL involving the novel use of the VestTM chest physiotherapy system thereby avoiding the need for extensive changes in patient position in the intraoperative period. In brief, it involves the induction of general anesthesia followed by single-lung ventilation while simultaneously performing large volume lavages on the nonventilated lung. The washout was enhanced using the VestTM system. PMID- 22495263 TI - Evidence that a single bioluminescent system is shared by all known bioluminescent fungal lineages. AB - Since the early 20th century, many researchers have attempted to determine how fungi are able to emit light. The first successful experiment was obtained using the classical luciferin-luciferase test that consists of mixing under controlled conditions hot (substrate/luciferin) and cold (enzyme/luciferase) water extracts prepared from bioluminescent fungi. Failures by other researchers to reproduce those experiments using different species of fungi lead to the hypothesis of a non-enzymatic luminescent pathway. Only recently, the involvement of a luciferase in this system was proven, thus confirming its enzymatic nature. Of the 100,000 described species in Kingdom Fungi, only 71 species are known to be luminescent and they are distributed unevenly amongst four distantly related lineages. The question we address is whether the mechanism of bioluminescence is the same in all four evolutionary lineages suggesting a single origin of luminescence in the Fungi, or whether each lineage has a unique mechanism for light emission implying independent origins. We prepared hot and cold extracts of numerous species representing the four bioluminescent fungal lineages and performed cross reactions (luciferin * luciferase) in all possible combinations using closely related non-luminescent species as controls. All cross-reactions with extracts from luminescent species yielded positive results, independent of lineage, whereas no light was emitted in cross-reactions with extracts from non luminescent species. These results support the hypothesis that all four lineages of luminescent fungi share the same type of luciferin and luciferase, that there is a single luminescent mechanism in the Fungi, and that fungal luciferin is not a ubiquitous molecule in fungal metabolism. PMID- 22495264 TI - Perceiving molecular themes in the structures and bonding of intermetallic phases: the role of Huckel theory in an ab initio era. AB - Qualitative molecular orbital theory is central to our understanding of the bonding and reactivity of molecules and materials across chemistry. Advances in computational technology and methodology, however, have made ab initio or density functional theory calculations a simpler alternative, offering reliable results on increasingly large systems in a reasonable time-scale without the need for concerns about the approximations and parameterization of semi-empirical one electron based methods. In this perspective, we illustrate how the availability of higher-level computational results can augment, rather than supplant, the insights provided by approaches such as the simple and extended Huckel methods. We begin by describing a way to parameterize Huckel-type Hamiltonians against DFT results for intermetallic systems. The potential for chemical understanding embodied by such orbital-based models is then demonstrated with two schemes of bonding analysis that originated in them (but can be extended to DFT results): the MU(3)-acid/base model and the MU(2)-Huckel chemical pressure analysis, which translate the molecular concepts of acidity and electronic/steric competition, respectively, into the context of intermetallic chemistry. PMID- 22495265 TI - All you always wanted to know about scarless surgery and never dare to ask. PMID- 22495266 TI - LESS and NOTES: rationale and terminology. AB - Laparoendoscopic single site surgery (LESS) and natural orifice transluminal endoscopic surgery (NOTES) are emerging platforms to further reduce the invasive profile of surgery. As feasibility of an increasing array of procedures in both platforms is being demonstrated, with out comes comparable to multiport laparoscopy, there has been a parallel proliferation of concepts, terminology and technology. In this article, we describe the rationale behind the evolving paradigm shift towards truly "scarless" surgery and address the terminology associated with these surgical approaches. PMID- 22495267 TI - Patient selection for LESS urological surgery. AB - Laparoendoscopic single-site surgery (LESS) should theoretically improve perioperative results and cosmesis minimizing skin incision. LESS surgery is technically demanding and the result of any procedure depends on the surgeon skill and experience, on the condition to be treated and finally on careful patient selection. As cosmesis is the main advantage over standard laparoscopy, LESS is particularly indicated in young patients with low BMI. While at the beginning LESS surgery was limited to demolitive procedures, increasing experience lead to widen indications to reconstructive and more challenging conditions. New technologies and robotics may increase LESS indications in the next future. PMID- 22495268 TI - Access techniques, platforms and instruments for LESS. AB - OBJECTIVES: To summarize the available tools available for performing LaparoEndoscopic Single-Site surgery in Urology. METHOD: A comprehensive electronic literature search was conducted in May 2011 using the Medline database to identify all publications relating to NOTES and LESS in urology and information on devices were also obtained by accessing company Websites. RESULTS: Multiple access ports are available and allow to insert several instruments through multiple channels inside a larger single port. Due to lack of triangulation intracorporally, companies developed various articulating and bent instruments, limiting clashing and allowing increased working space. The ideal endoscope for LESS should remove the light cord and camera head from the operative field. Articulating and low profile scopes are now available. Furthermore, surgeons can use extra-long scopes. CONCLUSION: Various tools currently are available for single-site surgery. Randomized studies are needed to determine the Platform selection. PMID- 22495269 TI - LESS nephrectomy: technique and outcomes. AB - Laparoendoscopic single-site surgery (LESS) represents the next step of laparoscopic surgery and a major advancement towards scarless surgery. LESS radical nephrectomy is an evolving technique based on technological advancement of laparoscopic instruments as well as the refinement of existing techniques.The current report describes LESS nephrectomy technique, presents the experience with the technique in a series of 42 patients and reviews current literature in the field of LESS nephrectomy. PMID- 22495270 TI - Nephron sparing LESS: technique and review of the current literature. AB - OBJECTIVES: Background. Nephron-sparing surgery (NSS)ensures excellent oncological and functional outcomes in treating small renal masses. Laparo- Endoscopic-Single-Site Surgery (LESS)is one of the major advances in the evolution of minimally invasive surgery. METHODS: A prospective evaluation of patients underwent LESS NSS at our institutions for a solitary, exophytic, enhancing, small (= 4.0 cm) renal masses and normal controlateral kidney was done. Peri-operative, pathological, hematological data together with a subjective evaluation of the pain (VAS) and the scars were collected. A comprehensive electronic literature search was conducted in May 2011 using the Medline database to identify all publications relating to LESS NSS. RESULTS: Fourteen patients were operated by a LESS unclamp NSS and 6 patients by a clamp LESS NSS (mean operative time: 125 min and 137.4 min; mean blood loss: 207 ml and 113 ml). The mean warm ischemia time in the LESS clamped NSS was 11.1+/-2.4 min using an early unclamped technique. Neither conversion to open surgery nor transfusions occurred. Three patients required conversion to standard laparoscopy. Postoperatively, we recorded 1 Clavien II (acute gastritis), 1 Clavien IIIa (urinary fistula after NSS) and 1 Clavien IV (cerebral stroke) complications. Pathology revealed 13 T1a clear cell carcinoma, 4 complex renal cysts, 2 oncocytoma and 1 angiomyolipoma (surgical margin positive). With a minimal postoperative pain (VAP: 1.8 in POD1) the patients were discharged after 4.4 days without variation in eGFR. No local or distant progression was detected. Current literature suggest that LESS NSS can safely and effectively be performed in a variety of urologic settings and represent one of the major interests among the LESS procedures . Although, the quality of evidence of all available studies remains low, mostly being small case series or case control studies from selected centers. CONCLUSIONS: LESS NSS in selected renal masses is feasible, provides postoperative outcomes overlapping the standard counterpart and ensures subjective satisfaction. A more extensive surgical experience and a prolonged follow-up are necessary to point out the role of this technique. PMID- 22495271 TI - Laparoendoscopic single site (LESS) nephroureterectomy: an overview of techniques & outcomes. AB - LaparoEndoscopic Single-Site (LESS) nephroureterectomy is a recent iteration of laparoscopic renal surgery whereby the minimally-invasive approach of laparoscopy has been condensed to a single operative access site in efforts to minimize convalescence and improve cosmesis. To date, LESS nephroureterectomy has been reported successful for both adult and pediatric patient populations, most commonly for treatment of upper tract urothelial carcinoma in adults. For the treatment of upper tract urothelial carcinomas, comparative oncologic effectiveness of LESS compared to conventional laparoscopy or open surgery is pending further investigation. Overall, LESS nephroureterectomy has proven its role as a feasible and safe option of minimally-invasive surgery, minimizing the number and length of the surgical incisions used. PMID- 22495272 TI - Laparo-endoscopic single-site donor nephrectomy: techniques and outcomes. AB - OBJECTIVES: Living donor nephrectomy is a unique surgical procedure in urological practice and must optimize the trifecta of: patient safety, minimal morbidity and successful graft function. The laparoscopic technique has become the gold standard over the last decade for harvesting the kidney from a living donor. Laparo-endoscopic single-site (LESS) surgery is an attempt to further enhance cosmetic benefits and reduce the morbidity for potential kidney donors. We have summarized and reviewed the literature of LESS-DN and described the techniques and outcomes. METHODS: Using the National Library of Medicine database, the English language literature was reviewed from 2006 to 2011. Keyword searches included LESS, Donor, Nephrectomy, Living, Single-site, e-NOTES, Mini-invasive, Laparoscopic, Single-port. Within the bibliography of selected references, additional sources were retrieved. RESULTS: After Gill's description of the first four patients to undergo LESS-DN, we found five series published describing the surgical techniques of LESS-DN as well as the outcomes. We have outlined in detail the various techniques of the trans-umbilical LESS-DN and compared the outcomes with conventional LDN. We also briefly discuss new innovative techniques of LESS-DN. CONCLUSIONS: LESS-DN is a safe albeit technically challenging alternative to LDN. LESS-DN appears to have comparable results to LDN in terms of graft function, patient morbidity, and cosmesis. Further long term results and the development in parallel with other LESS procedures is required before LESS-DN is to be considered a standard of care. PMID- 22495273 TI - LESS pyeloplasty & other reconstructive procedures. AB - OBJECTIVES: To review and synthesize the evidence available in the literature on laparoendoscopic single-site (LESS) pyeloplasty and other reconstructive procedures. METHODS: A literature search was performed to capture original articles related to LESS urological reconstructive procedures. We outlined the differences in technique and clinical outcomes related to their safety and efficacy. RESULTS: We found 28 retrospective studies, with a total of 146 patients. Procedures included pyeloplasty (91), ureterolithotomy (44), sacrocolpopexy (4), bladder diverticulectomy (4), partial cystectomy (2), one of which associated to augmentation cystoplasty, ureteroneocystostomy (1), ileal ureter (1), and retrocaval ureter (1). Mean operative time was 215 minutes for LESS pyeloplasty and 186 minutes for LESS ureterolithotomy. The mean estimated blood loss was 73 milliliters for pyeloplasty and 108 milliliters for ureterolithotomy. Mean length of stay was 2.7 days for pyeloplasty and 3.8 days for ureterolithotomy. CONCLUSION: Urological LESS reconstructive surgery is feasible and safe for different procedures. A solid laparoscopic experience is strongly advised prior attempting LESS reconstructive procedures due to its technical complexity. Future studies should prioritize prospective and randomized designs comparing LESS with standard laparoscopy. PMID- 22495274 TI - Laparoendoscopic single site adrenal surgery. AB - Laparoscopic adrenal surgery is a standard procedure for the management of benign adrenal pathology and small malignant tumors. There has been an increasing interest over the last few years in the use of laparoendoscopic single-site surgery (LESS). From recent literatures, LESS adrenalectomy was demonstrated that this technique was safe and feasible despite the relatively difficult anatomical location of the adrenal gland. We reviewed the surgical techniques and outcomes of LESS adrenalectomy including robot-assisted approach and gave an overview of the current role of LESS in adrenalectomy. PMID- 22495275 TI - Laparoendoscopic single site pelvic surgery: is there any room? AB - OBJECTIVES: Our purpose was to summarize the current status of Laparo-endocopic single site surgery (LESS) in the pelvis. METHODS: A comprehensive literature search was conducted in May 2011 using the medline database to identify publications relating to LESS surgery in the pelvis. RESULTS: LESS can be safely performed in the pelvis with comparable outcomes to standard minimally invasive approaches. Small series have demonstrated good outcomes in the hands of experienced surgeons in a number of urological settings in the pelvis. Challenges in LESS surgery are continual being overcome by advancing technologies such as with the robotic platform;however, significant improvements are necessary to reduce the difficulty with LESS surgery and dispersion amongst urological surgeons. CONCLUSION: LESS pelvic procedures are evolving. Wide ranges of procedures have been described using LESS approach, however, in small series and short follow-up. Further examination of LESS pelvic approach with well-designed studies will be crucial to determine the future role of such an approach. PMID- 22495276 TI - Critical review of laparoendoscopic single-site surgery versus multiport laparoscopy in urology. AB - Continued advancement in laparoscopy and a desire for less-invasive surgical approach has led to the development of novel surgical approaches, including laparoendoscopic single-site surgery (LESS). LESS in urology has not reached the pinnacle yet. Objective of this study is to provide an evidence-based analysis of the current status and future directions of minimal access and minimally invasive urological surgery represented by LESS in comparison with classic multiport laparoscopic surgery. Since the initial report of single-port nephrectomy in 2007, the majority of laparoscopic procedures in urology have been described with a single-site approach. Multi-center experience has validated Urological LESS procedures as technically feasible and safe for various urologic diseases. Certainly, several issues must be overcome before LESS can practiced universally in urology. Development of instrumentation and platform, long term follow up and large-scale randomized controlled trials are needed to provide an accurate comparative analysis with other procedures to confirm the significant benefits of LESS. PMID- 22495277 TI - Robotic laparoendoscopic single-site surgery: the way forward. AB - OBJECTIVES: LaparoEndoscopic Single-Site (LESS) surgery presents many technical and ergonomic obstacles. The solution to these current limitations may lie within emerging technologies, primarily the daVinci robotic platform. The purpose of this review was to examine the available literature as it pertains to robotic laparoendoscopic single-site surgery (R-LESS) and detail our experience with this approach at our institution. METHODS: An electronic literature search was conducted using the Medline database to identify all publications relating to R-LESS and/Mor robotic single port surgery in urology. Additionally, a retrospective review of our single center experience was completed. RESULTS: Fifteen original articles and two abstracts were identified in the literature and included dry lab investigation, animal experiments, single case reports, cumulative series, and two retrospective comparative analyses. Most detailed technique, perioperative outcomes, and associated procedural nuances. CONCLUSIONS: R-LESS urologic surgery is feasible and can be performed using several approaches. R-LESS reduces difficulties encountered with conventional LESS urologic surgery. An ideal robotic system is needed and would be task specific, deployable through a single incision, possess articulating instruments, and have reduced external housings. PMID- 22495278 TI - Minilaparoscopy, needlescopy and microlaparoscopy: decreasing invasiveness, maintaining the standard laparoscopic approach. AB - OBJECTIVES: To review the development of miniaturized laparoscopic instruments with particular attention to the urological field and focusing on nomenclature, history and outcomes. METHODS: A comprehensive literature search was conducted in order to find articles related to Minilaparoscopy, Needlescopy, Microlaparoscopy. The most relevant papers over the last 30 years were selected in base to the experience from the panel of experts, journal, authorship and /or content. RESULTS: 258 manuscripts were found, 14 of them review, 126 about general surgery, 86 gynecology, 55 urology, 31 thoracic surgery. Minilaparoscopy is the main topic in 169 papers, Needlescopy in 58 and Microlaparoscopy in 32. No clinical randomized trials are available in urology. Most significant articles are 4 prospective non-randomized match-case control. CONCLUSIONS: We are facing a Minilaparoscopy of second-generation with superior performance granted by new endoscopes and most effective instruments. Up to date, Minilaparoscopy has demonstrated in almost all urologic indication to be feasible, safe and able to improve cosmetic and postoperative pain control. Anyway, clinical randomized trials are still lacking and only studies from other discipline can corroborate this trend. PMID- 22495279 TI - Transvesical route for NOTES urological applications: advances & controversies. AB - Natural Orifice Transluminal Endoscopic Surgery (NOTES) has emerged recently in the experimental surgical field, innovating for the passage of luminal barrier, the absence of scars and reduction of post-operative pain. Among the various ports of access (transvaginal, transgastric, transvesical and transcolonic), this paper is an update on advances & controversies of transvesical port for NOTES Urological applications. PMID- 22495280 TI - Experimental NOTES in urology: are we moving forward? AB - This articles discusses the preclinical development of natural orifice surgery in urology. Rationale for this approach is provided. The description of transvaginal nephrectomy and NOTES prostatectomy is described. PMID- 22495281 TI - NOTES, hybrid NOTES, NOTES-assisted kidney surgery: what has been achieved so far? AB - With improved technologies and the development of new techniques, has emerged the concept of "scarless surgery" in an attempt to treat certain diseases obviating the need for incisions to access the peritoneal cavity, resulting in direct benefit to patients and assuming an improvement in quality of life and offering an advantage over conventional laparoscopy. Laparoendoscopic single-site surgery (LESS) and natural orifice transluminal endoscopic surgery (NOTES) are evolutions of laparoscopy, and they are complementary techniques that should be included in this new concept. NOTES is an emerging surgical modality that uses endoscopic instruments through hollow viscera to enter the peritoneal cavity and allow surgical procedures without incisions. The NOTES procedure may provide additional benefits when compared with current minimally invasive procedures. Potential advantages include no skin incisions, improved cosmetic result, reduced postoperative pain, diminished risk of postoperative hernias, and earlier recovery. NOTES surgery has still some inconvenient regarding instrumentals, viewing orientation, control of complications. Attempts to overcome the current limitations of the technique have given rise to the concept of hybrid NOTES, which is performed with the assistance of transabdominal ports for the use of conventional laparoscopy equipment. NOTES is a very promising technique although further investigation is necessary until implementing NOTES surgery in the common clinical practice. PMID- 22495282 TI - Natural orifice translumenal endoscopic radical prostatectomy (NOTES RP): the evolution of the technique. AB - Minimally invasive surgery is advancing to new frontiers that attempt to limit patient morbidities while providing excellent surgical outcomes. At the forefront of these efforts is natural orifice surgery, where surgical incisions can theoretically be eliminated. The purpose of this report is to describe the evolution of the clinical development of the natural orifice translumenal endoscopic radical prostatectomy (NOTES RP). It details the early experimental cadaver and animal work and the many challenges encountered to bring this procedure to clinical fruition. While the procedure remains in its infancy the clinical application to human patients shows its potential merit to positively impact the surgical control of prostate cancer. Early clinical experience does not allow the ability to draw definitive conclusions about the procedure at this time but the potential benefits for a new minimally invasive inexpensive treatment for prostate cancer patients is promising. PMID- 22495283 TI - Training in LESS and NOTES. AB - LESS and NOTES are the further step forward the "scarless" surgery recently, which have challenged the main principles of conventional multiport laparoscopy. To develop the surgical skills for these novel techniques, the guideline for training program should be neccesary for its clinical practice to reduce the complications. In this paper, we will summary the challenges of these new technique and introduce our experience of training courses. PMID- 22495284 TI - NOTES: basic and advanced surgical applications outside of the urological field. AB - Ten years ago the American gastroenterologist Anthony Kalloo described for the first time the concept of Natural Orifice Transluminal Endoscopic Surgery - NOTES. His revolutionary vision generated such an unprecedented worldwide momentum of creativity and renovation in the surgical community to push the current limit of the research in the minimal invasive surgery field toward the unimaginable goal of non visible scar surgery. At present time several NOTES applications are continuously reported by many teams all around the world and the aim of the present paper was to illustrate the clinical evidence registered up to now as well as to inform about the ongoing research efforts made to perform non visible scar surgery to treat more complex surgical diseases. PMID- 22495285 TI - New technology and applied research: what the future holds for LESS and NOTES. AB - Rapid technological developments in the 1970's contributed to the emergence of operative laparoscopy as a revolution in surgery. In recent years, there has been a surge of interest in laparoendoscopic single-site (LESS) and natural orifice translumenal endoscopic surgery (NOTES), novel techniques that have the potential to further minimize the invasiveness and morbidity of surgery. Innovations in instrument design and in novel surgical platforms including robotic technology have rapidly been developed in an effort to enhance the future clinical applicability of these techniques. In this chapter, we review the current status and future directions of LESS and NOTES technology, focusing on the current research in the field. PMID- 22495286 TI - Isolated lower limb ischaemia as an unusual presenting symptom of aortic dissection. AB - Acute aortic dissection is not common but usually presents with a severe, sharp chest pain and high blood pressure. Widening of the mediastinum is usually also evident on chest X-ray. Although acute onset of severe chest or back pain is the most common presenting symptom, some patients may present with atypical symptoms and signs. Establishing a diagnosis of aortic dissection can be difficult in the presence of atypical symptoms, especially in the absence of pain. Such presentation of aortic dissection is easily ignored. We report a case of painless aortic dissection with normal blood pressure, which resulted in acute isolated lower limb ischaemia at presentation. Atypical presentation of isolated limb arterial occlusions in an older patient without the classic symptoms are seldom reported as aortic dissection. However, aortic dissection should be included in the differential diagnosis of patients with arterial occlusive disease without chest pain and with normal blood pressure. PMID- 22495287 TI - Introduction to symposium: Poecilogony--a window on larval evolutionary transitions in marine invertebrates. AB - Poecilogony is the intraspecific variation in developmental mode that has been described in some marine invertebrates. Poecilogonous species produce different larval forms (e.g., free-swimming planktotrophic larvae as well as brooded lecithotrophic or adelphophagic larvae). Poecilogony can be a controversial topic, since it is difficult to identify and characterize the phenomenon with certainty. It has been challenging to determine whether poecilogony represents developmental polymorphism with a genetic basis or developmental polyphenism reflecting plastic responses to environmental cues. Other outstanding questions include whether common mechanisms underlie the developmental variation we observe in poecilogonous species, and whether poecilogony is maintained in different taxa through similar mechanisms or selective pressures. Poecilogonous species provide a unique opportunity to elucidate the cellular, developmental, and genetic mechanisms underlying evolutionary transitions in developmental mode, as well as to help clarify the selective pressures and possible ecological circumstances that might be involved. Here, we describe an integrative approach to the study of poecilogony and its role in larval evolutionary transitions highlighted during a symposium held at the 2012 annual meeting of the Society for Integrative and Comparative Biology. PMID- 22495288 TI - Phase diagrams and kinetics of phase transitions in protein solutions. AB - The phase behavior of proteins is of interest for fundamental and practical reasons. The nucleation of new phases is one of the last major unresolved problems of nature. The formation of protein condensed phases (crystals, polymers, and other solid aggregates, as well as dense liquids and gels) underlies pathological conditions, plays a crucial role in the biological function of the respective protein, or is an essential part of laboratory and industrial processes. In this review, we focus on phase transitions of proteins in their properly folded state. We first summarize the recently acquired understanding of physical processes underlying the phase diagrams of the protein solutions and the thermodynamics of protein phase transitions. Then we review recent findings on the kinetics of nucleation of dense liquid droplets and crystals. We explore the transition from nucleation to spinodal decomposition for liquid-liquid separation and introduce the new concept of solution-to-crystal spinodal. We review the two-step mechanism of protein crystal nucleation, in which mesoscopic metastable protein clusters serve as precursors to the ordered crystal nuclei. The concepts and mechanisms reviewed here provide powerful tools for control of the nucleation process by varying the solution thermodynamic parameters. PMID- 22495289 TI - A mechanistic investigation of carbon-hydrogen bond stannylation: synthesis and characterization of nickel catalysts. AB - The complex ((i)Pr(3)P)Ni(eta(2)-Bu(3)SnCH=CH(2))(2) (1a) was characterized by NMR spectroscopy and was identified as the active species for catalytic C-H bond stannylation of partially fluorinated aromatics, for example in the reaction between pentafluorobenzene and Bu(3)SnCH=CH(2), which generates C(6)F(5)SnBu(3) and ethylene. The crystalline complex ((i)Pr(3)P)Ni(eta(2)-Ph(3)SnCH=CH(2))(2) (1b) provides a more easily handled analogue, and is also capable of catalytic stannylation with added Ph(3)SnCH=CH(2) and C(6)F(5)H. Mechanistic studies on 1b show that the catalytically active species remains mononuclear. The rate of catalytic stannylation is proportional to [C(6)F(5)H] and inversely proportional to [Ph(3)SnCH=CH(2)]. This is consistent with a mechanism where reversible Ph(3)SnCH=CH(2) dissociation provides ((i)Pr(3)P)Ni(eta(2)-Ph(3)SnCH=CH(2)), followed by a rate-determining reaction with C(6)F(5)H to generate the stannylation products. Kinetic competition reactions between the fluorinated aromatics pentafluorobenzene, 1,2,4,5-tetrafluorobenzene, 1,2,3,5 tetrafluorobenzene, 1,2,4-trifluorobenzene, 1,3,5-trifluorobenzene and 1,3 difluorobenzene all suggest significant Ni-aryl bond formation in the rate determining step under catalytic conditions. Labelling studies are consistent with an insertion of the hydrogen of the arene into the vinyl group, followed by beta-elimination or beta-abstraction of the SnPh(3) moiety. PMID- 22495290 TI - Difference in graft maturity of the reconstructed anterior cruciate ligament 2 years postoperatively: a comparison between autografts and allografts in young men using clinical and 3.0-T magnetic resonance imaging evaluation. AB - BACKGROUND: Currently, there is an ongoing debate regarding the optimal graft choice between autograft and allograft tendons in reconstruction of the anterior cruciate ligament (ACL). It has been reported that allograft tendons have a slower onset and rate of revascularization compared with autograft tendons. HYPOTHESIS: Allograft tendons might have inferior graft maturity compared with autograft tendons in ACL reconstruction at 2 years postoperatively. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 52 participants with ACL reconstruction were recruited in this study, including 30 using allograft tendons and 22 using autograft tendons. All of them had unilateral ACL reconstruction and were followed up using 3.0-T magnetic resonance imaging (MRI) at least 2 years postoperatively. Clinical examination was performed on the same day when the MRI examination was performed, including subjective functional examinations (International Knee Documentation Committee [IKDC] and Tegner Lysholm Knee Scoring Scale [TLKS]) and physical examinations (anterior drawer test and Lachman test). Four measurements based on MRI were focused on graft orientation (including tibial tunnel position and graft angles), the edematous condition of the graft, intra-articular graft width at different sites, and signal intensity of the ACL graft using the signal/noise quotient (SNQ) from a region of interest analysis. Differences in each measurement were compared between the allograft group and the autograft group. RESULTS: All the participants returned to normal sports activities at the follow-up time point, as all of them acquired full functional strength and stability. There was no significant difference between the autograft and the allograft group with respect to IKDC or TLKS score. The knees in both of the groups were confirmed stable by physical examination before MRI. On MRI measurements, the allograft group displayed no significant difference in graft orientation compared with the autograft group (P > .05). Moreover, there was also no significant difference between allograft group and autograft group in graft width of the distal site (P > .05), middle site (P > .05), and proximal site (P > .05). However, the mean SNQ value of the allograft group was significantly higher than that of the autograft group in the distal site (6.54 +/ 6.58 vs 2.98 +/- 5.48; P = .0173), the middle site (7.21 +/- 6.31 vs 3.56 +/- 4.62; P = .0149), and the proximal site (6.61 +/- 8.08 vs 2.45 +/- 8.12; P = .0018). CONCLUSION: The allograft group had a significantly higher SNQ value compared with the autograft group in this study, indicating that allograft tendons might have inferior graft maturity than autograft tendons in ACL reconstruction at 2 years postoperatively. PMID- 22495291 TI - Laser microdissection and mass spectrometry-based proteomics aids the diagnosis and typing of renal amyloidosis. AB - Accurate diagnosis and typing of renal amyloidosis is critical for prognosis, genetic counseling, and treatment. Laser microdissection and mass spectrometry are emerging techniques for the analysis and diagnosis of many renal diseases. Here we present the results of laser microdissection and mass spectrometry performed on 127 cases of renal amyloidosis during 2008-2010. We found the following proteins in the amyloid deposits: immunoglobulin light and heavy chains, secondary reactive serum amyloid A protein, leukocyte cell-derived chemotaxin-2, fibrinogen-alpha chain, transthyretin, apolipoprotein A-I and A-IV, gelsolin, and beta-2 microglobulin. Thus, laser microdissection of affected areas within the kidney followed by mass spectrometry provides a direct test of the composition of the deposit and forms a useful ancillary technique for the accurate diagnosis and typing of renal amyloidosis in a single procedure. PMID- 22495292 TI - Mycophenolate and lower graft function reduce the seroresponse of kidney transplant recipients to pandemic H1N1 vaccination. AB - In late 2009 transplant organizations recommended that kidney recipients be vaccinated for pandemic H1N1 influenza (pH1N1); however, the vaccine efficacy was unknown. We had offered a monovalent non-adjuvanted pH1N1 vaccine to transplant recipients. Here we compared the pre- and post-vaccination seroresponses of 151 transplant recipients to that of 71 hemodialysis patients and 30 healthy controls. Baseline seroprotection was similar between groups but was significantly different at 1 month (44, 56, and 87%, respectively). Seroconversion was significantly less common for transplant recipients (32%) than dialysis patients (45%) and healthy controls (77%). After adjusting for age and gender, dialysis patients were significantly more likely (2.7-fold) to achieve new seroprotection than transplant recipients. The likelihood of seroprotection in transplant recipients was significantly reduced by mycophenolate use (adjusted odds ratio 0.24), in a dose-dependent manner, and by reduced eGFR (adjusted odds ratio 0.16 for worst to best). Seroprotection and geometric mean antibody titers increased substantially in 49 transplant recipients who subsequently received the 2010 seasonal influenza vaccine. Thus, patients requiring renal replacement therapy had reduced seroresponses to vaccination with the monovalent vaccine compared with healthy controls. Transplant recipient responses were further reduced if they were receiving mycophenolate or had significantly lower graft function. PMID- 22495293 TI - Endothelial cell transforming growth factor-beta receptor activation causes tacrolimus-induced renal arteriolar hyalinosis. AB - Arteriolar hyalinosis is a common histological finding in renal transplant recipients treated with the calcineurin inhibitor tacrolimus; however, the pathophysiologic mechanisms remain unknown. In addition to increasing transforming growth factor (TGF)-beta levels, tacrolimus inhibits calcineurin by binding to FK506-binding protein 12 (FKBP12). FKBP12 alone also inhibits TGF-beta receptor activation. Here we tested whether tacrolimus binding to FKBP12 removes an inhibition of the TGF-beta receptor, allowing ligand binding, ultimately leading to receptor activation and arteriolar hyalinosis. We found that specific deletion of FKBP12 from endothelial cells was sufficient to activate endothelial TGF-beta receptors and induce renal arteriolar hyalinosis in these knockout mice, similar to that induced by tacrolimus. Tacrolimus-treated and knockout mice exhibited significantly increased levels of aortic TGF-beta receptor activation as evidenced by SMAD2/3 phosphorylation, along with increased collagen and fibronectin expression compared to controls. Treatment of isolated mouse aortas with tacrolimus increased TGF-beta receptor activation and collagen and fibronectin expression. These effects were independent of calcineurin, absent in endothelial denuded aortic rings, and could be prevented by the small molecule TGF-beta receptor inhibitor SB-505124. Thus, endothelial cell TGF-beta receptor activation is sufficient to cause vascular remodeling and renal arteriolar hyalinosis. PMID- 22495294 TI - HIV-associated nephropathy patients with and without apolipoprotein L1 gene variants have similar clinical and pathological characteristics. AB - Recently, an association was found between nondiabetic kidney disease in African Americans and two independent sequence variants in the APOL1 gene, encoding apolipoprotein L1. In this study we determined the frequency of APOL1 risk variants in patients with biopsy-proven HIV-associated nephropathy (HIVAN) and distinctive pathological characteristics potentially driven by those risk variants. Among 76 patients with HIVAN, 60 were successfully genotyped for APOL1 G1 and G2 polymorphisms. In this cohort, 37 had two risk alleles, 18 were heterozygous, and 5 had neither risk variant. There were no differences in the pathological findings of HIVAN and the number of APOL1 risk alleles. Further, the progression to end-stage kidney disease or death did not differ by the number of risk alleles. Median renal survival was 9.3 months in patients with zero or one risk allele compared to 11.7 months in patients with two APOL1 risk alleles. Thus, our study suggests that although the majority of African-American patients with HIVAN have two APOL1 risk alleles other as yet unknown factors in the host, including genetic risk variants and environmental or viral factors, may influence the development of this disorder in those with zero or one APOL1 risk allele. PMID- 22495295 TI - In vivo regulation of the heme oxygenase-1 gene in humanized transgenic mice. AB - Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme degradation, producing equimolar amounts of carbon monoxide, iron, and biliverdin. Induction of HO-1 is a beneficial response to tissue injury in diverse animal models of diseases including acute kidney injury. In vitro analysis has shown that the human HO-1 gene is transcriptionally regulated by changes in chromatin conformation, but whether such control occurs in vivo is not known. To enable such an analysis, we generated transgenic mice, harboring an 87-kb bacterial artificial chromosome expressing human HO-1 mRNA and protein and bred these mice with HO-1 knockout mice to generate humanized BAC transgenic mice. This successfully rescued the phenotype of the knockout mice including reduced birth rates, tissue iron overload, splenomegaly, anemia, leukocytosis, dendritic cell abnormalities, and survival after acute kidney injury induced by rhabdomyolysis or cisplatin nephrotoxicity. Transcription factors such as USF1/2, JunB, Sp1, and CTCF were found to associate with regulatory regions of the human HO-1 gene in the kidney following rhabdomyolysis. Chromosome conformation capture and ChIP loop assays confirmed this in the formation of chromatin looping in vivo. Thus, these bacterial artificial chromosome humanized HO-1 mice are a valuable model to study the human HO-1 gene, providing insight to the in vivo architecture of the gene in acute kidney injury and other diseases. PMID- 22495296 TI - Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia-reperfusion injury by microRNA-dependent reprogramming of resident renal cells. AB - Endothelial progenitor cells are known to reverse acute kidney injury by paracrine mechanisms. We previously found that microvesicles released from these progenitor cells activate an angiogenic program in endothelial cells by horizontal mRNA transfer. Here, we tested whether these microvesicles prevent acute kidney injury in a rat model of ischemia-reperfusion injury. The RNA content of microvesicles was enriched in microRNAs (miRNAs) that modulate proliferation, angiogenesis, and apoptosis. After intravenous injection following ischemia-reperfusion, the microvesicles were localized within peritubular capillaries and tubular cells. This conferred functional and morphologic protection from acute kidney injury by enhanced tubular cell proliferation, reduced apoptosis, and leukocyte infiltration. Microvesicles also protected against progression of chronic kidney damage by inhibiting capillary rarefaction, glomerulosclerosis, and tubulointerstitial fibrosis. The renoprotective effect of microvesicles was lost after treatment with RNase, nonspecific miRNA depletion of microvesicles by Dicer knock-down in the progenitor cells, or depletion of pro angiogenic miR-126 and miR-296 by transfection with specific miR-antagomirs. Thus, microvesicles derived from endothelial progenitor cells protect the kidney from ischemic acute injury by delivering their RNA content, the miRNA cargo of which contributes to reprogramming hypoxic resident renal cells to a regenerative program. PMID- 22495297 TI - Chemokines play a critical role in the cross-regulation of Th1 and Th17 immune responses in murine crescentic glomerulonephritis. AB - Th1 and Th17 subtype effector CD4(+) T cells are thought to play a critical role in the pathogenesis of human and experimental crescentic glomerulonephritis. The time course, mechanism, and functions of Th1 and Th17 cell recruitment, and their potential interaction in glomerulonephritis, however, remain to be elucidated. We performed interventional studies using IL-17- and IFN-gamma-gene-deficient mice, as well as neutralizing antibodies that demonstrated the importance of the Th17 mediated immune response during the early phase of the disease. At a later stage, we found that Th1 cells were critical mediators of renal tissue injury. Early recruitment of IL-17-producing Th17 cells triggered expression of the chemokine CXCL9 in the kidney that drove the infiltration of Th1 cells bearing its receptor CXCR3. At a later stage, Th1 cell-derived IFN-gamma was found to inhibit local chemokine CCL20 expression, acting through its receptor CCR6 on Th17 cells, thereby limiting the renal Th17 immune response. Thus, our findings provide mechanistic evidence for a cytokine-chemokine-driven feedback loop that orchestrates the observed differential Th1 and Th17 cell infiltration into the inflamed kidney. This contributes to the observed time-dependent function of these two major pathogenic effector CD4(+) T cell subsets in crescentic glomerulonephritis. PMID- 22495298 TI - Anharmonic stacking in supercoiled DNA. AB - Multistep denaturation in a short circular DNA molecule is analyzed by a mesoscopic Hamiltonian model which accounts for the helicoidal geometry. Computation of melting profiles by the path integral method suggests that stacking anharmonicity stabilizes the double helix against thermal disruption of the hydrogen bonds. Twisting is essential in the model to capture the importance of nonlinear effects on the thermodynamical properties. In a ladder model with zero twist, anharmonic stacking scarcely affects the thermodynamics. Moderately untwisted helices, with respect to the equilibrium conformation, show an energetic advantage against the overtwisted ones. Accordingly moderately untwisted helices better sustain local fluctuational openings and make more unlikely the thermally driven complete strand separation. PMID- 22495299 TI - A C2-symmetric antimonato polyoxovanadate cluster [V16Sb4O42(H2O)](8-) derived from the {V18O42} archetype. AB - The new antimonato polyoxovanadate [V(IV)(16)Sb(III)(4)O(42)(H(2)O)](8-) cluster (1a) is the main structural motif of the solvothermally obtained compound {(trenH(2))Zn(tren)}(2)[V(16)Sb(4)O(42)(H(2)O)].xH(2)O (x = 6-10) (1) (tren = tris(2-aminoethyl)amine). The C(2)-symmetric cluster structure is closely related to the {V(18)O(42)} archetype. 1 crystallizes in the monoclinic space group C2/c with a = 30.7070(19) A, b = 13.9512(5) A, c = 23.1435(14) A, beta = 128.076(6) degrees , and V = 7804.8(7) A(3). The orientation of the [Sb(III)(2)O(5)](4-) groups in each cluster leads to intermolecular Sb...O contacts and the formation of channels between the clusters. [Zn(tren)(trenH(2))] complexes with trigonal bipyramidal coordination environments are located between the [V(16)Sb(4)O(42)(H(2)O)](8-) anions, and form a three dimensional network with them via strong N-H...O hydrogen bonds. Up to 250 degrees C crystal water molecules are emitted, which are reversibly incorporated in humid air. PMID- 22495300 TI - Topological domains in mammalian genomes identified by analysis of chromatin interactions. AB - The spatial organization of the genome is intimately linked to its biological function, yet our understanding of higher order genomic structure is coarse, fragmented and incomplete. In the nucleus of eukaryotic cells, interphase chromosomes occupy distinct chromosome territories, and numerous models have been proposed for how chromosomes fold within chromosome territories. These models, however, provide only few mechanistic details about the relationship between higher order chromatin structure and genome function. Recent advances in genomic technologies have led to rapid advances in the study of three-dimensional genome organization. In particular, Hi-C has been introduced as a method for identifying higher order chromatin interactions genome wide. Here we investigate the three dimensional organization of the human and mouse genomes in embryonic stem cells and terminally differentiated cell types at unprecedented resolution. We identify large, megabase-sized local chromatin interaction domains, which we term 'topological domains', as a pervasive structural feature of the genome organization. These domains correlate with regions of the genome that constrain the spread of heterochromatin. The domains are stable across different cell types and highly conserved across species, indicating that topological domains are an inherent property of mammalian genomes. Finally, we find that the boundaries of topological domains are enriched for the insulator binding protein CTCF, housekeeping genes, transfer RNAs and short interspersed element (SINE) retrotransposons, indicating that these factors may have a role in establishing the topological domain structure of the genome. PMID- 22495301 TI - Hsp72 preserves muscle function and slows progression of severe muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of the membrane-stabilizing protein dystrophin. Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca(2+), which activates inflammatory and muscle degenerative pathways. At present there is no cure for DMD, and existing therapies are ineffective. Here we show that increasing the expression of intramuscular heat shock protein 72 (Hsp72) preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy. Treatment with BGP-15 (a pharmacological inducer of Hsp72 currently in clinical trials for diabetes) improved muscle architecture, strength and contractile function in severely affected diaphragm muscles in mdx dystrophic mice. In dko mice, a phenocopy of DMD that results in severe spinal curvature (kyphosis), muscle weakness and premature death, BGP-15 decreased kyphosis, improved the dystrophic pathophysiology in limb and diaphragm muscles and extended lifespan. We found that the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA, the main protein responsible for the removal of intracellular Ca(2+)) is dysfunctional in severely affected muscles of mdx and dko mice, and that Hsp72 interacts with SERCA to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with Hsp72 upregulation. Treatment with BGP-15 similarly increased SERCA activity in dystrophic skeletal muscles. Our results provide evidence that increasing the expression of Hsp72 in muscle (through the administration of BGP-15) has significant therapeutic potential for DMD and related conditions, either as a self-contained therapy or as an adjuvant with other potential treatments, including gene, cell and pharmacological therapies. PMID- 22495302 TI - An inverse relationship to germline transcription defines centromeric chromatin in C. elegans. AB - Centromeres are chromosomal loci that direct segregation of the genome during cell division. The histone H3 variant CENP-A (also known as CenH3) defines centromeres in monocentric organisms, which confine centromere activity to a discrete chromosomal region, and holocentric organisms, which distribute centromere activity along the chromosome length. Because the highly repetitive DNA found at most centromeres is neither necessary nor sufficient for centromere function, stable inheritance of CENP-A nucleosomal chromatin is postulated to propagate centromere identity epigenetically. Here, we show that in the holocentric nematode Caenorhabditis elegans pre-existing CENP-A nucleosomes are not necessary to guide recruitment of new CENP-A nucleosomes. This is indicated by lack of CENP-A transmission by sperm during fertilization and by removal and subsequent reloading of CENP-A during oogenic meiotic prophase. Genome-wide mapping of CENP-A location in embryos and quantification of CENP-A molecules in nuclei revealed that CENP-A is incorporated at low density in domains that cumulatively encompass half the genome. Embryonic CENP-A domains are established in a pattern inverse to regions that are transcribed in the germline and early embryo, and ectopic transcription of genes in a mutant germline altered the pattern of CENP-A incorporation in embryos. Furthermore, regions transcribed in the germline but not embryos fail to incorporate CENP-A throughout embryogenesis. We propose that germline transcription defines genomic regions that exclude CENP A incorporation in progeny, and that zygotic transcription during early embryogenesis remodels and reinforces this basal pattern. These findings link centromere identity to transcription and shed light on the evolutionary plasticity of centromeres. PMID- 22495303 TI - Clusters of iron-rich cells in the upper beak of pigeons are macrophages not magnetosensitive neurons. AB - Understanding the molecular and cellular mechanisms that mediate magnetosensation in vertebrates is a formidable scientific problem. One hypothesis is that magnetic information is transduced into neuronal impulses by using a magnetite based magnetoreceptor. Previous studies claim to have identified a magnetic sense system in the pigeon, common to avian species, which consists of magnetite containing trigeminal afferents located at six specific loci in the rostral subepidermis of the beak. These studies have been widely accepted in the field and heavily relied upon by both behavioural biologists and physicists. Here we show that clusters of iron-rich cells in the rostro-medial upper beak of the pigeon Columbia livia are macrophages, not magnetosensitive neurons. Our systematic characterization of the pigeon upper beak identified iron-rich cells in the stratum laxum of the subepidermis, the basal region of the respiratory epithelium and the apex of feather follicles. Using a three-dimensional blueprint of the pigeon beak created by magnetic resonance imaging and computed tomography, we mapped the location of iron-rich cells, revealing unexpected variation in their distribution and number--an observation that is inconsistent with a role in magnetic sensation. Ultrastructure analysis of these cells, which are not unique to the beak, showed that their subcellular architecture includes ferritin-like granules, siderosomes, haemosiderin and filopodia, characteristics of iron-rich macrophages. Our conclusion that these cells are macrophages and not magnetosensitive neurons is supported by immunohistological studies showing co localization with the antigen-presenting molecule major histocompatibility complex class II. Our work necessitates a renewed search for the true magnetite dependent magnetoreceptor in birds. PMID- 22495304 TI - Spatial partitioning of the regulatory landscape of the X-inactivation centre. AB - In eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment. A prime example of this concerns the mouse X-inactivation centre (Xic), which orchestrates the initiation of X-chromosome inactivation (XCI) by controlling the expression of the non protein-coding Xist transcript. The extent of Xic sequences required for the proper regulation of Xist remains unknown. Here we use chromosome conformation capture carbon-copy (5C) and super-resolution microscopy to analyse the spatial organization of a 4.5-megabases (Mb) region including Xist. We discover a series of discrete 200-kilobase to 1 Mb topologically associating domains (TADs), present both before and after cell differentiation and on the active and inactive X. TADs align with, but do not rely on, several domain-wide features of the epigenome, such as H3K27me3 or H3K9me2 blocks and lamina-associated domains. TADs also align with coordinately regulated gene clusters. Disruption of a TAD boundary causes ectopic chromosomal contacts and long-range transcriptional misregulation. The Xist/Tsix sense/antisense unit illustrates how TADs enable the spatial segregation of oppositely regulated chromosomal neighbourhoods, with the respective promoters of Xist and Tsix lying in adjacent TADs, each containing their known positive regulators. We identify a novel distal regulatory region of Tsix within its TAD, which produces a long intervening RNA, Linx. In addition to uncovering a new principle of cis-regulatory architecture of mammalian chromosomes, our study sets the stage for the full genetic dissection of the X inactivation centre. PMID- 22495305 TI - An RNA interference screen uncovers a new molecule in stem cell self-renewal and long-term regeneration. AB - Adult stem cells sustain tissue maintenance and regeneration throughout the lifetime of an animal. These cells often reside in specific signalling niches that orchestrate the stem cell's balancing act between quiescence and cell-cycle re-entry based on the demand for tissue regeneration. How stem cells maintain their capacity to replenish themselves after tissue regeneration is poorly understood. Here we use RNA-interference-based loss-of-function screening as a powerful approach to uncover transcriptional regulators that govern the self renewal capacity and regenerative potential of stem cells. Hair follicle stem cells provide an ideal model. These cells have been purified and characterized from their native niche in vivo and, in contrast to their rapidly dividing progeny, they can be maintained and passaged long-term in vitro. Focusing on the nuclear proteins and/or transcription factors that are enriched in stem cells compared with their progeny, we screened ~2,000 short hairpin RNAs for their effect on long-term, but not short-term, stem cell self-renewal in vitro. To address the physiological relevance of our findings, we selected one candidate that was uncovered in the screen: TBX1. This transcription factor is expressed in many tissues but has not been studied in the context of stem cell biology. By conditionally ablating Tbx1 in vivo, we showed that during homeostasis, tissue regeneration occurs normally but is markedly delayed. We then devised an in vivo assay for stem cell replenishment and found that when challenged with repetitive rounds of regeneration, the Tbx1-deficient stem cell niche becomes progressively depleted. Addressing the mechanism of TBX1 action, we discovered that TBX1 acts as an intrinsic rheostat of BMP signalling: it is a gatekeeper that governs the transition between stem cell quiescence and proliferation in hair follicles. Our results validate the RNA interference screen and underscore its power in unearthing new molecules that govern stem cell self-renewal and tissue regenerative potential. PMID- 22495306 TI - De novo mutations revealed by whole-exome sequencing are strongly associated with autism. AB - Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, alpha subunit), a result that is highly unlikely by chance. PMID- 22495307 TI - Thermal and electrical conductivity of iron at Earth's core conditions. AB - The Earth acts as a gigantic heat engine driven by the decay of radiogenic isotopes and slow cooling, which gives rise to plate tectonics, volcanoes and mountain building. Another key product is the geomagnetic field, generated in the liquid iron core by a dynamo running on heat released by cooling and freezing (as the solid inner core grows), and on chemical convection (due to light elements expelled from the liquid on freezing). The power supplied to the geodynamo, measured by the heat flux across the core-mantle boundary (CMB), places constraints on Earth's evolution. Estimates of CMB heat flux depend on properties of iron mixtures under the extreme pressure and temperature conditions in the core, most critically on the thermal and electrical conductivities. These quantities remain poorly known because of inherent experimental and theoretical difficulties. Here we use density functional theory to compute these conductivities in liquid iron mixtures at core conditions from first principles- unlike previous estimates, which relied on extrapolations. The mixtures of iron, oxygen, sulphur and silicon are taken from earlier work and fit the seismologically determined core density and inner-core boundary density jump. We find both conductivities to be two to three times higher than estimates in current use. The changes are so large that core thermal histories and power requirements need to be reassessed. New estimates indicate that the adiabatic heat flux is 15 to 16 terawatts at the CMB, higher than present estimates of CMB heat flux based on mantle convection; the top of the core must be thermally stratified and any convection in the upper core must be driven by chemical convection against the adverse thermal buoyancy or lateral variations in CMB heat flow. Power for the geodynamo is greatly restricted, and future models of mantle evolution will need to incorporate a high CMB heat flux and explain the recent formation of the inner core. PMID- 22495308 TI - Systematic discovery of structural elements governing stability of mammalian messenger RNAs. AB - Decoding post-transcriptional regulatory programs in RNA is a critical step towards the larger goal of developing predictive dynamical models of cellular behaviour. Despite recent efforts, the vast landscape of RNA regulatory elements remains largely uncharacterized. A long-standing obstacle is the contribution of local RNA secondary structure to the definition of interaction partners in a variety of regulatory contexts, including--but not limited to--transcript stability, alternative splicing and localization. There are many documented instances where the presence of a structural regulatory element dictates alternative splicing patterns (for example, human cardiac troponin T) or affects other aspects of RNA biology. Thus, a full characterization of post transcriptional regulatory programs requires capturing information provided by both local secondary structures and the underlying sequence. Here we present a computational framework based on context-free grammars and mutual information that systematically explores the immense space of small structural elements and reveals motifs that are significantly informative of genome-wide measurements of RNA behaviour. By applying this framework to genome-wide human mRNA stability data, we reveal eight highly significant elements with substantial structural information, for the strongest of which we show a major role in global mRNA regulation. Through biochemistry, mass spectrometry and in vivo binding studies, we identified human HNRPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1, also known as HNRNPA2B1) as the key regulator that binds this element and stabilizes a large number of its target genes. We created a global post-transcriptional regulatory map based on the identity of the discovered linear and structural cis regulatory elements, their regulatory interactions and their target pathways. This approach could also be used to reveal the structural elements that modulate other aspects of RNA behaviour. PMID- 22495309 TI - Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. AB - It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected beta catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics. PMID- 22495310 TI - Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. AB - In the fasted state, increases in circulating glucagon promote hepatic glucose production through induction of the gluconeogenic program. Triggering of the cyclic AMP pathway increases gluconeogenic gene expression via the de phosphorylation of the CREB co-activator CRTC2 (ref. 1). Glucagon promotes CRTC2 dephosphorylation in part through the protein kinase A (PKA)-mediated inhibition of the CRTC2 kinase SIK2. A number of Ser/Thr phosphatases seem to be capable of dephosphorylating CRTC2 (refs 2, 3), but the mechanisms by which hormonal cues regulate these enzymes remain unclear. Here we show in mice that glucagon stimulates CRTC2 dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin-dependent Ser/Thr phosphatase calcineurin (also known as PP3CA). Glucagon increased cytosolic calcium concentration through the PKA-mediated phosphorylation of inositol-1,4,5 trisphosphate receptors (InsP(3)Rs), which associate with CRTC2. After their activation, InsP(3)Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2. During feeding, increases in insulin signalling reduced CRTC2 activity via the AKT-mediated inactivation of InsP(3)Rs. InsP(3)R activity was increased in diabetes, leading to upregulation of the gluconeogenic program. As hepatic downregulation of InsP(3)Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrate how interactions between cAMP and calcium pathways at the level of the InsP(3)R modulate hepatic glucose production under fasting conditions and in diabetes. PMID- 22495312 TI - Unexpected features of Drosophila circadian behavioural rhythms under natural conditions. AB - Circadian clocks have evolved to synchronize physiology, metabolism and behaviour to the 24-h geophysical cycles of the Earth. Drosophila melanogaster's rhythmic locomotor behaviour provides the main phenotype for the identification of higher eukaryotic clock genes. Under laboratory light-dark cycles, flies show enhanced activity before lights on and off signals, and these anticipatory responses have defined the neuronal sites of the corresponding morning (M) and evening (E) oscillators. However, the natural environment provides much richer cycling environmental stimuli than the laboratory, so we sought to examine fly locomotor rhythms in the wild. Here we show that several key laboratory-based assumptions about circadian behaviour are not supported by natural observations. These include the anticipation of light transitions, the midday 'siesta', the fly's crepuscular activity, its nocturnal behaviour under moonlight, and the dominance of light stimuli over temperature. We also observe a third major locomotor component in addition to M and E, which we term 'A' (afternoon). Furthermore, we show that these natural rhythm phenotypes can be observed in the laboratory by using realistic temperature and light cycle simulations. Our results suggest that a comprehensive re-examination of circadian behaviour and its molecular readouts under simulated natural conditions will provide a more authentic interpretation of the adaptive significance of this important rhythmic phenotype. Such studies should also help to clarify the underlying molecular and neuroanatomical substrates of the clock under natural protocols. PMID- 22495311 TI - Patterns and rates of exonic de novo mutations in autism spectrum disorders. AB - Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors. PMID- 22495313 TI - Climate science: Aerosols and Atlantic aberrations. PMID- 22495315 TI - Posterior ocular involvement in Behcet's disease and thrombophilic mutations. AB - It is not well established whether there is an association among common inherited gene defects, Factor V (FV) Leiden, the prothrombin (PT) G20210A mutation, C677T methylene tetrahydrofolate reductase (MTHFR) and ocular Behcet's disease (BD). We aimed to evaluate the association of these mutations with posterior ocular involvement in 89 BD patients from eastern Spain (48 men and 41 women) of whom 23 had posterior ocular involvement and 66 did not. None of the 23 BD patients with posterior ocular involvement was a carrier of either FV Leiden or the PTG20210A mutation. Only 1 patient was a carrier of the 677TT MTHFR mutation, whereas 4 patients carried FV Leiden, 3 the PTG20210A mutation and 10 the 677TT MTHFR mutation in the group without posterior ocular involvement (p = 0.227, p = 0.556, p = 0.144), respectively. In our geographical area, the commonest thrombophilic mutations do not seem to be related with posterior ocular involvement in BD patients. PMID- 22495314 TI - The clonal and mutational evolution spectrum of primary triple-negative breast cancers. AB - Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time-to our knowledge-in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes. PMID- 22495316 TI - Mechanism of endurance training-induced erythrocyte deformability in rats involves erythropoiesis. AB - Higher erythrocyte deformability may reduce the risk of circulatory diseases by enhancing oxygen delivery and reducing the load on the cardiovascular system. The effect of endurance training on erythrocyte deformability is not clear. This study explored the impact of endurance training on erythrocyte deformation and shape and investigated the underlying mechanisms of hemorheological alterations. Forty male Wistar rats were randomly divided into two groups: sedentary (S; n = 21) and exercised (E; n = 19). Hematological indices and erythrocyte shape were measured at the end of the 11th week. The gene expression of erythropoietin (Epo) and the Epo receptor (EpoR) was quantified using reverse transcription-PCR (RT PCR), and Epo protein expression was analyzed using Western blotting. Endurance training significantly decreased the abnormality ratio of erythrocyte shape (P < 0.01). The deformability indicator (DI) of red blood cells was lower in the E group than in the S group (P < 0.01). Eleven weeks of endurance training increased Epo mRNA and protein expression in the kidney (P < 0.01), EpoR mRNA expression in the bone marrow (P < 0.05), and relative circulating Epo (P < 0.01) compared to the sedentary group. The decrease in the erythrocyte morphological index and the maximum of deformability indicator were associated with an increase in relative circulating Epo. In conclusion, 11 weeks of endurance training increased erythrocyte deformability. Epo and EpoR may contribute to the decreased morphological index and deformability indicator in erythrocytes during endurance training in rats. PMID- 22495317 TI - Relevant impact of central pathology review on nodal classification in individual breast cancer patients. AB - BACKGROUND: In the MIRROR study, pN0(i + ) and pN1mi were associated with reduced 5-year disease-free survival (DFS) compared with pN0. Nodal status (N-status) was assessed after central pathology review and restaging according to the sixth AJCC classification. We addressed the impact of pathology review. PATIENTS AND METHODS: Early favorable primary breast cancer patients, classified pN0, pN0(i + ), or pN1(mi) by local pathologists after sentinel node procedure, were included. We assessed the impact of pathology review on N-status (n = 2842) and 5-year DFS for those without adjuvant therapy (n = 1712). RESULTS: In all, 22% of the 1082 original pN0 patients was upstaged. Of the 623 original pN0(i + ) patients, 1% was downstaged, 26% was upstaged. Of 1137 patients staged pN1mi, 15% was downstaged, 11% upstaged. Originally, 5-year DFS was 85% for pN0, 74% for pN0(i + ), and 73% for pN1mi; HR 1.70 [95% confidence interval (CI) 1.27-2.27] and HR 1.57 (95% CI 1.16-2.13), respectively, compared with pN0. By review staging, 5 year DFS was 86% for pN0, 77% for pN0(i + ), 77% for pN1mi, and 74% for pN1 + . CONCLUSION: Pathology review changed the N-classification in 24%, mainly upstaging, with potentially clinical relevance for individual patients. The association of isolated tumor cells and micrometastases with outcome remained unchanged. Quality control should include nodal breast cancer staging. PMID- 22495318 TI - An ionicity diagram for the family of [{Ru2(CF3CO2)4}2(TCNQR(x))] (TCNQR(x) = R substituted 7,7,8,8-tetracyano-p-quinodimethane). AB - A diagram of energies between the HOMO of donor (D) and LUMO of acceptor (A) vs.DeltaE(1/2)(DA) (= E(1/2)(D) - E(1/2)(A): E(1/2) = first-redox potential) clearly demonstrates the ionicity in the series of D/A assemblies, [{Ru(2)(CF(3)CO(2))(4)}(2)(TCNQR(x))].n(solv) (TCNQR(x) = 2,5- or 2,3,5,6-R substituted 7,7,8,8-tetracyano-p-quinodimethane; R(x) = H(4), F(2), Cl(2), Br(2), F(4), Me(2), (OMe)(2)). PMID- 22495319 TI - Screening for cancer with molecular markers: progress comes with potential problems. AB - Recent research has raised hopes for impressively accurate screening for cancer with molecular biomarkers. These molecular markers will probably be more sensitive and specific than older screening modalities, as well as easier to use. In this Essay, I argue that these sensitive screening tests might be clinically valuable - but that they will present unique issues in implementation and interpretation. These issues are likely to affect the way clinicians conduct screening and the way that they make diagnoses in individuals who screen positive for cancer. PMID- 22495320 TI - Hypoxia: New connections. PMID- 22495322 TI - Tumour heterogeneity: Darwin's finches. PMID- 22495323 TI - Cancer genetics: HIF enhances its reputation. PMID- 22495321 TI - The genetic architecture of multiple myeloma. AB - Based on the clinical features of myeloma and related malignancies of plasma cells, it has been possible to generate a model system of myeloma progression from a normal plasma cell through smouldering myeloma to myeloma and then plasma cell leukaemia. Using this model system we can study at which points the genetic alterations identified through whole-tumour molecular analyses function in the initiation and progression of myeloma. Further genetic complexity, such as intraclonal heterogeneity, and insights into the molecular evolution and intraclonal dynamics in this model system are crucial to our understandings of tumour progression, treatment resistance and the use of currently available and future treatments. PMID- 22495324 TI - Out of sight, out of mind: the presence of forensic evidence counts more than its absence. AB - Recent evidence suggests that decision makers in criminal procedures are susceptible to biases. We previously found support for the presence of a feature positive effect (FPE, i.e., people attach more meaning to present than to absent information) in legal-decision making. In this study, we tried to uncover the mechanisms behind the FPE. Taking a cue from the literature on situation models in language comprehension, we investigated whether a FPE manifests itself in the memorization and use of forensic evidence. Students read a case file about a fistfight as well as additional evidence. The forensic evidence was manipulated such that a FPE on guilt estimation and conviction rate could be assessed. While subjects read additional forensic evidence, their eye movements were recorded to explore the presence of FPE in online processing. Afterwards, subjects were asked to decide on the suspect's guilt. They had to recall all information they remembered from the case file and indicate which parts of information they considered relevant to this decision. The results provided evidence for the occurrence of FPE in memorization and use of information and can be explained by the theoretical construct of situation models. PMID- 22495325 TI - Swelling of the arcuate nerve fiber layer after internal limiting membrane peeling. AB - PURPOSE: The purpose of the study is to report the incidence of changes of the retinal nerve fiber layer in the early postoperative period after internal limiting membrane peeling for idiopathic macular hole and epiretinal membrane surgery. METHODS: Interventional, noncomparative retrospective case series. Fifty six eyes of 55 patients with an epiretinal membrane and 33 eyes of 31 patients with macular hole underwent pars plana vitrectomy and internal limiting membrane peeling. All patients received a complete ophthalmic examination, infrared and autofluorescence photography, and spectral-domain optical coherence tomography preoperatively and also at approximately 1 week, 1 month, and 3 months postoperatively. Vitrectomy and gas tamponade were performed with internal limiting membrane peeling after staining with Brilliant Peel. The main outcome measures were the presence of postoperative swelling of the arcuate retinal nerve fiber layer on spectral-domain optical coherence tomography, infrared and autofluorescence photographs, and its effect on best-corrected visual acuity. RESULTS: On infrared and autofluorescence photographs, 28 (31.46%) of 89 eyes with internal limiting membrane peeling exhibited swelling of the arcuate retinal nerve fiber layer 1 week to 1 month postoperatively. Swelling of the arcuate retinal nerve fiber layer increased during the first month after surgery and resolved after a mean period of 2 months. These features were best visualized by autofluorescence imaging, as three to five dark striae originating from the optic nerve head, radiating in an arcuate pattern toward the macula. Simultaneous spectral-domain optical coherence tomography scanning through the striae indicated that they correspond to areas of focal swelling of the arcuate nerve fiber layer. No significant differences were found in eyes with or without swelling of the arcuate retinal nerve fiber layer for mean age or pre- and postoperative best-corrected visual acuity (P > 0.05). CONCLUSION: Swelling of the arcuate retinal nerve fiber layer often occurs after internal limiting membrane peeling for macular hole and epiretinal membrane. It is a transient feature after surgery that does not affect visual recovery. It is best visualized using infrared and autofluorescence imaging. Simultaneous infrared and spectral domain optical coherence tomography imaging after macular surgery can detect transient inner retinal changes, which are not visible on clinical examination. PMID- 22495326 TI - Validation of tablet-based evaluation of color fundus images. AB - PURPOSE: To compare diabetic retinopathy (DR) referral recommendations made by viewing fundus images using a tablet computer with those made using a standard desktop display. METHODS: A tablet computer (iPad) and a desktop computer with a high-definition color display were compared. For each platform, 2 retinal specialists independently rated 1,200 color fundus images from patients at risk for DR using an annotation program Truthseeker. The specialists determined whether each image had referable DR and also how urgently each patient should be referred for medical examination. Graders viewed and rated the randomly presented images independently and were masked to their ratings on the alternative platform. Tablet-based and desktop display-based referral ratings were compared using cross-platform intraobserver kappa as the primary outcome measure. Additionally, interobserver kappa, sensitivity, specificity, and area under the receiver operating characteristic were determined. RESULTS: A high level of cross platform intraobserver agreement was found for the DR referral ratings between the platforms (kappa = 0.778) and for the 2 graders (kappa = 0.812). Interobserver agreement was similar for the 2 platforms (kappa = 0.544 and kappa = 0.625 for tablet and desktop, respectively). The tablet-based ratings achieved a sensitivity of 0.848, a specificity of 0.987, and an area under the receiver operating characteristic of 0.950 compared with desktop display-based ratings. CONCLUSION: In this pilot study, tablet-based rating of color fundus images for subjects at risk for DR was consistent with desktop display-based rating. These results indicate that tablet computers can be reliably used for clinical evaluation of fundus images for DR. PMID- 22495327 TI - Intravitreal injection of ranibizumab during cataract surgery in patients with diabetic macular edema. AB - PURPOSE: To investigate macular thickness and visual acuity changes after 1 intravitreal injection of 0.5-mg ranibizumab during phacoemulsification cataract surgery in eyes with diabetic macular edema refractory to laser treatment. METHODS: Eleven eyes of 11 patients with diabetic macular edema refractory to modified Early Treatment Diabetic Retinopathy Study laser therapy received intravitreal during phacoemulsification cataract surgery. Comprehensive ophthalmic evaluation was performed preoperatively and at 1, 4, 8 +/- 1, and 12 +/- 2 weeks postoperatively. Main outcome measures included central subfield thickness and best-corrected Early Treatment Diabetic Retinopathy Study visual acuity. RESULTS: Eleven patients completed the 12-week study visit. Mean central subfield thickness (+/- SEM) was 399.82 +/- 29.50 MUm at baseline and did not change significantly at any postoperative study visit (P > 0.05). Mean (+/- SEM) best-corrected Early Treatment Diabetic Retinopathy Study visual acuity was 0.95 +/- 0.13 logarithm of the minimum angle of resolution (20/200) at baseline and was significantly improved at Weeks 1 (0.38 +/- 0.13), 4 (0.38 +/- 0.11), 8 (0.35 +/- 0.08), and 12 (0.46 +/- 0.12) after treatment (P < 0.05). CONCLUSION: In this case series of patients with diabetic macular edema refractory to laser therapy, intravitreal ranibizumab administered during cataract surgery was associated with no significant change in central subfield thickness postoperatively. Significant improvement in best-corrected Early Treatment Diabetic Retinopathy Study visual acuity was observed after treatment, likely because of cataract removal. PMID- 22495328 TI - Maintenance of anticoagulant and antiplatelet agents for patients undergoing peribulbar anesthesia and vitreoretinal surgery. AB - PURPOSE: To establish the prevalence of anticoagulation (vitamin K antagonists) and antiplatelet agent therapy in patients undergoing vitreoretinal surgery and to compare the outcome of peribulbar anesthesia and vitreoretinal surgery between users and nonusers. METHODS: We conducted a retrospective case series study in one academic center. No changes in the treatment regimen were made before surgery. Patients were divided into 3 groups: G1, patients with no anticoagulant or antiplatelet therapy; G2, patients treated with anticoagulants; and G3, patients treated with aspirin, clopidogrel, or both. RESULTS: Two hundred and six eyes (206 patients) were included. G1, 144 eyes (69.9%) without any anticoagulant or antiplatelet therapy (69.9%); G2, 12 eyes (5.8%) with anticoagulants; and G3, 44 eyes (21.4%) with antiplatelet agents. Six patients (6 eyes) (2.9%) received both anticoagulant and antiplatelet agents. The incidence of overall and mild postoperative hemorrhagic complications was similar between groups, P = 0.075 and P = 0.127, respectively. However, potential sight-threatening hemorrhagic complications were more frequent in patients receiving antiplatelet agents, P < 0.003. CONCLUSION: Peribulbar anesthesia for vitreoretinal surgery can probably be performed safely in patients receiving anticoagulants. However, retinal surgeons should be aware that severe bleeding complications are more frequent in patients receiving antiplatelet therapy. PMID- 22495329 TI - Clinical and histopathologic findings after photodynamic therapy of choroidal melanoma. AB - BACKGROUND: Photodynamic therapy (PDT) has been used occasionally as an alternative treatment for uveal melanomas. The present study describes the clinical and histopathologic features of five choroidal melanomas after PDT. METHODS: Three patients with pigmented choroidal melanomas were treated with PDT and intravitreal bevacizumab 1 week before undergoing biopsy and brachytherapy to minimize the risks of bleeding during the biopsy. Another two patients received PDT as a primary treatment for peripapillary amelanotic melanomas, one of them also in combination with bevacizumab. RESULTS: The tumors treated with PDT and bevacizumab showed a marked reduction in tumor vascularity assessed by indocyanine angiography, and the biopsies were conducted without recognizable bleeding, showing viable tumor cells. The tumors receiving PDT as a primary treatment were followed by progressive tumor growth that led to enucleation years after. The histopathology revealed overlying fibrosis with invasion of sclera and optic nerve. CONCLUSION: Photodynamic therapy and bevacizumab can induce closure of the superficial vasculature of a pigmented choroidal melanoma, but in none of our cases, there was evidence of tumor destruction from this treatment. Preoperative PDT may be useful to reduce the potential of bleeding at the time of tumor biopsy. Our cases do not support the use of a single session of PDT as a primary treatment for pigmented small choroidal melanomas. PMID- 22495330 TI - "Intravitreal diclofenac versus intravitreal triamcinolone acetonide in the treatment of diabetic macular edema". PMID- 22495331 TI - Ocular neovascularization associated with central and hemicentral retinal vein occlusion. AB - PURPOSE: To investigate the incidence of ocular neovascularization (NV) in central and hemicentral retinal vein occlusion. METHODS: The study comprised consecutive 912 (673 nonischemic and 239 ischemic) central retinal vein occlusion and 190 (147 nonischemic, 43 ischemic) hemicentral retinal vein occlusion eyes. Ophthalmic evaluation at initial and follow-up visits included recording visual acuity, visual fields, and detailed anterior segment and fundus examinations and fluorescein fundus angiography. RESULTS: In ischemic central retinal vein occlusion, within 6 months from time of onset, the cumulative probability of development of iris NV was 49%, angle NV 37%, NV glaucoma 29%, retinal NV 9%, and disk NV 6%. More severe peripheral retinal hemorrhages were significantly associated with iris NV (P = 0.005), angle NV (P = 0.0004), and NV glaucoma (P = 0.012). Eyes that developed disk NV had more cotton wool spots (P = 0.058) than those without. In ischemic hemicentral retinal vein occlusion, within 12 months of onset, the cumulative probability of development of retinal NV was 29%, disk NV 12%, and iris NV 12%; within 6 months of onset, angle NV was found in 10% and NV glaucoma in 5%. Anterior chamber flare was associated with anterior segment NV and may precede the development of NV. Patients who developed NV were significantly younger, and there was a greater prevalence of NV glaucoma in patients with primary open angle glaucoma. CONCLUSION: In ischemic central retinal vein occlusion, anterior segment NV is much more common than posterior segment NV, and the cumulative chance of developing anterior segment NV is maximum during the first 6 months. In ischemic hemicentral retinal vein occlusion, posterior segment NV is much more common than anterior segment NV. PMID- 22495332 TI - Ocular manifestations of syphilitic uveitis in Chinese patients. AB - PURPOSE: To present the manifestations of syphilitic uveitis in Chinese patients. METHODS: This is a retrospective case series of 35 eyes of 19 patients with syphilitic uveitis. The data of these patients including complaints, ocular and systemic manifestations, human immunodeficiency virus status, results of auxiliary examinations, treatment, and follow-up were reviewed. RESULTS: Nineteen consecutive Chinese patients were diagnosed with syphilitic uveitis by serologic tests. Four patients had circulating human immunodeficiency virus antibodies. Ocular involvement was found in 35 eyes. Posterior segment involvement was found in 30 eyes of 17 patients (85.7%), whereas anterior segment involvement was found in 14 eyes of 8 patients (40.0%). Thirty eyes of 17 patients (85.7%) presented with vitreous opacities and 28 eyes of 16 patients (80.0%) with retinitis. Papillitis and retinal vasculitis were found in 10 eyes of 6 patients (28.6%) and 7 eyes of 4 patients (20.0%), respectively. Multiple precipitates on the retina and posterior vitreous membrane were observed in six eyes of three patients. A large iris granuloma was observed in one eye. CONCLUSION: Posterior uveitis was the most common ocular finding in these investigated Chinese patients with syphilis. Coinfection of syphilis and human immunodeficiency virus was less common in these patients. Syphilis should be considered in the differential diagnosis of patients presenting with large iris granulomas. PMID- 22495333 TI - New monoacylhydrazidate-coordinated Mn2+ and Pb2+ compounds. AB - By the simple hydrothermal self-assembly, four new monoacylhydrazidate coordinated compounds [Mn(APTH)(2)(H(2)O)] 1, [Pb(APTH)(2)].0.25H(2)O 2, [Pb(2)(EPDH)(4)(H(2)O)] 3 and [Pb(MPDH)(2)] 4 (APTH = 3-aminophthalhydrazidate, EPDH = 5-ethylpyridine-2,3-dicarboxylhydrazidate, MPDH = 6-methylpyrinde-2,3 dicarboxylhydrazidate) were obtained. It is noteworthy that APTH was derived from the in situ reduction reaction of NPTH (3-nitrophthalhydrazide) with N(2)H(4).H(2)O as the reducer, whereas EPDH and MPDH were derived respectively from the in situ acylation reactions of epdca and mpdca (epdca = 5-ethylpyridine 2,3-dicarboxylic acid, mpdca = 6-methylpyridine-2,3-dicarboxylic acid) with N(2)H(4).H(2)O. The photoluminescence analysis indicates that compounds 3 and 4 possess luminescence properties with maximum emissions at 531 nm for 3, and 600 nm for 4, respectively. The density functional theory (DFT) calculations indicate that the emission for compound 3 can be ascribed to a combination of the intra ligand and inter-ligand charge transfers, while the emission for compound 4 is assigned to the intra-ligand charge transfer. PMID- 22495334 TI - Stephen Frye. Interview by Asher Mullard. PMID- 22495335 TI - Apathy and aggression: the management of behavioral features in the dementia population. PMID- 22495336 TI - Road to the nursing home: costs and disease progression among medicare beneficiaries with ADRD. AB - OBJECTIVES: To estimate long-term care costs and disease progression among Medicare beneficiaries aged 65+ with ADRD. METHODS: Retrospective analysis of Medicare Part A claims and nursing home (NH) Minimum Data Set (MDS) records among beneficiaries 1999-2007. Expenditures were grouped into 3 periods; PRE, events occurring between date of ADRD diagnosis, before first NH admission; PERI, from first NH admission to at least 100 days; and, PERM, after 120 days. Utilization and reimbursements were computed for each period. RESULTS: Demographics of the3,681,702 ADRD beneficiaries showed average age of 83 (+/-7), female (67.7%) and white (87.4%). Medicare reimbursements per person increased by 58% from the PRE ($47,912) to PERM period ($75,654). Age, ethnicity, gender (male), and comorbidities were significantly related to total reimbursements in each phase. CONCLUSIONS: Applying a taxonomy of NH phases, Medicare expenditures per person year are higher among patients in their terminal phase and higher still with comorbidities. PMID- 22495337 TI - Facial expression in Alzheimer's disease: impact of cognitive deficits and neuropsychiatric symptoms. AB - In Alzheimer's disease (AD), nonverbal aspects of communication become increasingly important in caregiver-patient interactions when the ability to communicate verbally is fading with progression of the disease. We therefore investigated the impact of cognitive deficits and neuropsychiatric symptoms, particularly apathy, on facial expression in AD. While overall neuropsychiatric symptoms were not associated with facial expression, apathy exhibited substantial correlations, even after controlling for cognitive deficits. Moreover, apathy appeared to moderate the influence of cognitive deficits: without considering apathy, cognitive deficits were associated with less specific facial expressions. After controlling for apathy, cognitive decline was related to increased facial expressiveness. In conclusion, apathetic symptoms appear to be specifically associated with facial expression in AD and thus could contribute to a disregard for patients' needs in everyday life. PMID- 22495338 TI - Physical and cognitive stimulation in Alzheimer Disease. the GAIA Project: a pilot study. AB - Several data suggest that physical activity and cognitive stimulation have a positive effect on the quality of life (QoL) of people with Alzheimer's disease (AD), slowing the decline due to the disease. A pilot project was undertaken to assess the effect of cognitive stimulation, physical activity, and socialization on patients with AD and their informal caregiver's QoL and mood. Fourteen patients with AD were randomly divided into active treatment group and control group. At the end of treatment, a significant improvement in apathy, anxiety, depression, and QoL in the active treatment group was found. Considering caregivers, those of the active treatment group exhibited a significant improvement in their mood and in their perception of patients' QoL. This study provides evidence that a combined approach based on cognitive stimulation, physical activity, and socialization is a feasible tool to improve mood and QoL in patients with AD and their caregivers. PMID- 22495339 TI - Predicting facilitators' behaviors during Alzheimer's family support group meetings. AB - A social ecological model was used to predict facilitators' behaviors observed during Alzheimer's Association sponsored family support group meetings (N = 66). Information about group leaders was obtained via individual telephone interview prior to the observation of their support group by trained raters. Family dementia caregivers (N = 296) provided basic demographic and caregiving-related information at the end of the observed meeting. Caregiver- and group-level variables predicted ratings of observed leader support during support group meetings. The addition of leader characteristics such as years of experience or professional roles did not significantly contribute to the model. This study lends credence to ecological models emphasizing the influence of social context. Recommendations are made for facilitator training and management of Alzheimer's Association sponsored support group meetings. PMID- 22495340 TI - Cognitive stimulation in a-MCI: an experimental study. AB - Nowadays, preventing the effects of mental decline is an international priority, but there is little research into cognitive training in mild cognitive impairment (MCI). We present the results of a program aimed at teaching memory strategies and improving metacognitive abilities. This was associated with training to ameliorate caregivers' assistance. Two groups (A and B) were compared in a crossover design. After the first evaluation, group A (but not B) participated in a 6-month cognitive stimulation program. After a second assessment, only B received treatment and then a final evaluation was carried out on both the groups. The results show that (1) both the groups improved their performance as an effect of training; (2) improvements are specific to the functions trained; (3) in the interval without intervention, performance of group B worsened; and (4) group A has maintained their results over time. In conclusion, our results show that specific training may reduce memory impairment in MCI. PMID- 22495341 TI - Prevalence of dementia and mild cognitive impairment in a Bulgarian urban population. AB - BACKGROUND: Prevalence of cognitive impairment and dementia has not been studied in Bulgaria up to date. A 2-phase cross-sectional study was designed in order to determine the prevalence of dementia, its subtypes, and mild cognitive impairment in a Bulgarian population. METHODS: The study sample consisted of 605 participants over the age of 65, residents of the city of Varna. A total of 540 participants (89%) completed the screening phase of the study. All positive screens and a control group were included in the diagnostic phase of the study, where comprehensive neuropsychological, clinical, and imaging assessments were performed. RESULTS: Dementia was diagnosed in 39 persons (7.2%) and 36 had mild cognitive impairment (6.7%). Alzheimer's disease was the most frequent type of dementia (3.1%), followed by vascular dementia (2.0%). DISCUSSION: Our results support the hypothesis that prevalence of vascular cognitive impairment may be higher in Bulgaria than in most European countries. PMID- 22495343 TI - Co-occurrence of different pathologies in dementia: implications for dementia diagnosis. AB - The standard for differentiating between dementia subtypes is currently based on neuropathological changes and follows traditional nosological classifications. However, the high incidence of comorbid neuropathologies complicates the differentiation between dementia diagnoses in the clinic. The aim of this study was to investigate the grades of agreement between clinical and neuropathological diagnoses in neurodegenerative disorders, to compare them with rates found in previous studies, and to propose implications for dementia diagnostics. Patients, who donated their brains to the Brain Bank of Navarre (Pamplona, Spain), had been diagnosed with a neurodegenerative disorder during life (clinical diagnosis) and postmortem (neuropathological diagnosis). We studied a sample of patients with a short average time interval between the last clinical assessment and death (4.6 months). Overall, there was a mean grade of agreement of 44.0% between the clinical diagnosis and the pure neuropathological diagnosis (i.e., without co morbid neuropathological disorders). This grade of agreement differed between dementia subtypes: e.g., 85% for prion disease, 49% for Alzheimer's disease, and 0% for Lewy body dementia. Our data confirm that co-occurrence of multiple neuropathological disorders is very common in individuals with dementia, and that the underlying neuropathology often differs from the neuropathology implied by the clinical diagnosis. These findings support a multidimensional approach to diagnosing dementia, in which dementia syndromes are not categorized into diagnostic subtypes, but are seen as syndromes characterized by a combination of various neuropathological dimensions. PMID- 22495344 TI - Platelet tau pattern correlates with cognitive status in Alzheimer's disease. AB - Platelets are major reservoirs of circulating amyloid-beta and amyloid-beta protein precursor (AbetaPP) and have been postulated as a reliable source for biological markers of Alzheimer's disease (AD). We have recently demonstrated that tau is also present in platelets, and that there are differences in the electrophoretic patterns of platelet tau forms in AD subjects with respect to controls. Here, we demonstrate that modifications in platelet tau forms occur independently of age in a broad population of 104 neurologically healthy individuals. More interesting, a strong correlation of platelet markers with the degree of cognitive impairment was evidenced in a group of 47 AD patients in comparison with 19 cognitive healthy subjects. In our series, platelet tau forms ratio had a sensitivity of 75.7% and specificity of 73.7%, respectively. We also found that platelet tau displays a significantly higher correlation with the presence of AD than the analyses of platelet AbetaPP. PMID- 22495345 TI - Risk of Alzheimer's disease biological misdiagnosis linked to cerebrospinal collection tubes. AB - Tau proteins and amyloid-beta (Abeta) peptides are the current recognized cerebrospinal fluid (CSF) biomarkers used as an aid in the diagnosis of Alzheimer's disease (AD). However, there is no consensus on their clinical use due to non-qualified cut-off values, probably related to the observed high pre analytical and analytical variability. Standardized pre-analytical protocols have therefore been proposed. Importantly, these recommend the use of polypropylene collection/sampling tubes while, to date, no broad comparison of these types of tubes has been conducted. In this study, we first compared, as part of a real clinical workflow, the impact of four different collection tubes on the CSF concentration of Abeta peptides (Abeta42, Abeta40) and total (hTau) and phosphorylated (P-Tau181P) tau proteins measured using routine ELISA kits. We then extended this study to 11 polypropylene tubes used by different clinical laboratories, and investigated their plastic polymer composition using differential scanning calorimetry and Fourier Transformed Infrared spectroscopy. Significant concentration variations linked solely to the use of different types of tubes were observed. This was particularly marked for Abeta peptides, with >50% disparity occurring in less than five minutes. Polymer composition analysis revealed that most polypropylene tubes were in fact copolymers with at least polyethylene. There was no clear correlation between tube composition and pre analytical behavior. Our results show that the use of polypropylene tubes does not guarantee satisfactory pre-analytical behavior. They also point to collection/sampling tubes being a major pre-analytical source of variability that could impact the significance of AD biological diagnosis. PMID- 22495346 TI - Niemann-Pick C1 mice, a model of "juvenile Alzheimer's disease", with normal gene expression in neurons and fibrillary astrocytes show long term survival and delayed neurodegeneration. AB - Niemann-Pick C1 (NPC) disease, also known as "juvenile Alzheimer's disease", is a disease in which alterations in intracellular cholesterol trafficking occur. The contribution of various CNS cell types to the neurodegeneration has been of much interest. We have previously shown that expression of the normal gene only in fibrillary astrocytes could extend survival of Npc1-/- mice over 3-fold (Zhang et al., 2008 [13]). We have now studied expression only in neurons or in both neurons and fibrillary astrocytes. Neuron-only expression resulted in survivals of over a year (>5-fold) but motor symptoms started at about 6 months. As reflected in weight gain, this especially affected females who weighed less than wild-type starting at about 10 weeks while male differences in weight are delayed. Expression in both cell types led to a nearly normal phenotype with motor symptoms developing at about ten months and increased survival times. Purkinje cell loss was slowed, but severe, in both NSE- and NSE-GFAP-Npc1, transgenic Npc1-/- mice. MRI studies showed that myelination of the long tracts was significantly improved in NSE-Npc1 transgenics, perhaps less than in GFAP Npc1 transgenics, and not differently than in the double transgenics. Memory was improved in both single and double transgenics. Somatic disease had not been ameliorated and lungs were massively infiltrated with foamy macrophages at 10 months. Our results suggest that neuron-only expression does not completely prevent neurodegeneration and that the addition of astrocyte expression decreases the rate/degree of decline. PMID- 22495347 TI - Chronic allopregnanolone treatment accelerates Alzheimer's disease development in AbetaPP(Swe)PSEN1(DeltaE9) mice. AB - The endogenous neurosteroid allopregnanolone alters neuronal excitability via modulation of the GABAA receptor and causes decreased neurotransmission. In Alzheimer's disease (AD), neurotransmission seems to alter the levels of toxic intracellular amyloid-beta (Abeta) oligomers, which are implicated in AD pathogenesis and cause cognitive decline. Inhibition of synaptic activity has been shown to increase levels of intracellular Abeta. Allopregnanolone at endogenous stress levels inhibits synaptic activity and could have similar effects. By using a transgenic AbetaPP(Swe)PSEN1(DeltaE9) mouse model for AD, we observed that chronic allopregnanolone treatment for three months with stress levels of allopregnanolone impaired learning in the Morris water maze. The learning impairment was seen one month after the end of treatment. Chronic allopregnanolone treatment also led to increased levels of soluble Abeta in the brain, which could be a sign of advanced pathogenesis. Since the learning and memory of wild-type mice was not affected by the treatment, we propose that chronic allopregnanolone treatment accelerates the pathogenesis of AD. However, further studies are required in order to determine the underlying mechanism. PMID- 22495348 TI - Reelin depletion is an early phenomenon of Alzheimer's pathology. AB - Alterations in the expression of Reelin (RELN) have been implicated in the pathology of Alzheimer's disease (AD). However, whether these changes are cause or consequence of AD remains to be resolved. To better understand the role of RELN pathway in the development of AD, we examined the expression profile of RELN and its downstream signaling members APOER2, VLDLR, and DAB1 in AD-vulnerable regions of transgenic and wildtype mice as well as in AD patients and controls across disease stages and/or aging. We show that both AD pathology and aging are associated with perturbation of the RELN pathway in a species-, region-, and molecule-specific manner. Further, we show that depletion of RELN, but not its downstream signaling molecules, is detectable long before the onset of amyloid beta pathology in the murine hippocampus and in a pre-clinical AD stage in the human frontal cortex. This early event hints at a possible causative role of RELN decline in the precipitation of AD pathology and supports RELN's potential as a pre-clinical marker for AD. PMID- 22495350 TI - Superior antitumoral activity of dimerized targeted single-chain TRAIL fusion proteins under retention of tumor selectivity. AB - Although targeting of the death receptors (DRs) DR4 and DR5 still appears a suitable antitumoral strategy, the limited clinical responses to recombinant soluble TNF-related apoptosis inducing ligand (TRAIL) necessitate novel reagents with improved apoptotic activity/tumor selectivity. Apoptosis induction by a single-chain TRAIL (scTRAIL) molecule could be enhanced >10-fold by generation of epidermal growth factor receptor (EGFR)-specific scFv-scTRAIL fusion proteins. By forcing dimerization of scFv-scTRAIL based on scFv linker modification, we obtained a targeted scTRAIL composed predominantly of dimers (Db-scTRAIL), exceeding the activity of nontargeted scTRAIL ~100-fold on Huh-7 hepatocellular and Colo205 colon carcinoma cells. Increased activity of Db-scTRAIL was also demonstrated on target-negative cells, suggesting that, in addition to targeting, oligomerization equivalent to an at least dimeric assembly of standard TRAIL per se enhances apoptosis signaling. In the presence of apoptosis sensitizers, such as the proteasomal inhibitor bortezomib, Db-scTRAIL was effective at picomolar concentrations in vitro (EC(50) ~2 * 10(-12) M). Importantly, in vivo, Db-scTRAIL was well tolerated and displayed superior antitumoral activity in mouse xenograft (Colo205) tumor models. Our results show that both targeting and controlled dimerization of scTRAIL fusion proteins provides a strategy to enforce apoptosis induction, together with retained tumor selectivity and good in vivo tolerance. PMID- 22495349 TI - Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer's disease. AB - Thiazolidinediones (TZDs) are agonists at peroxisome proliferator-activated gamma type (PPAR-gamma) receptors and are used clinically for the treatment of type 2 diabetes where they have been shown to reestablish insulin sensitivity, improve lipid profiles, and reduce inflammation. Recent work also suggests that TZDs may be beneficial in Alzheimer's disease (AD), ameliorating cognitive decline early in the disease process. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. Starting at 10 months of age, the triple transgenic mouse model of AD (3xTg-AD) with accelerated amyloid-beta (Abeta) deposition and tau pathology was treated with the TZD pioglitazone (PIO-Actos) at 18 mg/Kg body weight/day. After four months, PIO treated animals showed multiple beneficial effects, including improved learning on the active avoidance task, reduced serum cholesterol, decreased hippocampal amyloid-beta and tau deposits, and enhanced short- and long-term plasticity. Electrophysiological membrane properties and post-treatment blood glucose levels were unchanged by PIO. Gene microarray analyses of hippocampal tissue identified predicted transcriptional responses following TZD treatment as well as potentially novel targets of TZDs, including facilitation of estrogenic processes and decreases in glutamatergic and lipid metabolic/cholesterol dependent processes. Taken together, these results confirm prior animal studies showing that TZDs can ameliorate cognitive deficits associated with AD-related pathology, but also extend these findings by pointing to novel molecular targets in the brain. PMID- 22495351 TI - Human Gyrovirus Apoptin shows a similar subcellular distribution pattern and apoptosis induction as the chicken anaemia virus derived VP3/Apoptin. AB - The chicken anaemia virus-derived protein Apoptin/VP3 (CAV-Apoptin) has the important ability to induce tumour-selective apoptosis in a variety of human cancer cells. Recently the first human Gyrovirus (HGyV) was isolated from a human skin swab. It shows significant structural and organisational resemblance to CAV and encodes a homologue of CAV-Apoptin/VP3. Using overlapping primers we constructed a synthetic human Gyrovirus Apoptin (HGyV-Apoptin) fused to green fluorescent protein in order to compare its apoptotic function in various human cancer cell lines to CAV-Apoptin. HGyV-Apoptin displayed a similar subcellular expression pattern as observed for CAV-Apoptin, marked by translocation to the nucleus of cancer cells, although it is predominantly located in the cytosol of normal human cells. Furthermore, expression of either HGyV-Apoptin or CAV-Apoptin in several cancer cell lines triggered apoptosis at comparable levels. These findings indicate a potential anti-cancer role for HGyV-Apoptin. PMID- 22495353 TI - Midterm outcomes of patients undergoing aortic valve replacement after previous coronary artery bypass grafting. AB - OBJECTIVES: Redo cardiac surgery for aortic valve replacement (AVR) after previous coronary artery bypass grafting (CABG) is technically challenging and carries a high incidence of peri-operative complications. However, experience in the field continues to evolve generating reproducible, and increasingly safer results. We anticipate an increased future role for catheter-based valve procedures and review our operative results to maintain current surgical outcomes for comparison. METHODS: A retrospective review was conducted from 1996 through 2010 of patients undergoing AVR as a re-operation after previous CABG. Data were obtained through query of the Society of Thoracic Surgeons (STS) database and chart review. Patient outcomes were compared with STS-predicted risk scores. RESULTS: One hundred and thirty-two patients met inclusion criteria (male 83%, female 17%). Average age was 76 (+/- 7). Thirty-seven patients (28%) required concomitant CABG. Average ejection fraction was 45 (+/- 14). Comorbid conditions included: diabetes 37% (49/132), hypertension 87% (115/132), NYHA class III/IV 83% (110/132), smoking 51% (67/132), chronic obstructive pulmonary disease 21% (27/132), history of myocardial infarction 61% (80/132), renal failure 16% (21/132) and peripheral arterial disease 38% (50/132).Operative (30-day + hospital) mortality was 6.1% (8/132; 95% CI = 2.9-12.0%), and 30-day mortality was 3.8% (5/132; 95% CI = 1.4-9.1%). One, three and five-year survival rates were 86, 74 and 62%, respectively. Complication rates were as follows: re-operation for bleeding 2.3% (3/132), permanent stroke 0.8% (1/132), prolonged ventilator requirement 18.2% (24/132), deep sternal wound infection 0% (0/132; CI = 0.0 3.5%) and renal failure 9.1% (12/132; none required dialysis). The mean STS predicted mortality risk score was 7.8% for 111 (applicable) patients for whom actual operative (30-day + hospital) mortality was 3.6%. CONCLUSIONS: Low initial operative mortality suggests that surgery is safe and reproducible. However, older age and multiple comorbidities in this patient population may significantly influence late outcomes. The data reported in this study: (i) support open surgical technique as a safe, reliable approach for redo AVR in patients who have undergone previous CABG, and (ii) add to the large body of evidence suggesting that STS scores overestimate risk. PMID- 22495354 TI - 1,25-Dihydroxycholecalciferol with low-calcium diet reduces acute rejection in rat lung allotransplantation. AB - OBJECTIVES: The effect of 1,25-dihydroxycholecalciferol (calcitriol, vitamin D3) with a low-calcium diet on the acute lung allograft rejection in a rat unilateral left lung transplantation model was evaluated. METHODS: Three transplantation groups were studied (n = 5, male Brown-Norway to Fischer F344, 235 +/- 15 g body weight): calcitriol and low-calcium diet, low-calcium diet and normal diet. Calcitriol (4 MUg/kg/day) was injected intraperitoneally for 5 days, starting from the day of transplantation. In addition, two non-transplantation groups were compared: (n = 3, Brown-Norway) to measure the level of cytokines, and Fischer F344 receiving calcitriol and a low-calcium diet to measure the serum calcium level. The recipients of transplantation were killed on Day 5 post-transplant. The contralateral right main bronchus and the pulmonary artery were occluded for 5 min and blood was drawn for the blood gas analysis, and the grafts were assessed for histology (International Society for Heart and Lung Transplantation 1996/rank scale). Lung levels of interleukin (IL)-2, IL-6, IL-12 and tumour necrosis factor-alpha (TNF-alpha) were assessed within the calcitriol and low calcium diet, low-calcium diet and Brown-Norway groups. The serum calcium level was assessed in the Fischer F344 group. An analysis of variance with Tukey's post hoc test was used to compare the arterial blood oxygen pressure and the lung cytokine expression between groups. A non-parametric Kruskal-Wallis test followed by the Siegel and Castellan post hoc test was used to assess the differences between the groups according to the lung graft rejection grading. Student's paired t-test was used to compare the serum calcium level. RESULTS: The arterial PaO(2) was significantly higher in the calcitriol and the low-calcium diet groups when compared with low-calcium diet or normal diet groups (356 +/- 72 mmHg; P < 0.05 vs other groups). The arterial and bronchial rejection observed in calcitriol and low-calcium diet group was significantly milder than in the low calcium diet or normal diet groups (A1-2, B1-2; P < 0.05 vs other groups). IL-2 and IL-6 levels were significantly higher in low-calcium diet vs calcitriol and low-calcium diet and Brown-Norway groups. IL-12 and TNF-alpha did not differ among the groups. There was no significant difference in serum calcium level before and after the treatment in the Fischer F344 group. CONCLUSIONS: Calcitriol with a low-calcium diet treatment improves lung function, reduces lung allograft acute rejection, decreases IL-2 and IL-6 allograft expression and does not change the serum calcium level significantly. PMID- 22495352 TI - Mss4 protein is a regulator of stress response and apoptosis. AB - Mss4 (mammalian suppressor of Sec4) is an evolutionarily highly conserved protein and shows high sequence and structural similarity to nucleotide exchange factors. Although Mss4 tightly binds a series of exocytic Rab GTPases, it exercises only a low catalytic activity. Therefore Mss4 was proposed to work rather as a chaperone, protecting nucleotide free Rabs from degradation than as a nucleotide exchange factor. Here we provide further evidence for chaperone-like properties of Mss4. We show that expression levels of cellular Mss4 mRNA and protein are rapidly changed in response to a broad range of extracellular stress stimuli. The alterations are regulated mostly via the (c-jun NH(2)-terminal kinase) JNK stress MAPK signaling pathway and the mode of regulation resembles that of heat shock proteins. Similar to heat shock proteins, upregulation of Mss4 after stress stimulation functions protectively against the programmed cell death. Molecular analysis of the Mss4-mediated inhibition of apoptosis showed that interaction of Mss4 with eIF3f (eukaryotic translation initiation factor 3 subunit f), a member of the translation initiation complex and a protein with distinct pro-apoptotic properties, is the critical event in the anti-apoptotic action of Mss4. PMID- 22495355 TI - Is elevated troponin associated with in-hospital mortality in emergency department patients admitted with chronic obstructive pulmonary disease? AB - The aim of this study was to determine the prevalence and prognostic value of troponin elevation at emergency department (ED) presentation in patients admitted with an exacerbation of chronic obstructive pulmonary disease (COPD). A retrospective cohort study of ED patients with acute exacerbations of COPD who were admitted to hospital and in whom troponin was assayed at ED presentation. Other data collected included demographics, clinical characteristics, test results, and outcome. Outcome of interest was in-hospital mortality. A total of 252 patients were studied, median age 73 years, 61% men. In-hospital mortality was 4.4% [n=11; 95% confidence interval (CI) 2.5-7.7%]. Seventy-eight patients had elevated troponin of greater than 99th centile (31%, 95% CI 26-37%). Factors independently associated with mortality were troponin elevation [odds ratio (OR) 8.3, 95% CI 1.58-43.7], pH less than 7.2 (OR 12.7, 95% CI 1.86-86.4), and requirement for noninvasive ventilation (OR 8.09, 95% CI 1.61-40.8). In conclusion, troponin elevation is associated with increased in-hospital mortality in ED patients with acute exacerbation of COPD. PMID- 22495356 TI - Malarial cases presenting to a European urban Emergency Department. AB - INTRODUCTION: Malaria accounts for approximately 225 million infections and 781 000 deaths annually worldwide. Malaria should be considered in the Emergency Department as an important cause of illness in returning travellers. We were interested in evaluating the malarial caseload presenting to an urban inner city Emergency Department in terms of the nature and severity of clinical presentations. METHODS: A retrospective study of all cases of malaria presenting to our Emergency Department from 1 January 2004 to the 31 December 2010 was conducted. Information about patient demographics, areas in which malaria was contracted, clinical course, treatment and complications was recorded from chart reviews. RESULTS: Fifty-six cases of malaria were diagnosed in the period studied. The majority of patients had falciparum malaria (80%), were originally from West or Central Africa (75%), were mainly from Nigeria (48%), and were visiting friends and relatives in their country of origin. A total of 79% had not taken appropriate antimalarial chemoprophylaxis. A total of 7% were classified as severe malaria according to the WHO criteria. There was one death. CONCLUSION: Malarial cases occurred predominantly in immigrants who were returning to endemic areas to visit friends and relatives in their country of origin. The majority of patients did not undergo antimalarial prophylaxis. Severe malaria is a medical emergency requiring urgent recognition and appropriate antimicrobial and critical care therapy. Improving public awareness and healthcare promotion regarding risks of travel-related malaria may help to improve compliance with prophylaxis and preventative measures, and thereby reduce the prevalence of malarial infection in this group. PMID- 22495357 TI - [Anti-VEGF therapy for neovascular age-related macular degeneration: therapeutic strategies]. PMID- 22495358 TI - Delay to formalin fixation alters morphology and immunohistochemistry for breast carcinoma. AB - BACKGROUND: Delay to formalin fixation (DFF) also known as cold ischemia has been known to have an adverse effect on breast biomarkers. The aim of the study was to further evaluate the effect of DFF on tumor histomorphology and immunohistochemistry. MATERIALS AND METHODS: Ten palpable invasive breast carcinomas were resected and underwent immediate gross evaluation. For each case, the procured tumor was divided into 8 equal parts and consecutively fixed after 0, 10, and 30 minutes, 1, 2, 4, and 8 hours; 1 section was kept in saline and stored overnight at 4 degrees C. Stains normally used in breast pathology including epidermal growth factor receptor, Ki-67, p53, AE 1/3, CAM-5.2, cytokeratin (CK)7, CK14, CK5/6, epithelial membrane antigen, E-cadherin, gross cystic disease fluid protein 15, and mammaglobin were studied. The change was considered significant if it had any pathologic or clinical consequence. RESULTS: DFF had spurious effect on 9 of 10 cases. However, significant alteration that affected the histomorphologic interpretation was observed in 3 cases. Significant immunohistochemistry alteration was seen only in the membranous markers (epidermal growth factor receptor and E-cadherin). Although the quality of the cytoplasmic markers was affected, the interpretation (positive vs. negative) was not affected by DFF. Ki-67 had minimal but insignificant change. Generally, these changes occurred at or after 2-hour mark. CONCLUSIONS: Therefore, specimens should be fixed within 1 hour from tissue harvesting and not stored without fixation overnight. PMID- 22495360 TI - KIT mutations and sequence changes in genes encoding SDH complex possibly need not be mutually exclusive in gastrointestinal stromal tumors. PMID- 22495359 TI - IMP3, NESP55, TTF-1 and CDX2 serve as an immunohistochemical panel in the distinction among small-cell carcinoma, gastrointestinal carcinoid, and pancreatic endocrine tumor metastasized to the liver. AB - Histopathologic distinction among small-cell carcinoma (SCC), pancreatic endocrine tumor (PET), and gastrointestinal carcinoids metastasized to the liver in needle core biopsies can be extremely challenging because of limited material, crush artifact, and lack of detailed clinical history. In this study, a total of 61 surgically resected or biopsied specimens, including 27 SCCs (lung, 17; colon, 1; gallbladder, 2; stomach, 1; and unknown primary, 6), 18 gastrointestinal carcinoid tumors (GICTs) (stomach, 2; small intestine, 14; colon, 2), and 16 PETs were immunohistochemically examined for the expression of IMP3, TTF-1, CDX2, and NESP55 to evaluate their diagnostic value. The results showed that 24 (89%) of 27 SCCs exhibited strong cytoplasmic staining for IMP3 in 60% to 100% of the tumor cells. Eighteen (67%) SCCs were strongly and diffusely positive for TTF-1. In the remaining 9 TTF-1-negative SCCs (including 4 extrapulmonary cases), 7 showed strong and diffuse IMP3 expression. All SCCs were negative for CDX2 except for 1 case of colonic origin that showed strong CDX2 immunoreactivity. All 16 metastatic PETs were positively stained for IMP3 with 12 cases (75%) showing a diffuse and moderate-to-strong staining pattern while they were negative for TTF 1. Six PETs exhibited moderate-to-strong positivity for CDX2 with nuclear staining in 5% to 40% of tumor cells, and 5 showed a varying degree of positivity for NESP55. Three (17%) of 18 metastatic GICTs showed moderate IMP3 staining in 50% to 90% of the tumor cells, whereas CDX2 was expressed in 17 (94%) cases with moderate-to-strong staining in 50% to 100% of tumor cells. No NESP55 immunoreactivity was detected in metastatic SCCs and GICTs. In conclusion, a panel of these 4 markers is useful in segregating among SCC, PET, and GICT to help determine the primary site of hepatic metastasis. PMID- 22495361 TI - MSH6 mutations are frequent in hereditary nonpolyposis colorectal cancer families with normal pMSH6 expression as detected by immunohistochemistry. AB - INTRODUCTION: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition accounting for 2% to 4% of all colorectal cancer cases worldwide. Families with germ line mutations in 1 of 6 mismatch repair genes are known as Lynch syndrome families. The largest number of mutations has been detected in the mismatch repair genes MLH1 and MSH2, but several mutations in MSH6 have also been demonstrated. AIM: : Whether HNPCC families are screened for mutations in mismatch repair genes often relies on their immunohistochemical profile. The aim of the present study was to evaluate this approach in Lynch families carrying mutations in MSH6. MATERIALS AND METHODS: Results of the screening of the MSH6 gene in HNPCC families were compared with those obtained on immunohistochemical protein analysis. RESULTS: In 56 (7%) of 815 families, at least 1 MSH6 mutation, 23 definitively pathogenic mutations and 38 missense mutations or unclassified variants, and several polymorphisms in the MSH6 gene were detected. In families carrying a pathogenic MSH6 mutation, 69.6% of 23 colon adenocarcinomas showed absence of pMSH6 in tumor tissue by immunohistochemical analysis. In 34.5%, all proteins could be detected, whereas in 34.5% pMSH6 was present and pMLH1/pPMS2 was absent. CONCLUSIONS: If genetic screening of HNPCC families depended on immunohistochemical results, a substantial number of families harboring a pathogenic mutation in MSH6 and the vast majority of families harboring an MSH6 unclassified variant would not be detected. PMID- 22495362 TI - Diagnostic utility of hepatocyte nuclear factor 1-beta immunoreactivity in endometrial carcinomas: lack of specificity for endometrial clear cell carcinoma. AB - Hepatocyte nuclear factor 1-beta (HNF1beta) has recently emerged as a relatively sensitive and specific marker for ovarian clear cell carcinoma. The purpose of this study is to assess the diagnostic utility of this marker for endometrial clear cell carcinoma. Immunohistochemical analysis was performed on 75 endometrial tissues using a goat polyclonal antibody raised against a peptide mapping at the C-terminus of human HNF1beta protein. The 75 cases included 15 clear cell carcinomas, 20 endometrioid carcinomas, 15 endometrial serous carcinomas/uterine papillary serous carcinomas, 20 cases of normal endometrium, 2 cases of clear cell metaplasia, and 3 cases of Arias Stella reaction. Staining interpretations were based on a semiquantitative scoring system, a 0 to 12+ continuous numerical scale that was derived by multiplying the extent of staining (0 to 4+ scale) by the intensity of staining (0 to 3+ scale) for each case. HNF1beta expression was found to be present in a wide spectrum of tissues. Twenty seven (54%) of the 50 carcinomas displayed at least focal nuclear HNF1beta expression, including 11 (73%) of 15, 9 (60%) of 15, and 7 (35%) of 20 clear cell, serous, and endometrioid carcinomas, respectively. The average nuclear staining scores for clear cell carcinomas, endometrioid carcinomas, and serous carcinomas were 5.2, 1.4, and 4.1, respectively. Clear cell carcinomas and endometrioid carcinomas displayed statistically significant differences regarding their nuclear staining scores (P = 0.0027), but clear cell carcinomas and endometrial serous carcinomas did not (P = 0.45). The calculated sensitivity of any nuclear HNF1beta expression in classifying a carcinoma as being of the clear cell histotype was 73%, whereas the specificity was 54%. Nineteen of 20 normal endometrium samples displayed at least focal nuclear expression of HNF1beta, and this expression was often diffuse. The 5 cases of benign histologic mimics of clear cell carcinomas (Arias Stella reaction and clear cell metaplasia) displayed some degree of HNF1beta immunoreactivity, with an average nuclear staining score of 7.3. We conclude that although HNF1beta is frequently expressed in clear cell carcinomas, it should be used with caution as a diagnostic marker because of its lack of specificity. It neither distinguishes endometrial serous carcinomas from clear cell carcinomas nor clear cell carcinomas from its benign mimics. The greatest diagnostic utility of HNF1beta expression may be in a supportive evidentiary role favoring clear cell carcinoma when the principal differential diagnostic consideration is endometrioid carcinoma. PMID- 22495363 TI - Urinary bladder sinuses: a novel morphologic lesion with clinical and pathologic significance. AB - BACKGROUND: We described urinary bladder sinuses (UBS) in the urinary bladder, characterized by segmental mucosal with muscularis mucosa invaginations into the submucosa (superficial UBS) and muscularis propria (deep UBS). MATERIALS: Radical cystectomy specimens and transurethral resections of the bladder were reviewed. RESULTS: Superficial UBS (extending up to the submucosa) were distinguished from cystitis cystica, and deep UBS differed from embryonic remnants, intramural ureters, and diverticulum by their cleft-like structures lined by the urothelium. In transurethral resections of the bladder specimens and bladder biopsy specimens, superficial UBS were identified in 13/20 cases. In radical cystectomy specimens, superficial UBS were identified in 15/50 cases, whereas deep UBS (all with associated superficial UBS) were seen in 23/50 additional cases. Deep UBS limited to the inner quarter of the muscularis propria and only reached the level of the inner third outer/middle third of the muscularis propria in 5 cases. Intraepithelial neoplasia involved the mucosa of UBS in 10 cases; this may pose diagnostic problems with invasive carcinoma. Furthermore, UBS were often associated with mucosal redundancy and hypertrophy of the muscularis propria, therefore mimicking muscle invasive cancer on pelvic examination and imaging techniques. CONCLUSIONS: Recognition of UBS is important to pathologically and clinically avoid over-staging of bladder malignancies. PMID- 22495364 TI - Lymphangiogenesis and podoplanin expression in oral squamous cell carcinoma and the associated lymph nodes. AB - The objective of this study was to evaluate lymphangiogenesis in oral squamous cell carcinoma and in the associated lymph nodes and podoplanin expression in neoplastic cells at the invasive front. In addition, the association of the above parameters with lymph node metastasis was also investigated. We used immunohistochemistry to examine primary tumors and lymph nodes, regardless of metastasis. Lymphatic vessel density (LVD) and microvessel density (MVD) were assessed by antibodies D2-40 and CD105, respectively, in intratumoral and peritumoral areas and in lymph node regions. Vascular endothelial growth factor-C and vascular endothelial growth factor receptor-3 expression was evaluated in tumor cells and D2-40 (podoplanin) expression in parenchymal cells found at the invasive front. The majority of cases with nodal involvement presented a high peritumoral LVD. In addition, a strong association of LVD with size and site of primary tumors could also be identified. MVD was statistically associated with metastasis, and a significant association between the lymphangiogenic factors and the density of vessels in the intratumoral region was also seen. The well differentiated tumors did not express podoplanin. LVD and MVD were higher in metastatic lymph nodes than in nonmetastatic lymph nodes. The enhanced vascular network in metastatic lymph nodes reinforces the previous reports of lymphangiogenesis occurrence in lymph nodes. Moreover, the expression of podoplanin by more undifferentiated tumor cells suggests that this protein could be an indicator of tumor aggressiveness. PMID- 22495365 TI - Evaluation of putative renal cell carcinoma markers PAX-2, PAX-8, and hKIM-1 in germ cell tumors: a tissue microarray study of 100 cases. AB - In a subset of cases, metastatic renal cell carcinoma can demonstrate significant morphologic overlap with germ cell neoplasms, making accurate diagnosis challenging. In such cases, immunohistochemistry is often used as an adjunct diagnostic tool. Expression of the putative renal cell carcinoma markers PAX-2, PAX-8, and hKIM-1 has been reported in a small series of certain germ cell tumors, raising doubt about their specificity for renal cell carcinoma. To further characterize these markers, we evaluated PAX-2, PAX-8, and hKIM-1 staining in 100 germ cell tumors using tissue microarrays. PAX-2 and PAX-8 staining was identified in 50% and 25% of yolk sac tumors (respectively), with hKIM-1 staining identified in 48% of embryonal carcinomas and 50% of yolk sac tumors. All other germ tumor cells (notably including 62 seminomas) were negative for all 3 markers, in contrast to prior reports of PAX-8 reactivity in seminoma. This study indicates that PAX-2, PAX-8, and hKIM-1 should be used cautiously in distinguishing renal cell carcinoma from nonseminomatous germ cell neoplasia and also adds to the growing list of nonrenal tumors that express these 3 markers. PMID- 22495366 TI - CK20 positivity in hepatocellular carcinoma: a potential diagnostic pitfall in liver biopsy. PMID- 22495367 TI - HER2/neu gene amplification heterogeneity: the significance of cells with a 3:1 HER2/CEP17 ratio. AB - College of American Pathologists published guidelines for the assessment of HER2/neu genetic heterogeneity. When 20 cells are counted for evaluation of HER2/neu amplification, a single 3:1 HER2/CEP17 ratio cell characterizes the sample as heterogneous. Heterogeneity for HER2/neu amplification may indicate biologically important characteristics including likelihood of amplification in metastases. We performed fluorescence in situ hybridization on 1546 cases. For each case, 20 cells of invasive carcinoma were analyzed for HER2/CEP17 ratio. Cases were assessed as nonamplified (ratio<1.8), borderline amplified (1.8 <= ratio <= 2.2), or amplified (ratio>2.20). Heterogeneity was present when the percentage of cell with ratios >2.20 was >=5% but <50%. Individual cells were typed by probe ratios and distribution of cell types determined. The distribution of HER2/CEP17 ratio was determined with the number of 3:1 HER2/CEP17 cells plotted against the number of amplified cells. 3:1 HER2/CEP17 ratio cells occur with low frequency (2.2%) but are the determining factor for heterogeneity in 46% of heterogenous cases. Thirty-five percent of heterogenous cases were due to a single 3:1 cell. Single 3:1 cells are a poor predictor for additional amplified cells. Inclusion of cells with a 3:1 HER2/CEP17 ratio in the definition of heterogeneity may be too broad as these cells are the determining factor in approximately one third of diagnoses of heterogeneity but are not strongly associated with other measures of amplification. Moreover, 3:1 HER2/CEP17 ratio cells are a poor predictor for the presence of additional amplified cells in a sample. PMID- 22495368 TI - Laser-assisted microdissection in translational research: theory, technical considerations, and future applications. AB - Molecular profiling already exerts a profound influence on biomedical research and disease management. Microdissection technologies contribute to the molecular profiling of diseases, enabling investigators to probe genetic characteristics and dissect functional physiology within specific cell populations. Laser-capture microdissection (LCM), in particular, permits collation of genetic, epigenetic, and gene expression differences between normal, premalignant, and malignant cell populations. Its selectivity for specific cell populations promises to greatly improve the diagnosis and management of many human diseases. LCM has been extensively used in cancer research, contributing to the understanding of tumor biology by mutation detection, clonality analysis, epigenetic alteration assessment, gene expression profiling, proteomics, and metabolomics. In this review, we focus on LCM applications for DNA, RNA, and protein analysis in specific cell types and on commercially available LCM platforms. These analyses could clinically be used as aids to cancer diagnosis, clinical management, genomic profile studies, and targeted therapy. In this review, we also discuss the technical details of tissue preparation, analytical yields, tissue selection, and selected applications using LCM. PMID- 22495369 TI - Expression of TMEM166 protein in human normal and tumor tissues. AB - Transmembrane protein 166 (TMEM166) is a novel human regulator involved in both autophagy and apoptosis. In this study, we generated a specific rabbit polyclonal antibody against human TMEM166 and assessed the expression of this protein in various human normal and tumor tissue samples by tissue microarray-based immunohistochemical analysis. Varying TMEM166 protein levels were expressed in a cell-type and tissue-type-specific manner in detected tissues or organs. Strong TMEM166 expression was shown in the glomerular zona of the adrenal cortex, chromophil cells of the pituitary gland, islet cells, squamous epithelium of the esophagus mucosa, the fundic gland, and hepatocytes. Moderate or weak TMEM166 staining was identified in the parathyroid gland, the testis, vaginal stratified squamous cells, lung macrophages, hematopoietic cells, renal tubular epithelial cells, macrophages in the spleen red pulp, and neuronal cells in the cerebral cortex. Some tissues failed to stain for TMEM166, such as adipose tissue, colon, cerebellum, lymph node, mammary gland, ovary, prostate, rectum, skin, small intestine, thyroid gland, tonsil, and thymus. In comparing human normal and tumor tissues, TMEM166 expression was widely downregulated in the cancer tissues. Our studies provide the basis for future investigations into cell-type-specific functions of this protein in human normal and tumor tissues. PMID- 22495370 TI - MIST1-a novel marker of plasmacytic differentiation. AB - BACKGROUND: Currently available plasma cell markers include CD138 and CD38. However, CD38 is not specific to plasma cells. It is also expressed by many epithelial cells and other hematopoietic cells. In addition, rare CD138-negative PCNs may be exceedingly difficult to diagnose. MIST1 is a transcription factor expressed by mouse and human neoplastic and non-neoplastic plasma cells. Our goals were to compare MIST1 expression to CD38/CD138 in neoplasms with plasmacytic differentiation, assess reactivity in normal samples and nonplasmacytic cell lineages, and to determine whether MIST1 is expressed in CD138-negative PCNs. DESIGN: Eighty-five neoplasms with plasma cell differentiation [marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), plasmablastic lymphoma (PB), plasma cell neoplasm (PCN)] and 2 non-neoplastic cases (normal marrow) were tested with MIST1 immunohistochemistry. CD138/38 expression for each case was compared with MIST1 reactivity. RESULTS: Plasma cells were MIST1 positive in all cases interrogated. CD38 and/or CD138 expression was reviewed in all cases and found to be concordant in 46/47 (97.8%) of tested cases, with the exception of 1 case of PB that showed MIST1 positivity and no CD138 expression. All other cell lineages were negative, with the exception of MZL and LPL, in which MIST1 highlighted a subset of the lymphocytes, with plasmacytic differentiation. CONCLUSIONS: MIST1 is a sensitive and specific marker of plasmacytic differentiation. CD138+ plasma cells expressed MIST1 in all tested cases; however, 1 PB showed MIST1 positivity and no CD138 expression, suggesting MIST1 may be useful in certain CD138-negative cases. In MZL and LPL, MIST1 highlights a subset of the lymphocytes in lymphomas with plasmacytic differentiation. PMID- 22495371 TI - Concordance between tissue microarray and whole-section estrogen receptor expression and intratumoral heterogeneity. AB - Hormone receptor status determination for breast cancer is an important part of pathologists' daily sign outs and many retrospective and prospective studies. In this study, we compared the estrogen receptor (ER) expression tested on tissue microarray (TMA) sections to those tested on whole sections (WS) to find out concordance and frequency of intratumoral heterogeneity. Five and one-half percent of all tumors showed discrepancy in ER expression between TMA and WS. The rate of discrepancy was lower with increasing number of cores from individual cases. In 1.4% of cases, there was discrepancy in ER expression between cores in which >1 core was available on TMA section. We concluded that TMA can be used to determine ER status with good concordance to ER determination done on WS. Whenever the size of the tumor in the block allows it, more cores should be taken to construct TMAs. PMID- 22495372 TI - Assessment of human epidermal growth factor receptor 2 status in urothelial carcinoma of the upper urinary tract: a study using dual-color in situ hybridization and immunohistochemistry. AB - AIM: Upper urinary tract urothelial carcinoma (UUTUC) is an uncommon neoplasm frequently discovered at a high-stage disease. The prognosis of disseminated UUTUCs is poor despite the use of platinum-based chemotherapy. The aim of the study was to evaluate HER2 overexpression and amplification in a series of 83 UUTUCs. MATERIALS AND METHODS: All tumors were formalin fixed. TNM stage, grade, lymphovascular invasion, surgical margins, morphologic variants were reviewed by 2 pathologists. All tumors were immunostained with anti-HER2 antibody. HER2 gene amplification was determined by dual-color in situ hybridization. Gene amplification was defined by an HER2/CEN 17 ratio >2.2. RESULTS: HER2 immunostaining was observed in 33/83 tumors. Twelve cases were 2+ score and 2 cases were 3+ score. HER2 in situ hybridization was evaluable in 75/83 cases. Amplification was observed in 6 (7%) cases. All amplified tumors were of high grade and 4/6 were stage pT3. A strong correlation between HER2 overexpression and amplification was noted (P<0.0001). HER2 overexpression and amplification were correlated with the pN+ stage but not with specific survival or recurrence. CONCLUSIONS: These results suggest that HER2 amplification is a rare event in UUTUC but may be of interest for targeted therapy in selected high-grade and high stage tumors. PMID- 22495373 TI - Nottingham-defined mitotic score: comparison with visual and image cytometric phosphohistone H3 labeling indices and correlation with Oncotype DX recurrence score. AB - Prognosis of breast cancer patients has been determined traditionally by lymph node status, tumor size, and histologic grade. In recent years the Oncotype DX recurrence score (RS) assay has emerged as an expensive adjunct prognostic tool. Markers of proliferation play a large role in determination of RS, and we have shown previously that immunohistochemical expression of proliferation markers Ki 67 and phosphohistone H3 (PPH3) correlates with RS. Our current goal is comparison of the hematoxylin and eosin (H&E) mitotic score, defined by the Nottingham grading system, with anti-PPH3 mitotic figure labeling assessed by both visual and automated image analysis and correlation of mitotic score results with RS. Estrogen receptor-positive breast carcinomas from 137 patients with Oncotype DX testing were selected. A representative H&E-stained tumor section was evaluated. Mitoses were counted per 10 high-power fields and tumors graded using the Nottingham criteria by 1 pathologist in accordance with College of American Pathologists-recommended mitotic count cutoffs for a field diameter of 0.55 mm. An additional section was immunostained with PPH3 antibody. PPH3 mitotic scores were determined visually and by automated imaging system. Statistical analysis was performed using univariate tests and Spearman coefficient. There was a statistically significant positive correlation among the 3 methods of mitotic score assessment. Specifically, correlation of tumor grades obtained using visual and automated methods of assessment of mitotic activity with PPH3 stain was the strongest and most statistically significant (weighted kappa value 0.84, P<0.001; Spearman coefficient 0.89, P<0.001). There was a statistically significant positive correlation between H&E mitosis score and RS (P<0.001, Spearman coefficient 0.30) and between visual PPH3 mitotic score and RS (P<0.001, Spearman coefficient 0.28). In conclusion, mitotic score by any of the 3 methods studied may be useful in assessing tumor grade, proliferation, and prognosis. PMID- 22495374 TI - Overexpression of GRP78 is associated with malignant transformation in epithelial ovarian tumors. AB - AIM: Glucose-regulated protein 78 (GRP78) is one of the best-characterized endoplasmic reticulum chaperone proteins. The aim of this study was to explore the potential implications of GRP78 in the development of epithelial ovarian carcinomas (EOCs) and the possible clinical usefulness of GRP78 expression as a prognostic biomarker for EOCs. MATERIALS AND METHODS: A total of 133 women were enrolled. This pilot study consisted of 96 cases of EOCs and 37 cases of benign ovarian tumors as controls. The expression of GRP78 protein was studied using tissue microarray technology and immunohistochemistry. RESULTS: Of the 96 invasive carcinomas analyzed, 25 cases (26.0%) showed moderate GRP78 expression and 65 cases (67.7%) showed strong GRP78 expression. Conversely, 17 (45.9%) of the 37 patients with benign ovarian tumors showed no or weak GRP78 staining. Our results demonstrated that GRP78 expression was significantly higher in EOCs than in benign ovarian tumors (P<0.001). However, no statistically significant association was found between GRP78 expression and survival. CONCLUSIONS: The present study suggests that GRP78 plays a significant role in malignant transformation of epithelial ovarian tumors and may represent an important biomarker for EOCs. PMID- 22495375 TI - Microwave heating of long-term formalin-fixed surgical pathology specimens improves quality of extracted DNA. AB - A large amount of DNA of high quality is essential for molecular analysis. The amount of DNA in routine paraffin sections is small. Surgical specimens retained in formalin for the long-term (several months) left over from the sampling required for wax embedding can be referred to as "long-term formalin-fixed" specimens, and clearly this material is a rich source of DNA; however, it is difficult to extract. In the current study, we designed a microwave-heating method for DNA extraction from these specimens. We found that the heating procedure achieved greater DNA yields than a common nonheating method used for comparison (DNA contents mean+/-SD, heating 2.16+/-0.95 MUg/MUL vs. common 1.75+/ 0.90 MUg/MUL, P<0.05). Fluorescence multiplex polymerase chain reaction-capillary electrophoresis successfully detected microsatellite instability (MSI) in the DNA samples derived from this heating procedure (98.4%, 689 of 700 sample tests), at significantly higher levels than from the conventional method (82.3%, 247 of 300 sample tests, P<0.05). We identified 10 (14.3%) MSI with high frequency and 6 (8.6%) MSI with low frequency colorectal cancers. MSI with high frequency cancers showed distinct clinicopathologic features including higher incidence of right sided location, high histologic grade, mucin-production, and prominent intraepithelial lymphocyte infiltration. We concluded that the microwave-heating method was efficient for DNA isolation from long-term formalin-fixed tissue samples. The successful fluorescence multiplex polymerase chain reaction capillary electrophoresis analysis in these samples might facilitate MSI detection in clinical practice. PMID- 22495376 TI - Nephrogenic adenoma: an immunohistochemical analysis using biotin-free methods. AB - Nephrogenic adenoma (NA) has been considered as a metaplastic process of the urothelium. It has been suggested that this lesion is of renal tubular cell origin or differentiation. Immunohistochemical studies of NA emphasize its staining with alpha-methylacyl-coenzyme A racemase (AMACR), and prostatic adenocarcinoma may be a possible differential diagnosis. This reactivity was recently discussed as an artifact due to endogenous biotin. Kidney-specific cadherin (Ksp-cad) is a marker of distal nephron. CD10 and KIT are also expressed in the kidney. We studied the immunohistochemical expression of AMACR, p63, Ksp cad, CD10, and KIT in 9 cases of NA (forming a total of 12 lesions). Practically all of the lesions stained for AMACR with 2 different antibodies and 2 high sensitivity (multimer or polymer based) biotin-free methods (83% and 100%). The staining was similar for both methods in 9 of these 12 lesions. All of the NAs were negative for p63 and KIT, except 1 case, with focal reactivity for KIT. CD10 was expressed very focally in 4 of the 12 lesions (33%). We observed weak staining for Ksp-cad in 6 lesions (50%) and 3 (25%) showed a moderate positivity in 15% to 50% of the cells. In conclusion, positivity of NA for AMACR is not an artifact, as we confirmed using 2 different methods. Besides, p63, a basal cell marker, is usually negative. Immunoreactivity for Ksp-cad seems to support the differentiation of NA to distal nephron cells, at least in some of the cases. Other markers expressed by the nephron, such as CD10 and KIT, are usually negative in NA. PMID- 22495377 TI - Sox10 and S100 in the diagnosis of soft-tissue neoplasms. AB - Despite a well-characterized lack of specificity, pathologists routinely employ S100 in the diagnosis of neural crest-derived tumors. Recent studies have shown that Sox10 is a reliable marker of neural crest differentiation that is consistently expressed in schwannian and melanocytic tumors. We sought to validate these results in a larger series of soft tissue neoplasms of both neural crest and non-neural crest origin, and to further characterize the sensitivity and specificity of Sox10 for use in clinical diagnosis. We evaluated Sox10 and S100 mRNA levels in 122 cases of peripheral nerve sheath tumors and synovial sarcoma and used immunohistochemistry for Sox10 and S100 protein expression in 1012 tissue specimens. This study includes 174 tissue microarray cases previously reported by Nonaka and colleagues, which include cases of melanoma, dermatofibrosarcoma protuberans, neurofibroma, synovial sarcoma, clear-cell sarcoma, malignant peripheral nerve sheath tumor (MPNST), perineurioma, and schwannoma. Synovial sarcomas expressed significantly higher levels of S100B than Sox10 (P=7.9*10), and no significant Sox10 mRNA expression was identified in synovial sarcoma (n=40), whereas 18/40 cases showed comparatively increased levels of S100 mRNA. The majority of schwannomas (n=26) and neurofibromas (n=28) showed relatively an increased expression of both Sox10 and S100 mRNA. MPNSTs (n=28) showed variable levels of Sox10 and S100 mRNA expression, and these expression levels were highly correlated (Pearson correlation coefficient r=0.79). In contrast, immunohistochemistry performed on a larger and more varied number of cases highlighted significant differences between the 2 proteins. We identified 5 non-neural, nonmelanocytic sarcoma types in which a subset of cases showed S100 protein expression: synovial sarcoma (12/79, 15%), Ewing sarcoma (3/14, 21%), rhabdomyosarcoma (4/17, 24%), chondrosarcoma (3/4, 75%), and extraskeletal myxoid chondrosarcoma (5/11, 45%). For each of these entities, we identified cases with strong and diffuse S100 staining. Of these cases, only 1 case of rhabdomyosarcoma showed focal Sox10 positivity. In 78 cases of MPNST, S100 increased the sensitivity (31/78, 40%) as compared with Sox10 (21/78, 27%), but the majority of these cases were negative for both Sox10 and S100 (44/78, 56%). Sox10 proved superior to S100 in the detection of desmoplastic melanoma (7/9, 78%) and clear-cell sarcoma (4/7, 57%). We also report for the first time Sox10 expression in 26 cases of granular cell tumor, further supporting the neural crest derivation of this tumor. Excluding MPNST, S100 and Sox10 showed similar sensitivity in tumors of neural crest origin (140/148, 95% and 137/148, 93%, respectively). In summary, Sox10 shows an increased specificity for tumors of neural crest origin compared with S100: Sox10 was positive in only 5 of 668 cases (99% specificity) in nonschwannian, nonmelanocytic tumors, whereas S100 was positive in 53 of 668 cases (91% specificity). Sox10 should be used in the place of or along with S100 in soft tissue tumor diagnosis. PMID- 22495378 TI - Study of squamous cell carcinoma associated with syringofibroadenoma for 105 types of human papillomavirus and for all currently known types of polyomaviruses. AB - Syringofibroadenoma is a benign tumor of the eccrine glands. Few cases of association with squamous cell carcinoma (SCC) have been published in the literature. In one of them, infection by human papillomavirus (HPV) type-107 was detected and the authors postulated that the virus might play a carcinogenic role. We studied a case of syringofibroadenoma associated with an SCC on the back of the right hand of an immunocompetent 95-year-old man. The lesion showed strong diffuse cytoplasmic staining for cytokeratin (CK) AE1/AE3, CK5/6, and 34betaE12 in the areas of syringofibroadenoma and in the areas of SCC. The marker p63 was expressed by the lower two thirds of the epithelium of the syringofibroadenoma. Epithelial membrane antigen and CK18 were expressed only by the superficial layers of the syringofibroadenomatous epithelium. The carcinomatous areas were epithelial membrane antigen positive. MIB1, p16, and p53 were mainly expressed by the SCC areas. The lesion was negative for all mucosal and cutaneous genus alpha HPV, and for cutaneous HPV from gamma-, MU-, and nu-genera. In 3 repeated genotyping experiments analyzing DNA from 2 consecutive biopsy sections, beta-HPV 9, 20, 36, 47, and 75, as well as FA-22 and 51 were found only once in the 6 possible reactions. beta-HPV-8 and 96 were detected 2 and 4 times, respectively, indicating very low viral loads of these HPV types. None of 8 known polyomaviruses was identified. beta-globin positivity was present in each assay, confirming sufficient quality of analyzed DNA. PMID- 22495379 TI - Desmoglein-3 and Napsin A double stain, a useful immunohistochemical marker for differentiation of lung squamous cell carcinoma and adenocarcinoma from other subtypes. AB - The treatment strategy of differentiating lung carcinomas into small-cell lung carcinoma and non-small-cell lung carcinoma has been satisfactory until recently. The introduction of novel cytotoxic agents that affect a patient's response to therapy has made further differentiation important. Non-small-cell carcinoma represents a heterogeneous group of cancers with varying histologic subtypes, hence the necessity to subgroup them. In the case of adenocarcinoma and squamous cell cancer, their different responses to novel therapeutic agents and their higher occurrence make differentiation between them even more important. New markers such as desmoglein-3 (positive for squamous carcinoma) and Napsin A (positive for adenocarcinoma), which show improved specificity and sensitivity, may be particularly useful for this type of differentiation. In our study, 124 surgically resected specimens were used: 57 adenocarcinoma, 42 squamous cell carcinoma, 16 large-cell carcinoma, 1 small-cell carcinoma, and 8 typical carcinoid tumor samples. The sensitivity to desmoglein-3 and Napsin A was 92.8% and 85.9%, whereas specificity was 100% and 97%, respectively. The use of a desmoglein-3 and Napsin A double-staining strategy in our study confirmed that these markers are useful in differentiating pulmonary squamous cell carcinoma and pulmonary adenocarcinoma from other subtypes. PMID- 22495380 TI - A simple method for generating multitissue blocks without special equipment. AB - The idea of multitumor block to expedite simultaneous analysis of multiple tissue specimens was pioneered by Battifora, and several variations have been published since then. More recently, microarray technology has been introduced to allow placement of up to several hundreds specimens in 1 block using manual or automated sampling devices. This paper reports a manual technique for preparation of a multitissue block. Generation of such blocks requires no special equipment, and flexible block design is possible depending on nature of available material and desired sample size. The first step is dissection of cubical or rectangular samples from paraffin blocks or processed tissue with a razor blade or scalpel. The tissue pieces can be tattooed on cut surface with a permanent marker to facilitate orientation and identification. This marking is preserved during embedding until the block is cut. If a "deep" block is desired, the tissue can be turned 90 degree to provide a greater vertical depth. For embedding, the pieces are laid in paraffin bath in desired order, and when completely melted, they are placed into a deep embedding mold and organized in multiple rows (5 to 10 pieces/row). Scaffolding and control tissue pieces (eg, placental liver or intestinal tissue) can be added as desired. Horizontal or vertical empty space should be preserved to allow for more effective separation of ribbons upon cutting, preventing unnecessary sacrifice of sections. Such blocks can accommodate 30 to 60 cases depending on the tissue size, and they can potentially generate up to several hundreds of sections. This technique is especially suitable when abundant tissue is available, for example, generating blocks containing libraries of normal tissues or defined tumors for antibody screening or tumor immunophenotyping. PMID- 22495381 TI - Use of IMP3, S100P, and pVHL immunopanel to aid in the interpretation of bile duct biopsies with atypical histology or suspicious for malignancy. AB - Histologic evaluation of an endoscopic bile duct biopsy for malignancy is a known challenge. Our prior study has shown that the insulin-like growth factor-II mRNA binding protein-3 (IMP3), S100P, and the von Hippel-Lindau gene product (pVHL) are a useful immunopanel for the distinction between adenocarcinoma and benign biliary epithelium. To further evaluate the usefulness of the IMP3, S100P, and pVHL immunopanel to aid in the interpretation of bile duct biopsies, 16 histologically challenging bile duct biopsies that exhibited atypical histology or features suspicious for malignancy were immunohistochemically stained for IMP3, S100P, and pVHL. Clinical follow-up data were obtained for each case. The results showed that in the 11 cases that showed adenocarcinoma during follow-up, the following staining patterns in atypical/suspicious cells in the initial biopsies were observed: IMP3-positive/S100P-positive/pVHL-negative or reduced (n=6), IMP3-negative/S100P-positive/pVHL-negative or reduced (n=4), and IMP3 positive/S100P-negative/pVHL-negative (n=1). In the 5 follow-up-proven benign cases, 2 biopsies showed an IMP3-negative/S100P-positive/pVHL-positive pattern in atypical cells and 1 was negative for all 3 proteins. The remaining 2 biopsies exhibited an IMP3-positive/S100P-positive/pVHL-negative or reduced pattern in atypical cells that were histologically considered dysplastic on retrospective review. These observations reaffirm that bile duct adenocarcinoma frequently shows positive IMP3 and/or S100P staining with reciprocal negative or reduced pVHL expression. This staining pattern can also be seen in dysplastic epithelium in the absence of invasive carcinoma. On the contrary, benign biliary epithelium typically lacks IMP3 immunoreactivity and may retain normal pVHL expression. However, caution should be exercised when using this immunopanel in the interpretation of challenging bile duct biopsies, because S100P and pVHL stains may give rise to variable patterns that can be difficult to interpret. PMID- 22495382 TI - DOG1 (clone K9) is seldom expressed and not useful in the evaluation of pancreatic neoplasms. AB - DOG1, a transmembrane calcium-regulated chloride channel protein, is a sensitive and specific marker for gastrointestinal stromal tumors compared with other spindle cell and epithelioid neoplasms. Overexpression has also been described in a variety of both benign and malignant epithelial neoplasms. Recently, DOG1 immunoreactivity has been reported in pancreatic solid pseudopapillary tumors (SPT), suggesting a role as a marker for SPT. Utilizing immunohistochemistry, we evaluated DOG1 expression in pancreatic neoplasms to determine the prevalence of staining and establish diagnostic utility. Multiple tissue microarrays (TMA) were created from cores of formalin-fixed paraffin-embedded blocks containing pancreatic adenocarcinomas (n=112), neuroendocrine tumors (n=99), serous cystadenomas (n=28), and SPT (n=14) as well as normal pancreas (n=12). Immunoreactivity for DOG1 (clone K9) was assessed for intensity (1 to 3+), percentage of tumor positivity and location. Of the 99 cases of neuroendocrine tumors, only 2 (2%) were focally positive. Patchy staining was identified in 8 cases (7%) of adenocarcinoma of 1 to 2+ intensity, involving 15% to 80% of the tumor cells and primarily seen in a membranous and luminal distribution. In contrast to a previous report, no DOG1 positivity was observed in SPT, evaluated by both TMA and full sections. The TMAs of serous cystadenomas and normal pancreas were negative for DOG1. Rarely, pancreatic islets displayed granular, cytoplasmic staining. DOG1 antibody clone K9 is not a useful marker for SPT or other primary pancreatic neoplasms. Additional studies may be helpful to evaluate differences between clones of DOG1. PMID- 22495383 TI - Immunolocalization of tenascin-C in vitiligo. AB - The disappearance of melanocytes because of defective adhesion is one of the accepted theories to explain vitiligo. Tenascin-C is a large, extracellular matrix glycoprotein that is thought to inhibit adhesion of melanocytes to fibronectin. The current study aimed to evaluate the pattern of tenascin-C expression in vitiligenous skin compared with normal pigmented skin by means of immunohistochemistry. The study was carried out on skin biopsies from lesional and perilesional skin of 30 patients with vitiligo and on normal skin of 10 healthy volunteers. Several histopathologic changes were observed in vitiliginous skin such as keratinocyte vacuolization, a thickened basement membrane, and dermal inflammatory changes. Tenascin-C was expressed in keratinocytes of the basal epidermal layer of normal skin biopsies at a mild intensity but it did not stain the dermis, whereas vitiligenous skin showed tenascin-C expression in most cases (93.3% ), in the papillary dermis, epidermis, and in both. Diffuse epidermal expression of tenascin-C correlated with more loss of pigment and continuous staining of tenascin-C in the papillary dermis correlated with progressive forms of vitiligo. Intense tenascin-C expression was associated with a more progressive course of the disease assessed by the vitiligo disease activity score. From this study, tenascin-C is highly expressed in the dermis, epidermis, and both of vitiligo as a secondary event for the disease. Keratinocyte is a source of tenascin-C in vitiligo, and diffuse epidermal expression of tenascin-C may induce more loss of melanocytes and melanin pigment. Dermal expression of tenascin-C in the vitiligenous lesion may be linked to the disease more than epidermal expression, because this pattern is only seen in a vitiligenous lesion and it is completely absent in normal and perilesional skin. PMID- 22495384 TI - Ion-specific effect on dynamics of polyelectrolyte chains. AB - The sedimentation of quaternized poly(4-vinyl pyridine) (QP4VP) or poly(N-methyl 4-vinyl pyridine iodide) in aqueous solution has been investigated by using an analytical ultracentrifuge (AUC) via sedimentation velocity (SV). When NaI is introduced, either the sedimentation coefficient (s) or apparent molar mass (Mw) of QP4VP increases with NaI concentration because the polyelectrolyte chains aggregate or even form precipitates due to hydrophobic interaction. Upon addition of NaCl, either s or Mw exhibits a maximum as NaCl concentration increases. The sedimentation in NaBr solution falls in between. Besides, the diffusion coefficient (D) shows a minimum as the added salt concentration increases when either of the salts is added. Isothermal titration calorimetry (ITC) measurements show that the enthalpy change increases from NaI over NaBr to NaCl when each of them is mixed with QP4VP, revealing that the order of the strength of the anion pyridinium interaction is I(-) > Br(-) > Cl(-). When I(-) ions are added, they only screen the electrostatic interaction and no counterion competition happens. Upon addition of Cl(-) or Br(-) ions, the original counterions (I(-)) win the competition at low Cl(-) or Br(-) concentration, so that the added anions only screen the electrostatic interaction. When the concentration of Cl(-) or Br(-) ions is high enough, they replace I(-) ions to interact with the polyelectrolyte chains due to osmotic pressure. The present study demonstrates that the complex dynamics of the polyelectrolyte is greatly influenced by the ion-specific effect. PMID- 22495385 TI - Extending patient simulation: a novel prototype to produce tympanic thermal output. AB - INTRODUCTION: Despite technologic advances in task trainers and manikins, there persists an inability to replicate key clinical skills as would occur in clinical settings. This report provides details of a project to develop a functional and reliable tympanic thermal simulator prototype that could be embedded into the ear of a manikin to enable tympanic thermometers to be used during simulation encounters. METHODS: A simple electrical circuit was built using (i) a standard 9 V battery, (ii) a switch, (iii) 5 * 62-Omega resistors in parallel for circuit stability, (iv) a 62-Omega resistor in parallel with (v) a 1-kOmega potentiometer to vary the infrared light-emitting diode (IRLED) intensity, and (vi) 2 IRLEDs. After confirming reliability of circuit performance, the IRLEDs were implanted into the ear of a manikin. Over 3 consecutive days, 3033 samples were recorded simulating a range of human body temperatures, controlled by altering current flow. RESULTS: Initial testing of the thermal simulator prototype indicates that a range of human temperatures (34.0 degrees C-41.9 degrees C) can be generated using high-intensity IRLEDs. Although, at higher applied current levels, the variation in measured temperature was larger (2.4 degrees C) than at lower applied currents (0.2 degrees C), reasonably precise temperatures were achieved. CONCLUSIONS: Testing and reporting initial prototype results are an important first step in developing and refining a useful product to enhance manikin capabilities associated with patient physical assessment in the simulation setting. Despite the undesired variation, the current design could still be used for teaching purposes in educational settings. Retrieving tympanic temperatures during "patient assessment" of the simulator benefits nursing, midwifery, and other health care students by enabling authentic practice. Further development of this prototype is required to improve the reliability, precision, and accuracy of the device. PMID- 22495386 TI - A novel approach to contextualized surgical simulation training. AB - INTRODUCTION: Decontextualized benchtop simulators play a key role in surgical training. Educational theory highlights the importance of context for effective learning, yet existing full-immersion simulation facilities are prohibitively expensive. This study explored the concept of contextualized training of a key surgical procedure in a novel, low-cost, high-fidelity simulation environment [distributed simulation (DS)] and compared it with decontextualized training in a traditional benchtop simulation. METHODS: Eleven novice surgeons performed a small bowel anastomosis in a benchtop simulation and in DS. Likert-type questionnaires and semistructured interviews captured surgeons' responses. RESULTS: Surgeons perceived the contextualized DS training as realistic, giving surgeons the opportunity to increase their confidence, motivation, and integration of technical and nontechnical skills. Distributed simulation would be of value after benchtop training and before surgery in a real operating room. CONCLUSIONS: Contextualized simulation training allows junior surgeons to gain the necessary confidence before operating in a real operating room. This article presents DS as a solution to widen access to contextualized surgical training. PMID- 22495388 TI - The role of antigen cross-presentation from leukemia blasts on immunity to the leukemia-associated antigen PR1. AB - Cross-presentation is an important mechanism by which exogenous tumor antigens are presented to elicit immunity. Because neutrophil elastase (NE) and proteinase 3 (P3) expression is increased in myeloid leukemia, we investigated whether NE and P3 are cross-presented by dendritic cells (DC) and B cells, and whether the NE and P3 source determines immune outcomes. We show that NE and P3 are elevated in leukemia patient serum and that levels correlate with remission status. We demonstrate cellular uptake of NE and P3 into lysosomes, ubiquitination, and proteasome processing for cross-presentation. Using anti-PR1/human leukocyte antigen-A2 monoclonal antibody, we provide direct evidence that B-cells cross present soluble and leukemia-associated NE and P3, whereas DCs cross-present only leukemia-associated NE and P3. Cross-presentation occurred at early time points but was not associated with DC or B-cell activation, suggesting that NE and P3 cross-presentation may favor tolerance. Furthermore, we show aberrant subcellular localization of NE and P3 in leukemia blasts to compartments that share common elements of the classic major histocompatibility class I antigen-presenting pathway, which may facilitate cross-presentation. Our data demonstrate distinct mechanisms for cross-presentation of soluble and cell-associated NE and P3, which may be valuable in understanding immunity to PR1 in leukemia. PMID- 22495387 TI - Cancer and innate immune system interactions: translational potentials for cancer immunotherapy. AB - Passive immunotherapy, including adoptive T-cell therapy and antibody therapy, has shown encouraging results in cancer treatment lately. However, active immunotherapy of solid cancers remains an elusive goal. It is now known that the human innate immune system recognizes pathogen-associated molecular patterns conserved among microbes or damage-associated molecular patterns released from tissue injuries to initiate adaptive immune responses during infection and tissue inflammation, respectively. In contrast, how the innate immune system recognizes endogenously arising cancer remains poorly understood at the molecular level, which poses a significant roadblock to the development of active cancer immunotherapy. We hereby review the current knowledge of how solid cancers directly and indirectly interact with cells of the human innate immune system, with a focus on the potential effect of such interactions to the resultant adaptive immune responses against cancer. We believe that understanding cancer and innate immune system interactions may allow us to better manipulate the adaptive immune system at the molecular level to develop effective active immunotherapy against cancer. Current and future perspectives in clinical development that exploits these molecular interactions are discussed. PMID- 22495389 TI - Immunologic evaluation of peptides derived from BCR/ABL-out-of-frame fusion protein in HLA A2.1 transgenic mice. AB - Philadelphia chromosome-positive chronic myelogenous leukemia and acute lymphocytic leukemia express, besides the main BCR/ABL transcripts, novel BCR/ABL transcripts derived from alternative splicing between BCR exons 1, 13, or 14 with ABL exons 4 and 5. Their translational products present at C-terminus an amino acid portion derived from out-of-frame (OOF) reading of the ABL gene. The presence of OOF-peptide-specific T cells in chronic myelogenous leukemia patients was demonstrated and a first study in in vivo model demonstrated that OOF ABL portion was immunogenic in human leukcocyte antigen (HLA)-A2.1 transgenic mice. Here we immunized HLA A2.1 mice with novel peptides designed on the ABL OOF sequence, containing epitopes with high affinity for HLA A2.1 molecule. The specific immune response, cellular and humoral, obtained ex vivo against HLA A2.1 positive human chronic myelogenous leukemia cells using peptide 22-53 and the cytotoxic activity induced by peptide 32mer confirm the possibility to use the ABL OOF portion as target to evoke a specific and multiple immune response in Philadelphia positive leukemic patients in cytogenetic remission. PMID- 22495390 TI - Changes in chemokine receptor expression of regulatory T cells after ex vivo culture. AB - By controlling and limiting inflammatory conditions, naturally occurring regulatory T cells (Tregs), defined as circulating CD4(+)CD25(bright)FoxP3(+) cells, play critical roles in maintaining tolerance and preventing autoimmunity and thus have tremendous potential for adoptive immunotherapy. Because they represent a scanty subset of the CD4(+) T-lymphocyte subset, several approaches have been developed to isolate and expand ex vivo polyclonal Tregs. However, one limitation of the functional analyses performed on these cultured Tregs is the incomplete characterization of their tissue-trafficking properties. As this aspect provides crucial information for their therapeutic effects, we have here explored the chemokine receptor expression profile and function of Tregs cultured ex vivo with validated expansion protocols. Our data show that ex vivo cultured Tregs retained the expression of CCR7 but dramatically downregulated CCR5 as compared with freshly isolated Tregs. The differential chemokine receptors expression pattern corroborated with their respective steady state messenger RNA expression and also with their migration toward specific chemokines. Our analyses suggest that ex vivo cultured Tregs may display impaired or suboptimal migration to the inflamed tissues releasing RANTES and MIP-1alpha chemokines. PMID- 22495391 TI - Interleukin-6 inhibits regulatory T cells and improves the proliferation and cytotoxic activity of cytokine-induced killer cells. AB - The presence of regulatory T cells in patients who received therapeutic cytokine induced killer (CIK) cells may inhibit host immunity, leading to failed immunotherapy. In this study, we investigated the impact of using interleukin-6 (IL-6) on the phenotype alteration, proliferation, and cytotoxic activity of CIK cells generated from the peripheral blood mononuclear cells of patients with hepatocellular carcinoma. We found that addition of IL-6 to CIK-cell culture medium decreased the percentage of Treg/CD4(+), Treg/CD3(+) T cells in the resultant CIK cells and simultaneously increased the proliferation ability, the expression of CD45RO(+)CD62L(low)CCR7(low) effector memory phenotype, and cytotoxicity of the CIK cells against hepatocellular carcinoma in vitro. Our results also showed that the percentage of Th17/CD4(+) cells was increased in CIK cells, but the proportion of Th17/CD4(+) cells was not affected by the addition of IL-6 to CIK-cell culture medium. Collectively, these data suggest that IL-6 may have the potential to improve antitumor activity of CIK cells in cancer immunotherapy. PMID- 22495392 TI - Monotherapeutically nonactive CTLA-4 blockade results in greatly enhanced antitumor effects when combined with tumor-targeted superantigens in a B16 melanoma model. AB - Immunotherapy aiming to block immune suppression with anti-cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) monoclonal antibodies is a recently clinically established strategy to enhance immune driven antitumor activities. To be successful, this approach depends on the existence of a suppressed immune response against the tumor that can be released by the treatment or alternatively needs to be combined with an immune-enhancing therapy. A tumor-targeted superantigen (TTS) fusion protein utilizes the strong T-cell activating property of bacterial superantigens in concert with the tumor cell binding capacity in antitumor Fab-fragments. Our purpose was to investigate the feasibility of combining anti-CTLA-4 with TTS therapy against the poorly immunogenic B16 mouse melanoma tumor transfected with the human tumor-associated antigen EpCAM recognized by the C215 monoclonal antibody. B16-EpCAM tumors growing in the lung were completely insensitive to anti-CTLA-4 monotherapy. C215Fab-SEA treatment of the B16-EpCAM tumors induced strong infiltration and targeting of both CD4(+) and CD8(+) T cells. In parallel, Foxp3(+)CTLA-4(high) regulatory T cells accumulated in the tumors. Combining activation with C215Fab-SEA and anti-CTLA-4 showed greatly enhanced antitumor effects and prolonged long-term survival. In parallel, when the expansion of regulatory T cells was inhibited, the number of specific effector T cells was enhanced and the cytotoxic T-lymphocyte activity was significantly improved. Collectively, these data emphasize the potential of combining cancer treatment using anti-CTLA-4 monoclonal antibodies with T-cell activation and directed killing by TTS therapy. PMID- 22495393 TI - Increase of circulating B7-H4-expressing CD68+ macrophage correlated with clinical stage of lung carcinomas. AB - Tumor-associated macrophages (TAM) influence diverse processes such as angiogenesis, tumor cell proliferation, and metastasis during tumor progression. In a variety of tumor types, the amount of TAM has been associated with prognosis, but their role in lung cancer has not been fully elucidated. The purpose of this study was to investigate the B7-H4-expressing TAM in a series of 56 cases of lung carcinoma. In peripheral blood, B7-H4-expressing macrophage (CD68(+) cells) was compared among patients with lung cancer, patients with tuberculosis, and healthy donors. B7-H4-expressing macrophage in peripheral blood from lung cancer patients was significantly higher than that from healthy donors and tuberculosis patients. B7-H4-expressing macrophage was thereafter related to tumor size, lymph node metastasis and TNM stage. On the basis of the data obtained from literature, it is suggestd that lung carcinomas increase B7-H4 expressing macrophages, which might favor tumor progression. PMID- 22495395 TI - Effects of natural organic matter type and concentration on the aggregation of citrate-stabilized gold nanoparticles. AB - The aggregation of 12 nm citrate-stabilized gold nanoparticles (cit-AuNPs) in the presence of four different natural organic matter (NOM) isolates and a monovalent electrolyte (KCl) was evaluated using time-resolved dynamic light scattering. All four NOM isolates stabilized the cit-AuNPs with respect to aggregation. However, specific effects varied among the different NOM isolates. At pH = 6 in 80 mM KCl, low concentrations (<0.25 mg C per L) of large molecular weight Suwannee River Humic Acid (SRHA) was required to stabilize cit-AuNPs, while larger concentrations (>2 mg C per L) of smaller Suwannee River Fulvic Acid (SRFA) were necessary at the same ionic strength. Suwannee River NOM (SRNOM) which contains both SRHA and SRFA behaved in a manner intermediate between the two. Pony Lake Fulvic Acid (PLFA), an autochthonous NOM isolate, provided substantial stability at low concentrations, yet aggregation was induced at NOM concentrations > 2 mg C per L, a trend that is hypothesized to be the result of favourable hydrophobic interactions between coated particles induced at increased surface coverage. For all NOM isolates, it appears that NOM adsorption or conformational changes at the AuNP surfaces result in significant increases in the hydrodynamic diameter that aren't attributable to NP-NP aggregation. PMID- 22495394 TI - Safety and immunogenicity of vaccination with MART-1 (26-35, 27L), gp100 (209 217, 210M), and tyrosinase (368-376, 370D) in adjuvant with PF-3512676 and GM-CSF in metastatic melanoma. AB - The effectivenes of cancer vaccines in inducing CD8(+) T-cell responses remains a challenge, resulting in a need for testing more potent adjuvants. Our objective was to determine the safety and immunogenicity of vaccination against melanoma related antigens employing MART-1, gp100, and tysosinase paptides combined with the TLR9 agonist PF-3512676 and local granulocyte macrophage-colony stimulating factor in oil emulsion. Using continuous monitoring of safety and a 2-stage design for immunologic efficacy, 20 immune response evaluable patients were targetted. Vaccinations were given subcutaneously on days 1 and 15 per cycle (1cycle=28 d) for up to 13 cycles. Interferon-gamma enzyme-linked immunosorbent spot was used as the primary assay measuring the frequency of peripheral antigen specific CD8(+) T cells at days 50 and 90 compared with baseline (target >= 9/20 immunologic responses). Clinical responses were measured by Response Evaluation Criteria In Solid Tumors every 8 weeks. Twenty-two (including 20 immune response evaluable) melanoma patients were enrolled. All had American Joint Committe on Cancer stage IV (5M1a, 6M1b, 11M1c) and most had previously received therapy. Eight had previously treated brain metastases. An average of 3.5 cycles of vaccination per patient was administered. Clinical response data were available for 21 patients. There were 2 partial response and 8 stable disease lasting 2-7 months. One patient with ongoing partial response continued on treatment. At a median follow-up of 7.39 months (range, 3.22-20.47 mo), median progression-free survival was 1.9 months (90% confidence interval, 1.84-3.68) and median overall survival was 13.4 months (90% confidence interval,11.3-infinity). No regimen related grade 3/4/5 toxicities were observed. There were 9/20 patients with positive enzyme-linked immunosorbent spot at day 50 and/or day 90. Our adjuvant regimen combining PF-3512676 and granulocyte macrophage-colony stimulating factor was safe and is worthy of further testing with these or alternative peptides, potentially in combination with antibodies that target immunoregulatory checkpoints. PMID- 22495396 TI - Management of retinal vascular diseases: a patient-centric approach. AB - Retinal vascular diseases are a leading cause of blindness in the Western world. Advancement in the clinical management of these diseases has been fast-paced, with new treatments becoming available as well as license extensions of existing treatments. Vascular endothelial growth factor (VEGF) has been implicated in certain retinal vascular diseases, including wet age-related macular degeneration (AMD), diabetic macular oedema (DMO), and retinal vein occlusion (RVO). Treatment of wet AMD and visual impairment due to either DMO or macular oedema secondary to RVO with an anti-VEGF on an as needed basis, rather than a fixed schedule, allows an individualised treatment approach; providing treatment when patients are most likely to benefit from it, while minimising the number of unnecessary intravitreal injections. Thus, an individualised treatment regimen reduces the chances of over-treatment and under-treatment, optimising both the risk/benefit profile of the treatment and the efficient use of NHS resource. Streamlining of treatment for patients with wet AMD and visual impairment due to either DMO or macular oedema secondary to RVO, by using one treatment with similar posology across all three diseases, may help to minimise burden of clinic capacity and complexity and hence optimise patient outcomes. Informed treatment decisions and efficient clinic throughput are important for optimal patient outcomes in the fast-changing field of retinal vascular diseases. PMID- 22495397 TI - Hepatocellular carcinoma in nonalcoholic fatty liver cirrhosis and alcoholic cirrhosis: risk factor analysis in liver transplant recipients. AB - BACKGROUND: Cirrhosis and hepatocellular carcinoma (HCC) evolving from nonalcoholic fatty liver disease (NAFLD) are being increasingly documented. However, clinicopathologic studies to support this are inadequate. Also, the pathogenesis of HCC in alcoholic cirrhosis (ALC) in which the pathologic and clinical features are very similar to those of nonalcoholic fatty liver cirrhosis (NAFLC) is unknown. METHODS: A clinicomorphologic study on 47 confirmed NAFLC cases, with HCC in eight of them and 75 confirmed ALC cases with HCC in five from among orthotopic liver transplant recipients, was performed. RESULTS: Patients with NAFLC were older by about 9 years than those with ALC. HCC in NAFLC occurred almost exclusively in men. The presence of NAFLD risk factors, obesity and diabetes both together, was significantly higher in NAFLC than in ALC cases and within the latter, in those with HCC than in those without HCC, whereas in the NAFLC group, this was no different between those with and without the tumor. The steatohepatitic variant of HCC, consistently accompanied by similar histologic changes in the nontumor part of liver, which is a histologic hallmark of association with NAFLC risk factors, was much more frequent in the NAFLC group compared with the ALC group. CONCLUSION: Hepatic alterations induced by risk factors of NAFLD not only have cirrhogenic but also, very likely, a carcinogenic effect. The incidence of HCC in NAFLC seems higher than in ALC. These findings and their bases need to be established by further studies. PMID- 22495398 TI - Bipolar patients can safely and successfully receive interferon-based hepatitis C antiviral treatment. AB - AIM: Patients with bipolar disease are often not considered for hepatitis C virus (HCV) antiviral treatment and are excluded from clinical trials because of the risk of interferon-induced exacerbation of their underlying mood disorder. As this risk has not been well quantified in bipolar patients, we evaluated the safety and efficacy of HCV treatment in this population. METHODS: A retrospective analysis of HCV patients evaluated at The Ottawa Hospital between January 2000 and February 2008 (n=910) was carried out. Information on demographics, psychiatric history and treatment, baseline liver biopsy and blood work, treatment initiation, adherence, and therapeutic outcomes was collected. This was compared between bipolar patients (B), those with a history of depression (D), and those with no mental health disorders (N). RESULTS: Of 38 bipolar patients (4.2%), 16 (42.1%) initiated HCV treatment, a rate similar to that in patients with a history of depression (41.4%) and in those without psychiatric illness (32.6%). On-treatment psychiatric complications were comparable between the bipolar and depression groups (B=68.8%, D=54.8%; P=0.29) and were higher than in those without psychiatric illness (N=37.1%; P=0.01). Manic episodes were rare. [B=2 (12.5%), D=1 (0.9%), N=1 (0.7%)]. Interferon dose reduction or discontinuation rates for psychiatric complications (B=12.5%, D=7.9%, N=7.4%; P=NS), completion rates (B=50%, D=69%, N=58%), and sustained virologic response rates (genotype 1: B=33%, D=45%, N=49%) were similar between the groups. CONCLUSION: Stable bipolar patients have similar rates of on-treatment psychiatric complications as patients with a history of depression. With pharmacologic intervention and close clinical monitoring, well-selected bipolar patients can successfully complete treatment and achieve outcomes comparable to those in nonbipolar patients. PMID- 22495399 TI - Autoimmune hepatitis in children: an overview of the disease focusing on current therapies. AB - Autoimmune hepatitis (AIH) is an immune-mediated necroinflammatory disease of the liver characterized by elevation of IgG, presence of characteristic autoantibodies, and histological features of interface hepatitis. Two types of juvenile AIH have been recognized according to seropositivity for smooth muscle and/or antinuclear antibody (AIH type 1) or liver kidney microsomal antibody (AIH type 2). The exact pathogenesis of AIH is still unclear, but it is known that unidentified environmental factors, and occasionally drugs, might trigger disease in genetically susceptible individuals. The clinical spectrum of this disease is very wide, ranging from asymptomatic individuals with abnormal liver function to those with fulminant liver failure. The diagnosis is based on a combination of biochemical and histological parameters and on exclusion of other liver diseases. It is a relatively rare but devastating disease, which progresses rapidly unless immunosuppressive treatment is started promptly. Standard therapy consists of a combination of corticosteroids and azathioprine, which is efficacious in 80% of patients. Alternative therapies are increasingly being explored in patients who do not respond to standard treatment and/or have intolerable side-effects. The purpose of this paper is to review our current knowledge about AIH in children, evaluating mainly the therapeutic options for its treatment, considering also the newer immunosuppressant agents used in difficult-to-treat cases. PMID- 22495401 TI - Fascin and cortactin expression is correlated with a poor prognosis in hepatocellular carcinoma. AB - OBJECTIVES: The aim of this study was to investigate the relationship between fascin and cortactin protein expression and clinicopathological parameters and survival time in patients with hepatocellular carcinoma (HCC). METHODS: A total of 77 specimens of HCC and seven specimens of normal liver tissues were collected. The expressions of fascin and cortactin were examined by immunohistochemical staining. The patients from whom the HCCs were taken were also followed up. In these 74 patients, Kaplan-Meier was used to assess survival outcomes. RESULTS: The data revealed that fascin and cortactin expressions were upregulated in the HCC samples. The positive expression of fascin significantly correlated with histological differentiation and metastasis. The positive expression of cortactin significantly correlated with histological differentiation, metastasis, and T stage (International Union Against Cancer). Survival time of the patients with positive fascin expression and positive cortactin expression was significantly decreased, and the median survival duration was short. CONCLUSION: Fascin and cortactin might be important indicators of the malignancy and metastasis of liver cancer, and may have predictive value in the prognosis of HCC. PMID- 22495400 TI - Clinical characteristics and prognosis of hepatocellular carcinoma with different sets of serum AFP and PIVKA-II levels. AB - OBJECTIVE: alpha-Fetoprotein (AFP) and prothrombin induced by the absence of vitamin K or antagonist-II (PIVKA-II) are useful tumor markers for hepatocellular carcinoma (HCC). However, little is known about the clinical characteristics and prognosis of HCC with different levels of AFP and PIVKA-II. METHODS: Consecutive 1447 HCC patients were assigned to four groups according to the cutoff values of AFP (400 ng/ml) and PIVKA-II (100 mAU/ml): both values high (AP), one of the values high (Ap and aP), and both values low (ap). The clinical characteristics and the prognosis of group ap were compared with those of the other groups. RESULTS: HCC patients in group ap were more asymptomatic at diagnosis, and had smaller size, fewer numbers, and earlier stages of HCC, and more preserved liver functions (all, P<0.001). The survival rate of group ap was significantly higher than those of the other groups (P<0.001). In multivariate analysis, the combined status of AFP and PIVKA-II values were independent predictors for survival (P<0.001), together with tumor size, number, portal vein thrombosis, Child-Pugh class, and treatment modality. CONCLUSION: HCC patients with low values of both AFP and PIVKA-II had more favorable clinical characteristics and showed a better prognosis than those with elevated levels of AFP or PIVKA-II. PMID- 22495402 TI - Relation of epicardial adipose tissue and carotid intima-media thickness in patients with nonalcoholic fatty liver disease. AB - OBJECTIVE: Currently, nonalcoholic fatty liver disease (NAFLD) itself has been accepted as an atherosclerotic risk factor and related to increased cardiovascular disease risk. In this study, we aimed to investigate the relationship of epicardial fat thickness (EFT), a parameter associated with atherosclerosis in recent years, with carotid artery intima-media thickness (C IMT), another parameter of subclinical atherosclerosis. DESIGN AND METHODS: We investigated 57 patients with biopsy-proven NAFLD and 30 age-matched and sex matched controls. EFT was obtained by transthoracic echocardiography and C-IMT was evaluated by an ultrasonographic measurement using a linear type B-mode probe. RESULTS: EFT and C-IMT were significantly higher in NAFLD patients compared with the controls (EFT: 0.58 +/- 0.18 vs. 0.36 +/- 0.17 cm, P<0.001 and C-IMT: 0.64 +/- 0.1 vs. 0.52 +/- 0.1 mm, P<0.001, respectively). We found a statistically significant correlation between EFT and BMI, C-IMT, waist circumference, homeostasis model assessment of insulin resistance, and nonalcoholic steatohepatitis scores in both groups. Stepwise regression analysis showed that C-IMT (beta=0.36, t=2.86, P=0.006) and waist circumference (beta=0.3, t=2.44, P=0.018), in the order they entered into the model, were independent predictors of EFT in patients with NAFLD. CONCLUSION: Our findings indicate that EFT and C-IMT were significantly higher in patients with NAFLD compared with the controls and waist circumference and C-IMT are independent predictors for EFT in patients with NAFLD. PMID- 22495403 TI - Incidence of oral cancer among South Asians and those of other ethnic groups by sex in West Yorkshire and England, 2001-2006. AB - In 2008 there were 11682 cases of oral cancer in the United Kingdom; this is 16.41/100000 population, and 3.7% of all cancers. Ethnic coding of these data is poor, and so databases were combined to report rates for the incidence of oral cancer in South Asians compared with those among other ethnic groups in West Yorkshire, 2001-2006. A total of 2157 patients with oral cancer were identified in West Yorkshire, 138 of whom were South Asian (6.4%). We analysed them by ethnicity, sex, area in which they lived, and site of cancer. Oral cancer was significantly more common among South Asian women than those from other ethnic groups in England and West Yorkshire, and in England alone it was significantly more common in men of other ethnic groups than those from South Asia. Patients from South Asia were at higher risk of being diagnosed with oral cancer than those of other ethnic groups within West Yorkshire, when data were adjusted for age at diagnosis and sex. In England and in West Yorkshire there was a significantly higher rate of oral cancer among Southern Asian women than among those of other ethnic groups, and men in other ethnic groups had a higher incidence than those from South Asia (England only). The excess of oral cancers gives further weight to the association between smokeless tobacco, smoking, alcohol, and dietary intake by ethnic group. This information is particularly pertinent in areas such as West Yorkshire where there are large groups of Asian people. PMID- 22495404 TI - Combined second metatarsophalangeal joint and extended dorsalis pedis flap for reconstruction of temporomandibular joint and oral mucosa. PMID- 22495405 TI - Vibrational spectroscopy and molecular dynamics of water monomers and dimers adsorbed on polycyclic aromatic hydrocarbons. AB - This paper reports structures, energetics, dynamics and spectroscopy of H2O and (H2O)2 systems adsorbed on coronene (C24H12), a compact polycyclic aromatic hydrocarbon (PAH). On-the-fly Born-Oppenheimer molecular dynamics simulations are performed for temperatures T varying from 10 to 300 K, on a potential energy surface obtained within the self-consistent-charge density-functional based tight binding (SCC-DFTB) approach. Anharmonic infrared (IR) spectra are extracted from these simulations. We first benchmark the SCC-DFTB semi-empirical hamiltonian vs. DFT (Density Functional Theory) calculations that include dispersion, on (C6H6)(H2O)1,2 small complexes. We find that charge corrections and inclusion of dispersion contributions in DFTB are necessary to obtain consistent structures, energetics and IR spectra. Using this Hamiltonian, the structures, energetics and IR features of the low-energy isomers of (C24H12)(H2O)1,2 are found to be similar to the DFT ones, with evidence for a stabilizing edge-coordination. The temperature dependence of the motions of H2O and (H2O)2 on the surface of C24H12 is analysed, revealing ultra-fast periodic motion. The water dimer starts diffusing at a higher temperature than the water monomer (150 K vs. 10 K respectively), which appears to be consistent with the binding energies. Qualitative and quantitative analyses of the effects of T on the IR spectra are performed. Anharmonic factors in particular are derived and it is shown that they can be used as signatures for the presence of PAH-water complexes. Finally, this paper lays the foundations for the studies of larger (PAH)m(H2O)n clusters, that can be treated with the efficient computational approach benchmarked in this paper. PMID- 22495406 TI - Advancing the knowledge base on work transitions in the 21st century. PMID- 22495408 TI - Transitions to work for persons with serious mental illness in northeastern Ontario, Canada: examining barriers to employment. AB - This paper considers the importance of place in the conceptualization of transitions to work for persons with serious mental illness (SMI). A qualitative case study was conducted to explore the influence of place on access to employment for persons with SMI. In-depth interviews, focus groups, and demographic data collected from urban and rural residing individuals who experience SMI, mental health and vocational service providers, and decision makers across northeastern Ontario inform this paper. The results highlight the primary theme, stuck in the mud, which explains how people with SMI, service providers and decision makers are stuck regarding employment. Ultimately, their being stuck creates a variety of place-related tensions and a tendency to settle for less in the area of employment for persons with SMI. The condition of being stuck in the mud is expressed as a metaphor depicting the existing tensions between ideas which govern provincial employment policy for persons with SMI and the mainstream or dominant discourse governing local organizations, programs and practices in the case communities and supports the need to consider place in policy implementation. PMID- 22495407 TI - Directions for advancing the study of work transitions in the 21st century. AB - OBJECTIVES: The purpose of this article is to share the details, outcomes and deliverables from an international workshop on work transitions in London, Ontario, Canada. PARTICIPANTS: Researchers, graduate students, and community group members met to identity ways to advance the knowledge base of strategies to enhance work participation for those in the most disadvantaged groups within society. METHODS: A participatory approach was used in this workshop with presentations by researchers and graduate students. This approach included dialogue and discussion with community members. In addition, small group dialogue and debate, world cafe discussions, written summaries of group discussion and reflection boards were used to bring new ideas to the discussion and to build upon what we know. FINDINGS: Two research imperatives and six research recommendations were identified to advance global dialogue on work transitions and to advance the knowledge base. Occupational justice can be used to support future research directions in the study of work transitions. CONCLUSIONS: Moving forward requires a commitment of community of researchers, clinicians and stakeholders to address work disparities and implement solutions to promote participation in work. PMID- 22495409 TI - Working for citizenship: the dangers of occupational deprivation. AB - OBJECTIVE: To examine published case examples of occupational deprivation in relation to Wilcock's 1989 theoretical proposal that it is caused by economic and political systems, institutional policies, or advances in technology that displace workers. CASE EXAMPLES: Eleven accounts of occupational deprivation centering on access to or maintenance of a work role. METHOD: A thematic review of articles reporting access to or maintenance of a worker role as a major concern were located in an electronic search of multiple databases using the keyword 'occupational deprivation'. RESULTS: While no examples pertaining to technological change were located, legislation enacted to protect national security or redress the ongoing affects of colonisation, a philosophy of punishing prisoners, and healthcare and employment structures were identified as causes of occupational deprivation. CONCLUSIONS: Economic and political systems and institutional policies are confirmed to cause occupational deprivation of worker roles in prison and indigenous populations, migrant workers and older female immigrants, young women displaced by war, refugees and asylum seekers, and people with disabilities. The ongoing economic burden of wasting human potential and the loss of cultural practices that support productive occupations are two negative outcomes. PMID- 22495410 TI - Using multiple stakeholders to define a successful return to work: a concept mapping approach. AB - OBJECTIVE: Currently no standard or universal outcome measure for return to work (RTW) programs exists making the evaluation and comparison of such programs difficult. RTW outcomes are often measured using nominal scales based on administrative data but these fail to take the perspectives of workers and other stakeholders into consideration. In order to gain that perspective this study was conducted to identify what outcomes are of interest and importance to RTW stakeholders. RTW stakeholders identified indicators of successful RTW in order to develop a conceptual framework of successful RTW. PARTICIPANTS: A total of 24 RTW stakeholders participated, representing both RTW consumers and providers from Southwestern Ontario. METHOD: This study used a mixed-method integrated form of concept mapping, which qualitatively generates and interprets data, and quantitatively analyzes data using multidimensional scaling and hierarchical cluster analysis. RESULTS: Participants generated 48 statements, which were subsequently clustered into the following six concepts; worker performance, worker job satisfaction, human rights, worker well-being, seamless RTW process through collaborative communication, and satisfaction of stakeholders other than workers. CONCLUSIONS: The results reflect the perspectives of stakeholders and suggest that RTW outcome measures are needed that not only evaluate all aspects of the worker's life, but the RTW process as well. Aside from confirming the inadequacy of nominal, administrative type outcomes, these findings imply that the actual RTW process is intimately tied to outcome. Implications and relevance are discussed for planning RTW programs and towards developing a RTW outcome tool. PMID- 22495411 TI - Untapped potential: perspectives on the employment of people with intellectual disability. AB - OBJECTIVE: While individuals with intellectual disabilities can make valuable contributions in community workplaces, they typically experience low rates of paid employment. The goal of this article is to explore the reasons for the limited involvement of this population in competitive employment, provide a rationale for including individuals with intellectual disabilities as employees, and propose policy, structural and attitudinal changes that would be necessary to include them more meaningfully in the workforce. METHODS: The authors conducted a review of the literature relevant to the key theoretical concepts of disability, employment, organizational management and inclusion. RESULTS: The analysis reveals a number of theoretical, philosophical, legal and business arguments for and against the inclusion of workers with intellectual disabilities as employees, and suggests system level changes needed to mitigate challenges to recruiting, hiring and retaining these workers. CONCLUSIONS: Changes to the employment situation for workers with intellectual disabilities will require major shifts in government policy, workplace practices and vocational preparation of youth with intellectual disabilities. Continued research is necessary to identify best practices. PMID- 22495412 TI - Perspectives on European work-related education, practice and research. PMID- 22495413 TI - The European employment strategy and opportunities for occupational therapy. PMID- 22495414 TI - Euro-Education: Employability for all (EEE4all). Design and implementation of an international course for future health-care professionals. AB - BACKGROUND: Employment is a priority in the European Union, and it is essential to address the needs of individuals disadvantaged at the labour market on grounds such as ethnicity, age, gender or disability, to increase the opportunities for these groups to gain employment. The Council of the European Union recognize the important role of national organisations in increasing gender equality and the need to integrate a gender perspective in all policies. Gender equality perspectives should also, according to the EU Plan of Action and Gender Equality be integrated in education. OBJECTIVES: To equip students in higher education with knowledge, about gender, age, disability and ethnicity in relation to employability, a European group initiated a project; Euro-Education: Employability for all (EEE4all). APPROACH: The project, funded by the European Lifelong Learning Programme, was aimed to develop and implement four course modules, each relating to employability with different focus: gender, age, disability or ethnicity. In this paper design, implementation, and evaluation of the course focused on gender, provided by the Occupational Therapy Programme at Linkoping University, is described. CONCLUSIONS: The students highlighted the importance of awareness and knowledge about gender theory and its application in relation to employability and client-centred approach. PMID- 22495415 TI - Student perspectives on the development and evaluation of a joint international education to promote employability in Europe. AB - OBJECTIVE: This article presents a student evaluation of a joint international education developed as part of a European project which sought to equip health care practitioners with the skills to support employability of individuals furthest removed from the labour market, disadvantaged on account of age, gender, migration or ethnicity. PARTICIPANTS: Thirty eight students out of the forty one students that participated in the pilot of four modules (NL, UK, SE, DE) returned completed digital questionnaires (92.6% response rate). METHODS: The study is descriptive by nature. A questionnaire was used to collect the data from students. Additionally students attending the module in the UK also took part in a series of qualitative interviews which sought to explore their experiences in more detail. These were recorded, transcribed and analyzed. RESULTS: Students reported that joint education facilitates competence development. The competencies they identified (Information Communications Technology) were recognised as being key to enhancing employability of disadvantaged groups. CONCLUSIONS: The joint international education exemplified by EEE4all offers one model of how to build a responsive international curriculum to ensure that the workforce of the future is well placed to meet the needs of this changing world. PMID- 22495416 TI - "Doing" social inclusion with ELSiTO: empowering learning for social inclusion through occupation. AB - OBJECTIVES: The European partnership ELSiTO aimed to develop understanding of the nature and processes of social inclusion for persons experiencing mental illness. PARTICIPANTS: Partners were from Belgium, Greece and The Netherlands with over 30 members including mental health service users, occupational therapists and other staff. APPROACH: A knowledge-creation learning process was used during four international, experiential, visits and local meetings, which included visiting and describing good practice, telling stories of experiences, reflection and discussion. RESULTS: The partnership developed understandings of the nature and process of social inclusion, including both subjective and objective aspects interrelated with the doing of daily activities in the community. Members' work related experiences, illustrated through their stories, depict the subjective aspects of social inclusion as they are shaped and framed by the objective conditions within a variety of work opportunities. Experiences in paid work, supported employment and voluntary work may both threaten and enhance mental health. Features of successful (voluntary) work experiences are identified. CONCLUSIONS: The importance is revealed of looking critically at current understandings of work and to move beyond a narrow focus on paid work in order to provide a range of work opportunities that will empower the individual's potential and promote inclusive communities. PMID- 22495417 TI - Social firms: a means for building employment skills and community integration. AB - BACKGROUND: Social firms are widely used in Europe as a means of affirmatively creating employment opportunities and training for employment challenged groups. These commercial businesses produce, market and sell goods and services to the public while providing opportunities for productive engagement, increased incomes, and social integration for their employees. METHODS: This article presents a case study of a Norwegian social firm that was created to improve employment and functional outcomes for workers with mental health disabilities and addictions. The case illustrates one model of social firm, and is used as the foundation for discussion of the relative contributions of social firms to employment outcomes for people who are marginalized in the labour market. RESULTS: The social firm represented a major change in philosophy and operations for mental health service provision in the local municipality. Numbers of individuals served increased dramatically, and changes were observed in the extent and nature of participant daily involvement, and in outcomes achieved. This model brings participants into contact with the public, and has served to break down barriers and reduce stigma. CONCLUSIONS: Social firms represent a viable alternative for creating employment options and training and for enhancing social integration of people with mental health disabilities. PMID- 22495420 TI - Getting the message across: principles for developing brief-Knowledge Transfer (b KT) communiques. AB - OBJECTIVE: This feature article on knowledge transfer presents principles and strategies to support the development of short communiques to end-users. PARTICIPANTS: Formal and informal knowledge brokers are the targeted users of the strategies. METHODS: Research studies and conceptual literature in knowledge transfer informed the development of brief-Knowledge Transfer (b-KT) principles. Principles are explained and a sample of how they informed the development of KIT Tip Sheets is offered to promote ways to use principles in knowledge dissemination. RESULTS: b-KT principles can be used as a framework to guide the development of short communiques by knowledge brokers in work practice but also in the health, social and rehabilitation domains. In addition, these principles promote the participation of end-users in the development of knowledge transfer. CONCLUSIONS: Formal evaluation is needed on the use of these principles in achieving the uptake and use of knowledge by end-users. PMID- 22495418 TI - A case study on the application of International Classification of Functioning, Disability and Health (ICF)-based tools for vocational rehabilitation in spinal cord injury. AB - OBJECTIVES: Vocational rehabilitation (VR) plays a key role in bringing persons with acquired disabilities back to work, while encouraging employment participation. The purpose of this case study is to illustrate the systematic application of International Classification of Functioning, Disability, and Health (ICF)-based documentation tools by using ICF Core Sets in VR shown with a case example of a client with traumatic spinal cord injury (SCI). PARTICIPANT: The client was a 26-year-old male with paraplegia (7th thoracic level), working in the past as a mover. METHODS: This case study describes the integration of the ICF Core Sets for VR into an interdisciplinary rehabilitation program by using ICF-based documentation tools. RESULTS: Improvements in the client's impairments, activity limitations, and participation restrictions were observed following rehabilitation. Goals in different areas of functioning were achieved. CONCLUSION: The use of the ICF Core Sets in VR allows a comprehensive assessment of the client's level of functioning and intervention planning. Specifically, the Brief ICF Core Set in VR can provide domains for intervention relevant to each member of an interdisciplinary team and hence, can facilitate the VR management process in a SCI center in Switzerland. PMID- 22495421 TI - Work transition tips: Helping workers get the right information at the right time. PMID- 22495424 TI - Individualization of valganciclovir prophylaxis for cytomegalovirus infection in pediatric kidney transplant patients. AB - BACKGROUND: Valganciclovir is used for the prophylaxis of cytomegalovirus infection in pediatric solid transplant patients. The current pediatric dose regimen resulted in large variability in drug exposure. A posterior dosage adaptation was required in children to achieve the daily target area under the curve (AUC) of 40-50 MUg.h.mL(-1). However, a clinically feasible tool for valganciclovir dosage adjustment based on individual AUC is not available. The objective of this study was to develop and validate a reliable and clinically applicable limited sampling strategy using Bayesian estimation for individualizing valganciclovir dose in pediatric kidney transplant patients. METHODS: The Bayesian estimator to calculate ganciclovir AUC was developed using the original pharmacokinetic dataset consisting of 28 full profiles from 22 pediatric kidney transplant patients. External validation was prospectively performed in an independent validation group consisting of 14 full pharmacokinetic profiles from 14 pediatric kidney transplant patients. RESULTS: The Bayesian estimator of exposure using T0-T2-T4 gave the best predictive performance. The mean prediction error was of 3.1% and Bland-Altman analysis shows that the average difference between referenced and estimated AUCs was 0.4 MUg.h.mL(-1). CONCLUSION: Valganciclovir dosage adaptation was required in children to achieve target AUC. The Bayesian estimator of valganciclovir, using 3 concentrations measured at T0-T2-T4 after drug intake, was validated and could be used to accurately estimate individual AUC. This approach will be useful for individualizing valganciclovir prophylaxis in pediatric kidney transplant patients. PMID- 22495426 TI - Oral pantoprazole-induced acute pancreatitis in an 11-year-old child. AB - This case report highlights a very rare adverse drug reaction caused by oral pantoprazole resulting in acute pancreatitis. An 11-year-old boy was diagnosed with gastroesophageal reflux disease. Apart from general advice for lifestyle and dietary changes, he was symptomatically prescribed oral pantoprazole 40 mg once daily 30 minutes before meals for 4 weeks. The symptoms of gastroesophageal reflux disease were improving gradually, but the patient developed progressive symptoms of acute pancreatitis and was admitted in the emergency department with acute abdominal pain. Relevant investigations were done, and it was diagnosed as a case of acute pancreatitis. There was no evidence of any other possible hereditary, traumatic, surgical, metabolic, infective, organic, or pathologic causes giving rise to this condition, and this acute pancreatitis was probably drug (pantoprazole) induced. Dechallenge was done, and the patient was treated conservatively resulting in reversal of the diseased state. Naranjo adverse drug reaction probability scale suggested that the likelihood that oral administration of pantoprazole was responsible for the acute pancreatitis was 'probable.' PMID- 22495425 TI - Methadone and metabolites in hair of methadone-assisted pregnant women and their infants. AB - INTRODUCTION: Methadone is the recommended pharmacotherapy for opioid-dependent pregnant women. The primary aims of this study were to determine whether a dose concentration relationship exists between cumulative maternal methadone dose, methadone and metabolite concentrations in maternal hair during pregnancy and whether maternal hair methadone and metabolite concentrations predict neonatal outcomes. MATERIALS AND METHODS: Hair specimens were collected monthly from opioid-dependent mothers enrolled in methadone treatment and 4 of their infants. Hair specimens were segmented (3 cm), washed (maternal hair only), and analyzed for methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), and 2 ethyl-5-methyl-3,3-diphenylpyrroline by liquid chromatography tandem mass spectrometry. RESULTS: There was large intersubject variability and no dose concentration relationship for cumulative methadone dose and methadone, EDDP, 2 ethyl-5-methyl-3,3-diphenylpyrroline, or total concentrations in hair. For individual women, a positive trend was noted for cumulative methadone dose and methadone and EDDP concentrations in hair. There was a positive linear trend for cumulative methadone dose and EDDP/methadone ratio in maternal hair, perhaps reflecting methadone's induction of its own metabolism. Maternal methadone concentrations were higher than those in infant hair, and infant EDDP hair concentrations were higher than those in maternal hair. Maternal methadone dose, and methadone and EDDP hair concentrations were not correlated with peak infant neonatal abstinence syndrome (NAS) scores, days to peak NAS, duration of NAS, time to NAS onset, birth length, head circumference, or amount of neonatal morphine pharmacotherapy. Maternal cumulative third trimester methadone dose was positively correlated with infant birth weight. CONCLUSIONS: Methadone and EDDP in pregnant women's hair are markers of methadone exposure and do not predict total methadone dose, nor neonatal outcomes from in utero methadone exposure. PMID- 22495427 TI - Polymorphism of genes involved in purine metabolism (XDH, AOX1, MOCOS) in kidney transplant recipients receiving azathioprine. AB - BACKGROUND: Xanthine dehydrogenase (XDH), aldehyde oxidase1 (AOX1), and molybdenum cofactor sulfurase (MOCOS) are enzymes involved in purine metabolism. The aim of this study was to investigate single nucleotide polymorphisms (SNPs) in XDH, AOX1, and MOCOS genes in relation to clinical parameters and risk of drug side effects in a cohort of kidney transplant recipients treated with azathioprine (AZA) as a part of standard immunosuppressive regimen. METHODS: One hundred fifty-six patients receiving AZA for the first year from the surgery were genotyped for the presence of common SNPs in the coding regions of XDH, AOX1, and MOCOS genes using TaqMan assays. RESULTS: AOX1 rs55754655 variant allele carriers received a higher mean AZA dose 3, 6, and 12 months after transplantation (P < 0.05). The patients inheriting rs594445 MOCOS minor allele required significantly lower doses of AZA for efficient treatment compared with wild-type heterozygotes at 3, 6, and 12 months from the transplantation (mean values: 1.39 versus 1.59, 1.38 versus 1.58, and 1.33 versus 1.53 mg.kg.24 h) and displayed lower mean RBC count at the time points evaluated. Multivariate analysis has shown that the effect of MOCOS rs594445 polymorphism is independent of other investigated gene variations and might influence AZA dosage, similarly to TPMT heterozygosity. The authors have not observed an association between any of the studied XDH SNPs and clinical parameters of AZA-treated patients. CONCLUSIONS: The results of this study should be regarded as preliminary. However, if the observed association between SNPs: AOX1 rs55754655, MOCOS rs594445, and AZA dose requirements would be positively confirmed in further independent studies, it could be introduced into clinical practice to individualize thiopurine treatment. PMID- 22495436 TI - Functional genomics: Complexities of occupancy and sequence. PMID- 22495438 TI - Cytoskeletal architecture regulates cyclooxygenase-2 in human endothelial cells: autocrine modulation by prostacyclin. AB - Endothelium is a highly dynamic tissue that controls vascular homeostasis. This requires constant rearrangements of the shape or function of endothelial cells that cannot set aside the role of the cytoskeleton. The aim of this study was to determine the mechanisms by means of which cytoskeletal alterations induce cyclooxygenase-2 (Cox-2) expression in human endothelial cells using compounds that interfere with microtubule or actin architecture. Microtubule disruption by nocodazole markedly increased Cox-2 expression and activity, and provoked paracellular gap formation, a cardinal feature of endothelial barrier dysfunction. The Cox-2 metabolite prostacyclin down-regulated Cox-2 through an autocrine receptor-mediated mechanism, and partially prevented the disassembly of endothelial monolayers. There was also an interaction between microtubules and actin filaments in nocodazole-induced Cox-2 expression. Nocodazole provoked the dissolution of the F-actin cortical ring and stress fiber formation, increased actin glutathionylation, and concomitantly lowered intracellular levels of reduced glutathione. The restoration of glutathione levels by N-acetylcysteine opposed Cox-2 expression and preserved the integrity of endothelial monolayers. Among the signaling pathways connecting microtubule disruption with Cox-2 up regulation, crucial roles are played by Src family kinase activation, serine/threonine phosphatase 2A inhibition, and the phosphorylation of mitogen activated protein kinase p38. Our findings provide a mechanistic insight into the observation that Cox-2 is induced in endothelial cells under cytoskeleton perturbing conditions such as those occurring in the presence of atherogenic/inflammatory stimuli and oxidative stress. In this scenario, Cox-2 up regulation by endothelia exposed to noxious conditions can be considered protective of the vasodilatory and anti-thrombotic properties of the vessel wall. PMID- 22495435 TI - Harnessing genomics and genome biology to understand malaria biology. AB - Malaria is an important human disease and is the target of a global eradication campaign. New technological and informatics advancements in population genomics are being leveraged to identify genetic loci under selection in the malaria parasite and to find variants that are associated with key clinical phenotypes, such as drug resistance. This article provides a timely Review of how population genetics-based strategies are being applied to Plasmodium falciparum both to identify genetic loci as key targets of interventions and to develop monitoring and surveillance tools that are crucial for the successful elimination and eradication of malaria. PMID- 22495439 TI - One pot synthesis of indene through copper(I)-catalyzed three-components coupling and cyclization reaction. AB - A new and efficient synthesis of substituted indene has been achieved via copper(I)-catalyzed domino three-component coupling and cyclization reaction in moderate to good yield. PMID- 22495440 TI - Naturally occurring norephedrine oxazolidine derivatives in khat (Catha edulis). AB - Khat (Catha edulis Forsk.) is a perennial shrub whose young leaves are chewed for their psychostimulating and anorectic properties. The main active principles of khat are believed to be the phenylpropylamino alkaloids, primarily (-)-cathinone [(S)-alpha-aminopropiophenone], (+)-cathine [(1S)(2S)-norpseudoephedrine], and ( )-norephedrine [(1R)(2S)-norephedrine]. GC-MS analyses of young leaf extracts indicated the presence of two oxazolidine derivatives, 2,4-dimethyl-5 phenyloxazolidine and 4-methyl-2-(trans-1-pentenyl)-5-phenyloxazolidine. To ascertain the chemical identity of these compounds, we synthesized the putative compounds by condensation of norephedrine and acetaldehyde or trans-2-hexenal, respectively. Spectroscopic analyses (GC-MS, NMR) of the structures of these synthetic compounds showed them to have identical retention indexes and mass spectra characteristic to 2,4-dimethyl-5-phenyloxazolidine and 4-methyl-2-(trans 1-pentenyl)-5-phenyloxazolidine. Marked differences in the ratios between each of these two norephedrine oxazolidine derivatives and total phenylpropylamino alkaloids were found among thirteen different khat accessions further indicating polymorphism in alkaloid ratios and content in C. edulis. PMID- 22495441 TI - On the novel action of melanolysis by a leaf extract of Aloe vera and its active ingredient aloin, potent skin depigmenting agents. AB - The present study was carried out to investigate the effects of an Aloe vera leaf extract, along with its standard active ingredient aloin, on the isolated tail melanophores of Bufo melanostictus tadpoles, which are a type of disguised smooth muscle cells offering excellent in vitro opportunities for studying the effects of pharmacological and pharmaceutical agents. It was found that the leaf extract of A. vera and its active ingredient aloin induced powerful, dose-dependent, physiologically significant melanin aggregating effects in the isolated tail melanophores of B. melanostictus similar to those of adrenaline per se. These preliminary findings clearly demonstrate that the extract of A. vera and its active ingredient aloin cause melanin aggregation leading to skin lightening via alpha adrenergic receptor stimulation. The present study opens new vistas for the use of A. vera regarding its clinical application as a new nontoxic melanolytic agent for the treatment of hyperpigmentation. PMID- 22495442 TI - Cytotoxicity and antimicrobial activity of the methanol extract and compounds from Polygonum limbatum. AB - The present study was designed to investigate the antimicrobial activity and the cytotoxicity of the methanol extract (PLA) as well as fractions (PLA1-4) and compounds [cardamomin (1), (+/-)-polygohomoisoflavanone (2), (S)-(-)-pinostrobin (3), 2',4'-dihydroxy-3',6'-dimethoxychalcone (4), (2S)-(-)-5-hydroxy-6,7 dimethoxyflavanone (5), and (2S)-(-)-5,7-dimethoxyflavanone (6)] obtained from leaves of Polygonum limbatum. The microbroth dilution was used to determine the minimal inhibitory concentration (MIC) of the samples against 11 microbial strains including Candida albicans, C. krusei, C. tropicalis, Aspergillus fumigatus, Pseudomonas aeruginosa, Escherichia coli, vancomycin-resistant Enterococcus faecalis (VRE), Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), S.epidermidis, and Mycobacterium tuberculosis H37Rv. The sulphorhodamine B cell growth inhibition assay was used to assess the cytotoxicity of the above samples on lung A549 adenocarcinoma, breast carcinoma MCF-7, prostate carcinoma PC-3, cervical carcinoma HeLa, and the acute monocytic leukemia cell line THP-1. The results of the MIC determination indicated that, apart from fraction PLA3, all other fractions as well as PLA and compound 3 were selectively active. MIC values were noted on 100 % of the 11 tested microorganisms for fraction PLA3, 72.7 % for PLA, fraction PLA2, and compound 4, 63.6 % for PLA1, and 54.5 % for fraction PLA4. The results of the cytotoxicity assay revealed that, except for A459 cells, more than 50 % inhibition of the proliferation was obtained with each of the tested samples on at least one of the four other cell lines. IC50 values below 4 ug/mL were obtained with 1 and 4 on THP-1 cells. The overall results of the present study provided baseline information for the possible use of Polygonum limbatum as well as some of the isolated compounds for the control of cancer diseases and mostly leukemia. PMID- 22495443 TI - Antimicrobially active hederagenin glycosides from Cephalaria elmaliensis. AB - A phytochemical investigation of the aerial parts of Cephalaria elmaliensis resulted in the isolation of ten hederagenin-type triterpene saponins (1-10) including three new ones, elmalienoside A (1), elmalienoside B (2), elmalienoside C (3), and two known flavonoid glycosides (11-12). Their structures were identified by extensive spectroscopic techniques (1D and 2D NMR, HR ESIMS) and chemical evidence. The antimicrobial activity of the extracts and the pure compounds was evaluated by the MIC method. According to the results, all pure compounds including the new ones were found to be very active against both gram positive and gram-negative bacteria. PMID- 22495444 TI - A new species of Hyphoderma (Meruliaceae, Polyporales) and its discrimination from closely related taxa. AB - Thirty-five corticioid collections from the Canary Islands and Azores Archipelago were examined morphologically and subjected to molecular phylogenetic analysis. These specimens, almost all collected on endemic and/or xerophilic vegetation, were similar in morphological and ecological characteristics to Hypochnicium prosopidis from the Sonoran Desert (Arizona, USA) and Hyphoderma amoenum. Thirty seven new ITS nrDNA sequences from these specimens, including the nomenclatural type of the above-mentioned species, were obtained and aligned with homologous sequences from GenBank. These collections were distributed in two strongly supported monophyletic clades. However, similar patterns of morphological variability shared by specimens included in both clades and their differences with related species suggest that they should be described as a single new species. Therefore Hyphoderma macaronesicum is proposed. Studies will be required to test, in a more robust multilocus genealogical framework, whether these populations constitute two cryptic species or whether they are the same taxon. The position of Hypochnicium prosopidis in the resolved tree and its morphological characters suggest that it should be included in Hyphoderma and the new combination Hyphoderma prosopidis is proposed. PMID- 22495445 TI - Sutorius: a new genus for Boletus eximius. AB - Sutorius is described as a new genus of Boletaceae to accommodate Boletus robustus originally named illegitimately by C.C. Frost from eastern North America. The legitimate name, Boletus eximius, provided by C.H. Peck, has been used since for a dark purple to chocolate brown bolete with finely scaly stipe and reddish brown spore deposit. This iconic taxon has been documented on five continents. Despite the straightforward species identification from morphology, the interpretation of stipe macro-morphology and spore color has led to equivocal generic placement. Phylogenetic analyses of genes encoding large subunit rRNA and translation elongation factor 1alpha confirm Sutorius as a unique generic lineage in the Boletaceae. Two species are recognized based on multiple accessions: S. eximius, represented by collections from North America, Costa Rica, Guyana, Indonesia and Japan (molecular data are lacking for only the Guyanan and Japanese material); and S. australiensis, represented by material from Queensland, Australia. Additional collections from Zambia and Thailand represent independent lineages, but sampling is insufficient to describe new species for these entities. PMID- 22495446 TI - Taxonomy of mayapple rust: the genus Allodus resurrected. AB - Mayapple rust is a common, disfiguring disease that is widespread in temperate eastern North America wherever the host, Podophyllum peltatum, occurs. Puccinia podophylli, the etiological agent of this rust, has been shown to be distantly related to both Puccinia and Uromyces as exemplified by their types. A systematic study was made to determine the generic classification of P. podophylli. Phylogenetic analyses of two rDNA loci from multiple specimens support the recognition of this taxon as a separate genus of Pucciniaceae. Based on historical literature and type material, P. podophylli was found to represent the type of the forgotten genus Allodus and it is correctly named Allodus podophylli. A neotype is designated for Puccinia podophylli Schwein. (= Allodus podophylli) and a lectotype is designated for Aecidium podophylli. PMID- 22495447 TI - Trichoderma matsushimae and T. aeroaquaticum: two aero-aquatic species with Pseudaegerita-like propagules. AB - Four isolates tentatively identified as Pseudaegerita matsushimae on the basis of the morphology of bulbil-like propagules were collected from substrates submerged in water in Thailand and Japan. In culture studies the two Thai isolates were found to produce phialoconidia on conidiogenous cells and phialoconidiophores whose morphology was similar to that of Trichoderma. Phylogenetic analysis based on D1/D2 regions of LSU rDNA sequences showed that the four isolates were nested in Hypocrea/Trichoderma (Hypocreales) while P. corticalis, the type species of Pseudaegerita, belongs to Hyaloscypha (Helotiales). Preliminary analysis by ISTH Web tools based on 5.8S-ITS rDNA and phylogenetic analysis based on rpb2 and tef1 int4 genes showed that the isolates have specific sequences of Trichoderma (anchors 1-5) and belong to the Hamatum clade but they grouped apart from any known species of Trichoderma. The sequences of the tef1-int4 gene, which were amplified from the authentic specimen of P. matsushimae (IMI 266915), also showed that it belongs to the Hamatum clade closely clustering with T. yunnanense but separate from our four isolates. The morphology of P. matsushimae (IMI 266915), especially the sizes of phialides and phialoconidia, were different from T. yunnanense. Thus, we conclude that IMI 266915 and our isolates are to be assigned to two different species in the Hamatum clade of Trichoderma, although both species have similar morphology of bulbils and phialoconidia. Morphology and molecular data revealed that P. matsushimae should be assigned to the genus Trichoderma as T. matsushimae and the Thai and Japanese isolates are placed in T. aeroaquaticum sp. nov. This finding supports the interpretation that aero-aquatic fungi have evolved from terrestrial fungi. We assume that these fungi probably were derived from typically soil-inhabiting species of Trichoderma; an adaptation to aquatic environments is shown by formation of bulbil-like propagules floating on water. PMID- 22495448 TI - Ectomycorrhizal iconoclasts: the ITS rDNA diversity and nitrophilic tendencies of fetid Russula. AB - Fetid Russula are frequently dominant ectomycorrhizal fungi, and some appear to be especially nitrophilic. However, little is known about their phylogenetic relationships or how common nitrophilic traits are in this group. This study addresses this gap and presents a phylogenetic analysis of ITS rDNA sequences and a meta-analysis of studies that examine ectomycorrhizal fungi response to nitrogen increase. The phylogenetic analysis indicates that (i) this lineage contains numerous unidentified taxa; (ii) the taxa have distinct geographic distributions; and (iii) the misuse of names such as R amoenolens, R. foetens or R. pectinatoides is common. Twenty-three well supported phylotypes were identified and include clades specific to western North America, eastern North America, Europe and Asia, while morphologically similar collections from tropical equatorial regions are distinct. The metaanalysis shows that nitrophilic tendencies appear throughout fetid Russulas suggesting that this character is not an isolated trait within this subgenus but instead is a more general feature of the group overall. Mapping these tendencies across a broader portion of the Russulaceae shows that this trait is more regularly found in the basal Russula lineages and Lactarius spp., suggesting that this ability evolved early in these fungi. PMID- 22495449 TI - Taxonomic revision of true morels (Morchella) in Canada and the United States. AB - Recent molecular phylogenetic studies have revealed the existence of at least 50 species of Morchella worldwide and demonstrated a high degree of continental endemism within the genus. Here we describe 19 phylogenetic species of Morchella from North America, 14 of which are new (M. diminutiva, M. virginiana, M. esculentoides, M. prava, M. cryptica, M. frustrata, M. populiphila, M. sextelata, M. septimelata, M. capitata, M. importuna, M. snyderi, M. brunnea and M. septentrionalis). Existing species names (M. rufobrunnea, M. tomentosa, M. punctipes and M. angusticeps) are applied to four phylogenetic species, and formal description of one species (M. sp. "Mel-8") is deferred pending study of additional material. Methods for assessing morphological features in Morchella are delineated, and a key to the known phylogenetic species of Morchella in North America is provided. Type studies of M. crassistipa, M. hotsonii, M. angusticeps and M. punctipes are provided. Morchella crassistipa is designated nomen dubium. PMID- 22495450 TI - Kabatiella bupleuri sp. nov. (Dothideales), a pleomorphic epiphyte and endophyte of the Mediterranean plant Bupleurum gibraltarium (Apiaceae). AB - Bupleurum gibraltarium is an evergreen shrub endemic to southern Spain and northern Algeria and Morocco. We have collected and cultured an undescribed Kabatiella species that is consistently associated with the flower rachises and leaves of B. gibraltarium in the province of Granada. The fungus forms melanized acervuli on overwintered flower rachises. It also can be isolated from yeast-like conidial masses that emerge from senescing leaves and from surface-disinfected healthy leaves. Like other Kabatiella species, the fungus forms blastic falcate to lunate conidia simultaneously from the apex of conidiogenous cells in acervuli. In culture, melanized single-septate conidia form blastically from the vegetative hyphae that accumulate in yeast-like masses. These conidia germinate by budding to form secondary yeast-like cells or directly as hyphae. In culture, the fungus behaves like, and could be confused with, Aureobasidium and Hormonema species. We describe the growth of this species in agar media and its phylogenetic position based on the analyses of nuclear ribosomal RNA gene sequences. This new species is a sister species of the morphologically similar clover pathogen, K. caulivora. PMID- 22495451 TI - Functional and phylogenetic analysis of the Aspergillus ochraceoroseus aflQ (ordA) gene ortholog. AB - Within the Aspergillus parasiticus and A. flavus aflatoxin (AF) biosynthetic gene cluster the aflQ (ordA) and aflP (omtA) genes encode respectively an oxidoreductase and methyltransferase. These genes are required for the final steps in the conversion of sterigmatocystin (ST) to aflatoxin B(1) (AFB(1)). Aspergillus nidulans harbors a gene cluster that produces ST, as the aflQ and aflP orthologs are either non-functional or absent in the genome. Aspergillus ochraceoroseus produces both AF and ST, and it harbors an AF/ST biosynthetic gene cluster that is organized much like the A. nidulans ST cluster. The A. ochraceoroseus cluster also does not contain aflQ or aflP orthologs. However the ability of A. ochraceoroseus to produce AF would indicate that functional aflQ and aflP orthologs are present within the genome. Utilizing degenerate primers based on conserved regions of the A. flavus aflQ gene and an A. nidulans gene demonstrating the highest level of homology to aflQ, a putative aflQ ortholog was PCR amplified from A. ochraceoroseus genomic DNA. The A. ochraceoroseus aflQ ortholog demonstrated 57% amino acid identity to A. flavus AflQ. Transformation of an O-methylsterigmatocystin (OMST)-accumulating A. parasiticus aflQ mutant with the putative A. ochraceoroseus aflQ gene restored AF production. Although the aflQ gene does not reside in the AF/ST cluster it appears to be regulated in a manner similar to other A. ochraceoroseus AF/ST cluster genes. Phylogenetic analysis of AflQ and AflQ-like proteins from a number of ST- and AF-producing Aspergilli indicates that A. ochraceoroseus might be ancestral to A. nidulans and A. flavus. PMID- 22495452 TI - Multiple microsurgical resections for repeated recurrence of glioblastoma multiforme. AB - OBJECTIVES: There has been little evidence so far supporting further surgical intervention in case of repeated recurrence of glioblastoma multiforme (GBM). Thus, the efficacy and utility of repeated resection remains unclear but worthy of consideration. The aim of this study was to review the efficacy of multiple repeated resections in patients with recurrent GBM. METHODS: Forty-two patients underwent repeated surgical resections for recurrent GBM. All patients who underwent >2 surgical interventions were clustered in group A. Group B were patients treated nonsurgically after resection of the first recurrence. Patients' treatment history, including surgical interventions, radiotherapy, chemotherapy regimens, postoperative complications, Karnofsky Performance Score, and survival rate were reviewed. RESULTS: Group A consisted of 10 patients (median age, 60.5 y) and group B of 32 patients (median age, 56.5 y). Histopathologic findings revealed typical GBM in 8 patients of group A and in 23 patients of group B. An oligodendroglial component was detected in 2 patients of group A and in 7 patients of group B. The median Karnofsky Performance Score after the first surgery for tumor recurrence was 80 in both groups (P=0.084). The median overall survival time was 26 months in patients of group A and 16 months in patients of group B (P=0.052). The 2-year survival rate of group A was 58.3% and significantly higher than in group B (29.0%; P=0.036). The 3-year survival rate of group A was 31.1% and 12.4% of group B (P=0.038). CONCLUSIONS: Microsurgical resection of repeatedly recurring GBM is likely to prolong survival. Repeated surgical resection may be considered as an effective treatment option in addition to radiochemotherapy in repeated GBM recurrence. PMID- 22495453 TI - Tumor-infiltrating lymphocytes, tumor characteristics, and recurrence in patients with early breast cancer. AB - BACKGROUND: The balance in the immune system between immune surveillance against non-self-antigens and tolerance of self-antigens is known to be associated with the prognosis of breast cancer patients. However, immunologic signals in tumor microenvironment according to biological characteristics of cancer cells have not been clearly elucidated. CD4(+) T cells, CD8(+) T cells, and forkhead box P3 positive (Foxp3) regulatory T cells (Tregs) are the main keys for immune surveillance and tolerance, respectively. We evaluated the correlations between the immunologic balance and tumor characteristics and their impact on recurrence. PATIENTS AND METHODS: CD8(+) T cells and Foxp3(+) Tregs were detected by immunohistochemistry using the paraffin-embedded tumor samples from the 72 patients with early stage (I to III) breast cancer. Clinicopathologic data including tumor size and grade, lymph node metastasis, stage, patient's age, expression status of estrogen receptor (ER), progesterone receptor, p53, Ki-67, and human epidermal growth factor receptor-2/neu, and recurrence were reviewed. RESULTS: The decreased number of CD8(+) T cells was significantly associated with tumors with lymph node metastasis (P=0.027), higher stage (stage III, P=0.013), and immunopositivity of Ki-67 (P=0.026). In contrast, the increased number of Foxp3(+) Tregs was significantly correlated with tumors with lymph node metastasis (P=0.027), immunopositivity for p53 (P=0.026), and positive for Ki-67 (P<0.001). There were significant correlations between the increased Foxp3(+) Treg/CD4(+) T-cell ratio and lymph node metastasis (P=0.011), the expression of ER (P=0.023), and immunopositivity of p53 (P=0.031) and Ki-67 (P= 0.003). Of note, lower Foxp3(+) Treg/CD4(+) T-cell ratio was significantly associated with triple-negative breast cancer (P=0.004). Disease-free survival of analyzed patients was significantly associated with the number of Foxp3(+) Tregs (dichotomized by a cutoff point of 17, P= 0.014) only. Univariate analysis indicated that tumor grade (P=0.017), the expression of ER (P=0.032), and non triple-negative breast cancer (P=0.022) were independent prognostic factors for disease-free survival. CONCLUSIONS: Our data showed that lymph node metastases, immunopositivity of p53 and Ki67, and non-triple-negative tumors were associated with high regulatory T-cell infiltration. The role of immunologic balance as a prognostic marker for recurrence must be evaluated more clearly in the future study. PMID- 22495454 TI - Clinical practice patterns of lung stereotactic body radiation therapy in the United States: a secondary analysis. AB - OBJECTIVES: Stereotactic body radiation therapy (SBRT) is a technique used to deliver high, ablative doses of radiation in a limited number of fractions to >=1 extracranial target(s). Although recent studies have shown that SBRT provides effective local tumor control in medically inoperable early-stage lung cancer patients, its implementation in clinical practice is unknown. METHODS: A random sample of 1600 American radiation oncologists was surveyed regarding lung SBRT usage, including year adopted, most common prescription, respiratory motion management, and target localization. A biological equivalent dose (BED) was calculated using the linear quadratic model with alpha/beta=10. Spearman rank correlation coefficients (r(s)) were calculated to identify factors associated with BED. RESULTS: Of 1373 contactable physicians, 551 responses (40%) were received. Of 510 evaluable responses, 275 physicians (54%) reported using lung SBRT, over half of whom adopted it in 2008 or later. The most commonly reported prescriptions were 20 Gy*3 (22%), 18 Gy*3 (21%), and 12 Gy*4 (17%). Three fraction regimens were most common (48%), with nearly all (89%) prescribing >=18 Gy/fraction. The median BED was 132 Gy, with 95% of reported prescriptions having BED>=100 Gy. Factors associated with increased BED included use of fiducial markers (r(s)=0.26, P<0.001), use of planar imaging (r(s)=0.18, P<0.01), and years of experience with lung SBRT (r(s)=0.13, P=0.04). CONCLUSIONS: Lung SBRT has rapidly become a widely adopted treatment approach in the United States with a range of varying implementations. Further research and additional prospective trials are necessary to optimize this novel approach. PMID- 22495455 TI - Poly (ADP-ribose) polymerase inhibitors in cancer treatment. AB - Recent research on inhibitors of poly (ADP-ribose) polymerase (PARP) has demonstrated their potential for improving cancer therapy. They inhibit protein poly (ADP-ribosyl)ation and thus affect numerous molecular and cellular functions, including DNA repair and cell survival, that are critical for such physiological and patho-physiological states as carcinogenesis, inflammation, and resistance to cancer therapy. In this review, we describe the biological basis underlying the use of these agents in cancer therapy, providing data from preclinical studies that demonstrate the synergistic interaction of PARP inhibitors with radiation and chemotherapeutics. We also summarize initial clinical trials of PARP inhibitors for cancer treatment. PMID- 22495456 TI - Locally advanced vulvar cancer in elderly women: is chemoradiation beneficial? AB - OBJECTIVES: There is a higher incidence of invasive vulvar cancer in the elderly population. With multiple medical comorbidities, radiation with sensitizing chemotherapy in the elderly can be complicated, yet the risks and benefits of chemoradiation have not been studied in this population. We investigate whether elderly patients are more likely to die of intercurrent disease (ICD) or of treatment complications. METHODS: A meta-analysis was performed to compare remission rates, death from ICD or treatment complications, and rates of surgery in elderly and nonelderly patients with vulvar cancer treated with chemoradiation. Data were searched in the Cochrane Review. Eligibility criteria included: woman with advanced primary squamous cell carcinoma of the vulva, women receiving preoperative or primary chemoradiation treatment with curative intent, and prospective studies that reported the necessary data of interest. Data collected included: age (elderly, defined as 65 years and above), stage, treatment, and mortality. RESULTS: Seventy subjects were identified from 7 studies that met eligibility criteria. Seventy-eight percent (25/32) of patients younger than 65 years were without evidence of disease after treatment versus 66% (25/38) of patients aged 65 years and above (P=0.30). Three percent (1/32) of patients younger than 65 years of age died of ICD or treatment complications versus 11% (4/38) of patients 65 years and above (P=0.37). CONCLUSIONS: We noticed a trend demonstrating death from ICD or treatment complications was higher for elderly patients. Future research should focus on treatment with chemoradiation in the elderly population with regard to survival benefit, toxicity, and death from ICD or treatment complications. PMID- 22495457 TI - A retrospective clinicopathologic study of remnant gastric cancer after distal gastrectomy. AB - INTRODUCTION: Remnant gastric cancer (RGC) is a unique clinical entity with relatively less frequency in gastric cancer series and often reported to be detected at advanced stages and had poor prognosis. METHODS: A total of 112 patients with RGCs from July 1991 to July 2008 were enrolled in this retrospective analysis. RESULTS: A total number of 112 cases were composed of 20 (17.8%) differentiated carcinomas and 92 (82.2%) undifferentiated carcinomas. There are 64 (57.1%) patients with tumor at anastomotic site and 48 (42.9%) tumor at nonanastomotic site. The diameter of tumors was >=4 cm in 83 (74.1%) patients. Borrmann III, IV accounted for 70.5% and 17.8% respectively. Three (2.6%) patients were classified as stage I, 16 as stage II (14.2%), 62 as stage III (55.3%), and 31 (27.6%) as stage IV. Percentage of T4 stage was 57.1%. Distant metastasis rate and lymph node metastasis rate were 27.6% and 58.9%, respectively. There were numerous clinicopathologic differences according to different original disease, initial reconstruction, and tumor location. The median overall survival time was 27.9 months. TNM stage and option of treatments were independent prognostic factors in multivariable analysis. CONCLUSIONS: The lifelong annual follow-up endoscopic examinations after the initial gastrectomy and radical resection may help to improve the prognosis of RGCs. PMID- 22495458 TI - Venous hypertension as the cause of intracranial hypertension in patients with transverse sinus dural arteriovenous fistula. AB - We describe 2 patients with transverse sinus dural arteriovenous fistulas (DAVFs) who presented with headache and papilledema due to intracranial hypertension. It has been proposed, but never proven, that venous hypertension causes the intracranial hypertension in DAVF. The data from our patients support this hypothesis. An additional factor leading to intracranial hypertension could be stenosis of the fellow transverse sinus. PMID- 22495459 TI - China makes an impressive breakthrough in avian influenza virus research - Discovering the "heart" of avian infl uenza virus. AB - The successive appearance of strains of epizootic avian influenza A virus with the subtype H5N1 in China has attracted considerable concern from the public and Chinese authorities. According to the latest WHO estimates as of February 2, 2009, the number of H5N1 virus deaths in China totaled 25, second only to Indonesia and Viet Nam (http://www.who.int/csr/disease/avian_influenza/country/cases_table_2009_02_02/en index.html). The H5N1 virus is highly contagious among birds and is fatal when transmitted to humans, though the means by which this occurs is still unknown. Owing to the possible variation of the H5N1 prototype virus, together with the fact that it has the propensity to exchange genes with influenza viruses from other species, humans have no natural immunity to the virus. Despite years of efforts, the exact pathogenesis of H5N1 transmission to humans is still not completely clear, nor is potential human-tohuman transmission as could lead to an epidemic or even worldwide pandemic (Enserink M. Science. 2009; 323:324). Unfortunately, current antiviral treatment and therapeutic measures cannot effectively overcome this virulent virus that causes highly pathogenic avian influenza (HPAI). Researchers from around the world are working to study the virology of influenza viruses, including their methods of infiltration, replication, and transcription, to elucidate the mechanisms of unremitting viral infection in terms of aspects such as the virus, host, and environment. These researchers are also working to identify potential molecular targets related to H5N1 for anti-influenza drug intervention. A recent H5N1-related study from China provides encouraging information. According to the People's Daily (Renmin Ribao), a newspaper out of Beijing, professor Liu Yingfang, academician Rao Zihe, and fellow researchers from more than 6 research centers, including the Institute of Biophysics Chinese Academy of Sciences, Nankai University, and Tsinghua University, have achieved exciting results in providing a detailed understanding of the mechanisms of action of the RNA polymerase PA subunit, the "heart" of the avian influenza virus, at the atomic level. They hope to provide clues to potential avian influenza therapy targets and a new platform for new drug discovery (http://202.123.110.5/jrzg/2009-02/06/content_1222973.htm, available as of February 6, 2009). According to Liu et al., influenza viruses are enveloped, negatively stranded RNA viruses with a segmented genome (consisting of 8 RNA segments) that can encode 11 kinds of viral proteins. Among these proteins, the complex of influenza polymerase, consisting of PB1, PB2, and PA subunits, is regarded to be what gives life to influenza viruses because of its essential catalytic role in viral RNA replication and mRNA transcription in the nucleus of infected cells. Notwithstanding earlier virology studies on the influenza virus that elucidated the functions of PB1 and PB2, the exact function of PA is still not completely clear. The group resolved the crystal structure of the carboxyl-terminus of PA in complex with the aminoterminus of PB1 peptides for the first time. This structure mode provides details for the interactions of PA and PB1, as well as the binding sites of PA and RNA. Results of the research, entitled the "Crystal structure of the polymerase PA(c)-CPB1(N) complex from an avian influenza H5N1 virus," were published in the August 28th issue of the respected international scientific journal Nature (He X, Zhou J, Bartlam M, et al. Nature. 2008; 454:1123-1126). Further efforts by the group served to indicate the fine three-dimensional structure of the N-terminal of PA protein. They revealed that the PA subunit holds an endonuclease active site and that it, rather than the PB1 subunit as was previously, plays a critical role in the endonuclease activity of influenza virus polymerase. In addition, PA's characteristics of being highly conserved and having little mutations make it an attractive target for anti-influenza therapeutics. Specifically, endonuclease can block the mRNA of host cells cached by the complex of polymerase, resulting in mRNA transcription. Results of the group's most recent research have been published in a recent February 4th issue of Nature (Yuan P, Bartlam M, Lou Z, et al. Nature. 2009; Epub ahead of print). PMID- 22495460 TI - Establishment of a new cell line for high-throughput evaluation of chemokine CCR5 receptor antagonists. AB - Chemokine receptors belong to a superfamily of proteins that signal through coupled heterotrimeric G proteins. Chemokine receptor CCR5 is the major co receptor essential for HIV entry into host cells, and now chemokine CCR5 receptor has become an important target in searching for anti-HIV drugs. Here, we describe the establishment of a human embryonic kidney (HEK) 293/CCR5-HA cell line stably expressing CCR5 receptor with influenza hemagglutinin (HA) tag at the N termini on the membrane surface of HEK293 cells. Plasmid pcDNA3.0-CCR5-HA was transfected into HEK293 cells, and monoclonal HEK293 cell lines expressing CCR5 receptor were generated under G418 selection. The expression of functional CCR5 receptor was tested by GTP?S assay, and the results showed about 5 monoclonal HEK293 cell lines expressed functional CCR5 receptor, and of which No.7 monoclonal cell line is the best. The FACS analysis results further confirmed that CCR5 receptor was positive in 96.89% of No.7 monoclonal HEK293/CCR5-HA cell line. Further results showed that RANTES significantly stimulated GTP?S binding in the dose-dependent manner, and CCR5 antagonist Sch-351125 inhibited RANTES stimulated GTP?S binding in the dose-dependent manner in No.7 monoclonal HEK293/CCR5-HA cell line. Our results suggest that the established HEK293/CCR5-HA cell line is suitable for highthroughput screening and is feasible to identify CCR5 receptor antagonists. PMID- 22495461 TI - Formulation and evaluation of in situ gelling thermoreversible mucoadhesive gel of fluconazole. AB - The purpose of the present study was to develop ophthalmic gel formulations of fluconazole. Intraocular delivery of topically applied drugs such as fluconazole is hampered by elimination of the solution due to tear turnover, so an in situ gelling thermoreversible mucoadhesive gel was formulated. Thermoreversible mucoadhesive gels were prepared using the cold method along with poloxamer 407 and different mucoadhesive polymers such as hydroxy ethyl cellulose (HEC), hydroxy propyl methyl cellulose (HPMC) K4M, and polyvinyl pyrrolidone (PVP) K30. Gels were evaluated for physical parameters like appearance, gelation temperature, pH, spreadability, drug content, gel strength, bioadhesion, and in vitro permeation. A modified device (modified K-C diffusion cell with a sheep's eye corneal membrane as a diffusion membrane) was used for evaluation of drug permeation through a sheep's corneal membrane. The formulated gels were transparent, uniform in consistency, and had spreadability with a pH range of 6.8 to 7.3. Satisfactory bioadhesion on the sheep's corneal surface and good gel strength were also observed. Diffusion studies have shown that a matrix is the best-fit model. As the concentration of mucoadhesive agent increases, the rate of permeation decreases. The order of drug permeation through the membrane was HEC > PVP K30 > HPMC K4M. This study found that a thermoreversible polymer and mucoadhesive polymers can be effectively used to prolong residence time. PMID- 22495462 TI - Computational study of the proton transfer of phenyl urea. AB - The proton transfer between two nitrogen atoms (N1 and N3) in a molecule of phenyl urea is an important process in the synthesis of 1-phenylimidazolidine-2,4 dione. Three pathways of the proton transfer have been investigated using Density Functional Theory (DFT). With negative N1 phenyl urea, the transformed double bond of N1-C2 connects N1, C2, and N3 into a benzene conjugate system, making the structure more stable than negative N3 phenyl urea. Intermolecular proton transfer was found to be the primary manner of protein transfer at 300 K. Both negative N1 and negative N3 exist and the former is primal. The proton transfer is very fast, and the diluted solution may slow down the rate but produce much more negative N1 as well. PMID- 22495463 TI - Liposomal oxytetracycline and doxycycline: studies on enhancement of encapsulation efficiency. AB - Liposomal encapsulations of oxytetracycline (OTC) and doxycycline (DC) with various lipid compositions and hydrating solutions have been studied in order to develop a new liposomal formulation to treat bacterial infections. Encapsulation efficiencies as a function of pH (pH 4.0-8.0) in ionic (phosphate buffers) and non-ionic (mannitol or glucose) hydrating solutions with various lipid compositions (lecithin or alpha-L-dipalmitoylphosphatidylcholine, with or without cholesterol) were determined and compared to the character of lipid vesicles. Based on our encapsulation efficiency studies and on the drug stability considerations it can be concluded that for OTC/DC encapsulation the use of non ionic solutions is the most promising. PMID- 22495464 TI - Study of the analgesic, anti-inflammatory, and gastric effects of gabapentin. AB - Gabapentin, a drug used to treat neuropathic pain, was evaluated in models of acute nociceptive pain, in instances of haloperidol-induced catalepsy, carrageenan-induced paw edema, gastric lesions caused by indomethacin or ethanol, and gastric acid secretion in rats. Reaction time in a hot plate assay was delayed by gabapentin. The antinociceptive effect of the drug was produced with a dose of 12.5 mg/kg and a maximal increase in hot plate latency of 68% 1 h after drug administration was produced at 100 mg/kg. Gabapentin (25, 50 or 100 mg/kg) caused a significant rise in current threshold in a tail electrical stimulation test in mice, resulting in values of 20, 30, and 60.5% vs. control values, 1 h post-dosing. With the agent, the duration of paw licking following intraplantar capsaicin injection decreased in a dose-dependent manner. In contrast, gabapentin failed to have antinociceptive action in a mouse acetic-acidinduced writhing assay. The drug (12.5-50 mg/kg) increased the duration of catalepsy induced by haloperidol by 33.5, 47.4, and 53.2%, respectively. It had an anti-inflammatory effect at doses of 25 or 50 mg/kg. Gabapentin (12.5-50 mg/kg) reduced the number and severity of gastric mucosal lesions induced by subcutaneous indomethacin (20 mg/kg) or intragastric 96% ethanol, but at doses of 50 and 100 mg/kg it increased gastric acid secretion. In conclusion, gabapentin decreased thermal, electrical, and chemogenic pain but not visceral pain and had a gastric protective effect. PMID- 22495465 TI - Enhancement of the dissolution profile of Tenoxicam by a solid dispersion technique and its analytical evaluation using HPLC. AB - The aim of the present study was to improve the dissolution, and therefore the bioavailability, of poorly water-soluble tenoxicam. Solid dispersions consisting of tenoxicam with two different types of polymers were prepared. The first type were PVP(30) and beta-cyclodextrin and the second type were two superdisintegrants, explotab and croscarmellose sodium. A solid dispersion with an explotab ratio of 1:1 (F(8)) had the best dissolution profile compared to all of the prepared solid dispersions as well as the pure drug, which was then formulated into tablets (T(2)F(8)). T(2)F(8) had far better dissolution than commercial tablets, releasing only 28.3% of the drug, while T(2)F(8) exhibited 96.5% drug release in 20 min. T(2)F(8) was subjected to analytical validation as well as stability studies. The formulation was found to be stable after storage at 40 degrees C for one month, 40 degrees C and 75% relative humidity (40 degrees C/75% RH) for one month, and 60 degrees C for 15 days; this was confirmed by the absence of degraded product prepared in the laboratory by refluxing the drug with 1 N NaOH for 15 min. Infrared (IR) spectroscopy and differential scanning calorimetry (DSC) were performed on T(2)F(8) to identify physicochemical interactions between the drug and carrier, hence its effect on dissolution. A simple and rapid HPLC method was also developed to determine tenoxicam in human plasma and was then used in a pharmacokinetic study. Plasma samples were analyzed on a C(18) column with a mobile phase of 0.02 M sodium acetate:acetonitrile: methanol (7:2.5:0.5, v/v/v) and UV detection at 375 nm. The linear range of the plasma concentration was 1-16 MUg/mL with a detection limit of 158 ng/mL. Within day and between-day precision expressed as the relative standard deviation was less than 2%. The proposed method was successfully used in a bioequivalence study in healthy volunteers and mean pharmacokinetic parameters were calculated. PMID- 22495466 TI - Effect of renal artery stenting on left ventricular mass: a randomized clinical trial. AB - BACKGROUND: Whether renal revascularization reduces left ventricular hypertrophy in patients with coronary artery disease is uncertain. STUDY DESIGN: Randomized clinical trial testing the effect of renal artery stenting versus medical therapy on left ventricular hypertrophy progression in patients affected by ischemic heart disease and renal artery stenosis. SETTING & PARTICIPANTS: Incident patients with ischemic heart disease undergoing cardiac catheterization with renal artery stenosis >50%-<=80%. INTERVENTION: Revascularization plus standard medical therapy versus medical therapy alone. OUTCOMES: Primary end point was change in echocardiographic left ventricular mass index (LVMI). MEASUREMENTS: Clinical and echocardiographic studies were performed at baseline and after 1 year. RESULTS: 84 patients were randomly assigned: 43 to revascularization plus standard medical therapy and 41 to medical therapy alone. At baseline, clinical characteristics were similar in the 2 study groups. After 1 year, there was no statistically significant difference between longitudinal change in the medical therapy group versus that in the medical therapy plus revascularization group for LVMI (2.1; 95% CI, -6.1 to 10.3 g/m(2)), blood pressure (systolic, -0.2 [95% CI, 9.1 to 8.8 mm Hg]; diastolic, -3.3 [95% CI, -8.4 to 1.8 mm Hg]), or estimated glomerular filtration rate (1.5; 95% CI, -5.8 to 8.9 mL/min/1.73 m(2)). The number of major cardiovascular events was similar in the 2 groups (revascularization plus standard medical therapy [fatal, n = 2; nonfatal, n = 11] and medical therapy alone [fatal, n = 2; nonfatal, n = 11]). LIMITATIONS: Patients with very severe renal artery stenosis were excluded from the study. CONCLUSIONS: Our study was unable to detect a clinically significant benefit of renal revascularization on LVMI in patients with coronary artery disease and renal artery stenosis of 50%-80%. PMID- 22495468 TI - Racial survival paradox of dialysis patients: robust and resilient. PMID- 22495467 TI - Accuracy of a GFR estimating equation over time in people with a wide range of kidney function. AB - BACKGROUND: Change in glomerular filtration rate (GFR) is important for clinical decision making. GFR estimates from serum creatinine level provide an unbiased but imprecise estimate of GFR at single time points. However, the accuracy of estimated GFR over time is not well known. STUDY DESIGN: Longitudinal study of diagnostic test accuracy. SETTINGS & PARTICIPANTS: 4 clinical trials with longitudinal measurements of GFR and serum creatinine on the same day, including individuals with and without kidney disease with a wide range of kidney function, diverse racial backgrounds, and varied clinical characteristics. INDEX TEST: GFR estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. REFERENCE TEST: GFR measured using urinary clearance of (125)I iothalamate. RESULTS: Data included 19,735 GFR measurements in 3,531 participants during a mean follow-up of 2.6 years. Mean values at baseline for measured and estimated GFR and error (measured GFR - estimated GFR) were 73.1 (95% CI, 71.6 to 74.5), 72.7 (95% CI, 71.5 to 74.0), and 0.14 (95% CI, -0.35 to 0.63) mL/min/1.73 m(2), respectively. Mean rates of change in measured and estimated GFR and error were -2.3 (95% CI, -2.4 to -2.1), -2.2 (95% CI, -2.4 to -2.1), and -0.09 (95% CI, -0.24 to 0.05) mL/min/1.73 m(2) per year (P < 0.001, P < 0.001, and P = 0.2, respectively). Variability (ie, standard deviation) among participants in rate of change in measured GFR, estimated GFR, and error was 4.3, 3.4, and 3.3 mL/min/1.73 m(2) per year, respectively. Only 15% of participants had a rate of change in error >3 mL/min/1.73 m(2) per year, and only 2% had a rate of change in error >5% per year. LIMITATIONS: Participants' characteristics were not available over time. CONCLUSION: The accuracy of GFR estimates did not change over time. Clinicians should interpret changes in estimated GFR over time as reflecting changes in measured GFR rather than changes in errors in the GFR estimates in most individuals. PMID- 22495469 TI - Association of symptoms of depression with progression of CKD. AB - BACKGROUND: Depression is related to morbidity and mortality in patients with kidney failure treated by dialysis, but its influence on patients with earlier stages of chronic kidney disease (CKD) is uncertain. This study investigates the association of depressive symptoms with clinical outcomes in patients with CKD not requiring dialysis. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 568 participants with CKD not requiring maintenance dialysis were recruited consecutively at a tertiary hospital in Southern Taiwan and followed up for 4 years. PREDICTORS: Baseline status of depressive symptoms. OUTCOMES: The primary outcome is a composite of progression to end-stage renal disease (ESRD), defined as requiring maintenance dialysis treatment, or all-cause mortality; and secondary outcome was first hospitalization. MEASUREMENTS: Depressive symptoms were assessed by Beck Depression Inventory. Estimated glomerular filtration rate (eGFR) was computed using the 4-variable MDRD (Modification of Diet in Renal Disease) Study equation. RESULTS: 428 participants completed the questionnaires and 160 (37%) had depressive symptoms. During a mean follow-up of 25.2 +/- 11.9 months, 136 participants (32%) reached the primary outcome (119 reached ESRD and 17 died) and 110 participants (26%) were hospitalized. High depressive symptoms increased the risk of progression to ESRD or death (HR, 1.66; 95% CI, 1.14-2.44) and first hospitalization (HR, 1.59; 95% CI, 1.03-2.47). Participants with high depressive symptoms had more rapid GFR decrease (eGFR slopes of -2.3 [25th-75th percentile, -5.3 to -0.4] vs -1.2 [25th 75th percentile, -3.5 to 0.3] mL/min/1.73 m(2) per year; P = 0.001) and initial dialysis treatment at a higher eGFR (OR for initiation of dialysis at eGFR >5 mL/min/1.73 m(2), 4.45; 95% CI, 1.44-13.78). LIMITATIONS: A single-center study of Taiwanese, Beck Depression Inventory evaluates only depressive symptom burden. CONCLUSIONS: Depressive symptoms in CKD are independent predictors of adverse clinical outcomes, including faster eGFR decrease, dialysis therapy initiation, death, or hospitalization. Depression should be evaluated early and treated in patients with CKD. PMID- 22495470 TI - Synthesis of carbazolones and 3-acetylindoles via oxidative C-N bond formation through PIFA-mediated annulation of 2-aryl enaminones. AB - A series of carbazolone derivatives and 3-acetylindoles have been achieved via PIFA-mediated intramolecular cyclization of 2-aryl enaminones. This process allows the N-moiety on the side-chain to be annulated to the benzene ring via the metal-free oxidative aromatic C-N bond formation. PMID- 22495471 TI - High-resolution through-space correlations between spin-1/2 and half-integer quadrupolar nuclei using the MQ-D-R-INEPT NMR experiment. AB - The multiple-quantum dipolar refocused-INEPT (MQ-D-R-INEPT) NMR experiment is presented. This new pulse sequence allows the generation of two-dimensional through-space NMR correlation spectra between spin-1/2 and quadrupolar nuclei under high-resolution. Compared to the existing sequences, the MQ-D-R-INEPT sequence benefits from increased robustness, due to the reduced sensitivity to offsets and radio-frequency field inhomogeneity of the R-INEPT recoupling scheme as compared to the classical cross-polarization transfer involving a quadrupolar nucleus, and applicability to quadrupolar nuclei with any half-integer spin value. Here, the heteronuclear dipolar couplings have been reintroduced using the rotary resonance recoupling (R(3)) sequence, chosen because it is gamma-encoded, and thus robust to spinning speed instabilities and to radio-frequency inhomogeneities in the case of nuclei subjected to large chemical shift anisotropy (e.g., (31)P). In the course of the article, a new definition of gamma encoding is introduced, more general and practical than the previous ones, as it does not depend on the implementation of the recoupling sequence, and is independent of the considered frame. The efficiency of the MQ-D-R-INEPT experiment is demonstrated for the observation of (31)P-(27)Al proximities. It is first tested on AlPO4-VPI-5, and then applied to a complex aluminophosphate AlPO4 (Al5P7)-DAE of incompletely established structure. For this latter sample, the high-resolution provided by the MQMAS filter allows the resolution of a large number of (31)P-(27)Al correlations, which represent an essential step towards the determination of its structural model. PMID- 22495472 TI - Recipient interleukin-28B Rs12979860 C/T polymorphism and acute cellular rejection after liver transplantation: role of the calcineurin inhibitor used. AB - BACKGROUND: Interleukin-28 (IL-28B) rs12979860 C/T polymorphism is known to predict the outcome of antiviral therapy in hepatitis C. In addition to its interferon-like and antiviral functions, IL-28B possesses the ability to modulate CD8 T cells function. This study aimed to investigate whether recipient IL-28B polymorphism may have a role in predicting the occurrence of acute cellular rejection (ACR) after liver transplantation (LT). METHODS: Two hundred fifty-one consecutive LT recipients were enrolled. All the patients underwent per protocol liver biopsies at 1, 3, and 12 months after LT. ACR episodes in the first post-LT year were recorded and graded according to the Banff score. RESULTS: At least one moderate to severe (Banff score >= 5) ACR episode was reported in 75 patients (29.9%). ACR was associated with IL-28B polymorphism: C/C=21/102 (20.6%), C/T=43/126 (34.1%), and T/T=11/23 (47.8%) (P=0.003). At logistic regression analysis, IL-28B polymorphism was found to be a predictor of ACR (P=0.012) together with cytomegalovirus reactivation (P=0.023). The association between IL 28B polymorphism and ACR occurrence was evident in tacrolimus but not in cyclosporine-treated patients. ACR episodes occurred more frequently from hepatitis C virus (HCV) negatives carrying the IL-28B C/C genotype (17.8%) to HCV negatives carrying at least one T allele or HCV positives carrying at least one C allele (33.3%) to HCV positives carrying the T/T genotype (50.0%, P=0.002). CONCLUSIONS: HCV etiology in association with the carriage of IL-28B T/T genotype predicted the highest frequency of ACR. Recipient's IL-28B genotyping could be a useful tool in individualizing immunosuppressive therapy according to the risk of ACR occurrence. PMID- 22495473 TI - Estimating the effects of multiple time-varying exposures using joint marginal structural models: alcohol consumption, injection drug use, and HIV acquisition. AB - The joint effects of multiple exposures on an outcome are frequently of interest in epidemiologic research. In 2001, Hernan et al (J Am Stat Assoc. 2001;96:440 448) presented methods for estimating the joint effects of multiple time-varying exposures subject to time-varying confounding affected by prior exposure using joint marginal structural models. Nonetheless, the use of these joint models is rare in the applied literature. Minimal uptake of these joint models, in contrast to the now widely used standard marginal structural model, is due in part to a lack of examples demonstrating the method. In this paper, we review the assumptions necessary for unbiased estimation of joint effects as well as the distinction between interaction and effect measure modification. We demonstrate the use of marginal structural models for estimating the joint effects of alcohol consumption and injection drug use on HIV acquisition, using data from 1525 injection drug users in the AIDS Link to Intravenous Experience cohort study. In the joint model, the hazard ratio (HR) for heavy drinking in the absence of any drug injections was 1.58 (95% confidence interval = 0.67-3.73). The HR for any drug injections in the absence of heavy drinking was 1.78 (1.10-2.89). The HR for heavy drinking and any drug injections was 2.45 (1.45-4.12). The P values for multiplicative and additive interaction were 0.7620 and 0.9200, respectively, indicating a lack of departure from effects that multiply or add. We could not rule out interaction on either scale due to imprecision. PMID- 22495474 TI - Prioritizing GM crop monitoring sites in the dynamics of cultivation systems and their environment. AB - EU legislation stipulates that GM crops have to be monitored for potential adverse environmental effects. Monitoring preferably should take place in the most exposed areas-the cultivated fields and their neighbouring environment. Current monitoring designs do not give detailed consideration to the different exposure intensities in agricultural practice. At the same time, the selection of specific, more exposed sites is difficult considering the dynamic and diversity of crop cultivation and rotation systems and their environments. We developed an approach for prioritising the monitoring of on-farm and neighbouring sites based on differing exposure levels using a minimum dataset of cultivation and land use information. Applying a Bt-maize cultivation scenario to Brandenburg, Germany, where presently no GM crops are cultivated, we systemised and categorised areas with different spatio-temporal exposure intensities including 50 m, 200 m and 1000 m buffers. These categories correspond to different suitabilities to serve as monitoring sites. Sites are prioritised using a sequential scheme. This yields an improved and objective spatial monitoring design providing detailed exposure information. This methodology is flexible and transferable to any agricultural setting, therefore enabling superior statistical comparisons between locations and regions and thus enhancing monitoring data quality. PMID- 22495475 TI - From chemotherapy to signal therapy (1909-2009): A century pioneered by Paul Ehrlich. AB - Paul Ehrlich (1854-1915), a German microbiologist who was awarded a 1908 Nobel Prize in Physiology/Medicine for his pioneer work on the antibody production, pioneered the modern chemotherapy by discovering his magic bullet for syphilis, called "606" or "Salvarsan" in 1909 with a Japanese young scientist, Sahachiro Hata (1873-1938) from "Denken" (Institute for Infectious Diseases, now called IMS for Institute for Medical Sciences) in Tokyo. His magic bullet was used to eradicate syphilis for more than a half century until a more safe and effective antibiotic called "Penicillin" was introduced to this world towards the end of WWII by Howard Florey (1898-1968). Celebrating this year the 100th anniversary of his discovery, this brief review will discuss how Ehrlich, now known as the Father of Chemotherapy, managed to design the first effective therapeutic for this then formidable sexually transmitted disease, which is equivalent to AIDS, HIV-infection, in the present century, and how so many new chemotherapeutics have been successfully developed during the past 100 years for other formidable diseases such as cancers and AIDS by his followers (microbe hunters and oncogene hunters) such as Alexander Fleming (1881-1955), Hamao Umezawa (1914-1986) and Brian Druker, culminating in the first signal therapeutics of cancers such as "Gleevec" that block the oncogenic signaling, around the turn of this century. PMID- 22495476 TI - QSAR studies of histone deacetylase (HDAC) inhibitors by CoMFA, CoMSIA, and molecular docking. AB - In order to develop highly potent antitumor agents, three-dimensional quantitative structure-activity relationship (3-D QSAR) studies were conducted using a series of thienyl-based hydroxamic acids. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were applied to provide the structural information for further chemical modification and optimization. ClogP was applied as an additional descriptor in the CoMFA analysis to study the effects of lipophilic parameters on the activity of these compounds, and it did improve the statistical significance of the model. Two molecules were designed based on the 3-D QSAR analysis, their activity values were predicted by the generated model, and their binding mode was elucidated by a docking approach compared to molecules in the dataset. PMID- 22495477 TI - Comparative analysis of free radical scavenging potential of several fruit peel extracts by in vitro methods. AB - We studied the radical scavenging potential of several fruit peel extracts using various standard chemical and biochemical in vitro methods. Peel extracts of C. sinensis (CS), P. granatum (PG), M. paradisiaca (MP), C. vulgaris (CV), C. melo (CM), M. indica (MI), and C. papaya (CP) were used in the present study and butylated hydroxyl anisole (BHA) was used as a standard. Marked 1,1-diphenyl-2 picrylhydrazyl (DPPH) radical scavenging activity was observed with 25 MUg/mL of CS and MP and 50 MUg/mL of PG, while all the studied doses of CP were found to be pro-oxidative. beta-Carotene bleaching revealed a higher singlet oxygen scavenging potential of all the peel extracts except MI. High NO-radical scavenging activity was observed at 25 MUg/mL of PG and MP. Inhibition test of H2O2-induced LPO in erythrocytes or in liver tissue showed that all the peels tested were effective on peroxy-radicals at one or other doses. The present study revealed the radical scavenging activity of the test peel extracts in a manner that was dose- and radical/methodspecific. Therefore, evaluation of the efficacy of herbal extracts should be carried out using different methods and not merely a single in vitro method. PMID- 22495478 TI - In vitro radical scavanging activities of Chrysaora quinquecirrha nematocyst venom. AB - The venom of Chrysaora quinquecirrha (sea nettle) contains several toxins that have bioactivity in mammals. In our study we aimed to extract proteins from Chrysaora quinquecirrha and to test the antioxidant potential of both crude protein and purified fractions. Proteins extracted from sea nettle nematocyst venom were purified through Sephadex G-100 column chromatography. The molecular weight of purified proteins was determined by gel filtration and SDS-PAGE and was found to be 105, 65, and 9 kDa for Frc-1, Frc-2, Frc-3, respectively. The in vitro antioxidant potential of Chrysaora quinquecirrha was evaluated in different systems viz. radical scavenging activity by DPPH reduction, superoxide radical scavenging activity in PMS/NADH-NBT system, hydroxyl radical by Fe(3+)-Ascorbate EDTA-H2O2 system and nitric oxide (NO) radical scavenging activity in sodium nitroprusside/Greiss reagent system. Frc-3 displayed the maximal antioxidant activity and found to have different levels of antioxidant properties in the models tested. In scavenging hydroxyl radicals, its activity was intense (IC(50) = 50.8 MUg/mL) while in scavenging NO radical, it was moderate (IC(50) = 381.4 MUg/mL). PMID- 22495479 TI - Beneficial effects of combined administration of sodium molybdate with atorvastatin in hyperlipidemic hamsters. AB - This study aims to evaluate the benefit of combined administration of sodium molybdate with atorvastatin in management of hyperlipidemia. Hyperlipidemic male Serian golden hamsters were administered either atorvastatin (40 or 80 mg/kg, p.o.) sodium molybdate (100 mg/kg, p.o.) or combination of atorvastatin (40 mg/kg, p.o.) with sodium molybdate (100 mg/kg, p.o.) for 30 consecutive days. Blood lipids (total cholesterol, triglycerides, HDL-cholesterol, Non-HDL cholesterol and anti-atherogenic index) in addition to the activities of liver transaminases (AST, ALT), as well as antioxidant status (lipid peroxidation, catalase, glutathione peroxidase) were estimated before and after 15 and 30 days of treatment. The results indicate that atorvastatin is effective in lowering the blood lipids with maximum effect achieved by the high dose (80 mg/kg, p.o.). However, this dose elevates the liver enzymes significantly after 15 and 30 days of treatment. Sodium molybdate lowers the blood lipids after 30 days from treatment without alteration in liver enzymes. Moreover, in this group, lipid peroxides were significantly reduced and activities of catalase as well as glutathione peroxidase were significantly elevated compared with the hyperlipidemic control group (saline). Combination of atorvastatin (40 mg/kg, p.o.) with sodium molybdate significantly reduced the elevated blood lipids in a similar degree as the high dose of atorvastatin. Meanwhile, in this group, the liver enzymes were not significantly elevated while, the antioxidants profile were significantly improved compared with that of control hyperlipidemic and atorvastatin groups. In conclusion, combination of sodium molybdate with atorvastatin is beneficial in management of hyperlipidemia as it allows maximum reduction in blood lipids, improves the antioxidant status with minimal disturbances in liver enzymes. PMID- 22495480 TI - Effects of oral curcumin on indomethacin-induced small intestinal damage in the rat. AB - Nonsteroidal anti-inflammatory drug (NSAID)-induced injury on gastrointestinal tract is well documented, and jejunal inflammation caused by indomethacin in rats is a broadly used experimental model of enteritis. We evaluated the effect of oral curcumin, a compound known to possess anti-inflammatory and anti-oxidant properties, on indomethacin-induced enteritis in the rat. Curcumin (50, 100, and 300 mg/kg) was given to rats by oral gavage 48, 24, and 1 h before enteritis was induced by intragastric administration of 20 mg/kg indomethacin. After 24 h, intestinal macroscopic lesions, myeloperoxidase activity and lipid peroxidation levels were assessed. Curcumin at the dose of 50 mg/kg was uneffective, while at the dose of 100 and 300 mg/kg significantly reduced macroscopic damage caused by indomethacin. By contrast, curcumin at all tested doses was unable to modify indomethacin-induced increases of myeloperoxidase and lipid peroxidation. Curcumin (100 and 300 mg/kg) significantly increased lipid peroxidation level in normal intestinal tissues of rats. Present data show that oral curcumin protects against macroscopic injury induced by indomethacin, leaving unaffected neutrophil infiltration and oxidative cell damage, thus suggesting that this beneficial effect is due to mechanisms not involving anti-inflammatory or antioxidant activities. PMID- 22495481 TI - Gaps in the information shared on consumer healthcare products. AB - We conducted a questionnaire survey of visitors to the Japan Drugstore Show 2006 and an additional questionnaire survey of pharmacists in 2008 to ascertain the current information gaps between consumers and manufacturers of consumer healthcare products (CHPs). Three main gaps were apparent: first was a gap between information that consumers wanted to receive and information that was widely disclosed by manufacturers of CHPs, second was a gap between the advisors whom consumers regarded as appropriate and the advisors who consumers had actually consulted, and a gap between what consumers expect pharmacists to know and pharmacists' actual knowledge. Manufacturers' efforts alone will not be able to close these gaps because of the number of regulations. Thus, a new social system should be constructed to supply adequate information on CHPs and consumers should enjoy free access to this information. PMID- 22495483 TI - [From medical education to continuing medical education - what can the professional societies do in partnership with the university hospitals?]. PMID- 22495484 TI - [Attitude of medical students towards a surgical career - a global phenomenon?]. AB - INTRODUCTION: Within the last few years several reports have observed an increasing decline of interest for medical students to become a general surgeon. A recent study among medical students from five medical schools in South-West Germany revealed that only 8.9 % of the students were considering a surgical career. In addition, the authors showed that there was a severe decrease of interest in a surgical career throughout medical school. The aim of the presented study is to analyse career preferences of medical students in several countries. METHODS: A Medline search for "surgical career", "medical students + general surgery" and "surgical career + influences" was performed. RESULTS: There are similar situations to that in Germany in the USA, Great Britain, New Zeeland and Switzerland with small proportions of medical students inclined towards a surgical career. In Kenya, Jordan, Pakistan and Iraq at least a higher percentage of male medical students favoured a surgical career. Independent of the country, more male medical students are pursuing a surgical career. Studies from different countries reported an increasing loss of interest in a surgical career throughout medical school. Positive influencing factors for specialisation in a field of surgery were identified: These are independent of the country, positive experiences in practical courses and positive role models. CONCLUSION: Further studies to analyse factors influencing students throughout medical school are required in the future. Internships, special tutorials, and final year rotations should be used to develop individual mentoring programmes to increase the student's interest in pursuing a general surgical career. PMID- 22495485 TI - [The Marburg surgical curriculum - improving the attraction of medical education by teaching central surgical competence]. AB - The quality of medical education is an ongoing challenge due to the continuing changes of the health-care politics and general social conditions. At many German university hospitals the dominating picture is overfilled courses, lack of hands on practice, reduced patient contact and the dull provision of theoretical, abstract knowledge. The reformed surgical curriculum at the University of Marburg university hospital is used to demonstrate that, in spite of large student numbers, a practice-oriented, small-group training at a high didactic level is possible. The surgical training courses are organized in detail and coordinated. Course contents and structure are media available in print and online versions for both students and teachers and thus fulfill not only transparency needs but also contemporary requirements. The strategy of a practice- and patient-oriented, small-group training is followed strictly in the surgical curriculum. In addition, accompanying tutorial possibilities for individual study in an up-to date learning center are offered. Here the students have the opportunity to intensify knowledge acquired in previous or future courses with numerous attractive education means. Continuous evaluation of the individual training courses at the end of each semester not only document motivation of the students but also serve to continuously improve the training concepts. PMID- 22495486 TI - [Improving continuing medical education: a valuable investment for the future of surgery]. AB - At present, surgery in Germany is suffering from the problem of poor attractivity jeopardizing nationwide availability of competent and high quality surgical care in the future. The causes for this have been repeatedly attributed to structural problems, above all in medical training and continuing medical education. In this article, we present the results of questionnaires of the National Society of German Surgeons and the German National Chamber of Physicians, identify the specific problem, and finally analyse them in an attempt to show how surgical training can be optimised and the attractivity of this specialty can be improved. In this context, the "Grosshadern Concept" for continuing surgical education is introduced as an example for an established and good functioning training curriculum. PMID- 22495487 TI - [Simulation training in surgical education - application of virtual reality laparoscopic simulators in a surgical skills course]. AB - BACKGROUND: Training and simulation are gaining importance in surgical education. Today, virtual reality surgery simulators provide sophisticated laparoscopic training scenarios and offer detailed assessment methods. This also makes simulators interesting for the application in surgical skills courses. The aim of the current study was to assess the suitability of a virtual surgery simulator for training and assessment in an established surgical training course. MATERIALS AND METHODS: The study was conducted during the annual "Practical Course for Visceral Surgery" (Warnemuende, Germany). 36 of 108 course participants were assigned at random for the study. Training was conducted in 15 sessions over 5 days with 4 identical virtual surgery simulators (LapSim) and 2 standardised training tasks. The simulator measured 16 individual parameters and calculated 2 scores. Questionnaires were used to assess the test persons' laparoscopic experience, their training situation and the acceptance of the simulator training. Data were analysed with non-parametric tests. A subgroup analysis for laparoscopic experience was conducted in order to assess the simulator's construct validity and assessment capabilities. RESULTS: Median age was 32 (27 - 41) years; median professional experience was 3 (1 - 11) years. Typical laparoscopic learning curves with initial significant improvements and a subsequent plateau phase were measured over 5 days. The individual training sessions exhibited a rhythmic variability in the training results. A shorter night's sleep led to a marked drop in performance. The participants' different experience levels could clearly be discriminated ( <= 20 vs. > 20 laparoscopic operations; p <= 0.001). The questionnaire showed that the majority of the participants had limited training opportunities in their hospitals. The simulator training was very well accepted. However, the participants severely misjudged the real costs of the simulators that were used. CONCLUSIONS: The learning curve on the simulator was successfully mastered during the course. Construct validity could be demonstrated within the course setting. The simulator's assessment system can be of value for the assessment of laparoscopic training performance within surgical skills courses. Acceptance of the simulator training is high. However, simulators are currently too expensive to be used within a large training course. PMID- 22495488 TI - [Modular postgraduate training in surgery - a national concept with future]. AB - BACKGROUND: The quality of postgraduate training is an important motivating factor for the career decisions of young doctors and has an impact on the satisfaction of postgraduate trainees. In Germany, we still lack a postgraduate training programme in surgery that defines the competency profile at the time of certification. This article describes the development of a national modular competency-based core curriculum for postgraduate surgery training as well as first experience and evaluation data from the initial period of implementation. METHODS: The curriculum was developed in a group of highly motivated surgeons according to the "Kern-cycle", a conceptual framework for curriculum development in medicine, and includs considerations from the "CanMEDS"-competency framework for physicians. The curriculum follows a "blended learning" concept with modular attendance courses and associated preparatory online courses. The didactics follows the principles of adult learning and are characterised by learner centred, self-directed learning processes in small groups with feedback. The initial implementation phase was accompanied by a detailed evaluation of the general concept as well as the quality of content and didactics of the attendance courses. RESULTS: Seven of the planned 12 attendance courses have been designed, 6 courses have been implemented2q1. Altogether 562 participants from hospitals of all levels of patient care took part in the attendance courses, some of them in several courses. The gender distribution was almost balanced with a slight female surplus. The majority of participants were supported by their clinics through exemption from clinical work or financial sponsoring. 80 % of the participants completed the evaluation of the attendance courses. The data show a high degree of participant satisfaction with the content and didactic concept of the courses, as well as with the surrounding conditions and the commitment of the trainers. CONCLUSIONS: The evaluation data on the attendance courses implemented reveal a high acceptance among participants concerning the overall concept of the modular postgraduate training programme as well as the support of the programme by surgeons responsible for postgraduate training. PMID- 22495489 TI - [Surgical education has its price]. AB - The radical economisation of the German health-care system has caused an increasing cost awareness. Following this trend, medical education has been identified as a possible expense factor. The theoretical and practical training of young doctors needs time and costs money. However, a detailed cost analysis is still not available, since the complex daily work schedule of young professionals only allows the calculation of single cost factors. Investigations in the USA estimate the costs of surgical training at US$ 80 000 per year and per resident. At present in Germany, surgical training is indirectly financed by the DRG flat rates of the health insurance companies. Possible alternatives include the implementation of a "training fond" which is financed by a percentage fee of the DRG's as well as an on-top funding by the federal government. This "training fond" would support only those surgical units that offer a structured and certified training to surgical residents. However, a systematic cost analysis of such a structured curriculum is necessary for any further discussion. PMID- 22495490 TI - Ipilimumab: a novel immunomodulating therapy causing autoimmune hypophysitis: a case report and review. AB - Ipilimumab (Yervoy; Medarex and Bristol-Myers Squibb) is a human MAB against cytotoxic T-lymphocyte antigen 4, which enhances co-stimulation of cytotoxic T lymphocytes, resulting in their proliferation and an anti-tumour response. It is licensed for the treatment of unresectable or metastatic malignant melanoma, while multiple clinical trials using this medication in the treatment of other malignancies are ongoing. As a clinical response to ipilimumab results from immunostimulation, predictably it generates autoimmunity as well, causing immune related adverse events in the majority of patients. Of those, endocrinopathies are frequently seen, and in particular, autoimmune lymphocytic hypophysitis with anterior panhypopituitarism has been reported a number of times in North America. We present a case of a male referred to our department with manifestations of anterior panhypopituitarism after his third dose of ipilimumab for metastatic malignant melanoma, and we discuss the management of his case in the light of previous reports. We also review the published literature on the presenting symptoms, time to presentation, investigations, imaging, treatment and follow-up of ipilimumab-induced autoimmune lymphocytic hypophysitis. PMID- 22495491 TI - Screening for primary aldosteronism in hypertensive subjects: results from two German epidemiological studies. AB - OBJECTIVE: The prevalence of primary aldosteronism in unselected hypertensive patients is currently unknown. We investigated the frequency of positive screening results for primary aldosteronism based on the aldosterone-to-renin ratio (ARR) in hypertensive subjects aged 30-79 years from two German epidemiological studies. We further examined the frequency of positive screening results in subjects with resistant hypertension or stage III hypertension and assessed possible disparities between untreated and treated hypertensive subjects. METHODS: Data were obtained from the first follow-ups of the population based study of health in Pomerania (SHIP; n=1392) and the cooperative health research in the region of Augsburg (KORA; n=1052). Study-specific reference ranges for plasma aldosterone concentration (PAC), plasma renin concentration (PRC) and the ARR were applied. Confirmation tests for primary aldosteronism were not performed in these epidemiological studies.Three definitions for a positive screening for primary aldosteronism were applied: A) increased ARR; B) increased ARR and decreased PRC; and C) increased ARR and increased PAC and decreased PRC. RESULTS: The frequency of positive screening results was 7.0, 3.8 and 0.2% according to definitions A-C respectively. In the subgroups of subjects with resistant hypertension (11.9, 5.5 and 0.9%) or stage III hypertension (18.3, 14.0 and 1.1%), these frequencies were markedly higher than those in the general hypertensive population. There was no difference in the frequency of positive screening results between the treated and untreated hypertensive subjects. CONCLUSIONS: A maximum of 7.0% of the hypertensive population in Germany shows a positive screening result for primary aldosteronism. Thus, primary aldosteronism may be less frequent than previously expected based on data from referred hypertensive patients. PMID- 22495492 TI - Cisplatin cytotoxicity: a theoretical study of induced mutations. AB - We investigate possible mutations in the genetic code induced by cisplatin with an approach combining molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. Specifically, the impact of platination on the natural tautomeric equilibrium in guanine-cytosine (GC) base pairs is assessed to disclose the possible role played by non-canonical forms in anti-tumour activity. To obtain valuable predictions, the main interactions present in a real DNA environment, namely hydration and stacking, are simultaneously taken into account. According to our results, the Pt-DNA adduct promotes a single proton transfer reaction in GC in the DNA sequence AG[combining low line]G[combining low line]C. Such rare tautomers might play an important role in the cisplatin biological activity since they meet the stability requirements necessary to promote a permanent mutation. PMID- 22495493 TI - Safety and feasibility of diet-treated donors with steatotic livers at the initial consultation for living-donor liver transplantation. AB - BACKGROUND: The purpose of this study was to evaluate both safety of diet-treated donors and the feasibility of their use for living-donor liver transplantation (LDLT). METHODS: A total of 128 living donors were enrolled in this study between April 2003 and March 2010. Of them, 41 were diagnosed with hepatic steatosis at the initial consultation. Donor selection was based on the findings of liver biopsy accompanied with normalization of liver function tests after diet treatment consisting of an 800 to 1400 kcal/day diet and a 100 to 400 kcal/day exercise without drug treatment, targeting body mass index of 22 kg/m2. RESULTS: Body mass index of diet-treated donors was significantly reduced with diet from 23.3 +/- 0.6 to 21.9 +/- 0.4 kg/m2 (P<0.0001). Liver function tests associated with fatty liver, including alanine aminotransferase, gamma-glutamyl transpeptidase, and total cholesterol levels, also improved with diet (P=0.0128, 0.0016, and 0.0004, respectively). The liver biopsy results of most of these donors showed stage 0/1 fibrosis and minimal/mild steatosis after the diet therapy. Surgical outcomes, including postoperative liver function tests, perioperative complications, and liver regeneration rates, did not significantly differ between nondiet-treated and diet-treated donors. Surgical outcomes and the overall survival did not significantly differ between recipients of grafts from nondiet-treated and diet-treated donors. CONCLUSION: The use of diet-treated donors for living-donor liver transplantation is feasible with respect to donor safety and the outcome of the recipient when strict selection criteria are used. PMID- 22495494 TI - Face transplantation program in France: a cost analysis of five patients. AB - BACKGROUND: Among 18 face transplantations (FTs) performed worldwide, seven were performed at the Henri Mondor Hospital, Paris, France. Their feasibility and risk benefit ratios have been reported, whereas this study analyzed the costs of FT for our first five patients. MATERIALS AND METHODS: The first five FT patients transplanted at the Henri Mondor Hospital presented disfigurements due to neurofibromatosis, severe burns, or ballistic trauma and had no relevant comorbidity. All were socially isolated and unemployed. We analyzed the costs of preoperative investigations, operative procedures, and hospitalization for each patient. A public research program (PHRC) financed the procedures, and the clinical research department refunded each FT's cost. To allow comparisons between health care systems, the cost of FT was compared with the mean costs of heart, liver, and kidney transplantations performed at the same institution. RESULTS: If all the five patients survived the FT procedure, one patient died during subsequent revisions procedures for sepsis. The overall costs for the operation and its subsequent hospitalization for each patient ranged from (20AC)103,108 to (20AC)170,071, depending on the transplant required, the technical pitfalls, the outcomes, and mainly postoperative intensive cares. CONCLUSIONS: In our institution, the transplantation of a face led to higher costs than heart or any other solid organ and represented twice the costs faced for a liver transplantation. FT is currently performed in a research setting, and cost might decrease with teams' experiences, which may shorten postoperative intensive care and overall hospital stays. PMID- 22495495 TI - Expanding the donor pool: living donor nephrectomy in the elderly and the overweight. AB - BACKGROUND: Increasing demand for donor kidneys, in parallel with trends toward more elderly and obese populations, make it important to continuously review donor pool inclusion criteria. Acceptance of elderly and obese living donors remains controversial, with a higher incidence of comorbidity and the greater risk of postoperative complications sighted as reasons for caution. Drawing on our center's experience, we aim to determine whether older age and obesity are in fact associated with greater perioperative risk, and longer term complications in donors undergoing nephrectomy. METHODS: Three hundred eighty-three living donor nephrectomies conducted at one of the United Kingdom's largest transplant units over the last 5 years were stratified into groups according to age and body mass index. Perioperative endpoints and postdonation follow-up data collected at 6-to 12-monthly intervals were analyzed and compared. RESULTS: No significant differences in operative parameters, including operative time and estimated blood loss, were reported between groups. Rates of early postoperative complications were not significantly different, although subgroup analysis showed a higher incidence of respiratory complications at the extremes of obesity (body mass index >= 40 kg/m2). On follow-up, renal function parameters showed significant change postnephrectomy, but between-group variation was not significant. Mortality and major complication rates were comparably low in all groups of study. CONCLUSIONS: In our unit's experience, nephrectomy in selected donors who may otherwise have been precluded from participation on account of their age or weight, is feasible and associated with perioperative and longer term outcomes comparable with their younger nonobese counterparts. It provides a basis for informed consent of "extended criteria" donors. PMID- 22495497 TI - Sleep patterns and sleep-impairing factors of persons providing informal care for people with cancer: a critical review of the literature. AB - BACKGROUND: Sleep is increasingly recognized as an area of functioning that may be greatly affected in persons who are practically and emotionally involved in the care of patients with cancer. Clinician awareness is required to ensure that effective care for informal caregivers with sleep problems is provided. OBJECTIVE: A 2-fold critical review of the published literature was conducted, which aimed at summarizing and critically analyzing evidence regarding sleep patterns of informal caregivers of adults with cancer and contributing factors to sleep-wake disturbances. METHODS: Using a wide range of key terms and synonyms, 3 electronic databases (MEDLINE, CINAHL, EMBASE) were systematically searched for the period between January 1990 and July 2011. RESULTS: Based on prespecified selection criteria, 44 articles were pooled to provide evidence on sleep impairing factors in the context of informal caregiving, 17 of which specifically addressed sleep patterns of caregivers of people with cancer. CONCLUSIONS: At least 4 of 10 caregivers may report at least 1 sleep problem. Short sleep duration, nocturnal awakenings, wakefulness after sleep onset, and daytime dysfunction seem to be the areas most affected irrespective of stage or type of disease, yet circadian activity remains understudied. In addition, despite a wide spectrum of potential sleep-impairing factors, underlying causal pathways are yet to be explored. IMPLICATIONS FOR PRACTICE: More longitudinal, mixed-methods, and comparison studies are warranted to explore caregiver sleep disorders in relation to the gravity of the caregiving situation in the context of diverse types of cancer and disease severity. PMID- 22495496 TI - Correlates of quality of life among African American and white cancer survivors. AB - BACKGROUND: African Americans continue to suffer disproportionately from cancer morbidity and mortality, with emerging evidence suggesting potential quality of life (QOL) disparities in the survivorship period. OBJECTIVE: The objective of the study was to assess sociodemographic, clinical, and psychosocial factors associated with physical and mental health QOL (PHQOL and MHQOL) among African American and white cancer survivors. METHODS: Patients were recruited from tumor registries. Telephone interviews were conducted with 248 African American and 244 white respondents with a history of breast, prostate, or colorectal cancers. Multivariate regression models were used to assess what factors were associated with PHQOL and MHQOL. RESULTS: Key racial differences in adjusted analyses included poorer MHQOL scores among African Americans compared with white survivors. Furthermore, race moderated the relationship between perceived social support and MHQOL, where higher social support levels were associated with increased MHQOL among African Americans. Other correlates of QOL impacted racial groups similarly. For example, factors associated with PHQOL scores included being unemployed, being uninsured, the presence of medical comorbidities, a longer time since diagnosis, and higher levels of cancer-related stress appraisals. Factors associated with MHQOL scores included being unemployed, higher levels of daily stress, higher levels of stress associated with the diagnosis, higher levels of education, higher levels of perceived social support, and higher levels of spirituality. CONCLUSION: Interventions aimed at increasing social support may have important implications for improving QOL outcomes among African Americans. IMPLICATIONS FOR PRACTICE: Measuring and understanding factors associated with QOL have important implications for patient adjustment and clinical decision making. PMID- 22495498 TI - Exercise behaviors in breast cancer survivors in Taiwan. AB - BACKGROUND: Although exercise is a recommended rehabilitation intervention for many breast cancer survivors, exercise activity after cancer treatment is rarely reported in this patient group in Taiwan. OBJECTIVE: The objectives of this study were to analyze trends in exercise activity in breast cancer survivors in Taiwan. INTERVENTIONS/METHODS: This prospective, longitudinal study with repeated measures design used standardized instruments to measure trends in exercise activity but performed no treatments or interventions. RESULTS: Of the 196 breast cancer survivors who participated in this study, 39% regularly engaged in light to-moderate intensity exercise for approximately 15 minutes per day throughout the 6-month period of the study. Of these, 40% indicated that their exercise stage had increased, and only 13% indicated that their exercise stage had decreased. The most common exercise activities were walking, hiking, calisthenics, folk dancing, chi kung and tai chi. Although most women reported that exercise made them feel better both physically and emotionally, most said that they exercised mainly for health maintenance reasons. CONCLUSIONS: Frequency, duration, and intensity of exercise significantly increased during the 6-month study but did not reach the recommended levels. Most women believed that physical activity enhanced their recovery from cancer treatment. IMPLICATIONS FOR PRACTICE: When planning patient education interventions for breast cancer survivors, healthcare professionals should consider not only the role of exercise in breast cancer recovery, but also trends in exercise behavior among breast cancer survivors. The findings of this study contribute to the literature on exercise trends in breast cancer survivors. PMID- 22495499 TI - A Chinese version of the City of Hope Quality of Life-Ostomy Questionnaire: validity and reliability assessment. AB - BACKGROUND: The City of Hope Quality of Life-Ostomy Questionnaire is a widely accepted scale to assess quality of life in ostomy patients. However, the validity and reliability of the Chinese version (C-COH) have not been studied. OBJECTIVE: The objective of the study was to assess the validity and reliability of the C-COH among ostomy patients sampled from Shanghai from August 2010 to June 2011. METHODS: Content validity was examined based on the reviews of a panel of 10 experts; test-retest was conducted to assess the item reliabilities of the scale; a pilot sample (n = 274) was selected to explore the factorial structure of the C-COH using exploratory factor analysis; a validation sample (n = 370) was selected to confirm the findings from the exploratory study using confirmatory factor analysis (CFA). Statistical package SPSS version 16.0 was used for the exploratory factor analysis, and Amos 17.0 was used for the CFA. RESULTS: The C COH was developed by modifying 1 item and excluding 11 items from the original scale. Four factors/subscales (physical well-being, psychological well-being, social well-being, and spiritual well-being) were identified and confirmed in the C-COH The scale reliabilities estimated from the CFA results for the 4 subscales were 0.860, 0.885, 0.864, and 0.686, respectively. CONCLUSIONS: Findings support the reliability and validity of the C-COH. IMPLICATIONS FOR PRACTICE: The C-COH could be a useful measure of the level of quality of life among Chinese patients with a stoma and may provide important intervention implications for healthcare providers to help improve the life quality of patients with a stoma. PMID- 22495500 TI - Preventive effect of electrical acupoint stimulation on lower-limb thrombosis: a prospective study of elderly patients after malignant gastrointestinal tumor surgery. AB - BACKGROUND: Lower deep venous thrombosis (DVT) is one of the major complications of patients with tumors or patients undergoing major surgery. Electrical acupoint stimulation, an established technique of traditional Chinese medicine (TCM), can be well combined with Western medicine to reduce the incidence of postoperative DVT, especially in elderly patients. OBJECTIVE: The objectives of this study were to assess the efficiency of electrical acupoint stimulation in the prevention of postsurgery DVT in elderly patients with gastrointestinal malignant tumors and to validate an effective and safe nursing approach that integrates TCM and Western medicine. METHODS: A total of 120 patients (none aged <60 years) who underwent malignant gastrointestinal tumor surgery between July 2005 and May 2007 were randomly divided into 3 groups: routine nursing group (group C1), graduated compression stockings group (group C2), and electrical acupoint stimulation group (group T). Hemorheological parameters (blood viscosity, etc) were measured and compared before and after surgery. RESULTS: Compared with groups C1 and C2, group T showed a significant difference in blood viscosity and blood flow velocity (P < .05). However, there were no statistical differences among groups C1, C2, and T in other hemorheological parameters. CONCLUSIONS: By speeding up the blood flow in patients' lower limbs, electrical acupoint stimulation showed a great potential to prevent symptomless DVT in elderly patients after malignant gastrointestinal tumor surgery. IMPLICATIONS FOR PRACTICE: Western medical care combined with TCM can reduce the occurrence of lower DVT in elderly patients suffering from gastrointestinal cancer. This approach may help nurses to plan effective care for elderly patients. PMID- 22495501 TI - Changes in motivational outcomes after a supervised resistance exercise training intervention in lung cancer survivors. AB - BACKGROUND: Short-term supervised exercise interventions improve health-related fitness in lung cancer survivors; however, sustained exercise is required to maintain the health benefits. The impact of exercise interventions on motivational outcomes may be important for long-term exercise adoption. OBJECTIVE: The objective of this study was to examine the effects of a 10-week supervised progressive resistance exercise training program on lung cancer survivors' motivational outcomes based on the Theory of Planned Behavior (TPB). METHODS: Posttreatment lung cancer survivors were recruited to undergo a 10-week supervised resistance exercise training intervention. The 2-component model of the TPB was measured at baseline and after intervention. RESULTS: Fifteen participants completed assessments of TPB measures. Significant increases in self efficacy (P = .022) and perceived controllability (P = .032) and a nonsignificant increase in affective attitude (P = .090) were observed after intervention. Intention was significantly lower at postintervention (P = .044). Significant correlates of postintervention intention were instrumental attitude (P = .001), self-efficacy (P = .004), perceived behavioral control (P = .009), and affective attitude (P = .044). At postintervention, self-efficacy was significantly correlated with planning (P < .046). CONCLUSIONS: Short-term supervised resistance exercise training may improve some motivational outcomes for lung cancer survivors. Intentions appeared to be weakened after the intervention, but there are methodological explanations for this finding. IMPLICATIONS FOR PRACTICE: Participation in short-term supervised resistance exercise may be an effective method to improve some motivational factors related to exercise in lung cancer survivors. More research is needed to examine the long-term effects of supervised resistance exercise on motivational outcomes in lung cancer survivors. Strategies to maintain motivational changes that occur following a supervised resistance exercise intervention need to be investigated. PMID- 22495502 TI - Arthralgia during aromatase inhibitor treatment in early breast cancer patients: prevalence, impact, and recognition by healthcare providers. AB - BACKGROUND: Many breast cancer patients experience arthralgia symptoms during aromatase inhibitor (AI) treatment, which leads to poor compliance and a lower quality of life. OBJECTIVE: The research questions of this study were as follows: (1) What is the incidence of arthralgia during AI treatment in early breast cancer patients, (2) what is the impact of AI-associated arthralgia on hand function, daily activities, and AI adherence, and (3) does the healthcare provider recognize AI-associated arthralgia as relevant in clinical practice? METHODS: A total of 57 breast cancer patients of a University Breast Cancer Clinic participated in this study. Each patient completed a questionnaire, performed 2 function tests (goniometry of the wrist and a handgrip strength measurement), and consented to a review of the medical chart. RESULTS: Forty-two breast cancer patients (74%) reported symptoms of arthralgia. All patients with arthralgia symptoms experienced an impact on their daily activities, and 65% had a decrease in hand and finger function. Sixty-nine percent of all patients were fully adherent in their medicine treatment. In 26% of cases with arthralgia, the symptoms were not reported in the medical chart. CONCLUSION: Given the large number of patients with AI-associated arthralgia and its impact on daily life and functioning, it is of great importance to improve the recognition and care of arthralgia symptoms during AI treatment. IMPLICATIONS FOR PRACTICE: Oncology nurses could play an important role in assessment of modifiable risk factors, providing lifestyle advice and support in coping. PMID- 22495503 TI - Effects of an internet support system to assist cancer patients in reducing symptom distress: a randomized controlled trial. AB - BACKGROUND: Cancer patients experience many physical and psychosocial problems for which they need support. WebChoice is an Internet-based, interactive health communication application that allows cancer patients to monitor their symptoms and problems, provides individually tailored information and self-management support, e-communication with expert cancer nurses, and an e-forum for group discussion with other patients. OBJECTIVE: The objective of this study was to examine the effects of WebChoice on symptom distress (primary outcome), depression, self-efficacy, health-related quality of life, and social support (secondary outcomes). METHODS: In this 1-year repeated-measures randomized controlled trial, 325 breast and prostate cancer patients were randomized into 1 experimental group with access to WebChoice and 1 control group who received URLs of publicly available cancer Web sites. RESULTS: Group differences on symptom distress were significant only for the global symptom distress index on the Memorial Symptom Assessment Scale (slope estimate, -0.052 [95% confidence interval, -0.101 to -0.004]; t = 4.42; P = .037). There were no significant group differences on secondary outcomes. Additional analyses showed significant within group improvements in depression in the experimental group only. In the control group, self-efficacy and health-related quality of life deteriorated significantly over time. CONCLUSION: This randomized controlled trial is one of the first to evaluate effects of an interactive health communication application to support cancer patients in illness management on symptoms. Although only 1 hypothesis was partially supported, the combined results show a clear trend toward better scores in the intervention group on most outcome measures. IMPLICATIONS FOR PRACTICE: If findings can be supported with additional research, WebChoice may become an important tool to support nursing care that can equip cancer patients to better manage their illness. PMID- 22495504 TI - Blogging through cancer: young women's persistent problems shared online. AB - BACKGROUND: Many young women have turned to illness blogs to describe their lived experience with cancer. Blogs represent an untapped source of knowledge for researchers and clinicians. OBJECTIVE: The purpose of this qualitative, exploratory study was to describe the life disruptions caused by cancer among young women, as well as to understand the facilitators and barriers in accessing healthcare services during and after active treatment. METHODS: Sixteen Internet illness blogs were analyzed among women, aged between 20 and 39 years, diagnosed with cancer. These blogs were analyzed based on phenomenological qualitative methods and thematic analysis. RESULTS: There were 4 dimensions of persistent problems that were articulated in the narratives of the young women without any relief. They included pain and fatigue, insurance and financial barriers, concerns related to fertility, and symptoms of posttraumatic stress and anxiety. CONCLUSION: The young women's narratives capture fear, uncertainty, anger, and the debilitating nature of these persistent issues. Many of the women expressed their lingering physical, psychosocial, and emotional problems. IMPLICATIONS FOR PRACTICE: Online illness narratives are a naturalistic form of inquiry that allows nurses to understand the experience of the patient through their own words and accounts. This study provides a foundation for nursing-based interventions that transcend traditional clinic experiences. PMID- 22495505 TI - A concern about the proposed DSM-V criteria reclassifying cognitive disorders. PMID- 22495506 TI - Is heparin needed for patients with an intra-aortic balloon pump? AB - We addressed the question of whether or not the currently available evidence base supports heparinization in the context of a patient requiring cardiovascular support with an intra-aortic balloon pump (IABP). A best evidence topic was written according to a previously defined structured protocol. A literature search returned 443 papers, 3 of which were deemed relevant. Jiang et al. randomized 153 patients requiring IABP to heparin or no heparin, matched for age, sex and comorbidities. There was no significant difference in limb ischaemia; however, incidence of bleeding was significantly increased in the heparinized group (14.1 vs 2.4%). One cohort study compared two management strategies of IABP in which patients either received heparin universally or selectively with heparin only given for certain pre-defined indications. They reported increased bleeding with universal heparinization (39.2 vs 31.8%) but similar other complication rates. Another cohort study in which patients with IABP were initially treated with glycoprotein IIb/IIIa antagonists only, reported bleeding and ischaemia rates within accepted ranges for heparinized patients. The use of anticoagulation with IABP is intended to reduce the risk of thrombus, thromboembolus or limb ischaemia whilst generating an increased risk of bleeding as a side-effect. The aforementioned studies demonstrate that omitting or implementing a selective use strategy of heparinization during IABP counterpulsation can significantly decrease the incidence of bleeding without an increase in ischaemic events. One study also performed angiography prior to IABP insertion on some of their patients, selecting the less diseased side to insert the IABP. Current evidence on this topic is sparse, especially as relates to patients in the context of cardiothoracic surgery. Just one study specifically looked at surgical patients. However, the existing data suggest that it is safe to omit heparinization when using IABP counterpulsation. The decision to heparinize should be weighed in the context of other indications or contraindications rather than being an automatic response to the use of IABP. PMID- 22495507 TI - Outcomes and predictors of prolonged ventilation in patients undergoing elective coronary surgery. AB - OBJECTIVES Despite the seriousness of prolonged mechanical ventilation (PMV) as a postoperative complication, previously proposed risk prediction models were met with limited success. The purpose of this study was to identify perioperative variables associated with PMV in elective primary coronary bypass surgery. PMV was defined as the need for intubation and mechanical ventilation for >72 h, after completion of the operation. METHODS Between April 1997 and September 2010, 10 ,977 consecutive patients were retrospectively reviewed. A series of two multivariate logistic regression analyses were carried out to identify preoperative predictors of prolonged ventilation and the impact of operative variables. RESULTS PMV occurred in 215 (1.96%) patients; 119 (55.3%) of these underwent tracheostomy. At multivariate analysis, predictors included NYHA higher than class II (odds ratio [OR], 1.77; 95% confidence intervals [CI], 1.34-2.34), renal dialysis (OR, 5.5; 95% CI, 2.08-14.65), age at operation (OR, 1.04; 95% CI, 1.02-1.06), reduced FEV(1) (OR, 0.99; 95% CI, 0.98-0.99), body mass index >35 kg/m(2) (OR, 1.73; 95% CI, 1.14-2.63). On serial logistic regression analyses, operative variables added little to the discriminatory power of the model. Kaplan Meier survival curves showed reduced survival among PMV patients (P < 0.001) with an improved survival in the tracheostomy subgroup. CONCLUSIONS PMV after coronary bypass is associated with a reduction in early and mid-term survival. Risk modelling for PMV remains problematic even when examining a more homogenous lower risk group. PMID- 22495508 TI - Investigation of in vivo microtubule and stress fiber mechanics with laser ablation. AB - Laser ablation has emerged as a useful technique to study the mechanical properties of the cytoskeleton in living cells. Laser ablation perturbs the force balance in the cytoskeleton, resulting in a dynamic response which can be imaged. Quantitative measurement of the dynamic response allows the testing of mechanical theories of the cytoskeleton in living cells. This review discusses recent work in applying laser ablation to study stress fiber and microtubule mechanics in living endothelial cells. These studies reveal that molecular motors are major determinants of the mechanical properties of the cytoskeleton in cells. PMID- 22495509 TI - Computational inference of mRNA stability from histone modification and transcriptome profiles. AB - Histone modifications play important roles in regulating eukaryotic gene expression and have been used to model expression levels. Here, we present a regression model to systematically infer mRNA stability by comparing transcriptome profiles with ChIP-seq of H3K4me3, H3K27me3 and H3K36me3. The results from multiple human and mouse cell lines show that the inferred unstable mRNAs have significantly longer 3'Untranslated Regions (UTRs) and more microRNA binding sites within 3'UTR than the inferred stable mRNAs. Regression residuals derived from RNA-seq, but not from GRO-seq, are highly correlated with the half lives measured by pulse-labeling experiments, supporting the rationale of our inference. Whereas, the functions enriched in the inferred stable and unstable mRNAs are consistent with those from pulse-labeling experiments, we found the unstable mRNAs have higher cell-type specificity under functional constraint. We conclude that the systematical use of histone modifications can differentiate non expressed mRNAs from unstable mRNAs, and distinguish stable mRNAs from highly expressed ones. In summary, we represent the first computational model of mRNA stability inference that compares transcriptome and epigenome profiles, and provides an alternative strategy for directing experimental measurements. PMID- 22495510 TI - Extracellular histones inhibit efferocytosis. AB - The uptake and clearance of apoptotic cells by macrophages and other phagocytic cells, a process called efferocytosis, is a major component in the resolution of inflammation. Increased concentrations of extracellular histones are found during acute inflammatory states and appear to contribute to organ system dysfunction and mortality. In these studies, we examined the potential role of histones in modulating efferocytosis. We found that phagocytosis of apoptotic neutrophils or thymocytes by macrophages was significantly diminished in the presence of histones H3 or H4, but not histone H1. Histone H3 demonstrated direct binding to macrophages, an effect that was diminished by preincubation of macrophages with the opsonins growth arrest-specific gene 6 (Gas6) and milk fat globule-epidermal growth factor (EGF) 8 (MFG-E8). Incubation of histone H3 with soluble alpha(v)beta5 integrin and Mer, but not with alpha(v)beta3, diminished its binding to macrophages. Phagocytosis of apoptotic cells by alveolar macrophages in vivo was diminished in the presence of histone H3. Incubation of histone H3 with activated protein C, a treatment that degrades histones, abrogated its inhibitory effects on efferocytosis under both in vitro and in vivo conditions. The present studies demonstrate that histones have inhibitory effects on efferocytosis, suggesting a new mechanism by which extracellular histones contribute to acute inflammatory processes and tissue injury. PMID- 22495511 TI - The role of family incomes in cigarette smoking: evidence from French students. AB - In this paper, we study the smoking behavior of students aged from 18 to 25 using four cross-section data sets collected in France from 1997 to 2006. We focus on the role played by student income and parental resources. We find that both the probability of smoking and the number of cigarettes smoked are positively correlated to family resources. Among students, only wages earned and transfers received from parents increase smoking participation. However, sensitivity to income remains weak since a rise of 1% in income of either the students or their parents leads to an increase in smoking prevalence of about 0.15-0.20%. PMID- 22495512 TI - A cross-sectional exploration of smoking status and social interaction in a large population-based Australian cohort. AB - We used cross-sectional data to investigate whether current, past and never smokers report different levels of social interaction and whether the level of social interaction varied according to the type of interaction being measured. Self-reported questionnaire data were obtained from 239,043 men and women aged 45 years or older living in Australia between February 2006 and February 2010. The study participation rate was 18%. Poisson regression models were used to estimate the percentage differences in the mean values of four social interaction outcomes according to smoking status after adjusting for age, place of residence, income, education, health insurance status, physical limitation, psychological distress and exposure to passive smoke: number of times 1) spent with friends/family, 2) spoken on the telephone, 3) attended social meetings in the past week, and 4) number of people outside of home that can be depended upon. 7.6% of males and 6.9% of females were current smokers, 43.6% of males and 28.6% of females were ex smokers and 48.8% of males and 64.5% of females had never smoked. Compared to never smokers, current smokers reported significantly fewer social interactions in the past week and had fewer people outside the home that they could depend on. Men and women current smokers attended 24.0% (95% CI, 20.3, 27.5) and 31.1% (95% CI, 28.1, 34.1) fewer social group meetings on average than never smokers. Smokers exposed to passive smoke reported higher levels of social interaction than those not exposed. Past smokers reported levels of social interaction that were intermediate to those of current and never smokers and the more years they had abstained from smoking, the more social interaction they reported on average. Our data are in line with previous research showing that smokers are not only worse off economically, physically and mentally, but are also less likely to be socially connected. PMID- 22495513 TI - HIV and chemoprophylaxis, the importance of considering social structures alongside biomedical and behavioral intervention. AB - This manuscript draws connections between chemoprophylaxis and the biomedical model of disease that emphasizes individual behavior. We argue that chemoprophylactic HIV interventions have limited utility at the population-level, and that structural interventions need to be prioritized. We use the recent CAPRISA 004 and iPrEx trials to (a) critique the utility of these trials from a public health perspective by highlighting the difference between efficacy and effectiveness, (b) apply an alternative theory of health behavior as a way to reorient the field toward the discussion of the need to employ structural interventions, and (c) examine two aspects of HIV prevention efforts - funding structures and iatrogenic effects of biomedical approaches - as a means of overcoming obstacles to more widespread adoption of structural interventions. PMID- 22495514 TI - Connexin 57 is expressed by the axon terminal network of B-type horizontal cells in the rabbit retina. AB - In the rabbit retina there are two types of horizontal cell (HC). A-type HCs (AHC) are axonless and extensively coupled via connexin (Cx)50 gap junctions. The B-type HC (BHC) is axon-bearing; the somatic dendrites form a second network coupled by gap junctions while the axon terminals (ATs) form a third independent network in the outer plexiform layer (OPL). The mouse retina has only one type of HC, which is morphologically similar to the B-type HC of the rabbit. Previous work suggested that mouse HCs express Cx57 (Hombach et al. [2004] Eur J Neurosci 19:2633-2640). Therefore, we cloned rabbit Cx57 and raised an antibody to determine the distribution of Cx57 gap junctions among rabbit HCs. Dye injection methods were used to obtain detailed fills for all three HC networks for analysis by confocal microscopy. We found that Cx57 was associated with the B-type AT plexus. Cx57 plaques were anticorrelated with the B-type somatic dendrites and the A-type HC network. Furthermore, there was no colocalization between Cx50 and Cx57. We conclude that in the rabbit retina, Cx57 is only found on BHC-AT processes. Thus, in species where there are two types of HC, different connexins are expressed. The absence of Cx57 labeling in the somatic dendrites of B-type HCs suggests the possibility of an additional unidentified HC connexin in the rabbit. PMID- 22495516 TI - High-throughput analysis of the plasmid bioproduction process in Escherichia coli by FTIR spectroscopy. AB - Monitoring plasmid production systems is a lab intensive task. This article proposes a methodology based on FTIR spectroscopy and the use of chemometrics for the high-throughput analysis of the plasmid bioproduction process in E. coli. For this study, five batch cultures with different initial medium compositions are designed to represent different biomass and plasmid production behavior, with the maximum plasmid and biomass concentrations varying from 11 to 95 mg L(-1) and 6.8 to 12.8 g L(-1), respectively, and the plasmid production per biomass varying from 0.4 to 5.1 mg g(-1). After a short sample processing consisting of centrifugation and dehydration, the FTIR spectra are recorded from the collected cellular biomass using microtiter plates with 96 wells. After spectral pre processing, the predictive FTIR spectra models are derived by using partial least squares (PLS) regression with the wavenumber selection performed by a Monte-Carlo strategy. Results show that it is possible to improve the PLS models by selecting specific spectral ranges. For the plasmid model, the spectral regions between 590 1,130, 1,670-2,025, and 2,565-3,280 cm(-1) are found to be highly relevant. Whereas for the biomass, the best wavenumber selections are between 900-1,200, 1,500-1,800, and 2,850-3,200 cm(-1). The optimized PLS models show a high coefficient of determination of 0.91 and 0.89 for the plasmid and biomass concentration, respectively. Additional PLS models for the prediction of the carbon sources glucose and glycerol and the by-product acetic acid, based on metabolism-induced correlations between the nutrients and the cellular biomass are also established. PMID- 22495517 TI - Protective effects of protocatechuic acid on TCDD-induced oxidative and histopathological damage in the heart tissue of rats. AB - 2,3,7,8-Tetracholorodibenzo-p-dioxin (TCDD) is a highly toxic environmental contaminant that causes severe toxic effects in animal and human. In this study, we investigated the toxic effects of TCDD and the preventive effects of protocatechuic acid (PCA), a widespread phenolic compound, in the heart tissue of rats. For this purpose, 3-4 months old 28 rats with 280-310 g body weights were equally divided into 4 groups (control, TCDD, PCA, TCDD + PCA group). A 2 MUg/kg dose of 2,3,7,8-TCDD and 100 mg/kg dose of PCA were dissolved in corn oil and given orally to the rats for 45 days. The results indicated that TCDD induced oxidative stress by increasing the level of thiobarbituric acid reactive substance and by decreasing the levels of glutathione, catalase, glutathione peroxidase and superoxide dismutase in the heart tissue of rats. In contrast, PCA treatment prevents the toxic effects of TCDD on oxidative stress. In addition, histopathological alterations such as necrosis and hemorrhage occurred in TCDD group, and PCA treatment partially prevents these alterations in heart tissue. In this study, it was concluded that TCDD exposure led to toxic effects in heart tissue and PCA treatment could prevent the toxicity of TCDD. PMID- 22495518 TI - Inulinase production by Geotrichum candidum OC-7 using migratory locusts as a new substrate and optimization process with Taguchi DOE. AB - Utilization of migratory locusts (Locusta migratoria) as a main substrate due to its high protein content for inulinase (2,1-beta-d-fructan fructanohydrolase) production by Geotrichum candidum OC-7 was investigated in this study. To optimize fermentation conditions, four influential factors (locust powder (LP) concentration, sucrose concentration, pH and fermentation time) at three levels were investigated using Taguchi orthogonal array (OA) design of experiment (DOE). Inulinase yield obtained from the designed experiments with regard to Taguchi L9 OA was processed with Minitab 15 software at 'larger is better' as quality character. The results showed that optimal fermentation conditions determined as LP 30 g/l, sucrose 20 g/l, pH 6.0 and time 48 h. Maximum inulinase activity was recorded as 30.12 U/ml, which was closer to the predicted value (30.56 U/ml). To verify the results, analysis of variance test was employed. LP had the greatest contribution (71.96%) among the other factors. Sucrose had lower contribution (13.96%) than LP. This result demonstrated that LP had a strong effect on inulinase activity and can be used for enzyme production. Taguchi DOE application enhanced enzyme activity to about 3.05-fold versus unoptimized condition and 2.34 fold versus control medium. Consequently, higher inulinase production can be achieved by the utilization of an edible insect material as an alternative substrate and Taguchi DOE presents suitable optimization method for biotechnological process. PMID- 22495519 TI - Effects of N,N-dimethylformamide on behaviour and regeneration of planarian Dugesia japonica. AB - In this study, the toxicity, behavioural and regeneration effects of dimethylformamide (DMF) on planarian Dugesia japonica were investigated. One control and six different concentrations of DMF (10 ppm, 100 ppm, 500 ppm, 1000 ppm, 5000 ppm and 10,000 ppm) were used in triplicate. The results showed that the mortality was directly proportional to the DMF concentration and planarian locomotor velocity (pLMV) was significantly reduced by increasing the exposure time and DMF concentration. pLMV of D. japonica was significantly reduced at a lower concentration of 10 ppm after 7 days of continuous exposure to DMF. The recovery of the motility of planarians pretreated with DMF was found to be time- and dose dependent, all planarians had complete recovery in their motility after 48 h. The appearance of auricles in regenerating animals was easily affected by DMF exposure in comparison with the appearance of eyespot. The present results suggest that the intact adult mobility in the aquatic planarian D. japonica is a more sensitive biomarker than mortality, and the appearance of auricles in regenerating animals is a more sensitive biomarker than eyespot. PMID- 22495522 TI - An evaluation of posttraumatic stress disorder and parent stress in children with orthopaedic injuries. AB - OBJECTIVES: Trauma has more than physical effects on pediatric patients and their families. The purpose of this study was to evaluate pediatric orthopaedic trauma patients and patients with isolated nonoperative upper extremity (UE) fractures for emotional/psychologic symptoms associated with posttraumatic stress disorder (PTSD) and parent stress. METHODS: An institutional review board-approved prospective study of patients aged 8-18 years who sustained a traumatic injury or isolated UE fracture from October 2009 to May 2010 was performed. Demographic data were obtained and the Child PTSD Symptom Scale was used. The Parent Stress Index was used to evaluate the stress of the parents/guardian. For 80% power, we needed 32 per group. P value was set at <0.05. RESULTS: A total of 76 children and their parents/guardians participated in the study. The mean age was 12.6 years (8-17 years). There were 56 males (74%) and 20 females (26%). The average time since injury was 12 months (3-89 months). The prevalence of PTSD between the high-energy trauma patients and the low-energy nonoperative UE patients was not significant. Overall, 33% of the children had PTSD. Involvement in music was significant between patients with and without PTSD (P = 0.037) and may be protective against PTSD. CONCLUSIONS: PTSD commonly affects pediatric patients who sustain injuries as a result of a traumatic event, whether low- or high energy mechanisms. We found no factors significantly associated with or predictive of PTSD and did not find an association of PTSD with parent stress. We need to maintain a high index of suspicion in pediatric trauma patients regardless of the energy associated with the traumatic event. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 22495521 TI - Quality of life after operative fixation of displaced acetabular fractures. AB - OBJECTIVE: The aim of this study was to determine quality of life (QoL) changes over time after internal fixation of acetabular fractures. DESIGN: This pertains to a prospective cohort study, which was single centered. SETTING: The study was conducted at the University Hospital. PATIENTS: One hundred thirty-six patients (108 men, 28 women), age 17-83 years operated for an acetabular fracture during 2004-2008 were prospectively included and followed up for 2 years. MAIN OUTCOME MEASURES: QoL was evaluated via Short Form-36 (SF-36) and Life Satisfaction-11 at 6, 12, and 24 months. Radiographs were evaluated according to Matta at 2 years. RESULTS: The most frequent fracture types were posterior wall (n31), associated anterior-posterior hemitransverse (n34), and associated both column (n29). One hundred twenty-nine patients could be assessed at 2 years, 4 did not respond, and 3 had died. The patients scored lower than norms in all 8 SF-36 domains with improvement over time for Physical Function (P < 0.0001) and Role Physical (P < 0.0001). The patients with postop reduction 0-1 mm scored better (P < 0.001 0.039) in 7 domains, all except vitality (P = 0.07), when compared with patients with residual displacement of >=2 mm. Life satisfaction did not change with time and showed lower scores than normative in 9 of 11 items. Nineteen patients had undergone total hip replacement, and the strongest predictor was acetabular or femoral head impaction. CONCLUSIONS: QoL in surgically treated patients with displaced acetabular fracture keeps improving in physical SF-36 domains over a 2 year period although still lower than norms, and anatomical reduction results in better QoL outcome in most dimensions. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22495523 TI - Nonoperative immediate weightbearing of minimally displaced lateral compression sacral fractures does not result in displacement. AB - OBJECTIVES: The purpose of this study was to compare the initial and follow-up radiographs of patients with minimally displaced lateral compression (LC) sacral fractures treated nonoperatively with immediate weightbearing to determine the amount of displacement that occurs during healing. DESIGN: Retrospective review. SETTING: Single academic urban Level I Trauma Center. PATIENTS/PARTICIPANTS: We evaluated 118 patients with a LC sacral fracture with <10 mm of displacement. There were 70 women and 48 men whose average age was 46 years and injury severity score was 15 +/- 11. INTERVENTION: Nonoperative treatment consisted of immediate foot-flat mobilization and advancement of weightbearing as tolerated. Repeat radiographs were routinely obtained once the patient had ambulated 50 feet or at 1 week to look for further displacement. Patients were followed with AP radiographs in the clinic at the 4- to 6-week and 10- to 12-week periods, and then every 6-8 weeks until they were healed. MAIN OUTCOME MEASURES: Specific measurements were made on the initial and follow-up radiographs by 2 observers not involved in the treatment of the patients. A vertical plumb line drawn through the center of the S1 and S2 bodies served as an anchoring point for measurements. Key landmarks were measured on each side of the pelvis, which allowed for determination of the initial and final displacements. RESULTS: All patients presenting to our center with LC sacral fractures with <10 mm of displacement were treated nonoperatively. One patient failed nonoperative management, demonstrating 5 mm of additional sacral displacement and having substantial pain with attempts to mobilize. This patient was treated with closed reduction and percutaneous pinning of the sacrum and an anterior external fixator. The other 117 patients (99%) healed with minimal additional displacement. CONCLUSIONS: : Immediate weightbearing, tempered by patient comfort, is a safe and acceptable treatment for minimally displaced LC sacral fractures and results in union with minimal additional displacement. PMID- 22495524 TI - Negative pressure wound therapy reduces the effectiveness of traditional local antibiotic depot in a large complex musculoskeletal wound animal model. AB - OBJECTIVES: Negative pressure wound therapy (NPWT) has been used to help manage open wounds. Surgeons also often use local antibiotic depot as adjunctive therapy in an effort to reduce infection rates. These 2 techniques have been reported to be used in conjunction, but there are little data to support this practice. We sought to compare the contamination levels of wounds treated with the commonly used antibiotic bead pouch technique to wounds that received both antibiotic beads and NWPT. METHODS: The effectiveness of a bead pouch was compared with antibiotic beads with NPWT. The anterior compartment and proximal tibia of goats were injured and inoculated with Staphylococcus aureus. Six hours later, the wounds were debrided and the animals were assigned to a group; the bacteria level was quantified immediately before and after initial debridement and 2 days after treatment. RESULTS: The wounds in the antibiotic bead pouch group had 6-fold less bacteria than the augmented NPWT group, 11 +/- 2% versus 67 +/- 11% of baseline values, respectively (P = 0.01). As expected, high levels of the antibiotic were consistently recovered from the augmented NPWT effluent samples at all time points. CONCLUSIONS: NPWT reduces the effectiveness of local antibiotic depot. These results can provide surgeons with the information to personalize the adjunctive therapies to individual patients, with the degree of difficulty in managing the wound and concern for infection being the 2 variables dictating treatment. PMID- 22495525 TI - Proximal tibial intra-articular osteotomy for treatment of complex Schatzker type IV tibial plateau fractures with lateral joint line impaction: description of surgical technique and report of nine cases. AB - This study presents a retrospective review of 8 patients with 9 cases of an uncommon variant of medial tibial plateau fracture treated with a surgical approach not previously described in the literature. The fracture pattern is characterized by a displaced medial tibial plateau fracture with significant central and posterior impaction of the lateral tibial articular surface but an intact lateral cortex. A novel surgical approach with an intra-articular osteotomy of the lateral tibial plateau was used to facilitate visualization, reduction, and instrumentation of the lateral articular injury. Early clinical and radiographic results of this treatment approach were reviewed. We describe the fracture pattern, surgical technique, and early results and propose this technique as a reasonable alternative for treatment of a challenging clinical entity. PMID- 22495526 TI - Normal tibiofibular relationships at the syndesmosis on axial CT imaging. AB - OBJECTIVES: Computed tomography (CT) is reported to be superior to plain radiography for imaging the syndesmosis, but CT criteria differentiating normal from abnormal tibiofibular relationships do not exist. The purpose of this study was to define normal tibiofibular relationships at the syndesmosis on axial CT imaging and to report the reliability of these measurements. METHODS: Thirty healthy volunteers underwent CT evaluation of bilateral ankles. Axial CT measurements consisted of tibiofibular clear space, tibiofibular overlap, anterior tibiofibular interval, and fibular rotation (theta(fib)). To assess reliability, 3 investigators independently made each CT measurement on 2 separate occasions. RESULTS: Sixty ankles were included for analysis. CT measurements demonstrated excellent intrarater and interrater reliability. There was significant anatomic variability between individuals. Specifically, statistically significant gender differences were discovered in CT measurements of tibiofibular overlap and anterior tibiofibular interval. Variance between ankles of each subject was calculated. In an uninjured population, tibiofibular intervals do not vary by more than 2.3 mm, and the rotation of the fibula does not vary by more than 6.5 degrees between ankles of the same person. CONCLUSIONS: Measurements of tibiofibular relationships made on axial CT images are reliable. Because of significant anatomic variation between individuals, using a patient's contralateral ankle for comparison provides a precise definition of normal tibiofibular relationships. These criteria allow for the detection of subtle variations in the tibiofibular relationships indicating instability and provide a tool for postoperatively assessing the reduction of the injured syndesmosis. PMID- 22495527 TI - Indirect reduction of the radial head in children with chronic Monteggia lesions. AB - OBJECTIVE: The purpose of this study was to report the long-term follow-up results of chronic Monteggia fractures treated with angulation-translation osteotomy of ulna and closed reduction of the radial head. DESIGN: Retrospective. SETTING: Level 1 trauma center. PATIENTS: We retrospectively reviewed 10 missed Monteggia fractures in children. The mean age of the patients was 7.5 years (range, 6-10 years), and there were 2 girls and 8 boys. The mean duration of time between initial injury and initial presentation was 1.7 years (range, 6 weeks to 5 years). INTERVENTION: Closed reduction with ulna osteotomy or lengthening was performed in all 10 cases. Annular ligament reconstruction (ALR) was done in 2 cases. Final follow-up ranged from 3 to 20 years (mean 10 years). MAIN OUTCOME MEASUREMENT: We assessed preoperative and postoperative radiographs to evaluate the quality of the radial head reduction. Clinical results were assessed according to the functional elbow score devised by Kim et al. RESULTS: Radial head reduction was achieved and maintained in 8 of 10 cases after primary or secondary surgery. The radial head was mildly subluxated in one case and dislocated in another case at final follow-up. ALR was performed in only 2 cases. Open reduction and ALR is not required in every case, and its need should depend on intraoperative stability of radial head. PMID- 22495528 TI - Does early fixation of posterior wall acetabular fractures lead to increased blood loss? AB - OBJECTIVE: Controversy exists regarding the ideal timing of acetabular fracture surgery. Surgery within the first 24 hours might put patients at risk for increased blood loss; however, early treatment might facilitate fracture reduction and patient mobilization. The purpose of this study was to determine whether early surgery for posterior wall acetabular fractures results in higher intraoperative blood loss. DESIGN: Retrospective review. SETTING: Level I academic trauma center. METHODS: A 1-year retrospective review of 49 consecutive posterior wall acetabular fractures from a single Level I trauma center. Outcome variables were analyzed with t tests, Pearson correlation coefficient, and multiple linear regression analysis. INTERVENTION: Surgery for posterior wall acetabular fractures. MAIN OUTCOME MEASURES: Estimated blood loss (EBL), preoperative and postoperative hematocrit levels, and intraoperative and postoperative blood product requirements as a function of the timing of surgery. RESULTS: No difference in EBL was shown between the fractures fixed within 24 hours of injury (mean = 644 mL) and those fixed later (573 mL, P = 0.50). No difference was observed when analyzing timing of surgery as a continuous variable (P = 0.45) or other outcome variables. A post hoc power analysis demonstrated that our sample could detect a difference in EBL of 166 mL. CONCLUSIONS: Our study suggests that posterior wall fractures might be a subset of acetabular fractures that can be treated immediately without increased risk of excessive blood loss. It should be emphasized that our findings should not be applied to other more complex types of fractures of the acetabulum. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 22495529 TI - Embolization of pelvic arterial injury is a risk factor for deep infection after acetabular fracture surgery. AB - OBJECTIVE: To determine whether embolization of pelvic arterial injuries before open reduction and internal fixation (ORIF) of acetabular fractures is associated with an increased rate of deep surgical site infection. METHODS: Retrospective review of patients who underwent ORIF of acetabular fractures at our institution from 1995 through 2007 (n = 1440). We compared patients with acetabular fractures who underwent angiography and embolization of a pelvic artery (n = 12) with those who underwent angiography but did not undergo embolization (n = 14). Primary outcome was presence of infection requiring return to the operating room. RESULTS: Seven (58%) of the 12 patients who underwent embolization developed deep surgical site infection compared with only 2 (14%) of the patients who underwent angiography but did not require pelvic vessel embolization (P < 0.05, Fisher exact test). CONCLUSIONS: The combination of an acetabular fracture that requires ORIF and a pelvic arterial injury that requires angiographic embolization is rare. However, the 58% infection rate of the patients who underwent embolization before ORIF is an order of magnitude higher than typical historical controls (2% 5%) and significantly higher than that of the control group of patients who underwent angiography without embolization (14%). In addition, a disproportionate number of the patients who developed infection had their entire internal iliac artery embolized. Surgeons should be aware that embolization of a pelvic arterial injury is associated with a high rate of infection after subsequent ORIF of an acetabular fracture. Embolization of the entire iliac artery should be avoided whenever possible. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 22495530 TI - Predrilling does not improve the pullout strength of external fixator pins: a biomechanical study. AB - OBJECTIVES: External fixator pins are thought to have improved pullout strength if inserted into both cortices and if pilot holes are drilled. We tested these hypotheses and investigated effects of osteoporosis and pin location on pin pullout strength. METHODS: Self-drilling external fixator pins were inserted using 4 techniques: 1) predrilled bicortically inserted, 2) not predrilled bicortically inserted, 3) not predrilled unicortically inserted, and 4) technique 2 with far cortex disengaged to test holding power of near cortex in isolation. Ninety-six samples were tested from four locations in 12 matched pairs of cadaveric femora [6 pairs osteoporotic (T <= -2.5), six pairs nonosteoporotic (T > -2.5)]. Pullout force was tested on materials testing system until failure of pin-bone interface. RESULTS: Bicortical pin placement and location within femur had substantial effects on the holding power of the pins. Osteoporosis had statistically significant effect but with smaller effect size (P = 0.05). No significant difference in holding power was observed between predrilling and no predrilling techniques (P = 0.27). We observed only a trend toward "stripping effect" in near cortex with technique 4. Bicortical placement rendered 69% greater holding power than unicortical. Proximal placement rendered 56% greater holding power than distal. Osteoporotic samples had 15% less holding power than nonosteoporotic samples. CONCLUSIONS: Single-cortex pin placement, osteoporotic bone, and more distal pin location decreased pin pullout strength. We did not observe a significant mechanical advantage of predrilling for modern external fixator pins. The near cortex of a pin inserted into 2 cortices without predrilling did not exhibit substantial stripping effect. PMID- 22495531 TI - Short-term physical and mental health outcomes for combat amputee and nonamputee extremity injury patients. AB - OBJECTIVES: The present study: (1) reports the early physical health complications, mental health outcomes, and outpatient health care utilization of patients with serious extremity injuries sustained during the Iraq or Afghanistan wars and (2) compares clinical outcomes between amputee and nonamputee extremity injury groups. METHOD: This was a retrospective review of clinical records in military health databases for patients injured in the Iraq and Afghanistan wars. Health outcomes of amputee (n = 382, injured 2001-2005) and nonamputee patients (n = 274, injured 2001-2007) with serious extremity injuries (abbreviated injury score >= 3) were followed up to 24 months post injury. This study was performed at Naval Health Research Center, San Diego. RESULTS: Amputee and nonamputee groups had similar injury severity scores. Amputees had nearly double the risk of certain adverse complications (infections, anemia, septicemia, and thromboembolic disease), but other complications (osteomyelitis and nonhealing wound) were similar between the 2 groups. Amputees had significantly greater odds of certain mental health disorders including mood, sleep, pain, and postconcussion syndrome. However, amputees had significantly reduced odds of posttraumatic stress disorder compared with nonamputees. Amputees used various outpatient clinics significantly more than nonamputees. CONCLUSIONS: Patients with serious combat extremity injuries showed high rates of adverse health outcomes in the short term. Amputees had higher rates of many but not all clinically important physical and mental health outcomes compared to nonamputees. These results are important for military orthopaedic surgeons and allied providers who care for and counsel these patients and clinicians and researchers who seek to understand and improve health outcomes in patients with extremity war injuries. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 22495532 TI - A seven-day study of the pharmacokinetics of intravenous levetiracetam in neonates: marked changes in pharmacokinetics occur during the first week of life. AB - INTRODUCTION: Levetiracetam (LEV) is increasingly used in the treatment of neonatal seizures. The aim of this study was to determine pharmacokinetics in neonates with seizures and to obtain preliminary safety and efficacy data. METHODS: Eighteen term neonates with seizures persisting after 20 mg/kg of phenobarbital received intravenous LEV for 1 wk. LEV was administered as a 20 or 40 mg/kg bolus followed by 5-10 mg/kg/d. Pharmacokinetic data were analyzed using a nonlinear mixed-effects population approach. Continuous electroencephalogram monitoring allowed preliminary assessment of the efficacy of LEV in this population. RESULTS: LEV clearance (CL) increased from a mean of 0.7 ml/min/kg (SD 0.27 ml/min/kg) on day 1 to 1.33 ml/min/kg (SD 0.35 ml/min/kg) by day 7. Mean half-life was 18.5 h (SD 7.1 h) on day 1 of the study and decreased to 9.1 h (SD 2.0 h) by day 7. The mean volume of distribution was 1.01 l/kg (SD 0.13 l/kg). No study-related serious adverse events were observed. DISCUSSION: CL of LEV in neonates was higher than expected on the basis of immature renal function in term infants and increased significantly during the first week of life. More frequent dosing of LEV is needed in term infants to maintain serum concentrations in the range seen in children and adults. PMID- 22495533 TI - Genome-scale profiling reveals a subset of genes regulated by DNA methylation that program somatic T-cell phenotypes in humans. AB - The aim of this study was to investigate the dynamics and relationship between DNA methylation and gene expression during early T-cell development. Mononuclear cells were collected at birth and at 12 months from 60 infants and were either activated with anti-CD3 for 24 h or cultured in media alone, and the CD4+ T-cell subset purified. DNA and RNA were co-harvested and DNA methylation was measured in 450 000 CpG sites in parallel with expression measurements taken from 25 000 genes. In unstimulated cells, we found that a subset of 1188 differentially methylated loci were associated with a change in expression in 599 genes (adjusted P value<0.01, beta-fold >0.1). These genes were enriched in reprogramming regions of the genome known to control pluripotency. In contrast, over 630 genes were induced following low-level T-cell activation, but this was not associated with any significant change in DNA methylation. We conclude that DNA methylation is dynamic during early T-cell development, and has a role in the consolidation of T-cell-specific gene expression. During the early phase of clonal expansion, DNA methylation is stable and therefore appears to be of limited importance in short-term T-cell responsiveness. PMID- 22495534 TI - Studies on tetrahydrocannabinolic acid synthase that produces the acidic precursor of tetrahydrocannabinol, the pharmacologically active cannabinoid in marijuana. AB - Tetrahydrocannabinol (THC), the psychoactive component of marijuana, is now regarded as a promising medicine because this cannabinoid has been shown to exert a variety of therapeutic activities. It has been demonstrated that THC is generated from the acidic precursor, tetrahydrocannabinolic acid (THCA) by nonenzymatic decarboxylation, and that THCA is biosynthesized by THCA synthase, which catalyzes a unique biosynthetic reaction, the stereospecific oxidative cyclization of the geranyl group of the substrate cannabigerolic acid. Molecular characterization of THCA synthase has revealed its structural characteristics and reaction mechanism. THCA synthase is the first cannabinoid synthase to be studied and is potentially attractive target for various biotechnological applications as it produces the direct precursor of THC. This review describes the research history of this enzyme, i.e., purification, molecular cloning, biochemical characterization, and possible biotechnological application of THCA synthase. PMID- 22495535 TI - Antidiabetic activity of standardized extract of Picrorhiza kurroa in rat model of NIDDM. AB - The present study was undertaken to investigate the effect of standardized aqueous extract of Picrorhiza kurroa Royle ex Benth. on diabetes. Diabetes mellitus was induced with streptozotocinnicotinamide and rats found diabetic were orally administered standardized aqueous extract of Picrorhiza kurroa (100 and 200 mg/kg, p.o.) or glibenclamide (10 mg/kg, p.o.) or vehicle (0.3% carboxy methyl cellulose suspension) for 14 days. Fasting blood glucose levels and lipid profiles were measured in control as well as diabetic rats after two week treatment. In addition, liver glycogen level of Picrorhiza kurroa extract (PkE) treated diabetic rats were compared to that of control and diabetic control rats. Oral glucose tolerance test was also performed on nondiabetic normal rats. Statistical analyses were performed by one way analysis of variance followed by Tukey-Kramer multiple comparisons test. PkE treatment induced significant reduction (p < 0.001) in elevated fasting blood glucose level in streptozotocinnicotinamide induced type-2 diabetic rats. In oral glucose tolerance test, oral administration of PkE increased the glucose tolerance. PkE treatment also significantly (p < 0.001) reversed the weight loss associated with streptozotocin treatment. These findings provide in vivo evidence that standardized extract of Picrorhiza kurroa possess significant antidiabetic activity in streptozotocin-nicotinamide induced type-2 diabetes mellitus in rats. PMID- 22495536 TI - Synthesis and reaction mechanism of 3-(4-methoxyphenylazo)acrylic acid. AB - Using 4-methoxylphenylhydra zine hydrochloride (1a) as starting material, 2-[2-(4 methoxyphenyl) hydrazono] acetic acid (2a) was prepared after treatment with 1 equivalent of 2-oxoacetic acid, and 3-(4-methoxyphenyldiazo) acrylic acid (3a) was obtained with 2 equivalents of 2-oxoacetic acid through a novel reaction. The mechanism of reaction was analyzed with the help of charge distribution computation. This suggests that the novel reaction depends on the electronegativity of C9, which can be mainly affected by the substituents of the benzene ring. PMID- 22495537 TI - A validated stability-indicating HPLC method for analysis of glabridin prodrugs in hydrolysis studies. AB - A simple, selective and precise stabilityindicating HPLC method for determination of glabridin diacetate and dihexanoate prodrugs was developed, validated and applied to the enzymatic and chemical hydrolysis studies. The chromatographic separation was achieved on a reverse phase C18 (Thermo Hypersil-Keystone, 250 * 4.6 mm, 5 micron) column using the mixture of acetonitrile and water as mobile phase. Elution of the mobile phase was operated on isocratic (acetonitrile 76%: water 24%) for 9 min, followed by gradient (acetonitrile from 76% to 90%) within 9 min and isocratic (acetonitrile 90%: water 10%) for 12 min at 1 mL/min flow rate, detected at 280 nm. The method was validated for specificity, accuracy, precision, linearity and limit of quantitation following the International Conference on Harmonization (ICH) guidelines. The method is effective for the separation of glabridin diacetate and glabridin dihexanoate from glabridin, its parent drug and successfully used in these prodrugs hydrolysis studies. PMID- 22495538 TI - Correlation of in vitro dissolution rate and apparent solubility in buffered media using a miniaturized rotating disk equipment: Part I. Comparison with a traditional USP rotating disk apparatus. AB - A correlation of the logarithmic values of the in vitro dissolution rate, G, and the apparent solubility, S, was evaluated in phosphate and ammonium acetate buffer at an initial pH of 7. The dissolution rates were determined with a newly designed and build miniaturized rotating disk equipment, as well as with a traditional rotating disk apparatus. The two apparatuses gave the same correlation pattern of logG and logS. Thirteen diverse drug substances from all of the classes in the Biopharmaceutics Classification System (BCS) were used for the correlation in the phosphate buffer system, with the results from the miniaturized apparatus only. A coefficient of determination, R2, of 0.982 was found if bases formulated as hydrochloride salts were excluded in the correlation. The miniaturized equipment is used for rapid screening of the dissolution rate, approximately 10 min for one run, and consumes small amounts of substance (about 5 mg) and dissolution media. All quantifications were performed by using reversed phase high-performance liquid chromatography (RPHPLC) with a diode array detector (DAD), integrated with the miniaturized rotating disk equipment. PMID- 22495539 TI - Correlation of in vitro dissolution rate and apparent solubility in buffered media using a miniaturized rotating disk equipment: Part II. Comparing different buffer media. AB - A correlation of the logarithmic values of the in vitro dissolution rate, G, and apparent solubility, S, was made for seven different drug substances from all of the classes in the Biopharmaceutics Classification System (BCS), in four different phosphate buffers. The effect of inorganic salts added as sodium chloride, sodium nitrate, sodium phosphate and sodium sulfate in the buffer media was investigated for the correlation. Triethanolammonium acetate buffer was also included in the study of the correlation of logG vs. logS. The pH was 7.0 +/- 0.1 in all of the buffers to mimic a pH condition in intestinal fluids. The dissolution rate was determined with a newly constructed miniaturized rotating disk equipment, which enables fast determinations and consumes only minute quantities of substance (about 5 mg). The solubility was determined by conventional shake-flask methodology, using 1.5 mL solution volumes. All quantifications were performed with reversed phase high-performance liquid chromatography (RP-HPLC) and diode array detection (DAD). The different inorganic anions seemed to affect the solubility more than the dissolution rate. The phosphate and nitrate ions decreased the solubility for amines compared to the chloride ion. The best correlations of logG and logS were however obtained with a triethanolammonium acetate buffer. The good correlation (R2 = 0.991) may be sufficient in initial screening of drug solubility, based on dissolution rates in aqueous buffer media. PMID- 22495540 TI - Formulation and optimization of sustained release terbutaline sulfate microspheres using response surface methodology. AB - The present study reports the optimization of sustained release microspheres of terbutaline sulfate (TS) and Eudragit RSPM using response surface methodology. The microspheres were prepared by the emulsion solvent evaporation process utilizing Eudragit RSPM as release retarding agent. A 3(2) full factorial design was utilized by taking the drug: Eudragit RSPM ratio (X(1)), the percent of Span 80 (X(2)) and the speed of rotation (X(3)) as the independent variables; particle size (Y(1)) and percent drug released (Y(2)) were the dependent variables. The resultant microspheres were subjected to various physicochemical analysis, viz., drug content, micrometrics, photo-microscopy and in vitro drug release. The percent of drug release at 8 h of dissolution decreased from 90.7% to 61.3% with increase in polymer concentration from 4 to 8%. It was observed that an increase in surfactant concentration from 1 to 2% and speed of rotation from 500 to 900 rpm decreased the size of microspheres (350-330 MUm). The results of the present study indicate that optimized sustained release microspheres of terbutaline sulfate could be successfully prepared by the emulsion solvent evaporation method by emulsifying the drug and polymer in the ratio of 1:8, at a speed of 500 rpm, utilizing 1.5% of span 80 as emulsifying agent. PMID- 22495541 TI - Stability studies of the effect of crosslinking on hydrochlorothiazide release. AB - The aim of this study was to determine the changes in the in vitro drug release from cross-linked hard gelatin capsules containing a water-insoluble drug. An immediate release hydrochlorothiazide (HCTZ) capsule formulations containing drug, lactose, starch 1500 were prepared and exposed to accelerated stability study (40 degrees C/ambient RH, 40 degrees C/60% RH, 40 degrees C/75% RH, and 40 degrees C/90% RH) in a closed dark bottles for 4 weeks. Notable decrease in drug dissolution was observed after the 4 weeks in all humidity conditions as compared with freshly prepared capsules. In an attempt to overcome capsule cross-linking, glycine alone, citric acid alone and both glycine and citric acid were added to the prepared formulations. In all humidity conditions, addition of glycine alone or citric acid alone did not affect the decrease in dissolution profile. On the other hand, addition of both glycine and citric acid together was found to prevent capsule cross-linking completely. Fourier transfer infra-red (FTIR) spectroscopy and differential scanning calorimetry (DSC) were performed on blank capsules and after storage for 4 weeks to identify the physicochemical changes in drug and other capsule components hence its effect on dissolution. PMID- 22495542 TI - SnS2 nanoparticle loaded graphene nanocomposites for superior energy storage. AB - SnS2 nanoparticle-loaded graphene nanocomposites were synthesized via one-step hydrothermal reaction. Their electrochemical performance was evaluated as the anode for rechargeable lithium-ion batteries after thermal treatment in an Ar environment. The electrochemical testing results show a high reversible capacity of more than 800 mA h g(-1) at 0.1 C rate and 200 mA h g(-1) for up to 5 C rate. The cells also exhibit excellent capacity retention for up to 90 cycles even at a high rate of 2 C. This electrochemical behavior can be attributed to the well defined morphology and nanostructures of these as-synthesized nanocomposites, which is characterized by high-resolution transmission electron microscopy and electron energy-loss spectroscopy. PMID- 22495543 TI - Effectiveness and serotype coverage: key criteria for pneumococcal vaccines for adults. PMID- 22495544 TI - Editorial commentary: should 13-valent protein-conjugate pneumococcal vaccine be used routinely in adults? PMID- 22495546 TI - Impact of appropriate antimicrobial therapy on mortality associated with Acinetobacter baumannii bacteremia: relation to severity of infection. AB - BACKGROUND: The efficacy of antimicrobial therapy for Acinetobacter baumannii bacteremia has been difficult to establish because of confounding by underlying diseases, severity of infection, and differences in the pathogenicity of Acinetobacter species. This retrospective study was conducted to evaluate the effect of appropriate antimicrobial therapy on 14-day mortality after adjustment for multiple risk factors. METHODS: The population consisted of 252 patients with monomicrobial A. baumannii bacteremia admitted to a large teaching hospital in Taiwan. The isolates were identified to species level using reference molecular methods. Predictors of 14-day mortality were determined by logistic regression analysis. The influence of severity of infection, determined by Acute Physiology and Chronic Health Evaluation (APACHE) II score, on the impact of appropriate use of antimicrobials on 14-day mortality was assessed by including an interaction term. RESULTS: The overall 14-day mortality rate was 29.8% (75 of 252 patients). The unadjusted mortality rate for appropriate antimicrobial therapy was 13.2% (12 of 91 patients). Appropriate therapy was independently associated with reduced mortality (odds ratio [OR], 0.22; 95% confidence interval [CI], .01-.50; P < .001), and the effect was influenced by APACHE II score (OR for interaction term, 0.90; 95% CI, .82-.98; P= .02). A subgroup analysis revealed that the benefit of appropriate therapy was limited to patients with high APACHE II scores (OR for patients with scores >25 and <= 35, 0.16 [95% CI, .07-.37]; OR for those with scores >35, 0.06; 95% CI, .01-.25). CONCLUSIONS: Appropriate antimicrobial therapy significantly reduced 14-day mortality for A. baumannii bacteremia in severely ill patients. PMID- 22495545 TI - Pneumococcal conjugate vaccine for adults: a new paradigm. AB - A 13-valent pneumococcal conjugate vaccine has been studied in adults aged >= 50 years to compare the immune response to that induced by the 23-valent pneumococcal polysaccharide vaccine, which has been the standard of care over the past 30 years. The results demonstrate that adults, regardless of whether they are naive or previously vaccinated with the polysaccharide vaccine, have an overall superior antibody response when vaccinated with the conjugate vaccine compared with the pneumococcal polysaccharide vaccine. More importantly, the nature of the response is indicative of a T-cell-dependent response that elicits immunological memory and, therefore, primes the immune system for either natural exposure or subsequent booster vaccination with either conjugate or polysaccharide vaccine. The conjugate vaccine, which has been successful in reducing pneumococcal disease in children, now provides a new approach to preventing pneumococcal disease, including community-acquired pneumonia, in adults. PMID- 22495547 TI - Flexible synthesis of montanine-like alkaloids: revisiting the structure of montabuphine. AB - An efficient and stereocontrolled synthetic strategy towards the synthesis of montanine-like alkaloids was developed. Our results suggest that the structure elucidation for natural montabuphine needs further elaboration. PMID- 22495548 TI - Chemical characteristics and antioxidant properties of crude water soluble polysaccharides from four common edible mushrooms. AB - Four crude water soluble polysaccharides, CABP, CAAP, CFVP and CLDP, were isolated from common edible mushrooms, including Agaricus bisporus, Auricularia auricula, Flammulina velutipes and Lentinus edodes, and their chemical characteristics and antioxidant properties were determined. Fourier Transform infrared analysis showed that the four crude polysaccharides were all composed of beta-glycoside linkages. The major monosaccharide compositions were D-galactose, D-glucose and D-mannose for CABP, CAAP and CLDP, while CFVP was found to consist of L-arabinose, D-galactose, D-glucose and D-mannose. The main molecular weight distributions of CABP and the other three polysaccharides were <5.1 * 10(4) Da and >66.0 * 10(4) Da, respectively. Antioxidant properties of the four polysaccharides were evaluated in in vitro systems and CABP showed the best antioxidant properties. The studied mushroom species could potentially be used in part of well-balanced diets and as a source of antioxidant compounds. PMID- 22495549 TI - Adsorption behavior of Fe(II) and Fe(III) ions on thiourea cross-linked chitosan with Fe(III) as template. AB - A new type of thiourea cross-linked chitosan with Fe(III) as template (TCCTS template) was synthesized. The adsorption of Fe(II) and Fe(III) on this TCCTS template was studied. The factors affecting adsorption such as pH and contact time were considered. The results showed that the optimum pH value for adsorption was pH = 5.0 and the adsorption equilibrium time was about 60 min. The adsorption isotherms and kinetics were investigated, and the equilibrium data agreed very well with the Langmuir model and the pseudo second-order model could describe adsorption process better than the pseudo first-order model. Results also showed that TCCTS template was a favourable adsorbent for Fe(II) and Fe(III) in aqueous solution. PMID- 22495551 TI - Advertisements: an untapped medium to communicate men's health information. PMID- 22495550 TI - Enhancing self-efficacy for optimized patient outcomes through the theory of symptom self-management. AB - BACKGROUND: In today's world, greater patient empowerment is imperative because 90 million Americans live with 1 or more chronic conditions such as cancer. Evidence reveals that healthy behaviors such as effective symptom self-management can prevent or reduce much of the suffering from cancer. Oncology nurses play a pivotal role in developing a symptom self-management plan that is critical to optimizing a patient's symptom self-management behaviors. OBJECTIVE: This article uses exemplars to describe how oncology nurses can apply a tested middle-range theory, the Theory of Symptom Self-management, to clinical practice by incorporating interventions to increase a patient's perceived self-efficacy to optimize patient outcomes. METHODS: The Theory of Symptom Self-management provides a means to understand the dynamic aspects of symptom self-management and provides a tested framework for the development of efficacy-enhancing interventions for use by oncology nurses in clinical practice. RESULTS: Exemplars based on the Theory of Symptom Self-management depict how oncology nursing can use perceived self-efficacy-enhancing symptom self-management interventions to improve the functional status and quality of life of their patients. CONCLUSION: Guided by a theoretical approach, oncology nurses can have a significant positive impact on the lives of their patients by reducing the symptom burden associated with cancer and its treatment. IMPLICATIONS FOR PRACTICE: Oncology nurses can partner with their patients to design tailored approaches to symptom self management. These tailored approaches provide the ability to implement patient specific behaviors that recognize, prevent, relieve, or decrease the timing, intensity, distress, concurrence, and unpleasant quality of symptoms. PMID- 22495553 TI - Palladium(0)-catalyzed cyclization of 1,6-diyn-3-yl carbonates with a nucleophilic functionality: efficient synthesis of polycyclic benzo[b]fluorene derivatives via allene intermediates. AB - We report in this paper an interesting tandem reaction involving sequential palladium(0)-catalyzed decarboxylation of diynylic carbonates, intramolecular nucleophilic cyclization and Schmittel reaction, which provides a facile method for the synthesis of a variety of polycyclic benzo[b]fluorene derivatives from easily accessible starting materials. PMID- 22495552 TI - Male dating violence victimization and adjustment: the moderating role of coping. AB - Dating violence is a prevalent problem. Research demonstrates that males and females are victimized at comparable rates in their dating relationships and experience a number of mental health and relationship problems. Less research has examined male dating violence victimization, its association to mental health and relationship satisfaction, and whether coping styles influence mental health symptoms and relationship satisfaction among victims. The current study examined physical and psychological aggression victimization, adjustment (posttraumatic stress disorder symptoms and relationship satisfaction), and problem-focused and emotion-focused coping among heterosexual college males in a current dating relationship (n = 184). Results identified that psychological victimization was associated with posttraumatic stress and relationship discord above and beyond physical victimization. Interaction findings identified that psychological victimization was associated with increased posttraumatic stress disorder symptoms at high levels of problem-focused coping, whereas psychological victimization was associated with less relationship satisfaction at low levels of emotion-focused coping. Implications of these findings for future research are discussed. PMID- 22495554 TI - Morbidity and mortality after non-curative gastrectomy for gastric cancer in elderly patients. AB - BACKGROUND AND OBJECTIVES: This study examined the surgical outcome of non curative resection in elderly patients with gastric cancer. METHODS: The study reviewed 278 patients who underwent non-curative resection for advanced gastric cancer. The clinicopathological features of elderly patients (>= 75 years, n = 257) and younger patients (<75 years, n = 21) were compared. RESULTS: Although no difference was observed in terms of preoperative performance, there were distinct differences in terms of albumin level, presence of symptoms, and the rate of comorbidities between the two groups. The postoperative morbidity and mortality rate did not differ between the two groups. Age, preoperative performance status, preoperative transfusion, and presence of comorbidity were not independent predictors of postoperative complications. However, the extent of gastric resection and combined resection were closely related to postoperative complications in patients with non-curative gastrectomy. CONCLUSIONS: In a setting of non-curative resection for gastric cancer, age was not a limiting factor. Rather, the risk of postoperative morbidity should be considered carefully in total gastrectomy and combined resection. PMID- 22495555 TI - Pitfalls in the diagnosis of congenital rubella syndrome in the first trimester of pregnancy. PMID- 22495556 TI - Clinical and microbiological characteristics of bacteremia caused by Eggerthella, Paraeggerthella, and Eubacterium species at a university hospital in Taiwan from 2001 to 2010. AB - We describe 16 patients with bacteremia caused by Eggerthella lenta (n = 7), Paraeggerthella hongkongensis (n = 3), Eubacterium limosum (n = 4), Eubacterium callanderi (n = 1), and concomitant Eubacterium limosum/Eggerthella lenta (n = 1). Nine (56%) patients had polymicrobial bacteremia. The overall 60-day mortality rate was 19%, and all deaths occurred in patients with E. lenta bacteremia. PMID- 22495557 TI - Japanese reference panel of blood specimens for evaluation of hepatitis C virus RNA and core antigen quantitative assays. AB - An accurate and reliable quantitative assay for hepatitis C virus (HCV) is essential for measuring viral propagation and the efficacy of antiviral therapy. There is a growing need for domestic reference panels for evaluation of clinical assay kits because the performance of these kits may vary with region-specific genotypes or polymorphisms. In this study, we established a reference panel by selecting 80 donated blood specimens in Japan that tested positive for HCV. Using this panel, we quantified HCV viral loads using two HCV RNA kits and five core antigen (Ag) kits currently available in Japan. The data from the two HCV RNA assay kits showed excellent correlation. All RNA titers were distributed evenly across a range from 3 to 7 log IU/ml. Although the data from the five core Ag kits also correlated with RNA titers, the sensitivities of individual kits were not sufficient to quantify viral load in all samples. As calculated by the correlation with RNA titers, the theoretical lower limits of detection by these core Ag assays were higher than those for the detection of RNA. Moreover, in several samples in our panel, core Ag levels were underestimated compared to RNA titers. Sequence analysis in the HCV core region suggested that polymorphisms at amino acids 47 to 49 of the core Ag were responsible for this underestimation. The panel established in this study will be useful for estimating the quality of currently available and upcoming HCV assay kits; such quality control is essential for clinical usage of these kits. PMID- 22495558 TI - Genetic diversity of Streptococcus equi subsp. zooepidemicus and doxycycline resistance in kennelled dogs. AB - The genetic diversity and antibiotic resistance profiles of 38 Streptococcus equi subsp. zooepidemicus isolates were determined from a kennelled canine population during two outbreaks of hemorrhagic pneumonia (1999 to 2002 and 2007 to 2010). Analysis of the szp gene hypervariable region and the 16S-23S rRNA intergenic spacer region and multilocus sequence typing (MLST) indicated a predominant tetO positive, doxycycline-resistant ST-10 strain during 1999 to 2002 and a predominant tetM-positive doxycycline-resistant ST-62 strain during 2007 to 2010. PMID- 22495559 TI - Routine identification of medical fungi by the new Vitek MS matrix-assisted laser desorption ionization-time of flight system with a new time-effective strategy. AB - We report here a clinical evaluation of the Vitek MS system for rapid fungal identification. A strategy that uses a single deposit without prior protein extraction was utilized to save time and money. Clinical isolates from the Toulouse University hospital were used to evaluate the performance of the Vitek MS compared to that of both routine laboratory techniques and Vitek2. The Vitek MS performed well in the identification of yeasts and Aspergillus fungi (93.2% of correct identifications). PMID- 22495560 TI - Genotyping reveals the presence of a predominant genotype of Coxiella burnetii in consumer milk products. AB - Real-time PCR shows the widespread presence of Coxiella burnetii DNA in a broad range of commercially available milk and milk products. MLVA genotyping shows that this is the result of the presence of a predominant C. burnetii genotype in the dairy cattle population. PMID- 22495561 TI - Macrolide resistance determination and molecular typing of Mycoplasma pneumoniae in respiratory specimens collected between 1997 and 2008 in The Netherlands. AB - An important role in the treatment regimens for Mycoplasma pneumoniae infections is played by macrolide (ML) antibiotics. In the past few years, however, a steady increase has been detected in the worldwide prevalence of ML-resistant (ML(r)) M. pneumoniae strains. It is obvious that this increase necessitates a continuous monitoring of ML(r) and, when detected, modification of antibiotic treatment modalities. Previously, we developed a pyrosequencing-based assay system for the genetic determination of ML(r) as well as molecular typing of M. pneumoniae. In this study, the sensitivity of this system was improved by the inclusion of a nested-PCR protocol. The modified system was applied to 114 M. pneumoniae positive specimens that were obtained from a collection of 4,390 samples from patients with acute respiratory tract infections. These samples were collected between 1997 and 2008 in The Netherlands. The pyrosequencing system produced reliable data in 86% of the specimens that contained >500 M. pneumoniae genome copies/ml of patient sample. Each of these samples contained DNA of the ML sensitive genotype. While 43% of the samples were found to harbor the M. pneumoniae subtype 1 genotype, 57% contained the subtype 2 genotype. We conclude that the pyrosequencing-based assay system is a useful tool for ML(r) determination and molecular typing of M. pneumoniae in patient samples. ML(r) associated M. pneumoniae genotypes, however, were not found in the current study population. PMID- 22495562 TI - Drug and multidrug resistance among Mycobacterium leprae isolates from Brazilian relapsed leprosy patients. AB - Skin biopsy samples from 145 relapse leprosy cases and from five different regions in Brazil were submitted for sequence analysis of part of the genes associated with Mycobacterium leprae drug resistance. Single nucleotide polymorphisms (SNPs) in these genes were observed in M. leprae from 4 out of 92 cases with positive amplification (4.3%) and included a case with a mutation in rpoB only, another sample with SNPs in both folP1 and rpoB, and two cases showing mutations in folP1, rpoB, and gyrA, suggesting the existence of multidrug resistance (MDR). The nature of the mutations was as reported in earlier studies, being CCC to CGC in codon 55 in folP (Pro to Arg), while in the case of rpoB, all mutations occurred at codon 531, with two being a transition of TCG to ATG (Ser to Met), one TCG to TTC (Ser to Phe), and one TCG to TTG (Ser to Leu). The two cases with mutations in gyrA changed from GCA to GTA (Ala to Val) in codon 91. The median time from cure to relapse diagnosis was 9.45 years but was significantly shorter in patients with mutations (3.26 years; P = 0.0038). More than 70% of the relapses were multibacillary, including three of the mutation carrying cases; one MDR relapse patient was paucibacillary. PMID- 22495564 TI - Fatal case of brucellosis misdiagnosed in early stages of Brucella suis infection in a 46-year-old patient with Marfan syndrome. AB - We report a fatal case of Brucella suis endocarditis initially misdiagnosed by automated identification systems as Ochrobactrum anthropi infection in a patient with a history of Marfan syndrome and recreational feral swine hunting. This report emphasizes the need to consider brucellosis as a part of the differential diagnosis of acute febrile illness, particularly in patients with known risk of exposure. PMID- 22495563 TI - Multilocus variable-number tandem-repeat analysis scheme for chlamydia felis genotyping: comparison with multilocus sequence typing. AB - Chlamydia felis is an important ocular pathogen in cats worldwide. A multilocus variable-number tandem-repeat analysis (MLVA) system for the detection of tandem repeats across the whole genome of C. felis strain Fe/C-56 was developed. Nine selected genetic loci were tested by MLVA in 17 C. felis isolates, including the C. felis Baker vaccine strain, and 122 clinical samples from different geographic origins. Analysis of the results identified 25 distinct C. felis MLVA patterns. In parallel, a recently described multilocus sequence typing scheme for the typing of Chlamydia was applied to 13 clinical samples with 12 different C. felis MLVA patterns. Rare sequence differences were observed. Thus, the newly developed MLVA system provides a highly sensitive high-resolution test for the differentiation of C. felis isolates from different origins that is suitable for molecular epidemiological studies. PMID- 22495565 TI - Performance of the Roche LightCycler real-time PCR assay for diagnosing extrapulmonary tuberculosis. AB - The Roche LightCycler mycobacterium detection molecular assay for Mycobacterium tuberculosis, M. avium, and M. kansasii, was applied to tissue specimens. It performed well on lymph node and cerebrospinal fluid specimens and less well on lung, liver, and bone marrow core biopsy specimens, but used in conjunction with a clinical suspicion of tuberculosis, it could augment patient management. PMID- 22495566 TI - Evaluation of the Bruker Biotyper and Vitek MS matrix-assisted laser desorption ionization-time of flight mass spectrometry systems for identification of nonfermenting gram-negative bacilli isolated from cultures from cystic fibrosis patients. AB - The Bruker Biotyper and Vitek MS matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry (MS) instruments were evaluated for the identification of nonfermenting gram-negative bacilli (NFGNB) by a blinded comparison to conventional biochemical or molecular methods. Two hundred NFGNB that were recovered from cultures from cystic fibrosis patients in the University of Iowa Health Care (UIHC) Microbiology Laboratory between 1 January 2006 and 31 October 2010 were sent to Mayo Clinic for analysis with the Bruker Biotyper (software version 3.0) and to bioMerieux for testing with Vitek MS (SARAMIS database version 3.62). If two attempts at direct colony testing failed to provide an acceptable MALDI-TOF identification, an extraction procedure was performed. The MS identifications from both of these systems were provided to UIHC for comparison to the biochemical or molecular identification that had been reported in the patient record. Isolates with discordant results were analyzed by 16S rRNA gene sequencing at UIHC. After discrepancy testing, the Bruker Biotyper result agreed with the biochemical or molecular method, with 72.5% of isolates to the species level, 5.5% to the complex level, and 19% to the genus level (3% not identified). The level of agreement for Vitek MS was 80% species, 3.5% complex, 6% genus, and 3.5% family (7% not identified). Both MS systems provided rapid (<=3 min per isolate) and reliable identifications. The agreement of combined species/complex/genus-level identification with the reference method was higher for the Bruker Biotyper (97% versus 89.5%, P = 0.004) but required an extraction step more often. Species-level agreement with the reference method was similar for both MS systems (72.5% and 80%, P = 0.099). PMID- 22495567 TI - Pheromones, attractants and other chemical cues of aquatic organisms and amphibians. AB - This review covers the subject of pheromones, attractants and other chemical cues of aquatic invertebrates, fishes and amphibians (including salamanders and anurans). Major topics include the sex pheromones of gastropods, salamanders and a giant tree frog, and the conspecific attraction of sperm to ova of some of the organisms and animals described in this review. PMID- 22495568 TI - US specialties list five tests and treatments that doctors and patients can safely avoid. PMID- 22495569 TI - Dentists can help detect alcohol misuse, say surgeons. PMID- 22495570 TI - Women who accused GP of sexual molestation may have colluded against him. PMID- 22495571 TI - UK to spend 250m pound on proton beam treatment despite no appraisal by NICE. PMID- 22495572 TI - Light controlled assembling of iodine-free dye-sensitized solar cells with poly(3,4-ethylenedioxythiophene) as a hole conductor reaching 7.1% efficiency. AB - We report the fabrication of indoline D205 dye-sensitized solar cells (DSSCs) with photoelectrochemically polymerized poly(3,4-ethylenedioxythiophene) (PEDOT) as a hole conductor. Different from conventional photoelectrochemical polymerization under continuous spectral light illumination (e.g. Xe lamp), we conduct the polymerization under monochromatic light. The device performance is found to be dependent on the wavelength of monochromatic light used for the polymerization of PEDOT. Under optimized conditions, the efficiency of DSSCs reaches 7.1%, which is better than that of devices fabricated via continuous spectral light illumination. Detailed characterization of these devices with photoelectrical and impedance measurements reveals that the wavelength of monochromatic light affects PEDOT penetration into TiO2 porous electrodes and photoelectron recombination at the FTO surface. The best device performance is obtained when penetration and recombination are optimized. PMID- 22495573 TI - Breastfeeding in children under 2 years old and household food and nutrition security status. AB - OBJECTIVE: To investigate the association between household food and nutrition security status and breastfeeding among children under 2 years old. METHODS: Data were analyzed from 1,635 children under 2 years old who had participated in the Brazilian National Demographic and Health Census in 2006. The outcome (breastfeeding) was evaluated according to data on the children's food intake on the day before the interview and food insecurity was assessed using the Brazilian Food Insecurity Scale. RESULTS: Approximately 58% of children were breastfeeding and 47% were living in households with food insecurity. There was an association between breastfeeding and households in a state of food insecurity, but only for children older than 12 months. In this age group, breastfeeding prevalence was higher (41%) among children living in households with food and nutrition insecurity than among those who lived in households considered secure (29%). There were no associations between food insecurity and breastfeeding in the first year of life or early introduction of foods other than breastmilk. CONCLUSION: Food insecurity is associated with a higher prevalence of breastfeeding in the second year of life. PMID- 22495574 TI - Prevalence of preventable medication-related hospitalizations in Australia: an opportunity to reduce harm. AB - OBJECTIVE: To identify the prevalence of potentially preventable medication related hospitalizations amongst elderly Australian veterans by applying clinical indicators to administrative claims data. DESIGN AND SETTING: Retrospective cohort study in the Australian veteran population from 1 January 2004 to 31 December 2008. PARTICIPANTS: A total of 109 044 veterans with one or more hospitalizations defined by the medication-related clinical indicator set, during the 5-year study period. MAIN OUTCOME MEASURE: The prevalence of potentially preventable medication-related hospitalizations as a proportion of all hospitalizations defined by the clinical indicator set. RESULTS: During the 5 year study period, there were a total of 1 630 008 hospital admissions of which 216 527 (13.3%) were for conditions defined by the medication-related clinical indicator set for 109 044 veterans. The overall proportion of potentially preventable medication-related hospitalizations was 20.3% (n= 43 963). Of the 109 044 veterans included in the study, 28 044 (25.7%) had at least one potentially preventable medication-related hospitalization and 7245 (6.6%) veterans had two or more potentially preventable admissions. Conditions with both a high prevalence of hospitalization and preventability included asthma/chronic obstructive pulmonary disorder, depression and thromboembolic cerebrovascular event (23.3, 18.5 and 18.3%, respectively, were potentially preventable). Other hospitalizations that were less common but had a high level of preventability (at least 20%) included hip fracture, impaction, renal failure, acute confusion, bipolar disorder and hyperkalaemia. CONCLUSIONS: The results of this study highlight those conditions where hospitalizations could potentially be avoided through improved medication management. Strategies to increase the awareness, identification and resolution of these medication-related problems contributing to these hospitalizations are required in Australia. PMID- 22495575 TI - CN-assisted oxidative cyclization of cyano cinnamates and styrene derivatives: a facile entry to 3-substituted chiral phthalides. AB - The asymmetric dihydroxylation (AD) of o-cyano cinnamates and styrene derivatives leads to efficient construction of chiral phthalide frameworks in high optical purities. This unique reaction is characterized by unusual synergism between CN and osmate groups resulting in rate enhancement of the AD process. The method is amply demonstrated by the synthesis and the structural/stereochemical assignment of the natural products. PMID- 22495576 TI - Therapeutic antitumor potential of endoglin-based DNA vaccine combined with immunomodulatory agents. AB - Therapy targeting tumor blood vessels ought to inhibit tumor growth. However, tumors become refractory to antiangiogenic drugs. Therefore, therapeutic solutions should be sought to address cellular resistance to antiangiogenic therapy. In this regard, reversal of the proangiogenic and immunosuppressive phenotype of cancer cells, and the shift of the tumor microenvironment towards more antiangiogenic and immune-stimulating phenotype may hold some promise. In our study, we sought to validate the effects of a combination therapy aimed at reducing tumor blood vessels, coupled with the abrogation of the immunosuppressive state. To achieve this, we developed an oral DNA vaccine against endoglin. This antigen was carried by an attenuated Salmonella Typhimurium and applied before or after tumor cell inoculation into immunocompetent mice. Our results show that this DNA vaccine effectively inhibited tumor growth, in both the prophylactic and therapeutic settings. It also activated both specific and nonspecific immune responses in immunized mice. Activated cytotoxic T-lymphocytes were directed specifically against endothelial and tumor cells overexpressing endoglin. The DNA vaccine inhibited angiogenesis but did not affect wound healing. In combination with interleukin-12-mediated gene therapy, or with cyclophosphamide administration, the DNA vaccine resulted in reduced microvessel density and lowered the level of Treg lymphocytes in the experimental tumors. This effectively inhibited tumor growth and prolonged survival of the treated animals. Polarization of tumor milieu, from proangiogenic and immunosuppressive, towards an immunostimulatory and antiangiogenic profile represents a promising avenue in anticancer therapy. PMID- 22495577 TI - Induced electric field and current density patterns in bone fractures. AB - We have used the low frequency solver of the computer program SEMCAD-X to model the induced electric field and current density patterns in simple models of a fractured femur embedded off-center in cylindrical muscle tissue; a 1 cm fracture gap is filled with callus. The model is exposed to a 1 kHz, 1 mT sinusoidal magnetic field. The frequency chosen is typical of the major Fourier components of many waveforms used to stimulate fracture healing using pulsed magnetic fields; the intensity is also a typical level. Models include fractures perpendicular to the bone and at an angle from the perpendicular, each exposed to a field applied parallel to the bone or parallel to either of the two axes perpendicular to it. We find that all directions of applied magnetic fields produce essentially parallel induced electric fields and current densities through the plane of the callus, but that a magnetic field applied parallel to the bone induces considerably higher fields and currents than the same strength field applied in either perpendicular direction. Because investigations of pulsed field devices, including modeling of induced fields and currents, peaked more than a decade ago, this is the first application to our knowledge of the current capabilities of computer modeling systems to biological systems at low frequencies. PMID- 22495578 TI - Reactivity of blood vessels in response to prostaglandin E2 in placentas from pregnancies complicated by fetal growth restriction. AB - OBJECTIVE: The authors aimed to study the contractility responses of normal and fetal growth restriction (FGR) placentas to prostaglandin E(2) (PGE(2) ) and to correlate the results to subsequent placental histological analysis. METHOD: A dual-perfused single cotyledon model was used. Placentas from pregnancies complicated by FGR and from normal pregnancies were obtained. Selected cotyledons were cannulated and dually perfused. Following stabilization, three concentrations of PGE(2) (0.05, 0.1, and 0.15 mg/mL) were administered to the fetal arterial side causing contraction/relaxation response. Fetal perfusion pressure was measured continuously during these contraction and relaxation phases. Following the perfusion experiments, the placentas were analyzed for fetal or maternal origin vascular lesions. RESULTS: A total of 21 complete experiments were performed (16 normal, 5 FGR). In response to PGE(2) , FGR placentas exhibited lower change in the perfusion pressure and lower relaxation time constant. Basal perfusion pressure did not differ significantly between the two groups. Placental histopathology lesions, fetal or maternal origin, were more common in the FGR compared with the controls placentas, 80% versus 25%, respectively, P= 0.047. CONCLUSIONS: The lower vascular reactivity in response to PGE(2) and the presence of fetal and maternal vascular placental lesions suggest a mechanism explaining the altered vascular supply in FGR. PMID- 22495579 TI - Nickel-catalyzed C-H direct amination of benzoxazoles with secondary amines. AB - In this article, a facile, efficient and practical method for Ni-catalyzed direct C-H amination of benzoxazole with secondary amines has been developed. This procedure requires Ni(OAc)(2).4H(2)O as catalyst, TBHP as oxidant and acid as the additive. A variety of substituted benzoxazol-2-amines were synthesized in moderate to good yields. PMID- 22495580 TI - Photoinduced reactions of bicycloalkylidenes with isatin and isoquinolinetrione. AB - Photoinduced reactions of isatin and N-methyl-1,3,4-isoquinolinetrione with bicycloalkylidenes such as bicyclopropylidene, cyclopropylidenecyclobutane, cyclopropylidenecyclohexane and bicyclohexylidene were investigated. The reactions gave spirooxetanes as the major products derived from the [2 + 2] photocycloaddition pathway via 1,4-biradical recombination. Unusual products including the [4 + 2 + 2] cycloadducts, the oxoisochroman derivatives and other ring-rearranged products were derived from competitive pathways via 1,6-biradical recombination. The presence of oxygen in the reaction solution was found to be relevant to the distribution of different types of products. Mechanisms were proposed to rationalize the chemo- and regioselectivity in the photoreactions and the origin of the different types of products. PMID- 22495581 TI - Infections may be causal in the pathogenesis of atherosclerosis. AB - There is a universal lack of exposure response between degree of lipid lowering and the outcome in clinical and angiographic trials questioning the current view on atherogenesis. However, there are numerous observations and experiments suggesting that microorganisms may play a causal role. A clue is the fact that the lipoproteins constitute an innate immune system by binding and inactivating microorganisms and their toxic products through formation of circulating complexes. Their size may increase in the presence of hyperhomocysteinemia because homocysteine reacts with low-density lipoprotein (LDL) to form homocysteinylated LDL aggregates. Autoantibodies against homocysteinylated or oxidized LDL may also enhance the aggregation. Because of the high extracapillary pressure, such aggregates may obstruct arterial vasa vasorum producing ischemia and cell death within the arterial wall leading to the creation of a vulnerable plaque. The many epidemiological observations, clinical findings and laboratory experiments that conflict with the cholesterol hypothesis are in good accordance with ours. PMID- 22495582 TI - Voltage-dependent amplification of synaptic inputs in respiratory motoneurones. AB - The role of persistent inward currents (PICs) in cat respiratory motoneurones (phrenic inspiratory and thoracic expiratory) was investigated by studying the voltage-dependent amplification of central respiratory drive potentials (CRDPs), recorded intracellularly, with action potentials blocked with the local anaesthetic derivative, QX-314. Decerebrate unanaesthetized or barbiturate anaesthetized preparations were used. In expiratory motoneurones, plateau potentials were observed in the decerebrates, but not under anaesthesia. For phrenic motoneurones, no plateau potentials were observed in either state (except in one motoneurone after the abolition of the respiratory drive by means of a medullary lesion), but all motoneurones showed voltage-dependent amplification of the CRDPs, over a wide range of membrane potentials, too wide to result mainly from PIC activation. The measurements of the amplification were restricted to the phase of excitation, thus excluding the inhibitory phase. Amplification was found to be greatest for the smallest CRDPs in the lowest resistance motoneurones and was reduced or abolished following intracellular injection of the NMDA channel blocker, MK-801. Plateau potentials were readily evoked in non-phrenic cervical motoneurones in the same (decerebrate) preparations. We conclude that the voltage dependent amplification of synaptic excitation in phrenic motoneurones is mainly the result of NMDA channel modulation rather than the activation of Ca2+ channel mediated PICs, despite phrenic motoneurones being strongly immunohistochemically labelled for CaV1.3 channels. The differential PIC activation in different motoneurones, all of which are CaV1.3 positive, leads us to postulate that the descending modulation of PICs is more selective than has hitherto been believed. PMID- 22495583 TI - Serotonin inhibits low-threshold spike interneurons in the striatum. AB - Low-threshold spike interneurons (LTSIs) are important elements of the striatal architecture and the only known source of nitric oxide in this nucleus, but their rarity has so far prevented systematic studies. Here, we used transgenic mice in which green fluorescent protein is expressed under control of the neuropeptide Y (NPY) promoter and striatal NPY-expressing LTSIs can be easily identified, to investigate the effects of serotonin on these neurons. In sharp contrast with its excitatory action on other striatal interneurons, serotonin (30 MUM) strongly inhibited LTSIs, reducing or abolishing their spontaneous firing activity and causing membrane hyperpolarisations.These hyperpolarisations persisted in the presence of tetrodotoxin, were mimicked by 5-HT(2C) receptor agonists and reversed by 5-HT(2C) antagonists. Voltage-clamp slow-ramp experiments showed that serotonin caused a strong increase in an outward current activated by depolarisations that was blocked by the specific M current blocker XE 991. In current-clamp experiments,XE 991 per se caused membrane depolarisations in LTSIs and subsequent application of serotonin (in the presence of XE 991) failed to affect these neurons.We concluded that serotonin strongly inhibits striatal LTSIs acting through postsynaptic 5-HT(2C) receptors and increasing an M type current. PMID- 22495584 TI - Regional brain blood flow in man during acute changes in arterial blood gases. AB - Despite the importance of blood flow on brainstem control of respiratory and autonomic function, little is known about regional cerebral blood flow (CBF) during changes in arterial blood gases.We quantified: (1) anterior and posterior CBF and reactivity through a wide range of steady-state changes in the partial pressures of CO2 (PaCO2) and O2 (PaO2) in arterial blood, and (2) determined if the internal carotid artery (ICA) and vertebral artery (VA) change diameter through the same range.We used near-concurrent vascular ultrasound measures of flow through the ICA and VA, and blood velocity in their downstream arteries (the middle (MCA) and posterior (PCA) cerebral arteries). Part A (n =16) examined iso oxic changes in PaCO2, consisting of three hypocapnic stages (PaCO2 =~15, ~20 and ~30 mmHg) and four hypercapnic stages (PaCO2 =~50, ~55, ~60 and ~65 mmHg). In Part B (n =10), during isocapnia, PaO2 was decreased to ~60, ~44, and ~35 mmHg and increased to ~320 mmHg and ~430 mmHg. Stages lasted ~15 min. Intra-arterial pressure was measured continuously; arterial blood gases were sampled at the end of each stage. There were three principal findings. (1) Regional reactivity: the VA reactivity to hypocapnia was larger than the ICA, MCA and PCA; hypercapnic reactivity was similar.With profound hypoxia (35 mmHg) the relative increase in VA flow was 50% greater than the other vessels. (2) Neck vessel diameters: changes in diameter (~25%) of the ICA was positively related to changes in PaCO2 (R2, 0.63+/-0.26; P<0.05); VA diameter was unaltered in response to changed PaCO2 but yielded a diameter increase of +9% with severe hypoxia. (3) Intra- vs. extra cerebral measures: MCA and PCA blood velocities yielded smaller reactivities and estimates of flow than VA and ICA flow. The findings respectively indicate: (1) disparate blood flow regulation to the brainstem and cortex; (2) cerebrovascular resistance is not solely modulated at the level of the arteriolar pial vessels; and (3) transcranial Doppler ultrasound may underestimate measurements of CBF during extreme hypoxia and/or hypercapnia. PMID- 22495585 TI - Quantitative measurement of mitochondrial membrane potential in cultured cells: calcium-induced de- and hyperpolarization of neuronal mitochondria. AB - Mitochondrial membrane potential (DeltaPsiM) is a central intermediate in oxidative energy metabolism. Although DeltaPsiM is routinely measured qualitatively or semi-quantitatively using fluorescent probes, its quantitative assay in intact cells has been limited mostly to slow, bulk-scale radioisotope distribution methods. Here we derive and verify a biophysical model of fluorescent potentiometric probe compartmentation and dynamics using a bis-oxonol type indicator of plasma membrane potential (DeltaPsiP) and the DeltaPsiM probe tetramethylrhodamine methyl ester (TMRM) using fluorescence imaging and voltage clamp. Using this model we introduce a purely fluorescence-based quantitative assay to measure absolute values of DeltaPsiM in millivolts as they vary in time in individual cells in monolayer culture. The DeltaPsiP-dependent distribution of the probes is modelled by Eyring rate theory. Solutions of the model are used to deconvolute DeltaPsiP and DeltaPsiM in time from the probe fluorescence intensities, taking into account their slow, DeltaPsiP-dependent redistribution and Nernstian behaviour. The calibration accounts for matrix:cell volume ratio, high- and low-affinity binding, activity coefficients, background fluorescence and optical dilution, allowing comparisons of potentials in cells or cell types differing in these properties. In cultured rat cortical neurons, DeltaPsiM is 139 mV at rest, and is regulated between -108 mV and -158 mV by concerted increases in ATP demand and Ca2+-dependent metabolic activation. Sensitivity analysis showed that the standard error of the mean in the absolute calibrated values of resting DeltaPsiM including all biological and systematic measurement errors introduced by the calibration parameters is less than 11 mV. Between samples treated in different ways, the typical equivalent error is ~5 mV. PMID- 22495586 TI - Phosphodiesterase-4 inhibition as a therapeutic approach to treat capillary leakage in systemic inflammation. AB - In sepsis and systemic inflammation, increased microvascular permeability and consecutive breakdown of microcirculatory flow significantly contribute to organ failure and death. Evidence points to a critical role of cAMP levels in endothelial cells to maintain capillary endothelial barrier properties in acute inflammation. However, approaches to verify this observation in systemic models are rare. Therefore we tested here whether systemic application of the phosphodiesterase-4-inhibitors (PD-4-Is) rolipram or roflumilast to increase endothelial cAMP was effective to attenuate capillary leakage and breakdown of microcirculatory flow in severe lipopolysaccharide (LPS)-induced systemic inflammation in rats. Measurements of cAMP in mesenteric microvessels demonstrated significant LPS-induced loss of cAMP levels which was blocked by application of rolipram. Increased endothelial cAMP by application of either PD-4 I rolipram or roflumilast led to stabilization of endothelial barrier properties as revealed by measurements of extravasated FITC-albumin in postcapillary mesenteric venules. Accordingly, microcirculatory flow in mesenteric venules was significantly increased following PD-4-I treatment and blood gas analyses indicated improved metabolism. Furthermore application of PD-4-I after manifestation of LPS-induced systemic inflammation and capillary leakage therapeutically stabilized endothelial barrier properties as revealed by significantly reduced volume resuscitation for haemodynamic stabilization. Accordingly microcirculation was significantly improved following treatment with PD-4-Is. Our results demonstrate that inflammation-derived loss of endothelial cAMP contributes to capillary leakage which was blocked by systemic PD-4-I treatment. Therefore these data suggest a highly clinically relevant and applicable approach to stabilize capillary leakage in sepsis and systemic inflammation. PMID- 22495588 TI - Mechanical regulation of fibroblast migration and collagen remodelling in healing myocardial infarcts. AB - Effective management of healing and remodelling after myocardial infarction is an important problem in modern cardiology practice. We have recently shown that the level of infarct anisotropy is a critical determinant of heart function following a large anterior infarction, which suggests that therapeutic gains may be realized by controlling infarct anisotropy. However, factors regulating infarct anisotropy are not well understood. Mechanical, structural and chemical guidance cues have all been shown to regulate alignment of fibroblasts and collagen in vitro, and prior studies have proposed that each of these cues could regulate anisotropy of infarct scar tissue, but understanding of fibroblast behaviour in the complex environment of a healing infarct is lacking. We developed an agent based model of infarct healing that accounted for the combined influence of these cues on fibroblast alignment, collagen deposition and collagen remodelling. We pooled published experimental data from several sources in order to determine parameter values, then used the model to test the importance of each cue for predicting collagen alignment measurements from a set of recent cryoinfarction experiments. We found that although chemokine gradients and pre-existing matrix structures had important effects on collagen organization, a response of fibroblasts to mechanical cues was critical for correctly predicting collagen alignment in infarct scar. Many proposed therapies for myocardial infarction, such as injection of cells or polymers, alter the mechanics of the infarct region. Our modelling results suggest that such therapies could change the anisotropy of the healing infarct, which could have important functional consequences. This model is therefore a potentially important tool for predicting how such interventions change healing outcomes. PMID- 22495587 TI - The regulation of K- and L-cell activity by GLUT2 and the calcium-sensing receptor CasR in rat small intestine. AB - Intestinal enteroendocrine cells (IECs) secrete gut peptides in response to both nutrients and non-nutrients. Glucose and amino acids both stimulate gut peptide secretion. Our hypothesis was that the facilitative glucose transporter, GLUT2, could act as a glucose sensor and the calcium-sensing receptor, CasR, could detect amino acids in the intestine to modify gut peptide secretion. We used isolated loops of rat small intestine to study the secretion of gluco insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) secretion stimulated by luminal perfusion of nutrients or bile acid. Inhibition of the sodium-dependent glucose cotransporter 1 (SGLT1) with phloridzin partially inhibited GIP, GLP-1 and PYY secretion by 45%, suggesting another glucose sensor might be involved in modulating peptide secretion. The response was completely abolished in the presence of the GLUT2 inhibitors phloretin or cytochalasin B. Given that GLUT2 modified gut peptide secretion stimulated by glucose, we investigated whether it was involved in the secretion of gut peptide by other gut peptide secretagogues. Phloretin completely abolished gut peptide secretion stimulated by artificial sweetener (sucralose), dipeptide (glycylsarcosine), lipid (oleoylethanolamine), short chain fatty acid (propionate) and major rat bile acid (taurocholate) indicating a fundamental position for GLUT2 in the gut peptide secretory mechanism. We investigated how GLUT2 was able to influence gut peptide secretion mediated by a diverse range of stimulators and discovered that GLUT2 affected membrane depolarisation through the closure of K+(ATP)-sensitive channels. In the absence of SGLT1 activity (or presence of phloridzin), the secretion of GIP, GLP-1 and PYY was sensitive to K+(ATP)-sensitive channel modulators tolbutamide and diazoxide. L-amino acids phenylalanine (Phe), tryptophan (Trp), asparagine (Asn), arginine (Arg) and glutamine (Gln) also stimulated GIP, GLP-1 and PYY secretion, which was completely abolished when extracellular Ca2+ was absent. The gut peptide response stimulated by the amino acids was also blocked by the CasR inhibitor Calhex 231 and augmented by the CasR agonist NPS-R568. GLUT2 and CasR regulate K- and L-cell activity in response to nutrient and non-nutrient stimuli. PMID- 22495589 TI - Lack of an endogenous GABAA receptor-mediated tonic current in hypoglossal motoneurons. AB - Tonic GABAA receptor-mediated current is an important modulator of neuronal excitability, but it is not known if it is present in mammalian motoneurons. To address this question studies were performed using whole-cell patch-clamp recordings from mouse hypoglossal motoneurons (HMs) in an in vitro slice preparation. In the presence of blockers of glutamatergic and glycinergic receptor-mediated transmission application of SR-95531 or bicuculline, while abolishing GABAA receptor-mediated phasic synaptic currents, did not reveal a tonic GABAA receptor-mediated current. Additionally, blockade of both GAT-1 and GAT-3 GABA transporters did not unmask this tonic current. In contrast, application of exogenous GABA (1 to 15 MUm) resulted in a tonic GABAergic current that was observed when both GAT-1 and GAT-3 transporters were simultaneously blocked, and this current was greater than the sum of the current observed when each transporter was blocked individually. We also investigated which GABAA receptor subunits may be responsible for the current. Application of the delta subunit GABAA receptor agonist THIP resulted in a tonic GABAA receptor current. Application of the delta subunit modulator THDOC resulted in an enhanced tonic current. Application of the alpha5 subunit GABAA receptor inverse agonist L 655,708 did not modulate the current. In conclusion, these data show that HMs have tonic GABAA receptor-mediated current. The level of GABA in the vicinity of GABAA receptors responsible for this current is regulated by GABA transporters. In HMs a tonic current in response to exogenous GABA probably arises from activation of GABAA receptors containing delta subunits. PMID- 22495590 TI - Sympathetic inhibition attenuates hypoxia induced insulin resistance in healthy adult humans. AB - Acute exposure to hypoxia decreases insulin sensitivity in healthy adult humans; the mechanism is unclear, but increased activation of the sympathetic nervous system may be involved. We have investigated the hypothesis that short-term sympathetic inhibition attenuates hypoxia induced insulin resistance. Insulin sensitivity (via the hyperinsulinaemic euglycaemic clamp) was determined in 10 healthy men (age 23 +/- 1 years, body mass index 24.2 +/- 0.8 kg m-2 (means +/- SEM)), in a random order, during normoxia (FIO2 =0.21), hypoxia (FIO2 =0.11), normoxia and sympathetic inhibition (via 48 h transdermal administration of the centrally acting alpha2-adrenergic receptor agonist, clonidine), and hypoxia and sympathetic inhibition.Oxyhaemoglobin saturation (pulse oximetry) was decreased (P<0.001) with hypoxia (63 +/- 2%) compared with normoxia (96 +/- 0%), and was unaffected by sympathetic inhibition (P>0.25). The area under the noradrenaline curve (relative to the normoxia response) was increased with hypoxia (137 +/- 13%; P =0.02); clonidine prevented the hypoxia induced increase (94 +/- 14%; P =0.43). The glucose infusion rate (adjusted for fat free mass and circulating insulin concentration) required to maintain blood glucose concentration at 5 mmol l-1 during administration of insulin was decreased in hypoxia compared with normoxia (225 +/- 23 vs. 128 +/- 30 nmol (kg fat free mass)-1 pmol l-1 min-1; P =0.03), and unchanged during normoxia and sympathetic inhibition (219 +/- 19; P =0.86) and hypoxia and sympathetic inhibition (169 +/- 23; P =0.23). We conclude that short-term sympathetic inhibition attenuates hypoxia induced insulin resistance. PMID- 22495591 TI - Exploiting mathematical models to illuminate electrophysiological variability between individuals. AB - Across individuals within a population, several levels of variability are observed, from the differential expression of ion channels at the molecular level, to the various action potential morphologies observed at the cellular level, to divergent responses to drugs at the organismal level. However, the limited ability of experiments to probe complex interactions between components has hitherto hindered our understanding of the factors that cause a range of behaviours within a population. Variability is a challenging issue that is encountered in all physiological disciplines, but recent work suggests that novel methods for analysing mathematical models can assist in illuminating its causes. In this review, we discuss mathematical modelling studies in cardiac electrophysiology and neuroscience that have enhanced our understanding of variability in a number of key areas. Specifically, we discuss parameter sensitivity analysis techniques that may be applied to generate quantitative predictions based on considering behaviours within a population of models, thereby providing novel insight into variability. Our discussion focuses on four issues that have benefited from the utilization of these methods: (1) the comparison of different electrophysiological models of cardiac myocytes, (2) the determination of the individual contributions of different molecular changes in complex disease phenotypes, (3) the identification of the factors responsible for the variable response to drugs, and (4) the constraining of free parameters in electrophysiological models of heart cells. Together, the studies that we discuss suggest that rigorous analyses of mathematical models can generate quantitative predictions regarding how molecular-level variations contribute to functional differences between experimental samples. These strategies may be applicable not just in cardiac electrophysiology, but in a wide range of disciplines. PMID- 22495593 TI - Effects of organic and conventional production systems and cultivars on the technological properties of winter wheat. AB - BACKGROUND: The current study aimed to estimate the effects of organic and conventional production systems and four winter wheat (Triticum aestivum L.) bread cultivars on the technological properties of grain, flour, dough and bread, to increase current knowledge regarding the interactions of the technological properties of winter wheat and assess the cultivars for their suitability for organic production systems. RESULTS: All the technological properties winter wheat which were investigated were significantly affected by the agricultural production system and cultivars, and some of them, mostly grain quality parameters, by the harvest year. Grain from organic winter wheat had significantly lower protein and gluten contents, lower sedimentation and flour water absorption values, shorter dough stability time and lower loaf volume, but higher values of starch content and stronger gluten, compared with grain from the conventional wheat. For both production systems significant positive correlations of protein content with gluten content, sedimentation value, dough stability time, loaf volume, farinograph water absorption, and negative with starch content, gluten index were determined. CONCLUSIONS: Statistically significant differences between agricultural production systems were found. The cultivars Ada and Alma had better technological properties that make them more suitable for the organic production system, compared to Sirvinta 1 and Zentos. PMID- 22495594 TI - Pulmonary hypertension and right ventricular failure in left ventricular systolic dysfunction. AB - PURPOSE OF REVIEW: Pulmonary hypertension and right ventricular failure (RVF) in left ventricular systolic dysfunction (LVSD) is associated with high morbidity and mortality. This review presents an overview of the classification, pathophysiology, natural history, clinical features, prevention and treatment of this common clinical problem with a focus on the most recent studies. Many of the current evidence-based therapeutic agents for pulmonary hypertension in the absence of systolic or diastolic heart failure (e.g. prostaglandins, endothelin antagonists) are not efficacious in pulmonary hypertension with LVSD. RECENT FINDINGS: Recent clinical evidence strongly supports an evolving role for phosphodiesterase type 5 (PDE5) inhibition in patients with pulmonary hypertension and LVSD. Chronic PDE5 inhibition in the short-to-intermediate duration studies to date significantly reduces pulmonary pressures and pulmonary vascular resistance (PVR), effects reverse right ventricle and left ventricle remodeling, improves ventilator efficiency, improves peak exercise capacity and improves quality of life in selected patients with stable, moderately symptomatic LVSD and pulmonary hypertension. SUMMARY: Although long-term outcome studies are currently lacking, chronic PDE5 inhibition should be considered in carefully selected LVSD patients who manifest persistent significant elevation of pulmonary hypertension or PVR or uncontrolled RVF after aggressive management with all standard current evidence-based LVSD therapies (neurohormonal antagonists, diuretics and cardiac resynchronization in appropriate candidates). PMID- 22495595 TI - Current world literature. PMID- 22495592 TI - Modelling cardiac calcium sparks in a three-dimensional reconstruction of a calcium release unit. AB - Triggered release of Ca2+ from an individual sarcoplasmic reticulum (SR) Ca(2+) release unit (CRU) is the fundamental event of cardiac excitation-contraction coupling, and spontaneous release events (sparks) are the major contributor to diastolic Ca(2+) leak in cardiomyocytes. Previous model studies have predicted that the duration and magnitude of the spark is determined by the local CRU geometry, as well as the localization and density of Ca(2+) handling proteins. We have created a detailed computational model of a CRU, and developed novel tools to generate the computational geometry from electron tomographic images. Ca(2+) diffusion was modelled within the SR and the cytosol to examine the effects of localization and density of the Na(+)/Ca(2+) exchanger, sarco/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA), and calsequestrin on spark dynamics. We reconcile previous model predictions of approximately 90% local Ca(2+) depletion in junctional SR, with experimental reports of about 40%. This analysis supports the hypothesis that dye kinetics and optical averaging effects can have a significant impact on measures of spark dynamics. Our model also predicts that distributing calsequestrin within non-junctional Z-disc SR compartments, in addition to the junctional compartment, prolongs spark release time as reported by Fluo5. By pumping Ca(2+) back into the SR during a release, SERCA is able to prolong a Ca(2+) spark, and this may contribute to SERCA-dependent changes in Ca(2+) wave speed. Finally, we show that including the Na(+)/Ca(2+) exchanger inside the dyadic cleft does not alter local [Ca(2+)] during a spark. PMID- 22495597 TI - Scanning tunnelling microscopy of suspended graphene. AB - Suspended graphene has been studied by STM for the first time. Atomic resolution on mono- and bi-layer graphene samples has been obtained after ridding the graphene surface of contamination via high-temperature annealing. Static local corrugations (ripples) have been observed on both types of structures. PMID- 22495598 TI - Poly(2,5-bis(2-octyldodecyl)-3,6-di(furan-2-yl)-2,5-dihydro-pyrrolo[3,4-c]pyrrole 1,4-dione-co-thieno[3,2-b]thiophene): a high performance polymer semiconductor for both organic thin film transistors and organic photovoltaics. AB - A new diketopyrrolopyrrole (DPP)-containing donor-acceptor polymer, poly(2,5 bis(2-octyldodecyl)-3,6-di(furan-2-yl)-2,5-dihydro-pyrrolo[3,4-c]pyrrole-1,4 dione-co-thieno[3,2-b]thiophene) (PDBF-co-TT), is synthesized and studied as a semiconductor in organic thin film transistors (OTFTs) and organic photovoltaics (OPVs). High hole mobility of up to 0.53 cm(2) V(-1) s(-1) in bottom-gate, top contact OTFT devices is achieved owing to the ordered polymer chain packing and favoured chain orientation, strong intermolecular interactions, as well as uniform film morphology of PDBF-co-TT. The optimum band gap of 1.39 eV and high hole mobility make this polymer a promising donor semiconductor for the solar cell application. When paired with a fullerene acceptor, PC71BM, the resulting OPV devices show a high power conversion efficiency of up to 4.38% under simulated standard AM1.5 solar illumination. PMID- 22495599 TI - Evaluation of the effects of freeze-dried soybean curd intake on cholesterol levels using a novel biomarker. AB - To evaluate the effects of freeze-dried soybean curd intake on serum cholesterol levels, we examined the subclasses of cholesterol for healthy adult volunteers who continued to eat a piece of freeze-dried soybean curd each day along with their ordinary diet for four weeks. Of 12 subjects, the soybean curd diet proved effective in 2 cases; small dense LDL (sd-LDL) cholesterol levels were significantly reduced in association with the decrease in LDL cholesterol levels. These results suggested that daily intake of freeze-dried soybean curd may lead to an improvement in cholesterol metabolism in subjects with originally higher cholesterol levels and that sd-LDL cholesterol can be a novel biomarker for evaluation of the cholesterol lowering-action of functional food. PMID- 22495600 TI - Effects of a hyaluronic acid and low molecular weight heparin injection on osteoarthritis in rabbits. AB - An osteoarthritis (OA) model was created in the knees of rabbits by injecting them with 0.3 mL of sterile papain solution in order to evaluate the effects of a hyaluronic acid (HA) and low molecular weight heparin (LMWH) injection on osteoarthritis. HA-LMWH, LMWH, and HA were injected into animals once weekly. After 5 weeks of treatment, the animals were sacrificed and the effects of the injections on osteoarthritis were evaluated by histological assessment. HA levels in cartilage and the levels of IL-1beta and TNF-alpha expression in synovial fluids were determined. As shown by histological observation, recovery of the synovium and cartilage of animals injected with HA-LMWH was better than that in animals injected with HA or LMWH. HA levels in cartilage of animals injected with HA-LMWH were much higher than those of the control group. The levels of IL-1beta expression in synovial fluids of animals injected with HA-LMWH were lower than those in other animals. The levels of TNF-alpha expression in synovial fluids of animals injected with HA-LMWH were much lower than those in the controls. In conclusion, HALMWH injection had a favorable anti-inflammatory and therapeutic effect on experimental OA. PMID- 22495601 TI - Pterocarpus marsupium extract reveals strong in vitro antioxidant activity. AB - Diabetes mellitus is a complex chronic disease characterized by hyperglycemia, which via several mechanism leads to an increase in production of reactive oxygen species (ROS) leading to various secondary complications. Thus, a drug having both antidiabetic and antioxidant properties would have great therapeutic value for overcoming the oxidative load in diabetes. The present study was aimed at extensively evaluating the antioxidant properties of an anti-diabetic plant extract of stem bark of Pterocarpus marsupium using various in vitro radical scavenging assays as well as by using liver slice cultures as a model system. Our results demonstrate that the whole aqueous extract showed high antioxidant activity in all different assays used and also protected mitochondria against oxidative damage. Ethanol was used as an inducer of oxidative stress in liver slice culture and cytotoxicity was estimated by quantitating release of cytotoxicity marker enzymes such as lactate dehydrogenase (LDH). Additionally, levels of antioxidant enzymes (AOEs) namely superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were also estimated. The whole aqueous extract significantly reduced LDH release along with reduction of lipid peroxidation compared to ethanol treated slices. These results indicate that the P. marsupium extract may serve as a potential source of natural antioxidant for treatment of diabetes. PMID- 22495602 TI - Antiaggressive activity of hyperforin: A preclinical study. AB - The aim of present study was to investigate the in vivo antiaggressive activity of hyperforin using defensive and offensive behavioral models in rodents. Adult male rats and mice were used for the present study. Animals were divided into three groups, with 6 animals in each. Lorazepam was used as standard antiaggressive agent. Animals were treated once daily, for seven consecutive days. Hyperforin (10 mg/kg, i.p.) was injected in a volume of 10 mL/kg for seven consecutive days. Standard group was treated with lorazepam (2.5 mg/kg, i.p.). The control group was treated with equal volume of vehicle (0.3% carboxy methyl cellulose suspension, i.p.). Animals were screened for aggressive behavior before dividing them into groups. At the end of 7 days, experiments were performed. Antiaggressive activity was evaluated using following validated models of aggression viz. foot shock-induced aggression, isolation-induced aggression, resident-intruder aggression and water competition test. Hyperforin treatment significantly (p < 0.001) reduced various aggressive parameters viz. latency to first attack and number of fights in isolation induced aggression, resident intruder aggression and foot shock induced aggression tests. In water competition test, hyperforin treatment significantly (p < 0.001) reduced the duration of water consumption and frequency of water spout possession. We conclude that hyperforin, the major lipophilic compound contained in extracts of Hypericum perforatum, is thus responsible for the antiaggressive activity, suggesting the therapeutic potential of hyperforin as an antiaggressive agent. PMID- 22495603 TI - A novel liquid effervescent floating delivery system for sustained drug delivery. AB - An effervescent floating liquid formulation with in situ gelling properties has been assessed for its potential for sustaining drug delivery and targeting. The formulation consisted of sodium alginate and glyceryl monooleate (GMO). The developed formulation met all pre-requisites to become an in situ gelling floating system and it gelled and floated instantaneously in the pH conditions of the stomach. Moreover, the gels formed in situ remained intact for more than 48 h to facilitate sustained release of drugs. Increasing the mannuronic acid ratio of sodium alginate and the GMO concentration significantly retarded the release rate and extent. The in vitro release of both hydrophilic and hydrophobic drugs from the prepared formulations followed root-time kinetics during the sustained release period. Replacing the free drug with drug encapsulated microspheres enabled tailoring of the release profile and achieved zero-order release kinetics. The system retained its appearance and rheological properties for 12 months at ambient conditions. The values of the similarity factor Sd proved the absence of any significant difference in the release profile upon storage. PMID- 22495604 TI - Microspheres of tramadol hydrochloride compressed along with a loading dose: A modified approach for sustaining release. AB - The purpose of this research was to study mucoadhesive microspheres of tramadol hydrochloride compressed into tablet along with a loading dose. Microspheres containing tramadol hydrochloride were prepared by employing sodium alginate in combination with a mucoadhesive polymer, i.e., Carbopol 971P. An orifice-ionic gelation method was used to prepare the microspheres. A 3(2) factorial design was used to investigate the combined effect of two independent formulation variables in the preparation of microspheres. The concentration of sodium alginate (X(1)) and carbopol 971P (X(2)) were selected as independent variables. Nine batches were used in the experimental design and evaluated for swelling index, mucoadhesion, and drug entrapment efficiency. A surface plot is presented to graphically represent the effect of the independent variables on the evaluation parameters. The best batch exhibited drug entrapment efficiency of 70.12%, swelling index of 2.3 and mucoadhesion of 95.42%. Microspheres showing maximum drug entrapment were compressed with the loading dose and subjected to in vitro dissolution studies. Drug release from tablets was found to follow a matrix model. Initial burst release from these tablets indicated the release of the loading dose and then a sustained effect over the time. This modified approach to formulation of tablets was found to be effective in sustaining drug release. PMID- 22495605 TI - Buccal mucoadhesive tablets of flurbiprofen: Characterization and optimization. AB - The aim of this work was to develop and optimize sustained-release mucoadhesive tablets of flurbiprofen. Mucoadhesive polymers used were chitosan as primary polymer and hydroxypropylmethyl celluose, hydroxypropyl cellulose, or sodium carboxymethyl cellulose as secondary polymer. Tablets were evaluated in terms of weight variation, thickness, hardness, friability, swelling, surface pH, in vitro mucoadhesive force, and in vitro release. The compatibility between flurbiprofen and the tablet excipients was confirmed by fourier transfer infrared studies. Both the primary and secondary polymers were found to have synergistic effects on tablet swelling, bioadhesion, and in vitro drug release. Formulations containing sodium carboxymethyl cellulose (F(1)) showed a maximum swelling index of 4.144 after 8 h, maximum mucoadhesive force (0.27 N), and convenient in vitro release over 8 h. D-optimal design was employed to evaluate the effect of the ratio of the primary polymer (X(1)) and the type of secondary polymer (X(2)) on the swelling index after 8 h (Y(1)), drug release after 8 h (Y(2)) and time taken for 30% drug release (Y(3)). PMID- 22495606 TI - Pathological gambling associated with cabergoline in a case of recurrent depression. AB - Pathological gambling has been described frequently in patients with Parkinson disease or other movement disorders who were treated with dopamine agonists. Here, we report a patient with recurrent depression who developed pathological gambling after administration of the dopamine agonist cabergoline. A 36-year-old male Japanese patient presented with his third episode of depression. His depressive symptoms responded minimally to fluvoxamine. Cabergoline was then added to augment the antidepressant's efficacy. Although this regimen resulted in dramatic improvement, he started to spend considerable money and time every day in pachinko parlors and go to the horse racing track every weekend. He spent more than twenty thousand US dollars in total. He tried to stop gambling many times but failed to control his urge. His gambling behavior did not stop even though he was experiencing a marital crisis. He had not displayed any manic symptoms during this entire period. This complication fulfilled the criteria for pathological gambling according to the Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition, Text Revision edition. The patient's perplexing behavior did not end until cabergoline was discontinued. Thus far, pathological gambling associated with cabergoline has rarely been reported while gambling associated with pramipexole and ropinirole, dopamine agonists, has frequently been documented. In addition, this is the first case of depression in which the patient developed pathological gambling during treatment with a dopamine agonist. In conclusion, clinicians should be aware of the potential for pathological gambling when prescribing cabergoline to patients with depression. PMID- 22495607 TI - Upregulation of the Na(+)-K(+)-2Cl(-) cotransporter 1 via histone modification in the aortas of angiotensin II-induced hypertensive rats. AB - The Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) is upregulated in diverse models of hypertension. We hypothesized that NKCC1 is upregulated via histone modification in the aortas of angiotensin II (Ang II)-induced hypertensive rats. An osmotic mini-pump containing Ang II was implanted in the subcutaneous tissues of the backs of Sprague-Dawley (SD) rats for 7 days. The systolic blood pressure was recorded every day by the tail-cuff method. On days 3 and 7, the mesenteric arteries were excised, cut into rings, mounted in organ baths and subjected to vascular contraction. The levels of Nkcc1 mRNA and protein in the aortas were measured using real-time PCR and Western blotting, respectively. The histone modifications and recruited proteins at the Nkcc1 promoter were determined by chromatin immunoprecipitation. The inhibition of concentration-response curves to phenylephrine by bumetanide, an inhibitor of NKCCs, was greater in Ang II-infused rats than in sham-operated (sham) rats . The levels of Nkcc1 mRNA and protein in the aortas increased gradually as Ang II was infused into the rats. Acetylated histone H3 (H3Ac), an activating histone code, was increased but trimethylated histone H3 at lysine 27 (H3K27me3), a repressive histone code, was greatly decreased in Ang II-infused rats compared with sham. RNA polymerase II was recruited to the Nkcc1 promoter with increased KDM6b. We conclude that the NKCC1 is upregulated via histone modification in the aortas of Ang II-induced hypertensive rats. Thus, we suggest that this ion transporter is epigenetically upregulated by histone modification or DNA demethylation upon the development of hypertension. PMID- 22495608 TI - Exercise stress testing as the significant clinical modality for management of hypertension. PMID- 22495609 TI - Chronic and intermittent hypoxia differentially regulate left ventricular inflammatory and extracellular matrix responses. AB - We evaluated the left ventricle (LV) response to hypoxia by comparing male Sprague Dawley rats exposed for 7 days to normoxia (control; n=18), chronic sustained hypoxia (CSH; n=12) and chronic intermittent hypoxia (CIH; n=12). Out of the 168 inflammatory, extracellular matrix and adhesion molecule genes evaluated, Ltb, Cdh4, Col5a1, Ecm1, MMP-11 and TIMP-2 increased in the LV (range: 87-138%), whereas Tnfrsf1a decreased 27%, indicating an increase in inflammatory status with CSH (all P<0.05). CIH decreased Ltb, Spp1 and Ccl5 levels, indicating reduced inflammatory status. While Laminin beta2 gene levels increased 123%, MMP 9 and fibronectin gene levels both decreased 74% in CIH (all P<0.05). Right ventricle/body weight ratios increased in CSH (1.1+/-0.1 g g(-1)) compared with control (0.7+/-0.1 g g(-1)) and CIH (0.8+/-0.1 g g(-1); both P<0.05). Lung to body weight increased in CSH, while LV/body weight ratios were similar among all three groups. With CIH, myocyte cross sectional areas increased 25% and perivascular fibrosis increased 100% (both P<0.05). Gene changes were independent of global changes and were validated by protein levels. MMP-9 protein levels decreased 94% and fibronectin protein levels decreased 42% in CIH (both P<0.05). Consistent with a decreased inflammatory status, HIF-2alpha and eNOS protein levels were 36% and 44% decreased, respectively, in CIH (both P<0.05). In conclusion, our results indicate that following 7 days of hypoxia, inflammation increases in response to CSH and decreases in response to CIH. This report is the first to demonstrate specific and differential changes seen in the LV during chronic sustained and CIH. PMID- 22495610 TI - Carotid arterial circumferential strain by two-dimensional speckle tracking: a novel parameter of arterial elasticity. AB - Recently, the development of two-dimensional speckle-tracking (2DST) technology has allowed the direct measurement of the elastic parameters of the carotid arterial wall. The aims of this study were to determine the feasibility of measuring peak circumferential strain (CS) of the carotid arterial wall using 2DST and to compare this value with conventional arterial stiffness parameters in subjects with and without hypertension. The study included 90 healthy subjects and 40 age-and sex-matched patients with hypertension. The short-axis view of the right common carotid artery was recorded. The CS in the posterior region of the carotid artery was calculated by 2DST using special software and corrected by the following equation: E(circ)=ln (systolic blood pressure/diastolic blood pressure)/CS. We simultaneously measured the stiffness index beta (beta) at the same location and the brachial-ankle pulse wave velocity (baPWV). Sixty randomly selected healthy subjects were used to assess the inter/intra-observer variability of E(circ) and beta. In healthy subjects, E(circ) was significantly correlated with beta, age and baPWV. These correlations were slightly better than the corresponding correlations of beta with age and baPWV. The hypertensive patients had a significantly larger E(circ) than the healthy subjects (0.112 +/- 0.074 vs. 0.066 +/- 0.029/%, P<0.001). The inter/intra-observer variability for E(circ) was significantly lower than that for beta. Our data suggest that the measurement of carotid E(circ) using 2DST is feasible and has better reproducibility than conventional carotid arterial stiffness. PMID- 22495611 TI - Langerhans cell histiocytosis of bone in children: a long-term retrospective study. AB - Langerhans cell histiocytosis is rare and frequently involves the bone. We retrospectively reviewed the orthopaedic aspects (symptoms, localizations, treatments) and the long-term outcome [disease status, overall survival (OS), event-free survival (EFS)] of 121 patients (June 1968-December 2009). The main symptom was local pain. The orthopaedic treatment was mainly conservative. The most frequent localization was osseous monofocal (62% of monosystemic diseases). Monosystemic and osseous monofocal localizations, treatment after 1991 (OS, P=0.007; EFS, P=0.03) and age older than 2 years (OS, P=0.003; EFS, P=0.001) were prognostic factors that were positively associated with survival. Oncologic treatment has improved over time, translating into better survival. A biopsy is often mandatory. PMID- 22495612 TI - Slipped capital femoral epiphysis: reduction as a risk factor for avascular necrosis. AB - Complication rates after the treatment of slipped capital femoral epiphysis (SCFE) were retrospectively evaluated to identify possible risk factors. Twenty six patients with SCFE underwent reduction and fixation with a single screw or multiple wires. The prevalence of avascular necrosis (AVN) of the hip or chondrolysis was 14.8 and 3.6%, respectively. The degree of SCFE (P=0.050) and reduction before the seventh day after the slip (P=0.028) were associated with AVN. The risk factors for AVN were found to be a higher grade of SCFE correction and reduction between the second and the seventh day after SCFE. PMID- 22495613 TI - Rapid growth of supracondylar process: a case report. AB - The supracondylar process, a bony, beak-like spur on the anteromedial surface of the distal humerus, is a rare congenital abnormality. We present a rare case of a 20-month-old child showing rapid growth of the supracondylar process over 16 months that required surgical excision. A supracondylar process in a young patient may show a tendency for rapid growth. PMID- 22495614 TI - Obturator internus pyomyositis: iatrogenic haematogenous spread. AB - Obturator internus pyomyositis is a rare disorder that should be on the differential diagnosis in a child who presents with a fever, limp, abdominal or groin pain. We present a case of a 5-year-old girl successfully treated with open drainage following failed medical management. We postulate the source of infection to be secondary to an infected elastic stable intramedullary nail in the forearm that was protruding through the skin. PMID- 22495615 TI - Outcome in early adolescent idiopathic scoliosis after deformity correction: assessed by SRS-22, psychometric and generic health measures. AB - The purpose of this study was to examine the health status of early adolescent patients with idiopathic scoliosis using depression-anxiety scales, a generic Quality-of-Life Inventory as well as the Scoliosis Research Society-22 (SRS-22) questionnaire to search for the most comprehensive approach for the measurement of outcomes. Thirty-seven early adolescent patients with idiopathic scoliosis were analyzed within 6-12 months of the postoperative time period. There was no statistically significant correlation between the total score of SRS-22 and the total scores of the pediatric quality-of-life inventory. However, the total scores of SRS-22 were positively correlated with the self-esteem level and negatively correlated with the depression level and State-Trait Anxiety Inventory for Children scores. In early adolescents with idiopathic scoliosis deformity correction, SRS-22 may be inadequate in terms of mental health and physical activity parameters to evaluate overall quality of life. PMID- 22495616 TI - Relationship of non-visualization of the fetal gallbladder and amniotic fluid digestive enzymes analysis to outcome. AB - OBJECTIVE: The aims of this study were evaluate the significance of non visualization of fetal gallbladder at routine ultrasound scan in a series of 102 cases and to determine the contribution of amniotic fluid digestive enzyme (AF DE) analysis towards the outcome. METHOD: This is a multicenter retrospective study. Outcome of pregnancies, karyotype, and result of screening for CFTR gene mutations were known in all cases. Amniotic fluid gamma-glutamyl-transpeptidase and intestinal alkaline phosphatase isoenzyme were assayed. RESULTS: Non visualization of the fetal gallbladder was associated with a severe disease in 25 cases (cystic fibrosis in ten, biliary duct atresia in eight, digestive tract anomalies in six, and chromosomal anomaly in one). In the remaining 77 cases, gallbladder agenesis was diagnosed in 22, and in 55, the gallbladder was subsequently demonstrated. Before 22 weeks of gestation (n=30), an abnormal AF-DE pattern had a 90% sensitivity and 80% specificity in detecting cystic fibrosis or biliary duct atresia. After 22 weeks, sensitivity fell to 53%. The AF-DE pattern was normal in 82% of gallbladder agenesis cases (benign) and in 91% of the cases where the gallbladder was subsequently detected. CONCLUSION: Non-visualization of the fetal gallbladder was associated with severe anomalies in 24% of cases. Prior to 22 weeks, determination of AF-DE contributes to the prediction of biliary atresia or the presence of cystic fibrosis. PMID- 22495617 TI - Poor-to-moderate agreement between self and proxy interviews of mobile phone use. AB - In epidemiological studies, cases cannot always be interviewed due to them being too ill or already deceased. Under these circumstances, proxy interviews are often conducted; however, the veridicality of information about mobile phone use gained by proxy interviews has been doubted. The issue is undecided due to the lack of empirical data. We conducted a study of 119 heterosexual couples. Both partners answered two questionnaires about mobile phone use, one about their own use and one about their partner's use. Overall agreement assessed using Cohen's kappa, Passing and Bablok regression, and concordance coefficients between self and proxy data was poor to moderate (e.g., concordance coefficients of 0.55 for duration of use). The only item with good agreement was whether or not a prepaid phone was used (Cohen's kappa 0.78 and 0.63 for male and female estimates, respectively), and to a lesser degree, the onset of mobile phone use (concordance coefficients of 0.66 and 0.61). Poorest agreement was obtained for the side of the head the mobile phone was held during calls (kappa coefficients of 0.20 and 0.24 for female and male estimates, respectively). We conclude that the assessment of mobile phone use by proxy data cannot be relied on except for information about onset of mobile phone use, use of prepaid or contract phones, and, to a lesser degree, duration of daily use. Agreement concerning the important information about side of the head the mobile phone is held during calls was poorest and only slightly better than chance. PMID- 22495618 TI - Growth-inhibitory and apoptosis-inducing effects of tanshinones on hematological malignancy cells and their structure-activity relationship. AB - This study has investigated the growth-inhibitory and apoptosis-inducing effects of dihydrotanshinone, tanshinone I, tanshinone IIA, and cryptotanshinone on hematological malignancy cell lines, aiming to explore their structure-activity relationship. The growth-inhibitory effects of the tanshinones on K562 and Raji cells were assessed using a modified MTT assay; the apoptosis-inducing effects were assessed by fluorescence microscopy and flow cytometry analysis. The changes in cellular morphology were observed using an inverted phase-contrast microscope. MTT results revealed that these tanshinones inhibited cell proliferation in a concentration-dependent and time-dependent manner. The IC50 values of dihydrotanshinone, tanshinone I, tanshinone IIA, and cryptotanshinone for K562 cells were 3.50, 13.52, 19.32, and 47.52 MUmol/l at 24 h; 1.36, 4.70, 5.67, and 22.72 MUmol/l at 48 h; and 1.15, 1.59, 2.82, and 19.53 MUmol/l at 72 h, and the values for Raji cells were 3.30, 4.37, 12.92, and 52.36 MUmol/l at 24 h; 1.55, 1.71, 6.54, and 25.45 MUmol/l at 48 h; and 1.07, 1.38, 1.89, and 18.47 MUmol/l at 72 h. The flow cytometry analysis demonstrated that these tanshinones induced apoptosis of K562 cells in a concentration-dependent manner, and dihydrotanshinone as well as tanshinone I were more potent than tanshinone IIA and cryptotanshinone. Some noticeable apoptotic morphologies could be observed by fluorescence microscopy on tanshinones-treated Raji cells. Collectively, these tanshinones caused growth inhibition and apoptosis in hematological malignancy cell lines, with dihydrotanshinone being the most potent, followed by tanshinone I, tanshinone IIA, and cryptotanshinone. These results suggested that the structure of aromatic ring A enhanced the cytotoxicity and the structure of ring C may have contributed to the cytotoxicity, but the mechanisms need to be further investigated. PMID- 22495619 TI - Collagen IV and CXC chemokine-derived antiangiogenic peptides suppress glioma xenograft growth. AB - Peptides are receiving increasing attention as therapeutic agents due to their high binding specificity and versatility to be modified as targeting or carrier molecules. Particularly, peptides with antiangiogenic activity are of high interest because of their applicability to a wide range of cancers. In this study, we investigate the biological activity of two novel antiangiogenic peptides in preclinical glioma models. One peptide SP2000 is derived from collagen IV and the other peptide SP3019 belongs to the CXC family. We have previously characterized the capacity of SP2000 and SP3019 to inhibit multiple biological endpoints linked to angiogenesis in human endothelial cells in several assays. Here, we report additional studies using endothelial cells and focus on the activity of these peptides against human glioma cell growth, migration and adhesion in vitro, and growth as tumor xenografts in vivo. We found that SP2000 completely inhibits migration of the glioma cells at 50 umol/l and SP3019 produced 50% inhibition at 100 umol/l. Their relative antiadhesion activities were similar, with SP2000 and SP3019 generating 50% adhesion inhibition at 4.9 +/ 0.82 and 21.3 +/- 5.92 umol/l, respectively. In-vivo glioma growth inhibition was 63% for SP2000 and 76% for SP3019 after 2 weeks of administration at daily doses of 10 and 20 mg/kg, respectively. The direct activity of these peptides against glioma cells in conjunction with their antiangiogenic activities warrants their further development as either stand-alone agents or in combination with standard cytotoxic or emerging targeted therapies in malignant brain tumors. PMID- 22495620 TI - Cannabidiol and clozapine reverse MK-801-induced deficits in social interaction and hyperactivity in Sprague-Dawley rats. AB - Recently, a novel paradigm has been designed to assess social investigative behaviour in pairs of Sprague-Dawley rats, which involves physical separation whilst ensuring they are able to maintain contact through other social cues. We have modified this set-up in order to assess not just social behaviour but also locomotor activity of the rats. Results showed that the MK-801- (0.3 mg/kg) treated rats displayed reduced social investigative behaviour, hyperactivity as well as reduced attention span. Pretreatment with the phytocannabinoid cannabidiol (3 mg/kg) not only normalised social investigative behaviour but increased it beyond control levels. Pretreatment with clozapine (1, 3 mg/kg) also normalised social investigative behaviour. Both cannabidiol and clozapine inhibited MK-801-induced hyperactivity. However, there were no effects of pretreatment on impairments to attention span. Our findings reinforce several aspects of the validity of the MK-801-induced model of social withdrawal and hyperactivity and also support the use of this novel set-up for further investigations to assess the antipsychotic potential of novel compounds. PMID- 22495621 TI - A randomized clinical study of Lu AA21004 in the prevention of relapse in patients with major depressive disorder. AB - The efficacy and tolerability of Lu AA21004 in the prevention of relapse of major depressive disorder (MDD) in patients in remission after acute treatment was evaluated. Patients (n=639) aged 18-75 years with a primary diagnosis of MDD with a current major depressive episode (MDE) >=4 weeks' duration, at least one prior MDE and a MADRS total score >=26 received 12-week, open-label Lu AA21004 at 5 or 10mg/day. Patients in remission (MADRS <=10) at both weeks 10 and 12 were assigned to double-blind treatment with either placebo or Lu AA21004 (fixed dose from Week 8).Patients (n=396) were treated, after random assignment to placebo (n=192) or Lu AA21004 (n=204). The primary analysis of time to relapse (full analysis set, Cox proportional hazard model) showed a statistically significant difference in favour of Lu AA21004 versus placebo with a hazard ratio of 2.01 (95% confidence interval: 1.26-3.21; p=0.0035). The proportion of patients who relapsed was 13% in the Lu AA21004 group (n=27) and 26% in the placebo group (n=50). The withdrawal rates due to adverse events were 8% (open-label), and 3% (placebo) and 8% (Lu AA21004) (double-blind). Thus, Lu AA21004 was effective in preventing relapse of MDD and was well tolerated as maintenance treatment. PMID- 22495622 TI - Current world literature. PMID- 22495624 TI - The first isocyanide of plant origin expands functional group diversity in cruciferous phytoalexins: synthesis, structure and bioactivity of isocyalexin A. AB - Although isocyanides are not rare amongst terrestrial microbes and marine organisms, despite tens of thousands of natural products isolated from plants, isocyanides are still missing. Isocyalexin A is the first isocyanide of plant origin. Isocyalexin A was isolated from UV-irradiated rutabaga roots and shown to be a new cruciferous phytoalexin. Its chemical structure was proven by analysis of NMR spectroscopic data and chemical synthesis. PMID- 22495626 TI - Ultrafast chemical dynamics. PMID- 22495625 TI - Association of metabolic syndrome, atherosclerosis risk factors, sex hormones in ED in aboriginal Taiwanese. AB - The overall prevalence of metabolic syndrome (MS) in aboriginal male Taiwanese is very high. Many studies have found that those with cardiovascular disease and MS have a significantly higher risk of ED. In this study, we attempted to find the correlation among MS risk factor, atherosclerosis risk factors and low serum testosterone in relation to the development of ED. This was a cross-sectional study of 238 cases, and collected data included demographic data, lifestyle questionnaires, sexual desire scale, sexual satisfaction scale and International Index of Erectile Function (IIEF) questionnaire. Among our 238 subjects, 146 had MS (61.3%) and 114 subjects with MS had ED (85.7%). Using age-adjusted multivariate logistic regressive analysis, this study showed that aboriginal males with ED had a significantly higher prevalence of MS (OR=12.02, 95% confidence intervals (CI): 6.33-22.83, P<0.001). Among the MS components, abnormal fasting blood sugar was the most significantly independent factor for ED in aboriginal males (OR=8.94, 95% CI: 4.71-16.97, P<0.001). The presence of MS had a significant correlation with lower IIEF-5 scores, lower sexual desire scores, lower testosterone serum level (P<0.01) and abnormal interleukin-6 (IL-6) and high sensitivity C-reactive protein (HsCRP). The results of this study support the idea that MS, low serum testosterone and HsCRP may predict ED in aboriginal Taiwanese males. Further studies with population-based and longitudinal design should be conducted to confirm this finding and design to compare rates of ED in aboriginal men with MS. PMID- 22495627 TI - Theoretical analysis of the optical excitation spectra of silver and gold nanowires. AB - The excitation spectra of linear atomic chains of silver and gold with various sizes have been calculated using time-dependent density functional theory. Silver chains show longitudinal and transverse peaks as well as a low-intensity d-band. The longitudinal peak, corresponding to the HOMO-LUMO transition (along the main axis of the chain), shifts linearly to the red as the length of the system increases, consistent with the particle-in-a-box model. The transverse peak remains at approximately constant energy for all systems studied and corresponds to ?(m)->Pi(m) transitions in the xy plane perpendicular to the chain. As the chain grows, transitions arising from d orbitals contribute to the transverse peak, which affects its oscillator strength. Contrary to silver, gold chains display a strong d-band that converges to a distinct pattern at a chain length of about twelve atoms. The transitions involved in the d-band originate from localized d-orbitals with a d(z(2)) character since they have the right symmetry to give transitions into the LUMO, LUMO + 1, ..., which have ? symmetry. Transitions arising from these localized d-orbitals also affect the position of the longitudinal peak and generate a wide transverse band. Although the majority of the transitions involved in the transverse band have a d?->Pi or dPi->? character, they are hidden by much stronger excitations of dPi->Pi character in gold nanowires. PMID- 22495628 TI - Intellectual property strategies for university spinoffs in the development of new drugs. AB - We will explain a new business model for university spinoffs involving the development of two types of products. The first are highly innovative, such as new drugs, while the second are typically less difficult to develop, such as functional foods. It is our belief that development of the second type of product can help solve the financial problems and stabilize management of Academic Start ups. The key to development of several different types of products is accumulation of knowledge consisting not only of technical knowhow, e.g. tips for use in injection, but also ideas obtained by researchers with the potential for future applications. Examination of the features of venture enterprises which have arisen from universities suggests that inventors, who are also professors, should participate in such start-ups. PMID- 22495629 TI - Microarray analysis of gene expression in medicinal plant research. AB - Expression profiling analysis offers great opportunities for the identification of novel molecular targets, drug discovery, development, and validation. The beauty of microarray analysis of gene expression is that it can be used to screen the expression of tens of thousands of genes in parallel and to identify appropriate molecular targets for therapeutic intervention. Toward identifying novel therapeutic options, natural products, notably from medicinal plants used in traditional Chinese medicine (TCM), have been thoroughly investigated. Increased knowledge of the molecular mechanisms of TCM-derived drugs could be achieved through application of modern molecular technologies including transcript profiling. In the present review, we introduce a brief introduction to the field of microarray technology and disclose its role in target identification and validation. Moreover, we provide examples for applications regarding molecular target discovery in medicinal plants derived TCM. This could be an attractive strategy for the development of novel and improved therapeutics. PMID- 22495630 TI - Structure analysis of short peptides by analytical ultracentrifugation: Review. AB - Short peptides are potential drug candidates for pharmaceutical and biotech industries. Short peptides are natural ligands for numerous G-protein coupled receptors (GPCR) and hence constitute a large number of drug candidates. Synthetic short peptides are also extensively developed as agonistic or antagonistic ligands that function in a similar manner to antibodies, soluble receptors and protein ligands. Characterization of the peptides in solution is often performed in the presence of organic solvents, which can presumably generate the structure bound to the target surface and also enhance the solubility of the peptides. Analytical ultracentrifugation (AUC) technique should provide information on the state of self-association of the peptide in solution. Its application for short peptides has been far less than the applications for proteins. We believe that AUC should be used to show the associated state of the peptides, as reviewed in this paper. PMID- 22495631 TI - Beneficial effects of a standardized Hypericum perforatum extract in rats with experimentally induced hyperglycemia. AB - The main aim of this study was to test the therapeutic potential of a standardized Hypericum perforatum extract in treating metabolic disturbances commonly associated with type-2 diabetes mellitus. Daily oral administration of the Hypericum perforatum extract (100, 200, and 300 mg/kg/day) for 14 consecutive days counteracted in a dose-dependent manner the alterations in blood glucose levels and lipid profile as well as liver glycogen content and body weight changes observed in a rat mode of nicotinamide-streptozotocininduced diabetes. In general, effects of the highest dose of the extract in this model were quite similar, but not identical, to those of a 10 mg/kg/day dose of glibenclamide. The effects of single oral doses of the extract in a rat oral glucose tolerance test conducted in fasted animals were also analogous to those of an antidiabetic drug therapeutic use. These observations not only further expand the therapeutic potentials of Hypericum extracts but also indicate that stimulation of insulin release could be involved in their modes of actions. The importance of an extract with diverse, therapeutically interesting pharmacological properties is also briefly discussed. PMID- 22495632 TI - Sedative and anxiolytic effects of different fractions of the Commelina benghalensis Linn. AB - The present study was designed to investigate sedative and anxiolytic properties of the four different fractions (chloroform, pet ether, n-butanol and hydromethanol soluble fractions, coded as CFCB, PECB, NBCB and HMCB, respectively) of the aerial parts of Commelina benghalensis using rodent behavioral models, such as hole cross, open field and thiopental sodium induced sleeping time tests for sedative property and elevated plus-maze (EPM) test for anxiolytic potential, respectively. All fractions, at the doses of 200 mg/kg, p.o. and 400 mg/kg, p.o., displayed dose dependent suppression of motor activity, exploratory behavior (in hole cross and open field tests) and prolongation of thiopental induced sleeping time in mice; maximum effect was shown by chloroform (CFCB) and pet ether (PECB) fractions. In EPM test, chloroform (CFCB) and pet ether (PECB) fractions with similar doses significantly (p < 0.05) increased exploration to and time spent by the treated mice in EPM open arms in a way similar to that of diazepam while the effect of NBCB and HMCB fractions on entry to and time spent in open arms was not found to be statistically significant. These findings provide in vivo evidence that aerial parts of C. benghalensis in general, and chloroform (CFCB) and pet ether (PECB) soluble fraction has significant sedative and anxiolytic effects. Furthermore, these results may justify the scientific basis for the use of this plant in traditional medicine as a modality for anxiety and related disorders. PMID- 22495633 TI - Vaginal delivery of protein drugs in rats by gene-transformed Lactococcus lactis. AB - A probiotic bacterium, Lactococcus lactis subsp. lactis (L. lactis) transformed with plasmid ss80, which made it capable of synthesizing and secreting beta lactamase, a 29 kDa protein, was used to deliver beta-lactamase via vaginal route. The vaginal absorption of beta-lactamase in rats was studied when delivered by this L. lactis system and compared to the beta-lactamase solution with or without the untransformed L. lactis. The vaginal administration of 1.2 * 10(7), 3 * 10(7), and 8 * 10(7) colony forming units (cfu) of L. lactis resulted in the amount absorbed of 77, 194, and 216 mU, with the respective doses. C(max), mean retention time and mean absorption time of beta-lactamase were also increased with the increase in the cfu of L. lactis administered. These results have demonstrated that L. lactis can significantly increase (p < 0.01) the beta lactamase vaginal absorption as compared to the beta-lactamase solution, which is probably due to the adhesion of L. lactis to and continuous synthesis and delivery of beta-lactamase directly to the vaginal mucosa. In conclusion, transformed normal flora may be an efficient method to deliver protein drugs through the vaginal route. PMID- 22495634 TI - Comparative development and evaluation of topical gel and cream formulations of psoralen. AB - The aim of the present investigation is to develop topical gel and cream formulations of psoralen for enhancing its transport through the skin, with the goal to shorten the delay between drug application and UVA irradiation. In our first studies, oil-in-water (O/W) creams of psoralen (0.05% concentration) were prepared using Apifil (PEG-8 Beeswax) and Plurol Stearique WL 1009 as emulsifying agents and aqueous cream (British Pharmaceutical Codex) as the cream base material. In our second studies, hydroalcoholic transparent gel formulations of this drug in a 0.05% concentration were prepared using hydroxypropylcellulose (HPC) as the gelling agent. The physicochemical compatibility between psoralen and formulation excipients used in the cream and gel formulations was confirmed by using differential scanning calorimetry and Fourier transform infrared spectroscopy. All prepared cream and gel formulations were evaluated for drug content uniformity, viscosity, pH, stability, and limpidity. The release of psoralen from all formulations via dialysis through a cellulose membrane into phosphate buffer pH 6.8 at 37 degrees C was studied. The penetration enhancing effect of menthol (0-12.5%, w/w) on the percutaneous flux of psoralen through excised rat epidermis from gel and cream formulations was also investigated. The release profile of psoralen from gel formulations was higher than that from cream formulations. The percutaneous flux and enhancement ratio of psoralen across rat epidermis was significantly enhanced by the addition of menthol in both gel and cream formulations as compared to gel and cream formulations prepared without menthol (p < 0.05). PMID- 22495635 TI - The emerging role of serotonin in liver regeneration. AB - Serotonin has a multifunctional role in many different organs serving either as a neurotransmitter in the central nervous system or a paracrine factor in the gastrointestinal tract. Over 90% of serotonin is synthesised in the enterochromaffin cells of the intestine and subsequently taken up by platelets. The involvement of platelet-derived serotonin in liver mass restoration after partial hepatectomy or toxic injury has been greatly investigated during the last decade. There is a growing body of evidence implicating serotonin in hepatic regeneration through altered expression of serotonin receptor subtypes in the liver. This review article provides a brief overview on the current knowledge about the actions of serotonin in liver regeneration. PMID- 22495636 TI - The effect of delay between heat treatment and cold storage on alleviation of chilling injury in banana fruit. AB - BACKGROUND: To understand the mechanisms leading to the enhanced chilling resistance of banana by hot-water dipping (HWD, 52 degrees C for 3 min), we investigated the effect of a 0.5-24 h delay between HWD and cold storage on chilling resistance and the change related to the metabolism of reactive oxygen species (ROS). RESULTS: The HWD-treated fruit with a delay of less than 6 h exhibited markedly less chilling injury than the non-heated control fruit, while a delay more than 6 h resulted in significant loss in chilling resistance. Increased hydrogen peroxide content and rate of superoxide radical production were detected in the fruit at 0.5-1.5 h after HWD treatment, and the levels declined with a longer delay, which may be correlated with the enhanced gene expression levels of the gene coding for a ROS-generating related enzyme, NADPH oxidase (MaNOX). Enhanced activities and gene expression of an ascorbate peroxidase (MaAPX) were recorded in the fruit at 1.5-6 h after the treatment, and after 6 h the ascorbate peroxidase levels decayed to the levels as the control fruit. The higher APX gene expression was maintained in the treated fruit with a 3 h delay during the subsequent cold storage at 7 degrees C, correlating with the enhanced chilling resistance. CONCLUSION: The HWD-treated fruit left at ambient temperature up to 6 h prior to cold storage maintained the effect of heat treatment and transiently increased ROS content, and the ascorbate peroxidase activity that occurred 0.5-6 h after the treatment may be correlated with the elevated chilling resistance induced by HWD treatment. PMID- 22495637 TI - Male genital abnormalities in intrauterine growth restriction. AB - OBJECTIVE: Previous studies have shown a correlation between hypospadias and intrauterine growth restriction (IUGR), suggesting an association between placental insufficiency and abnormal genital development. This study sought to analyze the association of IUGR and genital abnormalities apparent on fetal magnetic resonance imaging (MRI). METHODS: This retrospective study included 22 MRI scans of 20 male fetuses between 20 and 35 weeks of gestation presenting with IUGR. On MRI, penile length and testicular descent were evaluated. Student's t testing and analysis of covariance were used to compare MRI penile length measurements with published normative data obtained from fetal ultrasonography (US) and MRI. McNemar testing was used to evaluate testicular descent in IUGR, compared with reported fetal MRI normative data. RESULTS: The penile length in IUGR fetuses was shorter than in normal fetuses (p<0.001). Furthermore, six of 20 fetuses presented with a micropenis (2.5 SD below the mean value for age). Undescended testes were significantly more frequent in IUGR fetuses than in normal fetuses (p=0.004). CONCLUSION: Our data confirm that abnormal fetal growth may be associated with penile shortening and, potentially, also undescended testes. PMID- 22495638 TI - [The DOSE study]. PMID- 22495639 TI - [Conflict of interests in the Italian medical system]. PMID- 22495640 TI - [Conflict of interest policies and disclosure requirements among European Society of Cardiology National Cardiovascular Journals]. AB - Disclosure of potential conflicts of interest (COI) is used by biomedical journals to guarantee credibility and transparency of the scientific process. COI disclosure, however, is not systematically nor consistently dealt with by journals. Recent joint editorial efforts paved the way towards the implementation of uniform vehicles for COI disclosure. This paper provides a comprehensive editorial perspective on classical COI-related issues. New insights into current COI policies and practices among European Society of Cardiology national cardiovascular journals, as derived from a cross-sectional survey using a standardised questionnaire, are discussed. PMID- 22495641 TI - [Almanac 2011: Stable coronary artery disease. An editorial overview of selected research that has driven recent advances in clinical cardiology]. PMID- 22495642 TI - [From bench to bedside: new insights into the treatment of heart failure]. AB - Despite significant advances in pharmacological and clinical treatment, heart failure remains a leading cause of morbidity and mortality worldwide. G-protein coupled receptors are a wide superfamily of plasma membrane receptors which represent an important target of heart failure drug therapy. Since heart failure is characterized by the overactivity of different neurohormones, such as catecholamines and angiotensin II, responsible for several detrimental effects on the cardiovascular system, over the last decade therapeutic strategies targeting beta-adrenergic and angiotensin receptors have been developed. Despite the introduction of successful drug classes, such as beta-adrenergic receptor blockers, angiotensin-converting enzyme inhibitors and sartans, heart failure still poses an enormous challenge, thus indicating the urgent need to develop innovative treatments that might counteract mechanisms involved in heart failure onset and progression. It is now established that a single receptor, activated by the same agonist, can elicit several different signaling pathways often resulting in opposite cellular responses, some beneficial and some detrimental. However, drugs currently used in heart failure target receptors on their extracellular domain by competing with the endogenous agonists. Thus, they can inhibit non specifically all the receptor-related signaling pathways including those with beneficial activity whose blockade would not be desirable in heart failure. These observations stress the need for the generation of new therapeutic molecules able to target specific signaling pathways which might result in innovative therapies for cardiovascular disease. PMID- 22495643 TI - [Continuous infusion versus bolus injection of loop diuretics in acute heart failure: a literature review]. AB - Intravenous loop diuretics are increasingly used to treat symptoms and signs of fluid overload in acute heart failure, a clinical condition associated with high morbidity and mortality rates. Although diuretic therapy is widely used and strongly recommended by most recent clinical guidelines, prospective studies and randomized clinical trials are lacking and hence there is no reliable evidence regarding the best therapy in terms of doses, ways and methods of administration. With heart failure progression, the efficacy of loop diuretics is impaired by diuretic resistance characterized by a decreased diuretic and natriuretic effect of drugs. This review focuses on the current management of acute heart failure with diuretic therapy. Continuous diuretic infusion seems to be a good choice, from a pharmacokinetic point of view, when fluid overload is refractory to conventional therapy. Several available studies comparing bolus injection to continuous infusion of loop diuretics proved the latter to be an effective and safe method of administration. Continuous infusion seems to produce a constant plasma drug concentration with a more uniform daily diuretic and natriuretic effect and a greater safety profile (fewer adverse events such as worsening renal failure, electrolyte imbalance, ototoxicity). In addition, the analysis of available literature data did not provide conclusive evidence about the effects on clinical outcomes (mortality, rehospitalization rates, adverse events). PMID- 22495644 TI - [Physiological versus pathological left ventricular remodeling in athletes]. AB - Intense and chronic athletic training is associated with left ventricular remodeling, including an increase in wall thickness, cavity size and mass. The extent of morphological cardiac changes depends on a variety of factors, namely body size, gender, type of sport, ethnicity and, likely, genetic factors. A subset of male athletes engaged in intense endurance sports, such as cycling and rowing, develops a more substantial increase in left ventricular dimensions that may overlap with the phenotypic expression of cardiomyopathies. A common clinical challenge in sports cardiology is the differential diagnosis between physiological left ventricular hypertrophy (i.e., "athlete's heart") and hypertrophic cardiomyopathy, which is one of the most common causes of sudden cardiac death in young athletes. This review describes the physiological determinants, characteristics and upper limits of left ventricular hypertrophy in athletes, and analyzes the criteria that can be useful in the differential diagnosis between "athlete's heart" and hypertrophic cardiomyopathy. PMID- 22495645 TI - [The relationship between the heart and the kidney in acute heart failure: doubts of the cardiologist and the nephrologist's point of view]. AB - The pathophysiological interactions that link the heart and kidney in heart failure are multiple and complex. This issue constitutes one of the most vexing and difficult challenges facing cardiologists. In the setting of acute decompensated heart failure, worsening renal function has traditionally been directly associated with poor clinical prognosis and complicates treatment. In the last years, many reports suggest that worsening renal failure may represent the final common pathway of several mechanistically distinct processes, with different prognostic implications. In the clinical scenario, the clinical significance of transient worsening of renal function may be different as compared with irreversible or progressive renal failure. In addition, it can represent a relatively normal response to treatment-induced physiological derangements such as a reduction in renal perfusion and/or intravascular volume. We here focus on these highlights, with special reference to the diagnostic criteria of renal dysfunction and the management of fluid overload. Two expert nephrologists were asked to answer a few important clinical questions: how should renal dysfunction be recognized and monitored? Are there therapies to counteract it and when, and more importantly, for whom should be applied? Their answers serve as touchstones for cardiologists to provide better individualized care for their patients with acute heart failure. Only a multidisciplinary and collaborative management of cardio-renal interactions will help to mitigate the difficult day-to-day clinical practice and improve our understanding of this condition through a concerted and constructive approach. PMID- 22495646 TI - [Prevalence and subtypes of systemic hypertension in an unselected patient population with severe obesity undergoing bariatric surgery]. AB - BACKGROUND: Obesity plays a pivotal role in the development of systemic hypertension and the two diseases are often related. Severe obesity is getting more and more prevalent in our country. The aim of this study was to evaluate the prevalence of systemic hypertension in an unselected population of obese patients observed in the Regional Referral Center for Surgical Obesity of our hospital. METHODS: 233 consecutive patients (52 male, 181 female, mean age 42 years, mean weight 120 kg, mean body mass index [BMI] 43.7 kg/m2) were screened in order to plan a surgical procedure for severe obesity. Each patient underwent cardiovascular clinical evaluation, ECG and echocardiographic examination, blood pressure ambulatory monitoring, and 24h Holter monitoring. RESULTS: Thirty-five percent of patients were under drug treatment for hypertension or were at least aware of being hypertensive; among the remaining 65% of patients who declared having normal blood pressure, 33% suffered from systemic hypertension, 11% had isolated clinical hypertension, and 14% had masked hypertension. Thus, the global prevalence of systemic hypertension in this population raised to 72.5%. ECG and echocardiographic findings were normal in about 90% of the whole population, whereas 24h Holter monitoring showed minor or major abnormalities in approximately 25% of patients. At a follow-up of at least 18 months, a subgroup of 48 patients showed a decrease in body weight from 129 to 92 kg, BMI from 47 to 33 kg/m 2, blood pressure from 134.4/86.4 to 127.7/81.1 mmHg, and heart rate from 79.7 to 69.4 bpm. CONCLUSIONS: The prevalence of systemic hypertension in an unselected population of severely obese patients is much higher than in the general population. The surgical procedures performed in the Regional Referral Center for Surgical Obesity of our hospital were virtually free from serious adverse events and proved to be effective in reducing not only body weight and BMI but also blood pressure. We believe that ambulatory blood pressure and 24h Holter monitoring are the most relevant examinations to be performed in these patients in the preoperative period. PMID- 22495647 TI - [Management of refractory symptoms in hypertrophic cardiomyopathy with restrictive pathophysiology: novel perspectives for ranolazine]. AB - The management of patients with hypertrophic cardiomyopathy (HCM) and refractory symptoms due to massive hypertrophy and severe diastolic dysfunction represents a real challenge for the clinical cardiologist. Such patients often require novel therapeutic approaches, both invasive and pharmacological, involving multidisciplinary teamwork; however, the implementation of potentially viable treatment options is hindered by lack of disease-specific evidence. We report the case of a young woman with severe HCM and restrictive physiology, who underwent extensive myectomy via the transaortic and transapical approach, followed by biventricular pacing for cardiac resynchronization, with significant but incomplete symptomatic improvement. The subsequent introduction of ranolazine, based on promising preclinical data, has led to an excellent final result. An ongoing randomized clinical trial is currently testing the efficacy of ranolazine in symptomatic HCM. PMID- 22495648 TI - [Scimitar syndrome in adults: a rare anomaly completely characterized by cardiac magnetic resonance]. PMID- 22495649 TI - [Comment on the article by Enrico Donegani "nitrates at high altitude, that is the inappropriate use of a drug]. PMID- 22495650 TI - [A tribute to the New England Journal of Medicine]. PMID- 22495651 TI - Cap-dependent translation initiation factor eIF4E: an emerging anticancer drug target. AB - Cancer cells tend to be more highly dependent on cap-dependent translation than normal tissues. Thus, proteins involved in the initiation of cap-dependent translation have emerged as potential anti-cancer drug targets. Cap-dependent translation is initiated by the binding of the factor eIF4E to the cap domain of mRNA. Detailed x-ray crystal and NMR structures are available for eIF4E in association with cap-analogs, as well as domains of other initiation factors. This review will summarize efforts to design potential antagonist of eIF4E that could be used as new pharmacological tools and anti-cancer agents and. Insights drawn from these studies should aid in the design of future inhibitors of eIF4E dependent translation initiation. PMID- 22495652 TI - Supervised Bayesian latent class models for high-dimensional data. AB - High-grade gliomas are the most common primary brain tumors in adults and are typically diagnosed using histopathology. However, these diagnostic categories are highly heterogeneous and do not always correlate well with survival. In an attempt to refine these diagnoses, we make several immunohistochemical measurements of YKL-40, a gene previously shown to be differentially expressed between diagnostic groups. We propose two latent class models for classification and variable selection in the presence of high-dimensional binary data, fit by using Bayesian Markov chain Monte Carlo techniques. Penalization and model selection are incorporated in this setting via prior distributions on the unknown parameters. The methods provide valid parameter estimates under conditions in which standard supervised latent class models do not, and outperform two-stage approaches to variable selection and parameter estimation in a variety of settings. We study the properties of these methods in simulations, and apply these methodologies to the glioma study for which identifiable three-class parameter estimates cannot be obtained without penalization. With penalization, the resulting latent classes correlate well with clinical tumor grade and offer additional information on survival prognosis that is not captured by clinical diagnosis alone. The inclusion of YKL-40 features also increases the precision of survival estimates. Fitting models with and without YKL-40 highlights a subgroup of patients who have glioblastoma (GBM) diagnosis but appear to have better prognosis than the typical GBM patient. PMID- 22495653 TI - Gold(I)-catalyzed intramolecular hydroamination and ring-opening of sulfonamide substituted 2-(arylmethylene)cyclopropylcarbinols. AB - An interesting gold(I)-catalyzed intramolecular hydroamination and ring-opening of sulfonamide-substituted 2-(arylmethylene)cyclopropylcarbinols has been described in this context. A variety of 4-substituted isoxazolidine derivatives were obtained in good to high yields through a highly regioselective cleavage of a carbon-carbon single bond in the cyclopropane. PMID- 22495654 TI - Expanding the tools available for direct ortho cupration--targeting lithium phosphidocuprates. AB - Reaction of in situ generated lithium phosphides with 0.5 eq. Cu(I) is employed as a means of targeting lithium phosphidocuprates of either Gilman- or Lipshutz type formulation--e.g., (R(2)P)(2)CuLi.n(LiX) (n = 0, 1). For R = Ph, X = CN in toluene followed by thf or R = Ph, X = I in thf/toluene an unexpected product results. [(Ph(2)P)(6)Cu(4)][Li.4thf](2)1 reveals an ion-separated structure in the solid state, with solvated lithium cations countering the charge on an adamantyl dianion [(Ph(2)P)(6)Cu(4)](2-). Deployment of R = Ph, X = CN in thf affords a novel network based on the dimer of Ph(2)PCu(CN)Li.2thf 2 with trianions based on 6-membered (PCu)(3) rings acting as nodes in the supramolecular array and solvated alkali metal counter-ions completing the linkers. Cy(2)PLi (Cy = cyclohexyl) has been reacted with CuCN in thf/toluene to yield Gilman-type lithium bis(phosphido)cuprate (Cy(2)P)(2)CuLi.2thf 3 by the exclusion of in situ generated LiCN. A polymer is noted in the solid state. PMID- 22495656 TI - Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines. AB - Ivermectin is an old anti-parasitic antibiotic which selectively kills nematodes at a very low dose (0.2 mg/kg) by inhibiting their GABA (gamma-aminobutyric acid) receptor, but not mammalian counterpart. Interestingly, several years ago it was reported by a Russian group that Ivermectin can suppress almost completely the growth of human melanoma and a few other cancer xenografts in mice at the much higher doses (3-5 mg/kg) without any adverse effect on mice. However, its anti cancer mechanism still remained to be clarified at the molecular levels, that would determine the specific type of cancers susceptible to this drug. The first hint towards its anti-PAK1 potential was a recent finding that Ivermectin at its sublethal doses dramatically reduces the litter size (number of eggs laid) of the tiny nematode C. elegans. Interestingly, either a PAK1-deficiency (gene knock out) or treatment with natural anti-PAK1 products such as CAPE (caffeic acid phenethyl ester) and ARC (artepillin C), the major anti-cancer ingredients in propolis, also causes the exactly same effect on this nematode, suggesting the possibility that the kinase PAK1 might be a new target of Ivermectin. This kinase is required for the growth of more than 70% of human cancers such as pancreatic, colon, breast and prostate cancers and NF (neurofibromatosis) tumors. Here we demonstrate for the first time that Ivermectin blocks the oncogenic kinase PAK1 in human ovarian cancer and NF2-deficient Schwannoma cell lines to suppress their PAK1-dependent growth in cell culture, with the IC50 between 5-20 MUM depending on cell lines. PMID- 22495655 TI - Transparent metal oxide nanowire transistors. AB - With the features of high mobility, a high electric on/off ratio and excellent transparency, metal oxide nanowires are excellent candidates for transparent thin film transistors, which is one of the key technologies to realize transparent electronics. This article provides a comprehensive review of the state-of-the-art research activities that focus on transparent metal oxide nanowire transistors. It begins with the brief introduction to the synthetic methods for high quality metal oxide nanowires, and the typical nanowire transfer and printing techniques with emphasis on the simple contact printing methodology. High performance transparent transistors built on both single nanowires and nanowire thin films are then highlighted. The final section deals with the applications of transparent metal oxide nanowire transistors in the field of transparent displays and concludes with an outlook on the current perspectives and future directions of transparent metal oxide nanowire transistors. PMID- 22495657 TI - Pyrrolizidine alkaloid clivorine-induced oxidative stress injury in human normal liver L-02 cells. AB - Clivorine is an otonecine-type pyrrolizidine alkaloid isolated from the traditional Chinese medicine Ligularia hodgsonii Hook. Pyrrolizidine alkaloids (PAs) are well-known hepatotoxins widely distributed around the world. The present study sought to evaluate clivorineinduced oxidative injury in human normal liver L-02 cells. After cells were treated with various concentrations of clivorine for 48 h, cellular total antioxidant capacity, glutathione-S transferase (GST) and glutathione reductase (GR) were determined to evaluate oxidative injury. Results showed that cellular total antioxidant capacity and GST activity both increased in clivorine-treated L-02 cells, while clivorine decreased GR activity in cells. Further, the protective effects of some antioxidants such as ascorbic acid (vitamin C, Vc), Trolox, dithiothreitol (DTT) and mannitol against clivorine-induced cytotoxicity were observed. Results showed that Trolox, which is an analogue of tocopherol (vitamin E, Ve), prevented clivorine-induced cytotoxicity in L-02 cells. Taken together, these results revealed clivorineinduced oxidative injury in human liver L-02 cells. These results also indicated the possible use of Trolox in the reduction of clivorine induced hepatotoxicity. PMID- 22495658 TI - Induction of immune responses to a human immunodeficiency virus type 1 epitope by novel chimeric influenza viruses. AB - Mucosal and systemic immune responses play an important role in the prevention of infections, including infection with human immunodeficiency virus type 1 (HIV-1). Influenza virus can efficiently induce mucosal and systemic immune responses, and thus, chimeric influenza viruses expressing the peptides derived from HIV-1 proteins have been generated to elicit immune responses against the inserted peptide. Novel chimeric influenza viruses were generated with full length of the V3-loop of gp120 or cytotoxic T-lymphocyte epitope of gag from HIV-1 inserted into the stalk of NA (NA-V3 and NA-gag, respectively) and the V3-loop was inserted into the intracellular domain of M2 (M2-V3). The immune responses of mice infected with these chimeric influenza viruses were investigated. The intranasal infection of NA-gag induced gag epitopespecific CTLs and the intranasal infection of NA-V3 and M2-V3 induced V3-specific antibodies. The serum from mice infected with NA-V3 neutralized a clinical isolate of HIV-1 and the infection of NA-V3 induced V3-specific secretory antibodies. These results suggest that intranasal infection of these chimeric influenza viruses could induce both humoral and cellular immune responses against an inserted foreign peptide and therefore could be a potential candidate for use as an HIV-1 vaccine. PMID- 22495659 TI - A microplate-based screening assay for neuraminidase inhibitors. AB - Neuraminidase (NA) represents a highly promising new target for drug development in influenza virus genes. Rapid screening of enzyme inhibitors is a key method for the identification of leading compounds. In order to speed up the screening for enzyme inhibitors of natural and synthetic origin, effective and fast assays are needed. 2'-(4-Methylumbelliferyl)-alpha-D-N-acetylneuraminic acid (4-MUNANA) was selected as substrate for development of a microplate-based assay. The enzymatic reaction conditions were optimized as follows: in a 100 MUL reaction mixture, the final concentrations were 32.5 mM sodium acetate (pH 3.5), 20 MUM 4 MUNANA, 0.005% (w/v) bovine serum albumin, and 0.42 MUg/mL NA. In the study, the doseresponse relationship of oseltamivir carboxylate to NA activity was observed. In addition, an overall Z' value of 0.8 proved the systems robustness and potential for screening. The assay system developed will be a valuable tool to discover new structures for the therapeutic inhibition of NA used to treat Influenza. PMID- 22495660 TI - In vitro evaluation of different transnasal formulations of sumatriptan succinate: A comparative analysis. AB - Sumatriptan succinate is an agonist for a vascular 5-hydroxytryptamine (5-HT)1 receptor subtype (probably a member of the 5-HT1D family). It does not have significant affinity for the remaining 5-HT receptors. It does not have affinity for alpha1, alpha2 or beta-adrenergic, dopamine1, dopamine2, muscarinic or benzodiazepine receptors. The objective of the study was to evaluate the in vitro transnasal absorption of sumatriptan succinate through sheep nasal mucosa and to determine its in vitro permeation behavior from various formulations containing penetration enhancers. In this study four different thermoreversible gel formulations designed for nasal delivery of sumatriptan succinate were formulated. The formulations were prepared by using a poly(oxythylene) poly(oxypropylene) block copolymer (Pluronic F 127) based gel along with different permeation enhancers and a pluronic lecithin organogel base. The effect of different concentrations of sodium glycocolate, EDTA and transcutol on in vitro nasal diffusion of sumatriptan succinate was studied. The best permeation profile was obtained with a formulation containing transcutol at a concentration of 0.005% w/w. Pluronic lecithin organogel showed good gelling properties at a concentration in the 20% range. PMID- 22495661 TI - Positive inotropic effect of PHR0007 (2-(4-(4-(Benzyloxy)-3 methoxybenzyl)piperazin-1-)-N-(1-methyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolin 7-yl)acetamide) on atrial dynamics in beating rabbit atria. AB - The aim of the present study was to examine the positive inotropic effects and mechanism of action of PHR0007 (2-(4-(4-(Benzyloxy)-3-methoxybenzyl)piperazin-1-) N-(1-methyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide) on beating rabbit atria. Atria were obtained from New Zealand white rabbits, and experiments performed using a perfused beating atrial model. The effects of PHR0007 (1, 30, or 100 MUmol/L), and of the protein kinase inhibitors, staurosporine (1.0 MUmol/L) or H-89 (10 MUmol/L), plus PHR0007 (30 MUmol/L), on atrial pulse pressure and stroke volume were analyzed. PHR0007 significantly increased atrial pulse pressure and atrial stroke volume in beating rabbit atria compared with control baseline levels. These effects of PHR0007 were completely blocked by pretreatment with either staurosporine (a nonspecific protein kinase inhibitor) or H-89 (a cAMP-dependent protein kinase A inhibitor). In addition, 3-isobutyl-1 methylxanthine (IBMX), a non-specific inhibitor of phosphodiesterases (PDEs), completely blocked the positive inotropic effect of PHR0007 on atrial dynamics, but forskolin, an activator of adenylyl cyclases (AC), failed to modulate PHR0007 induced increases in atrial pulse pressure and stroke volume. In conclusion, these data suggest that PHR0007 produces a positive inotropic effect in rabbit atria via the PDE-cAMP-PKA signaling pathway. PMID- 22495662 TI - Spicatic acid: A 4-carboxygentisic acid from Gentiana spicata extract with potential hepatoprotective activity. AB - Due to our interest in bioactive plant derived materials, the hepatoprotective activity of the aqueous alcoholic extract of Gentiana spicata AEGS (Gentianaceae) on carbon tetrachloride treated rats was investigated. CCl4 used at a concentration of 1 mL/kg.b.wt. significantly increased the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). However, pre treatment with AEGS and its individual components significantly prevented the increase in these enzymes, which are the major indicators of liver injury. Biochemical assays of liver homogenate showed that AEGS and its components restored reduced glutathione (GSH) depletion reduced the level of thiobarbituric acid reactive substances (TBARS). Furthermore, liver histological observation also showed an obvious amelioration in liver cell necrosis, liver lesions, and fatty changes in pre-treated groups. Phytochemical investigation of the extract showed high phenolic content and led to the isolation and identification of the new carboxygentisic acid, 1,4-dicarboxy 2,5-dihydroxybenzene, for which we suggest the name spicatic acid, together with the known flavonoids, quercetin 3-O [(2,3,4-triacetyl-alpha-rhamnopyranosyl)1'''->6''] 3-acetyl-beta galactopyranoside and quercetin 3-O-[(2,3,4-triacetyl-alpha-rhamnopyranosyl)1''' >6'']-4-acetyl-beta-galactopyranoside, epicatechin, catechin and their gallolyated derivatives. All structures were elucidated on the basis of conventional analytical methods and confirmed by high resolution ESIMS, 1D- and 2D-NMR data. The new phenolic 4-carboxygentisic acid, spicatic acid is of special interest as it represents the first phenolic acid in nature which bears two carboxyl functions in one aromatic ring. PMID- 22495663 TI - Development of implants for sustained release of 5-fluorouracil using low molecular weight biodegradable polymers. AB - Anticancer drugs have poor efficacy especially against solid tumors that hinder drug penetration into the tumor. Thus, the dose has to be increased, but toxicity is a limiting factor. Local administration of a polymeric biodegradable poly-L lactic acid (PLA) and poly(L-lactic acid-co-glycolic acid) copolymer (PLGA) implant containing an anticancer drug may be an acceptable method of concentrating the drug near the tumor site. This work sought to synthesize low molecular weight PLA and PLGA by polycondensation to yield polymers with good physical properties to make them suitable for use in implantable therapy. The synthesized polymers were characterized by determining their molecular weight, melting point, and percentage crystallinity using DSC. Fourier transformationinfra red spectrum (FT-IR), nuclear magnetic resonance (NMR) and specific optical rotation measurement were also used to characterize the synthesized polymers. Morphological characteristics were assessed using scanning electron microscopy (SEM). Implants were manufactured using compression (C) and injection molding (IM) and were loaded with 12 mg 5-fluorouracil (5-FU) per 120 mg implant. In vitro release patterns of all implants were assessed in phosphate buffered saline pH 7.4 (PBS 7.4) at 37 degrees C. Factors affecting the release of 5-FU from implants were the polymer species, manufacturing technique, drug particle size, drug concentration, implant dimensions, and coating of the implant. Implants prepared with PLGA had significantly faster release of 5-FU than those prepared with PLA. Those manufactured using compression had significantly faster drug release than those prepared by injection molding. A PLA implant that contained 12 mg 5-FU/120 mg with a diameter of 0.3 cm and that was loaded with a drug particle size smaller than 150 MUm and prepared by injection molding and then subsequently coated with PLA had the longest release period of 45 days. PMID- 22495664 TI - Thymoquinone triggers anti-apoptotic signaling targeting death ligand and apoptotic regulators in a model of hepatic ischemia reperfusion injury. AB - Thymoquinone (TQ) has been reported as a potent inducer of apoptosis in cancer cells. However, the role of TQ as an apoptotic or antiapoptotic has not been established yet in other types of cell injuries. Our objective was to explore whether TQ exerts a hepatoprotective effect against hepatic ischemia reperfusion injury (I/R) and to identify its potential effect on apoptotic pathways. Rats were divided into eight groups: group I: shamoperated; group II: I/R (45 min ischemia-60 min reperfusion). The other six groups were given PO administration of TQ aqueous solution at 5, 20, and 50 mg/kg/day dose levels for 10 days. At the end of treatment three groups were not subjected to any intervention (groups III, IV, and V: TQ control groups) or subjected to 45 min ischemia followed by one hour reperfusion as in group II (groups VI, VII, and VIII: TQ pretreated I/R groups). Serum levels of liver enzymes, tissue levels of malondialdehyde (MDA), reduced glutathione (GSH) and TNF-alpha were measured. Activities of caspases 8, 9, and 3 were determined. Cytochrome c in cytosol was determined by solid phase ELISA. Expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax proteins as well as nuclear factor kappaB (NF-kappaB) were assessed using polymerase chain reaction. Apoptosis end point was detected using electrophoresis for analysis of DNA fragmentation. TQ administration before I/R resulted in a significant decrease in liver enzymes, MDA and TNF-alpha tissue levels with increased GSH content. It also inhibited cytochrome c release into the cytosol, down regulated the expression of NF-kappaB and Bax and up regulated the Bcl-2 proteins. Hepatic apoptosis was significantly attenuated as indicated by a significant decrease in all caspase activities and by DNA fragmentation. In conclusion, TQ exerts an antiapoptotic effect through attenuating oxidative stress and inhibiting TNF alpha induced NF-kappaB activation. Furthermore, it regulates the Bcl-2/Bax ratio and inhibits downstream caspases in this I/R model. PMID- 22495665 TI - Promising therapy for Alzheimer's disease targeting angiotensinconverting enzyme and the cyclooxygense-2 isoform. AB - Deposition of beta-amyloid in brain is one of the pathological hallmarks of Alzheimer's disease (AD) that is often associated with inflammatory response. Much evidence also points to a link between the renin-angiotensin system, hypertension and dementia. Accordingly, the potential use of anti-inflammatory and antihypertensives might be beneficial agents in AD therapy. In this study, we investigated the possible mechanisms of Celecoxib (cyclooxygenase-2 (COX-2) inhibitor), Perindopril (angiotensin converting enzyme (ACE) inhibitor) and their combination in a lipopolysaccharide (LPS) model of AD. Mice were injected with LPS (0.8 mg/ kg, i.p.) once then divided into three groups: the first was treated with Celecoxib (30 mg/kg/day, i.p.), the second with Perindopril (0.5 mg/kg/day, i.p.) and the last group with a combination of both drugs. Learning and memory function were tested using a Y-maze and locomotor activity was assessed using an open-field test. Cerebral specimens were subjected to histopathological studies. Brain tumor necrosis factor alpha (TNF-alpha), and interleukin (IL)-1beta levels were measured. LPS decreased locomotor activity and percentage of correct choices in the Y-maze test. It also produced a significant increase in the percentage area of vascular angiopathy, area of lamellated plaques, and apoptotic index. These were associated with increased TNF-alpha and IL-1beta. Administration of either Celecoxib or Perindopril partially improved cognitive impairment, decreased inflammatory cytokines and amyloid deposition. Combined therapy of both drugs completely prevented LPS induced neurodegenerative and cognitive changes. In conclusion, these findings establish a link between COX-2, ACE activity and cognitive impairment in AD and provided a promising strategy for the complete cure of AD. PMID- 22495666 TI - Differentiation of raw spirits of rye, corn and potato using chromatographic profiles of volatile compounds. AB - BACKGROUND: The origin of the raw spirits influences the sensory quality of rectified spirits that are subsequently used for the production of vodka. The aim of this research was to evaluate the effectiveness of two methods based on the comparison of profiles of volatile compounds [solid phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) and gas chromatography with flame ionisation detection (GC-FID)] for the determination of origin of raw spirits obtained from rye, corn (maize) and potato. RESULTS: Profiles obtained for the volatile compounds by using these methods were different and were influenced by the sample introduction method. The main groups of volatiles obtained using SPME GC-MS method were fatty acid ethyl esters, while in the case of GC-FID fusel alcohols and ethyl acetate dominated. Data obtained from these methods were treated using principal component analysis and linear discriminant analysis to test the possibility of sample differentiation and classification. It was relatively easy to differentiate potato spirits from the remainder; however, it was not possible to fully distinguish the corn samples from rye samples. The classification ability of the SPME-GC-MS method was 95% but the prediction ability was 97.4%. For the GC-FID method the classification ability was 90.1%, whereas the prediction ability was 94.27%. CONCLUSIONS: The methods presented can be used for reliable differentiation of potato spirits from corn and rye spirits. PMID- 22495667 TI - Outpatient prescriptions practice and writing quality in a paediatric university hospital. AB - BACKGROUND: The writing of prescriptions is an important aspect of medical practice. This activity presents some specific problems given a danger of misinterpretation and dispensing errors in community pharmacies. The objective of this study was to determine the evolution of the prescription practice and writing quality in the outpatient clinics of our paediatric university hospital. METHODS: Copies of prescriptions written by physicians were collected from community pharmacies in the region of our hospital for a two-month period in 2005 and 2010. They were analysed according to standard criteria, including both formal and pharmaceutical aspects. RESULTS: A total of 597 handwritten prescriptions were reviewed in 2005 and 633 in 2010. They contained 1,456 drug prescriptions in 2005 and 1,348 in 2010. Fifteen drugs accounted for 80% of all prescriptions and the most common drugs were paracetamol and ibuprofen. A higher proportion of drugs were prescribed as International Nonproprietary Names (INN) or generics in 2010 (24.7%) compared with 2005 (20.9%). Of the drug prescriptions examined, 55.5% were incomplete in 2005 and 69.2% in 2010. Moreover in 2005, 3.2% were legible only with difficulty, 22.9% were ambiguous, and 3.0% contained an error. These proportions rose respectively to 5.2%, 27.8%, and 6.8% in 2010. CONCLUSION: This study showed that fifteen different drugs represented the majority of prescriptions, and a quarter of them were prescribed as INN or generics in 2010; and that handwritten prescriptions contained numerous omissions and preventable errors. In our hospital computerised prescribing coupled with advanced decision support is eagerly awaited. PMID- 22495668 TI - Melanoma in the brain: biology and therapeutic options. AB - The development of brain metastases is a frequent occurrence in patients with disseminated melanoma and contributes to a disproportionate degree of morbidity and mortality. The prognosis is markedly reduced once a patient is diagnosed with central nervous system disease. Definitive therapeutic interventions with resection or stereotactic radiosurgery have improved outcomes and become standard approaches in the management of melanoma brain metastases. With the inclusion of whole-brain radiation in these interventions, there has been a reduction in local recurrences, but no improvement in the overall survival. Still, many patients are not candidates for surgery nor radiotherapy nor develop progressive central nervous system disease after definitive therapy. As new immune-based and targeted therapeutic agents are developed for the treatment of metastatic melanoma, understanding their activity in brain metastases is necessary for effective patient management. In this review, we discuss the biology of brain metastases in metastatic melanoma, current treatment approaches with surgery and radiotherapy, and future systemic therapeutic strategies. PMID- 22495669 TI - A murine monoclonal antibody directed against the carboxyl-terminal domain of GRP78 suppresses melanoma growth in mice. AB - The HSP70 family member GRP78 is a selective tumor marker upregulated on the surface of many tumor cell types, including melanoma, where it acts as a growth factor receptor-like protein. Receptor-recognized forms of the proteinase inhibitor alpha2-macroglobulin (alpha2M*) are the best-characterized ligands for GRP78, but in melanoma and other cancer patients, autoantibodies arise against the NH2-terminal domain of GRP78 that react with tumor cell-surface GRP78. This causes the activation of signaling cascades that are proproliferative and antiapoptotic. Antibodies directed against the COOH-terminal domain of GRP78, however, upregulate p53-mediated proapoptotic signaling, leading to cell death. Here, we describe the binding characteristics, cell signaling properties, and downstream cellular effects of three novel murine monoclonal antibodies. The NH2 terminal domain-reactive antibody, N88, mimics alpha2M* as a ligand and drives PI 3-kinase-dependent activation of Akt and the subsequent stimulation of cellular proliferation in vitro. The COOH-terminal domain-reactive antibody, C38, acts as an antagonist of both alpha2M* and N88, whereas another, C107, directly induces apoptosis in vitro. In a murine B16F1 melanoma flank tumor model, we demonstrate the acceleration of tumor growth by treatment with N88, whereas C107 significantly slowed tumor growth whether administered before (P<0.005) or after (P<0.05) tumor implantation. PMID- 22495670 TI - Sphere formation and self-renewal capacity of melanoma cells is affected by the microenvironment. AB - Melanomas contain subsets of cancer stem-like cells with tumor-initiating capacity. The frequency of these cells in the tumor is still a topic of debate. We investigated the phenotypic plasticity of cancer cells grown as melanospheres to elucidate the influence of the microenvironment on some features of melanoma stem-like cells. Cells from surgical specimens of nodular melanoma were grown as anchorage-independent melanospheres in a stem cell medium and as adherent monolayer cultures in the presence of serum. Proliferation and viability were measured by cell counting and an acid phosphatase assay; surface marker expression was evaluated by flow cytometry, and the clonogenic potential of single cells was assessed by growth in soft agar. Patient-derived melanoma cells could be maintained in cell culture for more than 16 months when grown as melanospheres. In the presence of serum, melanospheres completely changed their growth characteristics and formed adherent monolayers. The transition from melanospheres to monolayers was accompanied by an apparent loss of clonogenic potential, an increased proliferation rate, and altered expressions of cell surface markers ABCB5, CD133, and CD49f. These changes, however, were reversible. Compared with adherent monolayer cultures, melanospheres are enriched in cells with clonogenic potential, reflecting the self-renewing capacity of cancer stem like cells. This clonogenic potential can be lost and regained depending on the growth conditions. Our results demonstrate how easily melanoma cells change their function upon exposure to external stimuli and suggest that the frequency of melanoma stem-like cells strongly depends on the microenvironment. PMID- 22495671 TI - Prematurely elevating estradiol in early baboon pregnancy suppresses uterine artery remodeling and expression of extravillous placental vascular endothelial growth factor and alpha1beta1 and alpha5beta1 integrins. AB - We previously showed that advancing the increase in estradiol levels from the second to the first third of baboon pregnancy suppressed placental extravillous trophoblast (EVT) invasion and remodeling of the uterine spiral arteries. Cell culture studies show that vascular endothelial cell growth factor (VEGF) plays a central role in regulating EVT migration and remodeling of the uterine spiral arteries by increasing the expression/action of certain integrins that control extracellular matrix remodeling. To test the hypothesis that the estradiol induced reduction in vessel remodeling in baboons is associated with an alteration in VEGF and integrin expression, extravillous placental VEGF and integrin expression was determined on d 60 of gestation (term is 184 d) in baboons in which uterine artery transformation was suppressed by maternal estradiol administration on d 25-59. EVT uterine spiral artery invasion was 5 fold lower (P < 0.01), and VEGF protein expression, quantified by in situ proximity ligation assay, was 50% lower (P < 0.05) in the placenta anchoring villi of estradiol-treated than in untreated baboons. alpha1beta1 and alpha5beta1 mRNA levels in cells isolated by laser capture microdissection from the anchoring villi and cytotrophoblastic shell of estradiol-treated baboons were over 2-fold (P < 0.01) and 40% (P < 0.05) lower, respectively, than in untreated animals. In contrast, placental extravillous alphavbeta3 mRNA expression was unaltered by estradiol treatment. In summary, extravillous placental expression of VEGF and alpha1beta1 and alpha5beta1 integrins was decreased in a cell- and integrin specific manner in baboons in which EVT invasion and remodeling of the uterine spiral arteries were suppressed by prematurely elevating estradiol levels in early pregnancy. We propose that estrogen normally controls the extent to which the uterine arteries are transformed by placental EVT in primate pregnancy by regulating expression of VEGF and particular integrin extracellular remodeling molecules that mediate this process. PMID- 22495672 TI - Mechanism of prostacyclin-induced potentiation of glucose-induced insulin secretion. AB - Arachidonic acid metabolites are crucial mediators of inflammation in diabetes. Although eicosanoids are established modulators of pancreatic beta-cell function, the role of prostacyclin (prostaglandin I2) is unknown. Therefore, this study aimed to analyze the role of prostacyclin in beta-cell function. Prostacyclin synthase (PGIS) was weakly expressed in rat islet cells but nevertheless significantly increased by incubation with 30 mM glucose, especially in non-beta cells. PGIS was overexpressed in INS1E cells, and the regulation of insulin secretion was analyzed. PGIS overexpression strongly potentiated glucose-induced insulin secretion along with increased insulin content and ATP production. Importantly, overexpression of PGIS potentiated only nutrient-induced insulin secretion. The effect of PGIS overexpression was mediated by prostacyclin released from insulin-secreting cells and dependent on prostacyclin receptor (IP receptor) activation, with concomitant cAMP production. The cAMP-mediated potentiation of glucose-induced insulin secretion by prostacyclin was independent of the protein kinase A pathway but strongly attenuated by the knockdown of the exchange protein directly activated by cAMP 2 (Epac2), pointing to a crucial role for Epac2 in this process. Thus, prostacyclin is a powerful potentiator of glucose-induced insulin secretion. It improves the secretory capacity by inducing insulin biosynthesis and probably by stimulating exocytosis. Our findings open a new therapeutical perspective for an improved treatment of type 2 diabetes. PMID- 22495673 TI - Identification of critical residues involved in ligand binding and G protein signaling in human somatostatin receptor subtype 2. AB - G protein signaling through human somatostatin receptor subtype 2 (SSTR2) is well known, but the amino acids involved in stimulation of intracellular responses upon ligand binding have not been characterized. We constructed a series of point mutants in SSTR2 at amino acid positions 89, 139, and 140 in attempts to disrupt G protein signaling upon ligand binding. The aspartic acid changes at position 89 to either Ala, Leu, or Arg generated mutant receptors with varying expression profiles and a complete inability to bind somatostatin-14 (SST). Mutations to Asp 139 and Arg 140 also led to varying expression profiles with some mutants maintaining their affinity for SST. Mutation of Arg 140 to Ala resulted in a mutated receptor that had a B(max) and dissociation constant (K(d)) similar to wild-type receptor but was still coupled to the G protein as determined in both a cAMP assay and a calcium-release assay. In contrast, mutation of Asp 139 to Asn resulted in a mutated receptor with B(max) and K(d) values that were similar to wild type but was uncoupled from G protein-mediated cAMP signaling, but not calcium release. Thus, we identified mutations in SSTR2 that result in either receptor expression levels that are similar to wild type but is completely ablated for ligand binding or a receptor that maintains affinity for SST and is uncoupled from G protein-mediated cAMP signaling. PMID- 22495675 TI - Peritonitis activates transcription of the human prolactin locus in myeloid cells in a humanized transgenic rat model. AB - Prolactin (PRL) is mainly expressed in the pituitary in rodents, whereas in humans, expression is observed in many extrapituitary sites, including lymphocytes. Due to the lack of adequate experimental models, the function of locally produced PRL in the immune system is largely unknown. Using transgenic rats that express luciferase under the control of extensive human PRL regulatory regions, we characterized immune cell responses to thioglycollate (TG)-induced peritonitis. Resident populations of myeloid cells in the peritoneal cavity of untreated rats expressed barely detectable levels of luciferase. In contrast, during TG-induced peritonitis, cell-specific expression in both neutrophils and monocytes/macrophages in peritoneal exudates increased dramatically. Elevated luciferase expression was also detectable in peripheral blood and bone marrow CD11b(+) cells. Ex vivo stimulation of primary myeloid cells showed activation of the human extrapituitary promoter by TNF-alpha, lipopolysaccharide, or TG. These findings were confirmed in human peripheral blood monocytes, showing that the transgenic rat provided a faithful model for the human gene. Thus, the resolution of an inflammatory response is associated with dramatic activation of the PRL gene promoter in the myeloid lineage. PMID- 22495674 TI - Minireview: G protein-coupled estrogen receptor-1, GPER-1: its mechanism of action and role in female reproductive cancer, renal and vascular physiology. AB - Using cDNA cloning strategies commonly employed for G protein-coupled receptors (GPCR), GPCR-30 (GPR30), was isolated from mammalian cells before knowledge of its cognate ligand. GPR30 is evolutionarily conserved throughout the vertebrates. A broad literature suggests that GPR30 is a Gs-coupled heptahelical transmembrane receptor that promotes specific binding of naturally occurring and man-made estrogens but not cortisol, progesterone, or testosterone. Its "pregenomic" signaling actions are manifested by plasma membrane-associated actions familiar to GPCR, namely, stimulation of adenylyl cyclase and Gbetagamma-subunit protein dependent release of membrane-tethered heparan bound epidermal growth factor. These facts regarding its mechanism of action have led to the formal renaming of this receptor to its current functional designate, G protein-coupled estrogen receptor (ER) (GPER)-1. Further insight regarding its biochemical action and physiological functions in vertebrates is derived from receptor knockdown studies and the use of selective agonists/antagonists that discriminate GPER-1 from the nuclear steroid hormone receptors, ERalpha and ERbeta. GPER-1-selective agents have linked GPER-1 to physiological and pathological events regulated by estrogen action, including, but not limited to, the central nervous, immune, renal, reproductive, and cardiovascular systems. Moreover, immunohistochemical studies have shown a positive association between GPER-1 expression and progression of female reproductive cancer, a relationship that is diametrically opposed from ER. Unlike ER knockout mice, GPER-1 knockout mice are fertile and show no overt reproductive anomalies. However, they do exhibit thymic atrophy, impaired glucose tolerance, and altered bone growth. Here, we discuss the role of GPER-1 in female reproductive cancers as well as renal and vascular physiology. PMID- 22495676 TI - Estimating the annual economic burden of illness caused by contact lens associated corneal infiltrative events in the United States. AB - OBJECTIVES: The aim of this study was to estimate the annual cost of illness caused by contact lens-associated corneal infiltrative events (CL-CIEs) among soft CL wearers in the United States. METHODS: This study was conducted in the United States. The study population was comprised of daily wear contact lens users in the United States, which number approximately 35 million. A comprehensive review of the medical literature for data on the annual incidence of CL-CIEs was conducted. Cost estimates were drawn from the literature and published tariffs. The perspective of the study was a U.S. healthcare perspective and because of the short duration of most CL-CIEs, no discounting was performed. The main outcome measure involved the total annual number of persons with CL-CIEs and associated direct and indirect costs. RESULTS: In the United States in 2010, it was calculated that a total of 32,031 nonsevere and 17,248 severe CL-CIEs occurred, respectively. The cost per nonsevere and severe CL-CIEs was estimated to be $1,002.90 and $1,496.00, respectively. Overall, the total estimated direct and indirect cost of nonsevere CL-CIEs and severe CL-CIEs in the United States in 2010 was estimated to be $58 million. CONCLUSIONS: This study estimated the economic burden of illness imposed by CL-CIEs on both the healthcare system and individual patients in the United States. Strategies designed to minimize the occurrence and impact of CL-CIEs, such as using improved lens care regimens and lens case management, the use of daily disposable lenses, and more efficacious ocular antibiotics may be beneficial in reducing this economic burden. PMID- 22495677 TI - Stromal melting associated with a cosmetic contact lens over a Boston keratoprosthesis: treatment with a conjunctival flap. AB - OBJECTIVES: The aim was to discuss the use of a conjunctival flap for treatment of keratolysis of a keratoprosthesis (Kpro) donor graft in a patient fitted with a cosmetic contact lens. METHODS: Keratolysis developed in the donor graft of a Boston Kpro; this was associated with the use of a cosmetic contact lens. A conjunctival flap was used to stabilize the graft. The literature is reviewed for similar cases, and the rationale for the intervention is described and discussed. RESULTS: Reinforcement of the graft with a conjunctival flap resulted in an arrest in stromal melting and stabilization of visual acuity. CONCLUSIONS: Low Dk opaque contact lenses may be a risk factor for keratolysis after Kpro. A conjunctival flap technique can provide stabilization of keratolysis with arrest of corneal melting and merits further study. PMID- 22495678 TI - Bacterial contaminants of bandage contact lenses used after laser subepithelial or photorefractive keratectomy. AB - PURPOSE: To compare the locations and types of bacterial contamination of bandage disposable soft contact lenses after laser subepithelial keratectomy (LASEK) and photorefractive keratectomy (PRK). METHODS: Bandage disposable soft contact lenses were collected with sterile forceps from 30 eyes of 15 consecutive patients treated with LASEK (LASEK group) and 30 eyes of 15 consecutive patients who underwent PRK (PRK group) to correct myopia. Immediately after collection, each lens was cut in two parts with sterile scissors and placed onto chocolate agar with one piece outer face down and the inner face down for the other piece. The lenses were analyzed for bacterial colonization and evaluated for the amount of growth on the inner face and outer face, respectively. The antibiotic susceptibility tests were performed for the isolates using disk diffusion. RESULTS: Five positive cultures (16.7%) were found in LASEK group: 4 appeared in the inner face of the lens and1 appeared in the outer face. In PRK group, 2 of the 30 contact lenses (6.67%) had positive cultures; both of them appeared in the outer face of the lens. The difference of positive culture rate in the two groups was not statistically significant (chi=1.46, P=0.228). When comparing the positive colonization rate in location, the positive culture rate in the inner face of LASEK group was statistically significantly higher than that of PRK group (13.3% vs. 0%, chi=4.29, P=0.038); however, no clinical finding of infection was noted. In both groups, methicillin-sensitive coagulase-negative staphylococci (MSSCoN) were the most common isolate. Besides MSSCoN, the growth of methicillin resistant coagulase-negative staphylococci, Corynebacterium, and Micrococcus were also present in this study. All the microorganisms were sensitive to tobramycin, which was used in conjunction with dexamethasone to treat the cases. CONCLUSIONS: Previous literature reports that the risk of infectious keratitis after LASEK or PRK is relatively low. However, within this study, the rate of positive cultures was relatively higher in LASEK group (16.7%) compared with that of PRK group (6.67%), especially in the inner face of the lens. The reason may be related to the procedure of keeping the epithelial flap in place, which could develop a local environment suitable for bacterial colonization and potential infection. Coagulase-negative staphylococci, a major element of the natural conjunctival flora, remain a major potentially infectious agent after LASEK and PRK. PMID- 22495679 TI - The prevalence and impact of high myopia. AB - Myopia has gained increasing interest in recent years, particularly because of its increase in prevalence across populations worldwide. The onset of myopia has shifted to a younger age, and the number of high myopes with prescriptions of more than -5.00 D has increased over the last few decades. High myopia is strongly associated with a greater incidence of pathologic complications, has shown to impact vision-related quality of life in children and adults and is further associated with certain contact lens complications. Different pharmaceutical and optical treatment options are currently under investigation with a common goal to slow down the rate of myopia progression. PMID- 22495680 TI - Pan-antimicrobial failure of alexidine as a contact lens disinfectant when heated in Bausch & Lomb plastic containers: implications for the worldwide Fusarium keratitis epidemic of 2004 to 2006. AB - OBJECTIVE: ReNu with MoistureLoc (ReNuML), containing the antimicrobial agent alexidine 0.00045%, was associated with the Fusarium keratitis epidemic of 2004 to 2006. Although a single-point source contamination was ruled out, only Fusarium organisms were reported during the outbreak. This study investigated whether the reported loss of antimicrobial effectiveness toward Fusarium of ReNuML after exposure to heat in high-density polyethylene (HDPE) plastic containers could also be demonstrated with other common fungal and bacterial agents of keratitis. METHODS: A buffered solution of alexidine 0.00045% was incubated in glass and ReNu HDPE plastic containers at room temperature (RT) and 56 degrees C for 4 weeks, serially diluted, and tested for its ability to inhibit the growth of 20 bacterial isolates, 12 non-Fusarium fungal isolates, and 7 Fusarium isolates originally involved in the keratitis epidemic. RESULTS: A statistically significant loss of antimicrobial capability was seen with all fungi, all gram-positive bacteria, and all isolates of Klebsiella when alexidine 0.00045% was incubated at 56 degrees C in ReNu HDPE containers compared with RT or glass incubation (P<=0.0001). CONCLUSIONS: Heating of an alexidine solution in ReNu HDPE plastic (but not glass) containers results in the same loss of anti Fusarium activity as reported when testing the original ReNuML solution. This loss of inhibitory activity is not specific to Fusarium and occurs with other fungi and bacteria that cause keratitis. The reasons for the lack of reports of bacterial and/or non-Fusarium fungal keratitis during the original Fusarium keratitis epidemic remain unclear at this time. PMID- 22495681 TI - Malformations of cortical development: diagnostic accuracy of fetal MR imaging. AB - PURPOSE: To determine the diagnostic accuracy of fetal magnetic resonance (MR) imaging for malformations of cortical development by using postnatal MR imaging as reference standard. MATERIALS AND METHODS: Eighty-one patients who had undergone fetal and postnatal MR imaging of the brain were identified in this institutional review board-approved, HIPAA-compliant study. Images were retrospectively reviewed in consensus by two pediatric neuroradiologists who were blinded to clinical information. Sensitivity and specificity were calculated according to retrospective review of the images and clinical reports for fetal MR images. The Fisher exact test was used to compare results for fetuses imaged before and after 24 gestational weeks and for image review versus clinical reports for fetal MR images. RESULTS: Median gestational age at fetal MR imaging was 25.0 weeks (range, 19.71-38.14 weeks). Postnatal MR imaging depicted 13 cases of polymicrogyria, three cases of schizencephaly, and 15 cases of periventricular nodular heterotopia. Sensitivity and specificity of fetal MR imaging were 85% and 100%, respectively, for polymicrogyria; 100% each for schizencephaly; and 73% and 92%, respectively, for heterotopia. When heterotopia was seen in two planes, specificity was 100% and sensitivity was 67%. Sensitivity for heterotopia decreased to 44% for fetuses younger than 24 weeks. According to reports for fetal MR images, prospective sensitivity and specificity, respectively, were 85% and 99% for polymicrogyria, 100% and 99% for schizencephaly, and 40% and 91% for heterotopia. CONCLUSION: Fetal MR imaging had the highest sensitivity for polymicrogyria and schizencephaly. Specificity was 100% for all cortical malformations when the abnormality was seen in two planes. Sensitivity for heterotopia was lower for fetuses younger than 24 weeks. Knowledge of the gestational age is important, especially for counseling patients about heterotopia. PMID- 22495682 TI - Cardioembolic stroke: dual-energy cardiac CT for differentiation of left atrial appendage thrombus and circulatory stasis. AB - PURPOSE: To assess the diagnostic performance of dual-energy cardiac computed tomography (CT) in the detection of left atrial appendage (LAA) thrombi and differentiation between thrombus and circulatory stasis in patients with stroke, by using transesophageal echocardiography (TEE) as the reference standard. MATERIALS AND METHODS: The institutional review board approved this study, and patients provided informed consent. Thirty-two patients with stroke who had atrial fibrillation (AF) and either thrombus or the spontaneous echo contrast (SEC) echo pattern at TEE were prospectively enrolled. For the control group, 31 patients who were planning to undergo AF ablation and who had no abnormalities at TEE were enrolled. All patients underwent dual-energy cardiac CT that was not electrocardiographically gated. For quantitative analysis, iodine concentration was measured on CT images. The statistical significance of differences in mean iodine concentration between thrombus and SEC as measured at CT was assessed by using the Student t test. RESULTS: Among the 63 patients, a total of 13 thrombi and 19 instances of SEC were detected at TEE. Using TEE as the reference standard, the overall sensitivity, specificity, positive predictive value, and negative predictive value of dual-energy cardiac CT in the detection of thrombi and SEC in the LAA were 97% (95% confidence interval [CI]: 82%, 100%), 100% (95% CI: 86%, 100%), 100%, and 97%, respectively. At CT, the mean iodine concentration was 1.23 mg/mL +/- 0.34 (standard deviation) for thrombus and 3.61 mg/mL +/- 1.01 for SEC (P = .001). CONCLUSION: Dual-energy cardiac CT is a highly sensitive modality for detecting LAA thrombus and for differentiating thrombus from SEC in patients with stroke. PMID- 22495683 TI - Detection of urothelial tumors: comparison of urothelial phase with excretory phase CT urography--a prospective study. AB - PURPOSE: To compare contrast material-enhanced computed tomographic (CT) urography 60 seconds after injection of contrast material (urothelial phase [UP]) after intravenous administration of a diuretic with the standard 5-minute delayed excretory phase (EP) in a high-risk population for upper tract tumors. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Eighty CT urographic examinations in 77 patients known to have or at high risk for urothelial malignancy were included. After intravenous administration of a diuretic, dual-phase CT urography was performed at 60 seconds (UP) and 5 minutes (EP) after intravenous administration of contrast material. Two experienced abdominal radiologists independently interpreted each phase more than 1 month apart to minimize recall bias. Urinary tract distention and location and size of all lesions suspected of being urothelial tumors were recorded. Standard of reference was obtained from prospective study interpretation and surgical histopathologic findings. Generalized estimating equations for logistic regression were used to compare performance measures and adjust for the correlation of repeated measures within patients. RESULTS: There were 23 upper and 61 lower urinary tract tumors confirmed in 15 and 32 patients, respectively. For detection of bladder tumors, there was higher sensitivity for the UP than the EP (89.3% [109 of 122] vs 70.5% [86 of 122], respectively; P<.0001). For detection of upper tract tumors, there was higher sensitivity for the UP than the EP (82.6% [38 of 46] vs 69.6% [32 of 46], respectively; P=.0194). Distention of all upper urinary tract segments was better during the EP than the UP (P<.0001). CONCLUSION: UP CT urography after injection of a diuretic has a higher lesion detection rate than the EP for both upper and lower urinary tract tumors, which suggests its possible use as a single-phase protocol for evaluation of the entire urinary tract in patients at high risk for urothelial tumors. PMID- 22495684 TI - US-guided percutaneous microwave ablation of renal cell carcinoma: intermediate term results. AB - PURPOSE: To retrospectively review intermediate-term (median, 20.1 months) clinical outcomes after microwave ablation (MWA) of renal cell carcinoma (RCC). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board. The results from 46 patients with 49 RCC nodules (diameter, 0.6-7.7 cm; mean, 3.0 cm +/- 1.5 [standard deviation]) treated with ultrasonography (US) guided percutaneous MWA with cooled-shaft needle antenna from April 2006 to December 2010 were reviewed. One antenna was used for tumors smaller than 2 cm; two, for tumors 2 cm or larger. The patients were followed up with contrast material-enhanced US and computed tomography or magnetic resonance imaging at 1, 3, and 6 months and every 6 months thereafter. The effect of changes in key parameters (including overall survival, disease-free survival, and local tumor progression rate) was statistically analyzed by using the log-rank test. RESULTS: Technical effectiveness (complete ablation at follow-up enhanced imaging 1 month after MWA) was achieved in 48 of 49 (98.0%) tumors, and the metastasis-free rate was 100% (46 of 46). The 1-, 2-, and 3-year local tumor progression rates were 4.6%, 7.7%, and 7.7%, respectively. The cancer-specific survival rate was 100% (46 of 46), and 1-, 2-, and 3-year overall survival rates were 100%, 100%, and 97.8%, respectively. The 1-, 2-, and 3-year disease-free survival rates were 95.4%, 92.3%, and 92.3%, respectively. No major complications occurred. Multivariate analysis showed that tumor number (P = .046), tumor growth patterns (P = .003), and ablation time (P = .04) were independent unfavorable prognostic factors. CONCLUSION: In the intermediate term, US-guided percutaneous MWA appears to be a safe and effective technique for the management of RCC, especially small RCC, in selected patients. PMID- 22495685 TI - Spastic cerebral palsy in children: dynamic sonoelastographic findings of medial gastrocnemius. AB - PURPOSE: To study the elastic properties of the medial gastrocnemius (GCM) in children with spastic cerebral palsy. MATERIALS AND METHODS: The study protocol was approved by the Research Ethics Committee of the hospital, and informed consent was obtained from each child's parent. Fifteen children with spastic cerebral palsy (group 1) and 13 children without neurologic and musculoskeletal disabilities (group 2) were included. Because group 1 included three children with hemiplegia, the total number of legs examined was 27. Children in group 2 had both legs examined, for a total of 26 legs studied. The modified Ashworth scale score of the ankle in group 1 was assessed by a physical therapist. A physiatrist performed ultrasonography and dynamic sonoelastography (DS) together, measured the thickness of the GCM, and calculated the GCM ratio in both groups. On color-scaled DS images, the DS score of the GCM was graded from DS 1 (purple to green: soft) to DS 4 (red: stiff), and the color histogram of the GCM was subsequently analyzed. Strain ratio and local shear wave velocity were calculated in the GCM and the soleus muscle by using acoustic radiation force impulse imaging. RESULTS: The GCM ratio in group 1 was significantly smaller than that in group 2. The DS score of GCM in group 1 was significantly higher than that in group 2. The median red pixel values were significantly higher, and the blue pixel values were significantly lower on color histogram in group 1 than those in group 2. The strain ratio in group 1 was significantly lower than that in group 2, and the local shear wave velocity of GCM in group 1 was higher than that in group 2. There were significant correlations between the modified Ashworth scale scores and DS parameters. CONCLUSION: DS demonstrated a difference in muscle stiffness in the GCM between children with spastic cerebral palsy and those without neurologic and musculoskeletal disabilities. PMID- 22495686 TI - Osteoradionecrosis of the upper cervical spine after radiation therapy for head and neck cancer: differentiation from recurrent or metastatic disease with MR imaging. AB - PURPOSE: To compare the magnetic resonance (MR) imaging features of upper cervical spine osteoradionecrosis (ORN) with those of recurrent or metastatic disease after the treatment of head and neck malignancies. MATERIALS AND METHODS: This retrospective study was approved by the hospital institutional review board, and the requirement to obtain informed consent was waived. From January 2005 to December 2010, 35 patients who had undergone irradiation of head and neck cancer and who had subsequent C1 or C2 lesions at MR imaging were enrolled. Pathology reports, clinical records, and follow-up MR images were reviewed to classify patients into one of two groups-those with ORN or those with recurrence. The MR imaging characteristics in these patients were evaluated. Statistical significance of intergroup differences was assessed by means of the Pearson chi2 or Fisher exact test for categorical variables and the two-sample t test for continuous variables. RESULTS: ORN was diagnosed in 20 of the 35 patients (57%), and recurrent or metastatic disease was diagnosed in 15 (43%). Ten of the 35 patients (29%) had undergone biopsy of the cervical spine or paraspinal soft tissue. The MR images in the ORN group showed significantly more contiguous involvement of the atlantoaxial or atlanto-occipital bones with intervening joint change (P<.001), more cases of vertebral body collapse (P<.01), more bilateral symmetric involvement of the vertebral body (P<.01), and continuation of vertebral body changes with posterior pharyngeal wall ulceration (P<.01). Posterior arch or other cervical level involvement, paraspinal solid mass, epidural involvement, lateral border cortical destruction, and cervical lymphadenopathy were noted more frequently in the recurrence group than in the ORN group (P=.03, P<.001, P=.02, P<.001, and P<.01, respectively). CONCLUSION: Various MR imaging characteristics can be used to help differentiate between cervical ORN and recurrent disease. PMID- 22495687 TI - Degree of sialylation and fucosylation of plasma and amniotic immunoglobulin G changes progressively during normal pregnancy. AB - OBJECTIVE: Terminal-located glycotopes on immunoglobulin G (IgG) are potential ligands engaged in the interactions that may modulate the biological activities of IgG. The expressions of sialic acid and fucose residues on amniotic IgG were evaluated here in relation to the progression of normal human pregnancy. METHODS: Sialyl-glycotope and fucosyl-glycotope expressions on maternal plasma and amniotic IgG were determined by lectin-IgG-ELISA. RESULTS: The amniotic and maternal plasma IgG concentrations and a degree of alpha2,6-sialylation and alpha1,6-fucosylation of maternal plasma IgG were almost unaltered during the normal pregnancy. The plasma IgG of pregnant and nonpregnant women did not contain alpha2,3-linked sialic acid and alpha1,3-linked and alpha1,2-linked fucoses. In contrast, the amniotic IgG from the second trimester was decorated by alpha2,3-linked sialic acids, alpha2,6-linked sialic acids, and alpha1,6-linked fucose, whereas the alpha1,3-linked and alpha1,2-linked fucoses were weakly expressed. During 35-37 weeks of gestation, all the parameters increased significantly, and they remained almost at the same levels throughout 35-42 weeks, including the delivery. However, they were significantly higher in the postdate pregnancy group. CONCLUSION: The degree of sialylation and fucosylation of amniotic IgG was associated with the progression of normal pregnancy. PMID- 22495690 TI - Novel TiO2-Pt@SiO2 nanocomposites with high photocatalytic activity. AB - This article reports a facile and controllable two-step method to construct TiO(2)-Pt@SiO(2) nanocomposites. TiO(2) nanoparticles (NPs), with small size and high surface energy, were synthesized by a solvothermal reaction process. The TiO(2)-Pt@SiO(2) nanocomposites were fabricated by a reverse micro-emulsion method. SiO(2) shell coated NPs were adopted for further photocatalytic reaction. Because of their small size and high surface energy, TiO(2)@SiO(2) and TiO(2) Pt@SiO(2) nanocomposites show higher photocatalytic activity than commercial Degussa P25. Compared with TiO(2)@SiO(2), TiO(2)-Pt@SiO(2)nanocomposites have improved photocatalytic activity due to the Pt induced spatial separation of electrons and holes. The silica shells not only maintain the structure of the nanocomposites but also prevent their aggregation during the photocatalytic reactions, which is highly important for the good durability of the photocatalyst. This strategy is simple, albeit efficient, and can be extended to the synthesis of other composites of noble metals. It has opened a new window for the construction of hetero-nanocomposites with high activity and durability, which would serve as excellent models in catalytic systems of both theoretical and practical interest. PMID- 22495689 TI - Functional impairment, illness burden, and depressive symptoms in older adults: does type of social relationship matter? AB - OBJECTIVE: The nature of interpersonal relationships, whether supportive or critical, may affect the association between health status and mental health outcomes. We examined the potential moderating effects of social support, as a buffer, and family criticism, as an exacerbating factor, on the association between illness burden, functional impairment and depressive symptoms. METHODS: Our sample of 735 older adults, 65 years and older, was recruited from internal and family medicine primary care offices. Trained interviewers administered the Hamilton Rating Scale for Depression, Duke Social Support Inventory, and Family Emotional Involvement and Criticism Scale. Physician-rated assessments of health, including the Karnofsky Performance Status Scale and Cumulative Illness Rating Scale, were also completed. RESULTS: Linear multivariable hierarchical regression results indicate that social interaction was a significant buffer, weakening the association between illness burden and depressive symptoms, whereas perceived social support buffered the relationship between functional impairment and depressive symptoms. Family criticism and instrumental social support were not significant moderators. CONCLUSIONS: Type of medical dysfunction, whether illness or impairment, may require different therapeutic and supportive approaches. Enhancement of perceived social support, for those who are impaired, and encouragement of social interactions, for those who are ill, may be important intervention targets for treatment of depressive symptoms in older adult primary care patients. PMID- 22495688 TI - Serotonin transporter genotype differentially modulates neural responses to emotional words following tryptophan depletion in patients recovered from depression and healthy volunteers. AB - Previous studies have suggested that polymorphism in the serotonin transporter gene (5-HTTLPR) influences responses to serotonergic manipulation, with opposite effects in patients recovered from depression (rMDD) and controls. Here we sought to clarify the neurocognitive mechanisms underpinning these surprising results. Twenty controls and 23 rMDD subjects completed the study; functional magnetic resonance imaging (fMRI) and genotype data were available for 17 rMDD subjects and 16 controls. Following tryptophan or sham depletion, subjects performed an emotional-processing task during fMRI. Although no genotype effects on mood were identified, significant genotype*diagnosis*depletion interactions were observed in the hippocampus and subgenual cingulate in response to emotionally valenced words. In both regions, tryptophan depletion increased responses to negative words, relative to positive words, in high-expression controls, previously identified as being at low-risk for mood change following this procedure. By contrast, in higher-risk low-expression controls and high-expression rMDD subjects, tryptophan depletion had the opposite effect. Increased neural responses to negative words following tryptophan depletion may reflect an adaptive mechanism promoting resilience to mood change following perturbation of the serotonin system, which is reversed in sub-groups vulnerable to developing depressive symptoms. However, this interpretation is complicated by our failure to replicate previous findings of increased negative mood following tryptophan depletion. PMID- 22495692 TI - Anemia in the elderly. AB - PURPOSE OF REVIEW: There have been several large-scale epidemiologic studies, including the National Health and Nutrition Examination Survey III (NHANES III), which have described the prevalence and impact of anemia in the elderly. The information derived has been critically important. However, given the large number of patients surveyed, these reports necessarily relied substantially on the laboratory-based screening evaluations. There are now two recent reports describing the cause of anemia in elderly outpatients, and although the numbers are smaller than the large scale surveys, they constitute comprehensive hematologic evaluations with therapeutic interventions and clinical follow-up. The purpose of this review is to compare these different analyses. RECENT FINDINGS: There are distinct differences and similarities in the two types of studies, which are derived from patients seen in hematology clinics. Despite comprehensive hematologic evaluation, the puzzling entity of unexplained anemia of the elderly is confirmed and found to account for 30-46% of patients. NHANES III classified iron-deficiency anemia with other nutritional anemias, a classification that might be correct in the developing third world, but in North America and Western Europe, iron deficiency is more often caused by blood loss and the cause must be sought and dealt with. The myelodysplastic syndromes are an important cause of anemia in the elderly, with a prevalence of at least 4%. SUMMARY: Large-scale screening studies of anemia in the elderly are of great importance, and when complemented by comprehensive hematologic evaluations, provide a more accurate picture of the clinical situation. PMID- 22495693 TI - Current world literature. PMID- 22495694 TI - Lithium in the treatment of neutropenia: retraction. PMID- 22495697 TI - Hospital discharge database as a tool to monitor incidence, survival and burden of cancer in adolescents and young adults. AB - AIMS AND BACKGROUND: Cancer in young patients (15-39 years) is unique for the distribution of types, therapeutic options and clinical evolution. Administrative databases represent well-documented tools in epidemiology, and in oncology they are very important in those realities without cancer registries. Our study aimed to analyze the occurrence, outcomes and burden of cancer in young patients through the analysis of hospital discharge records. METHODS: Hospital discharge databases and civil registries were analyzed through record linkage technique. Annual incidence rate (AIR), standardized incidence rate (SR), overall survival, hospitalization rate, and mean number of hospitalizations were evaluated. RESULTS: Among 2,330,459 young adults, 1846 new cancer patients had been hospitalized in the analyzed period. The SR was 69.3/100,000/year: 1051, 56.9%, were females (AIR 91.0 and SR 76.0) and 795, 43.1%, were males (AIR 67.6 and SR 62.5). Hematological disease was more frequent in males than females (25.5% vs 14.7%, P <0.0001), whereas solid tumors were more frequent among females (85.3% vs 74.5, P <0.0001). The distribution by diagnostic group showed that among females breast cancer was the most frequent (n = 272, SR 17.2), whereas among males genitourinary tract cancer (n = 245, SR 19.2), especially testicular cancer (n = 187, SR 15.1), was the most frequent. Metastatic disease at diagnosis was already present in 198 patients with a solid cancer (13.3%), whereas 213 (11.5%) developed metastasis in the following years. At 12 months from the diagnosis, 87 of 1488 patients with solid cancers and 35 of 358 patients with hematologic disease failed: overall survival was 94% and 90%, respectively. Patients with a new diagnosis of cancer had produced 6663 hospitalizations, 4640 (69.6%) of which were due to solid tumors, 3992 (59.9%) produced by patients over 29 years old, and 3606 (54.1%) by females. The percentage of day hospital admissions increased proportionally with patient age: 25.7% of all hospitalizations among older adolescents (15-20 years) and 32.9% among young adults of 34-39 years. CONCLUSIONS: Administrative data have clear advantages in terms of availability and large numbers. Comparison of our results with the literature showed that a health care delivery database can provide useful information for clinical epidemiologic evaluations in oncology as well as for the analysis of health services utilization. PMID- 22495696 TI - Lifestyle and breast cancer recurrences: the DIANA-5 trial. AB - AIMS AND BACKGROUND: The DIANA (Diet and Androgens)-5 study is a multi institutional randomized controlled trial of the effectiveness of a diet based on Mediterranean and macrobiotic recipes and principles, associated with moderate physical activity, in reducing additional breast cancer events in women with early stage invasive breast cancer at high risk of recurrence because of metabolic or endocrine milieu. The intervention is expected to reduce serum insulin and sex hormones, which were associated with breast prognosis in previous studies. METHODS: Between 2008 and 2010, the study randomly assigned 1208 patients to an intensive diet and exercise intervention or to a comparison group, to be followed-up through 2015. General lifestyle recommendations for the prevention of cancer are given to both groups, and the intervention group is being offered a comprehensive lifestyle intervention, including cooking classes, conferences, common meals and exercise sessions. Adherence assessments occurred at baseline and at 12 months and are planned at 36 and 60 months. They include food frequency diaries, anthropometric measures, body fat distribution assessed with impedance scale, one week registration of physical activity with a multisensor arm-band monitor, metabolic and endocrine blood parameters. Outcome breast cancer events are assessed through self report at semi annual meetings or telephone interview and are validated through medical record verification. RESULTS: The randomized groups were comparable for age (51.8 years), proportion of ER-negative tumors (22%), axillary node metastasis (42%), reproductive variables, tobacco smoking, blood pressure, anthropometric measurements and hormonal and metabolic parameters. CONCLUSIONS: DIANA-5 has the potential to establish whether a Mediterranean-macrobiotic lifestyle may reduce breast cancer recurrences. We will assess evidence of effectiveness, first by comparing the incidence of additional breast cancer events (local or distant recurrence, second ipsilateral or contralateral cancer) in the intervention and in the control group, by an intention-to-treat analysis, and second by analyzing the incidence of breast cancer events in the total study population by compliance assessment score. PMID- 22495698 TI - Cervical cancer screening visit as an occasion for counseling female smokers to quit. AB - AIMS AND BACKGROUND: In the last decades in Italy, a smaller decrease in smoking among women than in men has been observed and a younger age at start in young women. Nevertheless, gender-specific strategies for smoking cessation have rarely been developed, except those for pregnant women. A study was conducted to evaluate the feasibility of carrying out an intervention of primary prevention by counseling for smoking cessation the female smokers attending cervical cancer screening programs in Florence, Italy. METHODS: All female smokers attending the services for cervical cancer prevention at the Cancer Prevention and Research Institute in Florence, Italy, between March 2004 and January 2005, who volunteered to participate in the study, received a brief motivational stage matched counseling for smoking cessation and a face to face interview at enrollment and after 6 and 12 months. The counseling was evaluated by comparing quit rates, changes in smoking intensity, and motivation to quit at the first and second follow-up periods to the same data collected at enrollment. Multivariate logistic regression analysis was performed to estimate the influence on smoking cessation of demographic characteristics, smoking habit and attitude to quit. RESULTS: 177 women participated in the study. After 1 year, a quit rate of 12.4% (95% CI, 7.5-17.3) was observed. Among those who never quit, there was a 39.3% reduction in the average daily cigarette consumption and a 51.9% reduction in smoking the first cigarette of the day immediately on awaking or just after breakfast. CONCLUSIONS: The results and the opportunity to contact a large number of female smokers on the occasion of cervical cancer screening suggest the importance to evaluate the efficacy of the intervention of primary prevention in this health setting. PMID- 22495699 TI - Lapatinib-based therapy in heavily pretreated HER2-positive metastatic breast cancer: a single institution experience. AB - AIMS AND BACKGROUND: Lapatinib in combination with capecitabine is feasible in patients with HER2-positive metastatic breast cancer pretreated with anthracyclines, taxanes and trastuzumab, but inferior results were reported in the global lapatinib expanded access program in comparison with the phase III registration trial. METHODS: and study design. Women with HER2-positive metastatic breast carcinoma after antracycline, taxane and trastuzumab-based regimens were treated at progression with lapatinib plus capecitabine. The outcome of these patients was evaluated. From April 2007 to August 2010, 68 patients were treated overall. RESULTS: Median progression-free survival was 6 months (range, 1-29), and median overall survival was 26 months (range, 1-39). Eight (12%; 95% CI, 4-25) patients experienced a complete response. Partial response was observed in 22 patients (31%; 95% CI, 20-42), for an overall response rate of 43% (95% CI, 31-55). The treatment with lapatinib plus capecitabine was well tolerated, with grade 3-4 toxicity reported in few patients, and no treatment-related deaths were noted. Of note, no cardiac toxicity was reported in this highly pretreated group of patients or in the subgroup of 10 elderly patients. CONCLUSIONS: Our data confirm that lapatinib plus capecitabine is an active regimen even in heavily pretreated patients with visceral and brain metastases and is feasible and active also in selected elderly patients. PMID- 22495700 TI - HER-3 status by immunohistochemistry in HER-2-positive metastatic breast cancer patients treated with trastuzumab: correlation with clinical outcome. AB - AIMS AND BACKGROUND: HER-3 signaling might contribute to resistance to trastuzumab. To clarify the role of HER-3 in HER-2-positive breast cancer, it is important to evaluate the level of HER-3 and its correlations with clinical outcome in metastatic breast cancer patients treated with trastuzumab. METHODS: HER-3 status by immunohistochemistry was evaluated in HER-2-positive metastatic breast cancer patients treated with trastuzumab-based therapy at our institution. Two scorings were utilized for interpreting staining for HER-3, and the correlation between HER-3 status and clinical outcome was evaluated. RESULTS: We evaluated HER-3 status in 61 of 76 HER-2-positive metastatic breast cancers treated with trastuzumab-based therapy at our institution from 4/1999 to 3/2006. We observed 55.2% objective responses; median time to progression and overall survival from start of trastuzumab therapy were 9.6 months (0.921-78.87) and 29.1 months (1.4-129.5+), respectively. With a cutoff of 50% staining tumor cells, we found 30 HER-3-negative and 31 HER-3-positive tumors. HER-3 status was not significantly associated with clinical outcome, but a shorter time to progression and overall survival were observed in patients with HER-3-positive tumors. CONCLUSIONS: HER-3 status by immunohistochemistry was not significantly associated with clinical outcome in HER-2-positive metastatic breast cancer patients. Further studies are necessary to evaluate the prognostic and predictive role of HER-3. PMID- 22495701 TI - Changes in lymphocyte count induced by repeated cycles with low-dose interleukin 2 and interferon-alpha in 146 patients with renal cell carcinoma. AB - AIMS AND BACKGROUND: The exact mechanism by which recombinant interleukine-2 and interferon-alpha modulate the immunological response, inducing long-term responses in metastatic renal cell carcinoma, is still not clear. The aim of the study was to analyze the modifications in peripheral blood lymphocytes during cycles of low-dose immunotherapy as a marker of the biological response to the treatment in 146 patients with renal cell carcinoma (advanced and localized disease). METHODS AND STUDY DESIGN: Peripheral blood lymphocytes were evaluated before and after every cycle of treatment. RESULTS: We found a statistically significant overall difference between pre- and post-cycle values (mean increase of 39%). The differences between pre- and post-cycle lymphocyte counts for each cycle were significant. Also, the post-cycle lymphocyte count of each cycle remained higher than the baseline value. Furthermore, pre-cycle lymphocyte counts of each cycle were still higher than the baseline value, with no difference between a pre-cycle lymphocyte mean value and the other one (except that between the first and second cycle). From the end of each cycle, but before starting the next one, the absolute value of lymphocytes fell on the average by 15-30%, concurring with the fact that, even starting from pre-cycle values higher than baseline, the immune system remains sensitive to chronically repeated stimulation by immunotherapy. We also found that non-metastatic patients had a higher number of peripheral blood lymphocytes than metastatic patients, whereas the latter had a lower immune response to therapy. CONCLUSIONS: The results support the idea that "maintenance" immunotherapy may not develop resistance over time in terms of biological response and thus may have a role as chronic therapy in combination with other drugs such as target therapy. We suppose that the immune system of patients with metastases is in a state of relative impairment, resulting in less sensitivity to immunostimulating agents. PMID- 22495702 TI - Limited-stage small-cell lung cancer treated with early chemo-radiotherapy: the impact of effective chemotherapy. AB - AIMS AND BACKGROUND: Small cell lung cancer is characterized by an aggressive clinical course and a high sensitivity to both chemotherapy and radiotherapy. We present the Florence University experience in concurrent early radio-chemotherapy in patients affected by limited-stage small cell lung cancer, with particular emphasis on treatment safety, disease outcome and prognostic factors. METHODS AND STUDY DESIGN: Fifty-seven patients were treated between June 2000 and February 2005. All patients underwent platinum-based chemotherapy, administered intravenously following two different regimens, for at least three cycles. Eighteen patients (31.6%) received epirubicin and ifosfamide in 3-week cycles alternating with etoposide and cisplatin, administered on day 1 to 3; 39 patients (68.4%) received etoposide and cisplatin. A total of 6 cycles were planned. Radiotherapy was administered concurrently to the first cycle of etoposide and cisplatin. RESULTS: Clinical stage (P = 0.036) and number of chemotherapy courses (P = 0.009) emerged as the only significant death predictors at univariate analysis. Number of chemotherapy courses persisted as a significant death predictor also at multivariate regression analysis, with a reduced death risk for 5-6 chemotherapy cycles in comparison to 3-4 cycles (hazard ratio, 0.44). At a mean follow up of 38.5 months (standard deviation, 3.24 years; range, 6-164 months), considering the best overall tumor response achieved at any time during the whole treatment period, we obtained 32 complete responses (56.1%), 23 partial responses (40.3%) and 2 stable diseases. CONCLUSIONS: Our analysis showed that concurrent early radio-chemotherapy in limited-stage small cell lung cancer treatment represents a safe and effective approach in patients. We confirmed the relevant impact on overall survival of effective chemotherapy delivery. PMID- 22495703 TI - Clinical study of concurrent chemoradiotherapy or radiotherapy alone for esophageal cancer patients with positive lymph node metastasis. AB - AIMS AND BACKGROUND: Esophageal cancer patients with pathologic lymph node involvement generally have a poor prognosis. Many randomized controlled trials have not achieved consistent results similar to those of the RTOG8501 trial, and the long-term survival rate has not increased. The present study aimed to compare the efficacy and toxic side effects of concurrent chemoradiotherapy and radiotherapy alone to treat N1 esophageal carcinoma. METHODS AND STUDY DESIGN: A total of 130 N1 esophageal carcinoma patients were enrolled and randomly divided into two groups: concurrent chemoradiotherapy group (n = 65) and radiotherapy group (n = 65). Both groups received three-dimensional conformal radiotherapy with a total dose of 64-66 Gy. Meanwhile, to the concurrent chemoradiotherapy group, an additional chemotherapy protocol (nedaplatin, 20 mg/m2/d, 5-FU, 500 mg/m2/d for four days) was given from day 1, and such treatment was repeated until day 29. From day 21 after radiotherapy, two cycles of a consolidated chemotherapy protocol were given at an interval of 28 days. RESULTS: The survival rates at one, two, and three years were 72.3%, 55.3%, and 40% in the concurrent chemoradiotherapy group, respectively, and 75.3%, 38.5%, and 18.5% in the radiotheray group (P = 0.007), respectively. The survival rates of the patients in the concurrent chemoradiotherapy group who completed one to two cycles and three to four cycles at one, two, and three years were 70%, 53.3%, and 30%, and 74.2%, 57.1%, 48.6% (P = 0.128), respectively. Three-year distant metastasis rates were 10.7% in the concurrent chemoradiotherapy group and 16.9% in the radiotherapy group. Acute toxicity in the concurrent chemoradiotherapy group was higher than in the radiotherapy group. Late toxic side effects were similar in the two groups. CONCLUSIONS: Compared with radiotherapy alone, concurrent chemoradiotherapy in the treatment of esophageal carcinoma with local lymph node enlargement can improve the three-year survival rate. Moreover, completion of three to four cycles of chemotherapy may have better efficacy than one to two cycles. PMID- 22495704 TI - Radiotherapy in Italy for non-small cell lung cancer: patterns of care survey. AB - AIMS AND BACKGROUND: Surveys in clinical practice are useful to find how current clinical approaches follow recommendations from evidence-based medicine, to stimulate discussion in a multidisciplinary team, and to hypothesize collaborative multicentric trials. To assess management strategies for the use of radiotherapy in the treatment of lung cancer in Italy, in 2009, the Italian Society of Radiation Oncology Lung Cancer Study Group proposed the survey to all Italian radiation oncology institutions. Results were compared with literature data and international reports. STUDY DESIGN: Questionnaires on patterns of care of non-small cell lung cancer were sent to radiation oncology centers active at June 2009 and evaluated data recorded in 2008. RESULTS: A total of 65 of 143 Italian centers responded to the questionnaire. The responding centers reflect the distribution of radiotherapy centers throughout the country. Of the treated patients, 55.2% were stage III, and most cases had a good performance status. FDG PET was routinely used by 51% of centers for diagnostic and contouring phases. Postoperative radiotherapy was prescribed to pN1 and pN2 patients in 42.2% and 98.5%, respectively. The possible use of neo-adjuvant concomitant chemoradiation was declared by 70% of responders. A sequential chemoradiation approach was actually used in 43.6% of cases, induction chemotherapy followed by concomitant radiochemotherapy in 42.4%, and upfront concomitant radiochemotherapy in only 14%. In 53% of the institutions, patients have a clinical examination by a radiation oncologist only after the beginning of chemotherapy and in 82.4% of cases they have already received 2-4 cycles of chemotherapy. Most of the institutions exclude elective nodal irradiation from routine application. Total dose and fractionation in adjuvant, neoadjuvant, curative and palliative settings confirm literature data. There were significant differences in treatment planning constraints applied for lung, esophageal and cardiac tissues. Of the responding centers, 41% had stereotactic therapy for primary inoperable lung cancer and for metastatic lesions. CONCLUSIONS: In Italy, daily practice differs in some ways from the evidence supported by the results of meta-analyses/clinical trials as regards concurrent chemoradiation approaches. It could be postulated that there is an urgent need for groups that collaborate with the other societies involved in the treatment of non-small cell lung cancer in order to offer the best therapy to our patients. PMID- 22495705 TI - A feasibility study of neo-adjuvant low-dose fractionated radiotherapy with two different concurrent anthracycline-docetaxel schedules in stage IIA/B-IIIA breast cancer. AB - AIMS AND BACKGROUND: The aim of the study was to evaluate the feasibility of neoadjuvant low-dose fractionated radiotherapy, in combination with two anthracycline-docetaxel regimens, in breast cancer treatment. MATERIALS AND METHODS: Women with stage IIA/B-IIIA breast cancer were assigned to receive the treatment of low-dose fractionated radiotherapy (0.4 Gy/per fraction, 2 fractions per day, for 2 days, every 21 days for 8-6 cycles) with concomitant neoadjuvant chemotherapy with non-pegylated liposomal doxorubicin and docetaxel. Two chemotherapy schedules were planned to be combined with low-dose fractionated radiotherapy. The first schedule consisted of four cycles of non-pegylated liposomal doxorubicin sequentially followed by four cycles of docetaxel, and the second schedule consisted of six cycles of non-pegylated liposomal doxorubicin plus concomitant docetaxel. Acute toxicity was evaluated according to the Radiation Therapy Oncology Group score system. Pathological response was evaluated by the Mandard score and expressed as tumor regression grade. RESULTS: Between March 2008 and February 2009, 10 patients underwent low-dose fractionated radiotherapy and concomitant chemotherapy. No grade 3-4 breast toxicity was observed. Five patients had a clinical complete response. Seven patients underwent conservative surgery. Overall, tumor regression grade 1 (absence of residual cancer) was achieved in one patient (10%) and grade 2 (residual isolated cells scattered through the fibrosis) in 4 patients (40%). The pathologic major response rate (tumor regression grade 1 + 2) was 20% in patients receiving low dose fractionated radiotherapy and sequential non-pegylated liposomal doxorubicin and docetaxel and 80% in the group receiving low-dose fractionated radiotherapy and concurrent non-pegylated liposomal doxorubicin and docetaxel treatment. CONCLUSIONS: Concomitant low-dose fractionated radiotherapy combined with anthracycline and docetaxel is feasible. The toxicity profile of radio chemotherapy was similar to that of chemotherapy alone: there was no acute skin or cardiac toxicity. The concurrent application of liposomal doxorubicin and docetaxel with low-dose fractionated radiation led to higher histological response rates compared to the sequential application of the same two drugs. PMID- 22495706 TI - Radiotherapy for inoperable non-small cell lung cancer using helical tomotherapy. AB - AIM: To investigate the impact of tomotherapy on the dose delivered to the lungs and other normal tissues. MATERIAL AND METHODS: From February 2008 to May 2009, 35 patients with stage IIIA/IIIB non-small cell lung cancer were treated with helical tomotherapy at the S. Camillo-Forlanini Hospital. For our study we selected 20 patients who underwent chemotherapy followed by sequential radiotherapy. The planning target volume was delineated using planning CT scan and FDG-PET. The mean prescribed radiation dose was 67.5 Gy delivered in 30 fractions at a dose of 2.25 Gy per fraction. RESULTS: Median follow-up was 12.3 months. All patients developed acute esophageal toxicity, 15 of RTOG grade 1 and 5 of RTOG grade 2. At first follow-up 15 patients presented stable disease or partial response, 4 patients presented complete response, and 1 patient presented disease progression. CONCLUSIONS: Helical tomotherapy is useful to achieve dose per-fraction escalation without increasing the treatment-related morbidity. Our results applying dose escalation were encouraging considering that we delivered doses that may be difficult to achieve with 3-dimensional treatments with no excessive complication rates. PMID- 22495708 TI - Morbidity of selective lymph node biopsy for melanoma: meta-analysis of complications. AB - BACKGROUND AND AIM: Intraoperative lymphatic mapping and selective lymph node biopsy is accepted worldwide as the standard procedure for staging regional lymph nodes of 1-4 mm thick melanomas, as well as for other neoplasms. Although it is often stated that selective lymph node biopsy is a minimally invasive procedure associated with few complications, few data exist concerning the morbidity associated with the procedure. The present analysis was performed to evaluate the morbidity associated with selective lymph node biopsy in a long-term follow-up. MATERIALS AND METHODS: The study provides a review of 437 selective lymph node biopsies on 269 patients, operated on between the 1994 and the 2009, for the lymph node biopsy of head and neck, groin, axilla, upper and lower limbs and nodal basins. Patients' history and follow-up were reviewed for 2 weeks after surgery, every 3 months for the first 2 years, every 4 months during the third year, and every 6 months subsequently, and postoperative morbidity was evaluated. RESULTS: After sentinel node biopsy, 14 patients developed one of the following complications: hematoma, 1 case (0.30%); lymphedema, 1 case (0.30%); seroma, 2 cases (0.61%); wound infection, 6 cases (1.83%); keloid scar, 2 cases (0.61%); and postoperative pain, 2 cases (0.61%). The total complication rate was 4.26%. CONCLUSIONS: Selective lymph node biopsy for melanoma, as for other tumors, in respect to radical lymphadenectomy, is not a complications-free procedure but is usually not severe. PMID- 22495707 TI - Pulmonary resections: cytostructural effects of different-wavelength lasers versus electrocautery. AB - AIMS AND BACKGROUND: There are few papers on the cytostructural effects of surgical instruments used during pulmonary resections. The aim of the present study was to evaluate the parenchymal damage caused by different surgical instruments: a new generation electrosurgical scalpel and two different wavelength lasers. METHODS: Six surgical procedures of pulmonary resection for nodules were performed using a new generation electrosurgical scalpel, a 1318 nm neodymium (Nd:YAG) laser or a 2010 nm thulium laser (two procedures for each instrument). Specimens were analyzed using optical microscopy and scansion electronic microscopy. RESULTS: Severe cytostructural damage was found to be present in an average of 1.25 mm in depth from the cutting surface in the patients treated using electrosurgical cautery. The depth of this zone dropped to less than 1 mm in patients treated by laser, being as small as 0.2 mm using the laser with a 2010 nm-wavelength and 0.6 mm with the 1318 nm-wavelength laser. DISCUSSION: These preliminary findings support the use of laser to perform conservative pulmonary resections (i.e., metastasectomies), since it is more likely to avoid damage to surrounding structures. Controlled randomized trials are needed to support the clinical usefulness and feasibility of new types of lasers for pulmonary resections. PMID- 22495709 TI - Prognostic effect of age on survival of patients with stage I adenocarcinoma of the lung. AB - AIMS AND BACKGROUND: It is still unclear whether age is an independent prognostic factor in patients with stage I NSCLC. METHODS: Five hundred and sixty-nine patients with stage I adenocarinoma who underwent surgical resection as first treatment were included. The effect on overall survival of age, gender, smoking habits, Charlson comorbidity index score (CCIS), type of surgery, tumor size and lymphatic or blood vessel invasion was analyzed. RESULTS: When the patients were divided into four groups according to quartiles of age, distributions of gender, smoking habit, CCIS, histology, blood vessel invasion and adjuvant chemotherapy were significantly different among the four groups. Age, gender, smoking habit, CCIS, tumor size and lymphatic and blood vessel invasion were significantly associated with overall survival of the patients in Kaplan-Meier analysis (logrank, P <0.001, P <0.001, P = 0.029, P <0.001, P = 0.001, P = 0.001 and P = 0.007, respectively). Moreover, the highest quartile of age (over 68 years old) was a prominent determinant for a worse prognosis after adjustment for the confounding variables using a Cox proportional hazard model (adjusted hazard ratio = 2.735, 95% confidence interval = 1.623-4.608, P <0.001). CONCLUSIONS: The findings suggest that age is an important determinant of overall survival in patients with stage I adenocarcinoma. Therefore, age should be considered in classifying the patients into groups of higher or lower risk for death as well as in designing clinical trials. PMID- 22495710 TI - Expression of the hepatocyte growth factor and c-Met in colon cancer: correlation with clinicopathological features and overall survival. AB - AIM AND BACKGROUND: The hepatocyte growth factor (HGF)/c-Met signaling system has been implicated in the development and progression of colon cancer, but the relationship between the expression of HGF or c-MET and clinicopathologic features remains controversial. In the study, we analyzed the expression of HGF and c-Met in colon cancer and assessed the influence of the expression of this growth factor and its receptor on clinical and histological parameters and patient survival. METHODS AND STUDY DESIGN: We investigated the mRNA expression of HGF and c-Met with real-time PCR in 90 unselected colon carcinomas and the corresponding normal mucosa. Furthermore, HGF and c-Met protein expression was investigated with immunohistochemistry in all the samples. RESULTS: The mRNA and protein expression levels of HGF and c-Met were significantly higher in colon cancer than in matched normal mucosa. The protein level in most of the cases investigated was correlated with the mRNA level. Overexpression of HGF and c-Met, at both protein and mRNA levels, was correlated with depth of invasion, lymph node metastases and overall AJCC stage. According to univariate analysis, the mean survival time was shorter in the HGF-positive and c-Met-positive groups. Multivariate Cox analysis showed that high M stage and the expression of c-Met independently had a negative impact on overall survival. CONCLUSIONS: The HGF/c Met signaling pathway may be involved in the pathogenesis and progression of colon cancer. C-Met overexpression can be used as a useful parameter to evaluate the prognosis of colon cancer. PMID- 22495711 TI - On the diagnostic accuracy of stereotactic vacuum-assisted biopsy of nonpalpable breast abnormalities. Results in a consecutive series of 769 procedures performed at the Trento Department of Breast Diagnosis. AB - AIMS AND BACKGROUND: To assess the diagnostic accuracy of stereotactic vacuum assisted biopsy of nonpalpable breast lesions. METHODS AND STUDY DESIGN: 769 consecutive vacuum-assisted biopsy procedures were retrospectively reviewed. Positive predictive value for carcinoma (B5) at vacuum-assisted biopsy was assessed on the overall series and by age, lesion morphology and size, degree of suspicion and calendar period. The accuracy of vacuum-assisted biopsy was based on surgical histology or follow-up (no change at 12 months was assumed as negative). RESULTS: Lesions were depicted as isolated microcalcifications, opacity + microcalcifications, or opacity in 716 (93.1%), 28 (3.6%), or 25 (3.2%) cases, respectively. Vacuum-assisted biopsy was negative (B1 = 63; B2 = 319) in 382 (49.7%), borderline (B3) in 142 (18.5%), suspicious (B4) in 2 (0.3%), and positive (B5) in 243 (31.6%) cases (in situ = 185, 24.1%), invasive = 58 (7.5%)), respectively. Age (chi2df3 = 19.50; P <0.002), size (chi2df4 = 51.02; P = 10-6) and degree of suspicion (chi2df2 = 146.68; P = 10-6) were associated with a B5 outcome, no significant association was evident for morphology (chi2df2 = 0,47; P <0.78), whereas calendar period had a moderate but significant inverse association (chi2df2 = 6.12; P <0.04). The positive predictive value for surgically confirmed carcinoma (in situ or invasive) was 0% for B1, 0.7% for B2, 12.3% for B3, 100% for B4, 92.7% for in situ B5, and 94.6% for invasive B5. Conversion from in situ B5 to invasive was 12.3% and was insignificantly associated with size (chi2df2 = 0.95; P = 0.62) and histology grade (chi2df2 = 3.64; P = 0.16). Down-grading of vacuum-assisted biopsy lesions to a less severe histology occurred in 13 (7.2%) in situ and in 16 (28.6%) invasive carcinomas. B3 cases upgrading to more severe lesions was 0%, 4.5% or 16.0% in the presence of no, mild, or severe atypia. CONCLUSIONS: The study confirmed a good performance of vacuum-assisted biopsy, possibly influenced by the local scenario (e.g., radiologist's and pathologist's interobserver variability and sampling modality). Conflicting results with the literature may have local explanations rather than being due to inadequate performance. PMID- 22495712 TI - Emotional distress and needs in Italian cancer patients: prevalence and associations with socio-demographic and clinical factors. AB - AIMS AND BACKGROUND: Since emotional distress is a relevant psycho-social component of an oncological disease experience, its study is useful in multidisciplinary patient cancer care. In the present research, emotional distress together with needs during hospitalization were recorded and their associations with several socio-demographic and clinical variables were verified. METHODS AND STUDY DESIGN: Five hundred and forty-four consecutive oncological inpatients completed two self-assessment questionnaires concerning emotional distress and needs (i.e., Hospital Anxiety and Depression Scale, Needs Evaluation Questionnaire). RESULTS: 27.4% and 20.8% of the enrolled patients were probable cases, respectively, for anxiety and depression; when possible cases were included the percentages raised to 52.5% and 39.3%, respectively. Furthermore, 11.9% and 20.2% of participants were simultaneously probable and possible cases for both conditions. Few differences in anxiety and depression according to socio demographic and clinical variables were demonstrated, whereas needs seemed to be more frequently associated to them. Finally, needs also seemed to be associated with both anxiety and depression, with possible and probable cases for anxiety and depression displaying more needs than non-cases. CONCLUSIONS: The implications for both the quality of care and disease adjustment by cancer patients are discussed together with study limitations. PMID- 22495713 TI - Analysis of gene copy number variations using a method based on lab-on-a-chip technology. AB - AIMS AND BACKGROUND: Copy number variations (CNVs) contribute to genome variability and their pathogenic role is becoming evident in an increasing number of human disorders. Commercial assays for routine diagnosis of CNVs are available only for a fraction of known genomic rearrangements. Thus, it is important to develop flexible and cost-effective methods that can be adapted to the detection of CNVs of interest, both in research and clinical settings. METHODS: We describe a new multiplex PCR-based method for CNV analysis that exploits automated microfluidic capillary electrophoresis through lab-on-a-chip technology (LOC CNV). We tested the reproducibility of the method and compared the results obtained by LOC-CNV with those obtained using previously validated semiquantitative assays such as multiplex ligation-dependent probe amplification (MLPA) and nonfluorescent multiplex PCR coupled to HPLC (NFMP-HPLC). RESULTS: The results obtained by LOC-CNV in control individuals and carriers of pathogenic MLH1 or BRCA1 genomic rearrangements (losses or gains) were concordant with those obtained by previously validated methods, indicating that LOC-CNV is a reliable method for the detection of genomic rearrangements. CONCLUSION: Because of its advantages with respect to time, costs, easy adaptation of previously developed multiplex assays and flexibility in novel assay design, LOC-CNV may represent a practical option to evaluate relative copy number changes in genomic targets of interest, including those identified in genome-wide analyses. PMID- 22495714 TI - Expression of A1 and A3 adenosine receptors in human breast tumors. AB - BACKGROUND: Adenosine receptors (A1, A2A, A2B, A3) play an important role in the regulation of growth, proliferation and death of cancer and normal cells. We recently showed the expression profile of A2A and A2B receptors in normal and tumor breast tissues. In the present study, we used semiquantitative RT-PCR to measure the A1 and A3 gene expression levels in normal and tumor breast tissues. METHODS: Breast tumors (n = 18) and non-neoplastic mammary tissues (n = 10) were collected and histologically confirmed to be neoplastic or non-neoplastic, respectively. Total RNA was extracted and reverse transcribed into cDNA, and PCR was performed under optimized condition for each receptor subtype. Amplification of beta-actin mRNA served as control for RT-PCR. The PCR products were separated on 1.7% agarose gels. The intensity of the bands was quantitated with ImageJ software after normalization against beta-actin expression. RESULTS: All breast tumor and normal tissue specimens expressed A1 and A3 adenosine receptor transcripts. However, we observed that the expression level of the A3 receptor in tumor tissues was 1.27-fold that of normal tissues, whereas there was no significant difference between the expression levels of A1 in normal and tumor tissues. CONCLUSIONS: Interestingly, the results of the present study indicate that breast tumors exhibit a higher level of A3 transcripts (than normal tissues) and support the possible key role of A3 adenosine receptor in tumor development. However, further studies based on real-time quantitative RT-PCR are needed to identify the exact gene expression levels. PMID- 22495715 TI - Dichloroacetate induces different rates of cell death in cancer and noncancer cell lines in vitro. AB - AIMS AND BACKGROUND: The pyruvate mimetic dichloroacetate (DCA) has been shown to induce cell death in cancer cells. A number of studies in vitro and in vivo have suggested this molecule may serve as an anticancer agent, but some cells are resistant. Here we wanted to examine the effects of DCA on cancerous and noncancerous cells grown in culture for a prolonged period of exposure and at increasing concentrations. METHODS: Six cancer cell lines (A549, SK-HEP-1, HCT116, UPCI:SCC070, HeLa and MES-SA) and three noncancerous lines (RPE, GM03349B and HEK293) were exposed to 0.5 mM DCA for seven days and cell counts were taken every day to determine viability and cell cycle progression. The same cell lines were also exposed to higher doses of DCA up to 10 mM and viability was scored. RESULTS: Five cancer cell lines showed high levels of cell death early in the trial, but three of the lines showed a second delayed increase in cell death at later stages. HCT116 cells were unaffected by 0.5 mM DCA. GM03349B and RPE cells also died when treated with DCA. At high concentrations, all cell lines exhibited high rates of death. No specific cell cycle arrest of the cells was observed. CONCLUSION: We found that there is considerable difference in the way cancer cells are affected by DCA. Some have populations that are highly resistant to treatment, while others have stronger rates of death only after prolonged exposure. We also found noncancerous cells are not all resistant to DCA, a significant finding that has not previously been observed in other in vitro DCA trials. PMID- 22495716 TI - Activation of aryl hydrocarbon receptor suppresses invasion of esophageal squamous cell carcinoma cell lines. AB - AIMS AND BACKGROUND: Esophageal cancer is the eighth most common malignancy and sixth leading cause of cancer deaths in the world. Recent studies have shown the potential role of the aryl hydrocarbon receptor (AhR) in tumor development; however, little is known about its role in esophageal squamous cell carcinoma. In the present study, we evaluated AhR expression in esophageal tumor tissues as well as cell lines and investigated the effects of AhR activation by its agonist BNF on esophageal squamous cell carcinoma invasion using Eca109 and TE-13 cells as a model. METHODS: Western blotting was performed to detect the AhR and CYP1A1 protein expression. Transwell migration assays were carried out to study the effects of BNF on esophageal squamous cell carcinoma cell invasion. AhR-specific siRNA was used to knock down the expression of AhR protein. RESULTS: Our results showed that AhR was highly expressed in esophageal squamous cell carcinoma tissues and cell lines when compared with its expression in normal tissue. AhR siRNA robustly decreased AhR protein expression in both Eca109 and TE-13 cells. BNF significantly inhibited invasion of human esophageal squamous cell carcinoma cells via activation of AhR. CONCLUSIONS: The obtained results provide critical information on the roles of BNF in mediating esophageal squamous cell carcinoma invasion. This information could be useful for future therapeutic intervention in this lethal human disease. PMID- 22495717 TI - Is the spiritual life of cancer patients a resource to be taken into account by professional caregivers from the time of diagnosis? AB - BACKGROUND AND AIM: Spiritual life can be defined as the search for personal contact with the transcendent. Careful assessment of spiritual life can help to value its importance to cancer patients from the moment of their diagnosis. METHODS: This is a cross-sectional study. Two hundred fifty-seven patients undergoing cancer treatment filled in the validated Italian version of the Systems of Belief Inventory (SBI-15R). Patients were also asked to attribute themselves to one of the following, mutually exclusive categories: believer and churchgoer, believer but no churchgoer, and non-believer. RESULTS: Five patients did not report their religious stance and were therefore excluded from the analysis. Of the remaining 252 patients, 49% declared to be believers and churchgoers, 43% believers but not churchgoers, and 8% non-believers. Of the 20 cancer patients who declared not to have a religious faith, 7 patients agreed with the statement that they felt certain that God exists in some form, and 4 had experienced peace of mind through prayer and meditation. Almost all of the patients who declared to have a religious faith and to be churchgoers explicitly affirmed to have been helped by prayer and meditation in coping with their illness. Among believer churchgoers, only 30% declared to seek out the religious or spiritual community when they needed help. CONCLUSIONS: A large proportion of cancer patients find themselves involved with the search for a personal contact with the transcendent, also beyond any specific religious affiliation. These spiritual issues may be important even when they are not expressed as participation in religious rituals or adherence to specific religious beliefs. On the other hand, participation in religious rituals often implies the need for a personal spiritual life, both through those rituals and beyond them, as through personal prayer and meditation. These results ask for more attention on the part of professionals towards spiritual resources among cancer patients. It might be appropriate to look systematically for these resources from the moment of the diagnosis, through the sensitive administration of an easy and valid assessment tool like the SBI-15R. PMID- 22495718 TI - High lapatinib plasma levels in breast cancer patients: risk or benefit? AB - AIMS AND BACKGROUND: Lapatinib is a tyrosine kinase inhibitor targeting epidermal growth factor receptors 1 (EGFR/HER1) and 2 (HER2) used in the treatment of patients with HER2-positive breast cancer. The aim of the present study was to determine lapatinib plasma levels in breast cancer patients treated with lapatinib plus capecitabine. PATIENTS AND METHODS: We assessed lapatinib plasma levels in blood samples from 21 breast cancer patients treated with lapatinib plus capecitabine using the standard regimen in an expanded access program. Liquid chromatography tandem mass spectrometry was used for measuring lapatinib plasma concentrations. The validated method was applied for measurement of 55 plasma samples. RESULTS: The median lapatinib plasma level was 5.09 MUg/mL, with large interindividual differences. Patients of lower weight tended to have higher lapatinib plasma levels (Spearman correlation coefficient R = -0.435, P = 0.055). One patient's lapatinib plasma levels were markedly higher than those of the others, with a median level of 11.25 MUg/mL and repeatedly exceeding 7.80 MUg/mL. The treatment was terminated after 8 months when hyperbilirubinemia occurred. CONCLUSIONS: The lapatinib plasma levels reported here are twice as high as the clinically effective steady-state geometric mean maximum concentration. We conclude that increased lapatinib body levels occur when patients are in a nonfasting state at the time of drug intake and when lapatinib doses are not adjusted to low body weight or weight loss during treatment. In Europe, dose adjustments are not recommended in the case of hepatic function impairment. Thus, attention should be paid to changes in liver function test results in clinical practice, especially in patients of small stature and weight, given the risk of high plasma concentrations. Prospective lapatinib plasma level assessment in treated patients might be useful to confirm or refute the possible correlation of high lapatinib plasma levels with hepatic and/or other toxicities. PMID- 22495719 TI - Prospective Registry On Mesothelioma Peritonei Treatment (PROMPT): study design and rationale. PMID- 22495720 TI - "Reirradiation: hopes and concerns of the radiation oncologist". PMID- 22495722 TI - Ewing sarcoma of the thoracic wall in a 54-year-old man. AB - Ewing tumor is the second most common bone tumor in children. Its variant, malignant small cell tumor of the thoracopulmonary region, is infrequent in children and extremely rare in adults. A multimodal treatment approach is preferred for this tumor. We describe a rare case of primitive neuroectodermal tumor/Ewing sarcoma arising from the thoracic wall in a 54-year-old man. He underwent extensive resection of the tumor followed by adjuvant chemotherapy and radiotherapy. PMID- 22495723 TI - Ileal Vanek's tumor mimicking cecal carcinoma. AB - Inflammatory fibroid polyps or Vanek's tumors are rare benign pseudotumoral lesions with morphological characteristics similar to those of submucosal mesenchymal tumors. They have been described in the gastrointestinal tract, most frequently in the gastric antrum. We present a case of ileal Vanek's tumor associated with a raised carcinoembryonic antigen level and with radiological and endoscopic features mimicking cecal carcinoma. PMID- 22495724 TI - Synchronous association of two neuroendocrine gastroenteropancreatic tumors, an adenocarcinoma of the cecum, and a Meckel's diverticulum: a case report. AB - Neuroendocrine gastroenteropancreatic tumors constitute a heterogeneous group of neoplasms, with the primary tumors being located in the gastric mucosa, pancreas, and small and large intestine. The development of a second primary malignancy in patients with these tumors is a well-described phenomenon, and the reported incidence ranges from 12% to 46%. The most common site of associated noncarcinoid malignancies is the gastrointestinal tract, which involves from 30% to 60% of the tumors. We report a case of concurrent colon carcinoma and two neuroendocrine tumors of the duodenum. PMID- 22495725 TI - Unexpected granular cell tumor in abdominal wall: case report and literature review. AB - Granular cell tumors (GCTs) are uncommon benign neoplasms deriving from Schwann cells of the peripheral nerve fibers. Although these tumors can be found anywhere in the body, the most frequent site is the tongue, followed by the chest wall and the arm. The abdominal wall is an extremely rare site for GCTs. These tumors are generally asymptomatic and have a slow growth rate. Today, thanks to their immunoreactivity to S-100 and CD68, the differential diagnosis is more straightforward than in the past. We report on a young patient affected by a GCT located in the upper third of the right rectus abdominis muscle. En bloc excision through a diamond-shaped skin incision allowed us to make a correct histological diagnosis, which was confirmed by the immunohistochemical findings. GCT, which is very rare in abdominal wall muscles, should be considered in the differential diagnosis, and surgical excision is the treatment of choice. PMID- 22495726 TI - Radiation therapy for pituitary metastasis: report of four cases. AB - AIMS AND BACKGROUND: To report the clinical outcomes of four patients with pituitary metastases treated with radiotherapy. METHODS: Retrospective chart review of four cases. RESULTS: The mean age of the patients was 66 years; two were women and two were men. The mean duration of symptoms at initial presentation of the primary tumor was 2.25 months. The location of the primary tumor was the breast in one case and the lung in three. Magnetic resonance imaging of the brain revealed sellar masses in all cases. The mean interval between the primary tumor diagnosis and the development of pituitary metastases was 22.5 months. The metastases were treated with radiation therapy (palliative/stereotactic/intensity modulated) at a mean dose of 3219 cGy. At the last follow-up, three patients were dead and one was alive. CONCLUSIONS: Treatment with three-dimensional conformal radiotherapy or stereotactic radiotherapy is a suitable non-surgical option for patients with pituitary metastases. PMID- 22495727 TI - Multifocal capillary hemangioma (hemangiomatosis) of the spleen. AB - BACKGROUND: The spleen is mainly affected by benign tumors that originate from the vascular endothelium. The most common is hemangioma, which presents as a small, localized lesion. Isolated diffuse hemangiomatosis of the spleen is a rare entity in which the entire splenic parenchyma is replaced by a proliferation of neoplastic blood vessels. Here we illustrate the case of a 26-year-old man presenting with splenomegaly due to diffuse hemangiomatosis of the white pulp who underwent a splenectomy. METHODS: Representative samples of the spleen were stained with hematoxylin and eosin, and immunohistochemical analysis was performed for Mib-1, CD20, CD30, CD15, CD34, CD31, CD8, factor VIII, D2-40, CD68PGM1, and LMP1. RESULTS: Macroscopically, the splenic parenchyma contained multiple, red-brown nodules ranging from 0.4 to 1.5 cm. Microscopically, the nodules were roundish and confluent with an angiomatoid appearance and high positivity for CD34 and factor VIII, while they were negative for D2-40. CONCLUSIONS: The differential diagnosis of splenic tumors includes lymphangioma, lymphangiomatosis, peliosis, littoral cell angioma, hemangioendothelioma, hamartoma, angiomatoid transformation of the spleen, and angiosarcoma. It is debated whether diffuse hemangiomatosis is a malformation of the postsinusoidal venous system or a slowly growing neoplasm arising from the splenic sinuses. The positivity of the cavernous vessels for CD8 seems to be in favor of the malformative nature of the tumor. PMID- 22495728 TI - Mirror therapy for phantom limb pain in an adolescent cancer survivor. AB - AIMS AND BACKGROUND: Several pediatric tumors require mutilating procedures in order to be treated effectively. Although the pain caused by the surgery is usually of a transient nature, the perception of pain in the amputated limb may persist. This prolonged pain, which is often refractory to pain-killing medication, may severely affect the patient's quality of life. The phenomenon of phantom limb pain (or phantom limb syndrome) has been investigated using neurological, neurophysiological and psychopathological approaches. Here we discuss the advantages of an unconventional rehabilitation technique, the recently reported mirror therapy, whose positive effects might be due, according to some researchers, to neuronal plasticity mechanisms. CASE REPORT: We describe the use of mirror therapy to treat phantom limb syndrome in a 39-year-old patient whose right leg had been amputated at the age of 17 because of an osteosarcoma. The patient suffered from frequent episodes of pain, with severely negative effects on his quality of life. RESULTS: We obtained positive subjective feedback from the patient, who reported having benefited significantly from using the mirror. The beneficial effect was still present six months after the start of mirror therapy. CONCLUSIONS: The reported case highlights the value of an integrated multidisciplinary approach including neurological/physiatric assessment, clinical psychological support, physiotherapy and other, unconventional treatment modalities. This report should guide future studies towards the application of mirror therapy in order to elucidate its effects and efficacy. PMID- 22495729 TI - Pericardial breast cancer metastasis 25 years after mastectomy. AB - Pericardial effusion in a patient with a history of cancer should always prompt a hypothesis of malignant involvement. We report the case of a 66-year-old white woman presenting with pericardial effusion 25 years after a mastectomy for ductal breast carcinoma. This is one of the cases with the latest recurrence ever reported. PMID- 22495730 TI - First evidence for the formation of technetium oxosulfide complexes: synthesis, structure and characterization. AB - The reaction of tetrabutylammonium pertechnetate with bis(trimethylsilyl) sulfide in solution was studied by UV-Visible spectroscopy and mass spectrometry. Experimental results and density functional calculations provide the first evidence for the formation of a TcO(3)S(-) precursor. Larger scale synthesis afforded a solid that was characterized by EDX and XANES spectroscopy. XANES showed the presence of technetium in tetravalent state. EDX indicated the solid contained technetium, sulfur and oxygen. PMID- 22495731 TI - The relationship between elderly suicide rates and the internet: a cross-national study. PMID- 22495734 TI - Heparosan-derived heparan sulfate/heparin-like compounds: one kind of potential therapeutic agents. AB - Heparan sulfate (HS) is a highly sulfated glycosaminoglycan and exists in all animal tissues. HS and heparin are very similar, except that heparin has higher level of sulfation and higher content of iduronic acid. Despite the fact that it is a century-old drug, heparin remains as a top choice for treating thrombotic disorders. Pharmaceutical heparin is derived from porcine intestine or bovine lung via a long supply chain. This supply chain is vulnerable to the contamination of animal pathogens. Therefore, new methods for manufacturing heparin or heparin-like substances devoid of animal tissues have been explored by many researchers, among which, modifications of heparosan, the capsular polysaccharide of Escherichia coli K5 strain, is one of the promising approaches. Heparosan has a structure similar to unmodified backbone of natural HS and heparin. It is feasible to obtain HS or heparin derivatives by modifying heparosan with chemical or enzymatic methods. These derivatives display different biological activities, such as anticoagulant, anti-inflammatory, anticancer, and antiviral activities. This review focuses on the recent studies of synthesis, activity, and structure-activity relationship of HS/heparin-like derivatives prepared from heparosan. PMID- 22495735 TI - Chemoselective synthesis of highly substituted 1,2-allenyl ketones, furans, and 2 alkynyl ketones from reaction of lithium selenolates with 1-(1 alkynyl)cyclopropyl ketones and electrophiles. AB - A homo-Michael addition reaction of lithium selenolates with 1-(1 alkynyl)cyclopropyl ketones and the subsequent reaction with electrophiles such as PhSeBr, NFSI and NCS is reported. Based on the nature of electrophiles, this reaction may afford highly substituted 1,2-allenyl ketones or furans (E(+) = PhSe(+)) and 2-alkynyl ketones (E(+) = F(+), Cl(+), active halides) as the final products, respectively. PMID- 22495733 TI - The parametric g-formula to estimate the effect of highly active antiretroviral therapy on incident AIDS or death. AB - The parametric g-formula can be used to contrast the distribution of potential outcomes under arbitrary treatment regimes. Like g-estimation of structural nested models and inverse probability weighting of marginal structural models, the parametric g-formula can appropriately adjust for measured time-varying confounders that are affected by prior treatment. However, there have been few implementations of the parametric g-formula to date. Here, we apply the parametric g-formula to assess the impact of highly active antiretroviral therapy on time to acquired immune deficiency syndrome (AIDS) or death in two US-based human immunodeficiency virus cohorts including 1498 participants. These participants contributed approximately 7300 person-years of follow-up (49% exposed to highly active antiretroviral therapy) during which 382 events occurred and 259 participants were censored because of dropout. Using the parametric g formula, we estimated that antiretroviral therapy substantially reduces the hazard of AIDS or death (hazard ratio = 0.55; 95% confidence limits [CL]: 0.42, 0.71). This estimate was similar to one previously reported using a marginal structural model, 0.54 (95% CL: 0.38, 0.78). The 6.5-year difference in risk of AIDS or death was 13% (95% CL: 8%, 18%). Results were robust to assumptions about temporal ordering, and extent of history modeled, for time-varying covariates. The parametric g-formula is a viable alternative to inverse probability weighting of marginal structural models and g-estimation of structural nested models for the analysis of complex longitudinal data. PMID- 22495736 TI - Normal morphometry of fetal posterior fossa at midtrimester: brainstem-tentorium angle and brainstem-vermis angle. AB - OBJECTIVE: To standardize the evaluation of normal tentorium insertion and normal rotation of the cerebellar vermis over the brainstem, using two novel measurements: the brainstem-tentorium angle (BT angle) and the brainstem-vermis angle (BV angle). We also aimed to test the reproducibility of these measurements. METHODS: Prospective observational study including normal fetuses at routine anomaly scan with confirmed normal follow-up. Three-dimensional volumes of the fetal head were acquired starting from standard trans-cerebellar views. In the sagittal plane, obtained by multiplanar reconstruction, the angle between the brainstem and the tentorium insertion in the fetal skull, and between the brainstem and the lower edge of the vermis were measured twice by two independent operators. Intraobserver and interobserver variations were calculated. RESULTS: Eighty cases were included. The estimated BT and BV angles lie in a wide interval among normal midtrimester fetuses with a median value (min max) of 25.65 (20.13-47.39) and 9.29 (3.87-19.36) respectively. Intraobserver and interobserver variation were good for both measurements. CONCLUSION: The BT and BV angle may be of help in assessing the fetal posterior fossa at midgestation and gives a standardized and reproducible measurement of normal tentorium insertion and normal rotation of the cerebellar vermis over the brainstem. PMID- 22495737 TI - Efficacy of cellulase and mannanase hydrolysates of konjac glucomannan to promote the growth of lactic acid bacteria. AB - BACKGROUND: Glucomannan polysaccharides may be hydrolysed to lower molecular weight molecules using acids or enzymes, specifically mannanases or cellulases. Mannanases (beta-mannanases) hydrolyse beta-(1-4)-linked mannose residues randomly in mannans whilst cellulases (beta-glucanase) hydrolyse beta-(1-4) linked glucose residues. The molecular weight of the hydrolysate is clearly dependent on the amount of hydrolysis. One use of such hydrolysates has been towards their capacity to function as prebiotics. The relative efficacy of cellulase and/or mannanase hydrolysates of konjac glucomannan to promote the growth of lactic acid bacteria (LAB) has been evaluated. RESULTS: The LAB growth profiles (expressed in colony forming units, as a function of time) in UHT milk containing konjac glucomannan hydrolysed with cellulase were significantly greater than those containing glucose (control) or konjac glucomannan mannanase hydrolysates. An equivalent mixture (1:1) of cellulase-mannanase hydrolysates added to the UHT milk also showed significant improvement on the LAB growth profiles (compared to the glucose or mannanase alone hydrolysates). Different LAB strains showed some variation in growth profiles on the hydrolysates although this was not significant as a function of carbon source. CONCLUSIONS: Glucomannan hydrolysates produced with either mannanase or cellulase enzymes were effective growth promoters (carbon sources) of LAB. However, cellulase hydrolysates were most effective. PMID- 22495738 TI - Steroids for LBP - from rationale to inconvenient truth. AB - Low back pain (LBP) and sciatica are highly prevalent and their treatment remains a clinical challenge. Systemic or local administration of corticosteroids is frequently prescribed for this indication, partly because its pathogenesis is believed to be a mix between mechanical and inflammatory phenomenon, and because corticosteroids do have some analgesic properties. Although there is some biological and animal data in favour of the use of corticosteroids in LBP and sciatica, clinical evidence remains scarce. Local epidural injection can have some short term benefit. However, we found no support for any type for systemic administration of corticosteroids, a practice that should definitively be banned. PMID- 22495739 TI - Interaction between HIV and Mycobacterium tuberculosis: HIV-1-induced CD4 T-cell depletion and the development of active tuberculosis. AB - PURPOSE OF REVIEW: HIV infection is the main driver of the HIV/tuberculosis (TB) syndemic in southern Africa since the early 1990s, when HIV infection rates started to increase exponentially and TB incidence rates quadruplet simultaneously. Here, we discuss pathogenic mechanisms of HIV-induced CD4 T-cell depletion and their potential impact on immune control of Mycobacterium tuberculosis. RECENT FINDINGS: Depletion of effector memory CD4 T cells from the air-tissue interphase, their dysfunctional regeneration and the preferential depletion of MTB-specific CD4 T cells from circulation and from the air-tissue interphase might be key factors for the increased susceptibility to develop active TB after HIV infection. SUMMARY: Early initiation of antiretroviral therapy or the development of an efficacious HIV vaccine would be the best options to reduce morbidity and mortality associated with the HIV/TB syndemic. PMID- 22495740 TI - Current world literature. PMID- 22495742 TI - Education and information for practicing school nurses: which technology supported resources meet their needs? AB - School nurses care for children with a variety of health-related conditions and they need information about managing these conditions, which is accessible, current, and useful. The goal of this literature review was to gather and synthesize information on technology-supported resources and to determine which met the educational needs of school nurses. Successful online educational programs were interactive and self-directed. The most common barriers were lack of time to find educational information, lack of knowledge about computers, technology, the Internet and specific programs, and lack of administrative support from school officials to use technology to access information and evidence for practice. Recommendations for successful use of technology to meet practicing school nurse's educational needs are offered. PMID- 22495743 TI - A focused immune response targeting the homotypic binding domain of the carcinoembryonic antigen blocks the establishment of tumor foci in vivo. AB - Metastatic forms of cancers remain the main cause of death in cancer patients. In this study, we demonstrate that directing a sustained antibody response towards the homotypic binding function of CEA interferes with the implantation and development of tumor foci in CEA-expressing transgenic (CEA.Tg) mice. Specifically, vaccinating CEA.Tg mice with a recombinant, altered self-form of the CEA Ig V-like N domain led to the production of circulating IgG1 and IgG2a antibodies that inhibited CEA-mediated adhesion of murine carcinoma expressing CEA (MC38.CEA) and mediated antibody-dependent lysis of tumor cells. Moreover, vaccinated CEA.Tg mice were resistant to the development of tumor nodules in the lungs and the peritoneal cavity, suggesting that mounting a focused antibody response to the CEA N domain may represent a simple therapeutic strategy to control the establishment of metastatic foci in cancer patients. PMID- 22495744 TI - Transmembrane estrogen receptor GPR30 is more frequently expressed in malignant than benign ovarian endometriotic cysts and correlates with MMP-9 expression. AB - OBJECTIVE: Molecular studies supporting the idea of malignant transformation of endometriosis are sparse and not well substantiated. The aims of this study were to detect expression levels of the novel estrogen-responsive receptor G protein coupled estrogen receptor 1 GPER, also termed GPR30, and to determine its correlation with matrix metalloproteinase-9 (MMP-9) in benign and malignant ovarian endometriotic cysts and to explore the significance of GPR30. METHODS: Immunohistochemical staining with the streptavidin-peroxidase method was conducted to determine the expression of GPR30 and MMP-9 in 24 cases of endometriosis-associated ovarian carcinoma (EAOC) and 32 specimens of ovarian endometriosis without malignant transformation. Reverse transcriptase polymerase chain reaction was performed to determine messenger RNA expression of GPR30 and MMP-9 in benign and malignant ovarian endometriotic cysts. We also investigated their associations with known clinic pathological parameters and the interrelationship between the expressions of the 2 proteins. RESULTS: The positive staining ratio of GPR30 was 95.8% (23/24) in EAOC cases, and the HScore was 268; whereas the positive ratio was 25% (8/32) in benign endometriotic cysts, and the Hscore was 95. Matrix metalloproteinase-9 was expressed in all 24 EAOC cases and 87.5% (28/32) of the benign samples, and the Hscores were 280 and 260, respectively (P > 0.05). The receptor GPR30 was significantly higher in EAOCs than in benign endometriotic cysts (P < 0.05). The expression of GPR30 messenger RNA was also significantly higher in malignant ovarian endometriotic cysts than in the benign group. The receptor GPR30 was positively related to tumor size, tumor stage, and lymph node metastasis. A positive relationship between GPR30 and MMP-9 was found (P = 0.002). CONCLUSIONS: The results suggest that the abnormal expression of GPR30 may be involved in malignant transformation, invasion, and metastasis of EAOCs. Testing of GPR30 expression levels may present both diagnostic and therapeutic options for the treatment of ovarian malignancies. PMID- 22495746 TI - A de novo metagenomic assembly program for shotgun DNA reads. AB - MOTIVATION: A high-quality assembly of reads generated from shotgun sequencing is a substantial step in metagenome projects. Although traditional assemblers have been employed in initial analysis of metagenomes, they cannot surmount the challenges created by the features of metagenomic data. RESULT: We present a de novo assembly approach and its implementation named MAP (metagenomic assembly program). Based on an improved overlap/layout/consensus (OLC) strategy incorporated with several special algorithms, MAP uses the mate pair information, resulting in being more applicable to shotgun DNA reads (recommended as >200 bp) currently widely used in metagenome projects. Results of extensive tests on simulated data show that MAP can be superior to both Celera and Phrap for typical longer reads by Sanger sequencing, as well as has an evident advantage over Celera, Newbler and the newest Genovo, for typical shorter reads by 454 sequencing. AVAILABILITY AND IMPLEMENTATION: The source code of MAP is distributed as open source under the GNU GPL license, the MAP program and all simulated datasets can be freely available at http://bioinfo.ctb.pku.edu.cn/MAP/ PMID- 22495745 TI - Functional connectivity for an "island of sparing" in autism spectrum disorder: an fMRI study of visual search. AB - Although autism is usually characterized with respect to sociocommunicative impairments, visual search is known as a domain of relative performance strength in this disorder. This study used functional MRI during visual search in children with autism spectrum disorder (n = 19; mean age = 13;10) and matched typically developing children (n = 19; mean age = 14;0). We selected regions of interest within two attentional networks known to play a crucial role in visual search processes, such as goal-directed selective attention, filtering of irrelevant distractors, and detection of behaviorally-relevant information, and examined activation and connectivity within and between these attentional networks. Additionally, based on prior research suggesting links between visual search abilities and autism symptomatology, we tested for correlations between sociocommunicative impairments and behavioral and neural indices of search. Contrary to many previous functional connectivity magnetic resonance imaging studies of autism that reported functional underconnectivity for task domains of weakness, we found atypically increased connectivity within and between attentional networks in autism. Additionally, we found increased functional connectivity for occipital regions, both locally and for long-distance connections with frontal regions. Both behavioral and neural indices of search were correlated with sociocommunicative impairment in children with autism. This association suggests that strengths in nonsocial visuospatial processing may be related to the development of core autistic sociocommunicative impairments. PMID- 22495747 TI - Ligand-binding site prediction using ligand-interacting and binding site-enriched protein triangles. AB - MOTIVATION: Knowledge about the site at which a ligand binds provides an important clue for predicting the function of a protein and is also often a prerequisite for performing docking computations in virtual drug design and screening. We have previously shown that certain ligand-interacting triangles of protein atoms, called protein triangles, tend to occur more frequently at ligand binding sites than at other parts of the protein. RESULTS: In this work, we describe a new ligand-binding site prediction method that was developed based on binding site-enriched protein triangles. The new method was tested on 2 benchmark datasets and on 19 targets from two recent community-based studies of such predictions, and excellent results were obtained. Where comparisons were made, the success rates for the new method for the first predicted site were significantly better than methods that are not a meta-predictor. Further examination showed that, for most of the unsuccessful predictions, the pocket of the ligand-binding site was identified, but not the site itself, whereas for some others, the failure was not due to the method itself but due to the use of an incorrect biological unit in the structure examined, although using correct biological units would not necessarily improve the prediction success rates. These results suggest that the new method is a valuable new addition to a suite of existing structure-based bioinformatics tools for studies of molecular recognition and related functions of proteins in post-genomics research. AVAILABILITY: The executable binaries and a web server for our method are available from http://sourceforge.net/projects/msdock/ and http://lise.ibms.sinica.edu.tw, respectively, free for academic users. PMID- 22495748 TI - Ranking viruses: measures of positional importance within networks define core viruses for rational polyvalent vaccine development. AB - MOTIVATION: The extraordinary genetic and antigenic variability of RNA viruses is arguably the greatest challenge to the development of broadly effective vaccines. No single viral variant can induce sufficiently broad immunity, and incorporating all known naturally circulating variants into one multivalent vaccine is not feasible. Furthermore, no objective strategies currently exist to select actual viral variants that should be included or excluded in polyvalent vaccines. RESULTS: To address this problem, we demonstrate a method based on graph theory that quantifies the relative importance of viral variants. We demonstrate our method through application to the envelope glycoprotein gene of a particularly diverse RNA virus of pigs: porcine reproductive and respiratory syndrome virus (PRRSV). Using distance matrices derived from sequence nucleotide difference, amino acid difference and evolutionary distance, we constructed viral networks and used common network statistics to assign each sequence an objective ranking of relative 'importance'. To validate our approach, we use an independent published algorithm to score our top-ranked wild-type variants for coverage of putative T-cell epitopes across the 9383 sequences in our dataset. Top-ranked viruses achieve significantly higher coverage than low-ranked viruses, and top ranked viruses achieve nearly equal coverage as a synthetic mosaic protein constructed in silico from the same set of 9383 sequences. CONCLUSION: Our approach relies on the network structure of PRRSV but applies to any diverse RNA virus because it identifies subsets of viral variants that are most important to overall viral diversity. We suggest that this method, through the objective quantification of variant importance, provides criteria for choosing viral variants for further characterization, diagnostics, surveillance and ultimately polyvalent vaccine development. PMID- 22495749 TI - CheShift-2: graphic validation of protein structures. AB - The differences between observed and predicted (13)C(alpha) chemical shifts can be used as a sensitive probe with which to detect possible local flaws in protein structures. For this reason, we previously introduced CheShift, a Web server for protein structure validation. Now, we present CheShift-2 in which a graphical user interface is implemented to render such local flaws easily visible. A series of applications to 15 ensembles of conformations illustrate the ability of CheShift-2 to locate the main structural flaws rapidly and accurately on a per residue basis. Since accuracy plays a central role in CheShift predictions, the treatment of histidine (His) is investigated here by exploring which form of His should be used in CheShift-2. AVAILABILITY: CheShift-2 is free of charge for academic use and can be accessed from www.cheshift.com PMID- 22495750 TI - ape 3.0: New tools for distance-based phylogenetics and evolutionary analysis in R. AB - Reflecting its continuously increasing versatility and functionality, the popularity of the ape (analysis of phylogenetics and evolution) software package has grown steadily over the years. Among its features, it has a strong distance based component allowing the user to compute distances from aligned DNA sequences based on most methods from the literature and also build phylogenetic trees from them. However, even data generated with modern genomic approaches can fail to give rise to sufficiently reliable distance estimates. One way to overcome this problem is to exclude such estimates from data analysis giving rise to an incomplete distance data set (as opposed to a complete one). So far their analysis has been out of reach for ape. To remedy this, we have incorporated into ape several methods from the literature for phylogenetic inference from incomplete distance matrices. In addition, we have also extended ape's repertoire for phylogenetic inference from complete distances, added a new object class to efficiently encode sets of splits of taxa, and extended the functionality of some of its existing functions. AVAILABILITY: ape is distributed through the Comprehensive R Archive Network: http://cran.r project.org/web/packages/ape/index.html Further information may be found at http://ape.mpl.ird.fr/pegas/ PMID- 22495751 TI - CistromeMap: a knowledgebase and web server for ChIP-Seq and DNase-Seq studies in mouse and human. AB - SUMMARY: Transcription and chromatin regulators, and histone modifications play essential roles in gene expression regulation. We have created CistromeMap as a web server to provide a comprehensive knowledgebase of all of the publicly available ChIP-Seq and DNase-Seq data in mouse and human. We have also manually curated metadata to ensure annotation consistency, and developed a user-friendly display matrix for quick navigation and retrieval of data for specific factors, cells and papers. Finally, we provide users with summary statistics of ChIP-Seq and DNase-Seq studies. PMID- 22495752 TI - GeneclusterViz: a tool for conserved gene cluster visualization, exploration and analysis. AB - MOTIVATION: Gene clusters are arrangements of functionally related genes on a chromosome. In bacteria, it is expected that evolutionary pressures would conserve these arrangements due to the functional advantages they provide. Visualization of conserved gene clusters across multiple genomes provides key insights into their evolutionary histories. Therefore, a software tool that enables visualization and functional analyses of gene clusters would be a great asset to the biological research community. RESULTS: We have developed GeneclusterViz, a Java-based tool that allows for the visualization, exploration and downstream analyses of conserved gene clusters across multiple genomes. GeneclusterViz combines an easy-to-use exploration interface for gene clusters with a host of other analysis features such as multiple sequence alignments, phylogenetic analyses and integration with the KEGG pathway database. AVAILABILITY: http://biohealth.snu.ac.kr/GeneclusterViz/; http://microbial.informatics.indiana.edu/GeneclusterViz/ PMID- 22495753 TI - Fast and accurate inference of local ancestry in Latino populations. AB - MOTIVATION: It is becoming increasingly evident that the analysis of genotype data from recently admixed populations is providing important insights into medical genetics and population history. Such analyses have been used to identify novel disease loci, to understand recombination rate variation and to detect recent selection events. The utility of such studies crucially depends on accurate and unbiased estimation of the ancestry at every genomic locus in recently admixed populations. Although various methods have been proposed and shown to be extremely accurate in two-way admixtures (e.g. African Americans), only a few approaches have been proposed and thoroughly benchmarked on multi-way admixtures (e.g. Latino populations of the Americas). RESULTS: To address these challenges we introduce here methods for local ancestry inference which leverage the structure of linkage disequilibrium in the ancestral population (LAMP-LD), and incorporate the constraint of Mendelian segregation when inferring local ancestry in nuclear family trios (LAMP-HAP). Our algorithms uniquely combine hidden Markov models (HMMs) of haplotype diversity within a novel window-based framework to achieve superior accuracy as compared with published methods. Further, unlike previous methods, the structure of our HMM does not depend on the number of reference haplotypes but on a fixed constant, and it is thereby capable of utilizing large datasets while remaining highly efficient and robust to over fitting. Through simulations and analysis of real data from 489 nuclear trio families from the mainland US, Puerto Rico and Mexico, we demonstrate that our methods achieve superior accuracy compared with published methods for local ancestry inference in Latinos. PMID- 22495754 TI - IDBA-UD: a de novo assembler for single-cell and metagenomic sequencing data with highly uneven depth. AB - MOTIVATION: Next-generation sequencing allows us to sequence reads from a microbial environment using single-cell sequencing or metagenomic sequencing technologies. However, both technologies suffer from the problem that sequencing depth of different regions of a genome or genomes from different species are highly uneven. Most existing genome assemblers usually have an assumption that sequencing depths are even. These assemblers fail to construct correct long contigs. RESULTS: We introduce the IDBA-UD algorithm that is based on the de Bruijn graph approach for assembling reads from single-cell sequencing or metagenomic sequencing technologies with uneven sequencing depths. Several non trivial techniques have been employed to tackle the problems. Instead of using a simple threshold, we use multiple depthrelative thresholds to remove erroneous k mers in both low-depth and high-depth regions. The technique of local assembly with paired-end information is used to solve the branch problem of low-depth short repeat regions. To speed up the process, an error correction step is conducted to correct reads of high-depth regions that can be aligned to highconfident contigs. Comparison of the performances of IDBA-UD and existing assemblers (Velvet, Velvet-SC, SOAPdenovo and Meta-IDBA) for different datasets, shows that IDBA-UD can reconstruct longer contigs with higher accuracy. AVAILABILITY: The IDBA-UD toolkit is available at our website http://www.cs.hku.hk/~alse/idba_ud PMID- 22495755 TI - RFMapp: ribosome flow model application. AB - The RFMapp is a graphical user interface application based on the RFM (ribosome flow model), enabling the estimation of the translation elongation rates of messenger ribonucleic acids (mRNAs) and the profile of ribosomal densities along the mRNAs, in a computationally efficient way. The RFMapp is based on the approach previously described by Reuveni et al., and unlike other traditional approaches in the field, which are mainly related to the genes' mean codon translation efficiency, the RFM additionally considers the codon order, the ribosomes' size and their order. Thus, it has been shown that RFM outperforms traditional predictors when analyzing both heterologous and endogenous genes. AVAILABILITY AND IMPLEMENTATION: Distributable cross-platform application and guideline are available for download at: http://www.cs.tau.ac.il/~tamirtul/RFM_Installers/install.htm. PMID- 22495756 TI - Hand function in 45 patients with sporadic inclusion body myositis. AB - The purpose of this study was to explore hand function in patients with sporadic inclusion body myositis (sIBM) using the Sollerman Hand function test, finger range of motion, hand- and pinch strength, and fine motor ability as well as subjective estimate of hand- and grip function. Forty-five outpatients with definite sIBM were investigated using handgrip-, lateral-, and pinch strength, active finger range of motion (AROM), fine motor ability with Purdue Pegboard test, Sollerman Hand function test, and patients' estimated hand- and grip function. The association between these variables were assessed using correlation statistics. A second test occasion was performed in 16 patients in order to investigate the intra-rater reliability. We found that the reduction of hand- and pinch strength was more pronounced (37% right, 31% left hand) than lateral strength (50%) in relation to normal values. AROM was impaired in 25 (56%) in the right and 29 (64%) in the left hand. Fine motor ability was fairly well preserved; mean right/ left 70 and 60% of normal. AROM deficit was found to be present in 50% of patients 7 years after perceived hand weakness. This is important since it was found to impair the usefulness of the different strength measures, while limitations due to AROM deficit were not found regarding the Sollerman and to a lesser extent the Purdue Pegboard tests. Results of the test retest showed very good reliability. Our results indicate that impairment of hand function is frequent and severe in sIBM patients. Reduction in AROM is frequent, and it is important to identify since it affects the usefulness of handgrip measurements, and further that may be treatable. Several different tests are probably needed in order to describe the patients' limitations and to capture changes over time. Compensatory strategies when gripping test items is a problem especially in patients with AROM deficits. Research on validity and reliability of these tests in sIBM patients are lacking. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 22495758 TI - Developmental toxicity evaluations of whole mixtures of disinfection by-products using concentrated drinking water in rats: gestational and lactational effects of sulfate and sodium. AB - A developmental toxicity bioassay was used in three experiments to evaluate water concentrates for suitability in multigenerational studies. First, chlorinated water was concentrated 135-fold by reverse osmosis; select lost disinfection by products were spiked back. Concentrate was provided as drinking water to Sprague Dawley and F344 rats from gestation day 6 to postnatal day 6. Maternal serum levels of luteinizing hormone on gestation day 10 were unaffected by treatment for both strains. Treated dams had increased water consumption, and increased incidences of polyuria, diarrhea, and (in Sprague-Dawley rats) red perinasal staining. Pup weights were reduced. An increased incidence of eye defects was seen in F344 litters. Chemical analysis of the concentrate revealed high sodium (6.6 g/l) and sulfate (10.4 g/l) levels. To confirm that these chemicals caused polyuria and osmotic diarrhea, respectively, Na2SO4 (5-20 g/l) or NaCl (16.5 g/l) was provided to rats in drinking water. Water consumption was increased at 5- and 10-g Na2SO4/l and with NaCl. Pup weights were reduced at 20-g Na2SO4/l. Dose related incidences and severity of polyuria and diarrhea occurred in Na2SO4 treated rats; perinasal staining was seen at 20 g/l. NaCl caused polyuria and perinasal staining, but not diarrhea. Subsequently, water was concentrated ~120 fold and sulfate levels were reduced by barium hydroxide before chlorination, yielding lower sodium (<=1.5 g/l) and sulfate (<=2.1 g/l) levels. Treatment resulted in increased water consumption, but pup weight and survival were unaffected. There were no treatment-related clinical findings, indicating that mixtures produced by the second method are suitable for multigenerational testing. PMID- 22495759 TI - A novel Phase I/IIa design for early phase oncology studies and its application in the evaluation of MK-0752 in pancreatic cancer. AB - The Cancer Research UK study CR0720-11 is a trial to determine the tolerability and effect on survival of using two agents in combination in patients with advanced pancreatic cancer. In particular, the trial is designed first to identify the most suitable combination of doses of the two agents in terms of the incidence of dose-limiting toxicities. Then, the survival of all patients who have received that dose combination in the study so far, together with additional patients assigned to that dose combination to ensure that the total number is sufficient, will be analysed. If the survival outcomes show promise, then a definitive randomised study of that dose combination will be recommended. The first two patients in the trial will be treated with the lowest doses of each agent in combination. An adaptive Bayesian procedure based only on monotonicity constraints concerning the risks of toxicity at different dose levels will then be used to suggest dose combinations for subsequent patients. The survival analysis will concern only patients who received the chosen dose combination, and will compare observed mortality with that expected from an exponential model based on the known survival rates associated with current treatment. In this paper, the Bayesian dose-finding procedure is described and illustrated, and its properties are evaluated through simulation. Computation of the appropriate sample size for the survival investigation is also discussed. PMID- 22495760 TI - Transient abnormal fetal cardiac flow patterns at 13 to 17 gestational weeks. AB - OBJECTIVE: To report the outcome of transient abnormal cardiac flow patterns (ABCFP) at 13 to 17 weeks' gestation. METHODS AND RESULTS: Observational single operator study of transvaginal sonography scans of 13,183 fetuses. Of the 22 fetuses with ABCFP (1:600) high pulmonary valvular velocity was detected in 11 (8 of them transient), an abnormal blood flow in the coronary region in 6, mitral regurgitation in 3, and high aortic valvular velocity in 2 cases. In over 90%, these findings were transient. At birth, there were two cases of mild pulmonary stenosis, one meconium ileus, and two cases of asymptomatic bicuspid aortic valve without stenosis. All the remaining neonates were healthy. CONCLUSIONS: The transient sonographic findings at 13 to 17 weeks' gestation of mitral regurgitation, pulmonary or aortic high valvular flow, and coronary sinus flow have a good prognosis, and in most cases are not associated with persistent cardiac anomalies. The etiology, incidence, and the prognosis of fetuses with transient ABCFP at 13 to 17 weeks' gestation are different from what is observed when the same occurs later in gestation. PMID- 22495761 TI - Iodine mediated/Bronsted acid-catalyzed dimerization of vinylarenes: a tandem reaction through Ritter trapping to produce N-(4-iodo-1,3-diarylbutyl) acetamides. AB - In the presence of p-toluenesulfonic acid and iodine, styrene derivatives undergo head-to-tail dimerization followed by trapping with nitriles to yield the corresponding Ritter-type products. PMID- 22495763 TI - Long-term high animal protein diet reduces body weight gain and insulin secretion in diet-induced obese rats. AB - BACKGROUND: The effects of a high protein diet on insulin secretion and glucose metabolism have been quite controversial. The aim of this study was to evaluate the effects of long-term isocaloric high animal protein intake on insulin secretion in diet-induced obese rats. RESULTS: After the experimental period (24 weeks), the high-fat diet-induced obese rats that were fed isocaloric high protein diets (HP) had lower body weight gain (P < 0.01) and lower visceral fat (P < 0.05) than normal protein (NP) rats. Fasting plasma glucagon-like peptide-1 (GLP-1) was also reduced significantly (P < 0.05), as well as serum insulin levels at 5 min and 10 min by intravenous insulin releasing test. In addition, insulin mRNA and pancreatic duodenal homeodomain-1 (PDX-1), GLP-1 protein expression were both markedly lower in HP rats (P < 0.05), while PDX-1 mRNA in HP rats had no difference from NP rats. CONCLUSION: These results suggest that long term isocaloric high animal protein intake reduces the acute insulin response in obese rats and the decrease of insulin is associated with both reduced weight gain and inhibition of PDX-1 expression. GLP-1 might be a negative feedback for the balance of energy metabolism secondary to changes of body weight and visceral fat. PMID- 22495762 TI - Initial immune reaction and angiogenesis in bone healing. AB - During hematoma formation following injury, an inflammatory reaction ensues as an initial step in the healing process. As granulation tissue matures, revascularization is a prerequisite for successful healing. The hypothesis of this study was that scarless tissue reconstitution in the regenerative bone healing process is dependent on a balanced immune reaction that initiates revasculatory steps. To test this hypothesis, cellular composition and expression profiles of a bone hematoma (regenerative, scarless) was compared with a muscle soft tissue hematoma (healing with a scar) in a sheep model. Upregulation of regulatory T helper cells and anti-inflammatory cytokine expression (IL-10) coincided with an upregulation of angiogenic factors (HIF1alpha and HIF1alpha regulated genes) in the regenerative bone hematoma but not in the soft tissue hematoma. These results indicate that the timely termination of inflammation and early onset of revascularization are interdependent and essential for a regenerative healing process. Prolonged pro-inflammatory signaling occurring in a delayed bone-healing model supports the finding that timely termination of inflammation furthers the regenerative process. Differing cellular compositions are due to different cell sources invading the hematoma, determining the ensuing cytokine expression profile and thus paving the path for regenerative healing in bone or the formation of scar tissue in muscle injury. PMID- 22495764 TI - Inherited mosaicism for the supernumerary marker chromosome in cat eye syndrome: inter- and intra-individual variation and correlation to the phenotype. AB - We have studied a family with repeated transmission of mosaicism for a supernumerary marker chromosome (SMC), giving rise to varying symptoms of the cat eye syndrome (CES) in the offspring. The frequency of the SMC was investigated using FISH with probes from the CES critical region on lymphocytes as well as buccal cells. The same probes were used to study the frequency of the SMC in spermatozoa from the father. The SMC was characterized in detail using array-CGH and was found to correspond to a symmetrical cat eye SMC type I, with two extra copies of the most proximal part of 22q11, not extending into the classical 22q11.2 deletion region. Mosaicism for the SMC was detected in 4 out of 7 family members, the father and all his three children. The degree of mosaicism varied greatly between individuals as well as between tissues, with twice as many cells with the SMC in epithelial cells compared to blood. The highest frequency (almost 50%) was found in spermatozoa from the father. There was a direct correlation between the degree of mosaicism and the symptoms, varying from no obvious symptoms to classical CES. The study confirms the occurrence of direct transmission of SMC-mosaicism in CES. The results indicate that examination of parental epithelial cells should be preferred compared to blood cells in order to exclude a recurrence risk in parents of a child with CES. Interphase FISH analysis of spermatozoa is the most sensitive method to exclude paternal germ line mosaicsm. PMID- 22495765 TI - Performance of a propensity score adjustment in longitudinal studies with covariate-dependent representation. AB - Longitudinal observational studies provide rich opportunities to examine treatment effectiveness during the course of a chronic illness. However, there are threats to the validity of observational inferences. For instance, clinician judgment and self-selection play key roles in treatment assignment. To account for this, an adjustment such as the propensity score can be used if certain assumptions are fulfilled. Here, we consider a problem that could surface in a longitudinal observational study and has been largely overlooked. It can occur when subjects have a varying number of distinct periods of therapeutic intervention. We evaluate the implications of baseline variables in the propensity model being associated with the number of post baseline observations per subject and refer to it as 'covariate-dependent representation'. An observational study of antidepressant treatment effectiveness serves as a motivating example. The analyses examine the first 20 years of follow-up data from the National Institute of Mental Health Collaborative Depression Study, a longitudinal, observational study. A simulation study evaluates the consequences of covariate-dependent representation in longitudinal observational studies of treatment effectiveness under a range of data specifications.The simulations found that estimates were adversely affected by underrepresentation when there was lower ICC among repeated doses and among repeated outcomes. PMID- 22495766 TI - Nrf2-mediated resistance to oxidant-induced redox disruption in embryos. AB - Events that control developmental changes occur during specific windows of gestation and if disrupted, can lead to dysmorphogenesis or embryolethality. One largely understudied aspect of developmental control is redox regulation, where the untimely disruption of intracellular redox potentials (E(h) ) may alter development, suggesting that tight control of developmental-stage-specific redox states is necessary to support normal development. In this study, mouse gestational day 8.5 embryos in whole embryo culture were treated with 10 MUM dithiole-3-thione (D3T), an inducer of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). After 14 hr, D3T-treated and -untreated conceptuses were challenged with 200 MUM hydrogen peroxide (H2O2) to induce oxidant-induced change to intracellular E(h) s. Redox potentials of glutathione (GSH), thioredoxin-1 (Trx1), and mitochondrial thioredoxin-2 (Trx2) were then measured over a 2-hr rebounding period following H2O2 treatment. D3T treatment increased embryonic expression of known Nrf2-regulated genes, including those responsible for redox regulation of major intracellular redox couples. Exposure to H2O2 without prior D3T treatment produced significant oxidation of GSH, Trx1, and Trx2, based on E(h) values, where GSH and Trx2 E(h) recovered, reaching to pre-H2O2 E(h) ranges, but Trx1 E(h) remained oxidized. Following H2O2 addition in culture to embryos that received D3T pretreatments, GSH, Trx1, and Trx2 were insulated from significant oxidation. These data show that Nrf2 activation may serve as a means to protect the embryo from chemically induced oxidative stress through the preservation of intracellular redox states during development, allowing normal morphogenesis to ensue. PMID- 22495767 TI - A population-based study on the patterns of use of different chemotherapy regimens in Swiss patients with early breast cancer. AB - BACKGROUND: There is considerable heterogeneity in the use of chemotherapy in early breast cancer (BC), despite international recommendations issued from the NCCN, NIH and the St.Gallen bi-annual conference. METHODS: We included 1,535 patients from seven Swiss cancer registries between 2003 and 2005 receiving chemotherapy for stage I to III BC. Chemotherapy was categorised into (a) FAC/FEC, anthracyclines followed by CMF or anthracycline-taxane combinations (FAC T) (781 patients) and (b) other chemotherapy regimens such as CMF/AC (EC) (754 patients). Predictors for choosing FAC-T over non-FAC-T chemotherapy were separately determined in all patients and in ER-negative patients (n = 496) by multivariate logistic regression analysis. RESULTS: The use of FAC-T increased significantly over time, from 44% in 2003 to 55% in 2005. BC stage III (versus stage I-II) and nodal positivity were the predominant predictors for using FAC-T chemotherapy in the adjusted model (odds ratio (OR) 4.1, 95%-confidence intervals (CI) 2.6-6.3 and OR 3.0, 95%-CI 2.0-4.4, respectively). In high-risk ER-negative BC patients, poor histological differentiation was more important to choose FAC-T chemotherapy (OR 3.8, 95%-CI 1.9-7.5) than tumour stage or nodal status. The use of FAC-T chemotherapy varied substantially among the seven geographic regions, from 20% in rural Grisons-Glarus to 73% in Zurich. CONCLUSIONS: Tumour biology is a predominant factor for choosing FAC-T over older chemotherapy regimens in patients with ER-negative early BC, but improvements should be made to reduce the substantial regional heterogeneity. Further epidemiological studies should assess how the use of FAC-T chemotherapy is affecting clinical outcome in patients with early BC and different risk profiles. PMID- 22495769 TI - Carotid magnetization-prepared rapid acquisition with gradient-echo signal is associated with acute territorial cerebral ischemic events detected by diffusion weighted MRI. AB - BACKGROUND: Carotid intraplaque hemorrhage has been associated with symptomatic stroke and can be accurately detected with magnetization-prepared rapid acquisition with gradient-echo (MPRAGE). Currently, there are no studies analyzing carotid MPRAGE signal and territorial ischemic events defined by diffusion restriction in the acute setting. Our aim was to determine the association of carotid MPRAGE signal with acute territorial ischemic events using carotid MPRAGE and brain diffusion tensor imaging. METHODS AND RESULTS: After the addition of the MPRAGE sequence to the neck MR angiographic protocol, 159 patients with suspected acute stroke were evaluated with both brain diffusion tensor imaging and carotid MPRAGE sequences over 2 years, providing 318 carotid artery and paired brain images for analysis. Forty-eight arteries were excluded due to extracarotid sources of brain ischemia and 4 were excluded due to carotid occlusion. Two hundred sixty-six arteries were eligible for data analysis. Carotid MPRAGE-positive signal was associated with an acute cerebral territorial ischemic event with a relative risk of 6.4 (P<0.001). The relative risk of a diffusion tensor imaging-positive territorial ischemic event with carotid MPRAGE positive signal was increased in mild, moderate, and severe stenosis categories (10.3, P<0.001; 2.9, P=0.01; and 2.2, P=0.01, respectively). CONCLUSIONS: In the workup of acute stroke, carotid MPRAGE-positive signal was associated with an increased risk of territorial cerebral ischemic events as detected objectively by brain diffusion tensor imaging. The relative risk of stroke was increased in all carotid stenosis categories but was most elevated in the mild stenosis category. PMID- 22495768 TI - A framework for understanding modifications to measures for diverse populations. AB - OBJECTIVE: Research on health disparities and determinants of health disparities among ethnic minorities and vulnerable older populations necessitates use of self report measures. Most established instruments were developed on mainstream populations and may need adaptation for research with diverse populations. Although information is increasingly available on various problems using these measures in diverse groups, there is little guidance on how to modify the measures. A framework of issues to consider when modifying measures for diverse populations is presented. METHODS: The authors describe reasons for considering modifications, the types of information that can be used as a basis for making modifications, and the types of modifications researchers have made. Recommendations are made to test modified measures to assure their appropriateness, and suggestions are provided on reporting modifications in publications using the measures. DISCUSSION: The issues open a dialogue about what appropriate guidelines would be for researchers adapting measures in studies of ethnically diverse populations. PMID- 22495770 TI - Synthesis of functional core, star polymers via RAFT polymerization for drug delivery applications. AB - Poly(oligoethylene glycol) methyl ether acrylate was polymerized via reversible addition fragmentation transfer polymerization (RAFT), and then chain extended in the presence of both a cross-linker and vinyl benzaldehyde (VBA), yielding monodisperse star polymers. The presence of aldehyde groups in the core was exploited to attach doxorubicin. The drug loading was controlled by the amount of VBA incorporated (until 28 wt% in drug). The doxorubicin release was studied at pH = 5.5 and 7.4; conditions representative of endosomal and extra cellular environments. In vitro studies revealed that the doxorubicin-conjugated star polymers had a level of cytotoxicity comparable to that found for free doxorubicin. Confocal microscopy and flow cytometry studies confirmed efficient cell uptake of the star polymers. PMID- 22495771 TI - Maternal mental health and social support: effect on childhood atopic and non atopic asthma symptoms. AB - BACKGROUND: Atopic and non-atopic asthma have distinct risk factors and immunological mechanisms, and few studies differentiate between the impacts of psychosocial factors on the prevalence of these disease phenotypes. The authors aimed to identify whether the effect of maternal mental health on prevalence of asthma symptoms differs between atopic and non-atopic children, taking into account family social support. METHODS: This is a cross-sectional study of 1013 children participating in the Social Change Allergy and Asthma in Latin America project. Psychosocial data were collected through a household survey utilising Self-Reporting Questionnaire and Medical Outcome Study Social Support Scale. Socioeconomic and wheezing information was obtained through the questionnaire of the International Study of Allergy and Asthma in Childhood, and level of allergen specific IgE was measured to identify atopy. Polytomous logistic regression was used to estimate the association between maternal mental health, social support and atopic and non-atopic wheezing. Effect modification was evaluated through stratified polytomous regression according to social support level. RESULTS: Maternal mental disorder had the same impact on atopic and non-atopic wheezing, even after adjusting for confounding variables. Affective, material and informational supports had protective effects on non-atopic asthma, and there is some evidence that social supports may act as a buffer for the impact of maternal mental disorder on non-atopic wheezing. CONCLUSION: Poor maternal mental health is positively associated with wheezing, independent of whether asthma is atopic or non-atopic, but perception of high levels of social support appears to buffer this relationship in non-atopic wheezers only. PMID- 22495772 TI - Personal, interpersonal and structural challenges to accessing HIV testing, treatment and care services among female sex workers, men who have sex with men and transgenders in Karnataka state, South India. AB - BACKGROUND: Despite high HIV prevalence rates among most-at-risk groups, utilisation of HIV testing, treatment and care services was relatively low in Karnataka prior to 2008. The authors aimed to understand the barriers to and identify potential solutions for improving HIV service utilisation. METHODS: Focus group discussions were carried out among homogeneous groups of female sex workers, men who have sex with men and transgenders, and programme peer educators in six districts across Karnataka in March and April 2008. RESULTS: 26 focus group discussions were conducted, involving 302 participants. Participants had good knowledge about HIV and HIV voluntary counselling and testing (VCT) services, but awareness of other HIV services was low. The fear of the psychological impact of a positive HIV test result and the perceived repercussions of being seen accessing HIV services were key personal and interpersonal barriers to HIV service utilisation. Previous experiences of discrimination at government healthcare services, coupled with discriminatory attitudes and behaviours by VCT staff, were key structural barriers to VCT service uptake among those who had not been HIV tested. Among those who had used government-managed prevention of parent to child transmission and antiretroviral treatment services, poor physical facilities, long waiting times, lack of available treatment, the need to give bribes to receive care and discriminatory attitudes of healthcare staff presented additional structural barriers. CONCLUSIONS: Embedding some HIV care services within existing programmes for vulnerable populations, as well as improving service quality at government facilities, are suggested to help overcome the multiple barriers to service utilisation. Increasing the uptake of HIV testing, treatment and care services is key to improving the quality and longevity of the lives of HIV-infected individuals. PMID- 22495773 TI - Trends in condom use among female sex workers in Andhra Pradesh, India: the impact of a community mobilisation intervention. AB - BACKGROUND: Community mobilisation interventions for HIV prevention among female sex workers (FSWs) aim to organise FSWs for collective action and challenge the structures of power that underlie HIV risk. Assessing intervention impact is challenging because the importance of direct individual exposure to intervention components may decrease over time as change occurs at social-normative, policy and other structural levels. In this paper, the authors examine changes over time in consistent condom use among FSWs in Rajahmundry, Andhra Pradesh, the location of a long-standing community mobilisation intervention. METHODS: The authors analyse cross-sectional data collected among FSWs at three time points (n=2276) using respondent-driven sampling. Multiple logistic regression was used to assess the association of programme exposure with consistent condom use and whether this association varied over time. RESULTS: The proportion of FSWs having no exposure or only receptive exposure to the intervention decreased over time, while active utilisation increased from 19.4% in 2006 to 48.5% in 2009-2010. Consistent condom use with clients also increased from 56.3% in 2006 to 75.3% in 2009-2010. Multivariate analysis showed that age, age at start of sex work, venue, living conditions and programme exposure were significantly associated with condom use. The positive association between programme exposure and consistent condom use did not vary significantly over time. CONCLUSIONS: Findings indicate improvements in HIV risk reduction behaviour among FSWs and suggest that the intervention has substantial reach in the FSW population. The intervention's strategies may be contributing to population-level HIV risk reduction among FSWs. PMID- 22495774 TI - Community advocacy groups as a means to address the social environment of female sex workers: a case study in Andhra Pradesh, India. AB - BACKGROUND: To examine the association between the presence of community advocacy groups (CAGs) and female sex workers' (FSWs) access to social entitlements and outcomes of police advocacy. METHODS: Data were used from a cross-sectional survey conducted in 2010-2011 among 1986 FSWs and 104 NGO outreach workers from five districts of Andhra Pradesh. FSWs were recruited using a probability-based sampling from 104 primary sampling units (PSUs). A PSU is a geographical area covered by one outreach worker and is expected to have an active CAG as per community mobilisation efforts. The presence of active CAGs was defined as the presence of an active committee or advocacy group in the area (PSU). Outcome indicators included acquisition of different social entitlements and measures of police response as reported by FSWs. Multivariate linear and logistic regression analyses were used to examine the associations. RESULTS: Areas with active CAGs compared with their counterparts had a significantly higher mean number of FSWs linked to ration cards (12.8 vs 6.8; p<0.01), bank accounts (9.3 vs 5.9; p=0.05) and health insurance (13.1 vs 7.0; p=0.02). A significantly higher percentage of FSWs from areas with active CAGs as compared with others reported that the police treat them more fairly now than a year before (79.7% vs 70.3%; p<0.05) and the police explained the reasons for arrest when arrested the last time (95.7% vs 87%; p<0.05). CONCLUSION: FSWs from areas with active CAGs were more likely to access certain social entitlements and to receive a fair response from the police, highlighting the contributions of CAGs in community mobilisation. PMID- 22495775 TI - Minding the gap: changes in life expectancy in the Baltic States compared with Finland. AB - BACKGROUND: In the 20 years since the three Baltic States, Estonia, Latvia and Lithuania, have been independent, they have converged progressively with a Western neighbours, politically economically and socially. In contrast, the health gap has widened. METHODS: Trends in life expectancy in the three Baltic States were compared with Finland and were decomposed by age for the years 1994, 1999, 2004 and 2009 and by cause of death for year 2009. 1994 was when life expectancy fell to its lowest level since the three countries regained independence. RESULTS: From the mid-1980s to the mid-1990s, the gap in life expectancy between the three Baltic States and Finland widened, especially for men. It then narrowed progressively, except Lithuania where it widened again after 1999. Decomposition by age reveals that the narrowing gap has been driven largely by reduced mortality at working ages, partly counteracted by a relative failure to improve at older ages, especially in Lithuania. Decomposition by cause of death identifies diseases of the circulatory system as the largest contributor to the gap, with the contribution largest at older ages. However, cancer deaths, especially among men, are also important as are deaths from external causes among younger men. CONCLUSIONS: Although the gaps in life expectancy between the Baltic States and Finland have reduced, improvements, especially in Latvia and Lithuania, have been fragile. There is a clear need to act on the leading causes of the persisting gap with Finland, in particular through action on hazardous drinking and other risk factors for cardiovascular disease. PMID- 22495777 TI - Development and validation of a highly sensitive LC-MS/MS-ESI method for the determination of bicalutamide in mouse plasma: application to a pharmacokinetic study. AB - A highly sensitive, rapid assay method has been developed and validated for the estimation of bicalutamide in mouse plasma using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the negative-ion mode. The assay procedure involves extraction of bicalutamide and tolbutamide (internal standard, IS) from mouse plasma with a simple protein precipitation method. Chromatographic separation was achieved using an isocratic mobile phase (0.2% formic acid:acetonitrile, 35:65, v/v) at a flow rate of 0.5 mL/min on an Atlantis dC18 column (maintained at 40 +/- 1 degrees C) with a total run time of 3.0 min. The MS/MS ion transitions monitored were m/z 428.9 -> 254.7 for bicalutamide and m/z 269.0 -> 169.6 for IS. Method validation was performed as per FDA guidelines and the results met the acceptance criteria. The lower limit of quantitation achieved was 1.04 ng/mL and the linearity range extended from 1.04 to 1877 ng/mL. The intra- and inter-day precisions were in the ranges of 0.49-4.68 and 2.62 4.15, respectively. PMID- 22495778 TI - Anti-obesity role of adzuki bean extract containing polyphenols: in vivo and in vitro effects. AB - BACKGROUND: The aim of this work was to evaluate the effects of polyphenol-rich adzuki bean extract on lipid metabolism, triglyceride accumulation and proinflammatory cytokine secretion in vivo and in vitro. RESULTS: For the in vivo study, rats were divided into four groups: group C was fed a control diet, group A was fed the control diet with 1% adzuki bean extract, group CF was fed a high fat diet, and group AF was fed a high fat diet with 1% adzuki bean extract. For the in vitro study, the ability of adzuki bean extract to suppress triglyceride incorporation, glycerol phosphate dehydrogenase activity and inflammatory response was investigated in cultured human adipocytes. Data from the animal study showed that adzuki bean extract improved lipid metabolism in both the normal and high-fat diet groups. Adzuki bean extract treatment in the high-fat group resulted in significant reductions in total hepatic lipid accumulation and lipid secretion into the feces. Incubation of adipocytes with adzuki bean extract significantly decreased triglyceride accumulation, glycerol phosphate dehydrogenase activity and inflammatory responses without affecting cell viability. CONCLUSION: The results of this study demonstrate that adzuki bean extract has high potential to serve as a natural anti-obesity agent. PMID- 22495779 TI - Developing and establishing school-based sexual health services: issues for school nursing practice. AB - School-based sexual health clinics are emerging as one of the key ways to promote sexual health among young people, and school nurses play an important role in developing and delivering these services. This study used a qualitative design to explore the experiences of health professionals and policy makers involved in setting up such services in U.K. schools. It presents the internationally transferable messages from this study for school nurses. Particularly, the ways in involving young people in developing and evaluating services, dealing with social and parental objections, and building alliances with school staff are important aspects of working in this important but socially sensitive area of school health. It also explores how sexual health services can be branded and marketed and highlights some of the barriers and facilitators for developing successful school-based or school-linked sexual health clinics. PMID- 22495780 TI - Generation n + 1: Projected numbers of babies born to women with PKU compared to babies with PKU in the United States in 2009. AB - Newborn PKU screening has been available since the mid-1960s, and the first group of screened babies is now a complete reproductive cohort (age 15-44). Untreated maternal PKU (MPKU) often results in significant developmental and physical disabilities in exposed fetuses, and could potentially offset some or all of the benefits produced by newborn PKU screening and dietary treatment. Based on the age distribution of the United States population in 2009, and using different estimates of PKU frequency (1/10,000; 1/15,000; 1/20,000), the projected number of babies born to women with PKU was compared to the projected number of babies born with PKU. In 2009, there were about 62,000,000 women age 15-44, with a fertility rate of 66.7 births/1,000 women. Of these women, depending on the incidence of PKU, 3,097-6,195 were estimated to have PKU, and they would have delivered 207-413 babies. In that same year, the number of births was 4,118,055, which would have resulted in 206-412 babies with PKU. Thus, in the United States, at all estimates of PKU frequency, the number of babies exposed to MPKU is equal to the number of babies born with PKU. This ratio varies with the fertility rate but is not dependent on the incidence of PKU. The benefits of newborn PKU screening and treatment could be significantly curtailed if adequate resources, education, and funding are not available to follow and monitor women with MPKU and their babies. PMID- 22495781 TI - Enhancing the Jacquez k nearest neighbor test for space-time interaction. AB - The Jacquez k nearest neighbor test, originally developed to improve upon shortcomings of existing tests for space-time interaction, has been shown to be a robust and powerful method of detecting interaction. Despite its flexibility and power, however, the test has three main shortcomings: (i) it discards important information regarding the spatial and temporal scales at which the detected interaction takes place; (ii) the results of the test have not been visualized; and (iii) recent research demonstrates the test to be susceptible to population shift bias. This study presents enhancements to the Jacquez k nearest neighbors test with the goal of addressing each of these three shortcomings and of improving the utility of the test. Data on Burkitt's lymphoma cases in Uganda between 1961 and 1975 are used to illustrate the modifications and enhanced visual output of the test. Output from the enhanced test is compared with that provided by alternative tests of space-time interaction. Results show the enhancements presented in this study transform the Jacquez test into a complete, descriptive, and informative metric that can be used as a stand-alone measure of global space-time interaction. PMID- 22495782 TI - Bibliography. Head and neck. Current world literature. PMID- 22495784 TI - Methoxychlor-induced ovarian follicle toxicity in mice: dose and exposure duration-dependent effects. AB - BACKGROUND: Methoxychlor (MXC) is specifically known to target ovarian antral follicles, increasing atresia (death via apoptosis) in them. This is of concern because females are born with a finite pool of ovarian follicles. Only limited studies have explored the phenomenon of a reduced fertility threshold for effect based on the percentage of antral follicle atresia. METHODS: In this article, we report on adult female CD-1 mice exposed intraperitoneally to various doses of MXC for 5, 10, 20, and 30 days. In the 20-day treatment, mice were dosed with either the vehicle or MXC at 64 or 96 mg/kg/day, whereas in the 30-day treatment, mice were dosed with vehicle or MXC at 48, 64, or 96 mg/kg/day. The mice that were dosed with MXC for 30 days were also mated with untreated males for a determination of overall fertility. RESULTS: A significantly increased percentage (50%) of atretic antral follicles was observed only after 20 and 30 days of treatment. Specifically, mice treated with MXC64 for 20 and 30 days had an increased percentage of atretic antral follicles compared with vehicle-treated mice. Interestingly, mice dosed with MXC96 had an increased percentage of atretic antral follicles after 30 days, but not after 20 days of treatment compared with vehicle-treated mice. Overall fertility of the mice was not different compared with controls. CONCLUSIONS: The results indicate that as much as a 50% increase in atretic antral follicles does not affect the immediate fertility of the mice. PMID- 22495785 TI - Synthesis and characterization of monodisperse thermosensitive dumbbell-shaped microgels. AB - Monodisperse thermosensitive dumbbell-shaped core-shell microgels are fabricated, which consist of a polystyrene core with a cross-linked poly (N isopropylacrylamide) shell. The morphology of the microgels was investigated through cryogenic transmission electron microscopy and depolarized dynamic light scattering. The effective volume fraction and aspect ratio of the system could be adjusted through the swelling of the thermosensitive shell. We observe a phase transition of the microgels to an ordered, crystal-like state, which is apparent through Bragg-reflections in the visible range. These observations are further supported by rheological measurements where the shear-melting of the crystal phase is clearly detected. PMID- 22495788 TI - Quantitative HPLC of pigments of irregularly coloured eggshells: application to aliquots of powdered shell from quail. AB - Twelve quail eggshells from farmed Coturnix coturnix japonica were separately ground to fine powder and two aliquots of each (average weights 13.86 mg and 51.90 mg) were extracted with formic acid. Biliverdin (38-284 pmol/mg) and protoporphyrin (841-1666 pmol/mg) were measured by HPLC. There was good agreement between the values for the corresponding samples and with those for two entire eggshells from the same source. The preparation of a homogenate as a powder from heterogeneously pigmented eggshells has the advantage that not all of the sample needs to be initially extracted for analysis and residual material can be stored in a stable form and used for repeat measurements and for longitudinal studies. PMID- 22495786 TI - Untreated HIV infection is associated with higher blood alcohol levels. AB - BACKGROUND: Alcohol abuse has been associated with HIV/AIDS progression, but the effects of HIV infection and treatment on alcohol exposure have not been explored to date. This pilot study examines the relationship of untreated HIV infection to blood alcohol concentrations (BAC) relative to BAC after initiation of antiretroviral therapy (ART). METHODS: Fifteen volunteers with untreated HIV/AIDS participated in 2 sets of alcohol or alcohol placebo administration studies before and after initiation of ART. Oral alcohol (1 g/kg) or alcohol placebo was administered, participants were followed for pharmacokinetics, subjective responses, and cognitive effects over 8 hours. After initial alcohol studies, the ART regimen selected by participant clinicians was instituted. Observed ART dosing took place for at least 2 weeks. Participants then returned for a second set of alcohol/placebo administration studies while on ART. RESULTS: Participants had significantly higher BAC (P < 0.001) before ART than after ART administration. Alcohol area under the curve was significantly higher in untreated HIV disease (P = 0.011) with significantly higher C(max) (P = 0.015) and C(min) (P = 0.05). The elimination rate was not different between pre-ART and post-ART conditions. Despite declines in BAC after ART initiation, no differences in subjective responses were observed with alcohol administration. CONCLUSIONS: Untreated HIV infection is associated with risk for higher BAC than that observed after ART. These findings indicate that patients with untreated HIV disease who ingest alcohol are at greater risk for alcohol associated adverse events and toxicities and underscores the need for simultaneous treatment of alcohol use disorders and HIV in patients with co-occurring conditions. PMID- 22495787 TI - The safety, persistence, and acceptability of an antiretroviral microbicide candidate UC781. AB - OBJECTIVE: : To evaluate the persistence and acceptability of a minimally absorbed vaginal gel antiretroviral designed to block the acquisition of HIV. METHODS: : Sixty healthy women aged 18-45 participated in a phase-1 randomized placebo-controlled trial of a vaginal gel containing the nonnucleoside reverse transcriptase inhibitor UC781. Women underwent a single timed exposure ranging from 0 to 8 hours and were followed for 35 days. Safety was assessed by symptoms, physical exam, laboratory evaluation, and colposcopy. Persistence was assessed by drug levels in cervicovaginal lavage (CVL) and vaginal swab specimens. RESULTS: : The participants' mean age was 26 years; 77% were white. The most frequently reported adverse events were genitourinary; however, the placebo and UC781 arms had a similar distribution of mild and moderate genitourinary events. All colposcopic findings were superficial. Measuring systemic UC781 levels in the plasma revealed that 2 (5%) women in the UC781 gel group had detectable UC781; however, the amount was below the limits of quantification (2.5 ng/mL) in both participants. UC781 was detected in 37 of 40 CVL samples obtained 1-2 days after drug exposure and initial CVL; the median level of UC781 was 4965 pmol/mL, significantly higher than the known IC50 of 10 pmol/mL. Eighty percent of participants reported that they would use the product if it were found to be protective against HIV. CONCLUSION: : In this population of HIV-uninfected women, the gel was well tolerated and acceptable. Active levels of drug were detected in CVL and vaginal swab specimens at 1-2 days at concentrations supporting the role for daily dosing. PMID- 22495789 TI - Middle East experience in palliative care. AB - Palliative Care (PC) is still a relatively new concept in the Middle East (ME). It was first introduced in Saudi Arabia in 1992 and only recently in countries such as Qatar, Bahrain, and the UAE. Although the majority of Middle-Eastern countries, including Palestine, Iraq, Oman and Lebanon are in the capacity building phase, others such as Saudi and Jordan already have localized provision. In the absence of any of the ME countries approaching integration with the mainstream service providers, Saudi Arabia and Jordan are currently setting examples of achievement in the field. There are still countries with little or no known Palliative Care activity (Yemen and Syria). Political issues, scarcity of resources, and lack of education and awareness seem to be the common factors restricting the progress of this field in most countries. In order to improve the suboptimal PC services in the ME, emphasis should be directed toward providing formal education to professionals and raising awareness of the public. It is also necessary to put all differences aside and develop cross-border collaborations, whether through third party organizations such as the Middle East Cancer Consortium (MECC) or otherwise. This review compiles the available literature on the history and progress of the field of PC in most ME countries, while pointing out the major obstacles encountered by the active parties of each country. PMID- 22495790 TI - The unlikely patient and the most likely patient: a personal reflection on 2 patients and the lessons learned regarding physician communication in the field of palliative medicine. AB - Palliative care is somewhat of a new field in medicine. A field which requires within it an intricate understanding of disease and its prognostic indicators. A field which considers the patient as a whole with the goal of patient-directed care. And a field which necessitates as much medicine as it does art. However, Palliative Care is often consulted by intensivists and primary teams during the last moments of life. And although we can be helpful during this time, we can be of more assistance when incorporated earlier by providing not only end-of-life care, but enhanced pain and symptomatic management, elucidating goals of care, as well as affording patients and their families with emotional, spiritual, and psychosocial support. Our expertise can be useful in all patients, not just the dying. PMID- 22495791 TI - Anticipatory grief among close relatives of persons with dementia in comparison with close relatives of patients with cancer. AB - Close relatives of persons with dementia self-reported reactions on the Anticipatory Grief Scale (AGS), were observed by nurses (Study I), and compared with relatives of cancer patients in a study using the same methodology (Study II). Study I showed an overall stressful situation including feelings of missing and longing, inability to accept the terminal fact, preoccupation with the ill, tearfulness, sleeping problems, anger, loneliness, and a need to talk. The ability to cope was, however, reported high. Self-assessments and nurses' observations did not always converge, e.g. for the acceptance of the illness. The reactions of the relatives in the dementia and the cancer groups showed more similarities than dissimilarities. However, the higher number of responding spouses in the cancer group may have influenced the outcome. PMID- 22495792 TI - Successful use of flupirtine in refractory neuropathic pain due to small fiber neuropathy. AB - Small fiber neuropathy typically involves the small diameter nerve fibers, is usually idiopathic, and presents with peripheral pain. It can be excruciatingly painful at times despite the best of treatments. We present the case of a 22-year old postoperative case of right frontoparietal oligodendroglioma who received multiple drugs for his severe neuropathic pain without significant relief. However, the pain almost completely subsided once flupirtine was added and substituted for some of the currently recommended first-line drugs. PMID- 22495793 TI - Olanzapine: palliative medicine update. AB - Olanzapine is an atypical antipsychotic agent of the thienobenzodiazepine class. Olanzapine blocks multiple neurotransmitter receptors, including dopaminergic (D(1), D(2), D(3), and D(4)), serotonergic (5-hydroxytryptamine 2A [5-HT(2A)], 5 HT(2C), 5-HT(3), and 5-HT(6)), adrenergic (alpha(1)), histaminic (H(1)), and muscarinic (M(1), M(2), M(3), and M(4)) receptors. Olanzapine has a high affinity for the 5HT(2A) receptor, which is up to 5 times greater than the dopamine receptor, resulting in less propensity to the development of extrapyramidal side effects. The affinity of olanzapine for multiple receptors has lead to the identification of olanzapine as an important agent in the treatment of delirium, nausea, and vomiting. Olanzapine has been demonstrated to have opioid-sparing properties. Olanzapine is principally metabolized by glucuronidation, with a smaller metabolic contribution from the cytochrome oxidase system. Adverse effects of olanzapine include somnolence, postural hypotension, constipation, dizziness, restlessness, and weight gain. The purpose of this article is to outline the pharmacodynamics, pharmacology, and evidence for the use of olanzapine in palliative care. PMID- 22495795 TI - Comfort measures only: agreeing on a common definition through a survey. AB - Despite how frequently we say "comfort measures only" (CMO) in the hospital setting, review of the medical literature yields poor representation and definition of the term. Through a survey in our hospital center, we aimed at understanding what doctors understand as CMO. A total of 176 physicians responded to the survey. We asked them about the moment in the patient care timeline when to use it and what degree of respiratory support, laboratory draws, antibiotic therapy, level of care, and code status should be a part of it. Disparities in responses were the norm, and common defining characteristics were the exception. PMID- 22495794 TI - Parental perceptions of care of children at end of life. AB - OBJECTIVE: Little is known regarding the perceptions of parents about end-of-life care for their children. This study describes parental perceptions of the care of hospitalized, terminally ill children in the areas of (1) clinical management, (2) interdisciplinary support, and (3) pain and symptom management. METHODS: Through a mixed methods design, researchers interviewed a representative sampling of bereaved parents via telephone. RESULTS: Data provided evidence of areas which lack satisfaction with elements of end-of-life care of hospitalized children. CONCLUSION: Parental satisfaction with their child's care during end of life indicates need for improvement in pain management, communication, and parental involvement in decision making. While education cannot guarantee desired changes in attitudes or behaviors, it may provide the essential foundation of knowledge, skills, and ethical understanding needed by professional providers. PMID- 22495796 TI - When surrogates collide. PMID- 22495797 TI - Pattern of hospitalization of patients with cancer in an acute palliative care setting: Qatar's experience. AB - Palliative care is an essential part of in cancer treatment. Specialized palliative care units are starting to be incorporated into advanced healthcare systems. Qatar, a wealthy country in the Middle East, opened its first acute palliative care unit within a specialty cancer hospital in 2008. The objective of this study is to report and analyze the patterns of admissions and discharges of the patients referred to this unit over a period of three years. Our unit received 241 total admissions from July 2008 to June 2011. The age of the patients was 60.5 years, with 41.6% being local Qataris. Gastrointestinal malignancies formed the most common (34.5%). The average length of stay per admission at this unit was 30.5 days. The in-hospital mortality in our unit was 61.7%. The LOS and mortality rates were higher than those reported in the literature. We attributed that to the lack of other models of palliative care in the country and to cultural factors. PMID- 22495798 TI - Pleiotropic effects of the sirtuin inhibitor sirtinol involves concentration dependent modulation of multiple nuclear receptor-mediated pathways in androgen responsive prostate cancer cell LNCaP. AB - Sirtinol is a purported specific inhibitor of the nicotinamide adenine dinucleotide (NAD)-dependent type III histone deacetylase (also known as sirtuin). Sirtinol has been used extensively to identify chemopreventive/chemotherapeutic agents that modulate the sirtuins. However, the molecular effect of sirtinol other than serving as sirtuin inhibitor in cells is less clear. The present study addressed this deficiency in the literature. Based on structural similarity with plant-derived cancer preventive/therapeutic compounds such as 3', 3'-diindolylmethane, resveratrol, and genistein, we hypothesized that sirtinol may act on pathways similar to that affected by these compounds in the human prostate cancer cell LNCaP. We found that treatment of LNCaP cells with sirtinol led to concentration-dependent effects on multiple pathways. Sirtinol inhibited LNCaP cell cycle and growth that was correlated with up-regulation of cyclin-dependent kinase inhibitor 1A mRNA and protein levels. This effect of sirtinol may due in part to modulation of androgen, estrogen, and insulin-like growth factor-1 mediated pathways as sirtinol treatment led to inhibition of mRNA and protein expression of marker genes involved in these pathways. We also found sirtinol activates aryl hydrocarbon-dependent pathways in LNCaP cells. The effects of sirtinol were observed at 25 uM, a concentration lower than Ki (38 uM) for sirtuin activity. Based on these results we reasoned that sirtinol exerts pleiotropic effects in cells and that biological effects of sirtinol may not be due solely to inhibition of sirtuin. PMID- 22495799 TI - Development and psychometric evaluation of the knowledge scale for adults with congenitally malformed hearts. AB - BACKGROUND AND RESEARCH OBJECTIVE: Adults with congenitally malformed hearts have knowledge gaps regarding their heart condition, and their level of knowledge is not routinely assessed during follow-up. One reason for this is that there are few validated, user-friendly questionnaires to assess knowledge about congenital heart disease and its effects on daily life. Failure to identify low levels of knowledge could lead to less motivated and insecure individuals not actively involved in treatment and care of their heart condition. Therefore, the objective of this study was to develop and test a knowledge scale for adults with congenitally malformed hearts. PARTICIPANTS AND METHODS: The development and psychometric evaluation of the Knowledge Scale for Adults With Congenitally Malformed Hearts (KnoCoMH) followed 2 phases: (1) development and evaluation of the initial version, with face validity and content validity assessed by experts and adults with congenitally malformed hearts, and (2) evaluation and refinement of the KnoCoMH in adults with congenitally malformed hearts, including item difficulty level, internal consistency, and test-retest reliability. RESULTS: The development and evaluation of a knowledge scale for adults with congenitally malformed hearts resulted in the KnoCoMH including 46 items in 4 domains: General Knowledge, with a Kuder-Richardson formula 20 (KR-20) value of 0.68; Medical Treatment, with a KR-20 value of 0.74; Endocarditis Prophylaxis, with a KR-20 value of 0.90; and Contraceptives and Pregnancy, with a KR-20 value of 0.65. Test retest evaluation showed significant correlations between 0.50 and 0.67 (P < .01) in all 4 domains. There was good variation in item difficulty, with a mean value of 0.56 in General Knowledge, 0.62 in Medical Treatment, 0.33 in Endocarditis Prophylaxis, and 0.48 in Contraceptives and Pregnancy. CONCLUSIONS: The KnoCoMH has acceptable psychometric properties for most of the knowledge domains included. It can be used for evaluating knowledge among adults with congenitally malformed hearts and its associations with other outcomes. However, further studies are advisable to test construct validity, predictive validity, and responsiveness. PMID- 22495801 TI - Critical review of factors predicting health-related quality of life in newly diagnosed coronary artery disease patients. AB - BACKGROUND: Newly diagnosed coronary heart disease patients can experience significant negative changes in their health-related quality of life (HRQoL). No existing literature review was found related to factors predicting HRQoL in newly diagnosed coronary heart disease patients. PURPOSE: The aim of this study was to identify factors predicting HRQoL in newly diagnosed coronary heart disease patients. REVIEW METHODS: We searched studies published between 1997 and 2009 with combinations of key words including factors, predictor, health-related quality of life, quality of life, first diagnosed coronary heart disease patients, and coronary heart disease patients. Data sources were ProQuest, ScienceDirect, CINAHL, PsychINFO, PubMed, and Scopus. Seventeen studies were identified that primarily examined HRQoL from 6 weeks to 12 months after diagnosis. CONCLUSIONS: Factors predicting HRQoL in newly diagnosed coronary heart disease patients can be divided into 3 groups: sociodemographic, clinical, and psychosocial. Characteristics in each category most strongly predictive of HRQoL in newly diagnosed coronary heart disease patients were: Sociodemographic positive predictors were baseline HRQoL, education level, and marital status; sociodemographic negative predictors included number of cardiovascular risks and female gender. Age was an inverse predictor. Clinical negative predictors included angina, physical functioning, and fatigue. Psychosocial positive predictors included social support and a sense of coherence, whereas depression, anxiety and depression, overall psychosocial characteristics or mood disturbance, anxiety, and hostility were negative predictors. CLINICAL IMPLICATIONS: This review identifies predictors of HRQoL and shows the importance of assessing factors that predict HRQoL at baseline and throughout the trajectory of this chronic illness because the concept of HRQoL changes over time but the predictors remain constant. PMID- 22495800 TI - Predictors of overall perceived health in patients with heart failure. AB - BACKGROUND: Overall perceived health (OPH) is a powerful and independent predictor of negative health outcomes and low health-related quality of life. Overall perceived health is conspicuously low in patients with heart failure (HF). OBJECTIVE: The purpose of this study was to determine the key predictors of OPH in persons with HF and explore possible mediating relationships. METHODS: This cross-sectional predictive correlational study was a secondary analysis of an existing data set. Individual characteristics, biophysiological variables, physical symptoms, psychological symptoms, and physical and social functioning were identified from the Wilson and Cleary Model and tested as predictors of OPH in a 5-step hierarchical regression analysis. RESULTS: The sample (n = 265) was primarily male (64.2%) and white (61.9%), with a mean age of 62 years, and had at least a high school education and a household income enough or more than enough to meet needs. Most (69.1%) had systolic dysfunction, and 78.5% were New York Heart Association class III or IV. The final model containing 15 predictors explained 39.2% of the variance in OPH. Six variables were significant independent predictors of OPH: perceived sufficiency of income, social functioning, comorbid burden, symptom stability, race, and the interaction of gender and social functioning, the last indicating social functioning as a stronger predictor for men than for women. In a multiple mediation analysis, the effects of shortness of breath and fatigue on OPH were mediated by physical and social functioning. Gender moderated the effect of fatigue through social functioning. CONCLUSIONS: These variables explained a significant portion of the variance in OPH and can be used to target individuals at risk for low OPH and to tailor interventions. If OPH is low, a focus on patient symptoms and ability to participate in life activities is appropriate, with particular attention to social functioning in men. PMID- 22495802 TI - The effects of smoking status on walking ability and health-related quality of life in patients with peripheral arterial disease. AB - BACKGROUND: Smoking is a leading risk factor for peripheral arterial disease (PAD), yet little is known about the interrelationships among smoking status, walking endurance, calf muscle tissue oxygenation, and quality of life in patients with PAD. OBJECTIVE: The aim of this study was to explore the differences in factors associated with walking endurance including walk distance, perceived walking ability, measures of skeletal muscle tissue oxygenation (StO2), claudication pain, peak oxygen consumption per unit time, and quality of life in smokers versus nonsmokers. METHODS: A total of 105 patients with PAD performed progressive, symptom-limited treadmill test. Ankle-brachial index was measured at baseline. Calf muscle tissue oxygenation measures were obtained during testing. The RAND Short Form-36 and Walking Impairment Questionnaire were used to measure health-related quality of life (HR-QoL). RESULTS: In the total sample (36 current smokers, 69 nonsmokers), smokers had steeper declines in StO2 from baseline to 2 minutes (42.3% vs 33%, P = .05) and shorter distance walked to onset of claudication pain (142.6 vs 247.7 m) than did nonsmokers (P < .0125), despite having no differences in ankle-brachial index, peak oxygen consumption per unit time, or any momentary measure of StO2 during walking. Smokers reported significantly lower HR-QoL on the Short Form-36 in several domains but no differences in the Walking Impairment Questionnaire measures. The smokers were younger than the nonsmokers; however, when age was entered as a covariate in the analyses, the results remained unchanged. CONCLUSIONS: These findings suggest that smokers have lower HR-QoL than do nonsmokers with PAD and that smoking confers risks for disrupted tissue oxygenation above those seen in patients who do not smoke. PMID- 22495803 TI - The development, refinement, and psychometric testing of the attitude toward advanced directive survey in implantable cardioverter defibrillator patients. AB - Implantable cardioverter defibrillators (ICDs) have been the treatment of choice for those who experienced or are at risk of sudden cardiac arrest. Many patients who receive these devices experience progressive comorbid and cardiac conditions and may not want the additional survival provided by an ICD. Clinicians will need to counsel patients and families about advanced directives when their ICD is no longer beneficial, to prevent unnecessary suffering near the end of life. The Attitude Towards Advanced Directive Survey was developed to assess patients' level of knowledge and identify the barriers that prevent them from completing advanced directives. This will help clinicians promote completion of advanced directives by addressing barriers and increasing knowledge of them. The purpose of this study was to develop and evaluate the psychometric properties of the survey and investigate reliability and validity from its use among ICD patients. A convenience sample of 200 patients who have an ICD participated in this study. Psychometric testing of the Attitude Towards Advanced Directive Survey provided evidence to support the validity and reliability of the survey. Moderate to strong factor intercorrelations and conceptual meaningfulness led to the combination of 5 factors. The 5 factors were as follows: factor 1: communication barriers; factor 2: informed confidence; factor 3: timing of discussion; factor 4: patient-family relationship; and factor 5: patient-provider relationship. Reliability coefficient alpha ranged from .67 to .95 for the factors and .75 for the total scale. Stability reliability of the survey was analyzed through test retest of the survey, with a response rate of 34% (n = 68), and revealed a significant positive correlation (r = .62; P < .001) between the first and second testing. The participants reported communication barriers and demonstrated poor understanding of their medical condition/treatments and were not comfortable discussing advanced directives with their families. They preferred to discuss advanced directives when they were first diagnosed and at every office visit because they felt more comfortable discussing advanced directives with their healthcare provider. This survey has the potential to be used in clinical practice and future research. PMID- 22495804 TI - Older women's prehospital experiences of their first myocardial infarction. AB - BACKGROUND: Few qualitative studies have been conducted on older women's experiences of myocardial infarction (MI) and, in particular, the time before they seek medical care. OBJECTIVE: The aim of this study was to explore older women's prehospital experiences of their first MI. METHODS: Qualitative content analysis was performed on data from individual interviews with 20 women, aged 65 to 80 years (mean, 73.0 years). The participants were interviewed 3 days after admission to a hospital for a confirmed first MI. RESULTS: The women perceived their symptoms as a strange and unfamiliar development from indistinct physical sensations to persistent and overwhelming chest pain. Throughout the prehospital phase, they used different strategies such as downplaying and neglecting the symptoms. The symptoms were seen as intrusions in their daily lives, against which the participants defended themselves to remain in control and to maintain social responsibilities. As their symptoms evolved into constant chest pain, the women began to realize the seriousness of their symptoms. When the pain became unbearable, the women took the decision to seek medical care. CONCLUSION: Understanding the complex experiences of older women in the prehospital phase is essential to reducing their patient decision times. The findings of this study should be incorporated into the education of professionals involved in the care of cardiac patients, including those who answer informational and emergency telephone lines. PMID- 22495805 TI - pH-responsive supramolecular polymerization in aqueous media driven by electrostatic attraction-enhanced crown ether-based molecular recognition. AB - All the previously reported supramolecular polymers based on crown ether-based molecular recognition have been prepared in anhydrous organic solvents. This is mainly due to the weakness of crown ether-based molecular recognition in the presence of water. Here we report a linear supramolecular polymer constructed from a heteroditopic monomer in an aqueous medium driven by crown ether-based molecular recognition through the introduction of electrostatic attraction. In addition, the reversible transition between the linear supramolecular polymer and oligomers is achieved by adding acid and base. This study realizes the breakthrough of the solvent for supramolecular polymerization driven by crown ether-based molecular recognition from anhydrous organic solvents to aqueous media. It is helpful for achieving supramolecular polymerization driven by crown ether-based molecular recognition in a completely aqueous medium. PMID- 22495806 TI - SUMOylation of AhR modulates its activity and stability through inhibiting its ubiquitination. AB - Aryl hydrocarbon receptor (AhR) is a transcription factor that belongs to the basic helix-loop-helix (bHLH) Per-Arnt-Sim homology domain (PAS) family. AhR can be activated by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (2, 3, 7, 8-TCDD) and once activated, it promotes the abnormal expression of cytochrome P450, leading to several diseases, including cancer. In this study, we showed that AhR is subjected to post-translational modification by SUMOylation and this modification could be reversed by SENP1. Two SUMOylation sites were identified, one in the bHLH domain (K63) and the other in the TAD domain (K510) of AhR. Substitution of either K63 or K510 with arginine resulted in reduced SUMOylation for AhR. Treatment of MCF-7 cells with TCDD led to a reduced level of SUMOylated AhR in a time-dependent manner, and this occurred mainly in the nucleus. SUMOylation of AhR enhanced its stability through inhibiting its ubiquitination. Moreover, SUMOylation also repressed the transactivation activity of AhR and this could be reversed by TCDD. These results suggested that SUMOylation of AhR might play an important role in the regulation of its function, and TCDD may activate the transcriptional activity of AhR through downregulating its SUMOylation. PMID- 22495807 TI - Simultaneous determination of drugs in human autopsy material using phase optimized liquid chromatography. AB - In legal medicine in many cases drugs are detected in autopsy material without connection to the cause of death, and until now no further investigations have taken place. In our study more than 50 drugs were measured directly in several compartments. The deceased had received continual therapeutic treatment, treatment during an operation or an unsuccessful emergency therapy. Liquid-liquid extraction and an LC-MS/MS method were developed for the determination of these drug concentrations. When measuring many transitions in a biological matrix, two problems should be excluded: ion suppression and too few measurement points per peak. A relatively short operation time and sufficient separation were achieved by column, eluent and gradient optimization with POPLC (phase-optimized liquid chromatography). Various autopsy materials from about 170 cases were investigated. In particular, in nine cases with four or more simultaneously determined drugs, their distribution in the compartments is very interesting for pharmacokinetic examinations. The distribution patterns of the drugs in the compartments of one individual deceased were compared. This meant that the great differences between subjects that are normally encountered these studies could be excluded. Measurements of drug concentrations in human autopsy material deepens knowledge of the respective drugs' pharmacokinetics. PMID- 22495808 TI - Sensitive windows of skeletal development in rabbits determined by hydroxyurea exposure at different times throughout gestation. AB - The critical periods of axial skeletal development in rats and mice have been well characterized, however the timing of skeletal development in rabbits is not as well known. It is important to have a more precise understanding of this timing of axial skeletal development in rabbits due to the common use of this species in standard nonclinical studies to assess embryo-fetal developmental toxicity. Hydroxyurea, a teratogen known to induce a variety of fetal skeletal malformations, was administered to New Zealand White rabbits as a single dose (500 mg/kg) on individual days during gestation (gestation day, GD 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 19) and fetal external, visceral, and skeletal morphology was examined following cesarean sections on GD 29. A wide range of fetal skeletal effects was observed following hydroxyurea treatment, with a progression of malformations from anterior to posterior structures over time, as well as from proximal to distal structures over time. The sensitive window of axial skeletal development was determined to be GD 8 to 13, while disruption of appendicular and cranio-facial skeletal development occurred primarily from GD 11 to 16 and GD 11 to 12, respectively. The results of this study provide a better understanding of the critical developmental window for different segments of the rabbit skeleton, which will aid in the design of window studies to investigate teratogenicity in rabbits. PMID- 22495809 TI - A simple sample size formula for analysis of covariance in cluster randomized trials. AB - For cluster randomized trials with a continuous outcome, the sample size is often calculated as if an analysis of the outcomes at the end of the treatment period (follow-up scores) would be performed. However, often a baseline measurement of the outcome is available or feasible to obtain. An analysis of covariance (ANCOVA) using both the baseline and follow-up score of the outcome will then have more power. We calculate the efficiency of an ANCOVA analysis using the baseline scores compared with an analysis on follow-up scores only. The sample size for such an ANCOVA analysis is a factor r2 smaller, where r is the correlation of the cluster means between baseline and follow-up. This correlation can be expressed in clinically interpretable parameters: the correlation between baseline and follow-up of subjects (subject autocorrelation) and that of clusters (cluster autocorrelation). Because of this, subject matter knowledge can be used to provide (range of) plausible values for these correlations, when estimates from previous studies are lacking. Depending on how large the subject and cluster autocorrelations are, analysis of covariance can substantially reduce the number of clusters needed. PMID- 22495810 TI - Association of genetic variants of human telomerase with colorectal polyps and colorectal cancer risk. AB - Human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase and is located on chromosome 5p15, a genomic region which was found to be associated with multiple cancer types. But no associations with colorectal cancer (CRC) have been reported until recently. Therefore, the purpose of this study was to investigate the influence of seven single-nucleotide polymorphisms (SNPs) of TERT on susceptibility to colorectal polyps and CRC. The study population of our ongoing colorectal cancer study of Austria (CORSA) comprised 3,842 Caucasian participants. A total of 3,264 participants was genotyped including 142 CRC cases, 492 high-risk polyps, 837 low-risk polyps, and 1,793 polyp-free controls verified by colonoscopy. Genotyping was performed by TaqMan assay using genomic DNA. The impact of each SNP was estimated by multiple logistic regression analyses performed with R Version 2.11.1. None of the investigated TERT SNPs (rs2736122, rs2853676, rs2735940, rs2736098, rs2075786, rs2736100, rs4975605) were found to be associated with risk of CRC nor colonic polyps. However, the haplotype CGTATGG was associated with a significantly increased risk of high-risk polyps (OR = 1.48, 95% CI 1.01-2.17, P = 0.043). In accordance with other studies our results suggest no major influence of the investigated TERT SNPs on CRC and colorectal polyp risk. However, relevance of telomerase in tumorigenesis of multiple malignancies demands further investigations of the 5p15 locus concerning CRC susceptibility. PMID- 22495812 TI - Proton pump inhibitor use and Clostridium difficile colitis: cause or coincidence? PMID- 22495811 TI - Multiple patient safety events within a single hospitalization: a national profile in US hospitals. AB - The objective was to examine co-occurrence of iatrogenic events in US hospitals. Using Agency for Healthcare Research and Quality patient safety indicators (PSIs), the authors defined multiple patient safety events (MPSEs) as the occurrence of multiple PSIs during a single hospitalization. The National Inpatient Sample was analyzed to estimate the national prevalence of MPSEs, risk factors for MPSEs, and the average length of stay and average hospital charges associated with MPSEs. MPSEs occurred in approximately 1 in every 1000 hospitalizations, affecting more than 30 000 patients in 2004. Significant risk factors for MPSEs include age, black race, Medicare coverage, and treatment at urban teaching hospitals. Compared with all admissions, the average length of stay for MPSE admissions was 4 times longer, and the average charge for MPSE admissions was 8 times greater. Despite the low prevalence, MPSEs affect large numbers of hospital patients in America. MPSEs have distinct characteristics and are far more resource intensive than hospital admissions generally. PMID- 22495813 TI - A comparison between lactose breath test and quick test on duodenal biopsies for diagnosing lactase deficiency in patients with self-reported lactose intolerance. AB - BACKGROUND: A lactose breath test (LBT) is usually used to diagnose lactase deficiency, and a lactose quick test (LQT) has been proposed as a new test on duodenal biopsies to detect this disorder. GOALS: We aimed to assess the diagnostic accuracy of LBT and LQT and their ability to predict the clinical response to a lactose-free diet in patients with self-reported lactose intolerance. STUDY: Fifty-five patients (age 47 +/- 14 y; M/F 15/36) underwent upper gastrointestinal endoscopy and 25g-LBT. Two duodenal biopsies were taken to determine lactase deficiency (normal, mild, or severe) by LQT and to rule out other causes of secondary lactose malabsorption. Patients with a positive LBT and normal LQT also underwent a glucose breath test to exclude small intestinal bacterial overgrowth as a cause of the former result. The severity of gastrointestinal symptoms was measured with a GSS questionnaire, under basal condition and 1 month after a lactose-free diet. RESULTS: Lactose malabsorption was detected in 31/51 patients with LBT and in 37/51 patients with LQT (P = NS). Celiac disease was found in 2 patients. Two LBT+ patients showed a positive glucose breath test for small intestinal bacterial overgrowth. Eight patients had a mild hypolactasia by LQT and a negative LBT, but they had a significant improvement of symptoms after diet. LQT and LBT were concordant in 83% of cases and predicted the response to a lactose-free diet in 98% and 81% of the cases, respectively (P = 0.03). CONCLUSIONS: LQT is as sensitive as LBT in detecting lactase deficiency; however, it seems to be more accurate than LBT in predicting the clinical response to a lactose-free diet. PMID- 22495814 TI - Colonoscopy in acute diverticulitis: when and why. PMID- 22495815 TI - Long-term follow-up study in Budd-Chiari syndrome: single-center experience in 22 years. AB - GOALS: We aimed to present our long-term surveillance experience in patients with Budd-Chiari syndrome (BCS), and we retrospectively evaluated the natural history, results of thrombophilia studies, and the factors related to mortality. BACKGROUND: Primary BCS is a rare form of vascular disease, secondary to underlying thrombophilia. Because of its rarity and heterogeneous nature, there is a scarcity of knowledge about the natural history of the disease. STUDY AND RESULTS: In 22 years, a total of 62 patients with primary BCS were followed in our tertiary hospital. We identified an acquired cause of BCS in 40 out of 62 patients (64.5%), whereas in 6 patients (9.7%), we found no identifiable cause. One or more thrombophilia causes were identified in 56 patients (90.3%). In 19 patients with myeloproliferative disease, 15 had Janus tyrosine kinase 2 mutation analysis and Janus tyrosine kinase 2 positivity was found in 10 patients. In regression analysis, portal vein thrombosis was found to be the only indicator of mortality, with an estimated instantaneous risk of 8.4. CONCLUSIONS: In this study, we present one of the largest series of BCS in the English literature. We have shown that the multifactorial nature of underlying thrombophilia should be thoroughly investigated. In a patient with BCS, a clinician should be alert for the development or coexistence of portal vein thrombosis due to its deleterious effect on mortality. PMID- 22495816 TI - Analysis of small-bowel capsule endoscopy reading by using Quickview mode: training assistants for reading may produce a high diagnostic yield and save time for physicians. AB - GOAL: The aim was to investigate the clinical utility of RAPID Access 6.5 Quickview software and to evaluate whether preview of the capsule endoscopy video by a trained nurse could detect significant lesions accurately compared with endoscopists. BACKGROUND: As reading capsule endoscopy is time consuming, one possible cost-effective strategy could be the use of trained nonphysicians or newly available software to preread and identify potentially important capsule images. STUDY: The 100 capsule images of a variety of significant lesions from 87 patients were investigated. The minimum percentages for settings of sensitivity that could pick up the selected images and the detection rate for significant lesions by a well-trained nurse, two endoscopists with limited experience in reading, and one well-trained physician were examined. RESULTS: The frequency of the selected lesions picked up by Quickview mode using percentages for sensitivity settings of 5%, 15%, 25%, and 35% were 61%, 74%, 93%, and 98%, respectively. The percentages for sensitivity significantly correlated (r=0.78, P<0.001) with the reading time. The detection rate by the nurse or the well trained physician was significantly higher than that by the physician with limited capsule experience (87% and 84.1% vs. 62.7%; P<0.01). The clinical use of Quickview at 25% did not significantly improve the detection rate. CONCLUSIONS: Quickview mode can reduce reading time but has an unacceptably miss rate for potentially important lesions. Use of a trained nonphysician assistant can reduce physician's time and improve diagnostic yield. PMID- 22495817 TI - Infratemporal fossa metastasis of papillary thyroid cancer. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) occasionally metastasizes to lung and bone, but rarely to skeletal muscles. In this study, we present an unusual case of metastasis of PTC to the infratemporal fossa of a previously treated patient with PTC. METHODS AND RESULTS: A 74-year-old man with a diagnosis of PTC underwent subtotal thyroidectomy and neck dissection on the left side. Metastasis to the infratemporal fossa developed 13 years after the initial treatment. The patient underwent extirpation of the tumor via the infratemporal fossa approach with semicoronal skin incision. Right neck dissection and resection of residual thyroid tissue were also performed simultaneously. The patient underwent 131 Iodine therapy and has been followed up for 12 months with no evidence of disease. CONCLUSIONS: The possibility of metastasis of PTC should be included as a differential diagnosis if an unusual mass manifests in any location in patients with PTC. PMID- 22495818 TI - MED28 regulates MEK1-dependent cellular migration in human breast cancer cells. AB - MED28, a mammalian Mediator subunit, exhibits several cellular roles, including a merlin, Grb2, and cytoskeleton-associated protein (magicin), a repressor of smooth muscle cell differentiation, and an endothelial-derived gene (EG-1). Overexpression of MED28 may stimulate cell proliferation which presumably results from the transcriptional activation of the Mediator function. Additionally, several tumors, including breast cancer, highly express MED28. We have found recently that MED28 potentiated epidermal growth factor (EGF)-induced migration in human breast cancer cells. Therefore, the objective of this study is to identify the role of MED28 in the aspect of cellular migration and invasion in human breast cancer cells. Suppression of MED28 blocked cellular migration and invasion with concomitant reduced expression levels of matrix metalloproteinase-2 (MMP2) and mitogen-activated protein kinase kinase 1 (MAP2K1; MEK1); overexpression of MED28 enhanced cellular migration and upregulated MMP2 and MEK1 expression. Moreover, suppression of MEK1, by dominant-negative, kinase-dead MEK1 cDNA construct or MEK1-specific small interfering RNA (siRNA) as well as MEK1 inhibitors, blocked MED28-induced MMP2 activation, cellular migration, and invasion in breast cancer cells. Furthermore, ectopic expression of MEK1 rescued the inhibitory effect of MED28 knockdown on invasion, and exogenous MMP2 recombinant protein recovered the suppression on invasion upon MED28 or MEK1 knockdown. Our data indicate that MED28 regulates cellular migration in a MEK1 dependent manner in human breast cancer cells, reinforcing the important cellular roles of MED28. PMID- 22495819 TI - Both osteopontin-c and osteopontin-b splicing isoforms exert pro-tumorigenic roles in prostate cancer cells. AB - BACKGROUND: Alternative splicing of the osteopontin (opn, spp1) gene generates three protein splicing isoforms (OPN-SI), designated as OPNa, OPNb, and OPNc, which have demonstrated specific roles in different tumor models. This work aims to investigate the roles of each OPN-SI in prostate cancer (PCa) progression by using in vivo and in vitro functional assays. METHODS: The expression levels of OPN-SI in prostate cell lines were analyzed by qRT-PCR. PC-3 was stably transfected with expression vectors containing OPNa, OPNb, and OPNc, as well as empty vector controls. PC-3 cells overexpressing each construct were analyzed for in vivo tumor growth and in relation to different aspects mimicking tumor progression, such as cell proliferation, migration, invasion, and soft agar colony formation. RESULTS: OPN-SI are overexpressed in PCa as compared to non tumoral prostate cell lines. OPNc and OPNb overexpressing cells significantly activated enhanced xenograft tumor growth and PC-3 proliferation, migration, invasion, and soft agar colony formation, as well as the expression of MMP-2, MMP 9, and VEGF. These isoforms also support sustained proliferative survival. We found that both OPNc and OPNb pro-tumorigenic roles are mainly mediated through PI3K signaling. Inhibition of this pathway by using LY294002 specifically inhibited tumor progression features evoked by OPNc and OPNb overexpression. CONCLUSIONS: Our data provide evidence that both OPNc and OPNb splicing isoforms promote distinct aspects of PCa progression by inducing PI3K signaling. These data give support to strategies aiming to downregulate OPNc and OPNb expression as an approach to inhibit PCa progression. PMID- 22495820 TI - Developmental toxicity of lersivirine in rabbits when administered throughout organogenesis and when limited to sensitive windows of axial skeletal development. AB - BACKGROUND: Lersivirine is a second-generation nonnucleoside reverse transcriptase inhibitor undergoing clinical development for the treatment of human immunodeficiency virus-1. An embryo-fetal development study was performed to evaluate the potential for maternal and developmental toxicity of lersivirine. METHODS: Pregnant New Zealand White rabbits were administered 0, 100, 250, and 500 mg/kg lersivirine by oral gavage once daily on gestation days (GDs) 7 to 19, followed by cesarean section on GD 29 and fetal evaluation. RESULTS: Maternal toxicity was noted at all dose levels (decreased food consumption and body weight gain), with fetal toxicity at 500 mg/kg (decreased fetal weights, increased postimplantation loss). Equivocal findings for axial skeletal malformations were observed in three fetuses at 500 mg/kg. To better understand if these malformations were related to treatment with lersivirine, a follow-up rabbit embryo-fetal development study was performed with 1000 mg/kg/day lersivirine (500 mg/kg BID, 12-hr interdose interval) for two different 3-day windows, GDs 8 to 10 or GDs 11 to 13, which represent the sensitive windows of axial skeletal development in rabbits. Control rabbits were administered vehicle following the same dosing regimen from GDs 8 to 13. Cesarean sections were performed on GD 29, and fetal skeletons were examined for the potential of lersivirine to cause skeletal malformations in rabbits. At maternal exposure levels higher than the initial study, lersivirine did not induce fetal skeletal malformations when administered in the sensitive windows of axial skeletal development. CONCLUSION: The results of these studies indicate that lersivirine did not exhibit any evidence of teratogenicity in rabbits. PMID- 22495821 TI - Functional studies of a novel germline p53 splicing mutation identified in a patient with Li-Fraumeni-like syndrome. AB - Most p53 mutations identified in Li-Fraumeni syndrome (LFS) are missense mutations; splicing mutations have rarely been reported. A novel splicing p53 mutation was identified in a patient with Li-Fraumeni-like syndrome (LFL). Usually, p53 missense mutants identified in LFS and cancer cells function as dominant negative mutations interfering with wild-type p53 function. However, the mechanism by which p53 haploinsufficiency causes carcinogenesis is not well characterized. In this study, we describe a novel splicing mutation that results in the loss-of-function of p53. These findings suggest a linkage between the loss of-function type p53 mutation and a LFL phenotype. PMID- 22495822 TI - On the equivalence of posterior inference based on retrospective and prospective likelihoods: application to a case-control study of colorectal cancer. AB - The paper develops a class of priors that leads to equivalent posterior inference for odds ratio parameters based on prospective and retrospective models for categorical response data. The results are applicable to both unmatched and matched case-control studies. The results hold for a general class of link functions for categorical response. The proposed method can accommodate multiple and possibly ordered disease states. The results are applied to the analysis of discrete subtypes in an ongoing case-control study of colorectal cancer. A simulation study illustrates the need for carefully considering prior choices in Bayesian analysis of data collected under retrospective design. PMID- 22495823 TI - Effects of epidermal growth factor receptor and insulin-like growth factor 1 receptor inhibition on proliferation and intracellular signaling in cutaneous SCCHN: potential for dual inhibition as a therapeutic modality. AB - BACKGROUND: Combined inhibition of epidermal growth factor receptor (EGFR) and insulin-like growth factor-1 receptor (IGF-1R) has been proposed as a therapy for cutaneous squamous cell carcinoma of the head and neck (SCCHN). METHODS: Receptor expression and downstream signaling were assessed in cutaneous squamous cell carcinoma (SCC) cell lines and patient samples. EGFR and IGF-1R signaling was inhibited in cutaneous SCC cell lines using erlotinib and/or picropodophyllin. RESULTS: EGFR and IGF-1R were overexpressed in cutaneous SCCHN specimens relative to normal skin. Dual inhibition of both receptors prevented cell growth and decreased activation of Akt and p42/44 mitogen-activated protein kinase (MAPK) more effectively than either inhibitor alone. CONCLUSION: Dual inhibition of EGFR and IGF-1R is effective at blocking cell growth, and is correlated with inhibition of Akt and p42/44 MAPK, suggesting that this may be a promising treatment for cutaneous SCCHN. PMID- 22495825 TI - Enzyme replacement therapy improves joint motion and outcome of the 12-min walk test in a mucopolysaccharidosis type VI patient previously treated with bone marrow transplantation. AB - Mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome, OMIM #253200) is a rare disorder involving multiple organs and manifested particularly by severe skeletal abnormalities. Bone marrow transplantation (BMT) improves cardiopulmonary function and facial features, but has limited success in ameliorating skeletal abnormalities and short stature. Here, we report the outcome of enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (ASB, Naglazyme, BioMarin, Novato, CA) in an MPS VI patient who received BMT 10 years prior to ERT induction. Administration of weekly Naglazyme for 18 months was effective in improving range of motion in several joints [shoulders (improvement of flexion (Right/Left): 40 degrees /55 degrees ; improvement of extension 30 degrees /40 degrees ; improvement of abduction 10 degrees /10 degrees ), elbows (improvement of flexion 25 degrees /25 degrees ; improvement of extension 10 degrees /15 degrees ), hips (improvement of flexion 25 degrees /10 degrees ), and knees (improvement of flexion 45 degrees /40 degrees ; improvement of extension 50 degrees /60 degrees )]. Improvement in the outcome of the 12-min walk test (70% increase) and 3-min stair-climbing test (29% increase) was also noted after ERT. Because ERT improved clinical features in an MPS VI patient who had undergone prior BMT, the role of ERT post successful BMT in MPS VI needs further investigation. PMID- 22495826 TI - Relearning the lessons of genomic stability of human cells during expansion in culture: implications for clinical research. PMID- 22495824 TI - Specificity of latent TGF-beta binding protein (LTBP) incorporation into matrix: role of fibrillins and fibronectin. AB - Fibrillin microfibrils are extracellular matrix structures with essential functions in the development and the organization of tissues including blood vessels, bone, limbs and the eye. Fibrillin-1 and fibrillin-2 form the core of fibrillin microfibrils, to which multiple proteins associate to form a highly organized structure. Defining the components of this structure and their interactions is crucial to understand the pathobiology of microfibrillopathies associated with mutations in fibrillins and in microfibril-associated molecules. In this study, we have analyzed both in vitro and in vivo the role of fibrillin microfibrils in the matrix deposition of latent TGF-beta binding protein 1 (LTBP 1), -3 and -4; the three LTBPs that form a complex with TGF-beta. In Fbn1(-/-) ascending aortas and lungs, LTBP-3 and LTBP-4 are not incorporated into a matrix lacking fibrillin-1 microfibrils, whereas LTBP-1 is still deposited. In addition, in cultures of Fbn1(-/-) smooth muscle cells or lung fibroblasts, LTBP-3 and LTBP 4 are not incorporated into a matrix lacking fibrillin-1 microfibrils, whereas LTBP-1 is still deposited. Fibrillin-2 is not involved in the deposition of LTBP 1 in Fbn1(-/-) extracellular matrix as cells deficient for both fibrillin-1 and fibrillin-2 still incorporate LTBP-1 in their matrix. However, blocking the formation of the fibronectin network in Fbn1(-/-) cells abrogates the deposition of LTBP-1. Together, these data indicate that LTBP-3 and LTBP-4 association with the matrix depends on fibrillin-1 microfibrils, whereas LTBP-1 association depends on a fibronectin network. PMID- 22495827 TI - Interstitial brachytherapy for lower lip carcinoma: global assessment in a retrospective study of 89 cases. AB - BACKGROUND: Infiltrating squamous cell carcinoma (SCC) of the lower lip is a highly curable cancer. We retrospectively analyzed oncologic, functional, and cosmetic outcomes after interstitial low-dose rate brachytherapy at 58 Gy (50-62) of lower lip SCC treated in our institution. METHODS: There were 89 patients (44 T1, 33 T2, 2 T3, and 10 after wedge-excision). All tumors were N0 at the time of treatment. We calculated survival rates and assessed functional and cosmetic results de visu. RESULTS: After a median follow-up of 36 months (range, 9-127), 5 year local control rate was 95% and 5-year disease-free survival was 82%. Only 6 patients (5 T2 and 1 T3) developed secondary cervical nodal involvement. Sixty one patients were reassessed and 11 patients presented mild functional troubles. Cosmetic results were good (77%) or fair (21%). CONCLUSION: Brachytherapy provided a high local disease control rate, excellent functional results, and good cosmetic outcomes for SCCs of the lip. Risk of cervical node involvement was low with small tumors. PMID- 22495828 TI - Knockdown of cathepsin B and uPAR inhibits CD151 and alpha3beta1 integrin mediated cell adhesion and invasion in glioma. AB - Glioma is a highly complex brain tumor characterized by the dysregulation of proteins and genes that leads to tumor metastasis. Cathepsin B and uPAR are overexpressed in gliomas and they are postulated to play central roles in glioma metastasis. In this study, efficient downregulation of cathepsin B and uPAR by siRNA treatments significantly reduced glioma cell adhesion to laminin as compared to vitronectin, fibronectin, or collagen I in U251 and 4910 glioma cell lines. Brain glioma tissue array analysis showed high expression of CD151 in clinical samples when compared with normal brain tissue. Cathepsin B and uPAR siRNA treatment led to the downregulation of CD151 and laminin-binding integrins alpha3 and beta1. Co-immunoprecipitation experiments revealed that downregulation of cathepsin B and uPAR decreased the interaction of CD151 with uPAR cathepsin B, and alpha3beta1 integrin. Studies on the downstream signaling cascade of uPAR/CD151/alpha3beta1 integrin have shown that phosphorylation of FAK, SRC, paxillin, and expression of adaptor cytoskeletal proteins talin and vinculin were reduced with knockdown of cathepsin B, uPAR, and CD151. Treatment with the bicistronic construct reduced interactions between uPAR and CD151 as well as lowering alpha3beta1 integrin, talin, and vinculin expression levels in pre established glioma tumors of nude mice. In conclusion, our results show that downregulation of cathepsin B and uPAR alone and in combination inhibit glioma cell adhesion by downregulating CD151 and its associated signaling molecules in vitro and in vivo. Taken together, the results of the present study show that targeting the uPAR-cathepsin B system has possible therapeutic potential. PMID- 22495829 TI - Human-induced pluripotent stem cells form functional neurons and improve recovery after grafting in stroke-damaged brain. AB - Reprogramming of adult human somatic cells to induced pluripotent stem cells (iPSCs) is a novel approach to produce patient-specific cells for autologous transplantation. Whether such cells survive long-term, differentiate to functional neurons, and induce recovery in the stroke-injured brain are unclear. We have transplanted long-term self-renewing neuroepithelial-like stem cells, generated from adult human fibroblast-derived iPSCs, into the stroke-damaged mouse and rat striatum or cortex. Recovery of forepaw movements was observed already at 1 week after transplantation. Improvement was most likely not due to neuronal replacement but was associated with increased vascular endothelial growth factor levels, probably enhancing endogenous plasticity. Transplanted cells stopped proliferating, could survive without forming tumors for at least 4 months, and differentiated to morphologically mature neurons of different subtypes. Neurons in intrastriatal grafts sent axonal projections to the globus pallidus. Grafted cells exhibited electrophysiological properties of mature neurons and received synaptic input from host neurons. Our study provides the first evidence that transplantation of human iPSC-derived cells is a safe and efficient approach to promote recovery after stroke and can be used to supply the injured brain with new neurons for replacement. PMID- 22495830 TI - Comparison of total laryngectomy with surgical (cricohyoidopexy) and nonsurgical organ-preservation modalities in advanced laryngeal squamous cell carcinomas: A multicenter retrospective analysis. AB - BACKGROUND: Functional outcome and quality of life (QOL) have become relevant endpoints in the field of laryngeal oncology, leading to the emergence of organ preserving strategies. METHODS: The medical records of 166 patients with advanced (stages III and IV) laryngeal squamous cell carcinoma (SCC) who were treated with a total laryngectomy, radiochemotherapy, or cricohyoidopexy (CHP) were reviewed. RESULTS: In the whole series, no statistically significant differences among the 3 treatment arms with respect to the overall survival (OS) and disease-specific survival (DSS) rates were observed. The organ-preservation rate was 45% for radiotherapy and 76.7% for CHP (p = .0002). Among the cT4a cases, a longer survival was observed for the patients treated with total laryngectomy (3 yr-OS = 78% vs 68% for CHP and 54% for radiochemotherapy, p = .031). CONCLUSIONS: In advanced laryngeal SCC, CHP shows survival rates comparable to those of radiochemotherapy and a higher larynx-preservation rate, although it may not replace radiochemotherapy because it can be recommended only in selected cases. PMID- 22495831 TI - Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: findings from a nationwide epidemiological survey. AB - Costello syndrome and cardio-facio-cutaneous (CFC) syndrome are congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, and intellectual disability. Germline mutations in HRAS cause Costello syndrome, and mutations in KRAS, BRAF, and MAP2K1/2 (MEK1/2) cause CFC syndrome. Since the discovery of the causative genes, approximately 150 new patients with each syndrome have been reported. However, the clinico-epidemiological features of these disorders remain to be identified. In order to assess the prevalence, natural history, prognosis, and tumor incidence associated with these diseases, we conducted a nationwide prevalence study of patients with Costello and CFC syndromes in Japan. Based on the result of our survey, we estimated a total number of patients with either Costello syndrome or CFC syndrome in Japan of 99 (95% confidence interval, 77-120) and 157 (95% confidence interval, 86-229), respectively. The prevalences of Costello and CFC syndromes are estimated to be 1 in 1,290,000 and 1 in 810,000 individuals, respectively. An evaluation of 15 adult patients 18-32 years of age revealed that 12 had moderate to severe intellectual disability and most live at home without constant medical care. These results suggested that the number of adult patients is likely underestimated and our results represent a minimum prevalence. This is the first epidemiological study of Costello syndrome and CFC syndrome. Identifying patients older than 32 years of age and following up on the patients reported here is important to estimate the precise prevalence and the natural history of these disorders. PMID- 22495832 TI - Your diagnosis? Pott's disease. PMID- 22495833 TI - Healio.com: specialty knowledge delivered in a more powerful platform. PMID- 22495834 TI - New tool for applying traction during open reduction and internal fixation of acetabular fractures. AB - Open reduction and internal fixation is used to treat complex acetabular fractures. Traction on the femur is necessary to reduce the acetabulum and is accomplished by surgical assistants or with mechanical devices. To overcome the disadvantages of various traction methods, the author designed a simple, novel traction device that can be used on an ordinary orthopedic or radiolucent operating table and has advantages over manual traction and commercial traction tables. The device consists of a horizontal cross-bar supported over the patient by 2 free-standing legs and is constructed from commercially available parts. PMID- 22495835 TI - Infections in orthopedics. PMID- 22495836 TI - Effect of social media in health care and orthopedic surgery. AB - With the growth of social media platforms, their potential to affect health care, and orthopedics specifically, continues to expand. We reviewed the literature to obtain all pertinent information on social media in health care and examined its strengths and weaknesses from patient and physician perspectives. Health care professionals have slowly begun to use social media to stay connected with patients. The recent use of networking sites aims to improve education, provide a forum to discuss relevant medical topics, and allow for improved patient care. The use of social media, with the understanding of its limitations, may help promote patient happiness and safety and serve as an educational platform. PMID- 22495837 TI - Preventing the harm of a closer look: contrast-induced nephropathy in adults. AB - Contrast media is administered to many patients in hospitals nationwide. Although the use of contrast and dyes is widespread and has a well accepted use among the medical profession, contrast-induced nephropathy can be a common and potentially harmful complication. Identifying patients at risk, attempting to minimize risk, and using preventative strategies should be priorities to decrease the harmful effects that are associated with the administration of contrast media. This article provides a general overview of contrast-induced nephropathy and a brief review of the risk factors and prophylactic treatment. PMID- 22495839 TI - Evolution and development of the Advanced Trauma Life Support (ATLS) protocol: a historical perspective. AB - The Advanced Trauma Life Support (ATLS) protocol is a successful course offered by the American College of Surgeons. Once based on didactic lectures and seminars taught by experts in the field, trauma training has evolved to become a set of standardized assessment and treatment protocols based on evidence rather than expert opinion. As the ATLS expands, indices to predict outcome, morbidity, and mortality have evolved to guide management and treatment based on retrospective data. This historical, perspective article attempts to tell the story of ATLS from its inception to its evolution as an international standard for the initial assessment and management of trauma patients. PMID- 22495841 TI - Management of an infected THA. PMID- 22495842 TI - Cam morphology in the human hip. AB - A growing interest exists in the diagnosis and treatment of femoroacetabular impingement. Although cam morphology of the proximal femur may conceptually appear to be a relatively simple topographical aberrancy, it is actually positioned amid a complex developmental, kinematic, and biomechanical region of the human body. The authors introduce a new classification scheme and review the historical and anthropological considerations, biomechanics, and genetic factors involved in cam morphology. PMID- 22495843 TI - Complications in total knee arthroplasty after high tibial osteotomy. AB - The outcome of total knee arthroplasty (TKA) after high tibial osteotomy remains uncertain. Compared with primary TKA, the results in some studies are not significantly different. Others report adverse effects on the outcome. The purpose of this study was to determine (1) the middle- and long-term survival of TKA performed after high tibial osteotomy, (2) their clinical and radiographic results, and (3) what complications could be expected in this group of patients.The study group comprised 31 patients (34 knees) undergoing cemented TKA after high tibial osteotomy. Average follow-up was 8 years (range, 6-213 months). Survival of the TKA was estimated using the Kaplan-Meier method. Outcomes were documented using the Hospital for the Special Surgery score. The results showed that the Kaplan-Meier survival rate was 82% at 5 years and 76% at 10 years. Excellent and good clinical results were obtained in 67% of patients. Complications occurred in 12 (35%) knees: stiffness in 4, aseptic loosening in 2, patellofemoral subluxation in 1, instability in 1, inexplicable pain in 1, and deep infection in 3.Great care with technical details is necessary when high tibial osteotomy is indicated because a future conversion to TKA may occur. PMID- 22495844 TI - Heat generated with pegged or keeled glenoid components fixed with defined amounts of cement. AB - Glenoid component loosening is a common complication of total shoulder arthroplasty and has been associated with the progression of radiolucent lines at the glenoid bone-cement interface. Generation of heat during the exothermic reaction of cement curing may cause osteonecrosis of bone, potentially leading to the development of radiolucent lines. The purpose of this study was to measure the heat generated with various defined amounts of cement used for glenoid component fixation.Ten fresh-frozen cadaver scapulas were randomized to receive a keeled or pegged component with 1, 2, 3, 5, or 7 g of cement for fixation. An infrared camera was used to record the surface temperature generated during the cement curing process to an accuracy of +/-2.0 degrees C. Computed tomography was used to evaluate the cement mantle. The maximum temperatures generated did not exceed the critical value for osteonecrosis (56 degrees C) in any of the specimens. The 4 specimens without a complete mantle were those fixed with a smaller quantity of cement (1, 2, or 3 g), and the largest cement mantle thicknesses were observed with the use of 7 g of cement.Up to 7 g of cement can be used without significant concern for thermal necrosis. Incomplete cement mantles were observed when <=3 g of cement was used for fixation. Our results suggest that surgeons should use >3 g of cement to avoid incomplete cement mantles and that up to 7 g of cement can safely be used for glenoid fixation. PMID- 22495845 TI - Matrix metalloproteinase levels as a marker for rotator cuff tears. AB - Although many studies report the role of matrix metalloproteinases (MMPs) in rotator cuff tears, a paucity of data exists correlating the clinical severity of the disease with the implicated MMP levels. The purpose of this study was to investigate and compare the levels of expression of MMP-1, -3, -9 and -13 in patients with rotator cuff tears. We hypothesized that patients with clinically worse symptoms as measured by a standardized pain and function scale would have a higher expression of MMPs.Rotator cuff specimens were obtained from 16 consecutive patients undergoing rotator cuff repair. Total protein was extracted from these specimens and quantified. Equalized total protein extracts were used for performing enzyme-linked immunosorbent assay for quantitative determination of MMP-1, -3, -9 and -13. Preoperatively, the University of California, Los Angeles (UCLA) Shoulder Rating Scale was administered to each patient. Statistical comparisons were performed using analysis of variance. The expression of MMP-13 was notably increased in the rotator cuff extracts of all patients (P=.02). In addition, MMP-13 levels showed a significant proportional correlation with the patient pain score as per their UCLA ratings (r=-0.5). Although higher MMP-9 levels were assayed, this was not statistically significant. Expression of MMP-1 and-3 was insignificant.Our data suggest a critical role for MMP-13 in rotator cuff tears; elevated levels are a possible indicator for an impending tear. Further studies with increased sample size are warranted to prove the possible use of MMP-13 as therapeutic targets that may be inhibited by anti inflammatory agents to limit disease progression. PMID- 22495846 TI - Bilateral anatomic total shoulder arthroplasty versus reverse shoulder arthroplasty. AB - The results of anatomic total shoulder arthroplasty and reverse shoulder arthroplasty have previously been reported separately. Although the indications differ, scenarios exist in which a patient may have a total shoulder arthroplasty on 1 shoulder and a reverse shoulder arthroplasty on the contralateral shoulder.Between 1992 and 2009, twelve patients underwent bilateral sequential primary shoulder arthroplasty with a total shoulder arthroplasty on 1 side and reverse shoulder arthroplasty on the contralateral side. Constant score, American Shoulder and Elbow Surgeons (ASES) score, subjective shoulder value, and patient satisfaction were obtained a minimum 1 year postoperatively. Mean postoperative Constant score was 77 after total shoulder arthroplasty and 73 after reverse shoulder arthroplasty (P<.2488). Mean postoperative active forward flexion was similar after total shoulder arthroplasty compared with reverse shoulder arthroplasty (P=.8910). Greater external rotation at the side (43 degrees vs 12 degrees ; P<.0001) and internal rotation (T8 vs L1; P<.0001) were observed after total shoulder arthroplasty. Mean ASES score was 89.6 after total shoulder arthroplasty compared with 82.4 after reverse shoulder arthroplasty (P=.0125). Patient satisfaction was 92% for both prostheses, and mean subjective shoulder value was similar (85.4% vs 82.5%; P=.6333).Bilateral shoulder arthroplasty performed with a total shoulder arthroplasty and reverse shoulder arthroplasty on opposite shoulders can provide good functional outcome and high patient satisfaction. Although range of motion is better following total shoulder arthroplasty, no difference was observed in final Constant score or subjective patient assessment. PMID- 22495847 TI - Treatment of compartment syndrome of the thigh associated with acute renal failure after the Wenchuan earthquake. AB - Compartment syndrome of the thigh is a rare emergency often treated operatively. The purpose of this study was to evaluate the effects of nonoperative treatment for compartment syndrome of the thigh associated with acute renal failure after the 2008 Wenchuan earthquake. Nonoperative treatment, which primarily involves continuous renal replacement therapy, was performed in 6 patients (3 men and 3 women) who presented with compartment syndrome of the thigh associated with acute renal failure. The mean mangled extremity severity score (MESS) and laboratory data regarding renal function were analyzed before and after treatment, and the clinical outcome was evaluated at 17-month follow-up. Laboratory data regarding renal function showed improvements. All 6 patients survived with the affected lower limbs intact after nonoperative treatment. Follow-up revealed active knee range of motion and increased muscle strength, as well as a recovery of sensation. A positive linear correlation was found between MESS and the time required to achieve a reduction in swelling, as well as the time required for the recovery of sensation and knee range of motion (r>0.8; P<.05). Satisfactory clinical outcomes were obtained in patients with compartment syndrome of the thigh associated with acute renal failure.Urine alkalization, electrolyte and water balance, and continuous renal replacement therapy have played an important role in saving lives and extremities. Nonoperative treatment should be considered in the treatment of compartment syndrome of the thigh associated with acute renal failure. PMID- 22495848 TI - Retrograde nailing of a femoral supracondyle. AB - Because standard femoral supracondylar nails have certain disadvantages, they are often replaced by traditional femoral or tibial locked nails. The purpose of this study was to make a biomechanical comparison between both types of traditional locked nails to determine which technique was more suitable for treating unstable femoral supracondylar fractures. Fourteen left Sawbones femurs (Pacific Research Laboratories, Vashon, Washington) were osteotomized in the femoral supracondylar area. One centimeter of the medial cortex in the proximal fragment was obliquely removed to simulate an unstable fracture without shortening. Seven specimens were treated with traditional retrograde dynamic femoral locked nails, and the other 7 with traditional retrograde dynamic tibial locked nails. All specimens were tested with a servohydraulic materials testing machine to compare their relative stability. Static compression, dynamic cyclic compression, and static compression to failure were tested. An extensometer was used to measure the displacement of fragments. Displacement between the fragments increased following the increment in loads in both nails. The load-displacement curve was nearly linear up to 1000 N for both nails. The femoral nail had a greater stiffness compared with the tibial nail at 100 and 200 N (P=.02 and P=.04, respectively) in static compression and at 700 to 1000 N (P=.01 in each case) in dynamic cyclic compression, as well as larger loads in static compression to failure (8663 vs 7547 N, respectively; P<.001). Clinically, a traditional femoral locked nail may be more suitable to replace a standard femoral supracondylar nail in a retrograde fashion to treat an unstable femoral supracondylar fracture. PMID- 22495849 TI - Arthroscopic pancapsular plication for multidirectional shoulder instability in overhead athletes. AB - Treating shoulder multidirectional instability with an open stabilization procedure has been reported to have good results. However, few studies exist of arthroscopic plication, especially in overhead athletes. The purpose of this study was to evaluate the clinical outcomes of arthroscopic pancapsular plication for multidirectional instability in overhead athletes.Twenty-three athletes with symptomatic multidirectional instability were treated with arthroscopic pancapsular plication and evaluated at a mean follow-up of 36.3 months (range, 24 61 months). Mean patient age was 23.3 years (range, 19-33 years). Functional outcomes were evaluated with the American Shoulder and Elbow Surgeons (ASES) score, Constant shoulder score, and Rowe instability score. The degree of pain and range of motion were also recorded. All postoperative functional scores were rated good to excellent, with an average ASES score of 88.4 (range, 82-95), average Constant shoulder score of 88.1 (range, 81-100), and average Rowe instability score of 86.7 (range, 80-100). Five patients returned to the same level of competitive sports, and 18 returned to a limited level. All patients were satisfied with the stability postoperatively. No significant change was observed in postoperative range of motion, but patients who returned to a limited level of sports had lower functional scores and more pain than did those who fully returned to sports.Arthroscopic pancapsular plication for treating multidirectional instability in overhead athletes can provide good stability. However, the low rate of return to a full level of overhead sports is a problem. Further evaluation of the benefits of this procedure for overhead athletes with symptomatic multidirectional instability is needed. PMID- 22495850 TI - Characterization of daptomycin-loaded antibiotic cement. AB - Antibiotics are commonly mixed with polymethylmethacrylate (PMMA) cement to suppress severe periprosthetic infections associated with total joint arthroplasty. The relationship between antibiotic concentration and the resulting elution kinetics remains unclear. The purpose of this study was to characterize the release of daptomycin from PMMA cement and the subsequent effects on mechanical properties.Varying concentrations of daptomycin and tobramycin were vacuum mixed in commercially available PMMA and subjected to an in vitro elution period. High-performance liquid chromatography was used to quantify the concentration of the amount of daptomycin eluted at predetermined time points. Samples were subjected to compressive loading to analyze the effect of antibiotic concentration on cement mechanical properties. Daptomycin elution increased when initial tobramycin concentration was increased. Furthermore, the addition of antibiotics increased the compressive strength of the cement in the postelution period. The binary addition of tobramycin with daptomycin antibiotics modifies the elution and mechanical properties of PMMA bone cement. Based on the findings of our study, 2 g of daptomycin and 3.6 g of tobramycin per 40-g packet of cement should be used to promote daptomycin elution without sacrificing PMMA mechanical properties. PMID- 22495851 TI - Hepatitis C viral infection as an associated risk factor for necrotizing fasciitis. AB - Necrotizing fasciitis is a rare soft tissue infection associated with a high mortality rate. Several risk factors for the development of necrotizing fasciitis have been studied, which has given surgeons insight into the types of patients who are more likely to present with this rapidly progressive infection. The concomitant diagnosis of hepatitis C viral infection has not been reported in the literature previously. In this retrospective study covering a 12-year period in 1 Level I trauma center, 10 (34%) of 29 patients presenting with necrotizing fasciitis had an underlying diagnosis of hepatitis C viral infection. The mortality rate in patients with hepatitis C viral infection was 30% compared with 21% for those without hepatitis C viral infection (P=.59). The proportion of patients presenting with the concomitant diagnosis of hepatitis C viral infection and necrotizing fasciitis was statistically greater than that expected from the prevalence of hepatitis C viral infection in the general population (1.8%; P<.001).Our study showed that hepatitis C viral infection is a risk factor for developing necrotizing fasciitis. Although our sample size was too small to show a statistical significance, we believe that a clinically significant increase in mortality of necrotizing fasciitis occurred in patients with concomitant hepatitis C viral infection. Therefore, the presence of hepatitis C viral infection in patients presenting with symptoms of necrotizing fasciitis should raise the clinical suspicion for this diagnosis, with the potential for a worse prognosis. PMID- 22495852 TI - Rate of adverse reactions to more than 1 series of viscosupplementation. AB - Viscosupplementation, hyaluronic acid treatment, is an ancillary method for treating patients with symptomatic stage I or II osteoarthritis. Previous studies reported that local reactions occurred more frequently in patients receiving >1 course of treatment compared with patients receiving their first course of treatment. One (2%) of 42 first series patients and 4 (21%) of 19 of repeated series patients had adverse reactions severe enough to seek unscheduled care.This study was performed to determine whether patients receiving >1 series of viscosupplementation had an increased adverse reaction rate. A retrospective chart review was performed on all patients who received >1 series of viscosupplementation during the study. A local adverse reaction was defined as acute swelling and pain in the knee, with no injury or trauma within 72 hours after hyaluronic acid injection.Twenty-eight knees received >1 series of viscosupplementation. The adverse reaction rate to second series injections was 1.28% (3.57% of knees). The adverse reaction rate to >=3 series was 0.9% (6.67% of knees). This adverse reaction rate was significantly less than the 21% reported in previous studies for multiple series injections (z=-1.90; P<.05) and is not significantly different than the 2% rate of adverse reactions reported for first series injections. No significant difference existed in the adverse reaction rates between 2 series and >=3 series of viscosupplementation.The current study suggests that the rate of adverse reaction was low at 1.28% of second series viscosupplementation. PMID- 22495853 TI - Platelet-rich plasma reverses the inhibition of tenocytes and osteoblasts in tendon-bone healing. AB - The purpose of this study was to investigate the effect of platelet-rich plasma on the proliferation of osteoblasts and tenocytes in tendon-bone healing. We cultured osteoblasts and tenocytes in an indirect coculture system with Transwell filters (Merck Millipore, Billerica, Massachusetts). The proliferation was examined using Cell Counting Kit-8 (Dojindo Chemistry Research Institute, Kumamoto, Japan).Four groups were studied: group 1, one cell type cultured without platelet-rich plasma; group 2, two cell types cultured together in an indirect coculture system without platelet-rich plasma; group 3, cells in the outer chamber and platelet-rich plasma in the inner chamber; and group 4, two different cell types in each of the 2 chambers with platelet-rich plasma in the inner chamber. The proliferation rates of groups 3 and 4 were the highest, followed by group 1 and then group 2, which was the lowest.Platelet-rich plasma abolishes the inhibition of osteoblasts or tenocytes in an indirect coculture system and improves the cell proliferation rate. PMID- 22495854 TI - Effects of pulsed electromagnetic field frequencies on the osteogenic differentiation of human mesenchymal stem cells. AB - The purpose of this study was to evaluate the effect of different frequencies of pulsed electromagnetic fields on the osteogenic differentiation of human mesenchymal stem cells. Third-generation human mesenchymal stem cells were irradiated with different frequencies of pulsed electromagnetic fields, including 5, 25, 50, 75, 100, and 150 Hz, with a field intensity of 1.1 mT, for 30 minutes per day for 21 days. Changes in human mesenchymal stem cell morphology were observed using phase contrast microscopy. Alkaline phosphatase activity and osteocalcin expression were also determined to evaluate human mesenchymal stem cell osteogenic differentiation.Different effects were observed on human mesenchymal stem cell osteoblast induction following exposure to different pulsed electromagnetic field frequencies. Levels of human mesenchymal stem cell differentiation increased when the pulsed electromagnetic field frequency was increased from 5 hz to 50 hz, but the effect was weaker when the pulsed electromagnetic field frequency was increased from 50 Hz to 150 hz. The most significant effect on human mesenchymal stem cell differentiation was observed at of 50 hz.The results of the current study show that pulsed electromagnetic field frequency is an important factor with regard to the induction of human mesenchymal stem cell differentiation. Furthermore, a pulsed electromagnetic field frequency of 50 Hz was the most effective at inducing human mesenchymal stem cell osteoblast differentiation in vitro. PMID- 22495855 TI - Knot security: how many throws does it really take? AB - The purpose of this study was to determine the minimum number of throws needed for knot security for square knots using 5 common suture materials and 3 common sizes by in vitro single load to failure biomechanical testing. The hypothesis was that each suture combination studied would share a common minimum of at least 5 throws to guarantee security. Five suture materials (FiberWire [Arthrex, Inc, Naples, Florida], Monosof, Surgipro, Maxon, and Polysorb [Covidien, Mansfield, Massachusetts]) with varying suture sizes (#5, #2, 0, 2-0, and 4-0) were tied in vitro, varying the number of square knot throws (3, 4, 5, and 6). Twenty knots for each combination were statically loaded to failure in tension; whether the knot failed by fracture or slippage and the tensile strength at knot failure was determined. For the tested materials, at least 5 flat square throws should be used to confer knot security based on a binomial proportion score 95% confidence interval (CI) 0.84 to 1.0 or at least 4 throws for a 95% CI of 0.76 to 0.99. FiberWire requires 6 flat square throws per knot for security at either 95% CI level. Unless a surgeon has specific knowledge of experimental evidence that fewer throws are necessary for a specific application, the default should be a minimum of 4 throws, with 5 conferring additional security in most situations, and FiberWire requiring 6 throws. PMID- 22495856 TI - Nonoperative treatment of displaced type II odontoid peg fractures with a Philadelphia collar. AB - Although a consensus exists on the nonoperative management of types I and III odontoid peg fractures, treatment of type II fractures remains controversial. An increasing trend exists toward primary fixation of type II peg fractures due to a high rate of nonunion, especially if the displacement is >4 mm. This article reports the results of nonoperative treatment of patients with displaced odontoid peg fractures (>4 mm) using a Philadelphia collar.A retrospective review of clinical and radiological records was performed for nonoperatively treated patients who sustained displaced type II peg fractures between January 2003 and April 2008. The study group comprised 9 patients (2 men and 7 women), and all patients were treated with Philadelphia collars. Patients were followed up for an average of 24.8 months (range, 8-28 months) for clinical and radiological outcomes. Functional outcomes were measured according to the Smiley-Webster scale. Fractures united uneventfully in 6 patients, but nonunion developed in 3 patients. Average time to union was 12.3+/-2.94 weeks (95% confidence interval, 9.97-14.68 weeks; range, 10-16 weeks). No patient had clinical or radiological signs of instability or delayed onset myelopathy at follow-up. Three patients had excellent, 4 had good, and 2 had fair results as per the Smiley-Webster functional scoring system.Displaced type II peg fractures can be managed nonoperatively in patients who refuse surgery or those with multiple comorbidities. Adequate patient counseling and compliance with close clinicoradiological follow-up is paramount to avoid adverse clinical events and achieve an optimal functional outcome. PMID- 22495857 TI - Expansive open-door laminoplasty with titanium miniplate versus sutures. AB - Expansive laminoplasty is an effective treatment for cervical myelopathy. Since the design of classic open-door laminoplasty with the use of suture, the procedure has been modified to reduce complications such as restenosis, axial symptoms, and segmental motor paralysis. Expansive open-door laminoplasty with the use of titanium miniplate is becoming popular. It is effective in expanding spinal canal dimensions with good clinical efficacy. However, a lack of studies exist comparing titanium miniplate fixation with classical suture fixation.We performed a retrospective study of 54 patients with cervical myelopathy. Twenty nine patients (4 women and 25 men) receiving expansive open-door laminoplasty by titanium miniplate fixation were classified as the modified group, and 25 patients (5 women and 20 men) fixed with suture served as the control group. Clinical and radiologic outcomes were assessed. No significant differences were observed in Japanese Orthopaedic Association scores and the recovery rate of C5 palsy. The incidence of axial symptoms in the modified group was significantly lower than that in control group. Radiologic examination showed that postoperative C2-C7 lordosis and range of motion of the cervical spine in the modified group were preserved. No significant differences were observed in mean anteroposterior diameter and open angle in the 2 groups. Both surgical protocols were effective in preventing reclosure of open laminae. Furthermore, the modified laminoplasty was superior in reducing the incidence of axial symptoms and loss of cervical lordosis and range of motion. PMID- 22495858 TI - Financial debt of orthopedic residents. AB - Many orthopedic residents accrue considerable debt by residency graduation. These debts for graduating medical students continue to increase due to the yearly increase of medical school tuition. The purpose of this study was to examine the causes of financial debt, as well the effects of debt on orthopedic residents.Orthopedic residents from postgraduate years 1 to 5 (N=27) completed an anonymous, optional financial survey. The survey asked questions regarding the characteristics of the residents' debt and their concern caused by their debt. All residents from our institute (N=27) voluntarily participated in the survey. The residents consisted of 4 (15%) women and 23 (85%) men, with 14 (56%) single residents and 12 (44%) married residents. No statistically significant difference existed in total debt >$100,000 between single and married residents or men and women. Forty-eight percent (n=13) of the residents had medical educational debt >$100,000, whereas 45% (n=12) had total debt >$200,000. Residents with total debt >$100,000 were concerned about their debt, whereas 1 of 4 residents with <$100,000 of total debt reported concern (P<.001).Debts affect orthopedic residents financially and may cause stress and hinder their medical training. Appropriate measures should be taken to help residents properly manage their debt and to provide supplemental assistance with their financial struggles. PMID- 22495859 TI - Trends in the orthopedic job market and the importance of fellowship subspecialty training. AB - Previous studies have examined possible incentives for pursuing orthopedic fellowship training, but we are unaware of previously published studies reporting the trends in the orthopedic job market since the acceptance of certain criteria for fellowship programs by the Accreditation Council for Graduate Medical Education (ACGME) in 1985. We hypothesized that, since the initiation of accredited postresidency fellowship programs, job opportunities for fellowship trained orthopedic surgeons have increased and job opportunities for nonfellowship-trained orthopedic surgeons have decreased. We reviewed the job advertisements printed in the Journal of Bone and Joint Surgery, American Volume, for the years 1984, 1994, 2004, and 2009. We categorized the job opportunities as available for either a general (nonfellowship-trained) orthopedic surgeon or a fellowship-trained orthopedic surgeon. Based on the advertisements posted in the Journal of Bone and Joint Surgery, American Volume, a trend exists in the orthopedic job market toward seeking fellowship-trained orthopedic surgeons. In the years 1984, 1994, 2004, and 2009, the percentage of job opportunities seeking fellowship-trained orthopedic surgeons was 16.7% (95% confidence interval [CI], 13.1%-20.3%), 40.6% (95% CI, 38.1%-43.1%), 52.2% (95% CI, 48.5%-55.9%), and 68.2% (95% CI, 65.0%-71.4%), respectively. These differences were statistically significant (analysis of variance, P<.05). Fellowship training is thus a worthwhile endeavor. PMID- 22495860 TI - Late liner disassociation of a Pinnacle system acetabular component. AB - This article describes a case of late locking mechanism failure and disassociation of a Pinnacle acetabular cup (DePuy, Warsaw, Indiana) and Marathon polyethylene liner (DePuy) 53 months after routine primary total hip arthroplasty in an active patient. Following an uncomplicated initial postoperative recovery, the patient felt a pop while kneeling for gardening activities. The patient had no prodromal symptoms but reported pain with range of motion and weight bearing following the episode. Radiographs appeared to show a fractured liner with intact acetabular and femoral components. Intraoperatively, the liner was disassociated and dislocated inferior to the acetabulum, and 3 consecutive antirotational tines were sheared off the liner at their bases. The acetabular cup and femoral stem were well fixed. Extensive metallosis existed from the femoral head and acetabular shell articulating in the absence of a liner. The patient underwent revision of the acetabular cup, polyethylene liner, and femoral head due to the concern for osteolysis given the extensive metallosis. Revision of the acetabular cup and liner were performed with no further complications. No conclusions could be made as to the exact mechanism of failure following laboratory analysis of the retrieved polyethylene liner. Several possible mechanisms of failure are possible. Although cases of acute disassociation of this system have been reported, this is the first article to our knowledge to report failure at such a late postoperative time. PMID- 22495861 TI - Deep external pudendal artery injury after percutaneous adductor tenotomy during THA in ankylosing spondylitis. AB - Arterial injuries following total hip arthroplasty (THA) are uncommon and are usually related to revision THA. Deep external pudendal artery injury and delayed bleeding due to percutaneous adductor tenotomy during THA has not been reported.A 62-year-old man with bilateral hip osteoarthritis and ankylosing spondylitis was treated with right cementless THA. Persistent severely limited hip abduction after prosthetic implantation required a percutaneous adductor tenotomy, which was performed bilaterally. No clinical signs of bleeding existed postoperatively. On postoperative day 3, the patient had a hypotensive attack, his right anteromedial thigh at the tenotomy site was distended, and the hemoglobin was 5.9 g/dL. Computed tomography angiography of the iliac and femoral vessels showed a right hematoma medial to the common femoral artery, with active contrast extravasation. Volumetric data reconstruction revealed active bleeding from the right external pudendal artery into an inguinal collection. Angiography was performed by the standard Seldinger technique via the contralateral femoral artery. A guiding catheter was placed as near to the lesion as possible. A microcatheter system and microguidewire were used for superselective catheterization, and 2 embolization coils were used to control the bleeding. The patient remained hemodynamically stable and was discharged 12 days later. Two year follow-up was uneventful.The deep external pudendal artery may be injured during percutaneous adductor tenotomy, especially in patients with fragile arterial walls, and life-threatening complications may occur. Angiography and embolization are the best treatment options. PMID- 22495862 TI - Acetabular liner revision using an anterolateral approach. AB - Total hip arthroplasty (THA) is recognized as a successful treatment for degenerative hip joint disease. An epidemiological study using the National Hospital Discharge Survey in the United States reported that the number of primary THAs increased from 119,000 in 1990 to 193,000 in 2002. According to nationwide inpatient sample data, the demand for primary THA was estimated to increase from 208,600 in 2005 to 572,000 (174%) in 2030 in the United States. The number of revision THAs in the United States has subsequently increased and is projected to increase from 40,800 in 2005 to 96,700 in 2030. Because revision THAs have a higher incidence of dislocation than primary THAs, preserving the soft tissue, including the gluteus medius muscle, is more necessary at revision THA. However, to our knowledge, few studies have reported soft tissue damage at revision THA. An anterolateral modified Watson-Jones approach, which is between the hip abductor and the tensor fascia lata, preserves the abductor muscles.This article describes 2 cases in which acetabular liner revision was performed through an anterolateral modified Watson-Jones approach. The anterolateral approach provided an excellent surgical field at acetabular liner revision, with no major complications, and has the possibility of being a useful for acetabular liner revision. PMID- 22495863 TI - Familial association of femoral trochlear dysplasia with recurrent bilateral patellar dislocation. AB - Femoral trochlear dysplasia is an anatomic deformity that predisposes patients to patellar instability, including patellar subluxation and dislocation, and can lead to severe patellofemoral joint degeneration if left untreated. Femoral trochlear dysplasia leading to recurrent bilateral patellar dislocation has rarely been reported as having a familial association. Orthopedic surgeons who encounter patients presenting with chronic patellar instability with no underlying disease or syndrome should be aware of the presence of femoral trochlear dysplasia leading to recurrent bilateral patellar dislocation. Although femoral trochlear dysplasia remains uncommon, the presence of bilateral recurrent patellar dislocation in multiple members of the same family is highly suggestive of genetic inheritance.This article describes 3 patients from 1 family who presented with femoral trochlear dysplasia leading to recurrent bilateral patellar dislocation. To our knowledge, this is the second article to describe a familial form of femoral trochlear dysplasia associated with recurrent bilateral patellar dislocation and is the first article in English. A lower threshold for screening and early intervention for symptomatic family members may be indicated to prevent the long-term effects of chronic patellar subluxation, dislocation, and patellofemoral arthritis. PMID- 22495864 TI - Collagen type V polymorphism in spontaneous quadriceps tendon ruptures. AB - Spontaneous simultaneous bilateral quadriceps tendon rupture is associated with multiple medical conditions and pharmacological treatments; however, identifying prior risk factors is impossible in most cases. Achilles tendon and anterior cruciate ligament ruptures are associated with collagen, type V, alpha 1 (COL5A1) polymorphism. This genetic variant may be implicated quadriceps tendon rupture. The COL5A1 encodes the protein for pro-alpha1 chains of the low-abundance heterotrimeric type V collagen. In most noncartilaginous tissues, type V collagen is a quantitatively minor component of type I collagen that has been implicated in the regulation of the size and configuration of type I collagen fibrils. The functional significance of COL5A1 polymorphism in relation to type V collagen expression or activity has not been determined.This article describes a patient with COL5A1 polymorphism and spontaneous simultaneous quadriceps tendon rupture. However, genetic and histologic studies performed on blood and tendon tissues and 3 consecutive sex- and age-matched controls showed a statistically significant reduction in collagen type V expression and an alteration in collagen structure in the tendon. These findings might explain the pathomechanisms of spontaneous tendon ruptures associated with COL5A1 polymorphism. PMID- 22495865 TI - Complete anterior knee dislocation 16 years after cruciate-retaining total knee arthroplasty. AB - Anterior dislocation after total knee arthroplasty (TKA) is rare; 9 cases have been reported in the English literature. Five patients sustained subluxation, with recurvatum as the clinical manifestation, and 4 patients sustained complete dislocation, usually accompanying other serious complications.This article describes a case of complete dislocation that developed atraumatically 16 years after TKA and was characterized by dislocation in extension and spontaneous reduction in flexion. Revision TKA was planned, with several alternative procedures under consideration, ranging in degree of invasiveness from simple polyethylene exchange to conversion to a hinge-typed prosthesis. Intraoperatively, extensive areas of blackened synovium and posterior-dominant polyethylene wear existed medially and laterally. Considering the patient's age of 82 years, low activity level in activities of daily living, edematous skin, and number of stable components, we performed simple polyethylene exchange to a cruciate-retaining component that left the partial metal defect in the tibial plate untouched. Successful outcome was achieved for >2 years. The dislocation mechanism was polyethylene thinning, leading to relative valgus and anteroposterior instability that aggravated the anterior cruciate ligament dysfunction, which is speculated as the inherent key causative factor in every TKA.Complete dislocation, usually accompanying other complications, requires prompt treatment because the possibility of serious consequences exists. Due to the absence of a gold standard, the treatment of choice needs to be made on a case-by-case basis. PMID- 22495866 TI - Neuritis ossificans of the radial nerve. AB - Neuritis ossificans is a rare reactive process affecting the peripheral nerves that is challenging to diagnose and treat. The usual presentation is mononeuropathy, pain, variable weakness, and a palpable mass along the nerve distribution. A paucity of literature exists on this disorder. It is often confused with myositis ossificans; many cases in the literature have reported myositic masses that have caused neuropathies. Diagnosing neuritis ossificans requires a high degree of clinical suspicion and excellent radiological and histopathological evaluation. The exact etiology of neuritis ossificans is unclear, but repeated localized trauma may be a factor. Treatment is mostly surgical, although conservative management with drugs has been reported to give good relief. The chance of iatrogenic nerve damage during microsurgical excision is high.This article describes a case of neuritis ossificans of the radial nerve, which was treated by surgical excision of the lesion without nerve resection. No iatrogenic neurodeficit occurred, and the patient made a full recovery.Neuritis ossificans should be considered in the differential diagnosis of painful mononeuropathies, particularly at atypical sites for compression neuropathy. Surgical resection of the mass may relieve pain and improve strength if the nerve can be sufficiently spared. Enucleation of this rare lesion is possible without neural compromise and should be considered as a treatment option for neuritis ossificans. PMID- 22495867 TI - Intraosseous median nerve entrapment following pediatric posterior elbow dislocation. AB - Intra-articular entrapment of the median nerve following reduction of a pediatric posterior elbow dislocation is a rare complication but has been reported in the literature.This article describes a case of a 7-year-old girl who sustained a posterior elbow dislocation associated with a medial epicondyle fracture and the subsequent intraosseous entrapment of her median nerve. The entrapment is believed to have resulted from new bone formation over the nerve that went unrecognized for nearly 2 years following injury. Routine imaging studies failed to detect the entrapment prior to exploratory surgery. Intra-articular entrapment of the median nerve must be suspected following pediatric elbow dislocation when concentric reduction fails, postreduction images demonstrate joint widening, or the patient has persistent clinical symptoms. This case demonstrates the potential for delay in diagnosis of the cause for neurological impairment following a relatively common injury in the pediatric population.Objective intraoperative findings and intraoperative micropathology aided in limiting the amount of nerve resected to nonviable portions. Our case demonstrates the potential use of a cable nerve graft to bridge segmental defects in peripheral nerves. PMID- 22495868 TI - Acute tibialis posterior tendon rupture associated with a distal tibial fracture. AB - Tibialis posterior tendon ruptures associated with closed medial malleolar fractures are rare. This article describes the association of tibialis posterior tendon ruptures with closed, high-energy, distal tibia fractures. Tendon ruptures are likely to be identified intraoperatively or missed if clinical evaluation at acute injury is limited. A high index of suspicion is required to diagnose this injury. The consequences of an unrecognized tibialis posterior tendon rupture include progressive, painful pes planus deformities due to the unopposed action of the peroneus brevis muscle and lack of support of the medial longitudinal arch. Secondary operative intervention may be required. This article describes an intraoperative tenodesis technique between the tibialis posterior and flexor digitorum longus tendons when direct repair is not possible.A 48-year-old woman sustained a closed AO/Orthopaedic Trauma Association type 43A right lower extremity distal tibia fracture and a traumatic left knee arthrotomy. Temporary stabilization with an external fixator was performed, followed by open reduction and internal fixation of the distal tibial fracture 6 days later. A periarticular nonlocking medial plate was applied, and the tibialis posterior tendon was shortened. We performed a direct tenodesis to the flexor digitorum longus tendon. At 1-year follow-up, the patient had made excellent progress, with no detectable muscle weakness, and was able to perform a single-leg toe raise.A review of the literature suggested which features of radiological evidence of tendon rupture should be examined, which may be useful in the current era considering most high energy distal tibia or pilon fractures undergo examination with computed tomography. PMID- 22495869 TI - Lower-extremity soft tissue infections with intra-abdominal sources. AB - This article describes a series of 3 patients who presented with lower-extremity soft tissue infections. Each patient was treated with prompt debridement by an orthopedic surgeon (J.F.G.) and required at least 1 additional procedure by another surgeon.These infections vary from superficial cellulitis to rapidly advancing necrotizing fasciitis. At times, the source of these infections is clear. Other times, no obvious source of infection exists, in which case the abdomen must be considered as a possible source of infection. A high level of suspicion, complete history and physical examination, and appropriate ancillary studies are required to make an accurate and prompt diagnosis. Options for the treatment of the intra-abdominal source of infection depend on the etiology of the infection and anatomic location of the process. Psoas abscesses can often be decompressed by an interventional radiologist using computed tomography guidance. In the case of bowel involvement, such as suspected carcinoma or diverticulitis, a general surgeon is necessary. When the appropriate diagnosis is made, soft tissue infections of the thigh often respond to appropriate surgical debridement and antibiotic therapy. It is important to remember the whole patient when evaluating soft tissue infections, especially in the thigh. A low threshold for imaging of the abdomen and pelvis is important, especially when the physical examination or medical history reveals the abdomen as a possible source of infection. PMID- 22495870 TI - Daptomycin resistance in prosthetic joint infections. AB - Antimicrobial resistance has been problematic since the advent of antibiotics. Patients with prosthetic joint infections often require prolonged courses of antibiotic therapy, with resistance commonly being the consequence. The rapid evolution of resistance poses a serious challenge in the treatment of infections and creates a need for new agents with novel mechanisms of bactericidal activity. Daptomycin, a cyclic lipopeptide naturally produced by Streptomyces roseosporus, is a newer agent approved for use in complicated skin, soft tissue, and prosthetic joint infections. To our knowledge, this article describes the first case of daptomycin-resistant heterogenous vancomycin intermediate-resistant Staphylococcus aureus (hVISA) in an 82-year-old man undergoing elective total knee arthroplasty in Queensland, Australia, with a subsequent deep prosthetic joint infection.A literature review is presented, and the increasing number of multi-resistant organisms and their implications for orthopedics are discussed. Worldwide reports of hVISA are reviewed. To our knowledge, this is the first article to describe daptomycin resistance in prosthetic joint infections. The role of newer antimicrobial agents, such as daptomycin, and strategies to minimize antibiotic resistance are examined. PMID- 22495871 TI - Tendon sheath fibroma in the thigh. AB - Tendon sheath fibromas are rare, benign soft tissue tumors that are predominantly found in the fingers, hands, and wrists of young adult men. This article describes a tendon sheath fibroma that developed in the thigh of a 70-year-old man, the only known tendon sheath fibroma to form in this location. Similar to tendon sheath fibromas that develop elsewhere, our patient's lesion presented as a painless, slow-growing soft tissue nodule. Physical examination revealed a firm, nontender mass with no other associated signs or symptoms. Although the imaging appearance of tendon sheath fibromas varies, our patient's lesion appeared dark on T1- and bright on T2-weighted magnetic resonance imaging. It was well marginated and enhanced with contrast.Histologically, tendon sheath fibromas are composed of dense fibrocollagenous stromas with scattered spindle-shaped fibroblasts and narrow slit-like vascular spaces. Most tendon sheath fibromas can be successfully removed by marginal excision, although 24% of lesions recur. No lesions have metastasized. Our patient's tendon sheath fibroma was removed by marginal excision, and the patient remained disease free 35 months postoperatively. Despite its rarity, tendon sheath fibroma should be included in the differential diagnosis of a thigh mass on physical examination or imaging, especially if it is painless, nontender, benign appearing, and present in men. PMID- 22495872 TI - Total en bloc spondylectomy of L3 vertebra for histiocytic sarcoma. AB - This article describes a rare malignant spinal tumor successfully treated with total en bloc spondylectomy via a posterior approach. The purpose of this study was to emphasize the occurrence of primary histiocytic sarcoma in the lumbar spine. Histiocytic sarcomas are rare, malignant neoplasms of the lymphohematopoietic system that usually occur in the skin, lymph nodes, and intestinal tracts. Primary spinal column histiocytic sarcoma is rare. To the authors' knowledge, no reports have been published of treating this tumor with total en bloc spondylectomy.A 27-year-old woman presented with a 2-month history of intermittent low back pain and right lower extremity pain. Magnetic resonance imaging and computed tomography (CT) revealed a lumbar vertebra tumor. Positron emission tomography/CT showed focal accumulation in the tumor site. The patient was diagnosed with a histiocytic sarcoma based on biopsy findings and underwent total en bloc spondylectomy of L3 and reconstruction via a posterior approach. The patient maintained normal neurologic function, and the pain was lessened. No major complications occurred. No radiotherapy or chemotherapy was administered postoperatively, and no local tumor recurrence or distant metastases existed at 2 year follow-up.The diagnosis of histiocytic sarcoma relies predominantly on the verification of histiocytic lineage and the exclusion of other, poorly differentiated, large-cell malignancies by immunohistochemical stain. Total en bloc spondylectomy at L3 via a posterior approach can be performed safely and is an important approach in the treatment of selected spinal tumors. PMID- 22495873 TI - Hematological features of pediatric systemic lupus erythematosus: suggesting management strategies in children. AB - AIM: The aim of this study was to analyze the hematological features in children with systemic lupus erythematosus (SLE) and to review our current treatment protocols. METHODS: We evaluated hematological findings of 43 children with SLE diagnosed and followed at the Pediatric Rheumatology Division of Hacettepe University, Turkey. Thirty-seven patients with hematological abnormalities were analyzed in detail. RESULTS: Median age at presentation was 13 years. Hematological involvement was seen in 86% of patients. The most common hematological finding was anemia (n = 30). Anemia was either a Coombs (+) hemolytic one, or was due to other causes. Hemolytic anemia was treated with steroids and intravenous gamma globulin (IVIG). Leucopenia and thrombocytopenia were detected in 35.1 % and 37.8 %, respectively. Bone marrow aspiration was performed in 15, mainly for cytopenia. Secondary dysplastic changes were common. Acute lymphoblastic leukemia (ALL) was diagnosed in one patient. Six patients were diagnosed as having macrophage activation syndrome (MAS). One patient died due to secondary infections and multiorgan failure despite aggressive treatment. In patients diagnosed early, treatment with steroids and cyclosporine resulted in an excellent response. Thrombotic microangiopathy was detected in two patients. Both were treated successfully with steroids and plasma exchange. Antiphospholipid and anticardiolipin antibodies were positive in 12 and 15 of the patients, respectively. Five developed deep vein thrombosis (DVT), one cerebral sinus thrombosis and one presented with purpura fulminans. They were effectively treated with anticoagulation protocol. CONCLUSION: Hematological findings should be carefully assessed and treated vigorously to prevent the morbidity and possible mortality. PMID- 22495874 TI - Decreased breast cancer risk in systemic lupus erythematosus: the search for a genetic basis continues. AB - PURPOSE: Recent work has demonstrated an important decrease in breast cancers for women with systemic lupus erythematosus (SLE). The reason behind this phenomenon is unknown. Our purpose was to explore whether the single nucleotide polymorphisms (SNPs) predisposing to SLE might be protective against breast cancer (in women in the general population). METHODS: We focused on loci relevant to 10 SNPs associated with SLE (with a p value of <10(-9)). We determined whether we could establish a decreased frequency of these SNPs in breast cancer cases versus controls, within the general population. To do this we used a large breast cancer genome-wide association study (GWAS) dataset, involving 3,659 breast cancer cases and 4,897 controls. These subjects were all primarily of European ancestry. RESULTS: The population-based GWAS breast cancer data we examined suggested little evidence for important associations between breast cancer and SLE-related SNPs. Within the general population GWAS data, a cytosine(C) nucleotide substitution at rs9888739 (on chromosome 16p11.2) showed a very weak inverse association with breast cancer. The odds ratio (OR) for the rs9888739-C allele was 0.907551 (p value 0.049899) in the GWAS breast cancer sample, compared to controls. There was a slightly stronger, positive, association with breast cancer for rs6445975-G (Guanine) on chromosome 3p14.3, with a breast cancer OR of 1.0911 (p value 0.0097). CONCLUSIONS: Within this large breast cancer dataset, we did not demonstrate important associations with 10 lupus-associated SNPs. If decreased breast cancer risk in SLE is influenced by genetic profiles, this may be due to complex interactions and/or epigenetic factors. PMID- 22495875 TI - Application of Reynolds Risk Score for younger generation with different ethnicities. PMID- 22495876 TI - Rituximab induced pulmonary fibrosis in a patient with lupus nephritis. AB - We describe a 26-year-old woman who was diagnosed eleven years ago with systemic lupus erythematosus and who had suffered multiple relapses. She presented with class IV lupus nephritis with thrombotic microangiopathy, for which she received three doses of rituximab along with plasmapheresis, with no response, and soon became dialysis dependent. One month after the last dose of rituximab, she presented with dyspnoea and hypoxia. A transbronchial lung biopsy revealed pulmonary fibrosis. A diagnosis of rituximab induced pulmonary fibrosis was made after excluding other causes and she was treated with intravenous methyl prednisolone with which there was marked improvement in symptoms and hypoxemia. This is the first report of rituximab induced pulmonary fibrosis in a patient with lupus nephritis. PMID- 22495877 TI - Human ether a-gogo K(+) channel 1 (hEag1) regulates MDA-MB-231 breast cancer cell migration through Orai1-dependent calcium entry. AB - Breast cancer (BC) has a poor prognosis due to its strong metastatic ability. Accumulating data present ether a go-go (hEag1) K(+) channels as relevant player in controlling cell cycle and proliferation of non-invasive BC cells. However, the role of hEag1 in invasive BC cells migration is still unknown. In this study, we studied both the functional expression and the involvement in cell migration of hEag1 in the highly metastatic MDA-MB-231 human BC cells. We showed that hEag1 mRNA and proteins were expressed in human invasive ductal carcinoma tissues and BC cell lines. Functional activity of hEag1 channels in MDA-MB-231 cells was confirmed using astemizole, a hEag1 blocker, or siRNA. Blocking or silencing hEag1 depolarized the membrane potential and reduced both Ca(2+) entry and MDA-MB 231 cell migration without affecting cell proliferation. Recent studies have reported that Ca(2+) entry through Orai1 channels is required for MDA-MB-231 cell migration. Down-regulation of hEag1 or Orai1 reduced Ca(2+) influx and cell migration with similar efficiency. Interestingly, no additive effects on Ca(2+) influx or cell migration were observed in cells co-transfected with sihEag1 and siOrai1. Finally, both Orai1 and hEag1 are expressed in invasive breast adenocarcinoma tissues and invaded metastatic lymph node samples (LNM(+)). In conclusion, this study is the first to demonstrate that hEag1 channels are involved in the serum-induced migration of BC cells by controlling the Ca(2+) entry through Orai1 channels. hEag1 may therefore represent a potential target for the suppression of BC cell migration, and thus prevention of metastasis development. PMID- 22495878 TI - Social marketing to plan a fall prevention program for Latino construction workers. AB - BACKGROUND: Latino construction workers experience disparities in occupational death and injury rates. The Occupational Safety and Health Administration funded a fall prevention training program at the University of Nevada, Las Vegas in response to sharp increases in fall-related accidents from 2005 to 2007. The grant's purpose was to improve fall protection for construction workers, with a focus on Latinos. This study assessed the effectiveness of social marketing for increasing fall prevention behaviors. METHODS: A multi-disciplinary team used a social marketing approach to plan the program. We conducted same day class evaluations and follow-up interviews 8 weeks later. RESULTS: The classes met trainee needs as evidenced by class evaluations and increased safety behaviors. However, Spanish-speaking Latinos did not attend in the same proportion as their representation in the Las Vegas population. CONCLUSIONS: A social marketing approach to planning was helpful to customize the training to Latino worker needs. However, due to the limitations of behavior change strategies, future programs should target employers and their obligation to provide safer workplaces. PMID- 22495880 TI - Mucolipidosis type II alpha/beta with a homozygous missense mutation in the GNPTAB gene. PMID- 22495879 TI - Why the US Center for Medicare and Medicaid Services should not extend reimbursement indications for carotid artery angioplasty/stenting. PMID- 22495881 TI - AlN/3C-SiC composite plate enabling high-frequency and high-Q micromechanical resonators. AB - An AlN/3C-SiC composite layer enables the third-order quasi-symmetric (QS(3)) Lamb wave mode with a high quality factor (Q) characteristic and an ultra-high phase velocity up to 32395 ms(-1). A Lamb wave resonator utilizing the QS(3) mode exhibits a low motional impedance of 91 Omega and a high Q of 5510 at a series resonance frequency (f(s)) of 2.92 GHz, resulting in the highest f(s).Q product of 1.61 * 10(13) Hz among the suspended piezoelectric thin film resonators reported to date. PMID- 22495882 TI - Lmx1a allows context-specific isolation of progenitors of GABAergic or dopaminergic neurons during neural differentiation of embryonic stem cells. AB - LIM homeobox transcription factor 1 alpha (Lmx1a) is required for the development of midbrain dopaminergic neurons, roof plate formation, and cortical hem development. We generated a reporter embryonic stem cell (ESC) line for Lmx1a and used it to track differentiation and extract neural progenitors from differentiating mouse ESCs. Lmx1a(+) cells gave rise to functional cortical upper layer GABAergic neurons or dopaminergic neurons depending on the culture conditions used for differentiation. Under chemically defined neurobasal conditions, ESC differentiation resulted in widespread and transient expression of Lmx1a, without the addition of exogenous factors such as sonic hedgehog (Shh), Wnts, and/or bone morphogenic proteins (BMPs). Under neutral conditions, Lmx1a(+) cells express genes known to be downstream of Lmx1a and cortical hem markers Wnt3a and p73. The majority of these cells did not express the ventral midbrain dopaminergic marker Foxa2 or dorsal roof plate marker BMP-2. Lmx1a(+) -Foxa2(-) cells were primed to become SatB2(+) GABAergic neurons and appeared to be resistant to dopaminergic patterning cues. PA6 coculture produced a substantial population of Lmx1a(+) progenitors that also expressed Foxa2 and on further differentiation gave rise to dopaminergic neurons at high frequency. We conclude that Lmx1a is a useful marker for the extraction of progenitors of GABAergic or dopaminergic neurons. We caution against the assumption that it indicates dopaminergic commitment during in vitro differentiation of ESCs. Indeed, in monolayer culture under neurobasal conditions, with or without the addition of Shh and fibroblast growth factor 8 (FGF8), Lmx1a(+) cells were predominantly progenitors of forebrain GABAergic neurons. We obtained dopaminergic cells in large numbers only by coculture with PA6 cells. PMID- 22495883 TI - Impact of testosterone on body fat composition. AB - An excessive food supply has resulted in an increasing prevalence of overweight and obesity, conditions accompanied by serious health problems. Several studies have confirmed the significant inverse correlation between testosterone and obesity. Indeed after decades of intense controversy, a consensus has emerged that androgens are important regulators of fat mass and distribution in mammals and that androgen status affects cellularity in vivo. The high correlation of testosterone levels with body composition and its contribution to the balance of lipid metabolism are also suggested by the fact that testosterone lowering is associated with important clinical disorders such as dyslipidemia, atherosclerosis, cardiovascular diseases, metabolic syndrome and diabetes. In contrast, testosterone supplementation therapy in hypogonadic men has been shown to improve the lipid profile by lowering cholesterol, blood sugar and insulin resistance. Leptin, ghrelin and adiponectin are some of the substances related to feeding as well as androgen regulation. Thus, complex and delicate mechanisms appear to link androgens with various tissues (liver, adipose tissue, muscles, coronary arteries and heart) and the subtle alteration of some of these interactions might be the cause of correlated diseases. This review underlines some aspects regarding the high correlations between testosterone physiology and body fat composition. PMID- 22495884 TI - Chemocauterization of the internal opening with trichloroacetic acid as first line treatment for pyriform sinus fistula. AB - BACKGROUND: Pyriform sinus fistula is a rare brachial pouch anomaly. However, it is difficult and risky to remove the fistula tract completely. Circumferential chemocauterization of the internal opening with trichloroacetic acid (TCA) for pyriform sinus fistula is simple, reproducible, reliable, and causes less morbidity. The aim of this study was to determine the feasibility of TCA chemocauterization for pyriform sinus fistula. METHODS: This retrospective study enrolled 44 patients who were diagnosed with pyriform sinus fistula and underwent TCA chemocauterization. We retrospectively reviewed the medical records of the patients to obtain their demography as well as treatment outcomes for them. RESULTS: The success rate of treatment for pyriform sinus fistula after the first TCA chemocauterization was 77.3% (34/44) and the cumulative success rate after the second treatment was 93.2% (41/44). There was no complication such as vocal fold palsy after TCA chemocauterization. CONCLUSIONS: It is suggested that TCA chemocauterization can be a reasonable first-line treatment for pyriform sinus fistula. PMID- 22495885 TI - In multiple myeloma, bone-marrow lymphocytes harboring the same chromosomal abnormalities as autologous plasma cells predict poor survival. AB - Chromosomal abnormalities in plasma cells (PCs) from multiple myeloma (MM) provide a clonal signature to identify malignant cells. BM-lymphocytes from MM aspirates, defined by stringent criteria, were screened for the same chromosomal abnormalities as autologous PCs, including translocations, deletions, and amplifications. For 200 MM patients, we evaluated BM mononuclear cells to identify lymphocytes and autologous PCs on the same slide, followed by interphase fluorescence in situ hybridization to characterize their chromosomal abnormalities. Of all patients having a given chromosomal abnormality(s) in PCs, 45% showed that same abnormality(s) in 2-37% (median = 5%) of BM-lymphocytes. Most translocations, amplifications, and deletions found in MM PCs were also detected in lymphocytes, above the healthy-donor "cut-off." In patients having chromosomally abnormal CD20(-) PCs, chromosomally abnormal lymphocytes were found among CD20+ cells confirming them as B cells. Exceptions were amplification of 1q21 or p53 deletion, which characterize PCs but were undetectable in BM lymphocytes, suggesting that processes leading to these abnormalities may be exclusive to PCs. For a set of 75 patients whose BM-lymphocytes and PCs were analyzed by all six probe sets, 58% of those with abnormal PC also had abnormal BM-lymphocytes harboring from one to five different abnormalities. Confirming the clinical significance of chromosomally abnormal BM-lymphocytes, MM patients having abnormalities in both lymphocytes and PC had significantly worse survival than those with abnormalities only in PC (HR = 2.68). The presence of at least one chromosomal abnormality in BM-lymphocytes appears to have greater clinical significance than particular abnormalities. Chromosomally abnormal BM-lymphocytes correlate with poor outcome and by extrapolation with more aggressive disease. PMID- 22495887 TI - The sperm epigenome and potential implications for the developing embryo. AB - Recent work in the field of male fertility has yielded significant increases in our understanding of the sperm epigenome and its potential role in embryonic development. These new findings have enabled a broad classification of a normal epigenetic state in the male gamete and have provided insight into the possible etiologies of some idiopathic male infertility cases. Histone retention and modification, protamine incorporation into the chromatin, DNA methylation, and spermatozoal RNA transcripts appear to play important roles in the epigenetic state of mature sperm. These epigenetic factors may reveal a historical record of spermatogenesis, portend future functions in embryogenesis, and help to elucidate mechanism of pluripotency. In contrast to the once held dogma regarding the importance of the paternal epigenome, the unique epigenetic landscape in sperm appears to serve more than the gamete itself and is likely influential in the developing embryo. In fact, growing evidence suggests that mature sperm provide appropriate epigenetic marks that drive specific genes toward activation and contribute to the pluripotent state of the embryonic cells. Although not definitive, the current literature provides evidence for the role of the sperm epigenome in the embryo. Future work must be focused on the characterization of epigenetic abnormalities commonly found in individuals with compromised fertility to further establish this role. Additionally, studies should target the effects of environment and aging on the sperm epigenetic program and subsequent fertility loss to determine the etiology of aberrant epigenetic profiles. PMID- 22495886 TI - Prevalence and work-relatedness of carpal tunnel syndrome in the working population, United States, 2010 National Health Interview Survey. AB - BACKGROUND: Patterns of prevalence and work-relatedness of carpal tunnel syndrome (CTS) among workers offer clues about risk factors and targets for prevention. METHODS: Data from an occupational health supplement to the 2010 National Health Interview Survey were used to estimate the prevalence of self-reported clinician diagnosed CTS overall and by demographic characteristics. The proportion of these cases self-reported to have been attributed to work by clinicians was also examined overall and by demographic characteristics. In addition, the distribution of industry and occupation (I&O) categories to which work-related cases of CTS were attributed was compared to the distribution of I&O categories of employment among current/recent workers. RESULTS: Data were available for 27,157 adults, including 17,524 current/recent workers. The overall lifetime prevalence of clinician-diagnosed CTS among current/recent workers was 6.7%. The 12-month prevalence was 3.1%, representing approximately 4.8 million workers with current CTS; 67.1% of these cases were attributed to work by clinicians, with overrepresentation of certain I&O categories. CONCLUSIONS: CTS affected almost 5 million U.S. workers in 2010, with prevalence varying by demographic characteristics and I&O. PMID- 22495888 TI - Bone morphogenetic protein 6 promotes FSH receptor and anti-Mullerian hormone mRNA expression in granulosa cells from hen prehierarchal follicles. AB - A growing body of literature provides evidence of a prominent role for bone morphogenetic proteins (BMPs) in regulating various stages of ovarian follicle development. Several actions for BMP6 have been previously reported in the hen ovary, yet only within postselection (preovulatory) follicles. The initial hypothesis tested herein is that BMP6 increases FSH receptor (FSHR) mRNA expression within the granulosa layer of prehierarchal (6-8 mm) follicles (6-8 GC). BMP6 mRNA is expressed at higher levels within undifferentiated (1-8 mm) follicles compared with selected (>=9 mm) follicles. Recombinant human (rh) BMP6 initiates SMAD1, 5, 8 signaling in cultured 6-8 GC and promotes FSHR mRNA expression in a dose-related fashion. In addition, a 21 h preculture with rhBMP6 followed by a 3 h challenge with FSH increases cAMP accumulation, STAR (StAR) expression, and progesterone production. Interestingly, rhBMP6 also increases expression of anti-Mullerian hormone (AMH) mRNA in cultured 6-8 GC. This related BMP family member has previously been implicated in negatively regulating FSH responsiveness during follicle development. Considering these data, we propose that among the paracrine and/or autocrine actions of BMP6 within prehierarchal follicles is the maintenance of both FSHR and AMH mRNA expression. We predict that before follicle selection, one action of AMH within granulosa cells from 6 to 8 mm follicles is to help suppress FSHR signaling and prevent premature granulosa cell differentiation. At the time of selection, we speculate that the yet undefined signal directly responsible for selection initiates FSH responsiveness. As a result, FSH signaling suppresses AMH expression and initiates the differentiation of granulosa within the selected follicle. PMID- 22495889 TI - Identification of a new mouse sperm acrosome-associated protein. AB - The binding of capacitated spermatozoa to the egg's extracellular coat and induction of acrosome reaction are necessary for successful fertilization in mammals. Biogenesis of acrosome is complicated, and not all proteins involved in this process are known. In this study, we have cloned a novel mouse gene, Spaca7, that is expressed exclusively in the testes. During the postnatal development, transcripts of the gene could be detected at a very low level in 18-day-old mouse testes and at a higher level in 21-day-old mouse testes and later, which corresponds to an expansion of round spermatids. In the stably transfected PT67 cells, SPACA7 fused with EGFP was predominantly localized in the Golgi apparatus. In transgenic mouse testes, the fusion protein was found in acrosome (starting from the first stages of acrosome formation in late pachytene spermatocytes and finally in spermatozoa isolated from caput and cauda of epididymis). Confocal microscopy studies revealed an intra-acrosomal not membrane-bound localization of SPACA7/EGFP, which suggests that the protein can be released during acrosome reaction and involved in fertilization. Acrosomal localization of endogenous SPACA7 protein was also found in human spermatozoa. PMID- 22495892 TI - Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val. AB - De novo heterozygous mutations in HRAS cause Costello syndrome (CS), a condition with high mortality and morbidity in infancy and early childhood due to cardiac, respiratory, and muscular complications. HRAS mutations predicting p.Gly12Val, p.Gly12Asp, and p.Gly12Cys substitutions have been associated with severe, lethal, CS. We report on molecular, clinical, and pathological findings in patients with mutations predicting HRAS p.Gly12Val that were identified in our clinical molecular genetic testing service. Such mutations were identified in four patients. Remarkably, three were deletion/insertion mutations affecting coding nucleotides 35 and 36. All patients died within 6 postnatal weeks, providing further evidence that p.Gly12Val mutations predict a very poor prognosis. High birth weight, polyhydramnios (and premature birth), cardiac hypertrophy, respiratory distress, muscle weakness, and postnatal growth failure were present. Dysmorphism was subtle or non-specific, with edema, coarsened facial features, prominent forehead, depressed nasal bridge, anteverted nares, and low-set ears. Proximal upper limb shortening, a small bell-shaped chest, talipes, and fixed flexion deformities of the wrists were seen. Neonatal atrial arrhythmia, highly suggestive of CS, was also present in two patients. One patient had congenital alveolar dysplasia, and another, born after 36 weeks' gestation, bronchopulmonary dysplasia. A rapidly fatal disease course, and the difficulty of identifying subtle dysmorphism in neonates requiring intensive care, suggest that this condition remains under-recognized, and should enter the differential diagnosis for very sick infants with a range of clinical problems including cardiac hypertrophy and disordered pulmonary development. Clinical management should be informed by knowledge of the poor prognosis of this condition. PMID- 22495893 TI - Calculated blood loss in severe obstetric hemorrhage and its relation to body mass index. AB - OBJECTIVE: To evaluate total calculated blood loss at the time of severe obstetric hemorrhage. STUDY DESIGN: This is a prospective observational study of women with obstetric hemorrhage. Women who received a blood transfusion for hypovolemia and those in which a body mass index (BMI) could be calculated were included. Total blood volume lost was calculated. Blood loss was analyzed in relation to maternal size as reflected in the BMI. RESULTS: Fourteen hundred forty-three women meeting inclusion criteria delivered at our hospital between March 2002 and June 2006. The median calculated volume of blood lost was 3529 mL, and 93% of women sustained losses >=3000 mL. The blood loss sufficient to provoke signs and symptoms of hypovolemia was proportional to the woman's BMI. CONCLUSION: Women who develop hypovolemia during childbirth have suffered very large losses of blood, and infusion of blood products is required to restore circulation and prevent further morbidity. PMID- 22495890 TI - Essential roles of the chromatin remodeling factor BRG1 in spermatogenesis in mice. AB - Mammalian spermatogenesis is a complex process that involves spatiotemporal regulation of gene expression and meiotic recombination, both of which require the modulation of chromatin structure. Proteins important for chromatin regulation during spermatogenesis remain poorly understood. Here we addressed the role of BRG1, the catalytic subunit of the mammalian Swi/Snf-like BAF chromatin remodeling complex, during spermatogenesis in mice. BRG1 expression is dynamically regulated in the male germline, being weakly detectable in spermatogonia, highly expressed in pachytene spermatocytes, and turned off in maturing round spermatids. This expression pattern overlaps that of Brm, the Brg1 homolog. While Brm knockout males are known to be fertile, germline-specific Brg1 deletion completely arrests spermatogenesis at the midpachytene stage, which is associated with spermatocyte apoptosis and apparently also with impaired homologous recombination and meiotic sex chromosome inactivation. However, Brg1 is dispensable for gammaH2AX formation during meiotic recombination, contrary to its reported role in DNA repair in somatic cells. Our study reveals the essential role of Brg1 in meiosis and underscores the differences in the mechanisms of DNA repair between germ cells and somatic cells. PMID- 22495894 TI - An immunologic basis for placental insufficiency in fetal growth restriction. AB - OBJECTIVE: We sought to determine whether chronic villitis, an immunologic disease of the placenta, was related to fetal growth restriction. METHODS: Beginning in October 1999, a protocol was instituted that required placentas of high-risk births be submitted for standardized histological examination. Chronic villitis was diagnosed when a lymphohistiocytic infiltrate involving placental villi was present and was graded according to the extent and location of the infiltrate. Fetal growth restriction was defined as weight less than 3rd, 5th, and 10th percentiles. Placental hypoplasia was defined as weight less than 10th percentile. RESULTS: In the 10,204 placental examinations that were performed, low-grade and high-grade chronic villitis was associated with hypoplastic placentas and fetal growth restriction. Infants with placentas with low-grade and high-grade chronic villitis were more likely to require cesarean delivery for nonreassuring fetal heart rate compared with controls (27% and 25% versus 21%; p < 0.05). Fetal acidemia (umbilical artery pH < 7.0) was associated with high grade chronic villitis compared with controls (4% versus 2%; p < 0.05). CONCLUSION: Chronic villitis was associated with anatomic and functional placental insufficiency manifested as placental hypoplasia, growth restriction, increased risk of cesarean for nonreassuring fetal heart rate, and fetal acidemia. These findings support an immunologic basis for fetal growth restriction. PMID- 22495895 TI - Recurrent shoulder dystocia: analysis of incidence and risk factors. AB - OBJECTIVES: To determine the rate and associated risk factors for recurrent shoulder dystocia (SD). STUDY DESIGN: A retrospective analysis was performed of patients delivered from January 1991 to June 2001. Patients with and without recurrent SD were identified and compared. RESULTS: Among the 267,228 vaginal births during the study period, there were 1904 cases of SD (0.7%) and 270 patients with one additional vaginal birth. The recurrent SD rate was higher than the general population (3.7% versus 0.7%, odds ratio 7.36, 95% confidence interval 3.68 to 14.23, p < 0.001). Patients with recurrent SD had a slightly higher mean birth weight with the second delivery, but this difference was not statistically significant (4173 +/- 544 g versus 4017 +/- 577 g, p = 0.39). CONCLUSION: Prior SD is a risk factor for recurrence in a subsequent delivery, but our results demonstrate that the rate appears to be lower than previously estimated. Most variables, including birth weight, do not appear to be useful parameters in predicting recurrence. PMID- 22495896 TI - Transabdominal and transcervical chorionic villus sampling models to teach maternal-fetal medicine fellows. AB - OBJECTIVE: Many fellowship programs in maternal-fetal medicine (MFM) lack sufficient exposure and training in chorionic villus sampling (CVS). We describe a novel training model of transabdominal and transcervical CVS. METHODS: A porcine heart simulated a 12-week human uterus with a cervical canal created at the apex of the heart. A piglet was placed within a water-filled condom, which was placed inside the "uterus." A second water-filled condom simulated a maternal bladder. Fresh human placenta was placed between the condom and uterine wall. A zipper-sealed freezer bag with ultrasonic gel simulated an abdominal wall. Transabdominal ultrasound was utilized with this model to perform CVS. RESULTS: The design involved four MFM specialists and three fellows. Twenty-three faculty MFM specialists and eight MFM fellows endorsed the fidelity of both models. One hundred percent of attendees of a procedural workshop agreed that these models could be used to teach proper technique to fellows and faculty. CONCLUSION: We report a novel training model for transabdominal and transcervical CVS to teach proper technique in a nonclinical setting. PMID- 22495897 TI - Assessing outcome in interhospital infant transport: the transport risk index of physiologic stability score at admission. AB - OBJECTIVE: To evaluate the performance of the Transport Risk Index of Physiologic Stability (TRIPS) score at admission for early mortality prediction. METHODS: The study included all consecutive outborn infants admitted to a single neonatal intensive care unit (NICU) over a 3-year period. The data collected included demographic variables, 7-day NICU mortality, and severe (>= grade 3) intraventricular hemorrhage (IVH), TRIPS score at admission, and Score for Neonatal Acute Physiology II (SNAP-II) and SNAP-Perinatal Extension-II (SNAPPE II) scores. RESULTS: A total of 175 neonates were enrolled. TRIPS at admission discriminated 7-day mortality from survival with a receiver operating characteristic (ROC) area of 0.80, and predictive performance of TRIPS for severe IVH showed a ROC area of 0.67. The TRIPS had good calibration for all strata (p = 0.49). For gestational age (GA) >32 weeks, the area under the curve (AUC) for TRIPS was 0.71, whereas the AUC for GA <=32 weeks was 0.99 for 7-day mortality. Predictive performance of TRIPS for 7-day mortality was similar to that of SNAP II and SNAPPE-II. CONCLUSION: TRIPS score at admission had a good performance to discriminate high-risk patients for 7-day mortality, mainly infants with GA <=32 weeks. TRIPS might be a useful triage tool if applied at the time of first contact with a transport service. PMID- 22495898 TI - Early administration of low-dose aspirin for the prevention of severe and mild preeclampsia: a systematic review and meta-analysis. AB - OBJECTIVE: To determine whether early administration of aspirin prevents severe and mild preeclampsia. STUDY DESIGN: A systematic review and meta-analysis of randomized controlled trials were performed. Studies in which women were randomized at or before 16 weeks' gestation to low-dose aspirin versus placebo or no treatment were included. The outcomes of interest were severe preeclampsia and mild preeclampsia. Pooled relative risks with their 95% confidence intervals (CIs) were calculated. RESULTS: Among 7941 citations retrieved, 352 were completely reviewed and four studies (392 women) fulfilled the inclusion criteria and were analyzed. When compared with controls, aspirin started at <=16 weeks was associated with a significant reduction in severe (relative risk: 0.22, 95% CI: 0.08 to 0.57) but not mild (relative risk: 0.81, 95% CI: 0.33 to 1.96) preeclampsia. CONCLUSION: Low-dose aspirin initiated at or before 16 weeks reduces the risk of severe preeclampsia, but not mild preeclampsia. PMID- 22495899 TI - Reliability of two-dimensional transvaginal sonographic measurement of lower uterine segment thickness using video sequences. AB - OBJECTIVES: To report the intra- and interobserver reliability of measurement of the lower uterine segment (LUS) thickness using transvaginal sonographic videos. METHODS: A prospective study of 60 women with previous, low-transverse cesarean undergoing LUS examination (36 to 39 weeks) was performed. Two observers independently measured full LUS thickness using transvaginal sonography. A video of the LUS was recorded and analyzed more than 2 months later by both observers. Intra- and interobserver reliability was assessed with median absolute differences and interquartile range (IQR), nonparametric limits of agreement, intraclass correlation coefficients (ICC) with 95% confidence interval (95% CI), and kappa coefficients. RESULTS: Median full LUS thickness was 3.6 mm (range: 0.9 to 8.0 mm). Intraobserver repeatability was excellent (median difference: 0.2 mm, IQR: 0.1 to 0.4; ICC: 0.94, 95% CI: 0.90 to 0.96; kappa: 1.00). Interobserver (median difference: 0.3 mm, IQR: 0.2 to 1.3; ICC: 0.91, 95% CI: 0.86 to 0.95; kappa: 0.76, 95% CI: 0.54 to 0.98) and intermethod reproducibility (median difference: 0.4 mm, IQR: 0.2 to 0.8; ICC: 0.82, 95% CI: 0.72 to 0.89; kappa: 0.69, 95% CI: 0.43 to 0.94) were good. However, both interobserver and intermethod reproducibility were improved when LUS thickness was below 3 mm. CONCLUSION: Full LUS thickness measured from transvaginal sonographic videos has excellent intra- and interobserver reproducibility and good reproducibility with live transvaginal ultrasound. PMID- 22495900 TI - Variation in the management of persistent pulmonary hypertension of the newborn: a survey of physicians in Canada, Australia, and New Zealand. AB - BACKGROUND: Despite advances in management of persistent pulmonary hypertension of the newborn (PPHN), the risk of mortality and adverse neurological sequelae remains high. Characterizing variation in practices is a crucial step toward improved patient outcome. OBJECTIVE: Evaluate intensive care practices in Canada and the Australia-New Zealand region (AUS-NZ). METHODS: A prospective cross sectional online survey of neonatologists was conducted. A 35-item questionnaire was developed, validated, and piloted to collect information on diagnosis, inhaled nitric oxide (iNO) practices, alternative vasodilators or cardiotropes, and echocardiography. Variation among survey respondents as well as intergroup comparison was performed. RESULTS: Data were collected from 217 respondents. Echocardiography and arterial blood gas were the most common diagnostic tests to assess the severity of PPHN. iNO administration is more frequently scrutinized in Canada (36% versus 10% [AUS-NZ], p < 0.001). Canadian physicians reported higher use of intravenous milrinone (p < 0.001), vasopressin (p = 0.02), and inhaled prostacyclin (p = 0.02), but lower use of sildenafil (p = 0.01) for refractory pulmonary hypertension. A greater proportion of neonatologists in AUS-NZ were trained to perform echocardiography (p < 0.001) to optimize treatment decisions. CONCLUSION: Wide variation exists in the management of PPHN. There is a need to provide more guidance regarding principles of management in PPHN, while recognizing the dynamic nature of cardiopulmonary physiology in individual patients. PMID- 22495901 TI - Recording of amplitude-integrated electroencephalography, oxygen saturation, pulse rate, and cerebral blood flow during massage of premature infants. AB - OBJECTIVE: Stimulation of the nervous system plays an important role in brain function and psychomotor development of children. Massage can benefit premature infants, but has limitations. STUDY DESIGN: The authors conducted a study to verify the direct effects of massage on amplitude-integrated electroencephalography (aEEG), oxygen saturation (SaO(2)), and pulse analyzed by color cerebral function monitor (CCFM) and cerebral blood flow assessed by the Doppler technique. RESULTS: The amplitude of the aEEG trend during massage significantly increased. Massage also impacted the dominant frequency delta waves. Frequency significantly increased during the massage and return to baseline after treatment. SaO(2) significantly decreased during massage. In four premature infants, massage was discontinued due to desaturation below 85%. Pulse frequency during the massage decreased but remained within physiological limits of greater than 100 beats per minute in all infants. Doppler flow values in the anterior cerebral artery measured before and after massage did not show statistically significant changes. Resistance index after massage decreased, which might provide greater perfusion of the brain, but this difference was not statistically significant. CONCLUSION: Use of the CCFM device allows for monitoring of three basic physiologic functions, namely aEEG, SaO(2), and pulse, and increases the safety of massage in preterm infants. PMID- 22495902 TI - Factors influencing visualization of the intracranial translucency during first trimester screening for aneuploidy. AB - OBJECTIVE: Neural tube defects occur in 1/2000 live births. Imaging of the intracranial translucency (IT) during first-trimester screening has been proposed as an early screen for open neural tube defects (ONTD). This study evaluates visualization of the IT and factors influencing its visualization during first trimester ultrasound screening for aneuploidy. METHODS: Ultrasound images for patients undergoing first-trimester screening for aneuploidy from January 1, 2009, through July 31, 2009, were reviewed for IT visualization, defined as an intracranial translucency parallel to the nuchal translucency. Second-trimester ultrasounds and delivery records were reviewed for the presence of fetal ONTD. RESULTS: The IT was visualized in 74.8% of 759 gestations studied at a mean gestational age of 12 weeks, 5 days. Among gestations where the IT was visualized, we found a larger crown-rump length, lower maternal weight, and more fetuses in the supine position (p < 0.0001). Predictive models for visualization of the IT were formulated based on these factors. CONCLUSION: The IT can be visualized in the majority of patients in the standard midsagittal plane used for measurement of the nuchal translucency. Visualization is significantly associated with crown-rump length, gestational age, maternal weight, and fetal position. Visualization of the IT is feasible. PMID- 22495903 TI - Confinement-induced ordering in dewetting and phase separation of polymer blend films. PMID- 22495904 TI - Fibroblast growth factor-2 maintains a niche-dependent population of self renewing highly potent non-adherent mesenchymal progenitors through FGFR2c. AB - Bone marrow (BM) mesenchymal stem/stromal cells (MSC) are a heterogeneous population of multipotent progenitors currently under investigation for a variety of applications in regenerative medicine. While self-renewal of stem cells in different tissues has been demonstrated to be regulated by specialized microenvironments called niches, it is still unclear whether a self-renewing niche also exists for MSC. Here, we show that primary human BM cultures contain a population of intrinsically non-adherent mesenchymal progenitors (NAMP) with features of more primitive progenitors than the initially adhering colony-forming units-fibroblast (CFU-f). In fact, NAMP could generate an adherent progeny: (a) enriched with early mesenchymal populations (CD146+, SSEA-1+, and SSEA-4+); (b) with significantly greater proliferation and multilineage differentiation potential in vitro; and (c) capable of threefold greater bone formation in vivo than the corresponding CFU-f. Upon serial replating, NAMP were able to regenerate and expand in suspension as non-adherent clonogenic progenitors, while also giving rise to an adherent progeny. This took place at the cost of a gradual loss of proliferative potential, shown by a reduction in colony size, which could be completely prevented when NAMP were expanded on the initially adhering BM fraction. Mechanistically, we found that NAMP crucially depend on fibroblast growth factor (FGF)-2 signaling through FGFR2c for their survival and expansion. Furthermore, NAMP maintenance depends at least in part on humoral signals distinct from FGF-2. In conclusion, our data show a niche/progenitor organization in vitro, in which the BM adherent fraction provides a self-renewing microenvironment for primitive NAMP. PMID- 22495905 TI - Prenatal diagnosis of cardiac defects: accuracy and benefit. AB - OBJECTIVE: The prenatal diagnosis of cardiac defects can potentially reduce postnatal morbidity and mortality. We wanted to evaluate prenatal cardiac diagnosis accuracy in a population referred for echocardiography. METHODS: Single centre retrospective study of echocardiography referrals between April 1999 and December 2008. We compared the prenatal and postnatal cardiac diagnoses, the modified Aristotle and Wald scores. The final diagnosis Wald score was used to evaluate benefit. RESULTS: Six hundred fetuses were included. Diagnoses included: normal heart (312, 52%); congenital heart defect (CHD) (231, 38.5%); primary arrhythmia (39, 6.5%); or cardiomyopathy, myocarditis or cardiac tumor (18, 3%). The prenatal and postnatal Aristotle and Wald scores correlated in 81% and 86%, respectively, each with significant differences in 22 cases. Four significant CHDs were misdiagnosed, the surgical prediction was incorrect in 7 and 13 false positive diagnoses of aortic coarctation were made. In 76% (455/600) fetuses prenatal diagnosis was considered beneficial. The average CHD Aristotle score was 9.5 +/- 5.0. In babies with CHDs and normal karyotype the score was either 6.5 +/ 5.0, 12.9 +/- 3.1 or 13.2 +/- 2.9, in survivors, cases of postnatal demise and cases of pregnancy termination, respectively. CONCLUSION: Prenatal diagnosis was accurate and the counselling appropriate in most cases; however, a few errors were made. The diagnosis of aortic coarctation remains challenging. PMID- 22495906 TI - Tailored 3D mechanical metamaterials made by dip-in direct-laser-writing optical lithography. AB - Dip-in direct-laser-writing (DLW) optical lithography allows fabricating complex three-dimensional microstructures without the height restrictions of regular DLW. Bow-tie elements assembled into mechanical metamaterials with positive/zero/negative Poisson's ratio and with sufficient overall size for direct mechanical characterization aim at demonstrating the new possibilities with respect to rationally designed effective materials. PMID- 22495907 TI - Gene variants in the folate-mediated one-carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defects. AB - We evaluated 35 variants among four folate-mediated one-carbon metabolism pathway genes, MTHFD1, SHMT1, MTHFR, and DHFR as risk factors for conotruncal heart defects. Cases with a diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. Odds ratios (OR) and the 95% confidence intervals (CI) were computed for each genotype (homozygous variant or heterozygote, vs. homozygous wildtype) and for increase of each less common allele (log-additive model). Interactions between each variant and three folate intake variables (maternal multivitamin use, maternal dietary folate intake, and combined maternal folate intake) were also evaluated under the log-additive model. In general, we did not identify notable associations. The A allele of MTHFD1 rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR = 1.7, 95% CI = 1.1-2.5) and Hispanic infants (OR = 1.7, 95% CI = 1.2-2.3). The T allele of MTHFR rs1801133 was associated with a 2.8-fold increase of risk among Hispanic women whose dietary folate intake was <= 25th centile. The C allele of MTHFR rs1801131 was associated with a two-fold increase of risk (OR = 2.0, 95% CI = 1.0-3.9) only among those whose dietary folate intake was >25th centile. Our study suggested that MTHFD1 rs11627387 may be associated with risk of conotruncal defects through both maternal and offspring genotype effect among the Hispanics. Maternal functional variants in MTHFR gene may interact with dietary folate intake and modify the conotruncal defects risk in the offspring. PMID- 22495908 TI - Efficacy of five-element gymnastics in glucose and lipid control in Taiwanese patients with type 2 diabetes. AB - The purpose of this quasi-experimental study was to determine the efficacy of Five-Element Gymnastics (FEG) in controlling glycosylated hemoglobin (HbA1C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) at the 8th and the 16th weeks of intervention for patients with type 2 diabetes in Taiwan. FEG consolidates several traditional Chinese exercises including Qigong, Xiang Gong, and martial arts with gymnastics. The experimental group (n = 31) practiced FEG at home for 16 weeks. The control group (n = 35) maintained usual activities. FEG was associated with decrease of HbA1C, TG, and LDL-C levels at the 8th week and continuous decrease of HbA1C through the 16th week. FEG could be an exercise choice for patients with type 2 diabetes. PMID- 22495909 TI - Psychopathological and clinical features of remitted anorexia nervosa patients: a six-year follow-up study. AB - OBJECTIVE: Remission from anorexia nervosa (AN) is a controversial issue, as remitted individuals have been found to show residual anorectic attitudes and concerns about weight and shape. The aims of this study were to evaluate the psychopathological features of remitted AN subjects 6 years after the end of a cognitive behavioural therapy and the predictors of reduction in psychopathology. METHODS: The sample was composed of 134 AN subjects, evaluated at baseline, at the end of treatment, 3 and 6 years after the end of treatment, by means of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and several self-reported questionnaires. RESULTS: Remitted patients at 6 years of follow-up still showed higher eating and shape concerns, compared with healthy controls. Duration of illness, obsessive compulsive and depressive symptoms were moderators of change in psychopathology across time. DISCUSSION: Psychopathological features represent an enduring trait for AN patients. General psychopathology showed different effects on symptoms reduction across time. PMID- 22495910 TI - Greenhouse gas emissions from the Brazilian Antarctic Station "Comandante Ferraz". AB - BACKGROUND: Climate change is a natural phenomenon that has been intensified due to increased emissions of greenhouse gases (GHG). It has become an indispensable issue in international negotiations related to global sustainability and is deeply related to the overall status of environmental health in our planet. METHODS: We compiled an inventory of GHG emissions that resulted from human activities at the Brazilian Antarctic Scientific Station "Comandante Ferraz" (EACF) and collected emissions data relating to these activities from January to March 2011. The present work aims to identify the sources of GHG emissions, their characteristics, and composition, using as methodology and framework basis the international ISO 14,064:07 and the GHG Protocol. RESULTS: We addressed emissions of CO(2), CH(4), and N(2)O arising from the use of vehicles, diesel-electric generators, boilers, and wastewater treatment for the sewage treatment plant. We identified that the main GHG emissions derived from the activities of power generation using diesel and boilers (more than 80% of the emissions), adding more than 772 t of CO(2) equivalents. CONCLUSIONS: We identified that the diesel generators and boilers are the most important sources of emission by Expedition XXIX (2010-2011). In that CO(2) is principally emitted in relation to electrical energy generation from diesel generators, we emphasize the need for fuel burning reduction through energy consumption reduction. PMID- 22495911 TI - Evaluation of hemostasis in flowing blood. AB - Hemostasis and thrombosis are now increasingly recognized as integrally related to blood rheology and blood flow. Platelets, for example, are known to access the vessel wall in ways which depend upon the small-scale motions of neighboring erythrocytes, and access one another via collisions driven by gradients in blood flow velocity. In this context, flow devices have become a subject of great interest in the clinical assessment of bleeding disorders, especially platelet function defects and von Willebrand disease. While these devices currently lack standardization and outcomes measures which establish clear clinical utility, their promise remains great, particularly in the potential to simulate the microenvironment of arteries vs. veins and in their ability to incorporate such intrinsically flow-dependent phenomena as co-localization of tissue-factor bearing microparticles with platelets, the weakness of the GPIb-vWF bond at very high shear stresses, and even the hemostatic and antithrombotic function of vascular endothelium. In contrast, currently utilized assays are often performed under static conditions that do not involve flow and therefore are not able to simulate the microenvironment of arteries and veins. PMID- 22495912 TI - Global prevalence of autism and other pervasive developmental disorders. AB - We provide a systematic review of epidemiological surveys of autistic disorder and pervasive developmental disorders (PDDs) worldwide. A secondary aim was to consider the possible impact of geographic, cultural/ethnic, and socioeconomic factors on prevalence estimates and on clinical presentation of PDD. Based on the evidence reviewed, the median of prevalence estimates of autism spectrum disorders was 62/10 000. While existing estimates are variable, the evidence reviewed does not support differences in PDD prevalence by geographic region nor of a strong impact of ethnic/cultural or socioeconomic factors. However, power to detect such effects is seriously limited in existing data sets, particularly in low-income countries. While it is clear that prevalence estimates have increased over time and these vary in different neighboring and distant regions, these findings most likely represent broadening of the diagnostic concets, diagnostic switching from other developmental disabilities to PDD, service availability, and awareness of autistic spectrum disorders in both the lay and professional public. The lack of evidence from the majority of the world's population suggests a critical need for further research and capacity building in low- and middle income countries. PMID- 22495914 TI - Clinical and molecular characterization of a second case of 7p22.1 microduplication. AB - The use of high-resolution microarray technology for investigation of patients with intellectual disability and/or congenital anomalies provided the unique possibility to identify new microdeletion/microduplication syndromes and discover the dosage sensitive genes, which are implicated in the manifestation of various genetic conditions. Microduplication of the 7p22.1 region, 1.7 Mb in size, has very recently been reported, representing the smallest interstitional 7p duplication, associated with specific facial features and speech delay. We report on a patient with an even smaller 7p22.1 de novo microduplication, 1 Mb in size, detected in a 14.5-year-old patient with mild intellectual disability and similar facial dysmorphism, including macrocephaly, ocular hypertelorism, low-set ears, and other features. There are 15 RefSeq genes included in this duplication. ACTB gene is a strong candidate gene for the alteration of craniofacial development. Further cases with similar duplications will contribute to the delineation of a potential new microduplication syndrome of 7p22.1. PMID- 22495913 TI - Drug use among persons with Type 2 diabetes mellitus prior to diagnosis in Belgium. PMID- 22495916 TI - [COPD: Living better with telehealthcare?]. PMID- 22495917 TI - [Immune reconstitution inflammatory syndrome in cryptococcal meningitis: a rare phenomenon?]. AB - HISTORY AND ADMISSION FINDINGS: A 38-year old patient with previously untreated HIV infection presented with progressive cephalgia, photophobia, polydpsia and nausea/vomiting. INVESTIGATIONS: Clinical findings revealed a reduced general state of health and focal neurological deficits. Laboratory findings demonstrated a lymphocytopenia. In addition to positive crytococcus culture and antigen titer in cerebrospinal fluid/serum, Cryptococcus neoformans was detected by light microscopy (India ink stain) in cerebrospinal fluid. DIAGNOSIS, TREATMENT AND COURSE: A cryptococcal meningitis was diagnosed. After initiating antifungal and antiretroviral treatment the clinical course worsened after months 2, 3, and 5, respectively. Apart from unspecific inflammation in the lab work, no signs of disease relapse or therapy refractory course were found in additional diagnostics. After critical evaluation of the clinical course and diagnostic results, immune reconstitution inflammatory syndrome (IRIS) was diagnosed. Clinical improvement was achieved during adjuvant treatment with steroids within six months. CONCLUSIONS: In the presence of neurological symptoms, cryptococcal meningitis is a rare but possible differential diagnosis in daily routine. Diagnosis can be easily achieved by India ink stain in combination with culture of cerebrospinal fluid as well as antigen detection in most cases. Tests of antifungal resistance should be reserved for patients who do not respond to initial treatment, patients with atypical course of disease or failing longterm antifungal therapy. The IRIS is no rare complication after initiation of antiretroviral treatment in HIV associated cryptococcal infections. It is an important differential diagnosis in an atypical course of disease, and sufficient treatment is usually achieved by steroids. PMID- 22495915 TI - Altruism in survivors of sexual violence: the typology of helping others. AB - BACKGROUND: Sexual violence is a significant and prevalent problem that affects many people in the United States. Helping others is one way people cope with, or heal from, sexual violence. OBJECTIVE: To develop of Typology of Helping Others describing how survivors of sexual violence engage in altruism. STUDY DESIGN: Qualitative descriptive methods were used to describe how survivors of sexual violence engaged in altruism in response to their experiences with violence. RESULTS: Helping others was a salient concern for most participants who experienced sexual violence. Participants indicated multiple and varied ways of helping others. Results also indicated that participants experienced some healing from their experiences before they were able to actively engage in, or be effective in, helping others. CONCLUSIONS: Clinicians working with survivors of sexual violence should be attuned to the different ways survivors engage in altruism and the potential influences of race and gender on helping others. PMID- 22495918 TI - [The first 24 hours: acute dyspnea]. AB - Acute dyspnea is a common presentation in the emergency department. Immediate diagnostic strategy and efficient management is crucial. Therefore, a diagnostic work up consisting of a brief medical history, physical examination and technical investigations, including laboratory tests, is presented. Identification of the cardio-vascular, pulmonary or other etiology enables the initiation of adequate therapy. This is outlined in detail for three common entities. PMID- 22495919 TI - [Use of medical treatment data outside of the patient supply: best way pseudonymisation]. AB - The use of data pending during the patient supply to research, quality assurance as also to education is desirable. However, this use is not allowed in every German federal land without approval of the patient. Just in the case of retrospective research an approval of the patient is often not to be received. For the use of medical routine data for the research the pseudonymisation is good therefore. Pseudonymisation is a procedure by which all person-related data within a data record is replaced by one artificial identifier. Therefore pseudonymisation facilitates the linking of medical data and the data identifying the patient only under certain, before defined and controllable conditions. Through that medical data can be passed on to third party without this third party being able to identify the person who the medical data belong to. Under consideration of the present possibilities of the information technology as also the available technical preparations for the use of the pseudonymisation and the advantages being inherent in the pseudonymisation the pseudonymisation represents the method of choice during the use of data of the patient supply to the research, quality assurance as well as education. PMID- 22495920 TI - [85-year-old woman with high erythrocyte sedimentation rate]. PMID- 22495921 TI - [Hepatocellular carcinoma: molecular pathogenesis and novel targets for therapy]. AB - Hepatocellular carcinomas rank among the most common cancers worldwide. They are characterized by phenotypic heterogeneity and poor response to treatment modalities. Although considerable progress in diagnosis and management of hepatocellular carcinomas has been made over the last decade, the exact biology of liver cancer remains poorly understood, overall hindering the development of new therapeutic strategies. The development of whole-genome analyses on different molecular levels greatly advanced our understanding of hepatocarcinogenesis by simultaneously investigating thousands of molecular targets. Although implementation of the results from these analyses in routine clinical practice is still limited, these next generation technologies offer unprecedented insights into the molecular mechanisms of the development of liver cancer. Overall, great promise rests on whole genomic approaches to improve the diagnostic testing and to identify novel targets for individualized treatment modalities in liver cancer. PMID- 22495922 TI - Bullying in undergraduate clinical nursing education. AB - Although a limited number of studies have focused on bullying in nursing education to date, all of those studies demonstrate the existence of bullying in clinical settings, where nursing students undertake a significant amount of their nursing education. The purpose of this study was to examine the state of bullying in clinical nursing education among Canadian undergraduate nursing students (N = 674) in all 4 years of their nursing program. Results suggest that nursing students experience and witness bullying behaviors at various frequencies, most notably by clinical instructors and staff nurses. Third-year and fourth-year students experience more bullying behaviors than first-year and second-year students. Implications for practice include ensuring that clinical instructors are well prepared for their role as educators. Policies must be developed that address the issue of bullying within nursing programs and within health care facilities where nursing students undertake their clinical nursing education. PMID- 22495923 TI - Using debriefing for meaningful learning to foster development of clinical reasoning in simulation. AB - Debriefing is critical to learning from simulation experiences, yet the literature reports little research describing best practices within nursing. Debriefing for Meaningful Learning (DML) is a systematic process for debriefing in which teachers and students explicate different aspects of reflection and generate new meanings from simulation experiences. The purpose of this exploratory, quasi-experimental, pretest-posttest study was to test the relationship of DML on the development of clinical reasoning skills in prelicensure nursing students when compared with customary debriefing strategies and on students' perception of quality of the debriefing experience. Analysis of data demonstrated a greater change in clinical reasoning skills and identification of higher-quality debriefing and a positive correlation between clinical reasoning and perception of quality. Findings demonstrate that DML is an effective debriefing method. It contributes to the body of knowledge supporting the use of debriefing in simulation learning and supports the development of best teaching practices. PMID- 22495924 TI - Strategies for success: crisis management model for remediation of at-risk students. AB - Student success is a concern for all nursing schools. Accountability for NCLEX((r)) pass rates, along with accountability for student attrition and progression, compel nursing schools to carefully select applicants and then actively manage their progress. One of the strategies of managing student progression is to use standardized, nationally normalized exit examinations to identify students at risk for NCLEX-RN failure. This article describes the response of one baccalaureate nursing program to an unacceptable number of exit examination failures among senior students preparing to graduate. As a unique approach to this matter, a crisis management process was used to assess the problem, to develop and implement an intervention for at-risk students, and to revise program policies to better support ongoing student success. PMID- 22495925 TI - Genetic polymorphisms inside and outside the MHC improve prediction of AS radiographic severity in addition to clinical variables. AB - OBJECTIVE: The aim of this study was to analyse if single nucleotide polymorphisms (SNPs) inside and outside the MHC region might improve the prediction of radiographic severity in AS. METHODS: A cross-sectional multi centre study was performed including 473 Spanish AS patients previously diagnosed with AS following the Modified New York Criteria and with at least 10 years of follow-up from the first symptoms of AS. Clinical variables and 384 SNPs were analysed to predict radiographic severity [BASRI-total (BASRI-t) corrected for the duration of AS since first symptoms] using multivariate forward logistic regression. Predictive power was measured by the area under the receiver operating characteristic curve (AUC), specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: The model with the best fit measured radiographic severity as the BASRI-t 60th percentile and combined eight variables: male gender, older age at disease onset and six SNPs at ADRB1 (rs1801253), NELL1 (rs8176785) and MHC (rs1634747, rs9270986, rs7451962 and rs241453) genes. The model predictive power was defined by AUC = 0.76 (95% CI 0.71, 0.80), being significantly better than the model with only clinical variables, AUC = 0.68 (95% CI 0.63, 0.73), P = 0.0004. Internal split sample analysis proved the validation of the model. Patient genotype for SNPs outside the MHC region, inside the MHC region and clinical variables account for 26, 38 and 36%, respectively, of the explained variability on radiographic severity prediction. CONCLUSION: Prediction of radiographic severity in AS based on clinical variables can be significantly improved by including SNPs both inside and outside the MHC region. PMID- 22495926 TI - The Polish National Registry for Fetal Cardiac Pathology: organization, diagnoses, management, educational aspects and telemedicine endeavors. AB - OBJECTIVE: We describe the National Registry for Fetal Cardiac Pathology, a program under the Polish Ministry of Health aimed at improving the prenatal diagnosis, care, and management of congenital heart disease (CHD). METHODS: An online database was created to prospectively record diagnosis, prenatal care, delivery, follow-up, and still images and video for fetuses with CHD. A certification program in fetal cardiac ultrasound was also implemented. Optimal screening and referral centers were identified by number of fetuses entered in the Registry yearly by each center. RESULTS: From 2004 to 2009, 2910 fetuses with CHD were registered (2473 structural, 437 functional anomalies). The most common reasons for referral for fetal echocardiography were abnormal four-chamber view (56.0%) and extra-cardiac anomalies (8.2% ), while the most common diagnoses were atrioventricular septal defects (10.2%) and hypoplastic left heart syndrome (9.7%). Prenatal diagnosis increased yearly, from 10.0% of neonatal diagnoses in 2003 to 38.0% in 2008. CONCLUSION: From inception of the registry up to 2009 there has been a fourfold increase in the number of neonates referred for cardiac surgery in whom the condition was prenatally diagnosed. Equally important achievements include the establishment of a certification program for fetal echocardiography and the organization of prenatal and neonatal management. PMID- 22495927 TI - Conditional cooperativity in toxin-antitoxin regulation prevents random toxin activation and promotes fast translational recovery. AB - Many toxin-antitoxin (TA) loci are known to strongly repress their own transcription. This auto-inhibition is often called 'conditional cooperativity' as it relies on cooperative binding of TA complexes to operator DNA that occurs only when toxins are in a proper stoichiometric relationship with antitoxins. There has recently been an explosion of interest in TA systems due to their role in bacterial persistence, however the role of conditional cooperativity is still unclear. We reveal the biological function of conditional cooperativity by constructing a mathematical model of the well studied TA system, relBE of Escherichia coli. We show that the model with the in vivo and in vitro established parameters reproduces experimentally observed response to nutritional stress. We further demonstrate that conditional cooperativity stabilizes the level of antitoxin in rapidly growing cells such that random induction of relBE is minimized. At the same time it enables quick removal of free toxin when the starvation is terminated. PMID- 22495928 TI - Postnatal development- and age-related changes in DNA-methylation patterns in the human genome. AB - Alterations in DNA methylation have been reported to occur during development and aging; however, much remains to be learned regarding post-natal and age associated epigenome dynamics, and few if any investigations have compared human methylome patterns on a whole genome basis in cells from newborns and adults. The aim of this study was to reveal genomic regions with distinct structure and sequence characteristics that render them subject to dynamic post-natal developmental remodeling or age-related dysregulation of epigenome structure. DNA samples derived from peripheral blood monocytes and in vitro differentiated dendritic cells were analyzed by methylated DNA Immunoprecipitation (MeDIP) or, for selected loci, bisulfite modification, followed by next generation sequencing. Regions of interest that emerged from the analysis included tandem or interspersed-tandem gene sequence repeats (PCDHG, FAM90A, HRNR, ECEL1P2), and genes with strong homology to other family members elsewhere in the genome (FZD1, FZD7 and FGF17). Our results raise the possibility that selected gene sequences with highly homologous copies may serve to facilitate, perhaps even provide a clock-like function for, developmental and age-related epigenome remodeling. If so, this would represent a fundamental feature of genome architecture in higher eukaryotic organisms. PMID- 22495929 TI - Negative regulation of miR-145 by C/EBP-beta through the Akt pathway in cancer cells. AB - MicroRNAs are master gene regulators that can also be under the control of transcriptional regulation. We have previously shown that miR-145 is a tumor suppressor capable of silencing c-Myc and the tumor suppressor p53 induces miR 145 by directly binding to the miR-145 promoter, demonstrating the role of miR 145 in p53-mediated c-Myc repression. However, little is known as to why miR-145 is often downregulated in tumors. In this study, we identify CCAAT/enhancer binding protein beta (C/EBP-beta) as a negative regulator for miR-145 expression by direct interaction with the putative C/EBP-beta binding site in the miR-145 promoter. In the wild-type p53 background, C/EBP-beta counteracts the ability of p53 to induce miR-145. Moreover, C/EBP-beta is able to suppress miR-145 in the mutant p53 background, suggesting the p53 independent regulation of miR-145. Of interest, both the large isoform (LAP-2) and the small isoform (LIP) of C/EBP beta can exert suppressive function for miR-145. Finally, we further show that, like serum starvation and PI3K inhibitor LY29, the antioxidant resveratrol suppresses pAkt and phosphorylation of C/EBP-beta and at the same time, it induces miR-145. Together, these results suggest a miR-145 regulatory system involving the Akt and C/EBP-beta, which may contribute to the downregulation of miR-145 in cancer cells. PMID- 22495930 TI - Structural mechanisms of the degenerate sequence recognition by Bse634I restriction endonuclease. AB - Restriction endonuclease Bse634I recognizes and cleaves the degenerate DNA sequence 5'-R/CCGGY-3' (R stands for A or G; Y for T or C, '/' indicates a cleavage position). Here, we report the crystal structures of the Bse634I R226A mutant complexed with cognate oligoduplexes containing ACCGGT and GCCGGC sites, respectively. In the crystal, all potential H-bond donor and acceptor atoms on the base edges of the conserved CCGG core are engaged in the interactions with Bse634I amino acid residues located on the alpha6 helix. In contrast, direct contacts between the protein and outer base pairs are limited to van der Waals contact between the purine nucleobase and Pro203 residue in the major groove and a single H-bond between the O2 atom of the outer pyrimidine and the side chain of the Asn73 residue in the minor groove. Structural data coupled with biochemical experiments suggest that both van der Waals interactions and indirect readout contribute to the discrimination of the degenerate base pair by Bse634I. Structure comparison between related enzymes Bse634I (R/CCGGY), NgoMIV (G/CCGGC) and SgrAI (CR/CCGGYG) reveals how different specificities are achieved within a conserved structural core. PMID- 22495931 TI - Non-specific protein-DNA interactions control I-CreI target binding and cleavage. AB - Homing endonucleases represent protein scaffolds that provide powerful tools for genome manipulation, as these enzymes possess a very low frequency of DNA cleavage in eukaryotic genomes due to their high specificity. The basis of protein-DNA recognition must be understood to generate tailored enzymes that target the DNA at sites of interest. Protein-DNA interaction engineering of homing endonucleases has demonstrated the potential of these approaches to create new specific instruments to target genes for inactivation or repair. Protein-DNA interface studies have been focused mostly on specific contacts between amino acid side chains and bases to redesign the binding interface. However, it has been shown that 4 bp in the central DNA sequence of the 22-bp substrate of a homing endonuclease (I-CreI), which do not show specific protein-DNA interactions, is not devoid of content information. Here, we analyze the mechanism of target discrimination in this substrate region by the I-CreI protein, determining how it can occur independently of the specific protein-DNA interactions. Our data suggest the important role of indirect readout in this substrate region, opening the possibility for a fully rational search of new target sequences, thus improving the development of redesigned enzymes for therapeutic and biotechnological applications. PMID- 22495932 TI - The SNORD115 (H/MBII-52) and SNORD116 (H/MBII-85) gene clusters at the imprinted Prader-Willi locus generate canonical box C/D snoRNAs. AB - The imprinted Snurf-Snrpn chromosomal domain contains two large arrays of tandemly repeated, paternally expressed box C/D small-nucleolar RNA (snoRNA) genes: the SNORD115 (H/MBII-52) and SNORD116 (H/MBII-85) gene clusters believed to play key roles in the fine-tuning of serotonin receptor (5-HT2C) pre-mRNA processing and in the etiology of the Prader-Willi Syndrome (PWS), respectively. SNORD115 and SNORD116 were recently proposed to undergo significant conversion into shorter RNA species, the so-called psnoRNAs. Here, we provide evidence that argues against the existence of abundant psnoRNAs in human or mouse brain. Instead, we characterize a previously unsuspected low-abundance, fibrillarin associated SNORD115-derived smaller RNA species. Based on these findings, we strongly recommend that PWS-encoded SNORD115 and SNORD116 be considered as bona fide box C/D snoRNAs. PMID- 22495933 TI - Characterization of a novel DNA polymerase activity assay enabling sensitive, quantitative and universal detection of viable microbes. AB - During the past 50 years, in vitro measurement of DNA polymerase activity has become an essential molecular biology tool. Traditional methods used to measure DNA polymerase activity in vitro are undesirable due to the usage of radionucleotides. Fluorescence-based DNA polymerase assays have been developed; however, they also suffer from various limitations. Herein we present a rapid, highly sensitive and quantitative assay capable of measuring DNA polymerase extension activity from purified enzymes or directly from microbial lysates. When tested with purified DNA polymerase, the assay detected as little as 2 * 10(-11)U of enzyme (~ 50 molecules), while demonstrating excellent linearity (R(2)=0.992). The assay was also able to detect endogenous DNA polymerase extension activity down to less than 10 colony forming units (cfu) of input Gram-positive or Gram negative bacteria when coupled to bead mill lysis while maintaining an R(2)=0.999. Furthermore, preliminary evidence presented here suggests that DNA polymerase extension activity is an indicator of microbial viability, as demonstrated by the reproducibly strong concordance between assay signal and bacterial colony formation. Together, the innovative methodology described here represents a significant advancement toward sensitive detection of potentially any microorganism containing active DNA polymerase within a given sample matrix. PMID- 22495934 TI - Emx2 is a dose-dependent negative regulator of Sox2 telencephalic enhancers. AB - The transcription factor Sox2 is essential for neural stem cells (NSC) maintenance in the hippocampus and in vitro. The transcription factor Emx2 is also critical for hippocampal development and NSC self-renewal. Searching for 'modifier' genes affecting the Sox2 deficiency phenotype in mouse, we observed that loss of one Emx2 allele substantially increased the telencephalic beta-geo (LacZ) expression of a transgene driven by the 5' or 3' Sox2 enhancer. Reciprocally, Emx2 overexpression in NSC cultures inhibited the activity of the same transgene. In vivo, loss of one Emx2 allele increased Sox2 levels in the medial telencephalic wall, including the hippocampal primordium. In hypomorphic Sox2 mutants, retaining a single 'weak' Sox2 allele, Emx2 deficiency substantially rescued hippocampal radial glia stem cells and neurogenesis, indicating that Emx2 functionally interacts with Sox2 at the stem cell level. Electrophoresis mobility shift assays and transfection indicated that Emx2 represses the activities of both Sox2 enhancers. Emx2 bound to overlapping Emx2/POU-binding sites, preventing binding of the POU transcriptional activator Brn2. Additionally, Emx2 directly interacted with Brn2 without binding to DNA. These data imply that Emx2 may perform part of its functions by negatively modulating Sox2 in specific brain areas, thus controlling important aspects of NSC function in development. PMID- 22495936 TI - Polar liquid molecule induced transport property modulation at LaAlO3/SrTiO3 heterointerface. PMID- 22495935 TI - A highly fluorescent DNA toolkit: synthesis and properties of oligonucleotides containing new Cy3, Cy5 and Cy3B monomers. AB - Cy3B is an extremely bright and stable fluorescent dye, which is only available for coupling to nucleic acids post-synthetically. This severely limits its use in the fields of genomics, biology and nanotechnology. We have optimized the synthesis of Cy3B, and for the first time produced a diverse range of Cy3B monomers for use in solid-phase oligonucleotide synthesis. This molecular toolkit includes phosphoramidite monomers with Cy3B linked to deoxyribose, to the 5 position of thymine, and to a hexynyl linker, in addition to an oligonucleotide synthesis resin in which Cy3B is linked to deoxyribose. These monomers have been used to incorporate single and multiple Cy3B units into oligonucleotides internally and at both termini. Cy3B Taqman probes, Scorpions and HyBeacons have been synthesized and used successfully in mutation detection, and a dual Cy3B Molecular Beacon was synthesized and found to be superior to the corresponding Cy3B/DABCYL Beacon. Attachment of Cy3, Cy3B and Cy5 to the 5-position of thymidine by an ethynyl linker enabled the synthesis of an oligonucleotide FRET system. The rigid linker between the dye and nucleobase minimizes dye-dye and dye DNA interactions and reduces fluorescence quenching. These reagents open up new future applications of Cy3B, including more sensitive single-molecule and cell imaging studies. PMID- 22495937 TI - Cytological and epidemiological findings in trisomies 13, 18, and 21: England and Wales 2004-2009. AB - This study describes the cytological and epidemiological findings in 985 trisomy 13 and 2512 trisomy 18 compared with 10,255 trisomy 21 diagnoses between 2004 and 2009 included in the National Down Syndrome Cytogenetic Register of England and Wales. The frequency of occurrence, proportions diagnosed prenatally, sex ratios, mean maternal age, and proportions of mothers with recurrences were analyzed. Ninety-seven, 98%, and 92% were free karyotypes for trisomy 21, 18, and 13, respectively; 3% of 21, 1% of 18, and 8% of trisomy 13 were translocations; and under 1% of trisomies 21 and 18 were double or triple aneuploids. Overall 1% of each trisomy had mosaicism, but 48% of the trisomy 21 double aneuploids, and 10% of trisomy 18 multiple aneuploids had mosaicism. The proportion of livebirths was 40% of trisomy 21, 11% of 18, and 13% of 13, respectively. Free trisomies 21 and 13 had an excess of males, and 18 had an excess of females, as did mosaic free trisomies 21 and 18. Mean maternal ages were 35.9 years in trisomy 21, 36.4 years in 18, and 34.6 years in 13. During the 6 years of data collection 1% of the mothers had recurrences, most recurrent trisomy 21 or 18 were identical translocations, but hetero-trisomic recurrences included 21 and 18, and 21 and 13. There are significant differences between the trisomic karyotypes and attributes, possibly related to their variable origins. Notable are the relative excess of trisomy 13 translocations, mosaicism in cases with multiple aneuploidy, and the types of homo- and hetero-recurrences. PMID- 22495938 TI - Gender differences in acute pesticide-related illnesses and injuries among farmworkers in the United States, 1998-2007. AB - BACKGROUND: Farmworkers have a high risk for acute pesticide-related illness and injury, and the rate among female farmworkers is approximately twice as high as that among males. Surveillance data were used to identify reasons for this gender difference. METHODS: We identified acute pesticide-related illness and injury cases among farmworkers from the Sentinel Event Notification System for Occupational Risks (SENSOR)-Pesticides Program and the California Department of Pesticide Regulation. Gender-specific associations with acute pesticide-related illness and injury were assessed using chi-square tests. National Agricultural Workers Survey data were also examined. RESULTS: The over-representation of females among farmworker illness and injury cases was confined to females who did not handle pesticides (non-handlers). Female non-handler farmworkers who were affected were more likely to be working on fruit and nut crops, to be exposed to off-target pesticide drift, and to be exposed to fungicides and fumigants compared to males. CONCLUSIONS: Although there is an increased risk for acute pesticide-related illness and injury among female farmworkers, the absolute number of farmworkers with acute pesticide-related illness and injury is far higher among males than females. Furthermore, farmworkers have little or no control over many of the identified contributing factors that led to illness and injury. Stringent enforcement of existing regulations and enhanced regulatory efforts to protect against off-target drift exposures may have the highest impact in reducing acute pesticide-related illness and injury among farmworkers. PMID- 22495939 TI - Toward the estimation of population impact in early posttraumatic stress disorder intervention trials. PMID- 22495940 TI - Competitive memory training (COMET) for treating low self-esteem in patients with depressive disorders: a randomized clinical trial. AB - BACKGROUND: Self-esteem is a major concern in mood disorders. Low self-esteem is a symptom of depressive disorders and is considered by some to be a predictor for relapse, whereas high self-esteem seems to buffer against depression. Recently, Competitive Memory Training (COMET) has shown to be effective for the enhancement of self-esteem in several psychopathological conditions. The current study assesses whether COMET is also an effective intervention for patients with depressive disorders. METHODS: Sixty-one patients with depressive disorders who were already in therapy in an outpatient mental health institution were randomly assigned to either eight group sessions of COMET in addition to their regular therapy (COMET + therapy as usual [TAU]: the experimental group) or to 8 weeks of ongoing regular therapy (TAU only: the control group). These latter (control) patients received COMET after their TAU only period. All patients in both groups that completed COMET were contacted 3 and 6 months later to assess whether the effects of COMET had remained stable. RESULTS: Compared to the patients who received TAU only, patients in the COMET + TAU condition showed significant improvement with large effect sizes on indices of self-esteem, depression, and depressive rumination. The therapeutic effects of COMET + TAU remained stable after 3 and 6 months on all outcome measures or improved even further. CONCLUSION: COMET for low self-esteem seems to be an efficacious trans-diagnostic intervention that can relatively easily be added to the regular treatment of patients with depressive disorders. PMID- 22495942 TI - Further evidence that the cutoff to define remission on the 17-item Hamilton Depression Rating Scale should be lowered. AB - BACKGROUND: In 1991, the recommendations of a consensus conference were that a cutoff of 7 on the 17-item Hamilton Depression Rating Scale (HAM-D) be used to define remission from depression, and since then this has been the most commonly used definition of remission. The cutoff was not derived from empirical study. In the present report from the MIDAS project, we examined the level of current psychosocial morbidity in depressed patients identified as being in remission according to different thresholds on the 17-item HAM-D. METHODS: We interviewed 274 depressed outpatients in ongoing treatment. The patients completed measures of depressive and anxious symptoms, psychosocial functioning, and quality of life. RESULTS: Compared to patients scoring 3-7 on the HAM-D, patients scoring 0 2 had significantly lower levels of depression and anxiety on self-report symptom scales, better psychosocial functioning, better quality of life, and greater satisfaction with their mental health. Similar results were found comparing patients scoring 0-2 versus 3-5. CONCLUSIONS: The results of this study indicate that significant heterogeneity exists among patients scoring 7 and below on the HAM-D. Whatever cutoff score is used to define remission on a symptom severity scale such as the HAM-D, some error will be inherent in dichotomizing a continuously distributed variable. We propose distinguishing between patients who are highly likely to be in remission (0-2 on the HAMD) from patients who are possibly in remission (scoring 3-7). PMID- 22495941 TI - Effect of concurrent substance use disorder on the effectiveness of single and combination antidepressant medications for the treatment of major depression: an exploratory analysis of a single-blind randomized trial. AB - BACKGROUND: The co-occurrence of substance use disorder (SUD) and major depressive disorder (MDD) is common and is often thought to impair response to antidepressant therapy. These patients are often excluded from clinical trials, resulting in a significant knowledge gap regarding optimal pharmacotherapy for the treatment of MDD with concurrent SUD. METHODS: In the Combining Medications to Enhance Depression Outcomes study, 665 adult outpatients with chronic and/or recurrent MDD were prospectively treated with either escitalopram monotherapy (escitalopram and placebo) or an antidepressant combination (venalfaxine-XR and mirtazapine or escitalopram and bupropion-SR). Participants with MDD and concurrent SUD (13.1%) were compared to those without SUD (86.9%) on sociodemographic and clinical characteristics at baseline and treatment response at 12- and 28-week endpoints. RESULTS: The participants with MDD and SUD were more likely to be male and have current suicidal thoughts/plans, and had a greater lifetime severity and number of suicide attempts, and a higher number of concurrent Axis I disorders, particularly concurrent anxiety disorders. There were no significant differences between the MDD with or without SUD groups in terms of dose, time in treatment, response or remission at week 12 and 28. Furthermore, no significant differences in response or remission rates were noted between groups on the basis of the presence or absence of SUD and treatment assignment. CONCLUSIONS: Although significant baseline sociodemographic and clinical differences exist, patients with MDD and concurrent SUD are as likely to respond and remit to a single or combination antidepressant treatment as those presenting without SUD. PMID- 22495943 TI - Implementing the new oral anticoagulants into the hospital formulary. AB - The new oral anticoagulants may prove to be one of most significant innovations in clinical practice in the past 60 years. Apixaban and rivaroxaban are direct inhibitors of Factor Xa, while dabigatran inhibits Factor IIa. The predictable pharmacological profile of these new agents allows physicians to prescribe these drugs without the need for routine coagulation monitoring, which is the mainstay of warfarin therapy. In addition, these new agents have not been shown to have any food interactions and minimal drug-drug interactions, interactions are limited to the p-glycoprotein (p-Gp) transporter or cytochrome P450 (CYP450) system, each drug is unique in its drug interaction profile, as will be discussed below. These unique pharmacokinetics profiles may usher in for clinicians a new era of managing thromboembolic disorders. In this article, the pharmacology of these new oral anticoagulants will be reviewed along with the major clinical trials evaluating the use of these agents for thromboembolic prophylaxis in patients undergoing total hip and knee arthroplastic surgery, the treatment of venous thromboembolic disorders and stroke prevention in atrial fibrillation. Am. J. Hematol., 2012. (c) 2012 Wiley Periodicals, Inc. PMID- 22495944 TI - Ethnicity and childhood overweight/obesity in England. AB - BACKGROUND: Some studies suggest that British Afro-Caribbean girls and Pakistani girls have higher levels of obesity than girls in the general population of England. However, the interplay between child obesity, ethnicity, mother's socioeconomic status and other parental characteristics is unclear and requires exploration. OBJECTIVES: This study examines the relationship between child ethnicity and child overweight/obesity after controlling for a wide range of mothers' socioeconomic characteristics and parental overweight/obesity. METHODS: Health Survey for England data (1999 and 2004) are used to examine 7047 children aged 2-15 years. Body mass index (BMI) for children is classified using the International Obesity Task Force age-specific BMI thresholds for obesity and overweight. RESULTS: After controlling for a wide range of maternal socioeconomic characteristics and parental overweight/obesity, there are no ethnic differences in childhood overweight/obesity. CONCLUSIONS: Having overweight or obese parents is a stronger predictor of childhood overweight/obesity than ethnic origin of the child. Interventions aimed at reducing childhood overweight/obesity should focus on parental characteristics rather than the ethnicity of the child, but they also need to be sensitive to gender and ethnic differences. Future research should aim to repeat the analyses using a measure of abdominal obesity such as waist circumference, if data become available. PMID- 22495945 TI - Spatiotemporal distribution of white matter lesions in relapsing-remitting and secondary progressive multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. MS lesions show a typical distribution pattern and primarily affect the white matter (WM) in the periventricular zone and in the centrum semiovale. OBJECTIVE: To track lesion development during disease progression, we compared the spatiotemporal distribution patterns of lesions in relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS). METHODS: We used T1 and T2 weighted MR images of 209 RRMS and 62 SPMS patients acquired on two different 1.5 Tesla MR scanners in two clinical centers followed up for 25 (+/- 1.7) months. Both cross-sectional and longitudinal differences in lesion distribution between RRMS and SPMS patients were analyzed with lesion probability maps (LPMs) and permutation-based inference. RESULTS: MS lesions clustered around the lateral ventricles and in the centrum semiovale. Cross-sectionally, compared to RRMS patients, the SPMS patients showed a significantly higher regional probability of T1 hypointense lesions (p <= 0.03) in the callosal body, the corticospinal tract, and other tracts adjacent to the lateral ventricles, but not of T2 lesions (peak probabilities were RRMS: T1 9%, T2 18%; SPMS: T1 21%, T2 27%). No longitudinal changes of regional T1 and T2 lesion volumes between baseline and follow-up scan were found. CONCLUSION: The results suggest a particular vulnerability to neurodegeneration during disease progression in a number of WM tracts. PMID- 22495946 TI - Detrimental role of granulocyte-colony stimulating factor in neuromyelitis optica: clinical case and histological evidence. AB - In a recent study, administration of granulocyte colony stimulating factor (G CSF) increased neuromyelitis optica (NMO) lesions in mice. Here we report a patient whose first episode of NMO may have been exacerbated by inadvertent administration of G-CSF. Histological examination of brain and spinal cord samples from three other NMO patients revealed markedly increased expression of G CSF in neurons located in and around the lesions, with little or no expression in multiple sclerosis lesions or normal white matter. Taken together, these cases support a detrimental role for G-CSF in NMO pathogenesis. PMID- 22495947 TI - The quality of reports of randomized trials in multiple sclerosis: a review. AB - Randomized clinical trials (RCT) in multiple sclerosis (MS) have a recent tradition, but their number has been exponentially increasing since the first study detecting the efficacy of a disease modifying drug in MS. To examine the methodological details of reports of RCT in MS, we extracted from five leading journals all the reports of RCT published between 1993 and 2010. Trial reports were compared for different periods (1993-2001, 2002-2006, 2007-2010) for a set of indicator variables reflecting methodological quality (including details about randomization and blinding, statistical methods, results reporting, subgroup analyses). Fifty-three reports were included in the analysis. All of the methodological items indicated an improvement over time in the quality of reporting, the main weaknesses being frequent and inappropriate use of significance testing for assessing baseline imbalances and the statistical approach to subgroup analysis. A complete and transparent reporting of trial methodology is becoming even more important in an era when new design strategies are required for the feasibility of future trials in MS. PMID- 22495948 TI - MRI-based clinical trials in relapsing-remitting MS: new sample size calculations based on a longitudinal model. AB - BACKGROUND: Sample sizes for magnetic resonance imaging (MRI)-based clinical trials in multiple sclerosis (MS) generally assume that lesion counts are reasonably described by the negative binomial (NB) model. OBJECTIVE: This study aimed to assess the appropriateness of the NB model for lesion count data and to provide sample sizes for placebo-controlled, MRI-based clinical trials in relapsing-remitting MS using a more realistic model. METHODS: The fit of the NB model in each arm of five MS clinical trials was assessed using Pearson's chi squared statistic. Required sample sizes associated with various tests of treatment effect were estimated by simulating data from a new, longitudinal model for repeated lesion count data on individual patients. RESULTS: Evidence (p < 0.05) against the NB model was found in at least one arm of four of the five trials. If a trial is designed using this model but the resulting clinical data do not follow its assumptions then this trial can be seriously under-powered for assessing differences in mean lesion counts. CONCLUSION: Sample sizes based on the longitudinal model are more realistic and often smaller than those previously reported using the NB model. PMID- 22495949 TI - Frequent but nonspecific venous narrowing in paediatric multiple sclerosis. PMID- 22495950 TI - Spondyloperipheral dysplasia as the mosaic form of platyspondylic lethal skeletal dyplasia torrance type in mother and fetus with the same COL2A1 mutation. AB - We describe a fetus with platyspondylic lethal skeletal dysplasia, Torrance type (PLSD-T), a rare skeletal dysplasia characterized by platyspondyly, extremely short limbs, and mild brachydactyly. Mutation analysis of COL2A1 identified a novel in-frame deletion c.4458_4460delCTT (p.Phe1486del) in the C-propeptide region of the molecule, confirming the clinical diagnosis. The phenotype in the mother was compatible with mild spondyloperipheral dysplasia (SPPD). Molecular studies documented somatic mosaicism for the same mutation in the mother. This observation further highlights the causal relationship between PLSD-T and SPPD and emphasizes the importance of evaluating parents when confronted with a skeletal dysplasia in a prenatal setting. PMID- 22495951 TI - Varenicline induced psychosis in schizophrenia. PMID- 22495952 TI - Disturbed sleep in ecstasy users reported by partners/roommates. PMID- 22495953 TI - Recurrent clozapine and lorazepam withdrawal psychosis with catatonia. PMID- 22495954 TI - Why change injection sites for depot antipsychotic medication? PMID- 22495955 TI - [Alterations of cell phenotype in Dupuytren's disease--an in vitro analysis]. AB - INTRODUCTION: Despite its potential complications, partial aponeurectomy still is the mainstay of treatment whenever it comes to significant contracture in Dupuytren's disease. With the goal in mind to identify new therapeutic strategies we isolated and characterised cells from healthy palmar aponeurosis (Kon) and compared them to cells isolated from palmar aponeurosis of patients with a primary manifestation of Dupuytren's disease (PrimDup) as well as from patients with recurrent Dupuytren's disease (RezDup). As cells from palmar aponeurosis from patients with Dupuytren's disease share characteristics with stem cells, such as the ability to differentiate into other cell types, we analysed the stemness, morphology and integrin receptor profiles of the cells. MATERIALS AND METHODS: A total of 15 Dupuytren samples were collected from regular partial aponeurectomy procedures. From these, 3 donors without extrinsic risk factors were selected per group (RezDup, PrimDup). Cells were isolated and expanded under standard cell culture conditions. Cells from healthy patients served as control (Kon). Growth curves were produced. Cells were subjected to osteogenic and adipogenic differentiation using standard protocols. Semiquantitative PCR analysis of the integrins alpha2, beta3, beta5 and fibronectin was performed. RESULTS: PrimDup cells proliferated significantly faster than control cells, which in turn proliferated faster than RezDup cells. Both PrimDup and control cells went into senescence after approximately 40 days whereas RezDup cells proliferated over the entire period of 100 days. Osteogenic and adipogenic differentiation was best in cells derived from Dupuytren patients while Kon cells differentiated poorly. PCR analysis revealed that fibronectin-binding integrins beta3 and beta5 are upregulated in Dupuytren's disease. CONCLUSIONS: PrimDup cells grow faster than the other cell types suggesting that their growth regulation may be altered. The fact that RezDup cells do not reach senescence over 100 days in culture indicates that senescence regulating factors may be altered. As cells from Dupuytren patients differentiate better along the osteogenic and adipogenic lineages, they probably possess a higher level of stemness. Their modified integrin profile may be a key to future therapies. PMID- 22495956 TI - [A composite osteomusculocutaneous free flap from the medial femoral condyle: anatomic characteristics, clinical aspects, new applications]. AB - Advances in plastic and reconstructive surgery allow an almost complete functional and aesthetic reconstruction after severe injuries. However, particularly the treatment of complex defects involving different tissue components is still challenging. The reconstruction requires a combined flap consisting of different tissues from an adequate donor area. In this context, we focused on anatomical and clinical aspects of transplants from the area of the medial femoral condyle. In this study, the anatomical characteristics and potentials of various flaps from the region of this region are described. Moreover, previous literature on this subject is put in context with both the results of our own anatomical study and our clinical experience. The supplying vessel is the descending genicular artery with its branches. In addition to the consistency in vessel length and diameter, the descending genicular artery has a continuous distribution in a periosteal, cutaneous and muscular branch. Due to this anatomical characteristic, this donor site offers the possibility for several customized transplants. Thus, the distal medial thigh is a versatile and reliable donor site for plastic surgical procedures. PMID- 22495957 TI - [The internal thoracic vessels as alternative recipient vessels for microsurgical reconstruction in the head and neck area in patients with a vessel-depleted neck]. AB - The microsurgical reconstruction of defects in the head and neck area after local recurrent or secondary tumours is a very demanding procedure, since the recipient vessels for free flap transfer are usually absent, strongly damaged or because of previous radiation therapy very vulnerable. In these cases, it is often necessary to search an alternative to the classical recipient vessels--branches of the external carotid artery and internal and external jugularis vein. The authors present a clinical series where the internal mammary vessels were chosen as free flap recipient in the vessel-depleted neck. 11 patients were examined, in whose the extended dissected internal mammary vessels were selected as recipient for free flaps. There was no flap loss in the series. A venous anastomosis had to be revised due to bleeding on the fourth postoperative day. In one patient both sides were used simultaneously for 2 different flaps (jejunum+VRAM "vertical rectus abdominis myocutaneous flap"). Despite the general opinion that this procedure has disadvantages--like short pedicle and morbidity of the donor side at the thoracic wall--which could bring intra- and postoperative complications, it shows that in patients with previous surgeries or radiation therapy of the neck the internal mammary (after further distal preparation) as recipient vessels represent an attractive alternative to the A-V Loops. PMID- 22495958 TI - Contralateral spinal accessory nerve: a suitable "new" donor nerve for heterotopic nerve transfer in total brachial plexus palsy. AB - Patients with complete brachial plexus palsy with avulsion of 4-5 roots often have a paucity of suitable donor nerves to provide for a proper functional recovery of the upper extremity. The spinal accessory nerve is routinely employed ipsilaterally for nerve transfer to the suprascapular nerve. The purpose of this paper is to describe the clinical use of the contralateral spinal accessory nerve as a donor nerve for brachial plexus surgery. Since 2005 the contralateral spinal accessory nerve has been used for neurotization of the axillary nerve in selected cases of total brachial plexus injuries. In this paper total plexus palsy surgical strategies, technical details and preliminary functional outcomes of a group of 6 consecutive patients with a minimum follow-up of 30 months (76-31, average 55) are described. The preliminary results are encouraging: the functional outcome of the deltoid muscle, evaluated according to the British Medical Research Council grading system, was M4 in 1 patient, M3 in 1 patient, M2 in 2 patients, M1 in 1 patient, and M0 in 1 patient. In conclusion, the use of the contralateral spinal accessory nerve shows good results in terms of functional recovery and the simplicity of the procedure. PMID- 22495959 TI - [Microscope-integrated intraoperative indocyanine green angiography in plastic surgery]. AB - The knowledge of tissue perfusion has not only a prognostic value in microvascular surgery but also the intraoperative detection of malperfusion can lead to a quick surgical intervention. Indocyanine green (ICG) angiography allows a topographic analysis of perfusion and is used to assess lymphatic drainage pathways and to analyse the depth of burn injuries. Integrating the technique into an operating microscope enables visualisation of the flow over microanastomoses and allows the assessment of the transit time of blood flow between arterial and venous anastomosis. Using this method we analysed 11 microsurgical free flaps (3 latissimus dorsi, 3 rectus abdominis, 1 gracilis muscle, 2 radial forearm, 1 ALT, and 1 DIEP flap). The topographic analysis was performed after the assessment of the microanastomoses. We observed no flap loss or partial flap necrosis. The transit time between arterial inflow and venous outflow was 32.8 s on average. Here we observed distinct differences between muscle flaps (27.7 s) on the one hand and fasciocutaneous and perforator flaps (47.5 s) on the other hand. We detected one venous thrombosis by ICG angiography in a case where the clinical patency test was not distinct. Revision was performed immediately. Particularly for intraoperative assessment, ICG angiography is a useful, reliable and safe technique. The integration into the operating microscope allows an "angiographic patency test" and the analysis of the transit time allows the evaluation of blood flow within the flap. Especially when planning perforator flaps the method of ICG angiography provides a new level of safety in flap design by quickly demonstrating the borders of perfusion. PMID- 22495960 TI - [Pyoderma gangraenosum as a major complication in breast reconstruction with free double-DIEP-flap]. AB - BACKGROUND: Pyoderma gangraenosum (PG) as an idiopathic, ulcerative inflammatory skin disease with varying clinical pictures has an estimated incidence of 0.3/100,000 and is due to the non-specific histology primarily a clinical exclusion diagnosis. The rapid progression, as well as the often fatal course of the pathergy phenomenon after surgical intervention is a therapeutic challenge. With the example of the complicated course of a 47-year-old patient with free DIEP flap for bilateral breast reconstruction due to PG, we want to direct attention to this often underrated disease. PATIENTS: For bilateral breast reconstruction, a 47-year-old patient received a double free DIEP flap, which had to be resected on the right due to multiple arterial thromboses. The clinical presumptive diagnosis of a PG arose and an IV steroid therapy was started immediately. After 13 days a further debridement and mesh graft transplantation were performed. Now, the histological examination was for the first time compatible with PG. Under the initiated steroid treatment the wounds could be stabilised and the remaining defects could be covered. After 6-week stay, the patient was finally discharged with healed wound conditions, but an unsatisfactory aesthetic result. CONCLUSIONS: If unclear, rapidly progressive ulcers occur in surgical interventions one should always think of pyoderma gangraenosum. In particular, since a surgical intervention can result in an uncontrolled exacerbation due to the pathergy phenomenon. Laboratory parameters and histology are not specific. Under a systemic immunomodulatory therapy, a sequential surgical wound management may accelerate wound healing. PMID- 22495961 TI - [The latissimus dorsi myocutaneous free flap--a salvage option for abdominal wall reconstruction in complex incisional hernias]. AB - Complex incisional hernias are a serious burden for the patient and a challenge for the surgeon. The main problem is the covering of the defect after the resection of large proportions of low-grade tissue. In this work, we describe 2 patients who underwent complex reconstruction of recurrent incisional hernias using a bovine pericardium mesh (Tutomesh(r)) and a latissimus dorsi myocutaneous free flap. PMID- 22495962 TI - [Options for regenerative therapy in the field of breast surgery]. AB - Besides the established techniques of pediculed and free tissue transplantations for breast reconstruction, adipose tissue engineering and structural fat grafting are being applied as options for regenerative therapy. While the initial euphoria about the foreseeable realisation of cell-matrix entities of sufficient size, functionality and long-term volume stability for use in humans has diminished somewhat, fat grafting as experienced a renaissance in recent years. One of the decisive factors for the engraftment of the tissue graft generated though tissue engineering is the formation of an adequate vascular network. Improvements of the matrix, which ideally should mimic natural tissue, such as the use of adipose derived stem cells (ASCs) that can contribute both to adipogenesis and neoangiogenesis represent promising new approaches. In autologous fat grafting, the mixing of adipocytes and cells of the stromal-vascular fraction (SVF) in order to generate the principle of an inductive microenvironment has already been applied successfully in clinical routine. On the basis of the experimental data that demonstrate an interaction of the adipocytes, ASCs and other progenitor cells with breast cancer cells and the insufficient clinical data regarding oncological safety, this procedure should only be used critically. A concluding evaluation will only be possible after long-term clinical studies have provided good results. PMID- 22495963 TI - [Development of DRGs in reconstructive breast surgery]. AB - Diagnosis-Related Groups (DRG) were introduced in Germany in 2004 as a medico economic classification system. In this analysis, we looked at reconstructive surgery after breast cancer, focusing on changes of the fee-per-case system in the last 6 years. Immediate, delayed, pedicle and free flaps as well as alloplastic reconstructive methods were analysed using data from German reference hospitals. We analysed the length of stay, reimbursements, costs and profits. The biggest profit margin was found in free perforator flaps. These were up to 3 times higher than in alloplastic reconstruction and pedicle flaps. Due to the fact that the underlying costs for the calculation of reimbursement are always retrospective, we accounted for the rate of price increase. In spite of increasing mean profits, foregone profits of up to ?574 per case due to inflation were not taken into consideration. Contrary to actual guidelines, neither the immediate reconstruction of the breast by autologous tissue, nor the bilateral reconstruction is taken into account economically. Although a more differentiated reimbursement of breast reconstruction by DRG has taken place in the last years, the subject still remains a classical example for insufficient mapping of new medical standards in our DRG system. As the choice of surgical therapy is increasingly influenced by free market mechanisms, the risk for economic selection in contradiction to clinical recommendations becomes a real problem. Even 9 years after its introduction, the German DRG system is far from being a learning or quick adapting system. PMID- 22495964 TI - The role of macrocyclic ligands in the peroxo/superoxo nature of Ni-O2 biomimetic complexes. AB - The impact of the macrocyclic ligand on the electronic structure of two LNi-O2 biomimetic adducts, [Ni(12-TMC)O2](+) (12-TMC = 1,4,7,10-tetramethyl-1,4,7,10 tetraazacyclododecane) and [Ni(14-TMC)O2](+) (14-TMC = 1,4,8,11-tetramethyl 1,4,8,11-tetraazacyclotetradecane), has been inspected by means of difference dedicated configuration interaction calculations and a valence bond reading of the wavefunction. The system containing the 12-membered macrocyclic ligand has been experimentally described as a side-on nickel(III)-peroxo complex, whereas the 14-membered one has been characterized as an end-on nickel(II)-superoxide. Our results put in evidence the relationship between the steric effect of the macrocyclic ligand, the O2 coordination mode and the charge transfer extent between the Ni center and the O2 molecule. The 12-membered macrocyclic ligand favors a side-on coordination, a most efficient overlap between Ni 3d and O2 pi* orbitals and, consequently, a larger charge transfer from LNi fragment to O2 molecule. The analysis of the ground-state electronic structure shows an enhancement of the peroxide nature of the Ni-O2 interaction for [Ni(12 TMC)O2](+), although a dominant superoxide character is found for both systems. PMID- 22495965 TI - A novel 13 base pair insertion in the sonic hedgehog ZRS limb enhancer (ZRS/LMBR1) causes preaxial polydactyly with triphalangeal thumb. AB - Mutations in the Sonic hedgehog limb enhancer, the zone of polarizing activity regulatory sequence (ZRS, located within the gene LMBR1), commonly called the ZRS), cause limb malformations. In humans, three classes of mutations have been proposed based on the limb phenotype; single base changes throughout the region cause preaxial polydactyly (PPD), single base changes at one specific site cause Werner mesomelic syndrome, and large duplications cause polysyndactyly. This study presents a novel mutation-a small insertion. In a Swedish family with autosomal-dominant PPD, we found a 13 base pair insertion within the ZRS, NG_009240.1:g.106934_106935insTAAGGAAGTGATT (traditional nomenclature: ZRS603ins13). Computational transcription factor-binding site predictions suggest that this insertion creates new binding sites and a mouse enhancer assay shows that this insertion causes ectopic gene expression. This study is the first to discover a small insertion in an enhancer that causes a human limb malformation and suggests a potential mechanism that could explain the ectopic expression caused by this mutation. PMID- 22495966 TI - A short PPR protein required for the splicing of specific group II introns in angiosperm chloroplasts. AB - A maize gene designated thylakoid assembly 8 (tha8) emerged from a screen for nuclear mutations that cause defects in the biogenesis of chloroplast thylakoid membranes. The tha8 gene encodes an unusual member of the pentatricopeptide repeat (PPR) family, a family of helical repeat proteins that participate in various aspects of organellar RNA metabolism. THA8 localizes to chloroplasts, where it associates specifically with the ycf3-2 and trnA group II introns. The splicing of ycf3-2 is eliminated in tha8 mutants, and trnA splicing is strongly compromised. Reverse-genetic analysis of the tha8 ortholog in Arabidopsis thaliana showed that these molecular functions are conserved, although null alleles are embryo lethal in Arabidopsis and seedling lethal in maize. Whereas most PPR proteins have more than 10 PPR motifs, THA8 belongs to a subfamily of plant PPR proteins with only four PPR motifs and little else. THA8 is the first member of this subfamily with a defined molecular function, and illustrates that even small PPR proteins have the potential to mediate specific intermolecular interactions in vivo. PMID- 22495967 TI - The bereavement exclusion and DSM-5. AB - BACKGROUND: Pre-DSM-III (where DSM is Diagnostic and Statistical Manual), a series of studies demonstrated that major depressive syndromes were common after bereavement and that these syndromes often were transient, not requiring treatment. Largely on the basis of these studies, a decision was made to exclude the diagnosis of a major depressive episode (MDE) if symptoms could be "better accounted for by bereavement than by MDE" unless symptoms were severe and very impairing. Thus, since the publication of DSM-III in 1980, the official position of American Psychiatry has been that recent bereavement may be an exclusion criterion for the diagnosis of an MDE. This review article attempts to answer the question, "Does the best available research favor continuing the 'bereavement exclusion' (BE) in DSM-5?" We have previously discussed the proposal by the DSM-5 Mood Disorders Work Group to remove the BE from DSM-5. METHODS: Prior reviews have evaluated the validity of the BE based on studies published through 2006. The current review adds research studies published since 2006 and critically examines arguments for and against retaining the BE in DSM-5. RESULTS: The preponderance of data suggests that bereavement-related depression is not different from MDE that presents in any other context; it is equally genetically influenced, most likely to occur in individuals with past personal and family histories of MDE, has similar personality characteristics and patterns of comorbidity, is as likely to be chronic and/or recurrent, and responds to antidepressant medications. CONCLUSIONS: We conclude that the BE should not be retained in DSM-5. PMID- 22495968 TI - Three-dimensional ultrasound prenatal diagnosis of congenital ichthyosis: contribution of molecular biology. PMID- 22495969 TI - Continuous infusion of 20-hydroxyecdysone increased mass of triceps brachii in C57BL/6 mice. AB - Phytoecdysteroids have been attributed with numerous pharmacological properties in animals, including increasing muscle mass, and 20-hydroxyecdysone (20E) is one of the most abundant phytoecdysteroids produced by plants. In this study, the physiological and gene expression effects of 20E were analyzed in C57BL/6 mice given a continuous infusion of saline or 20E (5 mg/kg/day) for 5 or 15 days using subcutaneously implanted Alzet(r) osmotic pumps. The masses of the total body, muscle groups and organs were determined. There was a significant increase ( p = 0.01) in the mass of triceps brachii in mice treated with 20E for 5 days (115 +/- 8 mg) compared with mice treated with saline for 5 days (88 +/- 3 mg), however, there were no differences in the other measured parameters. To determine potential mechanisms of 20E in skeletal muscle, Illumina's Mouse Whole Genome-6 v2.0 Expression BeadChips were used to evaluate changes in gene expression of the triceps brachii after 20E infusion. Ingenuity Pathways Analysis was used to identify genes with the most evidence for differential expression, of which, 16 genes involved in the skeletal and muscular system were identified. Overall, the data suggest that 20E does not have potent anabolic properties, however, a muscle specific increase was observed and genes were identified to provide an explanation for the muscle accretion. PMID- 22495970 TI - Adherence to the 2007 cystic fibrosis pulmonary guidelines: a national survey of CF care centers. AB - OBJECTIVE: To examine cystic fibrosis (CF) physician adherence to the 2007 CF Foundation (CFF) Pulmonary Guidelines for Chronic Medications. Specifically adherence and barriers to prescribing level A medication recommendations (i.e., inhaled tobramycin and dornase alfa) and level B medication recommendations (i.e., macrolide antibiotics and hypertonic saline) were studied. METHODS: During Spring 2010, the CFF emailed survey invitations to directors of 136 accredited CF care centers treating 50+ CF patients. Directors were asked to forward the invitations to their physician colleagues. One hundred thirty-three surveys were included in the analyses, representing 92 centers. Barriers were conceptualized based on Cabana et al.'s framework for adherence to guidelines. Adherence was assessed via a case vignette. RESULTS: Logistic regression analysis revealed that higher outcome expectancy (OR = 1.099, CI 1.010-1.196) and fewer environmental/system barriers (OR = 1.484, CI 1.158-1.902) were significantly associated with Vignette Adherence. A trend for an association between Familiarity and Vignette Adherence (OR = 1.642, CI 0.953-2.828) was evident, while no demographic variables were significantly associated with Vignette Adherence. CONCLUSION: Targeting outcome expectancy and external barriers with multifaceted, ongoing interventions may improve guideline adherence. Pulmonologists are clearly looking for empirical evidence that these medications benefit their patients over the long-term and offset patient treatment burden with improved health. PMID- 22495971 TI - Effect of interprotein polarization on protein-protein binding energy. AB - Molecular dynamics simulation in explicit water for the binding of the benchmark barnase-barstar complex was carried out to investigate the effect polarization of interprotein hydrogen bonds on its binding free energy. Our study is based on the AMBER force field but with polarized atomic charges derived from fragment quantum mechanical calculation for the protein complex. The quantum-derived atomic charges include the effect of polarization of interprotein hydrogen bonds, which was absent in the standard force fields that were used in previous theoretical calculations of barnase-barstar binding energy. This study shows that this polarization effect impacts both the static (electronic) and dynamic interprotein electrostatic interactions and significantly lowers the free energy of the barnase-barstar complex. PMID- 22495972 TI - Controversies in heparin monitoring. PMID- 22495973 TI - Bone metabolism in patients with primary hyperparathyroidism before and after surgery. AB - Primary hyperparathyroidism (PHPT) is accompanied with a reduced bone mineral density (BMD) and an increased risk of fracture. Surgery is the only option for cure. It is hypothesized that in patients with PHPT bone metabolism normalizes after parathyroidectomy (PTX) and that BMD gradually increases. Fifty-two patients with PHPT who underwent surgery were prospectively followed for 1 year. Biochemical analyses were performed at baseline and 1, 4, 7 days; 6 weeks; and 3, 6, and 12 months, and BMD before and one year after surgery. Parathyroid hormone (PTH), calcium, and the bone resorption marker dropped immediately, but transiently after PTX, bone formation decreased more slowly. Osteoprotegerin (OPG) as well as cathepsin K did not show significant changes. BMD of the lumbar spine, but not of the femoral neck, increased significantly within one year after surgery. Moderate correlations existed between the changes of total calcium, ionized calcium, as well as bone-specific alkaline phosphatase and changes of the lumbar BMD. Patients who needed postoperative supplementation with calcium and vitamin D had significantly higher PTH levels. Some gender-specific differences in patients with PHPT were observed. In patients with PHPT, males appear to be more severely affected than females. Within the first year after PTX, bone metabolism normalized, and BMD of the lumbar spine increased. Patients who needed a supplementation with calcium and vitamin D after PTX preoperatively had higher serum levels of PTH. PMID- 22495974 TI - Global methylation analysis identifies PITX2 as an upstream regulator of the androgen receptor and IGF-I receptor genes in prostate cancer. AB - The insulin-like growth factor-I (IGF-IR) and androgen (AR) receptors are important players in prostate cancer. Functional interactions between the IGF-I and androgen signaling pathways have crucial roles in the progression of prostate cancer from early to advanced stages. DNA methylation is a major epigenetic alteration affecting gene expression. Hypermethylation of tumor suppressor promoters is a frequent event in human cancer, leading to inactivation and repression of specific genes. The aim of the present study was to identify the entire set of methylated genes ("methylome") in a cellular model that replicates prostate cancer progression. The methylation profiles of the P69 (early stage, benign) and M12 (advanced stage, metastatic) prostate cancer cell lines were established by treating cells with the demethylating agent 5-aza-2'-deoxycytidine (5-Aza) followed by DNA microarray analysis. Comparative genome-wide methylation analyses of 5-Aza-treated versus untreated cells identified 297 genes overexpressed in P69 and 191 genes overexpressed in M12 cells. 102 genes were upregulated in both benign and metastatic cell lines. In addition, our analyses identified the PITX2 gene as a master regulator upstream of the AR and IGF-IR genes. The PITX2 promoter was semi-methylated in P69 cells but fully methylated (i. e., silenced) in M12 cells. Epigenetic regulation of PITX2 during the course of the disease may lead to orchestrated control of the AR and IGF signaling pathways. In summary, our results provide new insights into the epigenetic changes associated with progression of prostate cancer from an organ confined, androgen-sensitive disorder to an aggressive, androgen-insensitive disease. PMID- 22495975 TI - Percentage of gutta-percha in mesial canals of mandibular molars obturated by lateral compaction or single cone techniques. AB - The aim of this study was to compare the percentage of gutta-percha (PGP) in mesial root canals of mandibular molars obturated with LC (Lateral Compaction) or SC (Single Cone) ProTaper Universal System techniques at different levels of the root. Mesial root canals of 20 human permanent molars with similar anatomical characteristics were instrumented using the ProTaper Universal rotary system technique until the F2 instrument, with 20 canals filled by SC ProTaper Universal technique and 20 canals by the LC technique. The mesial roots were sectioned transversely to 3, 5, and 7 mm from the root apex. Digital images of specimens were obtained at MIC-D digital microscope in increases of 30 to 35X. The gutta percha area was measured using ImageTool software. Data were analyzed using two way ANOVA and Bonferroni test (alpha = 0.05). The SC technique provided greater PGP than the LC technique in the apical third (3 mm) (P < 0.001). In the other thirds (5 and 7 mm) there was no statistical difference between the two techniques regarding the PGP (P > 0.05). There was no statistically significant difference between thirds of the root canal for both techniques (P > 0.05). It was concluded that SC technique provided greater PGP than the LC technique in the apical third of mesial root canals of mandibular molars. There was no difference between the two techniques regarding the PGP in the cervical and middle thirds. PMID- 22495976 TI - A shared founder mutation underlies restrictive dermopathy in Old Colony (Dutch German) Mennonite and Hutterite patients in North America. PMID- 22495980 TI - Comment on 'Resveratrol in human cancer chemoprevention--choosing the 'right' dose'. PMID- 22495981 TI - Role of nutrition and microbiota in susceptibility to inflammatory bowel diseases. AB - Inflammatory bowel diseases (IBDs), Crohn's disease (CD), and ulcerative colitis (UC) are chronic inflammatory conditions, which are increasing in incidence, prevalence, and severity, in many countries. While there is genetic susceptibility to IBD, the probability of disease development is modified by diet, lifestyle, and endogenous factors, including the gut microbiota. For example, high intakes of mono- and disaccharides, and total fats consistently increases the risk developing both forms of IBD. High vegetable intake reduces the risk of UC, whereas increased fruit and/or dietary fiber intake appears protective against CD. Low levels of certain micronutrients, especially vitamin D, may increase the risk of both diseases. Dietary patterns may be even more important to disease susceptibility than the levels of individual foods or nutrients. Various dietary regimes may modify disease symptoms, in part through their actions on the host microbiota. Both probiotics and prebiotics may modulate the microflora, and reduce the likelihood of IBD regression. However, other dietary factors affect the microbiota in different ways. Distinguishing cause from effect, and characterizing the relative roles of human and microbial genes, diet, age of onset, gender, life style, smoking history, ethnic background, environmental exposures, and medications, will require innovative and internationally integrated approaches. PMID- 22495982 TI - Do cereal mixed-linked beta-glucans possess immune-modulating activities? AB - beta-glucans are known for their immune-modulating properties. However, the heterogeneity of these glucose polymers makes a distinction between the different sources and structures necessary-a fact that has been little allowed for in the literature. We have focused on beta-glucans from cereals as they are already used as functional food ingredients due to their established cholesterol lowering effect. Cereal beta-glucans have shown in vitro activity on cytokine secretion, phagocytic activity and cytotoxicity of isolated immune cells, and activation of the complement system. Animal studies suggest a possible protective effect against an intestinal parasite, against bacterial infection, and a synergistic effect in antibody-dependent cellular cytotoxicity. Animal studies have shown activity of orally applied cereal beta-glucans indicating uptake or interaction with cells of the gastrointestinal tract. However, uptake is still debated, interaction with intestinal epithelial cells has been suggested but not clarified, and mechanisms of action remain largely unknown. So far, cereal beta glucans have not shown immune modulation in the few conducted human studies and further studies are needed to clarify their effect. PMID- 22495983 TI - Trypsin resistance of the major peanut allergen Ara h 6 and allergenicity of the digestion products are abolished after selective disruption of disulfide bonds. AB - SCOPE: 2S-albumins Ara h 2 and Ara h 6 are the most widely recognized and potent allergens for peanut-allergic patients. These allergens are particularly resistant to proteolysis and the digestion products generally retain significant allergenicity. Five disulfide bridges (DB) stabilize Ara h 6 overall structure and their influence on the trypsin resistance and on the allergenicity of the digestion products was investigated. METHODS AND RESULTS: Progressive disruption of each DB was performed by site-directed mutagenesis. Successful refolding of Ara h 6 variants was confirmed by circular dichroism. Trypsin resistance, IgE binding capacity and allergenic potency, as assessed by in vitro mediator release assay with sera from peanut-allergic patients, was not affected by the deletion of the C-terminal DB at Cys(84) -Cys(124) . Additional disruption of DB at Cys(14) -Cys(71) or at Cys(73) -Cys(115) rendered Arg(16/20) or Arg(114) susceptible to trypsinolysis, respectively, but affected principally the IgE binding capacity of Ara h 6. DB disruption at Cys(26) -Cys(58) or at Cys(59) Cys(107) led to an extensive proteolytic degradation and a complete loss of allergenic potency of the digestion products. CONCLUSION: Selective disruption of the DB stabilizing the protease-resistant core of Ara h 6 eliminated the IgE binding capacity of the trypsin-degradation products and their ability to trigger mast cell degranulation. PMID- 22495984 TI - Nutraceutical-mediated restoration of wild-type levels of IKBKAP-encoded IKAP protein in familial dysautonomia-derived cells. AB - SCOPE: The reported ability to modulate the production of the wild-type transcript in cells bearing the splice-altering familial dysautonomia (FD) causing mutation in the IKBKAP gene prompted an evaluation of the impact of commonly consumed nutraceuticals on the splicing of this transcript. METHODS AND RESULTS: Screening efforts revealed the ability of the isoflavones, genistein, and daidzein, to impact splicing and increase the production of the wild-type, exon-20-containing, transcript, and the full-length IKBKAP-encoded IKappaB kinase complex associated protein(IKAP) in FD-derived cells. Genistein was also found to impact splicing in neuronal cells, a cell type profoundly impacted by FD. The simultaneous exposure of FD-derived cells to genistein and epigallocatechin gallate (EGCG) resulted in the almost exclusive production of the exon-20 containing transcript and the production of wild-type amounts of IKAP protein. CONCLUSION: This study represents the first demonstration that the isoflavones, genistein and daidzein, possess splice-altering capabilities and that simultaneous treatment with genistein and EGCG reverses the splice-altering impact of the FD-causing mutation. These findings support the clinical evaluation of the therapeutic impact of the combined administration of these two commonly consumed nutraceuticals on this patient population and suggest a broader evaluation of the impact of these nutraceuticals on the in vivo RNA splicing process. PMID- 22495985 TI - Green tea (-)-epigallocatechin gallate inhibits IGF-I and IGF-II stimulation of 3T3-L1 preadipocyte mitogenesis via the 67-kDa laminin receptor, but not AMP activated protein kinase pathway. AB - SCOPE: This study investigated the pathways involved in epigallocatechin gallate (EGCG) modulation of insulin-like growth factor (IGF)-I-stimulated and IGF-II stimulated mitogenesis in 3T3-L1 preadipocytes. METHODS AND RESULTS: We found that this process was dose and time dependent, and caused by suppression of IGF-I stimulated and IGF-II-stimulated phosphorylation of p66Shc and mitogen-activated protein kinase (MAPK) pathway proteins, including MEK1 kinase (RAF1), extracellular signal-regulated protein kinase (ERK) kinase (MEK1), and ERK 1 and ERK 2 (ERK1/2), but not phospho-Jun-N-terminal kinase, protein kinase B, p52Shc, or p46Shc. Furthermore, EGCG inhibited the IGF-I-stimulated phosphorylation of the IGF-I receptor-beta (IGF-IR beta), the association of IGF-IR with the p66Shc protein, and the IGF-II-stimulated associations of the IGF-II receptor with G(alphai-2) and p66Shc proteins, suggesting that EGCG selectively affects particular types of Shc and MAPK family members. Pretreatment with antiserum against the EGCG receptor (also known as the 67-kDa laminin receptor; 67LR), but not with an adenosine monophosphate (AMP)-activated protein kinase (AMPK) inhibitor, prevented the inhibitory actions of EGCG on IGF-I- and IGF-II stimulated ERK1/2 phosphorylation and subsequent preadipocyte proliferation. CONCLUSION: The results of this study suggest that EGCG mediates anti-IGF-I and anti-IGF-II signals in preadipocyte mitogenesis via the 67LR but not the AMPK pathway. PMID- 22495986 TI - Cyanidin-3-O-beta-glucoside upregulates hepatic cholesterol 7alpha-hydroxylase expression and reduces hypercholesterolemia in mice. AB - SCOPE: Although previous studies have shown that consumption of anthocyanin extract from plant foods reduces hypercholesterolemia and the severity of atherosclerosis in different animal models, the mechanisms of these actions remained unclear. This study investigated whether pure anthocyanin inhibit atherosclerosis development and reduce hypercholesterolemia in the apolipoprotein E (ApoE)-deficient mice through enhancement of fecal bile acid excretion, a critical pathway for eliminating circulation cholesterol from the body. METHODS AND RESULTS: Five-week-old male ApoE-deficient mice were fed the AIN-93G diet supplemented with or without cyanidin-3-O-beta-glucoside (0.06% w/w) for 12 weeks. Results showed that cyanidin-3-O-beta-glucoside consumption inhibited the formation of aortic sinus plaque and reduced hypercholesterolemia, along with promoted fecal bile acid excretion and upregulated hepatic cholesterol 7a hydroxylase expression (CYP7A1). In mouse primary hepatocytes, cyanidin-3-O-beta glucoside treatment increased bile acid synthesis and CYP7A1 expression in a liver X receptor alpha (LXRalpha)-)-dependent manner. Scintillation proximity and time-resolved fluorescence resonance energy transfer assays revealed that cyanidin-3-O-beta-glucoside functions as an agonist of LXRalpha. CONCLUSION: Our results indicate that the hypocholesterolemic activity of cyanidin-3-O-beta glucoside was, at least in part, mediated by activating the potential LXRalpha CYP7A1-bile acid excretion pathway, thus contributing to the antiatherogenic effect of cyanidin-3-O-beta-glucoside. Importantly, cyanidin-3-O-beta-glucoside could activate LXRalpha in an agonist-dependent manner. PMID- 22495987 TI - Dietary exposure to fumonisins and evaluation of nutrient intake in a group of adult celiac patients on a gluten-free diet. AB - SCOPE: The main objectives of this study were to estimate dietary fumonisin exposure and nutrient intake in a group of patients diagnosed with celiac disease compared to non-celiac subjects. METHODS AND RESULTS: The fumonisin level in 118 frequently consumed corn-based products was determined and dietary habits were recorded using a 7-day weighed food record. Data were then compared to those obtained for a control group. The fumonisin intake in the celiac patients was significantly higher than in controls, with mean values (+/- SE) of 0.395 +/- 0.049 and 0.029 +/- 0.006 MUg/kg body weight per day, respectively. With regard to nutritional habits, celiac patients showed a preference for a high fat diet, coupled with a high intake of sweets and soft drinks and a low intake of vegetables, iron, calcium and folate. CONCLUSION: These findings may have serious health implications for the celiac population due to the widespread occurrence of fumonisins in most of the widely consumed gluten-free products, leading to continuous exposure to this particular mycotoxin. Moreover, the recorded nutritional quality of the celiac patient's diet raises concerns regarding its long-term adequacy and its potential impact on chronic conditions such as type 2 diabetes and cardiovascular diseases. PMID- 22495988 TI - Regulation of colon gene expression by vitamin B6 supplementation. AB - SCOPE: Previous studies have shown that vitamin B6 supplementation suppresses the development of colonic aberrant crypt foci (ACF), precursor lesions of colon cancer, and cell proliferation in mice receiving the colonic carcinogen, azoxymethane (AOM). This study investigated the molecular mechanism of these effects of dietary vitamin B6. METHODS AND RESULTS: To date, the mechanism by which ACFs develop is not yet fully understood. In a search for factors that play a critical role during ACF development, we examined colon gene expression during early stage of ACF development in AOM-treated mice using DNA microarray analysis. AOM treatment significantly upregulated mRNA closely related to mast cell and cytotoxic T-cell activity. This study also investigated the effect of vitamin B6 supplementation on colon gene expression in AOM-treated mice. We found that vitamin B6 supplementation downregulates Cd8a and Ccl8 mRNA expression, suggesting these candidate genes may play a protective role against colonic ACF development. Furthermore, we examined genomic affects of dietary vitamin B6, and showed that Reg3gamma mRNA expression in colons is downregulated by vitamin B6. CONCLUSION: This study provides an insight into the genomic activities of dietary vitamin B6 that may be protective against colon tumor development. PMID- 22495989 TI - Urinary excretion and metabolism of procyanidins in pigs. AB - SCOPE: Aim of this study was to investigate urinary excretion and metabolism of procyanidins a group of secondary plant metabolites with many beneficial health effects described in literature. METHODS AND RESULTS: To investigate the metabolism of procyanidins in the absence of flavan-3-ols, centrifugal partition chromatography was used for their reduction in a grape seed extract to a level of almost zero. After administration of the monomer reduced grape seed extract (mredGSE) containing procyanidins B1, B2, B3, B4, C1 to pigs flavan-3-ols, their methyl derivatives, dimeric and trimeric procyanidins were determined in urine by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Maximal concentrations of procyanidins 6 h after administration vary from 5 to 30 ng/mg creatinine. Total excretion of flavan-3-ols and their methyl derivatives indicates an increasing trend for pigs given mredGSE in comparison to pigs of the control group. Flavan-3-ols were conjugated and methylated to a great extent in comparison to dimeric and trimeric procyanidins. In the case of low molecular weight metabolites, an increasing trend was observed for hippuric acid, not for phenolic acids. CONCLUSIONS: Ratios of total excretion of procyanidins to administrated amounts between 0.004% (C1) and 0.019% (B4) suggest a poor urinary excretion by pigs. A transfer of these results to humans is possible due to their similar gastrointestinal tract. PMID- 22495990 TI - Generalizability of clinical trial results for generalized anxiety disorder to community samples. AB - BACKGROUND: There has been little research on the generalizability of clinical trials for generalized anxiety disorder (GAD). The present study examines the generalizability of pharmacological and psychotherapy clinical trials' results of individuals with DSM-IV GAD to a large community sample. METHODS: Data were drawn from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC), a large national representative face-to-face sample of 43,093 adults of the United States population. We applied a standard set of eligibility criteria representative of GAD pharmacological and psychotherapy clinical trials to all adults with past 12 months GAD (n = 894), and to a subgroup of participants seeking treatment (n = 329). Our aim was to assess how many participants with GAD would fulfil typical eligibility criteria. RESULTS: We found that more than seven out of 10 participants with GAD were excluded by at least one criterion. In the subgroup of GAD participants who sought treatment, the exclusion rate by at least one criterion raised to more than eight out of 10 participants with GAD. For the overall sample and the treatment-seeking subsample, having a current depression was the criterion excluding the highest percentage of individuals. Having a lifetime history of bipolar disorder, a current significant medical condition, a current diagnosis of alcohol abuse or dependence, and a social or specific phobia also excluded a substantial proportion of individuals in both samples. CONCLUSIONS: Clinical trials exclude a majority of adults with GAD. Clinical trials should carefully consider the impact of eligibility criteria on the generalizability of their results. PMID- 22495991 TI - Probing the catalytic mechanism of a C-3'-methyltransferase involved in the biosynthesis of D-tetronitrose. AB - D-Tetronitrose is a nitro-containing tetradeoxysugar found attached to the antitumor and antibacterial agent tetrocarcin A. The biosynthesis of this highly unusual sugar in Micromonospora chalcea requires 10 enzymes. The fifth step in the pathway involves the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the C-3' carbon of dTDP-3-amino-2,3,6-trideoxy-4-keto-D-glucose. The enzyme responsible for this transformation is referred to as TcaB9. It is a monomeric enzyme with a molecular architecture based around three domains. The N terminal motif contains a binding site for a structural zinc ion. The middle- and C-terminal domains serve to anchor the SAM and dTDP-sugar ligands, respectively, to the protein, and the active site of TcaB9 is wedged between these two regions. For this investigation, the roles of Tyr 76, His 181, Tyr 222, Glu 224, and His 225, which form the active site of TcaB9, were probed by site-directed mutagenesis, kinetic analyses, and X-ray structural studies. In addition, two ternary complexes of the enzyme with bound S-adenosyl-L-homocysteine and either dTDP-3-amino-2,3,6-trideoxy-4-keto-D-glucose or dTDP-3-amino-2,3,6-trideoxy-D galactose were determined to 1.5 or 1.6 A resolution, respectively. Taken together, these investigations highlight the important role of His 225 in methyl transfer. In addition, the structural data suggest that the methylation reaction occurs via retention of configuration about the C-3' carbon of the sugar. PMID- 22495993 TI - [Communications of the 104th Annual Meeting of the Swiss Society of Ophthalmology SOG/SSO, Interlaken, August 31 - September 3, 2011]. PMID- 22495992 TI - Discovery of epigenetic biomarkers for the noninvasive diagnosis of fetal disease. AB - OBJECTIVES: The primary goal of this study was to identify CpG sites in the human genome that are differentially methylated in DNA obtained from chorionic villus sampling (CVS) samples and gestational age-matched maternal blood cell (MBC) samples. METHODS: We used the HumanMethylation27 DNA Analysis BeadChip to characterize DNA methylation in samples of CVS and MBC. We then selected a subset of differentially methylated CpG sites on chromsome 13 and subjected them to analysis by mass spectrometry using the Epityper platform. RESULTS: We identified 718 tissue-specific differentially methylated regions (DMRs) between MBC and CVS; 563 of these were hypermethylated in MBC and hypomethylated in CVS, whereas 155 sites were hypomethylated in MBC and hypermethylated in CVS. Further analysis of 13 DMRs on chromosome 13 by Epityper confirmed the microarray data and provided us with additional data about the methylation patterns of surrounding CpG sites. CONCLUSIONS: Analysis of the resulting data identified a large number of cytosine guanine dinucleotides that are potential biomarkers for the selective amplification of fetal DNA from maternal plasma and the subsequent noninvasive detection of trisomy 13. PMID- 22495994 TI - Classification of choroiditis based on inflammatory lesion process rather than fundus appearance: enhanced comprehension through the ICGA concepts of the iceberg and jellyfish effects. AB - Choroidal inflammatory diseases have been classically grouped under the term of white dot syndromes (WDS), a term only based on the appearance (white-yellow dots) of inflammatory fundus lesions. This purely descriptive and vague terminology, regrouping a pot-pourri of posterior inflammatory conditions, probably came into use because the precise exploration of the choroid was not possible, and also because many of the diseases were rare and not well understood. Since the availability of indocyanine green angiography (ICGA) that allows one to explore the choroidal compartment, it became possible to understand the lesion mechanism of choroiditides and to classify this group of diseases according to their pathophysiological behaviour. It was our aim to show here that the term WDS is applied to and encompasses inflammatory conditions that are characterized by completely different lesion mechanisms and should therefore be classified separately from each other. ICGA made it possible to differentiate two types of choroiditides, including on the one hand inflammatory diseases of the choroidal stroma and on the other hand inflammatory diseases of the choriocapillaris. Unfortunately, twenty years after its advent, ICGA is still not used routinely in uveitis centres and the traditional inappropriate but overall useless term of WDS is still used, maintaining the confusion about these diseases. The aim of this work was (i) to illustrate that meaningful exploration of choroidal inflammation, mostly occult and inaccessible to usual investigations, has to be performed using ICGA, (ii) to insist on the crucial importance of ICGA in the management of choroiditis and (iii) to enhance the comprehension of the ICGA-based classification of choroiditis, by using the demonstrative and striking analogue concepts of iceberg and jellyfish effects. PMID- 22495995 TI - Detection of retinal glial cell activation in glaucoma by time domain optical coherence tomography. AB - BACKGROUND: Activated retinal astrocytes and Muller cells (ARAM) have been found in glaucoma patients. This study investigated whether presumed ARAM can be detected by optical coherence tomography (OCT), and assessed their relationship to the retinal nerve fiber layer (RNFL) thickness. PATIENTS AND METHODS: Single center observational study involving 35 age-matched healthy controls and 19 patients with primary open-angle glaucoma (POAG) between 45 - 82 years of age. Presumed ARAM was defined as patchy, discrete glittering but transparent changes of the macula. The retina was documented by red-free photography to assess distribution of ARAM, and compared to the RNFL thickness measured around the fovea by OCT. A linear mixed effects model was used to detect a difference between eyes with ARAM versus eyes without ARAM. RESULTS: ARAM was not found in healthy subjects. The mean RNFL around the fovea was not significantly thicker in healthy controls (34.01 SD +/- 22.24) than in POAG patients with ARAM (30.86 microns SD +/- 15.09; p = 0.36) or without ARAM (33.19 microns SD +/- 19.87; p = 0.46). Furthermore, the median RNFL thickness was similar to the control group (29 microns) but slightly thinner in POAG patients (each 27 microns with ARAM and without ARAM). In a subgroup analysis of POAG patients with ARAM, the within subject standard deviation of RNFL was significantly lower in areas with ARAM (SD 10.12) than in areas without ARAM (SD 17.30) (p < 0.001). CONCLUSIONS: Although the mean and median RNFL thickness was comparable between the groups, the variability of the RNFL thickness was significantly lower in areas with ARAM than in areas without ARAM suggesting that ARAM may mask RNFL loss in POAG patients. PMID- 22495996 TI - [First experience with the Heidelberg Edge Perimeter(r) on patients with ocular hypertension and preperimetric glaucoma]. AB - BACKGROUND: The white-on-white computerised static perimetry is not very sensitive to detect a beginning visual field loss. A newer technique to test the central visual field with a flicker defined form technology (FDF) is the Heidelberg Edge Perimeter(r) (HEP). PATIENTS AND METHODS: A study with 90 eyes from 50 patients (mean age 59 +/- 14 years) with ocular hypertension and/or optic nerve suspicious for glaucoma without detectable visual field loss in the Octopus(r) perimetry (Program dG-2) with the Heidelberg Edge Perimeter(r) was performed. The "mean defect" (MD), the "pattern standard deviation" and the glaucoma hemifield test (GHT) were calculated and compared with the indices of the Octopus(r). RESULTS: Despite normal visual field findings in the Octopus(r) perimetry (MD < 2.0 dB) we detected in 48 out of 90 eyes (53 %) pathological visual fields in the HEP examination. CONCLUSIONS: As a new research method the Heidelberg Edge perimetry(r) seems to be more sensitive than conventional static perimetry in early detection of visual field alterations in patients between ocular hypertension and incipient glaucoma. PMID- 22495997 TI - New guidelines in the treatment of persistent central serous chorioretinopathy: PDT with half-dose verteporfin. AB - BACKGROUND: In persistent central serous chorioretinopathy (CSC) resolution of detachment can be achieved by photodynamic therapy. Our objective was to evaluate the efficacy of half-dose verteporfin compared to full-dose verteporfin. PATIENTS AND METHODS: In 2009 the standard PDT regimen for CSC in our clinic was changed from full-dose to half-dose verteporfin. After a retrospective analysis 11 cases of half-dose PDT with documented course in 11 patients are presented. A comparison was performed with a control group of 11 consecutive patients with documented course who had received full-dose PDT before 2009. RESULTS: Prior to PDT there were no statistically significant differences between the groups concerning age, central foveal thickness, thickness of detachment, BCVA (EDTRS) and size of spot. 6 weeks after PDT a significant reduction of foveal thickness and detachment was detected in both groups, as well as a significant increase in BCVA. No statistically significant differences in outcome could be found between the two groups (Mann-Whitney U-test, p < 0.05). CONCLUSIONS: PDT with half-dose verteporfin seems to be an effective and safe treatment for persistent CSC. Our data showed comparable results after half-dose and after full-dose PDT. PMID- 22495998 TI - Central foveal thickness before and after cataract surgery in normal and in diabetic patients without retinopathy. AB - BACKGROUND: This study aims to evaluate and compare central foveal thickness (CFT) changes after cataract surgery between normal and diabetic patients without retinopathy, using optical coherence tomography (OCT). PATIENTS AND METHODS: Ninety-eight patients (49 patients with type 2 diabetes and 49 healthy controls, sex- and age-matched) undergoing phacoemulsification in one eye were included. The presence of retinopathy was an exclusion criterion. The OCT examination was performed preoperatively as well as one, three, six and twelve months postoperatively. CFT was evaluated and compared between groups. RESULTS: Preoperative CFT showed no significant difference between the two groups (normals: 205 +/- 18 MUm vs. diabetics: 202 +/- 23 MUm, p > 0.1). Postoperative CFT in diabetics at all time-points of the follow-up period was significantly increased when compared to controls (first month, normals: 215 +/- 28 MUm vs. diabetics: 262 +/- 33 MUm, p < 0.05; third month, normals: 211 +/- 19 MUm vs. diabetics: 250 +/- 27 MUm, p < 0.05; sixth month, normals: 208 +/- 12 MUm vs. diabetics: 266 +/- 13 MUm, p < 0.05; and twelfth month, normals: 209 +/- 13 MUm vs. diabetics: 280 +/- 11 MUm, p < 0.05). The incidence of cystoid macular edema (CME) was 4.0 % and 28.6 % for the control group and the diabetic group, respectively, at the end of the follow-up period (p < 0.05). CONCLUSION: Eyes of diabetic patients without retinopathy present higher CFT and a higher incidence of CME after cataract surgery on OCT examination compared to eyes of healthy controls. This may explain the unsatisfactory visual acuity following cataract surgery in these patients. PMID- 22495999 TI - [Isolated cilioretinal artery occlusion - clinical findings and outcome in 31 cases]. AB - PURPOSE: The aim of this study was to evaluate the outcome of this rare type of retinal vascular occlusion in a large patient series. PATIENTS AND METHODS: A retrospective chart review of all patients with an isolated cilioretinal artery obstruction seen at the University Eye Clinic Mainz (Germany) between 1/1998 and 12/2009 was performed. Standard treatment was intravenous anticoagulation with heparin. Follow-up mean was 51 months. RESULTS: Included in this study were 31 eyes from 31 patients (mean patient age 49 years, range 25 - 71 years). Significant atherosclerotic carotid artery obstruction in 17/31 cases. All occlusions were located temporally and involved some portion of the fovea (2 * cholesterol emboli). Fluorescein angiography revealed no eye with complete occlusion of the cilioretinal artery, but late retrograde filling in all eyes and associated choroidal filling defects in 10/31 eyes. During follow-up the scotomatous visual field defect (centrocaecal in 25/31 eyes) usually reduced in size, but scotoma was a persisting remnant of this episode in all eyes. Optical coherence tomography during the acute injury revealed intraretinal oedema in the area of the infarct and months afterwards an attenuated retinal thickness, consistent with retinal atrophy. Visual outcome achieved 20/50 (reading vision) in 23/31 eyes, but in only 2 of 10 eyes with associatted choroidal perfusion defects. CONCLUSIONS: The visual prognosis of isolated cilioretinal artery obstructions seems to be significantly better than for other types of retinal artery occlusion, unless the entire perifoveal capillary network is affected and choroidal involvement is shown angiographically. PMID- 22496000 TI - The predictive value of OCT characteristics for the visual outcome in neovascular AMD. AB - BACKGROUND: The intravitreal injection of an anti-VEGF compound is the current standard of care in neovascular AMD. The response to this therapy varies greatly. To date it was not possible to determine clear predictive factors in regard to therapy response, thus making it difficult when counselling patients regarding the probability for visual improvement. The aim of this study was to evaluate baseline OCT characteristics in regard to their predictive value on the outcome of visual acuity (VA) after 12 months. PATIENTS AND METHODS: A retrospective analysis of 75 eyes with neovascular AMD treated with intravitreal anti-VEGF injections at the University Hospital of Zurich with a documented follow-up of at least 12 months. Measurement and comparison of the following OCT structures were undertaken: central retinal thickness (CRT), integrity of the IS/OS junction, and presence of intra- or subretinal fluid. VA at baseline and after 12 months was evaluated. OCT findings were compared between eyes that gained >= 5 letters ETDRS (group 1) and eyes that did not (group 2). RESULTS: 75 eyes with a mean baseline VA of 57.2 +/- 15 letters and a mean baseline CRT of 430 +/- 226 MUm were analyzed. Although baseline VA did not differ statistically significantly, eyes in group 2 had a higher VA than eyes in group 1 (60.2 +/- 16.2 vs. 54.9 +/- 13.6, p = 0.123). In group 1 the change of VA after 12 months was 12.6 +/- 8.0 letters while it was -5.0 +/- 7.8 letters in group 2. No statistically significant differences between the two groups with respect to the analyzed OCT parameters were found. None of the analyzed OCT factors had a predictive value regarding the VA outcome at month 12. CONCLUSIONS: Our study was not able to find baseline OCT parameters that could predict the course of VA after 12 months. However, eyes with a thicker central retinal thickness at presentation showed a greater reduction in CRT during the analyzed period. This was associated with a more favourable course in VA. Perhaps this might be due to a less pronounced initial morphological retinal damage. PMID- 22496001 TI - Indocyanine green angiography (ICGA) is essential for the early diagnosis of birdshot chorioretinopathy. AB - BACKGROUND: Birdshot chorioretinitis (BC) is a rare disease involving the retina and the choroid independently. The hallmark for BC is the presence of depigmented oval lesion of the choroid, the so called "birdshot lesions", however in the early phase of disease these lesions are often not visible. METHODS: A retrospective analysis of BC patients that were investigated in Centre for Ophthalmic Specialised Care, Lausanne, Switzerland between 1995 and 2010 was performed. Patients seen in the initial phase of BC disease devoid of a specific diagnosis when referred were included. Clinical investigations along with fluorescein angiography (FA), indocyanine green angiography (ICGA) and visual field testing (VF) were analysed. RESULTS: Three out of 7 patients (43 %) seen in the initial phase of the disease devoid of a diagnosis at presentation were analysed. These patients presented with no "birdshot" lesions whatsoever. All three patients were HLA-A29 positive, presented with vitreitis and retinal vasculitis on FA. On ICGA, all 3 patients presented bilateral evenly distributed choroidal hypofluorescent dark dots (HDD) representing choroidal granulomas. CONCLUSIONS: ICGA, by providing occult information on the choroid, is an essential tool for early diagnosis of BC. Because ICGA is still not universally practiced in uveitis centres early disease is often missed, its diagnosis delayed and proper treatment started late. PMID- 22496002 TI - Results of primary buckling procedures indicated with regard to recommendations of the SPR study in cases with rhegmatogenous retinal detachment. AB - BACKGROUND: It was the aim of this study to analyse the functional gain and anatomical success rate in a long-term observation of patients with rhegmatogenous retinal detachments treated primarily with scleral buckling (SB) indicated on the basis of results published in the SPR study. MATERIAL, PATIENTS AND METHODS: 43 of 200 eyes (21.5 %, 41 patients) with rhegmatogenous retinal detachment were selected for scleral buckling as a primary surgical intervention. 38 patients (93 %) completed 6 months, 35 patients (85 %) 12 months and 26 patients (63 %) 24 months of follow-up. Selection of surgical methods was guided by results from the SPR study. Cases were treated by scleral buckling if the chance of primary success was estimated to be at least 90 %. RESULTS: Primary retinal attachment was achieved in 42 of 43 eyes (98 %). The retina in one eye without primary success was attached by pp-vitrectomy and gas endotamponade. No further redetachments occurred until month 12. Two eyes developed regional retinal traction in the periphery resulting from mild PVR (1 * after 16 months, 1 * after 35 months). Both were permanently attached after pp vitrectomy. At the end of the follow-up all eyes presented complete retinal attachment. Visual acuity improved from a preoperative level of logMAR 0.39 to 0.19 at month 6, 0.16 at month 12 and 0.11 at month 24 (p < 0.03). Cases with partial or complete foveal detachment reached between month 12 and month 24 the same level of visual acuity than those without foveal involvement (p = 0.57). CONCLUSIONS: The results of this case series clearly indicate that scleral buckling is still an excellent choice of the treatment for approximately one fourth of all patients with rhegmatogenous retinal detachment and may lead to very good long-term results. PMID- 22496003 TI - Early onset of acquired comitant non-accommodative esotropia in childhood. AB - BACKGROUND: The aim of this study was to describe the clinical characteristics and surgical outcome of acquired comitant non-accommodative esotropia without obvious cause in children with an early onset <= three years of age. PATIENTS AND METHODS: 24 consecutive patients (13 females) with acquired comitant non accommodative esotropia underwent strabismus surgery. Outcome measures included amount of deviation and level of binocularity at last follow-up. RESULTS: An acute onset of strabismus was observed in 83 % of patients. Accompanying features such as diplopia, covering one eye or stumbling were observed in 40 % of the children. Cycloplegic retinoscopy revealed a mild to moderate hypermetropia in all children (mean hypermetropia + 2.2 diopters). 90.5 % of children were aligned within 8 PD of orthotropia. 81 % regained normal stereovision (Lang I/II). CONCLUSIONS: All children exhibited the typical features of acute acquired comitant esotropia (AACE) type II (Burian-Franceschetti). Collective characteristics of this form of strabismus are a comitant and relatively large deviation, mild hypermetropia, a potential of normal binocular cooperation and absence of an accommodative component and neurological pathology. Time and suddenness of strabismus onset may be less helpful in defining this entity. PMID- 22496004 TI - Anterior segment angiography in strabismus surgery. AB - BACKGROUND: Anterior ciliary arteries travelling along recti muscles provide anterior segment vascularization, which can be compromised by surgery involving more than 2 muscles. PATIENTS AND METHODS: We studied retrospectively the files of 10 patients in whom a fluorescein angiography of the iris had been performed as a pre-operative assessment prior to a second or third oculomotor surgery. RESULTS: The median age of the patients was 47.5 years (range 15 to 73 years). Relative iris ischemia was present in 4 patients following multiple surgeries, none of them presenting any general cardiovascular risk. The initial surgical protocol was modified according to angiographic results in these 4 patients. CONCLUSION: When further surgery has to be performed on previously multi-operated patients, anterior segment angiography can be useful in the planning of surgery in order to minimize the risks of anterior segment ischemia. PMID- 22496005 TI - [Mechanical dilatation of the pupil in phacoemulsification surgery: first experiences with the 6.25 mm Malyugin-ring]. AB - PURPOSE: Inadequate mydriasis may cause major problems in phacoemulsification surgery. Usually 4 iris retractors are used to allow adequate pupillary dilatation. Implantation of a Malyugin ring to maintain a 6.25 mm pupil is a new alternative. PATIENTS AND METHODS: A Malyugin ring was used in 46 eyes of 39 patients (aged 80.1 +/- 6.2 years). The ring is im- and explanted with a disposable shooter through the main incision. Indications for the use of the ring were inadequate mydriasis due to pseudoexfoliation (n = 27), intraoperative floppy iris syndrome (n = 5), the combination of PEX and IFIS (n = 11), extensive posterior synechiae (n = 2) or inadquate mydriasis after long-term pilocarpine treatment (n = 1). RESULTS: In 44/46 eyes phacoemulsification with implantation of foldable posterior chamber lens was performed without complications. In 2 eyes with massive phakodonesis an Artisan anterior chamber lens had to be implanted after anterior vitrectomy because of total zonulolysis. There where no complications associated to the use of the device and with increasing experience duration of implantation as well as explantation was reduced to 2 - 4.5 min (median 2:51 min). CONCLUSIONS: In cases of phacoemulsification surgery with inadequate mydriasis implantation of a Malyugin ring is a simple, safe and fast alternative to iris-retractors; it allows better pupil-size without additional stab incisions. PMID- 22496006 TI - Early visual evoked potentials: an indicator of bioelectrical activity of the lateral geniculate nucleus? AB - BACKGROUND: In non-human primate experiments Schroeder et al. (1992) demonstrated that visual evoked activity of the lateral geniculate nucleus (LGN) can be recorded on the frontolateral epidural surface of macaque monkeys. So far it is not known whether analogous visual evoked potentials can be found on the scalp surface of humans. METHODS: The search for early visual evoked responses was performed in healthy volunteers with the following technique: white Ganzfeld flash stimulation (< 100 usec, 0.81 cd/m2s, frequency 1.1 Hz), low frequency filter 1 Hz, high frequency filter 100 Hz (12 db/octave), averaging of 100 stimulations. A topographic map of responses was recorded at standard electroencephalography scalp positions. In addition to these methods the following parameters were modified: stimulation (flash versus checkerboard reversal, monocular versus binocular), recording of right and left hemisphere responses, frequency filtering and frequency analysis. RESULTS: Scalp mapping of VEP responses indicated an early reproducible response with a wide frontolateral distribution consisting of a small positive and a larger negative potential (= GER - presumed geniculatum evoked response). A closer analysis of responses was performed at 6 different standard electroencephalography scalp positions electrode positions (F2, F4, FC2, FC4, FC6, C4) in 7 healthy volunteers. At FC4 the amplitude of the GER was maximal (4.8 +/- 2.9 uV). The peak latencies were: positive wave 31.8 +/- 2.8 msec, negative wave 43.6 +/- 2.3 msec. Monocular stimulation resulted in nearly identical responses on both hemispheres. Amplitudes increase at binocular stimulation by + 44 % compared to monocular flashes. Frequency filtering and spectrum analysis clearly demonstrate that the GER mainly consists of < 30 Hz components. A comparable response with checkerboard reversal could not be detected after averaging of 100 stimulations and a rudimentary GER was found after 5000 sweeps. CONCLUSIONS: An early wide spread visually evoked potential could be identified in humans that seems to be identical to the surface recorded response of the LGN that was previously described in non-human primate experiments. PMID- 22496007 TI - Visual problems in young adults due to computer use. AB - BACKGROUND: Computer use can cause visual problems. The purpose of our study was to evaluate visual problems due to computer use in young adults. PATIENTS AND METHODS: Participants in our study were 87 adults, 48 male and 39 female, mean aged 31.3 years old (SD 7.6). All the participants completed a questionnaire regarding visual problems detected after computer use. RESULTS: The mean daily use of computers was 3.2 hours (SD 2.7). 65.5 % of the participants complained for dry eye, mainly after more than 2.5 hours of computer use. 32 persons (36.8 %) had a foreign body sensation in their eyes, while 15 participants (17.2 %) complained for blurred vision which caused difficulties in driving, after 3.25 hours of continuous computer use. 10.3 % of the participants sought medical advice for their problem. There was a statistically significant correlation between the frequency of visual problems and the duration of computer use (p = 0.021). 79.3 % of the participants use artificial tears during or after long use of computers, so as not to feel any ocular discomfort. CONCLUSIONS: The main symptom after computer use in young adults was dry eye. All visual problems associated with the duration of computer use. Artificial tears play an important role in the treatment of ocular discomfort after computer use. PMID- 22496008 TI - [Solitary fibrous tumour of the orbit: clinical, radiological, histological findings and differential diagnosis of an uncommon tumour]. AB - BACKGROUND: Solitary fibrous tumours (SFT) are mesenchymal neoplasias rarely found in the orbit. Due to their sharp delineation they are frequently mistaken for various benign neoplasma, such as cavernous hemangiomas, neurinomas and pleomorphic adenomas. We present two cases of SFT in the orbit and one in the lacrimal sac and discuss the radiological and histological differential diagnosis. PATIENTS AND METHODS: Among 9 patients diagnosed and operated in our department between 2008 and 2010 with an orbital tumour, three had the histological diagnosis of a solitary fibrous tumour. In 5 cases an MRI scan was performed preoperatively, in 4 cases a CT scan. RESULTS: Histology showed 2 pleomorphic adenomas, 2 cavernous hemangiomas, 2 neurinomas and 3 SFT. All SFT were intraoperatively well circumscribed and enucleated, showing histologically incomplete resection. No further treatment was given. There is no recurrence in any of the patients in the follow up of an average of 10 months (range 1 - 30 months). CONCLUSIONS: SFT are rare mesenchymal tumours of the orbit. The radiological differential diagnosis is difficult and they can be mistaken for more common tumours. The SFT has a wide range of histological appearances. Long term clinical follow-up is mandatory in all cases of SFT. PMID- 22496009 TI - Mucosal excision instead of fashioning nasolacrimal mucosae flaps during external dacryocystorhinostomy: a pilot study. AB - BACKGROUND: To report results of a simplified external dacryocytorhinostomy procedure in which nasal and lacrimal sac mucosal flaps are simply removed instead of being sutured together. PATIENTS AND METHODS: DESIGN: Retrospective non-comparative case-series study. PARTICIPANTS: Fourteen consecutive outpatients patients undergoing external dacryocytorhinostomy. INTERVENTION: Modified and simplified transcutaneous external dacryocytorhinostomy where basically the lacrimal sac and the nasal mucosae are widely excised in front of DCR's osteotomy instead of being used to fashion nasolacrimal flaps. OUTCOME: Assessment of dacryocytorhinostomy anatomical patency by syringing and patient's self perception of epiphora symptoms improvement about twelve weeks and one year after surgery, as well as patient's report of ocular air-reflux during Valsalva maneuver a year after surgery. RESULTS: Syringing showed anatomic patency in 93 % and 92 % of patients twelve weeks (mean +/- SD: 12 weeks +/- 6 weeks) and one year (15 months +/- 3 months) after surgery, respectively. One year after surgery, 62 % of patients reported ocular air-reflux. Twelve weeks and one year after surgery, mean symptom improvement was 82 % +/- 17 % and 79 % +/- 29 %, respectively. Furthermore, 79 % and 85 % of patients reported a postoperative improvement of their symptoms greater or equal to 80 % after twelve weeks and one year, respectively. CONCLUSIONS: Removing lacrimal sac and nasal mucosae in front of the osteotomy did not appear to have a major negative impact on the outcome of the external dacryocytorhinostomy. The findings of this pilot study need to be confirmed by a larger prospective trial. PMID- 22496010 TI - Delayed reconstruction after eyelid tumor excision. AB - BACKGROUND: The aim of this study is to report the feasibility of one to two weeks delayed reconstruction after eyelid tumor excision. PATIENTS AND METHODS: A retrospective case-series study was designed. Fourteen consecutive outpatients referred to a tertiary referral eye center for eyelid tumor management were enrolled. The intervention imvolved eyelid tumor excision (with four millimeters surrounding clinically tumor-free tissue), compressive patching of the excised area until reconstruction (with or without a therapeutic contact lens), extensive histological work-up to assess histological tumor clearance, and reconstruction one week after excision (in a couple of patients after two weeks when further excision was necessary to achieve tumor clearance). Excision and closure were performed by a single external trained oculoplastic surgeon (IOH) with a day per week (Fridays) operating slot. As outcome we assessed whether such an approach has led before, during, or after eyelid reconstruction to unusual major adverse events (follow-up time: 18 - 36 months). RESULTS: Delaying up to one week, in some cases even two weeks, reconstruction after eyelid tumor excision was not associated with any unusual major adverse events before, during, or after surgery. CONCLUSIONS: When necessary, after eyelid tumor excision, it is possible to delay for one week or even for two weeks reconstruction, apparently without experiencing major unusual adverse events. PMID- 22496011 TI - Scleritis after proton therapy in uveal melanoma. AB - BACKGROUND: Sclera is a very radioresistant tissue and scleritis after proton therapy has not been described so far. HISTORY AND SIGNS: Four female patients, aged between 31 and 74 years, were treated with proton therapy for uveal melanoma (height range: 2.2 - 3.5 mm), located in the macula, the superior equator and 2 in the ciliary body. All patients had a history of a previous or active inflammatory disease and developed scleritis after radiotherapy. THERAPY AND OUTCOME: Two patients had infectious scleritis and were treated with adequate antibiotic therapy. After systemic corticotherapy, 3 patients recovered completely; the remaining patient was managed with additional immunosuppressive treatment as well as a conjunctival and scleral graft, but has not become pain free yet. CONCLUSION: Scleritis is a possible complication after proton therapy, probably on an ischemic basis, where there is a predisposing factor such as inflammatory systemic disease. PMID- 22496012 TI - Multimodal imaging of autosomal dominant drusen. AB - BACKGROUND: Malattia Leventinese (ML) is a dominantly inherited macular dystrophy characterized by a radial pattern of drusen in the macular area and on the nasal edge of the optic disc. This case series describes the morphological features of drusen associated with ML using multimodal imaging. HISTORY AND SIGNS: Three patients (two of the same family but only one with the ML phenotype) were analyzed by multimodal imaging including spectral domain optical coherence tomography (SD OCT) and genetic testing. In two patients multiple drusen in the macular region and around the optic nerve head were observed bilaterally. A radial pattern was only seen in one patient. These drusenoid deposits showed early hyperfluorescence in fluorescein angiography (FA) and intense staining in indocyanine green angiography similar to cuticular drusen (basal laminar drusen). The corresponding SD OCT scan revealed two types of deposits. The first, more prominent type, were focal nodular sub-retinal pigment epithelium (RPE) deposits. The second type of deposit appears to be localized on the anterior part of the RPE comparable to subretinal drusenoid deposits (SDD; reticular pseudodrusen). THERAPY AND OUTCOME: A single nucleotide variation c.1033C>T (p.R345 W) in the EFEMP1 gene was found in case 1 (classic ML), but could not be detected in case 2 and 3. So far our patients have not suffered from any visual complaints and have not developed choroidal neovascularization. They will be followed up regularly. DISCUSSION: Multimodal imaging including SD OCT provided new information about the appearance of drusen in eyes with ML/early onset drusen. In addition to the sub-RPE deposits some deposits appear above the RPE, however have different characteristic findings on FA/ICG, autofluorescence, near infrared reflectance and blue light imaging than SDD observed in patients with age-related macular degeneration. SD OCT alone might not be sufficient to characterize these type of drusen in ML. PMID- 22496013 TI - [Analysis of choroidal folds of the posterior pole in excessive hyperopia using SD-OCT with enhanced depth imaging (EDI)]. AB - BACKGROUND: Until now the diagnostic possibilities for choroidal folds were limited to conventional methods like ICG angiography and ultrasound and in many cases additional diagnostic tools like MRI and OCT were necessary. With the introduction of high-resolution OCT new modalities of differential diagnostics are possible. METHODS: During the last year 3 patients with conspicious funduscopic findings were presented in our office. In 2 patients the changes were observed during the pre-operative examinations before cataract surgery, the third patient had problems with reading in the reading distance. After a complete ophthalmic examination we performed measurements of the choroidal complex using a Spectralis OCT (Heidelberg Engineering) with enhanced depth imaging (EDI) and detected choroidal folds in the area of the temporal vessels without hints for impressing changes from outside. Furthermore we performed a photo documentation. RESULTS: Best corrected visual acuity in patient 1 was at the right eye sph + 8.50 cyl -0.75/25 degrees = 0.6 and at the left eye sph + 9.25 cyl -0.75/170 degrees = 0.5. In patient 2 visual acuity was OD 0.6 and OS 0.5 (OD sph + 8.50 cyl -2.25/10 degrees und OS sph + 7.75 cyl -1.25/175 degrees ). The anterior ocular segment was normal besides the cataract, the posterior ocular segment showed parallel choroidal folds in the area of the temporal vessels. The choroid was preserved in full thickness and the folds were parallel in the retina and the choroid, without a distance between the two layers. In patient 3 visual acuity was OD/OS 1.0 with a correction of OD/OS sph + 3.75. The posterior ocular segment showed the same choroidal changes, all the other ocular findings were normal. CONCLUSION: Using the SD-OCT with enhanced depth resolution the characteristics of idiopathic choroidal folds in excessive hyperopia can be presented. Our observations can be used for the differentialdiagnostic judgement of idiopathic choroidal folds of the posterior pole. PMID- 22496014 TI - [Heavy tamponade in complicated inferior retinal detachment]. AB - BACKGROUND: Retinal detachment with inferior proliferative vitreoretinopathy is a difficult to treat problem. The aim of our study was to assess the safety and efficacy of Densiron in the clinical management of complicated retinal detachment. HISTORY AND SIGNS: 6 eyes of 6 consecutive patients presenting with a retinal detachment with inferior proliferative vitreoretinopathy grade 3 were treated with pars plana vitrectomy and injection of Densiron. The mean age of the patients was 61 years. 3 patients had a previous unsuccessful vitreoretinal surgery and 3 patients had Densiron as a first procedure. The extent of detachment was at least 2 or more quadrants with macular involvement in 3 cases. Preoperatively the mean visual acuity was 29.2 letters with ETDRS. THERAPY AND OUTCOME: Densiron was removed after an average of 58 days. 5 patients achieved retinal re-attachment without further tamponade, and 1 patient after additional injection of conventional silicon oil. 4 - 6 weeks after removal of Densiron the mean visual acuity was 50.2 letters with ETDRS. The most common complication was an elevated intraocular pressure during endotamponade, which resolved following removal of the agent. CONCLUSIONS: Densiron improves inferior tamponade, and in clinical practice may be considered to increase the anatomic success rate in selected cases of complicated retinal detachment with inferior proliferative vitreoretinopathy. PMID- 22496015 TI - Corneal cross-linking as supplementary treatment option in melting keratitis: a case series. AB - BACKGROUND: Corneal melting represents a serious condition that can result in corneal perforation and loss of vision. Treatment options include topical and systemic immunosuppression, cyanoacrylate gluing, and emergency keratoplasty, depending on the underlying disease and the stage of corneal melt. Recently, corneal cross-linking (CXL) has emerged as an additional treatment option. The present study evaluates whether CXL induces a clinical improvement in melting keratitis not responding to conventional treatment. HISTORY AND SIGNS: Six patients undergoing CXL for corneal melting of variable origin (including bacterial, fungal and Acanthamoeba keratitis) were reviewed retrospectively. THERAPY AND OUTCOME: Treatment parameters included riboflavin application following UV irradiation with a wavelength of 370 nm and an irradiance of 3 mW/cm2 for 30 minutes. Four patients with corneal melting due to contact lens related infectious keratitis showed healing without any need for further interventions up to date. In two patients, CXL stabilized the melting cornea and facilitated additional surgical procedures. CONCLUSIONS: By stabilizing corneal collagen fibres, CXL seems to represent an effective option to re-establish corneal integrity in the event of pending perforations. In established perforations, CXL facilitates further emergency procedures by stiffening the tissue. PMID- 22496016 TI - Clinical manifestations of mucous membrane pemphigoid in a tertiary center. AB - Mucous membrane pemphigoid (MMP) is a progressive inflammatory disease of autoimmune etiology. We performed a retrospective analysis of clinical signs and treatment on 16 patients. Conjunctival biopsies were performed in all patients and showed typical immuno-deposits at the basement membrane zone. The mean age at presentation was 69 years, 60 % were female.12 patients demonstrated ocular involvement (11 bilaterally). At the time of referral to our hospital, 92 % had reached an advanced stage III or IV. All patients presented conjunctival fibrosis with resultant fornix foreshortening. Trichiasis and symblepharon were found in 11 patients. Keratitis was found in 11 patients resulting in ulceration in 5 cases. Complications required surgical interventions included: entropion surgery (n = 2), tarsorrhaphy (n = 1), amniotic membrane transplantation (n = 2), keratoplasty (n = 1). Systemic immunomodulatory therapy is the treatment of choice. Dapsone (n = 8), steroids (n = 8), azathioprine (n = 5), cyclophosphamide (n = 2), mycophenolate mofetil (n = 4) and methotrexate (n = 1) were used concomitantly or consecutively. Early diagnosis can prevent ocular complications. Immunomodulatory therapy has provided an avenue for preserving vision. The management of MMP requires a multidisciplinary approach. PMID- 22496017 TI - Epibulbar osseous choristoma: a clinicopathological case series and review of the literature. AB - BACKGROUND: Choristomas are benign, congenital tumours composed of normal tissue in an abnormal location. Osseous choristomas represent the rarest form of epibulbar choristomas, with now 65 cases reported in the literature. We did a retrospective clinicopathological study of all patients with epibulbar osseous choristoma observed at our institution since 1982 and updated the last review of the literature. HISTORY AND SIGNS: Three Caucasian male patients, aged between 3 months and 11 years, were identified. All osseous choristomas were located under the superotemporal bulbar conjunctiva of the right eye. THERAPY AND OUTCOME: All lesions were managed with surgical excision. Histopathology revealed the presence of lamellar bone in all cases, one of which was associated with a dermolipoma. CONCLUSIONS: We report a small rare case series of 3 epibulbar osseous choristomas and did a review of the literature. In one patient, the osteoma was associated with a dermolipoma, corresponding to the fourth reported complex choristoma of this type, in an otherwise normal eye, in the literature. PMID- 22496019 TI - Indocyanine-green angiography findings in Susac's syndrome. PMID- 22496018 TI - Ocular cANCA-positive vasculitis: a case report. PMID- 22496020 TI - Total macular atrophy in subacute sclerosing panencephalitis. PMID- 22496021 TI - Bilateral optic neuropathy after short-term treatment with intravenous amiodarone. PMID- 22496022 TI - [Linezolid-associated optic neuropathy?]. PMID- 22496023 TI - Recurrent paroxysmal fever revealing ocular syphilis. PMID- 22496024 TI - Ocular involvement in idiopathic hypereosinophilic syndrome: a rare finding. PMID- 22496025 TI - [Peripheral occlusive retinal vasculopathy in a woman with combined preeclampsia and alpha thalassemia minor]. PMID- 22496026 TI - Paecilomyces lilacinus endophthalmitis following cataract surgery: a therapeutic challenge. PMID- 22496027 TI - [Tularemia as a rare cause of Parinaud's oculoglandular syndrome]. PMID- 22496028 TI - [Multiple excentric macular holes caused by epiretinal membranous traction after branch retinal vein occlusion]. PMID- 22496029 TI - Coats disease in a 14-year-old boy treated with intravitreal ranibizumab and retinal laser photocoagulation. PMID- 22496030 TI - Intravitreal administration of ranibizumab for idiopathic choroidal neovascularization in a pregnant woman. PMID- 22496031 TI - Atypical RPE-pigmentation in Prader-Willi syndrome. PMID- 22496032 TI - Stony intraocular foreign body (eye of stone). PMID- 22496033 TI - Iris varix as a cause of late-onset inflammation after implantation of a phakic iris claw lens. PMID- 22496034 TI - [Outcome of expectant management of epithelial ingrowth in two unequal cases after LASIK]. PMID- 22496035 TI - [Combined idiopathic orbital inflammation and Graves' orbitopathy]. PMID- 22496036 TI - [Non-penetrating glaucoma surgery]. PMID- 22496037 TI - Somatic mosaicism and the phenotypic expression of COL2A1 mutations. AB - Mutations in COL2A1, the gene for type II-collagen, can result in a wide variety of phenotypes depending upon the nature of the mutation. Dominant negative mutations tend to result in severe and often lethal skeletal dysplasias such as achondrogenesis type 2, Kniest dysplasia, and spondyloepiphyseal dysplasia congenita. Stickler syndrome, a condition characterized by ophthalmological and orofacial features, deafness and arthritis, usually, but not exclusively, results from haploinsufficiency. Overlapping features of all these disorders can also be seen in the same family. Rare reports have demonstrated that phenotypic variability can be explained in some families by somatic mosaicism. Here, we describe five further examples of somatic mosaicism of COL2A1 mutations illustrating the importance of detailed clinical evaluation and molecular testing even in clinically normal parents of affected individuals. PMID- 22496038 TI - DCMB that combines divide-and-conquer and mixed-basis set methods for accurate geometry optimizations, total energies, and vibrational frequencies of large molecules. AB - We present a method, named DCMB, for the calculations of large molecules. It is a combination of a parallel divide-and-conquer (DC) method and a mixed-basis (MB) set scheme. In this approach, atomic forces, total energy and vibrational frequencies are obtained from a series of MB calculations, which are derived from the target system utilizing the DC concept. Unlike the fragmentation based methods, all DCMB calculations are performed over the whole target system and no artificial caps are introduced so that it is particularly useful for charged and/or delocalized systems. By comparing the DCMB results with those from the conventional method, we demonstrate that DCMB is capable of providing accurate prediction of molecular geometries, total energies, and vibrational frequencies of molecules of general interest. We also demonstrate that the high efficiency of the parallel DCMB code holds the promise for a routine geometry optimization of large complex systems. PMID- 22496039 TI - Clinical microscopic analysis of ProTaper retreatment system efficacy considering root canal thirds using three endodontic sealers. AB - To evaluate the efficacy of ProTaper Universal rotary retreatment system and the influence of sealer type on the presence of filling debris in the reinstrumented canals viewed in an operative clinical microscope. Forty-five palatal root canals of first molars were filled with gutta-percha and one of the following sealers: G1, EndoFill; G2, AH Plus; G3, Sealapex. The canals were then reinstrumented with ProTaper Universal rotary system. Roots were longitudinally sectioned and examined under an operative clinical microscope (10*), and the amount of filling debris on canal walls was analyzed using the AutoCAD 2004 software. A single operator used a specific software tool to outline the canal area and the filling debris area in each third (cervical, middle, and apical), as well as the total canal area. Data were analyzed by Kruskal-Wallis test and Tukey test at P < 0.05. Sealapex demonstrated significant differences in the average of filling debris area/canal among the 3 thirds. This group revealed that apical third showed more debris than the both cervical and middle third (P < 0.0001). Endofill presented significantly more filling debris than Sealapex in the cervical third (P < 0.05). In the middle (P = 0.12) and apical third (P = 0.10), there were no differences amongst groups. Debris was left in all canal thirds, regardless of the retreatment technique. The greatest differences between techniques and sealers were found in the cervical third. PMID- 22496040 TI - Clearance of initial mucoid Pseudomonas aeruginosa in patients with cystic fibrosis. AB - BACKGROUND: Accelerated lung function decline in cystic fibrosis (CF) is associated with mucoid Pseudomonas aeruginosa infection. Recent data suggest that mucoid P. aeruginosa may amenable to elimination from the airway. We aim to determine whether the initiation of an aggressive antibiotic eradication regimen upon initial discovery of mucoid P. aeruginosa in the CF airway could be successful in clearing the organism from the CF lung. METHODS: We performed a retrospective analysis of patients with CF who demonstrated new growth of mucoid P. aeruginosa in an airway culture between January 2003 and December 2008. The primary endpoint was clearance of mucoid P. aeruginosa, based upon the Leeds criteria, with no further growth of mucoid P. aeruginosa cultures within 12 months of the initial discovery and treatment. Factors associated with successful clearance were also evaluated. RESULTS: Forty-eight of 355 patients with CF had a new diagnosis of mucoid P. aeruginosa during the study period; 15 patients underwent an eradication attempt, while 33 patients received no increase in therapy. We observed clearance of mucoid P. aeruginosa in 73.3% of patients undergoing an eradication attempt, whereas 36.6% of those that did not undergo attempted eradication cleared the organism at 1 year (P < 0.05). Prolonged mucoid P. aeruginosa airway clearance (>24 months) for mucoid P. aeruginosa was seen in 60.0% in subjects undergoing eradication compared to 21.2% (P = 0.02) in control patients. At the study conclusion, lung function was greater in subjects who underwent an eradication attempt than in patients who did not undergo an eradication attempt (FEV(1) %: 91.7% vs. 75.0%, P = 0.04). CONCLUSIONS: Clearance of initial mucoid P. aeruginosa from the airways of select patients with CF is possible with current antibiotic regimens, and the attempt may be associated with improved lung function. PMID- 22496042 TI - Fluorescently labeled branched polymers and thermal responsive nanoparticles for live cell imaging. AB - Branched poly(methoxy-PEG acrylate) and thermally responsive poly(methoxy-PEG acrylate)-block-poly(N-isopropylacrylamide) are synthesized by RAFT polymerization. After reduction, these polymers are fluorescently labeled by reacting the free thiol groups with N-(5-fluoresceinyl)maleimide. As shown by DLS, the labeled copolymer poly(methoxy-PEG acrylate)-block-poly(N isopropylacrylamide) forms nanoparticles at body temperature (37 degrees C) due to the presence of the thermosensitive poly(N-isopropylacrylamide). These materials were used as bioprobes for imaging HUVECs in vitro and chick embryo CAM in vivo. Both labeled polymer and nanoparticles are biocompatible and can be used as efficient fluorescent bioprobes. PMID- 22496044 TI - Genetic and environmental contributions to separation anxiety: a meta-analytic approach to twin data. AB - BACKGROUND: Separation anxiety disorder (SAD) and separation anxiety symptoms (SA) have been studied both epidemiologically and genetically; however, large between-studies discrepancies emerge relative to the role of genetic, shared-, and nonshared environmental influences on these conditions. METHODS: Based upon available literature, 18 cohorts and 31,859 subjects belonging to twin samples in Europe, the United States, and Australia were included in three meta-analytic estimations of: the standardized variance components of etiological influences on SAD/SA, and on the effect of sex and rater. RESULTS: Meta-analytic estimations carried out on all cohorts showed that within-family (genetic 43% and shared environmental 17%) factors explain most of individual differences for SAD/SA. Meta-heritability estimates were higher among females (.52) than males (.26), whereas nonshared environmental effects were stronger for the latter (.74) than for the former (.41). When SAD/SA was rated by parents, the shared environmental influences were higher than those obtained with self-assessment instruments (.23 versus .05), but this may reflect an age difference between subsamples. CONCLUSIONS: A shared environmental effect is present and important in SAD/SA. Our results support at an etiological level the involvement of parents in treating SAD/SA in children, and the provision of specific strategies to parents to manage their own anxiety. PMID- 22496045 TI - Introduction to this issue: international perspectives on juvenile crime. PMID- 22496046 TI - Prevalence of ADHD and its subtypes in male and female adult prison inmates. AB - There are few published studies of attention-deficit/hyperactivity disorder (ADHD) in adult inmates, and even fewer studies that have considered ADHD in adult inmates by gender. The present study examined the prevalence of ADHD, its subtypes, and associated psychological and neuropsychological comorbidity as a function of gender in a sample of 3,962 inmates (3,439 men and 523 women; mean age = 33.6 years, range 17-73) who had completed the 250-item, self-report, Diagnostic and Statistical Manual of Mental Disorders, 4th edition (Text Revision) (DSM-IV-TR)-aligned Coolidge Correctional Inventory (CCI). The overall ADHD prevalence rate found was 10.5%, which is substantially higher than the rate among adults in the general population (2-5%). The female inmate ADHD prevalence rate (15.1%) was higher than the male inmate ADHD rate (9.8%), consistent with some previous studies. The most prevalent ADHD subtype for both genders was the hyperactive-impulsive subtype. The combined and inattentive ADHD subtypes had higher levels of comorbid psychopathology than the hyperactive-impulsive ADHD subtype. As the presence of ADHD and associated gender differentials may impact the success of rehabilitation and educative programs with inmates, the assessment of ADHD and comorbid psychopathology should be a priority in initial inmate screening and evaluation. PMID- 22496047 TI - Anatomical and scanning electron microscopic investigations of the tongue and laryngeal entrance in the long-legged buzzard (Buteo rufinus, Cretzschmar, 1829). AB - This research aimed to examine the morphological features of the tongue and laryngeal entrance of long-legged buzzard by macroscopic and scanning electron microscopic methods. Two adult buzzards were used as material. The tongue was fairly elongated and terminated in oval shovel-like apex. Scale-like projections were localized on the apex and body of tongue. Both lateral sides of lingual body were contained considerably long thread-like projections. Many orifices of lingual posterior salivary glands were discerned among scale-like projections in median sulcus of the lingual body. Papillary crest of sharp conical papilla were observed on the between the body and root of the tongue. No conical papillae or other projections were existent on the root of the tongue, but numerous orifices of posterior salivary gland ducts were detected. In addition, orifices of anterior salivary gland ducts were present on the dorsal and lateral surfaces of the lingual body. Numerous conical papillae were observed on the caudal region of glottis and no conical papillae or any similar projection which were bordered the glottic fissure was noted. Anatomy of these organs in the long-legged buzzard and white tailed eagle which are the member of the same family, Accipitridae, revealed very high similarity. PMID- 22496048 TI - Can we use the frontomaxillary facial angle in the first trimester to predict facial cleft? PMID- 22496049 TI - Pancreatic insufficiency in Toriello-Carey syndrome: report of a second patient. AB - Toriello-Carey syndrome is characterized by multiple congenital anomalies. Pancreatic insufficiency is suspected when patients present with poor weight gain, diarrhea, or maldigestion. The diagnosis is confirmed by low stool elastase and pancreatic stimulation testing. To our knowledge, only one patient with Toriello-Carey syndrome has been reported to have pancreatic insufficiency. We report on a second patient with Toriello-Carey syndrome and pancreatic insufficiency, and describe the management of pancreatic insufficiency in patients with this syndrome. PMID- 22496050 TI - Reactivity ratios and sequence structures of the copolymers prepared using photo induced copolymerization of MMA with MTMP. AB - 4-Methacryloyl-2,2,6,6-tetramethyl-piperidine (MTMP) was applied as reactive hindered amine piperidine. Photo-induced copolymerization of methyl methacrylate (MMA, M(1)) with MTMP (M(2)) was carried out in benzene solution at ambient temperature. The reactivity ratios for these monomers were measured by running a series of reactions at various feed ratios of initial monomers, and the monomer incorporation into copolymer was determined using (1)H NMR. Reactivity ratios of the MMA/MTMP system were measured to be r(1)= 0.37 and r(2)= 1.14 from extended Kelen-Tudos method. The results show that monomer MTMP prefers homopolymerization to copolymerization in the system, whereas monomer MMA prefers copolymerization to homopolymerization. Sequence structures of the MMA/MTMP copolymers were characterized using (1)H NMR. The results show that the sequence structure for the main chain of the MMA/MTMP copolymers is mainly composed of a syndiotactic configuration, only with a little heterotactic configuration. Three kinds of the sequences of rr, rr', and lr' in the syndiotactic configuration are found. The sequence-length distribution in the MMA/MTMP copolymers is also obtained. For f(1)= 0.2, the monomer unit of MMA is mostly separated by MTMP units, and for f(1)= 0.6, the alternating tendency prevails and a large number of mono-sequences are formed; further up to f(1)= 0.8, the monomer unit of MTMP with the sequence of one unit is interspersed among the chain of MMA. PMID- 22496051 TI - Physical therapists' management of rheumatoid arthritis: results of a Dutch survey. AB - BACKGROUND AND AIM: For tailored implementation of evidence-based recommendations and guidelines on physical therapy in patients with rheumatoid arthritis (RA), insight into current physical therapy practice is needed. METHOD: Two hundred and fifty general physical therapists and 211 specialized physical therapists with advanced arthritis training were sent a questionnaire to assess the frequency with which they applied a set of assessments (n = 10) and interventions (n = 7) included in a Dutch physical therapy guideline for RA. Differences between general and specialist physical therapists were analysed using Student's t-tests or chi-square tests where appropriate. RESULTS: In total, 233 physical therapists (51%) responded. Of these, 96 (41%) had completed an additional arthritis course and were designated as specialist physical therapists. Among the physical therapists who returned the questionnaire, 69% (or more) reported that they 'always' assessed limitations in daily functioning, pain, morning stiffness, muscle strength, joint range of motion, joint stability, gait and limitations in leisure activities as part of their initial assessment, and 37% and 48% reported 'always' to assess aerobic capacity and limitations in work situations, respectively. Concerning interventions, exercise therapy and education were 'always' applied by 70% and 68% of the responders, respectively. Only a minority of responders reported 'always' applying ultrasound, electrical stimulation, heat therapy, massage and passive mobilizations (0%, 0%, 5%, 5% and 14%, respectively). Apart from aerobic capacity and work limitations, all other assessments were reported as 'always' applied by significantly (p < 0.05) more specialist physical therapists than general physical therapists. Regarding interventions, significantly more specialist physical therapists reported that they 'always' applied exercise therapy and education. Significantly fewer specialist physical therapists than in the general group reported 'always' using heat therapy, massage and mobilizations (p < 0.05). CONCLUSION: The majority of physical therapists reported that they 'always' applied most of the assessments and interventions recommended in a Dutch physical therapy guideline for the management of RA. Areas for improvement include the assessment of aerobic capacity and work limitations. The observed differences between specialist and general physical therapists support the added value of advanced arthritis courses. PMID- 22496052 TI - Dosimetry evaluation of a cylindrical waveguide chamber for unrestrained small rodents at 1.9 GHz. AB - An exposure system, consisting of four identical cylindrical waveguide chambers, was developed for studying the effects of radiofrequency (RF) energy on laboratory mice at a frequency of 1.9 GHz. The chamber was characterized for RF dose rate as a function of animal body mass and dose rate variations due to animal movement in the cage. Dose rates were quantified in terms of whole-body average (WBA) specific absorption rate (SAR), brain average (BA) SAR and peak spatial-average (PSA) SAR using measurement and computational methods. Measurements were conducted on mouse cadavers in a multitude of possible postures and positions to evaluate the variations of WBA-SAR and its upper and lower bounds, while computations utilizing the finite-difference time-domain method together with a heterogeneous mouse model were performed to determine variations in BA-SAR and the ratio of PSA-SAR to WBA-SAR. Measured WBA-SAR variations were found to be within the ranges of 9-23.5 W/kg and 5.2-13.8 W/kg per 1 W incident power for 20 and 40 g mice, respectively. Computed BA-SAR variations were within the ranges of 3.2-10.1 W/kg and 3.3-9.2 W/kg per 1 W incident power for 25 and 30 g mouse models, respectively. Ratios of PSA-SAR to WBA-SAR, averaged over 0.5 mg and 5 mg tissue volumes, were observed to be within the ranges of 6-15 and 4-10, respectively. PMID- 22496054 TI - First, do no harm: confronting the myths of psychiatric drugs. AB - The enduring psychiatric myth is that particular personal, interpersonal and social problems in living are manifestations of 'mental illness' or 'mental disease', which can only be addressed by 'treatment' with psychiatric drugs. Psychiatric drugs are used only to control 'patient' behaviour and do not 'treat' any specific pathology in the sense understood by physical medicine. Evidence that people, diagnosed with 'serious' forms of 'mental illness' can 'recover', without psychiatric drugs, has been marginalized by drug-focused research, much of this funded by the pharmaceutical industry. The pervasive myth of psychiatric drugs dominates much of contemporary 'mental health' policy and practice and raises discrete ethical issues for nurses who claim to be focused on promoting or enabling the 'mental health' of the people in their care. PMID- 22496053 TI - X-ray evidence of a native state with increased compactness populated by tryptophan-less B. licheniformis beta-lactamase. AB - beta-lactamases confer antibiotic resistance, one of the most serious world-wide health problems, and are an excellent theoretical and experimental model in the study of protein structure, dynamics and evolution. Bacillus licheniformis exo small penicillinase (ESP) is a Class-A beta-lactamase with three tryptophan residues located in the protein core. Here, we report the 1.7-A resolution X-ray structure, catalytic parameters, and thermodynamic stability of ESP(DeltaW), an engineered mutant of ESP in which phenylalanine replaces the wild-type tryptophan residues. The structure revealed no qualitative conformational changes compared with thirteen previously reported structures of B. licheniformis beta-lactamases (RMSD = 0.4-1.2 A). However, a closer scrutiny showed that the mutations result in an overall more compact structure, with most atoms shifted toward the geometric center of the molecule. Thus, ESP(DeltaW) has a significantly smaller radius of gyration (R(g)) than the other B. licheniformis beta-lactamases characterized so far. Indeed, ESP(DeltaW) has the smallest R(g) among 126 Class-A beta-lactamases in the Protein Data Bank (PDB). Other measures of compactness, like the number of atoms in fixed volumes and the number and average of noncovalent distances, confirmed the effect. ESP(DeltaW) proves that the compactness of the native state can be enhanced by protein engineering and establishes a new lower limit to the compactness of the Class-A beta-lactamase fold. As the condensation achieved by the native state is a paramount notion in protein folding, this result may contribute to a better understanding of how the sequence determines the conformational variability and thermodynamic stability of a given fold. PMID- 22496055 TI - Health and human rights advocacy: perspectives from a Rwandan refugee camp. AB - Working at the bedside and within communities as patient advocates, nurses frequently intervene to advance individuals' health and well-being. However, the International Council of Nurses' Code of Ethics asserts that nurses should expand beyond the individual model and also promote a rights-enabling environment where respect for human dignity is paramount. This article applies the results of an ethnographic human rights study with displaced populations in Rwanda to argue for a rights-based social advocacy role for nurses. Human rights advocacy strategies include sensitization, participation, protection, good governance, and accountability. By adopting a rights-based approach to advocacy, nurses contribute to health agendas that include more just social relationships, equitable access to opportunities, and health-positive living situations for all persons. PMID- 22496056 TI - Regulation of stem cell differentiation by control of retinoic acid gradients in hydrospun 3D scaffold. AB - Morphogen gradients have been associated with differential gene expression and are implicated in the triggering and regulation of developmental biological processes. This study focused on creating morphogenic gradients through the thickness of hydrospun scaffolds. Specifically, electrospun poly(epsilon caprolactone) fibers were loaded with all-trans-retinoic acid (ATRA), and designed to release ATRA at a predetermined rate. Multilayered scaffolds designed to present varied initial ATRA concentrations were then exposed to flow conditions in a bioreactor. Gradient formation was verified by a simple convection-diffusion mathematical model approving establishment of a continuous solute gradient across the scaffold. The biological value of the designed gradients in scaffolds was evaluated by monitoring the fate of murine embryonal carcinoma cells embedded within the scaffolds. Cell differentiation within the different layers matched the predictions set forth by the theoretical model, in accordance with the ATRA gradient formed across the scaffold. This tool bears powerful potential in establishing in vitro simulation models for better understanding the inner workings of the embryo. PMID- 22496057 TI - Regional cerebral blood flow and FDG uptake in asymptomatic HIV-1 men. AB - Despite advances in the treatment of patients with human immunodeficiency virus (HIV), HIV-associated neurocognitive disorder occurs in 15-50% of HIV-infected individuals, and may become more apparent as ageing advances. In the present study we investigated regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of glucose uptake (rCMRglc) in medically and psychiatrically stable HIV-1-infected participants in two age-groups. Positron emission tomography (PET) and magnetic resonance imaging (MRI)-based arterial spin labeling (ASL) were used to measure rCMRglc and rCBF, respectively, in 35 HIV infected participants and 37 HIV-negative matched controls. All participants were currently asymptomatic with undetectable HIV-1 viral loads, without medical or psychiatric comorbidity, alcohol or substance misuse, stable on medication for at least 6 months before enrolment in the study. We found significant age effects on both ASL and PET with reduced rCBF and rCMRglc in related frontal brain regions, and consistent, although small, reductions in rCBF and rCMRglc in the anterior cingulate cortex (ACC) in HIV, a finding of potential clinical significance. There was no significant interaction between HIV status and the ageing process, and no significant HIV-related changes elsewhere in the brain on PET or ASL. This is the first paper to combine evidence from ASL and PET method in HIV participants. These finding provide evidence of crossvalidity between the two techniques, both in ageing and a clinical condition (HIV). PMID- 22496058 TI - Extremely low-frequency magnetic fields modulate nitric oxide signaling in rat brain. AB - Our previous study has shown that an extremely low-frequency magnetic field (ELF MF) induces nitric oxide (NO) synthesis by Ca(2+) -dependent NO synthase (NOS) in rat brain. The present study was designed to confirm that ELF-MF affects neuronal NOS (nNOS) in several brain regions and to investigate the correlation between NO and nNOS activation. The exposure of rats to a 2 mT, 60 Hz ELF-MF for 5 days resulted in increases of NO levels in parallel with cGMP elevations in the cerebral cortex, striatum, and hippocampus. Cresyl violet staining and electron microscopic evaluation revealed that there were no significant differences in the morphology and number of neurons in the cerebral cortex, striatum, and hippocampus. Differently, the numbers of nNOS-immunoreactive (IR) neurons were significantly increased in those cerebral areas in ELF-MF-exposed rats. These data suggest that the increase in NO could be due to the increased expression and activation of nNOS in cells. Based on NO signaling in physiological and pathological states, ELF-MF created by electric power systems may induce various physiological changes in modern life. PMID- 22496059 TI - Exclusion of mutations in TGIF, ALX3, and ALX4 genes in patients with the syndrome of frontonasal dysgenesis, callosal agenesis, basal encephalocele, and eye anomalies. PMID- 22496060 TI - Early adoption of transoral robotic surgical program: preliminary outcomes. AB - OBJECTIVE: The objective of this study is to demonstrate the feasibility and safety of establishing a transoral robotic surgical (TORS) program in the post Food and Drug Administration (FDA) approval setting. Early outcomes are compared with the previously reported results of pioneering centers. STUDY DESIGN: Clinical data from a prospective TORS study. SETTING: Academic university institution. SUBJECTS AND METHODS: Sixty-one patients treated with 63 TORS procedures. MAIN OUTCOME MEASURES: intraoperative times, margin status, complications, time to diet, and percutaneous endoscopic gastrostomy (PEG) tube retention rate. The authors also report oncologic outcomes on their first 30 patients. RESULTS: The spectrum of subsites included tongue base, tonsil, parapharyngeal space, retromolar trigone, supraglottis, and posterior pharyngeal wall. Surgical console time averaged 79 +/- 53 minutes. After re-resection of 4 patients, final negative margin status was 94% (50/53). A subset of 30 patients with squamous cell carcinoma reaching an average of 18 months of follow-up had a local regional control rate of 97% with a disease-free survival rate of 90%. The PEG tube retention rate was 7%. Complications included 2 readmissions with dehydration, 1 aspiration pneumonia, and 2 with minor oropharyngeal bleeding. Ninety-one percent of patients resumed an oral diet by the first postoperative visit. CONCLUSION: The initiation of a TORS program in the post-FDA setting can be achieved in a safe and efficient manner. Early results of pioneering TORS centers are reproducible. Continued investigation of TORS as a treatment option for oropharyngeal carcinoma is warranted. PMID- 22496061 TI - Hijacking mitochondria: bacterial toxins that modulate mitochondrial function. AB - Bacterial infection has enormous global social and economic impacts stemming from effects on human health and agriculture. Although there are still many unanswered questions, decades of research has uncovered many of the pathogenic mechanisms at play. It is now clear that bacterial pathogens produce a plethora of proteins known as "toxins" and "effectors" that target a variety of physiological host processes during the course of infection. One of the targets of host targeted bacterial toxins and effectors are the mitochondria. The mitochondrial organelles are major players in many biological functions, including energy conversion to ATP and cell death pathways, which inherently makes them targets for bacterial proteins. We present a summary of the toxins targeted to mitochondria and for those that have been studied in finer detail, we also summarize what we know about the mechanisms of targeting and finally their action at the organelle. PMID- 22496063 TI - Does fetal gender affect nuchal skin-fold thickness? PMID- 22496064 TI - Facile fabrication of thermo-responsive and reduction-sensitive polymeric micelles for anticancer drug delivery. AB - The development of thermo-responsive and reduction-sensitive polymeric micelles based on an amphiphilic block copolymer poly[(PEG-MEMA)-co-(Boc-Cyst-MMAm)]-block PEG (denoted PEG-P-SS-HP) for the intracellular delivery of anticancer drugs is reported. PTX, as model drug, was loaded into the PEG-P-SS-HP micelles with an encapsulation efficiency >90%, resulting in a high drug loading content (up to 35 wt%). The PTX-loaded PEG-P-SS-HP micelles show slow drug release in PBS and rapid release after incubation with DTT. The PTX-loaded micelles display a better cytotoxic effect than the free drug, whereas empty micelles are found to be non toxic. The thermo-responsive and reduction-sensitive polymeric micelles described may serve as promising carriers for cytostatic drugs. PMID- 22496065 TI - Endovascular recanalization for chronic symptomatic middle cerebral artery total occlusion. AB - The optimal treatment of chronic middle cerebral artery (MCA) occlusion is unclear. Angioplasty and stenting may be an alternative treatment for patients with recurrent ischemic symptoms despite medical therapy. Two patients with chronic right MCA occlusion successfully treated with stenting are reported, together with their long term follow-up to illustrate the feasibility of endovascular recanalization. One patient remained asymptomatic at the 29-month follow-up. Another patient developed symptomatic in-stent restenosis at 12 months which resolved after repeat angioplasty. Further larger scale pilot studies are needed to determine the efficacy and long term outcome of this treatment. PMID- 22496066 TI - Impact of integrated cerebrovascular program on outcomes in patients with intracranial aneurysms. AB - BACKGROUND: Recent evidence indicates that multidisciplinary care improves patient outcomes in cerebrovascular (CV) disease. A multidisciplinary integrated CV program was recently instituted at a high-volume tertiary referral center, providing the opportunity to evaluate patient outcomes before and after its introduction. OBJECTIVE: To evaluate outcomes after treatment of patients with intracranial aneurysm in relation to the introduction of a CV program at our institution. METHODOLOGY: A retrospective chart review was performed on all new patient encounters for a 6-month period each before and immediately after the introduction of the CV program, as well as at a more recent 6-month period to evaluate long-term results. Data were collected on demographic variables, rupture status, medical comorbidities, hospital complications, in-hospital procedures, hospital course and modified Rankin score at discharge and follow up. RESULTS: The total number of patients treated increased from 55 in the 6-month period before the introduction of the CV program to 112 in the most recent time period (p<0.05). Both the surgical clipping and endovascular coiling procedures increased (p<0.05). A significant increase occurred in patients with multiple comorbidities (30.5% vs 34.7%, p=0.035). The mean length of stay decreased from 12.22 +/- 13.26 days before the program to 9.23 +/- 12.04 days in the most current data (p<0.05). CONCLUSIONS: Creation of an integrated CV program at a large-volume tertiary referral center resulted in better outcomes for an increased number of more medically complicated patients with intracranial aneurysms. This study provides preliminary data for developing an integrated model of multidisciplinary care for the management of CV disease. PMID- 22496067 TI - Imaging of muscle injury in the elite athlete. AB - Injuries to muscle in the elite athlete are common and may be responsible for prolonged periods of loss of competitive activity. The implications for the athlete and his/her coach and team may be catastrophic if the injury occurs at a critical time in the athlete's diary. Imaging now plays a crucial role in diagnosis, prognostication and management of athletes with muscle injuries. This article discusses the methods available to clinicians and radiologists that are used to assess skeletal muscle injury. The spectrum of muscle injuries sustained in the elite athlete population is both discussed and illustrated. PMID- 22496068 TI - Revisiting the ultra-high dose rate effect: implications for charged particle radiotherapy using protons and light ions. AB - OBJECTIVE: To reinvestigate ultra-high dose rate radiation (UHDRR) radiobiology and consider potential implications for hadrontherapy. METHODS: A literature search of cellular UHDRR exposures was performed. Standard oxygen diffusion equations were used to estimate the time taken to replace UHDRR-related oxygen depletion. Dose rates from conventional and novel methods of hadrontherapy accelerators were considered, including spot scanning beam delivery, which intensifies dose rate. RESULTS: The literature findings were that, for X-ray and electron dose rates of around 10(9) Gy s(-1), 5-10 Gy depletes cellular oxygen, significantly changing the radiosensitivity of cells already in low oxygen tension (around 3 mmHg or 0.4 kPa). The time taken to reverse the oxygen depletion of such cells is estimated to be over 20-30 s at distances of over 100 MUm from a tumour blood vessel. In this time window, tumours have a higher hypoxic fraction (capable of reducing tumour control), so the next application of radiation within the same fraction should be at a time that exceeds these estimates in the case of scanned beams or with ultra-fast laser-generated particles. CONCLUSION: This study has potential implications for particle therapy, including laser-generated particles, where dose rate is greatly increased. Conventional accelerators probably do not achieve the critical UHDRR conditions. However, specific UHDRR oxygen depletion experiments using proton and ion beams are indicated. PMID- 22496069 TI - Emergency department imaging protocol for suspected acute renal colic: re evaluating our service. AB - OBJECTIVES: The objective of our study is to determine the positive rate for urolithiasis in male and female patients, and evaluate whether there has been any change at our institution in the use and outcome of unenhanced multidetector CT (CT KUB) performed in the emergency department (ER) for patients presenting with suspected acute renal colic. METHODS: A retrospective review of all 1357 consecutive cases between August 2007 and August 2009 admitted to the ER and investigated with CT KUB. RESULTS: The positive rate for urolithiasis was 47.5% and the rate of other significant findings was 10%. Female patients had a significantly lower positive rate than male patients (26.8% vs 61.6%, p<0.001). Urological intervention was required in 37% and these patients had a larger average stone size. In young female patients with a significantly sized ureteric calculus (>4 mm), the presence of hydronephrosis vs no hydronephrosis was 83% vs 17%, respectively. Among them, only three patients required ureteroscopy for stone removal. CONCLUSION: Contrary to other studies there has been no "indication creep" in the use of CT KUB at our institution. However, the young female patient presenting with suspected urolithiasis presents a particular diagnostic problem, and the significant percentage of negative examinations in females implies that an improvement in current practice is needed. The indiscriminate use of CT KUB in all female patients with flank pain should be avoided, and it is suggested that they should be initially evaluated with ultrasound to detect the presence of hydronephrosis. PMID- 22496070 TI - Perforated tumours in the gastrointestinal tract: CT findings and clinical implications. AB - Perforation usually requires emergency surgery and may affect the prognosis of patients with gastrointestinal tumours. Accurate pre-operative diagnosis of these conditions is important because proper management such as curative surgical treatment may be needed. The aims of this article are to illustrate CT appearances of perforated tumours of the gastrointestinal tract and to discuss their impact on clinical management. PMID- 22496071 TI - Radiological and clinical findings of 25 patients with invasive pulmonary aspergillosis: retrospective analysis of 2150 liver transplantation cases. AB - OBJECTIVE: The purpose of this study was to evaluate the radiological and clinical findings of invasive pulmonary aspergillosis (IPA) after liver transplantation. METHODS: This study included 25 consecutive liver transplant recipients with histologically confirmed IPA after liver transplantation. Radiological examinations performed for diagnosis were available in all patients. Clinical findings and changes in clinical response and radiological findings after treatment were also evaluated. RESULTS: 3 main radiological findings were identified: nodules, 64% (16/25); masses, 36% (9/25); and consolidations in a patchy pattern, 20% (5/25). A tree-in-bud pattern was found in 12% (3/25) of patients. In 8 (32%) of 25 patients, we found a combination of 2 or more of these signs: 5 (20%) patients presented with concurrent nodules accompanied by patchy consolidations and/or tree-in-bud, and 3 (12%) patients showed masses accompanied by large consolidations. A halo sign was observed in 20 (80%) of 25 patients. Hypodense sign and cavitary lesions were encountered in 17 (68%) of 25 patients. Follow-up radiological findings after treatment showed improvement in 18 patients, no change in 4 patients and progression in 3 patients. There were three aspergillosis-associated deaths during the follow-up period. The onset time of IPA was a median of 31 days after transplantation. The most common symptom at diagnosis was fever (n=15). None of the 25 patients had leukopaenia at the time of the diagnosis of IPA. CONCLUSIONS: The most common radiological findings of IPA after liver transplantation are multiple nodules with or without halo sign, masses and consolidations, which usually appear about 1 month after transplantation. PMID- 22496073 TI - Comments on the article entitled "review of possible modulation-dependent biological effects of radiofrequency fields" by Juutilainen et al. PMID- 22496072 TI - Watching tumours gasp and die with MRI: the promise of hyperpolarised 13C MR spectroscopic imaging. AB - A better understanding of tumour biology has led to the development of "targeted therapies", in which a drug is designed to disrupt a specific biochemical pathway important for tumour cell survival or proliferation. The introduction of these drugs into the clinic has shown that patients can vary widely in their responses. Molecular imaging is likely to play an increasingly important role in predicting and detecting these responses and thus in guiding treatment in individual patients: so-called "personalised medicine". The aim of this review is to discuss how hyperpolarised (13)C MR spectroscopic imaging might be used for treatment response monitoring. This technique, which increases the sensitivity of detection of injected (13)C-labelled molecules by >10,000-fold, has allowed a new approach to metabolic imaging. The basic principles of the technique and its potential advantages over other imaging methods for detecting early evidence of treatment response will be discussed. Given that the technique is poised to translate to the clinic, I will also speculate on its likely applications. PMID- 22496074 TI - Study of the interaction between sodium salts of (2E)-3-(4'-halophenyl)prop-2 enoyl sulfachloropyrazine and bovine serum albumin by fluorescence spectroscopy. AB - Three sodium salts of (2E)-3-(4'-halophenyl)prop-2-enoyl sulfachloropyrazine (CCSCP) were synthesized and their structures were determined by (1)H and (13)C NMR, LC-MS and IR. The binding properties between CCSCPs and bovine serum albumin (BSA) were studied using fluorescence spectroscopy in combination with UV-vis absorbance spectroscopy. The results indicate that the fluorescence quenching mechanisms between BSA and CCSCPs were static quenching at low concentrations of CCSCPs or combined quenching (static and dynamic) at higher CCSCP concentrations of 298, 303 and 308 K. The binding constants, binding sites and corresponding thermodynamic parameters (DeltaH, DeltaS, DeltaG) were calculated at different temperatures. All DeltaG values were negative, which revealed that the binding processes were spontaneous. Although all CCSCPs had negative DeltaH and positive DeltaS, the contributions of DeltaH and DeltaS to DeltaG values were different. When the 4'-substituent was fluorine or chlorine, van der Waals interactions and hydrogen bonds were the main interaction forces. However, when the halogen was bromine, ionic interaction and proton transfer controlled the overall energetics. The binding distances between CCSCPs and BSA were determined using the Forster non-radiation energy transfer theory and the effects of CCSCPs on the conformation of BSA were analyzed by synchronous fluorescence spectroscopy. PMID- 22496075 TI - Hyperbranched polylysine: a versatile, biodegradable transfection agent for the production of recombinant proteins by transient gene expression and the transfection of primary cells. AB - The feasibility of a new transfection agent, HBPL, for the production of recombinant IgG antibody via TGE as well as for the transfection of primary cells is studied. Under the conditions investigated, transfection of CHO-DG44 cells using HBPL results in IgG yields that are comparable to those obtained with PEI. In experiments with CHO-K1 cells and MEFs the use of HPBL allows to achieve transfection efficiencies comparable to or better than those obtained with PEI or Fugene(r). HBPL-mediated transfection does not require complex pre-formation, works well in serum-containing media and is biodegradable, which may prevent cumulative cytotoxicity and facilitates downstream processing. PMID- 22496077 TI - Antifungal activity in thrips soldiers suggests a dual role for this caste. AB - The social insect soldier is perhaps the most widely known caste, because it often exhibits spectacular weapons, such as highly enlarged jaws or reinforced appendages, which are used to defend the colony against enemies ranging in size from wasps to anteaters. We examined the function of the enlarged forelimbs of soldiers (both male and female) of the eusocial, gall-inhabiting insect Kladothrips intermedius, and discovered that they have little impact on their ability to repel the specialized invading thrips Koptothrips species. While the efficacy of the enlarged forelimb appears equivocal, we show that soldiers secrete strong antifungal compounds capable of controlling the specialized insect fungal pathogen, Cordyceps bassiana. Our data suggest that these thrips soldiers have evolved in response to selection by both macro- and micro-organisms. While it is unknown whether specialized fungal pathogens have been major selective agents in the evolution of the soldier caste in general, they were probably present when sociality first evolved and may have been the primordial enemies of social insects. PMID- 22496076 TI - Low dose ionizing radiation produces too few reactive oxygen species to directly affect antioxidant concentrations in cells. AB - It has been hypothesized that radiation-induced oxidative stress is the mechanism for a wide range of negative impacts on biota living in radioactively contaminated areas around Chernobyl. The present study tests this hypothesis mechanistically, for the first time, by modelling the impacts of radiolysis products within the cell resulting from radiations (low linear energy transfer beta and gamma), and dose rates appropriate to current contamination types and densities in the Chernobyl exclusion zone and at Fukushima. At 417 uGy h(-1) (illustrative of the most contaminated areas at Chernobyl), generation of radiolysis products did not significantly impact cellular concentrations of reactive oxygen species, or cellular redox potential. This study does not support the hypothesis that direct oxidizing stress is a mechanism for damage to organisms exposed to chronic radiation at dose rates typical of contaminated environments. PMID- 22496078 TI - Group size elicits specific physiological response in herbivores. AB - With increasing group size, individuals commonly spend less time standing head-up (scanning) and more time feeding. In small groups, a higher predation risk is likely to increase stress, which will be reflected by behavioural and endocrine responses. However, without any predator cues, we ask how the predation risk is actually processed by animals as group size decreases. We hypothesize that group size on its own acts as a stressor. We studied undisturbed groups of sheep under controlled pasture conditions, and measured in situ the cortisol and vigilance responses of identified individuals in groups ranging from 2 to 100 sheep. Both vigilance and average cortisol concentration decreased as group size increased. However, the cortisol response varied markedly among individuals in small groups, resulting in a lack of correlation between cortisol and vigilance responses. Further experiments are required to explore the mechanisms that underlie both the decay and the convergence of individual stress in larger groups, and whether these mechanisms promote adaptive anti-predator responses. PMID- 22496079 TI - Soil-mediated indirect impacts of an invasive predator on plant growth. AB - While several studies have shown that invasive plant effects on soil biota influence subsequent plant performance, corresponding studies on how invasive animals affect plants through influencing soil biota are lacking. This is despite the fact that invasive animals often indirectly alter the below-ground subsystem. We studied 18 offshore islands in northern New Zealand, half of which have been invaded by rats that are predators of seabirds and severely reduce their densities, and half of which remain non-invaded; invasion of rats thwarts seabird transfer of resources from ocean to land. We used soil from each island in a glasshouse experiment involving soil sterilization treatments to determine whether rat invasion indirectly influences plant growth through the abiotic pathway (by impairing seabird-driven inputs to soil) or the biotic pathway (by altering the soil community). Rat invasion greatly impaired plant growth but entirely through the abiotic pathway. Plant growth was unaffected by the soil community or its response to invasion, meaning that the responses of plants and soil biota to invasion are decoupled. Our results provide experimental evidence for the powerful indirect effects that predator-instigated cascades can exert on plant and ecosystem productivity, with implications for the restoration of island ecosystems by predator removal. PMID- 22496080 TI - Care for kin: within-group relatedness and allomaternal care are positively correlated and conserved throughout the mammalian phylogeny. AB - With an increasing amount of data becoming available, comparative analyses have called attention to the associations between cooperative breeding, monogamy and relatedness. We focus here upon the association between allomaternal care and relatedness among females within a social unit. Previous studies found a positive association, but such results date back to before molecular tools were in common use, they considered only a few mammalian orders, neglected phylogenetic clustering and/or did not correct for group sizes. Here, we use molecular data on relatedness from 44 species of mammals to investigate the phylogenetic clustering of, and the association between, allomaternal care and relatedness among females within a social unit. We find (i) a strong phylogenetic signal for allomaternal care and a moderate one for relatedness and group size, and (ii) a positive association between relatedness and allomaternal care, even when correcting for the smaller than average group sizes in species with allomaternal care. We also find that, in species without allomaternal care, adult females often live with unrelated females even when groups are small. We discuss these results in the light of recent evidence for the role of kin selection and the monogamy hypothesis in cooperative breeding. PMID- 22496081 TI - Transcatheter aortic valve implantation in patients with severe left ventricular dysfunction: immediate and mid-term results, a multicenter study. AB - BACKGROUND: Few data exist about transcatheter aortic valve implantation (TAVI) in patients with low ejection fraction. The aim of the study was to analyze safety, feasibility, and efficacy of TAVI in patients with severe left ventricular dysfunction. METHODS AND RESULTS: The study sample (384 patients) was divided into 2 groups: group A (50 patients) with left ventricular ejection fraction (LVEF) <=35%, and group B (334 patients) with LVEF >35%. Clinical, anatomic, and hemodynamic variables, as well as procedural results and follow-up outcomes, were compared between the groups. Procedural success was reached in 88%, with no significant difference between the groups. The incidence of periprosthetic leak >2+/4 after TAVI was higher in group A. All other complications were similar between the 2 groups. Group A showed a significant and early improvement in LVEF (from 27.7+/-6.0-35.2+/-11.1 after TAVI; P<0.0001). Thirty-day mortality was 4%; however, this was higher in group A compared with group B (10% versus 3%; P=0.010). Predictors of the cumulative late mortality were congestive heart failure, logistic euroSCORE, and moderate-to-severe periprosthetic leakage after TAVI. Estimated survival by Kaplan Meier at 1 year was, respectively, 69% in group A and 87% in group B (log rank <0.0001). CONCLUSIONS: Transcatheter aortic valve implantation is a safe and effective procedure, even in patients with severe left ventricular dysfunction, leading to a high procedural success rate with an acceptable rate of complications and 30 day mortality. Also in these critically ill patients, TAVI provides clinical amelioration, with early improvement in LVEF. PMID- 22496082 TI - Impact of completeness of revascularization on long-term cardiovascular outcomes in patients with type 2 diabetes mellitus: results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D). AB - BACKGROUND: Patients with diabetes have more extensive coronary disease than those without diabetes, resulting in more challenging percutaneous coronary intervention or surgical (coronary artery bypass graft) revascularization and more residual jeopardized myocardium. The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial provided an opportunity to examine the long-term clinical impact of completeness of revascularization in patients with diabetes. METHODS AND RESULTS: This is a post hoc, nonrandomized analysis of the completeness of revascularization in 751 patients who were randomly assigned to early revascularization, of whom 264 underwent coronary artery bypass graft surgery and 487 underwent percutaneous coronary intervention. The completeness of revascularization was determined by the residual postprocedure myocardial jeopardy index (RMJI). RMJI is a ratio of the number of myocardial territories supplied by a significantly diseased epicardial coronary artery or branch that was not successfully revascularized, divided by the total number of myocardial territories. Mean follow-up for mortality was 5.3 years. Complete revascularization (RMJI=0) was achieved in 37.9% of patients, mildly incomplete revascularization (RMJI >0<=33) in 46.6%, and moderately to severely incomplete revascularization (RMJI >33) in 15.4%. Adjusted event-free survival was higher in patients with more complete revascularization (hazard ratio, 1.14; P=0.0018). CONCLUSIONS: Patients with type 2 diabetes mellitus and less complete revascularization had more long-term cardiovascular events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305. PMID- 22496084 TI - Exenatide reduces final infarct size in patients with ST-segment-elevation myocardial infarction and short-duration of ischemia. AB - BACKGROUND: Exenatide has been demonstrated to be cardioprotective as an adjunct to primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction (STEMI). The aim of the post hoc analysis study was to evaluate the effect of exenatide in relation to system delay, defined as time from first medical contact to first balloon. METHODS AND RESULTS: Patients with STEMI and Thrombolysis In Myocardial Infarction flow 0/1 were randomly assigned to intravenous exenatide or placebo continuous infusion. Study treatment was commenced 15 minutes before intervention and maintained for 6 hours after the procedure. The patients were stratified according to median system delay (132 minutes). Final infarct size and myocardial area at risk were measured by cardiovascular magnetic resonance. Among patients with a system delay <=132 minutes (n=74), treatment with exenatide resulted in a smaller infarct size (9 grams [interquartile range (IQR), 4-13] versus 13 grams [IQR, 8-24], P=0.008, corresponding to 8% [IQR, 4-12] versus 11% [IQR, 7-17] of the left ventricle, P=0.015). In a regression analysis adjusting for myocardial area at risk the data points of the exenatide group lay significantly lower than for the placebo group (P=0.006). In the patients with system delay >132 minutes (n=74) no difference was observed in infarct size expressed as grams (P=0.49) or percentage (P=0.46). There was significant interaction between system delay (less than or equal to median versus greater than median) and treatment allocation in terms of infarct size (P=0.018). CONCLUSIONS: In this post hoc analysis, exenatide treatment was associated with a 30% decrease in final infarct size in patients with short system delay, whereas no cardioprotective effect in patients with long system delay was seen. However, this finding must be confirmed in larger studies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00835848. PMID- 22496083 TI - Impact of drug-eluting stents on distal vessels. AB - BACKGROUND: Previous studies have not addressed vessel response >5 mm distal to the stent edge. Therefore, we investigated the impact of paclitaxel-eluting stents (PES) versus bare metal stents (BMS) on distal vessels in the serial intravascular ultrasound substudies of TAXUS IV, V, and VI. METHODS AND RESULTS: TAXUS IV, V, and VI were double-blind, randomized, multicenter, controlled trials comparing PES with BMS. In their intravascular ultrasound substudies, 103 patients (54 BMS, 49 PES) had intravascular ultrasound data >=10 mm distal to the stent both postprocedure and at 9 months follow-up. Baseline characteristics were similar between the 2 groups. Multilevel modeling was used to account for the variation between patients and within patients among distal segments. Effect of stent type, time, and their interaction was tested using a mixed effect model controlling for distal segments. Postprocedure lumen and vessel were not significantly different between PES versus BMS; however, lumen (P=0.006) and vessel (P=0.0001) were significantly reduced for BMS at 9-month follow-up but not for PES. Conversely, there was a significant plaque increase from postprocedure to 9-month follow-up for PES (P=0.0008) but not for BMS. These vessel responses were statistically consistent among 0- to 5-mm versus 5- to 10-mm versus 10- to 15-mm segments distal to the stent in both groups. CONCLUSIONS: PES use was associated with plaque increase from baseline to 9-month follow-up >5 mm distal to the stent along with positive remodeling, whereas BMS use was associated with negative remodeling and no plaque increase. These vessel responses were consistent in 5-mm long subsegments: 0 to 5 mm versus 5 to 10 mm versus 10 to 15 mm distal to the stent. CLINICAL TRIAL REGISTRATION: URL: HTTP://WWW.CLINICALTRIAL.GOV. Unique identifiers: TAXUS IV: NCT00292474; TAXUS V: NCT00301522; TAXUS VI: NCT00297804. PMID- 22496085 TI - Effect of iron chelation on myocardial infarct size and oxidative stress in ST elevation-myocardial infarction. AB - BACKGROUND: Experimental studies suggest that deferoxamine (DFO) limits the generation of reactive oxygen species by chelating redox-active iron and thereby may reduce ischemia-reperfusion injury and myocardial infarct (MI) size. We investigated whether DFO administered before reperfusion by primary percutaneous coronary intervention (PPCI) would ameliorate oxidative stress and MI size. METHODS AND RESULTS: We randomly assigned 60 patients with ST-elevation-MI to receive an intravenous bolus of DFO (500 mg) immediately before PPCI followed by a 12-hour infusion (50 mg/kg of body weight) (n=28) or normal saline bolus and infusion (placebo group, n=32). MI size was measured by contrast-enhanced cardiac MRI (CMRI; day 3+/-1), creatine kinase and troponin I area-under-the-curve, and severity of wall motion abnormality on echocardiography. Clinical follow-up including repeat CMRI and echocardiography were performed at 3 months (100+/-17 days). Oxidative stress was assessed by plasma F(2)-isoprostane levels. DFO and placebo groups were well balanced with respect to baseline characteristics, symptom- and door-to-balloon times, pre-PPCI coronary patency, and infarct related artery location. Serum iron levels were decreased with DFO treatment after PPCI compared with placebo (3.0+/-2.5 versus 12.6+/-5.5 MUmol/L, P<0.0001), which persisted until the end of the infusion. In DFO-treated patients, there was a significant reduction in plasma F(2)-isoprostane levels immediately after PPCI (2878+/-1461 versus 2213+/-579 pmol/L, P=0.04). However, there was no difference in CMRI-determined infarct size (DFO, 17.4+/-10.8%, versus placebo, 18.6+/-10.2%; P=0.73), myocardial salvage index at 3 days or at 3 months, or the area-under-the curve for creatine kinase or troponin I. CONCLUSIONS: Adjunctive DFO treatment after the onset of ischemia and continued periprocedurally ameliorates oxidative stress without limiting infarct size. CLINICAL TRIAL REGISTRATION: URL: http://www.anzctr.org.au/. Unique identifier: ACTRN12608000308392. PMID- 22496086 TI - Delay in diagnosis of pulmonary thromboembolism in emergency department: is it still a problem? AB - BACKGROUND AND AIM: Pulmonary embolism (PE) is a common and serious disease that can result in death unless emergent diagnosis is made and treatment is initiated. In this study, we aimed to identify whether there is still a delay in the diagnosis of PE and to identify the time to delay in diagnosis and factors leading to this delay. METHODS: This is a prospective observational cohort study performed in an emergency department (ED) of a tertiary care university hospital between September 2008 and September 2010. The rate and cause of delay in diagnosis were analyzed among patients with PE. The "delay" was defined as diagnosing after first 24 hours of symptom onset. RESULTS: Among the 53 patients who were diagnosed with PE, a delay in diagnosis was present in 49 (93%) of them. Total delay time was 6.8 +/- 7.7 days. In 33 (62%) patients, there was a delay of 4.6 +/- 6.5 days due to patient-related factors. Delay in diagnosis after admission to hospital was 2.2 +/- 2.9 days in 40 (75%) patients. In multivariate regression analysis, being female and having chest pain and cough were identified as significant factors causing patient-related delay. Unilateral leg edema, recent operation, and previous venous thromboembolism (VTE) history were the significant factors causing PE diagnosis without a delay. On the other hand, systemic hypertension as comorbidity was the only factor leading to physician related delay. CONCLUSION: The delay in diagnosis of PE in EDs still remains as an important problem. While being female and having chest pain and cough are significantly and independently associated with patient delay in diagnosis, the unilateral leg edema, recent operation, and previous VTE history cause physicians to diagnose on time. On the other hand, having hypertension as comorbidity may lead to physician delay. In order to prevent the delay in diagnosis, hospital associated factors must be elucidated totally and more interventions must be made to increase public and professional awareness of the disease. PMID- 22496087 TI - Thrombolysis with recombinant tissue plasminogen activator in 7 children. AB - The information about the thromboembolic events, the optimal treatment choice, the dose, and duration of antithrombotic therapy in children are limited. More clinical data are required. Recombinant tissue plasminogen activator (r-tPA) is increasingly used in pediatric thrombosis. We retrospectively analyzed the clinical course of 7 children (9.3 +/- 2.1 years; 34 days to 16 years) with arterial thrombosis (n = 1) and intracardiac thrombosis (n = 6). The children were treated with r-tPA. The dose ranged between 0.2 and 0.4 mg/kg per h infused for 3 to 4 hours. This dose was repeated between 2 to 7 times till the thrombolysis was achieved. Treatment side effects were closely monitored. Complete clot lysis was achieved in all cases. None of them had severe bleeding except mild recurrent epistaxis occurring in 2 cases. In conclusion, r-tPA is an effective and safe therapy under close hemostatic control in children. PMID- 22496088 TI - Modulation of platelet activation in chronic kidney disease patients on erythropoiesis-stimulating agents. AB - BACKGROUND: Clinical trials demonstrate either no benefit or increased risk of cardiovascular events and mortality in patients with chronic kidney disease (CKD) targeted for higher hemoglobin levels, who are treated with erythropoiesis stimulating agents (ESAs). The mechanism underlying this observation remains unexplained. METHODS AND RESULTS: We assessed platelet activation by measuring soluble P-selectin (sPsel), CD40 ligand (CD40L), and circulating microparticles (CMP) in patients with CKD. Higher hemoglobin levels were associated with increased Psel levels in patients on ESAs but not in ESA-naive anemic and nonanemic patients. Psel positively correlated with CMP and CD40L in both anemic and nonanemic patients. Multivariate linear regression analysis revealed an association between increased Psel levels and hemoglobin concentration in patients receiving ESAs. CONCLUSIONS: Anemic CKD patients on ESAs demonstrate increased levels of markers of platelet activation. These observations suggest a potentially complex interplay between platelet activation, impaired kidney function, and treatment of CKD anemia with ESAs. PMID- 22496089 TI - Hypercoagulability in end-stage liver disease: prevalence and its correlation with severity of liver disease and portal vein thrombosis. AB - Contrary to well-recognized bleeding diathesis in chronic liver disease, thrombotic events can occur in these patients due to reduction or loss of synthesis of anticoagulant proteins. Forty-seven consecutive patients with end stage liver disease (ESLD) were investigated for activity of protein C, protein S, antithrombin, and factor V Leiden mutation. Forty-two (89.4%) patients had low levels of at least 1 while 33 (70.2%) patients were deficient for all anticoagulant proteins studied. Forty-six (97.9%) patients were negative for factor V Leiden mutation. The deficiencies were more marked in hepatitis C virus positive patients and patients with model for end-stage liver disease (MELD) score >15. Six (12.8%) patients had portal vein thrombosis (PVT), and all had diminished protein S activity. In conclusions, deficiency of anticoagulant proteins occur in early phase of chronic liver disease. The severity of deficiency is proportional to the severity of liver disease. Despite the high prevalence of hypercoagulability, the incidence of PVT is low. Further studies with larger cohort of patients are needed to support these conclusions and to study other associated factors. PMID- 22496090 TI - Efficacy of recombinant human soluble thrombomodulin in severe postpartum hemorrhage with disseminated intravascular coagulation. AB - OBJECTIVE: To investigate the efficacy of recombinant human soluble thrombomodulin (rTM) in disseminated intravascular coagulation (DIC) associated with severe postpartum hemorrhage (PPH). PATIENTS AND METHODS: We conducted a retrospective review of 36 patients with severe PPH complicated by DIC admitted to a single tertiary center. The first 26 patients were treated without rTM (control group), and the next 10 consecutive patients were treated with rTM. Clinical parameters including bleeding symptoms and coagulation indices were evaluated. RESULTS: Baseline characteristics, total blood loss, and transfusion requirements were similar between the 2 groups. On day 2, there was a significant difference between the 2 groups in the decrease in d-dimer level from baseline. The incidence of bleeding symptoms was decreased in the rTM group compared with the control group. No adverse events were observed in the rTM group. CONCLUSION: Recombinant human thrombomodulin may be an effective adjunctive therapy in the management of DIC related to PPH. PMID- 22496091 TI - Value of patient self-assessment in the diagnosis and monitoring of post thrombotic syndrome: the Patient-Tracked Symptoms questionnaire. AB - The post-thrombotic syndrome (PTS) is a frequent and burdensome disease, but no gold standard test exists to diagnose it. The value of patient-reported outcomes (PROs) in recording transient signs/symptoms, thereby possibly improving diagnosis/monitoring and subsequent clinical care in some diseases, is increasingly being recognized. For example, PROs have been successfully used in cancer, rheumatoid arthritis, and endometriosis. In this context, we describe a patient-reported questionnaire (the Patient-Tracked Symptoms questionnaire) that contains questions on the presence of signs/symptoms of PTS. This questionnaire has face validity and was successfully used in the Home-LITE trial. It could prove valuable in monitoring patient symptoms, especially in home-based patients who do not have regular contact with hospital clinicians. Patients who report symptoms can then undergo follow-up assessment by health care professionals at their next clinic visit. The Patient-Tracked Symptoms questionnaire could help clinicians to recognize the PTS early, enabling them to initiate treatment promptly. PMID- 22496092 TI - Fine tuning of vesicle assembly and properties using dual hydrophilic triblock copolypeptides. AB - The design, synthesis, and self-assembly of the first dual hydrophilic triblock copolypeptide vesicles, R(H)(m)E(n)L(o) and K(P)(m)R(H)(n)L(o), is reported. Variation of the two distinct hydrophilic domains is used to tune cellular interactions without disrupting the self-assembled structure. The aqueous self assemblies of these triblock copolypeptides in water are characterized using microscopy and DLS. Cell culture studies are used to evaluate cytotoxicity as well as intracellular uptake of the vesicles. The ability of polypeptides to incorporate ordered chain conformations that direct self-assembly, combined with the facile preparation of functional, multiblock copolypeptide sequences of defined lengths, allow the design of vesicles attractive for development as drug carriers. PMID- 22496093 TI - Effects of music on immunity and physiological responses in healthcare workers: a randomized controlled trial. AB - Research-based evidence supports the effectiveness of soothing music in improving stress-related psycho-physiological indices in a clinical setting. However, there is currently insufficient scientific knowledge of the effects of music on immune markers of stress in humans. Therefore, the aims of the study were to compare the effects of music and quiet rest on the levels of interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), heart rate and mean arterial pressure among healthcare workers. By using a randomized controlled trial design, 60 nurses were randomly assigned to the stimulating or sedating music or rest groups for 30 min. Participants' psychoneuroimmunological parameters were measured using enzyme-linked immunosorbent assays. General estimating equation was used to analyse data. Results revealed that IL-6, TNF alpha and IL-10 were not detectable in this population. No significance differences in heart rate were found among the three groups. However, the stimulating music group had significantly higher mean arterial pressure levels than the sedating music group but no differences between the quiet rest group and the sedating music group. Music with different tempi had little effect on mean arterial pressure. Any effect of music on immune markers of stress requires further research. PMID- 22496094 TI - Profiling of toxicity and identification of distinct apoptosis profiles using a 384-well high-throughput flow cytometry screening platform. AB - Methods and techniques used to detect apoptosis have benefited from advances in technologies such as flow cytometry. With a large arsenal of lasers, fluorescent labels, and readily accessible biological targets, it is possible to detect multiple targets with unique combinations of fluorescent spectral signatures from a single sample. Traditional flow cytometry has been limited as a screening tool as the sample throughput has been low, whereas the data analysis and generation of screening relevant results have been complex. The HTFC Screening System running ForeCyt software is an instrument platform designed to perform high throughput, multiplexed screening with seamless transformation of flow cytometry data into screening hits. We report the results of a screen that simultaneously quantified caspase 3/7 activation, annexin V binding, cell viability, and mitochondrial integrity. Assay performance over 5 days demonstrated robustness, reliability, and performance of the assay. This system is high throughput in that a 384-well plate can be read and fully analyzed within 30 min and is sensitive with an assay window of at least 10-fold for all parameters and a Z' factor of >=0.75 for all endpoints and time points. From a screen of 231 compounds, 11 representative toxicity profiles highlighting differential activation of apoptotic pathways were identified. PMID- 22496095 TI - Feasibility of implementing cell-based pathway reporter assays in early high throughput screening assay cascades for antibody drug discovery. AB - Implementing functional cell-based screens in early antibody discovery has become increasingly important to select antibodies with the desired profile. However, this is limited by assay tolerance to crude antibody preparations and assay sensitivity. The current study aims to address this challenge and identify routes forward. Two common types of high-throughput screening (HTS) antibody sample, derived from either phage display or hybridoma techniques, have been screened across a wide range of CellSensor beta-lactamase reporter assays in a variety of cell backgrounds to more extensively characterize assay tolerance. Pathway-, sample-, and cell background-specific effects were observed. Reporter assays for agonism were less affected by crude antibody preparations, with 8 of 21 sample tolerant, and the potential to implement an additional 8 assays by choosing the best-tolerated sample type. Antagonist mode assays exhibited more complexity, with potentiating as well as inhibitory effects. However, 5 of 24 antagonist assays were fully tolerant, with the potential to implement an additional 11 assays. Different subsets of assays were affected in agonist versus antagonist mode, and hybridoma sample sets were better tolerated overall. The study clearly demonstrates the potential to use cell-based reporter assays in biologics HTS, particularly if the method of antibody production is considered in the context of the required assay mode (agonist/antagonist). PMID- 22496097 TI - Development of a label-free assay for sodium-dependent phosphate transporter NaPi IIb. AB - The most widely used assay format for characterizing plasma membrane transporter activity measures accumulation of radiolabeled substrates in tissues or cells expressing the transporters. This assay format had limitations and disadvantages; therefore, there was an unmet need for development of a homogeneous, nonradioactive assay for membrane transporter proteins. In this report, the authors describe the development of a label-free homogeneous assay for the sodium dependent phosphate transporter NaPi-IIb using the Epic system. The addition of phosphate stimulated a dynamic mass redistribution (DMR) profile unique to cells expressing NaPi-IIb but not on parental cells. This DMR profile was phosphate specific because sulfate or buffer alone did not elicit the same response. Furthermore, the DMR response observed was phosphate and sodium dependent, with Km values in the micromolar and millimolar range, respectively. A known NaPi-IIb noncompetitive inhibitor was shown to completely inhibit the phosphate-stimulated DMR response, suggesting that this observed DMR response is an NaPi-IIb-mediated cellular event. The results demonstrate that a novel label-free assay was developed for studying transporter-mediated cellular activity, and this DMR assay platform could be applicable to other membrane transporter proteins. PMID- 22496096 TI - High-throughput screening for small-molecule inhibitors of plasmodium falciparum glucose-6-phosphate dehydrogenase 6-phosphogluconolactonase. AB - Plasmodium falciparum causes severe malaria infections in millions of people every year. The parasite is developing resistance to the most common antimalarial drugs, which creates an urgent need for new therapeutics. A promising and attractive target for antimalarial drug design is the bifunctional enzyme glucose 6-phosphate dehydrogenase-6-phosphogluconolactonase (PfGluPho) of P. falciparum, which catalyzes the key step in the parasites' pentose phosphate pathway. In this study, we describe the development of a high-throughput screening assay to identify small-molecule inhibitors of recombinant PfGluPho. The optimized assay was used to screen three small-molecule compound libraries-namely, LOPAC (Sigma Aldrich, 1280 compounds), Spectrum (MicroSource Discovery Systems, 1969 compounds), and DIVERSet (ChemBridge, 49 971 compounds). These pilot screens identified 899 compounds that inhibited PfGluPho activity by at least 50%. Selected compounds were further studied to determine IC(50) values in an orthogonal assay, the type of inhibition and reversibility, and effects on P. falciparum growth. Screening results and follow-up studies for selected PfGluPho inhibitors are presented. Our high-throughput screening assay may provide the basis to identify novel and urgently needed antimalarial drugs. PMID- 22496098 TI - Screening and characterization of human monoglyceride lipase active site inhibitors using orthogonal binding and functional assays. AB - Endocannabinoids such as 2-arachidonylglycerol (2-AG) are ligands for cannabinoid receptors that contribute to the transmission and modulation of pain signals. The antinociceptive effect of exogenous 2-AG suggests that inhibition of monoglyceride lipase (MGLL), the enzyme responsible for degrading 2-AG and arresting signaling, may be a target for pain modulation. Here we describe the characterization of MGLL ligands following a high-throughput screening campaign. Ligands were discovered using ThermoFluor, a label-free affinity-based screening tool that measures ligand binding via modulation of protein thermal stability. A kinetic fluorescent assay using the substrate 4-methylcoumarin butyrate was used to counterscreen confirmed HTS positives. A comparison of results from binding and inhibition assays allowed elucidation of compound mechanism of action. We demonstrate the limit of each technology and the benefits of using orthogonal assay techniques in profiling compounds. PMID- 22496099 TI - Evaluating bone marrow oedema patterns in musculoskeletal injury. AB - MRI is a common tool in the evaluation of musculoskeletal injury that allows the clinician to pinpoint specific pathologies. The patient's history and physical exam play a critical role in the diagnosis of sports injuries, however, complementary imaging can play an important role in determining the nature and extent of injury. With the widespread use of MRI, attention has focused on the signals generated following injury. In particular, bone marrow oedema (BME) patterns can be used to aid in the diagnosis of musculoskeletal injury. In this pictorial essay, the authors will demonstrate common patterns of BME that accompany a wide range of musculoskeletal injuries. It is expected that by the end of this article, the reader will be able to (1) recognise BME is a phenomenon observed on MRI following sports injury; (2) recognise typical patterns of BME; (3) understand the relationship of oedema to the type of injury and (4) in the presence of oedema, understand other co-existing injuries that ultimately may have an impact on management. PMID- 22496101 TI - The role of proton pump inhibitors in adenoid hypertrophy in children. AB - OBJECTIVES: To establish the efficacy of proton pump inhibitors (PPI) in the treatment of adenoid hypertrophy in children. DESIGN: Randomized controlled double-blinded clinical trial. POPULATION: Forty children, aged 2 to 12 years, with adenoid hypertrophy fulfilling the inclusion and exclusion criteria. METHODS: Patients were randomly allocated into 2 groups: one to be treated with oral Losec MUPS for a period of 2 months (treatment group) and the other to be given a low-dose vitamin C tablet for the same period (control group). The patients were reviewed on 2 occasions during the 2-month study period, during which endoscopy was performed to examine the adenoid glands to assess their size and the larynx to assess signs of reflux disease. Examination of tonsillar size was also performed. RESULTS: There was a significant reduction in adenoid size in the treatment group, but the control group also demonstrated a significant reduction in adenoid size. Comparison between the 2 groups in terms of adenoid grade change between the first and second visits did not reveal any significant statistical difference. CONCLUSION: The results of this study do not demonstrate any efficacy of PPIs for adenoid hypertrophy in children, and these drugs should not be used for this purpose. PMID- 22496100 TI - The influence of altruism on influenza vaccination decisions. AB - Game theory is based on the assumption that individuals act according to self interest and make decisions that maximize their personal payoffs. To test this fundamental assumption, we conducted a survey study in the context of influenza vaccination decisions. Contrary to the assumption of self-interest, we found that altruism plays an important role in vaccination decisions. Nevertheless, altruistic motivation has not yet been considered in epidemiological models, in predictions of vaccination decisions or in the design of vaccination policies. To determine the impact of altruism on the adherence to optimal vaccination policies and on resulting disease burden, we incorporated altruism into a game-theoretic epidemiological model of influenza vaccination. We found that altruism significantly shifted vaccination decisions away from individual self-interest and towards the community optimum, greatly reducing the total cost, morbidity and mortality for the community. Therefore, promoting altruism could be a potential strategy to improve public health outcomes. PMID- 22496102 TI - Middle ear myxoma. PMID- 22496103 TI - Surgical site infections after gracilis free flap reconstruction for facial paralysis. AB - Compared with other free tissue transfer procedures, the gracilis free muscle transfer (GFMT) for facial reanimation is unique in that the recipient site is typically uninvolved by malignancy or infection. In this study, the authors examined the incidence, bacteriology, and outcomes of surgical site infection (SSI) after gracilis free muscle transfer for facial reanimation. From 2003 to 2011, 105 patients underwent 107 GFMT operations, with 6 SSIs. All cases of infection occurred in patients receiving clindamycin, levofloxacin, and/or cefazolin perioperatively. None of the patients who received ampicillin-sulbactam developed an SSI. Surgical site cultures grew oral flora, including alpha hemolytic streptococci, Haemophilus parainfluenzae, Fusobacterium and Neisseria species, and coagulase-negative staphylococci. Notably, there were no methicillin resistant Staphylococcus aureus (MRSA) infections. These data may have implications for the optimal perioperative antibiotic choice in facial reanimation cases. Further study is needed to determine the ideal antibiotic regimen for this category of free flap surgeries. PMID- 22496104 TI - Inulin-based hydrogel for oral delivery of flutamide: preparation, characterization, and in vivo release studies. AB - The ability of a hydrogel obtained by crosslinking INUDV and PEGBa to facilitate sustained release of flutamide is examined. The hydrogel is prepared in pH = 7.4 PBS and no toxic solvents or catalysts are used. It is recovered in microparticulate form and its size distribution is determined. Mucoadhesive properties are evaluated in vitro by reproducing gastrointestinal conditions. Flutamide is loaded into the hydrogel using a post-fabrication encapsulation procedure that allows a drug loading comparable to that of market tablets. Drug loaded microparticles are orally administered to cross-bred dogs and the in vivo study demonstrates their ability to prolong the half-life of the principal active metabolite approximately threefold and to significantly increase its bioavailability. PMID- 22496105 TI - Effects of chewing gum on stress and health: a replication and investigation of dose-response. AB - Research suggests that chewing gum may be associated with reduced stress, depression and a reduced likelihood of having high cholesterol and blood pressure. The present study aimed to replicate these findings and extend them by examining dose-response. A web-based survey was completed by a sample of 388 workers from public sector organisations (68.5% female; mean age: 42 years, range 17-64 years). The results showed that chewing gum was associated in a linear dose response manner with lower levels of perceived stress (both at work and life in general), anxiety and depression. Occasional gum chewers also reported a reduced risk of high cholesterol and blood pressure. Intervention studies are now required to extend these findings, and the mechanisms underlying the effects reported here need further investigation. PMID- 22496107 TI - Managing ambiguity in reference generation: the role of surface structure. AB - This article explores the role of surface ambiguities in referring expressions, and how the risk of such ambiguities should be taken into account by an algorithm that generates referring expressions, if these expressions are to be optimally effective for a hearer. We focus on the ambiguities that arise when adjectives occur in coordinated structures. The central idea is to use statistical information about lexical co-occurrence to estimate which interpretation of a phrase is most likely for human readers, and to avoid generating phrases where misunderstandings are likely. Various aspects of the problem were explored in three experiments in which responses by human participants provided evidence about which reading was most likely for certain phrases, which phrases were deemed most suitable for particular referents, and the speed at which various phrases were read. We found a preference for ''clear'' expressions to ''unclear'' ones, but if several of the expressions are ''clear,'' then brief expressions are preferred over non-brief ones even though the brief ones are syntactically ambiguous and the non-brief ones are not; the notion of clarity was made precise using Kilgarriff's Word Sketches. We outline an implemented algorithm that generates noun phrases conforming to our hypotheses. PMID- 22496108 TI - Utility-based generation of referring expressions. AB - This paper presents two cognitive models that simulate the production of referring expressions in the iMAP task-a task-oriented dialog. One general model is based on Dale and Reiter's (1995)incremental algorithm, and the other is a simple template model that has a higher correlation with the data but is specifically geared toward the properties of the iMAP task. The property of the iMAP task environment that is modeled here is that the color feature is unreliable for identifying referents while other features are reliable. The low computational cost of the incremental algorithm for generating referring expressions makes it an interesting starting point for a cognitive model. However, its explanatory power is limited, because it generates uniquely distinguishing referring expressions and because it considers features for inclusion in the referring expression in a fixed order. The first model extends the original incremental algorithm by an ability to adapt to feedback of whether a referring expression was used successfully, but it seems to overpredict the frequency with which distinguishing expressions are made and underpredict the frequency of overspecified referring expressions. The second model produces features for referring expressions purely based on its current estimate of a feature's utility. Both models predict the observed human behavior of decreasing use of color terms and increasing use of useful feature terms. PMID- 22496109 TI - Endovascular correction of cerebrovenous anomalies in multiple sclerosis: a retrospective review of an uncontrolled case series. AB - Endovascular intervention for obstruction to venous drainage of the head and neck is an established treatment for disorders such as superior vena cava syndrome. Some patients with multiple sclerosis have been observed to have anomalies of the veins draining the head and neck. It is possible that some symptoms associated with multiple sclerosis may be secondary to disturbed venous flow. In an uncontrolled clinical series of 40 patients who had been previously diagnosed with multiple sclerosis, anomalies of the venous drainage of the head and neck were observed, including venous stenoses of the internal jugular veins. In 38 of 40 patients, venous stents were placed with restoration of luminal dimensions and abrogation of the venous pressure gradient. The angiographic and hemodynamic improvement was associated with improvement in symptomatology, most particularly in cognitive and constitutional symptoms that may be related to cerebrovenous flow. Serious complications included death in one subject and stent embolization requiring open heart surgery in another. In conclusion, in this series, endovascular intervention to correct venous stenosis associated with multiple sclerosis was associated with improvement in symptoms possibly related to disturbed venous hemodynamics. However, given the serious adverse events in this small series, a randomized clinical trial is required to confirm these findings, and to determine if the procedure has any effect on the progression of multiple sclerosis, or untoward long-term adverse effects. PMID- 22496110 TI - Images in vascular medicine. Cystic adventitial disease of the popliteal artery. PMID- 22496111 TI - Long-term ECMO treatment in Jehovah's Witness patient without transfusions. AB - A previously healthy 60-year-old male presented with fever, general pain and a C reactive protein (CRP) of 160 mg/L. He was prescribed doxycycline. In the emergency room three days later, he was intubated and had a saturation of 70% on 100% oxygen. The chest X-ray showed bilateral lobar pneumonia. Streptococcus pneumonia was later verified. As a Jehovah's Witness, he had refused blood transfusions, but accepted albumin. Two days after admission, veno-venous extracorporeal membrane oxygenation (V-V ECMO) was started and the patient was then transported on ECMO to Stockholm. After two days, echocardiography showed right cardiac failure and the patient had to be converted to veno-arterial ECMO (VV-A ECMO) by cannulation of the left femoral artery. The haemoglobin decreased from 10.0 to 6.0 g/dL. Iron, folic acid, and erythropoietin were administered to stimulate erythropoesis. Romiplostim, to stimulate the production of platelets, was also started immediately. Blood samples were reduced to a minimum. The ECMO circuit was changed twice, using saline for priming, and the blood in the old circuit was then given back to the patient. The haemoglobin concentration varied between 4.5 and 6.0 g/dL during the ECMO treatment and the platelets between 80 and 140 x10(9)/L. After 44 days on ECMO, the patient was weaned off ECMO with 50% oxygen and nitric oxide (NO) at 20ppm in the ventilator. Four days after decannulation, he was transferred to a nearby intensive care unit. Long-term ECMO treatment without transfusion of blood products is possible. Being a Jehovah's Witness should not automatically be a contraindication for ECMO. PMID- 22496112 TI - Selecting for predisposition to cancer cachexia. PMID- 22496113 TI - Patient satisfaction at America's lowest performing hospitals. AB - BACKGROUND: Previous studies have identified hospitals with poor performance on cardiac process measures. How these hospitals fare in other domains, such as patient satisfaction, remains unknown. METHODS AND RESULTS: We used Hospital Compare data to identify hospitals reporting acute myocardial infarction (AMI) and heart failure (HF) process measures during 2006 to 2008, and calculated respective composite performance scores. Using these scores, we classified hospitals as low-performing (bottom decile for all 3 years), top-performing (top decile for all 3 years), and intermediate (all others). We used Hospital Consumer Assessment of Healthcare Providers and Systems 2008 data to compare overall satisfaction between low, intermediate, and top-performing hospitals. Low performing hospitals had fewer beds, fewer nurses per patient, and were more likely rural, safety-net hospitals located in the South, compared with intermediate and top-performing hospitals (P<0.01 for all). After adjusting for hospital characteristics, patients were less likely to recommend low-performing hospitals to family or friends, relative to intermediate and top-performing hospitals (AMI: 58.8% versus 63.9% versus 68.8%, HF: 61.3% versus 64.0% versus 66.8%; P<0.001 for all), or provide an overall rating of >= 9 out of 10 (AMI: 56.7% versus 60.7% versus 64.9%, HF: 57.8% versus 61.1% versus 63.6%; P<0.01 for all). Despite the association between the hospital's performance on process measures and patient satisfaction, we noted discordance between these measures (kappa statistic <0.20). CONCLUSIONS: Hospitals with consistently poor performance on cardiac process measures also have lower patient satisfaction on average, suggesting that these hospitals have overall poor quality of care. However, there is discordance between the 2 measures in profiling hospital quality. PMID- 22496114 TI - Do differences in repeat revascularization explain the antianginal benefits of bypass surgery versus percutaneous coronary intervention?: implications for future treatment comparisons. AB - BACKGROUND: Patients with multivessel coronary disease treated with coronary artery bypass graft (CABG) have less angina than those treated with percutaneous coronary intervention (PCI); however, there is uncertainty as to the mechanism of greater angina relief with CABG and whether more frequent repeat revascularization in patients treated with PCI could account for this treatment difference. METHODS AND RESULTS: In the Synergy between percutaneous coronary intervention (PCI) with TAXUS and Cardiac Surgery trial, 1800 patients with 3 vessel or left main coronary artery disease were randomized to CABG or PCI with paclitaxel-eluting stents. Health status was assessed at baseline, 1, 6, and 12 months, using the Seattle Angina Questionnaire and the Medical Outcomes Study Short Form General Health Survey, and the association between repeat revascularization and health status during follow-up was assessed using longitudinal models. In adjusted analyses, patients who underwent repeat revascularization had worse angina frequency scores than patients who did not in both treatment groups, with differences of 8.5 points at 6 months and 3.1 points at 12 months in patients treated with PCI and 19.8 points at 6 months and 11.2 points at 12 months in patients with patients treated with CABG. Among patients who did not require repeat revascularization, the adjusted effect of CABG versus PCI on 12-month angina frequency scores was nearly identical to the overall benefit in the intention-to-treat analysis. CONCLUSIONS: Among patients with multivessel coronary artery disease treated with PCI or CABG, the occurrence of repeat revascularization during follow-up did not fully explain the antianginal benefit of CABG in the overall population. The differential association between repeat revascularization and anginal status, according to the type of initial revascularization procedure, suggests that this end point should play a limited role in any direct comparison of the 2 treatment strategies. PMID- 22496115 TI - Radial artery versus femoral artery access options in coronary angiogram procedures: randomized controlled trial of a patient-decision aid. AB - BACKGROUND: Vascular access options in coronary angiography can be considered a preference-sensitive decision, where the benefits/risks have different levels of significance, depending on the individual patient. For preference-sensitive healthcare options, patient decision aids (PtDA) significantly improve the process of decision-making. The purpose of this trial was to evaluate the effectiveness of an evidence-based PtDA compared with usual care in patients eligible for radial and femoral artery access. METHODS AND RESULTS: We conducted a single-center, nonblinded, randomized controlled trial with patients eligible for both femoral and radial access as per their treating physician. The PtDA was designed to guide patients to make an informed choice, consistent with their preferences and values. The primary outcome, decisional conflict, was assessed using the validated decisional conflict scale. One hundred fifty patients were randomized (vascular access PtDA=76 versus usual care=74). The intervention group had a significantly reduced decisional conflict scale compared with control (unadjusted 14.8 versus 19.5, P=0.04) and were significantly more knowledgeable regarding risks/benefits associated with each vascular access (mean knowledge score 3/5 (95% confidence interval, 2.6 to 3.3) versus 2/5 (95% confidence interval, 1.7 to 2.3, P<0.01). PtDA patients had better informed value congruence with their vascular access received (47.3% versus 25.7%, P<0.01). There were no significant differences in procedural success or safety between the 2 groups. CONCLUSIONS: A vascular access PtDA for eligible patients undergoing coronary angiogram procedures reduces decisional conflict and improves value congruence and the patients' knowledge of their healthcare options; however, a multicenter study, powered to confirm these benefits and evaluate differences in procedural success or complications, is required. PMID- 22496118 TI - Decreased quality of life in children with hypothalamic hamartoma and treatment resistant epilepsy. AB - We evaluated health-related quality of life in patients with hypothalamic hamartoma, to see how it differs from that of children with more common neurologic disorders. We used the PedsQL 4.0, along with the Child Behavior Checklist, Hague Seizure Severity Scale, and Side Effects Scale, to evaluate presurgical patients with hypothalamic hamartoma and epilepsy (n = 21). The results were compared with those of age-matched cohorts with migraine (n = 19) and Benign Epilepsy with Central Temporal Spikes (n = 11). In comparison with the migraine group, the patients with hypothalamic hamartoma had decreased health related quality of life across all domains of the PedsQL 4.0. Compared with the benign epilepsy group, the hypothalamic hamartoma cohort has a significantly lower score in School Function. Comorbid psychomotor retardation was predictive of lower quality of life. Research examining the efficacy of recently developed surgical treatments for hypothalamic hamartoma should include health-related quality of life as an outcome measure. PMID- 22496116 TI - The chest pain choice decision aid: a randomized trial. AB - BACKGROUND: Cardiac stress testing in patients at low risk for acute coronary syndrome is associated with increased false-positive test results, unnecessary downstream procedures, and increased cost. We judged it unlikely that patient preferences were driving the decision to obtain stress testing. METHODS AND RESULTS: The Chest Pain Choice trial was a prospective randomized evaluation involving 204 patients who were randomized to a decision aid or usual care and were followed for 30 days. The decision aid included a 100-person pictograph depicting the pretest probability of acute coronary syndrome and available management options (observation unit admission and stress testing or 24-72 hours outpatient follow-up). The primary outcome was patient knowledge measured by an immediate postvisit survey. Additional outcomes included patient engagement in decision making and the proportion of patients who decided to undergo observation unit admission and cardiac stress testing. Compared with usual care patients (n=103), decision aid patients (n=101) had significantly greater knowledge (3.6 versus 3.0 questions correct; mean difference, 0.67; 95% CI, 0.34-1.0), were more engaged in decision making as indicated by higher OPTION (observing patient involvement) scores (26.6 versus 7.0; mean difference, 19.6; 95% CI, 1.6-21.6), and decided less frequently to be admitted to the observation unit for stress testing (58% versus 77%; absolute difference, 19%; 95% CI, 6%-31%). There were no major adverse cardiac events after discharge in either group. CONCLUSIONS: Use of a decision aid in patients with chest pain increased knowledge and engagement in decision making and decreased the rate of observation unit admission for stress testing. PMID- 22496119 TI - Attention skills in children with neurofibromatosis type 1. AB - Children with neurofibromatosis type 1 are at increased risk for the development of attention problems relative to their unaffected peers. Previous studies have reported deficits in sustained auditory attention, but other aspects of attention, including sustained visual attention, divided attention, response inhibition, and selective attention, have not been consistently documented. In the present study, we specifically investigated attention skills in children with neurofibromatosis type 1 using measures of visual and sustained auditory attention, divided attention, selective attention, and response inhibition. Consistent with previous reports, we confirmed the presence of deficits in sustained visual and auditory attention in children with neurofibromatosis type 1 but also identified deficits in divided attention and response inhibition. Based on the high frequency and wide spectrum of attention system impairments in this at-risk population, we advocate screening children with neurofibromatosis type 1 for attention problems and providing appropriate interventions that address all aspects of their executive functioning. PMID- 22496117 TI - Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak-independent death of cancer cells. AB - Overcoming the resistance of tumours to chemotherapy, often due to downregulation of Bax and Bak, represents a significant clinical challenge. It is therefore important to identify novel apoptosis inducers that bypass Bax and Bak. Potassium channels are emerging as oncological targets and a crucial role of mitochondrial Kv1.3 in apoptosis has been demonstrated. Here we report for the first time that Psora-4, PAP-1 and clofazimine, three distinct membrane-permeant inhibitors of Kv1.3, induce death by directly targeting the mitochondrial channel in multiple human and mouse cancer cell lines. Importantly, these drugs activated the intrinsic apoptotic pathway also in the absence of Bax and Bak, a result in agreement with the current mechanistic model for mitochondrial Kv1.3 action. Genetic deficiency or short interfering RNA (siRNA)-mediated downregulation of Kv1.3 abrogated the effects of the drugs. Intraperitoneal injection of clofazimine reduced tumour size by 90% in an orthotopic melanoma B16F10 mouse model in vivo, while no adverse effects were observed in several healthy tissues. The study indicates that inhibition of mitochondrial Kv1.3 might be a novel therapeutic option for the induction of cancer cell death independent of Bax and Bak. PMID- 22496120 TI - Cochlear implantation for children: opening doors to opportunity. AB - Cochlear implantation has altered the life-course of thousands of children who have significant hearing loss. Since the United States Food and Drug Administration approved multichannel cochlear implants for children in 1989, growing numbers of parents are choosing this option for their offspring and seeking opportunities to integrate them into the hearing world of our society. When paired with appropriate habilitation, cochlear implantation removes barriers for children who are deaf. This technology affords them the ability to circumvent the effects of deafness and participate academically, socially, culturally, and vocationally with their hearing family and peers. PMID- 22496121 TI - Inferring the emotions of friends versus strangers: the role of culture and self construal. AB - Three studies examined cross-cultural differences in empathic accuracy (the ability to correctly infer another's emotional experience) within the context of different relationships. East-West cultural differences in self-construal were hypothesized to differentiate levels of empathic accuracy across relationship types. In contrast to the independent self prevalent among members of Western cultures, members of Eastern cultures generally view the self as interdependent with those with whom they have a relationship. Easterners, relative to Westerners, are more concerned with the thoughts or feelings of close others and less concerned with the thoughts or feelings of those with whom they have no relational link (i.e., strangers). Across three studies, the authors found that East Asians, compared with European Americans, made more accurate inferences regarding the emotions of close others (i.e., friends), but less accurate inferences regarding the emotions of strangers. Furthermore, individual differences in interdependent self-construal among East Asians predicted the degree of empathic accuracy. PMID- 22496123 TI - Defining predictors of cleft lip and palate risk. AB - Individuals with clefts present considerably more dental anomalies than individuals without clefts. We also have shown that these individuals report cancer in their families more often than do unaffected individuals. We investigated how these conditions correlated with genetic variants associated with clefts to ascertain if specific molecular signatures exist that could help identify individuals at risk for having offspring with these defects. We examined 573 individuals, 158 with clefts, 254 unaffected family members, and 161 non related controls. Several clinical features, such as laterality, the presence of dental anomalies, medical history, and pregnancy history, were used to assess each individual's cleft status. Then, we performed molecular studies with genes that have been independently associated with oral clefts. We analyzed two datasets: nuclear families and case-control individuals where the case was the child from the family and controls were unrelated non-clefted individuals. In the family data, we confirmed association between clefts and rs987525 on chromosome 8 (p = 0.007) and found an association with rs987525 and tooth agenesis (p = 0.0003). In the case-control data, clefts, supernumerary teeth and familial cancer history were associated with ABCA4-rs481931 on chromosome 1 (p = 2E-19, 0.0007, 2E-06, respectively), and clefts and microdontia were associated with rs1325474 on chromosome 6 (p = 1E-06, 0.0002, respectively). PMID- 22496124 TI - Spontaneous tibioperoneal trunk and anterior tibial artery pseudoaneurysms. AB - Aneurysms of the tibioperoneal trunk and anterior tibial artery are extremely rare. There are only a few case reports of this entity, for which the majority are secondary to prior trauma or bacteremia and endocarditis. We describe a case of spontaneous pseudoaneurysms of the right anterior tibial artery and tibioperoneal trunk. The pseudoaneurysms were thrombosed on follow-up computed tomography angiography and the patient has been asymptomatic. The patient is being treated conservatively and remains asymptomatic at 1 year of follow-up. PMID- 22496125 TI - Femoral artery percutaneous revascularization for patients with critical limb ischemia: outcomes compared to patients with claudication over 2.5 years. AB - Patients with critical limb ischemia have higher rates of death and amputation after revascularization compared to patients with intermittent claudication. However, the differences in patency after percutaneous revascularization of the superficial femoral artery are uncertain and impact the long-term risk of amputation and function in critical limb ischemia. We identified 171 limbs from 136 consecutive patients who had angioplasty and/or stenting for superficial femoral artery stenoses or occlusions from July 2003 through June 2007. Patients were followed for primary and secondary patency, death and amputation up to 2.5 years, and 111 claudicants were retrospectively compared to the 25 patients with critical limb ischemia. Successful percutaneous revascularization occurred in 128 of 142 limbs (90%) with claudication versus 25 of 29 limbs (86%) with critical limb ischemia (p = 0.51). Overall secondary patency at 2.5 years was 91% for claudication and 88% for critical limb ischemia. In Cox proportional hazards models, percutaneous revascularization for critical limb ischemia had similar long-term primary patency (adjusted hazard ratio = 1.1, 95% CI = 0.4, 2.6; p = 0.89) and secondary patency (adjusted hazard ratio = 1.1, 95% CI = 0.2, 6.0; p = 0.95) to revascularization for claudication. Patients with critical limb ischemia had higher mortality and death rates compared to claudicants, with prior statin use associated with less death (p = 0.034) and amputation (p = 0.010), and prior clopidogrel use associated with less amputation (p = 0.034). In conclusion, percutaneous superficial femoral artery revascularization is associated with similar long-term durability in both groups. Intensive treatment of atherosclerosis risk factors and surveillance for restenosis likely contribute to improving the long-term outcomes of both manifestations of peripheral artery disease. PMID- 22496122 TI - Endothelial cell palmitoylproteomic identifies novel lipid-modified targets and potential substrates for protein acyl transferases. AB - RATIONALE: Protein S-palmitoylation is the posttranslational attachment of a saturated 16-carbon palmitic acid to a cysteine side chain via a thioester bond. Palmitoylation can affect protein localization, trafficking, stability, and function. The extent and roles of palmitoylation in endothelial cell (EC) biology is not well-understood, partly because of technological limits on palmitoylprotein detection. OBJECTIVE: To develop a method using acyl-biotinyl exchange technology coupled with mass spectrometry to globally isolate and identify palmitoylproteins in ECs. METHODS AND RESULTS: More than 150 putative palmitoyl proteins were identified in ECs using acyl-biotinyl exchange and mass spectrometry. Among the novel palmitoylproteins identified is superoxide dismutase-1, an intensively studied enzyme that protects all cells from oxidative damage. Mutation of cysteine-6 prevents palmitoylation, leads to reduction in superoxide dismutase-1 activity in vivo and in vitro, and inhibits nuclear localization, thereby supporting a functional role for superoxide dismutase-1 palmitoylation. Moreover, we used acyl-biotinyl exchange to search for substrates of particular protein acyl transferases in ECs. We found that palmitoylation of the cell adhesion protein platelet endothelial cell adhesion molecule-1 is dependent on the protein acyl transferase ZDHHC21. We show that knockdown of ZDHHC21 leads to reduced levels of platelet endothelial cell adhesion molecule-1 at the cell surface. CONCLUSIONS: Our data demonstrate the utility of EC palmitoylproteomics to reveal new insights into the role of this important posttranslational lipid modification in EC biology. PMID- 22496127 TI - PDGF-simvastatin delivery stimulates osteogenesis in heat-induced osteonecrosis. AB - Heat generated during implant osteotomy might lead to osteonecrosis and delayed bone repair, thus resulting in impaired early osseointegration and fixation of bone-anchoring devices. In this study, we proposed to overcome heat-induced injury to bone by fabricating core-shell polymeric biodegradable microspheres encapsulating a mitogenic factor, platelet-derived growth factor (PDGF), and a differentiation factor, simvastatin, in a simultaneous or sequential release profile. Microspheres encapsulating bovine serum albumin (BSA), PDGF, simvastatin, PDGF-in-core with simvastatin-in-shell, and simvastatin-in-core with PDGF-in-shell were delivered to fill standardized osteotomy sites on edentulous ridges of rat maxillae under irrigated or non-irrigated conditions. In the absence of irrigation, significant reduction of cell viability and increase in inflammation and sequestrum formation without evidence of osteogenesis were observed. Both PDGF and simvastatin deliveries facilitated cell viability and reduced osteonecrosis. Localized osteogenesis was seen under simvastatin treatment, while generalized but primitive osteogenesis was noted in PDGF-treated osteotomy sites. In addition, sequential PDGF-simvastatin delivery further augmented osteogenesis and promoted bone maturation. The results suggested that sequential PDGF-simvastatin delivery was an effective modality to prevent heat induced complications and facilitate bone apposition after implant osteotomy, potentially favoring the early fixation of bone-anchoring devices and oral implant osseointegration. PMID- 22496126 TI - Targets and delivery methods for therapeutic angiogenesis in peripheral artery disease. AB - Therapeutic angiogenesis utilizing genetic and cellular modalities in the treatment of arterial obstructive diseases continues to evolve. This is, in part, because the mechanism of vasculogenesis, angiogenesis, and arteriogenesis (the three processes by which the body responds to obstruction of large conduit arteries) is a complex process that is still under investigation. To date, the majority of human trials utilizing molecular, genetic, and cellular modalities for therapeutic angiogenesis in the treatment of peripheral artery disease (PAD) have not shown efficacy. Consequently, the current available knowledge is yet to be translated into novel therapeutic approaches for the treatment of PAD. The aim of this review is to discuss relevant scientific and clinical advances in therapeutic angiogenesis and their potential application in the treatment of ischemic diseases of the peripheral arteries. Additionally, this review article discusses past and recent developments, such as some unconventional approaches that have the potential to be applied as therapeutic targets. The article also includes advances in the delivery of genetic, cellular, and bioactive endothelial growth factors. PMID- 22496129 TI - Dissecting the role of g-protein-coupled receptor kinase 2 for excitation contraction coupling. PMID- 22496128 TI - Cardiac G-protein-coupled receptor kinase 2 ablation induces a novel Ca2+ handling phenotype resistant to adverse alterations and remodeling after myocardial infarction. AB - BACKGROUND: G-protein-coupled receptor kinase 2 (GRK2) is a primary regulator of beta-adrenergic signaling in the heart. G-protein-coupled receptor kinase 2 ablation impedes heart failure development, but elucidation of the cellular mechanisms has not been achieved, and such elucidation is the aim of this study. METHODS AND RESULTS: Myocyte contractility, Ca(2+) handling and excitation contraction coupling were studied in isolated cardiomyocytes from wild-type and GRK2 knockout (GRK2KO) mice without (sham) or with myocardial infarction (MI). In cardiac myocytes isolated from unstressed wild-type and GRK2KO hearts, myocyte contractions and Ca(2+) transients were similar, but GRK2KO myocytes had lower sarcoplasmic reticulum (SR) Ca(2+) content because of increased sodium-Ca(2+) exchanger activity and inhibited SR Ca(2+) ATPase by local protein kinase A mediated activation of phosphodiesterase 4 resulting in hypophosphorylated phospholamban. This Ca(2+) handling phenotype is explained by a higher fractional SR Ca(2+) release induced by increased L-type Ca(2+) channel currents. After beta adrenergic stimulation, GRK2KO myocytes revealed significant increases in contractility and Ca(2+) transients, which were not mediated through cardiac L type Ca(2+) channels but through an increased SR Ca(2+). Interestingly, post-MI GRK2KO mice showed better cardiac function than post-MI control mice, which is explained by an improved Ca(2+) handling phenotype. The SR Ca(2+) content was better maintained in post-MI GRK2KO myocytes than in post-MI control myocytes because of better-maintained L-type Ca(2+) channel current density and no increase in sodium-Ca(2+) exchanger in GRK2KO myocytes. An L-type Ca(2+) channel blocker, verapamil, reversed some beneficial effects of GRK2KO. CONCLUSIONS: These data argue for novel differential regulation of L-type Ca(2+) channel currents and SR load by GRK2. G-protein-coupled receptor kinase 2 ablation represents a novel beneficial Ca(2+) handling phenotype resisting adverse remodeling after MI. PMID- 22496130 TI - Magnetic resonance imaging with 3-dimensional analysis of left ventricular remodeling in isolated mitral regurgitation: implications beyond dimensions. AB - BACKGROUND: Although surgery is indicated in patients with mitral regurgitation (MR) when left ventricular (LV) end-systolic (LVES) dimension is >40 mm, LV ejection fraction may decrease after mitral valve surgery. We hypothesize that significant LV remodeling before surgery is not reflected by standard echocardiographic parameters measured at the base of the heart. METHODS AND RESULTS: Ninety-four patients (age, 54 +/- 11 years; 38% female) with degenerative isolated MR underwent cine magnetic resonance imaging with tissue tagging and 3-dimensional analysis. In 51 control subjects (age, 44 +/- 14 years; 53% female), the relation between LVES volume (LVESV) and LVES dimension was quadratic, whereas in 94 MR patients, this relation was cubic, indicating a greater increase in LVESV per LVES dimension among MR patients. Moreover, magnetic resonance imaging LVESV from summated serial short-axis slices was significantly greater than LVESV assessed with the Bullet formula in MR patients, attributed to a more spherical remodeling distal to the tips of the papillary muscles (P<0.001). Thirty-five patients underwent mitral valve repair per current guideline recommendations. LV ejection fraction decreased from 61 +/- 7% to 54 +/ 8% (P<0.0001) and maximum shortening decreased significantly below normal at 1 year postoperatively (P<0.0001). Despite normalization of LV stroke volume and LV end-diastolic volume/mass ratio, there was a persistent significant increase in distal LVES 3-dimensional radius/wall thickness ratio and LVESV index after surgery. CONCLUSIONS: Despite apparently preserved LVES dimension, MR patients demonstrate significant spherical mid to apical LVES remodeling that contributes to higher LVESV than predicted by standard geometry-based calculations. Decreased LV strain after surgery suggests that a volumetric analysis of LV remodeling and function may be preferred to evaluate disease progression in isolated MR. PMID- 22496131 TI - Evidence shows that epidural steroid is effective in sciatica. PMID- 22496132 TI - Editorial on treating sciatica was fundamentally flawed. PMID- 22496133 TI - Algorithm for investigating focal liver lesions doesn't apply to patients at high risk of hepatocellular carcinoma. PMID- 22496134 TI - Biopsy is not appropriate for incidentally detected liver lesions. PMID- 22496137 TI - Ice in the mouth for epistaxis. PMID- 22496138 TI - Opportunity to discuss voluntary family planning was missed in spotlight on climate change. PMID- 22496139 TI - Wake up and smell the coffee. PMID- 22496140 TI - Identify hearing impairment and take action. PMID- 22496141 TI - Don't let misinformation derail the trachoma elimination programme. PMID- 22496142 TI - Invest now in adaptive strategies to cope with weather instability. PMID- 22496144 TI - Risk register should have been published to inform public debate on a national institution, rights tribunal says. PMID- 22496145 TI - Herbal medicine might be responsible for high incidence of urinary tract cancer. PMID- 22496146 TI - Wellcome Trust backs campaign for open access to research. PMID- 22496147 TI - Bromide-associated lower airway disease: a retrospective study of seven cats. AB - Seven cats were presented for mild-to-moderate cough and/or dyspnoea after starting bromide (Br) therapy for neurological diseases. The thoracic auscultation was abnormal in three cats showing increased respiratory sounds and wheezes. Haematology revealed mild eosinophilia in one cat. The thoracic radiographs showed bronchial patterns with peribronchial cuffing in most of them. Bronchoalveolar lavage performed in two cats revealed neutrophilic and eosinophilic inflammation. Histopathology conducted in one cat showed endogenous lipid pneumonia (EnLP). All cats improved with steroid therapy after Br discontinuation. Five cats were completely weaned off steroids, with no recurrence of clinical signs. In one cat, the treatment was discontinued despite persistent clinical signs. The cat presenting with EnLP developed secondary pneumothorax and did not recover. Br-associated lower airway disease can appear in cats after months of treatment and clinical improvement occurs only after discontinuing Br therapy. PMID- 22496148 TI - Treatment-related toxicities in tumor-bearing cats treated with temozolomide alone or in combination with doxorubicin: a pilot assessment. AB - A retrospective study assessing treatment-related toxicities in tumor-bearing cats treated with temozolomide (TMZ) alone or in combination with doxorubicin was conducted. TMZ was administered orally once a day for 5 days every 3 weeks at a dose of 20 mg/cat. Tumor response was evaluated with standard World Health Organization criteria and toxicity was monitored using veterinary co-operative oncology group-common terminology criteria for adverse events (VCOG--CTCAE) criteria. Ten tumor-bearing cats with various types of malignancies were treated with TMZ-based chemotherapy. Eight cats were evaluable for response. Two cats achieved a complete response, one achieved stable disease and five achieved a partial response. Four grade III and one grade IV hematological toxicities, and one grade IV gastrointestinal toxicity were observed. Four cats were euthanased as a result of apparent toxicity. One cat was euthanased as a result of severe and prolonged myelosuppression with fever. Three were euthanased for grade III pleural and pericardial effusions. Effusion was seen in cats treated with higher cumulative dose of TMZ (P = 0.0046). Planned additional case accrual was discontinued because of unacceptable levels of toxicity despite evidence of efficacy in some of the cats. Additional investigation is needed to elucidate this unexpected apparent cumulative toxicity. PMID- 22496149 TI - Human cytomegalovirus-encoded UL33 and UL78 heteromerize with host CCR5 and CXCR4 impairing their HIV coreceptor activity. AB - Human cytomegalovirus (HCMV) encodes four 7-transmembrane-spanning (7TM) proteins, US28, US27, UL33, and UL78, which present important sequence homology with human chemokine receptors. Whereas US28 binds a large range of chemokines and disturbs host cell signaling at different levels, the others are orphans with largely unknown functions. Assembly of 2 different 7TM proteins into hetero oligomeric complexes may profoundly change their respective functional properties. We show that HCMV-encoded UL33 and UL78 form heteromers with CCR5 and CXCR4 chemokine receptors in transfected human embryonic kidney 293T cells and monocytic THP-1 cells. Expression of UL33 and UL78 had pleiotropic, predominantly negative, effects on CCR5 and CXCR4 cell surface expression, ligand-induced internalization, signal transduction, and migration without modifying the chemokine binding properties of CCR5 and CXCR4. Importantly, the coreceptor activity of CCR5 and CXCR4 for HIV was largely impaired in the presence of UL33 and UL78 without affecting expression of the primary HIV entry receptor CD4 and its interaction with CCR5 and CXCR4. Collectively, we identified the first molecular function for the HCMV-encoded orphan UL33 and UL78 7TM proteins, namely the regulation of cellular chemokine receptors through receptor heteromerization. PMID- 22496150 TI - Circulating IL-15 exists as heterodimeric complex with soluble IL-15Ralpha in human and mouse serum. AB - IL-15 is an important cytokine for the function of the immune system, but the form(s) of IL-15 produced in the human body are not fully characterized. Coexpression of the single-chain IL-15 and the IL-15 receptor alpha (IL-15Ralpha) in the same cell allows for efficient production, surface display, and eventual cleavage and secretion of the bioactive IL-15/IL-15Ralpha heterodimer in vivo, whereas the single-chain IL-15 is poorly secreted and unstable. This observation led to the hypothesis that IL-15 is produced and secreted only as a heterodimer with IL-15Ralpha. We purified human IL-15/IL-15Ralpha complexes from overproducing human cell lines and developed an ELISA specifically measuring the heterodimeric form of IL-15. Analysis of sera from melanoma patients after lymphodepletion revealed the presence of circulating IL-15/IL-15Ralpha complexes in amounts similar to the total IL-15 quantified by a commercial IL-15 ELISA that detects both the single-chain and the heterodimeric forms of the cytokine. Therefore, in lymphodepleted cancer patients, the serum IL-15 is exclusively present in its heterodimeric form. Analysis of the form of IL-15 present in either normal or lymphodepleted mice agrees with the human data. These results have important implications for development of assays and materials for clinical applications of IL-15. PMID- 22496151 TI - Emergence of T cells that recognize nonpolymorphic antigens during graft-versus- host disease. AB - Chronic GVHD is a major cause of morbidity and mortality in allogeneic stem cell transplantation recipients and typically develops from antecedent acute GVHD. In contrast to acute GVHD, chronic GVHD has much broader tissue involvement and clinical manifestations that bear striking similarity to what is observed in autoimmune diseases. How autoimmunity arises out of alloimmunity has been a longstanding unresolved issue. To address this question, in the present study, we performed a comprehensive analysis of the clonotypic T-cell response using complementary murine models that simulate what occurs during the transition from acute to chronic GVHD. These studies revealed repertoire skewing and the presence of high-frequency clonotypes that had undergone significant in vivo expansion, indicating that GVHD-associated autoimmunity was characterized by antigen-driven expansion of a limited number of T-cell clones. Furthermore, we observed that T cells with identical TCRbeta CDR3 nucleotide sequences were capable of recognizing donor and host antigens, providing evidence that the loss of self tolerance during acute GVHD leads to the emergence of self-reactive donor T cells that are capable of recognizing nonpolymorphic tissue or commensally derived antigens. These data provide a mechanistic framework for how autoimmunity develops within the context of preexisting GVHD and provide additional insight into the pathophysiology of chronic GVHD. PMID- 22496152 TI - Increased incidence of non-Hodgkin lymphoma, leukemia, and myeloma in patients with diabetes mellitus type 2: a meta-analysis of observational studies. AB - Hematologic malignancies are a heterogeneous group of conditions with an unclear etiology. We hypothesized that diabetes mellitus type 2 is associated with increased risk of developing lymphoma, leukemia, and myeloma. A literature search identified 26 studies (13 case-control and 13 cohort studies) evaluating such an association. Outcome was calculated as the odds ratio (OR) using a random effects model. Heterogeneity and publication bias were evaluated using the I(2) index and the trim-and-fill analysis, respectively. Quality was assessed using the Newcastle-Ottawa scale. The OR for non-Hodgkin lymphoma was increased at 1.22 (95% confidence interval [CI], 1.07-1.39; P < .01) but the OR for Hodgkin lymphoma was not. There was an increased OR for peripheral T-cell lymphoma (OR = 2.42, 95% CI, 1.24-4.72; P = .009) but not for other non-Hodgkin lymphoma subtypes. The OR for leukemia was 1.22 (95% CI, 1.03-1.44; P = .02) and the OR for myeloma was 1.22 (95% CI, 0.98-1.53; P = .08). Although diabetes mellitus type 2 seems to increase the risk of developing lymphoma, leukemia, and myeloma, future studies should focus on evaluating other potential confounders such as obesity, dietary habits, physical activity, and/or antidiabetic therapy. PMID- 22496153 TI - Reduced-intensity conditioning transplantation in acute leukemia: the effect of source of unrelated donor stem cells on outcomes. AB - We report the relative efficacy of co-infusing 2 umbilical cord blood units (dUCB) compared with peripheral blood progenitor cells (PBPCs) from 8 of 8 or 7 of 8 HLA-matched unrelated donors. All patients received reduced-intensity conditioning (RIC) regimens. Four treatment groups were evaluated: 4-6 of 6 matched dUCB-TCF (n = 120; TCF = total body irradiation [TBI] 200 cGy + cyclophosphamide + fludarabine), 4-6 of 6 matched dUCB-other (n = 40; alkylating agent + fludarabine +/- TBI), and 8 of 8 (n = 313) and 7 of 8 HLA-matched PBPCs (n = 111). Compared with matched 8 of 8 PBPC transplantations, transplantation related mortality (TRM), and overall mortality were similar after dUCB-TCF (relative risk [RR] 0.72, P = .72; RR 0.93, P = .60) but higher after dUCB-other RIC (hazard ratio [HR] 2.70, P = .0001; 1.79 P = .004). Compared with 7 of 8 PBPC transplantations, TRM (but not overall mortality) was lower after dUCB-TCF (RR 0.57, P = .04; RR 0.87 P = .41). The probabilities of survival after dUCB-TCF, dUCB-other RIC, and 8 of 8 PBPC and 7 of 8 PBPC transplantations were 38%, 19%, 44%, and 37%, respectively. With similar survival after 8 of 8, 7 of 8 matched PBPCs, and dUCB-TCF, these data support use of dUCB-TCF transplantation in adults with acute leukemia who may benefit from RIC transplantation urgently or lack a 7 8 of 8 unrelated donor. PMID- 22496154 TI - Prediction of cytogenetic abnormalities with gene expression profiles. AB - Cytogenetic abnormalities are important clinical parameters in various types of cancer, including multiple myeloma. We developed a model to predict cytogenetic abnormalities in patients with multiple myeloma using gene expression profiling and validated it by different cytogenetic techniques. The model has an accuracy rate up to 0.89. These results provide proof of concept for the hypothesis that gene expression profiling is a superior genomic method for clinical molecular diagnosis and/or prognosis. PMID- 22496155 TI - Cell-autonomous role of TGFbeta and IL-2 receptors in CD4+ and CD8+ inducible regulatory T-cell generation during GVHD. AB - FoxP3(+) regulatory T cells (Tregs) suppress GVHD while preserving graft-versus tumor effects, making them an attractive target for GVHD therapy. The donor derived Treg pool can potentially be derived from the expansion of preexisting natural Tregs (nTregs) or from de novo generation of inducible Tregs (iTregs) from donor Tconvs in the transplantation recipient. Using an MHC-mismatched model of acute GVHD, in the present study we found that the Treg pool was comprised equally of donor-derived nTregs and iTregs. Experiments using various combinations of T cells from wild-type and FoxP3-deficient mice suggested that both preexisting donor nTregs and the generation of iTregs in the recipient mice contribute to protection against GVHD. Surprisingly, CD8(+)FoxP3(+) T cells represented approximately 70% of the iTreg pool. These CD8(+)FoxP3(+) T cells shared phenotypic markers with their CD4(+) counterparts and displayed suppressive activity, suggesting that they were bona fide iTregs. Both CD4(+) and CD8(+) Tregs appeared to be protective against GVHD-induced lethality and required IL-2 and TGFbeta receptor expression for their generation. These data illustrate the complex makeup of the donor-derived FoxP3(+) Treg pool in allogeneic recipients and their potential role in protection against GVHD. PMID- 22496157 TI - Broadening the factor V Leiden paradox: pulmonary embolism and deep-vein thrombosis as 2 sides of the spectrum. AB - Risk factors for deep-vein thrombosis have been shown not to be always the same as for pulmonary embolism. A well-known example is the factor V Leiden (FVL) paradox: the FVL mutation poses a clearly higher risk for deep-vein thrombosis (DVT) than for pulmonary embolism. We aimed to expand this paradox and therefore present risk estimates for several established risk factors for DVT and pulmonary embolism separately. When such separate risk estimates could not be retrieved from the literature, we calculated these risks in our own data, a large population-based case-control study on venous thrombosis (the MEGA study). Our results showed that the FVL paradox can be broadened (ie, the risk factors oral contraceptive use, pregnancy, puerperium, minor leg injuries, and obesity have an effect comparable with FVL). Furthermore, we found that pulmonary conditions, such as chronic obstructive pulmonary disease, pneumonia, and sickle cell disease, were risk factors with an opposite effect: a higher risk of pulmonary embolism, but little or no effect on DVT. These findings suggest that pulmonary embolism and DVT may not always have the same etiology, and encourage unraveling this phenomenon in further studies. PMID- 22496156 TI - The impact of platelet transfusion characteristics on posttransfusion platelet increments and clinical bleeding in patients with hypoproliferative thrombocytopenia. AB - Platelet characteristics, such as platelet dose, platelet source (apheresis vs pooled), platelet donor-recipient ABO compatibility, and duration of platelet storage, can affect posttransfusion platelet increments, but it is unclear whether these factors impact platelet transfusion efficacy on clinical bleeding. We performed secondary analyses of platelet transfusions given in the prospective randomized Platelet Dose Study, which included 1272 platelet-transfused hematology-oncology patients who received 6031 prophylactic platelet transfusions. The primary outcome of these analyses was time from first transfusion to first World Health Organization >= grade 2 bleeding. Platelet transfusion increments were assessed at 0.25 to 4 hours and 16 to 32 hours after platelet transfusion. There were 778 patients evaluable for analysis of time to bleeding. Adjusted models showed that randomized dose strategy, platelet source, ABO compatibility, and duration of storage did not predict this outcome. Platelet increments were generally higher for transfusions of apheresis platelets, ABO identical platelets, and platelets stored 3 days versus 4 to 5 days. Thus, although platelet source, ABO compatibility, and duration of storage exert a modest impact on both absolute and corrected posttransfusion platelet increments, they have no measurable impact on prevention of clinical bleeding. This trial was registered at www.clinicaltrials.gov as #NCT00128713. PMID- 22496158 TI - Sustained expression of osteopontin is closely associated with calcium deposits in the rat hippocampus after transient forebrain ischemia. AB - The present study was designed to evaluate the extent and topography of osteopontin (OPN) protein expression in the rat hippocampus 4 to 12 weeks following transient forebrain ischemia, and to compare OPN expression patterns with those of calcium deposits and astroglial and microglial reactions. Two patterns of OPN staining were recognized by light microscopy: 1) a diffuse pattern of tiny granular deposits throughout the CA1 region at 4 weeks after ischemia and 2) non-diffuse ovoid to round deposits, which formed conglomerates in the CA1 pyramidal cell layer over the chronic interval of 8 to 12 weeks. Immunogold-silver electron microscopy and electron probe microanalysis demonstrated that OPN deposits were indeed diverse types of calcium deposits, which were clearly delineated by profuse silver grains indicative of OPN expression. Intracellular OPN deposits were frequently observed within reactive astrocytes and neurons 4 weeks after ischemia but rarely at later times. By contrast, extracellular OPN deposits progressively increased in size and appeared to be gradually phagocytized by microglia or brain macrophages and some astrocytes over 8 to 12 weeks. These data indicate an interaction between OPN and calcium in the hippocampus in the chronic period after ischemia, suggesting that OPN binding to calcium deposits may be involved in scavenging mechanisms. PMID- 22496159 TI - Metabolite profiling identifies pathways associated with metabolic risk in humans. AB - BACKGROUND: Although metabolic risk factors are known to cluster in individuals who are prone to developing diabetes mellitus and cardiovascular disease, the underlying biological mechanisms remain poorly understood. METHODS AND RESULTS: To identify pathways associated with cardiometabolic risk, we used liquid chromatography/mass spectrometry to determine the plasma concentrations of 45 distinct metabolites and to examine their relation to cardiometabolic risk in the Framingham Heart Study (FHS; n=1015) and the Malmo Diet and Cancer Study (MDC; n=746). We then interrogated significant findings in experimental models of cardiovascular and metabolic disease. We observed that metabolic risk factors (obesity, insulin resistance, high blood pressure, and dyslipidemia) were associated with multiple metabolites, including branched-chain amino acids, other hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites. We observed strong associations of insulin resistance traits with glutamine (standardized regression coefficients, -0.04 to -0.22 per 1-SD change in log-glutamine; P<0.001), glutamate (0.05 to 0.14; P<0.001), and the glutamine to-glutamate ratio (-0.05 to -0.20; P<0.001) in the discovery sample (FHS); similar associations were observed in the replication sample (MDC). High glutamine-to-glutamate ratio was associated with lower risk of incident diabetes mellitus in FHS (odds ratio, 0.79; adjusted P=0.03) but not in MDC. In experimental models, administration of glutamine in mice led to both increased glucose tolerance (P=0.01) and decreased blood pressure (P<0.05). CONCLUSIONS: Biochemical profiling identified circulating metabolites not previously associated with metabolic traits. Experimentally interrogating one of these pathways demonstrated that excess glutamine relative to glutamate, resulting from exogenous administration, is associated with reduced metabolic risk in mice. PMID- 22496160 TI - Left ventricular longitudinal function predicts life-threatening ventricular arrhythmia and death in adults with repaired tetralogy of fallot. AB - BACKGROUND: Sudden cardiac death and life-threatening ventricular arrhythmia remain a concern in adult patients with repaired tetralogy of Fallot. Longitudinal left ventricular (LV) function is sensitive in detecting early myocardial damage and may have prognostic implications in this setting. METHODS AND RESULTS: We included 413 tetralogy of Fallot patients (age, 36 +/- 13 years; QRS duration, 148 +/- 27 milliseconds; LV ejection fraction, 55 +/- 10%). A composite end point of sudden cardiac death/life-threatening ventricular arrhythmia (sustained ventricular tachycardia, resuscitated sudden cardiac death, or appropriate implantable cardioverter-defibrillator discharge) was used. During a median follow-up of 2.9 years, 5 patients died suddenly, 9 had documented sustained ventricular tachycardia, and another 5 had appropriate implantable cardioverter-defibrillator shocks. On univariate Cox analysis, QRS duration (hazard ratio [HR], 1.02 per 1 ms; P=0.046), right atrial area (HR, 1.05 per 1 cm(2); P=0.02), right ventricular fractional area change (HR, 0.94 per 1%; P=0.02), right ventricular outflow tract diameter (HR, 1.08 per 1 mm; P=0.01), mitral annular plane systolic excursion (HR, 0.84 per 1 mm; P=0.03), and LV global longitudinal 2-dimensional strain (HR, 0.87 per 1%; P=0.03) were related to the combined end point. On bivariable analysis, mitral annular plane systolic excursion and LV global longitudinal 2-dimensional strain were related to outcome independently of QRS duration (P=0.002 and P=0.01, respectively). In addition, a combination of echocardiographic variables, including right atrial area, right ventricular fractional area change, and LV global longitudinal 2-dimensional strain or mitral annular plane systolic excursion, was also found to be significantly related to outcome (P<0.001; c statistic, 0.70). CONCLUSIONS: LV longitudinal dysfunction was associated with greater risk of sudden cardiac death/life-threatening ventricular arrhythmias. In combination with echocardiographic right heart variables, also available from routine echocardiography, these measures provide important outcome information and should be considered a useful adjunct to established markers such as QRS duration in the estimation of prognosis in this challenging population. PMID- 22496161 TI - Chronic Inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. AB - BACKGROUND: cGMP phosphodiesterase type 5 protein is upregulated in myocardial hypertrophy. However, it has never been ascertained whether phosphodiesterase type 5 inhibition exerts an antiremodeling effect in nonischemic heart disease in humans. We explored the cardioreparative properties of a selective phosphodiesterase type 5 inhibitor, sildenafil, in a model of diabetic cardiomyopathy. METHODS AND RESULTS: Fifty-nine diabetic men (60.3 +/- 7.4 years) with cardiac magnetic resonance imaging consistent with nonischemic, nonfailing diabetic cardiomyopathy (reduced circumferential strain [sigma], -12.6 +/- 3.1; increased left ventricular [LV] torsion [theta], 18.4 +/- 4.6 degrees ; and increased ratio of LV mass to volume, 2.1 +/- 0.5 g/mL) were randomized to receive sildenafil or placebo (100 mg/d). At baseline, the metabolic indices were correlated with torsion, strain, N-terminal pro-B-type natriuretic peptide, vascular endothelial growth factor, monocyte chemotactic protein-1, and blood pressure. After 3 months, sildenafil produced a significant improvement compared with placebo in LV torsion (Deltatheta: sildenafil, -3.89 +/- 3.11 degrees versus placebo, 2.13 +/- 2.35 degrees ; P<0.001) and strain (Deltasigma: sildenafil, -3.30 +/- 1.86 versus placebo, 1.22 +/- 1.84; P<0.001). Sildenafil induced improvement of LV contraction was accompanied by consistent changes in chamber geometry and performance, with a 6.5 +/- 11 improvement in mass-to-volume ratio over placebo (P=0.021). Monocyte chemotactic protein-1 and transforming growth factor-beta were the only markers affected by active treatment (Deltamonocyte chemotactic protein-1: -75.30 +/- 159.28 pg/mL, P=0.032; Deltatransforming growth factor-beta: 5.26 +/- 9.67 ng/mL, P=0.009). No changes were found in endothelial function, afterload, or metabolism. CONCLUSIONS: The early features of diabetic cardiomyopathy are LV concentric hypertrophy associated with altered myocardial contraction dynamics. Chronic phosphodiesterase type 5 inhibition, at this stage, has an antiremodeling effect, resulting in improved cardiac kinetics and circulating markers. This effect is independent of any other vasodilatory or endothelial effects and is apparently exerted through a direct intramyocardial action. PMID- 22496162 TI - Bitter reproach or sweet revenge: cultural differences in response to racism. AB - Culture has been shown to influence response styles. The authors conducted two studies to test the notion that African Americans would be more likely to respond to racism directly, whereas Asian Americans would be more likely to respond indirectly and therefore more subtly. Study 1 showed that Black women subjected to a racist comment from a confederate during an online interaction were more likely than Asian women to verbally reproach the perpetrator. These group differences were not present when the outcome measure was indirect responding- administration of good/bad jellybeans. Study 2 used an online format to demonstrate that Asian women were more likely than Black women to say they would not respond directly to a racist comment. This group difference in unwillingness to confront was significantly mediated by a goal of maintaining peace with their interaction partner. Implications of these findings for the study of discrimination, coping, and well-being are discussed. PMID- 22496163 TI - Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia. AB - Whereas the improvement in outcome for children with acute lymphoblastic leukemia has been gratifying, the poor outcome of patients who relapse warrants novel treatment approaches. Previously, we identified a characteristic relapse-specific gene expression and methylation signature associated with chemoresistance using a large cohort of matched-diagnosis relapse samples. We hypothesized that "reversing" such a signature might restore chemosensitivity. In the present study, we demonstrate that the histone deacetylase inhibitor vorinostat not only reprograms the aberrant gene expression profile of relapsed blasts by epigenetic mechanisms, but is also synergistic when applied before chemotherapy in primary patient samples and leukemia cell lines. Furthermore, incorporation of the DNA methyltransferase inhibitor decitabine led to reexpression of genes shown to be preferentially methylated and silenced at relapse. Combination pretreatment with vorinostat and decitabine resulted in even greater cytotoxicity compared with each agent individually with chemotherapy. Our results indicate that acquisition of chemo-resistance at relapse may be driven in part by epigenetic mechanisms. Incorporation of these targeted epigenetic agents to the standard chemotherapy backbone is a promising approach to the treatment of relapsed pediatric acute lymphoblastic leukemia. PMID- 22496164 TI - TBL1XR1/TP63: a novel recurrent gene fusion in B-cell non-Hodgkin lymphoma. AB - Recently, the landscape of single base mutations in diffuse large B-cell lymphoma (DLBCL) was described. Here we report the discovery of a gene fusion between TBL1XR1 and TP63, the only recurrent somatic novel gene fusion identified in our analysis of transcriptome data from 96 DLBCL cases. Based on this cohort and a further 157 DLBCL cases analyzed by FISH, the incidence in de novo germinal center B cell-like (GCB) DLBCL is 5% (6 of 115). The fusion appears exclusive to GCB and was not seen in 138 non-GCB cases examined (P = .008, Fisher exact test) but was present at low incidence in follicular lymphoma (1 of 81). In all 7 cases identified, the 3' end of the fusion consists of exons 4 and onwards of TP63. The recurrence, subtype enrichment, and the remarkably conserved nature of the TP63 portion of the fusion suggest an important functional role in the lymphomas that harbor this event. PMID- 22496165 TI - A polymorphism in the XPD gene predisposes to leukemic transformation and new nonmyeloid malignancies in essential thrombocythemia and polycythemia vera. AB - Patients with essential thrombocythemia (ET) and polycythemia vera (PV) have an increased incidence of acute myeloid leukemia and new nonhematologic malignancies compared with the general population. However, information on the factors determining the risk for such complications is limited. In the present study, we investigated whether constitutional genetic variations in DNA repair predispose to leukemic transformation and new nonmyeloid neoplasias in patients with ET and PV. Case-control studies for predisposition to both types of malignancies were nested in a cohort of 422 subjects diagnosed with ET or PV during the period 1973 2010 in several institutions in Spain. A total of 64 incidence cases of leukemia and 50 cases of primary nonmyeloid cancers were accrued. At conditional regression analysis, the Gln/Gln genotype in the XPD codon 751 showed the strongest association with both leukemic transformation (odds ratio [OR] = 4.9; 95% confidence interval [95% CI], 2.0-12) and development of nonmyeloid malignancies (OR = 4.2; 95% CI, 1.5-12). Additional predictive factors were exposure to cytoreductive agents for leukemic transformation (OR = 3.5; 95% CI, 2.0-6.2) and age for nonmyeloid malignancies (OR = 2.0; 95% CI, 1.4-2.8). These findings provide further evidence about the contribution of inherited genetic variations to the pathogenesis and clinical course of myeloproliferative neoplasms. PMID- 22496167 TI - Dealing with errors on the job. PMID- 22496170 TI - RN seeks advice for psychiatric patients in EDs. PMID- 22496171 TI - Believing in the basics. PMID- 22496173 TI - Early pediatric emergency department return visits: a prospective patient-centric assessment. AB - BACKGROUND: A substantial percentage of emergency department (ED) patients return within 72 hours of their initial evaluation. Quality reviews typically demonstrate that most revisits do not seem to be directly related to problematic care provided on the first evaluation. We examined the possibility that return visits are related to nonmedical issues on the first visit, most notably patient discharge education. Objective We prospectively surveyed a convenience sample of caregivers in a pediatric ED to determine why they returned with their children within 72 hours of their initial ED visit. DESIGN/METHODS: All patients who returned within 72 hours of a previous visit were identified and prospectively interviewed using a survey instrument with nominal (multiple choice) and brief descriptive responses. RESULTS: Caregivers of 124 children were prospectively surveyed; 93 children (75%) returned because their symptoms had not improved or worsened. Only 50 (53%) had contacted their primary medical doctor (PMD) prior to the second visit; of these, 14 (28%) could not get an appointment, and 32 (64%) were told to return to the ED. Discharge instructions were felt to be informative by 94% (n = 86) of caregivers with the same number (94%) reported being satisfied with the first ED physician. Twenty-nine children (30%) were admitted on the second visit. CONCLUSIONS: Among children who are discharged from the emergency department and return within 72 hours, most caregivers are satisfied with the care and instructions provided on their first visits. Though most patients have a PMD, many do not call them prior to their return ED visit, and those who do either cannot schedule an appointment or are told to return to the ED. The majority of patients return for clinical progression of illness. PMID- 22496174 TI - Why parents value a brief required primary care intervention that teaches discipline strategies. AB - English- or Spanish-speaking caregivers of 1- to 5-year-old children were instructed to view a 5- to 10-minute educational intervention in a pediatric clinic as part of the well child visit. Almost all (128/129) parents reported that the program was a valuable component of the well child visit, and of these, all 128 (100%) gave at least one reason. Most parents valued the program at a personal level, reporting that the program was educational (76.6%), reinforced their parenting (8.6%), or facilitated a discussion with their physician (2.3%). A total of 16% valued the program because it might benefit other parents. A brief routine primary care intervention that teaches discipline strategies is valued by English- and Spanish-speaking parents of young children. These findings have implications for how to routinely teach parents about discipline in primary care and the primary prevention of violence. PMID- 22496175 TI - Early-childhood obesity: how do low-income parents of preschoolers rank known risk factors? AB - OBJECTIVES: To determine parental rankings of known factors related to early childhood obesity and compare reports between parents of healthy weight and overweight children. METHODS: Parents of 2- to 5-year-old children seeking well child care ranked card-sort statements including risks, barriers, and motivating factors for achieving a healthy weight child. Frequencies and means of ranked factors are reported and compared. RESULTS: Of the 150 participants, few parents (7.4%) considered low levels of physical activity a top risk factor compared with other known risks. Inability to control the food choices of alternate caregivers was the greatest perceived barrier to achieving a healthy child weight (34%). There were no differences in rankings by child weight groups. CONCLUSION: Low income parents of preschoolers are aware of high-risk feeding behaviors, but few recognize the risk of inactivity in their young child. Innovations that promote adequate physical activity and engage influential caregivers during counseling are necessary. PMID- 22496176 TI - A 6-year-old girl with chronic vaginal discharge. PMID- 22496177 TI - Chronic vomiting and abdominal pain in an adolescent male. PMID- 22496178 TI - Pediatric chest pain: findings on exercise stress testing. PMID- 22496179 TI - Changing spectrum of diabetes mellitus in children: challenges with initial classification. AB - OBJECTIVE: To determine the frequency of initial misclassification of diabetes mellitus (DM) in children and to compare the presenting features of DM1, DM2, and the misclassified cases. RESULTS: A total of 206 patients fulfilled the inclusion criteria. Of them, 74.75% had DM1 and 25.25% had DM2. Ten percent of studied patients had a subsequent change in classification. The mean HbA1c of the DM2 patients, who were initially misclassified, was 13.35% (SD = 1.96). The mean HbA1c of DM2 patients with correct initial classification was 8.83% (SD = 3.01). Diabetes ketoacidosis (DKA) was seen in 59.44% of DM1 and 23.91% of DM2 patients. Of the DM2 patients who were initially misclassified, 58.82% had presented in DKA as opposed to only 6.45% of patients who were correctly classified. CONCLUSION: The initial classification of DM frequently requires revision (10% in this study). The misclassification is highest among DM2 patients who initially present with higher HbA1c and DKA. PMID- 22496180 TI - Who is good at this game? Linking an activity to a social category undermines children's achievement. AB - Children's achievement-related theories have a profound impact on their academic success. Children who adopt entity theories believe that their ability to perform a task is dictated by the amount of natural talent they possess for that task--a belief that has well-documented adverse consequences for their achievement (e.g., lowered persistence, impaired performance). It is thus important to understand what leads children to adopt entity theories. In the experiments reported here, we hypothesized that the mere act of linking success at an unfamiliar, challenging activity to a social group gives rise to entity beliefs that are so powerful as to interfere with children's ability to perform the activity. Two experiments showed that, as predicted, the performance of 4- to 7-year-olds (N = 192) was impaired by exposure to information that associated success in the task at hand with membership in a certain social group (e.g., "boys are good at this game"), regardless of whether the children themselves belonged to that group. PMID- 22496181 TI - Primary malignant lymphoma in the deep palmar tissue. PMID- 22496182 TI - Intraosseous tophaceous gout in the proximal phalanx of the small finger. PMID- 22496183 TI - Management strategies for shoulder reconstruction in obstetric brachial plexus injury with special reference to loss of internal rotation after surgery. AB - We assessed the outcomes in 24 of 25 children (mean age 3 years) who had soft tissue shoulder reconstruction procedures for obstetric brachial plexus injuries. All had latissimus dorsi and teres major transfers to strengthen external rotation combined with subscapularis lengthening, reduction of posterior dislocation or subluxation, and humeral osteotomy, if necessary. At a mean follow up of 3.8 years, the mean Mallet score improved from 12.3 preoperatively to 17.4 postoperatively, active external rotation improved from 21 degrees to 32 degrees , and passive external rotation improved from 26 degrees to 67 degrees . The shoulder remained in joint in all patients. Active internal rotation deteriorated in nine shoulders, two requiring secondary internal rotation osteotomy. Combined soft tissue rebalancing and bony procedures gives reliable shoulder function improvement. Care is required regarding the effect on internal rotation. PMID- 22496184 TI - Three-dimensional deformity analysis of malunited distal radius fractures and their influence on wrist and forearm motion. AB - Little information exists about three-dimensional (3-D) deformity patterns of malunited distal radius fractures including axial deformity. The current study aimed to clarify the 3-D deformity pattern of malunited distal radius fractures and reveal the influence of osseous deformities, including axial rotation deformity, on wrist and forearm motion. The deformity of 20 dorsally tilted malunions were evaluated using 3-D computer models created from CT data, and correlations between deformity components and range of motion were assessed. The 3-D deformity analysis showed that axial malalignment in pronation, which showed a correlation with the degree of radial tilt deformity, was very common. A radial tilt deformity of > 5 degrees was observed in only 45% of cases. Although the range of wrist flexion and extension showed a correlation with dorsal tilt deformity, the range of forearm pronation and supination did not correlate with distal radius deformities. PMID- 22496186 TI - Upstroke wing flexion and the inertial cost of bat flight. AB - Flying vertebrates change the shapes of their wings during the upstroke, thereby decreasing wing surface area and bringing the wings closer to the body than during downstroke. These, and other wing deformations, might reduce the inertial cost of the upstroke compared with what it would be if the wings remained fully extended. However, wing deformations themselves entail energetic costs that could exceed any inertial energy savings. Using a model that incorporates detailed three-dimensional wing kinematics, we estimated the inertial cost of flapping flight for six bat species spanning a 40-fold range of body masses. We estimate that folding and unfolding comprises roughly 44 per cent of the inertial cost, but that the total inertial cost is only approximately 65 per cent of what it would be if the wing remained extended and rigid throughout the wingbeat cycle. Folding and unfolding occurred mostly during the upstroke; hence, our model suggests inertial cost of the upstroke is not less than that of downstroke. The cost of accelerating the metacarpals and phalanges accounted for around 44 per cent of inertial costs, although those elements constitute only 12 per cent of wing weight. This highlights the energetic benefit afforded to bats by the decreased mineralization of the distal wing bones. PMID- 22496185 TI - Warming alters community size structure and ecosystem functioning. AB - Global warming can affect all levels of biological complexity, though we currently understand least about its potential impact on communities and ecosystems. At the ecosystem level, warming has the capacity to alter the structure of communities and the rates of key ecosystem processes they mediate. Here we assessed the effects of a 4 degrees C rise in temperature on the size structure and taxonomic composition of benthic communities in aquatic mesocosms, and the rates of detrital decomposition they mediated. Warming had no effect on biodiversity, but altered community size structure in two ways. In spring, warmer systems exhibited steeper size spectra driven by declines in total community biomass and the proportion of large organisms. By contrast, in autumn, warmer systems had shallower size spectra driven by elevated total community biomass and a greater proportion of large organisms. Community-level shifts were mirrored by changes in decomposition rates. Temperature-corrected microbial and macrofaunal decomposition rates reflected the shifts in community structure and were strongly correlated with biomass across mesocosms. Our study demonstrates that the 4 degrees C rise in temperature expected by the end of the century has the potential to alter the structure and functioning of aquatic ecosystems profoundly, as well as the intimate linkages between these levels of ecological organization. PMID- 22496187 TI - The role of moulting in parasite defence. AB - Parasitic infections consist of a succession of steps during which hosts and parasites interact in specific manners. At each step, hosts can use diverse defence mechanisms to counteract the parasite's attempts to invade and exploit them. Of these steps, the penetration of parasites into the host is a key step for a successful infection and the epithelium is the first line of host defence. The shedding of this protective layer (moulting) is a crucial feature in the life cycle of several invertebrate and vertebrate taxa, and is generally considered to make hosts vulnerable to parasites and predators. Here, we used the crustacean Daphnia magna to test whether moulting influences the likelihood of infection by the castrating bacterium Pasteuria ramosa. This parasite is known to attach to the host cuticula before penetrating into its body. We found that the likelihood of successful parasite infection is greatly reduced if the host moults within 12 h after parasite exposure. Thus, moulting is beneficial for the host being exposed to this parasite. We further show that exposure to the parasite does not induce hosts to moult earlier. We discuss the implications of our findings for host and parasite evolution and epidemiology. PMID- 22496188 TI - Cooperation and the evolution of intelligence. AB - The high levels of intelligence seen in humans, other primates, certain cetaceans and birds remain a major puzzle for evolutionary biologists, anthropologists and psychologists. It has long been held that social interactions provide the selection pressures necessary for the evolution of advanced cognitive abilities (the 'social intelligence hypothesis'), and in recent years decision-making in the context of cooperative social interactions has been conjectured to be of particular importance. Here we use an artificial neural network model to show that selection for efficient decision-making in cooperative dilemmas can give rise to selection pressures for greater cognitive abilities, and that intelligent strategies can themselves select for greater intelligence, leading to a Machiavellian arms race. Our results provide mechanistic support for the social intelligence hypothesis, highlight the potential importance of cooperative behaviour in the evolution of intelligence and may help us to explain the distribution of cooperation with intelligence across taxa. PMID- 22496189 TI - Why is lifetime fertility higher in twinning women? PMID- 22496190 TI - Plant-soil feedbacks provide an additional explanation for diversity-productivity relationships. AB - Plant-soil feedbacks (PSFs) have gained attention for their role in plant community dynamics, but their role in productivity has been overlooked. We developed and tested a biomass-specific, multi-species model to examine the role of PSFs in diversity-productivity relationships. The model predicts a negative relationship between PSFs and overyielding: plants with negative PSFs grow more in communities than in monoculture (i.e. overyield), and plants with positive PSFs grow less in communities than in monoculture (i.e. underyield). This effect is predicted to increase with diversity and saturate at low species richness because the proportion of 'self-cultivated' soils rapidly decreases as species are added to a community. Results in a set of glasshouse experiments supported model predictions. We found that PSFs measured in one experiment were negatively correlated with overyielding in three-species plant communities measured in a separate experiment. Furthermore, when parametrized with our experimental PSF data, our model successfully predicted species-level overyielding and underyielding. The model was less effective at predicting community-level overyielding and underyielding, although this appeared to reflect large differences between communities with or without nitrogen-fixing plants. Results provide conceptual and experimental support for the role of PSFs in diversity productivity relationships. PMID- 22496191 TI - Biomineral ultrastructure, elemental constitution and genomic analysis of biomineralization-related proteins in hemichordates. AB - Here, we report the discovery and characterization of biominerals in the acorn worms Saccoglossus bromophenolosus and Ptychodera flava galapagos (Phylum: Hemichordata). Using electron microscopy, X-ray microprobe analyses and confocal Raman spectroscopy, we show that hemichordate biominerals are small CaCO(3) aragonitic elements restricted to specialized epidermal structures, and in S. bromophenolosus, are apparently secreted by sclerocytes. Investigation of urchin biomineralizing proteins in the translated genome and expressed sequence tag (EST) libraries of Saccoglossus kowalevskii indicates that three members of the urchin MSP-130 family, a carbonic anhydrase and a matrix metaloprotease are present and transcribed during the development of S. kowalevskii. The SM family of proteins is absent from the hemichordate genome. These results increase the number of phyla known to biomineralize and suggest that some of the gene regulatory 'toolkit', if not mineralized tissue themselves, may have been present in the common ancestor to hemichordates and echinoderms. PMID- 22496193 TI - Expanding the understanding of disability in persons with traumatic brain injury. PMID- 22496194 TI - Increased muscle expression of interleukin-17 in Duchenne muscular dystrophy. AB - OBJECTIVES: Duchenne muscular dystrophy (DMD) is a degenerative muscle wasting disease caused by mutations in the dystrophin gene. Dystrophic muscle is characterized by chronic inflammation, and inflammatory mediators could be promising targets for innovative therapeutic interventions. We analyzed muscle biopsy samples of DMD-affected children to characterize interleukin (IL)-17 and Forkhead box P3 (Foxp3) expression levels and to identify possible correlations with clinical status. METHODS: Expression levels of IL-17, Foxp3, tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), IL-6, and transforming growth factor-beta (TGF-beta) were analyzed by real-time PCR in muscle biopsy samples from patients with DMD (n = 27) and juvenile dermatomyositis (JDM) (n = 8). Motor outcome of patients with DMD was evaluated by North Star Ambulatory Assessment score. RESULTS: In DMD, we found higher levels of IL-17 and lower levels of Foxp3 mRNA compared with those for a typical inflammatory myopathy, JDM. Moreover, the IL-17/Foxp3 ratio was higher in DMD than in JDM biopsy samples. IL-17 mRNA levels appeared to be related to the expression levels of other proinflammatory cytokines (TNF-alpha and MCP-1) and significantly associated with clinical outcome of patients. CONCLUSIONS: The association of IL-17 expression with levels of other inflammatory cytokines and with the clinical course of DMD suggests a possible pathogenic role of IL-17. PMID- 22496195 TI - Treatment consent capacity in patients with traumatic brain injury across a range of injury severity. AB - OBJECTIVE: To investigate medical decision-making capacity (MDC) in patients with acute traumatic brain injury (TBI) across a range of injury severity. METHODS: We evaluated MDC cross-sectionally 1 month after injury in 40 healthy controls and 86 patients with TBI stratified by injury severity (28 mild [mTBI], 15 complicated mild [cmTBI], 43 moderate/severe [msevTBI]). We compared group performance on the Capacity to Consent to Treatment Instrument and its 5 consent standards (expressing choice, reasonable choice, appreciation, reasoning, understanding). Capacity impairment ratings (no impairment, mild/moderate impairment, severe impairment) on the consent standards were also assigned to each participant with TBI using cut scores referenced to control performance. RESULTS: One month after injury, the mTBI group performed equivalently to controls on all consent standards. In contrast, the cmTBI group was impaired relative to controls on the understanding standard. No differences emerged between the mTBI and cmTBI groups. The msevTBI group was impaired on almost all standards relative to both control and mTBI groups, and on the understanding standard relative to the cmTBI group. Capacity compromise (mild/moderate or severe impairment ratings) on the 3 clinically complex standards (understanding, reasoning, appreciation) occurred in 10%-30% of patients with mTBI, 50% of patients with cmTBI, and 50%-80% of patients with msevTBI. CONCLUSIONS: One month following injury, MDC is largely intact in patients with mTBI, but is impaired in patients with cmTBI and msevTBI. Impaired MDC is prevalent in acute TBI and is strongly related to injury severity. PMID- 22496196 TI - Blink reflex recovery cycle in patients with dystonic tremor: a cross-sectional study. PMID- 22496197 TI - Glad about SAD (PD). PMID- 22496198 TI - Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNbeta-1b trial. AB - OBJECTIVE: To examine the effects of interferon beta (IFNbeta)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments. METHODS: For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNbeta-1b 250 MUg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary. RESULTS: After a median of 21.1 years from RCT enrollment, 98.4%(366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNbeta-1b 250 MUg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNbeta-1b 250 MUg-treated patients (46.0% among IFNbeta-1b 50 MUg-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect. CONCLUSIONS: There was a significant survival advantage in this cohort of patients receiving early IFNbeta-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNbeta-1b benefit on all-cause mortality. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that early treatment with IFNbeta-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis. PMID- 22496200 TI - Macrostructural abnormalities in Korsakoff syndrome compared with uncomplicated alcoholism. AB - OBJECTIVE: To distinguish, in patients with Korsakoff syndrome (KS), the structural brain abnormalities shared with alcoholic patients without KS (AL), from those specific to KS. METHODS: MRI data were collected in 11 alcoholic patients with KS, 34 alcoholic patients without KS, and 25 healthy control subjects (CS). Gray and white matter volumes were compared in the 3 groups using a voxel-based approach. RESULTS: A conjunction analysis indicated a large pattern of shared gray and white matter volume deficits in AL and KS. There were graded effects of volume deficits (KS < AL < CS) in the medial portion of the thalami, hypothalamus (mammillary bodies), left insula, and genu of the corpus callosum. Abnormalities in the left thalamic radiation were observed only in KS. CONCLUSIONS: Our results indicate considerable similarities in the pattern of gray and white matter damage in AL and KS. This finding confirms the widespread neurotoxic effect of chronic alcohol consumption. Only a few cerebral regions, including the medial thalami, mammillary bodies, and corpus callosum, were more severely damaged in KS than in AL. The continuum of macrostructural damage from AL to KS is therefore restricted to key brain structures. Longitudinal investigations are required to determine whether alcoholic patients with medial thalamic volumes that are comparable to those of patients with KS are at increased risk of developing KS. PMID- 22496199 TI - A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease. AB - OBJECTIVE: To evaluate the efficacy and safety of a selective serotonin reuptake inhibitor (SSRI) and a serotonin and norepinephrine reuptake inhibitor (SNRI) in the treatment of depression in Parkinson disease (PD). METHODS: A total of 115 subjects with PD were enrolled at 20 sites. Subjects were randomized to receive an SSRI (paroxetine; n = 42), an SNRI (venlafaxine extended release [XR]; n = 34), or placebo (n = 39). Subjects met DSM-IV criteria for a depressive disorder, or operationally defined subsyndromal depression, and scored >12 on the first 17 items of the Hamilton Rating Scale for Depression (HAM-D). Subjects were followed for 12 weeks (6-week dosage adjustment, 6-week maintenance). Maximum daily dosages were 40 mg for paroxetine and 225 mg for venlafaxine XR. The primary outcome measure was change in the HAM-D score from baseline to week 12. RESULTS: Treatment effects (relative to placebo), expressed as mean 12-week reductions in HAM-D score, were 6.2 points (97.5% confidence interval [CI] 2.2 to 10.3, p = 0.0007) in the paroxetine group and 4.2 points (97.5% CI 0.1 to 8.4, p = 0.02) in the venlafaxine XR group. No treatment effects were seen on motor function. CONCLUSIONS: Both paroxetine and venlafaxine XR significantly improved depression in subjects with PD. Both medications were generally safe and well tolerated and did not worsen motor function. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that paroxetine and venlafaxine XR are effective in treating depression in patients with PD. PMID- 22496201 TI - LGI1 microdeletion in autosomal dominant lateral temporal epilepsy. AB - OBJECTIVES: To characterize clinically and genetically a family with autosomal dominant lateral temporal epilepsy (ADLTE) negative to LGI1 exon sequencing test. METHODS: All participants were personally interviewed and underwent neurologic examination. Most affected subjects underwent EEG and neuroradiologic examinations (CT/MRI). Available family members were genotyped with the HumanOmni1-Quad v1.0 single nucleotide polymorphism (SNP) array beadchip and copy number variations (CNVs) were analyzed in each subject. LGI1 gene dosage was performed by real-time quantitative PCR (qPCR). RESULTS: The family had 8 affected members (2 deceased) over 3 generations. All of them showed GTC seizures, with focal onset in 6 and unknown onset in 2. Four patients had focal seizures with auditory features. EEG showed only minor sharp abnormalities in 3 patients and MRI was unremarkable in all the patients examined. Three family members presented major depression and anxiety symptoms. Routine LGI1 exon sequencing revealed no point mutation. High-density SNP array CNV analysis identified a genomic microdeletion about 81 kb in size encompassing the first 4 exons of LGI1 in all available affected members and in 2 nonaffected carriers, which was confirmed by qPCR analysis. CONCLUSIONS: This is the first microdeletion affecting LGI1 identified in ADLTE. Families with ADLTE in which no point mutations are revealed by direct exon sequencing should be screened for possible genomic deletion mutations by CNV analysis or other appropriate methods. Overall, CNV analysis of multiplex families may be useful for identifying microdeletions in novel disease genes. PMID- 22496202 TI - Subclinical peripheral neuropathy is a common finding in colorectal cancer patients prior to chemotherapy. AB - PURPOSE: Of the numerous complications associated with cancer and cancer treatment, peripheral neuropathy is a deleterious and persistent patient complaint commonly attributed to chemotherapy. The present study investigated the occurrence of subclinical peripheral neuropathy in patients with colorectal cancer before the initiation of chemotherapy. EXPERIMENTAL DESIGN: Fifty-two patients underwent extensive quantitative sensory testing (QST) before receiving chemotherapy. Changes in multiple functions of primary afferent fibers were assessed and compared with a group of healthy control subjects. Skin temperature, sensorimotor function, sharpness detection, and thermal detection were measured, as was touch detection, using both conventional (von Frey monofilaments) and novel (Bumps detection test) methodology. RESULTS: Patients had subclinical deficits, especially in sensorimotor function, detection of thermal stimuli, and touch detection that were present before the initiation of chemotherapy. The measured impairment in touch sensation was especially pronounced when using the Bumps detection test. CONCLUSIONS: The patients with colorectal cancer in this study exhibited deficits in sensory function before undergoing chemotherapy treatment, implicating the disease itself as a contributing factor in chemotherapy-induced peripheral neuropathy. The widespread nature of the observed deficits further indicated that cancer is affecting multiple primary afferent subtypes. Specific to the finding of impaired touch sensation, results from this study highlight the use of newly used methodology, the Bumps detection test, as a sensitive and useful tool in the early detection of peripheral neuropathy. PMID- 22496203 TI - Bevacizumab-induced alterations in vascular permeability and drug delivery: a novel approach to augment regional chemotherapy for in-transit melanoma. AB - PURPOSE: To investigate whether the systemically administered anti-VEGF monoclonal antibody bevacizumab could improve regional chemotherapy treatment of advanced extremity melanoma by enhancing delivery and tumor uptake of regionally infused melphalan (LPAM). EXPERIMENTAL DESIGN: After treatment with systemic bevacizumab or saline, changes in vascular permeability were determined by spectrophotometric analysis of tumors infused with Evan's blue dye. Changes in vascular structure and tumor hemoglobin-oxygen saturation HbO(2) were determined by intravital microscopy and diffuse reflectance spectroscopy, respectively. Rats bearing the low-VEGF secreting DM738 and the high-VEGF secreting DM443 melanoma xenografts underwent isolated limb infusion (ILI) with melphalan (LPAM) or saline via the femoral vessels. The effect of bevacizumab on terminal drug delivery was determined by immunohistochemical analysis of LPAM-DNA adducts in tumor tissues. RESULTS: Single-dose bevacizumab given three days before ILI with LPAM significantly decreased vascular permeability (50.3% in DM443, P < 0.01 and 35% in DM738, P < 0.01) and interstitial fluid pressure (57% in DM443, P < 0.01 and 50% in DM738, P = 0.01). HbO(2) decreased from baseline in mice following treatment with bevacizumab. Systemic bevacizumab significantly enhanced tumor response to ILI with LPAM in two melanoma xenografts, DM443 and DM738, increasing quadrupling time 37% and 113%, respectively (P = 0.03). Immunohistochemical analyses of tumor specimens showed that pretreatment with systemic bevacizumab markedly increased LPAM-DNA adduct formation. CONCLUSIONS: Systemic treatment with bevacizumab before regional chemotherapy increases delivery of LPAM to tumor cells and represents a novel way to augment response to regional therapy for advanced extremity melanoma. PMID- 22496204 TI - Mutations in the Ras-Raf Axis underlie the prognostic value of CD133 in colorectal cancer. AB - PURPOSE: High expression of cancer stem cell (CSC) marker CD133 has been used as a predictor for prognosis in colorectal cancer (CRC), suggesting that enumeration of CSCs, using CD133, is predictive for disease progression. However, we showed recently that both CD133 mRNA and protein are not downregulated during differentiation of colon CSCs, pointing to an alternative reason for the prognostic value of CD133. We therefore set out to delineate the relation between CD133 expression and prognosis. EXPERIMENTAL DESIGN: A CRC patient series was studied for expression of CD133 and other CSC markers by microarray and quantitative PCR analysis. In addition, several common mutations were analyzed to determine the relation with CD133 expression. RESULTS: CD133 mRNA expression predicted relapse-free survival in our patient series, whereas several other CSC markers could not. Moreover, no correlation was found between expression of other CSC markers and CD133. Interestingly, high CD133 expression was related to mutations in K-Ras and B-Raf, and inhibition of mutant K-Ras or downstream mitogen-activated protein kinase kinase (MEK) signaling decreases CD133 expression. In addition, an activated K-Ras gene expression signature could predict CD133 expression in our patient set as well as data sets of other tumor types. CONCLUSION: CD133 expression is upregulated in CRC tumors that have a hyperactivated Ras-Raf-MEK-ERK pathway and is therefore related to mutations in K Ras or B-Raf. As mutations in either gene have been related to poor prognosis, we conclude that CD133 expression is not indicative for CSC numbers but rather related to the mutation or activity status of the Ras-Raf pathway. PMID- 22496205 TI - Bridging the gap between preclinical and clinical studies using pharmacokinetic pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. AB - PURPOSE: GDC-0973 is a potent and selective mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor. Pharmacokinetic-pharmacodynamic (PK-PD) modeling was used to relate GDC-0973 plasma and tumor concentrations, tumor pharmacodynamics and antitumor efficacy to establish pharmacokinetic endpoints and predict active doses in the clinic. EXPERIMENTAL DESIGN: A PK-PD model was used to characterize GDC-0973 tumor disposition and in vivo potency in WM-266-4 xenograft mice. Simulations were conducted using the PK-PD model along with human pharmacokinetics to identify a target plasma concentration and predict active doses. In vivo potency and antitumor efficacy were characterized in A375 melanoma xenograft mice, and a population-based integrated PK-PD-efficacy model was used to relate tumor pharmacodynamics (%pERK decrease) to antitumor activity. RESULTS: GDC-0973 showed a sustained tumor pharmacodynamic response due to longer residence in tumor than in plasma. Following single doses of GDC-0973, estimated in vivo IC(50) values of %pERK decrease based on tumor concentrations in xenograft mice were 0.78 (WM-266 4) and 0.52 MUmol/L (A375). Following multiple doses of GDC-0973, the estimated in vivo IC(50) value in WM-266-4 increased (3.89 MUmol/L). Human simulations predicted a minimum target plasma concentration of 83 nmol/L and an active dose range of 28 to 112 mg. The steep relationship between tumor pharmacodynamics (%pERK decrease) and antitumor efficacy suggests a pathway modulation threshold beyond which antitumor efficacy switches on. CONCLUSIONS: Clinical observations of %pERK decrease and antitumor activity were consistent with model predictions. This article illustrates how PK-PD modeling can improve the translation of preclinical data to humans by providing a means to integrate preclinical and early clinical data. PMID- 22496206 TI - MSH3 protein expression and nodal status in MLH1-deficient colorectal cancers. AB - PURPOSE: Patients with colorectal cancers (CRC) and high microsatellite instability (MSI) have a better outcome than their chromosome-unstable counterpart. Given the heterogeneity of microsatellite-unstable CRCs, we wanted to see whether any MSI-associated molecular features are specifically associated with prognosis. EXPERIMENTAL DESIGN: One hundred and nine MSI-high CRCs were typed for primary mismatch repair (MMR) defect and for secondary loss of MMR proteins. Frameshifts at seven target genes, mutations in the RAS pathway, and methylation at MLH1/CDKN2A promoters were also searched. The interplay of molecular findings with clinicopathologic features and patient survival was analyzed. RESULTS: Of 84 MLH1-deficient CRCs, 31 (36.9%) had MSH3 and 11 (13.1%) had MSH6 loss (P < 0.001), biallelic frameshift mutations at mononucleotide repeats accounting for most (78%) MSH3 losses. As compared with MSH3-retaining cancers, MLH1-deficient tumors with MSH3 loss showed a higher number of mutated target genes (3.94 +/- 1.56 vs. 2.79 +/- 1.75; P = 0.001), absence of nodal involvement at pathology [N0; OR, 0.11; 95% confidence interval (CI), 0.04-0.43, P < 0.001], and better disease-free survival (P = 0.06). No prognostic value was observed for KRAS status and for MLH1/CDKN2A promoter methylation. The association between MSH3 loss and N0 was confirmed in an independent cohort of 71 MLH1-deficient CRCs (OR, 0.23; 95% CI, 0.06-0.83, P = 0.02). CONCLUSIONS: MLH1 deficient CRCs not expressing MSH3 have a more severe MSI, a lower rate of nodal involvement, and a better postsurgical outcome. PMID- 22496208 TI - Performance evaluation of 3D polystyrene 96-well plates with human neural stem cells in a calcium assay. AB - In this study, we have generated a high-throughput screening (HTS)-compatible 3D cell culture platform by chemically "welding" polystyrene scaffolds into standard 2D polystyrene 96-well plates. The variability of scaffolds was minimized by introducing automation into the fabrication process. The fabricated 3D cell culture plates were compared with several commercially available 3D cell culture platforms with light and scanning electron microscopy. Voltage-gated calcium channel functionality was used to access the Z' factors of all plates, including a 2D standard plate control. It was found that with the No-Wash Fluo-4 calcium assay and neural progenitor cells, all plates display acceptable Z' factors for use in HTS. The plates with "welded" polystyrene scaffolds have several advantages, such as being versatile and economical, and are ready to use off the shelf. These characteristics are especially desired in HTS preclinical drug discovery applications. PMID- 22496209 TI - Investigating the effect of using granite and marble as a building material on the radiation exposure of humans. AB - The aim of this study was to comprehensively study the radiological hazards of granite and marble used as a building material in Egypt. The activity concentrations of (226)Ra, (232)Th and (40)K were determined using high resolution hyper-pure germanium detectors in 25 samples of different types of commercially available granite and marble. The measured activity concentrations for these natural radionuclides were compared with the reported data for Egypt and other countries. In order to assess the radiological impact, the radiation hazard parameters such as radium equivalent activity (Ra(eq)) and hazard level index (I(gamma)) were calculated. The internal and external dose rates due to natural radionuclides in granite and marble were also calculated. The data obtained were considered as helpful in regulating the use of building materials in Egypt. PMID- 22496207 TI - Effect of sulfasalazine on inflammation and endothelial function in patients with established coronary artery disease. AB - Inflammation is critical for atherosclerosis development and may be a target for risk-reduction therapy. In experimental studies, activation of the inflammatory regulator, nuclear factor kappa B (NFlB), contributes to endothelial activation and reduced nitric oxide production. We treated patients with coronary artery disease with sulfasalazine, an inhibitor of NFkappaB, and placebo in a randomized, double-blind, crossover study design. Brachial artery flow-mediated dilation (FMD) and digital vascular function were measured at baseline and after each 6-week treatment period. Of the 53 patients enrolled in the crossover study, 32 (age 60 +/- 10, 22% female) completed all the visits, with a high rate of study withdrawal due to gastrointestinal side effects. In a subset of 10 participants, we compared the effects of 4 days of sulfasalazine treatment (n = 5) to no treatment (n = 5) on NFkappaB-regulated gene expression in peripheral blood mononuclear cells. Tumor necrosis factor alpha-stimulated expression of CD69 and NFlB subunit p50 was significantly blunted after 4 days of sulfasalazine treatment but not after no treatment. However, FMD and digital vasodilator response did not significantly change from baseline with long-term sulfasalazine treatment. Short-term sulfasalazine inhibited NFlB activity; however, long-term treatment was poorly tolerated and did not improve endothelial function. Our findings suggest that sulfasalazine therapy is not the optimal anti-inflammatory treatment for reversing endothelial dysfunction in cardiovascular disease. Further studies are warranted to investigate the potential for NFlB inhibition to reduce cardiovascular risk. PMID- 22496210 TI - Cysteines in the stalk of the nipah virus G glycoprotein are located in a distinct subdomain critical for fusion activation. AB - Paramyxoviruses initiate entry through the concerted action of the tetrameric attachment glycoprotein (HN, H, or G) and the trimeric fusion glycoprotein (F). The ectodomains of HN/H/G contain a stalk region important for oligomeric stability and for the F triggering resulting in membrane fusion. Paramyxovirus HN, H, and G form a dimer-of-dimers consisting of disulfide-linked dimers through their stalk domain cysteines. The G attachment protein stalk domain of the highly pathogenic Nipah virus (NiV) contains a distinct but uncharacterized cluster of three cysteine residues (C146, C158, C162). On the basis of a panoply of assays, we report that C158 and C162 of NiV-G likely mediate covalent subunit dimerization, while C146 mediates the stability of higher-order oligomers. For HN or H, mutation of stalk cysteines attenuates but does not abrogate the ability to trigger fusion. In contrast, the NiV-G stalk cysteine mutants were completely deficient in triggering fusion, even though they could still bind the ephrinB2 receptor and associate with F. Interestingly, all cysteine stalk mutants exhibited constitutive exposure of the Mab45 receptor binding-enhanced epitope, previously implicated in F triggering. The enhanced binding of Mab45 to the cysteine mutants relative to wild-type NiV-G, without the addition of the receptor, implicates the stalk cysteines in the stabilization of a pre-receptor bound conformation and the regulation of F triggering. Sequence alignments revealed that the stalk cysteines were adjacent to a proline-rich microdomain unique to the Henipavirus genus. Our data propose that the cysteine cluster in the NiV-G stalk functions to maintain oligomeric stability but is more importantly involved in stabilizing a unique microdomain critical for triggering fusion. PMID- 22496211 TI - Deletion of UL21 causes a delay in the early stages of the herpes simplex virus 1 replication cycle. AB - The herpes simplex virus 1 (HSV-1) U(L)21 gene encodes a 62-kDa tegument protein with homologs in the alpha-, beta-, and gammaherpesvirus subfamilies. In the present study, we characterized a novel U(L)21-null virus and its genetic repair to determine whether this protein plays a role in early stages of the HSV-1 replication cycle. Single-step growth analyses, protein synthesis time courses, and mRNA quantifications indicated that the absence of U(L)21 results in a delay early in the HSV-1 replication cycle. PMID- 22496212 TI - A triclade DNA vaccine designed on the basis of a comprehensive serologic study elicits neutralizing antibody responses against all clades and subclades of highly pathogenic avian influenza H5N1 viruses. AB - Because of their rapid evolution, genetic diversity, broad host range, ongoing circulation in birds, and potential human-to-human transmission, H5N1 influenza viruses remain a major global health concern. Their high degree of genetic diversity also poses enormous burdens and uncertainties in developing effective vaccines. To overcome this, we took a new approach, i.e., the development of immunogens based on a comprehensive serologic study. We constructed DNA plasmids encoding codon-optimized hemagglutinin (HA) from 17 representative strains covering all reported clades and subclades of highly pathogenic avian influenza H5N1 viruses. Using DNA plasmids, we generated the corresponding H5N1 pseudotypes and immune sera. We performed an across-the-board pseudotype-based neutralization assay and determined antigenic clusters by cartography. We then designed a triclade DNA vaccine and evaluated its immunogenicity and protection in mice. We report here that (sub)clades 0, 1, 3, 4, 5, 6, 7.1, and 9 were grouped into antigenic cluster 1, (sub)clades 2.1.3.2, 2.3.4, 2.4, 2.5, and 8 were grouped into another antigenic cluster, with subclade 2.2.1 loosely connected to it, and each of subclades 2.3.2.1 and 7.2 was by itself. Importantly, the triclade DNA vaccine encoding HAs of (sub)clades 0, 2.3.2.1, and 7.2 elicited broadly neutralizing antibody responses against all H5 clades and subclades and protected mice against high-lethal-dose heterologous H5N1 challenge. Thus, we conclude that broadly neutralizing antibodies against all H5 clades and subclades can indeed be elicited with immunogens on the basis of a comprehensive serologic study. Further evaluation and optimization of such an approach in ferrets and in humans is warranted. PMID- 22496213 TI - Genetic analysis of cytomegalovirus in malignant gliomas. AB - Human cytomegalovirus (HCMV) has been found in malignant gliomas at variable frequencies with efforts to date focused on characterizing the role(s) of single gene products in disease. Here, we reexamined the HCMV prevalence in malignant gliomas using different methods and began to dissect the genetics of HCMV in tumors. HCMV DNA was found in 16/17 (94%) tumor specimens. Viral DNA copy numbers were found to be low and variable, ranging from 10(2) to 10(6) copies/500 ng of total DNA. The tumor tissues had incongruences between viral DNA copy numbers and protein levels. However, nonlatent protein expression was detected in many tumors. The viral UL83 gene, encoding pp65, was found to segregate into five cancer-associated genotypes with a bias for amino acid changes in glioblastoma multiforme (GBM) in comparison to the low-grade tumors. Deep sequencing of a GBM associated viral population resulted in 81,224 bp of genome coverage. Sequence analysis revealed the presence of intact open reading frames and higher numbers of high-frequency variations within the repeat long region compared to the unique long region, which harbors many core genes, and the unique short region (P = 0.001). This observation was in congruence with phylogenetic analyses across replication-competent viral strains in databases. The tumor-associated viral population was less variable (pi = 0.1% and pi(AA) = 0.08%) than that observed in other clinical infections. Moreover, 42/46 (91.3%) viral genes analyzed had dN/dS scores of <1, which is indicative of high amino acid sequence conservation. Taken together, these findings raise the possibility that replication-competent HCMV may exist in malignant gliomas. PMID- 22496214 TI - Endothelial cells elicit immune-enhancing responses to dengue virus infection. AB - Dengue viruses cause two severe diseases that alter vascular fluid barrier functions, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Preexisting antibodies to dengue virus disposes patients to immune-enhanced edema (DSS) or hemorrhagic (DHF) disease following infection by a discrete dengue virus serotype. Although the endothelium is the primary vascular fluid barrier, direct effects of dengue virus on endothelial cells (ECs) have not been considered primary factors in pathogenesis. Here, we show that dengue virus infection of human ECs elicits immune-enhancing EC responses. Our results suggest that rapid early dengue virus proliferation within ECs is permitted by dengue virus regulation of early, but not late, beta interferon (IFN-beta) responses. The analysis of EC responses following synchronous dengue virus infection revealed the high-level induction and secretion of immune cells (T cells, B cells, and mast cells) as well as activating and recruiting cytokines BAFF (119-fold), IL 6/8 (4- to 7-fold), CXCL9/10/11 (45- to 338-fold), RANTES (724-fold), and interleukin-7 (IL-7; 128-fold). Moreover, we found that properdin factor B, an alternative pathway complement activator that directs chemotactic anaphylatoxin C3a and C5a production, was induced 34-fold. Thus, dengue virus-infected ECs evoke key inflammatory responses observed in dengue virus patients which are linked to DHF and DSS. Our findings suggest that dengue virus-infected ECs directly contribute to immune enhancement, capillary permeability, viremia, and immune targeting of the endothelium. These data implicate EC responses in dengue virus pathogenesis and further rationalize therapeutic targeting of the endothelium as a means of reducing the severity of dengue virus disease. PMID- 22496216 TI - Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry. AB - The type II transmembrane protease TMPRSS2 activates the spike (S) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) on the cell surface following receptor binding during viral entry into cells. In the absence of TMPRSS2, SARS-CoV achieves cell entry via an endosomal pathway in which cathepsin L may play an important role, i.e., the activation of spike protein fusogenicity. This study shows that a commercial serine protease inhibitor (camostat) partially blocked infection by SARS-CoV and human coronavirus NL63 (HCoV-NL63) in HeLa cells expressing the receptor angiotensin-converting enzyme 2 (ACE2) and TMPRSS2. Simultaneous treatment of the cells with camostat and EST [(23,25)trans epoxysuccinyl-L-leucylamindo-3-methylbutane ethyl ester], a cathepsin inhibitor, efficiently prevented both cell entry and the multistep growth of SARS-CoV in human Calu-3 airway epithelial cells. This efficient inhibition could be attributed to the dual blockade of entry from the cell surface and through the endosomal pathway. These observations suggest camostat as a candidate antiviral drug to prevent or depress TMPRSS2-dependent infection by SARS-CoV. PMID- 22496215 TI - Mice deficient in STAT1 but not STAT2 or IRF9 develop a lethal CD4+ T-cell mediated disease following infection with lymphocytic choriomeningitis virus. AB - Interferon (IFN) signaling is crucial for antiviral immunity. While type I IFN signaling is mediated by STAT1, STAT2, and IRF9, type II IFN signaling requires only STAT1. Here, we studied the roles of these signaling factors in the host response to systemic infection with lymphocytic choriomeningitis virus (LCMV). In wild-type (WT) mice and mice lacking either STAT2 or IRF9, LCMV infection was nonlethal, and the virus either was cleared (WT) or established persistence (STAT2 knockout [KO] and IRF9 KO). However, in the case of STAT1 KO mice, LCMV infection was lethal and accompanied by severe multiorgan immune pathology, elevated expression of various cytokine genes in tissues, and cytokines in the serum. This lethal phenotype was unaltered by the coabsence of the gamma interferon (IFN-gamma) receptor and hence was not dependent on IFN-gamma. Equally, the disease was not due to a combined defect in type I and type II IFN signaling, as IRF9 KO mice lacking the IFN-gamma receptor survived infection with LCMV. Clearance of LCMV is mediated normally by CD8(+) T cells. However, the depletion of these cells in LCMV-infected STAT1 KO mice was delayed, but did not prevent, lethality. In contrast, depletion of CD4(+) T cells prevented lethality in LCMV-infected STAT1 KO mice and was associated with a reduction in tissue immune pathology. These studies highlight a fundamental difference in the role of STAT1 versus STAT2 and IRF9. While all three factors are required to limit viral replication and spread, only STAT1 has the unique function of preventing the emergence of a lethal antiviral CD4(+) T-cell response. PMID- 22496217 TI - The US16 gene of human cytomegalovirus is required for efficient viral infection of endothelial and epithelial cells. AB - The human cytomegalovirus (HCMV) US12 gene family comprises a set of 10 contiguous genes (US12 to US21), each encoding a predicted seven-transmembrane protein and whose specific functions have yet to be ascertained. While inactivation of individual US12 family members in laboratory strains of HCMV has not been found to affect viral replication in fibroblasts, inactivation of US16 was reported to increase replication in microvascular endothelial cells. Here, we investigate the properties of US16 further by ascertaining the expression pattern of its product. A recombinant HCMV encoding a tagged version of the US16 protein expressed a 33-kDa polypeptide that accumulated with late kinetics in the cytoplasmic virion assembly compartment. To elucidate the function(s) of pUS16, we generated US16-deficient mutants in the TR clinical strain of HCMV. According to previous studies, inactivation of US16 had no effect on viral replication in fibroblasts. In contrast, the US16-deficient viruses exhibited a major growth defect in both microvascular endothelial cells and retinal pigment epithelial cells. The expression of representative IE, E, and L viral proteins was impaired in endothelial cells infected with a US16 mutant virus, suggesting a defect in the replication cycle that occurs prior to IE gene expression. This defect must be due to an inefficient entry and/or postentry event, since pp65 and viral DNA did not move to the nucleus in US16 mutant-infected cells. Taken together, these data indicate that the US16 gene encodes a novel virus tropism factor that regulates, in a cell-specific manner, a pre-immediate-early phase of the HCMV replication cycle. PMID- 22496218 TI - Frequent and strong antibody-mediated natural killer cell activation in response to HIV-1 Env in individuals with chronic HIV-1 infection. AB - Natural killer (NK) cells play a critical role in the control of HIV-1 infection, and NK cells that respond to HIV-1 peptides have been recently described. However, the mechanisms by which NK cells recognize HIV-1 antigens are not fully understood. We investigated NK cell activation in response to HIV-1 peptides during early and chronic HIV-1 clade B infection using a whole-blood assay and multiparameter flow cytometry. Antibody-mediated NK cell activation in response to HIV-1 peptides was not detected in HIV-1-uninfected individuals. In contrast, 79% of individuals with chronic infection and 22% of individuals with early infection had detectable gamma interferon (IFN-gamma) NK cell responses to HIV-1 antigens (P < 0.00001). IFN-gamma- and tumor necrosis factor alpha (TNF-alpha) producing NK cells most frequently targeted Env gp120 (median of 4% and range of 0 to 31% of all NK cells). NK cells rarely targeted other HIV-1 proteins such as Gag, Pol, and Nef. Antibody-mediated NK cell responses to peptides mapped predominantly to Env protein, required the presence of plasma or plasma IgG, and resulted in lower CD16 expression on NK cells, suggesting an antibody-mediated activation of NK cells. Further studies are needed to assess the consequences of these antibody-mediated NK cell responses for HIV-1 disease progression and vaccine-induced protection from infection. PMID- 22496219 TI - Structural basis for RNA binding and homo-oligomer formation by influenza B virus nucleoprotein. AB - Influenza virus nucleoprotein (NP) is the major component of the viral ribonucleoprotein complex, which is crucial for the transcription and replication of the viral genome. We have determined the crystal structure of influenza B virus NP to a resolution of 3.2 A. Influenza B NP contains a head, a body domain, and a tail loop. The electropositive groove between the head and body domains of influenza B NP is crucial for RNA binding. This groove also contains an extended flexible charged loop (amino acids [aa] 125 to 149), and two lysine clusters at the first half of this loop were shown to be crucial for binding RNA. Influenza B virus NP forms a crystallographic homotetramer by inserting the tail loop into the body domain of the neighboring NP molecule. A deeply buried salt bridge between R472 and E395 and a hydrophobic cluster at F468 are the major driving forces for the insertion. The analysis of the influenza B virus NP structure and function and comparisons with influenza A virus NP provide insights into the mechanisms of action and underpin efforts to design inhibitors for this class of proteins. PMID- 22496220 TI - Characterization of a novel bipartite double-stranded RNA mycovirus conferring hypovirulence in the phytopathogenic fungus Botrytis porri. AB - The ascomycete Botrytis porri causes clove rot and leaf blight of garlic worldwide. We report here the biological and molecular features of a novel bipartite double-stranded RNA (dsRNA) mycovirus named Botrytis porri RNA virus 1 (BpRV1) from the hypovirulent strain GarlicBc-72 of B. porri. The BpRV1 genome comprises two dsRNAs, dsRNA-1 (6,215 bp) and dsRNA-2 (5,879 bp), which share sequence identities of 62 and 95% at the 3'- and 5'-terminal regions, respectively. Two open reading frames (ORFs), ORF I (dsRNA-1) and ORF II (dsRNA 2), were detected. The protein encoded by the 3'-proximal coding region of ORF I shows sequence identities of 19 to 23% with RNA-dependent RNA polymerases encoded by viruses in the families Totiviridae, Chrysoviridae, and Megabirnaviridae. However, the proteins encoded by the 5'-proximal coding region of ORF I and by the entire ORF II lack sequence similarities to any reported virus proteins. Phylogenetic analysis showed that BpRV1 belongs to a separate clade distinct from those of other known RNA mycoviruses. Purified virions of ~35 nm in diameter encompass dsRNA-1 and dsRNA-2, and three structural proteins (SPs) of 70, 80, and 85 kDa, respectively. Peptide mass fingerprinting analysis revealed that the 80- and 85-kDa SPs are encoded by ORF I, while the 70-kDa SP is encoded by ORF II. Introducing BpRV1 purified virions into the virulent strain GarlicBc-38 of B. porri caused derivative 38T reduced mycelial growth and hypovirulence. These combined results suggest that BpRV1 is a novel bipartite dsRNA virus that possibly belongs to a new virus family. PMID- 22496221 TI - A conserved N-terminal domain mediates required DNA replication activities and phosphorylation of the transcriptional activator IE1 of Autographa californica multicapsid nucleopolyhedrovirus. AB - IE1 is the principal transcriptional regulator of the baculoviruses. Like multifunctional transcription factors of other large DNA viruses, IE1 is an essential, site-specific DNA-binding phosphoprotein that activates virus gene expression and promotes genome replication. To define the poorly understood mechanisms by which IE1 achieves its diverse functions, we identified IE1 domains that contribute to productive infection of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV), the baculovirus prototype. Site-directed mutagenesis revealed that the N-terminal 23 residues of IE1 are required for origin-specific DNA replication and AcMNPV propagation, but not for DNA-binding dependent transcriptional activation. Within this defined replication domain, we identified an invariant TPXR/H motif that resembles a consensus cyclin-dependent kinase phosphorylation site. Amino acid substitutions of potential phosphorylation sites within or near this motif caused loss of IE1-mediated DNA replication activity. Remarkably, substitution of the single threonine (residue 15) within the TPXR/H motif caused complete loss of AcMNPV multiplication. The replication domain was required for IE1 phosphorylation. It was also sufficient for conferring phosphorylation of a heterologous protein. Importantly, IE1 hyperphosphorylation coincided exclusively with AcMNPV DNA replication. The temporal regulation of IE1 phosphorylation and the essential nature of the TPXR/H motif suggest that phosphorylation critically alters and possibly activates DNA replication activity of IE1 during infection. The striking conservation of the TPXR/H motif among IE1 proteins further suggests that this molecular switch may be a common mechanism by which the alphabaculoviruses coordinate DNA replication and gene expression by using a single regulator. PMID- 22496222 TI - Distinct effects of two HIV-1 capsid assembly inhibitor families that bind the same site within the N-terminal domain of the viral CA protein. AB - The emergence of resistance to existing classes of antiretroviral drugs necessitates finding new HIV-1 targets for drug discovery. The viral capsid (CA) protein represents one such potential new target. CA is sufficient to form mature HIV-1 capsids in vitro, and extensive structure-function and mutational analyses of CA have shown that the proper assembly, morphology, and stability of the mature capsid core are essential for the infectivity of HIV-1 virions. Here we describe the development of an in vitro capsid assembly assay based on the association of CA-NC subunits on immobilized oligonucleotides. This assay was used to screen a compound library, yielding several different families of compounds that inhibited capsid assembly. Optimization of two chemical series, termed the benzodiazepines (BD) and the benzimidazoles (BM), resulted in compounds with potent antiviral activity against wild-type and drug-resistant HIV 1. Nuclear magnetic resonance (NMR) spectroscopic and X-ray crystallographic analyses showed that both series of inhibitors bound to the N-terminal domain of CA. These inhibitors induce the formation of a pocket that overlaps with the binding site for the previously reported CAP inhibitors but is expanded significantly by these new, more potent CA inhibitors. Virus release and electron microscopic (EM) studies showed that the BD compounds prevented virion release, whereas the BM compounds inhibited the formation of the mature capsid. Passage of virus in the presence of the inhibitors selected for resistance mutations that mapped to highly conserved residues surrounding the inhibitor binding pocket, but also to the C-terminal domain of CA. The resistance mutations selected by the two series differed, consistent with differences in their interactions within the pocket, and most also impaired virus replicative capacity. Resistance mutations had two modes of action, either directly impacting inhibitor binding affinity or apparently increasing the overall stability of the viral capsid without affecting inhibitor binding. These studies demonstrate that CA is a viable antiviral target and demonstrate that inhibitors that bind within the same site on CA can have distinct binding modes and mechanisms of action. PMID- 22496223 TI - Structure of hepatitis C virus polymerase in complex with primer-template RNA. AB - The replication of the hepatitis C viral (HCV) genome is accomplished by the NS5B RNA-dependent RNA polymerase (RdRp), for which mechanistic understanding and structure-guided drug design efforts have been hampered by its propensity to crystallize in a closed, polymerization-incompetent state. The removal of an autoinhibitory beta-hairpin loop from genotype 2a HCV NS5B increases de novo RNA synthesis by >100-fold, promotes RNA binding, and facilitated the determination of the first crystallographic structures of HCV polymerase in complex with RNA primer-template pairs. These crystal structures demonstrate the structural realignment required for primer-template recognition and elongation, provide new insights into HCV RNA synthesis at the molecular level, and may prove useful in the structure-based design of novel antiviral compounds. Additionally, our approach for obtaining the RNA primer-template-bound structure of HCV polymerase may be generally applicable to solving RNA-bound complexes for other viral RdRps that contain similar regulatory beta-hairpin loops, including bovine viral diarrhea virus, dengue virus, and West Nile virus. PMID- 22496224 TI - A novel variant marking HLA-DP expression levels predicts recovery from hepatitis B virus infection. AB - Variants near the HLA-DP gene show the strongest genome-wide association with chronic hepatitis B virus (HBV) infection and HBV recovery/persistence in Asians. To test the effect of the HLA-DP region on outcomes to HBV infection, we sequenced the polymorphic HLA-DPB1 and DPA1 coding exons and the corresponding 3' untranslated regions (3'UTRs) in 662 individuals of European-American and African American ancestry. The genome-wide association study (GWAS) variant (rs9277535; 550A/G) in the 3'UTR of the HLA-DPB1 gene that associated most significantly with chronic hepatitis B and outcomes to HBV infection in Asians had a marginal effect on HBV recovery in our European- and African-American samples (odds ratio [OR] = 0.39, P = 0.01, combined ethnic groups). However, we identified a novel variant in the HLA-DPB1 3'UTR region, 496A/G (rs9277534), which associated very significantly with HBV recovery in both European and African-American populations (OR = 0.37, P = 0.0001, combined ethnic groups). The 496A/G variant distinguishes the most protective HLA-DPB1 allele (DPB1*04:01) from the most susceptible (DPB1*01:01), whereas 550A/G does not. 496A/G has a stronger effect than any individual HLA-DPB1 or DPA1 allele and any other HLA alleles that showed an association with HBV recovery in our European-American cohort. The 496GG genotype, which confers recessive susceptibility to HBV persistence, also associates in a recessive manner with significantly higher levels of HLA-DP surface protein and transcript level expression in healthy donors, suggesting that differences in expression of HLA-DP may increase the risk of persistent HBV infection. PMID- 22496225 TI - Herpes simplex virus glycoproteins gH/gL and gB bind Toll-like receptor 2, and soluble gH/gL is sufficient to activate NF-kappaB. AB - A number of sentinels sense incoming herpes simplex virus (HSV) virions and initiate an immediate innate response. The first line of defense at the cell surface is TLR2 (Toll-like receptor 2), whose signature signaling activity leads to activation of the key transcription factor NF-kappaB. We report that the HSV pathogen-associated molecular patterns for TLR2 are the virion glycoproteins gH/gL and gB, which constitute the conserved fusion core apparatus across the members of the Herpesviridae family. Specifically, virions devoid singly of one of essential fusion glycoproteins (gD, gB, or gH null), able to attach to cells but defective in fusion/entry, were sufficient to elicit the first wave of NF kappaB response to HSV. The most effective were the gD-null virions, positive for gH/gL and gB. A soluble form of gB, truncated upstream of the transmembrane sequence (gB(730t-st)), was produced in human cells and purified by means of a Strep tag. gH/gL and gB were each able to physically interact with TLR2 in coimmunoprecipitation assays, one independently of the other, yet gH(t-st)/gL, but not gB(730t-st), elicited an NF-kappaB response. Thus, whereas both HSV gH/gL and gB are ligands to TLR2, only gH/gL is sufficient to initiate a signaling cascade which leads to NF-kappaB activation. PMID- 22496226 TI - The Epstein-Barr virus (EBV)-induced tumor suppressor microRNA MiR-34a is growth promoting in EBV-infected B cells. AB - Epstein-Barr virus (EBV) infection of primary human B cells drives their indefinite proliferation into lymphoblastoid cell lines (LCLs). B cell immortalization depends on expression of viral latency genes, as well as the regulation of host genes. Given the important role of microRNAs (miRNAs) in regulating fundamental cellular processes, in this study, we assayed changes in host miRNA expression during primary B cell infection by EBV. We observed and validated dynamic changes in several miRNAs from early proliferation through immortalization; oncogenic miRNAs were induced, and tumor suppressor miRNAs were largely repressed. However, one miRNA described as a p53-targeted tumor suppressor, miR-34a, was strongly induced by EBV infection and expressed in many EBV and Kaposi's sarcoma-associated herpesvirus (KSHV)-infected lymphoma cell lines. EBV latent membrane protein 1 (LMP1) was sufficient to induce miR-34a requiring downstream NF-kappaB activation but independent of functional p53. Furthermore, overexpression of miR-34a was not toxic in several B lymphoma cell lines, and inhibition of miR-34a impaired the growth of EBV-transformed cells. This study identifies a progrowth role for a tumor-suppressive miRNA in oncogenic virus-mediated transformation, highlighting the importance of studying miRNA function in different cellular contexts. PMID- 22496227 TI - Cdk1 inhibition induces mutually inhibitory apoptosis and reactivation of Kaposi's sarcoma-associated herpesvirus. AB - Primary effusion lymphoma (PEL) cells are predominantly infected by the latent form of Kaposi's sarcoma-associated herpesvirus (KSHV), with virus reactivation occurring in a small percentage of cells. Latency enables KSHV to persist in the host cell and promotes tumorigenesis through viral gene expression, thus presenting a major barrier to the elimination of KSHV and the treatment of PEL. Therefore, it is important to identify cellular genes that are essential for PEL cell survival or the maintenance of KSHV latency. Here we report that cyclin dependent kinase 1 (Cdk1) inhibition can induce both apoptosis and KSHV reactivation in a population of PEL cells. Caspases, but not p53, are required for PEL cell apoptosis induced by Cdk1 inhibition. p38 kinase is activated by Cdk1 inhibition and mediates KSHV reactivation. Interestingly, upon Cdk1 inhibition, KSHV is reactivated predominantly in the nonapoptotic subpopulation of PEL cells. We provide evidence that this is due to mutual inhibition between apoptosis and KSHV reactivation. In addition, we found that KSHV reactivation activates protein kinase B (AKT/PKB), which promotes cell survival and facilitates KSHV reactivation. Our study thus establishes a key role for Cdk1 in PEL cell survival and the maintenance of KSHV latency and reveals a multifaceted relationship between KSHV reactivation and PEL cell apoptosis. PMID- 22496228 TI - Classical swine fever virus p7 protein is a viroporin involved in virulence in swine. AB - The nonstructural protein p7 of classical swine fever virus (CSFV) is a small hydrophobic polypeptide with an apparent molecular mass of 6 to 7 kDa. The protein contains two hydrophobic stretches of amino acids interrupted by a short charged segment that are predicted to form transmembrane helices and a cytosolic loop, respectively. Using reverse genetics, partial in-frame deletions of p7 were deleterious for virus growth, demonstrating that CSFV p7 function is critical for virus production in cell cultures. A panel of recombinant mutant CSFVs was created using alanine scanning mutagenesis of the p7 gene harboring sequential three- to six-amino-acid residue substitutions spanning the entire protein. These recombinant viruses allowed the identification of the regions within p7 that are critical for virus production in vitro. In vivo, some of these viruses were partially or completely attenuated in swine relative to the highly virulent parental CSFV Brescia strain, indicating a significant role of p7 in CSFV virulence. Structure-function analyses in model membranes emulating the endoplasmic reticulum lipid composition confirmed that CSFV p7 is a pore-forming protein, and that pore-forming activity resides in the C-terminal transmembrane helix. Therefore, p7 is a viroporin which is clearly involved in the process of CSFV virulence in swine. PMID- 22496229 TI - Human galectin 3 binding protein interacts with recombinant adeno-associated virus type 6. AB - Recombinant adeno-associated viruses (rAAVs) hold enormous potential for human gene therapy. Despite the well-established safety and efficacy of rAAVs for in vivo gene transfer, there is still little information concerning the fate of vectors in blood following systemic delivery. We screened for serum proteins interacting with different AAV serotypes in humans, macaques, dogs, and mice. We report that serotypes rAAV-1, -5, and -6 but not serotypes rAAV-2, -7, -8, -9, and -10 interact in human sera with galectin 3 binding protein (hu-G3BP), a soluble scavenger receptor. Among the three serotypes, rAAV-6 has the most important capacities for binding to G3BP. rAAV-6 also bound G3BP in dog sera but not in macaque and mouse sera. In mice, rAAV-6 interacted with another protein of the innate immune system, C-reactive protein (CRP). Furthermore, interaction of hu-G3BP with rAAV-6 led to the formation of aggregates and hampered transduction when the two were codelivered into the mouse. Based on these data, we propose that species-specific interactions of AAVs with blood proteins may differentially impact vector distribution and efficacy in different animal models. PMID- 22496230 TI - Murine cytomegalovirus targets transcription factor ATF4 to exploit the unfolded protein response. AB - The unfolded-protein response (UPR), activated by sensor molecules PERK, ATF6, and IRE1 to resolve endoplasmic reticulum (ER) stress, has emerged as a key target for host cells and viruses to control the infection outcomes. The UPR regulates ER protein folding, controls cell fate upon ER stress, and plays an important role in innate immunity. We and others have shown that human cytomegalovirus (HCMV) modulates the UPR. We show here that murine CMV (MCMV), the widely used CMV model for small animal infection, regulated the UPR in a manner similar to that of HCMV. This modulatory ability was triggered by virion entry and enhanced by viral immediate-early and early gene expression. Thus, while vulnerable at early times, MCMV became resistant to exogenous ER stress at late times of infection. MCMV activated the PERK-ATF4 pathway but only induced a subset of representative ATF4 targets at levels somewhat lower than those by the ER stress inducer tunicamycin. Moreover, MCMV induced ER chaperone Bip but actively blocked IRE1-mediated Xbp1(s) protein accumulation. ATF4 depletion severely attenuated viral growth at a low multiplicity of infection by modestly reducing viral DNA synthesis and more pronouncedly inhibiting late gene transcription. Collectively, we show that the UPR is a conserved target of CMVs and identify ATF4, a key UPR component, as a factor critical for MCMV infection. This work sets the stage for using the MCMV model to explore the role of this stress response in CMV biology, particularly during infection of the host, which is difficult to study in HCMV. PMID- 22496231 TI - A single amino acid at the hemagglutinin cleavage site contributes to the pathogenicity and neurovirulence of H5N1 influenza virus in mice. AB - H5 influenza viruses containing a motif of multiple basic amino acids at the hemagglutinin (HA) cleavage site (HACS) are highly pathogenic in chicken but display different virulence phenotypes in mammals. Previous studies have shown that multiple basic amino acids of H5N1 influenza virus are a prerequisite for lethality in mice. However, it remains unclear which specific residue at the cleavage site affects the pathogenicity of H5N1 in mammals. A comprehensive genetic analysis of the H5N1 HACS showed that residues at P6 (position 325, by H3 numbering) were the most polymorphic, including serine (S), arginine (R), deletion (*), glycine (G), and isoleucine (I). To determine whether a single residue at P6 could affect virulence, we introduced different mutations at P6 of an avirulent clade 7 H5N1 strain, rg325G, by reverse genetics. Among the recombinant viruses, the rg325S virus showed the highest cleavage efficiency in vitro. All these viruses were highly pathogenic in chicken but exhibited different virulences in mice. The rg325S virus exhibited the highest pathogenicity in terms of unrestricted organ tropism and neurovirulence. Remarkably, the HA-325S substitution dramatically increased the pathogenicity of H5N1 viruses of other clades, including clades 2.2, 2.3.2, and 2.3.4, indicating that this residue impacts genetically divergent H5N1 viruses. An analysis of predicted structures containing these mutations showed that the cleavage site loop with 325S was the most exposed, which might be responsible for the efficient cleavage and high virulence. Our results demonstrate that an amino acid substitution at the P6 cleavage site alone could modulate the virulence of H5N1 in mice. PMID- 22496232 TI - Integrin beta1 mediates vaccinia virus entry through activation of PI3K/Akt signaling. AB - Vaccinia virus has a broad range of infectivity in many cell lines and animals. Although it is known that the vaccinia mature virus binds to cell surface glycosaminoglycans and extracellular matrix proteins, whether additional cellular receptors are required for virus entry remains unclear. Our previous studies showed that the vaccinia mature virus enters through lipid rafts, suggesting the involvement of raft-associated cellular proteins. Here we demonstrate that one lipid raft-associated protein, integrin beta1, is important for vaccinia mature virus entry into HeLa cells. Vaccinia virus associates with integrin beta1 in lipid rafts on the cell surface, and the knockdown of integrin beta1 in HeLa cells reduces vaccinia mature virus entry. Additionally, vaccinia mature virus infection is reduced in a mouse cell line, GD25, that is deficient in integrin beta1 expression. Vaccinia mature virus infection triggers the activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling, and the treatment of cells with inhibitors to block P13K activation reduces virus entry in an integrin beta1 dependent manner, suggesting that integrin beta1-mediates PI3K/Akt activation induced by vaccinia virus and that this signaling pathway is essential for virus endocytosis. The inhibition of integrin beta1-mediated cell adhesion results in a reduction of vaccinia virus entry and the disruption of focal adhesion and PI3K/Akt activation. In summary, our results show that the binding of vaccinia mature virus to cells mimics the outside-in activation process of integrin functions to facilitate vaccinia virus entry into HeLa cells. PMID- 22496234 TI - Proteomic profiling of EBNA1-host protein interactions in latent and lytic Epstein-Barr virus infections. AB - The Epstein-Barr nuclear antigen 1 (EBNA1) protein of Epstein-Barr virus (EBV) is expressed in both latent and lytic modes of EBV infection and contributes to EBV associated cancers. Using a proteomics approach, we profiled EBNA1-host protein interactions in nasopharyngeal and gastric carcinoma cells in the context of latent and lytic EBV infection. We identified several interactions that occur in both modes of infection, including a previously unreported interaction with nucleophosmin and RNA-mediated interactions with several heterogeneous ribonucleoproteins (hnRNPs) and La protein. PMID- 22496233 TI - Uncommon pathways of immune escape attenuate HIV-1 integrase replication capacity. AB - An attenuation of the HIV-1 replication capacity (RC) has been observed for immune-mediated escape mutations in Gag restricted by protective HLA alleles. However, the extent to which escape mutations affect other viral proteins during natural infection is not well understood. We generated recombinant viruses encoding plasma HIV-1 RNA integrase sequences from antiretroviral-naive individuals with early (n = 88) and chronic (n = 304) infections and measured the in vitro RC of each. In contrast to data from previous studies of Gag, we observed little evidence that host HLA allele expression was associated with integrase RC. A modest negative correlation was observed between the number of HLA-B-associated integrase polymorphisms and RC in chronic infection (R = -0.2; P = 0.003); however, this effect was not driven by mutations restricted by protective HLA alleles. Notably, the integrase variants S119R, G163E, and I220L, which represent uncommon polymorphisms associated with HLA-C*05, -A*33, and B*52, respectively, correlated with lower RC (all q < 0.2). We identified a novel C*05-restricted epitope (HTDNGSNF(114-121)) that likely contributes to the selection of the S119R variant, the polymorphism most significantly associated with lower RC in patient sequences. An NL4-3 mutant encoding the S119R polymorphism displayed a ~35%-reduced function that was rescued by a single compensatory mutation of A91E. Together, these data indicate that substantial HLA driven attenuation of integrase is not a general phenomenon during HIV-1 adaptation to host immunity. However, uncommon polymorphisms selected by HLA alleles that are not conventionally regarded to be protective may be associated with impaired protein function. Vulnerable epitopes in integrase might therefore be considered for future vaccine strategies. PMID- 22496235 TI - Coordinate regulation of DNA damage and type I interferon responses imposes an antiviral state that attenuates mouse gammaherpesvirus type 68 replication in primary macrophages. AB - DNA damage response (DDR) is a sophisticated cellular network that detects and repairs DNA breaks. Viruses are known to activate the DDR and usurp certain DDR components to facilitate replication. Intriguingly, viruses also inhibit several DDR proteins, suggesting that this cellular network has both proviral and antiviral features, with the nature of the latter still poorly understood. In this study we show that irradiation of primary murine macrophages was associated with enhanced expression of several antiviral interferon (IFN)-stimulated genes (ISGs). ISG induction in irradiated macrophages was dependent on type I IFN signaling, a functional DNA damage sensor complex, and ataxia-telangiectasia mutated kinase. Furthermore, IFN regulatory factor 1 was also required for the optimal expression of antiviral ISGs in irradiated macrophages. Importantly, DDR mediated activation of type I IFN signaling contributed to increased resistance to mouse gammaherpesvirus 68 replication, suggesting that the coordinate regulation of DDR and type I IFN signaling may have evolved as a component of the innate immune response to virus infections. PMID- 22496236 TI - Replication-uncoupled histone deposition during adenovirus DNA replication. AB - In infected cells, the chromatin structure of the adenovirus genome DNA plays critical roles in its genome functions. Previously, we reported that in early phases of infection, incoming viral DNA is associated with both viral core protein VII and cellular histones. Here we show that in late phases of infection, newly synthesized viral DNA is also associated with histones. We also found that the knockdown of CAF-1, a histone chaperone that functions in the replication coupled deposition of histones, does not affect the level of histone H3 bound on viral chromatin, although CAF-1 is accumulated at viral DNA replication foci together with PCNA. Chromatin immunoprecipitation assays using epitope-tagged histone H3 demonstrated that histone variant H3.3, which is deposited onto the cellular genome in a replication-independent manner, is selectively associated with both incoming and newly synthesized viral DNAs. Microscopic analyses indicated that histones but not USF1, a transcription factor that regulates viral late gene expression, are excluded from viral DNA replication foci and that this is achieved by the oligomerization of the DNA binding protein (DBP). Taken together, these results suggest that histone deposition onto newly synthesized viral DNA is most likely uncoupled with viral DNA replication, and a possible role of DBP oligomerization in this replication-uncoupled histone deposition is discussed. PMID- 22496237 TI - CD4+ CD25+ regulatory T cells impair HIV-1-specific CD4 T cell responses by upregulating interleukin-10 production in monocytes. AB - T cell dysfunction in the presence of ongoing antigen exposure is a cardinal feature of chronic viral infections with persistent high viremia, including HIV 1. Although interleukin-10 (IL-10) has been implicated as an important mediator of this T cell dysfunction, the regulation of IL-10 production in chronic HIV-1 infection remains poorly understood. We demonstrated that IL-10 is elevated in the plasma of individuals with chronic HIV-1 infection and that blockade of IL-10 signaling results in a restoration of HIV-1-specific CD4 T cell proliferation, gamma interferon (IFN-gamma) secretion, and, to a lesser extent, IL-2 production. Whereas IL-10 blockade leads to restoration of IFN-gamma secretion by HIV-1 specific CD4 T cells in all categories of subjects investigated, significant enhancement of IL-2 production and improved proliferation of CD4 T helper cells are restricted to viremic individuals. In peripheral blood mononuclear cells (PBMCs), this IL-10 is produced primarily by CD14(+) monocytes, but its production is tightly controlled by regulatory T cells (Tregs), which produce little IL-10 directly. When Tregs are depleted from PBMCs of viremic individuals, the effect of the IL-10 signaling blockade is abolished and IL-10 production by monocytes decreases, while the production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), increases. The regulation of IL-10 by Tregs appears to be mediated primarily by contact or paracrine-dependent mechanisms which involve IL-27. This work describes a novel mechanism by which regulatory T cells control IL-10 production and contribute to dysfunctional HIV-1 specific CD4 T cell help in chronic HIV-1 infection and provides a unique mechanistic insight into the role of regulatory T cells in immune exhaustion. PMID- 22496239 TI - The N terminus and C terminus of herpes simplex virus 1 ICP4 cooperate to activate viral gene expression. AB - Infected cell polypeptide 4 (ICP4) activates transcription from most viral promoters. Two transactivation domains, one N-terminal and one C terminal, are largely responsible for the activation functions of ICP4. A mutant ICP4 molecule lacking the C-terminal activation domain (n208) efficiently activates many early genes, whereas late genes are poorly activated, and virus growth is severely impaired. The regions within the N terminus of ICP4 (amino acids 1 to 210) that contribute to activation were investigated by analysis of deletion mutants in the presence or absence of the C-terminal activation domain. The mutants were assessed for their abilities to support viral replication and to regulate gene expression. Several deletions in regions conserved in other alphaherpesviruses resulted in impaired activation and viral growth, without affecting DNA binding. The single small deletion that had the greatest effect on activation in the absence of the C terminus corresponded to a highly conserved stretch of amino acids between 81 and 96, rendering the molecule nonfunctional. However, when the C terminus was present, the same deletion had a minimal effect on activity. The amino terminus of ICP4 was predicted to be relatively disordered compared to the DNA-binding domain and the C-terminal 500 amino acids. Moreover, the amino terminus appears to be in a relatively extended conformation as determined by the hydrodynamic properties of several mutants. The data support a model where the amino terminus is an extended and possibly flexible region of the protein, allowing it to efficiently interact with multiple transcription factors at a distance from where it is bound to DNA, thereby enabling ICP4 to function as a general activator of polymerase II transcription. The C terminus of ICP4 can compensate for some of the mutations in the N terminus, suggesting that it either specifies redundant interactions or enables the amino terminus to function more efficiently. PMID- 22496238 TI - Structural insight into the unique properties of adeno-associated virus serotype 9. AB - Adeno-associated virus serotype 9 (AAV9) has enhanced capsid-associated tropism for cardiac muscle and the ability to cross the blood-brain barrier compared to other AAV serotypes. To help identify the structural features facilitating these properties, we have used cryo-electron microscopy (cryo-EM) and three-dimensional image reconstruction (cryo-reconstruction) and X-ray crystallography to determine the structure of the AAV9 capsid at 9.7- and 2.8-A resolutions, respectively. The AAV9 capsid exhibits the surface topology conserved in all AAVs: depressions at each icosahedral two-fold symmetry axis and surrounding each five-fold axis, three separate protrusions surrounding each three-fold axis, and a channel at each five-fold axis. The AAV9 viral protein (VP) has a conserved core structure, consisting of an eight-stranded, beta-barrel motif and the alphaA helix, which are present in all parvovirus structures. The AAV9 VP differs in nine variable surface regions (VR-I to -IX) compared to AAV4, but at only three (VR-I, VR-II, and VR-IV) compared to AAV2 and AAV8. VR-I differences modify the raised region of the capsid surface between the two-fold and five-fold depressions. The VR-IV difference produces smaller three-fold protrusions in AAV9 that are less "pointed" than AAV2 and AAV8. Significantly, residues in the AAV9 VRs have been identified as important determinants of cellular tropism and transduction and dictate its antigenic diversity from AAV2. Hence, the AAV9 VRs likely confer the unique infection phenotypes of this serotype. PMID- 22496240 TI - Temperature-dependent survival of Turnip crinkle virus-infected arabidopsis plants relies on an RNA silencing-based defense that requires dcl2, AGO2, and HEN1. AB - While RNA silencing is a potent antiviral defense in plants, well-adapted plant viruses are known to encode suppressors of RNA silencing (VSR) that can neutralize the effectiveness of RNA silencing. As a result, most plant genes involved in antiviral silencing were identified by using debilitated viruses lacking silencing suppression capabilities. Therefore, it remains to be resolved whether RNA silencing plays a significant part in defending plants against wild type viruses. We report here that, at a higher plant growth temperature (26 degrees C) that permits rigorous replication of Turnip crinkle virus (TCV) in Arabidopsis, plants containing loss-of-function mutations within the Dicer-like 2 (DCL2), Argonaute 2 (AGO2), and HEN1 RNA methyltransferase genes died of TCV infection, whereas the wild-type Col-0 plants survived to produce viable seeds. To account for the critical role of DCL2 in ensuring the survival of wild-type plants, we established that higher temperature upregulates the activity of DCL2 to produce viral 22-nucleotide (nt) small interfering RNAs (vsRNAs). We further demonstrated that DCL2-produced 22-nt vsRNAs were fully capable of silencing target genes, but that this activity was suppressed by the TCV VSR. Finally, we provide additional evidence supporting the notion that TCV VSR suppresses RNA silencing through directly interacting with AGO2. Together, these results have revealed a specialized RNA silencing pathway involving DCL2, AGO2, and HEN1 that provides the host plants with a competitive edge against adapted viruses under environmental conditions that facilitates robust virus reproduction. PMID- 22496242 TI - ClC-3 is a candidate of the channel proteins mediating acid-activated chloride currents in nasopharyngeal carcinoma cells. AB - Acid-activated chloride currents have been reported in several cell types and may play important roles in regulation of cell function. However, the molecular identities of the channels that mediate the currents are not defined. In this study, activation of the acid-induced chloride current and the possible candidates of the acid-activated chloride channel were investigated in human nasopharyngeal carcinoma cells (CNE-2Z). A chloride current was activated when extracellular pH was reduced to 6.6 from 7.4. However, a further decrease of extracellular pH to 5.8 inhibited the current. The current was weakly outward rectified and was suppressed by hypertonicity-induced cell shrinkage and by the chloride channel blockers 5-nitro-2-3-phenylpropylamino benzoic acid (NPPB), tamoxifen, and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt hydrate (DIDS). The permeability sequence of the channel to anions was I(-) > Br( ) > Cl(-) > gluconate(-). Among the ClC chloride channels, ClC-3 and ClC-7 were strongly expressed in CNE-2Z cells. Knockdown of ClC-3 expression with ClC-3 small interfering (si)RNA prevented the activation of the acid-induced current, but silence of ClC-7 expression with ClC-7 siRNA did not significantly affect the current. The results suggest that the chloride channel mediating the acid-induced chloride current was volume sensitive. ClC-3 is a candidate of the channel proteins that mediate or regulate the acid-activated chloride current in nasopharyngeal carcinoma cells. PMID- 22496241 TI - Hsp90 regulates O-linked beta-N-acetylglucosamine transferase: a novel mechanism of modulation of protein O-linked beta-N-acetylglucosamine modification in endothelial cells. AB - O-linked beta-N-acetylglucosamine (O-GlcNAc) modification of proteins is involved in many important cellular processes. Increased O-GlcNAc has been implicated in major diseases, such as diabetes and its complications and cardiovascular and neurodegenerative diseases. Recently, we reported that O-GlcNAc modification occurs in the proteasome and serves to inhibit proteasome function by blocking the ATPase activity in the 19S regulatory cap, explaining, at least in part, the adverse effects of O-GlcNAc modification and suggesting that downregulating O GlcNAc might be important in the treatment of human diseases. In this study, we report on a novel mechanism to modulate cellular O-GlcNAc modification, namely through heat shock protein 90 (Hsp90) inhibition. We observed that O-linked beta N-acetylglucosamine transferase (OGT) interacts with the tetratricopeptide repeat binding site of Hsp90. Inhibition of Hsp90 by its specific inhibitors, radicicol or 17-N-allylamino-17-demethoxygeldanamycin, destabilized OGT in primary endothelial cell cultures and enhanced its degradation by the proteasome. Furthermore, Hsp90 inhibition downregulated O-GlcNAc protein modifications and attenuated the high glucose-induced increase in O-GlcNAc protein modification, including high glucose-induced increase in endothelial or type 3 isoform of nitric oxide synthase (eNOS) O-GlcNAcylation. These results suggest that Hsp90 is involved in the regulation of OGT and O-GlcNAc modification and that Hsp90 inhibitors might be used to modulate O-GlcNAc modification and reverse its adverse effects in human diseases. PMID- 22496243 TI - Heme carrier protein 1 transports heme and is involved in heme-Fe metabolism. AB - Heme-Fe is an important source of dietary iron in humans; however, the mechanism for heme-Fe uptake by enterocytes is poorly understood. Heme carrier protein 1 (HCP1) was originally identified as mediating heme-Fe transport although it later emerged that it was a folate transporter. We asked what happened to heme-Fe and folate uptake and the relative abundance of hcp1 and ho1 mRNA in Caco-2 cells after knockdown by transfection with HCP1-directed short hairpin (sh)RNA. Control Caco-2 cells were cultured in bicameral chambers with 0-80 MUM heme-Fe for selected times. Intracellular Fe and heme concentration increased in Caco-2 cells reflecting higher external heme-Fe concentrations. Maximum Fe, heme, and heme oxygenase 1 (HO1) expression and activity were observed between 12 and 24 h of incubation. Quantitative RT-PCR for hcp1 revealed that its mRNA decreased at 20 MUM heme-Fe while ho1 mRNA and activity increased. When shRNA knocked down hcp1 mRNA, heme-(55)Fe uptake and [(3)H]folate transport mirrored the mRNA decrease, ho1 mRNA increased, and flvcr mRNA was unchanged. These data argue that HCP1 is involved in low-affinity heme-Fe uptake not just in folate transport. PMID- 22496244 TI - Epinephrine and AICAR-induced PGC-1alpha mRNA expression is intact in skeletal muscle from rats fed a high-fat diet. AB - Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) is a master regulator of mitochondrial biogenesis and is controlled, at least in part, through AMP-activated protein kinase and p38-dependent pathways. There is evidence demonstrating that activation of these kinases and induction of PGC 1alpha in skeletal muscle are regulated by catecholamines. The purpose of the present study was to determine if consumption of a high-fat diet (HFD) impairs epinephrine and 5-aminoimidazole-4-carboxamide-1beta-d-ribofuranoside (AICAR) signaling and induction of PGC-1alpha in rat skeletal muscle. Male Wistar rats were fed chow or a HFD for 6 wk and then given a weight-adjusted bolus injection of epinephrine (20, 10, or 5 MUg/100 g body wt sc) or saline, and triceps muscles were harvested 30 min (signaling) or 2 and 4 h (gene expression) postinjection. Despite blunted increases in p38 phosphorylation, the ability of epinephrine to induce PGC-1alpha was intact in skeletal muscle from HFD-fed rats and was associated with normal increases in activation of PKA and phosphorylation of cAMP response element-binding protein, reputed mediators of PGC-1alpha expression. The attenuated epinephrine-mediated increase in p38 phosphorylation was independent of increases in MAPK phosphatase 1. At 2 h following AICAR treatment (0.5 g/kg body wt sc), AMP-activated protein kinase and acetyl-CoA carboxylase phosphorylation were similar in skeletal muscle from chow- and HFD-fed rats. Surprisingly, AICAR-induced increases in PGC-1alpha mRNA levels were greater in skeletal muscle from HFD-fed rats. Our results demonstrate that the ability of epinephrine and AICAR to induce PGC-1alpha remains intact in skeletal muscle from HFD-fed rats. These results question the existence of reduced beta-adrenergic responsiveness in diet-induced obesity and demonstrate that increases in p38 phosphorylation are not required for induction of PGC-1alpha in muscle from obese rats. PMID- 22496246 TI - Double the keys, double the control: coupled phosphorylation sites provide novel molecular targets for precise control of ion channel function. Focus on "Differential regulation of a CLC anion channel by SPAK kinase ortholog-mediated multisite phosphorylation". PMID- 22496245 TI - Ablation of sarcolipin results in atrial remodeling. AB - Sarcolipin (SLN) is a key regulator of sarco(endo)plasmic reticulum (SR) Ca(2+) ATPase (SERCA), and its expression is altered in diseased atrial myocardium. To determine the precise role of SLN in atrial Ca(2+) homeostasis, we developed a SLN knockout (sln-/-) mouse model and demonstrated that ablation of SLN enhances atrial SERCA pump activity. The present study is designed to determine the long term effects of enhanced SERCA activity on atrial remodeling in the sln-/- mice. Calcium transient measurements show an increase in atrial SR Ca(2+) load and twitch Ca(2+) transients. Patch-clamping experiments demonstrate activation of the forward mode of sodium/calcium exchanger, increased L-type Ca(2+) channel activity, and prolongation of action potential duration at 90% repolarization in the atrial myocytes of sln-/- mice. Spontaneous Ca(2+) waves, delayed afterdepolarization, and triggered activities are frequent in the atrial myocytes of sln-/- mice. Furthermore, loss of SLN in atria is associated with increased interstitial fibrosis and altered expression of genes encoding collagen and other extracellular matrix proteins. Our results also show that the sln-/- mice are susceptible to atrial arrhythmias upon aging. Together, these findings indicate that ablation of SLN results in increased SERCA activity and SR Ca(2+) load, which, in turn, could cause abnormal intracellular Ca(2+) handling and atrial remodeling. PMID- 22496247 TI - Human colonic epithelial cells detect and respond to C5a via apically expressed C5aR through the ERK pathway. AB - Intestinal epithelial cells (IECs) exhibit numerous adaptations to maintain barrier function as well as play sentinel roles by expressing receptors for microbial products and antimicrobial peptides. The complement system is another important innate sensing and defense mechanism of the host against bacteria and increasing evidence shows that complement plays a role in colitis. The split component C5a is a potent proinflammatory molecule, and the C5a receptor (C5aR) CD88 has been reported on multiple cell types. Here, we examined the question of whether human colonic cell lines can detect activated complement via C5aR and what signaling pathway is critical in the subsequent responses. T84, HT29, and Caco2 cell lines all possessed mRNA and protein for C5aR and the decoy receptor C5L2. Polarized cells expressed the proteins on the apical cell membrane. C5a binding to the C5aR on human IECs activates the ERK pathway, which proved critical for a subsequent upregulation of IL-8 mRNA, increased permeability of monolayers, and enhanced proliferation of the cells. The fact that human IECs are capable of detecting complement activation in the lumen via this anaphylatoxin receptor highlights the potential for IECs to detect pathogens indirectly through complement activation and be primed to amplify the host response through heightened inflammatory mediator expression to further recruit immune cells. PMID- 22496248 TI - Characterization of Korean solid recovered fuels (SRFs): an analysis and comparison of SRFs. AB - To date, Korea has used four species of solid recovered fuels (SRFs) which have been certified by the Environmental Ministry of Korea: refuse-derived fuel (RDF), refused plastic fuel (RPF), tyre-derived fuel (TDF), and wood chip fuel (WCF). These fuels have been used in many industrial boilers. In this study, seven regulatory properties associated with each of the four species: particle size, moisture and ash content, lower heating value (LHV), total chlorine, sulfur, and heavy metals content (Pb, As, Cd, Hg, Cr) were analysed. These properties are the main regulation criteria for the usage and transfer of SRFs in Korea. Different properties of each SRF were identified on the basis of data collected over the last 3 years in Korea, and the manufacturing process problem associated with the production of SRFs were considered. It was found that the high moisture content of SRFs (especially WCF) could directly lead to the low LHV of SRFs and that the poor screening and sorting of raw materials could cause defective SRF products with high ash or chlorine contents. The information obtained from this study could contribute to the manufacturing of SRF with good quality. PMID- 22496249 TI - Detection of cells captured with antigens on shear horizontal surface-acoustic wave sensors. AB - Techniques to separate cells are widely applied in immunology. The technique to separate a specific antigen on a microfluidic platform involves the use of a shear horizontal surface-acoustic-wave (SH-SAW) sensor. With specific antibodies conjugated onto the surface of the SH-SAW sensors, this technique can serve to identify specific cells in bodily fluids. Jurkat cells, used as a target in this work, provide a model of cells in small abundance (1:1000) for isolation and purification with the ultimate goal of targeting even more dilute cells. T cells were separated from a mixed-cell medium on a chip (Jurkat cells/K562 cells, 1/1000). A novel microchamber was developed to capture cells during the purification, which required a large biosample. Cell detection was demonstrated through the performance of genetic identification on the chip. PMID- 22496250 TI - The cover. Flowers (fleurs). PMID- 22496251 TI - Can imaging help revive the autopsy? PMID- 22496252 TI - CDC: improve targeted screening for chlamydia. PMID- 22496253 TI - AHA statement calls attention to risk of peripheral artery disease in women. PMID- 22496254 TI - Collaborative effort seeks to curb hospital infections. PMID- 22496255 TI - CYP2C19 genotype and cardiovascular events. PMID- 22496256 TI - CYP2C19 genotype and cardiovascular events. PMID- 22496257 TI - CYP2C19 genotype and cardiovascular events. PMID- 22496258 TI - Cardiovascular events in adults taking medications for ADHD. PMID- 22496259 TI - Road crash fatalities on US income tax days. PMID- 22496260 TI - Statin therapy for healthy men identified as "increased risk". PMID- 22496261 TI - Healthy men should not take statins. PMID- 22496262 TI - Accountable care organizations and antitrust: restructuring the health care market. PMID- 22496263 TI - A piece of my mind. Subjective case. PMID- 22496264 TI - Association of major and minor ECG abnormalities with coronary heart disease events. AB - CONTEXT: In populations of older adults, prediction of coronary heart disease (CHD) events through traditional risk factors is less accurate than in middle aged adults. Electrocardiographic (ECG) abnormalities are common in older adults and might be of value for CHD prediction. OBJECTIVE: To determine whether baseline ECG abnormalities or development of new and persistent ECG abnormalities are associated with increased CHD events. DESIGN, SETTING, AND PARTICIPANTS: A population-based study of 2192 white and black older adults aged 70 to 79 years from the Health, Aging, and Body Composition Study (Health ABC Study) without known cardiovascular disease. Adjudicated CHD events were collected over 8 years between 1997-1998 and 2006-2007. Baseline and 4-year ECG abnormalities were classified according to the Minnesota Code as major and minor. Using Cox proportional hazards regression models, the addition of ECG abnormalities to traditional risk factors were examined to predict CHD events. MAIN OUTCOME MEASURE: Adjudicated CHD events (acute myocardial infarction [MI], CHD death, and hospitalization for angina or coronary revascularization). RESULTS: At baseline, 276 participants (13%) had minor and 506 (23%) had major ECG abnormalities. During follow-up, 351 participants had CHD events (96 CHD deaths, 101 acute MIs, and 154 hospitalizations for angina or coronary revascularizations). Both baseline minor and major ECG abnormalities were associated with an increased risk of CHD after adjustment for traditional risk factors (17.2 per 1000 person-years among those with no abnormalities; 29.3 per 1000 person-years; hazard ratio [HR], 1.35; 95% CI, 1.02-1.81; for minor abnormalities; and 31.6 per 1000 person-years; HR, 1.51; 95% CI, 1.20-1.90; for major abnormalities). When ECG abnormalities were added to a model containing traditional risk factors alone, 13.6% of intermediate-risk participants with both major and minor ECG abnormalities were correctly reclassified (overall net reclassification improvement [NRI], 7.4%; 95% CI, 3.1%-19.0%; integrated discrimination improvement, 0.99%; 95% CI, 0.32% 2.15%). After 4 years, 208 participants had new and 416 had persistent abnormalities. Both new and persistent ECG abnormalities were associated with an increased risk of subsequent CHD events (HR, 2.01; 95% CI, 1.33-3.02; and HR, 1.66; 95% CI, 1.18-2.34; respectively). When added to the Framingham Risk Score, the NRI was not significant (5.7%; 95% CI, -0.4% to 11.8%). CONCLUSIONS: Major and minor ECG abnormalities among older adults were associated with an increased risk of CHD events. Depending on the model, adding ECG abnormalities was associated with improved risk prediction beyond traditional risk factors. PMID- 22496265 TI - Association of treatment with losartan vs candesartan and mortality among patients with heart failure. AB - CONTEXT: The benefit of angiotensin II-receptor blockers (ARBs) in heart failure is thought to be a class effect, but no head-to-head randomized trials have compared individual ARBs. Results from observational studies suggest that losartan may be associated with increased mortality in patients with heart failure compared with other ARBs. OBJECTIVE: To assess the hypothesis that losartan use is associated with increased all-cause mortality in heart failure patients as compared with candesartan. DESIGN, SETTING, AND PARTICIPANTS: We conducted a nationwide Danish registry-based cohort study, linking individual level information on hospital contacts, filled prescriptions, and potential confounders. Patients aged 45 years and older with first-time hospitalization for heart failure in 1998-2008 were identified from the Danish National Patient Registry. New users of losartan and candesartan were selected for inclusion in the study cohort. MAIN OUTCOME MEASURES: We used Cox proportional hazards regression to compare the risk of all-cause mortality in users of losartan and candesartan. RESULTS: Among 4397 users of losartan, 1212 deaths occurred during 11,347 person-years of follow-up (unadjusted incidence rate [IR]/100 person years, 10.7; 95% CI, 10.1-11.3) compared with 330 deaths during 3675 person-years among 2082 users of candesartan (unadjusted IR/100 person-years, 9.0; 95% CI, 8.1 10.0). Compared with candesartan, losartan was not associated with increased all cause mortality (adjusted hazard ratio [HR], 1.10; 95% CI, 0.96-1.25) or cardiovascular mortality (adjusted HR, 1.14; 95% CI, 0.96-1.36). Compared with high doses of candesartan (16-32 mg), low-dose (12.5 mg) and medium-dose losartan (50 mg) were associated with increased mortality (HR, 2.79; 95% CI, 2.19-3.55 and HR, 1.39; 95% CI, 1.11-1.73, respectively); use of high-dose losartan (100 mg) was similar in risk (HR, 0.71; 95% CI, 0.50-1.00). CONCLUSIONS: Among patients with heart failure, overall use of losartan compared with candesartan was not associated with an increased mortality risk. Although low doses of losartan were associated with increased mortality, there was no increased mortality comparing high-dose losartan against the highest doses of candesartan. PMID- 22496267 TI - Vesicular eruption. PMID- 22496266 TI - Does this adult patient have a blunt intra-abdominal injury? AB - CONTEXT: Blunt abdominal trauma often presents a substantial diagnostic challenge. Well-informed clinical examination can identify patients who require further diagnostic evaluation for intra-abdominal injuries after blunt abdominal trauma. OBJECTIVE: To systematically assess the precision and accuracy of symptoms, signs, laboratory tests, and bedside imaging studies to identify intra abdominal injuries in patients with blunt abdominal trauma. DATA SOURCES: We conducted a structured search of MEDLINE (1950-January 2012) and EMBASE (1980 January 2012) to identify English-language studies examining the identification of intra-abdominal injuries. A separate, structured search was conducted for studies evaluating bedside ultrasonography. STUDY SELECTION: We included studies of diagnostic accuracy for intra-abdominal injury that compared at least 1 finding with a reference standard of abdominal computed tomography, diagnostic peritoneal lavage, laparotomy, autopsy, and/or clinical course for intra abdominal injury. Twelve studies on clinical findings and 22 studies on bedside ultrasonography met inclusion criteria for data extraction. DATA EXTRACTION: Critical appraisal and data extraction were independently performed by 2 authors. DATA SYNTHESIS: The prevalence of intra-abdominal injury in adult emergency department patients with blunt abdominal trauma among all evidence level 1 and 2 studies was 13% (95% CI, 10%-17%), with 4.7% (95% CI, 2.5%-8.6%) requiring therapeutic surgery or angiographic embolization of injuries. The presence of a seat belt sign (likelihood ratio [LR] range, 5.6-9.9), rebound tenderness (LR, 6.5; 95% CI, 1.8-24), hypotension (LR, 5.2; 95% CI, 3.5-7.5), abdominal distention (LR, 3.8; 95% CI, 1.9-7.6), or guarding (LR, 3.7; 95% CI, 2.3-5.9) suggest an intra-abdominal injury. The absence of abdominal tenderness to palpation does not rule out an intra-abdominal injury (summary LR, 0.61; 95% CI, 0.46-0.80). The presence of intraperitoneal fluid or organ injury on bedside ultrasound assessment is more accurate than any history and physical examination findings (adjusted summary LR, 30; 95% CI, 20-46); conversely, a normal ultrasound result decreases the chance of injury detection (adjusted summary LR, 0.26; 95% CI, 0.19-0.34). Test results increasing the likelihood of intra abdominal injury include a base deficit less than -6 mEq/L (LR, 18; 95% CI, 11 30), elevated liver transaminases (LR range, 2.5-5.2), hematuria (LR range, 3.7 4.1), anemia (LR range, 2.2-3.3), and abnormal chest radiograph (LR range, 2.5 3.8). Symptoms and signs may be most useful in combination, particularly in identification of patients who do not need further diagnostic workup. CONCLUSIONS: Bedside ultrasonography has the highest accuracy of all individual findings, but a normal result does not rule out an intra-abdominal injury. Combinations of clinical findings may be most useful to determine which patients do not require further evaluation, but the ideal combination of variables for identifying patients without intra-abdominal injury requires further study. PMID- 22496268 TI - Should the resting electrocardiogram be ordered as a routine risk assessment test in healthy asymptomatic adults? PMID- 22496269 TI - The debut of dueling viewpoints. PMID- 22496270 TI - JAMA patient page. Pancreatitis. PMID- 22496271 TI - Distinct signal transduction abnormalities and erythropoietin response in bone marrow hematopoietic cell subpopulations of myelodysplastic syndrome patients. AB - PURPOSE: Myelodysplastic syndromes (MDS) are heterogeneous clonal diseases characterized by cytopenias as a result of ineffective hematopoiesis. Little is known about alterations in signal transduction pathways in MDS. EXPERIMENTAL DESIGN: Multiparameter flow cytometry was used to evaluate the proteolytic activation of caspase-3 and the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), and STAT5 specifically in defined CD34(+), CD45(+), or CD71(+)CD45(-) bone marrow (BM) cells from 60 MDS cases and normal controls, both at baseline and following stimulation with granulocyte colony-stimulating factor (G-CSF) and erythropoietin. RESULTS: In CD71(+)CD45(-) cells from a subpopulation of 36 MDS cases who were predicted to be responsive by clinical parameters (endogenous erythropoietin levels, transfusion dependency, percentage of blasts in the BM), erythropoietin failed to activate ERK1/2 or STAT5 in 23 of 36 cases, but it was effective in 13 of 36 cases, although to a significantly lower degree than in CD71(+)CD45(-) cells from healthy donor BM. The erythropoietin response in vivo correlated with in vitro erythropoietin-dependent STAT5 activation in 20 of 22 cases. STAT5 was significantly activated at baseline in MDS cells compared with normal controls, whereas caspase-3 was activated in CD34(+) and CD45(+) MDS cells, and was activated more often in the RA and RAEB-1 MDS subtypes. G-CSF stimulation activated ERK1/2 and STAT5 equally in MDS and normal CD34(+) cells. CONCLUSIONS: Abnormalities in the response to growth factors are restricted to erythropoietin stimulation in CD71(+)CD45(-) cells and correlate with the clinical response to erythropoietin. Activation of baseline signal transduction for proliferative and apoptotic signals is altered in MDS but with different patterns among the various BM subpopulations. PMID- 22496273 TI - Endothelial microparticles: missing link in endothelial dysfunction? AB - Vascular homeostasis is an integral reflection of quiescent, but competent endothelium. Endothelial microparticles (EMPs) are circulating submicron-sized membranous vesicles released by endothelium that are increasingly recognized and play a multitude of biological roles reflecting competency of endothelial function and vascular biology. EMPs have been shown to act as primary and secondary messengers of vascular inflammation, thrombosis, vasomotor response, angiogenesis, and endothelial survival. These often-neglected vesicles are emerging as potentially useful indicators of dysfunctioning endothelium, whereby differential presence of EMPs is linked to disease manifestation. In this review, we outline the evolving understanding of EMPs from mere passive vesiculation to active messenger in pathophysiological responses. Current evidence implicating EMPs in cardiopulmonary, renal, cerebral, and metabolic disorders warrants vigorous clinical validation. While studies of EMPs face significant technical challenges that await standardization and consolidation, unravelling its biological significance in endothelial dysfunction could herald the advent of novel non-invasive surveillance platforms for vascular health, risk stratification, and disease prognostication. PMID- 22496272 TI - Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. AB - PURPOSE: Bcl-2 is a critical regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-x(L). The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy. EXPERIMENTAL DESIGN: Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. RESULTS: The most common toxicity associated with navitoclax was thrombocytopenia, which reached grade III-IV in 41% of patients. Partial response was observed in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 months and median OS was 3.2 months. A strong association between plasma pro-gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy number (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell number as correlates of clinical benefit. CONCLUSION: Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clinical benefit. Preclinical models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies. PMID- 22496274 TI - Screening for depression in patients with myocardial infarction by general practitioners. AB - BACKGROUND: Depression in patients with myocardial infarction (MI) is highly prevalent and associated with increased morbidity and mortality. Routine screening for post-MI depression is recommended. We studied general practitioners' practice of screening for post-MI depression and analysed whether the screening rate varied among subgroups of MI patients with a particular high risk of depression. DESIGN: Population-based cohort study in the Central Denmark Region. METHODS: All patients with a first-time MI in 2009 received a questionnaire 3 months after discharge from hospital. The questionnaire included information on anxiety and depression according to the Hospital Anxiety and Depression Scale (HADS), severity of the disease, and smoking habits. The responders' general practitioners received a questionnaire 1 year after the patient had been discharged from hospital. This questionnaire provided information on screening for depression, comorbidity, and previous mental illness of the patient. Nationwide registers supplied the patients' sociodemographic status the year before the MI. RESULTS: Response rates were 70.5% (908) among patients, and 64.9% (589) among general practitioners. According to the general practitioners, 27.3% (95% CI 23.7-30.9%) MI patients were screened for depression. The screening rate was higher among patients with a history of mental illness (50.0%, p < 0.001), and among patients with anxiety (37.0%, p = 0.002) or depression (37.5%, p = 0.007) as compared with those without these conditions. CONCLUSION: Screening for depression was neither complete among patients with MI or in subgroups of these with a particularly high risk of post-MI depression. More detailed guidelines and initiatives for implementing them may help to optimize general practitioners' screening for post-MI depression. PMID- 22496275 TI - Secondary prevention and risk factor target achievement in a global, high-risk population with established coronary heart disease: baseline results from the STABILITY study. AB - AIM: There is limited contemporary data on achievement of risk factor goals for secondary prevention of cardiovascular (CV) disease from countries in many regions of the world. This report describes the global and regional prevalence of CV risk factors and use of preventive medications at baseline in participants in the ongoing STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial. METHODS AND RESULTS: Detailed individual data on CV risk factors were obtained before randomization in 15,828 patients with chronic coronary heart disease (CHD) from 39 countries on five continents. Subjects had a history of myocardial infarction, prior coronary revascularization, or multi vessel CHD without revascularization and at least one additional CV risk factor. The majority were taking a statin (97%), antiplatelet therapy (96%), beta-blocker (79%), or angiotensin converting enzyme inhibitor/angiotensin receptor blocker (77%). However, a large proportion of patients did not achieve guideline recommended targets. For instance, in 29% low-density lipoprotein (LDL) cholesterol was >2.5 mmol/l and in 46% blood pressure was >=140/90 mmHg or >=130/80 mmHg in those with diabetes or renal impairment. The body mass index was >30 kg/m(2) in 36%, waist circumference >=102 cm for men or >=88 cm for women in 54%, and 18% were smoking. Regional differences in risk factor prevalence and target achievement were observed and were more marked for LDL cholesterol and obesity. CONCLUSION: The prevalence of modifiable CV risk factors was generally high in the STABILITY population. Although, most patients were receiving evidence based secondary preventive therapy many subjects from all regions did not reach recommended secondary prevention goals. PMID- 22496276 TI - Mediterranean diet, moderate-to-high intensity training, and health-related quality of life in adults with metabolic syndrome. AB - BACKGROUND: Much recent research has focused on the benefits of the Mediterranean diet on risk factors of metabolic syndrome (MetS). In addition numerous investigations have also demonstrated that moderate and high-intensity endurance training may induce greater beneficial adaptations in body composition and cardiometabolic risk than low-intensity endurance training. How a model of Mediterranean diet with and without moderate-to-high intensity training influences health-related quality of life (HRQoL) and physical fitness in MetS patients is unknown. DESIGN AND METHODS: A total of 45 sedentary MetS males and females (50?66 years) were randomly divided into two groups: (a) hypocaloric, normoproteic Mediterranean diet (MeD); and (b) the same diet plus periodized moderate-to-high intensity training (MeDE) for 12 weeks. HRQoL (EuroQol and SF-36 questionnaires), fitness, response to submaximal exercise, and risk factors of MetS were determined before and after treatment. RESULTS: MeD improved some physical and mental domains of HRQoL (physical function, vitality, general physical health, emotional role, and self-perception of health) and resulted in weight loss and improvement of MetS risk factors (intra-group p < 0.05). Moreover, the MeDE intervention resulted in greater improvement in these domains and the improvement of other HRQoL components (physical role, bodily pain, social function, and health profile). MeDE increased physical fitness, resulted in a better physiological response to submaximal effort and caused a greater weight loss (intra-group and inter-group, p < 0.05). CONCLUSIONS: A model of hypocaloric Mediterranean diet combined with periodized moderate-to-high intensity training may lead to greater improvement in HRQoL through a greater effect on physical and functional fitness, bodyweight, and risk factors than diet alone. PMID- 22496277 TI - Aestivation: signaling and hypometabolism. AB - Aestivation is a survival strategy used by many vertebrates and invertebrates to endure arid environmental conditions. Key features of aestivation include strong metabolic rate suppression, strategies to retain body water, conservation of energy and body fuel reserves, altered nitrogen metabolism, and mechanisms to preserve and stabilize organs, cells and macromolecules over many weeks or months of dormancy. Cell signaling is crucial to achieving both a hypometabolic state and reorganizing multiple metabolic pathways to optimize long-term viability during aestivation. This commentary examines the current knowledge about cell signaling pathways that participate in regulating aestivation, including signaling cascades mediated by the AMP-activated kinase, Akt, ERK, and FoxO1. PMID- 22496278 TI - Effects of host diet and thermal state on feeding performance of the flea Xenopsylla ramesis. AB - We examined feeding performance of the flea Xenopsylla ramesis on three different hosts: its natural, granivorous, rodent host, Sundevall's jird (Meriones crassus); the frugivorous Egyptian fruit bat (Rousettus aegyptiacus); and an insectivorous bat, Kuhl's pipistrelle (Pipistrellus kuhlii). Because these fleas are not known to occur on bats, we hypothesized that the fleas' feeding performance (i.e. feeding and digestion rates) would be higher when feeding on their natural host than on either of the bats that they do not naturally parasitize. We found that mass-specific blood-meal size of both male and female fleas was significantly lower when feeding on Kuhl's pipistrelles than on the other two species, but was not different in female fleas feeding on fruit bats or on jirds at all stages of digestion. However, more male fleas achieved higher levels of engorgement if they fed on Sundevall's jirds than if they fed on Egyptian fruit bats. The fleas digested blood of fruit bats and jirds significantly faster than blood of Kuhl's pipistrelle. In addition, after a single blood meal, the survival time of fleas fed on normothermic Kuhl's pipistrelles was significantly shorter than that of fleas fed on Sundevall's jirds and even lower when male fleas fed on Egyptian fruit bats. Thus, our prediction was partially supported: normothermic Kuhl's pipistrelles were inferior hosts for fleas compared with Sandevall's jirds and Egyptian fruit bats. Interestingly, the proportion of engorged fleas that fed on torpid Kuhl's pipistrelles was significantly higher than the proportion of the fleas that fed on normothermic individuals, indicating that becoming torpid might be a liability, rather than an effective defense against parasites. PMID- 22496279 TI - Audiogram and auditory critical ratios of two Florida manatees (Trichechus manatus latirostris). AB - Manatees inhabit turbid, shallow-water environments and have been shown to have poor visual acuity. Previous studies on hearing have demonstrated that manatees possess good hearing and sound localization abilities. The goals of this research were to determine the hearing abilities of two captive subjects and measure critical ratios to understand the capacity of manatees to detect tonal signals, such as manatee vocalizations, in the presence of noise. This study was also undertaken to better understand individual variability, which has been encountered during behavioral research with manatees. Two Florida manatees (Trichechus manatus latirostris) were tested in a go/no-go paradigm using a modified staircase method, with incorporated 'catch' trials at a 1:1 ratio, to assess their ability to detect single-frequency tonal stimuli. The behavioral audiograms indicated that the manatees' auditory frequency detection for tonal stimuli ranged from 0.25 to 90.5 kHz, with peak sensitivity extending from 8 to 32 kHz. Critical ratios, thresholds for tone detection in the presence of background masking noise, were determined with one-octave wide noise bands, 7-12 dB (spectrum level) above the thresholds determined for the audiogram under quiet conditions. Manatees appear to have quite low critical ratios, especially at 8 kHz, where the ratio was 18.3 dB for one manatee. This suggests that manatee hearing is sensitive in the presence of background noise and that they may have relatively narrow filters in the tested frequency range. PMID- 22496281 TI - Independently evolved upper jaw protrusion mechanisms show convergent hydrodynamic function in teleost fishes. AB - A protrusible upper jaw has independently evolved multiple times within teleosts and has been implicated in the success of two groups in particular: Acanthomorpha and Cypriniformes. We use digital particle image velocimetry (DPIV) to compare suction feeding flow dynamics in a representative of each of these clades: goldfish and bluegill. Using DPIV, we contrast the spatial pattern of flow, the temporal relationship between flow and head kinematics, and the contribution of jaw protrusion to the forces exerted on prey. As expected, the spatial patterns of flow were similar in the two species. However, goldfish were slower to reach maximal kinematic excursions, and were more flexible in the relative timing of jaw protrusion, other jaw movements and suction flows. Goldfish were also able to sustain flow speeds for a prolonged period of time as compared with bluegill, in part because goldfish generate lower peak flow speeds. In both species, jaw protrusion increased the force exerted on the prey. However, slower jaw protrusion in goldfish resulted in less augmentation of suction forces. This difference in force exerted on prey corresponds with differences in trophic niches and feeding behavior of the two species. The bluegill uses powerful suction to capture insect larvae whereas the goldfish uses winnowing to sort through detritus and sediment. The kinethmoid of goldfish may permit jaw protrusion that is independent of lower jaw movement, which could explain the ability of goldfish to decouple suction flows (due to buccal expansion) from upper jaw protrusion. Nevertheless, our results show that jaw protrusion allows both species to augment the force exerted on prey, suggesting that this is a fundamental benefit of jaw protrusion to suction feeders. PMID- 22496282 TI - Experimental evaluation of the anti-attachment effect of microalgal mats on grazing activity of the sea urchin Strongylocentrotus nudus in oscillating flows. AB - Algal mats can hinder the adhesion of the tube feet of sea urchins. This leads to the hypothesis that the restriction of sea urchin feeding activity by wave action can potentially be enhanced by the presence of algal mats, which will facilitate the survival of kelp recruits at sites with wave action in urchin barrens. To evaluate the potential anti-attachment effect of algal mats on sea urchins, a laboratory tank experiment was performed on the movement of Strongylocentrotus nudus sea urchins and their grazing on juvenile kelp plants at the center of 30*30 cm flat test substrates with or without a thin-layer microalgal mat at four levels of oscillatory flow (maximum orbital velocity: 10, 20, 30 and 40 cm s( 1)). The grazing loss of kelp slightly increased with increasing velocity up to 30 cm s(-1) in the absence of microalgal mats, while in contrast the loss substantially decreased at 30 cm s(-1) in their presence. Sea urchins were dislodged more frequently at 20 cm s(-1) or higher velocities in the presence of microalgal mats. Mats were frequently abraded by scraping by the adoral spines during urchin movement at high velocities (30 and 40 cm s(-1)) but were subject to no or only slight urchin grazing in most cases. The results indicate that the overall decrease in grazing loss of kelp within the microalgal mats was attributable to the anti-attachment effect on urchins during incursions rather than due to urchins grazing on the mats. PMID- 22496280 TI - Prolonged fasting increases purine recycling in post-weaned northern elephant seals. AB - Northern elephant seals are naturally adapted to prolonged periods (1-2 months) of absolute food and water deprivation (fasting). In terrestrial mammals, food deprivation stimulates ATP degradation and decreases ATP synthesis, resulting in the accumulation of purines (ATP degradation byproducts). Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) salvages ATP by recycling the purine degradation products derived from xanthine oxidase (XO) metabolism, which also promotes oxidant production. The contributions of HGPRT to purine recycling during prolonged food deprivation in marine mammals are not well defined. In the present study we cloned and characterized the complete and partial cDNA sequences that encode for HGPRT and xanthine oxidoreductase (XOR) in northern elephant seals. We also measured XO protein expression and circulating activity, along with xanthine and hypoxanthine plasma content in fasting northern elephant seal pups. Blood, adipose and muscle tissue samples were collected from animals after 1, 3, 5 and 7 weeks of their natural post-weaning fast. The complete HGPRT and partial XOR cDNA sequences are 771 and 345 bp long and encode proteins of 218 and 115 amino acids, respectively, with conserved domains important for their function and regulation. XOR mRNA and XO protein expression increased 3-fold and 1.7-fold with fasting, respectively, whereas HGPRT mRNA (4-fold) and protein (2 fold) expression increased after 7 weeks in adipose tissue and muscle. Plasma xanthine (3-fold) and hypoxanthine (2.5-fold) levels, and XO (1.7- to 20-fold) and HGPRT (1.5- to 1.7-fold) activities increased during the last 2 weeks of fasting. Results suggest that prolonged fasting in elephant seal pups is associated with increased capacity to recycle purines, which may contribute to ameliorating oxidant production and enhancing the supply of ATP, both of which would be beneficial during prolonged food deprivation and appear to be adaptive in this species. PMID- 22496283 TI - Differential limb loading in miniature pigs (Sus scrofa domesticus): a test of chondral modeling theory. AB - Variation in mechanical loading is known to influence chondrogenesis during joint formation. However, the interaction among chondrocyte behavior and variation in activity patterns is incompletely understood, hindering our knowledge of limb ontogeny and function. Here, the role of endurance exercise in the development of articular and physeal cartilage in the humeral head was examined in 14 miniature swine (Sus scrofa domesticus). One group was subjected to graded treadmill running over a period of 17 weeks. A matched sedentary group was confined to individual pens. Hematoxylin and eosin staining was performed for histomorphometry of cartilage zone thickness, chondrocyte count and cell area, with these parameters compared multivariately between exercised and sedentary groups. Comparisons were also made with femora from the same sample, focusing on humerus-femur differences between exercised and sedentary groups, within-cohort comparisons of humerus-femur responses and correlated changes within and across joints. This study shows conflicting support for the chondral modeling theory. The humeral articular cartilage of exercised pigs was thinner than that of sedentary pigs, but their physeal cartilage was thicker. While articular and physeal cartilage demonstrated between-cohort differences, humeral physeal cartilage exhibited load-induced responses of greater magnitude than humeral articular cartilage. Controlling for cohort, the humerus showed increased chondrocyte mitosis and cell area, presumably due to relatively greater loading than the femur. This represents the first known effort to evaluate chondral modeling across multiple joints from the same individuals. Our findings suggest the chondral response to elevated loading is complex, varying within and among joints. This has important implications for understanding joint biomechanics and development. PMID- 22496284 TI - Extending food deprivation reverses the short-term lipolytic response to fasting: role of the triacylglycerol/fatty acid cycle. AB - The effects of short-term food deprivation on lipid metabolism are well documented, but little is known about prolonged fasting. This study monitored the kinetics of glycerol (rate of appearance, R(a) glycerol) and non-esterified fatty acids (R(a) NEFA) in fasting rabbits. Our goals were to determine whether lipolysis is stimulated beyond values seen for short-term fasting, and to characterize the roles of primary (intracellular) and secondary (with transit through the circulation) triacylglycerol/fatty acid cycling (TAG/FA cycling) in regulating fatty acid allocation to oxidation or re-esterification. R(a) glycerol (9.62+/-0.72 to 15.29+/-0.96 MUmol kg(-1) min(-1)) and R(a) NEFA (18.05+/-2.55 to 31.25+/-1.93 MUmol kg(-1) min(-1)) were stimulated during the first 2 days of fasting, but returned to baseline after 4 days. An initial increase in TAG/FA cycling was followed by a reduction below baseline after 6 days without food, with primary and secondary cycling contributing to these responses. We conclude that the classic activation of lipolysis caused by short-term fasting is abolished when food deprivation is prolonged. High rates of re-esterification may become impossible to sustain, and TAG/FA cycling could decrease to reduce its cost to 3% of total energy expenditure. Throughout prolonged fasting, fatty acid metabolism gradually shifts towards increased oxidation and reduced re esterification. Survival is achieved by pressing fuel selection towards the fatty acid dominance of energy metabolism and by slowing substrate cycles to assist metabolic suppression. However, TAG/FA cycling remains active even after prolonged fasting, suggesting that re-esterification is a crucial mechanism that cannot be stopped without harmful consequences. PMID- 22496285 TI - Transport of selenium across the plasma membrane of primary hepatocytes and enterocytes of rainbow trout. AB - Transport of essential solutes across biological membranes is one of the fundamental characteristics of living cells. Although selenium is an essential micronutrient, little is known about the cellular mechanisms of chemical species specific selenium transport in fish. We report here the kinetic and pharmacological transport characteristics of selenite and its thiol (glutathione and l-cysteine) derivatives in primary cultures of hepatocytes and isolated enterocytes of rainbow trout. Findings from the current study suggest an apparent low-affinity linear transport system for selenite in both cell types. However, we recorded high-affinity Hill kinetics (K(d)=3.61+/-0.28 MUmol l(-1)) in enterocytes exposed to selenite in the presence of glutathione. The uptake of selenite in the presence of thiols was severalfold higher than uptake of selenite alone (at equimolar concentration) in both hepatocytes and enterocytes. Cellular accumulation of selenium was found to be energy independent. Interestingly, we observed a decrease in selenite transport with increasing pH, whereas selenite uptake increased with increasing pH in the presence glutathione in both cell types. The cellular uptake of selenite demonstrated a pronounced competitive interaction with a structurally similar compound, sulfite. The uptake of selenite as well as its thiol derivatives was found to be sensitive to the anion transport blocker DIDS, irrespective of the cell type. Inorganic mercury (Hg(2+)) elicited an inhibition of selenite transport in both cell types, but augmented the transport of reduced forms of selenite in hepatocytes. Based on the substrate choice and comparable pharmacological properties, we advocate that multiple anion transport systems are probably involved in the cellular transport of selenite in fish. PMID- 22496286 TI - Fracture toughness of locust cuticle. AB - Insect cuticle is one of the most common biological materials, yet very little is known about its mechanical properties. Many parts of the insect exoskeleton, such as the jumping legs of locusts, have to withstand high and repeated loading without failure. This paper presents the first measurements of fracture toughness for insect cuticle using a standard engineering approach. Our results show that the fracture toughness of cuticle in locust hind legs is 4.12 MPa m(1/2) and decreases with desiccation of the cuticle. Stiffness and strength of the tibia cuticle were measured using buckling and cantilever bending and increased with desiccation. A combination of the cuticle's high toughness with a relatively low stiffness of 3.05 GPa results in a work of fracture of 5.56 kJ m(-2), which is amongst the highest of any biological material, giving the insect leg an exceptional ability to tolerate defects such as cracks and damage. Interestingly, insect cuticle achieves these unique properties without using reinforcement by a mineral phase, which is often found in other biological composite materials. These findings thus might inspire the development of new biomimetic composite materials. PMID- 22496287 TI - Minimum cost of transport in Asian elephants: do we really need a bigger elephant? AB - Body mass is the primary determinant of an animal's energy requirements. At their optimum walking speed, large animals have lower mass-specific energy requirements for locomotion than small ones. In animals ranging in size from 0.8 g (roach) to 260 kg (zebu steer), the minimum cost of transport (COT(min)) decreases with increasing body size roughly as COT(min)?body mass (M(b))(-0.316+/-0.023) (95% CI). Typically, the variation of COT(min) with body mass is weaker at the intraspecific level as a result of physiological and geometric similarity within closely related species. The interspecific relationship estimates that an adult elephant, with twice the body mass of a mid-sized elephant, should be able to move its body approximately 23% cheaper than the smaller elephant. We sought to determine whether adult Asian and sub-adult African elephants follow a single quasi-intraspecific relationship, and extend the interspecific relationship between COT(min) and body mass to 12-fold larger animals. Physiological and possibly geometric similarity between adult Asian elephants and sub-adult African elephants caused body mass to have a no effect on COT(min) (COT(min)?M(b)(0.007+/ 0.455)). The COT(min) in elephants occurred at walking speeds between 1.3 and ~1.5 m s(-1), and at Froude numbers between 0.10 and 0.24. The addition of adult Asian elephants to the interspecific relationship resulted in COT(min)?M ( 0.277+/-0.046)(b). The quasi-intraspecific relationship between body mass and COT(min) among elephants caused the interspecific relationship to underestimate COT(min) in larger elephants. PMID- 22496288 TI - Control of D-octopine formation in scallop adductor muscle as revealed through thermodynamic studies of octopine dehydrogenase. AB - Octopine dehydrogenase (OcDH) from the adductor muscle of the great scallop, Pecten maximus (Linne, 1758), catalyses the NADH-dependent condensation of l arginine and pyruvate to d-octopine, NAD(+) and water during escape swimming and subsequent recovery. During exercise, ATP is mainly provided by the transphosphorylation of phospho-l-arginine and to some extent by anaerobic glycolysis. NADH resulting from the glycolytic oxidation of 3 phosphoglyceraldehyde to 1,3-bisphosphoglycerate is reoxidized during d-octopine formation. In some scallops d-octopine starts to accumulate during prolonged, strong muscular work, whereas in other species d-octopine formation commences towards the end of swimming and continues to rise during subsequent recovery. The activity of OcDH is regulated by a mandatory, consecutive mode of substrate binding in the order NADH, l-arginine and pyruvate, as demonstrated by isothermal titration calorimetry. The first regulatory step in the forward reaction comprises the binding of NADH to OcDH with a dissociation constant K(d) of 0.014+/-0.006 mmol l(-1), which reflects a high affinity and tight association of the apoenzyme with the co-substrate. In the reverse direction, NAD(+) binds first with a K(d) of 0.20+/-0.004 mmol l(-1) followed by d-octopine. The binary OcDH NADH complex associates with l-arginine with a K(d) of 5.5+/-0.05 mmol l(-1). Only this ternary complex combines with pyruvate, with an estimated K(d) of approximately 0.8 mmol l(-1) as deduced from pyruvate concentrations determined in the muscle of exhausted scallops. At tissue concentrations of pyruvate between 0.5 and 1.2 mmol l(-1) in the valve adductor muscle of fatigued P. maximus, binding of pyruvate to OcDH plays the most decisive role in initiating OcDH activity and, therefore, in controlling the onset of d-octopine formation. PMID- 22496289 TI - Head and body stabilization in blowflies walking on differently structured substrates. AB - Visually guided animals depend heavily on the quality of visual signals in order to obtain functionally relevant information about their environment. To support visual information processing, nature has evolved a large variety of physiological adaptations and behavioral strategies such as compensatory head movements. During self-movement, head rotations compensate for changes in body attitude in order to stabilize gaze. However, how walking animals cope with uneven structured substrates, which may affect body and gaze orientation, is still unknown. We used stereo high-speed video to analyze compensatory head movements of blowflies walking freely on differently structured substrates. We found that even a pronounced asperity of the ground structure, with bumps of almost the size of the animal, was largely compensated by the walking apparatus of the blowfly, which leads to body roll and pitch movements only marginally larger than those on flat substrate. Pitch and roll fluctuations of the head were smaller compared with body fluctuations on all tested substrates, emphasizing the significance of gaze stabilization during walking on structured substrates. Furthermore, we found no impairment in head and body stabilization during walks in darkness, which indicates that the control system mediating compensatory head movements works well without any visual input. Interestingly, blowflies changed their walking style in the dark and seemed to use their forelegs as tactile probes. PMID- 22496290 TI - Active electrolocation in pulse gymnotids: sensory consequences of objects' mutual polarization. AB - We examined non-linear effects of the presence of one object on the electric image of another placed at the foveal region in Gymnotus omarorum. The sensory consequences of object mutual polarization on electric images were also depicted using behavioral procedures. Image measurements show that objects whose electric image is not detectable may modify the electric image of another placed closer to the fish and suggest that detection range and discrimination parameters used for one object may be affected when the presence of others enriches the scene. Behavioral experiments confirm that these changes in object images resulting from mutual polarization may be exploited for improving perception. While conductive objects close to the skin allow the fish to detect other objects placed out of the active electrodetection range, non-conductive objects may hide objects that otherwise show clear electric images. This suggests that fish movements may orient the self-generated field to exploit object mutual polarization, increasing or decreasing the active electrolocation range. In addition, images of a nearby object may be modulated by the presence of another object placed outside the detection range and the corresponding behavioral responses suggest that a moving or impedance-changing context may modify a fish's discrimination abilities for closer objects. PMID- 22496291 TI - Olfactory coding in five moth species from two families. AB - The aim of the present study was to determine what impact phylogeny and life history might have on the coding of odours in the brain. Using three species of hawk moths (Sphingidae) and two species of owlet moths (Noctuidae), we visualized neural activity patterns in the antennal lobe, the first olfactory neuropil in insects, evoked by a set of ecologically relevant plant volatiles. Our results suggest that even between the two phylogenetically distant moth families, basic olfactory coding features are similar. But we also found different coding strategies in the moths' antennal lobe; namely, more specific patterns for chemically similar odorants in the two noctuid species than in the three sphingid species tested. This difference demonstrates the impact of the phylogenetic distance between species from different families despite some parallel life history traits found in both families. Furthermore, pronounced differences in larval and adult diet among the sphingids did not translate into differences in the olfactory code; instead, the three species had almost identical coding patterns. PMID- 22496292 TI - Developmental phenotypic plasticity in a marsupial. AB - Climate change is likely to substantially affect the distribution ranges of species. However, little is known about how different mammalian taxa respond morphologically and physiologically to a rapid change of climate. Our objective was to provide the first quantitative data on the effect of continuous cold exposure during development on morphological and functional variables of a marsupial. Fat-tailed dunnarts (Sminthopsis crassicaudata, Dasyuridae) were reared at an ambient temperature (T(a)) of 16 degrees C [cold-reared (CR)] or 22 degrees C [warm-reared (WR)] until they reached adult age (>200 days). Body and head length of CR animals were significantly longer than in WR animals (mean +/- s.e.m.; body: CR 80.8+/-6 mm, WR 76.4+/-5 mm; head: CR 29.4+/-3 mm, WR 27.5+/-2 mm), but other body attributes were not significantly different. Use of torpor was more frequent, torpor bout duration was longer and average daily metabolic rate and percentage of savings when using torpor were significantly higher (P<0.01) in CR than in WR animals at 16 degrees C T(a) but not at 24 degrees C. Furthermore, resting metabolic rates measured at 16 degrees C T(a) were significantly lower in CR than WR animals; at 30 degrees C T(a) values were similar. Our results do not conform to Allen's rule, but to some extent they do conform to Bergmann's rule. However, the data demonstrate that a relatively moderate cold exposure from birth until adulthood induces marked changes in the morphology and thermal energetics of small marsupials. Such short-term phenotypic responses without the need for long-term selection are likely important for the ability to cope with different climates over a wide range of distribution, but will also play a crucial role in enhancing the survival of species during climate change. PMID- 22496293 TI - Identified antennular near-field receptors trigger reflex flicking in the crayfish. AB - Near-field disturbances in the water column are known to trigger reflex antennular flicking in the crayfish Procambarus clarkii. We have identified the hydrodynamic sensors on the lateral antennular flagellum that constitute an afferent limb of this reflex and have measured the relative directionally dependent thresholds of the sensory neurons associated with these structures to hydrodynamic stimulation. Twenty-five individual standing feathered sensilla, comprising a sparse, linearly arrayed population of near-field sensors along the lateral and medial antennular flagella, were exposed to standardized pulsatile stimuli at 20 deg intervals along a 320 deg circular track. The results indicate that the sensilla are most sensitive to such stimulation in the plane of the flagellar axis. Identification and mechanical stimulation of single feathered sensilla in some preparations consistently evoked a flick reflex at maximal response latency, indicating that these sensors constitute at least one afferent limb for the reflex behavior. Experiments in which response latencies were measured following mechanical stimulation of truncated flagella, and were compared with the latencies in respective intact flagella, suggest that summation of inputs from the feathered sensillar pathways generates reflex flicking at minimal latencies. We discuss the possible central mechanisms that may underlie detection of critically important signals from this population of highly sensitive, inherently noisy sensors. PMID- 22496294 TI - Active sensing via movement shapes spatiotemporal patterns of sensory feedback. AB - Previous work has shown that animals alter their locomotor behavior to increase sensing volumes. However, an animal's own movement also determines the spatial and temporal dynamics of sensory feedback. Because each sensory modality has unique spatiotemporal properties, movement has differential and potentially independent effects on each sensory system. Here we show that weakly electric fish dramatically adjust their locomotor behavior in relation to changes of modality-specific information in a task in which increasing sensory volume is irrelevant. We varied sensory information during a refuge-tracking task by changing illumination (vision) and conductivity (electroreception). The gain between refuge movement stimuli and fish tracking responses was functionally identical across all sensory conditions. However, there was a significant increase in the tracking error in the dark (no visual cues). This was a result of spontaneous whole-body oscillations (0.1 to 1 Hz) produced by the fish. These movements were costly: in the dark, fish swam over three times further when tracking and produced more net positive mechanical work. The magnitudes of these oscillations increased as electrosensory salience was degraded via increases in conductivity. In addition, tail bending (1.5 to 2.35 Hz), which has been reported to enhance electrosensory perception, occurred only during trials in the dark. These data show that both categories of movements - whole-body oscillations and tail bends - actively shape the spatiotemporal dynamics of electrosensory feedback. PMID- 22496295 TI - Divalent metal (Ca, Cd, Mn, Zn) uptake and interactions in the aquatic insect Hydropsyche sparna. AB - Despite their ecological importance and prevalent use as ecological indicators, the trace element physiology of aquatic insects remains poorly studied. Understanding divalent metal transport processes at the water-insect interface is important because these metals may be essential (e.g. Ca), essential and potentially toxic (e.g. Zn) or non-essential and toxic (e.g. Cd). We measured accumulation kinetics of Zn and Cd across dissolved concentrations ranging 4 orders of magnitude and examined interactions with Ca and Mn in the caddisfly Hydropsyche sparna. Here, we provide evidence for at least two transport systems for both Zn and Cd, the first of which operates at concentrations below 0.8 MUmol l(-1) (and is fully saturable for Zn). We observed no signs of saturation of a second lower affinity transport system at concentrations up to 8.9 MUmol l(-1) Cd and 15.3 MUmol l(-1) Zn. In competition studies at 0.6 MUmol l(-1) Zn and Cd, the presence of Cd slowed Zn accumulation by 35% while Cd was unaffected by Zn. At extreme concentrations (listed above), Cd accumulation was unaffected by the presence of Zn whereas Zn accumulation rates were reduced by 58%. Increasing Ca from 31.1 MUmol l(-1) to 1.35 mmol l(-1) resulted in only modest decreases in Cd and Zn uptake. Mn decreased adsorption of Cd and Zn to the integument but not internalization. The L-type Ca(2+) channel blockers verapamil and nifedipine and the plasma membrane Ca(2+)-ATPase inhibitor carboxyeosin had no influence on Ca, Cd or Zn accumulation rates, while Ruthenium Red, a Ca(2+)-ATPase inhibitor, significantly decreased the accumulation of all three in a concentration dependent manner. PMID- 22496296 TI - Statistical parametric mapping of the regional distribution and ontogenetic scaling of foot pressures during walking in Asian elephants (Elephas maximus). AB - Foot pressure distributions during locomotion have causal links with the anatomical and structural configurations of the foot tissues and the mechanics of locomotion. Elephant feet have five toes bound in a flexible pad of fibrous tissue (digital cushion). Does this specialized foot design control peak foot pressures in such giant animals? And how does body size, such as during ontogenetic growth, influence foot pressures? We addressed these questions by studying foot pressure distributions in elephant feet and their correlation with body mass and centre of pressure trajectories, using statistical parametric mapping (SPM), a neuro-imaging technology. Our results show a positive correlation between body mass and peak pressures, with the highest pressures dominated by the distal ends of the lateral toes (digits 3, 4 and 5). We also demonstrate that pressure reduction in the elephant digital cushion is a complex interaction of its viscoelastic tissue structure and its centre of pressure trajectories, because there is a tendency to avoid rear 'heel' contact as an elephant grows. Using SPM, we present a complete map of pressure distributions in elephant feet during ontogeny by performing statistical analysis at the pixel level across the entire plantar/palmar surface. We hope that our study will build confidence in the potential clinical and scaling applications of mammalian foot pressures, given our findings in support of a link between regional peak pressures and pathogenesis in elephant feet. PMID- 22496297 TI - In ovo temperature manipulation differentially influences limb musculoskeletal development in two lines of chick embryos selected for divergent growth rates. AB - Selective breeding has led to diverging phenotypic evolution in layer and broiler chickens through genomic and epigenetic modifications. Here we show that in ovo environmental manipulation differentially influences embryonic limb muscle phenotype in these two breeds. We demonstrate that raising incubation temperature from 37.5 to 38.5 degrees C between embryonic days (ED) 4 and 7 increased motility and body mass in both layer and broiler embryos. In layers, this was accompanied by gastrocnemius muscle hypertrophy, increased fibre and nuclei numbers and a higher nuclei to fibre ratio (ED18), preceded by increased hindlimb Myf5 (ED5-8), Pax7 (ED5-10), BMP4 (ED6-9) and IGF-I (ED9-10, ED18) mRNAs. In broilers, the same temperature treatment led to reduced gastrocnemius cross sectional area with fewer fibres and nuclei and an unchanged fibre to nuclei ratio (ED18). This was preceded by a delay in the peak of hindlimb Myf5 expression, increased Pax7 (ED5, ED7-10) and BMP4 (ED6-8) but reduced IGF-I (ED8 10) mRNAs. Rather than promoting myogenesis as in layer embryos, the temperature treatment promoted gastrocnemius intramuscular fat deposition in broilers (ED18) preceded by increased hindlimb PPARgamma mRNA (ED7-10). The treatment increased tibia/tarsus bone length as well as femur cross-sectional area in both breeds, but femur length and bone to cartilage ratio in the femur and tibia/tarsus were only increased in treated layers (ED18). We conclude that in ovo temperature manipulation differentially affected the molecular regulation of hindlimb myogenic, adipogenic and growth factor expression in broiler and layer embryos, leading to differential changes in muscle phenotype. The underlying interactive mechanisms between genes and the environment need further investigation. PMID- 22496298 TI - Superficial spreading melanoma. PMID- 22496299 TI - Fever and rash in a returning traveller. PMID- 22496300 TI - Cluster headache. PMID- 22496301 TI - Antibiotic drug research and development. PMID- 22496302 TI - Investigation discovers fraud in more than half of first tranche of psychologist's research papers. PMID- 22496303 TI - Exploring the physiology of elite athletes. PMID- 22496304 TI - Lister and the reputation robbing historians. PMID- 22496305 TI - Number of people with dementia will reach 65.7 million by 2030, says report. PMID- 22496306 TI - Mathematics is bad for you: population risk reduction medicalises us all. PMID- 22496307 TI - The economist. PMID- 22496308 TI - Top adviser at the European Medicines Agency quits suddenly. PMID- 22496309 TI - Utilising behavioural family therapy (BFT) to help support the system around a person with intellectual disability and complex mental health needs: a case study. AB - There is a higher incidence of mental health problems amongst people with intellectual disabilities. Family members and support staff who provide support to people with intellectual disabilities with mental health difficulties are more likely to experience increased stress. In the mainstream mental health literature it has been demonstrated that psycho-educational family interventions have a positive impact on the person with mental health difficulties and on the family members who support them. This article uses a case study to illustrate the implementation of a family intervention with the support system around someone with intellectual disabilities, autism and chronic mental health difficulties. Following intervention the family member reported a marked decrease in levels of strain. Both the family and team members reported improvement in functioning within the support system. PMID- 22496311 TI - On the shifting balance: the case of Staphylococcus aureus CC398. AB - The recent study by L. Price et al. [mBio, 3(1):e00305-11, 2012] demonstrating the human origin of the livestock-associated CC398 Staphylococcus aureus provides an excellent example of how bacterial populations can explore a wide range of potential niches and acquire optimal adaptations for life in alternative hosts. The shifting balance theory proposed by Sewall Wright 80 years ago serves as a perfect model for understanding the observed facts: a possibly large CC398 population optimally positioned on the top of a fitness peak for living in a human host probably began evolving long ago by variation, drift, and migration, until it reached the low fitness edge of a neighboring alternative peak in the fitness landscape, one in a livestock host. The bacterial population then evolved again, moving uphill to reach a novel optimal "top of the peak" position in livestock. In the case of CC398, it is worrisome to think that it might readapt to human hosts without losing fitness in livestock; a double-host-adapted organism could certainly be in an optimal position for increasing its virulence and antibiotic resistance. PMID- 22496310 TI - FdeC, a novel broadly conserved Escherichia coli adhesin eliciting protection against urinary tract infections. AB - The increasing antibiotic resistance of pathogenic Escherichia coli species and the absence of a pan-protective vaccine pose major health concerns. We recently identified, by subtractive reverse vaccinology, nine Escherichia coli antigens that protect mice from sepsis. In this study, we characterized one of them, ECOK1_0290, named FdeC (factor adherence E. coli) for its ability to mediate E. coli adhesion to mammalian cells and extracellular matrix. This adhesive propensity was consistent with the X-ray structure of one of the FdeC domains that shows a striking structural homology to Yersinia pseudotuberculosis invasin and enteropathogenic E. coli intimin. Confocal imaging analysis revealed that expression of FdeC on the bacterial surface is triggered by interaction of E. coli with host cells. This phenotype was also observed in bladder tissue sections derived from mice infected with an extraintestinal strain. Indeed, we observed that FdeC contributes to colonization of the bladder and kidney, with the wild type strain outcompeting the fdeC mutant in cochallenge experiments. Finally, intranasal mucosal immunization with recombinant FdeC significantly reduced kidney colonization in mice challenged transurethrally with uropathogenic E. coli, supporting a role for FdeC in urinary tract infections. IMPORTANCE: Pathogenic Escherichia coli strains are involved in a diverse spectrum of diseases, including intestinal and extraintestinal infections (urinary tract infections and sepsis). The absence of a broadly protective vaccine against all these E. coli strains is a major problem for modern society due to high costs to health care systems. Here, we describe the structural and functional properties of a recently reported protective antigen, named FdeC, and elucidated its putative role during extraintestinal pathogenic E. coli infection by using both in vitro and in vivo infection models. The conservation of FdeC among strains of different E. coli pathotypes highlights its potential as a component of a broadly protective vaccine against extraintestinal and intestinal E. coli infections. PMID- 22496312 TI - Echovirus 7 entry into polarized intestinal epithelial cells requires clathrin and Rab7. AB - Enteroviruses invade the host by crossing the intestinal mucosa, which is lined by polarized epithelium. A number of enteroviruses, including echoviruses (EV) and group B coxsackieviruses (CVB), initiate infection by attaching to decay accelerating factor (DAF), a molecule that is highly expressed on the apical surface of polarized epithelial cells. We previously observed that entry of DAF binding CVB3 into polarized intestinal epithelial cells occurs by an unusual endocytic mechanism that requires caveolin but does not involve clathrin or dynamin. Here we examined the entry of a DAF-binding echovirus, EV7. We found that drugs, small interfering RNAs (siRNAs), and dominant negative mutants that target factors required for clathrin-mediated endocytosis, including clathrin and dynamin, inhibited both EV7 infection and internalization of virions from the cell surface. Once virus had entered the cell, it colocalized with markers of early endosomes (EEA1) and then late endosomes (LAMP-2). Inhibition of endosomal maturation-with siRNAs or dominant negative mutants targeting Rab5 and Rab7 inhibited infection and prevented release of viral RNA into the cell. These results indicate that EV7 is internalized by clathrin-mediated endocytosis and then moves to early and late endosomes before releasing its RNA. Trafficking through endosomes is known to be important for viruses that depend on low pH or endosomal cathepsin proteases to complete the entry process. However, we found that EV7 infection required neither low pH nor cathepsins. IMPORTANCE: The results demonstrate that echovirus 7 (EV7), after binding to decay-accelerating factor (DAF) on the cell surface, enters cells by clathrin-mediated endocytosis; this entry mechanism differs markedly from that of another DAF-binding enterovirus, coxsackievirus B3 (CVB3). Thus, after attachment to the same cell surface receptor, these closely related viruses enter the same cells by different mechanisms. The cellular cues required for release of viral RNA from the enterovirus capsid ("uncoating") remain poorly defined. We found that EV7 moved to late endosomes and that release of RNA depended on endosomal maturation; nonetheless, EV7 did not depend on the endosomal factors implicated in uncoating and entry by other viruses. The results suggest either that an unidentified endosomal factor is essential for uncoating of EV7 or that trafficking through the endosome is an essential step in a pathway that leads to another intracellular organelle where uncoating is completed. PMID- 22496313 TI - Low major histocompatibility complex class I (MHC I) variation in the European bison (Bison bonasus). AB - Variation in the major histocompatibility complex (MHC) class I of the European bison was characterized in a sample of 99 individuals using both classical cloning/Sanger sequencing and 454 pyrosequencing. Three common (frequencies: 0.348, 0.328, and 0.283) haplotypes contain 1-3 classical class I loci. A variable and difficult to estimate precisely number of nonclassical transcribed loci, pseudogenes, and/or gene fragments were also found. The presence of additional 2 rare haplotypes (frequency of 0.020 each), observed only in heterozygotes, was inferred. The overall organization of MHC I appears similar to the cattle system, but genetic variation is much lower with only 7 classical class I alleles, approximately one-tenth of the number known in cattle and a quarter known in the American bison. An extensive transspecific polymorphism was found. MHC I is in a strong linkage disequilibrium with previously studied MHC II DRB3 gene. The most likely explanation for the low variation is a drastic bottleneck at the beginning of the 20th century. Genotype frequencies conformed to Hardy-Weinberg expectations, and no signatures of selection in contemporary populations but strong signatures of historical positive selection in sequences of classical alleles were found. A quick and reliable method of MHC I genotyping was developed. PMID- 22496314 TI - Paediatric patients with a tracheostomy: a multicentre epidemiological study. AB - Changes in the indications for tracheostomy in children have led to the progressively greater involvement of the paediatric pulmonologist in the care of these patients. The aim of this study was to review the current profile of tracheostomised children in Spain. We undertook a longitudinal, multicentre study over 2 yrs (2008 and 2009) of all patients aged between 1 day and 18 yrs who had a tracheostomy. The study, involving 18 Spanish hospitals, included 249 patients, of whom 150 (60.2%) were <1 yr of age. The main indications for the procedure were prolonged ventilation (n=156, 62.6%), acquired subglottic stenosis (n=34, 13.6%), congenital or acquired craniofacial anomalies (n=25, 10%) and congenital airway anomalies (n=24, 9.6%). The most frequent underlying disorders were neurological diseases (n=126, 50.6%) and respiratory diseases (n=98, 39.3%). Over the 2-yr study period, 92 (36.9%) children required ventilatory support, and decannulation was achieved in 59 (23.7%). Complications arose in 117 patients (46.9%). Mortality attributed to the underlying condition was 12.5% and that related directly to the tracheostomy was 3.2%. Respiratory complexity of tracheostomised children necessitates prolonged, multidisciplinary follow-up, which can often extend to adulthood. PMID- 22496316 TI - Value of flexible bronchoscopy in the pre-operative work-up of solitary pulmonary nodules. AB - The diagnostic value of flexible bronchoscopy in the pre-operative work-up of solitary pulmonary nodules (SPN) is still under debate among pneumologists, radiologists and thoracic surgeons. In a prospective observational manner, flexible bronchoscopy was routinely performed in 225 patients with SPN of unknown origin. Of the 225 patients, 80.5% had lung cancer, 7.6% had metastasis of an extrapulmonary primary tumour and 12% had benign aetiology. Unsuspected endobronchial involvement was found in 4.4% of all 225 patients (or in 5.5% of patients with lung cancer). In addition, flexible bronchoscopy clarified the underlying aetiology in 41% of the cases. The bronchoscopic biopsy results from the SPN were positive in 84 (46.5%) patients with lung cancer. Surgery was cancelled due to the results of flexible bronchoscopy in four cases (involvement of the right main bronchus (impaired pulmonary function did not allow pneumonectomy) n=1, small cell lung cancer n=1, bacterial pneumonia n=2), and the surgical strategy had to be modified to bilobectomy in one patient. Flexible bronchoscopy changed the planned surgical approach in five cases substantially. These results suggest that routine flexible bronchoscopy should be included in the regular pre-operative work-up of patients with SPN. PMID- 22496315 TI - Cord blood angiogenic progenitor cells are decreased in bronchopulmonary dysplasia. AB - Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is associated with impaired vascular and alveolar growth. Antenatal factors contribute to the risk for developing BPD by unclear mechanisms. Endothelial progenitor cells, such as angiogenic circulating progenitor cells (CPCs) and late outgrowth endothelial colony-forming cells (ECFCs), may contribute to angiogenesis in the developing lung. We hypothesise that cord blood angiogenic CPCs and ECFCs are decreased in preterm infants with moderate and severe BPD. We quantified ECFCs and the CPC/nonangiogenic-CPC ratio (CPC/non-CPC) in cord blood samples from 62 preterm infants and assessed their relationships to maternal and perinatal risk factors as well as BPD severity. The CPC/non-CPC ratio and ECFC number were compared between preterm infants with mild or no BPD and those with moderate or severe BPD. ECFC number (p<0.001) and CPC/non-CPC ratio (p<0.05) were significantly decreased in cord blood samples of preterm infants who subsequently developed moderate or severe BPD. Gestational age and birth weight were not associated with either angiogenic marker. Circulating vascular progenitor cells are decreased in the cord blood of preterm infants who develop moderate and severe BPD. These findings suggest that prenatal factors contribute to late respiratory outcomes in preterm infants. PMID- 22496317 TI - Wash-out kinetics and efficacy of a modified lavage technique for alveolar proteinosis. AB - Whole lung lavage (WLL) is the standard treatment for pulmonary alveolar proteinosis (PAP). This study aimed to provide data about the kinetics of the protein wash-out, to identify factors influencing the protein concentration in the recovered fluid and to assess the efficacy of a modified lavage technique. Samples of 180 WLLs from 42 adult PAP patients were collected. 110 WLLs were performed according to the classical technique. In 70 WLLs, repeated manual ventilation was applied during the procedure. Spectrophotometry was used to measure the protein concentration in the recovered fluid. The initial protein concentration in the recovered fluid was 460 mg . dL(-1), the final concentration was 26 mg . dL(-1) and the total amount of removed proteins during a lavage was 17.5 g. A history of dust exposure was associated with a higher residual protein concentration in the recovered fluid (p=0.000013). The amount of removed proteins correlated inversely with the diffusing capacity of the lung for carbon monoxide (p=0.001) and oxygen tension (p=0.004). The modified technique removed a greater amount of proteins than the classical technique and prolonged the time to relapse (p=0.011). Exposure to dust seems to influence the kinetics of the protein wash out. Applying manual ventilation during the procedure can enhance the efficacy of WLL. PMID- 22496318 TI - The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement. AB - Tuberculosis (TB) is a possible complication of solid organ and hematopoietic stem cell transplantation. The identification of candidates for preventive chemotherapy is an effective intervention to protect transplant recipients with latent infection with Mycobacterium tuberculosis from progressing to active disease. The best available proxy for diagnosing latent infection with M. tuberculosis is the identification of an adaptive immune response by the tuberculin skin test or an interferon-gamma based ex vivo assay. Risk assessment in transplant recipients for the development of TB depends on, among other factors, the locally expected underlying prevalence of infection with M. tuberculosis in the target population. In areas of high prevalence, preventive chemotherapy for all transplant recipients may be justified without immunodiagnostic testing while in areas of medium and low prevalence, preventive chemotherapy should only be offered to candidates with positive M. tuberculosis specific immune responses. The diagnosis of TB in transplant recipients can be challenging. Treatment of TB is often difficult due to substantial interactions between anti-TB drugs and immunosuppressive medications. This management guideline summarises current knowledge on the prevention, diagnosis and treatment of TB related to solid organ and hematopoietic stem cell transplantation and provides an expert consensus on questions where scientific evidence is still lacking. PMID- 22496319 TI - Thoracoscore fails to predict complications following elective lung resection. AB - The Thoracoscore mortality risk model has been incorporated into the British Thoracic Society guidelines on the radical management of patients with lung cancer. The discriminative and predictive ability to predict mortality and post operative pulmonary complications (PPCs) in this group of patients is uncertain. A prospective observational study was carried out on all patients following lung resection via thoracotomy in a regional thoracic centre over 42 months. 128 out of 703 subjects developed a PPC. 16 (2%) patients died in hospital. In a logistic regression analysis the Thoracoscore was not a significant predictor of mortality (OR 1.07, 95% CI 0.99-1.17; p=0.11) but was a significant predictor of PPCs (OR 1.08, 95% CI 1.03-1.13; p=0.002). However, the area under the receiver operator characteristic curve for the Thoracoscore was 0.68 (95% CI 0.56-0.80) for predicting mortality and 0.64 (95% CI 0.59-0.69) for PPCs, indicating limited discriminative ability. In a logistic regression analysis, another risk model, the European Society Objective Score, was predictive of mortality (OR 1.43, 95% CI 1.11-1.83; p=0.006) and PPCs (OR 1.48, 95% CI 1.30-1.68; p<0.0001). Therefore, Thoracoscore may have poor discriminative and predictive ability for mortality and PPCs following elective lung resection. PMID- 22496320 TI - Double Y-stenting for tracheobronchial stenosis. AB - The purpose of the present study was to evaluate the feasibility, efficacy and safety of the double Y-stenting technique, by which silicone Y-stents are placed on both the main carina and another peripheral carina, for patients with tracheobronchial stenosis. Under general anaesthesia, using rigid and flexible bronchoscopes, a DumonTM Y-stent (Novatech, La Ciotat, France) was first placed on the primary right or secondary left carina followed by another Y-stent on the main carina so as to insert the bronchial limb of the stent into the first Y stent. Patients who underwent double Y-stent placement during 3 yrs and 1 month in a single centre were retrospectively reviewed. In the study period, 93 patients underwent silicone stent placement and 12 (13%) underwent double Y-stent placement (11 for right and one for left bronchus). A combination of Y-stents, 14 * 10 * 10 mm and 16 * 13 * 13 mm in outer diameter, were most frequently used. Dyspnoea was relieved in all patients. Six out of seven patients with supplemental oxygen before stent placement could be discharged without supplemental oxygen. Median survival after stenting was 94.5 days. One pneumothorax and one granuloma formation occurred. Double Y-stent placement for patients with tracheobronchial stenosis was technically feasible, effective and acceptably safe. PMID- 22496321 TI - Host response to mechanical ventilation for viral respiratory tract infection. AB - Respiratory syncytial virus (RSV) bronchiolitis causes severe respiratory tract infection in infants, frequently necessitating mechanical ventilatory support. However, life-saving, mechanical ventilation aggravates lung inflammation. We set up a model to dissect the host molecular response to mechanical ventilation in RSV infection. Furthermore, the response to induced hypercapnic acidosis, reported to dampen the inflammatory response to mechanical ventilation in non infectious models, was assessed. BALB/c mice were inoculated with RSV or mock suspension and ventilated for 5 h on day 5 post inoculation. Mechanical ventilation of infected mice resulted in enhanced cellular influx and increased concentrations of pro-inflammatory cytokines in the bronchoalveolar space. Microarray analysis showed that enhanced inflammation was associated with a molecular signature of a stress response to mechanical ventilation with little effect on the virus-induced innate immune response. Hypercapnic acidosis during mechanical ventilation of infected mice did not change host transcript profiles. We conclude that mechanical ventilation during RSV infection adds a robust but distinct molecular stress response to virus-induced innate immunity activation, emphasising the importance of lung-protective mechanical ventilation strategies. Induced hypercapnic acidosis has no major effect on host transcription profiles during mechanical ventilation for RSV infection, suggesting that this is a safe approach to minimise ventilator-induced lung injury. PMID- 22496322 TI - Is it time for home treatment of pulmonary embolism? AB - Acute pulmonary embolism (PE) is a frequent cause of death, but not all patients are at high risk of an adverse early outcome. It has been proposed that selected patients may be considered for early discharge and home treatment, but it was only recently that improved risk assessment strategies permitted advances in the identification of low-risk PE. Clinical prediction rules, such as the Pulmonary Embolism Severity Index (PESI), and laboratory biomarkers, particularly natriuretic peptides and cardiac troponins, appeared capable of excluding severe PE and serious comorbidity. Recently, two randomised trials and two prospective cohort studies investigated the feasibility and safety of outpatient treatment. All excluded patients with haemodynamic instability and serious comorbidity, but only one trial used a validated clinical score (PESI) for patient inclusion, and only one cohort study employed a biomarker test. Overall, 90-day outcome was favourable and the results appear promising. To optimise patient selection, future trials will need to test simplified clinical scores combined with high sensitivity biomarker assays, and it will have to be determined whether echocardiography and/or compression ultrasonography are also required before discharge. Furthermore, ongoing trials will show whether new oral anticoagulants are a safe and cost-effective option for managing patients out of hospital. PMID- 22496324 TI - Extracellular matrix composition in COPD. AB - Extracellular matrix (ECM) composition has an important role in determining airway structure. We postulated that ECM lung composition of chronic obstructive pulmonary disease (COPD) patients differs from that observed in smoking and nonsmoking subjects without airflow obstruction. We determined the fractional areas of elastic fibres, type-I, -III and -IV collagen, versican, decorin, biglycan, lumican, fibronectin and tenascin in different compartments of the large and small airways and lung parenchyma in 26 COPD patients, 26 smokers without COPD and 16 nonsmoking control subjects. The fractional area of elastic fibres was higher in non-obstructed smokers than in COPD and nonsmoking controls, in all lung compartments. Type-I collagen fractional area was lower in the large and small airways of COPD patients and in the small airways of non-obstructed smokers than in nonsmokers. Compared with nonsmokers, COPD patients had lower versican fractional area in the parenchyma, higher fibronectin fractional area in small airways and higher tenascin fractional area in large and small airways compartments. In COPD patients, significant correlations were found between elastic fibres and fibronectin and lung function parameters. Alterations of the major ECM components are widespread in all lung compartments of patients with COPD and may contribute to persistent airflow obstruction. PMID- 22496323 TI - Domestic use of cleaning sprays and asthma activity in females. AB - We aimed to study the associations between the household use of cleaning sprays and asthma symptoms and control of asthma, in females from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). Data were available for 683 females (mean age 44 yrs, 55% never smokers, 439 without asthma and 244 with current asthma). Both domestic exposures and asthma phenotypes (asthma symptom score, current asthma, poorly-controlled asthma (56%)) were evaluated as previously described in the European Community Respiratory Health Survey. Associations between the use of sprays and asthma phenotypes were evaluated using logistic and nominal regressions, adjusted for age, smoking, body mass index and occupational exposures. Significant associations were observed between the weekly use of at least two types of sprays and a high asthma symptom score (OR (95% CI) 2.50 (1.54-4.03)) compared with a null score. Consistent results were observed for current asthma (1.67 (1.08-2.56)) and poorly-controlled asthma (2.05 (1.25 3.35)) compared with females without asthma. The association for current asthma was higher in females not reporting avoidance of polluted places (2.12 (1.27 3.54)) than in those reporting such avoidance (0.99 (0.53-1.85)). The common use of household cleaning sprays is positively associated with a high asthma symptom score, current asthma and poorly-controlled asthma in females. PMID- 22496325 TI - Plumbagin reverses proliferation and resistance to apoptosis in experimental PAH. AB - Like cancer, pulmonary arterial hypertension (PAH) is characterised by a pro proliferative and anti-apoptotic phenotype. In PAH, pulmonary artery smooth muscle cell (PASMC) proliferation is enhanced and apoptosis suppressed. The sustainability of this phenotype requires the activation of pro-survival transcription factors, such as signal transducer and activator of transcription (STAT)3 and nuclear factor of activated T-cells (NFAT). There are no drugs currently available that are able to efficiently and safely inhibit this axis. We hypothesised that plumbagin (PLB), a natural organic compound known to block STAT3 in cancer cells, would reverse experimental pulmonary hypertension. Using human PAH-PASMC, we demonstrated in vitro that PLB inhibits the activation of the STAT3/NFAT axis, increasing the voltage-gated K(+) current bone morphogenetic protein receptor type II (BMPR2), and decreasing intracellular Ca(2+) concentration ([Ca(2+)](i)), rho-associated coiled-coil containing protein kinase (ROCK)1 and interleukin (IL)-6, contributing to the inhibition of PAH-PASMC proliferation and resistance to apoptosis (proliferating cell nuclear antigen (PCNA), TUNEL, Ki67 and anexine V). In vivo, PLB oral administration decreases distal pulmonary artery remodelling, mean pulmonary artery pressure and right ventricular hypertrophy without affecting systemic circulation in both monocrotaline- and suden/chronic hypoxia-induced PAH in rats. This study demonstrates that the STAT3/NFAT axis can be therapeutically targeted by PLB in human PAH-PASMC and experimental PAH rat models. Thus, PLB could be considered a specific and attractive future therapeutic strategy for PAH. PMID- 22496326 TI - Role of the QuantiFERON(R)-TB Gold In-Tube assay in screening new immigrants for tuberculosis infection. AB - This study aimed to estimate the risk of progression to active tuberculosis (TB) within 2 yrs after entry in newly arriving immigrants who were screened with the QuantiFERON(r)-TB Gold In-Tube assay (QFT-GIT; Cellestis, Carnegie, Australia). In a case-base design, we determined the prevalence QFT-GIT-positive subjects among a representative sample of immigrants aged >= 18 yrs who arrived between April 2009 and March 2011 (the base cohort). Active TB patients (cases) within 2 yrs post-arrival in 2005, 2006 or 2007 were extracted from the Netherlands Tuberculosis Register. The risk of progression to active TB was estimated using Bayesian analyses to adjust for the sensitivity of QFT-GIT. Among the base cohort, 20% of 1,468 immigrants were QFT-GIT positive. Stratified by TB incidence in the person's country of origin as low (<100 cases per 100,000 population), intermediate (100-199 cases per 100,000) or high (>= 200 cases per 100,000), the risk of progression to active TB per 100,000 arriving immigrants if QFT-GIT positive (95% credibility interval) was 456 (95% CI 307-589), 590 (397-762) and 386 (259-499), respectively, compared with 18 (0-46), 38 (0-97) and 28 (0-71) if QFT-GIT negative. Screening newly arriving immigrants with QFT-GIT contributes to detecting those at high risk of subsequent TB reactivation within 2 yrs after entry, which offers opportunities for prevention by targeted interventions. PMID- 22496327 TI - Decreased cerebrovascular response to CO2 in post-menopausal females with COPD: role of oxidative stress. AB - Chronic obstructive pulmonary disease (COPD) is associated with cerebrovascular abnormalities and an overproduction of reactive oxygen species. We hypothesised that COPD patients have oxidant-related cerebrovascular dysfunction. Our main objective was to evaluate cerebrovascular reactivity and its relationship with oxidative stress in females with COPD. We studied eight females with moderate COPD and 10 healthy female control subjects of similar age. Transcranial Doppler ultrasound assessed cerebral blood flow (CBF) velocity during hypercapnia. Plasma was assessed at rest for DNA oxidation, advanced oxidation protein products, lipid peroxidation, nitrotyrosine, antioxidant enzyme activity (glutathione peroxidase and catalase) and end-products of nitric oxide metabolism. Moderate COPD patients showed decreased cerebrovascular sensitivity to carbon dioxide (CO(2)) (COPD 1.17 +/- 0.54 versus control 2.15 +/- 0.73 cm . s(-1) . mmHg(-1); p<0.01). COPD patients had higher levels of DNA and lipid oxidation, advanced oxidation protein products and higher glutathione peroxidase activity (p<0.05). Controlling for measures of oxidative stress (DNA and lipid oxidation, and advanced oxidation protein product) eliminates statistically significant differences between the COPD and control groups in the CBF sensitivity to CO(2). Females with moderate COPD were found to have cerebrovascular dysfunction. Our results suggest that increased levels of systemic oxidative stress may have implications in the cerebrovascular dysfunction observed during hypercapnia in COPD. PMID- 22496328 TI - Early life lung function and respiratory outcome in the first year of life. AB - Abnormal early life lung function is related to wheezing in childhood; however, data on the association with cough are not available. We determined the relationship between early life lung function and wheeze and cough during the first year of life, adjusted for other possible risk factors. Infants were participants of the Wheezing Illnesses Study Leidsche Rijn (WHISTLER). Lung function measurements were performed before the age of 2 months. Information on pre- and perinatal factors, general characteristics and anthropometrics were assessed by questionnaires. Follow-up data on respiratory symptoms were assessed by daily questionnaires. 836 infants had valid lung function measurements and complete follow-up data for respiratory symptoms at 1 yr of age. Multivariable Poisson analysis showed that higher values of respiratory resistance (R(rs)) and time constant (tau(rs)) were associated with an increased risk for wheeze and cough during the first year of life. Higher values of respiratory compliance (C(rs)) were associated with a decreased risk for wheeze and cough. R(rs), C(rs) and tau(rs) measured shortly after birth were independently associated with wheeze and cough during the first year of life. As the strength of the relationships were different for wheeze and cough, they should be used as two separate entities. PMID- 22496329 TI - Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459. AB - CRTH2 (chemoattractant receptor expressed on T-helper (Th) type 2 cells) is a G protein-coupled receptor expressed by Th2 lymphocytes and eosinophils that mediates prostaglandin (PG)D(2)-driven chemotaxis. We studied the efficacy of the oral CRTH2 antagonist OC000459 in steroid-naive asthmatic patients. A randomised, double-blind, placebo-controlled, two-way crossover study of 16 days' treatment with OC000459 (200 mg twice daily) on the late (LAR) and early (EAR) asthmatic responses to bronchial allergen challenge was conducted, with 16 subjects completing the study. There was a 25.4% (95% CI 5.1-45.6%) reduction in the LAR area under the curve (AUC) for change in forced expiratory volume in 1 s with OC000459 compared with placebo (p=0.018) but no effect on the EAR. Sputum eosinophil counts at 1 day post-allergen challenge were lower after OC000459 treatment (p=0.002). PGD(2)-induced blood eosinophil shape change ex vivo was assessed at day 7 (n=7). The AUC of eosinophil shift for OC000459 was lower than placebo; the mean difference was -33.6% (95% CI -66.8- -0.4%; p=0.048). OC000459 treatment inhibited LAR and post-allergen increase in sputum eosinophils. This CRTH2 antagonist appears to inhibit allergic inflammation in asthma. PMID- 22496330 TI - Improvement of defective cystic fibrosis airway epithelial wound repair after CFTR rescue. AB - Airway damage and remodelling are important components of lung pathology progression in cystic fibrosis (CF). Although repair mechanisms are engaged to restore the epithelial integrity, these processes are obviously insufficient to maintain lung function in CF airways. Our aims were therefore to study how the basic cystic fibrosis transmembrane conductance regulator (CFTR) defect could impact epithelial wound healing and to determine if CFTR correction could improve it. Wound-healing experiments, as well as cell migration and proliferation assays, were performed to study the early phases of epithelial repair in human CF and non-CF airway cells. CFTR function was evaluated using CFTR small interferring (si)RNA and inhibitor GlyH101 in non-CF cells, and conversely after CFTR rescue with the CFTR corrector VRT-325 in CF cells. Wound-healing experiments first showed that airway cells from CF patients repaired slower than non-CF cells. CFTR inhibition or silencing in non-CF primary airway cells significantly inhibited wound closure. GlyH101 also decreased cell migration and proliferation. Interestingly, wild-type CFTR transduction in CF airway cell lines or CFTR correction with VRT-325 in CFBE-DeltaF508 and primary CF bronchial monolayers significantly improved wound healing. Altogether our results demonstrated that functional CFTR plays a critical role in wound repair, and CFTR correction may represent a novel strategy to promote the airway repair processes in CF. PMID- 22496331 TI - Emerging anti-inflammatory strategies for COPD. AB - The hallmark of chronic obstructive pulmonary disease (COPD) is an enhanced or abnormal inflammatory immune response of the lungs to inhaled particles and gases, usually from cigarette smoke, characterised by increased numbers of neutrophils, activated macrophages and activated T-lymphocytes (Tc1 and Th1 cells). Therefore, suppression of the inflammatory response is a logical approach to the treatment of COPD. Despite the inflammatory nature of COPD, currently available anti-inflammatory therapies provide little or no benefit in COPD patients and may have detrimental effects. For this reason, there is an urgent need to discover effective and safe anti-inflammatory treatments that might prevent the relentless progression of the disease. In recent years, attention has largely been focused on inhibition of recruitment and activation of inflammatory cells, and on antagonism of their products. In this review, we put together a summary of the state-of-the-art development of clearly and/or potentially useful anti-inflammatory strategies in COPD. PMID- 22496332 TI - Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. AB - Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis. 12 studies (11 countries from three continents) reporting complete information on safety, tolerability, efficacy of linezolid-containing regimes in treating MDR-TB cases were identified based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analysis was performed using the individual data of 121 patients with a definite treatment outcome (cure, completion, death or failure). Most MDR-TB cases achieved sputum smear (86 (92.5%) out of 93) and culture (100 (93.5%) out of 107) conversion after treatment with individualised regimens containing linezolid (median (inter-quartile range) times for smear and culture conversions were 43.5 (21-90) and 61 (29-119) days, respectively) and 99 (81.8%) out of 121 patients were successfully treated. No significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage <= 600 mg versus >600 mg). Adverse events were observed in 63 (58.9%) out of 107 patients, of which 54 (68.4%) out of 79 were major adverse events that included anaemia (38.1%), peripheral neuropathy (47.1%), gastro-intestinal disorders (16.7%), optic neuritis (13.2%) and thrombocytopenia (11.8%). The proportion of adverse events was significantly higher when the linezolid daily dosage exceeded 600 mg. The study results suggest an excellent efficacy but also the necessity of caution in the prescription of linezolid. PMID- 22496333 TI - Diagnosis-related deterioration of lung function after extracorporeal membrane oxygenation. AB - The aim of the study was to assess lung function longitudinally after neonatal extracorporeal membrane oxygenation (ECMO), and to identify any effects of diagnosis and perinatal characteristics. 121 neonatal ECMO-treated children (70 with meconium aspiration syndrome, 20 congenital diaphragmatic hernia and 31 with other diagnoses) performed a total of 191 lung function measurements at 5, 8 and/or 12 yrs. We assessed dynamic and static lung volumes, reversibility of airway obstruction and diffusion capacity. Mean SDS forced expiratory volume in 1 s (FEV(1)) at 5 yrs before and after bronchodilation (-0.51 and 0.07) was significantly higher than at 8 (-0.79 and -0.4; p<0.04) and 12 yrs (-1.10 and 0.52; p<0.003). Mean SDS for all spirometric parameters before and after bronchodilation were significantly lower in the congenital diaphragmatic hernia group compared with the other diagnostic groups (all p <= 0.025). A significant volume of trapped air was observed in 86% patients with congenital diaphragmatic hernia, 50% with meconium aspiration syndrome and 58% with other diagnoses. After bronchodilation, mean SDS FEV(1) and forced vital capacity were negatively influenced by duration of ventilation (both p<0.001) and duration of ECMO (p=0.003 and p=0.02, respectively). Long-term pulmonary sequelae after neonatal ECMO-treatment mainly occur in congenital diaphragmatic hernia patients and tend to deteriorate over time. PMID- 22496334 TI - Multicenter experience on eversion versus conventional carotid endarterectomy in symptomatic carotid artery stenosis: observations from the Stent-Protected Angioplasty Versus Carotid Endarterectomy (SPACE-1) trial. AB - BACKGROUND AND PURPOSE: Carotid endarterectomy (CEA) is beneficial in patients with symptomatic carotid artery stenosis. However, randomized trials have not provided evidence concerning the optimal CEA technique, conventional or eversion. METHODS: The outcome of 563 patients within the surgical randomization arm of the Stent-Protected Angioplasty versus Carotid Endarterectomy in Symptomatic Patients (SPACE-1) trial was analyzed by surgical technique subgroups: eversion endarterectomy versus conventional endarterectomy with patch angioplasty. The primary end point was ipsilateral stroke or death within 30 days after surgery. Secondary outcome events included perioperative adverse events and the 2-year risk of restenosis, stroke, and death. RESULTS: Both groups were similar in terms of demographic and other baseline clinical variables. Shunt frequency was higher in the conventional CEA group (65% versus 17%; P<0.0001). The risk of ipsilateral stroke or death within 30 days after surgery was significantly greater with eversion CEA (9% versus 3%; P=0.005). There were no statistically significant differences in the rate of perioperative secondary outcome events with the exception of a significantly higher risk of intraoperative ipsilateral stroke rate in the eversion CEA group (4% versus 0.3%; P=0.0035). The 2-year risk of ipsilateral stroke occurring after 30 days was significantly higher in the conventional CEA group (2.9% versus 0%; P=0.017). CONCLUSIONS: In patients with symptomatic carotid artery stenosis, conventional CEA appears to be associated with better periprocedural neurological outcome than eversion CEA. Eversion CEA, however, may be more effective for long-term prevention of ipsilateral stroke. These findings should be interpreted with caution noting the limitations of the post hoc, nonrandomized nature of the analysis. PMID- 22496335 TI - Role of the MMP9 gene in hemorrhagic transformations after tissue-type plasminogen activator treatment in stroke patients. AB - BACKGROUND AND PURPOSE: Despite the benefits of tissue-type plasminogen activator treatment, some stroke patients experience adverse hemorrhagic transformations (HT). Plasma protein levels of MMP9 have been associated with HT occurrence. We aimed to analyze the association of the MMP9 gene with HT occurrence. METHODS: We analyzed the MMP9 gene in blood samples from 885 stroke patients treated with tissue-type plasminogen activator by tag-SNP, imputed SNP, direct sequencing, and RNA expression. RESULTS: We did not observe any significant association between MMP9 genetic variations or MMP9 expression and HT occurrence. Moreover, no association was found between MMP9 expression and MMP9 polymorphisms. CONCLUSIONS: Genetic variations in the MMP9 gene are not associated with HT occurrence in tissue-type plasminogen activator-treated patients. PMID- 22496336 TI - Does the application of X-ray contrast agents impair the clinical effect of intravenous recombinant tissue-type plasminogen activator in acute ischemic stroke patients? AB - BACKGROUND AND PURPOSE: Experimental data suggest a negative interaction between x-ray contrast agents and fibrinolytic efficacy of recombinant tissue-type plasminogen activator (rtPA). We hypothesized that the application of a contrast agent before intravenous thrombolysis with rtPA reduces its clinical efficacy in acute ischemic stroke. METHODS: We retrospectively studied consecutive ischemic stroke patients receiving contrast agents for computed tomography angiography before intravenous treatment with rtPA. We compared functional outcomes with an historical control group from the Canadian Alteplase for Stroke Effectiveness Study who did not receive contrast agents before thrombolysis with rtPA. Primary end point was favorable functional outcome at 90 days defined as modified Rankin Scale scores 0 to 2. We performed logistic regression analysis and a propensity score matching analysis to estimate the effect size of contrast agent use as a negative predictor of outcome. RESULTS: We identified 111 patients for the computed tomography angiography and 1119 patients for the control group. Proportions of favorable functional outcome were 47.7% (53/111 patients) for the computed tomography angiography group and 49.5% (542/1094 patients) for the control group (P=0.77). Adjusted probabilities for favorable outcome were 0.48 (95% CI, 0.37-0.58) and 0.51 (95% CI, 0.47-0.54), respectively. Contrast use was associated with reduced odds of favorable outcome (OR, 0.62(;) 95% CI, 0.38 0.99). Propensity score matching suggested a larger effect size (OR, 10.0%; 95% CI, 0.5%-19.3%). CONCLUSIONS: Our study did not show a significant negative clinical effect of x-ray contrast agents applied before intravenous thrombolysis with rtPA. However, to confirm a possible small negative interaction between contrast agents and rtPA, additional experimental and prospective clinical studies are needed. PMID- 22496337 TI - Total and high-density lipoprotein cholesterol and stroke risk. AB - BACKGROUND AND PURPOSE: The association of total and high-density lipoprotein (HDL) cholesterol with stroke risk is unclear, especially regarding hemorrhagic stroke. METHODS: We prospectively investigated the associations of serum total and HDL cholesterol and total/HDL cholesterol ratio with total and type-specific stroke incidence among 58,235 Finnish people aged 25 to 74 years and free of coronary heart disease and stroke at baseline. RESULTS: During a mean follow-up period of 20.1 years, 3914 participants developed stroke events (3085 ischemic, 497 intracerebral hemorrhage, and 332 subarachnoid hemorrhage). The multivariable adjusted hazard ratios at different levels of total cholesterol (<5 [reference], 5-5.9, 6-6.0, >=7.0 mmol/L) were 1.00, 1.05, 1.16, and 1.22 for total stroke (Ptrend=0.036) and 1.00, 1.06, 1.19, and 1.27 for ischemic stroke (Ptrend=0.02) in men and 1.00, 0.58, 0.61, and 0.50 for intracerebral hemorrhagic stroke (Ptrend=0.02) in women, respectively. Low levels of HDL cholesterol and high total/HDL cholesterol ratio were associated with increased risks of total and ischemic stroke in both men and women. These associations disappeared in men but remained significant in women after further adjustment for body mass index, blood pressure, and history of diabetes. CONCLUSIONS: The study showed a positive association between total cholesterol and total and ischemic stroke risks in men and an inverse association between total cholesterol and intrahemorrhagic stroke risk in women. The inverse association of HDL cholesterol and a positive association of total/HDL cholesterol ratio with total and ischemic stroke risks were found in men and women. These associations attenuated after adjustment for body mass index, blood pressure, and history of diabetes. PMID- 22496339 TI - Effect of habitat fragmentation on the genetic diversity and structure of peripheral populations of beech in Central Italy. AB - Fragmentation can affect the demographic and genetic structure of populations near the boundary of their biogeographic range. Higher genetic differentiation among populations coupled with lower level of within-population variability is expected as a consequence of reduced population size and isolation. The effects of these 2 factors have been rarely disentangled. Given their high gene flow, anemophilous forest trees should be more affected, in terms of loss of genetic diversity, by small population size rather than geographic isolation alone. We studied the impact of distance from the main range (a measure of isolation) and reduced population size on the within-population and among population components of genetic variability. We assayed 11 isozyme loci in a total of 856 individuals in 27 marginal populations of European beech (Fagus sylvatica L.) in Central Italy. Populations were divided into 3 groups with an increasing level of fragmentation. In the most fragmented group, the within-population genetic variability was slightly smaller and the among population differentiation significantly larger than in the other 2 groups. Isolation-by-distance was lost when only pairs of populations involving at least one from the most fragmented group were considered and maintained in the other groups. These results support the role of random genetic drift having a larger impact on the most fragmented group, whereas gene flow seems to balance genetic drift in the 2 less fragmented ones. Given that average distance from the main range is not different between the intermediate and the most fragmented group, but average population size is smaller, we can conclude that gene flow is effective, even at relatively long distances, in balancing the effect of fragmentation if population size is not too small. PMID- 22496338 TI - A human ubiquitin conjugating enzyme (E2)-HECT E3 ligase structure-function screen. AB - Here we describe a systematic structure-function analysis of the human ubiquitin (Ub) E2 conjugating proteins, consisting of the determination of 15 new high resolution three-dimensional structures of E2 catalytic domains, and autoubiquitylation assays for 26 Ub-loading E2s screened against a panel of nine different HECT (homologous to E6-AP carboxyl terminus) E3 ligase domains. Integration of our structural and biochemical data revealed several E2 surface properties associated with Ub chain building activity; (1) net positive or neutral E2 charge, (2) an "acidic trough" located near the catalytic Cys, surrounded by an extensive basic region, and (3) similarity to the previously described HECT binding signature in UBE2L3 (UbcH7). Mass spectrometry was used to characterize the autoubiquitylation products of a number of functional E2-HECT pairs, and demonstrated that HECT domains from different subfamilies catalyze the formation of very different types of Ub chains, largely independent of the E2 in the reaction. Our data set represents the first comprehensive analysis of E2-HECT E3 interactions, and thus provides a framework for better understanding the molecular mechanisms of ubiquitylation. PMID- 22496342 TI - How will the US Supreme Court rule on health reform? PMID- 22496340 TI - Safety of pulmonary vein isolation and left atrial complex fractionated atrial electrograms ablation for atrial fibrillation with phased radiofrequency energy and multi-electrode catheters. AB - AIMS: Recently, a multi-electrode catheter system using phased radiofrequency (RF) energy was developed specifically for atrial fibrillation (AF) ablation: the pulmonary vein ablation catheter (PVAC), the multi-array septal catheter (MASC), and the multi-array ablation catheter (MAAC). Initial results of small trials have been promising: shorter procedure times and low adverse event rates. In a large single-centre registry, we evaluated the adverse events associated with multi-electrode ablation catheter procedures with PVAC alone, or combined with MASC and MAAC. METHODS AND RESULTS: In all, 634 consecutive patients with AF had 663 procedures with multi-electrode ablation catheters, 502 patients with the PVAC alone, 128 patients with PVAC/MASC/MAAC, 29 redo procedures with the PVAC or PVAC/MASC/MAAC, and 4 patients had a complicated transseptal puncture. Major and minor adverse events during 6 month follow-up were registered. In 15 cases (2.3%), major adverse events were seen within the first month after the procedure. These included complicated transseptal puncture (4), stroke (2), transient ischaemic attack (5), acute coronary syndrome (2), femoral pseudoaneurysm (1), and arteriovenous fistulae (1). Minor adverse events were seen in 10.7% at 6 months, mostly due to femoral haematoma (3.9%), and non significant PV stenosis (5.2%). There was no difference in the occurrence of major adverse events between PVAC alone, or PVAC/MASC/MAAC ablation. CONCLUSION: Ablation with phased RF and multi-electrode catheters is accompanied by a major adverse event rate of 2.3% within 1 month and a minor event rate of 10.7% at 6 months. PMID- 22496343 TI - Research bodies try to strengthen the integrity of UK research. PMID- 22496344 TI - Skeletal muscle respiratory capacity is enhanced in rats consuming an obesogenic Western diet. AB - Obesity-induced lipid oversupply promotes skeletal muscle mitochondrial biogenesis. Previous investigations have utilized extreme high-fat diets (HFD) to induce such mitochondrial perturbations despite their disparity from human obesogenic diets. Here, we evaluate the effects of Western diet (WD)-induced obesity on skeletal muscle mitochondrial function. Long-Evans rats were given ad libitum access to either a WD [40% energy (E) from fat, 17% protein, and 43% carbohydrate (30% sucrose); n = 12] or a control diet (CON; 16% of E from fat, 21% protein, and 63% carbohydrate; n = 12) for 12 wk. Rats fed the WD consumed 23% more E than CON (P = 0.0001), which was associated with greater increases in body mass (23%, P = 0.0002) and adiposity (17%, P = 0.03). There were no differences in fasting blood glucose concentration or glucose tolerance between diets, although fasting insulin was increased by 40% (P = 0.007). Fasting serum triglycerides were also elevated in WD (86%, P = 0.001). The maximal capacity of the electron transfer system was greater following WD (37%, P = 0.02), as were the maximal activities of several mitochondrial enzymes (citrate synthase, beta hydroxyacyl-CoA dehydrogenase, carnitine palmitoyltransferase). Protein expression of citrate synthase, UCP3, and individual respiratory complexes was greater after WD (P < 0.05) despite no differences in the expression of peroxisome proliferator-activated receptor (PPAR)alpha, PPARdelta, or PPARgamma coactivator-1 mRNA or protein abundance. We conclude that the respiratory capacity of skeletal muscle is enhanced in response to the excess energy supplied by a WD. This is likely due to an increase in mitochondrial density, which at least in the short term, and in the absence of increased energy demand, may protect the tissue from lipid-induced impairments in glycemic control. PMID- 22496345 TI - The role of CaMKII in regulating GLUT4 expression in skeletal muscle. AB - Contractile activity during physical exercise induces an increase in GLUT4 expression in skeletal muscle, helping to improve glucose transport capacity and insulin sensitivity. An important mechanism by which exercise upregulates GLUT4 is through the activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in response to elevated levels of cytosolic Ca(2+) during muscle contraction. This review discusses the mechanism by which Ca(2+) activates CaMKII, explains research techniques currently used to alter CaMK activity in cells, and highlights various exercise models and pharmacological agents that have been used to provide evidence that CaMKII plays an important role in regulating GLUT4 expression. With regard to transcriptional mechanisms, the key research studies that identified myocyte enhancer factor 2 (MEF2) and GLUT4 enhancer factor as the major transcription factors regulating glut4 gene expression, together with their binding domains, are underlined. Experimental evidence showing that CaMK activation induces hyperacetylation of histones in the vicinity of the MEF2 domain and increases MEF2 binding to its cis element to influence MEF2-dependent Glut4 gene expression are also given along with data suggesting that p300 might be involved in acetylating histones on the Glut4 gene. Finally, an appraisal of the roles of other calcium- and non-calcium-dependent mechanisms, including the major HDAC kinases in GLUT4 expression, is also given. PMID- 22496346 TI - Compartmentalization and regulation of iron metabolism proteins protect male germ cells from iron overload. AB - The universal importance of iron, its high toxicity, and complex chemistry present a challenge to biological systems in general and to protected compartments in particular. The high mitotic rate and avid mitochondriogenesis of developing male germ cells imply high iron requirements. Yet access to germ cells is tightly regulated by the blood-testis barrier that protects the meiotic and postmeiotic germ cells. To elucidate how iron is supplied to developing male germ cells, we analyzed iron deposition and iron transport proteins in testes of mice with iron overload and with genetic ablation of the iron regulators Hfe and iron regulatory protein 2. Iron accumulated mainly around seminiferous tubules, and only small amounts localized within the seminiferous tubules. The localization and regulation of proteins involved in iron import, storage, and export such as transferrin, transferrin receptor, the divalent metal transporter-1, cytosolic ferritin, and ferroportin strongly support a model of a largely autonomous iron cycle within seminiferous tubules. We show evidence that ferritin secretion from Sertoli cells may play an important role in iron acquisition of primary spermatocytes. During spermatogenic development iron is carried along from primary spermatocytes to spermatids, and from spermatids iron is recycled to the apical compartment of Sertoli cells, which traffic it back to a new generation of spermatocytes. Losses are replenished by the peripheral circulation. Such an internal iron cycle essentially detaches the iron homeostasis within the seminiferous tubule from the periphery and protects developing germ cells from iron fluctuations. This model explains how compartmentalization can optimize cellular and systemic nutrient homeostasis. PMID- 22496347 TI - Expression of functional TSH receptor in white adipose tissues of hyt/hyt mice induces lipolysis in vivo. AB - To determine the relative importance of TSH in white adipose tissue, we compared the adipose phenotypes of two distinct mouse models of hypothyroidism. These models differed in that the normal reciprocal relationship between thyroid hormone and TSH was intact in one and disrupted in the other. One model, thyroidectomized (THYx) mice, had a 100-fold increase in TSH and a normal TSH receptor (TSHR); in contrast, the other model, hyt/hyt mice, had a 120-fold elevation of TSH but a nonfunctional TSHR. Although both THYx and hyt/hyt mice were in a severe hypothyroid state, the epididymal fat (mg)/body wt (g) (F/B) ratio of THYx mice was much smaller than that of hyt/hyt mice (8.2 +/- 0.43 vs. 14.4 +/- 0.40, respectively, P < 0.001). The fat cell diameter in THYx mice was also smaller than that in hyt/hyt mice (79 +/- 2.8 vs. 105 +/- 2.2 MUm, respectively, P < 0.001), suggesting that TSH induced lipolysis in adipose tissues. When we transferred a functional mouse TSHR gene and a control plasmid into opposite sides of epididymal fat of hyt/hyt mice by plasmid injection combined with electroporation, fat weight of the TSHR side was decreased to 60% of that of the control side. Messenger RNA levels of hormone-sensitive lipase in epididymal fat containing the transferred TSHR gene were twofold higher than those in tissue from the control side. These results indicated that TSH worked as a lipolytic factor in white adipose tissues, especially in mice in a hypothyroid state. PMID- 22496349 TI - Increased intramyocellular lipids but unaltered in vivo mitochondrial oxidative phosphorylation in skeletal muscle of adipose triglyceride lipase-deficient mice. AB - Adipose triglyceride lipase (ATGL) is a lipolytic enzyme that is highly specific for triglyceride hydrolysis. The ATGL-knockout mouse (ATGL(-/-)) accumulates lipid droplets in various tissues, including skeletal muscle, and has poor maximal running velocity and endurance capacity. In this study, we tested whether abnormal lipid accumulation in skeletal muscle impairs mitochondrial oxidative phosphorylation, and hence, explains the poor muscle performance of ATGL(-/-) mice. In vivo 1H magnetic resonance spectroscopy of the tibialis anterior of ATGL(-/-) mice revealed that its intramyocellular lipid pool is approximately sixfold higher than in WT controls (P = 0.0007). In skeletal muscle of ATGL(-/-) mice, glycogen content was decreased by 30% (P < 0.05). In vivo 31P magnetic resonance spectra of resting muscles showed that WT and ATGL(-/-) mice have a similar energy status: [PCr], [P(i)], PCr/ATP ratio, PCr/P(i) ratio, and intracellular pH. Electrostimulated muscles from WT and ATGL(-/-) mice showed the same PCr depletion and pH reduction. Moreover, the monoexponential fitting of the PCr recovery curve yielded similar PCr recovery times (tauPCr; 54.1 +/- 6.1 s for the ATGL(-/-) and 58.1 +/- 5.8 s for the WT), which means that overall muscular mitochondrial oxidative capacity was comparable between the genotypes. Despite similar in vivo mitochondrial oxidative capacities, the electrostimulated muscles from ATGL(-/-) mice displayed significantly lower force production and increased muscle relaxation time than the WT. These findings suggest that mechanisms other than mitochondrial dysfunction cause the impaired muscle performance of ATGL(-/-) mice. PMID- 22496348 TI - Increased MMPs expression and decreased contraction in the rat myometrium during pregnancy and in response to prolonged stretch and sex hormones. AB - Normal pregnancy is associated with uterine relaxation to accommodate the stretch imposed by the growing fetus; however, the mechanisms underlying the relationship between pregnancy-associated uterine stretch and uterine relaxation are unclear. We hypothesized that increased uterine stretch during pregnancy is associated with upregulation of matrix metalloproteinases (MMPs), which in turn cause inhibition of myometrium contraction and promote uterine relaxation. Uteri from virgin, midpregnant (day 12), and late-pregnant rats (day 19) were isolated, and myometrium strips were prepared for measurement of isometric contraction and MMP expression and activity using RT-PCR, Western blot analysis, and gelatin zymography. Oxytocin caused concentration-dependent contraction of myometrium strips that was reduced in mid- and late-pregnant rats compared with virgin rats. Pretreatment with the MMP inhibitors SB-3CT (MMP-2/MMP-9 Inhibitor IV), BB-94 (batimastat), or Ro-28-2653 (cipemastat) enhanced contraction in myometrium of pregnant rats. RT-PCR, Western blot analysis, and gelatin zymography demonstrated increased mRNA expression, protein amount, and activity of MMP-2 and MMP-9 in myometrium of late-pregnant>midpregnant>virgin rats. Prolonged stretch of myometrium strips of virgin rats under 8 g basal tension for 18 h was associated with reduced contraction and enhanced expression and activity of MMP-2 and MMP-9, which were reversed by MMP inhibitors. Concomitant treatment of stretched myometrium of virgin rats with 17beta-estradiol (E2), progesterone (P4), or E2+P4 was associated with further reduction in contraction and increased MMP expression and activity. MMP-2 and MMP-9 caused significant reduction of oxytocin-induced contraction of myometrium of virgin rat. Thus, normal pregnancy is associated with reduced myometrium contraction and increased MMPs expression and activity. The results are consistent with the possibility that myometrium stretch and concomitant increase in sex hormones during pregnancy are associated with increased expression/activity of specific MMPs, which in turn inhibit uterine contraction and promote uterine relaxation. PMID- 22496350 TI - Global detection of protein kinase D-dependent phosphorylation events in nocodazole-treated human cells. AB - Protein kinase D (PKD) is a cytosolic serine/threonine kinase implicated in regulation of several cellular processes such as response to oxidative stress, directed cell migration, invasion, differentiation, and fission of the vesicles at the trans-Golgi network. Its variety of functions must be mediated by numerous substrates; however, only a couple of PKD substrates have been identified so far. Here we perform stable isotope labeling of amino acids in cell culture-based quantitative phosphoproteomic analysis to detect phosphorylation events dependent on PKD1 activity in human cells. We compare relative phosphorylation levels between constitutively active and kinase dead PKD1 strains of HEK293 cells, both treated with nocodazole, a microtubule-depolymerizing reagent that disrupts the Golgi complex and activates PKD1. We identify 124 phosphorylation sites that are significantly down-regulated upon decrease of PKD1 activity and show that the PKD target motif is significantly enriched among down-regulated phosphorylation events, pointing to the presence of direct PKD1 substrates. We further perform PKD1 target motif analysis, showing that a proline residue at position +1 relative to the phosphorylation site serves as an inhibitory cue for PKD1 activity. Among PKD1-dependent phosphorylation events, we detect predominantly proteins with localization at Golgi membranes and function in protein sorting, among them several sorting nexins and members of the insulin-like growth factor 2 receptor pathway. This study presents the first global detection of PKD1 dependent phosphorylation events and provides a wealth of information for functional follow-up of PKD1 activity upon disruption of the Golgi network in human cells. PMID- 22496351 TI - Deficiency of tumour necrosis factor-related apoptosis-inducing ligand exacerbates lung injury and fibrosis. AB - BACKGROUND: The death receptor ligand tumour necrosis factor-related apoptosis inducing ligand (TRAIL) shows considerable clinical promise as a therapeutic agent. TRAIL induces leukocyte apoptosis, reducing acute inflammatory responses in the lung. It is not known whether TRAIL modifies chronic lung injury or whether TRAIL has a role in human idiopathic pulmonary fibrosis (IPF). We therefore explored the capacity of TRAIL to modify chronic inflammatory lung injury and studied TRAIL expression in patients with IPF. METHODS: TRAIL(-/-) and wild-type mice were instilled with bleomycin and inflammation assessed at various time points by bronchoalveolar lavage and histology. Collagen deposition was measured by tissue hydroxyproline content. TRAIL expression in human IPF lung samples was assessed by immunohistochemistry and peripheral blood TRAIL measured by ELISA. RESULTS: TRAIL(-/-) mice had an exaggerated delayed inflammatory response to bleomycin, with increased neutrophil numbers (mean 3.19+/-0.8 wild type vs 11.5+/-5.4*10(4) TRAIL(-/-), p<0.0001), reduced neutrophil apoptosis (5.42+/-1.6% wild type vs 2.47+/-0.5% TRAIL(-/-), p=0.0003) and increased collagen (3.45+/-0.2 wild type vs 5.8+/-1.3 mg TRAIL(-/-), p=0.005). Immunohistochemical analysis showed induction of TRAIL in bleomycin-treated wild type mice. Patients with IPF demonstrated lower levels of TRAIL expression than in control lung biopsies and their serum levels of TRAIL were significantly lower compared with matched controls (38.1+/-9.6 controls vs 32.3+/-7.2 pg/ml patients with IPF, p=0.002). CONCLUSION: These data suggest TRAIL may exert beneficial, anti-inflammatory actions in chronic pulmonary inflammation in murine models and that these mechanisms may be compromised in human IPF. PMID- 22496352 TI - Reach and effectiveness of mailed nicotine replacement therapy for smokers: 6 month outcomes in a naturalistic exploratory study. AB - BACKGROUND: There are important inequities in smoker access to clinic-based smoking cessation services. Low barrier high-reach interventions are proposed as solutions to these inequities. Although effective, telephone quitlines, which provide multi-session counselling but no medication, have low utilization with high attrition. The objective of this study was to determine the effectiveness of free nicotine replacement therapy (NRT), brief advice and self-help materials on quit attempts and 6-month quit rates in motivated smokers. METHODS: In this open label naturalistic study, 14,000 treatments of 5 weeks in duration of either nicotine patch (n=10,000) or nicotine gum (n=4000) were made available to all eligible adult smokers in Ontario, Canada, who called a toll-free number to register with the STOP (Smoking Treatment for Ontario Patients) Study and receive a single brief intervention. The primary outcome measure was self-reported abstinence rates at 6 months post-treatment among STOP participants. These data were compared with quit rates that were reported in a concurrent no-intervention cohort of Ontario smokers matched for eligibility. RESULTS: 16 405 callers were assessed and 13143 eligible participants were mailed a treatment package with 5 weeks of NRT (choice of patch or gum), self-help and community resource materials. Among the 6261 participants who consented to follow-up, 2601 (42%) had complete follow-up data. Of those with complete follow-up data, the percentage reporting abstinence after 6 months in the treatment cohort was 21.4%, relative to 11.6% in the no-intervention cohort (rate ratio of 1.84; 95% CI 1.79 to 1.89), with the 30-day point prevalence of 17.8% and 9.8% for the intervention and no intervention cohorts, respectively (rate ratio 1.81; CI 1.75 to 1.87). CONCLUSIONS: Provision of free NRT by mail following a brief telephone intervention is an effective strategy to reach and assist a large number of smokers making a quit attempt. PMID- 22496353 TI - Tuberculosis diagnostics and biomarkers: needs, challenges, recent advances, and opportunities. AB - Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostics. PMID- 22496354 TI - Proprietary interests in human bodily material: Yearworth, recent Australian cases on stored semen and their implications: Kate Jane Bazley v Wesley Monash IVF Pty Ltd [2010] QSC 118; Jocelyn Edwards; Re the estate of the late Mark Edwards [2011] NSWSC 478. PMID- 22496355 TI - Arsenic trioxide induces abnormal mitotic spindles through a PIP4KIIgamma/Rho pathway. AB - Arsenite-induced spindle abnormalities result in mitotic cell apoptosis in several cancer cell lines, but how arsenite induces these effects is not known. Evidence to date has revealed that arsenite activates Rho guanosine triphosphatases (GTPases). Because Rho GTPases regulate spindle orientation, chromosome congression, and cytokinesis, we therefore examined the involvement of Rho GTPases and their modulators in arsenite-induced mitotic abnormalities. We demonstrated that arsenic trioxide (ATO) disrupted the positioning of bipolar mitotic spindles and induced centrosome and spindle abnormalities. ATO increased the level of the active guanosine triphosphate-bound form of Rho. Inhibition of Rho-associated protein kinases (ROCKs) by Y-27632 ameliorated ATO-induced spindle defects, mitotic arrest, and cell death. These results indicate that ATO may induce spindle abnormalities and mitotic cell death through a Rho/ROCK pathway. In addition, screening of a human kinase and phosphatase shRNA library to select genes that mediate ATO induction of spindle abnormalities resulted in the identification of phosphatidylinositol-5-phosphate 4-kinase type-2 gamma (PIP4KIIgamma), a phosphatidylinositol 4,5-biphosphate (PIP2) synthesis enzyme that belongs to the phosphatidylinositol phosphate kinase (PIPK) family. Sequestration of PIP2 by ectopic overexpression of the pleckstrin homology domain of phospholipase C-delta1 protected cells from ATO-induced cell death. Furthermore, depletion of PIP4KIIgamma, but not other isoforms of the PIPK family, not only reduced Rho GTPase activation in ATO-treated cells but also alleviated ATO-induced spindle defects, mitotic arrest, and mitotic cell apoptosis. Thus, our results imply that ATO induces abnormalities in mitotic spindles through a PIP4KIIgamma/Rho pathway, leading to apoptosis of mitotic cells. PMID- 22496356 TI - Inhibition of the heat shock response by PI103 enhances the cytotoxicity of arsenic trioxide. AB - Heat shock factor 1 (HSF1) is a key regulator of the cytoprotective and anti apoptotic heat shock response and can be activated by arsenite. Inhibition of HSF1 activation may therefore enhance the cytotoxicity of arsenic trioxide (ATO). We show that ATO induced HSF1 phosphorylation at serine 326 (S326) and induced HSF1-dependent expression of heat shock proteins (HSPs) 27 and 70 in cultured cells. HSF1 significantly reduced cell sensitivity to ATO by reducing apoptosis. Disruption of HSF1 function not only reduced ATO induction of HSP27 and 70 but also enhanced ATO cytotoxicity by elevating apoptosis. These results reveal that HSF1 activation and the resulting induction of HSPs may protect cells from ATO cytotoxicity. The diminished expression of HSPs and hypersensitivity to ATO in cells stably depleted of HSF1 was rescued by ectopic expression of wild-type HSF1 but not an S326A substitution mutant, indicating that phosphorylation at S326 was critical for the protective effect of HSF1. Simultaneous treatment of cells with ATO and PI103, an inhibitor of members of the phosphatidylinositol 3-kinase (PI3K) family, suppressed not only ATO-induced expression of an HSP70 promoter reporter construct and endogenous HSP70 but also phosphorylation of HSF1 S326. PI103 considerably reduced HSF1 transactivation in ATO-treated cells but had only a limited effect on HSF1 nuclear translocation and DNA binding. Furthermore, PI103 enhanced ATO cytotoxicity in an HSF1-dependent manner. Thus, inhibition of S326 phosphorylation by PI103 blocks the transactivation of HSF1 and may consequently suppress ATO induction of the heat shock response and sensitize cells to ATO. PMID- 22496357 TI - Immune regulation of Rab proteins expression and intracellular transport. AB - Compartmentalization in cells of the immune system, the focus of this review, facilitates the spatiotemporal organization of cellular responses essential for specialized immune functions. In this process of compartment maintenance, Rab proteins are central regulators of protein-mediated transport and fusion of intracellular structures. It is widely believed that the intracellular concentration of proteins that regulate intracellular transport, including Rab proteins, is constitutively mantained. However, there is a growing body of evidence indicating that transcriptional rates of Rab proteins can be modified. This process is especially evident during immune activation and argues that after activation, these cells require higher levels of Rab proteins. The aim of this review is to discuss evidence showing the increasing links between Rab protein expression and intracellular transport, particularly in monocytes and macrophages. We highlight here biological processes in which the expression of Rab GTPases is selectively regulated, leading to the activation of specific intracellular routes. Further, we focus on the immune regulation of intracellular transport after cytokine activation and microbial infection, with an emphasis in mycobacterial infection. PMID- 22496358 TI - Effects of periparturient events on subsequent culling and fertility in eight UK dairy herds. AB - The occurrence of five periparturient events and their effects on subsequent culling and fertility was recorded in eight herds in the UK. Combining data from all 2105 calvings, the proportion affected by assisted calving, dead calf, retained fetal membranes (RFM), milk fever or twins was 5.9, 8.2, 5.3, 5.0 or 3.3 per cent, respectively. Compared with unaffected herdmates, cows with an assisted calving or a dead calf had higher early (but not late) culling rates, (assisted calving: 8.8 per cent being culled before 100 days after calving compared with 5.7 per cent; P=0.05; dead calf: 12.2 per cent culled compared with 5.3 per cent; P=0.001). Compared with unaffected animals, cows with milk fever were four times more likely to be culled before 100 days after calving (16.2 per cent compared with 5.3 per cent; P=0.001), whereas those with RFM were twice as likely to be culled between 100 and 200 days (14.3 per cent compared with 7.6 per cent; P=0.003), and both groups were twice as likely to not be pregnant by 200 days. Cows with RFM or milk fever also had markedly reduced subsequent fertility: both conditions extended calving to pregnancy intervals (by 20 days; P=0.001, or by 13 days; P=0.03, respectively), lowered 100-day in-calf rates (by 24.5 per cent; P=0.001, or by 17.8 per cent; P=0.008, respectively) and lowered 200-day in-calf rates (by 20 per cent; P=0.001, or by 15 per cent; P=0.002, respectively). The birth of twins had no effect on subsequent culling or fertility. PMID- 22496359 TI - Phosphatidylinositol 3-kinase-binding protein, PI3KAP/XB130, is required for cAMP induced amplification of IGF mitogenic activity in FRTL-5 thyroid cells. AB - We previously demonstrated that long-term pretreatment of rat FRTL-5 thyroid cells with TSH or cAMP-generating reagents potentiated IGF-I-dependent DNA synthesis. Under these conditions, cAMP treatment increased tyrosine phosphorylation of a 125-kDa protein (p125) and its association with a p85 regulatory subunit of phosphatidylinositol 3-kinase (p85 PI3K), which were suggested to mediate potentiation of DNA synthesis. This study was undertaken to identify p125 and to elucidate its roles in potentiation of DNA synthesis induced by IGF-I. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis revealed p125 to be a rat ortholog of human XB130, which we named PI3K-associated protein (PI3KAP). cAMP treatment elevated PI3KAP/XB130 mRNA and protein levels as well as tyrosine phosphorylation and interaction with p85 PI3K leading to increased PI3K activities associated with PI3KAP/XB130, supporting the role of PI3KAP/XB130 in DNA synthesis potentiation. Importantly, PI3KAP/XB130 knockdown attenuated cAMP-dependent potentiation of IGF I-induced DNA synthesis. Furthermore, c-Src was associated with PI3KAP/XB130 and was activated in response to cAMP. Addition of Src family kinase inhibitors, PP1 or PP2, during cAMP treatment abolished tyrosine phosphorylation of PI3KAP/XB130 and its interaction with p85 PI3K. Finally, introduction of PI3KAP/XB130 into NIH3T3 fibroblasts lacking endogenous PI3KAP/XB130 enhanced IGF-I-induced DNA synthesis; however, a mutant Y72F incapable of binding to p85 PI3K did not show this response. Together, these data indicate that cAMP-dependent induction of PI3KAP/XB130, which is associated with PI3K, is required for enhancement of IGF mitogenic activities. PMID- 22496360 TI - The steroid and xenobiotic receptor negatively regulates B-1 cell development in the fetal liver. AB - The steroid and xenobiotic receptor (SXR) (also known as pregnane X receptor or PXR) is a broad-specificity nuclear hormone receptor that is well known for its role in drug and xenobiotic metabolism. SXR is activated by a wide variety of endobiotics, dietary compounds, pharmaceuticals, and xenobiotic chemicals. SXR is expressed at its highest levels in the liver and intestine yet is found in lower levels in other tissues, where its roles are less understood. We previously demonstrated that SXR(-/-) mice demonstrate elevated nuclear factor (NF)-kappaB activity and overexpression of NF-kappaB target genes and that SXR(-/-) mice develop lymphoma derived from B-1 lymphocytes in an age-dependent manner. In this work, we show that fetal livers in SXR(-/-) mice display elevated expression of NF-kappaB target genes and possess a significantly larger percentage of B-1 progenitor cells in the fetal liver. Furthermore, in utero activation of SXR in wild-type mice reduces the B-1 progenitor populations in the embryonic liver and reduces the size of the B-1 cell compartment in adult animals that were treated in utero. This suggests that activation of SXR during development may permanently alter the immune system of animals exposed in utero, demonstrating a novel role for SXR in the generation of B-1 cell precursors in the fetal liver. These data support our previous findings that SXR functions as a tumor suppressor in B-1 lymphocytes and establish a unique role for SXR as a modulator of developmental hematopoiesis in the liver. PMID- 22496361 TI - Evidence of a metabolic fatty acid-sensing system in the hypothalamus and Brockmann bodies of rainbow trout: implications in food intake regulation. AB - Enhanced lipid levels inhibit food intake in fish but no studies have characterized the possible mechanisms involved. We hypothesize that the presence of fatty acid (FA)-sensing mechanisms could be related to the control of food intake. Accordingly, we evaluated in the hypothalamus, hindbrain, and Brockmann bodies (BB) of rainbow trout changes in parameters related to fatty acid metabolism, transport of FA, nuclear receptors, and transcription factors involved in lipid metabolism, and components of the K(ATP) channel after intraperitoneal administration of different doses of oleic acid (long-chain fatty acid, LCFA) or octanoic acid (medium-chain fatty acid, MCFA). The increase in circulating LCFA or MCFA levels elicited an inhibition in food intake and induced in the hypothalamus a response compatible with fatty acid sensing in which fatty acid metabolism, binding to cluster of differentiation 36 (CD36), and mitochondrial activity are apparently involved, which is similar to that suggested in mammals except for the apparent capacity of rainbow trout to detect changes in MCFA levels. Changes in those hypothalamic pathways can be related to the control of food intake, since food intake was inhibited when FA metabolism was perturbed (using fatty acid synthase or acetyl-CoA carboxylase inhibitors) and changes in mRNA levels of specific neuropeptides such as neuropeptide Y and proopiomelancortin were also noticed. This response seems to be exclusive for the hypothalamus, since the other center controlling food intake (hindbrain) was unaffected by treatments. The results obtained in BB suggest that at least two of the components of a putative fatty acid-sensing system (based on fatty acid metabolism and binding to CD36) could be present. Therefore, the present study provides, for the first time in fish, evidence for a specific role for FA (MCFA and LCFA) as metabolic signals in hypothalamus and BB, where the detection of those FA can be associated with the control of food intake and hormone release. PMID- 22496362 TI - Exercise training prevents skeletal muscle afferent sensitization in rats with chronic heart failure. AB - An exaggerated exercise pressor reflex (EPR) contributes to exercise intolerance and excessive sympathoexcitation in the chronic heart failure (CHF) state, which is prevented by exercise training (ExT) at an early stage in the development of CHF. We hypothesized that ExT has a beneficial effect on the exaggerated EPR by improving the dysfunction of muscle afferents in CHF. We recorded the discharge of mechanically sensitive (group III) and metabolically sensitive (group IV) afferents in response to static contraction, passive stretch, and hindlimb intra arterial injection of capsaicin in sham+sedentary (Sed), sham+ExT, CHF+Sed, and CHF+ExT rats. Compared with sham+Sed rats, CHF+Sed rats exhibited greater responses of group III afferents to contraction and stretch, whereas the responses of group IV afferents to contraction and capsaicin were blunted. ExT prevented the sensitization of group III responses to contraction or stretch and partially prevented the blunted group IV responses to contraction or capsaicin in CHF rats. Furthermore, we investigated whether purinergic 2X (P2X) and transient receptor potential vanilloid 1 (TRPV1) receptors mediate the altered sensitivity of muscle afferents by ExT in CHF. We found that the upregulated P2X and downregulated TRPV1 receptors in L4/5 dorsal root ganglia of CHF rats were normalized by ExT. Hindlimb intra-arterial infusion of a P2X antagonist attenuated the group III response to contraction or stretch in CHF rats to a greater extent than in sham rats, which was normalized by ExT. These findings suggest that ExT improves the abnormal sensitization of muscle afferents in CHF at least, in part, via restoring the dysfunction of P2X and TRPV1 receptors. PMID- 22496364 TI - Magnetic resonance and confocal imaging of solute penetration into the lens reveals a zone of restricted extracellular space diffusion. AB - It has been proposed that in the absence of blood supply, the ocular lens operates an internal microcirculation system that delivers nutrients to internalized fiber cells faster and more efficiently than would occur by passive diffusion alone. To visualize the extracellular space solute fluxes potentially generated by this system, bovine lenses were organ cultured in artificial aqueous humor (AAH) for 4 h in the presence or absence of two gadolinium-based contrast agents, ionic Gd(3+), or a chelated form of Gd(3+), Gd-diethylenetriamine penta acetic acid (Gd-DTPA; mol mass = 590 Da). Contrast reagent penetration into the lens core was monitored in real time using inversion recovery-spin echo (IR-SE) magnetic resonance imaging (MRI), while steady-state accumulation of [Gd-DTPA]( 2) was also determined by calculating T1 values. After incubation, lenses were fixed and cryosectioned, and sections were labeled with the membrane marker wheat germ agglutinin (WGA). Sections were imaged by confocal microscopy using standard and reflectance imaging modalities to visualize the fluorescent WGA label and gadolinium reagents, respectively. Real-time IR-SE MRI showed rapid penetration of Gd(3+) into the outer cortex of the lens and a subsequent bloom of signal in the core. These two areas of signal were separated by an area in the inner cortex that limited entry of Gd(3+). Similar results were obtained for Gd-DTPA, but the penetration of the larger negatively charged molecule into the core could only be detected by calculating T1 values. The presence of Gd-DTPA in the extracellular space of the outer cortex and core, but its apparent absence from the inner cortex was confirmed using reflectance imaging of equatorial sections. In axial sections, Gd-DTPA was associated with the sutures, suggesting these structures provide a pathway from the surface, across the inner cortex barrier to the lens core. Our studies have revealed inner and outer boundaries of a zone within which a narrowing of the extracellular space restricts solute diffusion and acts to direct fluxes into the lens core via the sutures. PMID- 22496363 TI - Changes in glucose tolerance and leptin responsiveness of rats offered a choice of lard, sucrose, and chow. AB - Rats offered chow, lard, and 30% sucrose solution (choice) rapidly become obese. We tested metabolic disturbances in rats offered choice, chow+lard, or chow+30% sucrose solution [chow+liquid sucrose (LS)] and compared them with rats fed a composite 60% kcal fat, 7% sucrose diet [high-fat diet (HFD)], or a 10% kcal fat, 35% sucrose diet [low-fat diet (LFD)]. Choice rats had the highest energy intake, but HFD rats gained the most weight. After 23 days carcass fat was the same for choice, HFD, chow+lard, and chow+LS groups. Glucose clearance was the same for all groups during an intraperitoneal glucose tolerance test (GTT) on day 12, but fasting insulin was increased in choice, LFD fed, and chow+LS rats. By contrast, only choice and chow+LS rats were resistant to an intraperitoneal injection of 2 mg leptin/kg on day 17. In experiment 2 choice rats were insulin insensitive during an intraperitoneal GTT, but this was corrected in an oral GTT due to GLP-1 release. UCP-1 protein was increased in brown fat and inguinal white fat in choice rats, and this was associated with a significant increase in energy expenditure of choice rats during the dark period whether expenditure was expressed on a per animal or a metabolic body size basis. The increase in expenditure obviously was not great enough to prevent development of obesity. Further studies are required to determine the mechanistic basis of the rapid onset of leptin resistance in choice rats and how consumption of sucrose solution drives this process. PMID- 22496365 TI - Structural basis for inhibition of xyloglucan-specific endo-beta-1,4-glucanase (XEG) by XEG-protein inhibitor. AB - Microorganisms such as plant pathogens secrete glycoside hydrolases (GHs) to digest the polysaccharide chains of plant cell walls. The degradation of cell walls by these enzymes is a crucial step for nutrition and invasion. To protect the cell wall from these enzymes, plants secrete glycoside hydrolase inhibitor proteins (GHIPs). Xyloglucan-specific endo-beta-1,4-glucanase (XEG), a member of GH family 12 (GH12), could be a great threat to many plants because xyloglucan is a major component of the cell wall in most plants. Understanding the inhibition mechanism of XEG by GHIP is therefore of great importance in the field of plant defense, but to date the mechanism and specificity of GHIPs remain unclear. We have determined the crystal structure of XEG in complex with extracellular dermal glycoprotein (EDGP), a carrot GHIP that inhibits XEG. The structure reveals that the conserved arginines of EDGP intrude into the active site of XEG and interact with the catalytic glutamates of the enzyme. We have also determined the crystal structure of the XEG-xyloglucan complex. These structures show that EDGP closely mimics the XEG-xyloglucan interaction. Although EDGP shares structural similarity to a wheat GHIP (Triticum aestivum xylanase inhibitor-IA (TAXI-IA)) that inhibits GH11 family xylanases, the arrangement of GH and GHIP in the XEG-EDGP complex is distinct from that in the xylanase-TAXI-IA complex. Our findings imply that plants have evolved structures of GHIPs to inhibit different GH family members that attack their cell walls. PMID- 22496366 TI - Palmitoylation of MPP1 (membrane-palmitoylated protein 1)/p55 is crucial for lateral membrane organization in erythroid cells. AB - S-Acylation of proteins is a ubiquitous post-translational modification and a common signal for membrane association. The major palmitoylated protein in erythrocytes is MPP1, a member of the MAGUK family and an important component of the ternary complex that attaches the spectrin-based skeleton to the plasma membrane. Here we show that DHHC17 is the only acyltransferase present in red blood cells (RBC). Moreover, we give evidence that protein palmitoylation is essential for membrane organization and is crucial for proper RBC morphology, and that the effect is specific for MPP1. Our observations are based on the clinical cases of two related patients whose RBC had no palmitoylation activity, caused by a lack of DHHC17 in the membrane, which resulted in a strong decrease of the amount of detergent-resistant membrane (DRM) material. We confirmed that this loss of detergent-resistant membrane was due to the lack of palmitoylation by treatment of healthy RBC with 2-bromopalmitic acid (2-BrP, common palmitoylation inhibitor). Concomitantly, fluorescence lifetime imaging microscopy (FLIM) analyses of an order-sensing dye revealed a reduction of membrane order after chemical inhibition of palmitoylation in erythrocytes. These data point to a pathophysiological relationship between the loss of MPP1-directed palmitoylation activity and perturbed lateral membrane organization. PMID- 22496367 TI - Rhodanese functions as sulfur supplier for key enzymes in sulfur energy metabolism. AB - How microorganisms obtain energy is a challenging topic, and there have been numerous studies on the mechanisms involved. Here, we focus on the energy substrate traffic in the hyperthermophilic bacterium Aquifex aeolicus. This bacterium can use insoluble sulfur as an energy substrate and has an intricate sulfur energy metabolism involving several sulfur-reducing and -oxidizing supercomplexes and enzymes. We demonstrate that the cytoplasmic rhodanese SbdP participates in this sulfur energy metabolism. Rhodaneses are a widespread family of proteins known to transfer sulfur atoms. We show that SbdP has also some unusual characteristics compared with other rhodaneses; it can load a long sulfur chain, and it can interact with more than one partner. Its partners (sulfur reductase and sulfur oxygenase reductase) are key enzymes of the sulfur energy metabolism of A. aeolicus and share the capacity to use long sulfur chains as substrate. We demonstrate a positive effect of SbdP, once loaded with sulfur chains, on sulfur reductase activity, most likely by optimizing substrate uptake. Taken together, these results lead us to propose a physiological role for SbdP as a carrier and sulfur chain donor to these key enzymes, therefore enabling channeling of sulfur substrate in the cell as well as greater efficiency of the sulfur energy metabolism of A. aeolicus. PMID- 22496368 TI - Signal transducer and activator of transcription 3 (STAT3) protein suppresses adenoma-to-carcinoma transition in Apcmin/+ mice via regulation of Snail-1 (SNAI) protein stability. AB - STAT3 was recently reported to suppress tumor invasion in Apc(min)(/+) mice. We investigated the mechanisms by which STAT3 inhibits intestinal epithelial tumors using Apc(min)(/+)/Stat3(IEC-KO) mice (intestinal epithelial cell (IEC)-specific deletion of STAT3 in the Apc(min)(/+) background) to determine the role of STAT3 in carcinogenesis in vivo as well as colorectal cancer cell lines in vitro. To inhibit invasion of IEC tumors, STAT3 functions as a molecular adaptor rather than a transcription factor. Accordingly, the tumors in Apc(min)(/+)/Stat3(IEC KO) mice undergo adenoma-to-carcinoma transition and acquire an invasive phenotype. Similarly, STAT3 knockdown in a colorectal cell line enhances IEC invasion. We demonstrate that STAT3 down-regulates SNAI (Snail-1) expression levels and hence suppresses epithelial-mesenchymal transition of colorectal cancer cells. Mechanistically, STAT3 facilitates glycogen synthase kinase (GSK) 3beta-mediated degradation of SNAI by regulating phosphorylation of GSK3beta. Our data identified a new role for STAT3 in the adenoma-to-carcinoma sequence of intestinal tumors. PMID- 22496369 TI - Tumor suppressors p53, p63TAalpha, p63TAy, p73alpha, and p73beta use distinct pathways to repress telomerase expression. AB - The promoter of the telomerase catalytic subunit (TERT) is subject to tight regulation and remains repressed in somatic cells to ensure their limited life span and to prevent tumor initiation. Here we report that the hTERT promoter is strongly repressed by p53 and the related family members p63 and p73. We found that p53-mediated repression was different in human and mouse cells and occurred through p53-dependent transcription inhibition of c-Myc or through E-box/E2F pathways, respectively. Although p63TAalpha-mediated repression occurred through SP1, p63TAy-mediated repression occurred through E2F signaling. Finally, p73alpha and p73beta-mediated repression occurred through NF-YB2. Our results show a complex multifactorial mechanism used by p53 and its family members to keep hTERT expression under tight control. PMID- 22496370 TI - Paired helical filaments from Alzheimer disease brain induce intracellular accumulation of Tau protein in aggresomes. AB - Abnormal folding of tau protein leads to the generation of paired helical filaments (PHFs) and neurofibrillary tangles, a key neuropathological feature in Alzheimer disease and tauopathies. A specific anatomical pattern of pathological changes developing in the brain suggests that once tau pathology is initiated it propagates between neighboring neuronal cells, possibly spreading along the axonal network. We studied whether PHFs released from degenerating neurons could be taken up by surrounding cells and promote spreading of tau pathology. Neuronal and non-neuronal cells overexpressing green fluorescent protein-tagged tau (GFP Tau) were treated with isolated fractions of human Alzheimer disease-derived PHFs for 24 h. We found that cells internalized PHFs through an endocytic mechanism and developed intracellular GFP-Tau aggregates with attributes of aggresomes. This was particularly evident by the perinuclear localization of aggregates and redistribution of the vimentin intermediate filament network and retrograde motor protein dynein. Furthermore, the content of Sarkosyl-insoluble tau, a measure of abnormal tau aggregation, increased 3-fold in PHF-treated cells. An exosome related mechanism did not appear to be involved in the release of GFP-Tau from untreated cells. The evidence that cells can internalize PHFs, leading to formation of aggresome-like bodies, opens new therapeutic avenues to prevent propagation and spreading of tau pathology. PMID- 22496371 TI - Binding preferences, surface attachment, diffusivity, and orientation of a family 1 carbohydrate-binding module on cellulose. AB - Cellulase enzymes often contain carbohydrate-binding modules (CBMs) for binding to cellulose. The mechanisms by which CBMs recognize specific surfaces of cellulose and aid in deconstruction are essential to understand cellulase action. The Family 1 CBM from the Trichoderma reesei Family 7 cellobiohydrolase, Cel7A, is known to selectively bind to hydrophobic surfaces of native cellulose. It is most commonly suggested that three aromatic residues identify the planar binding face of this CBM, but several recent studies have challenged this hypothesis. Here, we use molecular simulation to study the CBM binding orientation and affinity on hydrophilic and hydrophobic cellulose surfaces. Roughly 43 MUs of molecular dynamics simulations were conducted, which enables statistically significant observations. We quantify the fractions of the CBMs that detach from crystal surfaces or diffuse to other surfaces, the diffusivity along the hydrophobic surface, and the overall orientation of the CBM on both hydrophobic and hydrophilic faces. The simulations demonstrate that there is a thermodynamic driving force for the Cel7A CBM to bind preferentially to the hydrophobic surface of cellulose relative to hydrophilic surfaces. In addition, the simulations demonstrate that the CBM can diffuse from hydrophilic surfaces to the hydrophobic surface, whereas the reverse transition is not observed. Lastly, our simulations suggest that the flat faces of Family 1 CBMs are the preferred binding surfaces. These results enhance our understanding of how Family 1 CBMs interact with and recognize specific cellulose surfaces and provide insights into the initial events of cellulase adsorption and diffusion on cellulose. PMID- 22496372 TI - Synergistic binding of DnaJ and DnaK chaperones to heat shock transcription factor sigma32 ensures its characteristic high metabolic instability: implications for heat shock protein 70 (Hsp70)-Hsp40 mode of function. AB - Escherichia coli heat shock transcription factor sigma(32) is rapidly degraded by ATP-dependent proteases, such as FtsH and ClpYQ. Although the DnaK chaperone system (DnaK, DnaJ, and GrpE) promotes sigma(32) degradation in vivo, the precise mechanism that is involved remains unknown. Our previous results indicated that sigma(32) mutants containing amino acid substitution in the N-terminal half of Region 2.1 are markedly stabilized in vivo. Here, we report the further characterization of these mutants by examining purified sigma(32) mutants in vitro. Surprisingly, I54A sigma(32), a very stable mutant, is more susceptible to ClpYQ and FtsH proteases than wild-type sigma(32), indicating that the stability of sigma(32) does not always reflect its susceptibility to proteases. Co precipitation and gel filtration analyses show that purified sigma(32) mutants exhibit a reduced affinity for DnaJ, leading to a marked decrease in forming a complex with DnaK in the presence of DnaJ and ATP. Other mutants with modestly increased stability (A50S sigma(32) and K51E sigma(32)) show an intermediate efficiency of complex formation with DnaK, suggesting that defects in binding to DnaK and DnaJ are well correlated with metabolic stability; effective interaction with DnaK promotes sigma(32) degradation in vivo. We argue that the stable and effective interaction of heat shock protein 70 (Hsp70) with a substrate polypeptide may generally require the simultaneous binding of heat shock protein 40 (Hsp40) to distinct sites on the substrate. PMID- 22496373 TI - Replication of hepatitis C virus RNA on autophagosomal membranes. AB - Previous studies indicated that hepatitis C virus (HCV) perturbs the autophagic pathway to induce the accumulation of autophagosomes in cells. To understand the role of autophagosomes in the HCV life cycle, we established a stable Huh7 hepatoma cell line that contained an HCV subgenomic RNA replicon and also expressed a GFP-LC3 fusion protein. The GFP-LC3 protein is localized to autophagosomes during autophagy and served as a convenient marker for autophagosomes. Our results indicate that the silencing of the expression of LC3 or Atg7, two protein factors critical for the formation of autophagosomes, suppresses the replication of HCV RNA. Confocal microscopy studies revealed the localization of HCV NS5A and NS5B proteins, which are two important components of the HCV RNA replication complex, and nascent HCV RNA to autophagosomes. The association of the HCV RNA replication complex with the autophagosomal membranes was further confirmed by co-immunoprecipitation and immunoelectron microscopy studies. Interestingly, inhibition of Class III PI3K activity had no effect on the autophagosomes induced by HCV. These results indicate that HCV induces autophagosomes via a Class III PI3K-independent pathway and uses autophagosomal membranes as sites for its RNA replication. PMID- 22496376 TI - Landmark tool assesses Canadian hospitals. PMID- 22496377 TI - The formerly fat physician. PMID- 22496374 TI - Hsp70 promotes epithelial sodium channel functional expression by increasing its association with coat complex II and its exit from endoplasmic reticulum. AB - The epithelial sodium channel (ENaC) plays an important role in the homeostasis of blood pressure and of the airway surface liquid, and inappropriate regulation of ENaC results in refractory hypertension (in Liddle syndrome) and impaired mucociliary clearance (in cystic fibrosis). The regulation of ENaC by molecular chaperones, such as the 70-kDa heat shock protein Hsp70, is not completely understood. Building on the previous suggestion by our group that Hsp70 promotes ENaC functional and surface expression in Xenopus oocytes, we investigated the mechanism by which Hsp70 acts upon ENaC in epithelial cells. In Madin-Darby canine kidney cells stably expressing epitope-tagged alphabetagamma-ENaC and with tetracycline-inducible overexpression of Hsp70, treatment with 1 or 2 MUg/ml doxycycline increased total Hsp70 expression ~2-fold and ENaC functional expression ~1.4-fold. This increase in ENaC functional expression corresponded to an increase in ENaC expression at the apical surface of the cells and was not present when an ATPase-deficient Hsp70 was similarly overexpressed. The increase in functional expression was not due to a change in the rate at which ENaC was retrieved from the apical membrane. Instead, Hsp70 overexpression increased the association of ENaC with the Sec24D cargo recognition component of coat complex II, which carries protein cargo from the endoplasmic reticulum to the Golgi. These data support the hypothesis that Hsp70 promotes ENaC biogenesis and trafficking to the apical surface of epithelial cells. PMID- 22496378 TI - Is "Obamacare' suddenly on the ropes? PMID- 22496379 TI - The global cancer epidemic: opportunities for Canada in low- and middle-income countries. PMID- 22496380 TI - Spontaneous tumour lysis syndrome. PMID- 22496381 TI - Brown urine and black hip. PMID- 22496382 TI - Unhealthy behaviours influenced by genes and environment. PMID- 22496384 TI - The road map to better hospitals. PMID- 22496383 TI - Prevalence of genetic variants associated with inflammatory bowel disease in a healthy First Nations cohort. AB - BACKGROUND: Inflammatory bowel disease is the result of both genes and environment. Canadian First Nations people, despite living in a region with a high prevalence of inflammatory bowel disease, are relatively protected from this disease. We aimed to compare the carriage of genetic variants associated with inflammatory bowel disease in healthy First Nations and white people. METHODS: DNA was extracted from the venous blood of healthy First Nations (n = 340) and white (n = 285) participants from Manitoba. Genotyping was performed for 69 single nucleotide polymorphisms (SNPs) with known or suspected associations with inflammatory bowel disease. We compared the genotypes between groups by logistic regression, adjusting for multiple testing. We calculated a risk score for the NOD2 gene by adding the number of risk alleles at three important NOD2 SNPs (G908R, R702W and 3020insC). RESULTS: We found genetic variation between white and First Nations participants at 45 of 69 SNPs. Notably, carriage of the ATG16L1 T300A mutation was lower in First Nations participants (p = 4.1 * 10(-30)). Cumulative carriage of important NOD2 variants was significantly lower among First Nations participants (3.9% v. 15.2%; p < 0.0001 for risk score) than among white participants. Risk variants in IL23R (p = 0.014) and IL12B (p = 1.2 * 10( 16)), among others, were more prevalent among First Nations participants than among white participants. INTERPRETATION: The low prevalence of variants associated with bacterial processing and handling in First Nations people may explain their relative protection from inflammatory bowel disease. Increased carriage of a number of risk variants, for example in the interleukin-23/Th17 pathway, is especially intriguing given their importance in other inflammatory diseases of high incidence in First Nations populations. PMID- 22496385 TI - Waging war against rotavirus at home and abroad. PMID- 22496386 TI - The inhibition of cholesteryl ester transfer protein: a long and winding road. PMID- 22496388 TI - A novel taspine derivative, HMQ1611, inhibits breast cancer cell growth via estrogen receptor alpha and EGF receptor signaling pathways. AB - Breast cancer is a common cancer with a leading cause of cancer mortality in women. Currently, the chemotherapy for breast cancer is underdeveloped. Here, we report a novel taspine derivative, HMQ1611, which has anticancer effects using in vitro and in vivo breast cancer models. HMQ1611 reduced cancer cell proliferation in four human breast cancer cell lines including MDA-MB-231, SK-BR-3, ZR-75-30, and MCF-7. HMQ1611 more potently reduced growth of estrogen receptor alpha (ERalpha)-positive breast cancer cells (ZR-75-30 and MCF-7) than ERalpha-negative cells (MDA-MB-231 and SK-BR-3). Moreover, HMQ1611 arrested breast cancer cell cycle at S-phase. In vivo tumor xenograft model, treatment of HMQ1611 significantly reduced tumor size and weight compared with vehicles. We also found that HMQ1611 reduced ERalpha expression and inhibited membrane ERalpha-mediated mitogen-activated protein kinase (MAPK) signaling following the stimulation of cells with estrogen. Knockdown of ERalpha by siRNA transfection in ZR-75-30 cells attenuated HMQ1611 effects. In contrast, overexpression of ERalpha in MDA-MB-231 cells enhanced HMQ1611 effects, suggesting that ERalpha pathway mediated HMQ1611's inhibition of breast cancer cell growth in ERalpha-positive breast cancer. HMQ1611 also reduced phosphorylation of EGF receptor (EGFR) and its downstream signaling players extracellular signal-regulated kinase (ERK)1/2 and AKT activation both in ZR-75-30 and MDA-MB-231 cells. These results showed that the novel compound HMQ1611 had anticancer effects, and partially via ERalpha and/or EGFR signaling pathways, suggesting that HMQ1611 may be a potential novel candidate for human breast cancer intervention. PMID- 22496387 TI - A risk model for lung cancer incidence. AB - Risk models for lung cancer incidence would be useful for prioritizing individuals for screening and participation in clinical trials of chemoprevention. We present a risk model for lung cancer built using prospective cohort data from a general population which predicts individual incidence in a given time period. We build separate risk models for current and former smokers using 169,035 ever smokers from the multicenter European Prospective Investigation into Cancer and Nutrition (EPIC) and considered a model for never smokers. The data set was split into independent training and test sets. Lung cancer incidence was modeled using survival analysis, stratifying by age started smoking, and for former smokers, also smoking duration. Other risk factors considered were smoking intensity, 10 occupational/environmental exposures previously implicated with lung cancer, and single-nucleotide polymorphisms at two loci identified by genome-wide association studies of lung cancer. Individual risk in the test set was measured by the predicted probability of lung cancer incidence in the year preceding last follow-up time, predictive accuracy was measured by the area under the receiver operator characteristic curve (AUC). Using smoking information alone gave good predictive accuracy: the AUC and 95% confidence interval in ever smokers was 0.843 (0.810-0.875), the Bach model applied to the same data gave an AUC of 0.775 (0.737-0.813). Other risk factors had negligible effect on the AUC, including never smokers for whom prediction was poor. Our model is generalizable and straightforward to implement. Its accuracy can be attributed to its modeling of lifetime exposure to smoking. PMID- 22496389 TI - Synapses and memory storage. AB - The synapse is the functional unit of the brain. During the last several decades we have acquired a great deal of information on its structure, molecular components, and physiological function. It is clear that synapses are morphologically and molecularly diverse and that this diversity is recruited to different functions. One of the most intriguing findings is that the size of the synaptic response in not invariant, but can be altered by a variety of homo- and heterosynaptic factors such as past patterns of use or modulatory neurotransmitters. Perhaps the most difficult challenge in neuroscience is to design experiments that reveal how these basic building blocks of the brain are put together and how they are regulated to mediate the information flow through neural circuits that is necessary to produce complex behaviors and store memories. In this review we will focus on studies that attempt to uncover the role of synaptic plasticity in the regulation of whole-animal behavior by learning and memory. PMID- 22496391 TI - Characterization of the in vitro and in vivo metabolism and disposition and cytochrome P450 inhibition/induction profile of saxagliptin in human. AB - Saxagliptin is a potent dipeptidyl peptidase-4 inhibitor approved for the treatment of type 2 diabetes mellitus. The pharmacokinetics and disposition of [(14)C]saxagliptin were investigated in healthy male subjects after a single 50 mg (91.5 MUCi) oral dose. Saxagliptin was rapidly absorbed (T(max), 0.5 h). Unchanged saxagliptin and 5-hydroxy saxagliptin (M2), a major, active metabolite, were the prominent drug-related components in the plasma, together accounting for most of the circulating radioactivity. Approximately 97% of the administered radioactivity was recovered in the excreta within 7 days postdose, of which 74.9% was eliminated in the urine and 22.1% was excreted in the feces. The parent compound and M2 represented 24.0 and 44.1%, respectively, of the radioactivity recovered in the urine and feces combined. Taken together, the excretion data suggest that saxagliptin was well absorbed and was subsequently cleared by both urinary excretion and metabolism; the formation of M2 was the major metabolic pathway. Additional minor metabolic pathways included hydroxylation at other positions and glucuronide or sulfate conjugation. Cytochrome P450 (P450) enzymes CYP3A4 and CYP3A5 metabolized saxagliptin and formed M2. Kinetic experiments indicated that the catalytic efficiency (V(max)/K(m)) for CYP3A4 was approximately 4-fold higher than that for CYP3A5. Therefore, it is unlikely that variability in expression levels of CYP3A5 due to genetic polymorphism will impact clearance of saxagliptin. Saxagliptin and M2 each showed little potential to inhibit or induce important P450 enzymes, suggesting that saxagliptin is unlikely to affect the metabolic clearance of coadministered drugs that are substrates for these enzymes. PMID- 22496390 TI - The role of oxysterols in control of endothelial stiffness. AB - Endothelial dysfunction is a key step in atherosclerosis development. Our recent studies suggested that oxLDL-induced increase in endothelial stiffness plays a major role in dyslipidemia-induced endothelial dysfunction. In this study, we identify oxysterols, as the major component of oxLDL, responsible for the increase in endothelial stiffness. Using Atomic Force Microscopy to measure endothelial elastic modulus, we show that endothelial stiffness increases with progressive oxidation of LDL and that the two lipid fractions that contribute to endothelial stiffening are oxysterols and oxidized phosphatidylcholines, with oxysterols having the dominant effect. Furthermore, endothelial elastic modulus increases as a linear function of oxysterol content of oxLDL. Specific oxysterols, however, have differential effects on endothelial stiffness with 7 ketocholesterol and 7alpha-hydroxycholesterol, the two major oxysterols in oxLDL, having the strongest effects. 27-hydroxycholesterol, found in atherosclerotic lesions, also induces endothelial stiffening. For all oxysterols, endothelial stiffening is reversible by enriching the cells with cholesterol. oxLDL-induced stiffening is accompanied by incorporation of oxysterols into endothelial cells. We find significant accumulation of three oxysterols, 7alpha-hydroxycholesterol, 7beta-hydroxycholesterol, and 7-ketocholesterol, in mouse aortas of dyslipidemic ApoE-/- mice at the early stage of atherosclerosis. Remarkably, these are the same oxysterols we have identified to induce endothelial stiffening. PMID- 22496392 TI - Pilomotor seizure: when paroxysmal gooseflesh heralds brain tumor. PMID- 22496393 TI - Shared loci for migraine and epilepsy on chromosomes 14q12-q23 and 12q24.2-q24.3. PMID- 22496394 TI - Teaching neuroImages: Cerebral and cervical venous air embolism. PMID- 22496395 TI - Teaching neuroImages: Seeing double: intercavernous sinus dural arteriovenous fistula causing bilateral abducens palsy. PMID- 22496396 TI - Identification of the cytochrome P450 and other enzymes involved in the in vitro oxidative metabolism of a novel antidepressant, Lu AA21004. AB - 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine (Lu AA21004) is a novel antidepressant that is currently in late-stage clinical development for major depressive disorder. In the present study, the metabolism of Lu AA21004 was investigated using human liver microsomes (HLM), human liver S9 fraction, and recombinant enzymes. Lu AA21004 was found in vitro to be oxidized to a 4-hydroxy phenyl metabolite, a sulfoxide, an N-hydroxylated piperazine, and a benzylic alcohol, which was further oxidized to the corresponding benzoic acid [3-methyl-4 (2-piperazin-1-yl-phenysulfanyl)-benzoic acid (Lu AA34443)]. The formation of the 4-hydroxy-phenyl metabolite was catalyzed by CYP2D6 with some contribution from CYP2C9, whereas the formation of the sulfoxide was mediated by CYP3A4/5 and CYP2A6. CYP2C9 and CYP2C19 were the primary enzymes responsible for formation of the N-hydroxylated metabolite. The benzylic alcohol was formed by CYP2D6 only. The oxidation of the benzylic alcohol to the corresponding benzoic acid of Lu AA21004 was catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase, with some contribution from aldehyde oxidase. CYP2D6 was also capable of catalyzing the formation of the benzoic acid of Lu AA21004; however, its overall contribution to this pathway was negligible. Enzyme kinetic parameters revealed that the rate-limiting step in the formation of the benzoic acid from Lu AA21004 is the formation of the corresponding alcohol. Thus, the intrinsic clearance (V(max)/K(m)) in HLM for metabolism of Lu AA21004 to the benzylic alcohol was 1.13 * 10(-6) l . min(-1) . mg(-1), whereas the subsequent metabolism of the benzylic alcohol to the benzoic acid of Lu AA21004 is characterized by an intrinsic clearance (V(max)/K(m)) in S9 fraction of 922 * 10(-6) l . min(-1) . mg(-1). PMID- 22496398 TI - A randomized recruitment intervention trial in Parkinson's disease to increase participant diversity: early stopping for lack of efficacy. AB - BACKGROUND: Failure to include participants of diverse race and ethnicity (i.e. those other than European Caucasian, non-Hispanic) in clinical trials impedes the safe development of new therapies given the potential for racial/ethnicity related variations in treatment response. Increasing diversity is problematic for low prevalence diseases, where most community-based approaches do not reach those with the disease. PURPOSE: Increase racial/ethnic diversity of participants in a Parkinson's disease therapeutic trial. METHODS: We incorporated a randomized Ancillary Trial into the multisite National Institute of Neurologic Disorders and Stroke Exploratory Trials in Parkinson's Disease Long-Term Study 1. Movement disorders clinics already participating in long-term trial 1 were eligible and were the unit of randomization and analysis. At least 14% of adult residents over age 55 and living within 30 miles of the eligible site were from a diverse population, or there was a near-by zip code with a highly diverse population. Eligible sites also agreed to be randomized. The intervention was designed to increase community physicians' trust in long-term trial 1 investigators and address recruitment barriers in diverse populations. Primary outcomes included percentage of participants from diverse racial/ethnic groups enrolled in long term trial 1, and qualitative findings from key informant interviews of the Ancillary Trial investigators and coordinators at the end of the trial. RESULTS: The Ancillary Trial stopped early for lack of efficacy, conditional power less than 1%. The 17 intervention sites had 12.6% diverse participants compared to 15.6% in 15 control clinics; odds ratio 0.82 (95% confidence interval = 0.32 2.16). In key informant interviews, high enrollers of diverse participants reported more use of existing physician relationships, untargeted community outreach, and extensive efforts to overcome participants' barriers. Low enrollers reported more use of patients in their practices and placed more responsibility for low enrollment on prospective participants. LIMITATIONS: The Ancillary Trial included only those with Parkinson's disease. Whether our findings generalize to trials in other low prevalence diseases is unknown. CONCLUSIONS: Increasing diversity in Parkinson's disease clinical trials requires new paradigms for trial investigator and coordinator interactions with community physicians and prospective trial participants. PMID- 22496397 TI - Coordinated regulation of hepatic phase I and II drug-metabolizing genes and transporters using AhR-, CAR-, PXR-, PPARalpha-, and Nrf2-null mice. AB - The transcription factors aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator activated receptor alpha (PPARalpha), and nuclear factor erythroid 2-related factor 2 (Nrf2) regulate genes encoding drug-metabolizing enzymes and transporters in livers of mice after chemical activation. However, the specificity of their transcriptional regulation has not been determined systematically in vivo. The purpose of this study was to identify genes encoding drug-metabolizing enzymes and transporters altered by chemical activators in a transcription factor-dependent manner using wild-type and transcription factor null mice. Chemical activators were administered intraperitoneally to mice once daily for 4 days. Livers were collected 24 h after the final dose, and total RNA was isolated for mRNA quantification of cytochromes P450, NAD(P)H quinone oxidoreductase 1 (Nqo1), aldehyde dehydrogenases (Aldhs), glutathione transferases (Gsts), sulfotransferases (Sults), UDP-glucuronosyltransferases (Ugts), organic anion-transporting polypeptides (Oatps), and multidrug resistance associated proteins (Mrps). Pharmacological activation of each transcription factor leads to mRNA induction of drug metabolic and transport genes in livers of male and female wild-type mice, but no change in null mice: AhR (Cyp1a2, Nqo1, Aldh7a1, Ugt1a1, Ugt1a6, Ugt1a9, Ugt2b35, Sult5a1, Gstm3, and Mrp4), CAR (Cyp2b10, Aldh1a1, Aldh1a7, Ugt1a1, Ugt2b34, Sult1e1, Sult3a1, Sult5a1, Papps2, Gstt1, Gsta1, Gsta4, Gstm1-4, and Mrp2-4), PXR (Cyp3a11, Ugt1a1, Ugt1a5, Ugt1a9, Gsta1, Gstm1-m3, Oatp1a4, and Mrp3), PPARalpha (Cyp4a14, Aldh1a1, mGst3, Gstm4, and Mrp4), and Nrf2 (Nqo1, Aldh1a1, Gsta1, Gsta4, Gstm1-m4, mGst3, and Mrp3-4). Taken together, these data reveal transcription factor specificity and overlap in regulating hepatic drug disposition genes by chemical activators. Coordinated regulation of phase I, phase II, and transport genes by activators of transcription factors can have implications in development of pharmaceuticals as well as risk assessment of environmental contaminants. PMID- 22496399 TI - Clinician-trialist rounds: 9. Mentoring - part 3: the structure and function of effective mentoring: advice and protection. PMID- 22496400 TI - Supplementation with galacto-oligosaccharides increases the percentage of NK cells and reduces colitis severity in Smad3-deficient mice. AB - The gut microbiota plays an essential role in intestinal immunity. Prebiotics, including galacto-oligosaccharides (GOS), are fermentable fibers that beneficially affect the host by stimulating the growth of specific microbial populations. We investigated the effect of GOS on colitis development and on immune variables in Smad3-deficient mice treated with the pathogen Helicobacter hepaticus. Mice were supplemented daily with 5000 mg GOS/kg body weight 2 wk prior to infection and 4 wk postinfection, a time period during which colitis severity peaks in this model. Mice (n = 4-8/treatment at each time) were killed preinfection (0 d) and at 3, 7, and 28 d postinfection to evaluate immune variables in the spleen and in mesenteric lymph nodes (MsLN) by flow cytometry. Colon and cecum samples were collected for histopathologic analysis. Fecal pellets (n = 8-9/treatment) were collected prior to infection to measure relative changes in Bifidobacterium ssp. and Lactobacillum ssp. by real-time PCR. GOS significantly reduced colitis severity in response to H. hepaticus (P < 0.0001). This was associated with a significant increase in the percentage of NK cells in the spleen (P < 0.001) and in MsLN (P < 0.001) at 3 d postinfection and a 1.5 fold increase in fecal Bifidobacterium ssp. (P = 0.003). GOS stimulated NK expression of CCR9, a chemokine receptor involved in lymphocyte trafficking to the gut preinfection (0 d) in the blood (P = 0.02), spleen (P = 0.033), and MsLN (P = 0.017). In addition, GOS stimulated colonic IL-15 production 3 d postinfection (P < 0.001). These data suggest that GOS reduces colitis by modulating the function and trafficking of NK cells and may provide a novel therapeutic strategy for individuals with inflammatory bowel disease. PMID- 22496401 TI - Early participation in a prenatal food supplementation program ameliorates the negative association of food insecurity with quality of maternal-infant interaction. AB - Food insecurity is detrimental to child development, yet little is known about the combined influence of food insecurity and nutritional interventions on child development in low-income countries. We proposed that women assigned to an early invitation time to start a prenatal food supplementation program could reduce the negative influence of food insecurity on maternal-infant interaction. A cohort of 180 mother-infant dyads were studied (born between May and October 2003) from among 3267 in the randomized controlled trial Maternal Infant Nutritional Interventions Matlab, which was conducted in Matlab, Bangladesh. At 8 wk gestation, women were randomly assigned an invitation time to start receiving food supplements (2.5 MJ/d; 6 d/wk) either early (~9 wk gestation; early invitation group) or at the usual start time (~20 wk gestation; usual-invitation group) for the government program. Maternal-infant interaction was observed in homes with the use of the Nursing Child Assessment Satellite Training Feeding Scale, and food-insecurity status was obtained from questionnaires completed when infants were 3.4-4.0 mo old. By using a general linear model for maternal-infant interaction, we found a significant interaction (P = 0.012) between invitation time to start a prenatal food supplementation program and food insecurity. Those in the usual-invitation group with higher food insecurity scores (i.e., more food insecure) had a lower quality of maternal-infant interaction, but this relationship was ameliorated among those in the early-invitation group. Food insecurity limits the ability of mothers and infants to interact well, but an early invitation time to start a prenatal food supplementation program can support mother-infant interaction among those who are food insecure. PMID- 22496402 TI - Circulating phylloquinone concentrations of adults in the United States differ according to race and ethnicity. AB - Differences in micronutrient status are reported to contribute to racial and ethnic differences in chronic diseases. Diseases related to vitamin K are reported to differ by race and ethnicity, but it is unclear if circulating vitamin K concentrations similarly differ. We examined racial and ethnic differences in serum phylloquionone (K1) in the Multiethnic Study of Atherosclerosis (MESA) (mean +/- SD age = 62 +/- 10 y; 52% female; 262 white, 180 African American, 169 Hispanic, 93 Chinese American). Overall, 25% had serum K1 <0.1 nmol/L (the lower limit of detection). The prevalence of low serum K1 was 4% in Chinese Americans compared with 24% of whites, 29% of African Americans, and 33% of Hispanics. Compared with whites, Chinese Americans were significantly less likely to have serum K1 <0.1 nmol/L [OR (95% CI): 0.23 (0.09-0.23), adjusted for serum TG, K1 intake, age, sex, BMI, smoking, total cholesterol, site, season, and lipid-lowering medication use]. African Americans and Hispanics had similar odds to whites for having serum K1 <0.1 nmol/L [OR(95% CI): 1.30 (0.79-2.15) and 1.19 (0.66-2.15), respectively; fully adjusted]. In participants with detectable concentrations (n = 523), (natural log) serum K1 was higher in the Chinese Americans compared with whites, African Americans, and Hispanics (geometric mean +/- SEM = 2.2 +/- 0.1 nmol/L vs. 1.2 +/- 0.1 nmol/L, 1.5 +/- 0.1 nmol/L, and 1.1 +/- 0.1 nmol/L, respectively, adjusted for serum TG, K1 intake, and additional covariates; all P < 0.001). These findings suggest circulating K1 differs by race and ethnicity in U.S. adults, especially among those of Chinese American descent, which merits consideration in the design and interpretation of future population based and clinical studies of vitamin K and related diseases. PMID- 22496403 TI - Osteoprotegerin, leptin and IL-6: association with silent myocardial ischemia in type 2 diabetes mellitus. AB - BACKGROUND: Diabetic patients often exhibit severe, asymptomatic coronary artery disease (CAD). The relationship between osteoprotegerin (OPG), inflammatory markers and silent myocardial ischemia remains to be elucidated. METHODS: We recruited 45 type 2 diabetic patients and 33 healthy controls and assessed them for silent myocardial ischemia (SMI) by myocardial perfusion imaging. Patient blood was tested for OPG, IL-6 and leptin concentrations. RESULTS: OPG, leptin and IL-6 levels were found significantly elevated in diabetic patients (p < 0.001, p < 0.01, p < 0.05). Based on our classification of presence/absence of SMI in our diabetic group, we found that there was a significant association between SMI and the biomarkers IL-6 (p < 0.001), leptin (p < 0.001) and OPG (p < 0.05). In multivariate regression analyses, OPG was found to be significantly related to diabetes mellitus and to SMI. Age, sex and smoking increased the association between OPG and SMI. CONCLUSION: High OPG, leptin and IL-6 levels are associated with the presence and severity of SMI in type 2 diabetic patients. PMID- 22496404 TI - Cardioprotective effects of incretin during ischaemia-reperfusion. AB - Incretin is a gut derived peptide hormone secreted in the intestine after food ingestion, and is degraded rapidly after secretion by dipeptidyl peptidase (DPP) 4. Incretin-based therapy, such as glucagon-like peptide (GLP)-1 and the DPP-4 inhibitor, has been proposed as a new therapeutic approach for the treatment of type 2 diabetic patients. In the past few years, growing evidence also demonstrated the cardioprotective effects of incretin-based therapy, especially during ischaemia-reperfusion (I/R) injury in both the animal models and in clinical studies. However, inconsistent reports exist regarding the use of these pharmacological interventions. In this article, a comprehensive review regarding both basic and clinical studies reporting the effects of GLP-1 and DPP-4 inhibitors on I/R hearts is presented and discussed. The consistent findings as well as controversial results are summarised, focusing on the effects of incretin on the infarct size, left ventricular function and haemodynamic improvement during an I/R injury. PMID- 22496405 TI - BMP-2 induces a profibrotic phenotype in adult renal progenitor cells through Nox4 activation. AB - Adult renal progenitor cells (ARPCs) isolated from the human kidney may contribute to repair featuring acute kidney injury (AKI). Bone morphogenetic proteins (BMPs) regulate differentiation, modeling, and regeneration processes in several tissues. The aim of this study was to evaluate the biological actions of BMP-2 in ARPCs in vitro and in vivo. BMP-2 was expressed in ARPCs of normal adult human kidneys, and it was upregulated in vivo after delayed graft function (DGF) of renal transplantation, a condition of AKI. ARPCs expressed BMP receptors, suggesting their potential responsiveness to BMP-2. Incubation of ARPCs with this growth factor enhanced reactive oxygen species (ROS) production, NADPH oxidase activity, and Nox4 protein expression. In vivo, Nox4 was localized in BMP-2 expressing CD133+ cells at the tubular level after DGF. BMP-2 incubation induced alpha-smooth muscle actin (SMA), collagen I, and fibronectin protein expression in ARPCs. Moreover, alpha-SMA colocalized with CD133 in vivo after DGF. The oxidative stimulus (H(2)O(2)) induced alpha-SMA expression in ARPCs, while the antioxidant N-acetyl-cysteine inhibited BMP-2-induced alpha-SMA expression. Nox4 silencing abolished BMP-2-induced NADPH oxidase activation and myofibroblastic induction. We showed that 1) ARPCs express BMP-2, 2) this expression is increased in a model of AKI; 3) BMP-2 may induce the commitment of ARPCs toward a myofibroblastic phenotype in vitro and in vivo; and 4) this profibrotic effect is mediated by Nox4 activation. Our findings suggest a novel mechanism linking AKI with progressive renal damage. PMID- 22496406 TI - Inhibition of bladder overactivity by a combination of tibial neuromodulation and tramadol treatment in cats. AB - Our recent study in cats revealed that inhibition of bladder overactivity by tibial nerve stimulation (TNS) depends on the activation of opioid receptors. TNS is a minimally invasive treatment for overactive bladder (OAB), but its efficacy is low. Tramadol (an opioid receptor agonist) is effective in treating OAB but elicits significant adverse effects. This study was to determine if a low dose of tramadol (expected to produce fewer adverse effects) can enhance the TNS inhibition of bladder overactivity. Bladder overactivity was induced in alpha chloralose-anesthetized cats by an intravesical infusion of 0.25% acetic acid (AA) during repeated cystometrograms (CMGs). TNS (5 Hz) at two to four times the threshold intensity for inducing toe movement was applied during CMGs before and after tramadol (0.3-7 mg/kg iv) to examine the interaction between the two treatments. AA irritation significantly reduced bladder capacity to 24.8 +/- 3.3% of the capacity measured during saline infusion. TNS alone reversibly inhibited bladder overactivity and significantly increased bladder capacity to 50-60% of the saline control capacity. Tramadol administered alone in low doses (0.3-1 mg/kg) did not significantly change bladder capacity, whereas larger doses (3-7 mg/kg) increased bladder capacity (50-60%). TNS in combination with tramadol (3-7 mg/kg) completely reversed the effect of AA. Tramadol also unmasked a prolonged (>2 h) TNS inhibition of bladder overactivity that persisted after termination of the stimulation. The results suggest a novel treatment strategy for OAB by combining tibial neuromodulation with a low dose of tramadol, which is minimally invasive with a potentially high efficacy and fewer adverse effects. PMID- 22496407 TI - Mammalian target of rapamycin and the kidney. II. Pathophysiology and therapeutic implications. AB - The mTOR pathway plays an important role in a number of common renal diseases, including acute kidney injury (AKI), diabetic nephropathy (DN), and polycystic kidney diseases (PKD). The activity of mTOR complex 1 (mTORC1) is necessary for renal regeneration and repair after AKI, and inhibition of mTORC1 by rapamycin has been shown to delay recovery from ischemic AKI in animal studies, and to prolong delayed graft function in humans who have received a kidney transplant. For this reason, administration of rapamycin should be delayed or discontinued in patients with AKI until full recovery of renal function has occurred. On the other hand, inappropriately high mTORC1 activity contributes to the progression of the metabolic syndrome, the development of type 2 diabetes, and the pathogenesis of DN. In addition, chronic hyperactivity of mTORC1, and possibly also mTORC2, contributes to cyst formation and enlargement in a number of forms of PKD. Inhibition of mTOR, using either rapamycin (which inhibits predominantly mTORC1) or "catalytic" inhibitors (which effectively inhibit both mTORC1 and mTORC2), provide exciting possibilities for novel forms of treatment of DN and PKD. In this second part of the review, we will examine the role of mTOR in the pathophysiology of DN and PKD, as well as the potential utility of currently available and newly developed inhibitors of mTOR to slow the progression of DN and/or PKD. PMID- 22496408 TI - Autophagy protects against necrotic renal epithelial cell-induced death of renal interstitial fibroblasts. AB - We recently reported that necrotic renal proximal tubular cells (RPTC) can induce the death of renal interstitial fibroblasts. Since autophagy plays either cytoprotective or cytodestructive roles depending on the experimental condition, the present study was carried out to investigate whether necrotic RPTC would induce autophagy of renal interstitial fibroblasts and, if so, whether autophagy would contribute to cell death or exert a protective effect. Exposure of necrotic RPTC supernatant (RPTC-Sup) induced autophagy in renal interstitial fibroblast cells (NRK-49F) in a time- and dose-dependent manner, and its induction was earlier than caspase-3 activation. Inhibition of autophagy with 3-methyladenine (3-MA) or knockdown of Beclin-1, a molecule involved in the initiation of autophagosome formation, with small interference RNA (siRNA) significantly enhanced necrotic RPTC-Sup-induced cell death. Necrotic RPTC-Sup induced phosphorylation of extracellular signal-regulated kinases (ERK1/2), p38, c-Jun NH(2)-terminal kinases (JNKs), and AKT. Treatment with an ERK1/2 pathway inhibitor, but not with specific inhibitors for p38, JNKs, or AKT pathways, blocked NRK-49F autophagy and cell death upon exposure to necrotic RPTC-Sup. Furthermore, knockdown of MEK1 with siRNA also reduced autophagy along with cell death in NRK-49F exposed to necrotic RPTC-Sup. In contrast, overexpression of MEK1/2 increased RPTC-Sup-induced fibroblast cell death without enhancing autophagy. Collectively, this study demonstrates that necrotic RPTC induce both autophagy and cell death and that autophagy plays a cytoprotective or prosurvival role in renal fibroblasts. Furthermore, necrotic RPTC-induced autophagy and cell death in renal fibroblasts is mediated by the activation of the MEK1-ERK1/2 signaling pathway. PMID- 22496409 TI - Enhanced intrarenal receptor-mediated prorenin activation in chronic progressive anti-thymocyte serum nephritis rats on high salt intake. AB - Despite suppression of the circulating renin-angiotensin system (RAS), high salt intake (HSI) aggravates kidney injury in chronic kidney disease. To elucidate the effect of HSI on intrarenal RAS, we investigated the levels of intrarenal prorenin, renin, (pro)renin receptor (PRR), receptor-mediated prorenin activation, and ANG II in chronic anti-thymocyte serum (ATS) nephritic rats on HSI. Kidney fibrosis grew more severe in the nephritic rats on HSI than normal salt intake. Despite suppression of plasma renin and ANG II, marked increases in tubular prorenin and renin proteins without concomitant rises in renin mRNA, non proteolytically activated prorenin, and ANG II were noted in the nephritic rats on HSI. Redistribution of PRR from the cytoplasm to the apical membrane, along with elevated non-proteolytically activated prorenin and ANG II, was observed in the collecting ducts and connecting tubules in the nephritic rats on HSI. Olmesartan decreased cortical prorenin, non-proteolytically activated prorenin and ANG II, and apical membranous PRR in the collecting ducts and connecting tubules, and attenuated the renal lesions. Cell surface trafficking of PRR was enhanced by ANG II and was suppressed by olmesartan in Madin-Darby canine kidney cells. These data suggest the involvement of the ANG II-dependent increase in apical membrane PRR in the augmentation of intrarenal binding of prorenin and renin, followed by nonproteolytic activation of prorenin, enhancement of renin catalytic activity, ANG II generation, and progression of kidney fibrosis in the nephritic rat kidneys on HSI. The origin of the increased tubular prorenin and renin remains to be clarified. Further studies measuring the urinary prorenin and renin are needed. PMID- 22496410 TI - Low plasma carnosinase activity promotes carnosinemia after carnosine ingestion in humans. AB - A polymorphism in the carnosine dipeptidase-1 gene (CNDP1), resulting in decreased plasma carnosinase activity, is associated with a reduced risk for diabetic nephropathy. Because carnosine, a natural scavenger/suppressor of ROS, advanced glycation end products, and reactive aldehydes, is readily degraded in blood by the highly active carnosinase enzyme, it has been postulated that low serum carnosinase activity might be advantageous to reduce diabetic complications. The aim of this study was to examine whether low carnosinase activity promotes circulating carnosine levels after carnosine supplementation in humans. Blood and urine were sampled in 25 healthy subjects after acute supplementation with 60 mg/kg body wt carnosine. Precooled EDTA-containing tubes were used for blood withdrawal, and plasma samples were immediately deproteinized and analyzed for carnosine and beta-alanine by HPLC. CNDP1 genotype, baseline plasma carnosinase activity, and protein content were assessed. Upon carnosine ingestion, 8 of the 25 subjects (responders) displayed a measurable increase in plasma carnosine up to 1 h after supplementation. Subjects with no measurable increment in plasma carnosine (nonresponders) had ~2-fold higher plasma carnosinase protein content and ~1.5-fold higher activity compared with responders. Urinary carnosine recovery was 2.6-fold higher in responders versus nonresponders and was negatively dependent on both the activity and protein content of the plasma carnosinase enzyme. In conclusion, low plasma carnosinase activity promotes the presence of circulating carnosine upon an oral challenge. These data may further clarify the link among CNDP1 genotype, carnosinase, and diabetic nephropathy. PMID- 22496411 TI - Effects of K+-deficient diets with and without NaCl supplementation on Na+, K+, and H2O transporters' abundance along the nephron. AB - Dietary potassium (K(+)) restriction and hypokalemia have been reported to change the abundance of most renal Na(+) and K(+) transporters and aquaporin-2 isoform, but results have not been consistent. The aim of this study was to reexamine Na(+), K(+) and H(2)O transporters' pool size regulation in response to removing K(+) from a diet containing 0.74% NaCl, as well as from a diet containing 2% NaCl (as found in American diets) to blunt reducing total diet electrolytes. Sprague Dawley rats (n = 5-6) were fed for 6 days with one of these diets: 2% KCl, 0.74% NaCl (2K1Na, control chow) compared with 0.03% KCl, 0.74% NaCl (0K1Na); or 2% KCl, 2%NaCl (2K2Na) compared with 0.03% KCl, 2% NaCl (0K2Na, Na(+) replete). In both 0K1Na and 0K2Na there were significant decreases in: 1) plasma [K(+)] (<2.5 mM); 2) urinary K(+) excretion (<5% of control); 3) urine osmolality and plasma [aldosterone], as well as 4) an increase in urine volume and medullary hypertrophy. The 0K2Na group had the lowest [aldosterone] (172.0 +/- 17.4 pg/ml) and lower blood pressure (93.2 +/- 4.9 vs. 112.0 +/- 3.1 mmHg in 2K2Na). Transporter pool size regulation was determined by quantitative immunoblotting of renal cortex and medulla homogenates. The only differences measured in both 0K1Na and 0K2Na groups were a 20-30% decrease in cortical beta-ENaC, 30-40% increases in kidney-specific Ste20/SPS1-related proline/alanine-rich kinase, and a 40% increase in medullary sodium pump abundance. The following proteins were not significantly changed in both the 0 K groups: Na(+)/H(+) exchanger isoform 3; Na(+)-K(+)-Cl(-) cotransporter; Na(+)-Cl(-) cotransporter, oxidative stress response kinase-1; renal outer medullary K(+) channel; autosomal recessive hypercholesterolemia; c-Src, aquaporin 2 isoform; or renin. Thus, despite profound hypokalemia and renal K(+) conservation, we did not confirm many of the changes that were previously reported. We predict that changes in transporter distribution and activity are likely more important for conserving K(+) than changes in total abundance. PMID- 22496412 TI - ATP mediates flow-induced NO production in thick ascending limbs. AB - Mechanical stimulation caused by increasing flow induces nucleotide release from many cells. Luminal flow and extracellular ATP stimulate production of nitric oxide (NO) in thick ascending limbs. However, the factors that mediate flow induced NO production are unknown. We hypothesized that luminal flow stimulates thick ascending limb NO production via ATP. We measured NO in isolated, perfused rat thick ascending limbs using the fluorescent dye DAF FM. The rate of increase in dye fluorescence reflects NO accumulation. Increasing luminal flow from 0 to 20 nl/min stimulated NO production from 17 +/- 16 to 130 +/- 37 arbitrary units (AU)/min (P < 0.02). Increasing flow from 0 to 20 nl/min raised ATP release from 4 +/- 1 to 21 +/- 6 AU/min (P < 0.04). Hexokinase (10 U/ml) plus glucose, which consumes ATP, completely prevented the measured increase in ATP. Luminal flow did not increase NO production in the presence of luminal and basolateral hexokinase (10 U/ml). When flow was increased with the ATPase apyrase in both luminal and basolateral solutions (5 U/ml), NO levels did not change significantly. The P2 receptor antagonist suramin (300 MUmol/l) reduced flow-induced NO production by 83 +/- 25% (P < 0.03) when added to both and basolateral sides. Luminal hexokinase decreased flow-induced NO production from 205.6 +/- 85.6 to 36.6 +/- 118.6 AU/min (P < 0.02). Basolateral hexokinase also reduced flow-induced NO production. The P2X receptor-selective antagonist NF023 (200 MUmol/l) prevented flow-induced NO production when added to the basolateral side but not the luminal side. We conclude that ATP mediates flow-induced NO production in the thick ascending limb likely via activation of P2Y receptors in the luminal and P2X receptors in the basolateral membrane. PMID- 22496413 TI - ENaC inhibition stimulates Cl- secretion in the mouse cortical collecting duct through an NKCC1-dependent mechanism. AB - In cortical collecting ducts (CCDs) perfused in vitro, inhibiting the epithelial Na(+) channel (ENaC) reduces Cl(-) absorption. Since ENaC does not transport Cl( ), the purpose of this study was to determine how ENaC modulates Cl(-) absorption. Thus, Cl(-) absorption was measured in CCDs perfused in vitro that were taken from mice given aldosterone for 7 days. In wild-type mice, we observed no effect of luminal hydrochlorothiazide on either Cl(-) absorption or transepithelial voltage (V(T)). However, application of an ENaC inhibitor [benzamil (3 MUM)] to the luminal fluid or application of a Na(+)-K(+)-ATPase inhibitor to the bath reduced Cl(-) absorption by ~66-75% and nearly obliterated lumen-negative V(T). In contrast, ENaC inhibition had no effect in CCDs from collecting duct-specific ENaC-null mice (Hoxb7:CRE, Scnn1a(loxlox)). Whereas benzamil-sensitive Cl(-) absorption did not depend on CFTR, application of a Na(+)-K(+)-2Cl(-) cotransport inhibitor (bumetanide) to the bath or ablation of the gene encoding Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) blunted benzamil sensitive Cl(-) absorption, although the benzamil-sensitive component of V(T) was unaffected. In conclusion, first, in CCDs from aldosterone-treated mice, most Cl( ) absorption is benzamil sensitive, whereas thiazide-sensitive Cl(-) absorption is undetectable. Second, benzamil-sensitive Cl(-) absorption occurs by inhibition of ENaC, possibly due to elimination of lumen-negative V(T). Finally, benzamil sensitive Cl(-) flux occurs, at least in part, through transcellular transport through a pathway that depends on NKCC1. PMID- 22496414 TI - Autoregulation and conduction of vasomotor responses in a mathematical model of the rat afferent arteriole. AB - We have formulated a mathematical model for the rat afferent arteriole (AA). Our model consists of a series of arteriolar smooth muscle cells and endothelial cells, each of which represents ion transport, cell membrane potential, and gap junction coupling. Cellular contraction and wall mechanics are also represented for the smooth muscle cells. Blood flow through the AA lumen is described by Poiseuille flow. The AA model's representation of the myogenic response is based on the hypothesis that changes in hydrostatic pressure induce changes in the activity of nonselective cation channels. The resulting changes in membrane potential then affect calcium influx through changes in the activity of the voltage-gated calcium channels, so that vessel diameter decreases with increasing pressure values. With this configuration, the model AA maintains roughly stable renal blood flow within a physiologic range of blood flow pressure. Model simulation of vasoconstriction initiated from local stimulation also agrees well with findings in the experimental literature, notably those of Steinhausen et al. (Steinhausen M, Endlich K, Nobiling R, Rarekh N, Schutt F. J Physiol 505: 493 501, 1997), which indicated that conduction of vasoconstrictive response decays more rapidly in the upstream flow direction than downstream. The model can be incorporated into models of integrated renal hemodynamic regulation. PMID- 22496415 TI - TFIIIC localizes budding yeast ETC sites to the nuclear periphery. AB - Chromatin function requires specific three-dimensional architectures of chromosomes. We investigated whether Saccharomyces cerevisiae extra TFIIIC (ETC) sites, which bind the TFIIIC transcription factor but do not recruit RNA polymerase III, show specific intranuclear positioning. We show that six of the eight known S. cerevisiae ETC sites localize predominantly at the nuclear periphery, and that ETC sites retain their tethering function when moved to a new chromosomal location. Several lines of evidence indicate that TFIIIC is central to the ETC peripheral localization mechanism. Mutating or deleting the TFIIIC binding consensus ablated ETC -site peripheral positioning, and inducing degradation of the TFIIIC subunit Tfc3 led to rapid release of an ETC site from the nuclear periphery. We find, moreover, that anchoring one TFIIIC subunit at an ectopic chromosomal site causes recruitment of others and drives peripheral tethering. Localization of ETC sites at the nuclear periphery also requires Mps3, a Sad1-UNC-84-domain protein that spans the inner nuclear membrane. Surprisingly, we find that the chromatin barrier and insulator functions of an ETC site do not depend on correct peripheral localization. In summary, TFIIIC and Mps3 together direct the intranuclear positioning of a new class of S. cerevisiae genomic loci positioned at the nuclear periphery. PMID- 22496416 TI - Phosphatidylserine dynamics in cellular membranes. AB - Much has been learned about the role of exofacial phosphatidylserine (PS) in apoptosis and blood clotting using annexin V. However, because annexins are impermeant and unable to bind PS at low calcium concentration, they are unsuitable for intracellular use. Thus little is known about the topology and dynamics of PS in the endomembranes of normal cells. We used two new probes-green fluorescent protein (GFP)-LactC2, a genetically encoded fluorescent PS biosensor, and 1-palmitoyl-2-(dipyrrometheneboron difluoride)undecanoyl-sn-glycero-3-phospho L-serine (TopFluor-PS), a synthetic fluorescent PS analogue-to examine PS distribution and dynamics inside live cells. The mobility of PS was assessed by a combination of advanced optical methods, including single-particle tracking and fluorescence correlation spectroscopy. Our results reveal the existence of a sizable fraction of PS with limited mobility, with cortical actin contributing to the confinement of PS in the plasma membrane. We were also able to measure the dynamics of PS in endomembrane organelles. By targeting GFP-LactC2 to the secretory pathway, we detected the presence of PS in the luminal leaflet of the endoplasmic reticulum. Our data provide new insights into properties of PS inside cells and suggest mechanisms to account for the subcellular distribution and function of this phospholipid. PMID- 22496417 TI - APC and Smad7 link TGFbeta type I receptors to the microtubule system to promote cell migration. AB - Cell migration occurs by activation of complex regulatory pathways that are spatially and temporally integrated in response to extracellular cues. Binding of adenomatous polyposis coli (APC) to the microtubule plus ends in polarized cells is regulated by glycogen synthase kinase 3beta (GSK-3beta). This event is crucial for establishment of cell polarity during directional migration. However, the role of APC for cellular extension in response to extracellular signals is less clear. Smad7 is a direct target gene for transforming growth factor-beta (TGFbeta) and is known to inhibit various TGFbeta-induced responses. Here we report a new function for Smad7. We show that Smad7 and p38 mitogen-activated protein kinase together regulate the expression of APC and cell migration in prostate cancer cells in response to TGFbeta stimulation. In addition, Smad7 forms a complex with APC and acts as an adaptor protein for p38 and GSK-3beta kinases to facilitate local TGFbeta/p38-dependent inactivation of GSK-3beta, accumulation of beta-catenin, and recruitment of APC to the microtubule plus end in the leading edge of migrating prostate cancer cells. Moreover, the Smad7-APC complex links the TGFbeta type I receptor to the microtubule system to regulate directed cellular extension and migratory responses evoked by TGFbeta. PMID- 22496418 TI - Regulation of myosin activation during cell-cell contact formation by Par3-Lgl antagonism: entosis without matrix detachment. AB - Cell-cell contact formation following cadherin engagement requires actomyosin contraction along the periphery of cell-cell contact. The molecular mechanisms that regulate myosin activation during this process are not clear. In this paper, we show that two polarity proteins, partitioning defective 3 homologue (Par3) and mammalian homologues of Drosophila Lethal (2) Giant Larvae (Lgl1/2), antagonize each other in modulating myosin II activation during cell-cell contact formation in Madin-Darby canine kidney cells. While overexpression of Lgl1/2 or depletion of endogenous Par3 leads to enhanced myosin II activation, knockdown of Lgl1/2 does the opposite. Intriguingly, altering the counteraction between Par3 and Lgl1/2 induces cell-cell internalization during early cell-cell contact formation, which involves active invasion of the lateral cell-cell contact underneath the apical-junctional complexes and requires activation of the Rho-Rho associated, coiled-coil containing protein kinase (ROCK)-myosin pathway. This is followed by predominantly nonapoptotic cell-in-cell death of the internalized cells and frequent aneuploidy of the host cells. Such effects are reminiscent of entosis, a recently described process observed when mammary gland epithelial cells were cultured in suspension. We propose that entosis could occur without matrix detachment and that overactivation of myosin or unbalanced myosin activation between contacting cells may be the driving force for entosis in epithelial cells. PMID- 22496419 TI - The C-terminal domain of Fcj1 is required for formation of crista junctions and interacts with the TOB/SAM complex in mitochondria. AB - Crista junctions (CJs) are tubular invaginations of the inner membrane of mitochondria that connect the inner boundary with the cristae membrane. These architectural elements are critical for mitochondrial function. The yeast inner membrane protein Fcj1, called mitofilin in mammals, was reported to be preferentially located at CJs and crucial for their formation. Here we investigate the functional roles of individual domains of Fcj1. The most conserved part of Fcj1, the C-terminal domain, is essential for Fcj1 function. In its absence, formation of CJ is strongly impaired and irregular, and stacked cristae are present. This domain interacts with full-length Fcj1, suggesting a role in oligomer formation. It also interacts with Tob55 of the translocase of outer membrane beta-barrel proteins (TOB)/sorting and assembly machinery (SAM) complex, which is required for the insertion of beta-barrel proteins into the outer membrane. The association of the TOB/SAM complex with contact sites depends on the presence of Fcj1. The biogenesis of beta-barrel proteins is not significantly affected in the absence of Fcj1. However, down-regulation of the TOB/SAM complex leads to altered cristae morphology and a moderate reduction in the number of CJs. We propose that the C-terminal domain of Fcj1 is critical for the interaction of Fcj1 with the TOB/SAM complex and thereby for stabilizing CJs in close proximity to the outer membrane. These results assign novel functions to both the C-terminal domain of Fcj1 and the TOB/SAM complex. PMID- 22496420 TI - An interdomain binding site on HIV-1 Nef interacts with PACS-1 and PACS-2 on endosomes to down-regulate MHC-I. AB - The human immunodeficiency virus type 1 (HIV-1) accessory protein Nef directs virus escape from immune surveillance by subverting host cell intracellular signaling and membrane traffic to down-regulate cell-surface major histocompatibility complex class I (MHC-I). The interaction of Nef with the sorting proteins PACS-1 and PACS-2 mediates key signaling and trafficking steps required for Nef-mediated MHC-I down-regulation. Little is known, however, about the molecular basis underlying the Nef-PACS interaction. Here we identify the sites on Nef and the PACS proteins required for their interaction and describe the consequences of disrupting this interaction for Nef action. A previously unidentified cargo subsite on PACS-1 and PACS-2 interacted with a bipartite site on Nef formed by the EEEE(65) acidic cluster on the N-terminal domain and W(113) in the core domain. Mutation of these sites prevented the interaction between Nef and the PACS proteins on Rab5 (PACS-2 and PACS-1)- or Rab7 (PACS-1)-positive endosomes as determined by bimolecular fluorescence complementation and caused a Nef mutant defective in PACS binding to localize to distorted endosomal compartments. Consequently, disruption of the Nef-PACS interaction repressed Nef induced MHC-I down-regulation in peripheral blood mononuclear cells. Our results provide insight into the molecular basis of Nef action and suggest new strategies to combat HIV-1. PMID- 22496421 TI - Lamin B1 loss is a senescence-associated biomarker. AB - Cellular senescence is a potent tumor-suppressive mechanism that arrests cell proliferation and has been linked to aging. However, studies of senescence have been impeded by the lack of simple, exclusive biomarkers of the senescent state. Senescent cells develop characteristic morphological changes, which include enlarged and often irregular nuclei and chromatin reorganization. Because alterations to the nuclear lamina can affect both nuclear morphology and gene expression, we examined the nuclear lamina of senescent cells. We show here than lamin B1 is lost from primary human and murine cell strains when they are induced to senesce by DNA damage, replicative exhaustion, or oncogene expression. Lamin B1 loss did not depend on the p38 mitogen-activated protein kinase, nuclear factor-kappaB, ataxia telangiectasia-mutated kinase, or reactive oxygen species signaling pathways, which are positive regulators of senescent phenotypes. However, activation of either the p53 or pRB tumor suppressor pathway was sufficient to induce lamin B1 loss. Lamin B1 declined at the mRNA level via a decrease in mRNA stability rather than by the caspase-mediated degradation seen during apoptosis. Last, lamin B1 protein and mRNA declined in mouse tissue after senescence was induced by irradiation. Our findings suggest that lamin B1 loss can serve as biomarker of senescence both in culture and in vivo. PMID- 22496422 TI - NHERF1 acts as a molecular switch to program metastatic behavior and organotropism via its PDZ domains. AB - Metastatic cells are highly plastic for differential expression of tumor phenotype hallmarks and metastatic organotropism. The signaling proteins orchestrating the shift of one cell phenotype and organ pattern to another are little known. Na(+)/H(+) exchanger regulatory factor (NHERF1) is a molecular pathway organizer, PDZ-domain protein that recruits membrane, cytoplasmic, and cytoskeletal signaling proteins into functional complexes. To gain insight into the role of NHERF1 in metastatic progression, we stably transfected a metastatic breast cell line, MDA-MB-231, with an empty vector, with wild-type NHERF1, or with NHERF1 mutated in either the PDZ1- or PDZ2-binding domains to block their binding activities. We observed that NHERF1 differentially regulates the expression of two phenotypic programs through its PDZ domains, and these programs form the mechanistic basis for metastatic organotropism. The PDZ2 domain promotes visceral metastases via increased invadopodia-dependent invasion and anchorage independent growth, as well as by inhibition of apoptosis, whereas the PDZ1 domain promotes bone metastases by stimulating podosome nucleation, motility, neoangiogenesis, vasculogenic mimicry, and osteoclastogenesis in the absence of increased growth or invasion. Collectively, these findings identify NHERF1 as an important signaling nexus for coordinating cell structure with metastatic behavior and identifies the "mesenchymal-to-vasculogenic" phenotypic transition as an essential step in metastatic progression. PMID- 22496423 TI - Expression of the inclusion body myopathy 3 mutation in Drosophila depresses myosin function and stability and recapitulates muscle inclusions and weakness. AB - Hereditary myosin myopathies are characterized by variable clinical features. Inclusion body myopathy 3 (IBM-3) is an autosomal dominant disease associated with a missense mutation (E706K) in the myosin heavy chain IIa gene. Adult patients experience progressive muscle weakness. Biopsies reveal dystrophic changes, rimmed vacuoles with cytoplasmic inclusions, and focal disorganization of myofilaments. We constructed a transgene encoding E706K myosin and expressed it in Drosophila (E701K) indirect flight and jump muscles to establish a novel homozygous organism with homogeneous populations of fast IBM-3 myosin and muscle fibers. Flight and jump abilities were severely reduced in homozygotes. ATPase and actin sliding velocity of the mutant myosin were depressed >80% compared with wild-type myosin. Light scattering experiments and electron microscopy revealed that mutant myosin heads bear a dramatic propensity to collapse and aggregate. Thus E706K (E701K) myosin appears far more labile than wild-type myosin. Furthermore, mutant fly fibers exhibit ultrastructural hallmarks seen in patients, including cytoplasmic inclusions containing aberrant proteinaceous structures and disorganized muscle filaments. Our Drosophila model reveals the unambiguous consequences of the IBM-3 lesion on fast muscle myosin and fibers. The abnormalities observed in myosin function and muscle ultrastructure likely contribute to muscle weakness observed in our flies and patients. PMID- 22496426 TI - Breast leukemia: an update. AB - BACKGROUND: Breast leukemia is extremely rare. The published data on this manifestation include predominantly case reports and do not provide any statistical information. PURPOSE: To identify clinical signs and radiological features of breast leukemia. MATERIAL AND METHODS: PubMed and Medline databases between 1980 and 2010 were screened using 'breast leukemia' and 'leukemia of the breast' as keywords. Secondary references were also reviewed. By this search, a total of 139 patients were identified from the literature. RESULTS: In most patients (n = 85, 61.2%) acute myeloid leukemia was diagnosed. Acute lymphatic leukemia occurred in 35 patients (25.2%). Isolated BL before bone marrow infiltration was seen in 24 patients (17.3%). Involvement of the breast during the course of leukemia was diagnosed in 25 cases (18%). Intramammary leukemic relapse after therapy/stem cell transplantation occurred in 59 patients (42.4%). In 71 cases (51.1%) the lesions were solitary and in 57 (41%) multiple. The number of lesions was not reported in 11 patients (7.9%). There was no significant difference between the number of lesions in ML and LL. Clinically, 73% of the patients presented with palpable breast masses. Most of them were painless. Mammography was performed in 39 patients, allowing the identification of the following three mammographic patterns: breast masses (28 patients, 72%), architectural distortion (5 patients, 13%), no abnormalities (6 patients, 15%). On ultrasound, most identified masses were homogeneously hypoechoic with microlobulated or indistinct margins. On MRI, on T2-weighted images breast lesions were hyperintense. After venous administration of contrast medium, BL showed marked inhomogeneous contrast enhancement. Treatment of BL is the same as for other localizations and is based on chemotherapy and/or radiotherapy. CONCLUSION: In the present study the clinical and radiological features of BL are described. They are non-specific. However, BL should be considered in the differential diagnosis of breast disorders, especially in patients with leukemia. PMID- 22496424 TI - Vitamin K epoxide reductase contributes to protein disulfide formation and redox homeostasis within the endoplasmic reticulum. AB - The transfer of oxidizing equivalents from the endoplasmic reticulum (ER) oxidoreductin (Ero1) oxidase to protein disulfide isomerase is an important pathway leading to disulfide formation in nascent proteins within the ER. However, Ero1-deficient mouse cells still support oxidative protein folding, which led to the discovery that peroxiredoxin IV (PRDX4) catalyzes a parallel oxidation pathway. To identify additional pathways, we used RNA interference in human hepatoma cells and evaluated the relative contributions to oxidative protein folding and ER redox homeostasis of Ero1, PRDX4, and the candidate oxidants quiescin-sulfhydryl oxidase 1 (QSOX1) and vitamin K epoxide reductase (VKOR). We show that Ero1 is primarily responsible for maintaining cell growth, protein secretion, and recovery from a reductive challenge. We further show by combined depletion with Ero1 that PRDX4 and, for the first time, VKOR contribute to ER oxidation and that depletion of all three activities results in cell death. Of importance, Ero1, PRDX4, or VKOR was individually capable of supporting cell viability, secretion, and recovery after reductive challenge in the near absence of the other two activities. In contrast, no involvement of QSOX1 in ER oxidative processes could be detected. These findings establish VKOR as a significant contributor to disulfide bond formation within the ER. PMID- 22496425 TI - Autophagy modulates dynamics of connexins at the plasma membrane in a ubiquitin dependent manner. AB - Different pathways contribute to the turnover of connexins, the main structural components of gap junctions (GJs). The cellular pool of connexins targeted to each pathway and the functional consequences of degradation through these degradative pathways are unknown. In this work, we focused on the contribution of macroautophagy to connexin degradation. Using pharmacological and genetic blockage of macroautophagy both in vitro and in vivo, we found that the cellular pool targeted by this autophagic system is primarily the one organized into GJs. Interruption of connexins' macroautophagy resulted in their retention at the plasma membrane in the form of functional GJs and subsequent increased GJ mediated intercellular diffusion. Up-regulation of macroautophagy alone is not sufficient to induce connexin internalization and degradation. To better understand what factors determine the autophagic degradation of GJ connexins, we analyzed the changes undergone by the fraction of plasma membrane connexin 43 targeted for macroautophagy and the sequence of events that trigger this process. We found that Nedd4-mediated ubiquitinylation of the connexin molecule is required to recruit the adaptor protein Eps15 to the GJ and to initiate the autophagy-dependent internalization and degradation of connexin 43. This study reveals a novel regulatory role for macroautophagy in GJ function that is directly dependent on the ubiquitinylation of plasma membrane connexins. PMID- 22496427 TI - Diffusion-weighted MRI in renal cell carcinoma: a surrogate marker for predicting nuclear grade and histological subtype. AB - BACKGROUND: Though previous investigators have attempted to evaluate its utility in characterization of focal renal lesions, diffusion-weighted MR imaging (DW MRI) in renal diseases is still an evolving field and its role in predicting the aggressiveness of renal cell carcinoma (RCC) is yet to be established. PURPOSE: To assess whether apparent diffusion coefficient (ADC) values can be used to determine the nuclear grade and histological subtype of RCCs and to identify the tumor attributes contributing to variation in ADC values. MATERIAL AND METHODS: The institutional ethics committee waived the requirement of informed consent for this retrospective study. The study cohort consisted of 33 patients who underwent MRI (with diffusion-weighted imaging at b values of 0 and 500 s/mm(2)) and were found to have 36 pathologically-proven RCCs. ADC values were determined for solid portions of RCC, cystic/hemorrhagic areas, and normal renal parenchyma. Histological subtype, nuclear grade, and cell count were determined for each lesion. ADC values were compared between different grades and subtypes and correlation with cell count was investigated. Receiver operating characteristic curves were drawn to establish cut-off ADC values. RESULTS: There were 23 low grade (grades I and II) and 13 high grade tumors (grades III and IV). There were 32 clear-cell and four non-clear-cell RCCs. A decreasing trend of ADC values was seen with increasing grade and mean ADC of high grade RCC was significantly lower than low grade (1.3145 vs 1.6982 * 10(-3) mm(2)/s) (P = 0.005). Mean ADC for clear-cell RCC was significantly higher than non-clear-cell RCC (1.6245 vs. 1.0412 * 10(-3) mm(2)/s) (P = 0.005). ADC values higher than 1.7960 * 10(-3) mm(2)/s were seen only with low grade and values greater than 1.4904 * 10(-3) mm(2)/s were seen only with clear-cell RCC. CONCLUSION: ADC values provide a non invasive means to predict the nuclear grade and histological subtype of RCC. Cellularity and morphology are other tumor attributes contributing to the variation in ADC values of RCCs. PMID- 22496428 TI - Multidetector computed tomography virtual bronchoscopy: comparison with fiberoptic bronchoscopy. PMID- 22496430 TI - Morin exerts antiosteoarthritic properties: an in vitro and in vivo study. AB - Morin is a flavonoid isolated from members of the Moraceae family. Morin has been reported to possess antioxidative and anticarcinogenic activities. However, the antiosteoarthritic properties of morin have not been investigated. In this study, we evaluate the antiarthritic properties of morin through in vitro and in vivo studies. We examined the effects of morin on the expression levels of matrix metalloproteinase (MMP)-3, MMP-13 and tissue inhibitors of metalloproteinase (TIMP)-1 in interleukin-1beta (IL-1beta)-induced rat chondrocytes by realtime polymerase chain reaction and Western blotting. The effects of morin on the phosphorylation of mitogen-activated protein kinases were also investigated. The in vivo antiosteoarthritic effects of morin were evaluated in the rat model of anterior cruciate ligament transection (ACLT)-induced osteoarthritis (OA). We found that morin inhibited the expression of MMP-3 and MMP-13 and increased the expression of TIMP-1 in IL-1beta-induced rat chondrocytes. In addition, morin inhibited IL-1beta-induced phosphorylation of extracellular signal-regulated kinase and p38. For the in vivo study in a rat model of OA induced by ACLT, in which morin was orally administered to rat, the results show that morin suppressed cartilage degradation. Our results suggest that morin may be considered as a possible therapeutic agent for the treatment of OA. PMID- 22496431 TI - Osteogenic activity of silymarin through enhancement of alkaline phosphatase and osteocalcin in osteoblasts and tibia-fractured mice. AB - Bone-remodeling imbalance induced by increased bone resorption and osteoclast formation is known to cause skeletal diseases such as osteoporosis. There has been growing interest in the anabolic natural agents that enhance bone formation. Silymarin is flavonolignans extracted from blessed milk thistle. Several studies suggest that silymarin possesses antihepatotoxic properties and anticancer effects against carcinoma cells. This study investigated promoting effects of silymarin on differentiation and mineralization of osteoblastic MC3T3-E1 mouse cells and on bone mineral density (BMD) by in vivo fracture experiments. Osteoblasts were treated with 1-20 MUmol/L silymarin for 15 days in a differentiating medium. In addition, this study explored signaling pathways implicated in the osteoblastogenesis of silymarin. It was found that silymarin stimulated alkaline phosphatase (ALP) activity and calcium nodule formation in a dose-dependent manner with a substantial effect on osteoblast proliferation. Silymarin treatment enhanced collagen secretion, osteocalcin transcription and bone morphogenetic protein (BMP) expression. The BMP inhibitor noggin suppressed the silymarin-promoted ALP activity in differentiated osteoblasts, suggesting that its osteoblastogenic actions entail the BMP pathway. This was proved by increased SMAD1/5/8 phosphorylation and runt-related transcription factor 2 (Runx2) expression in the presence of silymarin. In 21-day fracture-healing experiments, fractured and silymarin (10 mg/kg)-treated C57BL/6 mice showed better bone healing than fractured mice. Silymarin supplementation improved tibial bone strength with elevated BMD and serum levels of osteogenic ALP and osteocalcin. Taken together, these results demonstrate, for the first time, that silymarin has a potential to enhance osteoblastogenesis through accelerating BMP/SMAD/Runx2 signal pathways and to improve fracture healing and bone strength in mouse tibiae. PMID- 22496433 TI - Where should the IOL go when it does not go where it should? PMID- 22496434 TI - Pregnancy may trigger late onset of keratectasia after LASIK. PMID- 22496435 TI - Interface fluid syndrome associated with cataract surgery. PMID- 22496436 TI - Rotationally asymmetric multifocal IOL implantation with and without capsular tension ring: refractive and visual outcomes and intraocular optical performance. AB - PURPOSE: To ascertain whether the refractive, visual, and intraocular optical quality outcomes of a rotationally asymmetric multifocal intraocular lens (IOL) are enhanced by the use of a capsular tension ring. METHODS: Ninety consecutive eyes from 53 patients (age range: 36 to 82 years) were divided into two groups: the no ring group comprised 43 eyes implanted with the multifocal rotationally asymmetric Lentis Mplus LS-312 (Oculentis GmbH) without a capsular tension ring; and the ring group comprised 47 eyes with the same IOL with a capsular tension ring. Distance and near visual acuity and refractive outcomes were evaluated pre- and postoperatively. Contrast sensitivity, intraocular aberrations, and defocus curve were evaluated postoperatively. RESULTS: Significant postoperative differences between groups were found in sphere, spherical equivalent refraction, and near addition (P<.02). Regarding defocus curve, significantly better visual acuity was present in eyes with the capsular tension ring for intermediate vision conditions (P<.05). Intraocular aberrometry did not differ significantly between groups (P<.09). CONCLUSIONS: Refractive predictability and intermediate visual outcomes with the Lentis Mplus LS-312 IOL improved significantly when implanted in combination with a capsular tension ring. PMID- 22496437 TI - Intraocular lens tilt and decentration measured by Scheimpflug camera following manual or femtosecond laser-created continuous circular capsulotomy. AB - PURPOSE: To compare intraocular lens (IOL) decentration and tilt following a circular capsulotomy created with a femtosecond laser (laser CCC) to a manually performed continuous curvilinear capsulorrhexis (manual CCC). METHODS: In a prospective, randomized study, a laser CCC (Alcon LenSx Inc) was performed in 20 eyes from 20 patients and a manual CCC was performed in 25 eyes from 25 patients. Intraocular lens decentration and tilt were measured using a Scheimpflug camera (Pentacam, Oculus Optikgerate GmbH) 1 year after surgery. Uncorrected (UDVA) and corrected distance visual acuity (CDVA) and manifest refraction were also determined postoperatively. Between-group differences of IOL decentration and tilt as well as the correlation between IOL decentration and postoperative refractive changes and between IOL tilt and visual acuity were analyzed. RESULTS: Horizontal and vertical tilt were significantly higher in the manual CCC group (P=.007 and P<.001, respectively). Lenses implanted after manual CCC showed greater horizontal and total decentration (P=.034 and P=.022, respectively). Significant differences were found in the homogeneity of dichotomized IOL vertical tilt and both horizontal and total decentration distribution (P=.008, P=.036, and P=.017, respectively). Total IOL decentration showed a significant correlation with changes in manifest refraction values between 1 month and 1 year after surgery (R=0.33, P=.032). A significant correlation was noted between IOL vertical tilt and CDVA (R(2)=0.17, beta=-0.41, 95% confidence limit: -0.69 to 0.13, P=.005). CONCLUSIONS: Continuous curvilinear capsulorrhexis created with a femtosecond laser resulted in a more stable refractive result and less IOL tilt and decentration than manual CCC. PMID- 22496438 TI - The history of LASIK. AB - Keratomileusis, brainchild of Jose I. Barraquer Moner, was conceived and developed as the first stromal sculpting method to correct refractive error in 1948. The word "keratomileusis" literally means "sculpting" of the "cornea." Barraquer's first procedures involved freezing a disc of anterior corneal tissue before removing stromal tissue with a lathe. Over the years, the procedure continued to develop, first through the Barraquer-Krumeich-Swinger non-freeze technique where tissue was removed from the underside of the disc by a second pass of the microkeratome. In-situ keratomileusis was later developed by passing the microkeratome a second time directly on the stromal bed. The procedure became known as automated lamellar keratoplasty with the invention of an automated microkeratome and was further refined by replacing the disc without sutures and later by stopping the microkeratome before the end of the pass to create a hinged flap, as first demonstrated in 1989. The history of the excimer laser dates back to 1900 and the quantum theory, eventually leading to the discovery that 193-nm ultraviolet excimer laser pulses could photoablate tissue without thermal damage. Ultrastructural and wound healing studies confirmed that large area ablation could be performed in the central cornea. This was described as photorefractive keratectomy in 1986 and the first sighted eyes were treated in 1988. An excimer laser was first used to sculpt from the stromal bed under a hinged flap created manually using a trephine and scalpel in 1988. The incorporation of a microkeratome in 1990 finally led to laser in situ keratomileusis-LASIK-as we know it today. PMID- 22496439 TI - A "neural" enzyme in nonbilaterian animals and algae: preneural origins for peptidylglycine alpha-amidating monooxygenase. AB - Secreted peptides, produced by enzymatic processing of larger precursor molecules, are found throughout the animal kingdom and play important regulatory roles as neurotransmitters and hormones. Many require a carboxy-terminal modification, involving the conversion of a glycine residue into an alpha-amide, for their biological activity. Two sequential enzymatic activities catalyze this conversion: a monooxygenase (peptidylglycine alpha-hydroxylating monooxygenase or PHM) and an amidating lyase (peptidyl-alpha-hydroxyglycine alpha-amidating lyase or PAL). In vertebrates, these activities reside in a single polypeptide known as peptidylglycine alpha-amidating monooxygenase (PAM), which has been extensively studied in the context of neuropeptide modification. Bifunctional PAMs have been reported from some invertebrates, but the phylogenetic distribution of PAMs and their evolutionary relationship to PALs and PHMs is unclear. Here, we report sequence and expression data for two PAMs from the coral Acropora millepora (Anthozoa, Cnidaria), as well as providing a comprehensive survey of the available sequence data from other organisms. These analyses indicate that bifunctional PAMs predate the origins of the nervous and endocrine systems, consistent with the idea that within the Metazoa their ancestral function may have been to amidate epitheliopeptides. More surprisingly, the phylogenomic survey also revealed the presence of PAMs in green algae (but not in higher plants or fungi), implying that the bifunctional enzyme either predates the plant/animal divergence and has subsequently been lost in a number of lineages or perhaps that convergent evolution or lateral gene transfer has occurred. This finding is consistent with recent discoveries that other molecules once thought of as "neural" predate nervous systems. PMID- 22496441 TI - Drugs for type 2 diabetes mellitus: the imperative for cardiovascular outcome assessment. PMID- 22496440 TI - A voxel-based lesion study on facial emotion recognition after penetrating brain injury. AB - The ability to read emotions in the face of another person is an important social skill that can be impaired in subjects with traumatic brain injury (TBI). To determine the brain regions that modulate facial emotion recognition, we conducted a whole-brain analysis using a well-validated facial emotion recognition task and voxel-based lesion symptom mapping (VLSM) in a large sample of patients with focal penetrating TBIs (pTBIs). Our results revealed that individuals with pTBI performed significantly worse than normal controls in recognizing unpleasant emotions. VLSM mapping results showed that impairment in facial emotion recognition was due to damage in a bilateral fronto-temporo-limbic network, including medial prefrontal cortex (PFC), anterior cingulate cortex, left insula and temporal areas. Beside those common areas, damage to the bilateral and anterior regions of PFC led to impairment in recognizing unpleasant emotions, whereas bilateral posterior PFC and left temporal areas led to impairment in recognizing pleasant emotions. Our findings add empirical evidence that the ability to read pleasant and unpleasant emotions in other people's faces is a complex process involving not only a common network that includes bilateral fronto-temporo-limbic lobes, but also other regions depending on emotional valence. PMID- 22496442 TI - GLP-1 receptor agonists: a clinical perspective on cardiovascular effects. AB - The active incretin hormone glucagon-like peptide-1(7-36)amide (GLP-1) is a 30 amino acid peptide that exerts glucoregulatory and insulinotropic actions by functioning as an agonist for the GLP-1 receptor (GLP-1R). In addition to its anti-diabetic effects, GLP-1 has demonstrated cardioprotective actions. Here we review the cardiovascular effects of the GLP-1 analogues currently approved for the treatment of type 2 diabetes, namely exenatide and liraglutide. We discuss their anti-hyperglycaemic efficacy, and offer a clinical perspective of their effects on cardiovascular risk factors such as body weight, blood pressure, heart rate and lipid profiles, as well as their potential consequences on cardiovascular events, such as arrhythmias, heart failure, myocardial infarction and death. Lastly, we briefly review additional GLP-1R agonists in clinical development. PMID- 22496443 TI - Structurally conserved Nop56/58 N-terminal domain facilitates archaeal box C/D ribonucleoprotein-guided methyltransferase activity. AB - Box C/D RNA-protein complexes (RNPs) guide the 2'-O-methylation of nucleotides in both archaeal and eukaryotic ribosomal RNAs. The archaeal box C/D and C'/D' RNP subcomplexes are each assembled with three sRNP core proteins. The archaeal Nop56/58 core protein mediates crucial protein-protein interactions required for both sRNP assembly and the methyltransferase reaction by bridging the L7Ae and fibrillarin core proteins. The interaction of Methanocaldococcus jannaschii (Mj) Nop56/58 with the methyltransferase fibrillarin has been investigated using site directed mutagenesis of specific amino acids in the N-terminal domain of Nop56/58 that interacts with fibrillarin. Extensive mutagenesis revealed an unusually strong Nop56/58-fibrillarin interaction. Only deletion of the NTD itself prevented dimerization with fibrillarin. The extreme stability of the Nop56/58 fibrillarin heterodimer was confirmed in both chemical and thermal denaturation analyses. However, mutations that did not affect Nop56/58 binding to fibrillarin or sRNP assembly nevertheless disrupted sRNP-guided nucleotide modification, revealing a role for Nop56/58 in methyltransferase activity. This conclusion was supported with the cross-linking of Nop56/58 to the target RNA substrate. The Mj Nop56/58 NTD was further characterized by solving its three-dimensional crystal structure to a resolution of 1.7 A. Despite low primary sequence conservation among the archaeal Nop56/58 homologs, the overall structure of the archaeal NTD domain is very well conserved. In conclusion, the archaeal Nop56/58 NTD exhibits a conserved domain structure whose exceptionally stable interaction with fibrillarin plays a role in both RNP assembly and methyltransferase activity. PMID- 22496444 TI - Identification of a conserved interface between PUF and CPEB proteins. AB - Members of the PUF (Pumilio and FBF) and CPEB (cytoplasmic polyadenylation element-binding) protein families collaborate to regulate mRNA expression throughout eukaryotes. Here, we focus on the physical interactions between members of these two families, concentrating on Caenorhabditis elegans FBF-2 and CPB-1. To localize the site of interaction on FBF-2, we identified conserved amino acids within C. elegans PUF proteins. Deletion of an extended loop containing several conserved residues abolished binding to CPB-1. We analyzed alanine substitutions at 13 individual amino acids in FBF-2, each identified via its conservation. Multiple single point mutations disrupted binding to CPB-1 but not to RNA. Position Tyr-479 was particularly critical as multiple substitutions to other amino acids at this position did not restore binding. The complex of FBF 2 and CPB-1 repressed translation of an mRNA containing an FBF binding element. Repression required both proteins and was disrupted by FBF-2 alleles that failed to bind CPB-1 or RNA. The equivalent loop in human PUM2 is required for binding to human CPEB3 in vitro, although the primary sequences of the human and C. elegans PUF proteins have diverged in that region. Our findings define a key region in PUF/CPEB interactions and imply a conserved platform through which PUF proteins interact with their protein partners. PMID- 22496445 TI - Identification of intercellular cell adhesion molecule 1 (ICAM-1) as a hypoglycosylation marker in congenital disorders of glycosylation cells. AB - Many human inherited disorders cause protein N-glycosylation defects, but there are few cellular markers to test gene complementation for such defects. Plasma membrane glycoproteins are potential biomarkers because they may be reduced or even absent in plasma membranes of glycosylation-deficient cells. We combined stable isotope labeling by amino acids in cell culture (SILAC) with linear ion trap mass spectrometry (LTQ Orbitrap(TM)) to identify and quantify membrane proteins from wild-type CHO and glycosylation-deficient CHO (Lec9) cells. We identified 165 underrepresented proteins from 1447 unique quantified proteins, including 18 N-glycosylated plasma membrane proteins. Using various methods, we found that intercellular cell adhesion molecule 1 (ICAM-1) was reduced in Lec9 cells and in fibroblasts from 31 congenital disorder of glycosylation (CDG) patients compared with normal controls. Mannose supplementation of phosphomannose isomerase-deficient CDG-Ib (MPI-CDG) cells and complementation with PMM2 in PMM2 deficient CDG-Ia (PMM2-CDG) cells partially corrected hypoglycosylation based on increased ICAM-1 presence on the plasma membrane. These data indicate that ICAM-1 could be a useful hypoglycosylation biomarker to assess gene complementation of CDG-I patient cells and to monitor improved glycosylation in response to therapeutic drugs. PMID- 22496446 TI - Site-specific phosphorylation protects glycogen synthase kinase-3beta from calpain-mediated truncation of its N and C termini. AB - Glycogen synthase kinase-3beta (GSK-3beta), a key regulator of neuronal apoptosis, is inhibited by the phosphorylation of Ser-9/Ser-389 and was recently shown to be cleaved by calpain at the N terminus, leading to its subsequent activation. In this study calpain was found to cleave GSK-3beta not only at the N terminus but also at the C terminus, and cleavage sites were identified at residues Thr-38-Thr-39 and Ile-384-Gln-385. Furthermore, the cleavage of GSK 3beta occurred in tandem with Ser-9 dephosphorylation during cerebellar granule neuron apoptosis. Increasing Ser-9 phosphorylation of GSK-3beta by inhibiting phosphatase 1/2A or pretreating with purified active Akt inhibited calpain mediated cleavage of GSK-3beta at both N and C termini, whereas non phosphorylatable mutant GSK-3beta S9A facilitated its cleavage. In contrast, Ser 389 phosphorylation selectively inhibited the cleavage of GSK-3beta at the C terminus but not the N terminus. Calpain-mediated cleavage resulted in three truncated products, all of which contained an intact kinase domain: DeltaN-GSK 3beta (amino acids 39-420), DeltaC-GSK-3beta (amino acids 1-384), and DeltaN/DeltaC-GSK-3beta (amino acids 39-384). All three truncated products showed increased kinase and pro-apoptotic activity, with DeltaN/DeltaC-GSK-3beta being the most active form. This observation suggests that the GSK-3beta C terminus acts as an autoinhibitory domain similar to the N terminus. Taken together, these findings demonstrate that calpain-mediated cleavage activates GSK-3beta by removing its N- and C-terminal autoinhibitory domains and that Ser-9 phosphorylation inhibits the cleavage of GSK-3beta at both termini. In contrast, Ser-389 phosphorylation inhibits only C-terminal cleavage but not N-terminal cleavage. These findings also identify a mechanism by which site-specific phosphorylation and calpain-mediated cleavage operate in concert to regulate GSK 3beta activity. PMID- 22496447 TI - Invariant gly residue is important for alpha-defensin folding, dimerization, and function: a case study of the human neutrophil alpha-defensin HNP1. AB - The human alpha-defensins (HNP) are synthesized in vivo as inactive prodefensins, and contain a conserved glycine, Gly(17), which is part of a beta-bulge structure. It had previously been shown that the glycine main chain torsion angles are in a D-configuration, and that d-amino acids but not L-alanine could be substituted at that position to yield correctly folded peptides without the help of a prodomain. In this study, the glycine to L-alanine mutant defensin was synthesized in the form of a prodefensin using native chemical ligation. The ligation product folded correctly and yielded an active peptide upon CNBr cleavage. The L-Ala(17)-HNP1 crystal structure depicted a beta-bulge identical to wild-type HNP1. However, dimerization was perturbed, causing one monomer to tilt with respect to the other in a dimerization model. Inhibitory activity against the anthrax lethal factor showed a 2-fold reduction relative to wild-type HNP1 as measured by the inhibitory concentration IC(50). Self-association was slightly reduced, as detected by surface plasmon resonance measurements. According to the results of the virtual colony count assay, the antibacterial activity against Escherichia coli, Staphylococcus aureus, and Bacillus cereus exhibited a less than 2-fold reduction in virtual lethal dose values. Prodefensins with two other L-amino acid substitutions, Arg and Phe, at the same position did not fold, indicating that only small side chains are tolerable. These results further elucidate the factors governing the region of the beta-bulge structure that includes Gly(17), illuminating why glycine is conserved in all mammalian alpha defensins. PMID- 22496448 TI - Sorting of the yeast vacuolar-type, proton-translocating ATPase enzyme complex (V ATPase): identification of a necessary and sufficient Golgi/endosomal retention signal in Stv1p. AB - Subunit a of the yeast vacuolar-type, proton-translocating ATPase enzyme complex (V-ATPase) is responsible for both proton translocation and subcellular localization of this highly conserved molecular machine. Inclusion of the Vph1p isoform causes the V-ATPase complex to traffic to the vacuolar membrane, whereas incorporation of Stv1p causes continued cycling between the trans-Golgi and endosome. We previously demonstrated that this targeting information is contained within the cytosolic, N-terminal portion of V-ATPase subunit a (Stv1p). To identify residues responsible for sorting of the Golgi isoform of the V-ATPase, a random mutagenesis was performed on the N terminus of Stv1p. Subsequent characterization of mutant alleles led to the identification of a short peptide sequence, W(83)KY, that is necessary for proper Stv1p localization. Based on three-dimensional homology modeling to the Meiothermus ruber subunit I, we propose a structural model of the intact Stv1p-containing V-ATPase demonstrating the accessibility of the W(83)KY sequence to retrograde sorting machinery. Finally, we characterized the sorting signal within the context of a reconstructed Stv1p ancestor (Anc.Stv1). This evolutionary intermediate includes an endogenous W(83)KY sorting motif and is sufficient to compete with sorting of the native yeast Stv1p V-ATPase isoform. These data define a novel sorting signal that is both necessary and sufficient for trafficking of the V-ATPase within the Golgi/endosomal network. PMID- 22496449 TI - Expression of microphthalmia-associated transcription factor (MITF), which is critical for melanoma progression, is inhibited by both transcription factor GLI2 and transforming growth factor-beta. AB - The melanocyte-specific transcription factor M-MITF is involved in numerous aspects of melanoblast lineage biology including pigmentation, survival, and migration. It plays complex roles at all stages of melanoma progression and metastasis. We established previously that GLI2, a Kruppel-like transcription factor that acts downstream of Hedgehog signaling, is a direct transcriptional target of the TGF-beta/SMAD pathway and contributes to melanoma progression, exerting antagonistic activities against M-MITF to control melanoma cell invasiveness. Herein, we dissected the molecular mechanisms underlying both TGF beta and GLI2-driven M-MITF gene repression. Using transient cell transfection experiments with M-MITF promoter constructs, chromatin immunoprecipitation, site directed mutagenesis, and electrophoretic mobility shift assays, we identified a GLI2 binding site within the -334/-296 region of the M-MITF promoter, critical for GLI2-driven transcriptional repression. This region is, however, not needed for inhibition of M-MITF promoter activity by TGF-beta. We determined that TGF beta rapidly repressed protein kinase A activity, thus reducing both phospho-cAMP response element-binding protein (CREB) levels and CREB-dependent transcription of the M-MITF promoter. Increased GLI2 binding to its cognate cis-element, associated with reduced CREB-dependent transcription, allowed maximal inhibition of the M-MITF promoter via two distinct mechanisms. PMID- 22496450 TI - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces death receptor 5 networks that are highly organized. AB - Recent evidence suggests that TNF-related apoptosis-inducing ligand (TRAIL), a death-inducing cytokine with anti-tumor potential, initiates apoptosis by re organizing TRAIL receptors into large clusters, although the structure of these clusters and the mechanism by which they assemble are unknown. Here, we demonstrate that TRAIL receptor 2 (DR5) forms receptor dimers in a ligand dependent manner at endogenous receptor levels, and these receptor dimers exist within high molecular weight networks. Using mutational analysis, FRET, fluorescence microscopy, synthetic biochemistry, and molecular modeling, we find that receptor dimerization relies upon covalent and noncovalent interactions between membrane-proximal residues. Additionally, by using FRET, we show that the oligomeric structure of two functional isoforms of DR5 is indistinguishable. The resulting model of DR5 activation should revise the accepted architecture of the functioning units of DR5 and the structurally homologous TNF receptor superfamily members. PMID- 22496451 TI - Genetic screening for regulators of Prz1, a transcriptional factor acting downstream of calcineurin in fission yeast. AB - Calcineurin phosphatase plays crucial roles in a wide variety of cell types and organisms. Dephosphorylation of the nuclear factor of activated T-cell (NFAT) family of transcriptional factors by calcineurin is essential for activating immune-responsive genes in mammals. NFAT activity is also regulated by diverse signaling pathways, which affect NFAT kinases and nuclear partner proteins. In fission yeast, calcineurin dephosphorylates and activates Prz1, a C2H2-type zinc finger transcriptional factor. Calcineurin-Prz1 signaling regulates the expression of the Pmc1 Ca(2+) pump. Prz1-overexpressing cells showed extremely slow growth and high transcriptional activity of Prz1 in the absence of stimulation. Here, we isolated seven genes as dosage-dependent suppressors of this slow growth phenotype. These seven genes encode Rad24, Rad25, Pka1, Msn5 (SPAC328.01c), Pac1, Ape2, and Tfs1. All of them decreased the high transcriptional activity caused by Prz1 overexpression. Overexpression of Pka1, Rad24, and Rad25 also repressed the Ca(2+)-induced transcriptional activity in cells with Prz1 expressed at wild-type levels. Knock-out of rad24 or rad25 significantly enhanced the transcriptional activity of Prz1, whereas knock-out or mutation of other genes did not enhance the activity. The 14-3-3 proteins, Rad24 and Rad25, bound Prz1 and the Rad24-binding site located at residues 421-426 of Prz1. In msn5 deletion mutants, GFP-Prz1 localized at nucleus in the absence of Ca(2+) stimulation, suggesting that Msn5 functions as an exportin for Prz1. In summary, our data suggest that Rad24 and Rad25 negatively regulate Prz1 and that Pka1, Msn5, Pac1, Tfs1, and Ape2 also regulate Prz1. PMID- 22496452 TI - High motility of triple-negative breast cancer cells is due to repression of plakoglobin gene by metastasis modulator protein SLUG. AB - One of highly pathogenic breast cancer cell types are the triple negative (negative in the expression of estrogen, progesterone, and ERBB2 receptors) breast cancer cells. These cells are highly motile and metastatic and are characterized by high levels of the metastasis regulator protein SLUG. Using isogenic breast cancer cell systems we have shown here that high motility of these cells is directly correlated with the levels of the SLUG in these cells. Because epithelial/mesenchymal cell motility is known to be negatively regulated by the catenin protein plakoglobin, we postulated that the transcriptional repressor protein SLUG increases the motility of the aggressive breast cancer cells through the knockdown of the transcription of the plakoglobin gene. We found that SLUG inhibits the expression of plakoglobin gene directly in these cells. Overexpression of SLUG in the SLUG-deficient cancer cells significantly decreased the levels of mRNA and protein of plakoglobin. On the contrary, knockdown of SLUG in SLUG-high cancer cells elevated the levels of plakoglobin. Blocking of SLUG function with a double-stranded DNA decoy that competes with the E2-box binding of SLUG also increased the levels of plakoglobin mRNA, protein, and promoter activity in the SLUG-high triple negative breast cancer cells. Overexpression of SLUG in the SLUG-deficient cells elevated the motility of these cells. Knockdown of plakoglobin in these low motility non-invasive breast cancer cells rearranged the actin filaments and increased the motility of these cells. Forced expression of plakoglobin in SLUG-high cells had the reverse effects on cellular motility. This study thus implicates SLUG-induced repression of plakoglobin as a motility determinant in highly disseminating breast cancer. PMID- 22496455 TI - From biological warfare to the brighter side of rice research. PMID- 22496454 TI - Activation of archaeal transcription mediated by recruitment of transcription factor B. AB - Archaeal promoters consist of a TATA box and a purine-rich adjacent upstream sequence (transcription factor B (TFB)-responsive element (BRE)), which are bound by the transcription factors TATA box-binding protein (TBP) and TFB. Currently, only a few activators of archaeal transcription have been experimentally characterized. The best studied activator, Ptr2, mediates activation by recruitment of TBP. Here, we present a detailed biochemical analysis of an archaeal transcriptional activator, PF1088, which was identified in Pyrococcus furiosus by a bioinformatic approach. Operon predictions suggested that an upstream gene, pf1089, is polycistronically transcribed with pf1088. We demonstrate that PF1088 stimulates in vitro transcription by up to 7-fold when the pf1089 promoter is used as a template. By DNase I and hydroxyl radical footprinting experiments, we show that the binding site of PF1088 is located directly upstream of the BRE of pf1089. Mutational analysis indicated that activation requires the presence of the binding site for PF1088. Furthermore, we show that activation of transcription by PF1088 is dependent upon the presence of an imperfect BRE and is abolished when the pf1089 BRE is replaced with a BRE from a strong archaeal promoter. Gel shift experiments showed that TFB recruitment to the pf1089 operon is stimulated by PF1088, and TFB seems to stabilize PF1088 operator binding even in the absence of TBP. Taken together, these results represent the first biochemical evidence for a transcriptional activator working as a TFB recruitment factor in Archaea, for which the designation TFB-RF1 is suggested. PMID- 22496453 TI - Roles of Kruppel-associated Box (KRAB)-associated Co-repressor KAP1 Ser-473 Phosphorylation in DNA Damage Response. AB - The Kruppel-associated box (KRAB)-associated co-repressor KAP1 is an essential nuclear co-repressor for the KRAB zinc finger protein superfamily of transcriptional factors. Ataxia telangiectasia mutated (ATM)-Chk2 and ATM- and Rad3-related (ATR)-Chk1 are two primary kinase signaling cascades activated in response to DNA damage. A growing body of evidence suggests that ATM and ATR phosphorylate KAP1 at Ser-824 in response to DNA damage and regulate KAP1 dependent chromatin condensation, DNA repair, and gene expression. Here, we show that, depending on the type of DNA damage that occurs, KAP1 Ser-473 can be phosphorylated by ATM-Chk2 or ATR-Chk1 kinases. Phosphorylation of KAP1 at Ser 473 attenuated its binding to the heterochromatin protein 1 family proteins and inhibited its transcriptional repression of KRAB-zinc finger protein (KRAB-ZFP) target genes. Moreover, KAP1 Ser-473 phosphorylation induced by DNA damage stimulated KAP1-E2F1 binding. Overexpression of heterochromatin protein 1 significantly inhibited E2F1-KAP1 binding. Elimination of KAP1 Ser-473 phosphorylation increased E2F1-targeted proapoptotic gene expression and E2F1 induced apoptosis in response to DNA damage. Furthermore, loss of phosphorylation of KAP1 Ser-473 led to less BRCA1 focus formation and slower kinetics of loss of gammaH2AX foci after DNA damage. KAP1 Ser-473 phosphorylation was required for efficient DNA repair and cell survival in response to DNA damage. Our studies reveal novel functions of KAP1 Ser-473 phosphorylation under stress. PMID- 22496456 TI - Detection of redundant fusion transcripts as biomarkers or disease-specific therapeutic targets in breast cancer. AB - Fusion genes and fusion gene products are widely employed as biomarkers and therapeutic targets in hematopoietic cancers, but their applications have yet to be appreciated in solid tumors. Here, we report the use of SnowShoes-FTD, a powerful new analytic pipeline that can identify fusion transcripts and assess their redundancy and tumor subtype-specific distribution in primary tumors. In a study of primary breast tumors, SnowShoes-FTD was used to analyze paired-end mRNA Seq data from a panel of estrogen receptor (ER)(+), HER2(+), and triple-negative primary breast tumors, identifying tumor-specific fusion transcripts by comparison with mRNA-Seq data from nontransformed human mammary epithelial cell cultures plus the Illumina Body Map data from normal tissues. We found that every primary breast tumor that was analyzed expressed one or more fusion transcripts. Of the 131 tumor-specific fusion transcripts identified, 86 were "private" (restricted to a single tumor) and 45 were "redundant" (distributed among multiple tumors). Among the redundant fusion transcripts, 7 were unique to ER(+) tumors and 8 were unique to triple-negative tumors. In contrast, none of the redundant fusion transcripts were unique to HER2(+) tumors. Both private and redundant fusion transcripts were widely expressed in primary breast tumors, with many mapping to genomic loci implicated in breast carcinogenesis and/or risk. Our finding that some fusion transcripts are tumor subtype-specific suggests that these entities may be critical determinants in the etiology of breast cancer subtypes, useful as biomarkers for tumor stratification, or exploitable as cancer specific therapeutic targets. PMID- 22496458 TI - The Patient Protection and Affordable Care Act: opportunities for prevention and advocacy. AB - The Patient Protection and Affordable Care Act has come under intense scrutiny about its mandate for individual health insurance purchase, yet it has received little praise in the popular press for its prevention measures. Irrespective of the Supreme Court's decision regarding the "individual mandate," it is important for public health professionals to advocate for the preservation of the prevention and wellness provisions in the current law. The article addresses the Supreme Court's hearing for the "individual mandate," the likely impact of the general election in 2012, and specific prevention components of the law that should be championed by health education and health promotion advocates. PMID- 22496457 TI - RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. AB - Paracrine signaling through receptor activator of NF-kappaB (RANK) pathway mediates the expansion of mammary epithelia that occurs during pregnancy, and activation of RANK pathway promotes mammary tumorigenesis in mice. In this study we extend these previous data to human cells and show that the RANK pathway promotes the development of mammary stem cells and breast cancer. Overexpression of RANK (FL-RANK) in a panel of tumoral and normal human mammary cells induces the expression of breast cancer stem and basal/stem cell markers. High levels of RANK in untransformed MCF10A cells induce changes associated with both stemness and transformation, including mammary gland reconstitution, epithelial mesenchymal transition (EMT), increased migration, and anchorage-independent growth. In addition, spheroids of RANK overexpressing MCF10A cells display disrupted acinar formation, impair growth arrest and polarization, and luminal filling. RANK overexpression in tumor cells with nonfunctional BRCA1 enhances invasiveness in acinar cultures and increases tumorigenesis and metastasis in immunodeficient mice. High levels of RANK were found in human primary breast adenocarcinomas that lack expression of the hormone receptors, estrogen and progesterone, and in tumors with high pathologic grade and proliferation index; high RANK/RANKL expression was significantly associated with metastatic tumors. Together, our findings show that RANK promotes tumor initiation, progression, and metastasis in human mammary epithelial cells by increasing the population of CD44(+)CD24(-) cells, inducing stemness and EMT. These results suggest that RANK expression in primary breast cancer associates with poor prognosis. PMID- 22496459 TI - Results from an outreach program for health systems change in tobacco cessation. AB - INTRODUCTION: Washington state has experienced a dramatic reduction in adult smoking prevalence (22.4% in 1999 to 14.8% in 2010) because of a comprehensive tobacco control effort that includes a proactive health professional education and an outreach program. The outreach program uses academic detailing and online tools to increase routine identification and treatment of tobacco users. This article summarizes outcomes from the first 2 years of the program. METHOD: Outcome measures include the frequency of contact with providers, changes in the percentage of callers reporting that they had heard about the Quit Line from a health professional, and changes in provider Quit Line fax referrals. Data are compared between Initial, Expanded, and Never Outreach Counties. RESULTS: From 2008 to 2010, a total of 629 unique health care organizations and 3,989 unique health professionals received services. Between 2007 and 2010, the ratio of health professional "How Heard Abouts" to total Quit Line registrations increased by 142.6% and 95.4% in Initial and Expanded Outreach Counties, whereas Never Outreach Counties showed an 11.2% increase. Fax referrals to the Quit Line increased by 132% and 232% in Initial and Expanded Outreach Counties whereas they declined by 39% in Never Outreach Counties. DISCUSSION: Results suggests that health professionals can be an important and reliable source of referrals to a treatment resource such as a tobacco quitline. A field-based outreach program using academic detailing principles can be used to increase treatment referrals and holds application for other chronic disease areas and quality improvement programs. PMID- 22496460 TI - Search and ye shall find: practical literature review techniques for health educators. AB - Through a perusal of current published literature, health educators can locate resources for theses, dissertations, or manuscripts for scholarly publication or plan/develop health promotion programs or disease prevention interventions. Reviewing the literature, however, may be viewed as a nebulous or intimidating process. This article presents six steps intended to assist health educators to efficiently search the literature. The processes of assessing information needs, planning the search, choosing where to search, getting full-text articles, assessing the articles, and applying the evidence are outlined. PMID- 22496461 TI - SAP155-mediated splicing of FUSE-binding protein-interacting repressor serves as a molecular switch for c-myc gene expression. AB - The Far UpStream Element (FUSE)-binding protein-interacting repressor (FIR), a c myc transcriptional suppressor, is alternatively spliced removing the transcriptional repression domain within exon 2 (FIRDeltaexon2) in colorectal cancers. SAP155 is a subunit of the essential splicing factor 3b (SF3b) subcomplex in the spliceosome. This study aims to study the significance of the FIR-SAP155 interaction for the coordination of c-myc transcription, pre-mRNA splicing, and c-Myc protein modification, as well as to interrogate FIRDeltaexon2 for other functions relating to altered FIR pre-mRNA splicing. Knockdown of SAP155 or FIR was used to investigate their reciprocal influence on each other and on c-myc transcription, pre-mRNA splicing, and protein expression. Pull down from HeLa cell nuclear extracts revealed the association of FIR, FIRDeltaexon2, and SF3b subunits. FIR and FIRDeltaexon2 were coimmunoprecipitated with SAP155. FIR and FIRDeltaexon2 adenovirus vector (Ad-FIR and Ad-FIRDeltaexon2, respectively) were prepared to test for their influence on c-myc expression. FIR, SAP155, SAP130, and c-myc were coordinately upregulated in human colorectal cancer. These results reveal that SAP155 and FIR/FIRDeltaexon2 form a complex and are mutually upregulating. Ad-FIRDeltaexon2 antagonized Ad-FIR transcriptional repression of c-myc in HeLa cells. Because FIRDeltaexon2 still carries RRM1 and RRM2 and binding activity to FUSE, it is able to displace repression competent FIR from FUSE in electrophoretic mobility shift assays, thus thwarting FIR mediated transcriptional repression by FUSE. Thus aberrant FIRDeltaexon2 production in turn sustained c-Myc expression. In conclusion, altered FIR and c myc pre-mRNA splicing, in addition to c-Myc expression by augmented FIR/FIRDeltaexon2-SAP155 complex, potentially contribute to colorectal cancer development. PMID- 22496462 TI - Inflammation and positive affect are associated with subjective health in women of the general population. AB - Poor subjective health has been associated with higher levels of inflammatory cytokines. We investigated whether such an association would apply to women of the general population. Levels of cytokines, affect and subjective health were assessed in 347 women of the general population aged 45 to 90 years. Higher levels of interleukin-6 were associated with poor subjective health, especially in participants over 65 years of age. Positive affect was a more robust determinant of subjective health than negative affect. The presence of low-grade inflammation and absence of positive affect, rather than presence of negative affect, may be important determinants of subjective health. PMID- 22496467 TI - The occupational health nurse as the trusted clinician in the 21st century. AB - Occupational health nurses as trusted clinicians use their direct care skills in both on-site and off-site roles to protect human resources and contain health care costs. On-site clinics leverage the knowledge, skills, and abilities of occupational health nurses. To maximize the health of the work force, occupational health nurses use strategies aimed at improving health, engaging employees, enhancing accountability of employees, linking provider strategies, using technology creatively, and promoting healthy work environments. Occupational health nurses maintain a proactive and effective impact on occupational health and safety as part of a broader framework of holistic primary care. PMID- 22496463 TI - Mitigating age-related immune dysfunction heightens the efficacy of tumor immunotherapy in aged mice. AB - Although cancer tends to affect the elderly, most preclinical studies are carried out in young subjects. In this study, we developed a melanoma-specific cancer immunotherapy that shows efficacy in aged but not young hosts by mitigating age specific tumor-associated immune dysfunction. Both young and aged CD4(+)CD25(hi) regulatory T cells (Treg) exhibited equivalent in vitro T-cell suppression and tumor-associated augmentation in numbers. However, denileukin diftitox (DT) mediated Treg depletion improved tumor-specific immunity and was clinically effective only in young mice. DT-mediated Treg depletion significantly increased myeloid-derived suppressor cell (MDSC) numbers in aged but not young mice, and MDSC depletion improved tumor-specific immunity and reduced tumor growth in aged mice. Combining Treg depletion with anti-Gr-1 antibody was immunologically and clinically more efficacious than anti-Gr-1 antibody alone in aged B16-bearing mice, similar to Treg depletion alone in young mice. In contrast, DT increased MDSCs in young and aged mice following MC-38 tumor challenge, although effects were greater in aged mice. Anti-Gr-1 boosted DT effects in young but not aged mice. Aged antitumor immune effector cells are therefore competent to combat tumor when underlying tumor-associated immune dysfunction is appropriately mitigated, but this dysfunction varies with tumor, thus also varying responses to immunotherapy. By tailoring immunotherapy to account for age-related tumor associated immune dysfunctions, cancer immunotherapy for aged patients with specific tumors can be remarkably improved. PMID- 22496468 TI - Occupational and environmental health nursing: the foundations of quality practice. AB - This article discusses the various standards, regulations, and guidelines that practicing occupational and environmental health nurses follow to ensure the delivery of quality, competent care in all occupational and environmental health nursing practice settings. PMID- 22496469 TI - Professional autonomy of occupational health nurses in the United States. AB - Autonomy, the freedom to practice independently and to exercise professional judgment in practice activities, is a central element for professional practice. Numerous articles and studies have reported on professional autonomy in general nursing practice; however, professional autonomy for occupational health nurses has not been explored in depth. This article advances the development of a body of knowledge relative to professional autonomy in the practice of occupational health nursing. This article also provides an overview of professional autonomy in nursing practice; discusses the nature and importance of professional autonomy in the occupational health practice setting; reports findings from a seminal study of occupational health nurse autonomy; and addresses professional autonomy in the context of collaborative practice. PMID- 22496470 TI - Occupational health nursing education for the 21st century. AB - Occupational health nurses are the largest group of occupational health professionals, and are critical to the delivery of quality health care services to the nation's work force. Educational preparation of occupational health nurses has advanced in recent years, and the need for occupational health nurses with advanced degrees is expected to increase. Occupational health nurses use licensure, continuing education, certification, supervisor and peer assessment of job performance, formal education, and practice to maintain their professional competence and protect the public's health. New strategies must be developed to prepare nurses to promote a safe and healthful work force. Funding for programs to prepare occupational health nurses will be essential for meeting this demand. Continuing education programs for occupational health nurses must be developed that demonstrate effectiveness in developing occupational health nurses' skills while minimizing their time away from the workplace. PMID- 22496472 TI - Overtime work as a predictor of a major depressive episode. AB - Data from middle-aged civil servants in the Whitehall II Study suggest that working long hours of overtime may predispose workers to major depressive episodes. PMID- 22496474 TI - Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment. AB - OBJECTIVE: To report a case of dabigatran-induced overanticoagulation in a patient who developed acute renal failure and to inform health care providers of the need for appropriate patient selection and periodic monitoring of renal function in the elderly. CASE SUMMARY: A 66-year-old woman treated with dabigatran for atrial fibrillation developed acute renal failure and upper gastrointestinal bleeding. She had been taking dabigatran 150 mg twice daily for 2 months, with intermittent renal insufficiency during the previous 6 months. On admission, laboratory values included serum creatinine 3.6 mg/dL, hematocrit 21%, and international normalized ratio greater than 10. She was treated with packed red blood cells, prothrombin complex concentrate, and multiple sessions of dialysis. There were no further bleeding events or additional transfusions for the remainder of the hospitalization. Her renal function never recovered and she remained hemodialysis-dependent. After a 47-day length of stay, she was transferred to a nursing home where she died 2 months later. DISCUSSION: Renally eliminated drugs such as dabigatran place elderly patients at increased risk of drug accumulation and adverse drug events due to age-related decline in renal function. In a recent case series, dabigatran toxicity in the elderly with renal impairment was described with 1 fatal outcome. Recent literature, including the package insert, advises intermittent monitoring of renal function in the elderly and those with moderate renal impairment. Consideration should also include the appropriateness of dabigatran therapy in patients with fluctuating renal function. In our patient, the Naranjo probability scale indicated a probable cause between the bleeding event and dabigatran use. CONCLUSIONS: Our case report, along with 2 other recent reports on dabigatran toxicity, illustrates the importance for appropriate patient selection and the need to periodically monitor renal function in elderly patients receiving dabigatran. PMID- 22496475 TI - Role of raltegravir in HIV-1 management. AB - OBJECTIVE: To review the literature concerning the role of raltegravir in the treatment of HIV-1 in antiretroviral (ARV)-experienced and ARV-naive patients. DATA SOURCES: A PubMed search was conducted for published data through March 2012 using the search terms raltegravir, MK-0518, and integrase strand transfer inhibitor. An additional search of International Pharmaceutical Abstracts for unpublished data, including data from the Infectious Diseases Society of America, the Conference on Retroviruses and Opportunistic Infections, the International AIDS Society, and the Interscience Conference on Antimicrobial Agents and Chemotherapy, was conducted using similar search terms. STUDY SELECTION AND DATA EXTRACTION: In vitro and in vivo Phase 2, Phase 3, and postmarketing studies available in English, evaluating antiretroviral regimens that contain raltegravir for the treatment of HIV-1 infection in both ARV-naive and ARV-experienced patients, were evaluated. Studies assessing raltegravir pharmacokinetics and pharmacodynamics were included for review. DATA SYNTHESIS: The nucleoside-based regimen of raltegravir with tenofovir/emtricitabine provides an effective first line treatment option. However, nucleoside-sparing regimens appear unfavorable in ARV-naive subjects and should be reserved for patients with limited treatment options. Raltegravir used with optimized background therapy provides an alternative regimen for ARV-experienced patients. This review describes the available in vitro and in vivo data on raltegravir potency, defined as the ability to achieve undetectable viral load, and safety profile, as well as comparison to standard HIV-1 therapies. CONCLUSIONS: Raltegravir has demonstrated potent antiretroviral activity against HIV-1 in both ARV-naive and ARV experienced subjects, with the benefits of a favorable adverse effect profile and minimal drug interactions. Raltegravir must be dosed twice daily, as once daily raltegravir displays decreased virologic efficacy compared to twice daily dosing. However, the ongoing development of new integrase strand transfer inhibitors may provide potent once daily regimens. PMID- 22496476 TI - Artemether-lumefantrine: an option for malaria. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and efficacy of artemether-lumefantrine for the treatment of Plasmodium falciparum malaria. DATA SOURCES: English-language articles indexed in PubMed (1947-November 2011) were identified, using the search terms artemether-lumefantrine, artemether lumefantrine AND malaria, Coartem, and Coartem AND malaria. STUDY SELECTION AND DATA EXTRACTION: Available English-language articles were reviewed. In addition, the malaria treatment regimens recommended by region as provided by the World Health Organization and the treatment guidelines from the Centers for Disease Control and Prevention were reviewed. DATA SYNTHESIS: Artemether-lumefantrine is an artemisinin-derived combination antimalarial approved by the Food and Drug Administration in 2009 for the treatment of P. falciparum malaria. The dual mechanisms of action of artemether-lumefantrine provide rapid and sustained parasite clearance. In the reviewed studies, the polymerase chain reaction (PCR) corrected 28-day cure rates of artemether-lumefantrine were noninferior to the most common comparators, including chloroquine, dapsone, and other artemisinin derivatives (86-100% vs 51-100%, respectively). PCR-corrected day-42 cure rates were 92-99.3% for artemether-lumefantrine versus 62-100% for the comparator groups. The major adverse effects (gastrointestinal and central nervous system) were mild to moderate in severity and did not require a change in therapy. Although adherence to artemether-lumefantrine has been described as a potential problem due to the complicated dosing schedule, studies have described clinical cure rates similar to those of other antimalarials. CONCLUSIONS: Artemether lumefantrine is a safe and effective treatment for children and adults with P. falciparum malaria. PMID- 22496477 TI - Analgosedation: a paradigm shift in intensive care unit sedation practice. AB - OBJECTIVE: To critically evaluate the use of analgosedation in the management of agitation in critically ill mechanically ventilated patients. DATA SOURCES: Literature was accessed through MEDLINE (1948-November 2011) and Cochrane Library (2011, issue 1) using the terms analgosedation, analgosedation, or analgesia based sedation alone or in combination with intensive care unit or critically ill. Reference lists of related publications were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles published in English were evaluated. Randomized controlled trials examining critically ill mechanically ventilated patients older than 18 years were included. DATA SYNTHESIS: Limitations of current sedation practices include serious adverse drug events, prolonged mechanical ventilation time, and intensive care unit (ICU) length of stay. Studies have demonstrated that analgosedation, a strategy that manages patient pain and discomfort first, before providing sedative therapy, results in improved patient outcomes compared to standard sedative-hypnotic regimens. Nine randomized controlled trials comparing remifentanil-based analgosedation to other commonly used agents (fentanyl, midazolam, morphine, and propofol) for ICU sedation and 1 trial comparing morphine to daily sedation interruption with propofol or midazolam were reviewed. Remifentanil is an ideal agent for analgosedation due to its easy titratability and organ-independent metabolism. When compared to sedative hypnotic regimens, remifentanil-based regimens were associated with shorter duration of mechanical ventilation, more rapid weaning from the ventilator, and shorter ICU length of stay. Compared to fentanyl-based regimens, remifentanil had similar efficacy with the exception of increased pain requirements upon remifentanil discontinuation. Analgosedation was well tolerated, with no significant differences in hemodynamic stability compared to sedative-hypnotic regimens. CONCLUSIONS: Analgosedation is an efficacious and well-tolerated approach to management of ICU sedation with improved patient outcomes compared to sedative-hypnotic approaches. Additional well-designed trials are warranted to clarify the role of analgosedation in the management of ICU sedation, including trials with nonopioid analgesics. PMID- 22496479 TI - N-alpha-acetyltransferase 10 protein inhibits apoptosis through RelA/p65 regulated MCL1 expression. AB - N-alpha-Acetyltransferase 10 protein (Naa10p/ARD1), the catalytic subunit of N acetyltransferase A, catalyzes both N-alpha-acetylation and epsilon-acetylation, as well as autoacetylation. Naa10p is involved in controlling cell proliferation, apoptosis, autophagy and neuronal development. Our group and others had reported prognostic value of Naa10p expression in various types of cancer. Despite the efforts to elucidate the biological function of Naa10p, it remains controversial regarding its roles in tumor development. Herein, we report that depletion of Naa10p inhibited the growth of xenograft tumors in nude mice. Microarray analysis identified MCL1 gene as one of targets downstream of Naa10p. Naa10p positively regulated MCL1 expression, as exogenous Naa10p promoted MCL1 expression, whereas Naa10p silencing decreased MCL1 expression. Ablation of Naa10p sensitized cancer cells to stimuli-induced apoptosis, and the anti-apoptotic function of Naa10p was, at least in part, mediated by MCL1. Mechanistically, we found a physical interaction between Naa10p and RelA/p65. Transcriptional activation of the MCL1 gene required the recruitment of Naa10p-RelA/p65 complex to the p65-binding site of MCL1 promoter region. We also demonstrated a positive correlation between MCL1 and Naa10p messenger RNA levels in both colon cancer and lung cancer tissues. These results indicate that Naa10p inhibits apoptosis through Naa10p-RelA/p65 dependent MCL1 transcriptional activation. PMID- 22496481 TI - Identification and characterization of MEL-3, a novel AR antagonist that suppresses prostate cancer cell growth. AB - Antiandrogens are an important component of prostate cancer therapy as the androgen receptor (AR) is the key regulator of prostate cancer growth and survival. Current AR antagonists, such as bicalutamide and hydroxyflutamide, have a low affinity for the AR and as a result block AR signaling insufficiently. Moreover, many patients develop a resistance for bicalutamide or hydroxyflutamide during therapy or show a clinical improvement after withdrawal of the antiandrogen. New and more effective AR antagonists are needed to ensure follow up of these patients. We therefore developed a screening system to identify novel AR antagonists from a collection of compounds. MEL-3 [8-(propan-2-yl)-5,6-dihydro 4H-pyrazino[3,2,1-jk]carbazole] was selected as potent inhibitor of the AR and was further characterized in vitro. On different prostate cancer cell lines MEL-3 displayed an improved therapeutic profile compared with bicalutamide. Not only cell growth was inhibited but also the expression of androgen-regulated genes: PSA and FKBP5. Prostate cancer is often associated with mutated ARs that respond to a broadened spectrum of ligands including the current antiandrogens used in the clinic, hydroxyflutamide and bicalutamide. The activity of two mutant receptors (AR T877A and AR W741C) was shown to be reduced in presence of MEL-3, providing evidence that MEL-3 can potentially be a follow-up treatment for bicalutamide- and hydroxyflutamide-resistant patients. The mechanism of action of MEL-3 on the molecular level was further explored by comparing the structure activity relationship of different chemical derivatives of MEL-3 with the in silico docking of MEL-3 derivatives in the binding pocket of the AR. PMID- 22496480 TI - Dibenzophenanthridines as inhibitors of glutaminase C and cancer cell proliferation. AB - One hallmark of cancer cells is their adaptation to rely upon an altered metabolic scheme that includes changes in the glycolytic pathway, known as the Warburg effect, and elevated glutamine metabolism. Glutaminase, a mitochondrial enzyme, plays a key role in the metabolism of glutamine in cancer cells, and its inhibition could significantly impact malignant transformation. The small molecule 968, a dibenzophenanthridine, was recently shown to inhibit recombinantly expressed glutaminase C, to block the proliferation and anchorage independent colony formation of human cancer cells in culture, and to inhibit tumor formation in mouse xenograft models. Here, we examine the structure activity relationship that leads to 968-based inhibition of glutaminase and cancer cell proliferation, focusing upon a "hot-spot" ring previously identified as critical to 968 activity. We find that the hot-spot ring must be substituted with a large, nonplanar functionality (e.g., a t-butyl group) to bestow activity to the series, leading us to a model whereby the molecule binds glutaminase at a previously undescribed allosteric site. We conduct docking studies to locate potential 968-binding sites and proceed to test a specific set of docking solutions via site-directed mutagenesis. We verify the results from our initial assay of 968 and its analogues by cellular studies using MDA-MB-231 breast cancer cells. PMID- 22496482 TI - Predominance of mTORC1 over mTORC2 in the regulation of proliferation of ovarian cancer cells: therapeutic implications. AB - mTOR is a serine/threonine kinase that acts by binding different sets of proteins forming two complexes, termed mTORC1 and mTORC2. mTOR is deregulated in a substantial proportion of ovarian tumors. Despite the use of drugs directed to mTOR in ongoing clinical trials, the functional relevance of the individual mTORC branches in ovarian cancer is not known. Here, we show that mTORC1 and mTORC2 were constitutively active in ovarian cancer cell lines. Knockdown of raptor or rictor, proteins required for the function of mTORC1 or mTORC2, respectively, resulted in profound inhibition of ovarian cancer cell proliferation. The knockdown of raptor had a more important inhibitory effect than the knockdown of rictor, indicating mTORC1 had a predominant role over mTORC2 in the control of ovarian cancer cell proliferation. Rapamycin decreased the proliferation of ovarian cancer cells, and this was accompanied by inhibition of the phosphorylation of S6, a protein used as readout of mTORC1 function. However, rapamycin had only a marginal effect on the phosphorylation status of 4E-BP1, another mTORC1 substrate. Therefore, mTORC1 probably controls p4E-BP1 along two distinct pathways, one of them sensitive to rapamycin and another insensitive. The dual PI3K/mTOR inhibitor BEZ235 was more efficient than rapamycin in its inhibitory action on ovarian cancer cell proliferation. Biochemically, BEZ235 completely inhibited pS6, p4E-BP1, and pAkt. Our results suggest that broad spectrum mTOR inhibitors that block mTORC1 and mTORC2 are more desirable for their clinical development in ovarian cancer than agents exclusively targeting one of the mTOR branches. PMID- 22496483 TI - Roles of stromal microenvironment in colon cancer progression. AB - Although our understanding of epithelial cancer cells has advanced significantly, our understanding of the cancer microenvironment is still fragmentary. In contrast to our intuitive impression that our body always suppresses cancer growth, recent pieces of evidence show that cancer often exploits our body reactions to expand, invade local tissues and metastasize to distant organs. Accordingly, investigations of such body reactions in the tumour microenvironment should help us to design novel therapeutic strategies that can be combined with the traditional therapeutics targeted at the cancer cells themselves. In this article, I am going to review our recent efforts in search of novel therapeutic strategies against colon cancer using mouse models. PMID- 22496484 TI - SwrA regulates assembly of Bacillus subtilis DegU via its interaction with N terminal domain of DegU. AB - The Bacillus subtilis response regulator DegU controls many physiological events including swarming motility and exoprotease production. Swarming motility is a multicellular movement of hyper-flagellated cells on a surface. The swarming motility regulator SwrA and DegU cooperatively drive transcription of fla/che encoding flagella components, chemotaxis constituents and motility-specific sigma factor, which is regarded as the primary event in the development of motility. We have identified ycdA involved in swarming motility, encoding a putative lipoprotein. We showed that the ycdA gene is positively regulated by DegU and SwrA. Mutational analysis of ycdA-lacZ revealed that SwrA changes the use of cis acting sites for DegU. This suggested that SwrA operates the DegU-regulation mode through changes in the DegU assembly state. DegU binding to the ycdA-promoter region carrying an unusual arrangement of DegU-recognition sequences with low affinity was found to be stimulated by SwrA in electrophoretic mobility shift assay and DNase I footprinting. Yeast two- and three-hybrid analyses revealed that the N-terminal domain of DegU interacts with whole DegU, which is facilitated by SwrA. Together, these results demonstrate that SwrA can stabilize the binding of DegU to the ycdA promoter with low affinity. Thus, SwrA is a novel type of bacterial transcription factor in this regard. PMID- 22496485 TI - Alzheimer's disease-related protein hGas7b interferes with kinesin motility. AB - In the previous study, we reported the important properties of hGas7b (i) that binds to phospho-tau and facilitates microtubule polymerization and (ii) the level of hGas7b is very low in the brains of patients with Alzheimer's disease. These results led us to study the function of hGas7b in detail. We focused on the effect of hGas7b on microtubule dynamics in the absence of tau, on the assumption of healthy tau decrease in the brains of Alzheimer's disease. hGas7b binds to microtubule directly without tau, although this binding does not enhance microtubule polymerization. Excess hGas7b interferes with kinesin motility on microtubules. These results suggest that regulation to maintain an appropriate concentration of hGas7b is required for healthy neurotransmission. PMID- 22496486 TI - Transcriptional regulation of neutral sphingomyelinase 2 in all-trans retinoic acid-treated human breast cancer cell line, MCF-7. AB - Effects of all-trans retinoic acid (ATRA) on sphingomyelinase expression were examined using MCF-7 (ATRA-sensitive) and MDA-MB-231 (ATRA-resistant) breast cancer cells. Increased NSMase activity, NSMase2 mRNA and protein were observed in ATRA-treated MCF-7 but not in ATRA-treated MDA-MB-231. Increased NSMase2 mRNA of ATRA-treated MCF-7 was mostly due to enhanced transcription. Promoter analysis revealed the important 5'-promoter region of NSMase2 between -148 and -42 bp containing three Sp1 sites but no retinoic acid responsive elements. Experiments using mutated Sp1 sites of the NSMase2 promoter, Mithramycin A (a Sp inhibitor) and Sp family over-expression demonstrated the importance of Sp family protein and the three Sp1 sites for ATRA-induced NSMase2 transcription of MCF-7 cells. Although no quantitative change of bound Sp1 on NSMase2 promoter region after ATRA treatment was detected, Sp1 phosphorylation (activation) by ATRA was observed. Interestingly, PKCdelta was involved in ATRA-induced increased NSMase2 transcription. ATRA-induced PKCdelta phosphorylation and then activated PKCdelta phosphorylated Sp1. Chromatin immunoprecipitation (ChIP) assay showed Sp1, RARalpha and RXRalpha complex formation in MCF-7 cells regardless of ATRA treatment and ATRA-induced acetylated histone H3 of the 5'-promoter. Thus, NSMase2 mRNA expression enhanced by ATRA was due to increased transcription via phosphorylated Sp1 caused by PKCdelta activation, followed by chromatin remodelling with histone H3 acetylation. PMID- 22496487 TI - Silver deposition on a polymer substrate catalyzed by singly charged monodisperse copper nanoparticles. AB - Aerosol deposition of singly charged monodisperse copper nanoparticles was used to catalytically activate a polymer substrate for electroless silver deposition. An ambient spark discharge was used to produce aerosol copper nanoparticles, and the particles were electrostatically classified at an equivalent mobility diameter of 10 nm, using a nanodifferential mobility analyzer. Deposition of the copper particles onto the surface of the substrate was enhanced by thermophoresis. The copper-deposited substrate was then immersed in a Ag(I) solution, resulting in the electroless deposition of silver (~17 MUm line width) on the previously deposited copper (~12 MUm line width, using a shadow mask with a 100 MUm in width patterned stripe). The arithmetic mean roughness and electrical resistivity of the silver pattern were 44.7 nm and 7.9 MUOmega cm, respectively, which showed an enhancement compared to those from the nonclassified copper particles (roughness = 162.2 nm, resistivity = 13.3 MUOmega cm), because of a more-uniform copper deposition. PMID- 22496488 TI - QTL analysis of clinical-chemical traits in an F2 intercross between Landrace and Korean native pigs. AB - Clinical-chemical traits are essential when examining the health status of individuals. The aim of this study was to identify quantitative trait loci (QTL) and the associated positional candidate genes affecting clinical-chemical traits in a reciprocal F(2) intercross between Landrace and Korean native pigs. Following an overnight fast, 25 serum phenotypes related to clinical-chemical traits (e.g., hepatic function parameters, renal function parameters, electrolyte, lipids) were measured in >970 F(2) progeny. All experimental samples were subjected to genotyping analysis using 165 microsatellite markers located across the genome. We identified eleven genome-wide significant QTL in six chromosomal regions (SSC 2, 7, 8, 13, 14, and 15) and 59 suggestive QTL in 17 chromosomal regions (SSC 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, and 18). We also observed significant effects of reciprocal crosses on some of the traits, which would seem to result from maternal effect, QTL on sex chromosomes, imprinted genes, or genetic difference in mitochondrial DNA. The role of genomic imprinting in clinical-chemical traits also was investigated. Genome-wide analysis revealed a significant evidence for an imprinted QTL in SSC4 affecting serum amylase levels. Additionally, a series of bivariate linkage analysis provided strong evidence that QTL in SSC 2, 13, 15, and 18 have a pleiotropic effect on clinical-chemical traits. In conclusion, our study detected both novel and previously reported QTL influencing clinical-chemical traits in pigs. The identified QTL together with the positional candidate genes identified here could play an important role in elucidating the genetic structure of clinical-chemical phenotype variation in humans and swine. PMID- 22496489 TI - Association between the C242T polymorphism in the p22phox gene with arterial stiffness in the Brazilian population. AB - NADPH oxidase p22phox subunit is responsible for the production of reactive oxygen species in the vascular tissue. The C242T polymorphism in the p22phox gene has been associated with diverse coronary artery disease phenotypes, but the findings about the protective or harmful effects of the T allele are still controversial. Our main aim was to assess the effect of p22phox C242T genotypes on arterial stiffness, a predictor of late morbidity and mortality, in individuals from the general population. We randomly selected 1,178 individuals from the general population of Vitoria City, Brazil. Genotypes for the C242T polymorphism were detected by PCR-RFLP, and pulse wave velocity (PWV) values were measured with a noninvasive automatic device Complior. p22phox and TNF-alpha gene expression were quantified by real-time PCR in human arterial mammary smooth muscle cells. In both the entire and nonhypertensive groups: individuals carrying the TT genotype had higher PWV values and higher risk for increased arterial stiffness [odds ratio (OR) 1.93, 95% confidence interval (CI) 1.27-2.92 and OR 1.78, 95% CI 1.07-2.95, respectively] compared with individuals carrying CC+CT genotypes, even after adjustment for covariates. No difference in the p22phox gene expression according C242T genotypes was observed. However, TNF-alpha gene expression was higher in cells from individual carrying the T allele, suggesting that this genetic marker is associated with functional phenotypes at the gene expression level. In conclusion, we suggest that p22phox C242T polymorphism is associated with arterial stiffness evaluated by PWV in the general population. This genetic association shed light on the understanding of the genetic modulation on vascular dysfunction mediated by NADPH oxidase. PMID- 22496490 TI - Transcriptional profiling of the bovine hepatic response to experimentally induced E. coli mastitis. AB - The mammalian liver works to keep the body in a state of homeostasis and plays an important role in systemic acute phase response to infections. In this study we investigated the bovine hepatic acute phase response at the gene transcription level in dairy cows with experimentally Escherichia coli-induced mastitis. At time = 0, each of 16 periparturient dairy cows received 20-40 colony-forming units of live E. coli in one front quarter of the udder. A time series of liver biopsies was collected at -144, 12, 24, and 192 h relative to time of inoculation. Changes in transcription levels in response to E. coli inoculation were analyzed using the Bovine Genome Array and tested significant for 408 transcripts over the time series [adjusted p <= 0.05, abs(fold-change) > 2]. After 2-D clustering, transcripts represented three distinct transcription profiles: 1) regulation of gene transcription and apoptosis, 2) responses to cellular stress invoked by reactive metabolites, and 3) metabolism and turnover of proteins. The results showed that the liver went through a period of perturbations to its normal homeostatic condition during the first 24 h following the E. coli-induced intra-mammary inflammation. In previous studies, bacterial lipopolysaccharide, LPS, was used for intramammary stimulation to mimic E. coli infection. Comparing responses to LPS and E. coli, induced biochemical processes were similar but not identical (94 and 85% similarity between corresponding samples at early and late acute phase, respectively), but their kinetics were not. A notable difference concerned transcription of factors associated with oxidative stress in E. coli-induced liver responses. PMID- 22496491 TI - Effect of nanoclay loading on the thermal and mechanical properties of biodegradable polylactide/poly[(butylene succinate)-co-adipate] blend composites. AB - Polylactide/poly[(butylene succinate)-co-adipate] (PLA/PBSA)-organoclay composites were prepared via melt compounding in a batch mixer. The weight ratio of PLA to PBSA was kept at 70:30, while the weight fraction of the organoclay was varied from 0 to 9%. Small angle X-ray scattering patterns showed slightly better dispersion in PBSA than PLA, and there was a tendency of the silicate layers to delaminate in PBSA at low clay content. Thermal analysis revealed that crystallinity was dependent on the clay content as well its localization within the composite. On the other hand, thermal stability marginally improved for composites with <2 wt % clay content in contrast to the deterioration observed in composites with clay content >2 wt %. Tensile properties showed dependence on clay content and localization. Composite with 2 wt % clay content showed slight improvement in elongation at break. Overall, the optimum property was found for a composite with 2 wt % of the organoclay. This paper therefore has demonstrated the significance of the clay content and localization on the properties of the PLA/PBSA blends. PMID- 22496492 TI - In silico identification of epitopes in Mycobacterium avium subsp. paratuberculosis proteins that were upregulated under stress conditions. AB - Johne's disease in ruminants is caused by Mycobacterium avium subsp. paratuberculosis. Diagnosis of M. avium subsp. paratuberculosis infection is difficult, especially in the early stages. To date, ideal antigen candidates are not available for efficient immunization or immunodiagnosis. This study reports the in silico selection and subsequent analysis of epitopes of M. avium subsp. paratuberculosis proteins that were found to be upregulated under stress conditions as a means to identify immunogenic candidate proteins. Previous studies have reported differential regulation of proteins when M. avium subsp. paratuberculosis is exposed to stressors which induce a response similar to dormancy. Dormancy may be involved in evading host defense mechanisms, and the host may also mount an immune response against these proteins. Twenty-five M. avium subsp. paratuberculosis proteins that were previously identified as being upregulated under in vitro stress conditions were analyzed for B and T cell epitopes by use of the prediction tools at the Immune Epitope Database and Analysis Resource. Major histocompatibility complex class I T cell epitopes were predicted using an artificial neural network method, and class II T cell epitopes were predicted using the consensus method. Conformational B cell epitopes were predicted from the relevant three-dimensional structure template for each protein. Based on the greatest number of predicted epitopes, eight proteins (MAP2698c [encoded by desA2], MAP2312c [encoded by fadE19], MAP3651c [encoded by fadE3_2], MAP2872c [encoded by fabG5_2], MAP3523c [encoded by oxcA], MAP0187c [encoded by sodA], and the hypothetical proteins MAP3567 and MAP1168c) were identified as potential candidates for study of antibody- and cell-mediated immune responses within infected hosts. PMID- 22496493 TI - Efficacy of dart or booster vaccination with strain RB51 in protecting bison against experimental Brucella abortus challenge. AB - This study characterized the efficacy of the Brucella abortus strain RB51 vaccine in bison when delivered by single intramuscular vaccination (hand RB51), by single pneumatic dart delivery (dart RB51), or as two vaccinations approximately 13 months apart (booster RB51) in comparison to control bison. All bison were challenged intraconjunctivally in midgestation with 10(7) CFU of B. abortus strain 2308 (S2308). Bison were necropsied and sampled within 72 h of abortion or delivery of a live calf. Compared to nonvaccinated bison, bison in the booster RB51 treatment had a reduced (P < 0.05) incidence of abortion, uterine infection, or infection in maternal tissues other than the mammary gland at necropsy. Bison in single-vaccination treatment groups (hand RB51 and dart RB51) did not differ (P > 0.05) from the control group in the incidence of abortion or recovery of S2308 from uterine, mammary, fetal, or maternal tissues at necropsy. Compared to nonvaccinated animals, all RB51 vaccination groups had reduced (P < 0.05) mean colonization or incidence of infection in at least 2 of 4 target tissues, with the booster RB51 group having reduced (P < 0.05) colonization and incidence of infection in all target tissues. Our data suggest that booster vaccination of bison with RB51 enhances protective immunity against Brucella challenge compared to single vaccination with RB51 by hand or by pneumatic dart. Our study also suggests that an initial vaccination of calves followed by booster vaccination as yearlings should be an effective strategy for brucellosis control in bison. PMID- 22496494 TI - Peptide microarray analysis of in silico-predicted epitopes for serological diagnosis of Toxoplasma gondii infection in humans. AB - Toxoplasma gondii infections occur worldwide in humans and animals. In immunocompromised or prenatally infected humans, T. gondii can cause severe clinical symptoms. The identification of specific epitopes on T. gondii antigens is essential for the improvement and standardization of the serological diagnosis of toxoplasmosis. We selected 20 peptides mimicking linear epitopes on GRA1, GRA2, GRA4, and MIC3 antigenic T. gondii proteins in silico using the software ABCpred. A further 18 peptides representing previously published epitopes derived from GRA1, SAG1, NTPase1, and NTPase2 antigens were added to the panel. A peptide microarray assay was established to prove the diagnostic performance of the selected peptides with human serum samples. Seropositive human serum samples (n = 184) were collected from patients presenting with acute toxoplasmosis (n = 21), latent T. gondii infection (n = 53), and inactive ocular toxoplasmosis (n = 10) and from seropositive forest workers (n = 100). To adjust the cutoff values for each peptide, sera from seronegative forest workers (n = 75) and patients (n = 65) were used. Univariate logistic regression suggested the significant diagnostic potential of eight novel and two previously published peptides. A test based on these peptides had an overall diagnostic sensitivity of 69% (100% in ocular toxoplasmosis patients, 86% in acutely infected patients, 81% in latently infected patients, and 57% in seropositive forest workers). The analysis of seronegative sera performed with these peptides revealed a diagnostic specificity of 84%. The results of our study suggest that the use of a bioinformatic approach for epitope prediction in combination with peptide microarray testing is a powerful method for the selection of T. gondii epitopes as candidate antigens for serological diagnosis. PMID- 22496495 TI - A TSHr-LH/CGr chimera that measures functional TSAb in Graves' disease. AB - CONTEXT: Stimulating thyrotropin receptor (TSHr) autoantibodies (TSAb) are the cause of hyperthyroidism in Graves' disease. In a patient's serum, TSAb can coexist with antagonist TSHr autoantibodies that block TSAb stimulatory activity (TSBAb); both can vary in amount and time. OBJECTIVE: The objective of the study was to create a functional assay that detects only TSAb, thus having an increased accuracy for diagnosing Graves' disease. DESIGN: A TSHr chimera (Mc4) that retains an agonist-sensitive TSAb epitope but replaces a TSBAb epitope was stably transfected in cells to establish the Mc4 assay. SETTING: The study was conducted at the Chieti University (Outpatient Endocrine Clinic) and the University of Pisa (the Department of Endocrinology). PATIENTS: The assay was validated using sera from 170 individuals with Graves' disease, Hashimoto's thyroiditis, and nonautoimmune hyperthyroidism and normal subjects from Chieti University. A second blinded study evaluated sera from 175 patients with autoimmune thyroid disease (mainly Graves' disease) from the University of Pisa. INTERVENTIONS: Interventions included the assessment of patients' sera using human wild-type TSHr (WT-TSHr), Mc4 chimera, and binding (TRAb) assays. MAIN OUTCOME MEASURES: The Mc4 assay has the best accuracy for diagnosing Graves' disease. RESULTS: The Mc4 assay has a better diagnostic accuracy than WT-TSHr and second-generation TRAb assays. Indeed, the sensitivity of the WT-TSHr, TRAb, and Mc4 assays was 97.3, 86.5, and 100%, respectively, whereas the specificity was 93.1, 97, and 98.5%, respectively. CONCLUSION: The Mc4 assay is a functional assay with improved sensitivity and specificity for the detection of TSAb and is clinically useful in diagnosing Graves' disease. PMID- 22496496 TI - Pathophysiology of renal calcium handling in acromegaly: what lies behind hypercalciuria? AB - BACKGROUND: Hypercalciuria is frequent in patients with acromegaly, but it is unclear how GH/IGF-I regulate renal calcium handling. Elevated fasting plasma calcium levels despite increased glomerular filtration suggest enhanced renal calcium reabsorption. OBJECTIVE: The aim of this study was to investigate the impact of acromegaly on phosphocalcium metabolism. DESIGN AND SETTING: We conducted a prospective sequential study at a tertiary referral medical center and clinical investigation center (www.ClinicalTrials.gov Identifier: NCT00531908). INTERVENTION: Sixteen consecutive patients (five females/11 males) with acromegaly received a single iv infusion of 25 mg of furosemide to induce an acute increase in calcium and magnesium delivery to distal tubular segments during a high-sodium diet with stable dietary calcium, magnesium, and phosphate intake. MEASUREMENTS: Baseline plasma and urine electrolytes, plasma calciotropic hormones, and furosemide-induced changes in the fractional excretion and tubular reabsorption of Na, Ca, and Mg were measured before and 6 months (range, 1-12) after effective treatment of acromegaly. RESULTS: Serum IGF-I concentrations normalized in all the patients after acromegaly treatment. Compared with controlled acromegaly, active acromegaly was associated with higher fasting plasma (P = 0.0002) and urinary calcium (P = 0.0003) levels, lower PTH levels (P = 0.0075), higher calcitriol levels (P = 0.0137), higher phosphatemia (P<0.0001) and tubular phosphate reabsorption (P = 0.0002), and a lower calciuric (P = 0.0327) but not magnesiuric response to furosemide related to higher baseline and postfurosemide tubular calcium (P = 0.0034 and P = 0.0081, respectively), but not magnesium reabsorption. CONCLUSION: The IGF-I-mediated and PTH-independent increase in calcitriol synthesis in acromegaly is responsible for both absorptive hypercalciuria and increased fasting plasma calcium linked to enhanced distal tubular calcium reabsorption, as shown by the selectively diminished calciuric response to furosemide. PMID- 22496498 TI - Lithium titanate aerogel for advanced lithium-ion batteries. AB - This work details the synthesis and characterization of a novel lithium titanate aerogel as an anode material for lithium ion batteries. Excessive loss of lithium during supercritical drying can be overcome by increasing the lithium precursor concentration during synthesis. Chronopotentiometry shows the aerogel to have a capacity about 80 % of theoretical at a symmetric C/3 rate, which is comparable to a commercial product. Cyclic voltammetry reveals a batt-cap behavior for the high-surface area aerogel, implying the potential for improved rate capability if electrical conductivity can be maintained. PMID- 22496497 TI - The impact of age and gender on papillary thyroid cancer survival. AB - CONTEXT: Thyroid cancer predominately affects women, carries a worse prognosis in older age, and may have higher mortality in men. Superimposed on these observations is the fact that most women have attained menopause by age 55 yr. OBJECTIVE: The objective of the study was to determine whether men contribute disproportionately to papillary thyroid cancer (PTC) mortality or whether menopause affects PTC prognosis. DESIGN: Gender-specific mortality was normalized using age-matched subjects from the U.S. population. Multivariate Cox proportional hazard regression models incorporating gender, age, and National Thyroid Cancer Treatment Cooperative Study Group stage were used to model disease specific survival (DSS). PARTICIPANTS AND SETTING: Patients were followed in a prospective registry. MAIN OUTCOME MEASURE: The relationships between gender, age, and PTC outcomes were analyzed. RESULTS: The unadjusted hazard ratio (HR) for DSS for women was 0.40 [confidence interval (CI) 0.24-0.65]. This female advantage diminished when DSS was adjusted for age at diagnosis and stage with a HR encompassing unity (HR 0.72, CI 0.44-1.19). Additional multivariate models of DSS considering gender, disease stage, and various age groupings showed that the DSS for women diagnosed at under 55 yr was improved over men (HR 0.33, CI 0.13 0.81). However, the HR for DSS increased to become similar to men for women diagnosed at 55-69 yr (HR 1.01, CI 0.42-2.37) and at 70 yr or greater (HR 1.17, CI 0.48-2.85). CONCLUSIONS: Although the overall outcome of women with PTC is similar to men, subgroup analysis showed that this composite outcome is composed of two periods with different outcomes. The first period is a period with better outcomes for women than men when the diagnosis occurs at younger than 55 yr; the second is a period with similar outcomes for both women and men diagnosed at ages greater than 55 yr. These data raise the question of whether an older age cutoff would improve current staging systems. We hypothesize that older age modifies the effect of gender on outcomes due to menopause-associated hormonal alterations. PMID- 22496499 TI - Chemically modified graphene/polyimide composite films based on utilization of covalent bonding and oriented distribution. AB - Herein, we have developed a rather simple composite fabrication approach to achieving molecular-level dispersion and planar orientation of chemically modified graphene (CMG) in the thermosetting polyimide (PI) matrix as well as realizing strong adhesion at the interfacial regions between reinforcing filler and matrix. The covalent adhesion of CMG to PI matrix and oriented distribution of CMG were carefully confirmed and analyzed by detailed investigations. Combination of covalent bonding and oriented distribution could enlarge the effectiveness of CMG in the matrix. Efficient stress transfer was found at the CMG/PI interfaces. Significant improvements in the mechanical performances, thermal stability, electrical conductivity, and hydrophobic behavior were achieved by addition of only a small amount of CMG. Furthermore, it is noteworthy that the hydrophilic-to-hydrophobic transition and the electrical percolation were observed at only 0.2 wt % CMG in this composite system. This facile methodology is believed to afford broad application potential in graphene-based polymer nanocomposites, especially other types of high-performance thermosetting systems. PMID- 22496500 TI - The slow components of phosphocreatine and pulmonary oxygen uptake can be dissociated during heavy exercise according to training status. AB - To better understand the mechanisms underlying the pulmonary O(2) uptake (V(O(2P))) slow component during high-intensity exercise, we used (31)P magnetic resonance spectroscopy, gas exchange, surface electromyography and near-infrared spectroscopy measurements to examine the potential relationship between the slow components of V(O(2P)) and phosphocreatine (PCr), muscle recruitment and tissue oxygenation in endurance-trained athletes and sedentary subjects. Specifically, six endurance-trained and seven sedentary subjects performed a dynamic high intensity exercise protocol during 6 min at an exercise intensity corresponding to 35-40% of knee-extensor maximal voluntary contraction. The slow component of V(O(2P))(117 +/- 60 ml min(-1), i.e. 20 +/- 10% of the total response) was associated with a paradoxical PCr resynthesis in endurance-trained athletes ( 0.90 +/- 1.27 mm, i.e. -12 +/- 16% of the total response). Meanwhile, oxygenated haemoglobin increased throughout the second part of exercise and was significantly higher at the end of exercise compared with the value at 120 s (P < 0.05), whereas the integrated EMG was not significantly changed throughout exercise. In sedentary subjects, a slow component was simultaneously observed for V(O(2P)) and [PCr] time-dependent changes (208 +/- 14 ml min(-1), i.e. 38 +/- 18% of the total V(O(2P))response, and 1.82 +/- 1.39 mm, i.e. 16 +/- 13% of the total [PCr] response), but the corresponding absolute or relative amplitudes were not correlated. The integrated EMG was significantly increased throughout exercise in sedentary subjects. Taken together, our results challenge the hypothesis of a mechanistic link between [PCr] and V(O(2P)) slow components and demonstrate that, as a result of a tighter metabolic control and increased O(2) availability, the [PCr] slow component can be minimized in endurance-trained athletes while the V(O(2P)) slow component occurs. PMID- 22496501 TI - Influence of neural adjustments and muscle oxygenation on task failure during sustained isometric contractions with elbow flexor muscles. AB - This study investigated the adjustments in muscle activation and oxygenation in biceps and triceps brachii during two tasks sustained to failure at 20 and 60% of the maximal voluntary contraction (MVC) force. The tasks required participants either to push against a rigid restraint (force task) or to support an inertial load (position task) with the elbow flexor muscles. The surface EMG was recorded for biceps brachii, brachioradialis, triceps brachii and trapezius superior muscles. Muscle oxygenation of biceps and triceps brachii was measured by near infrared spectroscopy. The position task was briefer (404 +/- 159 s) than the force task (533 +/- 194 s) when performed at 20% MVC (P = 0.011), but endurance time did not differ at 60% MVC (54 +/- 19 versus 64 +/- 16 s, respectively; P = 0.13). Biceps brachii oxygenation decreased slightly (by ~7%) during tasks performed at 20% MVC, whereas it dropped (-40%) for tasks sustained at 60% MVC. However, the decrease in muscle oxygenation was not a significant predictor of time to failure at the two target forces, although its contribution to muscle fatigue cannot be completely ruled out at 60% MVC. In contrast, time to failure was predicted by the increase in EMG of biceps brachii for both tasks at 20% MVC, and EMG of brachioradialis and trapezius for both tasks at 60% MVC. These results suggest that neural adjustments rather than muscle oxygenation limited the time to failure for the force and position tasks at low and high target forces. PMID- 22496502 TI - Pro-inflammatory cytokines do not affect basal or hypoxia-stimulated discharge of rat vagal paraganglia. AB - Vagal paraganglia are structurally similar to the carotid body and are chemosensitive to reduction in the P(O(2)). We hypothesized that they may also mediate communication between the immune system and the central nervous system via pro-inflammatory cytokines or endotoxin. In vitro experiments with isolated superior laryngeal nerve (SLN) paraganglia were performed to test this hypothesis. We exposed the cells to increasing concentrations of interleukin 1beta, tumour necrosis factor-alpha or interleukin-6 (0.1, 0.3 and 1 ng ml(-1)) or bacterial lipopolysaccharide (LPS, 10 and 100 ng ml(-1)) during both normoxia ( P(O(2)) ~ 100 mmHg) and hypoxia (P(O(2)) < 40 mmHg) whilst single-fibre recordings were made from the main SLN trunk using a glass suction electrode. The results of these experiments confirmed previous findings that these cells respond strongly to changes in P(O(2)), significantly increasing their discharge rate in response to hypoxia (from 0.71 +/- 0.23 to 10.95 +/- 1.74 Hz, P < 0.0001). However, neither the cytokines nor LPS had any significant effect on the baseline discharge rate of the SLN units at any concentration. When compared with time matched controls, the cytokines and LPS also had no effect on the peak hypoxic discharge rate of the SLN (P = 0.59 and 0.65, respectively). In conclusion, neither the basal nor the hypoxic discharge rate of the SLN paraganglia is modulated by the inflammatory mediators tested above, suggesting that these structures are not the afferent limb of an 'immune reflex'. PMID- 22496503 TI - The cholinergic blockade of both thermally and non-thermally induced human eccrine sweating. AB - Thermally induced eccrine sweating is cholinergically mediated, but other neurotransmitters have been postulated for psychological (emotional) sweating. However, we hypothesized that such sweating is not noradrenergically driven in passively heated, resting humans. To test this, nine supine subjects were exposed to non-thermal stimuli (palmar pain, mental arithmetic and static exercise) known to evoke sweating. Trials consisted of the following four sequential phases: thermoneutral rest; passive heating to elevate (by ~1.0 degrees C) and clamp mean body temperature and steady-state sweating (perfusion garment and footbath); an atropine sulphate infusion (0.04 mg kg(-1)) with thermal clamping sustained; and following clamp removal. Sudomotor responses from glabrous (hairless) and non glabrous skin surfaces were measured simultaneously (precursor and discharged sweating). When thermoneutral, these non-thermal stimuli elicited significant sweating only from the palm (P < 0.05). Passive heating induced steady-state sweating ranging from 0.20 +/- 0.04 (volar hand) to 1.40 +/- 0.14 mg cm(-2) min( 1) (forehead), with each non-thermal stimulus provoking greater secretion (P < 0.05). Atropine suppressed thermal sweating, and it also eliminated the sudomotor responses to these non-thermal stimuli when body temperatures were prevented from rising (P > 0.05). However, when the thermal clamp was removed, core and skin temperatures became further elevated and sweating was restored (P < 0.05), indicating that the blockade had been overcome, presumably through elevated receptor competition. These observations establish the dependence of both thermal and non-thermal eccrine sweating from glabrous and non-glabrous surfaces on acetylcholine release, and challenge theories concerning the psychological modulation of sweating. Furthermore, no evidence existed for the significant participation of non-cholinergic neurotransmitters during any of these stimulations. PMID- 22496504 TI - Systemic blockade of nicotinic and purinergic receptors inhibits ventilation and increases apnoea frequency in newborn rats. AB - We hypothesized that the combined blockade of peripheral cholinergic and purinergic receptors alters the baseline breathing pattern and respiratory responses to carotid body stimuli (hypoxia, hyperoxia and hypercapnia). Rat pups at 4 (P4) and 12 days of postnatal age (P12) received an intraperitoneal injection of either saline vehicle or hexamethonium + suramin (Hex, 1 mg kg(-1), nicotinic receptor antagonist; Sur, 40 mg kg(-1), P2X receptor antagonist; both of which act mainly on peripheral receptors). Compared with the control animals (saline-injected rats), the Hex + Sur-treated rats demonstrated the following features: (1) decreased baseline ventilation and increased frequency of apnoea and breath-by-breath irregularities, with a larger effect in the P4 than in the P12 rats; (2) a decreased peak minute ventilation and respiratory frequency response to hypoxia (fractional inspired oxygen 12%), with a greater effect in the P12 than in the P4 rats; (3) an attenuated decline of the respiratory frequency during hyperoxia (fractional inspired oxygen 50%) to a similar magnitude in rats of both ages; and (4) a decreased hypercapnic ventilatory response (fractional inspired carbon dioxide 5%) to a similar magnitude in rats of both ages. We conclude that the cholinergic nicotinic and purinergic P2X receptors are essential to maintain an adequate baseline pattern in normoxia. They also contribute, albeit not exclusively, to the hypoxic ventilatory response, with an age-specific effect, most probably linked to the cholinergic component, which might partly underlie the postnatal maturation of peripheral chemoreceptors. PMID- 22496505 TI - Preferential utilization of perilipin 2-associated intramuscular triglycerides during 1 h of moderate-intensity endurance-type exercise. AB - The lipid droplet (LD)-associated protein perilipin 2 (PLIN2) appears to colocalize with LDs in human skeletal muscle fibres, although the function of PLIN2 in the regulation of intramuscular triglyceride (IMTG) metabolism is currently unknown. Here we investigated the hypothesis that the presence of PLIN2 in skeletal muscle LDs is related to IMTG utilisation during exercise. We therefore measured exercise-induced changes in IMTG and PLIN2 distribution and changes in their colocalization. Muscle biopsies from the vastus lateralis were obtained from seven lean, untrained men (22 +/- 2 years old, body mass index 24.2 +/- 0.9 kg m(-2) and peak oxygen uptake 3.35 +/- 0.13 l min(-1)) before and after 1 h of moderate-intensity cycling at ~65% peak oxygen uptake. Cryosections were stained for perilipin 2, IMTG and myosin heavy chain type I and viewed using wide field and confocal fluorescence microscopy. Exercise induced a 50 +/- 7% decrease in IMTG content in type I fibres only (P < 0.05), but no change in PLIN2 content. Colocalization analysis showed that the fraction of PLIN2 associated with IMTG was 0.67 +/- 0.03 before exercise, which was reduced to 0.51 +/- 0.01 postexercise (P < 0.05). Further analysis revealed that the number of PLIN2 associated LDs was reduced by 31 +/- 10% after exercise (P < 0.05), whereas the number of PLIN2-null LDs was unchanged. No such changes were seen in type II fibres. In conclusion, this study shows that PLIN2 content in skeletal muscle is unchanged in response to a single bout of endurance exercise. Furthermore, the PLIN2 and IMTG association is reduced postexercise, apparently due to preferential utilization of PLIN2-associated LDs. These results confirm the hypothesis that the PLIN2 association with IMTG is related to the utilization of IMTG as a fuel during exercise. PMID- 22496506 TI - Skeletal muscle lipid peroxidation and insulin resistance in humans. AB - OBJECTIVE: The relationships among skeletal muscle lipid peroxidation, intramyocellular lipid content (IMCL), and insulin sensitivity were evaluated in nine insulin-sensitive (IS), 13 insulin-resistant (IR), and 10 adults with type 2 diabetes (T2DM). DESIGN: Insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp [glucose disposal rate (GDR)]. Lipid peroxidation was assessed by 4-hydroxynonenal (HNE)-protein adducts and general oxidative stress by protein carbonyl content. All patients were sedentary. RESULTS: Protein-HNE adducts were elevated 1.6-fold in T2DM compared with IS adults, whereas IR showed intermediate levels of HNE-modified proteins. Protein-HNE adducts correlated with GDR, waist circumference, and body mass index. IMCL was increased by 4.0- and 1.9-fold in T2DM and IR patients, respectively, compared with IS, and was correlated with GDR and waist circumference but not BMI. Protein carbonyls were not different among groups and did not correlate with any of the measured variables. Correlations were detected between IMCL and protein-HNE. CONCLUSION: Our data show for the first time that skeletal muscle protein-HNE adducts are related to the severity of insulin resistance in sedentary adults. These results suggest that muscle lipid peroxidation could be involved in the development of insulin resistance. PMID- 22496507 TI - Testosterone treatment and mortality in men with low testosterone levels. AB - CONTEXT: Low testosterone levels in men have been associated with increased mortality. However, the influence of testosterone treatment on mortality in men with low testosterone levels is not known. OBJECTIVE: The objective of the study was to examine the association between testosterone treatment and mortality in men with low testosterone levels. DESIGN: This was an observational study of mortality in testosterone-treated compared with untreated men, assessed with time varying, adjusted Cox proportional hazards regression models. Effect modification by age, diabetes, and coronary heart disease was tested a priori. SETTING: The study was conducted with a clinical database that included seven Northwest Veterans Affairs medical centers. PATIENTS: Patients included a cohort of 1031 male veterans, aged older than 40 yr, with low total testosterone [<=250 ng/dl (8.7 nmol/liter)] and no history of prostate cancer, assessed between January 2001 and December 2002 and followed up through the end of 2005. MAIN OUTCOME MEASURE: Total mortality in testosterone-treated compared with untreated men was measured. RESULTS: Testosterone treatment was initiated in 398 men (39%) during routine clinical care. The mortality in testosterone-treated men was 10.3% compared with 20.7% in untreated men (P<0.0001) with a mortality rate of 3.4 deaths per 100 person-years for testosterone-treated men and 5.7 deaths per 100 person-years in men not treated with testosterone. After multivariable adjustment including age, body mass index, testosterone level, medical morbidity, diabetes, and coronary heart disease, testosterone treatment was associated with decreased risk of death (hazard ratio 0.61; 95% confidence interval 0.42-0.88; P = 0.008). No significant effect modification was found by age, diabetes, or coronary heart disease. CONCLUSIONS: In an observational cohort of men with low testosterone levels, testosterone treatment was associated with decreased mortality compared with no testosterone treatment. These results should be interpreted cautiously because residual confounding may still be a source of bias. Large, randomized clinical trials are needed to better characterize the health effects of testosterone treatment in older men with low testosterone levels. PMID- 22496508 TI - Oxidation-etching preparation of MnO2 tubular nanostructures for high-performance supercapacitors. AB - 1D hierarchical tubular MnO(2) nanostructures have been prepared through a facile hydrothermal method using carbon nanofibres (CNFs) as sacrificial template. The morphology of MnO(2) nanostructures can be adjusted by changing the reaction time or annealing process. Polycrystalline MnO(2) nanotubes are formed with a short reaction time (e.g., 10 min) while hierarchical tubular MnO(2) nanostructures composed of assembled nanosheets are obtained at longer reaction times (>45 min). The polycrystalline MnO(2) nanotubes can be further converted to porous nanobelts and sponge-like nanowires by annealing in air. Among all the types of MnO(2) nanostructures prepared, tubular MnO(2) nanostructures composed of assembled nanosheets show optimized charge storage performance when tested as supercapacitor electrodes, for example, delivering an power density of 13.33 kW.kg(-1) and a energy density of 21.1 Wh.kg(-1) with a long cycling life over 3000 cycles, which is mainly related to their features of large specific surface area and optimized charge transfer pathway. PMID- 22496509 TI - The chloroplast triggers developmental reprogramming when mutS HOMOLOG1 is suppressed in plants. AB - Multicellular eukaryotes demonstrate nongenetic, heritable phenotypic versatility in their adaptation to environmental changes. This inclusive inheritance is composed of interacting epigenetic, maternal, and environmental factors. Yet unidentified maternal effects can have a pronounced influence on plant phenotypic adaptation to changing environmental conditions. To explore the control of phenotypy in higher plants, we examined the effect of a single plant nuclear gene on the expression and transmission of phenotypic variability in Arabidopsis (Arabidopsis thaliana). MutS HOMOLOG1 (MSH1) is a plant-specific nuclear gene product that functions in both mitochondria and plastids to maintain genome stability. RNA interference suppression of the gene elicits strikingly similar programmed changes in plant growth pattern in six different plant species, changes subsequently heritable independent of the RNA interference transgene. The altered phenotypes reflect multiple pathways that are known to participate in adaptation, including altered phytohormone effects for dwarfed growth and reduced internode elongation, enhanced branching, reduced stomatal density, altered leaf morphology, delayed flowering, and extended juvenility, with conversion to perennial growth pattern in short days. Some of these effects are partially reversed with the application of gibberellic acid. Genetic hemicomplementation experiments show that this phenotypic plasticity derives from changes in chloroplast state. Our results suggest that suppression of MSH1, which occurs under several forms of abiotic stress, triggers a plastidial response process that involves nongenetic inheritance. PMID- 22496511 TI - Characterization of the plasma membrane H+-ATPase in the liverwort Marchantia polymorpha. AB - The plasma membrane H(+)-ATPase generates an electrochemical gradient of H(+) across the plasma membrane that provides the driving force for solute transport and regulates pH homeostasis and membrane potential in plant cells. Recent studies have demonstrated that phosphorylation of the penultimate threonine in H(+)-ATPase and subsequent binding of a 14-3-3 protein is the major common activation mechanism for H(+)-ATPase in vascular plants. However, there is very little information on the plasma membrane H(+)-ATPase in nonvascular plant bryophytes. Here, we show that the liverwort Marchantia polymorpha, which is the most basal lineage of extant land plants, expresses both the penultimate threonine-containing H(+)-ATPase (pT H(+)-ATPase) and non-penultimate threonine containing H(+)-ATPase (non-pT H(+)-ATPase) as in the green algae and that pT H(+)-ATPase is regulated by phosphorylation of its penultimate threonine. A search in the expressed sequence tag database of M. polymorpha revealed eight H(+)-ATPase genes, designated MpHA (for M. polymorpha H(+)-ATPase). Four isoforms are the pT H(+)-ATPase; the remaining isoforms are non-pT H(+)-ATPase. An apparent 95-kD protein was recognized by anti-H(+)-ATPase antibodies against an Arabidopsis (Arabidopsis thaliana) isoform and was phosphorylated on the penultimate threonine in response to the fungal toxin fusicoccin in thalli, indicating that the 95-kD protein contains pT H(+)-ATPase. Furthermore, we found that the pT H(+)-ATPase in thalli is phosphorylated in response to light, sucrose, and osmotic shock and that light-induced phosphorylation depends on photosynthesis. Our results define physiological signals for the regulation of pT H(+)-ATPase in the liverwort M. polymorpha, which is one of the earliest plants to acquire pT H(+)-ATPase. PMID- 22496510 TI - NaJAZh regulates a subset of defense responses against herbivores and spontaneous leaf necrosis in Nicotiana attenuata plants. AB - The JASMONATE ZIM DOMAIN (JAZ) proteins function as negative regulators of jasmonic acid signaling in plants. We cloned 12 JAZ genes from native tobacco (Nicotiana attenuata), including nine novel JAZs in tobacco, and examined their expression in plants that had leaves elicited by wounding or simulated herbivory. Most JAZ genes showed strong expression in the elicited leaves, but NaJAZg was mainly expressed in roots. Another novel herbivory-elicited gene, NaJAZh, was analyzed in detail. RNA interference suppression of this gene in inverted-repeat (ir)JAZh plants deregulated a specific branch of jasmonic acid-dependent direct and indirect defenses: irJAZh plants showed greater trypsin protease inhibitor activity, 17-hydroxygeranyllinalool diterpene glycosides accumulation, and emission of volatile organic compounds from leaves. Silencing of NaJAZh also revealed a novel cross talk in JAZ-regulated secondary metabolism, as irJAZh plants had significantly reduced nicotine levels. In addition, irJAZh spontaneously developed leaf necrosis during the transition to flowering. Because the lesions closely correlated with the elevated expression of programmed cell death genes and the accumulations of salicylic acid and hydrogen peroxide in the leaves, we propose a novel role of the NaJAZh protein as a repressor of necrosis and/or programmed cell death during plant development. PMID- 22496512 TI - Selective ATP-competitive inhibitors of TOR suppress rapamycin-insensitive function of TORC2 in Saccharomyces cerevisiae. AB - The target of rapamycin (TOR) is a critical regulator of growth, survival, and energy metabolism. The allosteric TORC1 inhibitor rapamycin has been used extensively to elucidate the TOR related signal pathway but is limited by its inability to inhibit TORC2. We used an unbiased cell proliferation assay of a kinase inhibitor library to discover QL-IX-55 as a potent inhibitor of S. cerevisiae growth. The functional target of QL-IX-55 is the ATP-binding site of TOR2 as evidenced by the discovery of resistant alleles of TOR2 through rational design and unbiased selection strategies. QL-IX-55 is capable of potently inhibiting both TOR complex 1 and 2 (TORC1 and TORC2) as demonstrated by biochemical IP kinase assays (IC(50) <50 nM) and cellular assays for inhibition of substrate YPK1 phosphorylation. In contrast to rapamycin, QL-IX-55 is capable of inhibiting TORC2-dependent transcription, which suggests that this compound will be a powerful probe to dissect the Tor2/TORC2-related signaling pathway in yeast. PMID- 22496513 TI - An improved ionic liquid-based headspace single-drop microextraction-liquid chromatography method for the analysis of camphor and trans-anethole in compound liquorice tablets. AB - A simple, accurate and sensitive ionic liquid-based headspace single-drop microextraction procedure followed by high-performance liquid chromatography was developed and validated for the determination of camphor and trans-anethole in compound liquorice tablets. The volume of the ionic liquid microdrop was increased to 12 uL by modifying the device of the suspended drop. The stability of the microdrop and the sensitivity of the method were improved. Under the optimum experimental conditions, the calculated calibration curves gave acceptable linearity for camphor and trans-anethole with correlation coefficients of 0.9990 and 0.9998, respectively. The repeatability of the proposed method, expressed as relative standard deviation, was below 4.5% (n = 5). The limits of detection for the two target analytes were found to be 9.77 and 1.95 * 10(-2) MUg/mL, respectively. In this study, the separation, purification and enrichment were achieved in one step in an airtight system, which reduced the interferences caused by other complicated constituents, increased the signal-to-noise of the method and ensured the accuracy of the results because there was no loss of volatile components. It is expected to be widely applied for sample pretreatment of volatile components with high boiling points in samples with complicated matrices such as the extractions of plants or Chinese traditional drugs. PMID- 22496514 TI - Cancers related to viral agents that have a direct role in carcinogenesis: pathological and diagnostic techniques. AB - The International Agency for Research on Cancer has recently reassessed the carcinogenicity of the biological agents classified as 'carcinogenic to humans'. Among the biological agents having a direct role in carcinogenesis, Epstein-Barr virus, Kaposi's sarcoma-associated herpes virus and human papillomavirus contribute to a variety of malignancies worldwide in humans including nasopharyngeal carcinoma, several types of lymphomas, genital tract carcinomas and Kaposi's sarcoma. The authors review the current knowledge on cancers that have been attributed to Epstein-Barr virus, Kaposi's sarcoma-associated herpes virus and human papillomavirus looking at the pathological classification of these cancers and description of the implicated viruses, highlighting a wide range of pathological and virological diagnostic techniques. This review also focuses on the new oncological scenario ahead, once strategies against carcinogenic infectious agents are found to be effective. PMID- 22496515 TI - Oligodendroglioma arising in the glial component of ovarian teratomas: a series of six cases and review of literature. AB - AIMS: To report the exceedingly rare occurrence of oligodendroglioma in the glial component of ovarian teratomas. METHODS: Six cases of oligodendrogliomas arising in the glial component of ovarian teratomas were studied and the literature was reviewed. Immunohistochemistry was performed by the Flex technique. RESULTS: The ages of the patients ranged from 12 to 28 years (mean 21 years). Four tumours were located in the right and one in the left ovary. The size of the ovarian cysts ranged from 7 cm to 29 cm (mean 19.6 cm). Four cases arose in immature and two cases in mature teratomas. In all cases, oligodendroglioma was WHO grade II. On immunohistochemistry, glial fibrillary acidic protein stain was positive in all cases. The Mib 1 (Ki 67) proliferative index was low and the tumour cells were negative for synaptophysin. Follow-up was available in five patients and ranged from 1 to 42 months. Two patients died of disease after 1 and 36 months of diagnosis, respectively. In both these cases oligodendroglioma arose in an immature teratoma. The remaining three patients are alive with a follow-up of 4 42 months. CONCLUSIONS: Oligodendroglioma arising in the glial component of ovarian teratomas is exceedingly rare. Ovarian teratomas should be extensively sampled and carefully evaluated to rule out the possibility of a glial tumour. This is the single and largest series of oligodendrogliomas arising in ovarian teratomas. The prognosis is good for oligodendrogliomas arising in mature teratomas compared with those arising in immature teratomas, although long-term follow-up is needed to determine the exact behaviour. PMID- 22496516 TI - High grade serous carcinoma of the ovary with a yolk sac tumour component in a postmenopausal woman: report of an extremely rare phenomenon. PMID- 22496517 TI - Genetic dissection of a model complex trait using the Drosophila Synthetic Population Resource. AB - Genetic dissection of complex, polygenic trait variation is a key goal of medical and evolutionary genetics. Attempts to identify genetic variants underlying complex traits have been plagued by low mapping resolution in traditional linkage studies, and an inability to identify variants that cumulatively explain the bulk of standing genetic variation in genome-wide association studies (GWAS). Thus, much of the heritability remains unexplained for most complex traits. Here we describe a novel, freely available resource for the Drosophila community consisting of two sets of recombinant inbred lines (RILs), each derived from an advanced generation cross between a different set of eight highly inbred, completely resequenced founders. The Drosophila Synthetic Population Resource (DSPR) has been designed to combine the high mapping resolution offered by multiple generations of recombination, with the high statistical power afforded by a linkage-based design. Here, we detail the properties of the mapping panel of >1600 genotyped RILs, and provide an empirical demonstration of the utility of the approach by genetically dissecting alcohol dehydrogenase (ADH) enzyme activity. We confirm that a large fraction of the variation in this classic quantitative trait is due to allelic variation at the Adh locus, and additionally identify several previously unknown modest-effect trans-acting QTL (quantitative trait loci). Using a unique property of multiparental linkage mapping designs, for each QTL we highlight a relatively small set of candidate causative variants for follow-up work. The DSPR represents an important step toward the ultimate goal of a complete understanding of the genetics of complex traits in the Drosophila model system. PMID- 22496518 TI - Novel transcriptome profiling analyses demonstrate that selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulators display attenuated and selective gene regulatory activity in comparison with PPARgamma full agonists. AB - Selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulators (SPPARgammaMs) have been actively pursued as the next generation of insulin sensitizing antidiabetic drugs, because the currently marketed PPARgamma full agonists, pioglitazone and rosiglitazone, have been reported to produce serious adverse effects among patients with type 2 diabetes mellitus. We conducted extensive transcriptome profiling studies to characterize and to contrast the activities of 70 SPPARgammaMs and seven PPARgamma full agonists. In both 3T3-L1 adipocytes and adipose tissue from db/db mice, the SPPARgammaMs generated attenuated and selective gene-regulatory responses, in comparison with full agonists. More importantly, SPPARgammaMs regulated the expression of antidiabetic efficacy-associated genes to a greater extent than that of adverse effect associated genes, whereas PPARgamma full agonists regulated both gene sets proportionally. Such SPPARgammaM selectivity demonstrates that PPARgamma ligand regulation of gene expression can be fine-tuned, and not just turned on and off, to achieve precise control of complex cellular and physiological functions. It also provides a potential molecular basis for the superior therapeutic window previously observed with SPPARgammaMs versus full agonists. On the basis of our profiling results, we introduce two novel, gene expression-based scores, the gamma activation index and the selectivity index, to aid in the detection and characterization of novel SPPARgammaMs. These studies provide new insights into the gene-regulatory activity of SPPARgammaMs as well as novel quantitative indices to facilitate the identification of PPARgamma ligands with robust insulin sensitizing activity and improved tolerance among patients with type 2 diabetes, compared with presently available PPARgamma agonist drugs. PMID- 22496521 TI - Effects of repeated walking in a perturbing environment: a 4-day locomotor learning study. AB - Previous studies have shown that when subjects repeatedly walk in a perturbing environment, initial movement error becomes smaller, suggesting that retention of the adapted locomotor program occurred (learning). It has been proposed that the newly learned locomotor program may be stored separately from the baseline program. However, how locomotor performance evolves with repeated sessions of walking with the perturbation is not yet known. To address this question, 10 healthy subjects walked on a treadmill on 4 consecutive days. Each day, locomotor performance was measured using kinematics and surface electromyography (EMGs), before, during, and after exposure to a perturbation, produced by an elastic tubing that pulled the foot forward and up during swing, inducing a foot velocity error in the first strides. Initial movement error decreased significantly between days 1 and 2 and then remained stable. Associated changes in medial hamstring EMG activity stabilized only on day 3, however. Aftereffects were present after perturbation removal, suggesting that daily adaptation involved central command recalibration of the baseline program. Aftereffects gradually decreased across days but were still visible on day 4. Separation between the newly learned and baseline programs may take longer than suggested by the daily improvement in initial performance in the perturbing environment or may never be complete. These results therefore suggest that reaching optimal performance in a perturbing environment should not be used as the main indicator of a completed learning process, as central reorganization of the motor commands continues days after initial performance has stabilized. PMID- 22496523 TI - Reduction in receptive field size of macaque MT neurons in the presence of visual noise. AB - The visual system faces a trade-off between increased spatial integration of disparate local signals and improved spatial resolution to filter out irrelevant noise. Increased spatial integration is beneficial when signals are weak, whereas increased spatial resolution is particularly beneficial when focusing on a small object in a cluttered natural scene. The receptive field (RF) size of visual cortical neurons can be modulated depending on various factors such as sensory context, allowing adaptive integration of sensory signals. In this study, we explored the spatial integration properties of neurons in macaque middle temporal visual area (MT). We hypothesized that spatial resolution would increase when high-contrast noise was presented simultaneously with a visual stimulus, enabling focus on a small object in a cluttered scene. To test this hypothesis, we mapped the RFs of MT neurons of two fixating monkeys in a 5 * 5 grid manner using a small patch of random-dot motion. To examine the effects of noise on RF profile, a dynamic noise (0% coherence dots) of varying diameter was concurrently presented at the RF center. We found that RF size decreased when noise diameter increased. Analyses based on the response normalization model and area summation provided evidence for the potential contribution of spatial summation properties within the RF and surround suppression to the apparent contraction of RF size. Our results suggest that MT neurons integrate smaller regions of motion signals when signals are embedded in noise, an efficient strategy to filter out surrounding noise. PMID- 22496522 TI - The function and molecular identity of inward rectifier channels in vestibular hair cells of the mouse inner ear. AB - Inner ear hair cells respond to mechanical stimuli with graded receptor potentials. These graded responses are modulated by a host of voltage-dependent currents that flow across the basolateral membrane. Here, we examine the molecular identity and the function of a class of voltage-dependent ion channels that carries the potassium-selective inward rectifier current known as I(K1). I(K1) has been identified in vestibular hair cells of various species, but its molecular composition and functional contributions remain obscure. We used quantitative RT-PCR to show that the inward rectifier gene, Kir2.1, is highly expressed in mouse utricle between embryonic day 15 and adulthood. We confirmed Kir2.1 protein expression in hair cells by immunolocalization. To examine the molecular composition of I(K1), we recorded voltage-dependent currents from type II hair cells in response to 50-ms steps from -124 to -54 in 10-mV increments. Wild-type cells had rapidly activating inward currents with reversal potentials close to the K(+) equilibrium potential and a whole-cell conductance of 4.8 +/- 1.5 nS (n = 46). In utricle hair cells from Kir2.1-deficient (Kir2.1(-/-)) mice, I(K1) was absent at all stages examined. To identify the functional contribution of Kir2.1, we recorded membrane responses in current-clamp mode. Hair cells from Kir2.1(-/-) mice had significantly (P < 0.001) more depolarized resting potentials and larger, slower membrane responses than those of wild-type cells. These data suggest that Kir2.1 is required for I(K1) in type II utricle hair cells and contributes to hyperpolarized resting potentials and fast, small amplitude receptor potentials in response to current inputs, such as those evoked by hair bundle deflections. PMID- 22496524 TI - Midbrain contributions to sensorimotor decision making. AB - Making decisions about future actions is a fundamental function of the nervous system. Classical theories hold that separate sets of brain regions are responsible for selecting and implementing an action. Traditionally, action selection has been considered the domain of high-level regions, such as the prefrontal cortex, whereas action generation is thought to be carried out by dedicated cortical and subcortical motor regions. However, increasing evidence suggests that the activity of individual neurons in cortical motor structures reflects abstract properties of "decision variables" rather than conveying simple motor commands. Less is known, though, about the role of subcortical structures in decision making. In particular, the superior colliculus (SC) is critical for planning and initiating visually guided, gaze-displacing movements and selecting visual targets, but whether and how it contributes more generally to sensorimotor decisions are unclear. Here, we show that the SC is intimately involved in orienting decisions based on odor cues, even though the SC does not explicitly process olfactory stimuli. Neurons were recorded from the intermediate and deep SC layers in rats trained to perform a delayed-response, odor-cued spatial choice task. SC neurons commonly fired well in advance of movement initiation, predicting the chosen direction nearly 1 s before movement. Moreover, under conditions of sensory uncertainty, SC activity varied with task difficulty and reward outcome, reflecting the influence of decision variables on the intercollicular competition thought to underlie orienting movements. These results indicate that the SC plays a more general role in decisions than previously appreciated, extending beyond visuomotor functions. PMID- 22496525 TI - Rapid changes in extracellular glutamate induced by natural arousing stimuli and intravenous cocaine in the nucleus accumbens shell and core. AB - Glutamate (Glu) is a major excitatory neurotransmitter, playing a crucial role in the functioning of the nucleus accumbens (NAc), a critical area implicated in somatosensory integration and regulation of motivated behavior. In this study, high-speed amperometry with enzyme-based biosensors was used in freely moving rats to examine changes in extracellular Glu in the NAc shell and core induced by a tone, tail pinch (TP), social interaction with a male conspecific (SI), and intravenous (iv) cocaine (1 mg/kg). To establish the contribution of Glu to electrochemical signal changes, similar recordings were conducted with null (Glu(0)) sensors, which were exposed to the same chemical and physical environment but were insensitive to Glu. TP, SI, and cocaine, but not a tone, induced relatively large and prolonged current increases detected by both Glu and Glu(0) sensors. However, current differentials revealed very rapid, much smaller, and transient increases in extracellular Glu levels, more predominantly in the NAc shell than core. In contrast to monophasic responses with natural stimuli, cocaine induced a biphasic Glu increase in the shell, with a transient peak during the injection and a slower postinjection peak. Therefore, Glu is phasically released in the NAc after exposure to natural arousing stimuli and cocaine; this release is rapid, stimulus dependent, and structure specific, suggesting its role in triggering neural and behavioral activation induced by these stimuli. This study also demonstrates the need for multiple in vitro and in vivo controls to reveal relatively small, highly phasic, and transient fluctuations in Glu levels occurring under behaviorally relevant conditions. PMID- 22496526 TI - Learning complex temporal patterns with resource-dependent spike timing-dependent plasticity. AB - Studies of spike timing-dependent plasticity (STDP) have revealed that long-term changes in the strength of a synapse may be modulated substantially by temporal relationships between multiple presynaptic and postsynaptic spikes. Whereas long term potentiation (LTP) and long-term depression (LTD) of synaptic strength have been modeled as distinct or separate functional mechanisms, here, we propose a new shared resource model. A functional consequence of our model is fast, stable, and diverse unsupervised learning of temporal multispike patterns with a biologically consistent spiking neural network. Due to interdependencies between LTP and LTD, dendritic delays, and proactive homeostatic aspects of the model, neurons are equipped to learn to decode temporally coded information within spike bursts. Moreover, neurons learn spike timing with few exposures in substantial noise and jitter. Surprisingly, despite having only one parameter, the model also accurately predicts in vitro observations of STDP in more complex multispike trains, as well as rate-dependent effects. We discuss candidate commonalities in natural long-term plasticity mechanisms. PMID- 22496527 TI - Local field potentials allow accurate decoding of muscle activity. AB - Local field potentials (LFPs) in primary motor cortex include significant information about reach target location and upper limb movement kinematics. Some evidence suggests that they may be a more robust, longer-lasting signal than action potentials (spikes). Here we assess whether LFPs can also be used to decode upper limb muscle activity, a complex movement-related signal. We record electromyograms from both proximal and distal upper limb muscles from monkeys performing a variety of reach-to-grasp and isometric wrist force tasks. We show that LFPs can be used to decode activity from both proximal and distal muscles with performance rivaling that of spikes. Thus, motor cortical LFPs include information about more aspects of movement than has been previously demonstrated. This provides further evidence suggesting that LFPs could provide a highly informative, long-lasting signal source for neural prostheses. PMID- 22496528 TI - Long-term actions of BDNF on inhibitory synaptic transmission in identified neurons of the rat substantia gelatinosa. AB - Peripheral nerve injury promotes the release of brain-derived neurotrophic factor (BDNF) from spinal microglial cells and primary afferent terminals. This induces an increase in dorsal horn excitability that contributes to "central sensitization" and to the onset of neuropathic pain. Although it is accepted that impairment of GABAergic and/or glycinergic inhibition contributes to this process, certain lines of evidence suggest that GABA release in the dorsal horn may increase after nerve injury. To resolve these contradictory findings, we exposed rat spinal cord neurons in defined-medium organotypic culture to 200 ng/ml BDNF for 6 days to mimic the change in spinal BDNF levels that accompanies peripheral nerve injury. Morphological and electrophysiological criteria and glutamic acid decarboxylase (GAD) immunohistochemistry were used to distinguish putative inhibitory tonic-islet-central neurons from putative excitatory delay radial neurons. Whole cell recording in the presence of 1 MUM tetrodotoxin showed that BDNF increased the amplitude of GABAergic and glycinergic miniature inhibitory postsynaptic currents (mIPSCs) in both cell types. It also increased the amplitude and frequency of spontaneous, action potential-dependent IPSCs (sIPSCs) in putative excitatory neurons. By contrast, BDNF reduced sIPSC amplitude in inhibitory neurons but frequency was unchanged. This increase in inhibitory drive to excitatory neurons and decreased inhibitory drive to inhibitory neurons seems inconsistent with the observation that BDNF increases overall dorsal horn excitability. One of several explanations for this discrepancy is that the action of BDNF in the substantia gelatinosa is dominated by previously documented increases in excitatory synaptic transmission rather than by impediment of inhibitory transmission. PMID- 22496529 TI - Diode probes for spatiotemporal optical control of multiple neurons in freely moving animals. AB - Neuronal control with high temporal precision is possible with optogenetics, yet currently available methods do not enable to control independently multiple locations in the brains of freely moving animals. Here, we describe a diode-probe system that allows real-time and location-specific control of neuronal activity at multiple sites. Manipulation of neuronal activity in arbitrary spatiotemporal patterns is achieved by means of an optoelectronic array, manufactured by attaching multiple diode-fiber assemblies to high-density silicon probes or wire tetrodes and implanted into the brains of animals that are expressing light responsive opsins. Each diode can be controlled separately, allowing localized light stimulation of neuronal activators and silencers in any temporal configuration and concurrent recording of the stimulated neurons. Because the only connections to the animals are via a highly flexible wire cable, unimpeded behavior is allowed for circuit monitoring and multisite perturbations in the intact brain. The capacity of the system to generate unique neural activity patterns facilitates multisite manipulation of neural circuits in a closed-loop manner and opens the door to addressing novel questions. PMID- 22496530 TI - beta-Adrenergic modulation of spontaneous spatiotemporal activity patterns and synchrony in hyperexcitable hippocampal circuits. AB - A description of healthy and pathological brain dynamics requires an understanding of spatiotemporal patterns of neural activity and characteristics of its propagation between interconnected circuits. However, the structure and modulation of the neural activation maps underlying these patterns and their propagation remain elusive. We investigated effects of beta-adrenergic receptor (beta-AR) stimulation on the spatiotemporal characteristics of emergent activity in rat hippocampal circuits. Synchronized epileptiform-like activity, such as interictal bursts (IBs) and ictal-like events (ILEs), were evoked by 4 aminopyridine (4-AP), and their dynamics were studied using a combination of electrophysiology and fast voltage-sensitive dye imaging. Dynamic characterization of the spontaneous IBs showed that they originated in dentate gyrus/CA3 border and propagated toward CA1. To determine how beta-AR modulates spatiotemporal characteristics of the emergent IBs, we used the beta-AR agonist isoproterenol (ISO). ISO significantly reduced the spatiotemporal extent and propagation velocity of the IBs and significantly altered network activity in the 1- to 20-Hz range. Dual whole cell recordings of the IBs in CA3/CA1 pyramidal cells and optical analysis of those regions showed that ISO application reduced interpyramidal and interregional synchrony during the IBs. In addition, ISO significantly reduced duration not only of the shorter duration IBs but also the prolonged ILEs in 4-AP. To test whether the decrease in ILE duration was model dependent, we used a different hyperexcitability model, zero magnesium (0 Mg(2+)). Prolonged ILEs were readily formed in 0 Mg(2+), and addition of ISO significantly reduced their durations. Taken together, these novel results provide evidence that beta-AR activation dynamically reshapes the spatiotemporal activity patterns in hyperexcitable circuits by altering network rhythmogenesis, propagation velocity, and intercellular/regional synchronization. PMID- 22496531 TI - Intrinsic voltage dynamics govern the diversity of spontaneous firing profiles in basal forebrain noncholinergic neurons. AB - Spontaneous firing and behavior-related changes in discharge profiles of basal forebrain (BF) neurons are well documented, albeit the mechanisms underlying the variety of activity modes and intermodal transitions remain elusive. With the use of cell-attached recordings, this study identifies a range of spiking patterns in diagonal band Broca (DBB) noncholinergic cells of rats and tentatively categorizes them into low-rate random, tonic, and cluster firing activities. It demonstrates further that the multiplicity of discharge profiles is sustained intrinsically and persists after blockade of glutamate-, glycine/GABA-, and cholinergic synaptic inputs. Stimulation of muscarinic receptors, blockade of voltage-gated Ca(2+)-, and small conductance (SK) Ca(2+)-activated K(+) currents as well as chelating of intracellular Ca(2+) concentration accelerate low-rate random and tonic firing and favor transition of neurons into cluster firing mode. A similar trend towards higher discharge rates with switch of neurons into cluster firing has been revealed by activation of neuropeptide Y (NPY) receptors with the NPY or NPY(1) receptor agonist [Leu(31),Pro(34)]-NPY. Whole cell current clamp analysis demonstrates that the variety of spiking modes and intermodal transitions could be induced within the same neuronal population by injection of bias depolarizing or hyperpolarizing currents. Taken together, these data demonstrate the intrinsic and highly variable character of regenerative firing in BF noncholinergic cells, subject to powerful modulation by classical neurotransmitters, NPY, and small membrane currents. PMID- 22496532 TI - Behavioral and neural correlates of visuomotor adaptation observed through a brain-computer interface in primary motor cortex. AB - Brain-computer interfaces (BCIs) provide a defined link between neural activity and devices, allowing a detailed study of the neural adaptive responses generating behavioral output. We trained monkeys to perform two-dimensional center-out movements of a computer cursor using a BCI. We then applied a perturbation by randomly selecting a subset of the recorded units and rotating their directional contributions to cursor movement by a consistent angle. Globally, this perturbation mimics a visuomotor transformation, and in the first part of this article we characterize the psychophysical indications of motor adaptation and compare them with known results from adaptation of natural reaching movements. Locally, however, only a subset of the neurons in the population actually contributes to error, allowing us to probe for signatures of neural adaptation that might be specific to the subset of neurons we perturbed. One compensation strategy would be to selectively adapt the subset of cells responsible for the error. An alternate strategy would be to globally adapt the entire population to correct the error. Using a recently developed mathematical technique that allows us to differentiate these two mechanisms, we found evidence of both strategies in the neural responses. The dominant strategy we observed was global, accounting for ~86% of the total error reduction. The remaining 14% came from local changes in the tuning functions of the perturbed units. Interestingly, these local changes were specific to the details of the applied rotation: in particular, changes in the depth of tuning were only observed when the percentage of perturbed cells was small. These results imply that there may be constraints on the network's adaptive capabilities, at least for perturbations lasting only a few hundreds of trials. PMID- 22496533 TI - Thalamic POm projections to the dorsolateral striatum of rats: potential pathway for mediating stimulus-response associations for sensorimotor habits. AB - The dorsolateral part of the striatum (DLS) represents the initial stage for processing sensorimotor information in the basal ganglia. Although the DLS receives much of its input from the primary somatosensory (SI) cortex, peripheral somesthetic stimulation activates the DLS at latencies that are shorter than the response latencies recorded in the SI cortex. To identify the subcortical regions that transmit somesthetic information directly to the DLS, we deposited small quantities of retrograde tracers at DLS sites that displayed consistent time locked responses to controlled whisker stimulation. The neurons that were retrogradely labeled by these injections were located mainly in the sensorimotor cortex and, to a lesser degree, in the amygdala and thalamus. Quantitative analysis of neuronal labeling in the thalamus indicated that the strongest thalamic input to the whisker-sensitive part of the DLS originates from the medial posterior nucleus (POm), a somesthetic-related region that receives inputs from the spinal trigeminal nucleus. Anterograde tracer injections in POm confirmed that this thalamic region projects to the DLS neuropil. In subsequent experiments, simultaneous recordings from POm and the DLS during whisker stimulation showed that POm consistently responds before the DLS. These results suggest that POm could transmit somesthetic information to the DLS, and this modality-specific thalamostriatal pathway may cooperate with the thalamostriatal projections that originate from the intralaminar nuclei. PMID- 22496534 TI - Electrophysiological classes of layer 2/3 pyramidal cells in monkey prefrontal cortex. AB - The activity of supragranular pyramidal neurons in the dorsolateral prefrontal cortex (DLPFC) neurons is hypothesized to be a key contributor to the cellular basis of working memory in primates. Therefore, the intrinsic membrane properties, a crucial determinant of a neuron's functional properties, are important for the role of DLPFC pyramidal neurons in working memory. The present study aimed to investigate the biophysical properties of pyramidal cells in layer 2/3 of monkey DLPFC to create an unbiased electrophysiological classification of these cells. Whole cell voltage recordings in the slice preparation were performed in 77 pyramidal cells, and 24 electrophysiological measures of their passive and active intrinsic membrane properties were analyzed. Based on the results of cluster analysis of 16 independent electrophysiological variables, 4 distinct electrophysiological classes of monkey pyramidal cells were determined. Two classes contain regular-spiking neurons with low and high excitability and constitute 52% of the pyramidal cells sampled. These subclasses of regular spiking neurons mostly differ in their input resistance, minimum current that evoked firing, and current-to-frequency transduction properties. A third class of pyramidal cells includes low-threshold spiking cells (17%), which fire a burst of three-five spikes followed by regular firing at all suprathreshold current intensities. The last class consists of cells with an intermediate firing pattern (31%). These cells have two modes of firing response, regular spiking and bursting discharge, depending on the strength of stimulation and resting membrane potential. Our results show that diversity in the functional properties of DLPFC pyramidal cells may contribute to heterogeneous modes of information processing during working memory and other cognitive operations that engage the activity of cortical circuits in the superficial layers of the DLPFC. PMID- 22496536 TI - Methylglyoxal, cognitive function and cerebral atrophy in older people. AB - BACKGROUND: The effects of advanced glycation endproducts on cognition and brain structure are poorly understood. We studied associations of the advanced glycation endproduct precursor methylglyoxal (MGO) with cognitive function and brain volumes in older people. METHODS: Nondemented participants in the Tasmanian Study of Cognition and Gait underwent cognitive testing and brain magnetic resonance imaging scans. Brain volumes were obtained by magnetic resonance imaging scan segmentation and statistical parametric mapping procedures. Serum MGO was measured after derivatization to methylquinoxaline by high pressure liquid chromatography and UV detection. Linear regression was used to examine associations of log-transformed MGO with cognitive scores and brain volumes adjusting for potential confounding by age, sex, education, mood, insulin resistance, history of stroke, vascular risk factors, alcohol intake, and psychoactive medication use. RESULTS: There were 378 participants, mean age 72.1 years (SD 7.1), 55% male. Greater MGO was associated with poorer memory (beta = .12, 95% confidence interval: -0.22, -0.02, p = .02) and executive function, the latter being greater among those with a history of stroke (MGO * stroke beta = .48, 95% confidence interval: 0.17, 0.79, p = .002). Greater MGO was associated with lower grey matter volume (beta = -6.42, 95% confidence interval -11.82, 1.11, p = .02) but not with white matter volume, white matter lesion volume, or hippocampal volume. CONCLUSIONS: These results support the investigation of the role of the advanced glycation endproduct precursor methylglyoxal in cognitive decline and neurodegeneration in older people. PMID- 22496535 TI - Intracortical circuits amplify sound-evoked activity in primary auditory cortex following systemic injection of salicylate in the rat. AB - A high dose of sodium salicylate temporarily induces tinnitus, mild hearing loss, and possibly hyperacusis in humans and other animals. Salicylate has well established effects on cochlear function, primarily resulting in the moderate reduction of auditory input to the brain. Despite decreased peripheral sensitivity and output, salicylate induces a paradoxical enhancement of the sound evoked field potential at the level of the primary auditory cortex (A1). Previous electrophysiologic studies have begun to characterize changes in thalamorecipient layers of A1; however, A1 is a complex neural circuit with recurrent intracortical connections. To describe the effects of acute systemic salicylate treatment on both thalamic and intracortical sound-driven activity across layers of A1, we applied current-source density (CSD) analysis to field potentials sampled across cortical layers in the anesthetized rat. CSD maps were normally characterized by a large, short-latency, monosynaptic, thalamically driven sink in granular layers followed by a lower amplitude, longer latency, polysynaptic, intracortically driven sink in supragranular layers. Following systemic administration of salicylate, there was a near doubling of both granular and supragranular sink amplitudes at higher sound levels. The supragranular sink amplitude input/output function changed from becoming asymptotic at approximately 50 dB to sharply nonasymptotic, often dominating the granular sink amplitude at higher sound levels. The supragranular sink also exhibited a significant decrease in peak latency, reflecting an acceleration of intracortical processing of the sound-evoked response. Additionally, multiunit (MU) activity was altered by salicylate; the normally onset/sustained MU response type was transformed into a primarily onset response type in granular and infragranular layers. The results from CSD analysis indicate that salicylate significantly enhances sound-driven response via intracortical circuits. PMID- 22496537 TI - Differences in blood pressure control in a large population-based sample of older African Americans and non-Hispanic whites. AB - BACKGROUND: Cardiovascular disease is the main cause of death in older adults. Uncontrolled blood pressure is an important risk factor for cardiovascular disease. African Americans have poorer blood pressure control than non-Hispanic whites. Little is known about whether this difference persists in older ages or the factors that contribute to this racial gap. METHODS: Data were obtained from participants of the Chicago Health and Aging Program. Blood pressure control was defined according to JNC-7 criteria. Univariate chi-square analyses were used to determine racial differences in hypertension and blood pressure control, whereas sequential multivariate logistic regression models were used to determine the effect of race on blood pressure control. RESULTS: African Americans had a higher prevalence of hypertension (74% vs 63%; p < .001), higher awareness of hypertension (81% vs 72%; p < .001), and poorer blood pressure control (45% vs 51%, p < .001) than non-Hispanic whites. Racial differences in blood pressure control persisted after adjustment for socioeconomic status, medical conditions, obesity, and use of antihypertensive medications (odds ratio = 0.84, 95% confidence interval = 0.70-0.94). From 1993 to 2008, blood pressure control improved more among non-Hispanic whites than among African Americans. CONCLUSIONS: Racial differences in blood pressure control in older adults were not explained by socioeconomic status. The racial disparity in the prevalence and control of hypertension remained consistent for older hypertensive individuals eligible for Medicare. Although the rates of hypertension control improved for both racial groups, the improvement was greater among whites, thus widening the gap in this older population at high risk for cardiovascular disease. PMID- 22496538 TI - Effect of 12-week resistance exercise program on body composition, muscle strength, physical function, and glucose metabolism in healthy, insulin resistant, and diabetic elderly Icelanders. AB - BACKGROUND: Insulin is a stimulator of skeletal muscle protein anabolism and insulin resistance might therefore negatively affect muscle protein metabolism. We investigated muscle mass and physical function before and after a resistance exercise program in participants with prediabetes or type 2 diabetes mellitus (T2DM) in comparison to healthy controls. METHODS: This was a secondary analysis of a randomized controlled intervention designed to investigate resistance training among older adults. Glucose metabolism status was not a selection criteria for the trial, and group designation was done retrospectively. Participants (N = 237, 73.7 +/- 5.7 y, 58.2% women) participated in a 12-week resistance exercise program (3 times/week; three sets, six to eight repetitions at 75%-80% of the one-repetition maximum), designed to increase strength and muscle mass of major muscle groups. Body composition, muscular strength, timed up and go test, 6-minute walk for distance, and blood chemical variables were measured at baseline and endpoint. RESULTS: Participants completing the study (n = 213) experienced significant changes in muscle strength or muscle function, which did not differ significantly between healthy (n = 198), prediabetic (n = 20), and T2DM participants (n = 17). Changes in serum glucose during the intervention differed by group: only glucose improved significantly in the prediabetic group, glucose and triacylglycerol improved significantly in the healthy group, whereas no serum parameter improved significantly in the T2DM group. CONCLUSIONS: A 12-week resistance exercise program improves muscle strength and muscle function to a similar extent in healthy, prediabetic, and T2DM elderly people. However, according to our data, T2DM participants do not experience favorable changes in fasting glucose or HbA(1C). PMID- 22496539 TI - Distinguishing between longevity and buffered-deleterious genotypes for exceptional human longevity: the case of the MTP gene. AB - The single nucleotide polymorphism, rs2866164, in the MTP gene, has been associated with human longevity but has not been validated by subsequent longevity studies. Using our population of Ashkenazi Jews, we find that the MTP CC genotype is significantly overrepresented in centenarians and their offspring, as compared with controls (p < .05). However, when we examined MTP CC genotype frequency pattern with aging, we observed a monotonic decline between ages 55-85 years followed by a dramatic enrichment after age 90 years, forming a U-shape pattern (p < .05). Furthermore, the MTP CC genotype was buffered by three validated longevity genotypes (p < .05). This buffering effect was found to confer an enrichment of the MTP CC genotype in centenarians, whereas their absence in CC controls resulted in poorer survivorship (p < .05). Thus, we conclude that MTP CC is a buffered-deleterious genotype and that assessing genotype frequency across aging is essential for discerning longevity from buffered-deleterious genotypes. PMID- 22496540 TI - Do specific early-life adversities lead to specific symptoms of psychosis? A study from the 2007 the Adult Psychiatric Morbidity Survey. AB - Previous studies have reported associations between childhood adversities, eg, loss of a parent, being raised in institutional care, sexual and other kinds of abuse by adults and bullying by peers, and psychosis in adulthood. However, the mechanisms by which these adversities lead to psychotic experiences are poorly understood. From models of the psychological processes involved in positive symptoms, it was predicted that childhood sexual abuse would be specifically associated with auditory hallucinations in adulthood, and that disruption of early attachment relations and more chronic forms of victimization such as bullying would be specifically associated with paranoid ideation. We therefore examined the associations between sexual trauma, physical abuse, bullying, and being brought up in institutional or local authority care and reports of auditory hallucinations and paranoid beliefs in the 2007 Adult Psychiatric Morbidity Survey. All simple associations between childhood adversities and the two symptom types were significant. Childhood rape was associated only with hallucinations (OR 8.9, CI = 1.86-42.44) once co-occurring paranoia was controlled for. Being brought up in institutional care (OR = 11.08, CI = 3.26-37.62) was specifically associated with paranoia once comorbid hallucinations had been controlled for. For each symptom, dose-response relationships were observed between the number of childhood traumas and the risk of the symptom. The specific associations observed are consistent with current psychological theories about the origins of hallucinations and paranoia. Further research is required to study the psychological and biological mediators of these associations. PMID- 22496541 TI - Age differences in responses to progressive social exclusion: the role of cognition and socioemotional functioning. AB - OBJECTIVES: In prior research, older adults were found to be less responsive to social slights than younger adults, but the mechanisms behind such effects have remained unclear. The present study examined age differences in susceptibility to the deleterious effects of social exclusion and investigated the explanatory role of cognitive and socioemotional variables. METHOD: Forty younger adults (aged 22 39) and 40 older adults (aged 58-89) played a modified version of "Cyberball," a virtual ball-tossing game, in which they were initially included by 2 other players and progressively excluded in subsequent rounds. After each round, participants reported their emotions and needs satisfaction. RESULTS: Older adults were less likely than younger adults to respond to mild levels of social exclusion, but both age groups responded similarly to more pronounced exclusion. Within the older group, participants with lower cognitive functioning were less responsive to mild exclusion, but this effect did not reach significance in the younger group. DISCUSSION: Future research on age differences in responses to social exclusion should further explore the role of cognition and examine possible implications for interpersonal functioning. PMID- 22496542 TI - Mouse development is not obviously affected by the absence of dermatan sulfate epimerase 2 in spite of a modified brain dermatan sulfate composition. AB - Dermatan sulfate epimerase 2 (DS-epi2), together with its homolog DS-epi1, transform glucuronic acid into iduronic acid in DS polysaccharide chains. Iduronic acid gives DS increased chain flexibility and promotes protein binding. DS-epi2 is ubiquitously expressed and is the predominant epimerase in the brain. Here, we report the generation and initial characterization of DS-epi2 null mice. DS-epi2-deficient mice showed no anatomical, histological or morphological abnormalities. The body weights and lengths of mutated and wild-type littermates were indistinguishable. They were fertile and had a normal lifespan. Chondroitin sulfate (CS)/DS isolated from the newborn mutated mouse brains had a 38% reduction in iduronic acid compared with wild-type littermates, and compositional analysis revealed a decrease in 4-O-sulfate and an increase in 6-O-sulfate containing structures. Despite the reduction in iduronic acid, the adult DS-epi2 /- brain showed normal extracellular matrix features by immunohistological stainings. We conclude that DS-epi1 compensates in vivo for the loss of DS-epi2. These results extend previous findings of the functional redundancy of brain extracellular matrix components. PMID- 22496543 TI - Toward precision medicine: a new social contract? PMID- 22496544 TI - From Lundberg to SIM-ICP: computational physiology and modeling intracranial pressure. AB - A simplified dynamic model generates patient-specific estimates of intracranial pressure and suggests a path forward for bringing simulated (SIM) physiologic models to the patient's bedside. PMID- 22496545 TI - Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. AB - Epidemiological studies link short sleep duration and circadian disruption with higher risk of metabolic syndrome and diabetes. We tested the hypotheses that prolonged sleep restriction with concurrent circadian disruption, as can occur in people performing shift work, impairs glucose regulation and metabolism. Healthy adults spent >5 weeks under controlled laboratory conditions in which they experienced an initial baseline segment of optimal sleep, 3 weeks of sleep restriction (5.6 hours of sleep per 24 hours) combined with circadian disruption (recurring 28-hour "days"), followed by 9 days of recovery sleep with circadian re-entrainment. Exposure to prolonged sleep restriction with concurrent circadian disruption, with measurements taken at the same circadian phase, decreased the participants' resting metabolic rate and increased plasma glucose concentrations after a meal, an effect resulting from inadequate pancreatic insulin secretion. These parameters normalized during the 9 days of recovery sleep and stable circadian re-entrainment. Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase the risk of obesity and diabetes. PMID- 22496546 TI - Model-based noninvasive estimation of intracranial pressure from cerebral blood flow velocity and arterial pressure. AB - Intracranial pressure (ICP) is affected in many neurological conditions. Clinical measurement of pressure on the brain currently requires placing a probe in the cerebrospinal fluid compartment, the brain tissue, or other intracranial space. This invasiveness limits the measurement to critically ill patients. Because ICP is also clinically important in conditions ranging from brain tumors and hydrocephalus to concussions, noninvasive determination of ICP would be desirable. Our model-based approach to continuous estimation and tracking of ICP uses routinely obtainable time-synchronized, noninvasive (or minimally invasive) measurements of peripheral arterial blood pressure and blood flow velocity in the middle cerebral artery (MCA), both at intra-heartbeat resolution. A physiological model of cerebrovascular dynamics provides mathematical constraints that relate the measured waveforms to ICP. Our algorithm produces patient-specific ICP estimates with no calibration or training. Using 35 hours of data from 37 patients with traumatic brain injury, we generated ICP estimates on 2665 nonoverlapping 60-beat data windows. Referenced against concurrently recorded invasive parenchymal ICP that varied over 100 millimeters of mercury (mmHg) across all records, our estimates achieved a mean error (bias) of 1.6 mmHg and SD of error (SDE) of 7.6 mmHg. For the 1673 data windows over 22 hours in which blood flow velocity recordings were available from both the left and the right MCA, averaging the resulting bilateral ICP estimates reduced the bias to 1.5 mmHg and SDE to 5.9 mmHg. This accuracy is already comparable to that of some invasive ICP measurement methods in current clinical use. PMID- 22496547 TI - Prognostic indicators of life-threatening malaria are associated with distinct parasite variant antigen profiles. AB - PfEMP1 is a family of cytoadhesive surface antigens expressed on erythrocytes infected with Plasmodium falciparum, the parasite that causes the most severe form of malaria. These surface antigens play a role in immune evasion and are thought to contribute to the pathogenesis of the malaria parasite. Previous studies have suggested a role for a specific subset of PfEMP1 called "group A" in severe malaria. To explore the role of group A PfEMP1 in disease, we measured the expression of the var genes that encode them in parasites from clinical isolates collected from children suffering from malaria. We also looked at the ability of these clinical isolates to induce rosetting of erythrocytes, which indicates a cytoadhesion phenotype that is thought to be important in pathogenesis. These two sets of data were correlated with the presence of two life-threatening manifestations of severe malaria in the children: impaired consciousness and respiratory distress. Using regression analysis, we show that marked rosetting was associated with respiratory distress, whereas elevated expression of group A like var genes without elevated rosetting was associated with impaired consciousness. The results suggest that manifestations of malarial disease may reflect the distribution of cytoadhesion phenotypes expressed by the infecting parasite population. PMID- 22496548 TI - Alexander disease. PMID- 22496549 TI - Motoneurons secrete angiogenin to induce RNA cleavage in astroglia. AB - Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder affecting motoneurons. Mutations in angiogenin, encoding a member of the pancreatic RNase A superfamily, segregate with ALS. We previously demonstrated that angiogenin administration shows promise as a neuroprotective therapeutic in studies using transgenic ALS mice and primary motoneuron cultures. Its mechanism of action and target cells in the spinal cord, however, are largely unknown. Using mixed motoneuron cultures, motoneuron-like NSC34 cells, and primary astroglia cultures as model systems, we here demonstrate that angiogenin is a neuronally secreted factor that is endocytosed by astroglia and mediates neuroprotection in paracrine. We show that wild-type angiogenin acts unidirectionally to induce RNA cleavage in astroglia, while the ALS-associated K40I mutant is also secreted and endocytosed, but fails to induce RNA cleavage. Angiogenin uptake into astroglia requires heparan sulfate proteoglycans, and engages clathrin-mediated endocytosis. We show that this uptake mechanism exists for mouse and human angiogenin, and delivers a functional RNase output. Moreover, we identify syndecan 4 as the angiogenin receptor mediating the selective uptake of angiogenin into astroglia. Our data provide new insights into the paracrine activities of angiogenin in the nervous system, and further highlight the critical role of non-neuronal cells in the pathogenesis of ALS. PMID- 22496550 TI - Comparative anatomy of marmoset and mouse cortex from genomic expression. AB - Advances in mouse neural circuit genetics, brain atlases, and behavioral assays provide a powerful system for modeling the genetic basis of cognition and psychiatric disease. However, a critical limitation of this approach is how to achieve concordance of mouse neurobiology with the ultimate goal of understanding the human brain. Previously, the common marmoset has shown promise as a genetic model system toward the linking of mouse and human studies. However, the advent of marmoset transgenic approaches will require an understanding of developmental principles in marmoset compared to mouse. In this study, we used gene expression analysis in marmoset brain to pose a series of fundamental questions on cortical development and evolution for direct comparison to existing mouse brain atlas expression data. Most genes showed reliable conservation of expression between marmoset and mouse. However, certain markers had strikingly divergent expression patterns. The lateral geniculate nucleus and pulvinar in the thalamus showed diversification of genetic organization between marmoset and mouse, suggesting they share some similarity. In contrast, gene expression patterns in early visual cortical areas showed marmoset-specific expression. In prefrontal cortex, some markers labeled architectonic areas and layers distinct between mouse and marmoset. Core hippocampus was conserved, while afferent areas showed divergence. Together, these results indicate that existing cortical areas are genetically conserved between marmoset and mouse, while differences in areal parcellation, afferent diversification, and layer complexity are associated with specific genes. Collectively, we propose that gene expression patterns in marmoset brain reveal important clues to the principles underlying the molecular evolution of cortical and cognitive expansion. PMID- 22496551 TI - A model of toxic neuropathy in Drosophila reveals a role for MORN4 in promoting axonal degeneration. AB - Axonal degeneration is a molecular self-destruction cascade initiated following traumatic, toxic, and metabolic insults. Its mechanism underlies a number of disorders including hereditary and diabetic neuropathies and the neurotoxic side effects of chemotherapy drugs. Molecules that promote axonal degeneration could represent potential targets for therapy. To identify such molecules, we designed a screening platform based on intoxication of Drosophila larvae with paclitaxel (taxol), a chemotherapeutic agent that causes neuropathy in cancer patients. In Drosophila, taxol treatment causes swelling, fragmentation, and loss of axons in larval peripheral nerves. This axonal loss is not due to apoptosis of neurons. Taxol-induced axonal degeneration in Drosophila shares molecular execution mechanisms with vertebrates, including inhibition by both NMNAT (nicotinamide mononucleotide adenylyltransferase) expression and loss of wallenda/DLK (dual leucine zipper kinase). In a pilot RNAi-based screen we found that knockdown of retinophilin (rtp), which encodes a MORN (membrane occupation and recognition nexus) repeat-containing protein, protects axons from degeneration in the presence of taxol. Loss-of-function mutants of rtp replicate this axonal protection. Knockdown of rtp also delays axonal degeneration in severed olfactory axons. We demonstrate that the mouse ortholog of rtp, MORN4, promotes axonal degeneration in mouse sensory axons following axotomy, illustrating conservation of function. Hence, this new model can identify evolutionarily conserved genes that promote axonal degeneration, and so could identify candidate therapeutic targets for a wide-range of axonopathies. PMID- 22496552 TI - HDAC1 regulates fear extinction in mice. AB - Histone acetylation has been implicated with the pathogenesis of neuropsychiatric disorders and targeting histone deacetylases (HDACs) using HDAC inhibitors was shown to be neuroprotective and to initiate neuroregenerative processes. However, little is known about the role of individual HDAC proteins during the pathogenesis of brain diseases. HDAC1 was found to be upregulated in patients suffering from neuropsychiatric diseases. Here, we show that virus-mediated overexpression of neuronal HDAC1 in the adult mouse hippocampus specifically affects the extinction of contextual fear memories, while other cognitive abilities were unaffected. In subsequent experiments we show that under physiological conditions, hippocampal HDAC1 is required for extinction learning via a mechanism that involves H3K9 deacetylation and subsequent trimethylation of target genes. In conclusion, our data show that hippocampal HDAC1 has a specific role in memory function. PMID- 22496553 TI - Survival motor neuron affects plastin 3 protein levels leading to motor defects. AB - The actin-binding protein plastin 3 (PLS3) has been identified as a modifier of the human motoneuron disease spinal muscular atrophy (SMA). SMA is caused by decreased levels of the survival motor neuron protein (SMN) and in its most severe form causes death in infants and young children. To understand the mechanism of PLS3 in SMA, we have analyzed pls3 RNA and protein in zebrafish smn mutants. We show that Pls3 protein levels are severely decreased in smn(-/-) mutants without a reduction in pls3 mRNA levels. Moreover, we show that both pls3 mRNA and protein stability are unaffected when Smn is reduced. This indicates that SMN affects PLS3 protein production. We had previously shown that, in smn mutants, the presynaptic protein SV2 is decreased at neuromuscular junctions. Transgenically driving human PLS3 in motoneurons rescues the decrease in SV2 expression. To determine whether PLS3 could also rescue function, we performed behavioral analysis on smn mutants and found that they had a significant decrease in spontaneous swimming and turning. Driving PLS3 transgenically in motoneurons rescued both of these defects. These data show that PLS3 protein levels are dependent on SMN and that PLS3 is able to rescue the neuromuscular defects and corresponding movement phenotypes caused by low levels of Smn suggesting that decreased PLS3 contributes to SMA motor phenotypes. PMID- 22496554 TI - Familial frontotemporal dementia-associated presenilin-1 c.548G>T mutation causes decreased mRNA expression and reduced presenilin function in knock-in mice. AB - Mutations in the presenilin-1 (PSEN1) gene are associated with familial Alzheimer's disease and frontotemporal dementia (FTD). Interestingly, neuropathological analysis of a Belgian FTD family carrying a PSEN1 c.548G>T mutation confirmed neurodegeneration in the absence of amyloid plaques. To investigate the impact of the c.548G>T mutation on presenilin-1 (PS1) function in vivo, we introduced this mutation into the genomic Psen1 locus. The resulting c.548G>T knock-in (KI) mice are viable but express markedly lower levels of Psen1 mRNA and protein in the brain. This reduction is due to production of aberrantly spliced transcripts lacking either exon 6 or exons 6 and 7 and their subsequent degradation via non-sense-mediated decay (NMD); inhibition of NMD by cycloheximide treatment stabilized these transcripts and restored the level of Psen1 mRNA in KI/KI brains. Interestingly, the reduction of Psen1 mRNA expression and the degradation of aberrant Psen1 splice products occur exclusively in the brain but not in other tissues. Consistent with decreased Psen1 expression, gamma secretase activity was strongly reduced in the cerebral cortex of KI mice, as measured by de novo gamma-secretase-mediated cleavage of APP and Notch. Moreover, PS1 expressed from Psen1 cDNA carrying the c.548G>T mutation displayed normal gamma-secretase activity in cultured cells, indicating that the corresponding p.183G>V amino acid substitution does not affect gamma-secretase activity. Finally, Psen1 c.548G>T(KI/KI);Psen2(-/-) mice exhibited mild spatial memory deficits in the Morris water maze task. Together, our findings demonstrate that the c.548G>T mutation results in a brain-specific loss of presenilin function due to decreased Psen1 mRNA expression. PMID- 22496555 TI - Gating the polarity of endocannabinoid-mediated synaptic plasticity by nitric oxide in the spinal locomotor network. AB - The final motor output underlying behavior arises from an appropriate balance between excitation and inhibition within neural networks. Retrograde signaling by endocannabinoids adapts synaptic strengths and the global activity of neural networks. In the spinal cord, endocannabinoids are mobilized postsynaptically from network neurons and act retrogradely on presynaptic cannabinoid receptors to potentiate the locomotor frequency. However, it is still unclear whether mechanisms exist within the locomotor networks that determine the sign of the modulation by cannabinoid receptors to differentially regulate excitation and inhibition. In this study, using the lamprey spinal cord in vitro, we first report that 2-AG (2-arachidonyl glycerol) is mobilized by network neurons and underlies a form of modulation that is embedded within the locomotor networks. We then show that the polarity of the endocannabinoid modulation is gated by nitric oxide to enable simultaneously potentiation of excitation and depression of inhibition within the spinal locomotor networks. Our results suggest that endocannabinoid and nitric oxide systems interact to mediate inversion of the polarity of synaptic plasticity within the locomotor networks. Thus, endocannabinoid and nitric oxide shift in the excitation-inhibition balance to set the excitability of the spinal locomotor network. PMID- 22496556 TI - Dopamine modulation of Ih improves temporal fidelity of spike propagation in an unmyelinated axon. AB - We studied how conduction delays of action potentials in an unmyelinated axon depended on the history of activity and how this dependence was changed by the neuromodulator dopamine (DA). The pyloric dilator axons of the stomatogastric nervous system in the lobster, Homarus americanus, exhibited substantial activity dependent hyperpolarization and changes in spike shape during repetitive activation. The conduction delays varied by several milliseconds per centimeter, and, during activation with realistic burst patterns or Poisson-like patterns, changes in delay occurred over multiple timescales. The mean delay increased, whereas the resting membrane potential hyperpolarized with a time constant of several minutes. Concomitantly with the mean delay, the variability of delay also increased. The variability of delay was not a linear or monotonic function of instantaneous spike frequency or spike shape parameters, and the relationship between these parameters changed with the increase in mean delay. Hyperpolarization was counteracted by a hyperpolarization-activated inward current (I(h)), and the magnitude of I(h) critically determined the temporal fidelity of spike propagation. Pharmacological block of I(h) increased the change in delay and the variability of delay, and increasing I(h) by application of DA diminished both. Consequently, the temporal fidelity of pattern propagation was substantially improved in DA. Standard measurements of changes in excitability or delay with paired stimuli or tonic stimulation failed to capture the dynamics of spike conduction. These results indicate that spike conduction can be extremely sensitive to the history of axonal activity and to the presence of neuromodulators, with potentially important consequences for temporal coding. PMID- 22496557 TI - Axonal thinning and extensive remyelination without chronic demyelination in spinal injured rats. AB - Remyelination following spinal cord injury (SCI) is thought to be incomplete; demyelination is reported to persist chronically and is proposed as a compelling therapeutic target. Yet most reports do not distinguish between the myelin status of intact axons and injury-severed axons whose proximal stumps persist but provide no meaningful function. We previously found full remyelination of spared, intact rubrospinal axons caudal to the lesion in chronic mouse SCI. However, the clinical concept of chronically demyelinated spared axons remains controversial. Since mouse models may have limitations in clinical translation, we asked whether the capacity for full remyelination is conserved in clinically relevant chronic rat SCI. We determined myelin status by examining paranodal protein distribution on anterogradely labeled, intact corticospinal and rubrospinal axons throughout the extent of the lesion. Demyelination was evident on proximal stumps of severed axons, but not on intact axons. For the first time, we demonstrate that a majority of intact axons exhibit remyelination (at least one abnormally short internode, <100 MUm). Remarkably, shortened internodes were significantly concentrated at the lesion epicenter and individual axons were thinned by 23% compared with their rostral and caudal zones. Mathematical modeling predicted a 25% decrease in conduction velocity at the lesion epicenter due to short internodes and axonal thinning. In conclusion, we do not find a large chronically demyelinated population to target with remyelination therapies. Interventions may be better focused on correcting structural or molecular abnormalities of regenerated myelin. PMID- 22496558 TI - Phosphorylation of Rpt6 regulates synaptic strength in hippocampal neurons. AB - It has become increasingly evident that protein degradation via the ubiquitin proteasome system plays a fundamental role in the development, maintenance and remodeling of synaptic connections in the CNS. We and others have recently described the activity-dependent regulation of proteasome activity and recruitment of proteasomes into spine compartments involving the phosphorylation of the 19S ATPase subunit, Rpt6, by the plasticity kinase Ca(2+)/calmodulin dependent protein kinase II alpha (CaMKIIalpha) (Bingol and Schuman, 2006; Djakovic et al., 2009; Bingol et al, 2010). Here, we investigated the role of Rpt6 phosphorylation on proteasome function and synaptic strength. Utilizing a phospho-specific antibody we verified that Rpt6 is phosphorylated at Serine 120 (S120) by CaMKIIalpha. In addition, we found that Rpt6 is phosphorylated by CaMKIIalpha in an activity-dependent manner. Furthermore, we showed that a serine 120 to aspartic acid phospho-mimetic mutant of Rpt6 (S120D) increases its resistance to detergent extraction in rat hippocampal dendrites, indicating phosphorylated Rpt6 may promote the tethering of proteasomes to scaffolds and cytoskeletal components. Expression of Rpt6 S120D decreased miniature EPSC (mEPSC) amplitude, while expression of a phospho-dead mutant (S120A) increased mEPSC amplitude. Surprisingly, homeostatic scaling of mEPSC amplitude produced by chronic application of bicuculline or tetrodotoxin is both mimicked and occluded by altered Rpt6 phosphorylation. Together, these data suggest that CaMKII dependent phosphorylation of Rpt6 at S120 may be an important regulatory mechanism for proteasome-dependent control of synaptic remodeling in slow homeostatic plasticity. PMID- 22496559 TI - Diabetes impairs cortical plasticity and functional recovery following ischemic stroke. AB - Diabetics are at greater risk of having a stroke and are less likely to recover from it. To understand this clinically relevant problem, we induced an ischemic stroke in the primary forelimb somatosensory (FLS1) cortex of diabetic mice and then examined sensory-evoked changes in cortical membrane potentials and behavioral recovery of forelimb sensory-motor function. Consistent with previous studies, focal stroke in non-diabetic mice was associated with acute deficits in forelimb sensorimotor function and a loss of forelimb evoked cortical depolarizations in peri-infarct cortex that gradually recovered over several weeks time. In addition, we discovered that damage to FLS1 cortex led to an enhancement of forelimb evoked depolarizations in secondary forelimb somatosensory (FLS2) cortex. Enhanced FLS2 cortical responses appeared to play a role in stroke recovery given that silencing this region was sufficient to reinstate forelimb impairments. By contrast, the functional reorganization of FLS1 and FLS2 cortex was largely absent in diabetic mice and could not be explained by more severe cortical infarctions. Diabetic mice also showed persistent behavioral deficits in sensorimotor function of the forepaw, which could not be rescued by chronic insulin therapy after stroke. Collectively these results indicate that diabetes has a profound effect on brain plasticity, especially when challenged, as is often the case, by an ischemic event. Further, our data suggest that secondary cortical regions play an important role in the restoration of sensorimotor function when primary cortical regions are damaged. PMID- 22496560 TI - Brain-targeted proanthocyanidin metabolites for Alzheimer's disease treatment. AB - While polyphenolic compounds have many health benefits, the potential development of polyphenols for the prevention/treatment of neurological disorders is largely hindered by their complexity as well as by limited knowledge regarding their bioavailability, metabolism, and bioactivity, especially in the brain. We recently demonstrated that dietary supplementation with a specific grape-derived polyphenolic preparation (GP) significantly improves cognitive function in a mouse model of Alzheimer's disease (AD). GP is comprised of the proanthocyanidin (PAC) catechin and epicatechin in monomeric (Mo), oligomeric, and polymeric forms. In this study, we report that following oral administration of the independent GP forms, only Mo is able to improve cognitive function and only Mo metabolites can selectively reach and accumulate in the brain at a concentration of ~400 nM. Most importantly, we report for the first time that a biosynthetic epicatechin metabolite, 3'-O-methyl-epicatechin-5-O-beta-glucuronide (3'-O-Me-EC Gluc), one of the PAC metabolites identified in the brain following Mo treatment, promotes basal synaptic transmission and long-term potentiation at physiologically relevant concentrations in hippocampus slices through mechanisms associated with cAMP response element binding protein (CREB) signaling. Our studies suggest that select brain-targeted PAC metabolites benefit cognition by improving synaptic plasticity in the brain, and provide impetus to develop 3'-O Me-EC-Gluc and other brain-targeted PAC metabolites to promote learning and memory in AD and other forms of dementia. PMID- 22496561 TI - Adaptor protein LNK is a negative regulator of brain neural stem cell proliferation after stroke. AB - Ischemic stroke causes transient increase of neural stem and progenitor cell (NSPC) proliferation in the subventricular zone (SVZ), and migration of newly formed neuroblasts toward the damaged area where they mature to striatal neurons. The molecular mechanisms regulating this plastic response, probably involved in structural reorganization and functional recovery, are poorly understood. The adaptor protein LNK suppresses hematopoietic stem cell self-renewal, but its presence and role in the brain are poorly understood. Here we demonstrate that LNK is expressed in NSPCs in the adult mouse and human SVZ. Lnk(-/-) mice exhibited increased NSPC proliferation after stroke, but not in intact brain or following status epilepticus. Deletion of Lnk caused increased NSPC proliferation while overexpression decreased mitotic activity of these cells in vitro. We found that Lnk expression after stroke increased in SVZ through the transcription factors STAT1/3. LNK attenuated insulin-like growth factor 1 signaling by inhibition of AKT phosphorylation, resulting in reduced NSPC proliferation. Our findings identify LNK as a stroke-specific, endogenous negative regulator of NSPC proliferation, and suggest that LNK signaling is a novel mechanism influencing plastic responses in postischemic brain. PMID- 22496562 TI - Schaffer-specific local field potentials reflect discrete excitatory events at gamma frequency that may fire postsynaptic hippocampal CA1 units. AB - Information processing and exchange between brain nuclei are made through spike series sent by individual neurons in highly irregular temporal patterns. Synchronization in cell assemblies, proposed as a network language for internal neural representations, still has little experimental support. We use a novel technique to extract pathway-specific local field potentials (LFPs) in the hippocampus to explore the ongoing temporal structure of a single presynaptic input, the CA3 Schaffer pathway, and its contribution to the spontaneous output of CA1 units in anesthetized rat. We found that Schaffer-specific LFPs are composed of a regular succession of pulse-like excitatory packages initiated by spontaneous clustered firing of CA3 pyramidal cells to which individual units contribute variably. A fraction of these packages readily induce firing of CA1 pyramidal cells and interneurons, the so-called Schaffer-driven spikes, revealing the presynaptic origin in the output code of single CA1 units. The output of 70% of CA1 pyramidal neurons contains up to 10% of such spikes. Our results suggest a hierarchical internal operation of the CA3 region based on sequential oscillatory activation of pyramidal cell assemblies whose activity partly gets in the output code at the next station. We conclude that CA1 output may directly reflect the activity of specific ensembles of CA3 neurons. Thus, the fine temporal structure of pathway-specific LFPs, as an accurate readout of the activity of a presynaptic population, is useful in searching for hidden presynaptic code in irregular spikes series of individual neurons and assemblies. PMID- 22496563 TI - A role for the calmodulin kinase II-related anchoring protein (alphakap) in maintaining the stability of nicotinic acetylcholine receptors. AB - alphakap, a muscle specific anchoring protein encoded within the Camk2a gene, is thought to play a role in targeting multiple calcium/calmodulin kinase II isoforms to specific subcellular locations. Here we demonstrate a novel function of alphakap in stabilizing nicotinic acetylcholine receptors (AChRs). Knockdown of alphakap expression with shRNA significantly enhanced the degradation of AChR alpha-subunits (AChRalpha), leading to fewer and smaller AChR clusters on the surface of differentiated C2C12 myotubes. Mutagenesis and biochemical studies in HEK293T cells revealed that alphakap promoted AChRalpha stability by a ubiquitin dependent mechanism. In the absence of alphakap, AChRalpha was heavily ubiquitinated, and the number of AChRalpha was increased by proteasome inhibitors. However, in the presence of alphakap, AChRalpha was less ubiquitinated and proteasome inhibitors had almost no effect on AChRalpha accumulation. The major sites of AChRalpha ubiquitination reside within the large intracellular loop and mutations of critical lysine residues in this loop to arginine increased AChRalpha stability in the absence of alphakap. These results provide an unexpected mechanism by which alphakap controls receptor trafficking onto the surface of muscle cells and thus the maintenance of postsynaptic receptor density and synaptic function. PMID- 22496564 TI - Glutamate controls tPA recycling by astrocytes, which in turn influences glutamatergic signals. AB - Tissue-type plasminogen activator (tPA) regulates physiological processes in the brain, such as learning and memory, and plays a critical role in neuronal survival and neuroinflammation in pathological conditions. Here we demonstrate, by combining mouse in vitro and in vivo data, that tPA is an important element of the cross talk between neurons and astrocytes. The data show that tPA released by neurons is constitutively endocytosed by astrocytes via the low-density lipoprotein-related protein receptor, and is then exocytosed in a regulated manner. The exocytotic recycling of tPA by astrocytes is inhibited in the presence of extracellular glutamate. Kainate receptors of astrocytes act as sensors of extracellular glutamate and, via a signaling pathway involving protein kinase C, modulate the exocytosis of tPA. Further, by thus capturing extracellular tPA, astrocytes serve to reduce NMDA-mediated responses potentiated by tPA. Overall, this work provides the first demonstration that the neuromodulator, tPA, may also be considered as a gliotransmitter. PMID- 22496565 TI - A common molecular basis for exogenous and endogenous cannabinoid potentiation of glycine receptors. AB - Both exogenous and endogenous cannabinoids can allosterically modulate glycine receptors (GlyRs). However, little is known about the molecular basis of cannabinoid-GlyR interactions. Here we report that sustained incubation with the endocannabinoid anandamide (AEA) substantially increased the amplitude of glycine activated current in both rat cultured spinal neurons and in HEK-293 cells expressing human alpha1, rat alpha2 and alpha3 GlyRs. While the alpha1 and alpha3 subunits were highly sensitive to AEA-induced potentiation, the alpha2 subunit was relatively insensitive to AEA. Switching a serine at 296 and 307 in the TM3 (transmembrane domain 3) of the alpha1 and alpha3 subunits with an alanine (A) at the equivalent position in the alpha2 subunit converted the alpha1/alpha3 AEA sensitive receptors to sensitivity resembling that of alpha2. The S296 residue is also critical for exogenous cannabinoid-induced potentiation of I(Gly). The magnitude of AEA potentiation decreased with removal of either the hydroxyl or oxygen groups on AEA. While desoxy-AEA was significantly less efficacious in potentiating I(Gly), desoxy-AEA inhibited potentiation produced by both Delta(9) tetrahydrocannabinol (THC), a major psychoactive component of marijuana, and AEA. Similarly, didesoxy-THC, a modified THC with removal of both hydroxyl/oxygen groups, did not affect I(Gly) when applied alone but inhibited the potentiation of I(Gly) induced by AEA and THC. These findings suggest that exogenous and endogenous cannabinoids potentiate GlyRs via a hydrogen bonding-like interaction. Such a specific interaction likely stems from a common molecular basis involving the S296 residue in the TM3 of the alpha1 and alpha3 subunits. PMID- 22496566 TI - Genetic evidence for a contribution of EphA:ephrinA reverse signaling to motor axon guidance. AB - Repulsive Eph forward signaling from limb-derived ephrins guides the axons of lateral motor column (LMC) motor neurons. LMC axons also express ephrinAs, while their EphA receptors are expressed in the limb mesenchyme. In vitro studies have suggested that reverse signaling from limb-derived EphA4 to axonal ephrinAs might result in attraction of LMC axons. However, genetic evidence for this function is lacking. Here we use the Dunn chamber turning assay to show that EphA proteins are chemoattractants and elicit fast turning responses in LMC neurons in vitro. Moreover, ectopic expression of EphA4 in chick hindlimb changes the limb trajectory of LMC axons. Nervous system-specific deletion of EphA4 in mice resulted in fewer LMC axon projection errors than the ubiquitous deletion of EphA4. Additionally, a signaling-incompetent EphA4 mutant partially rescued guidance errors in the hindlimb, suggesting that limb-derived EphA4 contributes to the establishment of LMC projections. In summary, we provide evidence for a role of EphA:ephrinA attractive reverse signaling in motor axon guidance and in vivo evidence of in-parallel forward Eph and reverse ephrin signaling function in the same neuronal population. PMID- 22496568 TI - Lysosomal dysfunction in a mouse model of Sandhoff disease leads to accumulation of ganglioside-bound amyloid-beta peptide. AB - Alterations in the lipid composition of endosomal-lysosomal membranes may constitute an early event in Alzheimer's disease (AD) pathogenesis. In this study, we investigated the possibility that GM2 ganglioside accumulation in a mouse model of Sandhoff disease might be associated with the accumulation of intraneuronal and extracellular proteins commonly observed in AD. Our results show intraneuronal accumulation of amyloid-beta peptide (Abeta)-like, alpha synuclein-like, and phospho-tau-like immunoreactivity in the brains of beta hexosaminidase knock-out (HEXB KO) mice. Biochemical and immunohistochemical analyses confirmed that at least some of the intraneuronal Abeta-like immunoreactivity (iAbeta-LIR) represents amyloid precursor protein C-terminal fragments (APP-CTFs) and/or Abeta. In addition, we observed increased levels of Abeta40 and Abeta42 peptides in the lipid-associated fraction of HEXB KO mouse brains, and intraneuronal accumulation of ganglioside-bound Abeta (GAbeta) immunoreactivity in a brain region-specific manner. Furthermore, alpha-synuclein and APP-CTFs and/or Abeta were found to accumulate in different regions of the substantia nigra, indicating different mechanisms of accumulation or turnover pathways. Based on the localization of the accumulated iAbeta-LIR to endosomes, lysosomes, and autophagosomes, we conclude that a significant accumulation of iAbeta-LIR may be associated with the lysosomal-autophagic turnover of Abeta and fragments of APP-containing Abeta epitopes. Importantly, intraneuronal GAbeta immunoreactivity, a proposed prefibrillar aggregate found in AD, was found to accumulate throughout the frontal cortices of postmortem human GM1 gangliosidosis, Sandhoff disease, and Tay-Sachs disease brains. Together, these results establish an association between the accumulation of gangliosides, autophagic vacuoles, and the intraneuronal accumulation of proteins associated with AD. PMID- 22496567 TI - Transcript-specific associations of SLC12A5 (KCC2) in human prefrontal cortex with development, schizophrenia, and affective disorders. AB - The neuron-specific K(+)-Cl(-) cotransporter SLC12A5, also known as KCC2, helps mediate the electrophysiological effects of GABA. The pattern of KCC2 expression during early brain development suggests that its upregulation drives the postsynaptic switch of GABA from excitation to inhibition. We previously found decreased expression of full-length KCC2 in the postmortem hippocampus of patients with schizophrenia, but not in the dorsolateral prefrontal cortex (DLPFC). Using PCR and rapid amplification of cDNA ends, we discovered several previously unrecognized alternative KCC2 transcripts in both human adult and fetal brain in addition to the previously identified full-length (NM_020708.3) and truncated (AK098371) transcripts. We measured the expression levels of four relatively abundant truncated splice variants, including three novel transcripts (DeltaEXON6, EXON2B, and EXON6B) and one previously described transcript (AK098371), in a large human cohort of nonpsychiatric controls across the lifespan, and in patients with schizophrenia and affective disorders. In SH-SY5Y cell lines, these transcripts were translated into proteins and expressed at their predicted sizes. Expression of the EXON6B transcript is increased in the DLPFC of patients with schizophrenia (p = 0.03) but decreased in patients with major depression (p = 0.04). The expression of AK098371 is associated with a GAD1 single nucleotide polymorphism (rs3749034) that previously has been associated with GAD67 expression and risk for schizophrenia. Our data confirm the developmental regulation of KCC2 expression, and provide evidence that KCC2 transcripts are differentially expressed in schizophrenia and affective disorders. Alternate transcripts from KCC2 may participate in the abnormal GABA signaling in the DLPFC associated with schizophrenia. PMID- 22496569 TI - Tumor necrosis factor activation of vagal afferent terminal calcium is blocked by cannabinoids. AB - The early proinflammatory cytokine tumor necrosis factor (TNF) is released in significant quantities by the activated immune system in response to infection, leukemia, autoimmune disorders, and radiation sickness. Nausea, emesis, and anorexia are common features of these disorders. TNF action on vagal afferent terminals in the brainstem is a likely cause of the malaise associated with these disorders. Our previous work has shown that TNF action to excite vagal afferents occurs as a result of sensitization of ryanodine channels in afferent nerve terminals. For millennia, cannabinoids (CB) have been used to combat the visceral malaise associated with chronic disease, although the mechanism of action has not been clear. Previous work in culture systems suggests that CB1 agonists can suppress neurotransmission by downregulating ryanodine channels through a protein kinase A (PKA)-dependent mechanism. Laser confocal calcium imaging methods were used to directly examine effects of CB1 cannabinoid agonists and TNF on visceral afferent signaling in the rat hindbrain. CB1 agonists blocked the effects of TNF to amplify vagal afferent responsiveness; blockade of PKA with H89 also eliminated the TNF amplification effect. These results help to explain the effectiveness of cannabinoids in blocking the malaise generated by TNF-releasing disease processes by opposing effects on ryanodine channels. PMID- 22496570 TI - Dynamical properties of BOLD activity from the ventral posteromedial cortex associated with meditation and attentional skills. AB - Neuroimaging data suggest a link between the spontaneous production of thoughts during wakeful rest and slow fluctuations of activity in the default mode network (DMN), a set of brain regions with high basal metabolism and a major neural hub in the ventral posteromedial cortex (vPMC). Meta-awareness and regulation of mind wandering are core cognitive components of most contemplative practices and to study their impact on DMN activity, we collected functional MRI (fMRI) data from a cohort of experienced Zen meditators and meditation-naive controls engaging in a basic attention-to-breathing protocol. We observed a significant group difference in the skewness of the fMRI BOLD signal from the vPMC, suggesting that the relative incidence of states of elevated vPMC activity was lower in meditators; furthermore, the same parameter was significantly correlated with performance on a rapid visual information processing (RVIP) test for sustained attention conducted outside the scanner. Finally, a functional connectivity analysis with the vPMC seed revealed a significant association of RVIP performance with the degree of temporal correlation between vPMC and the right temporoparietal junction (TPJ), a region strongly implicated in stimulus triggered reorienting of attention. Together, these findings suggest that the vPMC BOLD signal skewness and the temporal relationship of vPMC and TPJ activities reflect the dynamic tension between mind-wandering, meta-awareness, and directed attention, and may represent a useful endophenotype for studying individual differences in attentional abilities and the impairment of the latter in specific clinical conditions. PMID- 22496571 TI - Interactions between core and matrix thalamocortical projections in human sleep spindle synchronization. AB - Sleep spindles are bursts of 11-15 Hz that occur during non-rapid eye movement sleep. Spindles are highly synchronous across the scalp in the electroencephalogram (EEG) but have low spatial coherence and exhibit low correlation with the EEG when simultaneously measured in the magnetoencephalogram (MEG). We developed a computational model to explore the hypothesis that the spatial coherence spindles in the EEG is a consequence of diffuse matrix projections of the thalamus to layer 1 compared with the focal projections of the core pathway to layer 4 recorded in the MEG. Increasing the fanout of thalamocortical connectivity in the matrix pathway while keeping the core pathway fixed led to increased synchrony of the spindle activity in the superficial cortical layers in the model. In agreement with cortical recordings, the latency for spindles to spread from the core to the matrix was independent of the thalamocortical fanout but highly dependent on the probability of connections between cortical areas. PMID- 22496572 TI - Alignment of multimodal sensory input in the superior colliculus through a gradient-matching mechanism. AB - The superior colliculus (SC) is a midbrain structure that integrates visual, somatosensory, and auditory inputs to direct head and eye movements. Each of these modalities is topographically mapped and aligned with the others to ensure precise behavioral responses to multimodal stimuli. While it is clear that neural activity is instructive for topographic alignment of inputs from the visual cortex (V1) and auditory system with retinal axons in the SC, there is also evidence that activity-independent mechanisms are used to establish topographic alignment between modalities. Here, we show that the topography of the projection from primary somatosensory cortex (S1) to the SC is established during the first postnatal week. Unlike V1-SC projections, the S1-SC projection does not bifurcate when confronted with a duplicated retinocollicular map, showing that retinal input in the SC does not influence the topography of the S1-SC projection. However, S1-SC topography is disrupted in mice lacking ephrin-As, which we find are expressed in graded patterns along with their binding partners, the EphA4 and EphA7, in both S1 and the somatosensory recipient layer of the SC. Together, these data support a model in which somatosensory inputs into the SC map topographically and establish alignment with visual inputs in the SC using a gradient-matching mechanism. PMID- 22496573 TI - Weight-specific anticipatory coding of grip force in human dorsal premotor cortex. AB - The dorsal premotor cortex (PMd) uses prior sensory information for motor preparation. Here, we used a conditioning-and-map approach in 11 healthy male humans (mean age 27 years) to further clarify the role of PMd in anticipatory motor control. We transiently disrupted neuronal processing in PMd, using either continuous theta burst stimulation (cTBS) at 80% (inhibitory cTBS) or 30% (sham cTBS) of active motor threshold. The conditioning effects of cTBS on preparatory brain activity were assessed with functional MRI, while participants lifted a light or heavy weight in response to a go-cue (S2). An additional pre-cue (S1) correctly predicted the weight in 75% of the trials. Participants were asked to use this prior information to prepare for the lift. In the sham condition, grip force showed a consistent undershoot, if the S1 incorrectly prompted the preparation of a light lift. Likewise, an S1 that falsely announced a heavy weight produced a consistent overshoot in grip force. In trials with incorrect S1, preparatory activity in left PMd during the S1-S2 delay period predicted grip force undershoot but not overshoot. Real cTBS selectively abolished this undershoot in grip force. Furthermore, preparatory S1-S2 activity in left PMd no longer predicted the individual undershoot after real cTBS. Our results provide converging evidence for a causal involvement of PMd in anticipatory downscaling but not upscaling of grip force, suggesting an inhibitory role of PMd in anticipatory grip force control during object lifting. PMID- 22496574 TI - The actin-severing protein cofilin is downstream of neuregulin signaling and is essential for Schwann cell myelination. AB - Myelination is a complex process requiring coordination of directional motility and an increase in glial cell size to generate a multilamellar myelin sheath. Regulation of actin dynamics during myelination is poorly understood. However, it is known that myelin thickness is related to the abundance of neuregulin-1 (NRG1) expressed on the axon surface. Here we identify cofilin1, an actin depolymerizing and severing protein, as a downstream target of NRG1 signaling in rat Schwann cells (SCs). In isolated SCs, NRG1 promotes dephosphorylation of cofilin1 and its upstream regulators, LIM kinase (LIMK) and Slingshot-1 phosphatase (SSH1), leading to cofilin1 activation and recruitment to the leading edge of the plasma membrane. These changes are associated with rapid membrane expansion yielding a 35-50% increase in SC size within 30 min. Cofilin1-deficient SCs increase phosphorylation of ErbB2, ERK, focal adhesion kinase, and paxillin in response to NRG1, but fail to increase in size possibly due to stabilization of unusually long focal adhesions. Cofilin1-deficient SCs cocultured with sensory neurons do not myelinate. Ultrastructural analysis reveals that they unsuccessfully segregate or engage axons and form only patchy basal lamina. After 48 h of coculturing with neurons, cofilin1-deficient SCs do not align or elongate on axons and often form adhesions with the underlying substrate. This study identifies cofilin1 and its upstream regulators, LIMK and SSH1, as end targets of a NRG1 signaling pathway and demonstrates that cofilin1 is necessary for dynamic changes in the cytoskeleton needed for axon engagement and myelination by SCs. PMID- 22496575 TI - Distinct dendritic spine and nuclear phases of calcineurin activation after exposure to amyloid-beta revealed by a novel fluorescence resonance energy transfer assay. AB - Calcineurin (CaN) activation is critically involved in the regulation of spine morphology in response to oligomeric amyloid-beta (Abeta) as well as in synaptic plasticity in normal memory, but no existing techniques can monitor the spatiotemporal pattern of CaN activity. Here, we use a spectral fluorescence resonance energy transfer approach to monitor CaN activation dynamics in real time with subcellular resolution. When oligomeric Abeta derived from Tg2576 murine transgenic neurons or human AD brains were applied to wild-type murine primary cortical neurons, we observe a dynamic progression of CaN activation within minutes, first in dendritic spines, and then in the cytoplasm and, in hours, in the nucleus. CaN activation in spines leads to rapid but reversible morphological changes in spines and in postsynaptic proteins; longer exposure leads to NFAT (nuclear factor of activated T-cells) translocation to the nucleus and frank spine loss. These results provide a framework for understanding the role of calcineurin in synaptic alterations associated with AD pathogenesis. PMID- 22496576 TI - GABA site agonist gaboxadol induces addiction-predicting persistent changes in ventral tegmental area dopamine neurons but is not rewarding in mice or baboons. AB - Dopamine neurons of the ventral tegmental area (VTA) are involved at early phases of drug addiction. Even the first in vivo dose of various abused drugs induces glutamate receptor plasticity at the excitatory synapses of these neurons. Benzodiazepines that suppress the inhibitory GABAergic interneurons in the VTA via facilitation of synaptic GABA(A) receptors have induced neuroplasticity in dopamine neurons due to this disinhibitory mechanism. Here, we have tested a non benzodiazepine direct GABA site agonist 4,5,6,7-tetrahydroisoxazolol[4,5 c]pyridine-3-ol (THIP) (also known as gaboxadol) that acts preferentially via high-affinity extrasynaptic GABA(A) receptors. A single sedative dose of THIP (6 mg/kg) to mice induced glutamate receptor plasticity for at least 6 d after administration. Increased AMPA/NMDA receptor current ratio and increased frequency, amplitude, and rectification of AMPA receptor responses suggested persistent targeting of GluA2-lacking AMPA receptors in excitatory synapses of VTA dopamine neurons ex vivo after THIP administration. This effect was abolished in GABA(A) receptor delta(-/-) mice, which have a loss of extrasynaptic GABA(A) receptors. In behavioral experiments, we found neither acute reinforcement in intravenous self-administration sessions with THIP at relevant doses using a yoked control paradigm in mice nor in baboons using a standard paradigm for assessing drug abuse liability; nor was any place preference found after conditioning sessions with various doses of THIP but rather a persistent aversion in 6 mg/kg THIP-conditioned mice. In summary, we found that activation of extrasynaptic delta-subunit-containing GABA(A) receptors leads to glutamate receptor plasticity of VTA dopamine neurons, but is not rewarding, and, instead, induces aversion. PMID- 22496577 TI - Adenosine release during seizures attenuates GABAA receptor-mediated depolarization. AB - Seizure-induced release of the neuromodulator adenosine is a potent endogenous anticonvulsant mechanism, which limits the extension of seizures and mediates seizure arrest. For this reason several adenosine-based therapies for epilepsy are currently under development. However, it is not known how adenosine modulates GABAergic transmission in the context of seizure activity. This may be particularly relevant as strong activation of GABAergic inputs during epileptiform activity can switch GABA(A) receptor (GABA(A)R) signaling from inhibitory to excitatory, which is a process that plays a significant role in intractable epilepsies. We used gramicidin-perforated patch-clamp recordings to investigate the role of seizure-induced adenosine release in the modulation of postsynaptic GABA(A)R signaling in pyramidal neurons of rat hippocampus. Consistent with previous reports, GABA(A)R responses during seizure activity transiently switched from hyperpolarizing to depolarizing and excitatory. We found that adenosine released during the seizure significantly attenuated the depolarizing GABA(A)R responses and also reduced the extent of the after discharge phase of the seizure. These effects were mimicked by exogenous adenosine administration and could not be explained by a change in chloride homeostasis mechanisms that set the reversal potential for GABA(A)Rs, or by a change in the conductance of GABA(A)Rs. Rather, A(1)R-dependent activation of potassium channels increased the cell's membrane conductance and thus had a shunting effect on GABA(A)R currents. As depolarizing GABA(A)R signaling has been implicated in seizure initiation and progression, the adenosine-induced attenuation of depolarizing GABA(A)R signaling may represent an important mechanism by which adenosine can limit seizure activity. PMID- 22496578 TI - Frontostriatal white matter integrity mediates adult age differences in probabilistic reward learning. AB - Frontostriatal circuits have been implicated in reward learning, and emerging findings suggest that frontal white matter structural integrity and probabilistic reward learning are reduced in older age. This cross-sectional study examined whether age differences in frontostriatal white matter integrity could account for age differences in reward learning in a community life span sample of human adults. By combining diffusion tensor imaging with a probabilistic reward learning task, we found that older age was associated with decreased reward learning and decreased white matter integrity in specific pathways running from the thalamus to the medial prefrontal cortex and from the medial prefrontal cortex to the ventral striatum. Further, white matter integrity in these thalamocorticostriatal paths could statistically account for age differences in learning. These findings suggest that the integrity of frontostriatal white matter pathways critically supports reward learning. The findings also raise the possibility that interventions that bolster frontostriatal integrity might improve reward learning and decision making. PMID- 22496580 TI - Brief screening tests during acute admission in patients with mild stroke are predictive of vascular cognitive impairment 3-6 months after stroke. AB - OBJECTIVES: To determine the prognostic value of brief cognitive screening tests administered in the subacute stroke phase (initial 2 weeks) for the detection of significant cognitive impairment 3-6 months after stroke, the authors compared the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). METHODS: Patients with ischaemic stroke and transient ischaemic attack were assessed with both MoCA and MMSE within 14 days after index stroke, followed by a formal neuropsychological evaluation of seven cognitive domains 3-6 months later. Cognitive outcomes were dichotomised as either no-mild (impairment in <=2 cognitive domains) or moderate-severe (impairment in >= 3 cognitive domains) vascular cognitive impairment. Area under the receiver operating characteristic (ROC) curve analysis was used to compare discriminatory ability. RESULTS: 300 patients were recruited, of whom 239 received formal neuropsychological assessment 3-6 months after the stroke. 60 (25%) patients had moderate-severe VCI. The overall discriminant validity for detection of moderate-severe cognitive impairment was similar for MoCA (ROC 0.85 (95% CI 0.79 to 0.90) and MMSE (ROC 0.83 (95% CI 0.77 to 0.89)), p=0.96). Both MoCA (21/22) and MMSE (25/26) had similar discriminant indices at their optimal cutoff points; sensitivity 0.88 versus 0.88; specificity 0.64 versus 0.67; 70% versus 72% correctly classified. Moreover, both tests had similar discriminant indices in detecting impaired cognitive domains. CONCLUSIONS: Brief screening tests during acute admission in patients with mild stroke are predictive of significant vascular cognitive impairment 3-6 months after stroke. PMID- 22496579 TI - Pathways for emotions and attention converge on the thalamic reticular nucleus in primates. AB - How do emotional events readily capture our attention? To address this question we used neural tracers to label pathways linking areas involved in emotional and attentional processes in the primate brain (Macaca mulatta). We report that a novel pathway from the amygdala, the brain's emotional center, targets the inhibitory thalamic reticular nucleus (TRN), a key node in the brain's attentional network. The amygdalar pathway formed unusual synapses close to cell bodies of TRN neurons and had more large and efficient terminals than pathways from the orbitofrontal cortex and the thalamic mediodorsal nucleus, which similarly innervated extensive TRN sites. The robust amygdalar pathway provides a mechanism for rapid shifting of attention to emotional stimuli. Acting synergistically, pathways from the amygdala and orbitofrontal cortex provide a circuit for purposeful assessment of emotional stimuli. The different pathways to TRN suggest distinct mechanisms of attention to external and internal stimuli that may be differentially disrupted in anxiety and mood disorders and may be selectively targeted for therapeutic interventions. PMID- 22496581 TI - Why are upper motor neuron signs difficult to elicit in amyotrophic lateral sclerosis? AB - It is often difficult to identify signs of upper motor neuron lesion in the limbs of patients with amyotrophic lateral sclerosis, in whom there is neurogenic muscle wasting of varying severity. The reasons for this are complex and not related simply to the degree of lower motor neuron muscle wasting but, rather, depend on the pathophysiological abnormalities that develop in response to damage to descending motor pathways and to motor neurons and interneurons in the ventral horns of the spinal cord. The different mechanisms underlying the clinical phenomenology of the functional motor defect in amyotrophic lateral sclerosis, that lead to difficulty in detecting classical upper motor neuron signs, are discussed. PMID- 22496582 TI - Physiotherapists and patients with functional (psychogenic) motor symptoms: a survey of attitudes and interest. AB - BACKGROUND: Functional (psychogenic) motor symptoms are commonly encountered in clinical neurology. Physiotherapy has face validity as a treatment for such symptoms and, anecdotally, referral of patients with functional motor symptoms (FMS) to physiotherapy services is common practice by neurologists. Here the authors sought to explore exposure to and attitudes towards patients with FMS among neurophysiotherapists. METHOD: The authors used an internet survey to gather information on the knowledge and attitudes of patients with FMS among 1402 members of a UK neurophysiotherapy organisation. RESULTS: The response rate was 61%. Most physiotherapists saw patients with FMS, and for 25% of respondents these patients made up over 10% of their workload. Respondents were moderately interested in treating these patients (ranking them sixth out of 10 neurological conditions), but had low self-judged knowledge. Most respondents felt physiotherapy had more to offer patients with FMS, but felt poorly supported by referring neurologists and by inadequate service structures. CONCLUSIONS: Neurologists frequently refer patients with FMS to neurophysiotherapy services. Physiotherapists in general are interested in treating such patients and feel physiotherapy to be an appropriate treatment. However, inadequate service structures, knowledge and support from non-physiotherapy colleagues are judged to be barriers to provision of care. PMID- 22496583 TI - Repeatability of 18F-FDG uptake measurements in tumors: a metaanalysis. AB - PET with the glucose analog (18)F-FDG is increasingly used to monitor tumor response to therapy. To use quantitative measurements of tumor (18)F-FDG uptake for assessment of tumor response, the repeatability of this quantitative metabolic imaging method needs to be established. Therefore, we determined the repeatability of different standardized uptake value (SUV) measurements using the available data. METHODS: A systematic literature search was performed to identify studies addressing (18)F-FDG repeatability in malignant tumors. The level of agreement between test and retest values of 2 PET uptake measures, maximum SUV (SUV(max)) and mean SUV (SUV(mean)), was assessed with the coefficient of repeatability using generalized linear mixed-effects models. In addition, the influence of tumor volume on repeatability was assessed. Principal component transformation was used to compare the reproducibility of the 2 different uptake measures. RESULTS: Five cohorts were identified for this metaanalysis. For SUV(max) and SUV(mean), datasets of 86 and 102 patients, respectively, were available. Percentage repeatability is a function of the level of uptake. SUV(mean) had the best repeatability characteristics; for serial PET scans, a threshold of a combination of 20% as well as 1.2 SUV(mean) units was most appropriate. After adjusting for uptake rate, tumor volume had minimal influence on repeatability. CONCLUSION: SUV(mean) had better repeatability performance than SUV(max). Both measures showed poor repeatability for lesions with low (18)F-FDG uptake. We recommend the evaluation of biologic effects in PET by reporting a combination of minimal relative and absolute changes to account for test-retest variability. PMID- 22496584 TI - In vivo SPECT imaging with 111In-DOTA-c(RGDfK) to detect early pancreatic cancer in a hamster pancreatic carcinogenesis model. AB - Early detection of pancreatic cancer is key to overcoming its poor prognosis. alpha(v)beta(3)-integrin is often overexpressed in pancreatic tumor cells, whereas it is scarcely expressed in normal pancreatic cells. In this study, we investigated the usefulness of SPECT imaging with (111)In-1,4,7,10 tetraazacylododecane-N,N',N",N'''-tetraacetic acid-cyclo-(Arg-Gly-Asp-d-Phe-Lys) [(111)In-DOTA-c(RGDfK)], an imaging probe of alpha(v)beta(3)-integrin, for the early detection of pancreatic cancer in a hamster pancreatic carcinogenesis model. METHODS: Hamsters were subcutaneously injected with the pancreatic duct carcinogen N-nitrosobis(2-oxopropyl)amine to induce pancreatic cancer. N nitrosobis(2-oxopropyl)amine-treated hamsters underwent in vivo SPECT with (111)In-DOTA-c(RGDfK). After imaging, the tumor-to-normal pancreatic tissue radioactivity ratios in excised pancreatic samples were measured with autoradiography (ARG) and compared with the immunopathologic findings for alpha(v)beta(3)-integrin. In a mouse model in which inflammation was induced with turpentine, the uptake of (111)In-DOTA-c(RGDfK) in inflammatory regions was evaluated with ARG and compared with that of (18)F-FDG. RESULTS: (111)In-DOTA c(RGDfK) was clearly visualized in pancreatic cancer lesions as small as 3 mm in diameter. ARG analysis revealed high tumor-to-normal pancreatic tissue radioactivity ratios (4.6 +/- 1.0 [mean +/- SD] in adenocarcinoma and 3.3 +/- 1.4 in atypical hyperplasia). The uptake of (111)In-DOTA-c(RGDfK) strongly correlated with alpha(v)beta(3)-integrin expression. In the inflammatory model, inflammation to-muscle ratios for (18)F-FDG and (111)In-DOTA-c(RGDfK) were 8.37 +/- 4.37 and 1.98 +/- 0.60, respectively. These results imply that (111)In-DOTA-c(RGDfK) has a lower rate of false-positive tumor detection than (18)F-FDG. CONCLUSION: Our findings suggest that SPECT with (111)In-DOTA-c(RGDfK) has great potential for the early and accurate detection of pancreatic cancer. PMID- 22496585 TI - Cardiac mortality assessment improved by evaluation of cardiac sympathetic nerve activity in combination with hemoglobin and kidney function in chronic heart failure patients. AB - We examined prognostic interactions among cardiac autonomic function assessed by (123)I-labeled metaiodobenzylguanidine ((123)I-MIBG) activity, hemoglobin, and kidney function in chronic heart failure patients. Anemia, chronic kidney disease, and impairment of cardiac sympathetic function have been shown as determinants of prognosis in heart failure patients, but there has been little information on their synergistic correlations with cardiac mortality. METHODS: After evaluations of hemoglobin and estimated glomerular filtration rate (GFR), 468 heart failure patients with left ventricular ejection fraction less than 50% underwent cardiac (123)I-MIBG imaging before discharge and were then followed up for a mean interval of 60.5 mo with a primary endpoint of cardiac death. Cardiac (123)I-MIBG activity was quantified using heart-to-mediastinum ratio (HMR) and washout rate. RESULTS: For 89 fatal cardiac events documented (19.0%), besides New York Heart Association class, multivariate Cox analysis revealed HMR, hemoglobin, and estimated GFR as significant independent determinants, with hazard ratios of 0.215 (P = 0.0129; 95% confidence interval [CI], 0.064-0.718), 0.821 (P = 0.0062; 95% CI, 0.708-0.946), and 0.984 (P = 0.0243; 95% CI, 0.970 0.998), respectively. Receiver-operating-characteristic analysis determined the thresholds for identifying patients at increased risk for cardiac death to be 1.57 for HMR, 11.9 g/dL for hemoglobin, and 46.4 mL/min/1.73 m(2) for estimated GFR. Combining the 4 independent predictors incrementally (P < 0.05) improved prognostic powers maximally up to a global chi(2) value of 97.3 compared with sole or other combinations. CONCLUSION: Hemoglobin, kidney function, and alterations of cardiac sympathetic nerve activity are independently and synergistically associated with increased cardiac mortality in chronic heart failure patients, together with New York Heart Association functional class. PMID- 22496586 TI - Molecular imaging of very late antigen-4 (alpha4beta1 integrin) in the premetastatic niche. AB - Despite advances in cancer treatment over the past few decades, metastatic disease remains the primary cause of morbidity and mortality. Recent reports suggest the formation of a "premetastatic niche" before the metastatic cascade, where niche is defined as the microenvironment for tumor cells to be able to engraft and proliferate at secondary sites. Bone marrow-derived (BMD) cells that express vascular endothelial growth factor receptor-1 and very late antigen-4 (VLA-4) have been shown to arrive at sites of metastasis to form a receptive environment for tumor cells. Here we describe experiments toward imaging of VLA-4 positive BMD cells using a high-affinity PET probe, (64)Cu-labeled 11 bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2] hexadecane (CB-TE2A)-LLP2A. METHODS: VLA-4-negative MDA-MB-231/firefly luciferase (fluc) human breast tumor cells were injected intraarterially in the left ventricle in nude mice. Tumor metastasis in mice was monitored for 30 d by bioluminescence imaging and small animal PET/CT. Small-animal PET images were collected 2 h after mice were injected in the tail vein with (64)Cu-CB-TE2A-LLP2A (5.6-11.1 MBq [150-300 MUCi; specific activity, 400 MUCi/MUg]). Cellular uptake of (64)Cu-CB-TE2A-LLP2A was determined in VLA-4-positive B16F10 mouse melanoma cells and VLA-4-negative MDA MB-231/fluc human breast cancer tumor cells. Biodistribution experiments in nude mice bearing VLA-4-positive B16F10 subcutaneous tumors in the flank were conducted to validate targeting of VLA-4-positive cells in vivo. RESULTS: Uptake of (64)Cu-CB-TE2A-LLP2A was higher in VLA-4-positive human melanoma B16F10 cells than in VLA-4-negative MDA-MB-231 cells (P < 0.05). In B16F10 tumor-bearing mice, (64)Cu-CB-TE2A-LLP2A had high uptake in the VLA-4-rich organs marrow, spleen, and tumor (11.26% +/- 2.59%, 8.36% +/- 2.15%, and 3.09% +/- 0.58% injected dose/g, respectively). Cumulative standardized uptake value data from 2 independent studies (n = 7 and 8 mice) on nude mice implanted with VLA-4-negative MDA-MB 231/fluc human breast tumor cells suggested an influx of VLA-4-positive BMD cells that corresponded to metastasis (P < 0.05). Immunohistochemical analysis and flow cytometry also showed upregulation of VLA-4-positive cell clusters and BMD cells at the metastatic sites, providing evidence for noninvasive imaging of BMD cells in the premetastatic niche. CONCLUSION: The results of the study demonstrated the potential of PET with VLA-4-targeted (64)Cu-CB-TE2A-LLP2A to visualize BMD cell reorganization and expansion noninvasively in vivo. PMID- 22496587 TI - Reduction of renal uptake of radiolabeled octreotate by amifostine coadministration. AB - Megalin-mediated renal retention of radiolabeled somatostatin analogs may lead to nephrotoxicity during peptide receptor radionuclide therapy (PRRT). The cytoprotective agent amifostine protected rats from long-term nephrotoxicity after PRRT with (177)Lu-DOTA,Tyr(3)-octreotate. This study describes the direct effect of amifostine on kidney and tumor uptake of (111)In-DOTA,Tyr(3) octreotate. METHODS: In vivo biodistribution studies were performed using CA20948 tumor-bearing rats, with or without amifostine coadministration, via several routes. In vitro uptake was studied in somatostatin receptor-expressing CA20948 and megalin or cubilin receptor-expressing BN-16 cells, in the absence or presence of amifostine or its active metabolite WR-1065. RESULTS: Coadministration of amifostine decreased renal uptake of radiolabeled octreotate in vivo, whereas tumor uptake was not affected. In agreement, amifostine and WR 1065 coincubation reduced uptake in BN-16 but not in CA20948 cells. CONCLUSION: Amifostine may provide renal protection during PRRT using somatostatin analogs, both by mitigation of radiation damage and the currently observed reduction of absorbed kidney radiation dose. PMID- 22496588 TI - ParA-like protein uses nonspecific chromosomal DNA binding to partition protein complexes. AB - Recent data have shown that plasmid partitioning Par-like systems are used by some bacterial cells to control localization of protein complexes. Here we demonstrate that one of these homologs, PpfA, uses nonspecific chromosome binding to separate cytoplasmic clusters of chemotaxis proteins upon division. Using fluorescent microscopy and point mutations, we show dynamic chromosome binding and Walker-type ATPase activity are essential for cluster segregation. The N terminal domain of a cytoplasmic chemoreceptor encoded next to ppfA is also required for segregation, probably functioning as a ParB analog to control PpfA ATPase activity. An orphan ParA involved in segregating protein clusters therefore uses a similar mechanism to plasmid-segregating ParA/B systems and requires a partner protein for function. Given the large number of genomes that encode orphan ParAs, this may be a common mechanism regulating segregation of proteins and protein complexes. PMID- 22496589 TI - Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk. AB - Copy number variants (CNVs) are a recently recognized class of human germ line polymorphisms and are associated with a variety of human diseases, including cancer. Because of the strong genetic influence on prostate cancer, we sought to identify functionally active CNVs associated with susceptibility of this cancer type. We queried low-frequency biallelic CNVs from 1,903 men of Caucasian origin enrolled in the Tyrol Prostate Specific Antigen Screening Cohort and discovered two CNVs strongly associated with prostate cancer risk. The first risk locus (P = 7.7 * 10(-4), odds ratio = 2.78) maps to 15q21.3 and overlaps a noncoding enhancer element that contains multiple activator protein 1 (AP-1) transcription factor binding sites. Chromosome conformation capture (Hi-C) data suggested direct cis-interactions with distant genes. The second risk locus (P = 2.6 * 10( 3), odds ratio = 4.8) maps to the alpha-1,3-mannosyl-glycoprotein 4-beta-N acetylglucosaminyltransferase C (MGAT4C) gene on 12q21.31. In vitro cell-line assays found this gene to significantly modulate cell proliferation and migration in both benign and cancer prostate cells. Furthermore, MGAT4C was significantly overexpressed in metastatic versus localized prostate cancer. These two risk associations were replicated in an independent PSA-screened cohort of 800 men (15q21.3, combined P = 0.006; 12q21.31, combined P = 0.026). These findings establish noncoding and coding germ line CNVs as significant risk factors for prostate cancer susceptibility and implicate their role in disease development and progression. PMID- 22496590 TI - Loss of XLalphas (extra-large alphas) imprinting results in early postnatal hypoglycemia and lethality in a mouse model of pseudohypoparathyroidism Ib. AB - Maternal deletion of the NESP55 differentially methylated region (DMR) (delNESP55/ASdel3-4(m), delNAS(m)) from the GNAS locus in humans causes autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib(delNASm)), a disorder of proximal tubular parathyroid hormone (PTH) resistance associated with loss of maternal GNAS methylation imprints. Mice carrying a similar, maternally inherited deletion of the Nesp55 DMR (DeltaNesp55(m)) replicate these Gnas epigenetic abnormalities and show evidence for PTH resistance, yet these mice demonstrate 100% mortality during the early postnatal period. We investigated whether the loss of extralarge alphas (XLalphas) imprinting and the resultant biallelic expression of XLalphas are responsible for the early postnatal lethality in DeltaNesp55(m) mice. First, we found that DeltaNesp55(m) mice are hypoglycemic and have reduced stomach-to-body weight ratio. We then generated mice having the same epigenetic abnormalities as the DeltaNesp55(m) mice but with normalized XLalphas expression due to the paternal disruption of the exon giving rise to this Gnas product. These mice (DeltaNesp55(m)/Gnasxl(m+/p-)) showed nearly 100% survival up to postnatal day 10, and a substantial number of them lived to adulthood. The hypoglycemia and reduced stomach-to-body weight ratio observed in 2-d-old DeltaNesp55(m) mice were rescued in the DeltaNesp55(m)/Gnasxl(m+/p-) mice. Surviving double-mutant animals had significantly reduced Galphas mRNA levels and showed hypocalcemia, hyperphosphatemia, and elevated PTH levels, thus providing a viable model of human AD-PHP-Ib. Our findings show that the hypoglycemia and early postnatal lethality caused by the maternal deletion of the Nesp55 DMR result from biallelic XLalphas expression. The double-mutant mice will help elucidate the pathophysiological mechanisms underlying AD-PHP-Ib. PMID- 22496591 TI - Spontaneous spatiotemporal waves of gene expression from biological clocks in the leaf. AB - The circadian clocks that drive daily rhythms in animals are tightly coupled among the cells of some tissues. The coupling profoundly affects cellular rhythmicity and is central to contemporary understanding of circadian physiology and behavior. In contrast, studies of the clock in plant cells have largely ignored intercellular coupling, which is reported to be very weak or absent. We used luciferase reporter gene imaging to monitor circadian rhythms in leaves of Arabidopsis thaliana plants, achieving resolution close to the cellular level. Leaves grown without environmental cycles for up to 3 wk reproducibly showed spatiotemporal waves of gene expression consistent with intercellular coupling, using several reporter genes. Within individual leaves, different regions differed in phase by up to 17 h. A broad range of patterns was observed among leaves, rather than a common spatial distribution of circadian properties. Leaves exposed to light-dark cycles always had fully synchronized rhythms, which could desynchronize rapidly. After 4 d in constant light, some leaves were as desynchronized as leaves grown without any rhythmic input. Applying light-dark cycles to such a leaf resulted in full synchronization within 2-4 d. Thus, the rhythms of all cells were coupled to external light-dark cycles far more strongly than the cellular clocks were coupled to each other. Spontaneous desynchronization under constant conditions was limited, consistent with weak intercellular coupling among heterogeneous clocks. Both the weakness of coupling and the heterogeneity among cells are relevant to interpret molecular studies and to understand the physiological functions of the plant circadian clock. PMID- 22496592 TI - Long identical multispecies elements in plant and animal genomes. AB - Ultraconserved elements (UCEs) are DNA sequences that are 100% identical (no base substitutions, insertions, or deletions) and located in syntenic positions in at least two genomes. Although hundreds of UCEs have been found in animal genomes, little is known about the incidence of ultraconservation in plant genomes. Using an alignment-free information-retrieval approach, we have comprehensively identified all long identical multispecies elements (LIMEs), which include both syntenic and nonsyntenic regions, of at least 100 identical base pairs shared by at least two genomes. Among six animal genomes, we found the previously known syntenic UCEs as well as previously undescribed nonsyntenic elements. In contrast, among six plant genomes, we only found nonsyntenic LIMEs. LIMEs can also be classified as either simple (repetitive) or complex (nonrepetitive), they may occur in multiple copies in a genome, and they are often spread across multiple chromosomes. Although complex LIMEs were found in both animal and plant genomes, they differed significantly in their composition and copy number. Further analyses of plant LIMEs revealed their functional diversity, encompassing elements found near rRNA and enzyme-coding genes, as well as those found in transposons and noncoding DNA. We conclude that despite the common presence of LIMEs in both animal and plant lineages, the evolutionary processes involved in the creation and maintenance of these elements differ in the two groups and are likely attributable to several mechanisms, including transfer of genetic material from organellar to nuclear genomes, de novo sequence manufacturing, and purifying selection. PMID- 22496593 TI - Cavities determine the pressure unfolding of proteins. AB - It has been known for nearly 100 years that pressure unfolds proteins, yet the physical basis of this effect is not understood. Unfolding by pressure implies that the molar volume of the unfolded state of a protein is smaller than that of the folded state. This decrease in volume has been proposed to arise from differences between the density of bulk water and water associated with the protein, from pressure-dependent changes in the structure of bulk water, from the loss of internal cavities in the folded states of proteins, or from some combination of these three factors. Here, using 10 cavity-containing variants of staphylococcal nuclease, we demonstrate that pressure unfolds proteins primarily as a result of cavities that are present in the folded state and absent in the unfolded one. High-pressure NMR spectroscopy and simulations constrained by the NMR data were used to describe structural and energetic details of the folding landscape of staphylococcal nuclease that are usually inaccessible with existing experimental approaches using harsher denaturants. Besides solving a 100-year-old conundrum concerning the detailed structural origins of pressure unfolding of proteins, these studies illustrate the promise of pressure perturbation as a unique tool for examining the roles of packing, conformational fluctuations, and water penetration as determinants of solution properties of proteins, and for detecting folding intermediates and other structural details of protein-folding landscapes that are invisible to standard experimental approaches. PMID- 22496594 TI - Antarctic and Southern Ocean influences on Late Pliocene global cooling. AB - The influence of Antarctica and the Southern Ocean on Late Pliocene global climate reconstructions has remained ambiguous due to a lack of well-dated Antarctic-proximal, paleoenvironmental records. Here we present ice sheet, sea surface temperature, and sea ice reconstructions from the ANDRILL AND-1B sediment core recovered from beneath the Ross Ice Shelf. We provide evidence for a major expansion of an ice sheet in the Ross Sea that began at ~3.3 Ma, followed by a coastal sea surface temperature cooling of ~2.5 degrees C, a stepwise expansion of sea ice, and polynya-style deep mixing in the Ross Sea between 3.3 and 2.5 Ma. The intensification of Antarctic cooling resulted in strengthened westerly winds and invigorated ocean circulation. The associated northward migration of Southern Ocean fronts has been linked with reduced Atlantic Meridional Overturning Circulation by restricting surface water connectivity between the ocean basins, with implications for heat transport to the high latitudes of the North Atlantic. While our results do not exclude low-latitude mechanisms as drivers for Pliocene cooling, they indicate an additional role played by southern high-latitude cooling during development of the bipolar world. PMID- 22496595 TI - Power-law decay of the spatial correlation function in exciton-polariton condensates. AB - We create a large exciton-polariton condensate and employ a Michelson interferometer setup to characterize the short- and long-distance behavior of the first order spatial correlation function. Our experimental results show distinct features of both the two-dimensional and nonequilibrium characters of the condensate. We find that the gaussian short-distance decay is followed by a power law decay at longer distances, as expected for a two-dimensional condensate. The exponent of the power law is measured in the range 0.9-1.2, larger than is possible in equilibrium. We compare the experimental results to a theoretical model to understand the features required to observe a power law and to clarify the influence of external noise on spatial coherence in nonequilibrium phase transitions. Our results indicate that Berezinskii-Kosterlitz-Thouless-like phase order survives in open-dissipative systems. PMID- 22496596 TI - Estimating the effects of Cry1F Bt-maize pollen on non-target Lepidoptera using a mathematical model of exposure. AB - In farmland biodiversity, a potential risk to the larvae of non-target Lepidoptera from genetically modified (GM) Bt-maize expressing insecticidal Cry1 proteins is the ingestion of harmful amounts of pollen deposited on their host plants. A previous mathematical model of exposure quantified this risk for Cry1Ab protein. We extend this model to quantify the risk for sensitive species exposed to pollen containing Cry1F protein from maize event 1507 and to provide recommendations for management to mitigate this risk.A 14-parameter mathematical model integrating small- and large-scale exposure was used to estimate the larval mortality of hypothetical species with a range of sensitivities, and under a range of simulated mitigation measures consisting of non-Bt maize strips of different widths placed around the field edge.The greatest source of variability in estimated mortality was species sensitivity. Before allowance for effects of large-scale exposure, with moderate within-crop host-plant density and with no mitigation, estimated mortality locally was <10% for species of average sensitivity. For the worst-case extreme sensitivity considered, estimated mortality locally was 99.6% with no mitigation, although this estimate was reduced to below 40% with mitigation of 24-m-wide strips of non-Bt maize. For highly sensitive species, a 12-m-wide strip reduced estimated local mortality under 1.5%, when within-crop host-plant density was zero. Allowance for large scale exposure effects would reduce these estimates of local mortality by a highly variable amount, but typically of the order of 50-fold.Mitigation efficacy depended critically on assumed within-crop host-plant density; if this could be assumed negligible, then the estimated effect of mitigation would reduce local mortality below 1% even for very highly sensitive species.Synthesis and applications. Mitigation measures of risks of Bt-maize to sensitive larvae of non target lepidopteran species can be effective, but depend on host-plant densities which are in turn affected by weed-management regimes. We discuss the relevance for management of maize events where cry1F is combined (stacked) with a herbicide tolerance trait. This exemplifies how interactions between biota may occur when different traits are stacked irrespective of interactions between the proteins themselves and highlights the importance of accounting for crop management in the assessment of the ecological impact of GM plants. PMID- 22496597 TI - Effects of trauma-hemorrhage and IL-6 deficiency on splenic immune function in a murine trauma model. AB - Splenic immune function is known to be depressed following hemorrhage. The present study investigates the effects of femoral shaft fracture, isolated or in combination with hemorrhage, on early stage cytokine production capacity of splenocytes and observes the role of IL-6 under these conditions. Male IL-6 knockout (IL-6(-/-)) and wild-type mice (WT) were randomly divided into three groups: sham (S), isolated femoral fracture (Fx), and femoral fracture + volume controlled hemorrhage (TH-Fx) (n = 6 per group). Animals were sacrificed four hours after induction of hemorrhage and fracture. Cytokine release (TNF-alpha, IL 6, and IL-10) of isolated and LPS-stimulated splenocytes was determined by cytometric bead array. Femoral fracture with or without hemorrhage caused a suppression of in vitro cytokine production capacity of splenocytes at an early posttraumatic stage in WT and IL-6(-/-). In the absence of IL-6, the profile of splenic cytokine secretion is significantly altered, identifying this cytokine as a potential therapeutic target to modulate the posttraumatic immune response. PMID- 22496598 TI - Involvement of the ubiquitin-proteasome system in the formation of experimental postsurgical peritoneal adhesions. AB - We investigated the Ubiquitin-Proteasome System (UPS), major nonlysosomal intracellular protein degradation system, in the genesis of experimental postsurgical peritoneal adhesions. We assayed the levels of UPS within the adhered tissue along with the development of peritoneal adhesions and used the specific UPS inhibitor bortezomib in order to assess the effect of the UPS blockade on the peritoneal adhesions. We found a number of severe postsurgical peritoneal adhesions at day 5 after surgery increasing until day 10. In the adhered tissue an increased values of ubiquitin and the 20S proteasome subunit, NFkB, IL-6, TNF-alpha and decreased values of IkB-beta were found. In contrast, bortezomib-treated rats showed a decreased number of peritoneal adhesions, decreased values of ubiquitin and the 20S proteasome, NFkB, IL-6, TNF-alpha, and increased levels of IkB-beta in the adhered peritoneal tissue. The UPS system, therefore, is primarily involved in the formation of post-surgical peritoneal adhesions in rats. PMID- 22496599 TI - Activation of peroxisome proliferator-activated receptor-gamma by glitazones reduces the expression and release of monocyte chemoattractant protein-1 in human mesothelial cells. AB - Human peritoneal mesothelial cells (MC) play an important role in inflammatory processes of the peritoneal cavity by producing various cytokines and chemokines, such as monocyte chemoattractant protein-1 (MCP-1). The present study was designed to assess the effect of the peroxisome proliferator-activated receptor gamma- (PPARgamma-) activator rosiglitazone on the mesothelial MCP-1 expression and release. Primary cultures of MC were obtained from omental tissue. MCP-1 antigen concentrations were measured in the cell supernatant by ELISA and MCP-1 mRNA levels by real-time polymerase chain reaction. The presence of PPARgamma on MC was assayed in a Western Blot analysis. MC constitutively express PPARgamma. Activation of this receptor via rosiglitazone (0,1-10 MUmol/L) resulted in significantly reduced amounts of mesothelial MCP-1 release as well as MCP-1 mRNA. The use of the PPARgamma inhibitor GW-9662 could completely prevent the rosiglitazone effects. Rosiglitazone was also effective in reducing TNFalpha induced enhanced secretion of MCP-1. Our findings indicate that glitazones are effective in reducing constitutive and TNFalpha-stimulated mesothelial MCP-1 mRNA expression and release. PMID- 22496600 TI - Chemokine and free fatty acid levels in insulin-resistant state of successful pregnancy: a preliminary observation. AB - Increased insulin resistance and inflammatory action are observed in pregnancy induced hypertension (PIH), but similar insulin resistance is observed also in successful pregnancy. To estimate insulin resistance and inflammatory activity in normal pregnancy and PIH, serum concentrations of free fatty acids (FFA; corrected with albumin to estimate unbound FFA), monocyte chemoattractant protein (MCP)-1, and high-molecular weight (HMW) adiponectin were measured in severe PIH patients with a BMI less than 25 kg/m(2) and were measured 3 times during the course of pregnancy in women with normal pregnancies. FFA/albumin, MCP-1, and HMW adiponectin concentrations were significantly higher in PIH patients than in women with normal pregnancies. The 3 measurements of FFA/albumin showed a significant increase through the course of uncomplicated pregnancies. In contrast, MCP-1 and HMW adiponectin were significantly decreased during the course of pregnancy. These results suggest that the reduced MCP-1 concentration in normal pregnancy may be a pathway to inhibit the induction of pathological features from physiological insulin resistance and homeostatic inflammation. PMID- 22496601 TI - Expressions of CXCL12/CXCR4 in oral premalignant and malignant lesions. AB - OBJECTIVE: The chemokine receptor CXCR4 and its ligand CXCL12 have been suggested to play important roles in the initiation or progression of cancers. The goal of the present study was to investigate alterations of CXCL12/CXCR4 in oral premalignant lesions and oral squamous cell carcinoma (OSCC). METHODS: In 13 normal oral epithelia, 24 dysplastic oral leukoplakia (OLK), and 40 OSCC specimens, expressions of CXCL12 and CXCR4 were evaluated by immunohistochemistry. RESULTS: CXCR4 was expressed in 37.5% of OLK and 60% of OSCC. CXCL12 was detected in 50% of OLK and 62.5% of OSCC. In OLK, CXCR4 positive ratio showed no significant difference from normal epithelia, but the CXCL12 positive ratio was significantly higher. Significant relationship between CXCL12 and CXCR4 was found both in OLK and OSCC. CONCLUSION: Our results indicated that CXCL12/CXCR4 axis may play roles from early steps of oral malignant transformation and contribute to the progress of oral carcinogenesis. PMID- 22496602 TI - Consistency of Mycobacterium tuberculosis-specific interferon-gamma responses in HIV-1-infected women during pregnancy and postpartum. AB - BACKGROUND: We determined the consistency of positive interferon-gamma (IFN gamma) release assays (IGRAs) to detect latent TB infection (LTBI) over one-year postpartum in HIV-1-infected women. METHODS: Women with positive IGRAs during pregnancy had four 3-monthly postpartum IGRAs. Postpartum change in magnitude of IFN-gamma response was determined using linear mixed models. RESULTS: Among 18 women with positive pregnancy IGRA, 15 (83%) had a subsequent positive IGRA; 9 (50%) were always positive, 3 (17%) were always negative, and 6 (33%) fluctuated between positive and negative IGRAs. Women with pregnancy IGRA IFN-gamma>8 spot forming cells (SFCs)/well were more likely to have consistent postpartum IGRA response (odds ratio: 10.0; 95% confidence interval (CI): 0.9-117.0). Change in IFN-gamma response over postpartum was 10.2 SFCs/well (95% CI: -1.5-21.8 SFCs/well). CONCLUSION: Pregnancy positive IGRAs were often maintained postpartum with increased consistency in women with higher baseline responses. There were modest increases in magnitude of IGRA responses postpartum. PMID- 22496603 TI - Efficacy of the new double-layer stent for unresectable distal malignant biliary obstruction: a single-center retrospective study. AB - Background and Aims. For distal malignant biliary obstruction in cases with short life expectancy, occlusion of plastic stents (PSs) does not usually occur before death, and the application of such a procedure is considered adequate from the viewpoint of cost-effectiveness. Methods and Setting. A new commercially available DLS with side holes, a conventional DLS, and, uncovered self-expanding metal stents (SEMSs) were retrospectively evaluated in patients with jaundice due to unresectable distal malignant biliary obstruction. Results. A total of 64 patients received endoscopic biliary stenting (23 patients with the new DLS, 24 patients with conventional DLS, and 17 patients with uncovered SEMS) from December 2002 to August 2009. Median patency time was found to be 198 days for the new DLS group and 99 days for the conventional DLS group, revealing a significant difference between devices. There was, however, no significant difference in median patency time between the new DLS and the uncovered SEMS (198 days versus 344 days). Conclusion. The new DLS is efficient and safe and may be considered the first choice for unresectable distal malignant obstruction in cases with short life expectancy. PMID- 22496604 TI - Oil production from Yarrowia lipolytica Po1g using rice bran hydrolysate. AB - The purpose of this study was to produce microbial oil from Yarrowia lipolytica Po1g grown in defatted rice bran hydrolysate. After removing oil from rice bran by Soxhlet extraction, the bran is subjected to acid hydrolysis with various sulfuric acid concentrations (1-4% v/v), reaction times (1-8 h), and reaction temperatures (60-120 degrees C). The optimal conditions for maximum total sugar production from the hydrolysate were found to be 3% sulfuric acid at 90 degrees C for 6 h. Glucose was the predominant sugar (43.20 +/- 0.28 g/L) followed by xylose (4.93 +/- 0.03 g/L) and arabinose (2.09 +/- 0.01 g/L). The hydrolysate was subsequently detoxified by neutralization to reduce the amount of inhibitors such as 5-hydroxymethylfurfural (HMF) and furfural to increase its potential as a medium for culturing Y. lipolytica Po1g. Dry cell mass and lipid content of Y. lipolytica Po1g grown in detoxified defatted rice bran hydrolysate (DRBH) under optimum conditions were 10.75 g/L and 48.02%, respectively. PMID- 22496605 TI - Small interference RNA targeting TLR4 gene effectively attenuates pulmonary inflammation in a rat model. AB - OBJECTIVE: The present study was to investigate the feasibility of adenovirus mediated small interference RNA (siRNA) targeting Toll-like receptor 4 (TLR4) gene in ameliorating lipopolysaccharide- (LPS-) induced acute lung injury (ALI). METHODS: In vitro, alveolar macrophages (AMs) were treated with Ad-siTLR4 and Ad EFGP, respectively, for 12 h, 24 h, and 48 h, and then with LPS (100 ng/mL) for 2 h, and the function and expression of TLR4 were evaluated. In vivo, rats received intratracheal injection of 300 MUL of normal saline (control group), 300 MUL of Ad-EGFP (Ad-EGFP group), or 300 MUL of Ad-siTLR4 (Ad-siTLR4 group) and then were intravenously treated with LPS (50 mg/kg) to induce ALI. RESULTS: Ad-siTLR4 treatment significantly reduced TLR4 expression and production of proinflammatory cytokines following LPS treatment both in vitro and in vivo. Significant alleviation of tissue edema, microvascular protein leakage, and neutrophil infiltration was observed in the AdsiTLR4-treated animals. CONCLUSION: TLR4 plays a critical role in LPS-induced ALI, and transfection of Ad-siTLR4 can effectively downregulate TLR4 expression in vitro and in vivo, accompanied by alleviation of LPS-induced lung injury. These findings suggest that TLR4 may serve as a potential target in the treatment of ALI and RNA interfering targeting TLR4 expression represents a therapeutic strategy. PMID- 22496606 TI - An experimental model for resistance exercise in rodents. AB - This study aimed to develop an equipment and system of resistance exercise (RE), based on squat-type exercise for rodents, with control of training variables. We developed an operant conditioning system composed of sound, light and feeding devices that allowed optimized RE performance by the animal. With this system, it is not necessary to impose fasting or electric shock for the animal to perform the task proposed (muscle contraction). Furthermore, it is possible to perform muscle function tests in vivo within the context of the exercise proposed and control variables such as intensity, volume (sets and repetitions), and exercise session length, rest interval between sets and repetitions, and concentric strength. Based on the experiments conducted, we demonstrated that the model proposed is able to perform more specific control of other RE variables, especially rest interval between sets and repetitions, and encourages the animal to exercise through short-term energy restriction and "disturbing" stimulus that do not promote alterations in body weight. Therefore, despite experimental limitations, we believe that this RE apparatus is closer to the physiological context observed in humans. PMID- 22496607 TI - Viral bacterial artificial chromosomes: generation, mutagenesis, and removal of mini-F sequences. AB - Maintenance and manipulation of large DNA and RNA virus genomes had presented an obstacle for virological research. BAC vectors provided a solution to both problems as they can harbor large DNA sequences and can efficiently be modified using well-established mutagenesis techniques in Escherichia coli. Numerous DNA virus genomes of herpesvirus and pox virus were cloned into mini-F vectors. In addition, several reverse genetic systems for RNA viruses such as members of Coronaviridae and Flaviviridae could be established based on BAC constructs. Transfection into susceptible eukaryotic cells of virus DNA cloned as a BAC allows reconstitution of recombinant viruses. In this paper, we provide an overview on the strategies that can be used for the generation of virus BAC vectors and also on systems that are currently available for various virus species. Furthermore, we address common mutagenesis techniques that allow modification of BACs from single-nucleotide substitutions to deletion of viral genes or insertion of foreign sequences. Finally, we review the reconstitution of viruses from BAC vectors and the removal of the bacterial sequences from the virus genome during this process. PMID- 22496608 TI - Nanoparticulate adjuvants and delivery systems for allergen immunotherapy. AB - In the last decades, significant progress in research and clinics has been made to offer possible innovative therapeutics for the management of allergic diseases. However, current allergen immunotherapy shows limitations concerning the long-term efficacy and safety due to local side effects and risk of anaphylaxis. Thus, effective and safe vaccines with reduced dose of allergen have been developed using adjuvants. Nevertheless, the use of adjuvants still has several disadvantages, which limits its use in human vaccines. In this context, several novel adjuvants for allergen immunotherapy are currently being investigated and developed. Currently, nanoparticles-based allergen-delivery systems have received much interest as potential adjuvants for allergen immunotherapy. It has been demonstrated that the incorporation of allergens into a delivery system plays an important role in the efficacy of allergy vaccines. Several nanoparticles-based delivery systems have been described, including biodegradable and nondegradable polymeric carriers. Therefore, this paper provides an overview of the current adjuvants used for allergen immunotherapy. Furthermore, nanoparticles-based allergen-delivery systems are focused as a novel and promising strategy for allergy vaccines. PMID- 22496609 TI - Autism spectrum disorders: is mesenchymal stem cell personalized therapy the future? AB - Autism and autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders. They are enigmatic conditions that have their origins in the interaction of genes and environmental factors. ASDs are characterized by dysfunctions in social interaction and communication skills, in addition to repetitive and stereotypic verbal and nonverbal behaviours. Immune dysfunction has been confirmed with autistic children. There are no defined mechanisms of pathogenesis or curative therapy presently available. Indeed, ASDs are still untreatable. Available treatments for autism can be divided into behavioural, nutritional, and medical approaches, although no defined standard approach exists. Nowadays, stem cell therapy represents the great promise for the future of molecular medicine. Among the stem cell population, mesenchymal stem cells (MSCs) show probably best potential good results in medical research. Due to the particular immune and neural dysregulation observed in ASDs, mesenchymal stem cell transplantation could offer a unique tool to provide better resolution for this disease. PMID- 22496610 TI - Detection of target ssDNA using a microfabricated Hall magnetometer with correlated optical readout. AB - Sensing biological agents at the genomic level, while enhancing the response time for biodetection over commonly used, optics-based techniques such as nucleic acid microarrays or enzyme-linked immunosorbent assays (ELISAs), is an important criterion for new biosensors. Here, we describe the successful detection of a 35 base, single-strand nucleic acid target by Hall-based magnetic transduction as a mimic for pathogenic DNA target detection. The detection platform has low background, large signal amplification following target binding and can discriminate a single, 350 nm superparamagnetic bead labeled with DNA. Detection of the target sequence was demonstrated at 364 pM (<2 target DNA strands per bead) target DNA in the presence of 36 MUM nontarget (noncomplementary) DNA (<10 ppm target DNA) using optical microscopy detection on a GaAs Hall mimic. The use of Hall magnetometers as magnetic transduction biosensors holds promise for multiplexing applications that can greatly improve point-of-care (POC) diagnostics and subsequent medical care. PMID- 22496612 TI - Development of tyrosine-based radiotracer 99mTc-N4-Tyrosine for breast cancer imaging. AB - The purpose of this study was to develop an efficient way to synthesize (99m)Tc-O [3-(1,4,8,11-tetraazabicyclohexadecane)-propyl]-tyrosine ((99m)Tc-N4-Tyrosine), a novel amino acid-based radiotracer, and evaluate its potential in breast cancer gamma imaging. Precursor N4-Tyrosine was synthesized using a 5-step procedure, and its total synthesis yield was 38%. It was successfully labeled with (99m)Tc with high radiochemical purity (>95%). Cellular uptake of (99m)Tc-N4-Tyrosine was much higher than that of (99m)Tc-N4 and the clinical gold standard (18)F-2-deoxy 2-fluoro-glucose ((18)F-FDG) in rat breast tumor cells in vitro. Tissue uptake and dosimetry estimation in normal rats revealed that (99m)Tc-N4-Tyrosine could be safely administered to humans. Evaluation in breast tumor-bearing rats showed that although (99m)Tc-N4-Tyrosine appeared to be inferior to (18)F-FDG in distinguishing breast tumor tissue from chemical-induced inflammatory tissue, it had high tumor-to-muscle uptake ratios and could detect breast tumors clearly by planar scintigraphic imaging. (99m)Tc-N4-Tyrosine could thus be a useful radiotracer for use in breast tumor diagnostic imaging. PMID- 22496611 TI - Various jobs of proteolytic enzymes in skeletal muscle during unloading: facts and speculations. AB - Skeletal muscles, namely, postural muscles, as soleus, suffer from atrophy under disuse. Muscle atrophy development caused by unloading differs from that induced by denervation or other stimuli. Disuse atrophy is supposed to be the result of shift of protein synthesis/proteolysis balance towards protein degradation increase. Maintaining of the balance involves many systems of synthesis and proteolysis, whose activation leads to muscle adaptation to disuse rather than muscle degeneration. Here, we review recent data on activity of signaling systems involved in muscle atrophy development under unloading and muscle adaptation to the lack of support. PMID- 22496613 TI - Antiproliferative and anti-invasive effect of piceatannol, a polyphenol present in grapes and wine, against hepatoma AH109A cells. AB - Piceatannol is a stilbenoid, a metabolite of resveratrol found in red wine. Piceatannol and sera from rats orally given piceatannol were found to dose dependently suppress both the proliferation and invasion of AH109A hepatoma cells in culture. Its antiproliferative effect was based on cell cycle arrest at lower concentration (25~50 MUM) and on apoptosis induction at higher concentration (100 MUM). Piceatannol suppressed reactive oxygen species-potentiated invasive capacity by scavenging the intracellular reactive oxygen species. These results suggest that piceatannol, unlike resveratrol, has a potential to suppress the hepatoma proliferation by inducing cell cycle arrest and apoptosis induction. They also suggest that the antioxidative property of piceatannol, like resveratrol, may be involved in its anti-invasive action. Subsequently, piceatannol was found to suppress the growth of solid tumor and metastasis in hepatoma-bearing rats. Thus, piceatannol may be a useful anticancer natural product. PMID- 22496614 TI - Aberrant expression of N-methylpurine-DNA glycosylase influences patient survival in malignant gliomas. AB - AIM: To examine the expression of N-methylpurine-DNA glycosylase (MPG) gene and protein in glioma samples with different WHO grades and its association with patients' survival. METHODS: Immunohistochemistry assay, quantitative real-time PCR and Western blot analysis were carried out to investigate the expression of MPG gene and protein in 128 glioma and 10 non-neoplastic brain tissues. RESULTS: MPG gene expression level in glioma tissues was significantly higher than that in non-neoplastic brain tissues (P < 0.001). Immunohistochemistry also showed that MPG protein was over-expressed in glioma tissues, which was consistent with the resutls of Western blot analysis. Additionally, the expression levels of MPG gene and protein both increase from grade I to grade IV glioma according to the results of real-time PCR, immunohistochemistry and western blot analysis. Moreover, the survival rate of MPG-positive patients was significantly lower than that of MPG-negative patients (P < 0.001). We further confirmed that the over expression of MPG was a significant and independent prognostic indicator in glioma by multivariate analysis (P < 0.001). CONCLUSIONS: Our data showed the over-expression of MPG gene and protein in human gliomas, and also suggested for the first time that MPG be an unfavorable independent prognostic indicator for glioma patients. PMID- 22496615 TI - Dickkopf-1 expression is a novel prognostic marker for gastric cancer. AB - AIM: To investigate the involvement of Dickkopf-1 expression in gastric cancer. METHODS: Dickkopf-1 mRNA and protein expression were determined by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and immunohistochemistry in specimens of primary cancer and their adjacent noncancerous tissues in gastric cancer patients. RESULTS: Dickkopf-1 mRNA and protein expression levels were both significantly upregulated in gastric cancer lesions compared with adjacent noncancerous tissues. Its positive expression was correlated with depth of invasion, vessel invasion, lymph node and distant metastasis, and TNM stage of tumors. Additionally, in stages I, II, and III gastric cancers, the 5- year survival rate of patients with a high expression of Dickkopf-1 was significantly lower than that in patients with low expression. In stage IV, Dickkopf-1 expression did not correlate with the 5-year survival rate. Further multivariate analysis suggested that the up-regulation of Dickkopf-1 was an independent prognostic indicator for gastric cancer. CONCLUSION: A subset of cases with gastric cancer revealed the up-regulation of Dickkopf-1, which was associated with a progressive pathological feature and an aggressive clinical course. Therefore, Dickkopf-1 expression may be predictor for poor prognosis in patients with gastric cancer. This is the first report describing the involvement of Dickkopf-1 in gastric cancer. PMID- 22496616 TI - Detection of herplex simplex virus-1 and -2 in cardiac myxomas. AB - The etiology of sporadic cardiac myxomas remains elusive. The tendency for these lesions to recur following resection, their immunopathological characteristics, along with their histological and molecular profile, may implicate the presence of an infective agent in this type of tumor. In this study, we investigated the presence of herpes simplex virus (HSV) DNA in a cohort of cardiac myxomas in a tertiary referral centre. Twenty-nine formalin-fixed paraffin-embedded (FFPE) sporadic cardiac myxomas were obtained, 17 of which were shown to be informative. These were compared to 19 macroscopically and microscopically normal heart tissue specimens. The detection of HSV-1 and -2 genomic sequences was achieved with the use of a combined nested PCR-Restriction Fragment Length Polymorphism methodology. The presence of HSV-1 and/or -2 DNA was demonstrated in 6 of 17 (35%) informative sporadic cardiac myxomas, whereas no HSV DNA was detected in normal heart tissues (P < 0.01). The existence of HSV-1/2 DNA in sporadic cardiac myxomas, along with its absence from normal heart tissues, reinforces the possibility that HSV infection might be involved in the development of these lesions. Our findings raise the point of anti-HSV medication postsurgically with a potential benefit in reducing the rate of recurrences. PMID- 22496617 TI - Imaging therapeutic PARP inhibition in vivo through bioorthogonally developed companion imaging agents. AB - A number of small-molecule poly (ADP-ribose) polymerase (PARP) inhibitors are currently undergoing advanced clinical trials. Determining the distribution and target inhibitory activity of these drugs in individual subjects, however, has proven problematic. Here, we used a PARP agent for positron emission tomography computed tomography (PET-CT) imaging ((18)F-BO), which we developed based on the Olaparib scaffold using rapid bioorthogonal conjugation chemistries. We show that the bioorthogonal (18)F modification of the parent molecule is simple, highly efficient, and well tolerated, resulting in a half maximal inhibitory concentration (IC(50)) of 17.9 +/- 1.1 nM. Intravital imaging showed ubiquitous distribution of the drug and uptake into cancer cells, with ultimate localization within the nucleus, all of which were inhibitable. Whole-body PET-CT imaging showed tumoral uptake of the drug, which decreased significantly, after a daily dose of Olaparib. Standard (18)F-fludeoxyglucose imaging, however, failed to detect such therapy-induced changes. This research represents a step toward developing a more generic approach for the rapid codevelopment of companion imaging agents based on small-molecule therapeutic inhibitors. PMID- 22496618 TI - IkappaB kinases modulate the activity of the androgen receptor in prostate carcinoma cell lines. AB - Enhanced nuclear localization of nuclear factor kappaB (NF-kappaB) in prostate cancer (PCa) samples and constitutive NF-kappaB signaling in a class of PCa cell lines with low androgen receptor (AR) expression (PC3 and DU-145) imply an important role of the IkappaB kinase (IKK)/NF-kappaB system in PCa. However, most PCa and PCa cell lines depend on the activity of the AR, and the role of NF kappaB in these AR-expressing PCa remains unclear. Here, we demonstrate that inhibition of NF-kappaB signaling by the IKK inhibitor BMS345541 reduced proliferation and increased apoptosis in AR-expressing PCa cell lines. Furthermore, AR activity and target gene expression were distinctively reduced, whereas AR protein levels remained unaltered on BMS345541 treatment. Similar effects were observed particularly after small interfering RNA (siRNA)-mediated knockdown of IKK1, but not by siRNA-mediated suppression of IKK2. Moreover, IKK1 overexpression augmented 5alpha-dihydrotestosterone-induced nuclear AR translocation, whereas nuclear AR was reduced by IKK1 knockdown or BMS345541. However, because IKK1 also enhances the activity of a chronically nuclear AR mutant, modulation of the subcellular distribution seems not to be the only mechanism by which IKK1 enhances AR activity. Finally, reduced in vivo AR phosphorylation after BMS345541 treatment and in vitro AR phosphorylation by IKK1 or IKK2 imply that AR constitutes a novel IKK target. Taken together, our data identify IKK1 as a potentially target structure for future therapeutic intervention in PCa. PMID- 22496619 TI - Oncogenic KRAS impairs EGFR antibodies' efficiency by C/EBPbeta-dependent suppression of EGFR expression. AB - Oncogenic KRAS mutations in colorectal cancer (CRC) are associated with lack of benefit from epidermal growth factor receptor (EGFR)-directed antibody (Ab) therapy. However, the mechanisms by which constitutively activated KRAS (KRAS(G12V)) impairs effector mechanisms of EGFR-Abs are incompletely understood. Here, we established isogenic cell line models to systematically investigate the impact of KRAS(G12V) on tumor growth in mouse A431 xenograft models as well as on various modes of action triggered by EGFR-Abs in vitro. KRAS(G12V) impaired EGFR Ab-mediated growth inhibition by stimulating receptor-independent downstream signaling. KRAS(G12V) also rendered tumor cells less responsive to Fc-mediated effector mechanisms of EGFR-Abs-such as complement-dependent cytotoxicity (CDC) and Ab-dependent cell-mediated cytotoxicity (ADCC). Impaired CDC and ADCC activities could be linked to reduced EGFR expression in KRAS-mutated versus wild type (wt) cells, which was restored by small interfering RNA (siRNA)-mediated knockdown of KRAS4b. Immunohistochemistry experiments also revealed lower EGFR expression in KRAS-mutated versus KRAS-wt harboring CRC samples. Analyses of potential mechanisms by which KRAS(G12V) downregulated EGFR expression demonstrated significantly decreased activity of six distinct transcription factors. Additional experiments suggested the CCAAT/enhancer-binding protein (C/EBP) family to be implicated in the regulation of EGFR promoter activity in KRAS-mutated tumor cells by suppressing EGFR transcription through up-regulation of the inhibitory family member C/EBPbeta-LIP. Thus, siRNA-mediated knockdown of C/EBPbeta led to enhanced EGFR expression and Ab-mediated cytotoxicity against KRAS-mutated cells. Together, these results demonstrate that KRAS(G12V) signaling induced C/EBPbeta-dependent suppression of EGFR expression, thereby impairing Fc mediated effector mechanisms of EGFR-Abs and rendering KRAS-mutated tumor cells less sensitive to these therapeutic agents. PMID- 22496620 TI - Single nucleotide polymorphism microarray analysis in cortisol-secreting adrenocortical adenomas identifies new candidate genes and pathways. AB - The genetic mechanisms underlying adrenocortical tumor development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays (Affymetrix SNP 6.0) to detect copy number alterations (CNAs) and copy-neutral losses of heterozygosity (cnLOH) in 15 cortisol-secreting adrenocortical adenomas with matched blood samples. We focused on microalterations aiming to discover new candidate genes involved in early tumorigenesis and/or autonomous cortisol secretion. We identified 962 CNAs with a median of 18 CNAs per sample. Half of them involved noncoding regions, 89% were less than 100 kb, and 28% were found in at least two samples. The most frequently gained regions were 5p15.33, 6q16.1, 7p22.3-22.2, 8q24.3, 9q34.2-34.3, 11p15.5, 11q11, 12q12, 16q24.3, 20p11.1-20q21.11, and Xq28 (>=20% of cases), most of them being identified in the same three adenomas. These regions contained among others genes like NOTCH1, CYP11B2, HRAS, and IGF2. Recurrent losses were less common and smaller than gains, being mostly localized at 1p, 6q, and 11q. Pathway analysis revealed that Notch signaling was the most frequently altered. We identified 46 recurrent CNAs that each affected a single gene (31 gains and 15 losses), including genes involved in steroidogenesis (CYP11B1) or tumorigenesis (CTNNB1, EPHA7, SGK1, STIL, FHIT). Finally, 20 small cnLOH in four cases affecting 15 known genes were found. Our findings provide the first high-resolution genome wide view of chromosomal changes in cortisol-secreting adenomas and identify novel candidate genes, such as HRAS, EPHA7, and SGK1. Furthermore, they implicate that the Notch1 signaling pathway might be involved in the molecular pathogenesis of adrenocortical tumors. PMID- 22496621 TI - Netrin-4 promotes glioblastoma cell proliferation through integrin beta4 signaling. AB - Netrin-4 is a laminin-related secreted molecule originally found to have roles in neuronal axon migration. Recent studies have indicated that netrin-4 also participates in the development of nonneural tissues and modulates tumor cell proliferation and tumor metastasis. Here we have explored the functions and molecular mechanisms of netrin-4 in glioblastoma multiforme. The suppression of netrin-4 expression in glioblastoma cell lines significantly reduced cell proliferation and motility and increased serum deprivation-induced apoptosis. Using tandem affinity purification combined with protein identification by mass spectrometry, we found that integrin beta(4) interacts with netrin-4 and that it mediates mitogenic effects as well as AKT and mammalian target of rapamycin phosphorylation induced by netrin-4. Interestingly, netrin-4 acted as an inhibitor of cell proliferation in integrin beta(4)-silenced glioblastoma cells, and high concentrations of netrin-4 reduced cell proliferation. The negative effects of netrin-4 on proliferation were mediated by UNC5B. Analysis of more than 400 primary tumors from The Cancer Genome Atlas repository revealed that the expression of netrin-4 is significantly downregulated in glioblastoma and that the reduced expression is linked to poor patient survival time. The expression of integrin beta(4) is increased in glioblastoma, and it predicts poor patient survival time. Current results illustrate a novel mechanism for glioma progression, where glioma cells reduce netrin-4 expression to decrease its inhibitory effects. In parallel, the expression of integrin beta(4) is upregulated to sensitize the cells to low concentrations of netrin-4 for maintaining cell proliferation. PMID- 22496622 TI - Rapamycin inhibits lymphatic endothelial cell tube formation by downregulating vascular endothelial growth factor receptor 3 protein expression. AB - Mammalian target of rapamycin (mTOR) controls lymphangiogenesis. However, the underlying mechanism is not clear. Here we show that rapamycin suppressed insulin like growth factor 1 (IGF-1)- or fetal bovine serum (FBS)-stimulated lymphatic endothelial cell (LEC) tube formation, an in vitro model of lymphangiogenesis. Expression of a rapamycin-resistant and kinase-active mTOR (S2035T, mTOR-T), but not a rapamycin-resistant and kinase-dead mTOR (S2035T/D2357E, mTOR-TE), conferred resistance to rapamycin inhibition of LEC tube formation, suggesting that rapamycin inhibition of LEC tube formation is mTOR kinase activity dependent. Also, rapamycin inhibited proliferation and motility in the LECs. Furthermore, we found that rapamycin inhibited protein expression of VEGF receptor 3 (VEGFR-3) by inhibiting protein synthesis and promoting protein degradation of VEGFR-3 in the cells. Down-regulation of VEGFR-3 mimicked the effect of rapamycin, inhibiting IGF-1- or FBS-stimulated tube formation, whereas over-expression of VEGFR-3 conferred high resistance to rapamycin inhibition of LEC tube formation. The results indicate that rapamycin inhibits LEC tube formation at least in part by downregulating VEGFR-3 protein expression. PMID- 22496623 TI - Rare Drosha splice variants are deficient in microRNA processing but do not affect general microRNA expression in cancer cells. AB - Drosha is a key enzyme in microRNA biogenesis, generating the precursor miRNA (pre-miRNA) by excising the stem-loop embedded in the primary transcripts (pri miRNA). The specificity for the pri-miRNAs and determination of the cleavage site are provided by its binding partner DGCR8, which is necessary for efficient processing. The crucial Drosha domains for pri-miRNA cleavage are the middle part, the two enzymatic RNase III domains (RIIID), and the dsRNA binding domain (dsRBD) in the C-terminus. Here, we identify alternatively spliced transcripts in human melanoma and NT2 cell lines, encoding C-terminally truncated Drosha proteins lacking part of the RIIIDb and the entire dsRBD. Proteins generated from these alternative splice variants fail to bind to DGCR8 but still interact with Ewing sarcoma protein (EWS). In vitro as well as in vivo, the Drosha splice variants are deficient in pri-miRNA processing. However, the aberrant transcripts in melanoma cells do not consistently reduce mature miRNA levels compared with melanoma cell lines lacking those splice variants, possibly owing to their limited abundance. Our findings show that alternative processing-deficient Drosha splice variants exist in melanoma cells. In elevated amounts, these alternatively spliced transcripts could provide one potential mechanism accounting for the deregulation of miRNAs in cancer cells. On the basis of our results, the search for alternative inactive splice variants might be fruitful in different tumor entities to unravel the molecular basis of the previously observed decreased microRNA processing efficiency in cancer. PMID- 22496624 TI - Apoptosis resistance and PKC signaling: distinguishing features of high and low metastatic cells. AB - The complexity of the process of metastasis is widely recognized. We report herein on a recurrent feature of high compared to low metastatic cells that is linked to their ability to survive early after their arrival at secondary sites. Using novel fluorescent-based imaging strategies that assess tumor cell interaction with the lung microenvironment, we have determined that most high and low metastatic cells can be distinguished within 6 hours of their arrival in the lung and further that this difference is defined by the ability of high metastatic cells to resist apoptosis at the secondary site. Despite the complexity of the metastatic cascade, the performance of cells during this critical window is highly defining of their metastatic proclivity. To explore mechanisms, we next evaluated biochemical pathways that may be linked to this survival phenotype in highly metastatic cells. Interestingly, we found no association between the Akt survival pathway and this metastatic phenotype. Of all pathways examined, only protein kinase C (PKC) activation was significantly linked to survival of highly metastatic cells. These data provide a conceptual understanding of a defining difference between high and low metastatic cells. The connection to PKC activation may provide a biologic rationale for the use of PKC inhibition in the prevention of metastatic progression. PMID- 22496625 TI - Sinonasal undifferentiated carcinoma with intracranial extension. AB - AIM: To report our experience in the management of sinonasal undifferentiated carcinoma (SNUC) over a period of 15 years. STUDY DESIGN: A retrospective case review of 13 patients with SNUC treated at the University of California, Davis, Medical Center (UCDMC) Center for Skull Base Surgery, over the past 15 years. RESULTS: Most tumors arose in the ethmoid sinuses. All but 1 patient had a combined intracranial-extracranial resection through the anterior fossa transcranial route and postoperative irradiation. The 13th patient had a transfacial subcranial approach. There are 6 who have survived free of disease at 14 years' to 8 months' follow-up. The average follow-up was 6 years, 3 months. One patient died of a pulmonary embolism in the first postoperative week, a second died of a bowel infarction 3 months postoperatively. Three patients died of their disease at 20, 18, and 8 months postoperatively: 1 with local recurrence and distant metastasis and the other 2 with local control but distant disease. The 6 survivors are at 8, 20, 28, 62, 84, and 105 months. CONCLUSION: SNUC is a rare malignancy of the paranasal sinuses with a poor prognosis. Radical surgery and adjunctive therapy can achieve good survival in a significant proportion of patients who would hitherto have seemed incurable. PMID- 22496626 TI - Military Combat Deployments and Substance Use: Review and Future Directions. AB - Iraq and Afghanistan veterans experience extreme stressors and injuries during deployments, witnessing and participating in traumatic events. The military has organized prevention and treatment programs as a result of increasing suicides and posttraumatic stress disorder among troops; however, there is limited research on how to intervene with alcohol misuse and drug use that accompany these problems. This review presents statistics about post-deployment substance use problems and comorbidities, and discusses the military's dual role in 1) enforcing troop readiness with its alcohol and drug policies and resiliency building programs, and 2) seeking to provide treatment to troops with combat acquired problems including substance abuse. PMID- 22496627 TI - Comprehensive modelling of the Neurospora circadian clock and its temperature compensation. AB - Circadian clocks provide an internal measure of external time allowing organisms to anticipate and exploit predictable daily changes in the environment. Rhythms driven by circadian clocks have a temperature compensated periodicity of approximately 24 hours that persists in constant conditions and can be reset by environmental time cues. Computational modelling has aided our understanding of the molecular mechanisms of circadian clocks, nevertheless it remains a major challenge to integrate the large number of clock components and their interactions into a single, comprehensive model that is able to account for the full breadth of clock phenotypes. Here we present a comprehensive dynamic model of the Neurospora crassa circadian clock that incorporates its key components and their transcriptional and post-transcriptional regulation. The model accounts for a wide range of clock characteristics including: a periodicity of 21.6 hours, persistent oscillation in constant conditions, arrhythmicity in constant light, resetting by brief light pulses, and entrainment to full photoperiods. Crucial components influencing the period and amplitude of oscillations were identified by control analysis. Furthermore, simulations enabled us to propose a mechanism for temperature compensation, which is achieved by simultaneously increasing the translation of frq RNA and decreasing the nuclear import of FRQ protein. PMID- 22496628 TI - Circular permutation in proteins. PMID- 22496629 TI - Replication fork polarity gradients revealed by megabase-sized U-shaped replication timing domains in human cell lines. AB - In higher eukaryotes, replication program specification in different cell types remains to be fully understood. We show for seven human cell lines that about half of the genome is divided in domains that display a characteristic U-shaped replication timing profile with early initiation zones at borders and late replication at centers. Significant overlap is observed between U-domains of different cell lines and also with germline replication domains exhibiting a N shaped nucleotide compositional skew. From the demonstration that the average fork polarity is directly reflected by both the compositional skew and the derivative of the replication timing profile, we argue that the fact that this derivative displays a N-shape in U-domains sustains the existence of large-scale gradients of replication fork polarity in somatic and germline cells. Analysis of chromatin interaction (Hi-C) and chromatin marker data reveals that U-domains correspond to high-order chromatin structural units. We discuss possible models for replication origin activation within U/N-domains. The compartmentalization of the genome into replication U/N-domains provides new insights on the organization of the replication program in the human genome. PMID- 22496630 TI - Molecular machines in the synapse: overlapping protein sets control distinct steps in neurosecretion. AB - Activity regulated neurotransmission shapes the computational properties of a neuron and involves the concerted action of many proteins. Classical, intuitive working models often assign specific proteins to specific steps in such complex cellular processes, whereas modern systems theories emphasize more integrated functions of proteins. To test how often synaptic proteins participate in multiple steps in neurotransmission we present a novel probabilistic method to analyze complex functional data from genetic perturbation studies on neuronal secretion. Our method uses a mixture of probabilistic principal component analyzers to cluster genetic perturbations on two distinct steps in synaptic secretion, vesicle priming and fusion, and accounts for the poor standardization between different studies. Clustering data from 121 perturbations revealed that different perturbations of a given protein are often assigned to different steps in the release process. Furthermore, vesicle priming and fusion are inversely correlated for most of those perturbations where a specific protein domain was mutated to create a gain-of-function variant. Finally, two different modes of vesicle release, spontaneous and action potential evoked release, were affected similarly by most perturbations. This data suggests that the presynaptic protein network has evolved as a highly integrated supramolecular machine, which is responsible for both spontaneous and activity induced release, with a group of core proteins using different domains to act on multiple steps in the release process. PMID- 22496631 TI - Evolutionary game theory and social learning can determine how vaccine scares unfold. AB - Immunization programs have often been impeded by vaccine scares, as evidenced by the measles-mumps-rubella (MMR) autism vaccine scare in Britain. A "free rider" effect may be partly responsible: vaccine-generated herd immunity can reduce disease incidence to such low levels that real or imagined vaccine risks appear large in comparison, causing individuals to cease vaccinating. This implies a feedback loop between disease prevalence and strategic individual vaccinating behavior. Here, we analyze a model based on evolutionary game theory that captures this feedback in the context of vaccine scares, and that also includes social learning. Vaccine risk perception evolves over time according to an exogenously imposed curve. We test the model against vaccine coverage data and disease incidence data from two vaccine scares in England & Wales: the whole cell pertussis vaccine scare and the MMR vaccine scare. The model fits vaccine coverage data from both vaccine scares relatively well. Moreover, the model can explain the vaccine coverage data more parsimoniously than most competing models without social learning and/or feedback (hence, adding social learning and feedback to a vaccine scare model improves model fit with little or no parsimony penalty). Under some circumstances, the model can predict future vaccine coverage and disease incidence--up to 10 years in advance in the case of pertussis- including specific qualitative features of the dynamics, such as future incidence peaks and undulations in vaccine coverage due to the population's response to changing disease incidence. Vaccine scares could become more common as eradication goals are approached for more vaccine-preventable diseases. Such models could help us predict how vaccine scares might unfold and assist mitigation efforts. PMID- 22496632 TI - Automatic filtering and substantiation of drug safety signals. AB - Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions. PMID- 22496633 TI - What can causal networks tell us about metabolic pathways? AB - Graphical models describe the linear correlation structure of data and have been used to establish causal relationships among phenotypes in genetic mapping populations. Data are typically collected at a single point in time. Biological processes on the other hand are often non-linear and display time varying dynamics. The extent to which graphical models can recapitulate the architecture of an underlying biological processes is not well understood. We consider metabolic networks with known stoichiometry to address the fundamental question: "What can causal networks tell us about metabolic pathways?". Using data from an Arabidopsis Bay[Formula: see text]Sha population and simulated data from dynamic models of pathway motifs, we assess our ability to reconstruct metabolic pathways using graphical models. Our results highlight the necessity of non-genetic residual biological variation for reliable inference. Recovery of the ordering within a pathway is possible, but should not be expected. Causal inference is sensitive to subtle patterns in the correlation structure that may be driven by a variety of factors, which may not emphasize the substrate-product relationship. We illustrate the effects of metabolic pathway architecture, epistasis and stochastic variation on correlation structure and graphical model-derived networks. We conclude that graphical models should be interpreted cautiously, especially if the implied causal relationships are to be used in the design of intervention strategies. PMID- 22496634 TI - Parameters in dynamic models of complex traits are containers of missing heritability. AB - Polymorphisms identified in genome-wide association studies of human traits rarely explain more than a small proportion of the heritable variation, and improving this situation within the current paradigm appears daunting. Given a well-validated dynamic model of a complex physiological trait, a substantial part of the underlying genetic variation must manifest as variation in model parameters. These parameters are themselves phenotypic traits. By linking whole cell phenotypic variation to genetic variation in a computational model of a single heart cell, incorporating genotype-to-parameter maps, we show that genome wide association studies on parameters reveal much more genetic variation than when using higher-level cellular phenotypes. The results suggest that letting such studies be guided by computational physiology may facilitate a causal understanding of the genotype-to-phenotype map of complex traits, with strong implications for the development of phenomics technology. PMID- 22496635 TI - Energetic selection of topology in ferredoxins. AB - Models of early protein evolution posit the existence of short peptides that bound metals and ions and served as transporters, membranes or catalysts. The Cys X-X-Cys-X-X-Cys heptapeptide located within bacterial ferredoxins, enclosing an Fe4S4 metal center, is an attractive candidate for such an early peptide. Ferredoxins are ancient proteins and the simple alpha+beta fold is found alone or as a domain in larger proteins throughout all three kingdoms of life. Previous analyses of the heptapeptide conformation in experimentally determined ferredoxin structures revealed a pervasive right-handed topology, despite the fact that the Fe4S4 cluster is achiral. Conformational enumeration of a model CGGCGGC heptapeptide bound to a cubane iron-sulfur cluster indicates both left-handed and right-handed folds could exist and have comparable stabilities. However, only the natural ferredoxin topology provides a significant network of backbone-to-cluster hydrogen bonds that would stabilize the metal-peptide complex. The optimal peptide configuration (alternating alpha(L),alpha(R)) is that of an alpha-sheet, providing an additional mechanism where oligomerization could stabilize the peptide and facilitate iron-sulfur cluster binding. PMID- 22496637 TI - On conduction in a bacterial sodium channel. AB - Voltage-gated Na+-channels are transmembrane proteins that are responsible for the fast depolarizing phase of the action potential in nerve and muscular cells. Selective permeability of Na+ over Ca2+ or K+ ions is essential for the biological function of Na+-channels. After the emergence of the first high resolution structure of a Na+-channel, an anionic coordination site was proposed to confer Na+ selectivity through partial dehydration of Na+ via its direct interaction with conserved glutamate side chains. By combining molecular dynamics simulations and free-energy calculations, a low-energy permeation pathway for Na+ ion translocation through the selectivity filter of the recently determined crystal structure of a prokaryotic sodium channel from Arcobacter butzleri is characterised. The picture that emerges is that of a pore preferentially occupied by two ions, which can switch between different configurations by crossing low free-energy barriers. In contrast to K+-channels, the movements of the ions appear to be weakly coupled in Na+-channels. When the free-energy maps for Na+ and K+ ions are compared, a selective site is characterised in the narrowest region of the filter, where a hydrated Na+ ion, and not a hydrated K+ ion, is energetically stable. PMID- 22496636 TI - RNA-Seq mapping and detection of gene fusions with a suffix array algorithm. AB - High-throughput RNA sequencing enables quantification of transcripts (both known and novel), exon/exon junctions and fusions of exons from different genes. Discovery of gene fusions-particularly those expressed with low abundance- is a challenge with short- and medium-length sequencing reads. To address this challenge, we implemented an RNA-Seq mapping pipeline within the LifeScope software. We introduced new features including filter and junction mapping, annotation-aided pairing rescue and accurate mapping quality values. We combined this pipeline with a Suffix Array Spliced Read (SASR) aligner to detect chimeric transcripts. Performing paired-end RNA-Seq of the breast cancer cell line MCF-7 using the SOLiD system, we called 40 gene fusions among over 120,000 splicing junctions. We validated 36 of these 40 fusions with TaqMan assays, of which 25 were expressed in MCF-7 but not the Human Brain Reference. An intra-chromosomal gene fusion involving the estrogen receptor alpha gene ESR1, and another involving the RPS6KB1 (Ribosomal protein S6 kinase beta-1) were recurrently expressed in a number of breast tumor cell lines and a clinical tumor sample. PMID- 22496638 TI - Calcium influx rescues adenylate cyclase-hemolysin from rapid cell membrane removal and enables phagocyte permeabilization by toxin pores. AB - Bordetella adenylate cyclase toxin-hemolysin (CyaA) penetrates the cytoplasmic membrane of phagocytes and employs two distinct conformers to exert its multiple activities. One conformer forms cation-selective pores that permeabilize phagocyte membrane for efflux of cytosolic potassium. The other conformer conducts extracellular calcium ions across cytoplasmic membrane of cells, relocates into lipid rafts, translocates the adenylate cyclase enzyme (AC) domain into cells and converts cytosolic ATP to cAMP. We show that the calcium conducting activity of CyaA controls the path and kinetics of endocytic removal of toxin pores from phagocyte membrane. The enzymatically inactive but calcium conducting CyaA-AC- toxoid was endocytosed via a clathrin-dependent pathway. In contrast, a doubly mutated (E570K+E581P) toxoid, unable to conduct Ca2+ into cells, was rapidly internalized by membrane macropinocytosis, unless rescued by Ca2+ influx promoted in trans by ionomycin or intact toxoid. Moreover, a fully pore-forming CyaA-DeltaAC hemolysin failed to permeabilize phagocytes, unless endocytic removal of its pores from cell membrane was decelerated through Ca2+ influx promoted by molecules locked in a Ca2+-conducting conformation by the 3D1 antibody. Inhibition of endocytosis also enabled the native B. pertussis-produced CyaA to induce lysis of J774A.1 macrophages at concentrations starting from 100 ng/ml. Hence, by mediating calcium influx into cells, the translocating conformer of CyaA controls the removal of bystander toxin pores from phagocyte membrane. This triggers a positive feedback loop of exacerbated cell permeabilization, where the efflux of cellular potassium yields further decreased toxin pore removal from cell membrane and this further enhances cell permeabilization and potassium efflux. PMID- 22496639 TI - Fungal biofilms. PMID- 22496640 TI - Ross, macdonald, and a theory for the dynamics and control of mosquito transmitted pathogens. AB - Ronald Ross and George Macdonald are credited with developing a mathematical model of mosquito-borne pathogen transmission. A systematic historical review suggests that several mathematicians and scientists contributed to development of the Ross-Macdonald model over a period of 70 years. Ross developed two different mathematical models, Macdonald a third, and various "Ross-Macdonald" mathematical models exist. Ross-Macdonald models are best defined by a consensus set of assumptions. The mathematical model is just one part of a theory for the dynamics and control of mosquito-transmitted pathogens that also includes epidemiological and entomological concepts and metrics for measuring transmission. All the basic elements of the theory had fallen into place by the end of the Global Malaria Eradication Programme (GMEP, 1955-1969) with the concept of vectorial capacity, methods for measuring key components of transmission by mosquitoes, and a quantitative theory of vector control. The Ross-Macdonald theory has since played a central role in development of research on mosquito-borne pathogen transmission and the development of strategies for mosquito-borne disease prevention. PMID- 22496641 TI - CEACAM1 negatively regulates IL-1beta production in LPS activated neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex. AB - LPS-activated neutrophils secrete IL-1beta by activation of TLR-4. Based on studies in macrophages, it is likely that ROS and lysosomal destabilization regulated by Syk activation may also be involved. Since neutrophils have abundant expression of the ITIM-containing co-receptor CEACAM1 and Gram-negative bacteria such as Neisseria utilize CEACAM1 as a receptor that inhibits inflammation, we hypothesized that the overall production of IL-1beta in LPS treated neutrophils may be negatively regulated by CEACAM1. We found that LPS treated neutrophils induced phosphorylation of Syk resulting in the formation of a complex including TLR4, p-Syk, and p-CEACAM1, which in turn, recruited the inhibitory phosphatase SHP-1. LPS treatment leads to ROS production, lysosomal damage, caspase-1 activation and IL-1beta secretion in neutrophils. The absence of this regulation in Ceacam1-/- neutrophils led to hyper production of IL-1beta in response to LPS. The hyper production of IL-1beta was abrogated by in vivo reconstitution of wild type but not ITIM-mutated CEACAM1 bone marrow stem cells. Blocking Syk activation by kinase inhibitors or RNAi reduced Syk phosphorylation, lysosomal destabilization, ROS production, and caspase-1 activation in Ceacam1-/- neutrophils. We conclude that LPS treatment of neutrophils triggers formation of a complex of TLR4 with pSyk and pCEACAM1, which upon recruitment of SHP-1 to the ITIMs of pCEACAM1, inhibits IL-1beta production by the inflammasome. Thus, CEACAM1 fine-tunes IL-1beta production in LPS treated neutrophils, explaining why the additional utilization of CEACAM1 as a pathogen receptor would further inhibit inflammation. PMID- 22496642 TI - Neutrophils Promote Mycobacterial Trehalose Dimycolate-Induced Lung Inflammation via the Mincle Pathway. AB - Trehalose 6,6'-dimycolate (TDM), a cord factor of Mycobacterium tuberculosis (Mtb), is an important regulator of immune responses during Mtb infections. Macrophages recognize TDM through the Mincle receptor and initiate TDM-induced inflammatory responses, leading to lung granuloma formation. Although various immune cells are recruited to lung granulomas, the roles of other immune cells, especially during the initial process of TDM-induced inflammation, are not clear. In this study, Mincle signaling on neutrophils played an important role in TDM induced lung inflammation by promoting adhesion and innate immune responses. Neutrophils were recruited during the early stage of lung inflammation following TDM-induced granuloma formation. Mincle expression on neutrophils was required for infiltration of TDM-challenged sites in a granuloma model induced by TDM coated-beads. TDM-induced Mincle signaling on neutrophils increased cell adherence by enhancing F-actin polymerization and CD11b/CD18 surface expression. The TDM-induced effects were dependent on Src, Syk, and MAPK/ERK kinases (MEK). Moreover, coactivation of the Mincle and TLR2 pathways by TDM and Pam3CSK4 treatment synergistically induced CD11b/CD18 surface expression, reactive oxygen species, and TNFalpha production by neutrophils. These synergistically-enhanced immune responses correlated with the degree of Mincle expression on neutrophil surfaces. The physiological relevance of the Mincle-mediated anti-TDM immune response was confirmed by defective immune responses in Mincle-/- mice upon aerosol infections with Mtb. Mincle-mutant mice had higher inflammation levels and mycobacterial loads than WT mice. Neutrophil depletion with anti-Ly6G antibody caused a reduction in IL-6 and monocyte chemotactic protein-1 expression upon TDM treatment, and reduced levels of immune cell recruitment during the initial stage of infection. These findings suggest a new role of Mincle signaling on neutrophils during anti-mycobacterial responses. PMID- 22496643 TI - An "escape clock" for estimating the turnover of SIV DNA in resting CD4+ T cells. AB - Persistence of HIV DNA presents a major barrier to the complete control of HIV infection under current therapies. Most studies suggest that cells with latently integrated HIV decay very slowly under therapy. However, it is much more difficult to study the turnover and persistence of HIV DNA during active infection. We have developed an "escape clock" approach for measuring the turnover of HIV DNA in resting CD4+ T cells. This approach studies the replacement of wild-type (WT) SIV DNA present in early infection by CTL escape mutant (EM) strains during later infection. Using a strain-specific real time PCR assay, we quantified the relative amounts of WT and EM strains in plasma SIV RNA and cellular SIV DNA. Thus we can track the formation and turnover of SIV DNA in sorted resting CD4+ T cells. We studied serial plasma and PBMC samples from 20 SIV-infected Mane-A*10 positive pigtail macaques that have a signature Gag CTL escape mutation. In animals with low viral load, WT virus laid down early in infection is extremely stable, and the decay of this WT species is very slow, consistent with findings in subjects on anti-retroviral medications. However, during active, high level infection, most SIV DNA in resting cells was turning over rapidly, suggesting a large pool of short-lived DNA produced by recent infection events. Our results suggest that, in order to reduce the formation of a stable population of SIV DNA, it will be important either to intervene very early or intervene during active replication. PMID- 22496644 TI - Pseudomonas aeruginosa pili and flagella mediate distinct binding and signaling events at the apical and basolateral surface of airway epithelium. AB - Pseudomonas aeruginosa, an important opportunistic pathogen of man, exploits numerous factors for initial attachment to the host, an event required to establish bacterial infection. In this paper, we rigorously explore the role of two major bacterial adhesins, type IV pili (Tfp) and flagella, in bacterial adherence to distinct host receptors at the apical (AP) and basolateral (BL) surfaces of polarized lung epithelial cells and induction of subsequent host signaling and pathogenic events. Using an isogenic mutant of P. aeruginosa that lacks flagella or utilizing beads coated with purified Tfp, we establish that Tfp are necessary and sufficient for maximal binding to host N-glycans at the AP surface of polarized epithelium. In contrast, experiments utilizing a P. aeruginosa isogenic mutant that lacks Tfp or using beads coated with purified flagella demonstrate that flagella are necessary and sufficient for maximal binding to heparan sulfate (HS) chains of heparan sulfate proteoglycans (HSPGs) at the BL surface of polarized epithelium. Using two different cell-free systems, we demonstrate that Tfp-coated beads show highest binding affinity to complex N glycan chains coated onto plastic plates and preferentially aggregate with beads coated with N-glycans, but not with single sugars or HS. In contrast, flagella coated beads bind to or aggregate preferentially with HS or HSPGs, but demonstrate little binding to N-glycans. We further show that Tfp-mediated binding to host N-glycans results in activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway and bacterial entry at the AP surface. At the BL surface, flagella-mediated binding to HS activates the epidermal growth factor receptor (EGFR), adaptor protein Shc, and PI3K/Akt, and induces bacterial entry. Remarkably, flagella-coated beads alone can activate EGFR and Shc. Together, this work provides new insights into the intricate interactions between P. aeruginosa and lung epithelium that may be potentially useful in the development of novel treatments for P. aeruginosa infections. PMID- 22496646 TI - Modeling of the N-glycosylated transferrin receptor suggests how transferrin binding can occur within the surface coat of Trypanosoma brucei. AB - The transferrin receptor of bloodstream form Trypanosoma brucei is a heterodimer encoded by expression site associated genes 6 and 7. This low-abundance glycoprotein with a single glycosylphosphatidylinositol membrane anchor and eight potential N-glycosylation sites is located in the flagellar pocket. The receptor is essential for the parasite, providing its only source of iron by scavenging host transferrin from the bloodstream. Here, we demonstrate that both receptor subunits contain endoglycosidase H-sensitive and endoglycosidase H-resistant N glycans. Lectin blotting of the purified receptor and structural analysis of the released N-glycans revealed oligomannose and paucimannose structures but, contrary to previous suggestions, no poly-N-acetyllactosamine structures were found. Overlay experiments suggest that the receptor can bind to other trypanosome glycoproteins, which may explain this discrepancy. Nevertheless, these data suggest that a current model, in which poly-N-acetyllactosamine glycans are directly involved in receptor-mediated endocytosis in bloodstream form Trypanosoma brucei, should be revised. Sequential endoglycosidase H and peptide-N-glycosidase F treatment, followed by tryptic peptide analysis, allowed the mapping of oligomannose and paucimannose structures to four of the receptor N glycosylation sites. These results are discussed with respect to the current model for protein N-glycosylation in the parasite. Finally, the glycosylation data allowed the creation of a molecular model for the parasite transferrin receptor. This model, when placed in the context of a model for the dense variant surface glycoprotein coat in which it is embedded, suggests that receptor N glycosylation may play an important role in providing sufficient space for the approach and binding of transferrin to the receptor, without significantly disrupting the continuity of the protective variant surface glycoprotein coat. PMID- 22496645 TI - Productive hepatitis C virus infection of stem cell-derived hepatocytes reveals a critical transition to viral permissiveness during differentiation. AB - Primary human hepatocytes isolated from patient biopsies represent the most physiologically relevant cell culture model for hepatitis C virus (HCV) infection, but these primary cells are not readily accessible, display individual variability, and are largely refractory to genetic manipulation. Hepatocyte-like cells differentiated from pluripotent stem cells provide an attractive alternative as they not only overcome these shortcomings but can also provide an unlimited source of noncancer cells for both research and cell therapy. Despite its promise, the permissiveness to HCV infection of differentiated human hepatocyte-like cells (DHHs) has not been explored. Here we report a novel infection model based on DHHs derived from human embryonic (hESCs) and induced pluripotent stem cells (iPSCs). DHHs generated in chemically defined media under feeder-free conditions were subjected to infection by both HCV derived in cell culture (HCVcc) and patient-derived virus (HCVser). Pluripotent stem cells and definitive endoderm were not permissive for HCV infection whereas hepatic progenitor cells were persistently infected and secreted infectious particles into culture medium. Permissiveness to infection was correlated with induction of the liver-specific microRNA-122 and modulation of cellular factors that affect HCV replication. RNA interference directed toward essential cellular cofactors in stem cells resulted in HCV-resistant hepatocyte-like cells after differentiation. The ability to infect cultured cells directly with HCV patient serum, to study defined stages of viral permissiveness, and to produce genetically modified cells with desired phenotypes all have broad significance for host-pathogen interactions and cell therapy. PMID- 22496647 TI - Regulation of Mycobacterium tuberculosis-dependent HIV-1 transcription reveals a new role for NFAT5 in the toll-like receptor pathway. AB - Tuberculosis (TB) disease in HIV co-infected patients contributes to increased mortality by activating innate and adaptive immune signaling cascades that stimulate HIV-1 replication, leading to an increase in viral load. Here, we demonstrate that silencing of the expression of the transcription factor nuclear factor of activated T cells 5 (NFAT5) by RNA interference (RNAi) inhibits Mycobacterium tuberculosis (MTb)-stimulated HIV-1 replication in co-infected macrophages. We show that NFAT5 gene and protein expression are strongly induced by MTb, which is a Toll-like receptor (TLR) ligand, and that an intact NFAT5 binding site in the viral promoter of R5-tropic HIV-1 subtype B and subtype C molecular clones is required for efficent induction of HIV-1 replication by MTb. Furthermore, silencing by RNAi of key components of the TLR pathway in human monocytes, including the downstream signaling molecules MyD88, IRAK1, and TRAF6, significantly inhibits MTb-induced NFAT5 gene expression. Thus, the innate immune response to MTb infection induces NFAT5 gene and protein expression, and NFAT5 plays a crucial role in MTb regulation of HIV-1 replication via a direct interaction with the viral promoter. These findings also demonstrate a general role for NFAT5 in TLR- and MTb-mediated control of gene expression. PMID- 22496648 TI - Human nasal challenge with Streptococcus pneumoniae is immunising in the absence of carriage. AB - Infectious challenge of the human nasal mucosa elicits immune responses that determine the fate of the host-bacterial interaction; leading either to clearance, colonisation and/or disease. Persistent antigenic exposure from pneumococcal colonisation can induce both humoral and cellular defences that are protective against carriage and disease. We challenged healthy adults intra nasally with live 23F or 6B Streptococcus pneumoniae in two sequential cohorts and collected nasal wash, bronchoalveolar lavage (BAL) and blood before and 6 weeks after challenge. We hypothesised that both cohorts would successfully become colonised but this did not occur except for one volunteer. The effect of bacterial challenge without colonisation in healthy adults has not been previously assessed. We measured the antigen-specific humoral and cellular immune responses in challenged but not colonised volunteers by ELISA and Flow Cytometry. Antigen-specific responses were seen in each compartment both before and after bacterial challenge for both cohorts. Antigen-specific IgG and IgA levels were significantly elevated in nasal wash 6 weeks after challenge compared to baseline. Immunoglobulin responses to pneumococci were directed towards various protein targets but not capsular polysaccharide. 23F but not 6B challenge elevated IgG anti-PspA in BAL. Serum immunoglobulins did not increase in response to challenge. In neither challenge cohort was there any alteration in the frequencies of TNF, IL-17 or IFNgamma producing CD4 T cells before or after challenge in BAL or blood. We show that simple, low dose mucosal exposure with pneumococci may immunise mucosal surfaces by augmenting anti-protein immunoglobulin responses; but not capsular or cellular responses. We hypothesise that mucosal exposure alone may not replicate the systemic immunising effect of experimental or natural carriage in humans. PMID- 22496649 TI - The exopolysaccharide matrix modulates the interaction between 3D architecture and virulence of a mixed-species oral biofilm. AB - Virulent biofilms are responsible for a range of infections, including oral diseases. All biofilms harbor a microbial-derived extracellular-matrix. The exopolysaccharides (EPS) formed on tooth-pellicle and bacterial surfaces provide binding sites for microorganisms; eventually the accumulated EPS enmeshes microbial cells. The metabolic activity of the bacteria within this matrix leads to acidification of the milieu. We explored the mechanisms through which the Streptococcus mutans-produced EPS-matrix modulates the three-dimensional (3D) architecture and the population shifts during morphogenesis of biofilms on a saliva-coated-apatitic surface using a mixed-bacterial species system. Concomitantly, we examined whether the matrix influences the development of pH microenvironments within intact-biofilms using a novel 3D in situ pH-mapping technique. Data reveal that the production of the EPS-matrix helps to create spatial heterogeneities by forming an intricate network of exopolysaccharide enmeshed bacterial-islets (microcolonies) through localized cell-to-matrix interactions. This complex 3D architecture creates compartmentalized acidic and EPS-rich microenvironments throughout the biofilm, which triggers the dominance of pathogenic S. mutans within a mixed-species system. The establishment of a 3D matrix and EPS-enmeshed microcolonies were largely mediated by the S. mutans gtfB/gtfC genes, expression of which was enhanced in the presence of Actinomyces naeslundii and Streptococcus oralis. Acidic pockets were found only in the interiors of bacterial-islets that are protected by EPS, which impedes rapid neutralization by buffer (pH 7.0). As a result, regions of low pH (<5.5) were detected at specific locations along the surface of attachment. Resistance to chlorhexidine was enhanced in cells within EPS-microcolony complexes compared to those outside such structures within the biofilm. Our results illustrate the critical interaction between matrix architecture and pH heterogeneity in the 3D environment. The formation of structured acidic-microenvironments in close proximity to the apatite-surface is an essential factor associated with virulence in cariogenic-biofilms. These observations may have relevance beyond the mouth, as matrix is inherent to all biofilms. PMID- 22496650 TI - Group A Streptococcus secreted esterase hydrolyzes platelet-activating factor to impede neutrophil recruitment and facilitate innate immune evasion. AB - The innate immune system is the first line of host defense against invading organisms. Thus, pathogens have developed virulence mechanisms to evade the innate immune system. Here, we report a novel means for inhibition of neutrophil recruitment by Group A Streptococcus (GAS). Deletion of the secreted esterase gene (designated sse) in M1T1 GAS strains with (MGAS5005) and without (MGAS2221) a null covS mutation enhances neutrophil ingress to infection sites in the skin of mice. In trans expression of SsE in MGAS2221 reduces neutrophil recruitment and enhances skin invasion. The sse deletion mutant of MGAS5005 (Deltasse(MGAS5005)) is more efficiently cleared from skin than the parent strain. SsE hydrolyzes the sn-2 ester bond of platelet-activating factor (PAF), converting biologically active PAF into inactive lyso-PAF. K(M) and k(cat) of SsE for hydrolysis of 2-thio-PAF were similar to those of the human plasma PAF acetylhydrolase. Treatment of PAF with SsE abolishes the capacity of PAF to induce activation and chemotaxis of human neutrophils. More importantly, PAF receptor-deficient mice significantly reduce neutrophil infiltration to the site of Deltasse(MGAS5005) infection. These findings identify the first secreted PAF acetylhydrolase of bacterial pathogens and support a novel GAS evasion mechanism that reduces phagocyte recruitment to sites of infection by inactivating PAF, providing a new paradigm for bacterial evasion of neutrophil responses. PMID- 22496651 TI - beta-Microseminoprotein endows post coital seminal plasma with potent candidacidal activity by a calcium- and pH-dependent mechanism. AB - The innate immune factors controlling Candida albicans are mostly unknown. Vulvovaginal candidiasis is common in women and affects approximately 70-75% of all women at least once. Despite the propensity of Candida to colonize the vagina, transmission of Candida albicans following sexual intercourse is very rare. This prompted us to investigate whether the post coital vaginal milieu contained factors active against C. albicans. By CFU assays, we found prominent candidacidal activity of post coital seminal plasma at both neutral and the acid vaginal pH. In contrast, normal seminal plasma did not display candidacidal activity prior to acidification. By antifungal gel overlay assay, one clearing zone corresponding to a protein band was found in both post coital and normal seminal plasma, which was subsequently identified as beta-microseminoprotein. At neutral pH, the fungicidal activity of beta-microseminoprotein and seminal plasma was inhibited by calcium. By NMR spectroscopy, amino acid residue E(71) was shown to be critical for the calcium coordination. The acidic vaginal milieu unleashed the fungicidal activity by decreasing the inhibitory effect of calcium. The candidacidal activity of beta-microseminoprotein was mapped to a fragment of the C-terminal domain with no structural similarity to other known proteins. A homologous fragment from porcine beta-microseminoprotein demonstrated calcium dependent fungicidal activity in a CFU assay, suggesting this may be a common feature for members of the beta-microseminoprotein family. By electron microscopy, beta-microseminoprotein was found to cause lysis of Candida. Liposome experiments demonstrated that beta-microseminoprotein was active towards ergosterol-containing liposomes that mimic fungal membranes, offering an explanation for the selectivity against fungi. These data identify beta microseminoprotein as an important innate immune factor active against C. albicans and may help explain the low sexual transmission rate of Candida. PMID- 22496652 TI - Methicillin resistance alters the biofilm phenotype and attenuates virulence in Staphylococcus aureus device-associated infections. AB - Clinical isolates of Staphylococcus aureus can express biofilm phenotypes promoted by the major cell wall autolysin and the fibronectin-binding proteins or the icaADBC-encoded polysaccharide intercellular adhesin/poly-N-acetylglucosamine (PIA/PNAG). Biofilm production in methicillin-susceptible S. aureus (MSSA) strains is typically dependent on PIA/PNAG whereas methicillin-resistant isolates express an Atl/FnBP-mediated biofilm phenotype suggesting a relationship between susceptibility to beta-lactam antibiotics and biofilm. By introducing the methicillin resistance gene mecA into the PNAG-producing laboratory strain 8325-4 we generated a heterogeneously resistant (HeR) strain, from which a homogeneous, high-level resistant (HoR) derivative was isolated following exposure to oxacillin. The HoR phenotype was associated with a R602H substitution in the DHHA1 domain of GdpP, a recently identified c-di-AMP phosphodiesterase with roles in resistance/tolerance to beta-lactam antibiotics and cell envelope stress. Transcription of icaADBC and PNAG production were impaired in the 8325-4 HoR derivative, which instead produced a proteinaceous biofilm that was significantly inhibited by antibodies against the mecA-encoded penicillin binding protein 2a (PBP2a). Conversely excision of the SCCmec element in the MRSA strain BH1CC resulted in oxacillin susceptibility and reduced biofilm production, both of which were complemented by mecA alone. Transcriptional activity of the accessory gene regulator locus was also repressed in the 8325-4 HoR strain, which in turn was accompanied by reduced protease production and significantly reduced virulence in a mouse model of device infection. Thus, homogeneous methicillin resistance has the potential to affect agr- and icaADBC-mediated phenotypes, including altered biofilm expression and virulence, which together are consistent with the adaptation of healthcare-associated MRSA strains to the antibiotic-rich hospital environment in which they are frequently responsible for device-related infections in immuno-compromised patients. PMID- 22496653 TI - Small-molecule inhibitors of dengue-virus entry. AB - Flavivirus envelope protein (E) mediates membrane fusion and viral entry from endosomes. A low-pH induced, dimer-to-trimer rearrangement and reconfiguration of the membrane-proximal "stem" of the E ectodomain draw together the viral and cellular membranes. We found stem-derived peptides from dengue virus (DV) bind stem-less E trimer and mimic the stem-reconfiguration step in the fusion pathway. We adapted this experiment as a high-throughput screen for small molecules that block peptide binding and thus may inhibit viral entry. A compound identified in this screen, 1662G07, and a number of its analogs reversibly inhibit DV infectivity. They do so by binding the prefusion, dimeric E on the virion surface, before adsorption to a cell. They also block viral fusion with liposomes. Structure-activity relationship studies have led to analogs with submicromolar IC90s against DV2, and certain analogs are active against DV serotypes 1,2, and 4. The compounds do not inhibit the closely related Kunjin virus. We propose that they bind in a previously identified, E-protein pocket, exposed on the virion surface and although this pocket is closed in the postfusion trimer, its mouth is fully accessible. Examination of the E-trimer coordinates (PDB 1OK8) shows that conformational fluctuations around the hinge could open the pocket without dissociating the trimer or otherwise generating molecular collisions. We propose that compounds such as 1662G07 trap the sE trimer in a "pocket-open" state, which has lost affinity for the stem peptide and cannot support the final "zipping up" of the stem. PMID- 22496654 TI - Virion assembly factories in the nucleus of polyomavirus-infected cells. AB - Most DNA viruses replicate in the cell nucleus, although the specific sites of virion assembly are as yet poorly defined. Electron microscopy on freeze substituted, plastic-embedded sections of murine polyomavirus (PyV)-infected 3T3 mouse fibroblasts or mouse embryonic fibroblasts (MEFs) revealed tubular structures in the nucleus adjacent to clusters of assembled virions, with virions apparently "shed" or "budding" from their ends. Promyelocytic leukemia nuclear bodies (PML-NBs) have been suggested as possible sites for viral replication of polyomaviruses (BKV and SV40), herpes simplex virus (HSV), and adenovirus (Ad). Immunohistochemistry and FISH demonstrated co-localization of the viral T-antigen (Tag), PyV DNA, and the host DNA repair protein MRE11, adjacent to the PML-NBs. In PML-/- MEFs the co-localization of MRE11, Tag, and PyV DNA remained unchanged, suggesting that the PML protein itself was not responsible for their association. Furthermore, PyV-infected PML-/- MEFs and PML-/- mice replicated wild-type levels of infectious virus. Therefore, although the PML protein may identify sites of PyV replication, neither the observed "virus factories" nor virus assembly were dependent on PML. The ultrastructure of the tubes suggests a new model for the encapsidation of small DNA viruses. PMID- 22496655 TI - Cell-cell transmission enables HIV-1 to evade inhibition by potent CD4bs directed antibodies. AB - HIV is known to spread efficiently both in a cell-free state and from cell to cell, however the relative importance of the cell-cell transmission mode in natural infection has not yet been resolved. Likewise to what extent cell-cell transmission is vulnerable to inhibition by neutralizing antibodies and entry inhibitors remains to be determined. Here we report on neutralizing antibody activity during cell-cell transmission using specifically tailored experimental strategies which enable unambiguous discrimination between the two transmission routes. We demonstrate that the activity of neutralizing monoclonal antibodies (mAbs) and entry inhibitors during cell-cell transmission varies depending on their mode of action. While gp41 directed agents remain active, CD4 binding site (CD4bs) directed inhibitors, including the potent neutralizing mAb VRC01, dramatically lose potency during cell-cell transmission. This implies that CD4bs mAbs act preferentially through blocking free virus transmission, while still allowing HIV to spread through cell-cell contacts. Thus providing a plausible explanation for how HIV maintains infectivity and rapidly escapes potent and broadly active CD4bs directed antibody responses in vivo. PMID- 22496656 TI - Leishmania induces survival, proliferation and elevated cellular dNTP levels in human monocytes promoting acceleration of HIV co-infection. AB - Leishmaniasis is a parasitic disease that is widely prevalent in many tropical and sub-tropical regions of the world. Infection with Leishmania has been recognized to induce a striking acceleration of Human Immunodeficiency Virus Type 1 (HIV-1) infection in coinfected individuals through as yet incompletely understood mechanisms. Cells of the monocyte/macrophage lineage are the predominant cell types coinfected by both pathogens. Monocytes and macrophages contain extremely low levels of deoxynucleoside triphosphates (dNTPs) due to their lack of cell cycling and S phase, where dNTP biosynthesis is specifically activated. Lentiviruses, such as HIV-1, are unique among retroviruses in their ability to replicate in these non-dividing cells due, at least in part, to their highly efficient reverse transcriptase (RT). Nonetheless, viral replication progresses more efficiently in the setting of higher intracellular dNTP concentrations related to enhanced enzyme kinetics of the viral RT. In the present study, in vitro infection of CD14+ peripheral blood-derived human monocytes with Leishmania major was found to induce differentiation, marked elevation of cellular p53R2 ribonucleotide reductase subunit and R2 subunit expression. The R2 subunit is restricted to the S phase of the cell cycle. Our dNTP assay demonstrated significant elevation of intracellular monocyte-derived macrophages (MDMs) dNTP concentrations in Leishmania-infected cell populations as compared to control cells. Infection of Leishmania-maturated MDMs with a pseudotyped GFP expressing HIV-1 resulted in increased numbers of GFP+ cells in the Leishmania-maturated MDMs as compared to control cells. Interestingly, a sub population of Leishmania-maturated MDMs was found to have re-entered the cell cycle, as demonstrated by BrdU labeling. In conclusion, Leishmania infection of primary human monocytes promotes the induction of an S phase environment and elevated dNTP levels with notable elevation of HIV-1 expression in the setting of coinfection. PMID- 22496657 TI - Structural basis of cytotoxicity mediated by the type III secretion toxin ExoU from Pseudomonas aeruginosa. AB - The type III secretion system (T3SS) is a complex macromolecular machinery employed by a number of Gram-negative pathogens to inject effectors directly into the cytoplasm of eukaryotic cells. ExoU from the opportunistic pathogen Pseudomonas aeruginosa is one of the most aggressive toxins injected by a T3SS, leading to rapid cell necrosis. Here we report the crystal structure of ExoU in complex with its chaperone, SpcU. ExoU folds into membrane-binding, bridging, and phospholipase domains. SpcU maintains the N-terminus of ExoU in an unfolded state, required for secretion. The phospholipase domain carries an embedded catalytic site whose position within ExoU does not permit direct interaction with the bilayer, which suggests that ExoU must undergo a conformational rearrangement in order to access lipids within the target membrane. The bridging domain connects catalytic domain and membrane-binding domains, the latter of which displays specificity to PI(4,5)P2. Both transfection experiments and infection of eukaryotic cells with ExoU-secreting bacteria show that ExoU ubiquitination results in its co-localization with endosomal markers. This could reflect an attempt of the infected cell to target ExoU for degradation in order to protect itself from its aggressive cytotoxic action. PMID- 22496658 TI - Airborne signals from a wounded leaf facilitate viral spreading and induce antibacterial resistance in neighboring plants. AB - Many plants release airborne volatile compounds in response to wounding due to pathogenic assault. These compounds serve as plant defenses and are involved in plant signaling. Here, we study the effects of pectin methylesterase (PME) generated methanol release from wounded plants ("emitters") on the defensive reactions of neighboring "receiver" plants. Plant leaf wounding resulted in the synthesis of PME and a spike in methanol released into the air. Gaseous methanol or vapors from wounded PME-transgenic plants induced resistance to the bacterial pathogen Ralstonia solanacearum in the leaves of non-wounded neighboring "receiver" plants. In experiments with different volatile organic compounds, gaseous methanol was the only airborne factor that could induce antibacterial resistance in neighboring plants. In an effort to understand the mechanisms by which methanol stimulates the antibacterial resistance of "receiver" plants, we constructed forward and reverse suppression subtractive hybridization cDNA libraries from Nicotiana benthamiana plants exposed to methanol. We identified multiple methanol-inducible genes (MIGs), most of which are involved in defense or cell-to-cell trafficking. We then isolated the most affected genes for further analysis: beta-1,3-glucanase (BG), a previously unidentified gene (MIG-21), and non-cell-autonomous pathway protein (NCAPP). Experiments with Tobacco mosaic virus (TMV) and a vector encoding two tandem copies of green fluorescent protein as a tracer of cell-to-cell movement showed the increased gating capacity of plasmodesmata in the presence of BG, MIG-21, and NCAPP. The increased gating capacity is accompanied by enhanced TMV reproduction in the "receivers". Overall, our data indicate that methanol emitted by a wounded plant acts as a signal that enhances antibacterial resistance and facilitates viral spread in neighboring plants. PMID- 22496659 TI - Matrix metalloprotease 9 mediates neutrophil migration into the airways in response to influenza virus-induced toll-like receptor signaling. AB - The early inflammatory response to influenza virus infection contributes to severe lung disease and continues to pose a serious threat to human health. The mechanisms by which neutrophils gain entry to the respiratory tract and their role during pathogenesis remain unclear. Here, we report that neutrophils significantly contributed to morbidity in a pathological mouse model of influenza virus infection. Using extensive immunohistochemistry, bone marrow transfers, and depletion studies, we identified neutrophils as the predominant pulmonary cellular source of the gelatinase matrix metalloprotease (MMP) 9, which is capable of digesting the extracellular matrix. Furthermore, infection of MMP9 deficient mice showed that MMP9 was functionally required for neutrophil migration and control of viral replication in the respiratory tract. Although MMP9 release was toll-like receptor (TLR) signaling-dependent, MyD88-mediated signals in non-hematopoietic cells, rather than neutrophil TLRs themselves, were important for neutrophil migration. These results were extended using multiplex analyses of inflammatory mediators to show that neutrophil chemotactic factor, CCL3, and TNFalpha were reduced in the Myd88-/- airways. Furthermore, TNFalpha induced MMP9 secretion by neutrophils and blocking TNFalpha in vivo reduced neutrophil recruitment after infection. Innate recognition of influenza virus therefore provides the mechanisms to induce recruitment of neutrophils through chemokines and to enable their motility within the tissue via MMP9-mediated cleavage of the basement membrane. Our results demonstrate a previously unknown contribution of MMP9 to influenza virus pathogenesis by mediating excessive neutrophil migration into the respiratory tract in response to viral replication that could be exploited for therapeutic purposes. PMID- 22496660 TI - 2'-O methylation of internal adenosine by flavivirus NS5 methyltransferase. AB - RNA modification plays an important role in modulating host-pathogen interaction. Flavivirus NS5 protein encodes N-7 and 2'-O methyltransferase activities that are required for the formation of 5' type I cap (m(7)GpppAm) of viral RNA genome. Here we reported, for the first time, that flavivirus NS5 has a novel internal RNA methylation activity. Recombinant NS5 proteins of West Nile virus and Dengue virus (serotype 4; DENV-4) specifically methylates polyA, but not polyG, polyC, or polyU, indicating that the methylation occurs at adenosine residue. RNAs with internal adenosines substituted with 2'-O-methyladenosines are not active substrates for internal methylation, whereas RNAs with adenosines substituted with N6-methyladenosines can be efficiently methylated, suggesting that the internal methylation occurs at the 2'-OH position of adenosine. Mass spectroscopic analysis further demonstrated that the internal methylation product is 2'-O-methyladenosine. Importantly, genomic RNA purified from DENV virion contains 2'-O-methyladenosine. The 2'-O methylation of internal adenosine does not require specific RNA sequence since recombinant methyltransferase of DENV-4 can efficiently methylate RNAs spanning different regions of viral genome, host ribosomal RNAs, and polyA. Structure-based mutagenesis results indicate that K61 D146-K181-E217 tetrad of DENV-4 methyltransferase forms the active site of internal methylation activity; in addition, distinct residues within the methyl donor (S-adenosyl-L-methionine) pocket, GTP pocket, and RNA-binding site are critical for the internal methylation activity. Functional analysis using flavivirus replicon and genome-length RNAs showed that internal methylation attenuated viral RNA translation and replication. Polymerase assay revealed that internal 2'-O-methyladenosine reduces the efficiency of RNA elongation. Collectively, our results demonstrate that flavivirus NS5 performs 2'-O methylation of internal adenosine of viral RNA in vivo and host ribosomal RNAs in vitro. PMID- 22496661 TI - Sequential delivery of host-induced virulence effectors by appressoria and intracellular hyphae of the phytopathogen Colletotrichum higginsianum. AB - Phytopathogens secrete effector proteins to manipulate their hosts for effective colonization. Hemibiotrophic fungi must maintain host viability during initial biotrophic growth and elicit host death for subsequent necrotrophic growth. To identify effectors mediating these opposing processes, we deeply sequenced the transcriptome of Colletotrichum higginsianum infecting Arabidopsis. Most effector genes are host-induced and expressed in consecutive waves associated with pathogenic transitions, indicating distinct effector suites are deployed at each stage. Using fluorescent protein tagging and transmission electron microscopy immunogold labelling, we found effectors localised to stage-specific compartments at the host-pathogen interface. In particular, we show effectors are focally secreted from appressorial penetration pores before host invasion, revealing new levels of functional complexity for this fungal organ. Furthermore, we demonstrate that antagonistic effectors either induce or suppress plant cell death. Based on these results we conclude that hemibiotrophy in Colletotrichum is orchestrated through the coordinated expression of antagonistic effectors supporting either cell viability or cell death. PMID- 22496662 TI - The baculovirus uses a captured host phosphatase to induce enhanced locomotory activity in host caterpillars. AB - The baculovirus is a classic example of a parasite that alters the behavior or physiology of its host so that progeny transmission is maximized. Baculoviruses do this by inducing enhanced locomotory activity (ELA) that causes the host caterpillars to climb to the upper foliage of plants. We previously reported that this behavior is not induced in silkworms that are infected with a mutant baculovirus lacking its protein tyrosine phosphatase (ptp) gene, a gene likely captured from an ancestral host. Here we show that the product of the ptp gene, PTP, associates with baculovirus ORF1629 as a virion structural protein, but surprisingly phosphatase activity associated with PTP was not required for the induction of ELA. Interestingly, the ptp knockout baculovirus showed significantly reduced infectivity of larval brain tissues. Collectively, we show that the modern baculovirus uses the host-derived phosphatase to establish adequate infection for ELA as a virion-associated structural protein rather than as an enzyme. PMID- 22496663 TI - Probing the informational and regulatory plasticity of a transcription factor DNA binding domain. AB - Transcription factors have two functional constraints on their evolution: (1) their binding sites must have enough information to be distinguishable from all other sequences in the genome, and (2) they must bind these sites with an affinity that appropriately modulates the rate of transcription. Since both are determined by the biophysical properties of the DNA-binding domain, selection on one will ultimately affect the other. We were interested in understanding how plastic the informational and regulatory properties of a transcription factor are and how transcription factors evolve to balance these constraints. To study this, we developed an in vivo selection system in Escherichia coli to identify variants of the helix-turn-helix transcription factor MarA that bind different sets of binding sites with varying degrees of degeneracy. Unlike previous in vitro methods used to identify novel DNA binders and to probe the plasticity of the binding domain, our selections were done within the context of the initiation complex, selecting for both specific binding within the genome and for a physiologically significant strength of interaction to maintain function of the factor. Using MITOMI, quantitative PCR, and a binding site fitness assay, we characterized the binding, function, and fitness of some of these variants. We observed that a large range of binding preferences, information contents, and activities could be accessed with a few mutations, suggesting that transcriptional regulatory networks are highly adaptable and expandable. PMID- 22496664 TI - Sex reversal in C57BL/6J XY mice caused by increased expression of ovarian genes and insufficient activation of the testis determining pathway. AB - Sex reversal can occur in XY humans with only a single functional WT1 or SF1 allele or a duplication of the chromosome region containing WNT4. In contrast, XY mice with only a single functional Wt1, Sf1, or Wnt4 allele, or mice that over express Wnt4 from a transgene, reportedly are not sex-reversed. Because genetic background plays a critical role in testis differentiation, particularly in C57BL/6J (B6) mice, we tested the hypothesis that Wt1, Sf1, and Wnt4 are dosage sensitive in B6 XY mice. We found that reduced Wt1 or Sf1 dosage in B6 XY(B6) mice impaired testis differentiation, but no ovarian tissue developed. If, however, a Y(AKR) chromosome replaced the Y(B6) chromosome, these otherwise genetically identical B6 XY mice developed ovarian tissue. In contrast, reduced Wnt4 dosage increased the amount of testicular tissue present in Sf1+/- B6 XY(AKR), Wt1+/- B6 XY(AKR), B6 XY(POS), and B6 XY(AKR) fetuses. We propose that Wt1(B6) and Sf1(B6) are hypomorphic alleles of testis-determining pathway genes and that Wnt4(B6) is a hypermorphic allele of an ovary-determining pathway gene. The latter hypothesis is supported by the finding that expression of Wnt4 and four other genes in the ovary-determining pathway are elevated in normal B6 XX E12.5 ovaries. We propose that B6 mice are sensitive to XY sex reversal, at least in part, because they carry Wt1(B6) and/or Sf1(B6) alleles that compromise testis differentiation and a Wnt4(B6) allele that promotes ovary differentiation and thereby antagonizes testis differentiation. Addition of a "weak" Sry allele, such as the one on the Y(POS) chromosome, to the sensitized B6 background results in inappropriate development of ovarian tissue. We conclude that Wt1, Sf1, and Wnt4 are dosage-sensitive in mice, this dosage-sensitivity is genetic background dependant, and the mouse strains described here are good models for the investigation of human dosage-sensitive XY sex reversal. PMID- 22496665 TI - Defective membrane remodeling in neuromuscular diseases: insights from animal models. AB - Proteins involved in membrane remodeling play an essential role in a plethora of cell functions including endocytosis and intracellular transport. Defects in several of them lead to human diseases. Myotubularins, amphiphysins, and dynamins are all proteins implicated in membrane trafficking and/or remodeling. Mutations in myotubularin, amphiphysin 2 (BIN1), and dynamin 2 lead to different forms of centronuclear myopathy, while mutations in myotubularin-related proteins cause Charcot-Marie-Tooth neuropathies. In addition to centronuclear myopathy, dynamin 2 is also mutated in a dominant form of Charcot-Marie-Tooth neuropathy. While several proteins from these different families are implicated in similar diseases, mutations in close homologues or in the same protein in the case of dynamin 2 lead to diseases affecting different tissues. This suggests (1) a common molecular pathway underlying these different neuromuscular diseases, and (2) tissue-specific regulation of these proteins. This review discusses the pathophysiology of the related neuromuscular diseases on the basis of animal models developed for proteins of the myotubularin, amphiphysin, and dynamin families. A better understanding of the common mechanisms between these neuromuscular disorders will lead to more specific health care and therapeutic approaches. PMID- 22496666 TI - The functions of Mediator in Candida albicans support a role in shaping species specific gene expression. AB - The Mediator complex is an essential co-regulator of RNA polymerase II that is conserved throughout eukaryotes. Here we present the first study of Mediator in the pathogenic fungus Candida albicans. We focused on the Middle domain subunit Med31, the Head domain subunit Med20, and Srb9/Med13 from the Kinase domain. The C. albicans Mediator shares some roles with model yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, such as functions in the response to certain stresses and the role of Med31 in the expression of genes regulated by the activator Ace2. The C. albicans Mediator also has additional roles in the transcription of genes associated with virulence, for example genes related to morphogenesis and gene families enriched in pathogens, such as the ALS adhesins. Consistently, Med31, Med20, and Srb9/Med13 contribute to key virulence attributes of C. albicans, filamentation, and biofilm formation; and ALS1 is a biologically relevant target of Med31 for development of biofilms. Furthermore, Med31 affects virulence of C. albicans in the worm infection model. We present evidence that the roles of Med31 and Srb9/Med13 in the expression of the genes encoding cell wall adhesins are different between S. cerevisiae and C. albicans: they are repressors of the FLO genes in S. cerevisiae and are activators of the ALS genes in C. albicans. This suggests that Mediator subunits regulate adhesion in a distinct manner between these two distantly related fungal species. PMID- 22496667 TI - A shared role for RBF1 and dCAP-D3 in the regulation of transcription with consequences for innate immunity. AB - Previously, we discovered a conserved interaction between RB proteins and the Condensin II protein CAP-D3 that is important for ensuring uniform chromatin condensation during mitotic prophase. The Drosophila melanogaster homologs RBF1 and dCAP-D3 co-localize on non-dividing polytene chromatin, suggesting the existence of a shared, non-mitotic role for these two proteins. Here, we show that the absence of RBF1 and dCAP-D3 alters the expression of many of the same genes in larvae and adult flies. Strikingly, most of the genes affected by the loss of RBF1 and dCAP-D3 are not classic cell cycle genes but are developmentally regulated genes with tissue-specific functions and these genes tend to be located in gene clusters. Our data reveal that RBF1 and dCAP-D3 are needed in fat body cells to activate transcription of clusters of antimicrobial peptide (AMP) genes. AMPs are important for innate immunity, and loss of either dCAP-D3 or RBF1 regulation results in a decrease in the ability to clear bacteria. Interestingly, in the adult fat body, RBF1 and dCAP-D3 bind to regions flanking an AMP gene cluster both prior to and following bacterial infection. These results describe a novel, non-mitotic role for the RBF1 and dCAP-D3 proteins in activation of the Drosophila immune system and suggest dCAP-D3 has an important role at specific subsets of RBF1-dependent genes. PMID- 22496668 TI - Replication fork reversal after replication-transcription collision. AB - Replication fork arrest is a recognized source of genetic instability, and transcription is one of the most prominent causes of replication impediment. We analyze here the requirement for recombination proteins in Escherichia coli when replication-transcription head-on collisions are induced at a specific site by the inversion of a highly expressed ribosomal operon (rrn). RecBC is the only recombination protein required for cell viability under these conditions of increased replication-transcription collisions. In its absence, fork breakage occurs at the site of collision, and the resulting linear DNA is not repaired and is slowly degraded by the RecJ exonuclease. Lethal fork breakage is also observed in cells that lack RecA and RecD, i.e. when both homologous recombination and the potent exonuclease V activity of the RecBCD complex are inactivated, with a slow degradation of the resulting linear DNA by the combined action of the RecBC helicase and the RecJ exonuclease. The sizes of the major linear fragments indicate that DNA degradation is slowed down by the encounter with another rrn operon. The amount of linear DNA decreases nearly two-fold when the Holliday junction resolvase RuvABC is inactivated in recB, as well as in recA recD mutants, indicating that part of the linear DNA is formed by resolution of a Holliday junction. Our results suggest that replication fork reversal occurs after replication-transcription head-on collision, and we propose that it promotes the action of the accessory replicative helicases that dislodge the obstacle. PMID- 22496669 TI - A genome-wide screen for genetic variants that modify the recruitment of REST to its target genes. AB - Increasing numbers of human diseases are being linked to genetic variants, but our understanding of the mechanistic links leading from DNA sequence to disease phenotype is limited. The majority of disease-causing nucleotide variants fall within the non-protein-coding portion of the genome, making it likely that they act by altering gene regulatory sequences. We hypothesised that SNPs within the binding sites of the transcriptional repressor REST alter the degree of repression of target genes. Given that changes in the effective concentration of REST contribute to several pathologies-various cancers, Huntington's disease, cardiac hypertrophy, vascular smooth muscle proliferation-these SNPs should alter disease-susceptibility in carriers. We devised a strategy to identify SNPs that affect the recruitment of REST to target genes through the alteration of its DNA recognition element, the RE1. A multi-step screen combining genetic, genomic, and experimental filters yielded 56 polymorphic RE1 sequences with robust and statistically significant differences of affinity between alleles. These SNPs have a considerable effect on the the functional recruitment of REST to DNA in a range of in vitro, reporter gene, and in vivo analyses. Furthermore, we observe allele-specific biases in deeply sequenced chromatin immunoprecipitation data, consistent with predicted differenes in RE1 affinity. Amongst the targets of polymorphic RE1 elements are important disease genes including NPPA, PTPRT, and CDH4. Thus, considerable genetic variation exists in the DNA motifs that connect gene regulatory networks. Recently available ChIP-seq data allow the annotation of human genetic polymorphisms with regulatory information to generate prior hypotheses about their disease-causing mechanism. PMID- 22496670 TI - Improved statistics for genome-wide interaction analysis. AB - Recently, Wu and colleagues [1] proposed two novel statistics for genome-wide interaction analysis using case/control or case-only data. In computer simulations, their proposed case/control statistic outperformed competing approaches, including the fast-epistasis option in PLINK and logistic regression analysis under the correct model; however, reasons for its superior performance were not fully explored. Here we investigate the theoretical properties and performance of Wu et al.'s proposed statistics and explain why, in some circumstances, they outperform competing approaches. Unfortunately, we find minor errors in the formulae for their statistics, resulting in tests that have higher than nominal type 1 error. We also find minor errors in PLINK's fast-epistasis and case-only statistics, although theory and simulations suggest that these errors have only negligible effect on type 1 error. We propose adjusted versions of all four statistics that, both theoretically and in computer simulations, maintain correct type 1 error rates under the null hypothesis. We also investigate statistics based on correlation coefficients that maintain similar control of type 1 error. Although designed to test specifically for interaction, we show that some of these previously-proposed statistics can, in fact, be sensitive to main effects at one or both loci, particularly in the presence of linkage disequilibrium. We propose two new "joint effects" statistics that, provided the disease is rare, are sensitive only to genuine interaction effects. In computer simulations we find, in most situations considered, that highest power is achieved by analysis under the correct genetic model. Such an analysis is unachievable in practice, as we do not know this model. However, generally high power over a wide range of scenarios is exhibited by our joint effects and adjusted Wu statistics. We recommend use of these alternative or adjusted statistics and urge caution when using Wu et al.'s originally-proposed statistics, on account of the inflated error rate that can result. PMID- 22496671 TI - Regulation of budding yeast mating-type switching donor preference by the FHA domain of Fkh1. AB - During Saccharomyces cerevisiae mating-type switching, an HO endonuclease-induced double-strand break (DSB) at MAT is repaired by recombining with one of two donors, HMLalpha or HMRa, located at opposite ends of chromosome III. MATa cells preferentially recombine with HMLalpha; this decision depends on the Recombination Enhancer (RE), located about 17 kb to the right of HML. In MATalpha cells, HML is rarely used and RE is bound by the MATalpha2-Mcm1 corepressor, which prevents the binding of other proteins to RE. In contrast, in MATa cells, RE is bound by multiple copies of Fkh1 and a single copy of Swi4/Swi6. We report here that, when RE is replaced with four LexA operators in MATa cells, 95% of cells use HMR for repair, but expression of a LexA-Fkh1 fusion protein strongly increases HML usage. A LexA-Fkh1 truncation, containing only Fkh1's phosphothreonine-binding FHA domain, restores HML usage to 90%. A LexA-FHA-R80A mutant lacking phosphothreonine binding fails to increase HML usage. The LexA-FHA fusion protein associates with chromatin in a 10-kb interval surrounding the HO cleavage site at MAT, but only after DSB induction. This association occurs even in a donorless strain lacking HML. We propose that the FHA domain of Fkh1 regulates donor preference by physically interacting with phosphorylated threonine residues created on proteins bound near the DSB, thus positioning HML close to the DSB at MAT. Donor preference is independent of Mec1/ATR and Tel1/ATM checkpoint protein kinases but partially depends on casein kinase II. RE stimulates the strand invasion step of interchromosomal recombination even for non-MAT sequences. We also find that when RE binds to the region near the DSB at MATa then Mec1 and Tel1 checkpoint kinases are not only able to phosphorylate histone H2A (gamma-H2AX) around the DSB but can also promote gamma-H2AX spreading around the RE region. PMID- 22496672 TI - Dasatinib: the emerging evidence of its potential in the treatment of chronic myeloid leukemia. AB - INTRODUCTION: Current therapy options for chronic myeloid leukemia (CML) include conventional chemotherapy, allogeneic stem cell transplant, interferon-alfa, and imatinib mesylate, which has recently achieved gold standard status. Although the majority of patients initially respond well to treatment with imatinib, wider clinical experience with this drug has resulted in the development of imatinib resistance being increasingly documented. There is therefore an unmet medical need for novel therapies to override imatinib resistance in CML. AIMS: This review summarizes the emerging evidence for the potential use of dasatinib in the treatment of imatinib-resistant CML. DISEASE AND TREATMENT: Dasatinib is a novel small molecule that has shown potent antileukemic activity in imatinib-resistant cell lines, malignant marrow cells isolated from patients with imatinib-resistant CML, and in mouse xenograft models of imatinib-resistant CML. Preliminary data from an initial phase I dose escalation trial have been encouraging, indicating that dasatinib is generally well tolerated and produces hematologic and cytogenetic responses in patients with imatinib-resistant CML in all phases of the disease. The maximum tolerated dose (MTD) has not yet been reached, and dose escalation continues to determine the dose range that yields optimal results. PROFILE: Although dasatinib is still in the early stages of development, the potential impact of this molecule on the treatment of CML could be revolutionary, not only providing a much needed treatment option for patients with imatinib resistant CML, but also, combined with imatinib, could possibly prove useful in delaying the onset of resistance to treatment. Furthermore, combined with other agents active in CML, dasatinib could have potential utility in purging residual leukemic cells in patients whose disease is controlled by imatinib. PMID- 22496673 TI - Aliskiren in hypertension: evidence for its potential therapeutic value. AB - INTRODUCTION: Aliskiren is the first in a new class of antihypertensive drugs that inhibits the conversion of angiotensinogen to angiotensin I by renin, thereby inhibiting production of angiotensin II, the key mediator in the regulation of body fluid volume and blood pressure. Aliskiren is currently in phase III trials as monotherapy and phase II as combination therapy in patients with mild-to-moderate hypertension, and in phase II trials in patients with diabetic nephropathy. AIMS: The aim of this review is to evaluate the emerging evidence for use of aliskiren in patients with hypertension and to predict its preliminary place in therapy in clinical outcome terms. All randomized, controlled clinical trials of aliskiren (evidence level 2) were included for analysis of efficacy with the selected outcomes of blood pressure lowering, tolerability, and adherence; all other publications were excluded. EVIDENCE REVIEW: The available level 2 evidence, although limited to phase II trials, suggests that aliskiren is effective at lowering blood pressure, an accepted surrogate outcome of morbidity and mortality, in patients with mild-to-moderate uncomplicated essential hypertension. Preliminary evidence suggests aliskiren is as effective as the angiotensin receptor blocker irbesartan, but more studies are needed. The available evidence also suggests that aliskiren is well tolerated and that patients exhibit good adherence to therapy. Aliskiren's effect on outcomes such as all-cause mortality, reduction in cardiovascular mortality, and reduction in cardiovascular events in patients with mild-to-moderate essential hypertension as well as in special patient populations, remains to be determined. CLINICAL POTENTIAL: The evidence available regarding aliskiren's effect on outcomes, including blood pressure, tolerability, and adherence, supports its use in patients with mild-to-moderate hypertension. Although there is some preliminary evidence from small pilot trials, the use of aliskiren in combination with other antihypertensives, and the use of aliskiren in other patient populations, cannot be recommended without further evidence. PMID- 22496674 TI - Roflumilast: the evidence for its clinical potential in the treatment of chronic obstructive pulmonary disease. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD), characterized by a progressive deterioration of lung function caused primarily by the inhalation of toxic substances, is a leading cause of morbidity and mortality worldwide. Current treatment options for the management of its symptoms include the use of bronchodilators and glucocorticoid agents that are not universally beneficial and which are associated with limitations. Phosphodiesterase-4 (PDE4) inhibitors are a novel class of antiinflammatory agents being developed for COPD treatment. AIMS: The purpose of this article is to review the clinical potential of roflumilast, a PDE4 inhibitor currently in phase III clinical trials, in the management of patients with COPD. EVIDENCE REVIEW: Phase II studies indicate that roflumilast can be given orally once daily. Preliminary evidence from two phase III, randomized, double-blind, placebo-controlled studies suggest that roflumilast improves or stabilizes lung function, as measured by forced expiratory volume in 1 s and 6 s (FEV(1) and FEV(6)), forced vital capacity (FVC), and peak expiratory flow (PEF) in patients with COPD. Improvements in COPD exacerbation rate were also reported in these trials. Quality of life, as measured by the St George's Respiratory Questionnaire, also improved with roflumilast treatment. Clinical studies to date suggest that roflumilast is well tolerated. CLINICAL POTENTIAL: Current evidence supports the use of roflumilast in the management of COPD as shown by improvements in patients' symptoms and quality of life, and good tolerability profile. Its once-daily oral dosing regimen is unique among current therapies for COPD. This potential and the place of roflumilast in the stepwise management of the disease need to be confirmed as further evidence is published. Additional evidence will also be welcome to determine if its mechanism of action moderates the progression of lung function deterioration. PMID- 22496675 TI - Pramipexole in restless legs syndrome: an evidence-based review of its effectiveness on clinical outcomes. AB - INTRODUCTION: Restless legs syndrome (RLS) affects 5-15% of adults, but is often unrecognized and consequently misdiagnosed. The International Restless Legs Scale (IRLS) has been developed and validated to assess the severity of RLS. Currently, the most common treatment for RLS is levodopa, but this may lead to augmentation of symptoms. Pramipexole has been developed as an alternative treatment for patients diagnosed with RLS. AIMS: The objective of this article is to review the evidence of the effectiveness of pramipexole for the clinical management of patients with RLS. EVIDENCE REVIEW: There is clear evidence that pramipexole reduces the leg movements associated with RLS, as measured by improvements in both the IRLS and the Clinical Global Impression (CGI) score. There is also moderate evidence that the drug improves sleep quality. Pramipexole clearly improves the anxiety and depression often associated with RLS. Augmentation may be associated with pramipexole treatment, but the evidence is contradictory and augmentation may be more associated with patients pretreated with levodopa or with patients with primary RLS rather than those with secondary RLS. Pramipexole therapy appears to be well tolerated, with only mild-to-moderate adverse events reported. OUTCOMES SUMMARY: Pramipexole reduces leg movements in RLS, and is well tolerated. Further investigation is required to confirm the preliminary evidence that pramipexole restores normal sleep architecture and restores a normal quality of life in patients with RLS. Health economic studies would be valuable in demonstrating the true impact of pramipexole on the social burden of RLS. PMID- 22496676 TI - Sevelamer as a phosphate binder in adult hemodialysis patients: an evidence-based review of its therapeutic value. AB - INTRODUCTION: Patients on hemodialysis require phosphate binders to reduce dietary phosphate absorption and control serum phosphate. The standard therapy, calcium salts, can be associated with elevated serum calcium (hypercalcemia). Concern has been raised that hypercalcemia, especially combined with elevated serum phosphate, may be associated with arterial calcification, and this may contribute to increased risk of cardiovascular mortality and morbidity. Sevelamer is a nonmetal, nonabsorbed phosphate binder. AIMS: This review assesses the evidence for the therapeutic value of sevelamer as a phosphate binder in adult hemodialysis patients. EVIDENCE REVIEW: Strong evidence shows that sevelamer is as effective as calcium salts in controlling serum phosphate and calcium phosphate product, has less risk of inducing hypercalcemia and is more effective at lowering lipid levels. Some evidence indicates that sevelamer reduces arterial calcification progression and loss of bone mineral density, but it may be more likely to induce metabolic acidosis, compared with calcium salts. Sevelamer containing regimens may improve calcific uremic arteriolopathy, although the evidence is weak. Evidence is divided on whether the incidence of gastrointestinal adverse events with sevelamer is similar to or higher than that with calcium salts. Retrospective and modeling studies suggest lower cardiovascular morbidity and mortality with sevelamer than with calcium salts, with incremental cost-effectiveness of $US1100-2200 per life-year gained. Further direct evidence is needed on mortality, quality of life, and cost-effectiveness. PLACE IN THERAPY: Sevelamer is effective in controlling serum phosphate and lowering lipid levels in hemodialysis patients without inducing hypercalcemia, and may have beneficial effects on arterial calcification. PMID- 22496677 TI - Fosphenytoin for the treatment of status epilepticus: an evidence-based assessment of its clinical and economic outcomes. AB - INTRODUCTION: Status epilepticus (SE) is a life-threatening condition requiring prompt treatment in the emergency department to control seizures and limit potential neurologic damage. Fosphenytoin is a water-soluble prodrug of phenytoin (an established treatment option for SE) that has been developed to overcome the often severe venous adverse events that can occur following the intravenous administration of phenytoin. AIMS: The objective of this article is to review the evidence for the use of fosphenytoin in the treatment of SE. EVIDENCE REVIEW: Fosphenytoin can be infused more rapidly than phenytoin and there is evidence that therapeutic drug levels are achieved at least at a similar rate. Although few studies have been conducted in SE patients, there is evidence that fosphenytoin is at least as effective as phenytoin in terms of response and control of SE. There is also moderate evidence that there are fewer vascular adverse events following intravenous fosphenytoin compared with phenytoin administration when both drugs are infused at the recommended dosage and rate. Evidence from pharmacoeconomic studies indicates that a reduction in the incidence of adverse events and their subsequent management are critical factors for cost-effectiveness with fosphenytoin. CLINICAL VALUE: In conclusion, fosphenytoin is a valuable treatment option for the rapid treatment of SE; the risk of venous adverse events is lower than with phenytoin when administered at the recommended rate. PMID- 22496678 TI - Eltrombopag: the emerging evidence of its therapeutic value in thrombocytopenia. AB - INTRODUCTION: Idiopathic (immune) thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by low platelet counts and bleeding episodes. Current therapy options are associated with unwanted side effects, and although patients initially respond to treatment the platelet count is not sustained in many individuals. There is a need for safe and well-tolerated treatments that provide a sustained platelet response. AIMS: This review summarizes the emerging evidence for the potential use of eltrombopag in the treatment of ITP in adults. DISEASE AND TREATMENT: Eltrombopag is a nonpeptide, small molecular weight thrombopoietin receptor agonist that is orally administered. It mimics the activity of thrombopoietin, a cytokine that promotes growth and production of platelets, primarily inducing proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. PROFILE: Eltrombopag is still in the early stages of development but initial phase I and phase II results are promising. Potential advantages of eltrombopag may include a sustained platelet response and a good tolerability profile. Its once-daily oral dosing regimen would also be an advantage over many of the existing therapies. It is expected that patients who have failed first-line therapy with corticosteroids and wish to avoid the need for a splenectomy, and patients with chronic refractory ITP, may benefit from eltrombopag treatment. PMID- 22496679 TI - Ciclesonide in persistent asthma: the evidence of its therapeutic value. AB - INTRODUCTION: Asthma, a respiratory disease associated with airway inflammation and hyperresponsiveness, is one of the most prevalent chronic diseases worldwide affecting both children and adults. Inhaled corticosteroids are considered to be the cornerstone of asthma management. Ciclesonide, an airway-activated inhaled corticosteroid, has been developed for the management of persistent asthma. Its once-daily administration and airway activation may be advantageous in the treatment of asthma. AIMS: The purpose of this article is to review the place in therapy of ciclesonide in the management of patients with persistent asthma based on the available clinical evidence. EVIDENCE REVIEW: The available evidence indicates that ciclesonide has an effect on pulmonary function (forced expiratory volume in 1 s, forced vital capacity, and peak expiratory flow), as well as producing improvements in patient-reported symptoms that are equivalent to those achieved with other inhaled corticosteroids. A few studies have focused on health related quality of life and have demonstrated a positive effect with ciclesonide treatment. Its pharmacokinetic profile may offer advantages in terms of adverse effects, both local and systemic, although most of the data come from 12-week studies. PLACE IN THERAPY: The current evidence shows that ciclesonide offers another alternative among inhaled corticosteroids, with the potential for fewer adverse effects. The unique pharmacokinetic profile of ciclesonide allows once daily administration and the airway activation of the drug appears to confer clinical benefit in the treatment of asthma. Its lack of systemic adverse effects make it a viable option for pediatric use. PMID- 22496680 TI - Aripiprazole: the evidence of its therapeutic impact in schizophrenia. AB - INTRODUCTION: An ideal antipsychotic would rapidly stabilize acute psychotic symptoms and maintain the patient, without relapse, for prolonged periods in the absence of extrapyramidal, endocrine, diabetic, or cardiovascular side effects, and without weight gain. The dopamine partial agonist aripiprazole is compared with this ideal and with conventional antipsychotics, such as haloperidol, and with atypical antipsychotics. AIMS: To review the evidence for the clinical impact of aripiprazole in the treatment of patients with schizophrenia. EVIDENCE REVIEW: There is clear evidence that aripiprazole is as effective as haloperidol in reducing the positive and negative symptoms of schizophrenia and schizoaffective disorder. In patients with schizophrenia, aripiprazole has been shown to stabilize acute psychotic symptoms, prevent relapse in stabilized patients, and maintain patients with schizophrenia following acute relapse. Furthermore, in common with other atypical antipsychotics, aripiprazole appears to be associated with a lower incidence of side effects than typical antipsychotics and may reduce discontinuation of drug therapy. Evidence also suggests that aripiprazole may be associated with a lower incidence of extrapyramidal symptoms than conventional antipsychotics, but further long-term studies concerning tardive dyskinesia are required. Studies on the cost effectiveness of aripiprazole, as well as the quality of life and general functioning of patients taking the drug are still required, although there is some evidence of improved quality of life. Further evidence comparing aripiprazole with other atypical antipsychotics would be welcome. CLINICAL VALUE: In conclusion, aripiprazole is an atypical antipsychotic suitable for first-line use in patients with schizophrenia. Its clinical value in relation to other atypical antipsychotics remains to be elucidated. PMID- 22496682 TI - Tracking and treating malignant melanoma metastases. PMID- 22496681 TI - Bortezomib: the evidence of its clinical impact in multiple myeloma. AB - INTRODUCTION: Multiple myeloma is a relatively common and incurable form of hematologic malignancy for which there is currently no single standard therapy. Bortezomib inhibits the 20S proteasome involved in the degradation of intracellular proteins, induces apoptosis, reverses drug resistance in multiple myeloma cells, and influences their microenvironment by blocking cytokine circuits, cell adhesion and angiogenesis in vivo. AIMS: The objective of this review is to evaluate the evidence for the use of bortezomib in the treatment of multiple myeloma. EVIDENCE REVIEW: In patients with relapsed multiple myeloma bortezomib significantly prolongs overall survival and time to progression, and improves response rates, duration of response, and quality of life compared with oral high-dose dexamethasone. Although the incidence of grade 4 adverse events was similar, grade 3 events and herpes zoster infections occur more frequently in patients treated with bortezomib than with high-dose dexamethasone. Evidence from a pharmacoeconomic study indicates that the benefits of bortezomib compared to thalidomide plus best standard care may be achieved at a reasonable cost. CLINICAL VALUE: Bortezomib is a valuable treatment option in the management of relapsed multiple myeloma that improves survival and delays disease progression compared with oral high-dose dexamethasone treatment, albeit with an increased incidence of some adverse events such as grade 3 thrombocytopenia and neutropenia. PMID- 22496683 TI - Tangential Biopsy Thickness versus Lesion Depth in Longitudinal Melanonychia: A Pilot Study. AB - Longitudinal melanonychia can be caused by melanocyte activation (hypermelanosis) or proliferation (lentigo, nevus or melanoma). Histopathologic examination is mandatory for suspicious cases of melanomas. Tangential biopsy of the matrix is an elegant technique avoiding nail plate dystrophy, but it was unknown whether the depth of the sample obtained by this method is adequate for histopathologic diagnosis. Twenty-two patients with longitudinal melanonychia striata were submitted to tangential matrix biopsies described by Haneke. The tissue was stained with hematoxylin-eosin and the specimens were measured at 3 distinct points according to the total thickness: largest (A), intermediate (B) and narrowest (C) then divided into 4 groups according to the histopathologic diagnosis (G1: hypermelanosis; G2: lentigos; G3: nevus; G4: melanoma). The lesions were measured using the same method. The mean specimen/lesion thickness measure values for each group was: G1: 0,59/0,10 mm, G2: 0,67/0,08 mm, G3: 0,52/0,05 mm, G4: 0,58/0,10 mm. The general average thickness for all the specimens/lesions was 0,59/0,08 mm. We concluded that the tangential excision, for longitudinal melanonychia, provides an adequate material for histopathological diagnosis. PMID- 22496684 TI - Office-based deep sedation for pediatric ophthalmologic procedures using a sedation service model. AB - Aims. (1) To assess the efficacy and safety of pediatric office-based sedation for ophthalmologic procedures using a pediatric sedation service model. (2) To assess the reduction in hospital charges of this model of care delivery compared to the operating room (OR) setting for similar procedures. Background. Sedation is used to facilitate pediatric procedures and to immobilize patients for imaging and examination. We believe that the pediatric sedation service model can be used to facilitate office-based deep sedation for brief ophthalmologic procedures and examinations. Methods. After IRB approval, all children who underwent office based ophthalmologic procedures at our institution between January 1, 2000 and July 31, 2008 were identified using the sedation service database and the electronic health record. A comparison of hospital charges between similar procedures in the operating room was performed. Results. A total of 855 procedures were reviewed. Procedure completion rate was 100% (C.I. 99.62-100). There were no serious complications or unanticipated admissions. Our analysis showed a significant reduction in hospital charges (average of $1287 per patient) as a result of absent OR and recovery unit charges. Conclusions. Pediatric ophthalmologic minor procedures can be performed using a sedation service model with significant reductions in hospital charges. PMID- 22496685 TI - Reconstructing organophosphorus pesticide doses using the reversed dosimetry approach in a simple physiologically-based pharmacokinetic model. AB - We illustrated the development of a simple pharmacokinetic (SPK) model aiming to estimate the absorbed chlorpyrifos doses using urinary biomarker data, 3,5,6 trichlorpyridinol as the model input. The effectiveness of the SPK model in the pesticide risk assessment was evaluated by comparing dose estimates using different urinary composite data. The dose estimates resulting from the first morning voids appeared to be lower than but not significantly different to those using before bedtime, lunch or dinner voids. We found similar trend for dose estimates using three different urinary composite data. However, the dose estimates using the SPK model for individual children were significantly higher than those from the conventional physiologically based pharmacokinetic (PBPK) modeling using aggregate environmental measurements of chlorpyrifos as the model inputs. The use of urinary data in the SPK model intuitively provided a plausible alternative to the conventional PBPK model in reconstructing the absorbed chlorpyrifos dose. PMID- 22496687 TI - An in silico approach for evaluating a fraction-based, risk assessment method for total petroleum hydrocarbon mixtures. AB - Both the Massachusetts Department of Environmental Protection (MADEP) and the Total Petroleum Hydrocarbon Criteria Working Group (TPHCWG) developed fraction based approaches for assessing human health risks posed by total petroleum hydrocarbon (TPH) mixtures in the environment. Both organizations defined TPH fractions based on their expected environmental fate and by analytical chemical methods. They derived toxicity values for selected compounds within each fraction and used these as surrogates to assess hazard or risk of exposure to the whole fractions. Membership in a TPH fraction is generally defined by the number of carbon atoms in a compound and by a compound's equivalent carbon (EC) number index, which can predict its environmental fate. Here, we systematically and objectively re-evaluate the assignment of TPH to specific fractions using comparative molecular field analysis and hierarchical clustering. The approach is transparent and reproducible, reducing inherent reliance on judgment when toxicity information is limited. Our evaluation of membership in these fractions is highly consistent (~80% on average across various fractions) with the empirical approach of MADEP and TPHCWG. Furthermore, the results support the general methodology of mixture risk assessment to assess both cancer and noncancer risk values after the application of fractionation. PMID- 22496686 TI - Neurodegeneration in Alzheimer disease: role of amyloid precursor protein and presenilin 1 intracellular signaling. AB - Alzheimer disease (AD) is a heterogeneous neurodegenerative disorder characterized by (1) progressive loss of synapses and neurons, (2) intracellular neurofibrillary tangles, composed of hyperphosphorylated Tau protein, and (3) amyloid plaques. Genetically, AD is linked to mutations in few proteins amyloid precursor protein (APP) and presenilin 1 and 2 (PS1 and PS2). The molecular mechanisms underlying neurodegeneration in AD as well as the physiological function of APP are not yet known. A recent theory has proposed that APP and PS1 modulate intracellular signals to induce cell-cycle abnormalities responsible for neuronal death and possibly amyloid deposition. This hypothesis is supported by the presence of a complex network of proteins, clearly involved in the regulation of signal transduction mechanisms that interact with both APP and PS1. In this review we discuss the significance of novel finding related to cell-signaling events modulated by APP and PS1 in the development of neurodegeneration. PMID- 22496689 TI - Growth abnormalities in children with chronic hepatitis B or C. AB - Background. It has been suggested that chronic hepatitis B infection leads to growth impairment, but data are inconsistent and underlying factors are not defined. Methods. Children and adolescents with chronic hepatitis B (HBV) or C (HCV) were retrospectively evaluated for growth, weight, antiviral treatment, biochemical signs of liver inflammation, route of infection, and HBV DNA, respectively. Results. In all, 135 children (mean age 6.1 years, 81 male, 54 female) with HBV (n = 78) or HCV (n = 57) were studied. Route of infection was vertical in 50%, parenteral in 11%, and unknown in 39%. ALT levels were above 1.5 times above normal in 30% while 70% had normal/near normal transaminases. 80% were Caucasian, 14% Asian, 1% black, and 4% unknown. Mean baseline height measured in SDS was significantly lower in the study population than in noninfected children (boys -1.2, girls -0.4, P < 0.01). 28 children were below 2 standard deviations of the norm while 5 were above 2 standard deviations. SDS measures in relation to individual factors were as follows: elevated ALT: boys 1.4, females -0.5 (P < 0.01), ALT normal/near normal: boys +0.4, females +0.6; parenteral transmission: boys -3.3, girls -0.9 (P < 0.01), vertical transmission: boys -0.2, females -0.2. Antiviral treatment itself or HBV-DNA load did not reach statistically significant differences. Conclusions. Chronic HBV or HCV may lead to compromised growth which is mostly influenced by liver inflammation. Our data may argue for early antiviral treatment in children with significant ALT elevation. PMID- 22496688 TI - Socioeconomic, Rural-Urban, and Racial Inequalities in US Cancer Mortality: Part I-All Cancers and Lung Cancer and Part II-Colorectal, Prostate, Breast, and Cervical Cancers. AB - We analyzed socioeconomic, rural-urban, and racial inequalities in US mortality from all cancers, lung, colorectal, prostate, breast, and cervical cancers. A deprivation index and rural-urban continuum were linked to the 2003-2007 county level mortality data. Mortality rates and risk ratios were calculated for each socioeconomic, rural-urban, and racial group. Weighted linear regression yielded relative impacts of deprivation and rural-urban residence. Those in more deprived groups and rural areas had higher cancer mortality than more affluent and urban residents, with excess risk being marked for lung, colorectal, prostate, and cervical cancers. Deprivation and rural-urban continuum were independently related to cancer mortality, with deprivation showing stronger impacts. Socioeconomic inequalities existed for both whites and blacks, with blacks experiencing higher mortality from each cancer than whites within each deprivation group. Socioeconomic gradients in mortality were steeper in nonmetropolitan than in metropolitan areas. Mortality disparities may reflect inequalities in smoking and other cancer-risk factors, screening, and treatment. PMID- 22496690 TI - Early childhood caries and the impact of current u.s. Medicaid program: an overview. AB - Pediatric dental caries is the most common chronic disease among children. Above 40% of the U.S. children aged 2-11 years have dental caries; more than 50% of them come from low-income families. Under dental services of the Medicaid program, children enrolled in Medicaid must receive preventive dental services. However, only 1/5 of them utilize preventive dental services. The purpose of this overview is to measure the impact of Medicaid dental benefits on reducing oral health disparities among Medicaid-eligible children. This paper explains the importance of preventive dental care, children at high risk of dental caries, Medicaid dental benefits, utilization of dental preventive services by Medicaid eligible children, dental utilization influencing factors, and outcome evaluation of Medicaid in preventing dental caries among children. In conclusion, despite the recent increase of children enrolled in Medicaid, utilizing preventive dental care is still a real challenge that faces Medicaid. PMID- 22496691 TI - Novel Insights into the Interplay between Apoptosis and Autophagy. AB - For several decades, apoptosis has taken center stage as the principal mechanism of programmed cell death (type I cell death) in mammalian tissues. Autophagic cell death (type II) is characterized by the massive accumulation of autophagic vacuoles in the cytoplasm of cells. The autophagic process is activated as an adaptive response to a variety of extracellular and intracellular stresses, including nutrient deprivation, hormonal or therapeutic treatment, pathogenic infection, aggregated and misfolded proteins, and damaged organelles. Increasing evidence indicates that autophagy is associated with a number of pathological processes, including cancer. The regulation of autophagy in cancer cells is complex since it can enhance cancer cell survival in response to certain stresses, while it can also act to suppress the initiation of cancer growth. This paper focused on recent advances regarding autophagy in cancer and the techniques currently available to manipulate autophagy. PMID- 22496692 TI - The physiological role of mitophagy: new insights into phosphorylation events. AB - Mitochondria play an essential role in oxidative phosphorylation, fatty acid oxidation, and the regulation of apoptosis. However, this organelle also produces reactive oxygen species (ROS) that continually inflict oxidative damage on mitochondrial DNA, proteins, and lipids, which causes further production of ROS. To oppose this oxidative stress, mitochondria possess quality control systems that include antioxidant enzymes and the repair or degradation of damaged mitochondrial DNA and proteins. If the oxidative stress exceeds the capacity of the mitochondrial quality control system, it seems that autophagy degrades the damaged mitochondria to maintain cellular homeostasis. Indeed, recent evidence from yeast to mammals indicates that the autophagy-dependent degradation of mitochondria (mitophagy) contributes to eliminate dysfunctional, aged, or excess mitochondria. In this paper, we describe the molecular processes and regulatory mechanisms of mitophagy in yeast and mammalian cells. PMID- 22496693 TI - Casein kinase igamma2 impairs fibroblasts actin stress fibers formation and delays cell cycle progression in g1. AB - Actin cytoskeleton remodeling is under the regulation of multiple proteins with various activities. Here, we demonstrate that the gamma2 isoform of Casein Kinase I (CKIgamma2) is part of a novel molecular path regulating the formation of actin stress fibers. We show that overexpression of CKIgamma2 in fibroblasts alters cell morphology by impairing actin stress fibers formation. We demonstrate that this is concomitant with increased phosphorylation of the CDK inhibitor p27(Kip) and lower levels of activated RhoA, and is dependent on CKIgamma2 catalytic activity. Moreover, we report that roscovitine, a potent inhibitor of cyclin dependent kinases, including Cdk5, decreases p27(Kip) protein levels and restores actin stress fibers formation in CKIgamma2 overexpressing cells, suggesting the existence of a CKIgamma2-Cdk5-p27(Kip)-RhoA pathway in regulating actin remodeling. On the other hand, we also show that in a manner independent of its catalytic activity, CKIgamma2 delays cell cycle progression through G1. Collectively our findings reveal that CKIgamma2 is a novel player in the control of actin cytoskeleton dynamics and cell proliferation. PMID- 22496694 TI - Current status of new anticoagulants in the management of venous thromboembolism. AB - Venous Thromboembolism, manifested as deep venous thrombosis and pulmonary embolism, is a common problem associated with significant morbidity, mortality, and resource expenditure. Unfractionated heparin, low-molecular-weight heparin, and vitamin K antagonists are the most common treatment and prophylaxis, and have demonstrated their efficacy in a vast number of previous studies. Despite their broad use, these agents have important limitations that have led to the development of new drugs in a bid to overcome the disadvantages of the old ones without decreasing their therapeutic effect. These novel medications, some approved and others in different stages of development, include direct thrombin inhibitors like dabigatran etexilate, and direct activated factor X inhibitors like rivaroxaban. The current paper will review the characteristics, clinical trial results, and current and potential therapeutic uses of these new agents with a focus on the categories of direct thrombin inhibitors and activated factor X inhibitors. PMID- 22496695 TI - Fertility preservation in girls. AB - Children that undergo treatment for cancer are at risk of suffering from subfertility or hormonal dysfunction due to the detrimental effects of radiotherapy and chemotherapeutic agents on the gonads. Cryopreservation of ovarian tissue prior to treatment offers the possibility of restoring gonadal function after resumption of therapy. Effective counseling and management of pediatric patients is crucial for preserving their future reproductive potential. The purpose of this article is to review recent literature and to revise recommendations we made in a 2007 article. Pediatric hemato-oncology, reproductive endocrinology, surgery, anesthesia and bioethics perspectives are discussed and integrated to propose guidelines for offering ovarian cryopreservation to premenarcheal girls with cancer. PMID- 22496697 TI - Umbilical coiling index as a marker of perinatal outcome: an analytical study. AB - Objectives. To measure umbilical coiling index (UCI) postnatally and to study the association of normocoiling, hypocoiling and hypercoiling to maternal and perinatal outcome. Method(s). One thousand antenatal women who went into labour were studied and umbilical coiling index calculated at the time of delivery. UCI was determined by dividing the total number of coils by the total umbilical cord length in centimeters. Its association with various maternal and perinatal risk factors were noted. The statistical tests were the Chi-square test and assessed with SPSS version 13.0 software and statistically analyzed. P value of less than 0.05 was regarded as statistically significant. Results. The mean umbilical coiling index was found to be 0.24 +/- 0.09. Hypocoiling (<0.12) was found to be significantly associated with hypertensive disorders, abruptio placentae, preterm labour, oligohydramnios, and fetal heart rate abnormalities. Hypercoiling (>0.36) was found to be associated with diabetes mellitus, polyhydramnios, cesarean delivery, congenital anomalies, and respiratory distress of the newborn. Conclusion. Abnormal umbilical coiling index is associated with several antenatal and perinatal adverse features. PMID- 22496696 TI - Opioid dependent and pregnant: what are the best options for mothers and neonates? AB - Pregnancy in opioid-dependent women is a major public health issue. Women who are afflicted by opioid addiction are a highly vulnerable group of patients frequently becoming pregnant unplanned and at risk of adverse pregnancy outcomes and peri-natal complications. Opioid agonist maintenance treatment is the best option for the majority of women. Ideally, early and closely monitored treatment in an interdisciplinary team approach including social workers, nurses, psychologists, psychiatrists, gynecologists, anesthesiologists, and pediatricians should be provided. The treatment of comorbid psychiatric conditions, the resolution of financial, legal, and housing issues, and the psychosocial support provided have a significant effect on optimizing pregnancy outcomes. This paper aims to update health professionals in the field of gynecology and obstetrics on the latest optimal treatment approaches for mothers suffering from opioid dependence and their neonates. PMID- 22496698 TI - Ovarian volume correlates strongly with the number of nongrowing follicles in the human ovary. AB - A reliable indirect measure of ovarian reserve for the individual woman remains a challenge for reproductive specialists. Using descriptive statistics from a large scale study of ovarian volumes, we have developed a normative model for healthy females for ages 25 through 85. For average values, this model has a strong and positive correlation (r = 0.89) with our recent model of nongrowing follicles (NGFs) in the human ovary for ages 25 through 51. When both models are log adjusted, the correlation increases to r = 0.99, over the full range of ovarian volume. Furthermore we can deduce that an ovary of 3 cm(3) volume (or less) contains approximately 1000 NGF (or fewer). These strong correlations indicate that ovarian volume is a useful factor in the indirect estimation of human ovarian reserve for the individual woman. PMID- 22496699 TI - Interobserver agreement for endometrial cancer characteristics evaluated on biopsy material. AB - A shift toward a disease-based therapy designed according to patterns of failure and likelihood of nodal involvement predicted by pathologic determinants has recently led to considering a selective approach to lymphadenectomy for endometrial cancer. Therefore, it became critical to examine reproducibility of diagnosing the key determinants of risk, on preoperative endometrial tissue samples as well as the concordance between preoperative and postresection specimens. Six gynaecologic pathologists assessed 105 consecutive endometrial biopsies originally reported as positive for endometrial cancer for cell type (endometrioid versus nonendometrioid), tumor grade (FIGO 3-tiered and 2-tiered), nuclear grade, and risk category (low risk defined as endometrioid histology, grade 1 + 2 and nuclear grade <3). Interrater agreement levels were substantial for identification of nonendometrioid histology (kappa = 0.63; SE = 0.025), high tumor grade (kappa = 0.64; SE = 0.025), and risk category (kappa = 0.66; SE = 0.025). The overall agreement was fair for nuclear grade (kappa = 0.21; SE = 0.025). There is agreement amongst pathologists in identifying high-risk pathologic determinants on endometrial cancer biopsies, and these highly correlate with postresection specimens. This is ascertainment prerequisite adaptation of the paradigm shift in surgical staging of patients with endometrial cancer. PMID- 22496700 TI - Is There a Relationship between Ovarian Epithelial Dysplasia and Infertility? AB - Aim. Ovarian epithelial dysplasia was initially described in material from prophylactic oophorectomies performed in patients at genetic risk of ovarian cancer. Similar histopathological abnormalities have been revealed after ovulation stimulation. Since infertility is also a risk factor for ovarian neoplasia, the aim of this study was to study the relationship between infertility and ovarian dysplasia. Methods. We blindly reviewed 127 histopathological slides of adnexectomies or ovarian cystectomies according to three groups-an exposed group to ovulation induction (n = 30), an infertile group without stimulation (n = 35), and a spontaneously fertile control group (n = 62) in order to design an eleven histopathological criteria scoring system. Results. The ovarian dysplasia score was significantly higher in exposed group whereas dysplasia score was low in infertile and control groups (resp., 8.21 in exposed group, 3.69 for infertile patients, and 3.62 for the controls). In the subgroup with refractory infertility there was a trend towards a more severe dysplasia score (8.53 in ovulation induction group and 5.1 in infertile group). Conclusion. These results raise questions as to the responsibility of drugs used to induce ovulation and/or infertility itself in the genesis of ovarian epithelial dysplasia. PMID- 22496701 TI - Epidemiology, clinical manifestations, and long-term outcomes of a major outbreak of chikungunya in a hamlet in sri lanka, in 2007: a longitudinal cohort study. AB - Chikungunya outbreaks occurred in the central province, Sri Lanka in 2006. This community-based study reports the epidemiology and the natural history of the infection from an affected village. Of the 199 families and 1001 individuals in the village, 159 (80%) and 513 (51%) were affected, respectively, comprising 237 (46%) males with peak incidence at 40-50 years. The acute illness caused polyarthritis in 233 (46%), and of them 230 (98%) progressed to chronic arthritic disability (CAD). Of the CAD patients, 102 (44%) had recovered in 141 days (range 30-210 days) from the disability state whilst 128 (56%) had persisting disability which lasted 12, 24, and 36 months in 41 (17.8%), 22 (9.5%), and 14 (6.1%) individuals, respectively. Carpal tunnel syndrome (CTS) manifested in 110 (21%). Females showed preponderance for complications over males: acute arthritis 147 versus 86, P = 0.001; CAD 136 versus 84, P = 0.029; CTS 88 versus 22, P = 0.001; relapses 105 versus 68, P = 0.001. Chikungunya was highly communicable and caused lasting crippling complications. PMID- 22496702 TI - A systematic review of physical activity interventions in Hispanic adults. AB - Healthy People 2020 aims to achieve health equity, eliminate disparities, and improve the health of all groups. Regular physical activity (PA) improves overall health and fitness and has the capability to reduce risk for chronic diseases. Identifying barriers which relate to the Hispanic population is important when designing PA interventions. Therefore, the purpose was to review existing PA interventions targeting Hispanic adults published between 1988 and 2011. This paper was limited to interventions which included more than 35% Hispanic adults (n = 20). Most of the interventions were community based (n = 16), although clinical, family-based, and faith-based settings were also represented. Interventions incorporated theory (n = 16), with social cognitive theory and transtheoretical model being used most frequently. Social support was integral, building on the assumption that it is a strong motivator of PA. Each of the interventions reported success related to PA, social support, and/or BMI. Lessons learned should be incorporated into future interventions. PMID- 22496703 TI - Changes in Peak Flow value during immunotherapy administration. AB - Nasal allergies are prevalent affecting a large percentage of the population. Not only the upper respiratory tract but the whole body is involved. Allergies produce morbidity (and even occasional mortality) as they can lead to asthma development, and increased number of accidents. Immunotherapy results can be evaluated by following symptom scores, medication use, and objective measurements. Using a Peak Flow Meter (PFM) to evaluate immunotherapy results, it became evident that patients with and without asthma exhibited an improvement in the Peak Flow (PF) value, suggesting that lower airway involvement in allergic patients could be more prevalent than assumed. A consecutive chart review was performed including patients of any age with nasal allergies (with or without asthma) treated with immunotherapy for at least 6 months that had at least 2 complete evaluations. When immunotherapy was successful, most patients exhibited an increase in the PF value regardless of asthma status. A very significant finding was that most allergy sufferers may have lower airway inflammation. The use of the PF value to assess immunotherapy results and the potential failure to diagnose asthma in allergy sufferers are discussed. A better diagnosis of lower airway inflammation could be substantial in the management of these patients. PMID- 22496704 TI - Wider action plan and multidisciplinar approach could be a wining idea in creation of friendly environment. AB - Herein, we proposed planning of wide transdisciplinary actions, which bring a solution for economic activity such as transportation, strongly related to pollution output with possible repercussions on climate change and public health. To solve logistics problem by introduction of common intermodal policy, and creation of more friendly transport solution, it is possible to obtain sustainable development, climate change prevention, government policy, and regulation which are all related to human health and creation of health supportive environment. This approach permits environmental and biological monitoring same as economic results measurement by key performance indicators. This approach implementing emerging scientific knowledge in environmental health science such as genetic epidemiology aimed at understanding how genomic variation impacts phenotypic expression and how genes interact with the environment at the population level with subsequent translation into practical information for clinicians as well as for public health policy creation. PMID- 22496705 TI - A synthesis of the evidence for managing stress at work: a review of the reviews reporting on anxiety, depression, and absenteeism. AB - BACKGROUND: Psychosocial stressors in the workplace are a cause of anxiety and depressive illnesses, suicide and family disruption. METHODS: The present review synthesizes the evidence from existing systematic reviews published between 1990 and July 2011. We assessed the effectiveness of individual, organisational and mixed interventions on two outcomes: mental health and absenteeism. RESULTS: In total, 23 systematic reviews included 499 primary studies; there were 11 meta analyses and 12 narrative reviews. Meta-analytic studies found a greater effect size of individual interventions on individual outcomes. Organisational interventions showed mixed evidence of benefit. Organisational programmes for physical activity showed a reduction in absenteeism. The findings from the meta analytic reviews were consistent with the findings from the narrative reviews. Specifically, cognitive-behavioural programmes produced larger effects at the individual level compared with other interventions. Some interventions appeared to lead to deterioration in mental health and absenteeism outcomes.Gaps in the literature include studies of organisational outcomes like absenteeism, the influence of specific occupations and size of organisations, and studies of the comparative effectiveness of primary, secondary and tertiary prevention. CONCLUSIONS: Individual interventions (like CBT) improve individuals' mental health. Physical activity as an organisational intervention reduces absenteeism. Research needs to target gaps in the evidence. PMID- 22496706 TI - Human impairment from living near confined animal (hog) feeding operations. AB - PROBLEM: To determine whether neighbors around manure lagoons and massive hog confinement buildings who complained of offensive odors and symptoms had impaired brain and lung functions. METHOD: We compared near hog manure neighbors of lagoons to people living beyond 3 kilometers in Ohio and to unexposed people controls in a nearby state for neurophysiological, cognitive, recall and memory functions, and pulmonary performance. RESULTS: The 25 exposed subjects averaged 4.3 neurobehavioral abnormalities, significantly different from 2.5 for local controls and 2.3 for Tennessee controls. Exposed subjects mean forced vital capacity and expiratory volume in 1 sec were reduced significantly compared to local and regional controls. CONCLUSIONS: Near neighbors of hog enclosures and manure lagoon gases had impaired neurobehavioral functions and pulmonary functions and these effects extended to nearby people thought to be controls. Hydrogen sulfide must be abated because people living near lagoons cannot avoid rotten egg gas. PMID- 22496707 TI - The effects of transurethral resection of the prostate on morbidity and mortality in patients with nondialysis-requiring renal insufficiency. AB - OBJECTIVES: To compare the prevalence of preoperative co-morbid factors and complications of transurethral resection of prostate (TUR-P) in patients with normal and non-dialysis requiring elevated serum creatinine levels. METHODS: The records of 357 consecutive patients with IPSS>=20, serum creatinine level <= 3 mg/dl, residual urine volume <= 300 ml and with no upper urinary tract dilatation or evidence of prostate cancer that underwent TUR-P were retrospectively evaluated. 60 patients who did not fulfill the inclusion criteria were excluded. The preoperative Na, K, creatinine levels and the early changes observed in these parameters after TUR-P of the patients with normal (Group1, n = 272) and elevated (Group2, n = 25) serum creatinine levels, as well as the preoperative baseline data and postoperative complications were compared. RESULTS: Preoperative PSA, serum urea, creatinine and K levels were significantly higher in group2. No significant differences were observed between early and late postoperative complications of the two groups. Co-morbid diseases were significantly more common in group2. No progression in renal failure or de novo need for hemodialysis was observed in group2. CONCLUSIONS: TUR-P can be safely performed in BPH patients with mild serum creatinine elevations (1.6-3 mg/dl) and moderately increased prostate volumes without additional morbidity and mortality. PMID- 22496708 TI - Stentless pediatric robotic pyeloplasty. AB - OBJECTIVES: Open dismembered pyeloplasty remains the standard of care for the correction of ureteropelvic junction obstruction in children. We describe our experience with a tubeless, stentless pediatric robotic pyeloplasty technique. METHODS: Between October 2008 and September 2009, 12 consecutive children underwent robotic dismembered pyeloplasty. Ureteral stents or nephrostomy tubes were not used. Operative time, hospital stay, days of Jackson-Pratt drainage, and complications were analyzed. Postoperative renal ultrasonography was obtained at 4-6 weeks after surgery. RESULTS: The mean patient age was 9.1 years (3.5-16). The mean operative and console times were 178 (122-250) and 129 (96-193) minutes, respectively. The Jackson-Pratt drain was removed after a mean of 1.8 days (1-4). The mean hospital stay was 2.4 days (1-4.5). There were no complications. Mean follow up was 16 months (12-24 months). All patients had complete resolution of symptoms. Hydronephrosis either completely resolved or significantly decreased in all cases. In cases without complete resolution of hydronephrosis, 99m Tc-MAG-3 diuretic renography showed preservation of renal function without obstruction. CONCLUSIONS: Robot-assisted laparoscopic pyeloplasty can be safely performed without internal indwelling stent drainage. In children, this avoids the need for additional anesthesia and stent-related morbidity. PMID- 22496709 TI - Variations in the quality of care at radical prostatectomy. AB - Postoperative morbidity and mortality is low following radical prostatectomy (RP), though not inconsequential. Due to the natural history of the disease process, the implications of treatment on long-term oncologic control and functional outcomes are of increased significance. Structures, processes and outcomes are the three main determinants of quality of RP care and provide the framework for this review. Structures affecting quality of care include hospital and surgeon volume, hospital teaching status and patient insurance type. Process determinants of RP care have been poorly studied, by and large, but there is a developing trend toward the performance of randomized trials to assess the merits of evolving RP techniques. Finally, the direct study of RP outcomes has been particularly controversial and includes the development of quality of life measurement tools, combined outcomes measures, and the use of utilities to measure operative success based on individual patient priority. PMID- 22496710 TI - Optimizing the management of benign prostatic hyperplasia. AB - One of the challenges facing primary care physicians and specialists as the population ages is the management of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). While as many as 18% of men in their 40s report bother from an enlarged prostate, that figure rises dramatically, whereby 50% of men in their 50s and 90% of men in their 90s will complain of bothersome symptoms related to an enlarged prostate. Studies have shown that BPH is a progressive disease, which if left untreated can result in worsening of symptoms, acute urinary retention and renal failure. Until about 20 years ago the only management option available to urologists was surgery. In the early 1990s medical therapy emerged as the predominant treatment for BPH. Therapy may be tailored to target symptoms and progression of disease. PMID- 22496711 TI - Bone-modifying agents in the treatment of bone metastases in patients with advanced genitourinary malignancies: a focus on zoledronic acid. AB - Many patients with advanced genitourinary malignancies develop bone metastases, which can lead to potentially debilitating skeletal complications. Moreover, age related bone loss and cancer treatments such as hormonal therapy for prostate cancer can weaken bone, placing patients at risk for osteoporotic fractures in addition to skeletal-related events (SREs) from bone metastases. Zoledronic acid, a bisphosphonate, is approved worldwide to reduce the risk of SREs in patients with bone metastases from solid tumors or bone lesions from multiple myeloma. Zoledronic acid, although underutilized in genitourinary malignancies, has long been the mainstay of treatment in patients with bone metastases, and can also help preserve bone during anticancer therapy. Recently, denosumab, a monoclonal antibody directed against the receptor activator of nuclear factor kappa-B ligand, was approved in the United States and the European Union for reducing the risk of SREs in patients with bone metastases from solid tumors. Denosumab (at a lower dose) is also approved in the European Union and the United States to treat androgen deprivation-induced bone loss in men with prostate cancer. In addition, preclinical rationale and emerging clinical data suggest that bone-modifying agents may be able to delay disease progression in genitourinary cancers, just as newly developed anticancer treatments have produced reductions in SREs, possibly by indirect effects on the disease course. This review article summarizes current data and ongoing studies to preserve bone health in patients with advanced genitourinary cancers. PMID- 22496712 TI - Integrating eHealth With Human Services for Breast Cancer Patients. PMID- 22496713 TI - Genetic Screening of the Mitochondrial Rho GTPases MIRO1 and MIRO2 in Parkinson's Disease. AB - MIRO1 and MIRO2 (mitochondrial Ras homolog gene family, member T1 and T2) also referred to as RHOT1 and RHOT2, belong to the mitochondrial Rho GTPase family and are involved in axonal transport of mitochondria in neurons. Because mitochondrial dysfunction is strongly implicated in Parkinson's disease (PD), MIRO1 and MIRO2 can be considered as new candidate genes for PD. We analyzed two non-synonymous polymorphisms and one synonymous polymorphism in MIRO1 and two non synonymous polymorphisms in MIRO2, in a Swedish Parkinson case-control material consisting of 241 patients and 307 neurologically healthy controls. None of the analyzed polymorphisms in MIRO1 and MIRO2 were significantly associated with PD. Although we did not find a significant association with PD in our Swedish case control material, we cannot exclude these Rho GTPases as candidate genes for PD or other neurodegenerative disorders. PMID- 22496714 TI - Development and evaluation of an enzyme-linked immunosorbent assay for dengue capsid. AB - The astonishing speed with which Dengue has spread across the world and the severity of its infection make Dengue a prime threat to human life worldwide. Unfortunately, to date there are no effective vaccines or treatments against Dengue. Since only a few assays permit rapid and sensitive detection of Dengue, we developed a specific antigen capture enzyme-linked immunosorbent assay (ELISA) for the abundant structural Dengue-2 capsid protein. We showed that the ELISA allows rapid and sensitive detection of Dengue-2 replication in various cell lines including human and mosquito cells. Using anti-capsid antibodies, we demonstrated that the capsid ELISA is as accurate as other well-characterized Dengue assays such as intracellular FACS staining (IFSA) and fluorescent focus (FFA) assays. The capsid ELISA not only represents a useful tool for in vitro basic research, but it may also represent a valuable diagnostic tool for Dengue infection in patients. PMID- 22496715 TI - Scanning laser topography and scanning laser polarimetry: comparing both imaging methods at same distances from the optic nerve head. AB - PURPOSE: To compare the performance of scanning laser topography (SLT) and scanning laser polarimetry (SLP) on the rim of the optic nerve head and its surrounding area and thereby to evaluate whether these imaging technologies are influenced by other factors beyond the thickness of the retinal nerve fiber layer (RNFL). MATERIALS AND METHODOLOGY: A total of 154 eyes from 5 different groups were examined: young healthy subjects (YNorm), old healthy subjects (ONorm), patients with normal tension glaucoma (NTG), patients with open-angle glaucoma and early glaucomatous damage (OAGE) and patients with open-angle glaucoma and advanced glaucomatous damage (OAGA). SLT and SLP measurements were taken. Four concentric circles were superimposed on each of the images: the first one measuring at the rim of the optic nerve head (1.0 ONHD), the next measuring at 1.25 optic nerve head diameters (ONHD), at 1.5 ONHD and at 1.75 ONHD. The aligned images were analyzed using GDx/NFA software. RESULTS: Both methods showed peaks of RNFL thickness in the superior and inferior segments of the ONH. The maximum thickness, registered by the SLT device was at the ONH rim where the SLP device tended to measure the lowest values. SLT measurements at the ONH were influenced by other tissues besides the RNFL like blood vessels and glial tissues. SLT and SLP were most strongly correlated at distances of 1.25 and 1.5 ONHD. CONCLUSIONS: While both imaging technologies are valuable tools in detecting glaucoma, measurements at the ONH rim should be interpreted critically since both methods might provide misleading results. For the assessment of the retinal nerve fiber layer we would like to recommend for both imaging technologies, SLT and SLP, measurements in 1.25 and 1.5 ONHD distance of the rim of the optic nerve head. PMID- 22496716 TI - HIV Transmission Rates in the United States, 2006-2008. AB - National HIV incidence for a given year x [I(x)] equals prevalence [P(x)] times the transmission rate [T(x)]. Or, simply rearranging the terms, T(x) = [I(x)/P(x)]*100 (where T(x) is the number of HIV transmissions per 100 persons living with HIV in a given year). The transmission rate is an underutilized measure of the speed at which the epidemic is spreading. Here, we utilize recently updated information about HIV incidence and prevalence in the U.S. to estimate the national HIV transmission rate for 2006 through 2008, and present a novel method to express the level of uncertainty in these estimates. Transmission rate estimates for 2006 through 2008 are as follows (respectively): 4.39 (4.01 to 4.73); 4.90 (4.49 to 5.28); and 4.06 (3.70 to 4.38). Although there are methodological challenges inherent in making these estimates, they do give some indications that the U.S. HIV transmission rate is at a historically low level. PMID- 22496722 TI - A revision of male ants of the Malagasy Amblyoponinae (Hymenoptera: Formicidae) with resurrections of the genera Stigmatomma and Xymmer. AB - In a male-based revision of ants of the subfamily Amblyoponinae from the Southwest Indian Ocean islands (SWIO: Comoros, Madagascar, Mauritius, Mayotte, Reunion, and Seychelles), we explore and reconsider male morphological characters that distinguish genera within the group. Our investigation redefines Amblyopone Erichson sensu Brown (1960), here referred to as Amblyopone sensu lato, into three genera: Xymmer Santschi stat. rev.,Amblyopone sensu stricto, Stigmatomma Roger stat. rev. All species names under Amblyopone s. l. reassign into Xymmer and Amblyopone s. s., which are small, well-defined genera, and Stigmatomma, a large group with a generic delimitation that still needs further refinement. Based on a study of male mandible characters and our scenario for mandibular evolution of the worker caste within Amblyopone s. l, we conclude that Amblyopone s. s. nests outside of XMAS (Xymmer+Mystrium+Adetomyrma+Stigmatomma) clade. The following names are transferred from Amblyopone s. l. to Xymmer as comb. rev.: muticus. The following names are transferred from Amblyopone s. l. to Stigmatomma as comb. rev.: amblyops, armigerum, bellii, bierigi, bruni, celata, chilense, denticulatum, elongatum, emeryi, feae, impressifrons, luzonicum, minuta, normandi, oregonense, pallipes, quadratum, reclinatum, rothneyi, santschii, saundersi, silvestrii, zwaluwenburgi; as comb. nov.: agostii, annae, besucheti, boltoni, caliginosum, cleae, crenatum, degeneratum, egregium, electrinum, eminia, exiguum, falcatum, ferrugineum, fulvidum, gaetulicum, gingivalis, glauerti, gnoma, gracile, groehni, heraldoi, lucidum, lurilabes, monrosi, mystriops, noonadan, octodentatum, ophthalmicum, orizabanum, papuanum, pertinax, pluto, punctulatum, rubiginoum, sakaii, smithi, trigonignathum, trilobum, wilsoni, zaojun, and testaceum. A male-based key to the genera of Malagasy amblyoponine ants, their diagnoses, and a discussion of the evolution of the morphological character of males in the subfamily are given, and the distinguishing characters of each are illustrated. In addition, our results predict that Paraprionopelta belongs in the XMAS clade and that Concoctio should have males with two mandibular teeth. PMID- 22496723 TI - Late stage infection in sleeping sickness. AB - At the turn of the 19(th) century, trypanosomes were identified as the causative agent of sleeping sickness and their presence within the cerebrospinal fluid of late stage sleeping sickness patients was described. However, no definitive proof of how the parasites reach the brain has been presented so far. Analyzing electron micrographs prepared from rodent brains more than 20 days after infection, we present here conclusive evidence that the parasites first enter the brain via the choroid plexus from where they penetrate the epithelial cell layer to reach the ventricular system. Adversely, no trypanosomes were observed within the parenchyma outside blood vessels. We also show that brain infection depends on the formation of long slender trypanosomes and that the cerebrospinal fluid as well as the stroma of the choroid plexus is a hostile environment for the survival of trypanosomes, which enter the pial space including the Virchow-Robin space via the subarachnoid space to escape degradation. Our data suggest that trypanosomes do not intend to colonize the brain but reside near or within the glia limitans, from where they can re-populate blood vessels and disrupt the sleep wake cycles. PMID- 22496726 TI - Comparative analysis of Mycobacterium tuberculosis pe and ppe genes reveals high sequence variation and an apparent absence of selective constraints. AB - Mycobacterium tuberculosis complex (MTBC) genomes contain 2 large gene families termed pe and ppe. The function of pe/ppe proteins remains enigmatic but studies suggest that they are secreted or cell surface associated and are involved in bacterial virulence. Previous studies have also shown that some pe/ppe genes are polymorphic, a finding that suggests involvement in antigenic variation. Using comparative sequence analysis of 18 publicly available MTBC whole genome sequences, we have performed alignments of 33 pe (excluding pe_pgrs) and 66 ppe genes in order to detect the frequency and nature of genetic variation. This work has been supplemented by whole gene sequencing of 14 pe/ppe (including 5 pe_pgrs) genes in a cohort of 40 diverse and well defined clinical isolates covering all the main lineages of the M. tuberculosis phylogenetic tree. We show that nsSNP's in pe (excluding pgrs) and ppe genes are 3.0 and 3.3 times higher than in non pe/ppe genes respectively and that numerous other mutation types are also present at a high frequency. It has previously been shown that non-pe/ppe M. tuberculosis genes display a remarkably low level of purifying selection. Here, we also show that compared to these genes those of the pe/ppe families show a further reduction of selection pressure that suggests neutral evolution. This is inconsistent with the positive selection pressure of "classical" antigenic variation. Finally, by analyzing such a large number of genes we were able to detect large differences in mutation type and frequency between both individual genes and gene sub-families. The high variation rates and absence of selective constraints provides valuable insights into potential pe/ppe function. Since pe/ppe proteins are highly antigenic and have been studied as potential vaccine components these results should also prove informative for aspects of M. tuberculosis vaccine design. PMID- 22496727 TI - Conservation of tubulin-binding sequences in TRPV1 throughout evolution. AB - BACKGROUND: Transient Receptor Potential Vanilloid sub type 1 (TRPV1), commonly known as capsaicin receptor can detect multiple stimuli ranging from noxious compounds, low pH, temperature as well as electromagnetic wave at different ranges. In addition, this receptor is involved in multiple physiological and sensory processes. Therefore, functions of TRPV1 have direct influences on adaptation and further evolution also. Availability of various eukaryotic genomic sequences in public domain facilitates us in studying the molecular evolution of TRPV1 protein and the respective conservation of certain domains, motifs and interacting regions that are functionally important. METHODOLOGY AND PRINCIPAL FINDINGS: Using statistical and bioinformatics tools, our analysis reveals that TRPV1 has evolved about ~420 million years ago (MYA). Our analysis reveals that specific regions, domains and motifs of TRPV1 has gone through different selection pressure and thus have different levels of conservation. We found that among all, TRP box is the most conserved and thus have functional significance. Our results also indicate that the tubulin binding sequences (TBS) have evolutionary significance as these stretch sequences are more conserved than many other essential regions of TRPV1. The overall distribution of positively charged residues within the TBS motifs is conserved throughout evolution. In silico analysis reveals that the TBS-1 and TBS-2 of TRPV1 can form helical structures and may play important role in TRPV1 function. CONCLUSIONS AND SIGNIFICANCE: Our analysis identifies the regions of TRPV1, which are important for structure function relationship. This analysis indicates that tubulin binding sequence-1 (TBS-1) near the TRP-box forms a potential helix and the tubulin interactions with TRPV1 via TBS-1 have evolutionary significance. This interaction may be required for the proper channel function and regulation and may also have significance in the context of Taxol(r)-induced neuropathy. PMID- 22496728 TI - Pathway-based evaluation in early onset colorectal cancer suggests focal adhesion and immunosuppression along with epithelial-mesenchymal transition. AB - Colorectal cancer (CRC) has one of the highest incidences among all cancers. The majority of CRCs are sporadic cancers that occur in individuals without family histories of CRC or inherited mutations. Unfortunately, whole-genome expression studies of sporadic CRCs are limited. A recent study used microarray techniques to identify a predictor gene set indicative of susceptibility to early-onset CRC. However, the molecular mechanisms of the predictor gene set were not fully investigated in the previous study. To understand the functional roles of the predictor gene set, in the present study we applied a subpathway-based statistical model to the microarray data from the previous study and identified mechanisms that are reasonably associated with the predictor gene set. Interestingly, significant subpathways belonging to 2 KEGG pathways (focal adhesion; natural killer cell-mediated cytotoxicity) were found to be involved in the early-onset CRC patients. We also showed that the 2 pathways were functionally involved in the predictor gene set using a text-mining technique. Entry of a single member of the predictor gene set triggered a focal adhesion pathway, which confers anti-apoptosis in the early-onset CRC patients. Furthermore, intensive inspection of the predictor gene set in terms of the 2 pathways suggested that some entries of the predictor gene set were implicated in immunosuppression along with epithelial-mesenchymal transition (EMT) in the early onset CRC patients. In addition, we compared our subpathway-based statistical model with a gene set-based statistical model, MIT Gene Set Enrichment Analysis (GSEA). Our method showed better performance than GSEA in the sense that our method was more consistent with a well-known cancer-related pathway set. Thus, the biological suggestion generated by our subpathway-based approach seems quite reasonable and warrants a further experimental study on early-onset CRC in terms of dedifferentiation or differentiation, which is underscored in EMT and immunosuppression. PMID- 22496729 TI - Mineralization of acephate, a recalcitrant organophosphate insecticide is initiated by a pseudomonad in environmental samples. AB - An aerobic bacterium capable of breaking down the pesticide acephate (O,S dimethyl acetyl phosphoramidothioic acid) was isolated from activated sludge collected from a pesticide manufacturing facility. A phylogenetic tree based on the 16 S rRNA gene sequence determined that the isolate lies within the Pseudomonads. The isolate was able to grow in the presence of acephate at concentrations up to 80 mM, with maximum growth at 40 mM. HPLC and LC-MS/MS analysis of spent medium from growth experiments and a resting cell assay detected the accumulation of methamidophos and acetate, suggesting initial hydrolysis of the amide linkage found between these two moieties. As expected, the rapid decline in acephate was coincident with the accumulation of methamidophos. Methamidophos concentrations were maintained over a period of days, without evidence of further metabolism or cell growth by the cultures. Considering this limitation, strains such as described in this work can promote the first step of acephate mineralization in soil microbial communities. PMID- 22496730 TI - Regulation of mat responses by a differentiation MAPK pathway in Saccharomyces cerevisiae. AB - Fungal species exhibit diverse behaviors when presented with extracellular challenges. Pathogenic fungi can undergo cell differentiation and biofilm formation in response to fluctuating nutrient levels, and these responses are required for virulence. In the model fungal eukaryote Saccharomyces cerevisiae, nutrient limitation induces filamentous growth and biofilm/mat formation. Both responses require the same signal transduction (MAPK) pathway and the same cell adhesion molecule (Flo11) but have been studied under different conditions. We found that filamentous growth and mat formation are aspects of a related response that is regulated by the MAPK pathway. Cells in yeast-form mats differentiated into pseudohyphae in response to nutrient limitation. The MAPK pathway regulated mat expansion (in the plane of the XY-axis) and substrate invasion (downward in the plane of the Z-axis), which optimized the mat's response to extracellular nutrient levels. The MAPK pathway also regulated an upward growth pattern (in the plane of the Z-axis) in response to nutrient limitation and changes in surface rigidity. Upward growth allowed for another level of mat responsiveness and resembled a type of colonial chemorepulsion. Together our results show that signaling pathways play critical roles in regulating social behaviors in which fungal cells participate. Signaling pathways may regulate similar processes in pathogens, whose highly nuanced responses are required for virulence. PMID- 22496731 TI - Sialyl residues modulate LPS-mediated signaling through the Toll-like receptor 4 complex. AB - We previously reported that neuraminidase (NA) pretreatment of human PBMCs markedly increased their cytokine response to lipopolysaccharide (LPS). To study the mechanisms by which this occurs, we transfected HEK293T cells with plasmids encoding TLR4, CD14, and MD2 (three components of the LPS receptor complex), as well as a NFkappaB luciferase reporting system. Both TLR4 and MD2 encoded by the plasmids are alpha-2,6 sialylated. HEK293T cells transfected with TLR4/MD2/CD14 responded robustly to the addition of LPS; however, omission of the MD2 plasmid abrogated this response. Addition of culture supernatants from MD2 (sMD2) transfected HEK293T cells, but not recombinant, non-glycosylated MD2 reconstituted this response. NA treatment of sMD2 enhanced the LPS response as did NA treatment of the TLR4/CD14-transfected cell supplemented with untreated sMD2, but optimal LPS-initiated responses were observed with NA-treated TLR4/CD14 transfected cells supplemented with NA-treated sMD2. We hypothesized that removal of negatively charged sialyl residues from glycans on the TLR4 complex would hasten the dimerization of TLR4 monomers required for signaling. Co-transfection of HEK293T cells with separate plasmids encoding either YFP- or FLAG-tagged TLR4, followed by treatment with NA and stimulation with LPS, led to an earlier and more robust time-dependent dimerization of TLR4 monomers on co immunoprecipitation, compared to untreated cells. These findings were confirmed by fluorescence resonance energy transfer (FRET) analysis. Overexpression of human Neu1 increased LPS-initiated TLR4-mediated NFkappaB activation and a NA inhibitor suppressed its activation. We conclude that (1) sialyl residues on TLR4 modulate LPS responsiveness, perhaps by facilitating clustering of the homodimers, and that (2) sialic acid, and perhaps other glycosyl species, regulate MD2 activity required for LPS-mediated signaling. We speculate that endogenous sialidase activity mobilized during cell activation may play a role in this regulation. PMID- 22496732 TI - Beta-strand interfaces of non-dimeric protein oligomers are characterized by scattered charged residue patterns. AB - Protein oligomers are formed either permanently, transiently or even by default. The protein chains are associated through intermolecular interactions constituting the protein interface. The protein interfaces of 40 soluble protein oligomers of stoechiometries above two are investigated using a quantitative and qualitative methodology, which analyzes the x-ray structures of the protein oligomers and considers their interfaces as interaction networks. The protein oligomers of the dataset share the same geometry of interface, made by the association of two individual beta-strands (beta-interfaces), but are otherwise unrelated. The results show that the beta-interfaces are made of two interdigitated interaction networks. One of them involves interactions between main chain atoms (backbone network) while the other involves interactions between side chain and backbone atoms or between only side chain atoms (side chain network). Each one has its own characteristics which can be associated to a distinct role. The secondary structure of the beta-interfaces is implemented through the backbone networks which are enriched with the hydrophobic amino acids favored in intramolecular beta-sheets (MCWIV). The intermolecular specificity is provided by the side chain networks via positioning different types of charged residues at the extremities (arginine) and in the middle (glutamic acid and histidine) of the interface. Such charge distribution helps discriminating between sequences of intermolecular beta-strands, of intramolecular beta-strands and of beta-strands forming beta-amyloid fibers. This might open new venues for drug designs and predictive tool developments. Moreover, the beta-strands of the cholera toxin B subunit interface, when produced individually as synthetic peptides, are capable of inhibiting the assembly of the toxin into pentamers. Thus, their sequences contain the features necessary for a beta-interface formation. Such beta-strands could be considered as 'assemblons', independent associating units, by homology to the foldons (independent folding unit). Such property would be extremely valuable in term of assembly inhibitory drug development. PMID- 22496734 TI - Young aphids avoid erroneous dropping when evading mammalian herbivores by combining input from two sensory modalities. AB - Mammalian herbivores may incidentally ingest plant-dwelling insects while foraging. Adult pea aphids (Acyrthosiphon pisum) avoid this danger by dropping off their host plant after sensing the herbivore's warm and humid breath and the vibrations it causes while feeding. Aphid nymphs may also drop (to escape insect enemies), but because of their slow movement, have a lower chance of finding a new plant. We compared dropping rates of first-instar nymphs with those of adults, after exposing pea aphids to different combinations of simulated mammalian breath and vibrations. We hypothesized that nymphs would compensate for the greater risk they face on the ground by interpreting more conservatively the mammalian herbivore cues they perceive. Most adults dropped in response to breath alone, but nymphs rarely did so. Breath stimulus accompanied by one concurrent vibrational stimulus, caused a minor rise in adult dropping rates. Adding a second vibration during breath had no additional effect on adults. The nymphs, however, relied on a combination of the two types of stimuli, with a threefold increase in dropping rates when the breath was accompanied by one vibration, and a further doubling of dropping rates when the second vibration was added. The age specificity of the aphids' herbivore detection mechanism is probably an adaptation to the different cost of dropping for the different age groups. Relying on a combination of stimuli from two sensory modalities enables the vulnerable nymphs to avoid costly mistakes. Our findings emphasize the importance of the direct trophic effect of mammalian herbivory for plant-dwelling insects. PMID- 22496733 TI - Functional correlates of positional and gender-specific renal asymmetry in Drosophila. AB - BACKGROUND: In humans and other animals, the internal organs are positioned asymmetrically in the body cavity, and disruption of this body plan can be fatal in humans. The mechanisms by which internal asymmetry are established are presently the subject of intense study; however, the functional significance of internal asymmetry (outside the brain) is largely unexplored. Is internal asymmetry functionally significant, or merely an expedient way of packing organs into a cavity? METHODOLOGY/PRINCIPAL FINDINGS: Like humans, Drosophila shows internal asymmetry, with the gut thrown into stereotyped folds. There is also renal asymmetry, with the rightmost pair of renal (Malpighian) tubules always ramifying anteriorly, and the leftmost pair always sitting posteriorly in the body cavity. Accordingly, transcriptomes of anterior-directed (right-side) and posterior-directed (left-side) Malpighian (renal) tubules were compared in both adult male and female Drosophila. Although genes encoding the basic functions of the tubules (transport, signalling) were uniformly expressed, some functions (like innate immunity) showed positional or gender differences in emphasis; others, like calcium handling or the generation of potentially toxic ammonia, were reserved for just the right-side or left-side tubules, respectively. These findings correlated with the distinct locations of each tubule pair within the body cavity. Well known developmental genes (like dorsocross, dachshund and doublesex) showed continuing, patterned expression in adult tubules, implying that somatic tissues maintain both left-right and gender identities throughout life. Gender asymmetry was also noted, both in defence and in male-specific expression of receptors for neuropeptide F and sex-peptide: NPF elevated calcium only in male tubules. CONCLUSIONS/SIGNIFICANCE: Accordingly, the physical asymmetry of the tubules in the body cavity is directly adaptive. Now that the detailed machinery underlying internal asymmetry is starting to be delineated, our work invites the investigation, not just of tissues in isolation, but in the context of their unique physical locations and milieux. PMID- 22496735 TI - Autoantibodies to alphaS1-casein are induced by breast-feeding. AB - BACKGROUND: The generation of antibodies is impaired in newborns due to an immature immune system and reduced exposure to pathogens due to maternally derived antibodies and placental functions. During nursing, the immune system of newborns is challenged with multiple milk-derived proteins. Amongst them, caseins are the main constituent. In particular, human alphaS1-casein (CSN1S1) was recently shown to possess immunomodulatory properties. We were thus interested to determine if auto-antibodies to CSN1S1 are induced by breast-feeding and may be sustained into adulthood. METHODS: 62 sera of healthy adult individuals who were (n = 37) or were not (n = 25) breast-fed against human CSN1S1 were investigated by a new SD (surface display)-ELISA. For cross-checking, these sera were tested for anti Epstein-Barr virus (EBV) antibodies by a commercial ELISA. RESULTS: IgG antibodies were predominantly detected in individuals who had been nursed. At a cut-off value of 0.4, the SD-ELISA identified individuals with a history of having been breast-fed with a sensitivity of 80% and a specificity of 92%. Under these conditions, 35 out of 37 sera from healthy donors, who where breast-fed, reacted positively but only 5 sera of the 25 donors who were not breast-fed. The duration of breast-feeding was of no consequence to the antibody reaction as some healthy donors were only short term breast-fed (5 days minimum until 6 weeks maximum), but exhibited significant serum reaction against human CSN1S1 nonetheless. CONCLUSION: We postulate that human CSN1S1 is an autoantigen. The antigenicity is orally determined, caused by breast-feeding, and sustained into adulthood. PMID- 22496736 TI - In vivo outer hair cell length changes expose the active process in the cochlea. AB - BACKGROUND: Mammalian hearing is refined by amplification of the sound-evoked vibration of the cochlear partition. This amplification is at least partly due to forces produced by protein motors residing in the cylindrical body of the outer hair cell. To transmit power to the cochlear partition, it is required that the outer hair cells dynamically change their length, in addition to generating force. These length changes, which have not previously been measured in vivo, must be correctly timed with the acoustic stimulus to produce amplification. METHODOLOGY/PRINCIPAL FINDINGS: Using in vivo optical coherence tomography, we demonstrate that outer hair cells in living guinea pigs have length changes with unexpected timing and magnitudes that depend on the stimulus level in the sensitive cochlea. CONCLUSIONS/SIGNIFICANCE: The level-dependent length change is a necessary condition for directly validating that power is expended by the active process presumed to underlie normal hearing. PMID- 22496737 TI - Blood pressure variations real-time reflect the conditioned fear learning and memory. AB - The conditioned fear learning and memory occurs when a neutral conditioned stimulus (CS) is paired with an aversive unconditioned stimulus (US). This process is critically dependent on the amygdala and inevitably involves blood pressure (BP) alterations. We hypothesized that BP variations could instantaneously reveal individual steps during conditioned fear learning and memory. An implanted telemetric probe was used to monitor the BP real-time in rats during training and testing sessions of the fear-potentiated startle. Our results showed that (i) the conditioned fear learning during the training sessions was reflected by light (CS)-induced rapid BP elevations and by electric shock (US)-evoked sympathetic tone elevations; (ii) these two BP-related parameters were not only negatively correlated with each other but also coupled to each other in the training session trials; (iii) both parameters closely predicted the performance of fear-potentiated startle on the next day; and (iv) although local blocking of one of the two fear-conditioned pathways in the training session partially inhibited fear learning, the fear memory retrieval still used both pathways. Altogether, real-time blood pressure variations faithfully revealed the critical steps involved in conditioned fear learning and memory, and our results supported a coupling between the cued learning and the post-shock calmness. PMID- 22496738 TI - Associations of supermarket characteristics with weight status and body fat: a multilevel analysis of individuals within supermarkets (RECORD study). AB - PURPOSE: Previous research on the influence of the food environment on weight status has often used impersonal measures of the food environment defined for residential neighborhoods, which ignore whether people actually use the food outlets near their residence. To assess whether supermarkets are relevant contexts for interventions, the present study explored between-residential neighborhood and between-supermarket variations in body mass index (BMI) and waist circumference (WC), and investigated associations between brands and characteristics of supermarkets and BMI or WC, after adjustment for individual and residential neighborhood characteristics. METHODS: Participants in the RECORD Cohort Study (Paris Region, France, 2007-2008) were surveyed on the supermarket (brand and exact location) where they conducted their food shopping. Overall, 7 131 participants shopped in 1 097 different supermarkets. Cross-classified multilevel linear models were estimated for BMI and WC. RESULTS: Just 11.4% of participants shopped for food primarily within their residential neighborhood. After accounting for participants' residential neighborhood, people shopping in the same supermarket had a more comparable BMI and WC than participants shopping in different supermarkets. After adjustment for individual and residential neighborhood characteristics, participants shopping in specific supermarket brands, in hard discount supermarkets (especially if they had a low education), and in supermarkets whose catchment area comprised low educated residents had a higher BMI/WC. CONCLUSION: A public health strategy to reduce excess weight may be to intervene on specific supermarkets to change food purchasing behavior, as supermarkets are where dietary preferences are materialized into definite purchased foods. PMID- 22496741 TI - Diversity of Tanaidacea (Crustacea: Peracarida) in the world's oceans--how far have we come? AB - Tanaidaceans are small peracarid crustaceans which occur in all marine habitats, over the full range of depths, and rarely into fresh waters. Yet they have no obligate dispersive phase in their life-cycle. Populations are thus inevitably isolated, and allopatric speciation and high regional diversity are inevitable; cosmopolitan distributions are considered to be unlikely or non-existent. Options for passive dispersion are discussed. Tanaidaceans appear to have first evolved in shallow waters, the region of greatest diversification of the Apseudomorpha and some tanaidomorph families, while in deeper waters the apseudomorphs have subsequently evolved two or three distinct phyletic lines. The Neotanaidomorpha has evolved separately and diversified globally in deep waters, and the Tanaidomorpha has undergone the greatest evolution, diversification and adaptation, to the point where some of the deep-water taxa are recolonizing shallow waters. Analysis of their geographic distribution shows some level of regional isolation, but suffers from inclusion of polyphyletic taxa and a general lack of data, particularly for deep waters. It is concluded that the diversity of the tanaidomorphs in deeper waters and in certain ocean regions remains to be discovered; that the smaller taxa are largely understudied; and that numerous cryptic species remain to be distinguished. Thus the number of species currently recognized is likely to be an order of magnitude too low, and globally the Tanaidacea potentially rival the Amphipoda and Isopoda in diversity. PMID- 22496739 TI - Characterizing acupuncture stimuli using brain imaging with FMRI--a systematic review and meta-analysis of the literature. AB - BACKGROUND: The mechanisms of action underlying acupuncture, including acupuncture point specificity, are not well understood. In the previous decade, an increasing number of studies have applied fMRI to investigate brain response to acupuncture stimulation. Our aim was to provide a systematic overview of acupuncture fMRI research considering the following aspects: 1) differences between verum and sham acupuncture, 2) differences due to various methods of acupuncture manipulation, 3) differences between patients and healthy volunteers, 4) differences between different acupuncture points. METHODOLOGY/PRINCIPAL FINDINGS: We systematically searched English, Chinese, Korean and Japanese databases for literature published from the earliest available up until September 2009, without any language restrictions. We included all studies using fMRI to investigate the effect of acupuncture on the human brain (at least one group that received needle-based acupuncture). 779 papers were identified, 149 met the inclusion criteria for the descriptive analysis, and 34 were eligible for the meta-analyses. From a descriptive perspective, multiple studies reported that acupuncture modulates activity within specific brain areas, including somatosensory cortices, limbic system, basal ganglia, brain stem, and cerebellum. Meta-analyses for verum acupuncture stimuli confirmed brain activity within many of the regions mentioned above. Differences between verum and sham acupuncture were noted in brain response in middle cingulate, while some heterogeneity was noted for other regions depending on how such meta-analyses were performed, such as sensorimotor cortices, limbic regions, and cerebellum. CONCLUSIONS: Brain response to acupuncture stimuli encompasses a broad network of regions consistent with not just somatosensory, but also affective and cognitive processing. While the results were heterogeneous, from a descriptive perspective most studies suggest that acupuncture can modulate the activity within specific brain areas, and the evidence based on meta-analyses confirmed some of these results. More high quality studies with more transparent methodology are needed to improve the consistency amongst different studies. PMID- 22496740 TI - Proteomic analysis of Fusarium solani isolated from the Asian longhorned beetle, Anoplophora glabripennis. AB - Wood is a highly intractable food source, yet many insects successfully colonize and thrive in this challenging niche. Overcoming the lignin barrier of wood is a key challenge in nutrient acquisition, but full depolymerization of intact lignin polymers has only been conclusively demonstrated in fungi and is not known to occur by enzymes produced by insects or bacteria. Previous research validated that lignocellulose and hemicellulose degradation occur within the gut of the wood boring insect, Anoplophora glabripennis (Asian longhorned beetle), and that a fungal species, Fusarium solani (ATCC MYA 4552), is consistently associated with the larval stage. While the nature of this relationship is unresolved, we sought to assess this fungal isolate's ability to degrade lignocellulose and cell wall polysaccharides and to extract nutrients from woody tissue. This gut-derived fungal isolate was inoculated onto a wood-based substrate and shotgun proteomics using Multidimensional Protein Identification Technology (MudPIT) was employed to identify 400 expressed proteins. Through this approach, we detected proteins responsible for plant cell wall polysaccharide degradation, including proteins belonging to 28 glycosyl hydrolase families and several cutinases, esterases, lipases, pectate lyases, and polysaccharide deacetylases. Proteinases with broad substrate specificities and ureases were observed, indicating that this isolate has the capability to digest plant cell wall proteins and recycle nitrogenous waste under periods of nutrient limitation. Additionally, several laccases, peroxidases, and enzymes involved in extracellular hydrogen peroxide production previously implicated in lignin depolymerization were detected. In vitro biochemical assays were conducted to corroborate MudPIT results and confirmed that cellulases, glycosyl hydrolases, xylanases, laccases, and Mn- independent peroxidases were active in culture; however, lignin- and Mn- dependent peroxidase activities were not detected While little is known about the role of filamentous fungi and their associations with insects, these findings suggest that this isolate has the endogenous potential to degrade lignocellulose and extract nutrients from woody tissue. PMID- 22496742 TI - A survey of avian influenza in tree sparrows in China in 2011. AB - Tree sparrows (Passer montanus) are widely distributed in all seasons in many countries. In this study, a survey and relevant experiments on avian influenza (AI) in tree sparrows were conducted. The results suggested that the receptor for avian influenza viruses (AIVs), SAalpha2,3Gal, is abundant in the respiratory tract of tree sparrows, and most of the tree sparrows infected experimentally with two H5 subtype highly pathogenic avian influenza (HPAI) viruses died within five days after inoculation. Furthermore, no AIVs were isolated from the rectum eluate of 1300 tree sparrows, but 94 serological positives of AI were found in 800 tree sparrows. The serological positives were more prevalent for H5 subtype HPAI (94/800) than for H7 subtype AI (0/800), more prevalent for clade 2.3.2.1 H5 subtype HPAI (89/800) than for clade 2.3.4 (1/800) and clade 7.2 (4/800) H5 subtype HPAI, more prevalent for clade 2.3.2.1 H5 subtype HPAI in a city in southern China (82/800) than in a city in northern China (8/800). The serological data are all consistent with the distribution of the subtypes or clades of AI in poultry in China. Previously, sparrows or other passerine birds were often found to be pathogenically negative for AIVs, except when an AIV was circulating in the local poultry, or the tested passerine birds were from a region near waterfowl rich bodies of water. Taken together, the data suggest that tree sparrows are susceptible to infection of AIVs, and surveys targeting sparrows can provide good serological data about the circulation of AIVs in relevant regions. PMID- 22496743 TI - Genetic variant of AMD1 is associated with obesity in urban Indian children. AB - BACKGROUND: Hyperhomocysteinemia is regarded as a risk factor for cardiovascular diseases, diabetes and obesity. Manifestation of these chronic metabolic disorders starts in early life marked by increase in body mass index (BMI). We hypothesized that perturbations in homocysteine metabolism in early life could be a link between childhood obesity and adult metabolic disorders. Thus here we investigated association of common variants from homocysteine metabolism pathway genes with obesity in 3,168 urban Indian children. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped 90 common variants from 18 genes in 1,325 children comprising of 862 normal-weight (NW) and 463 over-weight/obese (OW/OB) children in stage 1. The top signal obtained was replicated in an independent sample set of 1843 children (1,399 NW and 444 OW/OB) in stage 2. Stage 1 association analysis revealed association between seven variants and childhood obesity at P<0.05, but association of only rs2796749 in AMD1 [OR = 1.41, P = 1.5*10(-4)] remained significant after multiple testing correction. Association of rs2796749 with childhood obesity was validated in stage 2 [OR = 1.28, P = 4.2*10(-3)] and meta-analysis [OR = 1.35, P = 1.9*10(-6)]. AMD1 variant rs2796749 was also associated with quantitative measures of adiposity and plasma leptin levels that was also replicated and corroborated in combined analysis. CONCLUSIONS/SIGNIFICANCE: Our study provides first evidence for the association of AMD1 variant with obesity and plasma leptin levels in children. Further studies to confirm this association, its functional significance and mechanism of action need to be undertaken. PMID- 22496744 TI - Helpers at the nest improve late-life offspring performance: evidence from a long term study and a cross-foster experiment. AB - BACKGROUND: Conditions during an individual's rearing period can have far reaching consequences for its survival and reproduction later in life. Conditions typically vary due to variation in parental quality and/or the environment, but in cooperative breeders the presence of helpers adds an important component to this. Determining the causal effect of helpers on offspring fitness is difficult, since high-quality breeders or territories are likely to produce high-quality offspring, but are also more likely to have helpers because of past reproductive success. This problem is best resolved by comparing the effect of both helping and non-helping subordinates on offspring fitness, however species in which both type of subordinates commonly occur are rare. METHODOLOGY/PRINCIPAL FINDINGS: We used multi-state capture-recapture models on 20 years of data to investigate the effect of rearing conditions on survival and recruitment in the cooperatively breeding Seychelles warbler (Acrocephalus sechellensis), with both helping and non-helping subordinates. The number of helpers in the rearing territory, but not territory quality, group- or brood size, was positively associated with survival of offspring in their first year, and later in life. This was not a result of group size itself since the number of non-helpers was not associated with offspring survival. Furthermore, a nestling cross-foster experiment showed that the number of helpers on the pre-foster territory was not associated with offspring survival, indicating that offspring from territories with helpers do not differ in (genetic) quality. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the presence of helpers not only increase survival of offspring in their first year of life, but also subsequent adult survival, and therefore have important fitness consequences later in life. This means that when calculating the fitness benefits of helping not only short-term but also the late-life benefits have to be taken into account to fully understand the evolution of cooperative breeding. PMID- 22496746 TI - Action versus result-oriented schemes in a grassland agroecosystem: a dynamic modelling approach. AB - Effects of agri-environment schemes (AES) on biodiversity remain controversial. While most AES are action-oriented, result-oriented and habitat-oriented schemes have recently been proposed as a solution to improve AES efficiency. The objective of this study was to compare action-oriented, habitat-oriented and result-oriented schemes in terms of ecological and productive performance as well as in terms of management flexibility. We developed a dynamic modelling approach based on the viable control framework to carry out a long term assessment of the three schemes in a grassland agroecosystem. The model explicitly links grazed grassland dynamics to bird population dynamics. It is applied to lapwing conservation in wet grasslands in France. We ran the model to assess the three AES scenarios. The model revealed the grazing strategies respecting ecological and productive constraints specific to each scheme. Grazing strategies were assessed by both their ecological and productive performance. The viable control approach made it possible to obtain the whole set of viable grazing strategies and therefore to quantify the management flexibility of the grassland agroecosystem. Our results showed that habitat and result-oriented scenarios led to much higher ecological performance than the action-oriented one. Differences in both ecological and productive performance between the habitat and result oriented scenarios were limited. Flexibility of the grassland agroecosystem in the result-oriented scenario was much higher than in that of habitat-oriented scenario. Our model confirms the higher flexibility as well as the better ecological and productive performance of result-oriented schemes. A larger use of result-oriented schemes in conservation may also allow farmers to adapt their management to local conditions and to climatic variations. PMID- 22496745 TI - Distinct cytoplasmic and nuclear functions of the stress induced protein DDIT3/CHOP/GADD153. AB - DDIT3, also known as GADD153 or CHOP, encodes a basic leucine zipper transcription factor of the dimer forming C/EBP family. DDIT3 is known as a key regulator of cellular stress response, but its target genes and functions are not well characterized. Here, we applied a genome wide microarray based expression analysis to identify DDIT3 target genes and functions. By analyzing cells carrying tamoxifen inducible DDIT3 expression constructs we show distinct gene expression profiles for cells with cytoplasmic and nuclear localized DDIT3. Of 175 target genes identified only 3 were regulated by DDIT3 in both cellular localizations. More than two thirds of the genes were downregulated, supporting a role for DDIT3 as a dominant negative factor that could act by either cytoplasmic or nuclear sequestration of dimer forming transcription factor partners. Functional annotation of target genes showed cell migration, proliferation and apoptosis/survival as the most affected categories. Cytoplasmic DDIT3 affected more migration associated genes, while nuclear DDIT3 regulated more cell cycle controlling genes. Cell culture experiments confirmed that cytoplasmic DDIT3 inhibited migration, while nuclear DDIT3 caused a G1 cell cycle arrest. Promoters of target genes showed no common sequence motifs, reflecting that DDIT3 forms heterodimers with several alternative transcription factors that bind to different motifs. We conclude that expression of cytoplasmic DDIT3 regulated 94 genes. Nuclear translocation of DDIT3 regulated 81 additional genes linked to functions already affected by cytoplasmic DDIT3. Characterization of DDIT3 regulated functions helps understanding its role in stress response and involvement in cancer and degenerative disorders. PMID- 22496747 TI - The role of the rat medial prefrontal cortex in adapting to changes in instrumental contingency. AB - In order to select actions appropriate to current needs, a subject must identify relationships between actions and events. Control over the environment is determined by the degree to which action consequences can be predicted, as described by action-outcome contingencies--i.e. performing an action should affect the probability of the outcome. We evaluated in a first experiment adaptation to contingency changes in rats with neurotoxic lesions of the medial prefrontal cortex. Results indicate that this brain region is not critical to adjust instrumental responding to a negative contingency where the rats must refrain from pressing a lever, as this action prevents reward delivery. By contrast, this brain region is required to reduce responding in a non-contingent situation where the same number of rewards is freely delivered and actions do not affect the outcome any more. In a second experiment, we determined that this effect does not result from a different perception of temporal relationships between actions and outcomes since lesioned rats adapted normally to gradually increasing delays in reward delivery. These data indicate that the medial prefrontal cortex is not directly involved in evaluating the correlation between action--and reward--rates or in the perception of reward delays. The deficit in lesioned rats appears to consist of an abnormal response to the balance between contingent and non-contingent rewards. By highlighting the role of prefrontal regions in adapting to the causal status of actions, these data contribute to our understanding of the neural basis of choice tasks. PMID- 22496748 TI - Identification of colorectal cancer related genes with mRMR and shortest path in protein-protein interaction network. AB - One of the most important and challenging problems in biomedicine and genomics is how to identify the disease genes. In this study, we developed a computational method to identify colorectal cancer-related genes based on (i) the gene expression profiles, and (ii) the shortest path analysis of functional protein association networks. The former has been used to select differentially expressed genes as disease genes for quite a long time, while the latter has been widely used to study the mechanism of diseases. With the existing protein-protein interaction data from STRING (Search Tool for the Retrieval of Interacting Genes), a weighted functional protein association network was constructed. By means of the mRMR (Maximum Relevance Minimum Redundancy) approach, six genes were identified that can distinguish the colorectal tumors and normal adjacent colonic tissues from their gene expression profiles. Meanwhile, according to the shortest path approach, we further found an additional 35 genes, of which some have been reported to be relevant to colorectal cancer and some are very likely to be relevant to it. Interestingly, the genes we identified from both the gene expression profiles and the functional protein association network have more cancer genes than the genes identified from the gene expression profiles alone. Besides, these genes also had greater functional similarity with the reported colorectal cancer genes than the genes identified from the gene expression profiles alone. All these indicate that our method as presented in this paper is quite promising. The method may become a useful tool, or at least plays a complementary role to the existing method, for identifying colorectal cancer genes. It has not escaped our notice that the method can be applied to identify the genes of other diseases as well. PMID- 22496749 TI - Human gamma oscillations during slow wave sleep. AB - Neocortical local field potentials have shown that gamma oscillations occur spontaneously during slow-wave sleep (SWS). At the macroscopic EEG level in the human brain, no evidences were reported so far. In this study, by using simultaneous scalp and intracranial EEG recordings in 20 epileptic subjects, we examined gamma oscillations in cerebral cortex during SWS. We report that gamma oscillations in low (30-50 Hz) and high (60-120 Hz) frequency bands recurrently emerged in all investigated regions and their amplitudes coincided with specific phases of the cortical slow wave. In most of the cases, multiple oscillatory bursts in different frequency bands from 30 to 120 Hz were correlated with positive peaks of scalp slow waves ("IN-phase" pattern), confirming previous animal findings. In addition, we report another gamma pattern that appears preferentially during the negative phase of the slow wave ("ANTI-phase" pattern). This new pattern presented dominant peaks in the high gamma range and was preferentially expressed in the temporal cortex. Finally, we found that the spatial coherence between cortical sites exhibiting gamma activities was local and fell off quickly when computed between distant sites. Overall, these results provide the first human evidences that gamma oscillations can be observed in macroscopic EEG recordings during sleep. They support the concept that these high frequency activities might be associated with phasic increases of neural activity during slow oscillations. Such patterned activity in the sleeping brain could play a role in off-line processing of cortical networks. PMID- 22496750 TI - The association between pro-social attitude and reproductive success differs between men and women. AB - The evolution of pro-social attitude and cooperation in humans is under debate. Most of the knowledge on human cooperation results from laboratory experiments and theoretic modeling. Evolutionary explanations, however, rest upon fitness consequences. We therefore examined fitness correlates of pro-social behavior in a real life setting, analyzing data from the Wisconsin Longitudinal Study (n = 2545 men, 2967 women). We investigated whether pro-social attitude, proxied by self reported voluntary work, is associated with lifetime reproductive success. We find a sex difference in the association between pro-social attitude and offspring number. In men, a pro-social attitude was associated with higher offspring number, whereas in women, it was associated with lower offspring count. To our knowledge, this is the first study to demonstrate fitness consequences of pro-social behavior towards strangers. We conclude that analysing real life settings may help to explain the evolutionary forces leading to pro-social behavior in humans and speculate that these factors might differ between the sexes. PMID- 22496751 TI - Differential inflammatory response to inhaled lipopolysaccharide targeted either to the airways or the alveoli in man. AB - Endotoxin (Lipopolysaccharide, LPS) is a potent inducer of inflammation and there is various LPS contamination in the environment, being a trigger of lung diseases and exacerbation. The objective of this study was to assess the time course of inflammation and the sensitivities of the airways and alveoli to targeted LPS inhalation in order to understand the role of LPS challenge in airway disease.In healthy volunteers without any bronchial hyperresponsiveness we targeted sequentially 1, 5 and 20 ug LPS to the airways and 5 ug LPS to the alveoli using controlled aerosol bolus inhalation. Inflammatory parameters were assessed during a 72 h time period. LPS deposited in the airways induced dose dependent systemic responses with increases of blood neutrophils (peaking at 6 h), Interleukin-6 (peaking at 6 h), body temperature (peaking at 12 h), and CRP (peaking at 24 h). 5 ug LPS targeted to the alveoli caused significantly stronger effects compared to 5 ug airway LPS deposition. Local responses were studied by measuring lung function (FEV(1)) and reactive oxygen production, assessed by hydrogen peroxide (H(2)O(2)) in fractionated exhaled breath condensate (EBC). FEV(1) showed a dose dependent decline, with lowest values at 12 h post LPS challenge. There was a significant 2-fold H(2)O(2) induction in airway-EBC at 2 h post LPS inhalation. Alveolar LPS targeting resulted in the induction of very low levels of EBC H(2)O(2).Targeting LPS to the alveoli leads to stronger systemic responses compared to airway LPS targeting. Targeted LPS inhalation may provide a novel model of airway inflammation for studying the role of LPS contamination of air pollution in lung diseases, exacerbation and anti-inflammatory drugs. PMID- 22496752 TI - Plasminogen activator inhibitor-1 4G/5G gene polymorphism and coronary artery disease in the Chinese Han population: a meta-analysis. AB - BACKGROUND: The polymorphism of plasminogen activator inhibitor-1 (PAI-1) 4G/5G gene has been indicated to be correlated with coronary artery disease (CAD) susceptibility, but study results are still debatable. OBJECTIVE AND METHODS: The present meta-analysis was performed to investigate the association between PAI-1 4G/5G gene polymorphism and CAD in the Chinese Han population. A total of 879 CAD patients and 628 controls from eight separate studies were involved. The pooled odds ratio (OR) for the distribution of the 4G allele frequency of PAI-1 4G/5G gene and its corresponding 95% confidence interval (CI) was assessed by the random effect model. RESULTS: The distribution of the 4 G allele frequency was 0.61 for the CAD group and 0.51 for the control group. The association between PAI-1 4G/5G gene polymorphism and CAD in the Chinese Han population was significant under an allelic genetic model (OR = 1.70, 95% CI = 1.18 to 2.44, P = 0.004). The heterogeneity test was also significant (P<0.0001). Meta-regression was performed to explore the heterogeneity source. Among the confounding factors, the heterogeneity could be explained by the publication year (P = 0.017), study region (P = 0.014), control group sample size (P = 0.011), total sample size (P = 0.011), and ratio of the case to the control group sample size (RR) (P = 0.019). In a stratified analysis by the total sample size, significantly increased risk was only detected in subgroup 2 under an allelic genetic model (OR = 1.93, 95% CI = 1.09 to 3.35, P = 0.02). CONCLUSIONS: In the Chinese Han population, PAI-1 4G/5G gene polymorphism was implied to be associated with increased CAD risk. Carriers of the 4G allele of the PAI-1 4G/5G gene might predispose to CAD. PMID- 22496753 TI - Comparative composition, diversity and trophic ecology of sediment macrofauna at vents, seeps and organic falls. AB - Sediments associated with hydrothermal venting, methane seepage and large organic falls such as whale, wood and plant detritus create deep-sea networks of soft sediment habitats fueled, at least in part, by the oxidation of reduced chemicals. Biological studies at deep-sea vents, seeps and organic falls have looked at macrofaunal taxa, but there has yet to be a systematic comparison of the community-level attributes of sediment macrobenthos in various reducing ecosystems. Here we review key similarities and differences in the sediment dwelling assemblages of each system with the goals of (1) generating a predictive framework for the exploration and study of newly identified reducing habitats, and (2) identifying taxa and communities that overlap across ecosystems. We show that deep-sea seep, vent and organic-fall sediments are highly heterogeneous. They sustain different geochemical and microbial processes that are reflected in a complex mosaic of habitats inhabited by a mixture of specialist (heterotrophic and symbiont-associated) and background fauna. Community-level comparisons reveal that vent, seep and organic-fall macrofauna are very distinct in terms of composition at the family level, although they share many dominant taxa among these highly sulphidic habitats. Stress gradients are good predictors of macrofaunal diversity at some sites, but habitat heterogeneity and facilitation often modify community structure. The biogeochemical differences across ecosystems and within habitats result in wide differences in organic utilization (i.e., food sources) and in the prevalence of chemosynthesis-derived nutrition. In the Pacific, vents, seeps and organic-falls exhibit distinct macrofaunal assemblages at broad-scales contributing to beta diversity. This has important implications for the conservation of reducing ecosystems, which face growing threats from human activities. PMID- 22496754 TI - Down-regulation of microRNA-26a promotes mouse hepatocyte proliferation during liver regeneration. AB - BACKGROUND: Inadequate liver regeneration (LR) is still an unsolved problem in major liver resection and small-for-size syndrome post-living donor liver transplantation. A number of microRNAs have been shown to play important roles in cell proliferation. Herein, we investigated the role of miR-26a as a pivotal regulator of hepatocyte proliferation in LR. METHODOLOGY/PRINCIPAL FINDINGS: Adult male C57BL/6J mice, undergoing 70% partial hepatectomy (PH), were treated with Ad5-anti-miR-26a-LUC or Ad5-miR-26a-LUC or Ad5-LUC vector via portal vein. The animals were subjected to in vivo bioluminescence imaging. Serum and liver samples were collected to test liver function, calculate liver-to-body weight ratio (LBWR), document hepatocyte proliferation (Ki-67 staining), and investigate potential targeted gene expression of miR-26a by quantitative real-time PCR and Western blot. The miR-26a level declined during LR after 70% PH. Down-regulation of miR-26a by anti-miR-26a expression led to enhanced proliferation of hepatocytes, and both LBWR and hepatocyte proliferation (Ki-67(+) cells %) showed an increased tendency, while liver damage, indicated by aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (T Bil), was reduced. Furthermore, CCND2 and CCNE2, as possible targeted genes of miR-26a, were up-regulated. In addition, miR-26a over-expression showed converse results. CONCLUSIONS/SIGNIFICANCE: MiR-26a plays crucial role in regulating the proliferative phase of LR, probably by repressing expressions of cell cycle proteins CCND2 and CCNE2. The current study reveals a novel miRNA-mediated regulation pattern during the proliferative phase of LR. PMID- 22496755 TI - CSF-biomarkers in Olympic boxing: diagnosis and effects of repetitive head trauma. AB - BACKGROUND: Sports-related head trauma is common but still there is no established laboratory test used in the diagnostics of minimal or mild traumatic brain injuries. Further the effects of recurrent head trauma on brain injury markers are unknown. The purpose of this study was to investigate the relationship between Olympic (amateur) boxing and cerebrospinal fluid (CSF) brain injury biomarkers. METHODS: The study was designed as a prospective cohort study. Thirty Olympic boxers with a minimum of 45 bouts and 25 non-boxing matched controls were included in the study. CSF samples were collected by lumbar puncture 1-6 days after a bout and after a rest period for at least 14 days. The controls were tested once. Biomarkers for acute and chronic brain injury were analysed. RESULTS: NFL (mean +/- SD, 532+/-553 vs 135+/-51 ng/L p = 0.001), GFAP (496+/-238 vs 247+/-147 ng/L p<0.001), T-tau (58+/-26 vs 49+/-21 ng/L p<0.025) and S-100B (0.76+/-0.29 vs 0.60+/-0.23 ng/L p = 0.03) concentrations were significantly increased after boxing compared to controls. NFL (402+/-434 ng/L p = 0.004) and GFAP (369+/-113 ng/L p = 0.001) concentrations remained elevated after the rest period. CONCLUSION: Increased CSF levels of T-tau, NFL, GFAP, and S-100B in >80% of the boxers demonstrate that both the acute and the cumulative effect of head trauma in Olympic boxing may induce CSF biomarker changes that suggest minor central nervous injuries. The lack of normalization of NFL and GFAP after the rest period in a subgroup of boxers may indicate ongoing degeneration. The recurrent head trauma in boxing may be associated with increased risk of chronic traumatic brain injury. PMID- 22496756 TI - Phloroglucinol inhibits the bioactivities of endothelial progenitor cells and suppresses tumor angiogenesis in LLC-tumor-bearing mice. AB - BACKGROUND: There is increasing evidence that phloroglucinol, a compound from Ecklonia cava, induces the apoptosis of cancer cells, eventually suppressing tumor angiogenesis. METHODOLOGY/PRINCIPAL FINDINGS: This is the first report on phloroglucinol's ability to potentially inhibit the functional bioactivities of endothelial progenitor cells (EPCs) and thereby attenuate tumor growth and angiogenesis in the Lewis lung carcinoma (LLC)-tumor-bearing mouse model. Although Phloroglucinol did not affect their cell toxicity, it specifically inhibited vascular endothelial growth factor (VEGF) dependent migration and capillary-like tube formation of EPCs. Our matrigel plug assay clearly indicated that orally injected phloroglucinol effectively disrupts VEGF-induced neovessel formation. Moreover, we demonstrated that when phloroglucinol is orally administered, it significantly inhibits tumor growth and angiogenesis as well as CD45(-)/CD34(+) progenitor mobilization into peripheral blood in vivo in the LLC tumor-bearing mouse model. CONCLUSIONS/SIGNIFICANCE: These results suggest a novel role for Phloroglucinol: Phloroglucinol might be a modulator of circulating EPC bioactivities, eventually suppressing tumorigenesis. Therefore, phloroglucinol might be a candidate compound for biosafe drugs that target tumor angiogenesis. PMID- 22496757 TI - Single nucleotide polymorphisms in the PRDX3 and RPS19 and risk of HPV persistence and cervical precancer/cancer. AB - BACKGROUND: Host genetic factors might affect the risk of progression from infection with carcinogenic human papillomavirus (HPV), the etiologic agent for cervical cancer, to persistent HPV infection, and hence to cervical precancer and cancer. METHODOLOGY/PRINCIPAL FINDINGS: We assessed 18,310 tag single nucleotide polymorphisms (SNPs) from 1113 genes in 416 cervical intraepithelial neoplasia 3 (CIN3)/cancer cases, 356 women with persistent carcinogenic HPV infection (median persistence of 25 months) and 425 randomly selected women (non-cases and non-HPV persistent) from the 10,049 women from the Guanacaste, Costa Rica HPV natural history cohort. For gene and SNP associations, we computed age-adjusted odds ratio and p-trend. Three comparisons were made: 1) association with CIN3/cancer (compared CIN3/cancer cases to random controls), 2) association with persistence (compared HPV persistence to random controls), and 3) progression (compared CIN3/cancers with HPV-persistent group). Regions statistically significantly associated with CIN3/cancer included genes for peroxiredoxin 3 PRDX3, and ribosomal protein S19 RPS19. The single most significant SNPs from each gene associated with CIN3/cancer were PRDX3 rs7082598 (P(trend)<0.0001), and RPS19 rs2305809 (P(trend)=0.0007), respectively. Both SNPs were also associated with progression. CONCLUSIONS/SIGNIFICANCE: These data suggest involvement of two genes, RSP19 and PRDX3, or other SNPs in linkage disequilibrium, with cervical cancer risk. Further investigation showed that they may be involved in both the persistence and progression transition stages. Our results require replication but, if true, suggest a role for ribosomal dysfunction, mitochondrial processes, and/or oxidative stress, or other unknown function of these genes in cervical carcinogenesis. PMID- 22496758 TI - Allelopathic interactions between the opportunistic species Ulva prolifera and the native macroalga Gracilaria lichvoides. AB - Allelopathy, one type of direct plant competition, can be a potent mechanism through which plant communities are structured. The aim of this study was to determine whether allelopathic interactions occur between the opportunistic green tide-forming species Ulva prolifera and the native macroalga Gracilaria lichvoides, both of which were collected from the coastline of East China sea. In laboratory experiments, the presence of G. lichvoides at 1.25 g wet weight L(-1) significantly inhibited growth and photosynthesis of U. prolifera at concentrations of 1.25, 2.50, and 3.75 g wet weight L(-1) (p<0.05) in both semi continuous co-culture assays and in co-culture assays without nutrient supplementation. In contrast, although U. prolifera had a density effect on G. lichvoides, the differences among treatments were not significant (p>0.05). Culture medium experiments further confirmed that some allelochemicals may be released by both of the tested macroalgae, and these could account for the observed physiological inhibition of growth and photosynthesis. Moreover, the native macroalgae G. lichvoides was a stronger competitor than the opportunistic species U. prolifera. Collectively, the results of the present study represent a significant advance in exploring ecological questions about the effects of green tide blooms on the macroalgal community. PMID- 22496759 TI - Decline in HIV prevalence among young women in Zambia: national-level estimates of trends mask geographical and socio-demographic differences. AB - BACKGROUND: A decline in HIV incidence has been reported in Zambia and a number of other sub-Saharan countries. The trend of HIV prevalence among young people is a good marker of HIV incidence. In this study, different data sources are used to examine geographical and sub-population group differentials in HIV prevalence trends among men and women aged 15-24 years in Zambia. DESIGN AND METHODS: We analysed ANC data for women aged 15-24 years from 22 sentinel sites consistently covered in the period 1994-2008, and HIV data for young men and women aged 15-24 years from the ZDHS 2001/2 and 2007. In addition, we systematically reviewed peer reviewed articles that have reported findings on HIV prevalence and incidence among young people. FINDINGS: Overall trends of the ANC surveillance data indicated a substantial HIV prevalence decline among young women in both urban and rural areas. However, provincial declines differed substantially, i.e. between 10% and 68% among urban women, and from stability to 86% among rural women. Prevalence declines were steeper among those with the highest educational attainments than among the least educated. The ZDHS data indicated a significant reduction in prevalence between the two survey rounds among young women only. Provincial-level ZDHS changes were difficult to assess because the sample sizes were small. ANC-based trend patterns were consistent with those observed in PMTCT based data (2002-2006), whereas population-based surveys in a selected urban community (1995-2003) suggested that the ANC-based data underestimated the prevalence declines in the general populations of both young both men and women. CONCLUSION: The overall HIV prevalence declined substantially among young women in Zambia and this is interpreted as indicating a decline in HIV incidence. It is noteworthy that overall national trends masked substantial differences by place and by educational attainment, demonstrating critical limitations in the current focus on overall country-level trends in epidemiological reports. PMID- 22496760 TI - Bounds and inequalities relating h-index, g-index, e-index and generalized impact factor: an improvement over existing models. AB - In this paper, we describe some bounds and inequalities relating h-index, g index, e-index, and generalized impact factor. We derive the bounds and inequalities relating these indexing parameters from their basic definitions and without assuming any continuous model to be followed by any of them. We verify the theorems using citation data for five Price Medalists. We observe that the lower bound for h-index given by Theorem 2, [formula: see text], g >= 1, comes out to be more accurate as compared to Schubert-Glanzel relation h is proportional to C(2/3)P(-1/3) for a proportionality constant of 1, where C is the number of citations and P is the number of papers referenced. Also, the values of h-index obtained using Theorem 2 outperform those obtained using Egghe-Liang Rousseau power law model for the given citation data of Price Medalists. Further, we computed the values of upper bound on g-index given by Theorem 3, g <= (h + e), where e denotes the value of e-index. We observe that the upper bound on g index given by Theorem 3 is reasonably tight for the given citation record of Price Medalists. PMID- 22496761 TI - Improving power of genome-wide association studies with weighted false discovery rate control and prioritized subset analysis. AB - The issue of large-scale testing has caught much attention with the advent of high-throughput technologies. In genomic studies, researchers are often confronted with a large number of tests. To make simultaneous inference for the many tests, the false discovery rate (FDR) control provides a practical balance between the number of true positives and the number of false positives. However, when few hypotheses are truly non-null, controlling the FDR may not provide additional advantages over controlling the family-wise error rate (e.g., the Bonferroni correction). To facilitate discoveries from a study, weighting tests according to prior information is a promising strategy. A 'weighted FDR control' (WEI) and a 'prioritized subset analysis' (PSA) have caught much attention. In this work, we compare the two weighting schemes with systematic simulation studies and demonstrate their use with a genome-wide association study (GWAS) on type 1 diabetes provided by the Wellcome Trust Case Control Consortium. The PSA and the WEI both can increase power when the prior is informative. With accurate and precise prioritization, the PSA can especially create substantial power improvements over the commonly-used whole-genome single-step FDR adjustment (i.e., the traditional un-weighted FDR control). When the prior is uninformative (true disease susceptibility regions are not prioritized), the power loss of the PSA and the WEI is almost negligible. However, a caution is that the overall FDR of the PSA can be slightly inflated if the prioritization is not accurate and precise. Our study highlights the merits of using information from mounting genetic studies, and provides insights to choose an appropriate weighting scheme to FDR control on GWAS. PMID- 22496762 TI - Functional annotation of hierarchical modularity. AB - In biological networks of molecular interactions in a cell, network motifs that are biologically relevant are also functionally coherent, or form functional modules. These functionally coherent modules combine in a hierarchical manner into larger, less cohesive subsystems, thus revealing one of the essential design principles of system-level cellular organization and function-hierarchical modularity. Arguably, hierarchical modularity has not been explicitly taken into consideration by most, if not all, functional annotation systems. As a result, the existing methods would often fail to assign a statistically significant functional coherence score to biologically relevant molecular machines. We developed a methodology for hierarchical functional annotation. Given the hierarchical taxonomy of functional concepts (e.g., Gene Ontology) and the association of individual genes or proteins with these concepts (e.g., GO terms), our method will assign a Hierarchical Modularity Score (HMS) to each node in the hierarchy of functional modules; the HMS score and its p-value measure functional coherence of each module in the hierarchy. While existing methods annotate each module with a set of "enriched" functional terms in a bag of genes, our complementary method provides the hierarchical functional annotation of the modules and their hierarchically organized components. A hierarchical organization of functional modules often comes as a bi-product of cluster analysis of gene expression data or protein interaction data. Otherwise, our method will automatically build such a hierarchy by directly incorporating the functional taxonomy information into the hierarchy search process and by allowing multi-functional genes to be part of more than one component in the hierarchy. In addition, its underlying HMS scoring metric ensures that functional specificity of the terms across different levels of the hierarchical taxonomy is properly treated. We have evaluated our method using Saccharomyces cerevisiae data from KEGG and MIPS databases and several other computationally derived and curated datasets. The code and additional supplemental files can be obtained from http://code.google.com/p/functional-annotation-of-hierarchical-modularity/ (Accessed 2012 March 13). PMID- 22496763 TI - A bayesian model for exploiting application constraints to enable unsupervised training of a P300-based BCI. AB - This work introduces a novel classifier for a P300-based speller, which, contrary to common methods, can be trained entirely unsupervisedly using an Expectation Maximization approach, eliminating the need for costly dataset collection or tedious calibration sessions. We use publicly available datasets for validation of our method and show that our unsupervised classifier performs competitively with supervised state-of-the-art spellers. Finally, we demonstrate the added value of our method in different experimental settings which reflect realistic usage situations of increasing difficulty and which would be difficult or impossible to tackle with existing supervised or adaptive methods. PMID- 22496764 TI - Role of the two component signal transduction system CpxAR in conferring cefepime and chloramphenicol resistance in Klebsiella pneumoniae NTUH-K2044. AB - BACKGROUND: Klebsiella pneumoniae is a gram-negative, non-motile, facultative anaerobe belonging to the Enterobacteriaceae family of the gamma-Proteobacteria class in the phylum Proteobacteria. Multidrug resistant K. pneumoniae have caused major therapeutic problems worldwide due to emergence of extended-spectrum beta lactamase producing strains. Two-component systems serve as a basic stimulus response coupling mechanism to allow organisms to sense and respond to changes in many different environmental conditions including antibiotic stress. PRINCIPAL FINDINGS: In the present study, we investigated the role of an uncharacterized cpxAR operon in bacterial physiology and antimicrobial resistance by generating isogenic mutant (DeltacpxAR) deficient in the CpxA/CpxR component derived from the hyper mucoidal K1 strain K. pneumoniae NTUH-K2044. The behaviour of DeltacpxAR was determined under hostile conditions, reproducing stresses encountered in the gastrointestinal environment and deletion resulted in higher sensitivity to bile, osmotic and acid stresses. The DeltacpxAR was more susceptible to beta-lactams and chloramphenicol than the wild-type strain, and complementation restored the altered phenotypes. The relative change in expression of acrB, acrD, eefB efflux genes were decreased in cpxAR mutant as evidenced by qRT-PCR. Comparison of outer membrane protein profiles indicated a conspicuous difference in the knock out background. Gel shift assays demonstrated direct binding of CpxR(KP) to promoter region of ompC(KP) in a concentration dependent manner. CONCLUSIONS AND SIGNIFICANCE: The Cpx envelope stress response system is known to be activated by alterations in pH, membrane composition and misfolded proteins, and this systematic investigation reveals its direct involvement in conferring antimicrobial resistance against clinically significant antibiotics for the very first time. Overall results displayed in this report reflect the pleiotropic role of the CpxAR signaling system and diversity of the antibiotic resistome in hyper virulent K1 serotype K. pneumoniae NTUH-K2044. PMID- 22496765 TI - Hysteresis in pressure-driven DNA denaturation. AB - In the past, a great deal of attention has been drawn to thermal driven denaturation processes. In recent years, however, the discovery of stress-induced denaturation, observed at the one-molecule level, has revealed new insights into the complex phenomena involved in the thermo-mechanics of DNA function. Understanding the effect of local pressure variations in DNA stability is thus an appealing topic. Such processes as cellular stress, dehydration, and changes in the ionic strength of the medium could explain local pressure changes that will affect the molecular mechanics of DNA and hence its stability. In this work, a theory that accounts for hysteresis in pressure-driven DNA denaturation is proposed. We here combine an irreversible thermodynamic approach with an equation of state based on the Poisson-Boltzmann cell model. The latter one provides a good description of the osmotic pressure over a wide range of DNA concentrations. The resulting theoretical framework predicts, in general, the process of denaturation and, in particular, hysteresis curves for a DNA sequence in terms of system parameters such as salt concentration, density of DNA molecules and temperature in addition to structural and configurational states of DNA. Furthermore, this formalism can be naturally extended to more complex situations, for example, in cases where the host medium is made up of asymmetric salts or in the description of the (helical-like) charge distribution along the DNA molecule. Moreover, since this study incorporates the effect of pressure through a thermodynamic analysis, much of what is known from temperature-driven experiments will shed light on the pressure-induced melting issue. PMID- 22496766 TI - Effects of the cryptochrome CryB from Rhodobacter sphaeroides on global gene expression in the dark or blue light or in the presence of singlet oxygen. AB - Several regulators are controlling the formation of the photosynthetic apparatus in the facultatively photosynthetic bacterium Rhodobacter sphaeroides. Among the proteins affecting photosynthesis gene expression is the blue light photoreceptor cryptochrome CryB. This study addresses the effect of CryB on global gene expression. The data reveal that CryB does not only influence photosynthesis gene expression but also genes for the non-photosynthetic energy metabolism like citric acid cycle and oxidative phosphorylation. In addition several genes involved in RNA processing and in transcriptional regulation are affected by a cryB deletion. Although CryB was shown to undergo a photocycle it does not only affect gene expression in response to blue light illumination but also in response to singlet oxygen stress conditions. While there is a large overlap in these responses, some CryB-dependent effects are specific for blue-light or photooxidative stress. In addition to protein-coding genes some genes for sRNAs show CryB-dependent expression. These findings give new insight into the function of bacterial cryptochromes and demonstrate for the first time a function in the oxidative stress response. PMID- 22496767 TI - Caffeine ingestion reverses the circadian rhythm effects on neuromuscular performance in highly resistance-trained men. AB - PURPOSE: To investigate whether caffeine ingestion counteracts the morning reduction in neuromuscular performance associated with the circadian rhythm pattern. METHODS: Twelve highly resistance-trained men underwent a battery of neuromuscular tests under three different conditions; i) morning (10:00 a.m.) with caffeine ingestion (i.e., 3 mg kg(-1); AM(CAFF) trial); ii) morning (10:00 a.m.) with placebo ingestion (AM(PLAC) trial); and iii) afternoon (18:00 p.m.) with placebo ingestion (PM(PLAC) trial). A randomized, double-blind, crossover, placebo controlled experimental design was used, with all subjects serving as their own controls. The neuromuscular test battery consisted in the measurement of bar displacement velocity during free-weight full-squat (SQ) and bench press (BP) exercises against loads that elicit maximum strength (75% 1RM load) and muscle power adaptations (1 m s(-1) load). Isometric maximum voluntary contraction (MVC(LEG)) and isometric electrically evoked strength of the right knee (EVOK(LEG)) were measured to identify caffeine's action mechanisms. Steroid hormone levels (serum testosterone, cortisol and growth hormone) were evaluated at the beginning of each trial (PRE). In addition, plasma norepinephrine (NE) and epinephrine were measured PRE and at the end of each trial following a standardized intense (85% 1RM) 6 repetitions bout of SQ (POST). RESULTS: In the PM(PLAC) trial, dynamic muscle strength and power output were significantly enhanced compared with AM(PLAC) treatment (3.0%-7.5%; p<=0.05). During AM(CAFF) trial, muscle strength and power output increased above AM(PLAC) levels (4.6% 5.7%; p<=0.05) except for BP velocity with 1 m s(-1) load (p = 0.06). During AM(CAFF), EVOK(LEG) and NE (a surrogate of maximal muscle sympathetic nerve activation) were increased above AM(PLAC) trial (14.6% and 96.8% respectively; p<=0.05). CONCLUSIONS: These results indicate that caffeine ingestion reverses the morning neuromuscular declines in highly resistance-trained men, raising performance to the levels of the afternoon trial. Our electrical stimulation data, along with the NE values, suggest that caffeine increases neuromuscular performance having a direct effect in the muscle. PMID- 22496768 TI - White matter abnormalities correlating with memory and depression in heroin users under methadone maintenance treatment. AB - Methadone maintenance treatment (MMT) has elevated rates of co-morbid memory deficit and depression that are associated with higher relapse rates for substance abuse. White matter (WM) disruption in MMT patients have been reported but their impact on these co-morbidities is unknown. This study aimed to investigate changes in WM integrity of MMT subjects using diffusion tensor image (DTI), and their relationship with history of heroin and methadone use in treated opiate-dependent individuals. The association between WM integrity changes from direct group comparisons and the severity of memory deficit and depression was also investigated. Differences in WM integrity between 35 MMT patients and 23 healthy controls were evaluated using DTI with tract-based spatial statistical analysis. Differences in DTI indices correlated with diminished memory function, Beck Depression Inventory, duration of heroin use and MMT, and dose of heroin and methadone administration. Changes in WM integrity were found in several WM regions, including the temporal and frontal lobes, pons, cerebellum, and cingulum bundles. The duration of MMT was associated with declining DTI indices in the superior longitudinal fasciculus and para-hippocampus. MMT patients had more memory and emotional deficits than healthy subjects. Worse scores in both depression and memory functions were associated with altered WM integrity in the superior longitudinal fasciculus, para-hippocampus, and middle cerebellar peduncle in MMT. Patients on MMT also had significant WM differences in the reward circuit and in depression- and memory-associated regions. Correlations among decreased DTI indices, disease severity, and accumulation effects of methadone suggest that WM alterations may be involved in the psychopathology and pathophysiology of co-morbidities in MMT. PMID- 22496769 TI - The GTPase activating Rap/RanGAP domain-like 1 gene is associated with chicken reproductive traits. AB - BACKGROUND: Abundant evidence indicates that chicken reproduction is strictly regulated by the hypothalamic-pituitary-gonad (HPG) axis, and the genes included in the HPG axis have been studied extensively. However, the question remains as to whether any other genes outside of the HPG system are involved in regulating chicken reproduction. The present study was aimed to identify, on a genome-wide level, novel genes associated with chicken reproductive traits. METHODOLOGY/PRINCIPAL FINDING: Suppressive subtractive hybridization (SSH), genome-wide association study (GWAS), and gene-centric GWAS were used to identify novel genes underlying chicken reproduction. Single marker-trait association analysis with a large population and allelic frequency spectrum analysis were used to confirm the effects of candidate genes. Using two full-sib Ningdu Sanhuang (NDH) chickens, GARNL1 was identified as a candidate gene involved in chicken broodiness by SSH analysis. Its expression levels in the hypothalamus and pituitary were significantly higher in brooding chickens than in non-brooding chickens. GWAS analysis with a NDH two tail sample showed that 2802 SNPs were significantly associated with egg number at 300 d of age (EN300). Among the 2802 SNPs, 2 SNPs composed a block overlapping the GARNL1 gene. The gene-centric GWAS analysis with another two tail sample of NDH showed that GARNL1 was strongly associated with EN300 and age at first egg (AFE). Single marker-trait association analysis in 1301 female NDH chickens confirmed that variation in this gene was related to EN300 and AFE. The allelic frequency spectrum of the SNP rs15700989 among 5 different populations supported the above associations. Western blotting, RT-PCR, and qPCR were used to analyze alternative splicing of the GARNL1 gene. RT PCR detected 5 transcripts and revealed that the transcript, which has a 141 bp insertion, was expressed in a tissue-specific manner. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that the GARNL1 gene contributes to chicken reproductive traits. PMID- 22496770 TI - Gender-specific associations of marine n-3 fatty acids and fish consumption with 10-year incidence of stroke. AB - BACKGROUND: There is some evidence that the association of fish and marine fatty acids with stroke risk differs between men and women. We investigated the gender specific associations of habitual intake of the marine fatty acids eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) and fish on incident stroke in a population-based study in the Netherlands. METHODS: We prospectively followed 20,069 men and women, aged 20-65 years, without cardiovascular diseases at baseline. Habitual diet was assessed with a validated 178-item food frequency questionnaire. Incidence of stroke was assessed through linkage with mortality and morbidity registers. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (95%CI). RESULTS: During 8-13 years of follow-up, 221 strokes occurred. In women, an inverse dose-response relation (P-trend = 0.02) was observed between EPA-DHA intake and incident stroke, with an HR of 0.49 (95% CI: 0.27-0.91) in the top quartile of EPA-DHA (median 225 mg/d) as compared to the bottom quartile (median 36 mg/d). In men, the HR (95%CI) for the top quartile of EPA-DHA intake was 0.87 (0.51-1.48) (P-trend = 0.36). Similar results were observed for fish consumption and stroke incidence. CONCLUSION: A higher EPA-DHA and fish intake is related to a lower stroke risk in women, while for men an inverse association could not be demonstrated. PMID- 22496771 TI - Analysis of context dependence in social interaction networks of a massively multiplayer online role-playing game. AB - Rapid advances in modern computing and information technology have enabled millions of people to interact online via various social network and gaming services. The widespread adoption of such online services have made possible analysis of large-scale archival data containing detailed human interactions, presenting a very promising opportunity to understand the rich and complex human behavior. In collaboration with a leading global provider of Massively Multiplayer Online Role-Playing Games (MMORPGs), here we present a network science-based analysis of the interplay between distinct types of user interaction networks in the virtual world. We find that their properties depend critically on the nature of the context-interdependence of the interactions, highlighting the complex and multilayered nature of human interactions, a robust understanding of which we believe may prove instrumental in the designing of more realistic future virtual arenas as well as provide novel insights to the science of collective human behavior. PMID- 22496772 TI - Modification of Ad5 hexon hypervariable regions circumvents pre-existing Ad5 neutralizing antibodies and induces protective immune responses. AB - The development of an effective malaria vaccine is a high global health priority. Vaccine vectors based on adenovirus type 5 are capable of generating robust and protective T cell and antibody responses in animal models and are currently being evaluated in clinical trials for HIV and malaria. They appear to be more effective in terms of inducing antigen-specific immune responses as compared with non-Ad5 serotype vectors. However, the high prevalence of neutralizing antibodies to Ad5 in the human population, particularly in the developing world, has the potential to limit the effectiveness of Ad5-based vaccines. We have generated novel Ad5-based vectors that precisely replace the hexon hypervariable regions with those derived from Ad43, a subgroup D serotype with low prevalence of neutralizing antibody in humans. We have demonstrated that these hexon-modified adenovectors are not neutralized efficiently by Ad5 neutralizing antibodies in vitro using sera from mice, rabbits and human volunteers. We have also generated hexon-modified adenovectors that express a rodent malaria parasite antigen, PyCSP, and demonstrated that they are as immunogenic as an unmodified vector. Furthermore, in contrast to the unmodified vector, the hexon-modified adenovectors induced robust T cell responses in mice with high levels of Ad5 neutralizing antibody. We also show that the hexon-modified vector can be combined with unmodified Ad5 vector in prime-boost regimens to induce protective responses in mice. Our data establish that these hexon-modified vectors are highly immunogenic even in the presence of pre-existing anti-adenovirus antibodies. These hexon-modified adenovectors may have advantages in sub-Saharan Africa where there is a high prevalence of Ad5 neutralizing antibody in the population. PMID- 22496774 TI - Spatial proximity and similarity of the epigenetic state of genome domains. AB - Recent studies demonstrate that the organization of the chromatin within the nuclear space might play a crucial role in the regulation of gene expression. The ongoing progress in determination of the 3D structure of the nuclear chromatin allows one to study correlations between spatial proximity of genome domains and their epigenetic state. We combined the data on three-dimensional architecture of the whole human genome with results of high-throughput studies of the chromatin functional state and observed that fragments of different chromosomes that are spatially close tend to have similar patterns of histone modifications, methylation state, DNAse sensitivity, expression level, and chromatin states in general. Moreover, clustering of genome regions by spatial proximity produced compact clusters characterized by the high level of histone modifications and DNAse sensitivity and low methylation level, and loose clusters with the opposite characteristics. We also associated the spatial proximity data with previously detected chimeric transcripts and the results of RNA-seq experiments and observed that the frequency of formation of chimeric transcripts from fragments of two different chromosomes is higher among spatially proximal genome domains. A fair fraction of these chimeric transcripts seems to arise post-transcriptionally via trans-splicing. PMID- 22496773 TI - Diabetic kidney disease in FVB/NJ Akita mice: temporal pattern of kidney injury and urinary nephrin excretion. AB - Akita mice are a genetic model of type 1 diabetes. In the present studies, we investigated the phenotype of Akita mice on the FVB/NJ background and examined urinary nephrin excretion as a marker of kidney injury. Male Akita mice were compared with non-diabetic controls for functional and structural characteristics of renal and cardiac disease. Podocyte number and apoptosis as well as urinary nephrin excretion were determined in both groups. Male FVB/NJ Akita mice developed sustained hyperglycemia and albuminuria by 4 and 8 weeks of age, respectively. These abnormalities were accompanied by a significant increase in systolic blood pressure in 10-week old Akita mice, which was associated with functional, structural and molecular characteristics of cardiac hypertrophy. By 20 weeks of age, Akita mice developed a 10-fold increase in albuminuria, renal and glomerular hypertrophy and a decrease in the number of podocytes. Mild-to moderate glomerular mesangial expansion was observed in Akita mice at 30 weeks of age. In 4-week old Akita mice, the onset of hyperglycemia was accompanied by increased podocyte apoptosis and enhanced excretion of nephrin in urine before the development of albuminuria. Urinary nephrin excretion was also significantly increased in albuminuric Akita mice at 16 and 20 weeks of age and correlated with the albumin excretion rate. These data suggest that: 1. FVB/NJ Akita mice have phenotypic characteristics that may be useful for studying the mechanisms of kidney and cardiac injury in diabetes, and 2. Enhanced urinary nephrin excretion is associated with kidney injury in FVB/NJ Akita mice and is detectable early in the disease process. PMID- 22496775 TI - Decreased pre-existing Ad5 capsid and Ad35 neutralizing antibodies increase HIV-1 infection risk in the Step trial independent of vaccination. AB - BACKGROUND: The Step trial raised the possibility that uncircumcised men with pre existing Ad5 neutralizing antibodies carried an increased risk of HIV infection after vaccination. Thus, understanding Ad seropositivity in humans is important to the development of an AIDS vaccine. Here, we analyze the impact of different Ad5-specific neutralizing antibodies on immune function and clinical outcome. METHODS AND FINDINGS: Ad seropositivity in the Step trial volunteers was analyzed using chimeric rAd5/35 vectors to characterize their specificity for Ad5 fiber and non-fiber external (capsid) proteins. Immune responses and HIV seropositivity were correlated with the specificity of Ad5-neutralizing antibodies. Neutralizing antibodies induced by the vaccine in Ad5 seronegative subjects were directed preferentially to Ad5 capsid proteins, although some fiber-neutralizing antibodies could be detected. Pre-vaccination Ad5 serostatus did not affect the capsid-directed response after three vaccinations. In contrast, anti-fiber antibody titers were significantly higher in volunteers who were Ad5 seropositive prior to vaccination. Those Ad5 seropositive subjects who generated anti-capsid responses showed a marked reduction in vaccine-induced CD8 responses. Unexpectedly, anti-vector immunity differed qualitatively in Ad5 seropositive participants who became HIV-1 infected compared to uninfected case controls; Ad5 seropositive participants who later acquired HIV had lower neutralizing antibodies to capsid. Moreover, Ad35 seropositivity was decreased in HIV-infected subjects compared with uninfected case controls, while seroprevalence for other serotypes including Ad14, Ad28 and Ad41 was similar in both groups. CONCLUSIONS: Together, these findings suggest that the case subjects were less immunologically responsive prior to infection. Subjects infected during the Step trial had qualitative differences in immunity that increased their risk of HIV-1 infection independent of vaccination. PMID- 22496776 TI - Fast and accurate taxonomic assignments of metagenomic sequences using MetaBin. AB - Taxonomic assignment of sequence reads is a challenging task in metagenomic data analysis, for which the present methods mainly use either composition- or homology-based approaches. Though the homology-based methods are more sensitive and accurate, they suffer primarily due to the time needed to generate the Blast alignments. We developed the MetaBin program and web server for better homology based taxonomic assignments using an ORF-based approach. By implementing Blat as the faster alignment method in place of Blastx, the analysis time has been reduced by severalfold. It is benchmarked using both simulated and real metagenomic datasets, and can be used for both single and paired-end sequence reads of varying lengths (>=45 bp). To our knowledge, MetaBin is the only available program that can be used for the taxonomic binning of short reads (<100 bp) with high accuracy and high sensitivity using a homology-based approach. The MetaBin web server can be used to carry out the taxonomic analysis, by either submitting reads or Blastx output. It provides several options including construction of taxonomic trees, creation of a composition chart, functional analysis using COGs, and comparative analysis of multiple metagenomic datasets. MetaBin web server and a standalone version for high-throughput analysis are available freely at http://metabin.riken.jp/. PMID- 22496777 TI - Biochemical characterization and evaluation of a Brugia malayi small heat shock protein as a vaccine against lymphatic filariasis. AB - Filarial nematodes enjoy one of the longest life spans of any human pathogen due to effective immune evasion strategies developed by the parasite. Among the various immune evasion strategies exhibited by the parasite, Interleukin 10 (IL 10) productions and IL-10 mediated immune suppression has significant negative impact on the host immune system. Recently, we identified a small heat shock protein expressed by Brugia malayi (BmHsp12.6) that can bind to soluble human IL 10 receptor alpha (IL-10R) and activate IL-10 mediated effects in cell lines. In this study we show that the IL-10R binding region of BmHsp12.6 is localized to its N-terminal region. This region has significant sequence similarity to the receptor binding region of human IL-10. In vitro studies confirm that the N terminal region of BmHsp12.6 (N-BmHsp12.6) has IL-10 like activity and the region containing the alpha crystalline domain and C-terminus of BmHsp12.6 (BmHsp12.6alphac) has no IL-10 like activity. However, BmHsp12.6alphac contains B cell, T cell and CTL epitopes. Members of the sHSP families are excellent vaccine candidates. Evaluation of sera samples from putatively immune endemic normal (EN) subjects showed IgG1 and IgG3 antibodies against BmHsp12.6alphac and these antibodies were involved in the ADCC mediated protection. Subsequent vaccination trials with BmHsp12.6alphac in a mouse model using a heterologous prime boost approach showed that 83% protection can be achieved against B. malayi L3 challenge. Results presented in this study thus show that the N-BmHsp12.6 subunit of BmHsp12.6 has immunoregulatory function, whereas, the BmHsp12.6alphac subunit of BmHsp12.6 has significant vaccine potential. PMID- 22496778 TI - TRAF6 promotes myogenic differentiation via the TAK1/p38 mitogen-activated protein kinase and Akt pathways. AB - p38 mitogen-activated protein kinase (MAPK) is an essential kinase involved in myogenic differentiation. Although many substrates of p38 MAPK have been identified, little is known about its upstream activators during myogenic differentiation. TRAF6 is known to function in cytokine signaling during inflammatory responses. However, not much is known about its role in myogenic differentiation and muscle regeneration. We showed here that TRAF6 and its intrinsic ubiquitin E3 ligase activity are required for myogenic differentiation. In mouse myoblasts, knockdown of TRAF6 compromised the p38 MAPK and Akt pathways, while deliberate activation of either pathway rescued the differentiation defect caused by TRAF6 knockdown. TAK1 acted as a key signal transducer downstream of TRAF6 in myogenic differentiation. In vivo, knockdown of TRAF6 in mouse muscles compromised the injury-induced muscle regeneration without impairing macrophage infiltration and myoblast proliferation. Collectively, we demonstrated that TRAF6 promotes myogenic differentiation and muscle regeneration via the TAK1/p38 MAPK and Akt pathways. PMID- 22496780 TI - Long-term decrease in VLA-4 expression and functional impairment of dendritic cells during natalizumab therapy in patients with multiple sclerosis. AB - Myeloid and plasmacytoid dendritic cells (mDCs, pDCs) are central to the initiation and the regulation of immune processes in multiple sclerosis (MS). Natalizumab (NTZ) is a humanized monoclonal antibody approved for the treatment of MS that acts by blocking expression of VLA-4 integrins on the surface of leukocytes. We determined the proportions of circulating DC subsets and analyzed expression of VLA-4 expression in 6 relapsing-remitting MS patients treated with NTZ for 1 year. VLA-4 expression levels on pDCs and mDCs decreased significantly during follow-up. In vitro coculture of peripheral blood mononuclear cells and pDCs, with different doses of NTZ in healthy controls (HC) and MS patients showed dose-dependent down-regulation of VLA-4 expression levels in both MS patients and HC, and reduced functional ability to stimulate antigen-specific T-lymphocyte responses. The biological impact of NTZ may in part be attributable to inhibition of transmigration of circulating DCs into the central nervous system, but also to functional impairment of interactions between T cells and DC. PMID- 22496779 TI - A preclinical assessment of neural stem cells as delivery vehicles for anti amyloid therapeutics. AB - Transplantation of neural stems cells (NSCs) could be a useful means to deliver biologic therapeutics for late-stage Alzheimer's disease (AD). In this study, we conducted a small preclinical investigation of whether NSCs could be modified to express metalloproteinase 9 (MMP9), a secreted protease reported to degrade aggregated Abeta peptides that are the major constituents of the senile plaques. Our findings illuminated three issues with using NSCs as delivery vehicles for this particular application. First, transplanted NSCs generally failed to migrate to amyloid plaques, instead tending to colonize white matter tracts. Second, the final destination of these cells was highly influenced by how they were delivered. We found that our injection methods led to cells largely distributing to white matter tracts, which are anisotropic conduits for fluids that facilitate rapid distribution within the CNS. Third, with regard to MMP9 as a therapeutic to remove senile plaques, we observed high concentrations of endogenous metalloproteinases around amyloid plaques in the mouse models used for these preclinical tests with no evidence that the NSC-delivered enzymes elevated these activities or had any impact. Interestingly, MMP9-expressing NSCs formed substantially larger grafts. Overall, we observed long-term survival of NSCs in the brains of mice with high amyloid burden. Therefore, we conclude that such cells may have potential in therapeutic applications in AD but improved targeting of these cells to disease-specific lesions may be required to enhance efficacy. PMID- 22496781 TI - Coexpression of nuclear receptors and histone methylation modifying genes in the testis: implications for endocrine disruptor modes of action. AB - BACKGROUND: Endocrine disruptor chemicals elicit adverse health effects by perturbing nuclear receptor signalling systems. It has been speculated that these compounds may also perturb epigenetic mechanisms and thus contribute to the early origin of adult onset disease. We hypothesised that histone methylation may be a component of the epigenome that is susceptible to perturbation. We used coexpression analysis of publicly available data to investigate the combinatorial actions of nuclear receptors and genes involved in histone methylation in normal testis and when faced with endocrine disruptor compounds. METHODOLOGY/PRINCIPAL FINDINGS: The expression patterns of a set of genes were profiled across testis tissue in human, rat and mouse, plus control and exposed samples from four toxicity experiments in the rat. Our results indicate that histone methylation events are a more general component of nuclear receptor mediated transcriptional regulation in the testis than previously appreciated. Coexpression patterns support the role of a gatekeeper mechanism involving the histone methylation modifiers Kdm1, Prdm2, and Ehmt1 and indicate that this mechanism is a common determinant of transcriptional integrity for genes critical to diverse physiological endpoints relevant to endocrine disruption. Coexpression patterns following exposure to vinclozolin and dibutyl phthalate suggest that coactivity of the demethylase Kdm1 in particular warrants further investigation in relation to endocrine disruptor mode of action. CONCLUSIONS/SIGNIFICANCE: This study provides proof of concept that a bioinformatics approach that profiles genes related to a specific hypothesis across multiple biological settings can provide powerful insight into coregulatory activity that would be difficult to discern at an individual experiment level or by traditional differential expression analysis methods. PMID- 22496782 TI - Chicken pleiotrophin: regulation of tissue specific expression by estrogen in the oviduct and distinct expression pattern in the ovarian carcinomas. AB - Pleiotrophin (PTN) is a developmentally-regulated growth factor which is widely distributed in various tissues and also detected in many kinds of carcinomas. However, little is known about the PTN gene in chickens. In the present study, we found chicken PTN to be highly conserved with respect to mammalian PTN genes (91 92.6%) and its mRNA was most abundant in brain, heart and oviduct. This study focused on the PTN gene in the oviduct where it was detected in the glandular (GE) and luminal (LE) epithelial cells. Treatment of young chicks with diethylstilbesterol induced PTN mRNA and protein in GE and LE, but not in other cell types of the oviduct. Further, several microRNAs, specifically miR-499 and miR-1709 were discovered to influence PTN expression via its 3'-UTR which suggests that post-transcriptional regulation influences PTN expression in chickens. We also compared expression patterns and CpG methylation status of the PTN gene in normal and cancerous ovaries from chickens. Our results indicated that PTN is most abundant in the GE of adenocarcinoma of cancerous, but not normal ovaries of hens. Bisulfite sequencing revealed that 30- and 40% of -1311 and -1339 CpG sites are demethylated in ovarian cancer cells, respectively. Collectively, these results indicate that chicken PTN is a novel estrogen-induced gene expressed mainly in the oviductal epithelia implicating PTN regulation of oviduct development and egg formation, and also suggest that PTN is a biomarker for epithelial ovarian carcinoma that could be used for diagnosis and monitoring effects of therapies for the disease. PMID- 22496783 TI - High visual working memory capacity in trait social anxiety. AB - Working memory capacity is one of the most important cognitive functions influencing individual traits, such as attentional control, fluid intelligence, and also psychopathological traits. Previous research suggests that anxiety is associated with impaired cognitive function, and studies have shown low verbal working memory capacity in individuals with high trait anxiety. However, the relationship between trait anxiety and visual working memory capacity is still unclear. Considering that people allocate visual attention more widely to detect danger under threat, visual working memory capacity might be higher in anxious people. In the present study, we show that visual working memory capacity increases as trait social anxiety increases by using a change detection task. When the demand to inhibit distractors increased, however, high visual working memory capacity diminished in individuals with social anxiety, and instead, impaired filtering of distractors was predicted by trait social anxiety. State anxiety was not correlated with visual working memory capacity. These results indicate that socially anxious people could potentially hold a large amount of information in working memory. However, because of an impaired cognitive function, they could not inhibit goal-irrelevant distractors and their performance decreased under highly demanding conditions. PMID- 22496784 TI - Epidermal transglutaminase (TGase 3) is required for proper hair development, but not the formation of the epidermal barrier. AB - Transglutaminases (TGase), a family of cross-linking enzymes present in most cell types, are important in events as diverse as cell-signaling and matrix stabilization. Transglutaminase 1 is crucial in developing the epidermal barrier, however the skin also contains other family members, in particular TGase 3. This isoform is highly expressed in the cornified layer, where it is believed to stabilize the epidermis and its reduction is implicated in psoriasis. To understand the importance of TGase 3 in vivo we have generated and analyzed mice lacking this protein. Surprisingly, these animals display no obvious defect in skin development, no overt changes in barrier function or ability to heal wounds. In contrast, hair lacking TGase 3 is thinner, has major alterations in the cuticle cells and hair protein cross-linking is markedly decreased. Apparently, while TGase 3 is of unique functional importance in hair, in the epidermis loss of TGase 3 can be compensated for by other family members. PMID- 22496785 TI - A glutathione transferase from Agrobacterium tumefaciens reveals a novel class of bacterial GST superfamily. AB - In the present work, we report a novel class of glutathione transferases (GSTs) originated from the pathogenic soil bacterium Agrobacterium tumefaciens C58, with structural and catalytic properties not observed previously in prokaryotic and eukaryotic GST isoenzymes. A GST-like sequence from A. tumefaciens C58 (Atu3701) with low similarity to other characterized GST family of enzymes was identified. Phylogenetic analysis showed that it belongs to a distinct GST class not previously described and restricted only in soil bacteria, called the Eta class (H). This enzyme (designated as AtuGSTH1-1) was cloned and expressed in E. coli and its structural and catalytic properties were investigated. Functional analysis showed that AtuGSTH1-1 exhibits significant transferase activity against the common substrates aryl halides, as well as very high peroxidase activity towards organic hydroperoxides. The crystal structure of AtuGSTH1-1 was determined at 1.4 A resolution in complex with S-(p-nitrobenzyl)-glutathione (Nb GSH). Although AtuGSTH1-1 adopts the canonical GST fold, sequence and structural characteristics distinct from previously characterized GSTs were identified. The absence of the classic catalytic essential residues (Tyr, Ser, Cys) distinguishes AtuGSTH1-1 from all other cytosolic GSTs of known structure and function. Site directed mutagenesis showed that instead of the classic catalytic residues, an Arg residue (Arg34), an electron-sharing network, and a bridge of a network of water molecules may form the basis of the catalytic mechanism. Comparative sequence analysis, structural information, and site-directed mutagenesis in combination with kinetic analysis showed that Phe22, Ser25, and Arg187 are additional important residues for the enzyme's catalytic efficiency and specificity. PMID- 22496786 TI - HDAC1 inactivation induces mitotic defect and caspase-independent autophagic cell death in liver cancer. AB - Histone deacetylases (HDACs) are known to play a central role in the regulation of several cellular properties interlinked with the development and progression of cancer. Recently, HDAC1 has been reported to be overexpressed in hepatocellular carcinoma (HCC), but its biological roles in hepatocarcinogenesis remain to be elucidated. In this study, we demonstrated overexpression of HDAC1 in a subset of human HCCs and liver cancer cell lines. HDAC1 inactivation resulted in regression of tumor cell growth and activation of caspase-independent autophagic cell death, via LC3B-II activation pathway in Hep3B cells. In cell cycle regulation, HDAC1 inactivation selectively induced both p21(WAF1/Cip1) and p27(Kip1) expressions, and simultaneously suppressed the expression of cyclin D1 and CDK2. Consequently, HDAC1 inactivation led to the hypophosphorylation of pRb in G1/S transition, and thereby inactivated E2F/DP1 transcription activity. In addition, we demonstrated that HDAC1 suppresses p21(WAF1/Cip1) transcriptional activity through Sp1-binding sites in the p21(WAF1/Cip1) promoter. Furthermore, sustained suppression of HDAC1 attenuated in vitro colony formation and in vivo tumor growth in a mouse xenograft model. Taken together, we suggest the aberrant regulation of HDAC1 in HCC and its epigenetic regulation of gene transcription of autophagy and cell cycle components. Overexpression of HDAC1 may play a pivotal role through the systemic regulation of mitotic effectors in the development of HCC, providing a particularly relevant potential target in cancer therapy. PMID- 22496787 TI - Cochlin, intraocular pressure regulation and mechanosensing. AB - Fluid shear modulates many biological properties. How shear mechanosensing occurs in the extracellular matrix (ECM) and is transduced into cytoskeletal change remains unknown. Cochlin is an ECM protein of unknown function. Our investigation using a comprehensive spectrum of cutting-edge techniques has resulted in following major findings: (1) over-expression and down-regulation of cochlin increase and decrease intraocular pressure (IOP), respectively. The overexpression was achieved in DBA/2J-Gpnmb(+)/SjJ using lentiviral vectors, down regulation was achieved in glaucomatous DBA/2J mice using targeted disruption (cochlin-null mice) and also using lentiviral vector mediated shRNA against cochlin coding region; (2) reintroduction of cochlin in cochlin-null mice increases IOP; (3) injection of exogenous cochlin also increased IOP; (4) increasing perfusion rates increased cochlin multimerization, which reduced the rate of cochlin proteolysis by trypsin and proteinase K; The cochlin multimerization in response to shear stress suggests its potential mechanosensing. Taken together with previous studies, we show cochlin is involved in regulation of intraocular pressure in DBA/2J potentially through mechanosensing of the shear stress. PMID- 22496788 TI - Diagnostic significance of serum HMGB1 in colorectal carcinomas. AB - High mobility group box 1 protein (HMGB1), a nuclear protein, can be translocated to the cytoplasm and secreted in colon cancer cells. However, the diagnostic significance of HMGB1 has not been evaluated in colorectal carcinomas. For this purpose, we have screened the expression and secretion of HMGB1 in 10 colon cancer cell lines and 1 control cell line and found that HMGB1 was detected in the culture medium. To evaluate the diagnostic value of HMGB1, we performed an enzyme-linked immunosorbent assay to measure HMGB1 levels and compared them to carcinoembryonic antigen (CEA) levels in the serum samples of 219 colorectal carcinoma patients and 75 healthy control subjects. We found that the serum HMGB1 level was increased by 1.5-fold in patients with colorectal carcinoma compared to those in healthy controls. When HMGB1 and CEA levels were compared, HMGB1 had similar efficacy as CEA regarding cancer detection (the sensitivity was 20.1% for HMGB1 vs. 25.6% for CEA, and the specificity was 96% for HMGB1 vs. 90.7% for CEA). Moreover, the diagnostic accuracy of HMGB1 for stage I cancer was significantly higher than that of CEA (sensitivity: 41.2% vs. 5.9%; specificity: 96% vs. 90.7). When we combined HMGB1 and CEA, the overall diagnostic sensitivity was higher than that of CEA alone (42% vs. 25.6%), and the diagnostic sensitivity for stage I was also elevated (47% vs. 5.9%). However, the prognosis of patients was not related with serum HMGB1 concentrations. Our findings indicate that serum HMGB1 levels are increased in a subset of colorectal carcinomas, suggesting their potential utility as a supportive diagnostic marker for colorectal carcinomas. PMID- 22496789 TI - Efficient commitment to functional CD34+ progenitor cells from human bone marrow mesenchymal stem-cell-derived induced pluripotent stem cells. AB - The efficient commitment of a specialized cell type from induced pluripotent stem cells (iPSCs) without contamination from unknown substances is crucial to their use in clinical applications. Here, we propose that CD34+ progenitor cells, which retain hematopoietic and endothelial cell potential, could be efficiently obtained from iPSCs derived from human bone marrow mesenchymal stem cells (hBMMSC iPSCs) with defined factors. By treatment with a cocktail containing mesodermal, hematopoietic, and endothelial inducers (BMP4, SCF, and VEGF, respectively) for 5 days, hBMMSC-iPSCs expressed the mesodermal transcription factors Brachyury and GATA-2 at higher levels than untreated groups (P<0.05). After culturing with another hematopoietic and endothelial inducer cocktail, including SCF, Flt3L, VEGF and IL-3, for an additional 7-9 days, CD34+ progenitor cells, which were undetectable in the initial iPSC cultures, reached nearly 20% of the total culture. This was greater than the relative number of progenitor cells produced from human-skin-fibroblast-derived iPSCs (hFib-iPSCs) or from the spontaneous differentiation groups (P<0.05), as assessed by flow cytometry analysis. These induced cells expressed hematopoietic transcription factors TAL-1 and GATA-2 [corrected]. They developed into various hematopoietic colonies when exposed to semisolid media with hematopoietic cytokines such as EPO and G-CSF. Hematopoietic cell lineages were identified by phenotype analysis with Wright-Giemsa staining. The endothelial potential of the cells was also verified by the confirmation of the formation of vascular tube-like structures and the expression of endothelial specific markers CD31 and VE-CADHERIN. Efficient induction of CD34+ progenitor cells, which retain hematopoietic and endothelial cell potential with defined factors, provides an opportunity to obtain patient-specific cells for iPSC therapy and a useful model for the study of the mechanisms of hematopoiesis and drug screening. PMID- 22496790 TI - Systematic identification of spontaneous preterm birth-associated RNA transcripts in maternal plasma. AB - BACKGROUND: Spontaneous preterm birth (SPB, before 37 gestational weeks) is a major cause of perinatal mortality and morbidity, but its pathogenesis remains unclear. Studies on SPB have been hampered by the limited availability of markers for SPB in predelivery clinical samples that can be easily compared with gestational age-matched normal controls. We hypothesize that SPB involves aberrant placental RNA expression, and that such RNA transcripts can be detected in predelivery maternal plasma samples, which can be compared with gestational age-matched controls. PRINCIPAL FINDINGS: Using gene expression microarray to profile essentially all human genes, we observed that 426 probe signals were changed by >2.9-fold in the SPB placentas, compared with the spontaneous term birth (STB) placentas. Among the genes represented by those probes, we observed an over-representation of functions in RNA stabilization, extracellular matrix binding, and acute inflammatory response. Using RT-quantitative PCR, we observed differences in the RNA concentrations of certain genes only between the SPB and STB placentas, but not between the STB and term elective cesarean delivery placentas. Notably, 36 RNA transcripts were observed at placental microarray signals higher than a threshold, which indicated the possibility of their detection in maternal plasma. Among them, the IL1RL1 mRNA was tested in plasma samples taken from 37 women. It was detected in 6 of 10 (60%) plasma samples collected during the presentation of preterm labor (<=32.9 weeks) in women eventually giving SPB, but was detected in only 1 of 27 (4%) samples collected during matched gestational weeks from women with no preterm labor (Fisher exact test, p = 0.00056). CONCLUSION: We have identified 36 SPB-associated RNA transcripts, which are possibly detectable in maternal plasma. We have illustrated that the IL1RL1 mRNA was more frequently detected in predelivery maternal plasma samples collected from women resulting in SPB than the gestational-age matched controls. PMID- 22496791 TI - A full suite of histone and histone modifying genes are transcribed in the dinoflagellate Lingulodinium. AB - BACKGROUND: Dinoflagellates typically lack histones and nucleosomes are not observed in DNA spreads. However, recent studies have shown the presence of core histone mRNA sequences scattered among different dinoflagellate species. To date, the presence of all components required for manufacturing and modifying nucleosomes in a single dinoflagellate species has not been confirmed. METHODOLOGY AND RESULTS: Analysis of a Lingulodinium transcriptome obtained by Illumina sequencing of mRNA shows several different copies of each of the four core histones as well as a suite of histone modifying enzymes and histone chaperone proteins. Phylogenetic analysis shows one of each Lingulodinium histone copies belongs to the dinoflagellate clade while the second is more divergent and does not share a common ancestor. All histone mRNAs are in low abundance (roughly 25 times lower than higher plants) and transcript levels do not vary over the cell cycle. We also tested Lingulodinium extracts for histone proteins using immunoblotting and LC-MS/MS, but were unable to confirm histone expression at the protein level. CONCLUSION: We show that all core histone sequences are present in the Lingulodinium transcriptome. The conservation of these sequences, even though histone protein accumulation remains below currently detectable levels, strongly suggests dinoflagellates possess histones. PMID- 22496794 TI - Nano-tubular cellulose for bioprocess technology development. AB - Delignified cellulosic material has shown a significant promotional effect on the alcoholic fermentation as yeast immobilization support. However, its potential for further biotechnological development is unexploited. This study reports the characterization of this tubular/porous cellulosic material, which was done by SEM, porosimetry and X-ray powder diffractometry. The results showed that the structure of nano-tubular cellulose (NC) justifies its suitability for use in "cold pasteurization" processes and its promoting activity in bioprocessing (fermentation). The last was explained by a glucose pump theory. Also, it was demonstrated that crystallization of viscous invert sugar solutions during freeze drying could not be otherwise achieved unless NC was present. This effect as well as the feasibility of extremely low temperature fermentation are due to reduction of the activation energy, and have facilitated the development of technologies such as wine fermentations at home scale (in a domestic refrigerator). Moreover, NC may lead to new perspectives in research such as the development of new composites, templates for cylindrical nano-particles, etc. PMID- 22496793 TI - An unexpected function of the Prader-Willi syndrome imprinting center in maternal imprinting in mice. AB - Genomic imprinting is a phenomenon that some genes are expressed differentially according to the parent of origin. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurobehavioral disorders caused by deficiency of imprinted gene expression from paternal and maternal chromosome 15q11-q13, respectively. Imprinted genes at the PWS/AS domain are regulated through a bipartite imprinting center, the PWS-IC and AS-IC. The PWS-IC activates paternal-specific gene expression and is responsible for the paternal imprint, whereas the AS-IC functions in the maternal imprint by allele-specific repression of the PWS-IC to prevent the paternal imprinting program. Although mouse chromosome 7C has a conserved PWS/AS imprinted domain, the mouse equivalent of the human AS-IC element has not yet been identified. Here, we suggest another dimension that the PWS-IC also functions in maternal imprinting by negatively regulating the paternally expressed imprinted genes in mice, in contrast to its known function as a positive regulator for paternal-specific gene expression. Using a mouse model carrying a 4.8-kb deletion at the PWS-IC, we demonstrated that maternal transmission of the PWS-IC deletion resulted in a maternal imprinting defect with activation of the paternally expressed imprinted genes and decreased expression of the maternally expressed imprinted gene on the maternal chromosome, accompanied by alteration of the maternal epigenotype toward a paternal state spread over the PWS/AS domain. The functional significance of this acquired paternal pattern of gene expression was demonstrated by the ability to complement PWS phenotypes by maternal inheritance of the PWS-IC deletion, which is in stark contrast to paternal inheritance of the PWS-IC deletion that resulted in the PWS phenotypes. Importantly, low levels of expression of the paternally expressed imprinted genes are sufficient to rescue postnatal lethality and growth retardation in two PWS mouse models. These findings open the opportunity for a novel approach to the treatment of PWS. PMID- 22496792 TI - Plakophilin-3 is required for late embryonic amphibian development, exhibiting roles in ectodermal and neural tissues. AB - The p120-catenin family has undergone a significant expansion during the evolution of vertebrates, resulting in varied functions that have yet to be discerned or fully characterized. Likewise, members of the plakophilins, a related catenin subfamily, are found throughout the cell with little known about their functions outside the desmosomal plaque. While the plakophilin-3 (Pkp3) knockout mouse resulted in skin defects, we find larger, including lethal effects following its depletion in Xenopus. Pkp3, unlike some other characterized catenins in amphibians, does not have significant maternal deposits of mRNA. However, during embryogenesis, two Pkp3 protein products whose temporal expression is partially complimentary become expressed. Only the smaller of these products is found in adult Xenopus tissues, with an expression pattern exhibiting distinctions as well as overlaps with those observed in mammalian studies. We determined that Xenopus Pkp3 depletion causes a skin fragility phenotype in keeping with the mouse knockout, but more novel, Xenopus tailbud embryos are hyposensitive to touch even in embryos lacking outward discernable phenotypes, and we additionally resolved disruptions in certain peripheral neural structures, altered establishment and migration of neural crest, and defects in ectodermal multiciliated cells. The use of two distinct morpholinos, as well as rescue approaches, indicated the specificity of these effects. Our results point to the requirement of Pkp3 in amphibian embryogenesis, with functional roles in a number of tissue types. PMID- 22496795 TI - A heuristic solution of the identifiability problem of the age-period-cohort analysis of cancer occurrence: lung cancer example. AB - BACKGROUND: The Age-Period-Cohort (APC) analysis is aimed at estimating the following effects on disease incidence: (i) the age of the subject at the time of disease diagnosis; (ii) the time period, when the disease occurred; and (iii) the date of birth of the subject. These effects can help in evaluating the biological events leading to the disease, in estimating the influence of distinct risk factors on disease occurrence, and in the development of new strategies for disease prevention and treatment. METHODOLOGY/PRINCIPAL FINDINGS: We developed a novel approach for estimating the APC effects on disease incidence rates in the frame of the Log-Linear Age-Period-Cohort (LLAPC) model. Since the APC effects are linearly interdependent and cannot be uniquely estimated, solving this identifiability problem requires setting four redundant parameters within a set of unknown parameters. By setting three parameters (one of the time-period and the birth-cohort effects and the corresponding age effect) to zero, we reduced this problem to the problem of determining one redundant parameter and, used as such, the effect of the time-period adjacent to the anchored time period. By varying this identification parameter, a family of estimates of the APC effects can be obtained. Using a heuristic assumption that the differences between the adjacent birth-cohort effects are small, we developed a numerical method for determining the optimal value of the identification parameter, by which a unique set of all APC effects is determined and the identifiability problem is solved. CONCLUSIONS/SIGNIFICANCE: We tested this approach while estimating the APC effects on lung cancer occurrence in white men and women using the SEER data, collected during 1975-2004. We showed that the LLAPC models with the corresponding unique sets of the APC effects estimated by the proposed approach fit very well with the observational data. PMID- 22496796 TI - Tracking subtle stereotypes of children with trisomy 21: from facial-feature based to implicit stereotyping. AB - BACKGROUND: Stigmatization is one of the greatest obstacles to the successful integration of people with Trisomy 21 (T21 or Down syndrome), the most frequent genetic disorder associated with intellectual disability. Research on attitudes and stereotypes toward these people still focuses on explicit measures subjected to social-desirability biases, and neglects how variability in facial stigmata influences attitudes and stereotyping. METHODOLOGY/PRINCIPAL FINDINGS: The participants were 165 adults including 55 young adult students, 55 non-student adults, and 55 professional caregivers working with intellectually disabled persons. They were faced with implicit association tests (IAT), a well-known technique whereby response latency is used to capture the relative strength with which some groups of people--here photographed faces of typically developing children and children with T21--are automatically (without conscious awareness) associated with positive versus negative attributes in memory. Each participant also rated the same photographed faces (consciously accessible evaluations). We provide the first evidence that the positive bias typically found in explicit judgments of children with T21 is smaller for those whose facial features are highly characteristic of this disorder, compared to their counterparts with less distinctive features and to typically developing children. We also show that this bias can coexist with negative evaluations at the implicit level (with large effect sizes), even among professional caregivers. CONCLUSION: These findings support recent models of feature-based stereotyping, and more importantly show how crucial it is to go beyond explicit evaluations to estimate the true extent of stigmatization of intellectually disabled people. PMID- 22496797 TI - Host immune transcriptional profiles reflect the variability in clinical disease manifestations in patients with Staphylococcus aureus infections. AB - Staphylococcus aureus infections are associated with diverse clinical manifestations leading to significant morbidity and mortality. To define the role of the host response in the clinical manifestations of the disease, we characterized whole blood transcriptional profiles of children hospitalized with community-acquired S. aureus infection and phenotyped the bacterial strains isolated. The overall transcriptional response to S. aureus infection was characterized by over-expression of innate immunity and hematopoiesis related genes and under-expression of genes related to adaptive immunity. We assessed individual profiles using modular fingerprints combined with the molecular distance to health (MDTH), a numerical score of transcriptional perturbation as compared to healthy controls. We observed significant heterogeneity in the host signatures and MDTH, as they were influenced by the type of clinical presentation, the extent of bacterial dissemination, and time of blood sampling in the course of the infection, but not by the bacterial isolate. System analysis approaches provide a new understanding of disease pathogenesis and the relation/interaction between host response and clinical disease manifestations. PMID- 22496798 TI - Identification of new hematopoietic cell subsets with a polyclonal antibody library specific for neglected proteins. AB - The identification of new markers, the expression of which defines new phenotipically and functionally distinct cell subsets, is a main objective in cell biology. We have addressed the issue of identifying new cell specific markers with a reverse proteomic approach whereby approximately 1700 human open reading frames encoding proteins predicted to be transmembrane or secreted have been selected in silico for being poorly known, cloned and expressed in bacteria. These proteins have been purified and used to immunize mice with the aim of obtaining polyclonal antisera mostly specific for linear epitopes. Such a library, made of about 1600 different polyclonal antisera, has been obtained and screened by flow cytometry on cord blood derived CD34+CD45dim cells and on peripheral blood derived mature lymphocytes (PBLs). We identified three new proteins expressed by fractions of CD34+CD45dim cells and eight new proteins expressed by fractions of PBLs. Remarkably, we identified proteins the presence of which had not been demonstrated previously by transcriptomic analysis. From the functional point of view, looking at new proteins expressed on CD34+CD45dim cells, we identified one cell surface protein (MOSC-1) the expression of which on a minority of CD34+ progenitors marks those CD34+CD45dim cells that will go toward monocyte/granulocyte differentiation. In conclusion, we show a new way of looking at the membranome by assessing expression of generally neglected proteins with a library of polyclonal antisera, and in so doing we have identified new potential subsets of hematopoietic progenitors and of mature PBLs. PMID- 22496799 TI - Propofol-induced changes in neurotrophic signaling in the developing nervous system in vivo. AB - Several studies have revealed a role for neurotrophins in anesthesia-induced neurotoxicity in the developing brain. In this study we monitored the spatial and temporal expression of neurotrophic signaling molecules in the brain of 14-day old (PND14) Wistar rats after the application of a single propofol dose (25 mg/kg i.p). The structures of interest were the cortex and thalamus as the primary areas of anesthetic actions. Changes of the protein levels of the brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), their activated receptors tropomyosin-related kinase (TrkA and TrkB) and downstream kinases Akt and the extracellular signal regulated kinase (ERK) were assessed by Western immunoblot analysis at different time points during the first 24 h after the treatment, as well as the expression of cleaved caspase-3 fragment. Fluoro-Jade B staining was used to follow the appearance of degenerating neurons. The obtained results show that the treatment caused marked alterations in levels of the examined neurotrophins, their receptors and downstream effector kinases. However, these changes were not associated with increased neurodegeneration in either the cortex or the thalamus. These results indicate that in the brain of PND14 rats, the interaction between Akt/ERK signaling might be one of important part of endogenous defense mechanisms, which the developing brain utilizes to protect itself from potential anesthesia-induced damage. Elucidation of the underlying molecular mechanisms will improve our understanding of the age-dependent component of anesthesia-induced neurotoxicity. PMID- 22496801 TI - A metapopulation model of tuberculosis transmission with a case study from high to low burden areas. AB - Tuberculosis (TB) is a growing problem worldwide, especially with the emergence and high prevalence of multidrug-resistant strains. We develop a metapopulation model for TB spread, which is particularly suited to investigating transmission between areas of high and low prevalence. A case study of cross-border transmission in the Torres Strait region of Australia and Papua New Guinea (PNG) is considered and a sensitivity analysis is conducted. We find that only 6 of the 50 parameters analysed are important to the cumulative number of clinically active TB patients in the entire region. Of these, only the detection rate in PNG is found to be an important intervention parameter. We therefore give insight into the extent the area with the high burden of TB (PNG in the case study) is dominating the TB dynamics of the entire region. Furthermore, the sensitivity analysis results give insight into the data that most important to collect and refine, which is found to be data relating to the PNG parameters. PMID- 22496800 TI - Transcriptional regulator PerA influences biofilm-associated, platelet binding, and metabolic gene expression in Enterococcus faecalis. AB - Enterococcus faecalis is an opportunistic pathogen and a leading cause of nosocomial infections, traits facilitated by the ability to quickly acquire and transfer virulence determinants. A 150 kb pathogenicity island (PAI) comprised of genes contributing to virulence is found in many enterococcal isolates and is known to undergo horizontal transfer. We have shown that the PAI-encoded transcriptional regulator PerA contributes to pathogenicity in the mouse peritonitis infection model. In this study, we used whole-genome microarrays to determine the PerA regulon. The PerA regulon is extensive, as transcriptional analysis showed 151 differentially regulated genes. Our findings reveal that PerA coordinately regulates genes important for metabolism, amino acid degradation, and pathogenicity. Further transcriptional analysis revealed that PerA is influenced by bicarbonate. Additionally, PerA influences the ability of E. faecalis to bind to human platelets. Our results suggest that PerA is a global transcriptional regulator that coordinately regulates genes responsible for enterococcal pathogenicity. PMID- 22496802 TI - A non-VH1-69 heterosubtypic neutralizing human monoclonal antibody protects mice against H1N1 and H5N1 viruses. AB - Influenza viruses are among the most important human pathogens and are responsible for annual epidemics and sporadic, potentially devastating pandemics. The humoral immune response plays an important role in the defense against these viruses, providing protection mainly by producing antibodies directed against the hemagglutinin (HA) glycoprotein. However, their high genetic variability allows the virus to evade the host immune response and the potential protection offered by seasonal vaccines. The emergence of resistance to antiviral drugs in recent years further limits the options available for the control of influenza. The development of alternative strategies for influenza prophylaxis and therapy is therefore urgently needed. In this study, we describe a human monoclonal antibody (PN-SIA49) that recognizes a highly conserved epitope located on the stem region of the HA and able to neutralize a broad spectrum of influenza viruses belonging to different subtypes (H1, H2 and H5). Furthermore, we describe its protective activity in mice after lethal challenge with H1N1 and H5N1 viruses suggesting a potential application in the treatment of influenza virus infections. PMID- 22496803 TI - Analysis of polymorphisms and haplotype structure of the human thymidylate synthase genetic region: a tool for pharmacogenetic studies. AB - 5-Fluorouracil (5FU), a widely used chemotherapeutic drug, inhibits the DNA replicative enzyme, thymidylate synthase (Tyms). Prior studies implicated a VNTR (variable numbers of tandem repeats) polymorphism in the 5'-untranslated region (5'-UTR) of the TYMS gene as a determinant of Tyms expression in tumors and normal tissues and proposed that these VNTR genotypes could help decide fluoropyrimidine dosing. Clinical associations between 5FU-related toxicity and the TYMS VNTR were reported, however, results were inconsistent, suggesting that additional genetic variation in the TYMS gene might influence Tyms expression. We thus conducted a detailed genetic analysis of this region, defining new polymorphisms in this gene including mononucleotide (poly A:T) repeats and novel single nucleotide polymorphisms (SNPs) flanking the VNTR in the TYMS genetic region. Our haplotype analysis of this region used data from both established and novel genetic variants and found nine SNP haplotypes accounting for more than 90% of the studied population. We observed non-exclusive relationships between the VNTR and adjacent SNP haplotypes, such that each type of VNTR commonly occurred on several haplotype backgrounds. Our results confirmed the expectation that the VNTR alleles exhibit homoplasy and lack the common ancestry required for a reliable marker of a linked adjacent locus that might govern toxicity. We propose that it may be necessary in a clinical trial to assay multiple types of genetic polymorphisms in the TYMS region to meaningfully model linkage of genetic markers to 5FU-related toxicity. The presence of multiple long (up to 26 nt), polymorphic monothymidine repeats in the promoter region of the sole human thymidylate synthetic enzyme is intriguing. PMID- 22496804 TI - GABAergic transmission and chloride equilibrium potential are not modulated by pyruvate in the developing optic tectum of Xenopus laevis tadpoles. AB - In the developing mammalian brain, gamma-aminobutyric acid (GABA) is thought to play an excitatory rather than an inhibitory role due to high levels of intracellular Cl(-) in immature neurons. This idea, however, has been questioned by recent studies which suggest that glucose-based artificial cerebrospinal fluid (ACSF) may be inadequate for experiments on immature and developing brains. These studies suggest that immature neurons may require alternative energy sources, such as lactate or pyruvate. Lack of these other energy sources is thought to result in artificially high intracellular Cl(-) concentrations, and therefore a more depolarized GABA receptor (GABAR) reversal potential. Since glucose metabolism can vary widely among different species, it is important to test the effects of these alternative energy sources on different experimental preparations. We tested whether pyruvate affects GABAergic transmission in isolated brains of developing wild type Xenopus tadpoles in vitro by recording the responsiveness of tectal neurons to optic nerve stimulation, and by measuring currents evoked by local GABA application in a gramicidin perforated patch configuration. We found that, in contrast with previously reported results, the reversal potential for GABAR-mediated currents does not change significantly between developmental stages 45 and 49. Partial substitution of glucose by pyruvate had only minor effects on both the GABA reversal potential, and the responsiveness of tectal neurons at stages 45 and 49. Total depletion of energy sources from the ACSF did not affect neural responsiveness. We also report a strong spatial gradient in GABA reversal potential, with immature cells adjacent to the lateral and caudal proliferative zones having more positive reversal potentials. We conclude that in this experimental preparation standard glucose based ACSF is an appropriate extracellular media for in vitro experiments. PMID- 22496806 TI - Burning in banksia woodlands: how does the fire-free period influence reptile communities? AB - Fire is an important management tool for both hazard reduction burning and maintenance of biodiversity. The impact of time since last fire on fauna is an important factor to understand as land managers often aim for prescribed burning regimes with specific fire-free intervals. However, our current understanding of the impact of time since last fire on fauna is largely unknown and likely dependent on vegetation type. We examined the responses of reptiles to fire age in banksia woodlands, and the interspersed melaleuca damplands among them, north of Perth, Western Australia, where the current prescribed burning regime is targeting a fire-free period of 8-12 years. The response of reptiles to fire was dependent on vegetation type. Reptiles were generally more abundant (e.g. Lerista elegans and Ctenophorus adelaidensis) and specious in banksia sites. Several species (e.g. Menetia greyii, Cryptoblepharus buchananii) preferred long unburnt melaleuca sites (>16 years since last fire, YSLF) compared to recently burnt sites (<12 YSLF). Several of the small elapids (e.g. the WA priority listed species Neelaps calonotus) were only detected in older-aged banksia sites (>16 YSLF). The terrestrial dragon C. adelaidensis and the skink Morethia obscura displayed a strong response to fire in banksia woodlands only. Highest abundances of the dragon were detected in the recently burnt (<7 YSLF) and long unburnt (>35 YSLF) banksia woodlands, while the skink was more abundant in older sites. Habitats from a range of fire ages are required to support the reptiles we detected, especially the longer unburnt (>16 YSLF) melaleuca habitat. Current burning prescriptions are reducing the availability of these older habitats. PMID- 22496805 TI - Transcriptome analysis reveals strain-specific and conserved stemness genes in Schmidtea mediterranea. AB - The planarian Schmidtea mediterranea is a powerful model organism for studying stem cell biology due to its extraordinary regenerative ability mediated by neoblasts, a population of adult somatic stem cells. Elucidation of the S. mediterranea transcriptome and the dynamics of transcript expression will increase our understanding of the gene regulatory programs that regulate stem cell function and differentiation. Here, we have used RNA-Seq to characterize the S. mediterranea transcriptome in sexual and asexual animals and in purified neoblast and differentiated cell populations. Our analysis identified many uncharacterized genes, transcripts, and alternatively spliced isoforms that are differentially expressed in a strain or cell type-specific manner. Transcriptome profiling of purified neoblasts and differentiated cells identified neoblast enriched transcripts, many of which likely play important roles in regeneration and stem cell function. Strikingly, many of the neoblast-enriched genes are orthologs of genes whose expression is enriched in human embryonic stem cells, suggesting that a core set of genes that regulate stem cell function are conserved across metazoan species. PMID- 22496807 TI - Differentiation of schizophrenia patients from healthy subjects by mismatch negativity and neuropsychological tests. AB - BACKGROUND: Schizophrenia is a heterogeneous disorder with diverse presentations. The current and the proposed DSM-V diagnostic system remains phenomenologically based, despite the fact that several neurobiological and neuropsychological markers have been identified. A multivariate approach has better diagnostic utility than a single marker method. In this study, the mismatch negativity (MMN) deficit of schizophrenia was first replicated in a Han Chinese population, and then the MMN was combined with several neuropsychological measurements to differentiate schizophrenia patients from healthy subjects. METHODOLOGY/PRINCIPAL FINDINGS: 120 schizophrenia patients and 76 healthy controls were recruited. Each subject received examinations for duration MMN, Continuous Performance Test, Wisconsin Card Sorting Test, and Wechsler Adult Intelligence Scale Third Edition (WAIS-III). The MMN was compared between cases and controls, and important covariates were investigated. Schizophrenia patients had significantly reduced MMN amplitudes, and MMN decreased with increasing age in both patient and control groups. None of the neuropsychological indices correlated with MMN. Predictive multivariate logistic regression models using the MMN and neuropsychological measurements as predictors were developed. Four predictors, including MMN at electrode FCz and three scores from the WAIS-III (Arithmetic, Block Design, and Performance IQ) were retained in the final predictive model. The model performed well in differentiating patients from healthy subjects (percentage of concordant pairs: 90.5%). CONCLUSIONS/SIGNIFICANCE: MMN deficits were found in Han Chinese schizophrenia patients. The multivariate approach combining biomarkers from different modalities such as electrophysiology and neuropsychology had a better diagnostic utility. PMID- 22496808 TI - Talin contains a C-terminal calpain2 cleavage site important in focal adhesion dynamics. AB - Talin is a large (~2540 residues) dimeric adaptor protein that associates with the integrin family of cell adhesion molecules in cell-extracellular matrix junctions (focal adhesions; FAs), where it both activates integrins and couples them to the actin cytoskeleton. Calpain2-mediated cleavage of talin between the head and rod domains has previously been shown to be important in FA turnover. Here we identify an additional calpain2-cleavage site that removes the dimerisation domain from the C-terminus of the talin rod, and show that an E2492G mutation inhibits calpain cleavage at this site in vitro, and increases the steady state levels of talin1 in vivo. Expression of a GFP-tagged talin1 E2492G mutant in CHO.K1 cells inhibited FA turnover and the persistence of cell protrusion just as effectively as a L432G mutation that inhibits calpain cleavage between the talin head and rod domains. Moreover, incorporation of both mutations into a single talin molecule had an additive effect clearly demonstrating that calpain cleavage at both the N- and C-terminal regions of talin contribute to the regulation of FA dynamics. However, the N-terminal site was more sensitive to calpain cleavage suggesting that lower levels of calpain are required to liberate the talin head and rod fragments than are needed to clip off the C-terminal dimerisation domain. The talin head and rod liberated by calpain2 cleavage have recently been shown to play roles in an integrin activation cycle important in FA turnover and in FAK-dependent cell cycle progression respectively. The half-life of the talin head is tightly regulated by ubiquitination and we suggest that removal of the C-terminal dimerisation domain from the talin rod may provide a mechanism both for terminating the signalling function of the talin rod and indeed for inactivating full-length talin thereby promoting FA turnover at the rear of the cell. PMID- 22496809 TI - Circadian behaviour in neuroglobin deficient mice. AB - Neuroglobin (Ngb), a neuron-specific oxygen-binding globin with an unknown function, has been proposed to play a key role in neuronal survival. We have previously shown Ngb to be highly expressed in the rat suprachiasmatic nucleus (SCN). The present study addresses the effect of Ngb deficiency on circadian behavior. Ngb-deficient and wild-type (wt) mice were placed in running wheels and their activity rhythms, endogenous period and response to light stimuli were investigated. The effect of Ngb deficiency on the expression of Period1 (Per1) and the immediate early gene Fos was determined after light stimulation at night and the neurochemical phenotype of Ngb expressing neurons in wt mice was characterized. Loss of Ngb function had no effect on overall circadian entrainment, but resulted in a significantly larger phase delay of circadian rhythm upon light stimulation at early night. A light-induced increase in Per1, but not Fos, gene expression was observed in Ngb-deficient mice. Ngb expressing neurons which co-stored Gastrin Releasing Peptide (GRP) and were innervated from the eye and the geniculo-hypothalamic tract expressed FOS after light stimulation. No PER1 expression was observed in Ngb-positive neurons. The present study demonstrates for the first time that the genetic elimination of Ngb does not affect core clock function but evokes an increased behavioural response to light concomitant with increased Per1 gene expression in the SCN at early night. PMID- 22496810 TI - Investigation of mitochondrial dysfunction by sequential microplate-based respiration measurements from intact and permeabilized neurons. AB - Mitochondrial dysfunction is a component of many neurodegenerative conditions. Measurement of oxygen consumption from intact neurons enables evaluation of mitochondrial bioenergetics under conditions that are more physiologically realistic compared to isolated mitochondria. However, mechanistic analysis of mitochondrial function in cells is complicated by changing energy demands and lack of substrate control. Here we describe a technique for sequentially measuring respiration from intact and saponin-permeabilized cortical neurons on single microplates. This technique allows control of substrates to individual electron transport chain complexes following permeabilization, as well as side-by side comparisons to intact cells. To illustrate the utility of the technique, we demonstrate that inhibition of respiration by the drug KB-R7943 in intact neurons is relieved by delivery of the complex II substrate succinate, but not by complex I substrates, via acute saponin permeabilization. In contrast, methyl succinate, a putative cell permeable complex II substrate, failed to rescue respiration in intact neurons and was a poor complex II substrate in permeabilized cells. Sequential measurements of intact and permeabilized cell respiration should be particularly useful for evaluating indirect mitochondrial toxicity due to drugs or cellular signaling events which cannot be readily studied using isolated mitochondria. PMID- 22496811 TI - A multi-stage model for fundamental functional properties in primary visual cortex. AB - Many neurons in mammalian primary visual cortex have properties such as sharp tuning for contour orientation, strong selectivity for motion direction, and insensitivity to stimulus polarity, that are not shared with their sub-cortical counterparts. Successful models have been developed for a number of these properties but in one case, direction selectivity, there is no consensus about underlying mechanisms. We here define a model that accounts for many of the empirical observations concerning direction selectivity. The model describes a single column of cat primary visual cortex and comprises a series of processing stages. Each neuron in the first cortical stage receives input from a small number of on-centre and off-centre relay cells in the lateral geniculate nucleus. Consistent with recent physiological evidence, the off-centre inputs to cortex precede the on-centre inputs by a small (~4 ms) interval, and it is this difference that confers direction selectivity on model neurons. We show that the resulting model successfully matches the following empirical data: the proportion of cells that are direction selective; tilted spatiotemporal receptive fields; phase advance in the response to a stationary contrast-reversing grating stepped across the receptive field. The model also accounts for several other fundamental properties. Receptive fields have elongated subregions, orientation selectivity is strong, and the distribution of orientation tuning bandwidth across neurons is similar to that seen in the laboratory. Finally, neurons in the first stage have properties corresponding to simple cells, and more complex-like cells emerge in later stages. The results therefore show that a simple feed-forward model can account for a number of the fundamental properties of primary visual cortex. PMID- 22496812 TI - Dual anti-OX40/IL-2 therapy augments tumor immunotherapy via IL-2R-mediated regulation of OX40 expression. AB - The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of OX40 can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, OX40 agonists are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressed on naive T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, the downstream signals that regulate OX40 itself remain unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3 mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2 augmented tumor immunotherapy against multiple tumor types. Dual therapy was also able to restore the function of anergic tumor-reactive CD8 T cells in mice with long-term well-established (>5 wks) tumors, leading to increased survival of the tumor bearing hosts. Together, these data reveal the ability of TCR/common gamma chain cytokine signaling to regulate OX40 expression and demonstrate a novel means of augmenting cancer immunotherapy by providing dual anti-OX40/common gamma chain cytokine-directed therapy. PMID- 22496813 TI - Activation of c-Jun N-terminal kinase (JNK) during mitosis in retinal progenitor cells. AB - Most studies of c-Jun N-terminal Kinase (JNK) activation in retinal tissue were done in the context of neurodegeneration. In this study, we investigated the behavior of JNK during mitosis of progenitor cells in the retina of newborn rats. Retinal explants from newborn rats were kept in vitro for 3 hours and under distinct treatments. Sections of retinal explants or freshly fixed retinal tissue were used to detect JNK phosphorylation by immunohistochemistry, and were examined through both fluorescence and confocal microscopy. Mitotic cells were identified by chromatin morphology, histone-H3 phosphorylation, and location in the retinal tissue. The subcellular localization of proteins was analyzed by double staining with both a DNA marker and an antibody to each protein. Phosphorylation of JNK was also examined by western blot. The results showed that in the retina of newborn rats (P1), JNK is phosphorylated during mitosis of progenitor cells, mainly during the early stages of mitosis. JNK1 and/or JNK2 were preferentially phosphorylated in mitotic cells. Inhibition of JNK induced cell cycle arrest, specifically in mitosis. Treatment with the JNK inhibitor decreased the number of cells in anaphase, but did not alter the number of cells in either prophase/prometaphase or metaphase. Moreover, cells with aberrant chromatin morphology were found after treatment with the JNK inhibitor. The data show, for the first time, that JNK is activated in mitotic progenitor cells of developing retinal tissue, suggesting a new role of JNK in the control of progenitor cell proliferation in the retina. PMID- 22496814 TI - The impact of imputation on meta-analysis of genome-wide association studies. AB - Genotype imputation is often used in the meta-analysis of genome-wide association studies (GWAS), for combining data from different studies and/or genotyping platforms, in order to improve the ability for detecting disease variants with small to moderate effects. However, how genotype imputation affects the performance of the meta-analysis of GWAS is largely unknown. In this study, we investigated the effects of genotype imputation on the performance of meta analysis through simulations based on empirical data from the Framingham Heart Study. We found that when fix-effects models were used, considerable between study heterogeneity was detected when causal variants were typed in only some but not all individual studies, resulting in up to ~25% reduction of detection power. For certain situations, the power of the meta-analysis can be even less than that of individual studies. Additional analyses showed that the detection power was slightly improved when between-study heterogeneity was partially controlled through the random-effects model, relative to that of the fixed-effects model. Our study may aid in the planning, data analysis, and interpretation of GWAS meta analysis results when genotype imputation is necessary. PMID- 22496815 TI - HTLV-1 Tax mediated downregulation of miRNAs associated with chromatin remodeling factors in T cells with stably integrated viral promoter. AB - RNA interference (RNAi) is a natural cellular mechanism to silence gene expression and is predominantly mediated by microRNAs (miRNAs) that target messenger RNA. Viruses can manipulate the cellular processes necessary for their replication by targeting the host RNAi machinery. This study explores the effect of human T-cell leukemia virus type 1 (HTLV-1) transactivating protein Tax on the RNAi pathway in the context of a chromosomally integrated viral long terminal repeat (LTR) using a CD4(+) T-cell line, Jurkat. Transcription factor profiling of the HTLV-1 LTR stably integrated T-cell clone transfected with Tax demonstrates increased activation of substrates and factors associated with chromatin remodeling complexes. Using a miRNA microarray and bioinformatics experimental approach, Tax was also shown to downregulate the expression of miRNAs associated with the translational regulation of factors required for chromatin remodeling. These observations were validated with selected miRNAs and an HTLV-1 infected T cells line, MT-2. miR-149 and miR-873 were found to be capable of directly targeting p300 and p/CAF, chromatin remodeling factors known to play critical role in HTLV-1 pathogenesis. Overall, these results are first in line establishing HTLV-1/Tax-miRNA-chromatin concept and open new avenues toward understanding retroviral latency and/or replication in a given cell type. PMID- 22496816 TI - Patient-specific computational modeling of upper extremity arteriovenous fistula creation: its feasibility to support clinical decision-making. AB - INTRODUCTION: Inadequate flow enhancement on the one hand, and excessive flow enhancement on the other hand, remain frequent complications of arteriovenous fistula (AVF) creation, and hamper hemodialysis therapy in patients with end stage renal disease. In an effort to reduce these, a patient-specific computational model, capable of predicting postoperative flow, has been developed. The purpose of this study was to determine the accuracy of the patient specific model and to investigate its feasibility to support decision-making in AVF surgery. METHODS: Patient-specific pulse wave propagation models were created for 25 patients awaiting AVF creation. Model input parameters were obtained from clinical measurements and literature. For every patient, a radiocephalic AVF, a brachiocephalic AVF, and a brachiobasilic AVF configuration were simulated and analyzed for their postoperative flow. The most distal configuration with a predicted flow between 400 and 1500 ml/min was considered the preferred location for AVF surgery. The suggestion of the model was compared to the choice of an experienced vascular surgeon. Furthermore, predicted flows were compared to measured postoperative flows. RESULTS: Taken into account the confidence interval (25(th) and 75(th) percentile interval), overlap between predicted and measured postoperative flows was observed in 70% of the patients. Differentiation between upper and lower arm configuration was similar in 76% of the patients, whereas discrimination between two upper arm AVF configurations was more difficult. In 3 patients the surgeon created an upper arm AVF, while model based predictions allowed for lower arm AVF creation, thereby preserving proximal vessels. In one patient early thrombosis in a radiocephalic AVF was observed which might have been indicated by the low predicted postoperative flow. CONCLUSIONS: Postoperative flow can be predicted relatively accurately for multiple AVF configurations by using computational modeling. This model may therefore be considered a valuable additional tool in the preoperative work-up of patients awaiting AVF creation. PMID- 22496817 TI - Pre-existing T- and B-cell defects in one progressive multifocal leukoencephalopathy patient. AB - Progressive multifocal leukoencephalopathy (PML) usually occurs in patients with severe immunosuppression, hematological malignancies, chronic inflammatory conditions or receiving organ transplant. Recently, PML has also been observed in patients treated with monoclonal antibodies. By taking advantage of the availability of samples from a multiple sclerosis (MS) patient treated with natalizumab, the antibody anti-alpha4 integrin, who developed PML and was monitored starting before therapy initiation, we investigated the fate of T and B lymphocytes in the onset of PML. Real-time PCR was used to measure new T- and B cell production by means of T-cell receptor excision circle (TREC) and K-deleting recombination excision circle (KREC) analysis and to quantify transcripts for CD34, terminal-deoxynucleotidyltransferase, and V pre-B lymphocyte gene 1. T- and B-cell subsets and T-cell heterogeneity were measured by flow cytometry and spectratyping. The data were compared to those of untreated and natalizumab treated MS patients and healthy donors. Before therapy, a patient who developed PML had a low TREC and KREC number; TRECs remained low, while KRECs and pre-B lymphocyte gene 1 transcripts peaked at 6 months of therapy and then decreased at PML diagnosis. Flow cytometry confirmed the deficient number of newly produced T lymphocytes, counterbalanced by an increase in TEMRA cells. The percentage of naive B cells increased by approximately 70% after 6 months of therapy, but B lymphocyte number remained low for the entire treatment period. T-cell heterogeneity and immunoglobulins were reduced. Although performed in a single patient, all results showed that an immune deficit, together with an increase in newly produced B cells a few months after therapy initiation, may predispose the patient to PML. These findings indicate the TREC/KREC assay is a potential tool to identify patients at risk of developing PML and may provide insights into the immunological involvement of monoclonal antibody-associated therapies. PMID- 22496819 TI - Mapping the knowledge structure of research on patient adherence: knowledge domain visualization based co-word analysis and social network analysis. AB - BACKGROUND: Patient adherence is an important issue for health service providers and health researchers. However, the knowledge structure of diverse research on treatment adherence is unclear. This study used co-word analysis and social network analysis techniques to analyze research literature on adherence, and to show their knowledge structure and evolution over time. METHODS: Published scientific papers about treatment adherence were retrieved from Web of Science (2000 to May 2011). A total of 2308 relevant articles were included: 788 articles published in 2000-2005 and 1520 articles published in 2006-2011. The keywords of each article were extracted by using the software Biblexcel, and the synonym and isogenous words were merged manually. The frequency of keywords and their co occurrence frequency were counted. High frequency keywords were selected to yield the co-words matrix. Finally the decomposition maps were used to comb the complex knowledge structures. RESULTS: Research themes were more general in the first period (2000 to 2005), and more extensive with many more new terms in the second period (2006 to 2011). Research on adherence has covered more and more diseases, populations and methods, but other diseases/conditions are not as hot as HIV/AIDS and have not become specialty themes/sub-directions. Most studies originated from the United States. CONCLUSION: The dynamic of this field is mainly divergent, with increasing number of new sub-directions of research. Future research is required to investigate specific directions and converge as well to construct a general paradigm in this field. PMID- 22496818 TI - The transcriptome of Lutzomyia longipalpis (Diptera: Psychodidae) male reproductive organs. AB - BACKGROUND: It has been suggested that genes involved in the reproductive biology of insect disease vectors are potential targets for future alternative methods of control. Little is known about the molecular biology of reproduction in phlebotomine sand flies and there is no information available concerning genes that are expressed in male reproductive organs of Lutzomyia longipalpis, the main vector of American visceral leishmaniasis and a species complex. METHODS/PRINCIPAL FINDINGS: We generated 2678 high quality ESTs ("Expressed Sequence Tags") of L. longipalpis male reproductive organs that were grouped in 1391 non-redundant sequences (1136 singlets and 255 clusters). BLAST analysis revealed that only 57% of these sequences share similarity with a L. longipalpis female EST database. Although no more than 36% of the non-redundant sequences showed similarity to protein sequences deposited in databases, more than half of them presented the best-match hits with mosquito genes. Gene ontology analysis identified subsets of genes involved in biological processes such as protein biosynthesis and DNA replication, which are probably associated with spermatogenesis. A number of non-redundant sequences were also identified as putative male reproductive gland proteins (mRGPs), also known as male accessory gland protein genes (Acps). CONCLUSIONS: The transcriptome analysis of L. longipalpis male reproductive organs is one step further in the study of the molecular basis of the reproductive biology of this important species complex. It has allowed the identification of genes potentially involved in spermatogenesis as well as putative mRGPs sequences, which have been studied in many insect species because of their effects on female post-mating behavior and physiology and their potential role in sexual selection and speciation. These data open a number of new avenues for further research in the molecular and evolutionary reproductive biology of sand flies. PMID- 22496820 TI - Alignment-free design of highly discriminatory diagnostic primer sets for Escherichia coli O104:H4 outbreak strains. AB - BACKGROUND: An Escherichia coli O104:H4 outbreak in Germany in summer 2011 caused 53 deaths, over 4000 individual infections across Europe, and considerable economic, social and political impact. This outbreak was the first in a position to exploit rapid, benchtop high-throughput sequencing (HTS) technologies and crowdsourced data analysis early in its investigation, establishing a new paradigm for rapid response to disease threats. We describe a novel strategy for design of diagnostic PCR primers that exploited this rapid draft bacterial genome sequencing to distinguish between E. coli O104:H4 outbreak isolates and other pathogenic E. coli isolates, including the historical haemolytic uraemic syndrome (HUSEC) E. coli HUSEC041 O104:H4 strain, which possesses the same serotype as the outbreak isolates. METHODOLOGY/PRINCIPAL FINDINGS: Primers were designed using a novel alignment-free strategy against eleven draft whole genome assemblies of E. coli O104:H4 German outbreak isolates from the E. coli O104:H4 Genome Analysis Crowd-Sourcing Consortium website, and a negative sequence set containing 69 E. coli chromosome and plasmid sequences from public databases. Validation in vitro against 21 'positive' E. coli O104:H4 outbreak and 32 'negative' non-outbreak EHEC isolates indicated that individual primer sets exhibited 100% sensitivity for outbreak isolates, with false positive rates of between 9% and 22%. A minimal combination of two primers discriminated between outbreak and non-outbreak E. coli isolates with 100% sensitivity and 100% specificity. CONCLUSIONS/SIGNIFICANCE: Draft genomes of isolates of disease outbreak bacteria enable high throughput primer design and enhanced diagnostic performance in comparison to traditional molecular assays. Future outbreak investigations will be able to harness HTS rapidly to generate draft genome sequences and diagnostic primer sets, greatly facilitating epidemiology and clinical diagnostics. We expect that high throughput primer design strategies will enable faster, more precise responses to future disease outbreaks of bacterial origin, and help to mitigate their societal impact. PMID- 22496822 TI - Assessing public engagement with science in a university primate research centre in a national zoo. AB - Recent years have seen increasing encouragement by research institutions and funding bodies for scientists to actively engage with the public, who ultimately finance their work. Animal behaviour as a discipline possesses several features, including its inherent accessibility and appeal to the public, that may help it occupy a particularly successful niche within these developments. It has also established a repertoire of quantitative behavioural methodologies that can be used to document the public's responses to engagement initiatives. This kind of assessment is becoming increasingly important considering the enormous effort now being put into public engagement projects, whose effects are more often assumed than demonstrated. Here we report our first attempts to quantify relevant aspects of the behaviour of a sample of the hundreds of thousands of visitors who pass through the 'Living Links to Human Evolution Research Centre' in Edinburgh Zoo. This University research centre actively encourages the public to view ongoing primate research and associated science engagement activities. Focal follows of visitors and scan sampling showed substantial 'dwell times' in the Centre by common zoo standards and the addition of new engagement elements in a second year was accompanied by significantly increased overall dwell times, tripling for the most committed two thirds of visitors. Larger groups of visitors were found to spend more time in the Centre than smaller ones. Viewing live, active science was the most effective activity, shown to be enhanced by novel presentations of carefully constructed explanatory materials. The findings emphasise the importance and potential of zoos as public engagement centres for the biological sciences. PMID- 22496821 TI - Age-related changes of myelin basic protein in mouse and human auditory nerve. AB - Age-related hearing loss (presbyacusis) is the most common type of hearing impairment. One of the most consistent pathological changes seen in presbyacusis is the loss of spiral ganglion neurons (SGNs). Defining the cellular and molecular basis of SGN degeneration in the human inner ear is critical to gaining a better understanding of the pathophysiology of presbyacusis. However, information on age-related cellular and molecular alterations in the human spiral ganglion remains scant, owing to the very limited availably of human specimens suitable for high resolution morphological and molecular analysis. This study aimed at defining age-related alterations in the auditory nerve in human temporal bones and determining if immunostaining for myelin basic protein (MBP) can be used as an alternative approach to electron microscopy for evaluating myelin degeneration. For comparative purposes, we evaluated ultrastructural alternations and changes in MBP immunostaining in aging CBA/CaJ mice. We then examined 13 temporal bones from 10 human donors, including 4 adults aged 38-46 years (middle aged group) and 6 adults aged 63-91 years (older group). Similar to the mouse, intense immunostaining of MBP was present throughout the auditory nerve of the middle-aged human donors. Significant declines in MBP immunoreactivity and losses of MBP(+) auditory nerve fibers were observed in the spiral ganglia of both the older human and aged mouse ears. This study demonstrates that immunostaining for MBP in combination with confocal microscopy provides a sensitive, reliable, and efficient method for assessing alterations of myelin sheaths in the auditory nerve. The results also suggest that myelin degeneration may play a critical role in the SGN loss and the subsequent decline of the auditory nerve function in presbyacusis. PMID- 22496823 TI - F-actin-dependent regulation of NESH dynamics in rat hippocampal neurons. AB - Synaptic plasticity is an important feature of neurons essential for learning and memory. Postsynaptic organization and composition are dynamically remodeled in response to diverse synaptic inputs during synaptic plasticity. During this process, the dynamics and localization of postsynaptic proteins are also precisely regulated. NESH/Abi-3 is a member of the Abl interactor (Abi) protein family. Overexpression of NESH is associated with reduced cell motility and tumor metastasis. Strong evidence of a close relationship between NESH and the actin cytoskeleton has been documented. Although earlier studies have shown that NESH is prominently expressed in the brain, its function and characteristics are yet to be established. Data from the present investigation suggest that synaptic localization of NESH in hippocampal neurons is regulated in an F-actin-dependent manner. The dynamic fraction of NESH in the dendritic spine was analyzed using FRAP (fluorescence recovery after photobleaching). Interestingly, F-actin stabilization and disruption significantly affected the mobile fraction of NESH, possibly through altered interactions of NESH with the F-actin. In addition, NESH was synaptically targeted from the dendritic shaft to spine after induction of chemical LTP (long-term potentiation) and the translocation was dependent on F actin. Our data collectively support the significance of the F-actin cytoskeleton in synaptic targeting of NESH as well as its dynamics. PMID- 22496824 TI - A gestational high protein diet affects the abundance of muscle transcripts related to cell cycle regulation throughout development in porcine progeny. AB - BACKGROUND: In various animal models pregnancy diets have been shown to affect offspring phenotype. Indeed, the underlying programming of development is associated with modulations in birth weight, body composition, and continual diet dependent modifications of offspring metabolism until adulthood, producing the hypothesis that the offspring's transcriptome is permanently altered depending on maternal diet. METHODOLOGY/PRINCIPAL FINDINGS: To assess alterations of the offspring's transcriptome due to gestational protein supply, German Landrace sows were fed isoenergetic diets containing protein levels of either 30% (high protein -HP) or 12% (adequate protein--AP) throughout their pregnancy. Offspring muscle tissue (M. longissimus dorsi) was collected at 94 days post conception (dpc), and 1, 28, and 188 days post natum (dpn) for use with Affymetrix GeneChip Porcine Genome Arrays and subsequent statistical and Ingenuity pathway analyses. Numerous transcripts were found to have altered abundance at 94 dpc and 1 dpn; at 28 dpn no transcripts were altered, and at 188 dpn only a few transcripts showed a different abundance between diet groups. However, when assessing transcriptional changes across developmental time points, marked differences were obvious among the dietary groups. Depending on the gestational dietary exposure, short- and long-term effects were observed for mRNA expression of genes related to cell cycle regulation, energy metabolism, growth factor signaling pathways, and nucleic acid metabolism. In particular, the abundance of transcripts related to cell cycle remained divergent among the groups during development. CONCLUSION: Expression analysis indicates that maternal protein supply induced programming of the offspring's genome; early postnatal compensation of the slight growth retardation obvious at birth in HP piglets resulted, as did a permanently different developmental alteration and responsiveness to the common environment of the transcriptome. The transcriptome modulations are interpreted as the molecular equivalent of developmental plasticity of the offspring that necessitates adaptation and maintenance of the organismal phenotype. PMID- 22496825 TI - Dysfunction of organic anion transporting polypeptide 1a1 alters intestinal bacteria and bile acid metabolism in mice. AB - Organic anion transporting polypeptide 1a1 (Oatp1a1) is predominantly expressed in liver and is able to transport bile acids (BAs) in vitro. Male Oatp1a1-null mice have increased concentrations of taurodeoxycholic acid (TDCA), a secondary BA generated by intestinal bacteria, in both serum and livers. Therefore, in the present study, BA concentrations and intestinal bacteria in wild-type (WT) and Oatp1a1-null mice were quantified to investigate whether the increase of secondary BAs in Oatp1a1-null mice is due to alterations in intestinal bacteria. The data demonstrate that Oatp1a1-null mice : (1) have similar bile flow and BA concentrations in bile as WT mice; (2) have a markedly different BA composition in the intestinal contents, with a decrease in conjugated BAs and an increase in unconjugated BAs; (3) have BAs in the feces that are more deconjugated, desulfated, 7-dehydroxylated, 3-epimerized, and oxidized, but less 7-epimerized; (4) have 10-fold more bacteria in the small intestine, and 2-fold more bacteria in the large intestine which is majorly due to a 200% increase in Bacteroides and a 30% reduction in Firmicutes; and (5) have a different urinary excretion of bacteria-related metabolites than WT mice. In conclusion, the present study for the first time established that lack of a liver transporter (Oatp1a1) markedly alters the intestinal environment in mice, namely the bacteria composition. PMID- 22496827 TI - Stable isotope analysis provides new information on winter habitat use of declining avian migrants that is relevant to their conservation. AB - Winter habitat use and the magnitude of migratory connectivity are important parameters when assessing drivers of the marked declines in avian migrants. Such information is unavailable for most species. We use a stable isotope approach to assess these factors for three declining African-Eurasian migrants whose winter ecology is poorly known: wood warbler Phylloscopus sibilatrix, house martin Delichon urbicum and common swift Apus apus. Spatially segregated breeding wood warbler populations (sampled across a 800 km transect), house martins and common swifts (sampled across a 3,500 km transect) exhibited statistically identical intra-specific carbon and nitrogen isotope ratios in winter grown feathers. Such patterns are compatible with a high degree of migratory connectivity, but could arise if species use isotopically similar resources at different locations. Wood warbler carbon isotope ratios are more depleted than typical for African-Eurasian migrants and are compatible with use of moist lowland forest. The very limited variance in these ratios indicates specialisation on isotopically restricted resources, which may drive the similarity in wood warbler populations' stable isotope ratios and increase susceptibility to environmental change within its wintering grounds. House martins were previously considered to primarily use moist montane forest during the winter, but this seems unlikely given the enriched nature of their carbon isotope ratios. House martins use a narrower isotopic range of resources than the common swift, indicative of increased specialisation or a relatively limited wintering range; both factors could increase house martins' vulnerability to environmental change. The marked variance in isotope ratios within each common swift population contributes to the lack of population specific signatures and indicates that the species is less vulnerable to environmental change in sub-Saharan Africa than our other focal species. Our findings demonstrate how stable isotope research can contribute to understanding avian migrants' winter ecology and conservation status. PMID- 22496826 TI - Differential expression of melanopsin isoforms Opn4L and Opn4S during postnatal development of the mouse retina. AB - Photosensitive retinal ganglion cells (pRGCs) respond to light from birth and represent the earliest known light detection system to develop in the mouse retina. A number of morphologically and functionally distinct subtypes of pRGCs have been described in the adult retina, and have been linked to different physiological roles. We have previously identified two distinct isoforms of mouse melanopsin, Opn4L and Opn4S, which are generated by alternate splicing of the Opn4 locus. These isoforms are differentially expressed in pRGC subtypes of the adult mouse retina, with both Opn4L and Opn4S detected in M1 type pRGCs, and only Opn4L detected in M2 type pRGCs. Here we investigate the developmental expression of Opn4L and Opn4S and show a differential profile of expression during postnatal development. Opn4S mRNA is detected at relatively constant levels throughout postnatal development, with levels of Opn4S protein showing a marked increase between P0 and P3, and then increasing progressively over time until adult levels are reached by P10. By contrast, levels of Opn4L mRNA and protein are low at birth and show a marked increase at P14 and P30 compared to earlier time points. We suggest that these differing profiles of expression are associated with the functional maturation of M1 and M2 subtypes of pRGCs. Based upon our data, Opn4S expressing M1 type pRGCs mature first and are the dominant pRGC subtype in the neonate retina, whereas increased expression of Opn4L and the maturation of M2 type pRGCs occurs later, between P10 and P14, at a similar time to the maturation of rod and cone photoreceptors. We suggest that the distinct functions associated with these cell types will develop at different times during postnatal development. PMID- 22496828 TI - Drilling predation on serpulid polychaetes (Ditrupa arietina) from the pliocene of the Cope Basin, Murcia Region, Southeastern Spain. AB - We report quantitative analyses of drilling predation on the free-living, tube dwelling serpulid polychaete Ditrupa arietina from the Cope Cabo marine succession (Pliocene, Spain). Tubes of D. arietina are abundant in the sampled units: 9 bulk samples from 5 horizons yielded ~5925 specimens of D. arietina. Except for fragmentation, tubes were well preserved. Complete specimens ranged from 3.1 to 13.4 mm in length and displayed allometric growth patterns, with larger specimens being relatively slimmer. Drilled Ditrupa tubes were observed in all samples. Drillholes, identified as Oichnus paraboloides, were characterized by circular to elliptical outline (drillhole eccentricity increased with its diameter), parabolic vertical profile, outer diameter larger than inner diameter, penetration of one tube wall only, narrow range of drill-hole sizes, and non random (anterior) distribution of drillholes. A total of 233 drilled specimens were identified, with drilling frequencies varying across horizons from 2.7% to 21% (3.9% for pooled data). Many tube fragments were broken across a drillhole suggesting that the reported frequencies are conservative and that biologically facilitated (drill-hole induced) fragmentation hampers fossil preservation of complete serpulid tubes. No failed or repaired holes were observed. Multiple complete drillholes were present (3.9%). Drilled specimens were significantly smaller than undrilled specimens and tube length and drill-hole diameter were weakly correlated. The results suggest that drillholes were produced by a size selective, site-stereotypic predatory organism of unknown affinity. The qualitative and quantitative patterns reported here are mostly consistent with previous reports on recent and fossil Ditrupa and reveal parallels with drilling patterns documented for scaphopod mollusks, a group that is ecologically and morphologically similar to Ditrupa. Consistent with previous studies, the results suggest that free-dwelling serpulid polychaetes are preyed upon by drilling predators and may provide a viable source of data on biotic interactions in the fossil record. PMID- 22496829 TI - O2-filled swimbladder employs monocarboxylate transporters for the generation of O2 by lactate-induced root effect hemoglobin. AB - The swimbladder volume is regulated by O(2) transfer between the luminal space and the blood In the swimbladder, lactic acid generation by anaerobic glycolysis in the gas gland epithelial cells and its recycling through the rete mirabile bundles of countercurrent capillaries are essential for local blood acidification and oxygen liberation from hemoglobin by the "Root effect." While O(2) generation is critical for fish flotation, the molecular mechanism of the secretion and recycling of lactic acid in this critical process is not clear. To clarify molecules that are involved in the blood acidification and visualize the route of lactic acid movement, we analyzed the expression of 17 members of the H(+)/monocarboxylate transporter (MCT) family in the fugu genome and found that only MCT1b and MCT4b are highly expressed in the fugu swimbladder. Electrophysiological analyses demonstrated that MCT1b is a high-affinity lactate transporter whereas MCT4b is a low-affinity/high-conductance lactate transporter. Immunohistochemistry demonstrated that (i) MCT4b expresses in gas gland cells together with the glycolytic enzyme GAPDH at high level and mediate lactic acid secretion by gas gland cells, and (ii) MCT1b expresses in arterial, but not venous, capillary endothelial cells in rete mirabile and mediates recycling of lactic acid in the rete mirabile by solute-specific transcellular transport. These results clarified the mechanism of the blood acidification in the swimbladder by spatially organized two lactic acid transporters MCT4b and MCT1b. PMID- 22496830 TI - A common genetic variant at 15q25 modifies the associations of maternal smoking during pregnancy with fetal growth: the generation R study. AB - OBJECTIVE: Maternal smoking during pregnancy is associated with fetal growth retardation. We examined whether a common genetic variant at chromosome 15q25 (rs1051730), which is known to be involved in nicotine metabolism, modifies the associations of maternal smoking with fetal growth characteristics. METHODS: This study was performed in 3,563 European mothers participating in a population-based prospective cohort study from early pregnancy onwards. Smoking was assessed by postal questionnaires and fetal growth characteristics were measured by ultrasound examinations in each trimester of pregnancy. RESULTS: Among mothers who did not smoke during pregnancy (82.9%), maternal rs1051730 was not consistently associated with any fetal growth characteristic. Among mothers who continued smoking during pregnancy (17.1%), maternal rs1051730 was not associated with head circumference. The T-allele of maternal rs1051730 was associated with a smaller second and third trimester fetal femur length [differences -0.23 mm (95%CI -0.45 to -0.00) and -0.41 mm (95%CI -0.69 to -0.13), respectively] and a smaller birth length [difference -2.61 mm (95%CI -5.32 to 0.11)]. The maternal T allele of rs1051730 was associated with a lower third trimester estimated fetal weight [difference -33 grams (95%CI -55 to -10)], and tended to be associated with birth weight [difference -38 grams (95%CI -89 to 13)]. This association persisted after adjustment for smoking quantity. CONCLUSIONS: Our results suggest that maternal rs1051730 genotype modifies the associations of maternal smoking during pregnancy with impaired fetal growth in length and weight. These results should be considered as hypothesis generating and indicate the need for large scale genome wide association studies focusing on gene--fetal smoke exposure interactions. PMID- 22496831 TI - Molecular dynamics simulation study and hybrid pharmacophore model development in human LTA4H inhibitor design. AB - Human leukotriene A4 hydrolase (hLTA4H) is a bi-functional enzyme catalyzes the hydrolase and aminopeptidase functions upon the fatty acid and peptide substrates, respectively, utilizing the same but overlapping binding site. Particularly the hydrolase function of this enzyme catalyzes the rate-limiting step of the leukotriene (LT) cascade that converts the LTA4 to LTB4. This product is a potent pro-inflammatory activator of inflammatory responses and thus blocking this conversion provides a valuable means to design anti-inflammatory agents. Four structurally very similar chemical compounds with highly different inhibitory profile towards the hydrolase function of hLTA4H were selected from the literature. Molecular dynamics (MD) simulations of the complexes of hLTA4H with these inhibitors were performed and the results have provided valuable information explaining the reasons for the differences in their biological activities. Binding mode analysis revealed that the additional thiophene moiety of most active inhibitor helps the pyrrolidine moiety to interact the most important R563 and K565 residues. The hLTA4H complexes with the most active compound and substrate were utilized in the development of hybrid pharmacophore models. These developed pharmacophore models were used in screening chemical databases in order to identify lead candidates to design potent hLTA4H inhibitors. Final evaluation based on molecular docking and electronic parameters has identified three compounds of diverse chemical scaffolds as potential leads to be used in novel and potent hLTA4H inhibitor design. PMID- 22496832 TI - Comparison of human and soil Candida tropicalis isolates with reduced susceptibility to fluconazole. AB - Infections caused by treatment-resistant non-albicans Candida species, such as C. tropicalis, has increased, which is an emerging challenge in the management of fungal infections. Genetically related diploid sequence type (DST) strains of C. tropicalis exhibiting reduced susceptibility to fluconazole circulated widely in Taiwan. To identify the potential source of these wildly distributed DST strains, we investigated the possibility of the presence in soil of such C. tropicalis strains by pulsed field gel electrophoresis (PFGE) and DST typing methods. A total of 56 C. tropicalis isolates were recovered from 26 out of 477 soil samples. Among the 18 isolates with reduced susceptibility to fluconazole, 9 belonged to DST149 and 3 belonged to DST140. Both DSTs have been recovered from our previous studies on clinical isolates from the Taiwan Surveillance of Antimicrobial Resistance of Yeasts (TSARY) program. Furthermore, these isolates were more resistant to agricultural azoles. We have found genetically related C. tropicalis exhibiting reduced susceptibility to fluconazole from the human hosts and environmental samples. Therefore, to prevent patients from acquiring C. tropicalis with reduced susceptibility to azoles, prudent use of azoles in both clinical and agricultural settings is advocated. PMID- 22496833 TI - Production of scFv-conjugated affinity silk powder by transgenic silkworm technology. AB - Bombyx mori (silkworm) silk proteins are being utilized as unique biomaterials for medical applications. Chemical modification or post-conjugation of bioactive ligands expand the applicability of silk proteins; however, the processes are elaborate and costly. In this study, we used transgenic silkworm technology to develop single-chain variable fragment (scFv)-conjugated silk fibroin. The cocoons of the transgenic silkworm contain fibroin L-chain linked with scFv as a fusion protein. After dissolving the cocoons in lithium bromide, the silk solution was dialyzed, concentrated, freeze-dried, and crushed into powder. Immunoprecipitation analyses demonstrate that the scFv domain retains its specific binding activity to the target molecule after multiple processing steps. These results strongly suggest the promise of scFv-conjugated silk fibroin as an alternative affinity reagent, which can be manufactured using transgenic silkworm technology at lower cost than traditional affinity carriers. PMID- 22496834 TI - Recombinant human endostatin normalizes tumor vasculature and enhances radiation response in xenografted human nasopharyngeal carcinoma models. AB - BACKGROUND: Hypoxic tumor cells can reduce the efficacy of radiation. Antiangiogenic therapy may transiently "normalize" the tumor vasculature to make it more efficient for oxygen delivery. The aim of this study is to investigate whether the recombinant human endostatin (endostar) can create a "vascular normalization window" to alleviate hypoxia and enhance the inhibitory effects of radiation therapy in human nasopharyngeal carcinoma (NPC) in mice. METHODOLOGY/PRINCIPAL FINDINGS: Transient changes in morphology of tumor vasculature and hypoxic tumor cell fraction in response to endostar were detected in mice bearing CNE-2 and 5-8F human NPC xenografts. Various treatment schedules were tested to assess the influence of endostar on the effect of radiation therapy. Several important factors relevant to the angiogenesis were identified through immunohistochemical staining. During endostar treatment, tumor vascularity decreased, while the basement membrane and pericyte coverage associated with endothelial cells increased, which supported the idea of vessel normalization. Hypoxic tumor cell fraction also decreased after the treatment. The transient modulation of tumor physiology caused by endostar improved the effect of radiation treatment compared with other treatment schedules. The expressions of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), MMP-9, and MMP-14 decreased, while the level of pigment epithelium-derived factor (PEDF) increased. CONCLUSIONS: Endostar normalized tumor vasculature, which alleviated hypoxia and significantly sensitized the function of radiation in anti-tumor in human NPC. The results provide an important experimental basis for combining endostar with radiation therapy in human NPC. PMID- 22496835 TI - Cytotoxic T lymphocyte trafficking and survival in an augmented fibrin matrix carrier. AB - Cell-based therapies have intriguing potential for the treatment of a variety of neurological disorders. One such example is genetically engineered cytotoxic T lymphocytes (CTLs) that are being investigated in brain tumor clinical trials. The development of methods for CTL delivery is critical to their use in the laboratory and clinical setting. In our study, we determined whether CTLs can migrate through fibrin matrices and if their migration, survival, and function could be modulated by adding chemokines to the matrix. Our results indicated that CTLs can freely migrate through fibrin matrices. As expected, the addition of the monocyte chemotactic protein-1 (MCP-1), also known as chemokine C-C motif ligand 2 (CCL2), to the surrounding media increased egress of the CTLs out of the fibrin clot. Interleukin (IL) -2 and/or IL-15 embedded in the matrix enhanced T cell survival and further promoted T cell migration. The interleukin-13 receptor alpha 2 specific (IL-13R alpha2) T cells that traveled out of the fibrin clot retained the capacity to kill U251 glioma cells. In summary, CTLs can survive and migrate robustly in fibrin matrices. These processes can be influenced by modification of matrix constituents. We conclude that fibrin matrices may be suitable T cell carriers and can be used to facilitate understanding of T cell interaction with the surrounding microenvironment. PMID- 22496836 TI - Populations of a susceptible amphibian species can grow despite the presence of a pathogenic chytrid fungus. AB - Disease can be an important driver of host population dynamics and epizootics can cause severe host population declines. Batrachochytrium dendrobatidis (Bd), the pathogen causing amphibian chytridiomycosis, may occur epizootically or enzootically and can harm amphibian populations in many ways. While effects of Bd epizootics are well documented, the effects of enzootic Bd have rarely been described. We used a state-space model that accounts for observation error to test whether population trends of a species highly susceptible to Bd, the midwife toad Alytes obstetricans, are negatively affected by the enzootic presence of the pathogen. Unexpectedly, Bd had no negative effect on population growth rates from 2002-2008. This suggests that negative effects of disease on individuals do not necessarily translate into negative effects at the population level. Populations of amphibian species that are susceptible to the emerging disease chytridiomycosis can persist despite the enzootic presence of the pathogen under current environmental conditions. PMID- 22496837 TI - Fast homozygosity mapping and identification of a zebrafish ENU-induced mutation by whole-genome sequencing. AB - Forward genetics using zebrafish is a powerful tool for studying vertebrate development through large-scale mutagenesis. Nonetheless, the identification of the molecular lesion is still laborious and involves time-consuming genetic mapping. Here, we show that high-throughput sequencing of the whole zebrafish genome can directly locate the interval carrying the causative mutation and at the same time pinpoint the molecular lesion. The feasibility of this approach was validated by sequencing the m1045 mutant line that displays a severe hypoplasia of the exocrine pancreas. We generated 13 Gb of sequence, equivalent to an eightfold genomic coverage, from a pool of 50 mutant embryos obtained from a map cross between the AB mutant carrier and the WIK polymorphic strain. The chromosomal region carrying the causal mutation was localized based on its unique property to display high levels of homozygosity among sequence reads as it derives exclusively from the initial AB mutated allele. We developed an algorithm identifying such a region by calculating a homozygosity score along all chromosomes. This highlighted an 8-Mb window on chromosome 5 with a score close to 1 in the m1045 mutants. The sequence analysis of all genes within this interval revealed a nonsense mutation in the snapc4 gene. Knockdown experiments confirmed the assertion that snapc4 is the gene whose mutation leads to exocrine pancreas hypoplasia. In conclusion, this study constitutes a proof-of-concept that whole-genome sequencing is a fast and effective alternative to the classical positional cloning strategies in zebrafish. PMID- 22496838 TI - GPR30, the non-classical membrane G protein related estrogen receptor, is overexpressed in human seminoma and promotes seminoma cell proliferation. AB - BACKGROUND: Testicular germ cell tumours are the most frequent cancer of young men with an increasing incidence all over the world. Pathogenesis and reasons of this increase remain unknown but epidemiological and clinical data have suggested that fetal exposure to environmental endocrine disruptors (EEDs) with estrogenic effects, could participate to testicular germ cell carcinogenesis. However, these EEDs (like bisphenol A) are often weak ligands for classical nuclear estrogen receptors. Several research groups recently showed that the non classical membrane G-protein coupled estrogen receptor (GPER/GPR30) mediates the effects of estrogens and several xenoestrogens through rapid non genomic activation of signal transduction pathways in various human estrogen dependent cancer cells (breast, ovary, endometrium). The aim of this study was to demonstrate that GPER was overexpressed in testicular tumours and was able to trigger JKT-1 seminoma cell proliferation. RESULTS: We report here for the first time a complete morphological and functional characterization of GPER in normal and malignant human testicular germ cells. In normal adult human testes, GPER was expressed by somatic (Sertoli cells) and germ cells (spermatogonia and spermatocytes). GPER was exclusively overexpressed in seminomas, the most frequent testicular germ cell cancer, localized at the cell membrane and triggered a proliferative effect on JKT-1 cells in vitro, which was completely abolished by G15 (a GPER selective antagonist) and by siRNA invalidation. CONCLUSION: These results demonstrate that GPER is expressed by human normal adult testicular germ cells, specifically overexpressed in seminoma tumours and able to trigger seminoma cell proliferation in vitro. It should therefore be considered rather than classical ERs when xeno estrogens or other endocrine disruptors are assessed in testicular germ cell cancers. It may also represent a prognosis marker and/or a therapeutic target for seminomas. PMID- 22496839 TI - Conservation of gene order and content in the circular chromosomes of 'Candidatus Liberibacter asiaticus' and other Rhizobiales. AB - 'Ca. Liberibacter asiaticus,' an insect-vectored, obligate intracellular bacterium associated with citrus-greening disease, also called "HLB," is a member of the Rhizobiales along with nitrogen-fixing microsymbionts Sinorhizobium meliloti and Bradyrhizobium japonicum, plant pathogen Agrobacterium tumefaciens and facultative intracellular mammalian pathogen Bartonella henselae. Comparative analyses of their circular chromosomes identified 514 orthologous genes shared among all five species. Shared among all five species are 50 identical blocks of microsyntenous orthologous genes (MOGs), containing a total of 283 genes. While retaining highly conserved genomic blocks of microsynteny, divergent evolution, horizontal gene transfer and niche specialization have disrupted macrosynteny among the five circular chromosomes compared. Highly conserved microsyntenous gene clusters help define the Rhizobiales, an order previously defined by 16S RNA gene similarity and herein represented by the three families: Bartonellaceae, Bradyrhizobiaceae and Rhizobiaceae. Genes without orthologs in the other four species help define individual species. The circular chromosomes of each of the five Rhizobiales species examined had genes lacking orthologs in the other four species. For example, 63 proteins are encoded by genes of 'Ca. Liberibacter asiaticus' not shared with other members of the Rhizobiales. Of these 63 proteins, 17 have predicted functions related to DNA replication or RNA transcription, and some of these may have roles related to low genomic GC content. An additional 17 proteins have predicted functions relevant to cellular processes, particularly modifications of the cell surface. Seventeen unshared proteins have specific metabolic functions including a pathway to synthesize cholesterol encoded by a seven-gene operon. The remaining 12 proteins encoded by 'Ca. Liberibacter asiaticus' genes not shared with other Rhizobiales are of bacteriophage origin. 'Ca. Liberibacter asiaticus' shares 11 genes with only Sinorhizobium meliloti and 12 genes are shared with only Bartonella henselae. PMID- 22496840 TI - Free cysteine modulates the conformation of human C/EBP homologous protein. AB - The C/EBP Homologous Protein (CHOP) is a nuclear protein that is integral to the unfolded protein response culminating from endoplasmic reticulum stress. Previously, CHOP was shown to comprise extensive disordered regions and to self associate in solution. In the current study, the intrinsically disordered nature of this protein was characterized further by comprehensive in silico analyses. Using circular dichroism, differential scanning calorimetry and nuclear magnetic resonance, we investigated the global conformation and secondary structure of CHOP and demonstrated, for the first time, that conformational changes in this protein can be induced by the free amino acid L-cysteine. Addition of L-cysteine caused a significant dose-dependent decrease in the protein helicity--dropping from 69.1% to 23.8% in the presence of 1 mM of L-cysteine--and a sequential transition to a more disordered state, unlike that caused by thermal denaturation. Furthermore, the presence of small amounts of free amino acid (80 uM, an 8:1 cysteine?CHOP ratio) during CHOP thermal denaturation altered the molecular mechanism of its melting process, leading to a complex, multi-step transition. On the other hand, high levels (4 mM) of free L-cysteine seemed to cause a complete loss of rigid cooperatively melting structure. These results suggested a potential regulatory function of L-cysteine which may lead to changes in global conformation of CHOP in response to the cellular redox state and/or endoplasmic reticulum stress. PMID- 22496841 TI - Structural disorder in eukaryotes. AB - Based on early bioinformatic studies on a handful of species, the frequency of structural disorder of proteins is generally thought to be much higher in eukaryotes than in prokaryotes. To refine this view, we present here a comparative prediction study and analysis of 194 fully described eukaryotic proteomes and 87 reference prokaryotes for structural disorder. We found that structural disorder does distinguish eukaryotes from prokaryotes, but its frequency spans a very wide range in the two superkingdoms that largely overlap. The number of disordered binding regions and different Pfam domain types also contribute to distinguish eukaryotes from prokaryotes. Unexpectedly, the highest levels--and highest variability--of predicted disorder is found in protists, i.e. single-celled eukaryotes, often surpassing more complex eukaryote organisms, plants and animals. This trend contrasts with that of the number of domain types, which increases rather monotonously toward more complex organisms. The level of structural disorder appears to be strongly correlated with lifestyle, because some obligate intracellular parasites and endosymbionts have the lowest levels, whereas host-changing parasites have the highest level of predicted disorder. We conclude that protists have been the evolutionary hot-bed of experimentation with structural disorder, in a period when structural disorder was actively invented and the major functional classes of disordered proteins established. PMID- 22496843 TI - From the trenches: a cross-sectional study applying the GRADE tool in systematic reviews of healthcare interventions. AB - BACKGROUND: GRADE was developed to address shortcomings of tools to rate the quality of a body of evidence. While much has been published about GRADE, there are few empirical and systematic evaluations. OBJECTIVE: To assess GRADE for systematic reviews (SRs) in terms of inter-rater agreement and identify areas of uncertainty. DESIGN: Cross-sectional, descriptive study. METHODS: We applied GRADE to three SRs (n = 48, 66, and 75 studies, respectively) with 29 comparisons and 12 outcomes overall. Two reviewers graded evidence independently for outcomes deemed clinically important a priori. Inter-rater reliability was assessed using kappas for four main domains (risk of bias, consistency, directness, and precision) and overall quality of evidence. RESULTS: FOR THE FIRST REVIEW, RELIABILITY WAS: kappa = 0.41 for risk of bias; 0.84 consistency; 0.18 precision; and 0.44 overall quality. Kappa could not be calculated for directness as one rater assessed all items as direct; assessors agreed in 41% of cases. For the second review reliability was: 0.37 consistency and 0.19 precision. Kappa could not be assessed for other items; assessors agreed in 33% of cases for risk of bias; 100% directness; and 58% overall quality. For the third review, reliability was: 0.06 risk of bias; 0.79 consistency; 0.21 precision; and 0.18 overall quality. Assessors agreed in 100% of cases for directness. Precision created the most uncertainty due to difficulties in identifying "optimal" information size and "clinical decision threshold", as well as making assessments when there was no meta-analysis. The risk of bias domain created uncertainty, particularly for nonrandomized studies. CONCLUSIONS: As researchers with varied levels of training and experience use GRADE, there is risk for variability in interpretation and application. This study shows variable agreement across the GRADE domains, reflecting areas where further guidance is required. PMID- 22496842 TI - Impaired inflammatory responses in murine Lrrk2-knockdown brain microglia. AB - LRRK2, a Parkinson's disease associated gene, is highly expressed in microglia in addition to neurons; however, its function in microglia has not been evaluated. Using Lrrk2 knockdown (Lrrk2-KD) murine microglia prepared by lentiviral-mediated transfer of Lrrk2-specific small inhibitory hairpin RNA (shRNA), we found that Lrrk2 deficiency attenuated lipopolysaccharide (LPS)-induced mRNA and/or protein expression of inducible nitric oxide synthase, TNF-alpha, IL-1beta and IL-6. LPS induced phosphorylation of p38 mitogen-activated protein kinase and stimulation of NF-kappaB-responsive luciferase reporter activity was also decreased in Lrrk2 KD cells. Interestingly, the decrease in NF-kappaB transcriptional activity measured by luciferase assays appeared to reflect increased binding of the inhibitory NF-kappaB homodimer, p50/p50, to DNA. In LPS-responsive HEK293T cells, overexpression of the human LRRK2 pathologic, kinase-active mutant G2019S increased basal and LPS-induced levels of phosphorylated p38 and JNK, whereas wild-type and other pathologic (R1441C and G2385R) or artificial kinase-dead (D1994A) LRRK2 mutants either enhanced or did not change basal and LPS-induced p38 and JNK phosphorylation levels. However, wild-type LRRK2 and all LRRK2 mutant variants equally enhanced NF-kappaB transcriptional activity. Taken together, these results suggest that LRRK2 is a positive regulator of inflammation in murine microglia, and LRRK2 mutations may alter the microenvironment of the brain to favor neuroinflammation. PMID- 22496844 TI - Alternative splicing of a multi-drug transporter from Pseudoperonospora cubensis generates an RXLR effector protein that elicits a rapid cell death. AB - Pseudoperonospora cubensis, an obligate oomycete pathogen, is the causal agent of cucurbit downy mildew, a foliar disease of global economic importance. Similar to other oomycete plant pathogens, Ps. cubensis has a suite of RXLR and RXLR-like effector proteins, which likely function as virulence or avirulence determinants during the course of host infection. Using in silico analyses, we identified 271 candidate effector proteins within the Ps. cubensis genome with variable RXLR motifs. In extending this analysis, we present the functional characterization of one Ps. cubensis effector protein, RXLR protein 1 (PscRXLR1), and its closest Phytophthora infestans ortholog, PITG_17484, a member of the Drug/Metabolite Transporter (DMT) superfamily. To assess if such effector-non-effector pairs are common among oomycete plant pathogens, we examined the relationship(s) among putative ortholog pairs in Ps. cubensis and P. infestans. Of 271 predicted Ps. cubensis effector proteins, only 109 (41%) had a putative ortholog in P. infestans and evolutionary rate analysis of these orthologs shows that they are evolving significantly faster than most other genes. We found that PscRXLR1 was up-regulated during the early stages of infection of plants, and, moreover, that heterologous expression of PscRXLR1 in Nicotiana benthamiana elicits a rapid necrosis. More interestingly, we also demonstrate that PscRXLR1 arises as a product of alternative splicing, making this the first example of an alternative splicing event in plant pathogenic oomycetes transforming a non-effector gene to a functional effector protein. Taken together, these data suggest a role for PscRXLR1 in pathogenicity, and, in total, our data provide a basis for comparative analysis of candidate effector proteins and their non-effector orthologs as a means of understanding function and evolutionary history of pathogen effectors. PMID- 22496845 TI - HIV-1 phenotypic reverse transcriptase inhibitor drug resistance test interpretation is not dependent on the subtype of the virus backbone. AB - To date, the majority of HIV-1 phenotypic resistance testing has been performed with subtype B virus backbones (e.g. HXB2). However, the relevance of using this backbone to determine resistance in non-subtype B HIV-1 viruses still needs to be assessed. From 114 HIV-1 subtype C clinical samples (36 ARV-naive, 78 ARV exposed), pol amplicons were produced and analyzed for phenotypic resistance using both a subtype B- and C-backbone in which the pol fragment was deleted. Phenotypic resistance was assessed in resulting recombinant virus stocks (RVS) for a series of antiretroviral drugs (ARV's) and expressed as fold change (FC), yielding 1660 FC comparisons. These Antivirogram(r) derived FC values were categorized as having resistant or sensitive susceptibility based on biological cut-off values (BCOs). The concordance between resistance calls obtained for the same clinical sample but derived from two different backbones (i.e. B and C) accounted for 86.1% (1429/1660) of the FC comparisons. However, when taking the assay variability into account, 95.8% (1590/1660) of the phenotypic data could be considered as being concordant with respect to their resistance call. No difference in the capacity to detect resistance associated with M184V, K103N and V106M mutations was noted between the two backbones. The following was concluded: (i) A high level of concordance was shown between the two backbone phenotypic resistance profiles; (ii) Assay variability is largely responsible for discordant results (i.e. for FC values close to BCO); (iii) Confidence intervals should be given around the BCO's, when assessing resistance in HIV-1 subtype C; (iv) No systematic resistance under- or overcalling of subtype C amplicons in the B backbone was observed; (v) Virus backbone subtype sequence variability outside the pol region does not contribute to phenotypic FC values. In conclusion the HXB2 virus backbone remains an acceptable vector for phenotyping HIV-1 subtype C pol amplicons. PMID- 22496846 TI - Imaging of bubonic plague dynamics by in vivo tracking of bioluminescent Yersinia pestis. AB - Yersinia pestis dissemination in a host is usually studied by enumerating bacteria in the tissues of animals sacrificed at different times. This laborious methodology gives only snapshots of the infection, as the infectious process is not synchronized. In this work we used in vivo bioluminescence imaging (BLI) to follow Y. pestis dissemination during bubonic plague. We first demonstrated that Y. pestis CO92 transformed with pGEN-luxCDABE stably emitted bioluminescence in vitro and in vivo, while retaining full virulence. The light produced from live animals allowed to delineate the infected organs and correlated with bacterial loads, thus validating the BLI tool. We then showed that the first step of the infectious process is a bacterial multiplication at the injection site (linea alba), followed by a colonization of the draining inguinal lymph node(s), and subsequently of the ipsilateral axillary lymph node through a direct connection between the two nodes. A mild bacteremia and an effective filtering of the blood stream by the liver and spleen probably accounted for the early bacterial blood clearance and the simultaneous development of bacterial foci within these organs. The saturation of the filtering capacity of the spleen and liver subsequently led to terminal septicemia. Our results also indicate that secondary lymphoid tissues are the main targets of Y. pestis multiplication and that colonization of other organs occurs essentially at the terminal phase of the disease. Finally, our analysis reveals that the high variability in the kinetics of infection is attributable to the time the bacteria remain confined at the injection site. However, once Y. pestis has reached the draining lymph nodes, the disease progresses extremely rapidly, leading to the invasion of the entire body within two days and to death of the animals. This highlights the extraordinary capacity of Y. pestis to annihilate the host innate immune response. PMID- 22496847 TI - Selective enrichment media bias the types of Salmonella enterica strains isolated from mixed strain cultures and complex enrichment broths. AB - For foodborne outbreak investigations it can be difficult to isolate the relevant strain from food and/or environmental sources. If the sample is contaminated by more than one strain of the pathogen the relevant strain might be missed. In this study mixed cultures of Salmonella enterica were grown in one set of standard enrichment media to see if culture bias patterns emerged. Nineteen strains representing four serogroups and ten serotypes were compared in four-strain mixtures in Salmonella-only and in cattle fecal culture enrichment backgrounds using Salmonella enrichment media. One or more strain(s) emerged as dominant in each mixture. No serotype was most fit, but strains of serogroups C2 and E were more likely to dominate enrichment culture mixtures than strains of serogroups B or C1. Different versions of Rappaport-Vassiliadis (RV) medium gave different patterns of strain dominance in both Salmonella-only and fecal enrichment culture backgrounds. The fittest strains belonged to serogroups C1, C2, and E, and included strains of S. Infantis, S. Thompson S. Newport, S. 6,8:d:-, and S. Give. Strains of serogroup B, which included serotypes often seen in outbreaks such as S. Typhimurium, S. Saintpaul, and S. Schwarzengrund were less likely to emerge as dominant strains in the mixtures when using standard RV as part of the enrichment. Using a more nutrient-rich version of RV as part of the protocol led to a different pattern of strains emerging, however some were still present in very low numbers in the resulting population. These results indicate that outbreak investigations of food and/or other environmental samples should include multiple enrichment protocols to ensure isolation of target strains of Salmonella. PMID- 22496848 TI - Reduced axonal transport and increased excitotoxic retinal ganglion cell degeneration in mice transgenic for human mutant P301S tau. AB - The effects of tau hyperphosphorylation and aggregation on axonal transport were investigated in the optic nerve of mice transgenic for human mutant P301S tau. Transport was examined using cholera toxin B tracing. Retrograde transport was reduced in transgenic mice at 3 and 5 months of age, when compared to C57/Bl6 control mice. Anterograde axonal transport was also reduced in 3-month-old transgenic mice. Mild excitotoxic injury of retinal ganglion cells resulted in greater nerve cell loss in retinas from 3- and 5-month old P301S transgenic mice, when compared to controls. In conjunction with the detection of abnormal tau in the optic nerve in human and experimental glaucoma, the present findings suggest that tau hyperphosphorylation and aggregation may constitute targets for neuroprotective therapies in glaucoma as well as tauopathies. PMID- 22496849 TI - Dose-response aligned circuits in signaling systems. AB - Cells use biological signal transduction pathways to respond to environmental stimuli and the behavior of many cell types depends on precise sensing and transmission of external information. A notable property of signal transduction that was characterized in the Saccharomyces cerevisiae yeast cell and many mammalian cells is the alignment of dose-response curves. It was found that the dose response of the receptor matches closely the dose responses of the downstream. This dose-response alignment (DoRA) renders equal sensitivities and concordant responses in different parts of signaling system and guarantees a faithful information transmission. The experimental observations raise interesting questions about the nature of the information transmission through DoRA signaling networks and design principles of signaling systems with this function. Here, we performed an exhaustive computational analysis on network architectures that underlie the DoRA function in simple regulatory networks composed of two and three enzymes. The minimal circuits capable of DoRA were examined with Michaelis-Menten kinetics. Several motifs that are essential for the dynamical function of DoRA were identified. Systematic analysis of the topology space of robust DoRA circuits revealed that, rather than fine-tuning the network's parameters, the function is primarily realized by enzymatic regulations on the controlled node that are constrained in limiting regions of saturation or linearity. PMID- 22496850 TI - Executive functions predict the success of top-soccer players. AB - While the importance of physical abilities and motor coordination is non contested in sport, more focus has recently been turned toward cognitive processes important for different sports. However, this line of studies has often investigated sport-specific cognitive traits, while few studies have focused on general cognitive traits. We explored if measures of general executive functions can predict the success of a soccer player. The present study used standardized neuropsychological assessment tools assessing players' general executive functions including on-line multi-processing such as creativity, response inhibition, and cognitive flexibility. In a first cross-sectional part of the study we compared the results between High Division players (HD), Lower Division players (LD) and a standardized norm group. The result shows that both HD and LD players had significantly better measures of executive functions in comparison to the norm group for both men and women. Moreover, the HD players outperformed the LD players in these tests. In the second prospective part of the study, a partial correlation test showed a significant correlation between the result from the executive test and the numbers of goals and assists the players had scored two seasons later. The results from this study strongly suggest that results in cognitive function tests predict the success of ball sport players. PMID- 22496851 TI - Complete chloroplast genome sequence of an orchid model plant candidate: Erycina pusilla apply in tropical Oncidium breeding. AB - Oncidium is an important ornamental plant but the study of its functional genomics is difficult. Erycina pusilla is a fast-growing Oncidiinae species. Several characteristics including low chromosome number, small genome size, short growth period, and its ability to complete its life cycle in vitro make E. pusilla a good model candidate and parent for hybridization for orchids. Although genetic information remains limited, systematic molecular analysis of its chloroplast genome might provide useful genetic information. By combining bacterial artificial chromosome (BAC) clones and next-generation sequencing (NGS), the chloroplast (cp) genome of E. pusilla was sequenced accurately, efficiently and economically. The cp genome of E. pusilla shares 89 and 84% similarity with Oncidium Gower Ramsey and Phalanopsis aphrodite, respectively. Comparing these 3 cp genomes, 5 regions have been identified as showing diversity. Using PCR analysis of 19 species belonging to the Epidendroideae subfamily, a conserved deletion was found in the rps15-trnN region of the Cymbidieae tribe. Because commercial Oncidium varieties in Taiwan are limited, identification of potential parents using molecular breeding method has become very important. To demonstrate the relationship between taxonomic position and hybrid compatibility of E. pusilla, 4 DNA regions of 36 tropically adapted Oncidiinae varieties have been analyzed. The results indicated that trnF-ndhJ and trnH-psbA were suitable for phylogenetic analysis. E. pusilla proved to be phylogenetically closer to Rodriguezia and Tolumnia than Oncidium, despite its similar floral appearance to Oncidium. These results indicate the hybrid compatibility of E. pusilla, its cp genome providing important information for Oncidium breeding. PMID- 22496852 TI - Constraints on energy intake in fish: the link between diet composition, energy metabolism, and energy intake in rainbow trout. AB - The hypothesis was tested that fish fed to satiation with iso-energetic diets differing in macronutrient composition will have different digestible energy intakes (DEI) but similar total heat production. Four iso-energetic diets (2 * 2 factorial design) were formulated having a contrast in i) the ratio of protein to energy (P/E): high (H(P/E)) vs. low (L(P/E)) and ii) the type of non-protein energy (NPE) source: fat vs. carbohydrate which were iso-energetically exchanged. Triplicate groups (35 fish/tank) of rainbow trout were hand-fed each diet twice daily to satiation for 6 weeks under non-limiting water oxygen conditions. Feed intake (FI), DEI (kJ kg(-0.8) d(-1)) and growth (g kg(-0.8) d(-1)) of trout were affected by the interaction between P/E ratio and NPE source of the diet (P<0.05). Regardless of dietary P/E ratio, the inclusion of carbohydrate compared to fat as main NPE source reduced DEI and growth of trout by ~20%. The diet induced differences in FI and DEI show that trout did not compensate for the dietary differences in digestible energy or digestible protein contents. Further, changes in body fat store and plasma glucose did not seem to exert a homeostatic feedback control on DEI. Independent of the diet composition, heat production of trout did not differ (P>0.05). Our data suggest that the control of DEI in trout might be a function of heat production, which in turn might reflect a physiological limit related with oxidative metabolism. PMID- 22496853 TI - Genome-wide association analysis of oxidative stress resistance in Drosophila melanogaster. AB - BACKGROUND: Aerobic organisms are susceptible to damage by reactive oxygen species. Oxidative stress resistance is a quantitative trait with population variation attributable to the interplay between genetic and environmental factors. Drosophila melanogaster provides an ideal system to study the genetics of variation for resistance to oxidative stress. METHODS AND FINDINGS: We used 167 wild-derived inbred lines of the Drosophila Genetic Reference Panel for a genome-wide association study of acute oxidative stress resistance to two oxidizing agents, paraquat and menadione sodium bisulfite. We found significant genetic variation for both stressors. Single nucleotide polymorphisms (SNPs) associated with variation in oxidative stress resistance were often sex-specific and agent-dependent, with a small subset common for both sexes or treatments. Associated SNPs had moderately large effects, with an inverse relationship between effect size and allele frequency. Linear models with up to 12 SNPs explained 67-79% and 56-66% of the phenotypic variance for resistance to paraquat and menadione sodium bisulfite, respectively. Many genes implicated were novel with no known role in oxidative stress resistance. Bioinformatics analyses revealed a cellular network comprising DNA metabolism and neuronal development, consistent with targets of oxidative stress-inducing agents. We confirmed associations of seven candidate genes associated with natural variation in oxidative stress resistance through mutational analysis. CONCLUSIONS: We identified novel candidate genes associated with variation in resistance to oxidative stress that have context-dependent effects. These results form the basis for future translational studies to identify oxidative stress susceptibility/resistance genes that are evolutionary conserved and might play a role in human disease. PMID- 22496854 TI - Small, N-terminal tags activate Parkin E3 ubiquitin ligase activity by disrupting its autoinhibited conformation. AB - Parkin is an E3 ubiquitin ligase, mutations in which cause Autosomal Recessive Parkinson's Disease. Many studies aimed at understanding Parkin function, regulation and dysfunction are performed using N-terminal epitope tags. We report here that the use of small tags such as FLAG, cMyc and HA, influence the physical stability and activity of Parkin in and out of cells, perturbing the autoinhibited native state of Parkin, resulting in an active-for autoubiquitination species. PMID- 22496855 TI - Increase human metapneumovirus mediated morbidity following pandemic influenza infection. AB - Human metapneumovirus (hMPV) is a recently discovered respiratory pathogen, infecting mainly young children. The infected patients suffer from influenza like symptoms (ILS). In Israel the virus is mainly circulating in February to March. Here we report on an increased rate of hMPV infection in the winter season of 2009-10. The 2009-10 infection had several unique characteristics when compared to previous seasons; it started around January and a large number of infants were infected by the virus. Genetic analysis based on the viral L and F genes of hMPV showed that only subtypes A2 and B2 circulated in Israel. Additionally, we have identified a novel variant of hMPV within subgroup A2b, which subdivide it into A2b1 and A2b2. Finally, we showed that the hMPV infection was detected in the country soon after the infection with the pandemic influenza virus had declined, that infection with the pandemic influenza virus was dominant and that it interfered with the infection of other respiratory viruses. Thus, we suggest that the unusual increase in hMPV infection observed in 2009-10 was due to the appearance of the pandemic influenza virus in the winter season prior to 2009-10. PMID- 22496856 TI - Genetic polymorphism in a VEGF-independent angiogenesis gene ANGPT1 and overall survival of colorectal cancer patients after surgical resection. AB - BACKGROUND: The VEGF-independent angiogenic signaling plays an important role in the development of colorectal cancer (CRC). However, its implication in the clinical outcome of CRC has not been reported. This study aimed to investigate the association between genetic variations in several major VEGF-independent signaling pathway genes and the overall survival of CRC patients. METHODS: Seven single nucleotide polymorphisms (SNPs) in four important VEGF-independent angiogenic genes (ANGPT1, AMOT, DLL4 and ENG) were genotyped in a Chinese population with 408 CRC patients. RESULTS: One SNP, rs1954727 in ANGPT1, was significantly associated with CRC overall survival. Compared to patients with the homozygous wild-type genotype of rs1954727, those with heterozygous and homozygous variant genotypes exhibited a favorable overall survival with a hazard ratio (HR) of 0.89 (95% confidence interval [CI] 0.55-1.43, P = 0.623), and 0.32 (95% CI 0.15-0.71, P = 0.005), respectively (P trend = 0.008). In stratified analysis, this association remained significant in patients receiving chemotherapy (P trend = 0.012), but not in those without chemotherapy. We further evaluated the effects of chemotherapy on CRC survival that was stratified by rs1954727 genotypes. We found that chemotherapy resulted in a significantly better overall survival in the CRC patients (HR = 0.44, 95% CI 0.26-0.75, P = 0.002), which was especially prominent in those patients with the heterozygous genotype of rs1954727 (HR = 0.45, 95%CI 0.22-0.92, P = 0.028). CONCLUSION: Our data suggest that rs1954727 in ANGPT1 gene might be a prognostic biomarker for the overall survival of CRC patients, especially in those receiving chemotherapy, a finding that warrants validation in larger independent populations. PMID- 22496858 TI - Radionuclide analysis on bamboos following the Fukushima nuclear accident. AB - In response to contamination from the recent Fukushima nuclear accident, we conducted radionuclide analysis on bamboos sampled from six sites within a 25 to 980 km radius of the Fukushima Daiichi nuclear power plant. Maximum activity concentrations of radiocesium (134)Cs and (137)Cs in samples from Fukushima city, 65 km away from the Fukushima Daiichi plant, were in excess of 71 and 79 kBq/kg, dry weight (DW), respectively. In Kashiwa city, 195 km away from the Fukushima Daiichi, the sample concentrations were in excess of 3.4 and 4.3 kBq/kg DW, respectively. In Toyohashi city, 440 km away from the Fukushima Daiichi, the concentrations were below the measurable limits of up to 4.5 Bq/kg DW. In the radiocesium contaminated samples, the radiocesium activity was higher in mature and fallen leaves than in young leaves, branches and culms. PMID- 22496857 TI - Modulation of GSK-3beta activity in Venezuelan equine encephalitis virus infection. AB - Alphaviruses, including Venezuelan Equine Encephalitis Virus (VEEV), cause disease in both equine and humans that exhibit overt encephalitis in a significant percentage of cases. Features of the host immune response and tissue specific responses may contribute to fatal outcomes as well as the development of encephalitis. It has previously been shown that VEEV infection of mice induces transcription of pro-inflammatory cytokines genes (e.g., IFN-gamma, IL-6, IL-12, iNOS and TNF-alpha) within 6 h. GSK-3beta is a host protein that is known to modulate pro-inflammatory gene expression and has been a therapeutic target in neurodegenerative disorders such as Alzheimer's. Hence inhibition of GSK-3beta in the context of encephalitic viral infections has been useful in a neuroprotective capacity. Small molecule GSK-3beta inhibitors and GSK-3beta siRNA experiments indicated that GSK-3beta was important for VEEV replication. Thirty-eight second generation BIO derivatives were tested and BIOder was found to be the most potent inhibitor, with an IC(50) of ~0.5 uM and a CC(50) of >100 uM. BIOder was a more potent inhibitor of GSK-3beta than BIO, as demonstrated through in vitro kinase assays from uninfected and infected cells. Size exclusion chromatography experiments demonstrated that GSK-3beta is found in three distinct complexes in VEEV infected cells, whereas GSK-3beta is only present in one complex in uninfected cells. Cells treated with BIOder demonstrated an increase in the anti apoptotic gene, survivin, and a decrease in the pro-apoptotic gene, BID, suggesting that modulation of pro- and anti-apoptotic genes contributes to the protective effect of BIOder treatment. Finally, BIOder partially protected mice from VEEV induced mortality. Our studies demonstrate the utility of GSK-3beta inhibitors for modulating VEEV infection. PMID- 22496859 TI - Contribution by polymorphonucleate granulocytes to elevated gamma glutamyltransferase in cystic fibrosis sputum. AB - BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive disorder characterized by a chronic neutrophilic airways inflammation, increasing levels of oxidative stress and reduced levels of antioxidants such as glutathione (GSH). Gamma glutamyltransferase (GGT), an enzyme induced by oxidative stress and involved in the catabolism of GSH and its derivatives, is increased in the airways of CF patients with inflammation, but the possible implications of its increase have not yet been investigated in detail. PRINCIPAL FINDINGS: The present study was aimed to evaluate the origin and the biochemical characteristics of the GGT detectable in CF sputum. We found GGT activity both in neutrophils and in the fluid, the latter significantly correlating with myeloperoxidase expression. In neutrophils, GGT was associated with intracellular granules. In the fluid, gel filtration chromatography showed the presence of two distinct GGT fractions, the first corresponding to the human plasma b-GGT fraction, the other to the free enzyme. The same fractions were also observed in the supernatant of ionomycin and fMLP-activated neutrophils. Western blot analysis confirmed the presence of a single band of GGT immunoreactive peptide in the CF sputum samples and in isolated neutrophils. CONCLUSIONS: In conclusion, our data indicate that neutrophils are able to transport and release GGT, thus increasing GGT activity in CF sputum. The prompt release of GGT may have consequences on all GGT substrates, including major inflammatory mediators such as S-nitrosoglutathione and leukotrienes, and could participate in early modulation of inflammatory response. PMID- 22496860 TI - Landscape encodings enhance optimization. AB - Hard combinatorial optimization problems deal with the search for the minimum cost solutions (ground states) of discrete systems under strong constraints. A transformation of state variables may enhance computational tractability. It has been argued that these state encodings are to be chosen invertible to retain the original size of the state space. Here we show how redundant non-invertible encodings enhance optimization by enriching the density of low-energy states. In addition, smooth landscapes may be established on encoded state spaces to guide local search dynamics towards the ground state. PMID- 22496861 TI - Image tracking study on courtship behavior of Drosophila. AB - BACKGROUND: In recent years, there have been extensive studies aimed at decoding the DNA. Identifying the genetic cause of specific changes in a simple organism like Drosophila may help scientists recognize how multiple gene interactions may make some people more susceptible to heart disease or cancer. Investigators have devised experiments to observe changes in the gene networks in mutant Drosophila that responds differently to light, or have lower or higher locomotor activity. However, these studies focused on the behavior of the individual fly or on pair wise interactions in the study of aggression or courtship. The behavior of these activities has been captured on film and inspected by a well-trained researcher after repeatedly watching the recorded film. Some studies also focused on ways to reduce the inspection time and increase the accuracy of the behavior experiment. METHODOLOGY: In this study, the behavior of drosophila during courtship was analyzed automatically by machine vision. We investigated the position and behavior discrimination during courtship using the captured images. Identification of the characteristics of drosophila, including sex, size, heading direction, and wing angles, can be computed using image analysis techniques that employ the Gaussian mixture model. The behavior of multiple drosophilae can also be analyzed simultaneously using the motion-prediction model and the variation constraint of heading direction. CONCLUSIONS: The overlapped fruit flies can be identified based on the relationship between body centers. Moreover, the behaviors and profiles can be correctly recognized by image processing based on the constraints of the wing angle and the size of the body. Therefore, the behavior of the male fruit flies can be discriminated when two or three fruit flies form a close cluster. In this study, the courtship behavior, including wing songs and attempts, can currently be distinguished with accuracies of 95.8% and 90%, respectively. PMID- 22496862 TI - A high-density EEG investigation into steady state binaural beat stimulation. AB - Binaural beats are an auditory phenomenon that has been suggested to alter physiological and cognitive processes including vigilance and brainwave entrainment. Some personality traits measured by the NEO Five Factor Model have been found to alter entrainment using pulsing light stimuli, but as yet no studies have examined if this occurs using steady state presentation of binaural beats for a relatively short presentation of two minutes. This study aimed to examine if binaural beat stimulation altered vigilance or cortical frequencies and if personality traits were involved. Thirty-one participants were played binaural beat stimuli designed to elicit a response at either the Theta (7 Hz) or Beta (16 Hz) frequency bands while undertaking a zero-back vigilance task. EEG was recorded from a high-density electrode cap. No significant differences were found in vigilance or cortical frequency power during binaural beat stimulation compared to a white noise control period. Furthermore, no significant relationships were detected between the above and the Big Five personality traits. This suggests a short presentation of steady state binaural beats are not sufficient to alter vigilance or entrain cortical frequencies at the two bands examined and that certain personality traits were not more susceptible than others. PMID- 22496863 TI - Human cytomegalovirus entry into dendritic cells occurs via a macropinocytosis like pathway in a pH-independent and cholesterol-dependent manner. AB - Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that is able to infect fibroblastic, epithelial, endothelial and hematopoietic cells. Over the past ten years, several groups have provided direct evidence that dendritic cells (DCs) fully support the HCMV lytic cycle. We previously demonstrated that the C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non integrin (DC-SIGN) has a prominent role in the docking of HCMV on monocyte derived DCs (MDDCs). The DC-SIGN/HCMV interaction was demonstrated to be a crucial and early event that substantially enhanced infection in trans, i.e., from one CMV-bearing cell to another non-infected cell (or trans-infection), and rendered susceptible cells fully permissive to HCMV infection. Nevertheless, nothing is yet known about how HCMV enters MDDCs. In this study, we demonstrated that VHL/E HCMV virions (an endothelio/dendrotropic strain) are first internalized into MDDCs by a macropinocytosis-like process in an actin- and cholesterol-dependent, but pH-independent, manner. We observed the accumulation of virions in large uncoated vesicles with endosomal features, and the virions remained as intact particles that retained infectious potential for several hours. This trans-infection property was specific to MDDCs because monocyte derived macrophages or monocytes from the same donor were unable to allow the accumulation of and the subsequent transmission of the virus. Together, these data allowed us to delineate the early mechanisms of the internalization and entry of an endothelio/dendrotropic HCMV strain into human MDDCs and to propose that DCs can serve as a "Trojan horse" to convey CMV from entry sites to other locations that may favor the occurrence of either latency or acute infection. PMID- 22496864 TI - A streamlined DNA tool for global identification of heavily exploited coastal shark species (genus Rhizoprionodon). AB - Obtaining accurate species-specific landings data is an essential step toward achieving sustainable shark fisheries. Globally distributed sharpnose sharks (genus Rhizoprionodon) exhibit life-history characteristics (rapid growth, early maturity, annual reproduction) that suggests that they could be fished in a sustainable manner assuming an investment in monitoring, assessment and careful management. However, obtaining species-specific landings data for sharpnose sharks is problematic because they are morphologically very similar to one another. Moreover, sharpnose sharks may also be confused with other small sharks (either small species or juveniles of large species) once they are processed (i.e., the head and fins are removed). Here we present a highly streamlined molecular genetics approach based on seven species-specific PCR primers in a multiplex format that can simultaneously discriminate body parts from the seven described sharpnose shark species commonly occurring in coastal fisheries worldwide. The species-specific primers are based on nucleotide sequence differences among species in the nuclear ribosomal internal transcribed spacer 2 locus (ITS2). This approach also distinguishes sharpnose sharks from a wide range of other sharks (52 species) and can therefore assist in the regulation of coastal shark fisheries around the world. PMID- 22496865 TI - The human operculo-insular cortex is pain-preferentially but not pain-exclusively activated by trigeminal and olfactory stimuli. AB - Increasing evidence about the central nervous representation of pain in the brain suggests that the operculo-insular cortex is a crucial part of the pain matrix. The pain-specificity of a brain region may be tested by administering nociceptive stimuli while controlling for unspecific activations by administering non nociceptive stimuli. We applied this paradigm to nasal chemosensation, delivering trigeminal or olfactory stimuli, to verify the pain-specificity of the operculo insular cortex. In detail, brain activations due to intranasal stimulation induced by non-nociceptive olfactory stimuli of hydrogen sulfide (5 ppm) or vanillin (0.8 ppm) were used to mask brain activations due to somatosensory, clearly nociceptive trigeminal stimulations with gaseous carbon dioxide (75% v/v). Functional magnetic resonance (fMRI) images were recorded from 12 healthy volunteers in a 3T head scanner during stimulus administration using an event related design. We found that significantly more activations following nociceptive than non-nociceptive stimuli were localized bilaterally in two restricted clusters in the brain containing the primary and secondary somatosensory areas and the insular cortices consistent with the operculo-insular cortex. However, these activations completely disappeared when eliminating activations associated with the administration of olfactory stimuli, which were small but measurable. While the present experiments verify that the operculo insular cortex plays a role in the processing of nociceptive input, they also show that it is not a pain-exclusive brain region and allow, in the experimental context, for the interpretation that the operculo-insular cortex splay a major role in the detection of and responding to salient events, whether or not these events are nociceptive or painful. PMID- 22496866 TI - The neuronal EGF-related gene Nell2 interacts with Macf1 and supports survival of retinal ganglion cells after optic nerve injury. AB - Nell2 is a neuron-specific protein containing six epidermal growth factor-like domains. We have identified Nell2 as a retinal ganglion cell (RGC)-expressed gene by comparing mRNA profiles of control and RGC-deficient rat retinas. The aim of this study was to analyze Nell2 expression in wild-type and optic nerve axotomized retinas and evaluate its potential role in RGCs. Nell2-positive in situ and immunohistochemical signals were localized to irregularly shaped cells in the ganglion cell layer (GCL) and colocalized with retrogradely-labeled RGCs. No Nell2-positive cells were detected in 2 weeks optic nerve transected (ONT) retinas characterized with approximately 90% RGC loss. RT-PCR analysis showed a dramatic decrease in the Nell2 mRNA level after ONT compared to the controls. Immunoblot analysis of the Nell2 expression in the retina revealed the presence of two proteins with approximate MW of 140 and 90 kDa representing glycosylated and non-glycosylated Nell2, respectively. Both products were almost undetectable in retinal protein extracts two weeks after ONT. Proteome analysis of Nell2 interacting proteins carried out with MALDI-TOF MS (MS) identified microtubule actin crosslinking factor 1 (Macf1), known to be critical in CNS development. Strong Macf1 expression was observed in the inner plexiform layer and GCL where it was colocalizied with Thy-1 staining. Since Nell2 has been reported to increase neuronal survival of the hippocampus and cerebral cortex, we evaluated the effect of Nell2 overexpression on RGC survival. RGCs in the nasal retina were consistently more efficiently transfected than in other areas (49% vs. 13%; n = 5, p<0.05). In non-transfected or pEGFP-transfected ONT retinas, the loss of RGCs was approximately 90% compared to the untreated control. In the nasal region, Nell2 transfection led to the preservation of approximately 58% more cells damaged by axotomy compared to non-transfected (n = 5, p<0.01) or pEGFP transfected controls (n = 5, p<0.01). PMID- 22496867 TI - The association between depressive symptoms and non-psychiatric hospitalisation in older adults. AB - BACKGROUND: It is known that people who suffer from depression are more likely to have other physical illnesses, but the extent of the association between depression and non-psychiatric hospitalisation episodes has never been researched in great depth. We therefore aimed to investigate whether depressed middle-aged and older people were more likely to be hospitalised for causes other than mental illnesses, and whether the outcomes for this group of people were less favourable. METHODS #ENTITYSTARTX00026; FINDINGS: Hospital events from 1995 to 2006 were obtained from the Dutch National Medical Register and linked to participants of the Longitudinal Aging Study Amsterdam (LASA). Linkage was accomplished in 97% of the LASA sample by matching gender, year of birth and postal code. Depression was measured at each wave point of the LASA study using the Centre for Epidemiologic Studies Depression (CES-D). Hospital outcomes including admission, length of stay, readmission and death while in hospital were recorded at 6, 12 and 24 months intervals after each LASA interview. Generalised Estimating Equation models were also used to investigate potential confounders. After 12 months, 14% of depressed people were hospitalised compared to 10% of non depressed individuals. There was a 2-fold increase in deaths while in hospital amongst the depressed (0.8% vs 0.4%), who also had longer total length of stay (2.6 days vs 1.4 days). Chronic illnesses and functional limitations had major attenuating effects, but depression was found to be an independent risk factor for length of stay after full adjustment (OR = 1.33, 95% CI: 1.22-1.46 after 12 months). CONCLUSIONS: Depression in middle and old age is associated with non psychiatric hospitalisation, longer length of stay and higher mortality in clinical settings. Targeting of this high-risk group could reduce the financial, medical and social burden related to hospital admission. PMID- 22496868 TI - Musashi2 is required for the self-renewal and pluripotency of embryonic stem cells. AB - Recent studies have shown that the RNA binding protein Musashi 2 (Msi2) plays important roles during development. Msi2 has also been shown to be elevated in several leukemias and its elevated expression has been linked with poorer prognosis in these cancers. Additionally, in embryonic stem cells (ESC) undergoing the early stages of differentiation, Msi2 has been shown to associate with the transcription factor Sox2, which is required for the self-renewal of ESC. These findings led us to examine the effects of Msi2 on the behavior of ESC. We determined that ESC express two isoforms of Msi2, the larger canonical isoform (isoform 1) and a shorter, splice-variant isoform (isoform 2). Using multiple shRNA lentiviral vectors, we determined that knockdown of Msi2 disrupts the self renewal of ESC and promotes their differentiation into cells that express markers associated with mesoderm, ectoderm, and trophectoderm. Moreover, our studies indicate that the extent of differentiation and the loss of self-renewal capacity correlate with the levels to which Msi2 levels were decreased. We extended these findings by engineering ESC to inducibly express either Msi2 isoform1 or isoform 2. We determined that ectopic expression of Msi2 isoform 1, but not isoform 2, enhances the cloning efficiency of ESC. In addition, we examined how Msi2 isoform 1 and isoform 2 affect the differentiation of ESC. Interestingly, ectopic expression of either Msi2 isoform 1 or isoform 2 does not affect the pattern of differentiation induced by retinoic acid. Finally, we show that ectopic expression of either isoform 1 or isoform 2 is not sufficient to block the differentiation that results from the knockdown of both isoforms of Msi2. Thus, it appears that both isoforms of Msi2 are required for the self-renewal of ESC. PMID- 22496869 TI - PRC1 and PRC2 are not required for targeting of H2A.Z to developmental genes in embryonic stem cells. AB - The essential histone variant H2A.Z localises to both active and silent chromatin sites. In embryonic stem cells (ESCs), H2A.Z is also reported to co-localise with polycomb repressive complex 2 (PRC2) at developmentally silenced genes. The mechanism of H2A.Z targeting is not clear, but a role for the PRC2 component Suz12 has been suggested. Given this association, we wished to determine if polycomb functionally directs H2A.Z incorporation in ESCs. We demonstrate that the PRC1 component Ring1B interacts with multiple complexes in ESCs. Moreover, we show that although the genomic distribution of H2A.Z co-localises with PRC2, Ring1B and with the presence of CpG islands, H2A.Z still blankets polycomb target loci in the absence of Suz12, Eed (PRC2) or Ring1B (PRC1). Therefore we conclude that H2A.Z accumulates at developmentally silenced genes in ESCs in a polycomb independent manner. PMID- 22496870 TI - Differential epigenetic regulation of TOX subfamily high mobility group box genes in lung and breast cancers. AB - Aberrant cytosine methylation affects regulation of hundreds of genes during cancer development. In this study, a novel aberrantly hypermethylated CpG island in cancer was discovered within the TOX2 promoter. TOX2 was unmethylated in normal cells but 28% lung (n = 190) and 23% breast (n = 80) tumors were methylated. Expression of two novel TOX2 transcripts identified was significantly reduced in primary lung tumors than distant normal lung (p<0.05). These transcripts were silenced in methylated lung and breast cancer cells and 5-Aza-2 deoxycytidine treatment re-expressed both. Extension of these assays to TOX, TOX3, and TOX4 genes that share similar genomic structure and protein homology with TOX2 revealed distinct methylation profiles by smoking status, histology, and cancer type. TOX was almost exclusively methylated in breast (43%) than lung (5%) cancer, whereas TOX3 was frequently methylated in lung (58%) than breast (30%) tumors. TOX4 was unmethylated in all samples and showed the highest expression in normal lung. Compared to TOX4, expression of TOX, TOX2 and TOX3 in normal lung was 25, 44, and 88% lower, respectively, supporting the premise that reduced promoter activity confers increased susceptibility to methylation during lung carcinogenesis. Genome-wide assays revealed that siRNA-mediated TOX2 knockdown modulated multiple pathways while TOX3 inactivation targeted neuronal development and function. Although these knockdowns did not result in further phenotypic changes of lung cancer cells in vitro, the impact on tissue remodeling, inflammatory response, and cell differentiation pathways suggest a potential role for TOX2 in modulating tumor microenvironment. PMID- 22496871 TI - In vivo analysis of MEF2 transcription factors in synapse regulation and neuronal survival. AB - MEF2 (A-D) transcription factors govern development, differentiation and maintenance of various cell types including neurons. The role of MEF2 isoforms in the brain has been studied using in vitro manipulations with only MEF2C examined in vivo. In order to understand specific as well as redundant roles of the MEF2 isoforms, we generated brain-specific deletion of MEF2A and found that Mef2aKO mice show normal behavior in a range of paradigms including learning and memory. We next generated Mef2a and Mef2d brain-specific double KO (Mef2a/dDKO) mice and observed deficits in motor coordination and enhanced hippocampal short-term synaptic plasticity, however there were no alterations in learning and memory, Schaffer collateral pathway long-term potentiation, or the number of dendritic spines. Since previous work has established a critical role for MEF2C in hippocampal plasticity, we generated a Mef2a, Mef2c and Mef2d brain-specific triple KO (Mef2a/c/dTKO). Mef2a/c/d TKO mice have early postnatal lethality with increased neuronal apoptosis, indicative of a redundant role for the MEF2 factors in neuronal survival. We examined synaptic plasticity in the intact neurons in the Mef2a/c/d TKO mice and found significant impairments in short-term synaptic plasticity suggesting that MEF2C is the major isoform involved in hippocampal synaptic function. Collectively, these data highlight the key in vivo role of MEF2C isoform in the brain and suggest that MEF2A and MEF2D have only subtle roles in regulating hippocampal synaptic function. PMID- 22496872 TI - Seasonal distribution of psychiatric births in England. AB - There is general consensus that season of birth influences the risk of developing psychiatric conditions later in life. We aimed to investigate whether the risk of schizophrenia (SC), bipolar affective disorder (BAD) and recurrent depressive disorder (RDD) is influenced by month of birth in England to a similar extent as other countries using the largest cohort of English patients collected to date (n = 57,971). When cases were compared to the general English population (n = 29,183,034) all diseases showed a seasonal distribution of births (SC p = 2.48E 05; BAD p = 0.019; RDD p = 0.015). This data has implications for future strategies of disease prevention. PMID- 22496873 TI - Differential expression of microRNAs in adipose tissue after long-term high-fat diet-induced obesity in mice. AB - Obesity is a major health concern worldwide which is associated with increased risk of chronic diseases such as metabolic syndrome, cardiovascular disease and cancer. The elucidation of the molecular mechanisms involved in adipogenesis and obesogenesis is of essential importance as it could lead to the identification of novel biomarkers and therapeutic targets for the development of anti-obesity drugs. MicroRNAs (miRNAs) have been shown to play regulatory roles in several biological processes. They have become a growing research field and consist of promising pharmaceutical targets in various fields such as cancer, metabolism, etc. The present study investigated the possible implication of miRNAs in adipose tissue during the development of obesity using as a model the C57BLJ6 mice fed a high-fat diet.C57BLJ6 wild type male mice were fed either a standard (SD) or a high-fat diet (HFD) for 5 months. Total RNA was prepared from white adipose tissue and was used for microRNA profiling and qPCR.Twenty-two of the most differentially expressed miRNAs, as identified by the microRNA profiling were validated using qPCR. The results of the present study confirmed previous results. The up-regulation of mmu-miR-222 and the down-regulation of mmu-miR 200b, mmu-miR-200c, mmu-miR-204, mmu-miR-30a*, mmu-miR-193, mmu-miR-378 and mmu miR-30e* after HFD feeding has also been previously reported. On the other hand, we show for the first time the up-regulation of mmu-miR-342-3p, mmu-miR-142-3p, mmu-miR-142-5p, mmu-miR-21, mmu-miR-146a, mmu-miR-146b, mmu-miR-379 and the down regulation of mmu-miR-122, mmu-miR-133b, mmu-miR-1, mmu-miR-30a*, mmu-miR-192 and mmu-miR-203 during the development of obesity. However, future studies are warranted in order to understand the exact role that miRNAs play in adipogenesis and obesity. PMID- 22496874 TI - Fingerprinting the Asterid species using subtracted diversity array reveals novel species-specific sequences. AB - BACKGROUND: Asterids is one of the major plant clades comprising of many commercially important medicinal species. One of the major concerns in medicinal plant industry is adulteration/contamination resulting from misidentification of herbal plants. This study reports the construction and validation of a microarray capable of fingerprinting medicinally important species from the Asterids clade. METHODOLOGY/PRINCIPAL FINDINGS: Pooled genomic DNA of 104 non-asterid angiosperm and non-angiosperm species was subtracted from pooled genomic DNA of 67 asterid species. Subsequently, 283 subtracted DNA fragments were used to construct an Asterid-specific array. The validation of Asterid-specific array revealed a high (99.5%) subtraction efficiency. Twenty-five Asterid species (mostly medicinal) representing 20 families and 9 orders within the clade were hybridized onto the array to reveal its level of species discrimination. All these species could be successfully differentiated using their hybridization patterns. A number of species-specific probes were identified for commercially important species like tea, coffee, dandelion, yarrow, motherwort, Japanese honeysuckle, valerian, wild celery, and yerba mate. Thirty-seven polymorphic probes were characterized by sequencing. A large number of probes were novel species-specific probes whilst some of them were from chloroplast region including genes like atpB, rpoB, and ndh that have extensively been used for fingerprinting and phylogenetic analysis of plants. CONCLUSIONS/SIGNIFICANCE: Subtracted Diversity Array technique is highly efficient in fingerprinting species with little or no genomic information. The Asterid-specific array could fingerprint all 25 species assessed including three species that were not used in constructing the array. This study validates the use of chloroplast genes for bar-coding (fingerprinting) plant species. In addition, this method allowed detection of several new loci that can be explored to solve existing discrepancies in phylogenetics and fingerprinting of plants. PMID- 22496875 TI - Recognition of Porphyromonas gingivalis gingipain epitopes by natural IgM binding to malondialdehyde modified low-density lipoprotein. AB - OBJECTIVE: Increased risk for atherosclerosis is associated with infectious diseases including periodontitis. Natural IgM antibodies recognize pathogen associated molecular patterns on bacteria, and oxidized lipid and protein epitopes on low-density lipoprotein (LDL) and apoptotic cells. We aimed to identify epitopes on periodontal pathogen Porphyromonas gingivalis recognized by natural IgM binding to malondialdehyde (MDA) modified LDL. METHODS AND RESULTS: Mouse monoclonal IgM (MDmAb) specific for MDA-LDL recognized epitopes on P. gingivalis on flow cytometry and chemiluminescence immunoassays. Immunization of C57BL/6 mice with P. gingivalis induced IgM, but not IgG, immune response to MDA LDL and apoptotic cells. Immunization of LDLR(-/-) mice with P. gingivalis induced IgM, but not IgG, immune response to MDA-LDL and diminished aortic lipid deposition. On Western blot MDmAb bound to P. gingivalis fragments identified as arginine-specific gingipain (Rgp) by mass spectrometry. Recombinant domains of Rgp produced in E. coli were devoid of phosphocholine epitopes but contained epitopes recognized by MDmAb and human serum IgM. Serum IgM levels to P. gingivalis were associated with anti-MDA-LDL levels in humans. CONCLUSION: Gingipain of P. gingivalis is recognized by natural IgM and shares molecular identity with epitopes on MDA-LDL. These findings suggest a role for natural antibodies in the pathogenesis of two related inflammatory diseases, atherosclerosis and periodontitis. PMID- 22496876 TI - Direct observation of strand passage by DNA-topoisomerase and its limited processivity. AB - Type-II DNA topoisomerases resolve DNA entanglements such as supercoils, knots and catenanes by passing one segment of DNA duplex through a transient enzyme bridged double-stranded break in another segment. The ATP-dependent passage reaction has previously been demonstrated at the single-molecule level, showing apparent processivity at saturating ATP. Here we directly observed the strand passage by human topoisomerase IIalpha, after winding a pair of fluorescently stained DNA molecules with optical tweezers for 30 turns into an X-shaped braid. On average 0.51 +/- 0.33 um (11 +/- 6 turns) of a braid was unlinked in a burst of reactions taking 8 +/- 4 s, the unlinked length being essentially independent of the enzyme concentration between 0.25-37 pM. The time elapsed before the start of processive unlinking decreased with the enzyme concentration, being ~100 s at 3.7 pM. These results are consistent with a scenario where the enzyme binds to one DNA for a period of ~10 s, waiting for multiple diffusional encounters with the other DNA to transport it across the break ~10 times, and then dissociates from the binding site without waiting for the exhaustion of transportable DNA segments. PMID- 22496877 TI - Parallel odor processing by two anatomically distinct olfactory bulb target structures. AB - The olfactory cortex encompasses several anatomically distinct regions each hypothesized to provide differential representation and processing of specific odors. Studies exploring whether or not the diversity of olfactory bulb input to olfactory cortices has functional meaning, however, are lacking. Here we tested whether two anatomically major olfactory cortical structures, the olfactory tubercle (OT) and piriform cortex (PCX), differ in their neural representation and processing dynamics of a small set of diverse odors by performing in vivo extracellular recordings from the OT and PCX of anesthetized mice. We found a wealth of similarities between structures, including odor-evoked response magnitudes, breadth of odor tuning, and odor-evoked firing latencies. In contrast, only few differences between structures were found, including spontaneous activity rates and odor signal-to-noise ratios. These results suggest that despite major anatomical differences in innervation by olfactory bulb mitral/tufted cells, the basic features of odor representation and processing, at least within this limited odor set, are similar within the OT and PCX. We predict that the olfactory code follows a distributed processing stream in transmitting behaviorally and perceptually-relevant information from low-level stations. PMID- 22496878 TI - Inverse correlation between serum levels of selenoprotein P and adiponectin in patients with type 2 diabetes. AB - BACKGROUND: We recently identified selenoprotein P (SeP) as a liver-derived secretory protein that causes insulin resistance in the liver and skeletal muscle; however, it is unknown whether and, if so, how SeP acts on adipose tissue. The present study tested the hypothesis that SeP is related to hypoadiponectinemia in patients with type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: We compared serum levels of SeP with those of adiponectin and other clinical parameters in 36 patients with type 2 diabetes. We also measured levels of blood adiponectin in SeP knockout mice. Circulating SeP levels were positively correlated with fasting plasma glucose (r = 0.35, P = 0.037) and negatively associated with both total and high-molecular adiponectin in patients with type 2 diabetes (r = -0.355, P = 0.034; r = -0.367, P = 0.028). SeP was a predictor of both total and high-molecular adiponectin, independently of age, body weight, and quantitative insulin sensitivity index (beta = -0.343, P = 0.022; beta = -0.357, P = 0.017). SeP knockout mice exhibited an increase in blood adiponectin levels when fed regular chow or a high sucrose, high fat diet. CONCLUSIONS/SIGNIFICANCE: These results suggest that overproduction of liver-derived secretory protein SeP is connected with hypoadiponectinemia in patients with type 2 diabetes. PMID- 22496879 TI - Effect of cyclic strain on cardiomyogenic differentiation of rat bone marrow derived mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are a potential source of material for the generation of tissue-engineered cardiac grafts because of their ability to transdifferentiate into cardiomyocytes after chemical treatments or co-culture with cardiomyocytes. Cardiomyocytes in the body are subjected to cyclic strain induced by the rhythmic heart beating. Whether cyclic strain could regulate rat bone marrow derived MSC (rBMSC) differentiation into cardiomyocyte-like lineage was investigated in this study. A stretching device was used to generate the cyclic strain for rBMSCs. Cardiomyogenic differentiation was evaluated using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR), immunocytochemistry and western-blotting. The results demonstrated that appropriate cyclic strain treatment alone could induce cardiomyogenic differentiation of rBMSCs, as confirmed by the expression of cardiomyocyte related markers at both mRNA and protein levels. Furthermore, rBMSCs exposed to the strain stimulation expressed cardiomyocyte-related markers at a higher level than the shear stimulation. In addition, when rBMSCs were exposed to both strain and 5-azacytidine (5-aza), expression levels of cardiomyocyte-related markers significantly increased to a degree suggestive of a synergistic interaction. These results suggest that cyclic strain is an important mechanical stimulus affecting the cardiomyogenic differentiation of rBMSCs. This provides a new avenue for mechanistic studies of stem cell differentiation and a new approach to obtain more committed differentiated cells. PMID- 22496880 TI - A family-wide RT-PCR assay for detection of paramyxoviruses and application to a large-scale surveillance study. AB - Family-wide molecular diagnostic assays are valuable tools for initial identification of viruses during outbreaks and to limit costs of surveillance studies. Recent discoveries of paramyxoviruses have called for such assay that is able to detect all known and unknown paramyxoviruses in one round of PCR amplification. We have developed a RT-PCR assay consisting of a single degenerate primer set, able to detect all members of the Paramyxoviridae family including all virus genera within the subfamilies Paramyxovirinae and Pneumovirinae. Primers anneal to domain III of the polymerase gene, with the 3' end of the reverse primer annealing to the conserved motif GDNQ, which is proposed to be the active site for nucleotide polymerization. The assay was fully optimized and was shown to indeed detect all available paramyxoviruses tested. Clinical specimens from hospitalized patients that tested positive for known paramyxoviruses in conventional assays were also detected with the novel family-wide test. A high throughput fluorescence-based RT-PCR version of the assay was developed for screening large numbers of specimens. A large number of samples collected from wild birds was tested, resulting in the detection of avian paramyxoviruses type 1 in both barnacle and white-fronted geese, and type 8 in barnacle geese. Avian metapneumovirus type C was found for the first time in Europe in mallards, greylag geese and common gulls. The single round family-wide RT-PCR assay described here is a useful tool for the detection of known and unknown paramyxoviruses, and screening of large sample collections from humans and animals. PMID- 22496881 TI - Assessment of chitosan-affected metabolic response by peroxisome proliferator activated receptor bioluminescent imaging-guided transcriptomic analysis. AB - Chitosan has been widely used in food industry as a weight-loss aid and a cholesterol-lowering agent. Previous studies have shown that chitosan affects metabolic responses and contributes to anti-diabetic, hypocholesteremic, and blood glucose-lowering effects; however, the in vivo targeting sites and mechanisms of chitosan remain to be clarified. In this study, we constructed transgenic mice, which carried the luciferase genes driven by peroxisome proliferator-activated receptor (PPAR), a key regulator of fatty acid and glucose metabolism. Bioluminescent imaging of PPAR transgenic mice was applied to report the organs that chitosan acted on, and gene expression profiles of chitosan targeted organs were further analyzed to elucidate the mechanisms of chitosan. Bioluminescent imaging showed that constitutive PPAR activities were detected in brain and gastrointestinal tract. Administration of chitosan significantly activated the PPAR activities in brain and stomach. Microarray analysis of brain and stomach showed that several pathways involved in lipid and glucose metabolism were regulated by chitosan. Moreover, the expression levels of metabolism associated genes like apolipoprotein B (apoB) and ghrelin genes were down regulated by chitosan. In conclusion, these findings suggested the feasibility of PPAR bioluminescent imaging-guided transcriptomic analysis on the evaluation of chitosan-affected metabolic responses in vivo. Moreover, we newly identified that downregulated expression of apoB and ghrelin genes were novel mechanisms for chitosan-affected metabolic responses in vivo. PMID- 22496882 TI - Selection of suitable reference genes for RT-qPCR analyses in cyanobacteria. AB - Cyanobacteria are a group of photosynthetic prokaryotes that have a diverse morphology, minimal nutritional requirements and metabolic plasticity that has made them attractive organisms to use in biotechnological applications. The use of these organisms as cell factories requires the knowledge of their physiology and metabolism at a systems level. For the quantification of gene transcripts real-time quantitative polymerase chain reaction (RT-qPCR) is the standard technique. However, to obtain reliable RT-qPCR results the use and validation of reference genes is mandatory. Towards this goal we have selected and analyzed twelve candidate reference genes from three morphologically distinct cyanobacteria grown under routinely used laboratory conditions. The six genes exhibiting less variation in each organism were evaluated in terms of their expression stability using geNorm, NormFinder and BestKeeper. In addition, the minimum number of reference genes required for normalization was determined. Based on the three algorithms, we provide a list of genes for cyanobacterial RT qPCR data normalization. To our knowledge, this is the first work on the validation of reference genes for cyanobacteria constituting a valuable starting point for future works. PMID- 22496883 TI - RAGE mediates accelerated diabetic vein graft atherosclerosis induced by combined mechanical stress and AGEs via synergistic ERK activation. AB - AIMS/HYPOTHESIS: Diabetes with hypertension rapidly accelerates vascular disease, but the underlying mechanism remains unclear. We evaluated the hypothesis that the receptor of advanced glycation end products (RAGE) might mediate combined signals initiated by diabetes-related AGEs and hypertension-induced mechanical stress as a common molecular sensor. METHODS: In vivo surgical vein grafts created by grafting vena cava segments from C57BL/6J mice into the common carotid arteries of streptozotocin (STZ)-treated and untreated isogenic mice for 4 and 8 weeks were analyzed using morphometric and immunohistochemical techniques. In vitro quiescent mouse vascular smooth muscle cells (VSMCs) with either knockdown or overexpression of RAGE were subjected to cyclic stretching with or without AGEs. Extracellular signal-regulated kinase (ERK) phosphorylation and Ki-67 expression were investigated. RESULTS: Significant increases in neointimal formation, AGE deposition, Ki-67 expression, and RAGE were observed in the vein grafts of STZ-induced diabetic mice. The highest levels of ERK phosphorylation and Ki-67 expression in VSMCs were induced by simultaneous stretch stress and AGE exposure. The synergistic activation of ERKs and Ki-67 in VSMCs was significantly inhibited by siRNA-RAGE treatment and enhanced by over-expression of RAGE. CONCLUSION: RAGE may mediate synergistically increased ERK activation and VSMC proliferation induced by mechanical stretching with and without AGEs. It may serve as a common molecular bridge between the two, accelerating vascular remodeling. This study provides potential drug targets and novel therapeutic strategies for the treatment of vascular diseases resulting from diabetes with hypertension. PMID- 22496884 TI - Computational comparative study of tuberculosis proteomes using a model learned from signal peptide structures. AB - Secretome analysis is important in pathogen studies. A fundamental and convenient way to identify secreted proteins is to first predict signal peptides, which are essential for protein secretion. However, signal peptides are highly complex functional sequences that are easily confused with transmembrane domains. Such confusion would obviously affect the discovery of secreted proteins. Transmembrane proteins are important drug targets, but very few transmembrane protein structures have been determined experimentally; hence, prediction of the structures is essential. In the field of structure prediction, researchers do not make assumptions about organisms, so there is a need for a general signal peptide predictor.To improve signal peptide prediction without prior knowledge of the associated organisms, we present a machine-learning method, called SVMSignal, which uses biochemical properties as features, as well as features acquired from a novel encoding, to capture biochemical profile patterns for learning the structures of signal peptides directly.We tested SVMSignal and five popular methods on two benchmark datasets from the SPdb and UniProt/Swiss-Prot databases, respectively. Although SVMSignal was trained on an old dataset, it performed well, and the results demonstrate that learning the structures of signal peptides directly is a promising approach. We also utilized SVMSignal to analyze proteomes in the entire HAMAP microbial database. Finally, we conducted a comparative study of secretome analysis on seven tuberculosis-related strains selected from the HAMAP database. We identified ten potential secreted proteins, two of which are drug resistant and four are potential transmembrane proteins.SVMSignal is publicly available at http://bio-cluster.iis.sinica.edu.tw/SVMSignal. It provides user-friendly interfaces and visualizations, and the prediction results are available for download. PMID- 22496885 TI - Effect of CCR5-Delta32 heterozygosity on HIV-1 susceptibility: a meta-analysis. AB - BACKGROUND: So far, many studies have investigated the distribution of CCR5 genotype between HIV-1 infected patients and uninfected people. However, no definite results have been put forward about whether heterozygosity for a 32 basepair deletion in CCR5 gene (CCR5-Delta32) can affect HIV-1 susceptibility. METHODS: We performed a meta-analysis of 18 studies including more than 12000 subjects for whom the CCR5-Delta32 polymorphism was genotyped. Odds ratio (OR) with 95% confidence interval (CI) were employed to assess the association of CCR5 Delta32 polymorphism with HIV-1 susceptibility. RESULTS: Compared with the wild type CCR5 homozygotes, the pooled OR for CCR5-Delta32 heterozygotes was 1.02 (95%CI, 0.88-1.19) for healthy controls (HC) and 0.95 (95%CI, 0.71-1.26) for exposed uninfected (EU) controls. Similar results were found in stratified analysis by ethnicity, sample size and method of CCR5-Delta32 genotyping. CONCLUSIONS: The meta-analysis indicated that HIV-1 susceptibility is not significantly affected by heterozygosity for CCR5-Delta32. PMID- 22496886 TI - Olfactory bulb glomerular NMDA receptors mediate olfactory nerve potentiation and odor preference learning in the neonate rat. AB - Rat pup odor preference learning follows pairing of bulbar beta-adrenoceptor activation with olfactory input. We hypothesize that NMDA receptor (NMDAR) mediated olfactory input to mitral cells is enhanced during training, such that increased calcium facilitates and shapes the critical cAMP pattern. Here, we demonstrate, in vitro, that olfactory nerve stimulation, at sniffing frequencies, paired with beta-adrenoceptor activation, potentiates olfactory nerve-evoked mitral cell firing. This potentiation is blocked by a NMDAR antagonist and by increased inhibition. Glomerular disinhibition also induces NMDAR-sensitive potentiation. In vivo, in parallel, behavioral learning is prevented by glomerular infusion of an NMDAR antagonist or a GABA(A) receptor agonist. A glomerular GABA(A) receptor antagonist paired with odor can induce NMDAR dependent learning. The NMDA GluN1 subunit is phosphorylated in odor-specific glomeruli within 5 min of training suggesting early activation, and enhanced calcium entry, during acquisition. The GluN1 subunit is down-regulated 3 h after learning; and at 24 h post-training the GluN2B subunit is down-regulated. These events may assist memory stability. Ex vivo experiments using bulbs from trained rat pups reveal an increase in the AMPA/NMDA EPSC ratio post-training, consistent with an increase in AMPA receptor insertion and/or the decrease in NMDAR subunits. These results support a model of a cAMP/NMDA interaction in generating rat pup odor preference learning. PMID- 22496887 TI - Functional and structural analysis of the internal ribosome entry site present in the mRNA of natural variants of the HIV-1. AB - The 5'untranslated regions (UTR) of the full length mRNA of the HIV-1 proviral clones pNL4.3 and pLAI, harbor an internal ribosomal entry site (IRES). In this study we extend this finding by demonstrating that the mRNA 5'UTRs of natural variants of HIV-1 also exhibit IRES-activity. Cap-independent translational activity was demonstrated using bicistronic mRNAs in HeLa cells and in Xenopus laevis oocytes. The possibility that expression of the downstream cistron in these constructs was due to alternative splicing or to cryptic promoter activity was ruled out. The HIV-1 variants exhibited significant 5'UTR nucleotide diversity with respect to the control sequence recovered from pNL4.3. Interestingly, translational activity from the 5'UTR of some of the HIV-1 variants was enhanced relative to that observed for the 5'UTR of pNL4.3. In an attempt to explain these findings we probed the secondary structure of the variant HIV-1 5'UTRs using enzymatic and chemical approaches. Yet subsequent structural analyses did not reveal significant variations when compared to the pNL4.3-5'UTR. Thus, the increased IRES-activity observed for some of the HIV-1 variants cannot be ascribed to a specific structural modification. A model to explain these findings is proposed. PMID- 22496888 TI - Macrophage-associated mesenchymal stem cells assume an activated, migratory, pro inflammatory phenotype with increased IL-6 and CXCL10 secretion. AB - Mesenchymal stem cells (MSCs) exhibit tropism for sites of tissue injury and tumors. However, the influence of the microenvironment on MSC phenotype and localization remains incompletely characterized. In this study, we begin to define a macrophage-induced MSC phenotype. These MSCs secrete interleukin-6 (IL 6), CCL5, and interferon gamma-induced protein-10 (CXCL10) and exhibit increased mobility in response to multiple soluble factors produced by macrophages including IL-8, CCL2, and CCL5. The pro-migratory phenotype is dependent on activation of a c-Jun N-terminal kinase (JNK) pathway. This work begins to identify the influence of macrophages on MSC biology. These interactions are likely to play an important role in the tissue inflammatory response and may provide insight into the migratory potential of MSCs in inflammation and tissue injury. PMID- 22496889 TI - Successful long-term preservation of rat sperm by freeze-drying. AB - BACKGROUND: Freeze-drying sperm has been developed as a new preservation method where liquid nitrogen is no longer necessary. An advantage of freeze-drying sperm is that it can be stored at 4 degrees C and transported at room temperature. Although the successful freeze-drying of sperm has been reported in a number of animals, the possibility of long-term preservation using this method has not yet been studied. METHODOLOGY/PRINCIPAL FINDINGS: Offspring were obtained from oocytes fertilized with rat epididymal sperm freeze-dried using a solution containing 10 mM Tris and 1 mM EDTA adjusted to pH 8.0. Tolerance of testicular sperm to freeze-drying was increased by pre-treatment with diamide. Offspring with normal fertility were obtained from oocytes fertilized with freeze-dried epididymal sperm stored at 4 degrees C for 5 years. CONCLUSIONS AND SIGNIFICANCE: Sperm with -SS- cross-linking in the thiol-disulfide of their protamine were highly tolerant to freeze-drying, and the fertility of freeze dried sperm was maintained for 5 years without deterioration. This is the first report to demonstrate the successful freeze-drying of sperm using a new and simple method for long-term preservation. PMID- 22496890 TI - Short-chain 3-hydroxyacyl-coenzyme A dehydrogenase associates with a protein super-complex integrating multiple metabolic pathways. AB - Proteins involved in mitochondrial metabolic pathways engage in functionally relevant multi-enzyme complexes. We previously described an interaction between short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD) and glutamate dehydrogenase (GDH) explaining the clinical phenotype of hyperinsulinism in SCHAD deficient patients and adding SCHAD to the list of mitochondrial proteins capable of forming functional, multi-pathway complexes. In this work, we provide evidence of SCHAD's involvement in additional interactions forming tissue-specific metabolic super complexes involving both membrane-associated and matrix-dwelling enzymes and spanning multiple metabolic pathways. As an example, in murine liver, we find SCHAD interaction with aspartate transaminase (AST) and GDH from amino acid metabolic pathways, carbamoyl phosphate synthase I (CPS-1) from ureagenesis, other fatty acid oxidation and ketogenesis enzymes and fructose-bisphosphate aldolase, an extra-mitochondrial enzyme of the glycolytic pathway. Most of the interactions appear to be independent of SCHAD's role in the penultimate step of fatty acid oxidation suggesting an organizational, structural or non-enzymatic role for the SCHAD protein. PMID- 22496891 TI - JC virus T-antigen regulates glucose metabolic pathways in brain tumor cells. AB - Recent studies have reported the detection of the human neurotropic virus, JCV, in a significant population of brain tumors, including medulloblastomas. Accordingly, expression of the JCV early protein, T-antigen, which has transforming activity in cell culture and in transgenic mice, results in the development of a broad range of tumors of neural crest and glial origin. Evidently, the association of T-antigen with a range of tumor-suppressor proteins, including p53 and pRb, and signaling molecules, such as beta-catenin and IRS-1, plays a role in the oncogenic function of JCV T-antigen. We demonstrate that T-antigen expression is suppressed by glucose deprivation in medulloblastoma cells and in glioblastoma xenografts that both endogenously express T-antigen. Mechanistic studies indicate that glucose deprivation-mediated suppression of T-antigen is partly influenced by 5'-activated AMP kinase (AMPK), an important sensor of the AMP/ATP ratio in cells. In addition, glucose deprivation-induced cell cycle arrest in the G1 phase is blocked with AMPK inhibition, which also prevents T-antigen downregulation. Furthermore, T-antigen prevents G1 arrest and sustains cells in the G2 phase during glucose deprivation. On a functional level, T-antigen downregulation is partially dependent on reactive oxygen species (ROS) production during glucose deprivation, and T antigen prevents ROS induction, loss of ATP production, and cytotoxicity induced by glucose deprivation. Additionally, we have found that T-antigen is downregulated by the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), and the pentose phosphate inhibitors, 6-aminonicotinamide and oxythiamine, and that T antigen modulates expression of the glycolytic enzyme, hexokinase 2 (HK2), and the pentose phosphate enzyme, transaldolase-1 (TALDO1), indicating a potential link between T-antigen and metabolic regulation. These studies point to the possible involvement of JCV T-antigen in medulloblastoma proliferation and the metabolic phenotype and may enhance our understanding of the role of viral proteins in glycolytic tumor metabolism, thus providing useful targets for the treatment of virus-induced tumors. PMID- 22496892 TI - Detection, mapping, and quantification of single walled carbon nanotubes in histological specimens with photoacoustic microscopy. AB - AIMS: In the present study, the efficacy of multi-scale photoacoustic microscopy (PAM) was investigated to detect, map, and quantify trace amounts [nanograms (ng) to micrograms (ug)] of SWCNTs in a variety of histological tissue specimens consisting of cancer and benign tissue biopsies (histological specimens from implanted tissue engineering scaffolds). MATERIALS AND METHODS: Optical resolution (OR) and acoustic-resolution (AR)--Photoacoustic microscopy (PAM) was employed to detect, map and quantify the SWCNTs in a variety of tissue histological specimens and compared with other optical techniques (bright-field optical microscopy, Raman microscopy, near infrared (NIR) fluorescence microscopy). RESULTS: Both optical-resolution and acoustic-resolution PAM, allow the detection and quantification of SWCNTs in histological specimens with scalable spatial resolution and depth penetration. The noise-equivalent detection sensitivity to SWCNTs in the specimens was calculated to be as low as ~7 pg. Image processing analysis further allowed the mapping, distribution, and quantification of the SWCNTs in the histological sections. CONCLUSIONS: The results demonstrate the potential of PAM as a promising imaging technique to detect, map, and quantify SWCNTs in histological specimens, and could complement the capabilities of current optical and electron microscopy techniques in the analysis of histological specimens containing SWCNTs. PMID- 22496893 TI - Long lasting modulation of cortical oscillations after continuous theta burst transcranial magnetic stimulation. AB - Transcranial magnetic theta burst stimulation (TBS) differs from other high frequency rTMS protocols because it induces plastic changes up to an hour despite lower stimulus intensity and shorter duration of stimulation. However, the effects of TBS on neuronal oscillations remain unclear. In this study, we used electroencephalography (EEG) to investigate changes of neuronal oscillations after continuous TBS (cTBS), the protocol that emulates long-term depression (LTD) form of synaptic plasticity. We randomly divided 26 healthy humans into two groups receiving either Active or Sham cTBS as control over the left primary motor cortex (M1). Post-cTBS aftereffects were assessed with behavioural measurements at rest using motor evoked potentials (MEPs) and at active state during the execution of a choice reaction time (RT) task in combination with continuous electrophysiological recordings. The cTBS-induced EEG oscillations were assessed using event-related power (ERPow), which reflected regional oscillatory activity of neural assemblies of theta (4-7.5 Hz), low alpha (8-9.5 Hz), u (10-12.5 Hz), low beta (13-19.5 Hz), and high beta (20-30 Hz) brain rhythms. Results revealed 20-min suppression of MEPs and at least 30-min increase of ERPow modulation, suggesting that besides MEPs, EEG has the potential to provide an accurate cortical readout to assess cortical excitability and to investigate the interference of cortical oscillations in the human brain post cTBS. We also observed a predominant modulation of beta frequency band, supporting the hypothesis that cTBS acts more on cortical level. Theta oscillations were also modulated during rest implying the involvement of independent cortical theta generators over the motor network post cTBS. This work provided more insights into the underlying mechanisms of cTBS, providing a possible link between synchronised neural oscillations and LTD in humans. PMID- 22496894 TI - Elucidating the role of the complement control protein in monkeypox pathogenicity. AB - Monkeypox virus (MPXV) causes a smallpox-like disease in humans. Clinical and epidemiological studies provide evidence of pathogenicity differences between two geographically distinct monkeypox virus clades: the West African and Congo Basin. Genomic analysis of strains from both clades identified a ~10 kbp deletion in the less virulent West African isolates sequenced to date. One absent open reading frame encodes the monkeypox virus homologue of the complement control protein (CCP). This modulatory protein prevents the initiation of both the classical and alternative pathways of complement activation. In monkeypox virus, CCP, also known as MOPICE, is a ~24 kDa secretory protein with sequence homology to this superfamily of proteins. Here we investigate CCP expression and its role in monkeypox virulence and pathogenesis. CCP was incorporated into the West African strain and removed from the Congo Basin strain by homologous recombination. CCP expression phenotypes were confirmed for both wild type and recombinant monkeypox viruses and CCP activity was confirmed using a C4b binding assay. To characterize the disease, prairie dogs were intranasally infected and disease progression was monitored for 30 days. Removal of CCP from the Congo Basin strain reduced monkeypox disease morbidity and mortality, but did not significantly decrease viral load. The inclusion of CCP in the West African strain produced changes in disease manifestation, but had no apparent effect on disease-associated mortality. This study identifies CCP as an important immuno-modulatory protein in monkeypox pathogenesis but not solely responsible for the increased virulence seen within the Congo Basin clade of monkeypox virus. PMID- 22496895 TI - HcRed, a genetically encoded fluorescent binary cross-linking agent for cross linking of mitochondrial ATP synthase in Saccharomyces cerevisiae. AB - Genetically encoded fluorescent cross-linking agents represent powerful tools useful both for visualising and modulating protein interactions in living cells. The far-red fluorescent protein HcRed, which is fluorescent only in a dimer form, can be used to promote the homo-dimerisation of target proteins, and thereby yield useful information about biological processes. We have in yeast cells expressed HcRed fused to a subunit of mitochondrial ATP synthase (mtATPase). This resulted in cross-linking of the large multi-subunit mtATPase complex within the inner-membrane of the mitochondrion. Fluorescence microscopy revealed aberrant mitochondrial morphology, and mtATPase complexes isolated from mitochondria were recovered as fluorescent dimers under conditions where complexes from control mitochondria were recovered as monomers. When viewed by electron microscopy normal cristae were absent from mitochondria in cells in which mATPase complexes were cross-linked. mtATPase dimers are believed to be the building blocks that are assembled into supramolecular mtATPase ribbons that promote the formation of mitochondrial cristae. We propose that HcRed cross-links mATPase complexes in the mitochondrial membrane hindering the normal assembly/disassembly of the supramolecular forms of mtATPase. PMID- 22496896 TI - Lipid composition of the human eye: are red blood cells a good mirror of retinal and optic nerve fatty acids? AB - BACKGROUND: The assessment of blood lipids is very frequent in clinical research as it is assumed to reflect the lipid composition of peripheral tissues. Even well accepted such relationships have never been clearly established. This is particularly true in ophthalmology where the use of blood lipids has become very common following recent data linking lipid intake to ocular health and disease. In the present study, we wanted to determine in humans whether a lipidomic approach based on red blood cells could reveal associations between circulating and tissue lipid profiles. To check if the analytical sensitivity may be of importance in such analyses, we have used a double approach for lipidomics. METHODOLOGY AND PRINCIPAL FINDINGS: Red blood cells, retinas and optic nerves were collected from 9 human donors. The lipidomic analyses on tissues consisted in gas chromatography and liquid chromatography coupled to an electrospray ionization source-mass spectrometer (LC-ESI-MS). Gas chromatography did not reveal any relevant association between circulating and ocular fatty acids except for arachidonic acid whose circulating amounts were positively associated with its levels in the retina and in the optic nerve. In contrast, several significant associations emerged from LC-ESI-MS analyses. Particularly, lipid entities in red blood cells were positively or negatively associated with representative pools of retinal docosahexaenoic acid (DHA), retinal very-long chain polyunsaturated fatty acids (VLC-PUFA) or optic nerve plasmalogens. CONCLUSIONS AND SIGNIFICANCE: LC ESI-MS is more appropriate than gas chromatography for lipidomics on red blood cells, and further extrapolation to ocular lipids. The several individual lipid species we have identified are good candidates to represent circulating biomarkers of ocular lipids. However, further investigation is needed before considering them as indexes of disease risk and before using them in clinical studies on optic nerve neuropathies or retinal diseases displaying photoreceptors degeneration. PMID- 22496897 TI - Rational incorporation of selenium into temozolomide elicits superior antitumor activity associated with both apoptotic and autophagic cell death. AB - BACKGROUND: The DNA alkylating agent temozolomide (TMZ) is widely used in the treatment of human malignancies such as glioma and melanoma. On the basis of previous structure-activity studies, we recently synthesized a new TMZ selenium analog by rationally introducing an N-ethylselenocyanate extension to the amide functionality in TMZ structure. PRINCIPAL FINDINGS: This TMZ-Se analog showed a superior cytotoxicity to TMZ in human glioma and melanoma cells and a more potent tumor-inhibiting activity than TMZ in mouse glioma and melanoma xenograft model. TMZ-Se was also effective against a TMZ-resistant glioma cell line. To explore the mechanism underlying the superior antitumor activity of TMZ-Se, we compared the effects of TMZ and TMZ-Se on apoptosis and autophagy. Apoptosis was significantly increased in tumor cells treated with TMZ-Se in comparison to those treated with TMZ. TMZ-Se also triggered greater autophagic response, as compared with TMZ, and suppressing autophagy partly rescued cell death induced by TMZ-Se, indicating that TMZ-Se-triggered autophagy contributed to cell death. Although mRNA level of the key autophagy gene, Beclin 1, was increased, Beclin 1 protein was down-regulated in the cells treated with TMZ-Se. The decrease in Beclin 1 following TMZ-Se treatment were rescued by the calpain inhibitors and the calpain mediated degradation of Beclin1 had no effect on autophagy but promoted apoptosis in cells treated with TMZ-Se. CONCLUSIONS: Our study indicates that incorporation of Se into TMZ can render greater potency to this chemotherapeutic drug. PMID- 22496898 TI - Exposure to ozone modulates human airway protease/antiprotease balance contributing to increased influenza A infection. AB - Exposure to oxidant air pollution is associated with increased respiratory morbidities and susceptibility to infections. Ozone is a commonly encountered oxidant air pollutant, yet its effects on influenza infections in humans are not known. The greater Mexico City area was the primary site for the spring 2009 influenza A H1N1 pandemic, which also coincided with high levels of environmental ozone. Proteolytic cleavage of the viral membrane protein hemagglutinin (HA) is essential for influenza virus infectivity. Recent studies suggest that HA cleavage might be cell-associated and facilitated by the type II transmembrane serine proteases (TTSPs) human airway trypsin-like protease (HAT) and transmembrane protease, serine 2 (TMPRSS2), whose activities are regulated by antiproteases, such as secretory leukocyte protease inhibitor (SLPI). Based on these observations, we sought to determine how acute exposure to ozone may modulate cellular protease/antiprotease expression and function, and to define their roles in a viral infection. We utilized our in vitro model of differentiated human nasal epithelial cells (NECs) to determine the effects of ozone on influenza cleavage, entry, and replication. We show that ozone exposure disrupts the protease/antiprotease balance within the airway liquid. We also determined that functional forms of HAT, TMPRSS2, and SLPI are secreted from human airway epithelium, and acute exposure to ozone inversely alters their expression levels. We also show that addition of antioxidants significantly reduces virus replication through the induction of SLPI. In addition, we determined that ozone-induced cleavage of the viral HA protein is not cell associated and that secreted endogenous proteases are sufficient to activate HA leading to a significant increase in viral replication. Our data indicate that pre-exposure to ozone disrupts the protease/antiprotease balance found in the human airway, leading to increased influenza susceptibility. PMID- 22496899 TI - Sex differences in risk factors for cardiovascular disease: the PERU MIGRANT study. AB - INTRODUCTION: Although men and women have similar risk factors for cardiovascular disease, many social behaviors in developing countries differ by sex. Rural-to urban migrants have different cardiovascular risk profiles than rural or urban dwellers. The objective of this study was to evaluate the sex differences with specific cardiovascular risk factors in rural-to-urban migrants. METHODS AND RESULTS: We used the rural-to-urban migrant group of the PERU MIGRANT cross sectional study to investigate the sex differences in specific cardiovascular risk factors: obesity, hypertension, metabolic syndrome, as well as exposures of socioeconomic status, acculturation surrogates and behavioral characteristics. Logistic regression analysis was used to characterize strength of association between sex and our outcomes adjusting for potential confounders. The sample of migrants was 589 (mean age 46.5 years) and 52.4% were female. In the adjusted models, women were more likely to be obese (OR=5.97; 95%CI: 3.21-11) and have metabolic syndrome (OR=2.22; 95%CI: 1.39-3.55) than men, explaining the greatest variability for obesity and metabolic syndrome but not for hypertension. CONCLUSIONS: Our results suggest that interventions for CVD in Peru should be sex specific and address the unique health needs of migrant populations living in urban shantytowns since the risk factors for obesity and metabolic syndrome differ between males and females. PMID- 22496900 TI - In vitro and in vivo antagonism of a G protein-coupled receptor (S1P3) with a novel blocking monoclonal antibody. AB - BACKGROUND: S1P(3) is a lipid-activated G protein-couple receptor (GPCR) that has been implicated in the pathological processes of a number of diseases, including sepsis and cancer. Currently, there are no available high-affinity, subtype selective drug compounds that can block activation of S1P(3). We have developed a monoclonal antibody (7H9) that specifically recognizes S1P(3) and acts as a functional antagonist. METHODOLOGY/PRINCIPAL FINDINGS: Specific binding of 7H9 was demonstrated by immunocytochemistry using cells that over-express individual members of the S1P receptor family. We show, in vitro, that 7H9 can inhibit the activation of S1P(3)-mediated cellular processes, including arrestin translocation, receptor internalization, adenylate cyclase inhibiton, and calcium mobilization. We also demonstrate that 7H9 blocks activation of S1P(3) in vivo, 1) by preventing lethality due to systemic inflammation, and 2) by altering the progression of breast tumor xenografts. CONCLUSIONS/SIGNIFICANCE: We have developed the first-reported monoclonal antibody that selectively recognizes a lipid-activated GPCR and blocks functional activity. In addition to serving as a lead drug compound for the treatment of sepsis and breast cancer, it also provides proof of concept for the generation of novel GPCR-specific therapeutic antibodies. PMID- 22496901 TI - Distribution of cortical endoplasmic reticulum determines positioning of endocytic events in yeast plasma membrane. AB - In many eukaryotes, a significant part of the plasma membrane is closely associated with the dynamic meshwork of cortical endoplasmic reticulum (cortical ER). We mapped temporal variations in the local coverage of the yeast plasma membrane with cortical ER pattern and identified micron-sized plasma membrane domains clearly different in cortical ER persistence. We show that clathrin mediated endocytosis is initiated outside the cortical ER-covered plasma membrane zones. These cortical ER-covered zones are highly dynamic but do not overlap with the immobile and also endocytosis-inactive membrane compartment of Can1 (MCC) and the subjacent eisosomes. The eisosomal component Pil1 is shown to regulate the distribution of cortical ER and thus the accessibility of the plasma membrane for endocytosis. PMID- 22496902 TI - Effect of dietary advanced glycation end products on mouse liver. AB - The exact pathophysiology of non-alcoholic steatohepatitis (NASH) is not known. Previous studies suggest that dietary advanced glycation end products (AGEs) can cause oxidative stress in liver. We aim to study the effects of dietary AGEs on liver health and their possible role in the pathogenesis of NASH. METHODS: Two groups of mice were fed the same diet except the AGE content varied. One group was fed a high AGE diet and the second group was fed a regular AGE diet. Liver histology, alanine aminotransferase, aspartate aminotransferase, fasting glucose, fasting insulin, insulin resistance and glucose tolerance were assessed. RESULTS: Histology revealed that neutrophil infiltration occurred in the livers of the high AGE group at week 26; steatosis did not accompany liver inflammation. At week 39 livers from both groups exhibited macro- or micro-steatosis, yet no inflammation was detected. Higher insulin levels were detected in the regular AGE group at week 26 (P = 0.034), compared to the high AGE group. At week 39, the regular AGE group showed higher levels of alanine aminotransferase (P<0.01) and aspartate aminotransferase (P = 0.02) than those of the high AGE group. CONCLUSIONS: We demonstrate that a high AGE diet can cause liver inflammation in the absence of steatosis. Our results show that dietary AGEs could play a role in initiating liver inflammation contributing to the disease progression of NASH. Our observation that the inflammation caused by high AGE alone did not persist suggests interesting future directions to investigate how AGEs contribute to pro oxidative and anti-oxidative pathways in the liver. PMID- 22496903 TI - Compound A, a dissociated glucocorticoid receptor modulator, inhibits T-bet (Th1) and induces GATA-3 (Th2) activity in immune cells. AB - BACKGROUND: Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has anti-inflammatory properties exerted by down modulating proinflammatory gene expression. By favouring GR monomer formation, CpdA does not enhance glucocorticoid (GC) response element-driven gene expression, resulting in a reduced side effect profile as compared to GCs. Considering the importance of Th1/Th2 balance in the final outcome of immune and inflammatory responses, we analyzed how selective GR modulation differentially regulates the activity of T-bet and GATA-3, master drivers of Th1 and Th2 differentiation, respectively. RESULTS: Using Western analysis and reporter gene assays, we show in murine T cells that, similar to GCs, CpdA inhibits T-bet activity via a transrepressive mechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPK-induction of GATA-3 phosphorylation and nuclear translocation. CpdA effects are reversed by the GR antagonist RU38486, proving the involvement of GR in these actions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts on cytokine production shown by a decrease in IFN gamma and an increase in IL-5 production, respectively. CONCLUSIONS: Taken together, through their effect favoring Th2 over Th1 responses, particular dissociated GR ligands, for which CpdA represents a paradigm, hold potential for the application in Th1-mediated immune disorders. PMID- 22496905 TI - Soil microbial properties and plant growth responses to carbon and water addition in a temperate steppe: the importance of nutrient availability. AB - BACKGROUND: Global climatic change is generally expected to stimulate net primary production, and consequently increase soil carbon (C) input. The enhanced C input together with potentially increased precipitation may affect soil microbial processes and plant growth. METHODOLOGY/PRINCIPAL FINDINGS: To examine the effects of C and water additions on soil microbial properties and plant growth, we conducted an experiment lasting two years in a temperate steppe of northeastern China. We found that soil C and water additions significantly affected microbial properties and stimulated plant growth. Carbon addition significantly increased soil microbial biomass and activity but had a limited effect on microbial community structure. Water addition significantly increased soil microbial activity in the first year but the response to water decreased in the second year. The water-induced changes of microbial activity could be ascribed to decreased soil nitrogen (N) availability and to the shift in soil microbial community structure. However, no water effect on soil microbial activity was visible under C addition during the two years, likely because C addition alleviated nutrient limitation of soil microbes. In addition, C and water additions interacted to affect plant functional group composition. Water addition significantly increased the ratio of grass to forb biomass in C addition plots but showed only minor effects under ambient C levels. Our results suggest that soil microbial activity and plant growth are limited by nutrient (C and N) and water availability, and highlight the importance of nutrient availability in modulating the responses of soil microbes and plants to potentially increased precipitation in the temperate steppe. CONCLUSIONS/SIGNIFICANCE: Increased soil C input and precipitation would show significant effects on soil microbial properties and plant growth in the temperate steppe. These findings will improve our understanding of the responses of soil microbes and plants to the indirect and direct climate change effects. PMID- 22496904 TI - NGF causes TrkA to specifically attract microtubules to lipid rafts. AB - Membrane protein sorting is mediated by interactions between proteins and lipids. One mechanism that contributes to sorting involves patches of lipids, termed lipid rafts, which are different from their surroundings in lipid and protein composition. Although the nerve growth factor (NGF) receptors, TrkA and p75(NTR) collaborate with each other at the plasma membrane to bind NGF, these two receptors are endocytosed separately and activate different cellular responses. We hypothesized that receptor localization in membrane rafts may play a role in endocytic sorting. TrkA and p75(NTR) both reside in detergent-resistant membranes (DRMs), yet they responded differently to a variety of conditions. The ganglioside, GM1, caused increased association of NGF, TrkA, and microtubules with DRMs, but a decrease in p75(NTR). When microtubules were induced to polymerize and attach to DRMs by in vitro reactions, TrkA, but not p75(NTR), was bound to microtubules in DRMs and in a detergent-resistant endosomal fraction. NGF enhanced the interaction between TrkA and microtubules in DRMs, yet tyrosine phosphorylated TrkA was entirely absent in DRMs under conditions where activated TrkA was detected in detergent-sensitive membranes and endosomes. These data indicate that TrkA and p75(NTR) partition into membrane rafts by different mechanisms, and that the fraction of TrkA that associates with DRMs is internalized but does not directly form signaling endosomes. Rather, by attracting microtubules to lipid rafts, TrkA may mediate other processes such as axon guidance. PMID- 22496906 TI - Independent risk factors for injury in pre-school children: three population based nested case-control studies using routine primary care data. AB - BACKGROUND: Injuries in childhood are largely preventable yet an estimated 2,400 children die every day because of injury and violence. Despite this, the factors that contribute to injury occurrence have not been quantified at the population scale using primary care data. We used The Health Improvement Network (THIN) database to identify risk factors for thermal injury, fractures and poisoning in pre-school children in order to inform the optimal delivery of preventative strategies. METHODS: We used a matched, nested case-control study design. Cases were children under 5 with a first medically recorded injury, comprising 3,649 thermal injury cases, 4,050 fracture cases and 2,193 poisoning cases, matched on general practice to 94,620 control children. RESULTS: Younger maternal age and higher birth order increased the odds of all injuries. Children's age of highest injury risk varied by injury type; compared with children under 1 year, thermal injuries were highest in those age 1-2 (OR = 2.43, 95%CI 2.23-2.65), poisonings in those age 2-3 (OR = 7.32, 95%CI 6.26-8.58) and fractures in those age 3-5 (OR = N 3.80, 95%CI 3.42-4.23). Increasing deprivation was an important modifiable risk factor for poisonings and thermal injuries (tests for trend p <= 0.001) as were hazardous/harmful alcohol consumption by a household adult (OR = 1.73, 95%CI 1.26-2.38 and OR = 1.39, 95%CI 1.07-1.81 respectively) and maternal diagnosis of depression (OR = 1.45, 95%CI 1.24-1.70 and OR = 1.16, 95%CI 1.02-1.32 respectively). Fracture was not associated with these factors, however, not living in single-adult household reduced the odds of fracture (OR = 0.88, 95%CI 0.82-0.95). CONCLUSIONS: Maternal depression, hazardous/harmful adult alcohol consumption and socioeconomic deprivation represent important modifiable risk factors for thermal injury and poisoning but not fractures in preschool children. Since these risk factors can be ascertained from routine primary care records, pre-school children's frequent visits to primary care present an opportunity to reduce injury risk by implementing effective preventative interventions from existing national guidelines. PMID- 22496907 TI - Gastrointestinal-sparing effects of novel NSAIDs in rats with compromised mucosal defence. AB - Nonsteroidal anti-inflammatory drugs are among the most commonly used prescription and over-the-counter medications, but they often produce significant gastrointestinal ulceration and bleeding, particularly in elderly patients and patients with certain co-morbidities. Novel anti-inflammatory drugs are seldom tested in animal models that mimic the high risk human users, leading to an underestimate of the true toxicity of the drugs. In the present study we examined the effects of two novel NSAIDs and two commonly used NSAIDs in models in which mucosal defence was expected to be impaired. Naproxen, celecoxib, ATB-346 (a hydrogen sulfide- and naproxen-releasing compound) and NCX 429 (a nitric oxide- and naproxen-releasing compound) were evaluated in healthy, arthritic, obese, and hypertensive rats and in rats of advanced age (19 months) and rats co administered low-dose aspirin and/or omeprazole. In all models except hypertension, greater gastric and/or intestinal damage was observed when naproxen was administered in these models than in healthy rats. Celecoxib-induced damage was significantly increased when co-administered with low-dose aspirin and/or omeprazole. In contrast, ATB-346 and NCX 429, when tested at doses that were as effective as naproxen and celecoxib in reducing inflammation and inhibiting cyclooxygenase activity, did not produce significant gastric or intestinal damage in any of the models. These results demonstrate that animal models of human co morbidities display the same increased susceptibility to NSAID-induced gastrointestinal damage as observed in humans. Moreover, two novel NSAIDs that release mediators of mucosal defence (hydrogen sulfide and nitric oxide) do not induce significant gastrointestinal damage in these models of impaired mucosal defence. PMID- 22496908 TI - Membrane progesterone receptor alpha as a potential prognostic biomarker for breast cancer survival: a retrospective study. AB - Classically, the actions of progesterone (P4) are attributed to the binding of nuclear progesterone receptor (PR) and subsequent activation of its downstream target genes. These mechanisms, however, are not applicable to PR- or basal phenotype breast cancer (BPBC) due to lack of PR in these cancers. Recently, the function of membrane progesterone receptor alpha (mPRalpha) in human BPBC cell lines was studied in our lab. We proposed that the signaling cascades of P4 >mPRalpha pathway may play an essential role in controlling cell proliferation and epithelial mesenchymal transition (EMT) of breast cancer. Using human breast cancer tissue microarrays, we found in this study that the average intensity of mPRalpha expression, but not percentage of breast cancer with high level of mPRalpha expression (mPRalpha-HiEx), was significantly lower in the TNM stage 4 patients compared to those with TNM 1-3 patients; and both average intensities of mPRalpha expression and mPRalpha-HiEx rates were significantly higher in cancers negative for ER, as compared with those cancers with ER+. However, after adjusting for age at diagnosis and/or TNM stage, only average intensities of mPRalpha expression were associated with ER status. In addition, we found that the rates of mPRalpha-HiEx were significantly higher in cancers with epithelial growth factor receptor-1 (EGFR+) and high level of Ki67 expression, indicating positive correlation between mPRalpha over expression and EGFR or Ki67. Further analysis indicated that both mPRalpha-HiEx rate and average intensity of mPRalpha expression were significantly higher in HER2+ subtype cancers (i.e. HER2+ER-PR-) as compared to ER+ subtype cancers. These data support our hypothesis that P4 modulates the activities of the PI3K and cell proliferation pathways through the caveolar membrane bound growth factor receptors such as mPRalpha and growth factor receptors. Future large longitudinal studies with larger sample size and survival outcomes are necessary to confirm our findings. PMID- 22496909 TI - Stimulus-related independent component and voxel-wise analysis of human brain activity during free viewing of a feature film. AB - Understanding how the brain processes stimuli in a rich natural environment is a fundamental goal of neuroscience. Here, we showed a feature film to 10 healthy volunteers during functional magnetic resonance imaging (fMRI) of hemodynamic brain activity. We then annotated auditory and visual features of the motion picture to inform analysis of the hemodynamic data. The annotations were fitted to both voxel-wise data and brain network time courses extracted by independent component analysis (ICA). Auditory annotations correlated with two independent components (IC) disclosing two functional networks, one responding to variety of auditory stimulation and another responding preferentially to speech but parts of the network also responding to non-verbal communication. Visual feature annotations correlated with four ICs delineating visual areas according to their sensitivity to different visual stimulus features. In comparison, a separate voxel-wise general linear model based analysis disclosed brain areas preferentially responding to sound energy, speech, music, visual contrast edges, body motion and hand motion which largely overlapped the results revealed by ICA. Differences between the results of IC- and voxel-based analyses demonstrate that thorough analysis of voxel time courses is important for understanding the activity of specific sub-areas of the functional networks, while ICA is a valuable tool for revealing novel information about functional connectivity which need not be explained by the predefined model. Our results encourage the use of naturalistic stimuli and tasks in cognitive neuroimaging to study how the brain processes stimuli in rich natural environments. PMID- 22496910 TI - Identification and characterization of microsporidia from fecal samples of HIV positive patients from Lagos, Nigeria. AB - BACKGROUND: Microsporidia are obligate intracellular parasites that infect a broad range of vertebrates and invertebrates. They have been increasingly recognized as human pathogens in AIDS patients, mainly associated with a life threatening chronic diarrhea and systemic disease. However, to date the global epidemiology of human microsporidiosis is poorly understood, and recent data suggest that the incidence of these pathogens is much higher than previously reported and may represent a neglected etiological agent of more common diseases indeed in immunocompetent individuals. To contribute to the knowledge of microsporidia molecular epidemiology in HIV-positive patients in Nigeria, the authors tested stool samples proceeding from patients with and without diarrhea. METHODOLOGY/PRINCIPAL FINDINGS: Stool samples from 193 HIV-positive patients with and without diarrhea (67 and 126 respectively) from Lagos (Nigeria) were investigated for the presence of microsporidia and Cryptosporidium using Weber's Chromotrope-based stain, Kinyoun stain, IFAT and PCR. The Weber stain showed 45 fecal samples (23.3%) with characteristic microsporidia spores, and a significant association of microsporidia with diarrhea was observed (O.R. = 18.2; CI: 95%). A similar result was obtained using Kinyoun stain, showing 44 (31,8%) positive samples with structures morphologically compatible with Cryptosporidium sp, 14 (31.8%) of them with infection mixed with microsporidia. The characterization of microsporidia species by IFAT and PCR allowed identification of Enterocytozoon bieneusi, Encephalitozoon intestinalis and E. cuniculi in 5, 2 and 1 samples respectively. The partial sequencing of the ITS region of the rRNA genes showed that the three isolates of E.bieneusi studied are included in Group I, one of which bears the genotype B. CONCLUSIONS/SIGNIFICANCE: To our knowledge, this is the first report of microsporidia characterization in fecal samples from HIV positive patients from Lagos, Nigeria. These results focus attention on the need to include microsporidial diagnosis in the management of HIV/AIDS infection in Nigeria, at the very least when other more common pathogens have not been detected. PMID- 22496911 TI - A BAC-based transgenic mouse specifically expresses an inducible Cre in the urothelium. AB - Cre-loxp mediated conditional knockout strategy has played critical roles for revealing functions of many genes essential for development, as well as the causal relationships between gene mutations and diseases in the postnatal adult mice. One key factor of this strategy is the availability of mice with tissue- or cell type-specific Cre expression. However, the success of the traditional molecular cloning approach to generate mice with tissue specific Cre expression often depends on luck. Here we provide a better alternative by using bacterial artificial chromosome (BAC)-based recombineering to insert iCreERT2 cDNA at the ATG start of the Upk2 gene. The BAC-based transgenic mice express the inducible Cre specifically in the urothelium as demonstrated by mRNA expression and staining for LacZ expression after crossing with a Rosa26 reporter mouse. Taking into consideration the size of the gene of interest and neighboring genes included in a BAC, this method should be widely applicable for generation of mice with tissue specific gene expression or deletions in a more specific manner than previously reported. PMID- 22496912 TI - Directed induction of functional motor neuron-like cells from genetically engineered human mesenchymal stem cells. AB - Cell replacement using stem cells is a promising therapeutic approach to treat degenerative motor neuron (MN) disorders, such as amyotrophic lateral sclerosis and spinal cord injury. Human bone marrow-derived mesenchymal stem cells (hMSCs) are a desirable cell source for autologous cell replacement therapy to treat nervous system injury due to their plasticity, low immunogenicity, and a lower risk of tumor formation than embryonic stem cells. However, hMSCs are inefficient with regards to differentiating into MN-like cells. To solve this limitation, we genetically engineered hMSCs to express MN-associated transcription factors, Olig2 and Hb9, and then treat the hMSCs expressing Olig2 and Hb9 with optimal MN induction medium (MNIM). This method of induction led to higher expression (>30% of total cells) of MN markers. Electrophysiological data revealed that the induced hMSCs had the excitable properties of neurons and were able to form functional connections with muscle fibers in vitro. Furthermore, when the induced hMSCs were transplanted into an injured organotypic rat spinal cord slice culture, an ex vivo model of spinal cord injury, they exhibited characteristics of MNs. The data strongly suggest that induced Olig2/Hb9-expressing hMSCs were clearly reprogrammed and directed toward a MN-like lineage. We propose that methods to induce Olig2 and Hb9, followed by further induction with MNIM have therapeutic potential for autologous cell replacement therapy to treat degenerative MN disorders. PMID- 22496913 TI - Non-financial conflicts of interest in academic grant evaluation: a qualitative study of multiple stakeholders in France. AB - BACKGROUND: Peer review is the most widely used method for evaluating grant applications in clinical research. Criticisms of peer review include lack of equity, suspicion of biases, and conflicts of interest (CoI). CoIs raise questions of fairness, transparency, and trust in grant allocation. Few observational studies have assessed these issues. We report the results of a qualitative study on reviewers' and applicants' perceptions and experiences of CoIs in reviews of French academic grant applications. METHODOLOGY AND PRINCIPAL FINDINGS: We designed a qualitative study using semi-structured interviews and direct observation. We asked members of assessment panels, external reviewers, and applicants to participate in semi-structured interviews. Two independent researchers conducted in-depth reviews and line-by-line coding of all transcribed interviews, which were also subjected to Tropes(r) software text analysis, to detect and qualify themes associated with CoIs. Most participants (73/98) spontaneously reported that non-financial CoIs predominated over financial CoIs. Non-financial CoIs mainly involved rivalry among disciplines, cronyism, and geographic and academic biases. However, none of the participants challenged the validity of peer review. Reviewers who felt they might be affected by CoIs said they reacted in a variety of ways: routine refusal to review, routine attempt to conduct an impartial review, or decision on a case-by-case basis. Multiple means of managing non-financial CoIs were suggested, including increased transparency throughout the review process, with public disclosure of non-financial CoIs, and careful selection of independent reviewers, including foreign experts and methodologists. CONCLUSIONS: Our study underscores the importance of considering non-financial CoIs when reviewing research grant applications, in addition to financial CoIs. Specific measures are needed to prevent a negative impact of non financial CoIs on the fairness of resource allocation. Whether and how public disclosure of non-financial CoIs should be accomplished remains debatable. PMID- 22496914 TI - Growth response of drought-stressed Pinus sylvestris seedlings to single- and multi-species inoculation with ectomycorrhizal fungi. AB - Many trees species form symbiotic associations with ectomycorrhizal (ECM) fungi, which improve nutrient and water acquisition of their host. Until now it is unclear whether the species richness of ECM fungi is beneficial for tree seedling performance, be it during moist conditions or drought. We performed a pot experiment using Pinus sylvestris seedlings inoculated with four selected ECM fungi (Cenococcum geophilum, Paxillus involutus, Rhizopogon roseolus and Suillus granulatus) to investigate (i) whether these four ECM fungi, in monoculture or in species mixtures, affect growth of P. sylvestris seedlings, and (ii) whether this effect can be attributed to species number per se or to species identity. Two different watering regimes (moist vs. dry) were applied to examine the context dependency of the results. Additionally, we assessed the activity of eight extracellular enzymes in the root tips. Shoot growth was enhanced in the presence of S. granulatus, but not by any other ECM fungal species. The positive effect of S. granulatus on shoot growth was more pronounced under moist (threefold increase) than under dry conditions (twofold increase), indicating that the investigated ECM fungi did not provide additional support during drought stress. The activity of secreted extracellular enzymes was higher in S. granulatus than in any other species. In conclusion, our findings suggest that ECM fungal species composition may affect seedling performance in terms of aboveground biomass. PMID- 22496915 TI - Body adiposity index utilization in a Spanish Mediterranean population: comparison with the body mass index. AB - BACKGROUND: Body fat content and fat distribution or adiposity are indicators of health risk. Several techniques have been developed and used for assessing and/or determining body fat or adiposity. Recently, the Body Adiposity Index (BAI), which is based on the measurements of hip circumference and height, has been suggested as a new index of adiposity. The aim of the study was to compare BAI and BMI measurements in a Caucasian population from a European Mediterranean area and to assess the usefulness of the BAI in men and women separately. RESEARCH METHODOLOGY/PRINCIPAL FINDINGS: A descriptive cross-sectional study was conducted in a Caucasian population. All participants in the study (1,726 women and 1,474 men, mean age 39.2 years, SD 10.8) were from Mallorca (Spain). Anthropometric data, including percentage of body fat mass obtained by Bioelectrical Impedance Analysis, were determined. Body Mass Index (BMI) and BAI were calculated. BAI and BMI showed a good correlation (r = 0.64, p<0.001). A strong correlation was also found between BAI and the % fat determined using BIA (r = 0.74, p<0.001), which is even stronger than the one between BMI and % fat (r = 0.54, p<0.001). However, the ROC curve analysis showed a higher accuracy for BMI than for the BAI regarding the discriminatory capacity. CONCLUSION: The BAI could be a good tool to measure adiposity due, at least in part, to the advantages over other more complex mechanical or electrical systems. Probably, the most important advantage of BAI over BMI is that weight is not needed. However, in general it seems that the BAI does not overcome the limitations of BMI. PMID- 22496916 TI - Rapid and sensitive detection of an intracellular pathogen in human peripheral leukocytes with hybridizing magnetic relaxation nanosensors. AB - Bacterial infections are still a major global healthcare problem. The quick and sensitive detection of pathogens responsible for these infections would facilitate correct diagnosis of the disease and expedite treatment. Of major importance are intracellular slow-growing pathogens that reside within peripheral leukocytes, evading recognition by the immune system and detection by traditional culture methods. Herein, we report the use of hybridizing magnetic nanosensors (hMRS) for the detection of an intracellular pathogen, Mycobacterium avium spp. paratuberculosis (MAP). The hMRS are designed to bind to a unique genomic sequence found in the MAP genome, causing significant changes in the sample's magnetic resonance signal. Clinically relevant samples, including tissue and blood, were screened with hMRS and results were compared with traditional PCR analysis. Within less than an hour, the hMRS identified MAP-positive samples in a library of laboratory cultures, clinical isolates, blood and homogenized tissues. Comparison of the hMRS with culture methods in terms of prediction of disease state revealed that the hMRS outperformed established culture methods, while being significantly faster (1 hour vs 12 weeks). Additionally, using a single instrument and one nanoparticle preparation we were able to detect the intracellular bacterial target in clinical samples at the genomic and epitope levels. Overall, since the nanoparticles are robust in diverse environmental settings and substantially more affordable than PCR enzymes, the potential clinical and field-based use of hMRS in the multiplexed identification of microbial pathogens and other disease-related biomarkers via a single, deployable instrument in clinical and complex environmental samples is foreseen. PMID- 22496917 TI - Role of miR-148a in hepatitis B associated hepatocellular carcinoma. AB - Hepatitis B virus encoded X antigen (HBx) is a trans-regulatory protein that alters the activity of selected transcription factors and cytoplasmic signal transduction pathways. HBx transcriptionally up-regulates the expression of a unique gene, URG11, which in turn transcriptionally up-regulates beta-catenin, thereby contributing importantly to hepatocarcinogenesis. HBx and URG11 also alter the expression of multiple microRNAs, and by miRNA array analysis, both were shown to promote the expression of miR-148a. Elevated miR-148a was also seen in HBx positive liver samples from infected patients. To study the function of miR-148a, anti-148a was introduced into HepG2 and Hep3B cells stably expressing HBx or stably over-expressing URG11. Anti-miR-148a suppressed cell proliferation, cell cycle progression, cell migration, anchorage independent growth in soft agar and subcutaneous tumor formation in SCID mice. Introduction of anti-miR-148a increased PTEN protein and mRNA expression, suggesting that PTEN was targeted by miR-148a. Anti-miR-148a failed to suppress PTEN expression when co-transfected with reporter gene mutants in the 3'UTR of PTEN mRNA. Introduction of anti-miR 148a also resulted in depressed Akt signaling by HBx and URG11, resulting in decreased expression of beta-catenin. Thus, miR-148a may play a central role in HBx/URG11 mediated HCC, and may be an early diagnostic marker and/or therapeutic target associated with this tumor type. PMID- 22496918 TI - Effects of smoking and cessation on subclinical arterial disease: a substudy of a randomized controlled trial. AB - BACKGROUND: The mechanisms by which smoking cessation reduces cardiovascular disease risk are unclear. We evaluated longitudinal changes in carotid intima media thickness among current smokers enrolled in a prospective, randomized smoking cessation clinical trial. METHODOLOGY/PRINCIPAL FINDINGS: Subjects were enrolled in a randomized, double-blind, placebo-controlled trial of 5 smoking cessation pharmacotherapies and underwent carotid ultrasonography with carotid intima-media thickness measurement. Subjects were classified as continuously abstinent (biochemically confirmed abstinence at 6 months, 1 year, and 3 years post-quit attempt), intermittently abstinent (reported smoking at one of the three time points), or smoked continuously (reported smoking at all three time points). The primary endpoint was the absolute change (mm) in carotid intima media thickness (DeltaCIMT(max)) before randomization and 3 years after the target quit date. Pearson correlations were calculated and multivariable regression models (controlling for baseline CIMT(max) and research site) were analyzed. Among 795 subjects (45.2 +/- 10.6 years old, 58.5% female), 189 (23.8%) were continuously abstinent, 373 (46.9%) smoked continuously, and 233 (29.3%) were abstinent intermittently. There was a greater increase in carotid intima media thickness among subjects who were continuously abstinent than among those who smoked continuously (p = 0.020), but not intermittently (p = 0.310). Antihypertensive medication use (p = 0.001) and research site (p<0.001) independently predicted DeltaCIMTmax--not smoking status. The greatest increase in carotid intima-media thickness among continuous abstainers was related to increases in body-mass index (p = 0.043). CONCLUSIONS/SIGNIFICANCE: Smoking status did not independently predict DeltaCIMT(max); increasing body-mass index and antihypertensive medication use were the most important independent predictors. The rapid reduction in cardiovascular disease events observed with smoking cessation is unlikely to be mediated by changes in subclinical atherosclerosis burden. TRIAL REGISTRATION: ClinicalTrials.gov NCT00332644. PMID- 22496919 TI - The extra domain A of fibronectin increases VEGF-C expression in colorectal carcinoma involving the PI3K/AKT signaling pathway. AB - The extra domain A (EDA)-containing fibronectin (EDA-FN), an alternatively spliced form of the extracellular matrix protein fibronectin, is predominantly expressed in various malignancies but not in normal tissues. In the present study, we investigated the potential pro-lymphangiogenesis effects of extra domain A (EDA)-mediated vascular endothelial growth factor-C (VEGF-C) secretion in colorectal carcinoma (CRC). We detected the expressions of EDA and VEGF-C in 52 human colorectal tumor tissues and their surrounding mucosae by immunohistochemical analysis, and further tested the correlation between the expressions of these two proteins in aforementioned CRC tissues. Both EDA and VEGF-C were abundantly expressed in the specimens of human CRC tissues. And VEGF C was associated with increased expression of EDA in human CRC according to linear regression analysis. Besides, EDA expression was significantly correlated with lymph node metastasis, tumor differentiation and clinical stage by clinicopathological analysis of tissue microarrays containing tumor tissues of 115 CRC patients. Then, human CRC cell SW480 was transfected with lentivectors to elicit expression of shRNA against EDA (shRNA-EDA), and SW620 was transfected with a lentiviral vector to overexpress EDA (pGC-FU-EDA), respectively. We confirmed that VEGF-C was upregulated in EDA-overexpressed cells, and downregulated in shRNA-EDA cells. Moreover, a PI3K-dependent signaling pathway was found to be involved in EDA-mediated VEGF-C secretion. The in vivo result demonstrated that EDA could promote tumor growth and tumor-induced lymphangiogenesis in mouse xenograft models. Our findings provide evidence that EDA could play a role in tumor-induced lymphangiogenesis via upregulating autocrine secretion of VEGF-C in colorectal cancer, which is associated with the PI3K/Akt-dependent pathway. PMID- 22496920 TI - Chronic infection drives expression of the inhibitory receptor CD200R, and its ligand CD200, by mouse and human CD4 T cells. AB - Certain parasites have evolved to evade the immune response and establish chronic infections that may persist for many years. T cell responses in these conditions become muted despite ongoing infection. Upregulation of surface receptors with inhibitory properties provides an immune cell-intrinsic mechanism that, under conditions of chronic infection, regulates immune responses and limits cellular activation and associated pathology. The negative regulator, CD200 receptor, and its ligand, CD200, have been shown to regulate macrophage activation and reduce pathology following infection. We show that CD4 T cells also increase expression of inhibitory CD200 receptors (CD200R) in response to chronic infection. CD200R was upregulated on murine effector T cells in response to infection with bacterial, Salmonella enterica, or helminth, Schistosoma mansoni, pathogens that respectively drive predominant Th1- or Th2-responses. In vitro chronic and prolonged stimuli were required for the sustained upregulation of CD200R, and its expression coincided with loss of multifunctional potential in T effector cells during infection. Importantly, we show an association between IL-4 production and CD200R expression on T effector cells from humans infected with Schistosoma haematobium that correlated effectively with egg burden and, thus infection intensity. Our results indicate a role of CD200R:CD200 in T cell responses to helminths which has diagnostic and prognostic relevance as a marker of infection for chronic schistosomiasis in mouse and man. PMID- 22496921 TI - Is Nitric Oxide (NO) the Last Word in Radiosensitization? A Review. AB - As a short-lived radical that diffuses across membranes, rather than interacting with membrane-bound receptors, nitric oxide (NO) represents a significant departure from synthetically derived radiosensitizers. An endogenous compound, NO may equal or surpass its molecular cousin, oxygen, as a hypoxic radiosensitizer, through pleiotropic phenotypic effects on tumor perfusion, cell signaling, mitochondrial respiration, the fixation of radiation-induced damage, and the radioprotection of normal tissue. However, unlike oxygen, in the context of radiosensitization, the clinical role and utility of NO are poorly understood, with often contradictory and controversial reported effects: whether NO functions as a radiosensitizer may ultimately be contextual to the tumor microenvironment. This may make NO manipulation an ideal candidate for a personalized radiosensitization approach tailored to specific patient and tumor types/microenvironmental characteristics. Effective delivery of NO both systemically and directly to the tumor may be critical to the success of this approach. Compounds that release NO or NO precursors have the potential to drive innovation and result in a new fertile branch of the radiosensitizer tree. PMID- 22496922 TI - Expression Profiles in Stage II Colon Cancer According to APC Gene Status. AB - Colorectal cancer is one of the most common cancers in the world. Histoclinical staging is efficient, but combination with molecular markers may improve the classification of stage II cancers. Several tumor-suppressor genes have been associated with colorectal cancer, and the most frequent allelic losses have been extensively studied for their prognosis effect, but the results remain controversial. In a previous study, we found a possible influence of the chromosome 5 status in the development of liver metastases in stage II colon cancers. We have here investigated the role of the APC gene, located in chromosome arm 5q, in a series of 183 colon adenocarcinomas through a combined analysis of gene expression, mutation, allelic loss and promoter methylation, and metastasis occurrence. Point mutations were found in 73% of cases and allelic losses were found in 39%; 59% of tumors presented with a biallelic inactivation, with a very strong interdependence of the two APC hits (P = 2.1 x 10(-9)). No association was found between expression, number and type of APC alterations, and metastatic evolution. Our results show that the determination of APC status cannot help in the prediction of metastasis and cannot be used to subclassify stage II colon cancers. PMID- 22496923 TI - Development of a novel preclinical pancreatic cancer research model: bioluminescence image-guided focal irradiation and tumor monitoring of orthotopic xenografts. AB - PURPOSE: We report on a novel preclinical pancreatic cancer research model that uses bioluminescence imaging (BLI)-guided irradiation of orthotopic xenograft tumors, sparing of surrounding normal tissues, and quantitative, noninvasive longitudinal assessment of treatment response. MATERIALS AND METHODS: Luciferase expressing MiaPaCa-2 pancreatic carcinoma cells were orthotopically injected in nude mice. BLI was compared to pathologic tumor volume, and photon emission was assessed over time. BLI was correlated to positron emission tomography (PET)/computed tomography (CT) to estimate tumor dimensions. BLI and cone-beam CT (CBCT) were used to compare tumor centroid location and estimate setup error. BLI and CBCT fusion was performed to guide irradiation of tumors using the small animal radiation research platform (SARRP). DNA damage was assessed by gamma-H2Ax staining. BLI was used to longitudinally monitor treatment response. RESULTS: Bioluminescence predicted tumor volume (R = 0.8984) and increased linearly as a function of time up to a 10-fold increase in tumor burden. BLI correlated with PET/CT and necropsy specimen in size (P < .05). Two-dimensional BLI centroid accuracy was 3.5 mm relative to CBCT. BLI-guided irradiated pancreatic tumors stained positively for gamma-H2Ax, whereas surrounding normal tissues were spared. Longitudinal assessment of irradiated tumors with BLI revealed significant tumor growth delay of 20 days relative to controls. CONCLUSIONS: We have successfully applied the SARRP to a bioluminescent, orthotopic preclinical pancreas cancer model to noninvasively: 1) allow the identification of tumor burden before therapy, 2) facilitate image-guided focal radiation therapy, and 3) allow normalization of tumor burden and longitudinal assessment of treatment response. PMID- 22496924 TI - Expression of Leukocyte Inhibitory Immunoglobulin-like Transcript 3 Receptors by Ovarian Tumors in Laying Hen Model of Spontaneous Ovarian Cancer. AB - Attempts to enhance a patient's immune response and ameliorate the poor prognosis of ovarian cancer (OVCA) have largely been unsuccessful owing to the suppressive tumor microenvironment. Leukocyte immunoglobulin-like transcript 3 (ILT3) inhibitory receptors have been implicated in immunosuppression in several malignancies. The expression and role of ILT3 in the progression of ovarian tumors are unknown. This study examined the expression and association of ILT3 in ovarian tumors in laying hens, a spontaneous preclinical model of human OVCA. White Leghorn laying hens were selected by transvaginal ultrasound scanning. Serum and normal ovaries or ovarian tumors were collected. The presence of tumors and the expression of ILT3 were examined by routine histology, immunohistochemistry, Western blot analysis, and reverse transcription-polymerase chain reaction. In addition to stromal immune cell-like cells, the epithelium of the ovarian tumors also expressed ILT3 with significantly high intensity than normal ovaries. Among different subtypes of ovarian carcinomas, serous OVCA showed the highest ILT3 staining intensity, whereas endometrioid OVCA had the lowest intensity. Similar to humans, an immunoreactive protein band of approximately 55 kDa for ILT3 was detected in the ovarian tumors in hens. The patterns of ILT3 protein and messenger RNA expression by ovarian tumors in different subtypes and stages were similar to those of immunohistochemical staining. The results of this study suggest that laying hens may be useful to generate information on ILT3-associated immunosuppression in OVCA. This animal model also offers the opportunity to develop and test anti-ILT3 immunotherapy to enhance antitumor immunity against OVCA in humans. PMID- 22496925 TI - Serpin-derived peptides are antiangiogenic and suppress breast tumor xenograft growth. AB - Angiogenesis is the formation of neovasculature from preexisting microvessels. Several endogenous proteins regulate the balance of vessel formation and regression in the body including pigment epithelium-derived factor (PEDF), which has been shown to be antiangiogenic and to suppress tumor growth. Using sequence homology and bioinformatics, we previously identified several peptide sequences homologous to an active region of PEDF existing in multiple proteins in the human proteome. These short 11-mer peptides are found in a DEAH box helicase protein, CKIP-1 and caspase 10, and show similar activity in altering endothelial cell adhesion, migration and inducing apoptosis.We tested the peptide derived from DEAH box helicase protein in a triple-negative MDA-MB-231 breast orthotopic xenograft model in severe combined immunodeficient mice and show significant tumor suppression. PMID- 22496926 TI - uPA and PAI-1-Related Signaling Pathways Differ between Primary Breast Cancers and Lymph Node Metastases. AB - The supporting role of urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor 1 (PAI-1) in migration and invasion is well known. In addition, both factors are key components in cancer cell-related signaling. However, little information is available for uPA and PAI-1-associated signaling pathways in primary cancers and corresponding lymph node metastases. The aim of this study was to compare the expression of uPA and PAI-1-associated signaling proteins in 52 primary breast cancers and corresponding metastases. Proteins were extracted from formalin-fixed paraffin-embedded tissue samples of the primary tumors and metastases. Protein lysates were subsequently analyzed by reverse phase protein array for the expression of members of the PI3K/AKT (FAK, GSK3-beta, ILK, pGSK3-beta, PI3K, and ROCK) and the MAPK pathways (pp38, pSTAT3, and p38). A solid correlation of uPA expression existed between primary tumors and metastases, whereas PAI-1 expression did not significantly correlate between them. The correlations of uPA and PAI-1 with signaling pathways found in primary tumors did not persist in metastases. Analysis of single molecules revealed that some correlated well between tumors and metastases (FAK, pGSK3-beta, ILK, Met, PI3K, ROCK, uPA, p38, and pp38), whereas others did not (PAI-1 and GSK3-beta). Whether the expression of a protein correlated between tumor and metastasis or not was independent of the pathway the protein is related to. These findings hint at a complete deregulation of uPA and PAI-1-related signaling in metastases, which might be the reason why uPA and PAI-1 reached clinical relevance only for lymph node-negative breast cancer tissues. PMID- 22496927 TI - hERG1 Channels and Glut-1 as Independent Prognostic Indicators of Worse Outcome in Stage I and II Colorectal Cancer: A Pilot Study. AB - BACKGROUND: There is a need to identify new markers to assess recurrence risk in early-stage colorectal cancer (CRC) patients. We explored the prognostic impact of ether-a-go-go-related gene 1 channels and some hypoxia markers, in patients with nonmetastatic (stage I, II, and III) CRC. METHODS: The expression of hERG1, vascular endothelial growth factor A (VEGF-A), glucose transporter 1, carbonic anhydrase IX (CA-IX), epidermal growth factor receptor (EGF-R), and p53 was tested by immunohistochemistry in 135 patients. The median follow-up was 35 months. Clinicopathologic parameters and overall survival were evaluated. RESULTS: hERG1 displayed a statistically significant association with Glut-1, VEGF-A, CA-IX, and EGF-R; p53 with VEGF-A and CA-IX; Glut-1 with the age of the patients; and EGF-R with TNM and mucin content. TNM and CA-IX were prognostic factors at the univariate analysis; TNM, hERG1, and Glut-1, at the multivariate analysis. Risk scores calculated from the final multivariate model allowed to stratify patients into four different risk groups: A) stage I-II, Glut-1 positivity, any hERG1; B) stage I-II, Glut-1 and hERG1 negativity; C) stage I-II, Glut-1 negativity, hERG1 positivity; D) stage III, any Glut-1 and any hERG1. CONCLUSIONS: hERG1 positivity with Glut-1 negativity identifies a patient group with poor prognosis within stage I-II CRC. The possibility that these patients might benefit from adjuvant therapy, independently from the TNM stage, is discussed. IMPACT: More robust prognostic and predictive markers, supplementing standard clinical and pathologic staging, are needed for node-negative patients. PMID- 22496928 TI - Down-regulation of ANAPC13 and CLTCL1: Early Events in the Progression of Preinvasive Ductal Carcinoma of the Breast. AB - Alterations in the gene expression profile in epithelial cells during breast ductal carcinoma (DC) progression have been shown to occur mainly between pure ductal carcinoma in situ (DCIS) to the in situ component of a lesion with coexisting invasive ductal carcinoma (DCIS-IDC) implying that the molecular program for invasion is already established in the preinvasive lesion. For assessing early molecular alterations in epithelial cells that trigger tumorigenesis and testing them as prognostic markers for breast ductal carcinoma progression, we analyzed, by reverse transcription-quantitative polymerase chain reaction, eight genes previously identified as differentially expressed between epithelial tumor cells populations captured from preinvasive lesions with distinct malignant potential, pure DCIS and the in situ component of DCIS-IDC. ANAPC13 and CLTCL1 down-regulation revealed to be early events of DC progression that anticipated the invasiveness manifestation. Further down-regulation of ANAPC13 also occurred after invasion appearance and the presence of the protein in invasive tumor samples was associated with higher rates of overall and disease free survival in breast cancer patients. Furthermore, tumors with low levels of ANAPC13 displayed increased copy number alterations, with significant gains at 1q (1q23.1-1q32.1), 8q, and 17q (17q24.2), regions that display common imbalances in breast tumors, suggesting that down-regulation of ANAPC13 contributes to genomic instability in this disease. PMID- 22496929 TI - Changes of transthyretin and clusterin after androgen ablation therapy and correlation with prostate cancer malignancy. AB - After androgen ablation therapy (AAT), advanced prostate cancer (Pca) eventually progresses to castration-resistant Pca (CRPC); however, the biomarkers that are used to predict its prognosis are limited. In this study, serum samples from four patients with advanced Pca were collected at the time of the initial diagnosis and 3 months after AAT. Proteomic changes were analyzed with two-dimensional differential in-gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Altogether, nine proteins were differentially expressed in the samples collected at diagnosis and in the samples collected after AAT. Among them, the expression of transthyretin (TTR) was 1.58-fold lower and clusterin (CLU) was 1.51-fold higher in the sera of post AAT patients compared with those in the sera from pre-AAT patients. The significant changes in serum TTR and CLU in post-AAT patients were further confirmed by a large-scale ELISA. Immunohistochemistical staining revealed that the expression levels of TTR and CLU were significantly higher in Pca tissue than in normal and benign prostate hyperplasia tissue. The expression levels of TTR and CLU in Pca tissue were found to be associated with the grade and stage of Pca. Overall, this study indicated that TTR and CLU might be used to monitor the efficacy of AAT therapy and serve as biomarkers for the prognosis of Pca. PMID- 22496931 TI - Are you my friends or are you my enemies? PMID- 22496930 TI - Cleavage of PGRP-LC receptor in the Drosophila IMD pathway in response to live bacterial infection in S2 cells. AB - Drosophila responds to Gram-negative bacterial infection by activating the immune deficiency (IMD) pathway, leading to production of antimicrobial peptides (AMPs). As a receptor for the IMD pathway, peptidoglycan-recognition protein (PGRP), PGRP LC is known to recognize and bind monomeric peptidoglycan (DAP-type PGN) through its PGRP ectodomain and in turn activate the IMD pathway. The questions remain how PGRP-LC is activated in response to pathogen infection to initiate the IMD signal transduction in Drosophila. Here we present evidence to show that proteases such as elastase and Mmp2 can also activate the IMD pathway but not the TOLL pathway. The elastase-dependent IMD activation requires the receptor PGRP LC. Importantly, we find that live Salmonella/E. coli infection modulates PGRP-LC expression/receptor integrity and activates the IMD pathway while dead Salmonella/E. coli or protease-deficient E. coli do neither. Our results suggest an interesting possibility that Gram-negative pathogen infection may be partially monitored through the structural integrity of the receptor PGRP-LC via an infection-induced enzyme-based cleavage-mediated activation mechanism. PMID- 22496932 TI - Study of the effects of total flavonoids of Astragalus on atherosclerosis formation and potential mechanisms. AB - Astragalus mongholicus Bunge has long been used to treat cardiovascular disease in Chinese traditional medicine. However, its mechanisms are not fully understood. In this study, we explored potential mechanisms and protective effects of total flavonoids of Astragalus (TFA) on cardiovascular disease using in vitro experiments and diet-induced atherosclerotic rabbits. We identified six components and their proportion in TFA. The animal experiments showed that TFA significantly reduced plasma levels of total cholesterol and LDL cholesterol (P < 0.05 to 0.01), increased HDL cholesterol levels (P < 0.01), and reduced the aortic fatty streak area by 43.6 to 63.6% (P < 0.01). We also found that TFA scavenged superoxide and hydroxyl radicals and this effect increased with higher TFA concentration. In in vivo experiments, TFA effectively inhibited the free radical spectrum in the ischemia-reperfusion module. In conclusion, TFA was the active component of Astragalus mongholicus Bunge, which benefits cardiovascular disease attributing to the potent antioxidant activity to improve the atherosclerosis profile. PMID- 22496933 TI - Functional results-oriented healthcare leadership: a novel leadership model. AB - This article modifies the traditional functional leadership model to accommodate contemporary needs in healthcare leadership based on two findings. First, the article argues that it is important that the ideal healthcare leadership emphasizes the outcomes of the patient care more than processes and structures used to deliver such care; and secondly, that the leadership must strive to attain effectiveness of their care provision and not merely targeting the attractive option of efficient operations. Based on these premises, the paper reviews the traditional Functional Leadership Model and the three elements that define the type of leadership an organization has namely, the tasks, the individuals, and the team. The article argues that concentrating on any one of these elements is not ideal and proposes adding a new element to the model to construct a novel Functional Result-Oriented healthcare leadership model. The recommended Functional-Results Oriented leadership model embosses the results element on top of the other three elements so that every effort on healthcare leadership is directed towards attaining excellent patient outcomes. PMID- 22496935 TI - Knowledge, Attitude and Practice of Vitamin Supplementation among Patients visiting Out-Patient Physicians in a Teaching Hospital in Karachi. AB - OBJECTIVE: To determine the knowledge, attitude and practices regarding the use of vitamin supplements among patients visiting Out-Patient clinics of a teaching hospital. METHODS: Four hundred patients were interviewed during the period of July to September 2008, at the Out-patient clinics, Aga Khan University hospital, Karachi. A pre-tested and structured questionnaire was used to collect information. It consisted of questions regarding demographics, awareness of vitamin supplements and its consumption, reasons for usage and its effects. The purpose of the study was explained and assurance of confidentiality was given. After obtaining written consent, eligible individuals were interviewed. Statistical Package for the Social Sciences version 19.0 was used to analyze the data. RESULTS: The results revealed that 98% of the respondents were aware of vitamin supplements. The most known vitamin was found to be Vitamin C (16.9%) with Vitamin K being the least well-known (0.4%); while 51.8% of the respondents were unaware of the harmful effects of vitamin supplements. The results also showed that 84.8% of the study population had taken vitamin supplements, and 79% of the participants considered that vitamin supplements to be helpful. Taking vitamin supplements as a compensation for the deficiencies in the body was the most frequently chosen answer (17.7%) as the reason for use of vitamin supplements. On the other hand, a majority of the population was unaware of the indications for use of vitamin supplements. CONCLUSION: This study highlights a very significant yet ignored issue of vitamin supplementation in Pakistan. A need exists to inform the general population about the use of vitamin supplementation. The media and the medical community are required to play their role in this regard. Short/ refresher training courses are needed for doctors to update and disseminate adequate knowledge of vitamin supplementation to their patients. PMID- 22496936 TI - Autosplenectomy of sickle cell disease in zaria, Nigeria: an ultrasonographic assessment. AB - OBJECTIVES: During infancy and early childhood, the spleen commonly enlarges in patients with sickle cell anemia (SCA), and it thereafter undergoes progressive atrophy due to repeated episodes of vaso-occlusion and infarction, leading to autosplenectomy in adult life. However, this may not always be the case as some studies have reported splenomegaly persisting into adult life. This study aims to determine and review the prevalence of autosplenectomy by abdominal ultrasonography in sickle cell anemic patients in Zaria, Nigeria. METHODS: An ex post-facto cross study of 74 subjects was carried out between May to July in 2010. Hematological parameters were determined by an analyzer while B mode Ultrasonography was used to determine the craniocaudal length of the spleen, if visualized. RESULTS: The mean age of the sickle cell subjects was 23.2 +/-5.3 years, while that of the controls was 22.7+/-12.4 years. Of the 74 sickle cell subjects, 55.4% were females; while of the 20 controls, 50% were females. Forty one subjects (55.4%) had autosplenectomy and a significant difference existed in the mean splenic size compared with the control (p<0.0001). Only 3 (4.05%) subjects had splenomegaly, while 23 (31%) had a shrunken spleen. CONCLUSION: Anatomical autosplenectomy is not an uncommon finding in SCA patients. This may be related to inadequate clinical care due to the lack of good health education, ignorance, poverty, and poor standard of care, as well as the lack of newer therapeutic agents. PMID- 22496934 TI - Estimated Glomerular Filtration Rate (eGFR): A Serum Creatinine-Based Test for the Detection of Chronic Kidney Disease and its Impact on Clinical Practice. AB - Chronic kidney disease (CKD) is an important epidemic and public health problem that is associated with a significant risk for vascular disease and early cardiovascular mortality as well as progression of kidney disease. Currently it is classified into five stages based on the glomerular filtration rate (GFR) as recommended by many professional guidelines. Radiolabelled methods for measuring GFR are accurate but not practical and can be used only on a very limited scale while the traditional methods require timed urine collection with its drawback of inaccuracy, cumbersomeness and inconvenience for the patients. However, the development of formula- based calculation of estimated GFR (eGFR) has offered a very practical and easy approach for converting serum creatinine value into GFR result taking into consideration patient's age, sex, ethnicity and weight (depending on equation type). The commonly used equations include Cockraft and Gault (1976), Modification of Diet in Renal Disease (MDRD) (1999) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) (2009). It is the implementation of these equations particularly the MDRD that has raised the medical awareness in the diagnosis and management of CKD and its adoption by many guidelines in North America and Europe. The impact and pitfalls of each of these equations in the screening, diagnosis and management of patients with CKD are presented and discussed in this review. PMID- 22496937 TI - The Values of CA-125, Progesterone, beta-HCG and Estradiol in the Early Prediction of Ectopic Pregnancy. AB - OBJECTIVE: To explore the diagnostic value and measurement of serum CA-125, the single measurement of progesterone (P), beta-HCG, and estradiol (E2) in the early diagnosis of ectopic pregnancy. METHODS: Serum levels of CA-125, progesterone, beta-HCG and estradiol were measured by Enzyme Linked Immuno Sorbent Assay (ELISA) techniques in 40 symptomatic women with ectopic pregnancy and 24 women with normal intrauterine pregnancy during gestational age of 4-10 weeks at Al Kadhmiya Teaching Hospital, Baghdad, Iraq, between November 2010 and June 2011. RESULTS: The mean +/-SEM serum levels of CA-125, progesterone, beta-HCG, and estradiol in patients with ectopic pregnancies (16.51+/-2.39U/ml; 2.54+/ 0.47ng/ml; 72.75+/-12.27mIU/ml; 13.4+/-2.14pg/ml; respectively) were significantly lower than the levels in normal intrauterine pregnancies (74.25+/ 18.5U/ml; 28.36+/-3.7ng/ml; 249.54+/-18.0mIU/ml; 112.7+/-23.6pg/ml; respectively). When using a CA-125 concentration of 20.5 U/ml as a cut-off value for the diagnosis of ectopic pregnancy, sensitivity was 75.7%, specificity 100%, the positive predictive value was 100% and the negative predictive value 71.4%. CONCLUSION: The measurement of CA-125 and progesterone levels is useful in discriminating ectopic from normal gestations. PMID- 22496938 TI - Morphological and morphometric analysis of supraorbital foramen and supraorbital notch: a study on dry human skulls. AB - OBJECTIVES: A clear knowledge of the location of the maxillo-facial foramina is essential for clinicians while performing endoscopic surgeries and regional nerve blocks. In the present study, a detailed analysis of the supraorbital foramen (SOF) and supraorbital notch (SON) of South Indian skulls is reported and the data are compared with those from other races and regions. METHODS: Anatomical variation of SOF/SON was studied in 83 adult human skulls bilaterally, using "travelling Vernier's microscope". The skulls belonged to the cadavers of South Indian origin. The parameters used were distanced between the SON/SOF and the nasal midline; distance between the SON/SOF and the frontozygomatic suture (FZS); shape and height of the SOF; transverse diameter of the SON; the presence of accessory foramina (ACF) and their number; as well as the location and distance from the main SON/SOF. RESULTS: SON was more frequently found than the SOF. The mean distance of SON/SOF to the nasal midline was 22.24 mm on the right side and 22.2 mm on the left side. The mean distance of SON/SOF to the frontozygomatic suture was 29.34 mm on the right side and 28.7 mm on the left side. While the mean height of SOF was 3.5 mm on the right side and 3.04 mm on the left side. Also, the mean transverse diameter of SON was 5.17 mm on the right side and 5.58 mm on the left side. The accessory supraorbital foramina were observed in 66.25% of cases. CONCLUSION: There is a difference in the position and dimensions of SOF /SON between different races and people of different regions. Anatomical knowledge of SON /SOF is important in facilitating local anesthetic, forehead lifting, blepharoplasty and other craniofacial surgical procedures. PMID- 22496939 TI - The Histological Spectrum of Early Mycosis Fungoides: A Study of 58 Saudi Arab patients. AB - OBJECTIVES: The histopathological diagnosis of Mycosis Fungoides (MF) is challenging in its early stages and can easily be confused with inflammatory dermatoses. This study aims to; (i) assess the frequency and significance of different histopathological parameters in early MF, seen in Saudi patients, and (ii) to study the utility of these parameters in differentiating between early MF and inflammatory dermatoses. METHODS: This is a five years study of 66 skin biopsies generated from 58 patients with clinically suspicious MF lesions or early patch stage MF. These cases were retrieved from the archives of the Department of Pathology, King Khalid University Hospital, Riyadh from the year 2002 to 2006. Histological criteria were assessed and graded semi-quantitatively on a four-point scale by a dermatopathologist and two pathologists independently. RESULTS: The histological parameters suggesting the diagnosis in early stages MF include epidermotropism, dermal fibrosis, Pautrier's micro abscesses, Basal alignment of neoplastic lymphocytes, hyperconvoluted dermal and epidermal lymphocytes and grandiosity sign (size of lymphocytes becoming larger as they migrate towards granular layer of epidermis). These parameters on univariate analysis achieved statistical significance (p<0.05) in differentiating MF from non-MF cases. In addition, hyperconvoluted dermal and epidermal lymphocytes proved to be highly reliable with high specificity and sensitivity. CONCLUSION: The histopathological diagnosis of early MF lesions and their discrimination from inflammatory simulators can be achieved by carefully observing the hyperconvoluted dermal and epidermal lymphocytes along with the constellation of the other parameters. PMID- 22496940 TI - Gestational diabetes mellitus: maternal and perinatal outcomes in 220 saudi women. AB - OBJECTIVES: To assess the maternal and fetal complications of pregnancy in mothers with gestational diabetes mellitus (GDM) compared with non-diabetic patients who delivered in the hospital during the study period. METHODS: The outcome of pregnancy in 220 Saudi patients with GDM identified from the delivery register/hospital database and matched for age, parity and body mass index with 220 non-diabetic controls were studied retrospectively from their case files. Patients with multiple pregnancies and abnormal presentation of the fetus were excluded from the study. RESULTS: The GDM patients were treated with either diet alone or with additional insulin in some patients who required better control of their blood sugar levels. Patients with GDM had a significantly higher incidence of pre-eclampsia (p<0.0001); preterm delivery (p=0.0226); induction of labor (p<0.0001); cesarean section (p=0.0019); higher mean birth weight (p<0.0001) of babies; large for gestational age infants (p=0.0011); macrosomia (p=0.0186); and admission to the neonatal intensive care unit (p=0.0003), compared with the control group. However, the rates of Apgar score <7 at 5 minutes, respiratory distress syndrome, neonatal hypoglycemia, hyperbilirubinemia and the need for phototherapy were similar in both groups of patients. Congenital anomalies and perinatal mortality rates were not significantly different in the two groups. CONCLUSION: GDM is recognized to be associated with increased rates of adverse maternal and neonatal outcomes, which are supported by the findings of this study. Even the mild form of GDM seems to have significant consequences for women and their offspring and is recommended to be aggressively treated. Evidence suggests that early diagnosis and strict control of blood sugar levels throughout the pregnancy can significantly reduce maternal and fetal complications. A multicenter, randomized controlled trial, based on universally accepted criteria for GDM screening test, standardized diagnostic OGTT and management of all patients with GDM versus the standard obstetric management of the control is warranted. PMID- 22496941 TI - High resolution computed tomography in asthma. AB - OBJECTIVES: High-resolution computed tomography (HRCT) can detect the structural abnormalities in asthma. This study attempts to correlate these abnormalities with clinical and pulmonary function test (PFT) data. METHODS: Consecutive stable asthma patients attending Mubarak Al Kabeer Hospital, Kuwait, were subjected to HRCT during a six month period from July 2004 to December 2004, after initial evaluation and PFT. RESULTS: Of the 28 cases, sixteen (57.1%) had moderate, 6 (21.4%) had mild and 6 (21.4%) had severe persistent asthma. Thirteen (46.4%) patients had asthma for 1 to 5 years and 12 (42.9%) were having asthma for >10 years. Bronchial wall thickening (57.1%), bronchiectasis (28.6%), mucoid impaction (17.9%), mosaic attenuation (10.7%), air trapping (78.6%) and plate like atelectasis (21.4%) were noted. Bronchial wall thickening (p=0.044) and bronchiectasis (p=0.063) were most prevalent in males. Ten (35.7%) patients exhibited mild, 9 (32.1%) had moderate and 3 (10.7%) had severe air trapping. The difference in Hounsfield units between expiratory and inspiratory slices (air trapping) when correlated with percent-predicted FEV1 in right upper (r=0.25; p=0.30), left upper (r=0.20; p=0.41), right mid (r=0.15; p=0.53), left mid (r= 0.04; p=0.60), right lower (r=0.04; p=0.86) and left lower zones (r=-0.13; p=0.58) showed no relation. The same when correlated as above with the percent predicted FEF 25-75 did not show any significant association. The presence of air trapping was compared with sex (p=0.640), nationality (p=1.000), disease duration (p=1.000) and severity of symptoms (p=0.581). CONCLUSION: Abnormal HRCT findings are common in asthma; however, air trapping when present was not related to the duration or severity of the illness or to the FEV1. PMID- 22496943 TI - Papillary cystadenocarcinoma of ovary presenting as obstructive jaundice: a rare presentation. AB - Obstructive jaundice resulting from malignancy of gastrointestinal tract and hepatobiliary tract has been reported in various studies. Ovarian malignancy leading to obstructive jaundice due to portal lymphadenopathy is of rare occurrence. We report a case presented with obstructive jaundice and on further evaluation, found to have ovarian papillary cyst adenocarcinoma with secondaries at porta hepatis which was managed successfully by neoadjuvant chemotherapy followed by cytoreductive surgery. PMID- 22496942 TI - A Comparative Study on Fine Needle Aspiration Cytology versus Fine Needle Capillary Cytology in Thyroid Nodules. AB - OBJECTIVES: Fine needle aspiration cytology (FNAC/FNA) is the primary investigation for thyroid nodules. Fine needle capillary cytology (FNCC/FNC) is an alternative technique not commonly used, though it is easy to perform. Both the techniques have their own advantages and disadvantages. This study aims to compare these two cytological techniques for better specimen and cytological diagnosis. METHODS: This prospective study was conducted on 50 patients attending the FR Muller Medical College Hospital from May 2006 to April 2008. The patients with thyroid nodules (diagnosed by palpation) were subjected to both the cytological techniques; FNA and FNC. The specimen and results were compared and then correlated with the final histopathological findings wherever surgical specimens were available (38 cases). RESULTS: The mean age of the patients was 39.16 with a female predominance. The majority of cases were diagnosed to have nodular goiters. The FNC technique yielded 88% diagnostic superiority and adequate specimens compared to 94% by FNA. Sensitivity was 50% for FNC and 100% for FNA while specificity was 100% for both techniques; accuracy score was 97.4% for FNC and 100% for FNA in predicting malignancy. While sensitivity was 75% for FNC and 100% for FNA; specificity was 100% for both techniques, and accuracy score was 97.4% for FNC and 100% for FNA in the prediction of neoplasia. CONCLUSION: The results indicated that there was no significant difference between the two techniques; if done in tandem can give better and accurate cytological diagnosis. In highly cellular lesions, in which abundant material was obtained, FNC was more likely to be diagnostically superior, but FNA can diagnose most of the lesions. In less cellular lesions, FNA is more likely to be diagnostically superior to FNC. PMID- 22496944 TI - Scapular bronchogenic cyst: a case report and literature review. AB - Bronchogenic cysts originate from abnormal budding of the tracheal diverticula during the embryological period. Inaccuracy in the process of growing of the ventral foregut will give rise to bronchogenic cyst. Scapular bronchogenic cyst is an extremely rare form of this anomaly. A three years old boy suffered for 2 years with left sided suprascapular cystic lesion which was gradually increasing in size. The swelling was 4 * 3 cm in size and non tender. The cyst was evaluated by CT scan that showed complex cystic lesion over the left scapular spine. Total excision of the cyst was done and histopathology showed cutaneous bronchogenic cyst. The proposed mechanism for such cutaneous lesion is that the accessory buds from the tracheobronchial tree/primitive foregut migrated from the thorax in an aberrant manner to lie in periscapular positions. The definitive treatment of scapular lesions is total surgical excision. The final diagnosis is based on the histopathological findings in the majority of cases. PMID- 22496945 TI - Hypertelorism in Charcot-Marie-Tooth disease 1A from the common PMP22 duplication: A Case Report. AB - The 1.4Mb tandem-duplication in the PMP22 gene at 17p11.2 usually manifests as hereditary sensorimotor polyneuropathy with foot deformity, sensorineural hearing loss, moderate developmental delay, and gait disturbance. Hypertelorism and marked phenotypic variability within a single family has not been reported. In a single family, the PMP22 tandem-duplication manifested as short stature, sensorimotor polyneuropathy, tremor, ataxia, sensorineural hearing-loss, and hypothyroidism in the 27 years-old index case, as mild facial dysmorphism, muscle cramps, tinnitus, intention tremor, bradydiadochokinesia, and sensorimotor polyneuropathy in the 31 year-old half-brother of the index-patient, and as sensorimotor polyneuropathy and foot-deformity in the father of the two. The half brother additionally presented with hypertelorism, not previously reported in PMP22 tandem-duplication carriers. The presented cases show that the tandem duplication 17p11.2 may present with marked intra-familial phenotype variability and that mild facial dysmorphism with stuck-out ears and hypertelorism may be a rare phenotypic feature of this mutation. The causal relation between facial dysmorphism and the PMP22 tandem-duplication, however, remains speculative. PMID- 22496946 TI - Assessing problem based learning in child and adolescent psychiatry at the trinity college dublin, ireland. PMID- 22496947 TI - Lifestyle Modification in the Prevention of Type II Diabetes Mellitus. PMID- 22496948 TI - Soft tissue swelling at the subscapular region. PMID- 22496949 TI - Quest for an ideal intubating device. PMID- 22496950 TI - Effects of Losartan vs. Enalapril on the Markers of Metabolic Syndrome. PMID- 22496951 TI - What else could it be? History - quintessential forever! PMID- 22496952 TI - Regional conference on quality management and enhancement in higher education 2012. PMID- 22496953 TI - Contact printing of colloidal nanocrystal thin films for hybrid organic/quantum dot optoelectronic devices. AB - Novel thin film optoelectronic devices containing both inorganic colloidal semiconductor quantum dots (QDs) and organic semiconductor thin films have been widely investigated in recent years for a variety of applications. Here, we review one of the most versatile and successful methods developed to integrate these two dissimilar material classes into a functional multilayered device: contact printing of colloidal QD films. Experimental details regarding the contact printing process are outlined, and the key advantages of this QD deposition method over other commonly encountered techniques are discussed. The use of tapping mode atomic force microscopy (AFM) to effectively characterize QD film morphology both on an elastomeric stamp (before contact printing) and as transferred to the organic semiconductor receiving film (after contact printing) is also described. Finally, we offer suggestions for future efforts directed toward the goal of rapid, continuous QD deposition over larger substrates for the advancement of hybrid optoelectronic thin film devices. PMID- 22496954 TI - Critical Dipole Length for the Wetting Transition Due to Collective Water-dipoles Interactions. AB - The wetting behavior of water on the solid surfaces is fundamental to various physical, chemical and biological processes. Conventionally, the surface with charges or charge dipoles is hydrophilic, whereas the non-polar surface is hydrophobic though some exceptions were recently reported. Using molecular dynamics simulations, we show that there is a critical length of the charge dipoles on the solid surface. The solid surface still exhibited hydrophobic behavior when the dipole length was less than the critical value, indicating that the water molecules on the solid surface seemed not "feel" attractive interactions from the charge dipoles on the solid surface. Those unexpected observations result from the collective interactions between the water molecules and charge dipoles on the solid surface, where the steric exclusion effect between water molecules greatly reduces the water-dipole interactions. Remarkably, the steric exclusion effect is also important for surfaces with charge dipole lengths greater than this critical length. PMID- 22496955 TI - Therapeutic potential of HIV protease-activable CASP3. AB - Development of a therapeutic application of CASP3/caspase 3/CPP32, an executor of apoptosis, has been challenging because regulation of its activation is complicated. This study aimed to inhibit cancer cell growth and human immunodeficiency virus type 1 (HIV-1) propagation through a CASP3 mutant, CASP3*, activable by HIV-1-encoded aspartate protease. Active CASP3* was delivered to leukemic cells using a protein transduction vehicle, the lentivirus-like nanoparticle (LENA), which should contain thousands of CASP3*-Gag protein molecules and release the activated CASP3* into the target cell cytoplasm. CASP3* LENA induced apoptosis in various types of leukemic cells. In addition to being effective against leukemic cells, constitutive expression of CASP3* restricted HIV-1 propagation in SUP-T1 cells. The attenuation of HIV-1 replication in SUP T1/CASP3* cells was attributed to the elimination of HIV-1-infected cells by apoptosis. These data suggest that CASP3* has therapeutic potential against both lymphoid malignancies and HIV-1 infection. PMID- 22496956 TI - Enabling universal memory by overcoming the contradictory speed and stability nature of phase-change materials. AB - The quest for universal memory is driving the rapid development of memories with superior all-round capabilities in non-volatility, high speed, high endurance and low power. Phase-change materials are highly promising in this respect. However, their contradictory speed and stability properties present a key challenge towards this ambition. We reveal that as the device size decreases, the phase change mechanism changes from the material inherent crystallization mechanism (either nucleation- or growth-dominated), to the hetero-crystallization mechanism, which resulted in a significant increase in PCRAM speeds. Reducing the grain size can further increase the speed of phase-change. Such grain size effect on speed becomes increasingly significant at smaller device sizes. Together with the nano-thermal and electrical effects, fast phase-change, good stability and high endurance can be achieved. These findings lead to a feasible solution to achieve a universal memory. PMID- 22496957 TI - Hydatid Cyst Protoscolices Induce Cell Death in WEHI-164 Fibrosarcoma Cells and Inhibit the Proliferation of Baby Hamster Kidney Fibroblasts In Vitro. AB - Both in vitro and in vivo models have demonstrated that some parasites can interfere with tumor cell growth. The present study investigates the anticancer activity of hydatid cyst protoscolices on WEHI-164 fibrosarcoma cells and baby hamster kidney (BHK) fibroblast cells in vitro. Those above two cell types were treated with live hydatid cyst protoscolices or left untreated for control groups. After 48 h, lactate dehydrogenase (LDH) and cell counts were assayed for both treated cells and control groups. Following treatment with hydatid cyst protoscolices, cell proliferation of both cell types was inhibited, and lysis of fibrosarcoma cells increased. Based on these results, it appears that hydatid cyst protoscolices have strong anticancer activity, and additional studies are needed to further clarify the mechanisms of this activity. PMID- 22496958 TI - Macrophage migration inhibitory factor in protozoan infections. AB - Macrophage migration inhibitory factor (MIF) is a cytokine that plays a central role in immune and inflammatory responses. In the present paper, we discussed the participation of MIF in the immune response to protozoan parasite infections. As a general trend, MIF participates in the control of parasite burden at the expense of promoting tissue damage due to increased inflammation. PMID- 22496960 TI - Femtosecond laser and big-bubble deep anterior lamellar keratoplasty: a new chance. AB - Purpose. To report the 12-month follow-up after big-bubble deep anterior lamellar keratoplasty (DALK) assisted by femtosecond laser that we have called IntraBubble. Methods. A 60 kHz IntraLase femtosecond laser (Abbott Medical Optics) firstly created a 30 degrees angled intrastromal channel to insert the air injection cannula, 50 MU above the thinnest corneal site measured by Sirius Scheimpflug camera (CSO, Firenze, Italy), then performed a full lamellar cut 100 MU above the thinnest corneal point, and from the same corneal depth, created a mushroom incision. The lamella was removed, and the smooth cannula of Fogla was inserted into the stromal channel and air was injected to achieve a big bubble. The follow up is 12 months, and sutures were removed by the 10th postoperative month in all patients. Best Corrected Visual Acuity (BCVA), spherical equivalent and, by Sirius Scheimpflug camera (CSO, Firenze, Italy) keratometric astigmatism were evaluated. Results. All procedures were completed as DALK except 2 converted to PK because an inadvertent intraoperative macroperforation occurred. Mean postoperative BCVA was 0.8, mean spherical equivalent was -3.5 +/- 1.7 D, and mean keratometric astigmatism was 4.8 +/- 3.1 D. Conclusion. The femtosecond laser could standardize the big-bubble technique in DALK, reducing the risk of intraoperative complications and allowing good refractive outcomes. PMID- 22496959 TI - The Immune Response to Trypanosoma cruzi: Role of Toll-Like Receptors and Perspectives for Vaccine Development. AB - In the past ten years, studies have shown the recognition of Trypanosoma cruzi associated molecular patterns by members of the Toll-like receptor (TLR) family and demonstrated the crucial participation of different TLRs during the experimental infection with this parasite. In the present review, we will focus on the role of TLR-activated pathways in the modulation of both innate and acquired immune responses to T. cruzi infection, as well as discuss the state of the art of vaccine research and development against the causative agent of Chagas disease (or American trypanosomiasis). PMID- 22496961 TI - Visual field loss morphology in high- and normal-tension glaucoma. AB - Purpose. To determine whether the patterns of visual field damage between high tension glaucoma (HTG) and normal-tension glaucoma (NTG) are equivalent. Methods. In this retrospective cross-sectional study, fifty-one NTG and 57 HTG patients were recruited. For each recruited patient only the left eye was chosen. Glaucomatous patients had abnormal visual fields and/or glaucomatous changes at the optic nerve head. They were classified as HTG or NTG on the basis of intraocular pressure (IOP) measurements. Patients' visual fields were analyzed by using Humphrey Field Analyzer (HFA), program 30-2, full threshold. The visual field sensitivity values and the pattern deviation map values of the 72 tested points were considered. Then a pointwise analysis and an area analysis, based on the Glaucoma Hemifield test criteria, were performed, and a comparison between the two subgroups was made by Student's t test. Results. Between NTG and HTG, no significant difference was found pointwise for almost all the visual field points, except for two locations. One was under the blind spot, and the other was in the inferior hemifield around the twenty-degree position. When area analysis was considered, three areas showed a significantly different sensitivity between HTG and NTG. Conclusions. These data suggested that there was no relevant difference in the pointwise analysis between NTG and HTG; however, when visual field areas were compared, no difference in paracentral areas was found between NTG and HTG, but superior nasal step and inferior and superior scotomata showed to be deeper in HTG than in NTG. PMID- 22496962 TI - Modulation of vasomotive activity in rabbit external ophthalmic artery by neuropeptides. AB - Purpose. To investigate the vasomotive activity upon the external ophthalmic artery of vasointestinal peptide (VIP) and neuropeptide Y (NPY) using a previously developed model. Methods. Isolated rabbit eyes (n = 12) were perfused in situ with tyrode through the external ophthalmic artery. Effects of intra arterial injections of NPY 200 MUg/ml (Group A; n = 6) and VIP 200 MUg/ml (Group B; n = 6) on the recorded pressure were obtained. For statistical analysis, Student's paired t-test and Fast Fourier Transform were used. Results. Spontaneous oscillations were observed before any drug administration in the 12 rabbit models. NPY produced an increase in total vascular resistance and a higher frequency and amplitude of oscillations, while VIP evoked the opposite effects. Conclusions. This study provides evidence of vasomotion in basal conditions in rabbit external ophthalmic artery. Concerning drug effects, NPY increased arterial resistance and enhanced vasomotion while VIP produced opposite effects which demonstrates their profound influence in arterial vasomotion. PMID- 22496963 TI - Bilateral circumscribed posterior keratoconus: visualization by ultrasound biomicroscopy and slit-scanning topography analysis. AB - This paper documents a rare nonprogressive developmental disorder-bilateral circumscribed posterior keratoconus-in a 60-year-old man referred for a cataract surgery. For the first time ultrasound biomicroscopy was used to visualise the local anterior bulging of the posterior corneal surface with concomitant thinning of the stroma. The amount of localized posterior depression, corneal thickness and the refractive power of both the posterior and anterior corneal curvature were measured using slit-scanning topography analysis (Orbscan). PMID- 22496964 TI - New Approach of Anti-VEGF Agents for Age-Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of visual loss in older population. Angiogenesis is an important factor associated with the development of CNV due to AMD. Treatment of CNV with intravitreal anti-VEGF monotherapy is currently the standard of care. However, not all patients respond to monotherapy, and modified anti-VEGF treatment regimen and combination therapy may target reducing treatment frequency or improving visual outcome. This paper reviews the many clinical trials that have been performed utilizing several treatment regimens. While many trials have shown that this variable therapy is justifiable, further study is required to determine correct regimens and dosage. PMID- 22496965 TI - Straightforward procedure for laboratory production of DNA ladder. AB - DNA ladder is commonly used to determine the size of DNA fragments by electrophoresis in routine molecular biology laboratories. In this study, we report a new procedure to prepare a DNA ladder that consists of 10 fragments from 100 to 1000 bp. This protocol is a combination of routinely employed methods: cloning, PCR, and partial digestion with restriction enzymes. DNA fragments of 100 bp with unique restriction site at both ends were self-ligated to create a tandem repeat. Once being cloned, the tandem repeat was rapidly amplified by PCR and partially digested by restriction enzymes to produce a ladder containing multimers of the repeated DNA fragments. Our procedure for production of DNA ladder could be simple, time saving, and inexpensive in comparison with current ones widely used in most laboratories. PMID- 22496966 TI - Microbial enzyme: applications in industry and in bioremediation. PMID- 22496967 TI - Gait and Function in Class III Obesity. AB - Walking, more specifically gait, is an essential component of daily living. Walking is a very different activity for individuals with a Body Mass Index (BMI) of 40 or more (Class III obesity) compared with those who are overweight or obese with a BMI between 26-35. Yet all obesity weight classes receive the same physical activity guidelines and recommendations. This observational study examined the components of function and disability in a group with Class III obesity and a group that is overweight or has Class I obesity. Significant differences were found between the groups in the areas of gait, body size, health condition, and activity capacity and participation. The Timed Up and Go test, gait velocity, hip circumference, and stance width appear to be most predictive of activity capacity as observed during gait assessment. The findings indicate that Class III-related gait is pathologic and not a normal adaptation. PMID- 22496969 TI - Blood Pressure-Lowering Mechanisms of the DASH Dietary Pattern. AB - Potential blood pressure- (BP-) lowering mechanisms of the DASH dietary pattern were measured in 20 unmedicated hypertensive adults in a controlled feeding study. At screening, participants averaged 44.3 +/- 7.8 years, BMI 33.9 +/- 6.6 Kg/m(2), and BP 144.2 +/- 9.38/88.5 +/- 6.03 mmHg. All consumed a control diet for one week, then were randomized to control or DASH for another two weeks (week one and two). With DASH, but not controls, SBP fell by 10.65 +/- 12.89 (P = 0.023) and 9.60 +/- 11.23 (P = 0.039) mmHg and DBP by 5.95 +/- 8.01 (P = 0.069) and 8.60 +/- 9.13 mmHg (P = 0.011) at the end of week one and two, respectively. Univariate regressions showed that changes in urinary sodium/potassium ratio (beta = 1.99) and plasma renin activity (beta = -15.78) and percent change in plasma nitrite after hyperemia were associated with SBP changes at week one (all P < 0.05). Plasma nitrite following hyperemia showed a treatment effect (P = 0.014) and increased at week two (P = 0.001). Pulse wave velocity decreased over time with DASH (trend P = 0.019), and reached significance at week two (P = 0.026). This response may be mediated by an improvement in upregulation of nitric oxide bioavailability. Early natriuresis and reductions in oxidative stress cannot be ruled out. Future studies are needed to verify these findings, assess the possibility of earlier effects, and examine other potential mediators. PMID- 22496970 TI - A Prospective Study Assessing Tumour Response, Survival, and Palliative Care Outcomes in Patients with HIV-Related Kaposi's Sarcoma at Queen Elizabeth Central Hospital, Blantyre, Malawi. AB - Background. Human-Immunodeficiency-Virus- (HIV-) related Kaposi's sarcoma (KS) has a high prevalence in Africa; however, there is minimal published data on treatment and outcomes in this population. Objective and Design. This was a prospective study of 50 patients, aiming to assess the impact of vincristine therapy on tumour response and survival and to assess palliative care outcomes in patients with HIV-related KS. Methods. 50 consecutive patients were recruited during 2008. Vincristine therapy and highly active antiretroviral therapy (HAART) were given. Tumour response, survival, and chemotherapy-related toxicities were documented. Palliative care outcomes were assessed using the African Palliative Care Association (APCA) Palliative Outcome Scale (POS). Results. The majority of patients were male, and the median age was 33 years. At baseline assessment, the median CD4 T-cell count was 263, and 50% patients had evidence of peripheral neuropathy. The overall response rate was 64% at 6 weeks, and median progression free survival was 30 weeks. Treatment was generally well tolerated, with peripheral neuropathy the main dose-limiting toxicity. Conclusion. The combination of vincristine and HAART is feasible and effective in a low resource setting, although peripheral neuropathy is a dose-limiting factor. This patient group carries a high mortality and as such adequate access to palliative care is crucial. PMID- 22496968 TI - Microarray Analyses of Genes Differentially Expressed by Diet (Black Beans and Soy Flour) during Azoxymethane-Induced Colon Carcinogenesis in Rats. AB - We previously demonstrated that black bean (BB) and soy flour (SF)-based diets inhibit azoxymethane (AOM)-induced colon cancer. The objective of this study was to identify genes altered by carcinogen treatment in normal-appearing colonic mucosa and those attenuated by bean feeding. Ninety-five male F344 rats were fed control (AIN) diets upon arrival. At 4 and 5 weeks, rats were injected with AOM (15 mg/kg) or saline and one week later administered an AIN, BB-, or SF-based diet. Rats were sacrificed after 31 weeks, and microarrays were conducted on RNA isolated from the distal colonic mucosa. AOM treatment induced a number of genes involved in immunity, including several MHC II-associated antigens and innate defense genes (RatNP-3, Lyz2, Pla2g2a). BB- and SF-fed rats exhibited a higher expression of genes involved in energy metabolism and water and sodium absorption and lower expression of innate (RatNP-3, Pla2g2a, Tlr4, Dmbt1) and cell cycle associated (Cdc2, Ccnb1, Top2a) genes. Genes involved in the extracellular matrix (Col1a1, Fn1) and innate immunity (RatNP-3, Pla2g2a) were induced by AOM in all diets, but to a lower extent in bean-fed animals. This profile suggests beans inhibit colon carcinogenesis by modulating cellular kinetics and reducing inflammation, potentially by preserving mucosal barrier function. PMID- 22496971 TI - Alcohol Consumption, Progression of Disease and Other Comorbidities, and Responses to Antiretroviral Medication in People Living with HIV. AB - The present paper describes the possible connection between alcohol consumption and adherence to medicine used to treat human deficiency viral (HIV) infection. Highly active antiretroviral therapy (HAART) has a positive influence on longevity in patients with HIV, substantially reducing morbidity and mortality, including resource-poor settings such as South Africa. However, in a systematic comparison of HAART outcomes between low-income and high-income countries in the treatment of HIV-patients, mortality was higher in resource-poor settings. Specifically, in South Africa, patients often suffer from concomitant tuberculosis and other infections that may contribute to these results. Alcohol influences the use of medicine for opportunistic infections (e.g., pneumonia, tuberculosis), or coinfections HIV-hepatitis viruses-B (HBV) and C (HCV), cytomegalovirus, or herpes simplex virus. Furthermore, alcohol use may negatively impact on medication adherence contributing to HIV progression. The materials used provide a data-supported approach. They are based on analysis of published (2006-2011) world literature and the experience of the authors in the specified topic. Intended for use by health care professionals, these recommendations suggest approaches to the therapeutic and preventive aspects of care. Our intention was to fully characterize the quality of evidence supporting recommendations, which are reflecting benefit versus risk, and assessing strength or certainty. PMID- 22496972 TI - Prevalence of HIV Drug Resistance Mutations in HIV Type 1 Isolates in Antiretroviral Therapy Naive Population from Northern India. AB - Objective. The increased use of antiretroviral therapy (ART) has reduced the morbidity and mortality associated with HIV, adversely leading to the emergence of HIV drug resistance (HIVDR). In this study we aim to evaluate the prevalence of HIVDR mutations in ART-naive HIV-1 infected patients from northern India. Design. Analysis was performed using Viroseq genotyping system based on sequencing of entire protease and two-thirds of the Reverse Transcriptase (RT) region of pol gene. Results. Seventy three chronic HIV-1 infected ART naive patients eligible for first line ART were enrolled from April 2006 to August 2008. In 68 patients DNA was successfully amplified and sequencing was done. 97% of HIV-1 strains belonged to subtype C, and one each to subtype A1 and subtype B. The overall prevalence of primary DRMs was 2.9% [2/68, 95% confidence interval (CI), 0.3%-10.2%]. One patient had a major RT mutation M184V, known to confer resistance to lamivudine, and another had a major protease inhibitor (PI) mutation D30N that imparts resistance to nelfinavir. Conclusion. Our study shows that primary HIVDR mutations have a prevalence of 2.9% among ART-naive chronic HIV-1 infected individuals. PMID- 22496973 TI - Thalassemic DNA-Containing Red Blood Cells Are under Oxidative Stress. AB - We studied the nature of enucleated RBCs containing DNA remnants, Howell-Jolly (HJ) RBCs and reticulocytes (retics), that are characteristically present in the circulation of thalassemic patients, especially after splenectomy. Using flow cytometry methodology, we measured oxidative status parameters of these cells in patients with beta-thalassemia. In each patient studied, these cells had higher content of reactive oxygen species and exposed phosphatidylserine compared with their DNA-free counterparts. These results suggest that oxidative stress in thalassemic developing erythroid precursors might, through DNA-breakage, generate HJ-retics and HJ-RBCs and that oxidative stress-induced externalization of phosphatidylserine is involved in the removal of these cells from the circulation by the spleen, a mechanism similar to that of the removal of senescent RBCs. PMID- 22496974 TI - Evidence map of prevention and treatment interventions for depression in young people. AB - Introduction. Depression in adolescents and young people is associated with reduced social, occupational, and interpersonal functioning, increases in suicide and self-harm behaviours, and problematic substance use. Age-appropriate, evidence-based treatments are required to provide optimal care. Methods. "Evidence mapping" methodology was used to quantify the nature and distribution of the extant high-quality research into the prevention and treatment of depression in young people across psychological, medical, and other treatment domains. Results. Prevention research is dominated by cognitive-behavioral- (CBT ) based interventions. Treatment studies predominantly consist of CBT and SSRI medication trials, with few trials of other psychological interventions or complementary/alternative treatments. Quality studies on relapse prevention and treatment for persistent depression are distinctly lacking. Conclusions. This map demonstrates opportunities for future research to address the numerous evidence gaps for interventions to prevent or treat depression in young people, which are of interest to clinical researchers, policy makers, and funding bodies. PMID- 22496976 TI - The Columbus Knee System: 4-Year Results of a New Deep Flexion Design Compared to the NexGen Full Flex Implant. AB - The Columbus knee system is designed as a standard knee implant to allow high flexion without additional bone resection. Between August, 2004 and March, 2010 we performed 109 total knee arthroplasties of the Columbus knee system in 101 consecutive patients suffering from primary arthrosis of the knee. Mean age was 72.4 years in women and 70.3 years in men. Mean followup was 47.3 months. The 4 year results of a group of patients who received the NexGen Full Flex implant operated by the same surgeon were used for comparison. Mean total knee score was Columbus: 175.6 and NexGen Flex: 183.4; P = 0.037. Mean operation time was 53 min for Columbus and 66 min for NexGen Flex; P < 0.001. With new streamlined instruments operative time became 60 min for the Columbus; P > 0.05. Radiological assessment showed no signs of loosening for both groups. Therefore, the Columbus knee system can be recommended for flexion angles up to 140 degrees . PMID- 22496975 TI - Diverse Roles of JNK and MKK Pathways in the Brain. AB - The c-Jun NH(2)-terminal protein kinase (JNK) plays important roles in a broad range of physiological processes. JNK is controlled by two upstream regulators, mitogen-activated protein kinase kinase (MKK) 4 and MKK7, which are activated by various MAPKKKs. Studies employing knockout mice have demonstrated that the JNK signaling pathway is involved in diverse phenomena in the brain, regulating brain development and maintenance as well as animal metabolism and behavior. Furthermore, examination of single or combined knockout mice of Jnk1, Jnk2, and Jnk3 has revealed both functional differences and redundancy among JNK1, JNK2, and JNK3. Phenotypic differences between knockouts of MKK4 and MKK7 have also been observed, suggesting that the JNK signaling pathway in the brain has a complex nature and is intricately regulated. This paper summarizes the functional properties of the major JNK signaling components in the developing and adult brain. PMID- 22496977 TI - Genotoxicity studies performed in the ecuadorian population. AB - Genotoxicity studies in Ecuador have been carried out during the past two decades. The focuses of the research were mainly the area of environmental issues, where the populations have been accidentally exposed to contaminants and the area of occupational exposure of individuals at the workplace. This paper includes studies carried out in the population of the Amazon region, a zone known for its rich biodiversity as well as for the ecological damage caused by oil spills and chemical sprayings whose consequences continue to be controversial. Additionally, we show the results of studies comprised of individuals occupationally exposed to toxic agents in two very different settings: flower plantation workers exposed to pesticide mixtures and X-ray exposure of hospital workers. The results from these studies confirm that genotoxicity studies can help evaluate current conditions and prevent further damage in the populations exposed to contaminants. As such, they are evidence of the need for biomonitoring employers at risk, stricter law enforcement regarding the use of pesticides, and increasingly conscientious oil extraction activities. PMID- 22496978 TI - Hematopoietic Stem Cell Mobilization and Homing after Transplantation: The Role of MMP-2, MMP-9, and MT1-MMP. AB - Hematopoietic stem/progenitor cells (HSPCs) are used in clinical transplantation to restore hematopoietic function. Here we review the role of the soluble matrix metalloproteinases MMP-2 and MMP-9, and membrane type (MT)1-MMP in modulating processes critical to successful transplantation of HSPC, such as mobilization and homing. Growth factors and cytokines which are employed as mobilizing agents upregulate MMP-2 and MMP-9. Recently we demonstrated that MT1-MMP enhances HSPC migration across reconstituted basement membrane, activates proMMP-2, and contributes to a highly proteolytic bone marrow microenvironment that facilitates egress of HSPC. On the other hand, we reported that molecules secreted during HSPC mobilization and collection, such as hyaluronic acid and thrombin, increase MT1-MMP expression in cord blood HSPC and enhance (prime) their homing-related responses. We suggest that modulation of MMP-2, MMP-9, and MT1-MMP expression has potential for development of new therapies for more efficient mobilization, homing, and engraftment of HSPC, which could lead to improved transplantation outcomes. PMID- 22496979 TI - Transvaginal ultrasound in fertile patients with suspected appendicitis: an experience report of current practice. AB - Background. Transvaginal ultrasound (TVU) in female patients with acute right lower quadrant (RLQ) abdominal pain is time and infrastructure intensive and not always available. This study aims to evaluate the role of TVU in these patients. Methods. Retrospective analysis identified 224 female patients with RLQ pain and TVU. Results. TVU revealed an underlying pathology in 34 (15%) patients, necessitating a diagnostic laparoscopy in 12 patients. Six patients (2%) had a true gynaecological emergency. The remaining 23 patients did not require surgery. The other 190 patients with RLQ pain had a bland TVU; 127 (67%) were discharged, while 63 patients (33%) received a diagnostic laparoscopy. Conclusion. The incidence of true gynaecological emergencies requiring urgent surgical intervention is very low in our patient cohort. TVU is a helpful tool if performed by a physician who is well trained in TVU. PMID- 22496980 TI - Cyclodextrin-containing polymers: versatile platforms of drug delivery materials. AB - Nanoparticles are being widely explored as potential therapeutics for numerous applications in medicine and have been shown to significantly improve the circulation, biodistribution, efficacy, and safety profiles of multiple classes of drugs. One leading class of nanoparticles involves the use of linear, cyclodextrin-containing polymers (CDPs). As is discussed in this paper, CDPs can incorporate therapeutic payloads into nanoparticles via covalent attachment of prodrug/drug molecules to the polymer (the basis of the Cyclosert platform) or by noncovalent inclusion of cationic CDPs to anionic, nucleic acid payloads (the basis of the RONDEL platform). For each of these two approaches, we review the relevant molecular architecture and its rationale, discuss the physicochemical and biological properties of these nanoparticles, and detail the progress of leading drug candidates for each that have achieved clinical evaluation. Finally, we look ahead to potential future directions of investigation and product candidates based upon this technology. PMID- 22496981 TI - Fatty Acid Oxidation and Cardiovascular Risk during Menopause: A Mitochondrial Connection? AB - Menopause is a consequence of the normal aging process in women. This fact implies that the physiological and biochemical alterations resulting from menopause often blur with those from the aging process. It is thought that menopause in women presents a higher risk for cardiovascular disease although the precise mechanism is still under discussion. The postmenopause lipid profile is clearly altered, which can present a risk factor for cardiovascular disease. Due to the role of mitochondria in fatty acid oxidation, alterations of the lipid profile in the menopausal women will also influence mitochondrial fatty acid oxidation fluxes in several organs. In this paper, we propose that alterations of mitochondrial bioenergetics in the heart, consequence from normal aging and/or from the menopausal process, result in decreased fatty acid oxidation and accumulation of fatty acid intermediates in the cardiomyocyte cytosol, resulting in lipotoxicity and increasing the cardiovascular risk in the menopausal women. PMID- 22496983 TI - Sex- and age-related differences in bone microarchitecture in men relative to women assessed by high-resolution peripheral quantitative computed tomography. AB - The trabecular and cortical compartments of bone each contributes to bone strength. Until recently, assessment of trabecular and cortical microstructure has required a bone biopsy. Now, trabecular and cortical microstructure of peripheral bone sites can be determined noninvasively using high-resolution peripheral quantitative computed tomography (HR-pQCT). Studies that have used HR pQCT to evaluate cohorts of both men and women have provided novel insights into the changes in bone microarchitecture that occur with age between the sexes, which may help to explain the lower fracture incidence in older men relative to women. This review will highlight observations from these studies on both the sex and age-related differences in trabecular and cortical microstructure that may underlie the differences in bone strength, and thereby fracture risk, between men and women. PMID- 22496982 TI - Laminoplasty techniques for the treatment of multilevel cervical stenosis. AB - Laminoplasty is one surgical option for cervical spondylotic myelopathy. It was developed to avoid the significant risk of complications associated with alternative surgical options such as anterior decompression and fusion and laminectomy with or without posterior fusion. Various laminoplasty techniques have been described. All of these variations are designed to reposition the laminae and expand the spinal canal while retaining the dorsal elements to protect the dura from scar formation and to preserve postoperative cervical stability and alignment. With the right surgical indications, reliable results can be expected with laminoplasty in treating patients with multilevel cervical myelopathy. PMID- 22496984 TI - Are selective serotonin reuptake inhibitors a secondary cause of low bone density? AB - Background. Osteoporosis is a chronic disease that can significantly impact numerous aspects of health and wellness. The individual consequences of osteoporosis can be devastating, often resulting in substantial loss of independence and sometimes death. One of the few illnesses with greater disease burden than low bone mineral density (BMD) is major depressive disorder (MDD). Both depression and antidepressant use have been identified as secondary causes of osteoporosis. The objective of this paper is to review and summarize the current findings on the relationship between antidepressant use and BMD. Methods. Relevant sources were identified from the Pubmed and MEDLINE databases, citing articles from the first relevant publication to September 1st, 2010. Results. 2001 articles initially met the search criteria, and 35 studies were thoroughly reviewed for evidence of an association between SSRI use and BMD, and 8 clinical studies were detailed and summarized in this paper. Conclusions. Current findings suggest a link between mental illness and osteoporosis that is of clinical relevance. Additional longitudinal studies and further research on possible mechanisms surrounding the association between SSRI use on bone metabolism need to be conducted. Treatment algorithms need to recognize this association to ensure that vulnerable populations are screened. PMID- 22496985 TI - Total parathyroidectomy with presternal intramuscular autotransplantation in renal patients: a prospective study of 66 patients. AB - Surgical treatment of secondary (SHPT) and tertiary hyperparathyroidism (THPT) may involve various surgical approaches. The aim of this paper was to evaluate presternal intramuscular autotransplantation of parathyroid tissue as a surgical option in SHPT and THPT treatment. 66 patients with renal chronic disease underwent surgery from April 2000 to April 2005 at Universidade Federal Sao Paulo, Brazil. There were 38 SHPT patients (24 women/14 men), mean age of 39.yrs (range: 14-58), and 28 THPT patients (14 women/14 men), mean age of 43.4 yrs (range: 24-62). Postoperative average followup was 42.9 months (range: 12-96). Postoperative intact PTH increased throughout followup from 73.5 pg/mL to 133 pg/mL on average from 1st to the 5th year, respectively, in SHPT and from 54.9 pg/mL to 94.7 pg/mL on average from 1st to 5th year, respectively, in THPT group. Definitive hypoparathyroidism was observed in 4 (6.06%) patients and graft dependent recurrence in 6 (9.09%). Presternal intramuscular autotransplantation of parathyroid tissue is a feasible and safe surgical option in SHPT and THPT treatment. PMID- 22496986 TI - Biomarkers in thyroid tumor research: new diagnostic tools and potential targets of molecular-based therapy. PMID- 22496987 TI - Determinants of extraocular muscle volume in patients with graves' disease. AB - Background. To examine factors contributing to extraocular muscle (EOM) volume enlargement in patients with Graves' hyperthyroidism. Methods. EOM volumes were measured with orbital magnetic resonance imaging (MRI) in 39 patients with recently diagnosed Graves' disease, and compared to EOM volumes of 13 normal volunteers. Thyroid function tests, uptake on thyroid scintigraphy, anti-TSH receptor antibody positivity and other parameters were then evaluated in patients with EOM enlargement. Results. 31/39 patients had one or more enlarged EOM, of whom only 2 patients had clinical EOM dysfunction. Compared to Graves' disease patients with normal EOM volumes, those with EOM enlargement had significantly higher mean serum TSH (0.020 +/- 0.005 versus 0.007 +/- 0.002 mIU/L; P value 0.012), free-T4 (52.9 +/- 3.3 versus 41.2 +/- 1.7 pmol/L; P value 0.003) and technetium uptake on thyroid scintigraphy (13.51 +/- 1.7% versus 8.55 +/- 1.6%; P value 0.045). There were no differences between the 2 groups in anti-TSH-receptor antibody positivity, the proportion of males, tobacco smokers, or those with active ophthalmopathy. Conclusions. Patients with recently diagnosed Graves' disease and EOM volume enlargement have higher serum TSH and more severe hyperthyroidism than patients with normal EOM volumes, with no difference in anti TSH-receptor antibody positivity between the two groups. PMID- 22496988 TI - Are verbal fluency and nonliteral language comprehension deficits related to depressive symptoms in Parkinson's disease? AB - Depression in Parkinson's disease (PD) is frequently associated with executive deficits, which can influence nonliteral comprehension and lexical access. This study explores whether depressive symptoms in PD modulate verbal fluency and nonliteral language comprehension. Twelve individuals with PD without depressive symptoms, 13 with PD and depressive symptoms (PDDSs), and 13 healthy controls completed a semantic and phonemic verbal fluency task and an indirect speech acts comprehension task. All groups had the same performance in the phonemic fluency task while the PDDS group was impaired in the semantic task. For the indirect speech act comprehension task, no difference was observed between the groups. However, the PDDS group had difficulty answering direct speech act questions. As some language impairments in PD become apparent when depressive symptoms are associated with the disease, it would appear to be important to take the presence of depressive symptoms into account when evaluating language abilities in PD. PMID- 22496989 TI - Dyskinesias and treatment with pramipexole in patients with Parkinson's disease. AB - Dopamine agonists such as pramipexole (PPX) have first been proposed as adjunctive treatment to levodopa (L-DOPA) for patients with Parkinson's disease (PD) and then as a monotherapy alternative to alleviate dyskinesia. Treatment with PPX has overall been associated with improvement in parkinsonian symptoms. Although the majority of placebo-controlled studies demonstrated that dyskinesia was more prevalent in the PPX compared to the placebo groups, some studies did not detect any dyskinesia as a side effect of this medication. PPX was consistently associated with lower risk for developing dyskinesia compared to L DOPA. Moreover, the presence of these symptoms in the placebo groups suggests involvement of non-PPX-related factors for developing dyskinesia. It is suggested that future research should aim at ascertaining whether cotherapy with L-DOPA, PPX dosage, and other patient characteristics are contributory factors for the development of PPX-related dyskinesia in patients with PD. PMID- 22496990 TI - Improving community healthcare for patients with Parkinson's disease: the dutch model. AB - Because of the complex nature of Parkinson's disease, a wide variety of health professionals are involved in care. Stepwise, we have addressed the challenges in the provision of multidisciplinary care for this patient group. As a starting point, we have gained detailed insight into the current delivery of allied healthcare, as well as the barriers and facilitators for optimal care. To overcome the identified barriers, a tertiary referral centre was founded; evidence-based guidelines were developed and cost-effectively implemented within regional community networks of specifically trained allied health professionals (the ParkinsonNet concept). We increasingly use ICT to bind these professional networks together and also to empower and engage patients in making decisions about their health. This comprehensive approach is likely to be feasible for other countries as well, so we currently collaborate in a European collaboration to improve community care for persons with Parkinson's disease. PMID- 22496991 TI - Noncontact atomic force microscopy study of the spinel MgAl(2)O(4)(111) surface. AB - Based on high-resolution noncontact atomic force microscopy (NC-AFM) experiments we reveal a detailed structural model of the polar (111) surface of the insulating ternary metal oxide, MgAl(2)O(4) (spinel). NC-AFM images reveal a 6?3*6?3R30 degrees superstructure on the surface consisting of patches with the original oxygen-terminated MgAl(2)O(4)(111) surface interrupted by oxygen deficient areas. These observations are in accordance with previous theoretical studies, which predict that the polarity of the surface can be compensated by removal of a certain fraction of oxygen atoms. However, instead of isolated O vacancies, it is observed that O is removed in a distinct pattern of line vacancies reflected by the underlying lattice structure. Consequently, by the creation of triangular patches in a 6?3*6?3R30 degrees superstructure, the polar stabilization requirements are met. PMID- 22496992 TI - Theoretical study of the frequency shift in bimodal FM-AFM by fractional calculus. AB - Bimodal atomic force microscopy is a force-microscopy method that requires the simultaneous excitation of two eigenmodes of the cantilever. This method enables the simultaneous recording of several material properties and, at the same time, it also increases the sensitivity of the microscope. Here we apply fractional calculus to express the frequency shift of the second eigenmode in terms of the fractional derivative of the interaction force. We show that this approximation is valid for situations in which the amplitude of the first mode is larger than the length of scale of the force, corresponding to the most common experimental case. We also show that this approximation is valid for very different types of tip-surface forces such as the Lennard-Jones and Derjaguin-Muller-Toporov forces. PMID- 22496993 TI - A measurement of the hysteresis loop in force-spectroscopy curves using a tuning fork atomic force microscope. AB - Measurements of the frequency shift versus distance in noncontact atomic force microscopy (NC-AFM) allow measurements of the force gradient between the oscillating tip and a surface (force-spectroscopy measurements). When nonconservative forces act between the tip apex and the surface the oscillation amplitude is damped. The dissipation is caused by bistabilities in the potential energy surface of the tip-sample system, and the process can be understood as a hysteresis of forces between approach and retraction of the tip. In this paper, we present the direct measurement of the whole hysteresis loop in force spectroscopy curves at 77 K on the PTCDA/Ag/Si(111) ?3 * ?3 surface by means of a tuning-fork-based NC-AFM with an oscillation amplitude smaller than the distance range of the hysteresis loop. The hysteresis effect is caused by the making and breaking of a bond between PTCDA molecules on the surface and a PTCDA molecule at the tip. The corresponding energy loss was determined to be 0.57 eV by evaluation of the force-distance curves upon approach and retraction. Furthermore, a second dissipation process was identified through the damping of the oscillation while the molecule on the tip is in contact with the surface. This dissipation process occurs mainly during the retraction of the tip. It reaches a maximum value of about 0.22 eV/cycle. PMID- 22496994 TI - Variations in the structure and reactivity of thioester functionalized self assembled monolayers and their use for controlled surface modification. AB - Thioester-functionalized, siloxane-anchored, self-assembled monolayers provide a powerful tool for controlling the chemical and physical properties of surfaces. The thioester moiety is relatively stable to long-term storage and its structure can be systematically varied so as to provide a well-defined range of reactivity and wetting properties. The oxidation of thioesters with different-chain-length acyl groups allows for very hydrophobic surfaces to be transformed into very hydrophilic, sulfonic acid-bearing, surfaces. Systematic variation in the length of the polymethylene chain has also allowed us to examine how imbedding reaction sites at various depths in a densely packed monolayer changes their reactivity. pi-Systems (benzene and thiophene) conjugated to the thioester carbonyl enable the facile creation of photoreactive surfaces that are able to use light of different wavelengths. These elements of structural diversity combine with the utility of the hydrophilic, strongly negatively charged sulfonate-bearing surface to constitute an important approach to systematic surface modification. PMID- 22496995 TI - An NC-AFM and KPFM study of the adsorption of a triphenylene derivative on KBr(001). AB - The adsorption on KBr(001) of a specially designed molecule, consisting of a flat aromatic triphenylene core equipped with six flexible propyl chains ending with polar cyano groups, is investigated by using atomic force microscopy in the noncontact mode (NC-AFM) coupled to Kelvin probe force microscopy (KPFM) in ultrahigh vacuum at room temperature. Two types of monolayers are identified, one in which the molecules lie flat on the surface (MLh) and another in which they stand approximately upright (MLv). The Kelvin voltage on these two structures is negatively shifted relative to that of the clean KBr surface, revealing the presence of surface dipoles with a component pointing along the normal to the surface. These findings are interpreted with the help of numerical simulations. It is shown that the surface-molecule interaction is dominated by the electrostatic interaction of the cyano groups with the K(+) ions of the substrate. The molecule is strongly adsorbed in the MLh structure with an adsorption energy of 1.8 eV. In the MLv layer, the molecules form pi-stacked rows aligned along the polar directions of the KBr surface. In these rows, the molecules are less strongly bound to the substrate, but the structure is stabilized by the strong intermolecular interaction due to pi-stacking. PMID- 22496996 TI - Modeling noncontact atomic force microscopy resolution on corrugated surfaces. AB - Key developments in NC-AFM have generally involved atomically flat crystalline surfaces. However, many surfaces of technological interest are not atomically flat. We discuss the experimental difficulties in obtaining high-resolution images of rough surfaces, with amorphous SiO(2) as a specific case. We develop a quasi-1-D minimal model for noncontact atomic force microscopy, based on van der Waals interactions between a spherical tip and the surface, explicitly accounting for the corrugated substrate (modeled as a sinusoid). The model results show an attenuation of the topographic contours by ~30% for tip distances within 5 A of the surface. Results also indicate a deviation from the Hamaker force law for a sphere interacting with a flat surface. PMID- 22496997 TI - Analysis of force-deconvolution methods in frequency-modulation atomic force microscopy. AB - In frequency-modulation atomic force microscopy the direct observable is the frequency shift of an oscillating cantilever in a force field. This frequency shift is not a direct measure of the actual force, and thus, to obtain the force, deconvolution methods are necessary. Two prominent methods proposed by Sader and Jarvis (Sader-Jarvis method) and Giessibl (matrix method) are investigated with respect to the deconvolution quality. Both methods show a nontrivial dependence of the deconvolution quality on the oscillation amplitude. The matrix method exhibits spikelike features originating from a numerical artifact. By interpolation of the data, the spikelike features can be circumvented. The Sader Jarvis method has a continuous amplitude dependence showing two minima and one maximum, which is an inherent property of the deconvolution algorithm. The optimal deconvolution depends on the ratio of the amplitude and the characteristic decay length of the force for the Sader-Jarvis method. However, the matrix method generally provides the higher deconvolution quality. PMID- 22496998 TI - Simultaneous current, force and dissipation measurements on the Si(111) 7*7 surface with an optimized qPlus AFM/STM technique. AB - We present the results of simultaneous scanning-tunneling and frequency-modulated dynamic atomic force microscopy measurements with a qPlus setup. The qPlus sensor is a purely electrical sensor based on a quartz tuning fork. If both the tunneling current and the force signal are to be measured at the tip, a cross talk of the tunneling current with the force signal can easily occur. The origin and general features of the capacitive cross-talk will be discussed in detail in this contribution. Furthermore, we describe an experimental setup that improves the level of decoupling between the tunneling-current and the deflection signal. The efficiency of this experimental setup is demonstrated through topography and site-specific force/tunneling-spectroscopy measurements on the Si(111) 7*7 surface. The results show an excellent agreement with previously reported data measured by optical interferometric deflection. PMID- 22496999 TI - Pulse-response measurement of frequency-resolved water dynamics on a hydrophilic surface using a Q-damped atomic force microscopy cantilever. AB - The frequency-resolved viscoelasticity of a hydration layer on a mica surface was studied by pulse-response measurement of a magnetically driven atomic force microscopy cantilever. Resonant ringing of the cantilever due to its 1st and 2nd resonance modes was suppressed by means of the Q-control technique. The Fourier Laplace transform of the deflection signal of the cantilever gave the frequency resolved complex compliance of the cantilever-sample system. The significant viscoelasticity spectrum of the hydration layer was successfully derived in a frequency range below 100 kHz by comparison of data obtained at a distance of 300 nm from the substrate with those taken in the proximity of the substrate. A positive value of the real part of the stiffness was determined and is attributed to the reported solidification of the hydration layers. PMID- 22497000 TI - Forming nanoparticles of water-soluble ionic molecules and embedding them into polymer and glass substrates. AB - This work describes a general method for the preparation of salt nanoparticles (NPs) made from an aqueous solution of ionic compounds (NaCl, CuSO(4) and KI). These nanoparticles were created by the application of ultrasonic waves to the aqueous solutions of these salts. When the sonication was carried out in the presence of a glass microscope slide, a parylene-coated glass slide, or a silicon wafer the ionic NPs were embedded in these substrates by a one-step, ultrasound assisted procedure. Optimization of the coating process resulted in homogeneous distributions of nanocrystals, 30 nm in size, on the surfaces of the substrates. The morphology and structure of each of the coatings were characterized by physical and chemical methods, such as X-ray diffraction (XRD), scanning electron microscopy (SEM), atomic force microscopy (AFM), Raman spectroscopy and X-ray photoelectron spectroscopy (XPS). After 24 h of leaching into water the nanoparticles of the inorganic salts were still present on the slides, and complete leaching of nanoparticles occurred only after 96 h. A mechanism of the ultrasound-assisted coating is proposed. PMID- 22497001 TI - Junction formation of Cu(3)BiS(3) investigated by Kelvin probe force microscopy and surface photovoltage measurements. AB - Recently, the compound semiconductor Cu(3)BiS(3) has been demonstrated to have a band gap of ~1.4 eV, well suited for photovoltaic energy harvesting. The preparation of polycrystalline thin films was successfully realized and now the junction formation to the n-type window needs to be developed. We present an investigation of the Cu(3)BiS(3) absorber layer and the junction formation with CdS, ZnS and In(2)S(3) buffer layers. Kelvin probe force microscopy shows the granular structure of the buffer layers with small grains of 20-100 nm, and a considerably smaller work-function distribution for In(2)S(3) compared to that of CdS and ZnS. For In(2)S(3) and CdS buffer layers the KPFM experiments indicate negatively charged Cu(3)BiS(3) grain boundaries resulting from the deposition of the buffer layer. Macroscopic measurements of the surface photovoltage at variable excitation wavelength indicate the influence of defect states below the band gap on charge separation and a surface-defect passivation by the In(2)S(3) buffer layer. Our findings indicate that Cu(3)BiS(3) may become an interesting absorber material for thin-film solar cells; however, for photovoltaic application the band bending at the charge-selective contact has to be increased. PMID- 22497002 TI - Dipole-driven self-organization of zwitterionic molecules on alkali halide surfaces. AB - We investigated the adsorption of 4-methoxy-4'-(3-sulfonatopropyl)stilbazolium (MSPS) on different ionic (001) crystal surfaces by means of noncontact atomic force microscopy. MSPS is a zwitterionic molecule with a strong electric dipole moment. When deposited onto the substrates at room temperature, MSPS diffuses to step edges and defect sites and forms disordered assemblies of molecules. Subsequent annealing induces two different processes: First, at high coverage, the molecules assemble into a well-organized quadratic lattice, which is perfectly aligned with the <110> directions of the substrate surface (i.e., rows of equal charges) and which produces a Moire pattern due to coincidences with the substrate lattice constant. Second, at low coverage, we observe step edges decorated with MSPS molecules that run along the <110> direction. These polar steps most probably minimize the surface energy as they counterbalance the molecular dipole by presenting oppositely charged ions on the rearranged step edge. PMID- 22497003 TI - Wavelet cross-correlation and phase analysis of a free cantilever subjected to band excitation. AB - This work introduces the concept of time-frequency map of the phase difference between the cantilever response signal and the driving signal, calculated with a wavelet cross-correlation technique. The wavelet cross-correlation quantifies the common power and the relative phase between the response of the cantilever and the exciting driver, yielding "instantaneous" information on the driver-response phase delay as a function of frequency. These concepts are introduced through the calculation of the response of a free cantilever subjected to continuous and impulsive excitation over a frequency band. PMID- 22497004 TI - Graphite, graphene on SiC, and graphene nanoribbons: Calculated images with a numerical FM-AFM. AB - BACKGROUND: Characterization at the atomic scale is becoming an achievable task for FM-AFM users equipped, for example, with a qPlus sensor. Nevertheless, calculations are necessary to fully interpret experimental images in some specific cases. In this context, we developed a numerical AFM (n-AFM) able to be used in different modes and under different usage conditions. RESULTS: Here, we tackled FM-AFM image calculations of three types of graphitic structures, namely a graphite surface, a graphene sheet on a silicon carbide substrate with a Si terminated surface, and finally, a graphene nanoribbon. We compared static structures, meaning that all the tip and sample atoms are kept frozen in their equilibrium position, with dynamic systems, obtained with a molecular dynamics module allowing all the atoms to move freely during the probe oscillations. CONCLUSION: We found a very good agreement with experimental graphite and graphene images. The imaging process for the deposited nanoribbon demonstrates the stability of our n-AFM to image a non-perfectly planar substrate exhibiting a geometrical step as well as a material step. PMID- 22497005 TI - A bioelectronic sensor based on canine olfactory nanovesicle-carbon nanotube hybrid structures for the fast assessment of food quality. AB - We developed an olfactory-nanovesicle-fused carbon-nanotube-transistor biosensor (OCB) that mimics the responses of a canine nose for the sensitive and selective detection of hexanal, an indicator of the oxidation of food. OCBs allowed us to detect hexanal down to 1 fM concentration in real-time. Significantly, we demonstrated the detection of hexanal with an excellent selectivity capable of discriminating hexanal from analogous compounds such as pentanal, heptanal, and octanal. Furthermore, we successfully detected hexanal in spoiled milk without any pretreatment processes. Considering these results, our sensor platform should offer a new method for the assessment of food quality and contribute to the development of portable sensing devices. PMID- 22497006 TI - Highly sensitive determination of enantiomeric composition of chiral acids based on aggregation-induced emission. AB - A new chiral tetraphenylethylene derivative with the AIE effect was synthesized and showed not only high enantioselectivity for a wide range of chiral acids but also a high sensitivity of 3.0 * 10(-6) M scale. The enantiomeric purity of chiral acids could be quantitatively determined by this chiral sensor. PMID- 22497007 TI - Hierarchical cooperative binary ionic porphyrin nanocomposites. AB - Cooperative binary ionic (CBI) solids comprise a versatile new class of opto electronic and catalytic materials consisting of ionically self-assembled pairs of organic anions and cations. Herein, we report CBI nanocomposites formed by growing nanoparticles of one type of porphyrin CBI solid onto a second porphyrin CBI substructure with complementary functionality. PMID- 22497008 TI - Heterogeneously catalyzed selective aerobic oxidative cross-coupling of terminal alkynes and amides with simple copper(II) hydroxide. AB - Simple copper(II) hydroxide Cu(OH)(2) could act as an efficient heterogeneous catalyst for selective oxidative cross-coupling of a broad range of terminal alkynes and amides using air as a sole oxidant, giving the corresponding ynamides in moderate to high yields (56-93% yields). PMID- 22497009 TI - Aqueous one-pot synthesis of bright and ultrasmall CdTe/CdS near-infrared emitting quantum dots and their application for tumor targeting in vivo. AB - CdTe/CdS core(small)/shell(thick) quantum dots (QDs) with tunable near-infrared fluorescence were directly synthesized in aqueous phase through a facile one-step strategy. The QDs possessed bright fluorescence, ultrasmall size, excellent photostability and good biocompatibility. Their applicability for biological imaging was demonstrated with the in vivo active tumor targeting of nude mice. PMID- 22497010 TI - Generation of 4-polyfluoroaryl pyrrolo[1,2-a]quinolines via C-H bond activation. AB - A novel and efficient preparation of 4-polyfluoroaryl pyrrolo[1,2-a]quinolines via a palladium-catalyzed reaction of 1-[2-(2,2-dibromoethenyl)phenyl]-1H-pyrrole with polyfluoroarene is described. This transformation is efficient, leading to the corresponding products in good yields. PMID- 22497011 TI - Pseudorotaxanes from self-assembly of two crown ether-based cryptands and a 1,2 bis(pyridinium) ethane derivative. AB - Pseudorotaxanes from self-assembly of two crown ether-based cryptand wheels and a 1,2-bis(pyridinium) ethane derivative axle were prepared. PMID- 22497012 TI - Pentavalent uranium trans-dihalides and -pseudohalides. AB - Pentavalent uranium complexes of the formula U(V)X(2)[N(SiMe(3))(2)](3) (X = F( ), Cl(-), Br(-), N(3)(-), NCS(-)) are accessible from the oxidation of U(III)[N(SiMe(3))(2)](3) through two sequential, one-electron oxidation reactions (halides) and substitution through salt metathesis (pseudohalides). Uranium(v) mixed-halides are also synthesized by successive one-electron oxidation reactions. PMID- 22497013 TI - Isolation of reactive intermediates in deprotonation reactions with zinc alkyls. AB - Using single crystal X-ray diffraction analysis and quantum chemical calculations, a model system for metalation reactions, the deprotonation of (tert butylamino)(piperidinomethyl)dimethyl-silane (1) with Et(2)Zn, was established allowing for the isolation of a reactive intermediate, the adduct structure [1.Et(2)Zn] (2). PMID- 22497014 TI - Interview with Jeremy Sanders. PMID- 22497015 TI - A technique to elevate the seminal vesicles during robotic prostatectomy. PMID- 22497016 TI - A simple stabilising technique for laparoscopic microwave ablation of liver tumours. PMID- 22497017 TI - Freehand technique for in situ pinning of slipped upper femoral epiphysis. PMID- 22497018 TI - Intraoperative localisation of a urachal bladder tumour prior to partial cystectomy. PMID- 22497019 TI - A simple aid to insertion of an irrigation catheter for flexor sheath washout. PMID- 22497020 TI - A simple technique for the reduction of phalangeal condylar fractures in children. PMID- 22497022 TI - Neurite transection produces cytosolic oxidation, which enhances plasmalemmal repair. AB - To survive, cells must rapidly repair (seal) plasmalemmal damage. Cytosolic oxidation has been shown to increase cell survival in some cases and produce cell death in other protocols. An antioxidant (melatonin; Mel) has been reported to decrease the probability of sealing plasmalemmal damage. Here we report that plasmalemmal damage produces cytosolic oxidation, as assayed by methylene blue (MB) color change in rat B104 hippocampal cells. Plasmalemmal sealing is affected by duration of Ca2+ deprivation and length of exposure to, and concentration of, oxidizing agents such as H2O2 and thimerosal (TH). Cytosolic oxidation by 10 MUM to 50 mM H2O2 or 100 MUM to 2 mM TH increases the probability of Ca2+-dependent plasmalemmal sealing, whereas higher concentrations of H2O2 decrease sealing probability and also damage uninjured cells. We also show that antioxidants (Mel, MB) or reducing agents (dithiothreitol) decrease sealing. Proteins, such as protein kinase A, SNAP-25, synaptobrevin, and N-ethylmaleimide-sensitive factor (previously reported to enhance sealing in other pathways), also enhance sealing in this oxidation pathway. In brief, our data show that plasmalemmal damage produces cytosolic oxidation that increases the probability of plasmalemmal sealing, which is strongly correlated with cell survival in other studies. Our results may provide new insights into the etiology and treatment of oxidation dependent neurodegenerative disorders, such as Parkinson's, Huntington's, and Alzheimer's diseases. PMID- 22497023 TI - New technology for toxicity testing. PMID- 22497024 TI - Randomized clinical trial of external stent drainage of the pancreatic duct to reduce postoperative pancreatic fistula after pancreaticojejunostomy. AB - BACKGROUND: Postoperative pancreatic fistula (POPF) remains one of the most common causes of morbidity following pancreaticoduodenectomy (PD). This randomized trial examined whether external stent drainage of the pancreatic duct decreases the rate of POPF after PD and subsequent pancreaticojejunostomy (PJ). METHODS: Consecutive patients who underwent PD with subsequent construction of a duct-to-mucosa PJ were randomized into a stented and a non-stented group. The primary outcome was the incidence of clinically relevant POPF. Secondary outcomes were morbidity and mortality rates, and hospital stay. RESULTS: Of 114 PD procedures, 93 were suitable for inclusion in the study after informed consent. The rate of clinically relevant POPF was significantly lower in the stented group than in the non-stented group: three of 47 (6 per cent) versus ten of 46 (22 per cent) (P = 0.040). Among patients with a dilated duct, rates of POPF were similar in both groups. Among patients with a non-dilated duct, clinically relevant POPF was significantly less common in the stented group than in the non-stented group: two of 21 (10 per cent) versus eight of 20 (40 per cent) (P = 0.033). No significant differences in morbidity or mortality were observed. Univariable analysis identified body mass index (BMI), pancreatic cancer,pancreatic texture, pancreatic duct size and duct stenting as risk factors related to clinically relevant POPF. Multivariable analysis taking these five factors into account identified high BMI (risk ratio(RR) 11.45; P = 0.008), non-dilated duct (RR 5.33; P = 0.046) and no stent (RR 10.38; P = 0.004) as significant risk factors. CONCLUSION: External duct stenting reduced the risk of clinically relevant POPF after PD and subsequent duct-to-mucosa PJ. PMID- 22497025 TI - The biology of EBV infection in human epithelial cells. AB - EBV-associated human malignancies may originate from B cells and epithelial cells. EBV readily infects B cells in vitro and transforms them into proliferative lymphoblastoid cell lines. In contrast, infection of human epithelial cells in vitro with EBV has been difficult to achieve. The lack of experimental human epithelial cell systems for EBV infection has hampered the understanding of biology of EBV infection in epithelial cells. The recent success to infect human epithelial cells with EBV in vitro has allowed systematic investigations into routes of EBV entry, regulation of latent and lytic EBV infection, and persistence of EBV infection in infected epithelial cells. Understanding the biology of EBV infection in human epithelial cells will provide important insights to the role of EBV infection in the pathogenesis of EBV associated epithelial malignancies including nasopharyngeal carcinoma and gastric carcinoma. PMID- 22497026 TI - Retraction. Functional nerve growth factor and trkA autocrine/paracrine circuits in adult rat cortex are revealed by episodic ethanol exposure and withdrawal. J. Neurochem. 2007;100, 1155-68. PMID- 22497027 TI - Capnography: new standard of care for sedation? PMID- 22497034 TI - Bones and other challenges. PMID- 22497035 TI - ACEI associated angioedema. PMID- 22497036 TI - International medical graduates. PMID- 22497037 TI - Charles L. Scott, MD: music, military, and medicine. PMID- 22497038 TI - A complete range of hyaluronic acid filler with distinctive physical properties specifically designed for optimal tissue adaptations. AB - A new range of hyaluronic acid (HA) dermal fillers has been designed using Optimal Balance TechnologyTM, which centers around three main parameters: the degree of cross-linking, the size of gel calibration and the HA concentration. The five different products in the range (HA E Touch, HA E Classic, HA E Lips, HA E Deep and HA E Volume) have the same concentration of HA (20 mg/mL) and various degrees of cross-linking and gel calibration, in order to have distinctive physical properties adapted to their specific indications. HA E Classic, HA E Deep, HA E Lips and HA E Volume are available in two different formulations either with or without lidocaine. The efficacy, safety and patient satisfaction of the HA E range in various indications have been assessed in several classical studies. In this study, the rheological measurements of HA E Deep being the firmest gel within the range. Addition of lidocaine did not change the rheological properties of the HA E fillers. HA E fillers have three different degrees of gel calibration, with HA E Touch, HA E Classic and HA E Lips having the same smallest gel calibration and HA E Volume having the largest gel calibration within the range. Injection of all HA E fillers was smooth, regular, and required low extrusion force when using the Ultra Thin Wall (UTW)needle provided for each product. In summary, the HA E fillers have distinctive physical properties in terms of gel firmness and gel calibration, which were designed to adapt to their specific indications. PMID- 22497039 TI - Sustained efficacy and high patient satisfaction after cheek enhancement with a new hyaluronic acid dermal filler. AB - BACKGROUND: Increasing volume is an important part of facial rejuvenation since volume loss is common and typically age-related. HA E Volume is a moderately firm gel designed to be injected into the subcutaneous tissue for volume enhancement. OBJECTIVE: To assess the efficacy, patient satisfaction, and safety fo HA E Volume in patients with bilateral volume loss of the cheeks. MATERIALS AND METHODS: This was a multi-center, six-month, open-label study. Subjects received HA E in the cheeks at baseline, and a touch-up injection was optional three weeks later. Global aesthetic improvement, cheek thickness (caliper measurements),changes in volume using three-dimensional (3-D) photo analysis, adverse events and injection site reactions were evaluated at each visit. Optimal correction was defined as results obtained three weeks after last injection. A subject satisfaction questionnaire was performed three weeks after the last injection. RESULTS: Investigators evaluated the great majority of subjects as much or very much improved in terms of aesthetic improvement of their cheeks at week 3 and at mounts 3 and 6 (89.3%, 90.9%, and 76.4%, respectively). After six months, 65.8 percent of the correction achieved at week 3 (optimal correction) was maintained in terms of cheek thickness (caliper assessments), confirmed by 67.7 percent of the volume maintained based on 3-D volume analyses. The majority of subjects (92.1%) were satisfied or very satisfied with their aesthetic outcome. A good tolerability profile was observed. CONCLUSIONS: Treatment with HA E Volume in cheeks led to good aesthetic improvement, sustained results confirmed by caliper and 3-D volume assessments, and high subject satisfaction. PMID- 22497040 TI - Perioral rejuvenation with a range of customized hyaluronic acid fillers: efficacy and safety over six months with a specific focus on the lips. AB - BACKGROUND: Injectable fillers are frequently used to restore volume and correct wrinkles in perioral region. However, evidence for perioral indications is scarce. OBJECTIVE: Assess the efficacy, patient satisfaction, and safety of new range of hyaluronic acid fillers (HA E) in perioral enhancement. MATERIALS AND METHODS: This was a multi-center, six-month, open-label study. At baseline, subjects could receive HA E Touch, HA E Classic, HA E Lips and HA E Deep for the treatments of lips, upper lip lines, nasolabial folds and marionette lines, and a touch-up infection was optional three weeks later. Lip Fullness Grading scale (for lips), wrinkle assessments (Lemperle Rating Scales for the remaining indications), adverse events, and local tolerance were evaluated at each visit, and 3-D volume analyses (for nasolabial folds and lips only) at each post baseline visit. Optimal correction was defined as results obtained three weeks after last injection. A subject satisfaction questionnaire was performed three weeks after last infection. RESULTS: Overall, HA E Lips was infected for lip enhancement, HA E Thouch and HA E Classic for upper lip lines, and HA E Classic and HA E Deep for both nasolabial folds and marionette lines. After six month, around a 1-grade improvement persisted according to the lip fullness and wrinkle assessment scales. The long duration of effect was confirmed by 3-D analyses, with 62.7-71.4 percent of volumes obtained at week 3 (optimal correction) maintained after six months. The majority of subjects (from 80% for upper lip lines with HA E Classic to 94.8% for nasolabial folds with HA E Deep) were satisfied or very satisfied with their aesthetic outcome. All products were safe and well-tolerated. CONCLUSIONS: Perioral enhancement with HA E fillers led to sustained effect in terms of lip fullness, wrinkle and 3-D volume assessments, and high subject satisfaction. PMID- 22497042 TI - [Isolated regional perfusion in the treatment of patients with soft tissue sarcomas of the extremities]. PMID- 22497041 TI - Correction of tear troughs and periorbital lines with a range of customized hyaluronic acid fillers. AB - BACKGROUND: The periorbital region is a challenging area for injectable filler. Overcorrection and/or the use of unsuitable fillers may lead to unwanted results. As evidence for this region is limited, most physicians follow a trial and error approach. OBJECTIVE: Assess the efficacy, patient satisfaction, and safety of the HA E filler range in periorbital rejuvenation. MATERIALS AND METHODS: This was a multi-center, six-month, open-label study. Subjects could receive HA E Touch, HA E Classic, and HA E Deep for the treatment of tear troughs and periorbital lines at baseline, and an optional touch-up three weeks later. Global aesthetic improvement for both indications, periorbital wrinkle assessments (Lemperle Rating Scale), 3-D volume analysis (for tear troughs only), adverse events and injection site reactions were evaluated at each visit. A subject satisfaction questionnaire was performed three weeks after last injection. RESULTS: Overall, HA E Classic and Deep were infected for tear troughs, and HA E Touch for periorbital lines. Mean aesthetic improvement in tear troughs was 1.5-2 grades for both products at each post-baseline visit, and results of the clinical evaluation were confirmed by results of 3-D volume analysis. Improvements of periorbital lines in both aesthetic outcomes and wrinkle severity were around 1.5 grades at week 3, and close to 1 grade at month 6. The majority of subjects were satisfied or very satisfied with their aesthetic outcome. Treatments of both indications were safe and well-tolerated, with only mild and transient injection site reactions reported. CONCLUSIONS: This HA E filler range is suitable for rejuvenation of the periorbital region, which leads to safe results, long-lasting efficacy and high levels of patient satisfaction. PMID- 22497043 TI - Arrhythmia management: current perspectives. PMID- 22497044 TI - Patients with disorders of heart rhythm. PMID- 22497045 TI - Identifying the mechanism of narrow QRS tachycardia from the ECG. PMID- 22497046 TI - Practical guide to ECG diagnosis of wide QRS tachycardia. PMID- 22497047 TI - Macro-reentrant atrial tachycardias. AB - Macro-reentrant atrial arrhythmias development is conditioned by the presence of fixed (anatomical or acquired) or functional barriers of conduction with areas of slow conduction at critical atrial sites. It may occur with or without underlying heart disease. Recent development of sophisticated 3D mapping systems has greatly contributed to a better understanding of these atrial arrhythmias. However, classical electrophysiological manoeuvres are usually efficient to locate the tachycardia circuit and to find critical isthmuses as well. In the vast majority of the cases, these techniques allow physicians to cure these tachycardias with a high success rate using catheter ablation. PMID- 22497048 TI - Brugada syndrome. PMID- 22497049 TI - The autonomic ether: emerging electrophysiologic associations. AB - As a result of large, multicenter trials supporting ICDs for prevention of sudden cardiac arrest, there has been an exponential increase in ICD device therapy. Cardiologists and general practitioners are increasingly faced with the challenge to evaluate and troubleshoot device problems. In this review, we provide an overview of basic ICD function and malfunction and show examples of common ICD problems and troubleshooting. PMID- 22497050 TI - How to approach sudden cardiac arrest: current knowledge and clinical practice. AB - SCA is a dynamic and unexpected event that remains a major and global public health problem. There can be multiple etiologies but coronary artery disease remains the major player. The initial approach to SCA requires a rapid community based response. Specific guidelines are available for provision of pre-hospital care and methodology continues to evolve. However, even with rapid response, survival from SCA is extremely low and there is significant regional variation. For SCA victims that survive to reach the hospital, a careful step-wise approach to immediate care and subsequent identification of SCA etiology is advisable. While primary prevention for sudden death has come a long way, significant enhancement of risk stratification techniques is needed to maximize benefit and efficiency of health care utilization. The persisting low survival rates following SCA continue to emphasize that achievement of efficient risk stratification and primary prevention must remain our major target for management of SCA. PMID- 22497051 TI - Optimal utilization of defibrillators and CRT in India--awareness, guidelines and financing--the cardiologist's viewpoint. PMID- 22497052 TI - Optimal use of defibrillators and CRT in India--awareness, guidelines and finances: the industry view point. PMID- 22497053 TI - Pacemaker trouble shooting and follow up. AB - Pacing system malfunction, although seemingly difficult to assess, can be categorized in relation to the dysfunction of the leads or the generator and apparent dysfunction related to the idiosyncratic characteristics of the pacemaker's timing algorithms. In contrast to the relative frequency of lead failure as a result of implantation error or deterioration of the lead materials, primary malfunction of the pulse generator is rare. Patient-specific problems or inappropriate program settings are relatively common. Consequently, the keys to understanding unexpected pacemaker behavior are meticulous evaluation of the integrity of the leads, assessment of capture and sensing thresholds, and an understanding of the timing cycles of the specific pacemaker, which is facilitated by access to event marker telemetry. Clues to the problem and its cause are founding the patient's history, physical examination, and the various diagnostic tests integral to the pacemaker that are retrieved through bidirectional telemetry. With respect to the hardware, the answer is usually lead dysfunction or a behavioral eccentricity detailed in the pacemaker's technical manual. One must always keep the patient's physiology and pathophysiology in mind, because they also affect the function of the pacing system. Furthermore, even if all components of the system are normal, the pacemaker may be programmed to a set of parameters that are no longer optimal for the patient. When the clinician presented with a suspected pacing system malfunction, it is essential to proceed in a meticulous and orderly manner, carefully assessing, each component of the system, including the pulse generator, the programmed settings, any unique algorithms, the leads, and the patient. If a complete assessment of capture and sensing thresholds, lead impedance, sensor response, and the behavior of any unique algorithms is performed on a periodic basis as part of the routine surveillance of the patient's pacing system, baseline data will be available for comparison with the results of evaluation when and if a problem is suspected. PMID- 22497054 TI - Catheter ablation of post myocardial infarction scar related ventricular tachycardia: role of entrainment. PMID- 22497055 TI - Advances in catheter ablation: a burning trail! AB - The last 15 years have literally witnessed a revaluation in the management of patients with cardiac arrhythmia. Although the visibility for these advances has come from successful catheter ablation of common arrhythmia, these advances could not have occurred without the preceding details where in painstaking anatomic and electrophysiological studies were done. The options available to patients with AF and certain ventricular arrhythmias were simply not present two decades ago. An appreciation of the role of extra cardiac structures including the thoracic veins, great arteries and retro-atrial ganglionated plexii along with the availability of accurate imaging and navigation techniques has fueled these great advances. The next five to ten years we will see even greater innovations as the complications and risks of arrhythmias and ablation have sought to be minimized while cardiac "electrophysiology techniques" permeate other organ systems including the brain. PMID- 22497056 TI - Implantable cardioverter defibrillators: function and troubleshooting. AB - As a result of large, multicenter trials supporting ICDs for prevention of sudden cardiac arrest, there has been an exponential increase in ICD device therapy. Cardiologists and general practitioners are increasingly faced with the challenge to evaluate and troubleshoot device problems. In this review, we provide an overview of basic ICD function and malfunction and show examples of common ICD problems and troubleshooting. PMID- 22497057 TI - Evaluation of health promotion programs: are we making progress? PMID- 22497058 TI - Impact of national smokefree environments laws on teachers, schools and early childhood centres. AB - ISSUE ADDRESSED: New Zealand's (NZ) smokefree legislation, implemented on 1 January 2004, requires that all school and early childhood centre buildings and grounds are 100% smokefree; one aim being to prevent young people being influenced by seeing people (including teachers) smoke there. This study, conducted in 2008, investigated teachers'smoking behaviour and perceived adherence to the legislation. METHODS: A national NZ cross-sectional survey of 2,004 teachers (oversampling Maori), who were randomly selected from the electoral roll of registered voters and sent postal invitations to complete an anonymous survey. RESULTS: The response rate was 70%. Current smokers numbered 7%, and proportionately more Maori and Pacific Island teachers (12% each) smoked than European/Other teachers (7%). Of current smokers, 37% smoked non-daily. Smokers smoked less on work than non-work days. Introducing smokefree legislation was associated with teachers changing when they smoked, cutting down, quitting or trying to quit. Perceived compliance with the legislation was high, although 30% of teachers reported seeing staff smoking. Proportionately, significantly more teachers from low than from high socioeconomic schools perceived poor compliance and staff visibly smoking. CONCLUSIONS: Smokefree legislation affects people's smoking behaviour. Smoking in NZ is becoming confined to population subgroups defined by socioeconomic status and ethnicity. Our findings argue for supporting cessation among those who work with children and young people, and for targeting support at school communities in areas of low socioeconomic status or with large populations of Maori or Pacific peoples. PMID- 22497059 TI - Content analysis of school anti-bullying policies: a comparison between New Zealand and Victoria, Australia. AB - ISSUE ADDRESSED: To undertake a detailed analysis of the content of anti-bullying policies in schools in New Zealand (NZ) and Victoria, Australia. METHODS: The content of anti-bullying policies from 253 NZ schools and 93 Victorian schools were analysed in terms of definitions of bullying behaviour; reporting, recording and responding to bullying incidents; communicating and evaluating the policy; and outlining strategies for preventing bullying. RESULTS: There was a wide range in 'policy scores' between schools, and Victorian schools scored higher on nearly every area compared with NZ schools. In both regions, definitions rarely included bullying on the grounds of homophobia, religion or disability; or bullying between adults and students. Policies also lacked detail about the responsibilities of non-teaching staff in dealing with bullying, and rarely described follow-up after a bullying incident. Few policies explained how the policy would be evaluated, and many failed to mention preventive strategies. CONCLUSION: This study highlights some important areas that are deficient in NZ and Victorian school anti-bullying policies, and emphasises the need for guidance on how schools can develop an effective anti-bullying policy. Having more comprehensive anti-bullying policies will give schools a much better chance of reducing bullying. PMID- 22497060 TI - The possible effect on frequency of cycling if mandatory bicycle helmet legislation was repealed in Sydney, Australia: a cross sectional survey. AB - ISSUE ADDRESSED: Australia has national, state and city targets to increase levels of cycling. The possible effect of repealing mandatory bicycle helmet legislation on the frequency of cycling in Sydney is examined. METHODS: A cross sectional survey by a market research company was conducted, using quota sampling, in Sydney, Australia. Participants were 600 residents aged 16 years and older. Data were collected in October 2010 using computer-assisted telephone interviews from randomly sampled households, with one respondent per household. The primary outcome measures were propensity to cycle more if a helmet was not required, how often a respondent who cycled would cycle without a helmet, and opinion on compulsory wearing of bicycle helmets. Frequency of cycling, and demographic questions were also assessed. Multiple logistic regression models were run for each of the three main outcomes. RESULTS: One in five (22.6%, 95% CI 18.8-26.4%) respondents said they would cycle more if they did not have to wear a helmet, particularly occasional cyclists (40.4% of those who had cycled in the past week and 33.1% of those who had cycled in the past month). Almost half (47.6%) of respondents said they would never ride without a helmet, 14.4% said'all the time, 30.4% said 'some of the time' and the rest were not sure. One third (32.7%, 95% CI 28.5-37.0%) of respondents did not support mandatory helmet legislation. CONCLUSIONS: While a hypothetical situation, if only half of the 22.6% of respondents who said they would cycle more if they did not have to wear a helmet did ride more, Sydney targets for increasing cycling would be achieved by repealing mandatory bicycle helmet legislation. A significant proportion of the population would continue to wear helmets even if they were not required to do so. PMID- 22497061 TI - Fast facts: The availability and accessibility of nutrition information in fast food chains. AB - ISSUE ADDRESSED: Nutrition information at the point-of-sale assists consumers to make informed fast food choices. This study provides a baseline measure of the availability and accessibility of nutrition information in fast food outlets in Australia, filling a gap in the literature. METHODS: An in-store observational survey was conducted in 222 outlets of five fast food chains in five states. The Australian websites for each chain were surveyed for nutrition information. RESULTS: At least some nutrition information was available in 66% of outlets. The availability of information was higher in lower socioeconomic areas. Significantly less information was available in signatory chains of the self regulatory marketing code. Information provided was generally incomplete; only one outlet (0.5%) provided information for all food and beverage items. In some instances information was old. Information was more available for 'healthier' products and less available for meal combinations. Information was provided on all chains' websites, however it was sometimes difficult to locate. CONCLUSIONS: While most outlets surveyed made some nutrition information available to consumers, it was generally incomplete. Fast food chains should provide comprehensive, up-to-date information for all menu items. Chains should also ensure their staff members are adequately trained in providing nutrition information. PMID- 22497062 TI - Evaluating NSW SmokeCheck: a culturally specific smoking cessation training program for health professionals working in Aboriginal health. AB - ISSUE ADDRESSED: This paper reports on the evaluation of a culturally specific smoking cessation training program (SmokeCheck) for health professionals working in Aboriginal health in NSW. Training aimed to increase professionals' knowledge, skills and confidence to offer an evidence-based quit smoking brief intervention to Aboriginal clients. METHODS: Using a quasi-experimental pre-post with 165 matched intervention participants, surveys were completed immediately before (baseline) and 6-months post training. The control group were on a waiting list for 6 months before receiving the intervention, and completed surveys at baseline, immediately before training and 3-6 months following training. Surveys assessed knowledge, skills and confidence to deliver the intervention, availability of resources, and smoke-free status of homes. RESULTS: Post training, a higher proportion of intervention group participants were more confident talking about health effects (22%, p=0.001), offering quit advice (27%, p=0.001), assessing readiness to quit (31%, p=0.001) and initiating a conversation about smoking (24%, p=0.001). After training, more participants reported providing advice about NRT (15%, p=0.001), ETS (12%, p=0.006), and reducing tobacco use (10%, p=0.034), but no changes were reported in smoking or intention to quit. Conversely, the control group showed no significant changes. CONCLUSIONS: SmokeCheck training strengthened participants' knowledge, skills and confidence to deliver a smoking cessation intervention to Aboriginal clients.' PMID- 22497063 TI - Enriching health research through consumer involvement--learning through atypical exemplars. AB - OBJECTIVE: The goal of this exploratory study was to identify and describe notable cases of consumer involvement in Australian health research to generate insights and concepts, and assist others to develop and build capacity in this area. METHODS: In-depth interviews were conducted with nine organisations known to be active in this area. The interviews were supplemented with content analysis of relevant documentation to further examine involvement strategies. RESULTS: Key attributes that aid consumer involvement competence and contribute to success in this area are identified, including the availability of time, resources and supporting policies, principles and attitudes that securely back opportunities for consumers to be involved in meaningful ways. CONCLUSION: This study provides an important contribution to our knowledge and understanding of consumer involvement practice in Australian health research. The examples do not offer definitive approaches but rather highlights and lessons drawn from experiences in consumer involvement across a diverse range of organisations. PMID- 22497064 TI - Sleep, structured and social time use and young Australian children's physical activity. AB - ISSUE ADDRESSED: Physical inactivity is a growing health concern for children, with the potential to undermine their health and wellbeing. While a range of factors have been associated with physical inactivity, the contribution of time spent in sleep, structured activities and children's social contexts has received limited attention. METHODS: This cross-sectional study employed data from Wave 1 of the Longitudina Study of Australian Children to examine the association between participation in physical activity and time spent in sleep, structured activity, and social contexts of 4-5 year old children. RESULTS: Young children who were more physically active were found to participate less in structured activities on weekdays (beta=-0.25, SE=0.05); spend more time with peers under adult supervision on weekends (beta=0.36, SE=0.15); and have parents who themselves reported enjoying physical activity (beta=-0.18, SE=0.06). Boys (beta= 0.13, SE=0.05) and young children who spoke only English at home (beta=-0.37, SE=0.11) were also found to be more physically active. Overa ll, young children participated in more physical activity on weekend days than weekdays (beta=0.57, SE=0.04). CONCLUSIONS: Young children who are highly scheduled in structured activities on weekdays and those with imited adult involvement, especially on weekends, tend to be less physically active. Interventions that promote physical activity in young children therefore need to be family focused and encourage the engagement of parents. PMID- 22497065 TI - Children's consumption of energy-dense nutrient-poor foods, fruit and vegetables: are they related? An analysis of data from a cross sectional survey. AB - ISSUE ADDRESSED: Many children consume excessive amounts of energy-dense, nutrient-poor (EDNP) or 'extra' foods and low intakes of fruit and vegetables. The aim of this study was to examine the associations between EDNP foods and ascertain whether certain EDNP foods and beverages are more likely to be eaten in association with other EDNP foods. METHODS: A cross-sectional representative population survey of children in preschool (n=764), and of school students in Years K, 2 and 4 (n=1,560) and in Years 6, 8 and 10 (n=1,685) residing in the Hunter New England region of New South Wales, Australia. Dietary data were collected using a short food frequency questionnaire. Multivariate logistic regression models examined the association between EDNP foods and fruit and vegetable intake. Data were stratified by sex and age cohort. RESULTS: More frequent consumption of some EDNP food types was significantly associated with more frequent consumption of other EDNP foods. Fast food and soft drinks consumption were associated with each other as well as with fried potato and salty snacks; and with lower intakes of fruit and vegetables in some but not all age groups. CONCLUSION: The positive associations found between EDNP foods point towards the existence of a high-risk group of children who frequently consume a variety of EDNP foods and drinks. PMID- 22497066 TI - "But they can't reach that high...": parental perceptions and knowledge relating to childhood poisoning. AB - ISSUE ADDRESSED: Preventing childhood poisoning is an important injury-control priority, requiring a multi-strategy approach. However, there remains a wide void between what is recommended by prevention programs and the evidence, and what is acted upon in the day-to-day family environment. This paper seeks to probe behind aspects of this void by examining parental perceptions in relation to childhood poisoning within a Health Belief Model framework. METHODS: Data were collected through telephone interviews from 200 randomly selected Western Australian parents/guardians of children aged 0-4 years. RESULTS: The uptake of poisoning prevention strategies was associated with the perceived susceptibility and seriousness of poisoning from different common household products. In particular, those products considered most fatally poisonous (workshop/garden chemicals) and a common cause of childhood poisoning were the most likely to be locked up and kept out of reach of children. Conversely, over-the-counter medicines were not considered by the majority of parents as fatally poisonous or as a common cause of poisoning, and were less likely to be locked up and placed out of reach. However, such medicines are the most common cause of unintentional childhood poisoning. CONCLUSION: The results suggest that perceptions of susceptibility and seriousness need to be targeted as part of efforts to encourage parents to reduce household risks of childhood poisoning. This is particularly warranted in relation to those common household products (e.g. medicines) where there is a misperception of lower likelihood of serious poisoning occurring. PMID- 22497067 TI - Smoking is rank! But, not as rank as other drugs and bullying say New Zealand parents of pre-adolescent children. AB - ISSUE ADDRESSED: Despite the established risks associated with smoking, 21% of New Zealand adults smoke. Prevalence among Maori (indigenous) and Pacific Island New Zealanders is disproportionately high. Prevention of smoking initiation is a key component of tobacco control. Keeping Kids Smokefree--a quasi-experimental trial--aimed to do this by changing parental smoking behaviour and attitudes. However, little is known about parents' attitudes to smoking in comparison with other concerns. METHOD: Parents of 4,144 children attending five urban schools in a high smoking prevalence population in Auckland, New Zealand, were asked to rank seven concerns on a paper-based questionnaire, including smoking, alcohol and bullying, from most to least serious. RESULTS: Methamphetamine and other illicit 'hard' drugs were ranked as most serious followed by marijuana smoking, alcohol drinking, bullying, cigarette smoking, sex and obesity. Never smokers ranked cigarette smoking as more serious than current or ex-smokers. CONCLUSION: Parents' under-estimation of the serious nature of tobacco smoking relative to other drugs could partly explain low participation rates in parent-focused smoking initiation prevention programs. PMID- 22497068 TI - Media reporting of global health issues and events in New Zealand daily newspapers. AB - ISSUE ADDRESSED: In the context of a globalised world, reports on health that extend personal or country borders have increasing relevance. Media can promote opportunities to identify and address gaps in important global health issues. In light of the potential role of media as an advocacy tool for global health, we examined how global health issues are represented in mainstream media in New Zealand. METHODS: We conducted a content analysis of media reports on global health issues in the four highest circulation newspapers in New Zealand between June 2007 and May 2009. Search terms included 'global health, 'international health' and 'world health'. RESULTS: Communicable disease was the most frequently reported global health issue in New Zealand newspapers, followed by environment (e.g. climate change), general health risks (unsafe pharmaceuticals) and substance use (tobacco and alcohol). Chronic disease, injury or their determinants were less frequently reported. CONCLUSIONS: Mainstream media favours health-related reports based on crisis, epidemic or acute conditions over chronic or non-communicable diseases or disability. Health issues facing the Asia Pacific region increasingly include chronic diseases, which would benefit from greater media coverage to increase advocacy and political awareness of global health challenges. PMID- 22497069 TI - Field testing of father-inclusive guidelines for web-based information and support aimed at families with perinatal depression. AB - ISSUE ADDRESSED: This study examines the application of father-inclusive guidelines to website information intended to address perinatal depression. METHODS: A set of evidence-based guidelines was developed and applied to a sample of Australian health and parenting websites to derive a 'father-inclusiveness' score for their perinatal depression-related material. The scores for each website's material and a rationale for the project were conveyed to the website managers. RESULTS: Father-inclusive scores overall were modest, with most websites obtaining less than half the possible points. Few websites provided information to support fathers' connection with their infants or provided opportunities for fathers to interact with other fathers. Most website managers responded positively when informed of their (relatively low) score and changes to the websites were indicated. CONCLUSIONS: Father-inclusive guidelines may assist health and parenting websites to more effectively target information and support for fathers in families with perinatal depression. PMID- 22497071 TI - Scaling up health promotion interventions: an emerging concept in implementation science. PMID- 22497070 TI - BEST at home: a pilot evaluation of a home-based strength and balance exercise program. AB - ISSUE ADDRESSED: Home-based exercise with home visits has been shown to improve strength and balance and reduce falls in older people. This pilot study aimed to determine whether a home-based exercise program (delivered via workshops instead of home visits) improved strength and balance and reduced falls in adults aged 60 years and over. METHODS: Participants attended two workshops over a six-month period and were instructed in the exercises by physiotherapists. Participants recorded their exercise and falls on a calendar and strength and balance measures were assessed at baseline and 12 weeks. Data was analysed using Wilcoxon signed rank tests, McNemar's test and regression. RESULTS: A total of 167 participants commenced the BEST at home program. The mean age was 69 years and 67% were female. Participants significantly improved in all measures of strength and balance. The number of falls was reduced during the six-month period but statistical significance was not achieved. CONCLUSIONS: The BEST at home program improved strength and balance in people aged 60 years and over. More research is required to determine long term adherence to BEST at home and whether this program can reduce falls. PMID- 22497072 TI - Do first time mothers need a guideline for maximum periods of sitting or being sedentary? PMID- 22497073 TI - Lessons learnt from a pilot bicycle program with community mental health service consumers. PMID- 22497074 TI - [4'-C-modified nucleosides: synthesis and antiviral properties]. AB - The synthetic methods for 4'-C-modified nucleosides as well as structure activity relationship of obtained compounds towards hepatitis C virus are reviewed. PMID- 22497075 TI - [Synthesis of low molecular weight mimetics of heparin]. AB - Natural hexosaminoglycan heparin remains the most commonly prescribed anticoagulant in hospitalized patients. However its administration could induce side clinical events, including thrombocytopenia and bleeding. This explaines the need of development of alternative anticoagulant drugs based on modified heparin and polyanionic oligo- and polysaccharide derivatives, such as sulfated glucans, phosphomannans and fucoidans. Here we review the works on the synthesis of oligosaccharides related to low molecular weight hepain fragments and their derivatives, as well as oligosaccharides, which imitate parts of heparin chain responsible for biological activity. These works were aimed to develop the pharmaceutical preparations lacking ofheparin disadvantages. PMID- 22497076 TI - [Classification of self-organizing peptides]. AB - Amino acid sequences of known natural and synthetic self-assembling peptides were searched and analyzed for their characteristic patterns. The attempted formal numerical description of the repeating motifs, which have been revealed, resulted in building of general classification system embracing core-sequences of the peptides capable of nanostructure formation. Advantages and potency of the proposed rational classification were demonstrated via its comparison with the output from the earlier system described by the others. PMID- 22497077 TI - [Cytotoxicity of lysomustine and its isomers, and their potential use for selection of cells]. AB - N epsilon-Nitroso-N epsilon- [N'-(2-chloroethyl)carbamoyl]-L-lysine (I) and N epsilon- [N'-(2-chloroethyl)-N'-nitrosocarbamoyl]-L-lysine (II), the isomers being the constituents of antitumor agent Lysomustine, were obtained by RFHPLC. The study of cytotoxicity of the above compounds against K562 cells showed that the lesions induced by isomer (II) produce a significant cytotoxic effect but can be efficiently repaired by the action of MGMT (O6-methylaguanine DNA methyltransferase). Under similar conditions, the lesions induced by isomer (I) produce substantially smaller effect but are weakly if at all repairable by MGMT. The effects of a clinically approved agent Lysomustine, which is the mixture of isomers (I) and (II), are similar to those of isomer (II). The results obtained point to a different chemical nature of DNA lesions induced by two Lysomustine isomers. Our data indicate that Lysomustine and its isomer (II) can be used for in vitro selection of cells expressing MGMT. PMID- 22497078 TI - [Direct incorporation of 18O isotopes into peptides and proteins for quantative analysis by mass spectrometry method]. AB - The method of direct introduction 18O isotopes in peptides and proteins carboxylic groups through the exchange with H218O in the presence of TFA is shown. The isotope label is steady enough in awide range of pH. Because the labeled compounds retain their physical and chemical characteristics, they can be used as an internal standard in quantitative determination of authentic compounds in the analyzed sites by mass spectrometry methods. The technique may be applicable for quantitative analysis of peptides and proteins in biological environments, for quantitative study of the kinetics of metabolism and enzymatic activity. For polypeptides and proteins the quantitative analysis is combined with trypsinolysis. If necessary, the isotope label may be introduced simultaneously in all peptides and proteins control bioassays, making it suitable for use as a standard for the comparative analysis of experimental bioassays. PMID- 22497079 TI - [The properties of the Pseudomonas aeruginosa bacteriophage phiPMG1]. AB - The properties of the isolated Pseudomonas aeruginosa bacteriophage phiPMG1 include the lytic infection cycle, and the formation of a broad halo (semi transparent zone) around the plaques. We consider phiPMG1 as a potential member of therapeutic cocktails of live phages, and as a source of peptidoglycan and lipopolysaccharide degrading enzymes. Partial sequencing of phiPMG1 genome has revealed high similarity with known temperate P. aeruginosa phage D3. An open reading frame encoding lytic transglycosilase was identified in the genome. This enzyme PMG MUR was obtained in recombinant form, and its activity and substrate specificity has been studied. PMID- 22497080 TI - [Characterization of new splicing mutation in steroid 21-hydroxylase gene]. AB - Novel mutation in CYP21A2 gene causing the steroid 21-hydroxylase deficiency - C to G substitution in 7-position ofintron 2 acceptor splice site (c.290-7C>G) was identified. The effect of the mutation on splicing was checked in the system of CYP21A minigene expression in the cultured mammalian cells. The mutation impairs the usage of intron 2 acceptor splice site resulting in intron retention. PMID- 22497081 TI - [Animal in vivo model of arrhythmia for genes target identification for 5-amino exo-3-azatricyclo[5.2.1.0(2,6)]decan-4-one]. AB - The goal of the current work is to study the molecular mechanisms underlay the action of 5- amino-exo-3-azatricyclo[5.2.1.0(2,6)]decan-4-one (P-11) with combined antiarrhythmic, nootropic, anti-inflammatory and anaesthetic activities. The aconitine-induced experimental rat model of cardiac arrhythmia has been used in our study. Aconitine was administered once intravenously in a dose 50 microg/kg whereas experimental animal group received P-11 in a dose 0.3 mg/kg (the compound was injected intravenously 2 min before acute aconitine treatment). Expression macroarray (Atlas Rat cDNA Expression Array, #7738-1; BD Biosciences) was used to identify the target genes for P-11 compound. Comparative analysis of changes in the status of expression of genes in the heart of rats induced by P-11 against the simulated in vivo arrhythmia identified 16 genes that reproducibly alter the level of expression.These genes encode the extracellular matrix proteins (glypican 1, Gpc1; tissue inhibitor of metalloproteinase 2, 3, Timp2, Timp 3); intracellular signaling molecules (rho GTPase activating protein 7, Dlc1; protein tyrosine phosphatase 4a1, Ptp4a1; phosphodiesterase 4D, PDE4D; PI3 kinase regulatory subunit alpha, PIK3R1; guanine nucleotide binding protein alpha 12, Gna12) and protein of intermediate junctions (junction plakoglobin, Jup), proteins involved in glycolysis (phosphofructokinase I, Pfk1) and hemostasis (tissue plasminogen activator, Plat), plasma membrane transporters (Solute carrier family 16, member 1, Slc16a1; ATPase, Na+/K+ transporting, Atp1a), and ets. (c-fos protooncogene, c-fos; telomerase protein component 1, tlp; Annexin 1, anxa 1). Thus, the data about the selective effect of P-11 on genes whose products are involved in the aritmogenesys mechanisms, allow us to consider this compound as a promising means of pathogenetically oriented pharmacotherapy of cardiac arrhythmias. PMID- 22497082 TI - [Synthesis of 2'-aminometylmorpholino nucleoside analogues containing 4' carboxymethyl lynker group]. AB - A simple and effective method for the synthesis of 2'-aminomethylmorpholino-4' carboxymethyl nucleoside analogues and Boc-modified derivatives as synthons for peptide synthesis was developed. PMID- 22497083 TI - [Research of imidazo[1,2-a]benzimidazole derivatives. XXX. Synthesis and properties of (imidazo[1,2-a]benzimidazolyl-2)acetic acid derivatives]. AB - Ethyl esters of (9-subtituted-imidazo[1,2-a]benzimidazolyl-2)acetic acids were synthesized. The chemical properties of these esters (hydrolysis, decarboxylation, hydrazinolysis) and biological activity (fungicidal, antimicrobial, antiarrhythmic activity, and also affects on the brain rhythmogenesis) of the prepared compounds were studied. PMID- 22497084 TI - [Synthesis of asymmetric tetraarylporphyrins and its ytterbium complexes]. AB - The synthesis of asymmetric meso-aryl-substituted porphyrins containing three 4 methoxycarbonylphenyl groups, and as a forth substituent 4-hydroxyphenyl or 4 hydroxy-3- methoxyphenyl radicals, or the isomeric 3- and 4-pyridyl substituents is described. O-alkyl derivatives of 4-hydroxyl residue are obtained. The ytterbium complexes ofthese porphyrins were synthesized and studied their luminescence spectral properties were studied. A significant difference in the lifetimes of the excited state ofytterbium complexes of esters and acids of asymmetric porphyrins is demonstrated. PMID- 22497085 TI - [Preparation of prokaryotic cDNA for high-throughput transcriptome analysis]. AB - High contents of non-coding RNA in total bacteria RNA complicates considerably transcriptome analysis using standard approaches like high-throughput sequencing, gene expression profiles, subtractive hybridization. We suggest a procedure of preparation of bacterial cDNA for transcriptomics that includes rRNA and tRNA depletion with preservation of relative abundance of coding sequences. The method is based on the second order hybridization kinetics and unique properties of Kanchatka crab duplex-specific nuclease. The method efficacy was demonstrated on a model experiments. PMID- 22497086 TI - Rhabdomyolysis: advances in diagnosis and treatment. AB - Rhabdomyolysis is a potentially life-threatening condition caused by a breakdown of skeletal muscle and the release of the intracellular contents into the circulatory system. There are many possible causes, including crush injury, excessive muscular activity, medications, infections, and varied metabolic, connective tissue, rheumatologic, and endocrine disorders. It is vital that emergency clinicians consider the diagnosis when patients present with circumstances known to be high-risk for rhabdomyolysis, including intoxication, prolonged immobilization, and/or altered mentation. Optimal crystalloid selection is still debated, but immediate, aggressive intravenous volume expansion is indicated to prevent myoglobinuric renal failure. Serum potassium levels must be obtained and electrocardiograms must be evaluated to identify life- and limb threatening complications of hyperkalemia. This review examines the current evidence on symptoms and diagnostic methods as well as standard first-line treatments of rhabdomyolysis. In addition, evidence from animal models on urine alkalinization with sodium bicarbonate infusion is discussed. PMID- 22497087 TI - [Examination of the head and neck region: a part of the routine mouth examination]. PMID- 22497088 TI - [Oral health care volunteering in developing countries 1. More than charity]. AB - Although limited in extent, oral health care volunteering in developing countries can contribute to sustainable improvement of oral health. However, it is questionable whether traditional care delivery based on the Western model, which many volunteers apply, has a sustainable effect and, presumably, it has negative consequences for the local health care system in many developing countries. Four i's should be involved when trying to make tactful policy: 1. 'ideas' evidence based interventions, 2. 'institutions', current regulatory processes and approvals of governments and participating societies, 3. 'interests', incentives and motives of societies to collaborate, 4. 'incidents', unexpected economic alterations in the country or an inspiring successful public prevention programme. PMID- 22497089 TI - [Automutilation of the palate in a psychiatric patient]. AB - A 46-year-old man with a history of alcohol abuse was referred to an oral and maxillofacial surgeon with a large necrotic wound with raised edges on the palate. After history taking, radiography and clinical assessment, together with a psychiatrist, the lesion was diagnosed as an automutilation resulting from a period of alcohol abstinence. After a period of care in a medical centre, the lesion improved quickly. Following this treatment, the patient was admitted to a psychiatric treatment centre for supplemental treatment of his addiction problems. PMID- 22497090 TI - [Peri-implantitis in the general oral and maxillofacial surgery practice. A pilot study]. AB - A peri-implant infection is a disorder with an annually increasing prevalence and incidence as a result of the increasing number of oral implants utilized. Based on existing literature, a patient-control study was carried out, as a pilot study, among patients who had been treated with oral implants at a department of oral and maxillofacial surgery in a general hospital. Significant relations were found between on the one hand the prevalence of peri-implantitis and on the other hand bone augmentation, a suprastructure of a fixed partial denture or a complete removable overdenture on a ball attachment mesostructure when compared to a crown, poor oral hygiene, poor periodontal condition, and the absence of keratinized mucosa surrounding the implant. PMID- 22497091 TI - [Cost-effectiveness when treating an edentulous mandible]. AB - When treating an edentulous patient with complaints of unsatisfactory retention of his complete mandibular denture, various treatment options are available: a new conventional denture, an implant-supported overdenture, and an implant supported fixed partial denture. Important considerations during the decision making process are patient satisfaction, cost of denture fabrication, and cost of maintenance. The outcome of the diagnostic procedure will have financial consequences. On that basis, a satisfactory treatment plan can be established and carried out. The need exists for a protocol which takes into account cost effectiveness and is useful in selecting the appropriate treatment option, adjusted to individual requirements. PMID- 22497092 TI - [An inventory of knowledge on tuberculosis among dentists in the Netherlands]. AB - By the nature of his work, a dentist has a higher risk of tuberculosis infection than the average Dutch population. Thus, the question arises whether dentists do have sufficient knowledge on tuberculosis. In order to determine their knowledge, an inventory was conducted among a sample of dentists in the Netherlands. Analysis of the dentists' response to 19 correct or incorrect statements revealed that their knowledge level on tuberculosis was rather low, did not vary with regard to gender, and was independent of the region where they were practising and of their explicit medical interest. The dentists indicated a desire for education on tuberculosis. PMID- 22497093 TI - Recovering from research: a no-fault proposal to compensate injured research participants. AB - National advisory committees have considered the obligations owed to research participants in the event of research-related injuries. These committees have repeatedly concluded that injured research participants are entitled to compensation for their injuries, that the tort system provides inadequate remedies, and that the United States should adopt no-fault compensation. But because the advisory committees have made no concrete proposals and have taken no steps toward implementing no-fault compensation, the United States continues to rely on the tort system to compensate injured research participants. This Article argues that recent legal developments and a transformation in the global research landscape make maintaining the status quo morally indefensible and practically unsustainable. Recent legal developments exacerbate the longstanding difficulties associated with the tort system as a method of compensation; nearly every injured research participant will have difficulty recovering damages, and certain classes of injured research participants--those in federal research and those abroad--are prevented from recovering altogether, resulting in substantial unfairness. In the past ten years, many of the countries substantially involved in research have mandated systematic compensation. By not mandating compensation, the United States has become a moral outlier and risks having its noncompliant research embargoed by foreign ethics committees, thereby delaying important biomedical advances. This Article examines alternative compensation mechanisms and offers a concrete no-fault compensation proposal built on systems already in place. The proposed system can be implemented in the United States and countries around the world to help harmonize various national compensation systems and to more equitably and effectively make those injured by research whole. PMID- 22497094 TI - Access to information and the right to health: the human rights case for clinical trials transparency. PMID- 22497095 TI - Semiconductor chips, genes, and stem cells: new wine for new bottles? AB - This Article analogizes early semiconductor technology and its surrounding economics with isolated genes, stem cells, and related bioproducts, and their surrounding economics, to make the case for sui generis (of its own class) intellectual property protection for isolated bioproducts. Just as early semiconductors failed to meet the patent social bargain requiring novelty and non obviousness in the 1980s, isolated genes and stem cells currently fail to meet the patent bargain requirements of non-obviousness and eligible subject matter that entitle them to traditional intellectual property protection. Like early semiconductor chip designs, nevertheless, the high cost of upstream bioproduct research and development, coupled with the need to sustain continued economic growth of the biotechnology industry, mandates that Congress provide some level of exclusive rights to ensure continued funding for this research. Sui generis intellectual property protection for isolated bioproducts would preserve the incentive to continue innovation in the field. As illustrated by the semiconductor industry, however, such sui generis protection for this technology must include limitations that address the need to provide an appropriate level of public access to facilitate downstream product development and enrich the public domain. PMID- 22497096 TI - The national residency exchange: a proposal to restore primary care in an age of microspecialization. AB - Healthcare deficiencies in the United States have long been perpetuated by a shortage of primary care providers. A core purpose of the Patient Protection and Affordable Care Act (PPACA) is to provide health insurance for America's approximately fifty million uninsured. Implementation of universal health insurance, however, does not mean sufficient healthcare access for all, since the supply of physicians does not and will not meet demand. For reasons reviewed in this Article, the current physician shortage mainly impacts primary care providers. This shortage is particularly troubling because increased provision of primary care relative to specialty care has been associated with improvement in health outcomes, disease prevention, cost effectiveness, and coordination of care. This Article highlights provisions in the PPACA that impact primary care physicians. Finally, this Article proposes the creation of a universal primary care loan repayment program and a national residency exchange designed to alleviate the U.S. primary care crisis by facilitating optimal distribution of resident physicians in each medical specialty based on community need. PMID- 22497097 TI - Cure unwanted? Exploring the chronic Lyme disease controversy and why conflicts of interest in practice guidelines may be guiding us down the wrong path. PMID- 22497098 TI - Minnesota Supreme Court hears whether the Genetic Privacy Act protects newborn blood spot samples obtained under the state's newborn screening statutes--Bearder v. State of Minnesota. PMID- 22497099 TI - Denying lawful immigrants access to state healthcare subsidies violates the equal protection provision of the Massachusetts Constitution--Finch v. Commonwealth Health Insurance Connector Authority. PMID- 22497100 TI - Ninth Circuit rules donors may receive compensation for blood-based bone marrow transplant donations--Flynn v. Holder. PMID- 22497101 TI - National review aims to reduce asthma deaths. PMID- 22497102 TI - Minor accidents in general practice. 1912. PMID- 22497103 TI - Early diagnosis improves survival in kidney cancer. AB - Kidney cancers account for 2-3% of all adult malignancies in the UK. Men are predominantly affected by renal cancer with an average age at diagnosis of 64 years. Renal (or clear) cell carcinoma (RCC) accounts for 90% of kidney cancers. Early diagnosis improves survival with five-year survival rates for renal cancer of 70-94% for localised tumours in the UK. RCC should be suspected in the presence of localising symptoms such as flank pain, a loin mass or haematuria; constitutional upset including weight loss, pyrexia and/or night sweats; or with unexplained laboratory tests. Smoking, obesity and hypertension are the most important and most common risk factors. Environmental exposure to asbestos, cadmium and trichloroethylene are less common risk factors. Patients on chronic dialysis and renal transplant recipients are at increased risk of RCC in their native kidneys. If kidney cancer is suspected on history, physical examination or initial screening tests then a red flag ultrasound examination of the renal tracts should be requested. Dipstick urinalysis is of great value as asymptomatic haematuria may be the only abnormal test in the presence of non-specific symptoms such as weight loss or loin pain. Visible or non-visible haematuria, in the absence of proteinuria, suggests an underlying structural abnormality is present in the kidneys, ureters or bladder. Surgical removal of RCCs, where feasible, may result in cure in up to 40-60% of cases. Individuals too frail for major surgery may benefit from thermal ablation and cryotherapy. Agents that target the VEGF and mTOR pathways are considered first line in the treatment of metastatic RCC. Sunitinib, recommended by NICE, is administered orally and acts by inhibiting the VEGF receptor. PMID- 22497104 TI - Improving recognition of inherited renal disease. AB - Polycystic kidney disease and Alport's syndrome are the most common causes of inherited renal disease in the UK. An average GP practice is likely to have at least six patients with autosomal dominant polycystic kidney disease (ADPKD). The disorder is characterised by the formation of fluid-filled cysts in the kidneys resulting in progressive renal impairment. Mutations in two genes have been identified. The PKD1 gene abnormality is responsible for 85% of cases of ADPKD, patients with PKD2 mutations typically present later and progress more slowly. Patients with ADPKD can present with a positive family history, hypertension, flank pain, haematuria, renal insufficiency or proteinuria. The diagnosis has traditionally been based on ultrasound imaging. Screening will reduce the incidence of a late diagnosis when renal disease is advanced but a normal ultrasound scan in those under 30 years old is not conclusive. It is not recommended that children are screened. The key to minimising the rate of progressive disease is tight BP control. ACE inhibitors are recommended as the initial antihypertensive agent unless contraindicated. Alport's syndrome is a disorder characterised by abnormal type IV collagen which is found in the kidney, eyes, skin and ears. Around one in ten practices are likely to have a patient with Alport's syndrome. Eighty per cent of patients have the X-linked form of the disease. All first-degree relatives of a patient with confirmed Alport's syndrome should be offered screening. The combination of reduced hearing and urinary abnormalities in a young boy should alert GPs to consider this as a possible diagnosis and initiate referral. Diagnosis can be confirmed by renal or skin biopsy. PMID- 22497105 TI - Diagnosing non-parkinson's movement disorders. AB - The risk of developing a movement disorder increases with age. Idiopathic Parkinson's disease (IPD), is probably the most well known. However, essential tremor is the most common movement disorder affecting older people. Although many sufferers can have very disabling symptoms it can be a very mild illness in some. Patients present with a symmetrical tremor of the upper limbs in 95% of cases. The tremor is less evident at rest, unlike the tremor of IPD, and there will be no rigidity or bradykinesia. Essential tremor is a mainly clinical diagnosis. A watchful waiting period may be tried. DaTSCAN can be helpful as the results will be normal in patients with essential tremor and abnormal in those with IPD. Vascular parkinsonism accounts for 4.4-12% of all cases of parkinsonism, although it is likely that many cases remain undiagnosed. The features are usually bilateral and symmetrical and often affect the lower more than the upper limbs. A history of previous stroke is common, as are the presence of cardiovascular risk factors such as hypertension and diabetes. Drug-induced parkinsonism is the second most common cause of parkinsonism behind IPD. All patients thought to have a diagnosis of possible IPD should be referred to secondary care. It would also be prudent to refer any patients whose diagnosis is unclear and where advice would be helpful on future management. PMID- 22497106 TI - Vesicular conditions. PMID- 22497107 TI - How supportive are your partners? PMID- 22497108 TI - Lawmakers need to hear from us before it's too late to make a difference. PMID- 22497109 TI - Your role as an advocate for your patients and your profession. PMID- 22497110 TI - IBM disciplinary actions--a mirror into enforcement activities. PMID- 22497111 TI - Medical research has health and wealth implications. PMID- 22497112 TI - Paying for value: your report card. PMID- 22497113 TI - IHC awarded the sole Iowa-based contract to serve Iowa hospitals. PMID- 22497114 TI - [Interaction between three isoflavones and different isomers of human serum albumin]. AB - The interaction mechanisms between isoflavones (Genistein, 3', 4', 7 trihydroxyisoflavone and Biochanin A) and different isomers of human serum albumin (HSA) were investigated by fluorescence spectroscopy. Various parameters (quenching rate constants, binding constants and number of binding sites) of isoflavones-human serum albumin complexes were calculated. The results showed that the isoflavones have only one binding site on human serum albumin, located at the Site I, and the binding constants were between 0.17 x 10(5) and 1.20 x 10(5) L x mol(-1). Fluorescence enhancement experiments showed that the fluorescence intensities of the drugs significantly increased after interacting with HSA, indicating that the combination of drug and HSA had occurred. The binding mechanisms between three isoflavones and HSA were discussed. PMID- 22497115 TI - [Optical characteristics of InGaN/GaN light emitting diodes on patterned sapphire substrate]. AB - In the present paper, optical characteristics of InGaN/GaN multiple quantum wells light emitting diodes fabricated on the conventional (C-LEDs) and patterned sapphire substrates (PSSLEDs) were investigated by electroluminescence (EL) and photoluminescence (PL). PSSLEDs show higher light output power and smaller full width at half maximum (FWHM) of EL than those of C-LEDs for their better crystalline quality. The FWHM of EL for PSSLEDs exhibits faster broadening as current increases than C-LEDs, while the same broadening of FWHM of PL as excitation power increases is shown in PSSLEDs and C-LEDs, which indicate that there is stronger band filling effect in PSSLEDs caused by relatively higher carrier density in their QWs at the same current injection level. Besides, smaller blue-shift of peak wavelength of EL as injection current increases in PSSLEDs suggests that piezoelectric field in PSSLEDs is weaker than that in C LEDs. Therefore, comparing the changes in external quantum efficiency as current increases for PSSLEDs and C-LEDs, more serious efficiency droop for PSSLEDs could not be mainly caused by piezoelectric field in QWs. PMID- 22497116 TI - [Direct determination of hyperfine structures and isotope shifts in the 6s5d 3D - > 6p5d 3F transitions of Ba I]. AB - In the present experiments, a new method of atomic spectral measurement using states optical pre-selection was proposed and demonstrated, and the measurement of hyperfine-structures and isotope shifts in the 6s5d 3D --> 6p5d 3F transitions of Ba I was taken as an example. A 791 nm laser was used to excite the different hyperfine transitions 6s6s 1S0 --> 6s6p 3P1 for different isotopes of barium and different hyperfine energy-levels of 6s5d 3D2 for these isotopes were populated by the 6s6p 3P1 --> 6s5d 3D2 spontaneous radiations, then the corresponding fluorescence spectra of 6s5d 3D2 --> 6p5d 3F2 transitions excited by another 778 nm laser were recorded. Comparing of these spectra, 22 lines were recognized and the hyperfine-structure constants of 6s5d 3D2 and 6p5d 3F2 of 135Ba and 137Ba were evaluated consequently while the isotope shifts of these transitions were also determined. PMID- 22497117 TI - [Vibrational levels and dissociation energies of diatomic systems using algebraic method]. AB - The fixed order in the algebraic method (AM) suggested by Sun et al. is changed to be a flexible one in the vibrational energy expansion because the order of diatomic potential energy expansion may not be a constant. The AM with a flexible order was used to tackle the possible "butterfly effect" that may be encountered in spectroscopic computations, and to study the full vibrational levels {E(v)} and the dissociation energies D(e) for N2 - a'(1) sigma(u)(-), Li2(+) - 2 2sigma(g)(+), 4HeD(+) - X 1sigma(-) and 39K 85Rb- (2) 3sigma(+) electronic systems. The results reproduced all known experimental vibrational energies, and predicted correct dissociation energies and all unknown high-lying levels that may not be given if one uses original AM. The calculations showed that the modified AM can be extended to study the full vibrational spectra for many more diatomic systems. PMID- 22497118 TI - [Study on the automatic recognition method of elemental spectra in laser induced breakdown spetroscopy]. AB - According to the spectral line broadening mechanism of laser induced breakdown spectroscopy, the emission lines from the standard spectral database of NIST were simulated, and they were compared with the spectral data of experiment. In the process of comparison similarity measure was used to measure the similarity between the simulative spectra and the experimental spectra. The automatic recognition method of elemental spectra was studied, and the spectral data of soil between 340 and 345 nm was recognized by computing the proportional coefficients of the spectral lines. Using principle of nonlinear least squares, the recognition process was completed. The feasibility and the advantage of the method were proved by the results of experiment. PMID- 22497119 TI - [Study on measurement of trace heavy metal Ni in water by laser induced breakdown spectroscopy technique]. AB - The spectroscopy emission characteristics and the detection limit of trace heavy metal nickel in water was studied based on laser induced breakdown spectroscopy technique, with a 1,064 nm wavelength Nd : YAG laser as excitation source, and the echelle spectrometer and ICCD detector were used for spectral separation and high sensitive detection with high resolution and wide spectral range. A round flat solid state graphite as matrix was used for element enrichment for reducing water splashing, extending the plasma lifetime and improving the detection sensitivity, and the experimental sample was prepared by titrating a fixed volume of nickel nitrate solution of different concentrations on a fixed area of the graphite matrix. The results show that the better detection delay time is about 700 ns, the spectrum intensity raises with the concentration increase, a good linear relationship is presented at low concentration with a correlation coefficient 0.996 1, and the lower limit of detection of nickel in water with 0.28 mg x L(-1) was retrieved. A measurement method for further study of trace heavy metals in water is provided with laser induced breakdown spectroscopy technique. PMID- 22497120 TI - [Photoionization ion mobility spectrometry (UV-IMS) for the isomeric volatile organic compounds]. AB - The construction and performance study is reported for a newly developed ultraviolet photoionization ion mobility spectrometry (UV-IMS). In the present paper, an UV-IMS technique was firstly developed to detect eleven isomeric volatile organic compounds including the differences in the structure of carbon chain, the style of function group and the position of function group. Their reduced mobility values were determined and increased in this order: linears < branches < cycles, primary < secondary < tertiary, para- < meta- < ortho- and alcohols < acetones < aromas. The concentrations of analytes were obtained by means of exponential dilution method, and the experiments show that the limit of detection of the homemade UV-IMS was around ppb-ppm. PMID- 22497121 TI - [Determination of electron density in atmospheric pressure radio frequency dielectric barrier discharges by Stark broadening]. AB - The use of high frequency power to generate plasma at atmospheric pressure is a relatively new development. An apparatus of atmospheric pressure radio frequency dielectric barrier discharge was constructed. Plasma emission based measurement of electron density in discharge columns from Stark broadening Ar is discribed. The spacial profile of electron density was studied. In the middle of the discharge column, as the input power increases from 138 to 248 W, the electron density rises from 4.038 x 10(21) m(-3) to 4.75 x 10(21) m(-3). PMID- 22497122 TI - [Research on radiation intensity of nanosecond pulse laser-induced soil plasma]. AB - To improve the quality of laser-induced breakdown spectroscopy, nanosecond pulse laser generated by Nd : YAG laser was used to excite soil sample. The laser induced plasma spectrum was observed using a grating spectrometer and a photoelectric detection system. The influence of laser output energy ranging from 100 to 500 mJ on the radiation intensity of plasma was studied. The results show that both the line intensity and signal-to-background ratio can be enhanced under the optimized condition that the laser energy is 200 mJ. The quality of spectrum was further improved after the laser beam used to excite the sample was defocused properly. When the defocusing position is + 6 mm, the spectral lines intensity of element Mg, Al, K and Fe increased about 46%, 63%, 59% and 45% compared to that without defocusing respectively. The spectral signal-to-background ratio increased about 11%, 31%, 35% and 38% respectively. This lays a foundation for detection of trace impurity element in soil. PMID- 22497123 TI - [Off-axis cavity enhanced absorption spectroscopy detection techniques for the measurement of carbon dioxide]. AB - The spectrum of carbon monoxide was obtained around 1. 573 microm using a tunable distributed feedback semiconductor laser with a high-finesse cavity at room temperature via off-axis cavity enhanced absorption (CEA) spectroscopic technique. The absorption line of carbon monoxide at 6 357. 311 6 cm(-1) was chosen for trace detection. Meanwhile, in order to get more accurate measurements, absorption path length of the cavity calibration methods was studied, and a simple and practical calibration method was given. The results show that, the equivalent absorption path length of high-precision optical resonator was -1 195.73 m. At last, we got the concentration of carbon monoxide in the real atmosphere to be -388.346 ppm (S/N = 22), and the detection limit of carbon monoxide was 17.65 ppm. By combination of wavelength modulation technology and OA-CEAS technology, a minimum detectable concentration of 0.36 ppm (S/N = 1 064) was achieved eventually. PMID- 22497124 TI - [Rapid detection of residual cyclohexanone in disposable medical devices by ultraviolet photoionization ion mobility spectrometry (UV-IMS)]. AB - In the manufacture of disposable PVC medical devices, cyclohexanone is frequently used as an adhesive reagent, which can be released into the tube airspace or stored solution and thus may cause some adverse effects on patients in therapy. In this paper, an ultraviolet photoionization ion mobility spectrometry (UV-IMS) technique has been developed to detect cyclohexanone through monitoring the gas composition within a package of infusion sets. The concentrations of cyclohexanone were prepared by means of exponential dilution method, and the experiments show that the UV-IMS has a limit of detection at 15 ppb and its measurable linear dynamics range is over three orders of magnitude. The concentrations of cyclohexanone in three brands of infusion sets packages were determined to be 16.78, 17.59 and 46.69 ppm respectively. The UV-IMS is proposed as a tool for the quality control of medical devices to monitor illegal uses of chemical solvents like cyclohexanone. PMID- 22497125 TI - [Influence of cold spot temperature on 253.7 nm resonance spectra line of electrodeless discharge lamps]. AB - As a kind of new electric light source, electrodeless discharge lamps are of long life, low mercury and non-stroboscopic light. The lighting effect of electrodeless discharge lamps depends on the radiation efficiency of 253.7 nm resonance spectra line to a large extent. The influence of cold temperature on 253.7 nm resonance spectra line has been studied experimentally by atomic emission spectral analysis. It was found that the radiation efficiency of 253.7 nm resonance spectra line is distributed in a nearly normal fashion with the variation of cold spot temperature, in other words, there is an optimum cold spot temperature for an electrodeless discharge lamp. At last, the results of experiments were analyzed through gas discharge theory, which offers guidance to the improvement of lighting effect for electrodeless discharge lamps. PMID- 22497126 TI - [Ideal white organic light emitting devices based on doped PFO]. AB - In the present paper, the electroluminescence emission from a doped polymer layer was studied. The blue fluorene PFO was used as the host material and MEH-PPV as the dopant. The spectral characteristics and color stability of the emission on CIE chromaticity diagram were investigated. With the doping ratio of 2.5 Wt%, the device shows turn-on voltage of 3 V, and color coordinates of (0.33, 0.33) at 11 V. The color coordinates of the device was stable with changing voltage in a large range, and located in the ideal white area in the range of 5-20 V voltage. PMID- 22497127 TI - [Effect of bivalent alkaline earth fluorides introduction on thermal stability and spectroscopic properties of Er3+/Tm3+ /Yb3+ co-doped oxyfluorogermanate glasses]. AB - Transparent Er3+/Tm3+ /Yb3+ co-doped oxyfluorogermanate glasses alone containing MgF2, CaF2, SrF2 or BaF2 and nano-glass-ceramics only containing BaF2 were prepared. The thermal stabilities and the up-conversion emission properties of the samples were investigated. Analyses of absorbance spectra reveal that the UV cutoff band moves slightly to shortwave band with the doping bivalent cation mass increasing. The results show that the emission color can be adjusted by changing the alkaline earth cation species in the glass matrixes, especially as Mg2+ is concerned, and the emission intensity can increase notably by heating the glass containing alkaline-earth fluoride into glass ceramic containing alkaline-earth fluoride nanocrystals or increasing the content of bivalent alkaline earth fluorides. PMID- 22497128 TI - [Upconversion properties of sodium and aluminum fluorides coated BaF2 material]. AB - Sodium and aluminum fluorides coated BaF2 was synthesized by hydrothermal method. It was characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and fluorescence spectrophotometer, respectively. The analysis results indicated that sodium and aluminum fluorides existed in the form of sodium fluoride and sodium fluoroaluminate, which combined with BaF2 surface via chemical bonds, and exhibited coated structure. Fluorescence spectroscopy testing showed that there were two wide upconversion emission peaks with maxima at 304 and 324 nm under the excitation at 583 and 863 nm, respectively. Its phosphorescence life time was greater than 18.4 ms, and the emission intensity exhibited a rising process from the beginning and a decaying process after 15 ms. The luminescence mechanism was proposed according to the energy conversion process of the upconversion emission, the results showed that the upconversion emission belonged to the quantum confinement effect-interface light emission center radiative recombination. PMID- 22497129 TI - [Effect of different excitation monitoring wavelengths on emission spectrum of red long afterglow phosphor Sr3Al2O6 : Eu2+, Dy3+]. AB - The Eu2+ and Dy3+ ion co-doped Sr3Al2O6 phosphor powders with long afterglow were prepared with high temperature solid-state reaction. The phase and the spectra properties of the material were characterized by X-ray diffraction (XRD) and fluorescence spectrophotometer. It was found that the sample is composed of pure Sr3Al2O6 phase. Furthermore, the emission peak of 537 nm under 360 nm excitation and that of 590 nm excited by 468 nm-light were obtained, respectively, and it is more interesting that the emission peaks were at 537 and 590 nm under 394 nm excitation. The effects of different excitation wavelengths on the emission spectrum were explained reasonably by the effect of nephelauxetic effect and crystal field. It revealed that the two types of luminescence with different color were caused by the differences of the center of gravity of the 5d excited state energy level and the split range of 5d energy level. PMID- 22497130 TI - [Spectral analysis of organic/microcavity organic light-emitting devices with the change in thickness of organic layer]. AB - Organic light-emitting devices (OLEDs) with emission peak at 520 nm were designed. The electroluminescence (EL) spectra including the integrated intensity, the peak width at half height, and the intensity and the position of the peak of the EL spectra of the OLEDs and microcavity OLEDs (MOLEDs), the total thickness of organic layers which is changeable, were calculated and theoretically analyzed with the thickness of the layer of NPB and light-emitting layer of Alq3 ranging from 10 to 100 nm, respectively. According to these studies, it was found that the optimized OLEDs should be constructed with 70 nm NPB and 62 nm Alq3, and this structure should be more suitable to configurate the MOLEDs. These results suggest that the suitable structure of OLEDs/MOLEDs could be designed with help of theoretical calculation, which is also helpful to the light-emitting properties of OLEDs and MOLEDs. PMID- 22497131 TI - [A novel flow injection chemiluminescence method with ferricyanide and luminol for the determination of ractopamine in biological samples]. AB - A novel chemiluminescence method coupled with flow injection technique for the determination of ractopamine was developed. It was based on the enhancement of the chemiluminescence by ractopamine derived from the chemiluminescence reaction between luminol and ferricyanide in sodium hydroxide medium. The linear calibration range of the chemiluminescence intensity with respect to the ractopamine concentration covers from 4.0 x 10(-9) - 8.0 x 10(-7) g x mL(-1). The relative standard deviation for ractopamine is 5.6% (n = 11), and the detection limit is 2.5 x 10(-9) g x mL(-1). The method was firstly applied to the determination of ractopamine in biological samples with satisfactory results. The recovery was between 69.3% and 101.3%. PMID- 22497132 TI - [Thermal infrared spectral variation and sensitive waveband of quartzy sandstone under pressure]. AB - In the present paper the thermal infrared spectral variation of quartz sandstone under uniaxial compression was detected by a spectroradiometer to study the sensitively responding waveband of infrared radiation excited by the pressure. The experimental result shows that the infrared spectrum varies with the load, and the variation feature is different in different wavebands. The infrared radiation intensity increases with the increase in the load within the waveband 8.0-11.5 microm (specially in 8.6-9.1 microm), and there is a quadratic correlation between them, meanwhile the signal-to-noise ratio of spectrum radiation is also higher in the waveband. But in other wavebands the correlation is worse and the signal-to-noise is also lower. This indicates that the waveband 8.0-11.5 microm is the sensitive waveband of infrared radiation to the pressure, and it is also the superior waveband for infrared remote sensing monitoring the stress and catastrophe of rock. The optimum waveband is 8.6-9.1 microm. PMID- 22497133 TI - [Measurement and evaluation of middle infrared and long infrared dual-band laser emitting spectrum]. AB - Remote sensing interferometer spectrometer Tensor37 was selected as measuring equipment based on spectrum characteristics of a middle infrared and long infrared dual-band (DF & CO2) laser on account of problems, such as blending of CO2 spectrum and the third level of DF spectrum, existing in grating monochromator and spectrophotometer. Simulating measurement and real measurement of dual-band laser spectrum were explored after validating blackbody radiation response function of Tensor37. Effective data including spectrum composition, peak fluctuation, wavelength accuracy and relative intensity were evaluated for calculating gain media parameters, optimizing operating parameters and infrared application of dual-band laser. PMID- 22497134 TI - [Research progress and application prospect of near infrared spectroscopy in soil nutrition analysis]. AB - "Digital agriculture" or "precision agriculture" is an important direction of modern agriculture technique. It is the combination of the modern information technique and traditional agriculture and becomes a hotspot field in international agriculture research in recent years. As a nondestructive, real time, effective and exact analysis technique, near infrared spectroscopy, by which precision agriculture could be carried out, has vast prospect in agrology and gradually gained the recognition. The present paper intends to review the basic theory of near infrared spectroscopy and its applications in the field of agrology, pointing out that the direction of NIR in agrology should based on portable NIR spectrograph in order to acquire qualitative or quantitative information from real-time measuring in field. In addition, NIRS could be combined with space remote sensing to macroscopically control the way crop is growing and the nutrition crops need, to change the current state of our country's agriculture radically. PMID- 22497135 TI - [Studies of the thermal radiation characteristics of urban typical surface features]. AB - The use of thermal infrared technology to monitor the land surface temperature has received mature development, and the acceleration of urbanization makes the urban heat effect emerge, thus, studies of the thermal radiation characteristics of urban typical surface features make great significance for the analysis of the causes and distribution of the thermal phenomenon. Based on the study of ground measured data of Baoding city, we have found that, the feature types, the observation time and wall orientations are principal factors that exert an influence on the thermal radiation brightness temperature of urban typical surface features. The results show that different types of surface features will significantly affect the brightness temperature, but "different things with the same spectrum" still exists; the observation time has direct impact on the intensity of thermal radiation and to a large extent on the brightness temperature difference of each channel; the brightness temperature of different wall orientations are also different, and the difference changes with the change in observation time. Studies of thermal radiation characteristics of urban typical surface features have theoretical and practical significance, providing basis for thermal infrared remote sensing to monitor the urban heat effect. PMID- 22497136 TI - [The relationship between FTIR spectra of PVA film and its heat preservation capability]. AB - Polyvinyl alcohol (PVA), polyethylene (PE) and ethylene-vinyl acetate copolymer (EVA) film was prepared. The optic capability, infrared transmittance and heat preservation capability of the films were studied respectively. The result indicated that the haze degree of the PVA film decreased about 15% and 12% than PE film and EVA film; PVA film transmittance of IR was more or less than other films in the 7-14 microm wavelength range so that the temperature of greenhouse could be increased effectively in daylight. It was just 16.2% about 20% less than EVA film, and 50% less than PE film. The PVA film could be used as agricultural film in greenhouse to promote heat preservation performance greatly. PMID- 22497137 TI - [Intercalation of polystyrene in kaolin via in-situ polymerization]. AB - The synergistic stabilization effect of different metal lanolin fatty acids as natural-based thermal stabilizers for poly (vinyl chloride) (PVC) including calcium lanolin fatty acid (Calan2), zinc lanolin fatty acid (Znlan2) and Lanthanum lanolin fatty acid (Lalan3) were studied. The processability of PVC was tested by torque rheometer, the mechanical properties were studied by universal testing machine, and the coupling effect of product in PVC/CaCO3 was also researched. The results indicated that the properties of Lan/Zn stabilizer was better than Ca/Zn stabilizer and compound lead salt except static stability and dynamic stability. PMID- 22497138 TI - [Study on spectral measurement methods in identification of maize variety authenticity based on near infrared spectra of single kernels]. AB - In order to establish the better maize variety identification models based on single kernel samples, the near-infrared spectral measurement methods were studied by comparing the direction of the maize seed's embryo, diffuse reflectance and transmission mode, devices of holding the sample according to their impacts on the performance of variety identification models. Partial least squares-discriminant analysis (PLSDA) was used to compress the pretreated spectral data into 9 variables, and then the identification models were built based on biomimetic pattern recognition (BPR). The results show that with the maize grain's embryo facing the light source the models can be made perform better than with embryo backing toward the light source, diffuse reflectance mode is better than transmission mode, and small sample pool performs better than the small aperture. The measurement method of acquiring the diffuse reflectance near infrared spectra of maize by small pool with the seed embryo facing the light source can make models have the best performance. The average correct identification rate of the models is 94.6%, and the average correct rejection rates for the varieties not belonging to the models reached 96.5%. PMID- 22497139 TI - [Intermolecular hydrogen bond between protein and flavonoid and its contribution to the stability of the flavonoids]. AB - The interactions between three proteins (BSA, lysozyme and myoglobin) and three flavonoids (quercetin, kaempferol and rutin) were analyzed, using three dimensional fluorescence spectrometry in combination with UV-Vis spectrometry and Fourier transform infrared (FTIR) spectroscopy. The stabilities of unbound flavonoids and protein-bound flavonoids were compared. The correlation between the interaction and stability was analyzed. The results showed that the hydrophobic interaction was the main binding code in all proteins and flavonoids systems. However, the hydrogen bond has been involved merely in the BSA system. The stability of all three flavonoids (quercetin, kaempferol and rutin) was improved by BSA. There was a great correlation between the hydrogen bonding and the stability of the flavonoids in the presence of BSA. It suggested that the protection of BSA on the flavonoids was due to the intermolecular hydrogen bonding between BSA and flavonoid, and the stronger hydrogen bonding resulted in more protection. PMID- 22497140 TI - [Synchrotron radiation-based FTIR microspectroscopy study of the hippocampus of 6 hydroxydopamine-lesioned rats]. AB - Synchrotron radiation based-Fourier transform infrared microspectroscopy (SR FTIR) was used to preliminarily investigate the biochemical composition of the hippocampal neurons for 6-hydroxydopamine-lesioned rats and normal rats. Spectral analysis showed that in PD samples, the CH2 asymmetric and symmetric vibrational absorption of integral area at 2 924 and 2 850 cm(-1) and the intensity of C=O vibrational absorption at 1 736 cm(-1) (assigned to the lipid functional group) increase compared to normal samples, which indicate that lipid content increased in PD sample; the PO2 asymmetric and symmetric vibrational absorption decrease compared to normal samples (assigned to the nucleic acid functional group; However no clear difference of the vibrational fingerprinting of protein between PD and normal samples was noticed. The present results suggest that the changes in biochemical composition in hippocampal neurons in PD rats probed by synchrotron radiation based-FTIR may contribute to the elucidation of PD pathology. PMID- 22497141 TI - [Investigation of thermal behaviors of gamma-form nylon 6 prepared by ammonia vapor from phosphoric acid solutions]. AB - In the present work, we prepared nylon 6 crystals via crystallization of nylon from phosphoric acid by using the vapors of ammonium hydroxide as a precipitation regent. Both XRD and FTIR results demonstrate that the obtained nylon 6 sample exhibit characteristic peaks of nylon 6 in gamma form. In addition, treatment of nylon 6 in boiling water for half an hour followed by FTIR and XRD characterization shows that the obtained nylon 6 sample is in gamma form rather than in meta-stable b form. DSC characterization indicates that the nylon 6 sample exhibits two melting peaks (213 and 220 degrees C) when the sample is heated at a heating rate of 10 degrees C x min(-1). The reason for this phenomenon is that the nylon 6 sample has different lamellar thickness. To investigate the thermal behavior of the nylon 6 sample, the sample underwent the following thermal treatment procedure. First, the sample was heated to a pre-set temperature (T(s)) and kept at that temperature for an hour. Subsequently, the sample was cooled down to 100 degrees C at a cooling rate of 1 degrees C x min( 1), and then cooled down to room temperature at a cooling rate of 10 degrees C x min(-1). The treated samples were characterized by FTIR and DSC method. Experimental results show that the treated nylon 6 samples exhibit different crystalline behavior. When T. ranges from 130 to 160 degrees C, no significant changes were observed. When T(s) is 170 degrees C, a small fraction nylon 6 crystals is destroyed and recrystallized into thin lamellae in a form. As a result, a pre-melting peak appears in DSC result. The pre-melting peak moves to higher temperature and its peak area increases significantly upon increasing T(s) from 170 to 198 degrees C. When T(s) amounts to 200 degrees C, the pre-melting peak and the melting peaks 213 degrees C merge into one melting peak and two melting peaks are observed at 212 and 220 degrees C in the DSC results. FTIR spectra indicate that significant amount of crystalline nylon 6 in a form appears but the majority of crystalline phase of the sample is still gamma phase. As T(s) increases from 200 to 209 degrees C, the melting peak at lower temperature moves to higher temperature with increasing its peak area. On the other hand, the melting peak at 220 degrees C decreases in intensity but does not show any peak shift. As T(s) reaches 209 degrees C, the two melting peaks merge into one peak and FTIR results demonstrate that nylon 6 in a form becomes dominate phase in the sample. In the whole heat-treatment process, the gamma phase nylon 6 sample began to transform to a phase at the heat-treatment temperature of 170 degrees C, which is far below the melting point of the original sample (221 degrees C). This is different from the results reported in the literature, which state that gamma phase nylon 6 will not transform to alpha-phase until nylon is melt. PMID- 22497142 TI - [Study on bladder cancer tissues with Raman spectroscopy]. AB - The scope of this research lies in diagnosis of bladder cancer through Raman spectra. The spectra of bladder cancer and normal bladder were measured by using laser confocal Raman micro-spectroscopy. Principal component analysis/support vector machines was applied to the spectral dataset to construct diagnostic algorithms, then to detect the accuracy of these algorithms to determine histological diagnosis by leave-one-out cross validation from its Raman spectrum. It was showed that the peak intensity of nucleic acid (782, 1 583 cm(-1)) in bladder cancer and protein (1 061, 1 295, 2 849, 2 881 cm(-1)) in normal bladder increased significantly. Additionally, Principal component analysis (PCA) and support vector machines (SVM) provided an effective tool for differentiating the bladder cancer from normal bladder tissue. Excellent sensitivity (86.7%), specificity (87.5%), positive predictive value (92.9%), and negative predictive value (72. 8%) for the diagnosis of bladder cancer were obtained by leave-one-out cross validation. It was concluded that Raman spectroscopy can be used to accurately identify bladder cancer in vitro, and it suggests the promising potential application of PCA/SVM-based Raman spectroscopy for the diagnosis of bladder cancer. PMID- 22497143 TI - [Microstructure study on bismuth triborate crystal and its melt at high temperature by Raman spectroscopy]. AB - Temperature dependent Raman spectra of BiB3 O6 crystal and its melt were recorded and the microstructure of BiB3 O6 melt was predicted. Multiple theoretical methods including quantum chemistry ab initio calculation and DFT (Density Function Theory) methods were applied to simulate the BiB3 O6 crystal and melt structure and Raman spectra. It was demonstrated that B-O triangles and Bi lattice in the crystal reveal little affected in structure while B-O tetrahedra shows severe distortion with increasing temperature, especially B-O tetrahedra disappears after being completely melt. The microstructure of BiB3 O6 melt consists of six-member ring, [B6 O12](6-), which varies in bond lengths and angles individually. Cation Bi behaves to balance the charge of anion cluster, and the oxygen coordination number of cation Bi is 3, different from the crystal situation in which cation Bi is coordinated with 6 oxygens. PMID- 22497144 TI - [Preliminary study on identification of oil products using laser-Raman fingerprint spectrum]. AB - Laser-Raman spectroscopy technology was used for measuring and analyzing properties of oil products. Through comparing with the Raman shifts and relative Raman intensity ratios of the main fingerprint peaks, different kinds of oil products were identified successfully. Furthermore, the Raman spectra of the same type of petroleum products obtained from different private gas stations were measured and the petroleum qualities were detected. The favorable results were obtained in both oil identification and quality test. The present work provides a feasible method for quick, sensitive and nondestructive identification of oil products. PMID- 22497145 TI - [Effect of pH perturbation on rainwater dissolved organic matter fluorescence characteristics]. AB - The influence of pH variation on the fluorescence characteristics of rainwater dissolved organic matter (DOM) was studied via excitation emission-matrix spectroscopy. A rainwater sample (pH 5.7) collected in Xiamen (China) in the summer of 2009 was adjusted to different pH values ranging from 3.2 to 10.7. Parallel factor analysis (PARAFAC) decomposed the fluorescence matrices into four humic-like components (C1, C3, C4, and C5), one protein-like component (C2) and an unknown component (C6). As pH values of the sample increased from the initial value of 5.7 to 10.7, the fluorescence intensities of C1, C3, and C5 also increased, while those of C4 and C6 decreased gradually, resulting in an increasing contribution of humic-like components to total fluorescence. The opposite trend was observed when pH decreased to more acidic conditions and the unknown component (< 250, 330/386 nm) became dominant. The relative contribution of the protein-like component to the total fluorescence remained more or less constant as pH varied. In addition, the fluorescence index (FI), humification index (HIX) and the index of recent autochthonous contribution (BIX) were also affected by pH perturbation. It is therefore recommended that the pH of rainwater samples should be measured and reported in future studies to effectively evaluate such "pH effects" on rainwater DOM fluorescence characteristics. PMID- 22497146 TI - [Application of hyperspectral fluorescence image technology in detection of early rotten oranges]. AB - Rottenness is most prevalent and devastating disease that threats citrus fruit. Automatic detection of early rottenness can enhance the competitiveness and profitability of the citrus industry. However, there is no efficient automatic detection technology at this time that could detect this disease. The navel orange was selected as research objective. Hyperspectral fluorescence imaging was used to detect early rottenness in orange. Optimum index factor (OIF) method was applied to identify the optimal band combination. 100% detection rate was achieved based on the optimal bands ratio image and two threshold values. The research showed that the proposed method can effectively overcome the affect from florescence effect because stem damage area and stem also can produce florescence under ultraviolet light. This study will lay a foundation for developing multispectral detection system used in on-line detection of early rottenness fruit. PMID- 22497147 TI - [Studies on fluorescence properties of a novel acylhydrazone ligands and its Sn metal complexes]. AB - The molecular structure and spectral properties of a novel acylhydrazone ligands 2-hydroxy-naphthaldehyde-5-chloro-salicyloylhydrazone (H3L) and its Sn metal complexes [(n-Bu2)Sn(HL)] in solution, crystal and thin films were investigated by using steady state and time resolved fluorescence spectrum. The experimental results show that for H3L, compared with it in solution, the fluorescence intensity is enhanced as it is crystal and thin films, the fluorescence peak is red-shift, and the excited state lifetime is longer. The transition energies of the unimolecule is 240.2 kJ x mol(-1). For (n-Bu2)Sn(HL), the fluorescence intensity is stronger as it is crystal than it is in solution and the fluorescence peak is red-shilft, the excited state lifetime is longer. The fluorescence is quenched as it is in thin films. The transition energies of the unimolecule is 230.4 kJ x mol(-1). The fluorescence intensity of (n-Bu2)Sn(HL) is four times higher than the H3L. The excited state lifetime of (n-Bu2) Sn(HL) is longer than H2L too. In theory, these phenomena could be explained by that with the increase of the conjugated system and the rigid construction, the fluorescence intensity is stronger and the excited state lifetime is longer. PMID- 22497148 TI - [Parallel factor analysis as an analysis technique for the ratio of three dimensional fluorescence peak in Taihu Lake]. AB - The present paper proposes a new method to find the ratio of three-dimensional fluorescence peak. At first, the excitation-emission fluorescence matrix of water samples was treated with parallel factor analysis (PARAFAC) and then fluorescence peaks intensity and ratio of fluorescence peak were obtained from the parallel factor analysis model. From the parallel factor analysis model, the same fluorescence peaks of different water samples lie at the same excitation-emission wavelength and the overlap of different fluorescence peaks of the same water sample is reduced. Analysing regional characteristic in Taihu Lake, the ratio of factor score and the ratio of fluorescence peak showed strong correlation. PMID- 22497149 TI - [Bulk heterojunction solar cell based on porphyrin compounds]. AB - Three kinds of porphyrins which can abbreviate as TPP, TPPCu and TMPPFeCl were synthesized by one-step method with mixed solvents. Then these porphyrin materials were used as donors to fabricate organic solar cells with PCBM as accepter by the solution processing of spin-coating method. The structure is ITO/porphyrin : PCBM/Al. The photovoltaic characterizations of these devices were investigated. The device based on TPP : PCBM shows the best performance with an open circuit voltage (V(OC)) of 0.52 V, a short circuit current (J(SC)) of 0.98 mA x cm(-2), and fill factor (FF) of 30.1%. Then the influence of different weight ratio of TPP : PCBM was researched. The best weight ratio of TPP : PCBM is 1 : 1. Increasing or decreasing the quatity of TPP would make J(SC) and V(OC) of the device deterioration and have little effect on the FF. PMID- 22497150 TI - [A comparison of different treatment conditions on the conformation changes of bovine lactoferrin]. AB - In this study, the tertiary, secondary structures and disulfide bond changes of bovine lactoferrin (bLF) under 6 differents physico-chemical treatments were investigated by fluorescence, circular dichroism(CD) and UV-Vis absorption. A red shift from 333 to 354 nm in the fluorescence emission maximum (lambda(max)) was observed in the bLF treated by 6 mol x L(-1) GdnHCl, 8 mol x L(-1) Urea and 50 mmol x L(-1) DTT simultaneously, meanwhile a large number of exposed hydrophobic groups were detected. However, there was no marked shift in lambda(max) of bLF treated by heating (100 degrees C, 5 min), Ultrosonic(450 W, 5 s, 6 pulses) or beta-ME (1%), of which fluorescence intensity decreased significantly compared with the untreated bLF. The results indicated that the mechanism of changes in tertiary structure of the former three methods were different from the latter three. The detection by CD showed that the alpha- helix structure vanished completely in the bLF treated by GdnHCl. However, there was no remarkable change in the secondary structure of the bLF treated by the other five methods. In addition, UV-Vis absorption suggested that disulfide bond was seriously destructed in the bLF treated by DTT and Ultrosonict, but GdnHCl, beta-ME and heating induced a little damage merely. This study is instructive and meaningful to the further research on relationship between structure and activity of bLF. PMID- 22497151 TI - [Structural and spectral study of a novel lanthanide 2-hydroxynicotinic acid coordination polymer]. AB - A novel lanthanide 2-hydroxynicotinic acid coordination polymer 1 {[LaL(HL) (H2O)3]1/3 (SO4)2/3 (H3O)2 H2O} (H2 L = 2-hydroxynicotinic acid) has been synthesized under hydrothermal condition and characterized by crystal X-ray diffraction, IR, UV, TGA, two-dimensional infrared (2D IR) correlation spectroscopy with magnetic and thermal perturbation. In 1, La ions are connected by 2-hydroxynicotinic acid through both carboxylate oxygen atoms and oxygen atoms from hydroxyl group in pyridine to generate a 2D layer in the ab plane, these layers are further connected by weak interactions to form a 3D framework along c axis. The response of out-of-plane bending vibrations of N-H and C-H are remarkable in the 2D IR correlation spectra under magnetic perturbation, this may attributes to the inducement of pi-electron cloud deformation under magnetic perturbation, v4 vibrations from SO4(2-) was also sensitive to magnetic perturbation. In addition, stretching vibrations from N-H are sensitive to thermal perturbation. PMID- 22497152 TI - [In-situ monitoring algorithm of gases poisonous elements concentration with ultraviolet optical absorption spectroscopy based on recursion iterative method]. AB - The key and challenge problem of in-situ monitoring poisonous elements of gases is how to separate the various gases absorption signal from mixed gases absorption spectroscopy and compute it's accuracy concentration? Here we present a new algorithms in return recursion iteration based on Lambert-Beer principle. In the algorithms, recurred by the character of absorption peak of various gases in the band of 190-290 nm UV rays continuous spectroscopy and the character of twin element fold for absorbance are used. Firstly, the authors suppose that there is no absorption for others gases in the character absorption band for a certain gas, the authors can inference the initial concentration of the gas. Then the authors switch to another character spectroscopy, and put the photons that gases absorption out of the total number of absorbed photons that are measured. So we could get the initial concentration of another gas. By analogy the authros can get the initial concentration of all kinds of other poisonous elements. Then come back to the character spectroscopy of the first gas, the authors can get a new concentration of the first gas from the difference between the total number of absorbed photons and the photons that other gases absorption. By analogy the authors can get the iterative concentration of other gases, by irterating this process repeatly for some times until the measurement error of the adjacent gas concentration is smaller than a certain numerical value. Finally the authors can get the real and accurate concentration of all kinds of gases. Experiment shows that the authors can get the accurate concentration of all kinds of gases with the algorithm. The accuracy can be within 2%, and at the same time, it is easy enough to satisfy the necessity of real-time requirement. In addition it could be used to measure the concentration of many kinds of gas at a time. It is robust and suitable to be taken into practice. PMID- 22497153 TI - [Construction and simplification of the calibration model for spectral analysis of fuel oil properties based on mutual information method]. AB - Near infrared diffuse reflectance (NIRS) and ultraviolet (UV) spectral analysis were adopted for quantitative determination of octane number and monoaromatics in fuel oil. Partial least squares regression (PLSR) was used for construction of vibrational spectral calibration models. Variables selection strategy based on mutual information (MI) theory was introduced to optimize the models for improving the precision and reducing the complexity. The results indicate that MI PLSR method can effectively improve the predictive ability of the models and simplify them. For octane number models, the root mean square error of prediction (RMSEP) and the number of calibration variables were reduced from 0.288 and 401 to 0.111 and 112, respectively, and correlation coefficient (R) was improved from 0.985 to 0.998. For monoaromatics models, RMSEP and the number of calibration variables were reduced from 0.753 and 572 to 0.478 and 37, respectively, and R was improved from 0.996 to 0.998. Vibrational spectral analysis combined with MI PLSR method can be used for quantitative analysis of fuel oil properties, and improve the cost-effectiveness. PMID- 22497154 TI - [Efficient computation of spectral flux normalization]. AB - Flux normalization is a key procedure in spectral data mining, and is important for the efficiency and accuracy of automatic processing of massive astronomical spectral data, information extraction and sharing. Since the usual implementation of flux normalizing methods is inefficient, the present work focuses on the algorithm designing of spectral flux normalization. Firstly, the authors investigated the limit efficiency characteristics of the available flux normalization methods, introduced four efficient flux normalizing algorithms, and studied their time complexity and space complexity. Secondly, the authors evaluated the efficiency of the proposed algorithms experimentally and horizontally based on the SDSS (Sloan Digital Sky Survey) released spectral data. In the theoretical research, the main consideration is the computational complexity characteristics of the flux normalization methods when the data size increases unlimitedly. The experimental research focuses on the difference in the computational burden between the basic operations in different flux normalization methods. It is shown that, although the four flux normalization methods S(max), S(median), S(mean) and S(unit) belong to the same limit efficiency type, on the spectra with usual observing scale, S(max) and S(median) are much more efficient than S(mean) and S(unit), and S(unit) is the most inefficient one. This work is helpful for choosing the appropriate flux normalization method based on the size of spectra database and the scientific needs in automatic spectra analysis. PMID- 22497155 TI - [Experimental study of offshore oil thickness hyperspectral inversion based on bio-optical model]. AB - Study on the regularity of thin oil film thickness and its reflectance plays an important role in understanding the mechanism of offshore oil slick and ocean hydrocarbon resources exploration. In this work, the thin oil film thickness of biological optical model is established, and introduced the simplified model of inversion thin oil film thickness information by using one single-band or by using two-band ratio image data. With the quantitative inversion test of thin oil film thickness through the natural shallow water and the crude oil sample, the variation rules of between oil spectral parameters and the thin oil film thickness are obtained. The study show that, the oil reflectance in visible and near infrared spectrum (450-800 nm) and the thin film thickness has high inverse correlation, and showed as negative exponent form decline with the increase of oil film thickness. Regarding the shallow water environment, the double band ratio inversion model of using ETM1/ETM3 band ratio can used to be eliminate the impact of sky scattering influence, and to overcome the single-band model fault of Inversion instability when used in different water quality regions, as the inversion result of the model's correlation coefficient can reach 0.98, which is considered to be the ideal hydrocarbon content remote sensing surveying band, and combined with other types of remote sensing technology (such as ultraviolet-laser or SAR), it would provide more economic and precision services of oil total amount infromation for offshore oil exploration and oil spill monitoring. PMID- 22497156 TI - [Non-invasive measurement of human blood cholesterol concentration based on dynamic spectrum method]. AB - For non-invasive measurement of human blood cholesterol concentration, this experiment was carried out on 80 volunteers clinically. In vivo dynamic spectra of fingers were achieved and biochemical examinations of blood components contents including cholesterol were get as soon as possible. BP artificial neural network with inputs of dynamic spectra plus energy of harmonic waves processed by Principal Components Analysis(PCA) was used to establish the model of the total cholesterol values. The correlation between the predicted value and the true value of cholesterol is 96.48%. The maximum relative error is 25.44% and root mean-square error of prediction is 0.242 6 mmol x L(-1). The results show that PCA can make the process of computing faster and this study is another advance of dynamic spectra. PMID- 22497157 TI - [Improving the signal to noise ratio of spectroscopy for tongue inspection by optical modulation]. AB - In order to solve the problem that the collected spectrum was influenced seriously by the environment light, optical modulation was used to improve the signal to noise ratio of spectroscopy-tongue inspection for the first time. First, reference light was modulated by reticle in this system; second, the reflect spectrum of the same measured object was collected under the condition that it was influenced by green, purple, red laser and environment light respectively; thirdly, the DFT was used to demodulate the collected spectrum data; the maximum harmonic components were extracted and normalized, then the spectral curve was drawn; by comparison, the spectral curves of the same measured object under different condition were almost the same. The experiment result showed that the optical modulation can remove the influence of the environment light; and this method can provide a new way to improve the signal to noise ratio of spectroscopy for tongue inspection. PMID- 22497158 TI - [Research on serum prostate-specific antigen measurement by characteristic spectral absorption method]. AB - A serum prostate-specific antigen (PSA) measurement method was studied using immunochromatography-based colloidal gold-marked test-strips and characteristic spectral absorption method. Some LEDs in the range from 520 to 535 nm irradiated the test-strips sampled by PSA, and then a photodiode in the range from 520 to 540 nm measured the reflex light at the specific area. Accordingly, the absorbency of the strip could be calculated, then the relationship between PSA level and strip absorbency could be ascertained by linear fit method. The experimental measurement system was calibrated by different PSA standard solutions in this research. As a result, in the range between 5 to 50 ng x mL( 1), the levels of PSA have a linear relationship with the absorbency of test strips. Some experiments were completed by 21 different PSA standard solutions within that range, and then the correlation coefficient of the results is equal to 0.910, which proves that the proposed method for serum PSA level measurement is feasible. PMID- 22497159 TI - [Research on accurate measurement of oxygen content in coal using laser-induced breakdown spectroscopy in air environment]. AB - A technique about accurate measurement of oxygen content in coal in air environment using laser-induced breakdown spectroscopy (LIBS) is introduced in the present paper. Coal samples were excited by the laser, and plasma spectra were obtained. Combining internal standard method, temperature correction method and multi-line methods, the oxygen content of coal samples was precisely measured. The measurement precision is not less than 1.37% for oxygen content in coal analysis, so is satisfied for the requirement of coal-fired power plants in coal analysis. This method can be used in surveying, environmental protection, medicine, materials, archaeological and food safety, biochemical and metallurgy application. PMID- 22497160 TI - [Study of photosynthetic characteristics of transgenic barley based on reflectance of single leaf]. AB - Analysis of leaf reflectance can provide a rich source of information about plant physiological process, surface properties of the leaf, as well as internal structure. In the present paper, the changes of reflectance spectra and spectral indices for transgenic barley and non-transgenic control variety based on measurements of single leaf were studied. The results showed that the ratio spectra that calculated by dividing one reflectance spectrum of transgenic barley by its' non-transgenic counterpart spectra were better to illustrate fine differences among spectra of leaves from different barley varieties. Ratio spectra varied between each pairs, but for most ratio spectrum indicated the reflectance differences between transgenic barley and non-transgenic counterpart were most obvious in the red spectrum around the chlorophyll peak and red edge (650-700 nm) and nearly identical in the green spectrum near 550 nm and within the near infrared region (beyond 750 nm). Across the entire calculated spectrum, the changes of reflectance within the region from 650 to 700 nm seem to be very sensitive to respond to possible unintended effects of genetic modification. Six published reflectance indices, the red edge (lambdaRE), the modified normalized difference vegetation index (mND), the structure-independent pigment index (SIPI), the ratio of reflectance in the red and green regions of the spectrum (R(Red)/R(Green)), the photochemical reflectance index (PRI) and the near infrared reflectance at 800 nm (NIRR(800)) were used to make comparisons possible between species. The analyses of changes of these indices indicated that they were highly dependent on growth stages and barley varieties. Once indices described above have significant changes will mean that photosynthetic process, function and status of plants may be changed. PMID- 22497161 TI - [Inversion of winter wheat water content with the relationship between canopy parameters and spectra based on different irrigations]. AB - In order to monitor the canopy water content of winter wheat, canopy spectrums of winter wheat with narrow-band were resampled to broad-band according to relative spectral response (RSR) function of TM5. And then, normalized different water index (NDWI) and simple water index (WI) were calculated with broad-band reflectance. Fuel moisture content (FMC) and equivalent water thickness for canopy (EWTc) were got using dry weight, fresh weight and leaf area (index). The results show that b7 of TM5 is better than b5 in inversing canopy water content of winter wheat. Meanwhile, NDWI is more suitable than WI. Suitable fitting equations are built with NDWI (b4, b7) for FMC and EWTc, whose R2 reaches to 0.576 9 and 0.695 6, respectively. Finally, the spatial mapping of canopy water content is done with fitting equations. The results demonstrate that canopy water content of winter wheat is high in west and low in east in the studied area, and it's high in booting stage and low in milk stage. PMID- 22497162 TI - [An optical-fiber-sensor-based spectrophotometer for soil non-metallic nutrient determination]. AB - In order to achieve rapid, convenient and efficient soil nutrient determination in soil testing and fertilizer recommendation, a portable optical-fiber-sensor based spectrophotometer including immersed fiber sensor, flat field holographic concave grating, and diode array detector was developed for soil non-metallic nutrient determination. According to national standard of ultraviolet and visible spectrophotometer with JJG 178-2007, the wavelength accuracy and repeatability, baseline stability, transmittance accuracy and repeatability measured by the prototype instrument were satisfied with the national standard of III level; minimum spectral bandwidth, noise and excursion, and stray light were satisfied with the national standard of IV level. Significant linear relationships with slope of closing to 1 were found between the soil available nutrient contents including soil nitrate nitrogen, ammonia nitrogen, available phosphorus, available sulfur, available boron, and organic matter measured by the prototype instrument compared with that measured by two commercial single-beam-based and dual-beam-based spectrophotometers. No significant differences were revealed from the above comparison data. Therefore, the optical-fiber-sensor-based spectrophotometer can be used for rapid soil non-metallic nutrient determination with a high accuracy. PMID- 22497163 TI - [Flow injection-spectrophotometric determination of total dissolved nitrogen in seawater based on quantificational solenoid valves]. AB - Using three pipe clamp solenoid valves to replace the traditional six-port valve for sample quota, a set of multi-channel flow injection analyzer was designed in the present paper. The authors optimized optimum instrumental testing condition, and realized determination and analysis of total dissolved nitrogen in seawaters. The construction of apparatus is simple and it has the potential to be used for analysis of total dissolved nitrogen. The sample throughput of total dissolved nitrogen was 27 samples per hour. The linear range of total dissolved nitrogen was 50.0-1 000.0 microgN x L(-3) (r > or = 0.999). The detection limit was 7.6 microgN x L(-3). The recovery of total dissolved nitrogen was 87.3%-107.2%. The relative standard deviation for total dissolved nitrogen was 1.35%-6.32% (n = 6). After the t-test analysis, it does not have the significance difference between this method and national standard method. It is suitable for fast analysis of total dissolved nitrogen in seawater. PMID- 22497164 TI - [Progress in combination of gel electrophoresis and laser ablation inductively coupled plasma mass spectrometry for trace elements determination in proteins]. AB - Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has become a very efficient and sensitive trace, ultratrace, and surface analytical technique for the in situ study of the concentration and distribution of the elements in life sciences with high spatial resolution. It is being used more and more frequently in biological, medical materials and protein research, which will lead to a better understanding of physiology and pathology process in cells and tissues. The present review mainly introduces the strategies of combination of gel electrophoresis (GE) with LA-ICP-MS for the quantification of trace elements in proteins, including the proteins separation, elements detection and calibration methods. The paper emphasizes the basic conditions of the proteins separation, focusing on the stability of proteins during GE and the treatment methods of staining and drying of the gel to enable successful detection of the elements by LA-ICP-MS. In addition, the application of GE-LA-ICP-MS in phosphoproteins, selenoproteins and metal-binding proteins is introduced in detail. The prospects and challenge for this technique are discussed as well for further study. PMID- 22497165 TI - Use of atomic absorption spectrometry in assessment of biomonitor plants for lead, cadmium and copper pollution. AB - Eleven plant species were collected from the vicinity of lead-battery plant in the city of Gaziantep, Turkey. Lead, cadmium and copper concentrations in the soil and leaves of plants were determined by atomic absorption spectrometry. Lead, Cd and Cu concentrations in the soil samples taken from battery area were found to be in the ranges of 304-602, 0.4-0.44 and 31-37 mg x kg(-1), respectively. Significantly increased lead concentration up to 2 750 mg x kg(-1) was found in the leaves of Eleagnus angustifolia L. plant. The lead concentrations in the other plant leaves taken from 50 m around battery factory followed the order Ailanthus altissima > Morus sp. > Juglans regia L. > Ficus carica L. > Cydonia oblonga Miller > Prunus x domestica L. The plants, Populus nigra L. , Eleagnus angustifolia L. and Salix sp. were found useful for Cd, and the plant, Eleagnus angusti folia L. for Pb, to be considered as potential biomonitor. Especially, leaves of trees and plants taken from the distance of 50 m from battery plant have relatively higher Pb concentrations. Therefore, people who and animals which live in this area and benefit from these soil and plants have vital risks. PMID- 22497166 TI - [Speciation analysis of Cd in PM10 and PM2.5 during heating period in Urumqi]. AB - PM2.5 and PM10 samples were collected on campus of Xinjiang Agricultural University during Dec. 14-28, 2009, and the speciation of Cd in PM10 and PM2.5 and its health risk index was analyzed. The results showed that the pollution caused by PM10 and PM2.5 was severe here during the heating period; Cd in PM10 and PM2.5 was of concentration 3.642 and 1.964 ng x m(-3) respectively, mainly in the form of residue; however, Cd in PM2.5 had a higher bioavailability than that in PM10. The carcinogenic risk of Cd in PM10 and PM2.5 was 6.56 x 10(-6) and 3.46 x 10(-6) respectively, which were both acceptable. PMID- 22497167 TI - [Determination of nine hazardous elements in textiles by inductively coupled plasma optical emission spectrometer after microwave-assisted dilute nitric acid extraction]. AB - Textiles are easily contaminated by heavy metals in the course of processing. In order to monitor the quality of textiles, a new method was developed for simultaneous determination of arsenic, antimony, lead, cadmium, chromium, cobalt, copper, nickel and mercury in textiles by inductively coupled plasma optical emission spectrometry (ICP-OES) after microwave-assisted dilute nitric acid extraction. After optimizing extraction conditions, we ultimately selected 5% nitric acid as extractant and 5 min as extraction time with the extraction temperature of 120 degrees C and instrument power of 400W in the microwave assisted extraction procedure. Nine hazardous elements were detected sequentially by ICP-OES. The results showed that the detection limits were 0.3-15 microg x L( 1) and the recoveries 73.6%-105% with the RSDs (n = 3) of 0.1%-3%. The proposed method was successfully used to determine nine elements in cotton, wool, terylene and acrylic. PMID- 22497168 TI - [The application of atomic absorption spectrometry in automatic transmission fault detection]. AB - The authors studied the innovative applications of atomic absorption spectrometry in the automatic transmission fault detection. After the authors have determined Fe, Cu and Cr contents in the five groups of Audi A6 main metal in automatic transmission fluid whose travel course is respectively 10-15 thousand kilometers, 20-26 thousand kilometers, 32-38 thousand kilometers, 43-49 thousand kilometers, and 52-58 thousand kilometers by atomic absorption spectrometry, the authors founded the database of primary metal content in the Audi A6 different mileage automatic transmission fluid (ATF). The research discovered that the main metal content in the automatic transmission fluid increased with the vehicles mileage and its normal metal content level in the automatic transmission fluid is between the two trend lines. The authors determined the main metal content of automatic transmission fluid which had faulty symptoms and compared it with its database value. Those can not only judge the wear condition of the automatic transmission which had faulty symptoms but also help the automobile detection and maintenance personnel to diagnose automatic transmission failure reasons without disintegration. This reduced automobile maintenance costs, and improved the quality of automobile maintenance. PMID- 22497169 TI - [The chemical and structural analysis of Tibetan medicine Fanshi]. AB - The element and microstructure of Tibetan medicine Fanshi were investigated, in order to explore the material basis of Fanshi. X-ray fluorescence spectroscope (XRF), inductively coupled plasma optical emission spectrometer (ICP-OES) and X ray diffraction (XRD) were used to assay the Fanshi samples from different Tibetan regions. XRF and ICP-OES analysis showthat the main elements in Fanshi are Ca, O and C, but also contain some kinds of minor elements, such as Mg, Al, Na, Si, K, Ag, Ba, Fe, Mn, S, Sr, Zn and so on. XRD analysis shows that the main material structures in Fanshi are (Mg(x)Ca(1-x))CO3 (rhombohedral, R-3c) and CaCO3 (rhombohedral, R-3c), but also exists a small quantity of CaCO3 (orthorhombic, Pmcn), SiO2 (hexagonal, P3221), etc. The data of element and structure in Tibetan medicine Fanshi have been acquired by XRD, ICP-OES and XRD, and that is beneficial to exploring the material basis of Fanshi. PMID- 22497170 TI - [Analysis of 14 elements for Jinhua bergamot by X-ray fluorescence spectrometry and elemental analyser]. AB - The content of the elements C, H, O and N in Jinhua bergamot was analysed by using Vario III elemental analyser, the bergamot sample was scanned by using X ray fluorescence spectrometer with PW2400 wavelength dispersion, and the content of the elements Mg, Al, P, S, Cl, K, Ca, Mn, Fe and Sr was analysed by using IQ+ analytical method. It turned out that the result is more ideal if the content of the elements C, H, O and N is processed as fix phase, and the analytical result is more ideal if, to prevent the sample skin from coming off, the sample is wrapped with mylar film with the film coefficient adjusted. PMID- 22497171 TI - [Rapid identification of variable star spectrum based on information entropy]. AB - Variable star is very important for mankind studying cosmic origin and evolution. For studying variable star, the chief difficulty results from the filtration and identification of variable star, that is how to validly identify variable star spectra from large high-dimensional star spectra data. The traditional outlier definition tries to find the difference between the outlier data and the general model by different ways, and then the result is quantitatively analyzed and filtrated. However, the time complexity of this method is over size and its results are inscrutable and unaccountable. Information entropy is a measure of the uncertainty associated with a random variable. In the present paper, information entropy is imported as the standard of dataset common mode. A novel method is proposed to identify the variable star spectrum rapidly based on information entropy. The time complexity of this method is observably reduced and the man-made impact is effectively overcome. The preliminary experimental results based on Sloan star spectrum data show that the method is workable for rapid identification of variable star spectrum. PMID- 22497172 TI - [Study on uniformity of optical field in static Fourier transform spectrometer]. AB - Since the Fourier transform spectrometer based on multi-micro mirrors samples the interferogram image which corresponds to each OPD in the transverse optical field, the spatial distribution of the irradiance has much effect on the quality of the interferogram. In the present paper, distribution function is introduced in this spectrometer system. By means of simulation, the contrast of the interferogram modulated by distribution function is depressed in the fringe area and the concomitant line appears in the spectrum. According to theory analysis, the decline of the contrast lies on the distribution function which scans the interferogram periodically. And the concomitant line is the effect of the spectrum shift, which belongs to the modulation function. Finally, the difference image and conversed recovery arithmetic are proposed. Via the simulation, the conversed recovery arithmetic can recover the interferogram and the spectrum evidently. PMID- 22497173 TI - [Solving resolution of diffraction gratings using coefficients of Zernike polynomials]. AB - It is hard and costly to test resolution directly, because the focal length of testing equipment could be nearly ten meters. Solving resolution by diffraction wavefront aberration indirectly is an effective solution to this problem. A normalization model of solving resolution using fitting coefficients of Zernike polynomials was established based on the spectral imaging theory of Fourier optics. The relationship between resolution and wavefront aberration of diffraction gratings was illustrated by this model. Finally, a new method of testing resolution using fitting coefficients of Zernike polynomials was proposed. According to this method, the resolution of a grating is tested by ZYGO interferometer indirectly. Compared with direct method, results indicate that the error of indirect method is less than 4.22%, and this method could be an effective way to avoid the difficulty of direct method to solve resolution. Meanwhile, this method can be used in ZYGO interferometer to solve resolution by wavefront testing easily. PMID- 22497174 TI - [Spectral calibration of the hyperspectral imager based on atmosphere absorption]. AB - The hyperspectral imager is a new type remote sensor which can collect both the image and the spectral information of the scene. The objective of the spectral calibration of the hyperspectral imager is to determine the central wavelength and spectral width of each channel. The spectral sampling interval of the hyperspectral imager calculated and the atmosphere absorption of the atmosphere were used to calibrate the central wavelength and spectral width of the channels of the hyperspectral imager in the present article. Comparison was made between the spectral calibration result and a spectrometer which has high spectral resolution and the results were improved. The results indicate that the spectral calibration of this method can achieve precision of 1 nm. PMID- 22497175 TI - [Research on the non-source temperature calibration of Multispectral pyrometer]. AB - At present, Multispectral pyrometer used in high-temperature measurement has already had high resolution and high signal to noise ratio. However, the non source temperature (higher than 3 000 degrees C) calibration falls far behind the development of multispectral pyrometer and has already seriously hindered the precision and application range of the pyrometer. In order to break through the limitation of calibration of non-source temperature, a new calibration method was put forward in the present paper. The temperature-voltage (T-U) model was formed based on power function where output voltage U of the multispectral pyrometer was derived from its corresponding known temperature point. Based on the model, derivative least square method was used to obtain the parameters of the model to realize the non-source temperature calibration. Both theoretical and experimental data proved the efficiency and precision of the calibration method. In addition, within the spectral range of high-temperature measurement pyrometer (0.4-1.1 microm), the range of non-source temperature calibration with precision better than 3 per thousand, 1% and 3% respectively have been divided theoretically. PMID- 22497176 TI - [Research on the interlaced encoding pixels in Hadamard transform spectral imager based on DMD]. AB - The key innovation in Hadamard transform spectral imager (HTSI) introduced recently is the use of digital micro-mirror device (DMD) to encode spectral information. However, it brings some new problems for us to solve synchronously. An interlaced encoding phenomenon caused by the application of DMD to our HTSI was investigated and analyzed. These interlaced encoding pixels were not encoded based on Hadamard transform; therefore they should be processed specially in spectrum recovery. To improve the quality of the recovered spectral images, a positioning method and a decoding method for the interlaced encoding pixels were proposed. In our experiment, we first directed a beam of laser into our HTSI to fill the field of view and labeled the positions of the interlaced encoding pixels. Then we recorded two groups of the encoded images of the target by changing the positions of all the encoding channels on the DMD. The interlaced encoding pixels could be distinguished easily by observing the number of non-zero constants and zero elements in a column vector which is made up of the gray values of a pixel of the encoded images in sequence. The interlaced encoding pixels of the first group of the encoded images turned into the normal Hadamard encoding pixels of the second group of the encoded images. The interlaced encoding pixels of the first group of the encoded images can be decoded through applying inverse Hadamard transform to the corresponding pixels of the second group of the encoded images. The experimental results prove the feasibility of the decoding method. PMID- 22497177 TI - [Small imaging spectrometer for the inspection of fruit quality]. AB - Imaging spectrometer can acquire spatial and spectral information of the target at the same time, achieve high-precision, non-destructive, non-contamination and large area instantaneous inspection of the fruit. In order to get the imaging spectrum of the fruit, compact imaging spectrometer with convex grating produced by self was designed, it has the advantages of good performance, small volume and low weight, its resolution at 578 nm is 2.1 nm, and spectral line bend and chromatic distortion are both smaller than 0.6%. Laboratory test of the imaging spectrometer and the experiment of getting the imaging spectrum of apple were done, and the result shows that the imaging spectrometer satisfies the design requirement and can acquire the imaging spectrum of apple rapidly with high precision for inspection of fruit quality. PMID- 22497178 TI - [Cell-assisted lipotransfer for breast augmentation: a report of 18 patients]. AB - OBJECTIVE: To evaluate the clinical effect of cell-assisted lipotransfer (CAL) for breast augmentation. METHODS: 18 patients accepted breast augmentation using CAL. 10 patients completed 6-month follow-up and were involved in the study. The adipose tissue was harvested from patients' thighs, flanks and lower abdomen with Lipokit. After standing, 250 ml fatty portion and 500 ml fluid portion of suction aspirates were processed according to the procedures reported in reference. Flow cytometry was used to detect the percentage of adipose-derived stem cells(ADSCs) in distilled stromal vascular fraction (SVF). The differentiation function of cultured cells also was assessed. The breast volume and images were evaluated by using MRI before operation, 3 and 6 months after operation. The breast volume was marked as V0, V3 and V6 respectively. The resorption rate of transplanted adipose tissue for each breast was calculated and marked as R3 and R6. RESULTS: Averagely, the percentage of ADSCs in freshly distilled SVF was 41.67%. The in vitro cultured cell grew well and could differentiate into fat, bone and cartilage. Statistics showed that V0, V3 and V6 was (416.19 +/- 40.43) ml, (551.72 +/- 59.86) ml and (538.81 +/- 68.35) ml respectively. R3 and R6 was (51.20 +/- 11.96)% and (54.22 +/- 12.73)%. There was significant difference between V3 and V0 (P < 0.05), V6 and V0. However, no significant difference was showed between V3 and V6 or R3 and R6. In addition, no cyst or calcification was seen in all MRI images. CONCLUSIONS: In process of breast augmentation using CAL, the distilled SVF contains 41.67% ADSCs which have adipogenic, osteogenic and chondrogenic function. Within 3-month post-operation, the breast volume decreases obviously but the volume sustains after that. Compared with the preoperative volume, the 6-month postoperative volume is significantly increased and the breasts' contour is improved greatly. This study indicates that CAL is a safe and effective way for breast augmentation. PMID- 22497179 TI - [A new procedure to correct the crow's feet by covering the orbicularis oculi muscles with the superficial temporal fascia flap in rhytidectomy]. AB - OBJECTIVE: To explore an ideal procedure with more lasting aesthetic results by covering the orbicularis oculi muscles with the superficial temporal fascia flap in rhytidectomy, which can help to correct the crow's feet successfully. METHODS: During rhytidectomy, dissection was performed subcutaneously and also under pericranium and superficial temporal fascia at temporal area. Then the superficial temporal fascia flap was formed by cutting between pericranium and superficial temporal fascia. The fascia flap was reversed to cover the lateral orbicularis oculi muscle with fixation. RESULTS: From May 2004 to May 2010, 18 cases were treated with a follow-up period of 6-12 months. The crow's feet was corrected better with long lasting results, compared with conventional rhytidectomy. No complication happened. CONCLUSIONS: The crow's feet can be corrected markedly with long lasting results by covering the orbicularis oculi muscles with the superficial temporal fascia flap in rhytidectomy. PMID- 22497180 TI - [Zygomatic reduction with midface L-shaped osteotomy and its effect on the maxillary sinus]. AB - OBJECTIVE: To investigate the result of zygomatic reduction with midface L-shaped osteotomy through intraoral approach. METHODS: From June 2006 to Aug. 2009, 67 cases received zygomatic reduction with midface L-shaped osteotomy through intraoral approach. 52 cases underwent CT scan before operation and 12 months after operation. The images were analyzed by software GE AW 4.1 for evaluation of clinical effect, maxillary sinus change and complication. SAS 6.12 software was applied for one-way ANOVA. RESULTS: Satisfactory results were achieved in all the patients. The volume of maxillary sinus at left and right side was (21233.96 +/- 4455.04) mm3, and (22020.64 +/- 3663.82) mm3, respectively before operation: (17840.91 +/- 4381.03) mm3 and (18511.85 +/- 3466.24) mm3 respectively 12 months after operation, showing a significant difference between them (P<0.05). No infection or dental pulp necrosis happened. CONCLUSIONS: Good results can be achieved with intraoral L-shaped osteotomy for zygomatic reduction. Exposure of maxillary sinus would not cause any complication. PMID- 22497181 TI - [Clinical application of mandibular osteomuscular flap pedicled with temporalis to repair maxillary bone defect]. AB - OBJECTIVE: To evaluate the clinical effect of mandibular osteomuscular flap pedicled with temporalis to repair maxillary defect. METHODS: From March 2008 to May 2010, ten cases of maxillary defects resulted from malignant tumor resection were treated with mandibular osteomuscular flap pedicled with temporalis. Ten cases of malignant tumor included six cases of Squamous cell carcinoma,one case of duct carcinoma, osteosarcoma, chondrosarcoma and malignant melanoma. One case was repaired by mandibular osteomuscular flap only, nine cases were repaired by mandibular osteomuscular flaps combined with other soft tissue flaps. RESULTS: All the 10 mandibular osteomuscular flaps survived completely with no complication. The patients were followed up for 12 to 36 months, with an average of 18 months. Satisfactory appearance and complete functional restoration were achieved except for one case of chondrosarcoma recurrence. CONCLUSIONS: The mandibular osteomuscular flap pedicled with temporalis is safe and easily performed with less complication. It is an ideal method for repairing the maxillary defect. PMID- 22497182 TI - [Management after expanded flap ulceration during auricular reconstruction]. AB - OBJECTIVE: To investigate the feasibility of Brent I methods for total auricular reconstruction when expanded flap ulceration happened. METHODS: The expanded flaps in the retroauricular region ulcerated during total auricular reconstruction in 8 patients with microtia. Then the expanders were removed and autologous rib cartilage frameworks were implanted. Brent I techniques for the total auricular reconstruction were employed. RESULTS: All the wounds in 8 patients with microtia healed primarily. The expanded flaps survived completely. The reconstructed ears had good shape and appearance with little hair. The size, shape and position of reconstructed ears were coordinated with the face. CONCLUSIONS: Brent I technique is an alternative method for total auricular reconstruction when the expanded flap ulceration occurs during total ear reconstruction. PMID- 22497183 TI - [Muscles reposition in correction of nasal deformity after unilateral cleft lip]. AB - OBJECTIVE: To investigate the effective method for correction of nasal deformity after unilateral cleft lip. METHODS: 50 cases with secondary nasal deformity after unilateral cleft lip were retrospectively analyzed. All the patients underwent nasal and lip muscle reposition operation to restore the symmetry of nasal alar. RESULTS: The nasal deformity was greatly improved in all the 50 cases. The malposition of nasal column and nasal alar was corrected. The symmetry was markedly improved. The measurement before and after operation showed significant difference ( P<0.05). CONCLUSIONS: The reasons of secondary nasal deformity after unilateral cleft lip are complicated. The muscle reposition operation can effectively improve the deformity. PMID- 22497184 TI - [Modified sural neurocutaneous vascular flap based on single dominant perforator arising from peroneal artery for coverage of defects over Achilles tendon]. AB - OBJECTIVE: To report the operative techniques and clinical results of specially designed sural neurocutaneous vascular flap pedicled on a dominant perforator (the diameter > or = 0.8 mm) of the peroneal artery for coverage of soft tissue defects overlying the Achilles tendon. METHODS: An approximately rectangular sural neurocutaneous vascular flap pedicled on the lowest dominant perforator arising from the peroneal artery was designed and harvested to repair defects over the Achilles tendon. The pedicle was located at a certain part of the flap, which divided the flap into the distal and the proximal parts. After the tendon was repaired, the flap was rotated 180 degrees based on the perforator and the position of the distal and proximal parts of the flap was changed to cover the defects and part of the donor site respectively. In most cases, skin graft was not needed. RESULTS: The modified flaps were applied in 15 cases. All flaps (ranged from 13 cm x 15 cm - 18 cm x 9 cm ) were transplanted successfully without necrosis, and no vascular problems occurred. Following up for 10-17 months showed both satisfactory functional and cosmetic results. CONCLUSIONS: The modified flap has reliable blood supply and the special design provides nearly normal outline of the ankle which favorites shoe wearing. It' s an excellent option for covering defects overlying the Achilles tendon. PMID- 22497185 TI - [Repair of skin defects at fingers by digital dorsal flaps based on vascular network]. AB - OBJECTIVE: To investigate the therapeutic effect of digital dorsal flap based on vascular network for skin defects at fingers. METHODS: From August 2005 to August 2010, 49 cases with 61 skin defects at fingers were treated with the digital dorsal flaps, including 19 at the index fingers, 19 at the middle fingers, 16 at the ring fingers and 3 at the little fingers. The defects were 42 at the distal end, 12 at the middle segment and 7 at the proximal segment. The flaps size ranged from 27 mm x 20 mm to 10 mm x 8 mm. RESULTS: 61 flaps in 49 cases survived completely. 52 fingers were followed up for 6-22 months. The aesthetic and functional results were both satisfactory. The flaps sensation was graded as S3, with a discrimination distance of 6-9 mm (median, 7.6 mm). No complication happened in donor sites. CONCLUSIONS: The digital dorsal flap based on vascular network has reliable blood supply with less morbidity to the main artery. It is safe and easily performed with good effect for skin defect at finger. PMID- 22497186 TI - [The reconstruction of erectile function with rabbit segmental gracilis musculocutaneous flap]. AB - OBJECTIVE: To design an animal model for the reconstruction of penile erectile function with segmental gracilis musculocutaneous flap. METHODS: The rabbit gracilis muscle was split longitudinally into two approximately equal halves completely according to the principles of muscle compartmentalization. An animal model was designed for the reconstruction of erectile function with segmental musculocutaneous flap based on the anterior gracilis muscle bundle, with a silicone stick implanted as a supporter. A multi-channel physiological signal acquisition and processing system were used to stimulate the reconstructed penis and its CMAP was measured synchronously. RESULTS: When its nerve was electric stimulated, the muscle bundle contracted, which made the reconstructed penis moving accordingly. It satisfactorily simulated the way of a normal penis's erection. CONCLUSIONS: The reconstructed penis with rabbit segmental gracilis musculocutaneous flap according to the principles of muscle compartmentalization has achieved the erectile function satisfactorily. It has met the requirements of both improving reconstructive penis's appearance and retaining muscle' s contractive function. PMID- 22497187 TI - [The tumorigenicity of immortalized cells differentiated from mouse embryonic stem cells]. AB - OBJECTIVE: To discuss the tumorigenicity of immortalized endothelial cells differentiated from embryonic stem cells. METHODS: The embryoid bodies (EB) formed in vitro from embryonic stem cells, were induced to differentiate into many "round cells" (the precursor of endothelial cells). These "round cells" later formed the vascular tube-like structures. To immortalize these cells, human telomerase reverse transcriptase (hTERT) cDNA was transfected into "round cells" by lipofectin, RT-PCR and immunocytochemistry were used to evaluate the immortalized cells. And the tumorigenicity of these cells were evaluated by being injected into nude mice subcutaneously. RESULTS: 95% of these transfected cells expressed Flk-1, CD34 and vWF, and could proliferate in large quantity in vitro (cell number was doubled in 2 days, and increased 12 times in 3 days), and were able to form tubular structures. CONCLUSIONS: These results suggest that hTERT cDNA transfection can immortalize induced endothelial cells and tumorigenicity is found after immortalized cells are injected into nude mice subcutaneously. PMID- 22497189 TI - [Hair follicle regeneration by injection of follicular cells]. AB - OBJECTIVE: To explore the mechanisms of hair follicle regeneration by injection of follicular cells isolated from murine skin. METHODS: Epidermis was peeled off from the dermis of 3-5 d C57BL/6J mouse by 0.2% Dispase digestion at 37 degrees C for 2 hours. Dermis was cut into small pieces and digested in 0.2% collagenase at 37 degrees C for 30 minute with low speed stirring to isolate hair follicles from dermis. Hair follicles were collected through filtration, low-speed centrifugation and density gradient centrifugation. Collagenase and trypsin were added to digest hair follicles into dissociated cells which were marked by Dio and injected into the nude mouse skin. RESULTS: 2 d after intradermal injection of hair follicle cells, a cyst was formed containing lots of round and elliptical cells and homogeneous eosin stained cell-free tissues. The cyst wall was composed of many spindle shaped fibroblast cells and showed sparsely localized green fluorescence. The contents of the cyst showed bright green fluorescence. 4 d after injection, the skin became slightly thicken with grey appearance, a lots of hair follicles formed with black bulb. 1 weeks after injection, the injection site became black and evaluated with a lots of black hair follicles and hyperproliferation of capillary blood. Newly formed hair follicles showed bright green fluorescence. 3 weeks after injection, a cyst containing lots of black hairs formed in the injection site. Newly formed hair follicles showed positive for Dio. Sebaceous gland can be seen accompanied with hair follicles. 6 weeks after injection, the cyst contained lots of sheded club hair shafts and hair follicles on the stage of anagen. Cultured follicular cells and injection below 1 x 10(5) failed to regenerate hairs. While the regenerated hair follicle was few when the hair follicle cells were injected subcutaneously. CONCLUSIONS: Follicular cells can aggregate spontaneously and develop synergistically into hair follicles with normal growth cycle after implantation. The regeneration depends on the interactions between follicular cells, as well as on the recipient sites and cell numbers. PMID- 22497188 TI - [Preliminary study on inhibition of the hair follicle development by siRNA targeting Wnt10b in the cultured rat embryonic skin]. AB - OBJECTIVE: To investigate whether the suppression of Wnt10b by siRNA could prevent the development of hair follicle in the cultured rat embryonic skin. METHODS: siRNA-Wnt10b was synthesized by chemosynthesis method. The dorsal skin of SD rat at embryos were cultured in DMEM in the presence of different percentage of interfering RNA targeting Wnt10b. Wnt10b/beta-catenin expression was analyzed by real-time PCR everyday and by Western blot on the third day. The cultured embryonic skin underwent paraffin embedding, section, HE staining on the third day,in which the number of de novo hair follicle was calculated and statistically analyzed. RESULTS: Wnt10b gene in the cultured embryonic skin could be knocked down with the siRNA-based method. Beta-catenin mRNA was not greatly influenced by the downregulation of Wnt10b mRNA. The number of de novo hair follicle placode in cultured embryonic skin decreased, along with the downregulation of Wnt10b and beta-catenin proteins expression. CONCLUSIONS: The downregulation of Wnt10b mRNA and protein by siRNA reduces the number of de novo hair follicle placode in the cultured rat embryonic skin. Wnt10b may control cytoplasm beta-catenin concentration at the protein level. PMID- 22497190 TI - [Preliminary study of in vitro chondrogenesis by co-culture of chondrocytes and adipose-derived stromal cells]. AB - OBJECTIVE: To explore the feasibility of in vitro chondrogenesis by co-culture of chondrocytes and adipose-derived stromal cells (ADSCs) so as to confirm the hypothesis that chondrocytes can provide chondrogenic microenvironment to induce chondrogenic differentiation of ADSCs. METHODS: Human ADSCs and porcine auricular chondrocytes were in vitro expanded respectively and then were mixed at the ratio of 7:3 (ADSCs: chondrocytes). 200 microl mixed cells (5.0 x 10(7)/ml) were seeded onto a polyglycolic acid/polylactic acid (PGA/PLA) scaffold, 8 mm in diameter and 2 mm in thickness, as co-culture group. Chondrocytes and ADSCs with the same cell number were seeded respectively onto the scaffold as positive control group and negative control group. 200 microl chondrocytes (1.5 x 10(7)/ml) were seeded as low concentration chondrocyte group. There were 6 specimens in each group. All specimens were harvested after in vitro culture for 8 weeks in DMEM plus 10% FBS. Gross observation, histology, immunohistochemistry, wet weight measurement and glycosaminoglycan (GAG) quantification were used to evaluate the results. Multiple-sample t-test statistics analysis was done to compare the difference of wet weight and glycosaminoglycan(GAG) content between the groups. RESULTS: Cells in all groups had fine adhesion to the scaffold and could secrete extracellular matrix. In co-culture group and positive control group, cell-scaffold constructs could maintain the original size and shape during in vitro culture. At 8 weeks, cartilage-like tissue formed in gross appearance and histological features, and abundant type II collagen could be detected by immunohistochemistry. Wet weight and glycosaminoglycan(GAG) content of co-culture group were respectively (174 +/- 12) mg and (7.6 +/- 0.4) mg. There were respectively 75% (P < 0.01) and 79% (P<0.01) of those of positive control group. In negative control group, however, constructs shrunk gradually without mature cartilage lacuna in histology. In low concentration chondrocyte group, constructs also shrunk obviously with small amount of cartilage formation at the edge area of the construct, and wet weight was (85 +/- 5) mg, which was 37% (P<0.01) of that of positive control group. CONCLUSIONS: Chondrocytes can provide chondrogenic microenvironment to induce chondrogenic differentiation of ADSCs and thus promote the in vitro chondrogenesis of ADSCs. PMID- 22497191 TI - [Construction of scaffold with human extracellular matrix from adipose tissue]. AB - OBJECTIVE: To investigate the feasibility of constructing scaffold for tissue engineering with human extracellular matrix from adipose tissue. METHODS: Fresh human adipose tissue was obtained by liposuction in 7 women who undergone liposuction. One part of the fat was used to isolate the adipose-derived stem cells (ADSCs), the other part was used to extract human extracellular matrix powder. After removing blood and oil components, the tissue was homogenized, centrifuged, freeze-dried, and crushed to powder by instrument. The structure of human ECM powder was observed with electron microscopy. The ADSCs were seeded and attached to the human extracellular matrix powder before and after labeled with fluorescent DiI, respectively. The adhesion rate was detected. The adhesion and growth of ADSCs were observed with Fluorescence microscope. The adhesion rate before and after DiI labeling was analyzed statistically with two-sample test of SPSS 13.0. RESULTS: The ADSCs and human extracellular matrix powder were obtained successfully from adipose tissue. The ADSCs could be differentiated into adipose cells, bone cells and chondrocytes. SEM images showed that the power had both rugged and smooth surface with a porous structure characteristics. ADSCs could adhere to the scaffold easily, and the adhesion rate was (88.81 +/- 4.81)% and (86.48 +/- 4.58)% before and after DiI labeling. There was no difference between two groups. DiI labeled ADSCs were adhered to extracellular matrix scaffold and could grow in good condition. CONCLUSIONS: Human adipose tissue extracellular matrix powder was easy to obtain, with diversity in size and shape which provided excellent substrates for cell adhesion and growth. It could be an ideal adipose tissue engineering scaffold. PMID- 22497192 TI - Antiretroviral therapy (ART): a boon to people living with HIV/AIDS. PMID- 22497193 TI - Mental illness: knowledge of family members in rural and urban areas in Assam. PMID- 22497194 TI - Risk factors of seizure disorders. PMID- 22497195 TI - Stress levels among wives of alcoholics and non-alcoholics. PMID- 22497196 TI - Quality of life in the care home: a qualitative study of the perspectives of residents with multiple sclerosis. AB - PURPOSE: Care home residents with multiple sclerosis (MS) are more physically dependent than the average residents. However, little is known about their quality of life (QoL). We investigated the experiences of residents with MS using qualitative research methods and developed a conceptual model of QoL. METHODS: Twenty-one people with MS (age range 43-80 years) residing in a range of care homes were interviewed. The interviews were transcribed verbatim and analyzed using the constant comparative method. RESULTS: Four core model domains identified were as follows: (i) What the care home means to the residents, (ii) Self, (iii) Environment and (iv) Relationships. Some residents reported that care homes can relieve the burden on family, address specific environmental issues regarding safety and act as a form of social support. However, some reported isolation and difficulties adjusting to life in the care home. Having access to rehabilitation strengthened the feelings of independence within the care home. CONCLUSIONS: QoL is a broad, multidimensional construct for residents with MS. QoL measures for residents with MS should incorporate broad domains, including environmental factors. The conceptual model highlighted several areas for improving QoL of residents with MS, including more involvement of family members, encouraging independence by providing access to rehabilitation and providing support in the transition process. PMID- 22497197 TI - Furosemide-loading vestibular evoked myogenic potential testing can suggest developing bilateral involvement of unilateral Meniere's disease. AB - CONCLUSIONS: Patients with positive results of furosemide-loading vestibular evoked myogenic potential (F-VEMP) testing in the unaffected ears of unilateral Meniere's disease have a high incidence of developing bilateral lesions. OBJECTIVE: To clarify the meaning of positive results of F-VEMP testing of the unaffected ear of patients with unilateral Meniere's disease. METHODS: Twenty five patients with unilateral Meniere's disease were investigated in this study. The positive group consisted of 6 patients with positive results of F-VEMP testing in the contralateral ear and the negative group consisted of 19 patients with negative results. The incidence of contralateral involvement was compared in both groups by the Kaplan-Meier method. RESULTS: Contralateral involvement was seen in three cases (50%) in the positive group after 2, 12, and 26 months and in three cases (16%) in the negative group after 27, 56, and 78 months. The positive group had a higher incidence of contralateral involvement than the negative group (p = 0.0017, according to a log-rank test). PMID- 22497198 TI - Biological effects of decreasing RBM15 on chronic myelogenous leukemia cells. AB - RNA binding motif protein 15 (RBM15) was originally described as a 5' translocation partner of the MAL gene in t(1;22)(p13;q13)infant acute megakaryocytic leukemia. Although previous investigations have shown that Rbm15 has broad regulatory effects within murine hematopoiesis through modulating Notch induced transcriptional activation, which plays key roles in leukemogenesis, it is not clear what the functions of RBM15 are in the regulation of hematological malignancies. In the present study, we show that RBM15 expression was significantly increased in patients with blast-crisis chronic myelogenous leukemia (CML) compared with chronic-phase or accelerated-phase disease by real time reverse transcription-polymerase chain reaction (RT-PCR) assay. To further elucidate the role of RBM15 in CML, we introduced RBM15 small interfering RNA (siRNA) using pSUPER into CML cells. Fluorescence activated cell sorting (FACS), real-time RT-PCR and Western blot were used to study changes in RBM15 expression levels in transduced cells by comparing with control cells. Decreasing RBM15 levels with RNA interference could inhibit the growth and proliferation, block the cell cycle and induce apoptosis in CML cells. Knockdown of RBM15 may also act to inhibit clonogenicity and induce differentiation of CML cells along the myeloid lineage. Our studies also show that the effects of RBM15 on CML cells may be mediated, at least in part, via its effect on Notch signaling. These findings demonstrate that RBM15 does indeed play a critical role in the survival of CML cells, which may have potential application in designing molecular therapies for CML treatment. PMID- 22497199 TI - Maternal and child health disparities: considering the influence of fathers. PMID- 22497200 TI - A call to action for health disparities in boys and men: innovative research on addiction, trauma, and related comorbidities. PMID- 22497201 TI - Risk compensation: a male phenomenon? Results from a controlled intervention trial promoting helmet use among cyclists. AB - Prevention tools are challenged by risky behaviors that follow their adoption. Speed increase following helmet use adoption was analyzed among bicyclists enrolled in a controlled intervention trial. Speed and helmet use were assessed by video (2621 recordings, 587 participants). Speeds were similar among helmeted and nonhelmeted female cyclists (16.5 km/h and 16.1 km/h, respectively) but not among male cyclists (helmeted: 19.2 km/h, nonhelmeted: 16.8 km/h). Risk compensation, observed only among male cyclists, was moderate, thus unlikely to offset helmet preventive efficacy. PMID- 22497202 TI - Diameter and polarization-dependent Raman scattering intensities of semiconductor nanowires. AB - Diameter-dependent Raman scattering in single tapered silicon nanowires is measured and quantitatively reproduced by modeling with finite-difference time domain simulations. Single crystal tapered silicon nanowires were produced by homoepitaxial radial growth concurrent with vapor-liquid-solid axial growth. Multiple electromagnetic resonances along the nanowire induce broad band light absorption and scattering. Observed Raman scattering intensities for multiple polarization configurations are reproduced by a model that accounts for the internal electromagnetic mode structure of both the exciting and scattered light. Consequences for the application of Stokes to anti-Stokes intensity ratio for the estimation of lattice temperature are discussed. PMID- 22497203 TI - Association of leptin genotypes with beef cattle characteristics. AB - A single nucleotide polymorphism (C/T) in bovine leptin, resulting in an arginine to cysteine amino acid substitution (p.Arg25Cys), has previously been shown to have an impact on carcass characteristics. Given the significant energetic relationship between fat and animal efficiency, further evaluation of this SNP across larger animal populations is warranted. Of the total number of 136 286 genotyped cattle in this study, 92 112 and 53 189 were analysed for backfat and body weight measurements, respectively. Results showed a significant positive relationship (P < 0.0001) between the T allele frequency and animal backfat, with TT, CT and CC animals having estimates of 6.79 +/- 0.02, 6.49 +/- 0.01 and 6.28 +/- 0.01 mm, respectively. Calculations using rate of backfat accretion showed that animals with CC genotypes would require more days to reach 12 mm of backfat (45 days) than animals with CT (42 days) and TT (38 days) genotypes. Animal weight was also shown to be positively associated (P < 0.0001) with genotype, as animals of the TT, CT and CC genotypes weighed 484.2 +/- 0.7, 488.0 +/- 0.5 and 487.3 +/- 0.6 kg, respectively, further underscoring the effects of this SNP on key market cattle characteristics. PMID- 22497204 TI - One-step synthesis and self-assembly of metal oxide nanoparticles into 3D superlattices. AB - A simple one-pot approach based on the "benzyl alcohol route" is introduced for the fabrication of highly ordered supercrystals composed of highly uniform 3-4 nm zirconia and rare-earth stabilized zirconia nanoparticles. The as-fabricated supercrystals reach sizes larger than 10 MUm and present well-defined 3D morphologies such as flower-like, rhombic dodecahedron, and bipyramids. This system is unique in that the supercrystals are formed in one-step directly in the reaction medium where the nanoparticles are synthesized. The uniformity in nanocrystal shape and size is attributed to the in situ formation of benzoate species that directs the nanoparticle growth and assembly. The low colloidal stabilization of the benzoate-capped nanoparticles in benzyl alcohol promotes the formation of supercrystals in solution by pi-pi interaction between the in situ formed benzoate ligands attached to neighboring particles. By varying the reaction temperature and the nature of the doping the way the nanobulding blocks assemble in the supercrystals could be controlled. Standard FCC superlattice packings were found together with more unusual ones with P6/mmm and R 3m symmetries. PMID- 22497205 TI - Recombination rates across porcine autosomes inferred from high-density linkage maps. AB - Studies of the variation in recombination rate across the genome provide a better understanding of evolutionary genomics and are also an important step towards mapping and dissecting complex traits in domestic animals. With the recent completion of the porcine genome sequence and the availability of a high-density porcine single nucleotide polymorphism (SNP) array, it is now possible to construct a high-density porcine linkage map and estimate recombination rate across the genome. A total of 416 animals were genotyped with the Porcine SNP60BeadChip, and high-density chromosome linkage maps were constructed using CRI-MAP, assuming the physical order of the Sscrofa10 assembly. The total linkage map length was 2018.79 cM, using 658 meioses and 14,503 SNPs. The estimated average recombination rate across the porcine autosomes was 0.86 cM/Mb. However, a large variation in recombination rate was observed among chromosomes. The estimated average recombination rates (cM/Mb) per chromosome ranged from 0.48 in SSC1 to 1.48 in SSC10, displaying a significant negative correlation with the chromosome sizes. In addition, the analysis of the variation in the recombination rates taking 1-Mb sliding windows has allowed us to demonstrate the variation in recombination rates within chromosomes. In general, a larger recombination rate was observed in the extremes than in the centre of the chromosome. Finally, the ratio between female and male recombination rates was also inferred, obtaining a value of 1.38, with the heterogametic sex having the least recombination. PMID- 22497206 TI - Women on men's sexual health and sexually transmitted infection testing: a gender relations analysis. AB - Sexual health and sexually transmitted infection (STI) testing is typically portrayed as a women's issue amid men's estrangement from healthcare services. While the underreporting of men's STIs has been linked to masculinities, little is known about how women interpret and respond to heterosexual men's sexual health practices. The findings drawn from this qualitative study of 34 young women reveal how femininities can be complicit in sustaining, as well as being critical of and disrupting masculine discourses that affirm sexual pleasure and resistance to health help-seeking as men's patriarchal privileges. Our analysis revealed three patterns: looking after the man's libido refers to women's emphasised femininity whereby the man's preference for unprotected sex and reticence to be tested for STIs was accommodated. Negotiating the stronger sex refers to ambivalent femininities, in which participants strategically resist, cooperate and comply with men's sexual health practices. Rejecting the patriarchal double standard that celebrates men as 'studs' and subordinates women as 'sluts' for embodying similar sexual practices reflects protest femininities. Overall, the findings reveal that conventional heterosexual gender relations, in which hegemonic masculinity is accommodated by women who align to emphasised femininity, continues to direct many participants' expectations around men's sexual health and STI testing. PMID- 22497207 TI - Loss of cytosolic NADP-malic enzyme 2 in Arabidopsis thaliana is associated with enhanced susceptibility to Colletotrichum higginsianum. AB - * While photosynthetic NADP-malic enzyme (NADP-ME) has a prominent role in the C(4) cycle, the biological function of nonphotosynthetic isoforms remains elusive. Here, we analysed the link between Arabidopsis thaliana cytosolic NADP ME2 and the plant defence response. * Arabidopsis thaliana plants with wild-type and modified NADP-ME2 expression levels were analysed after elicitation with pathogen-associated molecular patterns (PAMPs) and during the interaction with the hemibiotrophic fungal pathogen Colletotrichum higginsianum. * Under normal growth conditions, the lack or gain of NADP-ME2 activity produced large changes in plant metabolite pool sizes without any effect on morphology or development. Total NADP-ME activity and NADP-ME2 transcript level were enhanced after PAMP treatment and pathogen infection. During infection with C. higginsianum, loss-of function mutants of NADP-ME2 (nadp-me2) showed enhanced susceptibility. Transient apoplastic reactive oxygen species (ROS) production after elicitation and callose papilla formation after infection were dampened in nadp-me2. Late salicylic acid (SA)-dependent and SA-independent defence responses were not affected. * Taken together, our results indicate that NADP-ME2 is an important player in plant basal defence, where it appears to be involved in the generation of ROS. Moreover, NADP-ME2 was found to be dispensable for later defence responses. PMID- 22497208 TI - Structural identification of novel oligosaccharides produced by Lactobacillus bulgaricus and Lactobacillus plantarum. AB - beta-Galactosidases (beta-Gal) of lactic acid bacteria produce oligosaccharides from lactose when suitable acceptor carbohydrates are present. This study aimed to elucidate the structure of oligosaccharides formed by galactosylation of N acetylglucosamine (GlcNAc) and fucose. Crude cellular extract of Lactobacillus bulgaricus and LacLM of Lactobacillus plantarum were used as sources of beta Gal activity. Disaccharides obtained by galactosylation of GlcNAc were identified as Gal-beta-(1->4)-GlcNAc or Gal-beta-(1->6)-GlcNAc by liquid chromatography tandem mass spectrometry (LC-MS/MS) and comparison with external standards. Trisaccharides were identified as Gal-beta-(1->6)-Gal-beta-(1->[4 or 6])-GlcNAc by LC-MS, analysis of the MS/MS spectra of selected in-source fragment ions, and their relative retention times. LC-MS analysis revealed the presence of five galactosylated fucosides, but their linkage type could not be identified, partly due to the lack of reference compounds. beta-Gal of lactic acid bacteria may serve as suitable tools for the chemoenzymatic synthesis of therapeutic oligosaccharides. PMID- 22497209 TI - Dynamics of teacher-student relationships: stability and change across elementary school and the influence on children's academic success. AB - This study modeled teacher-student relationship trajectories throughout elementary school to predict gains in achievement in an ethnic-diverse sample of 657 academically at-risk students (mean age = 6.57 years, SD = .39). Teacher reports of warmth and conflict were collected in Grades 1-5. Achievement was tested in Grades 1 and 6. For conflict, low-stable (normative), low-increasing, high-declining, and high-stable trajectories were found. For warmth, high declining (normative) and low-increasing patterns were found. Children with early behavioral, academic, or social risks were underrepresented in the normative trajectory groups. Chronic conflict was most strongly associated with underachievement. Rising conflict but not declining Conflict coincided with underachievement. The probability of school failure increased as a function of the timing and length of time children were exposed to relational adversity. PMID- 22497211 TI - Differences in distribution and regulation of astrocytic aquaporin-4 in human and rat hydrocephalic brain. AB - AIMS: Aquaporin-4 (AQP4) is the most abundant cellular water channel in brain and could be a molecular basis for a cerebrospinal fluid absorption route additional to the arachnoid villi. In the search for 'alternative' cerebrospinal fluid absorption pathways it is important to compare experimental findings with human pathophysiology. This study compares expression of AQP4 in hydrocephalic human brain with human controls and hydrocephalic rat brain. METHODS: Cortical biopsies from patients with chronic hydrocephalus (n = 29) were sampled secondary to planned surgical intervention. AQP4 in human hydrocephalic cortex relative to controls was quantified by Western blotting (n = 28). A second biopsy (n = 13) was processed for immunohistochemistry [glial fibrillary acidic protein (GFAP), CD68, CD34 and AQP4] and double immunofluorescence (AQP4 + GFAP and AQP4 + CD34). Brain tissue from human controls and kaolin-induced hydrocephalic rats was processed in parallel. Immunohistochemistry and immunofluorescence were assessed qualitatively. RESULTS: Western blotting showed that AQP4 abundance was significantly increased (P < 0.05) in hydrocephalic human brain compared with controls. AQP4 immunoreactivity was present in both white and grey matter. In human brain (hydrocephalic and controls) AQP4 immunoreactivity was found on the entire astrocyte membrane, unlike hydrocephalic rat brain where pronounced endfeet polarization was present. Endothelial AQP4 immunoreactivity was not observed. CONCLUSIONS: This study shows a significant increase in astrocytic AQP4 in human hydrocephalic cortex compared with control. Cell type specific expression in astrocytes is conserved between rat and human, although differences of expression in specific membrane domains are seen. This study addresses direct translational aspects from rat to human, hereby emphasizing the relevance and use of models in hydrocephalus research. PMID- 22497212 TI - High microsatellite and mitochondrial diversity in Anatolian native horse breeds shows Anatolia as a genetic conduit between Europe and Asia. AB - The horse has been a food source, but more importantly, it has been a means for transport. Its domestication was one of the crucial steps in the history of human civilization. Despite the archaeological and molecular studies carried out on the history of horse domestication, which would contribute to conservation of the breeds, the details of the domestication of horses still remain to be resolved. We employed 21 microsatellite loci and mitochondrial control region partial sequences to analyse genetic variability within and among four Anatolian native horse breeds, Ayvacik Pony, Malakan Horse, Hinis Horse and Canik Horse, as well as samples from indigenous horses of unknown breed ancestry. The aims of the study were twofold: first, to produce data from the prehistorically and historically important land bridge, Anatolia, in order to assess its role in horse domestication and second, to analyse the data from a conservation perspective to help the ministry improve conservation and management strategies regarding native horse breeds. Even though the microsatellite data revealed a high allelic diversity, 98% of the genetic variation partitioned within groups. Genetic structure did not correlate with a breed or geographic origin. High diversity was also detected in mtDNA control region sequence analysis. Frequencies of two haplogroups (HC and HF) revealed a cline between Asia and Europe, suggesting Anatolia as a probable connection route between the two continents. This first detailed genetic study on Anatolian horse breeds revealed high diversity among horse mtDNA haplogroups in Anatolia and suggested Anatolia's role as a conduit between the two continents. The study also provides an important basis for conservation practices in Turkey. PMID- 22497213 TI - Effects of multiple agents on epithelial differentiation of rabbit adipose derived stem cells in 3D culture. AB - Mesenchymal stem cells have been given particular attention in tissue regeneration research due to their multipotency and proliferative activity. In this study, we investigated the possibility of epithelial differentiation of rabbit adipose-derived stem cells (rASCs) in an in vitro 3D culture system. The experimental procedure was performed with different contributing factors including all-trans retinoic acid (ATRA), epidermal growth factor (EGF), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), and hydrocortisone in air-liquid interface culture, for modulating proliferation and providing a synergistic effect on epithelial differentiation of rASCs. After induction, immunofluorescence staining, western blot analysis, flow cytometry analysis, and quantitative real-time polymerase chain reaction assay have been performed to detect the expression of epithelial-specific markers and mesenchymal marker alpha-smooth muscle actin (alpha-SMA). The growth pattern and viability of cells were evaluated by transmission electron microscopy and Hoechst 33258 assay, respectively. After treated with optimized induction medium (including 2.5 MUM ATRA, 20 ng/mL EGF, 10 ng/mL KGF, 10 ng/mL HGF, and 0.5 MUg/mL hydrocortisone), rASCs were observed to display a stratified epithelial-like morphology, with the expression of cytokeratin 19 and cytokeratin 13 in 63.69%+/-2.63% and 22.17%+/ 1.51%, respectively, and the relative expression level of cytokeratin 19 increased to 3.152 compared with 0.151 before induction. The expression of alpha SMA decreased to 19.40%+/-1.45% after induction, but almost no expression of involucrin was detected. The results showed that the establishment of an epithelial-specific microenvironment may be a feasible way for epithelial differentiation of ASCs in vitro, and provided an alternative for research on epithelium regeneration. PMID- 22497214 TI - Forging isopeptide bonds using thiol-ene chemistry: site-specific coupling of ubiquitin molecules for studying the activity of isopeptidases. AB - Chemical methods for modifying proteins can enable studies aimed at uncovering biochemical function. Herein, we describe the use of thiol-ene coupling (TEC) chemistry to report on the function of branched (also referred to as forked) ubiquitin trimers. We show how site-specific isopeptide (Nepsilon-Gly-L homothiaLys) bonds are forged between two molecules of Ub, demonstrating the power of TEC in protein conjugation. Moreover, we demonstrate that the Nepsilon Gly-L-homothiaLys isopeptide bond is processed to a similar extent by deubiquitinases (DUBs) as that of a native Nepsilon-Gly-L-Lys isopeptide bond, thereby establishing the utility of TEC in the generation of Ub-Ub linkages. TEC is then applied to the synthesis of branched Ub trimers. Interrogation of these branched derivatives with DUBs reveals that the relative orientation of the two Ub units has a dramatic impact on how they are hydrolyzed. In particular, cleavage of K48C-linkages is suppressed when the central Ub unit is also conjugated through K6C, whereas cleavage proceeds normally when the central unit is conjugated through either K11C or K63C. The results of this work presage a role for branched polymeric Ub chains in regulating linkage-selective interactions. PMID- 22497215 TI - Rapid screening for the mitochondrial DNA C1494T mutation in a deaf population in China using real-time quantitative PCR. AB - CONCLUSION: Real-time quantitative polymerase chain reaction (qPCR) with a TaqMan minor groove binding (MGB) probe is useful for large-scale screening for the C1494T mutation. The mitochondrial DNA(mtDNA) C1494T mutation has a low carrier frequency in Chinese patients with nonsyndromic hearing loss. OBJECTIVE: To develop a simple, rapid, and reliable real-time qPCR assay based on TaqMan technology using a new MGB probe for detecting the mtDNA C1494T mutation directly, and to investigate the carrier frequency in nonsyndromic deaf Chinese subjects. METHODS: A TaqMan-MGB probe was constructed. Peripheral blood samples were collected from 3133 nonsyndromic deaf patients and genomic DNA was extracted. A real-time qPCR using MGB probes (wild-type) in a single tube was used to detect the mtDNA C1494T mutation. The results were then compared to the DNA sequence of the PCR products. RESULTS: A total of 13 of 3133 (0.4%) Chinese nonsyndromic hearing loss patients were C1494T-positive. The results of the TaqMan-MGB probe method were consistent with those of sequencing. PMID- 22497217 TI - Mirror images as naturally competing conformations in protein folding. AB - Evolution has selected a protein's sequence to be consistent with the native state geometry, as this configuration must be both thermodynamically stable and kinetically accessible to prevent misfolding and loss of function. In simple protein geometries, such as coiled-coil helical bundles, symmetry produces a competing, globally different, near mirror image with identical secondary structure and similar native contact interactions. Experimental techniques such as circular dichroism, which rely on probing secondary structure content, cannot readily distinguish these folds. Here, we want to clarify whether the native fold and mirror image are energetically competitive by investigating the free energy landscape of three-helix bundles. To prevent a bias from a specific computational approach, the present study employs the structure prediction forcefield PFF01/02, explicit solvent replica exchange molecular dynamics (REMD) with the Amber94 forcefield, and structure-based simulations based on energy landscape theory. We observe that the native fold and its mirror image have a similar enthalpic stability and are thermodynamically competitive. There is evidence that the mirror fold has faster folding kinetics and could function as a kinetic trap. All together, our simulations suggest that mirror images might not just be a computational annoyance but are competing folds that might switch depending on environmental conditions or functional considerations. PMID- 22497216 TI - Interactions of intermediate semiquinone with surrounding protein residues at the Q(H) site of wild-type and D75H mutant cytochrome bo3 from Escherichia coli. AB - Selective (15)N isotope labeling of the cytochrome bo(3) ubiquinol oxidase from Escherichia coli with auxotrophs was used to characterize the hyperfine couplings with the side-chain nitrogens from residues R71, H98, and Q101 and peptide nitrogens from residues R71 and H98 around the semiquinone (SQ) at the high affinity Q(H) site. The two-dimensional ESEEM (HYSCORE) data have directly identified N(epsilon) of R71 as an H-bond donor carrying the largest amount of unpaired spin density. In addition, weaker hyperfine couplings with the side chain nitrogens from all residues around the SQ were determined. These hyperfine couplings reflect a distribution of the unpaired spin density over the protein in the SQ state of the Q(H) site and the strength of interaction with different residues. The approach was extended to the virtually inactive D75H mutant, where the intermediate SQ is also stabilized. We found that N(epsilon) of a histidine residue, presumably H75, carries most of the unpaired spin density instead of N(epsilon) of R71, as in wild-type bo(3). However, the detailed characterization of the weakly coupled (15)N atoms from selective labeling of R71 and Q101 in D75H was precluded by overlap of the (15)N lines with the much stronger ~1.6 MHz line from the quadrupole triplet of the strongly coupled (14)N(epsilon) atom of H75. Therefore, a reverse labeling approach, in which the enzyme was uniformly labeled except for selected amino acid types, was applied to probe the contribution of R71 and Q101 to the (15)N signals. Such labeling has shown only weak coupling with all nitrogens of R71 and Q101. We utilize density functional theory-based calculations to model the available information about (1)H, (15)N, and (13)C hyperfine couplings for the Q(H) site and to describe the protein-substrate interactions in both enzymes. In particular, we identify the factors responsible for the asymmetric distribution of the unpaired spin density and ponder the significance of this asymmetry to the quinone's electron transfer function. PMID- 22497219 TI - Benefits of predischarge echocardiography service for postnatal heart murmurs. AB - AIM: To review the findings and outcomes of predischarge echocardiography service for postnatal heart murmurs provided by neonatologists. METHODS: We retrospectively reviewed all predischarge echocardiograms performed on babies from the postnatal wards (PNW) over the last 3 years. We evaluated the indications, median age, findings and outcome. RESULTS: A total of 408 echocardiograms were performed on 350 babies on the PNW. The most common indication was presence of a murmur (58%). In babies with a heart murmur, 26% had a normal echocardiogram, 2% had major structural heart defects, 38% had minor structural heart defects and 34% had transient circulatory changes. 32% were discharged with no follow-up, 28% were followed up in the local cardiac clinic and 40% were referred to the cardiologist. CONCLUSION: Predischarge echocardiography service for postnatal heart murmurs provided by neonatologists has the benefit of providing an early diagnosis, counselling of the parents and arranging appropriate follow-up. It helps to triage the referrals to the cardiologist. We felt that we were able to alleviate parental anxieties by providing a definitive diagnosis and written information prior to discharge from hospital. We strongly believe that this service should only be provided by those appropriately trained and skilled in echocardiography. PMID- 22497218 TI - The missing link in coenzyme A biosynthesis: PanM (formerly YhhK), a yeast GCN5 acetyltransferase homologue triggers aspartate decarboxylase (PanD) maturation in Salmonella enterica. AB - Coenzyme A (CoA) is an essential cofactor for all forms of life. The biochemistry underpinning the assembly of CoA in Escherichia coli and other enterobacteria is well understood, except for the events leading to maturation of the L-aspartate alpha-decarboxylase (PanD) enzyme that converts pantothenate to beta-alanine. PanD is synthesized as pro-PanD, which undergoes an auto-proteolytic cleavage at residue Ser25 to yield the catalytic pyruvoyl moiety of the enzyme. Since 1990, it has been known that E. coli yhhK strains are pantothenate auxotrophs, but the role of YhhK in pantothenate biosynthesis remained an enigma. Here we show that Salmonella enterica yhhK strains are also pantothenate auxotrophs. In vivo and in vitro evidence shows that YhhK interacts directly with PanD, and that such interactions accelerate pro-PanD maturation. We also show that S. enterica yhhK strains accumulate pro-PanD, and that not all pro-PanD proteins require YhhK for maturation. For example, the Corynebacterium glutamicum panD(+) gene corrected the pantothenate auxotrophy of a S. enterica yhhK strain, supporting in vitro evidence obtained by others that some pro-PanD proteins autocleave at faster rates. We propose the name PanM for YhhK to reflect its role as a trigger of pro PanD maturation by stabilizing pro-PanD in an autocleavage-prone conformation. PMID- 22497220 TI - Factors which predict safe extubation in the operating room following cardiac surgery. AB - BACKGROUND: Extubation in the operating room (OR) after cardiac surgery is hampered by safety concerns, psychological reluctance, and uncertain economic benefit. We have studied the factors affecting the feasibility of extubation in the OR after cardiac surgery and its safety. METHODS: The outcomes of 78 patients extubated in the OR after open heart surgery were retrospectively compared to a matched control group of 80 patients with similar demographics, co-morbidities, and operative procedures, that were performed over the same time period, but extubated in the intensive care unit (ICU) following a standard weaning protocol. Variables collected included the incidence of subsequent unplanned tracheal reintubation in the ICU, postoperative complications, need for mediastinal re exploration, surgical and OR times, and ICU and hospital lengths of stay. RESULTS: Out of a total of 372 cardiac procedures performed during the designated time frame, 78 (21%) resulted in extubation in the OR, mostly after off-pump coronary revascularization (41%) and aortic valve replacement (19.4%). Preoperative hypertension, EF >=30%, off-bypass revascularization and shorter surgical times increased the likelihood of extubation in the OR. Extubation in the OR did not increase perioperative morbidity and mortality rates, but decreased the length of ICU and hospital stays. The incidence of unanticipated subsequent tracheal intubation in the ICU was comparable to noncardiac high-risk procedures (2.5%). CONCLUSIONS: Extubation in the OR can be safely performed in a select group of cardiac surgery patients without any increase in postoperative morbidity or mortality. The proposed mathematical model performed reasonably well in predicting a successful extubation in the OR. PMID- 22497221 TI - Fine-mapping the POLL locus in Brahman cattle yields the diagnostic marker CSAFG29. AB - The POLL locus has been mapped to the centromeric region of bovine chromosome 1 (BTA1) in both taurine breeds and taurine-indicine crosses in an interval of approximately 1 Mb. It has not yet been mapped in pure-bred zebu cattle. Despite several efforts, neither causative mutations in candidate genes nor a singular diagnostic DNA marker has been identified. In this study, we genotyped a total of 68 Brahman cattle and 20 Hereford cattle informative for the POLL locus for 33 DNA microsatellites, 16 of which we identified de novo from the bovine genome sequence, mapping the POLL locus to the region of the genes IFNAR2 and SYNJ1. The 303-bp allele of the new microsatellite, CSAFG29, showed strong association with the POLL allele. We then genotyped 855 Brahman cattle for CSAFG29 and confirmed the association between the 303-bp allele and POLL. To determine whether the same association was found in taurine breeds, we genotyped 334 animals of the Angus, Hereford and Limousin breeds and 376 animals of the Brangus, Droughtmaster and Santa Gertrudis composite taurine-zebu breeds. The association between the 303-bp allele and POLL was confirmed in these breeds; however, an additional allele (305 bp) was also associated but not fully predictive of POLL. Across the data, CSAFG29 was in sufficient linkage disequilibrium to the POLL allele in Australian Brahman cattle that it could potentially be used as a diagnostic marker in that breed, but this may not be the case in other breeds. Further, we provide confirmatory evidence that the scur phenotype generally occurs in animals that are heterozygous for the POLL allele. PMID- 22497222 TI - Genetic diversity and population structure of five Ethiopian chicken ecotypes. AB - This study aimed to analyse the genetic diversity and population structure of five Ethiopian chicken ecotypes (N = 155), which were compared with six commercial purebreds (N = 180). For the analysis of genetic diversity, 26 AVIANDIV microsatellite markers were used. The number of alleles in Ethiopian ecotypes ranged from 2 to 19 per locus, with a mean of 6.1. The average observed heterozygosity within ecotype varied between 0.53 and 0.57. The overall heterozygote deficiency (F(IT)) in Ethiopian ecotypes was 0.124 +/- 0.037. Over 68% of F(IT) was because of within-ecotype deficiency (F(IS)). In the phylogenetic tree, Ethiopian ecotypes clustered into two groups. The analysis of the relationship between populations using the structure program provided further evidence for the occurrence of at least two subgroups in the Ethiopian ecotypes. Findings of this study may provide the background for future studies to identify the origin of the two gene pools representing the Ethiopian chicken ecotypes and to characterize the gene variants influencing economically important traits. PMID- 22497223 TI - Association between the levels of circulating adhesion molecules and biopterins in type-2 diabetic normotensive patients adhesion molecules and biopterins. AB - Endothelial dysfunction is a common feature in type-2 diabetic patients and is associated with inflammation, increased levels of circulating soluble adhesion molecules and atherosclerosis. Insufficiency of tetrahydrobiopterin leads to uncoupling of the nitric oxide synthase enzyme an endothelial dysfunction. THE AIM OF THIS STUDY: was to evaluate if there is a relationship between the levels of circulating soluble adhesion molecules and the levels of biopterins in normotensive type-2 diabetic patients. METHODS: We studied 30 normotensive type-2 diabetic patients in whom VCAM-1, ICAM-1 and E-selectin were measured by ELISA. Additionally, Biopterins were measured by reverse phase high performance liquid chromatography with fluorescence detection. The levels of circulating adhesion molecules and biopterins were correlated using the Spearman correlation coefficient test. Statistical analysis was performed with ANOVA. RESULTS: We did not find any relationship between absolute values of biopterins and soluble adhesion molecules. However, we observed significant inverse correlations between the BH4/BH2 ratio and VCAM-1 (r= -0.65, p<0.001) with ICAM-1 (r= -0.69, p<0.001) and with E-selectin (r=-0.64 p<0.001), CONCLUSION: Our data suggest that systemic levels of adhesion molecules have an inverse association with the BH4/BH2 ratio in type 2 diabetic normotensive patients. PMID- 22497224 TI - Generation of free ubiquitin chains is up-regulated in stress and facilitated by the HECT domain ubiquitin ligases UFD4 and HUL5. AB - Polyubiquitin chains serve a variety of physiological roles. Typically the chains are bound covalently to a protein substrate and in many cases target it for degradation by the 26S proteasome. However, several studies have demonstrated the existence of free polyubiquitin chains which are not linked to a specific substrate. Several physiological functions have been attributed to these chains, among them playing a role in signal transduction and serving as storage of ubiquitin for utilization under stress. In the present study, we have established a system for the detection of free ubiquitin chains and monitoring their level under changing conditions. Using this system, we show that UFD4 (ubiquitin fusion degradation 4), a HECT (homologous with E6-AP C-terminus) domain ubiquitin ligase, is involved in free chain generation. We also show that generation of these chains is stimulated in response to a variety of stresses, particularly those caused by DNA damage. However, it appears that the stress-induced synthesis of free chains is catalyzed by a different ligase, HUL5 (HECT ubiquitin ligase 5), which is also a HECT domain E3. PMID- 22497225 TI - If they can put a man on the moon, they should be able to fix a neck injury: a mixed-method study characterizing and explaining pain beliefs about WAD. AB - PURPOSE: To use quantitative data characterizing whiplash-associated disorder (WAD)-related pain beliefs over time to develop qualitative analysis exploring experiences informing these beliefs. METHOD: A mixed-method design was used. Quantitative and qualitative data were collected concurrently at baseline and 3 and 6 months postmotor vehicle collision. WAD-related pain beliefs were quantitatively measured in a sample of adults with acute WAD. A subgroup of participants participated in an interview after each survey. Descriptive statistics quantitatively characterized beliefs at each measurement. High or low scores from survey beliefs subscales informed the semistructured interview. The qualitative component explored experiences informing endorsement of beliefs reported on the surveys using a meaning-focused approach. RESULTS: Adjunctive meaning informing endorsement of beliefs related to cure, control, emotions and mystery was achieved. Qualitative analysis revealed a meta-theme labeled restitution, representing a desire to be "fixed". Stigma also emerged as a potentially important contextual descriptor of WAD meaning. CONCLUSIONS: Restitution was the dominant underlying pattern of belief endorsement. While this may be adaptive early after WAD, it is problematic for meaning construction later on. Based on contemporary views on pain, identification of this narrative is important as it represents an incompatibility in the conceptualization of pain between patient and provider. PMID- 22497226 TI - Effect of intermittent PTH(1-34) on human periodontal ligament cells transplanted into immunocompromised mice. AB - Residual periodontal ligament (PDL) cells in the damaged tissue are considered a prerequisite for a successful regeneration of the periodontal architecture with all its components, including gingiva, PDL, cementum, and bone. Among other approaches, current concepts in tissue engineering aim at a hormonal support of the regenerative capacity of PDL cells as well as at a supplementation of lost cells for regeneration. Here, we investigated how far an anabolic, intermittent parathyroid hormone (iPTH) administration would enhance the osteoblastic differentiation of PDL cells and the cellular ability to mineralize the extracellular matrix in an in vivo transplantation model. PDL cells were predifferentiated in a standard osteogenic medium for 3 weeks before subcutaneous transplantation into CD-1 nude mice using gelatin sponges as carrier. Daily injections of 40 MUg/kg body weight PTH(1-34) or an equivalent dose of vehicle for 4 weeks were followed by explantation of the specimens and an immunohistochemical analysis of the osteoblastic marker proteins alkaline phosphatase (ALP), osteopontin, and osteocalcin. Signs of biomineralization were visualized by means of alizarin red staining. For verification of the systemic effect of iPTH application, blood serum levels of osteocalcin were determined. The osteogenic medium stimulated the expression of ALP and PTH1-receptor mRNA in the cultures. After transplantation, iPTH resulted in an increased cytoplasmic and extracellular immunoreactivity for all markers investigated. In contrast to only sporadic areas of mineralization under control conditions, several foci of mineralization were observed in the iPTH group. Blood serum levels of osteocalcin were elevated significantly with iPTH. These data indicate that the osteoblastic differentiation of human PDL cells and their ability for biomineralization can be positively influenced by iPTH in vivo. These findings hold out a promising prospect for the support of periodontal regeneration. PMID- 22497227 TI - Altered light-touch sensation after bilateral sagittal-split osteotomy: a prospective study of 50 patients. AB - OBJECTIVE: To prospectively evaluate the incidence of change in light-touch sensation in the innervated area of the lower alveolar nerve after bilateral sagittal-split osteotomy (BSSO) with attention on the time it takes to rebuild the function of the inferior alveolar nerve. MATERIALS AND METHODS: The sample consisted of 30 women and 20 men with a mean age of 22.14 +/- 3.30 years. The neurosensory test was conducted with a 20-mm long monofilament of suture material Prolene (3-0) connected to a plastic holder. These tests were performed 1 day before surgery and every 2 weeks during first 2 months after surgery. After that, patients were tested once every month until the end of the first year. RESULTS: All patients had a disturbance of light-touch sensation after BSSO, but none of these changes was permanent. The average duration of hypoesthesia was 6.6 +/- 1.2 with a range from 4 to 9 months. The average duration of hypoesthesia for women was 6.27 +/- 1.0 months, and men had hypoesthesia for 7.1 +/- 1.2 months on average. This difference was statistically significant. The two oldest female patients, who were 33 and 37 years old at the time of the surgery, experienced altered sensitivity for only 4 months. CONCLUSIONS: After BSSO, all patients experienced disturbed light-touch sensation in the innervated area of the lower alveolar nerve. A faster recovery in the oldest patients and a statistically significant difference between the sexes should be interpreted with caution. PMID- 22497228 TI - The reliability of assessing rotation of teeth on photographed study casts. AB - OBJECTIVE: To examine the intra- and interexaminer reliability of assessing rotation of teeth on photographed study casts. In addition, the reliability parameters of two examiners scoring in mutual consultation were compared with the reliability parameters by one observer. MATERIALS AND METHODS: Standardized photographs of sets of maxillary and mandibular plaster casts of 10 patients before treatment (T1), after treatment (T2), and a long time after retention (T3) were digitized. Tooth rotation was assessed relative to a correct position in the ideal dental arch form. A computer analysis program was used to process the measurements. Two examiners assessed each study cast twice with a washout period of 3 weeks. A third examiner assessed each cast, together with one of the other examiners. The intra- and interexaminer agreements were calculated using intraclass correlation coefficients (ICCs). Wilcoxon signed-rank tests were used to determine significant differences between the intra- and interexaminer reliability coefficients of the three examiners. RESULTS: The ICCs ranged from 0.430 to 0.991. Incisors showed the highest ICCs and molars showed the lowest ICCs. Intraexaminer ICCs of the experienced examiners were significantly higher than those of the examiner with less experience. No significant differences in the reliability between a single examiner and the combination of two examiners were found. CONCLUSION: The method of assessing tooth rotation in the present study has proved to be reproducible, except for the molars. This method can be helpful for clinicians assessing tooth rotation from photographed study casts. PMID- 22497229 TI - Effects of predrilling on the osseointegration potential of mini-implants. AB - OBJECTIVES: To determine a reliable method of drilling a pilot hole when using a self-tapping surface-treated mini-implant and to evaluate stability after placement. MATERIALS AND METHODS: Implant sites were predrilled in 12 rabbits with two devices: a conventional motor-driven handpiece and a newly developed hand drill. Mini-implants were then inserted in a complete random block design. Samples were divided into 1-week and 6-week groups to investigate osseointegration capacity in relation to the two time intervals. Mechanical and histomorphometric assessments were performed. RESULTS: Mechanical analysis revealed no difference in maximum removal torque or total removal energy between the motor-driven predrilling group and the hand-drilling group. No difference was found between the 1-week group and the 6-week group. Histomorphometric evaluation showed no difference in the bone-implant contact (BIC) ratio or the bone volume (BV) area. For the time interval, a statistically significant increase in BIC and BV area was found in the 6-week group when compared to the 1-week group. CONCLUSIONS: The osseointegration potential of the motor-driven predrilling method was not different from that of the manual predrilling method with the newly developed hand drill. Hand drilling may be an attractive predrilling method in preference to the conventional motor-driven pilot drilling. PMID- 22497230 TI - Rapamycin enhances dimethyl sulfoxide-mediated growth arrest in human myelogenous leukemia cells. AB - Rapamycin and its derivatives have been proposed in the treatment of leukemia based on their cytostatic effects, but their possible role in differentiation therapy is less explored. The aim of the present study was to investigate the possible beneficial effects of the combination of rapamycin and dimethyl sulfoxide (DMSO) on growth arrest and differentiation of acute myelogenous leukemia (AML) cells. In myeloblastic HL-60, promyelocytic NB4, monocytic U937, immature KG-1 and erythro-megakaryocytic K562 cell lines, rapamycin alone had modest inhibitory effects, DMSO inhibited proliferation in a dose-dependent manner, and the combination of rapamycin and DMSO reduced the number of viable cells significantly more than either agent alone. In NB4 cells, rapamycin had no statistically significant effects on the DMSO-mediated increase in expression of CD11b, but increased apoptosis. These results demonstrate that rapamycin enhances DMSO-mediated growth arrest, and suggest that mTOR (mammalian target of rapamycin) inhibitors may have beneficial effects in differentiation therapy of AML. PMID- 22497232 TI - The onset of allergic rhinitis in Japanese atopic children: a preliminary prospective study. AB - CONCLUSION: This preliminary prospective study suggests that background factors may differ among allergic diseases. The beneficial interventions for reducing development of allergic rhinitis (AR) are also effective for the prevention of subsequent onset of bronchial asthma (BA). OBJECTIVE: To determine the risk factors associated with onset of AR in atopic children in a prospective study. METHODS: All patients with atopic dermatitis (AD) or food allergy with or without BA who visited the Pediatric Unit of Chiba University Hospital from 2005 to 2006 were enrolled in the study and received allergy examinations every 3-6 months. RESULTS: A total of 100 patients were followed up for more than 2 years. Among the 60 patients without BA at entry to the study, 12 developed BA during the follow-up period. Development of AR preceded BA in 10 of the 12 patients (83.3%). In the background factors at the entry, positive sensitization to house dust mite (HDM) was significantly related to development of BA. Among the 48 patients without AR, 20 developed AR. High titers of serum HDM-specific IgE and high eosinophil counts in blood, and detection of eosinophils in nasal smears at the entry were significantly related to development of AR. PMID- 22497233 TI - Where does the metal cation stay in Gd@C2v(9)-C82? A single-crystal X-ray diffraction study. AB - Metal positions in endohedral metallofullerenes (EMFs) are of special importance because their molecular symmetry and intrinsic properties are strongly influenced by the location and motion of the encapsulated metals. X-ray analyses of the cocrystals of Gd@C(2v)(9)-C(82) with nickel(II) octaethylporphyrin [Ni(II)(OEP)] reveal that the Gd(3+) cation is off-center, being located under a hexagonal ring along the 2-fold axis of the C(2v)(9)-C(82) cage. This result is in sharp contrast to that of a previous study, showing that Gd@C(2v)(9)-C(82) has an anomalous endohedral structure, with the metal being positioned over a [6,6] bond, which is opposite to the hexagonal ring along the C(2) axis (Phys. Rev. B 2004, 69, 113412). In agreement with theoretical calculations and related studies, it is conclusive that the single rare-earth metal in M@C(2v)(9)-C(82) always tends to coordinate with the hexagonal ring along the 2-fold axis, instead of interacting with the [6,6] bond on the other end, regardless of the type of metal atom. PMID- 22497234 TI - Direct imaging of single Au atoms within GaAs nanowires. AB - Incorporation of catalyst atoms during the growth process of semiconductor nanowires reduces the electron mean free path and degrades their electronic properties. Aberration-corrected scanning transmission electron microscopy (STEM) is now capable of directly imaging single Au atoms within the dense matrix of a GaAs crystal, by slightly tilting the GaAs lattice planes with respect to the incident electron beam. Au doping values in the order of 10(17-18) cm(3) were measured, making ballistic transport through the nanowires practically inaccessible. PMID- 22497235 TI - Diagnosis and treatment of giant cell granuloma of the temporal bone: Report of eight cases. AB - Abstract Conclusions: It is impossible to make a diagnosis of temporal giant cell granuloma (GCG) before operation because of nonspecific clinical and imaging feature. Surgery is the first-line choice of treatment. OBJECTIVE: To evaluate the diagnosis and treatment of temporal GCG. METHODS: Eight patients with GCG receiving treatment in the Chinese PLA General Hospital between 2001 and 2010 were recruited for the study. These patients' clinical features, imaging and histopathological findings, types of surgery, and results of follow-up evaluations were noted. RESULTS: The group was made up of four males and four females, with a median age of 37 years (range 21-50 years). Four patients had a granuloma on the left side and four on the right of the head. The median duration of the disease was 21 months (range 5-60 months). All patients, except one referred to us for recurring disease, were managed in our hospital. The main symptoms were: hearing loss (n = 5), tinnitus (n = 4), otalgia (n = 3), dizziness (n = 2), and local masses (n = 2). Radiological examination of the masses revealed erosion of the temporal bone and base of the skull. There was no definitive diagnosis in any of the patients before surgery. All patients had surgical treatment, six of them by middle cranial fossa approach and two by combined cranio-auricular approach. Surgical complications included partial facial paralysis (three cases) and cerebral edema (one case) but they resolved soon after surgery. One patient was lost to follow-up, but the other seven were followed up over a mean period of 24 months; none has reported a recurrence. PMID- 22497236 TI - Negative differential photoconductance in gold nanoparticle arrays in the Coulomb blockade regime. AB - We investigate the photoconductance of gold nanoparticle arrays in the Coulomb blockade regime. Two-dimensional, hexagonal crystals of nanoparticles are produced by self-assembly. The nanoparticles are weakly coupled to their neighbors by a tunneling conductance. At low temperatures, the single electron charging energy of the nanoparticles dominates the conductance properties of the array. The Coulomb blockade of the nanoparticles can be lifted by optical excitation with a laser beam. The optical excitation leads to a localized heating of the arrays, which in turn gives rise to a local change in conductance and a redistribution of the overall electrical potential in the arrays. We introduce a dual-beam optical excitation technique to probe the distribution of the electrical potential in the nanoparticle array. A negative differential photoconductance is the direct consequence of the redistribution of the electrical potential upon lifting of the Coulomb blockade. On the basis of our model, we calculate the optically induced current from the dark current-voltage characteristics of the nanoparticle array. The calculations closely reproduce the experimental observations. PMID- 22497237 TI - Quantitative trait loci associated with chemical composition of the chicken carcass. AB - Major objectives of the poultry industry are to increase meat production and to reduce carcass fatness, mainly abdominal fat. Information on growth performance and carcass composition are important for the selection of leaner meat chickens. To enhance our understanding of the genetic architecture underlying the chemical composition of chicken carcasses, an F(2) population developed from a broiler * layer cross was used to map quantitative trait loci (QTL) affecting protein, fat, water and ash contents in chicken carcasses. Two genetic models were applied in the QTL analysis: the line-cross and the half-sib models, both using the regression interval mapping method. Six significant and five suggestive QTL were mapped in the line-cross analysis, and four significant and six suggestive QTL were mapped in the half-sib analysis. A total of eleven QTL were mapped for fat (ether extract), five for protein, four for ash and one for water contents in the carcass using both analyses. No study to date has reported QTL for carcass chemical composition in chickens. Some QTL mapped here for carcass fat content match, as expected, QTL regions previously associated with abdominal fat in the same or in different populations, and novel QTL for protein, ash and water contents in the carcass are presented here. The results described here also reinforce the need for fine mapping and to perform multi-trait analyses to better understand the genetic architecture of these traits. PMID- 22497238 TI - Cultivar variability of patatin biochemical characteristics: table versus processing potatoes (Solanum tuberosum L.). AB - Biochemical characteristics of patatin proteins purified by ion-exchange and affinity chromatography from tubers of 20 potato cultivars were studied to evaluate their genotype differences with respect to utility groups, table potato cultivars (TPCs) and processing potato cultivars (PPCs). Both groups of cultivars showed similar values of protein content in dry matter (3.98-7.39%) and of patatin relative abundance (5.40-35.40%). Three mass levels (~40.6, 41.8, and 42.9 kDa) of purified patatins were found by MALDI-TOF MS within all cultivars. Differences among mass levels corresponding with the mass of sugar antenna (~1.2 kDa) confirmed the previous concept of different glycosylation extentsin patatin proteins. It was showed that the individual types of patatin varying in their masses occur in the patatin family in a ratio specific for each of the cultivars, with the lowest mass type being the major one. Electrophoretic analyses demonstrated wide cultivar variability in number of patatin forms. Especially 2D PAGE showed 17-23 detected protein spots independently on the utility group. Specific lipid acyl hydrolase (LAH) activity of purified patatins from the individual tested cultivars varied between 0.92 and 5.46 MUmol/(min mg). Patatin samples within most of the TPCs exhibited higher values of specific LAH activity than samples of PPCs. It may be supposed that individual patatin forms do not have similar physiological roles. PMID- 22497239 TI - Chemical synthesis of intentionally misfolded homogeneous glycoprotein: a unique approach for the study of glycoprotein quality control. AB - Biosynthesis of glycoproteins in the endoplasmic reticulum employs a quality control system, which discriminates and excludes misfolded malfunctional glycoproteins from a correctly folded one. As chemical tools to study the glycoprotein quality control system, we systematically synthesized misfolded homogeneous glycoproteins bearing a high-mannose type oligosaccharide via oxidative misfolding of a chemically synthesized homogeneous glycopeptide. The endoplasmic reticulum folding sensor enzyme, UDP-glucose:glycoprotein glucosyltransferase (UGGT), recognizes a specific folding intermediate, which exhibits a molten globule-like hydrophobic nature. PMID- 22497240 TI - Conformational dynamics of the trp-cage miniprotein at its folding temperature. AB - The folding temperature of the trp-cage mini-protein was determined to be in the range 311-317 K depending on the method used. Our study is focused on determining the structure and dynamics of the polypeptide chain close to its unfolding or melting temperature. At T = 305 K, Trp6-Arg16 and Trp6-Pro12 long-range interactions are observed, and at T = 313 K, only the Trp6-Arg16 interactions remain, while all of mentioned interactions are observed in the native state of the protein. Partial (at T = 305 K) and complete (at T = 313 K) melting of the N terminal alpha-helix is observed, manifested by the appearance of minor sets of signals in NMR spectra. Our key findings are: (i) conformational phase transition (melting point) could be described as a cooperative breaking of the Trp6-Pro12 long-range hydrophobic interaction and the melting of the N-terminal alpha-helix; (ii) many ROE signals corresponding to local or short-range interactions vanish rapidly with temperature increase; however, long-range interaction such as Trp6 Arg16 remains until 313 K. The presence of the native long-range interaction at 313 K makes that conformational ensemble resemble a very diffuse native state structure, but it is not a simple mixture of the folded and unfolded states, as could be expected on the basis of the common two-state folding mechanism. PMID- 22497241 TI - Joint effects of porcine leptin and leptin receptor polymorphisms on productivity and quality traits. AB - Leptin signalling plays a fundamental role in growth, fatness and body composition. The aim of this study was to investigate the porcine LEP gene sequence in an Iberian * Landrace experimental cross to identify polymorphisms associated with productivity and quality traits. Because of the documented effects on these traits of the LEPR c.1987C>T polymorphism, the LEP and LEPR c.1987C>T polymorphisms and their interactions have been jointly investigated. The LEP gene sequencing has allowed the identification of 39 polymorphisms, eight of which are novel. Three intronic SNPs, LEP g.1382C>T, LEP g.1387C>T and LEP g.1723A>G, have been genotyped, and association analyses have been carried out. Analyses of LEP g.1387C>T, fully linked to LEP g.1382C>T, have revealed additive effects on live and carcass weights and dominant effects on several backfat thickness measurements. Novel effects of both LEP and LEPR polymorphisms on fatty acid composition in subcutaneous fat have been detected, probably mediated through the effects on fatness. The results reported here suggest that the T alleles of both LEP g.1387C>T and LEPR c.1987C>T, which are fixed in the Iberian pigs, would lead to an increase in growth, fatness and saturated fatty acid content in fat, which could be explained by an increased feed intake. PMID- 22497242 TI - The development of preschoolers' appreciation of communicative ambiguity. AB - Using a longitudinal design, preschoolers' appreciation of a listener's knowledge of the location of a hidden sticker after the listener was provided with an ambiguous or unambiguous description was assessed. Preschoolers (N=34) were tested at 3 time points, each 6 months apart (4, 41/2, and 5 years). Eye gaze measures demonstrated that preschoolers were sensitive to communicative ambiguity, even when the situation was unambiguous from their perspective. Preschoolers' explicit evaluations of ambiguity were characterized by an initial appreciation of message clarity followed by an appreciation of message ambiguity. Children's inhibitory control skills at 4 years old related to their explicit detection of ambiguity at later ages. Results are discussed in terms of the developmental progression of preschoolers' awareness of communicative ambiguity. PMID- 22497243 TI - MAP Kinase 6-mediated activation of vacuolar processing enzyme modulates heat shock-induced programmed cell death in Arabidopsis. AB - * Vacuolar processing enzyme (VPE), a cysteine protease, has been intensively studied in plant hypersensitive cell death, but the role and molecular mechanism of VPEs in response to abiotic stresses remain unclear. This work investigated the involvement of VPEs in Arabidopsis response to heat stress. * Under heat shock (HS), Arabidopsis VPE activity and the transcript level of gammaVPE were both upregulated, and gammaVPE deficiency suppressed vacuolar disruption and delayed caspase-3-like activation in HS-induced programmed cell death (PCD). Moreover, the change of VPE activity generally paralleled the alteration of caspase-1-like activity under HS treatment, indicating that HS-induced VPE activity might exhibit the caspase-1-like activity. * Further studies showed that MAP Kinase 6 (MPK6) activity was increased after HS treatment, and experiments with inhibitors and mutants suggested that MPK6 was responsible for the gammaVPE activation after HS treatment. In response to HS stress, reactive oxygen species (ROS) production, increase of cytoplasmic calcium concentration ([Ca(2+) ](cyt)) and the upregulation of calmodulin 3 (CaM3) transcript level occurred upstream of MPK6 activation. * Our results suggested that activation of Arabidopsis gammaVPE was mediated by MPK6 and played an important role in HS-induced Arabidopsis PCD, providing new insight into the mechanistic study of plant VPEs. PMID- 22497244 TI - A single nucleotide polymorphism on chromosome 10 is highly predictive for the polled phenotype in Australian Merino sheep. AB - The aim of this study was to fine map the genomic location of the Horns locus in the Australian Merino sheep population and to identify markers that can be used to predict the horn phenotype. A linkage disequilibrium analysis of horn data from Australian Merino sheep mapped the Horns locus to a small region on chromosome 10. A single nucleotide polymorphism in the region was found to be highly predictive for the polled phenotype in an experimental population of Merino sheep. This was owing to a dominance effect of one of the alleles when inherited maternally. It was suggested that a genetic test would provide a good predictor of the polled phenotype. Finally, an evaluation of industry data showed that the SNP is at very different frequencies in Poll Merino sheep that have been bred for polledness (based on phenotype alone) compared with the Merino sheep breed. PMID- 22497245 TI - Early and intermediate term results for surgical correction of total anomalous pulmonary venous connection. AB - BACKGROUND: This retrospective study evaluated factors associated with mortality and morbidity in patients having functionally biventricular heart (FBH) and functionally univentricular heart (FUH) undergoing total anomalous pulmonary venous connection (TAPVC) repair. METHODS: We reviewed medical records retrospectively and identified 72 patients undergoing TAPVC repair between July 2002 and December 2010; and 62 patients had FBH and 10 patients had FUH. The median age and weight at repair was 9.1 months (range, 8 days-16 years) and 6.7 kg (range, 2.5-57 kg). The TAPVC anatomy was supracardiac in 41 (56.9%), cardiac in 18 (25%), infracardiac in eight (11.1%), and mixed in five patients (6.9%). RESULTS: There were seven early deaths (2 FBH [25%] and 5 FUH [62.5%]) and one late death (FUH). Presence of FUH (p < 0.01), heterotaxy syndrome (p = 0.03), young age (p < 0.01), low weight (p < 0.01) and long CPB time (p = 0.04) at the time of surgery were statistically significant risk factors for mortality. Morbidity was related to long duration of postoperative mechanical ventilation, intensive care unit and hospital stay. Presence of FUH was the only significant risk factor for morbidity (p < 0.01). After a mean follow-up of 52.1 months (range, 3-74 months), 59 (92%) of 64 survivors were asymptomatic without any medication, and five have mild symptoms with regular physical activity. CONCLUSION: Operative results of TAPVC have dramatically improved in recent years. However, patients having FUH (especially with concomitant palliative surgery), heterotaxy syndrome, low weight, early age, and long CPB time still have an increased operative mortality. PMID- 22497246 TI - The Wzx translocases for Salmonella enterica O-antigen processing have unexpected serotype specificity. AB - Most Gram-negative bacteria have an O antigen, a polysaccharide with many repeats of a short oligosaccharide that is a part of the lipopolysaccharide, the major lipid in the outer leaflet of the outer membrane. Lipopolysaccharide is variable with 46 forms in Salmonella enterica that underpin the serotyping scheme. Repeat units are assembled on a lipid carrier that is embedded in the cell membrane, and are then translocated by the Wzx translocase from the cytoplasmic face to the outer face of the cell membrane, followed by polymerization. The O antigen is then incorporated into lipopolysaccharide and exported to the outer membrane. The Wzx translocase is widely thought to be specific only for the first sugar of the repeat unit, despite extensive variation in both O antigens and Wzx translocases. However, we found for S. enterica groups B, D2 and E that Wzx translocation exhibits significant specificity for the repeat-unit structure, as variants with single sugar differences are translocated with lower efficiency and little long chain O antigen is produced. It appears that Wzx translocases are specific for their O antigen for normal levels of translocation. PMID- 22497247 TI - Whole-genome analysis for backfat thickness in a tropically adapted, composite cattle breed from Brazil. AB - Backfat thickness affects the preservation of the beef carcass after slaughter and confers organoleptic characteristics assessed by the consumer. One of the breeding goals for Canchim, a tropically adapted breed, is to comprehensively increase fat thickness. Our goals were to identify genomic regions associated with backfat in Canchim populations and validate the association of single nucleotide polymorphisms (SNPs) overlapping previously identified QTL regions known to affect fat deposition. Fifteen animals with lower and 15 animals with higher residues for backfat, according to a linear model using the SAS GLM procedure, were selected from a population of 1171 animals and genotyped using the BovineSNP50 BeadChip. Initial analysis revealed more than 100 SNPs that discriminated the tails of phenotypic distribution. One extended region of association included the centromeric region of chromosome (Chr) 14. Because this region overlapped with QTL from previous reports, we developed SNP assays to interrogate two linkage disequilibrium blocks, one in the centromeric region and another in the middle region of Chr 14 to confirm the association. The analysis validated the presence of specific haplotypes affecting fat thickness. PMID- 22497248 TI - SNP-based association mapping of the polled gene in divergent cattle breeds. AB - Naturally, hornless cattle are called polled. Although the POLL locus could be assigned to a c. 1.36-Mb interval in the centromeric region of BTA1, the underlying genetic basis for the polled trait is still unknown. Here, an association mapping design was set up to refine the candidate region of the polled trait for subsequent high-throughput sequencing. The case group comprised 101 homozygous polled animals from nine divergent cattle breeds, the majority represented by Galloway, Angus, Fleckvieh and Holstein Friesian. Additionally, this group included some polled individuals of Blonde d'Aquitaine, Charolais, Hereford, Jersey and Limousin breeds. The control group comprised horned Belgian Blue, Fleckvieh, Holstein Friesian and Illyrian Busa cattle. A genome-wide scan using 49,163 SNPs was performed, which revealed one shared homozygous haplotype block consisting of nine neighbouring SNPs in all polled animals. This segment defines a 381-kb interval on BTA1 that we consider to be the most likely location of the POLL mutation. Our results further demonstrate that the polled-associated haplotype is also frequent in horned animals included in this study, and thus the haplotype as such cannot be used for population-wide genetic testing. The actual trait-associated haplotype may be revealed by using higher-density SNP arrays. For the final identification of the causal mutation, we suggest high-throughput sequencing of the entire candidate region, because the identification of functional candidate genes is difficult owing to the lack of a comparable model. PMID- 22497249 TI - Contradictions of value: between use and exchange in cord blood bioeconomy. AB - Umbilical cord blood (CB) has become established as an increasingly viable clinical alternative to bone marrow in the treatment of leukaemia leading to the construction of a global network of CB banks promoted through a moral ethos of gift. Additionally, some banks offer the opportunity to retain stem cells privately. CB is discursively presented as clinical 'waste', a 'by-product' of birthing. In this way CB units are made available to a global exchange-based bioeconomy. Crucially, CB collection has developed in parallel with several necessary obstetric practices, especially the immediate clamping of the cord following delivery, essential to high volume collection. However, this article strongly suggests the promotional basis of CB banking (such as by gift, waste or donation) is in tension with the growing preference of new parents to delay cord clamping. Based on focus groups with expectant parents, the promotion of CB banking can in fact be seen to feed into critical reflection on the value of CB for newborn infants, potentially reinvigorating a tradition of delayed umbilical cord clamping. Theoretically, these contradictory systems of valuing are conceptualised through recent literature on bioeconomy and Marx's writings on the contrasting tensions between use and exchange value. PMID- 22497250 TI - Embryonic poly(A)-binding protein (ePAB) phosphorylation is required for Xenopus oocyte maturation. AB - Oocyte maturation and early embryonic development require the cytoplasmic polyadenylation and concomitant translational activation of stored maternal mRNAs. ePAB [embryonic poly(A)-binding protein, also known as ePABP and PABPc1 like] is a multifunctional post-transcriptional regulator that binds to poly(A) tails. In the present study we find that ePAB is a dynamically modified phosphoprotein in Xenopus laevis oocytes and show by mutation that phosphorylation at a four residue cluster is required for oocyte maturation. We further demonstrate that these phosphorylations are critical for cytoplasmic polyadenylation, but not for ePAB's inherent ability to promote translation. Our results provide the first insight into the role of post-translational modifications in regulating PABP protein activity in vivo. PMID- 22497252 TI - Neovascularization in retinopathy of prematurity: opposing actions of neuronal factors GPR91 and semaphorins 3A. AB - Retinopathy of prematurity (ROP) is a major cause of severe visual deficits in children. This review focuses on the role of newly identified factors from retinal neurons, which through their opposing actions on vascular development contribute to ROP. These hypoxia-generated mediators include the Krebs cycle intermediate, succinate acting via GPR91, and the neuronal guidance molecule Semaphorin 3A. CONCLUSION: Neuron-derived factors guide retinal vascularization and are major contributors to the pathogenesis of ROP. PMID- 22497251 TI - Solution NMR structure, backbone dynamics, and heme-binding properties of a novel cytochrome c maturation protein CcmE from Desulfovibrio vulgaris. AB - Cytochrome c maturation protein E, CcmE, plays an integral role in the transfer of heme to apocytochrome c in many prokaryotes and some mitochondria. A novel subclass featuring a heme-binding cysteine has been identified in archaea and some bacteria. Here we describe the solution NMR structure, backbone dynamics, and heme binding properties of the soluble C-terminal domain of Desulfovibrio vulgaris CcmE, dvCcmE'. The structure adopts a conserved beta-barrel OB fold followed by an unstructured C-terminal tail encompassing the CxxxY heme-binding motif. Heme binding analyses of wild-type and mutant dvCcmE' demonstrate the absolute requirement of residue C127 for noncovalent heme binding in vitro. PMID- 22497253 TI - Incidence of diabetes and serum adipokines in Catalonian men: the ADIPOCAT study. AB - AIMS: To investigate the relationship of body mass index and serum adipokines with incidence of diabetes in men. MATERIAL AND METHODS: Ten-year cohort study of a random population sample of 1011 men aged 35-69 years from the MONICA-Catalonia survey (1986-1988). WHO-MONICA protocol and the US Hispanic NHANES diabetes questionnaire were applied. Fasting serum glucose and lipids were measured by enzymatic methods, adipokines and insulin by Luminex xMAP technology,and hs-CRP by nephelometry in stored baseline samples (-80 degrees C). Type2 diabetes was defined as fasting glucose >= 7.0 mmol/L or diagnosed diabetes. Incident diabetes was defined as absence of these criteria at baseline but presence at re examination. Cox regression analysis was used. RESULTS: Incidence of diabetes (n = 85) was 10.3/1000 person-years, increasing significantly with BMI but decreasing by quartiles of adiponectin. Incidence increased above median BMI and glucose (45.3/1000 person-years, OR = 19.97). Log-adiponectin associated with reduced risk of diabetes after multivariate adjustment (HR = 0.24, 95% CI 0.08 0.72), with significant modification of this effect by baseline glycaemia. C reactive protein was not a significant factor. Leptin lost strength when adjusted for BMI. CONCLUSIONS: In a population with relatively high diabetes incidence, BMI and glucose were strong risk factors, while adiponectin protected against diabetes, especially in men with high glycaemic level. PMID- 22497254 TI - Synthesis and properties of RNAs that contain a PNA-RNA dimer. AB - A practical synthesis of a peptide nucleic acid unit combined with an RNA nucleoside (PNA-RNA dimer) is reported. The dimer unit was placed within an RNA oligonucleotide via phosphoramidite chemistry and melting temperature data indicate destabilization relative to a native RNA duplex. Circular dichroism indicates that the overall shape of the duplex remains intact. This PNA-RNA dimer unit will permit future investigations within RNA-based systems, such as RNA interference. PMID- 22497255 TI - Genotyping of -374A/T, -429A/G, and 63 bp Ins/del polymorphisms of RAGE by rapid one-step hexaprimer amplification refractory mutation system polymerase chain reaction in breast cancer patients. AB - Several studies have focused on the RAGE genetic background and have demonstrated that its polymorphisms affect the receptor's activity, expression, and downstream signaling. However, there is only little information regarding RAGE polymorphism in breast cancer. In the present study, the authors studied RAGE polymorphisms in 71 patients with breast cancer and 93 healthy women. RAGE -374T/A, -429T/C, and 63 bp Ins/del polymorphisms were analyzed using a hexaprimer amplification refractory mutation system PCR (H-ARMS-PCR). The results showed that RAGE polymorphisms are not associated with breast cancer in the current study population. Larger studies are required to confirm these data in other populations. PMID- 22497256 TI - Design and synthesis of novel threosyl-5'- deoxyphosphonic acid purine analogues as potent anti-HIV agents. AB - The discovery of threosyl phosphonate nucleoside (PMDTA, EC50 = 2.53 MUM) as a potent anti-HIV agent has led to the synthesis and biological evaluation of 5 ' deoxyversions of threosyl phosphonate nucleosides from 1,4-dihydroxy-2-butene. The synthesized nucleoside phosphonic acid analogues 14 and 19 were tested for anti-HIV activity as well as cytotoxicity. The adenine analogue 14 exhibits moderate in vitro anti-HIV-1 activity (EC50 = 12.6 MUM). PMID- 22497257 TI - An improved protection-free one-pot chemical synthesis of 2'-deoxynucleoside-5' triphosphates. AB - A facile, straightforward, reliable, and an efficient method for the gram-scale chemical synthesis of both purine deoxynucleotides such as 2 '-deoxyguanosine-5 ' triphosphate (dGTP) and 2 '-deoxyadenosine-5 '-triphosphate (dATP) and pyrimidine deoxynucleotides such as 2 '-deoxycytidine-5 '-triphosphate (dCTP), thymidine-5 ' triphosphate (TTP), and 2 '-deoxyuridine-5 '-triphosphate (dUTP) starting from the corresponding nucleoside is described. This improved "one-pot, three step" Ludwig synthetic strategy involves the monophosphorylation of nucleoside followed by reaction with tributylammonium pyrophosphate and hydrolysis of the resulting cyclic intermediate to provide the corresponding dNTP in good yields (65%-70%). PMID- 22497258 TI - Structure-activity relationships of 2',5'-oligoadenylate analogue modifications of prostate-specific membrane antigen (PSMA) antagonists. AB - Prostate-specific membrane antigen (PSMA) is an ideal biomarker for prostate cancer. A previously reported 2-5A conjugate RBI1033 (3) showed binding affinity more than 10 times higher than the parent urea-based compound (S)-2-(3-((S)-5 amino-1-carboxypentyl)ureido) pentanedioic acid (1). The purpose of this work is to further optimize the structure of 3 to identify highly selective ligands of PSMA. It was found that conjugates having 2-5A in their structure showed extraordinary improved binding affinity to PSMA compared with compound 1. Removal of 2-5A significantly reduced its biological activity. The results will provide a path to agents for targeted imaging and treatment of prostate cancer. PMID- 22497259 TI - New bolus models for in vivo efficacy testing of mycotoxin-detoxifying agents in relation to EFSA guidelines, assessed using deoxynivalenol in broiler chickens. AB - In this study, three new models were developed for efficacy testing of mycotoxin detoxifying agents in relation to recent European guidelines. In the first model, deoxynivalenol was given to broiler chickens as an intra-crop bolus together with a mycotoxin-detoxifying agent in order to study the plasma concentration-time profile of deoxynivalenol. In the second model, the same oral bolus was given, preceded by an oral bolus of mycotoxin-detoxifying agent, to make sure the detoxifying agent was present in the whole intestinal tract when the mycotoxin was administered. In the third model, the mycotoxin-detoxifying agent was mixed in the feed of broiler chickens, and after 1 week's feeding, deoxynivalenol was given as an oral bolus. In order to evaluate the efficacy of these agents, plasma concentration-time profiles were set up and the main toxicokinetic parameters were compared. Two commercially available mycotoxin-detoxifying agents were tested, but they were not able to lower the oral availability of deoxynivalenol. As a positive control, activated carbon was used. We showed that activated carbon significantly reduces the absorption and oral availability of deoxynivalenol in all three models. Therefore, it can be concluded that these models are able to demonstrate the efficacy of mycotoxin-detoxifying agents in relation to European Food Safety Authority guidelines. PMID- 22497260 TI - Ehrlichia chaffeensis human monocytic ehrlichiosis with pancytopenia. PMID- 22497261 TI - In situ time-resolved XAFS study of the reaction mechanism of bromobenzene homocoupling mediated by [Ni(cod)(bpy)]. AB - A homocoupling reaction mechanism of bromobenzene mediated by the [Ni(cod)(bpy)] (cod = 1,5-cyclooctadiene; bpy = 2,2'-bipyridine) complex was investigated by means of in situ time-resolved X-ray absorption fine structure (XAFS) and factor analysis. A dimer intermediate [Ni(bpy)(Ph)Br](2) proposed in the previous studies by other groups is too dilute to observe with the XAFS technique; however, the structures and concentrations on the time course of a reactant [Ni(cod)(bpy)], an intermediate [Ni(bpy)(Ph)Br(dmf)(2)], and a byproduct [Ni(bpy)Br(2)(dmf)] during reaction are revealed by this combination. PMID- 22497262 TI - Investigation of the genetic architecture of a bone carcass weight QTL on BTA6. AB - A previous analysis of an F(2) /Backcross Charolais * Holstein cross population identified the presence of a highly significant QTL on chromosome 6 (BTA6) affecting the proportion of bone in the carcass. Two closely linked QTL affected birth weight (BW) and body length at birth (BBL). In this report, the marker density around the QTL on BTA6 was increased, adding four additional microsatellite markers across the chromosome and 46 SNPs within the target QTL confidence interval. Of the SNPs, 26 were in positional candidate genes and the remaining 20 provided an even distribution of markers in the target QTL region. As a bone-related trait, the sum of the bone weight for all the left fore- and hindquarter joints of the carcass was analysed. We also studied the BW and BBL. Analyses of the data substantially reduced the QTL confidence interval. No strong evidence was found that the QTL for the three traits studied are different, and we conclude that the results are consistent with a single pleiotropic QTL influencing the three traits, with the largest effects on the proportion of bone in the carcass. The analyses also suggest that none of the SNPs tested is the sole causative variant of the QTL effects. Specifically, the SNP in the NCAPG gene previously reported as a causal mutation for foetal growth and carcass traits in other cattle populations was excluded as the causal mutation for the QTL reported here. Polymorphisms located in other previously identified candidate genes including SPP1, ABCG2, IBSP, MEPE and PPARGC1A were also excluded. The results suggest that SNP51_BTA-119876 is the polymorphism in strongest linkage disequilibrium with the causal mutation(s). Further research is required to identify the causal variant(s) associated with this bone-related QTL. PMID- 22497263 TI - A novel technique for tailoring frontal osteoplastic flaps using the ENT magnetic navigation system. AB - CONCLUSION: The ENT magnetic navigation system is potentially useful and offers the most accurate technique for harvesting frontal osteoplastic flaps. It represents a valid tool in the wide range of instruments available to rhinologists. OBJECTIVE: Precise delineation of the boundaries of the frontal sinus is a crucial step when harvesting a frontal osteoplastic flap. We present a novel technique using the ENT magnetic navigation system. METHODS: Nineteen patients affected by different pathologies involving the frontal sinus underwent an osteoplastic flap procedure using the ENT magnetic navigation system between January 2009 and April 2011. RESULTS: The ENT magnetic navigation system was found to be a safe and accurate tool for delineating the frontal sinus boundaries. No intraoperative complications occurred during the osteoplastic procedures. PMID- 22497264 TI - Simplistic Coulomb forces in molecular dynamics: comparing the Wolf and shifted force approximations. AB - In this paper we compare the Wolf method to the shifted forces (SF) method for efficient computer simulation of bulk systems with Coulomb forces, taking results from the Ewald summation and particle mesh Ewald methods as representing the true behavior. We find that for the Hansen-McDonald molten salt model the SF approximation overall reproduces the structural and dynamical properties as accurately as does the Wolf method. It is shown that the optimal Wolf damping parameter depends on the property in focus and that neither the potential energy nor the radial distribution function are useful measures for the convergence of the Wolf method to the Ewald summation method. The SF approximation is also tested for the SPC/Fw model of liquid water at room temperature, showing good agreement with both the Wolf and the particle mesh Ewald methods; this confirms previous findings [Fennell, C. J.; Gezelter, J. D. J. Chem. Phys.2006, 124, 234104]. Besides its conceptual simplicity, the SF approximation implies a speed up of a factor of 2-3 compared to the Wolf method. We conclude that for the systems studied, whenever the Wolf method gives accurate results, it may be replaced by the simpler and faster SF method. PMID- 22497265 TI - Six years after deregulation of emergency contraception in Switzerland: has free access induced changes in the profile of clients attending an emergency pharmacy in Zurich? AB - OBJECTIVES: Emergency contraception (EC) has been freely accessible in Swiss pharmacies since November 2002. Today some groups are still concerned that free access might result in less use of efficient contraceptive methods, overuse and more risky sexual behaviour. METHODS: Profiles of EC users one and six years after deregulation were analysed with regard to age, contraceptive methods used, reasons for EC use, and last contact with a gynaecologist. Data were collected from a centrally located pharmacy. Written official assessment forms concerning 1500 women (750 in 2004 and 750 in 2009) were analysed. RESULTS: Free access to EC use had no impact on regular contraceptive behaviour. The percentage of pill and condom users was very high (85%). The percentage of EC-users without any contraception (17-18%) was the same over the years. In 2009, condom rupture was reported more frequently (p < 0.001). In addition significantly more women had used EC previously in their history. CONCLUSION: Free access to EC has not resulted in less use of efficient contraceptive methods. In the context of falling abortion rates our results are reassuring. This also applies to adolescents, who mainly used EC as a back-up method and seldom in the context of unprotected intercourse. PMID- 22497266 TI - Identification of aroma-active compounds in Jiashi muskmelon juice by GC-O-MS and OAV calculation. AB - To identify aromatic compounds in Jiashi melon juice, gas chromatography-mass spectrometry-olfactometry (GC-MS-O) analysis was used. Odor activity values (OAVs) were also calculated on the basis of the qualitative and quantitative analysis of volatile compounds. Results showed that 42 volatiles were identified, among which 4 compounds, namely, diethyl carbonate, isophorone, 2-butoxyethyl acetate, and menthol, were identified or tentatively identified for the first time as volatiles in melon fruit. Twelve compounds, namely, (2E,6Z)-nona-2,6 dienal, (3Z,6Z)-nona-3,6-dien-1-ol, ethyl butanoate, ethyl 2-methylbutyrate, ethyl 2-methylpropanoate, (Z)-non-6-enal, (E)-2-nonenal, heptanal, methyl 2 methylbutyrate, nonanal, hexanal, and 2-methylpropyl acetate, were identified as the potent odorants of Jiashi melon juice by both OAV and detection frequency analysis (DFA). In addition, seven odorants were detected by all of the panelists and showed higher OAVs, indicating that DFA and OAV resulted in relatively similar "Jiashi" melon aroma patterns. PMID- 22497267 TI - Enantioselective synthesis of dihydropyrazoles by formal [4+1] cycloaddition of in situ-derived azoalkenes and sulfur ylides. AB - An unprecedented strategy to access highly enantioenriched dihydropyrazoles is described. It involves formal [4+1] cycloadditions of in situ-derived azoalkenes and sulfur ylides catalyzed by a chiral copper/Tol-BINAP complex. A variety of synthetically and biologically important dihydropyrazoles have been obtained with high enantioselectivities (up to 97:3 er) in good yields (83-97%). PMID- 22497268 TI - Genetic variants affecting meat and milk production traits appear to have effects on reproduction traits in cattle. AB - Polymorphisms located in the genes ABCG2, DGAT1, LEP, PRLR, RORC, CAPN1 and CAST previously have been associated with milk or meat production traits. In this study, these polymorphisms were examined for significant effects on reproductive traits [age at puberty (AGECL), post-partum anoestrus interval (PPAI) and the ability ovulate prior to weaning (PW)] and on a panel of correlated traits such as weight, growth and serum concentration of insulin-like growth factor I. The effects of the polymorphisms were examined in two samples of tropically adapted beef cattle: Brahman (N = 932) and Tropical Composites (N = 1097). A polymorphism in the gene DGAT1 was associated with age at puberty in the combined sample (P = 0.042), and two polymorphisms in CAPN1 were associated with PPAI (P = 0.033) and with the ability ovulate PW (P = 0.017). The favourable allele for reproductive traits was not always the favourable allele associated with production traits. The effects of these polymorphisms on reproductive traits were small compared to their effects on the traits for which they were originally discovered. PMID- 22497269 TI - Exclusion of candidate genes for coat colour phenotypes of the American mink (Neovison vison). AB - In a previous project, we screened the American mink Bacterial Artificial Chromosome library, CHORI-231, for genes potentially involved in various coat colour phenotypes in the American mink. Subsequently, we 454 sequenced the inserts containing these genes and developed microsatellite markers for each of these genes. Here, we describe a lack of association between three different 'roan-type' phenotypes represented by Cross, Stardust and Cinnamon in American mink and six different genes that we considered to be potentially linked to these phenotypes. Thus, c-KIT (HUGO-approved symbol KIT), ATOH-1 (HUGO-approved symbol ATOH1) and POMC were excluded as potential candidates for these three phenotypes. In addition, MITF and SLC24A5 were excluded for Cross and Cinnamon, and KITL (HUGO-approved symbol KITLG) for Cross and Stardust. Although most of these genes have been implicated as the cause of similar phenotypes in other mammals, including horses, pigs, cows, dogs, cats, mice and humans, they do not appear to be responsible for comparable phenotypes found in American mink. PMID- 22497270 TI - A new tool for analysis of root growth in the spatio-temporal continuum. AB - * Quantification of overall growth and local growth zones in root system development is key to understanding the biology of plant growth, and thus to exploring the effects of environmental, genotypic and mutational variations on plant development and productivity. * We introduce a methodology for analyzing growth patterns of plant roots from two-dimensional time series images, treating them as a spatio-temporal three-dimensional (3D) image volume. The roots are segmented from the images and then two types of analysis are performed: 3D spatio temporal reconstruction analysis for simultaneous assessment of initiation and growth of multiple roots; and spatio-temporal pixel intensity analysis along root midlines for quantification of the growth zones. * The test measurements show simultaneous emergence of basal roots but sequential emergence of lateral roots in Phaseolus vulgaris, while lateral roots of Cicer arietinum emerge in a rhythmic pattern. Local growth analysis reveals multimodal transient growth zone in basal roots. At the initial stages after emergence, the roots oscillate rapidly, which slows down with time. * The methodology presented here allows detailed characterization of the phenomenology of roots, providing valuable information of spatio-temporal development, with applications in a wide range of growing plant organs. PMID- 22497271 TI - Calcified right atrial mass. PMID- 22497272 TI - Cordifolide A, a sulfur-containing clerodane diterpene glycoside from Tinospora cordifolia. AB - Cordifolide A (1), a novel unprecedented sulfur-containing clerodane diterpene glycoside, together with other two new diterpene glycosides, cordifolides B (2) and C (3), and four known analogues, was isolated from a methanol-soluble extract of the stems of Tinospora cordifolia. The structures of the new compounds were determined on the basis of spectroscopic data interpretation, with that of cordifolide A (1) confirmed by a single-crystal X-ray crystallographic analysis. All isolates were evaluated for their in vitro immunomodulatory activity using mouse bone marrow-derived dentritic cells (BMDCs). PMID- 22497273 TI - Family process and peer deviance influences on adolescent aggression: longitudinal effects across early and middle adolescence. AB - Beginning in sixth grade at an average age of 11.9 years, 416 adolescents and their parents participated in 4 waves of data collection involving family observations and multiple-reporter assessments. Ecological theory and the process person-context-time (PPCT) model guided the hypotheses and analyses. Lagged, growth curve models revealed that family hostility and peer deviance affiliation predicted adolescent aggression in the subsequent year. Family warmth played only a minor role in protecting against adolescent aggression. In hostile or low warmth families, peer deviance affiliation linked to a declining aggression trajectory consistent with the arena of comfort hypothesis. The longitudinal findings suggest a nonadditive, synergistic interplay between family and peer contexts across time in adding nuance to understanding the adolescent aggression. PMID- 22497274 TI - Microarray analysis of differential gene expression in sensitive and resistant pig to Escherichia coli F18. AB - In this study, Agilent two-colour microarray-based gene expression profiling was used to detect differential gene expression in duodenal tissues collected from eight full-sib pairs of Sutai pigs differing in adhesion phenotype (sensitivity and resistance to Escherichia coli F18). Using a two-fold change minimum threshold, we found 18 genes that were differentially expressed (10 up-regulated and eight down-regulated) between the sensitive and resistant animal groups. Our gene ontology analysis revealed that these differentially expressed genes are involved in a variety of biological processes, including immune responses, extracellular modification (e.g. glycosylation), cell adhesion and signal transduction, all of which are related to the anabolic metabolism of glycolipids, as well as to inflammation- and immune-related pathways. Based on the genes identified in the screen and the pathway analysis results, real-time PCR was used to test the involvement of ST3GAL1 and A genes (of glycolipid-related pathways), SLA-1 and SLA-3 genes (of inflammation- and immune-related pathways), as well as the differential genes FUT1, TAP1 and SLA-DQA. Subsequently, real-time PCR was performed to validate seven differentially expressed genes screened out by the microarray approach, and sufficient consistency was observed between the two methods. The results support the conclusion that these genes are related to the E. coli F18 receptor and susceptibility to E. coli F18. PMID- 22497275 TI - Investigation of allele frequencies for Lavender foal syndrome in the horse. PMID- 22497276 TI - Extended high cutoff on-line hemodiafiltration is superior to extended high cutoff hemodialysis in removal of free light chain immunoglobulin of myeloma cast nephropathy. PMID- 22497277 TI - The effect of omeprazole and esomeprazole on the maintenance dose of phenprocoumon. PMID- 22497278 TI - EBV up-regulates cytochrome c through VDAC1 regulations and decreases the release of cytoplasmic Ca2+ in the NPC cell line. AB - EBV (Epstein-Barr virus) is considered to be a major factor that causes NPC (nasopharyngeal carcinoma), which is one of the sneakiest cancers frequently occurring in Southeast Asia and Southern China. Apoptosis and pro-apoptotic signals have been studied for decades; however, few have extended the prevailing view of EBV to its impact on NPC in perspective of apoptosis. One of the important proteins named VDAC1 (voltage-dependent anion protein 1) on the mitochondrial outer membrane controls the pro-apoptotic signals in mammalian cells. The impact of EBV infection on VDAC1 and related apoptotic signals remains unclear. In order to study the VDAC1's role in EBV-infected NPC cells, we employ siRNA (small interfering RNA) inhibition to analyse the release of Ca2+ and Cyto c (cytochrome c) signals in the cytoplasm, as they are important pro-apoptotic signals. The results show a decrease of Ca2+ release and up-regulation of Cyto c with EBV infection. After siRNA transfection, the dysregulation of Cyto c is neutralized, which is evidence that the level of Cyto c release in virus-infected NPC cells is the as same as that of non-infected NPC cells. This result indicates that EBV infection changes the cytoplasmic level of Cyto c through regulating VDAC1. In summary, this study reports that EBV changes the release of Ca2+ and Cyto c in the cytoplasm of NPC cells, and that Cyto c changes are mediated by VDAC1 regulation. PMID- 22497279 TI - Cardiac responses of rats submitted to postnatal protein restriction. AB - Undernutrition during critical stages of development and childhood has important effects on cardiovascular homeostasis. The present study was undertaken to evaluate the in vivo and ex vivo cardiac function of rats submitted to postnatal protein restriction. Male Wistar rats (28 days old) were fed a regular (20%) or low-protein (6%) diet over 5 weeks. After this period, cardiac function was analyzed by echocardiography and isolated heart preparation. Furthermore, the density of cardiac noradrenergic fibers and hematological profile were evaluated. We found that malnourished rats exhibited elevated arterial blood pressure, increased fractional shortening (echocardiography), increased systolic tension, increased +/-dT/dt (isolated heart technique), impaired diastolic function characterized by a slight increase in the left ventricular end-diastolic diameter (echocardiography) and decreased diastolic tension (isolated heart technique), and cardiac hypertrophy evidenced by augmentation of the posterior left ventricular wall and discrete hematological changes. In addition, malnourished rats exhibited increased noradrenergic fiber density in their hearts (0.08% +/- 0.02% area in control rats vs. 0.17% +/- 0.03% area in malnourished rats). Our current data demonstrate that postnatal protein restriction causes cardiac adaptation characterized by an early overworking heart. This is at least in part mediated by an increase in the efferent sympathetic fibers to the heart. These findings provide important information for efforts to prevent and manage the consequences of undernutrition in the human population. PMID- 22497280 TI - Proteolytic regulation of alginate overproduction in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa, a Gram-negative bacterium, is a significant opportunistic pathogen associated with skin and soft tissue infections, nosocomial pneumonia and sepsis. In addition, it can chronically colonize the lungs of cystic fibrosis (CF) patients. Overproduction of the exopolysaccharide called alginate provides P. aeruginosa with a selective advantage and facilitates survival in the CF lung. The in vitro phenotype of alginate overproduction observed on solid culture media is referred to as mucoid. Expression of the alginate machinery and biosynthetic enzymes are controlled by the extracytoplasmic sigma factor, sigma(22) (AlgU/T). The key negative regulator of both sigma(22) activity and the mucoid phenotype is the cognate anti-sigma factor MucA. MucA sequesters sigma(22) to the inner membrane inhibiting the sigma factor's transcriptional activity. The well-studied mechanism for transition to the mucoid phenotype is mutation of mucA, leading to loss of MucA function and therefore activation of sigma(22) . Recently, regulated intramembrane proteolysis (RIP) has been recognized as a mechanism whereby proteolysis of the anti-sigma factor MucA leads to active sigma(22) allowing P. aeruginosa to respond to environmental stress conditions by overproduction of alginate. The goal of this review is to illuminate the pathways leading to RIP that have been identified and proposed. PMID- 22497281 TI - The N-terminal domain of a TonB-dependent transporter undergoes a reversible stepwise denaturation. AB - Gram-negative bacteria contain a family of outer membrane transport proteins that function in the uptake of rare nutrients, such as iron and vitamin B(12). These proteins are termed TonB-dependent because transport requires an interaction with the inner-membrane protein TonB. Using a combination of site-directed spin labeling and chemical denaturation, we examined the site-specific unfolding of regions of the Escherichia coli vitamin B(12) transporter, BtuB. The data indicate that a portion of the N-terminal region of the protein, which occupies the lumen of the BtuB barrel, denatures prior to the unfolding of the barrel and that the free energy of folding for the N-terminus is smaller than that typically seen for globular proteins. Moreover, the data indicate that the N-terminal domain does not unfold in a single event but unfolds in a series of independent steps. The unfolding of the N-terminus is reversible, and removal of denaturant restores the native fold of the protein. These data are consistent with proposed transport mechanisms that involve a transient rearrangement or unfolding of the N terminus of the protein, and they provide evidence of a specific protein conformation that might be an intermediate accessed during transport. PMID- 22497283 TI - Classification of the geographical origin of Italian donkey's milk based on differences in inorganic anions. AB - The content of chlorides, nitrites, nitrates, phosphates and sulphates was used to classify 45 donkey's milk samples collected from different Italian regions. A method employing ion exchange chromatography with conductivity detector and chemical suppression was used. The quantitative results indicated phosphates (569.4-1304.4 mg kg(-1)) and chlorides (545.9-1757.9 mg kg(-1)) as being the most abundant anions, followed by sulphates (109.5-200.7 mg kg(-1)). The concentrations of nitrites and nitrates were found to be lower at 5.6 and 5.5 mg kg(-1) respectively. The data set was subdivided into three groups according to the region of origin of milk, and was statistically evaluated by analysis of variance (ANOVA). Concentrations of chlorides and nitrites showed a significant difference among farms (p < 0.001). In a first discriminant analysis procedure, functions based on linear combinations of the log(e)-transformed element concentrations of anions were generated to classify donkey's milk samples from different regions. In an alternative approach, a three-step discriminant analysis procedure to classify a milk sample was tested. The results obtained led to a correct classification of donkey's milk samples based on their anions content with 91-98% of the samples being correctly classified. The procedure proved to be very simple, so it could be used as an evaluation method for the traceability of donkey's milk, thus defending this unique product against fraud or commercial disputes. PMID- 22497282 TI - Plasma lipid metabolites are associated with gestational age but not bronchopulmonary dysplasia. AB - AIM: To test the hypothesis that plasma lipid metabolite levels in premature infants are associated with the development of bronchopulmonary dysplasia (BPD). The studies also tested a secondary hypothesis that plasma lipid metabolite levels were correlated with gestational age. METHODS: Infants born <32 weeks' gestation were enrolled during the first 72 h of life. Plasma samples were obtained and lipid levels were measured by LC-MS/MS. Clinical data were collected to determine infant outcomes and BPD diagnosis. RESULTS: Following adjustment for confounders, lipid levels were not associated with BPD; however, levels of specific lipid metabolites were correlated with gestational age. CONCLUSION: Immature lipid metabolism pathways in premature infants may contribute to the pathogenesis of BPD and other diseases. PMID- 22497284 TI - Microbial remediation of explosive waste. AB - Explosives are synthesized globally mainly for military munitions. Nitrate esters, such as GTN and PETN, nitroaromatics like TNP and TNT and nitramines with RDX, HMX and CL20, are the main class of explosives used. Their use has resulted in severe contamination of environment and strategies are now being developed to clean these substances in an economical and eco-friendly manner. The incredible versatility inherited in microbes has rendered these explosives as a part of the biogeochemical cycle. Several microbes catalyze mineralization and/or nonspecific transformation of explosive waste either by aerobic or anaerobic processes. It is likely that ongoing genetic adaptation, with the recruitment of silent sequences into functional catabolic routes and evolution of substrate range by mutations in structural genes, will further enhance the catabolic potential of bacteria toward explosives and ultimately contribute to cleansing the environment of these toxic and recalcitrant chemicals. This review summarizes information on the biodegradation and biotransformation pathways of several important explosives. Isolation, characterization, utilization and manipulation of the major detoxifying enzymes and the molecular basis of degradation are also discussed. This may be useful in developing safer and economic microbiological methods for clean up of soil and water contaminated with such compounds. The necessity of further investigations concerning the microbial metabolism of these substances is also discussed. PMID- 22497285 TI - The clinical effectiveness of oseltamivir in mild cases of pandemic influenza A H1N1 2009 infection. AB - BACKGROUND: Oseltamivir is widely used for the treatment of influenza infection, but data on its effectiveness in treating infections with pandemic influenza A H1N1 2009 are scarce. Therefore, we compared the effectiveness of oseltamivir and routine symptomatic treatment in pandemic influenza A H1N1 2009 infection. METHODS: Between August and October 2009, among laboratory confirmed influenza cases who were aged over 15 y with no underlying disease, 90 patients with oseltamivir treatment and 72 patients with symptomatic treatment were evaluated by telephone interviews to compare clinical outcomes. No patient was hospitalized. The primary end-point was the duration of illness. We also assessed the time to attain a sense of well-being and the time to return to normal activity. RESULTS: There was no statistically significant difference in the duration of illness between the oseltamivir-treated group and the symptomatic treatment group (mean duration after the start of treatment, 6.50 +/- 3.75 days vs 7.04 +/- 3.75 days). There was also no statistically significant difference between the 2 groups in the time to a sense of well-being (1.70 +/- 1.57 days vs 2.00 +/- 2.12 days) and to return to normal activity (7.13 +/- 2.61 days vs 7.58 +/- 2.71 days). The complication rate was very low (only 2 cases of mild pneumonia in oseltamivir recipients) and no significant difference was found between the 2 groups (p = 0.50). CONCLUSIONS: Oral oseltamivir treatment does not significantly reduce the duration of illness or influenza-related complications in mild pandemic influenza A H1N1 2009 virus infection in previously healthy adults. PMID- 22497287 TI - Assessment of theoretical procedures for calculating barrier heights for a diverse set of water-catalyzed proton-transfer reactions. AB - Accurate electronic barrier heights are obtained for a set of nine proton transfer tautomerization reactions, which are either (i) uncatalyzed, (ii) catalyzed by one water molecule, or (iii) catalyzed by two water molecules. The barrier heights for reactions (i) and (ii) are obtained by means of the high level ab initio W2.2 thermochemical protocol, while those for reaction (iii) are obtained using the W1 protocol. These three sets of benchmark barrier heights allow an assessment of the performance of more approximate theoretical procedures for the calculation of barrier heights of uncatalyzed and water-catalyzed reactions. We evaluate initially the performance of the composite G4 procedure and variants thereof (e.g., G4(MP2) and G4(MP2)-6X), as well as that of standard ab initio procedures (e.g., MP2, SCS-MP2, and MP4). We find that the performance of the G4(MP2)-type thermochemical procedures deteriorates with the number of water molecules involved in the catalysis. This behavior is linked to deficiencies in the MP2-based basis-set-correction term in the G4(MP2)-type procedures. This is remedied in the MP4-based G4 procedure, which shows good performance for both the uncatalyzed and the water-catalyzed reactions, with mean absolute deviations (MADs) from the benchmark values lying below the threshold of "chemical accuracy" (arbitrarily defined as 1 kcal mol(-1) ~ 4.2 kJ mol(-1)). We also examine the performance of a large number of density functional theory (DFT) and double-hybrid DFT (DHDFT) procedures. We find that, with few exceptions (most notably PW6-B95 and B97-2), the performance of the DFT procedures that give good results for the uncatalyzed reactions deteriorates with the number of water molecules involved in the catalysis. The DHDFT procedures, on the other hand, show excellent performance for both the uncatalyzed and catalyzed reactions. Specifically, almost all of them afford MADs below the "chemical accuracy" threshold, with ROB2-PLYP and B2K-PLYP showing the best overall performance. PMID- 22497286 TI - Genome-wide association analysis for quantitative trait loci influencing Warner Bratzler shear force in five taurine cattle breeds. AB - We performed a genome-wide association study for Warner-Bratzler shear force (WBSF), a measure of meat tenderness, by genotyping 3360 animals from five breeds with 54 790 BovineSNP50 and 96 putative single-nucleotide polymorphisms (SNPs) within MU-calpain [HUGO nomenclature calpain 1, (mu/I) large subunit; CAPN1] and calpastatin (CAST). Within- and across-breed analyses estimated SNP allele substitution effects (ASEs) by genomic best linear unbiased prediction (GBLUP) and variance components by restricted maximum likelihood under an animal model incorporating a genomic relationship matrix. GBLUP estimates of ASEs from the across-breed analysis were moderately correlated (0.31-0.66) with those from the individual within-breed analyses, indicating that prediction equations for molecular estimates of breeding value developed from across-breed analyses should be effective for genomic selection within breeds. We identified 79 genomic regions associated with WBSF in at least three breeds, but only eight were detected in all five breeds, suggesting that the within-breed analyses were underpowered, that different quantitative trait loci (QTL) underlie variation between breeds or that the BovineSNP50 SNP density is insufficient to detect common QTL among breeds. In the across-breed analysis, CAPN1 was followed by CAST as the most strongly associated WBSF QTL genome-wide, and associations with both were detected in all five breeds. We show that none of the four commercialized CAST and CAPN1 SNP diagnostics are causal for associations with WBSF, and we putatively fine-map the CAPN1 causal mutation to a 4581-bp region. We estimate that variation in CAST and CAPN1 explains 1.02 and 1.85% of the phenotypic variation in WBSF respectively. PMID- 22497289 TI - Nanoscale fullerene compression of an yttrium carbide cluster. AB - The nanoscale parameters of metal clusters and lattices have a crucial influence on the macroscopic properties of materials. Herein, we provide a detailed study on the size and shape of isolated yttrium carbide clusters in different fullerene cages. A family of diyttrium endohedral metallofullerenes with the general formula of Y(2)C(2n) (n = 40-59) are reported. The high field (13)C nuclear magnetic resonance (NMR) and density functional theory (DFT) methods are employed to examine this yttrium carbide cluster in certain family members, Y(2)C(2)@D(5)(450)-C(100), Y(2)C(2)@D(3)(85)-C(92), Y(2)C(2)@C(84), Y(2)C(2)@C(3v)(8)-C(82), and Y(2)C(2)@C(s)(6)-C(82). The results of this study suggest that decreasing the size of a fullerene cage with the same (Y(2)C(2))(4+) cluster results in nanoscale fullerene compression (NFC) from a nearly linear stretched geometry to a constrained "butterfly" structure. The (13)C NMR chemical shift and scalar (1)J(YC) coupling parameters provide a very sensitive measure of this NFC effect for the (Y(2)C(2))(4+) cluster. The crystal structural parameters of a previously reported metal carbide, Y(2)C(3) are directly compared to the (Y(2)C(2))(4+) cluster in the current metallofullerene study. PMID- 22497288 TI - First-principle protocol for calculating ionization energies and redox potentials of solvated molecules and ions: theory and application to aqueous phenol and phenolate. AB - The effect of hydration on the lowest vertical ionization energy (VIE) of phenol and phenolate solvated in bulk water was characterized using the equation-of motion ionization potential coupled-cluster (EOM-IP-CCSD) and effective fragment potential (EFP) methods (referred to as EOM/EFP) and determined experimentally by valence photoemission measurements using microjets and synchrotron radiation. The computed solvent-induced shifts in VIEs (DeltaVIEs) are -0.66 and +5.72 eV for phenol and phenolate, respectively. Our best estimates of the absolute values of VIEs (7.9 and 7.7 eV for phenol and phenolate) agree reasonably well with the respective experimental values (7.8 +/- 0.1 and 7.1 +/- 0.1 eV). The EOM/EFP scheme was benchmarked against full EOM-IP-CCSD using microsolvated phenol and phenolate clusters. A protocol for calculating redox potentials with EOM/EFP was developed based on linear response approximation (LRA) of free energy determination. The oxidation potentials of phenol and phenolate calculated using LRA and EOM/EFP are 1.32 and 0.89 V, respectively; they agree well with experimental values. PMID- 22497290 TI - Preparation of human scFv antibody against nasopharyngeal carcinoma and identification of its specificity. AB - Abstract Conclusion: The selected scFv antibody could specifically recognize and target nasopharyngeal carcinoma (NPC), and could be applied to clinical diagnosis and therapy. OBJECTIVE: The aim was to construct and screen fully human anti-NPC single chain Fv fusion phage libraries, and to identify the specificity of the scFv antibody. METHODS: Peripheral blood mononuclear cells of patients with NPC were immunized in vitro by NPC cells and transformed by Epstein-Barr virus. The total RNAwas used to construct the scFv libraries. By means of ELISA and immunochemistry, the positively bound scFv was selected and identified. The positive scFv was fused to EGFP, and was then expressed in E. coli strain BL21 (DE3) and purified. Furthermore, we observed the binding bioactivity. RESULTS: The fusion protein has the biological activity of binding the NPC cells and emitting green fluorescence. In targeting experiments in vivo, the results showed that the fusion protein can successfully target the NPC. PMID- 22497291 TI - Agreement between anthropometric and dual-energy X-ray absorptiometry assessments of lower-limb volumes and composition estimates in youth-club rugby athletes. AB - The purpose of this study was to assess the agreement of lower-limb volume estimates based on anthropometry and dual-energy X-ray absorptiometry (DXA) as a reference method in male rugby athletes. Predictive models using body mass and skinfolds were tested to improve the relative agreement between protocols (anthropometry, DXA). Rugby players (n = 41; 19.9 +/- 2.2 years) volunteered for the study. Lower-limb total and fat-free volumes were estimated by anthropometry and also derived using DXA. Cross-validation between the anthropometry technique and DXA was then performed. Lower-limb volume estimates by anthropometry overestimated reference values and tended to be further from the reference values with the increase of scale. For the total sample, standard errors of measurement for volume estimates by anthropometry were 1.99 L and 1.34 L for total and fat free volumes, respectively. Correlations with reference values were 0.81 for lower-limb volume and 0.90 for lower-limb fat-free volume. Correlations between estimated prediction equations and reference values showed higher correlations (r = 0.96 for lower-limb volume and r = 0.93 for lower-limb fat-free volume) compared with anthropometric estimates. Overall, the agreement of anthropometry method to quantify lower-limb volumes with DXA as a reference in young adult rugby players is acceptable and is a practical method when more expensive and complex techniques are not available. The consideration of body mass and lower limb skinfolds increases the precision of lower-limb volume estimates using anthropometry in the young adult rugby players. PMID- 22497292 TI - Association of bovine fatty acid composition with missense nucleotide polymorphism in exon7 of peroxisome proliferator-activated receptor gamma gene. PMID- 22497293 TI - Performance of the woman's condom among couples in Shanghai, China. AB - BACKGROUND: The Woman's Condom, a second-generation female condom, is poised for introduction in China. STUDY DESIGN: This single-arm couples' use study was conducted in China in 2010 to assess performance and safety of the Woman's Condom and feasibility of mobile phone technology to record adherence data. RESULTS: Sixty couples were enrolled in this study, and 59 couples completed all four of the condom uses, resulting in 234 condom uses. Two condoms were opened but not used. Total breakage was 0.85% (two non-clinical breakages). Misdirection (2%), invagination (0.85%) and slippage (1%) were consistent with data on condom failure from other studies. Total clinical failure was 4%. Fifteen mild and no serious adverse events were reported during the study. CONCLUSIONS: This study has shown that in China, the Woman's Condom performs well. Mobile phones cannot yet replace the use of a coital log and questionnaire. Further work on effectiveness is required. PMID- 22497294 TI - Surgical repair of an unusual type of supra-cardiac total anomalous pulmonary venous connection to the superior vena cava. AB - Anomalies of the pulmonary venous drainage vary widely in their anatomic spectrum and clinical presentation. We describe an unusual case of supra-cardiac total anomalous pulmonary venous connection (TAPVC), where the pulmonary veins drained directly in the posterior aspect of proximal right superior vena cava (SVC) through separate ostia. The veins were re-routed with a patch to the left atrium via the secundum atrial septal defect (ASD). The continuity between distal SVC and right atrium was re-established by re-implanting the SVC to the right atrial appendage (Warden Procedure). PMID- 22497296 TI - Photoinduced radical processes on the spinel (MgAl2O4) surface involving methane, ammonia, and methane/ammonia. AB - The present study explored photoinduced radical processes caused by interaction of CH(4) and NH(3) with a photoexcited surface of a complex metal oxide: magnesium-aluminum spinel (MgAl(2)O(4); MAS). UV irradiation of MAS in vacuo yielded V-type color centers as evidenced by the 360 nm band in difference diffuse reflectance spectra. Interaction of these H-bearing molecules with photogenerated surface-active hole states (O(S)(-)*) yielded radical species which on recombination produced more complex molecules (including heteroatomic species) relative to the initial molecules. For the MAS/CH(4) system, photoinduced dissociative adsorption of CH(4) on surface-active hole centers produced *CH(3) radicals that recombined to yield CH(3)CH(3). For MAS/NH(3), a similar dissociative adsorption process led to formation of *NH(2) radicals with formation of NH(2)NH(2) as an intermediate product; continued UV irradiation ultimately yielded N(2). For the mixed MAS/CH(4)/NH(3) system, however, interaction of adsorbed NH(3) and CH(4) on the UV-activated surface of MAS yielded *NH(2) and *CH(3) radicals, respectively, which produced CH(3)-NH(2) followed by loss of the remaining hydrogens to form a surface-adsorbed cyanide, CN(S), species. Recombination of photochemically produced radicals released sufficient energy to re-excite the solid spinel, generating new surface-active sites and a flash luminescence (emission decay time at 520 nm, tau ~ 6 s for the MAS/NH(3) case) referred to as the PhICL effect. PMID- 22497295 TI - Genome-wide association analysis for feed efficiency in Angus cattle. AB - Estimated breeding values for average daily feed intake (AFI; kg/day), residual feed intake (RFI; kg/day) and average daily gain (ADG; kg/day) were generated using a mixed linear model incorporating genomic relationships for 698 Angus steers genotyped with the Illumina BovineSNP50 assay. Association analyses of estimated breeding values (EBVs) were performed for 41,028 single nucleotide polymorphisms (SNPs), and permutation analysis was used to empirically establish the genome-wide significance threshold (P < 0.05) for each trait. SNPs significantly associated with each trait were used in a forward selection algorithm to identify genomic regions putatively harbouring genes with effects on each trait. A total of 53, 66 and 68 SNPs explained 54.12% (24.10%), 62.69% (29.85%) and 55.13% (26.54%) of the additive genetic variation (when accounting for the genomic relationships) in steer breeding values for AFI, RFI and ADG, respectively, within this population. Evaluation by pathway analysis revealed that many of these SNPs are in genomic regions that harbour genes with metabolic functions. The presence of genetic correlations between traits resulted in 13.2% of SNPs selected for AFI and 4.5% of SNPs selected for RFI also being selected for ADG in the analysis of breeding values. While our study identifies panels of SNPs significant for efficiency traits in our population, validation of all SNPs in independent populations will be necessary before commercialization. PMID- 22497297 TI - Genome-wide association study uncovers four QTL predisposing to supernumerary teats in cattle. AB - Supernumerary teats (hyperthelia, SNTs) are a common abnormality of the bovine udder with a medium to high heritability and a postulated oligogenic or polygenic inheritance pattern. SNTs not only negatively affect machine milking ability but also act as a reservoir for bacteria. A genome-wide association study was carried out to identify genes involved in the development of SNTs in the dual-purpose Fleckvieh breed. A total of 2467 progeny-tested bulls were genotyped at 43 698 single nucleotide polymorphisms, and daughter yield deviations (DYDs) for 'udder clearness' (UC) were used as high-heritability phenotypes. Massive structuring of the study population was accounted for by principal components analysis-based and mixed model-based approaches. Four loci on BTA5, BTA6, BTA11 and BTA17 were significantly associated with the UC DYD. Three associated regions contain genes of the highly conserved Wnt signalling pathway. The four QTL together account for 10.7% of the variance of the UC DYD, whereas the major fraction of the DYD variance is attributable to chromosomes with no identified QTL. Our results support both an oligogenic and a polygenic inheritance pattern of SNTs in cattle. The identified candidate genes permit insights into the genetic architecture of teat malformations in cattle and provide clues to unravel the molecular mechanisms of mammary gland alterations in cattle and other species. PMID- 22497299 TI - Studies toward the total synthesis of nagelamide K. AB - A stereocontrolled strategy toward the synthesis of nagelamide K has been developed. The dimeric imidazole acrylate, diimidazolidenesuccinate, was constructed as a synthetic precursor by a Ni-catalyzed coupling reaction; the microwave-promoted intramolecular aza-Michael addition afforded the imidazo[1,5 a]pyridine core structure of nagelamide K in high stereoselectivity. A detaurine dediamino analogue of nagelamide K has been prepared. PMID- 22497298 TI - Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A. AB - AIM: The primary objective was to evaluate the pharmacokinetics (PK) of the novel EP(1) antagonist GSK269984A in human volunteers after a single oral and intravenous (i.v.) microdose (100 ug). METHOD: GSK269984A was administered to two groups of healthy human volunteers as a single oral (n= 5) or i.v. (n= 5) microdose (100 ug). Blood samples were collected for up to 24 h and the parent drug concentrations were measured in separated plasma using a validated high pressure liquid chromatography-tandem mass spectrometry method following solid phase extraction. RESULTS: Following the i.v. microdose, the geometric mean values for clearance (CL), steady-state volume of distribution (V(ss) ) and terminal elimination half-life (t(1/2) ) of GSK269984A were 9.8 l h(-1) , 62.8 l and 8.2 h. C(max) and AUC(0,infinity) were 3.2 ng ml(-1) and 10.2 ng ml(-1) h, respectively; the corresponding oral parameters were 1.8 ng ml(-1) and 9.8 ng ml( 1) h, respectively. Absolute oral bioavailability was estimated to be 95%. These data were inconsistent with predictions of human PK based on allometric scaling of in vivo PK data from three pre-clinical species (rat, dog and monkey). CONCLUSION: For drug development programmes characterized by inconsistencies between pre-clinical in vitro metabolic and in vivo PK data, and where uncertainty exists with respect to allometric predictions of the human PK profile, these data support the early application of a human microdose study to facilitate the selection of compounds for further clinical development. PMID- 22497300 TI - Comparison of joining and constant kappa-light chain regions in different cattle breeds. AB - A comparative transcription analysis of Ig kappa-light chains (IGK) of the cattle breeds Holstein Friesian (HF), German Black Pied (GBP), German Simmental (GS) and Aubrac (A) revealed three alleles coding for two putative allotypic variants of IGKC. The amino acid residues p.Asp100Asn and p.Thr116Ala were located at the outer edge of the constant domain as demonstrated by homology-based modelling. Alleles were distributed in unequal frequencies within the breeds examined. While cattle breeds HF, GS, and A possessed all alleles and allotypic variants, GBP exhibited alleles encoding allotypic variant IGKC(a) . All three IGKJ segments were detected in 320 sequences analysed. IGKJ1 was combined predominantly with IGKC. The ORF2 of IGKJ2 was detected for the first time on transcriptional level. PMID- 22497302 TI - The nucleotide sequence, DNA damage location, and protein stoichiometry influence the base excision repair outcome at CAG/CTG repeats. AB - Expansion of CAG/CTG repeats is the underlying cause of >14 genetic disorders, including Huntington's disease (HD) and myotonic dystrophy. The mutational process is ongoing, with increases in repeat size enhancing the toxicity of the expansion in specific tissues. In many repeat diseases, the repeats exhibit high instability in the striatum, whereas instability is minimal in the cerebellum. We provide molecular insights into how base excision repair (BER) protein stoichiometry may contribute to the tissue-selective instability of CAG/CTG repeats by using specific repair assays. Oligonucleotide substrates with an abasic site were mixed with either reconstituted BER protein stoichiometries mimicking the levels present in HD mouse striatum or cerebellum, or with protein extracts prepared from HD mouse striatum or cerebellum. In both cases, the repair efficiency at CAG/CTG repeats and at control DNA sequences was markedly reduced under the striatal conditions, likely because of the lower level of APE1, FEN1, and LIG1. Damage located toward the 5' end of the repeat tract was poorly repaired, with the accumulation of incompletely processed intermediates as compared to an AP lesion in the center or at the 3' end of the repeats or within control sequences. Moreover, repair of lesions at the 5' end of CAG or CTG repeats involved multinucleotide synthesis, particularly at the cerebellar stoichiometry, suggesting that long-patch BER processes lesions at sequences susceptible to hairpin formation. Our results show that the BER stoichiometry, nucleotide sequence, and DNA damage position modulate repair outcome and suggest that a suboptimal long-patch BER activity promotes CAG/CTG repeat instability. PMID- 22497304 TI - Ventricular assist device support in children and adolescents with heart failure: the Children's Medical Center of Dallas experience. AB - Children with heart failure unresponsive to medical therapy are left with few options for survival. Ventricular assist devices (VADs) are life-saving options for such patients, allowing for bridge to transplantation or cardiac recovery. Retrospective review of cases from May 2006 to October 2010 was undertaken. Fourteen patients underwent implantation of VADs for refractory heart failure. Mean age was 9 years (range 1-17 years), and weight was 41 kg (range 9.7-71 kg). Indications for support: end-stage cardiomyopathy (n = 8), myocarditis (n = 3), univentricular failure (n = 2), and congenital heart disease/postcardiotomy (n = 1). Level of limitation at time of implant included critical cardiogenic shock in six (43%) and progressive decline in eight (57%). Extracorporeal membrane oxygenation was used as a bridge to VAD in five (36%) patients. Preimplant variables: 86% of patients requiring mechanical ventilation (mean 10.3 days), hyperbilirubinemia in 75%, and acute renal insufficiency in 79%. Device selection was systemic VAD in 11 (79%) and biventricular assist device in three (21%). Berlin Heart EXCOR was used in eight patients, while six patients received a Thoratec implantable VAD or paracorporeal VAD. Mean duration of support was 68 days (range 8-363 days). Overall survival was 79%. Ten patients (71%) were successfully bridged to transplantation, three (21%) died while on a device, one remains on support, and no patients were weaned from VAD. Children supported for single ventricle heart failure had a 50% survival with none currently bridged to transplantation. Complications included bleeding requiring reoperation in 21% (n = 3), stroke in 29% (n = 4), and driveline infections in 7% (n = 1). In two patients, a total of six pump exchanges were performed for thrombus formation. Survival for pediatric patients of all ages is excellent using current device technology with a majority of patients being successfully bridged to transplantation. Morbidity is acceptably low considering the severity of illness. Significant challenges exist with long-term extracorporeal support due to lack of donor availability and the high incidence of preformed alloantibodies especially in the failing single ventricle. PMID- 22497303 TI - Unusual arginine formations in protein function and assembly: rings, strings, and stacks. AB - Protein-protein interfaces are often stabilized by a small number of dominant contacts, exemplified by the overrepresentation of arginine residues at oligomerization interfaces. Positively charged arginines are most commonly involved in ion pairs of opposite charge; however, previous work of Scheraga and co-workers described the stable, close range interaction between guanidinium pairs in a solvated environment. To extend this work, we searched over 70 thousand protein structures and complexes for unusual formations of arginine residues supported by the electron density. Symmetry transformations were used to generate full assemblies. Clusters of four to eight arginine residues with C(zeta)-C(zeta) distances <5 A, organized as rings with four to eight members, stacks of two arginines, and strings of stacked arginines, are commonly located at the interfaces of oligomeric proteins. The positive charge is properly balanced by negatively charged counterions in about 90% of the cases. We also observed planar stacking of guanidinium groups, bridged by hydrogen bonds and interactions with water molecules. The guanidinium groups are commonly involved in five hydrogen bonds with water molecules and acceptor groups from surrounding amino acids. Water molecules have a bridging effect on the arginine pairs, but in some cases, small molecular weight chemicals in the crystallization buffer may be misinterpreted as water molecules. In summary, despite electrostatic repulsion, arginines do form various clusters that are exposed to interact with and potentially be controlled or switched by charged metabolites, membrane lipids, nucleic acids, or side chains of other proteins. Control of the stability of arginine clusters may play an important role in protein-protein oligomerization, molecular recognition, and ligand binding. PMID- 22497305 TI - Obesity is the predominant predictor of impaired glucose tolerance and metabolic disturbance in polycystic ovary syndrome. AB - OBJECTIVE: To evaluate the contribution to glucose intolerance and metabolic syndrome of obesity combined with the diagnostic criteria of polycystic ovary syndrome (PCOS). DESIGN: Prospective study. SETTING: University teaching hospital from 31 August 2010 to 31 August 2011. POPULATION: Two hundred and twenty women with PCOS and seventy normal control women. METHODS: The clinical and biochemical characteristics of women with PCOS and control women were evaluated. Main outcome measures. The impact of obesity, hyperandrogenism, oligo-anovulation and polycystic ovary morphology on impaired glucose tolerance and metabolic disturbances. RESULTS: Obese women with PCOS had significantly higher insulin resistance than obese normal control women. Logistic regression analysis showed that obesity was the only factor that predicted impaired glucose tolerance and metabolic syndrome. Use of the area under the receiver operating characteristic curve (AUROC) for the body mass index to predict impaired glucose tolerance and metabolic syndrome was more accurate than AUROCs for serum total testosterone level and the average menstrual interval. CONCLUSIONS: Body weight status was the major factor determining the risk of impaired glucose tolerance and metabolic syndrome in women with PCOS. Obesity should be treated as the major factor determining long-term health consequences associated with PCOS. PMID- 22497307 TI - Single-nucleotide polymorphisms in the promoter of the growth hormone-releasing hormone receptor gene are associated with growth and reproduction traits in chickens. AB - Growth hormone-releasing hormone receptor (GHRHR) plays a critical role in growth hormone (GH) synthesis, release and regulation in animals. The objective of this study was to investigate variations of the chicken GHRHR gene and their associations with growth and reproduction traits in 768 Beijing You chickens. Results revealed three single nucleotide polymorphisms (SNPs) in the promoter region of the gene (g.-1654A>G, g.-1411A>G and g.-142T>C). Association analysis revealed that the novel SNP g.-1654A>G had significant effects on chicken body weight at 7, 9, 11, 13, 17 weeks of age and the age of first egg as well as egg number at 32, 36 and 40 weeks. Significant association was also observed between g.-1411A>G and g.-142T>C with EN24. Moreover, the age of first egg was distinctly related with g.-142T>C (P < 0.05). Although significant statistical difference was not detected in GHRHR mRNA levels among genotypes of the SNPs (P > 0.05), strong expression variations of the gene were found between the ages 17 and 20 weeks in the population (P < 0.05). These results suggest that the three SNPs in the GHRHR promoter could be used as potential genetic markers to improve the growth and reproductive traits in chickens. PMID- 22497308 TI - Spread of carbapenemase NDM-1 producers: the situation in India and what may be proposed. AB - New Delhi metallo-beta-lactamase 1 (NDM-1) producers, first identified from patients hospitalized in India, are now reported worldwide. The Indian subcontinent is clearly a main reservoir of NDM-1 producers. In order to slow down the spread of these NDM-1-positive Enterobacteriaceae, first in India and then worldwide, a series of measures must be implemented as soon as possible. These include discouraging the over-the-counter sale of antibiotics, improving basic and extended knowledge on hygiene, and the wide-scale detection of bla(NDM 1), in both infecting agents and in the carrier state for at-risk patients. PMID- 22497309 TI - Pulmonary artery bypass for in-stent stenosis following angioplasty for isolated pulmonary Takayasu arteritis. AB - Pulmonary artery (PA) stenosis due to Takayasu Arteritis (TA) is usually managed by angioplasty techniques. We present a patient with isolated PA stenosis with TA with in-stent stenosis. The surgical management and pathophysiology of this disease are reviewed. PMID- 22497311 TI - Effect of an exon 1 mutation in the myostatin gene on the growth traits of the Bian chicken. AB - Myostatin (MSTN), or growth and differentiation factor 8 (GDF8), is a member of the transforming growth factor (TGF)-beta superfamily. This family functions as a negative regulator of skeletal muscle development and growth in mammals. Single nucleotide polymorphisms in exon 1 of the Bian chicken myostatin gene were detected by polymerase chain reaction-restriction fragment length polymorphism. A mutation (c.234G>A) in exon 1 was found. Female Bian chickens of genotypes AA and GA had significantly higher body weights than those of genotype GG (P < 0.05 or P < 0.01) from 6 to 18 weeks of age. These results suggested that the mutation c.234G>A in exon 1 could be used as a genetic marker for Bian chicken growth traits. PMID- 22497310 TI - Develop and test a solvent accessible surface area-based model in conformational entropy calculations. AB - It is of great interest in modern drug design to accurately calculate the free energies of protein-ligand or nucleic acid-ligand binding. MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) and MM-GBSA (molecular mechanics generalized Born surface area) have gained popularity in this field. For both methods, the conformational entropy, which is usually calculated through normal mode analysis (NMA), is needed to calculate the absolute binding free energies. Unfortunately, NMA is computationally demanding and becomes a bottleneck of the MM-PB/GBSA-NMA methods. In this work, we have developed a fast approach to estimate the conformational entropy based upon solvent accessible surface area calculations. In our approach, the conformational entropy of a molecule, S, can be obtained by summing up the contributions of all atoms, no matter they are buried or exposed. Each atom has two types of surface areas, solvent accessible surface area (SAS) and buried SAS (BSAS). The two types of surface areas are weighted to estimate the contribution of an atom to S. Atoms having the same atom type share the same weight and a general parameter k is applied to balance the contributions of the two types of surface areas. This entropy model was parametrized using a large set of small molecules for which their conformational entropies were calculated at the B3LYP/6-31G* level taking the solvent effect into account. The weighted solvent accessible surface area (WSAS) model was extensively evaluated in three tests. For convenience, TS values, the product of temperature T and conformational entropy S, were calculated in those tests. T was always set to 298.15 K through the text. First of all, good correlations were achieved between WSAS TS and NMA TS for 44 protein or nucleic acid systems sampled with molecular dynamics simulations (10 snapshots were collected for postentropy calculations): the mean correlation coefficient squares (R2) was 0.56. As to the 20 complexes, the TS changes upon binding; TDeltaS values were also calculated, and the mean R2 was 0.67 between NMA and WSAS. In the second test, TS values were calculated for 12 proteins decoy sets (each set has 31 conformations) generated by the Rosetta software package. Again, good correlations were achieved for all decoy sets: the mean, maximum, and minimum of R2 were 0.73, 0.89, and 0.55, respectively. Finally, binding free energies were calculated for 6 protein systems (the numbers of inhibitors range from 4 to 18) using four scoring functions. Compared to the measured binding free energies, the mean R2 of the six protein systems were 0.51, 0.47, 0.40, and 0.43 for MM-GBSA WSAS, MM-GBSA-NMA, MM-PBSA-WSAS, and MM-PBSA-NMA, respectively. The mean rms errors of prediction were 1.19, 1.24, 1.41, 1.29 kcal/mol for the four scoring functions, correspondingly. Therefore, the two scoring functions employing WSAS achieved a comparable prediction performance to that of the scoring functions using NMA. It should be emphasized that no minimization was performed prior to the WSAS calculation in the last test. Although WSAS is not as rigorous as physical models such as quasi-harmonic analysis and thermodynamic integration (TI), it is computationally very efficient as only surface area calculation is involved and no structural minimization is required. Moreover, WSAS has achieved a comparable performance to normal-mode analysis. We expect that this model could find its applications in the fields like high throughput screening (HTS), molecular docking, and rational protein design. In those fields, efficiency is crucial since there are a large number of compounds, docking poses, or protein models to be evaluated. A list of acronyms and abbreviations used in this work is provided for quick reference. PMID- 22497312 TI - Antenatal counselling for parents facing an extremely preterm birth: limitations of the medical evidence. AB - When physicians are asked for a consult for women in premature labour, they face a complex set of challenges. Policy statements recommend that women be given detailed information about the risks of various outcomes, including death, long term disability and various specific neonatal problems. Both personal narratives and studies suggest that parents also base their decisions on factors other than the probabilistic facts about expected outcomes. Statistics are difficult to understand at any time. Rational decision-making may be difficult when taking life-and-death decisions. Furthermore, the role of emotions is not discussed in peri-viability guidelines. CONCLUSION: We argue against trying to tell parents every fact that we think might be relevant to their decision. This may be overwhelming for many parents. Instead, doctors should try to discern, on a case by-case basis, what particular parents want and need. Information and delivery of information should be personalized. Unfortunately, evidence in this area is limited. PMID- 22497313 TI - Combining quantitative trait loci and heterogeneous microarray data analyses reveals putative candidate pathways affecting mastitis in cattle. AB - Mastitis is a frequent disease and considerable problem for the global dairy industry. Identification of solutions leading to the development of new control strategies is therefore of high importance. In this study, we have integrated genomic data from genome-wide association mapping in cattle with transcriptomic data from microarray studies of several mastitis pathogens and host species in vitro and in vivo. To identify significant candidate pathways directly and indirectly involved in the immune response to mastitis, ingenuity pathway analysis (ipa) and database for annotation, visualization and integrated discovery bioinformatic (david) were applied. Several candidate pathways were found. Of great interest are IL-17 and IL-8 signalling pathways, responsible for the recruitment and migration of inflammatory cells into tissue during inflammation and infection. These results may emphasize further functional studies for identification of factors contributing to resistance to mastitis pathogens in cattle. PMID- 22497314 TI - Effects of modernisation and new population policies on reproductive health in Kars, Turkey. AB - BACKGROUND: The 1983 Turkish Population Planning Act aimed at improving reproductive health outcomes. We examined the effects of the Act and of modernisation in a small, underdeveloped city and province, Kars. METHODS: Between June 2009 and January 2010, 576 parous women at a hospital in Kars participated in a study of reproductive histories and living standards. Results were compared by decade during which the birth took place of the first child who survived its first year, and urban/rural residence. Correlation and multi-way analyses of variance (ANOVA), chi(2) and t tests were used as appropriate. We also examined women's education and living standards and use of hospital and family planning (FP) facilities. RESULT: From 1970 through 2009 maternal age at first live birth increased by 4.9 years (p < 0.05) from a baseline of 18.9 years. The number of pregnancies fell from a mean of 8.1 per woman in the 1970s to 5.6 in the 1980s (p < 0.05), with strong indications of continued decreases through the 2000-2009 decade. FP sites in Kars province increased in number and services, as did antenatal hospital visits and the proportions of women giving birth in a hospital. Concomitantly, delivery by caesarean section augmented markedly over the decades. Education levels of both urban and rural women rose from two years of schooling in the 1970s to ten years in the last decade. CONCLUSION: Modernisation, including increasing urbanisation, education, and new governmental policies that translated into maternal-child health and FP services were likely the backbone for improved reproductive health and lower fertility rates of women in Kars over the 40 year-period we studied. PMID- 22497315 TI - Fish oil induced hyperlipidemia and oxidative stress in BioF1B hamsters is attenuated by elderberry extract. AB - We have previously reported fish oil induced hyperlipidemia in BioF1B hamsters compared with Golden Syrian (GS) hamsters. Elderberry (Sambucus nigra L.) extract is abundant in anthocyanins and is believed to exert cardioprotective effects primarily by virtue of its hypolipidemic and antioxidant potential. In the current study, high-fat fish oil feeding increased oxidative stress in BioF1B hamsters compared with GS hamsters; this increase was associated with increased levels of omega-3 polyunsaturated fatty acids in plasma and liver. We then investigated whether cosupplementation with anthocyanin-rich elderberry extract would reverse fish oil induced hyperlipidemia and reduce lipid peroxidation in BioF1B hamsters. Plasma and hepatic lipids decreased significantly when hamsters were fed diets containing elderberry extract along with fish oil. Both plasma and liver thiobarbituric acid reactive substances showed significant reductions upon cosupplementation with elderberry extract in fish oil fed BioF1B hamsters. Our findings demonstrate that cosupplementation with elderberry extract reverses hyperlipidemia and lipid peroxidation observed with dietary fish oil alone in BioF1B hamsters. PMID- 22497317 TI - Decreased paediatric antibiotic consumption in France between 2000 and 2010. AB - BACKGROUND: Antibiotic consumption is one of the main causes of bacterial resistance to antibiotics and a major public health problem worldwide, especially in France. A national campaign was implemented in 2001 to reduce the inappropriate use of antibiotics in France, and guidelines for the management of respiratory tract infections were published in 2005. METHODS: In this study, data on paediatric outpatient antibiotic use in France between 2000 and 2010 were derived from prescribing panels of the Permanent Survey of Medical Prescription, which analyzed prescriptions by 835 French general practitioners and specialists. RESULTS: Overall, antibiotic prescriptions decreased by 57.2% between 2001 and 2010 in children aged 0-24 months, by 50.0% in children aged 25 months to 6 y, and by 45.8% in children older than 6 y of age. In the 3 age groups, the greatest reduction was for rhinopharyngitis (83.4%) and the lowest was for otitis (22.4%). Because otitis is one of the most common diseases in childhood, the proportion of antibiotic prescriptions due to otitis in children aged 0-24 months consequently increased from 22.5% in 2000 to 42.3% in 2010. CONCLUSION: Additional measures may be necessary to decrease antibiotic consumption related to otitis in young children. PMID- 22497316 TI - Different roles of TM5, TM6, and ECL3 in the oligomerization and function of human ABCG2. AB - ABCG2 is a member of the ATP-binding cassette transporter superfamily, and its overexpression causes multidrug resistance (MDR) in cancer chemotherapy. ABCG2 may also protect cancer stem cells by extruding cytotoxic materials. ABCG2 has previously been shown to exist as a high-order homo-oligomer consisting of possibly 8-12 subunits, and the oligomerization domain was mapped to the C terminal domain, including TM5, ECL3, and TM6. In this study, we further investigate this domain in detail for the role of each segment in the oligomerization and drug transport function of ABCG2 using domain swapping and site-directed mutagenesis. We found that none of the three segments (TM5, TM6, and ECL3) is essential for the oligomerization activity of ABCG2 and that any one of these three segments in the full-length context is sufficient to support ABCG2 oligomerization. While TM5 plays an important role in the drug transport function of ABCG2, TM6 and ECL3 are replaceable. Thus, each segment in the TM5-ECL3-TM6 domain plays a distinctive role in the oligomerization and function of ABCG2. PMID- 22497318 TI - Outcome of bone-anchored hearing aids for single-sided deafness: a prospective study. AB - CONCLUSION: The bone-anchored hearing aid (BAHA) system can offer significant benefits to patients with single-sided deafness (SSD), primarily by lifting the head shadow effect. OBJECTIVE: To evaluate the efficacy of BAHA for SSD by comparing pre- and postoperative speech, spatial and qualities of hearing scale (SSQ) scores. METHODS: This was a prospective study conducted within a tertiary auditory implant department. The inclusion criteria were unilateral profound hearing loss with normal or mild high frequency hearing loss in the hearing ear (pure tone average better than or equal to 25 dBHL measured at 0.5, 1, 2 and 3 kHz) and subjective benefits reported by patients following a home trial with a BAHA Softband. Patients who met the above criteria and opted for surgery were asked to complete the SSQ questionnaire. The postoperative SSQ response was collected after at least 6 months of consistent BAHA usage. RESULTS: This study included 25 adult patients (mean age at implantation 57.5 years). There was a statistically significant improvement in the average SSQ score in all three sections of the questionnaire with the use of the BAHA. Our patients experienced most marked benefits in speech hearing in challenging listening situations. All patients remain consistent users and there has been no explantation to date. PMID- 22497319 TI - Copper-catalyzed oxidative trifluoromethylation of terminal alkenes using nucleophilic CF3SiMe3: efficient C(sp3)-CF3 bond formation. AB - An efficient C(sp(3))-CF(3) bond-forming reaction via Cu-catalyzed oxidative trifluoromethylation of terminal alkenes has been developed, which proceeds under mild conditions using readily available, less expensive CF(3)SiMe(3) as the source of the CF(3) group. This method allows access to a variety of trifluoromethylated allylic compounds. PMID- 22497320 TI - Longitudinal study of the uterine body and cavity with three-dimensional ultrasonography in the puerperium. AB - OBJECTIVE: To describe uterine involution in the puerperium with three dimensional ultrasound. DESIGN: Prospective, longitudinal study. SETTING: Fetal medicine unit, department of obstetrics and gynecology, university referral hospital, Uppsala, Sweden. POPULATION: Fifty women with uncomplicated deliveries and puerperium between February 2009 and February 2010. METHODS: Three dimensional ultrasound was used to measure the uterine body and cavity volumes. The volume data set was analysed using virtual organ computer-aided analysis (VOCAL) with a 30 degree rotation step. Measurements were performed transabdominally on days 1, 7 and 14 and transvaginally on days 28 and 56 postpartum. Parity, gestational age, birthweight, smoking, breastfeeding and blood loss were recorded. MAIN OUTCOME MEASURES: Uterine body and cavity volumes. RESULTS: Median uterine body volume was 756 cm(3) on day 1, 440 cm(3) on day 7, 253 cm(3) on day 14, 125 cm(3) on day 28 and 68 cm(3) on day 56. Median cavity volume was 22 cm(3) on day 1, 18 cm(3) on day 7, 6 cm(3) on day 14, 1 cm(3) on day 28 and not measurable on day 56. The interindividual variation of uterine body and cavity volumes was most pronounced on day 1 and decreased throughout the observation period. Intrauterine content was found in 36% of the women on day 1, 95% on day 7, 87% on day 14 and 28% on day 28. CONCLUSIONS: Three-dimensional ultrasound is a non-invasive tool suitable for measurement of the uterine body and cavity volumes during the puerperium. The volumes decreased in a similar pattern in the study population. PMID- 22497321 TI - Genome-wide identification and initial characterization of bovine long non-coding RNAs from EST data. AB - It has become increasingly clear that the mammalian genomes produce many long non coding RNAs (lncRNAs). Accumulating evidence suggests important functions for lncRNAs in a variety of biological processes. However, little is known about lncRNA identity and characteristics in cattle. Using public bovine-specific expressed sequence tags sequences, we reconstructed transcript assemblies, from which reference sequences were obtained for RNAs. Intergenic regions with evidence of transcription were screened for putative lncRNAs using the combination of a gene-finding program and a support vector machine-based tool for the calculation of protein-coding potential. A total of 449 putative lncRNAs located in 405 intergenic regions were identified. Characterization of these putative bovine lncRNAs suggests that they are generally expressed in a tissue specific manner, their GC contents are higher than randomly selected intergenic sequences but are lower than protein-coding genes, and they are moderately conserved among mammals. This is the first genome-wide catalogue of putative intergenic lncRNAs in cattle and provides important targets for functional studies. PMID- 22497322 TI - An e-learning course in medical immunology: does it improve learning outcome? AB - BACKGROUND: E-learning is used by most medical students almost daily and several studies have shown e-learning to improve learning outcome in small-scale interventions. However, few studies have explored the effects of e-learning in immunology. AIM: To study the effect of an e-learning package in immunology on learning outcomes in a written integrated examination and to examine student satisfaction with the e-learning package. METHODS: All second-year students at a Norwegian medical school were offered an animated e-learning package in basic immunology as a supplement to the regular teaching. Each student's log-on-time was recorded and linked with the student's score on multiple choice questions included in an integrated end-of-the-year written examination. Student satisfaction was assessed through a questionnaire. RESULTS: The intermediate range students (interquartile range) on average scored 3.6% better on the immunology part of the examination per hour they had used the e-learning package (p = 0.0046) and log-on-time explained 17% of the variance in immunology score. The best and the less skilled students' examination outcomes were not affected by the e-learning. The e-learning was well appreciated among the students. CONCLUSION: Use of an e-learning package in immunology in addition to regular teaching improved learning outcomes for intermediate-range students. PMID- 22497323 TI - Lumbar posterolateral fusion using heparin-conjugated fibrin for sustained delivery of bone morphogenic protein-2 in a rabbit model. AB - We had devised a heparin-conjugated fibrin (HCF) system to deliver bone morphogenic proteins (BMPs) for a long-term period to enhance bone regeneration. In the present study, we tested the effectiveness of the delivery system for spinal fusion in a rabbit model. A total of 15 rabbits underwent posterolateral lumbar spine fusion with BMP-2 (50 ug per collagen sponge). The control group received only collagen sponges without BMP-2, another group (short-term delivery [SD] group) received collagen sponges filled with fibrin gel loaded with BMP-2, and the third group (long-term delivery [LD] group) received collagen sponges filled with HCF loaded with BMP-2. All animals were euthanized 8 weeks after surgery, and the fusion was assessed by radiographs, manual palpation, computed tomography, and mechanical testing. The fusion rate was significantly higher in the LD group using HCF than in the SD group or in the control group. Biomechanical testing showed the tensile strength was also significantly higher in the LD group using HCF than in other groups. The HCF system can provide a good option for the delivery of BMP-2 on posterolateral lumbar spine fusion. PMID- 22497324 TI - Association analysis of SNPs in the IL21R gene with recurrent airway obstruction (RAO) in Swiss Warmblood horses. PMID- 22497325 TI - pH effect on protein G orientation on gold surfaces and characterization of adsorption thermodynamics. AB - The pH effect on adsorbed antibody-binding protein (protein G) orientation on gold (Au) and its adsorption thermodynamic characteristics were investigated using quartz crystal microbalance (QCM) and X-ray photoelectron spectroscopy (XPS). The adsorbed protein G orientation was measured by binding response of two antibody-antigen systems: the model bovine serum albumin (BSA) and the foodborne pathogen E. coli O157:H7. Surface coverage was not significantly affected by pH, but its orientation was. The most properly oriented protein G for antibody binding was achieved at near-neutral pH. Adsorption was verified by XPS measurements using nitrogen (N) 1s, oxygen (O) 1s, and Au 4p peak heights. Adsorption energetics were determined by van't Hoff and Langmuir kinetic analyses of adsorption data obtained at 296, 303, and 308 K. Large characteristic entropy change of protein adsorption was observed (DeltaS degrees = 0.52 +/- 0.01 kcal/mol.K). The adsorption process was not classical physisorption but exhibited chemisorption characteristics based on significant enthalpy change (DeltaH degrees = -25 +/- 6 kcal/mol). PMID- 22497326 TI - Paradigms to reduce the risk of depression: the importance of women's work. PMID- 22497327 TI - Korean American women's preventive health care practices: stratified samples in California, USA. AB - Using data from a larger study, we explored the characteristics of preventive health care practices (influenza vaccination, mammogram, and Pap test) among a representative sample of 1,786 Korean American women residing in California by telephone. Three preventive health care practices were related to the goals set by Healthy People 2010. Participants with no education in the United States, who were born in Korea, resided in the United States longer, and had a primary care provider were more likely than others to reach these goals. Our findings indicate that a behavioral model was suitable to explain the three preventive health care practices. PMID- 22497328 TI - A decade after Guatemala's agreement on identity and rights of indigenous peoples: Mayan-Tz'utujil women's views on health, healing, and disease. AB - Mayan women have been called "guardians of life and ancestral culture." As such, one of their main responsibilities is the health of those in their care. Mothers are the ones who, as soon as a child, husband, or older relative falls sick, assess the symptoms and decide how to proceed. Although Mayan-Tz'utujil healing practices have been the subject of study on numerous occasions, the literature lacks women's views on health, healing, and disease. In this study I present those views within the framework of postcolonial studies, reflecting on the changes in Guatemala's national health policy. PMID- 22497329 TI - Relationship between low depressiveness and domain specific physical activity in women. AB - In this study we investigated how different domains of physical activity are associated with depressiveness among women, and how individual variables moderate this relationship. Participants were 956 women, and the data were collected by mail-out survey using the Global Physical Activity Questionnaire, Beck Depression Inventory, and International Personality Item Pool. Lower depressiveness was related to higher leisure time physical activity and to lower occupational physical activity. Income, health problems, level of neuroticism, and extraversion had strong effects on depressiveness, and mediated the link between the leisure and occupational activities and depression. PMID- 22497330 TI - Fatigue, worry, and fear--life events in the narratives of women with fibromyalgia. AB - In this article we explored narrated life stories of 20 women with a long history of fibromyalgia to reach a deeper understanding of how people interpret the causes and consequences of different life events and illness experiences. Based on narrative analysis, we identified three model narratives that illustrate the different life courses of women with fibromyalgia. In addition, we described a counternarrative that questions fibromyalgia as a chronic disease. In this narrative study, we give insights to the invisible symptoms and unheard experiences that are associated with fibromyalgia and to the ongoing discussion on the etiology and maintenance of fibromyalgia. PMID- 22497331 TI - Coping strategies and learned helplessness of employed and nonemployed educated married women from India. AB - In the present study, we compare three types of coping strategies (cognitive, physical, and social coping) and learned helplessness between married women who are either employed or nonemployed in Pune, India. A total of 100 employed women and 100 nonemployed women were surveyed. Employed women were found to have significantly higher cognitive, physical, and social coping, as well as lower learned helplessness than nonemployed women. Multiple roles of employed women and sense of control theories were used to explain the differences. We have found significant implications for the development of intervention programs for empowering women. PMID- 22497332 TI - Networking properties of cyclodextrin-based cross-linked polymers probed by inelastic light-scattering experiments. AB - An integrated experimental approach, based on inelastic light-scattering techniques, has been here employed for a multilength scale characterization of networking properties of cyclodextrin nanosponges, a new class of cross-linked polymeric materials built up from natural oligosaccharides cyclodextrins. By using Raman and Brillouin scattering experiments, we performed a detailed inspection of the vibrational dynamics of these polymers over a wide frequency window ranging from gigahertz to terahertz, with the aim of providing physical descriptors correlated to the cross-linking degree and elastic properties of the material. The results seem to suggest that the stiffness of cross-linked polymers can be successfully tuned by acting on the type and the relative amount of the cross-linker during the synthesis of a polymer matrix, predicting and controlling their swelling and entrapment properties. The proposed experimental approach is a useful tool for investigating the structural and physicochemical properties of polymeric network systems. PMID- 22497333 TI - Understanding the paradox of mercury pollution in China: high concentrations in environmental matrix yet low levels in fish on the market. PMID- 22497334 TI - High DNA affinity of a series of peptide linked diaromatic guanidinium-like derivatives. AB - In this paper we report the design and synthesis of a new family of asymmetric peptide linked diaromatic dications as potent DNA minor groove binders. These peptide-linked compounds, with a linear core, displayed a much larger affinity than other guanidinium-like derivatives from the same series with curved cores. As a first screening, the DNA affinity of these structures was evaluated by means of thermal denaturation experiments, finding that the nature of the cation (guanidinium vs 2-aminoimidazolinium) significantly influenced the binding strength. Their binding affinity was assessed by implementing further biophysical measurements such as surface plasmon resonance and circular dichroism. In particular, it was observed that compounds 6, 7, and 8 displayed both a strong binding affinity and significant selectivity for AT oligonucleotides. In addition, the thermodynamics of their binding was evaluated using isothermal titration calorimetry, indicating that the binding is derived from favorable enthalpic and entropic contributions. PMID- 22497335 TI - Genetic markers on BTA14 predictive for residual feed intake in beef steers and their effects on carcass and meat quality traits. AB - With the high cost of feed for animal production, genetic selection for animals that metabolize feed more efficiently could result in substantial cost savings for cattle producers. The purpose of this study was to identify DNA markers predictive for differences among cattle for traits associated with feed efficiency. Crossbred steers were fed a high-corn diet for 140 days and average daily feed intake (ADFI), average daily gain (ADG), and residual feed intake (RFI) phenotypes were obtained. A region on chromosome 14 was previously associated with RFI in this population of animals. To develop markers with the highest utility for predicting an animal's genetic potential for RFI, we genotyped additional markers within this chromosomal region. These polymorphisms were genotyped on the same animals (n = 1066) and tested for association with ADFI, ADG and RFI. Six markers within this region were associated with RFI (P <= 0.05). After conservative correction for multiple testing, one marker at 25.09 Mb remained significant (P = 0.02) and is responsible for 3.6% of the RFI phenotypic variation in this population of animals. Several of these markers were also significant for ADG, although none were significant after correction. Marker alleles with positive effects on ADG corresponded to lower RFI, suggesting an effect increasing growth without increasing feed intake. All markers were also assessed for their effects on meat quality and carcass traits. All of the markers associated with RFI were associated with adjusted fat thickness (AFT, P <= 0.009) and three were also associated with hot carcass weight (HCW, P <= 0.003). Marker alleles associated with lower RFI were also associated with reduced AFT, and if they were associated for HCW, the effect was an increase in weight. These markers may be useful as prediction tools for animals that utilize feed more efficiently; however, validation with additional populations of cattle is required. PMID- 22497336 TI - Thyroid hormone accelerates the differentiation of adult hippocampal progenitors. AB - Disrupted thyroid hormone function evokes severe physiological consequences in the immature brain. In adulthood, although clinical reports document an effect of thyroid hormone status on mood and cognition, the molecular and cellular changes underlying these behavioural effects are poorly understood. More recently, the subtle effects of thyroid hormone on structural plasticity in the mature brain, in particular on adult hippocampal neurogenesis, have come to be appreciated. However, the specific stages of adult hippocampal progenitor development that are sensitive to thyroid hormone are not defined. Using nestin-green fluorescent protein reporter mice, we demonstrate that thyroid hormone mediates its effects on hippocampal neurogenesis by influencing Type 2b and Type 3 progenitors, although it does not alter proliferation of either the Type 1 quiescent progenitor or the Type 2a amplifying neural progenitor. Thyroid hormone increases the number of doublecortin (DCX)-positive Type 3 progenitors, and accelerates neuronal differentiation into both DCX-positive immature neurones and neuronal nuclei-positive granule cell neurones. Furthermore, we show that this increase in neuronal differentiation is accompanied by a significant induction of specific transcription factors involved in hippocampal progenitor differentiation. In vitro studies using the neurosphere assay support a direct effect of thyroid hormone on progenitor development because neurospheres treated with thyroid hormone are shifted to a more differentiated state. Taken together, our results indicate that thyroid hormone mediates its neurogenic effects via targeting Type 2b and Type 3 hippocampal progenitors, and suggests a role for proneural transcription factors in contributing to the effects of thyroid hormone on neuronal differentiation of adult hippocampal progenitors. PMID- 22497337 TI - Subclavian flap aortoplasty and preservation of left upper extremity circulation using an interposition graft. AB - OBJECTIVES: To introduce a surgical technique to maintain left upper limb blood flow after subclavian flap aortoplasty (SFA). METHODS: Five patients (9 to 23 months of age) with a diagnosis of long-segment aortic coarctation underwent conventional SFA. A Gore-tex graft was interposed between the stump and the proximal descending aorta to maintain perfusion of subclavian artery. RESULTS: All patients had a patent Gore-tex graft and normal blood flow of the subclavian artery and left upper limb. One patient expired and four others were discharged with a mean follow-up of 48 months. On follow-up all patients had normal development of the left upper limb and no signs of limb ischemia. Echo findings revealed normal arch flow with normal flow in the Gore-tex graft and left upper extremity. CONCLUSIONS: Interposing a Gore-tex graft between the subclavian artery stump and proximal descending aorta concomitant with SFA can be safely performed in infants with long-segment aortic coarctation, with preservation of left upper extremity circulation. PMID- 22497338 TI - A premature stop codon in the ADAMTS2 gene is likely to be responsible for dermatosparaxis in Dorper sheep. AB - We have used polymerase chain reaction-single-strand conformational polymorphism analysis to investigate variation in exon 2 of the ADAM metalloproteinase with thrombospondin type I motif, 2 (ADAMTS2) gene in 598 sheep, including three white Dorper lambs that had a pathology consistent with dermatosparaxis. Four sequence variants (A, B, C and D) were identified at this exon, with the lambs having the dermatosparaxis phenotype being uniquely B homozygous and their mothers being B containing heterozygous for ADAMTS2. Analysis of the amplified exon 2 sequences revealed the B variant had a nucleotide substitution that creates a premature stop codon and would notionally abbreviate the ADAMTS2 peptide. The B variant was not found in any other breed aside from the white Dorper sheep that were studied. PMID- 22497339 TI - Upper limit of normal serum alanine and aspartate aminotransferase levels in Korea. AB - BACKGROUND AND AIM: The widely accepted range of upper limits of normal (ULN) alanine aminotransferase (ALT) levels (ULN < 40 U/L) was recently challenged by several reports. Both ALT and aspartate aminotransferase (AST) are commonly used as surrogate markers of liver disease, but almost all studies of aminotransferase activity were conducted on ALT. We investigated not only ULN of ALT but also AST activity and to identify factors modulating them in healthy Korean. METHODS: A cross-sectional study of 411,240 registered blood donors in all nationwide blood banks belonging to the Korean Red Cross were conducted. ULN of ALT and AST was evaluated adjusting their age according to the national population census database. "Decision tree model" was used to identify the affecting factors of ALT and AST and optimal cut-off points of affecting factors. RESULTS: "ULN of ALT" was 34 U/L in men and 24 U/L in women and "ULN of AST" was 32 U/L in men and 26 U/L in women in the blood donor database. Decision tree analysis showed that ALT levels were mostly influenced by body mass index level and its critical two cut off points were 23.5 kg/m2 and 25.8 kg/m2 , respectively. The most affecting factor of AST was gender. CONCLUSION: Upper limits of normal of ALT and AST in Koreans were lower than conventional accepted values (< 40 U/L) but higher than recently suggested values (male < 30 U/L and female < 19 U/L). Body mass index was the most determining factor for ALT and gender was the most influencing factor for AST activity. PMID- 22497340 TI - Is horizontal semicircular canal ocular reflex influenced by otolith organs input? AB - CONCLUSION: Otolith organs input influences the axis of horizontal semicircular canal ocular reflex; therefore, the plane of compensatory eye movements induced by the horizontal canal stimulation is not always parallel to the canal. OBJECTIVE: To clarify whether horizontal canal ocular reflex is influenced by otolith organs input. METHODS: The subjects were seven healthy humans. The right ear was stimulated using ice-water. Each subject was kept in a left-ear-down position for 20 s and then repositioned to a prone position, a right-ear-down position and a supine position with 20 s intervals. Nystagmus was analysed using three-dimensional video-oculography. RESULTS: Eye movements in the supine position and the prone position were not in a symmetric fashion. Nystagmus in the left-ear-down position and the right-ear-down position were not symmetric either. These phenomena indicate that the axis of the eyeball rotation was affected by the shift of the direction of gravity exerted on the head. PMID- 22497341 TI - The effects of sustained cognitive task performance on subsequent resting state functional connectivity in healthy young and middle-aged male schoolteachers. AB - Previous studies showed that functional connectivity (FC) within resting state (RS) networks is modulated by previous experience. In this study the effects of sustained cognitive performance on subsequent RS FC were investigated in healthy young (25-30 years; n=15) and middle-aged (50-60 years; n=14) male schoolteachers. Participants were scanned (functional magnetic resonance imaging [MRI]) after a cognitively demanding and a control intervention (randomized tester-blind within-subject design). Independent component analysis (ICA) was used to decompose the data into spatially independent networks. This study focused on the executive control (ExN), the left and right frontoparietal (FPN), and the default mode network (DMN). The effects of cognitive performance and age were calculated with a full-factorial analysis of variance (ANOVA). A main effect of age was found in the left inferior frontal gyrus for the ExN and in the middle frontal gyrus for the DMN with middle-aged teachers having reduced RS FC. Sustained cognitive performance increased subsequent RS FC between the ExN and a lingual/parahippocampal cluster, and between the left FPN and a right calcarine/precuneus cluster. In these clusters, FC strength correlated positively with the perceived amount of effort during the intervention. Further, sustained cognitive performance affected subsequent RS FC between the ExN and the right temporal superior gyrus differently in young and middle-aged men. The results suggest that effects of age on RS FC are already present at middle age. Sustained cognitive performance increased RS FC between task-positive networks and other brain regions, although a change in RS FC within the networks was not found. PMID- 22497342 TI - Male hormonal contraception: where do we stand? AB - BACKGROUND: The hormonal control of spermatogenesis was unravelled decennia before the recent advances in genetics and molecular biology. This explains why hormonally active agents, with the potential of suppressing pituitary gonadotropins, have been used in attempts to develop clinically applicable contraceptives for men. MALE HORMONAL CONTRACEPTION: Earlier studies indicated that high-normal or supraphysiological levels of androgens are needed to achieve an acceptable suppression of spermatogenesis, especially in some Caucasian men. Therefore, non-androgenic agents have been used instead to induce hypogonadism and suppression of spermatogenesis, the resultant hypoandrogenism being counteracted by exogenous testosterone supplementation. In spite of the considerable progress made in male hormonal contraception, further improvements, pertaining to different aspects, are still needed. The most promising regimen to date is a combination of testosterone and a progestin. CONCLUSIONS AND PERSPECTIVES: Now that male hormonal contraception is technically possible, its refinement and wide implementation depend solely on the willingness of the pharmaceutical industry to invest in the further development of this method. For the time being, condoms and vasectomy remain the only widely available methods for male contraception. PMID- 22497343 TI - Phenyliodine bis(trifluoroacetate)-mediated oxidative C-C bond formation: synthesis of 3-hydroxy-2-oxindoles and spirooxindoles from anilides. AB - The reaction of phenyliodine bis(trifluoroacetate) (PIFA) with a series of anilides 1 (E = CO(2)Et) in CF(3)CH(2)OH was found to give 3-hydroxy-2-oxindole derivatives 2, while that with various anilides 1' (E = CON(R(4))Ar) afforded the C(2)-symmetric or unsymmetric spirooxindoles 3. These processes feature a metal free oxidative C(sp(2))-C(sp(3)) bond formation, followed by oxidative hydroxylation or spirocyclization. PMID- 22497345 TI - Delayed peripheral venous catheter-related Staphylococcus aureus bacteremia: onset >= 24 hours after catheter removal. AB - Peripheral venous catheter (PVC)-associated bacteremia usually develops during the indwelling period. We present a review of 14 patients who developed delayed onset Staphylococcus aureus bacteremia (D-SAB), 1-6 days after PVC removal, and compare them to 29 patients with early onset PVC-related S. aureus bacteremia (E SAB). At the time of removal, the catheter site exhibited inflammation in 8 (57.1%) cases. At SAB onset, PVC site inflammation developed in all patients. Compared to E-SAB, patients with D-SAB were more often aged >= 65 y (71.4% vs. 34.5%; p = 0.03) and on corticosteroids (35.7% vs. 6.9%; p = 0.02). D-SAB was more complicated with persistent (> 3 days) bacteremia (42.9% vs. 13.8%; p = 0.04), metastatic infections (35.7% vs. 6.9%; p = 0.02), and slightly higher mortality (21.4% vs. 10.3%; p = 0.3). Logistic regression revealed that the predictors of D-SAB were corticosteroids (odds ratio (OR) 2.10, 95% confidence intervals (CI) 1.16-58.61) and age >= 65 y (OR 1.63, 95% CI 1.12-23.30). These patients may have impaired local/systemic defenses that lead to D-SAB, or a blunted host response with delayed recognition. PMID- 22497344 TI - Binding affects the tertiary and quaternary structures of the Shigella translocator protein IpaB and its chaperone IpgC. AB - Shigella flexneri uses its type III secretion system (T3SS) to promote invasion of human intestinal epithelial cells as the first step in causing shigellosis, a life-threatening form of dysentery. The Shigella type III secretion apparatus (T3SA) consists of a basal body that spans the bacterial envelope and an exposed needle that injects effector proteins into target cells. The nascent Shigella T3SA needle is topped with a pentamer of the needle tip protein invasion plasmid antigen D (IpaD). Bile salts trigger recruitment of the first hydrophobic translocator protein, IpaB, to the tip complex where it senses contact with a host membrane. In the bacterial cytoplasm, IpaB exists in a complex with its chaperone IpgC. Several structures of IpgC have been determined, and we recently reported the 2.1 A crystal structure of the N-terminal domain (IpaB(74.224)) of IpaB. Like IpgC, the IpaB N-terminal domain exists as a homodimer in solution. We now report that when the two are mixed, these homodimers dissociate and form heterodimers having a nanomolar dissociation constant. This is consistent with the equivalent complexes copurified after they had been co-expressed in Escherichia coli. Fluorescence data presented here also indicate that the N terminal domain of IpaB possesses two regions that appear to contribute additively to chaperone binding. It is also likely that the N-terminus of IpaB adopts an alternative conformation as a result of chaperone binding. The importance of these findings within the functional context of these proteins is discussed. PMID- 22497346 TI - Karyotyping and cytogenetic mapping of Atlantic cod (Gadus morhua Linnaeus, 1758). AB - The Atlantic cod (Gadus morhua) is an important natural resource for northern societies and is now also considered to be a promising candidate for aquaculture. In recent years, much effort has been directed towards the development of genomic tools, and genome initiatives for Atlantic cod have been established. Despite the growing attention devoted to the Atlantic cod genomics, basic aspects of its genome structure and organization remain unknown. Thus, the present work aims to study cytogenetic features of the Atlantic cod as a contribution to the knowledge of this species' genome. The Atlantic cod displays a diploid number of 46 chromosomes, with a karyotypic formula 16 m/sm + 30 st/t. Conventional karyotyping was improved by chromosomal mapping of two classes of repetitive sequences. 18S rDNA clusters were assigned to pairs 2 and 4; small amounts of 18S rDNA clusters were occasionally detected on pair 5. These findings could not be related to the geographical origin of the specimens, but were consistent with the variability of these repeated genes in fish in general. 5S ribosomal gene clusters, apparently corresponding to a single 5S rDNA class, were detected on twelve chromosomes (pairs 11, 12, 14, 17, 20 and 21). The present update of the existing but meagre information on the karyotype of Atlantic cod, plus the first physical mapping of repetitive genes in this species herein, opens the way for an integrated approach that combines genetic and physical mapping with the assembly of the genome of this commercially important species. PMID- 22497347 TI - Highly selective immobilization of Au nanoparticles onto isolated and dense nanopatterns of poly(2-vinyl pyridine) brushes down to single-particle resolution. AB - Chemical patterns consisting of poly(2-vinyl pyridine) (P2VP) brushes in a background of a cross-linked polystyrene (PS) mat enabled the highly selective placement of citrate-stabilized Au nanoparticles (NPs) in arrays on surfaces. The cross-linked PS mat prevented the nonspecific binding of Au NPs, and the regions functionalized with P2VP brushes allowed the immobilization of the particles. Isolated chemical patterns of feature sizes from hundreds to tens of nanometers were prepared by standard lithographic techniques. The number of 13 nm Au NPs bound per feature increased linearly with increasing area of the patterns. This behavior is similar to previous reports using 40 nm particles or larger. Arrays of single NPs were obtained by reducing the dimensions of patterned P2VP brushes to below ~20 nm. To generate dense (center-to-center distance = 80 nm) linear chemical patterns for the placement of rows of single NPs, a block-copolymer (BCP)-assisted lithographic process was used. BCPs healed defects associated with the standard lithographic patterning of small dimensions at high densities and led to highly registered, linear, single NP arrays. PMID- 22497348 TI - Mixed micellization and the dissociated Margules model for cationic/anionic surfactant systems. AB - The first and the second critical micelle concentration (CMC(1) and CMC(2)) for three alkyltrimethylammonium bromide (C(n)TAB)/sodium dodecylsulfonate (AS)/H(2)O mixed systems, and CMC(1) for trimethylene-1,3-bis(dodecyldimethylammonium bromide) (12-3-12)/AS/H(2)O mixed system have been measured. The largest negative beta(m) value means the strongest synergism between 12-3-12 and AS. The CMC(1) and CMC(2) for the C(n)TAB/AS/H(2)O mixed systems decrease with the increase of n. The equimolar mixed systems give the smallest CMC(1) values, whereas the CMC(2) values decrease with the increase of the composition of the surfactant with higher surface activity in the C(n)TAB/AS/H(2)O mixed systems. For the C(16)TAB/AS mixed systems far from equimolar, specific counterion effect on lowering CMC(1) enhances according to the Hofmeister series. There is slightly or no salt effect on the CMC(1) of the other wide composition range of C(16)TAB/AS/H(2)O mixed system. The pseudophase separation model coupled with the dissociated Margules model has been proposed and gives satisfactory description of the mixed CMC(1), the calculated micellar compositions are in well accordance with composition information from the zeta potential measurements. The addition of salt into the C(16)TAB/AS/H(2)O mixed system, leads to a certain degree of decrease in CMC(2). In addition to counterion effect, the co-ion effect on CMC(2) of the mixed system was explained using Collins' concept of matching water affinities. PMID- 22497349 TI - Delayed applications of L1 and chondroitinase ABC promote recovery after spinal cord injury. AB - The inhibitory environment of the injured spinal cord is an obstacle to functional recovery and axonal regeneration in adult mammals. We had previously shown that injection of adeno-associated virus (AAV) encoding the L1 cell adhesion molecule (AAV-L1) at the time of acute thoracic compression injury of adult mice promotes locomotor recovery, which is associated with ameliorated astrogliosis and improved axonal regeneration in the lumbar spinal cord. In the present study, we investigated whether delayed injection of AAV-L1, chondroitinase ABC (Chase), or the combination of the two agents into the mouse spinal cord 3 weeks after injury would also lead to improved recovery. The Basso Mouse Scale showed enhanced locomotor recovery 12 weeks after application of the agents in all treatment groups compared to the control group that was injected with AAV encoding green fluorescent protein (AAV-GFP). Investigation of hindlimb function using single-frame motion analysis revealed, however, that L1 overexpression, but not injection of Chase, improved voluntary movements without body weight support, whereas injection of Chase, but not L1 overexpression, enhanced body weight support during stepping. Mice with the combined application of AAV-L1 and Chase showed improvement in both parameters. Enhanced motor recovery after combined application correlated with increased densities of cholinergic and GABAergic terminals at motoneuronal cell bodies, and of lamina specific glutamatergic sensory afferents 15 weeks after injury, indicating enhanced synaptic rearrangements in the lumbar spinal cord below the lesion site. These findings suggest that L1 overexpression combined with Chase application may contribute to the treatment of sub-chronic spinal cord injury. PMID- 22497350 TI - Non-replication of genome-wide-based associations of efficient food conversion in dairy cows. AB - Animal growth relative to food energy input is of key importance to agricultural production. Several recent studies highlighted genetic markers associated with food conversion efficiency in beef cattle, and there is now a requirement to validate these associations in additional populations and to assess their potential utility for selecting animals with enhanced food-use efficiency. The current analysis tested a population of dairy cattle using 138 DNA markers previously associated with food intake and growth in a whole-genome association analysis of beef animals. Although seven markers showed point-wise significance at P < 0.05, none of the single-nucleotide polymorphisms tested were significantly associated with food conversion efficiency after correction for multiple testing. These data do not support the involvement of this subset of previously implicated markers in the food conversion efficiency of the physiologically distinct New Zealand Holstein-Friesian dairy breed. PMID- 22497351 TI - Molecular tools and analytical approaches for the characterization of farm animal genetic diversity. AB - Genetic studies of livestock populations focus on questions of domestication, within- and among-breed diversity, breed history and adaptive variation. In this review, we describe the use of different molecular markers and methods for data analysis used to address these questions. There is a clear trend towards the use of single nucleotide polymorphisms and whole-genome sequence information, the application of Bayesian or Approximate Bayesian analysis and the use of adaptive next to neutral diversity to support decisions on conservation. PMID- 22497352 TI - First to fulfil our responsibilities to addicted smokers: a response to Dalton. PMID- 22497353 TI - The affordable care act and long-term care: comprehensive reform or just tinkering around the edges? AB - The Patient Protection and Affordable Care Act (ACA) includes several provisions that aim to improve prevailing deficiencies in the nation's long-term care system. But just how effective is the ACA likely to be in addressing these challenges? Will it result in meaningful or marginal reform? This special issue of Journal of Aging & Social Policy seeks to answer these questions. The most prominent long-term care provision is the now-suspended Community Living Assistance Services and Supports Act. Others include incentives and options for expanding home- and community-based care, a number of research and demonstration projects in the areas of chronic care coordination and the dually eligible, and nursing home quality reforms. There are also elements that seek to improve workforce recruitment and retention, in addition to benefit improvements and spending reductions under Medicare. This article reviews the basic problems plaguing the long-term care sector and the provisions within the ACA meant to address them. It also includes a brief overview of issue content. PMID- 22497354 TI - The CLASS Act: is it dead or just sleeping? AB - The Affordable Care Act (ACA) established a voluntary public insurance program for long-term care: the Community Living Assistance Services and Supports (CLASS) Act. In October 2011, the Obama Administration announced that the program would not be implemented because of the high risk of fiscal insolvency. Under the legislative design, adverse selection was a major risk and premiums would have been very high. This article discusses several CLASS Act design and implementation issues, including the design features that led to the decision not to implement the program: the voluntary enrollment, the weak work requirement, the lifetime and cash benefits, and the premium subsidy for low-income workers and students. PMID- 22497355 TI - A 10-foot rope for a 50-yard drop: the CLASS Act in the patient protection and Affordable Care Act. AB - The Community Living Assistance Services and Supports (CLASS) Act, part of the 2010 health care reform, would have paid a daily cash payment toward the costs of long-term care. This article points out that although the CLASS Act may have been sufficient to cover the costs of most home- and community-based services, it was an inadequate response to the most pressing long-term care financing problem facing baby boomers: nursing home care costs. The risk of needing a nursing home is higher than other catastrophic risks. Boomers lack savings to pay those costs. CLASS aimed to encourage people to use home- and community-based services to substitute for nursing home care, but research spanning decades shows there is little substitution effect. PMID- 22497356 TI - Partnership long-term care insurance: lessons for CLASS program development. AB - The Community Living Assistance Services and Supports (CLASS) Act was a voluntary public insurance strategy intended to help people pay for long-term care. CLASS was passed as part of health reform to overcome aspects of private long-term care insurance market failure but came under close scrutiny from both its supporters and its detractors. Experience with the long-term care insurance market and State Partnership Programs provide insights about how to make CLASS fiscally viable. A CLASS program that offered one set of options to cover front-end risk (e.g., 1 to 3 years) and another set to cover catastrophic risk (after a high deductible) could have been offered as an alternative to the basic CLASS "long and lean" benefit model with all enrollees joined into a single risk pool. This would have broadened the risk pool and lowered premium costs under the program. PMID- 22497357 TI - Medicaid home- and community-based services: impact of the affordable care act. AB - The Affordable care Act (ACA) legislation of 2010 has three important voluntary provisions for the expansion of home- and community-based services (HCBS) under Medicaid: A state can choose to (1) offer a community first choice option to provide attendant care services and supports; (2) amend its state plan to provide an optional HCBS benefit; and (3) rebalance its spending on long term services and supports to increase the proportion that is community-based. The first and third provisions offer states enhanced federal matching rates as an incentive. Although the new provisions are valuable, the law does not set minimum standards for access to HCBS, and the new financial incentives are limited especially for the many states facing serious budget problems. Wide variations in access to HCBS can be expected to continue, while HCBS will continue to compete for funding with mandated institutional services. PMID- 22497358 TI - The impact of health care reform on the workforce caring for older adults. AB - This article summarizes the Patient Protection and Affordable Care Act (ACA) provisions that have a direct or indirect impact on the workforce caring for the elder population, explores the challenges to developing the workforce, and critiques the adequacy of the ACA provisions in meeting those challenges. The ACA is the first comprehensive federal legislation to acknowledge gaps in the workforce caring for the elder population. However, its provisions are inadequate given insufficient supply in the number and types of workers necessary both to meet the caregiving demand of the growing elder population and to implement the delivery system reforms instituted by the ACA. One of the challenges is that the workforce is not prepared for the new service delivery models specified in the legislation. They are not trained, supported, or held accountable for effective care coordination and service integration, and they lack the requisite skills, knowledge, and competencies. Moreover, it is likely to remain difficult to recruit and retain competent direct care workers, who represent the largest component of the long-term care workforce, because of the negative industry image, noncompetitive wages and benefits, a challenging work environment, and inadequate education and training. Several of the ACA provisions for developing the workforce have not received appropriations. Most are also demonstration projects of limited scope and duration. PMID- 22497359 TI - Nursing homes and the affordable care act: a cease fire in the ongoing struggle over quality reform. AB - Most provisions in the Affordable Care Act that affect nursing homes originated in two earlier attempts at reform, both of which failed multiple times in prior Congressional sessions: the Elder Justice Act and the Nursing Home Transparency and Improvement Act. Both of these earlier efforts focused on improving quality and reducing elder abuse in nursing homes by strengthening oversight and enforcement penalties, expanding staff training, and increasing the information on nursing home quality available to consumers and regulators. Each bill addressed problems that were serious, widespread, and had persisted for years, but each failed to pass on its own. The Affordable Care Act, with its own momentum, became the vehicle for their passage. However, the reasons the bills failed in these earlier efforts suggest implementation challenges now that they have ridden into law on the coattails of the more general effort to reform the health care sector. PMID- 22497360 TI - Care coordination for dually eligible medicare-medicaid beneficiaries under the affordable care act. AB - The coordination of Medicare and Medicaid benefits and services for dually eligible enrollees has been a longstanding policy challenge. Several provisions of the Affordable Care Act (ACA) attempt to address this lack of coordination, including the establishment of the Federal Coordinated Health Care Office. This paper reviews the major changes under the ACA directed at care coordination for the dually eligible population and then concludes with a discussion of the continuing legislative and legal challenges in integrating care for the dually eligible. PMID- 22497361 TI - Medicare and the affordable care act. AB - The recently enacted Patient Protection and Affordable Care Act made modest changes to improve Medicare and obtained a substantial share of funding for the Act's broader reforms from future spending reductions in the program. Drug benefits and preventive services were improved. While painful, the spending reductions will have only moderate impacts on beneficiaries and should help achieve the goals of health care reform: encouraging better primary and preventive care, making providers conscious of finding ways to increase the productivity of care delivered and changing the relative levels of payment across certain providers. Additional costs to beneficiaries will arise from changes in private plan payments and increasing income-related premiums. PMID- 22497362 TI - Identification of a sex-linked marker for channel catfish. PMID- 22497363 TI - Female urinary incontinence, from pregnancy to menopause: a review of epidemiological and pathophysiological findings. AB - Hypotheses that might explain urinary incontinence during pregnancy and after childbirth have been examined. The prevalence of urinary incontinence reaches a maximum during pregnancy and decreases after childbirth. Cesarean delivery is associated with lower rates of stress incontinence than vaginal delivery. Women delivered by cesarean section differ from women who had a vaginal delivery through pre-existing characteristics associated with the incontinence risk, producing a selection bias. The only randomized trial (intention of vaginal delivery vs. elective caesarean section) was not conclusive. The suspected etiological factors consist of congenital elements, obesity, aging, pregnancy and vaginal delivery. They are likely to have an effect at different times and on different portions of the urethral sphincter complex. Unfortunately, there exist no cohorts facilitating description of the natural history of female urinary incontinence. Given the small amount of usable data available, it is not possible to draw any conclusions concerning the possible long-term protective effects of cesarean section. PMID- 22497364 TI - Choline-based ionic liquids-enhanced biodegradation of azo dyes. AB - Industrial wastewaters such as tannery and textile processing effluents are often characterized by a high content of dissolved organic dyes, resulting in large values of chemical and biological oxygen demand (COD and BOD) in the aquatic systems into which they are discharged. Such wastewater streams are of rapidly growing concern as a major environmental issue in developing countries. Hence there is a need to mitigate this challenge by effective approaches to degrade dye contaminated wastewater. In this study, several choline-based salts originally developed for use as biocompatible hydrated ionic liquids (i.e., choline sacchrinate (CS), choline dihydrogen phosphate (CDP), choline lactate (CL), and choline tartarate (CT)) have been successfully employed as the cosubstrate with S. lentus in the biodegradation of an azo dye in aqueous solution. We also demonstrate that the azo dye has been degraded to less toxic components coupled with low biomass formation. PMID- 22497365 TI - Economic costs of achieving current conservation goals in the future as climate changes. AB - Conservation of biologically diverse regions has thus far been accomplished largely through the establishment and maintenance of protected areas. Climate change is expected to shift climate space of many species outside existing reserve boundaries. We used climate-envelope models to examine shifts in climate space of 11 species that are representative of the Mount Hamilton Project area (MHPA) (California, U.S.A.), which includes areas within Alameda, Santa Clara, San Joaquin, Stanislaus, Merced, and San Benito counties and is in the state's Central Coast ecoregion. We used Marxan site-selection software to determine the minimum area required as climate changes to achieve a baseline conservation goal equal to 80% of existing climate space for all species in the MHPA through 2050 and 2100. Additionally, we assessed the costs associated with use of existing conservation strategies (land acquisition and management actions such as species translocation, monitoring, and captive breeding) necessary to meet current species-conservation goals as climate changes. Meeting conservation goals as climate changes through 2050 required an additional 256,000 ha (332%) of protected area, primarily to the south and west of the MHPA. Through 2050 the total cost of land acquisition and management was estimated at US$1.67-1.79 billion, or 139-149% of the cost of achieving the same conservation goals with no climate change. To maintain 80% of climate space through 2100 required nearly 380,000 additional hectares that would cost $2.46-2.62 billion, or 209-219% of the cost of achieving the same conservation goals with no climate change. Furthermore, maintaining 80% of existing climate space within California for 27% of the focal species was not possible by 2100 because climate space for these species did not exist in the state. The high costs of conserving species as the climate changes-that we found in an assessment of one conservation project highlights the need for tools that will aid in iterative goal setting given the uncertainty of the effects of climate change and adaptive management that includes new conservation strategies and consideration of the long-term economic costs of conservation. PMID- 22497366 TI - The current status of elasmobranchs: biology, fisheries and conservation. PMID- 22497367 TI - A review of the taxonomy of chondrichthyan fishes: a modern perspective. AB - Taxonomic clarity is a fundamental requirement as it forms the foundation of all other life sciences. In the last decade, chondrichthyan taxonomy has undergone a scientific renaissance with >180 new species formally described. This effort encompasses c. 15% of the global chondrichthyan fauna, which consists of 1185 currently recognized species. The important role of chondrichthyan taxonomy for conservation management has been highlighted in recent years with new species descriptions or taxonomic resolution of a number of threatened species. These include Australian gulper (genus Centrophorus) and speartooth sharks (genus Glyphis) in coastal waters of Australia and Borneo. Closer examination of other wide-ranging species, for which the taxonomy was thought to be stable, has shown that they consist of species complexes, e.g. manta rays (Manta spp.) and spotted eagle rays (the Aetobatus narinari complex), and highlights the need for critical re-examination of other wide-ranging species. Molecular methods have provided another useful tool to taxonomists and they have proven to assist greatly with identifying cryptic species and species complexes. The limitations of particular molecular methods being used need, however, to be carefully considered and there are some concerns about how these are being integrated with classical taxonomy. The fundamental importance of taxonomic nomenclature to life sciences is often poorly understood but striving for nomenclatural stability is a critical component of taxonomy. Similarly, biological collections are an extremely vital asset to both taxonomists and the broader scientific community. These collections are becoming increasingly important due in part to molecular species identification initiatives such as the Barcode of Life which has resulted in a large number of voucher specimens linked to tissue samples being deposited. Biological collections are also proving to be imperative in biodiversity studies as they contain a 'gold mine' of historical collection information important for assessing changes in faunal assemblages. Resources are typically limited for taxonomic research and the ageing taxonomic community is another issue of concern for the future of taxonomy on this important group. Succession planning and better resource allocation will be essential to ensure that this fundamental discipline is maintained into the future. PMID- 22497368 TI - What is an 'elasmobranch'? The impact of palaeontology in understanding elasmobranch phylogeny and evolution. AB - The Subclass Elasmobranchii is widely considered nowadays to be the sister group of the Subclass Holocephali, although chimaeroid fishes were originally classified as elasmobranchs along with modern sharks and rays. While this modern systematic treatment provides an accurate reflection of the phylogenetic relationships among extant taxa, the classification of many extinct non holocephalan shark-like chondrichthyans as elasmobranchs is challenged. A revised, apomorphy-based definition of elasmobranchs is presented in which they are considered the equivalent of neoselachians, i.e. a monophyletic group of modern sharks and rays which not only excludes all stem and crown holocephalans, but also many Palaeozoic shark-like chondrichthyans and even close extinct relatives of neoselachians such as hybodonts. The fossil record of elasmobranchs (i.e. neoselachians) is reviewed, focusing not only on their earliest records but also on their subsequent distribution patterns through time. The value and limitations of the fossil record in answering questions about elasmobranch phylogeny are discussed. Extinction is seen as a major factor in shaping early elasmobranch history, especially during the Triassic. Extinctions may also have helped shape modern lamniform diversity, despite uncertainties surrounding the phylogenetic affinities of supposedly extinct clades such as cretoxyrhinids, anacoracids and odontids. Apart from these examples, and the supposed Cretaceous extinction of 'sclerorhynchids', elasmobranch evolution since the Jurassic has mostly involved increased diversification (especially during the Cretaceous). The biogeographical distribution of early elasmobranchs may be obscured by sampling bias, but the earliest records of numerous groups are located within the Tethyan realm. The break-up of Gondwana, and particularly the opening of the South Atlantic Ocean (together with the development of epicontinental seaways across Brazil and Africa during the Cretaceous), provided repeated opportunities for dispersal from both eastern (European) and western (Caribbean) Tethys into newly formed ocean basins. PMID- 22497369 TI - A review of elasmobranch research in the Red Sea. AB - Given the global concern about the status of elasmobranch fishes, the paucity of information on elasmobranchs in the Red Sea is worrisome. Management of elasmobranchs in areas other than the Red Sea has been helped by research on population ecology, reproductive biology and resource partitioning, subjects that are virtually absent in the Red Sea elasmobranch literature. This review provides the first comprehensive summary of elasmobranch biology in the Red Sea with the aim of facilitating research in a region that remains remarkably under-studied. PMID- 22497370 TI - An overview on the role of Hexanchiformes in marine ecosystems: biology, ecology and conservation status of a primitive order of modern sharks. AB - The large size, high trophic level and wide distribution of Hexanchiformes (cow and frilled sharks) should position this order as important apex predators in coastal and deep-water ecosystems. This review synthesizes available information on Hexanchiformes, including information not yet published, with the purpose of evaluating their conservation status and assessing their ecological roles in the dynamics of marine ecosystems. Comprising six species, this group has a wide global distribution, with members occurring from shallow coastal areas to depths of c. 2500 m. The limited information available on their reproductive biology suggests that they could be vulnerable to overexploitation (e.g. small litter sizes for most species and suspected long gestation periods). Most of the fishing pressure exerted on Hexanchiformes is in the form of commercial by-catch or recreational fishing. Comprehensive stock and impact assessments are unavailable for most species in most regions due to limited information on life history and catch and abundance time series. When hexanchiform species have been commercially harvested, however, they have been unable to sustain targeted fisheries for long periods. The potentially high vulnerability to intense fishing pressure warrants a conservative exploitation of this order until thorough quantitative assessments are conducted. At least some species have been shown to be significant apex predators in the systems they inhabit. Should Hexanchiformes be removed from coastal and deep-water systems, the lack of sympatric shark species that share the same resources suggests no other species would be capable of fulfilling their apex predator role in the short term. This has potential ecosystem consequences such as meso-predator release or trophic cascades. This review proposes some hypotheses on the ecology of Hexanchiformes and their role in ecosystem dynamics, highlighting the areas where critical information is required to stimulate research directions. PMID- 22497371 TI - Biology of the Greenland shark Somniosus microcephalus. AB - Greenland shark Somniosus microcephalus is a potentially important yet poorly studied cold-water species inhabiting the North Atlantic and Arctic Oceans. Broad scale changes in the Arctic ecosystem as a consequence of climate change have led to increased attention on trophic dynamics and the role of potential apex predators such as S. microcephalus in the structure of Arctic marine food webs. Although Nordic and Inuit populations have caught S. microcephalus for centuries, the species is of limited commercial interest among modern industrial fisheries. Here, the limited historical information available on S. microcephalus occurrence and ecology is reviewed and new catch, biological and life-history information from the Arctic and North Atlantic Ocean region is provided. Given the considerable by-catch rates in high North Atlantic Ocean latitudes it is suggested that S. microcephalus is an abundant predator that plays an important, yet unrecognized, role in Arctic marine ecosystems. Slow growth and large pup sizes, however, may make S. microcephalus vulnerable to increased fishing pressure in a warming Arctic environment. PMID- 22497372 TI - A review of the biology, fisheries and conservation of the whale shark Rhincodon typus. AB - Although the whale shark Rhincodon typus is the largest extant fish, it was not described until 1828 and by 1986 there were only 320 records of this species. Since then, growth in tourism and marine recreation globally has lead to a significant increase in the number of sightings and several areas with annual occurrences have been identified, spurring a surge of research on the species. Simultaneously, there was a great expansion in targeted R. typus fisheries to supply the Asian restaurant trade, as well as a largely un-quantified by-catch of the species in purse-seine tuna fisheries. Currently R. typus is listed by the IUCN as vulnerable, due mainly to the effects of targeted fishing in two areas. Photo-identification has shown that R. typus form seasonal size and sex segregated feeding aggregations and that a large proportion of fish in these aggregations are philopatric in the broadest sense, tending to return to, or remain near, a particular site. Somewhat conversely, satellite tracking studies have shown that fish from these aggregations can migrate at ocean-basin scales and genetic studies have, to date, found little graphic differentiation globally. Conservation approaches are now informed by observational and environmental studies that have provided insight into the feeding habits of the species and its preferred habitats. Notwithstanding these advances, there remain notable gaps in the knowledge of this species particularly with respect to the life history of neonates and adults who are not found in the feeding aggregations. PMID- 22497373 TI - An overview of the biology and status of undulate ray Raja undulata in the north east Atlantic Ocean. AB - The undulate ray Raja undulata is one of the lesser-known skates occurring on the continental shelf of the north-east Atlantic Ocean. It is patchily distributed throughout its range, with sites of local abundance in the central English Channel and off the coasts of Ireland, France, Spain and Portugal. Raja undulata is most abundant in coastal waters (<50 m deep) and is often found in proximity to large estuaries, rias and bays. It is a relatively large-bodied species, attaining a maximum total length (L(T) ) of at least 114 cm, with females maturing at an L(T) of c. 84 cm in Portuguese waters. Although infrequently taken in existing trawl surveys, it can be locally abundant in certain areas, where it can be the dominant skate species. Given its large size, patchy distribution and concern over the possibilities of localized depletions, the IUCN listed R. undulata as an endangered species and, since 2009, the European Union has established regulations to prohibit commercial fisheries landing the species. Given the increased interest in the species, a synopsis of current knowledge is provided, and available data from internationally co-ordinated trawl surveys presented. PMID- 22497374 TI - Biology, ecology and conservation of the Mobulidae. AB - The Mobulidae are zooplanktivorous elasmobranchs comprising two recognized species of manta rays (Manta spp.) and nine recognized species of devil rays (Mobula spp.). They are found circumglobally in tropical, subtropical and temperate coastal waters. Although mobulids have been recorded for over 400 years, critical knowledge gaps still compromise the ability to assess the status of these species. On the basis of a review of 263 publications, a comparative synthesis of the biology and ecology of mobulids was conducted to examine their evolution, taxonomy, distribution, population trends, movements and aggregation, reproduction, growth and longevity, feeding, natural mortality and direct and indirect anthropogenic threats. There has been a marked increase in the number of published studies on mobulids since c. 1990, particularly for the genus Manta, although the genus Mobula remains poorly understood. Mobulid species have many common biological characteristics although their ecologies appear to be species specific, and sometimes region-specific. Movement studies suggest that mobulids are highly mobile and have the potential to rapidly travel large distances. Fishing pressure is the major threat to many mobulid populations, with current levels of exploitation in target fisheries unlikely to be sustainable. Advances in the fields of population genetics, acoustic and satellite tracking, and stable isotope and fatty-acid analyses will provide new insights into the biology and ecology of these species. Future research should focus on the uncertain taxonomy of mobulid species, the degree of overlap between their large-scale movement and human activities such as fisheries and pollution, and the need for management of inter-jurisdictional fisheries in developing nations to ensure their long-term sustainability. Closer collaboration among researchers worldwide is necessary to ensure standardized sampling and modelling methodologies to underpin global population estimates and status. PMID- 22497375 TI - Molecular markers: progress and prospects for understanding reproductive ecology in elasmobranchs. AB - Application of modern molecular tools is expanding the understanding of elasmobranch reproductive ecology. High-resolution molecular markers provide information at scales ranging from the identification of reproductively isolated populations in sympatry (i.e. cryptic species) to the relationships among parents, offspring and siblings. This avenue of study has not only augmented the current understanding of the reproductive biology of elasmobranchs but has also provided novel insights that could not be obtained through experimental or observational techniques. Sharing of genetic polymorphisms across ocean basins indicates that for some species there may be gene flow on global scales. The presence, however, of morphologically similar but genetically distinct entities in sympatry suggests that reproductive isolation can occur with minimal morphological differentiation. This review discusses the recent findings in elasmobranch reproductive biology like philopatry, hybridization and polyandry while highlighting important molecular and analytical techniques. Furthermore, the review examines gaps in current knowledge and discusses how new technologies may be applied to further the understanding of elasmobranch reproductive ecology. PMID- 22497376 TI - Assessing the potential for post-copulatory sexual selection in elasmobranchs. AB - This review highlights the potential role that post-copulatory sexual selection plays in elasmobranch reproductive systems and the utility of this group to further understanding of evolutionary responses to the post-copulatory processes of sperm competition and cryptic female choice. The growing genetic evidence for female multiple mating (polyandry) in elasmobranchs is summarized. While polyandry appears to be common in this group, rates of multiple paternity are highly variable between species suggesting that there is large variance in the strength of post-copulatory sexual selection among elasmobranchs. Possible adaptations of traits important for post-copulatory sexual selection are then considered. Particular emphasis is devoted to explore the potential for sperm competition and cryptic female choice to influence the evolution of testes size, sperm morphology, genital morphology and sperm storage organs. Finally, it is argued that future work should take advantage of the wealth of information on these reproductive traits already available in elasmobranchs to gain a better understanding of how post-copulatory sexual selection operates in this group. PMID- 22497377 TI - Life history characteristics of a lightly exploited stock of Squalus suckleyi. AB - The purpose of this study was to examine the basic life history of a lightly exploited stock of Squalus suckleyi in the Gulf of Alaska to establish a baseline for future comparison and to provide critical information for stock assessments. Average total length (total length extended) of females (87.7 cm) was significantly larger (t-test, t = -12.57, d.f. = 1533, P < 0.01) than males (80.3 cm); size at 50% maturity (74.5 and 97.3 cm, males and females, respectively) and age at 50% maturity (21 and 36 years, respectively) were also significantly different between the sexes (i.e. bootstrapped 95% c.i. did not overlap). Total average fecundity was 8.5 pups per female, and individual fecundity was a linear function of either length or whole mass. The best estimate of instantaneous natural mortality was 0.097. The delayed age of maturity, low natural mortality and low rates of reproduction imply that only very low rates of fishing mortality are sustainable. Finally, this paper provides the first reported evidence that a small percentage of the adult females may undergo an extended resting period between pregnancies of >= 1 years. PMID- 22497378 TI - Biological vulnerability of two exploited sharks of the genus Deania (Centrophoridae). AB - Life-history parameters of Deania calcea and Deania quadrispinosa suggested that their productivity was very low. Maturity (L(T50) ) occurs at c. 80% of maximum observed total lengths (L(T) ) for both species and sexes. A large proportion of mature females were neither pre-ovulatory nor pregnant, and the reproductive cycle included a distinct resting phase after pregnancy. For D. calcea, mean ovarian fecundity was 12 and maximum observed litter size was 10 (average of six); D. quadrispinosa averaged 17 pups per litter. Birth L(T) was 28-33 cm for D. calcea and 23-25 cm for D. quadrispinosa. The male and female reproductive cycles were aseasonal, and consequently, the length of the reproductive cycle could not be determined. Preliminary ageing data from dorsal-spine growth bands suggested that female D. calcea lived to 31-36 years and males to 24-32 years. The L(T) -at-age data using external bands on the spines showed maturity occurring at 15.5 years (males) and 21.5 years (females), whereas banding on the internal dentine indicated maturity at 10.5 and 17.5 years for males and females. Thus, a female lifetime of 31-36 years allowed for a maximum of 7 litters if a 2 year cycle is assumed or only five litters with a 3 year cycle, resulting in a lifetime fecundity of only 42 pups (2 year cycle) or even lower (3 year cycle). PMID- 22497379 TI - Biological observations on the crocodile shark Pseudocarcharias kamoharai. AB - Sex ratios and gravid characteristics were analysed for the crocodile shark Pseudocarcharias kamoharai from the tropical eastern Pacific Ocean. Gravid females ranged from 80 to 102 cm fork length (L(F) ). The mode litter size was four (two embryos per uterus), mean embryo length was linearly correlated with maternal length (r = 0.465, n = 32); there was no significant difference in L(F) between female and male embryos. PMID- 22497380 TI - Reproductive biology of Zearaja chilensis (Chondrichthyes: Rajidae) in the south east Pacific Ocean. AB - Between 2000 and 2002, three artisanal landing sites were sampled in southern Chile, with data on population structure and reproductive development collected from 5477 yellownose skates Zearaja chilensis. Total length (L(T) ) ranged from 33 to 158 cm for females and 34 to 155 cm for males. No sexual dimorphism was evident in disc size (length or width) or in L(T)-mass relationships. The smallest mature female was 95 cm L(T) and the size at which 50% were mature (L(T50) ) was 109 cm. Males matured between 80 and 90 cm L(T) with a L(T50) of 88 cm. Although the largest Z. chilensis captured by the artisanal fishery was 155 cm L(T) , 89% of landings comprised relatively small, immature fish. This situation may compromise the stock integrity if intrinsic vulnerability and probable long-life span of Z. chilensis are considered. Consequences for the survival of the species and possible signs of a fishery collapse must be reviewed by management authorities by consideration of both artisanal and industrial landings in Chile. PMID- 22497381 TI - An elasmobranch maternity ward: female round stingrays Urobatis halleri use warm, restored estuarine habitat during gestation. AB - The habitat use and movements of the round stingray Urobatis halleri were compared between shallow restored and natural habitats of the Anaheim Bay Estuary (CA, U.S.A.) in relation to water temperature. Restored habitat remained significantly warmer than natural habitat from spring through to autumn. Strong sexual segregation occurred in the restored habitat with mature female U. halleri forming large unisex aggregations in summer, during months of peak seasonal water temperatures, and males only present during spring. Most mature females collected from restored habitat during months of high abundance were determined to be pregnant using non-invasive field ultrasonography. Tagged females typically spent <14 days in the restored habitat, using the habitat less as seasonal water temperatures decreased. Females tended to emigrate from the estuary by mid August, coinciding with the time of year for parturition. The elevated water temperatures of the restored habitat may confer an energetic cost to male U. halleri, but females (particularly pregnant females) may derive a thermal reproductive benefit by using warm, shallow habitats for short periods of time during months of peak water temperatures. These findings have management implications for the design of coastal habitat restoration projects and marine protected areas that incorporate thermal environments preferred by aggregating female elasmobranchs. PMID- 22497382 TI - Reproductive variables of Urotrygon rogersi (Batoidea: Urotrygonidae): a species with a triannual reproductive cycle in the eastern tropical Pacific Ocean. AB - Reproductive aspects of the round ray Urotrygon rogersi were studied based on 2005 specimens obtained in the artisanal shrimp fishery operating on the Colombian Pacific coast. Females reached greater maximum total length (L(T) ), disc width (W(D) ) and mass (M) (38.0 cm, 19.9 cm and 348 g) than males (32.5 cm, 17.0 cm and 165 g). Sex ratio of juveniles and adults was 1:1. Clasper length increased rapidly between 10.0 and 12.5 cm W(D) . The smallest mature male measured 10.5 cm W(D) and the largest immature individual 13.7 cm W(D) . Male first maturity was reached at 61.8% of maximum W(D) , and estimated W(D50) was between 11.5 and 11.8 cm. The smallest mature female measured 10.5 cm W(D) ; the size at first maturity was 52.8% of maximum W(D) , and estimated W(D50) was between 11.8 and 12.3 cm. Embryos were found in females >= 10.5 cm W(D) and maximum fecundity was three embryos per female (mode = 1) and varied with maternal size. Embryos were found in all months, but three birthing peaks per year were identified and a gestation period of 4-5 months estimated. Based on ovulation time, embryonic growth and parturition dates, a triannual reproductive cycle was inferred for this species, with overlapping ovarian and uterine cycles. These results suggest that U. rogersi has a reproductive strategy based on low fecundity, a rapid reproductive cycle (short ovulation and gestation time), three birth peaks per year and large embryos. This strategy probably allows U. rogersi to withstand the fishing pressure they are subject to on the Colombian Pacific coast. The results also suggest that the study area is an important nursery and reproductive area for this species. PMID- 22497383 TI - Biennial reproductive cycle in an extensive matrotrophic viviparous batoid: the sandyback stingaree Urolophus bucculentus from south-eastern Australia. AB - Urolophus bucculentus, the largest urolophid species found in southern Australia, exhibits a biennial reproductive cycle. Ovulation occurs during October to January followed by a 15-19 month period of gestation followed by parturition during April to May and a short rest period while the ovarian follicles continue to develop for subsequent ovulation. Male breeding condition peaks during April to June to coincide with the period of parturition. Urolophus bucculentus has the highest matrotrophic contribution reported for any urolophid species, with a mean wet mass gain from egg in utero (4 g) to full-term embryo in utero (250 g) of c. 6250% (maximum c. 7200%), and perhaps explains the biennial female reproductive cycle where 50% of females contribute to each year's recruitment. Litter size (one to five) increases with total length (L(T) ). Females reach a longer maximum L(T) (L(Tmax) ) than do males (885 v. 660 mm). The L(T) at maturity for males and females at 50% mature (L(T50) ) is c. 414 mm (63% of L(Tmax) ) for males and c. 502 mm (57% of L(Tmax) ) for females, length at maternity indicates that recruitment production occurs later in life at c. 632 mm L(T) (71% of L(Tmax) ). PMID- 22497384 TI - Micro-computed tomography: an alternative method for shark ageing. AB - Micro-computed tomography (microCT) produced 3D reconstructions of shark Carcharhinus brevipinna vertebrae that could be virtually sectioned along any desired plane, and upon which growth bands were readily visible. When compared to manual sectioning, it proved to be a valid and repeatable means of ageing and offers several distinct advantages over other ageing methods. PMID- 22497385 TI - Reassessment of spiny dogfish Squalus acanthias age and growth using vertebrae and dorsal-fin spines. AB - Male and female spiny dogfish Squalus acanthias were collected in the western North Atlantic Ocean in the Gulf of Maine between July 2006 and June 2009. Squalus acanthias ranged from 25 to 102 cm stretch total length and were caught during all months of the year except January. Age estimates derived from banding patterns visible in both the vertebrae and second dorsal-fin spines were compared. Vertebral growth increments were visualized using a modified histological staining technique, which was verified as appropriate for obtaining age estimates. Marginal increment analysis of vertebrae verified the increment periodicity, suggesting annual band deposition. Based on increased precision and accuracy of age estimates, as well as more biologically realistic parameters generated in growth models, the current study found that vertebrae provided a more reliable and accurate means of estimating age in S. acanthias than the second dorsal-fin spine. Age estimates obtained from vertebrae ranged from <1 year-old to 17 years for male and 24 years for female S. acanthias. The two parameter von Bertalanffy growth model fit to vertebrae-derived age estimates produced parameters of Linfinity = 94.23 cm and k = 0.11 for males and Linfinity = 100.76 cm and k = 0.12 for females. While these growth parameters differed from those previously reported for S. acanthias in the western North Atlantic Ocean, the causes of such differences were beyond the scope of the current study and remain to be determined. PMID- 22497386 TI - Biology of the silky shark Carcharhinus falciformis (Carcharhinidae) in the eastern Indian Ocean, including an approach to estimating age when timing of parturition is not well defined. AB - Biological data were recorded for 1265 silky sharks Carcharhinus falciformis collected from fish landing sites in eastern Indonesia. These represented catches taken in most calendar months by gillnetting and longlining in the eastern Indian Ocean and contained individuals ranging from embryos to fully mature adults. The growth zones in centra, which were shown to form annually, were counted in the vertebrae in a sub-sample of 200 fish for ageing purposes. The embryo lengths in the 5 months for which there were such data, and the presence of neonates in virtually all months, however, indicated that birth occurs throughout the year and thus there was no well-defined birth date for ageing individual fish. The approximate birth date of each individual was thus estimated from a combination of the total length (L(T) ) at capture and backcalculated L(T) at the formation of the birth zone and at the first and last growth zones in the vertebral centra, together with the period that had elapsed between the formation of those last two growth zones. The number of eggs or embryos in uteri ranged from two to 14, with a mean of 7.2. The estimated mean L(T) at birth of females (811 mm, range: 799 823 mm) and males (812 mm, range: 794-830 mm), derived from the backcalculations corresponding to the birth zones in the centra, were not significantly different (P > 0.05). The L(T) ranges in the catches of post-natal females (570-2592 mm) and males (553-2289 mm) taken by gillnetting were wider than those of the females (1177-2623 mm) and males (1184-2409 mm) taken by longlining. The oldest female and male were 19 and 20 years-old, respectively. The von Bertalanffy growth curves for the two sexes did not differ significantly. The growth coefficient, k, and the asymptotic length, L(Tinfinity). were 0.066 year-1 and 2994 mm for the curve fitted to the combined data for females and males. The lengths L(T50) and ages A(50) at which C. falciformis attained maturity were 2156 mm and 15 years for females and 2076 mm and 13 years for males. The very high proportion of C. falciformis with lengths 0.05). PMID- 22497395 TI - Pacific sleeper shark Somniosus pacificus trophic ecology in the eastern North Pacific Ocean inferred from nitrogen and carbon stable-isotope ratios and diet. AB - Stable-isotope ratios of nitrogen (delta15N) and lipid-normalized carbon (delta13C') were used to examine geographic and ontogenetic variability in the trophic ecology of a high latitude benthopelagic elasmobranch, the Pacific sleeper shark Somniosus pacificus. Mean muscle tissue delta13C' values of S. pacificus differed significantly among geographic regions of the eastern North Pacific Ocean. Linear models identified significant ontogenetic and geographic variability in muscle tissue delta15N values of S. pacificus. The trophic position of S. pacificus in the eastern North Pacific Ocean estimated here from previously published stomach-content data (4.3) was within the range of S. pacificus trophic position predicted from a linear model of S. pacificus muscle tissue delta15N (3.3-5.7) for fish of the same mean total length (L(T) ; 201.5 cm), but uncertainty in predicted trophic position was very high (95% prediction intervals ranged from 2.9 to 6.4). The relative trophic position of S. pacificus determined here from a literature review of delta15N by taxa in the eastern North Pacific Ocean was also lower than would be expected based on stomach-content data alone when compared to fishes, squid and filter feeding whales. Stable-isotope analysis revealed wider variability in the feeding ecology of S. pacificus in the eastern North Pacific Ocean than shown by diet data alone, and expanded previous conclusions drawn from analyses of stomach-content data to regional and temporal scales meaningful for fisheries management. PMID- 22497396 TI - Diet and scavenging habits of the smooth skate Dipturus innominatus. AB - The diet of smooth skate Dipturus innominatus was determined from examination of stomach contents of 321 specimens of 29.3-152.0 cm pelvic length, sampled from research and commercial trawlers at depths of 231-789 m on Chatham Rise, New Zealand. The diet was dominated by the benthic decapods Metanephrops challengeri and Munida gracilis, the natant decapod Campylonotus rathbunae and fishes from 17 families, of which hoki Macruronus novaezelandiae, sea perch Helicolenus barathri, various Macrouridae and a variety of discarded fishes were the most important. Multivariate analyses indicated the best predictors of diet variability were D. innominatus length and a spatial model. The diet of small D. innominatus was predominantly small crustaceans, with larger crustaceans, fishes and then scavenged discarded fishes increasing in importance as D. innominatus got larger. Scavenged discards were obvious as fish heads or tails only, or skeletal remains after filleting, often from pelagic species. Demersal fish prey were most frequent on the south and west Chatham Rise, in areas where commercial fishing was most active. Dipturus innominatus are highly vulnerable to overfishing, but discarding practices by commercial fishing vessels may provide a positive feedback to populations through improved scavenging opportunities. PMID- 22497397 TI - Feeding habits and trophic ecology of Dasyatis longa (Elasmobranchii: Myliobatiformes): sexual, temporal and ontogenetic effects. AB - Sexual, ontogenic and temporal effects in the diet of Dasyatis longa were evaluated to determine feeding habits and trophic ecology. Numeric indices and the index of relative importance were applied to establish the feeding strategy of the species. Independence of the diet with respect to sex, dry or rainy season and size was evaluated with contingency tables, correspondence analysis and multivariate analysis (MANOVA). The trophic relationships of D. longa (by sex and size intervals) were determined using Levin's niche breadth index and the Pianka's diet overlap index and their significance was determined by null models. The trophic level for each size interval and the species was also calculated. Dasyatis longa showed a narrow niche breadth feeding mainly on shrimps and fishes and its diet was dependent on size, but not on sex or season. Juvenile individuals (class I) fed on shrimps, sub-adults (class II) on fishes and adults (class III) on stomatopods. Significant overlaps between size classes I and II and classes II and III were found. The trophic level shows D. longa to be a secondary or tertiary consumer. Due to considerable fishing pressures on shrimps, the principal prey of D. longa, it will be important to determine their ability to adapt to changes in prey populations. PMID- 22497398 TI - Feeding ecology and dietary comparisons among three sympatric Neotrygon (Myliobatoidei: Dasyatidae) species. AB - The diets of Neotrygon picta, Neotrygon kuhlii and Neotrygon annotata are described using trophic level analysis, index of relative importance (I(RI) ) and non-metric multidimensional scaling ordination (nMDS). They were secondary consumers with trophic levels of between 3.55 and 3.58. Carids were the most important prey category in the diets of N. picta (82.0%I(RI) ) and N. annotata (69.4%I(RI) ); Polychaeta (72.3%I(RI) ) was the most important prey category for N. kuhlii. A significant difference was detected between the volumetric dietary data of all three species (ANOSIM, global R-statistic = 0.742, P < 0.01) and between sequential N. picta and N. kuhlii size classes (ANOSIM, global R statistics = 0.367-0.403, P < 0.01). Changes in polychaete and carid prey proportions were the primary sources of diet variability. Dietary differences may be linked to variations in disc width, mouth morphology and feeding strategies. This study provides insights into the level of variability within and between the diets and feeding behaviours of Neotrygon species, and the potential for resource partitioning to occur when these species coexist. PMID- 22497399 TI - Fisheries, management and conservation of the whale shark Rhincodon typus in Taiwan. AB - The Taiwanese government introduced a catch-and-report system for the whale shark Rhincodon typus in 2001, and in the following year limited the total allowable catch (TAC) to 80 individuals. This limit was reduced over the following years, reaching a low of 30 individuals in 2007. In November 2007, a comprehensive ban on R. typus fishing came into effect and protection measures were adopted for the species. This study measured and recorded the total length (L(T) ), body mass and sex of 810 R. typus, using fisheries and other released data for the period 1995 2008. The mean L(T) of individuals caught from June to October was smaller than that for individuals caught from November to May. Mean annual catches in set nets were higher in south-western Taiwan than in other regions of Taiwan. The sex ratio showed that males were caught more frequently than females in Taiwanese waters, indicating sex segregation. For the first time, the stock structure, conservation and management regulation of R. typus in the north-west Pacific Ocean have been reviewed. The results provide a useful resource for future assessment of the possible development of R. typus ecotourism in Taiwan. PMID- 22497400 TI - A preliminary survey of whale shark Rhincodon typus catch and trade in China: an emerging crisis. AB - This study gives an account of spatial and temporal distribution of whale shark Rhincodon typus catch events in China on the basis of historical records and information obtained from interviews with fishing industry stakeholders. A total of 186 R. typus were recorded with key harvest areas identified as in Hainan and Zhejiang, and the peak catching seasons were May to June and September to October. Aspects of the R. typus trade are discussed, including products, markets and the process. The results suggest that R. typus is increasingly becoming a targeted resource in China as a consequence of fierce competition for large shark fins and an emerging local market for consumption of all body parts. Current obstacles and potential measures for sustainable exploitation and trade of R. typus are discussed. PMID- 22497401 TI - Species, sex, size and male maturity composition of previously unreported elasmobranch landings in Kuwait, Qatar and Abu Dhabi Emirate. AB - This paper presents data from the first major survey of the diversity, biology and fisheries of elasmobranchs in the Persian (Arabian) Gulf. Substantial landings of elasmobranchs, usually as gillnet by-catch, were recorded in Kuwait, Qatar and the Emirate of Abu Dhabi (part of the United Arab Emirates), although larger elasmobranchs from targeted line fisheries were landed in Abu Dhabi. The elasmobranch fauna recorded was distinctive and included species that are undescribed, rare and have a highly restricted known distribution. Numerical abundance was dominated by sharks (c. 80%), of which carcharhinids were by far the most important. The milk shark Rhizoprionodon acutus and whitecheek shark Carcharhinus dussumieri together comprised just under half of all recorded individuals. Around 90% of recorded sharks were small (50-90 cm total length, L(T) ) individuals, most of which were mature individuals of species with a small maximum size (<100 cm L(T) ), although immature individuals of larger species (e.g. Carcharhinus sorrah and other Carcharhinus spp.) were also important. The most frequently recorded batoid taxa were cownose rays Rhinoptera spp., an undescribed whipray, and the granulated guitarfish Rhinobatos granulatus. The first size, sex and maturity data for a wide range of Gulf elasmobranch species are presented (including L(T) at 50% maturity for males of four shark species) and include some notable differences from other locations in the Indo-West Pacific Ocean. A number of concerns regarding the sustainability of the fishery were highlighted by this study, notably that most of the batoid species recorded are classed by the IUCN Red List as vulnerable, endangered, data deficient or not evaluated. Despite their considerable elasmobranch landings, none of the three countries sampled have developed a 'Shark Plan' as encouraged to do so under the FAO International Plan of Action: Sharks. Furthermore, Kuwait and Qatar currently report zero or no elasmobranch landings to the FAO. PMID- 22497402 TI - A global review of species-specific shark-fin-to-body-mass ratios and relevant legislation. AB - In this review, shark-fin-to-body-mass ratios, which have been legislated by several countries as a means of regulating and monitoring shark fisheries, have been compiled and reviewed. Observed and legislated wet-fin-mass-to-round-mass (M(fw) :M(r) ) ratios have been collected for 50 species and eight countries. Wet to dry-fin mass conversion factors have also been reviewed. Existing shark fishery legislation was compiled by political entity and regional fishery management organizations (RFMO). The mean observed M(fw) :M(r) ratio for all species was 3.0%, but actual fin to body-mass ratios varied considerably by species and location. Species-specific mean ratios ranged from 1.1 to 10.9%, and estimated mean ratios ranged from 1.5 to 6.1% by country, depending on fin cutting practices and the mix of exploited species. The mean conversion factor for wet to dry-fin mass was 0.43. Shark-related legislation was found to exist in 37 countries and the 22 maritime members of the European Union, and shark-related regulations have been designated by nine RFMOs. Results suggest that currently regulated ratios may not be appropriate for all species and fin-cutting practices, and regulations based on generalized ratios for all sharks may be inadequate. Alternative policies may be necessary for the effective management of global shark fisheries. PMID- 22497403 TI - Species composition of skates (Rajidae) in commercial fisheries around the British Isles and their discarding patterns. AB - Recent regulations have required European nations to report commercial landings of Rajidae (skates) to species level since 2008. Morphological similarities between some species, variability in colouration and regional differences in common names may compromise the accuracy of some of these data. An increased proportion of rajid landings reported by the U.K. (England, Wales and Northern Ireland) are now reported to species level (42% in 2008, rising to 92% in 2010). Recent landings (2007-2010) of Rajidae by the U.K. indicated that the majority of reported landings were made by otter trawl (55.9%), tangle and gillnet (18.7%) and beam trawl (15.5%). Approximately 70% of recent landings originated from four ICES Divisions: the Irish Sea (VIIa), western English Channel (VIIe), Bristol Channel (VIIf) and southern North Sea (IVc). Recent species-specific landings of Rajidae are appraised in terms of the species reported and the overall composition, and potential problems identified. Data from observer trips have been used to estimate the species composition of Rajidae taken in some of the main commercial fisheries operating around the British Isles, and these data are compared to landings. Although there was typically broad agreement between these data sets in terms of the main species landed, misidentification issues were apparent and Rajidae with highly patchy distributions may be under-represented in observer data. Data from observer trips were also used to examine the discard and retention pattern. Most rajid species were first retained from total lengths, L(T) , of 27-34 cm, with 50% retention occurring at between 49 and 51 cm and near full retention at L(T) of 60-67 cm. Beam trawls captured a higher proportion of smaller individuals, whilst gillnets (>150 mm mesh size) caught proportionally more larger rajids. PMID- 22497404 TI - Skate assemblage on the eastern Patagonian Shelf and Slope: structure, diversity and abundance. AB - The eastern Patagonian Shelf and continental slope of the south-west Atlantic Ocean support a high biodiversity and abundance of skates. In this study, meso scale differences in the assemblages, spatial and seasonal distributions of skates are revealed among six habitat zones of the eastern Patagonian Shelf characterized by distinctive oceanographic conditions. Most skates belonged to temperate fauna, and their abundance was much greater in habitats occupied by temperate waters (north-western outer shelf) or mixed waters (northern slope) than in habitats occupied by sub-Antarctic waters (SASW) (south-eastern outer shelf and southern slope). Sub-Antarctic skates were not abundant on the shelf even in habitats occupied by SASW, occurring mainly in deep areas of the lower continental slope. The majority of temperate skates migrated seasonally, shifting northward in winter and spreading southward with warming waters in summer. Most temperate species had two peaks in female maturity (mainly spring and autumn) and spawned in the same habitats where they fed. It is hypothesized that the high biodiversity and abundance of skates on the Patagonian Shelf and Slope are due to the practical absence of their natural competitors, flatfishes, which occupy similar eco-niches elsewhere. PMID- 22497405 TI - Ecological risk assessment and its application to elasmobranch conservation and management. AB - Ecological risk assessments (ERAs) are employed to quantify and predict the vulnerability of a particular species, stock or population to a specific stressor, e.g. pollution, harvesting, climate change, by-catch. Data generated from ERAs are used to identify and prioritize species for implementation of effective conservation and management strategies. At this time, ERAs are of particular importance to elasmobranchs, given the ecological importance and documented global population declines of some elasmobranch species. Here, ERAs as a tool for elasmobranch conservation and management are reviewed and a theoretical roadmap provided for future studies. To achieve these goals, a brief history of ERAs and approaches used within them (in the context of elasmobranchs) are given, and a comprehensive review conducted of all ERA studies associated with elasmobranchs published between 1998 and 2011. The hazards assessed, species evaluated and methodological approaches taken are recorded. Chronological and geographical patterns suggest that this tool has grown in popularity as a commercial fishery management instrument, while also signalling a recent precautionary approach to elasmobranch management in commercial fisheries globally. The analysis demonstrates that the predominant parameters incorporated in previous ERAs are largely based on life-history characteristics, and sharks have received the majority of attention; batoids (including skates) have received less attention. Recreational fishing and habitat degradation are discussed as hazards which warrant future investigation through ERA. Lastly, suggestions are made for incorporating descriptive ecological data to aid in the continued development and evolution of this management tool as it applies to future elasmobranch conservation. PMID- 22497406 TI - Relative abundance and size of coastal sharks derived from commercial shark longline catch and effort data. AB - In the north-west Atlantic Ocean, stock assessments conducted for some commercially harvested coastal sharks indicate declines from 64 to 80% with respect to virgin population levels. While the status of commercially important species is available, abundance trend information for other coastal shark species in the north-west Atlantic Ocean are unavailable. Using a generalized linear modelling (GLM) approach, a relative abundance index was derived from 1994 to 2009 using observer data collected in a commercial bottom longline fishery. Trends in abundance and average size were estimated for bull shark Carcharhinus leucas, spinner shark Carcharhinus brevipinna, tiger shark Galeocerdo cuvier and lemon shark Negaprion brevirostris. Increases in relative abundance for all shark species ranged from 14% for C. brevipinna, 12% for C. leucas, 6% for N. brevirostris and 3% for G. cuvier. There was no significant change in the size at capture over the time period considered for all species. While the status of shark populations should not be based exclusively on abundance trend information, but ultimately on stock assessment models, results from this study provide some cause for optimism on the status of these coastal shark species. PMID- 22497407 TI - Evidence of stability in a chondrichthyan population: case study of the spotted ratfish Hydrolagus colliei (Chondrichthyes: Chimaeridae). AB - Results presented here provide evidence of an exception to the generalization that all chondrichthyan populations are especially vulnerable to exploitation to the extent that they remain at low abundance for a protracted or indefinite duration even after exploitation rates are reduced. Delta log-normal generalized linear models (GLM) and cluster analysis of fishery-independent catch-per-unit effort (CPUE) data from 1977 to 2006 indicated the presence of at least two distinct stocks of spotted ratfish Hydrolagus colliei off the U.S. West Coast. CPUE of the continental slope and northern continental shelf and upper slope populations did not vary between 1977 and 1995 and increased from 1995 to 2006. On the basis of the timing of these changes, it is likely that both fishing and climate influenced these trends. Sex and size-specific differences in bathymetric distribution, along with the identification of nursery sites, indicate that fishery by-catch could have a significant effect on population growth. These aggregative behaviours, combined with low fecundity, indicate that H. colliei may be vulnerable to irreversible population depletion by fisheries mortality. Temporal abundance trends indicated, however, that their population size has increased significantly within the last decade, a demonstration of population stability. A literature review indicated that there is also evidence for population stability in other chondrichthyans. The paradigm that all chondrichthyan populations fail to rebuild in response to exploitation, therefore, may not be as broadly applicable as previously thought. Thus, it is not necessarily sufficient to make generalizations regarding the vulnerability of chondrichthyans across higher taxonomic scales. PMID- 22497408 TI - A review of the application of molecular genetics for fisheries management and conservation of sharks and rays. AB - Since the first investigation 25 years ago, the application of genetic tools to address ecological and evolutionary questions in elasmobranch studies has greatly expanded. Major developments in genetic theory as well as in the availability, cost effectiveness and resolution of genetic markers were instrumental for particularly rapid progress over the last 10 years. Genetic studies of elasmobranchs are of direct importance and have application to fisheries management and conservation issues such as the definition of management units and identification of species from fins. In the future, increased application of the most recent and emerging technologies will enable accelerated genetic data production and the development of new markers at reduced costs, paving the way for a paradigm shift from gene to genome-scale research, and more focus on adaptive rather than just neutral variation. Current literature is reviewed in six fields of elasmobranch molecular genetics relevant to fisheries and conservation management (species identification, phylogeography, philopatry, genetic effective population size, molecular evolutionary rate and emerging methods). Where possible, examples from the Indo-Pacific region, which has been underrepresented in previous reviews, are emphasized within a global perspective. PMID- 22497409 TI - Recovery potential and conservation options for elasmobranchs. AB - Many elasmobranchs have experienced strong population declines, which have been largely attributed to the direct and indirect effects of exploitation. Recently, however, live elasmobranchs are being increasingly valued for their role in marine ecosystems, dive tourism and intrinsic worth. Thus, management plans have been implemented to slow and ultimately reverse negative trends, including shark specific (e.g. anti-finning laws) to ecosystem-based (e.g. no-take marine reserves) strategies. Yet it is unclear how successful these measures are, or will be, given the degree of depletion and slow recovery potential of most elasmobranchs. Here, current understanding of elasmobranch population recoveries is reviewed. The potential and realized extent of population increases, including rates of increase, timelines and drivers are evaluated. Across 40 increasing populations, only 25% were attributed to decreased anthropogenic mortality, while the majority was attributed to predation release. It is also shown that even low exploitation rates (2-6% per year) can halt or reverse positive population trends in six populations currently managed under recovery plans. Management measures that help restore elasmobranch populations include enforcement or near-zero fishing mortality, protection of critical habitats, monitoring and education. These measures are highlighted in a case study from the south-eastern U.S.A., where some evidence of recovery is seen in Pristis pectinata, Galeocerdo cuvier and Sphyrna lewini populations. It is concluded that recovery of elasmobranchs is certainly possible but requires time and a combination of strong and dedicated management actions to be successful. PMID- 22497410 TI - Identification of factors influencing shark catch and mortality in the Marshall Islands tuna longline fishery and management implications. AB - Recent average annual catches of sharks by tuna longline vessels fishing in the Republic of the Marshall Islands (RMI) are estimated to be between 1583 and 2274 t. Although 22 shark species have been recorded by the observer programme for this fishery, 80% of the annual catch comprises only five species: blue shark Prionace glauca, silky shark Carcharhinus falciformis, bigeye thresher shark Alopias superciliosus, pelagic thresher shark Alopias pelagicus and oceanic whitetip shark Carcharhinus longimanus. Wire leaders (i.e. branch lines or traces) were also used by nearly all observed vessels. Generalized additive model (GAM)-based analyses of catch rates indicated that P. glauca and A. superciliosus are caught in higher numbers when vessels fish in relatively cooler waters, at night, close to the full moon, when the 27 degrees C thermocline is close to the surface and during El Nino conditions. In contrast, C. falciformis, A. pelagicus and C. longimanus are caught in higher numbers when shark lines are used (all three species) or hooks are set at a shallow depth (A. pelagicus and C. longimanus and, also, P. glauca). These findings are generally consistent with current knowledge of these species' habitat preferences, movement and distribution. The results of these analyses were combined with information pertaining to shark condition and fate upon capture to compare the likely effectiveness of a range of potential measures for reducing shark mortality in the longline fishery. Of the options considered, the most effective would be to combine measures that reduce the catch rate (e.g. restrictions on the use of wire leaders, shark baits and shark lines) with measures that increase survival rates after post-capture release (e.g. finning bans). PMID- 22497411 TI - Blue shark Prionace glauca fin-to-carcass-mass ratios in Spain and implications for finning ban enforcement. AB - This study examines the processing of fins from blue sharks Prionace glauca caught by the Spanish longline fleet and landed in Vigo, Spain, and implications of these practices for enforcing the E.U. ban on shark finning, which relies on a maximum fin-to-carcass-mass ratio. Two major sources of variability in fin-to carcass ratios are quantified and discussed: (1) the fin set (type and number of fins retained from each shark) and (2) the cutting method used to separate fins from carcasses. The significant differences in fin-to-carcass-mass ratios between fin sets or cutting procedure demonstrates that the ratio limit is problematic and, conclusively, in order to facilitate proper enforcement, fishermen should be required to land all sharks with the fins still naturally attached to the bodies. PMID- 22497412 TI - Muscle function and swimming in sharks. AB - The locomotor system in sharks has been investigated for many decades, starting with the earliest kinematic studies by Sir James Gray in the 1930s. Early work on axial muscle anatomy also included sharks, and the first demonstration of the functional significance of red and white muscle fibre types was made on spinal preparations in sharks. Nevertheless, studies on teleosts dominate the literature on fish swimming. The purpose of this article is to review the current knowledge of muscle function and swimming in sharks, by considering their morphological features related to swimming, the anatomy and physiology of the axial musculature, kinematics and muscle dynamics, and special features of warm-bodied lamnids. In addition, new data are presented on muscle activation in fast-starts. Finally, recent developments in tracking technology that provide insights into shark swimming performance in their natural environment are highlighted. PMID- 22497413 TI - Basics of skin structure and function in elasmobranchs: a review. AB - In contrast to the bony fishes, particularly the teleosts, the integument of elasmobranchs is rather unknown. Therefore, a description of the basic structural and functional features of shark and ray skin is given, based on a review of the literature and published or unpublished findings of the authors. The latter aspect makes it possible to document in more detail the specific structure of the skin layers regarding, particularly, the epidermis and its cell spectrum, the more or less robust dermis with its specific features, the very special scales with their derivates and the sophisticated sensoric integumental equipment. As far as possible, all important structures are discussed including their typical biological functions and results from applied scientific work. To some extent the information given is evaluated as compared with the much broader knowledge from the Osteichthyes. PMID- 22497414 TI - Neuroecology of cartilaginous fishes: the functional implications of brain scaling. AB - It is a widely accepted view that neural development can reflect morphological adaptations and sensory specializations. The aim of this review is to give a broad overview of the current status of brain data available for cartilaginous fishes and examine how perspectives on allometric scaling of brain size across this group of fishes has changed within the last 50 years with the addition of new data and more rigorous statistical analyses. The current knowledge of neuroanatomy in cartilaginous fishes is reviewed and data on brain size (encephalization, n = 151) and interspecific variation in brain organization (n = 84) has been explored to ascertain scaling relationships across this clade. It is determined whether similar patterns of brain organization, termed cerebrotypes, exist in species that share certain lifestyle characteristics. Clear patterns of brain organization exist across cartilaginous fishes, irrespective of phylogenetic grouping and, although this study was not a functional analysis, it provides further evidence that chondrichthyan brain structures might have developed in conjunction with specific behaviours or enhanced cognitive capabilities. Larger brains, with well-developed telencephala and large, highly foliated cerebella are reported in species that occupy complex reef or oceanic habitats, potentially identifying a reef-associated cerebrotype. In contrast, benthic and benthopelagic demersal species comprise the group with the smallest brains, with a relatively reduced telencephalon and a smooth cerebellar corpus. There is also evidence herein of a bathyal cerebrotype; deep-sea benthopelagic sharks possess relatively small brains and show a clear relative hypertrophy of the medulla oblongata. Despite the patterns observed and documented, significant gaps in the literature have been highlighted. Brain mass data are only currently available on c. 16% of all chondrichthyan species, and only 8% of species have data available on their brain organization, with far less on subsections of major brain areas that receive distinct sensory input. The interspecific variability in brain organization further stresses the importance of performing functional studies on a greater range of species. Only an expansive data set, comprised of species that span a variety of habitats and taxonomic groups, with widely disparate behavioural repertoires, combined with further functional analyses, will help shed light on the extent to which chondrichthyan brains have evolved as a consequence of behaviour, habitat and lifestyle in addition to phylogeny. PMID- 22497415 TI - Vision in elasmobranchs and their relatives: 21st century advances. AB - This review identifies a number of exciting new developments in the understanding of vision in cartilaginous fishes that have been made since the turn of the century. These include the results of studies on various aspects of the visual system including eye size, visual fields, eye design and the optical system, retinal topography and spatial resolving power, visual pigments, spectral sensitivity and the potential for colour vision. A number of these studies have covered a broad range of species, thereby providing valuable information on how the visual systems of these fishes are adapted to different environmental conditions. For example, oceanic and deep-sea sharks have the largest eyes amongst elasmobranchs and presumably rely more heavily on vision than coastal and benthic species, while interspecific variation in the ratio of rod and cone photoreceptors, the topographic distribution of the photoreceptors and retinal ganglion cells in the retina and the spatial resolving power of the eye all appear to be closely related to differences in habitat and lifestyle. Multiple, spectrally distinct cone photoreceptor visual pigments have been found in some batoid species, raising the possibility that at least some elasmobranchs are capable of seeing colour, and there is some evidence that multiple cone visual pigments may also be present in holocephalans. In contrast, sharks appear to have only one cone visual pigment. There is evidence that ontogenetic changes in the visual system, such as changes in the spectral transmission properties of the lens, lens shape, focal ratio, visual pigments and spatial resolving power, allow elasmobranchs to adapt to environmental changes imposed by habitat shifts and niche expansion. There are, however, many aspects of vision in these fishes that are not well understood, particularly in the holocephalans. Therefore, this review also serves to highlight and stimulate new research in areas that still require significant attention. PMID- 22497416 TI - Phylogenetic and ecological factors influencing the number and distribution of electroreceptors in elasmobranchs. AB - Electroreception is found throughout the animal kingdom from invertebrates to mammals and has been shown to play an important role in prey detection, facilitating social behaviours, the detection of predators and orientation to the earth's magnetic field for navigation. Electroreceptors in elasmobranchs, the ampullae of Lorenzini, detect minute electric fields and independently process these stimuli, thereby providing spatial information to the central nervous system on the location of a source, often potential prey. The ampullae of Lorenzini are individually connected to a single somatic pore on the surface of the skin, with the spatial separation of each pore directly influencing how electrical stimuli are detected and processed. Pore abundance varies across taxonomic groups resulting in unique species-specific differences. The intricate distribution patterns created by the specific positioning of somatic pores on the head are, however, consistent within families, resulting in patterns that are identifiable at higher taxonomic levels. As elasmobranchs evolved, the electrosensory system became more complex and highly specialized, which is evident by a general trend of increasing pore abundance over time. The elasmobranch electrosensory system has evolved to operate efficiently under the environmental conditions of the particular habitat in which a species lives. For example, reduced pore abundance is evident in oceanic pelagic elasmobranchs, for whom visual cues are thought to be of great importance. Pore abundance and spatial distribution may be influenced by multiple factors including head morphology, phylogeny, feeding behaviour and habitat. PMID- 22497417 TI - Cell and molecular biology of the spiny dogfish Squalus acanthias and little skate Leucoraja erinacea: insights from in vitro cultured cells. AB - Two of the most commonly used elasmobranch experimental model species are the spiny dogfish Squalus acanthias and the little skate Leucoraja erinacea. Comparative biology and genomics with these species have provided useful information in physiology, pharmacology, toxicology, immunology, evolutionary developmental biology and genetics. A wealth of information has been obtained using in vitro approaches to study isolated cells and tissues from these organisms under circumstances in which the extracellular environment can be controlled. In addition to classical work with primary cell cultures, continuously proliferating cell lines have been derived recently, representing the first cell lines from cartilaginous fishes. These lines have proved to be valuable tools with which to explore functional genomic and biological questions and to test hypotheses at the molecular level. In genomic experiments, complementary (c)DNA libraries have been constructed, and c. 8000 unique transcripts identified, with over 3000 representing previously unknown gene sequences. A sub-set of messenger (m)RNAs has been detected for which the 3' untranslated regions show elements that are remarkably well conserved evolutionarily, representing novel, potentially regulatory gene sequences. The cell culture systems provide physiologically valid tools to study functional roles of these sequences and other aspects of elasmobranch molecular cell biology and physiology. Information derived from the use of in vitro cell cultures is valuable in revealing gene diversity and information for genomic sequence assembly, as well as for identification of new genes and molecular markers, construction of gene-array probes and acquisition of full-length cDNA sequences. PMID- 22497418 TI - Effects of nonylphenol on vitellogenin synthesis in adult males of the spotted ray Torpedo marmorata. AB - The aim of this investigation was to assess the effects of nonylphenol (NP), an oestrogen-like environmental pollutant, on the vitellogenin (VTG) synthesis in adult males of the aplacental viviparous cartilaginous fish Torpedo marmorata. The VTG recovery in males is considered a biomarker of xeno-oestrogenic pollution as this lipophosphoglycoprotein is physiologically induced by oestrogens only in females of oviparous and ovoviparous vertebrates. Using in situ hybridization and immunohistochemistry, T. marmorata males injected with nonylphenol showed the presence of VTG in the liver and the kidney. In particular, vtg messenger (m)RNA and VTG protein were expressed in the liver, whereas in the kidney cells only the presence of VTG was recorded. By contrast, no expression for VTG was detected in the testis. These results demonstrate that in T. marmorata NP induces the expression of vtg only in the liver; the presence of VTG in the kidney and its absence in the testis are discussed. PMID- 22497420 TI - Antimicrobial photodynamic therapy and photodynamic inactivation, or killing bugs with dyes and light--a symposium-in-print. AB - In antimicrobial photodynamic therapy, the photosensitizer (PS) in its ground singlet state absorbs light to give the excited singlet state that can transition to the long-lived triplet state. This PS triplet may undergo energy transfer (Type 2) or electron transfer (Type 1) to oxygen to form reactive oxygen species (singlet oxygen and/or hydroxyl radicals) that can kill both Gram-positive and Gram-negative bacteria and fungi. Infections in animal models can also be treated. PMID- 22497422 TI - Failed early medical abortion: beware of the uterine scar!--Case report. AB - OBJECTIVES: To increase awareness of the possible existence of a morbidly adherent placenta in case of failed early medical abortion. CASE: We report a case of placenta increta which caused a massive haemorrhage during surgical aspiration following a failed medical abortion. CONCLUSION: Women with a history of caesarean section, who do not respond to a medical regimen for early termination of pregnancy should undergo an ultrasound examination to establish whether this may be due to a placenta accreta, increta or percreta. PMID- 22497423 TI - De novo mutation of the bovine EDA gene associated with anhidrotic ectodermal dysplasia in Japanese Black cattle. PMID- 22497421 TI - Structure-based design, synthesis, and characterization of dual hotspot small molecule HIV-1 entry inhibitors. AB - Cellular infection by HIV-1 is initiated with a binding event between the viral envelope glycoprotein gp120 and the cellular receptor protein CD4. The CD4-gp120 interface is dominated by two hotspots: a hydrophobic gp120 cavity capped by Phe43(CD4) and an electrostatic interaction between residues Arg59(CD4) and Asp368(gp120). The CD4 mimetic small-molecule NBD-556 (1) binds within the gp120 cavity; however, 1 and related congeners demonstrate limited viral neutralization breadth. Herein, we report the design, synthesis, characterization, and X-ray structures of gp120 in complex with small molecules that simultaneously engage both binding hotspots. The compounds specifically inhibit viral infection of 42 tier 2 clades B and C viruses and are shown to be antagonists of entry into CD4 negative cells. Dual hotspot design thus provides both a means to enhance neutralization potency of HIV-1 entry inhibitors and a novel structural paradigm for inhibiting the CD4-gp120 protein-protein interaction. PMID- 22497424 TI - Incidence of sternocutaneous fistulas following open heart surgery in a nationwide cohort. AB - We studied the incidence and characteristics of surgically treated sternocutaneous fistulas in a nationwide cohort of patients undergoing open heart surgery in Iceland. Between 2000 and 2010, sternocutaneous fistulas were treated surgically in 6 out of 2446 patients undergoing open heart surgery (incidence 0.25%, 95% confidence interval 0.11-0.53%). All patients were male, with a mean age of 71 +/- 9 y. In addition to antibiotic treatment, debridement of the wound was performed in all cases. Staphylococcus aureus and/or coagulase-negative staphylococci were identified as pathogens in 5 cases and Candida albicans in 1. Chronic infections developed in 3 patients who were treated repeatedly, 1 of them unsuccessfully. In-hospital stay ranged from 0 to 50 days (mean 19 days). Sternocutaneous fistulas are rare, but since they may have a devastating course, increased awareness of this infectious complication of open heart surgery is important. PMID- 22497425 TI - Efficient chiral monophosphorus ligands for asymmetric Suzuki-Miyaura coupling reactions. AB - A series of novel P-chiral monophosphorus ligands exhibit efficiency in asymmetric Suzuki-Miyaura coupling reactions, enabling the construction of an array of chiral biaryl products in high yields and excellent enantioselectivities (up to 96% ee) under mild conditions. The carbonyl-benzooxazolidinone moiety in these chiral biaryl products allows facile derivatization for further synthetic applications. A computational study has revealed that a pi-pi interaction between the two coupling partners can enhance the enantioselectivity of the coupling reaction. PMID- 22497426 TI - Progressive familial hearing loss in Muckle-Wells syndrome. AB - CONCLUSION: The age-dependent disease progression requires accelerating diagnosis of Muckle-Wells syndrome (MWS) in order to start treatment as early as possible. The most frequent, but not obligate symptoms are familial fatigue, hearing loss, and arthralgia. The design of further clinical trials should focus on hearing in order to document the long-term effect of anti-interleukin (IL)-1 drugs on hearing preservation. OBJECTIVES: This paper describes the otologic features of a genetically defined syndrome causing progressive hearing loss by cochlear degeneration. This is the first study reporting the pretreatment otologic presentation of a selected population with familial MWS. METHODS: A single-center cohort was examined by audiologic and neurotologic methods including pure tone audiograms, vestibular testing, and tinnitus questionnaire. The audiograms of members of the same family were compared to describe the family-specific risk of hearing loss progression. RESULTS: Nineteen patients (aged 3-72 years) belonging to four families with three different mutations of the NLRP3 gene were examined. Almost all patients (89%, 17/19) demonstrated bilateral sensorineural hearing loss. Hearing loss started in the high frequencies and led to profound deafness in the most severe cases. Even in cases of profound hearing loss the vestibular caloric reactivity was normal. Nearly half of the adults reported intermittent or permanent tinnitus. PMID- 22497427 TI - Prospective randomized controlled trial to compare the effects of omeprazole and famotidine in preventing delayed bleeding and promoting ulcer healing after endoscopic submucosal dissection. AB - BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are generally used to prevent delayed bleeding after endoscopic submucosal dissection (ESD) and to heal the artificial ulcers. However, it remains controversial whether PPIs or histamine-2 receptor antagonists (H(2) RAs) are more effective in preventing delayed bleeding after ESD. We prospectively compared the effects of omeprazole and famotidine in preventing delayed bleeding and promoting artificial ulcer healing after ESD. METHODS: A total of 158 patients (155 early gastric cancers and three adenomas) were randomly assigned to the PPI group (omeprazole 20 mg/day) or H(2) RA group (famotidine 40 mg/day) in a prospective randomized controlled trial. The primary end point was the incidence of hematemesis, melena, and/or a decrease in hemoglobin level of 2 g/dL or more requiring endoscopic hemostatic treatment. ESD induced ulcer healing and changes in ulcer size were also compared at 6 weeks after ESD as a secondary end point. RESULTS: Of the 158 patients, two were excluded from analysis because they had been treated with a PPI before the present study. Accordingly, data from 77 PPI and 79 H(2) RA subjects were included for analysis. Delayed bleeding after ESD occurred in 6.5% of subjects (PPI group) and in 6.3% (H(2) RA group); there was no significant difference between the two groups. Likewise, the two groups were not significantly different with respect to ulcer stage or ulcer size reduction rate. CONCLUSIONS: Proton pump inhibitors are not superior to H(2) RAs for the prevention of delayed bleeding or the healing of artificially induced ulcers after ESD. PMID- 22497428 TI - Changes in gene expression in a porcine preadipocyte cell line during differentiation. AB - Adipocyte differentiation plays an important role in the formation of fat tissues in pigs and affects meat quality and productivity. Clarification of the nature of the pig genes that participate in adipocyte differentiation will provide a clue to the regulation of fat content and thickness in pig carcases by dietary control; it will also help to find target genes for exploring potentially useful polymorphisms for molecular breeding aimed at fat traits. We constructed a DNA oligomer microarray based on pig transcripts, and we used the array to investigate time-dependent changes in gene expression in the PSPA porcine preadipocyte cell line during differentiation into adipocytes. We selected genes with markedly altered expression (at least fivefold difference in comparison with expression in undifferentiated cells) and classified them into five groups according to gene expression pattern. In the early stage after stimulation of adipocyte differentiation, we observed up-regulation of many genes encoding proteins involved in regulating cell proliferation and transcription. Among the probes corresponding to transcripts that showed marked changes in expression, 27 were located within previously reported QTL regions for traits related to adipose tissues. These results will be valuable resources for finding the genes responsible for fat-related traits that have been identified in previous studies using various pig resource families. PMID- 22497430 TI - The interleukin 4 receptor gene and its role in recurrent airway obstruction in Swiss Warmblood horses. AB - Recurrent airway obstruction (RAO) in horses is the result of an interaction of genetic and environmental factors and shares many characteristics with human asthma. Many studies have suggested that the interleukin-4 receptor gene (IL4R) is associated with this disease, and a QTL region on chromosome 13 containing IL4R was previously detected in one of the two Swiss Warmblood families. We sequenced the entire IL4R gene in this family and detected 93 variants including five non-synonymous protein-coding variants. The allele distribution at these SNPs supported the previously detected QTL signal. Subsequently, we investigated IL4R mRNA expression in bronchoalveolar lavage fluid cells. During exacerbation, IL4R expression was increased in RAO-affected offspring in the implicated family, but not in the other family. These findings support that IL4R plays a role in some cases of RAO. PMID- 22497429 TI - Green tea ingestion by rats does not affect iron absorption but does alter the composition of the saliva proteome. AB - We tested the hypothesis that rats adapt to the iron absorption inhibitory effects of tea by modifying the expression of salivary proteins. Thirty-six weanling rats were allocated into 6 groups. Two control groups were fed a semipurified diet containing 20 mg Fe(2+)/kg diet. Two groups were fed spray dried green tea infusion mixed into the diet (28.6 g tea/kg diet) and 2 groups were fed the control diet with a twice daily gavage of a tea solution (0.25 g tea/mL). Saliva samples were collected in 3 groups (control, gavage, and oral) on day 8 (acute) and in the remaining groups on day 31 (chronic). Iron absorption was assessed using a (58)Fe(3+) tracer administered on day 1 (acute) and day 24 (chronic). 2D gel electrophoresis and mass spectrometry were used to assess the composition of the saliva proteome. There was no significant difference in iron absorption between the 3 groups on either day 1 or day 24. Salivary proline-rich proteins and submandibular gland secretory protein increased to a greater extent in the oral group than in the gavage group, when compared to control, within the same exposure time period. Amylase, chitinase, deoxyribonuclease, cysteine-rich secretory protein 1, and parotid secretory protein all decreased to a greater extent in the oral tea group, compared to the control, within the same exposure time period. Our results show that green tea did not decrease iron absorption in rats but it did have a marked effect on the saliva proteome when given orally. PMID- 22497431 TI - Sleep and rhythm changes at the time of Trypanosoma brucei invasion of the brain parenchyma in the rat. AB - Human African trypanosomiasis (HAT), or sleeping sickness, is a severe disease caused by Trypanosoma brucei (T.b.). The disease hallmark is sleep alterations. Brain involvement in HAT is a crucial pathogenetic step for disease diagnosis and therapy. In this study, a rat model of African trypanosomiasis was used to assess changes of sleep-wake, rest-activity, and body temperature rhythms in the time window previously shown as crucial for brain parenchyma invasion by T.b. to determine potential biomarkers of this event. Chronic radiotelemetric monitoring in Sprague-Dawley rats was used to continuously record electroencephalogram, electromyogram, rest-activity, and body temperature in the same animals before (baseline recording) and after infection. Rats were infected with T.b. brucei. Data were acquired from 1 to 20 d after infection (parasite neuroinvasion initiates at 11-13 d post-infection in this model), and were compared to baseline values. Sleep parameters were manually scored from electroencephalographic electromyographic tracings. Circadian rhythms of sleep time, slow-wave activity, rest-activity, and body temperature were studied using cosinor rhythmometry. Results revealed alterations of most of the analyzed parameters. In particular, sleep pattern and sleep-wake organization plus rest-activity and body temperature rhythms exhibited early quantitative and qualitative alterations, which became marked around the time interval crucial for parasite neuroinvasion or shortly after. Data derived from actigrams showed close correspondence with those from hypnograms, suggesting that rest-activity could be useful to monitor sleep-wake alterations in African trypanosomiasis. PMID- 22497432 TI - Associations between chronotypes, psychopathology, and personality among incoming college students. AB - Chronotye is associated with age, sex, personality, and parental monitoring during childhood. The evening type is associated with poor school performance, sleep problems, anxious/depressive symptoms, tobacco smoking, caffeine consumption, alcohol drinking, and suicidality in adolescents. The present study tested the relationships between chronotype and a wide range of psychopathology and personality traits among 2919 incoming undergraduate students. Each participant completed a self-administered questionnaire that included demographics, plus the Morningness-Eveningness (M-E) scale, Brief Symptom Rating Scale (BSRS), Tridimensional Personality Questionnaire, and Maudesley Personality Inventory. The t-score distribution of the M-E scale was used to form the morning (t-score >60, n = 419), evening (t-score <40, n = 371), and intermediate (40 <= t score <= 60, n = 2129) groups. Multivariable regression was employed for data analysis. For males, the evening type scored higher on all subscales of the BSRS than the morning type, except phobic anxiety. For females, the evening type had higher scores than the other two types on all subscales, except in obsession/compulsion and phobic anxiety, where the evening type only scored higher than the intermediate type. The evening type of both sexes also scored higher than the morning type in novelty seeking, harm avoidance, and neurotic personality characteristics, but lower than the morning type in extraversion and social desirability. In reward dependence, the evening type scored lowest for males, but there was no difference for females. The findings of the evening type being associated with possible psychopathology and certain types of personality have public health implications, that is, chronotype needs to be taken into account in the development of mental health prevention programs and assessment of and intervention for mental problems in young adults. PMID- 22497434 TI - Characterisation of rectal motion during neo-adjuvant radiochemotherapy for rectal cancer with image-guided tomotherapy: implications for adaptive dose escalation strategies. AB - BACKGROUND: Interest in boosting the dose to the tumour during neo-adjuvant radiochemotherapy for rectal cancer is ever increasing, especially within the frame of adaptive radiotherapy. Rectal motion remains a potentially important obstacle to the full exploitation of this approach and needs to be carefully investigated. MATERIAL AND METHODS: The main purposes of this work were to: a) quantify rectal motion on all fractions of a treatment course; and b) assess margins for adaptive boosting in the second part of the treatment in order to benefit of tumour reduction during treatment. Ten consecutive patients treated with image-guided tomotherapy (41.4 Gy, 18 fractions) were selected. The cranial half of the rectum (subject to motion) was contoured by a single observer on daily MVCTs. The variations of rectal volume and of the envelope of rectum positions were investigated (169 MVCTs). The impact of applying different margins to the rectum in including all its possible positions was also investigated when considering the planning kVCT, the first fraction MVCT, the half-treatment MVCT or the median rectal contours of the whole or second half of treatment as reference volumes. RESULTS: Rectal volume reduced during treatment in all patients, with a significant time-trend in 6/10 patients. The median values of the envelope volumes were 129 cm(3) and 87 cm(3) in the first and second half of the treatment, respectively. On average, 95% of the rectal envelope was included by an isotropic expansion of 12 mm and 5 mm of the median contours when considering the whole or the second half of the treatment, respectively. CONCLUSION: A significant reduction of rectal volume was found in the second part of the treatment where rectal mobility was limited. As a consequence, relatively small margins may be used around the residual tumour volume when adaptive boost is delivered in the second half of the treatment. PMID- 22497433 TI - Biological rhythms during residence in polar regions. AB - At Arctic and Antarctic latitudes, personnel are deprived of natural sunlight in winter and have continuous daylight in summer: light of sufficient intensity and suitable spectral composition is the main factor that maintains the 24-h period of human circadian rhythms. Thus, the status of the circadian system is of interest. Moreover, the relatively controlled artificial light conditions in winter are conducive to experimentation with different types of light treatment. The hormone melatonin and/or its metabolite 6-sulfatoxymelatonin (aMT6s) provide probably the best index of circadian (and seasonal) timing. A frequent observation has been a delay of the circadian system in winter. A skeleton photoperiod (2 * 1-h, bright white light, morning and evening) can restore summer timing. A single 1-h pulse of light in the morning may be sufficient. A few people desynchronize from the 24-h day (free-run) and show their intrinsic circadian period, usually >24 h. With regard to general health in polar regions, intermittent reports describe abnormalities in various physiological processes from the point of view of daily and seasonal rhythms, but positive health outcomes are also published. True winter depression (SAD) appears to be rare, although subsyndromal SAD is reported. Probably of most concern are the numerous reports of sleep problems. These have prompted investigations of the underlying mechanisms and treatment interventions. A delay of the circadian system with "normal" working hours implies sleep is attempted at a suboptimal phase. Decrements in sleep efficiency, latency, duration, and quality are also seen in winter. Increasing the intensity of ambient light exposure throughout the day advanced circadian phase and was associated with benefits for sleep: blue enriched light was slightly more effective than standard white light. Effects on performance remain to be fully investigated. At 75 degrees S, base personnel adapt the circadian system to night work within a week, in contrast to temperate zones where complete adaptation rarely occurs. A similar situation occurs on high latitude North Sea oil installations, especially when working 18:00-06:00 h. Lack of conflicting light exposure (and "social obligations") is the probable explanation. Many have problems returning to day work, showing circadian desynchrony. Timed light treatment again has helped to restore normal phase/sleep in a small number of people. Postprandial response to meals is compromised during periods of desynchrony with evidence of insulin resistance and elevated triglycerides, risk factors for heart disease. Only small numbers of subjects have been studied intensively in polar regions; however, these observations suggest that suboptimal light conditions are deleterious to health. They apply equally to people living in temperate zones with insufficient light exposure. PMID- 22497435 TI - Insulin glargine use and short-term incidence of breast cancer - a four-year population-based observation. PMID- 22497436 TI - Quantitative trait loci segregating in crosses between New Hampshire and White Leghorn chicken lines: II. Muscle weight and carcass composition. AB - In order to identify genetic factors influencing muscle weight and carcass composition in chicken, a linkage analysis was performed with 278 F(2) males of reciprocal crosses between the extremely different inbred lines New Hampshire (NHI) and White Leghorn (WL77). The NHI line had been selected for high meat yield and the WL77 for low egg weight before inbreeding. Highly significant quantitative trait loci (QTL) controlling body weight and the weights of carcass, breast muscle, drumsticks-thighs and wings were identified on GGA4 between 151.5 and 160.5 cM and on GGA27 between 4 and 52 cM. These genomic regions explained 13.7-40.2% and 5.3-13.8% of the phenotypic F(2) variances of the corresponding traits respectively. Additional genome-wide highly significant QTL for the weight of drumsticks-thighs were mapped on GGA1, 5 and 7. Moreover, significant QTL controlling body weight were found on GGA2 and 11. The data obtained in this study can be used for increasing the mapping resolution and subsequent gene targeting on GGA4 and 27 by combining data with other crosses where the same QTL were found. PMID- 22497437 TI - Ionic liquid-assisted preparation of laccase-based biocathodes with improved biocompatibility. AB - Laccase enzyme has been widely used as the catalyst of the biocathodes in enzymatic biofuel cells (BFCs); the poor biocompatibility of this enzyme (e.g., poor catalytic activity in neutral media and low tolerance against chloride ion) and the lack of selectivity for oxygen reduction at the laccase-based biocathode against ascorbic acid, unfortunately, offer a great limitation to future biological applications of laccase-based BFCs. This study demonstrates a facial yet effective solution to these limitations with the assistance of hydrophobic room temperature ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate (Bmim(+)PF(6)(-)). With the Bmim(+)PF(6)(-) overcoating, the laccase-based biocathodes possess a good bioelectrocatalytic activity toward O(2) reduction in neutral media and a high tolerance against Cl(-). Moreover, the Bmim(+)PF(6)(-) overcoating applied to the laccase-based biocathodes also well suppresses the oxidation of ascorbic acid (AA) at the biocathodes and thereby avoids the AA induced decrease in the power output of the laccase-based BFCs. The mechanisms underlying the excellent properties of the Bmim(+)PF(6)(-) overcoating are proposed based on the intrinsic features of ionic liquid Bmim(+)PF(6)(-). To demonstrate the applications of the BFCs with the as-prepared biocathodes in biologically relevant systems, an AA/O(2) BFC is assembled with single-walled carbon nanotubes (SWNTs) as electrode materials both for accelerating AA oxidation at the bioanode and for promoting direct electron transfer of laccase at the biocathode. With the presence of 0.50 mM AA in 0.10 M quiescent phosphate buffer (pH 7.2), the assembled BFC has an open circuit voltage of 0.73 V and a maximum power output of 24 MUW cm(-2) at 0.40 V under ambient air and room temperature. This study essentially offers a new strategy for the development of enzymatic BFCs with a high biocompatibility. PMID- 22497438 TI - Complex surface chemistry of 4-mercaptopyridine self-assembled monolayers on Au(111). AB - The adsorption of 4-mercaptopyridine on Au(111) from aqueous or ethanolic solutions is studied by different surface characterization techniques and density functional theory calculations (DFT) including van der Waals interactions. X-ray photoelectron spectroscopy and electrochemical data indicate that self-assembly from 4-mercaptopyridine-containing aqueous 0.1 M NaOH solutions for short immersion times (few minutes) results in a 4-mercaptopyridine (PyS) self assembled monolayer (SAM) with surface coverage 0.2. Scanning tunneling microscopy images show an island-covered Au surface. The increase in the immersion time from minutes to hours results in a complete SAM degradation yielding adsorbed sulfur and a heavily pitted Au surface. Adsorbed sulfur is also the main product when the self-assembly process is made in ethanolic solutions irrespective of the immersion time. We demonstrate for the first time that a surface reaction is involved in PyS SAM decomposition in ethanol, a surface process not favored in water. DFT calculations suggest that the surface reaction takes place via disulfide formation driven by the higher stability of the S Au(111) system. Other reactions that contribute to sulfidization are also detected and discussed. PMID- 22497439 TI - The National Drug Strategy and Indigenous Australians: missed opportunities and future challenges. PMID- 22497440 TI - Quantitative trait loci for resistance to infection in sheep using a live Salmonella Abortusovis vaccine. AB - Quantitative trait loci (QTL) mapping for susceptibility to a Salmonella Abortusovis vaccinal strain was performed using an experimental design involving 30 Romane sheep sire families (1216 progenies). Nine QTL corresponding to bacterial load, weight variations and antibody response criteria were mapped on eight chromosomes, including the major histocompatibility complex area on chromosome 20. Surprisingly, none was found to be significant in the SLC11A1 region (formerly NRAMP1) that has been shown to influence Salmonella susceptibility in other species. PMID- 22497441 TI - Comparative analysis of caffeoylquinic acids and lignans in roots and seeds among various burdock (Arctium lappa) genotypes with high antioxidant activity. AB - Caffeoylquinic acids and lignans in the crude extracts of both roots and seeds from different burdock ( Arctium lappa L.) genotypes were simultaneously characterized and systematically compared by LC-MS and matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight mass spectrometry (MALDI QIT-TOF MS), and their antioxidant activities were also investigated. A total of 14 lignans were identified in burdock seeds and 12 caffeoylquinic acids in burdock roots. High levels of caffeoylquinic acids were also detected in burdock seeds, but only trace amounts of lignans were found in burdock roots. Burdock seeds contained higher concentrations of lignans and caffeoylquinic acids than burdock roots. Quantitative analysis of caffeoylquinic acids and lignans in roots and seeds of various burdock genotypes was reported for the first time. Great variations in contents of both individual and total phenolic compounds as well as antioxidant activities were found among different genotypes. Burdock as a root vegetable or medicinal plants possessed considerably stronger antioxidant activity than common vegetables and fruits. PMID- 22497442 TI - Climate change and the cost of conserving species in Madagascar. AB - We examined the cost of conserving species as climate changes. We used a Maxent species distribution model to predict the ranges from 2000 to 2080 of 74 plant species endemic to the forests of Madagascar under 3 climate scenarios. We set a conservation target of achieving 10,000 ha of forest cover for each species and calculated the cost of achieving this target under each scenario. We interviewed managers of projects to restore native forests and conducted a literature review to obtain the net present cost per hectare of management actions to maintain or establish forest cover. For each species, we added hectares of land from lowest to highest cost per additional year of forest cover until the conservation target was achieved throughout the time period. Climate change was predicted to reduce the size of species' ranges, the overlap between species' ranges and existing or planned protected areas, and the overlap between species' ranges and existing forest. As a result, climate change increased the cost of achieving the conservation target by necessitating successively more costly management actions: additional management within existing protected areas (US$0-60/ha); avoidance of forest degradation (i.e., loss of biomass) in community-managed areas ($160 576/ha); avoidance of deforestation in unprotected areas ($252-1069/ha); and establishment of forest on nonforested land within protected areas ($802 2710/ha), in community-managed areas ($962-3226/ha), and in unprotected areas ($1054-3719/ha). Our results suggest that although forest restoration may be required for the conservation of some species as climate changes, it is more cost effective to maintain existing forest wherever possible. PMID- 22497443 TI - Survey of Japanese infants younger than 3 months who were treated with oseltamivir for influenza: safety of oseltamivir treatment. AB - BACKGROUND: Young infants with influenza virus infection are frequently hospitalized, and are at risk of serious complications including death. With the emergence of pandemic influenza A/H1N1 2009, oseltamivir was approved for use in Europe and the USA, including use in infants aged < 3 months. However, few data are available regarding the safety of oseltamivir treatment for influenza in infants aged < 3 months. METHODS: The clinical data from Japanese infants aged < 3 months with laboratory-confirmed influenza virus infections, who were treated with oseltamivir between October 2009 and April 2011, were collected and analyzed. RESULTS: Forty-four infants were included in the study. The median age was 1 month (range 4 days to 2 months) and median body weight was 4.5 kg (range 2.6-7.6 kg). Thirty-eight infants (86%) had no underlying diseases. The most common presenting symptom was fever (42 infants, 95%). There were no cases of influenza-associated encephalopathy or myocarditis. The median time between the onset of influenza symptoms and initiation of oseltamivir treatment was 0 days (range 0-7 days), with treatment initiated within 1 day in 40 infants (91%). The oseltamivir dose was 1.5-2 mg/kg twice daily in 98% of infants. No serious adverse events were identified during treatment. All infants recovered completely. CONCLUSIONS: Treatment of influenza with oseltamivir 1.5-2 mg/kg twice daily may be safe in infants aged < 3 months. PMID- 22497444 TI - Discovery and characterization of an inhibitor of glucosylceramide synthase. AB - Targeting glycosphingolipid synthesis has emerged as a novel approach for treating metabolic diseases. 32 (EXEL-0346) represents a new class of glucosylceramide synthase (GCS) inhibitors. This report details the elaboration of hit 8 with the goal of achieving and maintaining maximum GCS inhibition in vivo. 32 inhibited GCS with an IC(50) of 2 nM and achieved maximum hepatic GCS inhibition after four or five daily doses in rodents. Robust improvements in glucose tolerance in DIO mice and ZDF rats were observed after 2 weeks of q.d. dosing. Four weeks of dosing resulted in decreased plasma triglycerides and reduced hepatic fat deposition. Thus, 32 provides insight into the amount of metabolic regulation that can be restored following achievement of maximal target knockdown. PMID- 22497445 TI - Tandem oxidative dearomatization/intramolecular Diels-Alder reaction for construction of the tricyclic core of palhinine A. AB - A concise construction of the 6/6/5 tricyclic core of Lycopodium alkaloid palhinine A (1) has been accomplished. The developed synthetic strategy featured a tandem oxidative dearomatization/intramolecular Diels-Alder reaction to construct C/D rings and an intramolecular 5-exo-trig radical cyclization to install the B ring of palhinine A (1). The developed approach paves the way for the total synthesis of palhinine A (1). PMID- 22497446 TI - A novel USP9Y polymorphism allowing a rapid and unambiguous classification of Bos taurus Y chromosomes into haplogroups. AB - A new sequence-tagged site (STS) was identified within intron 26 of the bovine USP9Y gene, showing an 81-base pair insertion (g.76439_76440ins81 in sequence with GenBank accession FJ195366) able to distinguish Y2 and Y3 Bos Y haplogroups from Y1. Moreover, four Y3-specific sequence variants allow a distinction from haplogroup Y2. The typing of a Bison bison Y chromosome indicates that the ancestral allele for the USP9Y 81-bp insertion is the short Y1 version. The results from typing the new STS in 1230 cattle Y chromosomes are fully consistent with their classification through standard methods. Thanks to the newly identified STS, it is now possible to assign cattle Y chromosomes to the currently known haplogroups using a single marker. PMID- 22497447 TI - Compound lipophilicity as a descriptor to predict binding affinity (1/K(m)) in mammals. AB - In bioaccumulation models, biotransformation is one of the processes decreasing the concentration of chemicals in an organism. In order to be metabolized, a compound needs to bind to an enzyme. In this study, we derived relationships between binding affinity and lipophilicity, expressed as Log (1/K(m)) and Log K(ow), respectively. We focused on oxidations in mammals catalyzed by alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), flavin-containing monooxygenase (FMO), and cytochrome P450 (CYP) enzymes. For all regressions, 1/K(m) increased with compound K(ow), which can be understood from the tendency to biotransform lipophilic compounds into more polar, thus more easily excretable metabolites. Lipophilicity was relevant to the binding of most of the substrate classes of ADH, ALDH, and CYP. The resulting slopes had 95% Confidence Intervals covering the value of 0.63, typically noted in protein-water distribution (Log K(pw)) and Log K(ow) regressions. A reduced slope (0.2-0.3) was found for FMO: this may be due to a different reaction mechanism involving a nucleophilic attack. The general patterns of metabolism were mechanistically interpreted in terms of partitioning theory. Information on the overall principles determining biotransformation may be helpful in predicting metabolic rates. PMID- 22497448 TI - Antifungal activity of two Lactobacillus strains with potential probiotic properties. AB - Aflatoxin (highly toxic and carcinogenic secondary metabolites produced by fungi) contamination is a serious problem worldwide. Modern agriculture and animal production systems need to use high-quality and mycotoxin-free feedstuffs. The use of microorganisms to preserve food has gained importance in recent years due to the demand for reduced use of chemical preservatives by consumers. Lactic acid bacteria are known to produce various antimicrobial compounds that are considered to be important in the biopreservation of food and feed. Lactobacillus rhamnosus L60 and Lactobacillus fermentum L23 are producers of secondary metabolites, such as organic acids, bacteriocins and, in the case of L60, hydrogen peroxide. The antifungal activity of lactobacilli strains was determined by coculture with Aspergillus section Flavi strains by two qualitative and one quantitative methods. Both L23 and L60 completely inhibited the fungal growth of all aflatoxicogenic strains assayed. Aflatoxin B (1) production was reduced 95.7 99.8% with L60 and 27.5-100% with L23. Statistical analysis of the data revealed the influence of L60 and L23 on growth parameters and aflatoxin B (1) production. These results are important given that these aflatoxicogenic fungi are natural contaminants of feed used for animal production, and could be effectively controlled by Lactobacillus L60 and L23 strains with probiotic properties. PMID- 22497449 TI - Outcome analysis of cervical adenosquamous carcinoma compared with adenocarcinoma. AB - OBJECTIVE: To compare survival between patients with cervical adenocarcinoma (AC) and adenosquamous carcinoma (ASC). DESIGN: Retrospective study. SETTING: National Taiwan University Hospital, Taipei, Taiwan. POPULATION: All patients with cervical AC or ASC who received definitive treatment from January 1995 to December 2009. METHODS: Medical and histopathological record review. MAIN OUTCOME MEASURES: Overall and recurrence-free survival. RESULTS: A total of 170 women received a histological diagnosis of AC and 42 of ASC. The median follow-up was 56.7 months. There were no significant differences in age, International Federation of Gynecology and Obstetrics (FIGO) stage, gravidity or treatment modality between women with AC and ASC. Patients with ASC had a higher percentage of poorly differentiated tumors than those with AC (33.3 vs. 15.3%, respectively; p= 0.014). Five year overall and recurrence-free survival was 66.8 and 58.9%, respectively, for women with AC and 69.5 and 61.9%, respectively, for those with ASC (p= 0.795 and p= 0.892, respectively). Survival outcomes in patients with early or advanced stage disease did not differ between the histological groups. No differences in failure patterns were found between the two groups. The FIGO stage and treatment modality were factors which affected overall and recurrence free survival. CONCLUSIONS: We did not find evidence to suggest that ASC subtypes indicate worse outcome. Cervical ASC could be categorized as one subtype of AC. The FIGO stage and treatment modalities have greater influence on outcomes than histological subtype. PMID- 22497450 TI - Antiviral efficacy of lamivudine versus entecavir in patients with hepatitis B virus-related advanced hepatocellular carcinoma. AB - BACKGROUND AND AIM: Little information is available about the antiviral efficacy of lamivudine (LAM) and entecavir (ETV) in patients with hepatitis B virus (HBV) related advanced hepatocellular carcinoma (HCC). Thus, we compared the antiviral efficacy of LAM and ETV in these patients. METHODS: The medical records of 134 antiviral therapy-naive patients with HBV-related advanced HCC (modified Union for International Cancer Control [UICC] Tumor, Nodes, and Metastases [TNM] stages III-IV) treated between January 2005 and September 2009 were reviewed. After HCC diagnosis, 87 (64.9%) and 47 (35.1%) patients received LAM and ETV, respectively. RESULTS: The mean age of patients (115 men, 19 women) was 53 years. Sixty-five (48.5%) and 69 (51.5%) patients had TNM stages III and IV HCC, respectively. Treatment outcomes during follow-up, including virologic, biochemical, and serologic responses and appearance of antiviral resistance, were similar in the LAM and ETV groups (all P>0.05). Multivariate analysis identified Child-Pugh class, alpha-fetoprotein, and TNM stage as independent predictors of overall survival (all P<0.05). Antiviral agent type (LAM vs ETV) did not influence overall survival (median 9.6 months in LAM vs 13.6 months in ETV group; P=0.493). HCC treatment was not interrupted due to HBV flare up in any patient. CONCLUSIONS: The antiviral efficacy of LAM and ETV was similar and the type of antiviral agent did not influence overall survival in patients with HBV-related advanced HCC. Thus, LAM, which is less expensive than ETV in Korea, might be sufficient to control HBV in these patients. PMID- 22497451 TI - Immunoelectron microscopic analysis of neurotoxic effect of glutamate in the vestibular end organs during ischemia. AB - CONCLUSION: The excessive glutamate released from the type I and type II hair cells and the supporting cells injure the bouton-type endings and the nerve chalices in 30 min ischemia, and neuronal damage of glutamate was slight in 10 min ischemia. OBJECTIVE: In the present study, we investigated by means of post embedding immunoelectron microscopic analysis whether neuronal damage in the vestibular end organs is associated with the change of cellular glutamate concentration during ischemia. METHODS: Transient local anoxia (10 min, 30 min) of guinea pig inner ear was induced by pressing the left labyrinthine artery. The right sides were used as controls. The morphological changes of the vestibular end organs and the areal gold particle densities representing glutamate were compared in the ischemia side and the control side. RESULTS: The areal gold particle densities of the type I and type II hair cells and the supporting cells in the ischemic side were lower than those of the control side. There were no remarkable morphological changes compared to the control side in 10 min ischemia. In 30 min ischemia, the bouton-type endings were swollen and intercellular spaces between the type I hair cells and the nerve chalices were enlarged. PMID- 22497452 TI - Allelic heterogeneity of Crooked Tail Syndrome: result of balancing selection? AB - We report the identification of a second loss-of-function mutation (c.1906T>C) in the bovine MRC2 gene causing the Crooked Tail Syndrome in Belgian Blue Cattle. We demonstrate that the ensuing substitution of the highly conserved Cysteine 636 with Arginine causes illegitimate receptor oligomerization, which is predicted to impair function of the MRC2 encoded protein, Endo180. We propose that this second MRC2 mutation was selected by breeders as a result of its favourable effect on muscularity in heterozygotes. PMID- 22497454 TI - Enzyme microheterogeneous hydration and stabilization in supercritical carbon dioxide. AB - Supercritical carbon dioxide is a promising green-chemistry solvent for many enzyme-catalyzed chemical reactions, yet the striking stability of some enzymes in such unconventional environments is not well understood. Here, we investigate the stabilization of the Candida antarctica Lipase B (CALB) in supercritical carbon dioxide-water biphasic systems using molecular dynamics simulations. The preservation of the enzyme structure and optimal activity depend on the presence of small amounts of water in the supercritical dispersing medium. When the protein is at least partially hydrated, water molecules bind to specific sites on the enzyme surface and prevent carbon dioxide from penetrating its catalytic core. Strikingly, water and supercritical carbon dioxide cover the protein surface quite heterogeneously. In the first solvation layer, the hydrophilic residues at the surface of the protein are able to pin down patches of water, whereas carbon dioxide solvates preferentially hydrophobic surface residues. In the outer solvation shells, water molecules tend to cluster predominantly on top of the larger water patches of the first solvation layer instead of spreading evenly around the remainder of the protein surface. For CALB, this exposes the substrate-binding region of the enzyme to carbon dioxide, possibly facilitating diffusion of nonpolar substrates into the catalytic funnel. Therefore, by means of microheterogeneous solvation, enhanced accessibility of hydrophobic substrates to the active site can be achieved, while preserving the functional structure of the enzyme. Our results provide a molecular picture on the nature of the stability of proteins in nonaqueous media. PMID- 22497453 TI - Epicatechin ameliorates ionising radiation-induced oxidative stress in mouse liver. AB - The current study was intended to evaluate the hepatoprotective effect of Epicatechin (EC) against radiation-induced oxidative stress, in terms of inflammation and lipid peroxidation. Swiss albino mice were administered with EC (15 mg/kg body weight) for three consecutive days before exposing them to a single dose of 5-Gy (60)Co gamma (gamma) irradiation. Mice were necropsied and livers were taken for immunohistochemistry, western blot analysis and biochemical tests for the detection of markers of hepatic oxidative stress. Nuclear translocation of nuclear factor kappa B (NF-kappaB) and lipid peroxidation were increased whereas the activities of superoxide dismutase (SOD) and catalase (CAT), reduced glutathione (GSH) content and ferric reducing antioxidant power (FRAP) were diminished upon radiation exposure compared to control. Translocation of NF-kappaB from cytoplasm to nucleus and lipid peroxidation were found to be inhibited whereas an increase in SOD, CAT, GSH and FRAP was observed in the mice treated with EC prior to irradiation. Thus, pre-treatment with EC offers protection against gamma-radiation induced hepatic alterations. PMID- 22497455 TI - Ultrasmall biocompatible nanocomposites: a new approach using seeded emulsion polymerization for the encapsulation of nanocrystals. AB - We report a novel approach of seeded emulsion polymerization in which nanocrystals are used as seeds. Ultrasmall biocompatible polymer-coated nanocrystal with sizes between 15 and 110 nm could be prepared in a process that avoids any treatment with high shear forces or ultrasonication. The number of nanocrystals per seed, the size of the seeds, and the shell thickness can be independently adjusted. Single encapsulated nanocrystals in ultrasmall nanobeads as well as clusters of nanocrystals can be obtained. Polysorbat-80 was used as surfactant. It consists of poly(ethylene glycol) (PEG) chains, giving the particles outstanding biofunctional characteristics such as a minimization of unspecific interactions. PMID- 22497456 TI - Controlled synthesis of O-glycopolypeptide polymers and their molecular recognition by lectins. AB - The facile synthesis of high molecular weight water-soluble O-glycopolypeptide polymers by the ring-opening polymerization of their corresponding N carboxyanhydride (NCA) in very high yield (overall yield > 70%) is reported. The per-acetylated-O-glycosylated lysine-NCA monomers, synthesized using stable glycosyl donors and a commercially available protected amino acid in very high yield, was polymerized using commercially available amine initiators. The synthesized water-soluble glycopolypeptides were found to be alpha-helical in aqueous solution. However, we were able to control the secondary conformation of the glycopolypeptides (alpha-helix vs nonhelical structures) by polymerizing racemic amino acid glyco NCAs. We have also investigated the binding of the glycopolypeptide poly(alpha-manno-O-lys) with the lectin Con-A using precipitation and hemagglutination assays as well as by isothermal titration calorimetry (ITC). The ITC results clearly show that the binding process is enthalpy driven for both alpha-helical and nonhelical structures, with negative entropic contribution. Binding stoichiometry for the glycopolypeptide poly(alpha manno-O-lys) having a nonhelical structure was slightly higher as compared to the corresponding polypeptide which adopted an alpha-helical structure. PMID- 22497457 TI - Fatty acid composition of 12 fish species from the Black Sea. AB - The long-chain polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are healthful to humans, particularly in promoting growth and cognitive development in infants and young children, and in reducing the risk of cardiovascular disease. Though the populations who inhabit the Trabzon province of Turkey include seafood from the Black Sea in their diet, knowledge of the fatty acid composition and content of these fish is scant. Fatty acid analysis was performed on freeze-dried muscle tissue of 12 species of fish purchased in markets in Trabzon. The fat content varied from 0.2% (garfish) to 12% (shad) of dry weight. The highest DHA and DHA plus EPA contents were found in horse mackerel 16.1 and 20.6 mg/g dry weight, respectively. Only in sea bass and sea bream did the essential fatty acid linoleic acid account for more than 10% of the fatty acid total. For all 12 species, arachidonic acid accounted for 0.09% to 7.64% of the fatty acid total. Oleic acid varied greatly from 0.14% (garfish) to 32.7% (shad). The omega-3/omega-6 fatty acid ratio ranged from 0.8 to 25. A 100 g serving of fresh horse mackerel would contribute 586 mg of DHA to the diet, which exceeds the recommended daily intake of 200 to 300 mg of DHA for pregnant and lactating women. These data indicate that some, but not all, of the 12 fish species from the Black Sea fish we studied could contribute significantly to satisfy the DHA and EPA needs of the inhabitants of the eastern Black Sea region of Turkey. PMID- 22497458 TI - PAH formation under single collision conditions: reaction of phenyl radical and 1,3-butadiene to form 1,4-dihydronaphthalene. AB - The crossed beam reactions of the phenyl radical (C(6)H(5), X(2)A(1)) with 1,3 butadiene (C(4)H(6), X(1)A(g)) and D6-1,3-butadiene (C(4)D(6), X(1)A(g)) as well as of the D5-phenyl radical (C(6)D(5), X(2)A(1)) with 2,3-D2-1,3-butadiene and 1,1,4,4-D4-1,3-butadiene were carried out under single collision conditions at collision energies of about 55 kJ mol(-1). Experimentally, the bicyclic 1,4 dihydronaphthalene molecule was identified as a major product of this reaction (58 +/- 15%) with the 1-phenyl-1,3-butadiene contributing 34 +/- 10%. The reaction is initiated by a barrierless addition of the phenyl radical to the terminal carbon atom of the 1,3-butadiene (C1/C4) to form a bound intermediate; the latter underwent hydrogen elimination from the terminal CH(2) group of the 1,3-butadiene molecule leading to 1-phenyl-trans-1,3-butadiene through a submerged barrier. The dominant product, 1,4-dihydronaphthalene, is formed via an isomerization of the adduct by ring closure and emission of the hydrogen atom from the phenyl moiety at the bridging carbon atom through a tight exit transition state located about 31 kJ mol(-1) above the separated products. The hydrogen atom was found to leave the decomposing complex almost parallel to the total angular momentum vector and perpendicularly to the rotation plane of the decomposing intermediate. The defacto barrierless formation of the 1,4 dihydronaphthalene molecule involving a single collision between a phenyl radical and 1,3-butadiene represents an important step in the formation of polycyclic aromatic hydrocarbons (PAHs) and their partially hydrogenated counterparts in combustion and interstellar chemistry. PMID- 22497459 TI - Genome-wide associations for investigating time-dependent genetic effects for milk production traits in dairy cattle. AB - Phenotypic variation in milk production traits has been described over the course of a lactation as well as between different parities. The objective of this study was to investigate whether variation in production is affected by different loci across lactations. A genome-wide association study (GWAS) using a 50-k SNP chip was conducted in 152 divergent German Holstein Friesian cows to test for association with milk production traits over different lactations. The first four lactations were analysed regarding milk yield, fat, protein, lactose, milk urea nitrogen yield and content as well as somatic cell score. Two approaches were used: (i) Wilmink curve parameters were used to assess the genetic effects over the course of a lactation and (ii) test-day yield deviations (YD) were used as a normative approach for a GWAS. The significant effects were largest for markers affecting curve parameters for which there was a statistical power <0.8 of detection even in this small design. While significant markers for YDs were detected in this study, the power to detect effects of a similar magnitude was only 0.11, suggesting that many loci may have been missed with this approach in the present design. Furthermore, all significant effects were specific for a single lactation, leading to the conclusion that the variance explained by a certain locus changes from lactation to lactation. We confirm the common evidence that most production traits vary in the degree of persistency after the peak as a result of genetic influence. PMID- 22497460 TI - Quantitative trait loci for body growth and sex determination in the hermaphrodite teleost fish Sparus aurata L. AB - Gilthead sea bream (Sparus aurata L.) is an important marine fish in Mediterranean aquaculture. Sex determination by age and/or body weight is a critical life-history trait, the genetic basis for which is largely unknown in this sequential hermaphrodite species. Herein, we performed a partial genome scan to map quantitative trait loci (QTL) affecting body weight and sex using 74 informative microsatellite markers from 10 paternal half-sib families to construct nine linkage groups (LG). In total, four growth-related QTL (two chromosome-wide and two genome-wide) and six QTL related to sex determination (three pairs in three different LGs) were detected (two chromosome-wide and one genome-wide). The proportion of phenotypic variation explained by the body-weight QTL ranged from 9.3% to 17.2%, showing their potential for use in marker-assisted selection. The results obtained offer solid ground to investigate the structure and function of the genomic regions involved in the mechanisms of sex reversal. PMID- 22497461 TI - PHLDA2 is an imprinted gene in cattle. AB - Genomic imprinting is an epigenetic non-Mendelian phenomenon found predominantly in placental mammals. Imprinted genes display differential expression in the offspring depending on whether the gene is maternally or paternally inherited. Currently, some 100 imprinted genes have been reported in mammals, and while some of these genes are imprinted across most mammalian species, others have been shown to be imprinted in only a few species. The PHLDA2 gene that codes for a pleckstrin homology-like domain, family A (member 2), protein has to date been shown to be a maternally expressed imprinted gene in humans, mice and pigs. Genes subject to imprinting can have major effects on mammalian growth, development and disease. For instance, disruption of imprinted genes can lead to aberrant growth syndromes in cloned domestic mammals, and it has been demonstrated that PHLDA2 mRNA expression levels are aberrant in the placenta of somatic clones of cattle. In this study, we demonstrate that PHLDA2 is expressed across a range of cattle foetal tissues and stages and provide the first evidence that PHLDA2 is a monoallelically expressed imprinted gene in cattle foetal tissues, and also in the bovine placenta. PMID- 22497462 TI - Analytical characterization of an orally-delivered peptide pharmaceutical product. AB - The characterization of orally-delivered peptide pharmaceuticals presents several challenges to analytical methods in comparison to characterization of conventional small-molecule drugs. These challenges include the analysis and characterization of difficult-to-separate impurities, secondary structure, the amorphous solid-state form, and the integrity of enteric-coated drug delivery systems. This work presents the multidisciplinary analytical characterization of a parathyroid hormone (PTH) peptide active pharmaceutical ingredient (API) and an oral formulation of this API within enteric-coated sucrose spheres. The analysis of impurities and degradation products in API and formulated drug product was facilitated by the development of an ultrahigh-performance liquid chromatography (UHPLC) method for analysis by high-resolution mass spectrometry (MS). The use of UHPLC allowed for additional resolution needed to detect impurities and degradation products of interest. The secondary structure was probed using a combination of solution-state NMR, infrared, and circular dichroism spectroscopic methods. Solid-state NMR is used to detect amorphous API in a nondestructive manner directly within the coated sucrose sphere formulation. Fluorescence and Raman microscopy were used in conjunction with Raman mapping to show enteric coating integrity and observe the distribution of API beneath the enteric-coating on the sucrose spheres. The methods are combined in a multidisciplinary approach to characterize the quality of the enteric-coated peptide product. PMID- 22497463 TI - Two cases of infectious purpura fulminans and septic shock caused by Capnocytophaga canimorsus transmitted from dogs. AB - We report 2 cases of Capnocytophaga canimorsus-induced septicaemia complicated by purpura fulminans in previously healthy individuals, both of whom had been exposed to dog saliva prior to disease. They both presented with purpuric skin lesions, as well as the tetrad of abdominal symptoms, haemolytic anaemia, metabolic acidosis, and renal failure, which may be common in C. canimorsus associated purpura fulminans. The patients survived after treatment with broad spectrum antibiotics and supportive intensive care. C. canimorsus should be considered as a possible cause of infectious purpura fulminans in the unresolved critically ill patient with a history of dog exposure. PMID- 22497464 TI - Editorial: Topological and electrotopological descriptors of molecules: fundamental principles and applications to computer aided molecular design - Part I. PMID- 22497465 TI - To Monty Kier, a friendly tribute. PMID- 22497466 TI - QSAR and QSPR model interpretation using partial least squares (PLS) analysis. AB - Carefully developed quantitative structure-activity and structure-property relationship models contain detailed information regarding how differences in the molecular structure of compounds correlate with differences in the observed biological or other physicochemical properties of those compounds. The ability to understand the behavior of existing molecules and to design new molecules is facilitated by using an objective method to extract and explain the details of the underlying structure-activity or structure-property relationship. Furthermore, a clear understanding of how and why compounds behave as they do can lead to new innovations through model-directed selection of compounds to be used in complex mixtures such as laundry detergents, fabric softeners, and shampoos. Such a method has been developed based on partial least-squares (PLS) regression analysis that allows for the identification of specific structural trends that relate to differences in observed properties. But the analysis of the completed model is only the last step of the process. The model development process itself affects the ability to extract a clear interpretation of the model. Everything from the selection of initial pool of molecular descriptors to evaluate to data set and model optimization impacts the ability to derive detailed molecular design information. This review describes the method details and examples of the use of PLS for model interpretation and also outlines suggestions regarding model development and model and data set optimization that enable the interpretation process. PMID- 22497467 TI - A core molecular theory of sleep and aging. AB - Models of water in the presence of amino acid side chains have revealed significant variability in the local water structure, reflecting the variations in the hydropathic states of the side chains. These models also reveal patterns of water cavities, termed chreodes, that may exist near the surface of a protein. These patterns have been invoked to explain the facilitated diffusion of ligands to an active site on the protein surface. The action of a volatile, general anesthetic agent has been proposed to occur from the interruption of these chreodes producing some loss of function from the receptor. The many similarities reported between the effects of a general anesthetic agent and sleep have produced a proposal of a common mechanism. In the case of sleep, it has been proposed that inhaled elemental nitrogen accumulates to produce a mild anesthesia. Sleep is the process of reversal of this accumulation. It is proposed that over a lifetime there is a continued accumulation of nitrogen with accompanying influences on many processes, leading to a gradual decline of many functions, called aging. The sequence of these concepts is reviewed here. PMID- 22497468 TI - Development of structure information from molecular topology for modeling chemical and biological properties: a tribute to the creativity of Lemont Burwell Kier on his 80th Birthday. AB - This review is a salute to Monty Kier's creativity. Emphasis is placed on creative aspects in the development of the representation of molecular topological structure information and the resultant formalisms: molecular connectivity and electrotopological state (E-State). Less attention is given to detailed analysis of individual papers and the generally well known books and book chapters. This discussion reveals creative paths that led to the concept of the atomic descriptors, simple connectivity delta, encoding local topology, and valence delta value which encodes valence electron information. The fundamental developments that led to the creation of molecular connectivity chi indices are described along with extensions to different chi and delta chi formalisms. Continued thinking about structure in the topological sense led to the development of the only valence state electronegativity formalism based entirely on structure, Kier-Hall electronegativity (KHE). That creation further inspired the development of the electronegativity/topology-based atomic intrinsic state along with perturbation terms that together give electrotopological state indices (E-State). Further creation led to atom and bond type E-State descriptors. All these developments are briefly illustrated with examples in QSAR, chemical similarity, and database searching. PMID- 22497469 TI - Electrotopological state atom (E-state) index in drug design, QSAR, property prediction and toxicity assessment. AB - Over the last two decades, a great deal of research has been oriented towards determination of correlation between molecular structures and a variety of responses exhibited by such molecules. Extensive attempts have been made to quantitatively determine the influence of structural fragments on the property profile of molecules through the development of quantitative structure activity/property/toxicity relationship (QSAR/QSPR/QSTR) models based on regression analysis using different descriptors. Among all descriptors, the topological ones constitute an essential class encoding the crucial structural fragments governing the activity/property or toxicity data of the molecules. To better indicate the important topological features and molecular fragments mediating a particular response, Kier and Hall developed the electrotopological state atom (E-state) indices in the early 90s. The ability to encode the topology and electronic environment of molecular fragments in unison portrayed the E-state indices as an indispensable tool in the field of QSAR/QSPR/QSTR studies. This review looks back at different applications of E-state indices in the field of quantitative analysis of molecular properties as a function of their structures for diverse groups of molecules with vivid range of response parameters. The studies summarized here would help to understand potential of the E-state indices to identify the structural attributes responsible for various responses of the molecules. Although the present review includes most of the important researches carried out employing E-state parameters as the major group of descriptors over the last 15 years, the search is not exhaustive one. Apart from the studies reviewed here, several other researches have also been performed where the E state indices have been engaged in association with several other descriptors to determine the influential molecular fragments for various endpoints. PMID- 22497470 TI - Importance of Kier-Hall topological indices in the QSAR of anticancer drug design. AB - An important area of theoretical drug design research is quantitative structure activity relationship (QSAR) using structural invariants. The impetus for this research trend comes from various directions. Researchers in chemical documentation have searched for a set of invariants which will be more convenient than the adjacency matrix (or connection table) for the storage and comparison of chemical structures. Molecular structure can be looked upon as the representation of the relationship among its various constituents. The term molecular structure represents a set of nonequivalent and probably disjoint concepts. There is no reason to believe that when we discuss diverse topics (e.g. chemical synthesis, reaction rates, spectroscopic transitions, reaction mechanisms, and ab initio calculations) using the notion of molecular structure, the different meanings we attach to the single term molecular structure originate from the same fundamental concept. On the contrary, there is a theoretical and philosophical basis for the non-homogeneity of concepts covered by the term molecular structure. In the context of molecular science, the various concepts of molecular structure (e.g. classical valence bond representations, various chemical graph-theoretic representations, ball and spoke model of a molecule, representation of a molecule by minimum energy conformation, semi symbolic contour map of a molecule, or symbolic representation of chemical species by Hamiltonian operators) are model objects derived through different abstractions of the same chemical reality. In each instance, the equivalence class (concept or model of molecular structure) is generated by selecting certain aspects while ignoring some unique properties of those actual events. This explains the plurality of the concept of molecular structure and their autonomous nature, the word autonomous being used in the same sense that one concept is not logically derived from the other. At the most fundamental level, the structural model of an assembled entity (e.g. a molecule consisting of atoms) may be defined as the pattern of relationship among its parts as distinct from the values associated with them. Constitutional formulae of molecules are graphs where vertices represent the set of atoms and edges represent chemical bonds. The pattern of connectedness of atoms in a molecule is preserved by constitutional graphs. A graph (more correctly a non-directed graph) G = [V, E] consists of a finite non-empty set V of points together with a prescribed set E of unordered pairs of distinct points of V. Thus the mathematical characterization of structures represents structural invariants having successful applications in chemical documentation, characterization of molecular branching, enumeration of molecular constitutional associated with a particular empirical formula, calculation of quantum chemical parameters for the generation of quantitative structure-property-activity correlations. Kier developed a number of structural invariants which are now-a-days called as topological indices with wide range of practical applications for QSAR and drug design. The present paper is restricted to the review of Kier-Hall topological indices for QSAR and anticancer drug design for 2,5-bis(1-aziridinyl) 1,4 benzoquinone (BABQ), pyridopyrimidine, 4-anilinoquinazoline and 2-Phenylindoles compounds utilizing various statistical multivariate regression analyses. PMID- 22497471 TI - Use of vertex index in structure-activity analysis and design of molecules. AB - The last few decades have witnessed application of graph theory and topological indices derived from molecular graph in structure-activity analysis. Such applications are based on regression and various multivariate analyses. Most of the topological indices are computed for the whole molecule and used as descriptors for explaining properties/activities of chemical compounds. However, some substructural descriptors in the form of topological distance based vertex indices have been found to be useful in identifying activity related substructures and in predicting pharmacological and toxicological activities of bioactive compounds. Another important aspect of drug discovery e.g. designing novel pharmaceutical candidates could also be done from the distance distribution associated with such vertex indices. In this article, we will review the development and applications of this approach both in activity prediction as well as in designing novel compounds. PMID- 22497472 TI - Photocatalytic degradation of aromatic pollutants: a pivotal role of conduction band electron in distribution of hydroxylated intermediates. AB - The modulation of the yield distribution of intermediates formed in the photocatalytic degradation of organic pollutants is of extreme importance for the application of photocatalysis in environmental cleanup, as different intermediates usually exhibit distinct biological toxicity and secondary reactivity. In this paper, we report that the distribution of monohydroxylated intermediates (m-, p- and o-) formed during the photocatalytic oxidation of aromatic compounds changes with the variation of reaction conditions, such as O(2) partial pressure and substrate concentration. By detailed product analysis, theoretical calculation, and oxygen isotope labeling experiments, we show that these changes are due to the selective reduction of HO-adduct radicals (the precursors of hydroxylated intermediates) by conduction band electrons (e(cb)(-)) back to the original substrate, that is, p- and o-HO-adduct radicals are more susceptible to e(cb)(-) than the m- one. Our experiments give an example that, even under oxidative conditions, the yield distribution of isomeric intermediates can be modulated by e(cb)(-)-initiated reduction. This study also illustrates that the unique redox characteristics of photocatalysis, that is, both oxidation and reduction reactions take place on or near the surface of a single nanoparticle, can provide opportunities for the reaction control. PMID- 22497473 TI - Hyaladione, an S-methyl cyclohexadiene-dione from Hyalangium minutum. AB - A bioassay-guided fractionation of the crude methanol extract of the myxobacterium Hyalangium minutum, strain NOCB-2(T) (DSM 14724(T)), led to the isolation of hyaladione (1), a novel S-methyl cyclohexadiene-dione. The structure of 1 was established by HRESIMS, NMR, and IR spectroscopy as well as X-ray crystallography. Compound 1 was active against growing mammalian cell lines, with IC(50) values ranging from 1.23 to 3.93 MUM, in addition to a broad spectrum of antibacterial and antifungal activities, including inhibition of pathogenic methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa with an MIC of 0.83 and 8.5 MUg mL(-1), respectively. PMID- 22497474 TI - Costs of expanding the network of protected areas as a response to climate change in the Cape Floristic Region. AB - The expansion of protected areas is a critical component of strategies to promote the continued existence of biodiversity (i.e., life at all levels of biological organization) as climate changes, but scientific, social, and economic uncertainties associated with climate change are some of the major obstacles preventing such expansion. New models of climate change and species distribution and new methods of conservation planning now make it possible to explore the uncertainties associated with climate changes and species responses. Yet few reliable estimates of the costs of expanding protected areas and methods for determining these costs exist, largely because of the many (and uncertain) determinants of these costs. We developed a cost-accounting model to estimate the range in costs of various options for expanding protected areas and to explore the variables that drive these costs. Model development was informed by an existing plan to expand protected areas in the Cape Floristic Region of South Africa to address species conservation under a scenario of climate change. The 50 year present value of total costs varied from US$260 million ($1077/ha) for an off-reserve option that involves agreements with landowners and no compensation of forgone production and associated revenue to $1020 million ($4228/ha) for an on-reserve option that involves land acquisition and protection. The costs of acquiring land or compensating landowners for forgone production and development opportunities were the major drivers of the total costs across all options because most of the area identified in the protected-area expansion plan consisted of urban and high-quality agricultural lands. Total costs were also affected by changes in protected area extent and discount rate. Model-generated outputs such as these may be useful for informing implementation strategies and the allocation of future efforts in monitoring, data collection, and model development. PMID- 22497475 TI - Asymmetric synthesis of polysubstituted 4-amino- and 3,4-diaminochromanes with a chiral multifunctional organocatalyst. AB - A series of multifunctional catalysts with two chiral diaminocyclohexane units were developed and successfully applied in the asymmetric oxa-Michael-aza-Henry cascade reaction of salicylaldimines with nitroolefins. This approach provides a simple and efficient entry to polysubstituted chiral 4-aminobenzopyrans with three consecutive stereocenters and in high yield (up to 97%) with excellent stereoselectivity (up to 98% ee and >99:1 dr). Facile access to the nonsymmetric optically pure 3,4-diaminochromanes was also obtained. PMID- 22497476 TI - Olmesartan medoxomil treatment potently improves cardiac myosin-induced dilated cardiomyopathy via the modulation of ACE-2 and ANG 1-7 mas receptor. AB - Angiotensin converting enzyme-2 (ACE-2) is a monocarboxypeptidase that metabolises angiotensin (ANG)-II into angiotensin 1-7 (ANG 1-7), thereby functioning as a negative regulator of the renin-angiotensin system. We investigated whether treatment with ANG-II type 1 receptor blocker, olmesartan medoxomil is associated with the attenuation of cardiac myosin-induced dilated cardiomyopathy (DCM) through recently established new axis of ACE-2/ANG 1-7 mas receptor. DCM was elicited in Lewis rats by immunisation with cardiac myosin, and 28 days after immunisation, the surviving Lewis rats were divided into two groups and treated with either olmesartan medoxomil (10 mg/kg/day) or vehicle. Myocardial protein and mRNA levels of ACE-2, ANG 1-7 mas receptor were upregulated in the olmesartan-treated group compared with those of vehicle treated DCM rats. In contrast, Olmesartan treatment effectively suppressed the myocardial protein and mRNA expressions of inflammatory markers in comparison to the vehicle-treated DCM rats. Olmesartan treatment significantly reduced fibrosis, hypertrophy and their marker molecules (OPN, CTGF, ANP and GATA-4, respectively), as well as matrix metalloproteinases compared with those of vehicle-treated DCM rats. Enhanced myocardial protein levels of phospho-p38 MAPK, phospho-JNK and phospho MAPKAPK-2 in the vehicle-treated DCM rats were prevented by olmesartan treatment. In addition, olmesartan treatment significantly lowered the protein expressions (Nitrotyrosine, p47phox and p67phox) and superoxide radical production compared with those of vehicle-treated DCM rats. Our present study might serve as a new therapeutic target of DCM in cardiovascular diseases and cardiac myosin-induced DCM via the modulation of ACE-2/ANG 1-7 mas receptor axis in rats with DCM after myosin-immunisation. PMID- 22497477 TI - MSTN genotypes in Thoroughbred horses influence skeletal muscle gene expression and racetrack performance. AB - Myostatin, encoded by the MSTN gene, is a member of the TGF-beta superfamily that regulates skeletal muscle development. A MSTN SNP significantly associated with Thoroughbred horse racing phenotypes has recently been identified as well as significant reductions in Thoroughbred skeletal muscle gene expression for three transcripts 400-1500 base pairs downstream of the MSTN gene following a period of training. Together, these findings indicate that MSTN genotypes may influence MSTN gene expression. To investigate this, MSTN mRNA expression was measured in biopsies from the middle gluteal muscle from 60 untrained yearling Thoroughbreds (C/C, n = 15; C/T, n = 28; T/T, n = 17) using two independent real-time qRT-PCR assays. MSTN gene expression was also evaluated in a subset (N = 33) of these animals using samples collected after a ten-month period of training. A significant association was observed between genotype and mRNA abundance for the untrained horses (assay I, P = 0.0237; assay II, P = 0.003559), with the C/C cohort having the highest MSTN mRNA levels, the T/T group the lowest levels and the C/T group intermediate levels. Following training, there was a significant decrease in MSTN mRNA (-3.35-fold; P = 6.9 * 10(-7) ), which was most apparent for the C/C cohort (-5.88-fold, P = 0.001). These data demonstrate the tight relationship between phenotype, genotype and gene expression at the MSTN gene in Thoroughbred racehorses. PMID- 22497479 TI - Effect of population stratification on false positive rates of population-based association analyses of quantitative traits. AB - It is now well established that population stratification can result in spurious association findings in genetic case-control studies. However, very few studies have addressed similar issues for mapping quantitative traits. Because quantitative phenotypes are often precursors of clinical endpoint traits and carry more information on within-genotype trait variability, it has been argued that studying these quantitative traits may be a more powerful strategy to map genes than the binary clinical endpoints. Thus, it is of interest to evaluate the adverse effects of population stratification on the analyses of quantitative traits. The popular statistical tests of association for quantitative traits using population level data are ANOVA, linear regression with an additive allelic effect and Kruskal-Wallis. We have theoretically studied the marginal effects of genetic heterogeneity and phenotypic heterogeneity as well as their joint effects on the false positive rates of these three tests. We have carried out extensive simulations under different genetic models and probability distributions of quantitative traits to assess the rate of false positives in the presence of population stratification. We find that the rate of false positives increases very quickly with simultaneous increase in differences in the standardized phenotypic means and marker allele frequencies in the subpopulations. PMID- 22497478 TI - Application of a novel hybrid study design to explore gene-environment interactions in orofacial clefts. AB - Orofacial clefts are common birth defects with strong evidence for both genetic and environmental causal factors. Candidate gene studies combined with exposures known to influence the outcome provide a highly targeted approach to detecting GxE interactions. We developed a new statistical approach that combines the case control and offspring-parent triad designs into a "hybrid design" to search for GxE interactions among 334 autosomal cleft candidate genes and maternal first trimester exposure to smoking, alcohol, coffee, folic acid supplements, dietary folate and vitamin A. The study population comprised 425 case-parent triads of isolated clefts and 562 control-parent triads derived from a nationwide study of orofacial clefts in Norway (1996-2001). A full maximum-likelihood model was used in combination with a Wald test statistic to screen for statistically significant GxE interaction between strata of exposed and unexposed mothers. In addition, we performed pathway-based analyses on 28 detoxification genes and 21 genes involved in folic acid metabolism. With the possible exception of the T-box 4 gene (TBX4) and dietary folate interaction in isolated CPO, there was little evidence overall of GxE interaction in our data. This study is the largest to date aimed at detecting interactions between orofacial clefts candidate genes and well established risk exposures. PMID- 22497481 TI - Exploring the different photocatalytic performance for dye degradations over hexagonal ZnIn2S4 microspheres and cubic ZnIn2S4 nanoparticles. AB - Different pathways for the degradation of rhodamine (RhB) as well as different activity order for the degradation of RhB and methyl orange (MO) were observed over hexagonal ZnIn(2)S(4) microspheres and cubic ZnIn(2)S(4) nanoparticles. A detailed study of the physicochemical and surface properties of these two ZnIn(2)S(4) polymorphs has been carried out to elucidate these phenomena. The results reveal that hexagonal ZnIn(2)S(4) microspheres are composed of nanolamella petals growing in the ab plane, i.e., the negative (0001) S plane. This negative (0001) S plane not only is favorable for the adsorption of the cationic dye RhB via -N(Et)(2) groups but also can accumulate the photogenerated holes. These make the hole-directed photocatalytic de-ethylation of RhB more expedient over hexagonal ZnIn(2)S(4) microspheres. This negative (0001) S plane of hexagonal ZnIn(2)S(4) microspheres also shows promoting effect for the degradation of cationic dye like MB, but not for the degradation of anionic dye like MO. Our result provides some new insights in how the surface facet can take effect on influencing the performance of a photocatalyst and why different polymorphs can exhibit different photocatalytic performance. PMID- 22497480 TI - Similarity-based multimarker association tests for continuous traits. AB - Testing multiple markers simultaneously not only can capture the linkage disequilibrium patterns but also can decrease the number of tests and thus alleviate the multiple-testing penalty. If a gene is associated with a phenotype, subjects with similar genotypes in this gene should also have similar phenotypes. Based on this concept, we have developed a general framework that is applicable to continuous traits. Two similarity-based tests (namely, SIMc and SIMp tests) were derived as special cases of the general framework. In our simulation study, we compared the power of the two tests with that of the single-marker analysis, a standard haplotype regression, and a popular and powerful kernel machine regression. Our SIMc test outperforms other tests when the average R(2) (a measure of linkage disequilibrium) between the causal variant and the surrounding markers is larger than 0.3 or when the causal allele is common (say, frequency = 0.3). Our SIMp test outperforms other tests when the causal variant was introduced at common haplotypes (the maximum frequency of risk haplotypes >0.4). We also applied our two tests to an adiposity data set to show their utility. PMID- 22497482 TI - Cochlear ossification in patients with profound hearing loss following bacterial meningitis. AB - CONCLUSION: Cochlear ossification following bacterial meningitis is related to causative pathogen, but not age at disease or time point of evaluation. However, progression may occur over time, especially in case of primary signs of ossification. OBJECTIVE: To investigate the occurrence and degree of cochlear ossification on CT and MRI in patients with bilateral profound hearing loss following bacterial meningitis, in relation to causative pathogen, age at disease, and time point of evaluation. Progression of ossification in cases that underwent more than one scan was evaluated. METHODS: In the period 1982-2008, 47 cochlear implantations were performed in 34 consecutive candidates suffering from bilateral profound hearing loss following bacterial meningitis. A retrospective review of patient files and preoperative CT and MR images was performed. RESULTS: Cochlear ossification was observed in 35% of patients and 26% of ears on CT. The corresponding values for MRI were 44 and 30% (difference not significant). Streptococcus pneumoniae infection caused ossification more frequently than Neisseria meningitidis. No difference was found between pediatric and adult cases, and the occurrence of ossification was not related to the time point of evaluation. Signs of progressive ossification were found in cases with two CT scans, especially if ossification was present at the first scan. PMID- 22497483 TI - Effect of heparin on protein aggregation: inhibition versus promotion. AB - The effect of heparin on both native and denatured protein aggregation was investigated by turbidimetry and dynamic light scattering (DLS). Turbidimetric data show that heparin is capable of inhibiting and reversing the native aggregation of bovine serum albumin (BSA), beta-lactoglobulin (BLG), and Zn insulin at a pH near pI and at low ionic strength I; however, the results vary with regard to the range of pH, I, and protein-heparin stoichiometry required to achieve these effects. The kinetics of this process were studied to determine the mechanism by which interaction with heparin could result in inhibition or reversal of native protein aggregates. For each protein, the binding of heparin to distinctive intermediate aggregates formed at different times in the aggregation process dictates the outcome of complexation. This differential binding was explained by changes in the affinity of a given protein for heparin, partly due to the effects of protein charge anisotropy as visualized by electrostatic modeling. The heparin effect can be further extended to include inhibition of denaturing protein aggregation, as seen from the kinetics of BLG aggregation under conditions of thermally induced unfolding with and without heparin. PMID- 22497484 TI - Aplasia ras homolog member I is downregulated in gastric cancer and silencing its expression promotes cell growth in vitro. AB - BACKGROUND AND AIM: Aplasia ras homolog member I (ARHI) is a maternally imprinted tumor suppressor gene. ARHI protein is widely expressed in many types of human tissues; however, its expression is frequently reduced or absent in various tumors and plays a tumor suppressor role for in vitro study. In this study, we investigated the expression level of ARHI in gastric cancer in order to investigate the function of ARHI and signaling pathways that might be linked during gastric cancer development. METHODS: ARHI mRNA and protein expression levels were analyzed in primary gastric cancer tissues, adjacent noncancerous gastric tissues and gastric cancer cell lines using semi-quantitative polymerase chain reaction, western blotting and immunohistochemistry, respectively. RESULTS: Our results showed that both mRNA and protein expression levels of the ARHI gene were significantly downregulated (P < 0.05) in gastric cancer tissues and cell lines compared to the corresponding normal control groups. The protein expression level of ARHI was not associated with age, gender, location of tumor, tumor size or metastasis in patients with gastric cancer. However, a significant correlation between the level of ARHI protein expression and the degree of tumor differentiation and Tumor-Node-Metastasis stage was observed (P < 0.05). Furthermore, results of the methyl thiazolyl tetrazolium and Transwell assays and flow cytometric analysis showed increased cell proliferation, migration and anti apoptotic capacities in the well-differentiated gastric cancer MKN-28 cell line, which has stably silenced ARHI protein expression. CONCLUSION: Our data indicate that ARHI expression is downregulated in human gastric cancer and it may be a novel tumor suppressive target for gastric cancer therapy. PMID- 22497485 TI - Transferrin-modified c[RGDfK]-paclitaxel loaded hybrid micelle for sequential blood-brain barrier penetration and glioma targeting therapy. AB - The effective chemotherapy for glioblastoma multiform (GBM) requires a nanomedicine that can both penetrate the blood-brain barrier (BBB) and target the glioma cells subsequently. In this study, Transferrin (Tf) modified cyclo-[Arg Gly-Asp-d-Phe-Lys] (c[RGDfK])-paclitaxel conjugate (RP) loaded micelle (TRPM) was prepared and evaluated for its targeting efficiency, antiglioma activity, and toxicity in vitro and in vivo. Tf modification significantly enhanced the cellular uptake of TRPM by primary brain microvascular endothelial cells (BMEC) to 2.4-fold of RP loaded micelle (RPM) through Tf receptor mediated endocytosis, resulting in a high drug accumulation in the brain after intravenous injection.The c[RGDfK] modified paclitaxel (PTX) was released from micelle subsequently and targeted to integrin overexpressed glioma cells in vitro, and showed significantly prolonged retention in glioma tumor and peritumoral tissue. Most importantly, TRPM exhibited the strongest antiglioma activity, as the mean survival time of mice bearing intracranial U-87 MG glioma treated with TRPM (42.8 days) was significantly longer than those treated with Tf modified PTX loaded micelle (TPM) (39.5 days), PTX loaded micelle (PM) (34.8 days), Taxol (33.6 days), and saline (34.5 days). Noteworthy, TRPM did not lead to body weight loss compared with saline and was less toxic than TPM. These results indicated that TRPM could be a promising nanomedicine for glioma chemotherapy. PMID- 22497486 TI - Genetic variation in PLAG1 associates with early life body weight and peripubertal weight and growth in Bos taurus. AB - Variation at the pleiomorphic adenoma gene 1 (PLAG1) locus has recently been implicated in the regulation of stature and weight in Bos taurus. Using a population of 942 outbred Holstein-Friesian dairy calves, we report confirmation of this effect, demonstrating strong association of early life body weight with PLAG1 genotype. Peripubertal body weight and growth rate were also significantly associated with PLAG1 genotype. Growth rate per kilogram of body weight, daily feed intake, gross feed efficiency and residual feed intake were not significantly associated with PLAG1 genotype. This study supports the status of PLAG1 as a key regulator of mammalian growth. Further, the data indicate the utility of PLAG1 polymorphisms for the selection of animals to achieve enhanced weight gain or conversely to aid the selection of animals with lower mature body weight and thus lower maintenance energy requirements. PMID- 22497488 TI - Polymorphic variants within a putative upstream open reading frame of the MC4R gene do not affect body weight of farmed red foxes. PMID- 22497487 TI - Genetic mapping of recurrent exertional rhabdomyolysis in a population of North American Thoroughbreds. AB - Recurrent exertional rhabdomyolysis is a heritable disorder that results in painful skeletal muscle cramping with exercise in up to 10% of all Thoroughbred racehorses. Here, we report a genome-wide association study with 48 282 SNPs analyzed among 48 case and 37 control Thoroughbreds. The most significant SNPs spanned approximately 13 Mb on ECA16, and the P-value of the most significant SNP after correcting for population structure was 8.0 * 10(-6) . This region on ECA16 was further evaluated by genotyping 247 SNPs in both the initial population and a second population of 34 case and 98 control Thoroughbreds. Several SNPs across the 13-Mb region on ECA16 showed significance when each population was analyzed separately; however, the exact positions of the most significant SNPs within this region on ECA16 varied between populations. This variability in location may be attributed to lack of power owing to insufficient sample sizes within each population individually, or to the relative distribution of long, conserved haplotypes, characteristic of the Thoroughbred breed. Future genome-wide association studies with additional horses would likely improve the power to resolve casual loci located on ECA16 and increase the likelihood of detecting any additional loci on other chromosomes contributing to disease susceptibility. PMID- 22497489 TI - Effects of onion (Allium cepa L.) and garlic (Allium sativum L.) essential oils on the Aspergillus versicolor growth and sterigmatocystin production. AB - In the present study the effects of individual and combined essential oils (EOs) extracted from onion (Allium cepa L.) bulb and garlic (Allium sativum L.) clove on the growth of Aspergillus versicolor and sterigmatocystin (STC) production were investigated. The EOs obtained by hydrodistillation were analyzed by GC/MS. Twenty one compounds were identified in onion EO. The major components were: dimethyl-trisulfide (16.64%), methyl-propyl-trisulfide (14.21%), dietil-1,2,4 tritiolan (3R,5S-, 3S,5S- and 3R,5R- isomers) (13.71%), methyl-(1-propenyl) disulfide (13.14%), and methyl-(1-propenyl)-trisulfide (13.02%). The major components of garlic EO were diallyl-trisulfide (33.55%), and diallyl-disulfide (28.05%). The mycelial growth and the STC production were recorded after 7, 14, and 21 d of the A. versicolor growth in Yeast extract sucrose (YES) broth containing different EOs concentrations. Compared to the garlic EO, the onion EO showed a stronger inhibitory effect on the A. versicolor mycelial growth and STC production. After a 21-d incubation of fungi 0.05 and 0.11 MUg/mL of onion EO and 0.11 MUg/mL of garlic EO completely inhibited the A. versicolor mycelial growth and mycotoxins biosynthesis. The combination of EOs of onion (75%) and garlic (25%) had a synergistic effect on growth inhibition of A. versicolor and STC production. PMID- 22497491 TI - Duty cycling influences current generation in multi-anode environmental microbial fuel cells. AB - Improving microbial fuel cell (MFC) performance continues to be the subject of research, yet the role of operating conditions, specifically duty cycling, on MFC performance has been modestly addressed. We present a series of studies in which we use a 15-anode environmental MFC to explore how duty cycling (variations in the time an anode is connected) influences cumulative charge, current, and microbial composition. The data reveal particular switching intervals that result in the greatest time-normalized current. When disconnection times are sufficiently short, there is a striking decrease in current due to an increase in the overall electrode reaction resistance. This was observed over a number of whole cell potentials. Based on these results, we posit that replenishment of depleted electron donors within the biofilm and surrounding diffusion layer is necessary for maximum charge transfer, and that proton flux may be not limiting in the highly buffered aqueous phases that are common among environmental MFCs. Surprisingly, microbial diversity analyses found no discernible difference in gross community composition among duty cycling treatments, suggesting that duty cycling itself has little or no effect. Such duty cycling experiments are valuable in determining which factors govern performance of bioelectrochemical systems and might also be used to optimize field-deployed systems. PMID- 22497492 TI - Theoretical investigation of the mechanisms and stereoselectivities of reductions of acyclic phosphine oxides and sulfides by chlorosilanes. AB - Computational studies were performed to explain the highly varied stereoselectivities obtained in the reductions of acyclic phosphine oxides and sulfides by different chlorosilanes. The reductions of phosphine oxides by HSiCl(3), HSiCl(3)/Et(3)N, and Si(2)Cl(6) and the reductions of phosphine sulfides by Si(2)Cl(6) (all in benzene) were explored by means of B3LYP, B3LYP-D, and SCS-MP2 calculations. For the reductions of phosphine oxides by HSiCl(3), the calculations support the mechanism proposed by Horner in which a hydride is transferred from silicon to phosphorus through a four-centered, frontside transition state. This mechanism leads to retention of stereochemistry at phosphorus. For the other three reductions, two classes of mechanisms were explored. Phosphorane-based mechanisms that were previously proposed by Mislow and involve SiCl(3)(-) were compared with novel alternative mechanisms that involve nonionic rearrangement processes. In one of these, donor-stabilized SiCl(2) is formed as an intermediate. The calculations support a phosphorane based mechanism for the reductions of phosphine oxides by HSiCl(3)/Et(3)N and Si(2)Cl(6) (which proceed with inversion) but favor the rearrangement pathways for the reductions of phosphine sulfides by Si(2)Cl(6) (which proceed with retention). PMID- 22497490 TI - Clearance of an epidemic clone of methicillin-resistant Staphylococcus aureus in a drug-use network: a follow-up study in Switzerland. AB - BACKGROUND: A single clone of methicillin-resistant Staphylococcus aureus (MRSA) was observed in a drug-use network starting in 1994, and was found to persist throughout 2001, with up to 19% MRSA colonization of intravenous drug users (IDUs). Recent clinical observations have shown low prevalences of this endemic drug clone among MRSA isolates. The goal of this study was to assess the evolution of MRSA carriage among IDUs. METHODS: The survey took place from November 2008 to September 2009. Ten drug dispensary facilities took part. Demographic and clinical data including sex, history of MRSA, past hospitalization, use of antibiotics, and presence of wounds were collected. Screening of the nares, throat, and wounds was done. RESULTS: Five hundred and fourteen swab specimens were obtained; 497 of them were nose/throat samples and 17 were wound swabs. MRSA was identified in 5 samples (1%). Four MRSA were found in nose/throat samples and 1 in a wound swab. Pulsed-field gel electrophoresis typing of the MRSA isolates revealed 2 different common endemic types: 4 were identified as the Zurich IDU clone and 1 as the Grison clone. CONCLUSIONS: The study shows a significant decline of MRSA colonization among IDUs. The underlying causes for this decline could not be determined fully, but we hypothesize a bundle of interventions as contributing: enhanced medical care, better wound management, isolation management, teaching IDUs basic hygiene techniques, and the national 'Four Pillars' policy. Hospital epidemiological policies such as pre emptive isolation, length of isolation time, and screening procedures were adapted accordingly. PMID- 22497493 TI - Association of the polymorphism g.8514C>T in the osteopontin gene (SPP1) with milk yield in the dairy cattle breed Girolando. PMID- 22497494 TI - Variation in the XKR4 gene was significantly associated with subcutaneous rump fat thickness in indicine and composite cattle. AB - Variation in the XK, Kell blood group complex subunit-related family, member 4 (XKR4) gene on BTA14 was associated with rump fat thickness in a recent genome wide association study. This region is also of interest because it is known to show evidence of a signature of population genetic selection. In this study, additional variation in this gene was genotyped in a sample of a total of 1283 animals of the Belmont Red (BEL) and Santa Gertrudis (SGT) breeds. The SNP rs41724387 was significantly (P < 0.001) associated with rump fat thickness and explained 5.9% of the genetic variance for the trait in this sample. Using the 4466 genotypes for the SNP rs42646708 from several data sets to estimate effects in seven breeds, this relatively large quantitative trait locus effect appears to be a result of the variation in indicine and taurine-indicine composite cattle. However, the only DNA variant found in Brahman cattle that altered the predicted amino acid sequence of XKR4 was not associated with rump fat thickness. This suggests that causative mutations lie outside the coding sequence of this gene. PMID- 22497495 TI - Interprofessional psychiatric teams: is multidimensionality evident in treatment conferences? AB - Interprofessional teamwork is practised when the care needs of patients are complex. Little is known about the extent to which team competence really determines patient interventions. The aim of the study was to examine the degree of multidimensionality in patient discussions in psychiatry, and to how different professions contribute. Psychiatric teams were observed during 30 team meetings. A content analysis was used to examine the amount of attention given to medical, psychological and social aspects. The results indicated difficulties in achieving multidimensionality in patient discussions during team meetings. The descriptive element of the discussion was dominated by the social aspect, to which all professions contributed. The analytical element was dominated by the psychological aspect, also to which all the professions contributed. In suggesting interventions, medical interventions were emphasized, principally by the physicians. Decisions on interventions concerned equally medical, social and psychological aspects. An interprofessional composition of teams offers no guarantee that interventions will be of a multidimensional nature. The results are discussed in relation to previous research and practical implications. PMID- 22497497 TI - Left atrial function assessed by tissue doppler imaging as a new predictor of cardiac events after non-ST-elevation acute coronary syndrome. AB - AIMS: Left ventricular (LV) function is a predictor for future cardiac events in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). The aim of this study was to assess whether left atrium (LA) function has additional predictive value for the prognosis of NSTE-ACS patients, especially when assessed by tissue Doppler imaging (TDI). METHODS AND RESULTS: This study prospectively recruited 164 patients with NSTE-ACS where clinical and echocardiographic parameters were collected within the first 72 hours of admission. Primary end point was assessed during the 6-month follow-up period which included cardiac mortality and/or rehospitalization for recurrent ACS or heart failure. Atrial function was assessed by conventional echocardiographic parameters and by TDI that measured the mean atrial contraction velocity at the midsegments of interatrial septum, anterior, inferior, and lateral wall of LA (mLA-V). The primary end point occurred in 33 (20.1%) patients who had lower mLV-A (5.4 +/- 1.6 vs 6.5 +/- 1.4 cm/sec, P < 0.01). Patients with mLA-V <6.3 cm/sec had more cardiac events (30.9% vs 9.6%, P < 0.01). By multivariate logistic regression analysis, mLA-V <6.3 cm/sec was an independent predictor for cardiac events (odds ratio: 2.79, 95% confidence interval: 1.07-7.30, P = 0.04). Furthermore, mLA V<6.3 cm/sec had an incremental predictive value for cardiac events to clinical data, LV ejection fraction, and LV diastolic function (E/E') (P = 0.02). CONCLUSIONS: In patients with NSTE-ACS, early assessment of LA function by TDI appears useful to predict the midterm cardiac events, which adds prognostic information in addition to that of LV function. PMID- 22497498 TI - Dithiafulvenyl unit as a new donor for high-efficiency dye-sensitized solar cells: synthesis and demonstration of a family of metal-free organic sensitizers. AB - This work identifies the dithiafulvenyl unit as an excellent electron donor for constructing D-pi-A-type metal-free organic sensitizers of dye-sensitized solar cells (DSCs). Synthesized and tested are three sensitizers all with this donor and a cyanoacrylic acid acceptor but differing in the phenyl (DTF-C1), biphenyl (DTF-C2), and phenyl-thiopheneyl-phenyl pi-bridges (DTF-C3). Devices based on these dyes exhibit a dramatically improved performance with the increasing pi bridge length, culminating with DTF-C3 in eta = 8.29% under standard global AM 1.5 illumination. PMID- 22497499 TI - Chromosome 6p25 deletion syndrome: report of a case with optic disc coloboma and review of published ophthalmic findings. AB - PURPOSE: The 6p25 deletion syndrome is a rare disorder characterized by Dandy Walker malformation, congenital heart defects, developmental delay, dysmorphic facial features, and malformations of the anterior segment of the eye with a risk for glaucoma. Here we report a child harboring a cryptic de novo 6p25 deletion, bilateral optic disc coloboma and characteristic anterior segment anomalies. We review reported ophthalmic findings in patients with this syndrome. MATERIALS AND METHODS: Retrospective case review of a 4-day-old male with Dandy-Walker malformation and cardiac defects who was referred with a suspected diagnosis of iris coloboma. RESULTS: The ophthalmic examination showed bilateral corectopia associated with posterior embryotoxon. Fundus examination revealed bilateral optic disc excavation, which was diagnosed as colobomatous because of its configuration and stability over time. Because of the association of posterior embryotoxon with Dandy-Walker malformation, a terminal 6p deletion syndrome was clinically suspected. Array comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) studies revealed a 3.2 Mb deletion at 6p25.2p25.3 including the FOXC1 gene. Neither unaffected parent carried this deletion. CONCLUSIONS: Optic disc colobomas may be found in patients carrying a 6p25 deletion. This has the potential to confound assessment of affected children for glaucoma and intracranial hypertension. PMID- 22497500 TI - Molecular cloning reveals nearly half of patients with Crohn's disease have an antibody to peroxiredoxin 6-like protein. AB - BACKGROUND AND AIM: Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) of unknown etiology. We aimed to identify the etiological agent of CD using a molecular cloning strategy that was particularly focused on identifying agents causing immune abnormalities and infectious agents. METHODS: We constructed a cDNA library derived from the inflamed intestinal tissue of a CD patient, and screened 1.5 million clones in this library with the serum from another typical CD patient. The expressed cDNA clones that positively reacted with the serum were then expressed as fusion proteins with glutathione S-transferase, and western blotting was performed using the sera of 22 CD, 13 ulcerative colitis (UC), and 16 non-IBD patients. RESULTS: We identified nine positive clones that did not contain any viral or bacterial genomic DNA. Of these, we selected one clone (clone 50) with which the typical CD patient's serum most strongly reacted. Clone 50 is highly homologous to the antioxidant protein peroxiredoxin 6. In western blotting, the sera of 47.6% CD patients (small intestine type 80%, large and small intestine type 43%, large intestine type 0%) showed strong reactivity to clone 50, none of the UC patients were reactive to clone 50, and 18.8% of non-IBD patients were very weakly reactive to it. We also found that the expression of peroxiredoxin 6 was significantly increased in inflamed intestinal epithelia of CD. CONCLUSION: The present study first showed that some CD patients have an antibody against peroxiredoxin 6-like protein, which may be involved in the pathogenesis of CD. PMID- 22497501 TI - A proteomics study of the induction of somatic embryogenesis in Medicago truncatula using 2DE and MALDI-TOF/TOF. AB - Medicago truncatula is a model legume, whose genome is currently being sequenced. Somatic embryogenesis (SE) is a genotype-dependent character and not yet fully understood. In this study, a proteomic approach was used to compare the induction and expression phases of SE of both the highly embryogenic line M9-10a of M. truncatula cv. Jemalong and its non-embryogenic predecessor line, M9. The statistical analysis between the lines revealed 136 proteins with significant differential expression (P < 0.05). Of these, 5 had a presence/absence pattern in M9 vs M9-10a and 22 showed an at least twofold difference in terms of spot volume, were considered of particular relevance to the SE process and therefore chosen for identification. Spots were excised in gel digested with trypsin and proteins were identified using matrix-assisted laser desorption ionization-time of flight/time of flight. Identified proteins indicated a higher adaptability of the embryogenic line toward the stress imposed by the inducing culture conditions. Also, some proteins were shown to have a dual pattern of expression: peroxidase, pyrophosphatase and aspartate aminotransferase. These proteins showed higher expression during the induction phases of the M9 line, whereas in the embryogenic line had higher expression at stages coinciding with embryo formation. PMID- 22497502 TI - Electronic spectra of gas-phase polycyclic aromatic nitrogen heterocycle cations: isoquinoline+ and quinoline+. AB - Electronic spectra of the gas-phase isoquinoline(+)-Ar and quinoline(+)-Ar complexes are recorded using photodissociation spectroscopy by monitoring the Ar loss channel. The D(3)<-D(0) and D(4)<-D(0) band origins for isoquinoline(+)-Ar are observed at 15245 +/- 15 cm(-1) and 21960 +/- 15 cm(-1), respectively, whereas for quinoline(+)-Ar they appear at 16050 +/- 15 cm(-1) and 21955 +/- 15 cm(-1), respectively. Strong vibronic progressions for the D(3)<-D(0) band systems of both isoquinoline(+)-Ar and quinoline(+)-Ar are modeled and assigned in terms of ring deformation and carbon-carbon stretch vibrational modes using time-dependent density functional theory calculations in conjunction with Franck Condon simulations. The properties of the isoquinoline(+) and quinoline(+) molecules are compared with those of the isoelectronic naphthalene(+) molecule. The existence of strong progressions in the visible spectra of isoquinoline(+)-Ar and quinoline(+)-Ar suggests that the corresponding isoquinoline(+) and quinoline(+) molecular cations are unlikely to be responsible for diffuse interstellar bands. PMID- 22497503 TI - Prevention of wound complications in salvage pharyngolaryngectomy by the use of well-vascularized flaps. AB - CONCLUSIONS: We successfully reduced the incidence of pharyngocutaneous fistulas (PCFs) in high-risk patients undergoing surgery by using pectoralis major myocutaneous flaps (PMMCFs) and deltopectoral flaps (DPFs) to cover suture lines. OBJECTIVES: We used coverage of suture lines with PMMCFs and DPFs in patients with high risk of PCFs undergoing total laryngectomy (TL) or total pharyngolaryngectomy (TPL) to determine whether coverage of suture lines during salvage surgery can reduce the incidence of PCFs. METHODS: This retrospective study was based on a review of 52 patients who underwent salvage TL or TPL between 2001 and 2011; we have been using PMMCFs or DPFs during salvage surgery since 2008. Details of postoperative complications including PCFs were analyzed. RESULTS: The incidence rate of PCF was lower in the flap group (7.7%) than that in the non-flap group (30.1%). No carotid ruptures were observed in the flap group (0%) as contrasted with patients in the non-flap group (7.7%). PMID- 22497504 TI - Nucleotide variability and haplotype heterogeneity at the porcine fat mass and obesity-associated (FTO) gene. AB - A large number of studies have confirmed that variants within the fat mass and obesity-associated (FTO) gene are associated with higher obesity risk in humans. We and others have shown that FTO polymorphisms are associated with fat deposition and related traits in several pig populations, thus confirming the role of this gene in fatness across species. However, some differences observed in different pig populations may be derived, at least in part, from genetic heterogeneity at this locus. Here, we characterise the nucleotide variability and haplotype diversity of the porcine FTO gene in breeds having different predispositions to fat deposition traits. We resequenced 4749 bp of coding and non-coding regions of the porcine FTO gene in 44 pigs of eight different breeds and identified 27 single nucleotide polymorphisms (SNPs) and four insertions/deletions. A positive Tajima's D-value (P < 0.10) obtained in Italian Duroc pigs may be compatible with putative balancing selection. From the sequenced pig panel, 20 haplotypes were inferred, some of which clustered according to the breed of origin (Meishan and Italian Duroc). Genetic heterogeneity at this locus could complicate the dissection of the effects of this gene on fat deposition and production traits in pigs. This situation resembles, to some extent, what has been reported in humans, thus making the study of the porcine FTO gene variability especially interesting, as it could be used as a model to understand the complex and elusive role of this gene in human obesity. PMID- 22497505 TI - Breastfed infants metabolize perchlorate. AB - Bifidobacteria are the dominant intestinal bacteria in breastfed infants. It is known that they can reduce nitrate. Although no direct experiments have been conducted until now, inferred pathways for Bifidobacterium bifidum include perchlorate reduction via perchlorate reductase. We show that when commercially available strains of bifidobacteria are cultured in milk, spiked with perchlorate, perchlorate is consumed. We studied 13 breastfed infant-mother pairs who provided 43 milk samples and 39 infant urine samples, and 5 formula-fed infant-mother pairs who provided 21 formula samples and 21 infant urine samples. Using iodine as a conservative tracer, we determined the average urinary iodine (UI) to milk iodine (MI) concentration ratio to be 2.87 for the breastfed infants. For the same samples, the corresponding perchlorate concentration ratio was 1.37 (difference significant, p < 0.001), indicating that perchlorate is lost. For the formula fed infant group the same ratios were 1.20 and 1.58; the difference was not significant (p = 0.68). However, the small number of subjects in the latter group makes it more difficult to conclude definitively whether perchlorate reduction does or does not occur. PMID- 22497506 TI - In vivo imaging of folate receptor positive tumor xenografts using novel 68Ga NODAGA-folate conjugates. AB - The overexpression of the folate receptor (FR) in a variety of malignant tumors, along with its limited expression in healthy tissues, makes it an attractive tumor-specific molecular target. Noninvasive imaging of FR using radiolabeled folate derivatives is therefore highly desirable. Given the advantages of positron emission tomography (PET) and the convenience of (68)Ga production, the aim of our study was to develop a new (68)Ga-folate-based radiotracer for clinical application. The chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7 acetic acid (NODAGA) was conjugated to folic acid and to 5,8-dideazafolic acid using 1,2-diaminoethane as a spacer, resulting in two novel conjugates, namely, P3246 and P3238, respectively. Both conjugates were labeled with (68/67)Ga. In vitro internalization, efflux, and saturation binding studies were performed using the FR-positive KB cell line. Biodistribution and small-animal PET imaging studies were performed in nude mice bearing subcutaneous KB xenografts. Both conjugates were labeled with (68)Ga at room temperature within 10 min in labeling yields >95% and specific activity ~30 GBq/MUmol. The K(d) values of (68/67)Ga P3246 (5.61 +/- 0.96 nM) and (68/67)Ga-P3238 (7.21 +/- 2.46 nM) showed high affinity for the FR. (68/67)Ga-P3246 showed higher cell-associated uptake in vitro than (68/67)Ga-P3238 (approximately 72 and 60% at 4 h, respectively, P < 0.01), while both radiotracers exhibited similar cellular retention up to 4 h (approximately 76 and 71%, respectively). Their biodistribution profile is characterized by high tumor uptake, fast blood clearance, low hepatobiliary excretion, and almost negligible background. Tumor uptake was already high at 1 h for both (68)Ga-P3246 and (68)Ga-P3238 (16.56 +/- 3.67 and 10.95 +/- 2.12% IA/g, respectively, P > 0.05) and remained at about the same level up to 4 h. Radioactivity also accumulated in the FR-positive organs, such as kidneys (91.52 +/- 21.05 and 62.26 +/- 14.32% IA/g, respectively, 1 h pi) and salivary glands (9.05 +/- 2.03 and 10.39 +/- 1.19% IA/g, respectively, 1 h pi). The specificity of the radiotracers for the FR was confirmed by blocking experiments where tumor uptake was reduced by more than 85%, while the uptake in the kidneys and the salivary glands was reduced by more than 90%. Reduction of the kidney uptake was achieved by administration of the antifolate pemetrexed 1 h prior to the injection of the radiotracers, which resulted in an improvement of tumor-to kidney ratios by more than a factor of 3. In line with the biodistribution results, small-animal PET images showed high uptake in the kidneys, clear visualization of the tumor, accumulation of radioactivity in the salivary glands, and no uptake in the gastrointestinal tract. (68)Ga-P3246 and (68)Ga-P3238 showed very high tumor-to-background contrast in PET images; however, the tumor-to kidney ratio remained low. The new radiotracers, especially (68)Ga-P3246, are promising as PET imaging probes for clinical application due to their facile preparation and improved in vivo profile as compared to the other folate-based PET radiotracers. PMID- 22497507 TI - Replication and refinement of a quantitative trait locus influencing milk protein percentage on ovine chromosome 3. AB - A previous genome scan that was conducted in Spanish Churra sheep identified a significant quantitative trait locus (QTL) for milk protein percentage (PP) on chromosome 3 (OAR3), between markers KD103 and OARVH34. The aim of this study was to replicate these results and to refine the mapped position of this QTL. To accomplish this goal, we analysed 14 new half-sib families of Spanish Churra sheep including 1661 ewes from 29 different flocks. These animals were genotyped for 21 microsatellite markers mapping to OAR3. In addition to a classical linkage analysis (LA), a combined linkage disequilibrium and linkage analysis (LDLA) was performed with the aim of enhancing the resolution of the QTL mapping. The LA that was performed in this sheep population identified the presence of a highly significant QTL for PP near marker KD103 (P(c) < 0.001; P(exp) < 0.001). The phenotypic variance that was owing to the QTL was 2.74%. Two segregating families for the target QTL were identified in this population with QTL effect estimates of 0.47 and 0.95 SD. The LDLA identified the same QTL as the previous analyses with a high level of statistical significance (P = 9.184 E-11) and narrowed the confidence interval (CI) to a 13 cM region. These results confirm the segregation of the previously identified OAR3 QTL that influences PP in Spanish Churra sheep. Future research will aim to increase the marker density across the refined CI and to analyse the corresponding candidate genes to identify the allelic variant or variants that underlie this genetic effect. PMID- 22497508 TI - Global regulatory requirements for xenotransplantation clinical trials. PMID- 22497509 TI - Xenotransplantation-associated infectious risk: a WHO consultation. AB - Xenotransplantation carries the potential risk of the transmission of infection with the cells or tissues of the graft. The degree of risk is unknown in the absence of clinical trials. The clinical application of xenotransplantation has important implications for infectious disease surveillance, both at the national and international levels. Preclinical data indicate that infectious disease events associated with clinical xenotransplantation from swine, should they occur, will be rare; data in human trials are limited but have demonstrated no transmission of porcine microorganisms including porcine endogenous retrovirus. Xenotransplantation will necessitate the development of surveillance programs to detect known infectious agents and, potentially, previously unknown or unexpected pathogens. The development of surveillance and safety programs for clinical trials in xenotransplantation is guided by a "Precautionary Principle," with the deployment of appropriate screening procedures and assays for source animals and xenograft recipients even in the absence of data suggesting infectious risk. All assays require training, standardization and validation, and sharing of laboratory methods and expertise to optimize the quality of the surveillance and diagnostic testing. Investigation of suspected xenogeneic infection events (xenosis, xenozoonosis) should be performed in collaboration with an expert data safety review panel and the appropriate public health and competent authorities. It should be considered an obligation of performance of xenotransplantation trials to report outcomes, including any infectious disease transmissions, in the scientific literature. Repositories of samples from source animals and from recipients prior to, and following xenograft transplantation are essential to the investigation of possible infectious disease events. Concerns over any potential hazards associated with xenotransplantation may overshadow potential benefits. Careful microbiological screening of source animals used as xenotransplant donors may enhance the safety of transplantation beyond that of allotransplant procedures. Xenogeneic tissues may be relatively resistant to infection by some human pathogens. Moreover, xenotransplantation may be made available at the time when patients require organ replacement on a clinical basis. Insights gained in studies of the microbiology and immunology of xenotransplantation will benefit transplant recipients in the future. This document summarizes approaches to disease surveillance in individual recipients of nonhuman tissues. PMID- 22497510 TI - Production of cloned pigs expressing human thrombomodulin in endothelial cells. AB - For long-term xenograft survival, coagulation control is one of the remaining critical issues. Our attention has been directed toward human thrombomodulin (hTM), because it is expected to exhibit the following beneficial effects on coagulation control and cytoprotection: (i) to solve the problem of molecular incompatibility in protein C activation; (ii) to exert a role as a physiological regulator, only when thrombin is formed; (iii) to suppress direct prothrombinase activity; and (iv) to have anti-inflammatory properties. hTM gene was transfected into pig (Landrace/Yorkshire) fibroblasts using pCAGGS expression vector and pPGK puro vector. After puromycin selection, only fibroblasts expressing a high level of hTM were collected by cell sorting and then applied to nuclear transfer. Following electroactivation and subsequent culture, a total of 1547 cleaved embryos were transferred to seven surrogate mother pigs. Two healthy cloned piglets expressing hTM were born, successfully grew to maturity and produced normal progeny. Immunohistochemical staining of organs from F1 generation pigs demonstrated hTM expression in endothelial cells as well as parenchymal cells. High expression was observed particularly in endothelial cells of kidney and liver. Aortic endothelial cells from cloned pigs were found to express hTM levels similar to human umbilical vein endothelial cells (HUVEC) and to make it possible to convert protein C into activated protein C. The blockade of human endothelial cell protein C receptor (hEPCR) significantly reduced APC production in HUVEC, but not in hTM-PAEC. Although no bleeding tendency was observed in hTM-cloned pigs, activated partial thromboplastin time (APTT) was slightly prolonged and soluble hTM was detected in pig plasma. hTM was expressed in platelets and mononuclear cells, but not in RBC. Cloned pigs expressing hTM in endothelial cells at a comparable level to HUVEC were produced. As complete suppression of antigen-antibody reaction in the graft is essential for accurate assessment of transgene related to coagulation control, production of genetically engineered pigs expressing hTM and complement regulatory protein based on galactosyltransferase knockout is desired. PMID- 22497511 TI - Identification of human preformed antibody targets in GTKO pigs. AB - BACKGROUND: Human preformed antibodies continue to recognize porcine xenografts, despite the advent of alpha-galactosyltransferase knockout (GTKO) pigs. This study examined the potential reactivity of human preformed IgG and IgM antibodies toward antigens in the GTKO pig liver. METHODS: Human serum was analyzed for the concentration of IgG, IgM, anti-alphagal antibody, anti-non-alphagal antibody and cytotoxicity toward domestic and GTKO fibroblasts and liver sinusoidal endothelial cells (LSEC). We detected preformed antibodies in human serum directed toward GTKO pig liver cells and tissue samples using advanced proteomic techniques. The targets of preformed antibodies were identified by MALDI TOF TOF mass spectrometry and validated by confocal microscopy, immunoblot, and immunoprecipitation. RESULTS: Human serum used in this study contained 2.06 MUg/ml IgG and 0.013 MUg/ml IgM directed toward GTKO fibroblasts. Human IgG and IgM bound to GTKO LSEC in a dose-dependent manner and were cytotoxic. We detected 357 protein spots recognized by human IgG and 233 by human IgM. Two hundred and nineteen proteins were common to both human IgG and IgM. Mass spectrometry identified numerous immunoreactive proteins, of which 19 were membrane proteins on liver cells. The most significant to this study were alpha-enolase, CFTR, and E-cadherin, which were abundant in GTKO pig tissues and expressed on the surface of GTKO LSEC. Human IgG captured alpha-enolase, CFTR, and E-cadherin by immunoprecipitation validating the proteomic identification. CONCLUSION: These experiments indicate that several membrane antigens in GTKO pigs could be recognized directly by human IgG or IgM. Further studies on the contribution of these antigens to antibody-mediated xenograft rejection are necessary. PMID- 22497512 TI - Ex-vivo expanded baboon CD4+ CD25 Hi Treg cells suppress baboon anti-pig T and B cell immune response. AB - BACKGROUND: CD4(+) CD25(+) FoxP3(+) regulatory T (Treg) cells play an important role in regulating immune responses. A very small number of Treg cells are present in peripheral blood and lymphoid organs, but due to their ability to suppress the immune response, they have a high potential for immunotherapy in clinics. Successful ex-vivo expansion of naturally occurring CD4(+) CD25(+) T cells has been achieved after TCR stimulation in the presence of T cell growth factors. In this study, we evaluated the role of these Treg cells in suppressing proliferative response of baboon T and B cells to pig xenoantigens. METHODS: Naturally occurring baboon CD4(+) CD25(+) regulatory T cells (nTreg) were sorted from peripheral blood and expanded in the presence of either anti-CD3/CD28 beads or irradiated pig peripheral blood mononuclear cells with IL-2. Treg cells were also enriched directly from CD4(+) T cells cultured in the presence of rapamycin (0.1-10 nm). Mixed lymphocyte culture and polyclonal B cell stimulation with ex vivo Treg cells were performed to assess the function of ex-vivo expanded Treg cells. RESULTS: The nTreg cells were expanded to more than 200-fold in 4 weeks and retained all the nTreg cell phenotypic characteristics, including high levels of FoxP3 expression. 2-fold increase in enrichment of CD4(+) CD25(+) FoxP3(+) Treg cells from CD4(+) cells was observed with rapamycin compared to cultures without rapamycin. The ex-vivo expanded Treg cells obtained from both methods were able to suppress the baboon anti-porcine xenogeneic T and B cell immune response in-vitro efficiently (more than 90% suppression at 1:1 ratio of T regulatory cells: T effector cells), and their suppression potential was retained even at 1:256 ratio. However, freshly isolated nTreg cells had only 70% suppression at 1:1 ratio, and their suppressive ability was reduced to <= 50% at 1:16 ratio. Furthermore, we have found that ex-vivo expanded Treg can also suppress the proliferation of B cells after polyclonal stimulation. Forty to 50 percent reduction in B cell proliferation was observed when ex-vivo expanded Treg cells were added to the culture at a 1:1 ratio. The addition of CD4(+) CD25(Neg) cells however induced vigorous proliferation. CONCLUSION: Ex-vivo expanded CD4(+) CD25(+) FoxP3(+) Treg cells can be used to efficiently suppress xenogeneic immune responses by inhibiting T and B cell proliferation. These ex-vivo expanded Treg cells may also be used with other immunosuppressive agents to overcome xenograft rejection in preclinical xenotransplantation models. PMID- 22497513 TI - Long-term effects of PERV-specific RNA interference in transgenic pigs. AB - BACKGROUND: Porcine endogenous retroviruses (PERVs) represent a risk of xenotransplantation using porcine cells, tissues, or organs, as they are integrated in the porcine genome and have been shown to be able to infect human cells in vitro. To increase viral safety by RNA interference, transgenic pigs expressing a PERV-specific small hairpin (sh)RNA targeted to a highly conserved sequence in the pol gene (pol2) were generated in which expression of PERVs was reduced (Xenotransplantation, 15, 2008, 38). However, it remains to be shown how long expression of the shRNA and the RNA interference is effective in reducing PERV expression. METHODS: To analyze the long-term duration of RNA interference, expression of the PERV-specific pol2 shRNA and inhibition of PERV expression was studied repeatedly in fibroblasts and peripheral blood mononuclear cells (PBMCs) of transgenic pigs over a period of 3 yr, when animals were sacrificed and expression was studied in different organs. Expression of the PERV-specific shRNA was measured using a newly developed real-time PCR, and expression of PERV was measured using a PERV-specific real-time PCR. RESULTS: Over a period of 3 yr, PERV-specific shRNA and green fluorescent protein (GFP) as reporter of the vector system were consistently expressed in transgenic animals. PERV expression was significantly reduced during the entire period. Levels of PERV and shRNA expression were different in the various organs. PERV expression was highest in the spleen and the lungs and lowest in liver and heart. However, in all organs of the transgenic pigs, PERV expression was inhibited compared with the vector control animals. CONCLUSIONS: Transgenic pigs expressing PERV-specific shRNA maintained their specific RNA interference long term, suggesting that PERV expression in the xenotransplants will be suppressed over extended periods of time. PMID- 22497514 TI - Evaluation of a novel reconstituted bone xenograft using processed bovine cancellous bone in combination with purified bovine bone morphogenetic protein. AB - BACKGROUND: Xenogeneic grafting represents an alternative to autogenous grafting in osseous reconstruction and exhibits many beneficial properties. However, the usefulness of xenogeneic bone relies on necessary processing procedures for removing antigens and viruses, and preserving biological activities simultaneously. By chemical treatment of bovine cancellous bone to make it an antigen-free scaffold, and extraction of bone morphogenetic protein (BMP) from bovine cortical bone, followed by recombination of the scaffold with the BMP, we developed a new grafting material, reconstituted bone xenograft (RBX). METHODS: In this study, scanning electron microscope and energy dispersive X-ray were first employed to observe the structure and components of RBX. Then the biomechanical property was evaluated by applying compression in a materials testing machine. Subsequently, the immunologic evaluation was performed by measuring galactose-alpha-1,3-galactose (alpha-gal) epitope in vivo and proinflammatory cytokine (TNF-alpha) secreted by human monocytic cell line (THP 1) in vitro. Finally, this RBX was implanted into segmental radial defects in a rabbit model, and its ability to treat large bone defects was specifically evaluated. RESULTS: Although the compressive strength of RBX was 10% lower than that of unprocessed bovine cancellous bone (UBCB), the basic porous structure and natural components were still kept in this composite. The alpha-gal xenoantigen level was significantly lower in RBX (P < 0.05) compared with UBCB. Moreover, the TNF-alpha level was significantly (P < 0.05) reduced compared with UBCB when THP 1 was exposed to RBX. On the other hand, RBX appeared to induce cartilage formation from immature cell populations and resulted in osteogenesis through endochondral-like ossification from 4 to 12 weeks in repairing segmental bone defects. CONCLUSIONS: These results demonstrate that RBX, with its natural microstructure and components, certain mechanical strength and strong osteoinductivity without evoking immune rejection, has significant potential for the treatment of bone defects. PMID- 22497515 TI - Xenotransplantation literature update, January-February 2012. PMID- 22497516 TI - Selective Ru(0)-catalyzed deuteration of electron-rich and electron-poor nitrogen containing heterocycles. AB - A highly selective Ru(3)(CO)(12)-catalyzed deuteration method using t-BuOD as deuterium source is reported. Electron-rich and electron-poor N-heteroarenes such as indoles, azaindoles, deazapurines, benzimidazole, quinolines, isoquinolines, and pyridines were efficiently deuterated at specific positions with high selectivity; in most cases, deuterium incorporation was close to the theoretically possible values. To further increase deuteration degrees, several cycles of the reaction protocol can be carried out which gave superior deuteration degrees employing a much lower excess of deuterating agent compared to established protocols. It was proved that the same protocol can in principle be applied to tritiation reactions important for radioactive labeling of bioactive molecules. PMID- 22497517 TI - Mapping and fine mapping of quantitative trait loci for the number of vertebrae in a White Duroc * Chinese Erhualian intercross resource population. AB - The number of vertebrae is associated with body size and meat production in pigs. To identify quantitative trait loci (QTL) for the number of vertebrae, phenotypic values were measured in 1029 individuals from a White Duroc * Chinese Erhualian intercross F(2) population. A whole genome scan was performed with 194 microsatellite markers in the F(2) population. Four genome-wide significant QTL and eight chromosome-wide significant QTL for the number of vertebrae were identified on pig chromosomes (SSC) 1, 2, 6, 7, 10 and 12. The most significant QTL was detected on SSC7 with a confidence interval of 1 cM, explaining 42.32% of the phenotypic variance in the thoracic vertebral number. The significant QTL on SSC1, 2 and 7 confirmed previous reports. A panel of 276 animals representing seven Western and Chinese breeds was genotyped with 34 microsatellite markers in the SSC7 QTL region. No obvious selective sweep effect was observed in the tested breeds, indicating that intensive selection for enlarged body size in Western commercial breeds did not wipe out the genetic variability in the QTL region. The Q alleles for increased vertebral number originated from both Chinese Erhualian and White Duroc founder animals. A haplotype block of approximately 900 kb was found to be shared by all Q-bearing chromosomes of F(1) sires except for one distinct Q chromosome. The critical region harbours the newly reported VRTN gene associated with vertebral number. Further investigations are required to confirm whether VRTN or two other positional candidate genes, PROX2 and FOS, cause the QTL effect. PMID- 22497518 TI - Diagnostic yield of post-bronchoscopy sputum smear in pulmonary tuberculosis. AB - BACKGROUND: The early definitive diagnosis of pulmonary tuberculosis (TB) is important for control of the disease in the community. We performed this study to evaluate the additional gain of post-bronchoscopy sputum in the diagnosis of pulmonary TB. METHODS: Bronchoscopy and bronchoalveolar lavage were performed for 126 patients suspected of pulmonary TB who either had 3 negative sputum smears for acid-fast bacilli or could not expectorate. After bronchoscopy the patients were asked to give sputum samples for 3 consecutive days. All of the obtained specimens were investigated for Mycobacterium tuberculosis by smear and culture. RESULTS: Pulmonary TB was confirmed in 56 patients. Among all confirmed cases, the sensitivity of bronchoalveolar lavage smear was 57.1% (32 of 56), sensitivity of post-bronchoscopy smear was 76.7% (43 of 56), and the yield of a combination of the 2 methods was 83.9% (47 of 56). Results of post-bronchoscopy sputum smears were not significantly related to sex, age, human immunodeficiency virus (HIV) infection, presence of cavitary lesions on chest X-ray, or the ability to expectorate before bronchoscopy (p > 0.05). CONCLUSION: Evaluation of post bronchoscopy sputum smears is helpful for earlier diagnosis of pulmonary TB and is an inexpensive and accessible assay. PMID- 22497520 TI - Surface plasmon microscopy: resolution, sensitivity and crosstalk. AB - This paper develops the theoretical framework to understand the capability of the interferometric surface plasmon microscope to quantify sample properties in a confined region. We use rigorous diffraction theory to quantify the ability of the system to measure local properties and eliminate crosstalk from adjacent regions. We argue that the interferometric system in the defocused condition defines the measured point of excitation and reradiation of the surface plasmons; which greatly improves localisation. We also present results for the noninterferometric microscope, which confirm that the interferometric based system can perform quantitative measurements over smaller regions. PMID- 22497519 TI - Dermoscopy, reflectance confocal microscopy and histopathology of an amelanotic melanoma from an individual heterozygous for MC1R and tyrosinase variant alleles. AB - We present a case of an amelanotic nodular melanoma occurring in a 26-year-old woman who carried a heterozygous (melancortin-1-receptor) MC1R 160R/W and tyrosinase (TYR) 402R/Q genotype and had a dark hair phenotype. We present dermoscopic, reflectance confocal microscopy (RCM) and histopathological images of the melanoma. We discuss the relationship between MC1R red hair colour (RHC) variants, TYR variants, phenotype and melanoma development. We also discuss the merits of RCM as an additional diagnostic aid for equivocal melanocytic lesions. PMID- 22497521 TI - Highly accurate chemical formula prediction tool utilizing high-resolution mass spectra, MS/MS fragmentation, heuristic rules, and isotope pattern matching. AB - Mass spectrometry is commonly applied to qualitatively and quantitatively profile small molecules, such as peptides, metabolites, or lipids. Modern mass spectrometers provide accurate measurements of mass-to-charge ratios of ions, with errors as low as 1 ppm. Even such high mass accuracy, however, is not sufficient to determine the unique chemical formula of each ion, and additional algorithms are necessary. Here we present a universal software tool for predicting chemical formulas from high-resolution mass spectrometry data, developed within the MZmine 2 framework. The tool is based on the use of a combination of heuristic techniques, including MS/MS fragmentation analysis and isotope pattern matching. The performance of the tool was evaluated using a real metabolomic data set obtained with the Orbitrap MS detector. The true formula was correctly determined as the highest-ranking candidate for 79% of the tested compounds. The novel isotope pattern-scoring algorithm outperformed a previously published method in 64% of the tested Orbitrap spectra. The software described in this manuscript is freely available and its source code can be accessed within the MZmine 2 source code repository. PMID- 22497522 TI - Design and synthesis of self-degradable antibacterial polymers by simultaneous chain- and step-growth radical copolymerization. AB - Self-degradable antimicrobial copolymers bearing cationic side chains and main chain ester linkages were synthesized using the simultaneous chain- and step growth radical polymerization of t-butyl acrylate and 3-butenyl 2 chloropropionate, followed by the transformation of t-butyl groups into primary ammonium salts. We prepared a series of copolymers with different structural features in terms of molecular weight, monomer composition, amine functionality, and side chain structures to examine the effect of polymer properties on their antimicrobial and hemolytic activities. The acrylate copolymers containing primary amine side chains displayed moderate antimicrobial activity against E. coli but were relatively hemolytic. The acrylate copolymer with quaternary ammonium groups and the acrylamide copolymers showed low or no antimicrobial and hemolytic activities. An acrylate copolymer with primary amine side chains degraded to lower molecular weight oligomers with lower antimicrobial activity in aqueous solution. This degradation was due to amidation of the ester groups of the polymer chains by the nucleophilic addition of primary amine groups in the side chains resulting in cleavage of the polymer main chain. The degradation mechanism was studied in detail by model reactions between amine compounds and precursor copolymers. PMID- 22497523 TI - Genetic variation in eggshell crystal size and orientation is large and these traits are correlated with shell thickness and are associated with eggshell matrix protein markers. AB - The size and orientation of calcium carbonate crystals influence the structure and strength of the eggshells of chickens. In this study, estimates of heritability were found to be high (0.6) for crystal size and moderate (0.3) for crystal orientation. There was a strong positive correlation (0.65) for crystal size and orientation with the thickness of the shell and, in particular, with the thickness of the mammillary layer. Correlations with shell breaking strength were positive but with a high standard error. This was contrary to expectations, as in man-made materials smaller crystals would be stronger. We believe the results of this study support the hypothesis that the structural organization of shell, and in particular the mammillary layer, is influenced by crystal size and orientation, especially during the initial phase of calcification. Genetic associations for crystal measurements were observed between haplotype blocks or individual markers for a number of eggshell matrix proteins. Ovalbumin and ovotransferrin (LTF) markers for example were associated with crystal size, while ovocleidin-116 and ovocalyxin-32 (RARRES1) markers were associated with crystal orientation. The location of these proteins in the eggshell is consistent with different phases of the shell-formation process. In conclusion, the variability of crystal size, and to a lesser extent orientation, appears to have a large genetic component, and the formation of calcite crystals are intimately related to the ultrastructure of the eggshell. Moreover, this study also provides evidence that proteins in the shell influence the variability of crystal traits and, in turn, the shell's thickness profile. The crystal measurements and/or the associated genetic markers may therefore prove to be useful in selection programs to improve eggshell quality. PMID- 22497524 TI - Advances in zebrafish high content and high throughput technologies. AB - The zebrafish has emerged as an excellent transitional screening model system between cell-based assays, which are rapid and inexpensive but have limited physiological relevance, and higher vertebrate models, which have better physiological relevance, but are more time-consuming and expensive to deploy. As vertebrates, zebrafish maintain significant evolutionary proximity to humans and have been validated as robust models for drug research, studies of mechanism and behavioral genetics. Unlike higher vertebrate models, zebrafish are well-suited to high-throughput applications owing to their high fecundity, rapid extrauterine development and transparency during organogenesis enabling in vivo labeling and imaging. Recent advances have been made in automating high content and high throughput zebrafish screens, with the goal of developing fully automated drug screening platforms. The application and continued development of these technologies holds potential clinical significance in drug discovery and elucidating disease mechanisms. PMID- 22497525 TI - Contributions of FASN and SCD gene polymorphisms on fatty acid composition in muscle from Japanese Black cattle. AB - The fatty acid synthase (FASN) and stearoyl-CoA desaturase (delta-9-desaturase) (SCD) genes affect fatty acid composition. This study evaluated the contributions of polymorphisms of these genes on fatty acid composition in muscle in two different populations: 1189 and 1058 Japanese Black cattle from the Miyagi and the Yamagata populations respectively. We sampled intramuscular fat from the longissimus thoracis muscle in the Miyagi population and from the trapezius muscle in the Yamagata population. The collective contributions of FASN and SCD polymorphisms to total additive genetic variance for oleic acid were 13.46% in the Miyagi population and 16.29% in the Yamagata population and to phenotypic variance were 5.45% and 6.54% respectively. Although the individual effects of FASN and SCD polymorphisms on fatty acid composition were small, overall gene substitution may effectively improve fatty acid composition. In addition, we found that gene polymorphism contributions of fatty acids varied by population even in the same breed. PMID- 22497526 TI - Time-resolved quantitative phosphoproteomics: new insights into Angiotensin-(1-7) signaling networks in human endothelial cells. AB - Angiotensin-(1-7) [Ang-(1-7)] is an endogenous ligand of the Mas receptor and induces vasodilation, positive regulation of insulin, and antiproliferative and antitumorigenic activities. However, little is known about the molecular mechanisms behind these biological properties. Aiming to identify proteins involved in the Ang-(1-7) signaling, we performed a mass spectrometry-based time resolved quantitative phosphoproteome study of human aortic endothelial cells (HAEC) treated with Ang-(1-7). We identified 1288 unique phosphosites on 699 different proteins with 99% certainty of correct peptide identification and phosphorylation site localization. Of these, 121 sites on 79 proteins had their phosphorylation levels significantly changed by Ang-(1-7). Our data suggest that the antiproliferative activity of Ang-(1-7) is due to the activation or inactivation of several target phosphoproteins, such as forkhead box protein O1 (FOXO1), mitogen-activated protein kinase 1 (MAPK), proline-rich AKT1 substrate 1 (AKT1S1), among others. In addition, the antitumorigenic activity of Ang-(1-7) is at least partially due to FOXO1 activation, since we show that this transcriptional factor is activated and accumulated in the nucleus of A549 lung adenocarcinoma cells treated with Ang-(1-7). Moreover, Ang-(1-7) triggered changes in the phosphorylation status of several known downstream effectors of the insulin signaling, indicating an important role of Ang-(1-7) in glucose homeostasis. In summary, this study provides new concepts and new understanding of the Ang-(1-7) signal transduction, shedding light on the mechanisms underlying Mas activation. PMID- 22497527 TI - Non-cirrhotic portal hypertension in HIV mono-infected patients. AB - BACKGROUND AND AIM: Unexplained liver injury including fibrosis and portal hypertension has rarely been reported among patients with HIV in the absence of co-infection with hepatitis B (HBV) or hepatitis C (HCV). We describe a series of HIV mono-infected patients with evidence of non-cirrhotic portal hypertension. METHODS: HIV-infected patients with evidence of portal hypertension who were anti HBV and anti-HCV negative and HBV and HCV RNA polymerase chain reaction (PCR) negative were identified from patients managed by the Victorian statewide HIV referral service located at The Alfred Hospital, Melbourne. Portal hypertension was defined as either radiological or endoscopic evidence of varices, portal vein flow obstruction, or elevated hepatic venous pressure gradient (HPVG). RESULTS: Five patients were found to have portal hypertension. These patients were male, aged 41 to 65 years, with known duration of HIV infection between 11 to 25 years. All had been treated with antiretroviral therapy, including didanosine. Tests for metabolic, autoimmune, and hereditary causes of liver disease failed to establish an etiology for the liver injury. All had radiological or endoscopic findings of varices, and four patients had radiological features of portal vein obstruction or flow reversal. Only one patient underwent HPVG measurement, which was elevated. Non-invasive fibrosis assessment revealed increased liver stiffness in three (out of four) patients, and no cirrhotic features were found on those who underwent liver biopsy. CONCLUSIONS: To our knowledge, this is the largest published series of non-cirrhotic portal hypertension in HIV mono-infected patients in Australia. Further research is needed to understand what relationship, if any, HIV or its treatments might have on liver injury over time. PMID- 22497529 TI - A literature review of the feasibility of glial fibrillary acidic protein as a biomarker for stroke and traumatic brain injury. AB - Traumatic brain injuries (TBIs) are potentially lethal medical conditions, with symptoms that can overlap with symptoms of injuries outside the brain. In many cases, current diagnostic methods do not fully distinguish acute brain injury from other organ damage. In the management of stroke patients, the choice of treatment depends on whether the stroke is ischemic or hemorrhagic; however, no quick lab diagnostic tests are available to distinguish between the two types of strokes. As a result, patient triage, disposition, and patient management decisions may be delayed for patients with suspected TBI and stroke. Glial fibrillary acidic protein (GFAP), a brain-specific biomarker that is released into the blood following TBI and stroke, is being explored for potential diagnostic and prognostic value in these indications. We therefore conducted a review of MEDLINE-indexed publications from 2004 to 2011 to evaluate the current status of GFAP as a prognostic and diagnostic tool for TBI and stroke within the context of current published guidelines. Our review suggests that GFAP could provide clinically valuable information for the prognosis of TBI and stroke, but it is still at an early stage of development as a biomarker. Several TBI studies have shown elevated GFAP levels following a TBI event to be associated with greater severity of injury, poorer outcomes, and increased mortality. Clinical studies also indicate that GFAP has potential clinical utility in the differential diagnosis of various types of stroke. However, more clinical research will be required to determine the ability of GFAP levels to diagnose TBI in heterogeneous patient populations, as well as the ability of GFAP to differentiate between ischemic stroke (IS), intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and non-stroke conditions in populations of patients with suspected rather than confirmed stroke. Additional clinical studies will also be required to define the temporal patterns of GFAP release in IS, ICH, SAH, and TBI, and their potential use in the differential diagnosis of these conditions. Finally, such research could demonstrate the ability of GFAP test results to provide unique clinical information that informs management decisions for TBI and stroke patients. PMID- 22497530 TI - C-reactive protein levels and vitamin d receptor polymorphisms as markers in predicting cachectic syndrome in cancer patients. AB - BACKGROUND AND OBJECTIVE: In patients with advanced cancer, cachexia correlates with low performance status and poor quality of life. In addition, cachexia may be associated with reduced response to chemoradiotherapy and a poor prognosis in cancer patients. Nearly all forms of cachexia are closely associated with chronic inflammation and elevated levels of inflammatory and pro-inflammatory circulating factors, including C-reactive protein (CRP), which is considered a valid laboratory and clinical marker. Among the different pathways involved in the production of inflammatory cytokines and chemokines, the vitamin D-vitamin D receptor (VDR) axis plays a fundamental role. In this study, we explore the possible association between CRP and key factors pertaining to the vitamin D axis -in particular, VDR gene polymorphisms--in cancer patients with cachexia. Although certain tumor types are more commonly associated with cachexia, even within the same tumor type there are significant differences in the extent and duration of cachexia. Such variations may be due to polymorphisms of the VDR gene that could lead to cachexia-prone genotypes or to cachexia-resistant genotypes. Identification of such genotypes could be very helpful in the management of cancer patients. METHODS: Forty-three cancer patients were recruited by the Nutritional Unit of the Prato Hospital. Data on age, gender, type of cancer, stage of cancer, and nutritional assessment, as well as transferrin, ferritin, albumin, and CRP levels, were collected. Genomic DNA was extracted from peripheral blood leukocytes and amplified by polymerase chain reaction. BsmI, ApaI, TaqI, and FokI polymorphisms of the VDR gene were investigated using the respective restriction enzymes. For the different VDR polymorphisms, the absence or presence of the restriction sites were designated with capital or small letters, respectively. For example, for the BsmI polymorphism, the presence of the undigested fragment identified the B allele, whereas the presence of the digested fragment identified the b allele. RESULTS: Cancer patients with cachexia have higher CRP levels compared with non-cachectic cancer patients, independently from the genotype. In cachectic patients, the presence of specific VDR BsmI and TaqI alleles was associated with higher CRP levels. In particular, the VDR b and T alleles were more frequent in cachectic cancer patients with elevated CRP levels than in cachectic patients with normal CRP levels. CONCLUSION: From these results, we hypothesize that there is an association between BsmI and TaqI VDR gene polymorphisms and the cachectic syndrome. In particular, we propose that in cancer patients, the concomitance of b and T alleles with elevated CRP levels may represent an early clinical predictor for the development of a more aggressive form of cachexia. PMID- 22497532 TI - Different COPD disease characteristics are related to different outcomes in the 6 minute walk test. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) can lead to severe disability as the disease advances. The 6-minute walk test (6MWT) is commonly used to measure functional capacity in COPD patients and has three potential outcomes; walking distance, oxygen desaturation, and self-perceived dyspnea assessed by the Borg scale, all reflecting different aspects of COPD. The aim of this study was to identify predictors of all 3 outcomes of 6MWT in patients with COPD. METHODS: 370 COPD patients, aged 40-75 yrs, were included from the first phase of the Bergen COPD cohort study. They were examined with spirometry, bioelectrical impedance measurements, 6MWT, Center for Epidemiologic Studies of Depression (CES-D) Scale, Medical Research Council (MRC) dyspnea scale, Charlson index for co-morbidities, self-reported physical activity questionnaire, plasma levels of C-reactive protein (CRP) and arterial blood gases. RESULTS: Significant predictors in the multivariate analyses were sex, age, FEV(1) in % predicted, symptoms of dyspnea (MRC), co-morbidities (Charlson Index) and self-reported physical activity for walking distance, FEV(1) in % predicted and PaO(2) for oxygen desaturation, and body composition, smoking and co-morbidities for self perceived dyspnea assessed by the Borg scale. CONCLUSION: Several COPD characteristics have predictive value for the 6MWT, and some COPD characteristics are more strongly related to specific 6MWT outcomes than others. PMID- 22497533 TI - Adherence to long-acting inhaled therapies among patients with chronic obstructive pulmonary disease (COPD). AB - BACKGROUND: Long-acting inhaled medications are an important component of the treatment of patients with chronic obstructive pulmonary disease (COPD), yet few studies have examined the determinants of medication adherence among this patient population. OBJECTIVE: We sought to identify factors associated with adherence to long-acting beta-agonists (LABA) and inhaled corticosteroids (ICS) among patients with COPD. METHODS: We performed secondary analysis of baseline data collected in a randomized trial of 376 Veterans with spirometrically confirmed COPD. We used electronic pharmacy records to assess adherence, defined as a medication possession ratio of >=0.80. We investigated the following exposures: patient characteristics, disease severity, medication regimen complexity, health behaviors, confidence in self-management, and perceptions of provider skill. We performed multivariable logistic regression, clustered by provider, to estimate associations. RESULTS: Of the 167 patients prescribed LABA, 54% (n = 90) were adherent to therapy while only 40% (n = 74) of 184 the patients prescribed ICS were adherent. Higher adherence to LABA and ICS was associated with patient perception of their provider as being an "expert" in diagnosing and managing lung disease [For LABA: OR = 21.70 (95% CI 6.79, 69.37); For ICS OR = 7.93 (95% CI 1.71, 36.67)]. Factors associated with adherence to LABA, but not ICS, included: age, education, race, COPD severity, smoking status, and confidence in self management. CONCLUSIONS: Adherence to long-acting inhaled medications among patients with COPD is poor, and determinants of adherence likely differ by medication class. Patient perception of clinician expertise in lung disease was the factor most highly associated with adherence to long-acting therapies. PMID- 22497528 TI - Molecular diagnosis and management of viral infections in hematopoietic stem cell transplant recipients. AB - Viral infections after allogeneic hematopoietic stem cell transplantation (HSCT) are important complications associated with high morbidity and mortality. In this setting, reactivations of persisting latent viral pathogens from donor and/or recipient cells play a central role whereas the sterile environment of transplant units renders new infections less likely. The viruses currently regarded as most relevant in the HSCT setting include particularly the herpes virus family- specifically cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6)--as well as human adenoviruses (AdVs) and the polyoma virus BK (BKV). Timely detection and monitoring of virus copy numbers are prerequisites for successful preemptive treatment approaches. Pre- and post-transplant surveillance by sensitive and quantitative molecular methods has therefore become an essential part of the diagnostic routine. In this review, we discuss diagnostic aspects and the clinical management of the most important viral infections in HSCT recipients, with a focus on pediatric patients. PMID- 22497534 TI - Chronic obstructive pulmonary disease and socioeconomic status: a systematic review. AB - BACKGROUND: Along with age and sex, socioeconomic status is one of the most powerful determinants of health. We conducted a systematic review to examine the consistency and magnitude of the association between socioeconomic status and COPD health outcomes to determine the potential impact of SES disparity on the COPD population. METHODS: Electronic databases to October 2011 were searched for studies of adults who had or were at risk for COPD that quantified an association between a measure of socioeconomic status and at least one COPD health outcome. Two authors independently reviewed studies, assessed study quality, and for eligible studies, extracted data. RESULTS: Regardless of the population, socioeconomic status measure or COPD outcome examined, with few exceptions, consistent significant inverse associations between socioeconomic status and COPD outcomes were found. Most studies found that individuals of the lowest socioeconomic strata were at least twice as likely to have poor outcomes as those of the highest (range from no difference to 10-fold difference). CONCLUSIONS: Social and economic disadvantage appears to have a significant consistent impact on COPD mortality and morbidity. These findings point to the need for public health strategies and research to address socioeconomic status disparity in individuals with COPD. PMID- 22497535 TI - Gaseous vanadium molybdate and tungstates: thermodynamic properties and structures. AB - The stability of gaseous vanadium molybdate and vanadium tungstates was confirmed by high-temperature mass spectrometry. A number of gas-phase reactions involving vanadium-containing salts were studied. On the basis of equilibrium constants, the standard formation enthalpies of gaseous VMoO(4) (-676 +/- 27 kJ/mol), VWO(3) (-331 +/- 29 kJ/mol), and VWO(4) (-706 +/- 23 kJ/mol) at 298 K were determined. A theoretical study of these salts revealed the structure with bidentate binding of the vanadium cation to the anion part to be the lowest-lying isomer, with a quartet spin state for VMoO(4) and VWO(4) molecules as well as a sextet spin state for the VWO(3) molecule. On the basis of critical analysis of the literature data concerning standard formation enthalpies of gaseous VO and VO(2), we adopted new values of Delta(f)H degrees (298) = 135 +/- 10 kJ/mol for VO(g) and -185 +/- 15.0 kJ/mol for VO(2)(g). Overall, the results obtained allowed us to estimate the standard formation enthalpy of VMoO(3) to be -318 kJ/mol with an accuracy near 40 kJ/mol. PMID- 22497536 TI - Three-dimensional geometry of honeycomb collagen promotes higher beating rate of myocardial cells in culture. AB - Myocardial cells were isolated from newborn rats, cultured on a novel three dimensional (3-D) honeycomb collagen scaffold (HC) and their morphology and beating rates compared with ones on conventional plastic dishes. On the first day, the cells attached to HC had already started beating. As time went on, the rate of beating increased as the pores of HC gradually filled with the cells, which integrated to form the cell-matrix complex. At day 8, beating reached the highest frequency of 162 beats per minute, which was twice that of the control cells on plastic dishes. It was concluded that 3-D geometry of the HC is conducive to functional growth of the myocardial tissues, and will potentially be useful for tissue engineering of myocardial regeneration. PMID- 22497537 TI - Inferring the recent ancestry of myostatin alleles affecting muscle mass in cattle. AB - Double muscling is an inherited condition in cattle characterised by large increases in muscle mass. Mutations in the myostatin (MSTN) gene, responsible for double muscling, were targeted in this study to estimate the time since the most recent common ancestor (TMRCA) for Q204X (p.Gln204*), E226X (p.Glu226*), 821del11 (c.821del11), E291X (p.Glu291*), C313Y (p.Cys313Tyr) and the more phenotypically moderate F94L (p.Phe94Leu) mutation. Genetic variability was examined in eight regions upstream and downstream of the MSTN locus. The molecular distance of the homozygous region associated with each MSTN allele was used to estimate the TMRCA. Long homozygous segments were associated with the MSTN alleles (mostly > 2 Mb), compared to short segments (130 kb) for cattle wild type at the double muscling and F94L sites. Estimates of time indicated that each MSTN allele had a recent common ancestor (<400 years ago). The results from this study, and the increasing frequency of these MSTN alleles in some cattle breeds, demonstrate recent positive selection. PMID- 22497538 TI - Two-dimensional speckle-tracking echocardiography reveals systolic abnormalities in granulomatosis with polyangiitis (Wegener's). AB - BACKGROUND: Two-dimensional speckle-tracking echocardiography (STE) is a novel technique providing accurate assessment of myocardial function. However, its value in granulomatosis with polyangiitis (Wegener's) (WG) has not been studied. OBJECTIVE: To assess the presence and frequency of systolic left ventricular (LV) dysfunction using STE and to determine incremental value of STE over standard echocardiography to detect myocardial abnormalities in WG. METHODS: Twenty-two WG patients (11 males, 11 females, mean age 46.8 +/- 12.3 years) and 22 sex- and age matched healthy subjects underwent standard and STE. Global longitudinal, circumferential, and rotational deformation parameters were calculated. RESULTS: All patients had LV ejection fraction (EF) >50%. LVEF was 65.0 +/- 7.5% and LV end-diastolic volume index 44.8 +/- 11.8 mL/m(2) . Regional LV wall motion abnormalities were found in 7 (32%), while abnormal global STE determined systolic dysfunction in 16 (73%) subjects (P = 0.008). Global longitudinal, circumferential and radial peak-systolic deformational parameters (strain or strain rate) were decreased in 11 (50%), 9 (41%), and 3 (14%) patients (P = 0.02), respectively. Comparing patients with abnormal and normal STE derived global systolic function, the former had higher cumulative disease extent index (10.6 +/- 3.0 vs 7.5 +/- 1.8; P = 0.03) and vasculitis damage index (7.9 +/- 1.9 vs 6.0 +/- 1.7; P = 0.04). CONCLUSIONS: Despite normal LVEF the global systolic LV abnormalities detected by STE are common in WG. They correspond to the extent and severity of WG and are more frequent than regional wall motion abnormalities in standard echocardiography. PMID- 22497539 TI - Differential treatment response of subtypes of patients with borderline personality organization, as assessed with theory-driven profiles of the Dutch short form of the MMPI: a naturalistic follow-up study. AB - We investigated the validity of different subtypes of borderline personality organization (BPO) as assessed by theory-driven profiles of the Minnesota Multiphasic Personality Disorder (MMPI; Hathaway & McKinley, 1943 ) Dutch Short Form (DSFM; Eurelings-Bontekoe, Onnink, Williams, & Snellen, 2008 ) in a naturalistic follow-up study among 2,062 psychiatric outpatients who received 6 months of ambulatory treatment. Patients were assessed at intake (T1) and 6 months later (T2). At T2, both patients and therapists rated the level of improvement, using the Global Assessment of Improvement. Patients with the high level BPO profile showed the largest increase in well-being and the largest decrease in severity of symptomatology, whereas severity of symptomatology and well-being of patients with psychotic BPO profiles did not change over time. Agreement between patients and therapists about improvement was good for the internalizing immature BPO and high-level BPO patients, but poor for the externalizing low-level BPO and narcissistic patients. PMID- 22497540 TI - In vitro fermentation characteristics and effective utilisable crude protein in leaves and green pods of Moringa stenopetala and Moringa oleifera cultivated at low and mid-altitudes. AB - This study was conducted to assess the in vitro nutrient digestibility and utilisation of leaves and green pods of two Moringa species in supplementing the feed of ruminant animals during the dry season. Samples were analysed for proximate nutrients using official methods. The metabolisable energy (ME), organic matter digestibility (OMD) and effective utilisable crude protein (uCP) were estimated using the Hohenheim in vitro gas test method. Gas volume in Moringa stenopetala leaves and green pods was generally higher than those of Moringa oleifera. Gas volume for leaves was similar between low and mid-altitudes but was higher for green pods at mid-altitude. M. stenopetala leaves contained significantly higher ME (9.8 MJ/kg DM) and OMD (75%) than those of M. oleifera. Similarly, M. stenopetala green pods had higher ME and OMD values than those of M. oleifera. For green pods, the ME and OMD values were significantly higher at mid-altitude than those at low altitude although these values for leaves were similar between both altitudes. Moringa oleifera leaves had higher effective uCP than those of M. stenopetala. Nevertheless, the effective uCP was higher for green pods of M. stenopetala than those of M. oleifera. The effective uCP for leaves cultivated at mid-altitude was slightly higher than those at low altitude. This study suggested that leaves and green pods could be used as alternative energy and protein supplements for tropical ruminants, particularly during dry periods. It was further concluded that leaves were generally better in nutrient compositions and in vitro nutrient digestibility characteristics than green pods. PMID- 22497541 TI - Purification and biochemical characterization of functional complement factor H from human plasma fractions. AB - BACKGROUND AND OBJECTIVES: Complement factor H (CFH) acts as major regulator of the alternative pathway of complement and its mutations and polymorphisms predispose to various human diseases. We aimed to develop a scalable purification process of CFH from human plasma fractions to supply a pathogen-safe and functional CFH concentrate. MATERIALS AND METHODS: Starting with intermediates of cold ethanol fractionation of plasma, CFH purification was performed with three chromatographic steps including solvent detergent treatment and nanofiltration. CFH functionality was tested by a haemolysis assay using sheep erythrocytes, by determining decay acceleration activity on C3 convertases and cofactor activity of C3b cleavage. CFH identity was confirmed by Western blot and mass spectrometry. RESULTS: Three scalable chromatographic steps highly purified full length and native CFH from human plasma fractions. The purification process enabled the removal of truncated and dysfunctional CFH species, yielding a native CFH concentrate as demonstrated in sensitive functional in vitro assays. CONCLUSION: This novel process provides a pathogen-safe and functional CFH concentrate that can be produced on an industrial scale and is suitable for pre /clinical studies. PMID- 22497543 TI - A general synthetic route to 3,5-substituted boron dipyrromethenes: applications and properties. AB - An efficient protocol for the direct synthesis of 3-substituted and 3,5 disubstituted BODIPY derivatives via electrophilic attack with NBS was developed. Various substituents like ethers, sugar, hydroxyl, thiophene, sulfur, azide, tertiary amines, alkyne, vinyl, or phosphonate groups were obtained in moderate to excellent yields. The amine-substituted derivatives display unusual spectroscopic and electrochemical properties which were analyzed in solution in the presence of HCl. The diethylamino-substituted derivative has a proton association constant of log beta = 4.7, and the disubstituted derivative has two association constants of log beta = 6.2 and 12.1 in ethanol. In both cases, the quenching of the fluorescence is explained by photoinduced electron transfer from the tertiary amine to the Bodipy excited state. PMID- 22497544 TI - Association analyses of porcine SERPINE1 reveal sex-specific effects on muscling, growth, fat accretion and meat quality. AB - The serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1 (SERPINE1) gene encodes plasminogen activator inhibitor type 1 (PAI), which is the major physiological inhibitor of tissue-type and urokinase type plasminogen activators and plays a role in obesity and insulin resistance in women but not in men. We detected SNP FN396538:g.566G>A in intron 3 and a non synonymous substitution NM_213910:c.612A>G in exon 3 (p.Ile159Val) and mapped the gene to position 8.4 cM on the linkage map of chromosome 3. Association analyses were conducted on the 12th-15th generation of the Meishan * Large White (MLW) cross (n = 565), with records for weight at the end of test, lifetime daily gain, test time daily gain, loin depth and backfat depth, as well as on a European wild boar * Meishan (W * M) F(2) population (n = 333) with 47 traits recorded for carcass composition and meat quality. Analyses performed across the entire MLW population or in the male animals did not show any trait significantly associated with the loci studied. In female animals, both SNPs were associated with loin depth at nominal P < 0.05 with adjusted P values equal to 0.051 (g.566) and 0.057 (c.612). Differences between homozygotes were up to 0.65 SD. In the entire W * M population and female animals, SERPINE1 was significantly associated at adjusted P < 0.05 in descending order with muscling, growth and fat accretion and in male animals with meat quality (R-value). In the studied populations, allele effects were in opposite directions, which implies that the SNPs are markers that are in linkage disequilibrium with a causative mutation. PMID- 22497545 TI - Replication and fine-mapping of a QTL for recurrent airway obstruction in European Warmblood horses. AB - Recurrent airway obstruction (RAO), or 'heaves', is a common performance-limiting allergic respiratory disease of mature horses. It is related to sensitization and exposure to mouldy hay and has a familial basis with a complex mode of inheritance. In a previous study, we detected a QTL for RAO on ECA 13 in a half sib family of European Warmblood horses. In this study, we genotyped additional markers in the family and narrowed the QTL down to about 1.5 Mb (23.7-25.2 Mb). We detected the strongest association with SNP BIEC2-224511 (24,309,405 bp). We also obtained SNP genotypes in an independent cohort of 646 unrelated Warmblood horses. There was no genome-wide significant association with RAO in these unrelated horses. However, we performed a genotypic association study of the SNPs on ECA 13 in these unrelated horses, and the SNP BIEC2-224511 also showed the strongest association with RAO in the unrelated horses (p(raw) = 0.00037). The T allele at this SNP was associated with RAO both in the family and the unrelated horses. Thus, the association study in the unrelated animals provides independent support for the previously detected QTL. The association study allows further narrowing of the QTL interval to about 0.5 Mb (24.0-24.5 Mb). We sequenced the coding regions of the genes in the critical region but did not find any associated coding variants. Therefore, the causative variant underlying this QTL is likely to be a regulatory mutation. PMID- 22497546 TI - Olfactory dysfunction in seasonal and perennial allergic rhinitis. AB - CONCLUSIONS: The limitation in olfactory function in patients with seasonal allergic rhinitis (AR) can be ascribed to an increase in eosinophilic and mast cell activity in the olfactory cleft. Therefore, the decrease in olfactory functions seems to be predominantly caused by the inflammation of the epithelium and not by the obstruction of the nose caused by the inflammation. OBJECTIVE: Olfactory dysfunction is frequently seen in patients with AR; however, little is known about the underlying pathophysiological mechanisms. Therefore, the aim of the present study was to examine the olfactory function in patients with seasonal or perennial AR, and to correlate the results with data obtained by analysis of nasal secretion and obstruction. METHODS: Olfactory function was tested using the Sniffin'Sticks test in patients with seasonal or perennial AR and in a control group. Nasal secretion analysis included eosinophilic cationic protein (ECP) and tryptase testing. Nasal obstruction was evaluated by rhinomanometry. RESULTS: Patients with AR (seasonal and perennial) showed impaired olfactory functions in comparison with the control group. Nasal secretion analysis showed increased values of ECP and tryptase in the seasonal group in comparison with controls. Rhinomanometry showed no differences in nasal flow between the three groups. PMID- 22497547 TI - Solution-processable triindoles as hole selective materials in organic solar cells. AB - We report the use of two solution-processable triindoles, triazatruxene (TAT), and N-trimethyltriindole (TMTI), as hole selective materials in organic solar cells. The unique optical and electronic properties of these molecules make them suitable as a hole extracting/electron blocking layer, i.e. transparency in the visible region due to a wide bandgap, high LUMO (lowest unoccupied molecular orbital) energy level, modest HOMO (highest occupied molecular orbital) level, and high hole carrier mobility. TAT is shown to have a LUMO at -1.68 eV, a HOMO at -5.03 eV, and a bandgap of 3.35 eV, whereas TMTI has a LUMO at -2.05 eV, a HOMO at -5.1 eV, and a bandgap of 3.05 eV, obtained from cyclic voltammetry measurements and absorption spectroscopy. Planar heterojunction photovoltaic devices, consisting of a solution processed transparent TAT (or TMTI) layer and a vapor-deposited C60 layer, exhibited efficiencies of up to 0.71 % (or 0.87 %). In these bilayer devices, the excitons are primarily generated in the C60 layer and undergo dissociation in the interfaces via hole transfer from the C60 layer to the TAT (or TMTI) layer. Additionally, spin-casting methanol solution of TAT on the top of P3HT:PCBM bulk heterojunction in an inverted device produced a hole selective interfacial layer between the photoactive layer and anode, leading to a 26% efficiency increase as compared to a control device without the TAT layer. PMID- 22497548 TI - Targeted delivery of a splice-switching oligonucleotide by cationic polyplexes of RGD-oligonucleotide conjugate. AB - Nanoparticle-based delivery has become an important strategy to advance therapeutic oligonucleotides into clinical reality. Delivery by nanocarriers can enhance access of oligonucleotides to their pharmacological targets within cells; preferably, targeting ligands are incorporated into nanoparticles for targeting oligonucleotides to disease sites, often by conjugation to delivery carriers. In this study, a splice-switching oligonucleotide (SSO) was conjugated to a bivalent RGD peptide, and then, the RGD-SSO conjugate was formulated into polyplexes with a cationic polymer polyethylenimine. The resultant polyplexes of RGD oligonucleotide conjugate demonstrated dramatic increase in the pharmacological response of splicing correction compared to free RGD-SSO conjugate or the polyplexes of unconjugated SSO, through integrin-mediated endocytosis and rapid endosomal release. This study has shown that coupling a targeting ligand to cargo oligonucleotide can maintain the integrin targeting ability after the peptide oligonucleotide conjugate is complexed with cationic polymer. Preliminary study also revealed that integrin targeting redirects intracellular trafficking of the polyplexes to caveolar pathway and thereby generates greater effectiveness of the oligonucleotide. This study provides a new platform technology to construct multifunctional delivery systems of therapeutic oligonucleotides. PMID- 22497549 TI - Identification and comparison of microRNAs from skeletal muscle and adipose tissues from two porcine breeds. AB - MicroRNAs (miRNAs) are an abundant class of small regulatory RNAs that negatively regulate gene expression at the post-transcriptional level. Although an increasing number of porcine miRNAs recently have been identified, research has yet to identify the full repertoire of miRNAs in pig skeletal and adipose tissues and their differences between breeds. We extracted small RNA from skeletal muscle and adipose tissues of Landrace and Lantang pigs, and the expression of a total of 184 known porcine miRNAs (113 from Solexa sequencing and 171 from miRNA chip hybridization) as well as 521 novel miRNA candidates was detected. Moreover, 20 miRNAs were selected randomly from the 184 miRNAs and analysed by quantitative real-time PCR to confirm the aforementioned results. In the skeletal muscle tissues, 21 miRNAs were up-regulated in Lantang and another 33 were highly expressed in Landrace pigs. In the adipose tissues, 25 miRNAs were down-regulated in Lantang and another 23 were lowly expressed in Landrace pigs. miRNA divergence between tissues was also detected in this study. Ten miRNAs were highly expressed in the skeletal muscle tissue in comparison with adipose tissue, and another 10 miRNAs exhibited the opposite expression profile. To investigate the regulatory mechanism of the miRNAs in muscle and adipose tissues, the 10 miRNAs with the most divergent expression profiles were functionally categorized using the Kyoto Encyclopedia of Genes and Genomes database. Most of the miRNAs strongly corresponded to myogenesis and adipogenesis processes. In addition, 84 of the 521 miRNA candidates were potentially porcine-specific miRNAs. This study adds new valuable information to comparative miRNA profiles of skeletal muscle and adipose tissues in porcine species. The great diversity of miRNA composition and expression levels both between breeds and between tissues suggests that a complex regulatory network exists in porcine subcutaneous fat development. PMID- 22497550 TI - Is sentinel node biopsy the standard of care in melanoma management? The opinions and practices of Australian specialists. AB - BACKGROUND/OBJECTIVE: There is international debate over the role of sentinel node biopsy (SNB) in invasive melanoma management. There is currently evidence that SNB offers prognostic information; however, the therapeutic benefit of SNB is yet to be elucidated. Many experts describe SNB as the standard of care in the management of patients with melanoma. Labelling a procedure as a standard of care has consequences from the perspectives of both patient care and cost. This study aims to determine the opinions of Australian dermatologists and plastic surgeons on the role of SNB, to compare these opinions between specialties and to compare self-reported practices with current evidence. METHODS: An online survey of 10 questions was distributed to members of the Australasian College of Dermatologists and the Australian Society of Plastic Surgeons. RESULTS: A total of 137 responses were received (66 dermatologists and 71 plastic surgeons), representing 16% of the dermatologists and 20% of the plastic surgeons in Australia. Just over half of the respondents (51%) said SNB should not be the standard of care. More dermatologists than plastic surgeons held this view. In total 15% of specialists were counselling patients outside current guidelines. CONCLUSIONS: Australian specialists are divided on the role of SNB in the management of patients with melanoma. There are differences in opinion on the role of SNB in melanoma management between speciality groups and regions. A significant percentage of specialists are counselling patients outside current guidelines. PMID- 22497551 TI - Evidence of alternative splicing of porcine beta-casein (CSN2). PMID- 22497552 TI - Study of prepolymerization complex formation in the synthesis of steroid-based molecularly imprinted polymers. AB - The preparation of steroid-based molecularly imprinted polymers (MIPs) based upon noncovalent interaction is particularly suited for selective capture of steroid hormones in biological and environmental samples. The success of this method lies in the optimization of the interaction between steroids (template) and methacrylic acid (functional monomer) in the prepolymerization mixture. NMR techniques coupled with DFT calculations were used to evaluate the capacity of the methacrylic acid to bind a steroid for future applications. The androstane derivative steroids considered in the present study have two functional groups at C(3) and C(17), which may interact with the methacrylic acid. These can be hydroxyl or ketone groups. Experimental results show that the steroids can be divided in three groups corresponding to the ketone type at C(3), the H-bond strength increasing with the number of double bonds. DFT calculations are in very good agreement with experimental results, showing increasing binding energy from no bonds, a single bond, and two double bond steroids. For steroids holding a hydroxyl group the binding energy obtained in the solvent model is comparable to the binding energy of single bond ketone steroids. PMID- 22497554 TI - Olmesartan medoxomil in children and adolescents with hypertension?: profile report. AB - ?Adapted and reproduced from the original article published in Drugs 2010; 70 (18): 2439-47. PMID- 22497553 TI - Management of children with multiple sclerosis. AB - Pediatric onset multiple sclerosis (MS) may be seen in 2-5% of patients with MS. It is characterized by high disease burden. As such, early treatment with preventative therapies should be considered. Although randomized controlled trials have not been conducted on therapies for pediatric MS, there is a growing body of literature suggesting safety of first-line agents approved for use in adult MS, including interferons and glatiramer acetate. The use of second-line therapies, such as natalizumab, cyclophosphamide, and mitoxantrone has been described in a small number of pediatric MS cases. These case series suggest benefit of these agents after limited follow-up. Little information on long-term effects of therapies such as cyclophosphamide, mitoxantrone, or natalizumab is available for this population, although concerns of increased risk for opportunistic infections (progressive multifocal leukoencephalopathy with natalizumab) and secondary hematologic cancers (with mitoxantrone) exist. Finally, although fatigue, motor, cognitive, and psychosocial difficulties are common in this population, no trials have been conducted on pharmacologic or non pharmacologic interventions for the management of these problems. Therapies for spasticity, including baclofen (including the baclofen pump), diazepam, and botulinum toxin have been evaluated in children with cerebral palsy and may be used safely in children. Psychiatric intervention is often necessary for affective disorders. Interventions for fatigue have not been studied, although evidence in the adult MS literature suggests possible benefit of exercise and modafinil. This article provides a practical guide to the diagnosis and treatment of multiple sclerosis in pediatric patients. PMID- 22497555 TI - Gallbladder and gastric motility in obese newborns, pre-adolescents and adults. AB - BACKGROUND AND AIM: Impaired gallbladder and gastric motility have been associated with obesity in adults. The timing of appearance of this dysfunction, however, is unclear. METHODS: Lean and obese subjects from three different age groups were studied noninvasively: 50 newborns (1-12 months old, six obese), 18 pre-adolescents (7-8 years old, seven obese), and 99 adults (22-80 years old, 32 obese) classified according to standard normal tables and body mass index. Changes of fasting/postprandial gallbladder and gastric motility were assessed simultaneously by functional ultrasonography in response to milk (newborns and pre-adolescents) and to a liquid test meal (adults). RESULTS: In newborns, fasting and postprandial gallbladder volumes and gastric emptying were similar between obese and lean subjects. In pre-adolescents, obese subjects had a larger fasting gallbladder volume, with slower postprandial gastric emptying than lean subjects. In obese adults, the most evident dysfunction emerged, with larger fasting and postprandial residual gallbladder volume, and slower postprandial gastric emptying than lean subjects. CONCLUSIONS: Obese subjects display abnormal gallbladder and gastric motility patterns, which first appear in pre-adolescents and deteriorate in adults. Such abnormalities are absent in obese newborns. Functional ultrasonography can detect altered cholecysto-gastric motility at the earliest stage. Our findings suggest an age-related decline of motility, probably secondary to excessive fat and insulin-resistance. PMID- 22497556 TI - Analysis of frequency loss as a prognostic factor in idiopathic sensorineural hearing loss. AB - CONCLUSION: The combination of systemic steroids with intratympanic dexamethasone injection (ITDI) did not result in significantly different outcomes from steroid treatment only and did not have any additional beneficial effects. OBJECTIVE: To evaluate hearing recovery in idiopathic sudden sensorineural hearing loss (ISSNHL) according to frequency and to compare treatment responses between patients treated with systemic steroids and systemic steroids with ITDI. METHODS: Ninety-nine patients with ISSNHL were selected to participate in the study by a retrospective medical chart review. Patients were divided into two groups, systemic steroid treatment only and systemic steroid with adjunctive ITDI. Hearing recovery was evaluated by pure tone audiometry (PTA). All patients underwent PTA examination before treatment and after 3 months. Thresholds were analyzed by frequency along with other factors. RESULTS: Low frequency hearing loss responded better than high frequency loss to PTA. When we analyzed pure tone audiogram patterns, all patterns except for the descending type showed better improvement in patients with lower frequency hearing loss than in patients with higher frequency hearing loss. PMID- 22497557 TI - C2-symmetric recyclable organocatalyst for enantioselective Strecker reaction for the synthesis of alpha-amino acid and chiral diamine--an intermediate for APN inhibitor. AB - Recyclable chiral amide-based organocatalyst 5 efficiently catalyzed asymmetric Strecker reaction of various aromatic and aliphatic N-benzhydrylimines with ethyl cyanoformate as cyanide source at -10 degrees C to give a high yield (95%) of alpha-aminonitriles with excellent chiral induction (ee, up to 99%) with the added advantage of recyclability. Based on experimental observations a probable mechanism was proposed for this reaction. This protocol with catalyst 5 was extended for the synthesis of (R)-phenylalanine and pharmaceutically important drug intermediate (R)-3-phenylpropane-1,2-diamine in high yield with high enantioselectivity. PMID- 22497558 TI - Impact of two types of complete pelleted, wild ungulate feeds and two pelleted feed to hay ratios on the development of urolithogenic compounds in meat goats as a model for giraffes. AB - Urolith formation has been documented in giraffes and goats. As research in giraffes poses logistical challenges, 16 buck goats were used as a model. The impact of two commercially available, pelleted feeds used for giraffes, ADF-16 and Wild Herbivore (WH), as well as the impact of alfalfa hay and pellet proportions (20% hay:80% pellets, 80P or 80% hay:20% pellet, 20P) on the formation of urolithogenic precursors in goat urine was accomplished in a 2 * 2 factorial balance study. Complete diets contained 0.60, 0.32, 0.35 and 0.26% phosphorus (P) with calcium:P ratios of 1.60, 4.16, 3.06 and 5.23, for 80P-ADF 16, 20P-ADF-16, 80P-WH and 20P-WH respectively. Total faeces and urine were collected over two 5-day periods to assess N and mineral balance. Fresh urine samples were collected and evaluated microscopically for urolithic crystal content. Urinary nitrogen (N) was lower and N retention was higher in goats fed 80P diets (p < 0.05). Intake of P was greatest for goats fed 80P-ADF-16; however, urinary P excretion and P retention were not affected by treatment. Crystal scores were higher in animals receiving 80P diets (p = 0.08), with crystals being composed predominantly of calcium phosphate. Urine pH was alkaline (>8) for all treatments. Urinary P concentration, a risk factor for urolithiasis, was highest (p <= 0.06) in the 80P-ADF-16 treatment (0.38 vs. 0.01, 0.02 and 0.04 mg/dl for 20P-ADF-16, 80P-WH and 20P-WH respectively), reflecting its highest dietary P level. Further investigation is recommended to determine the long-term effects of these diets on urolithogenic compound formation. PMID- 22497559 TI - Left ventricular remodeling in human heart failure: quantitative echocardiographic assessment of 1,794 patients. AB - BACKGROUND: The left ventricle (LV) undergoes significant architectural remodeling in heart failure (HF). However, the fundamental associations between cardiac function and LV size and performance have not been thoroughly characterized in this population. We sought to define the adaptive remodeling that occurs in chronic human HF through the detailed analyses of a large quantitative echocardiography database. METHODS: Baseline echocardiograms were performed in 1,794 patients with HF across a broad range of ejection fraction (EF), from less than 10% to greater than 70%. Core lab measurements of LV volumes and length were made, from which EF, mass, sphericity indices, stroke volume (SV), and stroke work were derived. Spearman correlation coefficients and linear regression methods were used to determine the relationships between remodeling parameters. RESULTS: The median EF was 28.6% (IQR 21.9-37.0). Across a multitude of parameters of cardiac structure and function, indexed end-systolic volumes (ESVs) explained the greatest proportion of the variance in EF (R =-0.87, P < 0.0001). Systolic sphericity index and LV mass were also strongly correlated with EF (R =-0.62 and -0.63, P < 0.0001), reflective of the alterations in LV shape and size that occur as EF declines. SV was rigorously maintained across a broad spectrum of EF, until the EF fell below 20%, at which point SV decreased significantly (P < 0.0001). CONCLUSIONS: In chronic HF, the LV undergoes extensive structural adaptive remodeling in order to maintain SV across a broad range of EF. However, when the EF falls below 20%, further modulation of SV is no longer possible through alterations in ventricular architecture. PMID- 22497560 TI - Automatic CPAP performance in patients with sleep apnea plus COPD. AB - BACKGROUND: Automatic CPAP devices have demonstrated good results in obtaining optimal fixed CPAP pressure to eliminate respiratory events in patients with sleep apnea-hypopnea syndrome (SAHS). However, automatic CPAP has not been fully studied in patients with COPD plus SAHS. OBJECTIVES: To analyse the performance of an automatic CPAP in severe COPD patients compared with SAHS patients with no associated co-morbidity. METHODS: We compared 10 consecutive patients with SAHS and no associated co-morbidity and 10 patients with SAHS plus severe COPD who required CPAP titration. Automatic CPAP performance was studied during full-night PSG. Inadequate pressure increase periods, absence of pressure increases in reaction to respiratory events, air leak periods, and pressure behaviour in the face of erratic breathing periods were analysed. RESULTS: The SAHS patients without co-morbidities vs. SAHS plus COPD patients presented: mean sleep efficiency, 80.2 (11.5)% vs. 76.5 (12.1)%; residual AHI, 6.3 (5.2) vs. 5.1 (7.7); residual CT90, 1 (3)% vs. 14 (1)%. The device's performance demonstrates a mean of 1.2 (1.5) vs. 1.3 (1.2) periods of inadequate pressure increases; absence of pressure increases in reaction to respiratory events, 4.1 (5.4) vs. 0.6 (0.7) times; periods of air leaks, 1.3 (3.8) vs. 13.9 (11.7); mean optimal pressure, 9.1 (1.4) vs. 9.0 (1.9) cm H(2)O. CONCLUSION: Titration with automatic CPAP could be as effective in patients with SAHS plus severe COPD as in patients with SAHS without COPD. However, the presence of more leakages must be taken into account. PMID- 22497561 TI - The COPD Assessment Test (CAT): short- and medium-term response to pulmonary rehabilitation. AB - BACKGROUND: The COPD Assessment Test (CAT) is a recently introduced instrument to assess health-related quality of life in COPD. We aimed to evaluate the longitudinal change in CAT following Pulmonary Rehabilitation (PR), and test the relationship between CAT and CRQ-Self Report (SR) over time. We hypothesised that the CAT would show similar responsiveness to PR as the CRQ-SR both in the short and medium-term. METHODS: 118 COPD patients completed an eight-week outpatient multidisciplinary PR programme. CAT, CRQ-SR and the incremental shuttle walk (ISW) were measured prior to starting PR (T1), completion of PR (T2) and 6 months after completion of PR (T3). RESULTS: There was a significant improvement in CAT, CRQ-SR and ISW immediately following PR (p < 0.001). Although there was decline between T2 and T3, CAT, CRQ-SR and ISW remained significantly better at T3 compared with T1 (ANOVA p < 0.001). Both between T1-T2 and between T2-T3, change in CAT correlated significantly with change in CRQ (both r = -0.44 and p < 0.001). The slope of the relationship between CAT change and CRQ-SR change at T1 T2 and T2-T3 was not significantly different (ANCOVA: intercept p = 0.79, interaction effect p = 0.95). CONCLUSIONS: In COPD, the CAT score is immediately responsive to PR and remains improved at 6 months. There is no significant difference in the short and medium term changes in the CAT and CRQ-SR following PR. We propose that for most clinical indications for assessing health-related quality of life in COPD, the CAT is a robust and practical alternative to longer established instruments such as the CRQ-SR. PMID- 22497562 TI - Lipids of erythrocyte membranes of COPD patients: a quantitative and qualitative study. AB - Chronic obstructive pulmonary disease (COPD) is characterized by inflammation of lung parenchyma and pulmonary hypoxemia with a proven systemic component. Tobacco smoke is the most important risk factor and plasma membrane plays a major role in the disease pathology and progression. The properties of biological membranes are a function of their lipid composition. Any change in its composition may lead to the pathophysiology. In COPD research, erythrocytes are emerging as a new therapeutic venture, as their shape and properties change in the disease. Therefore we studied the lipid composition of the erythrocyte membranes of COPD patients. The study included 30 patients having COPD, 10 healthy smokers and 10 non-smokers. Erythrocytes were separated from peripheral blood and their membranes prepared, followed by estimation of proteins, cholesterol and phospholipids. Individual phospholipids were identified and separated by TLC and fatty acid composition determined by gas chromatography. The data were analyzed statistically and P < 0.05 was considered significant. Our results demonstrate that in very severe COPD, proteins decrease, whereas phospholipids and cholesterol contents increase significantly, which showed a consistent negative correlation with FEV1%. The fatty acid analysis showed preponderance towards saturated fatty acids mainly arachidic and behenic acid, suggesting a decrease in membrane fluidity or a closer packing of lipid rafts. We are the first to report about preponderance of saturated fatty acids in plasma membrane of erythrocytes of COPD patients which may decrease the membrane fluidity and possibly impair the functions of the plasma membrane in the disease. PMID- 22497563 TI - Impact of changes in regular use of marijuana and/or tobacco on chronic bronchitis. AB - We sought to evaluate possible changes in the prevalence of chronic bronchitis in relation to continuing or changing smoking status for marijuana and/or tobacco. For this purpose we followed 299 participants in a longitudinal cohort study of the impact of heavy habitual use of marijuana alone or with tobacco on respiratory symptoms over a mean of 9.8 years during which subjects underwent repeated administration of a detailed drug use and respiratory questionnaire at intervals of >=1 yr. Using logistic regression, we calculated odds ratios to assess the relationship between chronic bronchitic symptoms and smoking status for marijuana and tobacco at the first visit (current smoking versus never smoking) and at the last follow-up visit (continuing smoking versus, separately, never smoking and former smoking). We found that continuing smokers of either marijuana or tobacco had a significantly increased likelihood of having chronic bronchitis at follow-up compared to both never smokers and former smokers. On the other hand, former smokers of either substance were no more likely to have chronic respiratory symptoms at follow-up than never smokers. These findings demonstrate the benefit of marijuana smoking cessation in resolving pre-existing symptoms of chronic bronchitis. PMID- 22497564 TI - On the structure of beta-molybdenum dichloride. AB - The structure of beta-molybdenum dichloride is compared with that of TcCl(2) using EXAFS spectroscopy. For TcCl(2), the Tc atom is surrounded by Tc atoms at 2.13(2), 3.45(3), 3.79(4), and 4.02(4) A. For beta-MoCl(2), the Mo is surrounded by Mo atoms at 2.21(2), 2.91(3), and 3.83(4) A. The latter distances are consistent with the presence of an [Mo(4)Cl(12)] unit in the solid state, one constituted by two triply Mo-Mo-bonded [Mo(2)Cl(8)] units. First-principles calculations show that beta-MoCl(2) with the TcCl(2) "structure type" is less stable than alpha-MoCl(2) (Mo(6)Cl(12)) or [Mo(4)Cl(12)] edge-sharing clusters. PMID- 22497565 TI - Characterization of the genetic diversity, structure and admixture of British chicken breeds. AB - The characterization of livestock genetic diversity can inform breed conservation initiatives. The genetic diversity and genetic structure were assessed in 685 individual genotypes sampled from 24 British chicken breeds. A total of 239 alleles were found across 30 microsatellite loci with a mean number of 7.97 alleles per locus. The breeds were highly differentiated, with an average F(ST) of 0.25, similar to that of European chicken breeds. The genetic diversity in British chicken breeds was comparable to that found in European chicken breeds, with an average number of alleles per locus of 3.59, ranging from 2.00 in Spanish to 4.40 in Maran, and an average expected heterozygosity of 0.49, ranging from 0.20 in Spanish to 0.62 in Araucana. However, the majority of breeds were not in Hardy-Weinberg Equilibrium, as indicated by heterozygote deficiency in the majority of breeds (average F(IS) of 0.20), with an average observed heterozygote frequency of 0.39, ranging from 0.15 in Spanish to 0.49 in Cochin. Individual-based clustering analyses revealed that most individuals clustered to breed origin. However, genetic subdivisions occurred in several breeds, and this was predominantly associated with flock supplier and occasionally by morphological type. The deficit of heterozygotes was likely owing to a Wahlund effect caused by sampling from different flocks, implying structure within breeds. It is proposed that gene flow amongst flocks within breeds should be enhanced to maintain the current levels of genetic diversity. Additionally, certain breeds had low levels of both genetic diversity and uniqueness. Consideration is required for the conservation and preservation of these potentially vulnerable breeds. PMID- 22497566 TI - Function and regulation of the Cyp2a5/CYP2A6 genes in response to toxic insults in the liver. AB - The mouse hepatic cytochrome P450 (CYP) 2A5 and its human orthologue CYP2A6 catalyse the metabolism of a number of drugs and toxins, such as halothane and aflatoxin B1. The enzymes are named "Coumarin 7-hydroxylase" and "Nicotine Hydroxylase", respectively, by virtue of their high affinity and specific activity towards these compounds. Bilirubin, the breakdown product of haem, has been suggested to be the endogenous substrate for both enzymes. Uniquely, CYP2A5 and CYP2A6 are induced during pathological conditions associated with liver injury when the function of most other CYP enzymes is compromised, which suggests an exceptional mode of regulation of the corresponding genes. Regulation of these genes is indeed complex where the promoters interact with multiple stress activated transcription factors. The Cyp2a5 promoter contains a "stress responding" cluster of binding motifs, which interact with major mediators of toxic insults including nuclear factor-E2 p45-related factor 2 (Nrf2) and aryl hydrocarbon receptor (AhR). These interactions are crucial in the up-regulation of the genes under stress conditions. Additionally, elevated transcription is also achieved through mRNA stabilisation mediated by interaction of the stress activated heterogenous ribonucleoprotein A1 (hnRNP A1) with the 3'UTR of the CYP2A5/CYP2A6 mRNA. The up-regulation via enhanced transcription combined with mRNA stabilisation, as seen in some of the stress situations, leads to a particularly strong, fast and persistent response. This review brings together knowledge obtained from studies in our laboratories and others' on regulation of Cyp2a5/CYP2A6 genes in response to toxic insults and toxicological significance of their catalytic activities that may provide clues to a functional role of the enzymes in relation to liver toxicity. PMID- 22497567 TI - Evaluation of the physicochemical and biopharmaceutical properties of fluoro indomethacin. AB - Drug nanocarriers have shown great potential in therapy and as diagnostic probes, e.g. in imaging of cancer and inflammation. Imaging can be applied to localize the carrier or the drug itself in the body and/or tissues. In this particular case it is important that drug molecules have the characteristics for possible detection, e.g. after modification with positron emission tomography compliant radioisotopes, without affecting their pharmacological behavior. In order to easily and efficiently follow the ADME profile of the drug after loaded into nanocarriers, the drug can be radiolabelled with, e.g. 18F-label, in order to assess its biodistribution after enteral and parenteral administration in rats. However, this is only possible if the derivative compound behaves similarly to the parent drug compound. In this study, indomethacin (a poorly water-soluble drug) was chosen as a model compound and aimed to evaluate the physicochemical and biopharmaceutical properties of an analog of indomethacin (IMC), fluoro indomethacin (F-IMC). Although some of the physicochemical and biopharmaceutical properties of IMC are already known, in order to establish a feasible comparison between IMC and F-IMC, the behavior of the former was also investigated in the same conditions as for F-IMC. In this context, both IMC and F-IMC were thermally and morphologically studied. Furthermore, the following properties were also studied for both compounds: pKa and logP, solubility and dissolution profiles at physiological pH values, and toxicity at different concentrations in Caco-2 cells. Finally, the transport across Caco- 2 monolayers of the IMC and F-IMC at physiological pH range was also investigated. The results obtained showed similar values in pKalogP, solubility, dissolution, cytotoxicity, and permeability for both compounds. Thus, there might be strong evidence that both IMC and F-IMC should have a similar ADME behavior and profiles in vivo. The results provide fundamental tools and ideas for further research with nanocarriers of 18F-IMC. PMID- 22497568 TI - Improving oral absorption via drug-loaded nanocarriers: absorption mechanisms, intestinal models and rational fabrication. AB - Although it is acknowledged that the main impediment of orally administered therapeutic agents is their extensive and changeable pre-systemic metabolism, low absorption and instability in harsh environment of the gastrointestinal (GI) tract are also main influential factors, resulting into inadequate and erratic drug bioavailability. To overcome these shortcomings, nanotechnology has offered new promising strategies to prevent and treat a wide variety of diseases by employing different oral drug-carrier structures capable to enhance therapeutic effects and minimize the toxicity of healthy organs or cells. This review, in general, elucidates some considerable features of in vitro oral drug delivery in three different parts. The first one summarizes the main challenges for oral drug delivery and available absorption mechanisms. The second part embodies an in depth discussion on the role of the intestinal absorption models used to predict permeability, cellular uptake or even toxicity of nanoparticles, resulting into the design of nanocarriers with optimum efficacy for oral delivery. The third section of the literature is devoted, more particularly, to nanocarriers developed for oral absorption in the past few years, including the behavior of nanovehicles upon oral administration with respect to membrane permeability, retention properties and stability, as well as methods which may lengthen residence time in the GI environment or improve drug absorption. PMID- 22497569 TI - Precision-cut intestinal slices as in vitro tool for studies on drug metabolism. AB - The role of the intestine in drug metabolism has long been underestimated as a consequence of the technical difficulty to discern the role of the intestine from that of the liver in in vivo experiments and of the lack of in vitro models that are sufficiently viable and fully representing the physiology and anatomy of the intestine. Recently the precision-cut slice model, which is widely used for liver and kidney, was also adapted for the small and large intestine. In this review the application of precision-cut intestinal slices (PCIS) for research in drug metabolism and transport is discussed. PCIS can be prepared from animal and human tissues from all regions of the intestine allowing investigation of species differences and regional gradients of activities of metabolizing enzymes. They are viable for 8-24 h of incubation and show high activity of drug metabolizing enzymes, representative for the in vivo activity. They have been successfully used to study drug-drug interactions such as induction, inhibition and regulation of drug metabolizing enzymes, transporters and nuclear factors. Moreover they appear to be a suitable model for studies on cold preservation of donor organs for transplantation, and allow exploring inter-organ interactions by co incubation with precision-cut slices of other organs. Their application as model for drug-induced intestinal toxicity is still in its infancy but appears to be promising. PCIS, prepared from human and animal tissues, represent a powerful translational model for drug metabolism, transport and toxicity studies and as such contributes to the reduction and replacement of animal experiments. PMID- 22497570 TI - In vitro methods to study the interplay of drug metabolism and efflux in the intestine. AB - This review provides an overview of the in vitro methods currently used in studies of intestinal drug metabolism and active efflux with a special emphasis on the efflux- metabolism interplay. These methods include e.g. expressed enzymes or efflux transporters, fractionated intestinal cells, cell lines, primary cells, intestinal segments and other tissue preparations. Pharmacokinetics of effluxmetabolism interplay is often very complicated, possibly involving saturation, stimulation and/or inhibition of one or both of these mechanisms. Parent drug and/or metabolite(s) can be substrates for several enzymes and/or efflux proteins. These detoxifying proteins may alter the exposure of drugs to each other and, consequently, their contributions to the overall drug elimination. Depending on the complexity of the in vitro system used, different kinds of information can be extracted from the results. Simple methods concentrating on single mechanisms provide easily interpretable information, but neglect the interplay between various mechanisms influencing the kinetics in a whole organism. More complex experimental systems mimic the mechanistic complexity of in vivo setting better, but at the same time the interpretation and utilization of the results becomes more challenging. Advantages and limitations of various in vitro systems are addressed and consideration is given to the physiological relevance of the results obtained and there is discussion of approaches for in vitro - in vivo translation of the data. PMID- 22497571 TI - Do the recommended standards for in vitro biopharmaceutic classification of drug permeability meet the "passive transport" criterion for biowaivers? AB - BCS based biowaivers are recognized by major regulatory agencies. An application for a biowaiver can be supported by or even based on "in vitro" measurements of drug permeability. However, guidelines limit the application of biowaivers to drug substances that are transported only by passive mechanisms. Regarding published permeability data as well as measurements obtained in our institution, one can rarely observe drug substances that conform to this very strict criterion. Therefore, we measured the apparent permeability coefficients of 13 drugs recommended by FDA's Guidance to be used as standards for "in vitro" permeability classification. The asymmetry of permeability data determined for both directions (mucosal-to-serosal and serosalto- mucosal) through the rat small intestine revealed significant active transport for four out of the nine high permeability standards and for all four low-permeability standard drugs. As could be expected, this asymmetry was abolished at 4 degrees C on rat intestine. The permeability of all nine high-permeability, but none of the low permeability standards, was also much lower when measured with intestinal tissue, Caco-2 cell monolayers or artificial membranes at 4 degrees C compared to standard conditions (37 degrees C). Additionally, concurrent testing of several standard drugs revealed that membrane transport can be affected by the use of internal permeability standards. The implications of the results are discussed regarding the regulatory aspects of biopharmaceutical classification, good practice in drug permeability evaluation and regarding the general relevance of transport proteins with broad specificity in drug absorption. PMID- 22497572 TI - Confirmation of the association between a single nucleotide polymorphism in the porcine LDHA gene and average daily gain and correlated traits in Italian Large White pigs. PMID- 22497573 TI - Detection of quantitative trait loci for growth- and fatness-related traits in a large-scale White Duroc * Erhualian intercross pig population. AB - Growth and fatness are economically important traits in pigs. In this study, a genome scan was performed to detect quantitative trait loci (QTL) for 14 growth and fatness traits related to body weight, backfat thickness and fat weight in a large-scale White Duroc * Erhualian F(2) intercross. A total of 76 genome-wide significant QTL were mapped to 16 chromosomes. The most significant QTL was found on pig chromosome (SSC) 7 for fatness with unexpectedly small confidence intervals of ~2 cM, providing an excellent starting point to identify causal variants. Common QTL for both fatness and growth traits were found on SSC4, 5, 7 and 8, and shared QTL for fat deposition were detected on SSC1, 2 and X. Time series analysis of QTL for body weight at six growth stages revealed the continuously significant effects of the QTL on SSC4 at the fattening period and the temporal-specific expression of the QTL on SSC7 at the foetus and fattening stages. For fatness traits, Chinese Erhualian alleles were associated with increased fat deposition except that at the major QTL on SSC7. For growth traits, most of White Duroc alleles enhanced growth rates except for those at three significant QTL on SSC6, 7 and 9. The results confirmed many previously reported QTL and also detected novel QTL, revealing the complexity of the genetic basis of growth and fatness in pigs. PMID- 22497574 TI - Effects of erythropoiesis-stimulating agents on survival and other outcomes in patients with lymphoproliferative malignancies: a study-level meta-analysis. AB - Erythropoiesis-stimulating agents (ESAs) are approved to treat anemia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy. ESAs reduce transfusion rates, but some clinical studies suggest that ESAs may reduce survival or increase disease progression. This study-level meta-analysis examined the effects of darbepoetin alfa, epoetin alfa or epoetin beta on mortality, disease progression and transfusion incidence in patients with lymphoproliferative malignancies, using randomized, controlled trials of patients receiving chemotherapy and ESAs or standard of care. The odds ratio (OR) for mortality was 1.04 (95% confidence interval [CI], 0.81-1.34, random-effects model, 10 studies); the risk difference was - 0.01 (95% CI, - 0.03-0.02). The OR for disease progression was 1.02 (95% CI 0.81-1.30, random-effects model, five studies). A lower proportion of ESA-treated patients than controls received transfusions (seven studies). In this meta-analysis, ESAs reduced transfusions with no clear effect on mortality or disease progression in patients with lymphoproliferative malignancies receiving chemotherapy. PMID- 22497575 TI - Single-nucleotide polymorphisms in the bovine CD209 candidate gene for susceptibility to infection by Mycobacterium avium subsp. paratuberculosis. PMID- 22497576 TI - Quantitative trait loci analysis of a Duroc commercial population highlights differences in the genetic determination of meat quality traits at two different muscles. AB - We performed a whole-genome scan with 110 informative microsatellites in a commercial Duroc population for which growth, fatness, carcass and meat quality phenotypes were available. Importantly, meat quality traits were recorded in two different muscles, that is, gluteus medius (GM) and longissimus thoracis et lumborum (LTL), to find out whether these traits are determined by muscle specific genetic factors. At the whole-population level, three genome-wide QTL were identified for carcass weight (SSC7, 60 cM), meat redness (SSC13, 84 cM) and yellowness (SSC15, 108 cM). Within-family analyses allowed us to detect genome wide significant QTL for muscle loin depth between the 3rd and 4th ribs (SSC15, 54 cM), backfat thickness (BFT) in vivo (SSC10, 58 cM), ham weight (SSC9, 69 cM), carcass weight (SSC7, 60 cM; SSC9, 68 cM), BFT on the last rib (SSC11, 48 cM) and GM redness (SSC8, 85 cM; SSC13, 84 cM). Interestingly, there was low positional concordance between meat quality QTL maps obtained for GM and LTL. As a matter of fact, the three genome-wide significant QTL for colour traits (SSC8, SSC13 and SSC15) that we detected in our study were all GM specific. This result suggests that QTL effects might be modulated to a certain extent by genetic and environmental factors linked to muscle function and anatomical location. PMID- 22497577 TI - Demographic predictors of consistency and change in heterosexuals' attitudes toward homosexual behavior over a two-year period. AB - This study investigated demographic predictors of consistency and change in heterosexual people's attitudes toward homosexual behavior. A nationally representative sample of Australian men and women were recruited via random digit dialling in 2004 through 2005. Participants completed annual computer-assisted telephone interviews over the next five years. Questions about attitudes toward male and female homosexual behavior were assessed at Wave 1 (2004-2005) and Wave 3 (2006-2007) of the study. The majority of the sample reported tolerance of both male and female homosexual behavior (with women slightly more tolerant than men). Multivariate analyses showed that those who regularly attended religious services were more likely to consistently disapprove of homosexual behavior and more likely to change from tolerant to disapproving. Among those who were initially tolerant, younger respondents and those with higher educations were less likely to become homophobic. The results of this study show that individual attitudes toward homosexual behavior are open to change, particularly toward a more tolerant position. Religiosity appears to be consistently associated with the development and reinforcement of homophobic tendencies. PMID- 22497578 TI - Advanced maternal age and obstetric morbidity for women giving birth in Victoria, Australia: A population-based study. AB - BACKGROUND: As the proportions of older women giving birth increase, there is a growing body of evidence on the increased risks of poorer maternal and perinatal outcomes for this group. However, the associations are not completely understood. This study aimed to establish the prevalence of selected maternal morbidities and examine whether advanced maternal age is associated with a higher risk of morbidity for women giving birth in Victoria. METHOD: Data on all births over 20 weeks? gestation for 2005 and 2006 were obtained from the Victorian Perinatal Data Collection. Unadjusted and adjusted analyses were undertaken using logistic regression to examine and quantify the association between advanced maternal age (35 years and older) and selected obstetric morbidities and complications. RESULTS: There was evidence of an association between older maternal age and selected morbidities and complications. Older nulliparous women were at highest odds of gestational diabetes (AdjOR, 1.83; 95% CI, 1.67-2.02), placenta praevia (AdjOR, 2.02; 95% CI, 1.68-2.44), multiple birth (AdjOR, 1.80; 95% CI, 1.58-2.06) and caesarean delivery (AdjOR, 1.93; 95% CI, 1.84-2.02). Older multiparous women were at highest odds of gestational diabetes (AdjOR, 2.01; 95% CI, 1.88-2.15) and placenta praevia (AdjOR, 2.11; 95% CI, 1.83-2.44). CONCLUSIONS: Older women giving birth in Victoria are at an increased risk of a range of obstetric morbidities. Delayed childbearing for an increasing number of women has societal and public health ramifications and will potentially place greater demand on healthcare services. PMID- 22497579 TI - Graphene-based high-efficiency surface-enhanced Raman scattering-active platform for sensitive and multiplex DNA detection. AB - We have developed a surface-enhanced Raman scattering (SERS)-active substrate based on gold nanoparticle-decorated chemical vapor deposition (CVD)-growth graphene and used it for multiplexing detection of DNA. Due to the combination of gold nanoparticles and graphene, the Raman signals of dye were dramatically enhanced by this novel substrate. With the gold nanoparticles, DNA capture probes could be easily assembled on the surface of graphene films which have a drawback to directly immobilize DNA. This platform exhibits extraordinarily high sensitivity and excellent specificity for DNA detection. A detection limit as low as 10 pM is obtained. Importantly, two different DNA targets could be detected simultaneously on the same substrate just using one light source. PMID- 22497580 TI - Lithium nickel cobalt manganese oxide synthesized using alkali chloride flux: morphology and performance as a cathode material for lithium ion batteries. AB - Li(Ni(0.8)Co(0.1)Mn(0.1))O(2) (NCM811) was synthesized using alkali chlorides as a flux and the performance as a cathode material for lithium ion batteries was examined. Primary particles of the powder were segregated and grown separately in the presence of liquid state fluxes, which induced each particle to be composed of one primary particle with well-developed facet planes, not the shape of agglomerates as appears with commercial NCMs. The new NCM showed far less gas emission during high temperature storage at charged states, and higher volumetric capacity thanks to its high bulk density. The material is expected to provide optimal performances for pouch type lithium ion batteries, which require high volumetric capacity and are vulnerable to deformation caused by gas generation from the electrode materials. PMID- 22497582 TI - Potential prognostic and therapeutic role for angiogenesis markers in laryngeal carcinoma. AB - Angiogenesis is a hallmark of cancer, fundamental to its growth. The 'angiogenic switch' occurs when pro-angiogenic factors are not balanced by anti-angiogenic factors. A correlation between angiogenic properties and oncological prognosis (for laryngeal squamous cell carcinoma (LSCC) too) was first hypothesized in the 1990s. An exhaustive literature review was performed to investigate available data on angiogenesis markers and their biological role and therapeutic potential in LSCC. The prognostic significance of microvascular density in LSCC was investigated with endothelial targets, e.g. CD105, CD34, and CD31. Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), VEGF receptor 2, angiogenin, hypoxia-inducible factor 1, and other biological markers were also studied. Only anti-EGFR therapy has been approved by the USFood and Drug Administration (FDA) for head and neck carcinoma in recent years, while several agents interfering with VEGF and its receptors are being studied. Experimental findings indicate that anti-CD105 monoclonal antibodies efficiently inhibit tumor angiogenesis. There are two main ways to approach the vascular profile of solid malignancies: by inhibiting new vessel formation (anti angiogenic therapy) or selectively damaging neoplastic vessels (vascular targeting therapy). In advanced LSCC, both these strategies seem promising and warrant further preclinical and clinical investigation. PMID- 22497581 TI - Pulmonary and systemic effects of mononuclear leukapheresis. AB - BACKGROUND AND OBJECTIVES: There is increasing evidence that monocytes play a key role in the pathogenesis of acute lung inflammation. Mononuclear cell (MNC) leukapheresis can be used to remove large numbers of monocytes from circulating blood; however, the detailed characteristics of monocyte subpopulations removed by MNC leukapheresis, and the biological effects on the lung, remain incompletely defined. MATERIAL AND METHODS: Six healthy male volunteers underwent MNC leukapheresis of four total blood volumes. Blood was collected at 0, 2, 4, 6, 8 and 24 h; bronchoscopy with bronchoalveolar lavage (BAL) was performed at 8-9 h. Multiparameter flow cytometry was used to identify subpopulations of monocytes in blood and monocyte-like cells in BAL fluid. RESULTS: A median of 5.57*10(9) monocytes were retrieved. Blood monocyte counts indicated that the circulating blood monocyte pool was actively replenished during leukapheresis and subsequently contained a greater proportion of classical (CD14(++) CD16(-)) monocytes. A particular subpopulation of monocyte-like cells, reminiscent of classical monocytes, was also prominent in BAL fluid after leukapheresis. CONCLUSION: Mononuclear cell leukapheresis was safe. The greater proportion of classical monocytes present in blood after MNC leukapheresis may be clinically significant. MNC leukapheresis also appears to affect the proportion of monocyte like cells in the lung; however, we found no evidence that leukapheresis has a clinically important pro-inflammatory effect in the human lung. PMID- 22497583 TI - Inbreeding and inbreeding depression of early life traits in a cooperative mammal. AB - Mating between relatives often results in negative fitness consequences or inbreeding depression. However, the expression of inbreeding in populations of wild cooperative mammals and the effects of environmental, maternal and social factors on inbreeding depression in these systems are currently not well understood. This study uses pedigree-based inbreeding coefficients from a long term study of meerkats (Suricata suricatta) in South Africa to reveal that 44% of the population have detectably non-zero (F > 0) inbreeding coefficients. 15% of these inbred individuals were the result of moderate inbreeding (F >= 0.125), although such inbreeding events almost solely occurred when mating individuals had no prior experience of each other. Inbreeding depression was evident for a range of traits: pup mass at emergence from the natal burrow, hind-foot length, growth until independence and juvenile survival. However, we found no evidence of significant inbreeding depression for skull and forearm length or for pup survival. This research provides a rare investigation into inbreeding in a cooperative mammal, revealing high levels of inbreeding, considerable negative consequences and complex interactions with the social environment. PMID- 22497584 TI - Inflammatory bowel disease in Asia: a systematic review. AB - The incidence and prevalence of inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are lower in Asia than in the West. However, across Asia the incidence and prevalence of IBD has increased rapidly over the last two to four decades. These changes may relate to increased contact with the West, westernization of diet, increasing antibiotics use, improved hygiene, vaccinations, or changes in the gut microbiota. Genetic factors also differ between Asians and the Caucasians. In Asia, UC is more prevalent than CD, although CD incidence is rapidly increasing in certain areas. There is a male predominance of CD in Asia, but a trend towards equal sex distribution for UC. IBD is diagnosed at a slightly older age than in the West, and there is rarely a second incidence peak as in the West. A positive family history is much less common than in the West, as are extra-intestinal disease manifestations. There are clear ethnic differences in incidence within countries in Asia, and an increased incidence in IBD in migrants from Asia to the West. Research in Asia, an area of rapidly changing IBD epidemiology, may lead to the discovery of critical etiologic factors that lead to the development of IBD. PMID- 22497585 TI - Development and validation of a multidimensional quality of life questionnaire for congenital aural atresia. AB - CONCLUSION: The psychometric characteristics of the Congenital Aural Atresia Questionnaire (CAAQ) are proposed to be reliable and sensitive to determine clinical changes in a patient's quality of life (QOL) and the questionnaire has potential for clinical application. OBJECTIVE: The aim of this study was to develop a quantifiable, self-assessed, and health-related QOL questionnaire for patients with congenital aural atresia and to explore its reliability and validity. METHODS: An initial QOL questionnaire for patients with congenital aural atresia was constructed according to widely used available QOL questionnaires. A total of 140 patients with congenital aural atresia were recruited into this study. After pretest and item sifting, the QOL questionnaire was constructed, and its reliability and validity were evaluated. RESULTS: An 18 item QOL questionnaire for patients with congenital aural atresia was constructed, which included 3 principal domains: symptoms and impact (physical, 8 items), mental status (psychological, 6 items), and social interaction (4 items). The retest reliability was 0.878; split-half reliability coefficient and Cronbach's alpha coefficient were 0.927 and 0.899, respectively. The factor analysis results indicated satisfactory construct validity. PMID- 22497586 TI - Extending the paramedic role in rural Australia: a story of flexibility and innovation. AB - INTRODUCTION: This article identifies trends in the evolving practice of rural paramedics and describes key characteristics, roles and expected outcomes for a Rural Expanded Scope of Practice (RESP) model. METHODS: A multiple case study methodology was employed to examine the evolution of rural paramedic practice. Paramedics, volunteer ambulance officers and other health professionals were interviewed in four rural regions of south-eastern Australia where innovative models of rural paramedic practice were claimed to exist. The research team collected and thematically analysed the data using the filter of a sociological framework throughout 2005 and 2006. RESULTS: The study found that paramedics are increasingly becoming first line primary healthcare providers in small rural communities and developing additional professional responsibilities throughout the cycle of care. CONCLUSIONS: Adoption of the RESP model would mean that paramedics undertake four broad activities as core components of their new role: (1) rural community engagement; (2) emergency response; (3) situated practice; and (4) primary health care. The model's key feature is a capacity to integrate existing paramedic models with other health agencies and health professionals to ensure that paramedic care is part of a seamless system that provides patients with well-organized and high quality care. This expansion of paramedics' scope of practice offers the potential to improve patient care and the general health of rural communities. PMID- 22497587 TI - Controlling the morphology of poly(N-cyanoethylpyrrole). AB - The morphology of poly(N-cyanoethylpyrrole) has been controlled through the polymerization process. This polymer has been prepared by anodic polymerization, chemical oxidative polymerization in emulsion medium, and layer-by-layer templating polymerization. Anodic polymerization using LiClO4 as supporting electrolyte provides compact films, in which the oxidation degree is controlled through the thickness, useful for the microdetection of dopamine. Chemical polymerization using FeCl3 as oxidant agent results in very well-defined microspheres with porous internal structure, which may be useful in molecular loading and transport processes. Finally, the layer-by-layer templating technique produces core-shell particles of controlled size and thickness. Moreover, these core-shell particles can be easily converted in hollow microspheres by removing the template. PMID- 22497588 TI - What is the role of the (1->3)-beta-D-glucan assay in the screening of patients undergoing autologous haematopoietic stem-cell transplantation? AB - The aim of this study is to determine the clinical contribution of (1->3)-beta-d glucan (BDG) screening in the case of patients undergoing autologous haematopoietic stem-cell transplantation (HSCT). The records at our stem-cell transplantation centre were reviewed to identify the patients who underwent autologous HSCT between April 2009 and December 2010. Patients were classified as having proven invasive aspergillosis (IA), probable IA, or possible IA on the basis of the criteria established by the European Organization for Research and Treatment of Cancer and Mycoses Study Group (independent of the BDG results). During the study period, the patients were screened for BDG twice a week from transplant (day 0) until engraftment. Three patients were diagnosed with probable IA and five were diagnosed with possible IA. A total of 354 serum samples from 79 patients who met the study inclusion criteria were used for statistical analysis. At the cut-off value of 80 pg ml(-1) , the sensitivity was 27.2% [95% confidence interval (CI); 7.3-60.6]; specificity, 94.4% (95% CI; 91.3-96.5); positive predictive value, 6.2%; and negative predictive, 93.7%. The clinical contribution of the BDG assay as a screening test was relatively limited in this cohort of patients undergoing autologous HSCT. PMID- 22497589 TI - Production of human milk fat analogue containing docosahexaenoic and arachidonic acids. AB - Human milk fat (HMF) analogue containing docosahexaenoic acid (DHA) and arachidonic acid (ARA) at sn-1,3 positions and palmitic acid (PA) at sn-2 position was produced. Novozym 435 lipase was used to produce palmitic acid enriched hazelnut oil (EHO). EHO was then used to produce the final structured lipid (SL) through interesterification reactions using Lipozyme RM IM. Reaction variables for 3 h reactions were temperature, substrate mole ratio, and ARASCO/DHASCO (A:D) ratio. After statistical analysis of DHA, ARA, total PA, and PA content at sn-2 position, a large-scale production was performed at 60 degrees C, 3:2 A:D ratio, and 1:0.1 substrate mole ratio. For the SL, those results were determined as 57.3 +/- 0.4%, 2.7 +/- 0.0%, 2.4 +/- 0.1%, and 66.1 +/ 2.2%, respectively. Tocopherol contents were 84, 19, 85, and 23 MUg/g oil for alpha-, beta-, gamma-, and delta-tocopherol. Melting range of SL was narrower than that of EHO. Oxidative stability index (OSI) value of SL (0.80 h) was similar to that of EHO (0.88 h). This SL can be used in infant formulas to provide the benefits of ARA and DHA. PMID- 22497590 TI - Fluoride bridges as structure-directing motifs in 3d-4f cluster chemistry. AB - The use of kinetically robust chromium(III) fluorido complexes as synthons for mixed 3d-4f clusters is reported. The tendency toward linear {Cr(III)-F-Ln(III)} units dictates the cluster topology. Specifically, we show that reaction of cis [Cr(III)F(2)(NN)(2)]NO(3) (NN = 1,10-phenanthroline ("phen") or 2,2'-bipyridine ("bpy")) with Ln(NO(3))(3).xH(2)O produces isostructural series of molecular {Ln(2)Cr(2)} squares (1-9) with linear fluoride bridges. In a parallel fashion, fac-[Cr(III)F(3)L], where L = N,N',N"-trimethyl-1,4,7-triazacyclononane ("Me(3)tacn"), reacts with Nd(NO(3))(3).6H(2)O to form a fluoride-centered penta nuclear complex and fac-[Cr(III)F(3)L'], with L' = 1,1,1-tris ((methylamino)methylethane) ("Me(3)tame"), reacts with [Ln(hfac)(3)(H(2)O)(2)] (hfacH = 1,1,1,5,5,5-hexafluoroacetylacetone) to yield an isostructural series of {Ln(3)Cr(2)} (10-14) trigonal bipyramids with no central ligand. The formation of the latter is accompanied by a partial solvolysis of the Cr(III) precursor but without formation of insoluble LnF(3). The magnetic properties of the gadolinium containing clusters allow quantification of fluoride-mediated, antiferromagnetic Gd-Cr exchange interactions of magnitude between 0.14 cm(-1) and 0.71 cm(-1) (H = J(12)S(1).S(2) formalism) and vanishingly small J(Gd-Gd) of 0.06(0) cm(-1). The large spin and small anisotropy together with weak exchange interactions in the {Gd(3)Cr(2)} (11) cluster give rise to a very large magneto-caloric effect of DeltaS(m) = 28.7 J kg(-1) K(-1) (MU(0)H = 90 to 0 kOe). PMID- 22497591 TI - Development of EST-SSRs in Japanese scallop (Mizuhopecten yessoensis) from cDNA libraries. PMID- 22497594 TI - Copy number variation in the genomes of domestic animals. AB - Copy number variation (CNV) might be one of the main contributors to phenotypic diversity and evolutionary adaptation in animals and plants, employing a wide variety of mechanisms, such as gene dosage and transcript structure alterations, to modulate organismal plasticity. In the past 4 years, considerable advances have been made in the characterization of the genomic architecture of CNV in domestic species. First, low-resolution CNV maps were produced for cattle, goat, sheep, pig, dog, chicken, duck and turkey, showing that these structural polymorphisms comprise a significant part of these genomes. Furthermore, CNVs have been associated with several pigmentation (white coat in horse, pig and sheep) and morphological (late feathering and pea comb in chicken) traits, as well as with susceptibility to a wide array of diseases and developmental disorders, for example osteopetrosis, anhidrotic ectodermal dysplasia, copper toxicosis, intersexuality, cone degeneration, periodic fever and dermoid sinus, among others. In the future, development of high-resolution tools for CNV detection and typing combined with the implementation of databases integrating CNV, QTL and gene expression data will be essential to identify and measure the impact of this source of structural variation on the many phenotypes that are relevant to animal breeders and veterinary practitioners. PMID- 22497592 TI - Cationic PAMAM dendrimers disrupt key platelet functions. AB - Poly(amidoamine) (PAMAM) dendrimers have been proposed for a variety of biomedical applications and are increasingly studied as model nanomaterials for such use. The dendritic structure features both modular synthetic control of molecular size and shape and presentation of multiple equivalent terminal groups. These properties make PAMAM dendrimers highly functionalizable, versatile single molecule nanoparticles with a high degree of consistency and low polydispersity. Recent nanotoxicological studies showed that intravenous administration of amine terminated PAMAM dendrimers to mice was lethal, causing a disseminated intravascular coagulation-like condition. To elucidate the mechanisms underlying this coagulopathy, in vitro assessments of platelet functions in contact with PAMAM dendrimers were undertaken. This study demonstrates that cationic G7 PAMAM dendrimers activate platelets and dramatically alter their morphology. These changes to platelet morphology and activation state substantially altered platelet function, including increased aggregation and adherence to surfaces. Surprisingly, dendrimer exposure also attenuated platelet-dependent thrombin generation, indicating that not all platelet functions remained intact. These findings provide additional insight into PAMAM dendrimer effects on blood components and underscore the necessity for further research on the effects and mechanisms of PAMAM-specific and general nanoparticle toxicity in blood. PMID- 22497595 TI - Direct synthesis of B-allyl and B-allenyldiisopinocampheylborane reagents using allyl or propargyl halides and indium metal under Barbier-type conditions. AB - We report the first one-pot process for the asymmetric addition of allyl, methallyl, and propargyl groups to aldehydes and ketones using B chlorodiisopinocampheylborane ((d)DIP-Cl) and indium metal. Under Barbier-type conditions, indium metal was used to generate allyl- and allenylindium intermediates, and subsequent reaction with (d)DIP-Cl successfully promoted the transfer of these groups to boron forming the corresponding chiral borane reagents. The newly formed borane reagents were reacted with aldehydes and ketones to produce the corresponding alcohol products in high yields and up to excellent enantioselectivity (98% ee). This method produced excellent enantioenriched secondary homoallylic alcohols from the allylation and methallylation of benzaldehyde. Using this method, the methallylation and cinnamylation of ketones afforded the highest enantioselectivities, while the propargylation of both aldehydes and ketones provided low enantiomeric excesses. In addition, this procedure provided the first synthesis of B allenyldiisopinocampheylborane, which was characterized by (1)H and (11)B NMR spectroscopy. This is the first example of the direct synthesis of allylboranes that contained substitutions from the corresponding allyl bromide and indium, thereby expanding the utility of the DIP-Cl reagent. Hence, a general and straightforward route to these chiral organoborane reagents in one-pot has been developed along with the asymmetric Barbier-type allylation and propargylation of aldehyde and ketone substrates using these chiral organoborane reagents in subsequent coupling reactions. PMID- 22497593 TI - Characterization of cytochrome b diversity in Chinese domestic horses. AB - Previous mitochondrial DNA (mtDNA) D-loop and microsatellite studies have shown that Chinese horses have multiple maternal origins and high genetic diversity. To better characterize maternal genetic origins and diversity of Chinese domestic horses, we conducted a comprehensive analysis of 407 complete 1140 bp sequences of the horse mitochondrially encoded cytochrome b (CYTB) gene, including 323 horses from 13 Chinese indigenous breeds and 84 reference sequences from GenBank. A total of 114 haplotypes were identified, of which 73 appeared among the 13 Chinese horse breeds. The high mitochondrially encoded cytochrome b haplotypic diversity suggests multiple maternal origins in Chinese horses. PMID- 22497597 TI - Systolic myocardial mechanics in patients with Anderson-Fabry disease with and without left ventricular hypertrophy and in comparison to nonobstructive hypertrophic cardiomyopathy. AB - OBJECTIVES: Anderson-Fabry disease (AFD) is a lysosomal storage disease, which can involve the heart, mimicking hypertrophic cardiomyopathy (HCM). The underlying mechanism of disease in AFD is an infiltrative, diffuse process, whereas HCM is a primary heart muscle condition with patchy distribution, which may prompt differences in myocardial mechanics. The aim of this study was to assess myocardial mechanics in AFD according to the presence of left ventricular hypertrophy (LVH) compared to nonobstructive HCM (NHCM) and healthy controls. METHODS AND RESULTS: We carried out a single-center, retrospective study in a small, genetically confirmed AFD cohort, which was divided into a subgroup with LVH (LVH+, n = 19), and without LVH (LVH-, n = 21). Comparison groups were healthy controls (n = 40) and NHCM patients (n = 19). Vector Velocity Imaging was applied to two-dimensional echocardiography studies for assessment of longitudinal strain (LS), circumferential strain (CS), and base-to-apex CS gradients. AFD LVH+ patients had lower global LS than AFD LVH- patients (-14 +/- 4% vs -17 +/- 3%, P < 0.05), but similarly lowered global CS (-24 +/- 5% vs -22 +/- 5%, P = ns). AFD LVH+ and NHCM had similarly lowered global LS compared to normals, but significantly lower global CS was observed in AFD LVH+ (-24 +/- 5% vs -28 +/- 4%, P < 0.05), whereas it was significantly increased in NHCM (-31 +/- 2% vs -28 +/- 4%, P < 0.05). Unlike NHCM, in both AFD subgroups, patients lost their normal base-to-apex CS gradient. CONCLUSIONS: AFD patients without LVH already show abnormal systolic myocardial mechanics. Relevant differences in myocardial mechanics between AFD patients with LVH compared to NHCM reflect the different underlying mechanisms of disease. PMID- 22497596 TI - Role of p53 family members p73 and p63 in human hematological malignancies. AB - p53, mutated in over half of human cancers and about 13% of all hematological malignancies, maintains genomic integrity and triggers cellular senescence and apoptosis of damaged cells. In contrast to p53, the homologs p73 and p63 play critical roles in development of the central nervous system and skin/limbs, respectively. Moreover, dependent on the context they can exert tumor suppressor activities that cooperate with p53. Unlike p53, p73 and p63 are rarely mutated in cancers. Instead, up-regulation of the anti-apoptotic dominant-negative DeltaNp73 and DeltaNp63 isoforms is the most frequent abnormality in solid cancers. In hematological malignancies the most frequent p73 defect is promoter methylation and loss of expression, associated with unfavorable clinical outcomes. This suggests an essential tumor suppressor role of p73 in blood cells, also supported by genetic mouse models. Many therapeutic approaches aiming to restore p73 activity are currently being investigated. In contrast, the most frequent p63 abnormality is protein overexpression, associated with higher disease grade and poorer prognosis. Surprisingly, although available data are still scarce, the emerging picture is up-regulation of transactivation-competent TAp63 isoforms, suggesting a tumor-promoting role in this context. PMID- 22497598 TI - Ribosomal therapy in patients with pharyngolaryngeal reflux. AB - CONCLUSIONS: Our data confirm the induction of specific and nonspecific immune responses of the upper respiratory tract mucosa and the consequent improvement of its physiology, through an oral ribosomal therapy in patients with pharyngolaryngeal reflux disease (PLRD). OBJECTIVES: The aim of this study was to investigate the efficiency and applicability of oral ribosomal immunotherapy in adult patients with PLRD. METHODS: One hundred adult patients with PLRD were enrolled. The patients were equally divided, at random, into two groups (A and B): group A patients underwent ribosomal prophylaxis with Immucytal(r) (one tablet daily, 8 days a month for 3 months), while group B received a placebo (same dosage for the same period). At the beginning, at the end, and 6 months after the beginning of the therapy, all patients underwent medical history, ENT examination, nasal-pharynx-laryngoscopy with optic fiber, plasma levels of immunoglobulins class E, A, G, M, subjective assessment of symptoms on a 10 cm visual analog scale (VAS), reflux symptoms index, and reflux finding score. RESULTS: At the end and 6 months after the beginning of the treatment, all the patients in group A presented a significant (p < 0.05) improvement of almost all the different items analyzed. PMID- 22497599 TI - Near IR scanning angle total internal reflection Raman spectroscopy at smooth gold films. AB - Total internal reflection (TIR) Raman and reflectivity spectra were collected for nonresonant analytes as a function of incident angle at sapphire or sapphire/smooth 50 nm gold interfaces using 785 nm excitation. For both interfaces, the Raman signal as a function of incident angle is well-modeled by the calculated interfacial mean square electric field (MSEF) relative to the incident field times the thickness of the layer being probed in the Raman measurement (D(RS)). The Raman scatter was reproducibly enhanced at the interface containing a gold film relative to the sapphire interface by a factor of 4.3-4.6 for aqueous pyridine or 2.2-3.7 for neat nitrobenzene, depending on the analyzed vibrational mode. The mechanism for the increased Raman signal is the enhanced MSEF at incident angles where propagating surface plasmons are excited in the metal film. The background from the TIR prism was reduced by 89-95% with the addition of the gold film, and the percent relative uncertainty in peak area was reduced from 15 to 1.7% for the 1347 cm(-1) mode of nitrobenzene. Single monolayers of benzenethiol (S/N = 6.8) and 4-mercaptopyridine (S/N = 16.5) on gold films were measured by TIR Raman spectroscopy with 785 nm excitation (210 mW) without resonant enhancement in 1 min. PMID- 22497600 TI - Microsatellite DNA markers indicate three genetic lineages in East Asian indigenous goat populations. AB - The genetic differentiation and phylogenetic relationships of 18 indigenous goat populations from seven East Asian countries were analysed based on data obtained from 26 microsatellite DNA markers. The mean number of alleles (MNA) per population ranged from 2.5 to 7.6, with an average of 5.8. Genetic variability estimated from MNA and heterozygosity (H(E) and H(O) ) were relatively low in coastal and island populations. A heterozygous deficiency within populations (F(IS) = 0.054, P < 0.001) and total inbreeding (F(IT) = 0.181, P < 0.01) were observed, and genetic differentiation in the populations (F(ST) ) was 13.4%. The results of Bayesian model-based clustering and a neighbour-joining tree based on Nei's genetic distance showed that Asian goat populations could be subdivided into at least the following three genetic clusters: East Asian, Southeast Asian and Mongolian. These results are in close accordance with conventional morphological and geographical classifications and migration history. PMID- 22497601 TI - Absorption, pharmacokinetics and disposition of biodegradable nanoscale preparations. PMID- 22497602 TI - The intracellular pharmacokinetics of terminally capped peptides. AB - With significant progress in delivery technologies, peptides and peptidomimetics are receiving increasing attention as potential therapeutics also for intracellular applications. However, analyses of the intracellular behavior of peptides are a challenge; therefore, knowledge on the intracellular pharmacokinetics of peptides is limited. So far, most research has focused on peptide degradation in the context of antigen processing, rather than on peptide stability. Here, we studied the structure-activity relationship of peptides with respect to intracellular residence time and proteolytic breakdown. The peptides comprised a collection of interaction motifs of SH2 and SH3 domains with different charge but that were of similar size and carried an N-terminal fluorescein moiety. First, we show that electroporation is a highly powerful technique to introduce peptides with different charge and hydrophobicity in uniform yields. Remarkably, the peptides differed strongly in retention of intracellular fluorescence with half-lives ranging from only 1 to more than 10 h. Residence times were greatly increased for retro-inverso peptides, demonstrating that rapid loss of fluorescence is a function of peptide degradation rather than the physicochemical characteristics of the peptide. Differences in proteolytic sensitivity were further confirmed using fluorescence correlation spectroscopy as a separation-free analytical technique to follow degradation in crude cell lysates and also in intact cells. The results provide a straightforward analytical access to a better understanding of the principles of peptide stability inside cells and will therefore greatly assist the development of bioactive peptides. PMID- 22497603 TI - Organophosphazenes. 26. Factors controlling the pathways observed in the reactions of ethynyl lithium reagents with hexafluorocyclotriphosphazene. AB - In contrast to previously studied reactions of ethynyl lithium reagents, the reactions of propynyl and hexynyl lithium with N(3)P(3)F(6) lead to predominantly nongeminal isomers. A modest cis stereo selectivity was observed. The sequential addition of a lithio acetylene reagent which follows a predominately geminal pathway (lithiophenylacetylene) and an aryl lithium reagent (p-propenylphenyl lithium) which follows a predominantly nongeminal pathway were examined. The relative order of addition of the two reagents was interchanged, resulting in a change of reaction pathway demonstrating ring substituent control of the regio and stereo chemical pathways. Hydrogenation of the ethynyl unit in the phosphazene derivatives provides a facile pathway to the difficult to prepare alkylphosphazenes. The chemical shift of the organosubstituted phosphorus center undergoes a remarkably large change (46-47 ppm) on going from the ethynyl to the alkyl derivatives, which reduces the complex (31)P and (19)F NMR spectra of the ethynyl derivatives to easily interpretable first-order spectra, thus allowing for structure assignment. The (13)C NMR data shows that nongeminal regio selectivity increases with the amount of s character on the ethynyl carbon atom attached to the phosphorus center. These observations allow for an understanding of the factors controlling regio and stereo chemical control in the reactions of carbanionic nucleophiles with N(3)P(3)F(6). PMID- 22497604 TI - Configuration-dependent diffusion dynamics of downhill and two-state protein folding. AB - Configuration-dependent diffusion (CDD) is important for protein folding kinetics with small thermodynamic barriers. CDD can be even more crucial in downhill folding without thermodynamic barriers. We explored the CDD of a downhill protein (BBL), and a two-state protein (CI2). The hidden kinetic barriers due to CDD were revealed. The increased ~1 k(B)T kinetic barrier is in line with experimental value based on other fast folding proteins. Compared to that of CI2, the effective free-energy profile of BBL is found to be significantly influenced by CDD, and the kinetics are totally determined by diffusion. These findings are consistent with both earlier bulk and single-molecule fluorescence measurements. In addition, we found the temperature dependence of CDD. We also found that the ratio of folding transition temperature against optimal kinetic folding temperature can provide both a quantitative measure for the underlying landscape topography and an indicator for the possible appearance of downhill folding. Our study can help for a better understanding of the role of diffusion in protein folding dynamics. PMID- 22497605 TI - Whole-genome association study for energy balance and fat/protein ratio in German Holstein bull dams. AB - The metabolic status of cows is important to health and fertility, especially in early lactation, and energy balance (EB) and fat/protein ratio (FPR) are considered as appropriate indicators for metabolic disorders. The aim of this study was to detect SNPs (single nucleotide polymorphisms) associated with EB and FPR in German Holstein bull dams belonging to the research herd Karkendamm. Bull dams were genotyped using the Illumina Bovine SNP 50K Bead chip((r)) comprising 54 001 SNPs. A total of 43 593 SNPs and 586 (EB) and 668 (FPR) bull dams passed the quality control criteria. Phenotypes were deregressed breeding values estimated via random regression animal models for lactation days 11, 20, 30, and 42 for EB and FPR. Whole-genome association analyses were carried out fitting principal components as covariates to adjust for genetic substructure. Permutation tests were applied to estimate genome-wise significance. Across all observed lactation days, 19 SNPs located in four different intervals on chromosomes 1, 14, 16, and 27 were detected. For EB, seven markers across four chromosomes were identified. There was no overlap between markers associated with FPR and EB. SNPs associated with FPR were mostly located in QTL regions for milk production traits, especially in the region of DGAT1, whereas SNPs associated with EB mainly showed positional relationships to previously described QTL regions affecting functional traits, especially fertility. PMID- 22497606 TI - Analysis of differentially expressed proteins involved in hand, foot and mouth disease and normal sera. AB - We implemented 2-D DIGE technology on proteins prepared from serum obtained from children with hand, foot and mouth disease (HFMD) and controls, to study the differentially expressed proteins in control and HFMD serum samples. Proteins found to be differentially expressed were identified with matrix-assisted laser desorption/ionization time-of-flight/ time-of-flight mass spectrometry (MALDI TOF/TOF MS) analysis. We identified 30 proteins from mild HFMD samples and 39 proteins from severe HFMD samples, compared with the normal controls. 25 proteins among them (14 up-regulated and 11 down-regulated proteins) are found in both HFMD groups. Classification analysis and protein-protein interaction map showed that they associate with multiple functional groups, including transporter activity and atalytic activity. These findings build up a comprehensive profile of the HFMD proteome and provide a useful basis for further analysis of the pathogenic mechanism and the regulatory network of HFMD. PMID- 22497607 TI - An interview with Fernanda Laezza, MD, PhD, by Vicki Glaser. PMID- 22497609 TI - Cause matters: a neuropathological challenge to human epilepsies. PMID- 22497610 TI - Long-term epilepsy-associated tumors. AB - The term long-term epilepsy associated tumor (LEAT) encompasses lesions identified in patients investigated for long histories (often 2 years or more) of drug-resistant epilepsy. They are generally slowly growing, low grade, cortically based tumors, more often arising in younger age groups and in many cases exhibit neuronal in addition to glial differentiation. Gangliogliomas and dysembryoplastic neuroepithelial tumors predominate in this group. LEATs are further united by cyto-architectural changes that may be present in the adjacent cortex which have some similarities to developmental focal cortical dysplasias (FCD); these are now grouped as FCD type IIIb in the updated International League Against Epilepsy (ILAE) classification. In the majority of cases, surgical treatments are beneficial from both perspectives of managing the seizures and the tumor. However, in a minority, seizures may recur, tumors may show regrowth or recurrence, and rarely undergo anaplastic progression. Predicting and identifying tumors likely to behave less favorably are key objectives of the neuropathologist. With immunohistochemistry and modern molecular pathology, it is becoming increasingly possible to refine diagnostic groups. Despite this, some LEATs remain difficult to classify, particularly tumors with "non-specific" or diffuse growth patterns. Modification of LEAT classification is inevitable with the goal of unifying terminological criteria applied between centers for accurate clinico-pathological-molecular correlative data to emerge. Finally, establishing the epileptogenic components of LEAT, either within the lesion or perilesional cortex, will elucidate the cellular mechanisms of epileptogenesis, which in turn will guide optimal surgical management of these lesions. PMID- 22497611 TI - Malformations of cortical development. AB - Structural abnormalities of the brain are increasingly recognized in patients that suffer from pharmacoresistant focal epilepsies by applying high-resolution imaging techniques. In many of these patients, epilepsy surgery results in control of seizures. Neuropathologically, a broad spectrum of malformations of cortical development (MCD) is observed in respective surgical brain samples. These samples provide a unique basis to further understand underlying pathomechanisms by molecular approaches and develop improved diagnostics and entirely new therapeutic perspectives. Here we provide a comprehensive description of neuropathological findings, available classification systems as well as molecular mechanisms of MCDs. We emphasize the recently published ILEA classification system for focal cortical dysplasias (FCDs), which are now histopathologically distinguished as types I to III. However, this revised classification system represents a major challenge for molecular neuropathologists, as the underlying pathomechanisms in virtually all FCD entities will need to be specified in detail. The fact that only recently, the mammalian target of rapamycin (mTOR)-antagonist Everolimus has been introduced as a treatment of epilepsies in the context of tuberous sclerosis-associated brain lesions is a striking example of a successful translational "bedside to bench and back" approach. Hopefully, the exciting clinico-pathological developments in the field of MCDs will in short term foster further therapeutic breakthroughs for the frequently associated medically refractory epilepsies. PMID- 22497612 TI - Defining clinico-neuropathological subtypes of mesial temporal lobe epilepsy with hippocampal sclerosis. AB - Hippocampal sclerosis (HS) is the most frequent cause of drug-resistant focal epilepsies (ie, mesial temporal lobe epilepsy with hippocampal sclerosis; mTLE HS), and presents a broad spectrum of electroclinical, structural and molecular pathology patterns. Many patients become drug resistant during the course of the disease, and surgical treatment was proven helpful to achieve seizure control. Hence, up to 40% of patients suffer from early or late surgical failures. Different patterns of hippocampal cell loss, involvement of other mesial temporal structures, as well as temporal neocortex including focal cortical dysplasia, may contribute to the extent of the epileptogenic network and will be discussed. An international consensus is mandatory to clarify terminology use and to reliably distinguish mTLE-HS subtypes. High-resolution imaging with confirmed histopathologic diagnosis, as well as advanced neurophysiologic and molecular genetic measures, will be a powerful tool in the future to address these issues and help to predict each patient's probability to control their epilepsy in mTLE HS conditions. PMID- 22497613 TI - Epileptic encephalitis: the role of the innate and adaptive immune system. AB - Seizures are a prominent clinical feature of encephalitis. Recent data suggest the adaptive as well as innate immune system to be involved directly in the pathomechanism of epileptogenesis. Cytotoxic T-cells and antibody-mediated complement activation are major components of the adaptive immune system, which can induce neurodegeneration, thereby probably contributing to epileptic encephalitis. The innate immune system operates via interleukin-1 and toll-like receptor-associated mechanisms and was shown to play a direct role in epileptogenesis. Here, we review neuropathology hallmarks of various encephalitis conditions such as Rasmussen encephalitis (RE) but also introduce the more recently discovered antibody-associated voltage-gated potassium channel complex (VGKC), N-methyl-D-aspartate receptor (NMDAR) or glutamic acid decarboxylase (GAD) 65 encephalitides. Neuropathological investigations are used to determine specific cellular components and molecular mechanisms used by the immune system to provoke neurodegeneration and to promote epileptogenesis. Based on recent findings, we propose concepts for the stratification of epileptic encephalitis. Knowledge of the role of the innate immunity has already translated into clinical treatment strategies and may help to discover novel drug targets for these epileptic disorders. PMID- 22497614 TI - Cystic tumor in a 4 month old male. AB - Cystic choroid plexus tumor is a rare variant of choroid plexus papilloma (CPP), reported mostly in infants. It is associated with the development of acute hydrocephalus in many cases. The presence of atypical CPP has recently been recognized by the WHO as a grade II tumor with increased mitotic activity. We are reporting a case of a 3.5 month infant who presented with seizures and features of increased intracranial pressure. He was found to have cystic atypical choroid plexus papilloma. PMID- 22497615 TI - 55-year-old female with low back pain. PMID- 22497616 TI - 23-year-old man with a superficial cortical brain tumor. AB - A 23-year-old male presented with a tonic-clonic generalized seizure. Neuroradiological examination revealed a superficial cystic mass with a mural nodule in the right fronto-parietal lobe. Histological and immunohistochemical examination were consistent with a pigmented (melanin producing) desmoplastic ganglioglioma.These tumors have been first described in childhood, one of them displaying melanin deposits. Only twenty cases of non-infantile desmoplastic gangliogliomas have been reported in the literature, none of them pigmented. According to the clinical and histomorphology (including the desmoplastic component) features, the differential diagnosis should include the ganglioglioma, the xanthoastrocytoma pleomorphic (both tumors also with pigmented forms) and the superficial desmoplastic infantile astrocytoma. PMID- 22497617 TI - A 38-year old woman with a dural based lesion. AB - Isolated intracranial xanthogranulomas arising from the dura mater are extremely rare.We present a case of a symptomatic large right frontoparietal dura based intracranial xanthogranuloma in a 38-year-old female. Xanthogranulomas are benign non-Langerhans cell histiocytic lesions. They are frequently described in the skin of infants and children. Extracutaneous manifestations especially in the central nervous system are highly uncommon. Dural xanthogranulomas usually arise in association with familial hypercholesterolemia, with Erdheim Chester disease (ECD), and with Weber-Christian disease. Our case however, had no such associations. In this report, the authors describe the clinical, radiological and microscopic presentation of this case and the differential diagnoses of intracranial xanthogranuloma. PMID- 22497619 TI - Occurrence and distribution study of residues from pesticides applied under controlled conditions in the field during rice processing. AB - The results of an experiment to study the occurrence and distribution of pesticide residues during rice cropping and processing are reported. Four herbicides, nine fungicides, and two insecticides (azoxystrobin, byspiribac sodium, carbendazim, clomazone, difenoconazole, epoxiconazole, isoprothiolane, kresoxim-methyl, propanil, quinclorac, tebuconazole, thiamethoxam, tricyclazole, trifloxystrobin, lambda-cyhalotrin) were applied to an isolated rice-crop plot under controlled conditions, during the 2009-2010 cropping season in Uruguay. Paddy rice was harvested and industrially processed to brown rice, white rice, and rice bran, which were analyzed for pesticide residues using the original QuEChERS methodology and its citrate variation by LC-MS/MS and GC-MS. The distribution of pesticide residues was uneven among the different matrices. Ten different pesticide residues were found in paddy rice, seven in brown rice, and eight in rice bran. The highest concentrations were detected in paddy rice. These results provide information regarding the fate of pesticides in the rice food chain and its safety for consumers. PMID- 22497620 TI - Metabolic profiling reveals metabolic shifts in Arabidopsis plants grown under different light conditions. AB - Plants have tremendous capacity to adjust their morphology, physiology and metabolism in response to changes in growing conditions. Thus, analysis solely of plants grown under constant conditions may give partial or misleading indications of their responses to the fluctuating natural conditions in which they evolved. To obtain data on growth condition-dependent differences in metabolite levels, we compared leaf metabolite profiles of Arabidopsis thaliana growing under three constant laboratory light conditions: 30 [low light (LL)], 300 [normal light (NL)] and 600 [high light (HL)]umol photons m(-2) s(-1). We also shifted plants to the field and followed their metabolite composition for 3 d. Numerous compounds showed light intensity-dependent accumulation, including: many sugars and sugar derivatives (fructose, sucrose, glucose, galactose and raffinose); tricarboxylic acid (TCA) cycle intermediates; and amino acids (ca. 30% of which were more abundant under HL and 60% under LL). However, the patterns differed after shifting NL plants to field conditions. Levels of most identified metabolites (mainly amino acids, sugars and TCA cycle intermediates) rose after 2 h and peaked after 73 h, indicative of a 'biphasic response' and 'circadian' effects. The results provide new insight into metabolomic level mechanisms of plant acclimation, and highlight the role of known protectants under natural conditions. PMID- 22497621 TI - Preventive care's forgotten women: life course, sexuality, and sexual health among homosexually and bisexually active women in France. AB - Although studies show that women who have sex with women (WSW) have poorer sexual health and more limited access to health care for gynecological problems than other women, the social processes giving rise to such health differences have not, so far, been explored. These processes may be formed in response to a dominant social norm, which assigns women to a heterosexual and monogamous sexuality. Based on data from a national random survey of sexuality (N = 6,824), enriched by qualitative interviews with WSW (n = 40), this analysis shows that bisexually active women had similar socio-demographic profiles to heterosexually active women, whereas homosexually active women appeared to be more highly educated than other women and less likely to live as couples than bisexually active women. Bisexually active women had more diversified sexual trajectories and sexual networks than other women. Chlamydia prevalence was found to be higher among bisexually active women, and homosexually active women reported fewer medical consultations for gynecological reasons. These analyses highlight the need to deconstruct the binary classification of homosexual versus heterosexual women. Because of constraint by the monogamous heterosexual norm, bisexually active women were less likely to be tested for sexually transmitted infections, and homosexually active women were less likely to have had gynecological follow ups. PMID- 22497622 TI - Differential mRNA expression and promoter methylation status of SYCP3 gene in testes of yaks and cattle-yaks. AB - Synaptonemal complex protein 3 (SYCP3) is a DNA-binding protein located on the lateral elements of the synaptonemal complex. This protein plays an important role in homologous chromosome pairing and is necessary for male meiosis of spermatogenesis. To further understand the SYCP3 gene function and its relationship to cattle-yak male sterility, we investigated the characteristics of the bovine SYCP3 (bSYCP3) gene as well as its transcription level and epigenetic modification status. The bSYCP3 gene encodes a 225-amino acid protein with the Cor1 motif and two coiled-coil-forming regions, homologous with other mammals (59 77% identity overall). Real-time PCR analysis indicated that the expression level of bSYCP3 mRNA in yak testes was significantly higher than that in cattle-yak (p < 0.05). The methylation level of the bSYCP3 promoter (mainly 7th, 13th and 17th CpG sites) in cattle-yaks (40%) was significantly higher than that in yaks (0%) (p < 0.05). This suggests that bSYCP3 plays an important role in meiosis of bovine spermatogenesis; further, interspecific hybridization between yak and cattle might influence bSYCP3 gene expression in cattle-yak testes, which might be influenced by bSYCP3 gene promoter methylation. PMID- 22497623 TI - Animal-level factors affecting ovarian function in Bos indicus heifers treated to synchronize ovulation with intravaginal progesterone-releasing devices and oestradiol benzoate. AB - The primary objective of this study was to investigate the impact of animal-level factors including energy balance and environmental/management stress, on the ovarian function of Bos indicus heifers treated to synchronize ovulation. Two year-old Brahman (BN) (n = 30) and BN-cross (n = 34) heifers were randomly allocated to three intravaginal progesterone-releasing device (IPRD) treatment groups: (i) standard-dose IPRD [Cue-Mate((r)) (CM) 1.56 g; n = 17]; (ii) half dose IPRD [0.78 g progesterone (P(4)); CM 0.78 g; n = 15]; (iii) half-dose IPRD + 300 IU equine chorionic gonadotrophin at IPRD removal (CM 0.78 g + G; n = 14); (iv) and a control group, 2* PGF(2alpha) [500 MUg prostaglandin F(2alpha) (PGF(2alpha))] on Day -16 and -2 (n = 18). Intravaginal progesterone-releasing device-treated heifers received 250 MUg PGF(2alpha) at IPRD insertion (Day -10) and IPRD removal (Day -2) and 1 mg oestradiol benzoate on Day -10 and -1. Heifers were managed in a small feedlot and fed a defined ration. Ovarian function was evaluated by ultrasonography and plasma P(4) throughout the synchronized and return cycles. Energy balance was evaluated using plasma insulin-like growth factor 1 (IGF-I) and glucose concentrations. The impact of environmental stressors was evaluated using plasma cortisol concentration. Heifers that had normal ovarian function had significantly higher IGF-I concentrations at commencement of the experiment (p = 0.008) and significantly higher plasma glucose concentrations at Day -2 (p = 0.040) and Day 4 (p = 0.043), than heifers with abnormal ovarian function. There was no difference between the mean pre ovulatory cortisol concentrations of heifers that ovulated or did not ovulate. However, heifers that ovulated had higher cortisol concentrations at Day 4 (p = 0.056) and 6 (p = 0.026) after ovulation than heifers that did not ovulate. PMID- 22497624 TI - Effects of cryopreservation on the meiotic spindle, cortical granule distribution and development of rabbit oocytes. AB - Although much progress has been made in oocyte cryopreservation since 1971, live offspring have only been obtained in a few species and in rabbits. The aim of our study was to evaluate the effect of vitrification and slow freezing on the meiotic spindle, cortical granule (CG) distribution and their developmental competence. Oocytes were vitrified in 16.84% ethylene glycol, 12.86% formamide, 22.3% dimethyl sulphoxide, 7% PVP and 1% of synthetic ice blockers using Cryotop as device or slow freezing in 1.5 m PROH and 0.2 m sucrose in 0.25 ml sterile French mini straws. Meiotic spindle and CG distribution were assessed using a confocal laser-scanning microscope. To determine oocyte competence, in vitro development of oocytes from each cryopreservation procedure was assessed using parthenogenesis activation. Our data showed that oocytes were significantly affected by both cryopreservation procedures. In particular, meiotic spindle organization was dramatically altered after cryopreservation. Oocytes with peripheral CG distribution have a better chance of survival in cryopreservation after slow-freezing procedures compared to vitrification. In addition, slow freezing of oocytes led to higher cleavage and blastocyst rates compared to vitrification. Our data showed that, in rabbits, structural alterations are more evident in vitrified oocytes than in slow-frozen oocytes, probably as a consequence of sensitivity to high levels of cryoprotectants. Slow-freezing method is currently the recommended option for rabbit oocyte cryopreservation. PMID- 22497625 TI - Tetrathyridiosis and tubulopapillary carcinoma occurring simultaneously in the mammary gland of a cat. AB - This report describes a case of tubulopapillary carcinoma and concomitant tetrathyridiosis in a 5-year-old female cross-breed cat. A mass was located at right inguinal mammary gland and measured 5.5 * 5 * 3 cm in size with multilobulated to solid appearance. The cut surface of the mass had a centrally located large cyst (approximately 3 cm in diameter) surrounded by other smaller cysts. Histologically, the mass was diagnosed as tubulopapillary mammary carcinoma, intensely positive for AE1/AE3 cytokeratins. The cyst found at post mortem examination was tetrathyridia of Mesocestoides species surrounded by inflammatory cells and a loose fibrous capsule. To the authors' best knowledge, this is the first description of a tubulopapillary carcinoma and tetrathyridiosis found simultaneously in the mammary gland of a cat. PMID- 22497626 TI - Clinicopathologic study of 1176 salivary gland tumors in a Chinese population: experience of one cancer center 1997-2007. AB - CONCLUSION: Chinese patients have a higher rate of lymphoepithelial carcinoma (LEC) and salivary duct carcinoma (SDC). Comprehensive use of diagnostic modalities, neck dissection, and postoperative radiation will improve the treatment results for salivary gland tumors (SGTs). OBJECTIVES: To study the clinicopathological characteristics of SGTs in a Chinese population. METHODS: The records of SGT patients operated in a tertiary cancer hospital of China were retrieved. RESULTS: From December 1997 to December 2007, 289 malignant and 887 benign SGTs were operated at Cancer Hospital, Shanghai, China. Pleomorphic adenoma and Warthin's tumor were the most common types of SGT. Mucoepidermoid carcinoma (24.6% of malignant cases) and adenoid cystic carcinoma (18.0%) were the most frequent malignant cases, followed by acinic cell carcinoma (12.1%), LEC (9.7%), and SDC (9.3%). The sensitivity and specificity of ultrasound scan, fine needle aspiration biopsy, and frozen section were 58.3 and 88.6%, 87.2 and 96.7%, 86.9 and 99.6%, respectively. Neck dissections and postoperative radiation were carried out for 48.6 and 48.0% of carcinomas, respectively. The percentage of tumors by pathologic TNM stage were 23.7% for stage I, 32.9% for stage II, 17.3% for stage III, and 26.1% for stage IV. The 5-year overall survival rate was 88.0%. PMID- 22497627 TI - Missense SNP of the MC1R gene is associated with plumage variation in the Gyrfalcon (Falco rusticolus). AB - A single nucleotide polymorphism (MC1R: c.376A>G) in the MC1R gene was found to be highly correlated with pigment phenotype in the Gyrfalcon. Homozygous genotypes c.376GG and c.376AA were found to dominate the extreme white and dark plumage types respectively, and heterozygotes occurred mainly in intermediate phenotypes. However, some heterozygotes were associated with extreme phenotypes, indicating that melanism/albinism might also involve other loci. PMID- 22497628 TI - Molecular genetic characterization of ovine CSN1S2 variants C and D reveal further important variability within CSN1S2. AB - Within this study, the recently identified ovine CSN1S2 variants C and D were characterized at the molecular genetic level. Sequencing of the cDNA and of parts of the DNA identified several sequence differences within CSN1S2*C and D in comparison to CSN1S2*A and B. CSN1S2*C is characterized by two non-synonymous single nucleotide polymorphisms (SNPs) within exon 7 (c.178A>G, c.187G>T) leading to the amino acid substitutions p.Val45Ile and p.Ala48Ser. CSN1S2*D is caused by the SNP c.183G>C, leading to an amino acid replacement at position 46 (p.Arg46Ser). A very common c.527G>A-SNP within exon 15, resulting in the amino acid substitution p.Arg161His and producing the new variant CSN1S2*G, not detectable by isoelectric focusing and previously misidentified as CSN1S2*A, was also identified. On the basis of the identified sequence differences, a new nomenclature is proposed and a possible phylogenetic pathway shown for ovine CSN1S2 variants. PMID- 22497629 TI - Comparison of SNPs and microsatellites for assessing the genetic structure of chicken populations. AB - Many studies in human genetics compare informativeness of single-nucleotide polymorphisms (SNPs) and microsatellites (single sequence repeats; SSR) in genome scans, but it is difficult to transfer the results directly to livestock because of different population structures. The aim of this study was to determine the number of SNPs needed to obtain the same differentiation power as with a given standard set of microsatellites. Eight chicken breeds were genotyped for 29 SSRs and 9216 SNPs. After filtering, only 2931 SNPs remained. The differentiation power was evaluated using two methods: partitioning of the Euclidean distance matrix based on a principal component analysis (PCA) and a Bayesian model-based clustering approach. Generally, with PCA-based partitioning, 70 SNPs provide a comparable resolution to 29 SSRs. In model-based clustering, the similarity coefficient showed significantly higher values between repeated runs for SNPs compared to SSRs. For the membership coefficients, reflecting the proportion to which a fraction segment of the genome belongs to the ith cluster, the highest values were obtained for 29 SSRs and 100 SNPs respectively. With a low number of loci (29 SSRs or <=100 SNPs), neither marker types could detect the admixture in the Godollo Nhx population. Using more than 250 SNPs allowed a more detailed insight into the genetic architecture. Thus, the admixed population could be detected. It is concluded that breed differentiation studies will substantially gain power even with moderate numbers of SNPs. PMID- 22497630 TI - S-carboxymethyl-L-cysteine. AB - S-carboxymethyl-L-cysteine, the side-chain carboxymethyl derivative of the sulfur containing amino acid, cysteine, has been known and available for almost 80 years. During this time, it has been put to a variety of uses, but it is within the field of respiratory medicine that, presently, it has found a clinical niche. Early studies indicated that this compound underwent a rather simplistic, predictable pattern of metabolism, whereas later investigations alluded to more subtle interactions with the pathways of intermediary metabolism, as may be expected for an amino acid derivative. In addition, suggestions of polymorphic influences and circadian rhythms within metabolic profiles have emerged. These latter factors may underlie the conflicting reports regarding the therapeutic efficacy of this compound: that it appears to work well in some patients, but has no measurable effects in others. The relevant literature pertaining to the fate of this compound within living systems has been reviewed and a comprehensive precis advanced. Hopefully, this article will serve as a vade mecum for those interested in S-carboxymethyl-L-cysteine and as a catalyst for future research. PMID- 22497631 TI - Chemoprevention, chemotherapy, and chemoresistance in colorectal cancer. AB - Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in industrialized countries. Chemoprevention is a promising approach, but studies demonstrating their usefulness in large populations are still needed. Among several compounds with chemopreventive ability, cyclooxygenase inhibitors have received particular attention. However, these agents are not without side effects, which must be weighed against their beneficial actions. Early diagnosis is critical in the management of CRC patients, because, in early stages, surgery is curative in >90% of cases. If diagnosis occurs at stages II and III, which is often the case, neoadjuvant chemotherapy and radiotherapy before surgery are, in a few cases, recommended. Because of the high risk of recurrence in advanced cancers, chemotherapy is maintained after tumor resection. Chemotherapy is also indicated when the patient has metastases and in advanced cancer located in the rectum. In the last decade, the use of anticancer drugs in monotherapy or in combined regimens has markedly increased the survival of patients with CRC at stages III and IV. Although the rate of success is higher than in other gastrointestinal tumors, adverse effects and development of chemoresistance are important limitations to pharmacological therapy. Genetic profiling regarding mechanisms of chemoresistance are needed to carry out individualized prediction of the lack of effectiveness of pharmacological regimens. This would minimize side effects and prevent the selection of aggressive, cross-resistant clones, as well as avoiding undesirable delays in the use of the most efficient therapeutic approaches to treat these patients. PMID- 22497632 TI - Selecting a prognostic renal surrogate for patients with hepatocellular carcinoma undergoing transarterial chemoembolization. AB - BACKGROUND AND AIM: Renal insufficiency (RI) often coexists with hepatocellular carcinoma (HCC) and predicts a poor outcome in patients receiving transarterial chemoembolization (TACE). The modification of diet in renal disease (MDRD) and chronic kidney disease epidemiology collaboration (CKD-EPI) equations are used to provide estimated glomerular filtration rate (eGFR). This study aimed to determine a prognsotic renal surrogate for outcome prediction in HCC patients receiving TACE. METHODS: A total of 684 patients with HCC undergoing TACE were retrospectively analyzed. The prognostic ability between the MDRD and CKD-EPI equation was compared by the Akaike information criterion (AIC). RESULTS: Patients were categorized by eGFR into > 60, 30-60 and < 30 mL/min per 1.73 m(2) (equivalent to CKD stages 1-2, 3, and 4-5, respectively) groups. The eGFR generated by the MDRD equation had a better predictive accuracy by having a lower AIC score (3234.5) compared to the CKD-EPI equation (3236.7). The adjusted risk ratio for patients with eGFR 30-60 mL/min per 1.73 m(2) by the MDRD was 1.313 (P = 0.041) compared with patients with eGFR > 60 mL/min per 1.73 m(2) in the multivariate Cox model. The eGFR defined by the MDRD equation consistently had better prognostic ability when patients were stratified by the Child-Turcotte Pugh score of 5 and > 5 and Cancer of the Liver Italian Program score 0 to 1 and > 1. CONCLUSIONS: The eGFR according the MDRD equation may provide better prognostic accuracy than the CKD-EPI equation independent of liver functional reserve and tumor staging, and is a more feasible renal surrogate for outcome prediction in CKD stage 1-3 HCC patients receiving TACE. PMID- 22497633 TI - Electing a candidate: a speculative history of the bacterial phylum OP10. AB - In 1998, a cultivation-independent survey of the microbial community in Obsidian Pool, Yellowstone National Park, detected 12 new phyla within the Domain Bacteria. These were dubbed 'candidate divisions' OP1 to OP12. Since that time the OP10 candidate division has been commonly detected in various environments, usually as part of the rare biosphere, but occasionally as a predominant community component. Based on 16S rRNA gene phylogeny, OP10 comprises at least 12 class-level subdivisions. However, despite this broad ecological and evolutionary diversity, all OP10 bacteria have eluded cultivation until recently. In 2011, two reference species of OP10 were taxonomically validated, removing the phylum from its 'candidate' status. Construction of a highly resolved phylogeny based on 29 universally conserved genes verifies its standing as a unique bacterial phylum. In the following paper we summarize what is known and what is suspected about the newest described bacterial phylum, the Armatimonadetes. PMID- 22497634 TI - Do women notice the effect of childbirth-related pelvic floor trauma? AB - INTRODUCTION: In 10-30% of women, vaginal birth results in levator ani tears ('avulsion') that are associated with pelvic floor dysfunction in later life. We hypothesised that women notice reduced pelvic floor muscle strength after childbirth, especially those with avulsion. METHODS: This is a secondary analysis of two perinatal studies. At 3-6 months postpartum, women were asked to estimate pelvic floor muscle strength relative to antepartum strength. Translabial ultrasound was performed to determine pelvic floor structure and function. RESULTS: Five hundred and thirteen primiparous women were seen at a median of 129 days after delivery of a singleton at a mean gestation of 40 weeks. At follow-up, 481 were able to rate pelvic floor strength (mean 89%). This reduction was associated with delivery mode (P < 0.001), episiotomy (P = 0.01), perineal tears (P = 0.025) and avulsion (n = 45, P = 0.04). CONCLUSION: After the birth of a first child, women notice a significant reduction in pelvic floor muscle strength, which is associated with delivery mode as well as perineal and pelvic floor muscle trauma. SUMMARY: Many women notice reduced pelvic floor function after childbirth, especially those who have suffered an avulsion of the puborectalis muscle. PMID- 22497636 TI - Evaluation of the porcine ACSL4 gene as a candidate gene for meat quality traits in pigs. AB - Long-chain acyl-CoA synthetase (ACSL) family members catalyse the formation of long-chain acyl-CoA from fatty acid, ATP and CoA, thus playing an important role in both de novo lipid synthesis and fatty acid catabolism. Previous studies in our group evaluated ACSL4 as a positional candidate gene for quantitative trait loci located on chromosome X in an Iberian * Landrace cross. A DQ144454:c.2645G>A SNP located in the 3' untranslated region of the ACSL4 gene was associated with the percentages of oleic and monounsaturated fatty acids. The aim of the present work was to evaluate the functional implication of this genetic variant. An expression analysis was performed for 120 individuals with different genotypes for the DQ144454:c.2645G>A polymorphism using real-time quantitative PCR. Differences between genotypes were identified in liver, with the ACSL4 mRNA expression levels higher in animals with the G allele than in animals with the A allele. A SNP genome-wide association study with ACSL4 relative expression levels showed significant positions on chromosomes 6 and 12. Description of positional candidate genes for ACSL4 regulation on chromosomes 6 and 12 is provided. PMID- 22497637 TI - Association between a polymorphism in the IGF2 gene and finishing weight in a commercial rabbit population. PMID- 22497638 TI - Dental care plan assessment using the CAHPS Dental Plan Survey. AB - OBJECTIVES: The performance of a recently developed survey instrument that inquires about patients' experiences with the receipt of dental care was examined to evaluate its potential utility as a patient-reported outcome measure for dental care plans. METHODS: Individuals with dental insurance (n = 1,216) were surveyed using the Consumer Assessment of Health Care Providers and Systems (CAHPS) Dental Plan Survey. The instrument's pre-established composite and rating scores were compared across dental insurance carriers (6 most common and all others combined) using ANOVA. In addition, each score was analyzed separately using multivariate regression with respondent and plan characteristics as independent variables. RESULTS: There was significant differentiation among dental insurance carriers for three of the six scores (dental care composite, access to care composite, and dentist rating). Several respondent characteristics were associated with higher scores, including age, race, income level, and oral health self-rating. Having a choice of dental plans, and years with one's dental plan were associated with higher dental plan ratings, while having to find a new dentist to use the plan tended to lower all scores except the cost and services composite. CONCLUSIONS: The results reported here reflect differences among dental insurance carriers, rather than among the many different dental plans offered by those carriers. Nevertheless, the CAHPS instrument scores reflected differences among patients' experiences (composite scores) and ratings (rating scores) across carriers, suggesting both that the instrument should be a useful tool for assessing patient-reported outcomes, and that comparisons of these outcomes should control for respondent characteristics as well as specific plan characteristics. PMID- 22497639 TI - Open-type congenital cholesteatoma: differential diagnosis for conductive hearing loss with a normal tympanic membrane. AB - CONCLUSION: In patients with progressive conductive hearing loss and a normal tympanic membrane (TM), and with soft tissue density in the middle ear cavity (MEC) on temporal bone computed tomography (TBCT) scan, open-type congenital cholesteatoma (OCC) should be highly suspected and a proper surgical plan that includes mastoid exploration and second-stage operation is required. OBJECTIVE: The clinical presentation of OCC is very similar to congenital ossicular anomaly (COA) presenting with a conductive hearing loss with intact TM. Therefore, it is challenging to make a correct preoperative diagnosis in patients with OCC. We evaluated the clinical characteristics of OCC compared with those of COA to find diagnostic clues useful in diagnosis of OCC. METHODS: The medical records of 12 patients with surgically proven OCC and 14 patients with surgically proven COA were reviewed for demographic data, otologic history, preoperative TBCT findings, intraoperative findings, and pre- and postoperative audiologic data. RESULTS: There was no difference between OCC and COA based on demographic data, preoperative hearing, and ossicular status on TBCT. However, the presence of progressive hearing loss, soft tissue density in the MEC on TBCT scan, and the need for mastoid surgery and second-stage operation were significantly more frequent in OCC patients. PMID- 22497640 TI - 1q21 amplification with additional genetic abnormalities but not isolated 1q21 gain is a negative prognostic factor in newly diagnosed patients with multiple myeloma treated with thalidomide-based regimens. PMID- 22497641 TI - Velocity vector imaging fails to quantify regional myocardial dysfunction in a mouse model of isoprenaline-induced cardiotoxicity. AB - BACKGROUND: Regional myocardial deformation patterns are important in a variety of cardiac diseases, including stress-induced cardiomyopathy. Velocity-vector based imaging is a speckle-tracking echocardiography (STE)-based algorithm that has been shown to allow in-depth cardiac phenotyping in humans. Regional posterior wall myocardial dysfunction occurs during severe isoprenaline stress in mice. We have previously shown that regional posterior wall end-systolic transmural strain decreases after severe isoprenaline toxicity in mice. We hypothesize that STE can detect and further quantify these perturbations. METHODS AND RESULTS: Twenty-three mice underwent echocardiographic examination using the VEVO2100 system. Regional transmural radial strain and strain rate were calculated in both parasternal short-axis and parasternal long-axis cine loops using the VisualSonics VEVO 2100 velocity vector imaging (VVI) STE algorithm. Eight C57BL/6 mice underwent baseline echocardiographic examination using the VisualSonics VEVO 770 system, which can acquire >1,000 frames/s cine loops. In a parasternal short-axis cine loop, the heart was divided into six segments, and regional fractional wall thickening (FWT) was assessed manually. The same protocols were also performed 90 minutes post 400 mg/kg intraperitoneally isoprenaline. Regional myocardial FWT is uniform at baseline but increases significantly in anterolateral segments, whereas it decreases significantly in posterior segments (P < 0.05). A similar pattern is seen using the VVI algorithm although the variance is larger, and differences are smaller and fail to reach significance. CONCLUSIONS: VVI is less sensitive in detecting regional perturbations in myocardial function than manual tracing, possibly due to the low frame rate in the cine loops used. PMID- 22497642 TI - Biofilters for stormwater harvesting: understanding the treatment performance of key metals that pose a risk for water use. AB - A large-scale stormwater biofilter column study was conducted to evaluate the impact of design configurations and operating conditions on metal removal for stormwater harvesting and protection of aquatic ecosystems. The following factors were tested over 8 months of operation: vegetation selection (plant species), filter media type, filter media depth, inflow volume (loading rate), and inflow pollutant concentrations. Operational time was also integrated to evaluate treatment performance over time. Vegetation and filter type were found to be significant factors for treatment of metals. A larger filter media depth resulted in increased outflow concentrations of iron, aluminum, chromium, zinc, and lead, likely due to leaching and mobilization of metals within the media. Treatment of all metals except aluminum and iron was generally satisfactory with respect to drinking water quality standards, while all metals met standards for irrigation. However, it was shown that biofilters could be optimized for removal of iron to meet the required drinking water standards. Biofilters were generally shown to be resilient to variations in operating conditions and demonstrated satisfactory removal of metals for stormwater-harvesting purposes. PMID- 22497643 TI - Common bile duct stones in infancy: a medical approach. AB - Symptomatic choledocholithiasis in infancy is not common. It usually presents with jaundice and acholic stools and is diagnosed on abdominal ultrasonography. Favourable outcome of conservative management has been reported, but specific management guidelines are not well defined in the literature. We describe three cases using a combination of ursodeoxycholic acid and antibiotics as a treatment paradigm, which could potentially negate more invasive treatment. All three patients had ultrasonography proven choledocholithiasis with concomitant obstructive liver function test. They were treated with a combination of ursodeoxycolic acid and antibiotics. Patient 1 had an Escherichia coli urinary tract infection and was treated with oral bactrim. Intravenous amoxicillin, gentamicin and metronidazole were used for the other two patients. All three patients responded with a return to normal-coloured stools within 48 h of combination treatment. Repeat ultrasonography done within 11 days after the first study for all three patients confirmed complete resolution of choledocholithiasis. It is postulated that this improvement is as a result of a reduction in inflammation and oedema, associated with a low-grade cholangitis, following antibiotic treatment. This is coupled with improved bile flow with ursodeoxycholic acid therapy. The findings suggest the potential application of this safe, non-invasive therapeutic strategy as initial management in infants with this condition. A follow-up prospective randomised controlled trial may be an answer to prove the validity of this observation but due to the rarity of this problem, it would be a challenge to recruit sufficient number of patients. PMID- 22497644 TI - Ursodeoxycholic acid protects colon cancer HCT116 cells from deoxycholic acid induced apoptosis by inhibiting apoptosome formation. AB - We previously demonstrated that ursodeoxycholic acid (UDC) requires prolonged (>=5 h) preincubation to exhibit effective protection of colon cancer HCT116 cells from deoxycholic acid (DC)-induced apoptosis. Although UDC diminished DC mediated caspase-9 activation, cytochrome c release from the mitochondria was not inhibited, indicating that UDC acts on the steps of caspase-9 activation. In the present study, therefore, we investigated the effects of UDC on the factors involved in caspase-9 activation. We found that UDC had no significant effect on the expression of antiapoptotic XIAP. Furthermore, UDC did not affect the expression or release of proapoptotic Smac/DIABLO, or the association of XIAP and Smac/DIABLO. In contrast, association of Apaf-1 and caspase-9 stimulated by 500 MUM DC was inhibited by UDC pretreatment. Although UDC caused remarkable activation of Akt/PKB, phosphatidylinositol-3-kinase (PI3K) inhibitor did not significantly reduce UDC-mediated cytoprotection. Furthermore, phosphorylation of threonine residues on caspase-9 after UDC pretreatment could not be detected. UDC mediated cytoprotection was independent of the MAPK pathway, and cyclic AMP (cAMP) analogue did not inhibit DC-induced apoptosis. Our results indicate that UDC protects colon cancer cells from apoptosis induced by hydrophobic bile acids, by inhibiting apoptosome formation independently of the survival signals mediated by the PI3K, MAPK, or cAMP pathways. PMID- 22497645 TI - Atypical fractures associated with bisphosphonate use post-renal transplantation. AB - Bone disease is a major cause of morbidity post renal transplantation. The authors present a case of adynamic bone disease and atypical fractures associated with the use of bisphosphonates following renal transplantation. The uncertain role of parathyroidectomy and bone mineral density scans is also reviewed. PMID- 22497646 TI - Disseminated microsporidiosis with Encephalitozoon species in a renal transplant recipient. AB - To our knowledge, 5 cases of disseminated microsporidiosis with Encephalitozoon species have been reported worldwide in transplant recipients. George et al. present the first such case in Australia, to be reported and treated with good clinical recovery. PMID- 22497647 TI - Hidden perils in a highly sensitized kidney transplant recipient. AB - Highly sensitised patients are at increased risk for antibody mediated rejection (AMR) and reduced graft survival. Highly sensitive assays for detecting recipient preformed anti-HLA antibodies have been developed and identify high immunological risk donors. A 62yo male with end stage renal failure secondary to glomerulonephritis received a T-cell crossmatch negative, deceased donor, renal transplant mismatched at 3 of 6 HLA loci. A donor specific antibody (DSAb) to DR17 (MFI 2073) was present. Given his advancing age, multiple medical comorbidities and broad HLA sensitisation the transplant was accepted, however, shortly before transplantation two atypical results were made available. Firstly a B-cell crossmatch was performed and found to be negative in current serum but strongly positive in peak serum, secondly a further potential DSAb was predicted based on linkage disequilibrium with known donor HLA typing. The donor HLA typing would not be clarified until after the transplant. Despite the increased risk of AMR the transplant proceeded with pre-emptive plasma exchange. The patient developed severe AMR requiring extensive therapy. Incomplete prospective donor HLA typing can generate uncertainty in the interpretation of the virtual crossmatch performed for deceased donor transplants. This may result in clinically relevant sequelae. Advances in antibody detection techniques need to be matched by timely donor HLA typing for its full benefit to be realised. PMID- 22497648 TI - Acute irreversible oxalate nephropathy in a lung transplant recipient treated successfully with a renal transplant. AB - We report a 29 year old male cystic fibrosis patient with end stage lung disease and normal renal function who underwent a sequential double lung transplant. Medical history included: an ileal resection and pancreatic exocrine dysfunction. The postoperative period was complicated with haemorrhage and repeat surgery, requiring multiple blood transfusions and extensive antibiotic cover. Pancreatic supplements were interrupted. Acute renal failure attributed to haemodynamically mediated acute tubular necrosis was managed expectantly. He remained dialysis dependent 8 weeks post surgery and was maintained on triple immunosuppression with tacrolimus, mycophenolate and prednisolone. A DTPA study was consistent with ATN. Renal biopsy revealed features consistent with tubular injury due to acute oxalate nephropathy (AON). Further biochemical characterization excluded primary hyperoxaluria but confirmed increased 24 hour urinary oxalate. He was maintained on enhanced frequency HDF and subsequently received an uncomplicated live related renal transplant 10 months post lung transplant with only additional basiliximab. Calcium carbonate was continued to manage post transplant hyperoxaluria and an early renal biopsy excluded recurrent oxalate injury. Enteric hyperoxaluria due to malabsorption in patients with CF especially with ileal resection, in addition to loss of gut Oxalobacter formigenes due to prolonged antimicrobials, increases the risk of AON. Increased awareness of this condition and screening prior to lung transplant is recommended. PMID- 22497649 TI - Recurrence of anti-neutrophil cytoplasmic antibody vasculitis in the kidney allograft. AB - We report a case of recurrent anti-cytoplasmic neutrophil antibody (ANCA) associated vasculitis post kidney transplantation. A 60-year-old woman underwent uncomplicated deceased-donor kidney transplantation for end-stage renal disease (ESRD) secondary to myeloperoxidase-specific ANCA-associated vasculitis, after six years of haemodialysis, and clinical remission. Immunosuppression was with tacrolimus/mycophenolate and prednisolone after basiliximab induction therapy. Five weeks post-transplantation, an allograft biopsy, done for a rising creatinine and glomerular haematuria, revealed pauci-immune crescentic glomerulonephritis. This was treated with pulse methylprednisolone, increase in maintenance prednisolone, 7 sessions of plasma exchange, and replacement of mycophenolate with cyclophosphamide. Tacrolimus was continued throughout. After 3 months of therapy a repeat allograft biopsy showed quiescent vasculitis. The cyclophosphamide was then ceased, and mycophenolate reinstituted. The patient has maintained clinical and histological stability. Reported rates of ANCA-associated vasculitis recurrence post-kidney transplantation have varied but are low compared with other types of glomerulonephritis and seemed to have further declined in the era of modern immunosuppression. Given the low recurrence rate and excellent outcomes in suitable patients, kidney transplantation remains the optimal form of renal replacement therapy for ESRD due to ANCA-associated vasculitis. Whilst re-introduction of cyclophosphamide has been the mainstay of therapy, additional reported successful therapeutic strategies have included pulse methylprednisolone, plasma exchange and rituximab. Further study on the most effective and safest treatment options would be of use given the current paucity of data in this area. PMID- 22497652 TI - Theory of the molecular transfer model for proteins with applications to the folding of the src-SH3 domain. AB - A theoretical basis for the molecular transfer model (MTM), which takes into account the effects of denaturants by combining experimental data and molecular models for proteins, is provided. We show that the MTM is a mean field-like model that implicitly takes into account denaturant-induced many body interactions. The MTM in conjunction with the coarse-grained self organized polymer model with side chains (SOP-SC) for polypeptide chains is used to simulate the folding of the src SH3 domain as a function of temperature (T) and guanidine hydrochloride (GdmCl) concentration [C]. Besides reproducing the thermodynamic aspects of SH3 folding, the SOP-SC also captures the cooperativity of the folding transitions. A number of experimentally testable predictions are also made. First, we predict that the melting temperature T(m)([C]) decreases linearly as [C] increases. Second, we show that the midpoints C(m,i) and melting temperatures T(m,i) at which individual residues acquire 50% of their native contacts differ from the global midpoint (C(m) ~ 2.5 M) and melting temperature (T(m) = 355 K) at which the folded and unfolded states coexist. Dispersion in C(m,i) is greater than that found for T(m,i). Third, folding kinetics at [C] = 0 M shows that the acquisition of contacts between all the secondary structural elements and global folding occur nearly simultaneously. Finally, from the free energy profiles as a function of the structural overlap function and the radius of gyration of the protein, we find that at a fixed T the transition state moves toward the folded state as [C] increases in accord with the Hammond postulate. In contrast, we predict that along the locus of points T(m)([C]) the location of the transition state does not change. The theory and the models used here are sufficiently general for studying the folding of other single domain proteins. PMID- 22497653 TI - Environmental and genetical aspects of the link between pregnancy, birth size, and type 2 diabetes. AB - Exposure of the fetus to the intrauterine milieu can have profound effects on the health of the offspring in adulthood. These observations are highly reproducible in many populations worldwide although the mechanisms behind them remain elusive. The 'thrifty phenotype' hypothesis proposes that poor fetal nutrition leads to programming of metabolism and an adult phenotype that is adapted to poor but not plentiful nutrition. Results of a series of studies demonstrate the powerful influence of the mother's metabolic state on whether the emerging adult develops obesity and hyperinsulinemia. Importantly, these attributes can be passed on to the next generation non-genetically and can be reversed and prevented. Such hypothesis has been expanded on by the "Developmental Origins of Health and Disease" (DOHaD) hypothesis which describes the origin of adult disease in terms of fetal developmental 'plasticity' or the ability of the fetus to respond to poor in-utero conditions. A wealth of epidemiological evidence has provided a convincing link between a sub-optimal gestational environment and an increased propensity to develop adult onset metabolic disease. In this paper the factors that participate in the programming of the fetus and infants that lead to endocrine dysfunction in postnatal life are reviewed. PMID- 22497654 TI - Coffee to reduce risk of type 2 diabetes?: a systematic review. AB - Type 2 DM is associated with high rates of morbidity and premature mortality. Various potential health effects of coffee have been extensively studied, but data on habitual coffee consumption and the risk of type 2 diabetes mellitus have only recently been published. We systematically reviewed cohort studies (identified after searching through MEDLINE) from the period of January 2001 to August 2011 to find out the relation of degree of coffee consumption with development of diabetes mellitus. Information on study design, participant characteristics, measurement of coffee consumption and outcomes, adjustment for potential confounders, and estimates of associations was reviewed independently by 3 reviewers. The review included 13 cohort studies including 12, 47,387 participants and 9473 incident cases of type 2 diabetes. We compared the risk of diabetes amongst people with different degrees of coffee consumption. We concluded that habitual coffee consumption is associated with a lower risk of type 2 diabetes. Participants who drank 4 to 6 cups and more than 6 to 7 cups of coffee per day had a lower risk of type 2 diabetes compared with those who drank less than 2 cups per day. Advantage of filtered coffee over pot boiled, decaffeinated coffee over caffeinated coffee and stronger inverse correlation in < 60 years age group was also noted. However, based on this review, increasing coffee consumption as a public health strategy can't be recommended. More detailed studies of coffee consumption, including appropriate measures of postprandial hyperglycemia and insulin sensitivity, are required. PMID- 22497655 TI - Opportunistic pathogens in diabetic foot lesions. AB - Accurate identification of infection in diabetic foot lesions is essential as the alternative can result in complicated medical and/or surgical interventions. The aim should be the differentiation between colonization and infection to avoid premature initiation of antimicrobial therapy. Diabetic foot ulcers provide a suitable environment for a diversity of microorganisms to first contaminate then subsequently colonize the wound. Infection can occur when a pathogenic factor produced by one or more microorganisms exceeds the capacity of the host immune system causing tissue damage and triggering both local and systemic inflammatory responses. The progression from wound colonization to infection is influenced by various factors including type and depth of the wound, blood supply, immune status of the patient. The quantity of microbial flora and pathogenicity expressed by the microorganisms involved will also have an effect. PMID- 22497656 TI - The release rate of curcumin from calcium alginate beads regulated by food emulsifiers. AB - Curcumin-loaded alginate beads, which contain different food emulsifiers, have been prepared using CaCl2 as the cross-linking agent. The controlled release of the curcumin from the beads was investigated at room temperature. For calcium alginate/Span-80/Tween-80 (A/S/T) formulations, almost all of the curcumin loaded in the beads was released into the medium within about 20 h, and the release rates could be regulated by changing the concentration of both Tween-80 and Span 80. However, for the systems of calcium alginate/Q-12A/F-18A (A/Q/F), about 60% of the curcumin loaded in the beads was released at the end of experiments. The studies of scanning electron microscopy indicated that the microstructure of the walls of beads could significantly vary with the concentration or type of emulsifiers. The Fourier transform infrared spectral measurements confirmed that the interactions between calcium alginate and polyglycerol fatty acid esters were stronger than that between calcium alginate and Tween-80/Span-80. The results of swelling studies demonstrated that the initial rates of water uptake for A/Q/F beads were higher than that for A/S/T beads. Moreover, the data of release rates were fitted by an empirical equation, which showed that the release mechanism of curcumin from the alginate gels varied with the composition of emulsifiers for the A/S/T systems. This work provides an important insight into the effect of food emulsifiers on the release rates of the curcumin from calcium alginate beads and will be helpful for the application of the systems in controlled release of other hydrophobic drug. PMID- 22497657 TI - Neither oxidized nor anti-oxidized low-density lipoprotein level is associated with atherosclerosis or mortality in hemodialysis patients. AB - It is anticipated that oxidized low-density lipoprotein (oxLDL) and anti-oxLDL are associated with atherosclerosis and mortality. However, data on this issue are controversial and limited. We aimed to investigate the effect of these two markers on the extent and progression of atherosclerosis and mortality in a group of hemodialysis patients. In this prospective observational study with a follow up of 36 months, 124 hemodialysis patients were studied. Ninety-five patients underwent carotid intima media thickness (CA-IMT) measurement by B-Mode ultrasonography both at baseline and at the end of the study. oxLDL and anti oxLDL were measured by enzyme-linked immunosorbent assay. The extent and progression of CA-IMT, along with overall and cardiovascular mortality, were assessed. The mean age at baseline was 54.0 +/- 14.8 years, 57.3% male and 20% diabetic. The mean oxLDL and anti-oxLDL levels were 8.11 +/- 3.16 mU/L and 1.30 +/- 0.31, respectively. Baseline mean CA-IMT was 0.82 +/- 0.20 mm. Fifteen patients died during a follow-up period of 28.5 +/- 6.6 months, 11 from cardiovascular causes. Only oxLDL, not anti-oxLDL, was correlated with the extent of atherosclerosis at baseline. However, both had no role in the progression of atherosclerosis. Also, in unadjusted and adjusted models, both parameters were not associated with overall or cardiovascular mortality. Neither oxLDL nor anti oxLDL level is associated with the progression of atherosclerosis or mortality in hemodialysis patients. PMID- 22497658 TI - Rapid genetic diversification within dog breeds as evidenced by a case study on Schnauzers. AB - As a result of strong artificial selection, the domesticated dog has arguably become one of the most morphologically diverse vertebrate species, which is mirrored in the classification of around 400 different breeds. To test the influence of breeding history on the genetic structure and variability of today's dog breeds, we investigated 12 dog breeds using a set of 19 microsatellite markers from a total of 597 individuals with about 50 individuals analysed per breed. High genetic diversity was noted over all breeds, with the ancient Asian breeds (Akita, Chow Chow, Shar Pei) exhibiting the highest variability, as was indicated chiefly by an extraordinarily high number of rare and private alleles. Using a Bayesian clustering method, we detected significant genetic stratification within the closely related Schnauzer breeds. The individuals of these three recently differentiated breeds (Miniature, Standard and Giant Schnauzer) could not be assigned to a single cluster each. This hidden genetic structure was probably caused by assortative mating owing to breeders' preferences regarding coat colour types and the underlying practice of breeding in separate lineages. Such processes of strong artificial disruptive selection for different morphological traits in isolated and relatively small lineages can result in the rapid creation of new dog types and potentially new breeds and represent a unique opportunity to study the evolution of genetic and morphological differences in recently diverged populations. PMID- 22497659 TI - Identification of BoLA-DRB3.2 alleles in Korean native cattle (Hanwoo) and Holstein populations using a next generation sequencer. AB - Bovine leucocyte antigen (encoded by BoLA) has been widely studied to identify the association with many traits related to immunity. Exon2 of BoLA-DRB3 is extremely polymorphic, and more than 100 alleles have been identified. We investigated polymorphisms of BoLA-DRB3.2 in Korean native cattle and Holstein populations using a next generation sequencer of the GS-FLX Titanium system. We found 38 alleles including 11 new alleles (BoLA-DRB3*1303, *4702, *7101, *7501, *7201, *7301, *7601, *1104, *7701, *7401 and *50021) in Hanwoo, and nine alleles including one new allele (BoLA-DRB3*7601) in Holstein. The 454 sequencing method is a promising alternative technology for high throughput genotyping of BoLA DRB3.2 because of its technical advantages that allow it to overcome the disadvantages of sequence-based typing methods. PMID- 22497660 TI - Impaired transport of nucleotides in a mitochondrial carrier explains severe human genetic diseases. AB - The mitochondrial ADP/ATP carrier (AAC) is a prominent actor in the energetic regulation of the cell, importing ADP into the mitochondria and exporting ATP toward the cytoplasm. Severe genetic diseases have been ascribed to specific mutations in this membrane protein. How minute, well-localized modifications of the transporter impact the function of the mitochondria remains, however, largely unclear. Here, for the first time, the relationship between all documented pathological mutations of the AAC and its transport properties is established. Activity measurements combined synergistically with molecular-dynamics simulations demonstrate how all documented pathological mutations alter the binding affinity and the translocation kinetics of the nucleotides. Throwing a bridge between the pathologies and their molecular origins, these results reveal two distinct mechanisms responsible for AAC-related genetic disorders, wherein the mutations either modulate the association of the nucleotides to the carrier by modifying its electrostatic signature or reduce its conformational plasticity. PMID- 22497661 TI - Welfare state regimes, health and health inequalities in adolescence: a multilevel study in 32 countries. AB - Comparative research on health and health inequalities has recently started to establish a welfare regime perspective. The objective of this study was to determine whether different welfare regimes are associated with health and health inequalities among adolescents. Data were collected from the 'Health Behaviour in School-aged Children' study in 2006, including 11- to 15-year-old students from 32 countries (N = 141,091). Prevalence rates and multilevel logistic regression models were calculated for self-rated health (SRH) and health complaints. The results show that between 4 per cent and 7 per cent of the variation in both health outcomes is attributable to differences between countries. Compared to the Scandinavian regime, the Southern regime had lower odds ratios for SRH, while for health complaints the Southern and Eastern regime showed high odds ratios. The association between subjective health and welfare regime was largely unaffected by adjusting for individual socioeconomic position. After adjustment for the welfare regime typology, the country-level variations were reduced to 4.6 per cent for SRH and to 2.9 per cent for health complaints. Regarding cross-level interaction effects between welfare regimes and socioeconomic position, no clear regime-specific pattern was found. Consistent with research on adults this study shows that welfare regimes are important in explaining variations in adolescent health across countries. PMID- 22497662 TI - Expansion and diversification of the SET domain gene family following whole genome duplications in Populus trichocarpa. AB - BACKGROUND: Histone lysine methylation modifies chromatin structure and regulates eukaryotic gene transcription and a variety of developmental and physiological processes. SET domain proteins are lysine methyltransferases containing the evolutionarily-conserved SET domain, which is known to be the catalytic domain. RESULTS: We identified 59 SET genes in the Populus genome. Phylogenetic analyses of 106 SET genes from Populus and Arabidopsis supported the clustering of SET genes into six distinct subfamilies and identified 19 duplicated gene pairs in Populus. The chromosome locations of these gene pairs and the distribution of synonymous substitution rates showed that the expansion of the SET gene family might be caused by large-scale duplications in Populus. Comparison of gene structures and domain architectures of each duplicate pair indicated that divergence took place at the 3'- and 5'-terminal transcribed regions and at the N and C-termini of the predicted proteins, respectively. Expression profile analysis of Populus SET genes suggested that most Populus SET genes were expressed widely, many with the highest expression in young leaves. In particular, the expression profiles of 12 of the 19 duplicated gene pairs fell into two types of expression patterns. CONCLUSIONS: The 19 duplicated SET genes could have originated from whole genome duplication events. The differences in SET gene structure, domain architecture, and expression profiles in various tissues of Populus suggest that members of the SET gene family have a variety of developmental and physiological functions. Our study provides clues about the evolution of epigenetic regulation of chromatin structure and gene expression. PMID- 22497663 TI - Rate of vertical transmission of human papillomavirus from mothers to infants: relationship between infection rate and mode of delivery. AB - BACKGROUND: In contrast to consistent epidemiologic evidence of the role of sexual transmission of human papillomavirus (HPV) in adults, various routes may be related to HPV infection in infants. We have assessed the extent of HPV infection during the perinatal period, and the relationship between mode of delivery and vertical transmission. RESULTS: A total of 291 pregnant women over 36 weeks of gestation were enrolled with informed consent. Exfoliative cells were collected from maternal cervix and neonatal buccal mucosa. HPV infection and genotypes were determined with an HPV DNA chip, which can recognise 24 types. The HPV-positive neonates were re-evaluated 6 months after birth to identify the presence of persistent infection. HPV DNA was detected in 18.9 % (55/291) of pregnant women and 3.4 % (10/291) of neonates. Maternal infection was associated with abnormal cytology (p = 0.007) and primiparity (p = 0.015). The infected neonates were all born to HPV-positive mothers. The rate of vertical transmission was estimated at 18.2 % (10/55) which was positively correlated with maternal multiple HPV infection (p = 0.003) and vaginal delivery (p = 0.050), but not with labour duration and premature rupture of membranes. The rate of concordance of genotype was 100 % in mother-neonate pairs with vertical transmission. The neonatal HPV DNAs found at birth were all cleared at 6 months after delivery. CONCLUSIONS: Vertical transmission of HPV DNA from HPV infected mother to the neonate increased when the infant was delivered through an infected cervix. However, the absence of persistent infection in infants at 6 months after delivery may suggest temporary inoculation rather than true vertical infection. PMID- 22497664 TI - Genetic diversity and naturally polymorphisms in HIV type 1 integrase isolates from Maputo, Mozambique: implications for integrase inhibitors. AB - HIV proviral DNA integration into the host chromosome is carried out by integrase becoming an important target antiretroviral therapy. Raltegravir was the first integrase inhibitor approved for use in HIV therapy and elvitegravir is in the late phase of clinical development; both show good results in monotherapy studies and may be used worldwide for rescue therapy. In this work we analyzed 57 integrase sequences obtained from samples from drug-naive and first line regime failing patients from Maputo, Mozambique, to evaluate the presence of natural polymorphisms and resistance mutations associated with raltegravir and elvitegravir. No major mutations conferring resistance to integrase inhibitors were found and polymorphic accessory mutations were solely observed in low frequency among subtype C sequences-L74M (3.4%), T97A (1.8%), and E157Q (1.8%) suggesting that this new antiretroviral drug class will be effective in Mozambique providing a good perspective to the introduction of this class of drugs in that country. PMID- 22497665 TI - Can the 1.8 mm transnasal biopsy forceps instead of standard 2.2 mm alter rapid urease test and histological diagnosis? AB - BACKGROUND AND AIM: Biopsy specimens are taken during transnasal esophagogastroduodenoscopy with 1.8 mm forceps. The aims of this study were to compare the concordance of the Campylobacter-like organism (CLO) test and histological diagnoses between biopsies taken with 1.8 mm and 2.2 mm forceps and to determine whether the concordance of the CLO test could be improved by increasing the number of specimens using 1.8 mm forceps. METHODS: A total of 200 patients were enrolled. We first performed the CLO test twice using each sample taken with both forceps in 100 patients. The CLO test was conducted three times again after confirming the difference in the CLO test between two forceps: (i) one sample with 1.8 mm forceps; (ii) two with 1.8 mm; and (iii) one with 2.2 mm in the other 100 patients. Additionally, each specimen was taken from the same gastric lesions in 200 patients for the histological diagnosis using both forceps types. RESULTS: The concordance rate of the CLO test between each sample with 1.8 mm and 2.2 mm forceps was 83% (kappa-value, 0.64), and that between two samples with 1.8 mm and one with 2.2 mm was 92% (kappa-value, 0.83). The concordance rate of the histological diagnosis with 1.8 and 2.2 mm was 97% (kappa-value, 0.84). CONCLUSIONS: At least two samples using 1.8 mm forceps might be needed to obtain similar results on the CLO test using 2.2 mm. But, the size difference between two forceps did not influence the histological diagnosis. PMID- 22497666 TI - Discharge-planning for long-term care needs: the values and priorities of older people, their younger relatives and health professionals. AB - Discharge-planning decisions about long-term care (LTC) can be difficult and distressing for older people, families and discharge-planning health professionals. Retrospective research suggests that despite good intentions and a shared focus on the best interests of the older person, stakeholders may hold very different values about good outcomes and how to decide them. We aimed to compare the opinions and values of frail elders living at home, younger relatives and health professionals experienced in discharge-planning, prospectively: before, not after, a LTC decision. We interviewed three types of stakeholders (10 older people, 8 relatives and 18 health professionals) using a hypothetical vignette about a frail elder leaving hospital. In a mixed methods design, we quantitatively compared the discharge plans and decision-makers that stakeholders suggested, and qualitatively analysed the 36 interview transcripts for participants' articulation of underlying values during these discussions. Older participants often suggested safe restrictive options (residential care, proxy decision-making) for the hypothetical frail elder, while advocating autonomy for themselves. Younger people generally endorsed autonomous decision-making and less restrictive discharge options especially if the elder was mentally competent, but reported difficult ethical tensions between safety and autonomy. Individual personality and preferences, mental capacity, and the importance of personal care in supporting autonomy were central themes consistent with the Ecological Theory of Aging. Accordingly, discharge planners can usefully articulate the balance of safety and autonomy, conceptualizing home care as maintaining independence rather than accepting dependence. Ethical training should incorporate sophisticated models of practice specifying both psychological and physical safety as components of beneficence. Few elders adopt a consumer approach to LTC: health professionals can encourage mid-life adults to consider later care needs when planning for retirement. PMID- 22497668 TI - Development of 23 microsatellite markers for assessing genetic variability in the tub gurnard (Trigla lucerna L.). PMID- 22497669 TI - Ultrasonographic assessment of abdominal lymph nodes in puppies. AB - The jejunal and medial iliac lymph nodes of 53 clinically normal dogs between the age of 4 and 6 weeks were examined ultrasonographically. At least two jejunal and both left and right medial iliac lymph nodes were seen in all dogs. One hundred forty-five jejunal, 53 right medial iliac and 53 left medial iliac lymph nodes in six litters of dogs, for a total of 251 lymph nodes, were measured for cross sectional maximum diameters. Mean jejunal lymph node length was 16.4 mm (range 6.4-34.9 mm) and mean width was 6.0 mm (range 2.3-15.7 mm). The mean medial iliac lymph node length was 13.6 mm (range 7.2-27.8 mm) and mean width was 4.4 mm (range 1.9-8.2 mm). Significant differences of lymph node size, noted between and within breeds, may not be of clinical significance. The mean size of the combined left and right medial iliac nodes was within previously published ranges for normal adult dogs. Lymph nodes were described in four litters of dogs (162 lymph nodes). Lymph nodes were either uniformly hypoechoic (108/163, 66%) or centrally hyperechoic with a hypoechoic rim (55/163, 34%). Although most (60%) lymph nodes were oval, a variety of shapes were seen, including vermiform and complex branching shapes. We concluded that in 4- to 6-week-old dogs, medial iliac lymph nodes are similar in size to adult dogs and jejunal lymph nodes are multiple, routinely seen, are larger than in adults and often have unconventional shapes. PMID- 22497667 TI - From genes to environment: using integrative genomics to build a "systems-level" understanding of autism spectrum disorders. AB - Autism spectrum disorders (ASD) are pervasive neurodevelopmental disorders that affect an estimated 1 in 110 individuals. Although there is a strong genetic component associated with these disorders, this review focuses on the multifactorial nature of ASD and how different genome-wide (genomic) approaches contribute to our understanding of autism. Emphasis is placed on the need to study defined ASD phenotypes as well as to integrate large-scale "omics" data in order to develop a "systems-level" perspective of ASD, which in turn is necessary to allow predictions regarding responses to specific perturbations and interventions. PMID- 22497670 TI - Integrated protocol of auricle reconstruction combined with hearing reconstruction. AB - CONCLUSIONS: Auricle reconstruction combined with hearing reconstruction can help patients with microtia to obtain practical hearing improvement as well as cosmetic improvement. The integrated procedures can facilitate the incision design and obtain a natural-looking three-dimensional shape of the reconstruction auricle. OBJECTIVES: To discuss the advantages of an integrated protocol for auricle reconstruction combined with hearing reconstruction. METHODS: We retrospectively analyzed the clinical information and follow-up results of 1300 cases (1460 ears) of congenital aural atresia with microtia who underwent auricle reconstruction combined with hearing reconstruction from January 1988 to December 2007 in Tongren Hospital. In the first stage, rib cartilage was harvested to sculpt the framework then implanted into the subcutaneous pockets in the desired position. In addition, hearing reconstruction was carried out by the antrum approach. In the second stage, the auricle framework was elevated to accomplish the auricle reconstruction. RESULTS: In all, 1445 of 1460 ears were closed by primary healing. The other 15 ears were successfully reconstructed with revision surgeries without graft failure complications. The three-dimensional profiles were well defined in 1248 ears. Total satisfaction rate was 85.5%. During the long-term follow-up, no cartilage resorption was found and all auricles retained good cosmetic effects. PMID- 22497671 TI - Which DSM-IV personality disorders are most strongly associated with indices of psychosocial morbidity in psychiatric outpatients? AB - The DSM-5 Work Group for Personality and Personality Disorders (PDs) recommended retaining 6 specific PD "types" (antisocial, avoidant, borderline, narcissistic, obsessive-compulsive, and schizotypal) and eliminating the other 4 PDs currently included in DSM-IV (paranoid, schizoid, histrionic, and dependent). One important clinical aspect of PDs is their association with indices of psychosocial morbidity. Because the literature on the relationship between PDs and psychosocial morbidity in psychiatric patients is limited, we undertook the current analysis of the Rhode Island Methods to Improve Diagnostic Assessment and Services project database to examine which PDs were most strongly associated with a variety of measures of psychosocial morbidity. We tested the hypothesis that the disorders recommended for retention in DSM-5 would be associated with more severe morbidity than the disorders recommended for deletion. A total of 2150 psychiatric outpatients were evaluated with semistructured diagnostic interviews for DSM-IV Axes I and II disorders and 7 measures of psychosocial morbidity. We examined the correlation between each PD dimensional score and each measure of morbidity and then conducted multiple regression analyses to determine which PDs were independently associated with the indices of morbidity. For the 6 PDs proposed for retention in DSM-5, 36 (85.7%) of the 42 correlations were significant, whereas for the 4 PDs proposed for deletion, 26 (92.9%) of the 28 correlations were significant. In the regression analyses for the 6 PDs proposed for retention in DSM-5, 19 (45.2%) of the 42 beta coefficients were significant, whereas for the 4 PDs proposed for deletion, 7 (25.0%) of the 28 beta coefficients were significant. The results of the present study, along with the results of other studies, do not provide clear evidence for the preferential retention of some PDs over others based on their association with indices of psychosocial morbidity. PMID- 22497672 TI - Surface-initiated group transfer polymerization mediated by rare earth metal catalysts. AB - We present the first example of a surface-initiated group transfer polymerization (SI-GTP) mediated by rare earth metal catalysts for polymer brush synthesis. The experimentally facile method allows rapid grafting of polymer brushes with a thickness of >150 nm in <5 min at room temperature. We show the preparation of common poly(methacrylate) brushes and demonstrate that SI-GTP is a versatile route for the preparation of novel polymer brushes. The method gives access to both thermoresponsive and proton-conducting brush layers. PMID- 22497673 TI - Role of nitrogen fixation in the autecology of Polaromonas naphthalenivorans in contaminated sediments. AB - Polaromonas naphthalenivorans strain CJ2 is a Gram-negative betaproteobacterium that was identified, using stable isotope probing in 2003, as a dominant in situ degrader of naphthalene in coal tar-contaminated sediments. The sequenced genome of strain CJ2 revealed several genes conferring nitrogen fixation within a 65.6 kb region of strain CJ2's chromosome that is absent in the genome of its closest sequenced relative Polaromonas sp. strain JS666. Laboratory growth and nitrogenase assays verified that these genes are functional, providing an alternative source of nitrogen in N-free media when using naphthalene or pyruvate as carbon sources. Knowing this, we investigated if nitrogen-fixation activity could be detected in microcosms containing sediments from the field site where strain CJ2 was isolated. Inducing nitrogen limitation with the addition of glucose or naphthalene stimulated nitrogenase activity in amended sediments, as detected using the acetylene reduction assay. With the use of fluorescence microscopy, we screened the microcosm sediments for the presence of active strain CJ2 cells using a dual-labelling approach. When we examined the carbon-amended microcosm sediments stained with both a strain CJ2-specific fluorescent in situ hybridization probe and a polyclonal fluorescently tagged antibody, we were able to detect dual-labelled active cells. In contrast, in sediments that received no carbon addition (showing no nitrogenase activity), no dual-labelled cells were detected. Furthermore, the naphthalene amendment enhanced the proportion of active strain CJ2 cells in the sediment relative to a glucose amendment. Field experiments performed in sediments where strain CJ2 was isolated showed nitrogenase activity in response to dosing with naphthalene. Dual-label fluorescence staining of these sediments showed a fivefold increase in active strain CJ2 in the sediments dosed with naphthalene over those dosed with deionized water. These experiments show that nitrogen fixation may play an important role in naphthalene biodegradation by strain CJ2 and contribute to its ecological success. PMID- 22497674 TI - Waiting for the National Cholesterol Education Program Adult Treatment Panel IV Guidelines, and in the meantime, some challenges and recommendations. AB - The National Cholesterol Education Program Adult Treatment Panel (ATP) has provided education and guidance for decades on the management of hypercholesterolemia. Its third report (ATP III) was published 10 years ago, with a white paper update in 2004. There is a need for translation of more recent evidence into a revised guideline. To help address the significant challenges facing the ATP IV writing group, this statement aims to provide balanced recommendations that build on ATP III. The authors aim for simplicity to increase the likelihood of implementation in clinical practice. To move from ATP III to ATP IV, the authors recommend the following: (1) assess risk more accurately, (2) simplify the starting algorithm, (3) prioritize statin therapy, (4) relax the follow-up interval for repeat lipid testing, (5) designate <70 mg/dl as an "ideal" low-density lipoprotein cholesterol target, (6) endorse targets beyond low-density lipoprotein cholesterol, (7) refine therapeutic target levels to the equivalent population percentile, (8) remove misleading descriptors such as "borderline high," and (9) make lifestyle messages simpler. In conclusion, the solutions offered in this statement represent ways to translate the totality of published reports into enhanced hyperlipidemia guidelines to better combat the devastating impact of hyperlipidemia on cardiovascular health. PMID- 22497675 TI - Angiographic lesion severity and subsequent myocardial infarction. AB - We sought to determine the angiographic severity of coronary lesions leading to ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) with a focus on determining the impact of interval from initial angiogram to subsequent clinical event. In the late 1980s angiographic data on lesion characteristics that culminated in STEMI and NSTEMI were obtained from angiograms obtained several months before MI. It is not clear whether the conclusions on lesion severity would be different if elapsed interval from baseline angiogram to clinical event was factored in the analysis. From 2003 through 2010, we identified 84 patients with NSTEMI and 41 patients with STEMI in vessels without previous intervention. These patients had >=1 previous angiographic study at our center. Angiograms were reanalyzed with quantitative coronary angiography, and relevant clinical data were obtained from medical records. Similar to previous studies, 71% of patients with STEMI and 63% of patients with NSTEMI had <50% baseline stenosis at the culprit site when the interval from initial angiogram to MI was >3 months. Interestingly, lesions that led to STEMI <=3 months after evaluation were more severe than those leading to STEMI in >3 months (59 +/- 31% vs 36 +/- 21%, p = 0.02) with 57% of lesions having >50% stenosis. Although most MIs occurred at sites that did not have significant obstruction when examined >3 months before MI, most baseline lesions showed significant luminal narrowing when examined <=3 months before STEMI. In conclusion, high-grade coronary stenosis may be an important predictor of STEMI in subsequent months. PMID- 22497676 TI - Left atrial deformation analysis by speckle tracking echocardiography for prediction of cardiovascular outcomes. AB - The incremental value of left atrial (LA) deformation analysis by speckle tracking echocardiography compared with LA volume or LA ejection fraction as a cardiovascular risk marker has not been evaluated prospectively. We sought to compare LA function by speckle tracking echocardiography to other conventional LA parameters for prediction of adverse cardiovascular outcomes. This prospective study included 312 adults (mean age 71 +/- 6 years, 56% men) in sinus rhythm who were followed for development of first atrial fibrillation, congestive heart failure, stroke, transient ischemic attack, myocardial infarction, coronary revascularization, and cardiovascular death. Global peak atrial longitudinal strain (PALS) by speckle tracking echocardiography was measured in all subjects by averaging all atrial segments. Left atrium was assessed with biplane LA volume, LA ejection fraction, 4-chamber LA area, and M-mode dimension. Of 312 subjects at baseline, 43 had 61 new events during a mean follow-up of 3.1 +/- 1.4 years. All LA parameters, traditional parameters, and parameters derived by speckle tracking echocardiography were independently predictive of combined outcomes (p <0.0001 for all comparisons). Overall performance for prediction of cardiovascular events was greatest for global PALS (area under receiver operator characteristic curve: global PALS 0.83, indexed LA volume 0.71, LA ejection fraction 0.69, LA area 0.64, LA diameter 0.59). A graded association between degree of LA enlargement and risk of cardiovascular events was evident only for global PALS and indexed LA volume. In conclusion, global PALS is a strong and independent predictor of cardiovascular events and appears to be superior to conventional parameters of LA analysis. PMID- 22497677 TI - Effect of bisoprolol on respiratory function and exercise capacity in chronic obstructive pulmonary disease. AB - Cardioselective beta blockers are considered to have little impact on lung function at rest in patients with chronic obstructive pulmonary disease (COPD). However, their effects on dynamic hyperinflation, an important mechanism contributing to symptoms and exercise tolerance in patients with COPD, have not been evaluated. Twenty-seven patients with moderate to severe COPD (forced expiratory volume in 1 second 52 +/- 13% predicted) completed pulmonary function tests, echocardiography, maximal exercise tests, and cycle endurance tests at baseline. Inspiratory capacity was measured at 2-minute intervals during the cycle endurance test to quantify dynamic hyperinflation. Pulmonary function and cycle endurance testing were repeated after 14 days of bisoprolol 10 mg/day and 14 days of placebo in a randomized, double-blind, placebo-controlled, crossover trial. The extent of dynamic hyperinflation at peak isotime exercise with bisoprolol and placebo was compared. Peak isotime was defined as the latest time point that was reached during the 2 cycle endurance tests. Changes in inspiratory capacity from rest to peak isotime were different with bisoprolol compared to placebo (-0.50 +/- 0.35 vs -0.41 +/- 0.33 L, p = 0.01). Exercise duration tended to be lower with bisoprolol compared to placebo (305 +/- 125 vs 353 +/- 172 seconds, p = 0.11). The magnitude of change in exercise duration between the bisoprolol and placebo conditions was correlated with the magnitude of change in inspiratory capacity (r = 0.57, p <0.01). In conclusion, bisoprolol was associated with modest worsening dynamic hyperinflation, whereas exercise duration remained unchanged in patients with moderate to severe COPD. The magnitude of these effects was small and should not contraindicate the use of bisoprolol in patients with COPD. PMID- 22497678 TI - The obesity paradox in men versus women with systolic heart failure. AB - Obesity is common in heart failure (HF) and is associated with improved outcomes, a finding often termed the "obesity paradox." Although fat distribution varies by gender, the role of obesity in the outcomes of women compared to men with HF has not been well studied. In a cohort of patients with advanced systolic HF followed at a single university center, 2,718 patients had body mass indexes (BMIs) measured at baseline, and 469 patients with HF had waist circumferences (WCs) measured at baseline. Elevated BMI was defined as >=25 kg/m(2). High WC was defined as >=88 cm in women and >=102 cm in men. The primary outcome was death, urgent heart transplantation, or ventricular assist device placement. The mean age was 53.0 +/- 12.4 years, 25% of subjects were women, and the mean left ventricular ejection fraction was 22.9 +/- 7.19%. In men, 2-year event-free survival was better for high versus normal BMI (63.2% vs 53.5%, p <0.001) and for high versus normal WC (78.8% vs 63.1%, p = 0.01). In women, 2-year event-free survival was better for elevated versus normal BMI (67.1% vs 56.6%, p = 0.01) but similar in the 2 WC groups. In multivariate analyses, normal BMI and normal WC were associated with higher relative risk for the primary outcome in men (BMI 1.34, WC 2.02) and women (BMI 1.38, WC 2.99). In conclusion, in patients with advanced HF, high BMI and WC were associated with improved outcomes in both genders. Further investigation of the interaction between body composition and gender in HF outcomes is warranted. PMID- 22497679 TI - Prognostic value of aortic valve area index in asymptomatic patients with severe aortic stenosis. AB - Recently, an aortic valve area (AVA) index (AVAI) <0.6 cm(2)/m(2) was proposed as an indicator of severe aortic stenosis. The purpose of the present study was to clarify the prognostic value of the AVAI. We identified 103 consecutive asymptomatic patients (mean age 72 +/- 11 years) with severe aortic stenosis, defined by an AVA of <1.0 cm(2), who had not undergone aortic valve replacement on initial evaluation. During follow-up (median 36 +/- 27 months), 31 aortic valve replacements and 20 cardiac deaths occurred. Multivariate analysis revealed that an AVAI <0.6 cm(2)/m(2) (hazard ratio 2.6, 95% confidence interval 1.1 to 6.3; p = 0.03) and peak aortic jet velocity (Vp) >4.0 m/s (hazard ratio 2.6, 95% confidence interval 1.2 to 5.8; p = 0.02) were associated with cardiac events but that an AVA <0.75 cm(2) was not. The event-free survival of patients with an AVAI of >=0.6 cm(2)/m(2) was better than that for those with an AVAI <0.6 cm(2)/m(2) (86% vs 41% at 3 years, p <0.01). Furthermore, patients with an AVAI of >=0.6 cm(2)/m(2) and Vp of <=4.0 m/s showed an excellent prognosis, but those without these findings had poorer outcomes. In conclusion, AVAI is a powerful predictor of adverse events in asymptomatic patients with severe aortic stenosis. Furthermore, the combination of AVAI and Vp provides additional prognostic information. Watchful observations are required for timely aortic valve replacement in patients with an AVAI of <0.6 cm(2)/m(2) or a Vp >4.0 m/s. PMID- 22497680 TI - Comparison of a priori versus provisional heparin therapy on radial artery occlusion after transradial coronary angiography and patent hemostasis (from the PHARAOH Study). AB - Systemic anticoagulation decreases the risk of radial artery occlusion (RAO) after transradial catheterization and standard occlusive hemostasis. We compared the efficacy and safety of provisional heparin use only when the technique of patent hemostasis was not achievable to standard a priori heparin administration after radial sheath introduction. Patients referred for coronary angiography were randomized in 2 groups. In the a priori group, 200 patients received intravenous heparin (50 IU/kg) immediately after sheath insertion. In the provisional group, 200 patients did not receive heparin during the procedure. After sheath removal, hemostasis was obtained using a TR band (Terumo corporation, Tokyo, Japan) with a plethysmography-guided patent hemostasis technique. In the provisional group, no heparin was given if radial artery patency could be obtained and maintained. If radial patency was not achieved, a bolus of heparin (50 IU/kg) was given. Radial artery patency was evaluated at 24 hours (early RAO) and 30 days after the procedure (late RAO) by plethysmography. Patent hemostasis was obtained in 67% in the a priori group and 74% in the provisional group (p = 0.10). Incidence of RAO remained similar in the 2 groups at the early (7.5% vs 7.0%, p = 0.84) and late (4.5% vs 5.0%, p = 0.83) evaluations. Women, patients with diabetes, patients having not received heparin, and patients without radial artery patency during hemostasis had more RAO. By multivariate analysis, patent radial artery during hemostasis (odds ratio [OR] 0.03, 95% confidence interval [CI] 0.004 to 0.28, p = 0.002) and diabetes (OR 11, 95% CI 3 to 38,p <0.0001) were independent predictors of late RAO, whereas heparin was not (OR 0.45 95% CI 0.13 to 1.54, p = 0.20). In conclusion, our results suggest that maintenance of radial artery patency during hemostasis is the most important parameter to decrease the risk of RAO. In selected cases, provisional use of heparin appears feasible and safe when patent hemostasis is maintained. PMID- 22497681 TI - NIH3T3 cells overexpressing CD98 heavy chain resist early G1 arrest and apoptosis induced by serum starvation. AB - CD98 is a heterodimeric glycoprotein of 125-kDa, which consists of a 90-kDa heavy chain (hc) subunit and 35-kDa to 55-kDa light chain (lc) subunits. It is strongly expressed on the surface of proliferating normal cells and almost all tumor cells. To investigate the participation of CD98 in cellular proliferation and malignant transformation, we analyzed cell-cycle progression of NIH3T3 clones transfected with cDNA of human CD98hc. Although NIH3T3 and control transfectant cells grown to the subconfluent state were arrested in the G0/G1 phase by serum starvation, considerable portions of CD98hc-transfected cells resided at S and G2/M phases. Under serum-starved and confluent conditions, significant fractions (20-25%) of NIH3T3 and control transfectant cells contained less than 2n content DNA, indicating occurrence of apoptosis, whereas no apoptotic cells were detected in CD98hc-transfectant cells. Under serum-starved conditions, a marked increase in the levels of cyclin D1 and cyclin E and a decrease in p16 were observed in CD98hc-transfectant cells. The reverse was true for NIH3T3 and control transfectant cells. Our results suggest that resistance to G1 arrest and apoptosis by CD98 overexpression are associated with high G1-cyclins and low p16 levels. PMID- 22497682 TI - The spectrum of pulmonary malformation in trisomy-21 patient. A review with emphasis on the molecular-genetic basis. AB - Gene overexpression has been identified as a primary determining factor for the distinct Down syndrome (DS) phenotypes. Previous genetic research has identified a spectrum of gene expressions responsible for many of the observed traits in DS patients including cardiovascular, brain, and GI anomalies. However, the molecular/genetic basis underlying pulmonary anomalies are yet to be identified, even though respiratory complications represent the leading cause of morbidity and mortality in DS patients. In this article, we will discuss the Etiopathogenesis and spectrum of pulmonary anomalies in DS patients. PMID- 22497683 TI - Hepatic pulmonary fusion: two cases with diaphragmatic hernia and one case with Pentalogy of Cantrell. AB - Hepatic pulmonary fusion (HPF) is characterized by a fibrous connection between the liver and lung tissue. We present two cases of hepatic pulmonary fusion diagnosed with right diaphragmatic hernia and a third case with Pentalogy of Cantrell exhibiting complete agenesis of the diaphragm and finger-like projections of liver adhered to the right lung. It has been proposed that this anomaly is secondary to developmental failure of the mesoderm between days 14-18 after conception and is attributed to diaphragmatic maldevelopment. Understanding the molecular-genetic basis of diaphragmatic hernias may shed light on this unusual presentation and explain why other cases show no fusion. PMID- 22497684 TI - Unusual presentation of extracardiac fetal rhabdomyoma of the larynx in a pediatric patient with tuberous sclerosis. AB - Tuberous sclerosis (TSC) is an autosomal-dominant genetic disease characterized by a spectrum of pathologic manifestations involving skin, brain, kidney, and heart. These manifestations include neuroectodermal, mesodermal, and skin lesions as well as a variety of associated tumors and hamartomas. We report an 11-year old male with previously diagnosed TSC who presented with a laryngeal mass shown on histology to be fetal cellular rhabdomyoma. Cardiac rhabdomyomas are common in TSC patients, but to our knowledge, the association between TSC and extracardiac rhabdomyomas has not been previously reported. PMID- 22497685 TI - Complex cardiac defect, bowing of lower limbs and multiple anomalies in trisomy 22. Ultrasound, post-mortem CT findings with necropsy confirmation. AB - Trisomy 22 is commonly associated with severe intrauterine growth retardation and congenital anomalies. The sonographic identification of a complex cardiac defect and bowing of the long bones associated with multiple structural anomalies add new clinical informations to our knowledge about the prenatal phenotype of trisomy 22. These findings have not been reported previously and are of critical importance as sonographic signs of trisomy 22 may overlap that of trisomy 13-18 and will help clinicians in indicating fetal karyotyping. Prenatal diagnosis of trisomy 22 is essential as trisomy 22 is a lethal condition. PMID- 22497686 TI - Nephropathic infantile form of cystinosis about one case. AB - Cystinosis is the major cause of inherited Fanconi syndrome, and should be suspected in young children with a failure to thrive and with signs of renal proximal tubular damage. This is a study of a case report of cystinosis revealed by a growth failure and chronic dehydration. A 9-month-old boy was referred to our department for evaluation of polyuria and polydipsia. Clinical examination showed dehydration and enlarged wrists and rachitic rosaries. The presence of metabolic acidosis, hypokalemia, hypochloremia with proteinuria, polyuria, and hypercalciuria was suggestive of inherited Fanconi syndrome. The diagnosis of cystinosis was confirmed by an increased leukocyte cystine level. PMID- 22497688 TI - Dimethylsulfoxide potentiates the nerve conduction-blocking effect of lidocaine without augmentation of the intracellular lidocaine concentration in the giant axon of crayfish in vitro. AB - The purpose of this study was to investigate how dimethylsulfoxide (DMSO) potentiates the blocking action of lidocaine. A giant axon removed from a crayfish was used to investigate nerve conduction and intracellular lidocaine concentration. The maximum values of the differential waveform (dV/dt max) calculated from evoked action potentials were used for evaluating an inhibition of nerve conduction. The inhibition of the dV/dt max in low-frequency stimulation (tonic block) and high-frequency stimulation (phasic block) after perfusion of 1 mm lidocaine with or without 0.2 vol % DMSO, in which the concentration of DMSO alone had no anesthetic effect, was measured to evaluate the potentiating action of DMSO. The intracellular lidocaine concentration was measured via a lidocaine sensitive glass microelectrode during 30 min of perfusion of 1 mm lidocaine alone or in combination with DMSO. When applied without lidocaine, DMSO caused a dose dependent nerve conduction block when used at concentrations >1 vol %. The dV/dt max in the tonic block was significantly decreased when 0.2 vol % DMSO was added to the lidocaine solution (P = 0.004). In the phasic block, there was no significant potentiating action of DMSO. There were no significant differences in the intracellular lidocaine concentrations with or without DMSO. The potentiating effects of DMSO were observed only in the condition of low-frequency stimulation and were not related to the intracellular lidocaine concentration in the giant axon of crayfish in vitro. PMID- 22497689 TI - A genome-wide association study for quantitative trait loci of show-jumping in Hanoverian warmblood horses. AB - Show-jumping is an economically important breeding goal in Hanoverian warmblood horses. The aim of this study was a genome-wide association study (GWAS) for quantitative trait loci (QTL) for show-jumping in Hanoverian warmblood horses, employing the Illumina equine SNP50 Beadchip. For our analyses, we genotyped 115 stallions of the National State stud of Lower Saxony. The show-jumping talent of a horse includes style and ability in free-jumping. To control spurious associations based on population stratification, two different mixed linear animal model (MLM) approaches were employed, besides linear models with fixed effects only and adaptive permutations for correcting multiple testing. Population stratification was explained best in the MLM considering Hanoverian, Thoroughbred, Trakehner and Holsteiner genes and the marker identity-by-state relationship matrix. We identified six QTL for show-jumping on horse chromosomes (ECA) 1, 8, 9 and 26 (-log(10) P-value >5) and further putative QTL with -log(10) P-values of 3-5 on ECA1, 3, 11, 17 and 21. Within six QTL regions, we identified human performance-related genes including PAPSS2 on ECA1, MYL2 on ECA8, TRHR on ECA9 and GABPA on ECA26 and within the putative QTL regions NRAP on ECA1, and TBX4 on ECA11. The results of our GWAS suggest that genes involved in muscle structure, development and metabolism are crucial for elite show-jumping performance. Further studies are required to validate these QTL in larger data sets and further horse populations. PMID- 22497690 TI - Prevalence of the Aleutian mink disease virus infection in Nova Scotia, Canada. AB - Despite many years of testing mink for serum antibodies against the Aleutian mink disease virus (AMDV) by counterimmunoelectrophoresis (CIEP) and elimination of reactors, this virus has remained the number one disease threat for the mink industry in Nova Scotia (NS). The objective of this study was to analyze CIEP test results to determine the success of the AMDV-control strategy in NS. A total of 2,964,920 CIEP test results from 82 ranches, spanning an eight-year period between 1998 and 2005, were analyzed. This survey included approximately 60% of the active ranchers in the province. The number of ranchers that tested their animals was 42 in 1998, gradually increased to 58 in 2003 and then showed some decline. The overall proportion of CIEP-positive mink was 3.34%, and varied between 5.22% in 1999 and 1.35% in 2005. The proportion of infected ranches ranged between 23.8% in 1998 and 70.7% in 2003. The overall trend was for a smaller proportion of infected animals but a larger proportion of infected ranches during this time period. Of the 82 ranches, 24 (29.3%) had negative CIEP in all tests, 15 (18.3%) had CIEP positive animals in every year tested, and 43 (52.4%) had positive and negative results in different years, indicating that AMDV infection was widespread in NS. There were 23 infected ranches with 8 years of uninterrupted testing. These ranchers performed 75.8% of the total samples tested (2,246,711), implying that they have diligently been trying to eradicate the virus. Infection persisted on three of these ranches for the entire 8 year period, and only two of the ranches remained CIEP negative for longer than four years. The average percentage of CIEP-positive mink on these ranches was 2.2, which was lower than 6.35% for the 33 infected ranches with occasional testing, and 73.6% and 82.4% for two ranches that had never used the CIEP test, showing that persistent test-and-removal strategy has been effective in reducing the prevalence of infected animals but has failed to eradicate the virus from most of the infected ranches. PMID- 22497691 TI - Orbital fractures in children. AB - In children, differences in the properties and proportions of bone in the craniofacial skeleton and the lack of development of the paranasal sinuses result in orbital fractures that present differently from those in adults. Facial growth may be disturbed by such injuries and also by surgical intervention, which should therefore be as conservative as possible. However, urgent operation is needed to prevent irreversible changes when fractures of the orbital floor involve entrapped muscle. We present an approach to such injuries. PMID- 22497692 TI - Delays in head and neck surgery-managers, theatre usage and suboptimal efficiency. PMID- 22497694 TI - First-principles modeling of dye-sensitized solar cells: challenges and perspectives. AB - Since dye-sensitized solar cells (DSSCs) appeared as a promising inexpensive alternative to the traditional silicon-based solar cells, DSSCs have attracted a considerable amount of experimental and theoretical interest. In contrast with silicon-based solar cells, DSSCs use different components for the light harvesting and transport functions, which allow researchers to fine-tune each material and, under ideal conditions, to optimize their overall performance in assembled devices. Because of the variety of elementary components present in these cells and their multiple possible combinations, this task presents experimental challenges. The photoconversion efficiencies obtained up to this point are still low, despite the significant experimental efforts spent in their optimization. The development of a low-cost and efficient computational protocol that could qualitatively (or even quantitatively) identify the promising semiconductors, dyes, and electrolytes, as well as their assembly, could save substantial experimental time and resources. In this Account, we describe our computational approach that allows us to understand and predict the different elementary mechanisms involved in DSSC working principles. We use this computational framework to propose an in silico route for the ab initio design of these materials. Our approach relies on a unique density functional theory (DFT) based model, which allows for an accurate and balanced treatment of electronic and spectroscopic properties in different phases (such as gas, solution, or interfaces) and avoids or minimizes spurious computational effects. Using this tool, we reproduced and predicted the properties of the isolated components of the DSSC assemblies. We accessed the microscopic measurable characteristics of the cells such as the short circuit current (J(sc)) or the open circuit voltage (V(oc)), which define the overall photoconversion efficiency of the cell. The absence of empirical or material-related parameters in our approach should allow for its wide application to the optimization of existing devices or the design of new ones. PMID- 22497693 TI - The safety profile of dalfampridine extended release in multiple sclerosis clinical trials. AB - BACKGROUND: Dalfampridine (fampridine outside the United States) is a broad spectrum potassium channel blocker. Dalfampridine extended-release tablets have been approved by the US Food and Drug Administration to improve walking in patients with multiple sclerosis (MS). OBJECTIVE: The objective of this article is to review the safety profile of dalfampridine extended-release tablets with respect to its expected use in patients with MS. METHODS: We reviewed published data relevant to patient safety profiles based on searches of articles in PubMed published up to December 31, 2010, using the search terms fampridine OR dalfampridine OR 4-aminopyridine AND (multiple sclerosis) in combination with toxicity, safety, clinical trial, pharmacokinetics, and seizures. These searches were supplemented with data derived from the approved package insert and relevant sections of the New Drug Application (22-250) as submitted to the US Food and Drug Administration. RESULTS: The literature searches returned 58 unique citations, of which 26 were considered relevant for characterizing the safety profile of dalfampridine; excluded citations were as follows: reviews (19), evaluation of 3,4-diaminopyridine (4), intravenous dosing (2), inadequate information on patient doses (2), preclinical models (2), and "other" (3). Dalfampridine is nearly completely (approximately 96%) eliminated unchanged in urine, with limited transformation to 2 inactive metabolites and low risk for interaction with drugs metabolized by hepatic P450 cytochromes. However, in patients with renal impairment (creatinine clearance [CrCl], <=80 mL/min), mean peak plasma concentrations were 68%-101% higher and apparent clearance was 43% 73% lower relative to those without impairment, precluding dalfampridine use in patients with moderate (CrCl, 30-50 mL/min) or severe renal impairment (CrCl, <30 mL/min). Dalfampridine has a narrow therapeutic range. At the therapeutic dose of 10 mg twice daily, adverse events were generally mild to moderate and, consistent with the mechanism of action of dalfampridine, were primarily related to stimulatory effects on the nervous system. A thorough QT study suggested a low risk of induction of QT prolongation and associated cardiac arrhythmias in healthy individuals at therapeutic (10 mg, twice daily) or supratherapeutic (30 mg, twice daily) doses. Although the incidence of seizures was dose related, data from the clinical trials of dalfampridine extended-release tablets suggest that the risk of seizure at the therapeutic dose, in patients with no history of seizure, is not likely to be higher than background rates in MS. CONCLUSION: In patients with MS, dalfampridine has a narrow therapeutic range but an acceptable safety profile when used at the therapeutic dose of 10 mg twice daily. PMID- 22497695 TI - Mucosal co-infections and HIV-1 transmission and pathogenesis. PMID- 22497696 TI - Hepatitis B virus variants in HBV mono-infected versus HBV/HIV co-infected patients. PMID- 22497697 TI - Week 96 outcomes of patients with less treatment experience versus more treatment experience receiving etravirine in the DUET trials. AB - BACKGROUND: The disease profile of treatment-experienced HIV-1 patients (TEPs) looks different today compared with that of 5 years ago. Because less highly treated DUET patients may more closely resemble today's TEPs, we conducted a post hoc efficacy and safety analysis of the pooled 96-week DUET data stratified by level of treatment experience. METHODS: TEPs with HIV-1 were randomised to etravirine (ETR) 200mg twice daily (bid) or placebo bid with a background regimen for 48 weeks (plus optional 48-week extension). TEPs were categorized using 10 demographic and disease characteristics that in prior studies of treatment experienced subjects had been associated with virologic response; patients meeting >=5 criteria were categorized as less TEP. RESULTS: 183 patients (men, 87.4%) who received ETR were less TEP and 413 patients (men, 91.0%) were more TEP. At baseline, more TEPs had more advanced disease, more previous antiretroviral (ARV) exposures and fewer options for active ARVs. At Week 96, for patients receiving ETR, response rates for the less TEP group and more TEP group were 68.3% and 52.8%, respectively. Incidence of adverse events (AEs) was similar between groups. A greater proportion of nonresponders in the more TEP group discontinued due to AEs (9.0% vs 5.5%) and virologic failure (18.9% vs 5.5%) compared with the less TEP group. CONCLUSION: Less TEPs had higher virologic response rates with ETR compared with more TEPs. Because the less TEP population from DUET more closely resembles TEPs with HIV-1 today, data from this subgroup may provide valuable information for real-life treatment decisions. PMID- 22497698 TI - Advances in efficient health communication: promoting prevention and detection of STDs. AB - Small changes in the wording of health related recommendations about Sexually Transmitted Diseases (STDs) can significantly influence their impact. In this paper, we review advances in research investigating the content and structure of these framed messages. We also summarize the results of a recent longitudinal study examining the effects of a brief risk awareness intervention (i.e., a brochure) targeting young adults-the population at highest risk of contracting STDs. Building on a leading theory and emerging data, we review key aspects of the psychological processes that underlie the impact of framed messages on prevention and detection of STDs, and we detail how these messages can be made more influential when accompanied by visual aids. Our review converges with other research indicating that well constructed visual aids are often among the most highly effective, transparent, and ethically desirable means of health risk communication. Larger scale implementation of these and other theory-based, custom-tailored methods holds the promise of relatively inexpensive yet highly effective systems for promoting prevention and detection of STDs. PMID- 22497699 TI - HIV drug resistance interpreted by cumulative versus last genotypes in HIV infected patients with multiple treatment failures. AB - Genotypic resistance test has been recommended to evaluate HIV drug resistance and guide the effective regimens of antiretroviral therapy (ART) in HIV-infected patients with treatment failure. In patients with multiple treatment failures, drug resistance-associated mutations may disappear due to the loss of selective drug pressure after switching regimens. A cohort study was conducted among HIV infected patients who had >=2 genotypic resistance tests during 2003-2011. HIV-1 pol nucleotide sequencing of reverse transcriptase and protease region was carried out using TRUGENE HIV-1 Genotypic Assay. Sequencing data was analyzed using Stanford rule-based interpretation algorithms. Of 54 patients with mean age of 30.1 years, 46.3% were males. HIV-1 subtype A/E was observed in 88.9% of patients. At the latest failure, 55.3% were receiving protease inhibitor-based regimens. Median CD4 and HIV RNA were 167 cells/mm(3) and 22,359 copies/mL. During a median duration of ART of 38.6 months, 72.2%, 22.2%, and 5.6% had 5, 3, and 2 genotype tests, respectively. When compared between using cumulative (CG) and last genotypes (LG), CG interpreted resistance to any drug 59.3% higher than LG did. For NRTI, NNRTI, and PI drug classes, CG interpreted as resistance 42.6%, 27.8%, and 7.4% higher than LG, respectively. The most common drugs that CG interpreted resistance with the higher rate than LG were lamivudine/emtricitabine, nevirapine, efavirenz, etravirine and abacavir. In conclusion, CG interprets HIV drug resistance at a higher rate than LG and may be more accurate to use for selecting the next effective regimen of ART among HIV infected patients with multiple treatment failures. PMID- 22497700 TI - The intersection of life expectancy and gender in a transitional state: the case of Russia. AB - This paper examines the gender-related features of the health crisis in Russia which has produced the largest gender gap in life expectancy in the world. Stress and negative health lifestyles are the two most likely causes of the long-term adverse longevity pattern in Russia. However, this development cannot be clarified by a simple cause and effect explanation. This is because gender roles and gender-based normative behaviour, along with class influences, intervened to help shape outcomes. Men and women responded to the crisis along gender lines, with stress the best single explanation for a stunted longevity for females and negative health lifestyles accounting for much of the premature mortality among males. PMID- 22497701 TI - Rapid analysis of caffeine in "smart drugs" and "energy drinks" by microemulsion electrokinetic chromatography (MEEKC). AB - A novel method based on microemulsion electrokinetic chromatography (MEEKC) with diode array detection (DAD) for rapid determination of caffeine in commercial and clandestine stimulants, known as "energy drinks" and "smart drugs", is described. Separations were carried out in 50 cm * 50 MUm (ID) uncoated fused silica capillaries. The optimized buffer electrolyte was composed of 8.85 mM sodium tetraborate pH 9.5, SDS 3.3% (w/v), n-hexane 1.5% (v/v) and 1-butanol 6.6% (v/v). Separations were performed at a voltage of 20 kV. Sample injection conditions were 0.5 psi, 3 s. Diprofilline was used as internal standard. The determination of the analytes was based on the UV signal recorded at 275 nm, corresponding to the maximum wavelength of absorbance of caffeine, whereas peak identification and purity check was performed on the basis of the acquisition of UV radiation between 200 and 400 nm wavelengths. Under the described conditions, the separation of the compounds was achieved in 6 min without any interference from the matrix. Linearity was assessed within a caffeine concentration range from 5 to 100 MUg/mL. The intra-day and inter-day precision values were below 0.37% for migration times and below 9.86% for peak areas. The present MEEKC method was successfully applied to the direct determination of caffeine in smart drugs and energy drinks. PMID- 22497702 TI - Dating human skeletal remains using a radiometric method: biogenic versus diagenetic 90Sr and 210Pb in vertebrae. AB - In forensic science, there is a strong interest in determining the post-mortem interval (PMI) of human skeletal remains up to 50 years after death. Currently, there are no reliable methods to resolve PMI, the determination of which relies almost exclusively on the experience of the investigating expert. Here we measured (90)Sr and (210)Pb ((210)Po) incorporated into bones through a biogenic process as indicators of the time elapsed since death. We hypothesised that the activity of radionuclides incorporated into trabecular bone will more accurately match the activity in the environment and the food chain at the time of death than the activity in cortical bone because of a higher remodelling rate. We found that determining (90)Sr can yield reliable PMI estimates as long as a calibration curve exists for (90)Sr covering the studied area and the last 50 years. We also found that adding the activity of (210)Po, a proxy for naturally occurring (210)Pb incorporated through ingestion, to the (90)Sr dating increases the reliability of the PMI value. Our results also show that trabecular bone is subject to both (90)Sr and (210)Po diagenesis. Accordingly, we used a solubility profile method to determine the biogenic radionuclide only, and we are proposing a new method of bone decontamination to be used prior to (90)Sr and (210)Pb dating. PMID- 22497703 TI - Virtual forensic entomology: improving estimates of minimum post-mortem interval with 3D micro-computed tomography. AB - We demonstrate how micro-computed tomography (micro-CT) can be a powerful tool for describing internal and external morphological changes in Calliphora vicina (Diptera: Calliphoridae) during metamorphosis. Pupae were sampled during the 1st, 2nd, 3rd and 4th quarter of development after the onset of pupariation at 23 degrees C, and placed directly into 80% ethanol for preservation. In order to find the optimal contrast, four batches of pupae were treated differently: batch one was stained in 0.5M aqueous iodine for 1 day; two for 7 days; three was tagged with a radiopaque dye; four was left unstained (control). Pupae stained for 7d in iodine resulted in the best contrast micro-CT scans. The scans were of sufficiently high spatial resolution (17.2 MUm) to visualise the internal morphology of developing pharate adults at all four ages. A combination of external and internal morphological characters was shown to have the potential to estimate the age of blowfly pupae with a higher degree of accuracy and precision than using external morphological characters alone. Age specific developmental characters are described. The technique could be used as a measure to estimate a minimum post-mortem interval in cases of suspicious death where pupae are the oldest stages of insect evidence collected. PMID- 22497704 TI - Selective culturing and genus-specific PCR detection for identification of Aeromonas in tissue samples to assist the medico-legal diagnosis of death by drowning. AB - The detection of autochthonous aquatic bacteria in tissue samples from drowning cases is increasingly considered as an alternative approach to assist the medico legal diagnosis of death by drowning. Bacteria belonging to the genus Aeromonas may be suitable candidates for this application as they are ubiquitous in natural aquatic environments but are generally not part of the human microbiota. The research aims of this study were (i) to develop a sensitive, specific and rapid screening and confirmation method for Aeromonas species in tissue samples and (ii) to evaluate aseptic sternal puncture as a post-mortem sample technique and bone marrow as an alternative matrix to provide evidence of death by drowning. The presence of Aeromonas in tissue samples was verified by cultivation using the selective media Ampicillin Dextrin Agar (ADA) and Ryan's Aeromonas Medium. The use of ADA medium was found most optimal for the sensitive, inexpensive and quick detection of aeromonads in human tissue samples. Positive culture plates were confirmed by harvesting all colonies for DNA extraction and subsequent PCR amplification using Aeromonas genus-specific primers. Aeromonads were detected in lung swab, blood and bone marrow of drowned bodies (n=3), but were negative in these three matrices for all negative controls (n=90) tested. Bone marrow proved to be a suitable alternative matrix and can be sampled post-mortem by an aseptic sternal puncture. In conclusion, this study confirms previous indications that aeromonads in cultures from blood of water bodies can be considered a potential marker for drowning. Given the fact that the number of immersed bodies (drowned and non-drowned) included in this study is statistically not significant, however, more tissue samples need to be investigated to confirm the validity of these methods to aid the diagnosis of death by wet drowning. PMID- 22497705 TI - Synthesis and properties of polyurethane foams prepared from heavy oil modified by polyols with 4,4'-methylene-diphenylene isocyanate (MDI). AB - The aim of the present study was to determine whether polyurethane (PU) foams can be prepared from heavy oil derived from biomass liquefaction. Since the hydroxyl number of the heavy oil was only 212 mg KOH/g, it was modified by polyols, and a hydroxyl number of 564.5 mg KOH/g was obtained. However, secondary hydroxyls rather than primary hydroxyls were introduced. As a result, when 10 wt.% activated heavy oil was added to bio-polyols, compressive strength of foams increased by 32% over that without the addition of heavy oil. When activated heavy oil wholly replaced polyethylene glycol 400, the high content of secondary hydroxyls depressed the foam reaction and resulted in partial dissociation of the heavy oil from the network structure and weakening of the thermal stability of the PU foams. Therefore, increasing the content of primary-hydroxyls by directional modification is necessary to make the process commercially feasible. PMID- 22497706 TI - Direct conversion of cellulose into polyols over Ni/W/SiO2-Al2O3. AB - The direct conversion of cellulose into polyols over Ni/W/SiO(2)-Al(2)O(3) catalysts with different Al molar fractions was examined. For comparison, Cu/W/SiO(2)-Al(2)O(3), Fe/W/SiO(2)-Al(2)O(3), and Co/W/SiO(2)-Al(2)O(3) were also evaluated. The bulk crystalline structure was determined using X-ray diffraction (XRD). The surface acidity was probed via temperature-programmed desorption of ammonia (NH(3)-TPD). The textural properties were investigated using N(2) physisorption. The metal contents were confirmed via inductively coupled plasma atomic emission spectroscopy (ICP-AES). Among the various metal catalysts, Ni/W/SiO(2)-Al(2)O(3) was confirmed to be the most favorable for hydrogenolysis of cellulose into polyols. The effect of the Al molar fraction in SiO(2) Al(2)O(3) on this reaction over Ni/W/SiO(2)-Al(2)O(3) was also investigated. It was found that the polyol yield was closely related to the total acidity of the support. Compared to Ni/W/SBA-15, Ni/W/SiO(2)-Al(2)O(3) (Al/(Al+Si)=0.6) showed better stability during the recycling test. The catalyst deactivation was confirmed to be caused by metal leaching. PMID- 22497707 TI - Enhanced humification by carbonated basic oxygen furnace steel slag--II. Process characterization and the role of inorganic components in the formation of humic like substances. AB - Enhanced humification by abiotic catalysts is a potentially promising supplementary composting method for stabilizing organic carbon from biowastes. In this study, the role of steel slag in the transformation of humic precursors was directly characterized by measuring the variance in dissolved organic carbon (DOC), spectroscopic parameters (E(600)), and the concentration and molecular weight change of humic-like substances (HLS) during the process. In addition, a mechanistic study of the process was explored. The results directly showed that steel slag greatly accelerated the formation of HLS. The findings indicate that Fe(III)-and Mn(IV)-oxides in steel slag act as oxidants and substantially enhance the polycondensation of humic precursors. Moreover, the reaction appears to suppress the release of metals from steel slag to a certain extent under acidic conditions. This can be attributed to the cover of HLS on the external surface of steel slag, which is significant for its environmentally sound reuse. PMID- 22497708 TI - Evaluation of sulfur-based autotrophic denitrification and denitritation for biological removal of nitrate and nitrite from contaminated waters. AB - Sulfur-based autotrophic denitrification and denitritation were investigated using an oil reservoir culture. In batch system nitrate up to 20 mM was reduced with concomitant sulfate production. With 20 mM nitrate, reduction of produced nitrite did not occur which was contrary to that under heterotrophic conditions. Reduction of nitrite as the sole substrate occurred even at 50 mM. When both sulfur and acetate were present, only acetate was used as the electron donor. In the continuous biofilm reactor maximum nitrate and nitrite removal rates of 17.3 and 13.2 mM/h, much higher than literature values, were achieved at residence times of 0.4 and 0.6 h, respectively. Bicarbonate functioned effectively as carbon source and alkaline, and eliminated the problems associated with lime addition. Based on these and our earlier findings the highest nitrate and nitrite removal rates are achieved under heterotrophic conditions with acetate, followed by autotrophic rates with sulfide, and then elemental sulfur. PMID- 22497709 TI - Fed-batch fermentation and supercritical fluid extraction of heterotrophic microalgal Chlorella protothecoides lipids. AB - Lipids obtained from Chlorella protothecoides in heterotrophic cultivation are considered a suitable feedstock for biodiesel production. In this study, glucose fed-batch fermentation was performed to increase final biomass and lipid production. The biomass productivity and lipid productivity were 6.28 and 2.06 g/L day, respectively. Biomass/glucose conversion and the lipid/glucose conversion were 43.3% and 14.2%, respectively. Extraction of lipids from algae has been identified as a key bottleneck in bioprocessing operations. Supercritical carbon dioxide (SC-CO(2)) was applied for neutral lipids extraction and the SC-CO(2) kinetics was investigated by the Goto et al. model. The modeling showed a good fit with experimental data. Additionally, neutral lipids extracted by SC-CO(2) displayed a suitable fatty acid profile for biodiesel [mainly C18:1 (60.0%), C18:2 (18.7%) and C16:0 (11.5%)]. Our study demonstrated the ability to produce high levels of neutral lipids through heterotrophic algal culture and subsequent extraction of lipids with SC-CO(2) method developed. PMID- 22497710 TI - Performance of hemicellulolytic enzymes in culture supernatants from a wide range of fungi on insoluble wheat straw and corn fiber fractions. AB - Filamentous fungi are a good source of hemicellulolytic enzymes for biomass degradation. Enzyme preparations were obtained as culture supernatants from 78 fungal isolates grown on wheat straw as carbon source. These enzyme preparations were utilized in the hydrolysis of insoluble wheat straw and corn fiber xylan rich fractions. Up to 14% of the carbohydrates in wheat straw and 34% of those in corn fiber were hydrolyzed. The degree of hydrolysis by the enzymes depended on the origin of the fungal isolate and on the complexity of the substrate to be degraded. Penicillium, Trichoderma or Aspergillus species, and some non identified fungi proved to be the best producers of hemicellulolytic enzymes for degradation of xylan rich materials. This study proves that the choice for an enzyme preparation to efficiently degrade a natural xylan rich substrate, is dependent on the xylan characteristics and could not be estimated by using model substrates. PMID- 22497711 TI - Surfactant organic molecules restore magnetism in metal-oxide nanoparticle surfaces. AB - The properties of magnetic nanoparticles tend to be depressed by the unavoidable presence of a magnetically inactive surface layer. However, outstanding magnetic properties with a room-temperature magnetization near the bulk value can be produced by high-temperature synthesis methods involving capping with organic acid. The capping molecules are not magnetic, so the origin of the enhanced magnetization remains elusive. In this work, we present a real-space characterization on the subnanometer scale of the magnetic, chemical, and structural properties of iron-oxide nanoparticles via aberration-corrected scanning transmission electron microscopy. For the first time, electron magnetic chiral dichroism is used to map the magnetization of nanoparticles in real space with subnanometer spatial resolution. We find that the surface of the nanoparticles is magnetically ordered. Combining the results with density functional calculations, we establish how magnetization is restored in the surface layer. The bonding with the acid's O atoms results in O-Fe atomic configuration and distances close to bulk values. We conclude that the nature and number of molecules in the capping layer is an essential ingredient in the fabrication of nanoparticles with optimal magnetic properties. PMID- 22497713 TI - Apneic crises: a clue for MECP2 testing in severe neonatal hypotonia-respiratory failure. AB - Males with methyl-CpG-binding protein 2 (MECP2) mutations may present with neonatal encephalopathy. We report on an infant with a MECP2 mutation who exhibited complex constellation of symptoms, including severe hypotonia, respiratory failure, and apneic episodes. In the neonatal period these symptoms are common to other disorders, including Ondine syndrome. Our observation confirms that the triad of severe hypotonia, apneic episodes, and respiratory failure may be caused by MECP2 mutations. Neonatologist and neuropediatricians must be alert to the presence of these symptoms to exclude this rare but severe disorder. Clinical suspicion and molecular confirmation of MECP2 mutation is of great importance for defining the diagnosis of this rare affection. PMID- 22497714 TI - Predicting resting energy expenditure in boys with Duchenne muscular dystrophy. AB - BACKGROUND: Understanding how best to predict energy needs in Duchenne muscular dystrophy (DMD) is fundamental to weight management in clinical practice; however there is a large gap in the literature regarding information on the most appropriate method. We aimed to ascertain the most valid predictive equation that can be used to predict REE in steroid treated ambulatory boys with DMD. METHODS: REE was measured in 9 boys with DMD using indirect calorimetry after an overnight fast. REE was predicted using five different equations, based on height, weight, or body composition variables. RESULTS: Mean measured REE was 5.4 (SD 0.4) MJ/day. The inclusion of fat free mass in the prediction equation provided no benefit over body weight. The exclusion of height, when compared with weight alone, improved predictive performance, as seen with the Schofield equations, in which a minimal bias and root means squared error is seen. CONCLUSIONS: The most accurate and precise equation was the Schofield weight equation (Bias -0.2 MJ, 95% CI: -1.3-0.9 MJ), which can easily be calculated in a clinical setting and provides a solid foundation from which clinicians can establish energy requirements to support nutritional management in boys with DMD. PMID- 22497712 TI - Nuclear carrier and RNA-binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma (FUS) pathological changes. AB - AIMS: We aimed to investigate the role of the nuclear carrier and binding proteins, transportin 1 (TRN1) and transportin 2 (TRN2), TATA-binding protein associated factor 15 (TAF15) and Ewing's sarcoma protein (EWS) in inclusion body formation in cases of frontotemporal lobar degeneration (FTLD) associated with fused in sarcoma protein (FTLD-FUS). METHODS: Eight cases of FTLD-FUS (five cases of atypical FTLD-U, two of neuronal intermediate filament inclusion body disease and one of basophilic inclusion body disease) were immunostained for FUS, TRN1, TRN2, TAF15 and EWS. Ten cases of FTLD associated with TDP-43 inclusions served as reference cases. RESULTS: The inclusion bodies in FTLD-FUS contained TRN1 and TAF15 and, to a lesser extent, EWS, but not TRN2. The patterns of immunostaining for TRN1 and TAF15 were very similar to that of FUS. None of these proteins was associated with tau or TDP-43 aggregations in FTLD. CONCLUSIONS: Data suggest that FUS, TRN1 and TAF15 may participate in a functional pathway in an interdependent way, and imply that the function of TDP-43 may not necessarily be in parallel with, or complementary to, that of FUS, despite each protein sharing many similar structural elements. PMID- 22497715 TI - Genetic stability in the Icelandic horse breed. AB - Despite the Icelandic horse enjoying great popularity worldwide, the breed's gene pool is small. This is because of a millennium of isolation on Iceland, population crashes caused by natural disasters and selective breeding. Populations with small effective population sizes are considered to be more at risk of selection pressures such as disease and environmental change. By analysing historic and modern mitochondrial DNA sequences and nuclear coat colour genes, we examined real-time population dynamics in the Icelandic horse over the last 150 years. Despite the small gene pool of this breed, we found that the effective population size and genetic profile of the Icelandic horse have remained stable over the studied time period. PMID- 22497716 TI - Application of flow cytometric in situ hybridization assay to Epstein-Barr virus associated T/natural killer cell lymphoproliferative diseases. AB - Epstein-Barr virus (EBV) infects various types of lymphocytes and is associated with not only B cell-origin lymphoma, but also T or natural killer cell lymphoproliferative diseases (T/NK LPD). Recently, we established a novel assay to identify EBV-infected cells using FISH. Using this assay, dual staining with antibodies to both surface antigens and an EBV-encoded small RNA (EBER) probe can be performed. In the present study, we applied this recently developed FISH assay to EBV-associated T/NK LPD to confirm its diagnostic utility. Using FISH, we prospectively analyzed peripheral blood from patients with suspected EBV associated T/NK LPD. The results were compared with those obtained using immunobead sorting followed by quantitative PCR. In all, 26 patients were included study. Using FISH, 0.15-67.0% of peripheral blood lymphocytes were found to be positive for EBER. Dual staining was used to determine EBER-positive cell phenotypes in 23 of 26 subjects (88.5%). In five of seven patients with hydroa vacciniforme-like lymphoma (an EBV-positive cutaneous T cell lymphoma), EBER positive cells were identified as CD3(+) CD4(-) CD8(-) TCRgammadelta(+) T cells. Furthermore, in a 25-year-old male patient with systemic EBV-positive T cell LPD, two lymphocyte lineages were positive for EBER: CD4(+) CD8(-) and CD4(-) CD8(+) T cells. Thus, we confirmed that our newly developed assay is useful for quantifying and characterizing EBV-infected lymphocytes in EBV-associated T/NK LPD and that it can be used not only to complement the pathological diagnosis, but also to clarify the pathogenesis and to expand the spectrum of EBV-associated diseases. PMID- 22497718 TI - Selection and application of endophytic bacterium Achromobacter xylosoxidans strain F3B for improving phytoremediation of phenolic pollutants. AB - While phytoremediation has been considered as an in situ bioprocess to remediate environmental contaminants, the application of functional endophytic bacteria within plants remains a potential strategy that could enhance the plants' efficiency in phytoremediation. In this study, 219 endophytes were isolated from plants that are predominantly located in a constructed wetland, including reed (Phragmites australis) and water spinach (Ipomoea aquatica). Twenty-five strains of the isolated endophytes utilize aromatic compounds as sole carbon source; Achromobacter xylosoxidans strain F3B was chosen for the in planta studies using the model plant Arabidopsis thaliana. Phylogenetic analysis indicated that those endophytic isolates of A. xylosoxidans formed a cluster within its species, and a specific real-time PCR detection method was developed for confirming the stability of the isolates in plants. In the presence of either catechol or phenol, inoculation of A. thaliana with F3B could extend into the root lengths and fresh weights to promote pollutants removal rates. These results demonstrate the potential of the endophytic F3B strain for helping plants to tolerate stress from aromatic compounds and to improve phytoremediation of phenolic pollutants. PMID- 22497717 TI - Synthesis of TiO2 nanorod-decorated graphene sheets and their highly efficient photocatalytic activities under visible-light irradiation. AB - The titanium dioxide (TiO(2)) nanorod-decorated graphene sheets photocatalysts with different TiO(2) nanorods population have been synthesized by a simple non hydrolytic sol-gel approach. Electron microscopy and X-ray diffraction analysis indicated that the TiO(2) nanorods are well-dispersed and successfully anchored on the graphene sheet surface through the formation of covalent bonds between Ti and C atoms. The photocatalytic activities are evaluated in terms of the efficiencies of photodecomposition and adsorption of methylene blue (MB) in aqueous solution under visible-light irradiation. The as-synthesized TiO(2) nanorod-decorated graphene sheets showed unprecedented photodecomposition efficiency compared to the pristine TiO(2) nanorods and the commercial TiO(2) (P 25, Degussa) under visible-light. It is believed that this predominant photocatalytic activity is due to the synergistic contribution of both a retarded charge recombination rate caused by a high electronic mobility of graphene and an increased surface area originated from nanometer-sized TiO(2) nanorods. Furthermore, photoelectrochemical study is performed to give deep insights into the primary roles of graphene that determines the photocatalytic activity. PMID- 22497719 TI - Schiff base-chitosan grafted multiwalled carbon nanotubes as a novel solid-phase extraction adsorbent for determination of heavy metal by ICP-MS. AB - A novel Schiff base-chitosan-grafted multiwalled carbon nanotubes (S-CS-MWCNTs) solid-phase extraction adsorbent was synthesized by covalently grafting a Schiff base-chitosan (S-CS) onto the surfaces of oxidized MWCNTs. The adsorbent was characterized by Fourier-transform infrared spectroscopy, transmission electron microscopy, and thermal gravimetric analysis. The results showed that S-CS was successfully grafted onto the surfaces of MWCNTs. A method was developed for the determination of heavy metals, namely V(V), Cr(VI), Cu(II), As(V) and Pb(II) in biological and environmental samples by inductively coupled plasma mass spectrometry coupled with preconcentration with S-CS-MWCNTs. The parameters influencing preconcentration of target ions, such as the pH of the sample solution, the flow rate of sample loading, the eluent concentration, and eluent volume, were investigated and optimized. Under the optimal conditions, the enrichment factors of V(V), Cr(VI), Cu(II), As(V), and Pb(II) reached 111, 95, 60, 52, and 128, respectively, and the detection limits were as low as 1.3-3.8 ng L(-1). The developed method was successfully applied to the determination of trace-metal ions in herring, spinach, river water, and tap water with good recoveries ranging from 91.0% to 105.0%. PMID- 22497720 TI - Young and free? A study of independent mobility among urban and rural dwelling Australian children. AB - OBJECTIVES: To examine urban/rural differences in children's independent mobility; associations between mobility licences and children's independent mobility; and potential correlates of mobility licences. DESIGN: Cross-sectional study of 430 primary (48% boys; 72% urban) and 258 secondary schoolchildren (52% boys; 51.6% urban) and their parents. METHODS: Parents survey reported the mobility licences they granted to their children (e.g. allowing them to cross main roads on their own), access to outdoor playspaces and mobile phone ownership. Children survey reported their independent mobility on school journeys and on weekends. Differences were examined in mobility licences and independent mobility by sex, urban/rural setting and age-group. Regression analyses examined associations between mobility licences and independent mobility; and how access to playspaces, and mobile phone ownership, were associated with mobility licences. RESULTS: Overall, on average, boys were granted more mobility licences, than were girls, but there were no significant differences by urban/rural location. Variations in independent mobility by urban/rural locality were identified on the school journey but not on weekends. Boys attending urban primary schools had highest rates (44%) of walking/cycling independently to school; those attending rural secondary schools had the lowest (14%). Among urban boys and rural primary school-aged girls access to outdoor playspaces was associated with mobility licences. Mobile phone ownership was associated with mobility licences only among boys attending urban primary schools. CONCLUSIONS: Many Australian children in urban and rural areas lack independent mobility. Further research should examine social/physical environmental influences on parental restrictions, to inform interventions that aim to promote children's independent mobility. PMID- 22497721 TI - Step-rate thresholds for moderate and vigorous-intensity activity in persons with Down syndrome. AB - OBJECTIVES: Monitoring physical activity intensity in persons with Down syndrome (DS) may be affected by an altered relationship between metabolic equivalent units (METs) and step-rate. This study examined whether the relationship between METs and step-rate is altered in persons with DS and developed step-rate thresholds for activity intensity for these persons. DESIGN: Cross-sectional. METHODS: Eighteen persons with DS (25+/-7years; 8 women) and 22 persons without DS (26+/-5 years; 9 women) completed six over-ground walking trials each lasting 6 min at their preferred speed and at 0.5, 0.75, 1.0, 1.25, and 1.5 ms-1. METs were measured with portable spirometry and step-rate with hand-tally. Random effects models were used to predict METs from step-rate, squared step-rate, height, presence of DS, sex, and body mass index (BMI). RESULTS: Step-rate, squared step-rate, height, and presence of DS contributed significantly to the model (SE=0.20 METs; R2=0.63); sex and BMI did not contribute. As height increased, step-rate thresholds for moderate and vigorous-intensity activity decreased. For a given height, participants with DS had lower step-rate at the moderate-intensity threshold than participants without DS. Across participant heights, the moderate-intensity cut-off ranged between 101 and 76 steps min-1 in persons with DS and between 103 and 80 steps min-1 in persons without DS. For persons with DS, step-rate at the vigorous-intensity threshold ranged between 136 and 126 steps min-1. CONCLUSIONS: Persons with DS showed altered relationship between METs and step-rate and had lower step-rate thresholds for moderate intensity activity than persons without DS. PMID- 22497722 TI - The incidence of behaviours associated with body checking among youth ice hockey players. AB - OBJECTIVES: To determine if a difference exists between the incidence and intensity of the physical contacts of Pee Wee (aged 11-12 years) ice hockey players according to whether the players participate in a league in which body checking is permitted (Calgary, Canada) compared to a league in which body checking is not permitted (Quebec City, Canada). DESIGN: Cohort study conducted in Quebec City and Calgary during the 2007-2008 Pee Wee ice hockey season. METHODS: Ten games were randomly selected for each city (n=20) and analysed. Games were videotaped and subsequently analysed with a validated observation system allowing quantification of the intensity of the various physical contacts. Incidence rate ratios (RR) based on multivariate Poisson regression were used to compare the physical contacts between provinces. All analyses were controlling for game period, score difference, and zone on the playing surface. RESULTS: A total of 2418 physical contacts with the trunk and 757 other physical contacts were observed. Very light intensity trunk physical contacts were more frequent in Quebec City (adjusted incidence RR [ARR]: 0.68; 95% CI: 0.48-0.97). Very high intensity trunk physical contacts were more frequent in Calgary (ARR: 12.72; 95% CI: 4.48-36.14). Hooking (ARR: 0.89; 95% CI: 0.84-0.95) and slashing (ARR: 0.91; 95% CI: 0.85-0.97) were more frequent in Quebec City. CONCLUSIONS: Results suggest that players' behaviours are different in leagues where body checking is permitted compared to leagues where it is not permitted. Policy allowing body checking in Pee Wee ice hockey increases the frequency and intensity of physical contacts. PMID- 22497723 TI - Opioid rotation: what is the rush? PMID- 22497724 TI - Opioid use patterns and association with pain severity and mental health functioning in chronic pain patients. AB - OBJECTIVE: The objective of this study was to explore the relationship between patterns of opioid use, pain severity, and pain-related mental health in chronic pain patients prescribed opioids. DESIGN: The study was designed as a one-time patient interview with structured pain and opioid use assessments. SETTING: The study was set in a tertiary care medical center in the United States Department of Veterans Affairs. PATIENTS. Study participants were primary care patients with a pain condition for greater than 6 months who received at least one prescription for an opioid in the prior 12 months. OUTCOME MEASURES: The Prescription Drug Use Questionnaire was used to assess patterns of opioid use. The Pain Outcomes Questionnaire was used to assess pain-related functioning. RESULTS: Symptomatic use of opioid medication (e.g., taking an opioid in response to increased pain) was more common than scheduled (i.e., taking an opioid at regular times) or strategic use of opioid medication (e.g., taking an opioid specifically to engage in activities). Symptomatic use of opioids was associated with poorer pain-related mental health, after controlling for pain duration and pain-related physical functioning. Use of opioids in a scheduled pattern was associated with better pain-related mental health. Patients rarely reported that they used opioids strategically to facilitate functional activities. CONCLUSIONS: The patterns in which patients use their opioid medications are associated with their psychological functioning. This is consistent with theory regarding the potential impact of reinforcing effects of opioid medication on functional outcomes. Interventions to encourage strategic or scheduled opioid use warrant investigation as methods to improve pain outcomes with opioids. PMID- 22497725 TI - CYP2D6 poor metabolizer genotype and smoking predict severe postoperative pain in female patients on arrival to the recovery room. AB - Recent studies have shown that CYP2D6 acts at critical steps for endogenous morphine biosynthesis. The present study assessed the contribution of CYP2D6 genetic polymorphisms, smoking, and other factors on acute severe postoperative pain (linear analog pain scores >=8). METHODS: Two hundred thirty-six female patients were found to have adequate information in a previously developed female surgical patient database to be included in this current analysis. Multiple logistic regression analysis was used to assess the predictors for acute severe postoperative pain. DNA had been previously extracted from blood samples in all patients and was genotyped by the Amplichip to determine the specific CYP2D6 genotypes. RESULTS: It was noted that the incidence of acute severe postoperative pain (linear analog pain scores >=8) was more frequent in patients with the CYP2D6 poor metabolizer (PM) genotype, 71%, compared with 28% in intermediate metabolizers (IMs), 26% in extensive metabolizers (EMs), and 27% in ultrarapid metabolizers (UMs). The overall association between metabolizer groups and severe postoperative pain was significant (P=0.023). PMs were significantly more likely to suffer from severe postoperative pain than IMs, EMs, and UMs (P=0.007, 0.002, and 0.050, respectively). There were no significant differences among IMs, EMs, and UMs. Additionally, it was noted that there was an increased frequency of acute severe postoperative pain in smokers vs nonsmokers (P=0.014). CONCLUSION: This study demonstrated that female patients possessing the PM genotype of CYP2D6 and patients who smoke had a higher incidence of acute severe postoperative pain. PMID- 22497726 TI - Toll-like receptor signal adaptor protein MyD88 is required for sustained endotoxin-induced acute hypoferremic response in mice. AB - Hypoferremia, associated with immune system activation, involves a marked reduction in the levels of circulating iron, coupled with iron sequestration within macrophages. Toll-like receptor (TLR) signaling plays an important role in the development of the hypoferremic response, but how downstream signaling events affect genes involved in iron metabolism is incompletely understood. We investigated the involvement of MyD88-dependent (MyD88) and MyD88-independent (TRIF) TLR signaling in the development of hypoferremia. Using MyD88-deficient and TRIF-deficient mice, we show that MyD88 and TRIF signaling pathways are critical for up-regulation by lipopolysaccharide (LPS) of the iron regulator hepcidin. In addition, MyD88 signaling is required for the induction of lipocalin 2 secretion and iron sequestration in the spleen. Activation of TLR4 and TLR3 signaling through LPS and polyinosinic:polycytidylic acid [poly(I:C)] treatments resulted in rapid down-regulation of HFE protein [encoded by the hemochromatosis gene (Hfe)] and ferroportin [encoded by solute carrier family 40 (iron-regulated transporter), member 1 (Slc40a1)] expression in the spleen, independent of MyD88 or TRIF signaling and proinflammatory cytokine production. However, lack of MyD88 signaling significantly impaired the hypoferremic response triggered by LPS, indicating that ferroportin and HFE protein down-regulation alone are insufficient to maintain hypoferremia. The extent of the hypoferremic response was found to be limited by initial, basal iron levels. Together, these results suggest that targeting specific TLR signaling pathways by affecting the function of adaptor molecules may provide new strategies to counteract iron sequestration within macrophages during inflammation. PMID- 22497727 TI - In situ regeneration of NADH via lipoamide dehydrogenase-catalyzed electron transfer reaction evidenced by spectroelectrochemistry. AB - NAD/NADH is a coenzyme found in all living cells, carrying electrons from one reaction to another. We report on characterizations of in situ regeneration of NADH via lipoamide dehydrogenase (LD)-catalyzed electron transfer reaction to regenerate NADH using UV-vis spectroelectrochemistry. The Michaelis-Menten constant (K(m)) and maximum velocity (V(max)) of NADH regeneration were measured as 0.80+/-0.15 mM and 1.91+/-0.09 MUM s(-1) in a 1-mm thin-layer spectroelectrochemical cell using gold gauze as the working electrode at the applied potential -0.75 V (vs. Ag/AgCl). The electrocatalytic reduction of the NAD system was further coupled with the enzymatic conversion of pyruvate to lactate by lactate dehydrogenase to examine the coenzymatic activity of the regenerated NADH. Although the reproducible electrocatalytic reduction of NAD into NADH is known to be difficult compared to the electrocatalytic oxidation of NADH, our spectroelectrochemical results indicate that the in situ regeneration of NADH via LD-catalyzed electron transfer reaction is fast and sustainable and can be potentially applied to many NAD/NADH-dependent enzyme systems. PMID- 22497728 TI - Retinal neuropathy precedes vasculopathy in diabetes: a function-based opportunity for early treatment intervention? AB - Diabetes, now at epidemic levels, can have devastating effects on the eye and vision. Treatments of the ocular complications are currently focused on relatively advanced stages and are limited to the slowing down of the progressive sight-threatening retinal vasculopathy (diabetic retinopathy). Tiny signals from the neural retina have been shown to reveal early diabetic neuropathy prior to vascular retinopathy. These signals, in a clinical test format, are predictive, by precise retinal location, of impending vasculopathy in the retina within a year, including sight-threatening oedema. The discovery opens possibilities for the future development of treatments to prevent the onset of retinopathy and the more sight-threatening retinal oedema and changes patient management strategies. PMID- 22497729 TI - Oxidative stress in chronic otitis media with effusion. AB - CONCLUSIONS: The high oxidant levels in chronic otitis media with effusion (OME) observed in our research and the improvement seen in children with chronic OME after antioxidant treatment suggest that oxygen-derived free radicals play an important role in chronic OME. OBJECTIVES: OME is a common pathologic condition characterized by nonpurulent fluid in the middle ear (ME) that leads to moderate conductive hearing loss and flat tympanogram. During OME inflammatory cells generate large amounts of superoxide radicals to improve bactericidal activity. Overproduction of oxygen-derived free radicals induces oxidative damage in humans. Glutathione (GSH) is one of the major components of the antioxidant system that protects cells from oxidative stress. The aim of the study was to evaluate oxidative stress in chronic OME by investigation of ME fluids collected during myringotomy. METHODS: During myringotomy, fluid was collected from the ME to evaluate lipid peroxide levels in the effusion. Fifty-nine children with ME effusion without any resolution after repeated medical treatments were enrolled in the study. RESULTS: Lipid peroxide levels in all samples were high (mean 11.5 nmole/million cells), similar to the values found in other chronic diseases. GSH might be employed during surgery while applying ventilation tubes and after surgery to prevent oxidative stress. PMID- 22497730 TI - Impaired responsiveness to clopidogrel and aspirin in patients with recurrent stent thrombosis following percutaneous intervention for peripheral artery disease. AB - Patients with peripheral artery disease (PAD) following peripheral percutaneous transluminal angioplasty (PTA) with stent implantation are prone to stent thrombosis despite treatment with aspirin and clopidogrel. Impaired clopidogrel responsiveness is associated with increased risk of ischemic events in patients following coronary stent implantation. We sought to assess platelet responsiveness to clopidogrel and aspirin in patients with PAD and recurrent stent thrombosis. Platelet aggregation induced by 5 and 20 umol/l adenosine diphosphate (ADP) and 0.5 mmol/l arachidonic acid (AA), together with platelet reactivity index (PRI) and serum thromboxane B(2) (TXB(2)), were determined in 11 patients with PAD and a history of stent thrombosis (mean, 3.1 +/- 1.14) after PTA and in 15 patients with PAD with no such history, also in 11 controls with coronary artery disease (CAD) and previous stent thrombosis. Platelet aggregation to 5 umol/l ADP was higher in subjects with PAD and stent thrombosis than in those without stent thrombosis (p = 0.0003) and CAD subjects (p = 0.002). Aggregation induced by 20 umol/l ADP was higher in PAD group with stent thrombosis than in PAD subjects without thrombosis (p = 0.004). The PAD group with stent thrombosis had higher AA-induced platelet aggregation than CAD controls (p = 0.007) and serum TXB(2) concentrations higher than PAD group without thrombosis (p = 0.002) and CAD group (p = 0.02). Concluding, platelet responsiveness to clopidogrel and aspirin is impaired in patients with PAD and recurrent stent thrombosis following PTA, as compared with similar individuals with CAD, and PAD with no history of stent thrombosis. This indicates that atherosclerosis burden affects platelet function and might contribute to stent thrombosis following percutaneous intervention in peripheral arteries. PMID- 22497731 TI - Non-invasive evaluation of vasomotor and metabolic functions of microvascular endothelium in human skin. AB - Correlation between metabolic and microhemodynamic processes in skin was assessed through acute pharmacological test with metabolically active Actovegin in 28 healthy volunteers. Laser Doppler flowmetry in combination with wavelet analysis of blood flow oscillations was used to identify functional state of arteriolar venular areas of microvascular bed in the right forearm skin; capillary blood flow parameters were assessed through computer capillaroscopy in the nail bed of the right hand on the 4th finger. The metabolic effect (improved oxygen uptake and glucose disposal by tissues) was accompanied by significant increase in endothelial rhythm amplitude by 98% (p<0.00006), neurogenic rhythm amplitude by 50% (p<0.003) and myogenic rhythm amplitude by 54% (p<0.03), with capillary blood flow rate increasing by 90MUm/s (p<0.04), pericapillary zone reducing by 15MUm (p<0.0001) and diastolic blood pressure dropping by 4mm Hg (p<0.02). These results show close correlation between metabolic and microhemodynamic processes, which suggests that the amplitude activity within the range of endothelial rhythm (0.0095-0.021Hz) during laser Doppler flowmetry reflects not only solely vasomotor function but also metabolic function of microvascular endothelium. PMID- 22497732 TI - Highly pathogenic porcine reproductive and respiratory syndrome virus impairs LPS and poly(I:C)-stimulated tumor necrosis factor-alpha release by inhibiting ERK signaling pathway. AB - Atypical porcine reproductive and respiratory syndrome (PRRS) characterized by high morbidity and mortality emerged in China in 2006. The causative agent was confirmed to be a highly pathogenic PRRS virus (HP-PRRSV). However, the pathogenesis of HP-PRRSV is still uncertain. Here, the ability of the highly pathogenic strains (HV and JX) to induce tumor necrosis factor alpha (TNF-alpha) was studied. Our results showed that HV and JX were weaker inducers of TNF-alpha than the conventional strain CH-1a. Moreover, HV infection was demonstrated to suppress extracellular signal-regulated kinase (ERK) phosphorylation at the early time points. Pharmacologic inhibition or activation of ERK revealed that TNF alpha production in HV-infected macrophages was associated with the activation status of ERK. Furthermore, HV- and JX-infection could potently impair lipopolysaccharide (LPS)- and poly(I:C)-stimulated TNF-alpha release in a dose dependent manner whereas synergistic effects were observed at mRNA level. The observation suggested the involvement of posttranslational impact of HP-PRRSV on TNF-alpha production, which might be attributed to the reduced ERK1/2 phosphorylation in response to toll-like receptor (TLR)-ligation. Taken together, our results indicated that HP-PRRSV infection could impair TNF-alpha production by inhibiting ERK signaling pathway, which might partially contribute to the pathogenesis of HP-PRRSV. PMID- 22497733 TI - LC-MS/MS determination and pharmacokinetic study of four lignan components in rat plasma after oral administration of Acanthopanax sessiliflorus extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acanthopanax sessiliflorus (Rupr. et Maxim.) Seem. is a shrub mainly present in China, Japan and Korea, the root bark of which is considered as one of the sources of Wujiapi and widely used for its various pharmacological effects. AIM OF THE STUDY: A selective and sensitive UPLC-MS/MS method was developed and validated for the determination and pharmacokinetic study of asarinin, sesamin, helioxanthin and savinin in rat plasma. MATERIALS AND METHODS: Sample preparation involved a liquid-liquid extraction of the analytes with methyl tert-butyl ether (MTBE). LC separation was achieved on a UPLC C(18) column at 30 degrees C with a mobile phase consisting of methanol-2 mM ammonium acetate (68:32, v/v). The detection was accomplished by multiple-reaction monitoring (MRM) scanning with electrospray ionization (ESI) source operating in the positive ionization mode. The optimized mass transition ion-pairs (m/z) monitored for asarinin, sesamin, helioxanthin, savinin and IS were 372.2/233.0, 372.2/233.0, 349.1/319.0, 352.9/334.9 and 180.0/109.7, respectively. RESULTS: The current LC-MS/MS assay was validated for linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability and was suitable for pharmacokinetic studies of the four lignans after oral administration of Acanthopanax sessiliflorus extract. The time to reach the maximum plasma concentration (T(max)) was 2.50+/-0.15 h for asarinin, 1.94+/-0.28 for sesamin, 2.22+/-0.48 h for helioxanthin and 2.83+/-0.29 h for savinin. The elimination half-time (t(1/2)) of asarinin, sesamin, helioxanthin and savinin was 6.08+/ 1.10, 11.69+/-0.50, 7.16+/-0.52 and 6.26+/-0.57 h, respectively. CONCLUSION: This paper described a simple, sensitive and validated UPLC-MS/MS method for simultaneous determination of four lignans in rat plasma after oral administration of Acanthopanax sessiliflorus extract, and investigated on their pharmacokinetic studies as well. PMID- 22497734 TI - Gut and airways relaxant effects of Carum roxburghianum. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Carum roxburghianum is traditionally used in hyperactive gastrointestinal and respiratory disorders. The present study was carried out to investigate the possible gut and airways relaxant potential of Carum roxburghianum to rationalize its folk uses. MATERIALS AND METHODS: Crude extract of Carum roxburghianum (Cr.Cr) was studied in in vivo and in vitro techniques. RESULTS: Cr.Cr exhibited protective effect against castor oil-induced diarrhea in mice at 100-1000 mg/kg. In rabbit jejunum preparations, Cr.Cr (0.03 3.0 mg/mL) caused relaxation of spontaneous and K(+) (80 mM)-induced contractions at similar concentrations, like papaverine. Pretreatment of tissues with Cr.Cr (0.1-1.0 mg/mL) shifted Ca(++) concentration-response curves (CRCs) to right, like verapamil. Cr.Cr (0.03 and 0.1 mg/mL) caused leftward shift of isoprenaline induced inhibitory CRCs, similar to papaverine. In isolated guinea-pig ileum, Cr.Cr (0.01 and 0.03 mg/mL) produced rightward parallel shift of acetylcholine curves, like atropine. Cr.Cr (1.0-30 mg/kg) caused suppression of carbachol (CCh, 100 MUg/kg)-induced increase in inspiratory pressure of anaesthetized rats. In guinea-pig trachea, Cr.Cr (0.03-1.0 mg/mL) relaxed CCh and high K(+)-induced contractions, shifted isoprenaline-induced inhibitory CRCs to left at 0.1 and 0.3 mg/mL and CCh-curves parallel to right (0.01 and 0.03 mg/mL). Cr.Cr did not cause any mortality of mice up to 10 g/kg dose. CONCLUSION: These results indicate that Carum roxburghianum possess combination of antidiarrheal, antispasmodic and bronchodilatory effects, which provides pharmacological basis to its traditional use in the disorders of gut and airways hyperactivity, like diarrhea, colic and asthma. PMID- 22497735 TI - Forty-five years of schizophrenia trials in Italy: a survey. AB - BACKGROUND: Well-designed and properly executed randomized controlled trials (RCTs) provide the best evidence on the efficacy of healthcare interventions. Mental health has a strong tradition of using trial to evaluate treatments, but the translation of research to clinical practice is not always easy. Even well conducted trials do not necessarily address the needs of every day care and trials can reflect local needs and the specific culture in which they are undertaken. Generalizing results to other contexts can become problematic but these trials may, nevertheless, be very helpful within their own context. Moreover, pathways for drug approval can be different depending on local regulatory agencies. Local trials are helpful for decision-making in the region from which they come, but should not be viewed in isolation. National quantity and quality of trials may vary across nations.The aim of this study is to quantify trialing activity in Italy from 1948 until 2009 and to describe characteristics of these trials. In addition, we evaluated change over time in three keys aspects: sample size, follow-up duration, and number of outcomes. METHODS: We used the Cochrane Schizophrenia Group's register that contains 16,000 citations to 13,000 studies relating only to people with schizophrenia or schizophrenia-like illness. Randomized controlled trials and controlled clinical trials undertaken in Italy and involving pharmacological interventions were included. RESULTS: The original search identified 155 records of potentially eligible studies, 74 of which were excluded because do not meet inclusion criteria. A total of 81 studies were included in the analysis. The majority of trials were conducted in north Italy, and published in international journals between 1981 and 1995. The majority of studies (52 out of 81) used standardized diagnostic criteria for schizophrenia disorder. They were defined as randomized and used blind methods to administer treatment. However, most failed to report detail regarding methodological procedures and it is difficult to ascertain which studies are associated with a low risk of bias. CONCLUSIONS: Trials should be designed to address the needs of everyday care with the aim of following large samples of typical patients in the long term. The Italian tradition in the area of trialing treatments for people with schizophrenia is not as strong as in many other similar countries and Italy should be producing more, better, independent, and clinically relevant trials. PMID- 22497736 TI - The expression of one ankyrin pk2 allele of the WO prophage is correlated with the Wolbachia feminizing effect in isopods. AB - BACKGROUND: The maternally inherited alpha-Proteobacteria Wolbachia pipientis is an obligate endosymbiont of nematodes and arthropods, in which they induce a variety of reproductive alterations, including Cytoplasmic Incompatibility (CI) and feminization. The genome of the feminizing wVulC Wolbachia strain harboured by the isopod Armadillidium vulgare has been sequenced and is now at the final assembly step. It contains an unusually high number of ankyrin motif-containing genes, two of which are homologous to the phage-related pk1 and pk2 genes thought to contribute to the CI phenotype in Culex pipiens. These genes encode putative bacterial effectors mediating Wolbachia-host protein-protein interactions via their ankyrin motifs. RESULTS: To test whether these Wolbachia homologs are potentially involved in altering terrestrial isopod reproduction, we determined the distribution and expression of both pk1 and pk2 genes in the 3 Wolbachia strains that induce CI and in 5 inducing feminization of their isopod hosts. Aside from the genes being highly conserved, we found a substantial copy number variation among strains, and that is linked to prophage diversity. Transcriptional analyses revealed expression of one pk2 allele (pk2b2) only in the feminizing Wolbachia strains of isopods. CONCLUSIONS: These results reveal the need to investigate the functions of Wolbachia ankyrin gene products, in particular those of Pk2, and their host targets with respect to host sex manipulation. PMID- 22497737 TI - Validating the impact of a molecular subtype in ovarian cancer on outcomes: a study of the OVCAD Consortium. AB - Most patients with epithelial ovarian cancer (EOC) are diagnosed at advanced stage and have a poor prognosis. However, a small proportion of these patients will survive, whereas others will die very quickly. Clinicopathological factors do not allow precise identification of these subgroups. Thus, we have validated a molecular subclassification as new prognostic factor in EOC. One hundred and ninety-four patients with Stage II-IV EOC were characterized by whole-genome expression profiling of tumor tissues and were classified using a published 112 gene set, derived from an International Federation of Gynecology and Obstetrics (FIGO) stage-directed supervised classification approach. The 194 tumor samples were classified into two subclasses comprising 95 (Subclass 1) and 99 (Subclass 2) tumors. All nine FIGO II tumors were grouped in Subclass 1 (P = 0.001). Subclass 2 (54% of advanced-stage tumors) was significantly correlated with peritoneal carcinomatosis and non-optimal debulking. Patients with Subclass 2 tumors had a worse overall survival for both serous and non-serous histological subtypes, as revealed by univariate analysis (hazard ratios [HR] of 3.17 and 17.11, respectively; P <= 0.001) and in models corrected for relevant clinicopathologic parameters (HR 2.87 and 12.42, respectively; P <= 0.023). Significance analysis of microarrays revealed 2082 genes that were differentially expressed in advanced-grade serous tumors of both subclasses and the focal adhesion pathway as the most deregulated pathway. In the present validation study, we have shown that, in advanced-stage serous ovarian cancer, two approximately equally large molecular subtypes exist, independent of classical clinocopathological parameters and presenting with highly different whole-genome expression profiles and a markedly different overall survival. Similar results were obtained in a small cohort of patients with non-serous tumors. PMID- 22497738 TI - Towards standardization of canine STRs: a proposed nomenclature for six markers from the ISAG comparison-test panel. AB - Eight short tandem repeat markers included in the International Society for Animal Genetics panel of 24 loci investigated in canine comparison tests were analysed in a sample of pure-breed dogs, with the purpose of defining an allele nomenclature based on the number of repeats. A regression analysis of the raw data produced by the sequencer, coupled with the direct sequencing of selected alleles, allowed us to propose a system of nomenclature for six of the eight loci (four di-nucleotidic: AHT121, AHTh137, REN169018 and REN64E19, and two tetra nucleotidic: FH2001 and FH2328). The remaining two loci (INU055 and FH2848) showed a pattern of fragments that did not resolve in a simple allele series. This work may be useful to establish a basis for comparing data across different laboratories for a set of validated canine markers, which can be used in population genetics, forensics and other analyses. PMID- 22497739 TI - Extracavitary/solid variant of primary effusion lymphoma. AB - Primary effusion lymphoma (PEL) is a distinct clinicopathologic entity associated with human herpesvirus 8 (HHV8) infection that mostly affects patients with immunodeficiency. Primary effusion lymphoma usually presents as a malignant effusion involving the pleural, peritoneal, and/or pericardial cavities without a tumor mass. Rare cases of HHV8-positive lymphoma with features similar to PEL can present as tumor masses in the absence of cavity effusions and are considered to represent an extracavitary or solid variant of PEL. Here, we report 3 cases of extracavitary PEL arising in human immunodeficiency virus-infected men. Two patients had lymphadenopathy and underwent lymph node biopsy. One patient had a mass involving the ileum and ascending colon. In lymph nodes, the tumor was predominantly sinusoidal. The tumor involving the ileum and ascending colon presented as 2 masses, 12.5 * 10.6 * 2.6 cm in the colon and 3.6 * 2.7 * 1.9 cm in the ileum. In each case, the neoplasms were composed of large anaplastic cells, and 2 cases had "hallmark cells." Immunohistochemistry showed that all cases were positive for HHV8 and CD138. One case also expressed CD4 and CD30, and 1 case was positive for Epstein-Barr virus-encoded RNA. Evidence of B-cell differentiation was poorly developed in all tumors. These cases highlight the importance of assessing HHV8 in an anaplastic tumor that arises in a human immunodeficiency virus-positive patient and further contributes to the limited literature currently available for extracavitary PEL. PMID- 22497740 TI - The irrelevant sound effect under articulatory suppression is a suffix effect even with five-item lists. AB - The relationship between the suffix effect and the effect of irrelevant sound on serial recall of auditorily presented lists is investigated in this study. Contrary to the predictions of the phonological loop model, Hanley and Hayes (2012) reported that the irrelevant sound effect was abolished under articulatory suppression when a spoken suffix was added at the end of the list. The experiment reported in this paper uses a shorter list length (five items per list) than that employed by Hanley and Hayes. This is because it cannot realistically be argued that participants will abandon the use of phonological codes to retain the list items with sequences as short as this. Results replicated those of Hanley and Hayes (2012). There was a significant effect of irrelevant sound under articulatory suppression when the list items were followed by an auditory tone. Crucially, however, the effect of irrelevant sound under articulatory suppression was abolished when the list items were followed by a spoken suffix. PMID- 22497741 TI - Optimizing the assessment of pain in children who are cognitively impaired through the quality improvement process. AB - Pain assessment in children with cognitive impairment (CI) is challenging. A quality improvement (QI) project involving evidence-based review of pain assessment tools, feedback from the Family Advisory Council, trialing of selected tools within clinical settings including obtaining feedback from nurses, and parents caring for nonverbal children with developmental delay was reported. Synthesized evidence supported the adoption of revised Faces, Legs, Activity, Cry, and Consolability pain assessment tool into clinical practice. Results of postimplementation audit and challenges of staff nurse involvement in the QI process were also discussed. The 24-month-long QI process and its impact on changing practice were described in detail. PMID- 22497742 TI - The effects of oral motor stimulation on feeding behaviors of infants born with univentricle anatomy. AB - The purpose of this pilot study was to determine the effects of oral motor stimulation on infants born with complex univentricle anatomy who required surgery shortly after birth. A quasi-experimental group design was used to compare 18 infants receiving an oral motor stimulation program with 10 infants who did not receive any oral motor intervention. Infants in the treatment group received the oral motor treatment prior to cardiac surgery and immediately following surgery, one time a day, 6 days a week. Outcomes data were collected for length of time to reach full bottle-feeds and length of hospital stay. A statistically significant difference was seen in the overall length of hospital stay between the two groups (p = .04). Infants in the experimental group were hospitalized for a mean of 28.6 days and infants in the comparison group for a mean of 35.3 days. Infants in the treatment group achieved full bottle-feeds 2 days earlier than infants in the comparison group, although this was not statistically significant. There is positive support for the use of oral motor stimulation for infants born with univentricle anatomy, but further study is needed to determine the long-lasting effects of this intervention. PMID- 22497743 TI - Here today, gone tomorrow: diagnostic and treatment challenges created by medication shortages and discontinuations. PMID- 22497744 TI - Prevalence and relevance of pain in older persons. AB - SETTING: With the ageing of the world's population, any health problem which adversely affects quality of life in older persons becomes increasingly salient. Persistent pain is one of the most prevalent health conditions faced by adults of advanced age, and is recognized as a major concern for this segment of the population. RESULTS: Numerous epidemiologic surveys suggest that pain is most common during the late middle-aged phase of life (55-65 years) and continues at approximately the same prevalence into older age (65+). This is true regardless of the anatomical site or the pathogenic cause of pain. The one exception appears to be pain associated with degenerative joint disease (e.g., osteoarthritis) which shows an exponential increase until at least 90 years of age. Common age associated conditions like dementia may result in a reduced frequency and intensity of pain. Daily pain is a major risk factor for developing disability and the oldest age cohorts are most vulnerable. Discretionary and higher order physical activities appear most affected, while basic activities of daily living may be modified but are rarely ceased altogether. Similar relationships have been documented for risk of depression and mood disturbance in older persons with persistent pain. Despite such well characterized adverse impacts, pain often remains poorly treated in older persons. This occurs across all health care settings examined (i.e., emergency, acute, outpatient, long-term care). CONCLUSION: Improved knowledge for both health professionals and patients, addressing the current research gaps and expansion of age-appropriate pain management services will be required to better meet the needs of our rapidly ageing population. PMID- 22497745 TI - The effects of age on pain sensitivity: preclinical studies. AB - OBJECTIVE: Preclinical studies of pain and aging represent an area of research where considerations of age, strain, gender, and method of behavioral assessment are but some of the challenges that must be addressed. The results of studies related to the impact of age on pain sensitivity have ranged from increased to decreased sensitivity to no change. Examining the design of these studies one discovers that cross-sectional designs using animals of different ages have been used to evaluate age-related effects in normal animals as well as animals with inflammatory and neuropathic pain conditions. In the present review a summary of these studies is presented along with a discussion of potential mechanisms responsible for changes that have been described. OUTCOME MEASURES: The dominant method of behavioral assessment in the majority of studies involving rodents has been reflex-based strategies that unfortunately do not reveal the same effects of experimental manipulations known to affect pain sensitivity in humans. A comparison of results obtained with reflex-based methods versus those obtained with cortically dependent operant methods reveals significant differences. CONCLUSIONS: Increases in pain sensitivity under different experimental conditions have been suggested to result from age-related anatomical, physiological, and biochemical changes as well as compensatory changes in homeostatic mechanisms and intrinsic plasticity of somatosensory pathways involved in the processing and perception of pain. Other factors that may contribute to the impact of age on pain sensitivity include dysregulation of the hypothalamic-pituitary-adrenal axis and changes in autonomic function that occur with advancing age. In the future translational research in the field of pain and aging will need to focus on establishing clinically relevant animal models and assessment strategies to evaluate the causal relationships between the biological changes associated with advancing age and the varied behavioral changes in pain sensitivity. PMID- 22497746 TI - Age-related changes in the structure and function of brain regions involved in pain processing. AB - OBJECTIVE: This review summarizes the scientific literature addressing the effects of aging on pain processing in the brain. DESIGN: A literature search was undertaken using PubMed and search terms including pain, aging, and brain. SETTINGS AND PATIENTS: Studies including healthy older people and older people with painful disorders were reviewed. MEASURES: Publications reporting the outcomes of neuroimaging techniques including positron emission tomography, structural and functional magnetic resonance imaging, and electroencephalography in samples incorporating older people were reviewed. RESULTS: Age-related decreases in regional brain volume occur in structures implicated in pain processing, and are most pronounced in the prefrontal cortex and hippocampus, whereas age-related atrophy in brainstem regions involved in pain modulation is less pronounced. Functional brain imaging has revealed decreased pain activation in the putamen and insula among older people during extrinsic stimuli, but any effects of aging on the processing of clinical pain are yet to be reported. CONCLUSIONS: The network of brain regions involved in pain processing are subject to age-related changes in structure, but that the functional implications of these changes are yet to be determined. PMID- 22497747 TI - Experimental approaches in the study of pain in the elderly. AB - The present review summarizes experimental data on age-related changes in pain processing. These data suggest an increase in pain threshold and a decrease in tolerance threshold, which both are dependent on the physical nature of the stressor, as well as a developing deficiency in endogenous pain inhibition, which might be paralleled by an enhanced disposition to central sensitization (stronger temporal summation). These findings are arranged in a model that allows for explaining the two seemingly divergent perspectives: age both dulls the pain sense and increases the prevalence of pain complaints. This model is based on the assumption that both excitatory and inhibitory processes are dampened with age but that the later processes age at a faster rate, leading to increasingly unbalanced pain excitation. PMID- 22497748 TI - Pain education and current curricula for older adults. AB - OBJECTIVE: The objectives of this study were 1) to determine the level of education around the world and to identify strong evidence upon which future educational initiatives could be established; and 2) to establish a collaboration who could lead the way in terms of recommendations and educational developments for the care of older adults around the world. DESIGN: A two-phase approach was used to achieve the above objectives. Phase I involved a survey conducted through the International Association for the Study of Pain (IASP) Special Interest Group (SIG) to determine the variations and availability of pain education for older adults from around the world. Phase II involved the setting up of an expert panel to review the guidelines on pain management currently available and therefore make some recommendations around the curriculum content. SETTING: The small-scale study was conducted within 15 countries through the IASP discussion forum. SUBJECTS: A range of health-care professionals from medicine, nursing, psychology, and allied health professionals were involved in this study. RESULTS: Fifteen countries responded to the survey, providing evidence of huge variation in courses available around the world. Fourteen documents were reviewed by the expert panel, which provided evidence for education, assessment, and management of pain. CONCLUSION: Several recommendations can be made from this work: 1) establish an expert working group who can provide the experience and skills necessary to develop a multidisciplinary curriculum on pain in older adults--this has been achieved through this current work; 2) conduct a thorough systematic review of the literature around pain assessment and management, which could inform a curriculum; and 3) seek representation for membership of the expert group on the IASP core curriculum working group. PMID- 22497749 TI - Treatment guidelines for the pharmacological management of pain in older persons. AB - BACKGROUND: Chronic or persistent pain is a common problem in older adults and is often associated with significant physical disability and psychosocial problems. The potential benefits, risks, and costs of pharmacotherapy as a mainstay in the treatment of moderate to severe pain in this population must be well-understood and weighed accordingly. Recent treatment guidelines have been introduced that can guide decision making to optimize pain-related treatment outcomes in older individuals OBJECTIVES AND RESULTS: This review article describes and summarizes key evidence-based recommendations that were derived by a committee convened by the American Geriatrics Society in order to provide guidance to optimize pharmacotherapy in the management of persistent pain in older individuals. CONCLUSIONS: It is postulated that ongoing education of clinicians who treat older patients with persistent moderate to severe pain will lead to improved outcomes in this vulnerable population. PMID- 22497750 TI - Self-management of pain in older persons: helping people help themselves. AB - OBJECTIVE: This article has the following two primary objectives: 1) to provide a discussion of the self-management of pain for older adults in relation to therapist-assisted cognitive behavioral procedures; and 2) to review the main features of a recently developed manualized pain self-management program for older adults. DESIGN: Literature review. RESULTS: The term self-management has been used loosely in the pain literature to describe a wide variety of programs in which the individual plays an active role in the management of his or her pain. Many of these programs are therapist-/facilitator-assisted and have many commonalities with cognitive behavior therapy. Efficacy evidence for self management in older adults is mixed although arthritis self-management programs show considerable promise. The incorporation of a therapist/facilitator appears to enhance the effects of self-management programs. CONCLUSIONS: Self-management outcomes may be inconsistent across studies partly because there is very limited standardization and manualization of self-management approaches. A manualized self-management program is described as an example of an approach that could easily be standardized and facilitate future investigations. It would be important for subsequent research to focus on the identification of subgroups of older patients who are most likely to benefit from self-management, and to determine whether self-management improves outcomes of future professionally administered treatments. PMID- 22497751 TI - The science and art of pain management in older persons: case study and discussion. AB - INTRODUCTION: Evidence-based medicine has been adopted as a means of achieving optimal medical care and to reduce variations in clinical practice. Randomised controlled trials are considered the highest level of scientific evidence. Older individuals are either excluded or underrepresented in these studies, and those who are included are often atypical of patients seen in clinical practice. OBJECTIVE: To examine the approach to clinical decision making in frail older persons when there is little or no scientific evidence to guide management. METHODS: A case study is presented of refractory post herpetic neuralgia in a frail older person. Management plans were developed combining the scientific evidence from the pain literature with the practice known as Comprehensive Geriatric Assessment. The rationale and evidence for clinical decision making is explored. RESULTS: Standard therapies for post herpetic neuralgia had been ineffective or limited by side effects in this patient. By a process of trial and error a combination of treatments was found that improved pain and mood but adversely affected cognition. Adjustment in treatments over time resulted in improved pain, mood, and cognition. CONCLUSIONS: The art of medicine is not the antithesis of the scientific approach. The art of medicine involves balancing the scientific evidence with the circumstances and the preferences of the patient. Combining the practices of Pain Medicine and Comprehensive Geriatric Assessment may result in a better outcome. When treating older people, clinicians not only need to take into consideration the severity of pain, but also the impact of pain and its treatment on cognition, mood and functional status. PMID- 22497752 TI - A randomised, placebo- and active-controlled dose-finding study of aclidinium bromide administered twice a day in COPD patients. AB - This Phase IIb, double-blind, double-dummy, placebo- and active-comparator controlled crossover study (ClinicalTrials.gov identifier: NCT01120093) assessed efficacy and safety of three doses of aclidinium bromide in patients with moderate to severe chronic obstructive pulmonary disease. Patients were randomised to one of five treatment sequences each consisting of twice-daily (BID) aclidinium 100 MUg, 200 MUg, 400 MUg (via Genuair(r)*), formoterol 12 MUg (via Aerolizer(r)) and matched placebo for 7 days, with a 5- to 9-day washout period. Primary endpoint was mean change from baseline in forced expiratory volume in 1 s (FEV1) normalised area under the curve (AUC)0-12 on Day 7. Secondary endpoints were: change from baseline in FEV1 normalised AUC12-24, FEV1 normalised AUC0-24 and morning pre-dose FEV1 on Day 7. Adverse events were monitored throughout the study. Of 79 randomised patients, 68 (86.1%) completed the study. After 7 days of treatment, aclidinium and formoterol produced statistically significantly greater changes from baseline in FEV1 normalised AUC0 12 vs placebo (p<0.0001). FEV1 normalised AUC12-24, FEV1 normalised AUC0-24, and morning pre-dose FEV1 were also statistically significantly greater with all aclidinium doses vs placebo (p<0.0001). Improvements in primary and secondary endpoints were statistically significantly greater with aclidinium 400 MUg vs 100 MUg. The safety profile of aclidinium was comparable to placebo. These results demonstrated that twice-daily aclidinium produced dose-dependent clinically meaningful improvements in FEV1 compared with placebo. This study also confirmed the use of an aclidinium BID dosing regimen and established aclidinium 200 MUg and 400 MUg as suitable doses for further investigation in Phase III trials. PMID- 22497753 TI - Callosal tissue loss parallels subtle decline in psychomotor speed. a longitudinal quantitative MRI study. The LADIS Study. AB - Cross-sectional studies have suggested that corpus callosum (CC) atrophy is related to impairment in global cognitive function, mental speed, and executive functions in the elderly. Longitudinal studies confirming these findings have been lacking. We investigated whether CC tissue loss is associated with change in cognitive performance over time in subjects with age-related white matter lesions (WML). Two-hundred-fifty-three subjects, aged 65-84 years, were evaluated by using repeated MRI and neuropsychological evaluation at baseline and after 3 years. The effect of overall and regional CC tissue loss on cognitive decline was analyzed with hierarchical linear regression models. After controlling for age, sex, education, and baseline cognitive performance, the rates of tissue loss in the total CC area, and in rostrum/genu and midbody subregions were significantly associated with decline in a compound measure of cognitive speed and motor control, but not in those of executive functions, memory, or global cognitive function. Total CC area and midbody remained significant predictors of speed also after adjusting for baseline WML volume, WML progression, and global brain atrophy. However, the relationship between anterior CC and speed performance was mediated by WML volume. In conclusion, the overall and regional rate of CC tissue loss parallels longitudinal slowing of psychomotor performance. The adverse effect of CC tissue loss on psychomotor function may be driven by altered interhemispheric information transfer between homologous cortical areas. PMID- 22497754 TI - Analysis of three lamotrigine extended-release clinical trials: comparison of pragmatic ITT and LOCF methodologies. AB - Early withdrawal of patients from a clinical trial can compromise the robustness of the data by introducing bias into the analysis. This is most commonly addressed by using the "intent to treat" (ITT) population and "last observation carried forward" (LOCF) methodology, where a patient's last assessment is carried forward. This can lead to overstatement of treatment efficacy especially if events indicative of treatment failure are infrequent. An alternative methodology, labeled "pragmatic ITT" (P-ITT), requires patients to have a positive outcome and to complete the trial in order to be considered a treatment success by that outcome measure. Data from 3 randomized multicenter lamotrigine extended-release (LTG XR) trials were analyzed and response (proportions seizure free and with 50% response) were compared using LOCF and P-ITT methodologies. In 2 of the 3 trials, a lower response for both seizure freedom and 50% response was seen during the Maintenance phase using the P-ITT methodology. In the trial that did not show a difference, only a small number of patients withdrew early, thus negating the benefit brought by the P-ITT method. Differences between methodologies were not noted when evaluation was applied to the entire treatment period, most likely a reflection of the fact that a therapeutic dose of lamotrigine is not rapidly achieved. We propose that the P-ITT may be a simpler, more informative method for evaluating the effectiveness of a drug, especially in comparison to another active drug(s). PMID- 22497756 TI - Conserved haplotype blocks within the sheep MHC and low SNP heterozygosity in the Class IIa subregion. AB - This report describes single-nucleotide polymorphisms (SNPs) in the sheep major histocompatibility complex (MHC) class II and class III regions and provides insights into the internal structure of this important genomic complex. MHC haplotypes were deduced from sheep family trios based on genotypes from 20 novel SNPs representative of the class II region and 10 previously described SNPs spanning the class III region. All 30 SNPs exhibited Hardy-Weinberg proportions in the sheep population studied. Recombination within an extended sire haplotype was observed within the class II region for 4 of 20 sheep chromosomes, thereby supporting the presence of separated IIa and IIb subregions similar to those present in cattle. SNP heterozygosity varied across the class II and III regions. One segment of the class IIa subregion manifested very low heterozygosity for several SNPs spanning approximately 120 Kbp. This feature corresponds to a subregion within the human MHC class II region previously described as a 'SNP desert' because of its paucity of SNPs. Linkage disequilibrium (LD) was reduced at the junction separating the putative class IIb and IIa subregions and also between the class IIa and the class III subregions. The latter observation is consistent with either an unmapped physical separation at this location or more likely a boundary characterized by more frequent recombination between two conserved subregions, each manifesting high within-block LD. These results identify internal blocks of loci in the sheep MHC, within which recombination is relatively rare. PMID- 22497757 TI - Ultrasound-guided hysteroscopy to remove a levonorgestrel intrauterine system in early pregnancy. AB - BACKGROUND: Correctly placed levonorgestrel-releasing intrauterine systems (LNG IUSs) are rarely associated with intrauterine pregnancy when pregnancy occurs. LNG-IUS retrieval, termination of pregnancy and conservative management if retracted strings prevent ready removal are the usual clinical options given to women. The conservative course raises concerns about teratogenesis related to high local progestin exposure for the developing fetus. STUDY DESIGN: This case report describes combined saline hysteroscopy and ultrasound to retrieve an LNG IUS at less than 9 weeks of gestational age. A systematic review of the literature was performed to identify similar case reports by contacting the manufacturer and searching Pubmed from 1900 through November 2011 using the terms ((levonorgestrel AND intrauterine) OR mirena) AND (pregnan* OR fetal OR fetus OR teratogen*) NOT (menorrhagia OR hyperplas* OR ectopic OR malig* OR cancer). RESULTS: We identified 37 cases of LNG-IUS pregnancy exposures in the absence of spontaneous expulsion or myometrial or intraperitoneal placement of LNG-IUS. Given the presence of two congenital anomalies reported in the group, the anomaly rate is 5.4%, 95% confidence interval 0% to 11.5%. CONCLUSIONS: Intrauterine LNG IUS exposure is associated with a low frequency of congenital anomalies. Combining hysteroscopy with ultrasound facilitates surgically precise LNG-IUS removal despite retracted strings. PMID- 22497758 TI - Polycyclic aromatic hydrocarbons on indoor/outdoor glass window surfaces in Guangzhou and Hong Kong, south China. AB - Organic films were collected from indoor and outdoor window surfaces in two large cities in southern China, Guangzhou and Hong Kong, and analyzed to quantify the polycyclic aromatic hydrocarbons (PAHs). In the glass films, the highest concentration of total PAHs, predominantly phenanthrene, fluorene, fluoranthene, and pyrene, was found to be l400 ng/m(2). The concentrations of PAHs in Guangzhou were usually higher than those in Hong Kong. In general, higher concentrations of PAHs on exterior window films in comparison with interior window films in both cities indicated that the outdoor air acted as a major source of pollution to the indoor environment. However, indoor air was a major source of some light-weight PAHs. Measurements made over time indicated that the growth rates of light-weight PAHs on window surfaces were fast at the beginning and then gradually reached a consistent level, whereas heavy-weight PAHs exhibited near-linear accumulation during the 40 days sampling period. PMID- 22497759 TI - Synthesis and potent in vitro activity of novel 1H-benzimidazoles as anti-MRSA agents. AB - A new class of 1H-benzimidazolecarboxamidines was synthesized and evaluated for in vitro antibacterial and antifungal activities, including drug-resistant bacterial strains. The most potent compound (32) has the same ratio of anti-MRSA activity as Vancomycin (minimal inhibitory concentrations value 0.78 MUg/mL). The mechanism of action for 1H-benzimidazolecarboxamidine appears to be different from existing antibacterial agents. These compounds have potential for development as a new class of potent anti-MRSA agent. PMID- 22497760 TI - Discovery of new quinoline ether inhibitors with high affinity and selectivity for PDGFR tyrosine kinases. AB - A new series of quinoline ether inhibitors, which potently and selectively inhibit PDGFR tyrosine kinases, is described in this Letter. Compounds 23 and 33 are selective, low nanomolar inhibitors of PDGFRalpha and beta, display good pharmacokinetics in rat and dog and are active in vivo at low doses when given orally twice daily. Further evaluation of these compounds is warranted. PMID- 22497761 TI - Design, synthesis and structure-activity-relationship of 1,5 tetrahydronaphthyridines as CETP inhibitors. AB - This Letter describes the discovery and SAR optimization of 1,5 tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC(50)=23 and 22nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/hApoA1 dual heterozygous mice model. PMID- 22497762 TI - Triazoloamides as potent gamma-secretase modulators with reduced hERG liability. AB - Synthesis and SAR studies of novel aryl triazoles as gamma secretase modulators (GSMs) are presented in this communication. Starting from our aryl triazole leads, optimization studies were continued and the series progressed towards novel amides and lactams. Triazole 57 was identified as the most potent analog in this series, displaying single-digit nanomolar Abeta42 IC(50) in cell-based assays and reduced affinity for the hERG channel. PMID- 22497763 TI - Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: part 2. AB - Melanin concentrating hormone receptor 1 (MCHR1) antagonists have potential for the treatment of obesity and several CNS disorders. In the preceding article, we have described a novel series of quinazolines as MCHR1 antagonists and demonstrated in vivo proof of principle with an early lead. Herein we describe the detailed SAR and SPR studies to identify an optimized lead candidate having good efficacy in a sub-chronic DIO model with a good cardiovascular safety window. PMID- 22497764 TI - Preclinical metabolism of LB42908, a novel farnesyl transferase inhibitor, and its effects on the cytochrome P450 isozyme activities. AB - Metabolism of LB42908, a novel farnesyl transferase inhibitor, was investigated for preclinical development. In vitro hepatic metabolism of LB42908 gave rise to at least 9 metabolites via phase I biotransformation pathways, which were characterized by HPLC-UV, LC-MS, and LC-MS/MS analyses. N-Dealkylation was shown to be a major phase I metabolic pathway. Species-specific in vitro metabolism of LB42908 was studied in liver fractions of rat, dog, monkey, and human. Order of metabolic stability is human~dog>rat~monkey in both S9 and microsomal fractions. Tissue-specific metabolism of LB42908 in various tissue homogenates of rats demonstrated that the liver was the major organ responsible for phase I metabolism of LB42908. The results from both qualitative and quantitative metabolism studies such as metabolic profiling and metabolic clearance indicated that dog would be the animal model of choice for preclinical toxicology studies. In addition, LB42908 was a potent CYP3A4 inhibitor in human liver microsomes and induced the activities of several CYP isozymes, implying that it has the potential for drug-drug interactions. Repeated dosing of LB42908 in rats did not significantly affect its own metabolism, indicating that long-term administration of LB42908 would not alter its pharmacokinetic profiles. PMID- 22497766 TI - [Reducing the risk of vascular complications during percutaneous aortic valve replacement]. AB - The percutaneous aortic valve replacement (TAVI) is the most recent and promising procedure in the area of interventional cardiology with a rapidly growing number of interventions worldwide. The transfemoral approach being less invasive, it has become the predominant access for the device delivery. The prevention of vascular complications by an optimal risk stratification using appropriate imaging techniques (vascular CT scan and angiography), optimised techniques for femoral puncture (active control of the arterial punction, crossover...) and skilled teams for peripheral angioplasty and percutaneous arterial closure devices (Prostar) has become mandatory given the fragile target population for TAVI. Vascular complications remain indeed one of the most frequent complication although the trend toward reduced sheeths size led to significant reduction This is mandatory regarding the needed size of the vascular arterial access - itself with constant improvement by minimising the initial 24 French with mandatory real chirurgical closure to the actual 18-19 French and soon 16 French. The improvement of the implanted devices is due to the recent evidence of the promising future of this technique and the important technological effort realised by the industry not only on the implanted aortic prosthesis but also on their delivering catheters. PMID- 22497765 TI - Overcoming fluconazole resistance in Candida albicans clinical isolates with tetracyclic indoles. AB - Continuing efforts to discover novel means of combating fluconazole resistance in Candida albicans have identified an indole derivative that sensitizes strains demonstrating resistance to fluconazole. This tetracycle (3, ML229) does not appear to act through established Hsp90 or calcineurin pathways to chemosensitize C. albicans, as determined in Saccharomyces cerevisiae models, and may be a useful probe to uncover alternative resistance pathways. PMID- 22497767 TI - Intermittent operation of ultra-low pressure ultrafiltration for decentralized drinking water treatment. AB - River water was treated by ultrafiltration at a relatively low transmembrane pressure (40 mbar). As observed before, flux stabilization occurred after several days of operation although no back-flushing or cross flow was applied. Interruptions in flux were applied by temporary offset of the transmembrane pressure. After restoration of the transmembrane pressure, the initial flux was higher than the stable flux level, and the flux recovery depended on the standstill time. Furthermore, if a short cross flow was applied after standstill, the flux was restored to an even higher level. In all cases, the flux decreased again during operation to reach finally the same stable level as before standstill. In order to evaluate the influence of intermittent operation as practiced for water treatment on a household level, daily interruptions of flux were applied. An optimum of total daily water production rate was obtained at 21 h of operation and 3 h of standstill per day. A model was developed which can describe the impact of intermittent operation on the flux depending on the duration of the standstill and operating periods. This enables the prediction of production capacity of the system operated intermittently. The flux increase during standstill could be explained by a relaxation and expansion of the biofouling layer, while the higher flux after forward-flushing was caused by this layer being partially sloughed off. Household water treatment with the process presented here will generally be operated on a discontinuous basis. The results show that such operation schemes do not compromise the permeability of the system, but actually lead to higher fluxes after standstill. PMID- 22497768 TI - A fluorimetric assay for human reticulocyte 15-lipoxygenase-1 activity. AB - A rapid and sensitive fluorescence-based assay for the determination of human 15 lipoxygenase-1 (15-LOX-1) activity is described in this article. The assay utilizes the ability of 15-LOX-1-generated lipid hydroperoxides to oxidize nonfluorescent dihydrorhodamine 123, producing the highly fluorescent dye rhodamine 123. Formation of rhodamine 123 can be monitored through fluorescence spectroscopy using Ex/Em of 500 nm/536 nm. The IC(50) values of three well-known 15-LOX-1 inhibitors, nordihydroguaiaretic acid, quercetin, and fisetin, were evaluated in 96- and 384-well formats, and they conform to previously reported data. We believe this assay can be broadly used for the discovery of novel lipoxygenase inhibitors. PMID- 22497769 TI - Fish peripheral blood mononuclear cells preparation for future monitoring applications. AB - Fish species possess many specific characteristics that support their use in ecotoxicology. Widely used in clinical research, peripheral blood mononuclear cells (PBMCs) can reasonably be exploited as relevant target cells in the assessment of environmental chemical toxicity. The current article focuses on the methods necessary to isolate, characterize, and culture fish PBMCs. These procedures were successfully applied on an endangered species, the European eel (Anguilla anguilla L.), and on an economically important and worldwide exported species, the Asian catfish (Pangasianodon hypophthalmus S.). Proteomic approaches can be useful to screen xenobiotic exposure at the protein expression level, giving the opportunity to develop early warning signals thanks to molecular signatures of toxicity. To date, a major limitation of proteomic analyses is that most protein expression profiles often reveal the same predominant and frequently differentially expressed families of proteins regardless of the experimental stressing conditions. The current study describes a methodology to get a postnuclear fraction of high quality isolated from fish PBMCs in order to perform subsequent subproteomic analyses. Applied on samples from eel, the subproteomic analysis (two-dimensional differential in-gel electrophoresis) allowed the identification by liquid chromatography-tandem mass spectrometry and searches in the full NCBInr (National Center for Biotechnology Information nonredundant) database of 66 proteins representing 36 different proteins validated through Peptide and Protein Prophet of Scaffold software. PMID- 22497770 TI - Is symptom relief associated with reduction in gastric retention after gastric electrical stimulation treatment in patients with gastroparesis? A sensitivity analysis with logistic regression models. AB - BACKGROUND: Enterra gastric electrical stimulation (GES) is an alternative treatment for gastroparesis (GP) when standard medical therapy fails. The aims of this study were to evaluate the association between total symptom score (TSS) and reduction in gastric retention (GR) after GES by GP etiology and to examine the sensitivity of the association to varying cutpoints used to define GR and TSS improvement. METHODS: Gastric retention assessed with a standardized (99m) Tc radio-labeled egg meal and TSS measured by a five-point Likert scale in 221 GP patients treated with Enterra GES therapy for at least 1 year were analyzed. Bivariate chi-square test and multivariable logistic regression with all possible cutpoints were used to assess the consistency of association and quantitate the relationship across three GP etiologies. KEY RESULTS: Symptom relief in diabetic GP was more likely attributable to GR reduction as indicated by the consistently significant odds ratios (P < 0.01) across all cutpoints. The association in idiopathic GP was inconclusive because odds ratios were sensitive to cutpoints with P-values ranging from 0.01 to 0.47. No association was found for patients with post surgical gastroparesis (P > 0.1 for all cutpoints). Patient age, gender, baseline TSS and baseline GR had no significant effect at 5% level on clinical improvement regardless of cutpoints for GR. CONCLUSIONS & INFERENCES: Association between clinical improvements and GR reduction following GES treatment depends on patient etiology and was able to be demonstrated in diabetic GP. The association for idiopathic GP was inconclusive and no such association was found for post surgical GP across all possible cutpoint combinations. PMID- 22497772 TI - Teleradiology with uncompressed digital mammograms: clinical assessment. AB - PURPOSE: The purpose of our study was to demonstrate the feasibility of sending uncompressed digital mammograms in a teleradiologic setting without loss of information by comparing image quality, lesion detection, and BI-RADS assessment. MATERIALS AND METHODS: CDMAM phantoms were sent bidirectionally to two hospitals via the network. For the clinical aspect of the study, 200 patients were selected based on the BI-RAD system: 50% BI-RADS I and II; and 50% BI-RADS IV and V. Two hundred digital mammograms (800 views) were sent to two different institutions via a teleradiology network. Three readers evaluated those 200 mammography studies at institution 1 where the images originated, and in the two other institutions (institutions 2 and 3) where the images were sent. The readers assessed image quality, lesion detection, and BI-RADS classification. RESULTS: Automatic readout showed that CDMAM image quality was identical before and after transmission. The image quality of the 200 studies (total 600 mammograms) was rated as very good or good in 90-97% before and after transmission. Depending on the institution and the reader, only 2.5-9.5% of all studies were rated as poor. The congruence of the readers with respect to the final BI-RADS assessment ranged from 90% and 91% at institution 1 vs. institution 2, and from 86% to 92% at institution 1 vs. institution 3. The agreement was even higher for conformity of content (BI-RADS I or II and BI-RADS IV or V). Reader agreement in the three different institutions with regard to the detection of masses and calcifications, as well as BI-RADS classification, was very good (kappa: 0.775-0.884). Results for interreader agreement were similar. CONCLUSION: Uncompressed digital mammograms can be transmitted to different institutions with different workstations, without loss of information. The transmission process does not significantly influence image quality, lesion detection, or BI-RADS rating. PMID- 22497771 TI - Pathway-directed weighted testing procedures for the integrative analysis of gene expression and metabolomic data. AB - We explore the utility of p-value weighting for enhancing the power to detect differential metabolites in a two-sample setting. Related gene expression information is used to assign an a priori importance level to each metabolite being tested. We map the gene expression to a metabolite through pathways and then gene expression information is summarized per-pathway using gene set enrichment tests. Through simulation we explore four styles of enrichment tests and four weight functions to convert the gene information into a meaningful p value weight. We implement the p-value weighting on a prostate cancer metabolomic dataset. Gene expression on matched samples is used to construct the weights. Under certain regulatory conditions, the use of weighted p-values does not inflate the type I error above what we see for the un-weighted tests except in high correlation situations. The power to detect differential metabolites is notably increased in situations with disjoint pathways and shows moderate improvement, relative to the proportion of enriched pathways, when pathway membership overlaps. PMID- 22497774 TI - When does a conceptual framework become a theory? Reflections from an accidental theorist. AB - In this short paper I reflect on the application of a program logic modeling approach to visualizing evaluation theory as it relates to practical participatory evaluation (PPE). The work of Hansen, Alkin and associates presented in this volume is well-thought out, carefully done, rigorous, and important. I found that their application of the approach resonated well with my understanding of PPE with a few notable exceptions. Specifically, the essence of the partnership aspect of the approach was underemphasized as was stakeholders' role in augmenting the credibility of evaluation findings and PPEs contribution to conceptual use. I then reminisce about the development and evolution of the participatory evaluation framework that we have been working with for so many years. I raise the point that we think of it as a theoretical framework to bound inquiry, not as an evaluation theory per se, which raises an interesting question: when does a theoretical framework become a theory? PMID- 22497773 TI - Surgical treatment of zygomatic bone fracture using two points fixation versus three point fixation--a randomised prospective clinical trial. AB - BACKGROUND: The zygoma plays an important role in the facial contour for both cosmetic and functional reasons; therefore zygomatic bone injuries should be properly diagnosed and adequately treated. Comparison of various surgical approaches and their complications can only be done objectively using outcome measurements which in turn require protocol management and long-term follow up. The preference for open reduction and internal fixation of zygomatic fractures at three points has continued to grow in response to observations of inadequate results from two point and one point fixation techniques.The objectives of this study were to compare the efficacy of zygomatic bone after treatment with ORIF using 2 point fixation and ORIF using 3 point fixation and compare the outcome of two procedures. METHODS: 100 patients were randomly divided equally into two groups. In group A, 50 patients were treated by ORIF using two point fixation by miniplates and in group B, 50 patients were treated by ORIF using three point fixation by miniplates. They were evaluated for their complications during and after surgery with their advantages and disadvantages and the difference between the two groups was observed. RESULTS: A total of 100 fractures were sustained. We found that postoperative complication like decreased malar height and vertical dystopia was more common in those patients who were treated by two point fixation than those who were treated with three point fixation. CONCLUSIONS: Based on this study open reduction and internal fixation using three point fixation by miniplates is the best available method for the treatment zygomatic bone fractures. PMID- 22497775 TI - Towards a performance measurement system for health equity in a local health integration network. AB - While there is a growing literature on building performance measurement systems for health equities, this literature for the most part has not dealt with the challenges of coordinating the various parts of the system, the heterogeneous nature of such systems, or how evaluations and measurement can themselves improve performance. This paper describes the initial steps taken to build a performance measurement system to coordinate health equity across 18 hospitals led by the Toronto Central Local Health Integration Network, which is a regional health authority serving a population of more than 2.5 million residents (near in population to Chicago and Rome) and the most socially diverse urban network in Ontario, Canada. This paper also describes some principles that can help inform a performance measurement system. The innovative aspect of this paper is that these principles were developed through feedback by the hospitals. PMID- 22497776 TI - Small fiber neuropathy in Fabry disease. AB - Previous studies have explicitly shown that small nerve fibers are affected in Fabry disease which is assumed to cause the severe neuropathic pain that patients may have from childhood on. Neuropathic pain and small fiber neuropathy characteristics have therefore been considered as appropriate study endpoints in studies on the efficacy of enzyme replacement therapy. However, the relationship between small fiber neuropathy characteristics and pain, as well as the course of small fiber neuropathy in Fabry disease is still uncertain. In this article a comprehensive overview of the existing literature on small nerve fiber function and structure and the relationship with pain, age and disease severity is presented supplemented with data from the Dutch Fabry cohort, with the aim to identify consensus as well as controversies and to propose a hypothesis on the evolution of neuropathy in Fabry disease. PMID- 22497778 TI - Localised ascending aortic dissection managed conservatively. PMID- 22497777 TI - Increased risk of lung cancer associated with a functionally impaired polymorphic variant of the human DNA glycosylase NEIL2. AB - Human NEIL2, one of five oxidized base-specific DNA glycosylases, is unique in preferentially repairing oxidative damage in transcribed genes. Here we show that depletion of NEIL2 causes a 6-7-fold increase in spontaneous mutation frequency in the HPRT gene of the V79 Chinese hamster lung cell line. This prompted us to screen for NEIL2 variants in lung cancer patients' genomic DNA. We identified several polymorphic variants, among which R103Q and R257L were frequently observed in lung cancer patients. We then characterized these variants biochemically, and observed a modest decrease in DNA glycosylase activity relative to the wild type (WT) only with the R257L mutant protein. However, in reconstituted repair assays containing WT NEIL2 or its R257L and R103Q variants together with other DNA base excision repair (BER) proteins (PNKP, Polbeta, Lig IIIalpha and XRCC1) or using NEIL2-FLAG immunocomplexes, an ~5-fold decrease in repair was observed with the R257L variant compared to WT or R103Q NEIL2, apparently due to the R257L mutant's lower affinity for other repair proteins, particularly Polbeta. Notably, increased endogenous DNA damage was observed in NEIL2 variant (R257L)-expressing cells relative to WT cells. Taken together, our results suggest that the decreased DNA repair capacity of the R257L variant can induce mutations that lead to lung cancer development. PMID- 22497779 TI - The effect of nesiritide on renal function and other clinical parameters in patients with decompensated heart failure and preserved ejection fraction. AB - The role of nesiritide in patients with decompensated heart failure with preserved ejection fraction (dHFpEF) has not been previously studied. In this investigation, the authors retrospectively analyzed the effect of nesiritide on renal function and clinical outcomes in patients admitted with dHFpEF. Of the 658 patients included, 328 were treated with nesiritide while 330 patients were treated with standard diuretic therapy. In both the nesiritide and no nesiritide groups, there was a significant change in mean glomerular filtration rate (GFR) and creatinine at 72 hours as well as at day of discharge (P<.001). This trend did not progress at 1 month in the nesiritide group, although it did in the no nesiritide group. At 1 month after therapy, however, there was a significant difference between the two groups in the mean change of GFR and creatinine (P<.001). There was no significant difference in >25% decrease of GFR anytime through day 30 (25% vs 29.69%, P=.236) between the two groups. On multivariate analysis, nesiritide was an important predictor of renal function at 1 month (P<.05). Thus, nesiritide can be administered safely without negatively impacting long-term renal function in patients admitted with dHFpEF. PMID- 22497780 TI - Chronic exogenous kisspeptin administration accelerates gonadal development in basses of the genus Morone. AB - The present study assesses the effects of chronic administration of peptides to fish, termed kisspeptins, which are the products of the KISS1 and KISS2 genes, and have been shown to control the development of puberty in animals. Using ecologically and commercially important species (white bass, Morone chrysops, striped bass, Morone saxatilis, and their hybrid) as comparative models, we determined that repeated bi-weekly injections (over 7 weeks) differentially accelerate puberty, as evidenced by increases in the prevalence of spermatozoa in the testes of juvenile fish. Moreover, in sexually mature fish, kisspeptin treatment led to increased gonad weight, gonadosomatic index, and spermatocrit in some white and striped bass. Additionally, mature white bass treated with kisspeptins showed an advancement in oocyte development as determined by histological examination. These gonadal changes occurred in the absence of any photothermal manipulation or hormone injections. To date, this is the first description of kisspeptin-mediated pubertal initiation in fish, and the first evidence that kisspeptins could modulate gonad maturation. Although it remains to be determined how kisspeptins may best be utilized in practice, our findings are a basis for future studies to characterize the molecular underpinnings of the KISS system in various fish species. PMID- 22497781 TI - The ARIC predictive model reliably predicted risk of type II diabetes in Asian populations. AB - BACKGROUND: Identification of high-risk individuals is crucial for effective implementation of type 2 diabetes mellitus prevention programs. Several studies have shown that multivariable predictive functions perform as well as the 2-hour post-challenge glucose in identifying these high-risk individuals. The performance of these functions in Asian populations, where the rise in prevalence of type 2 diabetes mellitus is expected to be the greatest in the next several decades, is relatively unknown. METHODS: Using data from three Asian populations in Singapore, we compared the performance of three multivariate predictive models in terms of their discriminatory power and calibration quality: the San Antonio Health Study model, Atherosclerosis Risk in Communities model and the Framingham model. RESULTS: The San Antonio Health Study and Atherosclerosis Risk in Communities models had better discriminative powers than using only fasting plasma glucose or the 2-hour post-challenge glucose. However, the Framingham model did not perform significantly better than fasting glucose or the 2-hour post-challenge glucose. All published models suffered from poor calibration. After recalibration, the Atherosclerosis Risk in Communities model achieved good calibration, the San Antonio Health Study model showed a significant lack of fit in females and the Framingham model showed a significant lack of fit in both females and males. CONCLUSIONS: We conclude that adoption of the ARIC model for Asian populations is feasible and highly recommended when local prospective data is unavailable. PMID- 22497782 TI - Breast reconstruction using permanent Becker expander implants: an 18 year experience. AB - BACKGROUND: Single-stage reconstruction using permanent expander implants is an established technique following mastectomy. Short and long-term outcome data following breast reconstruction using Becker tissue expanders is limited. METHOD: A retrospective case note review of patients undergoing expander-based procedures between 1989 and 2007 was undertaken. Data recorded included postoperative symptoms and complications, the use of radiotherapy, revisional surgery, and device failure. RESULTS: Three hundred and thirteen expanders were used in 276 patients with a mean age of 48.3 (17-78) years, over the 18 year study period. The mean follow up period was 64.6 (1-199) months. 256 Becker expanders were used during 175 latissimus dorsi (LD) and 52 subpectoral (SP) reconstructions, 13 contralateral augmentations and 16 implant replacements. The postoperative infection rate was 5.8%, leading to an expander loss rate of 3.8%. The use of prophylactic antibiotics was associated with an increased postoperative infection rate (p = 0.046). Six haematomas (2.5%) and 12 cases of skin envelope necrosis (5.0%) required unscheduled intervention. Symptoms of pain, distortion and hardness were experienced by 21.3% of patients, and radiotherapy was associated with a significantly higher risk of adverse symptoms (p < 0.0001). No patient developed symptomatic implant rupture or silicone granuloma but 17.9% of reconstructions underwent revisional surgery, the rate being highest following SP reconstruction (p = 0.029). Nine patients developed injection port complications (3.8%), and the overall device failure rate was 1.3%. The original expander has been retained by 74.2% of women. CONCLUSION: The Becker permanent expander is a reliable implant associated with a low complication rate and a high retention rate when used during breast reconstruction. PMID- 22497783 TI - Screening estrogenic activity of environmental contaminants and water samples using a transgenic medaka embryo bioassay. AB - Many natural or synthetic chemicals may act as exogenous estrogens and affect the reproductive health of humans and wildlife. Since these xenoestrogens are ubiquitous, it is essential to monitor their presence in the environment. Hence, we developed a bioassay using the transgenic medaka (Oryzias latipes) embryo, in which the green fluorescent protein (GFP) was placed under the control of the gnrh3 promoter, one of the three paralogous gonadotropin-releasing hormone (GnRH) genes that regulate reproductive function and behavior. As medaka embryos are transparent, the fluorescent expression of GFP can be easily observed in vivo during development. We exposed newly fertilized medaka embryos to varying solutions of bisphenol A (BPA), nonylphenol (NP), 17beta-estradiol (E2), or a river water sample, and monitored their development. During embryonic development, the mRNA levels of GnRHs, GnRH receptors, and estrogen receptors (ERs) were measured with quantitative real-time reverse transcription-PCR. Our results showed that the chemicals and the river water significantly decreased the fluorescent intensity of the GnRH3 neurons, postponed the eye development, and retarded the growth of the embryos. The three xenoestrogens also lowered the heart rate, lengthened the time to hatch, suppressed the expression of the three GnRH genes, and up-regulated the ERalpha mRNA level. In addition, the GnRH3 mRNA level was significantly correlated with the fluorescence intensity of the GnRH neurons. We concluded that the transgenic medaka embryo is a rapid and sensitive bioassay for screening environmental water samples. We also found that xenoestrogens had significant effects on GnRH gene expression and embryonic development. PMID- 22497784 TI - Leaching of azoxystrobin and its degradation product R234886 from Danish agricultural field sites. AB - The objective was to estimate leaching of the fungicide azoxystrobin (methyl (alphaE)-2-[[6-(2-cyanophenoxy)-4-pyrimidinyl]oxy]-alpha (methoxymethylene)benzene-acetate) and one of its primary degradation products R234886 ([(E)-2-(2-[6-cyanophenoxy)-pyrimidin-4-yloxyl]-phenyl-3-methoxyacrylic acid], major fraction) at four agricultural research fields (one sandy and three loamy) in Denmark. Water was sampled from tile drains, suction cups and groundwater wells for a minimum period of two years after application of azoxystrobin. Neither azoxystrobin nor R234886 were detected at the sandy site, but did leach through loamy soils. While azoxystrobin was generally only detected during the first couple of months following application, R234886 leached for a longer period of time and at higher concentrations (up to 2.1MUgL(-1)). Azoxystrobin is classified as very toxic to aquatic organisms and R234886 as very harmful. Our study shows that azoxystrobin and R234886 can leach through loamy soils for a long period of time following application of the pesticide and thereby pose a potential threat to vulnerable aquatic environments and drinking water resources. We thus recommend the inclusion of azoxystrobin and R234886 in pesticide monitoring programmes and further investigation of their long-term ecotoxicological effects. PMID- 22497785 TI - Nitrate-induced photodegradation of atenolol in aqueous solution: kinetics, toxicity and degradation pathways. AB - The extensive utilization of beta-blockers worldwide led to frequent detection in natural water. In this study the photolysis behavior of atenolol (ATL) and toxicity of its photodegradation products were investigated in the presence of nitrate ions. The results showed that ATL photodegradation followed pseudo-first order kinetics upon simulated solar irradiation. The photodegradation was found to be dependent on nitrate concentration and increasing the nitrate from 0.5 mML( 1) to 10 mML(-1) led to the enhancement of rate constant from 0.00101 min(-1) to 0.00716 min(-1). Hydroxyl radical was determined to play a key role in the photolysis process by using isopropanol as molecular probe. Increasing the solution pH from 4.8 to 10.4, the photodegradation rate slightly decreased from 0.00246 min(-1) to 0.00195 min(-1), probably due to pH-dependent effect of nitrate-induced .OH formation. Bicarbonate decreased the photodegradation of ATL in the presence of nitrate ions mainly through pH effect, while humic substance inhibited the photodegradation via both attenuating light and competing radicals. Upon irradiation for 240 min, only 10% reduction of total organic carbon (TOC) can be achieved in spite of 72% transformation rate of ATL, implying a majority of ATL transformed into intermediate products rather than complete mineralization. The main photoproducts of ATL were identified by using solid phase extraction-liquid chromatography-mass spectrometry (SPE-LC-MS) techniques and possible nitrate-induced photodegradation pathways were proposed. The toxicity of the phototransformation products was evaluated using aquatic species Daphnia magna, and the results revealed that photodegradation was an effective mechanism for ATL toxicity reduction in natural waters. PMID- 22497786 TI - The toxicity of phthalocyanines to the aquatic plant Lemna minor (duckweed) - testing of 31 compounds. AB - Phthalocyanines are prospective chemicals that have applications in industry, medicine and biology due especially to their architectural flexibility and production of reactive oxygen species. Although they are used in so many areas of human activities nowadays, there is still little knowledge of their ecotoxicity. Here we present the first observation of their toxic effects on representatives of the aquatic plants Lemna minor. The tested phthalocyanines possess a wide spectrum of phytotoxicity ranging from seldom (>50 mg L(-1)) to highly toxic 0.11 mg L(-1). Moreover, the potential of phthalocyanines to be used as selective cyanocides or herbicides is discussed as well. PMID- 22497787 TI - Toxin modulators and blockers of hERG K(+) channels. AB - The K(+) channel encoded by the Ether-a-go-go-Related Gene (ERG) is expressed in different tissues of different animal species. There are at least three subtypes of this channel, being the sub-type 1 (ERG1) crucial in the repolarization phase of the cardiac action potential. Mutations in this gene can affect the properties of the channel producing the type II long QT syndrome (LQTS2) and many drugs are also known to affect this channel with a similar side effect. Various scorpion, spider and sea anemone toxins affect the ERG currents by blocking the ion conducting pore from the external side or by modulating channel gating through binding to the voltage-sensor domain. By doing so, these toxins become very useful tools for better understanding the structural and functional characteristics of these ion channels. This review discusses the interaction between the ERG channels and the peptides isolated from venoms of these animals. Special emphasis is placed on scorpion toxins, although the effects of several spider venom toxins and anemone toxins will be also revised. PMID- 22497788 TI - Cone snail milked venom dynamics--a quantitative study of Conus purpurascens. AB - Milked venom from cone snails represent a novel biological resource with a proven track record for drug discovery. To strengthen this correlation, we undertook a chromatographic and mass spectrometric study of individual milked venoms from Conus purpurascens. Milked venoms demonstrate extensive peptide differentiation amongst individual specimens and during captivity. Individual snails were found to lack a consistent set of described conopeptides, but instead demonstrated the ability to change venom expression, composition and post-translational modification incorporation; all variations contribute to an increase in chemical diversity and prey targeting strategies. Quantitative amino acid analysis revealed that milked venom peptides are expressed at ranges up to 3.51-121.01 MUM within single milked venom samples. This provides for a 6.37-20,965 fold-excess of toxin to induce apparent IC50 for individual conopeptides identified in this study. Comparative molecular mass analysis of duct venom, milked venom and radula tooth extracts from single C. purpurascens specimens demonstrated a level of peptide continuity. Numerous highly abundant and unique conopeptides remain to be characterized. This study strengthens the notion that approaches in conopeptide drug lead discovery programs will potentially benefit from a greater understanding of the toxinological nature of the milked venoms of Conus. PMID- 22497789 TI - Protective effects of guanosine against sepsis-induced damage in rat brain and cognitive impairment. AB - The development of cognitive impairment in sepsis is associated with neurotoxic effects caused by oxidative stress. We have assessed the effects of acute and extended administration of guanosine (GUA) on brain oxidative stress parameters and cognitive impairment in rats submitted to sepsis by cecal ligation and perforation (CLP). To achieve this goal, male Wistar rats underwent either sham operation or CLP with GUA. Rats subjected to CLP were treated with intraperitoneal injection of GUA (8 mg/kg after CLP) or vehicle. Twelve and 24 h after CLP, the rats were sacrificed, and samples from brain (hippocampus, striatum, cerebellum, prefrontal cortex and cortex) were obtained and assayed for thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. On the 10th day, another group of rats was submitted to the behavioral tasks. GUA administration reduced TBARS and carbonyl levels in some brain regions between 12 and 24 h after CLP, and ameliorated cognitive impairment evaluated 10 days after CLP. Our data provide the first experimental demonstration that GUA was able to reduce the consequences of CLP-induced sepsis in rats, by decreasing oxidative stress parameters in the brain and recovering the memory impairment. PMID- 22497790 TI - A randomized trial of catheters of different lengths to achieve right atrium versus superior vena cava placement for continuous renal replacement therapy. AB - BACKGROUND: The aim was to assess whether inserting a longer soft silicone short term dialysis catheter targeting tip placement in the right atrium could improve dialyzer circuit life span compared with inserting a shorter dialysis catheter targeting tip placement in the superior vena cava. STUDY DESIGN: Randomized unblinded controlled study. SETTING & PARTICIPANTS: A tertiary multidisciplinary intensive care unit enrolling 100 critically ill patients requiring continuous renal replacement therapy (CRRT). INTERVENTION: Placement of longer (20-24 cm) versus shorter dialysis catheters (15-20 cm) within one of the major thoracic veins for initiation of CRRT. OUTCOMES: The primary study outcome was duration of dialysis circuit life span. Secondary outcomes included delivered daily dialysis dose, incidence and cause of CRRT circuit failure, complications potentially related to the position of the short-term dialysis catheter, mortality, and patient length of stay. RESULTS: Placing the longer dialysis catheters was associated with an increased average dialyzer life span of 6.5 hours (24 hours [25th-75th percentile, 11-32] vs 17.5 hours [25th-75th percentile, 8-23]; P = 0.001), improved delivered daily dialysis dose (91% [25th-75th percentile, 85% 100%] vs 81% [25th-75th percentile, 72%-97%]; P < 0.001), and reduced number of dialyzers clotted (2.3 vs 3.6; P = 0.04) or circuits taken down due to vascular access problem (0.19 vs 0.53; P = 0.04) per patient compared with placing shorter dialysis catheters. The incidence of atrial arrhythmias was similar between groups (28% vs 21%; P = 0.6) and the only mechanical complication was the malposition of one dialysis catheter tip in the longer dialysis catheter group. LIMITATIONS: Single-center study design. CONCLUSIONS: The use of longer soft silicone short-term dialysis catheters targeting right atrial placement appeared to be safe and could improve dialyzer life span and daily dialysis dose of CRRT delivered compared with the use of shorter catheters targeting superior vena cava placement. PMID- 22497792 TI - Risk stratification of patients with IgA nephropathy. AB - In this review, we summarize recent advances in the risk stratification of patients with immunoglobulin A (IgA) nephropathy. Several clinical variables have consistent and independent associations with worse kidney prognosis, including blood pressure, proteinuria, and baseline kidney function. Although one-time cross-sectional assessments of blood pressure and proteinuria are important, a more thorough understanding of risk can be achieved when these variables are considered over a follow-up period. IgA nephropathy is unique compared with other glomerular diseases in that a much lower threshold of proteinuria (protein excretion, 1 g/d) is associated with glomerular filtration rate (GFR) loss. Controlling proteinuria and blood pressure over time is important to reduce the risk of future loss of kidney function. The recently described Oxford classification has helped standardize the pathologic characterization of IgA nephropathy using a scoring system that is readily reproducible and associated with increased risk of GFR loss independent of clinical variables. We suggest an approach to risk stratification in IgA nephropathy when considering potential treatment with immunosuppression. Despite our current understanding of risk stratification in IgA nephropathy, the ability to accurately predict individual patient-level risk currently is limited, and further research into additional biomarkers or risk prediction tools is needed to improve the care of patients with IgA nephropathy. PMID- 22497793 TI - Effect of an electronic alert on risk of contrast-induced acute kidney injury in hospitalized patients undergoing computed tomography. AB - BACKGROUND: Prophylaxis against contrast-induced acute kidney injury (AKI) in hospitalized patients is underused. We evaluated the impact of a computerized alert program for contrast-induced AKI for hospitalized patients undergoing contrast-enhanced computed tomography (CT). STUDY DESIGN: Quality improvement report. SETTING & PARTICIPANTS: 463 adult inpatients in a single center with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2). QUALITY IMPROVEMENT PLAN: We developed a computer alert program in which the responsible physician was alerted to a patient's risk of contrast-induced AKI in the form of a warning message box and was recommended to consider prophylactic measures for contrast-induced AKI when he or she ordered contrast-enhanced CT for patients with eGFR <60 mL/min/1.73 m(2). The intervention was applied simultaneously to all hospitalized patients from March 18, 2010. The hospital's contrast-induced AKI preventive guidelines included prehydration, posthydration, and oral N acetylcysteine. OUTCOME & MEASUREMENTS: Use of prophylactic interventions, development of contrast-induced AKI. Contrast-induced AKI was defined as an increase in serum creatinine level (>=0.3 mg/dL or >=50%) 24-72 hours after contrast medium exposure. RESULTS: 258 adult inpatients with eGFR <60 mL/min/1.73 m(2) were identified as undergoing contrast-enhanced CT before application of the computer alert program (from October 28, 2009, to March 17, 2010), and 205, after its application (from March 18, 2010, to August 5, 2010). Individuals in the postalert group received contrast-induced AKI prophylaxis more often than those in the prealert group (55% vs 25% for total prophylaxis; P < 0.001). The incidence of contrast-induced AKI was lower in the postalert group than in the prealert group (3% vs 10%; P = 0.02). LIMITATIONS: Observation bias; only 61.5% of participants were evaluated for contrast-induced AKI. CONCLUSIONS: Implementation of a computerized alert program in hospitalized patients was followed by increased use of prophylaxis and decreased risk of contrast-induced AKI. PMID- 22497795 TI - Grandparental and parental age effects suggest epigenetic transmission on both X and Y chromosomes. PMID- 22497796 TI - Slr0967 and Sll0939 induced by the SphR response regulator in Synechocystis sp. PCC 6803 are essential for growth under acid stress conditions. AB - Two-component signal transduction is the primary signaling mechanism for global regulation of the cellular response to environmental changes. We used DNA microarray analysis to identify genes that were upregulated by acid stress in the cyanobacterium Synechocystis sp. PCC 6803. Several of these genes may be response regulators that are directly involved in this type of stress response. We constructed deletion mutants for the response regulator genes and compared the growth rates of cells transfected with mutant and wild-type genes in a low pH medium. Of these mutants, deletion of sphR affected the growth rate under acid stress (pH 6.0) conditions. We examined genome-wide expression in DeltasphR mutant cells using DNA microarray to determine whether SphR was involved in the regulation of other acid stress responsive genes. Microarray and real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analyses of wild-type cells showed that the expression of phoA, pstS1, and pstS2, which are upregulated under phosphate-limiting conditions, increased (2.48-, 1.88-, and 5.07-fold, respectively) after acid stress treatment for 0.5h. In contrast, pstS2 expression did not increase in the DeltasphR mutant cells after acid stress, whereas the phoA and sphX mRNA levels increased. Furthermore, qRT-PCR and northern blot analysis indicated that downregulation of the acid-responsive genes slr0967 and sll0939 occurred with the deletion of sphR. Indeed, mutants of these genes were more sensitive to acid stress than the wild-type cells. Thus, induction of Slr0967 and Sll0939 by SphR may be essential for growth under acid stress conditions. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial. PMID- 22497794 TI - Association between schizophrenia and common variation in neurocan (NCAN), a genetic risk factor for bipolar disorder. AB - A recent study found genome-wide significant association between common variation in the gene neurocan (NCAN, rs1064395) and bipolar disorder (BD). In view of accumulating evidence that BD and schizophrenia partly share genetic risk factors, we tested this single-nucleotide polymorphism for association with schizophrenia in three independent patient-control samples of European ancestry, totaling 5061 patients and 9655 controls. The rs1064395 A-allele, which confers risk for BD, was significantly over-represented in schizophrenia patients compared to controls (p=2.28*10(-3); odds ratio=1.11). Follow-up in non overlapping samples from the Schizophrenia Psychiatric GWAS Consortium (5537 patients, 8043 controls) provided further support for our finding (p=0.0239, odds ratio=1.07). Our data suggest that genetic variation in NCAN is a common risk factor for BD and schizophrenia. PMID- 22497791 TI - Factors associated with depressive symptoms and use of antidepressant medications among participants in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic CRIC Studies. AB - BACKGROUND: Depressive symptoms are correlated with poor health outcomes in adults with chronic kidney disease (CKD). The prevalence, severity, and treatment of depressive symptoms and potential risk factors, including level of kidney function, in diverse populations with CKD have not been well studied. STUDY DESIGN: Cross-sectional analysis. SETTINGS & PARTICIPANTS: Participants at enrollment into the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC (H-CRIC) Studies. CRIC enrolled Hispanics and non-Hispanics at 7 centers in 2003 2007, and H-CRIC enrolled Hispanics at the University of Illinois in 2005-2008. MEASUREMENT: Depressive symptoms measured by Beck Depression Inventory (BDI). PREDICTORS: Demographic and clinical factors. OUTCOMES: Elevated depressive symptoms (BDI score >=11) and antidepressant medication use. RESULTS: Of 3,853 participants, 27.4% had evidence of elevated depressive symptoms and 18.2% were using antidepressant medications; 31.0% of persons with elevated depressive symptoms were using antidepressants. The prevalence of elevated depressive symptoms varied by level of kidney function: 23.6% for participants with estimated glomerular filtration rate (eGFR) >=60 mL/min/1.73 m(2) and 33.8% of those with eGFR <30 mL/min/1.73 m(2). Lower eGFR (OR per 10-mL/min/1.73 m(2) decrease, 1.10; 95% CI, 1.04-1.17), and non-Hispanic black race (OR, 1.42; 95% CI, 1.16-1.74) were each associated with increased odds of elevated depressive symptoms after controlling for other factors. In regression analyses incorporating BDI score, whereas female sex was associated with greater odds of antidepressant use, Hispanic ethnicity, non-Hispanic black race, and higher urine albumin levels were associated with decreased odds of antidepressant use (P < 0.05 for each). LIMITATIONS: Absence of clinical diagnosis of depression and use of nonpharmacologic treatments. CONCLUSIONS: Although elevated depressive symptoms were common in individuals with CKD, use of antidepressant medications is low. Individuals of racial and ethnic minority background and with more advanced CKD had a greater burden of elevated depressive symptoms and lower use of antidepressant medications. PMID- 22497797 TI - Characterization of the peridinin-chlorophyll a-protein complex in the dinoflagellate Symbiodinium. AB - The water-soluble peridinin-chlorophyll a-proteins (PCPs) are one of the major light harvesting complexes in photosynthetic dinoflagellates. PCP contains the carotenoid peridinin as its primary pigment. In this study, we identified and characterized the PCP protein and the PCP gene organization in Symbiodinium sp. CS-156. The protein molecular mass is 32.7kDa, revealing that the PCP is of the monomeric form. The intronless PCP genes are organized in tandem arrays. The PCP gene cassette is composed of 1095-bp coding regions and spacers in between. Despite the heterogeneity of PCP gene tandem repeats, we identified a single form of PCP, the sequence of which exactly matches the deduced sequence of PCP gene clone 7 (JQ395030) by LC-MS/MS analysis of tryptic digested PCP, revealing the mature PCP apoprotein is 312 amino acids in length. Pigment analysis showed a peridinin-to-Chl a ratio of 4. The peridinin-to-Chl a Q(y) energy transfer efficiency is 95% in this complex. PMID- 22497798 TI - Primary sellar neuroblastoma. A new case and review of literature. AB - The primary intracranial development of olfactory neuroblastomas, outside olfactory epithelium, is rare. We report a case of primary sellar neuroblastoma without any aggressive histopathological features, managed solely surgically without adjuvant therapy, with good outcomes at 3 years. Primary sellar neuroblastomas mostly occur in women in the 4th decade with a context of a non secreting pituitary tumour. Diagnosis is made on histopathological examination (small cells, fibrillary intercellular background, strong immunoreactivity for neurons markers, negative immunoreactivity for anterior pituitary hormones). Management is based on surgery. Adjuvant treatment is not consensual, largely depends on patient's conditions and aggressive histopathological features. PMID- 22497799 TI - A robust algorithm for high-resolution dynamic MRI based on the partially separable functions model. AB - A recently developed partially separable functions (PSF) model can be used to generate high-resolution dynamic magnetic resonance imaging (MRI). However, this method could not robustly reconstruct high-quality MR images because the estimation of the PSF parameters is often interfered by the noise of the sampled MR data. To improve the robustness of MRI reconstruction using the PSF model, we proposed a new algorithm to estimate the PSF parameters by jointly using robust principal component analysis and modified truncated singular value decomposition regularization methods, instead of using the least square fitting method in the original PSF model. The experiment results of in vivo cardiac MRI demonstrated that the proposed algorithm can robustly reconstruct dynamic MR images with higher signal-to-noise ratio and clearer anatomical structures in comparison with the previous PSF model. PMID- 22497800 TI - Do we activate specifically somatosensory thin fibres with the concentric planar electrode? A scalp and intracranial EEG study. AB - Laser-evoked potentials (LEPs) are acknowledged as the most reliable laboratory tool for assessing thermal and pain pathways. Electrical stimulation with a newly developed planar concentric electrode, delivering stimuli limited to the superficial skin layers, has been suggested to provide selective activation of Adelta fibres without the inconveniences linked to laser stimulation. The aim of our study was to compare the scalp and intracranial responses to planar concentric electrode stimulation (CE-SEPs) with those of LEPs and standard somatosensory-evoked potentials (SEPs). Sixteen healthy subjects, 6 patients with intracortical electrodes, and 2 patients with selective lesions of the spinothalamic pathway were submitted to Neodymium:Yttrium-Aluminium-Perovskite laser stimulations, and electrical stimulations using standard electrodes or planar concentric electrodes (CE). In both healthy controls and epileptic implanted patients, CE- and standard SEPs showed significantly shorter latencies than LEPs. This is consistent with Abeta-fibre activation, peripheral activation time being unable to account for longer LEP latencies. In the patients with spinothalamic lesions, LEPs were absent after stimulation of the affected territory, while CE-SEPs were still present. For these 2 reasons, we conclude that the planar CE does not selectively activate the Adelta and C fibers, but coexcites a significant proportion of large myelinated Abeta fibres that dominate the ensuing cortical response. The use of CE-SEPs for the detection of spinothalamic system lesions is therefore not warranted; the planar electrode can, however, represent a useful tool to study nociceptive reflexes, which can be reliably elicited even in the presence of Abeta coactivation. PMID- 22497801 TI - Limited polymorphisms of two Y-chromosomal SNPs in Chinese and Iranian sheep. PMID- 22497802 TI - An experimental investigation of kernels on graphs for collaborative recommendation and semisupervised classification. AB - This paper presents a survey as well as an empirical comparison and evaluation of seven kernels on graphs and two related similarity matrices, that we globally refer to as "kernels on graphs" for simplicity. They are the exponential diffusion kernel, the Laplacian exponential diffusion kernel, the von Neumann diffusion kernel, the regularized Laplacian kernel, the commute-time (or resistance-distance) kernel, the random-walk-with-restart similarity matrix, and finally, a kernel first introduced in this paper (the regularized commute-time kernel) and two kernels defined in some of our previous work and further investigated in this paper (the Markov diffusion kernel and the relative-entropy diffusion matrix). The kernel-on-graphs approach is simple and intuitive. It is illustrated by applying the nine kernels to a collaborative-recommendation task, viewed as a link prediction problem, and to a semisupervised classification task, both on several databases. The methods compute proximity measures between nodes that help study the structure of the graph. Our comparisons suggest that the regularized commute-time and the Markov diffusion kernels perform best on the investigated tasks, closely followed by the regularized Laplacian kernel. PMID- 22497803 TI - Feasibility of 2 different water-based exercise training programs in patients with Parkinson's disease: a pilot study. AB - OBJECTIVE: To compare the effects of 2 different water-based exercise training programs on functional mobility, motor symptoms, and quality of life (QOL) on patients with mild to moderate Parkinson's disease (PD). DESIGN: Matched, controlled, pilot study. SETTING: Outpatient Parkinson's disease center. PARTICIPANTS: Patients (N=21) with PD (Hoehn and Yahr stage range, 1-3). INTERVENTIONS: Participants were assigned to a low-intensity water exercise program (group 1) or a muscular resistance water exercise intervention (group 2). Group sessions were held for 12 weeks, twice a week for 60 minutes per session. MAIN OUTCOME MEASURES: Functional mobility was measured by means of the Five Times Sit-to-Stand Test, while the motor part of the Unified Parkinson's Disease Rating Scale was used to assess motor impairment. Patients' QOL was rated by means of the 39-item Parkinson's Disease Questionnaire. RESULTS: Once the intervention ended, the participants' QOL improved significantly, regardless of the program undertaken (P=.02 for group 1; P=.005 for group 2). Only participants in group 2 showed a significant change in functional mobility (P=.001) and Parkinsonian motor symptoms (P=.012). CONCLUSIONS: Water-based exercise training programs are a helpful therapy in PD. Muscular resistance programs of this kind seem to be of value in improving functional mobility, motor symptoms, and QOL in patients with PD. Some of the methodologic aspects detailed here can be used to design larger controlled trials. PMID- 22497804 TI - Development of a measure of skin care belief scales for persons with spinal cord injury. AB - OBJECTIVES: To develop and validate a measure of skin care beliefs and to describe the skin care behaviors of persons with spinal cord injury (SCI). DESIGN: A mixed-methods design was used to develop the Skin Care Beliefs Scales (SCBS). The health belief model framed the hypotheses. Phase 1 included item development, content validity testing, and pilot testing. Phase 2 included testing the scale structure (principal components analysis), internal consistency reliability, test-retest reliability, and relationships between the belief scales and care behaviors. SETTING: Two acute rehabilitation hospitals and Internet websites. PARTICIPANTS: Patients with SCI (N=462; qualitative/pilot n=56; psychometric study n=406) participated. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The pilot and phase 2 studies, respectively, used 146-item and 114-item versions of the SCBS. A skin care activity log was used to record skin care behaviors. RESULTS: Content validity indicated that the items were relevant and clear. The analysis resulted in 11 independent scales reflecting 3 general beliefs (susceptibility, severity, self-efficacy) and barrier and benefit behavior-specific scales for skin checks, wheelchair pressure reliefs, and turning and sitting times. With the exception of skin check barriers (alpha=.65), Cronbach alphas of the scale ranged from .74 to .94. Test-retest intraclass correlations were fair to excellent (range, .42-.75). Construct validity was supported. Hierarchical linear regression indicated that turning benefits, barriers, susceptibility, and self-efficacy were significant predictors of turning time. Benefits or barriers were correlated significantly with skin check and pressure relief adherence (rho range, -.17 to -.33). Self-efficacy was correlated with wheelchair pressure relief (rho=.18). Skin care behavior adherence varied widely (eg, 0%-100%). CONCLUSIONS: The scales showed acceptable reliability and validity. Further testing with larger samples is desirable. PMID- 22497805 TI - The hymenochirins: a family of host-defense peptides from the Congo dwarf clawed frog Hymenochirus boettgeri (Pipidae). AB - Skin secretions of frogs from the subfamily Xenopodinae (Xenopus+Silurana) within the family Pipidae are a rich source of antimicrobial peptides with therapeutic potential but species from the sister taxon Hymenochirus in the subfamily Pipinae (Hymenochirus+Pseudhymenochirus+Pipa) have not been investigated. Peptidomic analysis of norepinephrine-stimulated skin secretions from two distinct populations of the Congo dwarf clawed frog Hymenochirus boettgeri (Tornier, 1896) has led to identification of five structurally related peptides with broad spectrum antimicrobial activity. Hymenochirin-1B (IKLSPETKDNLKKVLKGAIKGAIAVAKMV.NH(2)) is C-terminally alpha-amidated whereas hymenochirins-2B-5B have the general structure XKIPX(2)VKDTLKKVAKGX(2)SX(2)AGAX(3).COOH. Hymenochirin-3B (IKIPAVVKDTLKKVAKGVLSAVAGALTQ) was the most abundant peptide in the secretions. The hymenochirins show very low structural similarity with the antimicrobial peptides isolated from skin secretions of Silurana tropicalis and Xenopus laevis consistent with the proposed ancient divergence of the Pipinae and Xenopodinae. Synthetic replicates of hymenochirin-1B-4B inhibit the growth of Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Staphylococcus aureus (MIC in the range 10-40 MUM) and Candida albicans (MIC=80 MUM). The peptides display relatively weak hemolytic activity against human erythrocytes (LC(50) in the range 160 to >300 MUM). PMID- 22497806 TI - Two novel antimicrobial peptides purified from the symbiotic bacteria Xenorhabdus budapestensis NMC-10. AB - Symbiotic bacteria, which are carried in the intestinal vesicle of the infective stage of juvenile entomopathogenic nematodes, produce broad-spectrum antibiotics. In this study, we aimed to isolate the antimicrobial peptides from the culture of the entomopathogenic bacterium Xenorhabdus budapestensis NMC-10. By screening chromatography columns and optimizing flow rate, pH, salinity and other purification conditions, we identified the final purification procedures which consisted of Q ion-exchange chromatography, gel filtration chromatography and two step reverse-phase chromatography. Two novel antimicrobial peptides were identified via Q-TOF-TOF and de novo sequencing, and designated as GP-19 and EP 20. Both natural and synthetic peptides demonstrated broad-spectrum antimicrobial activities. The synthetic GP-19 peptide was active against Verticillium dahlia with EC(50) values of 17.54 MUg/ml and highly inhibited the growth of a variety of bacteria, while the synthetic EP-20 peptide was highly active against Phytophthora capsici with EC(50) values of 3.14 MUg/ml. PMID- 22497807 TI - Human cytomegalovirus US3 modulates destruction of MHC class I molecules. AB - Human cytomegalovirus (HCMV), a member of the Herpesviridae family, is proficient at establishing lifelong persistence within the host in part due to immune modulating genes that limit immune recognition. HCMV encodes at least five glycoproteins within its unique short (US) genomic region that interfere with MHC class I antigen presentation, thus hindering viral clearance by cytotoxic T lymphocytes (CTL). Specifically, US3 retains class I within the endoplasmic reticulum (ER), while US2 and US11 induce class I heavy chain destruction. A cooperative effect on class I down-regulation during stable expression of HCMV US2 and US3 has been established. To address the impact of US3 on US11-mediated MHC class I down-regulation, the fate of class I molecules was examined in US3/US11-expressing cells and virus infection studies. Co-expression of US3 and US11 resulted in a decrease of surface expression of class I molecules. However, the class I molecules in US3/US11 cells were mostly retained in the ER with an attenuated rate of proteasome destruction. Analysis of class I levels from virus infected cells using HCMV variants either expressing US3 or US11 revealed efficient surface class I down-regulation upon expression of both viral proteins. Cells infected with both US3 and US11 expressing viruses demonstrate enhanced retention of MHC class I complexes within the ER. Collectively, the data suggests a paradigm where HCMV-induced surface class I down-regulation occurs by diverse mechanisms dependent on the expression of specific US genes. These results validate the commitment of HCMV to limiting the surface expression of class I levels during infection. PMID- 22497808 TI - Hepatitis C virus and the brain. AB - Hepatitis C virus (HCV) is an enveloped, positive-strand RNA virus of the family Flaviviridae that primarily infects hepatocytes, causing acute and chronic liver disease. HCV is also associated with a variety of extrahepatic symptoms including central nervous system (CNS) abnormalities, cognitive dysfunction, fatigue and depression. These symptoms do not correlate with the severity of liver disease and are independent of hepatic encephalopathy. HCV RNA has been associated with CNS tissue, and reports of viral sequence diversity between brain and liver tissue suggest independent viral evolution in the CNS and liver. This review will explore the data supporting HCV infection of the CNS and how this fits into our current understanding of HCV pathogenesis. PMID- 22497809 TI - Neuropsychological tools in hepatology: a survival guide for the clinician. AB - Neuropsychological assessment has three main applications in clinical hepatology: (i) to detect, grade and monitor liver failure-related cognitive alterations in end-stage liver disease (hepatic encephalopathy), (ii) to substantiate complaints of attention or concentration difficulties in patients with non-cirrhotic chronic hepatitis C viral infection, and (iii) to screen patients who are being considered for liver transplantation for early signs of dementia. However, there is limited agreement on how cognitive assessment should be conducted in these patients, and how results should be interpreted and used to implement clinical decisions. In this review, we summarize the available literature on neuropsychological dysfunction in patients with cirrhosis and with chronic hepatitis C viral infection and provide some guidance on how to utilize neuropsychological assessment in practice. PMID- 22497810 TI - Reliability and validity of a self-efficacy instrument for hepatitis C antiviral treatment regimens. AB - Self-efficacy or confidence in one's ability to successfully engage in goal directed behaviour has been shown to influence medication adherence across many chronic illnesses. In the present study, we investigated the psychometric properties of a self-efficacy instrument used during treatment for chronic hepatitis C viral infection (HCV). Baseline (n = 394) and treatment week 24 (n = 254) data from the prospective, longitudinal Viral Resistance to Antiviral Therapy of Chronic Hepatitis C study were examined. Baseline participants were randomly split into two equal-sized subsamples (S(1) and S(2) ). Initial exploratory and confirmatory factor analyses (EFA/CFA) were performed on S(1), while S(2) was used to validate the factor structure of the S(1) results using CFA. An additional CFA was performed on the treatment week 24 participants. Convergent and discriminant validity were assessed by comparing the revised instrument with other psychosocial measures: depression, social support, quality of life and medication-taking behaviour. Our findings supported a reduced 17-item global measure of HCV treatment self-efficacy (HCV-TSE) with four underlying factors: patient communication self-efficacy, general physical coping self efficacy, general psychological coping self-efficacy and adherence self-efficacy. The global score (0.92-0.94) and four factors (0.85-0.96) demonstrated good internal consistency. Correlations of convergent and discriminant validity yielded low to moderate associations with other measures of psychosocial functioning. The revised HCV-TSE instrument provides a reliable and valid global estimate of confidence in one's ability to engage in and adhere to HCV antiviral treatment. The four-factor structure suggests different types of efficacy beliefs may function during HCV treatment and should be explored further in relation to clinical outcomes. PMID- 22497811 TI - Increased serum N-terminal pro-B-type natriuretic peptide and left ventricle diastolic dysfunction in patients with hepatitis C virus infection. AB - Prior studies demonstrated that patients with hepatitis C virus (HCV) infection had higher plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, which may indicate the presence of a subclinical cardiac dysfunction. However, there are few data regarding the echocardiographic assessment in HCV-infected patients. The objectives of this study were to investigate changes in the left ventricle (LV) with echocardiography and to identify echocardiographic correlates of serum NT-proBNP levels in HCV-infected patients. Ninety HCV-infected patients and 90 age and gender-matched healthy controls were included. The level of serum NT-proBNP was higher in the patient group (P < 0.001). The proportion of patients whose serum NT-proBNP levels were higher than 125 pg/mL was greater than that of controls (15.56%vs 3.33%, P = 0.011). Echocardiography did not show any significant difference of cardiac structural abnormalities between groups. In the patient group, E, E' and E/A were lower, and E/E' was higher. The proportion of patients (13, 14.44%) with impaired diastolic filling (E/A <= 0.75; 0.75 < E/A < 1.5 and E/E' >= 10) was greater than that of the control group (3, 3.33%; P = 0.018). Simple regression analysis demonstrated a statistically significant linear correlation between NT-proBNP levels and left ventricular diastolic diameter (LVDd) (r = 0.178, P = 0.013), left ventricular posterior wall diastolic thickness (LVPWd) (r = 0.147, P = 0.023) and mitral E/E' (r = 0.414, P = 0.027). Independent correlates of NT-proBNP levels (R(2) = 0.34) were older age (beta' = 0.034, P = 0.011) and E/E' ratio (beta' = 0.026, P = 0.018). In conclusion, the combined analysis of NT-proBNP and echocardiography showed a possible subclinical left ventricular diastolic dysfunction as evidence of a pathogenic link between HCV and CVD. PMID- 22497813 TI - Association of hepatitis C with insulin resistance and type 2 diabetes in US general population: the impact of the epidemic of obesity. AB - Studies from tertiary care medical centres have linked hepatitis C virus (HCV) to the development of insulin resistance (IR) and type 2 diabetes. The aim of the study is to assess the relationship between HCV positivity and insulin resistance/diabetes in the US population. Three cycles of the National Health and Nutrition Examination Survey (NHANES) conducted between 1988 and 2008 were used. HCV infection was diagnosed using a positive serologic anti-HCV test. Additionally, diabetes was diagnosed as fasting blood glucose >=126 mg/dL and/or the use of hypoglycaemic medications. Insulin resistance was defined as a homeostasis of model assessment (HOMA) score of >3.0. Logistic regression was used to estimate the odds ratios (ORs) of each of the potential risk factors for diabetes mellitus (DM). The SUDAAN 10.0 was used to run descriptive and regression analyses. A total of 39 506 individuals from three NHANES cycles (1988 1994, 1999-2004 and 2005-2008) with complete demographic and relevant clinical data were included. Over these three NHANES cycles, prevalence of hepatitis C did not significantly change. During the first NHANES cycle (1988-1994), insulin and diabetes were independently associated with hepatitis C. However, during the later study cycles (1998-2008), these associations were no longer significant. In contrast, other important known risk factors for diabetes and IR (male gender, non-Caucasian race, age and obesity) remained significant over all three NHANES cycles. Although HCV infection was independently associated with an increased risk of diabetes and IR in the US population over a decade ago, assessment of the later NHANES cycles shows that this relationship may have become diluted by the rapid rise of other risks for diabetes, specifically, the prevalence of obesity. PMID- 22497812 TI - Interleukin 28B polymorphisms are the only common genetic variants associated with low-density lipoprotein cholesterol (LDL-C) in genotype-1 chronic hepatitis C and determine the association between LDL-C and treatment response. AB - Low-density lipoprotein cholesterol (LDL-C) levels and interleukin 28B (IL28B) polymorphism are associated with sustained viral response (SVR) to peginterferon/ribavirin (pegIFN/RBV) for chronic hepatitis C (CHC) infection. IL28B has been linked with LDL-C levels using a candidate gene approach, but it is not known whether other genetic variants are associated with LDL-C, nor how these factors definitively affect SVR. We assessed genetic predictors of serum lipid and triglyceride levels in 1604 patients with genotype 1 (G1) chronic hepatitis C virus (HCV) infection by genome-wide association study and developed multivariable predictive models of SVR. IL28B polymorphisms were the only common genetic variants associated with pretreatment LDL-C level in Caucasians (rs12980275, P = 4.7 * 10(-17), poor response IL28B variants associated with lower LDL-C). The association was dependent on HCV infection, IL28B genotype was no longer associated with LDL-C in SVR patients after treatment, while the association remained significant in non-SVR patients (P < 0.001). LDL-C was significantly associated with SVR for heterozygous IL28B genotype patients (P < 0.001) but not for homozygous genotypes. SVR modelling suggested that IL28B heterozygotes with LDL-C > 130 mg/dL and HCV RNA <=600 000 IU/mL may anticipate cure rates >80%, while the absence of these two criteria was associated with an SVR rate of <35%. IL28B polymorphisms are the only common genetic variants associated with pretreatment LDL-C in G1-HCV. LDL-C remains significantly associated with SVR for heterozygous IL28B genotype patients, where LDL-C and HCV RNA burden may identify those patients with high or low likelihood of cure with pegIFN/RBV therapy. PMID- 22497814 TI - Steatosis is the predictor of relapse in HCV genotype 3- but not 2-infected patients treated with 12 weeks of pegylated interferon-alpha-2a plus ribavirin and RVR. AB - HCV genotypes 2- or 3-infected patients with a rapid virological response (RVR) to therapy with pegylated interferon and ribavirins who have a low viral load, noncirrhotic and nonobese may be considered for a shorter course of treatment. However, no studies have assessed host-viral factors associated with relapse in genotype 2 and 3 separately. Accordingly, we assessed whether 12 weeks of pegylated interferon and ribavirin was an optimized regimen for treatment of HCV genotype 2 and 3 with positive predictors of response. Power and sample size were a priori calculated and 96 consecutive chronic hepatitis C patients (53, genotype 2 and 43, genotype 3) without cirrhosis who were not obese and who achieved a RVR to therapy with peg-IFN-alpha-2a and ribavirin were enrolled. Fibrosis, steatosis, homeostatic model assessment-insulin resistance and HCV RNA were predefined variables to be evaluated in relapse. An intention-to-treat analysis was performed. SVR rates were 98% and 84% for genotype 2 and 3, respectively. Analysis of genotype 3 patients who had relapse showed a negative correlation with steatosis (P < 0.0001) and HCV RNA (P < 0.015). Multivariate analysis showed that steatosis was the independent predictor of relapse (OR, 0.988; 95% CI, 0.981 0.993; P < 0.001). Genotype 3 patients with steatosis had a relapse rate of 36.4% and 15.8% in those with high and low viral load, respectively, whereas there was no relapse in those without steatosis. In conclusion, a 12-week course of therapy is sufficient for patients without cirrhosis, not obese and infected with HCV genotype 2 achieve a RVR. This is not the case for genotype 3. Steatosis is the independent predictor of relapse. New therapeutic strategies are necessary for this subgroup of HCV genotype 3. PMID- 22497815 TI - Nonstructural 5A protein of hepatitis C virus regulates heat shock protein 72 for its own propagation. AB - We identified heat shock protein 72 (Hsp72) as a host factor that was differentially expressed in cells expressing nonstructural 5A (NS5A) protein. To investigate how NS5A modulates Hsp72 in hepatitis C virus (HCV) life cycle, we examined the role of Hsp72 in HCV replication and virus production. NS5A specifically interacted with Hsp72. Both Hsp72 and nuclear factor of activated T cells 5 (NFAT5) levels were increased in cells expressing NS5A protein. Treatments of N-acetylcysteine and glutathione markedly reduced protein levels of both NFAT5 and Hsp72. Knockdown of NFAT5 resulted in decrease in Hsp72 level in cells expressing NS5A. Importantly, silencing of Hsp72 expression resulted in decrease in both RNA replication and virus production in HCV-infected cells. These data indicate that NS5A modulates Hsp72 via NFAT5 and reactive oxygen species activation for HCV propagation. PMID- 22497816 TI - Anti-hepatitis C virus activity of 3-hydroxy caruilignan C from Swietenia macrophylla stems. AB - Chronic hepatitis C virus (HCV) infection ultimately leads to chronic hepatitis, hepatic cirrhosis and hepatocellular carcinoma (HCC). As the standard treatment is not completely efficacious, a safer and more effective agent against HCV infection needs to be developed. In this report, we demonstrated that 3-hydroxy caruilignan C (3-HCL-C) isolated from Swietenia macrophylla stems exhibited high anti-HCV activity at both protein and RNA levels at nontoxic concentrations, with an EC(50) value of 10.5 +/- 1.2 MUm. Combinations of 3-HCL-C and interferon-alpha (IFN-alpha), an HCV NS5B polymerase inhibitor (2'-C-methylcytidine; NM-107) or an HCV NS3/4A protease inhibitor (Telaprevir; VX-950) increased the suppression of HCV RNA replication. The results suggested that 3-HCL-C may be a potential anti viral agent. We then demonstrated that 3-HCL-C interfered with HCV replication by inducing IFN-stimulated response element transcription and IFN-dependent anti viral gene expression. PMID- 22497817 TI - End-stage renal disease and African American race are independent predictors of mild liver fibrosis in patients with chronic hepatitis C infection. AB - Recipients of haemodialysis for end-stage renal disease (ESRD) have a higher prevalence of hepatitis C virus (HCV) infection relative to the general US population. However, the natural course of HCV infection in patients with renal failure, including African Americans (AAs) and Caucasian Americans (CAs), is not well known. We compared the degree of liver inflammation and fibrosis in AA and CA patients with HCV infection, with and without ESRD. This was a cross-sectional study of 156 HCV patients with ESRD (130 AAs and 26 CAs) with a liver biopsy between 1992 and 2005. The control group consisted of 138 patients (50 AAs; 88 CAs) with HCV infections and a serum creatinine <1.5 mg/dL with a liver biopsy between 1995 and 1998. Specimens were graded for inflammation and fibrosis using Knodell histological activity index. Compared to patients without renal impairment, HCV patients with renal failure were older and more likely to be AA. Patients with renal impairment had lower mean serum transaminases, a higher mean serum alkaline phosphatase levels (all P < 0.0001) and less hepatic necro inflammation (Knodell histological activity index -I, II and III; P < 0.05) and fibrosis (Knodell histological activity index -IV; P < 0.0001). There were no racial differences in serum liver chemistry and histology scores among patients with renal failure. In a multivariate analysis, younger age, ESRD, AA race and a lower serum alkaline phosphatase were associated with lower odds for advanced liver fibrosis. Thus, HCV patients with ESRD had a lower degree of hepatic inflammation and fibrosis compared to those without renal disease, independent of race. PMID- 22497818 TI - The presentation and diagnosis of coronary allograft vasculopathy in pediatric heart transplant recipients. AB - One of the most important causes for long-term graft failure in pediatric heart transplant recipients is coronary allograft vasculopathy (CAV). Graft survival is approximately 50% at 5 years postdiagnosis of CAV. CAV can be difficult to detect largely because of its variability in presentation and in the definition of CAV. Making the diagnosis of CAV can be challenging, and to date, the current gold standard test is angiography, which is an expensive and invasive procedure. A number of studies in the pediatric and adult heart transplant literature exist for noninvasive methods of diagnosing CAV, ranging from biochemical markers and echocardiographic techniques to computed tomography and magnetic resonance imaging. In addition, there is evidence to show that hemodynamic and function evaluation of the coronary arteries in transplanted patients may provide diagnostic clues to the potential development of CAV. These methodologies add to the armamentarium that can compliment angiography for the purposes of diagnosis. Clinical suspicion for CAV should be heightened in patients who have had recurrent rejection, new onset arrhythmias, unexplained recurrent chest or abdominal pain, and/or the development of systolic or diastolic dysfunction in the absence of rejection. This review strives to highlight the current literature with respect to the investigations available for the diagnosis of CAV, recognizing that our understanding of this disease process is still currently in evolution. PMID- 22497819 TI - Lipid destabilisation in a ternary admixture for paediatric parenteral nutrition due to heparin and trigger factors. AB - The preparation of paediatric parenteral nutrition admixtures varies greatly. There is still a clear lack of consensus on many points. These points include the use of organic or inorganic phosphate or calcium salts, preparing binary or ternary mixtures, the type of lipid used, and the addition or suppression of heparin or carnitine, etc. The process must be standardised in order to guarantee that prepared mixtures will be stable. However, there is still no information on how to predict their stability with any degree of precision, particularly for ternary mixtures. For that reason, any change applied may trigger a destabilisation process that places patient safety at risk. We describe a case of a ternary paediatric parenteral nutrition admixture in which creaming was observed. We indicate the factors that gave rise to this phenomenon and the measures taken to avoid it. PMID- 22497820 TI - New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease position paper. AB - Until recently, vitamin K antagonists were the only available oral anticoagulants, but with numerous limitations that prompted the introduction of new oral anticoagulants targeting the single coagulation enzymes thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban, and edoxaban) and given in fixed doses without coagulation monitoring. Here we review the pharmacology and the results of clinical trials with these new agents in stroke prevention in atrial fibrillation and secondary prevention after acute coronary syndromes, providing perspectives on their future incorporation into clinical practice. In phase III trials in atrial fibrillation, compared with warfarin, dabigatran etexilate 150 mg B.I.D. reduced the rates of stroke/systemic embolism without any difference in major bleeding; dabigatran etexilate 110 mg B.I.D. had similar efficacy with decreased bleeding; apixaban 5 mg B.I.D. reduced stroke, systemic embolism, and mortality as well as major bleeding; and rivaroxaban 20 mg Q.D. was noninferior to warfarin for stroke and systemic embolism without a difference in major bleeding. All these agents reduced intracranial hemorrhage. Edoxaban is currently being evaluated in a further large phase III trial. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischemia in patients with acute coronary syndromes who were mostly receiving dual antiplatelet therapy, with conflicting results on efficacy but consistent results for increased major bleeding. Overall, the new oral anticoagulants are poised to replace vitamin K antagonists for many patients with atrial fibrillation and may have a role after acute coronary syndromes. Although convenient to administer and manage, they present challenges that need to be addressed. PMID- 22497822 TI - Counterregulation rules in atherothrombosis. PMID- 22497821 TI - Oxidized phospholipids are present on plasminogen, affect fibrinolysis, and increase following acute myocardial infarction. AB - OBJECTIVES: This study sought to assess whether plasminogen, which is homologous to lipoprotein (a) [Lp(a)], contains proinflammatory oxidized phospholipids (OxPL) and whether this has clinical relevance. BACKGROUND: OxPL measured on apolipoprotein B-100 (OxPL/apoB), primarily reflecting OxPL on Lp(a), independently predict cardiovascular disease (CVD) events. METHODS: The authors examined plasminogen from commercially available preparations and plasma from chimpanzees; gorillas; bonobos; cynomolgus monkeys; wild-type, apoE(-/-), LDLR(-/ ), and Lp(a)-transgenic mice; healthy humans; and patients with familial hypercholesterolemia, stable CVD, and acute myocardial infarction (AMI). Phosphocholine (PC)-containing OxPL (OxPC) present on plasminogen were detected directly with liquid chromatography-mass spectrometry (LC-MS/MS) and immunologically with monoclonal antibody E06. In vitro clot lysis assays were performed to assess the effect of the OxPL on plasminogen on fibrinolysis. RESULTS: LC-MS/MS revealed that OxPC fragments were covalently bound to mouse plasminogen. Immunoblot, immunoprecipitation, density gradient ultracentrifugation, and enzyme-linked immunosorbent assay analyses demonstrated that all human and animal plasma samples tested contained OxPL covalently bound to plasminogen. In plasma samples subjected to density gradient fractionation, OxPL were present on plasminogen (OxPL/plasminogen) in non-lipoprotein fractions but on Lp(a) in lipoprotein fractions. Plasma levels of OxPL/apoB and OxPL/apo(a) varied significantly (>25*) among subjects and also strongly correlated with Lp(a) levels. In contrast, OxPL/plasminogen levels were distributed across a relatively narrow range and did not correlate with Lp(a). Enzymatic removal of OxPL from plasminogen resulted in a longer lysis time for fibrin clots (16.25 vs. 11.96 min, p = 0.007). In serial measurements over 7 months, OxPL/plasminogen levels did not vary in normal subjects or in patients with stable CVD, but increased acutely over the first month and then slowly decreased to baseline in patients following AMI. CONCLUSIONS: These data demonstrate that plasminogen contains covalently bound OxPL that influence fibrinolysis. OxPL/plasminogen represent a second major plasma pool of OxPL, in addition to those present on Lp(a). OxPL present on plasminogen may have pathophysiological implications in AMI and atherothrombosis. PMID- 22497823 TI - Assessment of dyspnea in acute decompensated heart failure: insights from ASCEND HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) on the contributions of peak expiratory flow. AB - OBJECTIVES: This study hypothesized that peak expiratory flow rate (PEFR) would increase with acute heart failure (AHF) treatment over the first 24 h, related to a Dyspnea Index (DI) change and treatment effect. BACKGROUND: Dyspnea is a key symptom and clinical trial endpoint in AHF, yet objective assessment is lacking. METHODS: In a clinical trial substudy, 421 patients (37 sites) underwent PEFR testing at baseline, 1, 6, and 24 h after randomization to nesiritide or placebo. DI (by Likert scale) was collected at hours 6 and 24. RESULTS: Patients were median age 70 years, and 34% were female; no significant differences between nesiritide or placebo patients existed. Median baseline PEFR was 225 l/min (interquartile range [IQR]: 160 to 300 l/min) and increased to 230 l/min (2.2% increase; IQR: 170 to 315 l/min) by hour 1, 250 l/min (11.1% increase; IQR: 180 to 340 l/min) by hour 6, and 273 l/min (21.3% increase; IQR: 200 to 360 l/min) by 24 h (all p < 0.001). The 24-h PEFR change related to moderate or marked dyspnea improvement by DI (adjusted odds ratio: 1.04 for each 10 l/min improvement [95% confidence interval (CI): 1.07 to 1.10]; p < 0.01). A model incorporating time and treatment over 24 h showed greater PEFR improvement after nesiritide compared with placebo (p = 0.048). CONCLUSIONS: PEFR increases over the first 24 h in AHF and could serve as an AHF endpoint. Nesiritide had a greater effect than placebo on PEFR, and this predicted patients with moderate/marked improvement in dyspnea, thereby providing an objective metric for assessing AHF. (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure [ASCEND-HF]; NCT00475852). PMID- 22497824 TI - Acute decompensated heart failure: the quest to live longer and feel better: can we have it all? PMID- 22497825 TI - Do bisphosphonates slow the progression of aortic stenosis? AB - OBJECTIVES: The aim of this study was to investigate the impact of bisphosphonates on the progression of aortic stenosis. BACKGROUND: Valvular calcification is associated with the development and progression of aortic stenosis. Bisphosphonates have been suggested to slow this progression. METHODS: Female patients older than the age of 60 years with an aortic valve area (AVA) between 1.0 and 2.0 cm(2) were identified and studied retrospectively. Only those who had follow-up echocardiograms at least a year apart were included. Primary outcomes were the change in AVA and valvular gradients over time. Mortality and freedom from aortic valve replacement were also studied. A propensity-matching method was applied for the probability of the use of bisphosphonates. RESULTS: The study included 801 female patients (mean age, 76 +/- 7.6 years) with a mean follow-up of 5.1 +/- 2.4 years. The mean duration of bisphosphonate use was 3.1 +/- 2.6 years. At the time of the initial echocardiogram, 323 patients (38%) were taking bisphosphonates. The mean ejection fraction at baseline was 56.7 +/- 9.6% with a mean AVA of 1.32 +/- 0.25 cm(2). Peak and mean gradients were 28.4 +/- 11 mm Hg and 15.6 +/- 6.8 mm Hg, respectively. Propensity matching was successfully performed for 438 patients. On follow-up, there were no differences in the rate of change in AVA or peak and mean gradients when patients were stratified based on the use of bisphosphonates. Bisphosphonates also had no impact on survival or freedom from aortic valve replacement. CONCLUSIONS: In this retrospective analysis of older female patients, bisphosphonates do not have a significant impact on the hemodynamic or clinical progression of aortic stenosis. PMID- 22497826 TI - Prolongation of QTc and risk of stroke: The REGARDS (REasons for Geographic and Racial Differences in Stroke) study. AB - OBJECTIVES: The purpose of this study was to examine the association between prolongation of QT interval corrected for heart rate (QTc) with incident stroke. BACKGROUND: Unlike cardiovascular morbidity and mortality, little is known about the relationship between QTc and risk of stroke. METHODS: A total of 27,411 participants age 45 years and older without previous stroke from the REGARDS (REasons for Geographic and Racial Differences in Stroke) study were included in this analysis. QTc was calculated using Framingham formula (QTc(Fram)). Stroke cases were identified and adjudicated during up to 8.2 years of follow-up (median, 5.1 years). RESULTS: The risk of incident stroke in study participants with prolonged QTc(Fram) was almost 3 times the risk in those with normal QTc(Fram) (hazard ratio [HR] [95% confidence interval (CI)]: 2.88 [2.12 to 3.92], p < 0.0001). After adjustment for demographics (age, race, and sex), traditional stroke risk factors (antihypertensive medication use, systolic blood pressure, current smoking, diabetes, left ventricular hypertrophy, atrial fibrillation, and previous cardiovascular disease), warfarin use, aspirin use, QRS duration and use of QTc-prolonging drugs, the risk of stroke remained significantly high (HR [95% CI]: 1.67 [1.16 to 2.41], p = 0.0061) and was consistent across several subgroups of REGARDS study participants. Similar results were obtained when the risk of stroke was estimated per 1-SD increase in QTc(Fram), (HR [95% CI]: 1.12 [1.03 to 1.21], p = 0.0053 in multivariable-adjusted model) and when other QTc correction formulas including those of Hodge, Bazett, and Fridericia were used. CONCLUSIONS: QTc prolongation is associated with a significantly increased risk of incident stroke independent of traditional stroke risk factors. Examining the risk of stroke associated with QTc-prolonging drugs may be warranted. PMID- 22497827 TI - Long-term outcome following catheter valvotomy for pulmonary atresia with intact ventricular septum. AB - OBJECTIVES: This study investigated the outcome for all patients undergoing catheter valve perforation for pulmonary atresia with intact ventricular septum (PAIVS) 21 years after the first procedure at their center. BACKGROUND: Catheter perforation for PAIVS is now an established procedure. However, the management of the borderline right ventricle (RV) is controversial, and there may be a place for novel techniques such as stenting of the arterial duct. METHODS: There were 37 successful valve perforations (total 39 patients). Median length of follow-up was 9.2 years (range 2.2 to 21.0 years). Seventeen patients had stenting of the arterial duct. The mean (SD) initial z-score for the tricuspid valve was -5.1 (+/ 3.4), and a further 142 sets of measurements were taken to assess the growth of the RV of survivors. RESULTS: There were 8 deaths (21%), and no deaths after the first 35 days. There were no late arrhythmias or ischemic events. Twenty-five patients (83% of survivors) have a biventricular circulation. For patients who had stenting of the arterial duct, significant reductions in early reintervention (0 vs. 7 patients, p = 0.009) and hospital stay (17.4 +/- 18.1 days vs. 33.8 +/- 28.6 days, p = 0.012) occurred, with no increase in mortality or morbidity. There was no catch-up growth of the RV in patients who had a biventricular outcome (z score increase +0.08/year, p = 0.26). CONCLUSIONS: Long-term survival is good, and even small RVs may be amenable to this procedure. Multiple interventions may be required to achieve biventricular circulation, but stenting of the arterial duct may reduce hospital stay and repeat procedures. PMID- 22497828 TI - Angiotensin II plays a critical role in alcohol-induced cardiac nitrative damage, cell death, remodeling, and cardiomyopathy in a protein kinase C/nicotinamide adenine dinucleotide phosphate oxidase-dependent manner. AB - OBJECTIVES: The purpose of this study was to examine the cellular and molecular mechanisms underlying alcoholic cardiomyopathy. BACKGROUND: The mechanism for alcoholic cardiomyopathy remains largely unknown. METHODS: The chronic cardiac effects of alcohol were examined in mice feeding with alcohol or isocaloric control diet for 2 months. Signaling pathways of alcohol-induced cardiac cell death were examined in H9c2 cells. RESULTS: Compared with controls, hearts from alcohol-fed mice exhibited increased apoptosis, along with significant nitrative damage, demonstrated by 3-nitrotyrosine abundance. Alcohol exposure to H9c2 cells induced apoptosis, accompanied by 3-nitrotyrosine accumulation and nicotinamide adenine dinucleotide phosphate oxidase (NOX) activation. Pre-incubation of H9c2 cells with urate (peroxynitrite scavenger), N(G)-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor), manganese(III) tetrakis(1-methyl-4 pyridyl)porphyrin (a superoxide dismutase mimetic), and apocynin (NOX inhibitor) abrogated alcohol-induced apoptosis. Furthermore, alcohol exposure significantly increased the expression of angiotensin II and its type 1 receptor (AT1). A protein kinase C (PKC)-alpha/beta1 inhibitor or PKC-beta1 small interfering RNA and an AT1 blocker prevented alcohol-induced activation of NOX, and the AT1 blocker losartan significantly inhibited the expression of PKC-beta1, indicating that alcohol-induced activation of NOX is mediated by PKC-beta1 via AT1. To define the role of AT1-mediated PKC/NOX-derived superoxide generation in alcohol induced cardiotoxicity, mice with knockout of the AT1 gene and wild-type mice were simultaneously treated with alcohol for 2 months. The knockout AT1 gene completely prevented cardiac nitrative damage, cell death, remodeling, and dysfunction. More importantly, pharmacological treatment of alcoholic mice with superoxide dismutase mimetic also significantly prevented cardiac nitrative damage, cell death, and remodeling. CONCLUSIONS: Alcohol-induced nitrative stress and apoptosis, which are mediated by angiotensin II interaction with AT1 and subsequent activation of a PKC-beta1-dependent NOX pathway, are a causal factor in the development of alcoholic cardiomyopathy. PMID- 22497829 TI - A primary cardiac sarcoma spreading along the pacing leads of a permanent pacemaker. PMID- 22497830 TI - Scientific misconduct, retractions, and errata. PMID- 22497832 TI - Dabigatran is not a direct Xa inhibitor. PMID- 22497833 TI - Staphylococcus aureus endocarditis complicated by aortic root abscess, coronary fistula, and mitral valve perforation. PMID- 22497834 TI - Low density solvent based dispersive liquid-liquid microextraction with gas chromatography-electron capture detection for the determination of cypermethrin in tissues and blood of cypermethrin treated rats. AB - A simple and rapid method to determine the cypermethrin (CYP) insecticide in rat tissues (kidney, liver and brain) and blood has been developed for the first time using low density solvent-dispersive liquid-liquid microextraction (LDS-DLLME) followed by gas chromatography-electron capture detector (GC-ECD) analysis. Initially, tissue samples containing CYP were homoginized in acetone. Subsequently, homogenate was mixed with n-hexane (extraction solvent) and the mixture was rapidly injected into water. The upper n-hexane layer was collected in a separate microtube and injected into GC-ECD for analysis. Blood samples were diluted with ultrapure water and subjected to DLLME through similar procedure. Parameters such as type and volume of disperser and extraction solvent, salting out effect and extraction time, which can affect the extraction efficiency of DLLME, were optimized. Method was validated by investigating linearity, precision, recovery, limit of detection (LOD) and quantification (LOQ). LODs in tissue were in the range of 0.043-0.314 ng mg(-1) and for blood it was 8.6 ng mL( 1) with a signal to noise ratio of 3:1. LOQs in tissue were in the range of 0.143 1.03 ng mg(-1) and for blood it was 28.3 ng mL(-1) with a signal to noise ratio of 10:1. Mean recoveries of CYP at three different concentation levels in all the matrices were found to be in the range of 81.6-103.67%. The results show that, LDS-DLLME coupled with GC-ECD offers a simple, rapid and efficient technique for extraction and determination of CYP in rat tissues and blood samples, which in turn would be useful for toxicological studies of CYP. PMID- 22497835 TI - Reverse injection capillary electrophoresis UV detection for serotonin quantification in human whole blood. AB - We describe the first capillary electrophoresis UV detection method to measure serotonin in human whole blood (WB). Procedural parameters such as concentration and pH of run buffer and injection mode were investigated. The reverse injection allows to decrease the analysis time by injecting samples at the outlet end of the silica capillary close to the detection window, so reducing the migration distance. Thus, when a capillary with an effective length of 10 cm and a 400 mmol/L Tris phosphate as background electrolyte at pH 3.25 was used, the migration time of the serotonin peak was 2.6 min. These conditions gave a good reproducibility of migration times (CV, 0.77%) and peak areas (CV, 2.44%). Intra- and inter-assay CV were 3.85% and 7.32%, respectively, and the analytical recovery was between 96.8% and 99.4%. PMID- 22497836 TI - Antibiotic resistance profiles of Salmonella serovars isolated from retail pork and chicken meat in North Vietnam. AB - The spread of antibiotic resistance via meat poses a serious public health concerns. During 2007-2009, a total of 586 retail meat samples (318 pork and 268 chicken meats) were collected from three provinces (Bac Ninh, Ha Noi and Ha Tay) of North Vietnam to determine the prevalence of Salmonella. Isolates were characterized by serotyping and antibiotic susceptibility testing. Approximately 39.6% (n=126) of pork and 42.9% (n=115) of chicken samples were Salmonella positive, and 14 Salmonella serovars were identified. Anatum (15.8%) was the most common serovar, followed by Infantis (13.3%), Emek (10.4%), Derby and Rissen (9.5%), Typhimurium (9.1%), Reading (7.5%) and London (6.2%). The isolation frequency of serovars Enteritidis, Albany, Hadar, Weltevreden, Newport and Blockey ranged from 1.2%-5.8%. Resistance to at least one antibiotic agent was detected in 78.4% of isolates (n=189) and the most frequent resistance were to tetracycline (58.5%), sulphonamides (58.1%), streptomycin (47.3%), ampicillin (39.8%), chloramphenicol (37.3%), trimethoprim (34.0%) and nalidixic acid (27.8%). No Salmonella isolates were resistant to ceftazidime. Chicken isolates had higher resistance to antibiotic agents than pork isolates (P<0.05). It showed that 159 Salmonella isolates belong to the 14 serovars were multidrug resistant (MDR) and 50 MDR patterns were found. This study indicated that Salmonella serovars isolated from retail meat samples were resistant to multiple antibiotics and this resistance was widespread among different serovars. The widespread resistance may have arisen from misuse or overuse of antibiotics during animal husbandry in North Vietnam. PMID- 22497837 TI - Fate of Yersinia enterocolitica during manufacture, ripening and storage of Lighvan cheese. AB - This study aimed to evaluate the behavior of virulent Yersinia enterocolitica (YE) during the manufacture, ripening and storage of Lighvan cheese with particular reference to strains of YE, initial inoculation level, and storage time. Three strains of YE with low (1 log cfu/ml) and high (3 log cfu/ml) inoculation levels were inoculated to raw whole ewe's milk which was then used for manufacturing of Lighvan cheese. Throughout the manufacturing, ripening and storage periods the number of YE was counted on selective media. Enumerated colonies were then confirmed by duplex PCR using ail and virF genes. Moreover, some microbial and physiochemical characteristics of the cheese samples were examined. According to the results, initial inoculation level and storage time had statistically significant (P<0.01) effects on persistency of YE, while strain type exhibited no statistically significant (P>0.01) impact on survival of the pathogen. Results showed a rapid increase in the number of YE during manufacturing, however, in the ripening and storage periods the number of YE was decreased and eventually it was eliminated in all cheese batches after 4 months of storage. PMID- 22497838 TI - Microbiological and physicochemical characterisation of caxiri, an alcoholic beverage produced by the indigenous Juruna people of Brazil. AB - Caxiri is a traditional fermented alcoholic beverage produced from cassava and sweet potatoes by the indigenous Juruna or Yudja people in Brazil. Our results showed that caxiri fermentation is invariably associated with the following: (i) an increase in the total microbial population, with yeast being the largest group detected; (ii) a decrease in reducing sugars, malic, tartaric, succinic, oxalic and propionic acid; and (iii) a final product characterised by a high content of ethanol and a high concentration of lactic acid. The microbial community dynamics were investigated by culture-based and culture-independent approaches. Fermentation was assisted by a complex microbial community that changed in structure and composition during the fermentative process. The bacterial population ranged from 3.05 to 5.33 log/mL, and the yeast population varied from 3.27 log CFU/mL to 7.34 log CFU/mL, showing that yeasts dominated the fermentation process after 48 h. A total of 343 colonies of bacteria and 205 colonies of yeasts were isolated and initially grouped by Amplified Ribosomal DNA Restriction Analysis (ARDRA) and by biochemical features. Phylogenetic analysis of the 16S rRNA gene sequences of representative isolates showed that the bacteria were mainly represented by endospore-forming low-G+C content Gram positive bacilli (Bacillus spp.; 61.5% of the isolates), with Bacillus pumilus, Bacillus spp. (Bacillus cereus group), and Bacillus subtilis being the main species identified. The species Sphingomonas sp. and Pediococcus acidilactici were also found. The dominant yeast identified was Saccharomyces cerevisiae. Rhodotorula mucilaginosa, Pichia membranifaciens, Pichia guilliermondii and Cryptococcus luteolus were also found. According to the Polymerase Chain Reaction and Denaturing Gradient Gel Electrophoresis (PCR-DGGE) analysis, the microbial communities present during fermentation were probably from the raw materials, ambient or present on the utensils used during beverage preparation. The results indicated the necessity to combine both culture-dependent and culture-independent methods for a better description of the microbial communities in indigenous starch fermentations. Also, pH values decreased from 4.76 to 3.15 during fermentation. The ethanol concentration was 83.9 g/L and lactic acid reached 27.89 g/L by the end of the fermentation process. PMID- 22497839 TI - Effect of acculturation and mutuality on family loyalty among Mexican American caregivers of elders. AB - PURPOSE: Informal family care for elders is conventional in Mexican American communities despite increasing intergenerational gaps in filial values. In our study, we explored whether acculturation and dyadic mutuality, as perceived by Mexican American family caregivers, explain the caregivers' expectations of family loyalty toward elderly relatives. DESIGN: A nonexperimental, correlational design with convenience sampling was used in El Paso, Texas, from October 2007 to January 2008. METHODS: Three bilingual promotoras collected data from 193 Mexican American adult caregivers of community-dwelling elders using three scales designed for Mexican Americans: the Acculturation Rating Scale for Mexican Americans II-Short Form, the Mutuality Scale, and the Expectations of Family Loyalty of Children Toward Elderly Relatives Scale. Confirmatory factor analysis was used to analyze the data. FINDINGS: Acculturation had a marginal effect (r = .21, p < .05), but mutuality presented a strong correlation (r = .45, p < .001) with the expectations of family loyalty toward elderly relatives. There was no significant correlation between acculturation and mutuality (r = .05). CONCLUSIONS: Although Mexican American caregivers with strong Mexican orientation may have high expectations of family loyalty toward elderly relatives, mutuality exhibits more significant effects on expectations. Among Mexican Americans, mutuality between the caregiving dyad, as perceived by caregivers, may be a better predictor of filial values than caregivers' acculturation alone. CLINICAL RELEVANCE: It may be useful to incorporate the dual paradigm of acculturation and mutuality into immigrant family care for elderly relatives. PMID- 22497840 TI - Case report: A unique pediatric case of a primary CD8 expressing ALK-1 positive anaplastic large cell lymphoma of skeletal muscle. AB - Primary involvement of skeletal muscle is a very rare event in ALK-1 positive anaplastic large cell lymphoma (ALCL). We describe a case of a 10-year old boy presenting with a three week history of pain and a palpable firm swelling at the dorsal aspect of the left thigh. Histological examination of the lesion revealed a tumoral and diffuse polymorphic infiltration of the muscle by large lymphoid cells. Tumor cells displayed eccentric, lobulated "horse shoe" or "kidney-shape" nuclei. The cells showed immunohistochemical positivity for CD30, ALK-1, CD2, CD3, CD7, CD8, and Perforin. Fluorescence in situ hybridization analysis revealed a characteristic rearrangement of the ALK-1 gene in 2p23 leading to the diagnosis of ALK-1 positive ALCL. Chemotherapy according to the ALCL-99-NHL-BFM protocol was initiated and resulted in a complete remission after two cycles. This case illustrates the unusual presentation of a pediatric ALCL in soft tissue with a good response to chemotherapy. PMID- 22497841 TI - Selective PDE inhibitors as novel treatments for respiratory diseases. AB - Phosphodiesterases (PDEs) are a family of enzymes which catalyse the metabolism of the intracellular cyclic nucleotides, c-AMP and c-GMP that are expressed in a variety of cell types and in the context of respiratory diseases, It is now recognised that the use of PDE3, PDE4 and mixed PDE3/4 inhibitors can provide clinical benefit to patients with asthma or chronic obstructive pulmonary disease (COPD). The orally active PDE4 inhibitor Roflumilast-n-oxide has been approved for treatment of severe exacerbations of COPD as add-on therapy to standard drugs. This review discusses the involvement of PDEs in airway diseases and various strategies that are currently being pursued to improve efficacy and reduce side-effects of PDE4 inhibitors, including delivery via the inhaled route, mixed PDE inhibitors and/or antisense biologicals targeted towards PDE4. PMID- 22497842 TI - Treatment of COPD: no longer nihilism, but there is still an urgent need for new therapies. PMID- 22497843 TI - Neighbor of Punc E 11: expression pattern of the new hepatic stem/progenitor cell marker during murine liver development. AB - We have previously identified Neighbor of Punc E 11 (Nope) as a specific cell surface marker of stem/progenitor cells in the murine fetal liver that is also expressed in hepatocellular carcinoma. Here, we focus on the differential expression pattern of Nope during murine fetal and postnatal liver development as well as in a normal and regenerating adult liver including oval cell activation. In the fetal liver, Nope shows a constantly high expression level and is a useful surface marker for the identification of Dlk, E-cadherin, and CD133-positive hepatoblasts by flow cytometry. Postnatally, Nope expression declines rapidly and remains barely detectable in the adult liver as shown by quantitative real-time reverse-transcriptase polymerase chain reaction and western blot analyses. Immunohistochemically, costainings for Nope- and epithelial-specific markers (E cadherin), markers of early hepatoblasts (alpha-fetoprotein), and biliary marker proteins (CK19) demonstrate that Nope is initially expressed on bipotent hepatoblasts and persists thereafter on commited hepatocytic as well as cholangiocytic progenitor cells during late fetal liver development. Postnatally, Nope loses its circular expression pattern and is specifically directed to the sinusoidal membrane of early hepatocytes. While Nope is only weakly expressed on cholangiocytes in the normal adult liver, activated stem/progenitor (oval) cells clearly coexpress Nope together with the common markers A6, EpCAM, and CD24 in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse model. In conclusion, Nope should be most useful in future research to define the differentiation stage of hepatic-specified cells of various sources and is a promising candidate to identify and isolate hepatic stem cells from the adult liver. PMID- 22497844 TI - Gender and health: relational, intersectional, and biosocial approaches. PMID- 22497845 TI - Systematic review of behavior change research on point-of-use water treatment interventions in countries categorized as low- to medium-development on the human development index. AB - Point-of-use water treatment (i.e., water purification at the point of consumption) has proven effective in preventing diarrhea in developing countries. However, widespread adoption has not occurred, suggesting that implementation strategies have not motivated sustained behavior change. We conducted a systematic literature review of published behavioral research on factors influencing adoption of point-of-use water treatment in countries categorized as low- to medium-development on the United Nations Development Programme Human Development Index. We used 22 key words to search peer-reviewed literature from 1950 to 2010 from OVID Medline, CINAHL, and PsycINFO. Twenty-six (1.7%) of 1551 papers met our four inclusion criteria: 1) implemented a point-of-use water treatment intervention, 2) applied a behavioral intervention, 3) evaluated behavior change as the outcome, and 4) occurred in a low- or medium-development country. We reviewed these 26 publications for detailed descriptions of the water treatment intervention, theoretical rationales for the behavioral intervention, and descriptions of the evaluation. In 5 (19%) papers, details of the behavioral intervention were fully specified. Seven (27%) papers reported using a behavioral theory in the design of the intervention and evaluation of its impact. Ten (38%) studies used a comparison or control group; 5 provided detailed descriptions. Seven (27%) papers reported high sustained use of point-of-use water treatment with rates >50% at the last recorded follow-up. Despite documented health benefits of point-of-use water treatment interventions in reducing diarrheal diseases, we found limited peer-reviewed behavioral research on the topic. In addition, we found the existing literature often lacked detailed descriptions of the intervention for replication, seldom described the theoretical and empirical rationale for the implementation and evaluation of the intervention, and often had limitations in the evaluation methodology. The scarcity of papers on behavior change with respect to point-of-use water treatment technologies suggests that this field is underdeveloped. PMID- 22497846 TI - The relationship between state abortion-restrictions and homicide deaths among children under 5 years of age: a longitudinal study. AB - The purpose of this study is to explore whether, in the U.S., there are associations between state-level variations in mortality among young children and state abortion restriction policies - such as parental-consent requirements, parental-notification requirements, mandatory delay laws, and restrictions on Medicaid funding for abortion. To investigate this, we used NCHS Multiple Cause of Deaths public-use data files for the period 1983-2002, and compiled data on children ages 0-4 identified as having died as a result of assault/homicide in each state and year. Medicaid funding of abortion, mandatory delay laws, and parental involvement laws for minors seeking abortions were included as the main predictor variables of interest. Multivariate count data models using pooled state-year-age cohort data, with state and time fixed effects and other state level controls, were estimated. Results indicated that, between 1983 and 2002, the average increase in the number of homicide deaths for children under 5 years of age was 5.70 per state among states that implemented stricter abortion policies over that time, and 2.00 per state for states that did not. In the count data models, parental-consent laws were associated with a 13 percent increase in child homicide deaths; parental-notification laws were associated with an 8 percent increase in child homicide deaths though the results were less robust to alternate model specifications; mandatory delay requirements were associated with a 13 percent increase in child homicide deaths. While these data do not allow us to discern precise pathways via which state abortion-restrictions can lead to more child homicide deaths, we speculate that state restrictions on abortion may result in a disproportionate increase in children born into relatively high-risk environments. Additional research is called for to explore the association of state abortion-restrictions with other measures of infant/child health and well being. PMID- 22497847 TI - Using quantile regression to examine the effects of inequality across the mortality distribution in the U.S. counties. AB - The U.S. has experienced a resurgence of income inequality in the past decades. The evidence regarding the mortality implications of this phenomenon has been mixed. This study employs a rarely used method in mortality research, quantile regression (QR), to provide insight into the ongoing debate of whether income inequality is a determinant of mortality and to investigate the varying relationship between inequality and mortality throughout the mortality distribution. Analyzing a U.S. dataset where the five-year (1998-2002) average mortality rates were combined with other county-level covariates, we found that the association between inequality and mortality was not constant throughout the mortality distribution and the impact of inequality on mortality steadily increased until the 80th percentile. When accounting for all potential confounders, inequality was significantly and positively related to mortality; however, this inequality-mortality relationship did not hold across the mortality distribution. A series of Wald tests confirmed this varying inequality-mortality relationship, especially between the lower and upper tails. The large variation in the estimated coefficients of the Gini index suggested that inequality had the greatest influence on those counties with a mortality rate of roughly 9.95 deaths per 1000 population (80th percentile) compared to any other counties. Furthermore, our results suggest that the traditional analytic methods that focus on mean or median value of the dependent variable can be, at most, applied to a narrow 20 percent of observations. This study demonstrates the value of QR. Our findings provide some insight as to why the existing evidence for the inequality mortality relationship is mixed and suggest that analytical issues may play a role in clarifying whether inequality is a robust determinant of population health. PMID- 22497848 TI - Multiple risk behaviors and suicidal ideation and behavior among Israeli and Palestinian adolescents. AB - Based conceptually on Problem Behavior Theory, Normalization Theory and theories of adolescent ethnic identity formation this study explores relationships between individual and cumulative multiple risk behaviors and suicidal ideation and behavior among mid-adolescents in three different populations in the Middle East. Data from the 2004 Health Behavior in School-Aged Children in the Middle-East (HBSC-ME) study included 8345 10th-grade pupils in three populations: Jewish Israelis (1770), Arab Israelis (2185), and Palestinians in Gaza and the West Bank (4390). We considered risk behaviors and factors including tobacco use, bullying, medically-attended injuries, excessive time with friends, parental disconnectedness, negative school experience, truancy and poor academic performance. Substantial population differences for suicidal tendency and risk behaviors were observed, with notably high levels of suicidal ideation and behavior among Arab-Israeli youth and higher levels of risk behaviors among the Jewish and Arab-Israeli youth. For all populations suicidal tendency was at least 4 times higher among adolescents reporting 4+ risk behaviors, suggesting that similar psychosocial determinants affect patterns of risk behaviors and suicidal tendency. Results highlight the importance of understanding cultural contexts of risk behaviors and suicidal ideation and behavior. PMID- 22497849 TI - Spirulina platensis versus silymarin in the treatment of chronic hepatitis C virus infection. A pilot randomized, comparative clinical trial. AB - BACKGROUND: Spirulina platensis, a cynobacterium used frequently as a dietary supplement had been found to exhibit many immune-stimulating and antiviral activities. It had been found to activate macrophages, NK cells, T cells, B cells, and to stimulate the production of Interferon gamma (IFN-gamma) and other cytokines. Natural substances isolated from Spirulina platensis had been found to be potent inhibitors against several enveloped viruses by blocking viral absorption/penetration and some replication stages of progeny viruses after penetration into cells. We aimed to study whether this dietary supplement possesses any therapeutically feasible activity worthy of further larger controlled clinical evaluation. METHODS: Sixty six patients with chronic hepatitis C virus infection and eligible for inclusion had been randomized to either Spirulina or Silymarin treated groups for a period of six months treatment.The two groups were followed up and blindly compared for early (after 3 months) and end of 6 months treatment virological response. The effects of both treatments on each of alanine aminotransferase (ALT), Chronic Liver Disease Questionnaire scores (CLDQ), Arizona Sexual Experience Scale scores (ASEX) and the occurrence of any attributable adverse events were also compared. RESULTS: Among the 30 patients who had been treated with Spirulina and completed the 6 months protocol, 4 patients (13.3%) had a complete end of treatment virological response and 2 patients (6.7%) had a partial end of treatment response defined as significant decrease of virus load of at least 2-logs10. Though the proportion of responders in Spirulina group was greater than in the Silymarin group, the difference was not statistically significant at the end of both 6 months (p = 0.12) and 3 months treatment (p = 0.22) by Exact test. Alanine aminotransferase as well as CLDQ and ASEX scores were found to be more significantly improved in Spirulina than in Silymarin treated group. CONCLUSIONS: Our results could suggest a therapeutically feasible potential for Spirulina platensis in chronic HCV patients, worthy to conduct a larger sized and longer study to confirm these safety and efficacy encouraging results. TRIAL REGISTRATION: WHO Clinical Trial Registration ID: ACTRN12610000958088http://apps.who.int/trialsearch/trial.aspx?trialid=ACTRN126100 0958088. PMID- 22497850 TI - Oncofetal protein IMP3: a useful diagnostic biomarker for leiomyosarcoma. AB - An accurate diagnosis between leiomyoma and leiomyosarcoma is essential for patient management. IMP3 is a member of the insulin-like growth factor (IGF-II) mRNA binding protein (IMP) family that consist of IMP1, IMP2, and IMP3. IMP3 is an oncofetal protein associated with aggressive and advanced tumors and is specifically expressed in malignant tumors but not found in benign tissues. The aim of this study was to determine the expression and diagnostic value of IMP3 in leiomyoma and leiomyosarcoma. A total of 216 cases (resection, n = 183; biopsy, n = 33) consisting of 82 leiomyosarcomas (uterine, n = 15; soft tissue, n = 67), 62 leiomyomas (uterine, n = 50; soft tissue, n = 12), and 72 uterine-variant leiomyomas (atypical, n = 19 [14%]; cellular, n = 21 [16%]; mitotically active, n = 12 [9%]; myxoid, n = 11 [8%]; vascular, n = 3 [2%]; epithelioid, n = 1 [1%]; benign metastasizing, n = 1 [1%]; and smooth muscle tumors of uncertain malignant potential, n = 4) were examined by immunohistochemistry for IMP3 expression. IMP3 showed strong cytoplasmic staining in 43 (52%) of 82 leiomyosarcomas, regardless of histologic grades. There was no difference in IMP3 expression between uterine and soft tissue leiomyosarcomas. In contrast to malignant tumors, IMP3 expression was not found in any of the typical leiomyomas (0/62 cases). All uterine-variant leiomyomas were negative, except for 3 cases (atypical variant, n = 2; cellular variant, n = 1) for IMP3 staining. In summary, we are the first to describe IMP3 expression in smooth muscle tumors. Our findings indicate that the expression of IMP3 in both uterine and soft tissue leiomyosarcomas can be used as a positive biomarker to increase the level of confidence in establishing a definitive diagnosis of a malignant smooth muscle tumor. PMID- 22497851 TI - Infant brain tumors: a neuropathologic population-based institutional reappraisal. AB - The factors that impact the long-term functional outcome for infants with brain tumor are unclear. The clinicopathologic features of all infant brain tumors occurring at our institution (1982-2005) were reexamined to explore the factors influencing prognosis. The details of the neuropathologic review are reported herein. Thirty-five cases were identified and included 7 astrocytomas (6 low grade and 1 glioblastoma), 6 atypical teratoid rhabdoid tumors, 5 choroid plexus papillomas, 4 ependymomas (3 anaplastic), 4 teratomas (3 immature), 2 supratentorial primitive neuroectodermal tumors, 2 gangliogliomas, 2 desmoplastic tumors of infancy, and 1 each of "medulloblastoma with extensive nodularity," adamantinomatous craniopharyngioma, and 1 "malignancy not otherwise specified." The original diagnosis was changed in 8 cases (23%), and atypical teratoid rhabdoid tumors was the most common revision (n = 5). Case 9 was unusual in that both the patient and her 2-year-old sister displayed INI-1 immunonegative posterior fossa tumors and extended survival. Tumor grade was altered in 6 cases (17%), the most significant instance being the downgrading from the World Health Organization grade IV to I (case 18: supratentorial primitive neuroectodermal tumors to desmoplastic tumors of infancy). As opposed to other reports in the literature, our cohort contained a substantially higher frequency of atypical teratoid rhabdoid tumors and a lower frequency of medulloblastoma. Changes in the histologic diagnosis/grade in a significant subset of cases most likely reflect the continual evolution of brain tumor classification schemes. INI-1 immunohistochemistry was instrumental in the pathologic assessment of select cases and raised the possibility that atypical teratoid rhabdoid tumors may be the most common infant brain malignancy. PMID- 22497852 TI - Psychiatry should not become hostage to placebo: an alternative interpretation of antidepressant-placebo differences in the treatment response in depression. AB - BACKGROUND: It is widely believed that in randomized controlled trials of antidepressants the difference between drug and placebo response rates is rather small (around 20%), leading to a common perception that antidepressants have limited efficacy. AIM: The aim of the present paper was to present an alternative calculation and interpretation of antidepressant-placebo difference in the treatment response to antidepressant in drug trials which may shed a new light on the efficacy of antidepressants. ISSUES: We have previously highlighted several controversial points concerning the calculation of antidepressant and placebo response rates in randomised controlled trials, which may influence views concerning the efficacy of drugs, and demonstrated several factors which may lead to overestimation of the placebo effect and underestimation of antidepressant efficacy. The traditional interpretation of antidepressant-placebo difference in randomized controlled trials on major depression has been also challenged previously from at least five points of view but all leading to a conclusion that currently prevailing opinions concerning relative placebo and antidepressant response rates overestimate placebo response, and thereby underestimate efficacy of antidepressant drugs. In our present paper we propose another method for calculating placebo and antidepressant response rates which may shed new light on an overlooked aspect of the efficacy of these drugs. CONCLUSIONS: We contend that opinions on the effectiveness of antidepressants should be reconsidered, and comparisons with placebo should be more carefully applied. Interpretation of the placebo response is of crucial importance for establishing the efficacy of antidepressive medications, and psychiatry should not become the hostage of placebo. PMID- 22497853 TI - The rapid and direct determination of ATPase activity by ion exchange chromatography and the application to the activity of heat shock protein-90. AB - Adenosine nucleotides are involved as substrates or co-factors in several biochemical reactions, catalyzed by enzymes, which modulate energy production, signal transduction and cell proliferation. We here report the development and optimization of an ion exchange liquid chromatography (LC) method for the determination of ATP, ADP and AMP. This method is specifically aimed at the determination of the ATP-ase activity of human heat shock protein 90 (Hsp90), a molecular chaperone that has emerged as target enzyme in cancer therapy. Separation of the three nucleotides was achieved in a 15-min run by using a disk shaped monolithic ethylene diamine stationary phase of small dimensions (2mm*6mm i.d.), under a three-solvent gradient elution mode and UV detection at 256nm. The described direct LC method resulted highly specific as a consequence of the baseline separation of the three adenosine nucleotides and could be applied to the determination of the enzymatic activity of ADP/ATP generating or consuming enzymes (such as kinases). Furthermore, comparison of the LOD and LOQ values of the LC method with those obtained with the malachite green assay, which is one of the most used indirect screening methodologies for ATP-ase activity, showed that the LC method has a similar range of application without presenting the drawbacks related to contamination by inorganic phosphate ions and glycerol, which are present in Hsp90 commercial samples. PMID- 22497854 TI - Application of ionic surfactant as a carrier and emulsifier agent for the microextraction of fluoroquinolones. AB - A simple microextraction method based on emulsification of organic extraction solvent in aqueous sample using an ionic surfactant was evaluated for extraction and preconcentration of trace amounts of ofloxacin and ciprofloxacin as polar model drugs. In this method, the surfactant was used as carrier and disperser agent simultaneously. The target analytes were converted into their ion-pair complexes with Aliquat-336 and then extracted into an organic solvent (1-octanol) dispersed in aqueous solution. After extraction and phase separation, the organic solvent on top of the solution was withdrawn into the syringe and 20 MUL of it was injected into a HPLC instrument for analysis. The factors influential to extraction were investigated and optimized. Under optimum extraction conditions, the limits of detection (LODs) as small as 0.06 and 0.02 ng mL(-1) and linear dynamic range of 0.1-100 and 0.06-100 ng mL(-1) were obtained for ofloxacin and ciprofloxacin, respectively. For analysis of real samples such as waste water, river water and urine samples, solid-phase extraction (SPE) was applied prior to liquid phase microextraction in order to avoid/remove matrix effect. The obtained results indicate that the proposed method is efficient, fast and inexpensive for extraction and determination of fluoroquinolones in environmental aqueous and urine samples. PMID- 22497855 TI - Thermal analysis and FTIR spectral curve-fitting investigation of formation mechanism and stability of indomethacin-saccharin cocrystals via solid-state grinding process. AB - The cocrystal formation of indomethacin (IMC) and saccharin (SAC) by mechanical cogrinding or thermal treatment was investigated. The formation mechanism and stability of IMC-SAC cocrystal prepared by cogrinding process were explored. Typical IMC-SAC cocrystal was also prepared by solvent evaporation method. All the samples were identified and characterized by using differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) microspectroscopy with curve-fitting analysis. The physical stability of different IMC-SAC ground mixtures before and after storage for 7 months was examined. The results demonstrate that the stepwise measurements were carried out at specific intervals over a continuous cogrinding process showing a continuous growth in the cocrystal formation between IMC and SAC. The main IR spectral shifts from 3371 to 3,347 cm( 1) and 1693 to 1682 cm(-1) for IMC, as well as from 3094 to 3136 cm(-1) and 1718 to 1735 cm(-1) for SAC suggested that the OH and NH groups in both chemical structures were taken part in a hydrogen bonding, leading to the formation of IMC SAC cocrystal. A melting at 184 degrees C for the 30-min IMC-SAC ground mixture was almost the same as the melting at 184 degrees C for the solvent-evaporated IMC-SAC cocrystal. The 30-min IMC-SAC ground mixture was also confirmed to have similar components and contents to that of the solvent-evaporated IMC-SAC cocrystal by using a curve-fitting analysis from IR spectra. The thermal-induced IMC-SAC cocrystal formation was also found to be dependent on the temperature treated. Different IMC-SAC ground mixtures after storage at 25 degrees C/40% RH condition for 7 months had an improved tendency of IMC-SAC cocrystallization. PMID- 22497856 TI - Membrane and lipopolysaccharide interactions of C-terminal peptides from S1 peptidases. AB - The mechanisms underlying antimicrobial and anti-endotoxic effects were investigated for a series of structurally related peptides derived from the C terminal region of S1 peptidases. For this purpose, results on bacterial killing were compared to those on peptide-induced liposome leakage, and to ellipsometry and dual polarization interferometry results on peptide binding to, and disordering of, supported lipid bilayers. Furthermore, the ability of these peptides to block endotoxic effects caused by bacterial lipopolysaccharide (LPS), monitored through NO production in macrophages, was compared to the binding of these peptides to LPS, and to secondary structure formation in the peptide/LPS complex. Bacteria killing, occurring through peptide-induced membrane lysis, was found to correlate with liposome rupture, and with the extent of peptide binding to the lipid membrane, no adsorption threshold for peptide insertion being observed. Membrane and LPS binding was found to depend on peptide net charge, illustrated by LPS binding increasing with increasing peptide charge, and peptides with net negative charge being unable to lyse membranes, kill bacteria, and block LPS-induced endotoxic effect. These effects were, however, also influenced by peptide hydrophobicity. LPS binding was furthermore demonstrated to be necessary, but not sufficient, for anti-endotoxic effect of these peptides. Circular dichroism spectroscopy showed that pronounced helix formation occurs in peptide/LPS complexes for all peptides displaying anti-endotoxic effect, hence potentially linked to this functionality. Similarly, ordered secondary structure formation was correlated to membrane binding, lysis, and antimicrobial activity of these peptides. Finally, preferential binding of these peptides to LPS over the lipid membrane was demonstrated. PMID- 22497857 TI - [Evaluation of the grade of application of the recommendations of screening for Chagas disease in pregnant women]. PMID- 22497858 TI - [Testicular pain and ruptured abdominal aorta aneurysm]. PMID- 22497859 TI - Gene expression in honey bee (Apis mellifera) larvae exposed to pesticides and Varroa mites (Varroa destructor). AB - Honey bee (Apis mellifera) larvae reared in vitro were exposed to one of nine pesticides and/or were challenged with the parasitic mite, Varroa destructor. Total RNA was extracted from individual larvae and first strand cDNAs were generated. Gene-expression changes in larvae were measured using quantitative PCR (qPCR) targeting transcripts for pathogens and genes involved in physiological processes, bee health, immunity, and/or xenobiotic detoxification. Transcript levels for Peptidoglycan Recognition Protein (PGRPSC), a pathogen recognition gene, increased in larvae exposed to Varroa mites (P<0.001) and were not changed in pesticide treated larvae. As expected, Varroa-parasitized brood had higher transcripts of Deformed Wing Virus than did control larvae (P<0.001). Varroa parasitism, arguably coupled with virus infection, resulted in significantly higher transcript abundances for the antimicrobial peptides abaecin, hymenoptaecin, and defensin1. Transcript levels for Prophenoloxidase-activating enzyme (PPOact), an immune end product, were elevated in larvae treated with myclobutanil and chlorothalonil (both are fungicides) (P<0.001). Transcript levels for Hexameric storage protein (Hsp70) were significantly upregulated in imidacloprid, fluvalinate, coumaphos, myclobutanil, and amitraz treated larvae. Definitive impacts of pesticides and Varroa parasitism on honey bee larval gene expression were demonstrated. Interactions between larval treatments and gene expression for the targeted genes are discussed. PMID- 22497860 TI - The correlation between tick (Ixodes persulcatus Sch.) questing behaviour and synganglion neuronal responses to odours. AB - We examined the behavioural and electrophysiological responses of taiga ticks (Ixodes persulcatus) to several olfactory stimuli: Osmopherone(r) (5-a-androst-16 en-3-ol), Osmopherine(r) (butanoic and 3-methylbutanoic acids), DEET(r) (N,N diethyl-meta-toluamide), ethanol (96%), and water (control stimulus). To study individual tick behavioural reactions to these stimuli, we used a Y-shaped glass maze (n=50). To study the electrophysiological reactions of the ticks' synganglia to these olfactory stimuli, we recorded the shifts of total potential (TP) of pre oesophageal neurons in response to odour stimulation of Haller's organ (n=25). We found that Osmopherine(r) attracted ticks and frequently evoked negative shifts of TP, whereas the response to Osmopherone(r) did not differ from the reaction to water. DEET(r) and ethanol acted as tick repellents and generally evoked positive shifts of TP. We also tested each tick for its questing height (QH) on a glass rod that was at an incline of 75 degrees , and we tested for the presence of pathogens i.e., DNA of Borrelia burgdorferi sp. s.l. and RNA of tick-borne encephalitis virus (TBEV). The degree of response to Osmopherine(r) positively correlated with the QH. The ticks with the highest values of QH showed a greater prevalence of the tick-borne pathogen Borrelia sp. s.l. compared with the ticks that did not reach the maximum QH. The present results show a correlation between the electrophysiological reaction of the synganglia of ticks and their behavioural responses to different odours. PMID- 22497861 TI - Sporadic haemangioblastoma of the kidney with rhabdoid features and focal CD10 expression: report of a case and literature review. AB - We present here an intriguing case of sporadic renal haemangioblastoma occurring in a 61-year-old male. The tumor consisted of nests of polygonal cells and abundant capillary networks. The neoplastic cells generally showed abundant eosinophilic cytoplasm and prominent eccentric nuclei, resembling the rhabdoid cells. Pronounced intranuclear cytoplasmic pseudoinclusions were another significant feature seen. NSE, a-inhibin and S100 were positive in tumor cells and particularly, focal CD10 expressions were observed. This is possibly the first reported case of a haemangioblastoma showing a rhabdoid phenotype and CD10 immunopositivity. Malignant rhabdoid tumor and renal cell carcinoma with rhabdoid features were probably the most challenging mimics need to be differentiated. The result of focal CD10 staining in our case may further lead to confusion with renal cell carcinoma. To avoid misdiagnosis, more considerations should be attached to the rare neoplasm. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1068858553657049. PMID- 22497862 TI - Modifications of mechanoelectric feedback induced by 2,3-butanedione monoxime and Blebbistatin in Langendorff-perfused rabbit hearts. AB - AIM: Myocardial stretching is an arrhythmogenic factor. Optical techniques and mechanical uncouplers are used to study the mechanoelectric feedback. The aim of this study is to determine whether the mechanical uncouplers 2,3-butanedione monoxime and Blebbistatin hinder or modify the electrophysiological effects of acute mechanical stretch. METHODS: The ventricular fibrillation (VF) modifications induced by acute mechanical stretch were studied in 27 Langendorff perfused rabbit hearts using epicardial multiple electrodes and mapping techniques under control conditions (n = 9) and during the perfusion of 2,3 butanedione monoxime (15 mM) (n = 9) or Blebbistatin (10 MUm) (n = 9). RESULTS: In the control series, myocardial stretch increased the complexity of the activation maps and the dominant frequency (DF) of VF from 13.1 +/- 2.0 Hz to 19.1 +/- 3.1 Hz (P < 0.001, 46% increment). At baseline, the activation maps showed less complexity in both the 2,3-butanedione monoxime and Blebbistatin series, and the DF was lower in the 2,3-butanedione monoxime series (11.4 +/- 1.2 Hz; P < 0.05). The accelerating effect of mechanical stretch was abolished under 2,3-butanedione monoxime (maximum DF = 11.7 +/- 2.4 Hz, 5% increment, ns vs baseline, P < 0.0001 vs. control series) and reduced under Blebbistatin (maximum DF = 12.9 +/- 0.7 Hz, 8% increment, P < 0.01 vs. baseline, P < 0.0001 vs. control series). The variations in complexity of the activation maps under stretch were not significant in the 2,3-butanedione monoxime series and were significantly attenuated under Blebbistatin. CONCLUSION: The accelerating effect and increased complexity of myocardial activation during VF induced by acute mechanical stretch are abolished under the action of 2,3-butanedione monoxime and reduced under the action of Blebbistatin. PMID- 22497863 TI - Effects of aberrant estrogen on the endometrial transcriptional profile in pigs. AB - Estrogen prepares the uterus for implantation and is highly conserved in mammals. However, administration of estrogen to pigs earlier than normal conceptus secretion is characterized by complete embryonic mortality by days 15-18. The objective of this study was to characterize the direct effects of early estrogen administration on uterine endometrial gene expression. The study evaluated the effects of estrogen when administered early on days 9 and 10 of the estrous cycle or day 11.5 which is the normal period of conceptus estrogen secretion in pigs. Uterine endometrium was removed either Day 13 or 15. Endometrial gene expression was evaluated using the GeneChip((r)) Porcine Genome Array. Fifty-five candidate genes were successfully identified as differentially expressed due to aberrant estrogen exposure, and quantitative RT-PCR mRNA expression was supportive of the array data. These data provide insight into global uterine transcriptional changes associated with estrogen disruption of the endometrium. PMID- 22497864 TI - A conceptual framework for two phases of anticoagulant treatment of venous thromboembolism. AB - Four observations support that anticoagulant therapy for venous thromboembolism (VTE) has an 'active treatment' phase that is limited to about 3 months. First, <3 months of treatment is associated with a higher risk of recurrent VTE than treatment for 3 months or longer, suggesting that <3 months is inadequate therapy. Second, treatment for 3 months is associated with the same risk of recurrent VTE as treatment for 6 months or longer, suggesting that 3 months is adequate therapy. Third, the increase in recurrent VTE with too short a course of treatment is predominantly at the site of the initial thrombosis, suggesting reactivation of initial thrombosis. Fourth, the increase in recurrent VTE with too short a course of treatment occurs immediately after treatment is stopped and is short lived, again suggesting reactivation of initial thrombosis. Once the initial thrombosis has been adequately treated (i.e. the first phase of treatment), further anticoagulation serves as 'secondary prevention' of new, unrelated, episodes of thrombosis (i.e. the second phase of treatment). For most patients, therefore, anticoagulant therapy for VTE should be stopped at 3 months when the acute episode has completed treatment, or should be continued indefinitely as 'secondary prevention' if the risk of recurrence remains unacceptably high having completed 'active treatment'. PMID- 22497865 TI - Biologics in oral medicine: Sjogren syndrome. AB - Oral Diseases (2012) doi:10.1111/j.1601-0825.2012.01932.x Biologic therapy has a potential to benefit patients with orofacial manifestations of Sjogren syndrome (SS). The most appropriate use of biologics would appear to be in patients with severe or multisystem features of SS, but their use early in the pathogenesis has the potential to prevent disease progression. Tumour necrosis factor-alpha blockade has not proven effective in SS. B-cell depletion using rituximab has been of benefit, mainly in relation to extraglandular features, and to some extent in relation to hyposalivation where there is still residual salivary function. Rituximab is also effective in the treatment of SS-associated (extrasalivary) lymphomas, although the therapeutic response in salivary lymphoma is poorer. Rituximab is given as a single or periodic intravenous infusion. Potential adverse effects exist, notably infusion reactions and infection, and so a full risk/benefit analysis is indicated for prospective patients. This and clinical use is best performed and monitored in conjunction with rheumatologists with appropriate training and experience in biologic therapies. Further studies of rituximab in SS are ongoing, and newer agents under trial include belimumab. PMID- 22497866 TI - Up-regulation of galectin-3 and Sambucus nigra agglutinin binding site is associated with invasion, metastasis and poor-progression of the gallbladder adenocarcinoma. AB - BACKGROUND/AIMS: To study the expression of galectin-3 (gal-3) and Sambucus nigra agglutinin (SNA) binding site and to detect their clinicopathological significances in the benign and malignant lesions of gallbladder. METHODOLOGY: We used immunohistochemistry to detect gal-3 expression and ABC affinity cytochemistry to detect SNA binding site in specimens of adenocarcinoma, peritumoral tissues, polyp and chronic cholecystitis. RESULTS: The positive expression rates of gal-3 and SNA binding site were significantly higher in adenocarcinoma (62.0%, 66.7%) than those in peritumoral tissues (39.1%, 45.6%), polyp (26.7%, 33.3%) and chronic cholecystitis (11.4%, 11.4%) (p<0.05). A high consistency was found between the levels of expression of gal-3 expression and SNA binding site in adenocarcinoma (chi2=9.51, p<0.01). Univariate Kaplan-Meier analysis showed that increased expression of gal-3 (p=0.028) or SNA binding site (p=0.030) was associated with decreased overall survival. Multivariate Cox regression analysis showed that increased expression of gal-3 (p=0.012) or SNA binding site (p=0.030) was an independent prognostic predictor in gallbladder adenocarcinoma. CONCLUSIONS: These results suggest that expression of gal-3 and SNA binding site might have important effects on the carcinogenesis, progression and biological behaviors of gallbladder cancer. PMID- 22497868 TI - Seeing visual word forms: spatial summation, eccentricity and spatial configuration. AB - We investigated observers' performance in detecting and discriminating visual word forms as a function of target size and retinal eccentricity. The contrast threshold of visual words was measured with a spatial two-alternative forced choice paradigm and a PSI adaptive method. The observers were to indicate which of two sides contained a stimulus in the detection task, and which contained a real character (as opposed to a pseudo- or non-character) in the discrimination task. When the target size was sufficiently small, the detection threshold of a character decreased as its size increased, with a slope of -1/2 on log-log coordinates, up to a critical size at all eccentricities and for all stimulus types. The discrimination threshold decreased with target size with a slope of -1 up to a critical size that was dependent on stimulus type and eccentricity. Beyond that size, the threshold decreased with a slope of -1/2 on log-log coordinates before leveling out. The data was well fit by a spatial summation model that contains local receptive fields (RFs) and a summation across these filters within an attention window. Our result implies that detection is mediated by local RFs smaller than any tested stimuli and thus detection performance is dominated by summation across receptive fields. On the other hand, discrimination is dominated by a summation within a local RF in the fovea but a cross RF summation in the periphery. PMID- 22497867 TI - Hematopoietic growth factors: personalization of risks and benefits. AB - A common side effect of cancer treatment is bone marrow suppression. The resulting myelosuppression and anemia can cause significant morbidity and mortality for patients. Agents such as granulocyte colony stimulating factors (GCSF) and erythropoietin stimulating agents (ESAs) may be helpful to ameliorate this depression of blood counts; however these agents have risks which also need to be carefully weighed. PMID- 22497869 TI - Recirculating elutriator for extracting gastrointestinal nematode larvae from pasture herbage samples. AB - Gastrointestinal nematode (GIN) parasites present an important limitation to ruminant production worldwide. Methods for quantifying infective larvae of GIN on pastures are generally tedious, time-consuming, and require bulky equipment set ups. This limitation to expedient data collection is a bottleneck in development of pasture management practices that might reduce pasture infectivity. We modified a soil elutriator concept for extracting GIN larvae from fresh herbage samples. Elutriators were constructed from readily available parts and compared to the Baermann funnel sedimentation method for larvae extraction. More samples could be extracted per day in the elutriator than in a Baermann unit with extraction times of 8 min versus 24h, respectively. Accuracy, measured as maximum recovery of larvae seeded onto herbage samples, did not differ between extraction methods (62.3 vs. 69.8% for elutriator and Baermann, respectively, P>0.05). Larvae recovery from herbage in elutriators showed a strong log(e) relationship with extraction time (r(2)>0.98), which will allow development of accurate correction factors for specific herbages to predict total larvae densities at extraction times less than those needed for maximum recovery. An extraction time of 8 min per sample gave the best compromise of speed, accuracy, and precision as measured by regression confidence bands and root mean square error of analysis of variance. Precision of the elutriator extraction for pasture samples was comparable to published methods and was not affected by forage species or canopy strata. The elutriator method was sensitive enough to detect differences in larvae density as small as 8 larvae g(-1) DM among pasture treatments. Elutriators extracted nematode larvae from herbage samples with accuracy and precision similar to existing methods, but did it much faster. Elutriation shows promise as a rapid method for extracting infective GIN larvae from pasture herbage. PMID- 22497870 TI - Serological survey of Toxoplasma gondii, Dirofilaria immitis, Feline Immunodeficiency Virus (FIV) and Feline Leukemia Virus (FeLV) infections in pet cats in Bangkok and vicinities, Thailand. AB - The seroprevalence of Toxoplasma gondii, Dirofilaria immitis (heartworm), feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) infections was examined using serum or plasma samples from 746 pet cats collected between May and July 2009 from clinics and hospitals located in and around Bangkok, Thailand. The samples were tested for heartworm, FIV, and FeLV using a commercial ELISA. Of the 746 samples, 4.6% (34/746) were positive for heartworm antigen, 24.5% (183/746) had circulating FeLV antigen, and 20.1% (150/746) had antibodies against FIV. In addition, the first 348 submitted samples were tested for T. gondii antibodies using a modified agglutination test (MAT, cut off 1:25); 10.1% (35/348) were seropositive. Of the 348 cats sampled for all four pathogens, 11, 10, and 1 were positive for T. gondii antibodies and FIV antibodies, FeLV antigen, or D. immitis antigen, respectively. Of the 35 T. gondii-seropositive cats, 42.9% (15/35) were co-infected with at least one of the other three pathogens. The presence of antibodies to FIV was significantly associated with both age and gender, while FeLV antigen presence was only associated with age. In the case of FIV, males were twice as likely to be infected as females, and cats over 10 years of age were 13.5 times more likely to be infected than cats less than 1 year of age. FeLV antigen was more common in younger cats, with cats over 10 years of age being 10 times less likely to be FeLV positive than cats under 1 year of age. This is the first survey for these four pathogens affecting feline health in Thailand. PMID- 22497872 TI - The surface lipids of non-tuberculous mycobacteria suppress production of phagocyte activating cytokines in human peripheral blood mononuclear cells. AB - The genus Mycobacterium includes obligate pathogens as well as opportunistic and non-pathogenic species ubiquitous in the environment. Mycobacteria have a unique cell wall abundant in lipids. Here we investigated cytokine production by human peripheral blood mononuclear cells (PBMC) in response to the opportunistic mycobacteria Mycobacterium avium and Mycobacterium abscessus, the non-pathogenic Mycobacterium gordonae and extracted surface lipids from the three species. The cytokine response elicited by mycobacteria, regardless of their pathogenic potential, differed distinctly from that induced by control Gram-positive (Enterococcus faecalis, Streptococcus mitis) and Gram-negative (Escherichia coli) bacteria. Mycobacteria induced no IL-12 and less TNF and IFN-gamma compared with conventional Gram-positive bacteria. IL-10 was induced by all the mycobacteria and this production was partly responsible for the down-regulation of IL-12 and IFN-gamma. The capacity of the Gram-positive bacterium E. faecalis to induce IL 12, as well as TNF and IFN-gamma, in human PBMCs was strongly reduced when mycobacterial lipids were added. The mycobacterial surface lipids down-regulated the production of IL-12 and IFN-gamma without eliciting IL-10 production. Our results show that mycobacteria evade triggering production of phagocyte activating cytokines (IL-12, TNF and IFN-gamma) and that the mycobacterial cell wall surface lipids may play a significant role in this process. PMID- 22497871 TI - Pharmaceutical treatments of gastrointestinal nematode infections of sheep- future of anthelmintic drugs. AB - Various interacting factors have been identified to explain why health plans for nematode parasite control, based on conventional epidemiological knowledge and involving pharmaceutical treatments of their sheep hosts have become unsustainable. Of these, the emergence of anthelmintic resistance has had a major impact on the economics of sheep farming, necessitating fundamental managemental changes. This review focusses on the use of anthelmintic drugs for the control of gastrointestinal nematode infections in sheep, emphasising the need to develop sustainable strategies in the face of inevitable parasite evolution in response to exposure to anthelmintic drugs and other noxious stimuli, or favourable opportunities resulting from changing animal management and climatic factors. PMID- 22497873 TI - Three-dimensional self-assembling of gold nanorods with controlled macroscopic shape and local smectic B order. AB - We describe a method of controlled evaporation on a textured substrate for self assembling and shaping gold-nanorod-based materials. Tridimensional wall features are formed over areas as large as several square millimeters. Furthermore, analyses by small-angle X-ray scattering and scanning electron microscopy techniques demonstrate that colloids are locally ordered as a smectic B phase. Such crystallization is in fact possible because we could finely adjust the nanoparticle charge, knowledge that additionally enables tuning the lattice parameters. In the future, the type of ordered self-assemblies of gold nanorods we have prepared could be used for amplifying optical signals. PMID- 22497874 TI - Rotavirus vaccine RIX4414 efficacy sustained during the third year of life: a randomized clinical trial in an Asian population. AB - RIX4414 (RotarixTM), has shown high efficacy during the first 2-years of life. A 2-year randomized, double-blind, placebo-controlled trial in Singapore, Hong Kong, and Taiwan was extended for another year. Infants (6-17 weeks) received 2 doses (1-2 months apart) of RIX4414 (n=5359) or placebo (n=5349). During the third-year follow-up, 4359 (RIX4414) and 4328 (placebo) infants were monitored. 64 (1.2%) and 2 (0.04%) infants in the placebo and RIX4414 groups, respectively, reported severe rotavirus-gastroenteritis (RVGE), resulting in a vaccine efficacy of 96.9% (95% CI [88.3-99.6]). Efficacy was 100% (67.5-100) in the third-year. RIX4414 was efficacious against G1 (100.0% [84.8-100]) and pooled non-G1 RV types (94.9% [80.2-99.4]). This study shows that the vaccine is highly efficacious, regardless of circulating RV-types, up to the first 3 years of life in affluent Asian urban populations. PMID- 22497875 TI - High-efficiency transduction of human monocyte-derived dendritic cells by capsid modified recombinant AAV2 vectors. AB - Phosphorylation of surface-exposed tyrosine residues negatively impacts the transduction efficiency of recombinant AAV2 vectors. Pre-treatment of cells with specific cellular serine/threonine kinase inhibitors also significantly increased the transduction efficiency of AAV2 vectors. We reasoned that site-directed mutagenesis of surface-exposed serine residues might allow the vectors to evade phosphorylation and thus lead to higher transduction efficiency. Each of the 15 surface-exposed serine (S) residues was substituted with valine (V) residues, and the transduction efficiency of three of these mutants, S458V, S492V and S662V, was increased by up to ~ 20-fold in different cell types. The S662V mutant was efficient in transducing human monocyte-derived dendritic cells (moDCs), a cell type not readily amenable to transduction by the conventional AAV vectors, and did not induce any phenotypic changes in these cells. Recombinant S662V-AAV2 vectors encoding a truncated human telomerase (hTERT) gene were generated and used to stimulate cytotoxic T cells (CTLs) against target cells. S662V-AAV2-hTERT vector-transduced DCs resulted in rapid, specific T-cell clone proliferation and generation of robust CTLs, which led to specific cell lysis of K562 cells. These studies suggest that high-efficiency transduction of moDCs by serine-modified AAV2 vectors is feasible, which supports the potential utility of these vectors for future human DCs vaccine studies. PMID- 22497877 TI - Microstructural white matter damage at orbitofrontal areas in borderline personality disorder. AB - OBJECTIVES: Prefrontal cortex plays a major role in the modulation of behaviors and emotions through regulation of both information processing and impulse control. Low prefrontal function in borderline personality disorder (BPD) has been consistently reported by a number of studies using neuropsychological assessments and functional neuroimaging techniques. To further explore this findings, this study aimed to investigate microstructural damage of prefrontal white matter tracts in subjects with BPD by using the novel, voxel-based approach, tract-based spatial statistics (TBSS). METHODS: A Diffusion Tensor Image (DTI) study was performed in 28 patients with DSM-IV BPD (13 males and 15 females) and in 26 healthy control subjects. Voxel wise analysis was performed using TBSS (diffusion toolbox of FSL - functional MRI Software Library) to localize regions of white matter showing significant changes of fractional anisotropy (FA). RESULTS: TBSS analysis revealed a statistically significant decrease of FA in the genu and rostral areas of the corpus callosum (p<0.005), as well as in left and right prefrontal white matter fasciculi (p<0.002) in BPD participants compared with controls. White matter abnormalities were not correlated with age, neurological symptoms or comorbid ADHD. CONCLUSIONS: Despite the reduced sample size, the results are in line with previous findings on reduced orbitofrontal functions in BPD with prominent affective-depressive feature and suggest that emotional and behavioral symptoms of BPD patients might be associated to damage at the connectivity tracts in these brain areas. PMID- 22497878 TI - Why ruminators won't stop: the structural and resting state correlates of rumination and its relation to depression. AB - BACKGROUND: Rumination is a good predictor of major depression. The current study explores the structural and functional neural correlates of rumination. METHODS: To explore structural correlates of rumination (RRS, Treynor et al., 2003) we used voxel-based morphometry. We relate these correlates of rumination to concurrence of grey matter reductions in depressed patients by means of a quantitative meta-analysis on 16 VBM studies. Resting state data was used to compute maps of the amplitude of low frequency fluctuations. RESULTS: Rumination correlated negatively with grey matter volume in bilateral inferior frontal gyrus (IFG), left anterior cingulate cortex (ACC), and bilateral mid cingulate cortex. The volume reductions were within proximity of grey matter reductions identified in the meta-analysis on depressed patients in bilateral IFG and ACC. Moreover reductions in resting state activity were overlapping with volume reductions correlated with rumination in ACC and right IFG. LIMITATIONS: The participants were all healthy control subjects. Future research is needed to explore the neural correlates of rumination in major depression. CONCLUSIONS: The results show that rumination is associated with volume and resting state reductions in brain areas that have been related to cognitive control process of inhibition and thought suppression. We conclude that rumination not only qualifies as a behavioural predictor of major depression but also goes along with neuroanatomical abnormalities that are similar to those identified for depression. PMID- 22497879 TI - Parental perceptions of neighborhood effects in Latino Comunas: the script of "the Delinquent" in understanding drug use, violence, and social disorganization. AB - OBJECTIVES: To obtain rich information about how adult Latinos living in high poverty/high-drug use neighborhoods perceive and negotiate their environment. METHODS: In 2008, 13 adult caregivers in Santiago, Chile, were interviewed with open-ended questions to ascertain beliefs about neighborhood effects and drug use. ANALYSIS: Inductive analysis was used to develop the codebook/identify trends. DISCUSSION: Residents externalized their understanding of drug use and misuse by invoking the concept of delinquent youth. A typology of their perceptions is offered. Learning more about residents' circumstances may help focus on needs-based interventions. More research with Latino neighborhoods is needed for culturally competent models of interventions. PMID- 22497876 TI - Can bipolar disorder be viewed as a multi-system inflammatory disease? AB - BACKGROUND: Patients with bipolar disorder are known to be at high risk of premature death. Comorbid cardio-vascular diseases are a leading cause of excess mortality, well above the risk associated with suicide. In this review, we explore comorbid medical disorders, highlighting evidence that bipolar disorder can be effectively conceptualized as a multi-systemic inflammatory disease. METHODS: We conducted a systematic PubMed search of all English-language articles recently published with bipolar disorder cross-referenced with the following terms: mortality and morbidity, cardio-vascular, diabetes, obesity, metabolic syndrome, inflammation, auto-antibody, retro-virus, stress, sleep and circadian rhythm. RESULTS: Evidence gathered so far suggests that the multi-system involvement is present from the early stages, and therefore requires proactive screening and diagnostic procedures, as well as comprehensive treatment to reduce progression and premature mortality. Exploring the biological pathways that could account for the observed link show that dysregulated inflammatory background could be a common factor underlying cardio-vascular and bipolar disorders. Viewing bipolar disorder as a multi-system disorder should help us to re conceptualize disorders of the mind as "disorders of the brain and the body". LIMITATIONS: The current literature substantially lacks longitudinal and mechanistic studies, as well as comparison studies to explore the magnitude of the medical burden in bipolar disorder compared to major mood disorders as well as psychotic disorders. It is also necessary to look for subgroups of bipolar disorder based on their rates of comorbid disorders. CONCLUSIONS: Comorbid medical illnesses in bipolar disorder might be viewed not only as the consequence of health behaviors and of psychotropic medications, but rather as an early manifestation of a multi-systemic disorder. Medical monitoring is thus a critical component of case assessment. Exploring common biological pathways of inflammation should help biomarkers discovery, ultimately leading to innovative diagnostic tools, new methods of prevention and personalized treatments. PMID- 22497880 TI - A brief alternative for identifying alcohol use disorders. AB - This study sought to evaluate the clinical utility of a brief assessment interview in accurately classifying inmates manifesting an alcohol use disorder (AUD) based on a structured diagnostic assessment interview. Data were derived from routine clinical assessments of 7,672 inmates (89.6% male) incarcerated in the Minnesota Department of Corrections state prison system. An automated version of the Substance Use Disorder Diagnostic Schedule-IV (SUDDS-IV), which included a subset of the items comprising the Triage Assessment for Addictive Disorders (TAAD), was administered to all inmates from 2000 to 2003. Approximately 99% of the DSM-IV dependence and no diagnosis cases were appropriately classified by the TAAD. Although the TAAD identified nearly all cases with any diagnosis, 20%-24% of cases classified as abuse by the TAAD were found to be dependent by the longer instrument. Similar findings were noted when DSM-5 criteria were applied. The TAAD has the potential to provide a more clinically defensible means of identifying AUDs than brief screens when time constraints may preclude a comprehensive assessment. Limitations and implications for routine clinical practice are discussed. PMID- 22497881 TI - Emergence of dengue virus 4 genotype II in Guangzhou, China, 2010: survey and molecular epidemiology of one community outbreak. AB - BACKGROUND: The re-emergence of dengue virus 4 (DENV-4) has become a public health concern in South America, Southeast Asia and South Asia. However, it has not been known to have caused a local outbreak in China for the past 20 years. The purpose of this study was to elucidate the epidemiology of one local community outbreak caused by DENV-4 in Guangzhou city, China, in 2010; and to determine the molecular characteristics of the genotype II virus involved. CASE PRESENTATIONS: During September and October of 2010, one imported case, a Guangzhou resident who travelled back from Thailand, resulted in 18 secondary autochthonous cases in Guangzhou City, with an incidence rate of 5.53 per 10,000 residents. In indigenous cases, 14 serum samples tested positive for IgM against DENV and 7 for IgG from a total of 15 submitted serum samples, accompanied by 5 DENV-4 isolates. With identical envelope gene nucleotide sequences, the two isolates (D10168-GZ from the imported index case and Guangzhou 10660 from the first isolate in the autochthonous cases) were grouped into DENV-4 genotype II after comparison to 32 previous DENV-4 isolates from GenBank that originated from different areas. CONCLUSIONS: Based on epidemiological and phylogenetic analyses, the outbreak, which was absent for 20 years after the DENV-4 genotype I outbreak in 1990, was confirmed as DENV-4 genotype II and initially traced to the imported index case, a Guangzhou resident who travelled back from Thailand. PMID- 22497883 TI - [Analysis of a register for reporting adverse events to a mutual insurance society for accidents at work. Adverse event reporting of occupational injuries]. AB - OBJECTIVES: To describe the results of a voluntary reporting system for adverse events in a Patient Safety Program of an occupational injuries mutual insurance company. METHOD: In 2008 a system of notification and registration of adverse events (actual or potential) was introduced in 2008 by the Union de Mutuas, an occupational injuries insurance company with 36 health centres, and provides coverage for 259,922 workers. The reporting questionnaire covers all areas of health care provided by the mutual company. Access to the questionnaire was conducted through the intranet, was voluntary and anonymous. The notifications registered between 1 January 2009 and 31 December 2010 are analysed. RESULTS: A total of 16 questionnaires were completed, with a total of 205 incidents. The profile of the reporter was first-level health care (57.7%), and seniority in their job for 5-10 years. Of all the notifications, a health care cause of the incident was seen in 43.5% of cases, of which 85.9% of the incidents were preventable. Of all reported events, 71.7% were related to an ambulatory care medical centre, and only 2.4% was related to a surgical procedure. CONCLUSIONS: Most of the notifications were preventable incidents, and recorded by first-level medical care. The reporting questionnaire was shown to be a valid tool in our work environment for the detection of adverse events in the care process. PMID- 22497884 TI - The relationship between aortic aneurysm sac thrombus volume on coagulation, fibrinolysis and platelet activity. AB - AIM: Abdominal aortic aneurysm (AAA) is associated with chronic mural inflammation and a pro-thrombotic diathesis. It has been suggested that both may be related to biologically active intra-sac thrombus. The aim of this study was to examine the relationship between thrombin generation, fibrinolysis, platelet activity and AAA sac thrombus volume. METHODS: 30 patients (29 men) of median (IQR) age 75 (71-82) years with an infra-renal AAA >5.5 cm in antero-posterior diameter were prospectively studied. AAA, lumen and thrombus volumes were calculated using a CT workstation (Vitrea). Plasma thrombin-antithrombin (TAT), plasminogen activator inhibitor (PAI)-1, and soluble (s) P-selectin were measured as biomarkers of coagulation, fibrinolysis and platelet activity, respectively RESULTS: Median (IQR) AAA total, lumen and thrombus volumes were 188 (147-247) cm(3), 80 (54.3-107) cm(3) and 97.6 (63-127) cm(3) respectively. TAT levels were significantly higher (median, QR, 7.15 [4.7-31.3] MUg/L, p=<0.001) and sP selectin levels significantly lower (median, IQR, 80.5 [68-128] ng/ml, p=<0.0001) than the normal range. PAI-1 levels (median, IQR, 20.9 [8.4-50.7] ng/ml) were normal. There was no correlation between AAA thrombus volume and PAI-1 (r=-0.25, p=0.47), sP-Selectin (r=0.26, p=0.43) or TAT plasma levels (r=-0.21, p=0.54). CONCLUSION: The present study confirms that patients with AAA demonstrate haemostatic derangement, but the extent of the haemostatic derangement does not correlate with AAA sac thrombus volume. PMID- 22497885 TI - Differential effects of fondaparinux and bemiparin on angiogenic and vasculogenesis-like processes. AB - INTRODUCTION: Conventional therapy for venous thromboembolism or acute coronary syndrome involves the administration of glycoanticoagulants (heparins) or oligosaccharides (fondaparinux). We evaluated the effects of such drugs on angiogenesis and vasculogenesis-like models. MATERIALS AND METHODS: Human umbilical vein endothelial cells or human endothelial progenitor cells were treated with bemiparin, fondaparinux or unfractionated heparin, at concentrations reflecting the doses used in clinical practice. After 24h, cell viability, proliferation, tubule formation and angiogenic molecular mechanisms, such as activation of the serine/threonine kinase AKT, were assessed. In vivo angiogenesis was studied using a Matrigel sponge assay in mice. RESULTS: Bemiparin gave a significant decrease of in vitro angiogenesis as shown by the reduction of endothelial cell tubule network, while both fondaparinux and unfractionated heparin did not show any significant effect. In assays of Matrigel sponge invasion in mice, unfractionated heparin was able to stimulate angiogenesis and, conversely, bemiparin inhibited angiogenesis. Furthermore, both bemiparin and fondaparinux caused a significant reduction in an in vitro vasculogenesis-like model, as demonstrated by the decrease of tubule network after co-seeding of endothelial progenitor cells and human umbilical vein endothelial cells. In addition, unfractionated heparin but not bemiparin was able to increase AKT phosphorylation. CONCLUSIONS: In in vitro experiments, bemiparin was the only drug to show an anti-angiogenic and vasculogenic-like effect, unfractionated heparin showed only a trend to increase in angiogenesis assay and fondaparinux affected only the vasculogenesis-like model. Notably, the in vivo experiments corroborated these data. Such results are important for the choice of a patient-tailored therapy. PMID- 22497886 TI - Protease-activated receptor-2 (PAR2) mediates VEGF production through the ERK1/2 pathway in human glioblastoma cell lines. AB - Glioblastoma (GBM) is a highly aggressive cancer type characterized by intense neovascularization. Several lines of evidence indicate that blood clotting enzymes play an important role in the tumor microenvironment, mainly through the activation of protease-activated receptors (PAR). In particular, PAR1 and PAR2 isoforms may activate signal transduction pathways that promote a number of pro tumoral responses. However, little is known concerning the role of PAR1/PAR2 in GBM progression. In this study, we investigated the expression and function of PAR1 and PAR2 in the human GBM cell lines A172 and U87-MG. We also evaluated the effect of agonist peptides for PAR1 (PAR1-AP) and PAR2 (PAR2-AP) on signaling pathways and the expression of vascular endothelial growth factor (VEGF). Immunoblotting assays showed that A172 and U87-MG constitutively express PAR1 and PAR2. Treatment of GBM cells with PAR1-AP or PAR2-AP enhanced Akt (protein kinase B) and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in a time-dependent manner. LY29042 and PD98059, inhibitors of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways, decreased PAR-mediated activation of Akt and ERK1/2, respectively. In addition, we observed that PAR2, but not PAR1, activation increased VEGF secretion in U87-MG and A172 cells. Notably, only PD98059 reduced PAR2-mediated VEGF production by GBM cells. Our results suggest that PAR2 modulates VEGF production through the MAPK/ERK1/2 pathway, and not the PI3K/Akt pathway, in human GBM cell lines. Therefore, the PAR2/MAPK signaling axis might be regarded as a relevant target for adjuvant treatment of GBM with a possible impact on tumor angiogenesis. PMID- 22497887 TI - Promoting crystallisation of the Salmonella enteritidis fimbriae 14 pilin SefD using deuterium oxide. AB - The use of heavy water (D(2)O) as a solvent is commonplace in many spectroscopic techniques for the study of biological macromolecules. A significant deuterium isotope effect exists where hydrogen-bonding is important, such as in protein stability, dynamics and assembly. Here we illustrate the use of D(2)O in additive screening for the production of reproducible diffraction-quality crystals for the Salmonella enteritidis fimbriae 14 (SEF14) putative tip adhesin, SefD. PMID- 22497888 TI - The role of microglia in the neurogenesis of zebrafish retina. AB - Microglia are cells from non-neuronal lineages that reside in the central nervous system. In zebrafish, early macrophages migrate from the yolk sac to the brain and retina at 26-30 hour post fertilization (hpf) and transform into microglia at 55-60 hpf. The migration of macrophages into the central nervous system requires signaling by macrophage colony stimulating factor-1 receptor (csf-1r), which is encoded by the gene fms. In this study, we show that the targeted knockdown of csf-1r with morpholino oligonucleotides delays migration of macrophages from the yolk sac to the retina, and this delay in macrophage migration results in microphthalmia, delay in cell cycle withdrawal among retinal progenitors and the absence of neuronal differentiation. When embryos were allowed to survive beyond the time when morpholino-dependent translation inhibition is lost, microglia re occupy the retina and neuronal differentiation partially recovers. Our data demonstrate that microglia are required for normal retinal growth and neurogenesis. This study provides new insight into the neurogenic role of microglia during retinal development in zebrafish. PMID- 22497889 TI - Splicing transitions of the anchoring protein ENH during striated muscle development. AB - The ENH (PDLIM5) protein acts as a scaffold to tether various functional proteins at subcellular sites via PDZ and three LIM domains. Splicing of the ENH primary transcript generates various products with different repertories of protein interaction modules. Three LIM-containing ENH predominates in neonatal cardiac tissue, whereas LIM-less ENHs are abundant in adult hearts, as well as skeletal muscles. Here we examine the timing of splicing transitions of ENH gene products during postnatal heart development and C2C12 myoblast differentiation. Real-time PCR analysis shows that LIM-containing ENH1 mRNA is gradually decreased during postnatal heart development, whereas transcripts with the short exon 5 appear in the late postnatal period and continues to increase until at least one month after birth. The splicing transition from LIM-containing ENH1 to LIM-less ENHs is also observed during the early period of C2C12 differentiation. This transition correlates with the emergence of ENH transcripts with the short exon 5, as well as the expression of myogenin mRNA. In contrast, the shift from the short exon 5 to the exon 7 occurs in the late differentiation period. The timing of this late event corresponds to the appearance of mRNA for the skeletal myosin heavy chain MYH4. Thus, coordinated and stepwise splicing transitions result in the production of specific ENH transcripts in mature striated muscles. PMID- 22497890 TI - Influence of divalent cations on the cytoskeletal dynamics of K562 cells determined by nano-scale bead tracking. AB - Cytoskeletal reorganization processes can be analyzed by studying the nanometer scale spontaneous motion of beads bound to the cytoskeleton. The bead motion is determined by force fluctuations within the cytoskeletal network that originates from myosin motor activity and dynamic restructuring of cytoskeletal filaments. We investigated to what extend the spontaneous bead motion is influenced by the dynamics of the link between the bead and the cytoskeleton in the presence of divalent cations. Our data show that, when K562 cells expressing constitutively (alpha 5 beta 1) integrin and when stably transfected with (alpha v beta 3) integrin, spontaneous bead motion is dramatically affected by the presence of 1mM Mn(2+) (integrin, activate state) compared to 1mM Ca(2+)/Mg(2+) ions (integrin, inactive state). The directionality of the bead motion, which is influenced by the overall stability of the cytoskeletal network and by actomyosin-generated forces, is markedly different, whilst the persistence remained similar due to the specific binding of either Mn(2+) or Mg(2+)/Ca(2+) ions. PMID- 22497891 TI - Genome-wide screening of Escherichia coli genes involved in execution and promotion of cell-to-cell transfer of non-conjugative plasmids: rodZ (yfgA) is essential for plasmid acceptance in recipient cells. AB - Acquisition of new genetic traits by horizontal gene transfer is a bacterial strategy for adaptation to the environment. We previously showed that Escherichia coli can transmit non-conjugative plasmids laterally in a co-culture containing strains with and without the plasmid. In this study, using the Keio collection, a comprehensive library of E. coli knock-out mutants for non-essential genes, we screened for genes responsible for the execution and promotion of cell-to-cell plasmid transfer in recipient cells. By stepwise screening of 'transfer-down' mutants, two essential genes and six promoting genes were obtained. One of the essential genes was priA, which is involved in DNA replication. This priA mutant was also unable to be transformed by artificial transformation methods, probably due to the deficiency of the plasmid maintenance function. The other essential gene was rodZ (yfgA), a gene involved in the regulation of rod-shaped structure of E. coli cells. This rodZ mutant was transformable by all three methods of artificial transformation tested, suggesting that this gene is essential for cell to-cell plasmid transfer but not for artificial transformation. These are the first data that suggest that rodZ plays an essential role in DNA acquisition. PMID- 22497892 TI - Annexin A4 is a possible biomarker for cisplatin susceptibility of malignant mesothelioma cells. AB - Mesothelioma is a highly malignant tumor with a poor prognosis and limited treatment options. Although cisplatin (CDDP) is an effective anticancer drug, its response rate is only 20%. Therefore, discovery of biomarkers is desirable to distinguish the CDDP-susceptible versus resistant cases. To this end, differential proteome analysis was performed to distinguish between mesothelioma cells of different CDDP susceptibilities, and this revealed that expression of annexin A4 (ANXA4) protein was higher in CDDP-resistant cells than in CDDP susceptible cells. Furthermore, ANXA4 expression levels were higher in human clinical malignant mesothelioma tissues than in benign mesothelioma and normal mesothelial tissues. Finally, increased susceptibility was observed following gene knockdown of ANXA4 in mesothelioma cells, whereas the opposite effect was observed following transfection of an ANXA4 plasmid. These results suggest that ANXA4 has a regulatory function related to the cisplatin susceptibility of mesothelioma cells and that it could be a biomarker for CDDP susceptibility in pathological diagnoses. PMID- 22497893 TI - Ahnak1 interaction is affected by phosphorylation of Ser-296 on Cavbeta2. AB - Ahnak1 has been implicated in protein kinase A (PKA)-mediated control of cardiac L-type Ca(2+) channels (Cav1.2) through its interaction with the Cavbeta(2) regulatory channel subunit. Here we corroborate this functional linkage by immunocytochemistry on isolated cardiomyocytes showing co-localization of ahnak1 and Cavbeta(2) in the T-tubule system. In previous studies Cavbeta(2) attachment sites which impacted the channel's PKA regulation have been located to ahnak1's proximal C-terminus (ahnak1(4889-5535), ahnak1(5462-5535)). In this study, we mapped the ahnak1-interacting regions in Cavbeta(2) and investigated whether Cavbeta(2) phosphorylation affects its binding behavior. In vitro binding assays with Cavbeta(2) truncation mutants and ahnak1(4889-5535) revealed that the core region of Cavbeta(2) consisting of Src-homology 3 (SH3), HOOK, and guanylate kinase (GK) domains was important for ahnak1 interaction while the C- and N terminal regions were dispensable. Furthermore, Ser-296 in the GK domain of Cavbeta(2) was identified as novel PKA phosphorylation site by mass spectrometry. Surface plasmon resonance (SPR) binding analysis showed that Ser-296 phosphorylation did not affect the high affinity interaction (K(D)~35 nM) between Cavbeta(2) and the alpha(1C) I-II linker, but affected ahnak1 interaction in a complex manner. SPR experiments with ahnak1(5462-5535) revealed that PKA phosphorylation of Cavbeta(2) significantly increased the binding affinity and, in parallel, it reduced the binding capacity. Intriguingly, the phosphorylation mimic substitution Glu-296 fully reproduced both effects, increased the affinity by ~2.4-fold and reduced the capacity by ~60%. Our results are indicative for the release of a population of low affinity interaction sites following Cavbeta(2) phosphorylation on Ser-296. We propose that this phosphorylation event is one mechanism underlying ahnak1's modulator function on Cav1.2 channel activity. PMID- 22497894 TI - Acute hand ischemia after intra-arterial injection of meprobamate powder. AB - BACKGROUND: Meprobamate tablets contain microcrystalline cellulose, a potent embolic agent that has been shown to cause gangrene in animal studies. Microvascular embolization caused by microcrystalline cellulose can contribute to the ischemic process. OBJECTIVE: We report a case of acute hand ischemia after accidental intra-arterial injection of crushed meprobamate powder in a 23-year old male drug abuser. CASE REPORT: The distal tips of the patient's right thumb, index finger, ring finger, and little finger continued to develop gangrene despite medical therapy with heparinization, low molecular-weight dextran infusion, corticosteroid administration, and hyperbaric oxygen therapy. CONCLUSION: We believe this is the first case of acute limb ischemia caused by intra-arterial injection of meprobamate powder documented in humans. Emergency physicians should be aware that accidental intra-arterial injection of crushed oral drug formulations is potentially limb threatening and prompt recognition of similar clinical scenarios is of vital importance. PMID- 22497895 TI - Geriatric nursing assessment and intervention in an emergency department: a pilot study. AB - AIM: To describe and test a model for structured nursing assessment and intervention to older people discharged from emergency department (ED). BACKGROUND: Older people recently discharged from hospital are at high risk of readmission. This risk may increase when they are discharged straight home from an ED as time pressure requires staff to focus on the presenting problem although many have complex, unresolved, care needs. METHOD: A prospective descriptive pilot study was conducted. Older people aged 70 and over and at risk of adverse health and functional outcome were included. INTERVENTION: At discharge, and at 1 and 6 months follow-up, a brief standardised nursing assessment (ISAR 2) developed by McCusker et al. was carried out. The focus was on unresolved problems that required medical or nursing intervention, new or different home care services or comprehensive geriatric assessment. After assessment, the nurse made relevant referrals to the geriatric outpatient clinic, community health centre, general practitioner or made arrangements with next of kin. RESULTS: One hundred and fifty people participated, mean age was 81.7. At discharge, they had a mean of 1.9 unresolved problems, after 1 month 0.8, and after 6 months 0.4. Older people receiving home care services increased from 79% at discharge to 89% at 1 month and 90% at 6 months follow-up. CONCLUSION: ISAR 2 works well in a Danish ED setting and intercepts older peoples' problems. It seems that unresolved problems decrease when a nurse assesses and intervenes at discharge from ED, and at follow-up. However, a randomised controlled test should be carried out to confirm this. IMPLICATIONS FOR PRACTICE: Nursing assessment and intervention should be implemented in the ED to reduce older peoples' unrevealed problems. PMID- 22497897 TI - Executive functioning performance predicts subjective and physiological acute stress reactivity: preliminary results. AB - Individual differences in baseline executive functioning (EF) capacities have been shown to predict state anxiety during acute stressor exposure. However, no previous studies have clearly demonstrated the relationship between EF and physiological measures of stress. The present study investigated the efficacy of several well-known EF tests (letter fluency, Stroop test, and Wisconsin Card Sorting Test) in predicting both subjective and physiological stress reactivity during acute psychosocial stress exposure. Our results show that letter fluency served as the best predictor for both types of reactivity. Specifically, the higher the letter fluency score, the lower the acute stress reactivity after controlling for the baseline stress response, as indicated by lower levels of state anxiety, negative mood, salivary cortisol, and skin conductance. Moreover, the predictive power of the letter fluency test remained significant for state anxiety and cortisol indices even after further adjustments for covariates by adding the body mass index (BMI) as a covariate. Thus, good EF performance, as reflected by high letter fluency scores, may dampen acute stress responses, which suggests that EF processes are directly associated with aspects of stress regulation. PMID- 22497898 TI - Hemagglutinating activity of polyphenols extracts from six grain legumes. AB - The erythrocyte agglutinating activity of polyphenol extracts from six grain legumes was investigated. Polyphenols are amphipathic molecules that can bind to proteins and lipids through hydrophobic and polar interactions, leading to agglutination of liposomes and bacteria. The extracts from four of the six legumes that were studied caused erythrocyte agglutination at concentrations in the MUM range. Soybean extracts had the highest activity, followed by the extracts from lentils, broad bean, and chickpea. As a good representative of these legumes, binding of the polyphenols extracted from lentils to erythrocytes was investigated in more detail, showing that agglutination was mediated by binding of 84% of the polyphenols present in the incubation, which corresponds to 2.42 MUg bound polyphenols/mg erythrocytes, and a maximum polyphenol binding of 96% according to Lineweaver-Burk plots. The relatively high concentrations that are required for agglutination justify that polyphenols more probably do not agglutinate erythrocytes in vivo, but the possibility still exists that in vivo binding without agglutination could occur, which could have some effects on the metabolism and health-promoting properties of polyphenols. PMID- 22497899 TI - Toona sinensis Roem leaf extracts improve antioxidant activity in the liver of rats under oxidative stress. AB - Toona sinensis Roem (TS) is an herbal plant widely cultivated in Asia. Recently, several antioxidant compounds in TS leaf (TSL) extracts were chemically identified including quercetin, gallic acid, and others. However, in vivo experiments regarding the antioxidative function of TSL are limited. In this study, Sprague Dawley (SD) rats with oxidative stress were successfully established by intraperitoneal injection of hydrogen peroxide (H(2)O(2)) (1mmol/kg BW) and fed with different TSL extracts for in vivo antioxidation evaluation. Among the TSLs tested in this study, TSL6 exhibited the best antioxidative effects which increased the enzyme activities of catalase, cupper/zinc superoxide dismutase (Cu/Zn SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and Glutathione S transferase (GST) activities in liver compared to those in TSL-2 and TSL-2P groups. In conclusion, we provide the strong in vivo evidences for the first time that TSL extracts ameliorate the antioxidant enzymes (AOEs) activity in liver and is beneficial for the hepatic detoxification. PMID- 22497900 TI - Quantitative imaging of arsenic and its species in goat following long term oral exposure. AB - Severity of arsenic toxicity was reported to vary depending on its species. The present study reflects the status of different species of arsenic in goat following long-term exposure of arsenic leading to hepatic damage. The experiment was conducted with six black Bengal goats, which were administered with sodium arsenite orally at a dose rate of 2 mgkg(-1) daily for 84 days. Faeces, urine, hair and blood samples were collected from those animals at 14 days interval. Excretion of total arsenic was reduced from 56 days onwards through both faeces and urine indicating higher accumulation of arsenic in body. The speciation study revealed that urinary arsenic was mainly of organic type, whereas hair accumulated almost equal proportion of arsenite, arsenate and organo arsenicals. Goats excreted high proportion of organo arsenicals through faeces possibly due to hepatobiliary secretion of organo arsenic into the gut. Significantly elevated serum alanine aminotransferase and aspartate aminotransferase activities (p<0.05) along with histopathological changes in liver indicated hepatotoxicity. The arsenite fraction increased and organic proportion decreased in urine as the time progressed, which indicates that arsenite gets methylated in liver of goat. The study thus alluded that the toxicity of arsenic would aggravate if the animals were exposed for long time as the hepatotoxicity progressed resulting in decreased methylation and formation of organo arsenicals and decreased excretions through urine. PMID- 22497901 TI - Nutraceutical potential of monofloral honeys produced by the Sicilian black honeybees (Apis mellifera ssp. sicula). AB - In the light of the growing interest in food and food products obtained through organic and environmentally friendly techniques, the present work represents the first approach to the evaluation of the biological profile of some Sicilian honeys produced in purity by the local black honeybees. Samples exhibited up to 10 times more total phenolics and higher antioxidant capacity than what already reported for the same variety of honeys produced by other honeybee subspecies from Sicily, other Italian regions and abroad. Noteworthy, the gallic acid contents in medlar and almond honeys represented the highest level of single phenolic acid reported in honey so far. A broad antimicrobial spectrum was showed by all of the honey samples and a good correlation between their inhibition capacity and polyphenolic contents was measured. Experimental results highlighted samples among the honeys characterised by the highest nutraceutical added value and most excellent quality. PMID- 22497902 TI - Glaucoma and Helicobacter pylori: eyes wide shut? PMID- 22497903 TI - Prevalence of coeliac disease in healthy blood donors: a study from north India. AB - BACKGROUND: Blood donor screening can help predict prevalence of coeliac disease in population. METHODS: Between December 2010 and June 2011, healthy blood donors were screened using anti-tissue glutaminase antibodies. Those positive underwent duodenoscopy. Their age, gender, body mass index and haemoglobin and histological changes were recorded. RESULTS: Of the 1610 blood donors screened, 1581 (98.2%) were males. The mean age of donors was 31.51 +/- 9.66 years and the mean body mass index was 22.12 +/- 4.24 kg/m(2). Nine (0.56%) men were seropositive. Endoscopic features included reduced fold height (9), scalloping (8), grooving (7) and mosaic mucosal pattern (3). Eight had Marsh IIIa changes whilst one had IIIb change. The prevalence of coeliac disease was 1:179 (0.56%, 95% confidence interval 1/366-1/91, 0.27-1.1%). None of the 9 patients had any symptoms. Their mean haemoglobin and body-mass index was similar to rest of the cohort. CONCLUSION: The prevalence of coeliac disease amongst apparently healthy blood donors was 1:179 (0.56%). PMID- 22497904 TI - Lymphocytic duodenosis: aetiology and long-term response to specific treatment. AB - BACKGROUND: The clinical significance of lymphocytic duodenosis remains unclear. AIM: To prospectively assess the aetiology of lymphocytic duodenosis and the patterns of clinical presentation. METHODS: Ninety consecutive patients with lymphocytic duodenosis and clinical symptoms of the coeliac disease spectrum were prospectively included. All subjects underwent serological testing and HLA genotyping for coeliac disease, assessment of Helicobacter pylori infection, and parasite stool examination. Intake of non-steroidal anti-inflammatory drugs was also recorded. The final aetiology of lymphocytic duodenosis was evaluated on the basis of the long-term response to specific therapy. RESULTS: More than one initial potential aetiology was observed in 44% of patients. The final diagnosis was gluten-sensitive enteropathy alone or associated with Helicobacter pylori infection in 43.3%, Helicobacter pylori infection (without gluten-sensitive enteropathy) in 24.4%, non-steroidal anti-inflammatory drugs intake in 5.5%, autoimmune disease in 3.3%, and parasitic infection in 2.2%. Among first degree relatives and patients with chronic diarrhoea, the most common final diagnosis was gluten-sensitive enteropathy. In contrast, in the group presenting with chronic dyspepsia the most common diagnosis was Helicobacter pylori infection ('Diarrhoea' vs 'Dyspepsia' groups, p=0.008). CONCLUSIONS: Lymphocytic duodenosis is often associated with more than one potential initial aetiology. Clinical presentation may be useful to decide the initial therapeutic approach with these patients. PMID- 22497905 TI - Risk factors and outcome of acute severe lower gastrointestinal bleeding in Crohn's disease. AB - BACKGROUND: Acute severe lower gastrointestinal bleeding in Crohn's disease is uncommon, but is a diagnostic and therapeutic challenge. We aimed to identify risk factors for acute lower gastrointestinal bleeding in patients with Crohn's disease and assess the cumulative probability of rebleeding in relation to therapeutic modality. METHODS: We retrospectively reviewed the medical records of 70 Crohn's patients (4.0%) with acute severe lower gastrointestinal bleeding and compared these with matched 140 Crohn's patients without bleeding. RESULTS: The cumulative probability of bleeding after diagnosis of Crohn's disease was 1.7%, 3.6%, 6.5%, and 10.3% after 1, 5, 10, and 20 years respectively. At presentation, the median haemoglobin concentration was 8.4g/dL (range, 4.7-11.6g/dL). Use of azathioprine/6-mercaptopurine decreased the risk of lower gastrointestinal bleeding (OR: 0.525, 95% CI: 0.304-0.906, p=0.021). Bleeding recurred in 29 patients (41.4%) after a median time of 3.2 months (range, 15 days-94.7 months). One out of eleven patients treated with infliximab rebled. The cumulative probability of rebleeding tended to be lower in patients treated with infliximab than in those receiving other treatments (p=0.076). CONCLUSIONS: Azathioprine/6 mercaptopurine may reduce the risk of acute severe lower gastrointestinal bleeding. The rebleeding is common, but infliximab may decrease rebleeding. PMID- 22497906 TI - Early skin-to-skin care in extremely preterm infants: thermal balance and care environment. AB - OBJECTIVE: To evaluate infant thermal balance and the physical environment in extremely preterm infants during skin-to-skin care (SSC). STUDY DESIGN: Measurements were performed in 26 extremely preterm infants (gestational age 22 26 weeks; postnatal age, 2-9 days) during pretest (in incubator), test (during SSC), and posttest (in incubator) periods. Infants' skin temperature and body temperature, ambient temperature, and relative humidity were measured. Evaporimetry was used to determine transepidermal water loss, and insensible water loss through the skin was calculated. RESULTS: The infants maintained a normal body temperature during SSC. Transfer to and from SSC was associated with a drop in skin temperature, which increased during SSC. Ambient humidity and temperature were lower during SSC than during incubator care. Insensible water loss through the skin was higher during SSC. CONCLUSION: SSC can be safely used in extremely preterm infants. SSC can be initiated during the first week of life and is feasible in infants requiring neonatal intensive care, including ventilator treatment. During SSC, the conduction of heat from parent to infant is sufficiently high to compensate for the increase in evaporative and convective heat loss. The increased water loss through the skin during SSC is small and should not affect the infant's fluid balance. PMID- 22497907 TI - RICH (rapidly involuting congenital hemangioma): not only a definition of wealth. PMID- 22497908 TI - A prospective study of cutaneous findings in newborns in the United States: correlation with race, ethnicity, and gestational status using updated classification and nomenclature. AB - OBJECTIVE: To provide incidence data based on ethnicity, prematurity, and body site for vascular, pigmented, and other common congenital cutaneous findings; to compare these results with previously published prospective studies; and to define updated nomenclature, classification, clinical course, and prognostic factors for the pediatric practitioner to promote a better understanding of benign versus more worrisome birthmarks. STUDY DESIGN: This prospective study enrolled 594 infants in San Diego, California. Cutaneous examination was performed by pediatric dermatologists in the first 48 hours of life, with subsequent longitudinal contact via telephone, and repeat evaluations if any new lesions were reported by parents. Incidence rates were calculated by ethnicity and prematurity status. RESULTS: The most common vascular lesion was nevus simplex (83%), followed by infantile hemangioma (4.5% by age 3 months), capillary malformation (0.3%), and rapidly involuting congenital hemangioma (0.3%). Pigmented lesions seen at birth included dermal melanocytosis (20%), congenital melanocytic nevi (2.4%), and cafe au lait macules (2%). Other common skin findings were erythema toxicum neonatorum (7%), milia (8%), and sebaceous gland hyperplasia (42.6%). CONCLUSION: This study of congenital cutaneous lesions, using current nomenclature and data acquired by pediatric cutaneous lesion experts, provides data regarding the role of race and ethnicity in the incidence of birthmarks, and provides valid data on the prevalence of infantile hemangioma. PMID- 22497909 TI - Fixation of ProSealTM laryngeal mask airway in a child with facial burns. PMID- 22497910 TI - Splenic re-irradiation for waldenstrom's macroglobulinemia. AB - We report on a case of Waldenstrom's macroglobulinemia (WM) treated with splenic re-irradiation. To the best of our knowledge this has not been reported before. A 69-year-old Asian female patient with WM received a three-dimensional conformal radiotherapy, with 24 Gy in 12 treatment fractions in the first stage. She tolerated the treatment well, with a 37% reduction of the monoclonal immunoglobulin, an impalpable spleen, and improved hematological laboratory tests for 4 months. She was then treated with splenic re-irradiation up to 24 Gy for tumor progression. She showed no evidence of progression one year after re irradiation, with a 55% reduction of the monoclonal immunoglobulin. Our experience demonstrates that splenic irradiation is an effective treatment to control the progression of WM. PMID- 22497911 TI - Influence of cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms in periodontitis. AB - AIM: Persistent host inflammatory immune response against the pathogens results in the destruction of periodontal tissues. Cytotoxic T lymphocyte antigen 4 (CTLA 4) is a particularly important molecule in down-regulating T-cell expansion and cytokine production. This study aimed to assess three functional SNPs within CTLA 4 gene, -1722 T/C, -318 C/T, and +49 A/G in patients with aggressive or chronic periodontitis. MATERIALS AND METHODS: A total of 197 patients with periodontitis (71 aggressive and 126 chronic periodontitis) and 218 healthy controls were recruited. All samples were genotyped for CTLA-4 gene polymorphisms by polymerase chain reaction-amplification refractory mutation system (PCR-ARMS). RESULTS: The allelic and genotype frequencies of only +49 A/G SNP were more prominence in patients with chronic periodontitis (CP) than that controls (0.0005 and 0.001, respectively). Multivariate logistic regression analysis was demonstrated that homozygosity in +49 G/G had profoundly increased susceptibility for CP, OR=3.7 (95% CI; 1.6-8.5, P=0.001). In addition, comparison of CTLA-4 SNPs between patients with CP and aggressive periodontitis (AgP) revealed that heterozygosity in -1722 T/C polymorphism of CTLA-4 gene had a significantly higher risk for CP compared with AgP with a calculated odds ratio of 2.18 (95% CI; 1.17-4.06, P=0.01). CONCLUSION: These results suggest that CTLA-4 gene variants might be associated to susceptibility to specific form of periodontitis and participate in the CP development. PMID- 22497912 TI - What's in this issue? Thai Buddhist's perspective of a peaceful death. PMID- 22497913 TI - Privacy, dignity and confidentiality: a time to reflect on practice. PMID- 22497914 TI - Strategies to increase organ donation: the role of critical care practitioners. PMID- 22497915 TI - Oral care and oropharyngeal and tracheal colonization by Gram-negative pathogens in children. AB - BACKGROUND: Critical care nursing interventions to oral care can reduce microorganisms in the oropharynx available for translocation. OBJECTIVES: To analyse the effect of 0.12% chlorhexidine digluconate on the colonization of oropharyngeal and tracheal secretions by Gram-negative pathogens in mechanically ventilated children. METHODS: A randomized, controlled and double-blinded study was performed in the paediatric intensive care unit (PICU) of a Brazilian university hospital. Exclusion criteria included child age under 28 days, pneumonia diagnosis at admission, use of tracheostomy, PICU length of stay (LOS) less than 48 h and refusal to participate. Children were randomly allocated to the interventional group (IG), in which oral care with chlorhexidine was administered, or to the placebo group (PG), which received oral care without antiseptic use. The data were analysed through Pearson's chi(2) test, Fisher's exact and ANOVA tests with significance levels set at 0.05. RESULTS: The demographic characteristics of the 74 children were not statistically different between groups. No between-group differences in oropharyx colonization by Gram negative pathogens were identified (p = 0.316). Pathogens were isolated in the tracheal secretions of two (10.0%) children in the PG and four (19.0%) children in the IG (p = 0.355). CONCLUSION: The use of chlorhexidine did not significantly influence the colonization of oropharyngeal and tracheal secretions by Gram negative pathogens of the studied sample. RELEVANCE TO CLINICAL PRACTICE: This study demonstrated no influence of a specific antiseptic agent on colonization profile of mechanically ventilated children in PICU. Further research in this field is necessary to promote evidence-based nursing practice on oral care of critically ill children. PMID- 22497916 TI - Central line insertion bundle: experiences and challenges in an adult ICU. AB - BACKGROUND: Central venous catheters are used frequently in the intensive care unit (ICU). However, there is an associated morbidity, mortality and cost derived from their infectious and mechanical complications. The Scottish Patient Safety Programme (SPSP) has developed a multi faceted care bundle, with the aim of reducing catheter-related blood stream infections. AIM: This paper aims to identify and describe the experience and challenges in implementing the SPSP central line insertion bundle in one adult ICU, in a large inner city teaching hospital. INTERVENTIONS: 'Plan-Do-Study-Act' cycles, checklists for insertion and a standardized trolley were adopted to implement the central line insertion bundle in clinical practice. CONCLUSION/IMPLICATIONS: Improving the reliability of the central line insertion bundle has reduced infections. Key steps in the process were setting clear aims and ensuring staff understand the change process and measurement of results. This is fundamental to the success of any quality improvement process. PMID- 22497917 TI - Postoperative ambulation in thoracic surgery patients: standard versus modern ambulation methods. AB - AIM: A single-subject study of two methods of postoperative ambulation of patients recovering from thoracic surgery. BACKGROUND: During the postoperative setting, patients are often burdened by their condition that reduces their ability to ambulate. This problem is compounded by the addition of devices that make walking more cumbersome. To simplify the process of ambulation during the postoperative period, an intravenous pole/walker (IVPW) was specifically designed to allow all patient devices and attachments to accompany the patient during ambulation, without the need for supplemental caregiver assistance. METHODS: The IVPW method of ambulation was compared with standard method of ambulation (SMA) in a single-subject clinical trial. Thirty-nine consecutive thoracic surgery patients with at least an IV and chest tube were ambulated using alternatively either the IVPW or the SMA. Immediately following the ambulation periods, the patient and patient's health care worker assessed both methods using satisfaction surveys consisting of several questions about the episodes of ambulation and the number of health care workers needed to assist during ambulation. RESULTS: Patient satisfaction was significantly higher in the ability of the IVPW to provide support and assist in ambulation in comparison with the SMA (p < 0.001). Nurses felt the IVPW both facilitated and provided a safer method for ambulation compared with the SMA (p < 0.001). On average, one less employee was required during ambulation with the IVPW (p < 0.001). CONCLUSION: The IVPW provided better support and was perceived as a safer method for ambulation compared with the SMA. The IVPW also required one less person to assist with ambulation. RELEVANCE TO CLINICAL PRACTICE: Facilitation of ambulation in the postoperative setting can impact nursing care and patient satisfaction. PMID- 22497918 TI - Injury severity scoring systems: a review of application to practice. AB - AIM: This study reviews the historical development of injury severity scoring systems and their application to clinical practice. BACKGROUND: A variety of injury severity scoring systems have been developed and applied since more than four decades. It is increasingly important for nurses to be familiar with these scoring systems, their strengths and weaknesses, and their applications to nursing practice. DESIGN: Systematic literature review. METHODS: The injury severity scoring systems developed from the 1970s to 2011 were identified via electronic database searches, footnote chasing and contact with clinical experts. The most frequently used scoring systems in the literature were classified according to the criteria used in each scoring system. CONCLUSIONS: All injury severity scoring systems are valuable but have certain problems. A universal scoring system applicable for various purposes appears difficult to achieve. However, the understanding and proper use of scoring systems will allow us to perform critical evaluations and continual refinement of trauma management. RELEVANCE TO CLINICAL PRACTICE: As nurses and researchers, it is critical that we should know the application of these injury severity scoring systems to ensure their quality and appropriate utilization. PMID- 22497919 TI - Thai Buddhist families' perspective of a peaceful death in ICUs. AB - AIM: To describe the concept of a peaceful death in intensive care units (ICUs) from the perspective of Thai Buddhist family members. METHODS: This descriptive qualitative study was based on data generated from individual in-depth interviews of nine Thai Buddhist family members from the southern region of Thailand whose loved ones died in adult ICUs. Colaizzi's phenomenological approach was used to analyse the data. Rigour for the study was established by Lincoln and Guga's guidelines for qualitative research studies. FINDINGS: Five core qualities emerged that made-up the concept of a peaceful death as described by Thai Buddhist family members who cared for their loved ones while they were dying in ICUs. These core qualities were 'knowing death was impending, preparing for a peaceful state of mind, not suffering, being with family members and not alone, and family members were not mourning'. CONCLUSION: Thai Buddhist family members described what they meant by a peaceful death. 'This was: preparing for a peaceful state of mind in knowing that one's impending death is not a situation of suffering or being alone, but rather a time of being with family members who are not yet mourning one's death.' The findings support that family members should participate in promoting a peaceful death for their loved ones dying in ICUs. IMPLICATIONS FOR PRACTICE: The five core qualities of a peaceful death reported in this study could be used as a framework for nurses to create nursing practice interventions for quality end-of-life care for Thai Buddhists. PMID- 22497926 TI - Oxidative stress in children with attention deficit hyperactivity disorder. AB - OBJECTIVE: The aim of this study was to investigate oxidative stress in ADHD children. DESIGN AND METHODS: Levels of oxidant parameters malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHDG), advanced oxidation protein products (AOPP) and antioxidant parameters paraoxonase (PON1) and thiol levels were measured in thirty children with ADHD (27 boys, 3 girls) who were firstly diagnosed according to DSM-IV and thirty healthy children (18 boys, 12 girls) aged 6-12 years. RESULTS: The levels of the oxidant parameters MDA and 8-OHDG were statistically significantly lower in ADHD children compared to the controls. We did not find a significant difference between the groups regarding AOPP, PON1, and thiol levels. CONCLUSION: We found low levels of some oxidants and no difference of antioxidant parameters in ADHD children. Our study points out that there may not be a direct relationship between oxidative stress and ADHD. PMID- 22497927 TI - ER stress is associated with reduced ABCA-1 protein levels in macrophages treated with advanced glycated albumin - reversal by a chemical chaperone. AB - ATP-binding cassette transporter A1 mediates the export of excess cholesterol from macrophages, contributing to the prevention of atherosclerosis. Advanced glycated albumin (AGE-alb) is prevalent in diabetes mellitus and is associated with the development of atherosclerosis. Independently of changes in ABCA-1 mRNA levels, AGE-alb induces oxidative stress and reduces ABCA-1 protein levels, which leads to macrophage lipid accumulation. These metabolic conditions are known to elicit endoplasmic reticulum (ER) stress. We sought to determine if AGE-alb induces ER stress and unfolded protein response (UPR) in macrophages and how disturbances to the ER could affect ABCA-1 content and cholesterol efflux in macrophages. AGE-alb induced a time-dependent increase in ER stress and UPR markers. ABCA-1 content and cellular cholesterol efflux were reduced by 33% and 47%, respectively, in macrophages treated with AGE-alb, and both were restored by treatment with 4-phenyl butyric acid (a chemical chaperone that alleviates ER stress), but not MG132 (a proteasome inhibitor). Tunicamycin, a classical ER stress inductor, also impaired ABCA-1 expression and cholesterol efflux (showing a decrease of 61% and 82%, respectively), confirming the deleterious effect of ER stress in macrophage cholesterol accumulation. Glycoxidation induces macrophage ER stress, which relates to the reduction in ABCA-1 and in reverse cholesterol transport, endorsing the adverse effect of macrophage ER stress in atherosclerosis. Thus, chemical chaperones that alleviate ER stress may represent a useful tool for the prevention and treatment of atherosclerosis in diabetes. PMID- 22497928 TI - Exchange protein activated by cyclic adenosine monophosphate regulates the switch between adipogenesis and osteogenesis of human mesenchymal stem cells through increasing the activation of phosphatidylinositol 3-kinase. AB - Epac, exchange protein activated by cyclic adenosine monophosphate (cAMP), could regulate the trans-differentiation between adipogenesis and osteogenesis of human mesenchymal stem cells (hMSCs). Epac activated by 8-pCPT-2'-O-Me-cAMP, a cAMP analog preferentially activating Epac, resulted in the increase of adipogenic gene expression and the decrease of osteogenic gene expression. The pro adipogenic and anti-osteogenic effect of 8-pCPT-2'-O-Me-cAMP was attributed to that 8-pCPT-2'-O-Me-cAMP led to the activation of protein kinase B (PKB) and cAMP response element-binding protein (CREB) as well as the inhibition of Ras homolog gene family member A (RhoA), focal adhesion kinase (FAK), extracellular-signal regulated kinase (ERK) and runt-related transcription factor 2 (Runx2) activities. Inhibition of Epac by a dominant-negative form of Epac1 resulted in the decrease of phosphatidylinositol 3-kinase (PI3K), PKB and CREB activities as well as down-regulation of peroxisome proliferator activated receptor-gamma (PPARgamma) expression. Inhibition of PI3K by a specific inhibitor or inhibition of Arf and Rho GAP adapter protein 3 (ARAP3, a phosphatidylinositol (PtdIns)(3,4,5)P(3) binding protein) by ARAP3 siRNA led to the recovery of RhoA and FAK activities. RhoA-V14, a constitutively active form of RhoA, could activate the MEK/ERK/Runx2 signaling. Therefore, we conclude that PI3K activated by Epac leads to the activation of PKB/CREB signaling and the up-regulation of PPARgamma expression, which in turn activate the transcription of adipogenic genes; whereas osteogenesis is driven by Rho/FAK/MEK/ERK/Runx2 signaling, which can be inhibited by Epac via PI3K. These results should be helpful to provide new targets for treatment of osteoporosis and related bone-wasting diseases. PMID- 22497930 TI - Mobile acute stroke units: bringing the hospital to the patient. PMID- 22497929 TI - Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial. AB - BACKGROUND: Only 2-5% of patients who have a stroke receive thrombolytic treatment, mainly because of delay in reaching the hospital. We aimed to assess the efficacy of a new approach of diagnosis and treatment starting at the emergency site, rather than after hospital arrival, in reducing delay in stroke therapy. METHODS: We did a randomised single-centre controlled trial to compare the time from alarm (emergency call) to therapy decision between mobile stroke unit (MSU) and hospital intervention. For inclusion in our study patients needed to be aged 18-80 years and have one or more stroke symptoms that started within the previous 2.5 h. In accordance with our week-wise randomisation plan, patients received either prehospital stroke treatment in a specialised ambulance (equipped with a CT scanner, point-of-care laboratory, and telemedicine connection) or optimised conventional hospital-based stroke treatment (control group) with a 7 day follow-up. Allocation was not masked from patients and investigators. Our primary endpoint was time from alarm to therapy decision, which was analysed with the Mann-Whitney U test. Our secondary endpoints included times from alarm to end of CT and to end of laboratory analysis, number of patients receiving intravenous thrombolysis, time from alarm to intravenous thrombolysis, and neurological outcome. We also assessed safety endpoints. This study is registered with ClinicalTrials.gov, number NCT00153036. FINDINGS: We stopped the trial after our planned interim analysis at 100 of 200 planned patients (53 in the prehospital stroke treatment group, 47 in the control group), because we had met our prespecified criteria for study termination. Prehospital stroke treatment reduced the median time from alarm to therapy decision substantially: 35 min (IQR 31-39) versus 76 min (63-94), p<0.0001; median difference 41 min (95% CI 36-48 min). We also detected similar gains regarding times from alarm to end of CT, and alarm to end of laboratory analysis, and to intravenous thrombolysis for eligible ischaemic stroke patients, although there was no substantial difference in number of patients who received intravenous thrombolysis or in neurological outcome. Safety endpoints seemed similar across the groups. INTERPRETATION: For patients with suspected stroke, treatment by the MSU substantially reduced median time from alarm to therapy decision. The MSU strategy offers a potential solution to the medical problem of the arrival of most stroke patients at the hospital too late for treatment. FUNDING: Ministry of Health of the Saarland, Germany, the Werner-Jackstadt Foundation, the Else-Kroner-Fresenius Foundation, and the Rettungsstiftung Saar. PMID- 22497931 TI - Polarization optical-histochemical characterization and supramolecular structure of carbohydrate fibrils. AB - Topo-optical staining reactions were used to investigate the structures of bacterial cellulose, insect chitosan and alginic acid from brown algae. Polysaccharide complexes, glycosaminoglycans and sulfate groups were presented and demonstrated selectively. Chitosan and alginic acid are structurally similar to glycosaminoglycans (GAGs), which are constituents of human amyloid fibrils. The staining sequences shown can be used as reliable methods for histochemistry with light and polarization microscopy. They will help to clarify the complex protein-polysaccharide structure of amyloid fibrils. PMID- 22497932 TI - Heritability. PMID- 22497933 TI - Reward creates oculomotor salience. PMID- 22497934 TI - Axon degeneration: where the Wlds things are. AB - Expression of the Wld(s) protein significantly delays axon degeneration in injuries and diseases, but the mechanism for this protection is unknown. Two recent reports present evidence that axonal mitochondria are required for Wld(S) mediated axon protection. PMID- 22497935 TI - Visual perception: knowing what to expect. AB - If perception is hypothesis, where do the hypotheses come from? A new study suggests that the human visual system uses the history of past stimulation to predict its current input. PMID- 22497936 TI - Fungal morphogenesis: in hot pursuit. AB - Temperature affects diverse biological processes. In fungi such as the pathogen Candida albicans, temperature governs a morphogenetic switch between yeast and hyphal growth. A new report connects the thermosensor Hsp90 to a CDK-cyclin transcription factor module that controls morphogenesis. PMID- 22497937 TI - Olfactory coding: tagging and tuning odor-activated synapses for memory. AB - A recent study in the locust olfactory system shows how neuromodulators can alter the rules of synaptic plasticity to form associative memories through the use of 'tagged' synapses. PMID- 22497938 TI - Microtubule organization: a pericentriolar material-like structure in yeast meiosis. AB - During meiotic prophase in fission yeast, the nucleus undergoes dramatic oscillatory movements. A newly identified structure, the radial microtubule organizing center (rMTOC), mediates these movements and shares some of the features of the pericentriolar material in higher eukaryotes. PMID- 22497939 TI - Neuroimaging: a scanner, colourfully. AB - Two recent studies report changes in human brain responses after exposure to psilocybin, the active ingredient of hallucinogenic mushrooms. Psilocybin increased sensory cortex responses during emotional recollection, but decreased resting-state blood flow in prefrontal cortex, with potential implications for treating depression. PMID- 22497940 TI - Chromosomal Instability: Mad2 beyond the spindle checkpoint. AB - What specific defects can cause chromosomal instability in cancer cells? Overexpression of the mitotic checkpoint protein Mad2 triggers chromosome missegregation but, surprisingly, Mad2 exerts this effect through a previously unknown effect on microtubule dynamics. PMID- 22497941 TI - B-cell differentiation: instructive one day, stochastic the next. AB - Three recent papers provide striking insight into the mechanisms used to regulate B-cell differentiation. They demonstrate that B-cell fate choice can be stochastic, directed, inherited, or some combination of these, depending on the circumstances. The trick is going to be working out which is important when. PMID- 22497942 TI - Neuroecology: avoiding the unpleasant experience of being the uninvited guest. AB - The navigation system of the desert ant Cataglyphis fortis helps it avoid the lethal mistake of entering the wrong nest by suppressing its attraction to nest odors until it is near its home. PMID- 22497944 TI - Risk factors of pancreatic fistula after pancreaticoduodenectomy - patients with low drain amylase level on postoperative day 1 are safe from developing pancreatic fistula. AB - BACKGROUND/AIMS: Based on the criteria of International Study Group on Pancreatic Fistula (ISGPF), the risk factors for grade B/C pancreatic fistula (PF) after pancreaticoduodenectomy (PD) were analyzed in this study. METHODOLOGY: Between October 2006 and August 2010, 114 consecutive patients underwent PD at National Hospital Organization Osaka National Hospital. We compared the clinicopathological features between patients with grade B/C PF and those with PF free/grade A PF. We also examined the relationship between PF formation and the drain amylase level on post-operative day (POD) 1 and POD 3. RESULTS: Eighteen patients (15.8%) developed grade B/C P. Of these patients, four patients underwent reoperation. The mortality rate in patients with grade B/C PF was 5.6%(1/18). The non-dilated pancreatic duct (<= 3mm) was the only independent risk factor for grade B/C PF by a multivariate analysis (p=0.026). There were 45 patients who showed low (<= three times serum amylase level)drain amylase level on POD 1 and none of them developed PF. CONCLUSIONS: Although our study demonstrated that the non-dilated pancreatic duct is significantly correlated with the increased incidence of grade B/CPE patients with low amylase level of drainage fluid on POD 1 are thought to be safe from developing PE. PMID- 22497945 TI - Multidisciplinary treatment strategy for advanced pancreatic neuroendocrine tumors- a single center experience. AB - BACKGROUND/AIMS: Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms. Little is known about the mode of recurrence and long term prognosis after resection. We aimed to evaluate the surgical indication, especially for the patients with concomitant multiple liver metastases or extreme local invasions. METHODOLOGY: The overall survival (OS) and the disease free survival (DFS) were statistically analyzed for twenty one patients with PNETs who underwent surgical intervention in our institute. The patients were divided into 2 groups, G1 NET (grade 1 neuroendocrine tumor: n=11) and G2 NET (grade 2 neuroendocrine tumor: n=10), according to WHO 2010 classification. The radical operation was indicated if curative resection were expected to be achievable. Otherwise,alternative multi disciplinary treatments were introduced especially for the hepatic metastasis or repeated recurrences. RESULTS: Median follow-up period was 37 months (range 7 69). OS was 100% at 3 years and 86% at 5 years. DFS was 62% at 3 years and 39% at 5 years. Disease recurrence developed more frequently in G2 NET, compared to G1 NET. However, there was statistically no difference for the OS between these two groups. CONCLUSIONS: Appropriate radical operation with multi-disciplinary treatments could contribute to the patients' survival in the treatment strategy of PNETs. PMID- 22497943 TI - The ancient and evolving roles of cohesin in gene expression and DNA repair. AB - The cohesin complex, named for its key role in sister chromatid cohesion, also plays critical roles in gene regulation and DNA repair. It performs all three functions in single cell eukaryotes such as yeasts, and in higher organisms such as man. Minor disruption of cohesin function has significant consequences for human development, even in the absence of measurable effects on chromatid cohesion or chromosome segregation. Here we survey the roles of cohesin in gene regulation and DNA repair, and how these functions vary from yeast to man. PMID- 22497946 TI - Effectiveness of a surgical glove port with homemade trocars made of syringes for single incision laparoscopic cholecystectomy. AB - BACKGROUND/AIMS: Single incision laparoscopic cholecystectomy (SILC) has two serious problems; its feasibility and cost. We report our experience and benefits of our original SILC procedure using homemade trocars that can solve those problems. METHODOLOGY: SILC was attempted for thirty-four patients at our hospital. The SILST" Port (Covidien, Inc) was used in 16 patients (SPgroup) and the original method using a surgical glove port with homemade trocars was performed in 18 patients (GP-HT group). A homemade trocar was made ofa 2.5mL and a 5mL syringe. We performed the retrospective comparison of the operative and postoperative results between those two groups. RESULTS: Thirty patients (14 in the SP group and 16 in the GP-HT group)successfully underwent SILC. No patient had a grade IIor more severe postoperative complication based on the Clavien Dindo classification. Our original home made trocar was slim and compact enough to avoid clashes among surgical instruments and surgeon's hands. Operative time in the GP-HT group was significantly short-er than that in the SP group (p=0.0044). CONCLUSIONS: Although further prospective studies of larger series should be performed, this simple and cost-effective system can be one of the promising ways for SILC. PMID- 22497948 TI - Intraoperative assessment of the resectability of hilar cholangiocarcinoma. AB - Major hepatectomy combined with extrahepatic bile duct resection has gained acceptance as a standard radical procedure for hilar cholangiocarcinoma. Here, we describe an operative technique, "taping of the right hepatic artery behind Calot's triangle", for assessing the resectability of hilar lesions for which left-sided hepatectomy is planned. Briefly, after retracting the gall-bladder anteriorly, the lateral peritoneum of the hepatoduodenal ligament is incised longitudinally (3-4cm in length) behind Calot's triangle and just to the left of the fissure of Ganz. By dividing the adipose tissue, the distal portion of the right hepatic artery is identified and secured with tape. Any suspicious tissues around the right hepatic artery should be submitted to frozen-section analysis. If no cancer cells were found, the planned resection goes ahead. Conversely, if they were found, the resection should be abandoned. Since 2003, 14 patients for whom left-sided hepatectomy was planned for hilar cholangio-carcinoma involvement, underwent this technique. Three patients were judged to have irresectable tumors and the planned resection could be avoided. In conclusion, this simple technique, isolation of the right hepatic artery behind Calot's triangle before starting resection, should be applied to all hilar malignancies when a left-sided hepatectomy is planned. PMID- 22497947 TI - Diagnosis and surgical treatment of mucin-producing bile duct tumors. AB - BACKGROUND/AIMS: To summarize the experience of diagnosis and surgical treatment of mucin-producing bile duct tumors (MPBTs). METHODOLOGY: A retrospective analysis was undertaken to determine the radiography characteristics and results of surgical treatment of MPBTs over the past 9 years. Only eight patients underwent such treatment. The detailed data of diagnosis, treatment and prognosis were carefully studied. RESULTS: Intermittent jaundice was the most frequently clinical manifestation of MPBTs, with unique characteristics on magnetic resonance cholangiopancreatography (MPCP) when compared with gallbladder carcino ma, hilar cholangiocarcinoma and distal bile duct can-cer. All the 8 patients with MPBTs received appropriate surgical procedure and were cured. CONCLUSIONS: Appropriate diagnosis and curative hepatectomy for MPBTs made it possible to achieve long-term survival. PMID- 22497949 TI - Identification of the biomarkers for the prediction of efficacy in first-line chemotherapy of metastatic colorectal cancer patients using SELDI-TOF-MS and artificial neural networks. AB - BACKGROUND/AIMS: For patients with metastatic colorectal cancer, both FOLFOX regimen and FOLFIRI regimen are considered as first-line choices. There are no clinically useful markers that could predict the response to these regimens respectively. We aimed at identifying serum protein patterns which could predict the efficacy of chemotherapy. METHODOLOGY: Serum from 70 patients diagnosed as metastatic colorectal cancer before first-line chemotherapy were collected and analyzed for protein patterns using ANN analysis of SELDI-TOF-MS. Among the 70 cases, 44 patients received FOLFOX chemotherapy, while the other 26 patients received FOLFIRI chemotherapy. After four cycles of the treatment, RECIST criteria were used to define the responders (R) and non-responders (NR). RESULTS: A potential predicting pattern consisting of 6 biomarkers was identified in the patients receiving FOLFOX chemotherapy. Using this predicting pattern, the responders could be separated from the non-responders with a sensitivity of 92.9% and a specificity of 81.3%. Another potential predicting pattern that consisted of 7 bio-markers was identified in the patients who have received FOLFIRI chemotherapy. The sensitivity and the specificity of this predicting pattern were 92.3% and 92.3% respectively. CONCLUSIONS: Two potential pat-terns for the prediction of efficacy of FOLFOX or FOLFIRI chemotherapy were established in this preliminary study. PMID- 22497950 TI - The efficacy of self-expanding metal stents for colorectal obstruction with unresectable stage IVB colorectal cancer. AB - BACKGROUND/AIMS: Acute colorectal obstruction with stage IVB colorectal cancer has a poor prognosis and short life expectancy. The effectiveness of self expanding metal stents (SEMS) has been demonstrated in colorectal cancer patients with obstruction. However, little is known about the palliative efficacy of stent placement inpatients with unresectable colorectal cancer. METHODOLOGY: The medical records of patients who received SEMS for stage IVB colorectal cancer with acute colorectal obstruction between March 2004 and July 2010 were retrospectively reviewed. A total of 24 patients with unresectable Stage IVB colorectal cancer with acute colorectal obstruction were enrolled in this study. RESULTS: Twenty-four patients received SEMS placement during the study period. The mean age of the patients was 63.0 years (range 35-84 years). Fifteen patients were male and nine were female. The most common obstructive lesion was in the sigmoid colon (70.8%), including the sigmoid-descending and rectosigmoid junctions. Un-covered SEMS were used in 62.5% of patients. On the first attempt, the technical success rate of SEMS was 95.8%. The estimated duration of primary stent patency and overall survival periods after SEMS were 332.0 and 231.8 days, respectively. CONCLUSIONS: SEMS insertion may be a useful therapeutic choice for acute colorectal obstruction in patients with unresectable stage IVB colorectal cancer. PMID- 22497951 TI - Computed tomography with histological correlation for evaluating tumor regression of rectal carcinoma after preoperative chemoradiation therapy. AB - BACKGROUND/AIMS: Preoperative chemoradiation therapy (CRT) is standard procedure for locally advanced rectal cancer. The correlation of tumor response evaluated using CT according to response evaluation criteria in solid tumors (RECIST) with the histo-logical tumor regression grade (TRG) is not well-documented. METHODOLOGY: Ninety-one patients with rectal cancer underwent CT examinations before and after preoperative CRT and following surgery. Clinical tumor staging and tumor response assessed according to RECIST were done on paired CT scans. Pathological tumor staging and TRGs were reviewed in resected specimens.Post-CRT CT findings and histological findings were compared. Survival analysis for 73 patients was done. RESULTS: TRG was positively correlated with the CT-assessed tumor response (r=0.276, p=0.009). Thickened fibrotic areas and muscle disarray caused by fibrosis were more frequently seen in cases of patients over-diagnosed as having residual tumors. The ycT status was positively correlated with ypT status (r=0.44, p<0.001;accuracy=61.5%). Downstaging of cT status was cor-related with a lower TRG (p=0.001). CONCLUSIONS: Fibrosis emerges after neoadjuvant therapy and is usual-ly accompanied by tumor reduction on CT scans of rec-tal cancer patients following preoperative CRT. There-fore, tumor response assessed using CT according to RECIST may serve as a supplementary tool for preoperative planning other than tumor restaging. PMID- 22497952 TI - Can pre-endoscopic assessment predict active upper gastrointestinal bleeding? A retrospective study in patients with symptoms of upper gastrointestinal bleeding outside regular working hours. AB - BACKGROUND/AIMS: To evaluate the usefulness of pre-endoscopic assessment for predicting active up-per gastrointestinal bleeding (UGI-B) at emergency esophagogastroduodenoscopy (E-EGD, within 6 hours). METHODOLOGY: We retrospectively analysed the medical records of patients that had an E-EGD performed outside working hours and considered 15 pre-endoscopic variables in a univariate analysis. Active UGI-Bat E-EGD was taken as end-point. RESULTS: Of 228 E-EGD performed during 75 months, 195 were motivated by the suspicion of UGI-B. We excluded 83 cases as they were hospitalised at the time of first symptoms of bleeding. Thus, 112 cases were included. The following clinical signs triggered E EGD: hematemesis (56/50%),melena (55/49.1%), hematochezia (20/17.8%), anae- mia (7/6.2%). Patients' age was 65.5+14.2 years. Sixty nine (61.6%) cases were male. The relative risk and p-value of the variables for the presence of active bleeding at E-EGD were as follows: hematemesis: 1.54/0.3; malignancy and cirrhosis: 1.73/0.07; haemoglobin <8g/dL: 1.38/0.3; white blood count >12,000/tL: 1.18/0.6;systolic blood pressure (SBP) <100 mmHg: 0.53/0.03;pulse >100/min: 1.42/0.2; platelets <14000/nL:1.5/0.2; INR >1.17: 1.89/0.049. In the multivariate analysis none of these variables independently predicted UGI-B. CONCLUSIONS: No relevant pre-endoscopic variables for the prediction of active UGI-B at E-EGD could be found. Our data suggest that pre-endoscopic evaluation cannot replace rapid endoscopy. PMID- 22497953 TI - Factors contributing to the overall survival in patients with hepatocellular carcinoma treated by sorafenib. AB - BACKGROUND/AIMS: In both SHARP and Asia-Pacific Study, sorafenib was proved to improve the overall survival of the patients with hepatocellular carcinoma. However, factors contributing to the improvement of overall survival of the patients treated by sorafenib have not been fully evaluated. In this study, patient-derived, background liver disease-derived and tumor-derived factors before treatment were evaluated whether they have contributed to the improvement of the overall survival. METHODOLOGY: Forty-seven cases with HCC treated by sorafenib between Sept 2009 and Feb 2011 were included in this analysis. The survival of these cases was analyzed by Kaplan-Meier Method. Factors used for univariate analysis were two patient-derived parameters, two background liver disease-derived, five tumor-derived. Factors related to the over-all survival were analyzed by multivariate analysis using Cox regression model. RESULTS: In the multivariate analysis, only background liver disease-derived parameter Child Pugh class A vs. B, (p=0.007, HR=0.21 (0.07-0.65)) was significant. No other parameters including tumor-derived factors were statistically significant by multivariate analysis. CONCLUSIONS: We undertook the statistical analysis on the three categories. Surprisingly, no tumor derived parameter contributed to the overall survival. Background liver disease-derived parameter rather than tumor derived parameter was found to define the prognosis of patients with advanced HCC treated by sorafenib. PMID- 22497954 TI - GSTP1 gene methylation profiles in Helicobacter pylori (+) and (-) antral intestinal metaplasia and distal gastric tumour patients in Turkish population. AB - BACKGROUND/AIMS: Gastric cancer (GC) is the second most common malignancy worldwide, with a high mortality rate. The incidence of GC has declined in the western countries during the last decades. The glutathione S-transferases comprise a group of enzymes that are critical in the detoxification of carcinogens. In this study we aimed at the relationship GSTP-1 methylation in patients with intestinal metaplasia with and without Helicobacter pylori infection, gastric cancer and controls. METHODOLOGY: The methylation status of GSTP1 gene was analyzed by methylation specific PCR after bisulfate modification in H. pylori (+) (n=25) and (-) (n=25) intestinal metaplasia (IM) patients, GC (n=25) and control subjects (n=15) between September 2009 to November 2011. RESULTS: During the study period 90 patients who underwent endoscopic examination were included in the study. When we considered the GSTP1 gene methylation profile in all of the groups; 26 (28%)patients had methylated GSTP1 gene, 31 (34%) patients had unmethylated GSTP1 gene and 33 (36%) patients had heterogeneously methylated GSTPI gene. CONCLUSIONS: GSTP1 gene methylation profile is not appropriate for early diagnosis of cases with gastric cancer. PMID- 22497956 TI - Associations between sedentary behaviour and metabolic parameters in patients with schizophrenia. AB - This study examined the association between sedentary behaviour and metabolic parameters among patients with schizophrenia. A total of 76 patients and 38 healthy age-, gender- and BMI-matched volunteers were included. Participants were asked for their overall sitting and physical activity behaviour using the International Physical Activity Questionnaire. Patients were additionally screened for psychiatric symptoms and extrapyramidal side-effects of antipsychotic medication. On average, patients with schizophrenia spent 8.5h per day sitting (versus 6.21h in healthy controls). Patients sitting more than 10.4h per day had a higher BMI, waist circumference and fasting glucose concentrations and experienced more negative and cognitive symptoms than those sitting less than 5.8h per day. Overall sitting time was associated with a significantly greater likelihood of metabolic syndrome. A stepwise backward-elimination multivariate regression analysis demonstrated that sitting time is a significant predictor for BMI. Current results suggest patients with schizophrenia may benefit from reducing total sitting time. PMID- 22497955 TI - Peroxisomes, cell senescence, and rates of aging. AB - The peroxisome is functionally integrated into an exquisitely complex network of communicating endomembranes which is only beginning to be appreciated. Despite great advances in identifying essential components and characterizing molecular mechanisms associated with the organelle's biogenesis and function, there is a large gap in our understanding of how peroxisomes are incorporated into metabolic pathways and subcellular communication networks, how they contribute to cellular aging, and where their influence is manifested on the initiation and progression of degenerative disease. In this review, we summarize recent evidence pointing to the organelle as an important regulator of cellular redox balance with potentially far-reaching effects on cell aging and the genesis of human disease. The roles of the organelle in lipid homeostasis, anaplerotic reactions, and other critical metabolic and biochemical processes are addressed elsewhere in this volume. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease. PMID- 22497957 TI - Gender effects in bullying: results from a national sample. AB - This study presents gender effects in sociodemographics and psychiatric correlates of bullying in the United States. Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative sample of U.S. adults. Face-to-face interviews of more than 43,000 adults were conducted during the 2001-2002 period. The present study compared 2460 respondents who ever bullied with 39,501 respondents who did not, stratified by gender. The prevalence of this behavior in the U.S. was significantly higher in men (8.5%) than in women (4.2%). Multivariate logistic regression analyses indicated strong associations in both genders with numerous psychiatric and addictive disorders with significant gender effects. Following adjustments for sociodemographic characteristics and other antisocial behaviors, women who ever bullied were significantly more likely to have any lifetime externalizing, including conduct disorder, as well as any lifetime internalizing spectrum disorder compared to men with such behavior. Bullying in women may be a symptom of a broader syndrome than in men, including more prevalent impairment of impulse control and more frequent affective disorders. PMID- 22497958 TI - Impaired predictive timing with spared time interval production in individual with schizophrenia. AB - There is evidence for timing dysfunctions in schizophrenia. However, few studies have evaluated the processing of intervals in the hundreds of milliseconds range, despite their role in the timing of speech, music and movements. This study looked into the prediction and estimation mechanisms for intervals in that time range in individuals with schizophrenia and age-matched neurotypical controls. Specifically, we questioned the capacity of the patients to detect a phase shift that requires the processing of a deviation from 'what should happen when' given prior event regularity. The minimum detectable phase shift was estimated from an adaptive staircase procedure with or without the need for sensorimotor synchronization. Results revealed that patients were significantly impaired relative to controls, at each of the tested inter-onset intervals (IOI=300, 600 and 900ms). A control experiment used the method of repeated interval production to show that both groups performed similarly in the production of target intervals (T=500ms and 1000ms). We conclude that schizophrenia is associated with predictive timing deficits, which cannot be attributed directly to a faster or slower running internal clock. PMID- 22497959 TI - A comparison of in vitro methods for determining the membrane receptor expression in cell lines. AB - INTRODUCTION: Determining the number of expressed receptors per cell (NRPC) in cell lines is an important prerequisite for many experimental procedures in biomedical research. This paper focuses on the comparison of a newly developed method of determining NRPC - the Kinetic extrapolation method (KEX) - with the standard saturation method. These two methods, both based on radiolabeled ligand receptor binding, were compared with the data on receptor expression found using quantified western blotting. METHODS: Four cell lines with different expressions of epidermal growth factor receptor (EGFR) were chosen for the experiment: A431, HaCaT, HCT116 and HepG2. Two radiolabeled monoclonal antibodies specific for EGFR were used as ligands: [(131)I]-cetuximab and [(131)I]-panitumumab. The classic manual technique based on the saturation of cell receptors was performed on cells seeded in 24-well plates. The KEX method uses the LigandTracer, a special instrument which detects ligand retention in real time from seeded cells onto a rotating Petri dish. The western blot analysis was performed according to the routinely used procedure. RESULTS: A very close accordance between the manual saturation technique and the KEX method was found in all four cell lines used. The NRPC in the cell lines follows the same order using both ligands: A431>HaCaT>HCT116~HepG2. Similarly, consistent data on EGFR expression in the studied cell lines were obtained using western blot analysis and the radiolabeled ligand binding assays. CONCLUSIONS: The KEX method could be as similarly useful for determining receptor expression as is the classic saturation method and western blotting. PMID- 22497960 TI - Re-evaluation of in vivo selectivity of [(11)C]SA4503 to sigma(1) receptors in the brain: contributions of emopamil binding protein. AB - INTRODUCTION: Carbon-11-labeled 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3 phenylpropyl)piperazine ([(11)C]SA4503) was shown to be a promising PET ligand for mapping sigma(1) receptors, and was applied to human subjects. However, an in vitro study indicated that SA4503 also binds to the emopamil binding protein (EBP), vertebral Delta8-Delta7 sterol isomerase. To our knowledge, no information is available about the possibility of [(11)C]SA4503 binding to EBP in the brain in vivo. METHODS: To confirm the selectivity of [(11)C]SA4503, we carried out an in vivo blocking experiment using high-affinity EBP and sigma(1) selective blocker. RESULTS: The brain uptake of [(11)C]SA4503 was dose-dependently decreased by SA4503 and the high-affinity sigma(1) blockers haloperidol, ifenprodil, and trifluperidol. On the other hand, the effects of the high affinity EBP blockers tamoxifen and trifluoperazine were negligible. CONCLUSIONS: Our results confirmed the sigma(1)-selective binding of [(11)C]SA4503 in the brain. PMID- 22497961 TI - Diagnostic performance of line-immunoassay based algorithms for incident HIV-1 infection. AB - BACKGROUND: Serologic testing algorithms for recent HIV seroconversion (STARHS) provide important information for HIV surveillance. We have previously demonstrated that a patient's antibody reaction pattern in a confirmatory line immunoassay (INNO-LIATM HIV I/II Score) provides information on the duration of infection, which is unaffected by clinical, immunological and viral variables. In this report we have set out to determine the diagnostic performance of Inno-Lia algorithms for identifying incident infections in patients with known duration of infection and evaluated the algorithms in annual cohorts of HIV notifications. METHODS: Diagnostic sensitivity was determined in 527 treatment-naive patients infected for up to 12 months. Specificity was determined in 740 patients infected for longer than 12 months. Plasma was tested by Inno-Lia and classified as either incident (< = 12 m) or older infection by 26 different algorithms. Incident infection rates (IIR) were calculated based on diagnostic sensitivity and specificity of each algorithm and the rule that the total of incident results is the sum of true-incident and false-incident results, which can be calculated by means of the pre-determined sensitivity and specificity. RESULTS: The 10 best algorithms had a mean raw sensitivity of 59.4% and a mean specificity of 95.1%. Adjustment for overrepresentation of patients in the first quarter year of infection further reduced the sensitivity. In the preferred model, the mean adjusted sensitivity was 37.4%. Application of the 10 best algorithms to four annual cohorts of HIV-1 notifications totalling 2'595 patients yielded a mean IIR of 0.35 in 2005/6 (baseline) and of 0.45, 0.42 and 0.35 in 2008, 2009 and 2010, respectively. The increase between baseline and 2008 and the ensuing decreases were highly significant. Other adjustment models yielded different absolute IIR, although the relative changes between the cohorts were identical for all models. CONCLUSIONS: The method can be used for comparing IIR in annual cohorts of HIV notifications. The use of several different algorithms in combination, each with its own sensitivity and specificity to detect incident infection, is advisable as this reduces the impact of individual imperfections stemming primarily from relatively low sensitivities and sampling bias. PMID- 22497962 TI - Highly effective and inexpensive parasitological technique for diagnosis of intestinal parasites in developing countries: spontaneous sedimentation technique in tube. AB - Millions of low-income people in the world are affected by intestinal parasites. Inexpensive, simple, and effective techniques for diagnosis are necessary. The spontaneous sedimentation technique in tube (SSTT), for application in poor healthcare settings and under field-work conditions, was described 25 years ago in Peru by Tello. The advantages of the SSTT are its ability to detect the majority of intestinal parasites, including eggs, larvae, cysts, and trophozoites, and its low cost. PMID- 22497963 TI - Predictors of septic shock in patients with methicillin-resistant Staphylococcus aureus bacteremia. AB - OBJECTIVES: Risk factors for septic shock associated with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia are not well described. We designed this study to assess the independent predictors of septic shock in patients with MRSA bacteremia. METHODS: This retrospective chart review included 234 patients with MRSA bacteremia admitted to a tertiary care academic medical center. Cases of septic shock and non-septic shock MRSA bacteremia were compared in terms of patient baseline characteristics and co-morbidities, modes of acquisition, and MRSA genotyping. Independent risk factors were determined by multivariable analysis. RESULTS: On univariate analysis the presence of chronic kidney disease, respiratory failure, acute renal failure, staphylococcal cassette chromosome (SCCmec) type II, and higher APACHE II scores were significantly correlated with the presence of septic shock. On multivariate analysis, baseline APACHE II score (adjusted odds ratio (AOR) for 1-point increase 1.13, 95% confidence interval (CI) 1.04-1.22, p=0.005), acute renal failure (AOR 2.57, 95% CI 1.02-6.48, p=0.045), and SCCmec type II (AOR 2.60, 95% CI 1.01-6.75, p=0.049) were independently associated with MRSA bacteremic septic shock. CONCLUSIONS: The development of septic shock associated with MRSA bacteremia was independently correlated with baseline severity of illness, presence of acute renal failure, and an MRSA genotyping consistent with nosocomially acquired MRSA infection. PMID- 22497965 TI - Characterization of Staphylococcus lugdunensis endocarditis in patients with cardiac implantable electronic devices. AB - OBJECTIVES: Although the application of cardiac implantable electronic devices (CIED) has greatly increased over the past few decades, CIED endocarditis is becoming a challenging scenario in clinical practice. Recently, Staphylococcus lugdunensis has emerged as a pathogen in CIED endocarditis. However, a detailed phenotypic characterization has not been addressed. METHODS: We conducted a systematic literature review covering the period between 1989 and 2011 using the PubMed, Medline, Cochrane, and Embase databases. All cases included had a CIED in use and met the modified Duke criteria for infective endocarditis, and all had isolates of S. lugdunensis. The clinical features, predisposing conditions, echocardiographic findings, and therapeutic strategies/outcomes were evaluated. Polymorphonuclear neutrophil functions were examined to test whether the defect of innate immunity may play a permissive role in host susceptibility to tissue destruction in S. lugdunensis endocarditis. RESULTS: Eleven patients with CIED endocarditis caused by S. lugdunensis were identified. Their mean age was 61.7+/ 11.2 years, and there was a male preponderance (72.7%). Six patients (54.5%) had undergone re-manipulation of the pacing system within a few months to years before the occurrence of clinical symptoms. The median time of symptoms before the diagnosis of CIED endocarditis was 60 days. On echocardiography, vegetations in the CIED were detected in nine cases (81.8%). Nine patients (81.8%) underwent surgical removal of the entire device, and one patient received medical treatment alone. The overall mortality rate was 18.2%. One patient had a septic perforation of the ventricular septum, with a high serum level of N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP) in the absence of pump failure. The assessment of polymorphonuclear neutrophil (PMN) functions revealed normal PMN responses to the various stimuli and normal oxidative burst responses. CONCLUSIONS: Identification and differentiation of staphylococcal species in a timely manner would allow us to intervene more aggressively at an earlier stage to prevent unfavorable outcomes. Clinicians should never consider the isolation of S. lugdunensis as contamination. In selected individuals, therapeutic abstention may be preferable to exposing patients to a high risk of S. lugdunensis CIED endocarditis due to re-manipulation of the pacing system. The prognostic value of NT-pro-BNP warrants further investigations. PMID- 22497964 TI - Epidemiology of Japanese encephalitis in South Korea, 2007-2010. AB - BACKGROUND: Japanese encephalitis (JE) was the leading cause of viral encephalitis among children in South Korea in the 20(th) century. This study summarizes recent changes in the epidemiology of JE following the implementation of a vigorous immunization program in the country. METHODS: Epidemiological investigations were performed for all reported laboratory-confirmed JE cases, and the cumulative incidence was calculated for the surveillance years 2007-2010. RESULTS: During the surveillance period, 45 cases of JE were confirmed in the country, resulting in a cumulative incidence of 0.013-0.055 cases per 100 000 population. The median age of cases was 49.4 years, and by age group, 44.4% were aged 40-49 years. Just under a quarter (22.2%) of the cases were found to live close to a pigsty, while 42.2% of the cases were found to reside in the metropolitan areas of Seoul, Incheon, and Gyeonggi-do. None of the cases had a history of vaccination. CONCLUSIONS: Although JE has traditionally been regarded as a children's disease, the majority of cases now occur in adults in countries where strong immunization programs exist, such as in South Korea. Consideration should be given to an adult vaccination policy in the near future. PMID- 22497966 TI - Healthcare-associated vs. hospital-acquired Staphylococcus aureus bacteremia. AB - OBJECTIVE: To analyze clinical features and outcomes of patients with hospital acquired (HA) and healthcare-associated (HCA) Staphylococcus aureus bacteremia. METHODS: A retrospective cohort study was conducted from 1988 to 2007. We compared patients with clinically significant HA with those with HCA S. aureus bacteremia. Risk factors for 30-day all-cause mortality were assessed using multivariable logistic regression analysis. Cox regression analysis was used to estimate the hazard ratio (HR) for 5-year mortality with 95% confidence intervals (CI). RESULTS: Of 1261 episodes, 735 (58.3%) were HA and 526 (41.7%) were HCA. The percentage of MRSA was 48.2% (354/735) in HA vs. 42.2% (222/526) in HCA bacteremia; p=0.04. The percentages of HCA S. aureus bacteremia and MRSA bacteremia did not vary throughout the study period. Mortality at 30 days was 40.2% (507/1261) and at 1 year was 63.4% (800/1261); this was comparable for HA and HCA bacteremia. Five-year survival curves in both settings followed very similar patterns (HR 1.01, 95% CI 0.89-1.15). Risk factors for 30-day mortality were similar, except for primary bacteremia and pre-existing heart valve disease in the HA group. CONCLUSIONS: HCA S. aureus bacteremia shares many similarities with HA bacteremia with respect to the prevalence of MRSA strains, mortality rates, and risk factors for death, and should be managed similarly. PMID- 22497967 TI - A gastroretentive gabapentin formulation for the treatment of painful diabetic peripheral neuropathy: efficacy and tolerability in a double-blind, randomized, controlled clinical trial. AB - AIMS: A randomized, double-blind, placebo-controlled study was conducted in 147 patients to determine the efficacy and safety of a gastroretentive formulation of gabapentin (G-GR) in treating painful diabetic peripheral neuropathy (DPN). METHODS: Diabetic patients with symmetrical painful symptoms in distal extremities for 1-5 years and a baseline average daily pain (ADP) score of >=4 received G-GR 3000mg, as a single evening daily dose (G-GR-QD) or a divided dose (G-GR-DD, 1200mg AM/1800mg PM), or placebo for 4 weeks. G-GR was titrated from 300 to 3000mg/day over 2 weeks, followed by 2 additional weeks at 3000mg/day. Efficacy measures included changes from baseline to Week 4 in ADP score and average daily sleep interference score (SIS). RESULTS: A significantly larger decrease in ADP score was observed in the G-GR-QD dose group compared with placebo (-2.50 versus -1.30; p=0.002). A >=50% reduction in ADP score was achieved in 34.8% of G-GR-QD recipients compared with 7.8% of placebo recipients (p=0.001). Similar results were observed for changes in SIS. The incidences of dizziness and somnolence, commonly associated with gabapentin, were low. CONCLUSIONS: Once-daily G-GR was effective and well tolerated for the treatment of pain due to DPN. PMID- 22497968 TI - Links among type 2 diabetes, cancer and metformin use: what have we learned? PMID- 22497969 TI - Plasminogen activator inhibitor-1 is associated with renal dysfunction independent of BMI and serum lipid levels in patients with type 2 diabetes. AB - We investigated a possible association between serum plasminogen activator inhibitor-1 (PAI-1) levels and renal dysfunction in 124 type 2 diabetes patients. Multiple linear regression analyses indicated that the PAI-1 levels were significantly inversely correlated with estimated glomerular filtration rate (eGFR) independent of albuminuria, BMI, LDL-C, and triglyceride. PMID- 22497970 TI - The protective effect of resveratrol on islet insulin secretion and morphology in mice on a high-fat diet. AB - The aim of this study was to investigate the effect of resveratrol on beta cells in male C57BL/6J mice fed a high-fat diet and the possible mechanisms. Male C57BL/6J mice were randomly divided into three groups: normal control (NC) group, high-fat diet (HF) group and high-fat diet and resveratrol treatment (HFR) group (15 in each group). HFR group was fed with high fat diet for 8 weeks and then orally administered resveratrol at 400mg/kg daily. Twenty-four weeks later, the function of insulin secretion in vivo and in vitro was improved robustly in HFR group compared with HF group. The levels of glucose and lipid metabolism, beta cell mass, lipid content, and oxidative stress were lower in HFR group than in HF group. Simultaneously, resveratrol administration promoted the expression of SIRT1 in islets, while the expression of uncoupling protein 2 (UCP2) was restrained. Resveratrol, as well, also had a beneficial effect on the ratios of expressions of Bcl-2/Bax and levels of malondialdehyde/glutathione peroxidase. Resveratrol can protect islets from abnormal insulin secretion and morphological changes induced by a high-fat diet. The effect might be partly related to activated SIRT1 signal pathway, improved oxidative stress induced damage and incidence of apoptosis. PMID- 22497971 TI - Single-nucleotide polymorphisms and haplotypes in the adiponectin gene contribute to the genetic risk for type 2 diabetes in Tunisian Arabs. AB - Adiponectin is an adipocyte-produced protein involved in regulating glucose, lipid, and energy metabolism, and is encoded by ADIPOQ (APM1) gene. ADIPOQ polymorphisms were previously associated with type 2 diabetes (T2DM) in Caucasian and non-Caucasian populations. We investigated the contribution of 13 polymorphisms in the promoter, coding regions, and 3'untranslated region of ADIPOQ gene to T2DM in 917 patients and 748 normoglycemic control subjects. ADIPOQ genotyping was done by allelic discrimination method. Of the 13 ADIPOQ variants analyzed, higher minor allele frequency of rs16861194 (P<0.001), rs17300539 (P<0.001), rs266729 (P<0.001), rs822396 (P=0.02), rs2241767 (P=0.03), and rs1063538 (P=0.02) were seen in T2DM cases. Varied association of ADIPOQ genotypes with T2DM was seen according to the genetic model used: rs17300539 and rs266729 were significantly associated with T2DM under the three models, while rs16861194 was association with T2DM under additive and dominant models, and rs822396, rs2241766, and rs1063538 were associated with T2DM under the dominant models only. Haploview analysis revealed low linkage disequilibrium between the ADIPOQ variants, resulting in high haplotype diversity, and two blocks were identified, each differentially associated with T2DM. These results support a significant association of ADIPOQ gene polymorphism with T2DM in Tunisian Arabs. PMID- 22497972 TI - Absorption spectrophotometric, NMR and theoretical investigations on ground state non-covalent interaction of C60 and C70 with a designed trihomocalix[6]arene in solution. AB - The present paper reports the spectroscopic investigations on non-covalent interaction of fullerenes C(60) and C(70) with a designed trihomocalix[6]arene (2) in toluene. UV-vis studies reveal appreciable ground state interaction between fullerenes and 2. Jobs method of continuous variation establishes 1:1 stoichiometry for fullerene-2 complexes. Binding constant (K) data reveals that 2 binds C(70) more strongly compared to C(60), i.e. K(C60-2)-47,540 dm(3)mol(-1) and K(C70-2)-86,360 dm(3)mol(-1). Proton NMR studies provide very good support in favor of strong binding between C(70) and 2. Estimation of solvent reorganization energy (R(S)) evokes that C(70)-2 complex is stabilized more compared to C(60)-2 complex as R(S(C60-2))- -1.162 eV and R(S(C70-2))- -1.244eV. Semiempirical calculations at third parametric level of theory in vacuo evoke the single projection structures of the fullerene-2 complexes and interpret the stability difference between C(60) and C(70) complexes of 2 in terms of enthalpies of formation values. PMID- 22497973 TI - Mechanisms underlying the relationship between health literacy and glycemic control in American Indians and Alaska Natives. AB - OBJECTIVE: Research suggests that health literacy (HL) is associated with clinical outcomes. Few studies, however, have examined the mechanisms accounting for this relationship. To understand why HL is related to outcomes, we tested a theoretical framework proposing that diabetes-related knowledge and behavior mediate (explain) the relationship between HL and glycemic control (i.e., A1c). METHODS: Analyses used baseline data from the Special Diabetes Program for Indians Healthy Heart Project (N=2594), an intervention to reduce cardiovascular risk among American Indians/Alaska Natives (AI/ANs) with diabetes. Three nested structural equation models tested the theoretical framework. RESULTS: Model 1 demonstrated that participants with stronger HL skills had better glycemic control. Model 2 tested whether diabetes-related behaviors accounted for this relationship. Self-monitoring of blood glucose significantly mediated the HL-A1c relationship. Model 3 examined the role of diabetes knowledge, showing that it mediated the relationship between HL and dietary behavior. When knowledge was included, behavior was no longer a significant mediator, suggesting that knowledge was the main driver of the relationship between HL with A1c. CONCLUSION: Interventions to improve knowledge may be particularly important in enhancing outcomes among AI/ANs with diabetes. PRACTICE IMPLICATIONS: Strategies known to enhance patient comprehension may enable low-literate patients to develop needed diabetes knowledge. PMID- 22497974 TI - Multiple virus infection alters rotavirus replication and expression of cytokines and Toll-like receptors in intestinal epithelial cells. AB - Two live oral rotavirus vaccines have shown to be effective in protecting young children from severe illness in developed and middle income countries, but their efficacy is significantly lower in low income countries. One of the reasons for this lower efficacy may be mixed virus infection in the gut that is commonly encountered among infants in the developing world. We investigated whether multiple virus infection interferes with rotavirus replication and alters host response by comparing single and mixed enteric virus infections in Caco-2 cells. We observed a dramatic reduction in rotavirus replication and growth in mixed rotavirus, astrovirus and enterovirus infection compared to single rotavirus infection. By contrast, the levels of astrovirus and enterovirus RNA in mixed infection remained unchanged when compared to those of the corresponding single virus infection. We then examined cells with single or multiple virus infections for the expression of 10 cytokine genes and demonstrated elevated expressions for 7 (IFN-alpha, IFN-beta, IFN-gamma, TNF-alpha, IL-6, IL-8, and IL-17) in dual rotavirus and enterovirus or triple rotavirus, enterovirus and astrovirus infected cells but only 3 (IFN-beta, TNF-alpha, and IL-8) in dual rotavirus and astrovirus-infected cells. We further observed elevated levels of TLR4, TLR5, TLR7 and TLR9 mRNAs in cells with rotavirus and enterovirus or rotavirus, enterovirus and astrovirus infections when compared to single rotavirus infections. Our data suggest that rotavirus infection is susceptible to interference by other enteric viruses in the gut, which could result in reduced virus replication and contribute to lower immunogenicity and efficacy of oral rotavirus vaccines in low income countries. PMID- 22497975 TI - Cancers in patients with hemophilia: a retrospective study from the Italian Association of Hemophilia Centers: a rebuttal. PMID- 22497976 TI - Infections due to Nocardia species. PMID- 22497978 TI - High glycemic diet and breast cancer occurrence in the Italian EPIC cohort. AB - BACKGROUND AND AIMS: There are theoretical reasons for suspecting that a high glycemic index (GI) or glycemic load (GL) diet may increase breast cancer risk, perhaps via an effect on the insulin-like growth factor (IGF) axis. However observational studies have produced inconsistent findings and it is controversial whether breast cancer risk is influenced by the carbohydrate characteristics of the diet. We prospectively investigated the association between dietary GI and GL and breast cancer in the Italian section of the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS AND RESULTS: Women were recruited from 1993 to 1998 at five centers: Varese and Turin (north Italy), Florence (central Italy), and Ragusa and Naples (south Italy). Participants completed validated food frequency questionnaires from which GI and GL were estimated. Multivariable Cox proportional hazard regression models quantified the association between breast cancer risk and total carbohydrate intake, GI, and GL. During 11 years of follow-up, 879 breast cancer (797 invasive and 82 in situ) cases were indentified. High dietary GL was associated with increased breast cancer risk (RR 1.45, 95% CI = 1.06-1.99; highest vs. lowest quintile; p-trend 0.029), whereas dietary GI and total carbohydrate had no influence. The association was not modified by menopausal status or body mass index. CONCLUSION: Our data indicate that, in a Mediterranean population characterized by traditionally high and varied carbohydrate intake, a diet high in GL plays a role in the development of breast cancer. PMID- 22497979 TI - Multidisciplinary lifestyle intervention in the obese: its impact on patients' perception of the disease, food and physical exercise. AB - BACKGROUND AND AIMS: To be successful, lifestyle intervention in obesity must take into account patients' views. The aim of the present study, conducted using a narrative-autobiographical approach, was to report on the perception of disease, food and physical exercise in a group of 80 obese patients during a structured multidisciplinary lifestyle intervention. METHODS AND RESULTS: Patients underwent lifestyle intervention, of three months' duration, structured in the following steps: 1) an initial medical examination; 2) an interview by a psychologist; 3) an assessment by a dietician, 4) a physical examination by a specialist in sports medicine; 5) an individualized program consisting of 24 sessions (two per week) of structured indoor exercise 6) eight sessions of group therapeutic education; 7) Nordic walking activity combined with walking excursions during weekends. All the narrative autobiographic texts obtained during the lifestyle intervention were submitted for content analysis; data were analysed according to the ''grounded theory'' method. According to patients' descriptions at the end of the intervention, lifestyle intervention resulted in enhanced self-efficacy and a reduction in their dependency on food and people; their fear of change was also diminished because, by undergoing intervention, they had experienced change. CONCLUSION: The findings made in the present qualitative analysis suggest that whenever multidisciplinary lifestyle intervention is planned for patients with obesity, it is of the utmost importance to tailor the approach while taking the following key aspects into account: motivation, barriers and/or facilitators in lifestyle change, patients' perceptions of obesity and relationship with food, diet and exercise. PMID- 22497980 TI - Voltage-gated Na+ channel blockers reduce functional bladder capacity in the conscious spontaneously hypertensive rat. AB - OBJECTIVE: To evaluate the consequence of pharmacologic inhibition of voltage gated Na(+) channels (Nav) in the conscious rat, based on Nav having been implicated as modulators of rodent urodynamics using knockout as well as antisense oligodeoxynucleotide approaches. METHODS: The urodynamic response to standard Nav blockers, lamotrigine, amitriptyline, mexiletine, and carbamazepine were evaluated using conscious, continuous-filling cystometry in spontaneously hypertensive rats (SHRs). As a selectivity evaluation, the activity of the Nav blockers at muscarinic receptors was assessed via effect on carbachol-evoked bladder contractions. RESULTS: Lamotrigine, amitriptyline, mexiletine, and carbamazepine decreased peak micturition pressure, micturition interval, and void volume. These effects were markedly similar to observations with muscarinic antagonists. Therefore, we evaluated the selectivity of these agents against bladder muscarinic receptors. Lamotrigine, mexiletine, and carbamazepine had no effect on muscarinic bladder contractions, whereas amitriptyline displayed a robust antagonism of carbachol-induced contractility. CONCLUSION: Three Nav blockers--lamotrigine, mexiletine, and carbamazepine--demonstrated a reduction in micturition pressure and functional bladder capacity, similar to previous observations with muscarinic antagonists. These 3 Nav blockers are free of muscarinic antagonism, consistent with their cystometric effects being mediated via their Nav blocking activities. The negative findings reported here with Nav blockers suggest that Nav channel blockade is unlikely to reflect an improved treatment strategy for bladder disorders over currently prescribed muscarinic antagonists. PMID- 22497981 TI - Use of a vascularized tunica vaginalis flap for repair of testicular rupture in a pediatric patient. AB - The management of testicular rupture in children with a large tunical defect is challenging. We describe a technique suitable when primary closure cannot be achieved. A 16-year-old boy presented with right testicular rupture. Owing to the large tunical separation and excessive edema, primary closure could not be achieved. A tunica vaginalis flap was then fashioned with a broad-based pedicle to complete closure. The patient had an uneventful recovery. At 4 months postoperatively, the testis was of normal size and position, and the ultrasound findings were normal. The vascularized tunica vaginalis flap provides an excellent alternative method for closure of pediatric testicular rupture. PMID- 22497982 TI - Efficacy and safety of udenafil for erectile dysfunction: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: To systematically review the evidence on the efficacy and safety of udenafil as treatment of erectile dysfunction from randomized controlled trials. METHODS: We searched PubMed, Embase, and the Cochrane Library database up to October 2011. The outcome measures assessed were the change from baseline for the International Index of Erectile Function erectile function domain score (primary), the change from baseline for Sexual Encounter Profile questions 2 and 3, the shift to normal rate (erectile function domain >= 26), the response to the Global Assessment Questionnaire and adverse effects (secondary). Two of us independently assessed the study quality and extracted data. All data were analyzed using Review Manager, version 5.0.2. RESULTS: Five randomized controlled trials totaling 1109 patients were included. At the follow-up endpoints, udenafil was found to be more effective than placebo, and the tolerability was good. The pooled results showed that the udenafil group was significantly greater than the placebo group in the change from baseline for the International Index of Erectile Function erectile function domain score (mean difference 5.65, 95% confidence interval 4.41-6.89, P < .00001). All included studies indicated that most adverse events were mild or moderate in severity, and no serious adverse events were reported during the study period. The most common drug-related adverse events were flushing and headache (udenafil vs placebo, 5.6% vs 1.8% and 3.1% vs 0%, respectively). CONCLUSION: The results from the current meta-analysis have suggested that udenafil is an effective and well-tolerated therapy for erectile dysfunction. The findings of the present review highlight the need for more efficient performance of higher quality, large-sample, various-race, long-term, randomized controlled trials to verify the efficacy and safety of udenafil. PMID- 22497983 TI - Retrograde endoureterotomy for persistent ureterovesical anastomotic strictures in renal transplant kidneys after failed antegrade balloon dilation. AB - OBJECTIVE: To evaluate the long-term outcomes and complications of retrograde endoureterotomy for persistent ureterovesical anastomotic strictures in renal transplant patients after percutaneous balloon dilation failure. METHODS: From January 2000 to May 2010, 26 (2.6%) of 1004 renal transplant patients developed ureterovesical anastomotic stricture after surgery. Seven of these patients and five additional referred patients with similar characteristics were treated with retrograde endoureterotomy after >=1 previous unsuccessful attempt at percutaneous balloon dilation. All strictures treated were <1 cm in length. The clinical characteristics and outcomes were analyzed. Success was defined as the absence of symptoms and the resolution of obstruction on imaging after the procedure. RESULTS: The median interval from initial treatment to endoureterotomy was 2.9 months (range 1.3-62.1). Before endoscopic treatment, 8 patients (67%) were treated with a single trial of balloon dilation and 4 (33%) with multiple trials. Endoureterotomy was performed using cold knife, holmium:yttrium-aluminum garnet laser, and Bugbee electrode in 9, 2, and 1 patients, respectively. The median follow-up period was 44.4 months (range 2.4-68.6). Recurrent stricture developed in 2 patients during a mean follow-up of 4.7 months. Thus, the overall success rate was 83%. Postoperative complications appeared in 3 patients (25%) with culture-positive urinary tract infection. One graft failure occurred but was not related to a recurrent stricture. CONCLUSION: After failure of antegrade percutaneous balloon dilation, retrograde endoureterotomy is an effective salvage procedure for well-selected cases of renal transplant patients with a short ureterovesical anastomotic stricture. PMID- 22497985 TI - Associations between success and failure in a face-to-face competition and psychobiological parameters in young women. AB - Within an evolutionary framework, in recent years some questions have been raised about whether women have a pattern of psychobiological response to social stress similar to that described in men. The main objective of this study was to analyze women's patterns of neuroendocrine, cardiovascular and mood responses to an individual competitive task, taking into account the outcome obtained. For this purpose, we measured salivary testosterone (T) and cortisol (C) levels, heart rate (HR) and blood pressure (BP), in addition to mood changes, in 40 healthy young women before, during and after a face-to-face laboratory competition. We also assessed some relevant psychological traits. Our results indicate that women who became winners presented greater T and positive mood increases, together with higher cardiovascular (CV) responses, than those who lost and did not show significant changes during the period studied. These results suggest a biological and psychological pattern of response to a laboratory competition differentially associated with outcome. Furthermore, these findings suggest that women who are involved in competitive situations, use both passive and active coping strategies, which can be explained by integrating the existing hypotheses. PMID- 22497986 TI - A review of Atypical depression in relation to the course of depression and changes in HPA axis organization. AB - Depression is a clinically heterogenous condition defined by sub-types that can have diametrically opposed features, such as sleep and appetite. Within the same individual these features may change over time, and different symptom clusters may respond selectively to different treatments. It has been hypothesized that different pathophysiological processes may be operating in the different sub types of depression and specifically that Melancholic depression may be associated with relative overactivity, and Atypical depression with relative hypoactivity, of the hypothalamic drive of the HPA axis. A consistent finding that emerges from the literature is that the experience of depression alters over the course of the illness with the features of Atypical depression dominating a more chronic clinical picture. This suggests that different stress states characterize the different profiles of depression as the illness becomes more chronic. There is evidence that the corticotropin-releasing hormone (CRH) control of HPA axis output is reduced in Atypical, compared to Melancholic, sub-types, but there is no convincing evidence that overall HPA activity, i.e., cortisol output, reduces. We suggest that there is a "switch" in the regulation of the HPA system from CRH to arginine vasopressin (AVP) control as stress becomes more sustained or repeated; resulting in an altered homeostasis within the HPA system. Cortisol, and the neuropeptides CRH and AVP, have different neurobiological, behavioural and experiental effects. The "switch" process should result in different neuropeptide/cortisol combinations and ratios and may explain the changing profile of depression over time. The heuristic merit in making a distinction between the different clinical states of depression will be discussed. PMID- 22497987 TI - Developmental patterns of hair cortisol in male and female nonhuman primates: lower hair cortisol levels in vervet males emerge at puberty. AB - Studies have yielded inconsistent results with regard to effects of age and sex on short-term markers of hypothalamic pituitary adrenal (HPA) activity. Hair cortisol provides a retrospective proxy measure of the cumulative activity of the HPA axis over the preceding 3- to 4-month period. In order to describe potential developmental trends in this biomarker, we assessed hair cortisol levels between 1 and 12 years of age in a cross-sectional study of 350 vervets (222 females and 128 males). Monkeys were grouped according to age as 1 (young juvenile), 2 (juvenile), 3 (early adolescent), 4 (late adolescent-young adult), and 5-12 (adult) years of age such that fully mature animals were included in the 5-12 year old age group. We observed that hair cortisol level was higher among the younger monkeys and declined with age (p<.001). More importantly the effect of age significantly interacted with sex (p=.02), such that hair cortisol was consistently lower in males than females beginning at age 3 (p<.05 or better). The developmental decline began one year earlier in females than males suggesting an influence of the earlier maturational processes typical in both human and nonhuman primates. The advantage of lower cortisol levels in the males may be related to social group patterns of male emigration during adolescence in many nonhuman primate species. PMID- 22497984 TI - Sex and estradiol influence glial pro-inflammatory responses to lipopolysaccharide in rats. AB - There is a greater prevalence of neuroinflammatory diseases in females than males. Microglia, the major immunocompetent cells of the central nervous system, play a key role in neuroinflammation. We aimed to determine if inherent differences in toll-like receptor 4 mediated pro-inflammatory response in glia could possibly contribute to the skewed female prevalence of neuroinflammatory disorders. In addition, in order to identify if estradiol (E2), the major female sex steroid contributes to a heightened pro-inflammatory response, estradiol was added both in vivo and in vitro. Microglia and astrocytes were isolated from neonatal pups and stimulated with lipopolysaccharide (LPS) in the presence and absence of E2. Hippocampal microglia were isolated from adult male and female rats and stimulated ex vivo with LPS. Male neonatal microglia and astrocytes produced greater IL-1beta mRNA than females. However, when co-incubated with varying doses of estradiol (E2), the E2 produced anti-inflammatory effects in the male microglia but a pro-inflammatory effect in female microglia. LPS-induced IL 1beta mRNA was attenuated by E2 in female but not male adult hippocampal microglia. However, females supplemented with E2 in vivo produced a potentiated IL-1beta mRNA response. TLR4 mRNA was decreased by LPS in both microglia and astrocytes but was not affected by sex or E2. CD14 mRNA was increased by LPS and may be elevated more in females than males in microglia but not astrocytes. Therefore, sexual dimorphic differences do occur in both neonatal and adult microglia though maturity of the microglia at the time of isolation influences the pro-inflammatory response. PMID- 22497988 TI - Effects of submental neuromuscular electrical stimulation on pharyngeal pressure generation. AB - OBJECTIVE: To investigate the immediate and late effects of submental event related neuromuscular electrical stimulation (NMES) on pharyngeal pressure generation during noneffortful and effortful saliva swallows. DESIGN: Before after trial. SETTING: Swallowing rehabilitation research laboratory. PARTICIPANTS: Sex-matched (N=20) healthy research volunteers. INTERVENTIONS: Participants received 80Hz NMES of 4-second duration to floor of mouth muscles that was time-locked to 60 volitional saliva swallows. MAIN OUTCOME MEASURES: Manometry measures of peak pressures and duration of pressure events in the oropharynx, hypopharynx, and the upper esophageal sphincter (UES) were derived during execution of noneffortful and effortful saliva swallows. Measures were taken at baseline, during stimulation, and at 5-, 30-, and 60-minutes poststimulation. RESULTS: Baseline pharyngeal and UES pressures did not differ between stimulated and nonstimulated swallows. At 5- and 30-minutes poststimulation, peak pressure decreased at the hypopharyngeal and at the UES sensor during noneffortful swallows. The effect lasted up to an hour only in the hypopharynx. No changes in duration of pressure events were observed. CONCLUSIONS: Using this treatment paradigm, decreased peak amplitude in the hypopharynx up to an hour after treatment indicates a potential risk of decreased bolus flow associated with NMES. On the other hand, decreased UES relaxation pressure may facilitate bolus transit into the esophagus. PMID- 22497989 TI - Underestimating physical function gains: comparing FIM motor subscale and interRAI post acute care activities of daily living scale. AB - OBJECTIVE: To investigate the construct validity of the activities of daily living (ADLs) sections of 2 major systems developed to measure functional ability in rehabilitation settings. Health assessment systems can inform care planning as well as policy decision-making on service effectiveness. Frailty, comorbidity, and heterogeneity make it difficult to accurately measure health outcomes for older adults. Objective investigation of the value of geriatric rehabilitation services requires assessment systems that are comprehensive, reliable, valid, and sensitive to clinically relevant changes in older patients. DESIGN: Trained health care workers assessed patients with both tools at admission and discharge. We used Rasch analysis to compare the instruments' dimensionality, item difficulty, item fit, differential item function, and number of response options. SETTING: Musculoskeletal and geriatric rehabilitation units in 2 Ontario hospitals. PARTICIPANTS: Older adults receiving rehabilitation (N=209; mean age +/- SD, 78.5+/-9.3; 67% women). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FIM and the interRAI Post Acute Care Assessment (interRAI PAC). RESULTS: For both the FIM motor and the interRAI PAC ADLs items, the difficulty level of the items was much lower than the participant's level of ability, resulting in a large ceiling effect. Also, on both scales, less actual change in functional ability was required to move between the midlevel response options. CONCLUSIONS: Both scales have limited ability to discriminate between subjects with higher functional ability, which indicates that they may underestimate the effectiveness of inpatient rehabilitation for this group of patients when used alone. PMID- 22497990 TI - Behcet's disease. AB - DEFINITION OF THE DISEASE: Behcet disease (BD) is a chronic, relapsing, multisystemic disorder characterized by mucocutaneous, ocular, vascular and central nervous system manifestations. EPIDEMIOLOGY: BD seems to cluster along the ancient Silk Road, which extends from eastern Asia to the Mediterranean basin. European cases are often described, not exclusively in the migrant population. CLINICAL DESCRIPTION: The clinical spectrum includes oral and genital ulcerations, uveitis, vascular, neurological, articular, renal and gastrointestinal manifestations. ETIOLOGY: The etiopathogenesis of the disease remains unknown, although genetic predisposition, environmental factors and immunological abnormalities have been implicated. DIAGNOSTIC METHODS: Diagnosis is only based on clinical criteria. DIFFERRENTIAL DIAGNOSIS: It depends on the clinical presentation of BD, but sarcoidosis, multiple sclerosis, Crohn's disease, Takayasu's arteritis, polychondritis or antiphospholipid syndrome need to be considered. MANAGEMENT: Treatment is symptomatic using steroids and immunomodulatory therapy. It is efficient depending on the rapidity of initiation, the compliance, and the duration of therapy. PROGNOSIS: The prognosis is severe due to the ocular, neurological and arterial involvement. PMID- 22497991 TI - Dopaminergic D2-like agonists produce yawning in the myelin mutant taiep and Sprague-Dawley rats. AB - Systemic administration of D2-like dopaminergic-receptor agonists increases yawning behavior. However, only a few studies have been done in animals with pathological conditions. The taiep rat is a myelin mutant with an initial hypomyelination followed by progressive demyelination, being the brainstem one of the most affected areas. In our experiments, we analyzed the effects of systemic administration of the D2-family agonists and antagonists on yawning behavior, and correlated them with the lipid myelin content in the brainstem and other areas in the central nervous system (CNS) in 8 month old male taiep and Sprague-Dawley rats. Subjects were maintained under standard conditions in Plexiglas cages with a 12:12 light-dark cycle, lights on at 0700 and free access to rodent pellets and tap water. Drugs were freshly prepared injected ip at 0800 and subjects were observed for 60 min. When antagonists were used it was administered 15 min before the agonist. Sprague-Dawley and taiep rats significantly increased their yawning frequency after systemic injection of (-)-quinpirole hydrochloride, R(+)-7 Hydroxy-2-(dipropylamino)tetralin hydrobromide (7-OH-DPAT) or trans-(+/-) 3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano [4,3-b]-1,4-oxazin-9-ol hydrochloride ((+/-)-PD 128,907). Among D2-like agonists used higher effects are obtained with (-)-quinpirole. The effects caused by (-)-quinpirole can be reduced by (-)-sulpiride; and yawning caused by 7-OH-DPAT was decreased by tiapride only in taiep rats. In Sprague-Dawley only (-)-sulpiride is able to decrease (-) quinpirole-caused yawning. In conclusion, dopaminergic D2-like agonists are still able to cause yawning despite the severe myelin loss in taiep rats. Similarly, patients with various CNS illnesses that affect myelin, such as stroke or multiple sclerosis, are able to yawn suggesting that trigger neurons are still able to command this innate behavior. PMID- 22497992 TI - Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets. AB - NK1 receptor antagonists have been shown to have a variety of physiological and potential therapeutic effects in animal models and in humans. The present studies demonstrate that Rolapitant (SCH 619734, (5S)-8(S)-[[1(R)-[3,5 bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4,5]decan-2 one) is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high affinity for the human NK1 receptor of 0.66 nM and high selectivity over the human NK2 and NK3 subtypes of >1000 fold, as well as preferential affinity for human, guinea pig, gerbil and monkey NK1 receptors over rat, mouse and rabbit. Rolapitant is a functionally competitive antagonist, as measured by calcium efflux, with a calculated Kb of 0.17 nM. Rolapitant reversed NK1 agonist-induced foot tapping in gerbils following both intravenous and oral administration up to 24 hours at a minimal effective dose (MED) of 0.1 mg/kg. Rolapitant was active at 0.1 and 1 mg/kg in both acute and delayed emesis models in ferrets, respectively, consistent with clinical data for other NK1 antagonists. Clinical efficacy of anti-emetics is highly correlated with efficacy in the ferret emesis model, suggesting rolapitant is a viable clinical candidate for this indication. PMID- 22497993 TI - Toluene impairs learning and memory, has antinociceptive effects, and modifies histone acetylation in the dentate gyrus of adolescent and adult rats. AB - Toluene misuse usually initiates at an early age when the central nervous system is still immature, causing deleterious effects such as cognitive impairment. Epigenetic regulatory mechanisms have been proposed to explain long-term changes involved not only in memory, but also in toluene's actions. The aim of this study was to evaluate the effects of acute and chronic toluene exposure on learning, memory and histone acetylation in the rat hippocampus during two stages of life: adolescence and young adulthood. Because the memory tests used in this work involved object exploration and the perception of a noxious stimulus, general activity and nociception tests were also conducted. Acute and chronic toluene inhalation impaired learning, short-term and long-term memory in an object recognition test and in an inhibitory avoidance task in both groups of age. This effect was concentration-dependent and occurred even at low toluene concentrations (1000, 2000 ppm) that were otherwise non-effective. Acute toluene inhalation produced antinociception, and tolerance to this effect developed after chronic exposure. Histone acetylation in the dentate gyrus showed differences depending on the histone, treatment and age: a single toluene exposure increased H4 acetylation in adolescents and young adult rats, whereas chronic exposure decreased H3 acetylation, but only in adults. In conclusion, this work provides evidence of toluene-induced impairment on learning, short- and long-term memory in adolescent and young adult rats, and shows that even a single toluene exposure can induce epigenetic modifications in the rat hippocampus. PMID- 22497994 TI - Increase in dopaminergic, but not serotoninergic, receptors in T-cells as a marker for schizophrenia severity. AB - Schizophrenia is characterized by a slow deteriorating mental illness. Although the pathophysiology mechanisms are not fully understood, different studies have suggested a role for the immune system in the pathogenesis of schizophrenia. To date, an altered expression or signaling of neurotransmitters receptors is observed in immune cells during psychiatric disorders. In the present study, we investigated the expression of different serotonin and dopamine receptors in T cells of schizophrenic and control patients. We used flow cytometry to determine the pattern of expression of dopamine (D2 and D4) and serotonine receptors (SR1A, SR1C, SR2A, SR2B), as well as serotonin transporter (ST), in T-cell subsets (CD4 and CD8). Expression of serotonin receptors and ST in T-cells of schizophrenic patients were not different from controls. However, the percentages of CD4+D4+ and CD8+D4+ were increased in schizophrenic patients as compared to controls. In addition, increased percentages of CD8+D2+ cells were also observed in schizophrenic patients, albeit this population revealed lower CD4+D2+ cells in comparison to controls. Interestingly, a relationship between clinical symptoms and immunological parameters was also observed. We showed that the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS) and the Abnormal Involuntary Movement Scale (AIMS) were positively related to CD8+D2+ cells, though AIMS was inversely related to CD4+D4+ cells. In conclusion, the alteration in the pattern of cell population and molecules expressed by them might serve as a promising biomarker for diagnosis of schizophrenia. PMID- 22497995 TI - Effectiveness of qPCR permutations, internal controls and dilution as means for minimizing the impact of inhibition while measuring Enterococcus in environmental waters. AB - AIMS: Draft criteria for the optional use of qPCR for recreational water quality monitoring have been published in the United States. One concern is that inhibition of the qPCR assay can lead to false-negative results and potentially inadequate public health protection. We evaluate the effectiveness of strategies for minimizing the impact of inhibition. METHODS AND RESULTS: Five qPCR method permutations for measuring Enterococcus were challenged with 133 potentially inhibitory fresh and marine water samples. Serial dilutions were conducted to assess Enterococcus target assay inhibition, to which inhibition identified using four internal controls (IC) was compared. The frequency and magnitude of inhibition varied considerably among qPCR methods, with the permutation using an environmental master mix performing substantially better. Fivefold dilution was also effective at reducing inhibition in most samples (>78%). ICs were variable and somewhat ineffective, with 54-85% agreement between ICs and serial dilution. CONCLUSIONS: The current IC methods appear to not accurately predict Enterococcus inhibition and should be used with caution; fivefold dilution and the use of reagents designed for environmental sample analysis (i.e. more robust qPCR chemistry) may be preferable. SIGNIFICANCE AND IMPACT OF THE STUDY: Suitable approaches for defining, detecting and reducing inhibition will improve implementation of qPCR for water monitoring. PMID- 22497996 TI - The N-terminal region of the human 5-HT2C receptor has as a cleavable signal peptide. AB - The 5-hydroxytryptamine 2C (5-HT(2C)) receptor has a single nucleotide polymorphism (SNP) site at amino acid position 23 in its N-terminal tail. The polymorphism involves conversion of a cysteine to serine. The site, designated C23S, is located within a 32 amino acid long predicted signal peptide. The aim of the present study was to investigate whether the 5-HT(2C) receptor indeed has a functional cleavable signal peptide. For this purpose, ten N-terminally modified 5-HT(2C) receptors were constructed. Modifications included addition of the influenza virus hemagglutinin signal peptide, addition of a FLAG epitope, truncation of the N-terminal tail, and combinations of these changes. The receptors were transiently expressed in COS-7 cells. The relative amounts of receptors expressed at the membranes were quantified by [(3)H]-mesulergine radioligand binding. In one of the receptor constructs the FLAG epitope was inserted just after the endogenous putative signal peptide. Immunostaining with the M1 antibody, which recognizes the FLAG epitope only as free N-terminal entity, was used to detect whether the putative signal peptide preceding the FLAG epitope was cleaved off. The results suggest the following conclusions. The predicted signal peptide in the N-terminal tail of the 5-HT(2C) receptor acts as a cleavable signal peptide. Cleaving of the signal peptide is important for translocation of the wild type receptor to the plasma membrane. The two amino acids differentially encoded by the C23S SNP are likely absent from the mature 5 HT(2C) receptor. PMID- 22497997 TI - (-)-Epigallocatechin-3-gallate, a green tea-derived catechin, synergizes with celecoxib to inhibit IL-1-induced tumorigenic mediators by human pancreatic adenocarcinoma cells Colo357. AB - Despite their toxic side effects prostaglandin H(2) synthase-2 (PGHS-2) inhibitors hold promise for cancer chemoprevention. In order to overcome adverse effects lower doses of PGHS-2 inhibitors could be applied in combination with other agents exhibiting complementary effects. Herein, the effects of the PGHS-2 specific inhibitor celecoxib either alone or in combination with the green tea derived catechin (-)-epigallocatechin-3-gallate (EGCG) were studied on the expression of interleukin (IL)-1-induced tumorigenic factors in Colo357 human pancreatic adenocarcinoma cells. This approach mimics tumor-associated pancreatic inflammation which is considered as a key player in pancreatic malignancy. We found that co-incubation of Colo357 with celecoxib and EGCG synergistically diminished metabolic activity via apoptosis induction and down-regulated release of pro-angiogenic vascular endothelial growth factor (VEGF) and invasiveness promoting matrix metalloproteinase (MMP)-2 to a maximum of 30%. Celecoxib and EGCG synergistically reduced IL-1-induced production of pro-inflammatory IL-6 and pro-angiogenic IL-8 to 23-50%. Celecoxib dose-dependently increased PGHS-2 levels. Whereas EGCG was able to compensate for celecoxib-mediated increase of PGHS-2, it failed to potentiate celecoxib-mediated suppression of prostaglandin E(2) (PGE(2)) release. Thus, in Colo357, EGCG synergistically boosts celecoxib mediated effects and reduces the levels of celecoxib required to elicit beneficial effects on tumorigenic mediators by a factor of ten. PMID- 22497998 TI - Spermidine decreases Na+,K+-ATPase activity through NMDA receptor and protein kinase G activation in the hippocampus of rats. AB - Spermidine is an endogenous polyamine with a polycationic structure present in the central nervous system of mammals. Spermidine regulates biological processes, such as Ca(2+) influx by glutamatergic N-methyl-d-aspartate receptor (NMDA receptor), which has been associated with nitric oxide synthase (NOS) and cGMP/PKG pathway activation and a decrease of Na(+),K(+)-ATPase activity in rats' cerebral cortex synaptosomes. Na(+),K(+)-ATPase establishes Na(+) and K(+) gradients across membranes of excitable cells and by this means maintains membrane potential and controls intracellular pH and volume. However, it has not been defined whether spermidine modulates Na(+),K(+)-ATPase activity in the hippocampus. In this study we investigated whether spermidine alters Na(+),K(+) ATPase activity in slices of hippocampus from rats, and possible underlying mechanisms. Hippocampal slices and homogenates were incubated with spermidine (0.05-10 MUM) for 30 min. Spermidine (0.5 and 1 MUM) decreased Na(+),K(+)-ATPase activity in slices, but not in homogenates. MK-801 (100 and 10 MUM), a non competitive antagonist of NMDA receptor, arcaine (0.5MUM), an antagonist of the polyamine binding site at the NMDA receptor, and L-NAME (100MUM), a NOS inhibitor, prevented the inhibitory effect of spermidine (0.5 MUM). ODQ (10 MUM), a guanylate cyclase inhibitor, and KT5823 (2 MUM), a protein kinase G inhibitor, also prevented the inhibitory effect of spermidine on Na(+),K(+)-ATPase activity. Spermidine (0.5 and 1.0 MUM) increased NO(2) plus NO(3) (NOx) levels in slices, and MK-801 (100 MUM) and arcaine (0.5 MUM) prevented the effect of spermidine (0.5 MUM) on the NOx content. These results suggest that spermidine-induced decrease of Na(+),K(+)-ATPase activity involves NMDA receptor/NOS/cGMP/PKG pathway. PMID- 22497999 TI - Helium-induced cardioprotection of healthy and hypertensive rat myocardium in vivo. AB - Helium protects healthy myocardium against ischemia/reperfusion injury by early and late preconditioning (EPC, LPC) and postconditioning (PostC). We investigated helium-induced PostC of the hypertensive heart and enhancement by addition of LPC and EPC. We also investigated involvement of signaling kinases glycogen synthase kinase 3 beta (GSK-3beta) and protein kinase C-epsilon (PKC-epsilon). To assess myocardial cell damage, we performed infarct size measurements in healthy Wistar Kyoto (WKY rats, n=8-9) and Spontaneous Hypertensive rats (SHR, n=8-9) subjected to 25 min ischemia and 120 min reperfusion. Rats inhaled 70% helium for 15 min after index ischemia (PostC), combined with 15 min helium 24h prior to index ischemia (LPC+PostC), a triple intervention with additional 3 short cycles of 5 min helium inhalation shortly before ischemia (EPC+LPC+PostC), or no further treatment. In WKY rats, PostC reduced infarct size from 46 +/- 2% (mean +/- S.E.M) in the control group to 29 +/- 2%. LPC+PostC or EPC+LPC+PostC reduced infarct sizes to a similar extent (30 +/- 3% and 32 +/- 2% respectively). In SHR, EPC+LPC+PostC reduced infarct size from 53 +/- 3% in control to 39 +/- 3%, while PostC or LPC+PostC alone were not protective; infarct size 48 +/- 4% and 44 +/- 4%, respectively. Neither PostC in WKY rats nor EPC+LPC+PostC in SHR was associated with an increase in phosphorylation of GSK-3beta and PKC-epsilon after 15 min of reperfusion. Concluding, a triple intervention of helium conditioning results in cardioprotection in SHR, whereas a single intervention does not. In WKY rats, the triple intervention does not further augment protection. Helium conditioning is not associated with a mechanism involving GSK-3beta and PKC epsilon. PMID- 22498000 TI - Resveratrol augments nitric oxide generation and causes store calcium release in chromaffin cells. AB - The cardiovascular protecting effect of the grape fruit trans-resveratrol has been explained among other factors, through augmentation of nitric oxide (NO) production in cardiovascular tissues. Another effect of low resveratrol concentration is the inhibition of single-vesicle quantal release of catecholamine from bovine adrenal chromaffin cells, that was recently suggested to be an additional factor contributing to its beneficial cardiovascular effects. We have investigated here the effects of a low concentration of trans-resveratrol (1 MUM) on Ca(2+) and NO signaling pathways in bovine chromaffin cells, in an attempt to understand the mechanism underlying its previously reported inhibitory effects on quantal secretion. In cells loaded with fura-2 acetoxymethyl ester (fura-2), we have found that 1 MUM resveratrol produces a transient elevation of the cytosolic Ca(2+) concentration ([Ca(2+)](c)). This Ca(2+) transient was drastically reduced when the Ca(2+) store was depleted by ryanodine and dantrolene; it was also inhibited by N(omega)-nitro-l-arginine methyl ester hydrochloride (L-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Furthermore, the Ca(2+) transient was mimicked by NO donor S-nitroso-N-acetyl penicillamine (SNAP). Resveratrol also enhanced the production of nitrites and NO, and L-NAME blocked both responses; in contrast, augmentation by SNAP of nitrites and NO was unaffected by ODQ and was only partially inhibited by L-NAME. On the basis of these results, we are proposing that resveratrol is mitigating the catecholamine surge occurring during stress, through its ability to elicit mild local [Ca(2+)](c) transients and enhanced NO production, that blocks the last steps of exocytosis. PMID- 22498001 TI - Effects of topiramate on diabetes mellitus induced by streptozotocin in rats. AB - Topiramate currently approved for marketing as antiepileptic drug also possesses anti-diabetic activity. The aim of this study was to determine the antidiabetic effect of topiramate in a rat model of diabetes mellitus. Diabetes was induced by a single injection of streptozotocin to fasted rats. Diabetic animals were divided into untreated; insulin treated; topiramate treated with 25, 50 and 100 mg/kg; and combined insulin plus topiramate treatment in the previous doses. All medications were given once daily started after the rise of blood glucose for three weeks. Control rats were divided into untreated; vehicle treated and rats given topiramate in the previous doses. Body weight, blood-glucose and insulin levels were measured. Histopathological examination, immunohistochemical and morphometric studies of islets of the pancreas were done. Topiramate 50 and 100mg/kg resulted in a significant decrease in the blood glucose and increase in the insulin levels as well as the number of islets and the count and mass of beta cells. Combined treatment to diabetic rats with insulin and topiramate induced a better response than either alone. Further experimental and clinical studies are needed to explore the different mechanisms of action of topiramate as antidiabetic both in insulin dependent and non-insulin-dependent diabetes mellitus. PMID- 22498003 TI - Ileostomy obstruction in the third trimester of pregnancy. PMID- 22498002 TI - In vivo participation of nitric oxide in hyperproliferative epidermal phenomena in mice. AB - A significant involvement of nitric oxide (NO) in the process of keratinocyte proliferation is reported with many divergences. To determine the involvement of NO in the hyperproliferative process of epidermis in vivo, non-selective inhibitor (N(G)-nitro-L-arginine-methyl ester.HCl: L-NAME) and selective inhibitors for inducible NO synthase (iNOS) and neuronal NO synthase (nNOS) (Aminoguanidine: AG and 7-Nitroindazole: 7-NI, respectively) and a NO-donor (Sodium nitroprusside: SNP) were topically applied twice a day in mice ear treated with multiple applications of croton oil. L-NAME and 7-NI treatments decreased and SNP increased ear edema formation. However, ear weight was reduced in groups that received L-NAME and 7-NI, while the AG and SNP groups presented an increment. The histological evaluation of epidermis thickness showed that all NOS inhibitors were able to prevent the increase in epidermis width caused by croton oil, while SNP contributed to enlargement. The same results were observed in the PCNA staining, where treatments with NOS inhibitors caused a reduction in the number of cells in the epidermis, while SNP caused an enhancement. 7-NI treatment reduced polymorphonuclear and mononuclear leukocytes migration when compared to the control group. The AG application increased the migration of polymorphonuclear and mononuclear cells, while the SNP enhanced only the polymorphonuclear cells. Therefore, in the skin NO produced by nNOS is involved in the control of keratinocyte hyperproliferation, with the contribution of iNOS. In the animal model of cutaneous chronic inflammation by croton oil, NO is involved in the exudation and leukocyte migration, with participation of all three enzymes. PMID- 22498004 TI - Bovine haptoglobin as an adipokine: serum concentrations and tissue expression in dairy cows receiving a conjugated linoleic acids supplement throughout lactation. AB - The present study aimed to characterize serum haptoglobin (Hp) concentrations throughout an entire lactation period in both primi- and multiparous cows and to compare them to the Hp mRNA expression in liver and - in view of Hp being potentially an adipokine - also in different subcutaneous (s.c.) and visceral fat depots. In addition, potential anti-inflammatory effects of long-term supplementation with conjugated linoleic acids (CLA) were evaluated by assessing Hp. Trial 1 comprised 33 cows and 16 Holstein heifers from day 21 ante partum until day 252 postpartum. The animals received 100 or 50 g/day CLA or a control fat supplement. Blood samples and biopsy (tail head fat and liver) samples were collected. Trial 2 included 25 Holstein heifers, 5 animals were slaughtered on the day of parturition, the remaining animals were allocated to either CLA (100 g/day, n=10) or control fat supplement (n=10) and slaughtered on days 42 and 105 postpartum, respectively. At slaughter, fat samples were collected from 3 different visceral depots, 3 s.c. depots and from liver tissue. Results indicated no effects of CLA on serum Hp and liver Hp mRNA for both trials and on Hp mRNA in biopsies from s.c. tail head fat. In omental and s.c. withers fat from trial 2, CLA reduced Hp mRNA on both day 42 and day 105. Hp mRNA was detectable in fat tissues from both trials with abundance values being significantly lower than in liver. The Hp mRNA abundance in the s.c. fat depots was generally higher than in the visceral depots. Haptoglobin mRNA abundance in the different tissues from trial 2 was correlated whereby all s.c. depots were interrelated. The evidence of Hp mRNA expression in adipose tissues and the presence of Hp-immune staining in histological fat sections confirm that Hp can be classified as a bovine adipokine. The lack of an evident relationship between circulating Hp concentrations and normal body fat portions in dairy cattle demonstrates that varying degrees of adiposity are not confounding factors when using Hp as inflammatory marker. The physiological changes in serum Hp concentration seem to be limited to parity and parturition. In view of the lack of effects of CLA on serum Hp concentrations, the observed reaction in two out of six different fat depots seems of marginal importance for the organisms as an entity. PMID- 22498005 TI - Novel solid self-emulsifying drug delivery system of coenzyme Q10 with improved photochemical and pharmacokinetic behaviors. AB - The present study was undertaken to develop a solid self-emulsifying drug delivery system of coenzyme Q(10) (CoQ(10)/s-SEDDS) with high photostability and oral bioavailability. The CoQ(10)/s-SEDDS was prepared by spray-drying an emulsion preconcentrate containing CoQ(10), medium-chain triglyceride, sucrose ester of fatty acid, and hydroxypropyl cellulose, and its physicochemical, photochemical, and pharmacokinetic properties were evaluated. The CoQ(10)/s-SEDDS powder with a diameter of ca. 15 MUm was obtained by spray-drying, in which the CoQ(10) was mostly amorphized. The CoQ(10)/s-SEDDS exhibited immediate self emulsification when introduced to aqueous media under gentle agitation, forming uniform fine droplets with a mean diameter of ca. 280 nm. There was marked generation of reactive oxygen species, in particular superoxide, from CoQ(10) exposed to simulated sunlight (250W/m(2)), suggesting potent photoreactivity. Nano-emulsified solution of CoQ(10) under light exposure underwent photodegradation with 22-fold higher degradation kinetics than crystalline CoQ(10), although the CoQ(10)/s-SEDDS was less photoreactive. After the oral administration of CoQ(10)/s-SEDDS (100 mg-CoQ(10)/kg) in rats, enhanced exposure of CoQ(10) was observed with increases in both C(max) and AUC of ca. 5-fold in comparison with those of orally administered crystalline CoQ(10). From the improved physicochemical and pharmacokinetic data, the s-SEDDS approach upon spray-drying might be a suitable dosage option for enhancing nutraceutical and pharmaceutical values of CoQ(10). PMID- 22498006 TI - Increased zymogen activity of thrombin-activatable fibrinolysis inhibitor prolongs clot lysis. AB - BACKGROUND AND OBJECTIVES: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a zymogen that can be activated by proteolytic cleavage into the active enzyme TAFIa. Hydrolysis of the C-terminal lysines on fibrin by TAFIa results in a down regulation of fibrinolysis. Recent studies demonstrated that the zymogen also exerts an intrinsic enzymatic activity. Our objective was to identify and characterize zymogen-stimulatory nanobodies. METHODS AND RESULTS: The screening of 24 nanobodies against TAFI revealed that two nanobodies (i.e. Vhh-TAFI-a51 and Vhh-TAFI-i103) were able to stimulate the zymogen activity 10- to 21-fold compared with the baseline zymogen activity of TAFI. The increase in catalytic efficiency can be attributed mainly to an increased catalytic rate, as no change in the K(M) -value was observed. The stability, the susceptibility towards PTCI and GEMSA and the kinetics of the stimulated zymogen activity differ significantly from those of TAFIa activity. Epitope mapping revealed that both Asp(75) and Thr(301) are major determinants in the binding of these nanobodies to TAFI. Localization of the epitope strongly suggests that this instability is as a result of a disruption of the stabilizing interactions between the activation peptide and the dynamic flap region (residues 296-350). In TAFI-depleted plasma reconstituted with a non-activatable variant of TAFI (TAFI-R92A), clot lysis could be prolonged by nanobody-induced stimulation of its zymogen activity as well as by increasing its concentration. CONCLUSIONS: Increasing the zymogen activity of TAFI results in an antifibrinolytic effect. PMID- 22498008 TI - Laparoscopic management of pediatric renal and ureteric stones. AB - OBJECTIVE: To assess the feasibility of laparoscopy in the treatment of pediatric urolithiasis, we report our experience with the transperitoneal laparoscopic removal of stones. METHOD: Renal pelvic stones of size >=1 cm on ultrasound were included for laparoscopic pyelolithotomy while smaller stones were managed with shock-wave lithotripsy monotherapy. Intrarenal stones, calyceal stones, complete staghorn stones, multiple stones and kidneys with intrarenal pelvis were excluded. Ureteric stones included for laparoscopic ureterolithotomy were of size >=1 cm in the upper, mid or lower ureter, and smaller stones not responding to non-operative treatment. RESULTS: A total of 22 procedures were performed: 12 pyelolithotomies, and 8 lower and 2 upper ureterolithotomies. Complete removal of calculi was accomplished in 21 (95.45%) procedures. Complications associated with laparoscopic lithotomy included urinoma (4.54%), failure (4.54%) and omental prolapse (4.54%). CONCLUSION: Laparoscopic lithotomy is safe and feasible in pediatric urolithiasis with pyelic and ureteric stones, with minimal complications and failure rate. PMID- 22498007 TI - Carbonic anhydrase IX promotes tumor growth and necrosis in vivo and inhibition enhances anti-VEGF therapy. AB - PURPOSE: Bevacizumab, an anti-VEGFA antibody, inhibits the developing vasculature of tumors, but resistance is common. Antiangiogenic therapy induces hypoxia and we observed increased expression of hypoxia-regulated genes, including carbonic anhydrase IX (CAIX), in response to bevacizumab treatment in xenografts. CAIX expression correlates with poor prognosis in most tumor types and with worse outcome in bevacizumab-treated patients with metastatic colorectal cancer, malignant astrocytoma, and recurrent malignant glioma. EXPERIMENTAL DESIGN: We knocked down CAIX expression by short hairpin RNA in a colon cancer (HT29) and a glioblastoma (U87) cell line which have high hypoxic induction of CAIX and overexpressed CAIX in HCT116 cells which has low CAIX. We investigated the effect on growth rate in three-dimensional (3D) culture and in vivo, and examined the effect of CAIX knockdown in combination with bevacizumab. RESULTS: CAIX expression was associated with increased growth rate in spheroids and in vivo. Surprisingly, CAIX expression was associated with increased necrosis and apoptosis in vivo and in vitro. We found that acidity inhibits CAIX activity over the pH range found in tumors (pK = 6.84), and this may be the mechanism whereby excess acid self-limits the build-up of extracellular acid. Expression of another hypoxia inducible CA isoform, CAXII, was upregulated in 3D but not two dimensional culture in response to CAIX knockdown. CAIX knockdown enhanced the effect of bevacizumab treatment, reducing tumor growth rate in vivo. CONCLUSION: This work provides evidence that inhibition of the hypoxic adaptation to antiangiogenic therapy enhances bevacizumab treatment and highlights the value of developing small molecules or antibodies which inhibit CAIX for combination therapy. PMID- 22498009 TI - Commentary to 'Long-term incidence of urinary tract infection after ureteral reimplantation for primary vesicoureteral reflux'. PMID- 22498010 TI - Longitudinal seroepidemiologic study of the 2009 pandemic influenza A (H1N1) infection among health care workers in a children's hospital. AB - BACKGROUND: To probe seroepidemiology of the 2009 pandemic influenza A (H1N1) among health care workers (HCWs) in a children's hospital. METHODS: From August 2009 to March 2010, serum samples were drawn from 150 HCWs in a children's hospital in Taipei before the 2009 influenza A (H1N1) pandemic, before H1N1 vaccination, and after the pandemic. HCWs who had come into direct contact with 2009 influenza A (H1N1) patients or their clinical respiratory samples during their daily work were designated as a high-risk group. Antibody levels were determined by hemagglutination inhibition (HAI) assay. A four-fold or greater increase in HAI titers between any successive paired sera was defined as seroconversion, and factors associated with seroconversion were analyzed. RESULTS: Among the 150 HCWs, 18 (12.0%) showed either virological or serological evidence of 2009 pandemic influenza A (H1N1) infection. Of the 90 unvaccinated HCWs, baseline and post-pandemic seroprotective rates were 5.6% and 20.0%. Seroconversion rates among unvaccinated HCWs were 14.4% (13/90), 22.5% (9/40), and 8.0% (4/50) for total, high-risk group, and low-risk group, respectively. Multivariate analysis revealed being in the high-risk group is an independent risk factor associated with seroconversion. CONCLUSION: The infection rate of 2009 pandemic influenza A (H1N1) in HCWs was moderate and not higher than that for the general population. The majority of unvaccinated HCWs remained susceptible. Direct contact of influenza patients and their respiratory samples increased the risk of infection. PMID- 22498011 TI - Design and optimization of self-nanoemulsifying drug delivery systems (SNEDDS) for enhanced dissolution of gemfibrozil. AB - Self-nanoemulsifying drug delivery systems of gemfibrozil were developed under Quality by Design approach for improvement of dissolution and oral absorption. Preliminary screening was performed to select proper components combination. Box Behnken experimental design was employed as statistical tool to optimize the formulation variables, X(1) (Cremophor((r)) EL), X(2) (Capmul((r)) MCM-C8), and X(3) (lemon essential oil). Systems were assessed for visual characteristics (emulsification efficacy), turbidity, droplet size, polydispersity index and drug release. Different pH media were also assayed for optimization. Following optimization, the values of formulation components (X(1), X(2), and X(3)) were 32.43%, 29.73% and 21.62%, respectively (16.22% of gemfibrozil). Transmission electron microscopy demonstrated spherical droplet morphology. SNEEDS release study was compared to commercial tablets. Optimized SNEDDS formulation of gemfibrozil showed a significant increase in dissolution rate compared to conventional tablets. Both formulations followed Weibull mathematical model release with a significant difference in t(d) parameter in favor of the SNEDDS. Equally amodelistic parameters were calculated being the dissolution efficiency significantly higher for SNEDDS, confirming that the developed SNEDDS formulation was superior to commercial formulation with respect to in vitro dissolution profile. This paper provides an overview of the SNEDDS of the gemfibrozil as a promising alternative to improve oral absorption. PMID- 22498012 TI - Categorical 12-step involvement and continuous abstinence at 2 years. AB - A longitudinal analysis of 12-step involvement was conducted among a U.S. sample of patients exiting treatment for substance dependence. Categorical involvement in a set of 12-step activities and summary scores of involvement from the Alcoholics Anonymous Affiliation Scale were examined in relation to continuous abstinence and aftercare (Oxford House or usual care) condition. Participants who were categorically involved in 12-step activities were significantly more likely to maintain continuous abstinence at 2 years compared with those who were less involved, predicting a greater likelihood of complete abstinence than summary scores of involvement. In addition, participants in the Oxford House condition were significantly more likely to remain continuously abstinent throughout the course of this randomized clinical trial. Findings suggest that categorical involvement in a set of 12-step activities and communal-living settings such as Oxford Houses are independent factors associated with continuous abstinence from both alcohol and illicit drugs among substance dependent persons. PMID- 22498013 TI - The role of transcription enhancer factors in cardiovascular biology. AB - The transcriptional enhancer factor (TEF) multigene family is primarily functional in muscle-specific genes through binding to MCAT elements that activate or repress transcription of many genes in response to physiological and pathological stimuli. Among the TEF family, TEF-1, RTEF-1, and DTEF-1 are critical regulators of cardiac and smooth muscle-specific genes during cardiovascular development and cardiac disorders including cardiac hypertrophy. Emerging evidence suggests that in addition to functioning as muscle-specific transcription factors, members of the TEF family may be key mediators of gene expression induced by hypoxia in endothelial cells by virtue of its multidomain organization, potential for post-translational modifications, and interactions with numerous transcription factors, which represent a cell-selective control mediator of nuclear signaling. We review the recent literature demonstrating the involvement of the TEF family of transcription factors in the regulation of differential gene expression in cardiovascular physiology and pathology. PMID- 22498014 TI - Hemostatic abnormalities and relationships to metabolic and hormonal status in polycystic ovarian syndrome. AB - Polycystic ovarian syndrome (PCOS), diagnosed based on hyperandrogenism, ovulatory dysfunction, and polycystic ovaries, is one of the most common disorders of reproductive-aged females. Etiology includes both genetic and environmental/lifestyle factors contributing to both insulin resistance and hyperandrogenism. Clinically, PCOS has reproductive, psychological, and metabolic features, the latter predisposing to cardiovascular disease (CVD). Hemostatic abnormalities have an association with and a demonstrated pathophysiological role in CVD in non-PCOS populations but have not been adequately explored in PCOS. This review focuses on the hemostatic system in PCOS, exploring also relationships to the metabolic and hormonal abnormalities of the syndrome, and aims to identify whether hemostatic abnormalities are present as potential contributors to increased cardiovascular risk. Ultimately, this area may reveal preventative and therapeutic opportunities, which could improve the cardiovascular health of women with PCOS. PMID- 22498015 TI - Genetic predictors for cardiovascular disease in hispanics. AB - A less favorable cardiovascular risk factor profile but paradoxically lower cardiovascular morbidity and mortality have been observed in Hispanics--a pattern often referred to as the Hispanic paradox. It has been proposed that the specific genetic susceptibility of this admixed population and gene-environment interactions may partly explain the paradox. During the past few years, there have been major advances in the identification of genetic risk factors using genome-wide association studies (GWAS) for cardiovascular disease, especially in Caucasians. However, no GWAS of cardiovascular disease have been reported in Hispanics. In the Costa Rican Heart Study, we reported both the consistency and disparity of genetic effects on risk of coronary heart disease (CHD) between Hispanics and other ethnic groups. We demonstrated that the improvement in the identified genetic markers on discrimination of CHD in Hispanics was modest. Future genetic research on Hispanics should consider the diversity in genetic structure, lifestyle, and socioeconomics among various subpopulations and comprehensively evaluate potential gene-environment interactions in relation to cardiovascular risk. PMID- 22498016 TI - Resistin and cardiovascular disease. AB - Resistin has been implicated in coronary atherosclerotic disease and congestive heart failure. Recent studies have extended its involvement in peripheral artery disease. Despite some controversial data, the mainstream clinical literature supports that resistin is associated with both coronary and peripheral artery diseases including ischemic stroke. In this review, the multiple roles of resistin as screening, diagnostic, and prognostic marker for cardiovascular disease are discussed. The independence of resistin in disease prediction and diagnosis appears complicated by its confounders, such as C-reactive protein. A clear-cut biomarker function of resistin in cardiovascular disease needs be clarified by additional large-scale, well-designed prospective studies. PMID- 22498019 TI - Severe hypertriglyceridaemia in patients treated with lipid-modifying agents. PMID- 22498018 TI - Humanizing thrombi in mice. AB - Antiplatelet therapies form the cornerstone of atherothrombosis prevention, reducing the morbidity and mortality associated with cardiovascular disease. Despite these benefits, there is still an unmet need for more effective and safer pharmacological agents. To expedite this process, biological platforms that better reflect the intravascular environment in humans will be required in order to shorten drug development time, enable better determination of dosing regimes, and aid in the design of clinical studies. This article focuses on a unique genetically modified animal model that predicts the in vivo response of antiplatelet agents in humans more accurately than is currently possible using conventional murine models of thrombosis. PMID- 22498017 TI - Protection of the heart against ischemia/reperfusion by silent information regulator 1. AB - Myocardial ischemia followed by ischemia/reperfusion (I/R) induces irreversible damage to cardiac muscle. Medical treatment that effectively prevents I/R injury would alleviate the consequent development of cardiac remodeling and failure. Mechanisms that extend life span often make organisms resistant to stress, and an accumulation of such mechanisms may prevent aging and susceptibility to age associated diseases. Sirtuins are a group of molecules involved in longevity and stress resistance. Stimulation of silent information regulator 1 (Sirt1), the mammalian ortholog of yeast Sir2 and a member of the sirtuin family, extends the life span of mice fed a high-fat diet and retards aging in the heart. Recent evidence suggests that stimulation of Sirt1 mimics ischemic preconditioning and protects the heart from I/R injury, suggesting an intriguing possibility of using longevity factors to treat cardiac disease. Here, we discuss the cardioprotective effects of Sirt1 and possible underlying mechanisms. PMID- 22498020 TI - [Impact of an asthma educational intervention programme on teachers]. AB - OBJECTIVE: Our objective was to measure the impact of an educational intervention program on teacher's knowledge about asthma and its management. MATERIAL AND METHOD: Before and after quasi-experimental study, with control group, of an educational intervention, which had as its aim to improve the teacher's knowledge of asthma and its management, was conducted in some schools of San Sebastian (Gipuzkoa), Spain. The Newcastle Asthma knowledge Questionnaire (NAKQ) was used as a measuring tool, and an adaptation of the asthma, sport and health program was used as an educational intervention. The Wilcoxon signed rank test was used to compare the total score of the questionnaire before and after the intervention, and the McNemar test was performed to compare the percentages of correct answers to each item. The Mann-Whitney U test was also performed to compare the baseline score and the score at three months between the intervention group and control group. The size of the effect and the standardised mean response were studied. RESULTS: A total of 138 teachers from 6 schools, which were chosen at random (study group), and 43 teachers in the control group participated in the study. In the study group, the mean score of the NAKQ before the educational intervention was 16.1+/-3.4 points, with a median of 16 (range 7 to 23). After the intervention the mean score increased to 22.3+/-4.1, with a median of 23 (range, 6 to 29). The mean difference in the overall score of the NAKQ was 7.0+/-4.2 points, with a median of 8 (range, -2 to17). Furthermore, the size of the effect was 2.0 (> 0.8) and the standardised mean response was 1.7. After 3 months of the intervention the mean score of the NAKQ was 21.4+/-3.0 points, with a median of 22 (range, 12 to 29) which was significantly higher than the score obtained before the intervention (P<.001) and slightly lower than the score obtained immediately after the intervention, assuming a size of the effect of 1.6 and a standardised mean response of 1.2. In the control group, the level of knowledge did not change modified and was lower than the level of the intervention group (P<.001). CONCLUSIONS: An educational intervention program conducted among teachers significantly increases their knowledge of asthma. Moreover, the increase reduces slightly but maintains its higher level for at least 3 months. In spite of the fact that some aspects of knowledge improved with the educational intervention, they were not optimal. PMID- 22498021 TI - Acceptability of narratives to promote colorectal cancer screening in an online community. AB - OBJECTIVE: To assess the acceptability of narratives to promote colorectal cancer (CRC) screening among members of an online weight loss community. METHOD: Members of online weight loss community completed an Internet survey in 2010. Multiple logistic regression models examined demographic and attitudinal correlates of interest in sharing and receiving CRC screening narratives. RESULTS: Participants (n=2386) were 92% female with mean (SD) age 58 (6) years; 68% were up-to-date with CRC screening. Among those who were up-to-date, 39% were interested in sharing their narratives with other members. African-Americans were more likely than other racial groups to be interested in sharing narratives (adjusted OR 2.02, 95% CI 1.14-3.57). Older, married members and those with greater CRC screening worries were less likely to be interested in sharing narratives. Among those not up-to-date, 63% were interested in receiving narratives from online community members, and those with higher perceived salience of CRC screening were more likely to be interested in receiving narratives (adjusted OR 1.86, 95% CI 1.31-2.65). CONCLUSIONS: Members of this online weight loss community expressed interest in sharing and receiving narratives for CRC screening promotion. Attitudes and demographic characteristics may predict successful recruitment of those who would share and receive narratives. PMID- 22498022 TI - A community-based randomized trial of a faith-placed intervention to reduce cervical cancer burden in Appalachia. AB - OBJECTIVE: Faith Moves Mountains assessed the effectiveness of a faith-placed lay health advisor (LHA) intervention to increase Papanicolaou (Pap) test use among middle-aged and older women in a region disproportionately affected by cervical cancer and low screening rates (regionally, only 68% screened in prior 3 years). METHOD: This community-based RCT was conducted in four Appalachian Kentucky counties (December 2005-June 2008). Women aged 40-64 and overdue for screening were recruited from churches and individually randomized to treatment (n=176) or wait-list control (n=169). The intervention provided LHA home visits and newsletters addressing barriers to screening. Self-reported Pap test receipt was the primary outcome. RESULTS: Intention-to-treat analyses revealed that treatment group participants (17.6% screened) had over twice the odds of wait-list controls (11.2% screened) of reporting Pap test receipt post-intervention, OR=2.56, 95% CI: 1.03-6.38, p=0.04. Independent of group, recently screened participants (last Pap >1 but <5 years ago) had significantly higher odds of obtaining screening during the study than rarely or never screened participants (last Pap >=5 years ago), OR=2.50, 95% CI: 1.48-4.25, p=0.001. CONCLUSIONS: The intervention was associated with increased cervical cancer screening. The faith-placed LHA addressing barriers comprises a novel approach to reducing cervical cancer disparities among Appalachian women. PMID- 22498023 TI - The effect of exposure to chlorfenvinphos on lipid metabolism and apoptotic and necrotic cells death in the brain of rats. AB - This study investigated the influence of chlorfenvinphos (0.3 mg/kg bw/24 h corresponding to 0.02 LD50; orally by gastric gavage for 14 and 28 days) on lipid metabolism, and apoptotic and necrotic cells death in the brain of rats as the possible mechanism of neurotoxic action of organophosphate (OP) pesticides at low exposure. Total cholesterol (TCh), triglycerides (TG), phospholipids (PL), and free fatty acids (FFA) were determined and apoptotic, necrotic, and living cells were quantified in the brain. Moreover, the serum and brain acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were assayed as biomarkers of neurotoxicity. The treatment with chlorfenvinphos increased (duration dependently) the concentrations of TCh and TG and the ratio of TCh/PL, and decreased PL concentration. The prevalence of apoptotic and necrotic cells increased and that of the living brain cells depressed (by 10%) already after 14 days of the exposure. The brain activities of AChE and BChE decreased by 12% and 15%, and by 18% and 25% after 14 and 28 days, respectively, whereas the serum activities of these enzymes were inhibited (by 24% and 18%, respectively) only after the longer treatment. The changes in lipid metabolism and distribution of the living, apoptotic, and necrotic brain cells correlated with AChE and BChE activities in the serum and brain. The results show that chlorfenvinphos may disturb lipid metabolism and induce apoptosis and necrosis in the brain even at the exposure not affecting the serum activities of cholinesterases, and causing only moderate inhibition of their brain activities. Based on the findings it can be concluded that low repeated exposure to OP pesticides may influence the nervous system through disrupting the lipid profile of the nervous tissue and decreasing the number of the nervous cells. PMID- 22498024 TI - Smoking cessation-specific parenting and parental smoking as precursors of adolescent smoking cognitions and quitting. AB - Relatively little is known about if and through which mechanisms parents influence adolescents' smoking cessation. The present study used Social Cognitive Theory as a theoretical framework to test whether parental smoking and smoking cessation-specific parenting (SCSP) predicted readiness to quit smoking and actual smoking cessation one year later. Both direct paths between parent factors and outcomes, and indirect paths via adolescents' smoking-specific cognitions (pros of smoking and quitting, and self-efficacy) were examined in a sample of 530 adolescents in the ages of 13 to 18 who smoked daily and weekly at baseline. The main findings show that although parental smoking and SCSP were significantly associated with cognitions (cross-sectionally), neither the parent factors nor cognitions predicted readiness to quit smoking or actual cessation one year later. Baseline SCSP did predict readiness to quit one year later. Parents may be more influential in shaping adolescents' beliefs and readiness to quit than in facilitating actual cessation. PMID- 22498025 TI - Do angry women choose alcohol? AB - Women's alcohol treatment usually includes anger management, predicated on the hypothesis that anger increases their drinking. Studies show strong association between anger and drinking but to date there is no laboratory support for this hypothesis. We examined effects of a "female-specific" anger provocation on young adult women's drinking behavior by randomly assigning 30 women (age 21-30) to one of two conditions: Provocation (n=15) or Non-Provocation (n=15). In the Provocation condition, a female confederate was both annoying and condescending to the participant for 8min. A manipulation check showed heightened anger and hostility (but not anxiety or depression) in the Provocation participants. In a subsequent taste-task, all participants could drink placebo "beer" and ginger ale. When the data analysis controlled for participants' baseline negative emotions, Provocation participants consumed more "beer" (M=172.33ml, SD=78.90) than did Non-Provocation participants (M=118.60ml, SD=75.74) (p<.04), with no differences in ginger ale consumption. Results support a causal relationship between young women's anger and their specific choice to drink alcohol. PMID- 22498026 TI - The inhibitory effect of alendronate-hydroxyapatite composite coating on wear debris-induced peri-implant high bone turnover. AB - BACKGROUND: Bisphosphonate (BP) has been confirmed as the most potent drug for enhancing implant stability. There have been few studies focused on BP hydroxyapatite (HA) composite coatings, and the mechanisms through which BPs inhibit wear debris-induced high bone turnover have not been comprehensively discussed. MATERIALS AND METHODS: Thirty rabbits were divided into three groups. HA-coated implants were inserted into the proximal region of the medullary cavity of the left tibia. In groups II and III, particles were injected around the implant and into the knee joint during implantation. Low-dose alendronate (ALN) was combined with the HA coating in group III. The efficacy of the composite coating was evaluated using several parameters, including the intra-articular pressure, histology of the synovial membranes and bone-implant interfaces, bone histomorphometry and mineralization, implant stability, osteolysis-related cytokine levels, and the duration of ALN release in vitro. RESULTS: The results indicate that the ALN-HA composite coating reduces peri-implant high bone turnover; improves bone-implant integration, bone quality, and implant stability; and inhibits particle migration. In vitro results suggest that the ALN-HA composite coating can afford long release duration. CONCLUSIONS: This study may help us further realize the mechanisms through which BPs enhance bone-implant integration in a state of peri-implant high bone turnover. BP-HA composite coatings are promising materials, particularly in revision surgeries. PMID- 22498027 TI - Expression of intestinal myeloid differentiation primary response protein 88 (Myd88) following experimental traumatic brain injury in a mouse model. AB - BACKGROUND: Traumatic brain injury (TBI) can cause gastrointestinal dysfunction and increase intestinal permeability. Nuclear factor kappa B (NF-kappaB) has been shown to be associated with these intestinal events, but it is not well known how NF-kappaB is activated in the intestine after TBI. Based on previous studies, we hypothesize that myeloid differentiation primary response protein 88 (Myd88) may have an important role in NF-kappaB activation in the intestine, which mediates the inflammation and ultimately results in acute intestinal mucosal injury. METHODS: We randomly divided adult male C57BL/6 mice into control groups and TBI groups at different time points. We induced a closed head injury model by weight drop (a 333-g metal rod dropping from a 2.5-cm height). We detected Myd88 protein level and NF-kappaB binding activity in ileum tissue by Western blot and electrophoretic mobility shift assay, respectively. Meanwhile, we detected the mRNA levels of Myd88, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and intercellular adhesion molecule-1 by real-time polymerase chain reaction. RESULTS: The Myd88 protein and mRNA levels, as well as NF-kappaB binding activity in the ileum tissue, significantly increased at 6 h after TBI, peaked at 3 d, and remained elevated by 5 d post-injury. The levels of TNF-alpha, IL-1beta, and intercellular adhesion molecule-1 also remarkably increased after TBI. There was a positive relationship between the expression of Myd88 and that of NF-kappaB, TNF-alpha, and IL-1beta. CONCLUSIONS: Traumatic brain injury induced a rapid and persistent up-regulation of Myd88, NF-kappaB, and proinflammatory cytokines in the intestine. This up-regulation which might have an important role in the pathogenesis of acute intestinal mucosal injury. PMID- 22498028 TI - Ipsilateral nodal recurrence after axillary dissection for breast cancer. AB - INTRODUCTION: Level I/II axillary lymph node dissection (ALND) is the standard operation for patients with node-positive breast cancer. The objective of this study was to assess the incidence of regional nodal recurrence (RNR) after ALND performed for definitive operative treatment for primary breast cancer. MATERIALS AND METHODS: A retrospective, Institutional Review Board-approved query of our single-institution National Comprehensive Cancer Network database was performed for patients undergoing ALND who developed subsequent RNR. All patients were treated from 1999 to 2009. A detailed chart review was performed and clinical, pathologic, treatment, and outcome data were collected. RESULTS: A total of 1614 patients had an ALND for initial staging; 14/1614 (0.9%) patients had RNR. Two other patients had contralateral breast/axillary recurrences and were excluded. The mean age at diagnosis for the sample group was 52.7 y (range 34-77); mean follow-up time was 47.1 mo (range 12.6-114.6). The median number of nodes for ALND was 16 (range 8-27). The median number of positive nodes was 2.5 (range 0 7). Nine (64.3%) cases were estrogen receptor/progesterone receptor negative. Twelve (85.7%) patients had axillary recurrences, and six of 12 (50.0%) had concurrent chest wall lesions. Twelve patients (85.7%) had distant metastases; nine of 12 (75.0%) died; two were lost to follow-up. Mean time from RNR to distant recurrence was 6.0 mo (range 0-29.3 mo). CONCLUSIONS: RNR after ALND is rare but a harbinger of poor outcome. This is apparent regardless of treatment used for initial disease or recurrence. Specifically, RNR after primary ALND is related to increased risk of mortality and distant metastatic disease. PMID- 22498029 TI - Potential mechanism of alendronate inhibition of osteophyte formation in the rat model of post-traumatic osteoarthritis: evaluation of elemental strontium as a molecular tracer of bone formation. AB - OBJECTIVE: To employ elemental Strontium as a tracer of bone turnover, in the presence (or absence) of the bisphosphonate drug Alendronate, in order to spatially map osteophytogenesis and other bone turnover in rats developing post traumatic secondary osteoarthritis (PTOA). METHODS: PTOA was induced in rats by medial meniscectomy surgery. We utilized in-vivo microfocal computed tomography (CT) to follow bony adaptations in groups for 8 weeks after surgery, either with or without alendronate treatment. Electron probe microanalysis (EPMA) was used to detect Strontium incorporation in mineralizing tissues. Histologic studies were conducted on the same samples using Safranin-O/fast green and Tetrachrome staining of decalcified sections to examine articular cartilage health and osteophyte formation at the sites of elemental Strontium deposition. RESULTS: EPMA revealed uniform incorporation of Strontium over actively remodeling trabecular surfaces in normal control rats. That pattern was significantly altered after meniscectomy surgery resulting in greater Strontium signal at the developing osteophyte margins. Alendronate treatment inhibited osteophyte development by 40% and 51% quantified by micro-CT volumetric measurements at 4 and 8 weeks after surgery, respectively. Osteophytes in the alendronate group were more cartilaginous in composition [i.e., lower bone mineral density (BMD)] compared to the untreated group. Histological analysis confirmed the osteophyte inhibitory effect of alendronate, and also verified reduced degeneration of the articular cartilage compared to untreated rats. CONCLUSION: Our study confirmed that alendronate administration will reduce osteophyte formation in a rat model of post-traumatic osteoarthritis, partially through the inhibition of secondary remodeling of osteophytes. Our study is the first to employ elemental Strontium as a tracer of bone turnover in the pathogenesis of osteoarthritis and to assess the efficacy of bisphosphonate antiresorptive drug interventions on osteophytogenesis. PMID- 22498030 TI - DNA methylation differences at growth related genes correlate with birth weight: a molecular signature linked to developmental origins of adult disease? AB - BACKGROUND: Infant birth weight is a complex quantitative trait associated with both neonatal and long-term health outcomes. Numerous studies have been published in which candidate genes (IGF1, IGF2, IGF2R, IGF binding proteins, PHLDA2 and PLAGL1) have been associated with birth weight, but these studies are difficult to reproduce in man and large cohort studies are needed due to the large inter individual variance in transcription levels. Also, very little of the trait variance is explained. We decided to identify additional candidates without regard for what is known about the genes. We hypothesize that DNA methylation differences between individuals can serve as markers of gene "expression potential" at growth related genes throughout development and that these differences may correlate with birth weight better than single time point measures of gene expression. METHODS: We performed DNA methylation and transcript profiling on cord blood and placenta from newborns. We then used novel computational approaches to identify genes correlated with birth weight. RESULTS: We identified 23 genes whose methylation levels explain 70-87% of the variance in birth weight. Six of these (ANGPT4, APOE, CDK2, GRB10, OSBPL5 and REG1B) are associated with growth phenotypes in human or mouse models. Gene expression profiling explained a much smaller fraction of variance in birth weight than did DNA methylation. We further show that two genes, the transcriptional repressor MSX1 and the growth factor receptor adaptor protein GRB10, are correlated with transcriptional control of at least seven genes reported to be involved in fetal or placental growth, suggesting that we have identified important networks in growth control. GRB10 methylation is also correlated with genes involved in reactive oxygen species signaling, stress signaling and oxygen sensing and more recent data implicate GRB10 in insulin signaling. CONCLUSIONS: Single time point measurements of gene expression may reflect many factors unrelated to birth weight, while inter-individual differences in DNA methylation may represent a "molecular fossil record" of differences in birth weight-related gene expression. Finding these "unexpected" pathways may tell us something about the long-term association between low birth weight and adult disease, as well as which genes may be susceptible to environmental effects. These findings increase our understanding of the molecular mechanisms involved in human development and disease progression. PMID- 22498032 TI - Using soybean trypsin inhibitor as an external loading control for Western blot analysis of tear proteins: application to corneal disease. PMID- 22498031 TI - Avian influenza in shorebirds: experimental infection of ruddy turnstones (Arenaria interpres) with avian influenza virus. AB - BACKGROUND: Low pathogenic avian influenza viruses (LPAIV) have been reported in shorebirds, especially at Delaware Bay, USA, during spring migration. However, data on patterns of virus excretion, minimal infectious doses, and clinical outcome are lacking. The ruddy turnstone (Arenaria interpres) is the shorebird species with the highest prevalence of influenza virus at Delaware Bay. OBJECTIVES: The primary objective of this study was to experimentally assess the patterns of influenza virus excretion, minimal infectious doses, and clinical outcome in ruddy turnstones. METHODS: We experimentally challenged ruddy turnstones using a common LPAIV shorebird isolate, an LPAIV waterfowl isolate, or a highly pathogenic H5N1 avian influenza virus. Cloacal and oral swabs and sera were analyzed from each bird. RESULTS: Most ruddy turnstones had pre-existing antibodies to avian influenza virus, and many were infected at the time of capture. The infectious doses for each challenge virus were similar (10(3.6) 10(4.16) EID(50)), regardless of exposure history. All infected birds excreted similar amounts of virus and showed no clinical signs of disease or mortality. Influenza A-specific antibodies remained detectable for at least 2 months after inoculation. CONCLUSIONS: These results provide a reference for interpretation of surveillance data, modeling, and predicting the risks of avian influenza transmission and movement in these important hosts. PMID- 22498033 TI - Prognostic clinical prediction rules to identify a low-risk pulmonary embolism: a systematic review and meta-analysis. AB - BACKGROUND: Prognostic assessment is important for the management of patients with a pulmonary embolism (PE). A number of clinical prediction rules (CPRs) have been proposed for stratifying PE mortality risk. The aim of this systematic review was to assess the performance of prognostic CPRs in identifying a low-risk PE. METHODS: MEDLINE and EMBASE databases were systematically searched until August 2011. Derivation and validation studies that assessed the performance of prognostic CPRs in predicting adverse events-risk in PE patients were included. Weighted mean proportion and 95% confidence intervals (CIs) of adverse events were then calculated and pooled using a fixed and a random-effects model. Statistical heterogeneity was evaluated through the use of I(2) statistics. RESULTS: Of 1125 references in the original search, 33 relevant articles were included. Nine CPRs were assessed in 37 cohorts, for a total of 35,518 patients. Pulmonary Embolism Severity Index and prognostic Geneva CPR were investigated in 22 and 6 cohorts, respectively. Eleven (29.7%) cohorts were of high quality. The median follow-up was 30 days. In low-risk PE patients, pooled short-term mortality (within 14 days or less) was 0.7% (95% CI 0.3-1.1%, random-effects model; I(2) = 49.6%), 30-day mortality was 1.7% (95% CI 1.1-2.3%, random-effects model; I(2) = 82.4%) and 90-day mortality was 2.2% (95% CI 1.2-3.4%, random effects model; I(2) = 59.8%). CONCLUSIONS: Prognostic CPRs efficiently identify PE patients at a low risk of mortality. Before implementing prognostic CPRs in the routine care of PE patients, well-designed management studies are warranted. PMID- 22498035 TI - The double mortality burden among adults in Addis Ababa, Ethiopia, 2006-2009. AB - INTRODUCTION: In Ethiopia, lack of reliable data on causes of death prevents full understanding of the double mortality burden of communicable and noncommunicable diseases. Our objective was to help bridge this research gap by analyzing surveillance data on causes of death in Addis Ababa. METHODS: Burial surveillance identified 58,010 deaths in Addis Ababa from 2006 through 2009, of which 49,309 were eligible for verbal autopsies, a method of interviewing caregivers of the deceased about the circumstances, signs, and symptoms preceding death. We randomly selected 10% from the eligible sample, of whom 91% were defined as adults (aged >= 15 y). Verbal autopsies were completed and causes of death were assigned for 3,709 adults. RESULTS: Overall, 51% (95% confidence interval [CI], 49.7%-52.9%) of deaths were attributed to noncommunicable diseases, 42% (95% CI, 40.6%-43.8%) to communicable diseases, and 6% (95% CI, 5.5%-7.0%) to injuries. Similar proportions of male and female deaths were caused by noncommunicable and communicable diseases. Adults aged 55 to 84 were more likely, and those aged 15 to 44 were less likely, to die from noncommunicable diseases compared with the age group 85 or older. Premature deaths (defined as earlier than age 65) from noncommunicable diseases were mainly due to certain cancers, type 1 and type 2 diabetes, hypertension, stroke, and genitourinary disease. CONCLUSION: Noncommunicable diseases are the leading cause of death among adults in Addis Ababa, where the health care system is still geared toward addressing communicable diseases. Health policy attention is needed to remedy this situation. This observed double mortality burden is unlikely to be unique to Addis Ababa and provides new insight into the epidemiological transition in urban Ethiopia. Nationwide studies should be conducted in Ethiopia to examine the pattern of epidemiological transition and the magnitude of double mortality burden. PMID- 22498034 TI - Testing the contributions of striatal dopamine loss to the genesis of parkinsonian signs. AB - The diverse and independently-varying signs of Parkinson's disease (PD) are often attributed to one simple mechanism: degeneration of the dopaminergic innervation of the posterolateral striatum. However, growing recognition of the dopamine (DA) loss and other pathology in extra-striatal brain regions has led to uncertainty whether loss of DA in the striatum is sufficient to cause parkinsonian signs. We tested this hypothesis by infusing cis-flupenthixol (cis-flu; a broad-spectrum D1/D2 receptor antagonist) into different regions of the macaque putamen (3 hemispheres of 2 monkeys) while the animal performed a visually-cued choice reaction time task in which visual cues indicated the arm to reach with and the peripheral target to contact to obtain food reward. Following reward delivery, the animal was required to self-initiate release of the peripheral target and return of the chosen hand to its home position (i.e., without the benefit of external sensory cues or immediate rewards). Infusions of cis-flu at 15 of 26 sites induced prolongations of reaction time (9 of 15 cases), movement duration (6 cases), and/or dwell time of the hand at the peripheral target (8 cases). Dwell times were affected more severely (+95%) than visually-triggered reaction times or movement durations (+25% and +15%, respectively). Specifically, the animal's hand often 'froze' at the peripheral target for up to 25-s, similar to the akinetic freezing episodes observed in PD patients. Across injections, slowing of self-initiation did not correlate in severity with prolongations of visually-triggered reaction time or movement duration, although the latter two were correlated with each other. Episodes of slowed self-initiation appeared primarily in the arm contralateral to the injected hemisphere and were not associated with increased muscle co-contraction or global alterations in behavioral state (i.e., inattention or reduced motivation), consistent with the idea that these episodes reflected a fundamental impairment of movement initiation. We found no evidence for an anatomic topography within the putamen for the effects elicited. We conclude that acute focal blockade of DA transmission in the putamen is sufficient to induce marked akinesia-like impairments. Furthermore, different classes of impairments can be induced independently, suggesting that specific parkinsonian signs have unique pathophysiologic substrates. PMID- 22498036 TI - Preventable hospitalizations for congestive heart failure: establishing a baseline to monitor trends and disparities. AB - INTRODUCTION: Preventable hospitalization for congestive heart failure (CHF) is believed to capture the failure of the outpatient health care system to properly manage and treat CHF. In anticipation of changes in the national health care system, we report baseline rates of these hospitalizations and describe trends by race over 15 years. METHODS: We used National Hospital Discharge Survey data from 1995 through 2009, which represent approximately 1% of hospitalizations in the United States each year. We calculated age-, sex-, and race-stratified rates and age- and sex-standardized rates for preventable CHF hospitalizations on the basis of the Agency for Healthcare Research and Quality's specifications, which use civilian population estimates from the US Census Bureau as the denominator for rates. RESULTS: Approximately three-fourths of the hospitalizations occurred among people aged 65 years or older. In each subgroup and period, rates were significantly higher (P < .05) for blacks than whites. Only black men aged 18 to 44 showed a linear increase (P = .004) in crude rates across time. Subpopulations aged 65 or older, except black men, showed a linear decrease (P < .05) in crude rates over time. Age- and sex-standardized rates showed a significant linear decrease in rates for whites (P = .01) and a borderline decrease for blacks (P = .06) CONCLUSION: Before implementation of the Patient Protection and Affordable Care Act, we found that blacks were disproportionately affected by preventable CHF hospitalizations compared with whites. Our results confirm recent findings that preventable CHF hospitalization rates are declining in whites more than blacks. Alarmingly, rates for younger black men are on the rise. PMID- 22498037 TI - Binge drinking intensity and health-related quality of life among US adult binge drinkers. AB - INTRODUCTION: Binge drinking (men, >= 5 drinks, women, >= 4 on an occasion) accounts for more than half of the 79,000 annual deaths due to excessive alcohol use in the United States. The frequency of binge drinking is associated with poor health-related quality of life (HRQOL), but the association between binge drinking intensity and HRQOL is unknown. Our objective was to examine this association. METHODS: We used 2008-2010 Behavioral Risk Factor Surveillance System data and multivariate linear regression models to examine the association between binge drinking intensity (largest number of drinks consumed on any occasion) among US adult binge drinkers and 2 HRQOL indicators: number of physically and mentally unhealthy days. RESULTS: Among binge drinkers, the highest-intensity binge drinkers (women consuming >= 7 drinks and men consuming >= 8 drinks on any occasion) were more likely to report poor HRQOL than binge drinkers who reported lower levels of intensity (women who consumed 4 drinks and men who consumed 5 drinks on any occasion). On average, female binge drinkers reported more physically and mentally unhealthy days (2.8 d and 5.1 d, respectively) than male binge drinkers (2.5 d and 3.6 d, respectively). After adjustment for confounding factors, women who consumed >= 7 drinks on any occasion reported more mentally unhealthy days (6.3 d) than women who consumed 4 drinks (4.6 d). Compared with male binge drinkers across the age groups, female binge drinkers had a significantly higher mean number of mentally unhealthy days. CONCLUSION: Our findings underscore the importance of implementing effective population-level strategies to prevent binge drinking and improve HRQOL. PMID- 22498038 TI - Genotoxicity of the cancer chemopreventive drug candidates CP-31398, SHetA2, and phospho-ibuprofen. AB - The genotoxic activities of three cancer chemopreventive drug candidates, CP 31398 (a cell permeable styrylquinazoline p53 modulator), SHetA2 (a flexible heteroarotinoid), and phospho-ibuprofen (PI, a derivative of ibuprofen) were tested. None of the compounds were mutagenic in the Salmonella/Escherichia coli/microsome plate incorporation test. CP-31398 and SHetA2 did not induce chromosomal aberrations (CA) in Chinese hamster ovary (CHO) cells, either in the presence or absence of rat hepatic S9 (S9). PI induced CA in CHO cells, but only in the presence of S9. PI, its parent compound ibuprofen, and its moiety diethoxyphosphoryloxybutyl alcohol (DEPBA) were tested for CA and micronuclei (MN) in CHO cells in the presence of S9. PI induced CA as well as MN, both kinetochore-positive (Kin+) and -negative (Kin-), in the presence of S9 at <=100MUg/ml. Ibuprofen was negative for CA, positive for MN with Kin+ at 250MUg/ml, and positive for MN with Kin- at 125 and 250MUg/ml. DEPBA induced neither CA nor MN at <=5000MUg/ml. The induction of chromosomal damage in PI treated CHO cells in the presence of S9 may be due to its metabolites. None of the compounds were genotoxic, in the presence or absence of S9, in the GADD45alpha-GFP Human GreenScreen assay and none induced MN in mouse bone marrow erythrocytes. PMID- 22498040 TI - Implementing microbicides in low-income countries. AB - The magnitude of the global human immunodeficiency virus (HIV) epidemic is determined by women from lower income countries, specifically sub-Saharan Africa. Microbicides offer women who are unable to negotiate safe sex practices a self initiated HIV prevention method. Of note, is its potential to yield significant public health benefits even with relatively conservative efficacy, coverage and user adherence estimates, making microbicides an effective intervention to invest scarce healthcare resources. Existing healthcare delivery systems provide an excellent opportunity to identify women at highest risk for infection and to also provide an access point to initiate microbicide use. Innovative quality improvement approaches, which strengthen existing sexual reproductive health services and include HIV testing, and linkages to care and treatment services, provide an opportunity to lay the foundations for wide-scale provision of microbicides. The potential to enhance health outcomes in women and infants and potentially affect rates of new HIV infection may soon be realised. PMID- 22498042 TI - Di-arginine signals and the K-rich domain retain the Ca2+ sensor STIM1 in the endoplasmic reticulum. AB - STIM1 is a core component of the store-operated Ca2+-entry channel involved in Ca2+-signaling with an important role in the activation of immune cells and many other cell types. In response to cell activation, STIM1 protein senses low Ca2+ concentration in the lumen of the endoplasmic reticulum (ER) and activates the channel protein Orai1 in the plasma membrane by direct physical contact. The related protein STIM2 functions similar but its physiological role is less well defined. We found that STIM2, but not STIM1, contains a di-lysine ER-retention signal. This restricts the function of STIM2 as Ca2+ sensor to the ER while STIM1 can reach the plasma membrane. The intracellular distribution of STIM1 is regulated in a cell-cycle-dependent manner with cell surface expression of STIM1 during mitosis. Efficient retention of STIM1 in the ER during interphase depends on its lysine-rich domain and a di-arginine ER retention signal. Store-operated Ca2+-entry enhanced ER retention, suggesting that trafficking of STIM1 is regulated and this regulation contributes to STIM1s role as multifunctional component in Ca2+-signaling. PMID- 22498043 TI - Change in frequency of periodic limb movements during sleep with usage of continuous positive airway pressure in obstructive sleep apnea syndrome. AB - Periodic limb movements during sleep (PLMS) sometimes newly appear on the night of continuous positive airway pressure (CPAP) titration in patients with obstructive sleep apnea syndrome (OSAS). To ascertain the incidence and causative factors of this phenomenon, we investigated differences in its prevalence and the factors associated with newly appeared and persistent PLMS on CPAP titration night. We retrospectively analyzed polysomnographic data of 997 consecutive OSAS outpatients who had undergone overnight CPAP titration. On the basis of changes in periodic limb movements index (PLMI) values (cut off level>=15/h) from baseline polysomnography (BPSG) to CPAP titration PSG, patients were assigned to one of four groups: persistent, CPAP-emergent, CPAP-disappeared, and non-PLMS. The rate of patients was 6.7% in the persistent group, 8.0% in the CPAP-emergent group, 4.0% in the CPAP-disappearance group, and 81.2% in the non-PLMS group. Multivariate logistic regression analysis revealed that a higher apnea-hypopnea index (AHI) on BPSG and >=47years of age appeared to be associated with the CPAP emergent group. The results suggest that elderly patients with higher AHI at BPSG may present with CPAP-emergent PLMS. PMID- 22498044 TI - Anatomic guidelines for harvesting a quadriceps free tendon autograft for anterior cruciate ligament reconstruction. AB - PURPOSE: The purpose of this study was to review the anatomy of the quadriceps tendon and provide guidelines for harvesting the quadriceps tendon for anterior cruciate ligament (ACL) reconstruction. METHODS: Eleven cadaveric knees were dissected, and the quadriceps tendon was analyzed. Multiple measurements of length, depth, and width were taken in a standardized manner for each cadaver and recorded. RESULTS: The quadriceps tendon superficial morphology showed 2 distinct peaks, with the maximum length correlating with the lateral peak. The mean tendon peak length was 88.3 +/- 8.4 mm (range, 78.3 to 99.7 mm). The mean width of the quadriceps tendon at its insertion onto the patella was 43.3 +/- 5.8 mm (range, 34.3 to 54.1 mm). The quadriceps tendon was noted to be asymmetric, with the maximum tendon length located at 61.6% +/- 4.1% of the width from the medial border of the quadriceps tendon insertion. This point was also the maximum tendon depth at insertion. CONCLUSIONS: Quadriceps free tendon graft harvesting should begin by locating the apex (maximum length) of the quadriceps tendon (61% of the distance from the patella's medial edge). The surgeon should then harvest a 10-mm wide graft centered about 2 mm medial to this point, using the depth of a No. 10 scalpel blade (7 mm) as a guide to thickness to harvest an optimal quadriceps free tendon graft for ACL reconstruction. CLINICAL RELEVANCE: This anatomic study identifies the site of harvest of a quadriceps free tendon autograft (without a patellar bone block) to maximize the length and bulk of the graft for its use in ACL reconstruction. PMID- 22498041 TI - Valid and reliable instruments for arm-hand assessment at ICF activity level in persons with hemiplegia: a systematic review. AB - BACKGROUND: Loss of arm-hand performance due to a hemiparesis as a result of stroke or cerebral palsy (CP), leads to large problems in daily life of these patients. Assessment of arm-hand performance is important in both clinical practice and research. To gain more insight in e.g. effectiveness of common therapies for different patient populations with similar clinical characteristics, consensus regarding the choice and use of outcome measures is paramount. To guide this choice, an overview of available instruments is necessary. The aim of this systematic review is to identify, evaluate and categorize instruments, reported to be valid and reliable, assessing arm-hand performance at the ICF activity level in patients with stroke or cerebral palsy. METHODS: A systematic literature search was performed to identify articles containing instruments assessing arm-hand skilled performance in patients with stroke or cerebral palsy. Instruments were identified and divided into the categories capacity, perceived performance and actual performance. A second search was performed to obtain information on their content and psychometrics. RESULTS: Regarding capacity, perceived performance and actual performance, 18, 9 and 3 instruments were included respectively. Only 3 of all included instruments were used and tested in both patient populations. The content of the instruments differed widely regarding the ICF levels measured, assessment of the amount of use versus the quality of use, the inclusion of unimanual and/or bimanual tasks and the inclusion of basic and/or extended tasks. CONCLUSIONS: Although many instruments assess capacity and perceived performance, a dearth exists of instruments assessing actual performance. In addition, instruments appropriate for more than one patient population are sparse. For actual performance, new instruments have to be developed, with specific focus on the usability in different patient populations and the assessment of quality of use as well as amount of use. Also, consensus about the choice and use of instruments within and across populations is needed. PMID- 22498045 TI - Are femoral nerve blocks effective for early postoperative pain management after hip arthroscopy? AB - PURPOSE: To evaluate the utility of femoral nerve blocks in postoperative pain control after hip arthroscopy. METHODS: Forty consecutive patients scheduled for hip arthroscopy were randomized into 2 groups for postoperative pain control. Half were to receive routine intravenous narcotics for pain scores of 7 or above in the postanesthesia care unit (PACU), and the other half were to receive a femoral nerve block in the PACU for the same pain scores. Data were compared with respect to patient sex, patient age, traction times, type of procedure, nausea, overall patient satisfaction with analgesia, and duration of time in the PACU. RESULTS: Thirty-six patients had initial pain scores of 7 of 10 or greater on a visual analog scale. Of these patients, 16 were randomized to receive postoperative morphine and 20 to receive a femoral nerve block. There were no significant differences between the 2 groups with respect to sex, age, traction times, or type of procedure performed. Patients who received morphine had a significantly longer time to discharge from the PACU (216 minutes) than the femoral nerve block group (177 minutes). The morphine group was also significantly more likely to report postoperative nausea (75%) than the femoral nerve block group (10%). Patients receiving femoral nerve blocks were significantly more likely to be satisfied with their postoperative pain control (90%) than those who had received morphine (25%). All of the patients receiving a femoral nerve block stated that they would undergo the block again if they needed another hip arthroscopy. CONCLUSIONS: On the basis of all criteria studied (quality of pain relief, length of stay in the PACU, side effects, and patient satisfaction), a femoral nerve block is an excellent alternative to routine narcotic pain medication in patients undergoing hip arthroscopy. LEVEL OF EVIDENCE: Level II, randomized controlled trial. PMID- 22498046 TI - A radioenzymatic assay to identify three groups of phospholipase A(2) in platelets. AB - Phospholipases A(2) (PLA(2)) are key enzymes in membrane metabolism. The release of fatty acids and lysophospholipids by PLA(2) activates several intra-cellular second messenger cascades that regulate a wide variety of physiological responses. The aim of the present study is to describe a radioenzymatic assay to determine the activity of three main PLA(2) subtypes in platelets, namely extracellular calcium-dependent PLA(2) (sPLA(2)) and intracellular calcium dependent (cPLA(2)) and calcium-independent PLA(2) (iPLA(2)). The differentiation of these distinct PLA(2) subtypes was based on the enzyme substrate preference (arachdonic acid or palmitoyl acid) and calcium concentration. Our results indicate that this new assay is feasible, precise and specific to measure the activity of the aforementioned subtypes of PLA(2). Therefore, this protocol can be used to investigate modifications of PLA(2) homeostasis in distinct biological models addressing the pathophysiology of many medical and neuropsychiatric disorders such as schizophrenia and Alzheimer's disease. PMID- 22498047 TI - Selective expression of a neuromodulatory cytokine (IL-2) in specific brainstem neurovegetative centers: a possible final common neuro-molecular pathway in dying patients. AB - Cytokines interact with neurotransmitters and modify neuronal and neuroimmune functions. Intense in situ neuronal IL-2 immunoreactivity was detected in vital human brainstem neuronal centers which are principally implicated in cardio respiratory control mechanisms. These observations were made in critically-ill aging adult as well as in young infant patients dying from various clinico pathological conditions. We suggested that this in situ cytokine over-expression might tip a delicate balance in molecular interactions in those vital neuro vegetative centers, causing disturbed homeostatic control of cardio-respiratory functions and impaired arousal responses; we further hypothesized that this IL-2 induced neuro-molecular disequilibrium in the brainstem microenvironment might thus be part of a final common pathway leading to death. PMID- 22498048 TI - Inner mitochondrial maxi-K+ channels in neonatal renal tubular cells: novel therapeutic targets to control apoptosis. AB - In developing kidneys, the total cell population is partly regulated by apoptosis. Despite our understanding of the molecular involvement in the regulatory pathway of apoptosis, we know little about the physiological involvement. Cardiomyocytes express large conductance voltage- and Ca(2+) activated K(+) (maxi-K(+)) channels in their inner mitochondrial membranes. Triggering the mitochondrial K(+) influx necessary to inhibit apoptosis, the channels play cytoprotective roles during ischemic injury. Since proximal tubular cells in neonatal kidneys are physiologically under hypoxic stress, and since the channel activity is stimulated by hypoxia, those cells would share the same regulatory mechanism of apoptosis with ischemic cardiomyocytes. Therefore, we hypothesize here that the proximal tubular cells in neonatal kidneys would also express the maxi-K(+) channels in their inner mitochondrial membranes, and that the channels would play regulatory roles in apoptosis. Our hypothesis is unique because it sheds light for the first time on a physiological mechanism that involves the mitochondrial membranes in developing kidneys. It is also important because the idea could have novel therapeutic implications for kidney diseases that are associated with apoptosis. PMID- 22498049 TI - Histopathologic evaluation of the anterior segment of eyes enucleated due to glaucoma secondary to primary lens displacement in 13 canine globes. AB - PURPOSE To describe histologic anterior segment changes in eyes affected with primary lens displacement (PLD) and secondary glaucoma. METHODS Histologic sections stained with H&E from canine eyes enucleated because of PLD and secondary glaucoma were examined. RESULTS Thirteen eyes from 12 patients were evaluated. Four dogs were castrated males and eight spayed females. Median age was 8 years of age (range 3-13). Breeds included seven terriers and five other breeds. All eyes examined demonstrated varying degrees of inflammation involving the iris and cleft. Mononuclear and melanophagic infiltration of the cleft was found in all specimens. Four globes also showed polymorphonuclear infiltrate. Pre iridal fibrovascular membranes were clearly identified in 10 of 13 eyes. Total inflammatory score was significantly greater in all globes examined compared with an age-matched group of normal dogs. The posterior pigmented iris epithelium demonstrated a consistent pattern of hyperplasia and/or hypertrophy and cystic degeneration, more prominent in the more central regions. In some cases, hyperplasia was of greatest severity in the mid-iris and associated with thinning or flattening of the pupillary region. CONCLUSIONS These results suggest that lens instability may be associated with chronic inflammation and secondary glaucoma. Mechanical irritation from an unstable lens may result in hypertrophy and/or hyperplasia of the posterior pigmented iris epithelium and subsequent cellular exfoliation and release of melanin. An inflammatory reaction directly or indirectly related to melanin release may obstruct the outflow pathways ultimately leading to glaucoma and loss of vision. Use of topical steroids may be warranted in dogs with PLD. PMID- 22498050 TI - Alcohol ablation of the vein of Marshall: Is it the answer for mitral isthmus ablation? PMID- 22498051 TI - Riata externalized conductors: cosmetic defect or manifestation of a more serious design flaw? PMID- 22498052 TI - Increased reactions to pediatric influenza vaccination following concomitant pneumococcal vaccination. AB - BACKGROUND: Influenza in children causes significant morbidity and hospitalizations and also some mortality particularly in children < 5 years of age. Influenza vaccination in children has been shown to be safe and effective, but in 2010 the pediatric influenza vaccination program was suspended in Western Australia after the rate of febrile convulsions observed (9/1000 doses) was 55 times the previously reported rate. In 2009, over 80% of all children in New Brunswick were vaccinated with an adjuvanted monovalent H1N1 vaccine shown to have very high effectiveness, raising the prospect of potential hyper responsiveness because of residual protection. We conducted enhanced post marketing surveillance to monitor local and general reactions. METHODS: Parents of participating children seen at dedicated vaccination clinics were given influenza vaccine survey kits to record local and general symptoms up to 3 days following receipt of season influenza vaccine. RESULTS: Febrile reactions of >= 38 degrees occurred in <10% of children who received a first dose of seasonal influenza vaccine (n = 660) and severe febrile incidents with fever >= 39 degrees were uncommon. Concurrent administration of other vaccine(s) including conjugated pneumococcal vaccine appeared to increase reactogenicity. No child in the study had a febrile convulsion. CONCLUSION: Influenza vaccines in children are safe, and this study provides a baseline for rapid assessment studies at the start of a vaccine season. Parents should be aware of increased fevers with concurrent vaccine administration, and antipyretics should be considered. PMID- 22498054 TI - International Journal of Dental Hygiene. President's address. PMID- 22498075 TI - Interleukin-10 modulates [Ca2+]i response induced by repeated NMDA receptor activation with brief hypoxia through inhibition of InsP(3)-sensitive internal stores in hippocampal neurons. AB - The goal of this study was to evaluate an effect of interleukin-10 (IL-10) on the Ca(2+) response induced by repeated NMDA receptor activation with brief hypoxia in cultured hippocampal neurons. We focused on the importance of internal Ca(2+) stores in the modulation of this Ca(2+) response by IL-10. To test this, we compared roles of InsP(3)- and ryanodine-sensitive internal stores in the effects of IL-10. Measurements of intracellular cytosolic calcium concentration ([Ca(2+)](i)) in cultured hippocampal neurons were made by imaging Fura-2AM loaded hippocampal cells. Repeated episodes of NMDA receptor activation with brief hypoxia induced the spontaneous (s) [Ca(2+)](i) increases about 3 min after each hypoxic episode. The amplitude of the s[Ca(2+)](i) increases was progressively enhanced from the first hypoxic episode to the third one. IL-10 (1 ng/ml) abolished these s[Ca(2+)](i) increases. Exposure of cultured hippocampal neurons with thapsigargin (1 MUM) or an inhibitor of phospholipase C (U73122, 1 MUM) for 10 min also abolished the s[Ca(2+)](i) increases. On the other hand, antagonist of ryanodine receptors (ryanodine, 1 MUM) did not affect this Ca(2+) response. These studies appear to provide the first evidence that Ca(2+) release from internal stores is affected by anti-inflammatory cytokine IL-10 in brain neurons. It is suggested that these data increase our understanding of the neuroprotective mechanisms of IL-10 in the early phase of hypoxia. PMID- 22498053 TI - The SNARE complex in neuronal and sensory cells. AB - Transmitter release at synapses ensures faithful chemical coding of information that is transmitted in the sub-second time frame. The brain, the central unit of information processing, depends upon fast communication for decision making. Neuronal and neurosensory cells are equipped with the molecular machinery that responds reliably, and with high fidelity, to external stimuli. However, neuronal cells differ markedly from neurosensory cells in their signal transmission at synapses. The main difference rests in how the synaptic complex is organized, with active zones in neuronal cells and ribbon synapses in sensory cells (such as photoreceptors and hair cells). In exocytosis/neurosecretion, SNAREs (soluble N ethylmaleimide-sensitive fusion protein attachment protein receptors) and associated proteins play a critical role in vesicle docking, priming, fusion and synchronization of neurotransmitter release. Recent studies suggest differences between neuronal and sensory cells with respect to the molecular components of their synaptic complexes. In this review, we will cover current findings on neuronal and sensory-cell SNARE proteins and their modulators. We will also briefly discuss recent investigations on how deficits in the expression of SNARE proteins in humans impair function in brain and sense organs. PMID- 22498076 TI - Schizophrenia with preserved insight is associated with increased perfusion of the precuneus. AB - BACKGROUND: Preserved insight into illness has been suggested to be predictive of outcome in patients with schizophrenia. We aimed to investigate the functional substrate underlying preserved insight in these patients. METHODS: We recruited patients with paranoid schizophrenia and healthy controls matched for age and sex. Patients were grouped according to preserved or impaired insight into illness using the Scale to assess Unawareness of Mental Disorder (SUMD). Whole brain technetium-99m ethyl cysteinate dimer single photon emission computed tomography regional cerebral blood flow was compared at the voxel level between the 2 groups using a statistical parametric map (voxel-level significance of p < 0.001, uncorrected; cluster level significance of p < 0.05, uncorrected). RESULTS: We enrolled 31 right-handed patients with schizophrenia and 18 controls in our study. Twenty-one (67.7%) patients had preserved insight. The 2 groups did not differ significantly in demographic and clinical characteristics or in treatment. Compared with controls, the whole group of patients showed bilateral frontotemporal hypoperfusions, with no statistical difference between patients with preserved or impaired insight for these areas. Patients with preserved insight showed significantly increased perfusion of the bilateral precuneus relative to those with impaired insight. LIMITATIONS: Patients with subtypes other than paranoid schizophrenia have to be investigated to assess whether involvement of the precuneus in patients with preserved insight can be identified across the full spectrum of subtypes and symptoms of schizophrenia. Moreover, our study concerned only the central dimension (awareness of mental disorder) of 1 scale (SUMD); other dimensions of insight could be studied. CONCLUSION: Our results show that schizophrenia with preserved insight is associated with greater perfusion of the precuneus, a brain area known to be involved in self- consciousness, suggesting a compensatory mechanism of fronto-temporal impairment. PMID- 22498077 TI - Impaired interhemispheric connectivity in medication-naive patients with major depressive disorder. AB - BACKGROUND: Abnormalities in the anterior interhemispheric connections provided by the corpus callosum (CC) have long been implicated in major depressive disorder (MDD). The purpose of this study was to investigate interhemispheric connectivity in medication-naive patients with MDD by measuring fractional anisotropy in the CC with diffusion tensor imaging (DTI) techniques. METHODS: We obtained DTI scans from medication-naive patients with MDD and from matched healthy controls. Fractional anisotropy values were compared using semiautomatic region of interest methods to localize the regional CC differences between these 2 groups. RESULTS: We enrolled 27 patients and 27 controls in our study. Fractional anisotropy values were significantly lower in the anterior genu of the CC in the MDD group than in the control group (p = 0.009, corrected); results were not significantly different in any other CC subregions. LIMITATIONS: As patients with MDD were already experiencing acute episodes, future studies of individuals at risk for MDD are warranted to elucidate the interhemispheric connectivity abnormalities associated with the predisposition to MDD. CONCLUSION: The findings demonstrate abnormalities in the structural integrity of the anterior genu of the CC in medication-naive individuals with MDD, which may contribute to impairment of interhemispheric connectivity in patients with this disorder. PMID- 22498078 TI - Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis. AB - BACKGROUND: Smaller hippocampal volumes relative to controls are among the most replicated neuroimaging findings in individuals with unipolar but not bipolar depression. Preserved hippocampal volumes in most studies of participants with bipolar disorder may reflect potential neuroprotective effects of lithium (Li). METHODS: To investigate hippocampal volumes in patients with bipolar disorder while controlling for Li exposure, we performed a meta-analysis of neuroimaging studies that subdivided patients based on the presence or absence of current Li treatment. To achieve the best coverage of literature, we categorized studies based on whether all or a majority, or whether no or a minority of patients were treated with Li. Hippocampal volumes were compared by combining standardized differences between means (Cohen d) from individual studies using random-effects models. RESULTS: Overall, we analyzed data from 101 patients with bipolar disorder in the Li group, 245 patients in the non-Li group and 456 control participants from 16 studies. Both the left and right hippocampal volumes were significantly larger in the Li group than in controls (Cohen d = 0.53, 95% confidence interval [CI] 0.18 to 0.88; Cohen d = 0.51, 95% CI 0.21 to 0.81, respectively) or the non-Li group (Cohen d = 0.93, 95% CI 0.56 to 1.31; Cohen d = 1.07, 95% CI 0.70 to 1.45, respectively), which had smaller left and right hippocampal volumes than the control group (Cohen d = -0.36, 95% CI -0.55 to 0.17; Cohen d = -0.38, 95% CI -0.63 to -0.13, respectively). There was no evidence of publication bias. LIMITATIONS: Missing information about the illness burden or lifetime exposure to Li and polypharmacy in some studies may have contributed to statistical heterogeneity in some analyses. CONCLUSION: When exposure to Li was minimized, patients with bipolar disorder showed smaller hippocampal volumes than controls or Li-treated patients. Our findings provide indirect support for the negative effects of bipolar disorder on hippocampal volumes and are consistent with the putative neuroprotective effects of Li. The preserved hippocampal volumes among patients with bipolar disorder in most individual studies and all previous meta-analyses may have been related to the inclusion of Li-treated participants. PMID- 22498079 TI - Food motivation circuitry hypoactivation related to hedonic and nonhedonic aspects of hunger and satiety in women with active anorexia nervosa and weight restored women with anorexia nervosa. AB - BACKGROUND: Previous studies have provided evidence of food motivation circuitry dysfunction in individuals with anorexia nervosa. However, methodological limitations present challenges to the development of a cohesive neurobiological model of anorexia nervosa. Our goal was to investigate the neural circuitry of appetite dysregulation across states of hunger and satiety in active and weight restored phases of anorexia nervosa using robust methodology to advance our understanding of potential neural circuitry abnormalities related to hedonic and nonhedonic state and trait. METHODS: We scanned women with active anorexia nervosa, weight-restored women with anorexia nervosa and healthy-weight controls on a 3-T Siemens magnetic resonance scanner while they viewed images of high- and low-calorie foods and objects before (premeal) and after (postmeal) eating a 400 kcal meal. RESULTS: We enrolled 12 women with active disease, 10 weight-restored women with anorexia nervosa and 11 controls in our study. Compared with controls, both weight-restored women and those with active disease demonstrated hypoactivity premeal in the hypothalamus, amygdala and anterior insula in response to high-calorie foods (v. objects). Postmeal, hypoactivation in the anterior insula persisted in women with active disease. Percent signal change in the anterior insula was positively correlated with food stimuli ratings and hedonic and nonhedonic appetite ratings in controls, but not women with active disease. LIMITATIONS: Our findings are limited by a relatively small sample size, which prevented the use of an analysis of variance model and exploration of interaction effects, although our substantial effect sizes of between-group differences suggest adequate power for our statistical analysis approach. Participants taking psychotropic medications were included. CONCLUSION: Our data provide evidence of potential state and trait hypoactivations in food motivation regions involved in the assessment of food's reward value and integration of these with interoceptive signalling of one's internal state of well-being, with important relations between brain activity and homeostatic and hedonic aspects of appetite. Our findings give novel evidence of disruption in neurobiological circuits and stress the importance of examining both state and trait characteristics in the investigation of brain phenotypes in individuals with anorexia nervosa. PMID- 22498080 TI - Toxaphene affects the levels of mRNA transcripts that encode antioxidant enzymes in Hydra. AB - We evaluated toxaphene-induced acute toxicity in Hydra magnipapillata. The median lethal concentrations of the animals (LC(50)) were determined to be 34.5 mg/L, 25.0 mg/L and 12.0 mg/L after exposure to toxaphene for 24 h, 48 h and 72 h, respectively. Morphological responses of hydra polyps to a range of toxaphene concentrations suggested that toxaphene negatively affects the nervous system of H. magnipapillata. We used real-time quantitative PCR of RNA extracted from polyps exposed to two concentrations of toxaphene (0.3 mg/L and 3 mg/L) for 24 h to evaluate the differential regulation of levels of transcripts that encode six antioxidant enzymes (CAT, G6PD, GPx, GR, GST and SOD), two proteins involved in detoxification and molecular stress responses (CYP1A and UB), and two proteins involved in neurotransmission and nerve cell differentiation (AChE and Hym-355). Of the genes involved in antioxidant responses, the most striking changes were observed for transcripts that encode GPx, G6PD, SOD, CAT and GST, with no evident change in levels of transcripts encoding GR. Levels of UB and CYP1A transcripts increased in a dose-dependent manner following exposure to toxaphene. Given that toxaphene-induced neurotoxicity was not reflected in the level of AChE transcripts and only slight accumulation of Hym-355 transcript was observed only at the higher of the two doses of toxaphene tested, there remains a need to identify transcriptional biomarkers for toxaphene-mediated neurotoxicity in H. magnipapillata. Transcripts that respond to toxaphene exposure could be valuable biomarkers for stress levels in H. magnipapillata and may be useful for monitoring the pollution of aquatic environments. PMID- 22498081 TI - Long-term outcomes of patients bridged to recovery versus patients bridged to transplantation. AB - OBJECTIVE: The proportion of patients who can be bridged with left ventricular assist devices to myocardial recovery and the long-term outcome of these patients is unknown. METHODS: We investigated the outcomes of patients bridged to recovery compared with those bridged to transplantation. All left ventricular assist devices were implanted as a bridge to transplantation with a very proactive program of promoting myocardial recovery. A total of 40 patients were bridged to recovery and 52 to transplantation. Of the bridged to recovery (explanted) group, 33 were men (age, 32.8 +/- 11.8 years), 37 had dilated cardiomyopathy (familial in 3, peripartum cardiomyopathy in 3) and 3 had myocarditis. Of the bridged to transplantation (transplanted) group, 42 were men (age, 42.3 +/- 12.5 years; P < .0005 vs bridged to recovery). The diagnosis was ischemic heart disease in 24, dilated cardiomyopathy in 21 (only 13 received drug therapy), hypertrophic obstructive cardiomyopathy in 2, arrythmogenic right ventricular dysplasia in 2, myocarditis in 1, and congestive heart disease in 2. RESULTS: The survival rate was 89.9%, 73.9%, and 73.9% and 80.4%, 78.3, and 78.3% in the explanted and transplanted groups at 1, 5, and 7 years, respectively. In total, 12 (23%) patients bridged transplantation either died from, or required ventricular assist device support, for primary graft failure. Of the explanted patients, 4 (10%) subsequently required transplantation at 34, 512, 1019, and 1213 days (2 died 25 and 1867 days after transplantation and 2 were well after 1523 and 3199 days). The rate of transplant or ventricular assist device-free survival less noncardiac death for the bridged to recovery and bridged to transplantation groups, respectively, was 89.9%, 73.9%, and 73.9% and 80.4%, 78.3%, and 78.3% at 1, 3, and 7 years. At latest follow-up (1394 +/- 1195 days for the bridged to recovery and 1913 +/- 941 days for the bridged to transplantation group), 5 of the bridged to transplantation patients (9.6%) had malignancy, 34 (65.4%) had hypercholesterolemia, 25 (48.1%) had hypertension, and 7 (13.5%) had coronary disease. The creatinine was 125.5 +/- 43.5 vs 95.2 +/- 16.5 MUmol/L for the bridged to transplantation and bridged to recovery groups (P < .001). CONCLUSIONS: The outcome after explantation for myocardial recovery is comparable, if not better than, after bridge to transplantation. PMID- 22498082 TI - Causes and management of aortic valve regurgitation after aortic valve reimplantation. AB - OBJECTIVE: Recurrent aortic regurgitation can occur after valve-preserving aortic replacement. Little is known about the exact mechanisms of valve failure and the best reoperative strategies. We analyzed our experience with reoperation after aortic valve reimplantation. METHODS: From November 1995 to August 2011, 13 patients (10 men; age, 18-58 years) underwent reoperation for valve failure after aortic valve reimplantation. The reason for reoperation was aortic regurgitation in 11 and endocarditis in 2 after 6 weeks to 13 years. The morphologic causes of regurgitation were cusp prolapse in 6, cusp retraction in 4, cusp perforation in 6, inadequate commissural height in 5, commissural dehiscence in 2, and inadequate valve configuration in 1, alone or combined. The patients were treated by valve replacement (n = 4) or cusp repair (n = 2). In 3 patients, composite replacement of the valve and root was necessary, in 1 with a pulmonary autograft. In 4 patients the aortic valve was spared. All patients were followed up regularly. RESULTS: No patient died early; 1 patient died 4 years after reoperation. One patient required reoperation 2 years after the cusp repair procedure. All patients with repeat valve-preserving root replacement had stable valve function postoperatively. The 5-year survival rate after reoperation was 86% +/- 13%. The 5-year rate of freedom from valve-related complications was 78% +/- 14%. CONCLUSIONS: Recurrent aortic regurgitation early after aortic valve reimplantation frequently involves cusp prolapse and a low commissural height; later, cusp retraction becomes more important. Reoperation within the first 6 postoperative months allows for preservation of the native aortic valve; however, beyond this period, valve replacement within the graft will mostly be required. PMID- 22498084 TI - Clinical efficacy of intermittent pressure augmented-retrograde cerebral perfusion. AB - OBJECTIVE: During aortic surgery under hypothermic circulatory arrest, retrograde cerebral perfusion (RCP) is commonly used as a cerebroprotective method to extend the duration of circulatory arrest safely. Kitahori and colleagues described a novel protocol of RCP using intermittent pressure augmented (IPA)-RCP in 2005. The aim of the present study was to determine the clinical effectiveness of this novel protocol. METHODS: A total of 20 consecutive patients undergoing total replacement of the aortic arch were assigned to a conventional RCP (n = 10) or an IPA-RCP group (n = 10). Cerebral perfusion was provided at a continuous venous pressure of 25 mm Hg in the conventional RCP, and venous pressure was intermittently provided at 20 mm Hg for 120 seconds and at 45 mm Hg for 30 seconds in the IPA-RCP group. The clinical outcomes were compared between the 2 groups. Regional cerebral oxygen saturation (rSO(2)) was measured using near infrared spectroscopy every 10 minutes from the beginning of RCP initiation. To represent the brain oxygen consumption, the decline ratio of rSO(2) was calculated. RESULTS: There was no surgical mortality or major neurologic complications in either group. The interval from the end of surgery to full wakefulness was significantly shorter in the IPA-RCP group (85 +/- 64 minutes) than in the conventional RCP group (310 +/- 282 minutes; P < .05). Although the initial rSO(2) value did not show significant difference in both groups, the rSO(2) with IPA-RCP was greater than that with conventional RCP from 10 to 70 minutes (P < .05). The decline ratio of rSO(2) was lower in the IPA-RCP group than in the RCP perfusion group at all points (P < .05). CONCLUSIONS: IPA-RCP might provide more homogenous cerebral perfusion and a more effective oxygen supply to the brain with better clinical results than conventional RCP. PMID- 22498085 TI - Optimization of mediastinal staging in potential candidates for stereotactic radiosurgery of the chest. AB - OBJECTIVE: Patients with medically inoperable nonsmall-cell lung cancer generally have limited staging of the mediastinum using computed tomography and combined positron emission tomography and computed tomography, before stereotactic radiosurgery. Historical data have demonstrated the superiority of tissue sampling techniques such as endobronchial ultrasonography and mediastinoscopy compared with imaging studies in accurately determining the nodal stage. We believe, that at a minimum, mediastinal interrogation with endobronchial ultrasonography should be performed before patients undergo stereotactic radiosurgery. METHODS: A retrospective review of 59 consecutive patients undergoing bronchoscopic fiducial marker placement as potential candidates for stereotactic radiosurgery was done. All these patients had undergone endobronchial ultrasonography to assess the mediastinum. Transbronchial needle aspirates were taken using standard criteria defined by a lymph node size greater than 5 mm in diameter and/or in the appropriate lymph node drainage pathway. The biopsies were reviewed by the institution's pathologists. RESULTS: Mediastinal lymph node specimens were not taken in 9 patients because they did not meet our criteria. Of the 50 patients who underwent mediastinal lymph node sampling, 10 had evidence of nodal involvement. On review, 2 of these 10 patients had evidence of mediastinal adenopathy on computed tomography. After excluding those 2 patients, the mediastinal lymph nodes were positive for metastatic disease in 8 (16%) of 50 patients without previous radiographic evidence of disease. These patients were previously thought to be suitable candidates for stereotactic radiosurgery. Also 5 of 10 patients with endobronchial ultrasound-positive lymph nodes had had positron emission tomography-negative findings in the mediastinum. Finally, 10% of the patients suspected to have stage II or III were downstaged with endobronchial ultrasonography and considered for stereotactic radiosurgery. CONCLUSIONS: Endobronchial ultrasonography-transbronchial needle aspirates is more accurate than computed tomography and positron emission tomography in staging the mediastinum, can be performed with minimal morbidity, and should be considered for all patients considered candidates for stereotactic radiosurgery. PMID- 22498086 TI - Mortality in hypoplastic left heart syndrome: review of 216 autopsy cases of aortic atresia with attention to coronary artery disease. AB - OBJECTIVES: Aortic atresia (AA) in hypoplastic left heart syndrome (HLHS) has been associated with increased mortality in several prior studies. We reviewed our autopsy series to explore the relationship of coronary abnormalities to anatomic subsets of HLHS with AA. METHODS: We retrospectively reviewed all pathology specimens with AA/MS (mitral stenosis) and AA/MA (mitral atresia) in the Cardiac Registry of Children's Hospital Boston between 1955 and 2009 including autopsy reports, operative notes, and imaging studies. Formalin-fixed hearts were examined, and cases found to have macroscopic coronary artery abnormalities were sectioned at mid-left ventricular level in the transverse plane and at mid-right ventricular level in the longitudinal plane for histologic analysis of coronary arteries using tissue sections stained with hematoxylin and eosin. RESULTS: A total of 216 autopsy cases were identified with AA/MS (134) and AA/MA (82). Coronary anomalies were found in 49 cases, left ventricle-coronary fistula in 39, all in AA/MS, and 10 other coronary abnormalities, all in AA/MA. Histologic study confirmed fistulas only in the AA/MS group with no evidence of fistulas in the AA/MA group. CONCLUSIONS: The occurrence of left ventricle coronary fistulas appears limited to the AA/MS group, and coronary fistula specimens were disproportionately more prevalent in postoperative specimens. Further clinical studies are required to validate this finding and to identify subgroups that carry a higher mortality risk. PMID- 22498087 TI - Evolving surgical techniques for pulmonary endarterectomy according to the changing features of chronic thromboembolic pulmonary hypertension patients during 17-year single-center experience. AB - OBJECTIVE: An increasing number of elderly patients are referred for pulmonary endarterectomy. The distinction between operable and inoperable lesions has been challenged over time. Hence, we developed alternative cardiopulmonary bypass management and cerebral protection strategies to obtain satisfactory surgical results according to the changing patient features. METHODS: From April 1994 to March 2011, 347 pulmonary endarterectomies were performed at our center. We began with the technique championed by the San Diego Group, adopting a single period of deep hypothermic circulatory arrest for each side (group A). Since 2003, we began to perform short periods of intermittent deep hypothermic circulatory arrest followed by periods of reperfusion (group B). We then adopted moderate, instead of deep, hypothermia (group C). Finally, we modified our technique further performing shorter (5-7-minute) periods of circulatory arrest (group D). RESULTS: The hemodynamic results after surgery were excellent in all 4 groups. The patients' age increased significantly. A trend toward an increase in the number of Jamieson type 3 lesions was observed. Associated with our protocol changes, we observed better postoperative respiratory function, a reduction in the length of mechanical ventilation and postoperative infections, and a remarkable improvement in uneventful postoperative courses. Despite the increased total circulatory arrest time, a trend toward a reduction in the incidence of transient neurologic events was observed, and operative mortality was not affected. CONCLUSIONS: In our experience, our alternative strategy resulted in a better combination of surgical accuracy and cerebral protection and improved outcomes. PMID- 22498088 TI - Comprehensive surgical approach to treat atrial fibrillation in patients with variant pulmonary venous anatomy. AB - OBJECTIVES: Catheter radiofrequency ablation procedures yield fairly successful results for the treatment of atrial fibrillation; however, patients with anatomic variant pulmonary veins (PV) are generally thought not to benefit from catheter ablation technique, with recurrence rates observed as high as 78%. We report a comprehensive surgical approach to treat this subset of patients with a modified full maze procedure. METHODS: From January 2002 to December 2009, 72 patients undergoing cardiac surgery who had drug-refractory and/or recurrent AF after catheter ablation were identified. PV variance was observed on preoperative multislice chest computed tomography. All patients underwent multiple PV epicardial circumferential isolation and epicardial-endocardial longitudinal PV ablations along with standard maze as an adjunct to the cardiac surgical procedure. Patients were followed up at 6 months, 1 year, and 2 years postoperatively. RESULTS: Typical patterns of PV variation were observed in 72 patients. Left common PV trunk was found in 49 patients (68%), with a mean length of 21 +/- 4.6 mm, diameter of 28.6 +/- 4.9 mm, and wall thickness of 2.1 +/- 1.7 mm. Right PV variants, including right middle and right top PVs, were found in 23 patients (32%), with a length of 20 +/- 2.1 mm, diameter of 9.9 +/- 3.4 mm, and wall thickness of 1.9 +/- 1.7 mm. Overall restoration of sinus rhythm was confirmed in 64 patients (94%) at 1-year follow-up. Twelve patients were defibrillated into sinus rhythm within 90 days after the operation. CONCLUSIONS: A modified full maze procedure should be considered as a first choice treatment for atrial fibrillation with variant drainage of PVs because of the nature of PV size, wall thickness, and specific foci in the arrhythmogenic veins. Multiple PV isolation and epicardial-endocardial longitudinal PV ablations along with the standard maze are essential to success. Early referral for surgical ablation allows higher success rates. PMID- 22498089 TI - Reduction of sternal wound infections in diabetic patients undergoing off-pump coronary artery bypass surgery and using modified pedicle bilateral internal thoracic artery harvest technique. AB - OBJECTIVE: We compared sternal wound infections between diabetic patients undergoing off-pump coronary artery bypass surgery using bilateral internal thoracic artery grafting or single internal thoracic artery grafting and nondiabetic patients receiving bilateral internal thoracic artery or single internal thoracic artery grafting using a modified pedicled harvest technique of internal thoracic artery. METHODS: This retrospective study was conducted to analyze the data from 3072 patients who underwent primary coronary artery bypass surgery using an off-pump technique from August 2004 to October 2010. Of the 1211 diabetic patients, 181 received bilateral internal thoracic artery grafts (group 1) and 1030 received single internal thoracic artery grafts (group 2). Of the 1861 nondiabetic patients, 161 received bilateral internal thoracic artery grafts (group 3) and 1700 received single internal thoracic artery grafts (group 4). The incidence of postoperative sternal wound infections in diabetic patients who received bilateral internal thoracic artery grafting was compared with the incidence in other groups (group 2, 3, and 4). A modified technique of pedicled harvesting of the internal thoracic artery was done in patients receiving bilateral internal thoracic artery grafting, and a standard pedicled harvest was used in patients receiving single internal thoracic artery grafts. RESULTS: No significant differences were present in the preoperative variables among the groups. The observed rate of superficial sternal wound infections in groups 1, 2, 3, and 4 was 1.1% (2 patients), 1.65% (17 patients), 1.86% (3 patients), and 1.65% (28 patients), respectively (P=.9941). Deep sternal infections were observed in 1 (0.55%), 5 (0.48%), 1 (0.62%), and 14 patients (0.82%) in groups 1 through 4, respectively (P=.8380). Multivariate analysis showed that bilateral internal thoracic artery harvesting (P=.889), diabetes mellitus (P=.96), and patient age were not predictors of sternal wound infection. CONCLUSIONS: The results of the present study show that there is no increase in the incidence of sternal wound infections in diabetic patients undergoing coronary artery bypass surgery with bilateral internal thoracic artery grafting by using a modified pedicle bilateral internal thoracic artery harvesting technique with sparing of the communicating bifurcation of internal thoracic artery to the chest wall and preservation of pericardiacophrenic artery branch. PMID- 22498090 TI - Immunohistochemical studies of pulmonary large cell neuroendocrine carcinoma: a possible association between staining patterns with neuroendocrine markers and tumor response to chemotherapy. AB - OBJECTIVE: Pulmonary large cell neuroendocrine carcinoma is a rare high-grade malignant tumor. Because large cell neuroendocrine carcinoma is rare, the optimal treatment, including perioperative chemotherapy, has not been defined. We retrospectively analyzed the correlation among the effectiveness of perioperative chemotherapy in treating large cell neuroendocrine carcinoma, pathologic stage, and immunoreactivity to neuroendocrine markers. METHODS: A total of 63 patients with pulmonary large cell neuroendocrine carcinoma undergoing surgical resection from 2001 to 2009 were included. The resected tumors were immunohistochemically stained with the 3 neuroendocrine markers synaptophysin, chromogranin A, and neural cell adhesion molecule. We categorized patients who were positive for all 3 markers as the triple-positive group and those who were negative for 1 or 2 markers as the non-triple-positive group. RESULTS: Perioperative chemotherapy resulted in better overall survival than surgery alone (P = .042). Multivariate analysis of survival revealed that perioperative chemotherapy was a significant independent prognostic factor (hazard ratio, 0.323; 95% confidence interval, 0.112-0.934; P = .0371). Among the patients who received perioperative chemotherapy, the non-triple-positive group had a significantly greater 5-year survival rate than the triple-positive group (P = .0216). Moreover, among the non triple-positive group, a significantly greater 5-year survival rate was observed for the patients who underwent surgery with chemotherapy than for those who underwent surgery without chemotherapy (P = .0081). In contrast, no difference was found in 5-year survival between patients with chemotherapy and those without chemotherapy when the tumors were triple positive. CONCLUSIONS: Our results suggest that perioperative chemotherapy might benefit the survival of patients with pulmonary large cell neuroendocrine carcinoma, in particular when the tumors are not immunoreactive to all 3 neuroendocrine markers. PMID- 22498091 TI - Chronic solvent-induced encephalopathy: European consensus of neuropsychological characteristics, assessment, and guidelines for diagnostics. AB - INTRODUCTION: The presence of neuropsychological impairment is a hallmark of chronic solvent-induced encephalopathy (CSE), and using clinical neuropsychological procedures to generate a valid assessment of the condition is crucial for its diagnosis. The goals of this consensus document are to provide updated knowledge of the neuropsychological characteristics of CSE and to provide internationally acceptable guidelines for using neuropsychological assessments in the process of diagnosing patients who are suspected of having CSE. MATERIALS AND METHODS: A European working group that was composed of experts in the field of the clinical diagnosis of CSE met at several round-table meetings and prepared this report. The first section of the consensus paper addresses a review of the relevant literature that was published between 1985 and March 2012. The second section addresses recommendations for the clinical neuropsychological assessment of patients who are suspected of having CSE. RESULTS: The literature review indicates that the most common neuropsychological impairments in CSE patients are within the domains of attention, particularly the speed of information processing, memory, and motor performance. It appears that the influence of CSE on memory processes mainly involves immediate recall and generally involves verbal, visual and visuospatial material. In the second section, six recommendations are presented regarding important functional domains for the neuropsychological diagnostic process of CSE that relate to the evaluation of neuropsychological impairment, the assessment and evaluation of symptoms, differential diagnostic considerations, the reliability and validity of neuropsychological test results, and the retesting of patients. DISCUSSION AND CONCLUSIONS: These recommendations will contribute to the improvement of the process for accurately diagnosing CSE, better counselling for CSE patients, the comparability of epidemiological data between countries, and finally, by raising awareness, these recommendations will contribute to combating the adverse health effects of occupational exposure to solvents. PMID- 22498093 TI - Organophosphate-induced brain damage: mechanisms, neuropsychiatric and neurological consequences, and potential therapeutic strategies. AB - Organophosphate (OP)-induced brain damage is defined as progressive damage to the brain, resulting from the cholinergic neuronal excitotoxicity and dysfunction induced by OP-induced irreversible AChE inhibition. This delayed secondary neuronal damage that occurs mainly in the cholinergic regions of the brain that contain dense accumulations of cholinergic neurons and the majority of cholinergic projection, might be largely responsible for persistent profound neuropsychiatric and neurological impairments (memory, cognitive, mental, emotional, motor and sensory deficits) in the victims of OP poisoning. Neuroprotective strategies for attenuating OP-induced brain damage should target different development stages of OP-induced brain damage, and may include but not limited to: (1) Antidote therapies with atropine and related efficient anticholinergic drugs; (2) Anti-excitotoxic therapies targeting attenuation of cerebral edema and inflammatory reaction, blockage of calcium influx, inhibition of apoptosis program, and the control of seizures; (3) Neuroprotective strategies using cytokines, antioxidants and NMDAR antagonists (a single drug or a combination of drugs) to slow down the process of secondary neuronal damage; and (4) Therapies targeting individual symptoms or clusters of chronic neuropsychiatric and neurological symptoms. These neuroprotective strategies may help limit or prevent secondary neuronal damage at the early stage of OP poisoning and attenuate the subsequent neuropsychiatric and neurological impairments, thus reducing the long-term disability caused by exposure to OPs. PMID- 22498092 TI - Manganese exposure and cognitive deficits: a growing concern for manganese neurotoxicity. AB - This symposium comprised five oral presentations dealing with recent findings on Mn-related cognitive and motor changes from epidemiological studies across the life span. The first contribution highlighted the usefulness of functional neuroimaging of the central nervous system (CNS) to evaluate cognitive as well as motor deficits in Mn-exposed welders. The second dealt with results of two prospective studies in Mn-exposed workers or welders showing that after decrease of Mn exposure the outcome of reversibility in adverse CNS effects may differ for motor and cognitive function and, in addition the issue of plasma Mn as a reliable biomarker for Mn exposure in welders has been addressed. The third presentation showed a brief overview of the results of an ongoing study assessing the relationship between environmental airborne Mn exposure and neurological or neuropsychological effects in adult Ohio residents living near a Mn point source. The fourth paper focused on the association between blood Mn and neurodevelopment in early childhood which seems to be sensitive to both low and high Mn concentrations. The fifth contribution gave an overview of six studies indicating a negative impact of excess environmental Mn exposure from air and drinking water on children's cognitive performance, with special attention to hair Mn as a potential biomarker of exposure. These studies highlight a series of questions about Mn neurotoxicity with respect to cognitive processes, forms and routes of exposure, adequate biomarkers of exposure, gender differences, susceptibility and exposure limits with regard to age. PMID- 22498094 TI - [Dosimetric comparison between the intensity modulated radiotherapy with fixed field and Rapid Arc of cervix cancer]. AB - PURPOSE: Concurrent radiochemotherapy is the standard treatment for locally advanced cervical cancer. This treatment is responsible for bowel and hematologic toxicities. The use of intensity-modulated radiotherapy (IMRT), in static beams, allows a decrease of this toxicity. The technique of RapidArc((r)) IMRT could lower the dose delivered to the organs at risk and improve the homogeneity of the planning target volume coverage, while decreasing the processing time. PATIENTS AND MATERIALS: For 20 patients, treatment plans performed with IMRT and RapidArc((r)) were compared. The target volumes were: the clinical target volume (gross tumour volume, uterus, upper third of the vagina, the hypogastric, iliac and presacral nodal regions), and the planning target volume (clinical target volume+1cm). The delineated organs at risk were: rectum, bladder, bowel and bone marrow. The dose was 45 Gy in 25 fractions. IMRT were delivered with five beams and RapidArc((r)) with two arcs. The comparisons were made by the non-parametric test of Wilcoxon. RESULTS: Medium coverage of the planning target volume was better with RapidArc((r)) (P=0.01). It was also better regarding the sparing of bowel (P=0.01) and IMRT was better regarding the sparing of bladder (P=0.01) and rectum (P=0.05). The total volume receiving 20 Gy was less important with RapidArc((r)) (P<0.001). RapidArc((r)) allowed to decrease the treatment time (3 versus 12 minutes with IMRT) and the number of monitor units (MU) (376.5 versus 962.2, on average, P=0.0001). CONCLUSION: The technique of RapidArc((r)) seems to obtain better dosimetric results compared to RCMI, with fewer MU, and a significant decrease in treatment time. PMID- 22498095 TI - Association of interleukin 1beta polymorphisms and haplotypes with Alzheimer's disease. AB - Our study aimed to associate IL-1beta and IL-1RN polymorphisms with AD disease in comparison with elderly control group from Sao Paulo - Brazil. We genotyped 199 Alzheimer's disease (AD) patients, 165 elderly control and 122 young control samples, concerning VNTR (IL-1RN) and -511C>T and -31T>C (IL-1beta) polymorphisms. Our findings revealed that -511C/-31T/2-repetitions VNTR haplotype had a protective effect for AD when compared to EC (p=0.005), whereas -511C/ 31C/1-repetition VNTR haplotype was associated as a risk factor for AD (p=0.021). Taken together, we may suggest that there is a relevant role of IL-1 genes cluster in AD pathogenesis in this Brazilian population. PMID- 22498096 TI - Active Abeta vaccination fails to enhance amyloid clearance in a mouse model of Alzheimer's disease with Abeta42-driven pathology. AB - Abeta vaccination has been shown to induce remarkable clearance of brain amyloid plaques in mouse models of Alzheimer's disease (AD). However, the extent to which antibody-mediated Abeta clearance is affected by predominant formation of Abeta42 over Abeta40 is unclear. Here we demonstrate for the first time that in a mouse model carrying the human APP mutations KM670/671NL and the human PS1 mutation P166L, Abeta vaccination does not result in plaque clearance. This was in spite of the strong T- and B-cell immune responses evoked under the DR1501 genetic background and the activation of microglia at sites of Abeta plaques. Our findings suggest the existence of antibody-resistant forms of Abeta deposits in the brain consisting of primarily Abeta42, and shed light on the mechanisms of antibody-dependent amyloid clearance as well as novel therapeutic strategies for AD. PMID- 22498097 TI - Full and partial peroxisome proliferation-activated receptor-gamma agonists, but not delta agonist, rescue of dopaminergic neurons in the 6-OHDA parkinsonian model is associated with inhibition of microglial activation and MMP expression. AB - BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear hormone receptor that has been shown to have anti-inflammatory and matrix metalloproteinase (MMP) inhibitor properties. PPARgamma agonists have been shown to have neuroprotective effects in various neurodegeneration models where inflammation is implicated, including models of Parkinson's disease. However, no studies have looked at the effects of partial PPARgamma agonists. EXPERIMENTAL APPROACH: The neuroprotective effects of the PPARgamma full agonist, pioglitazone (20 mg/kg), partial PPARgamma agonist GW855266X (15 mg/kg) and PPAR-delta full agonist GW610742X (10 mg/kg) were investigated in the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease when administered prior to or post 6-OHDA lesioning. The integrity of the nigrostriatal system was assessed by assessing the numbers dopaminergic neurons in the substantia nigra (SN) and by assessing striatal dopamine content. The degree of microglia activation in the SN was also immunohistochemistry assessed utilizing the marker OX-6 for activated microglia and CD-68 a marker for phagocytic microglia. Additionally we performed immunocytochemistry for MMP3 in the SN. Finally, we investigated whether a period of drug withdrawal for a further 7 days affected the neuroprotection produced by the PPARgamma agonists. KEY RESULTS: Both pioglitazone and GW855266X protected against 6-OHDA induced loss of dopaminergic neurons in the substantia nigra and depletion of striatal dopamine when administered orally twice daily for either 1) 7 day prior to and 7 days post lesioning or 2) for 7 days starting 2 days post lesioning when neurons will be severely traumatized. 6-OHDA lesioning was associated with an increase in microglia activation and in numbers of MMP-3 immunoreactive cells which was attenuated by pioglitazone and GW855266X. Neuroprotective effects were not replicated using the PPARdelta agonist GW610742X. Subsequent withdrawal of both pioglitazone and GW855266X, for a further 7 days negated any neuroprotective effect suggesting that long-term administration may be required to attenuate the inflammatory response. CONCLUSIONS AND IMPLICATIONS: For the first time a partial PPAR-gamma agonist has been shown to be neuroprotectory when administered post lesioning in a parkinsonian model. Effects may be via the inhibition of microglial and MMP activation and support further research. PMID- 22498098 TI - Serum and CSF measles antibody levels increase over time in patients with multiple sclerosis or clinically isolated syndrome. AB - In general, measles virus (MV) immunoglobulin G (IgG) antibody titres decline over time. However, we found that serum and CSF MV antibody titres increased with age (slope=0.038, p<0.001 and slope=0.022, p=0.008), respectively, and disease duration (slope=0.031, p=0.002 and slope=0.032, p=0.005), respectively, in patients with multiple sclerosis (MS) or clinically isolated syndrome (CIS). The age dependency of serum antibody levels differed between patients and controls (slope=0.038 versus -0.004, p<0.001). The increasing MV antibody titres over time in MS/CIS patients support a general nonspecific stimulation of B cells and plasma cells that is not confined only to the CNS/CSF compartment. PMID- 22498099 TI - Increased expression of Toll-like receptors 2 and 4 is associated with poor outcome in intracerebral hemorrhage. AB - Inflammatory response in intracerebral hemorrhage (ICH) is associated with poor outcome and could be a consequence of Toll-like receptor (TLR) activation. We investigated the influence of TLR2 and TLR4 expression on the outcome of ICH patients. Expression levels of TLR2 and TLR4 in monocytes at admission were independently associated with poor functional outcome. On the other hand, TLR2 and TLR4 expression at admission in both monocytes and neutrophils was independently associated with residual lesion volume. In conclusion, increased expression of TLR2 and TLR4 is associated with poor functional outcome and greater residual volume in ICH patients. PMID- 22498100 TI - Neuronal antigens recognized by cerebrospinal fluid IgM in multiple sclerosis. AB - Axonal injury is the major cause of disability in patients with multiple sclerosis (MS), but the mechanisms leading to axonal damage are poorly understood. Oligoclonal IgM against lipids predicts an aggressive disease course in MS; however, the antigen that elicits the immune response has not yet been identified. We screened the CSF of 12 patients with MS, 7 patients with neuromyelitis optica (NMO), and 5 controls with non-inflammatory neurological disease (NIND) for the presence of IgM-type antibodies (IgM-Ab) against neuronal surface antigens, and analyzed the relationship between IgM-Ab level and the extent of brain atrophy. The CSF of MS patients displayed significantly higher levels of IgM-Ab compared to NIND or NMO patients. Furthermore, we document for the first time that these IgM-Ab recognize neuronal surface antigens, and that the levels of neuronal-bound IgM-Ab were independent of the IgM concentration and correlate with brain atrophy. Our findings suggest a role for the CSF IgM-Ab in the development of MS pathophysiology. PMID- 22498101 TI - [Athlete's heart or hypertrophic cardiomyopathy?]. AB - High level of physical training can lead cardiovascular quantitative and qualitative adaptations. These clinical, electrical and echocardiographic adaptations are called athlete's heart. These mainly moderated adaptations raise generally no diagnostic issue. However, in rare cases, the question of the limits of athlete's heart may arise. The differential diagnosis with the hypertrophic cardiomyopathy is important because this pathology, even treated, excludes for intense physical activity. On the contrary, an inequitable contraindication for competitive sport is not acceptable. In most cases, the athlete's heart diagnosis is easy in case of a good knowledge of its signs and a good rigor of exam. However, sometimes, the good diagnosis is proposed only on a beam of arguments. PMID- 22498102 TI - [Visit-to-visit variability: Prognostic significance?]. AB - Hypertension is the most prevalent treatable risk factor for stroke. Treatment of hypertension is based on usual blood pressure, which is evaluated by repeated measurement. When only few measurements show high blood pressure, this is considered as a background noise generally due to white coat effect. Rothwell et al. challenged this notion and presented data from post-hoc analyses of three randomized trials and one meta-analysis, where 3 parameters are strongly associated with the risk of stroke: visit-to-visit variability of systolic blood pressure, increased residual variability in treated patients, and episodic hypertension. These findings are not proof of a causal link between variability and vascular risk. However, a new window has been opened in clinical practice, giving new implications in the choice of treatment, and, for next trials, highlighting the importance of including variability and patients with episodic hypertension. PMID- 22498103 TI - Mild traumatic brain injury in the rat alters neuronal number in the limbic system and increases conditioned fear and anxiety-like behaviors. AB - Recent reports suggest that experiencing a mild closed head trauma or mild traumatic brain injury (mTBI) is associated with a greater incidence of anxiety disorders. Dysfunction of limbic structures, such as the medial prefrontal cortex, amygdala and hippocampus, is associated with the symptoms of anxiety disorders. Therefore, the goal of the current studies was to characterize the consequences of closed mTBI on these limbic structures and associated fear and anxiety-related behaviors. A weight-drop procedure was employed to induce mTBI in male rats. Rats were transcardically perfused 4 or 9 days following exposure to mTBI or control procedures, and neuronal number, brain region area, and the number of apoptotic cells in each region were determined. In separate groups of rats, the effects of mTBI on anxiety-like behaviors, motor function, nociception, and acquisition, retention and extinction of contextual fear were also assessed. Findings suggest that mTBI was associated with significant neuronal cell loss in the CA1 region of the dorsal hippocampus and increased cell number in subregions of the amygdala, both of which appear to be related to alterations to apoptosis in these regions following mTBI. Furthermore, mTBI increased expression of anxiety-like behaviors and conditioned fear, with no effect on motor performance or nociception. Overall, a single impact to the skull to mimic mTBI in rats produces discrete alterations to neuronal numbers within the limbic system and specific emotional deficits, providing a potential neurobiological link between mTBI and anxiety disorders. PMID- 22498104 TI - The roles of neuronal and glial precursors in overcoming chondroitin sulfate proteoglycan inhibition. AB - The extension of axons through the major inhibitory component of the glial scar, chondroitin sulfate proteoglycans (CSPGs), remains a key obstacle for regeneration following spinal cord injury (SCI). We have previously shown that transplants composed of neuronal and glial restricted precursors (NRP and GRP respectively) promote regeneration and connectivity in the injured spinal cord (Bonner et al., 2010, 2011), however, little is known about the properties of these precursors at a cellular level. We now report that NRP-derived neurons, in contrast to dorsal root ganglion (DRG) neurons, have the ability to extend axons and cross over from a permissive substratum (laminin) onto inhibitory CSPG in vitro. Growth cones of neurons derived from NRP, compared to DRG, exhibit significantly lower levels of the CSPG receptors protein tyrosine phosphatase sigma (PTPsigma) and leukocyte common antigen-related phosphatase (LAR). GRP conditioned medium prepared from the same cell densities did not affect the response of primary sensory neurons to CSPG confirming that the ability of NRP derived neurons to cross onto CSPG is determined intrinsically. However, GRP conditioned medium collected from high density cultures increased the probability of DRG axons to cross from LN onto CSPG and increased the length of DRG axons extending on CSPG. Collectively, these results suggest that (1) neurons derived from NRPs are intrinsically insensitive to CSPGs due to low levels of receptor expression, and (2) high levels of factors secreted by GRP can reduce the inhibitory effects of CSPG and promote axonal growth. These observations provide mechanistic insights into the specific roles of NRPs and GRPs in promoting regeneration and repair following SCI. PMID- 22498105 TI - The synergistic action of imidacloprid and flumethrin and their release kinetics from collars applied for ectoparasite control in dogs and cats. AB - BACKGROUND: The control of tick and flea burdens in dogs and cats has become essential to the control of important and emerging vector borne diseases, some of which are zoonoses. Flea worry and flea bite hypersensitivity are additionally a significant disease entity in dogs and cats. Owner compliance in maintaining the pressure of control measures has been shown to be poor. For these reasons efforts are continuously being made to develop ectoparasiticides and application methods that are safe, effective and easy to apply for pet owners. A new polymer matrix collar has recently been developed which is registered for 8 months use in cats and dogs. The basic properties of this collar have been investigated in several in vitro and in vivo studies. METHODS: The effects of imidacloprid, flumethrin and the combination were evaluated in vitro by means of whole cell voltage clamp measurement experiments conducted on isolated neuron cells from Spodoptera frugiperda. The in vitro efficacy of the two compounds and the combination against three species of ticks and their life stages and fleas were evaluated in a dry surface glass vial assay. The kinetics of the compounds over time in the collar were evaluated by the change in mass of the collar and measurement of the surface concentrations and concentrations of the actives in the collar matrix by HPLC. Hair clipped from collar treated dogs and cats, collected at various time points, was used to assess the acaricidal efficacy of the actives ex vivo. RESULTS: An in vitro isolated insect nerve model demonstrated the synergistic neurotoxic effects of the pyrethroid flumethrin and the neonicotinoid imidacloprid. An in vitro glass vial efficacy and mortality study against various life stages of the ticks Ixodes ricinus, Rhipicephalus sanguineus and Dermacentor reticulatus and against the flea (Ctenocephalides felis) demonstrated that the combination of these products was highly effective against these parasites. The release kinetics of these actives from a neck collar (compounded with 10% imidacloprid and 4.5% flumethrin) was extensively studied in dogs and cats under laboratory and field conditions. Acaricidal concentrations of the actives were found to be consistently released from the collar matrix for 8 months. None of the collar studies in dogs or cats were associated with any significant collar related adverse event. CONCLUSION: Here we demonstrated the synergism between the pyrethroid flumethrin and the neonicotinoid imidacloprid, both provided in therapeutically relevant doses by a slow release collar matrix system over 8 months. This collar is therefore a convenient and safe tool for a long-term protection against ectoparasites. PMID- 22498106 TI - Is cat-keeping the main determinant of new-onset adulthood cat sensitization? PMID- 22498108 TI - HOXA1 is overexpressed in oral squamous cell carcinomas and its expression is correlated with poor prognosis. AB - BACKGROUND: HOX genes encode homeodomain-containing transcription factors involved in the regulation of cellular proliferation and differentiation during embryogenesis. However, members of this family demonstrated oncogenic properties in some malignancies. The present study investigated whether genes of the HOXA cluster play a role in oral cancer. METHODS: In order to identify differentially expressed HOXA genes, duplex RT-PCR in oral samples from healthy mucosa and squamous cell carcinoma was used. The effects of HOXA1 on proliferation, apoptosis, adhesion, invasion, epithelial-mesenchymal transition (EMT) and anchorage-independent growth were assessed in cells with up- and down-regulation of HOXA1. Immunohistochemical analysis using a tissue microarray (TMA) containing 127 oral squamous cell carcinomas (OSCC) was performed to determine the prognostic role of HOXA1 expression. RESULTS: We showed that transcripts of HOXA genes are more abundant in OSCC than in healthy oral mucosa. In particular, HOXA1, which has been described as one of the HOX members that plays an important role in tumorigenesis, was significantly more expressed in OSCCs compared to healthy oral mucosas. Further analysis demonstrated that overexpression of HOXA1 in HaCAT human epithelial cells promotes proliferation, whereas downregulation of HOXA1 in human OSCC cells (SCC9 cells) decreases it. Enforced HOXA1 expression in HaCAT cells was not capable of modulating other events related to tumorigenesis, including apoptosis, adhesion, invasion, EMT and anchorage-independent growth. A high number of HOXA1-positive cells was significantly associated with T stage, N stage, tumor differentiation and proliferative potential of the tumors, and was predictive of poor survival. In multivariate analysis, HOXA1 was an independent prognostic factor for OSCC patients (HR: 2.68; 95% CI: 1.59-2.97; p = 0.026). CONCLUSION: Our findings indicate that HOXA1 may contribute to oral carcinogenesis by increasing tumor cell proliferation, and suggest that HOXA1 expression might be helpful as a prognostic marker for patients with OSCC. PMID- 22498109 TI - COPD among non-smokers - report from the obstructive lung disease in Northern Sweden (OLIN) studies. AB - BACKGROUND: In westernized countries smoking and increasing age are the most important risk factors for COPD. Prevalence and risk factors of COPD among non smokers are not well studied. AIM: To study the prevalence and risk factors of COPD among non-smokers and to determine the proportion of non-smokers among subjects with COPD. METHODS: A random sample of 2470 subjects drawn from a population-based postal survey of 10,040 (85-88% participation) adults (aged 20 77) in Norrbotten, Sweden, were invited to structured interviews and lung function tests, and 1897 participated. COPD was classified using the fixed ratio (GOLD) definition and for comparison the lower limit of normal (LLN). RESULTS: The prevalence of airway obstruction was 6.9% among non-smokers and strongly age related. The prevalence of GOLD stage >=II among non-smokers was 3.5%. Both among subjects with airway obstruction and among subjects with GOLD stage >=II, the proportions of non-smokers were 20%. Of men with airway obstruction, 14.1% were non-smokers versus 26.8% among women. Non-smokers with GOLD stage >=II had significantly more symptoms and higher co-morbidity than non-smokers without airway obstruction. Sex, area of domicile and exposure to environmental tobacco smoke was not significantly associated to airway obstruction among non-smokers. Using LLN for defining airway obstruction yielded a similar prevalence. CONCLUSION: The prevalence of airway obstruction among non-smokers was close to 7% and was associated with increasing age. One out of seven men with airway obstruction, defined using the fixed ratio, versus one out of four women had never smoked. PMID- 22498110 TI - A randomized, double-blind dose-ranging study of the novel LAMA GSK573719 in patients with COPD. AB - BACKGROUND: This study evaluated the dose-response and dosing interval of the novel long-acting muscarinic receptor antagonist (LAMA) GSK573719 in patients with COPD. METHODS: This randomized, double-blind, placebo-controlled, 3-way cross-over, incomplete block study evaluated 5 once-daily doses of GSK573719 (62.5-1000 MUg), 3 twice-daily doses (62.5-250 MUg), and open-label tiotropium for 14 days in patients (N = 176) with COPD (FEV(1) of 35-70% predicted). The primary endpoint was morning trough FEV(1) at Day 15. Secondary endpoints included 0-24 h weighted mean FEV(1) and serial FEV(1) values over 28 h. Safety measures and pharmacokinetics were assessed. RESULTS: All once-daily doses of GSK573719 significantly increased trough FEV(1) at Day 15 with improvements ranging from 95 to 186 mL over placebo (p <= 0.006), from 79 to 172 mL with twice daily dosing (p <= 0.03), and 105 mL with tiotropium (p = 0.003). No clear dose ordering was observed. Once-daily doses significantly (p < 0.001) increased 0-24 h weighted mean FEV(1) at Day 14 by 131-143 mL over placebo, comparable to increases with the twice-daily doses (120-142 mL) and tiotropium (127 mL). Significant reductions in rescue albuterol use and improvements in FVC were also observed with once-daily dosing. Plasma C(max) occurred within 5-15 min of dosing after which the drug was rapidly cleared and eliminated. GSK573719 was well tolerated, with no apparent treatment-related changes in vital signs, ECG and Holter assessments, or clinical laboratory parameters. CONCLUSION: Once-daily dosing with GSK573719 in COPD provides clinically significant and sustained improvement in lung function over 24 h with similar efficacy to twice-daily dosing. PMID- 22498111 TI - Overexpression and potential targeting of the oncofoetal antigen 5T4 in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is resistant to conventional treatments. Novel, targeted treatments are hampered by the relative lack of MPM-associated tumour antigens. The aim of this study was to evaluate the level of expression and the relevance of 5T4 as a tumour-associated antigen in MPM. 5T4 expression was assessed by Western blotting, flow cytometry, immuno-cytochemistry and histochemistry in 11 mesothelioma cell lines, 21 tumour biopsies, and ex vivo tumour cells obtained from the pleural fluid (PF) of 10 patients. 5T4 antibody levels were also determined in the plasma of patients and healthy donors. The susceptibility of MPM cells to 5T4-specific T-cell-mediated killing was determined using an HLA-A2(+), CD8(+) T-cell line, developed against the 5T4(17 25) peptide. We report here that cell surface 5T4 expression was detected in all mesothelioma cell lines and PF cell samples. Mesothelin and CD200, a suggested mesothelioma marker, were co-expressed with 5T4 on tumour cells in PF. Immunohistochemistry confirmed overexpression of 5T4, similar to mesothelin, on tumour cells but not on reactive stroma in all tissue sections tested. Median 5T4 antibody levels were 46% higher in patient than in healthy donor plasma, indicating immune recognition. Importantly, 5T4-specific CD8(+) T-cells were able to kill four out of six HLA-A2(+) MPM cell lines but not an HLA-A2(-) cell line, demonstrating immune recognition of MPM-associated 5T4 antigen at the effector T cell level. We conclude that 5T4 is a potential new antigen for targeted therapies such as immunotherapy in MPM, as it is overexpressed on mesothelioma cells and recognised by 5T4-specific cytotoxic T-cells. Our findings have been translated into a Phase II clinical trial applying 5T4-targeted therapies in MPM patients. PMID- 22498112 TI - Prognostic factors in patients with advanced non-small cell lung cancer: data from the phase III FLEX study. AB - The FLEX study demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). In the FLEX intention to treat (ITT) population, we investigated the prognostic significance of particular baseline characteristics. Individual patient data from the treatment arms of the ITT population of the FLEX study were combined. Univariable and multivariable Cox regression models were used to investigate variables with potential prognostic value. The ITT population comprised 1125 patients. In the univariable analysis, longer median survival times were apparent for females compared with males (12.7 vs 9.3 months); patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 compared with 1 compared with 2 (13.5 vs 10.6 vs 5.9 months); never smokers compared with former smokers compared with current smokers (14.6 vs 11.1 vs 9.0); Asians compared with Caucasians (19.5 vs 9.6 months); patients with adenocarcinoma compared with squamous cell carcinoma (12.4 vs 9.3 months) and those with metastases to one site compared with two sites compared with three or more sites (12.4 months vs 9.8 months vs 6.4 months). Age (<65 vs >=65 years), tumor stage (IIIB with pleural effusion vs IV) and percentage of tumor cells expressing EGFR (<40% vs >=40%) were not identified as possible prognostic factors in relation to survival time. In multivariable analysis, a stepwise selection procedure identified age (<65 vs >=65 years), gender, ECOG PS, smoking status, region, tumor histology, and number of organs involved as independent factors of prognostic value. In summary, in patients with advanced NSCLC enrolled in the FLEX study, and consistent with previous analyses, particular patient and disease characteristics at baseline were shown to be independent factors of prognostic value. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. PMID- 22498113 TI - Inhibition of RalA signaling pathway in treatment of non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and relatively resistant to chemotherapy. The most prevalent molecular abnormality in NSCLC is the overactivation of K-Ras proto-oncogene; therefore, elucidating down stream Ras signaling in NSCLC is significantly important in developing novel therapies against this malignancy. Our work indicates that RalA, an important effector of Ras, is activated in NSCLC cell lines. While RalA was also overactivated in fetal human broncho-epithelial cells, RalBP1 (Ral binding protein-1), an important down-stream effector of RalA, was expressed at higher levels in cancer cell lines. Aurora kinase-A (AKA), an upstream activator of RalA, was also found to be active only in malignant cells. The outcome of inhibition of RalA (by gene specific silencing using a lentivirus) on the malignant phenotype of A549 cells was also studied. While proliferation and invasiveness of A549 cells were reduced upon silencing RalA, apoptosis and necrosis were elevated in such conditions. Additionally, the in vivo tumorigenesis of A549 cells was reduced upon partial inhibition of RalA and AKA using pharmacological inhibitors. Finally, we were interested in evaluating the level of active RalA in the fraction of NSCLC cells expressing cancer stem cell markers. For this purpose cells with increased expression of CD44 were separated from A549 cells and compared with cells with low level of expression of this marker and an unsorted population. A significant enhancement of RalA activation in high CD44+ cells was found as potential evidence for involvement of RalA signaling in initiation of the neoplastic procedure and an important contributor for tumor maintenance in NSCLC. Further studies can reveal therapeutic, preventive and diagnostic value of RalA pathway in this deadly disease. PMID- 22498114 TI - A diagnostic program for patients suspected of having lung cancer. AB - BACKGROUND: A standardized diagnostic program, initiated to reduce the length of the diagnostic track and to improve application of diagnostic tools for patients referred with suspicious abnormalities on standard chest radiographs, was evaluated. METHODS: The findings on integrated positron emission tomography/computed tomography (PET-CT) determined the choice of invasive investigations to be performed the same day. Diagnostic results, time courses, and number and sorts of applied invasive investigations were assessed. RESULTS: In 297 eligible patients, malignant disease was diagnosed in 72% and benign disease was diagnosed in 26% of patients. One percent of the patients had no abnormalities at all. For 85% of patients with malignancy, investigations were completed in 1 day, resulting in a diagnosis and definitive clinical disease stage. The median time from start of the analysis to informing the patient about diagnosis and tumor stage was 7 days. One invasive investigation was performed in 53% of patients in the study group, and at least 2 investigations were performed in 33% of patients. Bronchoscopies formed a part of the diagnostic process in 59% of patients. Surgical diagnostic procedures were performed in 8% of patients. CONCLUSION: The diagnostic program resulted in a short time to diagnosis, with finalization of invasive investigations in 1 day in the majority of patients. The imaging-based choice of invasive investigations precluded bronchoscopies in a substantial portion of the patients. PMID- 22498115 TI - Challenges of an ageing and dispersed population for delivering cancer services in Australia: more than just doctors needed. PMID- 22498116 TI - Access to the kidney transplant waiting list: a time for reflection. AB - The limited availability of deceased donor kidneys for transplantation in Australia continues to be a matter of concern. Analysis of registry data suggests that the current renal transplant waiting list under-represents the real demand for three reasons. Firstly, a very low proportion of dialysis patients across all age groups are wait-listed for kidney transplantation; secondly, the percentage of dialysis patients listed for transplantation has fallen over time across all Australian states and territories; and thirdly, the number of patients wait listed varies significantly across the country. We explore possible reasons for these issues and call for new eligibility criteria that are both transparent and justifiable and balance equity and utility. PMID- 22498117 TI - How to select the doctors of the future. AB - Although previous academic performance is acknowledged as the best predictor of achievement in medical school, no one has succeeded in finding a selection method which will choose students who will become doctors with the qualities the community expect. Australian medical schools use various selection methods. It could well be argued that the most important phase in the selection process is informed decision-making by potential applicants. More effort should be made by medical schools to achieve this. PMID- 22498118 TI - When should iron chelation therapy be considered in patients with myelodysplasia and other bone marrow failure syndromes with iron overload? AB - Despite the absence of a robust evidence base, there is growing consensus that effective treatment of iron overload leads to decreased morbidity and premature mortality in patients with good prognosis myelodysplastic syndromes (MDSs). Furthermore, new treatment modalities, including disease-modifying therapies (lenalidamide and azacytidine) and reduced intensity conditioning therapies for allogeneic blood stem cell transplants, are offering the prospect of longer survival for patients with traditionally less favourable prognosis MDS, who might also benefit from iron chelation. This article proposes assessment of patients with MDS and related bone marrow failure syndromes to determine suitability for iron chelation. Iron chelation therapy options and monitoring are discussed. PMID- 22498119 TI - Changes in liquid emptying in migraine patients: diagnosed with liquid phase gastric emptying scintigraphy. AB - Gastric stasis is suspected mostly to be encountered during acute migraine attack. The aim of this study is to evaluate the liquid phase gastric emptying and motility in migraine patients in ictal and interictal periods in comparison to normal subjects with gastric emptying scintigraphy. Seven women with migraine and age, sex matched controls who applied to the Neurology Department from May 2009 to May 2010 were compared. Gastric emptying study with a standard liquid was performed one time in the non-migraineur group and two times in the migraineur group. Non-migraineur controls and migraineurs were compared. The mean T1/2 was longer in ictal period in migraineurs. The T1/2 of migraineurs interictally and the control groups were similar. The T1/2 of migraineurs ictally and migraineurs interictally were also compared. We also considered the percentage of the radioactive material remaining in the stomach. There were no significant differences between non-migraineurs and migraineurs interictally. However, increased amount of radioactive material remaining in the stomach was observed in migraineurs ictally. We concluded that the liquid emptying was delayed in spontaneous migraine attacks in migraine without aura, however in the interictal period the emptying of liquids did not differ between migraineurs and non migraineurs. PMID- 22498120 TI - Intravenous immunoglobulins as treatment of severe cutaneous polyarteritis nodosa. AB - We describe three patients with severe refractory cutaneous polyarteritis nodosa, resulting in painful ulcers involving the lower limbs and causing toe necrosis. Due to the severity of the cutaneous manifestations, the three patients received intravenous immunoglobulins at a dose of 1 g/kg/day for 2 days monthly. After the second intravenous immunoglobulin infusion, skin signs dramatically improved and completely healed after the third intravenous immunoglobulin infusion. Our findings indicate that intravenous immunoglobulins can be included in a therapeutic strategy to treat refractory cutaneous polyarteritis nodosa. PMID- 22498121 TI - Utility, or not, of estimates of glomerular filtration rate in modifying drug dosage, with particular reference to enoxaparin. AB - A reduced clearance of some drugs in renal failure is a problem, particularly with drugs that are excreted by the kidney substantially unmetabolised and also have significant toxicity and a low therapeutic ratio. The problem is compounded by the significant inaccuracy of estimated glomerular filtration rate (eGFR). The aim was to develop general recommendations to reduce the risk of drug toxicity in renal failure, with particular reference to enoxaparin. The substantial inaccuracies in eGFR (eGFR in 32% of patients is different from measured GFR by 20-30%) are compounded when using a dichotomous decision tree (renal failure or not). As the eGFR approaches the GFR decision boundary, for classification as renal failure or not, misclassification approaches 50%. Recommendations, when patients are at risk, include the following: acknowledge inaccuracies of eGFR, particularly in anthropometrically diverse populations; measure drug levels wherever possible; realise that drug levels after early doses relate more to volume of distribution, rather than renal function, allowing time for modification of the drug dose; where accurate urine collection is feasible, use creatinine clearance as an estimate of GFR; and use eGFR as a (more) continuous, rather than dichotomous, variable to adjust dosage, exampled by enoxaparin. PMID- 22498122 TI - Cancer and quackery. AB - The Internal Medicine Journal published an article by two senior oncologists who were contesting the supposed miracle cure of a cancer survivor. This paper draws on the history of medicine to explore the conflict between biomedicine and alternative therapies. I suggest that the Internal Medicine Journal article, written about an episode that occurred more than 30 years ago, can best be explained by some oncologists' discomfort with losing their authority to dictate patient choices. I propose a compromise that rejects paternalism but accepts the possibility of worse patient outcomes. PMID- 22498123 TI - Unusual lung mass. PMID- 22498124 TI - Rosai-Dorfman disease. PMID- 22498125 TI - Obstructive nephropathy secondary to a massive vesical calculus. PMID- 22498126 TI - Timeline errors undermine hypothesis; 'famous patient' did have secondary osteogenic sarcoma and tuberculosis. PMID- 22498128 TI - Lack of adherence to scientific principles of objectivity. PMID- 22498130 TI - The importance of a histological diagnosis.... PMID- 22498131 TI - Reply: Treatment of refractory neurosarcoidosis with tumour necrosis factor inhibitors--what lies ahead? PMID- 22498132 TI - Wegener's granulomatosis: treatment and survival characteristics in a high prevalence southern hemisphere region. AB - Our aim was to describe the treatment and survival characteristics of Wegener's granulomatosis (WG) in Canterbury, New Zealand. The medical records of 48 patients diagnosed between 1 July 1997 and 31 December 2008 and fulfilling validated classification criteria for WG were reviewed to characterise survivorship in the province of Canterbury, New Zealand. The age at diagnosis was 61 years (range 20 to 83 years) with an equal number of males and females. Using Kaplan-Meier product-limit analysis, the probability of survival at 1 and 10 years was 91% and 62% respectively. Of the 12 deaths in the cohort, four occurred within 12 months of diagnosis: two from pulmonary haemorrhage and two from renal failure. Beyond 12 months, two patients died of renal failure, two of myocardial infarction and one from cardiac arrhythmia, one from cerebrovascular disease and two from colorectal carcinoma. The median time to relapse was 6.75 years, and the probability of relapse within 10 years was 67%. Survivorship, treatment response rate and the rate of relapse from WG in a cohort of patients from this high prevalence southern hemisphere region were similar to that reported for northern hemisphere cohorts with a similar prevalence. PMID- 22498133 TI - Coexistence of renal malakoplakia and myelodysplastic syndrome. AB - Malakoplakia is a protean systemic chronic granulomatous disease that usually targets the genito-urinary system and most particularly the bladder. Only in rare occasions do the kidneys get involved. Myelodysplastic syndrome is a heterogeneous clonal haematopoietic disorder characterised by either a hyper- or hypocellular bone marrow dysmyelopoiesis and peripheral blood pancytopenia. The synchronous association of these two unrelated disorders has never been reported. We report a 62-year-old woman who initially developed vague, relapsing gastrointestinal symptoms synchronous with renal malakoplakia and myelodysplastic syndrome. PMID- 22498134 TI - Primary central nervous system lymphoma masquerading as bilateral vitreous floaters. AB - A 72-year-old female presented with a 6-month history of bilateral floaters and visual blurring. Clinically, the posterior vitreous was cellular bilaterally, with no signs of subretinal infiltrates, retinal vasculitis, disc oedema or macula oedema. A vitreous biopsy and vitrectomy were scheduled following left cataract surgery because of the presence of a dense cataract. One month after cataract surgery, the patient developed signs of florid left arteritis involving the first-order branches of the central retinal artery. A 23-gauge vitreous biopsy and vitrectomy were performed, and preservative-free triamcinolone was injected. Cytology of the biopsy demonstrated benign T-lymphocytes and histiocytes suggestive of mild chronic inflammation only. Magnetic resonance imaging (MRI) of the brain was normal as was lumbar puncture. Subsequently, the patient developed right upper motor neuron facial nerve palsy. MRI imaging on this occasion demonstrated multiple hyper-intense white matter lesions. A third MRI was subsequently obtained due to new neurological deficits and demonstrated enlargement of the pre-existing lesions. Brain biopsy confirmed the presence of primary cerebral lymphoma. The present case highlights the role of various tissue biopsies, including vitreous, cerebrospinal fluid and brain tissue, to establish an elusive diagnosis of primary central nervous system lymphoma presenting as benign vitreous floaters. PMID- 22498135 TI - Effect of pork fat addition on the volatile compounds of foal dry-cured sausage. AB - The effect of fat content on volatile compounds from foal dry-cured sausage was studied. Three batches (10 units per batch) of dry fermented sausages with different pork back fat content (5%, 10% and 20%) were manufactured; low fat (LF), medium fat (MF) and high fat (HF), respectively. A total of 45 volatile compounds were extracted by purge-and-trap and identified by GC-MS in the headspace of the batches. The mixture comprised 11 terpenes, 15 esters, 14 hydrocarbons and 2 alcohols. Spices were responsible for the generation of 14 volatile compounds comprising terpenes and hydrocarbons. After 49 days of ripening volatile compounds from spices represented 52.9, 38.9 and 31.2% of the total area for samples from LF, MF and HF batches, respectively, while lipid autooxidation was responsible for the generation of 8 volatile compounds. The PCA offered a good separation of the mean samples according to their fat content. PMID- 22498136 TI - Effects of muscle cortisol concentration on muscle fiber characteristics, pork quality, and sensory quality of cooked pork. AB - The effect of muscle cortisol concentration on muscle fiber characteristics and technological and sensory quality of pork was investigated. With the exception of the percentage of type IIA fibers, muscle fiber characteristics were not associated to cortisol levels. However, muscle cortisol concentration was positively associated with muscle pH(24h) (r = 0.23, P<0.05) and negatively associated with drip loss (r = -0.49, P<0.001), lightness (r = -0.24, P<0.05), shear force (r = -0.25, P<0.05), and texture profile analysis-hardness (r = 0.35, P<0.01). Additionally, the water-holding capacity of meat samples was affected by cortisol levels, with lower cortisol concentrations associated with less tender samples. These results indicate that the concentration of cortisol in the muscle is related with meat quality as well as the sensory quality of cooked pork. PMID- 22498137 TI - Electroretinogram responses of the normal thoroughbred horse sedated with detomidine hydrochloride. AB - PURPOSE: The main objective was to record electroretinogram (ERG) parameters of normal thoroughbred mares using the HMsERG, a mini-Ganzfeld electroretinographic unit, and a contact lens electrode. The second objective was to determine whether IV detomidine hydrochloride at 0.015 mg/kg is consistently an effective choice for sedation of horses undergoing this ERG protocol. METHODS: The study population consisted of 30 normal thoroughbred mares. ERG data were harvested using a protocol that included three different light intensities (10, 3000, and 10,000 mcd s/m(2)) and a 30-Hz flicker at 3000 mcd s/m(2). RESULTS: Mean, median, standard deviation, and estimated normal ranges using the 5-95% of the data for a and b-wave implicit times (IT), amplitudes (AMP), and b/a ratios were reported. Scotopic results at low intensity (10 mcd s/m(2)) had estimated ranges for b-wave IT of 41.8-72.9 ms and AMP of 19.8-173.3 MUV. Middle intensity (3000 mcd s/m(2)) a-wave IT was 13.2-14.7 ms with a-wave AMP of 68.4-144 MUV; the b-wave IT was 28.7-41.5 ms with b-wave AMP of 105.7-271.5 MUV; and the b/a ratio was 0.95-2.71. The high-intensity (10,000 mcd s/m(2)) average recordings showed an a-wave IT of 13-14.9 ms, a-wave AMP of 85.7-186.8 MUV; b-wave IT of 26.6-45.4 ms, b-wave AMP of 104.7-250.6 MUV; and a b/a wave ratio of 0.7-2.0. The 30-Hz cone flicker showed an IT of 22.8-28.9 ms and AMP of 44.1-117.1 MUV. CONCLUSIONS: Results of normal thoroughbred ERG responses are reported. The protocol proved to be simple and safe and provided consistent results. PMID- 22498138 TI - Reorganization of cellular retinol-binding protein type 1 and lecithin:retinol acyltransferase during retinyl ester biosynthesis. AB - BACKGROUND: Cellular retinol-binding protein, type 1 (Crbp1), chaperones retinyl ester (RE) biosynthesis catalyzed by lecithin:retinol acyltransferase (LRAT). METHODS: We monitored the subcellular loci of LRAT and Crbp1 before and during RE biosynthesis, and compared the results to diacylglycerol:acyltransferase type 2 (DGAT2) during triacylglycerol biosynthesis in three cell lines: COS7, CHO and HepG2. RESULTS: Before initiation of RE biosynthesis, LRAT distributed throughout the endoplasmic reticulum (ER), similar to DGAT2, and Crpb1 localized with mitochondria associated membranes (MAM), surrounded by LRAT. Upon initiating RE biosynthesis in cells transfected with low amounts of vector to simulate physiological expression levels, Crpb1 remained with MAM, and both Crbp1 and MAM re-localized with LRAT. LRAT formed rings around the growing lipid droplets. LRAT activity was higher in these rings relative to the general ER. LRAT-containing rings colocalized with the lipid-droplet surface proteins, desnutrin/adipose triglyceride lipase and perilipin 2. Colocalization with lipid droplets required the 38 N-terminal amino acid residues of LRAT, and specifically K36 and R38. Formation of rings around the growing lipid droplets did not require functional microtubules. GENERAL SIGNIFICANCE: These data indicate a relationship between LRAT and Crbp1 during RE biosynthesis in which MAM-associated Crpb1 and LRAT colocalize, and both surround the growing RE-containing lipid droplet. The N terminus of LRAT, especially K36 and R38, is essential to colocalization with the lipid droplet. PMID- 22498141 TI - MRI brain abnormalities in cochlear implant candidates: how common and how important are they? AB - OBJECTIVE: To investigate the incidence of abnormal findings on brain MRI in paediatric cochlear implantation candidates. METHODS: Retrospective review of brain MRI scans of cochlear implant patients between 2000 and 2009 who underwent MRI brain as part of their pre-operative work-up. RESULTS: MRI scans of 162 patients were reviewed (76 female patients and 86 male patients). The mean age at time of MRI scan was 3 years 8 months. Abnormalities were detected/ reported in 49 patients (30%). The total number of abnormalities detected was 51 (two patients had two separate abnormalities each). Of the abnormalities 82% could be related to known pre-existing conditions. 18% of the abnormalities were incidental/unexpected. Incidental/unexpected abnormalities were found in 9 patients (6%). Four of the patients with incidental abnormalities required referral and further investigations (2.5%). The most common abnormality detected was white matter changes (70%). All the white matter changes were related to pre existing known medical conditions. CONCLUSION: At our institution abnormalities detected by pre-operative brain MRI scans on cochlear implant candidates are common (30%). The majority of abnormalities are related to known pre-existing medical conditions. Incidental findings are rare (4%) and approximately half of them required further investigation or referral. PMID- 22498140 TI - Evaluation of in vitro and in vivo anti-melanogenic activity of a newly synthesized strong tyrosinase inhibitor (E)-3-(2,4 dihydroxybenzylidene)pyrrolidine-2,5-dione (3-DBP). AB - BACKGROUND: Tyrosinase inhibitors have become increasingly important because of their ability to inhibit the synthesis of the pigment melanin. A search for new agents with strong tyrosinase activity led to the synthesis of the tyrosinase inhibitor (E)-3-(2,4-dihydroxybenzylidene)pyrrolidine-2,5-dione (3-DBP). METHODS: The inhibitory effect of 3-DBP on tyrosinase activity and melanin production was examined in murine melanoma B16F10 cells. Additional experiments were performed using HRM2 hairless mice to demonstrate the effects of 3-DBP in vivo. RESULTS: The novel compound, 3-DBP, showed an inhibitory effect against mushroom tyrosinase (IC50=0.53 MUM), which indicated that it was more potent than the well known tyrosinase inhibitor kojic acid (IC50=8.2 MUM). When tested in B16F10 melanoma cells treated with alpha-melanocyte stimulating hormone (alpha-MSH), 3 DBP also inhibited murine tyrosinase activity, which in turn induced a decrease in melanin production in these cells. The anti-melanogenic effect of 3-DBP was further verified in HRM2 hairless mice. The skin-whitening index (L value) of HRM2 hairless mice treated with 3-DBP before irradiation with UVB was greater than that of UVB-irradiated mice that were not treated with 3-DBP. GENERAL SIGNIFICANCE: The newly synthesized 3-DBP has a potent inhibitory effect on tyrosinase. In addition to an in vitro investigation of the effects of 3-DBP on tyrosinase, in vivo studies using an HRM2 hairless mouse model demonstrated the anti-melanogenic potency of 3-DBP. Our newly synthesized 3-DBP showed efficient tyrosinase inhibitory effect in vivo and in vitro. Our finding suggests that 3 DBP can be an effective skin-whitening agent. PMID- 22498139 TI - Genomic imprinting of the type 3 thyroid hormone deiodinase gene: regulation and developmental implications. AB - BACKGROUND: In recent years, findings in a number of animal and human models have ignited renewed interest in the type 3 deiodinase (D3), the main enzyme responsible for the inactivation of thyroid hormones. The induction of D3 in models of illness and injury has raised critical questions about the physiological significance of reduced thyroid hormone availability in those states. Phenotypes in transgenic mice lacking this enzyme also point to important developmental roles for D3. A critical determinant of D3 expression is genomic imprinting, an epigenetic phenomenon that regulates a small number of dosage critical genes in the mammalian genome. The D3 gene (Dio3) is imprinted and preferentially expressed from one of the alleles in most tissues. SCOPE OF REVIEW: In the context of the physiological significance of D3 and the characteristics and purported origins of genomic imprinting, we review the current knowledge about the epigenetic mechanisms specifying gene dosage in the Dio3 locus. MAJOR CONCLUSIONS: Altered Dio3 dosage is detrimental to development, suggesting that the level of thyroid hormone action needs to be exquisitely tailored in a timely fashion to the requirements of particular tissues. An appropriate Dio3 dosage is the result of the coordinated action of certain genomic elements and epigenetic marks in the Dlk1-Dio3 domain. GENERAL SIGNIFICANCE: The imprinting of Dio3 prompts intriguing questions about why the level of thyroid hormone signaling should be regulated in this rare epigenetic manner, and to what extent altered Dio3 expression due to aberrant imprinting may be implicated in human conditions. This article is part of a Special Issue entitled Thyroid hormone signalling. PMID- 22498142 TI - Healing of laser-induced tympanic membrane perforations in rats: no contribution of granulocyte colony-stimulating factor or Gelfoam. AB - OBJECTIVES: To study whether granulocyte colony-stimulating factor together with Gelfoam (absorbable gelatin sponge, USP) could enhance the healing of freshly perforated tympanic membranes. The frequency and occurrence of different immunocompetent cells and collagen types was noted. METHODS: Laser perforations were made in the tympanic membrane of rats that were sacrificed at different time intervals post-myringotomy: Day 1, 3, 6, and 12. Tympanic membrane specimens were embedded and sections were stained with hematoxylin/eosin and an immunohistochemical technique was used, with antibodies against macrophages, B cells, T-cells, and type I-IV collagens. Semi-quantification was performed after counting positive cells, mean values were calculated and analyzed statistically. RESULTS: All perforations, except one, had closed by Day 12 and no difference was observed between experimental and control ears at the other time points. Gelfoam was still present in a high amount at Day 12. The sections were initially stained positive for type I and II collagen, but after Day 6, the regenerating tissue stained positive for mainly type III and IV collagens. Results showed that the recruitment of macrophages, B-cells, and T-cells could not be mapped with a statistical significance. CONCLUSIONS: This study showed that at 6-12 days post laser myringotomy, type III and IV collagen has replaced the collagen type II that normally constitutes the healthy tympanic membrane. There is a concern for excessive scarring involving adjacent structures. It was also seen that the combination of Gelfoam and granulocyte colony-stimulating factor or saline did not affect the healing times in perforated tympanic membranes. No significant results regarding the inflammatory cell recruitment could be obtained on the studied time points or between experimental and control ears, except for in the Gelfoam matrix. PMID- 22498143 TI - Single cell analysis using surface enhanced Raman scattering (SERS) tags. AB - Fluorescence is a mainstay of bioanalytical methods, offering sensitive and quantitative reporting, often in multiplexed or multiparameter assays. Perhaps the best example of the latter is flow cytometry, where instruments equipped with multiple lasers and detectors allow measurement of 15 or more different fluorophores simultaneously, but increases beyond this number are limited by the relatively broad emission spectra. Surface enhanced Raman scattering (SERS) from metal nanoparticles can produce signal intensities that rival fluorescence, but with narrower spectral features that allow a greater degree of multiplexing. We are developing nanoparticle SERS tags as well as Raman flow cytometers for multiparameter single cell analysis of suspension or adherent cells. SERS tags are based on plasmonically active nanoparticles (gold nanorods) whose plasmon resonance can be tuned to give optimal SERS signals at a desired excitation wavelength. Raman resonant compounds are adsorbed on the nanoparticles to confer a unique spectral fingerprint on each SERS tag, which are then encapsulated in a polymer coating for conjugation to antibodies or other targeting molecules. Raman flow cytometry employs a high resolution spectral flow cytometer capable of measuring the complete SERS spectra, as well as conventional flow cytometry measurements, from thousands of individual cells per minute. Automated spectral unmixing algorithms extract the contributions of each SERS tag from each cell to generate high content, multiparameter single cell population data. SERS-based cytometry is a powerful complement to conventional fluorescence-based cytometry. The narrow spectral features of the SERS signal enables more distinct probes to be measured in a smaller region of the optical spectrum with a single laser and detector, allowing for higher levels of multiplexing and multiparameter analysis. PMID- 22498144 TI - Lower limb functional tests. PMID- 22498145 TI - Clinical evaluation and rehabilitation prescription for knee motion loss. AB - INTRODUCTION: Range-of-motion (ROM) loss of the knee is commonly treated in rehabilitation settings. Variables that contribute to ROM loss include trauma to the knee joint, surrounding soft tissue, or surgery. The skilled clinician identifies how abnormalities in specific anatomic structures contribute to motion loss and then formulates a logical treatment plan to target these structures. A thorough understanding of the arthrokinematic characteristics of the knee is necessary in order to treat knee ROM loss by guiding effective mobilization techniques. METHODS DESCRIBED: An evaluative algorithm is described for the clinical management of knee ROM loss. Methods to identify specific anatomical structures contributing to motion loss leading to the formulation of a logical and effective treatment plan that targets these structures are outlined. The rehabilitation prescription which specifies paramaters of treatment, such as frequency, duration, order, and total volume of interventions should be designed within the context of providing optimal mechanical signal to the healing tissue for remodeling and repair. PURPOSE: This paper describes evaluative strategies to identify how soft tissue structures contribute to ROM. Formulation of an optimal rehabilitation prescription is discussed. PMID- 22498146 TI - Trunk muscle activity during spine stabilization exercises performed in a pool. AB - OBJECTIVES: To compare trunk muscle activity levels among a variety of therapeutic aquatic exercises designed for patients with low back pain. STUDY DESIGN: Quantitative observational laboratory study. SETTING: Sports medicine clinic housed in a University. PARTICIPANTS: Eleven physically active males aged 25.7 +/- 5.53 years. MAIN OUTCOME MEASURES: Surface electromyographic (EMG) data from muscles rectus abdominis (RA), external oblique (EO), lower abdominals (LA), multifidus (MT), and erector spinae (ES) were recorded and then normalized to a maximal voluntary contraction. RESULTS: EMG values during abdominal bracing and Swiss ball exercises for muscles RA, EO, LA, and ES were significantly greater than most other exercises tested that included pelvic tilt, marching, hip abduction, and alternating arm exercises (P = .04-.001). EMG values of muscle LA were also greater for the abdominal hollowing exercise, whereas muscle MT displayed the greatest EMG values during the hip abduction exercise when compared to most other exercises tested (P = .02-.001). CONCLUSIONS: The aquatic exercises that maximize trunk muscle activity in the healthy males studied are abdominal bracing and Swiss ball exercises. Some muscles were selectively activated during abdominal hollowing (LA) and hip abduction (MT) exercises when compared to most other exercises. PMID- 22498147 TI - Time to peak force is related to frontal plane landing kinematics in female athletes. AB - OBJECTIVES: Determine the relationship between unilateral lower extremity closed kinetic chain muscle performance and unilateral frontal plane landing kinematics. DESIGN: Descriptive. SETTING: Outpatient physical therapy clinic. PARTICIPANTS: Twenty adolescent female athletes. MAIN OUTCOME MEASURES: Unilateral lower extremity muscle performance was quantified at 25 degrees of knee flexion on a computerized leg press. Unilateral frontal plane tibiofemoral kinematics were captured with a bi-axial electrogoniometer during a drop jump maneuver from a 40 cm platform. RESULTS: Peak and average force and force normalized to body weight were not significantly related to frontal plane landing kinematics. Time to peak force however was related to both frontal plane initial contact (r = -0.54; P = 0.013) and peak angles at 100 ms post-contact (r = -0.53; P = 0.016). As time to peak force increased, tibiofemoral angles were in greater amounts of valgus. CONCLUSIONS: During an isometric closed kinetic chain unilateral squat test at 25 degrees of knee flexion, the time to peak force is related to frontal plane landing kinematics. Females who take longer to generate peak force are more likely to exhibit valgus kinematic patterns during the landing task. However, strength measures (peak force, average force or peak and average force normalized to body weight) are not associated with unilateral landing kinematics in female athletes. PMID- 22498148 TI - An examination, correlation, and comparison of static and dynamic measures of postural stability in healthy, physically active adults. AB - OBJECTIVE: To examine the relationship and differences between static and dynamic postural stability in healthy, physically active adults. DESIGN: Descriptive laboratory study. SETTING: Research laboratory. PARTICIPANTS: Ten females (age: 21.6 +/- 1.2 yrs, mass: 60.8 +/- 7.6 kg, height: 165.0 +/- 5.0 cm) and ten males (age: 25.1 +/- 3.0 yrs, mass: 73.9 +/- 8.7 kg, height: 173.5 +/- 9.0 cm). MAIN OUTCOME MEASURES: Static postural stability was measured during a single-leg standing task (standard deviation of the ground reaction forces). Dynamic postural stability was measured during a single-leg landing task using the Dynamic Postural Stability Index. Pearson's r-coefficients were calculated to examine relationships between the two tests and a one-way ANOVA was calculated to examine potential differences in test scores (p < 0.05). RESULTS: None of the Pearson's r-coefficients achieved statistical significance. The one-way ANOVA and post hoc comparisons demonstrated that dynamic postural stability scores were significantly higher than static postural stability scores. CONCLUSIONS: A lack of a correlation between static and dynamic measures and increase in difficulty during dynamic measures indicates differences in the type and magnitude of challenge imposed by the different postural stability tasks. The more challenging dynamic measures of postural stability may be more suitable for prospective studies examining risk of ankle and knee injury in healthy, physically active individuals. PMID- 22498149 TI - Physiotherapist agreement when visually rating movement quality during lower extremity functional screening tests. AB - OBJECTIVES: To investigate physiotherapist agreement in rating movement quality during lower extremity functional tests using two visual rating methods and physiotherapists with differing clinical experience. DESIGN: Clinical measurement. PARTICIPANTS: Six healthy individuals were rated by 44 physiotherapists. These raters were in three groups (inexperienced, novice, experienced). MAIN MEASURES: Video recordings of all six individuals performing four lower extremity functional tests were visually rated (dichotomous or ordinal scale) using two rating methods (overall or segment) on two occasions separated by 3-4 weeks. Intra and inter-rater agreement for physiotherapists was determined using overall percentage agreement (OPA) and the first order agreement coefficient (AC1). RESULTS: Intra-rater agreement for overall and segment methods ranged from slight to almost perfect (OPA: 29-96%, AC1: 0.01 to 0.96). AC1 agreement was better in the experienced group (84-99% likelihood) and for dichotomous rating (97-100% likelihood). Inter-rater agreement ranged from fair to good (OPA: 45-79%; AC1: 0.22-0.71). AC1 agreement was not influenced by clinical experience but was again better using dichotomous rating. CONCLUSIONS: Physiotherapists' visual rating of movement quality during lower extremity functional tests resulted in slight to almost perfect intra-rater agreement and fair to good inter-rater agreement. Agreement improved with increased level of clinical experience and use of dichotomous rating. PMID- 22498150 TI - Elbow isokinetic strength characteristics among collegiate baseball players. AB - OBJECTIVES: To compare the bilateral strength characteristics of the wrist flexors, extensors, pronators, and supinators among baseball players. DESIGN: Cross-sectional. SETTING: Laboratory. PARTICIPANTS: 30 collegiate baseball players with no recent history of upper extremity injury. MAIN OUTCOME MEASURES: Bilateral pronation, supination, wrist flexion, and wrist extension peak torque (PT) and peak torque to body weight (PT/BW) strength were measured at speeds of 90 and 180 degrees /second. RESULTS: Paired t-tests showed that the throwing arm of baseball players produced significantly less PT/BW strength for supination at 90 degrees /second compared to the non-throwing arm (P = .001). The throwing arm produced significantly more PT/BW strength for pronation (P = .001) at 180 degrees /second compared to the non-throwing arm. Furthermore, the throwing arm had more PT and PT/BW strength for wrist extension (P < .005) at 180 degrees /second. Conversely, the throwing arm had less PT and PT/BW strength for supination (P < .004) and wrist flexion (P < .004) at 180 degrees /second compared to the non-throwing arm. CONCLUSIONS: Significant bilateral strength differences exist in pronation, supination, wrist flexion, and wrist extension among collegiate baseball players. With the steady increase in ulnar collateral ligament injuries of the elbow among baseball players and the proven resistance to valgus force provided by the flexor-pronator mass of the elbow, the results of this study may prove beneficial in the prevention, evaluation, and rehabilitation of such dysfunctions. PMID- 22498151 TI - Evidence of the physiotherapeutic interventions used currently after exercise induced muscle damage: systematic review and meta-analysis. AB - INTRODUCTION: Exhaustive and/or unaccustomed exercise, mainly involving eccentric muscle actions, induces temporary muscle damage, evidenced by delayed onset muscle soreness (DOMS) and decreased muscle function. Different strategies to recover from its signs and symptoms have been studied and, as a result, a significant number of articles on this issue have been published. OBJECTIVE: To assess whether some modalities currently used in physiotherapy such as massage, cryotherapy, stretching and low-intensity exercise are effective for treating the signs and symptoms of exercise-induced muscle damage. METHODS: Randomized controlled trials (RCTs), written in English or Portuguese, that included physiotherapeutic interventions [i.e., massage, cryotherapy, stretching and low intensity exercise, on adult human subjects (18-60 years old) of both gender] were searched on electronic databases including MEDLINE, CINHAL, EMBASE, PEDro and SPORTDiscus. MAIN OUTCOME MEASURES: "Muscle soreness" and "muscle strength" were the outcome measures included in the meta-analysis. RESULTS: Thirty-five studies were included; nine analysed the effects of massage, 10 examined the effects of cryotherapy, nine investigated the effects of stretching and seven focused on low-intensity exercise intervention. Massage was the only intervention with positive effects, reducing soreness at 24 h, on average, 0.33 on 10 cm visual analog scale (95 percent CI: -0.59, -0.07) and increasing muscle recovery by 1.87 percent (95 percent CI: 0.30, 3.44). Additionally, there is inconclusive evidence to support the use of cryotherapy, while there is little evidence to prove the efficacy of stretching and low-intensity exercise. CONCLUSION: Massage proved slightly effective in the relief of symptoms and signs of exercise-induced muscle damage. Therefore, its mean effect was too small to be of clinical relevance. There is a lack of evidence to support the use of cryotherapy, stretching and low-intensity exercise. PMID- 22498152 TI - Treatment of chronic Achilles tendon pain by Kinesio taping in an amateur badminton player. AB - OBJECTIVE: To evaluate the effects of Kinesio taping on a patient with chronic Achilles tendon pain. DESIGN: Case report. CASE DESCRIPTION: A 22-year-old male amateur badminton player slipped on the ground as he landed after jumping while playing badminton, resulting in chronic Achilles tendon pain of the dominant (right) leg. We performed Achilles tendon taping (ATT) over 5 weeks. RESULTS: The patient's ultrasonography showed that the tendon thickness was moderately reduced from 0.42 cm to 0.37 cm and that the angles of active dorsiflexion and active plantar flexion without pain increased from 15 degrees to 20 degrees and from 20 degrees to 45 degrees , respectively. The Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire score increased from 64 to 95, and the load-induced pain assessment score decreased from 6 to 0. The pain threshold increased from 0.8 kg to 10 kg. The tenderness at 3 kg, assessed on a numeric rating scale, decreased from 7 to 0, and the patient was able to play badminton and soccer without pain. CONCLUSIONS: We verified the effect with an increase in the active ankle joint range of motion and the VISA-A questionnaire score, which was achieved by a decrease in tenderness and pain from repeated ATT application. PMID- 22498153 TI - Rapid point-of-care tests for HIV and sexually transmissible infection control in remote Australia: can they improve Aboriginal people's and Torres Strait Islanders' health. PMID- 22498154 TI - Prevalence and genotype distribution of cervical human papillomavirus infection among female sex workers in Asia: a systematic literature review and meta analysis. AB - Cervical human papillomavirus (HPV) infection is highly transmissible. Although there are many studies on HPV infection in general population of women globally, little attention has been paid to female sex workers (FSWs) in Asia. In this study, we used a meta-analytic approach to systematically analyse the literature to elucidate the prevalence and genotype distribution of cervical HPV infection among FSWs in Asia. Fourteen eligible studies were identified in five databases, and data including 4198 FSWs from nine Asian countries were aggregated. Crude estimates of cervical HPV prevalence among FSWs in this region ranged from 12.8% to 84.8%. FSWs had a nearly 10-fold risk of HPV infection than the general population of women. Stratified analysis showed that HPV prevalence was higher in East Asia than other subregions and in younger FSWs than older FSWs. HPV genotype distribution was statistically different between East Asia and South-east Asia. In East Asia, the most prevalent genotypes were HPV 16 (23.9%), 18 (11.0%), 58 (9.4%), 56 (6.3%) and 52 (5.3%), while they were HPV 52 (12.9%), 16 (8.5%), 58 (5.2%), 18 (5.0%) and 66 (4.9%) in South-east Asia. HPV 31, 33 and 35 were less frequently found in both subregions. HPV infection was substantial among FSWs in some Asian countries. More studies are necessary to illustrate the overall picture of HPV infection in this region. PMID- 22498155 TI - Men's attitudes towards chlamydia screening: a narrative review. AB - OBJECTIVES: Chlamydia trachomatis is a sexually transmissible infection (STI) that affects significant numbers of men. Research on men's perspectives on chlamydia screening (or testing) has been limited. We conducted a narrative review to examine: (1) what factors encourage or discourage men from attending health services for chlamydia screening, and/or from accepting screening once it has been offered to them, and (2) where men want chlamydia screening services to be located. METHODS: A narrative review of the recent peer-reviewed literature (published between 1999 and 2009) on men's attitudes towards chlamydia screening. To be included, articles had to explore men's perspectives on screening (which could be ascertained through quantitative or qualitative studies, or from relevant discussion papers or reviews). RESULTS: Forty-eight articles were included in all. Men's attitudes towards chlamydia screening are influenced by their knowledge about the infection, their perceived vulnerability to the infection, the degree of embarrassment and shame that they associate with screening and the stigma that they associate with screening. Men prefer to be offered urine testing for chlamydia. Men want to be offered screening by non judgemental professionals. Men's attitudes towards screening for chlamydia in general practice, genito-urinary medicine clinics, home and outreach settings are also explored in this review. CONCLUSIONS: Several factors influence men's attitudes towards screening. Two central themes underlie and influence many of these factors: men's needs to make positive impressions on others, and men's identification with particular ideals of masculinity. The review concludes with suggestions for future research on this topic. PMID- 22498156 TI - Challenges to the effective delivery of health care to people with chronic hepatitis B in Australia. AB - BACKGROUND: The complexity of the hepatitis B natural history and its prevalence in specific populations in Australia challenges the capacity of the health system to deliver health care effectively to affected people. This study explores the challenges in delivering health care to people with chronic hepatitis B (CHB) in Australia. METHODS: We conducted a grounded theory based qualitative study in which data were gathered from 70 in-depth interviews with government program officers, clinicians and health and community workers across Australia, and four focus group discussions with 40 health and community workers from the communities most at risk of CHB. RESULTS: A systematic approach to screening populations at risk, including people born in countries with intermediate or high prevalence of CHB; consensus on clinical guidelines; development of a shared care framework for CHB involving general practitioners; and effective communication between patients and health professionals were identified as essential. Workforce development, particularly for primary health care professionals, and developing the knowledge and capacity of health professionals to communicate effectively with people with HBV were described as other major factors in reducing the barriers to CHB treatment in Australia. CONCLUSION: To improve the clinical management of people with CHB in Australia, the health system needs to encourage the screening of people at risk, improve access to clinical services, and the knowledge and communication skills of primary health care and community health service providers. This study supported developing a shared care model and related infrastructures including training programs, referral pathways and clinical guidelines. PMID- 22498157 TI - HIV incidence trends vary between jurisdictions in Australia: an extended back projection analysis of men who have sex with men. AB - BACKGROUND: Trends in HIV diagnoses differ across Australia and are primarily driven by men who have sex with men (MSM). We use national population surveillance data to estimate the incidence of HIV infections among MSM by jurisdiction and infer the proportion of undiagnosed infections. METHODS: Annual surveillance data for AIDS diagnoses, HIV diagnoses and recently acquired HIV infections were obtained from 1980 to 2009. A modified statistical back projection method was used to reconstruct HIV incidence by jurisdiction. RESULTS: HIV incidence among MSM peaked for all jurisdictions in the early 1980s and then declined into the early 1990s, after which incidence increased. Trends then differ between jurisdictions. In New South Wales (NSW) and South Australia, estimated HIV incidence peaked at 371 and 50 cases respectively in 2003, and has since decreased to 258 and 24 cases respectively in 2009. HIV infections in Queensland (Qld) have more than doubled over the past decade, from 84 cases in 2000 to 192 cases in 2009. Victoria and Western Australia have seen a rise in HIV incidence from 2000 to 2006 (to a peak of 250 and 38 incident cases respectively), followed by a plateau to 2009. HIV incidence in the Northern Territory, Tasmania and Australian Capital Territory have increased since 2000; however, case numbers remain small (<20 per year). The estimated proportion of HIV infections not yet diagnosed to 2009 ranges from 10% (NSW) to 18% (Qld), with an average of 12% across Australia. CONCLUSIONS: HIV diagnosis trends among MSM in Australia reflect changes in estimated incidence to 2009, and reveal the largest increase in the past 10 years in Qld. PMID- 22498158 TI - Could implementation of Australia's national gay men's syphilis action plan have an indirect effect on the HIV epidemic? AB - OBJECTIVES: The number of incident infections of syphilis and HIV have increased over the past decade across Australia, particularly among gay men. In other industrialised settings, syphilis epidemics have also resurged coincidentally with increases in HIV diagnoses. Sexually transmissible infections (STI) are a biologically plausible cofactor for increasing HIV transmission. We pose the question: could strategies purely targeting syphilis also have an indirect impact on HIV incidence? METHODS: We developed an agent-based computer model that simulates the transmission and disease progression of HIV and syphilis among a population of sexually active gay men, calibrated to reflect the epidemics in Victoria, Australia. The model was informed by detailed behavioural data from a variety of sources and was used to investigate the potential epidemiological impact of different public health interventions. RESULTS: Assuming that syphilis could act as a biological cofactor for HIV transmission, from no effect to increasing risk by five-fold, our model indicates that if Australia's syphilis action plan is effectively implemented then the number of HIV infections could decrease by up to 48% over the next decade in the absence of any specific HIV interventions. CONCLUSION: It is plausible that effective implementation of interventions targeting syphilis epidemics can have an indirect effect of mitigating the spread of HIV. The possible effects of STI should be considered in the design, implementation and evaluation of public health strategies and programs. PMID- 22498159 TI - When online becomes offline: attitudes to safer sex practices in older and younger women using an Australian internet dating service. AB - BACKGROUND: The prevalence of sexually transmissible infections (STIs) is increasing among older Australian women, partly due to re-partnering after divorce or death of a spouse. Older women may be less likely to use condoms with new sexual partners, exposing themselves to STIs. An online survey compared characteristics of internet dating women aged 40 and above with 18 to 39 year olds, and determined the factors associated with protective safer sex attitudes. METHODS: An email directed women who had logged onto the internet dating service 'RSVP' in the previous 6 months to a survey hosted by Family Planning New South Wales. The survey explored demographic factors, STI-related knowledge and attitudes towards safer sex practices. Factors associated with discussing STIs before sex and refusing sex without a condom with a new partner were analysed using logistic regression. RESULTS: The questionnaire was completed by 1788 women. Almost two-thirds (62.2%) were aged 40 or over. The majority (64.8%) were seeking a long-term partner. In the previous year, 41.5% of all women met a new sexual partner via the internet. Women aged >40 years were significantly more likely to discuss STIs with a new partner but less likely to refuse sex without a condom compared with younger women. CONCLUSIONS: The internet is a useful venue for women of all ages to meet new sexual partners. Older women are vulnerable to STI acquisition through failure to use condoms with a new partner. Research is needed to determine effective interventions to increase condom use in this age group. PMID- 22498160 TI - Providing HIV-negative results to low-risk clients by telephone. AB - BACKGROUND: In Australia, Health Department policies differ on the recommended method of providing HIV results. Traditionally, all results have been provided in person. Our aim was to trial provision of HIV-negative test results by telephone to low-risk clients attending sexual health services and to assess clients' preferences for delivery method. METHODS: During 4 months in 2009 at two sexual health services in Sydney, all clients assessed as low-risk for HIV infection were invited to receive their HIV result by telephone. Non-receipt of results was defined as failure to receive results within 30 days of the test being performed. RESULTS: Of 763 clients tested, 328 (43%) were excluded following risk assessment, 30 (4%) declined to participate and 405 (53%) were enrolled. Among enrolled clients, 86% received their HIV result by telephone within 30 days, 97% were satisfied with delivery of the result by telephone and 93% preferred telephone delivery for their next HIV result. Only one enrolled client returned a positive HIV result. Independent predictors of receiving results within the 30 day timeframe were clinic attendance for sexually transmissible infection screening (P=0.021), lack of anogenital symptoms (P=0.015) and not being a sex worker (P=0.001). CONCLUSIONS: In this study of telephone provision of HIV results to low HIV-risk clients, there were no adverse events and clients expressed satisfaction with the process plus a strong preference for telephone delivery of future results. There was a decreased rate of failure to receive HIV results compared with other Australian studies. PMID- 22498161 TI - The relationship between pornography use and sexual behaviours among at-risk HIV negative men who have sex with men. AB - OBJECTIVES: Although pornography is widely available and frequently used among many adults in the USA, little is known about the relationship between pornography and risk factors for HIV transmission among men who have sex with men. METHODS: Baseline assessments from a behavioural intervention trial for at risk men who have sex with men were conducted in Atlanta, GA in 2009. Univariate and multivariate generalised linear models were used to assess the relationships between known risk factors for HIV infection, time spent viewing pornography, and sex behaviours. RESULTS: One hundred forty-nine men reporting HIV-negative status and two or more unprotected anal sex partners in the past 6 months were enrolled in an intervention trial and completed survey assessments. Time spent viewing pornography was significantly associated with having more male sexual partners (B=0.45, SE=0.04, P<0.001) and unprotected insertive anal sex acts (B=0.28, SE=0.04, P<0.001). Moreover, increased substance use (drug use, B=0.61, SE=0.14, P<0.001; alcohol use, B=0.03, SE=0.01, P<0.01) and decreased perception of risk for HIV infection (B=-0.09, SE=0.04, P<0.05) were found to be significantly associated with greater time spent viewing pornography. CONCLUSIONS: This exploratory study is novel in that it sheds light on the associations between viewing pornography and sexual risk taking for HIV infection. Future studies in this area should focus on understanding how the content of pornography; in particular, the viewing of unprotected and protected sex acts, may affect sexual risk taking behaviour. PMID- 22498162 TI - Perceived stigma and social risk of HIV testing and disclosure among Iranian Australians living in the Sydney metropolitan area. AB - BACKGROUND: Fear of being stigmatised is a major social risk for seeking help in the HIV/AIDS arena. However, little is known about the social perceptions that people hold about the disease. This study explores the level of perceived stigma and its effect on the social risk of HIV testing and disclosure among Iranian Australians immigrants living in the Sydney metropolitan area. METHODS: A total of 236 Iranian-Australians immigrants aged 20-65 years participated in this cross sectional study. RESULTS: The majority of respondents (73.3%) perceived that HIV infected people face a great deal of or some stigma. Participants were concerned about being stigmatised if they tested positive or were known to be HIV-positive in the future. A significant majority expressed that such concerns would affect their decision-making related to HIV testing and disclosure. Females were more likely to perceive HIV/AIDS stigma. Multiple regression analyses showed that perceived HIV/AIDS stigma could explain 28.6% of the variance in social risk of HIV testing and disclosure (B=0.89, beta=0.53, P<0.0001) and 24.6% of the variance in decision-making related to HIV testing and disclosure (B=0.62, beta=0.49, P<0.0001) after controlling for sociodemographic factors. Time since migration (predictive power of 4.8-6.78%) strongly influenced the associations. CONCLUSIONS: If social stigma is left unaddressed, individuals would be reluctant to undertake HIV testing or disclose their HIV status if tested positive. Further attempts are needed to change the current social construction of HIV/AIDS among Iranians-Australians living in Sydney. PMID- 22498164 TI - Sexual behaviour of inmates with Chlamydia trachomatis infection in the prisons of Catalonia, Spain. AB - OBJECTIVE: To determine the prevalence of Chlamydia trachomatis (CT) and high risk factors for acquisition in preventive prisoners in Catalonia. METHODS: Cross sectional study of a convenience sample of 478 prisoners aged between 18 and 35 years was analysed using real-time polymerase chain reaction. A standardized questionnaire was used to collect behavioural data. Significant differences were analysed in the descriptive study using Pearson's chi(2). The association between CT and its determinants was analysed using the Mantel-Haenszel test and a multivariate logistic regression model. RESULTS: The overall prevalence of CT was 5.4%. The independent risk factors for infection by CT were as follows: foreign origin, having had concurrent sexual partners, and alcohol consumption. CONCLUSIONS: This is the first study performed in prisons of Catalonia that shows the prevalence of CT in young prisoners. The high mobility of young detainees could explain the similarity in prevalence obtained about young people in Catalonia. Systematic monitoring of CT infection in young preventive prisoners is important in order to prevent further problems in themselves and in the general population, since they become a 'bridge population' in sexually transmissible infection spreading. PMID- 22498163 TI - Gender, peer and partner influences on adolescent HIV risk in rural South Africa. AB - BACKGROUND AND METHODS: In preparation for a school-based intervention in KwaZulu Natal, South Africa, a cross-sectional survey of potential HIV risk factors in youth aged 14-17 (n=983) was conducted. RESULTS: Boys were significantly more likely than girls to report lifetime sexual activity (37.7% v. 13.8%, P<0.01). Among boys and girls, 46.1% reported condom use at last sex. Discussion of condom use with a partner was the strongest predictor of condom use (boys, odds ratio (OR)=7.39; girls, OR=5.58, P<0.0001). Age was independently associated with sexual activity for boys (OR=1.49, P<0.0001) and girls (OR=1.74, P=0.02). For boys, perceptions of male peer behaviour were associated with both ever having participated in sexual activity (OR=1.48, P<0.01) and condom use at last sex (OR=1.79, P<0.01). Girls who equated condom use with having numerous partners were more likely to use them. Among boys, results challenged some expected gender beliefs: support for girls' initiative in relationship formation and refusal of sex were significant predictors of sexual activity. Among girls, higher pregnancy risk perception (OR=1.32, P=0.02) and knowledge (OR=4.85, P=0.055) were associated with sexual activity. CONCLUSIONS: Creating more gender equitable norms can reduce HIV risk behaviours. HIV prevention interventions should build on existing gender equitable beliefs, and work to promote others, including sexual communication and negotiation skills, and modelling of positive peer norms. PMID- 22498165 TI - Rectal self-sampling in non-clinical venues for detection of sexually transmissible infections among behaviourally bisexual men. AB - Rectal sexually transmissible infections are a common health concern for men who have sex with men but little is known about these infections among men who have sex with both men and women. Self-obtained rectal specimens were collected from a diverse sample of behaviourally bisexual men. From a total sample of 75 bisexual men, 58 collected specimens. A relatively high prevalence of rectal Chlamydia trachomatis infection was found. Participants who collected specimens reported overall acceptability and comfort with self-sampling. Future efforts are needed focusing on increasing awareness of and options for rectal sexually transmissible infection testing among bisexual men. PMID- 22498166 TI - Clients' views on a piloted telemedicine sexual health service for rural youth. AB - BACKGROUND: Given the high rate of sexually transmissible infections among young people and limited rural access to specialist healthcare, an Australian telemedicine service was piloted. Clients' views were investigated. METHODS: All clients aged 15-24 were given a questionnaire. A sub-sample was interviewed. RESULTS: The service was used by 25 rural youths aged 15-24; 18 returned the questionnaire, 4 were interviewed. All had a telephone consultation. They reported being satisfied with the service; most preferred the telemedicine service to consulting a doctor in person. CONCLUSIONS: Online video consultations for sexual health may not yet be acceptable to young people in Australia. PMID- 22498167 TI - 'Yes wee can' - a nurse-driven asymptomatic screening program for chlamydia and gonorrhoea in a remote emergency department. AB - BACKGROUND: A nurse-driven, urine-based screening program for Neisseria gonorrhoeae and Chlamyida trachomatis was conducted in a remote emergency department targeting asymptomatic youth. METHODS: Individuals who presented to the Emergency Department with non-genitourinary complaints between the ages of 16 and 34 were offered free opportunistic urinary testing for gonorrhoea and chlamydia. RESULTS: In total, 178 eligible patients were offered screening, 65% consented for testing and 14 patients (12%) returned positive results, with 10 diagnoses of chlamydia, 9 of gonorrhoea and 5 with both. DISCUSSION: Emergency departments are an underutilised interface between difficult to reach at risk youth populations and public health services. PMID- 22498168 TI - HIV/AIDS related knowledge among school-going adolescents from the Middle East and North Africa. AB - The aim of this secondary analysis was to present cross-national data about HIV/AIDS related knowledge among 13- to 15-year-old school-going adolescents from the Middle East and North Africa. Data from 23673 school-going adolescents from seven countries (Jordan, Lebanon, Libyan Arab Jamahiriya, Morocco, Oman, Tunisia and United Arab Emirates) that undertook the Global School-Based Student Health Survey between 2004 and 2008 were analysed. HIV/AIDS related knowledge varied significantly between countries and gender. Research for this sensitive topic is scarce in this region. In addition, schools could be among the many key players for HIV/AIDS education. PMID- 22498169 TI - Use of alcohol, nicotine and other drugs in the Western Australian HIV Cohort study. AB - Self-report questionnaires on alcohol, nicotine and other drugs were administered to assess the current prevalence of alcohol, drug and nicotine use in our tertiary HIV service and inform the establishment of effective interventions. Many respondents reported use of alcohol over the preceding month (111 out of 152, 73%), and recent drug use (48 out of 137, 35%) and frequently both. Sessional alcohol consumption was prevalent among drinkers (52 out of 111, 47%), and correlated with both early treatment phase (P=0.009) and non-adherence (P=0.03). Encouraged by a notable proportion of patients expressing interest in clinic-based smoking cessation counselling, we recommend a targeted education strategy to motivate patients in health-seeking behaviours. PMID- 22498170 TI - Modified model of VX2 tumor overexpressing vascular endothelial growth factor. AB - PURPOSE: To determine whether upregulated expression of vascular endothelial growth factor (VEGF) in VX2 cells can increase vessel density (VD) and reduce tumor necrosis. MATERIALS AND METHODS: The VX2 cell line was transfected with expression vectors containing cDNA for rabbit VEGF. Stable clones producing rabbit VEGF (VEGF-VX2) were selected. VEGF-VX2 cells (n = 5 rabbits) or nontransfected VX2 cells (controls; n = 5 rabbits) were implanted into leg muscle of 10 rabbits. The animals were sacrificed at day 21. Tumor volume, percentage of necrosis, VD, and VEGF concentration in tumor protein extract were quantified. RESULTS: Overexpression of VEGF by VX2 cells augmented tumor implantation efficiency 100% and favored cyst formation. The tumor volume was significantly larger for VEGF-VX2 transfected tumors versus controls (P = .0143). Overexpression of VEGF in VX2 cells significantly increased the VD of the tumors (P = .0138). The percentage of necrosis was reduced in VEGF-VX2 tumors versus controls (19.5% vs 38.5 %; P = .002). VEGF concentration in VEGF-VX2 tumors was significantly higher than in control tumors (P = .041) and was correlated with tumor volume (rho = .883, P = .012). CONCLUSIONS: The overexpression of VEGF increased tumor growth and vascularization, favored cyst formation, and reduced tumor necrosis. This new phenotype of the VX2 tumor may offer some advantages over classic models of VX2 tumor for evaluating anticancer therapies. PMID- 22498171 TI - Dental anxiety and symptoms of general anxiety and depression in 15-year-olds. AB - OBJECTIVES: The objective of the study was to analyse the relationship between dental anxiety and symptoms of general anxiety and depression among 15-year-old individuals. METHODS: The sample analysed included 221 randomly selected 15-year old individuals living in the city of Jonkoping, Sweden. One questionnaire captured sociodemography and dental history, while dental anxiety was assessed by the Dental Fear Survey (DFS) and symptoms of general anxiety and depression by the Hospital Anxiety and Depression Scale (HADS). RESULTS: About 6% of the adolescents were classified as dentally anxious. Symptoms of general anxiety and depression were significantly correlated with dental anxiety in both the bivariate and multivariate analyses. The latter analyses were adjusted for gender and previous painful experiences of dental care. Individuals with high dental anxiety showed general anxiety scores on a clinical level (mean=9.8, SD=4.3). CONCLUSIONS: Symptoms of general anxiety and depression were shown to be significantly correlated with dental anxiety among 15-year-old individuals. PMID- 22498172 TI - Alterations in expression of specific microRNAs by combination of 4-HPR and EGCG inhibited growth of human malignant neuroblastoma cells. AB - Malignant neuroblastomas are childhood tumors that remain mostly incurable. We explored efficacy of N-(4-hydroxyphenyl) retinamide (4-HPR) and (-) epigallocatechin-3-gallate (EGCG) in altering expression of oncogenic microRNAs (OGmiRs) and tumor suppressor miRs (TSmiRs) for controlling growth of human malignant neuroblastoma SK-N-BE2 and IMR-32 cells. Combination of 4-HPR and EGCG most significantly decreased expression of OGmiRs (miR-92, miR-93, and miR-106b) and increased expression of TSmiRs (miR-7-1, miR-34a, and miR-99a) in both cell lines. Overexpression of miR-93 and miR-7-1, respectively, decreased and increased efficacy of treatments. Thus, alterations in expression of specific OGmiRs and TSmiRs by 4-HPR and EGCG inhibited growth of malignant neuroblastomas. PMID- 22498173 TI - Event-related potential evidence for separable automatic and controlled retrieval processes in proactive interference. AB - Interference between competing memories is a major source of retrieval failure, yet, surprisingly little is known about how competitive memory activation arises in the brain. One possibility is that interference during episodic retrieval might be produced by relatively automatic conceptual priming mechanisms that are independent of strategic retrieval processes. Such priming-driven interference might occur when the competing memories have strong pre-existing associations to the retrieval cue. We used ERPs to measure the neural dynamics of retrieval competition, and investigated whether the ERP correlates of interference were affected by varying task demands for selective retrieval. Participants encoded cue words that were presented either two or four times, paired either with the same or different strongly associated words across repetitions. In a subsequent test, participants either selectively recalled each cue's most recent associate, or simply judged how many times a cue had been presented, without requiring selective recall. Interference effects on test performance were only seen in the recall task. In contrast, ERPs during test revealed an early posterior positivity for high interference items that was present in both retrieval tasks. This early ERP effect likely reflects a conceptual priming-related N400 reduction when many associations to a cue were pre-activated. A later parietal positivity resembling the ERP correlate of conscious recollection was found only in the recall task. The results suggest that early effects of proactive interference are relatively automatic and independent of intentional retrieval processes, consistent with suggestions that interference can arise through conceptual priming. PMID- 22498174 TI - Sentence pitch change detection in the native and unfamiliar language in musicians and non-musicians: behavioral, electrophysiological and psychoacoustic study. AB - Previous ERP studies have shown that musicians detect a pitch change in spoken sentences better than non-musicians in both native (French, Schon et al., 2004) and unfamiliar (Portuguese, Marques et al., 2007) language. The aim of the present study was to further investigate differences between musicians and non musicians in processing pitch changes in spoken sentences. To study the effects of familiarity of intonational contour and of the presence of meaningful context, behavioral and electrophysiological data from Italian musicians and non-musicians were compared in a pitch incongruity detection task using sentences in the native (Italian) and foreign (French) language and in jabberwocky (meaningless sentences formed by pseudowords). Moreover, to examine whether these differences depend on enhanced auditory sensitivity to pitch, the frequency discrimination threshold (FDT) for tones was obtained using a psychophysical procedure. Musicians were more accurate than non-musicians in detecting small pitch changes in all languages showing a smaller response bias, as well as much lower FDTs than non musicians. The ERP data revealed shorter latencies of a late positivity over parietal sites in musicians than in non-musicians for weak and strong incongruities. Overall results confirmed musicians' advantage in detection of subtle pitch changes not only with tones but also with speech sentences in both native and unfamiliar languages. Such effect appears to emerge from more efficient pitch analysis trained by musical experience. PMID- 22498175 TI - Socially isolated mice exhibit a blunted homeostatic sleep response to acute sleep deprivation compared to socially paired mice. AB - Sleep is an important physiological process underlying maintenance of physical, mental and emotional health. Consequently, sleep deprivation (SD) is associated with adverse consequences and increases the risk for anxiety, immune, and cognitive disorders. SD is characterized by increased energy expenditure responses and sleep rebound upon recovery that are regulated by homeostatic processes, which in turn are influenced by stress. Since all previous studies on SD were conducted in a setting of social isolation, the impact of the social contextual setting is unknown. Therefore, we used a relatively stress-free SD paradigm in mice to assess the impact of social isolation on sleep, wakefulness and delta electroencephalogram (EEG) power during non-rapid eye movement (NREM) sleep. Paired or isolated C57BL/6J adult chronically-implanted male mice were exposed to SD for 6h and telemetric polygraphic recordings were conducted, including 18 h recovery. Recovery from SD in the paired group showed a significant decrease in wake and significant increase in NREM sleep and rapid eye movement (REM), and a similar, albeit less robust response occurred in the isolated mice. Delta power during NREM sleep was increased in both groups immediately following SD, but paired mice exhibited significantly higher delta power throughout the dark period. The increase in body temperature and gross motor activity observed during the SD procedure was decreased during the dark period. In both open field and elevated plus maze tests, socially isolated mice showed significantly higher anxiety than paired mice. The homeostatic processes altered by SD are differentially affected in paired and isolated mice, suggesting that the social context of isolation stress may adversely affect the quantity and quality of sleep in mice. PMID- 22498176 TI - Kynurenic acid and 3-hydroxykynurenine production from D-kynurenine in mice. AB - Kynurenic acid (KYNA), an antagonist of the alpha7 nicotinic acetylcholine receptor and the N-methyl-D-aspartate receptor, and 3-hydroxykynurenine (3-HK), a generator of reactive oxygen species, are neuroactive metabolites of the kynurenine pathway of tryptophan degradation. In the mammalian brain as elsewhere, both compounds derive from a common bioprecursor, L-kynurenine (L KYN). Recent studies in rats demonstrated that D-kynurenine (D-KYN), a metabolite of the bacterial amino acid D-tryptophan, can also function as a bioprecursor of brain KYNA. We now investigated the conversion of systemically administered D-KYN to KYNA in mice and also explored the possible production of 3-HK in the same animals. Thirty min after an injection of D-KYN or L-KYN (30 mg/kg, i.p.), newly produced KYNA and 3-HK were recovered from plasma, liver, forebrain and cerebellum in all cases. Using a new chiral separation method, 3-HK produced from D-KYN was positively identified as D-3-HK. L-KYN was the more effective precursor of KYNA in all tissues and also exceeded D-KYN as a precursor of brain 3-HK. In contrast, D-KYN was more potent as a precursor of 3-HK in the liver. The production of both KYNA and 3-HK from D-KYN was rapid in all tissues, peaking at 15-30 min following a systemic injection of D-KYN. These results show that biosynthetic routes other than those classically ascribed to L-KYN can account for the synthesis of both KYNA and 3-HK in vivo. This new insight may be of significant physiological or pathological relevance. PMID- 22498177 TI - Dynamic changes of mitochondrial fission proteins after transient cerebral ischemia in mice. AB - With fusion or fission, mitochondria alter their morphology in response to various physiological and pathological stimuli resulting in either elongated, tubular, interconnected or fragmented form. Immunohistochemistry and Western blot analyses were performed at 2, 7, 14 and 28 d after 90 min of transient middle cerebral artery occlusion (tMCAO) in mice. The present study showed that mitochondrial fission protein fission 1 (Fis1) and phosphorylated dynamin-related protein 1 (P-Drp1) both progressively increased with the peak at 14 d after tMCAO. Double immunofluorescent analysis showed the number of double positive cells with Fis1/Drp1 reduced between 2 and 28 d after 90 min of tMCAO, and also showed some double positive cells with Fis1/terminal deoxynucleotidyl transferase mediated dUTP-digoxigenin nick end labeling (TUNEL) in the peri-infract regions at 2d after the reperfusion. The present study suggests a progressive activation of mitochondrial fission proteins Fis1 and P-Drp1 in relation to apoptotic process in neural cells of the peri-infract regions after tMCAO. PMID- 22498179 TI - Colonoscopy screening markedly reduces the occurrence of colon carcinomas and carcinoma-related death: a closed cohort study. AB - BACKGROUND: Colonoscopy with a possible polypectomy is an efficient and preferred screening method to reduce the incidence of colorectal cancer (CRC). However, critics argue that, to date, a reduction of incidence and mortality from CRC has not been demonstrated in a population-based setting. OBJECTIVE: To compare the incidence of and mortality from CRC among individuals screened by colonoscopy and non-screened individuals. DESIGN: A closed cohort study. SETTING: Population based setting in a precisely defined area with a low level of population migration. PATIENTS: This study involved 1912 screened and 20,774 control participants. INTERVENTION: CRC cases in this closed cohort study were prospectively collected during the screening period of 1 year and the follow-up period of 6 years. MAIN OUTCOME MEASUREMENTS: Follow-up data were corrected for negligible migration balance in the area. Tumor characteristics and risk or protective factors, age and sex, participation in general health screening examinations, history of CRC in a first-degree relative, smoking status, body mass index, frequency of sports activity, eating habits, and patients' professions were recorded. RESULTS: Overall cancer incidence was significantly lower in the screened group compared with the non-screened group (adjusted odds ratio [OR] 0.31; 95% confidence interval [CI], 0.16-0.59; P < .001). Colon cancer associated mortality also was clearly lower (adjusted OR 0.12; 95% CI, 0.01-0.93; P = .04). Risk factors such as lifestyle, smoking, and body mass index as well as family history were similar in both groups. Blue-collar workers had a higher incidence of CRC compared with professionals. The risk factors for CRC were a positive family history and smoking. LIMITATIONS: Number and ethnicity of the participants, non-randomized study. CONCLUSION: Colonoscopy with polypectomy significantly reduces CRC incidence and cancer-related mortality in the general population. PMID- 22498178 TI - Characterization of the pancreas in vivo using EUS spectrum analysis with electronic array echoendoscopes. AB - BACKGROUND: Spectral analysis of the radiofrequency (RF) signals that underlie grayscale EUS images has been used to provide quantitative, objective information about tissue histology. OBJECTIVE: Our purpose was to validate RF spectral analysis as a method to distinguish between chronic pancreatitis (CP) and pancreatic cancer (PC). DESIGN AND SETTING: A prospective study of eligible patients was conducted to analyze the RF data obtained by using electronic array echoendoscopes. PATIENTS: Pancreatic images were obtained by using electronic array echoendoscopes from 41 patients in a prospective study, including 15 patients with PC, 15 with CP, and 11 with a normal pancreas. MAIN OUTCOME MEASUREMENTS: Midband fit, slope, intercept, correlation coefficient, and root mean square deviation from a linear regression of the calibrated power spectra were determined and compared among the groups. RESULTS: Statistical analysis showed that significant differences were observable between groups for mean midband fit, intercept, and root mean square deviation (t test, P < .05). Discriminant analysis of these parameters was then performed to classify the data. For CP (n = 15) versus PC (n = 15), the same parameters provided 83% accuracy and an area under the curve of 0.83. LIMITATIONS: Moderate sample size and spatial averaging inherent in the technique. CONCLUSIONS: This study shows that mean spectral parameters of the backscattered signals obtained by using electronic array echoendoscopes can provide a noninvasive method to quantitatively discriminate between CP and PC. PMID- 22498180 TI - A plea for delivery of high-voltage shocks during implantable cardioverter defibrillator replacement or system upgrade. AB - We report the case of a faulty lead that led to failure to defibrillate during defibrillation threshold testing at the time of elective generator replacement. Standard lead measurements failed to detect the malfunction. Many centres perform neither defibrillation threshold testing nor commanded high-energy shock delivery. Even changes in the position of the lead in relation to the generator may cause problems that will go undetected without high-voltage shock delivery. We therefore caution against the wholesale abandonment of high-voltage shock testing in patients with pre-existing implanted leads. PMID- 22498182 TI - Imaging tracheobronchomalacia in the 21st century. PMID- 22498181 TI - Therapeutic benefit of internet-based lifestyle counselling for hypertension. AB - BACKGROUND: Preventive electronic (e)-counselling has been shown to reduce cardiovascular risk factors. However, heterogeneity in outcomes is commonly reported due to differences in e-protocols. We incorporated key features of an established behavioural therapy, motivational interviewing, to help standardize e counselling in order to reduce blood pressure in patients with hypertension. METHODS: Subjects (n = 387, mean age = 56 years, 59% female, 72% taking >= 1 antihypertensive drug) were diagnosed with stage 1 or 2 hypertension. Subjects were randomized to a 4-month protocol of e-counselling (beta version of the "Blood Pressure Action Plan", Heart and Stroke Foundation of Canada) vs waitlist control (general e-information on heart-healthy living). Outcomes were systolic, diastolic, and pulse pressures, and total lipoprotein cholesterol after treatment. RESULTS: Intention to treat analysis did not find a significant group difference in outcomes due to contamination across the 2 arms of this trial. However, per protocol analysis indicated that subjects receiving >= 8 e counselling messages (a priori therapeutic dose) vs 0 e-counselling messages (control) demonstrated greater reduction in systolic blood pressure (mean, -8.9 mm Hg; 95% confidence interval [CI], -11.5 to -6.4 vs -5.0 mm Hg; 95% CI, -6.7 to -3.3, P = 0.03), pulse pressure (-6.1 mm Hg; 95% CI, -8.1 to -4.1 vs -3.1 mm Hg; 95% CI, -4.3 to -1.8, P = 0.02) and total cholesterol (-0.24 mmol/L; 95% CI, 0.43 to -0.06 vs 0.05 mmol/L; 95% CI, -0.06 to 0.16, P = 0.03), but not diastolic blood pressure. CONCLUSIONS: These findings support the merit of evaluating whether e-counselling can improve blood pressure control and reduce cardiovascular risk over the long-term. PMID- 22498183 TI - 18F-FDG and new positron emitter radiotracers for detecting recurrent medullary thyroid carcinoma. PMID- 22498184 TI - 18F-FDG-PET and 18F-FDG-PET/CT in the detection of recurrent or metastatic medullary thyroid carcinoma: a systematic review and meta-analysis. AB - The aim of this study was to investigate diagnostic performance of (18) F fluorodeoxyglucose position emission tomography (FDG-PET) and PET/computed tomography (PET/CT) for detection of recurrent or metastatic medullary thyroid carcinoma (MTC) in patients after surgery with a meta-analysis. MEDLINE and EMBASE databases were searched for relevant articles. Two investigators independently extracted the data about study characteristics and examination results. Pooled estimates of sensitivity of FDG-PET or FDG-PET/CT were obtained. Fifteen studies met all inclusion criteria. The sensitivity of FDG-PET ranged from 0.47 (95% confidence intervals (CI): 0.21-0.73) to 0.96 (95%CI: 0.86-0.99), the sensitivity of FDG-PET/CT ranger from 0.47 (95% CI: 0.31-0.64) to 0.80 (95% CI: 0.65-0.90). The pooled sensitivities of FDG-PET and PET/CT were 0.68 (95% CI: 0.64-0.72) and 0.69 (95% CI: 0.64-0.74), respectively. There was no statistic significant between FDG-PET and PET/CT. Our results indicate that FDG-PET or FDG PET/CT has reasonable sensitivity in detecting recurrent or metastatic MTC after primary surgery. However, no single diagnostic technique is able to reliably demonstrate the full extent of disease in patients with recurrent or metastatic MTC, the combination of cross-sectional radiography with FDG-PET or PET/CT is recommended. PMID- 22498185 TI - CT features of peripheral T-cell lymphoma in the gastrointestinal tract in Chinese population and literature review. AB - INTRODUCTION: The aim of the study was to retrospectively investigate the CT features in peripheral T-cell lymphoma (PTCL) of the gastrointestinal tract in the Chinese population. METHODS: Computed tomography scans of 15 histopathologically proven cases of PTCL involving the gastrointestinal tract were retrospectively reviewed for characteristics such as sites, multiplicity, morphological features, the pattern and degree of contrast enhancement, lymphadenopathy, involvement of other organs and complications such as perforation, intussusceptions, ascites and so on. By reviewing the literature, CT findings of PTCL involving the gastrointestinal tract were compared with that involved by B-cell lymphoma. RESULTS: PTCLs involved the stomach and intestine in six and nine patients, respectively. Multiplicity was seen in seven patients, and solitary involvement was seen in eight. At CT, wall thickening was the predominant finding in all cases with an exception of one intestinal PTCL case presented as polypoid mass. Among the 14 patients, the gastric or bowel wall thickening was mild (<10 mm) in three, moderate (10-20 mm) in 10 and severe (>20 mm) in one. Nine cases demonstrated mild homogeneous enhancement, whereas six showed mild heterogeneous enhancement. Lymphadenopathy was present in eight patients, five of which were non-bulky (diameter <5 cm) and diffuse type and the rest (three) were non-bulky and localised type. Other organs were involved in four patients. Perforation as complication was evident in one gastric and five intestinal lymphomas (55.6%). Among the nine intestinal PTCLs, seven of the patients were male (77.9%) and the rest (two) were female with a median age of 37.1 years old. Intestinal PTCLs predominantly involved colon (n = 5). Other sites of involvement were ileum (n = 1), ileocaecum (n = 1), ileum and ileocaecum (n = 1) and entire bowel segment from distal ileum to transverse colon (n = 1). CONCLUSION: PTCLs have some distinguishing radiological features from B-cell type gastrointestinal lymphomas as mild or moderate gastric or bowel wall thickening and higher incidence of perforation with multiplicity. In China, intestinal PTCLs are not usually associated with coeliac disease and commonly present in a young male population with colon being the most frequent site of involvement. PMID- 22498186 TI - Evaluation of image quality and patient safety: paired inspiratory and expiratory MDCT assessment of tracheobronchomalacia in paediatric patients under general anaesthesia with breath-hold technique. AB - OBJECTIVE: The purpose of our investigation was to evaluate image quality and patient safety in infants and young children who required general anaesthesia with breath-hold technique for paired inspiratory and expiratory multidetector CT (MDCT) assessment of tracheobronchomalacia (TBM). MATERIALS AND METHODS: Our hospital's institutional review board approved the review of radiological and clinical data of a consecutive series of 20 paediatric patients who underwent MDCT under general anaesthesia with breath-hold technique for evaluation of TBM from May 2006 to December 2008. For each MDCT study, two fellowship-trained paediatric radiologists reviewed the inspiratory and expiratory MDCT images in an independent, randomised and blinded fashion for the presence of motion artefact at three anatomic levels (upper, middle and lower central airways). The clinical history and anaesthesia outcome, including the occurrence of any adverse events during or following the MDCT examinations until discharge, were also reviewed and recorded. RESULTS: The study population consisted of 20 infants and young children (13 boys/seven girls, mean age 1.7 +/- 1.4 years, age range 11 days to 4 years). The imaging quality of all 20 MDCT studies was diagnostic with no motion artefact in 16 studies (80%) and minimal motion artefact in the remaining four studies (20%). Minor adverse events occurred in three patients (15%) that included one patient (5%) with a brief (<60 s) oxygen desaturation during MDCT study, which resolved with oxygen, and two patients (5%) with either a brief (<60 s) oxygen desaturation (n = 1, 5%) or cough (n = 1, 5%) during recovery period, which were completely resolved with oxygen and dexamethasone, respectively. CONCLUSION: Diagnostic quality paired inspiratory and expiratory MDCT imaging with breath-hold technique can be safely performed in infants and young children under general anaesthesia for evaluation of TBM. PMID- 22498187 TI - Low-lying placenta: who should be recalled for a follow-up scan? AB - INTRODUCTION: The incidence of low-lying placenta or placenta praevia in the second trimester has been reported at 1-5%; however, recent unpublished audits suggest our recall rates are higher. We wanted to assess our recall rates in a large sample size and determine whether we could reduce the placenta-os distance for recalling women with low-lying placenta, while still identifying all cases of placenta praevia at delivery. METHODS: We undertook a retrospective analysis from March 2005 to March 2008 of women attending for 18-20-week obstetric ultrasounds. Patients with a singleton pregnancy and a placenta <=2 cm from the internal cervical os were included. Follow-up scan results and delivery data were collected. RESULTS: Four hundred eight women were identified as having a low lying placenta at the 18-20-week scan (107 (9%) at Dunedin Hospital and 301 (5%) at Otago Radiology). Fifty-eight women (14%) were excluded, leaving 350 women included in the analysis. Three hundred seventeen (91%) had a placenta clear of the internal os on their follow-up scan while 33 women (9%) had persistent placenta praevia. At a distance of >=1.9 cm, there was 100% sensitivity for detection of placenta praevia on the 18-20-week scan. As the placenta-os distance decreases the sensitivity for detection of placenta praevia reduces. CONCLUSIONS: Placenta praevia at term can occur where the placenta is up to 1.9 cm from the internal cervical os on the 18-20-week anatomy scan. Consequently, we will continue to recall women for a follow-up scan where the placenta is <=2 cm from the internal os. PMID- 22498188 TI - Study of patients with intravenous contrast extravasation on CT studies, with radiology staff and ward staff cannulations. AB - INTRODUCTION: Intravenous (IV) contrast extravasation is an adverse outcome of computed tomography (CT) studies. This study evaluates for any differences in rates of extravasation between radiology (radiographer) staff and ward medical staff cannulations, and secondarily by cannula size and study type. METHOD: A prospective study of 26,854 studies in adults between September 2004 and April 2008 accumulated 119 extravasations. Patients were divided into two groups, those cannulated by radiology staff and those cannulated by non-radiology staff. Patients with extravasations were followed for treatment outcomes. Statistical analysis between our groups was undertaken. RESULTS: The total extravasation rate was 0.44%. The extravasation rate for those patients cannulated by radiology staff was 0.34% (n= 11,470 cannulations) and those cannulated by non-radiology staff was 0.52% (n = 15,384 cannulations). This was not statistically significantly different. The site where most extravasations occurred was at the elbow (71.4%). The injection rate where most extravasations occurred was in the 1 2 mL/s range (42%). No patient required surgical intervention or had any significant morbidity. CONCLUSION: Radiology radiographer staff can provide safe administration of IV contrast in CT scanning with low rates of extravasation. Extravasation may occur with high or low injection rates and when small or large size cannulas are used. PMID- 22498189 TI - Efficacy of patient questionnaire in predicting renal dysfunction in outpatients older than 60 years of age prior to contrast-enhanced computed tomography. AB - INTRODUCTION: Contrast-induced nephropathy (CIN), a common iatrogenic cause of acute renal failure, is preventable. Identification of impaired renal function prior to intravenous contrast is important. Questionnaire screening has been useful to negate the need for cumbersome and costly renal function testing on all patients prior to contrast-enhanced CT (CECT). The Royal Australian and New Zealand College of Radiologists guidelines include age older than 60 as a risk marker requiring renal function testing. The aim of this retrospective study is to assess the efficacy of the pre-CT questionnaire in identifying patients with pre-existing renal impairment even in this older than 60 age group. METHODS: All outpatients were given questionnaires containing 11 CIN risk markers prior to CECT. Radiographers documented age, gender, serum creatinine and/or estimated glomerulofiltration rate (eGFR mL/min/1.72 m(2) ) within 3 months of CT. Questionnaires of all patients older than 60 years were collated. The data was tabulated and analyzed. Incomplete questionnaires were excluded. RESULTS: 134/171 (78.4%) patients had eGFR >= 60 and 37/171 (21.6%) had eGFR < 60, with 31/171 (18.1%) having eGFR between 30 and 60 and 3/171 (1.8%) having eGFR < 30. 47/171 (27.5%) circled 'no' to all risk markers. Percentage for sensitivity is 81.1% (95% confidence interval (CI) 64.8-92%), for specificity 29.9% (95% CI 22.3 38.4%), for positive predictive value 24.2% (95% CI 17-32.7%) and for negative predictive value 85.1% (95%CI 71.7-93.8%). Kidney disease, anaemia, myeloma and vasculitis seem to be statistically significant risk factors (P < 0.05). All three true-positive patients with eGFR < 30 indicated known kidney disease. Seven false-negative patients had eGFR 30-60, with 4/7 (57.1%) having CIN risk markers in their medical records. CONCLUSION: Questionnaire screening for CIN risk has a high negative predictive value (85.1%) even in patients older than 60 years. PMID- 22498190 TI - Common patterns in 558 diagnostic radiology errors. AB - INTRODUCTION: As a Quality Improvement initiative our department has held regular discrepancy meetings since 2003. We performed a retrospective analysis of the cases presented and identified the most common pattern of error. METHODS: A total of 558 cases were referred for discussion over 92 months, and errors were classified as perceptual or interpretative. The most common patterns of error for each imaging modality were analysed, and the misses were scored by consensus as subtle or non-subtle. RESULTS: Of 558 diagnostic errors, 447 (80%) were perceptual and 111 (20%) were interpretative errors. Plain radiography and computed tomography (CT) scans were the most frequent imaging modalities accounting for 246 (44%) and 241 (43%) of the total number of errors, respectively. In the plain radiography group 120 (49%) of the errors occurred in chest X-ray reports with perceptual miss of a lung nodule occurring in 40% of this subgroup. In the axial and appendicular skeleton missed fractures occurred most frequently, and metastatic bone disease was overlooked in 12 of 50 plain X rays of the pelvis or spine. The majority of errors within the CT group were in reports of body scans with the commonest perceptual errors identified including 16 missed significant bone lesions, 14 cases of thromboembolic disease and 14 gastrointestinal tumours. Of the 558 errors, 312 (56%) were considered subtle and 246 (44%) non-subtle. CONCLUSION: Diagnostic errors are not uncommon and are most frequently perceptual in nature. Identification of the most common patterns of error has the potential to improve the quality of reporting by improving the search behaviour of radiologists. PMID- 22498191 TI - Magnetic resonance features of primary central nervous system lymphoma in the immunocompetent patient: a pictorial essay. AB - Primary central nervous system lymphoma (PCNSL) is an uncommon but important variant of non-Hodgkin lymphoma and represents up to 6% of all primary central nervous system (CNS) malignancies. Recognition of this entity by radiologist on MRI may avoid unnecessary neurosurgical resection and redirect to biopsy. The pretreatment MRI of patients with biopsy proven PCNSL from the last 5 years at our institution was reviewed. Selected examples were used to construct a pictorial essay to illustrate some of the typical and atypical MR features of PCNSL. MRI of other CNS conditions with imaging similarities to PCNSL was included to demonstrate possible mimics. The typical features of PCNSL lymphoma are intra-axial homogenous single or multiple contrast enhancing lesions, with marked surrounding oedema and restricted diffusion, usually contacting a cerebrospinal fluid (CSF) surface. Necrosis, peripheral enhancement, haemorrhage or calcification are unusual and other diagnoses should be considered if any of these features are present. Potential mimics include high grade glioma, infarcts, metastatic disease, demyelination, abscess and secondary lymphoma. Careful assessment of the MR features and correlation with the clinical findings should enable the radiologists to raise the possibility of PCNSL and minimise the risk of unnecessary resection. PMID- 22498192 TI - Advantages of blood pool contrast agents in MR angiography: a pictorial review. AB - Gadofosveset trisodium (Ablavar(r), formerly Vasovist(r)) is the first intravascular contrast agent approved for clinical use in peripheral vascular disease. The purpose of this review is to illustrate the clinical uses of gadofosveset-enhanced magnetic resonance angiography in patients referred for assessment of arteriovenous disease. Superior T1 shortening enables first pass renal and peripheral arteriography of quality comparable with larger doses of extracellular agents. In applications such as thoracic outlet syndrome, there may be other advantages such as superior venous imaging and need for only one injection. Steady-state delayed imaging provides high resolution mapping of both arterial and venous systems and imaging of multiple territories. A combination of dynamic and delayed steady-state imaging can provide detailed anatomy and flow characteristics of vascular malformations and mapping for percutaneous sclerotherapy at one investigation. The ability to image in the steady state can provide minimally invasive imaging of thrombo-occlusive disease of central veins. PMID- 22498193 TI - Uncommon pulmonary metastasis presenting as pulmonary infarction with tumour emboli in two cases. AB - We report two cases of pathologically proven pulmonary metastases presenting as pulmonary infarction with tumour emboli. In two cases, high-resolution CT showed multiple small subpleural consolidations in both lungs. The patients had breast cancer and uterine cervix cancer, respectively. Although various pulmonary diseases show subpleural consolidations on CT, pulmonary metastases by tumour emboli should be primarily considered in differential diagnosis especially when the patient has known malignancy. PMID- 22498194 TI - Impact of FDG-PET on lung cancer delineation for radiotherapy. AB - PURPOSE: The purpose of this study is to assess the impact of fused diagnostic F 18 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) and planning FDG-PET/CT scans on voluming of lung cancer for radiotherapy. METHODS: Five radiation oncologists (ROs), five radiation oncology trainees and a radiologist contoured five cases of non-small cell lung cancer. The CT alone, the diagnostic FDG-PET/CT and planning FDG-PET/CT each registered to the CT, were used to contour three volumes. The concordance index (CI) was used to compare each volume with a reference RO. RESULTS: Although there was considerable inter-observer variability in CT contouring, there was no significant difference between mean volumes of the gross tumour volume for the RO and radiation oncology trainees using any technique. There was no increase in CI with the addition of PET/CT, either diagnostic or planning, for the RO. However, the volumes of the radiation oncology trainees showed a significant increase in CI from 65.8% with CT alone to 68.0% and 72.3% with diagnostic PET/CT and planning PET/CT, respectively (P = 0.028). Mean variation at the tumour/mediastinum interface was significantly reduced with addition of registered PET/CT. CONCLUSIONS: The concordance of RO with the reference RO did not significantly increase with use of integrated FDG PET/CT images. However, the contouring of radiation oncology trainees' became more concordant with the reference. PMID- 22498195 TI - Radiotherapy with concurrent or sequential temozolomide in elderly patients with glioblastoma multiforme. AB - OBJECTIVE: The objective of this article was to evaluate therapeutic outcomes of elderly patients with glioblastoma multiforme (GBM) treated by surgery followed by combined modality therapy and compare achievable outcomes to those of a younger age population. METHODS AND MATERIALS: Seventy-eight adult patients with histologically confirmed grade IV astrocytoma were treated at King Hussein Cancer Center (Amman, Jordan) between September 2004 and December 2008. Records were retrospectively reviewed and included 55 males and 23 females between 19 and 78 years of age (median age 50 years). This case series included 20 patients aged 60 years or older. All patients underwent craniotomy followed radiotherapy and concurrent or sequential temozolomide. The follow-up ranged from 1 to 56 months (median 9.4 months). RESULTS: The median survival for the whole cohort was 13.8 months. The median survival for patients less than 60 years was 14.3 months and for patients 60 years or older was 12.3 months (P = 0.19). Among elderly patients, radical surgical resection (P = 0.002), concurrent delivery of chemoradiation (0.041) and radiotherapy dose >= 5400 cGy (P = 0.0001) conferred statistically significant improvements in overall survival. CONCLUSION: Management of GBM in elderly patients should include maximal surgical resection followed by radiotherapy and temozolomide whenever medically feasible. Outcomes comparable to those obtained in younger age groups can be expected. Our results indicate that concurrent chemoradiation is superior to sequential chemoradiation in these patients. PMID- 22498196 TI - Optimising the dosimetric quality and efficiency of post-prostatectomy radiotherapy: a planning study comparing the performance of volumetric-modulated arc therapy (VMAT) with an optimised seven-field intensity-modulated radiotherapy (IMRT) technique. AB - PURPOSE: The purpose of this study was to compare and evaluate radiotherapy treatment plans using volumetric modulated arc therapy (VMAT) and intensity modulated radiotherapy (IMRT) for post-prostatectomy radiotherapy. METHODS AND MATERIALS: The quality of radiotherapy plans for 10 patients planned and treated with a seven-field IMRT technique for biochemical failure post-prostatectomy were subsequently compared with 10 prospectively planned single-arc VMAT plans using the same computed tomography data set and treatment planning software. Plans were analysed using parameters to assess for target volume coverage, dose to organs at risk (OAR), biological outcomes, dose conformity and homogeneity, as well as the total monitor units (MU), planning and treatment efficiency. RESULTS: The mean results for the study population are reported for the purpose of comparison. For IMRT, the median dose to the planning target volume, V(95%) and D(95%) was 71.1 Gy, 98.9% and 68.3 Gy compared with 71.2 Gy, 99.2% and 68.6 Gy for VMAT. There was no significant difference in the conformity index or homogeneity index. The VMAT plans achieved better sparing of the rectum and the left and right femora with a reduction in the median dose by 7.9, 6.3 and 3.6 Gy, respectively. The total number of monitor units (MU) was reduced by 24% and treatment delivery time by an estimated 3 min per fraction without a significant increase in planning requirements. CONCLUSIONS: VMAT can achieve post-prostatectomy radiotherapy plans of comparable quality to IMRT with the potential to reduce dose to OAR and improve the efficiency of treatment delivery. PMID- 22498197 TI - HDR brachytherapy combined with external beam radiation for localised prostate cancer: early experience from the Sydney Cancer Centre. AB - INTRODUCTION: To report the toxicity and early efficacy of high-dose rate brachytherapy (HDR) as a boost to external beam radiation (EBRT) in the treatment of localised prostate cancer. METHODS: Between December 2002 and November 2007, 101 consecutive patients with intermediate or high risk prostate cancer were treated with EBRT plus an HDR boost. The HDR boost was initially delivered in three fractions of 6.5 Gy each via one implant; this was subsequently modified to a two-fraction technique with separate implants 2 weeks apart (8.5 Gy each). Most patients also received at least 3 months of androgen ablation. RESULTS: Our cohort included 65 intermediate risk and 36 high-risk patients. Sixty-seven patients received the three-fraction regime; 34 the two-fraction schedule. Median follow-up was 56 months, at which time 82% of patients were free from failure. The 4-year disease-free survival for intermediate and high-risk groups was 95% and 66%, respectively (overall 85%). Significant acute toxicities included clot retention (eight patients), one traumatic urethral injury, one case of retention requiring suprapubic catheter placement, one case of new onset atrial fibrillation and three cases of pulmonary emboli. At 4 years, the rate of late grade 2 genitourinary toxicity was 8%; two patients experienced grade 3 toxicity. No late grade 3 gastrointestinal toxicity was observed. Potency was preserved in 72% of those patients reporting normal pre-treatment sexual function. CONCLUSIONS: Our cohort experienced toxicity similar to previously published HDR boost series with very promising early efficacy results. PMID- 22498198 TI - Medulloblastoma: progress over time. AB - INTRODUCTION: Medulloblastoma is the most common central nervous system tumour in children aged 0-4 years, with 75% of cases occurring in patients <16 years, and rare in adults. The intent of this audit is to review a single centre's experience and to compare outcomes with other centres' outcomes. METHODS: This Ethics approved retrospective audit evaluates the paediatric population aged <16 years who received radiotherapy as their initial or salvage treatment at the Prince of Wales Hospital Cancer Centre between 1972 and 2007. The primary and secondary end-points were progression-free survival (PFS) and cancer-specific survival (CSS), with comparisons made between patients treated before and after 1990, and the impact of high- and low-risk disease. RESULTS: There were 80 eligible patients, 78 who had radiotherapy at initial presentation, and 2 at the time of recurrence. Median age was 6.5 years, 52 were boys and 28 were girls. Seventy-eight patients had a surgical procedure and ultimately received craniospinal radiotherapy. Of these 78 patients, 32 (40%) had a macroscopically complete resection. The 5-year PFS was 69.7%. The 5-year PFS for patients treated pre and post 1990 was 66.1% and 71.8%, respectively. The 5-year CSS for high- and low-risk patients was 61.1% and 78.4%, respectively. Ultimately, 33% of patients were dead due to disease. CONCLUSION: This audit demonstrates those children referred to this facility for treatment have comparable survival to that of other major centres. PMID- 22498199 TI - Cost analysis of lung cancer management in South Western Sydney. AB - INTRODUCTION: Lung cancer is the leading cause of cancer mortality in Western nations, and associated health-care costs are escalating. The aim of this study was to describe the current pattern of resource use and direct medical costs associated in managing lung cancer in South Western Sydney, Australia. METHODS: All new cases of primary lung carcinoma discussed at the Liverpool and Macarthur Cancer Therapy Centre (CTC) Lung Cancer Multidisciplinary Team meeting or seen at CTC between 1 December 2005 and 21 December 2006 were reviewed. Staging investigations, hospitalisation, treatment and follow-up investigations were documented from first consultation to last follow-up (31 October 2008 or death). Cost estimates were based on the Australian Medicare Benefits Schedule and reported in Australian dollars. Infrastructure, staff and non-medical costs were excluded. RESULTS: There were 210 patients, median age 68.2 years (range 39-90) with median follow-up of 16.6 months. The pathology and stage distribution were: 3.8% limited stage small cell lung cancer (SCLC), 10.0% extensive stage SCLC, 13.4% stage I and II non-small cell lung cancer (NSCLC), 28.5% stage III NSCLC and 44.3% stage IV NSCLC. The estimated total cost for managing this patient cohort was A$2.91 million. The cost components were: staging investigations (10.1%), treatment 41.2% (2.8% surgery, 15.8% radiotherapy and 22.6% chemotherapy), hospitalisation (43.7%) and follow-up investigations (5%). The median costs for managing NSCLC and SCLC subgroups were A$10,675 (range A$669 612,789) and A$14,799 (range A$908-31,057), respectively. CONCLUSION: Hospitalisation and cancer treatment, particularly chemotherapy, accounted for the major components of direct medical costs in the management of lung cancer. PMID- 22498201 TI - Individualized recording chambers for non-human primate neurophysiology. AB - While neural recording chambers for non-human primates can be purchased commercially, these generic chambers do not contour to the animal's skull. In order to seal gaps, a cap of dental acrylic (methyl methacrylate) is often applied around the chamber. There are multiple disadvantages associated with this method. Applying acrylic delays and further complicates surgical procedure, and overheating during the curing process can cause damage to the bone. Post-surgery, acrylic margins can give rise to bacterial growth and infection. Here we describe a method to develop custom implants which conform to the individual's skull, thereby eliminating the need for acrylic. This method shortens surgery time and significantly improves the hygiene of chamber margins. PMID- 22498203 TI - In vivo dynamics of the internal fibrous structure in smooth adhesive pads of insects. AB - Many insects with smooth adhesive pads can rapidly enlarge their contact area by centripetal pulls on the legs, allowing them to cope with sudden mechanical perturbations such as gusts of wind or raindrops. The short time scale of this reaction excludes any neuromuscular control; it is thus more likely to be caused by mechanical properties of the pad's specialized cuticle. This soft cuticle contains numerous branched fibrils oriented almost perpendicularly to the surface. Assuming a fixed volume of the water-filled cuticle, we hypothesized that pulls could decrease the fibril angle, thereby helping the contact area to expand laterally and longitudinally. Three-dimensional fluorescence microscopy on the cuticle of smooth stick insect pads confirmed that pulls significantly reduced the fibril angle. However, the fibril angle variation appeared insufficient to explain the observed increase in contact area. Direct strain measurements in the contact zone demonstrated that pulls not only expand the cuticle laterally, but also add new contact area at the pad's outer edge. PMID- 22498204 TI - Editorial comment. PMID- 22498205 TI - Prostate cancer foci detected on multiparametric magnetic resonance imaging are histologically distinct from those not detected. AB - PURPOSE: We identified histological differences between prostate cancer foci that are detected and missed using multiparametric magnetic resonance imaging. MATERIALS AND METHODS: A total of 49 patients who underwent multiparametric magnetic resonance imaging, including T2-weighted imaging, including diffusion weighted imaging and dynamic contrast enhanced imaging, before prostatectomy were enrolled in the study. One radiologist identified areas highly suspicious for tumor. One pathologist identified and categorized tumors in terms of size, Gleason score, solid tumor growth, intermixed benign glands, loose stroma, desmoplastic stroma and a high malignant epithelium-to-stroma ratio. Differences between detected and missed tumors were assessed using logistic regression analyses based on generalized estimating equations for correlated data. RESULTS: All histological features showed significant differences between detected and missed tumors on multiparametric magnetic resonance imaging (p<0.0001). Independent predictors of detection on multivariate analysis were size (OR 5.38, p=0.0077), Gleason score (OR 5.12, p=0.0094) and solid growth (OR 17.83, p<0.0001). Size, Gleason score and loose stroma were significant predictors of identification with diffusion weighted imaging on univariate analysis (p<=0.0245), while Gleason score (OR 17.05, p=0.0212) and solid growth (OR 34.90, p=0.0103) were independent predictors of identification with diffusion weighted imaging on multivariate analysis. Identification with T2-weighted imaging was associated with size and Gleason score (p<=0.01876). Identification with dynamic contrast enhanced imaging was associated with intermixed benign epithelium, loose stroma and a high malignant epithelium-to-stroma ratio (p<=0.0499). No combination of features served as independent predictors on multivariate analysis for T2-weighted imaging or dynamic contrast enhanced imaging. CONCLUSIONS: There are fundamental histological differences between detected and missed prostate tumors using magnetic resonance imaging. Insights into these differences may facilitate the prospective role of magnetic resonance imaging in counseling and treatment selection for patients with prostate cancer. PMID- 22498202 TI - Relationships between the amyloid precursor protein and its various proteolytic fragments and neuronal systems. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease and in its familial form is associated with mutations in the amyloid precursor protein (APP) and the presenilins (PSs). Much data regarding the interactions of APP, its proteolytic fragments and PS have been generated, expanding our understanding of the roles of these proteins in mechanisms underlying cognitive function and revealing many complex relationships with wide ranging cellular systems. In this review, we examine the multiple interactions of APP and its proteolytic fragments with other neuronal systems in terms of feedback loops and use these relationships to build a map. We highlight the complexity involved in the APP proteolytic system and discuss alternative perspectives on the roles of APP and its proteolytic fragments in dynamic processes associated with disease progression in AD. We highlight areas where data are missing and suggest potential confounding factors. We suggest that a systems biology approach enhances representations of the data and may be more useful in modelling both normal cognition and disease processes. PMID- 22498206 TI - Is there a financial disincentive to perform partial nephrectomy? AB - PURPOSE: Despite the explicit endorsement of the American Urological Association guidelines of partial nephrectomy as the treatment of choice for T1a renal cell carcinoma, a considerable underuse of nephron sparing surgery characterizes general practice patterns in the United States. We explored possible financial disincentives associated with partial nephrectomy that may contribute to this important quality of care deficit. MATERIALS AND METHODS: A PubMed(r) query on perioperative outcomes identified 10 series on open or laparoscopic radical nephrectomy and 16 on open, laparoscopic or robot-assisted partial nephrectomy. Mean operative time and hospital length of stay were calculated for each group. Using these data in conjunction with Health Care Financing Administration data on physician work time, which guides the current Resource-Based Relative Value Scale Medicare fee schedule, we calculated global physician time expenditure and hourly Medicare reimbursement rates for each of these 5 surgical services. RESULTS: Mean+/-SD operative time for open and laparoscopic radical nephrectomy, and open, laparoscopic and robot-assisted partial nephrectomy was 180.7+/-24.7 minutes (95% CI 119.3-242.0) in 3 studies, 178.8+/-16.5 (95% CI 163.5-194.1) in 7, 226.0+/ 36.9 (95% CI 187.2-264.8) in 6, 227.9+/-40.2 (95% CI 185.8-270.1) in 6 and 227.9+/-37.8 (95% CI 167.7-288.1) in 4, respectively (p=0.028). Mean length of stay (days) after open and laparoscopic radical nephrectomy, and open, laparoscopic and robot-assisted partial nephrectomy was 5.8+/-0.7 days (95% CI 4.0-7.7) in 3 studies, 2.5+/-1.1 (95% CI 1.4-3.6) in 6, 5.8+/-0.4 (95% CI 5.3 6.2) in 5, 2.9+/-0.3 (95% CI 2.6-3.3) in 6 and 2.8+/-1.0 (95% CI 1.2-4.4) in 4, respectively (p<0.001). The hourly reimbursement rate was calculated at $200.61, $242.03, $185.66, $231.27 and $231.97 for open and laparoscopic radical nephrectomy, and open, laparoscopic and robot-assisted partial nephrectomy, respectively. Hence, open partial nephrectomy emerged as the lowest paying of these procedures. CONCLUSIONS: Inferior compensation for open partial nephrectomy relative to that of laparoscopic or open radical nephrectomy may impede the dissemination of nephron sparing surgery for small renal masses. This may occur particularly in a general practice setting, where the expertise required for laparoscopic or robot-assisted partial nephrectomy may be lacking. We propose rectifying this inequity to facilitate wider use of nephron sparing surgery in the clinically appropriate setting. PMID- 22498207 TI - Urological laparoendoscopic single site surgery: multi-institutional analysis of risk factors for conversion and postoperative complications. AB - PURPOSE: We analyzed the incidence of and risk factors for complications and conversions in a large contemporary series of patients treated with urological laparoendoscopic single site surgery. MATERIALS AND METHODS: The study cohort consisted of consecutive patients treated with laparoendoscopic single site surgery between August 2007 and December 2010 at a total of 21 institutions. A logistic regression model was used to analyze the risks of conversion, and of any grade and only high grade postoperative complications. RESULTS: Included in analysis were 1,163 cases. Intraoperatively complications occurred in 3.3% of cases. The overall conversion rate was 19.6% with 14.6%, 4% and 1.1% of procedures converted to reduced port laparoscopy, conventional laparoscopic/robotic surgery and open surgery, respectively. On multivariable analysis the factors significantly associated with the risk of conversion were oncological surgical indication (p=0.02), pelvic surgery (p<0.001), robotic approach (p<0.001), high difficulty score (p=0.004), extended operative time (p=0.03) and an intraoperative complication (p=0.001). A total of 120 postoperative complications occurred in 109 patients (9.4%) with major complications in only 2.4% of the entire cohort. Reconstructive procedure (p=0.03), high difficulty score (p=0.002) and extended operative time (p=0.02) predicted high grade complications. CONCLUSIONS: Urological laparoendoscopic single site surgery can be done with a low complication rate, resembling that in laparoscopic series. The conversion rate suggests that early adopters of the technique have adhered to the principles of careful patient selection and safety. Besides facilitating future comparisons across institutions, this analysis can be useful to counsel patients on the current risks of urological laparoendoscopic single site surgery. PMID- 22498208 TI - Perioperative outcomes of robotic and open partial nephrectomy for moderately and highly complex renal lesions. AB - PURPOSE: We compared outcomes in patients undergoing robotic vs open partial nephrectomy stratified by moderately and highly complex tumor nephrometry scores. MATERIALS AND METHODS: Patients treated with partial nephrectomy from 2007 to 2010 were grouped by tumor characteristics into low-nephrotomy score 4 to 6, moderate-7 to 9 and high-10 to 12 anatomical complexity cohorts. Lesions with low complexity were excluded from study. Demographic, surgical and pathological outcomes were compared between patients undergoing robotic vs open partial nephrectomy in the moderately and highly complex cohorts. RESULTS: A total of 281 patients, of whom 63.3% were male, with a mean+/-SD age of 58.1+/-11.7 years and a mean followup of 21.3+/-16.3 months underwent partial nephrectomy. Moderately complex lesions were noted in 81 robotic and 136 open partial nephrectomy cases with a mean tumor size of 3.8+/-2.2 cm. Highly complex lesions were noted in 10 robotic and 54 open partial nephrectomy cases with a mean tumor size of 4.8+/-3.0 cm. There were no differences between the groups in patient age, race, gender, body mass index or American Society of Anesthesiologists classification. Cases treated with open partial nephrectomy for moderately or highly complex lesions were of higher pathological stage (p=0.02 and 0.01, respectively). The percent change in creatinine and the glomerular filtration rate were similar for robotic and open partial nephrectomy in the moderately and highly complex tumor groups. In patients undergoing robotic vs open partial nephrectomy for moderately complex lesions we noted differences in pathological tumor size (mean 3.2+/-1.8 vs 4.1+/ 2.3 cm, p<0.0001) and operative time (205.9+/-52.5 vs 189.5+/-52.0 minutes, p<0.01) while decreased estimated blood loss (131.3+/-127.8 vs 256.5+/-291.3 ml) and hospital length of stay (3.7+/-1.6 vs 5.6+/-3.9 days, each p<0.001) were observed in the robotic group. Comparison of highly complex lesions revealed decreased hospital length of stay (2.9+/-1.4 vs 6.1+/-4.1 days, p<0.0001) in the robotic partial nephrectomy group. CONCLUSIONS: In our large institutional series of patients with moderate and highly complex solid renal tumors classified by the nephrometry score robotic partial nephrectomy offered comparable perioperative and functional outcomes with the added benefit of decreased hospital length of stay. PMID- 22498209 TI - Conflict of interest in urology. AB - PURPOSE: We provide an overview of the current landscape of conflicts of interest relevant to urology practitioners and researchers. MATERIALS AND METHODS: We conducted an extensive literature review to gather data to define the current state of conflicts of interest in the urological community and beyond. RESULTS: In this work we examine the history and emergence of conflicts of interest in the public forum. In addition, we elucidate and define the types of conflicts of interest that exist. We examine the effects of conflicts of interest on practice patterns and on peer reviewed literature. We outline the current conflict of interest policies that exist. Finally, we discuss future trends in the management of conflicts of interest that will be important in the urological community. CONCLUSIONS: Conflicts of interest in the field of urology are prevalent and are becoming increasingly important to manage. PMID- 22498210 TI - Bias due to missing SEER data in D'Amico risk stratification of prostate cancer. AB - PURPOSE: We examined the degree of exclusion bias that may occur due to missing data when grouping prostate cancer cases from the SEER (Surveillance, Epidemiology and End Results) database into D'Amico clinical risk groups. Exclusion bias may occur since D'Amico staging requires all 3 variables to be known and data may not be missing at random. MATERIALS AND METHODS: From the SEER database we identified 132,606 men with incident prostate cancer from 2004 to 2006. We documented age, race, Gleason score, clinical T stage, PSA and geographic region. Men were categorized into D'Amico risk groups. Those with 1 or more unknown tumor variables (prostate specific antigen, T stage and/or Gleason score) were labeled unclassified. We compared the value of the other 2 known clinical variables for men with known vs unknown prostate specific antigen, Gleason score and T stage. Demographics were compared for those with and without missing data. Results were compared using chi-square and logistic regression. RESULTS: Of the men 33% had 1 or more unknown tumor variables with T stage the most commonly missing variable. There was no clinically significant difference in the value of the other 2 known tumor variables when T stage or prostate specific antigen was missing. Men older than 75 years were more likely to have unknown variables than younger men. There was significant geographic variation in the frequency of unclassified D'Amico data. CONCLUSIONS: In studies in which the data set is limited to men who can be classified into a D'Amico risk group 33% of eligible patients are excluded from analysis. Such men are older and from certain SEER registries but they have tumor characteristics similar to those with complete data. PMID- 22498211 TI - The impact of real-time elastography guiding a systematic prostate biopsy to improve cancer detection rate: a prospective study of 353 patients. AB - PURPOSE: We evaluated whether real-time elastography guided biopsy improves prostate cancer detection compared to conventional systematic gray scale ultrasound guidance. MATERIALS AND METHODS: A total of 353 consecutive patients suspicious for prostate cancer were prospectively randomized for real-time elastography (178) or gray scale ultrasound (175). Each patient enrolled in the study underwent a 10-core prostate biopsy. Six lateral prostate sectors (base, mid, apex) were scanned for cancer suspicious areas, defined as stiffer blue lesions using real-time elastography and hypoechoic lesions using gray scale ultrasound. Suspicious areas were sampled by a single targeted biopsy and considered representative of a defined prostate sector. If real-time elastography or gray scale ultrasound did not visualize a suspicious area in a sector, the biopsy core was taken systematically. Imaging findings were correlated with histopathological reports. Real-time elastography and gray scale ultrasound cases were compared in terms of cancer detection rate and imaging guidance accuracy. RESULTS: Characteristics of patients undergoing real-time elastography and gray scale ultrasound, including age, prostate specific antigen, prostate volume and digital rectal examination, were not significantly different (p>0.05). Prostate cancer was detected in 160 of 353 patients (45.3%). The prostate cancer detection rate was significantly higher in patients who underwent biopsy with the real-time elastography guided approach compared to the gray scale ultrasound guided biopsy at 51.1% (91 of 178) vs 39.4% (69 of 175) (p=0.027). Overall sensitivity and specificity to detect prostate cancer was 60.8% and 68.4% for real-time elastography vs 15% and 92.3% for gray scale ultrasound, respectively. CONCLUSIONS: Sensitivity to visualize and detect prostate cancer improved using real-time elastography in addition to gray scale ultrasound during prostate biopsy. Overall sensitivity did not reach levels to omit a systematic biopsy approach. PMID- 22498212 TI - Posttreatment prostate specific antigen nadir predicts prostate cancer specific and all cause mortality. AB - PURPOSE: We investigated whether the prostate specific antigen nadir predicts prostate cancer specific and all cause mortality in men treated in a randomized trial of radiation with or without 6 months of androgen deprivation therapy. MATERIALS AND METHODS: The study included 204 men with cT1b-T2bN0M0 prostate adenocarcinoma and at least 1 unfavorable factor, including prostate specific antigen less than 10 to 40 ng/ml, Gleason 7 or greater, or T3 on magnetic resonance imaging. We performed Fine and Gray regression, and Cox multivariable analysis to determine whether an increasing prostate specific antigen nadir was associated with prostate cancer specific and all cause mortality, adjusting for treatment, age, Adult Comorbidity Evaluation 27 score and cancer prognostic factors. RESULTS: At a 6.9-year median followup median prostate specific antigen nadir was 0.7 ng/ml for radiation alone and 0.1 ng/ml for radiation plus androgen deprivation therapy. The prostate specific antigen nadir (adjusted HR 1.18/ng/ml increase, 95% CI 1.07-1.31, p=0.001) and Gleason 8 or greater (adjusted HR 8.05, 95% CI 1.01-64.05, p=0.049) significantly predicted increased prostate cancer specific mortality. Moderate/severe comorbidity carried a decreased risk (adjusted HR 0.13, 95% CI 0.02-0.96, p=0.045). Higher prostate specific antigen nadir (adjusted HR 1.10/ng/ml increase, 95% CI 1.04-1.17), older age (adjusted HR 1.10/year, 95% CI 1.04-1.15) and interaction between comorbidity score and randomization arm (each p<0.001) increased the all cause mortality risk. Men who achieved a prostate specific antigen nadir of the median value or less had lower estimated prostate cancer specific and all cause mortality at 7 years (3.7% vs 18.3%, p=0.0005 and 31.5% vs 55.0%, p=0.002). CONCLUSIONS: Posttreatment prostate specific antigen nadir is significantly associated with the risk of prostate cancer specific and all cause mortality after radiation with or without androgen deprivation therapy. A suboptimal prostate specific antigen nadir may identify candidates for earlier intervention to prolong survival. PMID- 22498213 TI - Editorial comment. PMID- 22498214 TI - Core length in prostate biopsy: size matters. AB - PURPOSE: The diagnostic yield of prostate biopsy is limited. Increasing the number of cores enhances the cancer detection rate by sampling additional sites and obtaining more tissue. An alternative way to inspect more tissue would be to obtain longer cores. However, the impact of biopsy core length on cancer detection rate is an undervalued topic. We assessed the role of biopsy core length in prostate biopsy and determined the minimal tissue length to serve as quality assurance. MATERIALS AND METHODS: We retrospectively analyzed the records of 331 patients who underwent transrectal ultrasound guided initial prostate biopsy with 12 to 18 cores. The biopsy procedure and pathological evaluation were standardized. Core length was compared in patients with vs without cancer. Statistical analysis was done to determine a minimally acceptable cutoff for biopsy length. RESULTS: We analyzed data on 245 patients. The overall cancer detection rate was 30.2%. Mean core length in patients with vs without cancer was 12.3+/-2.6 vs 11.4+/-2.4 mm (p=0.015). Thus, core length was significantly longer in patients with cancer. Core length greater than 11.9 mm was associated with an increased prostate cancer detection rate (OR 2.57, 95% 1.46-4.52). The cancer detection rate for cores less vs greater than 11.9 mm was 23% vs 39%. CONCLUSIONS: Needle core length is an important morphometric parameter of transrectal prostate biopsy that directly influences the cancer detection rate. Results suggest a core length of greater than 11.9 mm as a cutoff for quality assurance. PMID- 22498216 TI - The association of the human development index with global kidney cancer incidence and mortality. AB - PURPOSE: We describe contemporary worldwide age standardized incidence and mortality rates for kidney cancer, and their association with social and economic development metrics. MATERIALS AND METHODS: We obtained gender specific, age standardized incidence and mortality rates for 184 countries and 16 major world regions from the GLOBOCAN 2008 database. We compared the mortality-to-incidence ratio on the national and regional levels in males and females, and assessed the association with the development level of each country using the United Nations Human Development Index. RESULTS: The age standardized incidence rate varied twentyfold worldwide with the highest rate in North America, and the lowest in Africa and South Central Asia (11.8 vs 1.2 and 1.0/100,000 individuals, respectively). The geographic distribution of the age standardized mortality rate was similar to that of the age standardized incidence rate with the highest rates in Europe and North America (3.1 and 2.6/100,000 individuals, respectively) and the lowest rates in Asian and African regions (0.6 to 1.5). Age standardized incidence and mortality rates were 4.5 and 2.8 times higher, respectively, in more developed countries than in developing countries. However, the mortality-to incidence ratio was highest in Africa and Asia, and lowest in North America (0.6 to 0.8 vs 0.2/100,000 individuals). There was a strong inverse relationship between the Human Development Index and the mortality-to-incidence ratio (regression coefficient -0.79, p<0.0001). CONCLUSIONS: Kidney cancer incidence and mortality rates vary widely throughout the world while the mortality-to incidence ratio is highest in less developed nations. These observations suggest significant health care disparities and may reflect differences in risk factors, health care access, quality of care, diagnostic modalities and treatment options available. Future research should assess whether the mortality-to-incidence ratio decreases with increasing development. PMID- 22498217 TI - Identifying biomarkers for interstitial cystitis/bladder pain syndrome. PMID- 22498218 TI - Are repeat prostate biopsies safe? A cohort analysis from the SEARCH database. AB - PURPOSE: Patients question whether multiple biopsy sessions cause worse prostate cancer outcomes. Therefore, we investigated whether there is an association between the number of prior biopsy sessions and biochemical recurrence after radical prostatectomy. MATERIALS AND METHODS: Men in the SEARCH (Shared Equal Access Regional Cancer Hospital) database who underwent radical prostatectomy between 1988 and 2010 after a known number of prior biopsies were included in the analysis. Number of biopsy sessions (range 1 to 8) was examined as a continuous and categorical (1, 2 and 3 to 8) variable. Biochemical recurrence was defined as a prostate specific antigen greater than 0.2 ng/ml, 2 values at 0.2 ng/ml or secondary treatment for an increased prostate specific antigen. The association between number of prior biopsy sessions and biochemical recurrence was analyzed using the Cox proportional hazards model. Kaplan-Meier estimates of freedom from biochemical recurrence were compared among the groups. RESULTS: Of the 2,739 men in the SEARCH database who met the inclusion criteria 2,251 (82%) had only 1 biopsy, 365(13%) had 2 biopsies and 123 (5%) had 3 or more biopsies. More biopsy sessions were associated with higher prostate specific antigen (p<0.001), greater prostate weight (p<0.001), lower biopsy Gleason sum (p=0.01) and more organ confined (pT2) disease (p=0.017). The Cox proportional hazards model demonstrated no association between number of biopsy sessions as a continuous or categorical variable and biochemical recurrence. Kaplan-Meier estimates of freedom from biochemical recurrence were similar across biopsy groups (log rank p=0.211). CONCLUSIONS: Multiple biopsy sessions are not associated with an increased risk of biochemical recurrence in men undergoing radical prostatectomy. Multiple biopsy sessions appear to select for a low risk cohort. PMID- 22498219 TI - Prostate specific antigen levels and prostate cancer detection rates in patients with end stage renal disease. AB - PURPOSE: Patients with end stage renal disease plus prostate cancer are ineligible to receive a renal transplant at most centers until an acceptable cancer-free period is demonstrated. To our knowledge previously established prostate specific antigen reference ranges have not been validated in patients with end stage renal disease. We determined age stratified 95th percentile prostate specific antigen reference ranges and the prostate cancer detection rate at specific prostate specific antigen intervals for patients with end stage renal disease. MATERIALS AND METHODS: We retrospectively reviewed the records of 775 male patients with end stage renal disease on the waiting list for a renal transplant who had undergone a serum prostate specific antigen test. Prostate specific antigen was stratified by age at the time of the blood test and 95th percentile reference ranges were calculated for each decade. A total of 80 patients underwent prostate biopsy for increased prostate specific antigen and/or abnormal digital rectal examination. The cancer detection rate was calculated for specific prostate specific antigen reference ranges. RESULTS: The age specific 95th percentile prostate specific antigen references ranges were 0 to 4.0 ng/ml for ages 40 to 49 in 137 patients, 0 to 5.3 ng/ml for ages 50 to 59 in 257, 0 to 10.5 ng/ml for ages 60 to 69 in 265 and 0 to 16.6 ng/ml for ages 70 to 79 years in 69. The cancer detection rate was 44%, 38% and 67% for prostate specific antigen 2.5 to 4.0, 4 to 10 and greater than 10 ng/ml, respectively. CONCLUSIONS: In our study population of patients with end stage renal disease age stratified prostate specific antigen was higher than in the general population. The cancer detection rate was increased in our patients with end stage renal disease compared to that in patients with normal renal function at specific prostate specific antigen intervals. Lower prostate specific antigen cutoffs may be appropriate to recommend prostate biopsy in patients with end stage renal disease. PMID- 22498220 TI - Evaluation of vitamin E and selenium supplementation for the prevention of bladder cancer in SWOG coordinated SELECT. AB - PURPOSE: Epidemiological and biological evidence suggests a preventive effect of selenium and vitamin E on bladder cancer. We assessed the effect of selenium and/or vitamin E on bladder cancer development. MATERIALS AND METHODS: This was a secondary analysis of the randomized, placebo controlled SELECT (Selenium and Vitamin E Cancer Prevention Trial), which included 34,887 men randomly assigned to 4 groups (selenium, vitamin E, selenium plus vitamin E and placebo) in double blind fashion between August 22, 2001 and June 24, 2004. The primary end point was bladder cancer incidence, as determined by routine clinical management. RESULTS: During a median followup of 7.1 years (IQR 6.4-8.0) 224 bladder cancer cases were recorded. Patients with bladder cancer were older, and more likely to be white and have a smoking history than those without bladder cancer. Most cancers were urothelial and nonmuscle invasive. There was no significant difference in the bladder cancer incidence between the 53 men in the placebo group and the 56 in the vitamin E group (HR 1.05, IQR 0.64-1.73, p=0.79), the 60 in the selenium group (HR 1.13, 0.70-1.84, p=0.52) or the 55 in the vitamin E plus selenium group (HR 1.05, 0.63-1.70, p=0.86). CONCLUSIONS: This secondary analysis showed no preventive effect of selenium or vitamin E alone or combined on bladder cancer in this population of men. Further studies are needed to assess the effect in women, and at different doses and formulations. PMID- 22498221 TI - Pelvic lymph node dissection for prostate cancer: frequency and distribution of nodal metastases in a contemporary radical prostatectomy series. AB - PURPOSE: We determined the frequency and distribution of metastases to pelvic lymph nodes in a contemporary American radical prostatectomy series. MATERIALS AND METHODS: In 642 consecutive patients with clinically localized prostate cancer treated by a single surgeon between 2002 and 2009 pelvic lymph nodes were removed and submitted to the pathologist in separate packets (external iliac, obturator and hypogastric). We assessed the total number of nodes and the number with metastases in each packet. RESULTS: Complete pathological information was available for 427 patients, who had a median of 16 lymph nodes removed. Of the patients 35 (8.2%) had lymph node metastases, including 1.7% with low, 8.6% with intermediate and 23.9% with high risk cancer. Of those with nodal metastases 24 (69%) had positive lymph nodes in only 1 of the 3 areas, including the external iliac in 4 (11%), the obturator in 9 (26%) and the hypogastric in 11 (31%). Only 37% of the patients had positive nodes only in the external iliac area above the obturator nerve while 60% and 49% had at least 1 positive node in the obturator and the hypogastric area, respectively. Of the patients 80% had only 1 (49%) or 2 (31%) positive nodes. CONCLUSIONS: In contemporary American patients with clinically localized prostate cancer lymph node metastases were found more often and frequently exclusively in the obturator and hypogastric areas than in the external iliac area. Pelvic lymph node dissection limited to the external iliac area above the obturator nerve would identify and remove lymph node metastases in only a third of the patients with positive nodes found at full pelvic lymph node dissection. PMID- 22498222 TI - Volume-outcome relationships in the treatment of renal tumors. AB - PURPOSE: Outcomes of complex surgical procedures tend to be better for high volume providers, although this has not been clearly established for renal cell carcinoma. We determined the relationship of provider volume with partial nephrectomy and morbidity for renal cell carcinoma treatment. MATERIALS AND METHODS: We performed a population based, observational study using data on 24,579 patients treated surgically for a renal mass from April 1998 to March 2008. Surgeon and hospital volume quartiles were created using the total number of nephrectomies during the 10-year observation period. The effect of provider volume on partial nephrectomy use, complications and mortality was determined by multivariable logistic regression adjusted for covariates. RESULTS: Partial nephrectomy was done by 10.9% of low vs 24.7% of very high volume surgeons (p<0.0001). A modest decrease in complications was observed with increasing surgeon volume (low vs very high 37.6% vs 34.5%, p<0.0001). The effect of in hospital mortality was more dramatic with a 1.71%, 1.20%, 0.97% and 0.92% rate for low, intermediate, high and very high volume surgeons, respectively (p<0.0001). After adjusting for covariates, compared to low volume surgeons patients treated by very high volume surgeons had 1.54 times the odds of undergoing partial nephrectomy (95% CI 1.37-1.72, p<0.0001), 0.84 times the odds of an in-hospital complication (95% CI 0.77-0.92, p<0.0001) and 0.69 times the odds of in-hospital death (95% CI 0.47-1.01, p=0.16). CONCLUSIONS: Higher volume surgeons perform partial nephrectomy more often, show a lower complication rate and may have a lower in-hospital mortality rate than lower volume surgeons. PMID- 22498223 TI - Outcomes of pregnancy following surgery for stress urinary incontinence: a systematic review. AB - PURPOSE: Although few data have been published on the safety of childbearing after surgery for stress urinary incontinence, a large proportion of physicians recommend that women wait to complete childbearing before pursuing surgical treatment for stress urinary incontinence. We systematically reviewed the available literature to examine the safety of pregnancy after stress urinary incontinence surgery, and to measure the effect of such pregnancy on continence outcomes. MATERIALS AND METHODS: The review was conducted according to the recommendations of the MOOSE (Meta-Analysis of Observational Studies in Epidemiology) group. We performed a systematic review to identify articles published before January 2011 on pregnancy after incontinence surgery. Databases searched include PubMed(r), EMBASE(r) and the Cochrane Review. Our literature search identified 592 titles, of which 20 articles were ultimately included in the review. RESULTS: Data were tabulated from case reports, case series and physician surveys. The final analysis in each category included 32, 19 and 67 patients, respectively. Urinary retention developed during pregnancy in 2 women, 1 of whom was treated with a sling takedown and the other with intermittent catheterization. Of these 2 women 1 also had an episode of pyelonephritis during pregnancy, possibly related to the intermittent catheterization. The incidence of postpartum stress urinary incontinence ranged from 5% to 18% after cesarean delivery and from 20% to 30% after vaginal delivery. CONCLUSIONS: Although the data on outcomes in the literature are limited and further studies need to be performed on the subject, the current data suggests that any increase in risks for pregnancy after surgery for stress incontinence may be small. A low risk of urinary retention during pregnancy may exist. Although some data suggest that cesarean deliveries may result in a lower rate of recurrent stress urinary incontinence than vaginal deliveries, a formal analysis could not be performed with the available data. PMID- 22498224 TI - Editorial comment. PMID- 22498226 TI - Accuracy of primary systematic template guided transperineal biopsy of the prostate for locating prostate cancer: a comparison with radical prostatectomy specimens. AB - PURPOSE: We determined whether systematic template guided transperineal biopsies can accurately locate and sensitively detect prostate cancer. In addition, we reported discrepancies between diagnostic and pathological Gleason scores, and investigated whether prostate size had an effect on the cancer detection rate. MATERIALS AND METHODS: This retrospective diagnostic accuracy study compares the results of primary transperineal biopsies with the radical prostatectomy pathology of 414 consecutive patients treated at a single institution between November 2002 and August 2010. RESULTS: The average sensitivity and specificity for the detection of cancer in all prostates across all biopsy zones was 48% (95% CI 42.6-53.4) and 84.1% (95% CI 80-88.2), respectively. There was a statistically significant decrease in the sensitivity of transperineal biopsy in larger prostates (t11=4.687, p=0.001). The overall Kappa value was 0.255 (95% CI 0.212 0.298). Grading concordance between biopsy and pathology specimens was achieved in 65.7% of patients. Upgrading of Gleason scores occurred in 25.6% of patients and downgrading occurred in 8.8%. CONCLUSIONS: Our current transperineal biopsy method has only demonstrated fair agreement with the histopathology findings of the corresponding radical prostatectomy specimens. This finding is most likely due to the small, multifocal nature of prostate cancer in the patient series. The cancer detection rate was lower in larger prostates. Thus, clinicians may consider increasing the number of cores in larger prostates as a strategy to improve cancer detection. PMID- 22498228 TI - Editorial comment. PMID- 22498227 TI - Contemporary open and robotic radical prostatectomy practice patterns among urologists in the United States. AB - PURPOSE: We describe current trends in robotic and open radical prostatectomy in the United States after examining case logs for American Board of Urology certification. MATERIALS AND METHODS: American urologists submit case logs for initial board certification and recertification. We analyzed logs from 2004 to 2010 for trends and used logistic regression to assess the impact of urologist age on robotic radical prostatectomy use. RESULTS: A total of 4,709 urologists submitted case logs for certification between 2004 and 2010. Of these logs 3,374 included 1 or more radical prostatectomy cases. Of the urologists 2,413 (72%) reported performing open radical prostatectomy only while 961 (28%) reported 1 or more robotic radical prostatectomies and 308 (9%) reported robotic radical prostatectomy only. During this 7-year period we observed a large increase in the number of urologists who performed robotic radical prostatectomy and a smaller corresponding decrease in those who performed open radical prostatectomy. Only 8% of patients were treated with robotic radical prostatectomy by urologists who were certified in 2004 while 67% underwent that procedure in 2010. Median age of urologists who exclusively performed open radical prostatectomy was 43 years (IQR 38-51) vs 41 (IQR 35-46) for those who performed only robotic radical prostatectomy. CONCLUSIONS: While the rate was not as high as the greater than 85% industry estimate, 67% of radical prostatectomies were done robotically among urologists who underwent board certification or recertification in 2010. Total radical prostatectomy volume almost doubled during the study period. These data provide nonindustry based estimates of current radical prostatectomy practice patterns and further our understanding of the evolving surgical treatment of prostate cancer. PMID- 22498229 TI - The implications of hospital acquired adverse events on mortality, length of stay and costs for patients undergoing radical cystectomy for bladder cancer. AB - PURPOSE: The incidence of hospital acquired adverse events in radical cystectomy and their implications for hospital outcomes and costs remain poorly described. We describe the incidence of hospital acquired adverse events in radical cystectomy, and characterize its relationship with in-hospital mortality, length of stay and hospitalization costs. MATERIALS AND METHODS: We identified 10,856 patients who underwent radical cystectomy for bladder cancer at 1,175 hospitals in the Nationwide Inpatient Sample from 2001 to 2008. We used hospital claims to identify adverse events for accidental puncture, decubitus ulcer, deep vein thrombosis/pulmonary embolus, methicillin-resistant Staphylococcus aureus, Clostridium difficile, surgical site infection and sepsis. Logistic regression and generalized estimating equation models were used to test the associations of hospital acquired adverse events with mortality, predicted prolonged length of stay and total hospitalization costs. RESULTS: Hospital acquired adverse events occurred in 11.3% of all patients undergoing radical cystectomy (1,228). Adverse events were associated with a higher odds of in-hospital death (OR 8.07, p<0.001), adjusted prolonged length of stay (41.3%) and total costs ($54,242 vs $26,306; p<0.001) compared to no adverse events on multivariate analysis. The incremental total costs attributable to hospital acquired adverse events were $43.8 million. Postoperative sepsis was associated with the highest risk of mortality (OR 17.56, p<0.001), predicted prolonged length of stay (62.22%) and adjusted total cost ($79,613). CONCLUSIONS: With hospital acquired adverse events occurring in approximately 11% of radical cystectomy cases, they pose a significant risk of in-hospital mortality and higher hospitalization costs. Therefore, increased attention is needed to reduce adverse events by improving patient safety, while understanding the economic implications for tertiary referral centers with possible policy changes such as denial of payment for hospital acquired adverse events. PMID- 22498231 TI - Predictors of spontaneous reduction in multiple pregnancies conceived following assisted reproductive technology. AB - OBJECTIVE: To identify patient and cycle parameters that relate to spontaneous reduction in multiple pregnancies following in vitro fertilization (IVF) and embryo transfer (ET). STUDY DESIGN: A retrospective cohort study was conducted in an academic infertility center. All IVF cycles between January 2007 and June 2008 were evaluated and 69 infertile women were diagnosed with multiple gestation following IVF. Multiple pregnancy was diagnosed by transvaginal sonography at 6-7 weeks gestation following embryo transfer (ET). Repeat ultrasonography undertaken in late first trimester assessed ongoing multiple pregnancy versus occurrence of spontaneous reduction. Patient and IVF cycle parameters were compared between patients experiencing spontaneous reduction (n=26, cases) compared to those where the multiple pregnancy proceeded uneventfully (n=43, controls). RESULTS: Spontaneous reduction (SR) was observed in almost 38% of the studied multiple gestations (n=69). Women experiencing SR were significantly older (p=.047), of a leaner body mass (p=.049), and exhibited significantly higher serum estradiol (E(2)) levels in the early follicular phase (p=.016) compared to the controls. Endometrial thickness (EMT) on the day of hCG administration related inversely (p=.017), whereas the number of embryos transferred (ET) related positively with the likelihood of SR (p=.027). On multivariate analyses, EMT and the number of ET were identified as independent predictors of SR following IVF-ET; EMT of less than 10mm was associated with a fourfold increased likelihood of SR (OR 4.18; 95% CI 1.02-17.01) whereas each additional embryo transferred doubled the risk of SR in multiple pregnancies resulting from IVF (OR 2.39; CI 1.02-5.58). CONCLUSIONS: In multiple pregnancies conceived following IVF, occurrence of SR is relatively common. Increasing number of ET and EMT measuring <10mm are identified as independent predictors of likelihood of SR. While advancing age, body mass and baseline E(2) levels were associated with likelihood of SR, these associations disappeared on adjusted analyses. The observed relationship between EMT and SR is novel: the underlying mechanisms are unclear and merit further investigation. PMID- 22498230 TI - The FinnProstate Study VII: intermittent versus continuous androgen deprivation in patients with advanced prostate cancer. AB - PURPOSE: We conducted a randomized trial to compare intermittent and continuous androgen deprivation in patients with advanced prostate cancer. We studied time to progression, overall and prostate cancer specific survival, and time to treatment failure. MATERIALS AND METHODS: Between May 1997 and February 2003, 852 men with locally advanced or metastatic prostate cancer were enrolled to receive androgen deprivation therapy for 24 weeks. Patients in whom prostate specific antigen decreased to less than 10 ng/ml, or by 50% or more if less than 20 ng/ml at baseline, were randomized to intermittent or continuous androgen deprivation. In the intermittent therapy arm androgen deprivation therapy was withdrawn and resumed again for at least 24 weeks based mainly on prostate specific antigen decrease and increase. RESULTS: There were 298 patients who did not meet the randomization criteria. The remaining 554 patients were randomized, with 274 (49.5%) to intermittent androgen deprivation and 280 (50.5%) to the continuous androgen deprivation arm. Median followup was 65.0 months. Of these patients 392 (71%) died, including 186 (68%) in the intermittent androgen deprivation arm and 206 (74%) in the continuous androgen deprivation arm (p=0.12). There were 248 prostate cancer deaths, comprised of 117 (43%) in the intermittent androgen deprivation and 131 (47%) in the continuous androgen deprivation arm (p=0.29). Median times from randomization to progression were 34.5 and 30.2 months in the intermittent androgen deprivation and continuous androgen deprivation arms, respectively. Median times to death (all cause) were 45.2 and 45.7 months, to prostate cancer death 45.2 and 44.3 months, and to treatment failure 29.9 and 30.5 months, respectively. CONCLUSIONS: Intermittent androgen deprivation is a feasible, efficient and safe method to treat advanced prostate cancer compared with continuous androgen deprivation. PMID- 22498232 TI - Diabetic ketoacidosis or positional asphyxia? PMID- 22498233 TI - A case in which a bone fragment caused by a bullet made a second channel in addition to the bullet channel. AB - A 64-year-old male was found dead in his house with his face covered with blood and a 38-caliber revolver between his legs. He had been suffering from type 2 diabetes mellitus and aftereffects of cerebral infarction. Autopsy revealed a normal round contact wound in the left lateral cervical region. A bullet from the firearm had entered through the left lateral cervical region and traveled to the outer right sternocleidomastoid muscle. This also triggered another wound from the fifth cervical vertebra to the muscle tissue near the right cartilage thyroid. At the end of this channel, there were three bone fragments. Here, we report this interesting case with two channels caused by a bullet and by a resulting bone fragment. We also discuss the characteristics of an ear lobe injury found on the victim and show how this injury and blood and skin on the revolver were used as clues to determine the posture at the time of the shot. PMID- 22498234 TI - Fatal pediatric head injury due to toppled television: does the injury pattern overlap with abusive head trauma? AB - Pediatric head injuries can occur from abusive head trauma (AHT) or accidents. Accidental pediatric head injuries caused by cathode-ray tube televisions (CRTT) toppling have become a 'silent epidemic'. Differentiation between a fatal case of AHT and CRTT toppling could be vexing when the historical and scene evidence are subtle. A 2-year-old girl was found unresponsive in her house and could not be resuscitated. A 27" CRTT was found fallen from its stand onto the floor at the scene. The siblings report that the deceased was climbing on the television stand when it toppled. Autopsy revealed a spectrum of head injuries including, contusions, fractures, bilateral acute subdural hemorrhages, subarachnoid hemorrhages, brain contusion-lacerations and corpus callosal hemorrhages. Microscopy of the eyes revealed bilateral acute retinal hemorrhages. The cause of death was given as crushing injuries of head and brain. The skull fracture pattern is compatible with an accident causing crush injury due to the toppled CRTT rather than AHT. The injury pattern reconfirms that the head is the most vulnerable site in case of CRTT tipover. Although there may be an overlap between the injury pattern in AHT and in CRTT tipover cases, a careful evaluation of the history and scene and autopsy findings such as the crushing nature of the skull fractures and distribution of injury, can solve this problem. PMID- 22498235 TI - Identification of nasal blood by real-time RT-PCR. AB - A new approach for the identification of body fluid stains by comparing specific mRNA expression levels has been extensively studied in recent years. Here, we examine whether nasal blood, which is regarded as one of the most difficult types of blood to identify, can be identified by comparing mRNA expression levels of target genes specific to saliva, nasal secretion, and blood. The saliva-specific statherin gene (STATH) was found to be expressed at high levels in not only saliva (dCt value: 1.32+/-1.39, n=5), but also nasal secretions (dCt value: 0.90+/-1.14, n=5), while the histatin gene (HTN3) was only expressed at high levels in saliva (dCt value: 1.08+/-2.35, n=5). We also confirmed that the hemoglobin-beta gene (HBB) showed high expression levels in blood (dCt value: 9.51+/-0.40, n=5). Four nasal blood stains were found to highly express STATH (dCt value: 5.65+/-3.98) and HBB (dCt value: -8.79+/-1.67) but not HTN3, suggesting that the stain samples contained both nasal secretions and blood and can therefore be identified as nasal blood stains. Although menstrual blood showed the same expression pattern as nasal blood, the menstrual blood-specific protein matrix metallopeptidase 7 (MMP7) was not expressed in all nasal blood stain samples. Therefore, its expression levels could be used to discriminate between nasal and menstrual blood. In conclusion, real-time RT-PCR was able to identify nasal blood, although the stability of gene expression in nasal blood stains was low over time, suggesting that this assay may not be effective for older stains. Future work should examine the usefulness of this assay under various environmental conditions. PMID- 22498236 TI - University students' attitudes towards Voluntary Interruption of Pregnancy. AB - An evaluation of the future professional trends was performed by analyzing the attitudes of university students to the Voluntary Interruption of Pregnancy (VIP). An anonymous questionnaire was distributed to 300 students (Medicine, Nursing and Law) of the University of Santiago de Compostela, with questions on their personal beliefs, opinion on the law and intention to participate in VIP. Of the 245 respondents (response rate 82%), 66.5% were pro-abortion and their attitudes towards VIP were consistent with their opinion on the beginning of life and with the ethical arguments related to the fetus and the mother. No differences were found with age, sex or degree. The students showed to be well informed on the VIP law, and the majority of them considered unsuitable termination of pregnancy in minors without parental consent. Students' intentions to take part in abortion provision were influenced by their views on abortion, level of participation and circumstances of pregnancy. Although the majority of participants would be willing to perform VIP in situations that affect fetus and mother's life or health (87-66%), their intentions clearly diminished in other situations, such as abortion on demand (17%). These data suggest that conscientious objection of health professionals can even increase with the new policy, a fact that might affect VIP availability. It is important to stress the need of ethical training to help in the solution of conflicts between patient and health professional values. PMID- 22498238 TI - RNA silencing in white petunia flowers creates pigmentation patterns invisible to the human eye. AB - Modern commercial petunias exhibit a wide range of flower colors, which can be observed in gardens. In this study, we present a petunia cultivar that exhibits a floral pattern that is invisible to humans but is possibly visible to pollinating insects. We show that this hidden pattern is established by differentially localized accumulation of flavonols and cinnamic acid derivatives in the corolla limb. This accumulation is caused by a combination of two distinct mechanisms that inhibit anthocyanin biosynthesis: a loss-of-function mutation in the ANTHOCYANIN2, and localized RNA-silencing of CHALCONE SYNTHASE-A. PMID- 22498239 TI - Salt stress induced proteome and transcriptome changes in sugar beet monosomic addition line M14. AB - Sugar beet monosomic addition line M14 displays interesting phenotypes such as apomixis and salt stress tolerance. Here we reported proteomic and transcriptomic analysis of M14 leaves and roots under 500mM NaCl treatment for seven days. Proteins from control and treated samples were extracted and separated using two dimensional difference gel electrophoresis (2D-DIGE). A total of 40 protein spots from leaf gels and 36 protein spots from root gels exhibited significant changes. Using mass spectrometry and database searching, 38 unique proteins in leaves and 29 unique proteins in roots were identified. The proteins included those involved in metabolism, protein folding, photosynthesis, and protein degradation. In addition, cDNA libraries of differentially expressed genes were constructed using suppression subtractive hybridization (SSH). Fifty-eight unigenes including 14 singletons and 44 contigs were obtained. Some salt-responsive genes were identified to function in metabolism, photosynthesis, stress and defense, energy, protein synthesis and protein degradation. This research has revealed candidate genes and proteins for detailed functional characterization, and set the stage for further investigation of the salt tolerance mechanisms in sugar beet. PMID- 22498237 TI - The cortical organization of lexical knowledge: a dual lexicon model of spoken language processing. AB - Current accounts of spoken language assume the existence of a lexicon where wordforms are stored and interact during spoken language perception, understanding and production. Despite the theoretical importance of the wordform lexicon, the exact localization and function of the lexicon in the broader context of language use is not well understood. This review draws on evidence from aphasia, functional imaging, neuroanatomy, laboratory phonology and behavioral results to argue for the existence of parallel lexica that facilitate different processes in the dorsal and ventral speech pathways. The dorsal lexicon, localized in the inferior parietal region including the supramarginal gyrus, serves as an interface between phonetic and articulatory representations. The ventral lexicon, localized in the posterior superior temporal sulcus and middle temporal gyrus, serves as an interface between phonetic and semantic representations. In addition to their interface roles, the two lexica contribute to the robustness of speech processing. PMID- 22498240 TI - Assessing sub-seafloor microbial activity by combined stable isotope probing with deuterated water and 13C-bicarbonate. AB - Sub-seafloor sediments are populated by large numbers of microbial cells but not much is known about their metabolic activities, growth rates and carbon assimilation pathways. Here we introduce a new method enabling the sensitive detection of microbial lipid production and the distinction of auto- and heterotrophic carbon assimilation. Application of this approach to anoxic sediments from a Swedish fjord allowed to compare the activity of different functional groups, the growth and turnover times of the bacterial and archaeal communities. The assay involves dual stable isotope probing (SIP) with deuterated water (D(2) O) and (13) C(DIC) (dissolved inorganic carbon). Culture experiments confirmed that the D content in newly synthesized lipids is in equilibrium with the D content in labelled water, independent of whether the culture grew hetero- or autotrophically. The ratio of (13) C(DIC) to D(2) O incorporation enables distinction between these two carbon pathways in studies of microbial cultures and in environmental communities. Furthermore, D(2) O-SIP is sufficiently sensitive to detect the formation of few hundred cells per day in a gram of sediment. In anoxic sediments from a Swedish fjord, we found that > 99% of newly formed lipids were attributed to predominantly heterotrophic bacteria. The production rate of bacterial lipids was highest in the top 5 cm and decreased 60 fold below this depth while the production rate of archaeal lipids was rather low throughout the top meter of seabed. The contrasting patterns in the rates of archaeal and bacterial lipid formation indicate that the factors controlling the presence of these two lipid groups must differ fundamentally. PMID- 22498241 TI - Duel of the fates: the role of transcriptional circuits and noise in CD4+ cells. AB - CD4+ T cells play key roles in orchestrating adaptive immune responses, and are a popular model for mammalian cell differentiation. While immune regulation would seem to require exactly adjusted mRNA and protein expression levels of key factors, there is little evidence that this is strictly the case. Stochastic gene expression and plasticity of cell types contrast the apparent need for precision. Recent work has provided insight into the magnitude of molecular noise, as well as the relationship between noise, transcriptional circuits and epigenetic modifications in a variety of cell types. These processes and their interplay will also govern gene expression patterns in the different CD4+ cell types, and the determination of their cellular fates. PMID- 22498242 TI - Genetics of metabolism and diabetes. Preface. PMID- 22498243 TI - Genetics for clinicians: from candidate genes to whole genome scans (technological advances). AB - Human genetics has progressed at an unprecedented pace during the past 10 years. DNA microarrays currently allow screening of the entire human genome with high level of coverage and we are now entering the era of high-throughput sequencing. These remarkable technical advances are influencing the way medical research is conducted and have boosted our understanding of the structure of the human genome as well as of disease biology. In this context, it is crucial for clinicians to understand the main concepts and limitations of modern genetics. This review will describe key concepts in genetics, including the different types of genetic markers in the human genome, review current methods to detect DNA variation, describe major online public databases in genetics, explain key concepts in statistical genetics and finally present commonly used study designs in clinical and epidemiological research. This review will therefore concentrate on human genetic variation analysis. PMID- 22498244 TI - Genetic testing in patients with obesity. AB - The obesity epidemic is associated with the recent availability of highly palatable and inexpensive caloric food as well as important changes in lifestyle. Genetic factors, however, play a key role in regulating energy balance and numerous twin studies have estimated the BMI heritability between 40 and 70%. While common variants, identified through genome-wide association studies (GWAS) point toward new pathways, their effect size are too low to be of any use in the clinic. This review therefore concentrates on genes and genomic regions associated with very high risks of human obesity. Although there are no consensus guidelines, we review how the knowledge on these "causal factors" can be translated into the clinic for diagnostic purposes. We propose genetic workups guided by clinical manifestations in patients with severe early-onset obesity. While etiological diagnoses are unequivocal in a minority of patients, new genomic tools such as Comparative Genomic Hybridization (CGH) array, have allowed the identification of novel "causal" loci and next-generation sequencing brings the promise of accelerated pace for discoveries relevant to clinical practice. PMID- 22498245 TI - Metabolic insights from extreme human insulin resistance phenotypes. AB - As well as improving diagnostic and clinical outcomes for affected patients, understanding the genetic basis of rare human metabolic disorders has resulted in several fundamental biological insights. In some cases understanding extreme phenotypes has also informed thinking about more prevalent metabolic diseases. Insulin resistance underpins the twin epidemics of obesity and type 2 diabetes as well as accounting for many of the metabolic problems encompassed by the term metabolic syndrome. This review provides a brief update on current understanding of human severe insulin resistance syndromes, before highlighting recent insights provided by studies in these rare syndromes into the molecular pathogenesis of elements of the metabolic syndrome. PMID- 22498246 TI - Genetic determinants of glucose homeostasis. AB - Type 2 diabetes is a complex metabolic disorder characterised by varying degrees of impairment in insulin secretion and resistance to the action of insulin. Considerable progress has been made recently in understanding the genetic determinants of diabetes. A logical next step is to describe how these variants relate to the underlying pathophysiological processes that lead to diabetes as this may provide insights into pathways to disease. These quantitative traits are, of course, of direct interest in themselves and a growing literature is now emerging on the genetic determinants of insulin secretion and insulin resistance. This review article focuses on describing the complex associations between type 2 diabetes risk variants and quantitative glycaemic traits and the relationship between variants initially discovered in association studies of these traits and risk of type 2 diabetes. PMID- 22498247 TI - The lessons of early-onset monogenic diabetes for the understanding of diabetes pathogenesis. AB - Monogenic diabetes consists of different subtypes of single gene disorders comprising a large spectrum of phenotypes, namely neonatal diabetes mellitus or monogenic diabetes of infancy, dominantly inherited familial forms of early-onset diabetes (called Maturity-Onset Diabetes of the Young) and rarer diabetes associated syndromic diseases. All these forms diagnosed at a very-young age are unrelated to auto-immunity. Their genetic dissection has revealed major genes in developmental and/or functional processes of the pancreatic beta-cell physiology, and various molecular mechanisms underlying the primary pancreatic defects. Most of these discoveries have had remarkable consequences on the patients care and patient's long-term condition with outstanding examples of successful genomic medicine, which are highlighted in this chapter. Increasing evidence also shows that frequent polymorphisms in or near monogenic diabetes genes may contribute to adult polygenic type 2 diabetes. In this regard, unelucidated forms of monogenic diabetes represent invaluable models for identifying new targets of beta-cell dysfunction. PMID- 22498249 TI - Genetic determinants of lipid homeostasis. AB - Circulating levels of blood lipids are heritable risk factors for atherosclerosis and heart disease, and are the target of therapeutic intervention. Studies of monogenic disorders and - more recently - genome-wide association studies have identified several important genetic determinants of blood lipid levels. These have the potential to provide new drug targets to alter blood lipid levels and may improve prediction of cardiovascular disease. Better functional validation of lipid loci is required to clarify the biological role of proteins encoded by specific genomic regions and understand how they influence lipid metabolism and confer disease risk. PMID- 22498248 TI - Is genetic testing useful to predict type 2 diabetes? AB - The early identification of individuals at risk for type 2 diabetes (T2D) enables prevention. Recent genome-wide association studies (GWAS) have added at least 40 genetic variants to the list of already well characterized T2D risk predictors, including family history, obesity, and elevated fasting plasma glucose levels. Although these variants can significantly predict T2D alone and as a part of genotype risk scores, they do not yet offer clinical discrimination beyond that achieved with common clinical measurements. Future progress on at least two research fronts may improve the predictive performance of genotype information. First, expanded GWAS efforts in non-European populations will allow targeted sequencing of risk loci and the identification of true causal variants. Second, studies with longer prediction time horizons may demonstrate that genotype information performs better than clinical risk predictors over a longer period of the life course. At present, however, genetic testing cannot be recommended for clinical T2D risk prediction in adults. PMID- 22498250 TI - Genetic determinants of common obesity and their value in prediction. AB - Genome-wide association studies (GWAS) have revolutionised the discovery of genes for common traits and diseases, including obesity-related traits. In less then four years time, 52 genetic loci were identified to be unequivocally associated with obesity-related traits. This vast success raised hope and expectations that genetic information would become soon an integral part of personalised medicine. However, these loci have only small effects on obesity-susceptibility and explain just a fraction of the total variance. As such, their accuracy to predict obesity is poor and not competitive with the predictive ability of traditional risk factors. Nevertheless, some of these loci are being used in commercially available personal genome tests to estimate individuals' lifetime risk of obesity. While proponents believe that personal genome profiling could have beneficial effects on behaviour, early reports do not support this hypothesis. To conclude, the most valuable contribution of GWAS-identified loci lies in their contribution to elucidating new physiological pathways that underlie obesity susceptibility. PMID- 22498251 TI - Solitary osteochondroma of the twelfth rib with intraspinal extension and cord compression in a middle-aged patient. AB - BACKGROUND: Osteochondroma is a disease of growing bone and thus typically presents in younger patients. It has rarely been described in middle-aged and elderly patients. Data on the occurrence of osteochondroma show that the reported incidence of costal osteochondroma is very low. Moreover, costal osteochondroma arising at the costovertebral junction with neural foraminal extension and spinal cord compression is extremely rare. CASE PRESENTATION: This study reports the case of a 58-year-old patient with a solitary osteochondroma of the 12th rib with intraspinal extension and spinal cord compression. The clinical history, plain radiographs, computed tomography (CT), magnetic resonance imaging, and pathologic findings of the reported patient have been reviewed. The relevant medical literature has also been reviewed. The patient was treated with surgery for complete tumour excision to avoid tumour recurrence. After surgery, the patient's symptoms improved. An additional CT scan obtained at 1 year after surgery did not show any evidence of recurrence. CONCLUSIONS: This patient is the oldest patient reported to have this rare form of costal osteochondroma. The age of the patient and the erosion of the adjacent bones raised clinical suspicion of malignancy; therefore, surgical management involved complete tumour excision with thoracolumbar fixation and fusion. PMID- 22498253 TI - CD95 signaling in colorectal cancer. AB - CD95 and its ligand (CD95L) are widely expressed in colorectal tumors, but their role in shaping tumor behavior is unclear. CD95 activation on tumor cells can lead to apoptosis, while CD95L attracts neutrophils, suggesting a function in tumor suppression. However, CD95 can also promote tumorigenesis, at least in part by activating non-apoptotic signaling pathways that stimulate tumor cell proliferation, invasion and survival. In addition, CD95 signaling in stromal cells and tumor-infiltrating inflammatory cells has to be taken into account when addressing the function of CD95 and its ligand in colorectal tumor biology. We present a model in which the tumor-suppressing and tumor-promoting activities of CD95/CD95L together determine colorectal tumor behavior. We also discuss how these multiple activities are changing our view of CD95 and CD95L as potential therapeutic targets in the treatment of colorectal cancer. We conclude that locking CD95 in apoptosis-mode may be a more promising anti-cancer strategy than simply inhibiting or stimulating CD95. PMID- 22498254 TI - [Transcatheter aortic valve-in-valve implantation for failed aortic bioprosthesis]. AB - Percutaneous valve replacement for severe aortic stenosis has been shown to be an alternative treatment option for high surgical risk patients. We describe our first valve-in-valve procedure in a patient with a degenerated aortic bioprosthesis and severe regurgitation. PMID- 22498252 TI - Small nucleolar RNAs in cancer. AB - Non-coding RNAs (ncRNAs) are important regulatory molecules involved in various physiological and cellular processes. Alterations of ncRNAs, particularly microRNAs, play crucial roles in tumorigenesis. Accumulating evidence indicates that small nucleolar RNAs (snoRNAs), another large class of small ncRNAs, are gaining prominence and more actively involved in carcinogenesis than previously thought. Some snoRNAs exhibit differential expression patterns in a variety of human cancers and demonstrate capability to affect cell transformation, tumorigenesis, and metastasis. We are beginning to comprehend the functional repercussions of snoRNAs in the development and progression of malignancy. In this review, we will describe current studies that have shed new light on the functions of snoRNAs in carcinogenesis and the potential applications for cancer diagnosis and therapy. PMID- 22498255 TI - Visceral abdominal fat accumulation predicts the progression of noncalcified coronary plaque. AB - BACKGROUND: Excess visceral abdominal tissue (VAT) is more strongly associated with risk factors of coronary artery disease (CAD) than body mass index (BMI) or waist circumference. However, whether adding VAT measurements to CAD risk factors provides better risk assessment for CAD progression has not been fully evaluated. METHODS AND RESULTS: This prospective cohort study comprised 553 CAD patients with coronary plaque with <=50% coronary stenosis as assessed by computed tomography (CT) angiography. Quantification of VAT area was performed together with CT angiography using abdominal CT scanning. After a mean 38+/-8 months follow-up, 320 patients underwent repeated CT scans for worsening angina symptoms without findings of positive ischemia. Increased segments of noncalcified plaque were seen in 152 (48%) and an increased calcium score was seen in 261 (82%) patients. The risk for progression of noncalcified plaque increased steadily with higher VAT quartiles, independent of CAD risk factors. Patients in the higher quartiles were at increased risk of progression of noncalcified plaque (quartiles IV OR 4.7; 95% CI 2.3-9.4, p-value<0.001). In contrast, increases above the median calcium score showed no independent correlation to VAT. Compared to VAT, progression of noncalcified plaque showed no phased increase with higher waist circumference and weaker increase with higher BMI quartiles. CONCLUSION: VAT accumulation was positively associated with progression of coronary noncalcified plaque, but not of calcified plaque. This suggests that risk assessment of progression of noncalcified plaque can be improved by combining VAT measurements and CAD risk factors. PMID- 22498256 TI - Platelets enter atherosclerotic plaque via intraplaque microvascular leakage and intraplaque hemorrhage: a histopathological study in carotid plaques. AB - BACKGROUND: Platelets foster an inflammatory environment that influences atherosclerotic lesion progression and facilitates plaque rupture, in addition to their role in acute thrombus formation. The route of entry of platelets into the atherosclerotic plaque and their exact location inside the plaque are however not completely understood. METHODS AND RESULTS: 188 carotid plaques were examined for the presence of platelets using immunohistochemistry (CD42b), and 76/188 (40.4%) were platelet positive. Platelets were observed in intraplaque hemorrhages, around plaque microvessels, mostly without leakage of erythrocytes; and in mural thrombi. Platelet positive staining was associated with a higher plaque microvessel density, and elevated plaque-levels of interleukin-8. CONCLUSION: Due to their short life span, platelets reflect recent bleeding. It can be hypothesized that platelets might serve as a marker for leaky microvessels inside atherosclerotic plaques that are at risk for development, or progression of plaque hemorrhage. PMID- 22498257 TI - Power injectable peripherally inserted central catheters in the ICU: not only a question of flow. PMID- 22498259 TI - Novel approach for the generation of recombinant African swine fever virus from a field isolate using GFP expression and 5-bromo-2'-deoxyuridine selection. AB - Generation of African swine fever virus (ASFV) recombinants has so far relied mainly on the manipulation of virus strains which had been adapted to growth in cell culture, since field isolates do not usually replicate efficiently in established cell lines. Using wild boar lung cells (WSL) which allow for propagation of ASFV field isolates, a novel approach for the generation of recombinant ASFV directly from field isolates was developed which includes the integration into the viral thymidine kinase (TK) locus of an ASFV p72-promoter driven expression cassette for enhanced green fluorescent protein (EGFP) embedded in a 16 kbp mini F-plasmid into the genome of the ASFV field strain NHV. This procedure enabled the monitoring of recombinant virus replication by EGFP autofluorescence. Selection for the TK-negative (TK(-)) phenotype of the recombinants on TK(-) Vero (VeroTK(-)) cells in the presence of 5-bromo-2' deoxyuridine (BrdU) led to efficient isolation of recombinant virus due to the elimination of TK(+) wild type virus by BrdU-phosporylation in infected VeroTK(-) cells. The recombinant NHV-dTK-GFP produced titres of both cell-associated and secreted viral progeny in WSL cells similar to parental NHV indicating that insertion of large heterologous sequences into the viral TK locus and EGFP expression do not impair viral replication in these cells. In summary, a novel method has been developed for generation of ASFV recombinants directly from field isolates, providing an efficacious method for further manipulations of wild-type virus genomes. PMID- 22498260 TI - A simple, rapid and efficient way to obtain infectious clones of potyviruses. AB - The availability of an infectious cDNA clone is a prerequisite for genetic studies on RNA viruses. However, despite important improvement in molecular biology techniques during the last decades, obtaining such clones often remains tedious, time-consuming and rather unpredictable. In the case of potyviruses, cDNA clones are frequently unstable due to the toxicity of some viral proteins for bacteria. The problem can be overcome by inserting introns into the viral sequence but this requires additional steps in the cloning process and depends on the availability of suitable restriction sites in the viral sequence or adjunction of such sites by mutagenesis. Homologous recombination in yeast rather than in vitro restriction and ligation can be used to build infectious clones or other viral constructs. This paper describes how, by using recombination in yeast and fusion PCR, infectious intron-containing clones were obtained within a few weeks for two strains of watermelon mosaic virus (WMV, Potyvirus), whereas previous attempts using "classical" cloning techniques had failed repeatedly. Using the same approach, intronless infectious clones of two other potyviruses, zucchini yellow mosaic virus (ZYMV) and papaya ringspot virus (PRSV), were obtained in less than two weeks. PMID- 22498258 TI - Melanoma-derived conditioned media efficiently induce the differentiation of monocytes to macrophages that display a highly invasive gene signature. AB - The presence of tumor-associated macrophages (TAMs) in melanomas is correlated with a poor clinical prognosis. However, there is limited information on the characteristics and biological activities of human TAMs in melanomas. In this study, we developed an in vitro method to differentiate human monocytes to macrophages using modified melanoma-conditioned medium (MCM). We demonstrate that factors from MCM-induced macrophages (MCMI-Mphi) express both M1-Mphi and M2-Mphi markers and inhibit melanoma-specific T-cell proliferation. Furthermore, microarray analyses reveal that the majority of genes up-regulated in MCMI-Mphi are associated with tumor invasion. The most strikingly up-regulated genes are CCL2 and MMP-9. Consistent with this, blockade of both CCL-2 and MMPs diminish MCMI-Mphi-induced melanoma invasion. Finally, we demonstrated that both MCMI-Mphi and in vivo TAMs express the pro-invasive, melanoma-associated gene, glycoprotein non-metastatic melanoma protein B. Our study provides a framework for understanding the mechanisms of cross-talk between TAMs and melanoma cells within the tumor microenvironment. PMID- 22498261 TI - Effect of Silastic sheeting over the round window niche on sound transmission in the intact human middle ear. AB - BACKGROUND: Silastic sheeting is commonly used in middle ear surgery to prevent the formation of adhesions between the tympanic membrane and the medial bony wall of the middle ear cavity. This sheeting is often placed, advertently or inadvertently, so as to cover the round window niche. The effects of mechanically shielding the round window niche in the presence of an intact tympanic membrane and ossicular chain have not been empirically studied to date. OBJECTIVE: To investigate the effect of acoustically shielding the round window with 1 mm thick Silastic sheeting on middle ear sound transmission in otherwise intact cadaveric human temporal bones. METHODS: Using a fresh human cadaveric temporal model, a computerized laser Doppler vibrometry system was used to measure vibrations at the umbo and on the stapes footplate in response to sound introduced into the ear canal. Stapes displacement was used as a measure of sound transmission. The measurements were repeated after shielding the round window using 1 mm thick Silastic sheeting. RESULTS: We found that shielding the round window with Silastic produced no significant difference in the measurements at the stapes footplate. At the umbo, a slight increase in vibrations at 250 to 500 Hz was measured after shielding. This was on the order of 3 dB and was not statistically significant. CONCLUSION: In the presence of an intact tympanic membrane and ossicular chain, shielding the round window with Silastic sheeting has no clinically significant effect on sound transmission by the human middle ear. PMID- 22498262 TI - Acoustic features of voice in patients with severe hearing loss. AB - OBJECTIVE: The aim of this study was to evaluate changes in the acoustic features of voice in patients with sensorineural hearing loss. DESIGN: Thirty male patients, between 35 and 53 years of age with postlingual bilateral symmetric severe sensorineural hearing loss, were included (group A). As a control group (group B), 30 normal-hearing male adults, aged 38 to 51 years, were identified. SETTING: ENT Department, University of Genoa (Italy). METHODS: Phonetically balanced sentences and sustained vowels a, e, and i were digitally recorded with the Multidimensional Voice Program (Kay Elemetrics) in all subjects. MAIN OUTCOME MEASURES: The parameters estimated were the average of fundamental frequency (F0), jitter percent (jitter), shimmer, noise to harmonics ratio (NHR), voice turbulence index (VTI), soft phonation index (SPI), degree of voicelessness (DUV), degree of voice breaks (DVB), and peak amplitude variation (vAm). RESULTS: Compared to the control group, in group A, the following acoustic parameters presented a statistically significantly higher value (p < .05) of F0 (137.2 Hz vs 120.0 Hz), jitter (1.93% vs 0.67%), shimmer (6.67% vs 3.81%), NHR (0.19 vs 0.10), SPI (12.9 vs 8.76), DVB (2.12% vs 0.01%), DUV (9.53% vs 0.51%), and vAm (23.12 % vs 12.06%). In group A, F0 was also significantly higher in the balanced sentences (126 Hz vs 111 Hz). CONCLUSIONS: This study demonstrates that hearing loss affects voice production by changing its parameters, especially in subjects with marked hearing loss. PMID- 22498263 TI - Effect of type I tympanoplasty on the resonant frequency of the middle ear: comparison between chondrotympanoplasty and temporalis fascia grafting. AB - AIMS: To evaluate the effect of type I chondrotympanoplasty on the resonant frequency (RF) of the middle ear and compare it to the respective outcomes of type I tympanoplasty using temporalis fascia grafting (TFG). Hearing results and respective graft integration rates were also assessed. MATERIALS AND METHODS: A retrospective comparative study was conducted of patients who had undergone type I tympanoplasty at a tertiary university hospital. Selection criteria included tympanic membrane perforation following chronic otitis media, trauma, or grommet insertion; an intact ossicular chain; a dry ear for at least 3 months; and normal middle ear mucosa. Patients with ossicular discontinuity, ossiculoplasty, cholesteatoma, previous ear surgery, syndromes affecting the middle ear, or younger than 16 years old were excluded. RESULTS: Sixty-nine patients met the inclusion criteria; chondrotympanoplasty was performed in 39 and TFG in 30. Three patients showed incomplete tympanic membrane closure at follow-up. The graft integration rate was 97.4% in the chondrotympanoplasty group and 93.3% in the TFG group. An air-bone gap closure within 10 dB was achieved in 73.7% of the chondrotympanoplasty patients versus 67.9% of the TFG patients. Hearing gain of 21 to 30 dB in air conduction thresholds was obtained in 65.8% of the chondrotympanoplasty patients and 60.7% of their TFG counterparts. RF was 808 +/- 458 Hz in the chondrotympanoplasty group and 628 +/- 256 Hz in the TFG group. The RF remained within the normal range in 73.7% of chondrotympanoplasty patients versus 42.9% of TFG patients. CONCLUSIONS: Chondrotympanoplasty has hearing results comparable to those of TFG myringoplasty. The cartilage can be used without concerns regarding its impact on the middle ear mechanics as the sound conducive properties of the tympanic membrane remain unchanged. PMID- 22498264 TI - Usefulness of the melanoma antigen gene (MAGE) in making the differential diagnosis between pleomorphic adenoma and adenoid cystic carcinoma. AB - OBJECTIVE: The aim of this study was to examine the clinical usefulness of the melanoma antigen gene (MAGE) in making the differential diagnosis between pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC). In addition, using real-time reverse transcriptase polymerase chain reaction (RT-PCR), we examined which melanoma antigen gene was actually expressed in each tumour. MATERIALS AND METHOD: Immunohistochemical staining was performed on samples of paraffin embedded tissue specimens. Fifty-eight patients were diagnosed as PA (n = 31), ACC (n = 17), and nontumoral salivary tissue (n = 10) using MAGEA and MAGEA4. Using primers that could express MAGEA1, -A2, -A3, -A4, -A6, -A10, and -A12 subtypes, real-time RT-PCR was performed in three cases of PA and four cases of ACC that occurred in fresh tissues. RESULT: We found no immunohistochemical expression of MAGEA or MAGEA4 in the nontumoral tissue. There was a mild degree of expression with no statistical significance in cases of PA. In ACC, however, in 17 cases (100%) and 16 cases (95%), there was a positive reaction to MAGEA and MAGEA4, respectively. In the RT-PCR analysis, PA showed no MAGE gene expression. However, both MAGEA3 and MAGEA4 were expressed in ACC. CONCLUSION: These results suggest that MAGE could be used as a biologic marker in the differential diagnosis between PA and ACC. Our results also indicate that the expression of MAGE, as confirmed in the RT-PCR analysis, could be used as an alternative method for the early diagnosis of salivary gland tumours. PMID- 22498265 TI - Hyalinizing trabecular tumour: review and new insights into the molecular biology. AB - OBJECTIVE: To review the current literature on hyalinizing trabecular tumor (HTT) and the relationship to other, more sinister neoplasms of the thyroid including papillary thyroid carcinoma (PTC). To apply this information to clinical practice and thus elucidate the best approach regarding the management of patients with thyroid tumours. METHODS: A thorough literature search was performed on articles published on HTT thus far. Articles were then reviewed for epidemiology, discussion of categorization, and possible areas of differentiation from other thyroid tumor types. Our own hospital records were all reviewed for any possible cases of HTT. RESULTS: There have been many attempts made to find objective ways of categorizing HTT from other thyroid tumors. The articles found highlighted the difficulties in understanding the classification, molecular genetics, and pathology of HTT, especially with regard to the differentiation from PTC. In our own institution, we found only one such case of confirmed HTT. CONCLUSIONS: The ability to differentiate between HTT and PTC remains imperfect. Currently, permanent histologic sections are the best means for obtaining a diagnosis. Once this relationship is elucidated further, the treatment approach can be tailored, and patients will possibly avoid a total thyroidectomy and radioactive iodine ablation, as currently indicated for PTC. PMID- 22498266 TI - Retrospective review of three antiemetic regimens versus no therapy in the prevention of postoperative and vomiting following adenotonsillar surgery. AB - OBJECTIVE: To study the effect of intraoperative ondansetron and dexamethasone on postoperative vomiting in children undergoing tonsillectomy, adenotonsillectomy, or adenoidectomy. STUDY DESIGN: Retrospective chart review. SETTING: Academic tertiary care referral centre in the west of Scotland. SUBJECTS AND METHODS: A retrospective chart review was conducted on 432 children admitted to our institute between 2004 and 2006. Of these, 285 (66%) patients underwent a tonsillectomy, 50 (11.6%) an adenotonsillectomy, and 97 (22.4%) an adenoidectomy. There was an equal gender distribution, with a mean age of 7.4 years (interquartile range 4.6-10.0). Patients were divided into four groups: group 1 received ondansetron plus dexamethasone (n = 64, 14.7%), group 2 received ondansetron only (n = 189, 43.6%), group 3 received dexamethasone only (n = 17, 3.9%), and group 4 did not receive ondansetron or dexamethasone (n = 162, 37.4%). RESULTS: Overall, 98 (22.7%) patients experienced postoperative vomiting (5 at the time of recovery and 93 on the ward). Patients in group 1 had a significantly lower incidence of postoperative vomiting than those in group 2 (10.9% vs 22.8%, p = .04) and group 4 (10.9% vs 27.2%, p < .01). The incidence of postoperative vomiting was also lower in group 1 than in group 3, but this did not reach statistical significance (10.9% vs 23.5%, p = .18). CONCLUSION: The combined intraoperative use of ondansetron and dexamethasone appears to be superior to no antiemetic or ondansetron alone in reducing the incidence of vomiting in children undergoing adenotonsillar surgery. PMID- 22498267 TI - Medialization thyroplasty for unilateral vocal cord paralysis secondary to advanced extralaryngeal malignant disease: review of operative morbidity and patient life expectancy. AB - OBJECTIVE: To review the operative morbidity and the overall length of survival following medialization thyroplasty for unilateral vocal cord paralysis (UVCP) due to advanced extralaryngeal malignancy. DESIGN: Retrospective review. SETTING: Tertiary care laryngology practice. METHOD: All cases of medialization thyroplasty over a 3-year period were reviewed. Only patients who had UVCP due to advanced extralaryngeal malignancy were included. Any cases from iatrogenic causes or for any other reason were excluded. Survival days were calculated from the date of the thyroplasty. MAIN OUTCOME MEASURE: Survival days postmedialization thyroplasty. RESULTS: Twenty-one patients met the inclusion criteria. Two distinct groups within this cohort were identified: (1) those suffering from advanced lung cancer and (2) those with metastatic cancer of another origin (ie, breast, renal cell, esophageal). There were 11 patients in the lung cancer group and 10 in the other group. Average survival was 538 days in the lung cancer group and 668 days in the other group. The procedure was well tolerated, with only one postoperative complication, which was a minor wound infection. CONCLUSION: For patients suffering from advanced malignancy, medialization thyroplasty is a safe procedure and an excellent modality for voice palliation. PMID- 22498268 TI - One-stop evaluation of globus pharyngeus symptoms with transnasal esophagoscopy and swallowing function test. AB - OBJECTIVE: To evaluate the feasibility of a one-stop assessment of patients complaining of globus sensation with transnasal esophagoscopy (TNE) and functional endoscopic evaluation of swallowing (FEES). DESIGN: Prospective, nonrandomized, experimental investigation. SETTING: Tertiary referral centre. METHODS: Sixty-three consecutive patients complaining of a lump in the throat were evaluated by this combined approach. MAIN OUTCOME MEASURES: The safety and feasibility of performing a one-stop TNE plus FEES were explored by subjective measurement of the patients' tolerance and satisfaction and comments from surgeons. The possible therapeutic effects were also assessed 2 months after the procedure. RESULTS: All 63 patients completed the TNE and FEES without any complications. The average duration of the examination was 6.27 +/- 2.52 (95% CI 5.63-6.91) minutes. The findings included arytenoid cyst, epiglottic cyst, vocal cord nodules, vocal cord palsy, esophageal reflux, and foveolar gland hyperplasia. Two patients (3.2%) demonstrated some degree of fluid penetration or aspiration. Nine specialists all scored highly on a visual analogue scale on the manipulation, visualization, and satisfaction of the TNE procedure (median = 8 of 10). Patients also rated a low pain score (median = 1 of 10) and a high satisfaction score (median = 9 of 10). CONCLUSION: The combined technique of TNE and FEES can be used safely as a one-stop examination tool for patients with globus pharyngeus symptoms. PMID- 22498269 TI - Immunologic properties and clinical features of local allergic rhinitis. AB - OBJECTIVE: There is still no study involving the immunologic properties of local allergic rhinitis (LAR). We aimed to determine the immunologic profile of patients with LAR by analyzing cytokines in the serum and nasal secretions and correlated the results with clinical characteristics. METHODS: Ten healthy volunteers (group A), nine patients with allergic rhinitis (group B), and seven patients with LAR (group C) were enrolled. MAIN OUTCOME MEASURES: Changes in nasal symptoms, total nasal volume (TNV), and minimal cross-sectional area (MCA) were compared. We performed a Quantibody array for interleukin (IL)-4, IL-13, IL 3, IL-5, granulocyte-macrophage colony-stimulating factor, stem cell factor, IL 10, and transforming growth factor beta (TGF-beta) using serum and nasal secretions. RESULTS: Patients in group C had more aggravated rhinorrhea and itching than patients in group B (p < .05). The change in TNV and MCA was greater in groups B and C than in group A (p < .01). The serum concentration of IL-10 in group C was higher than in group A or B (p < .001). The concentration of IL-13, IL-5, IL-10, and TGF-beta in group C was higher than in group A or B in the nasal secretions (p < .001). CONCLUSIONS: Patients with LAR have similar symptoms, similar changes in TNV and MCA, and a similar profile of cytokine production and nasal secretions than those with allergic rhinitis. More prominent immunomodulating properties of LAR patients could in part explain the absence of systemic allergic responses. PMID- 22498270 TI - Neurofibromatosis and velopharyngeal insufficiency: is there an association? AB - OBJECTIVE: Velopharyngeal insufficiency (VPI) is an often underrecognized disorder of palatal and nasopharyngeal closure that leads to the production of hypernasal speech. However, the potential clinical association between VPI and neurofibromatosis type 1 (NF1) remains undefined in the literature. The purpose of this study sought to identify and describe the potential clinical association of VPI in NF1 patients. DESIGN: A combined retrospective and prospective study. SETTING: Tertiary referral centre. METHODS: The NF1 database from 1998 to 2007 from the Medical Genetics Unit of our institution was used for this project. All NF1 patients seen during this period were sent a letter soliciting their participation in the study, which was designed to screen for the presence of VPI. MAIN OUTCOME MEASURES: Perceptual testing was undertaken using the American Cleft Palate-Craniofacial Association (ACPA) clinical database form and acoustic measurement of nasal flow, including standard nasometry and nasalance scores. A comprehensive chart review was also performed. RESULTS: One hundred forty-nine NF1 patients were identified from the database; 18 patients responded to our request for participation, with 3 additional participants recruited from recent clinical visits. Eleven of these 21 patients exhibited VPI based on perceptual evaluation and nasometry screening. CONCLUSIONS: This preliminary study attempted to identify a potential association between NF1 and VPI. Although this sample of NF1 patients was small, the finding of 11 of 21 patients being positively identified with some degree of VPI is of clinical interest, and further research is warranted. PMID- 22498271 TI - Laryngology in Canada: results of a national survey. AB - OBJECTIVE: Laryngology is a rapidly evolving and growing field in Canada. Recent technologies and trends, including endoscopic techniques, KTP and pulsed dye lasers, injection materials, and in-office procedures, are changing the nature and depth of services offered to patients. Our objective was to understand the current state of laryngology practice in Canada. DESIGN: Survey. SETTING: Adult laryngology practices in Canada. METHODS: We identified otolaryngologists working in Canada who self-identified as having a significant laryngology practice. We then asked them to complete an anonymous survey, with questions regarding composition of practice time, endoscopic equipment, electromyography, vocal cord medialization techniques, laser technologies, and plans for the future. MAIN OUTCOME MEASURES: Practice composition and use rates of available technology. RESULTS: Ten of 11 respondents reported that laryngology represents at least 20% of their practice (mean = 53%). All employed rigid laryngoscopy, stroboscopy, and exclusively CO2 laser. Six used distal chip endoscopes, whereas three perform transnasal esophagoscopy. CONCLUSIONS: The survey results demonstrate that laryngology practice in Canada is approaching state of the art and that most laryngologists plan to increase the breadth and scope of their practice as newer technologies become available. Limited funding and national regulations limit the adoption of some cutting-edge techniques. PMID- 22498272 TI - Undergraduate otolaryngology education at the University of Toronto: a review using a curriculum mapping system. AB - BACKGROUND/PURPOSE: The aim of Canadian medical school curricula is to provide educational experiences that satisfy the specific objectives set out by the Medical Council of Canada. However, for specialties such as otolaryngology, there is considerable variability in student exposure to didactic and clinical teaching across Canadian medical schools, making it unclear whether students receive sufficient teaching of core otolaryngology content and clinical skills. The goal of this review was to assess the exposure to otolaryngology instruction in the undergraduate medical curriculum at the University of Toronto. METHOD: Otolaryngology objectives were derived from objectives created by the Medical Council of Canada and the University of Toronto. The University of Toronto's recently developed Curriculum Mapping System (CMap) was used to perform a keyword search of otolaryngology objectives to establish when and to what extent essential topics were being taught. RESULTS: All (10 of 10) major topics and skills identified were covered in the undergraduate medical curriculum. Although no major gaps were identified, an uneven distribution of teaching time exists. The majority (> 90%) of otolaryngology education occurs during year 1 of clerkship. The amount of preclerkship education was extremely limited. DISCUSSION AND CONCLUSIONS: Essential otolaryngology topics and skills are taught within the University of Toronto curriculum. The CMap was an effective tool to assess the otolaryngology curriculum and was able to identify gaps in otolaryngology education during the preclerkship years of medical school. As a result, modifications to the undergraduate curriculum have been implemented to provide additional teaching during the preclerkship years. PMID- 22498273 TI - Lidocaine in the middle ear may not be without risk. PMID- 22498274 TI - Snapping joint of the hyoid bone. PMID- 22498275 TI - Transient facial baroparesis. PMID- 22498276 TI - Staphylococcus aureus nasal septal abscess complicated by extradural abscess in an infant. PMID- 22498277 TI - Ultrasonic studies of intermolecular interactions in binary mixtures of 4-methoxy benzoin with various solvents: Excess molar functions of ultrasonic parameters at different concentrations and in different solvents. AB - Density (rho), ultrasonic velocity (U), for the binary mixtures of 4-methoxy benzoin (4MB) with ethanol, chloroform, acetonitrile, benzene, and di-oxane were measured at 298K. The solute-solvent interactions and the effect of the polarity of the solvent on the type of intermolecular interactions are discussed here. From the above data, adiabatic compressibility (beta), intermolecular free length (L(f)), acoustic impedance (Z), apparent molar volume (O), relative association (RA) have been calculated. Other useful parameters such as excess density, excess velocity and excess adiabatic compressibility have also been calculated. These parameters were used to study the nature and extent of intermolecular interactions between component molecules in the binary mixtures. PMID- 22498278 TI - Structure and micro-computed tomography-based finite element modeling of Toucan beak. AB - Bird beaks are one of the most fascinating sandwich composites in nature. Their design is composed of a keratinous integument and a bony foam core. We evaluated the structure and mechanical properties of a Toucan beak to establish structure property relationships. We revealed the hierarchical structure of the Toucan beak by microscopy techniques. The integument consists of 50 MUm polygonal keratin tiles with ~7.5 nm embedded intermediate filaments. The branched intermediate filaments were visualized by TEM tomography techniques. The bony foam core or trabecular bone is a closed-cell foam, which serves as a stiffener for the beak. The tridimensional foam structure was reconstructed by MU-CT scanning to create a model for the finite element analysis (FEA). The mechanical response of the beak foam including trabeculae and cortical shell was measured in tension and compression. We found that Young's modulus is 3 (S.D. 2.2) GPa for the trabeculae and 0.3 (S.D. 0.2) GPa for the cortical shell. After obtaining the material parameters, the deformation and microscopic failure of foam were calculated by FEA. The calculations agree well with the experimental results. PMID- 22498279 TI - Sterculia crosslinked PVA and PVA-poly(AAm) hydrogel wound dressings for slow drug delivery: mechanical, mucoadhesive, biocompatible and permeability properties. AB - The present study deals with the synthesis and characterization of sterculia crosslinked PVA and PVA-AAm hydrogel wound dressings. The hydrogels have been characterized by SEMs, FTIR, TGA and swelling studies. This article also discusses comparison of swelling, drug release and biomedical properties such as blood compatibility, antimicrobial activity, mucoadhesion, tensile strength, burst strength, water vapour permeability, oxygen diffusion and microbial penetration of both hydrogel wound dressings. These polymeric films have absorbed 4.80 +/- 0.15 and 6.32 +/- 0.15 gram/g of gel of simulated wound fluid respectively and swelling occurred through Case II diffusion mechanism. The release of antibiotic drugs occurred through non-Fickian and Case II diffusion mechanisms, respectively. These polymeric films have been observed to be permeable for oxygen and water vapour but have shown impermeability to the micro organism. Sterculia-PVA hydrogel wound dressing has shown more blood compatibility as compared to the other film. All these results indicate that these hydrogel films may be used as wound dressings for the slow release of antibiotic drug to the wound. PMID- 22498280 TI - Mechanical properties, electrochemical corrosion and in-vitro bioactivity of yttria stabilized zirconia reinforced hydroxyapatite coatings prepared by gas tunnel type plasma spraying. AB - Yttria stabilized zirconia reinforced hydroxyapatite coatings were deposited by a gas tunnel type plasma spray torch under optimum spraying conditions. For this purpose, 10, 20 and 30 wt% of yttria stabilized zirconia (YSZ) powders were premixed individually with hydroxyapatite (HA) powder and were used as the feedstocks for the coatings. The effect of YSZ reinforcement on the phase formation and mechanical properties of the coatings such as hardness, adhesive strength and sliding wear rates was examined. The results showed that the reinforcement of YSZ in HA could significantly enhance the hardness and adhesive strength of the coatings. The potentiodynamic polarization and impedance measurements showed that the reinforced coatings exhibited superior corrosion resistance compared to the HA coating in SBF solution. Further the results of the bioactivity test conducted by immersion of coatings in SBF showed that after 10 days of immersion of the obtained coatings with all the above compositions commonly exhibited the onset of bioactive apatite formation except for HA+10%YSZ coating. The cytocompatibility was investigated by culturing the green fluorescent protein (GFP)-labeled marrow stromal cells (MSCs) on the coating surface. The cell culture results revealed that the reinforced coatings have superior cell growth than the pure HA coatings. PMID- 22498281 TI - Development and mechanical characterization of porous titanium bone substitutes. AB - Commercially Pure Porous Titanium (CPPTi) can be used for surgical implants to avoid the stress shielding effect due to the mismatch between the mechanical properties of titanium and bone. Most researchers in this area deal with randomly distributed pores or simple architectures in titanium alloys. The control of porosity, pore size and distribution is necessary to obtain implants with mechanical properties close to those of bone and to ensure their osseointegration. The aim of the present work was therefore to develop and characterize such a specific porous structure. First of all, the properties of titanium made by Selective Laser Melting (SLM) were characterized through experimental testing on bulk specimens. An elementary pattern of the porous structure was then designed to mimic the orthotropic properties of the human bone following several mechanical and geometrical criteria. Finite Element Analysis (FEA) was used to optimize the pattern. A porosity of 53% and pore sizes in the range of 860 to 1500 MUm were finally adopted. Tensile tests on porous samples were then carried out to validate the properties obtained numerically and identify the failure modes of the samples. Finally, FE elastoplastic analyses were performed on the porous samples in order to propose a failure criterion for the design of porous substitutes. PMID- 22498282 TI - Assessment of a chair-side argon-based non-thermal plasma treatment on the surface characteristics and integration of dental implants with textured surfaces. AB - The biomechanical effects of a non-thermal plasma (NTP) treatment, suitable for use in a dental office, on the surface character and integration of a textured dental implant surface in a beagle dog model were evaluated. The experiment compared a control treatment, which presented an alumina-blasted/acid-etched (AB/AE) surface, to two experimental treatments, in which the same AB/AE surface also received NTP treatment for a period of 20 or 60 s per implant quadrant (PLASMA 20' and PLASMA 60' groups, respectively). The surface of each specimen was characterized by electron microscopy and optical interferometry, and surface energy and surface chemistry were determined prior to and after plasma treatment. Two implants of each type were then placed at six bilateral locations in 6 dogs, and allowed to heal for 2 or 4 weeks. Following sacrifice, removal torque was evaluated as a function of animal, implant surface and time in vivo in a mixed model ANOVA. Compared to the CONTROL group, PLASMA 20' and 60' groups presented substantially higher surface energy levels, lower amounts of adsorbed C species and significantly higher torque levels (p=.001). Result indicated that the NTP treatment increased the surface energy and the biomechanical fixation of textured surface dental implants at early times in vivo. PMID- 22498284 TI - The role of property gradients on the mechanical behavior of human enamel. AB - In this study, the mechanical design principles of human enamel were evaluated using a hybrid experimental and computational approach. Nanoindentation was applied to evaluate the load-depth response of human enamel, and Vickers indentations were used to assess the damage behavior. An elastic-plastic numerical model was then developed to analyze the stress and strain distribution about the indentations, and to characterize energy dissipation about indents in three locations including inner, middle and outer enamel. Results confirm that enamel exhibits a gradient in its mechanical behavior. Outer enamel has a limited potential for energy dissipation by inelastic deformation, indicating that the ability of outer enamel to resist fracture is low. While inner enamel, the region close Dentin Enamel Junction (DEJ), possesses less resistance to penetration deformation, it has a much higher capacity to dissipate energy by inelastic deformation than outer enamel. The computational simulations identified that the gradients in mechanical properties of human enamel promote resistance to penetration, energy dissipation and mitigation of fracture, all critical performance requirements of human teeth. PMID- 22498283 TI - The tribological difference between biomedical steels and CoCrMo-alloys. AB - In orthopedic surgery, different self-mating metal couples are used for sliding wear applications. Despite the fact that in mechanical engineering, self-mating austenitic alloys often lead to adhesion and seizure in biomedical engineering, the different grades of Co-base alloys show good clinical results, e.g., as hip joints. The reason stems from the fact that they generate a so-called tribomaterial during articulation, which consists of a mixture of nanometer small metallic grains and organic substances from the interfacial medium, which act as a boundary lubricant. Even though stainless steel also generate such a tribomaterial, they were ruled out from the beginning already in the 1950s as "inappropriate". On the basis of materials with a clinical track record, this contribution shows that the cyclic creep characteristics within the shear zone underneath the tribomaterial are another important criterion for a sufficient wear behavior. By means of sliding wear and torsional fatigue tests followed by electron microscopy, it is shown that austenitic materials generate wear particles of either nano- or of microsize. The latter are produced by crack initiation and propagation within the shear fatigue zone which is related to the formation of subsurface dislocation cells and, therefore, by the fact that an Ni containing CrNiMo solid solution allows for wavy-slip. In contrast to this, an Ni free CrMnMo solid solution with further additions of C and N only shows planar slip. This leads to the formation of nanosize wear particles and distinctly improves the wear behavior. Still, the latter does not fully achieve that of CoCrMo, which also shows a solely planar-slip behavior. This explains why for metallurgical reasons the Ni-containing 316L-type of steels had to fail in such boundary lubricated sliding wear tribosystems. PMID- 22498285 TI - The influence of irradiation dose on mechanical properties and wear resistance of molded and extruded ultra high molecular weight polyethylene. AB - Ultra high molecular weight polyethylene (UHMWPE) is a type of biomedical material used in total joint replacement. In this study, molded and extruded UHMWPE was used to investigate the influence of irradiation dose on its mechanical properties and wear resistance. The results of tensile and compressive tests showed that tensile properties decreased as the irradiation dose increased. Compressive properties decreased significantly after irradiation, but then increased as the irradiation dose increased. Microhardness also had a similar variety tendency as compressive properties. It could be corresponding to the variety of crystallinity for UHMWPE. The fracture surfaces of tensile samples indicated that molded and extruded UHMWPE had a similar fracture mechanism, although the tensile properties were significantly different. The wear tests of knee joint moving simulator showed that the wear rate of molded and extruded UHMWPE decreased as the irradiation dose increased, and a significant reduction of wear rate was exhibited till the irradiation dose of 100 kGy under saline lubrication, and 150 kGy under calf serum lubrication. The IR results indicated that packaging and remelting in vacuum was an effective method to remove oxygen in UHMWPE blocks. PMID- 22498286 TI - Microstructure and mechanical behavior of superelastic Ti-24Nb-0.5O and Ti-24Nb 0.5N biomedical alloys. AB - In this study, the microstructure and the mechanical properties of two new biocompatible superelastic alloys, Ti-24Nb-0.5O and Ti-24Nb-0.5N (at.%), were investigated. Special attention was focused on the role of O and N addition on alpha(") formation, supereleastic recovery and mechanical strength by comparison with the Ti-24Nb and Ti-26Nb (at.%) alloy compositions taken as references. Microstructures were characterized by optical microscopy, X-ray diffraction and transmission electron microscopy before and after deformation. The mechanical properties and the superelastic behavior were evaluated by conventional and cyclic tensile tests. High tensile strength, low Young's modulus, rather high superelastic recovery and excellent ductility were observed for both superelastic Ti-24Nb-0.5O and Ti-24Nb-0.5N alloys. Deformation twinning was shown to accommodate the plastic deformation in these alloys and only the {332}<113> twinning system was observed to be activated by electron backscattered diffraction analyses. PMID- 22498287 TI - Mechanical properties and microstructural evolution of vacuum hot-pressed titanium and Ti-6Al-7Nb alloy. AB - Hot-pressing is a powder metallurgy process where loose powder is loaded into a mould, usually of graphite, and sintered by the simultaneous application of high temperature and pressure. In this study elemental titanium and Ti-6Al-7Nb alloy powders are hot-pressed under different conditions in order to study the influence of the processing parameters on the microstructure and mechanical properties. The samples are characterised in terms of relative density, microstructure, XRD, percentage of interstitials, three-point bending test and hardness. Relative densities as high as 99% are obtained, the oxygen and carbon content remains almost constant but nitrogen percentage increases. This is due to the interaction with the BN coated mould and leads to the formation of a reacted layer in the surface, composed by different titanium compounds, which greatly affect the mechanical properties. Nevertheless, the removal of this reacted layer leads to an important improvement of the ductility, especially for elemental titanium. PMID- 22498288 TI - Synthesis, structure and properties of poly(L-lactide-co-epsilon-caprolactone) statistical copolymers. AB - Four poly(L-lactide-co-epsilon-caprolactone) (PLCL) copolymers were synthesized at 120, 130, 140 and 150 degrees C by ring opening polymerization using stannous octoate catalyst at a 2000:1 comonomer:catalyst ratio. Gel permeation chromatography (GPC) and (1)H NMR measurements were performed to determine the molecular weight, composition and chain microstructure of copolymers of L lactide(LA):epsilon-caprolactone(CL) synthesized using 90:10, 80:20, 75:25 and 70:30 feed ratios. The overall conversion of these PLCL copolymers was in the range of 80%-90% leading to weight average molecular weights (M(w)) between 98,500 and 226,000 g mol(-1) depending on feed composition and polymerization temperature. At temperatures lower than 140 degrees C, the incorporation of CL units into polymer chains was incomplete because of the low reactivity of CL, thus at 120 degrees C the copolymer composition was difficult to control obtaining more LA in the copolymer than the desired, hence the blocky character of PLCL copolymers also increased. At 150 degrees C the catalyst was less effective and the molecular weights of the copolymers took lower values. A temperature of 140 degrees C was established as optimal to obtain highest yields and molecular weight. The number average crystallizable lactide sequence lengths (l(LA)) shifted from 6.5 to 16.7 LA repeat units for PLCL polymerized at 140 degrees C while the randomness character (R) value shifted from 0.4 for polymerization at 130 degrees C to 0.6, at 150 degrees C. Increasing the LA content in the copolymers the glass transition temperature and the crystallizability and melting temperature of PLCLs approached to that of PLLA homopolymer. The aging sensitivity of PLCLs increased with CL content. A double T(g) behavior due to phase separation associated to crystallizing LA blocks was observed during aging. The mechanical properties, however, evolved toward the PLLA character when the molar content of LA in PLCL was increased from 66% to 90%, observing a shift from an elastomeric thermoplastic behavior to that of a glassy plastic, reflected by an increase in tensile modulus (from 12.0 to 1343.1 MPa) and a decrease in strain recovery after break (from 93.5% to 25.0%). Small amounts of CL content in the copolymers produced large improvements in their deformability with regard to PLLA. In addition, thermogravimetric analysis demonstrated that PLCLs are more stable to thermal degradation than PLLA and they undergo a more complex degradation mechanism than those of the corresponding homopolymers. PMID- 22498289 TI - Tuning liver stiffness against tumours: an in vitro study using entrapped cells in tumour-like microcapsules. AB - Liver fibrosis is a reversible pathology characterized by the up-regulated secretion and deposition of ECM proteins and inhibitors of metalloproteinases, which increase the stiffness and viscosity of this organ. Since recent studies have shown that fibrosis preceded the generation of hepatocellular carcinomas, we hypothesize that liver fibrosis could play a role as a mechanism for restricting uncontrolled cell proliferation, inducing the mortality of cancer cells and subsequent development of primary tumours. With this purpose, in this work we analysed in vitro how the modulation of stiffness can influence proliferation, viability and aggregation of hepatocarcinoma cells (HepG(2)) embedded in 3D micromilieus mimicking values of elasticity of fibrotic liver tissues. Experiments were performed by immobilizing up to 10 HepG(2) cells within microcapsules made of 0.8%, 1.0% and 1.4% w/v alginate which, besides having values of elasticity from the lower-healthy to the upper-fibrotic range liver tissues, lacked domains for proteases, mimicking the micromilieu existing in hepatic primary tumours. Our results show that entrapped cells exhibited a short duplication phase followed by an irreversible decay stage, in which cell mortality could be mediated by two mechanisms: mechanical stress, in the case of cells entrapped in a stiffer micromilieu; and mass transfer limitations produced by pore coarsening at the interface cell-matrix, in softer micromilieus. According to the authors' knowledge, this work represents the first attempt to elucidate the role of liver fibrosis during Hepatocarcinoma pathologies, suggesting that the generation of a non-biodegradable and mechanically unfavourable environment surrounding cancer cells could control the proliferation, migration of metastatic cells and the subsequent development of primary tumours. PMID- 22498290 TI - Apparent behaviour of charged and neutral materials with ellipsoidal fibre distributions and cross-validation of finite element implementations. AB - Continuous fibre distribution models can be applied to a variety of biological tissues with both charged and neutral extracellular matrices. In particular, ellipsoidal models have been used to describe the complex material behaviour of tissues such as articular cartilage and their engineered tissue equivalents. The choice of material parameters is more difficult than in classical anisotropic models and the impact that changes to these parameters can have on the predictions of such models are poorly understood. The objective of this study is to demonstrate the apparent behaviour of this class of materials over a range of material parameters. We further introduce a scaling approach to overcome certain counter-intuitive aspects related to the choice of anisotropy parameters and outline the integration method used in our implementations. User material codes for the commercial FE software packages Abaqus and MSC Marc are provided for use by other investigators. Cross-validation of our code against similar implementations in FEBio is also presented. PMID- 22498291 TI - Shear mechanical properties of the spleen: experiment and analytical modelling. AB - This paper aims at providing the first shear mechanical properties of spleen tissue. Rheometric tests on porcine splenic tissues were performed in the linear and nonlinear regime, revealing a weak frequency dependence of the dynamic moduli in linear regime and a distinct strain-hardening effect in nonlinear regime. These behaviours are typical of soft tissues such as kidney and liver, with however a less pronounced strain-hardening for the spleen. An analytical model based on power laws is then proposed to describe the general shear viscoelastic behaviour of the spleen. PMID- 22498292 TI - Mechanical characterization of injection-molded macro porous bioceramic bone scaffolds. AB - Bioactive ceramic materials like tricalcium phosphate (TCP) have been emerging as viable material alternatives to the current therapies of bone scaffolding to target fracture healing and osteoporosis. Both material and architectural characteristics play a critical role in the osteoconductive capacity and strength of bone scaffolds. Thus, the objective of this research was to investigate the sintering temperature effect of a cost-effective manufacturing process on the architecture and mechanical properties of a controlled macro porous bioceramic bone scaffold. In this study the physical and mechanical properties of beta-TCP bioceramic scaffolds were investigated as a function of the sintering temperature in the range of 950-1150 degrees C. Physical properties investigated included bulk dimensions, pore size, and strut thickness; and, compressive mechanical properties were evaluated in air at room temperature and in saline solution at body temperature. Statistically significant increases in apparent elastic modulus were measured for scaffolds sintered at higher temperatures. Structural stiffness for all the specimens was significantly reduced when tested at body temperature in saline solution. These findings support the development of clinically successful bioceramic scaffolds that may stimulate bone regeneration and scaffold integration while providing structural integrity. PMID- 22498293 TI - Microstructure, mechanical properties, biocorrosion behavior, and cytotoxicity of as-extruded Mg-Nd-Zn-Zr alloy with different extrusion ratios. AB - Recently, commercial magnesium (Mg) alloys containing Al (such as AZ31 and AZ91) or Y (such as WE43) have been studied extensively for biomedical applications. However, these Mg alloys were developed as structural materials, not as biomaterials. In this study, a patented Mg-Nd-Zn-Zr (denoted as JDBM) alloy was investigated as a biomedical material. The microstructure, mechanical properties, biocorrosion behavior, and cytotoxicity of the alloy extruded at 320 degrees C with extrusion ratios of 8 and 25 were studied. The results show that the lower extrusion ratio results in finer grains and higher strength, but lower elongation, while the higher extrusion ratio results in coarser grains and lower strength, but higher elongation. The biocorrosion behavior of the alloy was investigated by hydrogen evolution and mass loss tests in simulated body fluid (SBF). The results show that the alloy extruded with lower extrusion ratio exhibits better corrosion resistance. The corrosion mode of the alloy is uniform corrosion, which is favorable for biomedical applications. Aging treatment on the as-extruded alloy improves the strength and decreases the elongation at room temperature, and has a small positive influence on the corrosion resistance in SBF. The cytotoxicity test indicates that the as-extruded JDBM alloy meets the requirement of cell toxicity. PMID- 22498294 TI - Finite element modeling of passive material influence on the deformation and force output of skeletal muscle. AB - The pattern of deformation of different structural components of a muscle-tendon complex when it is activated provides important information about the internal mechanics of the muscle. Recent experimental observations of deformations in contracting muscle have presented inconsistencies with current widely held assumption about muscle behavior. These include negative strain in aponeuroses, non-uniform strain changes in sarcomeres, even of individual muscle fibers and evidence that muscle fiber cross sectional deformations are asymmetrical suggesting a need to readjust current models of contracting muscle. We report here our use of finite element modeling techniques to simulate a simple muscle tendon complex and investigate the influence of passive intramuscular material properties upon the deformation patterns under isometric and shortening conditions. While phenomenological force-displacement relationships described the muscle fiber properties, the material properties of the passive matrix were varied to simulate a hydrostatic model, compliant and stiff isotropically hyperelastic models and an anisotropic elastic model. The numerical results demonstrate that passive elastic material properties significantly influence the magnitude, heterogeneity and distribution pattern of many measures of deformation in a contracting muscle. Measures included aponeurosis strain, aponeurosis separation, muscle fiber strain and fiber cross-sectional deformation. The force output of our simulations was strongly influenced by passive material properties, changing by as much as ~80% under some conditions. The maximum output was accomplished by introducing anisotropy along axes which were not strained significantly during a muscle length change, suggesting that correct costamere orientation may be a critical factor in the optimal muscle function. Such a model not only fits known physiological data, but also maintains the relatively constant aponeurosis separation observed during in vivo muscle contractions and is easily extrapolated from our plane-strain conditions into a three-dimensional structure. Such modeling approaches have the potential of explaining the reduction of force output consequent to changes in material properties of intramuscular materials arising in the diseased state such as in genetic disorders. PMID- 22498295 TI - Experimental and numerical characterisation of the elasto-plastic properties of bovine trabecular bone and a trabecular bone analogue. AB - The inelastic pressure dependent compressive behaviour of bovine trabecular bone is investigated through experimental and computational analysis. Two loading configurations are implemented, uniaxial and confined compression, providing two distinct loading paths in the von Mises-pressure stress plane. Experimental results reveal distinctive yielding followed by a constant nominal stress plateau for both uniaxial and confined compression. Computational simulation of the experimental tests using the Drucker-Prager and Mohr-Coulomb plasticity models fails to capture the confined compression behaviour of trabecular bone. The high pressure developed during confined compression does not result in plastic deformation using these formulations, and a near elastic response is computed. In contrast, the crushable foam plasticity models provide accurate simulation of the confined compression tests, with distinctive yield and plateau behaviour being predicted. The elliptical yield surfaces of the crushable foam formulations in the von Mises-pressure stress plane accurately characterise the plastic behaviour of trabecular bone. Results reveal that the hydrostatic yield stress is equal to the uniaxial yield stress for trabecular bone, demonstrating the importance of accurate characterisation and simulation of the pressure dependent plasticity. It is also demonstrated in this study that a commercially available trabecular bone analogue material, cellular rigid polyurethane foam, exhibits similar pressure dependent yield behaviour, despite having a lower stiffness and strength than trabecular bone. This study provides a novel insight into the pressure dependent yield behaviour of trabecular bone, demonstrating the inadequacy of uniaxial testing alone. For the first time, crushable foam plasticity formulations are implemented for trabecular bone. The enhanced understanding of the inelastic behaviour of trabecular bone established in this study will allow for more realistic simulation of orthopaedic device implantation and failure. PMID- 22498296 TI - Nanoindentation of osteonal bone lamellae. AB - Variations in Young's modulus of individual lamellae around a single bone osteon have been measured in three orthogonal planes by nanoindentation. The objective of these measurements was to establish a correlation between the mechanical properties and the microstructure of the osteonal lamellae. When indentation was performed in a plane perpendicular to the osteon axis (OA), the modulus of the lamella closest to the canal appears to be higher than the modulus of all other lamellae. No such difference was observed in planes parallel to the OA. However, in the parallel planes, an unexpected asymmetry in modulus was detected on opposing sides of the canal, potentially supporting the validity of the rotated plywood structure model of bone lamellae. Finally, based on the experimentally measured Young's modulus values, most osteonal lamellae appear to exhibit structural anisotropy. PMID- 22498297 TI - Development of thermo-mechanical processing for fabricating highly durable beta type Ti-Nb-Ta-Zr rod for use in spinal fixation devices. AB - The mechanical strength of a beta titanium alloy such as Ti-Nb-Ta-Zr alloy (TNTZ) can be improved significantly by thermo-mechanical treatment. In this study, TNTZ was subjected to solution treatment, cold caliber rolling, and cold swaging before aging treatment to form a rod for spinal fixation. The {110}(beta) are aligned parallel to the cross-section with two strong peaks approximately 180 degrees apart, facing one another, in the TNTZ rods subjected to cold caliber rolling and six strong peaks at approximately 60 degrees intervals, facing one another, in the TNTZ rods subjected to cold swaging. Therefore, the TNTZ rods subjected to cold swaging have a more uniform structure than those subjected to cold caliber rolling. The orientation relationship between the alpha and beta phases is different. A [110](beta)//[121](alpha), (112)(beta)//(210)(alpha) orientation relationship is observed in the TNTZ rods subjected to aging treatment at 723 K after solution treatment and cold caliber rolling. On the other hand, a [110](beta)//[001](alpha), (112)(beta)//(200)(alpha) orientation relationship is observed in TNTZ rod subjected to aging treatment at 723 K after cold swaging. A high 0.2% proof stress of about 1200 MPa, high elongation of 18%, and high fatigue strength of 950 MPa indicate that aging treatment at 723 K after cold swaging is the optimal thermo-mechanical process for a TNTZ rod. PMID- 22498298 TI - The prolongation of the lifespan of rats by repeated oral administration of [60]fullerene. AB - Countless studies showed that [60]fullerene (C(60)) and derivatives could have many potential biomedical applications. However, while several independent research groups showed that C(60) has no acute or sub-acute toxicity in various experimental models, more than 25 years after its discovery the in vivo fate and the chronic effects of this fullerene remain unknown. If the potential of C(60) and derivatives in the biomedical field have to be fulfilled these issues must be addressed. Here we show that oral administration of C(60) dissolved in olive oil (0.8 mg/ml) at reiterated doses (1.7 mg/kg of body weight) to rats not only does not entail chronic toxicity but it almost doubles their lifespan. The effects of C(60)-olive oil solutions in an experimental model of CCl(4) intoxication in rat strongly suggest that the effect on lifespan is mainly due to the attenuation of age-associated increases in oxidative stress. Pharmacokinetic studies show that dissolved C(60) is absorbed by the gastro-intestinal tract and eliminated in a few tens of hours. These results of importance in the fields of medicine and toxicology should open the way for the many possible -and waited for- biomedical applications of C(60) including cancer therapy, neurodegenerative disorders, and ageing. PMID- 22498299 TI - Hollow silica and silica-boron nano/microparticles for contrast-enhanced ultrasound to detect small tumors. AB - Diagnosing tumors at an early stage when they are easily curable and may not require systemic chemotherapy remains a challenge to clinicians. In order to improve early cancer detection, gas filled hollow boron-doped silica particles have been developed, which can be used for ultrasound-guided breast conservation therapy. The particles are synthesized using a polystyrene template and subsequently calcinated to create hollow, rigid nanoporous microspheres. The microshells are filled with perfluoropentane vapor. Studies were performed in phantoms to optimize particle concentration, injection dose, and the ultrasound settings such as pulse frequency and mechanical index. In vitro studies have shown that these particles can be continuously imaged by US up to 48 min and their signal lifetime persisted for 5 days. These particles could potentially be given by intravenous injection and, in conjunction with contrast-enhanced ultrasound, be utilized as a screening tool to detect smaller breast cancers before they are detectible by traditional mammography. PMID- 22498300 TI - Vitamin E TPGS as a molecular biomaterial for drug delivery. AB - D-alpha-tocopheryl polyethylene glycol succinate (Vitamin E TPGS, or simply TPGS) is a water-soluble derivative of natural Vitamin E, which is formed by esterification of Vitamin E succinate with polyethylene glycol (PEG). As such, it has advantages of PEG and Vitamin E in application of various nanocarriers for drug delivery, including extending the half-life of the drug in plasma and enhancing the cellular uptake of the drug. TPGS has an amphiphilic structure of lipophilic alkyl tail and hydrophilic polar head with a hydrophile/lipophile balance (HLB) value of 13.2 and a relatively low critical micelle concentration (CMC) of 0.02% w/w, which make it to be an ideal molecular biomaterial in developing various drug delivery systems, including prodrugs, micelles, liposomes and nanoparticles, which would be able to realize sustained, controlled and targeted drug delivery as well as to overcome multidrug resistance (MDR) and to promote oral drug delivery as an inhibitor of P-glycoprotein (P-gp). In this review, we briefly discuss its physicochemical and pharmaceutical properties and its wide applications in composition of the various nanocarriers for drug delivery, which we call TPGS-based drug delivery systems. PMID- 22498301 TI - Tissue engineered regeneration of completely transected spinal cord using human mesenchymal stem cells. AB - The present study employed a combinatorial strategy using poly(D,L-lactide-co glycolide) (PLGA) scaffolds seeded with human mesenchymal stem cells (hMSCs) to promote cell survival, differentiation, and neurological function in a completely transected spinal cord injury (SCI) model. The SCI model was prepared by complete removal of a 2-mm length of spinal cord in the eighth-to-ninth spinal vertebra, a procedure that resulted in bilateral hindlimb paralysis. PLGA scaffolds 2 mm in length without hMSCs (control) or with different numbers of hMSCs (1 * 10(5), 2 * 10(4), and 4 * 10(3)) were fitted into the completely transected spinal cord. Rats implanted with hMSCs received Basso-Beattie-Bresnahan scores for hindlimb locomotion of about 5, compared with ~2 for animals in the control group. The amplitude of motor-evoked potentials (MEPs) averaged 200-300 MUV in all hMSC implanted SCR model rats. In contrast, the amplitude of MEPs in control group animals averaged 135 MUV at 4 weeks and then declined to 100 MUV at 8 weeks. These results demonstrate functional recovery in a completely transected SCI model under conditions that exclude self-recovery. hMSCs were detected at the implanted site 4 and 8 weeks after transplantation, indicating in vivo survival of implanted hMSCs. Immunohistochemical staining revealed differentiation of implanted hMSCs into nerve cells, and immunostained images showed clear evidence for axonal regeneration only in hMSC-seeded PLGA scaffolds. Collectively, our results indicate that hMSC-seeded PLGA scaffolds induced nerve regeneration in a completely transected SCI model, a finding that should have significant implications for the feasibility of therapeutic and clinical hMSC-delivery using three-dimensional scaffolds, especially in the context of complete spinal cord transection. PMID- 22498303 TI - [Duodenopancreatectomy in the elderly. Evaluation of results]. AB - INTRODUCTION: With the increase in life expectancy, more and more resectable periampullary tumours are being diagnosed in the geriatric population. Despite the decrease in post-operative mortality, there continues to be a debate on the risk-benefit of cephalic duodenopancreatectomy (CPD) in the elderly. OBJECTIVE: To analyse the morbidity and mortality of CPD in patients over 70 years-old. DESIGN: Prospective observational study. PATIENTS: A total of 54 duodenopancreatectomies were performed between January 2005 and December 2010. Two groups of patients were compared: Group 1 (patients>70 years-old, n: 24), and Group 2 (patients<70 years-old, n: 30). The morbidity and mortality, transfusion, reinterventions, mean hospital stay, and survival were analysed. RESULTS: The>70 years group included more ASA 2 and 3 patients (P=.010), and had a higher number of previous medical problems per patient (P=.037). The post-operative mortality was higher in the older age group, although the difference was not significant (8.3 vs 3.3%). There were also no significant differences in post-operative morbidity (45.8 v. 46.6%), reintervention rate (16.6 vs 13.3%), length of hospital stay (18 vs 13%), and survival at 6 and 12 months (84 and 72% vs 90 and 86%). CONCLUSIONS: Age, in itself, does not seem to be a contraindication for CPD, but the elderly do have a higher risk of complications due to the physiological changes associated with ageing. The disparity of results demonstrates the need for more population studies at national level that may give an overall view of morbidity and mortality in CPD. PMID- 22498302 TI - Drosophila visual transduction. AB - Visual transduction in the Drosophila compound eye functions through a pathway that couples rhodopsin to phospholipase C (PLC) and the opening of transient receptor potential (TRP) channels. This cascade differs from phototransduction in mammalian rods and cones, but is remarkably similar to signaling in mammalian intrinsically photosensitive retinal ganglion cells (ipRGCs). In this review, I focus on recent advances in the fly visual system, including the discovery of a visual cycle and insights into the machinery and mechanisms involved in generating a light response in photoreceptor cells. PMID- 22498304 TI - [Is the claiming of costs justifiable in Jehovah's witness surgical patients after healthcare that is not part of the public health system?]. AB - INTRODUCTION: Jehovah's witnesses refuse blood transfusions. The conflict arises when the patient, entitled to public health treatment, come to surgical centres without blood, to later claim the costs incurred. OBJECTIVES: To analyse the legal claims for the refunding of costs by Jehovah's witnesses treated outside the public health system. To make a cost comparison regarding this, using Diagnosis Related Groups (DRGs) in a similar hypothetical healthcare model and equal to a stay in our hospital. MATERIAL AND METHODS: A retrospective study was made of the High, Constitutional, and Supreme Court rulings. A cost analysis was made using the clinical information obtained in the rulings, to process this in the DRG in our hospital using 3MHealth Information Systems. RESULTS/CONCLUSIONS: The State is not obliged to finance religious aspects or those outside the general interest. The establishment of working protocols would avoid ethical conflicts. There are very difficult to justify differences in the costs demanded, 431,001.66 ?, and compared to a model with an equal stay, 397,404.48 ?. PMID- 22498305 TI - Knowledge about complementary, alternative and integrative medicine (CAM) among registered health care providers in Swedish surgical care: a national survey among university hospitals. AB - BACKGROUND: Previous studies show an increased interest and usage of complementary and alternative medicine (CAM) in the general population and among health care workers both internationally and nationally. CAM usage is also reported to be common among surgical patients. Earlier international studies have reported that a large amount of surgical patients use it prior to and after surgery. Recent publications indicate a weak knowledge about CAM among health care workers. However the current situation in Sweden is unknown. The aim of this study was therefore to explore perceived knowledge about CAM among registered healthcare professions in surgical departments at Swedish university hospitals. METHOD: A questionnaire was distributed to 1757 registered physicians, nurses and physiotherapists in surgical wards at the seven university hospitals in Sweden from spring 2010 to spring 2011. The questionnaire included classification of 21 therapies into conventional, complementary, alternative and integrative, and whether patients were recommended these therapies. Questions concerning knowledge, research, and patient communication about CAM were also included. RESULT: A total of 737 (42.0%) questionnaires were returned. Therapies classified as complementary; were massage, manual therapies, yoga and acupuncture. Alternative therapies; were herbal medicine, dietary supplements, homeopathy and healing. Classification to integrative therapy was low, and unfamiliar therapies were Bowen therapy, iridology and Rosen method. Therapies recommended by > 40% off the participants were massage and acupuncture. Knowledge and research about CAM was valued as minor or none at all by 95.7% respectively 99.2%. Importance of possessing knowledge about it was valued as important by 80.9%. It was believed by 61.2% that more research funding should be addressed to CAM research, 72.8% were interested in reading CAM-research results, and 27.8% would consider taking part in such research. Half of the participants (55.8%) were positive to learning such therapy. Communication about CAM between patients and the health care professions was found to be rare. CONCLUSION: There is a lack of knowledge about CAM and research about it among registered health care professions in Swedish surgical care. However, in contrast to previous studies the results revealed that the majority perceived it as important to gain knowledge in this field. PMID- 22498306 TI - MicroRNA-199a targets CD44 to suppress the tumorigenicity and multidrug resistance of ovarian cancer-initiating cells. AB - In ovarian cancer, CD44(+) /CD117(+) stem cells, also known as cancer-initiating cells (CICs), are highly proliferative, have a low degree of differentiation, and are resistant to chemotherapeutics. Therefore, the CD44(+) /CD117(+) subpopulation is thought to be an important target for novel therapeutic strategies. In this study, we investigated the role of microRNA-199a (miR-199a) in ovarian cancer stem cells. Luciferase reporter gene assays confirmed that miR 199a targets CD44 via an miR-199a-binding site in the 3'-UTR. CD44(+) /CD117(+) ovarian CICs were enriched from human primary ovarian tumor tissues and confirmed by flow cytometric sorting. miR-199a was cloned and transfected into ovarian CICs. CD44 mRNA and protein expression was significantly decreased in miR-199a transfected ovarian CICs as compared with miR-199a mutant-transfected and untransfected cells. Cell cycle analysis, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl-tetrazolium bromide proliferation assays, the colony formation assay and the transwell migration assay indicated that miR-199a significantly affected cell cycle regulation and suppressed the proliferation and invasive capacity of ovarian CICs in vitro. miR-199a significantly increased the chemosensitivity of ovarian CICs to cisplatin, pacitaxel, and adriamycin, and reduced mRNA expression of the multidrug resistance gene ABCG2 as compared with miR-199a mutant transfected and untransfected cells. The expression of stemness markers was also significantly reduced in miR-199a-transfected CICs as compared with miR-199a mutant-transfected and untransfected ovarian cells. Furthermore, xenograft experiments confirmed that miR-199a suppressed the growth of xenograft tumors formed by ovarian CICs in vivo. Thus, expression of endogenous mature miR-199a may prevent tumorigenesis in human ovarian cancer by regulating expression of its target gene CD44. PMID- 22498307 TI - Cognitive functions and serum levels of brain-derived neurotrophic factor in patients with major depressive disorder. AB - OBJECTIVE: We assessed major cognitive domains in major depressive disorder (MDD) compared to a healthy control group using neurocognitive tests. We hypothesized that lower serum brain-derived neurotrophic factor (BDNF) levels would be associated with poorer neurocognitive performance in patients with major depression and that these associations would be shown in healthy controls as well. METHOD: Executive functions, sustaining and focusing of attention, memory functions, and verbal fluency were assessed in this study using the Trail-Making Test (TMT), Stroop Color Word Interference Test-TBAG Form (SCWT), Wisconsin Card Sorting Test (WCST), Test of Variables of Attention (TOVA), Auditory Consonant Trigram test (ACTT), Digit Span subtest of the Wechsler Memory Scale (DST), Rey Auditory Verbal Learning Test (RAVLT), and Controlled Oral Word Association Test (COWAT). RESULTS: The MDD group showed significantly poorer performance than the control group in cognitive functions; they also had lower levels of BDNF than the control group. However, there was no correlation between cognitive performances and BDNF levels except in the TMT, Part B. CONCLUSIONS: The current understanding of the importance of neurocognitive assessment and related biological markers in depression is improving. Further studies with larger sample sizes evaluating neurocognitive functions with molecular analyses of BDNF levels may reveal a novel marker for predicting and monitoring neurocognitive deficits in depression. PMID- 22498308 TI - The protective effects of tanshinone IIA on beta-amyloid protein (1-42)-induced cytotoxicity via activation of the Bcl-xL pathway in neuron. AB - The deposition of beta-amyloid protein(Abeta) and loss of neurons within the brain are the pathologic hallmarks of Alzheimer's disease (AD). Apoptosis is a crucial pathway in neuronal loss in AD. Tanshinone IIA (tanIIA) is one of ingredients of tanshinone which is the major component of the traditional Chinese herb Danshen. The present study explores the effects of tanIIA on Abeta(1-42) induced cytotoxicity. Cultured cortical neurons that were treated with 4 MUM Abeta(1-42) showed shrunken perikaryon with loss of neurite processes; the survival rate of neurons decreased almost to 57% and the apoptotic rate of neurons increased to 47%. In addition, the level of gene bcl-xl mRNA and Bcl-xL protein decreased significantly. These changes, however, were prevented by pretreatment of neurons with tanIIA for 24h before Abeta(1-42), which markedly increased neuron survival rate compared to neurons treated with Abeta(1-42) alone; the apoptotic rate of neurons decreased to 15%, and the decrease in level of gene bcl-xl mRNA and Bcl-xL protein in Abeta-treated neurons, were prevented. Thus, we conclude that tanIIA might serve as an obvious neuroprotection. TanIIA protected neurons against the Abeta-induced cytotoxicity most likely via activation of the Bcl-xL pathway. PMID- 22498309 TI - The evolution of metabolic enzymes in Plasmodium and trypanosomatids as compared to Saccharomyces and Schizosaccharomyces. AB - Understanding how the biological connectivity of genes and gene products affects evolution is an important aspect of understanding evolution. Genes encoding enzymes are frequently used to carry out such analyses. Interestingly, studies have shown that connectivity in the metabolic networks in parasitic protists, including Plasmodium falciparum and Trypanosoma brucei, have been substantially altered as compared to free living eukaryotes, such as Saccharomyces cerevisiae. Herein, we have determined K(a) values, which are a measure of the non-synonymous substitution rate, and used them to examine the differences between the evolution of genes in T. brucei, P. falciparum, S. cerevisiae, and Schizosaccharomyces pombe. All four organisms share similar traits with respect to the evolution of genes encoding metabolic enzymes. First, genes encoding metabolic enzymes have lower K(a) values than genes encoding non-metabolic proteins. In addition, perturbations of the metabolic network appear to have limited affects on the genes encoding enzymes near the perturbation. In most cases, there is a negative relationship between connectivity in the metabolic network of the gene product and the K(a) value for the gene, i.e. examining how much constraint there is on gene evolution when it is connected to many other genes. In addition, we find that the K(a) values of orthologs encoding for metabolic enzymes in each organism are significantly correlated, indicating similar patterns of non-synonymous substitutions. In total, our results indicate that the evolution of genes encoding metabolic enzymes do not tend to be greatly affected by changes in the metabolic network. PMID- 22498310 TI - Metacognitive therapy in treatment-resistant depression: a platform trial. AB - Patients with treatment-resistant depression received up to 8 sessions of metacognitive therapy (MCT) targeting attentional control, rumination, worry, and metacognitive beliefs. A baseline period was followed by weekly sessions with follow-up assessments at 6 and 12 months post treatment. Large and statistically significant improvements occurred in all symptom measures at post treatment and were maintained over follow-up. Two out of 3 process measures significantly improved at post treatment and all of these measures were improved at follow-up. Treatment was associated with similar response rates on the BDI and Hamilton rating scale. Using liberal criteria 80% of completers were classified as recovered at post treatment and 70% at follow-up on the BDI. In the intention to treat sample 66.6% were recovered at post treatment and 58.3% at follow-up. More stringent criteria showed 60% recovery rates at post treatment and at 12 m. The results suggest that MCT could be a brief and effective treatment and they provide a precedent for more definitive randomized controlled trials. PMID- 22498311 TI - Investigating trajectories of change in psychological distress amongst patients with depression and generalised anxiety disorder treated with internet cognitive behavioural therapy. AB - Internet based cognitive behavioural therapy (CBT) is efficacious for the treatment of anxiety and depression. The current study aimed to examine the effectiveness of internet based CBT prescribed by primary care clinicians for the treatment of depression and generalised anxiety disorder. Psychological distress data from 302 patients who completed an online CBT course for depression and 361 patients who completed an online CBT course for generalised anxiety disorder were subjected to growth mixture analysis. For both disorders psychological distress decreased across each lesson in a quadratic trend. Two classes of individuals were identified with different trajectories of change: a large group of individuals who responded well to the courses and a smaller group of individuals with a lower response. Both groups were similar with respect to socio-demographic characteristics however the Low Responders tended to have higher levels of symptom severity and psychological distress at baseline in comparison to the responders. For the majority of patients (75-80%) the internet CBT courses for depression and generalised anxiety disorder were effective. Further research is required to identify and effectively treat the smaller proportion of patients who did not improve during internet CBT. PMID- 22498312 TI - Microbubble-induced sonoporation involved in ultrasound-mediated DNA transfection in vitro at low acoustic pressures. AB - In the present work, human breast cancer cells MCF-7 mixed with polyethylenimine: deoxyribonucleic acid complex and microbubbles were exposed to 1-MHz ultrasound at low acoustic driving pressures ranging from 0.05 to 0.3 MPa. The sonoporation pores generated on the cell membrane were examined with scanning electron microscopy. The transfection efficiency and cell viability were evaluated with flow cytometry. The results showed that ultrasound sonication under the current exposure condition could generate cell pores with mean size ranging from about 100 nm to 1.25 MUm, and that larger sonoporation pores would be generated with the increasing acoustic pressure or longer treatment time, leading to the enhancement of transfection efficiency and the reduction of cell viability. The simulations based on the Marmottant model were performed to test the hypothesis that the microstreaming-induced shear stress might be involved in the mechanisms of the low-intensity ultrasound induced sonoporation. The calculated shear stress resulting from the micro-streaming ranged from 15 to 680 Pa corresponding to the applied acoustic pressures 0.05-0.3 MPa, which is sufficient to induce reversible sonoporation. This study indicates that the shear stress related bio-effects may provide a base for strategies aimed at targeted drug delivery. PMID- 22498313 TI - Sagittal plane hip motion reversals during walking are associated with disease severity and poorer function in subjects with hip osteoarthritis. AB - A midstance reversal of sagittal plane hip motion during walking, or motion discontinuity (MD), has previously been observed in subjects with endstage hip osteoarthritis (OA) and in patients with femoroacetabular impingement. The goal of the present study was to evaluate whether this gait pattern is a marker of OA presence or radiographic severity by analyzing a large IRB approved motion analysis data repository. We also hypothesized that subjects with the MD would show more substantial gait impairments than those with normal hip motion. We identified 150 subjects with symptomatic unilateral hip OA and Kellgren-Lawrence OA severity data on file, and a control group of 159 asymptomatic subjects whose ages fell within 2 standard deviations of the mean OA group age. From the gait data, the MD was defined as a reversal in the slope of the hip flexion angle curve during midstance. Logistic regressions and general linear models were used to test the association between the MD and OA presence, OA severity and, other gait variables. 53% of OA subjects compared to 7.5% of controls had the MD (p<0.001); occurrence of the MD was associated with OA severity (p=0.009). Within the OA subject group, subjects with the MD had reduced dynamic range of motion, peak, extension, and internal rotation moments compared to those who did not (MANCOVA p <= 0.042) after controlling for walking speed. We concluded that sagittal plane motion reversals are indeed associated with OA presence and severity, and with more severe gait abnormalities in subjects with hip OA. PMID- 22498314 TI - Detecting and quantifying global instability during a dynamic task using kinetic and kinematic gait parameters. AB - OBJECTIVES: Instability during gait can be identified in many different ways. Recent studies have suggested utilizing spatiotemporal parameters to detect instability during gait. Detecting instability using kinetic and kinematic gait parameters has not yet been examined fully. In addition, these studies have not yet identified measures that are capable of assessing the magnitude of instability. The objective of the present study was to identify kinetic and kinematic gait parameters that can best identify instability and quantify its magnitude. METHODS: Ten healthy men underwent successive gait analysis testing under three controlled settings: (1) Stage 0 instability (control setting), (2) Stage 1 instability and (3) Stage 2 instability. The levels of instability were precisely applied with the use of a controlled perturbation device (AposTherapy System). Differences between all stages and between stages were identified using Friedman and Wilcoxon tests. RESULTS: Stride-to-stride variability (STSV) in kinetic and kinematic measures increased significantly between stages 0 and 1 or between stages 0 and 2 for almost all parameters (all P<0.05). A significant increase between stage 0 and both stages 1 and 2 was found for knee flexion moment, knee varus moment, knee flexion angle and hip adduction angle. The increase between stages 1 and 2 was variable. Only the knee varus moment parameter showed a significant increase in STSV between stages 1 and 2 (P=0.026). CONCLUSIONS: Almost all kinetic and kinematic gait parameters are sensitive to changes in global instability in a dynamic task. The most sensitive are parameters measured at the knee. Of these, STSV in knee varus moment can be used to quantify the magnitude of dynamic instability. PMID- 22498315 TI - Review of oil and HNS accidental spills in Europe: identifying major environmental monitoring gaps and drawing priorities. AB - The European Atlantic area has been the scene of a number of extensive shipping incidents with immediate and potential long-term impacts to marine ecosystems. The occurrence of accidental spills at sea requires an effective response that must include a well executed monitoring programme to assess the environmental contamination and damage of the affected marine habitats. Despite a number of conventions and protocols developed by international and national authorities that focused on the preparedness and response to oil and HNS spills, much remains to be done, particularly in relation to the effectiveness of the environmental monitoring programmes implemented after oil and HNS spills. Hence, the present study reviews the status of the environmental monitoring programmes established following the major spill incidents over the last years in European waters, aiming at identifying the key monitoring gaps and drawing priorities for an effective environmental monitoring of accidental spills. PMID- 22498316 TI - Biodegradation of crude oil using an efficient microbial consortium in a simulated marine environment. AB - Ochrobactrum sp. N1, Brevibacillus parabrevis N2, B. parabrevis N3 and B. parabrevis N4 were selected when preparing a mixed bacterial consortium based on the efficiency of crude oil utilization. A crude oil degradation rate of the N series microbial consortium reached upwards of 79% at a temperature of 25 degrees C in a 3.0% NaCl solution in the shake flask trial. In the mesocosm experiment, a specially designed device was used to simulate the marine environment. The internal tank size was 1.5 m (L)*0.8 m (W)*0.7 m (H). The microbial growth conditions, nutrient utilization and environmental factors were thoroughly investigated. Over 51.1% of the crude oil was effectively removed from the simulated water body. The escalation process (from flask trials to the mesocosm experiment), which sought to represent removal under conditions more similar to the field, proved the high efficiency of using N-series bacteria in crude oil degradation. PMID- 22498317 TI - A high-resolution real-time forecasting system for predicting the fate of oil spills in the Strait of Bonifacio (western Mediterranean Sea). AB - The Strait of Bonifacio is a long and narrow area between Corsica and Sardinia. To manage environmental emergencies related to the spill of oil from vessels, an innovative forecasting system was developed. This tool is capable of operationally predicting the dispersion of hydrocarbon spills in the coastal area of the Bonifacio Strait, either from an instantaneous or continuous spill and either in forward or backward mode. Experimental datasets, including ADCP water current measurements and the trajectories of drifter buoys released in the area, were used to evaluate the accuracy of this system. A comparison between the simulation results and experimental data revealed that both the water circulation and the surface transport processes are accurately reproduced by the model. The overall accuracy of the system in reproducing the transport of an oil spill at sea was estimated for both forward and backward prediction mode and in relation to different forecasting time lags. PMID- 22498318 TI - Phytoplankton community composition in nearshore coastal waters of Louisiana. AB - Phytoplankton community compositions within near-shore coastal and estuarine waters of Louisiana were characterized by group diversity, evenness, relative abundance and biovolume. Sixty-six taxa were identified in addition to eight potentially harmful algal genera including Gymnodinium sp. Phytoplankton group diversity was lowest at Vermillion Bay in February 2008, but otherwise ranged between 2.16 and 3.40. Phytoplankton evenness was also lowest at Vermillion Bay in February 2008, but otherwise ranged between 0.54 and 0.77. Dissolved oxygen increased with increased biovolume (R2 = 0.85, p < 0.001) and biovolume decreased with increased light attenuation (R2 = 0.34, p = 0.007), which supported the importance of light in regulating oxygen dynamics. Diatoms were dominant in relative abundance and biovolume at almost all stations and all cruises. Brunt Vaisala frequency was used as a measure of water column stratification and was negatively correlated (p = 0.02) to diatom relative percent total abundance. PMID- 22498319 TI - Two highly pathogenic avian influenza H5N1 viruses of clade 2.3.2.1 with similar genetic background but with different pathogenicity in mice and ducks. AB - A number of genetic markers for virulence of avian influenza viruses (AIVs) in different hosts have been identified. However, we isolated two H5N1 AIVs, A/Chicken/Jiangsu/k0402/2010(CK/10) and A/Goose/Jiangsu/k0403/2010(GS/10) with similar genetic background, but most well-defined molecular markers for virulence in mammals and avian species were not found in both viral genomes. In addition, pathogenicity of this pair of viruses in different hosts remains unclear. Therefore, we evaluated their pathogenicity in chickens, mice, ducks and guinea pigs. Infection of CK/10 and GS/10 in chickens caused 100% mortality within 24 h. Mouse experiment showed that CK/10 was highly pathogenic (MLD50 = 0.33 log10 EID50), whereas GS/10 was avirulent (MLD50 > 6.32 log10 EID50). Interestingly, the virulence of CK/10 in ducks (DLD50 = 3.83 log10 EID50) was higher than that of GS/10 (DLD50 = 7.7 log10 EID50), which correlated with viral pathogenicity in mice. Although CK/10 and GS/10 showed distinct pathogenicity in mice, they both were lethal to guinea pigs, with CK/10 replicating to higher titres in airways than GS/10. Collectively, these findings suggest that AIVs with similar genetic backgrounds may exhibit distinct pathogenicity in specific hosts and that some unknown molecular markers for virulence may exist and need to be identified. PMID- 22498320 TI - Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson's disease occurring with Type 2 diabetes in a Taiwanese population cohort. AB - OBJECTIVES: Type 2 diabetes (T2DM) may increase the risk of Parkinson's disease (PD). We evaluated the role of oral anti-hyperglycemic agents (OAA) in any diabetes-PD linkage. METHODS: From the Taiwan National Health Insurance database on 01-01-2000, a representative cohort of 800,000 was obtained between 1996-01-01 and 2007-12-31. Those >= 20 years were classified by presence (n = 64,166) or absence (n = 698,587) of T2DM, and whether any OAA (n = 41,003) or not (n = 23,163) was used. Those with T2DM were matched with those diabetes-free by birth date and gender for the comparison of PD incidence. We considered those >= 50 years and matched PD-free diabetes patients with and without OAAs by age, gender, locality, health service, Charlson comorbidity index and T2DM diagnosis-date to avoid 'immortal time bias'. PD incidence densities (PID, per 10,000 person-years) and hazard ratios (HRs) were calculated. RESULTS: HRs (95% confidence interval, CI), related to diabetes-free, were 2.18 (1.27-3.73) and 1.30 (0.77-2.19) for T2DM without and with OAAs. For sulfonylurea alone, PID (95% CI) increased from 58.3 (46.6-70.1) to 83.2 (68.6-97.7), with similar findings by gender, but little difference if metformin was used. The metformin-alone HR (95% CI) was 0.95 (0.53 1.71), sulfonylurea-alone 1.57 (1.15-2.13), and combined therapy 0.78 (0.61-1.01) and these differences persisted when incident PD was excluded for 4 years after T2DM diagnosis. The use of metformin first, in those without insulin, provided an HR of 0.40 (0.17-0.94). CONCLUSIONS: Incident PD risk in T2DM increases 2.2-fold. Sulfonylureas further increase risk by 57%, which is avoided by combination with metformin. PMID- 22498321 TI - Influence of chronic tethering of the mitral valve on mitral leaflet size and coaptation in functional mitral regurgitation. AB - OBJECTIVES: The purposes of this study were to examine whether tethering of the mitral leaflets affects coaptation in patients with functional mitral regurgitation (FMR) and to assess the interaction between the mitral coaptation and mitral regurgitation severity. BACKGROUND: Functional mitral regurgitation causes restriction of leaflet closure as a result of enhanced tethering of the mitral leaflets and papillary muscle (PM) displacement. METHODS: Three dimensional transesophageal echocardiography was performed in 44 patients with FMR related to the bilateral PM displacement and in 56 controls. The distance between the tip of the anterior or posterior PM and the intervalvular fibrosa were measured as the lateral or medial tethering length (TL) in midsystole. To evaluate the degree of coaptation, coaptation length (CL) at medial, middle, and lateral sites of mitral valve and an estimate of coaptation area (CA) were measured. RESULTS: The FMR group showed the significantly decreased CA (1.3 +/- 0.4 cm(2) vs. 1.6 +/- 0.4 cm(2), p = 0.005) and CL (medial 3.2 +/- 0.9 mm vs. 4.8 +/- 0.6 mm, middle 3.8 +/- 1.3 mm vs. 5.8 +/- 0.7 mm, lateral 3.3 +/- 0.9 mm vs. 4.8 +/- 0.6 mm; all p < 0.0001) compared with the controls. Each CL correlated negatively and significantly with both medial and lateral TL (all p < 0.0001). Annular area (p = 0.004) was significantly smaller and leaflet-to-annular area ratio (p < 0.0001) was significantly larger in patients with nonsignificant FMR than in the patients with significant (moderate to severe) FMR. Significant correlations were found between effective regurgitant orifice area and CA or each CL (all p < 0.0001). CONCLUSIONS: Coaptation decreased significantly in patients with FMR. The CL at each region was related to PM displacement and the indexes of coaptation were associated with mitral regurgitation severity. PMID- 22498322 TI - 3D echocardiographic quantification in functional mitral regurgitation. PMID- 22498323 TI - Femoral plaque echogenicity and cardiovascular risk in claudicants. AB - OBJECTIVES: The present study was designed to verify whether the evaluation of femoral plaque echogenicity might be a useful tool for cardiovascular risk assessment in patients affected by lower extremity peripheral arterial disease. BACKGROUND: Lower extremity peripheral arterial disease is a common manifestation of atherosclerosis and is associated with a high risk of developing major cardiovascular events. Vulnerable atherosclerotic plaque plays a central role in the occurrence of acute ischemic events in different vascular territories. Furthermore, atherosclerosis is a systemic disease, and the presence of an unstable atherosclerotic plaque in a certain vascular district, characterized by low echogenicity at B-mode ultrasound, is associated to a greater prevalence of unstable plaques in other vascular beds. METHODS: Femoral plaque echogenicity of 246 claudicants with ankle/brachial index <=0.90 was evaluated at B-mode ultrasound by visual analysis and by calculating the grayscale median (GSM) value. In these patients, the occurrence of myocardial infarction and stroke was prospectively assessed. RESULTS: Femoral GSM values and plaque types assessed by visual analysis were highly correlated by Spearman analysis (rho = 0.905, p < 0.001). During a median follow-up of 30 months, 32 patients (13%) had a major cardiovascular event. Compared with patients without events, those who experienced an event during the follow-up had a lower femoral plaque GSM value (42.9 +/- 26.2 vs. 58.8 +/- 19.3, p = 0.002) and a higher prevalence of hypoechoic femoral plaque at visual analysis (68.8% vs. 19.6%, p < 0.001). At Cox analysis, femoral GSM showed an inverse relationship with cardiovascular risk, even after adjustment for possible confounders (hazard ratio: 0.96, 95% confidence interval [CI]: 0.95 to 0.98, p < 0.001). Furthermore, patients with hypoechoic femoral plaques at visual analysis had a 7.24-fold increased cardiovascular risk compared with patients with hyperechoic plaques after adjustment for possible confounders (95% CI: 3.23 to 16.22, p < 0.001). CONCLUSIONS: This study demonstrates that the presence of hypoechoic atherosclerotic femoral plaques is associated with higher cardiovascular risk in lower extremity peripheral arterial disease patients. PMID- 22498324 TI - Metabolic syndrome, diabetes, and incidence and progression of coronary calcium: the Multiethnic Study of Atherosclerosis study. AB - OBJECTIVES: This study sought to examine and compare the incidence and progression of coronary artery calcium (CAC) among persons with metabolic syndrome (MetS) and diabetes mellitus (DM) versus those with neither condition. BACKGROUND: MetS and DM are associated with subclinical atherosclerosis as evidenced by CAC. METHODS: The MESA (Multiethnic Study of Atherosclerosis) included 6,814 African American, Asian, Caucasian, and Hispanic adults 45 to 84 years of age, who were free of cardiovascular disease at baseline. Of these, 5,662 subjects (51% women, mean age 61.0 +/- 10.3 years) received baseline and follow-up (mean 2.4 years) cardiac computed tomography scans. We compared the incidence of CAC in 2,927 subjects without CAC at baseline and progression of CAC in 2,735 subjects with CAC at baseline in those with MetS without DM (25.2%), DM without MetS (3.5%), or both DM and MetS (9.0%) to incidence and progression in subjects with neither MetS nor DM (58%). Progression of CAC was also examined in relation to coronary heart disease events over an additional 4.9 years. RESULTS: Relative to those with neither MetS nor DM, adjusted relative risks (95% confidence intervals [CI]) for incident CAC were 1.7 (95% CI: 1.4 to 2.0), 1.9 (95% CI: 1.4 to 2.4), and 1.8 (95% CI: 1.4 to 2.2) (all p < 0.01), and absolute differences in mean progression (volume score) were 7.8 (95% CI: 4.0 to 11.6; p < 0.01), 11.6 (95% CI: 2.7 to 20.5; p < 0.05), and 22.6 (95% CI: 17.2 to 27.9; p < 0.01) for those with MetS without DM, DM without MetS, and both DM and MetS, respectively. Similar findings were seen in analysis using Agatston calcium score. In addition, progression predicted coronary heart disease events in those with MetS without DM (adjusted hazard ratio: 4.1, 95% CI: 2.0 to 8.5, p < 0.01) and DM (adjusted hazard ratio: 4.9 [95% CI: 1.3 to 18.4], p < 0.05) among those in the highest tertile of CAC increase versus no increase. CONCLUSIONS: Individuals with MetS and DM have a greater incidence and absolute progression of CAC compared with individuals without these conditions, with progression also predicting coronary heart disease events in those with MetS and DM. PMID- 22498325 TI - Vascular calcification, diabetes, and cardiovascular disease: connecting the dots. PMID- 22498326 TI - Prognostic value of late gadolinium enhancement in clinical outcomes for hypertrophic cardiomyopathy. AB - OBJECTIVES: The objective of this study was to perform a systematic review and meta-analysis of the predictive value of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) for future cardiovascular events and death in hypertrophic cardiomyopathy (HCM). BACKGROUND: The utility of LGE for detecting myocardial fibrosis is well established. The prognostic value of LGE in HCM has been described in several studies, but controversy exists given the limited power of these studies to predict future events. METHODS: We searched multiple databases including PubMed for studies of LGE in HCM that reported selected clinical outcomes (cardiovascular mortality, sudden cardiac death [SCD], aborted SCD, and heart failure death). We performed a systematic review of the literature and meta-analysis to determine pooled odds ratios for these clinical events. RESULTS: Four studies evaluated 1,063 patients over an average follow-up of 3.1 years. The pooled prevalence of LGE was 60%. The pooled odds ratios (OR) demonstrate that LGE by CMR correlated with cardiac death (pooled OR: 2.92, 95% confidence interval [CI]: 1.01 to 8.42; p = 0.047), heart failure death (pooled OR: 5.68, 95% CI: 1.04 to 31.07; p = 0.045), and all-cause mortality (pooled OR: 4.46, 95% CI: 1.53 to 13.01; p = 0.006), and showed a trend toward significance for predicting sudden death/aborted sudden death (pooled OR: 2.39, 95% CI: 0.87 to 6.58; p = 0.091). CONCLUSIONS: Late gadolinium enhancement by CMR has prognostic value in predicting adverse cardiovascular events among HCM patients. There are significant relationships between LGE and cardiovascular mortality, heart failure death, and all-cause mortality in HCM. Additionally, LGE and SCD/aborted SCD displayed a trend toward significance. The assessment of LGE by CMR has the potential to provide important information to improve risk stratification in HCM in clinical practice. PMID- 22498327 TI - RV dysfunction in pulmonary hypertension is independently related to pulmonary artery stiffness. AB - OBJECTIVES: This study investigated whether right ventricular (RV) adaptation to chronic pressure overload is associated with pulmonary artery (PA) stiffness beyond the degree of severity of pulmonary hypertension (PH). BACKGROUND: Increased PA stiffness has been associated with reduced survival in PH. The mechanisms for this association remain unclear. METHODS: Right heart catheterization and cardiac magnetic resonance were performed within 1 week in 124 patients with known or suspected chronic PH. Pulmonary vascular resistance index (PVRI) and PA pressures were quantified from right heart catheterization. Cardiac magnetic resonance included standard biventricular cine sequences and main PA flow quantification with phase-contrast imaging. Indexes of PA stiffness (elasticity, distensibility, capacitance, stiffness index beta, and pulse pressure) were quantified combining right heart catheterization and cardiac magnetic resonance data. RV performance and adaptation were measured by RV ejection fraction, right ventricular mass index (RVMI), RV end-systolic volume index, and right ventricular stroke work index (RVSWI). RESULTS: All indexes of PA stiffness were significantly correlated with measures of RV performance (Spearman rho coefficients ranging from -0.20 to 0.61, p < 0.05). Using multivariate regression analysis, PA elasticity, distensibility, and index beta were independently associated with all measures of RV performance after adjusting PVRI (p <= 0.024). PA capacitance was independently associated with RV ejection fraction, RVMI, and RVSWI (p < 0.05), whereas PA pulse pressure was associated with RVMI and RVSWI (p <= 0.027). Compared with PVRI, PA elasticity, distensibility, capacitance, and index beta explained 15% to 68% of the variability in RV ejection fraction, RVMI, and RV end-systolic volume index. Relative contributions of PA stiffness for RVSWI were 1.2* to 18.0* higher than those of PVRI. CONCLUSIONS: PA stiffness is independently associated with the degree of RV dysfunction, dilation, and hypertrophy in PH. RV adaptation to chronic pressure overload is related not only to the levels of vascular resistance (steady afterload), but also to PA stiffness (pulsatile load). PMID- 22498328 TI - Plaque features associated with increased cerebral infarction after minor stroke and TIA: a prospective, case-control, 3-T carotid artery MR imaging study. AB - OBJECTIVES: The goal of this study was to determine whether a 3-T magnetic resonance imaging (MRI) protocol combining carotid atherosclerotic plaque and brain imaging can identify features of high-risk acutely symptomatic plaque that correlate with brain injury. BACKGROUND: It has previously been demonstrated that, in asymptomatic patients, MRI can identify features of carotid plaque that are associated with stroke, such as the presence of a large lipid core. We hypothesized that the early phase (<7 days) after a cerebrovascular event, when risk of recurrence is highest, may be associated with particular plaque characteristics that associate with cerebral injury. METHODS: Eighty-one patients (41 presenting acutely with transient ischemic attack [TIA] or minor stroke and 40 asymptomatic controls) underwent multicontrast carotid artery MRI on 2 separate occasions, each accompanied by diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) imaging of the brain. RESULTS: Complex (American Heart Association [AHA] type VI) plaques were seen in 22 of 41 patients (54%) in the symptomatic group versus 8 of 40 (20%) in the asymptomatic group (p < 0.05). They were caused by intraplaque hemorrhage (34% vs. 18%; p = 0.08), surface rupture (24% vs. 5%; p = 0.03), or luminal thrombus (7% vs. 0%; p = 0.24). Noticeably, 17 of 30 (57%) cases of AHA type VI plaque were in vessels with <70% stenosis. At follow-up scanning (>6 weeks later), only 2 cases of symptomatic AHA type VI plaque showed evidence of full healing. The presence of fibrous cap rupture was associated with higher DWI brain injury at presentation and higher total cerebral FLAIR signal at follow-up (p < 0.05). CONCLUSIONS: Early carotid wall MRI in patients experiencing minor stroke or TIA showed a higher proportion of "complex" plaques compared with asymptomatic controls; a majority were in arteries of <70% stenosis. Fibrous cap rupture was associated with increases in DWI and FLAIR lesions in the brain. Combined carotid plaque and brain MRI may aid risk stratification and treatment selection in acute stroke and TIA. PMID- 22498329 TI - Prevalence of nonstenosing, complicated atherosclerotic plaques in cryptogenic stroke. AB - OBJECTIVES: Our goal was to assess the prevalence of complicated American Heart Association (AHA) lesion type VI plaques in the carotid arteries of patients with cryptogenic stroke. BACKGROUND: In up to 40% of ischemic stroke patients, no definite cause can be established despite extensive workup (i.e., cryptogenic stroke). To test the hypothesis if nonstenosing complicated carotid plaques may be the underlying etiology in some of these patients, we used high-resolution black-blood carotid magnetic resonance imaging (MRI), which can quantitatively assess plaque composition and morphology with good correlation to histopathology. Specifically, we focused on AHA type VI plaques, which are characterized by hemorrhage, thrombus, or fibrous cap rupture. METHODS: Thirty-two consecutive patients (22 male; mean age 71.7 +/- 11.9 years) with cryptogenic stroke and nonstenosing (<50%) eccentric carotid plaques were recruited from a single stroke unit. All patients underwent extensive clinical workup (brain MRI, duplex sonography, electrocardiography and Holter monitoring, transthoracic and transesophageal echocardiography, and laboratory investigations) to exclude other causes of stroke. All patients received a black-blood carotid MRI at 3-T with fat saturated pre- and post-contrast T-1-, proton density-, and T-2-weighted and time of-flight images using surface coils and parallel imaging techniques. Prevalence of AHA type VI plaque was determined in both carotid arteries on the basis of previously published MRI criteria. RESULTS: AHA type VI plaques were found in 12 of 32 arteries (37.5%) ipsilateral to the stroke, whereas there were no AHA type VI plaques contralateral to the stroke (p = 0.001). The most common diagnostic feature of AHA type VI plaques was intraplaque hemorrhage (75%), followed by fibrous plaque rupture (50%) and luminal thrombus (33%). CONCLUSIONS: This pilot study suggests that arterio-arterial embolism from complicated, nonstenosing carotid atherosclerotic plaques may play a role in a subgroup of patients previously diagnosed with cryptogenic stroke. To further evaluate the significance of AHA type VI plaques in cryptogenic stroke, future studies will have to analyze both clinical and imaging follow-up data, including event rates for secondary strokes. PMID- 22498330 TI - Stroke: cause and effect--seek and ye shall find. PMID- 22498331 TI - Molecular imaging of human ACE-1 expression in transgenic rats. AB - OBJECTIVES: The aim of this study was to develop a molecular imaging strategy that can monitor myocardial angiotensin-converting enzyme (ACE)-1 upregulation as a function of progressive heart failure. BACKGROUND: High-affinity technetium-99m labeled lisinopril (Tc-Lis) has been shown to specifically localize in tissues that express ACE in vivo, such as the lungs. Whether Tc-Lis can also detect upregulation of ACE in the heart, by external in vivo imaging, has not been established. METHODS: Twenty-one ACE-1 over-expressing transgenic (Tg) and 18 wild-type control rats were imaged using in vivo micro single-positron emission computed tomography (SPECT)-computed tomography (CT) at 10, 30, 60, and 120 min after Tc-Lis injection. A subgroup of rats received nonradiolabeled (cold) lisinopril before the Tc-Lis injection to evaluate nonspecific binding. After imaging, the rat myocardium was explanted, ex vivo images were acquired, and percent injected dose per gram gamma-well was counted, followed by an assessment of enzyme-linked immunosorbent assay-verified ACE activity and messenger ribonucleic acid expression. RESULTS: On micro SPECT-CT, myocardial ACE-1 uptake was best visualized in Tg rats at 120 min after Tc-Lis injection. The quantitative uptake of Tc-Lis in the myocardium was 5-fold higher in mutant Tg than in control rats at each time point after tracer injection. The percent injected dose per gram uptake was 0.74 +/- 0.13 in Tg myocardium at 30 min and was reduced substantially to 0.034 +/- 0.003% when pre-treated with cold lisinopril (p = 0.029). Enzyme activity assay showed a >30-fold higher level of ACE-1 activity in the myocardium of Tg rats than in controls. The ACE-1 messenger ribonucleic acid was quantified, and lisinopril was found to have no effect on ACE-1 gene expression. CONCLUSIONS: The Tc-Lis binds specifically to ACE, and the activity can be localized in Tg rat hearts that over-express human ACE-1 with a signal intensity that is sufficiently high to allow external imaging. Such a molecular imaging strategy may help identify susceptibility to heart failure and may allow optimization of pharmacologic intervention. PMID- 22498332 TI - Personalized medicine in heart failure: are we there yet? PMID- 22498333 TI - Role of FDG PET-CT in Takayasu arteritis: sensitive detection of recurrences. AB - OBJECTIVES: The aim of this study was to investigate whether the maximum standardized uptake value (max SUV) of (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) provides a quantitative indication of disease activity in Takayasu arteritis (TA) cases. BACKGROUND: The clinical value of FDG-PET for assessing TA has been investigated. Clinical evaluation of disease activity is often difficult, because most patients develop recurrent inflammation while receiving corticosteroid treatment. METHODS: Thirty nine TA patients underwent FDG-PET/CT at Tokyo Medical and Dental University from 2006 to 2010 (35 women and 4 men; median age, 30 years). Disease activity was defined according to National Institutes of Health criteria. Biomarkers including C-reactive protein and erythrocyte sedimentation rate were measured. Forty subjects without vasculitis served as control subjects. RESULTS: The max SUV was significantly higher in active than in inactive cases and control subjects (active [n = 27], median value, 2.7 vs. inactive [n = 12], 1.9; control [n = 40], 1.8; p < 0.001 each). Given a max SUV cutoff of 2.1, sensitivity for active-phase TA was 92.6%, specificity 91.7%, positive predictive value 96.2%, and negative predictive value 84.6%. In receiver-operating characteristic curves comparison, max SUV was superior to C-reactive protein (p < 0.05) and erythrocyte sedimentation rate (p < 0.05). Max SUV was significantly higher in relapsing on treatment cases (n = 17) than in stable on treatment cases (n = 12) (median value, 2.6 vs. 1.9; p < 0.001). CONCLUSIONS: FDG-PET/CT is useful for detection of active inflammation not only in patients with active TA before treatment but also in relapsing patients receiving immunosuppressive agents. The max SUV is useful for assessing subtle activity of TA with high sensitivity. PMID- 22498334 TI - Integrating noninvasive absolute flow, coronary flow reserve, and ischemic thresholds into a comprehensive map of physiological severity. AB - Noninvasive, absolute myocardial perfusion and coronary flow reserve (CFR) can be imaged by many techniques. However, such data must be interpreted for clinical application regardless of its source. Currently, no guide exists for physiological integration. Therefore, we propose 2-dimensional scatter plots of stress flow and CFR with superimposed thresholds for normal flow, reduced flow without ischemia, definite ischemia, and transmural infarction to allow for automatic and objective classification. Application of this schema to 1,500 studies demonstrates that flow capacity relates inversely to risk factors and atherosclerotic burden. Interpreting stress flow to make clinical decisions requires rest flow or CFR for broad application to all patients. Although relative uptake images alone are adequate for some patients, it can either under- or over-estimate flow capacity in many persons. Our standardized framework could prompt future studies leading to a trial of revascularization guided by absolute flow measurements. PMID- 22498335 TI - A practical guide to multimodality imaging of transcatheter aortic valve replacement. AB - The advent of transcatheter aortic valve replacement (TAVR) is one of the most widely anticipated advances in the care of patients with severe aortic stenosis. This procedure is unique in many ways, one of which is the need for a multimodality imaging team-based approach throughout the continuum of the care of TAVR patients. Pre-procedural planning, intra-procedural implantation optimization, and long-term follow-up of patients undergoing TAVR require the expert use of various imaging modalities, each of which has its own strengths and limitations. Divided into 3 sections (pre-procedural, intraprocedural, and long term follow-up), this review offers a single source for expert opinion and evidence-based guidance on how to incorporate the various modalities at each step in the care of a TAVR patient. Although much has been learned in the short span of time since TAVR was introduced, recommendations are offered for clinically relevant research that will lead to refinement of best practice strategies for incorporating multimodality imaging into TAVR patient care. PMID- 22498336 TI - Anatomy of pulmonary veins by real-time 3D TEE: implications for catheter-based pulmonary vein ablation. PMID- 22498337 TI - Angiographic correlates in type 1 and 2 MI by the universal definition. PMID- 22498338 TI - Progression of coronary calcium scores: harder gets the evidence. PMID- 22498339 TI - High cellular organization of pyoverdine biosynthesis in Pseudomonas aeruginosa: clustering of PvdA at the old cell pole. AB - Pyoverdine I (PVDI) is the major siderophore produced by Pseudomonas aeruginosa PAO1 to import iron. Its biosynthesis requires the coordinated action of cytoplasmic, periplasmic and membrane proteins. The individual enzymatic activities of these proteins are well known. However, their subcellular distribution in particular areas of the cytoplasm, periplasm, or within the membrane has never been investigated. We used chromosomal replacement to generate P.aeruginosa strains producing fluorescent fusions with PvdA, one of the initial enzymes in the biosynthetic pathway of PVDI in the cytoplasm, and PvdQ, involved in the maturation of PVDI in the periplasm. Cellular fractionation indicated that a substantial amount of PvdA-YFP was located in the membrane fraction. Epifluorescence microscopy imaging showed that PvdA-YFP was mainly clustered at the old cell pole of bacteria, indicating a polar segregation of the protein. Epifluorescence and TIRF imaging on cells expressing labelled PvdQ showed that this enzyme was uniformly distributed in the periplasm, in contrast with PvdA YFP. The description of the intracellular distribution of these enzymes contributes to the understanding of the PVDI biosynthetic pathway. PMID- 22498340 TI - CD105 and placental growth factor--potent prognostic factors in childhood acute lymphoblastic leukaemia. AB - The studies aimed at identifying a prognostic significance of angiogenesis related factors: CD105 and placental growth factor (PlGF) in a course of acute lymphoblastic leukaemia (ALL). Research protocol was based on detection of RNA and protein expressions in bone marrow blasts using quantitative PCR and immunocytochemical assays respectively. Kaplan-Meier statistics revealed CD105 and PlGF expression as managed separately do not correlate with relapse-free time in ALL patients. On the other hand, an associated analysis of CD105 and PlGF demonstrated a significantly shorter progression-free time in children who were CD105+ and PlGF+ or CD105- and PlGF+ at the moment of ALL diagnosis. PMID- 22498341 TI - Serum BAFF levels are related to angiogenesis and prognosis in patients with multiple myeloma. AB - B-cell activating factor (BAFF) is a B-cell growth factor. We measured its serum levels and correlated them with parameters of disease activity, as serum levels of tumor necrosis factor-alpha and lactate dehydrogenase, bone marrow microvascular density and proliferating cell nuclear antigen expression, in 50 myeloma patients, in 22 of them in plateau phase and in 20 controls. All of them were higher in patients and in advanced disease while reduced in plateau phase. BAFF correlated with all the above markers. Higher BAFF levels predicted a shorter survival, suggesting an important prognostic marker and a possible therapeutic target in myeloma. PMID- 22498342 TI - The chimney graft, a systematic review. AB - BACKGROUND: Approximately 20% to 30% of the patients are considered not eligible for standard endovascular aneurysm repair because of aortic neck morphology. Most of these patients have an aortic neck situated in the vicinity of the aortic side branches, requiring extensive open surgery. The introduction of fenestrated and branched stent grafts has made endovascular branch preservation possible, but these procedures are time-consuming and expensive. The chimney procedure offers a readily available endovascular alternative for the treatment in patients with acute aneurysms and challenging anatomy. We conducted a systematic review to evaluate the short- and long-term results of the chimney procedure. METHODS: A comprehensive literature search for studies describing the chimney procedure was performed using MEDLINE and Excerpta Medica Database. All articles were critically appraised and included, based on relevance, validity, and outcome measures. Patient characteristics, details of the surgical intervention, and short- and long-term outcomes were studied. RESULTS: A total of 75 patients were included who underwent a chimney procedure for the preservation of a total of 96 branches. Used operating techniques differed considerably between all studies, with an overall technical success rate of 98.9%. Three perioperative deaths were reported, of which one patient died from intervention-related complication. The follow-up duration ranged from 2 days to 54 months. Late complications included three deaths, none of which was device or aneurysm related. Three chimney grafts occluded during follow-up, of which two required reintervention. CONCLUSION: The chimney procedure appears as an acceptable alternative for patients in an emergency setting, although data regarding long-term follow-up are not yet available. PMID- 22498343 TI - Measuring diversity in medical reports based on categorized attributes and international classification systems. AB - BACKGROUND: Narrative medical reports do not use standardized terminology and often bring insufficient information for statistical processing and medical decision making. Objectives of the paper are to propose a method for measuring diversity in medical reports written in any language, to compare diversities in narrative and structured medical reports and to map attributes and terms to selected classification systems. METHODS: A new method based on a general concept of f-diversity is proposed for measuring diversity of medical reports in any language. The method is based on categorized attributes recorded in narrative or structured medical reports and on international classification systems. Values of categories are expressed by terms. Using SNOMED CT and ICD 10 we are mapping attributes and terms to predefined codes. We use f-diversities of Gini-Simpson and Number of Categories types to compare diversities of narrative and structured medical reports. The comparison is based on attributes selected from the Minimal Data Model for Cardiology (MDMC). RESULTS: We compared diversities of 110 Czech narrative medical reports and 1119 Czech structured medical reports. Selected categorized attributes of MDMC had mostly different numbers of categories and used different terms in narrative and structured reports. We found more than 60% of MDMC attributes in SNOMED CT. We showed that attributes in narrative medical reports had greater diversity than the same attributes in structured medical reports. Further, we replaced each value of category (term) used for attributes in narrative medical reports by the closest term and the category used in MDMC for structured medical reports. We found that relative Gini-Simpson diversities in structured medical reports were significantly smaller than those in narrative medical reports except the "Allergy" attribute. CONCLUSIONS: Terminology in narrative medical reports is not standardized. Therefore it is nearly impossible to map values of attributes (terms) to codes of known classification systems. A high diversity in narrative medical reports terminology leads to more difficult computer processing than in structured medical reports and some information may be lost during this process. Setting a standardized terminology would help healthcare providers to have complete and easily accessible information about patients that would result in better healthcare. PMID- 22498345 TI - Anti-neuroinflammatory constituents from Polygala tricornis Gagnep. AB - Two new compounds (S)-(+)-butyl-4-methylene-5-oxo-pyrrolidin-2-carboxylate (1) and (5-formylfuran-2-yl)methyl 4-hydroxy-2-methylenebutanoate (2), together with four known compounds (3-6) were isolated from the roots of Polygala tricornis Gagnep. Their structures were determined on the basis of 1D- and 2D-NMR experiments and by comparison with physical data of known compounds. All the isolated compounds were examined for their inhibitory effect on the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in BV-2 microglial cells, and compounds 1 and 2 exhibited pronounced inhibition on the NO production with IC(50) values of 14.1 MUM and 1.77 MUM, respectively. PMID- 22498344 TI - An LC-MS/MS method for concurrent determination of nicotine metabolites and the role of CYP2A6 in nicotine metabolite-mediated oxidative stress in SVGA astrocytes. AB - BACKGROUND: Nicotine is known to generate oxidative stress through cytochrome P450 2A6 (CYP2A6)-mediated metabolism in the liver and other organs, including macrophages. This study has been designed to examine the role of CYP2A6 in nicotine metabolism and oxidative stress in SVGA cells, an immortalized human astrocyte cell line. METHODS: SVGA astrocytes were treated with 1 MUM nicotine, followed by determination of mRNA and protein levels of several CYPs using quantitative RT-PCR and western blot analyses, respectively. Quantitation of nicotine and the nicotine metabolites, cotinine and nicotine-derived nitrosamine ketones (NNK), was performed using an LC-MS/MS method. The generation of reactive oxygen species (ROS) was measured using flow cytometry. RESULTS: Nicotine significantly upregulated mRNA and protein expression of the most abundantly expressed CYPs in SVGA astrocytes, CYP2A6 and CYP1A1. To characterize the metabolism of nicotine in astrocytes, a highly sensitive LC-MS/MS method was developed which is capable of quantifying very low concentrations of nicotine (0.3 ng/mL), cotinine and NNK (0.11 ng/mL). The LC-MS/MS results showed that nicotine is steadily metabolized to cotinine and NNK from 0.5 to 4h. Finally, we showed that nicotine initially causes an increase in ROS formation which is then gradually decreased, perhaps due to the increase in superoxide dismutase level. Nicotine metabolism and ROS formation by CYP2A6 were further confirmed by using tryptamine, a selective inhibitor of CYP2A6, which significantly lowered the levels of cotinine and NNK and inhibited ROS formation. CONCLUSIONS: CYP2A6 plays a key role in nicotine metabolism and oxidative stress in astrocytes, and this has implications in nicotine-associated brain toxicity. PMID- 22498346 TI - Protein quality control in organelles - AAA/FtsH story. AB - This review focuses on organellar AAA/FtsH proteases, whose proteolytic and chaperone-like activity is a crucial component of the protein quality control systems of mitochondrial and chloroplast membranes. We compare the AAA/FtsH proteases from yeast, mammals and plants. The nature of the complexes formed by AAA/FtsH proteases and the current view on their involvement in degradation of non-native organellar proteins or assembly of membrane complexes are discussed. Additional functions of AAA proteases not directly connected with protein quality control found in yeast and mammals but not yet in plants are also described shortly. Following an overview of the molecular functions of the AAA/FtsH proteases we discuss physiological consequences of their inactivation in yeast, mammals and plants. The molecular basis of phenotypes associated with inactivation of the AAA/FtsH proteases is not fully understood yet, with the notable exception of those observed in m-AAA protease-deficient yeast cells, which are caused by impaired maturation of mitochondrial ribosomal protein. Finally, examples of cytosolic events affecting protein quality control in mitochondria and chloroplasts are given. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids. PMID- 22498347 TI - [Prevalence and economic impact of obesity in adults during 2003-2010]. PMID- 22498348 TI - [Thalidomide associated to endoscopic treatment with argon plasma coagulation in rectal bleeding caused by vascular injury secundary to severe actinic proctitis]. PMID- 22498349 TI - [Secondary syphilis with pulmonary involvement]. PMID- 22498350 TI - Burden of disease assessment with summary measures of population health for the Region of Valencia, Spain: a population-based study. AB - BACKGROUND AND OBJECTIVE: An important input to decision-making and health planning is a consistent and comparative description of the population health status. The purpose of this study was to describe the burden of disease in the Region of Valencia (Spain). MATERIAL AND METHODS: Disability-adjusted life years (DALYs) were calculated and divided into years of life lost (YLLs) and years lived with disability (YLDs). Using death registry data and Valencian population estimates in 2008, we calculated the number of deaths and YLLs. YLDs were based on age- and sex-specific data for countries of the EURO-A subregional level (which includes the Region of Valencia) from the Global Burden of Disease study. The results were stratified by age group, sex and underlying cause of death. The DALY values were used to rank the leading conditions of disease burden. RESULTS: In 2008, the total number of DALYs lost was about 551 thousands (53% in men). The main categories of DALYs lost were neuropsychiatric conditions (30%; 167 thousands), malignant tumors (15%; 85 thousands), cardiovascular diseases (13%; 72 thousands) and sense organ diseases (8%; 46 thousands). Depression (8% of DALYs; 47 thousands), dementias (8%; 42 thousands), ischaemic heart disease (5%; 27 thousands), hearing loss (4%; 22 thousands), stroke (4%; 20 thousands) and lung cancer (3%; 19 thousands) were the leading specific causes of disease burden. CONCLUSIONS: We provide for the first time ever information on the burden of disease in the Valencian population. At this local level, the use of DALYs can help to monitor the population health status and guide the debates on rational priority-setting. PMID- 22498351 TI - Rapid whole protein quantitation of staphylococcal enterotoxins A and B by liquid chromatography/mass spectrometry. AB - Staphylococcus aureus is an important pathogen and has been indicated as the fifth causative agent of food-borne human illness throughout the world. Staphylococcal enterotoxins (SEs) are toxic compounds excreted mainly by strains of S. aureus. Among these toxins, enterotoxins A (SEA) and B (SEB) are both of the most prevalent compounds in staphylococcal food poisoning. In this work, reverse phase liquid chromatography coupled to ESI mass spectrometry (LC-ESI/MS) has been applied for its rapid identification and quantification. Limit of detection (LOD) values were 0.5 and 0.2 ng for SEA and SEB, respectively and limit of quantification (LOQ) value was 1 ng for both enterotoxins. SEA and SEB have been analyzed as intact proteins in milk and fruit juices. Analytical methods are essential for routine monitoring purposes and safeguard public health and the proposed technique can detect and quantify successfully SEA and SEB in food samples. PMID- 22498352 TI - Comparison of various ternary simulated moving bed separation schemes by multi objective optimization. AB - Over the past decade, many modifications have been proposed in simulated moving bed (SMB) chromatography in order to effectively separate a binary mixture. However, the separation of multi-component mixtures using SMB is still one of the major challenges. In addition, the performance of SMB system highly depends on its operating conditions. Our study address this issue by formulating a multi objective optimization problem that maximizes the productivity and purity of intermediate eluting component at the same time. A number of optimized isocractic ternary SMB operating schemes are compared both in terms of productivity and amount of desorbent to feed ratio. Furthermore, we propose a generalized full cycle (GFC) formulation based on superstructure formulation encompassing numerous operating schemes proposed in the literature. We also demonstrate that this approach has a potential to find the best ternary separation strategy among various alternatives. PMID- 22498353 TI - A validated ultra-high performance liquid chromatography coupled to high resolution mass spectrometry analysis for the simultaneous quantification of the three known boar taint compounds. AB - Boar taint is an off-odour that can occur when meat or fat from entire male pigs is heated. Most of the currently available analytical methods are not capable of detecting the three known boar taint compounds (indole, skatole and androstenone) simultaneously, which renders their analysis often labour-intensive and time consuming as separate analyses are required. In this study a validated U-HPLC-HR Orbitrap-MS analysis method is described for the quantitative determination of the three boar taint compounds in fat. The sample pre-treatment involves a melting step followed by extraction with methanol and clean-up consisting of a freezing step and solid phase extraction (HLB cartridges). The analytes are then chromatographically separated and detected with an Exactive high-resolution mass spectrometer. Due to the absence of guidelines for the analysis of boar taint in fat, the Commission Decision 2002/657/EC [18] and ISO 17025 [19] guidelines were used as guideline for validation of the developed detection method. This resulted in limits of detection and limits of quantification between 2.5 and 7 MUg kg(-1) and between 5 and 10 MUg kg(-1) for the three compounds, respectively, which is far below the threshold values set at 100 MUg L(-1) for indole, 200 MUg L(-1) for skatole and 1000 MUg L(-1) for androstenone in pig fat samples. The method obtained for the three compounds a repeatability (RSD) lower then 12.7% and a within-laboratory reproducibility (RSD) lower than 16.9%. The recovery of the three compounds ranged between 99 and 112 and an excellent linearity (R(2) >= 0.99) was found. In the future, this method may be extended with other compounds that turn out to be correlated with boar taint. PMID- 22498354 TI - Aniline-silica nanocomposite as a novel solid phase microextraction fiber coating. AB - A new unbreakable solid phase microextraction (SPME) fiber coating based on aniline-silica nanocomposite was electrodeposited on a stainless steel wire. The electropolymerization process was carried out at a constant deposition potential, applied to the corresponding aqueous electrolyte containing aniline and silica nanoparticles. The scanning electron microscopy (SEM) images showed the non smooth and the porous surface structure of the prepared nanocomposite. The applicability of the new fiber coating was examined by headspace-solid phase microextraction (HS-SPME) of some environmentally important polycyclic aromatic hydrocarbons (PAHs), as model compounds, from aqueous samples. Subsequently, the extracted analytes were transferred into a gas chromatography (GC) by thermal desorption. Parameters affecting the synthesizing and extraction processes including the voltage of power supply, the weight ratio of components, the time of electrodeposition, extraction time and temperature, the ionic strength, and desorption temperature and time were optimized. Eventually, the developed method was validated by gas chromatography-mass spectrometry (GC-MS). At the optimum conditions, the relative standard deviation (%RSD) values for a double distilled water spiked with the selected PAHs at 40 ng L(-1) were 6-13% (n=3) while the limit of detection (LOD) results were between 1 and 3 ng L(-1). The calibration graphs were linear in the concentration range from 20 to 4000 ng L(-1) (R(2)>0.995). Finally the developed method was applied to the analysis of Kalan dam, rain and tap water samples and the relative recovery values were found to be in the range of 76-109%, under optimized conditions. In addition, the synthesis of the nanocomposite coating was carried out conveniently while it is rather inexpensive, easy, simple, rapid and highly durable and can be used frequently. PMID- 22498355 TI - Selectivity by host plants affects the distribution of arbuscular mycorrhizal fungi: evidence from ITS rDNA sequence metadata. AB - BACKGROUND: Arbuscular mycorrhizal fungi (AMF) can form obligate symbioses with the vast majority of land plants, and AMF distribution patterns have received increasing attention from researchers. At the local scale, the distribution of AMF is well documented. Studies at large scales, however, are limited because intensive sampling is difficult. Here, we used ITS rDNA sequence metadata obtained from public databases to study the distribution of AMF at continental and global scales. We also used these sequence metadata to investigate whether host plant is the main factor that affects the distribution of AMF at large scales. RESULTS: We defined 305 ITS virtual taxa (ITS-VTs) among all sequences of the Glomeromycota by using a comprehensive maximum likelihood phylogenetic analysis. Each host taxonomic order averaged about 53% specific ITS-VTs, and approximately 60% of the ITS-VTs were host specific. Those ITS-VTs with wide host range showed wide geographic distribution. Most ITS-VTs occurred in only one type of host functional group. The distributions of most ITS-VTs were limited across ecosystem, across continent, across biogeographical realm, and across climatic zone. Non-metric multidimensional scaling analysis (NMDS) showed that AMF community composition differed among functional groups of hosts, and among ecosystem, continent, biogeographical realm, and climatic zone. The Mantel test showed that AMF community composition was significantly correlated with plant community composition among ecosystem, among continent, among biogeographical realm, and among climatic zone. The structural equation modeling (SEM) showed that the effects of ecosystem, continent, biogeographical realm, and climatic zone were mainly indirect on AMF distribution, but plant had strongly direct effects on AMF. CONCLUSION: The distribution of AMF as indicated by ITS rDNA sequences showed a pattern of high endemism at large scales. This pattern indicates high specificity of AMF for host at different scales (plant taxonomic order and functional group) and high selectivity from host plants for AMF. The effects of ecosystemic, biogeographical, continental and climatic factors on AMF distribution might be mediated by host plants. PMID- 22498356 TI - Neighborhood deprivation and inequities in coronary heart disease among patients with diabetes mellitus: a multilevel study of 334,000 patients. AB - We used multilevel models to investigate whether the odds of coronary heart disease (CHD) is higher in patients with diabetes mellitus (DM) living in deprived neighborhoods versus those living in wealthy neighborhoods. The Swedish nationwide prescription register was used to identify 334,000 patients aged 30 years and older with DM. The OR of CHD was significantly higher among patients with DM living in deprived neighborhoods than among patients with DM living in wealthy neighborhoods. These findings are useful for clinicians working in deprived neighborhoods. Future research could focus on how to reduce inequities in CHD among patients with DM. PMID- 22498357 TI - Laparoscopic sleeve gastrectomy followed by duodenal switch in selected patients versus single-stage duodenal switch for superobesity: case-control study. AB - BACKGROUND: The prevalence of superobesity (body mass index [BMI] >=50 kg/m(2)) has increased steadily during the past decade, and the most suitable surgical strategy for these patients is still controversial. Our objective was to test the hypothesis that in selected superobese patients, laparoscopic sleeve gastrectomy (SG) followed by laparoscopic duodenal switch (DS) might reduce the rate of postoperative complications and the need for the second step duodenal switch. The setting was a university hospital in France. METHODS: A retrospective analysis was performed of a prospective database of 110 consecutive patients with a BMI of >=50 kg/m(2) undergoing the staged approach and matched for age, gender, and BMI with 110 consecutive patients undergoing single-stage DS. The excess weight loss (EWL), co-morbidity improvement, and incidence of postoperative complications were compared between the 2 groups. RESULTS: One patient died in the staged strategy group (mortality rate .9%). The postoperative complication rate was 8.2% in the staged strategy group (110 patients) and 15.5% in the single-stage DS group (110 patients; P = 1). Multivariate analysis showed that single-stage DS surgery is the only variable significantly associated with the occurrence of postoperative complications (odds ratio 2.36; 95% confidence interval 1.001 5.61). In the staged strategy group, at a mean follow-up of 36.4 +/- 13 months, 39 patients (35.5%) required the second-stage procedure. The mean %EWL was 50.8% +/- 17.5% for SG alone (35% failed to maintain 50% EWL after SG), 61.5% +/- 19.3% for the staged strategy, 72.7% +/- 14.1% for 2-step DS (3.3% failed to maintain 50% EWL after 2-step DS), and 73.3% +/- 17.6% for single-stage DS (7.3% failed to maintain 50% EWL after single-stage DS). CONCLUSIONS: At 3 years of follow-up, staged DS surgery avoided biliopancreatic diversion in 72.7% of the patients. Single-stage DS increases the risk of postoperative complications but not of anastomotic leak. PMID- 22498358 TI - Routine single-port sleeve gastrectomy: a study of 60 consecutive patients. AB - BACKGROUND: Single-port surgery has been developed for many digestive procedures, such as cholecystectomy and colectomy. Our objective was to present our preliminary results for laparoscopic single-port sleeve gastrectomy (SPSG), performed in our department for the treatment of morbid obesity, at Antoine Beclere Hospital and Paris XI University. METHODS: From July 2010 to February 2011, all patients evaluated by our multidisciplinary team for morbid obesity and eligible for sleeve gastrectomy underwent SPSG. The data were collected prospectively. RESULTS: Sixty consecutive patients underwent SPSG. The median age was 40.1 years; 6 patients were men and 48 were white. The median body mass index was 46.5 kg/m(2). The co-morbidities included diabetes in 12, essential hypertension in 31, sleep apnea in 39, dyslipidemia in 33, and coronary artery disease in 9. Of the 60 patients, 9 had previously undergone laparotomy and 5 had undergone bariatric surgery. The median operating time was 86 minutes. All procedures were achieved laparoscopically, with 10 patients requiring a second trocar and 3 patients 2 additional trocars. No conversion to open surgery was required. One leak was reported, and 1 patient experienced cubital nerve compression. The median hospital stay was 4 days. During a median follow-up of 8 months, most preoperative co-morbidities resolved, and the Bariatric Analysis and Reporting Outcome System score for care efficacy was 6.8 of 9. CONCLUSION: SPSG is feasible in routine bariatric surgery. The results for weight loss and co morbidity resolution seem to be equivalent to those with "multiple port" laparoscopy. New instruments and specific training are required. We believe that this technique is a natural evolution of minimally invasive surgery requiring additional investigation in prospective studies. PMID- 22498359 TI - Comment on: Revisional surgery after adjustable gastric banding: a growing practice. PMID- 22498360 TI - Weight loss is more sustained after biliopancreatic diversion with duodenal switch than Roux-en-Y gastric bypass in superobese patients. AB - BACKGROUND: Although biliopancreatic diversion with duodenal switch (BPD-DS) is not the most performed procedure, Roux-en-Y gastric bypass (RYGB) is challenged by weight regain and insufficient weight loss, especially in patients with a body mass index >50 kg/m(2). The aim of our retrospective study was to compare the weight loss after 2 types of primary bariatric surgery. A total of 83 BPD-DS and 97 RYGB procedures were performed from March 2002 to October 2009 for an initial mean body mass index of 55 kg/m(2). METHODS: All RYGB patients underwent surgery at a private practice hospital and BPD-DS patients underwent surgery at a university hospital before February 2007 and at the same private hospital thereafter. The patients were seen in follow-up every 4 months the first year, every 6 months the second, and yearly thereafter. The maximum weight loss was assessed, as well as the weight regain beyond the first postoperative year. Weight loss success was defined as a percentage of excess weight loss (%EWL) of >=50%. RESULTS: The patients did not differ by age, gender, or length of follow up (mean 46 mo, range .5-102 for RYGB and 44.3 mo, range 9-111 for BPD-DS). Of the patients, 17 RYGB and 7 BPD-DS patients were lost to follow-up within 3 years postoperatively. At 3 years of follow-up, the mean %EWL was 63.7% +/- 17.0% after RYGB and 84.0% +/- 14.5% after BPD-DS (P < .0001). Weight loss success was achieved by 83.5% of the RYGB and 98.7% of the BPD-DS patients (P = .0005). CONCLUSION: After 12 months postoperatively, the number of patients regaining 10% of the weight lost during the first postoperative year was significantly greater after RYGB than after BPD-DS. PMID- 22498361 TI - Asymptotic analysis of value prediction by well-specified and misspecified models. PMID- 22498362 TI - Cloning and expression of porcine Dicer and the impact of developmental stage and culture conditions on MicroRNA expression in porcine embryos. AB - MicroRNA (miRNA) is a class of small, single-stranded ribonucleic acids that regulate gene expression post-transcriptionally and are involved in somatic cell, germ cell, and embryonic development. As the enzyme responsible for producing mature miRNA, Dicer is crucial to miRNA production. Characterization of Dicer and its expression at the nucleotide level, as well as the identification of miRNA expression in reproductive tissues, have yet to be reported for the domestic pig (Sus scrofa), a species important for disease modeling, biomedical research, and food production. In this study we determined the primary cDNA sequence of porcine Dicer (pDicer), confirmed its expression in porcine oocytes and early stage embryos, and evaluated the expression of specific miRNA during early embryonic development and between in vivo (IVO) and in vitro (IVF) produced embryos. Total cellular RNA (tcRNA) was isolated and subjected to end point RT-PCR, subcloning, and sequencing. The pDicer coding sequence was found to be highly conserved, and phylogenetic analysis showed that pDicer is more highly conserved to human Dicer (hDicer) than the mouse homolog. Expression of pDicer mRNA was detected in oocytes and in IVO produced blastocyst embryos. Two RT-PCR procedures were conducted to identify and quantitate miRNA expressed in metaphase II oocytes (MII) and embryos. RT-PCR array was conducted using primers designed for human miRNA, and 86 putative porcine miRNA in MII and early embryos were detected. Fewer miRNAs were detected in 8-cell (8C) embryos compared to MII and blastocysts (B) (P=0.026 and P<0.0001, respectively). Twenty-one miRNA (of 88 examined) were differentially expressed between MII and 8C, 8C and B, or MII and B. Transcripts targeted by the differentially expressed miRNA were enriched in gene ontology (GO) categories associated with cellular development and differentiation. Further, we evaluated the effects of IVF culture on the expression of specific miRNA at the blastocyst stage. Quantitative RT-PCR was conducted on blastocyst tcRNA isolated from individual IVO and IVF produced embryos for miR-18a, -21, and -24. Only the expression level of miR-24 differed due to culture conditions, with lower levels detected in the IVO embryos. These data show that pDicer and miRNA are present in porcine oocytes and embryos. In addition, specific miRNA levels are altered due to stage of embryonic development and, in the case of miR-24, due to culture conditions, making this miRNA a candidate for screening of embryo quality. Additional studies characterizing Dicer and miRNA expression during early embryonic development from IVO and IVF sources are required to further examine and evaluate the use of miRNA as a marker for embryo quality. PMID- 22498363 TI - Comorbidity of GJB2 and WFS1 mutations in one family. AB - It is rarely reported that two distinct genetic mutations affecting hearing have been found in one family. We report on a family exhibiting comorbid mutation of GJB2 and WFS1. A four-generation Japanese family with autosomal dominant sensorineural hearing loss was studied. In 7 of the 24 family members, audiometric evaluations and genetic analysis were performed. We detected A-to-C nucleotide transversion (c.2576G>C) in exon 8 of WFS1 that was predicted to result in an arginine-to-proline substitution at codon 859 (R859P), G-to-A transition (c.109G>A) in exon 2 of GJB2 that was predicted to result in a valine to-isoleucine substitution at codon 37 (V37I), and C-to-T transition (c.427C>T) in exon 2 of GJB2 that was predicted to result in an arginine-to-tryptophan substitution at codon 143 (R143W). Two individuals who had heterozygosity of GJB2 mutations and heterozygosity of WFS1 mutations showed low-frequency hearing loss. One individual who had homozygosity of GJB2 mutation without WFS1 mutation had moderate, gradual high tone hearing loss. On the other hand, a moderate flat loss configuration was seen in one individual who had compound heterozygosity of GJB2 and heterozygosity of WFS1 mutations. Our results indicate that the individual who has both GJB2 and WFS1 mutations can show GJB2 phenotype. PMID- 22498365 TI - Electroless deposition of Ni-P-nano-ZrO2 composite coatings in the presence of various types of surfactants. AB - Ni-P-nano-ZrO(2) coatings were produced using the electroless deposition technique. To prevent agglomeration of zirconia nanoparticles in the plating bath, various surfactant additives (anionic, cationic, and nonionic) were used. The most stable bath was obtained with the addition of dodecyltrimethylammonium bromide (DTAB). The impact of this surfactant on the deposition rate, coating composition, and topography, as well as zeta potential of particles, was examined. Surface morphology and composition of the Ni-P-nano-ZrO(2) composite coatings was analyzed by various techniques including scanning electron microscopy (SEM) equipped with in situ energy-dispersive X-ray (EDX) spectroscopy. Coatings with a clearly greater amount of zirconia (21.88-22.10 wt.%) were obtained from baths containing DTAB in concentrations equal to or above its critical micelle concentration (cmc). For these surfactant concentrations, the reduction of Ni and P content was observed. PMID- 22498364 TI - Molecular monitoring of Plasmodium falciparum drug susceptibility at the time of the introduction of artemisinin-based combination therapy in Yaounde, Cameroon: implications for the future. AB - BACKGROUND: Regular monitoring of the levels of anti-malarial resistance of Plasmodium falciparum is an essential policy to adapt therapy and improve malaria control. This monitoring can be facilitated by using molecular tools, which are easier to implement than the classical determination of the resistance phenotype. In Cameroon, chloroquine (CQ), previously the first-line therapy for uncomplicated malaria was officially withdrawn in 2002 and replaced initially by amodiaquine (AQ) monotherapy. Then, artemisinin-based combination therapy (ACT), notably artesunate-amodiaquine (AS-AQ) or artemether-lumefantrine (AL), was gradually introduced in 2004. This situation raised the question of the evolution of P. falciparum resistance molecular markers in Yaounde, a highly urbanized Cameroonian city. METHODS: The genotype of pfcrt 72 and 76 and pfmdr1 86 alleles and pfmdr1 copy number were determined using real-time PCR in 447 P. falciparum samples collected between 2005 and 2009. RESULTS: This study showed a high prevalence of parasites with mutant pfcrt 76 (83%) and pfmdr1 86 (93%) codons. On the contrary, no mutations in the pfcrt 72 codon and no samples with duplication of the pfmdr1 gene were observed. CONCLUSION: The high prevalence of mutant pfcrt 76T and pfmdr1 86Y alleles might be due to the choice of alternative drugs (AQ and AS-AQ) known to select such genotypes. Mutant pfcrt 72 codon was not detected despite the prolonged use of AQ either as monotherapy or combined with artesunate. The absence of pfmdr1 multicopies suggests that AL would still remain efficient. The limited use of mefloquine or the predominance of mutant pfmdr1 86Y codon could explain the lack of pfmdr1 amplification. Indeed, this mutant codon is rarely associated with duplication of pfmdr1 gene. In Cameroon, the changes of therapeutic strategies and the simultaneous use of several formulations of ACT or other anti-malarials that are not officially recommended result in a complex selective pressure, rendering the prediction of the evolution of P. falciparum resistance difficult. This public health problem should lead to increased vigilance and regular monitoring. PMID- 22498366 TI - A new strategy for the controlled deposition of gold nanoparticle aggregates on two-dimensional polystyrene arrays and its application in glucose oxidase immobilization. AB - Nano/microstructures play an important role in nanoparticle applications. This paper describes an innovative strategy to fabricate a variety of gold nanoparticle aggregates (AuNPs) on large-scale arrays of up to ~1 cm(2) made from polystyrene (PS). A dendritic surfactant, C18N3, has multi-amine head groups that can control the thickness of a double layer adsorbed on the PS sphere surface in a pH-dependent manner. Controlling the pH and immersion time in the C18N3 solution allows the morphology of AuNPs deposited on the PS spheres (PS@AuNP) to be regulated. The influence of nano/microstructures on the activity enhancement of glucose oxidase (GOD) was investigated. The results indicated that well ordered PS@AuNP arrays performed much better in the specific activity enhancement of GOD compared with free GOD and GOD immobilized on PS arrays. Furthermore, it was observed that the immobilized GOD on 2D PS@AuNP arrays maintained a highly improved operational stability compared to free GOD. The mechanism behind this effect is discussed. For practical applications, prepared PS@AuNP arrays can be used as an effective chip for GOD immobilization and application. PMID- 22498367 TI - Multimodal Zr-Silicalite-1 zeolite nanocrystal aggregates with interconnected hierarchically micro-meso-macroporous architecture and enhanced mass transport property. AB - Hierarchical porous architecture with interconnected trimodal micro-meso macroporous systems constructed from uniform zeolite Zr-doped silicalite-1 nanocrystals has been prepared. The synthesis has been made by using glycerin as a reaction medium via a quasi-solid-state crystallization of hierarchically meso macroporous zirconosilicate precursor under the effect of the structure directing agent TPAOH. The presence of glycerin is crucial in the synthesis systems to maintain the porous hierarchy. The pores inter-connectivity, Zr location in the framework, the acidity and the catalytic activity have been studied by laser hyperpolarized (129)Xe NMR spectroscopy, UV-visible spectroscopy, temperature programmed desorption of ammonia and the catalytic isopropylbenzene cracking probe reaction, respectively. The products possess well-defined macrochannels interconnected with mesopores located in the macropore walls, which in turn have been constructed from microporous MFI-type zeolite units. (129)Xe NMR study indicated that the hierarchically micro-, meso-, macro-pore systems are homogeneously distributed throughout the final materials and well interconnected, which is important for molecular diffusion. The TPD-NH(3) investigation revealed that the hierarchically micro-meso-macroporous materials constructed from zeolite Zr-Silicalite-1 nanocrystals present strong acidity. PMID- 22498368 TI - The complexation of uranium(VI) and atmospherically derived CO2 at the ferrihydrite-water interface probed by time-resolved vibrational spectroscopy. AB - The sorption reactions of uranium(VI) at the ferrihydrite(Fh)-water interface were investigated in the absence and presence of atmospherically derived CO(2) by time-resolved in situ vibrational spectroscopy. The spectra clearly show that a single uranyl surface species, most probably a mononuclear bidentate surface complex, is formed irrespective of the presence of atmospherically derived CO(2). The character of the carbonate surface species correlates with the presence of the actinyl ions and changes from a monodentate to a bidentate binding upon sorption of U(VI). From the in situ sorption experiments under mildly acid conditions, the formation of a ternary surface complex is derived where the carbonate ligands coordinate bidentately to the uranyl moiety (=UO(2)(O(2)CO)(x)). Furthermore, the release reaction of the carbonate ligands from the ternary surface complex is found to be considerably retarded compared to those from the pristine surface suggesting a tighter bonding of the carbonate ions in the ternary complex. Simultaneous sorption of U(VI) and atmospherically derived carbonate onto pristine Fh shows formation of binary monodentate carbonate surface complexes prior to the formation of the ternary complexes. PMID- 22498369 TI - Reversible crosslinking density stimulated diffraction wavelength tuning of hydrogel-encapsulated crystalline colloidal arrays. AB - The reversible variation in the observed stop band of a hydrogel-encapsulated crystalline colloidal array was achieved through the selective formation and destruction of -S-Pb-S- linkages within the hydrogel. A reversible 45 nm stop band shift could be achieved with a cyclical treatment of Pb(2+) and then dithiothreitol solution. PMID- 22498370 TI - ZnO/graphene-oxide nanocomposite with remarkably enhanced visible-light-driven photocatalytic performance. AB - In this work, a high-performance photocatalyst of ZnO/graphene-oxide (ZnO/GO) nanocomposite was synthesized via a facile chemical deposition route and used for the photodegradation of organic dye from water under visible light. The nanocomposite was characterized by X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscopy, Brunauer-Emmett-Teller N(2) adsorption-desorption analysis, and UV-Vis diffusion reflectance spectroscopy. The ZnO/GO nanocomposite consisting of flower-like ZnO nanoparticles anchored on graphene-oxide sheets has a high surface area and hierarchical porosity, which is benefit to the adsorption and mass transfer of dye and oxygen species. For the photodegradation of organic dyes under visible light, ZnO/GO nanocomposite exhibited remarkably enhanced photocatalytic efficiency than graphene-oxide sheets and flower-like ZnO particles. Moreover, the photocatalytic efficiency of ZnO/GO nanocomposite could be further improved by annealing the product in N(2) atmosphere. The outstanding photocatalytic performance was ascribed to the efficient photosensitized electron injection and repressed charge carriers recombination in the composite with GO as electron collector and transporter, thus leading to continuous generation of reactive oxygen species for the degradation of methylene blue. PMID- 22498371 TI - Pharyngocele. PMID- 22498372 TI - Endoscopic endonasal approach for the treatment of anterior skull base tumours. AB - INTRODUCTION: The increasing expertise of transnasal endoscopic surgery has recently expanded its indications to include the management of tumours affecting the skull base. We report our experience with endoscopic management of these tumours, emphasising the indications and surgical technique used. MATERIAL AND METHOD: A retrospective analysis was performed of patients treated by an endoscopic endonasal approach (EEA) in our department from 2004 until 2011. RESULTS: Sixty-three patients were analysed. We performed an endoscopic craniofacial resection in 32 patients (51%), an expanded EEA in 22 (35%), a transclival approach in 6 (9%) and a transpterygoid approach in 3 (5%). The most frequent benign tumour was nasopharyngeal angiofibroma (24%), while adenocarcinoma (30%) was the most common among malignancies. Mean follow-up was 26 months (range: 6 to 84 months). The complication rate was 5% and resection was complete in 56 cases (89%). The 5-year overall-survival was 71% in patients with malignant tumours and the effectiveness was 100% in benign tumours. CONCLUSION: Our results support that endoscopic surgery, when properly planned, represents a valid alternative to standard surgical approaches for the management of skull base tumours. PMID- 22498373 TI - Congenital diaphragmatic hernia: to repair on or off extracorporeal membrane oxygenation? AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) can be repaired on or off extracorporeal membrane oxygenation (ECMO). In many centers, operating off ECMO is advocated to prevent bleeding complications. We aimed to compare surgery related bleeding complications between repair on or off ECMO. METHODS: All patients with CDH repair and ECMO treatment between January 1, 1995, and May 31, 2008, were retrospectively reviewed. Tranexamic acid was routinely given to all patients repaired on ECMO for 24 hours perioperatively after 2003. Extra-fluid expansion, transfusion, or relaparotomy caused by postoperative bleeding were scored as surgery-related bleeding complications and were related to the Extracorporeal Life Support Organization (ELSO) registry. We used chi(2) test and t test for statistics. RESULTS: Demographic data and surgery-related bleeding complications in the on-ECMO group were not significantly different compared with the off-ECMO group (P = .331) in our institute. In contrast, more surgery-related bleeding complications were reported by ELSO in their on-ECMO group (P < .0001). CONCLUSION: In contrast to the data from the ELSO registry, we did not observe significantly more surgery-related bleeding complications after CDH repair on ECMO. Using a specific perioperative hemostatic treatment enabled us to perform CDH repair on ECMO with a low frequency of bleeding complications, thereby taking advantage of having the physiologic benefits of ECMO available perioperatively. PMID- 22498374 TI - Patch repair for congenital diaphragmatic hernia: is it really a problem? AB - BACKGROUND: Large congenital diaphragmatic hernia (CDH) defects often require the use of synthetic patches for tension-free repair. Although high rates of recurrence and other morbidities have been previously reported, our favorable perception of patch repair prompted this review. METHODS: A single-center retrospective chart review of CDH cases repaired between January 1, 1999, and October 1, 2010. Patch repairs were performed by multiple surgeons with an effort to construct a tension-free dome-shaped patch. RESULTS: One hundred eighty-four children underwent CDH repair of whom 99 (53.8%) required a patch. Seventy-four (74.7%) of the 99 patients who underwent patch repair survived to discharge and were compared with 75 primary repair survivors. Of those undergoing patch repair, 88% were prenatally diagnosed, 55% had liver herniation, and 22 (29.9%) were repaired on extracorporeal membrane oxygenation. Two patients experienced a recurrence after a patch repair and 3 after a primary repair for a rate of 5.4% and 4.0%, respectively (P = 1.0). CONCLUSIONS: These results demonstrate that synthetic patch repair for CDH can be performed with a very low rate of recurrence challenging the need for alternative approaches to diaphragmatic replacement. High rates of recurrence reported for patch repair may be technical rather than intrinsic to the patch. PMID- 22498375 TI - Is radical lobectomy required in congenital cystic adenomatoid malformation? AB - BACKGROUND: The extent of surgical resection in the management of congenital cystic adenomatoid malformation (CCAM) located in 1 pulmonary lobe remains controversial. Although lobectomy seems to be the best treatment to avoid recurrent pulmonary infection and neoplasia, neither retrospective nor prospective studies have been done to our knowledge. Besides, many reports claim that there are advantages of parenchyma-saving resections. The aim of our study was to determine whether it was necessary to perform an extended resection in these cases. MATERIALS AND METHODS: We retrospectively reviewed all patients who had undergone a thoracoscopic lobectomy for CCAM located to 1 pulmonary lobe between January 2007 and January 2009. A thoracic radiologist performed a single blind review of all preoperative computed tomographic (CT) scans, mentioning the presence or absence of distant lesions from the main cysts of CCAM within the pulmonary lobe. The pathologist who analyzed the pulmonary lobectomy specimen was aware of the diagnosis but not the CT report. RESULTS: Twenty-five patients underwent thoracoscopic lobectomy for congenital lung malformations, including 12 with CCAM. All had a positive prenatal sonogram. The median age at surgery was 12 months (range, 2-24 months). The preoperative CT showed only 2 cases with distant lesions within the affected pulmonary lobe, whereas the histologic study of the surgical specimen identified 6 cases. The sensitivity of the CT scan was low, 33%, whereas its specificity was high, 100%. Furthermore, the preoperative CT negative predictive value was 60%. The median time of follow-up was 7.5 months. CONCLUSION: Adequate treatment of CCAM in children requires a lobectomy because of poor sensitivity and very poor negative predictive value (60%) of the preoperative CT to determine distal adjacent lesions. A prospective study on a larger number of patients is required to confirm these observations. PMID- 22498376 TI - Cluster of 4 cases of esophageal squamous cell cancer developing in adults with surgically corrected esophageal atresia--time for screening to start. AB - BACKGROUND: Currently, no recommendations exist for the endoscopic screening of patients in adulthood, with surgically corrected esophageal atresia (EA), for the development of esophageal cancer. A small number of individual case reports in the literature have raised concern that these cancers pose an increased risk (2 adenocarcinoma and 3 squamous cell carcinoma). METHODS: St Vincent's hospital has set up an EA clinic to review adult patients previously operated on for correction of EA. These patients underwent clinical review and were offered endoscopic evaluation if they had symptoms of dysphagia or gastroesophageal reflux. Among those patients, 3 have developed esophageal squamous cell carcinoma (SCC). A retrospective review of the EA database from the Royal Children's Hospital (798 patients [309 patients older than 40 years]) was then performed to identify any other cases of esophageal cancer developing in this cohort. One further patient was identified. RESULTS: To date, 4 of 309 patients have developed esophageal SCC over the age of 40 years. The cumulative incidence of esophageal SCC in this age group was 50 times that expected in the general population. CONCLUSIONS: (1) This cluster provides strong evidence that there is a substantial risk of SCC in these adults with surgically repaired EA. (2) We believe that long-term surveillance endoscopy enhanced by advanced imaging techniques is indicated in all adults from the age of 20 years who have had surgical repair of EA. PMID- 22498377 TI - Continuing promise 2009--assessment of a recent pediatric surgical humanitarian mission. AB - PURPOSE: Surgical organizations have begun to focus their efforts on providing humanitarian assistance in international communities. Most surgeons do not have previous international experience and lack an understanding of what is expected and what care they can provide. The unknown factors include case types, patient volume, postoperative care, and equipment. This abstract presents humanitarian assistance mission and highlights the importance of preparation, host nation involvement, and understanding the local politics of each country. METHODS: In April to July 2009, the USNS (United States Naval Ship) Comfort deployed to provide humanitarian assistance to 7 countries through Central and South America. Data collected included numbers and types of procedures, rate of rejection of patients for operation, patient age, American Society of Anesthesiology (ASA) score, and length of procedure. RESULTS: These data represent the total mission of Continuing Promise 2009 including a total of 1137 surgical procedures of which 340 were pediatric (<18 years old). The average number of pediatric cases for each country in 7 days was 48.3 +/- 21.4, with a range of 24 to 84. The average age was 7.5 years (range, 1 month to 18 years). In partnership with host physicians, preoperative screening occurred over 2 to 3 days for every 7 operative days. We maintained a low threshold for rejection (rate of 43%; range, 21%-62%) and average ASA score of 1.3. Including all pediatric subspecialties, the most frequent procedures were inguinal (23%) and umbilical (14%) hernias. Although these were the most frequent procedure, the range and variety of cases varied widely. We had a very low early complication rate (1.2%), including 3 wound infections and 1 early hernia recurrence. CONCLUSIONS: Our data represent the largest collection to date on the pediatric surgical care of children in a humanitarian effort. Our experience can be used to identify the most likely types of cases in South and Central America and as a model for the safe and efficient treatment of children in a developing country. PMID- 22498378 TI - Late vs early ostomy closure for necrotizing enterocolitis: analysis of adhesion formation, resource consumption, and costs. AB - BACKGROUND: Surgeons prefer to close ostomies at least 6 weeks after the primary operation because of the anticipated postoperative abdominal adhesions. Limited data support this habit. Our aim was to evaluate adhesion formation-together with an analysis of resource consumption and costs-in patients with necrotizing enterocolitis who underwent early closure (EC), compared with a group of patients who underwent late closure (LC). METHODS: Chart reviews and cost analyses were performed on all patients with necrotizing enterocolitis undergoing ostomy closure from 1997 to 2009. Operative reports were independently scored for adhesions by 2 surgeons. RESULTS: Thirteen patients underwent EC (median, 39 days; range, 32-40), whereas 62 patients underwent LC (median, 94 days; range, 54 150). Adhesion formation in the EC group (10/13 patients, or 77%) was not significantly different (P = 1.000) from the LC group (47/59 patients, or 80%). No differences were found in the costs of hospital stay, surgical interventions, and outpatient clinic visits. CONCLUSIONS: Ostomy closure within 6 weeks of the initial procedure was not associated with more adhesions or with changes in direct medical costs. Therefore, after stabilization of the patient, ostomy closure can be considered within 6 weeks during the same admission as the initial laparotomy. PMID- 22498379 TI - HIV exposure does not worsen outcome in stage III necrotizing enterocolitis with current treatment protocols. AB - BACKGROUND/PURPOSE: The heavy burden of maternal HIV infection in developing countries such as South Africa has resulted in a high prevalence of premature birth and necrotizing enterocolitis (NEC). Uninfected infants born to HIV infected mothers also demonstrate immune deficiencies. It is, therefore, essential to have a better understanding of how to mitigate HIV as an independent risk factor for surgically treated NEC and to evaluate the relevant contributing factors in the presence of an aggressive strategy of pasteurized breast milk feeding and antiretroviral prophylaxis. METHODS: Infants with stage IIIb NEC presenting over a 4-year period were retrospectively reviewed. HIV-exposed infants were compared with non-HIV-exposed infants. Contributing factors were evaluated and studied by systematic statistical methods to evaluate risk. RESULTS: Twenty percent (17/87) infants were HIV-exposed, and 80% (70/87), unexposed, whereas a further 10 (total, n = 97) had unknown HIV exposure status. Demographics and other perinatal risk factors between the 2 groups were not significantly different other than that HIV-exposed infants received pasteurized breast milk and nonexposed infants received unpasteurized breast milk. There were no statistically significant differences between the groups with respect to disease presentation or severity, surgical findings or type of surgery, postoperative complications, survival, or timing of death. Trends toward higher antenatal steroid exposure and increased postoperative sepsis in the HIV-exposed group (P = .03) were noted but were not related. All HIV-exposed infants received antiretrovirals; there were no significant differences on subanalysis between different antiretroviral regimens. CONCLUSIONS: HIV-exposed infants do not have a more severe disease course nor more adverse outcomes in stage IIIb NEC than unexposed infants. Significant factors were antenatal steroids and post-NEC infective episodes. PMID- 22498380 TI - Surgeon volume trumps specialty: outcomes from 3596 pediatric cholecystectomies. AB - BACKGROUND: Laparoscopic cholecystectomy is the standard surgical management of biliary disease in children, but there has been a paucity of studies addressing outcomes after pediatric cholecystectomies, particularly on a national level. We conducted the first study to address the effect of surgeon specialty and volume on clinical and economic outcomes after pediatric cholecystectomies on a population level. METHODS: We conducted a retrospective cross-sectional study using the Health Care Utilization Project Nationwide Inpatient Sample. Children (<= 17 years) who underwent laparoscopic cholecystectomy from 2003 to 2007 were selected. Pediatric surgeons performed 90% or higher of their total cases in children. High-volume surgeons were in the top tertile (n >= 37 per year) of total cholecystectomies performed. chi(2), Analyses of variance, and multivariate linear and logistic regression analyses were used to assess in-hospital complications, median length of hospital stay (LOS), and total hospital costs (2007 dollars). RESULTS: A total of 3596 pediatric cholecystectomies were included. Low-volume surgeons had more complications, longer LOS, and higher costs than high-volume surgeons. After adjustment in multivariate regression, surgeon volume, but not specialty, was an independent predictor of LOS and cost. CONCLUSIONS: High-volume surgeons have better outcomes after pediatric cholecystectomy than low-volume surgeons. To optimize outcomes in children after cholecystectomy, surgeon volume and laparoscopic experience should be considered above surgeon specialty. PMID- 22498381 TI - Malignant pancreatic tumors in children: a single-institution series. AB - BACKGROUND: Pancreatic tumors in children represent a very rare entity. We reviewed the clinical and pathologic features of pediatric patients with pancreatic tumors at a single institution. METHODS: We conducted a retrospective review of cases diagnosed at the Hospital for Sick Children between 1986 and 2010. RESULTS: Twenty-seven patients were diagnosed during the study period: 18 with solid pseudopapillary neoplasm (SPN), 6 with pancreatic endocrine neoplasia, and 3 with other tumors. Of the 27 children, 3 had associated syndromes, in specific tuberous sclerosis, von Hippel-Lindau, and polycystic ovarian syndrome. The most common symptoms were pain and vomiting in SPN and hypoglycemia and seizures in insulinomas. Magnetic resonance imaging and computed tomographic scan were equally accurate in determining size and site of origin of the tumor, and both were better than ultrasound. All patients underwent surgery (distal pancreatectomy in 14 cases, Whipple procedure in 8, other procedures in 5), which represented the only treatment for all but 3 cases. Seventeen patients (94%) with SPN are alive (median follow-up, 32 months), 3 of whom had positive margins. Two patients died: 1 male with SPN with malignant transformation and 1 with fibrosarcoma. CONCLUSIONS: We describe the largest single-institution study of pediatric pancreatic tumors. Females with SPN have an excellent outcome, even in presence of positive margins, suggesting that limited surgical resection may be appropriate for these patients. PMID- 22498382 TI - Mesoportal bypass using a constructed saphenous vein graft for extrahepatic portal vein obstruction--technique, feasibility, and outcomes. AB - BACKGROUND: The internal jugular vein is routinely used as a graft for the Rex shunt. We analyzed results of mesoportal bypass using an alternative autologous graft. METHODS: Twenty-one children with extrahepatic portal vein obstruction were treated with a Rex shunt constructed using both greater saphenous veins. Follow-up included ultrasound and blood count screening at 3, 6, and 12 months and annually thereafter. RESULTS: Median age was 8.7 years (range, 3.6-14 years), and follow-up time, 5.3 years (range, 0.6-7.1 years). Occlusion or narrowing occurred in 6 patients after a median of 20 months (range, 2.6-52 months). In 2 cases, patency was restored, giving an overall success rate of 81%. During follow up, no variceal bleeding occurred while hemoglobin, platelet count, and leukocyte levels increased (P <= .02 for all) and spleen size decreased (P = .001). Patients with occlusive shunt complications weighed less (P = .01), had higher preoperative platelet levels (P = .02), and tended to have a smaller spleen preoperatively (P = .06) than patients without shunt complications. Cumulative graft patency at 6 months, 1 year, 3 years, and 5 years was 100%, 89%, 82%, and 74%, respectively. CONCLUSIONS: Rex shunt constructed using the greater saphenous veins is a valuable alternative to the internal jugular vein graft, allowing long term reversal of portal hypertension, splenomegaly, and hypersplenism. Low patient weight and high platelet count predicted shunt occlusion. PMID- 22498383 TI - Feasibility and safety of thoracoabdominal approach in children for resection of upper abdominal neuroblastoma. AB - BACKGROUND: A thoracoabdominal incision provides excellent exposure in the upper abdominal region. We present our experience with the use of this approach in children for resection of upper abdominal neuroblastoma. METHODS: Fifty-one of the 106 consecutive patients with abdominal neuroblastoma who underwent tumor resection using the thoracoabdominal approach between June 2006 and May 2011 were selected from the prospective database for this interim analysis. RESULTS: The median age was 3.1 years (range, 10 months-14 years), with 8 younger than 18 months and 22 younger than 4 years. Gross total resection was achieved in 44 patients. There were no major vascular injuries or perioperative mortality. Forty two patients could be extubated immediate postoperatively, whereas 9 were extubated within 24 hours. Good pain relief was achieved in all patients, and prolonged analgesia was not required in any patient. There were no pulmonary complications, and wound infection occurred in 2 patients. The 2-year local control was 92%. The 2-year survival for stages 1 and 2 is 100%, 71.6% for stage 3, and 40.4% for stage 4. CONCLUSION: The thoracoabdominal incision for difficult upper abdominal neuroblastoma is tolerated well in pediatric patients with no added morbidity. The enhanced exposure facilitates resection and improves local control. PMID- 22498385 TI - Propranolol treatment of infantile hemangioma: clinical and radiologic evaluations. AB - BACKGROUND: There is no way to predict the size that proliferative infantile hemangiomas (IHs) can reach and to expect the occurrence of complications. Moreover, there are no well-known characteristics that can affect the rate of involution of IHs and to predict its completion. Accordingly, intervention is frequently indicated. Different modalities have been reported for treatment of IHs. The possible mechanisms of action of propranolol on IHs are complex. METHODS: Fifty infants presented with 80 IHs treated by oral propranolol at a dose of 2 mg/kg body weight per day. Treatment outcomes were clinically and radiologically evaluated. RESULTS: The first noticeable effects on propranolol treatment were the changes in color and softening of IHs, followed by regression of their sizes. The clinically elicited color changes of superficial IHs and superficial components of compound IHs have been objectively proven by statistically significant color clearance (P <= .001) and resisting index (P <= .01) (~50% increase) as a good indicator of lower vascular activity within IHs. Moreover, the softening of lesions followed by the clinically elicited regression of sizes of deep IHs and deep components of compound IHs has been objectively proven by statistically significant changes at lesions' thickness (P <= .01) (~50% regression) and resisting index (P <= .01) (~50% increase). CONCLUSIONS: Collectively, high efficacy and tolerance of propranolol treatment have been elicited. However, propranolol treatment of IHs is still an issue suitable for more studies to confirm the safety and efficacy of the drug and to investigate whether there are some hemangiomas that are, perhaps, nonresponsive to propranolol treatment. PMID- 22498384 TI - Lymph node involvement in Wilms tumor: results from National Wilms Tumor Studies 4 and 5. AB - PURPOSE: The aim of the study was to determine the prognostic impact of lymph node (LN) involvement and sampling in patients with Wilms tumor (WT) and the minimum number of LNs needed for accurate staging. METHODS: We reviewed all patients with unilateral, nonmetastatic WT enrolled in the National Wilms Tumor Study 4 or 5. Data were abstracted on patient demographics, tumor histology, staging, number of LNs sampled, and disease-specific and overall patient outcomes. RESULTS: A total of 3409 patients had complete information on LN sampling. Five-year event-free survival (EFS) was lower in patients with nodal disease (P < .001); the effect of LN positivity was greater for patients with anaplastic (P = .047) than with favorable histology (P = .02). The likelihood of obtaining a positive LN was higher when sampling at least 7 LNs. However, after controlling for tumor histology and stage, the number of LNs sampled did not predict EFS variations (P = .75). Among patients with stage II disease, patients with LN sampling (P = .055) had improved EFS, largely reflecting poorer EFS in patients with anaplastic tumors (P = .03). CONCLUSIONS: Lymph node sampling is particularly important for patients with stage II anaplastic WT. Although the likelihood of finding a positive LN was greater when more than 7 LNs were sampled, EFS was not impacted by the number of LNs sampled. PMID- 22498386 TI - Pleomorphic adenoma of the salivary glands in children and adolescents. AB - BACKGROUND: Pleomorphic adenomas (PAs) of the salivary glands are rare in children and adolescents. We reviewed the clinical manifestations, pathologic features, treatment, and prognosis of salivary gland PA in 90 children and adolescents. METHODS: Clinical data including age, sex, location, symptoms, the period of evolution of the symptoms, pathologic type, and surgical treatment were evaluated. RESULTS: The median age was 16.5 years old. There was a 1.43:1 female to-male ratio. The parotid gland was the most commonly affected major gland (56.7%), and the palate, the most common site of minor salivary gland involvement. Ultrasonography and computed tomography were performed in most cases for diagnosis. Superficial parotidectomy or total parotidectomy with facial nerve dissection and preservation was the most common surgical procedure. Submandibular triangle dissection was applied to all submandibular PAs. Classic-type PA was the most common histologic subtype (43.3%). CONCLUSIONS: Salivary gland PAs in children and adolescents have different characteristics compared with their adult counterparts in regard to histologic subtype and location. Surgical removal is the best treatment option for PAs in children and adolescents. PMID- 22498387 TI - Spontaneous perforation of the colon and rectum complicating anorectal malformations in neonates. AB - BACKGROUND: Spontaneous perforation of the colon is a rare complication in neonates with anorectal malformations (ARMs). There are no detailed studies concerning this complication. MATERIALS AND METHODS: A retrospective review of hospital records between 1994 and 2010 revealed 8 cases of bowel perforation among 136 cases of ARM. Eighteen additional cases were culled from the literature by searching Pubmed, Indmed, Embase, and Google Scholar. RESULTS: Perforations occurred more commonly in males with ARM (85%). Low and high anomalies were equally affected. The median age at diagnosis was 48 hours. Pneumoscrotum and abdominal wall erythema were occasionally suggestive of perforation. In addition to the Rigler sign and collapsed bowel on plain radiographs, a newly described "rectal-tail sign" was useful in recognizing pneumoperitoneum in the lateral view invertogram. A lower midline incision offered optimal surgical access. Two distinct patterns of perforation were identified: type 1 (88%) occurred before surgical decompression of the obstructed colon, whereas type 2 (12%) occurred postoperatively. Type 1 cases were subdivided into cecal (type 1a, 16%), transverse colon (type 1b, 8%), rectosigmoid (type 1c, 60%), and miscellaneous (type 1d, 4%) perforations. Type 1a is best treated with cecostomy and distal colostomy; type 1b, with exteriorization of the perforation; and types 1c and 1d, with closure of the perforation and proximal colostomy. Dense fibrous adhesions caused by extravasated meconium posed technical difficulty during the definitive pull-through operation and was responsible for considerable morbidity. The overall mortality was 19%. CONCLUSIONS: Colorectal perforation is associated with considerable morbidity and mortality in neonates with ARM. Radiographs rather than clinical examination should be relied on for diagnosis of bowel perforation in ARM. Treatment options are chosen according to the subtype of perforation. Because most perforations occurred more than 24 hours after birth, early referral and surgical decompression of the colon may avoid this complication. PMID- 22498388 TI - Long-term testicular position and growth of acquired undescended testis after prepubertal orchidopexy. AB - PURPOSE: The aim of the study was to determine long-term testicular position and growth of acquired undescended testis (UDT) after prepubertal orchidopexy. METHODS: Patients who had undergone prepubertal orchidopexy for acquired UDT at our hospital between 1986 and 1999 were recruited to assess long-term testicular position and volume. Testis position was assessed by physical examination. Testis volume was measured with Prader orchidometry and ultrasound and was compared with normative values reported in the literature. RESULTS: A total of 105 patients (aged 14.0-31.6 years) were included with 137 acquired UDT (32 bilateral, 33 left sided, and 40 right sided). All but 1 of the orchidopexied testes (99.3%) were in low scrotal position. The mean volume of the orchidopexied testes in unilateral UDT (n = 73, 10.57 +/- 3.74 mL) differed significantly from the size of the testes at the contralateral side (14.11 +/- 4.23 mL) (P = .000). The operated testes (10.28 +/- 3.45 mL) were smaller than the mean adult testis volume reported in the literature (13.4-13.6 mL; cutoff, 13.2 mL). CONCLUSION: Testis position after prepubertal orchidopexy for acquired UDT was nearly always low scrotal. The volume of the orchidopexied testes was smaller than both the volume of the contralateral testes and the normative values reported in the literature. PMID- 22498389 TI - Inhaled hydrogen gas therapy for prevention of testicular ischemia/reperfusion injury in rats. AB - PURPOSE: This study evaluated whether 2% hydrogen (H(2)) gas therapy protects against testicular ischemia/reperfusion injury which results in increased formation of reactive oxygen species and/or reactive nitrogen species, leading to testicular apoptosis and impaired spermatogenesis. METHODS: Pubertal six-week-old Spraque-Dawley rats were assigned to 5 groups (10 animals/group) as follows: group A was a sham operated group; groups B, C, D, and E underwent 5 hours of left testicular ischemia followed by 0, 30, 60, and 120 minutes of 2% H(2) gas therapy, respectively. Histological analysis was performed to verify structure and morphology of the testes and to investigate Johnsen scores, mean seminiferous tubule diameter, and the number of germ cell layers to classify spermatogenesis. Germ cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and Bax/Bcl-2 ratio real-time polymerase chain reaction. We also investigated malondialdehyde levels as an indicator of lipid peroxidation. RESULTS: Compared to the sham group (A), germ cell apoptosis and lipid peroxidation in the ischemia group (B) were significantly increased with abnormal morphology and impaired spermatogenesis. In contrast, amelioration of testicular damages was evident in the H(2) therapy groups (C, D, and E). CONCLUSIONS: Our results showed that inhalation of 2% H(2) gas may be a promising therapy with anti-apoptotic and anti-oxidant properties in cases of testicular ischemia/reperfusion injury. PMID- 22498390 TI - The long-term protective effects of short-interval postconditioning in testicular ischemia-reperfusion injury in rats. AB - AIM: Even with prompt diagnosis and treatment, testicular torsion may lead to infertility and atrophy after testicular salvage. The aims of this study were to investigate the long-term protective effects of short-interval postconditioning on testicular atrophy and to optimize the reperfusion period. MATERIALS AND METHODS: Forty adult male rats were divided into 5 subgroups: sham operated; torsion + detorsion; torsion + postconditioning, 5 seconds (PC5); torsion + postconditioning, 10 seconds; and torsion + postconditioning, 20 seconds. Torsion was created by rotating the left testis 1080 degrees counterclockwise and then fixing the testis to the scrotum with 3 sutures. Torsion was maintained for 4 hours. The testicular artery was visualized, and an atraumatic vascular clamp was applied to prevent reperfusion in all study groups. Detorsion of the testis was then performed. In the torsion + detorsion group, the clamp was released just after detorsion. In all the other intervention groups, the subsequent procedures were repeated 10 times. In the PC5 group, the clamp was released for 5 seconds and applied for 10 seconds; in the torsion + postconditioning, 10 seconds group, the clamp was released for 10 seconds and applied for 10 seconds; and in the torsion + postconditioning, 20 seconds group, the clamp was released for 20 seconds and applied for 10 seconds. Then, reperfusion was allowed. After 60 days, rats in all study groups were killed, both testes were removed, and the histopathology was evaluated. The chi(2) test was used for statistical analysis. RESULTS: Compared with the other groups, the extent of tissue injury determined by histopathologic grades according to Cosentino et al (J Androl. 1986;7:23-31) was significantly less in group PC5 (P < .05). CONCLUSION: We conclude that short interval postconditioning can protect against long-term testicular reperfusion injury. Furthermore, the optimal time for reperfusion during postconditioning was 5 seconds in our rat model of testicular torsion. This technique seems easily applicable, and evidence suggests that similar techniques may be useful during testicular surgery. PMID- 22498391 TI - Mental health and quality of life after feminizing genitoplasty. AB - PURPOSE: The aim of the study was to evaluate mental health and quality of life (QoL) aspects in women operated on because of disorders of sexual differentiation (DSDs) in childhood. METHODS: Questionnaires were mailed to 45 women older than 15 years who had been operated on because of DSD, of which 24 patients (53%) responded. Of these, 16 had been prenatally exposed to androgens. Eight females had 46,XY karyotype. Mental health was measured with the 90-item Symptom Checklist, QoL with the 20-item Life Situation Survey questionnaire, and health related QoL (HRQoL) with the 15D questionnaire. RESULTS: The QoL and HRQoL scores appeared normal in most of the patients. Furthermore, mental health of the patients was similar or better compared with previously published scores of a Finnish community sample in all dimensions (somatization, obsessive compulsivity, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism). However, 5 patients had poorer scores in some of the 3 questionnaires. These 5 had either distressful memories because of a too-late operation, the operative treatment itself, or current poor sexual function. CONCLUSIONS: The QoL, HRQoL, and overall mental health of female patients with DSD are usually normal. PMID- 22498392 TI - Nonobstructive urinary tract dilatation in children with diabetes insipidus. AB - We report 4 boys with diabetes insipidus associated with renal impairment and hydroureteronephrosis. The high flow states caused the bladder to become trabeculated in the absence of infravesical obstruction. Urodynamics have shown the bladder itself to be compliant, but drainage is poor leading to further renal impairment and overflow incontinence. All 4 boys have been managed with cystostomy button drainage and have done well on close follow-up. PMID- 22498393 TI - Foreskin preputioplasty and intralesional triamcinolone: a valid alternative to circumcision for balanitis xerotica obliterans. AB - BACKGROUND: We previously reported our short-term experience of foreskin preputioplasty as an alternative to circumcision for the treatment of foreskin balanitis xerotica obliterans (BXO). In this study, we aimed to compare this technique with circumcision over a longer period. METHODS: Between 2002 and 2007, boys requiring surgery for BXO were offered either foreskin preputioplasty or primary circumcision. The preputioplasty technique involved triradiate preputial incisions and injection of triamcinolone intralesionally. Retrospective case-note analysis was performed to identify patient demographics, symptoms, and outcomes. RESULTS: One hundred thirty-six boys underwent primary surgery for histologically confirmed BXO. One hundred four boys opted for foreskin preputioplasty, and 32, for circumcision. At a median follow-up of 14 months (interquartile range, 2.5 17.8), 84 (81%) of 104 in the preputioplasty group had a fully retractile and no macroscopic evidence of BXO. Of 104, 14 (13%) developed recurrent symptoms/BXO requiring circumcision or repeat foreskin preputioplasty. In the circumcision group, 23 (72%) of 32 had no macroscopic evidence of BXO. The incidence of meatal stenosis was significantly less in the foreskin preputioplasty group, 6 (6%) of 104 vs 6 (19%) of 32 (P = .034). CONCLUSION: Our results show a good outcome for most boys undergoing foreskin preputioplasty and intralesional triamcinolone for BXO. There is a small risk of recurrent BXO, but rates of meatal stenosis may be reduced. PMID- 22498394 TI - Role of trace elements in parenteral nutrition support of the surgical neonate. AB - BACKGROUND: Parenteral nutrition (PN) has transformed the outcome for neonates with surgical problems in the intensive care unit. Trace element supplementation in PN is a standard practice in many neonatal intensive care units. However, many of these elements are contaminants in PN solutions, and contamination levels may, in themselves, be sufficient for normal metabolic needs. Additional supplementation may actually lead to toxicity in neonates whose requirements are small. METHODS: An electronic search of the MEDLINE, Cochrane Collaboration, and SCOPUS English language medical databases was performed for the key words "trace elements," "micro-nutrients," and "parenteral nutrition additives." Studies were categorized based on levels of evidence offered, with randomized controlled trials and meta-analyses accorded the greatest importance at the apex of the data pool and case reports and animal experiments the least importance. Articles were reviewed with the primary goal of developing uniform recommendations for trace element supplementation in the surgical neonate. The secondary goals were to review the physiologic role, metabolic demands, requirements, losses, deficiency syndromes, and toxicity symptoms associated with zinc, copper, chromium, selenium, manganese, and molybdenum supplementation in PN. RESULTS: Zinc supplementation must begin at initiation of PN. All other trace elements can be added to PN 2 to 4 weeks after initiation. Copper and manganese need to be withheld if the neonate develops PN-associated liver disease. The status of chromium supplementation is currently being actively debated, with contaminant levels in PN being sufficient in most cases to meet neonatal requirements. Selenium is an important component of antioxidant enzymes with a role in the pathogenesis of neonatal surgical conditions such as necrotizing enterocolitis and bronchopulmonary dysplasia. Premature infants are often selenium deficient, and early supplementation has shown a reduction in sepsis events in this age group. CONCLUSION: Appropriate supplementation of trace elements in surgical infants is important, and levels should be monitored. In certain settings, it may be more appropriate to individualize trace element supplementation based on the predetermined physiologic need rather than using bundled packages of trace elements as is the current norm. Balance studies of trace element requirements should be performed to better establish clinical recommendations for optimal trace element dosing in the neonatal surgical population. PMID- 22498395 TI - A review of pathophysiology and management of fetuses and neonates with meconium ileus for the pediatric surgeon. AB - PURPOSE: Meconium ileus (MI) is the earliest clinical manifestation of cystic fibrosis (CF), occurring in up to 20% of patients with CF. Our aim was to review and integrate current knowledge about the diagnosis and management of fetuses and neonates with MI that may aid the pediatric surgeon in caring for these patients. METHODS: We identified areas of interest including pathophysiology, prenatal diagnosis, nonoperative and operative management, postoperative management, and prognosis. We performed a Medline search using the search term meconium ileus for English language articles published in the last 20 years. We reviewed reference lists to identify other articles of historical significance. RESULTS: Meconium ileus is primarily associated with CF transmembrane (conductance) regulator mutations F508del, G542X, W1282X, R553X, and G551D, and modifier genes have been found to explain approximately 17% of the phenotypic variability. Mouse, pig, and ferret models for CF demonstrate neonatal bowel obstruction mimicking MI. Sonographic findings of hyperechoic masses and dilated bowel in a high-risk fetus are suggestive of MI. Less than 7% of low-risk fetuses with hyperechoic bowel will have MI. Contemporary series of noninvasive management with Gastrografin enema report success rates of 36% to 39%, significantly lower than historical values. The optimal surgical technique remains controversial, although primary anastomosis results in surgical complication rates between 21% and 31%, higher than those noted with delayed anastomosis. Pulmonary function for patients with CF and MI at 15 and 25 years old is similar to those without MI, although height and weight percentiles may be lower. CONCLUSIONS: This review for pediatric surgeons presents an examination of the literature and synthesizes current information about the pathophysiology, prenatal diagnosis, nonoperative and operative management, postoperative management, and prognosis of the patient with CF and MI. PMID- 22498396 TI - Unusual cases: melanomatosis and nephroblastomatosis treated with hyperthermic intraperitoneal chemotherapy. AB - Hyperthermic intraperitoneal chemotherapy (HIPEC) is a well-established therapy for carcinomas, mesotheliomas, and some sarcomas. However, HIPEC has not been reported in melanomatosis or nephroblastomatosis. Here we present 2 unique cases of cytoreductive surgery and HIPEC. Cytoreductive surgery followed by HIPEC was performed in a 4-year old with melanomatosis and a 12-year old with nephroblastomatosis. A 4-year-old girl presented with leptomeningeal melanoma that metastasized from a congenital nevus. She had a ventricular peritoneal shunt placed as an infant. Melanomatosis involving the meninges and peritoneal surfaces was identified by positron emission tomographic scan imaging. Extensive plaques of melanoma were removed at the time of surgery, followed by HIPEC. She had no significant postoperative complications. Her abdomen remained free of disease 7 months after treatment. A 13-year-old girl presented with a Wilms' tumor at age 10 years. She then presented to us at the second local recurrence with multiple intraabdominal tumor implants (ie, nephroblastomatosis). We performed cytoreductive surgery followed by HIPEC. She had no postoperative complications and, at 1 year post-HIPEC, had no abdominal recurrence. We conclude that HIPEC can be performed safely for rare diseases such as melanomatosis and nephroblastomatosis. Although abdominal disease control can be realized, further systemic treatment options are necessary. A review of indications for HIPEC is included. PMID- 22498397 TI - Transluminal migration of ingested foreign body without peritonitis. AB - The authors present 2 cases of transluminal migration of an ingested foreign body into the peritoneal cavity without causing peritonitis. Clinical and radiologic features and surgical approach are described, focusing on the absence of an acute abdomen in transluminal migration and the use of laparoscopy in achieving extraction of the foreign object. PMID- 22498398 TI - Late volvulus of an intrathoracic gastric pull-up. AB - Although volvulus of a gastric pull-up may acutely result from iatrogenic twist at the time of gastric transposition, we have recently encountered a patient in whom a gastric volvulus developed in the late postoperative period, resulting in gastric outlet obstruction. The perioperative evaluation and operative management are discussed. PMID- 22498399 TI - Torsed reactive nodular fibrous pseudotumor in an adolescent: case report and review of the literature. AB - We describe a case of a 13-year-old girl presenting with acute abdominal pain and imaging suggesting acute appendicitis. Upon laparoscopy, she was found to have a mass attached to the jejunum that had torsed upon its blood supply. On histopathologic studies, the mass was determined to be a reactive nodular fibrous pseudotumor. This lesion is a benign neoplasm that may arise from the gastrointestinal tract and has only been recently described in the literature. Our case is unique because it is the first report of reactive nodular fibrous pseudotumor presenting as a torsed polypoid lesion and the first arising in an adolescent. PMID- 22498400 TI - Undiagnosed ureteroinguinal hernia with solitary kidney in a child with ureteric injury during herniotomy. AB - Iatrogenic ureteric injuries are an uncommon but difficult problem to manage. Although ureteric injury has been reported during hernia surgery in adults, it has not been reported in children during herniotomy. An 18-month-old male child underwent repair of an inguinal hernia and developed postoperative anuria. Investigations revealed that the patient had a solitary kidney and had injury to the solitary ureter. We successfully managed this patient using the vermiform appendix to replace a segment of the injured ureter. The possible mechanism of injury and the relevant literature are discussed. PMID- 22498401 TI - Endoscopic specimen pouch technique for removal of giant fibroadenomas of the breast. AB - Giant (juvenile or cellular) fibroadenoma of the breast is the most common tumor that present in adolescent girls. As benign tumors that can exceed 10 cm in diameter, giant fibroadenomas have historically necessitated large incisions to remove these masses, resulting in large unsightly scars. We describe the novel use of an endoscopic specimen pouch to facilitate the removal of these large tumors through minimal incisions in 3 patients. In follow-up, all 3 patients have had excellent cosmetic outcomes, no recurrences, and no postoperative complications. PMID- 22498402 TI - Fournier's gangrene in a child with congenital genitourinary anomalies. AB - Fournier's gangrene is a rare urologic emergency in childhood that requires prompt diagnosis to deliver definitive and supportive care. Host susceptibility risk factors differ between adult and pediatric age groups with affected children usually otherwise systemically healthy. We present a case of Fournier's gangrene in a 2-year-old, from a genitourinary source of sepsis secondary to previously unreported genitourinary anatomical anomalies of congenital buried penis and hypospadias. Illustrative applied anatomy identifies the pathogenesis of this case, aiding recognition and understanding of this rapidly progressive and destructive pathology. PMID- 22498403 TI - A novel technique of permanent self-catheterizable feeding jejunostomy. AB - Long-term/permanent jejunal feeding in children and adults is prone to significant complications, such as leakage, skin excoriation, and difficulty in reinsertion after dislodgement of the jejunostomy tube. Our innovative jejunostomy technique uses a pedicle segment of jejunum, which is retubularized using the principle of Monti. The jejunal segment is reinserted through a submucosal tunnel back into the jejunum. The other end is brought out onto the abdominal wall. The technique achieves a continent catheterizable jejunal stoma for enteral feeding. PMID- 22498404 TI - Laparoscopic rectal pull-through for persistent cloaca: an easier approach for a complex anomaly. AB - AIM: The aim of this study was to describe the surgical technique and initial outcomes of laparoscopic-assisted anorectal pull-through for persistent cloaca. MATERIALS AND METHODS: From January 2008 to June 2010, laparoscopic-assisted rectal pull-through was performed for 10 patients with persistent cloaca. The patient ages ranged from 3 to 9 months. The operation was carried out using 4 trocars. CO(2) pressure was maintained between 8 and 12 mm Hg. RESULTS: Laparoscopic-assisted rectal pull-through was successfully performed in all patients. Operative time ranged from 80 to 120 minutes (mean, 91.5 +/- 10 minutes). There were no intraoperative or postoperative deaths or complications. The mean hospital stay was 4.4 +/- 0.5 days (range, 4-5 days). The length of follow-up varied from 6 to 24 months (mean, 12.9 +/- 5.7 months) in all 10 patients. Anal stenosis was not observed in any patient. Seven patients had 1 to 2 stools per day, 2 patients had 3 stools per day, and 1 patient had 1 stool every 2 days. No patient had fecal incontinence. CONCLUSION: Laparoscopic rectal pull-through is a feasible, effective, and less traumatic approach for anorectoplasty in patients with persistent cloaca. PMID- 22498405 TI - Hepatocellular carcinoma in an infant with biliary atresia younger than 1 year. PMID- 22498406 TI - We read with interest the article by Shimotakahara et al. PMID- 22498408 TI - Congenital infantile fibrosarcoma in a very low-birth-weight infant. AB - We describe a prenatally diagnosed case with congenital infantile fibrosarcoma, which is a rare malignant tumor, of which there have been only 14 cases reported in the English literature. A giant mass on the left thigh was detected at 24 weeks' gestation by prenatal ultrasonography. Because of its rapid growth and nonreassuring fetal status in utero, the baby was delivered by cesarean delivery at 27 weeks' gestation. The case was complicated by hemorrhagic anemia, coagulopathy, and cardiac failure, and a tumor resection was performed on day 3. As of age 2.5 years, he was healthy without evidence of recurrence. Because some fetal cases with congenital infantile fibrosarcoma have a poor prognosis, termination of pregnancy at an appropriate time and postnatal early treatment are crucial for successful treatment. PMID- 22498409 TI - Laparoscopic-assisted perineal pull-through vaginoplasty. AB - Hematometrocolpos is the result of vaginal obstruction and can become an emergency in the pubertal period. The treatment of imperforate hymen is well defined, but the treatment of vaginal atresia is more complex. We report a case of hematometrocolpos secondary to distal vaginal atresia that was operated on in the pubertal period. The patient had isolated distal atresia without persistence of the urogenital sinus. A combined abdominal laparoscopic and perineal approach and a posterior vaginoplasty were carried out. Finally, an abdominoperineal pull through was successfully performed. Neovagina was successfully developed with this method. The embryology and literature are reviewed. The classification, indications, and surgical technique are discussed. We suggest that this procedure is suitable for patients with vaginal agenesis and a normal uterus. PMID- 22498410 TI - Swyer-James-MacLeod syndrome in a surgically treated child: a case report and brief literature review. AB - Swyer-James-Macleod syndrome (SJMS) is a rare, complex disease characterized by unilateral hyperlucent lung or lobe owing to loss of pulmonary vasculature and alveolar hyperdistention. Treatment is generally conservative, and surgical management is rare. In fact, only 4 reports on surgically treated children with SJMS are available in the literature. We describe an 8-year-old patient with a history of recurrent respiratory infections since 2 months old. The patient presented with cough and dyspnea on effort. Chest radiograph showed hyperlucency and reduction of the right lung. Computed tomography revealed reduced volume and vasculature in the right lung, whereas pulmonary scintigraphy showed that 85% of ventilation and perfusion occurred in the left lung. Pulmonary function tests showed a forced expiratory volume in 1 second of 0.85 L (56% of expected value) and a forced vital capacity of 1.20 L (70% of expected value). The child underwent right pneumonectomy because of severe compromise of pulmonary function and recurrent respiratory infections. Histologic examination revealed panacinar emphysema and chronic bronchitis/bronchiolitis. At 6-month follow-up, the child showed improved symptoms and a forced expiratory volume in 1 second of 1.15 L (77% of expected value) and a forced vital capacity of 1.4 L (83% of expected value). This report shows that although rarely indicated, surgical treatment can improve quality of life and pulmonary function in SJMS. PMID- 22498411 TI - Hemopneumothorax caused by vascularized bullae and a pulmonary hemangioma in an adolescent boy. AB - Spontaneous hemopneumothorax is a rare, potentially life-threatening condition occurring in adolescence. In general, spontaneous hemopneumothorax has not been associated with other pulmonary vascular malformations in adolescents. We present a case of a 17-year-old adolescent boy with hemopneumothorax from vascularized pleural blebs who was also noted to have a pulmonary hemangioma. PMID- 22498412 TI - Laparoscopic ureteroureterostomy in children with a duplex collecting system plus obstructed ureteral ectopia. AB - One of the complex upper urinary tract anomalies is a duplicated collecting system. In cases with a functioning upper moiety, ureteroureterostomy (UU) is the preferred operation to redirect the urine to the normal collecting system. Although open UU is a well-described operation, experience with laparoscopic repair pediatric patients is scarce. We describe the successful application of laparoscopic UU in 2 children and suggest that laparoscopic UU for the duplicated collecting system is a promising minimally invasive procedure. PMID- 22498413 TI - Schwannoma of the diaphragm--a pediatric case report and review of the literature. AB - Diaphragmatic tumors are uncommon and difficult to diagnose in the pediatric population. Schwannoma is a benign, slow-growing peripheral nerve sheath tumor that is most commonly associated with the extremities in childhood. We herein report a schwannoma of the diaphragm in a pediatric patient and review the pediatric literature. PMID- 22498414 TI - Meconium pseudocyst with particular pathologic findings: a case report and review of the literature. AB - Meconium peritonitis is a sterile chemical peritonitis caused by bowel perforation with intraperitoneal extravasation of the meconium in utero. When the inflamed intestinal loops become fixed, meconium peritonitis leads to a cystic cavity with a fibrous wall, and the result is termed cystic-type meconium peritonitis. On the contrary, a meconium pseudocyst has a muscle layer continuous with the normal intestine and is distinguished from cystic-type meconium peritonitis based on the histopathologic findings. This report describes the rare case of a neonate complicated by a meconium pseudocyst, which was successfully treated with 1-stage resection and primary anastomosis. There have been few cases of meconium pseudocysts reported in the literature. Meconium peritonitis should be considered in the differential diagnosis in patients who develop large abdominal cysts with air and fluid content. Cystic-type meconium peritonitis is usually treated using drainage with subsequent elective surgery. However, for a meconium pseudocyst, 1-stage intestinal resection with primary anastomosis may be recommended. A meconium pseudocyst may be treatable using 1-stage resection based on histopathologic features. PMID- 22498415 TI - Clinical implication of right bundle branch block in hospitalized patients with acute heart failure: data from the Korean Heart Failure (KorHF) Registry. PMID- 22498416 TI - Pseudoaneurysm of the mitral-aortic intervalvular fibrosa. AB - Pseudoaneurysm of the mitral-aortic intervalvular fibrosa (P-MAIVF) is a rare but potentially fatal complication of infective endocarditis and aortic valve surgery. 149 patients with P-MAIVF, including 7 cases in our hospital and 142 cases from the literatures, were comprehensively analyzed. P-MAIVF is located in the mitral-aortic intervalvular fibrosa area, which communicates with the left ventricular outflow tract. The cavity of P-MAIVF expands during systole and collapses during diastole. Endocarditis and aortic valve surgery are the most frequent causes. Symptoms of endocarditis, chest pain, heart failure, dyspnea, cerebrovascular accidents and systemic embolism are important clinical presentations. The formation of a fistulous tract, coronary artery compression, and rupture into pericardium are important complications. Transesophageal echocardiography is superior to transthoracic echocardiography in identifying P MAIVF. Surgery is the treatment of choice with P-MAIVF repair and aortic valve replacement. PMID- 22498417 TI - Serial cardiac imaging in peripartum cardiomyopathy. PMID- 22498418 TI - Alstrom syndrome: cardiac magnetic resonance findings. AB - BACKGROUND: Alstrom Syndrome (ALMS) is an extremely rare multiorgan disease caused by mutations in ALMS1. Dilated cardiomyopathy (DCM) is a common finding but only one series has been investigated by Cardiac Magnetic Resonance (CMR). METHODS: Eight genetically proven ALMS patients (ages 11-41) underwent CMR performed by standard cine steady state, T1, T2 and late gadolinium enhancement (LGE) sequences. Ejection fraction (EF), Diastolic Volume (EDV) and Systolic Volume normalized for body surface area (ESV), and mass indices were determined, as well as EDV/Mass ratio, an index expressing the adequacy of cardiac mass to heart volume. Regional fibrosis was assessed by LGE; diffuse fibrosis was measured by a TI scout sequence acquired at 5, 10 and 15 min after gadolinium by comparing inversion time values (TI) at null time in ALMS and control group. RESULTS: In one patient severe DCM was present with diffuse LGE. There were seven cases without clinical DCM. In these patients, EF was at lower normal limits or slightly reduced and ESV index increased; six patients had decreased mass index and EDV/Mass ratio. Mild regional non ischemic fibrosis was detected by LGE in three cases; diffuse fibrosis was observed in all cases, as demonstrated by shorter TI values in ALMS in comparison with controls (5 min: 152 +/- 12 vs 186 +/- 16, p 0.0002; 10 min: 175 +/- 8 vs 204 +/- 18, p 0.0012; 15 min: 193 +/- 9 vs 224 +/- 16, p 0.0002). CONCLUSIONS: Cardiac involvement in ALMS is characterized by progressive DCM, associated with systolic dysfunction, myocardial fibrosis and reduced myocardial mass. PMID- 22498419 TI - Association between gamma-glutamyltransferase and coronary artery calcification. AB - BACKGROUND: The exact mechanisms behind the association between atherosclerosis and gamma-glutamyltransferase (GGT) are unclear. Coronary artery calcification (CAC) detected by computerized tomography is an important marker of atherosclerosis and its severity correlates with coronary plaque burden. The aim of this study was to investigate if serum GGT levels are associated with CAC in patients without known coronary heart disease (CHD) who had low-intermediate risk for CHD. METHODS: Two hundred and seventy two patients who had low-intermediate risk for coronary artery disease were included in the study. Serum GGT levels were measured spectrophotometrically. CACS (Agatston method) were performed using a 64-slice computerized tomography scanner. The patients were grouped according to their GGT values in four quartiles. RESULTS: Patients in higher GGT quartiles had elevated CAC score (P<0.001). Patients in higher GGT quartiles were predominantly males (P<0.001) and were more likely to be smoking (P=0.004), and have elevated uric acid (P<0.001), fasting blood glucose (P<0.001), CRP levels (P=0.003) and 10-year total cardiovascular risk (P=0.007) and low HDL levels (P<0.001). Positive correlations were found between log GGT and CAC (r=0.233, P<0.001). In the multivariate analysis GGT, age, smoking and serum uric acid levels appeared as independent factors predictive of presence of CAC. CONCLUSIONS: We demonstrated a significant correlation between serum GGT levels and CAC and CHD risk factors. Serum GGT level was an independent marker of CAC. PMID- 22498420 TI - Incidence, treatment and outcome of acute coronary syndromes: a community-based study in the era of myocardial infarction networks. PMID- 22498421 TI - Endothelial dysfunction predicts regression of hypertensive cardiac mass. AB - BACKGROUND: Subclinical organ damage is a condition with an increased risk for fatal and nonfatal cardiovascular events. Particularly, endothelial dysfunction and left ventricular mass (LVM) are recognized as independent predictors of cardiovascular events in hypertensive patients. Besides, LVM in hypertensives is inversely related to forearm blood flow (FBF) responses to the endothelium dependent vasodilating agent. We evaluated the role of endothelium-dependent vasodilation in the progression/regression of LVM in a group of hypertensive subjects. METHODS: We enrolled 170 hypertensive outpatients (88 men, 92 women; age 47 +/- 11 years). LVM was calculated with the Devereux formula and indexed by surface area (LVMI). Endothelium-dependent vasodilation was investigated by intra arterial infusions of acetylcholine (ACh). RESULTS: During the follow-up blood pressure (BP) decreased from 150/91 +/- 17/11 to 135/80 +/- 14/9 mm Hg (P=0.0001), and LVMI from 120 +/- 28 to 118 +/- 28 g/m(2) (P=0.194). The mean annual rate of variation of LVMI was -0.38 +/- 3.9 g/m(2), which was not statistically different in men and women. It was correlated with baseline ACh stimulated FBF (r=-0.272, P=0.0001) and BMI (r=0.164, P=0.016). At multivariate analysis, FBF was the only baseline covariate that remained significantly associated with LVMI variation, also after correction for antihypertensive treatment and BP reduction. The interaction between baseline LVM and ACh stimulated FBF was investigated in a multiple linear regression model showing that a fixed reduction in ACh-stimulated FBF (100%) induces different variation of annual rate of LVMI at different levels of baseline LVM. CONCLUSIONS: Our data demonstrate, for the first time, the role of endothelial function in the progression/regression of LVMI, independently of traditional cardiovascular risk factors and antihypertensive therapy. PMID- 22498422 TI - Exercise training plays cardioprotection through the oxidative stress reduction in obese rats submitted to myocardial infarction. PMID- 22498423 TI - Phytoremediation potential of duckweed (Lemna minor L.) in degradation of C.I. Acid Blue 92: artificial neural network modeling. AB - In present study, the potential of duckweed (Lemna minor L.) for degradation of an azo dye C.I. Acid Blue 92 (AB92) has been investigated. The effect of operational parameters such as initial dye concentration, pH, temperature and amount of plant on the efficiency of biological decolorization process was determined. The reusability of Lemna minor L. in long term repetitive operations was also examined. Growth and some biochemical parameters (photosynthetic pigments content, superoxide dismutase, catalase and peroxidase activity) were used to detect the toxic effects of AB92 on duckweed plant. The biological degradation compounds formed in the present process were analyzed by GC-MS technique. In addition, an artificial neural network (ANN) model was expanded to predict the biological decolorization efficiency. The obtained data indicated that ANN provide realistic predictive performance (R(2)=0.954). PMID- 22498424 TI - Assessment of metal bioavailability in smelter-contaminated soil before and after lime amendment. AB - In this study, changes in bioavailable concentrations of Pb, Zn, Cu and As in former smelter site soils (J1 and J2) were investigated before and after lime amendment. The immobilization efficiencies of metal(loid)s were evaluated by Toxicity Characteristic Leaching Procedure (TCLP). Their bioavailable concentrations in the soils were evaluated by the acid-extractable and -reducible fractions in Standard Measurement and Testing Program (i.e., SM&T(I+II)), in vitro physiologically based extraction test (PBET) and diffusive gradients in thin-films (DGT). The results showed that the bioavailable concentrations remarkably decreased after lime amendment in both J1 and J2 soils. DGT uptake and resupply (R) of Zn, Cu and As from soil to soil solution increased but that of Pb decreased. This pattern was consistent with SM&T(I+II)- and PBET-extractable concentrations after lime amendment. This indicates that lime amendment is highly effective for the immobilization of Zn, Cu and As, but not for Pb. Our results implicate that DGT can be used to estimate bioavailability of metal(loid)s in soils and further extended to estimate risk reduction after soil remediation. PMID- 22498425 TI - Explaining poorer stroke outcomes in women: women surviving 3 months have more severe strokes than men despite a lower 3-month case fatality. AB - BACKGROUND: Women who survive stroke are more disabled and more often institutionalized than men. OBJECTIVE: We explore this phenomenon by studying case fatality and stroke severity in stroke survivors separately for men and women. METHODS: A Danish stroke registry (2000-2007) contains information about 26,818 patients with first-ever ischemic stroke, including stroke severity (Scandinavian Stroke Scale, 0 worst to 58 best), computed tomography scan, cardiovascular risk factors, and death 3 months after stroke. We modeled stroke severity by generalized additive linear model and 3-month case fatality with logistic model adjusting for age and cardiovascular risk factors. RESULTS: Male to female ratio was 51.5% to 48.5%. Mean age was 68.8 (SD 12.6) years in men; 73.7 (13.8) years in women. Stroke was more severe in women (mean [SD] Scandinavian Stroke Scale, 42.2 [16.0]) than in men (mean [SD] Scandinavian Stroke Scale, 45.6 [14.2]) also after adjustment for age and cardiovascular risk factors; significant in patients older than 75 years. In survivors at 3 months, stroke was more severe in women than men, given same age and cardiovascular risk factor profile; significant in patients older than 75 years. More women (11.9%) had died within 3 months than men (8.6%). However, adjusting for age, stroke severity, and risk factor profile, 3-month case fatality was lower in women than men; significant in patients older than 78 years. CONCLUSIONS: Although 3-month case fatality was lower in women than men, strokes were more severe among survivors at 3 months in women than in men. In addition, strokes were more severe in women. Our data help elucidate why women survive stroke better but have poorer functional outcomes that require more care than men. PMID- 22498427 TI - Clinical outcomes of congenital diaphragmatic hernia without extracorporeal membrane oxygenation. AB - BACKGROUND: Neonatal extracorporeal membrane oxygenation (ECMO) is not available in Hong Kong. OBJECTIVES: To document the survival of neonates with symptomatic congenital diaphragmatic hernia at birth, but without access to ECMO. METHODS: Twenty-two patients diagnosed to have CDH within a ten year period (1999-2009) at Prince of Wales Hospital were systematically reviewed. CDH patients who presented after the neonatal period were excluded. RESULTS: There were 17 neonates with symptomatic CDH at birth and the overall survival, including infants with multiple anomalies, was 14/17 (82%). 6 of 17 (35%) infants met the ECMO criteria and the survival rate for these serious cases was 4/6 (67%). CONCLUSIONS: Our results are comparable with centers which provide ECMO and suggest that there may be only marginal benefit for using ECMO to improve survival. A territory-wide registry for documenting risk factors and outcomes would be important, especially in light of improving neonatal intensive care and survival. PMID- 22498426 TI - Agonistic autoantibodies to the angiotensin II type I receptor cause pathophysiologic characteristics of preeclampsia. AB - BACKGROUND: Preeclampsia (PE), new-onset hypertension with proteinuria during pregnancy, is associated with increased reactive oxygen species, the vasoactive peptide endothelin-1 (ET-1), T and B lymphocytes, soluble antiangiogenic factors sFlt-1 and sEndoglin (sFlt-1 and sEng), and agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA). OBJECTIVES: One important area of investigation for our laboratory was to determine what role AT1-AA plays in the pathophysiology associated with PE. METHODS: To achieve this goal, we examined the effect of AT1-AA suppression on hypertension in response to placental ischemia as well as the effect of AT1-AA on increased blood pressure, ET-1, reactive oxygen species, and sFlt-1 in normal pregnant rats (NP). RESULTS: We demonstrated reductions in uterine perfusion pressure (RUPP) to be a stimulus for AT1-AA during pregnancy. We utilized the technique of B-cell depletion to suppress circulating AT1-AA in RUPP rats and found that AT1-AA suppression in RUPP rats was associated with lower blood pressure and ET-1 activation. To determine a role for AT1-AA to mediate hypertension during pregnancy, we infused purified rat AT1-AA (1:50) into NP rats, and analyzed blood pressure and soluble factors. We consistently found that AT1-AA infused rats had significantly increased AT1-AA and blood pressure above NP rats. This hypertension was associated with significantly increased ET-1 in renal cortices (11-fold) and placenta (4-fold), and there was an approximately 2- to 3-fold increase in placental oxidative stress. Furthermore, antiangiogenic factors sFlt-1 and sEng were significantly increased in the AT1-AA induced hypertensive group compared with the NP controls. CONCLUSIONS: Collectively, these data indicated an important role for AT1-AA stimulated in response to placental ischemia that caused hypertension during pregnancy. PMID- 22498428 TI - Author's specialty and conflicts of interest contribute to conflicting guidelines for screening mammography. AB - OBJECTIVE: To examine the relationship between guideline panel members' conflicts of interest and guideline recommendations on screening mammography in asymptomatic, average-risk women aged 40-49 years. STUDY DESIGN AND SETTING: We searched the National Guideline Clearinghouse and MEDLINE for relevant guidelines published between January 2005 and June 2011. We examined the disclosures and specialties of the lead and secondary authors of these guidelines, as well as the publications of the lead authors. RESULTS: Twelve guidelines were identified with a total of 178 physician authors from a broad range of specialties. Of the four guidelines not recommending routine screening, none had a radiologist member, whereas of the eight guidelines recommending routine screening, five had a radiologist member (comparison of the proportions, P=0.05). A guideline with radiologist authors was more likely to recommend routine screening (odds ratio=6.05, 95% confidence interval=0.57-infinity, P=0.14). The proportion of primary care physicians on guideline panels recommending routine vs. nonroutine screening was significantly different (38% vs. 90% of authors; P=0.01). The odds of a recommendation in favor of routine screening were related to the number of recent publications on breast disease diagnosis and treatment by the lead guideline author (P=0.02). CONCLUSION: Recommendations regarding mammography screening in this target population may reflect the specialty and intellectual interests of the guideline authors. PMID- 22498429 TI - Decisions about lumping vs. splitting of the scope of systematic reviews of complex interventions are not well justified: a case study in systematic reviews of health care professional reminders. AB - OBJECTIVES: Lumping and splitting refer to the scope of a systematic review question, where lumped reviews are broad and split are narrow. The objective was to determine the frequency of lumping and splitting in systematic reviews of reminder interventions, assess how review authors justified their decisions about the scope of their reviews, and explore how review authors cited other systematic reviews in the field. STUDY DESIGN AND SETTING: A descriptive approach involving a content analysis and citation bibliometric study of an overview of 31 systematic reviews of reminder interventions. RESULTS: Twenty-four of 31 reminder reviews were split, most frequently across one category (population, intervention, study design, outcome). Review authors poorly justified their decisions about the scope of their reviews and tended not to cite other similar reviews. CONCLUSION: This study demonstrates that for systematic reviews of reminder interventions, splitting is more common than lumping, with most reviews split by condition or targeted behavior. Review authors poorly justify the need for their review and do not cite relevant literature to put their reviews in the context of the available evidence. These factors may have contributed to a proliferation of systematic reviews of reminders and an overall disorganization of the literature. PMID- 22498431 TI - Ochratoxin A induces oxidative DNA damage and G1 phase arrest in human peripheral blood mononuclear cells in vitro. AB - Ochratoxin A is one of the most abundant food-contaminating mycotoxins worldwide, and its immunosuppressive effects in human caused more and more concern in biomedical field. In the present study, the toxicity of OTA on human peripheral blood mononuclear cells (hPBMC) was explored by analyzing the involvement of oxidative pathway. It was found that OTA treatment led to the release of reactive oxygen species (ROS) and the increase of 8-hydroxydeoxyguanosine (8-OHdG), an important biomarker of oxidative DNA stress. Moreover, we found that OTA treatment induced DNA strand breaks in hPBMC as evidenced by DNA comet tails formation and increased gamma-H2AX expression. In addition, OTA could induce cell cycle arrest at G1 phase by down-regulating the expression of CDK4 and cyclinD1 protein, as well as apoptosis in hPBMC in vitro. Pre-treatment of hPBMC with antioxidant, N-acetyl-L-cysteine (NAC), could reduce OTA-induced ROS release and DNA damage, thus confirming the involvement of oxidative DNA damage in the OTA genotoxicity in hPBMC. NAC pre-treatment could also significantly prevent OTA induced down-regulation of CDK4 and cyclinD1 expression in hPBMC. All the results demonstrated the involvement of oxidative pathway in OTA mediated cytotoxicity in human immune cells, which including the ROS accumulation-oxidative DNA damage-G1 arrest and apoptosis. Our results provide new insights into the molecular mechanisms by which OTA might promote immunotoxicity. PMID- 22498430 TI - Novel therapeutic strategies targeting HIV integrase. AB - Integration of the viral genome into host cell chromatin is a pivotal and unique step in the replication cycle of retroviruses, including HIV. Inhibiting HIV replication by specifically blocking the viral integrase enzyme that mediates this step is an obvious and attractive therapeutic strategy. After concerted efforts, the first viable integrase inhibitors were developed in the early 2000s, ultimately leading to the clinical licensure of the first integrase strand transfer inhibitor, raltegravir. Similarly structured compounds and derivative second generation integrase strand transfer inhibitors, such as elvitegravir and dolutegravir, are now in various stages of clinical development. Furthermore, other mechanisms aimed at the inhibition of viral integration are being explored in numerous preclinical studies, which include inhibition of 3' processing and chromatin targeting. The development of new clinically useful compounds will be aided by the characterization of the retroviral intasome crystal structure. This review considers the history of the clinical development of HIV integrase inhibitors, the development of antiviral drug resistance and the need for new antiviral compounds. PMID- 22498432 TI - All-trans-retinoic acid induces short forelimb malformation during mouse embryo development by inhibiting chondrocyte maturation rather than by evoking excess cell death. AB - Various biochemical and physiological stimuli may interfere with endoplasmic reticulum (ER) homeostasis, causing aggregation and accumulation of unfolded or malfolded proteins in the ER and resulting in ER stress (ERS), and the ER attenuates ERS through unfolded protein response (UPR). All-trans-retinoic acid (ATRA) can enhance or attenuate some ERS-induced physiological or pathological changes. Our previous studies showed that there was UPR in short forelimbs induced by ATRA. Many kinds of malformations induced by ATRA may correlate with cell death, and knowing that UPR is closely associated with cell death, so we speculate that the short forelimbs may caused by UPR-induced cell death. To test this hypothesis, the present study investigated the expression of UPR-related genes and proteins in the same short forelimb malformation model to determine whether ATRA-induced short forelimb malformation occurred through UPR-induced cell death. Subsequently, we further observed the differentiation and proliferation of chondrocytes and the expression of related genes and/or proteins. It was found that ATRA evoked UPR in this short forelimb model, thus activating the anti-cell death pathway and inhibiting the cell death-promoting pathway. Cell death was not evident in short forelimb, and ATRA inhibited the expression of Ccnb1 and Ccna1, thus retarding chondrocyte maturation. As a result, the number of immature chondrocytes in short forelimb was greater than the normal level. We therefore believe that ATRA induces short forelimb malformation most likely by inhibiting chondrocyte maturation rather than by evoking excess cell death. PMID- 22498433 TI - Evolution of clinical and electrophysiologic data in patients with a preexcitation syndrome. AB - The purpose of the study is to report the natural changes of preexcitation syndrome (PS). METHODS: Electrophysiologic study was performed for syncope (n = 8), atrioventricular reentrant tachycardia (AVRT) (n = 42), atrial fibrillation (n = 3), adverse presentation (n = 4), or for asymptomatic PS (n = 22) and was repeated 1 to 21 years later. RESULTS: Clinically, 12 patients initially asymptomatic became symptomatic (54.5%), and 12 symptomatic patients became asymptomatic (21%). At electrophysiologic study 2, maximal rate conducted over accessory pathway (AP) was slower. Anterograde conduction disappeared in 22 patients, but 10 of them had inducible AVRT. Among 27 patients with initially rapid conduction over AP, 7 had a benign form; 20 had always a rapid conduction over AP, and 3 of them initially asymptomatic developed rapid atrial fibrillation. CONCLUSIONS: Asymptomatic patients with a PS frequently became symptomatic (54.5%), whereas symptomatic patients rarely became asymptomatic (21%). Maximal rate conducted over AP decreased during life, but AVRT remained inducible. PMID- 22498434 TI - A comprehensive structure-function analysis shed a new light on molecular mechanism by which a novel smart copolymer, NY-3-1, assists protein refolding. AB - An in-depth understanding of molecular basis by which smart polymers assist protein refolding can lead us to develop a more effective polymer for protein refolding. In this report, to investigate structure-function relationship of pH sensitive smart polymers, a series of poly(methylacrylic acid (MAc)-acrylic acid (AA))s with different MAc/AA ratios and molecular weights were synthesized and then their abilities in refolding of denatured lysozyme were compared by measuring the lytic activity of the refolded lysozyme. Based on our analysis, there were optimal MAc/AA ratio (44% MAc), M(w) (1700 Da), and copolymer concentration (0.1%, w/v) at which the highest yield of protein refolding was achieved. Fluorescence, circular dichroism, and RP-HPLC analysis reported in this study demonstrated that the presence of P(MAc-AA)s in the refolding buffer significantly improved the refolding yield of denatured lysozyme without affecting the overall structure of the enzyme. Importantly, our bioseparation analysis, together with the analysis of zeta potential and particle size of the copolymer in refolding buffers with different copolymer concentrations, suggested that the polymer provided a negatively charged surface for an electrostatic interaction with the denatured lysozyme molecules and thereby minimized the hydrophobic-prone aggregation of unfolded proteins during the process of refolding. PMID- 22498435 TI - Optimization of fermentation conditions for the production of human soluble catechol-O-methyltransferase by Escherichia coli using artificial neural network. AB - The aim of this work was to optimize the temperature, pH and stirring rate of the production of human soluble catechol-O-methyltransferase (hSCOMT) in a batch Escherichia coli culture process. A central composite design (CCD) was firstly employed to design the experimental assays used in the evaluation of these operational parameters on the hSCOMT activity for a semi-defined and complex medium. Predictive artificial neural network (ANN) models of the hSCOMT activity as function of the combined effects of these variables was proposed based on this exploratory experiments performed for the two culture media. The regression coefficients (R(2)) for the final models were 0.980 and 0.983 for the semi defined and complex medium, respectively. The ANN models predicted a maximum hSCOMT activity of 183.73 nmol/h, at 40 degrees C, pH 6.5 and stirring rate of 351 rpm, and 132.90 nmol/h, at 35 degrees C, pH 6.2 and stirring rate of 351 rpm, for semi-defined and complex medium, respectively. These results represent a 4-fold increase in total hSCOMT activity by comparison to the standard operational conditions used for this bioprocess at slight scale. PMID- 22498436 TI - Label-free and high-sensitive detection of Salmonella using a surface plasmon resonance DNA-based biosensor. AB - A method based on surface plasmon resonance (SPR) DNA biosensor has been developed for label-free and high-sensitive detection of Salmonella. A biotinylated single-stranded oligonucleotide probe was designed to target a specific sequence in the invA gene of Salmonella and then immobilized onto a streptavidin coated dextran sensor surface. The invA gene was isolated from bacterial cultures and amplified using a modified semi-nested asymmetric polymerase chain reaction (PCR) technique. In order to investigate the hybridization detection, experiments with different concentration of synthetic target DNA sequences have been performed. The calibration curve of synthetic target DNA had good linearity from 5 nM to 1000 nM with a detection limit of 0.5 nM. The proposed method was applied successfully to the detection of single stranded invA amplicons from three serovars of Salmonella, i.e., Typhimurium, Enterica and Derby, and the responses to PCR products were related to different S. typhimurium concentrations in the range from 10(2) to 10(10) CFU mL(-1). While with this system to detect E. coli and S. aureus, no significant signal was observed, demonstrating good selectivity of the method. In addition, the hybridization can be completed within 15 min, and the excellent sensor surface regeneration allows at least 300 assay cycles without obvious loss of performance. PMID- 22498437 TI - Asymmetric bioreduction of activated alkenes to industrially relevant optically active compounds. AB - Ene-reductases from the 'Old Yellow Enzyme' family of flavoproteins catalyze the asymmetric reduction of various alpha,beta-unsaturated compounds at the expense of a nicotinamide cofactor. They have been applied to the synthesis of valuable enantiopure products, including chiral building blocks with broad industrial applications, terpenoids, amino acid derivatives and fragrances. The combination of these highly stereoselective biocatalysts with a cofactor recycling system has allowed the development of cost-effective methods for the generation of optically active molecules, which is strengthened by the availability of stereo complementary enzyme homologues. PMID- 22498438 TI - Applications of dual-energy CT in urologic imaging: an update. AB - This article discusses modern dual-energy computed tomography (DECT) and the unique material-specific information these scanners can provide. A description of the technical aspects of the various DECT techniques is provided. Specific clinical applications in urologic imaging, including chemical composition of urolithiasis, evaluation of renal masses, detection of urothelial neoplasms, and adrenal adenoma imaging, are discussed. The unique postprocessed image sets, including virtual noncontrast, iodine overlay, and stone composition, are described. PMID- 22498439 TI - Advances in uroradiologic imaging in children. AB - Diagnostic imaging of pediatric urologic disorders is continuously changing as technologic advances are made. Although the backbone of pediatric urologic imaging has been ultrasound, voiding cystourethrography, and radionuclide scintigraphy, newer and advanced modalities are becoming increasingly important. This article discusses the techniques and clinical applications of three such imaging modalities as they pertain to pediatric urologic disorders: (1) MR urography; (2) advanced ultrasound (harmonic imaging, three-dimensional, and voiding urosonography); and (3) CT angiography. PMID- 22498440 TI - Adrenal imaging: a comprehensive review. AB - The discovery of an incidental adrenal mass (adrenal incidentaloma) continues to rise with the increasing use of cross-sectional imaging. Although most adrenal lesions are benign and asymptomatic, radiologists should guide evaluation of these lesions, whether benign or malignant. This article reviews the various imaging techniques used to evaluate adrenal masses and their relative strengths and weaknesses. It focuses on the most prevalent adrenal pathologies and their typical imaging characteristics, and concludes with a brief discussion of developing techniques, including diffusion-weighted imaging and dual-energy CT. PMID- 22498441 TI - Common and less-common renal masses and masslike conditions. AB - As an increasing number of imaging examinations are performed, a greater number of incidental renal lesions are detected. Apart from the usual cysts and solid renal cell carcinomas, a variety of unusual benign and malignant renal lesions exist. Imaging is invaluable in characterizing these lesions and is confirmatory in some benign lesions. Renal cell carcinoma remains the diagnosis of exclusion; however, assessment of the imaging pattern in the appropriate clinical context can improve diagnostic accuracy. The objective of this article is to familiarize the radiologist with the imaging appearance of unusual non-neoplastic and neoplastic lesions and correlate with histopathologic studies when available. PMID- 22498442 TI - Infectious and inflammatory diseases of the kidney. AB - Although the most common renal infection, acute pyelonephritis, can typically be diagnosed on clinical and laboratory examinations, radiologic studies play a role in evaluating for complications and in examining the high-risk patient for more serious complications and atypical infections. It is imperative that the radiologist be familiar with renal infections beyond the common acute pyelonephritis. PMID- 22498443 TI - Multimodality imaging of ureteric disease. AB - The proximal ureter (upper) extends from the ureteropelvic junction to where the ureter crosses the sacroiliac joint, the middle ureter courses over the bony pelvis and iliac vessels, and the distal or pelvic (lower) ureter extends from the iliac vessels to the bladder. Benign and malignant lesions can affect the ureter and these may be caused by contiguous involvement from the kidney or bladder. The ureter can be imaged by computed tomography; magnetic resonance imaging; direct pyelography, both antegrade and retrograde; nuclear medicine diuretic scan; and voiding cystourethrography. This article discusses benign, malignant, neoplastic, nonneoplastic processes involving the ureter. PMID- 22498444 TI - Imaging features of common and uncommon bladder neoplasms. AB - In this article, the authors discuss imaging features of common and less-common epithelial and nonepithelial bladder neoplasms. Epithelial tumors include entities, such as urothelial cell carcinoma, squamous cell carcinoma, and adenocarcinoma, along with less-common entities, such as small cell and carcinoid tumors. Nonepithelial or mesenchymal tumors are also less commonly encountered and include benign entities, such as leiomyoma and neurofibroma, and malignant entities, including leiomyosarcoma and lymphoma. Their imaging features with an emphasis on computed tomography and magnetic resonance imaging are described. PMID- 22498445 TI - Ultrasound evaluation of scrotal pathology. AB - Palpable scrotal mass, acute scrotal pain, and enlarged scrotum are common scenarios in clinical practice. The imaging modality of choice to evaluate scrotal pathology is ultrasound (US). US is key in determining if a palpable abnormality is extratesticular or intratesticular and cystic or solid. US findings help narrow the differential to benign or malignant causes. Extratesticular lesions are more common and usually benign. Rarely, extratesticular solid lesions are malignant but US features are nonspecific. Accurately diagnosing rare benign intratesticular lesions is vital to avoid unnecessary orchiectomy. This article reviews extratesticular and intratesticular lesions presenting as a palpable mass and other conditions commonly seen. PMID- 22498446 TI - Imaging of the retroperitoneum. AB - The retroperitoneum is the compartmentalized space bounded anteriorly by the posterior parietal peritoneum and posteriorly by the transversalis fascia. It extends from the diaphragm superiorly to the pelvic brim inferiorly. This article discusses clinically relevant anatomy of the abdominal retroperitoneal spaces, their cross-sectional imaging evaluation with computed tomography and magnetic resonance imaging, and the imaging features of common retroperitoneal pathologic processes. PMID- 22498447 TI - Genitourinary imaging. Preface. PMID- 22498448 TI - [Contact dermatitis in the 21st century: the mission of the Spanish Contact Dermatitis and Skin Allergy Research Group (GEIDAC)]. PMID- 22498449 TI - A rare combination of left ventricular noncompaction, patent ductus arteriosus, and persistent left superior vena cava demonstrated by multidetector computed tomography and echocardiography. AB - Noncompaction of the ventricular myocardium (NCM) is a disorder characterized by numerous prominent ventricular trabeculations and deep intertrabecular recesses. It may present in an isolated form or in association with other cyanotic heart diseases, obstructions of the ventricular outflow tract, and anomalies of coronary arteries. We report on a rare combination of NCM, patent ductus arteriosus, and persistent left superior vena cava in a 27-year-old man examined via echocardiography and multidetector computed tomography. PMID- 22498450 TI - Evolution of jasmonate and salicylate signal crosstalk. AB - The evolution of land plants approximately 470 million years ago created a new adaptive zone for natural enemies (attackers) of plants. In response to attack, plants evolved highly effective, inducible defense systems. Two plant hormones modulating inducible defenses are salicylic acid (SA) and jasmonic acid (JA). Current thinking is that SA induces resistance against biotrophic pathogens and some phloem feeding insects and JA induces resistance against necrotrophic pathogens, some phloem feeding insects and chewing herbivores. Signaling crosstalk between SA and JA commonly manifests as a reciprocal antagonism and may be adaptive, but this remains speculative. We examine evidence for and against adaptive explanations for antagonistic crosstalk, trace its phylogenetic origins and provide a hypothesis-testing framework for future research on the adaptive significance of SA-JA crosstalk. PMID- 22498451 TI - Cell-specific expression and immunolocalization of nitric oxide synthase isoforms and soluble guanylyl cyclase alpha1 and beta1 subunits in the ovary of fetal, neonatal and immature pigs. AB - The present study is designed to investigate the cellular expression and immunolocalization of three different nitric oxide synthase (NOS) isoforms and soluble guanylyl cyclase (sGC) subunits in the porcine ovary. Our results showed that in the fetal and neonatal pigs, all three isoforms of NOS were mainly localized in the oocyte and showed the expression of gradual increase in the granulosa cell and theca cell with the growing follicle. In addition, subunits of the sGC, sGC alpha1 and beta1 were mainly expressed in the granulosa cell in precious studies. The bioactivity of total NOS, eNOS, iNOS and nNOS was detected in the ovary and were higher at prenatal stages compared to postnatal stages. However, the activities of nNOS were no different between prenatal stages and postnatal stages. Taken together, our findings suggested that the NOS/sGC pathway may be involved in the follicular formation and development in the porcine ovary. PMID- 22498453 TI - Probing the metal-insulator phase transition in the (DMEDO-EBDT)2PF6 single crystal by optical measurements. AB - The temperature and polarization dependence of the optical reflectivity spectra of a quasi-one-dimensional 1/4-filled band system, (DMEDO-EBDT)(2)PF(6), have been investigated. We observed clear anisotropy in the electronic structures corresponding to the anisotropic transport properties. The appearance of a charge gap (E(g) > 0.1 eV) and transfer of the spectral weight accompanied by the metal insulator phase transition were clearly observed. In addition, a split of the intramolecular vibrational modes was observed, which strongly suggested the existence of charge disproportionation in the low temperature phase. We also observed a photoinduced reflectivity change, which implied the occurrence of a photoinduced phase transition from the low temperature insulating phase to the high temperature metallic phase. PMID- 22498452 TI - Very small embryonic/epiblast-like stem cells (VSELs) and their potential role in aging and organ rejuvenation--an update and comparison to other primitive small stem cells isolated from adult tissues. AB - Very small embryonic-like stem cells (VSELs) are a population of developmentally early stem cells residing in adult tissues. These rare cells, which are slightly smaller than red blood cells, i) become mobilized during stress situations into peripheral blood, ii) are enriched in the Sca1+Lin-CD45- cell fraction in mice and the CD133+ Lin-CD45- cell fraction in humans, iii) express markers of pluripotent stem cells (e.g., Oct4, Nanog, and SSEA), and iv) display a distinct morphology characterized by a high nuclear/cytoplasmic ratio and undifferentiated chromatin. Recent evidence indicates that murine VSELs are kept quiescent in adult tissues and protected from teratoma formation by epigenetic modification of imprinted genes that regulate insulin/insulin like growth factor signaling (IIS). The successful reversal of these epigenetic changes in VSELs that render them quiescent will be crucial for efficient expansion of these cells. The most recent data in vivo from our and other laboratories demonstrated that both murine and human VSELs exhibit some characteristics of long-term repopulating hematopoietic stem cells (LT-HSCs), are at the top of the hierarchy in the mesenchymal lineage, and may differentiate into organ-specific cells (e.g., cardiomyocytes). Moreover, as recently demonstrated the number of these cells positively correlates in several murine models with longevity. Finally, while murine BM-derived VSELs have been extensively characterized more work is needed to better characterize these small cells at the molecular level in humans. PMID- 22498455 TI - Monodispersed molecularly imprinted polymer for creatinine by modified precipitation polymerization. AB - A monodispersed molecularly imprinted polymer (MIP) for creatinine was prepared by modified precipitation polymerization. The retention and molecular recognition properties of the prepared MIP were evaluated by the hydrophilic interaction chromatography mode using a mixture of ammonium acetate buffer and acetonitrile as a mobile phase in liquid chromatography. The MIP had a specific recognition ability for creatinine, while other structurally related compounds, such as hydantoin, 1-methylhydantoin, 2-pyrrolidone, N-hydroxysuccinimide and creatine, could not be recognized on the MIP. In addition to shape recognition, hydrophilic interactions could work for the recognition of creatinine on the MIP. PMID- 22498456 TI - Vertical immobilization of viable bacilliform bacteria into polypyrrole films. AB - We have successfully developed a novel technique for inserting viable bacilliform bacteria into polypyrrole films. All of the five different bacterial cells (Pseudomonas aeruginosa, Acinetobacter calcoaceticus, Serratia marcescens, Bacillus subtilis and Escherichia coli) studied in this work were inserted normal to the film surface, and the viability of P. aeruginosa was unaffected by this immobilization procedure. It was also found that the polypyrrole layer was important to keep the cells alive. PMID- 22498457 TI - Highly selective determination of copper corrosion products by voltammetric reduction in a strongly alkaline electrolyte. AB - Until recently, there had been two conflicting views about the order of copper oxides (Cu(2)O and CuO) in their cathodic reduction with a neutral or weak alkaline electrolyte (typically 0.1 M KCl). In 2001, we successfully employed a strongly alkaline electrolyte (SAE; i.e., 6 M KOH + 1 M LiOH) to achieve a perfect separation of the reduction peaks of the two oxides. It was then found that the oxides were reduced in SAE according to a thermodynamic order, i.e., "CuO -> Cu(2)O", and also that the reduction of CuO occurred in one step. At an extremely slow scan rate of <0.2 mV s(-1), however, CuO appears to be reduced in two steps via Cu(2)O. It has also been shown that the developed method with SAE can be applied to analysis of various corrosion products, including Cu(2)S, Cu(OH)(2), and patinas. Use of the developed method has allowed researchers to clarify the mechanism of the atmospheric corrosion of copper. PMID- 22498458 TI - Visual and on-site detection of mercury(II) ions on lateral flow strips using DNA functionalized gold nanoparticles. AB - A test strip for detection of Hg(2+) in aqueous solution based on the DNA functionalized gold nanoparticles (DNA-AuNPs) was developed and evaluated. When Hg(2+) ions were introduced, the biotinylated DNA(2) hybridized with thiolated DNA(1) functionalized on the AuNPs (DNA(1)-AuNPs) to form mismatch complexes through thymine-Hg(2+)-thymine (T-Hg(2+)-T) coordination. The formed mismatch complexes and excess DNA(1)-AuNPs could be captured on the test line formed by streptavidin and the control line formed by DNA(3)-BSA, respectively. Two red lines appeared due to the accumulation of AuNPs, enabling visual detection of Hg(2+) with a detection limit of about 6 nM. The assay results can be obtained within 5 min. The results show that the test strip has excellent sensitivity and selectivity for detection of Hg(2+); thus it holds a great potential for rapid, on-site and real time detection of Hg(2+). PMID- 22498459 TI - Liposome solubilization induced by surfactant molecules in a microchip. AB - The dynamics of liposome solubilization was monitored by dynamic light scattering and optical microscopy. A newly designed Y-shape microchannel connected to a room was incorporated into a microchip and the reaction processes of the liposome suspension and surfactant solution were observed in the room after mixing the two fluids and stopping the flow. By using this microchip, we succeeded in real-time monitoring of liposome solubilization and the following dynamic processes of solubilization were proposed: 1) Deformed liposomes become spherical. 2) The liposome size increases until the surfactant/liposome ratio in the liposome membrane reaches a threshold value. 3) Mixed micelles of surfactants and phospholipids are released and the liposomes collapse. PMID- 22498460 TI - Anomalous solubilization behavior of dimyristoylphosphatidylcholine liposomes induced by sodium dodecyl sulfate micelles. AB - The solubilization dynamics of dimyristoylphosphatidylcholine (DMPC) liposomes, as induced by sodium dodecyl sulfate (SDS), were investigated; this investigation was motivated by several types of atypical behavior that were observed in the solubilization in this system. The liposomes and surfactants were mixed in a microchip, and the solubilization reaction of each liposome was observed using a microscope. We found that solubilization occurred not only via a uniform dissolution of the liposome membrane, but also via a dissolution involving the rapid motion of the liposome, or via active emission of protrusions from the liposome surface. We statistically analyzed the distribution of these patterns and considered hypotheses accounting for the solubilization mechanism based on the results. When the SDS concentration was lower than the critical micelle concentration (CMC), the SDS monomers entered the liposome membrane, and mixed micelles were emitted. When the SDS concentration was higher than the CMC, the SDS micelles directly attacked the liposome membrane, and many SDS molecules were taken up; this caused instability, and atypical solubilization patterns were triggered. The size dependence of the solubilization patterns was also investigated. When the particle size was smaller, the SDS molecules were found to be homogeneously dispersed throughout the whole membrane, which dissolved uniformly. In contrast, when the particle size was larger, the density of SDS molecules increased locally, instability was induced, and atypical dissolution patterns were often observed. PMID- 22498461 TI - Biomolecule analyses in an open-tubular capillary chromatography using ternary mixed carrier solvents with chemiluminescence detection. AB - We examined the elution behavior of isoluminol isothiocyanate (ILITC)-labeled biomolecules (alpha-amino acids, peptides, and proteins) in an open-tubular capillary chromatography system using an untreated fused-silica capillary tube and a water-acetonitrile-ethyl acetate mixture carrier solution. Such an open tubular capillary chromatography is called "tube radial distribution chromatography (TRDC)" for convenience. A mixture of ILITC and ILITC-labeled biomolecules was analyzed using TRDC with chemiluminescence detection that provided simple instrument without a light source and complex optical devises. The ILITC and the labeled twenty alpha-amino acids were separated, in this order or the reverse order, or not separated with an organic solvent-rich and water rich carrier solution. Their elution behavior was considered to be of hydrophilic or hydrophobic nature of ILITC and the labeled alpha-amino acids. The ILITC and the labeled protein, alcohol dehydrogenase and bovine serum albumin, were separated in this order with an organic solvent-rich carrier solution, while they were eluted in the reverse order with a water-rich carrier solution, based on the TRDC separation performance. The TRDC system worked with the untreated open-tubular capillary tube not using any specific capillary tubes, such as coated, packed, or monolithic. PMID- 22498462 TI - Wide-bore capillary hydrodynamic chromatography with ICP-MS detection for evaluation of lanthanide uptake by molecular aggregates. AB - Wide-bore capillary hydrodynamic chromatography (W-HDC) resolves analytes on the basis of a difference in the extent of radial diffusion simply by their passage through an empty capillary. The combination of this method with ICP-MS proves efficient for the evaluation of the interaction of metal ions with molecular aggregates. Lecithin vesicles are suitable molecular aggregates for the uptake of the lanthanide ions in the presence of the first row transition metal ions, suggesting that the present method is applicable to the screening of the molecular aggregate system suitable for selective extraction of a particular targeted small molecule. The visual inspection of the elution profiles gives us qualitative but useful information on the interaction between the vesicle and metal ions. In addition, studying the slope of the front edge of an elution curve provides more quantitative implications. PMID- 22498463 TI - Simultaneous determination of inorganic cations by capillary ion chromatography with a non-suppressed contactless conductivity detector. AB - A non-suppressed capillary ion chromatographic method with a laboratory-made packed cation-exchange column (100 mm * 0.32 mm i.d.) was developed for the separation and simultaneous determination of five common inorganic cations (sodium, ammonium, potassium, magnesium and calcium). Cation exchangers were prepared by the reaction of the hydroxyl group on the surface of diol-group bonded silica gel with 1,3-propanesultone in methanol. Simultaneous separation of these five common inorganic cations were achieved within 17 min using 1 mM methanesulfonic acid and 0.1 mM 15-crown-5 ether in methanol-water (8:2, v/v) as the eluent. The effects of organic solvents and crown ethers in the eluent on the retention of analytes were investigated. The limits of detection (S/N = 3) of the cations were in the range of 18-124 ug/l, the linear correlation coefficients were 0.9991-0.9998, and the RSD values of retention time and peak height were all smaller than 2.1%. The present analytical method was successfully applied to the rapid and direct determination of inorganic cations in samples of river water and commercial drinks, with satisfactory results. PMID- 22498464 TI - Preparation of a cellulose-based enzyme membrane using ionic liquid to lengthen the duration of enzyme stability. AB - A novel method for preparing enzyme membranes was developed. The enzyme was attached onto the electrode surface by dropping the enzyme solution and allowing it to dry. Glucose oxidase was used for entrapment. Then, the electrode surface was coated with an ionic liquid containing cellulose, and the ionic liquid was removed by immersing the electrode into water. Enzyme activity was retained in the membrane; the enzyme electrode can be used for detecting glucose in the range of 10 uM to 1 mM, and the response time was ~10 s. The stability duration of the electrode was examined: the enzyme electrode could be used for glucose detection for 6 months. The membrane was observed by atomic force microscopy in the force modulation mode; crystalline and amorphous parts were intermingled. In conclusion, the cellulose membrane can be a suitable immobilization matrix for enzymes. PMID- 22498465 TI - Vitamin C-silver: an environmentally benign choice for DNA visualization on polyacrylamide gels. AB - A practical, sensitive and environment-benign protocol for the detection of DNA on polyacrylamide gels was described. In this method, the most commonly used formaldehyde-based developer in DNA silver stain, which poses potential hazards to the health of operators, is firstly replaced by vitamin C (Vc) in sodium thiosulfate solution. This allows user-friendly and efficient visualization of DNA that takes about 20 min to complete all the procedures, and provides comparable sensitivity (8 pg of single band) to the most sensitive formaldehyde based silver staining method developed before. PMID- 22498466 TI - Measurement of volatile organic compounds in vehicle exhaust using single-photon ionization time-of-flight mass spectrometry. AB - For the real-time measurements of volatile organic compounds (VOCs) in vehicle exhaust, we employed a vacuum ultraviolet single-photon ionization time-of-flight mass spectrometer (VUV-SPI-TOFMS). Exhaust measurements from gasoline and diesel engine vehicles were performed using a chassis dynamometer. Hydrocarbons such as alkylbenzenes, alkenes, alkanes, and dienes were the major organic compounds present in both gasoline and diesel engine exhaust. The concentrations of organic compounds in gasoline exhaust were higher under running conditions than during idling. The VOC concentrations in diesel exhaust were higher during idling than during running conditions. The VUV-SPI-TOFMS measured composition and emission profiles of many hydrocarbons, including aliphatics and aromatics, in vehicle exhaust simultaneously with real time response. PMID- 22498467 TI - Simultaneous determination of nitrite and nitrate in potato and water samples using negative electrospray ionization ion mobility spectrometry. AB - Nowadays, nitrite and nitrate ions are analyzed in biological samples using laborious and expensive methods; such as HPLC, CE, MS-MS. In this work, the simultaneous analysis of nitrite and nitrate ions was conducted by electrospray ionization-ion mobility spectrometry (ESI-IMS), without using any complicated or laborious derivitization step. Ion mobility spectrometry with low cost, inexpensive maintenance and very fast analysis makes an attractive technique for the simultaneous determination of these ions in foodstuff and drinking water samples. The analyte interference was systematically investigated for binary mixture analysis. The obtained results provided detection limits of 3.8 and 4.7 ug/L for nitrite and nitrate, respectively. A linear dynamic range of about 2 orders of magnitude, and relative standard deviations below 5% were obtained by the proposed method for the analysis of both ions. Also, the proposed method was used to analyze various real samples of potato and drinking water samples, and the obtained results confirmed the capability of negative ESI-IMS for the simultaneous detection of nitrite and nitrate. PMID- 22498468 TI - Development and validation of a sensitive and fast solid-phase spectrophotometric procedure for phenol determination in pharmaceuticals. AB - A very sensitive, simple, and fast solid-phase spectrophotometric procedure for the determination of phenol using the p-nitrobenzenediazonium reagent (DAR reagent) was developed. This procedure is based on the simultaneous concentration of the orange product on a Dowex 1-X2 anion exchanger within 15 min, and a direct absorbance measurement of the sorbed species at both 530 nm (the absorption maximum of the phenol-DAR in the resin phase) and 700 nm (the range where only the resin absorbs light). Quality control and evaluation of the analytical parameters was carried out using a comprehensive prevalidation strategy. The linearity of the method was confirmed within an analyte working range from 0.01 to 0.10 umol (0.2 to 2.0 nmol mL(-1)). The precision ranged from +/-1.17 to +/ 9.61%; the accuracy ranged from -17.50 to +17.81%. The evaluated limiting values were L(D) = 0.0013 umol and L(Q) = 0.0082 umol. The DAR-SPS method was successfully applied to the determination of phenol in a pharmaceutical sample of salicylic acid (98.0-100.0%) and vaccines (98.0-103.4%). PMID- 22498469 TI - A novel nitrite biosensor based on gold dendrites with egg white as template. AB - Gold dendrites (AuD) were synthesized with egg white as the soft template and a novel nitrite (NO(2)(-)) biosensor was fabricated by assembly of a myoglobin (Mb) L-cysteamine (Cys)-AuD biological hybrid. The results of Fourier transform infrared spectra and UV-visible spectra indicated that Mb retained its original structure in the resulting Mb-Cys-AuD. Electrochemical investigation of the biosensor showed a pair of well-defined, quasi-reversible redox peaks with E(pa) = -0.314 V and E(pc) = -0.344 V (vs. SCE) in 0.1 M, pH 7.0 sodium phosphate buffered saline at the scan rate of 200 mV/s. The transfer rate constant (k(s)) was 1.49 s(-1). The Mb-Cys-AuD showed a good electrochemical catalytic response for the reduction of NO(2)(-), with the linear range from 0.5 to 400 uM and the detection limit of 0.3 uM (S/N = 3). The apparent Michaelis-Menten constant (K(M)(app)) was estimated to be 0.2 mM. Therefore, the assembled bio-hybrid as a novel matrix opened up a further possibility for study on the design of enzymatic biosensors with potential applications. PMID- 22498470 TI - Voltammetric determination of dinitronaphthalenes using a silver solid amalgam paste electrode. AB - The electrochemical behavior and application of a new sensor, a silver solid amalgam paste electrode (AgSA-PE), based on the mixture of a fine silver solid amalgam powder (60:40 (w(Hg)/w(Ag))) and a suitable organic pasting liquid (Paraffin oil) in a ratio of 20:1 (w/w), was investigated in an aqueous methanolic media (1:1). This alternative working electrode provides simple preparation and handling, adequate mechanical stability, easily renewable electrode surface, sufficiently wide cathodic potential window (up to -1200 mV within a pH range of 2.7-12.3), and sufficient sensitivity without any necessary pretreatment. The practical usability of the AgSA-PE was verified by the development of voltammetric methods for the determination of selected environmentally important pollutants (1,3-, 1,5-, and 1,8-dinitronaphthalenes) in an aqueous-methanolic media (1:1). The differential pulse voltammetric methods at AgSA-PE give linear concentration dependences in the range of 1-100 umol l(-1) with limits of detection of about 1 umol l(-1) in a mixture of Britton-Robinson buffer of appropriate pH and methanol (1:1). PMID- 22498471 TI - Solid phase extraction using a sulfoxide adsorbent for preconcentration and separation of Hg(II) in natural water followed by ICP-MS measurements. AB - A separation and preconcentration method based on solid-phase extraction using sulfoxide adsorbent was developed for the determination of Hg(II) in natural water samples by inductively coupled plasma mass spectrometry (ICP-MS). The sulfoxide adsorbent was packed into a commercially available syringe-driven column (with a bed volume of 1.0 mL), which permitted off-line sample loading and on-line elution/measurement. The optimized operating conditions were as follows: sample condition for Hg(II) adsorption, 0.5% HCl; sample-loading flow rate, 10 mL min(-1); eluent for recovering Hg(II), 1% cysteine water solution. A test using multi-element mixed solution showed that most trace elements in natural water, except for Bi, could be completely separated from Hg(II). The recoveries of Hg(II) were 99.0 +/- 3.2 and 100.7 +/- 4.3%, respectively, when 0.64 and 0.16 ng mL(-1) of Hg(II) were added into the test sample. The detection limit of Hg(II) using a quadrupole ICP-MS after 10-fold preconcentration was 1.5 pg mL(-1). The blank value was 2.8 +/- 0.5 pg mL(-1). PMID- 22498472 TI - Mixing process of ternary solvents prepared through microchannels in a microchip under laminar flow conditions. AB - The mixing process of ternary solvents (water-hydrophilic/hydrophobic organic mixture) prepared in microchannels in a microchip was examined by fluorescence observation of the dyes dissolved in the solvents under laminar flow conditions. A microchip incorporating microchannels was used. In it, three narrow channels were combined to form one wide channel. Water-acetonitrile (hydrophilic) mixture containing relatively hydrophilic Eosin Y (green) was fed into the narrow center channel and an acetonitrile-ethyl acetate (hydrophobic) mixture containing hydrophobic perylene (blue) was fed into the two narrow side channels in the microchip. The mixtures in the narrow channels combined in the wide channel to prepare the ternary solvents of water-acetonitrile-ethyl acetate, causing the tube radial distribution of the solvents. We observed the mixing process of the ternary solvents in the wide channel through fluorescence of the green and blue dyes, including an aqueous-organic interface. For example, the green dye that was fed into the center channel was distributed near the inner side walls and the blue dye that was fed into the two side channels was distributed around the center area in the wide channel. Such specific mixing behavior was not observed for two-component solvents in the wide channel, such as water-acetonitrile mixture and water-ethyl acetate mixture. PMID- 22498473 TI - A competing risk approach for the European Heart SCORE model based on cause specific and all-cause mortality. AB - BACKGROUND: The European Heart SCORE model constitutes the basis for national guidelines for primary prevention and treatment of cardiovascular disease (CVD) in several European countries. The model estimates individuals' 10-year CVD mortality risks from age, sex, smoking status, systolic blood pressure, and total cholesterol level. The SCORE model, however, is not mathematically consistent and does not estimate all-cause mortality. Our aim is to modify the SCORE model to allow consistent estimation of both CVD-specific and all-cause mortality. METHODS: Using a competing risk approach, we first re-estimated the cause specific risk of dying from cardiovascular disease, and secondly we incorporated non-CVD mortality. Finally, non-CVD mortality was allowed to also depend on smoking status, and not only age and sex. From the models, we estimated CVD specific and all-cause 10-year mortality risk, and the expected residual lifetime together with corresponding expected effects of statin treatment. RESULTS: The modified model provided CVD-specific 10-year mortality risks similar to those of the European Heart SCORE model. Incorporation of non-CVD mortality increased 10 year mortality risks, in particular for older individuals. When non-CVD mortality was assumed unaffected by smoking status, the absolute risk reduction due to statin treatment ranged from 0.0% to 3.5%, whereas the gain in expected residual lifetime ranged from 3 to 11 months. Statin effectiveness increased for non smokers and declined for smokers, when smoking was allowed to influence non-CVD mortality. CONCLUSION: The modified model provides mathematically consistent estimates of mortality risk and expected residual lifetime together with expected benefits from statin treatment. PMID- 22498474 TI - Autophagy, neuron-specific degradation and neurodegeneration. AB - Degradation of membrane compartments, organelles and other debris through macroautophagy (hereafter referred to as autophagy) is thought to occur in most, maybe all, cells. We recently reported the discovery of a neuron-specific endomembrane degradation mechanism that depends on the vesicle SNARE neuronal Synaptobrevin (n-Syb) and the vesicle ATPase component V100 (the V(0)a1 subunit). Loss of n-Syb causes degeneration of adult photoreceptor neurons in Drosophila, reminiscent of adult-onset degeneration in neurons with defective autophagy. Here we explore the potential importance of this newly discovered neuron-specific degradation mechanism in comparison with ubiquitous autophagy machinery for adult onset neurodegeneration. PMID- 22498475 TI - Mammalian PIK3C3/VPS34: the key to autophagic processing in liver and heart. AB - PIK3C3/Vps34 is the class III PtdIns3K that is evolutionarily conserved from yeast to mammals. Its central role in mammalian autophagy has been suggested through the use of pharmacological inhibitors and the study of its binding partners. However, the precise role of PIK3C3 in mammals is not clear. Using mouse strains that allow tissue-specific deletion of PIK3C3, we have described an essential role of PIK3C3 in regulating autophagy, and liver and heart function. PMID- 22498476 TI - ATG5, autophagy and lung function in asthma. AB - Reactive oxidative species (ROS) are essential in cellular survival; however, excessive production and chronic exposure to ROS pose serious health threats. Excessive production of ROS is thought to play a pivotal role in the pathogenesis of asthma, where exhaled levels of ROS have been found to positively correlate with disease severity. Autophagy is induced by ROS to remove oxidized proteins or organelles to minimize tissue damage, and presents itself as a good candidate pathway for investigation in asthma pathogenesis. Given the role of oxidative stress in the pathogenesis of asthma and disease severity, we hypothesized that autophagy is associated with asthma pathogenesis, and sought to detect its presence using both genetic and histological approaches. We found variant rs12212740, an intronic SNP of ATG5, to be associated with asthma and forced expiratory volume in 1 second (FEV(1)) percent predicted in the French Canadian population and with FEV(1) in an American Caucasian cohort. Furthermore, double membrane autophagosomes were more easily detected in fibroblast and epithelial cells from a bronchial biopsy tissue of a moderately severe asthma patient compared with corresponding cells of a healthy subject. Asthma is associated with a cytokine milieu [e.g., interleukin (IL)-13] that promotes transforming growth factor-beta1 (TGFbeta1) affiliated airway remodeling, and agonistic relationships existed among these cytokines and ROS. Hence, autophagy may be a cellular mechanism that promotes TGFbeta1 airway remodeling and loss of lung function in asthma. PMID- 22498477 TI - The anti-apoptotic Bcl-B protein inhibits BECN1-dependent autophagic cell death. AB - Bcl-2 family members are key modulators of apoptosis that have recently been shown to also regulate autophagy. It has been previously reported that Bcl-2 and Bcl-X(L) bind and inhibit BECN1, an essential mediator of autophagy. Bcl-B is an anti-apoptotic member of the Bcl-2 family that possesses the four BH (Bcl-2 homology) domains (BH1, BH2, BH3 and BH4) and a predicted C-terminal trans membrane domain. Although the anti-apoptotic properties of Bcl-B are well characterized, its physiological function remains to be established. In the present study, we first established that Bcl-B interacts with the BH3 domain of BECN1. We also showed that Bcl-B overexpression reduces autophagy triggered by a variety of pro-autophagic stimuli. This impairment of autophagy was closely related to the capacity of Bcl-B to bind to BECN1. Importantly, we have demonstrated that Bcl-B knockdown triggers autophagic cell death and sensitizes cells to amino acid starvation. The cell death induced by Bcl-B knockdown was partially dependent on components of the autophagy machinery (LC3; BECN1; ATG5). These findings reveal a new role of Bcl-B in the regulation of autophagy. PMID- 22498479 TI - Towards combination HIV prevention for injection drug users: addressing addictophobia, apathy and inattention. AB - PURPOSE OF REVIEW: Recent breakthroughs in HIV-prevention science led us to evaluate the current state of combination HIV prevention for injection drug users (IDUs). We review the recent literature focusing on possible reasons why coverage of prevention interventions for HIV, hepatitis C virus (HCV) and tuberculosis among IDUs remains dismal. We make recommendations for future HIV research and policy. RECENT FINDINGS: IDUs disproportionately under-utilize voluntary HIV counseling and testing (VCT), primary care and antiretroviral therapy (ART), especially in countries that have the largest burden of HIV among IDUs. IDUs present later in the course of HIV infection and experience greater morbidity and mortality. Why are IDUs under-represented in HIV-prevention research, access to treatment for both HIV and addiction, and access to HIV combination prevention? Possible explanations include addictophobia, apathy, and inattention, which we describe in the context of recent literature and events. SUMMARY: This commentary discusses the current state of HIV-prevention interventions for IDUs including VCT, needle and syringe program (NSP), opioid substitution therapy (OST), ART and pre-exposure chemoprophylaxis (PrEP), and discusses ways to work towards true combination HIV prevention for IDU populations. Communities need to overcome tacit assumptions that IDUs can navigate through systems that are maintained as separate silos, and begin to take a rights-based approach to HIV prevention to ensure that IDUs have equitable access to life-saving prevention and treatments. PMID- 22498481 TI - Racial and ethnic disparities and implications for the prevention of HIV among persons who inject drugs. AB - PURPOSE OF REVIEW: There are now an estimated 16 million people who inject drugs (PWID) throughout the world, 3 million of whom are estimated to be infected with HIV. In many countries, substantial proportions of PWID belong to racial/ethnic/nationality minority groups, and are at increased likelihood of being infected with HIV. This article reviews current evidence on ethnic disparities in HIV infection among PWID and assesses the issues that would need to be addressed to reduce these disparities. RECENT FINDINGS: An ongoing systematic review of ethnic disparities has found that, in a pooled weighted odds ratio, ethnic minority PWID are twice as likely to be HIV seropositive than ethnic majority, PWID from the same geographic area. If implemented with sufficient quality and coverage, current HIV prevention programs probably have the capability of ending HIV transmission among both ethnic majority and minority PWID. Large-scale, evidence-based prevention programs need to be implemented in the contexts of patterns of injecting drug use that continue to evolve-with injecting practices spreading to new areas, changes in drugs injected, and some transitions from injecting to noninjecting drug use. Lack of financial resources and policies against evidence-based programming are increasingly important problems that are likely to have particularly adverse effects on ethnic minority PWID. SUMMARY: Racial/ethnic/nationality disparities in HIV infection are quite common among PWID. Addressing these disparities will be a fundamental challenge within a human rights approach to public health. PMID- 22498480 TI - Dual HIV risk and vulnerabilities among women who use or inject drugs: no single prevention strategy is the answer. AB - PURPOSE OF REVIEW: This article examines the dual HIV and sexually transmitted infection (STI) risk behaviors engaged in by women who use or inject drugs; the individual, social, and structural drivers of HIV and STI risk; prevention strategies; and the implications for multilevel, combined, sex-specific HIV prevention strategies. RECENT FINDINGS: Women who use or inject drugs, especially female sex workers, are at dual risk for HIV, the hepatitic C virus (HCV), and other STIs. In countries with HIV prevalence higher than 20% among injecting drug users (IDUs), female IDUs have slightly higher HIV prevalence than male IDUs. Women who use or inject drugs face multilevel drivers that increase their vulnerabilities to HIV, HCV, and STIs. Despite advances in behavioral HIV prevention strategies for this population, most prevention studies have not sufficiently targeted dyadic, social, and structural levels. Few recent advances in biomedical HIV prevention have focused on women who use drugs and their unique needs. SUMMARY: HIV prevention strategies and services need to address the unique and multilevel drivers that increase the vulnerabilities to HIV, HCV, and STIs among women who use drugs including those who engage in sex work. Scaling-up and improving access to multilevel and combined HIV prevention strategies for these women is central to combating the HIV epidemic. PMID- 22498478 TI - Suppression of autophagy is protective in high glucose-induced cardiomyocyte injury. AB - Hyperglycemia is linked to increased heart failure among diabetic patients. However, the mechanisms that mediate hyperglycemia-induced cardiac damage remain poorly understood. Autophagy is a cellular degradation pathway that plays important roles in cellular homeostasis. Autophagic activity is altered in the diabetic heart, but its functional role has been unclear. In this study, we determined if mimicking hyperglycemia in cultured cardiomyocytes from neonatal rats and adult mice could affect autophagic activity and myocyte viability. High glucose (17 or 30 mM) reduced autophagic flux compared with normal glucose (5.5 mM) as indicated by the difference in protein levels of LC3-II (microtubule associated protein 1 light chain 3 form II) or the changes of punctate fluorescence patterns of GFP-LC3 and mRFP-LC3 in the absence and presence of the lysosomal inhibitor bafilomycin A(1). Unexpectedly, the inhibited autophagy turned out to be an adaptive response that functioned to limit high glucose cardiotoxicity. Indeed, suppression of autophagy by 3-methyladenine or short hairpin RNA-mediated silencing of the Becn1 or Atg7 gene attenuated high glucose induced cardiomyocyte death. Conversely, upregulation of autophagy with rapamycin or overexpression of Becn1 or Atg7 predisposed cardiomyocytes to high glucose toxicity. Mechanistically, the high glucose-induced inhibition of autophagy was mediated at least partly by increased mTOR signaling that likely inactivated ULK1 through phosphorylation at serine 467. Together, these findings demonstrate that high glucose inhibits autophagy, which is a beneficial adaptive response that protects cardiomyocytes against high glucose toxicity. Future studies are warranted to determine if autophagy plays a similar role in diabetic heart in vivo. PMID- 22498482 TI - HIV and viral hepatitis C coinfection in people who inject drugs: implications of new direct acting antivirals for hepatitis C virus treatment. AB - PURPOSE OF REVIEW: The recent major shift toward oral direct acting hepatitis C virus (HCV) treatments has the potential to revolutionize the global response to HCV. People who inject drugs (PWID) are a large key affected population who stand to benefit from these new medications. RECENT FINDINGS: There is a large number of new drug classes and targets with activity against HCV. Although effective for HCV treatment in monoinfection and coinfection with HIV, most direct-acting antivirals (DAAs) remain within the research pipeline, with only two having achieved regulatory approval to date. Clinical trial data are not available regarding HCV treatment for PWID with DAAs. This article reviews clinical data on HCV treatment for a number of promising compounds in HCV monoinfection and coinfection with HIV and discusses the barriers facing PWID in scale-up and roll out of DAAs in the coming years. SUMMARY: DAAs have the potential to revolutionize HCV treatment. There will be significant access barriers for people who inject drugs to these new medications. PMID- 22498483 TI - Nurses lead from where we stand. PMID- 22498484 TI - Transition to an elastomeric infusion pump in home care: an evidence-based approach. AB - A fatal overdose of a chemotherapeutic agent delivered to a patient via an electronic infusion device served as a stark reminder of the risks that infusion therapy poses to patients and health care providers and as the impetus for a strategy to optimize safe and efficient delivery of home infusion therapy. The Academic Center for Evidence-Based Practice Star Model of Knowledge Transformation was used as the evidence-based framework for the implementation of a portable infusion pump that supports home infusion of high-risk medications, leading to increased patient and caregiver satisfaction. Evaluation of this implementation supports the use of an elastomeric infusion device for a high-risk therapy. PMID- 22498485 TI - Subcutaneous drug delivery: a route to increased safety, patient satisfaction, and reduced costs. AB - The subcutaneous (SC) route of administration is generally preferred over intravenous administration because it enables at-home injection, improves quality of life, and reduces health care costs. In general, a volume of no greater than 1 to 2 mL is injected SC; however, for high-dose agents with limited solubility, such as monoclonal antibodies, larger volumes must be administered, which requires divided doses, smaller volumes, or more frequent dose administration. Therapeutics are being formulated with an enzyme, recombinant human hyaluronidase, to enhance the dispersion and absorption of SC administered therapeutics by transiently depolymerizing hyaluronan, a major component of the interstitial matrix. PMID- 22498486 TI - Needlestick injuries, short peripheral catheters, and health care worker risks. AB - Percutaneous exposure (PCE) and mucocutaneous exposure (MCE) to blood and blood containing body fluids pose risks to health care workers worldwide. Although PCEs have been greatly reduced in the United States, they have not been eliminated and continue to be a significant problem worldwide. MCE seems to be a much smaller problem than PCE; however, the data are limited and confusing. Venipuncture procedures can easily be associated with PCE, but there are no published reports of MCE occurring during insertion, use, and removal of peripheral catheters. This integrative, systematic literature review identifies the risks associated with venipuncture and the insertion of short peripheral catheters. PMID- 22498487 TI - The environmental impact of health care: implications for infusion nursing. AB - Health care provision is a dangerous business. Health professionals recognize the potential for miscommunication, medication errors, and other possible threats to patient safety. Less evident are the hazards to the environment inherent in the everyday practice of patient care. This article addresses 3 areas of practice in which infusion nurses can make a positive impact on the environment: preferable intravenous (IV) supply purchasing, proper management of electronic equipment (including purchasing, servicing, and disposal), and appropriate medication use and disposal practices. The article aims to inform IV nurses of the alarming environmental effects that the health care industry has on the environment and to suggest a clear, direct course of action to improve our environmental impact. PMID- 22498488 TI - Evidence-based guidelines for blood transfusion. AB - The AABB has initiated a process to develop evidence-based guidelines for blood transfusion to assist clinicians, other health professionals, and patients in their transfusion decisions. In this article, the author discusses the process of developing the recently published guidelines for plasma transfusion using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology. PMID- 22498489 TI - Biopsy vs. brushing: comparison of two sampling methods for the detection of HPV DNA in squamous cell carcinoma of the oral cavity. AB - BACKGROUND: HR HPV infection was proposed as aetiological factor of oral squamous cell carcinomas (OSCC). HPV frequency in OSCC is highly variable, due to the discrepancy in oral sampling procedures, HPV testing methods and inclusion criteria regarding tumour site (strictly oral cavity vs. nearby structures). Our aim was to compare HPV DNA frequency and type-specific distribution in paired cytological and histological samples of SCC strictly located in oral cavity. The correlation between HPV detection rate by each method of sampling and demographical, behavioural and clinical-pathological variables was also examined. PATIENTS AND METHODS: HPV DNA was detected in brushed cells and formalin-fixed paraffin-embedded biopsies obtained from 83 consecutive unselected immunocompetent adults with OSCC. HPV DNA detection was performed in all samples by nPCR followed by direct DNA sequencing and the assay INNO-LiPA HPV Genotyping. Univariate and multivariate statistics were used, including Cohen kappa index to evaluate agreement between two methods and association between HPV infection and demographical, behavioural and clinical-pathological variables for each method of sampling (p<0.05 statistically significant). RESULTS: HPV DNA was detected in 15.7% (13/83) of brushings and 12.1% (10/83) of biopsies (p>0.05). High risk HPV 51, 16 and 39 were genotypes more frequently detected, especially among biopsies; no concordance between two methods was found (Cohen kappa index=0.04, p=0.34). CONCLUSION: A fraction of OSCC could be linked to HR HPV infection in the Mediterranean area. Although without a statistical significance, biopsy specimen demonstrated more accurate for HR HPV detection than brushing in OSCC. PMID- 22498490 TI - Attenuation of constitutive DNA damage signaling by 1,25-dihydroxyvitamin D3. AB - In addition to its traditional role in the regulation of calcium homeostasis and bone metabolism, vitamin D also exhibits immunomodulatory, anti-proliferative and cancer preventive activities. Molecular mechanisms that confer the chemo preventive properties to vitamin D are poorly understood. We previously reported that constitutive phosphorylation of histone H2AX on Ser139 (gammaH2AX) and activation of ATM (Ser1981 phosphorylation), seen in untreated normal or tumor cells predominantly in S phase of the cell cycle, is to a large extent indicative of DNA replication stress occurring as a result of persistent DNA damage caused by endogenous oxidants, by-products of oxidative metabolism. In the present study we observed that exposure of mitogenically stimulated human lymphocytes, pulmonary carcinoma A549 and lymphoblastoid TK6 cells to 1,25-dihydroxyvitamin D3 (1,25-VD) reduced the level of constitutive expression of gammaH2AX and ATM S1981P. We also observed that the H2O2-induced rise in the level of gammaH2AX in lymphocytes was attenuated by 1,25-VD. Whereas in lymphocytes 1,25-VD reduced by 50-70% the level of endogenous oxidants as determined by their ability to oxidize 2,7-dichlorodihydrofluorescein (DCFH) in A549 and TK6 cells the attenuation of DNA damage signaling by 1,25-VD was seen in the absence of detectable reduction in DCFH oxidation. These findings suggest that while the anti-oxidant activity of 1,25-VD may contribute to a reduction in the intensity of DNA replication stress in lymphocytes, other factors play a role in the 1,25-VD effects seen in A549 and TK6 cells. The data are consistent with the recent report on the interaction between DNA damage signaling (ATM activation) and 1,25D receptor (VDR) phosphorylation that lead to enhancement of DNA repair efficiency, and provide further support for the chemo-preventive and anti-aging properties of this vitamin/hormone. PMID- 22498491 TI - Real-time characterization of cytotoxicity using single-cell impedance monitoring. AB - Cellular impedance sensors have attracted great attention as a powerful characterization tool for real-time, label-free detection of cytotoxic agents. However, impedance measurements with conventional cell-based sensors that host multiple cells on a single electrode neither provide optimal cell signal sensitivity nor are capable of recording individual cell responses. Here we use a single-cell based platform to monitor cellular impedance on planar microelectrodes to characterize cellular death. In this study, individual cells were selectively patterned on microelectrodes with each hosting one live cell through ligand-mediated natural cell adhesion. Changes in cellular morphology and cell-electrode adherence were monitored after the patterned cells were treated with varying concentrations of hydrogen peroxide, sodium arsenite, and disodium hydrogen arsenate, three potent toxicants related to neurotoxicity and oxidative stress. At low toxicant concentrations, impedance waveforms acquired from individual cells showed variable responses. A time- and concentration-dependent response was seen in the averaged single-cell impedance waveform for all three toxicants. The apoptosis and necrosis characterizations were performed to validate cell impedance results. Furthermore, time constants of apoptosis and necrosis in response to toxicant exposure were analytically established using an equivalent circuit model that characterized the mechanisms of cell death. PMID- 22498492 TI - The TP53 tumor suppressor and autophagy in malignant lymphoma. AB - The TP53 (p53) protein is a well-known tumor suppressor that plays a crucial role in maintaining genome stability under various cellular stresses. Loss of TP53 causes lymphomagenesis in mouse models and/or promotes tumor progression. However, the prognostic significance of TP53 has been inconsistent in human cancers including malignant lymphoma. In our recent review of TP53 dysfunction in lymphoid malignancies, we discussed the fact that the TP53 function in autophagy may be one of the important mechanisms responsible for the inconsistency of TP53 prognostic value, in that autophagy can promote survival of lymphoma cells by recycling toxic intracellular materials and inhibiting apoptosis. Here we discuss the biological mechanisms of TP53 functional switches from apoptosis to autophagy, and provide a brief summary of how TP53 regulates autophagy through its transcriptional activity on 14 genes of the TP53 pathway. PMID- 22498494 TI - Pulmonary rehabilitation and palliative care in COPD: Two sides of the same coin? AB - Pulmonary rehabilitation and palliative care are two important components of the integrated care of the patient with chronic respiratory disease such as chronic obstructive pulmonary disease (COPD). These two interventions are remarkably similar in many respects. Both utilize a multidisciplinary team that focuses on the specific needs of the individual patient. Care in both is goal defined and includes relief of symptoms and improvements in functional status and quality of life. Pulmonary rehabilitation is commonly given in a specific setting, such as a hospital-based outpatient setting, while palliative care is often hospital based, with its services extending into the home setting in the form of hospice. Components of pulmonary rehabilitation and palliative care should be administered as part of good medical care. Both pulmonary rehabilitation and palliative care are currently underutilized in the respiratory patient, and often provided relatively late in the patient's clinical course. The case provided illustrates the often-overwhelming symptom burden of advanced COPD and demonstrates opportunities for the application of these twin interventions. PMID- 22498493 TI - Dual functions of autophagy in the response of breast tumor cells to radiation: cytoprotective autophagy with radiation alone and cytotoxic autophagy in radiosensitization by vitamin D 3. AB - In MCF-7 breast tumor cells, ionizing radiation promoted autophagy that was cytoprotective; pharmacological or genetic interference with autophagy induced by radiation resulted in growth suppression and/or cell killing (primarily by apoptosis). The hormonally active form of vitamin D, 1,25D 3, also promoted autophagy in irradiated MCF-7 cells, sensitized the cells to radiation and suppressed the proliferative recovery that occurs after radiation alone. 1,25D 3 enhanced radiosensitivity and promoted autophagy in MCF-7 cells that overexpress Her-2/neu as well as in p53 mutant Hs578t breast tumor cells. In contrast, 1,25D 3 failed to alter radiosensitivity or promote autophagy in the BT474 breast tumor cell line with low-level expression of the vitamin D receptor. Enhancement of MCF 7 cell sensitivity to radiation by 1,25D 3 was not attenuated by a genetic block to autophagy due largely to the promotion of apoptosis via the collateral suppression of protective autophagy. However, MCF-7 cells were protected from the combination of 1,25D 3 with radiation using a concentration of chloroquine that produced minimal sensitization to radiation alone. The current studies are consistent with the premise that while autophagy mediates a cytoprotective function in irradiated breast tumor cells, promotion of autophagy can also confer radiosensitivity by vitamin D (1,25D 3). As both cytoprotective and cytotoxic autophagy can apparently be expressed in the same experimental system in response to radiation, this type of model could be utilized to distinguish biochemical, molecular and/or functional differences in these dual functions of autophagy. PMID- 22498495 TI - The association between body mass index and musculoskeletal foot disorders: a systematic review. AB - The primary aim of this systematic review was to investigate the relationship between body mass index (BMI) and foot disorders. The secondary aim was to investigate whether weight loss is effective for reducing foot pain. Five electronic databases (Ovid MEDLINE, Ovid EMBASE, Ovid AMED, CINAHL and The Cochrane Library) and reference lists from relevant papers were searched in April 2011. Twenty-five papers that reported on the association between BMI and musculoskeletal foot disorders met our inclusion criteria and were reviewed. The evidence indicates: (i) a strong association between increased BMI and non specific foot pain; and (ii) a strong association between increased BMI and chronic plantar heel pain in a non-athletic population. The evidence is inconclusive regarding the relationship between BMI and the following specific disorders of the foot; hallux valgus, tendonitis, osteoarthritis and flat foot. With respect to our second aim, there were only two prospective cohort studies that reported a reduction in foot symptoms following weight loss surgery. In summary, increased BMI is strongly associated with non-specific foot pain in the general population and chronic plantar heel pain in a non-athletic population. However, there is currently limited evidence to support weight loss to reduce foot pain. PMID- 22498497 TI - Monoclonal antibodies for the treatment of the C3 glomerulopathies. PMID- 22498496 TI - Renal replacement therapy in critically ill patients receiving extracorporeal membrane oxygenation. AB - Extracorporeal membrane oxygenation (ECMO) is a lifesaving procedure used in neonates, children, and adults with severe, reversible, cardiopulmonary failure. On the basis of single-center studies, the incidence of AKI occurs in 70%-85% of ECMO patients. Those with AKI and those who require renal replacement therapy (RRT) are at high risk for mortality, independent of potentially confounding variables. Fluid overload is common in ECMO patients, and is one of the main indications for RRT. RRT to maintain fluid balance and metabolic control is common in some but not all centers. RRT on ECMO can be performed via an in-line hemofilter or by incorporating a standard continuous renal replacement machine into the ECMO circuit. Both of these methods require specific technical considerations to provide safe and effective RRT. This review summarizes available epidemiologic data and how they apply to our understanding of AKI pathophysiology during ECMO, identifies indications for RRT while on ECMO, reviews technical elements for RRT application in the setting of ECMO, and finally identifies specific research-focused questions that need to be addressed to improve outcomes in this at-risk population. PMID- 22498499 TI - Dialysis at a crossroads--Part II: A call for action. AB - A previous commentary pointed out that the renal community has led American healthcare in the development and continuous improvement of quality outcomes. However, survival, hospitalization, and quality of life for US dialysis patients is still not optimal. This follow-up commentary examines the obstacles, gaps, and metrics that characterize this unfortunate state of affairs. It posits that current paradigms are essential contributors to quality outcomes but are no longer sufficient to improve quality. New strategies are needed that arise from a preponderance of evidence, in addition to beyond a reasonable doubt standard. This work offers an action plan that consists of new pathways of care that will lead to improved survival, fewer hospitalizations and rehospitalizations, and better quality of life for patients undergoing dialysis therapy. Nephrologists in collaboration with large and small dialysis organizations and other stakeholders, including the Centers for Medicare and Medicaid Services, can implement these proposed new pathways of care and closely monitor their effectiveness. We suggest that our patients deserve nothing less and must receive even more. PMID- 22498498 TI - Derivation and validation of a cytokine-based assay to screen for acute rejection in renal transplant recipients. AB - BACKGROUND AND OBJECTIVES: Acute rejection remains a problem in renal transplantation. This study sought to determine the utility of a noninvasive cytokine assay in screening of acute rejection. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this observational cross-sectional study, 64 patients from two centers were recruited upon admission for allograft biopsy to investigate acute graft dysfunction. Blood was collected before biopsy and assayed for a panel of 21 cytokines secreted by PBMCs. Patients were classified as acute rejectors or nonrejectors according to a classification rule derived from an initial set of 32 patients (training cohort) and subsequently validated in the remaining patients (validation cohort). RESULTS: Although six cytokines (IL-1beta, IL-6, TNF-alpha, IL-4, GM-CSF, and monocyte chemoattractant protein-1) distinguished acute rejectors in the training cohort, logistic regression modeling identified a single cytokine, IL-6, as the best predictor. In the validation cohort, IL-6 was consistently the most accurate cytokine (area under the receiver-operating characteristic curve, 0.85; P=0.006), whereas the application of a prespecified cutoff level, as determined from the training cohort, resulted in a sensitivity and specificity of 92% and 63%, respectively. Secondary analyses revealed a strong association between IL-6 levels and acute rejection after multivariate adjustment for clinical characteristics (P<0.001). CONCLUSIONS: In this pilot study, the measurement of a single cytokine can exclude acute rejection with a sensitivity of 92% in renal transplant recipients presenting with acute graft dysfunction. Prospective studies are needed to determine the utility of this simple assay, particularly for low-risk or remote patients. PMID- 22498500 TI - The effects of modifying RhoA and Rac1 activities on heterotypic contact inhibition of locomotion. AB - Contact inhibition of locomotion (CIL) occurs when a cell ceases moving in the same direction following contact with another cell. Homotypic and heterotypic CIL occur between cells of the same and different types, respectively. Using Abercrombie's confronted explants assay we studied the effect of changing Rac1 or RhoA activities on heterotypic CIL between NIH3T3 and chicken heart fibroblasts. Both dominant active (L61) and dominant negative (N17) Rac1 expressed in NIH3T3 cells resulted in loss of heterotypic CIL. N17Rac1 expression caused RhoA activation. Increasing RhoA activity directly (V14RhoA) or indirectly (downregulation of N-cadherin or p120-catenin) also resulted in loss of CIL. High RhoA activity has been associated with tumour invasion and our results are consistent with loss of heterotypic CIL playing a role. PMID- 22498501 TI - The conformational behavior and H-bond structure of asparagine: a theoretical and experimental matrix-isolation FT-IR study. AB - Due to the high importance of the structural properties of peptides, the conformational behavior of one of their elementary building blocks, asparagine, has been investigated in this work. Matrix-isolation FT-IR spectroscopy is a suitable technique to investigate the intrinsic properties of small molecules. Asparagine has been subjected to matrix-isolation FT-IR spectroscopy supported with DFT and MP2 calculations. DFT optimization of asparagine resulted in 10 stable conformations with ?E(DFT)<10 kJ.mol(-1). Compared to a previous study, one new conformation has been revealed. Further optimization at the MP2/6-31++G** level resulted in seven conformations with ?E(MP)<10 kJ.mol(-1). A conformation containing the three intramolecular H-bonds, i.e. C=O(sc)...HN(bb), C=O(bb)...HN(sc) and OH(bb)...N(bb) appeared to be the most stable one at both levels despite the large negative entropy contribution due to these 3 H-bonds. At the sublimation temperature of 353 K, the DFT method predicts four and the MP2 method six conformations to be present in the experimental matrix-isolation spectrum. These conformations have different intramolecular H-bonds, which has allowed to identify at least 4 low energy conformations in the FT-IR spectrum. Detailed comparison between theory and experiment resulted in a mean frequency deviation of 7.6 cm(-1). PMID- 22498502 TI - Potential of levitated drops to serve as microreactors for biophysical measurements. AB - Microreactors are desirable for exploring chemical and biological processes, as reactant consumption is minimal and safety issues are easily managed. Levitated drops are a class of microreactors for which mixing is continuous and solid/liquid interfaces are absent or of lesser importance than in channeled microfabricated flow reactors. Thus, reactant adsorption or wall catalysis possibly of importance in ordinary microfluidic systems is absent in levitated drops. Transport of gaseous reactants or products is facile. Levitated drop microreactors are amenable to batch or continuous flow study of biochemical reactions. The possibility of studying oscillatory enzyme-catalyzed reactions in drops is apparent. This review explains the physics and chemistry of levitated drop microreactors and describes practical aspects of their design, fabrication, implementation, and optimization. Such considerations as drop evaporation, thermal control, protein behavior at the gas/liquid interface, and observation with spectroscopic and electrochemical probes are discussed. PMID- 22498503 TI - Structure and dynamics of beta-lactoglobulin in complex with dodecyl sulfate and laurate: a molecular dynamics study. AB - Bovine beta-lactoglobulin (betalg) is able to recognize a wide variety of hydrophobic ligands. Although binding promiscuity is characteristic of highly hydrophobic interactions, the structural plasticity of the betalg binding cavity entrance seems to be crucial for the interaction with polar moieties of different ligands. On the other hand, thermodynamic studies have shown that betalg can associate to cognate ligands with distinctly different binding energetics, as in the case of the closely related molecules lauric acid (LA) and dodecyl sulfate (DS). In the recognition of LA, betalg shows a classical hydrophobic signature (entropically driven), whereas the interaction of betalg with DS exhibits a nonclassical hydrophobic signature (enthalpically driven). To gain insights into these opposed binding behaviors, MD simulations were carried out on betalg in apo form and bound to DS or LA. Overall, the results suggested that the distinct energetic signatures of these ligands come from distinct optimizations of both hydrophilic and hydrophobic contacts with the protein. PMID- 22498504 TI - [Safety and efficacy of a new preservative-free levocabastine ophthalmic solution (Levofree(r)) using the conjunctival provocation test]. AB - OBJECTIVES: To evaluate the safety and efficacy of preservative-free levocabastine 0.05 % ophthalmic solution compared to placebo (vehicle) and to preserved levocabastine 0.05 % ophthalmic suspension in the prevention of allergic conjunctivitis induced by a conjunctival provocation test. METHODS: Ninety-two subjects (18-50 years) with a previous history of allergic conjunctivitis to pollen were randomised to receive either preservative-free levocabastine solution in one eye and preserved levocabastine suspension in the fellow eye (n=69), or preservative-free levocabastine in one eye and placebo in the fellow eye (n=23). One drop of each product was administered 10 minutes (visit 3) and 4 hours (visit 4) prior to the provocation test. The primary efficacy criterion was the sum of the itching and conjunctival hyperemia scores assessed at 3, 5 and 10 minutes after the provocation test. The safety evaluation included adverse events, visual acuity, intra-ocular pressure and study drug drop sensation. RESULTS: The efficacy of the preservative-free solution was significantly higher than that of placebo at all time points (P<=0.01) with one exception at visit 4 (3 minutes after the provocation test). It was significantly higher than that of the preserved suspension at visit 3, and equivalent at visit 4. The incidence of adverse events was lower with the preservative-free solution than with the preserved suspension. 94.2 % and 95.7 % subjects rated preservative free levocabastine drop sensation as "good" or "very good" at visits 3 and 4 respectively, whereas these rates were 68.1 % and 63.8 % with preserved levocabastine. This difference between the two formulations was highly statistically significant (P<0.001). CONCLUSIONS: The efficacy of preservative free levocabastine was superior to that of the placebo and of the preserved suspension at visit 3, at least as effective as the preserved suspension at visit 4, and better tolerated at each visit. PMID- 22498505 TI - [What remains today of neonatal conjunctivitis in prefecture of Kozah in Togo?]. AB - AIM: The purpose of this study is to screen the neonatal conjunctivitis in order to evaluate its incidence and especially to seek for the causative germs. PATIENTS AND METHODS: We have realized cross-sectional study in three health centers of the prefecture of Kozah from March 24 to May 12, 2009. All the newborns followed in these centers are examined in the search of signs of conjunctivitis. A biological diagnosis of conjunctival secretions was carried out at the suspect newborns. RESULTS: During the study period, 348 newborns were examined including 185 boys and 163 girls corresponding to a sex-ratio (M/F) of 1.1. The middle age was 3.7 days. Twenty-eight newborns presented conjunctivitis, that is to say a rate of incidence of 8%. The cases of conjunctivitis were observed the first four days of life in 39.3% of cases. Eighteen of the newborns presenting conjunctivitis were vaginal deliveries (64.3%) against ten (35.7%) by caesarian. All the mothers of the ill newborns had a syndrome of sexually transmissible infection (STI) during the third quarters of pregnancy. After biological diagnosis, Staphylococcus aureus was found in 25% of the cases. CONCLUSION: Despite the common herd of neonatal conjunctivitis prophylaxis by Crede's method, its remains in the prefecture of Kozah. In hope for neonatal conjunctivitis eradication, treatment of STI on pregnant women associated to education and communication on the prevention of the infection in neonatal health care centers and at home by hygiene rule application are necessary. PMID- 22498506 TI - [Bullous keratopathy following accidental exposure to hydrogen peroxide]. PMID- 22498507 TI - Conceptual design of flapping-wing micro air vehicles. AB - Traditional micro air vehicles (MAVs) are miniature versions of full-scale aircraft from which their design principles closely follow. The first step in aircraft design is the development of a conceptual design, where basic specifications and vehicle size are established. Conceptual design methods do not rely on specific knowledge of the propulsion system, vehicle layout and subsystems; these details are addressed later in the design process. Non traditional MAV designs based on birds or insects are less common and without well-established conceptual design methods. This paper presents a conceptual design process for hovering flapping-wing vehicles. An energy-based accounting of propulsion and aerodynamics is combined with a one degree-of-freedom dynamic flapping model. Important results include simple analytical expressions for flight endurance and range, predictions for maximum feasible wing size and body mass, and critical design space restrictions resulting from finite wing inertia. A new figure-of-merit for wing structural-inertial efficiency is proposed and used to quantify the performance of real and artificial insect wings. The impact of these results on future flapping-wing MAV designs is discussed in detail. PMID- 22498508 TI - Trifluoromethyl acting as stopper in [2]rotaxane. AB - A modified dumbbell obtained by replacing one of the phenyl groups of the dibenzylammonium with a strong electron-withdrawing trifluoromethyl group templated the synthesis of the smallest [2]rotaxane reported so far. The trifluoromethyl group not only enhances the templating effect of the dumbbell but also acts as the stopper to prevent dethreading of a [20]crown ether macrocycle. PMID- 22498509 TI - Self-trapping of single and paired electrons in Ge2Se3. AB - We report the theoretical prediction of single and paired electron self-trapping in Ge(2)Se(3). In finite atomic cluster, density functional calculations, we show that excess single electrons in Ge(2)Se(3) are strongly localized around single germanium dimers. We also find that two electrons prefer to trap around the same germanium dimer, rupturing a neighboring Ge-Se bond. Localization is less robust in periodic, density functional calculations. While paired electron self-trapping is present, as shown by wavefunction localization around a distorted Ge-Ge dimer, single-electron trapping is not. This discrepancy appears to depend only on the boundary conditions and not on the exchange-correlation potential or basis set. For single- and paired-electron trapping, we report the adiabatic barriers to motion and we estimate hopping rates and freeze-in temperatures. For the single trapped electron, we also predict the (73)Ge and (77)Se hyperfine coupling constants. PMID- 22498511 TI - Inevitable deskilling. PMID- 22498512 TI - A year wiser? PMID- 22498513 TI - Unrecognisable world. PMID- 22498514 TI - Urgent attention and treatment. PMID- 22498515 TI - Interpretation consideration. PMID- 22498516 TI - Blow away the inertia. PMID- 22498517 TI - Wagging tongues. PMID- 22498518 TI - Third molar vision. PMID- 22498529 TI - Post-brushing rinsing for the control of dental caries: exploration of the available evidence to establish what advice we should give our patients. AB - Post-tooth brushing rinsing behaviours have the potential to either reduce or enhance the effectiveness of fluoride toothpaste and show wide variation in the general population. There is a lack of high-quality evidence to support definitive guidance in this area. However, the currently available international guidelines provide consistent recommendations despite the limited evidence. To explore the available evidence base and recommendations on optimal post-brushing rinsing behaviour relating to the use of both water and mouth rinses, a meeting was held between the authors and other experts. This paper reports the consensus views of those present at the meeting concerning what advice we should give our patients. A full list of meeting attendees is provided at the end of this article. PMID- 22498530 TI - Notes on coronectomy. AB - Coronectomy involves removal of a crown from roots of a healthy tooth in healthy patients indicated to prevent inferior alveolar nerve injury in a high risk case. Since the original paper in 2005 ( 2005; 43: 7-12) describing a prospective randomised study on coronectomy, there has been a lot of interest in this procedure and it has become routine practice in many oral surgery departments within the UK and USA. A significant variance in thresholds for prescribing coronectomy and also for the technique of its delivery has been highlighted by a recent review. This has resulted in frequent queries about the technique and which patients may be suitable. Thus this paper aims to highlight some finer points of the coronectomy technique and how to avoid potential pitfalls. PMID- 22498535 TI - An evaluation of the multiple mini-interview as a selection tool for dental students. AB - OBJECTIVE: This research evaluated the mutliple mini-interview (MMI) process as part of the admissions procedure for a dental school. DESIGN: The thematic analysis of a paper-based questionnaire. MATERIALS AND METHODS: Following screening an MMI was arranged for 190 candidates applying to study dentistry with written feedback obtained from candidates and interviewers. RESULTS: A 100% response rate to the paper-based questionnaire was achieved for candidates and a 90% response rate was obtained from interviewers. With specific reference to how candidates perceived their performance, 127 (67.9%) felt they had performed well with 24 (19.3%) unsure and 36 (12.8%) saying their performance was not ideal. Candidates generally thought that they had prepared as well as they could have done for the MMIs and 146 (77.2%) thought that they had done enough at interview to merit being offered a place to study dentistry. The MMI experience was considered favourable and from 137 written comments received by candidates 39 were most positive with reference to the MMIs. A thematic analysis of the comments identified a number of emergent themes including lack of control, anxiety and nervousness, preparedness and comparisons with conventional interviews. CONCLUSION: The MMI appears to be useful in the selection of dental students. PMID- 22498554 TI - Rotation or reciprocation: a contemporary look at NiTi instruments? AB - Successful root canal therapy relies on many factors, not least of all mechanical shaping. Traditionally stainless steel files were used, but the introduction of nickel titanium (NiTi) alloys significantly broadened the instrument design options available to the practitioner. NiTi has allowed manufacturers to produce larger more flexible instruments that can be used mechanically which speeds up canal preparation and reduces fatigue. However, they are relatively expensive and are susceptible to fracture. Recently the use of NiTi instruments in a reciprocating motion have been introduced which claim to reduce the fracture incidence, and negate the need for a glide path. PMID- 22498555 TI - Caring for children: little teeth, big challenges. AB - Dental care for young children with carious primary teeth may pose a number of challenges in terms of assessment and diagnosis, behaviour management and treatment planning. These challenges, together with some misconceptions about the value of restoring the primary dentition, have led to a reduction in the proportion of restorations provided for young children in primary care settings. The aim of my presentation at the forthcoming BDA conference is to provide an overview of current practices for caries management in young children. It will particularly focus on restorative interventions, including preformed metal crowns (using the Hall technique), and will consider the evidence-base for a variety of restorative options. In addition, the child's perspective of restorative care will be considered. PMID- 22498562 TI - Hydrogen peroxide enhances vasodilatation by increasing dimerization of cGMP dependent protein kinase type Ialpha. AB - BACKGROUND: cGMP-dependent protein kinase type I (PKG I) plays a key role in vasodilatation caused by cGMP-elevating agents. It is a homodimer in mammalian cells, existing as 2 isoforms, Ialpha and Ibeta. The aim of the present study was both to determine whether PKG I dimerization and activity are modulated by hydrogen peroxide (H(2)O(2)) and its influence on vasodilatation. METHODS AND RESULTS: The dimers and monomers of total PKG I and PKG Ibeta were analyzed by Western blotting. PKG I activity was assayed by measuring the incorporation of (32)P into BPDEtide. Changes in vessels tension were determined by organ chamber technique. In isolated porcine coronary arteries, H(2)O(2) increased the dimers of total PKG I in a concentration-dependent manner, but had no effect on dimerization of PKG Ibeta. The dimerization of PKG I caused by H(2)O(2) was prevented by catalase but not by deferoxamine and tiron. H(2)O(2) promoted the translocation of PKG I from cytoplasm to membrane. H(2)O(2) enhanced the activity of PKG I and relaxations of porcine coronary arteries to the nitric oxide donor and 8-Br-cGMP. Inhibition of catalase under in vivo conditions significantly decreased rat mean arterial pressure, which was associated with increased dimerization of PKG I. CONCLUSIONS: The present study suggests that H(2)O(2) may enhance the activity of PKG Ialpha-and PKG I-dependent vasodilatation via increased dimerization of the enzyme. PMID- 22498563 TI - Association between plasma high-molecular-weight adiponectin and coronary plaque characteristics assessed by computed tomography angiography in conditions of visceral adipose accumulation. AB - BACKGROUND: Our group has previously reported that visceral adipose tissue (VAT) accumulation was associated with the extent and vulnerable characteristics of coronary plaques using coronary computed tomography angiography (CTA). An investigation of the associations between these coronary lesions with plasma adiponectin and leptin was performed. METHODS AND RESULTS: A total of 394 patients (220 men and 174 women) in the study were referred for CTA. Plain abdominal scanning was simultaneously performed to evaluate VAT areas. The median level of plasma high-molecular-weight (HMW) adiponectin in patients with CTA based obstructive coronary artery disease was significantly lower than that in patients without (men: 1.45 vs. 1.88 ug/ml, P=0.002; women: 2.49 vs. 3.44 ug/ml, P<0.001). Multivariate analyses revealed that a lower HMW adiponectin concentration was significantly associated with the presence (men: P=0.019; women: P=0.018) and involved segment numbers (men: P=0.001; women: P=0.003) of coronary plaques. Furthermore, it was significantly related to coronary plaque with all 3 vulnerable characteristics of positive remodeling, low CT density (<=38 Hounsfield units), and adjacent spotty calcium (men: P=0.019; women: P=0.016). These associations were also observed with VAT areas, but not with plasma leptin concentrations, in both genders. CONCLUSIONS: Lower plasma HMW adiponectin is associated with the presence, extent, and vulnerable characteristics of coronary plaques assessed by CTA in both genders. PMID- 22498564 TI - Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: a pilot study. AB - BACKGROUND: Treatment of critical limb ischemia (CLI) by bypass operation or percutaneous vascular intervention is occasionally difficult. The safety and efficacy of multiple intramuscular adipose tissue-derived mesenchymal stem cells (ATMSC) injections in CLI patients was determined in the study. METHODS AND RESULTS: The study included 15 male CLI patients with ischemic resting pain in 1 limb with/without non-healing ulcers and necrotic foot. ATMSC were isolated from adipose tissue of thromboangiitis obliterans (TAO) patients (B-ATMSC), diabetes patients (D-ATMSC), and healthy donors (control ATMSC). In a colony-forming unit assay, the stromal vascular fraction of TAO and diabetic patients yielded lesser colonies than that of healthy donors. D-ATMSC showed lower proliferation abilitythan B-ATMSC and control ATMSC, but they showed similar angiogenic factor expression with control ATMSC and B-ATMSC. Multiple intramuscular ATMSC injections cause no complications during the follow-up period (mean follow-up time: 6 months). Clinical improvement occurred in 66.7% of patients. Five patients required minor amputation during follow-up, and all amputation sites healed completely. At 6 months, significant improvement was noted on pain rating scales and in claudication walking distance. Digital subtraction angiography before and 6 months after ATMSC implantation showed formation of numerous vascular collateral networks across affected arteries. CONCLUSIONS: Multiple intramuscular ATMSC injections might be a safe alternative to achieve therapeutic angiogenesis in patients with CLI who are refractory to other treatment modalities. PMID- 22498565 TI - Prognostic value of cardiac magnetic resonance imaging for idiopathic pulmonary arterial hypertension before initiating intravenous prostacyclin therapy. AB - BACKGROUND: Because few have reported the prognostic significance of cardiac magnetic resonance imaging (CMR) for idiopathic pulmonary arterial hypertension (IPAH), in this study we evaluated the value of CMR measurements as a prognostic predictor of IPAH before starting intravenous prostacyclin therapy. METHODS AND RESULTS: A total of 121 consecutive CMR studies for evaluating right ventricular (RV) function were reviewed. Forty-one patients were diagnosed with IPAH and served as the study group. Factors, such as age, sex, New York Heart Association functional class (NYHAFC), 6-min walk test, plasma brain natriuretic peptide level, serum uric acid level and CMR measurements were analyzed as predictors of first hospitalization and death. The mean follow-up period was 1,350+/-769 days. Nine patients were hospitalized because of heart failure, and 4 patients died from cardiopulmonary causes. The univariate analyses suggested that the left ventricular (LV) mass index, the left and right ventricular end-diastolic volume indices (LVEDVI, RVEDVI), the LV and RV end-systolic volume indices (LVESVI, RVESVI) and NYHAFC predicted the risk for hospitalization and that RVEDVI, RVESVI and NYHAFC predicted mortality. The multivariate analyses suggested that RVEDVI and NYHAFC are independent predictors of both hospitalization and mortality. The effects of RVEDVI and NYHAFC on hospitalization were not substantially affected by the concomitant medication. CONCLUSIONS: In IPAH patients, the RVEDVI predicts both hospitalization for right heart failure and mortality before initiating intravenous prostacyclin therapy. PMID- 22498566 TI - Interleukin-18 and interleukin-12 together downregulate ATP-binding cassette transporter A1 expression through the interleukin-18R/nuclear factor-kappaB signaling pathway in THP-1 macrophage-derived foam cells. AB - BACKGROUND: Interleukin (IL)-18 and IL-12 synergize for the production of interferon (IFN)-gamma, which can downregulate ATP-binding cassette transporter A1 (ABCA1) expression. The aim of the present study was to investigate the effect of IL-18 and/or IL-12 on ABCA1 expression. METHODS AND RESULTS: IL-18 combined with IL-12 decreased ABCA1 expression and cellular cholesterol efflux in THP-1 macrophage-derived foam cells, whereas IL-18 or IL-12 alone had no effect. IL-12 increased IL-18 receptor (IL-18R) expression, which was suppressed by small interfering RNA (siRNA) for signal transducer and activator of transcription 3. IL-18R but not IL-12 receptor siRNA completely reversed the effects of IL-18 and IL-12 on ABCA1 expression and cellular cholesterol efflux. Treatment with IL-18 plus IL-12 markedly augmented nuclear translocation of nuclear factor (NF)-kappaB but had no effect on expression and activity of liver X receptor alpha. IL-18 and IL-12 also significantly increased zinc finger protein 202 (ZNF202) levels and IFN-gamma secretion. Furthermore, siRNA for ZNF202 or IFN-gamma significantly impaired IL-18/IL-12-induced suppression of ABCA1, whereas NF-kappaB siRNA treatment blocked IL-18/IL-12' action on ZNF202 levels, IFN-gamma secretion, and ABCA1 expression. CONCLUSIONS: IL-18 and IL-12 together can decrease ABCA1 expression and cellular cholesterol efflux in THP-1 macrophage-derived foam cells through the IL-18R/NF-kappaB signaling pathway. PMID- 22498567 TI - Genetic analysis of essential cardiac transcription factors in 256 patients with non-syndromic congenital heart defects. AB - BACKGROUND: The genetic basis of most congenital heart defects (CHDs), especially non-syndromic and non-familial conditions, remains largely unknown. METHODS AND RESULTS: DNA samples were collected from immortalized cell lines and original genomes of 256 non-syndromic, non-familial patients with cardiac outflow tract (OFT) defects. Genes encoding NKX2.5, GATA4, GATA6, MEF2C, and ISL1, essential for heart development, were analyzed using PCR-based bidirectional sequencing. The transcriptional activity of proteins with identified sequence variations was analyzed using a luciferase assay. A novel sequence variant (A103V in MEF2C) was identified, in addition to 4 unreported non-synonymous sequence variants in 3 known causative genes (A6V in NKX2.5, T330R and S339R in GATA4, and E142K in GATA6) in 5 individuals. None of these was found in 500 controls without CHDs. In vitro functional assay showed that all proteins with identified sequence variations exhibited significant changes in transcriptional activity and/or synergistic activity with other transcription factors. Furthermore, overexpression of the A103V MEF2C variant in a fish system disturbed early cardiac development. CONCLUSIONS: New mutations in the transcription factors NKX2.5, GATA4, GATA6, and MEF2C that affect their protein function were identified in 2.3% (6/256) of patients with OFT defects. Our results provide the first demonstration of MEF2C mutation and suggest that disturbances in the regulatory circuits involving these cardiac transcription factors may cause a subset of non-syndromic and non-familial CHDs. PMID- 22498568 TI - Electrocardiogram for the diagnosis of right ventricular hypertrophy and dilation in idiopathic pulmonary arterial hypertension. AB - BACKGROUND: Currently, there are no data on the association between right ventricular (RV) structure and ECG changes specific for idiopathic pulmonary arterial hypertension (IPAH). Therefore, we aimed to assess the accuracy of the recommended ECG criteria for predicting RV hypertrophy (RVH) and dilation in patients with IPAH. METHODS AND RESULTS: Twelve-lead ECG and cardiovascular magnetic resonance imaging (CMR) were performed in 23 consecutive patients with IPAH aged 49.8+/-16.3 years. ECG criteria were referred to RV mass index and RV end-diastolic volume index as measured by CMR. Only the ECG voltage criteria based on R wave amplitude in lead V1, R wave amplitude in aVR, P wave amplitude in II and ventricular activation time in V1 were useful for differentiating between patients with and without RVH. A ventricular activation time in lead V1 of <0.01 s excluded RVH, whereas R in V1 >6 mm, R:S in V1 >1, R in aVR >4 mm, R:S in V5 to R:S in V1 <0.04 and P in II >2.5 mm confirmed the diagnosis. Only the ventricular activation time in V1 correlated with RV dilation and when >0.045s confirmed its diagnosis. CONCLUSIONS: Only a few of the recommended ECG criteria proved to be useful in the diagnosis of RVH or RV dilation in patients with IPAH. Changes in the cut-off values improved their accuracy. PMID- 22498569 TI - Increased incidence of tachyarrhythmias and heart failure hospitalization in patients with implanted cardiac devices after the great East Japan earthquake disaster. AB - BACKGROUND: After the East Japan Earthquake disaster there may have been a deterioration of patients with cardiovascular diseases. METHODS AND RESULTS: We examined the data from 189 consecutive patients implanted with cardiovascular devices for the 6-month period before and after the Earthquake. In 170 patients with defibrillators, the number who experienced tachyarrhythmias increased significantly after the Earthquake (28 +/- 5 vs. 34 +/- 3 patients/month, P<0.05). In 74 patients with biventricular pacemakers, the number of heart failure hospitalizations significantly increased after the Earthquake (1.2 +/- 1.0 vs. 2.7 +/- 1.2 patients/month, P<0.05). CONCLUSIONS: The East Japan Earthquake disaster unfavorably affected patients implanted with defibrillators or biventricular pacemakers. PMID- 22498571 TI - Evaluation of conservative therapy for intermittent claudication. PMID- 22498570 TI - Genetic, molecular and cellular mechanisms underlying the J wave syndromes. AB - An early repolarization (ER) pattern in the ECG, distinguished by J-point elevation, slurring of the terminal part of the QRS and ST-segment elevation has long been recognized and considered to be a benign electrocardiographic manifestation. Experimental studies conducted over a decade ago suggested that some cases of ER may be associated with malignant arrhythmias. Validation of this hypothesis was provided by recent studies demonstrating that an ER pattern in the inferior or inferolateral leads is associated with increased risk for life threatening arrhythmias, termed ER syndrome (ERS). Because accentuated J waves characterize both Brugada syndrome (BS) and ERS, these syndromes have been grouped under the term "J wave syndromes". ERS and BS share similar ECG characteristics, clinical outcomes and risk factors, as well as a common arrhythmic platform related to amplification of I(to)-mediated J waves. Although BS and ERS differ with respect to the magnitude and lead location of abnormal J wave manifestation, they can be considered to represent a continuous spectrum of phenotypic expression. Although most subjects exhibiting an ER pattern are at minimal to no risk, mounting evidence suggests that careful attention should be paid to subjects with "high risk" ER. The challenge ahead is to be able to identify those at risk for sudden cardiac death. Here I review the clinical and genetic aspects as well as the cellular and molecular mechanisms underlying the J wave syndromes. PMID- 22498572 TI - Treatment options for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, who progress after platinum-based chemotherapy. AB - PURPOSE OF REVIEW: After multimodal treatment, 50-60% of patients with locally advanced squamous cell carcinoma of the head and neck will present locoregional and/or distant relapse within 2 years. This article will review chemotherapy and/or targeted agents as treatment options for patients who progress after platinum-based chemotherapy. RECENT FINDINGS: After years when the only therapeutic option was palliative chemotherapy, monoclonal antibodies targeting the epidermal growth factor receptor have emerged as new treatments. In particular, cetuximab and panitumumab have demonstrated progression-free survival and/or overall survival benefits in the first-line palliative treatment when given in combination with platinum-based chemotherapy. Recently, second generation compounds (zalutumumab) or irreversible pan-human epidermal receptor (pan-HER) inhibitors have also shown promising activity after platinum failure. SUMMARY: Because median overall survival after platinum failure is less than 1 year, there is a clear requirement for new phase II/III studies with agents that have the potential to improve overall survival and quality of life. The previous use of platinum-based chemotherapy and the type of tumor response observed may substantially impact prognosis. Therefore, prior platinum use should be clearly defined in future clinical trials to enable a more accurate interpretation of the data. PMID- 22498573 TI - Sustainable waste management in Africa through CDM projects. AB - Only few Clean Development Mechanism (CDM) projects (traditionally focussed on landfill gas combustion) have been registered in Africa if compared to similar developing countries. The waste hierarchy adopted by many African countries clearly shows that waste recycling and composting projects are generally the most sustainable. This paper undertakes a sustainability assessment for practical waste treatment and disposal scenarios for Africa and makes recommendations for consideration. The appraisal in this paper demonstrates that mechanical biological treatment of waste becomes more financially attractive if established through the CDM process. Waste will continue to be dumped in Africa with increasing greenhouse gas emissions produced, unless industrialised countries (Annex 1) fund carbon emission reduction schemes through a replacement to the Kyoto Protocol. Such a replacement should calculate all of the direct and indirect carbon emission savings and seek to promote public-private partnerships through a concerted support of the informal sector. PMID- 22498574 TI - Solidification/stabilization of landfill leachate concentrate using different aggregate materials. AB - The application of reverse osmosis for the treatment of landfill leachate is becoming widespread in Turkey as well as in Europe. A major drawback of this process is the production of concentrate, which could be as much as 30% of the feed stream, and high concentrations of salts and contaminants. The reverse osmosis concentrate is disposed of by using several methods including re infiltration, drying, incineration and solidification/stabilization. In this study, solidification/stabilization (S/S) technology was studied for the treatment of reverse osmosis concentrate produced from landfill leachate. In order to benefit from its capability to absorb heavy metals, ammonia and some other pollutants, zeolite and different aggregate materials were used in solidification experiments. Main pollutants in the leachate concentrate, TOC, DOC, TDS and ammonia were successfully solidified and approximately 1% of TOC, DOC, TDS and ammonia remained in the eluate water. The results indicated that the landfill disposal limits could be attained by solidification/stabilization process. PMID- 22498575 TI - Hybrid sensor for metal grade measurement of a falling stream of solid waste particles. AB - A hybrid sensor system for accurate detection of the metal grade of a stream of falling solid waste particles is investigated and experimentally verified. The system holds an infrared and an electromagnetic unit around a central tube and counts all the particles and only the metal particles, respectively. The count ratio together with the measured average particle mass ratio (k) of non-metal and metal particles is sufficient for calculation of grade. The performance of the system is accurately verified using synthetic mixtures of sand and metal particles. Towards an application a case study is performed using municipal solid waste incineration bottom ash in size fractions 1-6mm, which presents a major challenge for nonferrous metal recovery. The particle count ratio was inherently accurate for particle feed rates up to 13 per second. The average value and spread of k for bottom ash was determined as 0.49 +/- 0.07 and used to calculate grade within 2.4% from the manually analysed grade. At higher feed rates the sensors start missing particles which fall simultaneously through the central tube, but the hybrid system still counted highly repeatable. This allowed for implementation of a count correction ratio to eliminate the stationary error. In combination with averaging in measurement intervals for suppression of stochastic variations the hybrid system regained its accuracy for particle feed rates up to 143 per second. This performance and its special design, intended to render it insensitive to external interference and noise when applied in an eddy current separator, make the hybrid sensor suitable for applications such as quality control and sensor controlled separation. PMID- 22498576 TI - Molecular and functional characterization of HdHSP20: a biomarker of environmental stresses in disk abalone Haliotis discus discus. AB - Heat shock proteins (HSPs) production in cell is inducible by many physical and chemical stressors, providing adaptive significance for organisms when faced with environmental changes. In this study, we characterized a novel small HSP gene from disk abalone, designated as HdHSP20, and investigated its temporal expression by different environmental stimuli. The full-length genome sequence of HdHSP20 is composed of three exons and two introns. The 5' flanking region contains multiple putative transcription factor binding sites related to stress response. The open reading frame of the HdHSP20 cDNA is 480 bp and encodes 160 amino acid residues with 18.76 kDa molecular mass. The deduced amino acid sequence shares highest similarity with HSP20 genes from other invertebrates. HdHSP20 also shows several structural signatures of small HSP, including the conserved alpha-crystallin domain, the absence of cysteine residues, a high number of Glx/Asx residues and the compact beta-sandwich structure in the C terminal region. Overexpression of recombinant HdHSP20 protein conveyed enhanced thermotolerance to Escherichia coli cells, suggesting its functional activity in the cellular chaperone network. qRT-PCR measurements of HdHSP20 mRNA level have shown rapid and drastic induction by extreme temperatures, extreme salinities, heavy metals and the microbial infections. Collectively, our results suggest that HdHSP20 gene is likely involved in the stress resistant mechanisms in disk abalone. Its expression may serve as a potential biomarker capable to indicate a stress state in abalone due to extreme environmental change and pathogen infection. PMID- 22498577 TI - Leptin as a link between the immune system and kidney-related diseases: leading actor or just a coadjuvant? AB - Food intake and nutritional status modify the physiological responses of the immune system to illness and infection and regulate the development of chronic inflammatory processes, such as kidney disease. Adipose tissue secretes immune related proteins called adipokines that have pleiotropic effects on both the immune and neuroendocrine systems, linking metabolism and immune physiology. Leptin, an adipose tissue-derived adipokine, displays a variety of immune and physiological functions, and participates in several immune responses. Here, we review the current literature on the role of leptin in kidney diseases, linking adipose tissue and the immune system with kidney-related disorders. The modulation of this adipose hormone may have a major impact on the treatment of several immune- and metabolic-related kidney diseases. PMID- 22498578 TI - Statistical analysis of surgical pathology data using the R program. AB - An understanding of statistics is essential for analysis of many types of data including data sets typically reported in surgical pathology research papers. Fortunately, a relatively small number of statistical tests apply to data relevant to surgical pathologists. An understanding of when to apply these tests would greatly benefit surgical pathologists who read and/or write papers. In this review, we show how the publicly available statistical program R can be used to analyze recently published surgical pathology papers to replicate the p-values and survival curves presented in these papers. Areas covered include: T-test, chi square and Fisher exact tests of proportionality, Kaplan-Meier survival curves, the log rank test, and Cox proportional hazards. PMID- 22498579 TI - Value of PAX 8 immunostaining in tumor diagnosis: a review and update. AB - PAX 8 is a transcription factor involved in the regulation of organogenesis of the thyroid gland, kidney, and Mullerian system. Recent studies have shown that, among tumors, PAX 8 is commonly expressed in epithelial tumors of the thyroid and parathyroid glands, kidney, thymus, and female genital tract. Although PAX 8 expression has also been reported in certain neuroendocrine tumors, including well-differentiated pancreatic neuroendocrine tumors, and duodenal and rectal carcinoids, as well as in B-cell lymphomas, it has recently been shown that the PAX 8 positivity reported in these tumors was due to a cross-reactivity of the antibody used with the N-terminal region of PAX 6 and PAX 5, respectively. Owing to its restricted expression, PAX 8 has proved to be a useful immunohistochemical marker with a wide range of diagnostic applications in surgical pathology, some of which are briefly reviewed. PMID- 22498580 TI - Whole-slide imaging: routine pathologic diagnosis. AB - Digital pathology systems offer pathologists an alternate, emerging mechanism to manage and interpret information. They offer increasingly fast and scalable hardware platforms for slide scanning and software that facilitates remote viewing, slide conferencing, archiving, and image analysis. Deployed initially and validated largely within the research and biopharmaceutical industries, WSI is increasingly being implemented for direct patient care. Improvements in image quality, scan times, and imageviewing browsers will hopefully allow pathologists to more seamlessly convert to digital pathology, much like our radiology colleagues have done before us. However, WSI creates both opportunities and challenges. Although niche applications of WSI technology for clinical, educational, and research purposes are clearly successful, it is evident that several areas still require attention and careful consideration before more widespread clinical adoption of WSI takes place. These include regulatory issues, development of standards of practice and validation guidelines, workflow modifications, as well as defining situations where WSI technology will really improve practice in a cost-effective way. Current progress on these and other issues, along with improving technology, will no doubt pave the way for increased adoption over the next decade, allowing the pathology community as a whole to harness the true potential of WSI for patient care. The digital decade will likely redefine how pathology is practiced and the role of the pathologist. PMID- 22498581 TI - Thyroid fine needle aspirate: a post-Bethesda update. AB - The Bethesda system for reporting thyroid cytopathology formulated in 2007 has standardized reporting of thyroid cytology specimens and streamlined management algorithms. Although 3 of the categories (benign, malignant, and nondiagnostic) are standardized and improved, the remaining 3 (follicular lesion of undetermined significance, follicular neoplasm, and suspicious for malignancy) remain fraught with interobserver variability and uncertainty regarding management algorithms. Recent and ongoing morphologic and molecular studies that aim to resolve these issues are summarized. PMID- 22498583 TI - Hashimoto thyroiditis: a century later. AB - More than a century has passed since the first description of Hashimoto thyroiditis (HT) as a clinicopathologic entity. HT is an autoimmune disease in which a breakdown of immune tolerance is caused by interplay of a variety of immunologic, genetic, and environmental factors. Thyrocyte injury resulting from environmental factors results in expression of new or hidden epitopes that leads to proliferation of autoreactive T and B cells. Infiltration of thyroid by these cells results in HT. In addition to the usual type of HT, several variants such as the fibrous type and Riedal thyroiditis are also recognized. The most recently recognized variant is immunoglobulin G4(+) HT, which may occur as isolated thyroid limited disease or as part of a generalized Ig4-related sclerosing disease. The relationship between HT and Riedel thyroiditis remains unclear; however, recent evidence seems to suggest that it may also be part of the spectrum of Ig4-related sclerosing disease. HT is frequently associated with papillary thyroid carcinoma and may indeed be a risk factor for developing this type of cancer. The relationship between thyroid lymphoma and HT on the other hand appears well established. PMID- 22498584 TI - The role of pathology experts in defining practice gaps in continuing pathology education: what do we need to know and how can we find them? AB - Two of the most important issues in continuing pathology education are the definition of a content expert and the issue of recognizing the "practice gaps." Purposeful definition of these concepts are critical in recognizing how the expert can be utilized to maintain an effective continuing pathology education, and what really constitutes the educational needs of the practicing pathologists. In this manuscript, we review the definition and significance of these 2 key concepts and challenging issues in how experts can aid in the identification of educational needs and closing of practice gaps. PMID- 22498582 TI - New therapeutic targets in soft tissue sarcoma. AB - Soft tissue sarcomas are an uncommon and diverse group of more than 50 mesenchymal malignancies. The pathogenesis of many of these is poorly understood, but others have begun to reveal the secrets of their underlying mechanisms. With considerable effort over recent years, soft tissue sarcomas have increasingly been classified on the basis of underlying molecular alterations. In turn, this has allowed the development and application of targeted agents in several specific, molecularly defined, sarcoma subtypes. This review will focus on the rationale for targeted therapy in sarcoma, with emphasis on the relevance of specific molecular factors and pathways in both translocation-associated sarcomas and in genetically complex tumors. In addition, we will address some of the early successes in sarcoma-targeted therapy as well as a few challenges and disappointments in this field. Finally, we will discuss several possible opportunities represented by poorly understood, but potentially promising new therapeutic targets, as well as several novel biological agents currently in preclinical and early phase I/II trials. This will provide the reader with the context for understanding the current state of this field and a sense of where it may be headed in the coming years. PMID- 22498585 TI - Additional thoughts about juvenile hyaline fibromatosis and infantile systemic hyalinosis. PMID- 22498587 TI - Buyer beware. PMID- 22498588 TI - Honest work. PMID- 22498589 TI - Scientists and bankers - a new model army. PMID- 22498601 TI - China's stem-cell rules go unheeded. PMID- 22498602 TI - Post-mortem on mutant flu. PMID- 22498603 TI - Slow progress to cleaner coal. PMID- 22498604 TI - Roche chases stake in medical sequencing. PMID- 22498605 TI - Dreams of water on Mars evaporate. PMID- 22498606 TI - Giant telescope may get two homes. PMID- 22498608 TI - Policy: Bold strategies for Indian science. PMID- 22498607 TI - Children of the 90s: Coming of age. PMID- 22498609 TI - Policy: Cleaning China's air. PMID- 22498613 TI - Primate studies: Hear the public's views. PMID- 22498615 TI - Particle physics: Higgs can claim name of massive boson. PMID- 22498614 TI - Primate studies: Trials don't always translate. PMID- 22498616 TI - Government: More credit due to India's scientists. PMID- 22498617 TI - Primate studies: Fix welfare issues first. PMID- 22498618 TI - F. Sherwood Rowland (1927-2012). PMID- 22498620 TI - Astrophysics: Fresh light on stardust. PMID- 22498619 TI - Gene expression: Running to stand still. PMID- 22498621 TI - Microbiology: Adaptation by target remodelling. PMID- 22498623 TI - High-valent organometallic copper and palladium in catalysis. AB - Copper and palladium catalysts are critically important in numerous commercial chemical processes. Improvements in the activity, selectivity and scope of these catalysts could drastically reduce the environmental impact, and increase the sustainability, of chemical reactions. One rapidly developing strategy for achieving these goals is to use 'high-valent' organometallic copper and palladium intermediates in catalysis. Here we describe recent advances involving both the fundamental chemistry and the applications of these high-valent metal complexes in numerous synthetically useful catalytic transformations. PMID- 22498625 TI - An elementary quantum network of single atoms in optical cavities. AB - Quantum networks are distributed quantum many-body systems with tailored topology and controlled information exchange. They are the backbone of distributed quantum computing architectures and quantum communication. Here we present a prototype of such a quantum network based on single atoms embedded in optical cavities. We show that atom-cavity systems form universal nodes capable of sending, receiving, storing and releasing photonic quantum information. Quantum connectivity between nodes is achieved in the conceptually most fundamental way-by the coherent exchange of a single photon. We demonstrate the faithful transfer of an atomic quantum state and the creation of entanglement between two identical nodes in separate laboratories. The non-local state that is created is manipulated by local quantum bit (qubit) rotation. This efficient cavity-based approach to quantum networking is particularly promising because it offers a clear perspective for scalability, thus paving the way towards large-scale quantum networks and their applications. PMID- 22498624 TI - Emerging fungal threats to animal, plant and ecosystem health. AB - The past two decades have seen an increasing number of virulent infectious diseases in natural populations and managed landscapes. In both animals and plants, an unprecedented number of fungal and fungal-like diseases have recently caused some of the most severe die-offs and extinctions ever witnessed in wild species, and are jeopardizing food security. Human activity is intensifying fungal disease dispersal by modifying natural environments and thus creating new opportunities for evolution. We argue that nascent fungal infections will cause increasing attrition of biodiversity, with wider implications for human and ecosystem health, unless steps are taken to tighten biosecurity worldwide. PMID- 22498626 TI - A close halo of large transparent grains around extreme red giant stars. AB - An intermediate-mass star ends its life by ejecting the bulk of its envelope in a slow, dense wind. Stellar pulsations are thought to elevate gas to an altitude cool enough for the condensation of dust, which is then accelerated by radiation pressure, entraining the gas and driving the wind. Explaining the amount of mass loss, however, has been a problem because of the difficulty of observing tenuous gas and dust only tens of milliarcseconds from the star. For this reason, there is no consensus on the way sufficient momentum is transferred from the light from the star to the outflow. Here we report spatially resolved, multiwavelength observations of circumstellar dust shells of three stars on the asymptotic giant branch of the Hertzsprung-Russell diagram. When imaged in scattered light, dust shells were found at remarkably small radii (less than about two stellar radii) and with unexpectedly large grains (about 300 nanometres in radius). This proximity to the photosphere argues for dust species that are transparent to the light from the star and, therefore, resistant to sublimation by the intense radiation field. Although transparency usually implies insufficient radiative pressure to drive a wind, the radiation field can accelerate these large grains through photon scattering rather than absorption--a plausible mass loss mechanism for lower-amplitude pulsating stars. PMID- 22498627 TI - Layered boron nitride as a release layer for mechanical transfer of GaN-based devices. AB - Nitride semiconductors are the materials of choice for a variety of device applications, notably optoelectronics and high-frequency/high-power electronics. One important practical goal is to realize such devices on large, flexible and affordable substrates, on which direct growth of nitride semiconductors of sufficient quality is problematic. Several techniques--such as laser lift-off- have been investigated to enable the transfer of nitride devices from one substrate to another, but existing methods still have some important disadvantages. Here we demonstrate that hexagonal boron nitride (h-BN) can form a release layer that enables the mechanical transfer of gallium nitride (GaN)-based device structures onto foreign substrates. The h-BN layer serves two purposes: it acts as a buffer layer for the growth of high-quality GaN-based semiconductors, and provides a shear plane that makes it straightforward to release the resulting devices. We illustrate the potential versatility of this approach by using h-BN buffered sapphire substrates to grow an AlGaN/GaN heterostructure with electron mobility of 1,100 cm(2) V(-1) s(-1), an InGaN/GaN multiple-quantum-well structure, and a multiple-quantum-well light-emitting diode. These device structures, ranging in area from five millimetres square to two centimetres square, are then mechanically released from the sapphire substrates and successfully transferred onto other substrates. PMID- 22498628 TI - Aerosols implicated as a prime driver of twentieth-century North Atlantic climate variability. AB - Systematic climate shifts have been linked to multidecadal variability in observed sea surface temperatures in the North Atlantic Ocean. These links are extensive, influencing a range of climate processes such as hurricane activity and African Sahel and Amazonian droughts. The variability is distinct from historical global-mean temperature changes and is commonly attributed to natural ocean oscillations. A number of studies have provided evidence that aerosols can influence long-term changes in sea surface temperatures, but climate models have so far failed to reproduce these interactions and the role of aerosols in decadal variability remains unclear. Here we use a state-of-the-art Earth system climate model to show that aerosol emissions and periods of volcanic activity explain 76 per cent of the simulated multidecadal variance in detrended 1860-2005 North Atlantic sea surface temperatures. After 1950, simulated variability is within observational estimates; our estimates for 1910-1940 capture twice the warming of previous generation models but do not explain the entire observed trend. Other processes, such as ocean circulation, may also have contributed to variability in the early twentieth century. Mechanistically, we find that inclusion of aerosol cloud microphysical effects, which were included in few previous multimodel ensembles, dominates the magnitude (80 per cent) and the spatial pattern of the total surface aerosol forcing in the North Atlantic. Our findings suggest that anthropogenic aerosol emissions influenced a range of societally important historical climate events such as peaks in hurricane activity and Sahel drought. Decadal-scale model predictions of regional Atlantic climate will probably be improved by incorporating aerosol-cloud microphysical interactions and estimates of future concentrations of aerosols, emissions of which are directly addressable by policy actions. PMID- 22498629 TI - Adaptation at the output of the chemotaxis signalling pathway. AB - In the bacterial chemotaxis network, receptor clusters process input, and flagellar motors generate output. Receptor and motor complexes are coupled by the diffusible protein CheY-P. Receptor output (the steady-state concentration of CheY-P) varies from cell to cell. However, the motor is ultrasensitive, with a narrow operating range of CheY-P concentrations. How the match between receptor output and motor input might be optimized is unclear. Here we show that the motor can shift its operating range by changing its composition. The number of FliM subunits in the C-ring increases in response to a decrement in the concentration of CheY-P, increasing motor sensitivity. This shift in sensitivity explains the slow partial adaptation observed in mutants that lack the receptor methyltransferase and methylesterase and why motors show signal-dependent FliM turnover. Adaptive remodelling is likely to be a common feature in the operation of many molecular machines. PMID- 22498630 TI - Genome-wide protein-DNA binding dynamics suggest a molecular clutch for transcription factor function. AB - Dynamic access to genetic information is central to organismal development and environmental response. Consequently, genomic processes must be regulated by mechanisms that alter genome function relatively rapidly. Conventional chromatin immunoprecipitation (ChIP) experiments measure transcription factor occupancy, but give no indication of kinetics and are poor predictors of transcription factor function at a given locus. To measure transcription-factor-binding dynamics across the genome, we performed competition ChIP (refs 6, 7) with a sequence-specific Saccharomyces cerevisiae transcription factor, Rap1 (ref. 8). Rap1-binding dynamics and Rap1 occupancy were only weakly correlated (R(2) = 0.14), but binding dynamics were more strongly linked to function than occupancy. Long Rap1 residence was coupled to transcriptional activation, whereas fast binding turnover, which we refer to as 'treadmilling', was linked to low transcriptional output. Thus, DNA-binding events that seem identical by conventional ChIP may have different underlying modes of interaction that lead to opposing functional outcomes. We propose that transcription factor binding turnover is a major point of regulation in determining the functional consequences of transcription factor binding, and is mediated mainly by control of competition between transcription factors and nucleosomes. Our model predicts a clutch-like mechanism that rapidly engages a treadmilling transcription factor into a stable binding state, or vice versa, to modulate transcription factor function. PMID- 22498631 TI - Proteomics: The interaction map. PMID- 22498633 TI - Amino-functionalized monolithic spin-type columns for high-throughput lectin affinity chromatography of glycoproteins. AB - Hydrophilic poly(ethylene glycol)-based monoliths were synthesized in the spin tip format for high-throughput applications via pulsed electron beam irradiation. Monoliths with a homogeneous porous structure and a total porosity of 69% were obtained. The cross-linked polymeric structure was further mechanically stabilized via the incorporation of silica nanoparticles. Amino-functionalization of the monoliths was accomplished by a straightforward, water-based, one-step approach that entailed the electron-beam irradiation-induced grafting of poly(allylamine). The amine functionalized spin columns showed very low unspecific protein adsorption and were successfully applied as adsorbents in lectin affinity chromatography for the purification of ovalbumin. The novel columns also outperformed a commercially available system. PMID- 22498634 TI - Individual surgeon's impact on the risk of re-exploration for excessive bleeding after coronary artery bypass surgery. AB - OBJECTIVE: Excessive bleeding requiring re-exploration is a severe complication that may affect the outcome after coronary artery bypass grafting. The authors hypothesized that surgeon performance may contribute significantly to such a complication. DESIGN: Retrospective. SETTING: Tertiary referral center in a university hospital. PARTICIPANTS: Two thousand one patients. INTERVENTIONS: Isolated coronary artery bypass grafting. RESULTS: Re-exploration for bleeding was performed in 113 patients (5.3%). Re-exploration was performed >=3 days after surgery in 11 patients. The surgical site of bleeding was identified in 83 patients (73.5%). Rates of re-exploration for excessive bleeding ranged from 1.4% to 11.7% according to different surgeons (p < 0.0001). When adjusted for the additive European System for Cardiac Operative Risk Evaluation, re-exploration for bleeding was associated with increased risks of low-cardiac-output syndrome (odds ratio [OR] 2.239, 95% confidence interval [CI] 1.328-3.777), prolonged need for inotropes (OR 1.894, 95% CI 1.198-2.994), and an intensive care unit stay >=5 days (OR 2.129, 95% CI 1.202-3.770). Logistic regression showed that an individual surgeon (p < 0.0001), preoperative body mass index <25 kg/m(2) (OR 2.733, 95% CI 2.145-3.481), and estimated glomerular filtration rate <30 mL/min/1.73 m(2) (OR 3.891, 95% CI 1.669-9.076) were independent predictors of re exploration for excessive bleeding. An individual surgeon also was an independent predictor of a postoperative blood loss >=1,600 mL. CONCLUSIONS: An individual surgeon has a major impact on postoperative bleeding, and a meticulous surgical technique is expected to decrease significantly such a severe complication. PMID- 22498636 TI - Re: Anup Patel. Re: Office based transrectal saturation biopsy improves prostate cancer detection compared to extended biopsy in the repeat biopsy population. Eur Urol. 2012;61:223-4. PMID- 22498635 TI - Prevalence of kidney stones in the United States. AB - BACKGROUND: The last nationally representative assessment of kidney stone prevalence in the United States occurred in 1994. After a 13-yr hiatus, the National Health and Nutrition Examination Survey (NHANES) reinitiated data collection regarding kidney stone history. OBJECTIVE: Describe the current prevalence of stone disease in the United States, and identify factors associated with a history of kidney stones. DESIGN, SETTING, AND PARTICIPANTS: A cross sectional analysis of responses to the 2007-2010 NHANES (n=12 110). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Self-reported history of kidney stones. Percent prevalence was calculated and multivariable models were used to identify factors associated with a history of kidney stones. RESULTS AND LIMITATIONS: The prevalence of kidney stones was 8.8% (95% confidence interval [CI], 8.1-9.5). Among men, the prevalence of stones was 10.6% (95% CI, 9.4-11.9), compared with 7.1% (95% CI, 6.4-7.8) among women. Kidney stones were more common among obese than normal-weight individuals (11.2% [95% CI, 10.0-12.3] compared with 6.1% [95% CI, 4.8-7.4], respectively; p<0.001). Black, non-Hispanic and Hispanic individuals were less likely to report a history of stone disease than were white, non-Hispanic individuals (black, non-Hispanic: odds ratio [OR]: 0.37 [95% CI, 0.28-0.49], p<0.001; Hispanic: OR: 0.60 [95% CI, 0.49-0.73], p<0.001). Obesity and diabetes were strongly associated with a history of kidney stones in multivariable models. The cross-sectional survey design limits causal inference regarding potential risk factors for kidney stones. CONCLUSIONS: Kidney stones affect approximately 1 in 11 people in the United States. These data represent a marked increase in stone disease compared with the NHANES III cohort, particularly in black, non-Hispanic and Hispanic individuals. Diet and lifestyle factors likely play an important role in the changing epidemiology of kidney stones. PMID- 22498637 TI - Chiroptical properties of an alternatingly functionalized cellotriose bearing two porphyrin groups. AB - Right-handedness derived from bisporphyrins attached to a cellotriose backbone at O-6 and O''-6 positions is revealed for the first time. This cellotriose is proposed as a model of alternatingly functionalized cellulosics, which have promising properties for applications in optoelectronics and molecular receptors owing to the chirality and rigid backbone effects. PMID- 22498638 TI - Clinical and economic burden of Clostridium difficile infection in Europe: a systematic review of healthcare-facility-acquired infection. AB - PubMed, EMBASE and conference abstracts were reviewed systematically to determine the clinical and economic burden associated with Clostridium difficile infection (CDI) acquired and treated in European healthcare facilities. Inclusion criteria were: published in the English language between 2000 and 2010, and study population of at least 20 patients with documented CDI acquired/treated in European healthcare facilities. Data collection was completed by three unblinded reviewers using the Cochrane Handbook and PRISMA statement. The primary outcomes were mortality, recurrence, length of hospital stay (LOS) and cost related to CDI. In total, 1138 primary articles and conference abstracts were identified, and this was narrowed to 39 and 30 studies, respectively. Data were available from 14 countries, with 47% of studies from UK institutions. CDI mortality at 30 days ranged from 2% (France) to 42% (UK). Mortality rates more than doubled from 1999 to 2004, and continued to rise until 2007 when reductions were noted in the UK. Recurrent CDI varied from 1% (France) to 36% (Ireland); however, recurrence definitions varied between studies. Median LOS ranged from eight days (Belgium) to 27 days (UK). The incremental cost of CDI was L4577 in Ireland and L8843 in Germany, after standardization to 2010 prices. Country-specific estimates, weighted by sample size, ranged from 2.8% to 29.8% for 30-day mortality and from 16 to 37 days for LOS. CDI burden in Europe was most commonly described using 30 day mortality, recurrence, LOS and cost data. The continued spread of CDI and resultant healthcare burden underscores the need for judicious use of antibiotics. PMID- 22498639 TI - Klebsiella pneumoniae susceptibility to biocides and its association with cepA, qacDeltaE and qacE efflux pump genes and antibiotic resistance. AB - BACKGROUND: Although antiseptics are some of the most widely used antibacterials in hospitals, there is very little information on reduced susceptibility to these biocides and its relationship with resistance to antibiotics. AIM: To determine the relationship between reduced susceptibility to biocides and the carriage of antiseptic resistance genes, cepA, qacDeltaE and qacE, as well as identifying the role of efflux pumps in conferring reduced susceptibility. METHODS: Susceptibility was assessed for five biocides: chlorhexidine, benzalkonium chloride, Trigene, MediHex-4, Mediscrub; and for 11 antibiotics against 64 isolates of Klebsiella pneumoniae. Susceptibility to all compounds was tested by the agar double dilution method (DDM) and the effect of efflux pumps on biocides determined by repeating the susceptibility studies in the presence of the efflux pump inhibitor carbonyl cyanide m-chlorophenyl hydrazone (CCCP). The presence of the cepA, qacDeltaE and qacE genes was identified by polymerase chain reaction. FINDINGS: The bacteria were not widely antibiotic resistant though a few showed reduced susceptibility to cefoxitin, chloramphenicol and rifampicin and later generation cephalosporins but not to carbapenems. Biocide susceptibility, tested by DDM, showed that 50, 49 and 53 strains had reduced susceptibility to chlorhexidine, Trigene and benzalkonium chloride, respectively. The antiseptic resistance genes cepA, qacDeltaE and qacE were found in 56, 34 and one isolates respectively and their effects as efflux pumps were determined by CCCP (10 mg/L), which decreased the minimum inhibitory concentrations (MICs) of chlorhexidine and Medihex-4 by 2-128-fold but had no impact on the MICs of benzalkonium chloride, Trigene and Mediscrub. CONCLUSION: There was a close link between carriage of efflux pump genes, cepA, qacDeltaE and qacE genes and reduced biocide susceptibility, but not antibiotic resistance, in K. pneumoniae clinical isolates. PMID- 22498640 TI - The dependence of the optoelectrical properties of silver nanowire networks on nanowire length and diameter. AB - We have characterized the optoelectrical properties of networks of silver nanowires as a function of nanowire dimension by measuring transmittance (T) and sheet resistance (R(s)) for a large number of networks of different thicknesses fabricated from wires of different diameters (D) and lengths (L). We have analysed these data using both bulk-like and percolative models. We find the network DC conductivity to scale linearly with wire length while the optical conductivity is approximately invariant with nanowire length. The ratio of DC to optical conductivity, often taken as a figure of merit for transparent conductors, scales approximately as L/D. Interestingly, the percolative exponent, n, scales empirically as D2, while the percolative figure of merit, Pi, displays large values at low D. As high T and low R(s) are associated with low n and high Pi, these data are consistent with improved optoelectrical performance for networks of low-D wires. We predict that networks of wires with D = 25 nm could give sheet resistance as low as 25 Omega/? for T = 90%. PMID- 22498641 TI - Real time monitoring of the cell viability during treatment with tumor-targeted toxins and saponins using impedance measurement. AB - This work describes the application of an impedance-based measurement for the real time evaluation of targeted tumor therapies in cell culture (HeLa cells). We used a treatment procedure that is well established in cells and mice. Therein, tumor cells are treated with a combination of an epidermal growth factor-based targeted toxin named SE and particular plant glycosides called saponins. In the present study HeLa cells were seeded in different numbers onto interdigitated electrode structures integrated into the bottom of a 96 well plate. The cells were treated with SE in the presence and absence of the saponin SpnS-1 (isolated from Saponaria officinalis roots). The impedance was directly correlated with the viability of the cells. As expected from known end point measurements, a concentration dependent enhancement of toxicity was observed; however, with the impedance measurement we were for the first time able to trace the temporal changes of cell death during the combination treatment. This substantially added to the understanding of initial cellular mechanisms in the augmentation of the toxicity of targeted toxins by saponins and indicated the superiority of real time monitoring over end point assays. The method is less labor intensive and label-free with ease of monitoring the effects at each time point. PMID- 22498642 TI - Leg-adjustment strategies for stable running in three dimensions. AB - The dynamics of the center of mass (CoM) in the sagittal plane in humans and animals during running is well described by the spring-loaded inverted pendulum (SLIP). With appropriate parameters, SLIP running patterns are stable, and these models can recover from perturbations without the need for corrective strategies, such as the application of additional forces. Rather, it is sufficient to adjust the leg to a fixed angle relative to the ground. In this work, we consider the extension of the SLIP to three dimensions (3D SLIP) and investigate feed-forward strategies for leg adjustment during the flight phase. As in the SLIP model, the leg is placed at a fixed angle. We extend the scope of possible reference axes from only fixed horizontal and vertical axes to include the CoM velocity vector as a movement-related reference, resulting in six leg-adjustment strategies. Only leg-adjustment strategies that include the CoM velocity vector produced stable running and large parameter domains of stability. The ability of the model to recover from perturbations along the direction of motion (directional stability) depended on the strategy for lateral leg adjustment. Specifically, asymptotic and neutral directional stability was observed for strategies based on the global reference axis and the velocity vector, respectively. Additional features of velocity-based leg adjustment are running at arbitrary low speed (kinetic energy) and the emergence of large domains of stable 3D running that are smoothly transferred to 2D SLIP stability and even to 1D SLIP hopping. One of the additional leg-adjustment strategies represented a large convex region of parameters where stable and robust hopping and running patterns exist. Therefore, this strategy is a promising candidate for implementation into engineering applications, such as robots, for instance. In a preliminary comparison, the model predictions were in good agreement with the experimental data, suggesting that the 3D SLIP is an appropriate model to describe human running in three dimensions. The prediction of stable running based on movement-related leg adjustment strategies indicates that both humans and robots may not require external targets directing the movement to run in three dimensions based on compliant leg function. This new movement-based reference enables the control of 3D running because leg adjustment is less sensitive and gait stability is separated from directional stability. PMID- 22498644 TI - Involvement of ubiquitination in the decrease of intestinal P-glycoprotein in a streptozotocin-induced diabetic mouse model. AB - P-Glycoprotein (P-gp), one of the drug efflux pumps, is expressed in some tissues and may affect the pharmacokinetics of its substrates. We have previously reported that a decrease of intestinal P-gp expression affects the pharmacokinetics of orally-administered P-gp substrate drugs in a streptozotocin (STZ)-induced type 1 diabetic mice model. Although we have found the participation of nitric oxide synthase (NOS) activation as a mechanism of the decrease in intestinal P-gp expression under diabetic conditions, more detailed mechanisms other than NOS remain unknown. Here, we studied the involvement of the ubiquitin-proteasome system in the mechanism of the decrease in intestinal P-gp expression under diabetic conditions. Nine days after STZ administration (diabetic condition), ubiquitination levels of ileal P-gp were significantly increased, accompanied by an decrease of intestinal P-gp protein expression levels. Furthermore, treatment with an NO donor could increase the intestinal ubiquitinated P-gp levels. On the other hand, activity of 26S proteasome, an important enzyme in ubiquitin-proteasome system, did not change, suggesting the first step of the system (i.e., ubiquitination) but not the second step (i.e., degradation)-specific up-regulation under diabetic conditions. Our results reveal the participation of the acceleration of the ubiquitin-preotasome system by NO in the decrease of intestinal P-gp expression levels under diabetic conditions. PMID- 22498643 TI - The HIF-pathway inhibitor NSC-134754 induces metabolic changes and anti-tumour activity while maintaining vascular function. AB - BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) mediates the transcriptional response to hypoxic stress, promoting tumour progression and survival. This study investigated the acute effects of the small-molecule HIF-pathway inhibitor NSC 134754. METHODS: Human PC-3LN5 prostate cancer cells were treated with NSC-134754 for 24 h in hypoxia. Orthotopic prostate tumour-bearing mice were treated with a single dose of NSC-134754 for 6, 24 or 48 h. Treatment response was measured using magnetic resonance spectroscopy and imaging. Ex-vivo histological validation of imaging findings was also sought. RESULTS: In vitro, NSC-134754 significantly reduced lactate production and glucose uptake (P<0.05), while significantly increasing intracellular glucose (P<0.01) and glutamine uptake/metabolism (P<0.05). Increased glutamine metabolism was independent of c Myc, a factor also downregulated by NSC-134754. In vivo, a significantly higher tumour apparent diffusion coefficient was determined 24 h post-treatment (P<0.05), with significantly higher tumour necrosis after 48 h (P<0.05). NSC 134754-treated tumours revealed lower expression of HIF-1alpha and glucose transporter-1, at 6 and 24 h respectively, while a transient increase in tumour hypoxia was observed after 24 h. Vessel perfusion/flow and vascular endothelial growth factor levels were unchanged with treatment. CONCLUSION: NSC-134754 induces metabolic alterations in vitro and early anti-tumour activity in vivo, independent of changes in vascular function. Our data support the further evaluation of NSC-134754 as an anti-cancer agent. PMID- 22498645 TI - Inter-individual variability in OCT1 expression and its relationship with OCT1 genotype in liver samples from a Korean population. AB - To clarify inter-individual variation in the expression of organic cation transporter 1 (OCT1), the levels of OCT1 mRNA and protein from 65 human liver samples were examined by real-time PCR and Western blot analysis and were associated with OCT1 genotypes. The expression levels of OCT1 mRNA and protein in 65 liver samples of Korean origin were not normally distributed and varied by 23.6- and 15.9-fold, respectively. OCT1 mRNA expression was correlated with OCT1 protein expression with a correlation coefficient of 0.641 (p < 0.0001). However, non-genetic factors, such as age, gender, and cholestasis, were not significantly associated with OCT1 expression. When quantitative expression levels were compared in relation to OCT1 promoter SNPs, there was no significant difference in OCT1 expression levels among the -1795 GG, GA, and AA genotypes. Moreover, expression levels of OCT1 were not changed in relation to the -1756 genotypes. Inter-individual variation in OCT1 mRNA and protein expression levels in the liver did not correlate with OCT1 genotypes or non-genetic factors, such as age, gender, and cholestasis. These results suggest that genetic and non-genetic factors may not be a significant contributing factor of variations in OCT1 expression from liver samples of Korean origin. PMID- 22498647 TI - Reliable high-throughput method for inhibition assay of 8 cytochrome P450 isoforms using cocktail of probe substrates and stable isotope-labeled internal standards. AB - A significant number of new chemical entities (NCEs) disappear due to cytochrome P450 (CYP)-mediated clinical drug-drug interactions in drug discovery. Therefore, a high throughput assay of CYP activities is necessary in order to evaluate the inhibitory or inducible potencies of CYP isoforms with NCEs in early drug discovery. Here, we developed and validated a high-throughput assay to simultaneously monitor the in vitro activities of 8 CYP isoforms. A cocktail of 9 probe substrates for the 8 major CYPs (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5) was incubated with human liver microsomes. Each substrate-derived metabolite was simultaneously analyzed by multiple reactions monitoring with a single ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) run using stable isotope-labeled internal standards. The ultra-fast UPLC gradient allowed each metabolite to be separated within 1 min, providing quantitative linearity of over 2 orders of magnitude. CYP inhibition by 8 well-known inhibitors was confirmed by comparing single substrates with the substrate cocktail. The inhibition curve profiles and IC50 values for all CYPs in the cocktail substrate were similar to those of single substrates. UPLC-MS/MS using a CYP substrate cocktail is a reliable and robust high-throughput method to accurately assess CYP inhibition potencies of newly developed drugs. PMID- 22498646 TI - Reduction of cytotoxic p-quinone metabolites of tert-butylhydroquinone by human aldo-keto reductase (AKR) 1B10. AB - 2-tert-Butylhydroquinone (BHQ), an antioxidant used as a food additive, exhibits an anticancer effect, whereas it is carcinogenic in rodents at high doses. BHQ is metabolized into cytotoxic tert-butylquinone (BQ), which is further converted to 6-tert-butyl-2,3-epoxy-4-hydroxy-5-cyclohexen-1-one (TBEH) through 6-tert-butyl 2,3-epoxy-4-benzoquinone (TBE), which induces chromosomal aberration. The reductases for BQ and TBE may be protective against the toxicity of the two p quinones, but the responsible human enzymes remain unidentified. In this study, we compared the ability of 12 human recombinant enzymes in the aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase superfamilies to reduce BQ and TBE. Among them, AKR1B10 was the most efficient catalyst of the stoichiometric two-electron reduction of BQ and TBE into BHQ and TBEH, respectively. BQ and TBE are more cytotoxic towards endothelial cells than BHQ and TBEH, and their cytotoxicity was decreased by the overexpression of AKR1B10 in the cells. Additionally, AKR1B10 gene expression in human HCT116 cells was up regulated by treatments with BHQ, BQ and TBE. These results suggest a role for the enzyme in protection at least against the toxicity of the two p-quinone metabolites of BHQ. PMID- 22498648 TI - Renal dysfunction and the liver transplant recipient; novel strategies for determination of reversibility and renal protective therapies pretransplant and posttransplant. AB - PURPOSE OF REVIEW: Renal dysfunction is one of the most common and important complications in liver transplant candidates and recipients. Recent publications have highlighted important developments in this field. RECENT FINDINGS: Inclusion of the serum creatinine in the Model for Endstage Liver Disease (MELD) score has led to an increased number of liver transplant candidates and recipients with renal dysfunction. The development of posttransplant renal dysfunction negatively impacts patient survival. Therefore, the careful identification of appropriate candidates for simultaneous liver-kidney (SLK) transplant is critical. Recent publications have helped in the appropriate selection of SLK recipients. One of the most important strategies to help mitigate renal dysfunction in liver transplant recipients is the careful management of immunosuppression. SUMMARY: Important contributing factors to posttransplant renal dysfunction include pretransplant renal disease and immunosuppression, namely calcineurin inhibitors (CNIs). One of the most effective means of preventing posttransplant renal failure is observation of the defined criteria for selecting patients for SLK. In addition, avoidance and minimization of CNIs may help to mitigate posttransplant renal disease. PMID- 22498649 TI - Recurrent diseases following liver transplantation: current concepts. AB - PURPOSE OF REVIEW: Liver transplantation is the treatment of choice for patients with chronic end-stage liver disease. The posttransplant setting is complex, and an improved long-term graft and patient survival adds to the complexity. There are often multiple causes of graft dysfunction and the associated morbidity and disorder are varied. This review focuses on the current concepts of several recurrent diseases, emphasizing the interpretation of the posttransplant liver biopsies in long-term survivors as challenging and clinically more relevant then ever. It confirms the importance and the necessity of clinico-pathologic correlation in the posttransplant setting. RECENT FINDINGS: The long-term graft and patient survival following liver transplantation has improved significantly over the past decade. The spectrum of histopathologic patterns seen in liver biopsies and our understanding of them have evolved and expanded considerably, so much so, that both pathologists and clinicians alike now recognize new and emerging disease patterns not previously encountered in the nontransplant setting. SUMMARY: Typical histopathologic features are usually easily identified and interpreted in liver biopsies. There are, however, a number of atypical histopathologic patterns, especially in the setting of recurrent diseases, often modified by immunosuppression, or altered by other immune-mediated processes, autoimmunity, or hepatotoxicity. Several conditions and entities, especially in the late posttransplant setting, including atypical allograft rejection, idiopathic posttransplant hepatitis, the spectrum of changes seen in recurrent hepatitis C, nodular regenerative hyperplasia, and de-novo disease occurrence, to name a few, have all been recognized in the past several years. PMID- 22498650 TI - Antibody-mediated rejection of the cardiac allograft: where do we stand in 2012? AB - PURPOSE OF REVIEW: The review will discuss the current pathological criteria for the diagnosis and classification of antibody-mediated rejection (AMR) in the cardiac allograft. RECENT FINDINGS: Until recently, the diagnosis of AMR required clinical dysfunction, presence of donor specific antibodies and pathological alterations. The concept of asymptomatic AMR and its adverse long-term outcomes created, in part the need to reevaluate diagnostic criteria. The results of a recent consensus meeting sponsored by International Society For Heart And Lung Transplantation are discussed. SUMMARY: The diagnosis of AMR rests on histopathological and immunophenotypic findings. These provide the basis for a new grading scheme. PMID- 22498651 TI - Plasma cell hepatitis (de-novo autoimmune hepatitis) developing post liver transplantation. AB - PURPOSE OF REVIEW: Cases of de-novo autoimmune hepatitis/plasma cell hepatitis (PCH) are increasingly being diagnosed by liver transplant centers. Its pathogenesis is poorly understood but this entity appears to be a variant of rejection. Herein, we review recent clinical reports of patients developing PCH. RECENT FINDINGS: Histologically, PCH is a challenging diagnosis, especially in the setting of recurrent hepatitis C and, in some cases, can be mistaken for acute cellular rejection. Recent case reports and case-control studies have shown that interferon appears to trigger PCH in hepatitis C posttransplant patients. Optimization of the immunosuppression regimen was found to prevent the development of PCH. In the nonhepatitis C posttransplant patient, tacrolimus based immunosuppression appears to have some protective effect from PCH development. A combination therapy of cyclosporine and everolimus has also been shown to be effective in treating PCH. SUMMARY: PCH is a variant of rejection and is a cause of late graft loss post liver transplantation, especially in patients with hepatitis C. It should be part of the differential diagnosis of abnormal liver enzyme tests occurring in the post-liver transplant setting. PMID- 22498652 TI - Intestinal transplantation: where are we? Where are we going? PMID- 22498653 TI - Molecular phenotyping of aging in single yeast cells using a novel microfluidic device. AB - Budding yeast has served as an important model organism for aging research, and previous genetic studies have led to the discovery of conserved genes/pathways that regulate lifespan across species. However, the molecular causes of aging and death remain elusive, because it is very difficult to directly observe the cellular and molecular events accompanying aging in single yeast cells by the traditional approach based on micromanipulation. We have developed a microfluidic system to track individual mother cells throughout their lifespan, allowing automated lifespan measurement and direct observation of cell cycle dynamics, cell/organelle morphologies, and various molecular markers. We found that aging of the wild-type cells is characterized by an increased general stress and a progressive lengthening of the cell cycle for the last few cell divisions; these features are much less apparent in the long-lived FOB1 deletion mutant. Following the fate of individual cells revealed that there are different forms of cell death that are characterized by different terminal cell morphologies, and associated with different levels of stress and lifespan. We have identified a molecular marker - the level of the expression of Hsp104, as a good predictor for the lifespan of individual cells. Our approach allows detailed molecular phenotyping of single cells in the process of aging and thus provides new insight into its mechanism. PMID- 22498654 TI - Mapping the electrophysiological marker of sleep depth reveals skill maturation in children and adolescents. AB - Electroencephalographically (EEG) recorded slow wave activity (SWA, 1-4.5Hz), reflecting the depth of sleep, is suggested to play a crucial role in synaptic plasticity. Mapping of SWA by means of high-density EEG reveals that cortical regions showing signs of maturational changes (structural and behavioral) during childhood and adolescence exhibit more SWA. Moreover, the maturation of specific skills is predicted by the topographical distribution of SWA. Thus, SWA topography may serve as a promising neuroimaging tool with prognostic potential. Finally, our data suggest that deep sleep SWA in humans is involved in cortical development that optimizes performance. PMID- 22498657 TI - Combined structural and resting-state functional MRI analysis of sexual dimorphism in the young adult human brain: an MVPA approach. AB - There has been growing interest recently in the use of multivariate pattern analysis (MVPA) to decode information from high-dimensional neuroimaging data. The present study employed a support vector machine-based MVPA approach to identify the complex patterns of sex differences in brain structure and resting state function. We also aimed to assess the role of anatomy on functional sex differences during rest. One hundred and forty healthy young Chinese adults (70 men and 70 women) underwent structural and resting-state functional MRI scans. Gray matter density and regional homogeneity (ReHo) were used to map brain structure and resting-state function, respectively. After combining these two feature vectors into one union-vector, a pattern classifier was designed using principal component analysis and linear support vector machine to identify brain areas that had distinct characteristics between the groups. We found that: (1) male and female brains were different with a mean classification accuracy of 89%; (2) sex differences in gray matter density were widely distributed in the brain, notably in the occipital lobe and the cerebellum; (3) men primarily showed higher ReHo in their right hemispheres and women tended to show greater ReHo in their left hemispheres; (4) about 50% of brain areas with functional sex differences exhibited significant positive correlations between gray matter density and ReHo. Our results suggest that sex is an important factor that account for interindividual variability in the healthy brain. PMID- 22498656 TI - Atlas-based analysis of resting-state functional connectivity: evaluation for reproducibility and multi-modal anatomy-function correlation studies. AB - Resting state functional connectivity MRI (rsfc-MRI) reveals a wealth of information about the functional organization of the brain, but poses unique challenges for quantitative image analysis, mostly related to the large number of voxels with low signal-to-noise ratios. In this study, we tested the idea of using a prior spatial parcellation of the entire brain into various structural units, to perform an analysis on a structure-by-structure, rather than voxel-by voxel, basis. This analysis, based upon atlas parcels, potentially offers enhanced SNR and reproducibility, and can be used as a common anatomical framework for cross-modality and cross-subject quantitative analysis. We used Large Deformation Diffeomorphic Metric Mapping (LDDMM) and a deformable brain atlas to parcel each brain into 185 regions. To investigate the precision of the cross-subject analysis, we computed inter-parcel correlations in 20 participants, each of whom was scanned twice, as well as the consistency of the connectivity patterns inter- and intra-subject, and the intersession reproducibility. We report significant inter-parcel correlations consistent with previous findings, and high test-retest reliability, an important consideration when the goal is to compare clinical populations. As an example of the cross-modality analysis, correlation with anatomical connectivity is also examined. PMID- 22498658 TI - The advantage of brief fMRI acquisition runs for multi-voxel pattern detection across runs. AB - Functional magnetic resonance imaging (fMRI) studies are broken up into runs (or 'sessions'), frequently selected to be long to minimize across-run signal variations. For investigations that use multi-voxel pattern analysis (MVPA), however, employing many short runs might improve a classifier's ability to generalize across irrelevant pattern variations and detect condition-related activity patterns. We directly tested this hypothesis by scanning participants with both long and short runs and comparing MVPA performance using data from each set of runs. Every run included presentations of faces, places, man-made objects and fruit in a blocked 1-back design. MVPA performance significantly improved from using a large number of short runs, compared to several long runs, in across run classifications with identical amounts of data. Superior classification was found across variations in the classifier employed, feature selection procedure and region of interest. Performance improvements also extended to an information brain mapping 'searchlight' procedure. These results suggest that investigators looking to maximize the detection of subtle multi-voxel patterns across runs might consider employing short fMRI runs. PMID- 22498659 TI - Crotamine pharmacology revisited: novel insights based on the inhibition of KV channels. AB - Crotamine, a 5-kDa peptide, possesses a unique biological versatility. Not only has its cell-penetrating activity become of clinical interest but, moreover, its potential selective antitumor activity is of great pharmacological importance. In the past, several studies have attempted to elucidate the exact molecular target responsible for the crotamine-induced skeletal muscle spasm. The aim of this study was to investigate whether crotamine affects voltage-gated potassium (K(V)) channels in an effort to explain its in vivo effects. Crotamine was studied on ion channel function using the two-electrode voltage clamp technique on 16 cloned ion channels (12 K(V) channels and 4 Na(V) channels), expressed in Xenopus laevis oocytes. Crotamine selectively inhibits K(V)1.1, K(V)1.2, and K(V)1.3 channels with an IC(50) of ~300 nM, and the key amino acids responsible for this molecular interaction are suggested. Our results demonstrate for the first time that the symptoms, which are observed in the typical crotamine syndrome, may result from the inhibition of K(V) channels. The ability of crotamine to inhibit the potassium current through K(V) channels unravels it as the first snake peptide with the unique multifunctionality of cell-penetrating and antitumoral activity combined with K(V) channel-inhibiting properties. This new property of crotamine might explain some experimental observations and opens new perspectives on pharmacological uses. PMID- 22498660 TI - Effects of nucleotide analogs at the P2X3 receptor and its mutants identify the agonist binding pouch. AB - In this study, we investigated the effects of single alanine substitutions of amino acid residues in the supposed ATP binding site of the human P2X3 receptor on the agonistic effect of nucleotide analogs. The wild-type and mutant receptors were expressed in HEK293 cells, and the nucleotide effects were measured by means of the whole-cell patch-clamp method. Modifications in the receptor binding site changed the concentration-response relationship, the current kinetics, and the recovery from desensitization during fast, pulsed, local agonist applications. On the basis of this fact, we were able to distinguish binding from other effects, such as gating/desensitization, by using a hidden Markov model that describes the complete channel behavior with a matrix of rate constants. The binding energies of the nucleotide analogs were calculated and compared with the binding energies of ATP at both the wild-type receptor and its alanine mutants. Changes in the binding energies caused by alterations in the receptor and/or agonist structures were concluded to be attributable to the preferential binding of certain structural constituents of ATP to certain amino acid moieties of the receptor. The results were also checked for consistency with a P2X3 homology model that we developed from the known zebrafish P2X4 crystal structure in the closed state. The functional data correlated well with the predictions of the agonist dockings to the structural model. PMID- 22498662 TI - Isonicotinamide self-association: the link between solvent and polymorph nucleation. AB - We show that, in a controlled and reproducible way, specific solvents lead to specific polymorphic forms of isonicotinamide. We argue on the basis of Raman and FTIR spectroscopy that the hydrogen bonding in solution kinetically drives the nucleation towards a specific form. This generally may lead to good understanding and control of polymorphism and crystal nucleation. PMID- 22498663 TI - Effects of peripheral sensory nerve stimulation plus task-oriented training on upper extremity function in patients with subacute stroke: a pilot randomized crossover trial. AB - OBJECTIVE: To investigate the feasibility of peripheral sensory nerve stimulation combined with task-oriented training in patients with stroke during inpatient rehabilitation. DESIGN: A pilot randomized crossover trial. SETTING: Two rehabilitation hospitals. SUBJECTS: Twenty-two patients with subacute stroke. INTERVENTIONS: Participants were randomly assigned to two groups and underwent two weeks of training in addition to conventional inpatient rehabilitation. The immediate group underwent peripheral sensory nerve stimulation combined with task oriented training in the first week, followed by another week with task-oriented training alone. The delayed group underwent the same training in reverse order. MAIN MEASURES: Outcome measures were the level of fatigue and Wolf Motor Function Test. Patients were assessed at baseline, one and two weeks. RESULTS: All participants completed the study with no adverse events. There was no significant difference in level of fatigue between each treatment. From baseline to one week, the immediate group showed larger improvements than the delayed groups in the Wolf Motor Function Test (decrease in mean time (+/- SD) from 41.9 +/- 16.2 seconds to 30.6 +/- 11.4 seconds versus from 46.8 +/- 19.4 seconds to 42.9 +/- 14.7 seconds, respectively) but the difference did not reach significance after Bonferroni correction (P = 0.041). Within-group comparison showed significant improvements in the Wolf Motor Function Test mean time after the peripheral sensory nerve stimulation combined with task-oriented training periods in each group (P < 0.01). CONCLUSION: Peripheral sensory nerve stimulation is feasible in clinical settings and may enhance the effects of task-oriented training in patients with subacute stroke. PMID- 22498664 TI - Postural control in elderly women with osteoporosis: comparison of balance, strengthening and stretching exercises. A randomized controlled trial. AB - OBJECTIVE: To compare the efficacy of balance training associated with muscle strengthening or stretching, relative to no intervention, in the postural control of elderly women with osteoporosis. DESIGN: A randomized, controlled trial. SUBJECTS AND INTERVENTIONS: Sample consisted of 50 women aged 65 years or older, with osteoporosis, randomized into one of three groups: strengthening group (n = 17) performed balance training with muscle strengthening; stretching group (n = 17) performed balance training with stretching; and control group (n = 16), no activities. Interventions lasted eight weeks, twice a week, 60 minutes a day. MAIN MEASURES: Postural control was evaluated by the modified Clinical Test of Sensory Interaction for Balance (CTSIBm) and Limits of Stability Test. Strength was assessed by dynamometry and the shortening of the hamstrings by goniometry. RESULTS: Relative to controls, participants in the strengthening group displayed significantly increased dorsiflexion strength and knee flexion strength, as well as centre of pressure velocity, directional control, and oscillation velocity (CTSIBm test). The stretching group had significantly improvements in hamstring length, knee flexion strength, centre of pressure velocity, and amplitude of movements. Relative to the stretching group, the strengthening group yielded better knee extension strength and directional control. CONCLUSION: The results suggest that both interventions are effective in improving postural control when compared to the control group, and the strengthening group was superior to the stretching group in knee extension strength and in directional control. PMID- 22498665 TI - Optimized thermal desorption for improved sensitivity in trace explosives detection by ion mobility spectrometry. AB - In this work we evaluate the influence of thermal desorber temperature on the analytical response of a swipe-based thermal desorption ion mobility spectrometer (IMS) for detection of trace explosives. IMS response for several common high explosives ranging from 0.1 ng to 100 ng was measured over a thermal desorber temperature range from 60 degrees C to 280 degrees C. Most of the explosives examined demonstrated a well-defined maximum IMS signal response at a temperature slightly below the melting point. Optimal temperatures, giving the highest IMS peak intensity, were 80 degrees C for trinitrotoluene (TNT), 100 degrees C for pentaerythritol tetranitrate (PETN), 160 degrees C for cyclotrimethylenetrinitramine (RDX) and 200 degrees C for cyclotetramethylenetetranitramine (HMX). By modifying the desorber temperature, we were able to increase cumulative IMS signal by a factor of 5 for TNT and HMX, and by a factor of 10 for RDX and PETN. Similar signal enhancements were observed for the same compounds formulated as plastic-bonded explosives (Composition 4 (C 4), Detasheet, and Semtex). In addition, mixtures of the explosives exhibited similar enhancements in analyte peak intensities. The increases in sensitivity were obtained at the expense of increased analysis times of up to 20 seconds. A slow sample heating rate as well as slower vapor-phase analyte introduction rate caused by low-temperature desorption enhanced the analytical sensitivity of individual explosives, plastic-bonded explosives, and explosives mixtures by IMS. Several possible mechanisms that can affect IMS signal response were investigated such as thermal degradation of the analytes, ionization efficiency, competitive ionization from background, and aerosol emission. PMID- 22498655 TI - Multi-source feature learning for joint analysis of incomplete multiple heterogeneous neuroimaging data. AB - Analysis of incomplete data is a big challenge when integrating large-scale brain imaging datasets from different imaging modalities. In the Alzheimer's Disease Neuroimaging Initiative (ADNI), for example, over half of the subjects lack cerebrospinal fluid (CSF) measurements; an independent half of the subjects do not have fluorodeoxyglucose positron emission tomography (FDG-PET) scans; many lack proteomics measurements. Traditionally, subjects with missing measures are discarded, resulting in a severe loss of available information. In this paper, we address this problem by proposing an incomplete Multi-Source Feature (iMSF) learning method where all the samples (with at least one available data source) can be used. To illustrate the proposed approach, we classify patients from the ADNI study into groups with Alzheimer's disease (AD), mild cognitive impairment (MCI) and normal controls, based on the multi-modality data. At baseline, ADNI's 780 participants (172AD, 397 MCI, 211 NC), have at least one of four data types: magnetic resonance imaging (MRI), FDG-PET, CSF and proteomics. These data are used to test our algorithm. Depending on the problem being solved, we divide our samples according to the availability of data sources, and we learn shared sets of features with state-of-the-art sparse learning methods. To build a practical and robust system, we construct a classifier ensemble by combining our method with four other methods for missing value estimation. Comprehensive experiments with various parameters show that our proposed iMSF method and the ensemble model yield stable and promising results. PMID- 22498666 TI - A subject-independent method for automatically grading electromyographic features during a fatiguing contraction. AB - Many studies have attempted to monitor fatigue from electromyogram (EMG) signals. However, fatigue affects EMG in a subject-specific manner. We present here a subject-independent framework for monitoring the changes in EMG features that accompany muscle fatigue based on principal component analysis and factor analysis. The proposed framework is based on several time- and frequency-domain features, unlike most of the existing work, which is based on two to three features. Results show that latent factors obtained from factor analysis on these features provide a robust and unified framework. This framework learns a model from EMG signals of multiple subjects, that form a reference group, and monitors the changes in EMG features during a sustained submaximal contraction on a test subject on a scale from zero to one. The framework was tested on EMG signals collected from 12 muscles of eight healthy subjects. The distribution of factor scores of the test subject, when mapped onto the framework was similar for both the subject-specific and subject-independent cases. PMID- 22498667 TI - Sub-20 nm laser ablation for lithographic dry development. AB - Pattern collapse of small or high aspect ratio lines during traditional wet development is a major challenge for miniaturization in nanolithography. Here we report on a new dry process which combines high resolution resist exposure with selective laser ablation to achieve high resolution with high aspect ratios. Using a low power 532 nm laser, we dry develop a normally negative tone methyl acetoxy calix(6)arene in positive tone to reveal sub-20 nm half-pitch features in a ~100 nm film at aspect ratios unattainable with conventional development with ablation time of 1-2 s per laser pixel (~600 nm diameter spot). We also demonstrate superior negative tone wet development by combining electron beam exposure with subsequent laser exposure at a non-ablative threshold that requires far less electron beam exposure doses than traditional wet development. PMID- 22498668 TI - Distal soft tissue realignment and proximal metatarsal countersinking osteotomy for moderate to severe hallux valgus. AB - BACKGROUND: Hallux valgus is a common condition and surgical correction has remained a challenge. OBJECTIVE: To evaluate the results of distal soft tissue realignment and proximal 1st metatarsal countersinking osteotomy for the treatment of moderate to severe hallux valgus deformity. MATERIALS AND METHODS: This prospective study included 33 ft in 28 patients. The deformity was moderate in 27 ft (23 patients), severe in six ft (five patients) and bilateral in five patients. All operations were performed as a primary procedure with an average duration of follow-up of 28.2 months (range 10-45 months). RESULTS: The average hallux valgus angle was improved from 32.5 degrees to 8 degrees and the first intermetatarsal angle from 16.5 degrees to 7.7 degrees . According to the symptomatic score of Broughton and Winson, 22 ft (18 patients) were rated excellent, nine good and two poor. The average American Orthopedic Foot Ankle Society score at the final follow-up was 89.3 (range 65-100). Recurrence of the valgus deformity was seen in three patients and hallux varus in two patients. CONCLUSIONS: The current procedure proved to be effective to correct all components of hallux valgus deformity regardless of its severity. PMID- 22498669 TI - A 6-antibody panel for the classification of lung adenocarcinoma versus squamous cell carcinoma. AB - Non-small cell lung cancer can be classified into several histologic subtypes, most commonly lung adenocarcinoma (LADC) or squamous cell carcinoma (SqCC). With the introduction of targeted therapies that can result in dramatically different outcomes based on subtype, the importance of accurate classification has been amplified. Six antibodies (Napsin A, Desmoglein 3, TTF-1, CK5, p63, and tripartite motif-containing 29) were selected for evaluation on cases of LADC of lung SqCC. Guided by the sensitivities and specificities determined for individual antibodies, a protocol was developed using a sequential series of 2 antibody cocktails that resulted in the classification of 93% of cases with 100% specificity. Importantly, the initial step in this method, a napsin A+Desmoglein 3 antibody cocktail classified >85% of cases, resulting in <15% of cases requiring further evaluation beyond a single test. Two new antibodies specifically developed and optimized for the diagnosis of LADC and lung SqCC, a rabbit polyclonal Napsin A and a mouse monoclonal Desmoglein 3 [BC11], were the key elements of the antibody panel. Most importantly, the described protocol uses routine interpretation methods and an uncomplicated algorithm for classification. Given the increased difficulty of diagnosing poorly differentiated tumors, the ability of this 6-antibody panel to classify 96% and 87% of moderately and poorly differentiated cases, respectively, is of particular value, especially when limited tissue for molecular testing is an issue. PMID- 22498670 TI - Utility of cytokeratin 5/6, cytokeratin 20, and p16 in the diagnosis of reactive urothelial atypia and noninvasive component of urothelial neoplasia. AB - BACKGROUND: The utility of cytokeratin (CK)5/6 in distinguishing reactive urothelial atypia (RA) from urothelial carcinoma in situ (CIS) and from noninvasive component of high-grade papillary urothelial carcinoma (PUC) is unknown. DESIGN: Twenty RA with or without papillary hyperplasia and 90 noninvasive components of neoplastic urothelial lesions were submitted for immunostaining with CK5/6, CK20, and p16. RESULTS: Diffuse and strong reactivity involving the full or nearly full thickness of urothelium was observed with CK5/6 in 90% of RA cases. CK20 and p16 were negative in 90% and 85% of the RA cases, respectively. For CIS and noninvasive components of high-grade PUC without squamous differentiation, there was no CK5/6 staining or reactivity in the basal layer only. CK20 and p16 showed strong positivity in full thickness of urothelium in 75% to 85% of cases. CIS with weak/focal or negative reactivity for p16 or CK20 exhibited moderate cytologic atypia. Low-grade PUC displayed variable reactivity for CK5/6, CK20, and p16. Urothelial lesions with squamoid or basaloid features showed positive reactivity for CK5/6. Urothelial lesions with glandular differentiation showed negative reactivity for CK5/6. CONCLUSIONS: Diffuse CK5/6 reactivity in RA and negative CK5/6 reactivity in CIS and PUC may be helpful in distinguishing between these 2 entities. PMID- 22498671 TI - Is PAX2 a reliable marker in differentiating diffuse malignant mesotheliomas of peritoneum from serous carcinomas of mullerian origin? AB - Diffuse peritoneal malignant mesotheliomas (DPMM) are often disseminated in the peritoneal cavity as multiple nodules including localized masses in the ovaries that are clinically and histologically similar to serous adenocarcinomas of mullerian origin. It is imperative to differentiate these tumors given their diverse responses to chemotherapy and/or radiotherapy. PAX2 gene was recently demonstrated in benign epithelial cells of the female genital tract and in serous carcinomas (SC) of mullerian origin. The aim of our study was to determine if PAX2 can reliably be used in differentiating DPMM from SC. A total of 59 cases to include 25 cases of DPMM and 34 cases of SC were retrieved. All cases were stained with PAX2, Wilm tumor gene 1, calretinin and the results were compared. Our results demonstrate that PAX2 can be used reliably as a Mullerian marker in formulating an efficient panel to differentiate DPMM and SC. PMID- 22498672 TI - EXIT procedure for fetal neck masses. AB - PURPOSE OF REVIEW: The ex-utero intrapartum treatment (EXIT procedure) can be life-saving for fetuses with large neck masses. Advances in fetal imaging and access to prenatal care have improved the ability to anticipate and plan for the treatment of these fetuses. This review will highlight advances in imaging techniques, modification of anesthesia and case selection for the EXIT procedure. Long-term maternal and fetal outcomes will also be discussed. RECENT FINDINGS: There have been relatively few articles published on this subject in the past 18 months. A better understanding of the effect of inhalational anesthetics on fetal cardiac function and some insight into the pharmacokinetics of narcotics while on uteroplacental support has been gained. Imaging characteristics that may improve patient selection have been proposed. The long-term outcomes of mothers undergoing fetal surgical procedures in general and specifically those undergoing EXIT procedures suggest that the EXIT procedure can be performed with minimal maternal morbidity in skilled hands. Furthermore, long-term neonatal outcomes appear to be improving, but further studies are needed. SUMMARY: The EXIT procedure can be performed safely in a skilled multidisciplinary setting with minimal maternal and fetal morbidity and excellent fetal outcomes. Recent reports have helped further identify which fetuses will benefit from the EXIT procedure. PMID- 22498673 TI - Neuromuscular disease and the pulmonologist. AB - PURPOSE OF REVIEW: The heterogeneous nature of neuromuscular disorders (NMDs) continues to promote slow but steady advances in diagnosis, classification, and treatment. This review focuses on the updates in the general management and treatment of NMDs, with emphasis on key updates in muscular dystrophy, myotonic dystrophy, mitochondrial myopathy, spinal muscular atrophy, and hereditary neuropathies. RECENT FINDINGS: Current research shows that improvements in morbidity and mortality in various NMDs may be possible. Key components include advances in identification and classification of individual NMDs; attention to anesthetic and surgical risks; aggressive pulmonary care; and implementations of a proactive, multidisciplinary, standard-of-care approach. Innovative molecular and pharmaceutical therapeutic options are being investigated in many of these disorders, but unfortunately no new intervention has borne out. SUMMARY: Important advances were made in the last year in the field of neuromuscular disease. However, because of their heterogeneous nature and rarity, diagnosis and treatment of these disorders either as a single disorder or as a group continue to be both a clinical and a research challenge. It is of utmost importance that clinicians and researchers be aware of these disorders to aid in identification and treatment. PMID- 22498674 TI - Pressure ulcers in the pediatric patient. AB - PURPOSE OF REVIEW: In contrast to adult literature, data for pressure ulcers in children is limited. Incidence and prevalence of this skin integrity issue in pediatric hospitals is still widely unknown, perhaps because increased awareness and prevention of the phenomenon have been slow to develop. Moreover, identification of at-risk patients is lacking, and current guidelines and interventions to prevent skin breakdown are those that have been adapted from adult care and are not supported by evidence-based data in children. RECENT FINDINGS: Awareness and prevention of pressure ulcers in the pediatric acute care setting are becoming a priority. In 2008, the Centers for Medicare and Medicaid Services listed certain hospital acquired conditions for which facilities would no longer be additionally reimbursed. A pressure ulcer, stage III or higher, is included in that list and referred to as a 'never event' as it is a condition that could be reasonably prevented by use of evidence-based guidelines. SUMMARY: Pediatric pressure ulcers are a serious and largely preventable condition. Increased awareness, and accurate and timely assessment to recognize at-risk children, can lead to pressure ulcer prevention. More studies are needed to better define risk factors and effective prevention of pediatric pressure ulcers. PMID- 22498675 TI - Chylothorax after surgery for congenital heart disease. AB - PURPOSE OF REVIEW: Postoperative chylothorax is a frequently encountered pathology in the cardiac intensive care unit. The continuous loss of chyle is a challenging problem to treat and is associated with increased morbidity and mortality. The purpose of this article is to review the pathophysiology of chylothorax in patients after surgery for congenital heart disease, its implications and the current therapies available. RECENT FINDINGS: The incidence of chylothorax has been increasing over the last two decades. Multiple uncontrolled case series describe octreotide as an effective treatment, and octreotide usage is increasing around the world for patients nonresponsive to dietary modifications. Most centers reserve surgical treatment for patients nonresponsive after 4 weeks of medical treatment. Less-invasive surgical procedures such as thoracic duct ligation by video-assisted thoracoscopy are gaining popularity. SUMMARY: Chylothorax is commonly seen in children after surgery for congenital heart disease. The multiple and serious complications associated with chylous effusions are well known. Conservative therapy with diet modification and octreotide remain the standard initial approach. Thoracic duct ligation has been reported as a highly successful treatment but has considerable risk. Thus, this procedure should be reserved for patients nonresponsive to conservative therapy. PMID- 22498676 TI - [Impairment of emotional behaviors induced by early postnatal stress]. PMID- 22498677 TI - [Functional analysis of stress-responsible transcription factor Npas4 in stress induced brain dysfunction]. PMID- 22498678 TI - [Role of prostaglandin signaling in stress and its implication in pharmaceutical development of antidepressants]. PMID- 22498679 TI - [Pharmacological treatment strategies targeting cognitive impairment associated with aging]. AB - Amnestic mild cognitive impairment (aMCI) is associated with increased activation in the CA3-dentate region of hippocampus. Excess CA3 activity also occurs in aged rats with memory impairment. Therapies to counter such excess activity might include antiepileptics or agonists for GABA(A) alpha5 receptors, which regulate tonic inhibition. Use of GABA(A) alpha5 agonists may seem unexpected because GABA(A) alpha5 inverse agonists were developed as cognitive enhancers. We found that inverse agonists, while yielding benefit in normal young adult rats, are not effective in treating memory loss in aged rats. Instead, aged rats showed improved memory after treatment with selective GABA(A) alpha5 agonists and with certain antiepileptics. These benefits of treatment are consistent with the concept that excess activity in the CA3 of the hippocampus is a dysfunctional condition contributing to age-associated memory impairment. Because excess hippocampal activation is also observed in aMCI, our findings support the use of antiepileptic or GABA(A) alpha5 agonist therapy in aMCI. Such therapy, in addition to memory improvement, may also have disease modifying potential because hippocampal overactivity in aging/MCI predicts further cognitive decline and conversion to Alzheimer's disease. PMID- 22498680 TI - [Mechanisms of itch and the pharmacology of anti-pruritic agents]. PMID- 22498681 TI - [Glutamate signaling in non-neuronal tissues]. PMID- 22498682 TI - [Introduction to Good Manufacturing Practice for investigational agents]. PMID- 22498683 TI - [Pharmacological and clinical profiles of the DPP-4 inhibitor linagliptin (Trazenta)]. PMID- 22498684 TI - Development of an algorithm for the diagnosis of otitis media. PMID- 22498686 TI - Norepinephrine-mediated emotional arousal facilitates subsequent pattern separation. AB - Pattern separation, the process by which similar experiences can be stored as distinct memories, has been ascribed to the dentate gyrus (DG) of the hippocampus. The DG is the target of noradrenergic modulation directly and indirectly via the basolateral amygdala. We tested the hypothesis that noradrenergic activation (tested using salivary alpha-amylase) potentiates DG function, enhancing pattern separation, by showing participants fearful stimuli in a pre-training task and then testing their capacity for pattern separation in a later test. Consistent with our hypothesis, we found that increased levels of salivary alpha-amylase were positively correlated with enhanced pattern separation performance even after accounting for general enhancements in recognition. PMID- 22498687 TI - Evaluation of specialized medication packaging combined with medication therapy management: adherence, outcomes, and costs among Medicaid patients. AB - BACKGROUND: This study evaluates the effect of a program combing specialized medication packaging and telephonic medication therapy management on medication adherence, health care utilization, and costs among Medicaid patients. RESEARCH DESIGN: A retrospective cohort design compared Medicaid participants who voluntarily enrolled in the program (n = 1007) compared with those who did not (n = 13,614). Main outcome measures were medication adherence at 12 months, hospital admissions and emergency department visits at 6 and 12 months, and total paid claim costs at 6 and 12 months. Multivariate regression models were used to adjust for the effect of age, sex, race, comorbidities, and 12-month preenrollment health care utilization. RESULTS: Measures of medication adherence were significantly improved in the program cohort compared with the usual care cohort. At 6 months, adjusted all-cause hospitalization was marginally less in the program cohort compared with the usual care cohort [odds ratio = 0.73, 95% confidence interval (CI), 0.54-1.0, P = 0.05]. No statistically significant differences were observed between the 2 cohorts for any of the other adjusted utilization endpoints at 6 or 12 months. Adjusted total cost at 6 and 12 months were higher in the program cohort (6-month cost ratio = 1.76, 95% CI,1.65-1.89; 12-month cost ratio = 1.84, 95% CI,1.72-1.97), primarily because of an increase in prescription costs. Emergency department visits and hospitalization costs did not differ between groups. CONCLUSIONS: : The program improved measures of medication adherence, but the effect on health care utilization and nonpharmacy costs at 6 and 12 months was not different from the usual care group. Reasons for these findings may reflect differences in the delivery of the specialized packaging and the medication therapy management program, health care behaviors in this Medicaid cohort, unadjusted confounding, or time required for the benefit of the intervention to manifest. PMID- 22498688 TI - Can naive viewers put themselves in the patients' shoes?: reliability and validity of the analogue patient methodology. AB - BACKGROUND: Analogue patients (APs) are untrained viewers given the task of viewing and rating their impressions of a medical interaction while taking on the patient role. This methodology is often used to assess patient perceptions when using real patient (RP) populations is unethical or impractical. OBJECTIVES: This study examines the reliability and validity of the AP methodology and its optimal implementation. RESEARCH DESIGN: Forty-six videotaped interactions of RP physician interactions, where RP satisfaction scores existed, were viewed by 216 APs, who rated satisfaction. Interrater reliability for AP satisfaction scores was evaluated. AP and RP satisfaction scores were compared with each other and correlated with the physician's observer-coded patient-centeredness. MEASURES: RP satisfaction was measured with a 15-item scale after the whole interaction. Physicians' patient-centered behavior was coded with the Four Habits Coding Scheme. AP satisfaction was measured after viewing the entire interaction with a single satisfaction question, a 4-item satisfaction scale including that single item, and the original 15-item satisfaction scale used by the RPs. RESULTS: AP satisfaction ratings were reliable (=0.70 for 4 APs). AP satisfaction was a significant predictor of RP satisfaction (r=0.29, P=0.05), especially when the analysis was limited to the RPs who reported being less than perfectly satisfied (r=0.65, P=0.002). AP satisfaction was a better predictor than RP satisfaction of providers' patient-centered behaviors in the interaction. CONCLUSIONS: The AP methodology is a valid and reliable approach to gathering patient perception data about provider-patient interactions. Results suggest practical advice for researchers using the AP methodology. PMID- 22498689 TI - An integrated region-, boundary-, shape-based active contour for multiple object overlap resolution in histological imagery. AB - Active contours and active shape models (ASM) have been widely employed in image segmentation. A major limitation of active contours, however, is in their 1) inability to resolve boundaries of intersecting objects and to 2) handle occlusion. Multiple overlapping objects are typically segmented out as a single object. On the other hand, ASMs are limited by point correspondence issues since object landmarks need to be identified across multiple objects for initial object alignment. ASMs are also are constrained in that they can usually only segment a single object in an image. In this paper, we present a novel synergistic boundary and region-based active contour model that incorporates shape priors in a level set formulation with automated initialization based on watershed. We demonstrate an application of these synergistic active contour models using multiple level sets to segment nuclear and glandular structures on digitized histopathology images of breast and prostate biopsy specimens. Unlike previous related approaches, our model is able to resolve object overlap and separate occluded boundaries of multiple objects simultaneously. The energy functional of the active contour is comprised of three terms. The first term is the prior shape term, modeled on the object of interest, thereby constraining the deformation achievable by the active contour. The second term, a boundary-based term detects object boundaries from image gradients. The third term drives the shape prior and the contour towards the object boundary based on region statistics. The results of qualitative and quantitative evaluation on 100 prostate and 14 breast cancer histology images for the task of detecting and segmenting nuclei and lymphocytes reveals that the model easily outperforms two state of the art segmentation schemes (geodesic active contour and Rousson shape-based model) and on average is able to resolve up to 91% of overlapping/occluded structures in the images. PMID- 22498690 TI - Gaussian process models of dynamic PET for functional volume definition in radiation oncology. AB - In routine oncologic positron emission tomography (PET), dynamic information is discarded by time-averaging the signal to produce static images of the "standardised uptake value" (SUV). Defining functional volumes of interest (VOIs) in terms of SUV is flawed, as values are affected by confounding factors and the chosen time window, and SUV images are not sensitive to functional heterogeneity of pathological tissues. Also, SUV iso-contours are highly affected by the choice of threshold and no threshold, or other SUV-based segmentation method, is universally accepted for a given VOI type. Gaussian Process (GP) time series models describe macro-scale dynamic behavior arising from countless interacting micro-scale processes, as is the case for PET signals from heterogeneous tissue. We use GPs to model time-activity curves (TACs) from dynamic PET and to define functional volumes for PET oncology. Probabilistic methods of tissue discrimination are presented along with novel contouring methods for functional VOI segmentation. We demonstrate the value of GP models for voxel classification and VOI contouring of diseased and metastatic tissues with functional heterogeneity in prostate PET. Classification experiments reveal superior sensitivity and specificity over SUV calculation and a TAC-based method proposed in recent literature. Contouring experiments reveal differences in shape between gold-standard and GP VOIs and correlation with kinetic models shows that the novel VOIs contain extra clinically relevant information compared to SUVs alone. We conclude that the proposed models offer a principled data analysis technique that improves on SUVs for oncologic VOI definition. Continuing research will generalize GP models for different oncology tracers and imaging protocols with the ultimate goal of clinical use including treatment planning. PMID- 22498691 TI - Investigation of a bio-inspired lift-enhancing effector on a 2D airfoil. AB - A flap mounted on the upper surface of an airfoil, called a 'lift-enhancing effector', has been shown in wind tunnel tests to have a similar function to a bird's covert feathers, which rise off the wing's surface in response to separated flows. The effector, fabricated from a thin Mylar sheet, is allowed to rotate freely about its leading edge. The tests were performed in the NCSU subsonic wind tunnel at a chord Reynolds number of 4 * 10(5). The maximum lift coefficient with the effector was the same as that for the clean airfoil, but was maintained over an angle-of-attack range from 12 degrees to almost 20 degrees , resulting in a very gentle stall behavior. To better understand the aerodynamics and to estimate the deployment angle of the free-moving effector, fixed-angle effectors fabricated out of stiff wood were also tested. A progressive increase in the stall angle of attack with increasing effector angle was observed, with diminishing returns beyond the effector angle of 60 degrees . Drag tests on both the free-moving and fixed effectors showed a marked improvement in drag at high angles of attack. Oil flow visualization on the airfoil with and without the fixed-angle effectors proved that the effector causes the separation point to move aft on the airfoil, as compared to the clean airfoil. This is thought to be the main mechanism by which an effector improves both lift and drag. A comparison of the fixed-effector results with those from the free-effector tests shows that the free effector's deployment angle is between 30 degrees and 45 degrees . When operating at and beyond the clean airfoil's stall angle, the free effector automatically deploys to progressively higher angles with increasing angles of attack. This slows down the rapid upstream movement of the separation point and avoids the severe reduction in the lift coefficient and an increase in the drag coefficient that are seen on the clean airfoil at the onset of stall. Thus, the effector postpones the stall by 4-8 degrees and makes the stall behavior more gentle. The benefits of using the effector could include care-free operations at high angles of attack during perching and maneuvering flight, especially in gusty conditions. PMID- 22498692 TI - Targeting the DNA-topoisomerase complex in a double-strike approach with a topoisomerase inhibiting moiety and covalent DNA binder. AB - Ru(II)(arene)-flavonoids with high in vitro antitumour activity were synthesised. These compounds are capable of inhibiting human topoisomerase IIalpha and binding covalently to DNA. PMID- 22498693 TI - Isotocin regulates paternal care in a monogamous cichlid fish. AB - While the survival value of paternal care is well understood, little is known about its physiological basis. Here we investigate the neuroendocrine contributions to paternal care in the monogamous cichlid, Amatitlania nigrofasciata. We first explored the dynamic range of paternal care in three experimental groups: biparental males (control fathers housed with their mate), single fathers (mate removed), or lone males (mate and offspring removed). We found that control males gradually increase paternal care over time, whereas single fathers increased care immediately after mate removal. Males with offspring present had lower levels of circulating 11-ketotestosterone (11-KT) yet still maintained aggressive displays toward brood predators. To determine what brain regions may contribute to paternal care, we quantified induction of the immediate early gene c-Fos, and found that single fathers have more c-Fos induction in the forebrain area Vv (putative lateral septum homologue), but not in the central pallium (area Dc). While overall preoptic area c-Fos induction was similar between groups, we found that parvocellular preoptic isotocin (IST) neurons in single fathers showed increased c-Fos induction, suggesting IST may facilitate the increase of paternal care after mate removal. To functionally test the role of IST in regulating paternal care, we treated biparental males with an IST receptor antagonist, which blocked paternal care. Our results indicate that isotocin plays a significant role in promoting paternal care, and more broadly suggest that the convergent evolution of paternal care across vertebrates may have recruited similar neuroendocrine mechanisms. PMID- 22498695 TI - Plasticity of boldness in rainbow trout, Oncorhynchus mykiss: do hunger and predation influence risk-taking behaviour? AB - Boldness, a measure of an individual's propensity for taking risks, is an important determinant of fitness but is not necessarily a fixed trait. Dependent upon an individual's state, and given certain contexts or challenges, individuals may be able to alter their inclination to be bold or shy in response. Furthermore, the degree to which individuals can modulate their behaviour has been linked with physiological responses to stress. Here we attempted to determine whether bold and shy rainbow trout, Oncorhynchus mykiss, can exhibit behavioural plasticity in response to changes in state (nutritional availability) and context (predation threat). Individual trout were initially assessed for boldness using a standard novel object paradigm; subsequently, each day for one week fish experienced either predictable, unpredictable, or no simulated predator threat in combination with a high (2% body weight) or low (0.15%) food ration, before being reassessed for boldness. Bold trout were generally more plastic, altering levels of neophobia and activity relevant to the challenge, whereas shy trout were more fixed and remained shy. Increased predation risk generally resulted in an increase in the expression of three candidate genes linked to boldness, appetite regulation and physiological stress responses - ependymin, corticotrophin releasing factor and GABA(A) - but did not produce a significant increase in plasma cortisol. The results suggest a divergence in the ability of bold and shy trout to alter their behavioural profiles in response to internal and exogenous factors, and have important implications for our understanding of the maintenance of different behavioural phenotypes in natural populations. PMID- 22498694 TI - Neuroprotection with non-feminizing estrogen analogues: an overlooked possible therapeutic strategy. AB - Although many of the effects of estrogens on the brain are mediated through estrogen receptors (ERs), there is evidence that neuroprotective activity of estrogens can be mediated by non-ER mechanisms. Herein, we review the substantial evidence that estrogens neuroprotection is in large part non-ER mediated and describe in vitro and in vivo studies that support this conclusion. Also, we described our drug discovery strategy for capitalizing on enhancement in neuroprotection while at the same time, reducing ER binding of a group of synthetic non-feminizing estrogens. Finally, we offer evidence that part of the neuroprotection of these non-feminizing estrogens is due to enhancement in redox potential of the synthesized compounds. PMID- 22498696 TI - Cardiovascular autonomic neuropathy and subclinical cardiovascular disease in normoalbuminuric type 1 diabetic patients. AB - Cardiovascular autonomic neuropathy (CAN) is associated with increased mortality in diabetes. Since CAN often develops in parallel with diabetic nephropathy as a confounder, we aimed to investigate the isolated impact of CAN on cardiovascular disease in normoalbuminuric patients. Fifty-six normoalbuminuric, type 1 diabetic patients were divided into 26 with (+) and 30 without (-) CAN according to tests of their autonomic nerve function. Coronary artery plaque burden and coronary artery calcium score (CACS) were evaluated using computed tomography. Left ventricular function was evaluated using echocardiography. Blood pressure and electrocardiography were recorded through 24 h to evaluate nocturnal drop in blood pressure (dipping) and pulse pressure. In patients +CAN compared with -CAN, the CACS was higher, and only patients +CAN had a CACS >400. A trend toward a higher prevalence of coronary plaques and flow-limiting stenosis in patients +CAN was nonsignificant. In patients +CAN, left ventricular function was decreased in both diastole and systole, nondipping was more prevalent, and pulse pressure was increased compared with -CAN. In multivariable analysis, CAN was independently associated with increased CACS, subclinical left ventricular dysfunction, and increased pulse pressure. In conclusion, CAN in normoalbuminuric type 1 diabetic patients is associated with distinct signs of subclinical cardiovascular disease. PMID- 22498697 TI - In vivo role of focal adhesion kinase in regulating pancreatic beta-cell mass and function through insulin signaling, actin dynamics, and granule trafficking. AB - Focal adhesion kinase (FAK) acts as an adaptor at the focal contacts serving as a junction between the extracellular matrix and actin cytoskeleton. Actin dynamics is known as a determinant step in insulin secretion. Additionally, FAK has been shown to regulate insulin signaling. To investigate the essential physiological role of FAK in pancreatic beta-cells in vivo, we generated a transgenic mouse model using rat insulin promoter (RIP)-driven Cre-loxP recombination system to specifically delete FAK in pancreatic beta-cells. These RIPcre(+)fak(fl/fl) mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced beta-cell viability and proliferation resulting in decreased beta-cell mass was observed in these mice, which was associated with attenuated insulin/Akt (also known as protein kinase B) and extracellular signal-related kinase 1/2 signaling and increased caspase 3 activation. FAK-deficient beta-cells exhibited impaired insulin secretion with normal glucose sensing and preserved Ca(2+) influx in response to glucose, but a reduced number of docked insulin granules and insulin exocytosis were found, which was associated with a decrease in focal proteins, paxillin and talin, and an impairment in actin depolymerization. This study is the first to show in vivo that FAK is critical for pancreatic beta-cell viability and function through regulation in insulin signaling, actin dynamics, and granule trafficking. PMID- 22498698 TI - Effects of hyperglycemia and effects of ketosis on cerebral perfusion, cerebral water distribution, and cerebral metabolism. AB - Diabetic ketoacidosis (DKA) may cause brain injuries in children. The mechanisms responsible are difficult to elucidate because DKA involves multiple metabolic derangements. We aimed to determine the independent effects of hyperglycemia and ketosis on cerebral metabolism, blood flow, and water distribution. We used magnetic resonance spectroscopy to measure ratios of cerebral metabolites (ATP to inorganic phosphate [Pi], phosphocreatine [PCr] to Pi, N-acetyl aspartate [NAA] to creatine [Cr], and lactate to Cr) and diffusion-weighted imaging and perfusion weighted imaging to assess cerebral water distribution (apparent diffusion coefficient [ADC] values) and cerebral blood flow (CBF) in three groups of juvenile rats (hyperglycemic, ketotic, and normal control). ATP-to-Pi ratio was reduced in both hyperglycemic and ketotic rats in comparison with controls. PCr to-Pi ratio was reduced in the ketotic group, and there was a trend toward reduction in the hyperglycemic group. No significant differences were observed in NAA-to-Cr or lactate-to-Cr ratio. Cortical ADC was reduced in both groups (indicating brain cell swelling). Cortical CBF was also reduced in both groups. We conclude that both hyperglycemia and ketosis independently cause reductions in cerebral high-energy phosphates, CBF, and cortical ADC values. These effects may play a role in the pathophysiology of DKA-related brain injury. PMID- 22498699 TI - Autophagy and phagocytosis-like cell cannibalism exert opposing effects on cellular survival during metabolic stress. AB - Understanding mechanisms controlling neuronal cell death and survival under conditions of altered energy supply (e.g., during stroke) is fundamentally important for the development of therapeutic strategies. The function of autophagy herein is unclear, as both its beneficial and detrimental roles have been described. We previously demonstrated that loss of AMP-activated protein kinase (AMPK), an evolutionarily conserved enzyme that maintains cellular energy balance, leads to activity-dependent degeneration in neuronal tissue. Here, we show that energy depletion in Drosophila AMPK mutants results in increased autophagy that convincingly promotes, rather than rescues, neurodegeneration. The generated excessive autophagic response is accompanied by increased TOR and S6K activity in the absence of an AMPK-mediated negative regulatory feedback loop. Moreover, energy-depleted neurons use a phagocytic-like process as a means to cellular survival at the expense of surrounding cells. Consequently, phagocytosis stimulation by expression of the scavenger receptor Croquemort significantly delays neurodegeneration. This study thus reveals a potentially novel strategy for cellular survival during conditions of extreme energy depletion, resembling xeno-cannibalistic events seen in metastatic tumors. We provide new insights into the roles of autophagy and phagocytosis in the neuronal metabolic stress response and open new avenues into understanding of human disease and development of therapeutic strategies. PMID- 22498701 TI - First EACR Conference on Cell Death in Cancer, Amsterdam, Netherlands, 26-28 January 2012. PMID- 22498700 TI - Caspase-2 deficiency promotes aberrant DNA-damage response and genetic instability. AB - Caspase-2 is an initiator caspase, which has been implicated to function in apoptotic and non-apoptotic signalling pathways, including cell-cycle regulation, DNA-damage signalling and tumour suppression. We previously demonstrated that caspase-2 deficiency enhances E1A/Ras oncogene-induced cell transformation and augments lymphomagenesis in the EMUMyc mouse model. Caspase-2(-/-) mouse embryonic fibroblasts (casp2(-/-) MEFs) show aberrant cell-cycle checkpoint regulation and a defective apoptotic response following DNA damage. Disruption of cell-cycle checkpoints often leads to genomic instability (GIN), which is a common phenotype of cancer cells and can contribute to cellular transformation. Here we show that caspase-2 deficiency results in increased DNA damage and GIN in proliferating cells. Casp2(-/-) MEFs readily escape senescence in culture and exhibit increased micronuclei formation and sustained DNA damage during cell culture and following gamma-irradiation. Metaphase analyses demonstrated that a lack of caspase-2 is associated with increased aneuploidy in both MEFs and in EMUMyc lymphoma cells. In addition, casp2(-/-) MEFs and lymphoma cells exhibit significantly decreased telomere length. We also noted that loss of caspase-2 leads to defective p53-mediated signalling and decreased trans-activation of p53 target genes upon DNA damage. Our findings suggest that loss of caspase-2 serves as a key function in maintaining genomic integrity, during cell proliferation and following DNA damage. PMID- 22498702 TI - Towards a biomarker of motor adaptation: integration of kinematic and neural factors. AB - We propose an experimental protocol for the integrated study of motor adaptation during target-based movements. We investigated how motor adaptation affects both cerebral activity and motor performance during the preparation and execution of a pointing task, under different conditions of external perturbation. Electroencephalography (EEG) and movement analysis were simultaneously recorded from 16 healthy subjects enrolled in the study. EEG signal was preprocessed by means of independent component analysis and empirical mode decomposition based Hilbert Huang transform, in order to extract event-related synchronization (ERS) and desynchronization (ERD) parameters. Movement analysis provided several kinematic indexes, such as movement durations, average jerk, and inter-quartile ranges. Significant correlations between score, neural, and kinematic parameters were found. Specifically, the duration of the going phase of movement was found to correlate with synchronization in the beta brain rhythm, in both the planning and executive phases of movement. Inter-quartile ranges and average jerk showed correlations with executive brain parameters and ERS/ERDcueBeta, respectively. Results indicate the presence of links between the primary motor cortex and the farthest ending point of the upper limb. In the present study, we assessed significant relationship between neural and kinematic descriptors of motor adaptation, during a protocol requiring short-term learning, through the modulation of the external perturbations. PMID- 22498703 TI - Electroencephalography (EEG)-based brain-computer interface (BCI): a 2-D virtual wheelchair control based on event-related desynchronization/synchronization and state control. AB - This study aims to propose an effective and practical paradigm for a brain computer interface (BCI)-based 2-D virtual wheelchair control. The paradigm was based on the multi-class discrimination of spatiotemporally distinguishable phenomenon of event-related desynchronization/synchronization (ERD/ERS) in electroencephalogram signals associated with motor execution/imagery of right/left hand movement. Comparing with traditional method using ERD only, where bilateral ERDs appear during left/right hand mental tasks, the 2-D control exhibited high accuracy within a short time, as incorporating ERS into the paradigm hypothetically enhanced the spatiotemoral feature contrast of ERS versus ERD. We also expected users to experience ease of control by including a noncontrol state. In this study, the control command was sent discretely whereas the virtual wheelchair was moving continuously. We tested five healthy subjects in a single visit with two sessions, i.e., motor execution and motor imagery. Each session included a 20 min calibration and two sets of games that were less than 30 min. Average target hit rate was as high as 98.4% with motor imagery. Every subject achieved 100% hit rate in the second set of wheelchair control games. The average time to hit a target 10 m away was about 59 s, with 39 s for the best set. The superior control performance in subjects without intensive BCI training suggested a practical wheelchair control paradigm for BCI users. PMID- 22498705 TI - Spine and brain malformations in a patient obligate carrier of MTHFR with autism and mental retardation. PMID- 22498704 TI - Closing the loop for memory prosthesis: detecting the role of hippocampal neural ensembles using nonlinear models. AB - A major factor involved in providing closed loop feedback for control of neural function is to understand how neural ensembles encode online information critical to the final behavioral endpoint. This issue was directly assessed in rats performing a short-term delay memory task in which successful encoding of task information is dependent upon specific spatio-temporal firing patterns recorded from ensembles of CA3 and CA1 hippocampal neurons. Such patterns, extracted by a specially designed nonlinear multi-input multi-output (MIMO) nonlinear mathematical model, were used to predict successful performance online via a closed loop paradigm which regulated trial difficulty (time of retention) as a function of the "strength" of stimulus encoding. The significance of the MIMO model as a neural prosthesis has been demonstrated by substituting trains of electrical stimulation pulses to mimic these same ensemble firing patterns. This feature was used repeatedly to vary "normal" encoding as a means of understanding how neural ensembles can be "tuned" to mimic the inherent process of selecting codes of different strength and functional specificity. The capacity to enhance and tune hippocampal encoding via MIMO model detection and insertion of critical ensemble firing patterns shown here provides the basis for possible extension to other disrupted brain circuitry. PMID- 22498706 TI - Mass spectrometry-based detection and quantification of plasma glycoproteins using selective reaction monitoring. AB - Mass spectrometry-based targeted proteomics is a rapidly expanding method for quantifying proteins in complex clinical samples such as plasma. In conjunction with the stable isotope dilution method, selected reaction monitoring (SRM) assays provide unparalleled sensitivity and selectivity for detection and quantification. A crucial factor for robust SRM assays is the reduction of interference by lowering the background. This can be achieved by the selective isolation of a subproteome, such as N-glycosylated proteins, from the original sample. The present protocol includes the development and optimization of SRM assays associated with each peptide of interest and the qualification of assays in the biological matrix to establish the limits of detection and quantification. The protocol also describes the enrichment of formerly N-glycosylated peptides relying on periodate oxidation of glycan moieties attached to the proteins, their immobilization on solid supports through hydrazide chemistry, proteolysis and enzymatic release of the formerly N-glycosylated peptides. PMID- 22498707 TI - A positive/negative ion-switching, targeted mass spectrometry-based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue. AB - The revival of interest in cancer cell metabolism in recent years has prompted the need for quantitative analytical platforms for studying metabolites from in vivo sources. We implemented a quantitative polar metabolomics profiling platform using selected reaction monitoring with a 5500 QTRAP hybrid triple quadrupole mass spectrometer that covers all major metabolic pathways. The platform uses hydrophilic interaction liquid chromatography with positive/negative ion switching to analyze 258 metabolites (289 Q1/Q3 transitions) from a single 15-min liquid chromatography-mass spectrometry acquisition with a 3-ms dwell time and a 1.55-s duty cycle time. Previous platforms use more than one experiment to profile this number of metabolites from different ionization modes. The platform is compatible with polar metabolites from any biological source, including fresh tissues, cancer cells, bodily fluids and formalin-fixed paraffin-embedded tumor tissue. Relative quantification can be achieved without using internal standards, and integrated peak areas based on total ion current can be used for statistical analyses and pathway analyses across biological sample conditions. The procedure takes ~12 h from metabolite extraction to peak integration for a data set containing 15 total samples (~6 h for a single sample). PMID- 22498708 TI - Analysis of protein mixtures from whole-cell extracts by single-run nanoLC-MS/MS using ultralong gradients. AB - The majority of proteome-wide studies rely on the high separation power of two dimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS), often combined with protein prefractionation. Alternative approaches would be advantageous in order to reduce the analysis time and the amount of sample required. On the basis of the recent advances in chromatographic and mass spectrometric instrumentation, thousands of proteins can be identified in a single-run LC-MS/MS experiment using ultralong gradients. Consequently, the analysis of simple proteomes or clinical samples in adequate depth becomes possible by performing single-run LC-MS/MS experiments. Here we present a generally applicable protocol for protein analysis from unseparated whole-cell extracts and discuss its potential and limitations. Demonstrating the practical applicability of the method, we identified 2,761 proteins from a HeLa cell lysate, requiring around 10 h of nanoLC-MS/MS measurement time. PMID- 22498710 TI - CoO octahedral nanocages for high-performance lithium ion batteries. AB - Pure-phase CoO octahedral nanocages were successfully fabricated by a novel simple method. The coordination etching agents play key roles in the formation of these non-spherical hollow structures. When tested as anode materials in lithium ion batteries (LIBs), these nanocages showed excellent cycling performance, good rate capability and enhanced lithium storage capacity. PMID- 22498709 TI - Parallel detection of antigen-specific T cell responses by combinatorial encoding of MHC multimers. AB - Fluorescently labeled multimeric complexes of peptide-MHC, the molecular entities recognized by the T cell receptor, have become essential reagents for detection of antigen-specific CD8(+) T cells by flow cytometry. Here we present a method for high-throughput parallel detection of antigen-specific T cells by combinatorial encoding of MHC multimers. Peptide-MHC complexes are produced by UV mediated MHC peptide exchange and multimerized in the form of streptavidin fluorochrome conjugates. Eight different fluorochromes are used for the generation of MHC multimers and, by a two-dimensional combinatorial matrix, these eight fluorochromes are combined to generate 28 unique two-color codes. By the use of combinatorial encoding, a large number of different T cell populations can be detected in a single sample. The method can be used for T cell epitope mapping, and also for the monitoring of CD8(+) immune responses during cancer and infectious disease or after immunotherapy. One panel of 28 combinatorially encoded MHC multimers can be prepared in 4 h. Staining and detection takes a further 3 h. PMID- 22498711 TI - Instantaneous gelation of a new copper(II) metallogel amenable to encapsulation of a luminescent lanthanide cluster. AB - Combining copper(II) chloride, 4-(1H-pyrazol-3-yl)pyridine and triethylamine in dimethylformamide (DMF) results in the instantaneous formation of a metallogel with as little as 0.51 wt% of gelator. The metallogel was found to encapsulate a luminescent lanthanide cluster, yielding a luminescent metallogel. PMID- 22498712 TI - Ice-assisted electron beam lithography of graphene. AB - We demonstrate that a low energy focused electron beam can locally pattern graphene coated with a thin ice layer. The irradiated ice plays a crucial role in the process by providing activated species that locally remove graphene from a silicon dioxide substrate. After patterning the graphene, the ice resist is easily removed by sublimation to leave behind a clean surface with no further processing. More generally, our findings demonstrate that ice-assisted e-beam lithography can be used to pattern very thin materials deposited on substrate surfaces. The procedure is performed in situ in a modified scanning electron microscope. Desirable structures such as nanoribbons are created using the method. Defects in graphene from electrons backscattered from the bulk substrate are identified. They extend several microns from the e-beam writing location. We demonstrate that these defects can be greatly reduced and localized by using thinner substrates and/or gentle thermal annealing. PMID- 22498713 TI - Development of human locomotion. AB - Neural control of locomotion in human adults involves the generation of a small set of basic patterned commands directed to the leg muscles. The commands are generated sequentially in time during each step by neural networks located in the spinal cord, called Central Pattern Generators. This review outlines recent advances in understanding how motor commands are expressed at different stages of human development. Similar commands are found in several other vertebrates, indicating that locomotion development follows common principles of organization of the control networks. Movements show a high degree of flexibility at all stages of development, which is instrumental for learning and exploration of variable interactions with the environment. PMID- 22498714 TI - Building retinal connectomes. AB - Understanding vertebrate vision depends on knowing, in part, the complete network graph of at least one representative retina. Acquiring such graphs is the business of synaptic connectomics, emerging as a practical technology due to improvements in electron imaging platform control, management software for large scale datasets, and availability of data storage. The optimal strategy for building complete connectomes uses transmission electron imaging with 2 nm or better resolution, molecular tags for cell identification, open-access data volumes for navigation, and annotation with open-source tools to build 3D cell libraries, complete network diagrams and connectivity databases. The first forays into retinal connectomics have shown that even nominally well-studied cells have much richer connection graphs than expected. PMID- 22498715 TI - Thalamocortical interactions. AB - Glutamatergic pathways dominate information processing in the brain, but these are not homogeneous. They include two distinct types: Class 1, which carries the main information for processing, and Class 2, which serves a modulatory role. Identifying the Class 1 inputs in a circuit can lead to a better understanding of its function. Also, identifying Class 1 inputs to a thalamic nucleus tells us its main function (e.g. the lateral geniculate nucleus, or LGN, is the relay of retinal Class 1 input), and such identification leads to a division of thalamic relays into first and higher order: the former receives Class 1 inputs from subcortical sources; the latter, from layer 5 of cortex, which it then relays to another cortical area. When a cortical area directly connects with another, it often has a parallel, transthalamic connection through these higher order relays. This leads to a novel appreciation of cortical functioning and raises many new questions. PMID- 22498716 TI - [Budget impact analysis of antiretroviral therapy. A reflection based on the GESIDA guidelines]. AB - OBJECTIVE: The latest version of the Spanish clinical practice guidelines on antiretroviral therapy (ART) in HIV-infected adults, developed by the Spanish AIDS Study Group (GESIDA) and the National AIDS Plan, recommends initiating ART early in certain circumstances. The aim of this study was to estimate the budget impact of this recommendation by using the data from the VACH cohort. METHODS: We considered a scenario in which all naive asymptomatic patients would initiate ART if they had <500 lymphocytes, or a CD4/MUL count >500/MUL if they were older than 55 years, or had high viral load, liver disease, chronic kidney disease or high cardiovascular risk. The study was designed as a cost analysis in terms of annual pharmaceutical expenditure. The only costs included were those relating to the ART combinations analyzed. To estimate these costs, we assumed that this guideline had a penetration of 80%, an adherence of 95% and 12% dropouts. RESULTS: A total of 12,500 patients were reviewed. Of these, 1,127 (10%) had not initiated ART; CD4 lymphocyte count was 350-500 in 294 (26.1%) and > 500 in 685 (60.8%). If the new clinical practice guideline were applied, 45.2% of naive patients (95% CI: 42.4%-48.2%) would be advised to start ART. Carrying out this recommendation in hospitals of the VACH cohort would require an additional annual investment of ? 3,270,975 and would increase the overall cost of antiretroviral drugs by 3%. CONCLUSIONS: In the framework of health economics, incorporating economic impact estimates - such as those performed in this study - into clinical practice guidelines would be advisable to increase their feasibility. PMID- 22498718 TI - Effect of RhoA on transforming growth factor beta1-induced rat hepatic stellate cell migration. AB - BACKGROUND: Although the migration of hepatic stellate cells (HSCs) is essential to the hepatic fibrotic response, the intracellular and extracellular signals that regulate their migration are poorly understood. AIMS: To investigate the role of Rho guanosine triphosphatase (Rho GTPase) signalling, specifically via RhoA, in transforming growth factor beta1 (TGFbeta1)-induced HSC migration. METHODS: Both primary rat HSCs and the HSC-T6 rat hepatic stellate cell line were used in this study. Cell migration was evaluated using the Transwell Boyden Chamber assay, whereas cytoskeletal changes were observed using laser confocal microscopy. Western blotting was used to detect the expression of Rho GTPases (RhoA, Rac1 and Cdc42) in HSCs, and their activation was determined using glutathione S-transferase (GST) pull-down assays. Finally, the specific effects of RhoA on TGFbeta1-induced cell migration were analysed in HSC-T6 cells stably transfected with constitutively active (CA, Q63L) or dominant-negative (DN, T19N) RhoA mutants. RESULTS: Transforming growth factor beta1 induced cytoskeletal remodelling and migration of rat HSCs following RhoA activation. The level of RhoA activation determined the motility of the HSCs. CONCLUSIONS: These findings broaden our understanding of the intracellular and extracellular signals that regulate HSC migration. Furthermore, RhoA may be a candidate therapeutic target for hepatic fibrosis. PMID- 22498717 TI - Amides of gold(I) diphosphines prepared from N-heterocyclic sources and their in vitro and in vivo screening for anticancer activity. AB - A series of new neutral mononuclear or dinuclear gold(I) complexes and a cyclic cationic tetranuclear amidogold(I) complex comprising of the phosphines 1,2 bis(dimethylphosphino)ethane (dmpe), MU-1,2-bis(diphenylphosphino)ethane (dppe), MU-1,3-bis(diphenylphosphino)propane (dppp), MU-1,5-bis(diphenylphosphino)pentane (dpppe), MU-1,6-bis(diphenylphosphino)hexane (dpph) or trimethylphosphine, and several N-heterocyclic ring systems (imidazolate, pyrazolate, 1,2,3-triazolate, 1,2,4-triazolate, pyrrolate, 9H-purine-9-ate or 9H-purine-6-amine-9-ate) as ligands, reveal intermolecular aurophilic interactions and 2D channels available for solvent molecules in some of their crystal structures. The antitumour activity of the acyclic gold(I) compounds is highly dependent on the substituents on the phosphorus atoms being highest for phenyl groups and lower for methyl groups. The activity of these compounds against selected cell lines is linked to the length of the carbon bridge between the two phosphorus atoms being highest with a bridge consisting of 5 or 6 carbons. Two compounds with the highest tumour specifities that contain dpppe and pyrazolate (a lipophilic compound) or 1,2,4 triazolate (a hydrophilic compound) induce an apoptotic cell death pathway and a maximum dose to Balb/C mice is tolerated. PMID- 22498719 TI - Analysis of immunoarrays using a gold grating-based dual mode surface plasmon coupled emission (SPCE) sensor chip. AB - We have developed a novel dual mode immunoassay platform that combines the advantages of real-time, label free measurement of surface plasmon resonance (SPR) and the highly directional surface plasmon-coupled emission (SPCE) using a gold grating-based sensor chip. Since only fluorophore-labeled analyte molecules that are close to the metal surface of the sensor chip will couple to the surface plasmon, SPCE detection is highly surface-specific leading to background suppression and increased sensitivity. Theoretical calculations were done to find SPR and SPCE angles for a sensor chip optimized for Alexa Fluor 647. We have confirmed the SPR and SPCE responses on the dual mode sensor chip using Alexa Fluor 647 labeled anti-mouse IgG. Signal fluctuation of the dual mode sensor chip reader was below 1.2% and 0.8% for SPR and SPCE, respectively. The SPR response in this configuration showed a minimum detection level of 1 MUg ml(-1), and the SPCE response showed a minimum detection level of 1 ng ml(-1) for the same sample. A range of human IgG concentrations in human serum was also analyzed with the dual mode sensor chip. The SPCE measurement is more sensitive than the SPR real-time measurement, and substantially extends the dynamic range of the assay platform, as well as enabling independent measurements of co-localized analytes on the same sensor chip region of interest. Since this assay platform is capable of measuring more than 1000 spatially encoded regions of interest on a 1 cm(2) sensor chip, it has the potential for high-content analyses of biological samples with both research and clinical applications. PMID- 22498721 TI - The radiation dose-regulated AND gate genetic circuit, a novel targeted and real time monitoring strategy for cancer gene therapy. AB - The AND gate functions such that when all inputs are activated the downstream gene will be transcribed and it is off otherwise. To accomplish optimal and targeted gene therapy in solid tumor patients, we have constructed an AND gate genetic circuit and investigated whether it could be activated by low-dose radiation in vitro and in vivo. The enhancement green fluorescent protein (EGFP) expression in different tumor cells transfected with control vector plxsn-EGFP confirmed that 2 Gy of radiation and 1% O(2) for 3 h could activate our AND gate. Besides, the obvious different levels of EGFP expression between 2 and 6 Gy of radiation demonstrated that the AND gate could be regulated by radiation doses. Additionally, through EGFP expression and the codistribution of p53 and HIF 1alpha in xenografts, we illustrated the targeted activation property of the AND gate and real-time monitoring to hypoxic districts in vivo. Moreover, significant growth inhibition and cell cycle arrest in vitro and apoptosis-inducing effects in vitro and in vivo proved that the AND gate induced ideal antitumor effects. In conclusion, the radiation dose-regulated AND gate genetic circuit could not only effectively monitor the therapeutic process in real-time but also induce ideal antitumor efficacy, and can be further exploited for personal therapy in clinical tumor patients. PMID- 22498722 TI - Phase 1/2a, dose-escalation, safety, pharmacokinetic and preliminary efficacy study of intratumoral administration of BC-819 in patients with unresectable pancreatic cancer. AB - BC-819 is a DNA plasmid that was developed to target the expression of diphtheria toxin gene under the control of H19 regulatory sequences. BC-819 has the potential to treat pancreatic cancer that overexpresses the H19 gene. The objectives were to assess the safety, tolerability, pharmacokinetics and preliminary efficacy of BC-819 administered intratumorally in subjects with unresectable, locally advanced, non-metastatic pancreatic cancer. Nine patients with unresectable pancreatic adenocarcinoma were enrolled in an open-label, dose escalation trial. Subjects were entered into one out of two cohorts with escalating doses of BC-819. Each cohort received 2 weeks of twice weekly intratumoral injection of BC-819 under computerized tomography (CT) (n = 3) or endoscopic ultrasound (EUS) (n = 6) guidance. Patients were assessed by CT or positron emission tomography (PET)/CT during week 4 for tumor response. The maximum tolerated dose of BC-819 was not reached in this study at the highest dose. Asymptomatic elevation of lipase, which was considered as an adverse event with dose-limiting toxicity, occurred in only one subject in the high-dose group and was resolved spontaneously. The tumors did not increase in size 4 weeks after initiating treatment. Two weeks after completing the treatment, the two subjects who went on to receive subsequent chemotherapy or chemoradiation therapy, pancreatic tumors were downstaged and considered surgically resectable. Remarkably, three of the six subjects in cohort no. 2 evaluated at month 3 had a partial response. BC-819 can be safely administered intratumorally via EUS- or CT guided injection at a dose of at least 8 mg per injection weekly twice. BC-819 given locally in combination with systemic chemotherapy may provide an additional therapeutic benefit for the treatment of pancreatic cancer. PMID- 22498720 TI - Design and rationale for Home Blood Pressure Telemonitoring and Case Management to Control Hypertension (HyperLink): a cluster randomized trial. AB - BACKGROUND: Patients with high blood pressure (BP) visit a physician an average of 4 times or more per year in the U.S., yet BP is controlled in fewer than half. Practical, robust and sustainable models are needed to improve BP in patients with uncontrolled hypertension. OBJECTIVES: The Home Blood Pressure Telemonitoring and Case Management to Control Hypertension study (HyperLink) is a cluster-randomized trial designed to determine whether an intervention that combines home BP telemonitoring with pharmacist case management improves BP control compared to usual care at 6 and 12 months in patients with uncontrolled hypertension. Secondary outcomes are maintenance of BP control at 18 months, patient satisfaction with their health care, and costs of care. METHODS: HyperLink enrolled 450 hypertensive patients with uncontrolled BP from 16 primary care clinics. Eight clinics were randomized to provide usual care (UC) to their patients (n=222) and 8 were randomized to provide the telemonitoring intervention (TI) (n=228). TI patients received home BP telemonitors that internally store and electronically transmit BP data to a secure database. Pharmacist case managers adjust antihypertensive therapy based on the home BP data under a collaborative practice agreement with the clinics' primary care teams. The length of the intervention is 12 months, with follow-up to 18 months to determine the durability of the intervention. CONCLUSIONS: We will test in a real primary care setting whether combining BP telemonitoring and pharmacist case management can achieve and maintain high rates of BP control compared to usual care. PMID- 22498723 TI - Combining transfer of TTF-1 and Pax-8 gene: a potential strategy to promote radioiodine therapy of thyroid carcinoma. AB - Cotransfer of thyroid-specific transcription factor (TTF)-1 and Pax-8 gene to tumor cells, resulting in the re-expression of iodide metabolism-associated proteins, such as sodium iodide symporter (NIS), thyroglobulin (Tg), thyroperoxidase (TPO), offers the possibility of radioiodine therapy to non iodide-concentrating tumor because the expression of iodide metabolism-associated proteins in thyroid are mediated by the thyroid transcription factor TTF-1 and Pax-8. The human TTF-1 and Pax-8 gene were transducted into the human thyroid carcinoma (K1 and F133) cells by the recombinant adenovirus, AdTTF-1 and AdPax-8. Re-expression of NIS mRNA and protein, but not TPO and Tg mRNA and protein, was detected in AdTTF-1-infected F133 cells, following with increasing radioiodine uptake (6.1-7.4 times), scarcely iodide organification and rapid iodide efflux (t(1/2) ~ 8-min in vitro, t(1/2) ~ 4.7-h in vivo). On contrast, all of the re expression of NIS, TPO and Tg mRNA and proteins were detected in F133 cells coinfected with AdTTF-1 and AdPax-8. AdTTF-1- and AdPax-8-coinfected K1 and F133 cells could effectively accumulate radioiodine (6.6-7.5 times) and obviously retarded radioiodine retention (t(1/2) ~ 25-30-min in vitro, t(1/2) ~ 12-h in vivo) (P<0.05). Accordingly, the effect of radioiodine therapy of TTF-1 and Pax-8 cotransducted K1 and F133 cells (21-25% survival rate in vitro) was better than that of TTF-1-transducted cells (40% survival rate in vitro) (P<0.05). These results indicate that single TTF-1 gene transfer may have limited efficacy of radioiodine therapy because of rapid radioiodine efflux. The cotransduction of TTF-1 and Pax-8 gene, with resulting NIS-mediated radioiodine accumulation and TPO and Tg-mediated radioiodine organification and intracellular retention, may lead to effective radioiodine therapy of thyroid carcinoma. PMID- 22498724 TI - Human amniotic fluid-derived stem cells expressing cytosine deaminase and thymidine kinase inhibits the growth of breast cancer cells in cellular and xenograft mouse models. AB - As human amniotic fluid-derived stem cells (hAFSCs) are capable of multiple lineage differentiation, extensive self-renewal and tumor targeting, they may be valuable for clinical anticancer therapies. In this study, we used hAFSCs as vehicles for targeted delivery of therapeutic suicide genes to breast cancer cells. hAFSCs were engineered to produce AF2.CD-TK cells in order to express two suicide genes encoding bacterial cytosine deaminase (CD) and herpes simplex virus thymidine kinase (HSV-TK) that convert non-toxic prodrugs, 5-fluorocytosine (5 FC) and mono-phosphorylate ganciclovir (GCV-MP), into cytotoxic metabolites, 5 fluorouracil (5-FU) and triphosphate ganciclovir (GCV-TP), respectively. In cell viability test in vitro, AF2.CD-TK cells inhibited the growth of MDA-MB-231 human breast cancer cells in the presence of the 5-FC or GCV prodrugs, or a combination of these two reagents. When the mixture of 5-FC and GCV was treated together, an additive cytotoxic effect was observed in the cell viability. In animal experiments using female BALB/c nude mouse xenografts, which developed by injecting MDA-MB-231 cells, treatment with AF2.CD-TK cells in the presence of 5 FC and GCV significantly reduced tumor volume and weight to the same extent seen in the mice treated with 5-FU. Histopathological and fluorescent staining assays further showed that AF2.CD-TK cells were located exactly at the site of tumor formation. Furthermore, breast tissues treated with AF2.CD-TK cells and two prodrugs maintained their normal structures (for example, the epidermis and reticular layers) while breast tissue structures in 5-FU-treated mice were almost destroyed by the potent cytotoxicity of the drug. Taken together, these results indicate that AF2.CD-TK cells can serve as excellent vehicles in a novel therapeutic cell-based gene-directed prodrug system to selectively target breast malignancies. PMID- 22498726 TI - A need to broaden our perspective to address workers' health effectively in the 21st century. PMID- 22498725 TI - The tammar wallaby: a model system to examine domain-specific delivery of milk protein bioactives. AB - The role of milk extends beyond simply providing nutrition to the suckled young. Milk has a comprehensive role in programming and regulating growth and development of the suckled young, and provides a number of potential autocrine factors so that the mammary gland functions appropriately during the lactation cycle. This central role of milk is best studied in animal models such as marsupials that have evolved a different lactation strategy to eutherians and allow researchers to more easily identify regulatory mechanisms that are not as readily apparent in eutherian species. For example, the tammar wallaby (Macropus eugenii) has evolved with a unique reproductive strategy of a short gestation, birth of an altricial young and a relatively long lactation during which the mother progressively changes the composition of the major, and many of the minor components of milk. Consequently, in contrast to eutherians, there is a far greater investment in development of the young during lactation and it is likely that many of the signals that regulate development of eutherian embryos in utero are delivered by the milk. This requires the co-ordinated development and function of the mammary gland since inappropriate timing of these signalling events may result in either limited or abnormal development of the young, and potentially a higher incidence of mature onset disease. Milk proteins play a significant role in these processes by providing timely presentation of signalling molecules and antibacterial protection for the young and the mammary gland at times when there is increased susceptibility to infection. This review describes studies exploiting the unique reproductive strategy of the tammar wallaby to investigate the role of several proteins secreted at specific times during the lactation cycle and that are correlated with potential roles in the young and mammary gland. Interestingly, alternative splicing of some milk protein genes has been utilised by the mammary gland to deliver domain-specific functions at specific times during lactation. PMID- 22498727 TI - Occupational safety and health in the USA: now and the future. AB - In the USA, national worker protection legislation was enacted in 1970. The legislation required that research, recommendations and guidance be developed to aid employers and workers, that workplace health and safety standards be adopted, that employer comply with those rules and that the government police employer compliance, and that assistance be offered to employers and workers to help them maintain a safe and healthful workplace. In the 40 yr since passage of the Occupational Safety and Health Act of 1970, worker injury, illness and fatalities have declined but not been eliminated. Efforts to accelerate the standards adoption process are much discussed in the USA along with how to protect workers from emerging hazards like nanotechnology. New strategies which seek to eliminate not only the causes of work-related injury and illness, but also more broadly, worker injury and illness, are on the horizon. PMID- 22498728 TI - Proficiency in reading pneumoconiosis radiographs examined by the 60-film set with 4-factor structuring 8-index. AB - 29 physicians (A1-Group) and 24 physicians (A2-Group) attending the 1st and 2nd "Asian Intensive Reader of Pneumoconiosis" (AIR Pneumo) training course, respectively, and 22 physicians (B-Group) attending the Brazilian training course took the examination of reading the 60-film set. The objective of the study was firstly to investigate the factor structure of physicians' proficiency of reading pneumoconiosis chest X-ray, and secondly to examine differences in factor scores between groups. Reading results in terms of the 8-index of all examinees (Examinee Group) were subjected to the exploratory factor analysis. A 4-factor was analyzed to structure the 8-index: the specificity for pneumoconiosis, specificity for large opacities, specificity for pleural plaque and shape differentiation for small opacities loaded on the Factor 1; the sensitivity for pneumoconiosis and sensitivity for large opacities loaded on the Factor 2; the sensitivity for pleural plaque loaded on the Factor 3; the profusion increment consistency loaded on the Factor 4. 4-Factor scores were compared between each other of the three groups. The Factor 2 scores in A1 and A2 groups were significantly higher than in B-Group. Four factors could reflect four aspects of reading proficiency of pneumoconiosis X-ray, and it was suggested that 4-factor scores could also assess the attained skills appropriately. PMID- 22498729 TI - Hydrodynamic pressure sensing with an artificial lateral line in steady and unsteady flows. AB - With the overall goal being a better understanding of the sensing environment from the local perspective of a situated agent, we studied uniform flows and Karman vortex streets in a frame of reference relevant to a fish or swimming robot. We visualized each flow regime with digital particle image velocimetry and then took local measurements using a rigid body with laterally distributed parallel pressure sensor arrays. Time and frequency domain methods were used to characterize hydrodynamically relevant scenarios in steady and unsteady flows for control applications. Here we report that a distributed pressure sensing mechanism has the capability to discriminate Karman vortex streets from uniform flows, and determine the orientation and position of the platform with respect to the incoming flow and the centre axis of the Karman vortex street. It also enables the computation of hydrodynamic features which may be relevant for a robot while interacting with the flow, such as vortex shedding frequency, vortex travelling speed and downstream distance between vortices. A Karman vortex street was distinguished in this study from uniform flows by analysing the magnitude of fluctuations present in the sensor measurements and the number of sensors detecting the same dominant frequency. In the Karman vortex street the turbulence intensity was 30% higher than that in the uniform flow and the sensors collectively sensed the vortex shedding frequency as the dominant frequency. The position and orientation of the sensor platform were determined via a comparative analysis between laterally distributed sensor arrays; the vortex travelling speed was estimated via a cross-correlation analysis among the sensors. PMID- 22498730 TI - Diffusion-weighted MRI of adult male pelvic cancers. AB - Magnetic resonance imaging (MRI), with its superior soft-tissue delineation, plays a pivotal role in the staging and surveillance of cancers affecting adult males, in particular, rectal, urinary bladder, and prostate cancers. There has been much recent interest in the complementary roles of diffusion-weighted imaging (DWI) for imaging of pelvic cancers. DWI measures the diffusivity of water molecules in biological tissue. Cancer, with its high cellular density and nuclear:cytoplasmic ratio, and extracellular disorganization, typically shows significant restricted diffusivity compared with surrounding normal tissue. In theory, diffusivity of water molecules may vary according to degree of tumour aggressiveness and changes in cell density and extracellular fluid content after treatment. Information regarding these variations may be used to study the histological grades of cancers and their response to treatment. In this article, we present the currently available evidence on the potential roles of DWI for the assessment of pelvic cancers in men, and demonstrate with imaging examples how this knowledge may be applied to daily clinical practice. PMID- 22498731 TI - Blood patch for persistent air leak: a review of the current literature. AB - PURPOSE OF REVIEW: Persistent air leak (PAL) poses a significant challenge to the thoracic surgeon. Of the numerous methods employed to manage this problem, autologous blood 'patch' pleurodesis (ABPP) remains one of the most controversial, seemingly due to a lack of robust data and consensus of opinion regarding its efficacy, technique of application and its role in clinical practice. Despite a lack of randomized control trials, the evidence to-date has shown ABPP to be an efficacious, cheap, simple, well tolerated and readily available treatment, with minimal side effects and broad range of applications, allowing for earlier chest drain removal, decreased complications and decreased hospital stay. A review is therefore required to assess the role for ABPP in contemporary clinical practice. RECENT FINDINGS: Recent studies have demonstrated that ABPP is an effective management for PAL in specific patient groups and there is an argument that it has the potential to be the gold-standard or first-line treatment in certain clinical scenarios such as for patients with interstitial lung disease or acute respiratory distress syndrome. SUMMARY: This review aims to discuss the relevance of recent findings and to suggest a firm role for ABPP in current practice. In addition, the evidence for the efficacy of ABPP will be assessed and compared with other established methods of pleurodesis. Finally, the review will include a summary of relevant research to-date in order to suggest an evidence-based standardized protocol for the application of ABPP. PMID- 22498732 TI - Pleural effusion in pulmonary embolism. AB - PURPOSE OF REVIEW: Pulmonary embolism is a common and potentially lethal disease that recurs frequently and is associated with long-term impairment and suffering. Patients with pulmonary embolism are at risk of death, recurrence of embolism, or chronic morbidity. Appropriate therapy can reduce the incidence of all. Pulmonary embolism is the most commonly overlooked disorder in patients with pleural effusion. Recent findings of pleural effusions due to pulmonary embolism are discussed in this review. RECENT FINDINGS: The presence of pleuritic chest pain in a patient with a pleural effusion is highly suggestive of pulmonary embolism. Nearly all pleural effusions due to pulmonary embolism are exudates, frequently hemorrhagic, and with a marked mesothelial hyperplasia. Patients with a pleural effusion are likely to have an embolus in the central, lobar, segmental, or subsegmental pulmonary arteries and these are the regions in which spiral computed tomography pulmonary angiography (CTPA) can detect an embolus. No specific treatment is required for pleural effusion. The presence of bloody pleural fluid is not a contraindication for the administration of anticoagulant therapy. SUMMARY: Pulmonary embolism is probably responsible for a significant percentage of undiagnosed exudative pleural effusions. Spiral CTPA is the best way to evaluate the possibility of pulmonary embolism in a patient with a pleural effusion. The treatment protocol of the patient with pleural effusion secondary to pulmonary embolism is the same as that for any patient with pulmonary embolism. PMID- 22498733 TI - Utility of draining pleural effusions in mechanically ventilated patients. AB - PURPOSE OF REVIEW: Pleural effusions are prevalent in mechanically ventilated patients, and clinicians frequently consider draining the effusions. It is controversial whether patients benefit from pleural drainage in terms of either physiological or clinical outcomes. RECENT FINDINGS: Pleural drainage may be undertaken for a variety of reasons. Effusions are an important potential source of infection in patients with undifferentiated sepsis. Pleural drainage may improve hypoxemia or lung mechanics, but the physiological response depends on a complex interplay between lung and chest wall compliance, applied positive end expiratory pressure and drainage volume. Pleural effusions may be associated with significant cyclic lung recruitment and collapse during tidal ventilation. Because effusions are primarily accommodated by descent of the diaphragm, they can also impair diaphragm mechanics significantly. There is very limited data in the literature to support the use of pleural drainage to accelerate liberation from mechanical ventilation, and there are no randomized controlled trials published to date. SUMMARY: Pleural drainage may benefit certain patient populations based on individual physiological considerations, but randomized controlled trials evaluating the impact on weaning outcomes are lacking. Future research efforts should focus on identifying patient populations most likely to benefit and clarify the mechanisms by which weaning may be accelerated after pleural drainage. PMID- 22498734 TI - Tracheal transplantation. AB - PURPOSE OF REVIEW: This review discusses the important advances in the reconstruction of airway wall defects resulting from stenosis and tumor resection. RECENT FINDINGS: Recent insights concerning regeneration, revascularization, and transplantation of the trachea are presented. The current study reviews tracheal transplantation as a new treatment modality. SUMMARY: This will enable wider application of tracheal allotransplantation for patients in need of complex reconstructive surgery for airway defects that are not amenable to standard methods of repair. Ongoing research suggests that tracheal allotransplantation may become available as a new treatment modality. Additional data are needed to define optimal withdrawal of immunosuppressants without loss of airway lumen. PMID- 22498735 TI - Preoperative assessment of patients for lung cancer surgery. AB - PURPOSE OF REVIEW: The aim of this work was to present and analyze the latest published documents about the functional evaluation of patients undergoing lung resection and review articles from the past two years addressing the same topic. RECENT FINDINGS: In 2009 and 2010, two important task forces, appointed by international scientific societies, have published documents to guide the preoperative evaluation and risk stratification of lung resection candidates. In both documents, cardiac evaluation is prioritized. Detailed cardiologic guidelines have been proposed. After this first step, functional assessment should include a spirometric assessment, asystematic measurement of carbon monoxide diffusion capacity and a cardiopulmonary exercise test evaluation. Differences in the relative importance of these tests in the two guidelines were discussed. Most recent evidences focused on the role of cardiopulmonary exercise test and the use of several direct and indirect ergometric parameters that may refine risk assessment. SUMMARY: The use of evidence-based clinical guidelines on preoperative evaluation is recommendable. Nevertheless, scientific evidence is still suboptimal in this field. Aggregate analyses on larger series are needed to improve risk stratification. PMID- 22498736 TI - PRMT1 interacts with AML1-ETO to promote its transcriptional activation and progenitor cell proliferative potential. AB - Fusion protein AML1-ETO, resulting from t(8;21) translocation, is highly related to leukemia development. It has been reported that full-length AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. We have previously shown that the expression of AE9a, a splice isoform of AML1-ETO, can rapidly cause leukemia in mice. To understand how AML1-ETO is involved in leukemia development, we took advantage of our AE9a leukemia model and sought to identify its interacting proteins from primary leukemic cells. Here, we report the discovery of a novel AE9a binding partner PRMT1 (protein arginine methyltransferase 1). PRMT1 not only interacts with but also weakly methylates arginine 142 of AE9a. Knockdown of PRMT1 affects expression of a specific group of AE9a-activated genes. We also show that AE9a recruits PRMT1 to promoters of AE9a-activated genes, resulting in enrichment of H4 arginine 3 methylation, H3 Lys9/14 acetylation, and transcription activation. More importantly, knockdown of PRMT1 suppresses the self-renewal capability of AE9a, suggesting a potential role of PRMT1 in regulating leukemia development. PMID- 22498737 TI - Smad2/Smad3 in endothelium is indispensable for vascular stability via S1PR1 and N-cadherin expressions. AB - Transforming growth factor-beta (TGF-beta) is involved in vascular formation through activin receptor-like kinase (ALK)1 and ALK5. ALK5, which is expressed ubiquitously, phosphorylates Smad2 and Smad3, whereas endothelial cell (EC) specific ALK1 activates Smad1 and Smad5. Because ALK5 kinase activity is required for ALK1 to transduce TGF-beta signaling via Smad1/5 in ECs, ALK5 knockout (KO) mice were not able to give us the precise mechanisms by which TGF beta/ALK5/Smad2/3 signaling is implicated in angiogenesis. To delineate the role of Smad2/3 signaling in endothelium, the Smad2 gene in Smad3 KO mice was selectively deleted in ECs using Tie2-Cre transgenic mice, termed EC-specific Smad2/3 double KO (EC-Smad2/3KO) mice. EC-Smad2/3KO embryos revealed hemorrhage leading to embryonic lethality around E12.5. EC-Smad2/3KO embryos exhibited no abnormality of vasculogenesis and angiogenesis in both the yolk sac and the whole embryo, whereas vascular maturation was incomplete because of inadequate assembly of mural cells in the vasculature. Wide gaps between ECs and mural cells could be observed in the vasculature of EC-Smad2/3KO mice because of reduced expression of N-cadherin and sphingosine-1-phosphate receptor-1 (S1PR1) in ECs from those mice. These results indicated that Smad2/3 signaling in ECs is indispensable for maintenance of vascular integrity via the fine-tuning of N-cadherin, VE-cadherin, and S1PR1 expressions in the vasculature. PMID- 22498738 TI - PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells. AB - The transcription factor PU.1 is a master regulator of myeloid differentiation and function. On the other hand, only scarce information is available on PU.1 regulated genes involved in cell survival. We now identified the glycolytic enzyme hexokinase 3 (HK3), a gene with cytoprotective functions, as transcriptional target of PU.1. Interestingly, HK3 expression is highly associated with the myeloid lineage and was significantly decreased in acute myeloid leukemia patients compared with normal granulocytes. Moreover, HK3 expression was significantly lower in acute promyelocytic leukemia (APL) compared with non-APL patient samples. In line with the observations in primary APL patient samples, we observed significantly higher HK3 expression during neutrophil differentiation of APL cell lines. Moreover, knocking down PU.1 impaired HK3 induction during neutrophil differentiation. In vivo binding of PU.1 and PML-RARA to the HK3 promoter was found, and PML-RARA attenuated PU.1 activation of the HK3 promoter. Next, inhibiting HK3 in APL cell lines resulted in significantly reduced neutrophil differentiation and viability compared with control cells. Our findings strongly suggest that HK3 is: (1) directly activated by PU.1, (2) repressed by PML-RARA, and (3) functionally involved in neutrophil differentiation and cell viability of APL cells. PMID- 22498740 TI - Clonal competition with alternating dominance in multiple myeloma. AB - Emerging evidence indicates that tumors can follow several evolutionary paths over a patient's disease course. With the use of serial genomic analysis of samples collected at different points during the disease course of 28 patients with multiple myeloma, we found that the genomes of standard-risk patients show few changes over time, whereas those of cytogenetically high-risk patients show significantly more changes over time. The results indicate the existence of 3 temporal tumor types, which can either be genetically stable, linearly evolving, or heterogeneous clonal mixtures with shifting predominant clones. A detailed analysis of one high-risk patient sampled at 7 time points over the entire disease course identified 2 competing subclones that alternate in a back and forth manner for dominance with therapy until one clone underwent a dramatic linear evolution. With the use of the Vk*MYC genetically engineered mouse model of myeloma we modeled this competition between subclones for predominance occurring spontaneously and with therapeutic selection. PMID- 22498739 TI - Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: the Medical Research Council Myeloma IX Trial. AB - The Medical Research Council Myeloma IX Trial (ISRCTNG8454111) examined traditional and thalidomide-based induction and maintenance regimens and IV zoledronic acid (ZOL) and oral clodronate (CLO) in 1960 patients with newly diagnosed multiple myeloma. Overall survival (OS) and skeletal-related event (SRE) data have been reported for the overall trial population. The present analysis investigated optimal therapy regimens for different patient populations in Myeloma IX. Patients were assigned to intensive or nonintensive treatment pathways and randomized to induction cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) versus cyclophosphamide, thalidomide, and dexamethasone (CTD; intensive) or melphalan and prednisolone versus attenuated oral CTD (CTDa; nonintensive). Patients were also randomized to ZOL or CLO. In the nonintensive pathway, CTDa produced better responses and lower SRE rates than melphalan and prednisolone. ZOL improved OS compared with CLO independently of sex, stage, or myeloma subtype, most profoundly in patients with baseline bone disease or other SREs. In patients treated for >= 2 years, ZOL improved OS compared with CLO from randomization (median not reached for either; P = .02) and also from first on study disease progression (median, 34 months for ZOL vs 27 months for CLO; P = .03). Thalidomide-containing regimens had better efficacy than traditional regimens, and ZOL demonstrated greater benefits than CLO. PMID- 22498741 TI - Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors. AB - Connexin-43 (Cx43), a gap junction protein involved in control of cell proliferation, differentiation and migration, has been suggested to have a role in hematopoiesis. Cx43 is highly expressed in osteoblasts and osteogenic progenitors (OB/P). To elucidate the biologic function of Cx43 in the hematopoietic microenvironment (HM) and its influence in hematopoietic stem cell (HSC) activity, we studied the hematopoietic function in an in vivo model of constitutive deficiency of Cx43 in OB/P. The deficiency of Cx43 in OB/P cells does not impair the steady state hematopoiesis, but disrupts the directional trafficking of HSC/progenitors (Ps) between the bone marrow (BM) and peripheral blood (PB). OB/P Cx43 is a crucial positive regulator of transstromal migration and homing of both HSCs and progenitors in an irradiated microenvironment. However, OB/P Cx43 deficiency in nonmyeloablated animals does not result in a homing defect but induces increased endosteal lodging and decreased mobilization of HSC/Ps associated with proliferation and expansion of Cxcl12-secreting mesenchymal/osteolineage cells in the BM HM in vivo. Cx43 controls the cellular content of the BM osteogenic microenvironment and is required for homing of HSC/Ps in myeloablated animals. PMID- 22498742 TI - Engineering lymph node homing of ex vivo-expanded human natural killer cells via trogocytosis of the chemokine receptor CCR7. AB - Natural killer (NK) cells have gained significant attention in adoptive immunotherapy for cancer. Consequently, novel methods of clinical-grade expansion of NK cells have emerged. Subsets of NK cells express a variety of chemokine receptors. However, to expand the scope of adoptively transferred NK cell homing to various malignancies, expression of corresponding chemokine receptors on NK cells is essential. Here, we have explored the use of trogocytosis as a tool to transiently express the chemokine receptor CCR7 on expanded human NK cells with the aim to enhance their homing to lymph nodes. We generated a K562-based "donor" cell line expressing CCR7, Clone9.CCR7, to transfer CCR7 onto NK cells via trogocytosis. CCR7 expression occurred in 80% of expanded NK cells within 1 hour after coculture with Clone9.CCR7. After removal of the donor cells from the coculture, the CCR7 expression on NK cells steadily declined to baseline levels by 72 hours. The acquired CCR7 receptors mediated in vitro migration of NK cells toward CCL19 and CCL21 and increased the lymph node homing by 144% in athymic nude mice. This is the first report on exploiting trogocytosis to rapidly and transiently modify lymphocytes, without direct genetic intervention, for adoptive transfer. PMID- 22498743 TI - Infectivity in chimpanzees (Pan troglodytes) of plasma collected before HCV RNA detectability by FDA-licensed assays: implications for transfusion safety and HCV infection outcomes. AB - Serial plasma aliquots (50 mL) obtained from 10 commercial donors who converted from hepatitis C virus (HCV) RNA negative to positive were transfused into 2 chimpanzees to assess infectivity during early HCV infection. Plasma, obtained 4 days before HCV RNA detectability by licensed assays, transmitted HCV infection to chimpanzee X355. The infectious PCR-negative plasma was subsequently shown to be positive in 2 of 23 replicates using a sensitive transcription-mediated amplification (TMA) assay, and estimated to contain 1.2 HCV RNA copies/mL (60 copies/50 mL transfused). Plasma units obtained up to 8 weeks earlier were not infectious in a second susceptible chimp, even when from donors with low-level, intermittent HCV RNA detection. Chimp x355 developed acute viremia with subsequent seroconversion, but cleared both virus and Ab in 17 weeks. When rechallenged 38 months later with 6000 RNA copies/mL from the same donor, X355 was transiently reinfected and again rapidly lost all HCV markers. We conclude that: (1) transfusions can transmit HCV infection before RNA detection, but the interval of test-negative infectivity is very brief; (2) early "blips" of HCV RNA appear noninfectious and can be ignored when calculating residual transfusion risk; and (3) markers of HCV infection can be lost rapidly after exposure to low dose inocula. PMID- 22498744 TI - Heme-regulated eIF2alpha kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis. AB - Heme-regulated eIF2alpha kinase (Hri) is necessary for balanced synthesis of heme and globin. In addition, Hri deficiency exacerbates the phenotypic severity of beta-thalassemia intermedia in mice. Activation of Hri during heme deficiency and in beta-thalassemia increases eIF2alpha phosphorylation and inhibits globin translation. Under endoplasmic reticulum stress and nutrient starvation, eIF2alpha phosphorylation also induces the Atf4 signaling pathway to mitigate stress. Although the function of Hri in regulating globin translation is well established, its role in Atf4 signaling in erythroid precursors is not known. Here, we report the role of the Hri-activated Atf4 signaling pathway in reducing oxidative stress and in promoting erythroid differentiation during erythropoiesis. On acute oxidative stress, Hri(-/-) erythroblasts suffered from increased levels of reactive oxygen species (ROS) and apoptosis. During chronic iron deficiency in vivo, Hri is necessary both to reduce oxidative stress and to promote erythroid differentiation. Hri(-/-) mice developed ineffective erythropoiesis during iron deficiency with inhibition of differentiation at the basophilic erythroblast stage. This inhibition is recapitulated during ex vivo differentiation of Hri(-/-) fetal liver erythroid progenitors. Importantly, the Hri-eIF2alphaP-Atf4 pathway was activated and required for erythroid differentiation. We further demonstrate the potential of modulating Hri eIF2alphaP-Atf4 signaling with chemical compounds as pharmaceutical therapies for beta-thalassemia. PMID- 22498746 TI - Blood consult: monosomal karyotype acute myeloid leukemia. PMID- 22498747 TI - Modification of an exposed loop in the C1 domain reduces immune responses to factor VIII in hemophilia A mice. AB - Development of neutralizing Abs to blood coagulation factor VIII (FVIII) provides a major complication in hemophilia care. In this study we explored whether modulation of the uptake of FVIII by APCs can reduce its intrinsic immunogenicity. Endocytosis of FVIII by professional APCs is significantly blocked by mAb KM33, directed toward the C1 domain of FVIII. We created a C1 domain variant (FVIII-R2090A/K2092A/F2093A), which showed only minimal binding to KM33 and retained its activity as measured by chromogenic assay. FVIII R2090A/K2092A/F2093A displayed a strongly reduced internalization by human monocyte-derived dendritic cells and macrophages, as well as murine BM-derived dendritic cells. We subsequently investigated the ability of this variant to induce an immune response in FVIII-deficient mice. We show that mice treated with FVIII-R2090A/K2092A/F2093A have significantly lower anti-FVIII Ab titers and FVIII-specific CD4(+) T-cell responses compared with mice treated with wild-type FVIII. These data show that alanine substitutions at positions 2090, 2092, and 2093 reduce the immunogenicity of FVIII. According to our findings we hypothesize that FVIII variants displaying a reduced uptake by APCs provide a novel therapeutic approach to reduce inhibitor development in hemophilia A. PMID- 22498748 TI - Amelioration of the severity of heparin-binding antithrombin mutations by posttranslational mosaicism. AB - The balance between actions of procoagulant and anticoagulant factors protects organisms from bleeding and thrombosis. Thus, antithrombin deficiency increases the risk of thrombosis, and complete quantitative deficiency results in intrauterine lethality. However, patients homozygous for L99F or R47C antithrombin mutations are viable. These mutations do not modify the folding or secretion of the protein, but abolish the glycosaminoglycan-induced activation of antithrombin by affecting the heparin-binding domain. We speculated that the natural beta-glycoform of antithrombin might compensate for the effect of heparin binding mutations. We purified alpha- and beta-antithrombin glycoforms from plasma of 2 homozygous L99F patients. Heparin affinity chromatography and intrinsic fluorescence kinetic analyses demonstrated that the reduced heparin affinity of the alpha-L99F glycoform (K(D), 107.9 +/- 3nM) was restored in the beta-L99F glycoform (K(D), 53.9 +/- 5nM) to values close to the activity of alpha wild type (K(D), 43.9 +/- 0.4nM). Accordingly, the beta-L99F glycoform was fully activated by heparin. Similar results were observed for recombinant R47C and P41L, other heparin-binding antithrombin mutants. In conclusion, we identified a new type of mosaicism associated with mutations causing heparin-binding defects in antithrombin. The presence of a fully functional beta-glycoform together with the activity retained by these variants helps to explain the viability of homozygous and the milder thrombotic risk of heterozygous patients with these specific antithrombin mutations. PMID- 22498745 TI - Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. AB - In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484. PMID- 22498749 TI - All major prion types recognised by a multiplex immunofluorometric assay for disease screening and confirmation in sheep. AB - Prion diseases or transmissible spongiform encephalopathies (TSEs) in small ruminants are presented in many forms: classical scrapie, Nor98/atypical scrapie, CH1641 scrapie and bovine spongiform encephalopathy (BSE). We previously described a multiplex immunofluorometric assay (mIFMA), based on a bead array flow cytometry technology, which provided, in a single assay, discrimination between BSE (in cattle and sheep) and classical scrapie (Tang et al., 2010). In this study, we extended the mlFMA to differentiate classical scrapie, atypical scrapie, BSE (experimentally infected sheep and naturally infected cattle) and CH1641 (both experimental and natural CH1641-like infections in sheep). Three capture antibodies were used, two distinct PrP N-terminus specific antibodies 12B2 and 9A2, and a PrP core specific antibody 94B4. All three antibodies were shown to bind classical scrapie PrP(res) strongly, whereas in Nor98/atypical scrapie PrP(res) only 12B2 and 9A2 binding was observed. PrP(res) binding of 12B2 was low for both BSE and CH1641, as expected. Furthermore, analysis of serially diluted samples indicated that the assay provided a similar level of sensitivity for atypical scrapie as that found using a well established commercial test. Unexpectedly, 9A2 binding to CH1641 PrP(res) was reduced by 2.1 fold both for experimental CH1641 and CH1641-like scrapie when compared with BSE, suggesting that major cleavage of the N-terminus occurs further towards the C-terminus in CH1641 than in BSE. The ratios of 12B2/94B4 and 9A2/94B4 were similar between experimental CH1641 and CH1641-like cases, although two CH1641-like subjects displayed slightly elevated ratios of both 12B2/94B4 and 9A2/94B4. To verify this finding for PrP(res), mass spectrometry based quantification was used to determine the absolute abundance of the peptides associated with all three antibody binding regions. There was a 2.2 fold reduction of peptides containing the 9A2 epitope for experimental CH1641 PrP(res) in comparison to BSE PrP(res). Observation of reduced PrP(res) may serve as a new marker for CH1641. This mIFMA may thus provide the basis for simplified TSE diagnosis with capability for simultaneous screening and differential diagnosis. PMID- 22498750 TI - Guidelines for the diagnosis and treatment of Merkel cell carcinoma - Cutaneous Oncology Group of the French Society of Dermatology. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin. The epidemiological factors strongly associated with this tumor are: age over 65 years, fair skin, chronic sun exposure and immune suppression. Data are sparse in the literature and many questions remain unanswered regarding the diagnosis and treatment of this tumor. OBJECTIVE: To provide clinical practice guidelines for the diagnosis and treatment of MCC. METHOD: The literature data were analyzed and the current American and German practice guidelines were compared. Consensus items between these two guidelines were adopted as recommendations. Regarding discordant points, a formalized expert consensus process was devised. The guidelines were then written up by an editorial panel and validated by the Cutaneous Oncology Group of the French Society of Dermatology. RESULTS: The guidelines were drawn up according to three levels of scientific evidence: (a) complete agreement between the American and German guidelines; (b) the results of the formalized expert consensus process; and (c) the expert opinion of the steering group, based on analysis of the available evidence. The guidelines presented here are up-to-date recommendations on the clinical and pathological procedures for MCC diagnosis, staging, surgical treatment, sentinel node biopsy, radiotherapy and follow-up. CONCLUSION: These guidelines for diagnosis and treatment of MCC should standardize MCC management, which may not be optimal in France today. PMID- 22498751 TI - Drug development risk and the cost of capital. PMID- 22498753 TI - ADHD and nicotine use in schizophrenia or Asperger syndrome: a controlled study. AB - OBJECTIVE: To examine ADHD prevalence, rating scales, and relationship to nicotine use in adults with schizophrenia or Asperger syndrome. METHOD: Ninety five individuals, 41 with schizophrenia and 54 with Asperger syndrome, were included. Self-rating of adult ADHD symptoms with the Wender-Reimherr Adult Attention Deficit Diagnostic Rating Scale (WRAADDS), parent rating of proband's ADHD childhood and adult life symptoms using the Swanson, Nolan, and Pelham Questionnaire (SNAP), and report of clinical ADHD diagnosis were included as ADHD measures. Nicotine use data were compared with data from a population sample. RESULTS: In all, 10% of the schizophrenia group and 30% of the Asperger syndrome group had a clinical ADHD diagnosis. Nicotine dependency in the whole sample was closely linked to ADHD. CONCLUSION: The prevalence of comorbid ADHD was high in schizophrenia and Asperger syndrome. The WRAADDS self-rating scale for ADHD can be one useful tool for assessing comorbid ADHD in these patient groups. PMID- 22498754 TI - Distinguishing comorbidity and successful management of adult ADHD. AB - OBJECTIVE: Given high rates of comorbidity, lack of awareness and global acceptance, and varying guidelines for its management, adult ADHD may be an especially difficult condition to diagnose and treat. The objective of this review was to explore and characterize similarities and differences among comorbidities associated with adult ADHD. METHOD: A review of the literature over the past 10 years was performed using Ovid. RESULTS: A myriad of comorbid conditions such as impulse-control/personality, anxiety, mood, substance use, learning, and sleep disorders overlap with adult ADHD. Furthermore, a number of such conditions have symptoms that can mimic those of ADHD, including hyperactivity, impulsivity, inattention, and disruption of circadian rhythms, adding to the complexity of recognition and diagnosis of ADHD in adults. Extensive research shows that adults with ADHD appear to benefit from treatment with stimulant medications in similar ways as children, including significant improvements on driving performance. However, fear surrounding the abuse of stimulants is an important issue. Nevertheless, evidence suggests that children with ADHD who are treated with stimulant medication are less likely to develop a substance use disorder in adolescence and adulthood. CONCLUSION: There are a wide range of comorbidities with adult ADHD with many having overlapping symptoms. The benefits observed with ADHD treatment, however, emphasize the importance of recognition and treatment of adult ADHD. PMID- 22498755 TI - Simple and versatile selective synthesis of neutral and cationic copper(I) N heterocyclic carbene complexes using an electrochemical procedure. AB - An electrochemical approach for the preparation of copper(I) N-heterocyclic carbene complexes has been developed to include a diverse range of ligand precursors. Importantly, the method is effective for a ligand precursor that contains several acidic protons and for which traditional methods of carbene formation are not suitable. PMID- 22498756 TI - Efficient "green" quantum dot-sensitized solar cells based on Cu2S-CuInS2-ZnSe architecture. AB - A Cu(2)S-CuInS(2)-ZnSe quantum dot (QD)-sensitized solar cell with cascaded energy gap structures has been fabricated. Under simulated illumination (AM 1.5, 100 mW cm(-2)), the best device is obtained with a Cu(2)S-CuInS(2)-ZnSe QD sensitized solar cell, yielding a power conversion efficiency of 2.52%. PMID- 22498752 TI - Epigenetic protein families: a new frontier for drug discovery. AB - Epigenetic regulation of gene expression is a dynamic and reversible process that establishes normal cellular phenotypes but also contributes to human diseases. At the molecular level, epigenetic regulation involves hierarchical covalent modification of DNA and the proteins that package DNA, such as histones. Here, we review the key protein families that mediate epigenetic signalling through the acetylation and methylation of histones, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones. These protein families are emerging as druggable classes of enzymes and druggable classes of protein-protein interaction domains. In this article, we discuss the known links with disease, basic molecular mechanisms of action and recent progress in the pharmacological modulation of each class of proteins. PMID- 22498757 TI - A molecularly imprinted polymer based on functionalized multiwalled carbon nanotubes for the electrochemical detection of parathion-methyl. AB - A novel composite of vinyl group functionalized multiwalled carbon nanotubes (MWCNTs) molecularly imprinted polymer (MIP) was synthesized and applied as a molecular recognition element to construct an electrochemical sensor for parathion-methyl in this paper. The special molecular recognition properties of parathion-methyl mainly dominated by pi-pi, p-pi interaction and hydrogen bonding formed among functional monomer, template and matrix. A series of electrochemical experiment results proved that the prepared material had good adsorption capacity and fast mass transfer rate to parathion-methyl. The good selectivity of the sensor allowed fine discrimination between parathion and paraoxon, which had similar structures to parathion-methyl. The response of the MIPs was linearly proportional to the concentration of parathion-methyl over the range of 2.0 * 10( 7) to 1.0 * 10(-5) mol L(-1) with a lower detection limit of 6.7 * 10(-8) mol L( 1) (S/N = 3). This sensor was also applied in the detection of parathion-methyl in pear and cucumber with average recoveries of between 94.9% and 106.2% (RSD < 5%) being obtained. The results mentioned above show that the novel electrochemical sensor is an ideal device for the real-time determination of parathion-methyl in real samples. PMID- 22498758 TI - An optical sensor for Cu(II) detection with upconverting luminescent nanoparticles as an excitation source. AB - The first optical sensor for Cu(II) detection, with upconverting luminescent nanoparticles as an excitation source, showing high selectivity and good linear Stern-Volmer characteristics, has been achieved through a fluorescence resonance energy transfer (FRET) process between NaYF(4):Yb(3+)/Er(3+) and RB-hydrazide. The sensing mechanism is then discussed. PMID- 22498759 TI - Reduced perfusion in pulmonary infiltrates of high-risk hematologic patients is a possible discriminator of pulmonary angioinvasive mycosis: a pilot volume perfusion computed tomography (VPCT) study. AB - RATIONALE AND OBJECTIVES: The aim of this study was to assess perfusion parameters in atypical pneumonia of heavily immunocompromised hematologic patients suspected of having invasive mycosis using volume perfusion computed tomography and establish their diagnostic role. MATERIALS AND METHODS: Volume perfusion computed tomographic data from 21 consecutive immunocompromised patients presenting with atypical parenchymal opacity of consolidation were analyzed with respect to the degree of perfusion of their pneumonias. All patients presented with clinical and laboratory signs of infection. Seventeen patients (10 men, seven women; mean age, 57 years; age range, 19-76 years) were found with proven (n = 9), probable (n = 2), or possible (n = 6) angioinvasive mycosis. One patient was diagnosed with bronchoinvasive aspergillosis. Four patients (all men; mean age, 71 years; age range, 67-79 years) were diagnosed with bacterial pneumonia. Volume perfusion computed tomography of the involved pulmonary areas was performed at 80 kV and 60 mAs, with 26 measurement points distributed over 65.9 seconds. Fifty milliliters of contrast material was injected at a rate of 5 mL/s, followed by a 50-mL saline chaser. Entire coverage of the pneumonic parenchymal consolidation was obtained in all patients, with the generation of parametric maps of blood flow (BF) using the maximal slope model and blood volume (BV) using Patlak analysis. The results of perfusion measurements were then analyzed and evaluated for all patients. RESULTS: Patients with proven, probable, or possible angioinvasive pulmonary fungal infection revealed very low levels of perfusion of their parenchymal consolidations, with BFs ranging from 0.01 to 23.86 mL/100 mL tissue/min and BVs ranging from 0.88 to 10.67 mL/100 mL tissue, lower than those of the adjacent thoracic musculature and of bacterial pneumonias. Bacterial pneumonias showed all increased perfusion parameters, with BFs ranging from 30.49 to 41.65 mL/100 mL tissue/min and BVs ranging from 10.07 to 49.90 mL/100 mL tissue. The cutoff BF value for differentiation was 23.89 mL/100 mL tissue/min, and the cutoff BV value was 9.6 mL/100 mL tissue. CONCLUSIONS: Patients with angioinvasive pulmonary mycosis showed lower perfusion parameters on volume perfusion computed tomography compared to those experiencing bacterial pneumonia. PMID- 22498761 TI - Time-dependent effect of in vivo inflammation on eicosanoid and endocannabinoid levels in plasma, liver, ileum and adipose tissue in C57BL/6 mice fed a fish-oil diet. AB - Eicosanoids and endocannabinoids/N-acylethanolamines (NAEs) are fatty acid derived compounds with a regulatory role in inflammation. Considering their complex metabolism, it is likely that inflammation affects multiple compounds at the same time, but how lipid profiles change in plasma and other tissues after an inflammatory stimulus has not been described in detail. In addition, dietary fish oil increases levels of several n-3 fatty acid derived eicosanoids and endocannabinoids, and this may lead to a broader change in the profiles of bioactive lipids. In the present study mice were fed a diet containing 3% w/w fish oil for 6 weeks before receiving i.p. saline or 3 mg/kg lipopolysaccharide (LPS) to induce an inflammatory response. Eicosanoid and endocannabinoid/NAE levels (in total 61 metabolites) in plasma, liver, ileum, and adipose tissue were quantified using targeted lipidomics after 2, 4, 8, and 24 h, respectively. Tissue- and time-dependent effects of LPS on bioactive lipid profiles were observed. For example, levels of CYP derived eicosanoids in the ileum were markedly affected by LPS, whereas this was less pronounced in the plasma and adipose tissue. For some compounds, such as 9,10-DiHOME, opposing effects of LPS were seen in the plasma compared to the other tissues, suggesting differential regulation of bioactive lipid levels after an inflammatory stimulus. Taken together, our results show that plasma levels do not always correlate with the effects found in the tissues, which underlines the need to measure profiles and pathways of mediators involved in inflammation, including endocannabinoid-like structures, in both plasma and tissues. PMID- 22498762 TI - Curcumin induces apoptosis in tumor necrosis factor-alpha-treated HaCaT cells. AB - Psoriasis is a benign, chronic skin disease characterized by keratinocyte hyperproliferation and abnormal differentiation. Curcumin, a selective phosphorylase kinase inhibitor, is a natural phytochemical present in turmeric. Curcumin has been confirmed to have anti-inflammatory properties as well as the ability to inhibit proliferation and decrease the expression of pro-inflammatory cytokines in psoriatic keratinocytes. However, the pro-apoptotic effect of curcumin in keratinocytes remains unclear. In the present study, we investigated the effect of curcumin on apoptosis induction in TNF-alpha-treated HaCaT cells. These results show that curcumin exhibited a significant pro-apoptotic effect on HaCaT cells only in the presence of TNF-alpha and/or TRAIL. The pro-apoptotic effect of curcumin resulted from the increased expression of TRAIL-R1/R2 and the decreased expression of anti-apoptotic proteins. Our results indicate that both curcumin and TNF-alpha up-regulated the expression of TRAIL-R1/R2. In addition, the expression of anti-apoptotic proteins (IAP1, IAP2, Bcl-X(L)) was up-regulated by TNF-alpha but suppressed by curcumin in HaCaT cells. Because these proteins are regulated by NF-kappaB, we examined the role of curcumin in NF-kappaB activation. As expected, curcumin inhibited TNF-alpha-induced activation of NF kappaB, including NF-kappaB-P65. Curcumin also inhibited the TNF-alpha-induced production of IL-6/IL-8 in HaCaT cells. These results imply that curcumin-induced apoptosis of HaCaT cells only occurs when TNF-alpha or/and TRAIL are present. Therefore, we believe that curcumin is able to reverse the anti-apoptotic function of TNF-alpha in HaCaT cells and thus expect curcumin to be successful in the treatment of psoriasis. PMID- 22498764 TI - Plasmonic dimer antennas for surface enhanced Raman scattering. AB - Electron beam induced deposition (EBID) has recently been developed into a method to directly write optically active three-dimensional nanostructures. For this purpose a metal-organic precursor gas (here dimethyl-gold(III)-acetylacetonate) is introduced into the vacuum chamber of a scanning electron microscope where it is cracked by the focused electron beam. Upon cracking the aforementioned precursor gas, 3D deposits are realized, consisting of gold nanocrystals embedded in a carbonaceous matrix. The carbon content in the deposits hinders direct plasmonic applications. However, it is possible to activate the deposited nanostructures for plasmonics by coating the EBID structures with a continuous silver layer of a few nanometers thickness. Within this silver layer collective motions of the free electron gas can be excited. In this way, EBID structures with their intriguing precision at the nanoscale have been arranged in arrays of free-standing dimer antenna structures with nanometer sized gaps between the antennas that face each other with an angle of 90 degrees . These dimer antenna ensembles can constitute a reproducibly manufacturable substrate for exploiting the surface enhanced Raman effect (SERS). The achieved SERS enhancement factors are of the order of 104 for the incident laser light polarized along the dimer axes. To prove the signal enhancement in a Raman experiment we used the dye methyl violet as a robust test molecule. In future applications the thickness of such a silver layer on the dimer antennas can easily be varied for tuning the plasmonic resonances of the SERS substrate to match the resonance structure of the analytes to be detected. PMID- 22498763 TI - Effects of triptolide on the synaptophysin expression of hippocampal neurons in the AD cellular model. AB - Due to the immunoinflammatory pathology of Alzheimer's disease (AD) brain, recent studies have begun to focus attention on the role of anti-inflammatory drugs or immunomodulators in AD. Triptolide isolated from the herb Tripterygium wilfordii Hook F has anti-inflammatory and immunosuppressive activities. In this study, we observed the effects of triptolide on synaptophysin expression in AD cellular model. AD cellular model was established by action of Abeta-stimulated microglial conditioned medium (MCM) on cultured rat hippocampal neurons (HN). Immunocytochemical staining, western blot and RT-PCR were used to observe the effects of triptolide at different dosages on the synaptophysin expression of hippocampal neurons in AD cellular model at different time points during incubation of cultures. After 24 h of cultivation, the expression level of synaptophysin in MCM/HN model group was decreased as compared with normal HN group and MCM/HN control group, and the expression level of synaptophysin in MCM/HN low-dose triptolide group and MCM/HN high-dose triptolide group was increased as compared with MCM/HN model group. It is concluded that triptolide can promote the synaptophysin expression of hippocampal neurons in the AD cellular model. PMID- 22498766 TI - Regulatory T cells in atherogenesis. AB - Atherosclerosis is believed to be an inflammatory condition of the arterial wall. It has become apparent that various types of cells of innate and adaptive immunity participate in atherogenesis. T cells are of particular interest because they mediate pathogenic immune responses involved in the acceleration of atherosclerosis. Recent studies from several independent groups indicated that subsets of regulatory T cells (Tregs) actively mediate immunologic tolerance and inhibit atherosclerosis development or progression through the down-regulation of effector T-cell responses. It is likely that there is an imbalance between pathogenic effector T cells and Tregs under atherosclerotic conditions. Recent evidence suggests that in addition to the thymus, gut-associated lymphoid tissues are the main sites for the generation of several subsets of peripherally inducible Tregs. This indicates that intervention in the gut environment to promote an endogenous regulatory immune response may serve as a possible therapeutic approach to suppress atherosclerotic diseases. In this review, we discuss not only the possible role of Tregs in the prevention of atherosclerosis, but also promising strategies to prevent or cure atherosclerotic diseases by promoting an endogenous regulatory immune response, particularly by oral immune modulation. PMID- 22498765 TI - Epigallocatechin-3-gallate has an anti-platelet effect in a cyclic AMP-dependent manner. AB - AIM: In this study, we investigated the effect of (-)-epigallocatechin-3-gallate (EGCG) on cyclic nucleotide production and vasodilator-stimulated phosphoprotein (VASP) phosphorylation in collagen (10 ug/mL)-stimulated platelet aggregation. METHODS: Washed platelets (10(8)/mL) from Sprague-Dawley rats (6-7 weeks old, male) were preincubated for 3 min at 37 degrees C in the presence of 2 mM exogenous CaCl(2) with or without EGCG or other materials, stimulated with collagen (10 ug/mL) for 5 min, and then used for the determination of intracellular cytosolic Ca(2+) ([Ca(2+)](i)), thromboxane A(2) (TXA(2)), adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP), and VASP phosphorylation. RESULTS: EGCG dose-dependently inhibited collagen-induced platelet aggregation by inhibiting both [Ca(2+)](i) mobilization and TXA(2) production. Of two aggregation-inhibiting molecules, cAMP and cGMP, EGCG significantly increased intracellular levels of cAMP, but not cGMP. EGCG elevated cAMP level was decreased by SQ22536, an adenylate cyclase inhibitor, but not by etazolate, a cAMPspecific phosphodiesterase inhibitor. In addition, EGCG elevated the phosphorylation of VASP-Ser(157), a cAMP-dependent protein kinase (A kinase) substrate, but not the phosphorylation of VASP-Ser(239), a cGMP-dependent protein kinase substrate, in intact platelets and collagen-induced platelets, and VASP-Ser(157) phosphorylation by EGCG was inhibited by both an adenylate cyclase inhibitor SQ22536 and an A-kinase inhibitor Rp-8-Br-cAMPS. We have demonstrated that EGCG increases cAMP via adenylate cyclase activation and subsequently phosphorylates VASP-Ser(157) through A-kinase activation to inhibit [Ca(2+)](i) mobilization and TXA(2) production on collagen-induced platelet aggregation. CONCLUSIONS: These results strongly indicate that EGCG is a beneficial compound elevating cAMP level in collagen-platelet interaction, which may result in the prevention of platelet aggregation-mediated thrombotic diseases. PMID- 22498767 TI - Ezetimibe ameliorates early diabetic nephropathy in db/db mice. AB - AIM: Lipid-lowering medications have been suggested to have a potential benefit in the treatment of chronic kidney disease (CKD) such as diabetic nephropathy. Although ezetimibe has been widely used to lower serum cholesterol levels, the effect of this drug on diabetic nephropathy remains unclear. In the present study, therefore, we examined the protective effect of ezetimibe on diabetic nephropathy in db/db mice. METHOD: Db/db mice were fed a standard diet with 0.01% (w/w) of ezetimibe for 8 weeks from 8 weeks of age. RESULTS: Treatment with ezetimibe did not affect food intake, body weight gain, adiposity, or blood pressure in db/db mice. Ezetimibe also had no effect on glucose metabolism such as fasting plasma glucose and insulin; however, it markedly reduced plasma lipid levels and hepatic lipid contents and reduced the urinary excretion of albumin by 50% in db/db mice, suggesting the effect of ezetimibe on diabetic nephropathy. Furthermore, ezetimibe improved glomerular hypertrophy. Although ezetimibe had no effect on oxidative stress measured by urinary 8-OHdG in db/db mice, the plasma adiponectin level was normalized, and the expression of adiponectin receptor 1 in the kidney was increased by ezetimibe treatment. CONCLUSION: Our data suggest that ezetimibe can improve early diabetic nephropathy through its hypolipidemic effect, and the amelioration of adiponectin resistance may also be responsible for the renoprotective effect of ezetimibe as its underlying mechanism. PMID- 22498768 TI - There's more to flow-mediated dilation than nitric oxide. AB - Flow-mediated dilation (FMD) is the standard tool used to assess endothelial function. The premise behind the standard FMD test is that it serves as an endothelial-dependant nitric oxide bioassay; however, the endothelium may release additional dilatory molecules which contribute to FMD, most notably prostacyclin and endothelial-derived hyperpolarizing factor. The relative importance of these molecules to the dilatory response may vary substantially among individuals, particularly in response to a number of diseased states. This review discusses how each of these molecules may contribute to vasodilation, and considers the circumstances in which they may vary. PMID- 22498769 TI - Impact of low-and high-density lipoprotein cholesterol levels on carotid intima media thickness differs by smoking status in middle-aged men. AB - AIM: Cigarette smoking is a strong risk factor for atherosclerotic disease; however, it remains unclear whether the impact of other risk factors differs by smoking status. The aim of this study was to investigate this issue, especially with regard to low-density and high-density lipoprotein (LDL/HDL) levels. METHODS: In total, 448 healthy, middle-aged men (aged 37 to 61) participated in this study. Smoking habits were recorded, carotid intima-media thickness (IMT) was measured by B-mode ultrasound, and serum lipids and other biochemical parameters were determined from fasted blood samples. RESULTS: Among the overall subjects, multivariate regression analyses showed that IMT was significantly associated with age (p < 0.0001 for mean IMT, p= 0.002 for max IMT), body mass index (BMI, mean IMT, p= 0.028), LDL-C levels (mean/max IMT, p= 0.001), HDL-C levels (max IMT, p= 0.022) and current smoking habit (mean IMT, p=0.012). Subgroup analyses according to smoking status revealed that LDL-C levels were significantly associated with mean/max IMT in current smokers (p=0.001) but not in ex- or nonsmokers (never smoked subjects). After adjusting for age, BMI, systolic blood pressure, hemoglobin A1c and serum lipids, mean IMT respectively increased and decreased progressively across LDL-C and HDL-C quartiles (p= 0.004 and 0.045) in the overall subjects. These associations were observed in current smokers (p= 0.01) but not in ex- or nonsmokers for LDL-C, and were observed in ex and nonsmokers (p= 0.025, 0.017, respectively) but not in current smokers for HDL-C. CONCLUSION: The impact of LDL-C/HDL-C levels on carotid IMT differs by smoking status. These observations imply that distinct mechanisms are involved in the (anti) atherogenesis of LDL/HDL according to smoking status. PMID- 22498770 TI - Gold-assisted E' centres formation on the silica surface of Au/SBA-15 catalysts for low temperature CO oxidation. AB - SH-functionalized SBA-15 was synthesized and gold nanoclusters were grafted inside its channels. Different portions of such gold-containing material were subjected to a variety of thermal treatments, including calcination in the 300 560 degrees C temperature range and further treatments under a hydrogen atmosphere at diverse temperatures (up to 600 degrees C). The resulting materials were thoroughly characterized by CHS elemental analysis, X-ray diffraction, transmission electron microscopy, N2 physisorption and H2 chemisorption, as well as by Raman, NMR, FTIR and EPR spectroscopies, in order to investigate the influence of the temperature and atmosphere of the pretreatment on the gold particle size and oxidation state, the formation of defective E' centres on the silica support and their ability to induce the formation of reactive O2(-) surface species. Catalytic testing for the CO oxidation reaction was carried out in the 40-150 degrees C temperature range. Significant differences in catalytic behaviour were observed among the catalysts, which are discussed in the light of the characterization results. A mechanism for the "activation" of the non-reducible ("inert") SBA-15 support involving Au(0)-> Au(+) transformation is proposed, where gold metal plays an essential twofold role: it induces the formation of atomic hydrogen by dissociatively adsorbing H2 and triggers the formation of E' centres by transferring an electron to positively charged silicon species. PMID- 22498771 TI - Testing the sign-changing superconducting gap in iron-based superconductors with quasiparticle interference and neutron scattering. AB - We present a phenomenological calculation of the quasiparticle interference (QPI) pattern and inelastic neutron scattering (INS) spectra in iron-pnictide and layered iron-selenide compounds by using material specific band structure and superconducting (SC) gap properties. As both the QPI and the INS spectra arise due to scattering of the Bogolyubov quasiparticles, they exhibit a one-to-one correspondence of the scattering vectors and the energy scales. We show that these two spectroscopies complement each other in such a way that a comparative study allows one to extract quantitative and unambiguous information about the underlying pairing structure and the phase of the SC gap. Due to the nodeless and isotropic nature of the SC gaps, both the QPI and INS maps are concentrated at only two energies in pnictide (two SC gaps) and one energy in iron-selenide, while the associated scattering vectors q for scattering of sign-changing and same sign of the SC gaps change between these spectroscopies. The results presented, particularly for the newly discovered iron-selenide compounds, can be used to test the nodeless d-wave pairing in this class of high temperature superconductor. PMID- 22498773 TI - Proteomics and metabolomics of Arabidopsis responses to perturbation of glucosinolate biosynthesis. AB - To understand plant molecular networks of glucosinolate metabolism, perturbation of aliphatic glucosinolate biosynthesis was established using inducible RNA interference (RNAi) in Arabidopsis. Two RNAi lines were chosen for examining global protein and metabolite changes using complementary proteomics and metabolomics approaches. Proteins involved in metabolism including photosynthesis and hormone metabolism, protein binding, energy, stress, and defense showed marked responses to glucosinolate perturbation. In parallel, metabolomics revealed major changes in the levels of amino acids, carbohydrates, peptides, and hormones. The metabolomics data were correlated with the proteomics results and revealed intimate molecular connections between cellular pathways/processes and glucosinolate metabolism. This study has provided an unprecedented view of the molecular networks of glucosinolate metabolism and laid a foundation towards rationale glucosinolate engineering for enhanced defense and quality. PMID- 22498772 TI - Map-based cloning of zb7 encoding an IPP and DMAPP synthase in the MEP pathway of maize. AB - IspH is a key enzyme in the last step of the methyl-D-erythritol-4-phosphate (MEP) pathway. Loss of function of IspH can often result in complete yellow or albino phenotype in many plants. Here, we report the characterization of a recessive mutant of maize, zebra7 (zb7), showing transverse green/yellow striped leaves in young plants. The yellow bands of the mutant have decreased levels of chlorophylls and carotenoids with delayed chloroplast development. Low temperature suppressed mutant phenotype, while alternate light/dark cycle or high temperature enlarged the yellow section. Map-based cloning demonstrated that zb7 encodes the IspH protein with a mis-sense mutation in a conserved region. Transgenic silencing of Zb7 in maize resulted in complete albino plantlets that are aborted in a few weeks, confirming that Zb7 is important in the early stages of maize chloroplast development. Zb7 is constitutively expressed and its expression subject to a 16-h light/8-h dark cycle regulation. Our results suggest that the less effective or unstable IspH in zb7 mutant, together with its diurnal expression, are mechanistically accounted for the zebra phenotype. The increased IspH mRNA in the leaves of zb7 at the late development stage may explain the restoration of mutant phenotype in mature stages. PMID- 22498774 TI - A short amino-terminal part of Arabidopsis phytochrome A induces constitutive photomorphogenic response. AB - Phytochrome A (phyA) is the dominant photoreceptor of far-red light sensing in Arabidopsis thaliana. phyA accumulates at high levels in the cytoplasm of etiolated seedlings, and light-induced phyA signaling is mediated by a complex regulatory network. This includes light- and FHY1/FHL protein-dependent translocation of native phyA into the nucleus in vivo. It has also been shown that a short N-terminal fragment of phyA (PHYA406) is sufficient to phenocopy this highly regulated cellular process in vitro. To test the biological activity of this N-terminal fragment of phyA in planta, we produced transgenic phyA-201 plants expressing the PHYA406-YFP (YELLOW FLUORESCENT PROTEIN)-DD, PHYA406-YFP-DD NLS (nuclear localization signal), and PHYA406-YFP-DD-NES (nuclear export signal) fusion proteins. Here, we report that PHYA406-YFP-DD is imported into the nucleus and this process is partially light-dependent whereas PHYA406-YFP-DD-NLS and PHYA406-YFP-DD-NES display the expected constitutive localization patterns. Our results show that these truncated phyA proteins are light-stable, they trigger a constitutive photomorphogenic-like response when localized in the nuclei, and neither of them induces proper phyA signaling. We demonstrate that in vitro and in vivo PHYA406 Pfr and Pr bind COP1, a general repressor of photomorphogenesis, and co-localize with it in nuclear bodies. Thus, we conclude that, in planta, the truncated PHYA406 proteins inactivate COP1 in the nuclei in a light-independent fashion. PMID- 22498775 TI - Immune response to bacteria induces dissemination of Ras-activated Drosophila hindgut cells. AB - Although pathogenic bacteria are suspected contributors to colorectal cancer progression, cancer-promoting bacteria and their mode of action remain largely unknown. Here we report that sustained infection with the human intestinal colonizer Pseudomonas aeruginosa synergizes with the Ras1V12 oncogene to induce basal invasion and dissemination of hindgut cells to distant sites. Cross-talk between infection and dissemination requires sustained activation by the bacteria of the Imd-dTab2-dTak1 innate immune pathway, which converges with Ras1V12 signalling on JNK pathway activation, culminating in extracellular matrix degradation. Hindgut, but not midgut, cells are amenable to this cooperative dissemination, which is progressive and genetically and pharmacologically inhibitable. Thus, Drosophila hindgut provides a valuable system for the study of intestinal malignancies. PMID- 22498776 TI - Learning individual talkers' structural preferences. AB - Listeners are often capable of adjusting to the variability contained in individual talkers' (speakers') speech. The vast majority of findings on talker adaptation are concerned with learning the contingency between phonological characteristics and talker identity. In contrast, the present study investigates representations at a more abstract level - the contingency between syntactic attachment style and talker identity. In a 'visual-world' experiment, participants were exposed to semi-realistic scenes depicting several objects (e.g., an adult man, a young girl, a motorbike, a carousel, and other objects) accompanied by a spoken sentence with a structurally ambiguous relative clause (e.g., 'The uncle of the girl who will ride the motorbike/carousel is from France.' In the context of the scene, 'motorbike' suggested the uncle as the agent of the riding, whereas 'carousel' suggested the girl as the agent). For half the experimental items, one version of the sentence was read by one talker, who always uttered sentences that resolved, pragmatically, to the high attachment (the uncle as the agent), and the other by another talker, who always uttered sentences resolving to the low attachment (the girl as the agent). For the other half of the experimental items, both versions were read by a third talker who produced both high and low attachments. It was found that, after exposure to these stimuli, and for new sentences not heard previously, participants learnt to anticipate the 'appropriate' attachment depending on talker identity (with no attachment preference for the talker who produced both attachment types). The data suggest that listeners can learn the relationship between talker identity and abstract, structural, properties of their speech, and that syntactic attachment decisions in comprehension can reflect sensitivity to talker-specific syntactic style. PMID- 22498777 TI - Protein nitration as footprint of oxidative stress-related nitric oxide signaling pathways in developing Ciona intestinalis. AB - Developmental processes in the ascidian Ciona intestinalis depend on a complex interplay of events including, during metamorphosis, a caspase-dependent apoptosis which is regulated by the nitric oxide (NO)-cGMP signaling pathway. Herein we disclose an alternate NO-mediated signaling pathway during Ciona development which appears to be critically dependent on local redox control. Evidence in support of this conclusion includes: (a) inhibitors of NO synthase (NOS) and scavengers of NO-derived nitrating agents markedly decrease the rate of Ciona metamorphosis; (b) an NO donor or peroxynitrite caused an opposite effect; (c) increased protein nitration is observed at larva stage. Integrated proteomic and immunochemical methodologies identified nitrated tyrosine residues in ERK and snail. Overall, these results point to protein nitration as a hitherto overlooked NO-dependent regulatory mechanism in Ciona which is specifically triggered by elevated ROS production during developmental processes. PMID- 22498778 TI - Microarray-based detection of specific IgE against recombinant omega-5-gliadin in suspected wheat-dependent exercise-induced anaphylaxis. AB - Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a rare IgE-mediated food allergy. Component-resolved measurement of specific IgE (sIgE) against omega-5 gliadin by fluorescence enzyme immunoassay (FEIA) has been postulated as a good predictive decision criterion in the diagnosis of WDEIA. More recently, microarray technology has been introduced into component-resolved diagnostics. The aim of this study was to evaluate the performance of an allergen microarray in the detection of sIgE against omega-5-gliadin in 10 patients with suspected WDEIA and high levels of sIgE against omega-5-gliadin (mean: 9.31+/-7.53 kU/L, range: 4.24-25.8) as measured by FEIA. Using an old version of the microarray assay (ImmunoCAP ISACTM, Phadia), sIgE against omega-5-gliadin was detected in only 3 of the first 6 patients. The same samples and those of another 4 patients were then analysed with an improved version of the microarray system, yielding elevated levels of sIgE against omega-5-gliadin in all patients. In conclusion, the old version of the microarray was not reliable for the detection of sIgE against omega-5-gliadin in the examined individuals with suspected WDEIA. In contrast, the improved version of the microarray seems to be as adequate as FEIA in the detection of sIgE against omega-5-gliadin. However, further large-scale studies are warranted to confirm these results. PMID- 22498779 TI - Mucosal immunology: the good the gut bugs do. PMID- 22498780 TI - Development: Pulling RANK. PMID- 22498781 TI - Kinetic effects of tartaric acid on the growth of chiral J-aggregates of tetrakis(4-sulfonatophenyl)porphyrin. AB - The kinetics of growth for chiral J-aggregates of H(4)TPPS(4) porphyrin have been investigated under different experimental conditions in the presence of tartaric acid. The observed rate constants and the anisotropy factor g show a defined dependence on the enantiomer used as a chiral templating agent. PMID- 22498782 TI - Effects of protonation of pyridine moieties on the 2D assembly of porphyrin layers on Au(111) at electrochemical interfaces. AB - Unique molecular assemblies of a porphyrin derivative are prepared on Au(111) by controlling the protonation/unprotonation of the pyridine groups. The porphyrin derivative, driven by the protonation of the pyridine groups, can provide characteristic assemblies with specific molecular conformations on an Au(111) surface at the electrochemical interface. In situ scanning tunneling microscopy images revealed clear differences in the adlayer structures for the unprotonated and the protonated forms of the molecules that depended upon the electrochemical potential. PMID- 22498783 TI - Crystal phase-controlled synthesis of Cu2FeSnS4 nanocrystals with a band gap of around 1.5 eV. AB - Cu(2)FeSnS(4) (CFTS) nanocrystals with tunable crystal phase have been synthesized using a solution-based method. As-synthesized CFTS nanocrystals in the shape of oblate spheroid and triangular plate with band gaps of 1.54 +/- 0.04 and 1.46 +/- 0.03 eV, respectively, appear attractive as a low-cost substitute for thin film solar cells. PMID- 22498784 TI - The innate immune response of the bovine mammary gland to bacterial infection. AB - Intra-mammary (IM) bacterial infection in cattle can result in clinical outcomes that range from being acute and life-threatening to those that are chronic and sub-clinical. The typical bacteria involved in IM bacterial infections activate the mammary immune system in different ways which can influence the severity of the outcome. A clear understanding of the mechanisms that activate and regulate this response is central to the development of effective preventative and treatment regimes. This review focuses on the different immune responses of the bovine mammary gland to common mastitis-causing pathogens. There is special emphasis on comparing the responses to Escherichia coli and Staphylococcus aureus infections, as these are typically associated, respectively, with acute/severe and chronic/sub-clinical forms of the disease. PMID- 22498785 TI - Oral squamous cell carcinoma: like owner, like cat. PMID- 22498786 TI - Effect of age and maternally-derived antibody status on humoral and cellular immune responses to vaccination of pigs against Erysipelothrix rhusiopathiae. AB - The effects of age and maternally-derived antibodies (MDA) on the immune response to Erysipelothrix rhusiopathiae were investigated in piglets orally vaccinated with a live E. rhusiopathiae vaccine at 6, 8 or 10 weeks of age. Seroconversion, determined by ELISA, was evident in MDA positive piglets vaccinated at 8 or 10 weeks of age and in all MDA negative vaccinates. Two weeks after vaccination in the presence of MDA, a T cell response, measured by a lymphocyte proliferation assay, was observed in 25% of piglets vaccinated at 6 weeks of age and in 100% of piglets vaccinated at 8 or 10 weeks of age. The post-vaccinal response to E. rhusiopathiae was more strongly influenced by the maternal antibody status of the piglet at the time of vaccination than the age of the piglet. PMID- 22498787 TI - Cerium oxide nanoparticles scavenge nitric oxide radical (NO). AB - In this study we have obtained evidence that cerium oxide nanoparticles (CeO(2) NPs) are able to scavenge nitric oxide radical. Surprisingly, this activity is present in CeO(2) NPs with a lower level of cerium in the 3+ state (CeO(2) NPs with low 3+/4+ ratio and therefore a reduced number of oxygen vacancies), in contrast to the superoxide scavenging properties which are correlated with an increased level of cerium in the 3+ state (CeO(2) NPs with high 3+/4+ ratio and therefore an increased number of oxygen vacancies). PMID- 22498788 TI - Systemic lupus erythematosus and infections: clinical importance of conventional and upcoming biomarkers. AB - Infection is a common problem and has become one of the leading causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). The reasons for the high incidence of infection are immunosuppressive therapy and immune disturbances of lupus itself. Infections may mimic exacerbations of SLE, leading to confusion over the diagnosis and appropriate treatment. It can be notoriously difficult to differentiate between infection and disease flare in some cases. Indeed they may co-exist. Along with the conventional biomarkers of lupus flares as hypocomplementemia, anti-double-stranded-DNA antibodies and erythrocyte sedimentation rate, other biomarkers as procalcitonin, and autoantibodies against complement fraction C1q, have been investigated to distinguish infections from other inflammatory processes. Recent research has provided data about new potential biomarkers to assist clinical decision-making in the management of SLE patients (e.g. percentage of circulating CD27 high plasma cells from the peripheral blood, 2'5'-oligoadenylate synthetase isoforms, soluble triggering receptor expressed on myeloid cells-1 and pentraxin 3), but only some of them are supported by convincing evidence, such as CD 64-Fc receptor expression. We reviewed the literature on the available tests to discriminate between SLE activity and infections, focusing on conventional and upcoming biomarkers. PMID- 22498789 TI - Immune-mediated myelitis following hepatitis B vaccination. AB - The hepatitis B virus (HBV) is an important international cause of infectious acute and chronic liver diseases. HBV vaccines were developed to combat the potential life-threatening effects of HBV infection. Published case histories, retrospective reviews and analyses of epidemiological data report on the onset of immune-mediated myelitis after recombinant HBV vaccination, mostly in adults with a presumed genetic/immunologic predisposition. However, HBV vaccination has not borne out to be a significant trigger of serious autoimmune events, including acute myelitis, in populations at large over prolonged observation periods after immunization. Published study methods lack the sensitivity to categorically establish a causal relationship between exposure to HBV vaccine components and immune mediated myelitis, but in practice the faint possibility of such a link should not be totally rejected. PMID- 22498790 TI - ITPKC susceptibility in Kawasaki syndrome as a sensitizing factor for autoimmunity and coronary arterial wall relaxation induced by thimerosal's effects on calcium signaling via IP3. AB - Recently, a single nucleotide polymorphism (SNP) of the inositol 1,4,5 triphosphate kinase C (ITPKC), rs28493229, was found to passively confer susceptibility for Kawasaki syndrome (KS) and subsequent coronary arterial lesions. This association is believed to be the result of defective phosphorylation of inositol 1,4,5-triphosphate (IP3), which releases calcium from intracellular stores, resulting from reduced genetic expression of ITPKC in carriers of the SNP. Reduced ITPKC activity would increase IP3 levels, and thus, increase calcium release. We hypothesized that an environmental agent which influences IP3-mediated calcium release is potentiated by the ITPKC SNP. This led us to an attractive candidate, thimerosal, an organomercurial medical preservative still used in several pediatric vaccines. Thimerosal is well-known to sensitize IP3 receptors via its induction of oxidative stress, resulting in enhanced release of intracellular calcium with distinctive consequences for various cell types. Dysregulated calcium signaling in T cells and other immune cells can result in autoimmunity, while hyperpolarization of vascular smooth muscle cells secondary to the stimulation of calcium-activated potassium channels can result in increased vascular permeability and arterial relaxation. We propose that ITPKC susceptibility in KS is related to its synergy with environmental triggers, such as thimerosal, which alter calcium homeostasis and promote oxidative stress. Therefore, carriers of the ITPKC SNP are more susceptible to thimerosal-induced autoimmunity and coronary arterial lesions observed in KS. This would explain why only a susceptible subset of children develops KS although pediatric thimerosal exposure is nearly universal due to vaccination. As was experienced with the infantile acrodynia epidemic, only 1 in 500 children developed the disease although pediatric mercury exposure was nearly ubiquitous due to the use calomel teething powders. This hypothesis also mirrors the current leading theory for KS in which a widespread infection only induces the disease in susceptible children. We conclude that KS may be the acute febrile form of acrodynia. PMID- 22498791 TI - Pattern transfer nanomanufacturing using magnetic recording for programmed nanoparticle assembly. AB - We report a novel nanomanufacturing technique that incorporates patterned arrays built entirely from Fe3O4 nanoparticles into a flexible and transparent polymer film. First, the nanoparticles are patterned using the enormous magnetic field gradients at the surface of commercial disk drive media, and then the resulting architecture is transferred to the surface of a polymer film by spin-coating and peeling. Since the particles are immobilized by the field gradients during the spin-coating process, the patterned array is preserved after peeling. To demonstrate the potential of this technology, we fabricate a 5 mm diameter all nanoparticle diffraction grating capable of producing a white-light optical spectrum. We also demonstrate several extensions to this technology, where, by adding an external magnetic field during assembly, we create both periodic variations in topography, as well as a nanocomposite with two vertically and horizontally separated nanoparticle layers. As this technique leverages the nanometer resolution inherent in current magnetic recording technology, strong potential exists for low-cost nanomanufacturing of optical and electronic devices from a variety of nanomaterials with ~10 nm resolution. PMID- 22498792 TI - Air radioactivity levels following the Fukushima reactor accident measured at the Laboratoire Souterrain de Modane, France. AB - The radioactivity levels in the air of the radionuclides released by the Fukushima accident were measured at the Laboratoire Souterrain de Modane, in the South-East of France, during the period 25 March-18 April 2011. Air-filters from the ventilation system exposed for one or two days were measured using low background gamma-ray spectrometry. In this paper we present the activity concentrations obtained for the radionuclides (131)I, (132)Te, (134)Cs, (137)Cs, (95)Nb, (95)Zr, (106)Ru, (140)Ba/La and (103)Ru. The activity concentration of (131)I was of the order of 100 MUBq/m(3), more than 100 times higher than the activities of other fission products. The highest activities of (131)I were measured as a first peak on 30 March and a second peak on 3-4 April. The activity concentrations of (134)Cs and (137)Cs varied from 5 to 30 MUBq/m(3). The highest activity concentration recorded for Cs corresponded to the same period as for (131)I, with a peak on 2-3 April. The results of the radioactivity concentration levels in grass and mushrooms exposed to the air in the Modane region were also measured. Activity concentrations of (131)I of about 100 mBq/m(2) were found in grass. PMID- 22498793 TI - Visual impairment certification secondary to ARMD in Leeds, 2005-2010: is the incidence falling? AB - AIM: The aim of this study was to evaluate trends in visual impairment certification due to age-related macular degeneration (ARMD) in the Leeds metropolitan area between 2005 and 2010. METHODS: In this retrospective study, the primary causes of visual impairment certification in the Leeds metropolitan area between 2005 and 2010 were reviewed. ARMD was considered to be the cause of certification when recorded as the primary factor contributing to visual impairment in one or both eyes. The incidence of visual impairment certification due to ARMD was calculated using population estimates from the Office of National Statistics. RESULTS: ARMD was the primary cause of visual impairment certification in all study years, accounting for 58.7 and 50.8% of certifications in 2005 and 2010, respectively. For the same period, the incidence of certification due to ARMD fell from 364 to 248 per million population per year. This was largely the result of a fall in the incidence of visual impairment certification due to neovascular ARMD from 225 to 137 per million population per year, beginning in 2008 after the introduction of a local commissioning policy on the use of intra-vitreal ranibizumab. CONCLUSION: The incidence of visual impairment certification due to ARMD in the Leeds metropolitan area appears to be falling. This is largely the result of a decrease in certification secondary to neovascular ARMD. This represents a change in the previously described trend for ARMD visual impairment certification. PMID- 22498794 TI - Agreement between specially trained and accredited optometrists and glaucoma specialist consultant ophthalmologists in their management of glaucoma patients. AB - AIMS: Optometrists are becoming increasingly involved in the co-management of glaucoma patients as the burden on the Hospital Eye Service continues to escalate. The aim of this study was to assess the agreement between specially trained optometrists and glaucoma-specialist consultant ophthalmologists in their management of glaucoma patients. METHODS: Four optometrists examined 23-25 patients each and the clinical findings, up to the point of dilation, were documented in the hospital records. The optometrist, and one of two consultant ophthalmologists, then independently examined and documented the optic-disc appearance before recording their decisions regarding the stability and management of the patient on a specially designed proforma. Percentage agreement was calculated together with kappa or weighted kappa statistics, where appropriate. RESULTS: Agreement between consultants and optometrists in evaluating glaucoma stability was 68.5% (kappa (kappa)=0.42-0.50) for visual fields, 64.5% (weighted kappa=0.17-0.31) for optic discs, and 84.5% (weighted kappa=0.55-0.60) for intraocular pressures. Agreement regarding medical management was 96.5% (kappa=0.73-0.81) and for other glaucoma management decisions, including timing of follow-up, referral to a consultant ophthalmologist, and discharge, was 72% (weighted kappa=0.65). This agreement increased to 90% following a retrospective independent then consensus review between the two consultants and when qualified agreements were included. Of the 47 glaucoma and non-glaucoma queries generated during the study, 42 resulted in a change of management. CONCLUSION: Confirming the ability of optometrists to make appropriate decisions regarding the stability and management of glaucoma patients is essential if their involvement is to continue to develop to meet the demand of an aging population. PMID- 22498796 TI - Lipomatosis of the orbits: possibly a form of Madelung's disease. PMID- 22498797 TI - Recurrent giant orbital apocrine hidrocystoma. PMID- 22498799 TI - Paediatric adjustable strabismus surgery. PMID- 22498798 TI - Visual acuity testability and comparability in Australian preschool children: the Sydney Paediatric Eye Disease Study. AB - PURPOSE: To establish standardised protocols for vision screening, testability and comparability of three different vision tests were examined in a population based, cross-sectional sample of preschool children (Sydney Paediatric Eye Disease Study). METHODS: Measurement of presenting monocular distance visual acuity (VA) using the Amblyopia Treatment Study (ATS) HOTV protocol, was attempted by all (1774) children aged>=24 months. In addition, in children aged>=60 months (576), VA was also tested using the logMAR retro-illuminated HOTV or Early Treatment Diabetic Retinopathy Study (ETDRS) linear charts (CSV 1000). Children able to have both eyes tested monocularly were considered. RESULTS: Testability significantly increased with age for all VA tests. The ATS HOTV with an overall testability of 80% (females: 82%, males: 78%) was the most testable of the VA tests (P<0.0001). In children aged <3 years testability was low (<=47%) rising to>=80% in children aged>=3. In children>=60 months, testability was higher for the HOTV (94%) than the ETDRS (59%) chart. In those that did two VA tests, mean difference of the ATS HOTV compared with the HOTV(CSV) was -0.1, and compared with ETDRS was -0.12 (P<0.0001). CONCLUSIONS: Children aged <3 years had poor VA testability, whereas those 3 years and above were highly testable using the ATS HOTV. The HOTV (CSV) retro-illuminated test was appropriate for children aged >5 years, and may be possible in younger children with early educational exposure. When comparing VA measures using these tests, the higher VA attained using the ATS HOTV, needs to be taken into account. PMID- 22498800 TI - Surgical repair of bilateral full thickness macular holes in a patient with blue sclera secondary to osteogenesis imperfecta. PMID- 22498801 TI - Endothelial cell's biomechanical properties are regulated by invasive cancer cells. AB - Most cancer-related deaths are caused by the ability of cancer cells to metastasize. This process includes the dissemination of cancer cells from the primary tumor side and their migration to targeted organ sites. During the migration of cancer cells through the connective tissue microenvironment, which consists of endothelial cells and extracellular matrix components, biomechanical properties are crucial for the efficiency and speed of cancer cell invasion and subsequently, metastases formation. Biomechanics can enable cancer cells to migrate through tissue, transmigrate through basement membranes as well as endothelial monolayers and form metastases in targeted organs. The current focus of cancer research still lies on the investigation of cancer cell's biochemical and molecular capabilities such as molecular genetics and gene signaling, but these approaches ignore the mechanical nature of the invasion process of cancer cells. Moreover, even the role of the endothelium during the transmigration and invasion of cells is not clear, it has been seen as a passive barrier, but this could not explain all novel findings. This review discusses how cancer cells alter the structural, biochemical and mechanical properties of the endothelium to regulate their own invasiveness through extracellular matrices and hence, through the tissue microenvironment. Finally, this review sheds light on the mechanical properties of cancer cells and the interacting endothelium and points out the importance of the mechanical properties as a critical determinant for the efficiency of cancer cell invasion and the overall progression of cancer. In conclusion, the regulation of the endothelial cell's biomechanical properties by cancer cells is a critical determinant of cancer cell invasiveness and may affect the future development of new cancer treatments. PMID- 22498802 TI - Artificial distinction and real discrimination. AB - In this paper we consider the hawk-dove game played by a finite population formed by two types of individual who fail to recognize their own type but do observe the type of their opponent. In this game we find two evolutionarily stable strategies and show that in each of them one type of individuals suffers more aggression than the other. When a continuum of individuals is considered there are no evolutionarily stable strategies but neutrally stable strategies. PMID- 22498803 TI - Intra-individual conflicts between autosomal and X-linked altruistic genes: evolutionary perspectives of sex-specific grandmothering. AB - Alloparental care by females toward their grandoffspring can evolve by kin selection. Previous theoretical studies predicted that selection favors autosomal and X-chromosomal genes, causing altruism toward maternal grandoffspring and paternal granddaughters, respectively, and two corresponding types of biased grandparental investment are suggested by empirical studies on human populations. Using discrete-time two-locus-two-allele models, I examined a possible conflict between the autosomal and the X-chromosomal altruistic genes over the carrier female's time and resources. This conflict is expected to occur when each grandmother has access to only maternal or paternal grandchildren as a result of her residence situation. The conditions under which each or both kinds of altruistic genes evolve (against non-altruistic genes) mainly represent the conflicting relationship between the autosomal and X-chromosomal altruistic genes. In addition, depending on the settings, the models exhibit bistable or periodic behaviors, and one type of gene can be considered parasitic in the latter behavior. On the whole, the results suggest that the X-chromosomal altruistic genes rather than the autosomal ones exhibit more difficulty increasing or fixing with this kind of conflict. PMID- 22498804 TI - Distribution of microcrack lengths in bone in vivo and in vitro. AB - It is well known that bone contains small cracks; in vivo these microcracks are constantly growing and being repaired. Too rapid crack growth leads to stress fractures or fragility fractures. In vitro, changes occur in this population of microcracks when subjected to cyclic loading up to and including failure. Normally, the only parameters reported from such investigations are the number density of cracks and their average length. In the present work we examined the microcrack population in more detail. We analysed ten different sets of experimental data including in vivo and in vitro microcracks, plus two theoretical simulations. We showed for the first time that the distribution of crack lengths can be described using the two-parameter Weibull equation. The values of the two constants in the equation varied depending on bone type/species and showed consistent trends during in vitro testing. This is the most detailed study to be conducted on microcrack populations in bone; the results will be useful in future studies including the development of theoretical models and computer simulations of bone damage and failure. PMID- 22498805 TI - Hypomagnesemia in type 2 diabetic nephropathy: a novel predictor of end-stage renal disease. AB - OBJECTIVE: There is now growing evidence that magnesium (Mg) deficiency is implicated in type 2 diabetes and its complications. However, it has not been fully elucidated whether hypomagnesemia is a predictor of end-stage renal disease (ESRD) in type 2 diabetic nephropathy. RESEARCH DESIGN AND METHODS: This retrospective cohort study included 455 chronic kidney disease (CKD) patients (144 with type 2 diabetic nephropathy and 311 with nondiabetic CKD) who were hospitalized at Osaka General Medical Center for a CKD educational program between April 2001 and December 2007. The primary outcome was progression to renal replacement therapy. Participants were categorized based on serum Mg level into Low-Mg (serum Mg level <=1.8 mg/dL) and High-Mg (serum Mg level >1.8 mg/dL) groups with the previously published normal lower limit chosen as the cutoff point. RESULTS: Of the subjects with type 2 diabetic nephropathy, 102 progressed to ESRD during follow-up (median, 23 months). A multivariate Cox proportional hazards model showed that after adjustment for various demographic factors and laboratory data, the Low-Mg group had a 2.12-fold higher risk of ESRD than the High-Mg group (95% CI 1.28-3.51; P = 0.004). In contrast, 135 of the nondiabetic CKD subjects progressed to ESRD during follow-up (median, 44 months). No significant difference in outcome was found between the Low- and High-Mg groups of this population (adjusted hazard ratio, 1.15; 95% CI 0.70-1.90; P = 0.57). CONCLUSIONS: Hypomagnesemia is a novel predictor of ESRD in patients with type 2 diabetic nephropathy. PMID- 22498806 TI - Diabetes knowledge and its relationship with achieving treatment recommendations in a national sample of people with type 2 diabetes. AB - OBJECTIVE: We examined the prevalence of knowledge of A1C, blood pressure, and LDL cholesterol (ABC) levels and goals among people with diabetes, its variation by patient characteristics, and whether knowledge was associated with achieving levels of ABC control recommended for the general diabetic population. RESEARCH DESIGN AND METHODS: Data came from 1,233 adults who self-reported diabetes in the 2005-2008 National Health and Nutrition Examination Survey. Participants reported their last ABC level and goals specified by their physician (not validated by medical record data). Analysis included descriptive statistics and logistic regression. RESULTS: Among participants tested in the past year, 48% stated their last A1C level. Overall, 63% stated their last blood pressure level and 22% stated their last LDL cholesterol level. Knowledge of ABC levels was greatest in non-Hispanic whites, lowest in Mexican Americans, and higher with more education and income (all P <= 0.02). Demographic associations were similar for those reporting physician-specified ABC goals at the American Diabetes Association recommended levels (A1C <7%, blood pressure <130/80 mmHg, and LDL cholesterol <100 mg/dL). Nineteen percent of participants stated that their provider did not specify an A1C goal compared with 47% and 41% for blood pressure and LDL cholesterol goals, respectively. For people who self-reported A1C <7.0%, 83% had an actual A1C <7.0%. Otherwise, participant knowledge was not significantly associated with risk factor control, except for in those who knew their last LDL cholesterol level (P = 0.046 for A1C <7.0%). Results from logistic regression corroborated these findings. CONCLUSIONS: Ample opportunity exists to improve ABC knowledge. Diabetes education should include behavior change components in addition to information on ABC clinical measures. PMID- 22498807 TI - State differences in the reporting of diabetes-related incorrect cause-of-death causal sequences on death certificates. AB - OBJECTIVE: To examine state differences in the reporting of diabetes-related incorrect cause-of-death (COD) causal sequences on death certificates in the U.S. RESEARCH DESIGN AND METHODS: We conducted a cross-sectional descriptive study to determine the prevalence of two types of incorrect COD causal sequences with data from the Multiple Cause Mortality File of the year 2004. RESULTS: Among deaths in which diabetes was reported as the first diagnosis on line a, b, c, or d in Part I of the death certificate in the U.S., 21% had below diabetes placement error (ranged from 30% in Maryland to 7% in Hawaii) and 11% had above diabetes placement error (ranged from 18% in Kentucky to 5% in California). The net effects of the two types of error ranged from -0.7% in Nevada to 19.6% in the District of Columbia. CONCLUSIONS: Because the rates of incorrect reporting of diabetes-related COD causal sequence varied across states, the comparability of the diabetes death rate between states may have been compromised. PMID- 22498808 TI - Circulating levels of phthalate metabolites are associated with prevalent diabetes in the elderly. AB - OBJECTIVE: Phthalates are ubiquitous industrial high-volume chemicals known as ligands to peroxisome proliferator-activated receptors (PPARs). Because PPAR gamma agonists modulate insulin sensitivity and are used to treat type 2 diabetes, we investigated whether circulating levels of phthalate metabolites are related to prevalent type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 1,016 subjects, aged 70 years, were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors Study. Four phthalate metabolites were detected in almost all participant sera by an API 4000 liquid chromatograph/tandem mass spectrometer. Type 2 diabetes was defined as the use of pharmacological hypoglycemic agents or a fasting plasma glucose >7.0 mmol/L. RESULTS: A total of 114 subjects were shown to have diabetes. Following adjustment for sex, BMI, serum cholesterol and triglycerides, educational level, and smoking and exercise habits, high levels of the phthalate metabolites monomethyl phthalate (MMP) (P < 0.01), monoisobutyl phthalate (MiBP) (P < 0.05), and monoethyl phthalate (MEP) (P < 0.05), but not mono(2-ethylhexyl) phthalate, were associated with an increased prevalence of diabetes. Using the fasting proinsulin-to-insulin ratio as a marker of insulin secretion and the homeostasis model assessment-insulin resistance index as a marker of insulin resistance, MiBP was mainly related to poor insulin secretion, whereas MEP and MMP mainly were related to insulin resistance. CONCLUSIONS: The findings in this cross-sectional study showed that several phthalate metabolites are related to diabetes prevalence, as well as to markers of insulin secretion and resistance. These findings support the view that these commonly used chemicals might influence major factors that are regulating glucose metabolism in humans at the level of exposure of phthalate metabolites seen in the general elderly population. PMID- 22498809 TI - The order of filling transitions in acute wedges. AB - Using a square-gradient density functional model we test the prediction that the filling transition for a fluid in a wedge geometry changes from continuous to first-order as the wedge becomes more acute. Our numerical findings confirm such a change of order, but the value of the tilt angle at which it occurs, alpha* ~ 45 degrees , is considerably smaller than the original theoretical prediction. We critically reassess this work, which was based on allowing for the self interaction of the fluid interface, and argue that the interfacial curvature and effective wavevector dependent surface tension can further lower the predicted value of alpha*, in keeping with our numerical findings. Interfacial fluctuation effects, occurring beyond mean-field level, are also discussed using effective Hamiltonian theory and are shown to substantially increase the value of alpha*. PMID- 22498811 TI - Identification and interconversion of diastereomeric oligo-Troger bases probed by ion mobility mass spectrometry. AB - Oligo-Troger bases are auspicious scaffolds of molecular engineering, which motivates studies on the mechanism of their interconversion and on the facile determination of the relative configuration of their diastereoisomers. Protonated, sodiated, and argentated species of those compounds were therefore studied via ion-mobility mass spectrometry (IM-MS), allowing differentiation on the basis of the shapes of the ions. First, the isomerization was confirmed to be acid-catalyzed as it takes place readily in the case of protonated Troger bases, whereas the metallated bases are configurationally stable. Second, the corrected arrival times of the various isomers of the cationized bases were found to show distinct differences in IM-MS, and their excellent correlation with the cross sections obtained from quantum chemical calculations paves the way toward the easy identification of diastereoisomers. PMID- 22498810 TI - Using bioinformatics and systems genetics to dissect HDL-cholesterol genetics in an MRL/MpJ x SM/J intercross. AB - A higher incidence of coronary artery disease is associated with a lower level of HDL-cholesterol. We searched for genetic loci influencing HDL-cholesterol in F2 mice from a cross between MRL/MpJ and SM/J mice. Quantitative trait loci (QTL) mapping revealed one significant HDL QTL (Apoa2 locus), four suggestive QTL on chromosomes 10, 11, 13, and 18 and four additional QTL on chromosomes 1 proximal, 3, 4, and 7 after adjusting HDL for the strong Apoa2 locus. A novel nonsynonymous polymorphism supports Lipg as the QTL gene for the chromosome 18 QTL, and a difference in Abca1 expression in liver tissue supports it as the QTL gene for the chromosome 4 QTL. Using weighted gene co-expression network analysis, we identified a module that after adjustment for Apoa2, correlated with HDL, was genetically determined by a QTL on chromosome 11, and overlapped with the HDL QTL. A combination of bioinformatics tools and systems genetics helped identify several candidate genes for both the chromosome 11 HDL and module QTL based on differential expression between the parental strains, cis regulation of expression, and causality modeling. We conclude that integrating systems genetics to a more-traditional genetics approach improves the power of complex trait gene identification. PMID- 22498812 TI - Effect of postactivation treatment with latrunculin A on in vitro and in vivo development of cloned embryos derived from kidney fibroblasts of an aged Clawn miniature boar. AB - The objective of this study was to examine the effect of postactivation treatment with latrunculin A (LatA), an actin polymerization inhibitor, on in vitro and in vivo development of somatic cell nuclear transfer (SCNT) embryos derived from kidney fibroblasts of an aged Clawn miniature boar (12 years old). After electric activation, SCNT embryos were treated with 0, 0.5 or 1 MUM LatA and cultured in vitro. The rate of blastocyst formation was significantly higher (P<0.05) in SCNT embryos treated with 0.5 MUM LatA (38%) than those in control (14%). When cloned embryos treated with 0.5 MUM LatA were transferred into the oviducts of two recipient miniature gilts to assess their development in vivo, both recipients became pregnant; one maintained pregnancy to term, and a live piglet (weighing 220 g) was delivered by Caesarean section. The results of this study indicated that the postactivation treatment with LatA was effective in improving in vitro developmental capacity of SCNT miniature pig embryos derived from kidney fibroblasts of an aged animal and that miniature pig cloned embryos treated with LatA had the ability to develop to term. PMID- 22498813 TI - Generation of human beta-thalassemia induced pluripotent stem cells from amniotic fluid cells using a single excisable lentiviral stem cell cassette. AB - Induced pluripotent stem cells (iPSCs) derived from somatic cells of patients represent a powerful tool for biomedical research and may have a wide range of applications in cell and gene therapy. However, the safety issues and the low efficiency associated with generating human iPSCs have limited their usage in clinical settings. The cell type used to create iPSCs can significantly influence the reprogramming efficiency and kinetics. Here, we show that amniotic fluid cells from the prenatal diagnosis of a beta-thalassemia patient can be efficiently reprogrammed using a doxycycline (DOX)-inducible humanized version of the single lentiviral "stem cell cassette" vector flanked by loxP sites, which can be excised with Cre recombinase. We also demonstrated that the patient derived iPSCs can be characterized based on the expression of pluripotency markers, and they can be differentiated into various somatic cell types in vitro and in vivo. Moreover, microarray analysis demonstrates a high correlation coefficient between human beta-thalassemia iPS cells and human embryonic stem (hES) cells but a low correlation coefficient between human beta-thalassemia amniotic fluid cells and human beta-thalassemia iPS cells. Our data suggest that amniotic fluid cells may be an ideal human somatic cell resource for rapid and efficient generation of patient-specific iPS cells. PMID- 22498814 TI - Seasonal changes in luteal progesterone concentration and mRNA expressions of progesterone synthesis-related proteins in the corpus luteum of mares. AB - Although circulating progesterone (P4) levels tend to change with the season, little is known about the seasonal changes of P4 synthesis-related proteins in the corpus luteum (CL) of mares. To examine these changes, seventy-four ovaries containing a CL were collected from Anglo-Norman mares at a local abattoir in Kumamoto, Japan (~N32 degrees ), five times during one year. The stages of the CLs were classified as early, mid and regressed by macroscopic observation of the CL and follicles. The mid CL, which had the highest P4 concentration, was used to evaluate the seasonal changes in P4 synthesis. The luteal P4 concentration and mRNA expression of luteinizing hormone receptor (LHCGR) were lowest during early winter and highest during late winter. The mRNA expressions of steroidogenic acute regulatory protein (StAR), P450 cholesterol side-chain cleavage enzyme (P450scc) and 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase (3beta HSD) were lowest during early winter and increased during late winter. These results suggest that P4 synthesis in the CL is affected by the seasonal changes in the mRNA expressions of P4 synthesis-related proteins in mares. PMID- 22498815 TI - X-irradiation removes endogenous primordial germ cells (PGCs) and increases germline transmission of donor PGCs in chimeric chickens. AB - Primordial germ cells (PGCs) are embryonic precursors of germline cells with potential applications in genetic conservation, transgenic animal production and germline stem cell research. These lines of research would benefit from improved germline transmission of transplanted PGCs in chimeric chickens. We therefore evaluated the effects of pretransplant X-irradiation of recipient embryos on the efficacy of germline transmission of donor PGCs in chimeric chickens. Intact chicken eggs were exposed to X-ray doses of 3, 6 and 9 Gy (dose rate = 0.12 Gy/min) after 52 h of incubation. There was no significant difference in hatching rate between the 3-Gy-irradiated group and the nonirradiated control group (40.0 vs. 69.6%), but the hatching rate in the 6-Gy-irradiated group (28.6%) was significantly lower than in the control group (P<0.05). No embryos irradiated with 9 Gy of X-rays survived to hatching. X-irradiation significantly reduced the number of endogenous PGCs in the embryonic gonads at stage 27 in a dose-dependent manner compared with nonirradiated controls. The numbers of endogenous PGCs in the 3-, 6- and 9-Gy-irradiated groups were 21.0, 9.6 and 4.6% of the nonirradiated control numbers, respectively. Sets of 100 donor PGCs were subsequently transferred intravascularly into embryos irradiated with 3 Gy X-rays and nonirradiated control embryos. Genetic cross-test analysis revealed that the germline transmission rate in the 3-Gy-irradiated group was significantly higher than in the control group (27.5 vs. 5.6%; P<0.05). In conclusion, X-irradiation reduced the number of endogenous PGCs and increased the germline transmission of transferred PGCs in chimeric chickens. PMID- 22498816 TI - Manual rupture versus transvaginal ultrasound-guided aspiration of allanto amniotic fluid in multiple pregnancies: a clinical approach to embryo reduction in dairy cattle. AB - To avoid the problems associated with twinning in dairy cattle, one of the embryos may be eliminated. This study compares the effect on pregnancy maintenance of two embryo reduction techniques, manual rupture (MR) and transvaginal ultrasound-guided aspiration (TUGA) of allanto-amniotic fluid, in Holstein-Friesian cows with multiple pregnancies. In the first experiment, 61 lactating cows bearing unilateral twins (n=27), bilateral twins (n=30) or triplets/quadruplets (n=4) were subjected to MR (n=45) or TUGA using a 17-G neddle (n=16) on day 28-34 of gestation. In 21 and 10 cows undergoing MR and TUGA embryo reduction, respectively, pregnancy loss occurred before day 90 (46.7 vs. 62.5%, P= 0.28). Through binary logistic regression, the type of pregnancy was identified as the only variable significantly affecting pregnancy maintenance (P=0.03). Based on the odds ratio, the risk of pregnancy loss was 4.1 times higher for unilateral twins than for bilateral twins (70.4 vs. 36.7%, respectively, P=0.01). No effect was detected on pregnancy maintenance of the technique used (P=0.17) or of the interaction technique by type of pregnancy (P=0.22). In the second experiment, a 22-G needle was used to perform TUGA on 22 lactating cows. The pregnancy loss rates were 44.4% (4/9), 18.2% (2/11) and 50% (1/2) for cows bearing unilateral twins, bilateral twins and triplets, respectively. The total pregnancy loss rate following TUGA using the 22-G needle tended to be lower than that using the 17-G needle (31.8 vs. 62.5%; P=0.06). Our results suggest that TUGA using a 22-G needle could be the method of choice to perform embryo reduction in cows carrying multiple pregnancies. PMID- 22498817 TI - Immunolocalization and expression pattern of Gpr3 in the ovary and its effect on proliferation of ovarian granulosa cells in pigs. AB - Gpr3, a member of the G protein-coupled receptor superfamily, was known as a critical factor for the maintenance of meiotic prophase arrest in oocytes via a Gs protein-mediated pathway. The present studies were conducted to examine the ovarian immunolocalization of Gpr3, its expression pattern in different stages of fetal, postnatal and developmental pigs and its effect on proliferation of ovarian granulosa cells in pigs. Immunohistochemical analysis indicated that Gpr3 was localized in egg nests, oocytes and granulosa cells (GCs) of the follicle ranging from the primordial to Graafian stages and the corpora lutea. Staining was faintly present in the corpora lutea and weak in GCs but was strong in oocytes. Real-time PCR and Western blotting indicated that Gpr3 mRNA and protein were both present in the different ages of ovaries, and there were wavy changes in the expression levels from postpartum 1 to 180 days. Moreover, both the mRNA and protein levels of Gpr3 were upregulated significantly during follicle growth, suggesting that Gpr3 might play potential roles in regulating ovarian follicle development in the pig. MTT and flow cytometry analyses indicated that Gpr3 knockdown significantly promoted proliferation of porcine GCs while increasing the proportion of cells in the S phase and the expression of Cyclin B1 and Cyclin D2, providing new insights into how Gpr3 signaling regulates the proliferation of porcine GCs. In conclusion, the stage- and cell-specific expression pattern of Gpr3 in the porcine ovary suggested that Gpr3 might play an important role during the entire process of follicular development and luteinization. PMID- 22498818 TI - Resource provision and environmental change for the prevention of skin cancer: systematic review of qualitative evidence from high-income countries. AB - This paper presents the findings of a systematic review of qualitative studies from high-income (OECD) countries relating to sun protection and skin cancer, with a focus on barriers and facilitators for the following interventions: resource provision; environmental change; and multi-component interventions. Twenty-three study reports were included in the review. Data were analysed using a thematic analysis methodology with the Health Belief Model as a framework. The risk and potential severity of skin cancer are not seen as important concerns, and tanning which is not deliberate is seen as less dangerous. There are a number of social and practical barriers to the use of sun protection resources, including cost, inconvenience and social norms. There are important differences between age groups and between men and women in attitudes. PMID- 22498819 TI - TFE3 rearrangements in adult renal cell carcinoma: clinical and pathologic features with outcome in a large series of consecutively treated patients. AB - Renal cell carcinoma (RCC) with chromosomal rearrangement of transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) at Xp11.2 is a distinct subtype that was initially described in children and has been reported to display an indolent course. Recent reports have identified RCC with TFE3 rearrangements in adults and have suggested a more aggressive course in this population. However, only a few studies have examined these tumors in a large series of consecutively treated adults. We screened 632 RCCs from patients consecutively treated by surgery at a single institution by fluorescence in situ hybridization to detect TFE3 rearrangements. We identified 6 RCCs with TFE3 rearrangement. Patient ages ranged from 25 to 78 years and included 4 women and 2 men. Tumors showed significant histologic variability. Comparison of the clinical and pathologic features between RCCs with TFE3 rearrangements and RCCs without TFE3 rearrangements showed no significant differences. Follow-up period for patients with TFE3-rearranged RCC ranged from 0.8 to 16.5 years, with 4 of 6 dying from the disease. Cancer-specific survival for patients with TFE3-rearranged RCC was significantly worse than for patients with TFE3-rearrangement-negative papillary type RCC (P<0.001) but not different from that for TFE3-rearrangement-negative clear cell-type RCC. In conclusion, we present an assessment of TFE3 rearrangement status in a large series of adults consecutively treated by surgery for RCC. Our findings confirm that RCCs with TFE3 rearrangement account for only approximately 1% of adult RCCs. The results also suggest that adult RCC with TFE3 rearrangement may be a clinically aggressive tumor. PMID- 22498820 TI - Endometriosis does not confer improved prognosis in ovarian carcinoma of uniform cell type. AB - The role of endometriosis in ovarian cancer, disease progression, and survival is a subject of active investigation. A series of 144 ovarian cancers with clear cell or endometrioid histology or associated endometriosis, all classified on the basis of strict histologic criteria, was evaluated to further explore the relationship between endometriosis-associated ovarian cancer and age at presentation, FIGO stage, histology, presence of synchronous primary disease elsewhere in the mullerian tract, and survival. Patients with endometrioid carcinomas were significantly younger (mean, 52 y) in comparison with patients with either clear cell carcinoma (mean, 55 y) or mixed tumors (mean, 59 y; P=0.002). Clear cell carcinoma presented as low-stage disease (FIGO I) in 33% of cases compared with endometrioid carcinomas in 97% of cases and mixed carcinomas in 27% of cases. Endometriosis was associated with 53% of clear cell carcinomas, 33% of endometrioid carcinomas, and 45% of mixed tumors (P<0.001). Synchronous primary tumors, observed in 31% of endometrioid tumors, 5% of mixed tumors, and in 2% of clear cell tumors (P<0.001), were unlikely to be associated with endometriosis (P=0.04). Univariate analysis of the aggregate cohort demonstrated that the single best overall predictor of disease-free survival was FIGO stage at presentation (P<0.001), followed by histologic subtype (P=0.003). Endometriosis did not have a significant relationship with disease-free survival (P=0.7). We conclude that the link between endometriosis and ovarian cancer is much stronger for clear cell carcinoma than for other histologic subtypes (P<0.001). Furthermore, when uniform histologic criteria are applied, true mixed endometrioid and clear cell carcinomas are uncommon; most endometriosis associated mixed tumors are heterogenous mixtures of endometrioid, mucinous, and serous histology with areas of clear cell cytoplasm. Endometriosis per se does not appear to predict prognosis in clear cell and endometrioid tumors, with the possible exception of tumors with mixed histology. Until more data are collected, pathologists should classify ovarian tumors with mixed histology as a separate and potentially unique biological and prognostic group. PMID- 22498821 TI - Reticulin loss in benign fatty liver: an important diagnostic pitfall when considering a diagnosis of hepatocellular carcinoma. AB - Reticulin stains are commonly used in surgical pathology to assess mass lesions for the possibility of hepatocellular carcinoma. The loss of normal reticulin staining can help support a diagnosis of hepatocellular carcinoma, and this stain has proven to be particularly helpful on limited biopsies and fine-needle aspirates. However, an underappreciated diagnostic pitfall is that non-neoplastic liver tissue can also show reticulin loss when there is fatty change. To further characterize this important diagnostic pitfall, reticulin staining was studied in cases of nonalcoholic steatosis, nonalcoholic steatohepatitis, and hepatic adenomas with fatty change. A total of 112 cases with varying degrees of steatosis were collected from 4 academic centers, including 49 cases of steatosis, 49 cases of steatohepatitis, and 14 hepatic adenomas with fatty change. Steatosis was graded as mild (5% to 30% macrovesicular steatosis), moderate (31% to 60%), and marked (>60%). Reticulin stains were scored as the number of foci with diminished reticulin staining in 10 hpf. A focus of diminished reticulin was scored when the extent of reticulin loss was similar to that seen in hepatocellular carcinomas. In the total study set, 28 cases showed mild steatosis, 40 cases showed moderate steatosis, and 44 cases showed marked steatosis. Interestingly, increasing amounts of fat were associated with decreased reticulin staining. For mild steatosis, reticulin loss was rare, with the number of foci of reticulin loss per 10 hpf averaging 0.8 (range, 0 to 3); however, this increased for moderate steatosis, which showed a mean of 3.0 foci per 10 hpf (range, 0 to 5), and was most prominent with marked steatosis, which showed an average of 5.8 foci of reticulin loss per 10 hpf (range, 5 to 8). An almost identical pattern was seen in cases of nonalcoholic steatohepatitis. Overall, reticulin loss was not associated with the degree of inflammation or with the presence or absence of balloon cell change. Reticulin loss also did not correlate with fibrosis stage. In hepatic adenomas, reticulin loss was seen only in areas of fatty change, and decreased reticulin again paralleled the amount of steatosis, with more prominent reticulin loss in those cases with marked steatosis. In conclusion, reticulin loss that reaches levels seen in hepatocellular carcinoma can be seen focally in benign liver tissues with fatty change. Overall, loss of reticulin is more common and more extensive with marked fatty change and does not seem to be linked to inflammation or fibrosis stage. Loss of reticulin can also be seen in hepatic adenomas with fatty change. Increased awareness of this important diagnostic pitfall will help prevent overcalling of reticulin loss when evaluating biopsies and resections of hepatic neoplasms with fatty change. PMID- 22498822 TI - Microcystic serous cystadenoma of the pancreas with subtotal cystic degeneration: another neoplastic mimic of pancreatic pseudocyst. AB - BACKGROUND: Pancreatic serous cystadenomas are benign cystic neoplasms. Extensive degeneration mimicking a pancreatic pseudocyst has been described in several types of pancreatic neoplasms but has not been documented in serous cystadenomas. We report subtotal cystic degeneration of microcystic serous cystadenomas (MSCA) that produces radiographic, gross, and microscopic overlap with pancreatic pseudocyst. MATERIALS AND METHODS: Resected MSCA with degenerative change were identified from the pathology archives of Memorial Sloan-Kettering Cancer Center and Johns Hopkins Hospital. The clinical, radiographic, gross, and microscopic findings were reviewed. RESULTS: Eight MSCAs with subtotal cystic degeneration were retrieved from among 397 resected serous cystadenomas (2.0%). There were 2 men and 6 women (mean age, 52 y). Available radiographic studies showed classic features of MSCA in 2 of 4 cases. Four cysts were unilocular, and 4 were multilocular. Gross features of MSCA were noted focally in the multilocular cases but were not evident in the unilocular examples. The predominant histologic features were those of pancreatic pseudocyst, including a fibrotic cyst wall lacking epithelium and instead composed of myofibroblastic proliferation, hemorrhage, and inflammation. Residual foci of MSCA were embedded in fibrosis, comprising 5% to 60% of the tumor volume. CONCLUSIONS: Most pancreatic serous cystadenomas display characteristic morphology, including a glycogen-rich epithelial lining and prominent subepithelial capillaries; however, extensive degenerative macrocystic change can obscure these classic features. This phenomenon is to be distinguished from macrocystic serous cystadenoma, in which thin-walled macrocystic spaces are epithelium lined. Thus, serous cystadenoma should be included in the differential diagnosis of pancreatic masses with extensive degenerative cystic change. PMID- 22498823 TI - Evaluation of langerhans cell infiltrate by CD1a immunostain in liver biopsy for the diagnosis of primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is characterized by chronic nonsuppurative destructive cholangitis, which is considered to be a cell-mediated immune reaction. Antigen-presenting cells, including Langerhans cells and dendritic cells, have been found in portal tracts and in bile duct epithelium and may play a role in the pathogenesis of PBC, but the importance of identifying these cells for diagnosing PBC has not been studied yet. In this study, we sought to evaluate the importance of identifying Langerhans cells using a CD1a immunostain in the diagnosis of PBC. Liver biopsies from adult patients diagnosed with PBC (n=60), primary sclerosing cholangitis (n=29), obstructive cholangitis (n=13), chronic viral hepatitis B or C (n=19), autoimmune hepatitis (AIH, n=15), acute cellular rejection (n=11), and chronic rejection (n=10) at our institution were retrospectively reviewed. An immunohistochemical stain for CD1a was used to detect Langerhans cells, and the distribution of CD1a-positive Langerhans cell infiltrate was recorded as lobular, portal with bile duct sparing, and intraepithelial. Intraepithelial Langerhans cells were identified in 58% of PBC including antimitochondrial antibody-negative PBC and PBC-AIH overlap cases, 14% of primary sclerosing cholangitis, 15% of obstructive cholangitis, 9% of acute cellular rejection, 6% of AIH, and no cases of chronic viral hepatitis or chronic rejection. The number of intraepithelial Langerhans cells was significantly higher in PBC than in other conditions, with the mean number of CD1a-positive intraepithelial Langerhans cells per bile duct in PBC calculated as 2.2 compared with <1 per duct for the other control cases. Thirty-three of 60 (55%) PBC cases showed at least one bile duct containing >=2 CD1a-positive Langerhans cells. This was statistically significant (P<0.01) when compared with control groups. The overall sensitivity and specificity of using >=2 CD1a-positive Langerhans cells per bile duct as the diagnostic criteria for PBC were 55% and 96%. Given the heterogenous nature of liver involvement by PBC, a review of cases with morphologic features of duct damage yielded an increased sensitivity (79%) with no reduction in specificity. In conclusion, the detection of a Langerhans cell infiltrate of >=2 cells by CD1a in a given bile duct on needle biopsy may be a valuable tool in the diagnosis of PBC. PMID- 22498824 TI - PDX-1, CDX-2, TTF-1, and CK7: a reliable immunohistochemical panel for pancreatic neuroendocrine neoplasms. AB - Neuroendocrine tumors (NETs) occur in virtually all sites of the body. As NETs arising in different organs share similar morphologic features, distinguishing metastatic from primary NETs on the basis of morphologic grounds alone is difficult. Pancreatic duodenal homeobox 1 (PDX-1) is a Hox-type transcription factor that is essential for both exocrine and endocrine pancreatic differentiation and maintenance of beta-cell function. We investigated PDX-1 as an immunohistochemical (IHC) marker in primary pancreatic NETs. Eighty primary NETs [25 pancreatic, 29 bronchopulmonary, and 26 in the gastrointestinal (GI) tract] and 13 metastatic NETs in the liver were studied. Clinical and radiologic data were reviewed to confirm the stated primary sites. IHC analysis for PDX-1, CDX-2, thyroid transcription factor-1 (TTF-1), keratin 7 (CK7), and keratin 20 (CK20) was performed, and the results were based on review blinded to the primary sites. PDX-1 was seen in 18 of 25 (72%) pancreatic NETs; in contrast, only 3 of 29 (10%) bronchopulmonary NETs and 1 of 26 (4%) GI NETs were positive. PDX-1 was therefore 93% specific and 72% sensitive for pancreatic NETs. TTF-1 was expressed only in bronchopulmonary NETs; all other NETs were negative for TTF-1. CK7 was also very specific (92%) and moderately sensitive (66%) for bronchopulmonary NETs. CDX-2 was seen in 22 of 26 (85%) cases of GI NETs and in only 1 of 51 (2%) cases of extra-GI NETs. Thus, CDX-2 was 98% specific and 85% sensitive for GI NETs. In terms of metastatic NETs found in the liver, PDX-1 was positive in 5 of 5 cases of metastatic pancreatic NETs and 2 of 2 cases of metastatic duodenal NETs. PDX-1 is highly specific, with very good overall diagnostic accuracy for pancreatic NETs. An IHC panel including PDX-1, CDX-2, TTF-1, CK7, and CK20 may be useful in distinguishing NETs of pancreatic origin from other primaries. PMID- 22498825 TI - Molecular profile of grade 3 endometrioid endometrial carcinoma: is it a type I or type II endometrial carcinoma? AB - Two types of endometrial carcinoma (EC) have been delineated on the basis of clinicopathologic studies. Low-grade endometrioid carcinoma (EEC) is the prototype of type I EC and is characterized by microsatellite instability and PTEN, K-ras, and/or beta-catenin gene mutations, whereas type II EC is typically represented by serous and clear cell carcinomas (SCs/CCCs), the former frequently showing p53 mutations and c-erb-2 overexpression; however, the molecular profile of grade 3 EEC has not yet been well characterized. The goal of this study was to define the immunohistochemical and molecular profile of grade 3 EEC. We studied 25 patients with grade 3 EEC ranging in age from 35 to 87 (mean 61) years. At the time of initial diagnosis, 16 patients had stage I tumors, whereas 3, 5, and 1 had stages II, III, and IV tumors, respectively. Only 1 patient with stage IV tumor had disease in the peritoneum because of direct extend of tumor through the uterine wall. Two tissue microarrays were constructed from paraffin-embedded blocks and stained for MLH-1, MSH-2, p16, cyclin D1, C-erb-B2, WT-1, and p53. Loss of MLH-1 and MSH-2 was seen in 3 of 25 and 1 of 24 tumors, respectively; none showed loss of both. Diffuse p16 nuclear expression was found in 7 of 23 cases; diffuse and strong nuclear immunostaining for p53, cyclin D1, and Her-2 was seen in 9 of 24 neoplasms, 9 of 25, and 3 of 25 carcinomas, respectively. WT 1 was negative in all 25 tumors. One of the 3 grade 3 EECs with Her-2 overexpression showed gene amplification by fluorescence in situ hybridization analysis. No gene amplification for cyclin D1 was found. Follow-up information was available for all patients. Sixteen had stage I tumors. Of these patients, 11 were alive and well (AW), 3 died of disease (DOD), and 2 died of unrelated causes (DUC), with a mean follow-up time of 56 months (range, 24 to 96 mo); 2 of 3 patients with stage II tumors DOD, and 1 was AW with a mean follow-up time of 81 months (range, 6 to 66 mo); of the 5 patients with stage III tumors, 2 DOD, 1 was AW, 1 was alive with lung metastases, and 1 DUC [mean follow-up of 29 months (range, 12 to 74 mo)]; the only patient who had a stage IV tumor DOD 12 months later. Interestingly, patients with grade 3 EECs showing loss of MLH-1/MSH-2 had stage I tumors, and all were AW (60 to 84 mo). Seventy-seven percent (7 of 9) of patients with tumors showing cyclin D1 overexpression were stage I, and none died of disease, whereas 85% (6 of 7) of patients with p16-positive tumors were high stage (2 stage II, 3 stage III, and 1 stage IV), and 5 DOD. All but one of these patients had tumors that also had p53 overexpression. All 3 patients with Her-2 overexpression DOD (stages I, III, and IV). In conclusion, this study shows that grade 3 EEC shares with low-grade EEC the overexpression but not amplification of cyclin D1 and low frequency of Her-2 overexpression and amplification. Grade 3 EEC shares with SC the relatively common p53 and p16 overexpression and low frequency of loss of mismatch repair genes. However, in contrast to SC ECs, which often show WT-1, cyclin D1 amplification, and Her-2 overexpression and/or amplification, grade 3 EECs rarely overexpressed any of these markers. Moreover, in this study, patients with tumors showing loss of MLH-1/MSH-2 or cyclin D1 overexpression were more likely to have low-stage tumors (stage I), whereas patients with tumors that overexpressed p53, p16, or Her-2 were frequently associated with high-stage tumors. PMID- 22498826 TI - Immunohistochemistry-based cell cycle detection (iCCD): a novel system to visualize cell kinetics on formalin-fixed paraffin-embedded tissues. AB - Carcinogenesis is widely believed to occur when regulatory systems governing cellular proliferation and differentiation are compromised. To date, various methods have been devised to determine cell cycle. However, these methods have not gained popularity in the diagnostic field. We developed a multiplex immunohistochemical method that can simultaneously stain cells in the G1 and S/G2/M phases and those undergoing apoptosis with the 3 markers Cdt1, geminin, and gamma H2A.X. The staining procedure can be performed using an autoimmunostainer. The nuclei of cells in the G1 phase stain red with the antibody for Cdt1, those in the S/G2/M phases stain blue with the antibody for geminin, and the nuclei of cells undergoing apoptosis stain brown with the antibody for H2A.X. The present method enables accurate cell cycle assessments using paraffin-embedded tissue specimens, which are superior to other forms of specimens in terms of morphologic observation. PMID- 22498827 TI - Pulmonary hyalinizing granuloma with associated elevation in serum and tissue IgG4 occurring in a patient with a history of sarcoidosis. AB - Pulmonary hyalinizing granulomas (PHGs) are unusual fibrosclerotic inflammatory lung lesions. The organ-based manifestations of the recently defined IgG4-related sclerosing disease typically show dense fibrosis and heavy lymphoplasmacytic infiltrates. IgG4-related sclerosing disease is also defined by increased serum IgG4 levels and increased tissue levels of IgG4-positive plasma cells. The morphologic features of PHG overlap with those seen in IgG4-related sclerosing disease, and this suggests that PHG may be a form of IgG4-related sclerosing disease. We present a case of a 51-year-old man with a history of sarcoidosis who presented with slowly enlarging pulmonary nodules. Histologic evaluation of one of the nodules yielded a diagnosis of PHG. Further investigation demonstrated both elevated serum IgG4 and elevated tissue IgG4-positive plasma cells in the PHG. In previous reports, lesions that are now considered part of IgG4-related sclerosing disease were documented in patients also diagnosed with PHG, although these reports date from before the description of IgG4 sclerosing disease. This case provides the first definitive evidence that PHG is part of the spectrum of IgG4-related sclerosing disease. PMID- 22498828 TI - Malignant transformation of mastocytoma developed on skin mastocytosis into cutaneous mast cell sarcoma. AB - Mastocytosis is a group of disorders characterized by abnormal mast cell proliferation, involving the skin in 80% of cases. Cutaneous mastocytosis, which appears in childhood in 60% of cases, usually has a benign course with a gradually regressive evolution before puberty. Mast cell sarcomas, part of the systemic forms of mastocytosis, are very rare tumors characterized by a destructive growth of highly atypical mast cells, with secondary spread, poor prognosis, and low survival rates. We report the first known case of primary cutaneous mast cell sarcoma due to the transformation of a benign solitary mastocytoma in an adult suffering from an unregressive localized cutaneous mastocytosis. Histologic characteristics of the tumor, mutation analysis, and c Kit expression were compared with available data. Wide surgical excision of the tumor followed by adjuvant local radiotherapy were performed, and for the first time the use of imatinib was attempted, as neoplastic mast cells expressed the CD117 marker. However, they failed to control the progression of sarcoma. To date, no treatment is known to be effective for this disease, which is associated with short-term survival of the patients. PMID- 22498829 TI - The ubiquitin-activating enzyme (E1) of the early-branching eukaryote Giardia intestinalis shows unusual proteolytic modifications and play important roles during encystation. AB - Giardia intestinalis is considered an early-branching eukaryote and is therefore a valuable model for studying primordial cellular processes. This work reports the characterization of the ubiquitin-activating enzyme (E1) during growth and different stages of trophozoite differentiation into cysts. We found that in Giardia E1 expression (both at mRNA and protein levels) is regulated during encystation. The enzyme is proteolytically processed mainly into two fragments of 68kDa (N-terminal) and 47kDa (C-terminal). This phenomenon has not been described for any other E1. In trophozoites, this enzyme localized at spots within the cytoplasm as detected by using polyclonal antibodies against either E1 N- or C terminal fragments. This pattern changed during encystation into a diffuse localization throughout the cytoplasm of encysting cells. E1 localizes in mature cysts at cytoplasmic spots and in the cyst wall. Our antisense silencing experiments suggested that E1 is an essential gene for parasite viability. On the other hand, E1 over-expression greatly increased the encystation rate, indicating a relationship between E1 and Giardia differentiation. PMID- 22498830 TI - Relaying membrane status. PMID- 22498831 TI - Rho1 keeps an eye on TORC1. PMID- 22498833 TI - Ligand dependence of the synthetic approach and chiroptical properties of a magic cluster protected with a bicyclic chiral thiolate. AB - Chiral gold clusters stabilised by enantiopure thiolates were prepared, size selected and characterised by circular dichroism and mass spectrometry. The product distribution is found to be ligand dependent. Au(25) clusters protected with camphorthiol show clear resemblance of their chiroptical properties with their glutathionate analogue. PMID- 22498832 TI - Getting active: protein sorting in endocytic recycling. AB - Endocytic recycling returns proteins to the plasma membrane in many physiological contexts. Studies of these events have helped to elucidate fundamental mechanisms that underlie recycling. Recycling was for some time considered to be the exception to a general mechanism of active cargo sorting in multiple intracellular pathways. In recent years, studies have begun to reconcile this seeming disparity and also suggest explanations for why early recycling studies did not detect active sorting. Further articulation of this emerging trend has far-reaching implications for a deeper understanding of many physiological and pathological events that require recycling. PMID- 22498834 TI - Pain in neurological conditions. AB - PURPOSE OF REVIEW: To address the issues of the scale and diversity of chronic pain in neurological disorders and the evidence for effective treatment of pain in these conditions. RECENT FINDINGS: Contemporary literature supports the notion that pain in neurological conditions is common and has tended to be underestimated. SUMMARY: Pain in neurological disease displays great diversity in putative mechanisms and clinical presentation. Rational management requires an analysis of likely mechanisms of pain generation as a guide to treatment. Some common neurological disorders are briefly discussed, primarily to provide an indication of the range of pain phenotypes observed across the spectrum of neurological disease. Treatments are reviewed with an emphasis on systemic drugs and the current best evidence for their use. PMID- 22498835 TI - Occupational therapy interventions for breathlessness at the end of life. AB - PURPOSE OF REVIEW: This review aims to define and explore the contribution of occupational therapy in end-of-life care, with a particular focus on breathlessness. It examines occupational therapy interventions for the management of breathlessness and makes recommendations for future research. RECENT FINDINGS: An emerging body of research demonstrates people with advanced disease continue to strive for active participation in everyday activities in the face of debilitating symptoms such as breathlessness. It is through active participation that people adjust to bodily decline. When specific everyday activities are targeted for intervention, implantation of strategies to manage breathlessness within the context of these activities has been found to optimize function and well being for those with chronic obstructive pulmonary disease. Evidence examining the efficacy of energy conservation and relaxation is limited and requires more robust examination. SUMMARY: Symptoms such as dyspnoea need to be considered within the contexts in which they exist - that is, the bodily experience of breathlessness and its impact on everyday activities or occupations. The clinical and theoretical focus of occupational therapy supports the enablement of continued participation in valued and essential activities and offers a unique focal point for research. Emerging research demonstrates the importance of translating the benefits of effective symptom management into everyday activities and informs a future research agenda. PMID- 22498836 TI - Breathlessness in an age of noncommunicable diseases. PMID- 22498837 TI - Evidence-based spiritual care: a literature review. AB - PURPOSE OF REVIEW: As spiritual care has increasingly been considered an integral component of a healthcare treatment plan, spiritual care practitioners have been encouraged to adopt an evidence-based orientation, just as evidence-based practice is encouraged in every other aspect of healthcare. Though the notion of 'evidence-based spiritual care' is still developing, increasingly research is conducted in order to provide an evidence base to the practice of spiritual care. This article reviews spirituality and spiritual care literature from June 2010 to December 2011 that employ empirical research methods. RECENT FINDINGS: The majority of patient-focused studies concentrate on oncology and palliative care patients. In the review period, studies of care giver perceptions and experience came from multiple disciplines, including medicine, nursing, and chaplaincy. A discrepancy exists between the provision of spiritual care and the theoretical commitment of practitioners to offer such care. Practitioners continue to view spiritual care as part of their role to a greater extent than they provide it. This is often attributed to the absence of consensus in the field regarding the definition of spirituality, a lack of clarity of disciplinary role, and inadequate education for nurses and doctors about spiritual care. Research has further indicated that care givers' explorations of their own spirituality correlate with the provision of spiritual care. Although historically spiritual care has been most integrated into the care of palliative and oncology patients, researchers are developing and testing spiritual care assessment tools with other medical populations. In addition, they are evaluating these tools in diverse religious, cultural and national contexts. SUMMARY: Conceptual analysis combined with empirical study of care giver understandings of spiritual care will assist in developing clarity and consensus about the definition of spirituality and spiritual care. Investigation and conceptualization of interdisciplinary roles and provision of spiritual care is needed for optimizing collaborative care. More knowledge is needed about how to effectively teach spiritual care. PMID- 22498838 TI - [Editorial]. PMID- 22498839 TI - [Comparison of results after primary and secondary shoulder arthroplasty for proximal humeral fractures]. AB - BACKGROUND: The purpose of this retrospective cohort study was to evaluate, compare and discuss the results and complications after primary and secondary shoulder arthoplasty in proximal humeral fractures. PATIENTS AND METHODS: Thirteen consecutive patients (mean 76 years [range, 65-85] years) were at a mean of 29 (8-37) months after primary humeral head replacement (group 1), and 15 patients (mean 74 years [range, 43-80] years) at a mean of 18 (7-36) months after secondary shoulder arthoplasty (n = 8 anatomic prostheses, n = 7 reversed prostheses) due to complications/fracture sequelae (group 2) examined clinically and radiologically according to a standardised follow-up protocol. Patient satisfaction, the simple shoulder test (SST), the American shoulder elbow score (ASES) as well as the Constant score (CS) were assessed, and radiological parameters as well as complications analysed. RESULTS: 85 % of patients in group 1 and 73 % in group 2 were satisfied with the results. The SST did not show a significant difference between both groups. The adjusted ASES did not differ significantly with 70 (27-95)% in group 1 and 73 (28-100)% in group 2, as well as the adjusted CS with a mean of 53 (27-83)% in group 1 and of 49 (27-87)% in group 2. Radiological analysis resulted in a correctly centred prosthesis in 6/13 patients, and healed tuberosities in 7/13 of group 1. In group 2 4/8 anatomic prostheses were centered and 7/8 showed healed tuberosities. In the subgroup of the reversed prostheses 6/7 were centered, 3/7 patients had an inferior "notching". The rate of complications and revisions were 2/13 (15 %) in group 1 and 1/15 (7 %) in group 2. CONCLUSION: In summary, the functional results did not differ significantly between primary and secondary shoulder arthroplasty after proximal humeral fractures. The relatively low expectation of elderly patients is reflected in a high rate of patient satisfaction in spite of moderate functional results. The primary humeral head replacement showed higher rates of complications and revisions compared to secondary arthroplasty. PMID- 22498841 TI - [Do German-speaking paediatric orthopaedic surgeons agree on diagnostics and treatment of the neonatal hip?]. AB - BACKGROUND: Ultrasound examination of the neonatal hip has been an integral part of the German programme for the "early detection of disease in childhood" since 01.01.1996. The aim of this study is to determine if any consensus exists among German-speaking paediatric orthopaedic specialists concerning diagnosis and treatment of the neonatal hip 15 years after legal implementation of hip ultrasound screening by the Graf technique. MATERIALS AND METHODS: A questionnaire was sent to all members of the German speaking Association of Paediatric Orthopaedic Surgeons (Vereinigung fur Kinderorthopadie - VKO). The query included questions concerning education and field of activity of the member as well as information on the diagnostics of neonatal hip with regard to examiner, technical equipment, and type of screening. In addition, four cases were presented with clinical history, clinical findings, and rateable Graf sonogram (case 1: 3 days old ?, type D; case 2: 2 days old ?, type IV; case 3: 4 weeks old ?, type II a; case 4: 4 months old ?, type III a) and a treatment recommendation was requested for each case. RESULTS: 78 of 179 contactable VKO members participated in this survey. 75.6 % of the participants are specialists with additional qualification in paediatric orthopaedic surgery. 68 % of the participants work in a hospital. As stated by 61.5 % of the participants the ultrasound examination of the neonatal hip is primarily done by orthopaedic surgeons. One participant stated that the examination is performed primarily by medical-technical assistants. The majority of participants use a 7.5-MHz linear transducer for ultrasound examination, a positioning device according to Graf and a foot switch as technical equipment. State-of-the-art equipment as recommended by Graf including in addition to the above mentioned an upright image display and a transducer guiding arm system is available to only 21.8 % of the participating VKO members. 23 of 50 participants stated that a general screening is performed at their institution where all newborns get an ultrasound examination within the first week of life regardless of medical history and clinical findings. Therapeutic recommendations for the first case (type D hip) were in 15.4 % wait and check by some colleagues, supplemented by double diapering. 56.4 % would use a flexion-abduction splint and 26.9 % would perform reduction with consecutive retention. To treat case 2 (type IV hip) 3.8 % of participants suggest a flexion abduction splint and 88.5 % reduction and retention. Concerning the type of reduction the participants do not agree. Pavlik harness as well as closed reduction under anaesthesia or without anaesthesia is recommended. In case 3 (type II a hip) 67.9 % of the colleagues suggest to wait and check, some with supplementary double diapering. 25.6 % suggest a flexion-abduction splint. One colleague would prescribe a Pavlik harness. In case 4 (type III a hip) 14.1 % of the participants suggest a flexion-abduction splint, 80.8 % reduction and retention as described before with disagreement concerning the preferred type of reduction. On combining the therapeutic suggestions for all four cases, 66 % of the participants recommend a type of treatment that is concordant with Graf's guidelines. CONCLUSION: Despite the existence of clear recommendations the German speaking paediatric orthopaedic surgeons are quite discordant concerning diagnostics and treatment of the neonatal hip. Uncertainty particularly concerning the evaluation of sonograms of physiologically immature and dysplastic unstable hips bears the risk of overtreatment as well as of delayed diagnosis of hip dysplasia. PMID- 22498840 TI - [Measurement on printed paper strips or on the ultrasound device with computer assistance - which technique is more accurate in paediatric hip ultrasound?]. AB - AIM: Two different measurement techniques of ultrasonograms of the infant hip were evaluated with respect to reproducibility of the Graf classification and variation of alpha- and beta-angles. MATERIAL AND METHODS: In a cross-sectional, blinded study, the hips of 207 consecutive newborn babies (101 male; 106 female) were sonographically screened at an average of 2.64 days after birth. Each hip was measured twice by three investigators with different levels of experience - a paediatric orthopaedic surgeon, a senior surgeon and a trained medical student. A mobile ultrasound system (SONOLINE G60S(r), Siemens, Erlangen, Germany), equipped with a 7.5 MHz linear transducer, was used. Both hip joints were measured twice by all three investigators. The measurement was performed 6-8 weeks later in a blinded manner. The sonograms were initially printed out on high-quality paper strips and measured by pencil, ruler and goniometer. Finally, each investigator evaluated the same sonograms computer-assisted, using the trackball and dashboard of the ultrasound system. RESULTS: Concerning intraobserver reliability, we observed a significant reduction of variation both for alpha- and beta-angles in favour of the classic measurement on printed strips (p < 0.05). The interobserver calculation also detected a trend for higher angle variation when the angles were measured electronically. The reproducibility of Graf classification was not influenced by the kind of measurement technique. The outcome was not affected by investigator's level of experience (p > 0.05). CONCLUSIONS: This study demonstrated considerable advantages for the classic measurement of paediatric hip ultrasonograms with pencil and goniometer on printed paper strips compared to computer-aided measurement concerning variation of alpha- and beta-angles. PMID- 22498842 TI - [Retrospective calculation of the workload in emergency departments in case of a mass accident. An analysis of the Love Parade 2010]. AB - BACKGROUND: For the clinical planning of mass events the emergency departments are of critical importance, but there are still no data available for the workload in these cases. As this is essential for an effective medical preparation, we calculated the workload based on the ICD codes of the vicitims at the Loveparade 2010 in Duisburg. MATERIAL AND METHODS: Based on the patient data of the Loveparade 2010 we used a filter diagnosis to estimate the number of shock room patients, regular admittances, surgical wound treatments, applications of casts or splints, and diagnosis of drug abuse. In addition every patient was classified to a Manchester Triage System category. This resulted in a chronological and quantitative work-load profile of the emergency department, which was evaluated by the clinical experiences of the departmental medical staff. RESULTS: The workload profile as a whole displayed a realistic image of the real true situation on July 24, 2010. While only the number, diagnosis and chronology of medical surgical patients was realistic, the MTS classification was not. The emergency department had a maximum of 6 emergency room admittances, 6 regular admittances, 4-5 surgical wound treatments, 3 casts and 2 drug abuse patients per hour. CONCLUSION: The calculation of workload from the ICD data is a reasonable tool for retrospective estimation of the workload of an emergency department, the data can be used for future planning. The retrospective MTS grouping is at present not suitable for a realistic calculation. Retrospective measures in the MTS groups are at present not sufficiently suitable for valid data publication. PMID- 22498843 TI - [Dislocation after total hip arthroplasty]. AB - Dislocations after total hip arthroplasties are one of the most common complications of the procedure. According to registers, recurrent hip dislocations account for up to 30 % of the indications for a revision operation. The incidence of a dislocation is influenced by indication-associated, patient dependent and operation-specific risk factors. 50 % of the dislocations occur within the first 3 months which confirms the high relevance of operation-specific influencing factors. The diagnosis is almost always made with the help of computed tomography, as this is the only method to determine the three dimensional relationship of the components. A dynamic fluoroscopic examination can verify an increased translation (reduced soft-tissue tension) and thus enables a functional examination to determine the mechanism of the dislocation. By means of a classification of dislocations into five types under consideration of the implant position, the sufficiency of the pelvitrochantar musculature, the presence of an impingement, the congruence of head and acetabular liner as well as combinations of these factors it is possible to plan an adequate therapy. From the therapeutic point of view the correct positioning of the stem and head is of decisive importance. In addition therapeutic success can be realized by using larger head diameters through to tripolar sockets, reconstruction of soft tissues and, last but not least, an adequate postoperative immobilization. Even so, this treatment is associated with a high rate of complications and in the literature failure rates of up to one third, i.e., the reoccurrence of a dislocation, are reported. PMID- 22498844 TI - Effectiveness of a condensed protocol for disclosing APOE genotype and providing risk education for Alzheimer disease. AB - PURPOSE: Brief, effective models of patient genetic education are needed for common, complex diseases. Using Alzheimer disease as a model, we compared participants' risk knowledge and recall in extended versus condensed education protocols. METHODS: A four-site randomized clinical trial enrolled 280 first degree relatives of individuals with Alzheimer disease (mean age = 58 years, 71% female); each received lifetime Alzheimer disease risk information (range: 13 74%) that incorporated apolipoprotein E genotype. In the condensed protocol, participants received an educational brochure in place of an in-person education session. Outcomes were assessed at 6 weeks and 6 months following risk disclosure. RESULTS: The condensed protocol required less clinician time than the extended protocol (mean = 34 min vs. 77 min). The groups did not differ on recall of apolipoprotein E genotype or lifetime risk, and most participants in both groups recalled and retained this information over time. Both groups showed improvement from baseline in Alzheimer disease risk knowledge (e.g., understanding the magnitude of apolipoprotein E genotype effect on risk). CONCLUSION: A condensed protocol for communicating genetic risk for Alzheimer disease achieved similar educational results as an extended protocol in this study. Further research should explore the efficacy of brief genetic education protocols for complex diseases in diverse populations. PMID- 22498845 TI - Clinical observation of patients with Fabry disease after switching from agalsidase beta (Fabrazyme) to agalsidase alfa (Replagal). AB - PURPOSE: Fabry disease is a rare, X-linked, inherited lysosomal storage disorder that can be treated with the enzymes agalsidase alfa (Replagal) and agalsidase beta (Fabrazyme). Currently, there is a global shortage of agalsidase beta, and this has increased global demand for agalsidase alfa. We assess the feasibility of switching patients on agalsidase beta treatment to agalsidase alfa instead. METHODS: This analysis is part of an ongoing observational study involving 11 patients with Fabry disease in whom the treatment was switched from agalsidase beta (1 mg/kg every other week) to agalsidase alfa (0.2 mg/kg every other week). Data were collected for a minimum of 36 months: 24 months before and 12 months after the switch. Serial data were evaluated with respect to renal function, cardiac mass, pain, quality of life, and tolerability/safety. RESULTS: Indexes of renal function (estimated glomerular filtration rate) and cardiac mass (left ventricular mass index), pain (Brief Pain Inventory), and quality of life (EuroQoL-Dimensions) clearly showed that, in patients switched to agalsidase alfa, Fabry disease stabilized during the 12 months of follow-up. CONCLUSION: Despite the limitations of this preliminary observational study, it was found that all the patients maintained disease stability when treated with agalsidase alfa, as evidenced by estimated glomerular filtration rate, left-ventricular mass index, pain scores, and quality-of-life indexes, throughout 12 months of follow up. PMID- 22498846 TI - AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome. AB - PURPOSE: The ability to accurately predict the likelihood of expansion of the CGG repeats in the FMR1 gene to a full mutation is of critical importance for genetic counseling of women who are carriers of premutation alleles (55-200 CGG repeats) and who are weighing the risk of having a child with fragile X syndrome. The presence of AGG interruptions within the CGG repeat tract is thought to decrease the likelihood of expansion to a full mutation during transmission, thereby reducing risk, although their contribution has not been quantified. METHODS: We retrospectively analyzed 267 premutation alleles for number and position of AGG interruptions, length of pure CGG repeats, and CGG repeat lengths present in the offspring of the maternal transmissions. In addition, we determined the haplotypes of four markers flanking the 5'-UTR locus in the premutation mothers. RESULTS: We found that the presence of AGG interruptions significantly increased genetic stability, whereas specific haplotypes had a marginal association with transmission instability. CONCLUSION: The presence of AGG interruptions reduced the risk of transmission of a full mutation for all maternal (premutation) repeat lengths below ~100 CGG repeats, with a differential risk (0 vs. 2 AGG) exceeding 60% for alleles in the 70- to 80-CGG repeat range. PMID- 22498848 TI - Vibrational dynamics of oxygenated heme proteins. AB - Advanced spectroscopic techniques coupled with DFT calculations reveal the vibrational dynamics of the iron in stable dioxygen complexes with myoglobin and with a mutant engineered to model the catalytic site of heme-copper oxidases. The unprecedented level of detail will constrain computational modelling of reactions with oxygen. PMID- 22498847 TI - Telegenetics: a systematic review of telemedicine in genetics services. AB - PURPOSE: Telemedicine is being increasingly used in many areas of health care, particularly to reduce the barriers that rural populations face in accessing health-care services. Telemedicine may also be effectively utilized in clinical genetics services-an application that has been termed "telegenetics." METHODS: A systematic review of the literature was conducted to identify studies of genetic consultations carried out through videoconferencing so as to determine whether conclusions can be drawn about the value of telegenetics. A total of 14 articles reporting data from 12 separate studies met the inclusion criteria. RESULTS: In a majority of these studies, patients received their telegenetics consultation at a local clinic or outreach center, from where they communicated via a synchronous video link with a genetics practitioner. All the studies reported high levels of patient satisfaction with telegenetics, and patients were generally more receptive to telegenetics than the genetics practitioners were. The studies had limitations of small sample sizes and lack of statistical analyses. CONCLUSIONS: This review suggests that telegenetics may be a useful tool for providing routine counseling and has the potential to evaluate pediatric patients with suspected genetic conditions. Prospective, fully powered studies of telegenetics that explore the accuracy of diagnoses and patient outcomes are needed to allow informed decisions to be made about the appropriate use of telemedicine in genetics service delivery. PMID- 22498849 TI - Anisotropy of proton transport in an organic-inorganic compound [(C6H10N2)2(SO4)23H2O]n (C6H10N2 = phenylenediammonium dication). AB - Proton transport along different axes in an organic-inorganic compound [(C(6)H(10)N(2))(2)(SO(4))(2).3H(2)O](n) (1) was investigated, revealing that proton transport is not only influenced by the structure of the proton transport pathway, but also by the order-disorder extent of proton carriers. PMID- 22498850 TI - Current strategies in management of Duchenne muscular dystrophy: allowing patients to live with hope. PMID- 22498851 TI - Recognising the many faces of cancer. PMID- 22498852 TI - A population-based survey of mental disorders in Singapore. AB - INTRODUCTION: Mental illnesses are not only a growing public health concern but also a major social and economic issue affecting individuals and families throughout the world. The prevalence of mental disorders, the extent of disability caused by these disorders, and services utilisation of these patients has been well studied in developed countries. The aim of this study was to establish the prevalence of select mental disorders and their associated sociodemographic correlates in the adult Singapore resident population. MATERIALS AND METHODS: This was a cross-sectional, populationbased, epidemiological study of adult Singapore residents aged 18 years and above. The subjects were randomly selected using a disproportionate stratified sampling method. The diagnoses of selected mental disorders including major depressive disorder (MDD), dysthymia, bipolar (bipolar I & II) disorders, generalised anxiety disorder (GAD), obsessive compulsive disorder (OCD), alcohol abuse and alcohol dependence were established using the Composite International Diagnostic Interview, which is a fully structured diagnostic instrument that assesses lifetime and 12-month prevalence of mental disorders. RESULTS: Among the 6616 respondents (response rate of 75.9%), 12.0% had at least one lifetime affective, anxiety, or alcohol use disorders. The lifetime prevalence of MDD was 5.8% and that of bipolar disorder was 1.2%. The combined lifetime prevalence of the 2 anxiety disorders, GAD and OCD was 3.6%, with the latter being more common than GAD (0.9% and 3.0% respectively). The lifetime prevalence of alcohol abuse and dependence were found to be 3.1% and 0.5% respectively. Age, gender, ethnicity, marital status and chronic physical illnesses were all significant correlates of mental disorders. CONCLUSION: The identified associated factors would help guide resource allocation, policy formulation and programme development in Singapore. PMID- 22498853 TI - Geriatric syndromes and depressed mood in lower-income Singaporeans with diabetes: implications for diabetes management and health promotion. AB - INTRODUCTION: This study aims to determine the association of geriatric syndromes and depressed mood among respondents with diabetes in a lower income community; and their association with self-management, lifestyle behaviour, and healthcare utilisation. This paper focuses primarily on the 114 respondents with diabetes aged 50+ to inform policy formulation at the community level. MATERIALS AND METHODS: A pilot community health assessment was conducted in 4 blocks of 1- and 2-room apartments in Toa Payoh district from July to November 2009. Using a standard questionnaire, interviewers conducted face-to-face interviews with household members on chronic diseases, geriatric syndromes and health-related behaviour. Data were analysed using SPSSv15. RESULTS: A total of 795 respondents were assessed with a response rate of 61.8%. Of 515 (64.8%) aged 50+ analysed in this study, 22.1% reported having diabetes, of whom 31.6% reported being depressed. Respondents with diabetes who reported being depressed had a higher prevalence of geriatric syndromes compared with those non-depressed; i.e. functional decline (30.6% vs 5.1%, P <0.001); falls (33.3% vs 10.3%, P = 0.003); stumbling (30.6% vs 10.3%, P = 0.007); urinary incontinence (33.3% vs 5.1%, P <0.001), progressive forgetfulness (27.8% vs 6.4%, P = 0.002) and poor eyesight (22.2% vs 6.4%, P = 0.014). They were less likely to comply with medications (86.1% vs 97.3%, P = 0.026) and performed exercise (13.9% vs 53.8%, P <0.001). More had hospital admissions (13.9% vs 7.7%); and they had more outpatient visits per person (2.4 visits vs 0.9 visits, P = 0.03) at Specialist Outpatient Clinics. CONCLUSION: Geriatric syndromes were associated with the presence of depressed mood among persons with diabetes in the lower income group. As those with depressed mood had more unfavourable self-management and lifestyle behaviour, and utilise higher healthcare services, diabetes management must take these findings into consideration. PMID- 22498854 TI - Vancomycin-resistant Enterococci in Singaporean hospitals: 5-year results of a multi-centre surveillance programme. AB - INTRODUCTION: Vancomycin-resistant enterococci (VRE) have emerged as one of the major nosocomial antimicrobial-resistant pathogens globally. In this article, we describe the epidemiology of VRE in Singaporean public hospitals in the 5 years following the major local VRE outbreak in 2005. MATERIALS AND METHODS: A passive laboratory surveillance programme identified non-duplicate VRE isolates from 7 hospitals from 2006 to 2010. Descriptive statistics and time-series analysis was performed on all clinical VRE isolates for each individual hospital as well as for the combined dataset. RESULTS: There were a total of 418 VRE isolates over 5 years, of which 102 isolates (24.4%) were from clinical cultures. Between 0.4% and 0.7% of all clinical enterococcal isolates were resistant to vancomycin. The overall incidence-density of VRE did not change over time in Singapore despite 2 separate outbreaks in tertiary hospitals in 2009 and 2010. Incidence-density of clinical VRE cases fell in 2 secondary hospitals, while another 2 hospitals experienced no significant VRE infections after 2008. CONCLUSION: The prevalence of VRE clinical isolates remains low in Singaporean public sector hospitals. However, the presence of at least 2 outbreaks in separate hospitals over the past 5 years indicates the need for continued vigilance in order to prevent any further increase in VRE prevalence locally. PMID- 22498855 TI - Safety and clinical efficacy of laparoscopic appendectomy for pregnant women with acute appendicitis. AB - INTRODUCTION: The aim of this study was to investigate the clinical efficacy and safety of laparoscopic appendectomy (LA) during pregnancy by comparing the operative and obstetric outcomes of patients who during pregnancy underwent LA performed by an expert gynaecologic laparoscopist (LA group) with those patients who underwent an open appendectomy (OA) by a general surgeon (OA group). MATERIALS AND METHODS: In this retrospective study, we evaluated all patients consecutively who had undergone appendectomy for acute appendicitis during pregnancy from January 2000 to December 2010. Twenty-eight patients underwent OA and 15 were treated by LA. We reviewed the clinical charts and analysed the data for each patient's age, parity, body mass index, gestational age at appendectomy, type of appendectomy, operating time, haemoglobin change, hospital stay, histopathological results, postoperative analgesics, complications, and obstetric outcomes. RESULTS: There were no significant differences between the OA and LA groups in terms of clinical characteristics, hospital stay, haemoglobin change, return of bowel activity, complication rates, gestational age at delivery, and birth weight. However, there were significantly shorter operating time and less usage of postoperative analgesics in LA group. CONCLUSION: LA performed by an expert gynaecologist can be a safe and effective method for treating acute appendicitis during the first and second trimester of pregnancy. PMID- 22498856 TI - 6th College of Surgeons lecture: the philosophy of balance: the art of healing. AB - With the rise of high tech medicine, and emphasis on the scientific aspects of medicine, there is danger that we may lose the balanced approach to healing, and lose the benefit of the traditional medical wisdom and emotional support, to improve the care of our patients. Allopathic or the mainstream medicine (Western medicine) is not the only way. With over-emphasis on the anatomy and pathology, the biochemistry and the molecular biology, we tend to treat the disease, and somehow neglect the patient. That is one of the reasons why many patients still turn to alternative medicine to relieve their ailments.We need to remember that the patient is a person, consisting of not just the body, but also the mind and the spirit. We therefore need to treat not just the body but also the mind and to heal the spirit. That would be the balanced approach in the management of patients. To treat our patients optimally, we need to understand the natural history of diseases, and not make our treatment worse than the disease itself, carefully balancing the risks and benefits in our treatment for that individual patient. The mind has more influence over the body in health and diseases than we used to think. We need to be optimistic and give patients hope through counseling, and help to minimise the harmful effects of stress and anxiety on the body. It is as important to improve the immunity of the body to diseases (infection as well as cancer) as to get rid of every bacteria or cancer cell. It may not be possible to get rid of all the cancer cells in the body, but it may be possible to keep them under control. The most important factor in improving the immunity is for the patient to have a relaxed mind. He would need emotional support from family and friends. Exercise, proper diet with plenty of fresh fruits and vegetables would help to improve immunity and speed up the healing process. The art of healing is the art of balancing the Science and the Art of Medicine, treating the disease and the patient as a whole, incorporating the best in allopathic (Western) medicine as well as complementary medical practices. With this, we hope to provide the best care to our patients. PMID- 22498857 TI - Generalised pruritus and elevated levels of immunoglobulin E acting as biomarkers of a malignant peritoneal mesothelioma. PMID- 22498858 TI - An unusual case of rudimentary uterine horn ectopic pregnancy. PMID- 22498859 TI - Biventricular noncompaction and mitral cleft. PMID- 22498860 TI - [A rare coexistence: Atrioventricular nodal reentry tachycardia and Mahaim accessory pathway mediated atrioventricular tachycardia]. PMID- 22498861 TI - Closure of nonrestrictive aortopulmonary window in an infant by the transcatheter approach. PMID- 22498862 TI - An unusual clinical state: atrial fibrillation due to mad-honey intoxication. PMID- 22498863 TI - [Familial arterial tortuosity syndrome]. PMID- 22498864 TI - Cardiac hydatid cyst: a comment/ Cardiac hydatid cyst case recovered with medical treatment. PMID- 22498865 TI - The importance of Himalayan P-wave in differentiation of cardiomyopathies. PMID- 22498866 TI - Sex proportion of offspring in mothers with cardiac disease. PMID- 22498867 TI - Comparison of blood lipid levels of people of Armenian and non-Armenian origin living in Istanbul, Turkey. PMID- 22498868 TI - Anesthesia for percutaneous transcatheter closure of atrial septal defects in adults. PMID- 22498869 TI - Simultaneous percutaneous peripheral arterial intervention and transfemoral transcatheter aortic valve implantation in bilateral iliac artery occlusive disease. PMID- 22498870 TI - A case of left circumflex artery supplying the left ventricular apex. PMID- 22498871 TI - [Left main coronary artery-to- pulmonary artery fistula and concomitant severe coronary artery disease]. PMID- 22498872 TI - Pericardial cyst: a rare cause of recurrent palpitation episodes. PMID- 22498873 TI - Transected common hepatic artery and treatment. PMID- 22498874 TI - Long-term adverse effect of Kawasaki syndrome: Two- vessel coronary artery by pass surgery for coronary artery aneurysm in a 16-year old male patient. PMID- 22498875 TI - [Cuba-Iran axis, Copyright, "Sutures de plaiesarterielles"]. PMID- 22498876 TI - [Ord. Prof. Dr. Cemil Topuzlu (1866-1958)]. PMID- 22498877 TI - Endogenous testosterone increases leukocyte-endothelial cell interaction in spontaneously hypertensive rats. AB - AIMS: Inflammation may have an important role in the beginning and in the progress of cardiovascular diseases. Testosterone exerts important effects on vascular function, which is altered in arterial hypertension. Thus, the aim of this study was to evaluate the influence of endogenous testosterone on leukocyte behavior in post-capillary venules of the mesenteric bed of spontaneously hypertensive rats (SHR). MAIN METHODS: 18 week-old intact SHR, castrated SHR and normotensive rats (intact Wistar) were used. Blood pressure was measured by tail plethysmography and serum testosterone levels by ELISA. Leukocyte rolling, adhesion and migration were evaluated in vivo in situ by intravital microscopy. KEY FINDINGS: Castration significantly reduced blood pressure and reversed the increased leukocyte rolling and adhesion observed in SHRs. Leukocyte counts and other hemodynamic parameters did not differ among groups. SHRs displayed increased protein expression of P-selectin and ICAM-1 in mesenteric venules when compared to intact Wistar. Castration of SHRs restored the protein expression of the cell adhesion molecules. SIGNIFICANCE: The findings of the present study demonstrate the critical role of endogenous testosterone mediating the effects of hypertension increasing leukocyte-endothelial cell interaction. Increased expression of cell adhesion molecules contribute to the effects of endogenous testosterone promoting increased leukocyte rolling and adhesion in SHRs. PMID- 22498879 TI - CO2 gas induced drug release from pH-sensitive liposome to circumvent doxorubicin resistant cells. AB - A novel pH-sensitive liposome encapsulating doxorubicin was prepared by a NH(4)HCO(3) gradient method. The liposomes were able to release the drug at pH 5.0 by the production of CO(2) gas. More importantly, the drug-loaded liposome effectively circumvented the breast cancer cells resistant to doxorubicin. PMID- 22498878 TI - The anti-herpetic activity of trichosanthin via the nuclear factor-kappaB and p53 pathways. AB - AIMS: Trichosanthin (TCS) is a type I ribosome-inactivating protein. We have previously shown that TCS induces a more potent apoptosis in infected cells over uninfected cells, but the mechanism underlying it is unclear. In this study, we explored the anti-HSV-1 mechanism of TCS through the nuclear factor-kappaB (NF kappaB) and p53 pathways in human epithelial carcinoma (HEp-2) cells with wild type p53. MAIN METHODS: The western blot, electrophoretic mobility shift assay, chromatin immunoprecipitation assay, enzyme-linked immunosorbent assay and cytokinesis-block micronucleus were applied in this study. KEY FINDINGS: It was shown that TCS inhibited the HSV-1-induced NF-kappaB activation. Meanwhile, in HSV-1 infected cells, TCS treatment activated significantly more p53 and BAX, with no DNA damage and less S phase arrest compared with uninfected cells. The activation of BAX in infected cells correlated with the cell death signaling of p53. SIGNIFICANCE: Taken together, these results suggest that the anti-HSV-1 effect of TCS is related to its suppression of NF-kappaB activation and regulation of p53-dependent cell death in infected cells. PMID- 22498880 TI - Metabolomic analysis of the plasma of patients with high-altitude pulmonary edema (HAPE) using 1H NMR. AB - Upon rapid ascent to a high altitude, non-acclimatized individuals, although healthy, are highly prone to contracting high-altitude pulmonary edema (HAPE). Early diagnosis is difficult and there is no reliable biomarker available. We used proton ((1)H) NMR metabolomics to profile the altered metabolic patterns of blood plasma from HAPE patients. The plasmas of ten patients with HAPE and ten individuals without HAPE were collected and compared using (1)H NMR spectroscopy. Data were evaluated with several multivariate statistical analyses, including the principal components, the orthogonal partial least-squares discriminant, and the orthogonal signal correction partial least-squares discriminant. Multivariate statistical analyses revealed a significant disparity between subjects with HAPE and those in the control group. Compared to the plasma of the controls, the HAPE patients had significant increases in valine, lysine, leucine, isoleucine, glycerol phosphoryl choline, glycine, glutamine, glutamic acid, creatinine, citrate, and methyl histidine. These were accompanied by decreases in alpha- and beta-glucose, trimethylamine, and the metabolic products of lipids. The data demonstrate that metabolomics may be effective for the diagnosis of HAPE in the future, and can be used for further understanding HAPE pathogenesis. PMID- 22498882 TI - Urinary proteomics revealed prostaglandin H(2)D-isomerase, not Zn-alpha2 glycoprotein, as a biomarker for active lupus nephritis. AB - Although renal histopathology is the gold standard for the diagnosis and prognosis of lupus nephritis (LN), the invasiveness of renal biopsy warrants the discovery of novel non-invasive diagnostic and prognostic biomarkers. In the present study, urine samples from 10 LN patients (5 active and 5 inactive) were analyzed by two-dimensional gel electrophoresis (2-DE) to screen for potential biomarkers of active LN. Quantitative analysis and statistics revealed 16 protein spots whose levels significantly differed between groups. These proteins were successfully identified by electrospray ionization quadrupole time-of-flight tandem mass spectrometry (ESI-Q-TOF MS/MS). Among these potential candidates, differential levels of urinary Zn-alpha2-glycoprotein (ZA2G) and prostaglandin H(2)D-isomerase (PGDS) were further validated by enzyme-linked immunosorbent assay (ELISA) in another independent group of 78 subjects, including 30 active LN, 26 inactive LN, 14 non-LN glomerular diseases, and 8 healthy normal individuals. Whereas ZA2G levels were elevated in urine of patients with active LN and non-LN glomerular diseases, PGDS was elevated only in the urine of the active LN group. Urinary PGDS, not ZA2G, may serve as a biomarker for active LN and upon validation in larger studies, may become the non-invasive test to evaluate the disease activity in future management of LN. PMID- 22498881 TI - Mass spectrometry imaging and profiling of single cells. AB - Mass spectrometry imaging and profiling of individual cells and subcellular structures provide unique analytical capabilities for biological and biomedical research, including determination of the biochemical heterogeneity of cellular populations and intracellular localization of pharmaceuticals. Two mass spectrometry technologies-secondary ion mass spectrometry (SIMS) and matrix assisted laser desorption/ionization mass spectrometry (MALDI MS)-are most often used in micro-bioanalytical investigations. Recent advances in ion probe technologies have increased the dynamic range and sensitivity of analyte detection by SIMS, allowing two- and three-dimensional localization of analytes in a variety of cells. SIMS operating in the mass spectrometry imaging (MSI) mode can routinely reach spatial resolutions at the submicron level; therefore, it is frequently used in studies of the chemical composition of subcellular structures. MALDI MS offers a large mass range and high sensitivity of analyte detection. It has been successfully applied in a variety of single-cell and organelle profiling studies. Innovative instrumentation such as scanning microprobe MALDI and mass microscope spectrometers enables new subcellular MSI measurements. Other approaches for MS-based chemical imaging and profiling include those based on near-field laser ablation and inductively-coupled plasma MS analysis, which offer complementary capabilities for subcellular chemical imaging and profiling. PMID- 22498883 TI - Pilot and feasibility study: comparative proteomic analysis by 2-DE MALDI TOF/TOF MS reveals 14-3-3 proteins as putative biomarkers of response to neoadjuvant chemotherapy in ER-positive breast cancer. AB - Neoadjuvant chemotherapy is used to treat oestrogen receptor-positive breast cancer however chemo-resistance is a major obstacle in this molecular subtype. The ability to predict tumour response would allow chemotherapy administration to be directed towards patients who would most benefit, thus maximising treatment efficacy. We aimed to identify protein biomarkers associated with response to neoadjuvant chemotherapy, in a pilot study using comparative 2-DE MALDI TOF/TOF MS proteomic analysis of breast tumour samples. A total of 3 comparative proteomic experiments were performed, comparing protein expression between chemotherapy-sensitive and chemotherapy-resistant oestrogen receptor-positive invasive ductal carcinoma tissue samples. This identified a list of 132 unique proteins that were significantly differentially expressed (>= 2 fold) in chemotherapy resistant samples, 57 of which were identified in at least two experiments. Ingenuity(r) Pathway Analysis was used to map the 57 DEPs onto canonical signalling pathways. We implicate several isoforms of 14-3-3 family proteins (theta/tau, gamma, epsilon, beta/alpha and zeta/delta), which have previously been associated with chemotherapy resistance in breast cancer. Extensive clinical validation is now required to fully assess the role of these proteins as putative markers of chemotherapy response in luminal breast cancer subtypes. PMID- 22498884 TI - Rapid direct detection of the major fish allergen, parvalbumin, by selected MS/MS ion monitoring mass spectrometry. AB - Parvalbumins beta (beta-PRVBs) are considered the major fish allergens. A new strategy for the rapid and direct detection of these allergens in any foodstuff is presented in this work. The proposed methodology is based on the purification of beta-PRVBs by treatment with heat, the use of accelerated in-solution trypsin digestion under an ultrasonic field provided by High-Intensity Focused Ultrasound (HIFU) and the monitoring of only nineteen beta-PRVB peptide biomarkers by Selected MS/MS Ion Monitoring (SMIM) in a linear ion trap (LIT) mass spectrometer. The present strategy allows the direct detection of the presence of fish beta-PRVBs in any food product in less than 2 hours. PMID- 22498885 TI - PROTEOMICS in aquaculture: applications and trends. AB - Over the last forty years global aquaculture presented a growth rate of 6.9% per annum with an amazing production of 52.5 million tonnes in 2008, and a contribution of 43% of aquatic animal food for human consumption. In order to meet the world's health requirements of fish protein, a continuous growth in production is still expected for decades to come. Aquaculture is, though, a very competitive market, and a global awareness regarding the use of scientific knowledge and emerging technologies to obtain a better farmed organism through a sustainable production has enhanced the importance of proteomics in seafood biology research. Proteomics, as a powerful comparative tool, has therefore been increasingly used over the last decade to address different questions in aquaculture, regarding welfare, nutrition, health, quality, and safety. In this paper we will give an overview of these biological questions and the role of proteomics in their investigation, outlining the advantages, disadvantages and future challenges. A brief description of the proteomics technical approaches will be presented. Special focus will be on the latest trends related to the aquaculture production of fish with defined nutritional, health or quality properties for functional foods and the integration of proteomics techniques in addressing this challenging issue. PMID- 22498886 TI - Discovery of biomarkers for gastric cancer: a proteomics approach. AB - Gastric cancer is the second leading cause of cancer-related deaths worldwide. Although many treatment options exist for patients with gastric tumors, the incidence and mortality rate of gastric cancer are on the rise. The early stages of gastric cancer are non-symptomatic, and the treatment response is unpredictable. This situation is further aggravated by a lack of diagnostic biomarkers that can aid in the early detection and prognosis of gastric cancer and in the prediction of chemoresistance. Moreover, clinical surgical specimens are rarely obtained, and traditional biomarkers of gastric cancer are not very effective. Many studies in the field of proteomics have contributed to the discovery and establishment of powerful diagnostic tools (e.g., ProteinChip array) in the management of cancer. The evolution in proteomic technologies has not only enabled the screening of a large number of samples but also enabled the identification of pathologically significant proteins, such as phosphoproteins, and the quantitation of difference in protein expression under different conditions. Multiplexed assays are used widely to accurately fractionate various complex samples such as blood, tissue, cells, and Helicobacter pylori-infected specimens to identify differentially expressed proteins. Biomarker detection studies have substantially contributed to the areas of secretome, metabolome, and phosphoproteome. Here, we review the development of potential biomarkers in the natural history of gastric cancer, with specific emphasis on the characteristics of target protein convergence. PMID- 22498887 TI - Defect-induced conductance oscillations in short atomic chains. AB - Electronic transport through a junction made of two gold electrodes connected with a gold chain containing a silver impurity is analyzed with a tight binding model and the density-functional theory. It is shown that the conductance depends in a simple way on the position of the impurity in the chain and the parity of the total number of atoms of the chain. For an odd chain the conductance takes on a higher value when the Ag impurity substitutes an even Au atom in the chain, and a lower one for an odd position of the Ag atom. In the case of an even chain the conductance hardly depends on the position of the Ag atom. This new kind of a defect-induced parity oscillation of the conductance is significantly more prominent than the well-known even-odd effect related to the dependence of the conductance on the parity of number of atoms in perfect chains. PMID- 22498888 TI - Patterned direct-write and screen-printing of NIR-to-visible upconverting inks for security applications. AB - Two methods of direct-write printing for producing highly resolved features of a polymer impregnated with luminescent upconversion phosphors for security applications are presented. The printed polymer structures range in shape from features to text. The thin polymer features were deposited by direct-write printing of atomized material as well as by screen-printing techniques. These films contain highly luminescent lanthanide-doped, rare-earth nanocrystals, beta NaYF4:3%Er, 17%Yb, which are capped with oleic acid. This capping agent allows the nanocrystals to disperse throughout the films for full detailing of printed features. Upconversion of deposited features was obtained using a 980 nm wavelength laser with emission of upconverted light in the visible region at both 540 and 660 nm. Features were deposited onto high bond paper, Kapton(r), and glass to demonstrate possible covert and forensic security printing applications, as they are printed in various features and invisible to 'naked-eye' viewing at low concentrations of nanocrystals. PMID- 22498889 TI - Triphasic low-dose response in zebrafish embryos irradiated by microbeam protons. AB - The microbeam irradiation system (Single-Particle Irradiation System to Cell, acronym as SPICE) at the National Institute of Radiological Sciences (NIRS), Japan, was employed to irradiate dechorionated zebrafish embryos at the 2-cell stage at 0.75 h post fertilization (hpf) by microbeam protons. Either one or both of the cells of the embryos were irradiated with 10, 20, 40, 50, 80, 100, 160, 200, 300 and 2000 protons each with an energy of 3.37 MeV. The embryos were then returned back to the incubator until 24 hpf for analyses. The levels of apoptosis in zebrafish embryos at 25 hpf were quantified through terminal dUTP transferase mediated nick end-labeling (TUNEL) assay, with the apoptotic signals captured by a confocal microscope. The results revealed a triphasic dose-response for zebrafish embryos with both cells irradiated at the 2-cell stage, namely, (1) increase in apoptotic signals for < 200 protons (< 30 mGy), (2) hormesis to reduce the apoptotic signals below the spontaneous number for 200-400 protons (at doses of 30-60 mGy), and (3) increase in apoptotic signals again for > 600 protons (at doses > 90 mGy). The dose response for zebrafish embryos with only one cell irradiated at the 2-cell stage was also likely a triphasic one, but the apoptotic signals in the first zone (< 200 protons or < 30 mGy) did not have significant differences from those of the background. At the same time, the experimental data were in line with induction of radiation-induced bystander effect as well as rescue effect in the zebrafish embryos, particular in those embryos with unirradiated cells. PMID- 22498890 TI - Breaking multiple covalent bonds with Hartree-Fock-based quantum chemistry: Quasi Variational Coupled Cluster theory with perturbative treatment of triple excitations. AB - We enhance the recently proposed Optimized-orbital Quasi-Variational Coupled Cluster Doubles (OQVCCD) method for the calculation of ground-state molecular electronic structure by augmenting it with the standard perturbative (T) correction for the effects of connected triple excitations. We demonstrate the OQVCCD(T) ansatz to be outstandingly robust and accurate in the description of the breaking of the triple bond in diatomic nitrogen, N2, where traditional CCSD and CCSD(T) completely fail, yet with a computational cost that is nearly the same as that of CCSD(T). This result provides insight into the failure of CCSD(T) and related methods and how it may be overcome. PMID- 22498891 TI - Risk of gastric pouch enlargement with adjustable gastric banding in premenopausal women: sex hormones may play a role. AB - OBJECTIVE: To examine the influence of age and gender on the development of proximal gastric pouch distension (PPD) after laparoscopic adjustable gastric banding (LAGB) surgery. BACKGROUND: PPD is the most common reason for revision with adjustable gastric banding surgery. Maintaining the anatomical integrity of bariatric surgery is a key to long-term success. It is therefore important to understand risk factors for complications. METHODS: We extracted details of 3000 consecutive individuals who underwent primary LAGB procedures at a single center between February 2005 and May 2011. Contemporaneous details of all complications were recorded in a database. The characteristics of those that subsequently required revision surgery for PPD were assessed and compared with those that did not. RESULTS: There were 132 cases for PPD requiring surgical intervention before September 2011. Incident PPD occurred in 5.1% and 1.3% of women and men, respectively. The mean age of those with PPD was 39.9 +/- 9.25 compared with 43.9 +/- 11.0 for those without it. The age and gender effects were independent, and the age effect was restricted to women. The adjusted odds ratios were 0.971 (95% CI [confidence interval], 0.954-0.986, P < 0.001) for age and 0.26 (95% CI, 0.12 0.56, P = 0.001) for male gender and younger women were more likely to have asymmetrical distension. CONCLUSIONS: Younger women are at higher risk of PPD after LAGB surgery than men and women older than 50 years. Sex hormones may play a role in predisposing to gastric stretch after surgery. These findings may apply more broadly to the gastric "restrictive" component of other bariatric procedures. PMID- 22498892 TI - Bile exposure inhibits expression of squamous differentiation genes in human esophageal epithelial cells. AB - OBJECTIVE: This study aimed to identify pathways and cellular processes that are modulated by exposure of normal esophageal cells to bile and acid. BACKGROUND: Barrett's esophagus most likely develops as a response of esophageal stem cells to the abnormal reflux environment. Although insights into the underlying molecular mechanisms are slowly emerging, much of the metaplastic process remains unknown. METHODS: We performed a global analysis of gene expression in normal squamous esophageal cells in response to bile or acid exposure. Differentially expressed genes were classified into major biological functions using pathway analysis and interaction network software. Array data were verified by quantitative PCR and western blot both in vitro and in human esophageal biopsies. RESULTS: Bile modulated expression of 202 genes, and acid modulated expression of 103 genes. Genes involved in squamous differentiation formed the largest functional group (n = 45) all of which were downregulated by bile exposure. This included genes such as involucrin (IVL), keratinocyte differentiation-associated protein (KRTDAP), grainyhead-like 1 (GRHL1), and desmoglein1 (DSG1) the downregulation of which was confirmed by quantitative PCR and western blot. Bile also caused expression changes in genes involved in cell adhesion, DNA repair, oxidative stress, cell cycle, Wnt signaling, and lipid metabolism. Analysis of human esophageal biopsies demonstrated greatly reduced expression of IVL, KRTDAP, DSG1, and GRHL1 in metaplastic compared to squamous epithelia. CONCLUSIONS: We report for the first time that bile inhibits the squamous differentiation program of esophageal epithelial cells. This, coordinated with induction of genes driving intestinal differentiation, may be required for the development of Barrett's esophagus. PMID- 22498893 TI - The importance of blood loss during colon cancer surgery for long-term survival: an epidemiological study based on a population based register. AB - OBJECTIVE: This study tested the hypothesis that the amount of blood loss during surgery for colonic cancer influences long-term survival. BACKGROUND: The perioperative blood loss during surgery for colorectal cancer relates to the risk for complications and early mortality. METHODS: All patients who underwent surgery for colon cancer between 1997 and 2003 in the health-care region of Uppsala/Orebro were prospectively registered at the regional oncological center. Data on patients who underwent radical surgery for stages I to III disease were analyzed. Patients who died within 6 months after surgery were excluded. Hazard ratios were calculated with uni- and multivariate Cox proportional hazard regression. Because of covariation, blood loss, blood transfusion, and complications were tested in separate multivariate analyses. RESULTS: Blood loss of 250 mL or more during surgery, male gender, occurrence of complications, age more than 75 years, and stage III disease were risk factors for overall mortality in the uni- and multivariate analyses. Perioperative blood transfusion was shown to be a risk factor in the univariate analysis only. CONCLUSIONS: The results support the hypothesis that degree of blood loss during surgery for colon cancer is a factor that influences long-term survival. PMID- 22498894 TI - Nano-advantage in enhanced drug delivery with biodegradable nanoparticles: contribution of reduced clearance. AB - The aim of this study was to investigate the contribution of reduced apparent clearance to the enhanced exposure reported for biodegradable nanoparticles after extravascular and intravascular routes of administration. Plasma concentration profiles for drug and nanoparticle formulations after administration by intravenous, intraduodenal, and oral routes were extracted from the literature. Data were fit to pharmacokinetic models using BOOMER. The compartmental pharmacokinetic analysis of literature data for six drugs (camptothecin, 9 nitrocamptothecin, epirubicin, vinpocetine, clozapine, and cyclosporine) showed that the encapsulation of drug molecules in nanoparticles significantly reduced the apparent clearance and prolonged the apparent circulation half-life compared with those for the plain drug. Positively charged nanoparticles assessed in this study had lower apparent clearance, lower elimination rate constant values, and longer apparent circulation half-life than neutral and negatively charged nanoparticles. After oral administration, a reduction in apparent clearance contributed substantially to elevations in plasma drug exposure with nanoparticles. For the drugs and delivery systems examined, the nano-advantage in drug delivery enhancement can be explained, in part, by reduced clearance. PMID- 22498895 TI - Quantification of human hepatocyte cytochrome P450 enzymes and transporters induced by HIV protease inhibitors using newly validated LC-MS/MS cocktail assays and RT-PCR. AB - Human immunodeficiency virus (HIV) protease inhibitors (PIs) produce profound and unpredictable drug-drug interactions (DDIs) that cannot be explained fully by their inhibition/inactivation of CYP3A enzymes. Delineating and quantifying the CYPs and transporters inducible by PIs are crucial in developing an integrative mechanistic understanding and prediction of PI-based DDIs. To do so, two LC-MS/MS cocktail assays were modified and validated simultaneously to quantify the CYP activity of CYP3A, 2B6, 2C8, 2C9, 2C19, 1A, 2E1, 2A6 and 2D6 enzymes. These new assays were applied to evaluate the induction potential of eight PIs in microsomes isolated from PI-treated human hepatocytes. The mRNA expression of these CYPs and transporters (OATP1B1, OATP1B3, OATP1A2, MDR1, MRP2 and MRP4) was also evaluated using relative RT-PCR. The majority of PIs were net inducers of CYP3As and 2B6 at both the mRNA and activity level (> 2-fold), while ritonavir, saquinavir, nelfinavir or lopinavir did not induce CYP3A activity (< 2-fold), presumably due to CYP3A inactivation. OATP1B1 and MDR1 were the only two hepatic transporters induced (> 2-fold) by the PIs. Amprenavir was the most potent net inducer. In conclusion, our validated cocktail assays can be implemented to comprehensively quantify CYP activities in human liver microsomes and hepatocyte studies. The results also provide the much needed data on the net induction potential of the PIs for hepatic CYPs and transporters. A qualitative agreement was observed between our results and published PI-based DDIs, suggesting that human hepatocytes are a useful platform for more extensive and quantitative in vitro-in vivo prediction of PI-based DDIs. PMID- 22498896 TI - Bipolar disorder ANK3 risk variant effect on sustained attention is replicated in a large healthy population. AB - Independent genome-wide association studies have implicated a common single nucleotide polymorphism within the ANK3 gene (rs10994336) in bipolar disorder (BD) susceptibility, thus establishing rs10994336 marker as a strong candidate predisposing genetic factor for BD. Furthermore, recent findings demonstrate that this variant impacts on cognitive functioning in BD patients, their unaffected relatives, and healthy controls by influencing sustained attention. Here, we aimed to replicate this finding in a large population-based sample of healthy young adults (n=1808). Sustained attention was evaluated using the Continuous Performance Test as in the original study and working memory was assessed with the n-back task. Individuals carrying the BD risk T-allele showed significantly reduced sensitivity in target detection, increased errors of commission, and atypical response latency variability. In addition, we confirmed the lack of an association between the rs10994336 variant and working memory, as well as general intellectual ability, suggesting a specific effect on the Continuous Performance Test performance. PMID- 22498897 TI - The economy of brain network organization. AB - The brain is expensive, incurring high material and metabolic costs for its size- relative to the size of the body--and many aspects of brain network organization can be mostly explained by a parsimonious drive to minimize these costs. However, brain networks or connectomes also have high topological efficiency, robustness, modularity and a 'rich club' of connector hubs. Many of these and other advantageous topological properties will probably entail a wiring-cost premium. We propose that brain organization is shaped by an economic trade-off between minimizing costs and allowing the emergence of adaptively valuable topological patterns of anatomical or functional connectivity between multiple neuronal populations. This process of negotiating, and re-negotiating, trade-offs between wiring cost and topological value continues over long (decades) and short (millisecond) timescales as brain networks evolve, grow and adapt to changing cognitive demands. An economical analysis of neuropsychiatric disorders highlights the vulnerability of the more costly elements of brain networks to pathological attack or abnormal development. PMID- 22498898 TI - Artificial activation of a memory trace. PMID- 22498901 TI - The most important diagnostic modalities for Helicobacter pylori, now and in the future. AB - CURRENT DIAGNOSTIC METHODS: Helicobacter pylori infection plays a central role in the pathophysiology of gastrointestinal disease, and its accurate diagnosis and successful eradication is crucial in a wide range of different circumstances. Currently, serology is recommended for initial screening, followed by histology and/or culture to confirm the diagnosis before treatment. Since H. pylori is developing greater resistance to certain antibiotics, culture is becoming increasingly important in some populations to test for susceptibility to antibiotics. To confirm eradication after treatment, the urea breath test is used. This test is presently the best non-invasive test to determine eradication. NEW APPROACHES: Considerable efforts are being made to improve diagnostic methods, and a host of new or improved approaches can be expected in the near future. For general screening, tests are being developed that use whole blood and can be used by general practitioners to give rapid results in a cost-effective manner. The evidence so far suggests that these new 'office' tests are not as accurate as laboratory tests, but they are nevertheless important for general diagnostic purposes. Serological tests for cagA antibodies and immunoblot tests are also under development. New biopsy-based tests include the development of a true rapid urease test which will give accurate results in 1 h. Polymerase chain reaction/DNA enzyme immunoassay detection is another field receiving attention. Non-invasive direct tests of the future are likely to include the use of the polymerase chain reaction in faeces. This paper reviews current diagnostic modalities for H. pylori and gives an overview of expected future developments. PMID- 22498902 TI - Management of Helicobacter pylori-related disorders. AB - The discovery of Helicobacter pylori has opened new opportunities in the management of gastrointestinal disorders, with the cure of chronic ulcer disease now being possible for the first time. The 1994 United States National Institutes of Health Consensus Conference recommended that patients with duodenal or gastric ulcers unrelated to the use of non-steroidal anti-inflammatory drugs (NSAID) should be given eradication therapy. These guidelines were refined at a conference held recently in Maastricht. The updated guidelines strongly recommend treatment in patients with duodenal or gastric ulcer disease, low-grade mucosa associated lymphoid tissue (MALT) gastric lymphoma, gastritis with severe macro or microscopic changes and after resection of early gastric cancer. Despite a lack of hard scientific evidence, the guidelines also suggest that eradication treatment is advisable in patients with unequivocally diagnosed functional dyspepsia, a family history of gastric cancer, long-term treatment with proton pump inhibitors for gastro-oesophageal reflux disease (GORD), planned or existing NSAID treatment, after gastric surgery for ulcer or cancer, or if the patient wants to be treated. Many different therapeutic regimens have been used previously, but at present the best treatment is proton-pump inhibitor-based triple therapy, comprising a proton-pump inhibitor plus two drugs out of clarithromycin, a nitroimidazole and amoxycillin. One-week low-dose triple therapy cures 85-95% of infected patients. PMID- 22498903 TI - Economics of Helicobacter pylori eradication therapy. AB - The annual incidence of peptic ulcer disease in developed countries is around one to three per thousand inhabitants. Since the introduction of acid-secretion inhibitors, the indirect costs of this disease, which has a high rate of relapse, have steadily decreased, although direct costs have been increasing. The possibility of healing the patient through Helicobacter pylori eradication has the potential for a huge economic impact considering the long-term cost: benefit ratio. A recent study has shown that H. pylori eradication therapy can save between US$750,000 and US$1,000,000 per year per million inhabitants in western Europe compared to maintenance or episodic therapy. This paper reviews the cost implications of various management strategies for peptic ulcer disease, comparing the cost: benefit ratios of five different treatment regimens. PMID- 22498904 TI - Panel discussion. PMID- 22498899 TI - Axonal mRNA localization and local protein synthesis in nervous system assembly, maintenance and repair. AB - mRNAs can be targeted to specific neuronal subcellular domains, which enables rapid changes in the local proteome through local translation. This mRNA-based mechanism links extrinsic signals to spatially restricted cellular responses and can mediate stimulus-driven adaptive responses such as dendritic plasticity. Local mRNA translation also occurs in growing axons where it can mediate directional responses to guidance signals. Recent profiling studies have revealed that both growing and mature axons possess surprisingly complex and dynamic transcriptomes, thereby suggesting that axonal mRNA localization is highly regulated and has a role in a broad range of processes, a view that is increasingly being supported by new experimental evidence. Here, we review current knowledge on the roles and regulatory mechanisms of axonal mRNA translation and discuss emerging links to axon guidance, survival, regeneration and neurological disorders. PMID- 22498905 TI - Heterogeneity of Helicobacter pylori. AB - Although many physicians view Helicobacter pylori strains as a homogenous groupof organisms, it has become increasingly clear that populations in humans are highly diverse. This heterogeneity can be analyzed at two different levels: genotypic variation among strains and variations in H. pylori populations within an individual host. Genotypic variation includes point mutations in conserved genes (e.g. ureC), variation in the gene order on physical maps, mosaicism in conserved genes (e.g. vacAs1a), non-conserved genes (e.g. cagA) and extragenetic elements (e.g. IS605). Population differences include the observations that humans can be simultaneously infected with two or more H. pylori strains and that a single strain may represent a cluster of closely related organisms (a 'quasispecies'). The presence of multiple organisms within a host may occur as a result of recombination events leading to genetic shift, whereas ongoing mutation within a strain can lead to the formation of quasispecies by genetic drift. Over recent years it has become increasingly clear that observations on the fundamental biology of H. pylori have considerable clinical relevance. Several genotypic markers (e.g. cagA, vacA, s1a and iceA1) are associated with an increased risk of disease. Also, the multiplicity of infection and quasispecies indicates that analysis of a single H. pylori isolate is inaccurate for defining the genotype of H. pylori strains present in a patient. Global assays, such as serology, are more suitable. The aim of this paper is to review the general phenomenon of diversity in H. pylori and to describe particular heterogeneities that are related to clinical outcome. PMID- 22498906 TI - Pathophysiology of duodenal ulcer disease. AB - : Before the discovery of Helicobacter pylori infection some 12 years ago, three major disturbances in gastric physiology had been identified in patients with duodenal ulcer disease. These abnormalities were: impaired acid inhibition of gastrin release from the antral mucosa, increased basal and stimulated acid secretion by the body of the stomach and increased acid load in the duodenum. Some of these abnormalities in gastric function can now be explained by the effects of H. pylori infection. The increased release of gastrin by the antral mucosa in duodenal ulcer patients, for example, can be entirely explained by the effects of this organism. Other abnormalities, however, appear to have a genetic basis or may be due to environmental factors. Much work has been conducted on the relationship between H. pylori and the development of duodenal ulcer disease, and this paper aims to review recent studies in the field and to give an overview of the latest understanding of the pathophysiology of this disease. PMID- 22498907 TI - Selective iron-catalyzed transfer hydrogenation of terminal alkynes. AB - A novel iron-catalyzed transfer hydrogenation of alkynes to the corresponding alkenes applying formic acid as a hydrogen donor is reported. An in situ combination of Fe(BF(4))(2).6H(2)O and tetraphos allows for highly selective hydrogenation of a broad range of aromatic and aliphatic alkynes tolerating different functional groups. PMID- 22498908 TI - Development of recombinant cell line co-expressing mutated Nav1.5, Kir2.1, and hERG for the safety assay of drug candidates. AB - To provide a high-throughput screening method for human ether-a-go-go-gene related gene (hERG) K(+) channel inhibition, a new recombinant cell line, in which single action potential (AP)-induced cell death was produced by gene transfection. Mutated human cardiac Na(+) channel Nav1.5 (IFM/Q3), which shows extremely slow inactivation, and wild-type inward rectifier K(+) channel, Kir2.1, were stably co-expressed in HEK293 cells (IFM/Q3+Kir2.1). In IFM/Q3+Kir2.1, application of single electrical stimulation (ES) elicited a long AP lasting more than 30 s and led cells to die by more than 70%, whereas HEK293 co-transfected with wild-type Nav1.5 and Kir2.1 fully survived. The additional expression of hERG K(+) channels in IFM/Q3+Kir2.1 shortened the duration of evoked AP and thereby markedly reduced the cell death. The treatment of the cells with hERG channel inhibitors such as nifekalant, E-4031, cisapride, terfenadine, and verapamil, recovered the prolonged AP and dose-dependently facilitated cell death upon ES. The EC(50) values to induce the cell death were 3 uM, 19 nM, 17 nM, 74 nM, and 3 uM, respectively, whereas 10 uM nifedipine did not induce cell death. Results indicate the high utility of this cell system for hERG K(+) channel safety assay. PMID- 22498909 TI - Evaluation of a luciferase-based reporter assay as a screen for inhibitors of estrogen-ERalpha-induced proliferation of breast cancer cells. AB - Estrogens, acting through estrogen receptor alpha (ERalpha), stimulate breast cancer proliferation, making ERalpha an attractive drug target. Since 384-well format screens for inhibitors of proliferation can be challenging for some cells, inhibition of luciferase-based reporters is often used as a surrogate end point. To identify novel small-molecule inhibitors of 17beta-estradiol (E(2))-ERalpha stimulated cell proliferation, we established a cell-based screen for inhibitors of E(2)-ERalpha induction of an estrogen response element (ERE)(3)-luciferase reporter. Seventy-five "hits" were evaluated in tiered follow-up assays to identify where hits failed to progress and evaluate their effectiveness as inhibitors of E(2)-ERalpha-induced proliferation of breast cancer cells. Only 8 of 75 hits from the luciferase screen inhibited estrogen-induced proliferation of ERalpha-positive MCF-7 and T47D cells but not control ERalpha-negative MDA-MB-231 cells. Although 12% of compounds inhibited E(2)-ERalpha-stimulated proliferation in only one of the ERalpha-positive cell lines, 40% of compounds were toxic and inhibited growth of all the cell lines, and ~37% exhibited little or no ability to inhibit E(2)-ERalpha-stimulated cell proliferation. Representative compounds were evaluated in more detail, and a lead ERalpha inhibitor was identified. PMID- 22498910 TI - Simultaneous detection of enterovirus 71 and coxsackievirus A16 using dual-colour upconversion luminescent nanoparticles as labels. AB - We highlight a novel fluorescence analysis for sensitive and selective detection of EV-71 and CV-A16 by combining labelling technology based on dual-colour upconversion fluorescence nanoparticles (UCNPs) with magnetic bioseparation and concentration technology based on magnetite nanoparticles (MNPs). PMID- 22498911 TI - Real-time MRI of speaking at a resolution of 33 ms: undersampled radial FLASH with nonlinear inverse reconstruction. AB - Dynamic MRI studies of the upper airway during speaking, singing or swallowing are complicated by the need for high temporal resolution and the presence of air tissue interfaces that may give rise to image artifacts such as signal void and geometric distortions. This work exploits a recently developed real-time MRI technique to address these challenges for monitoring speech production at 3 T. The method combines a short-echo time radial FLASH MRI sequence (pulse repetition time/echo time = 2.22/1.44 ms; flip angle 5 degrees ) with pronounced undersampling (15 radial spokes per image) and image reconstruction by regularized nonlinear inversion. The resulting serial images at 1.5 mm in-plane resolution and 33.3 ms acquisition time are free of motion or susceptibility artifacts. This application focuses on a dynamic visualization of the main articulators during natural speech production (Standard Modern German). Respective real-time MRI movies at 30 frames per second clearly demonstrate the spatiotemporal coordination of lips, tongue, velum, and larynx for generating vowels, consonants, and coarticulations. The quantitative results for individual phonetic events are in agreement with previous non-MRI findings. PMID- 22498912 TI - Solvent free chemical oxidative polymerization as a universal method for the synthesis of ultra high molecular weight conjugated polymers based on 3,4 propylenedioxythiophenes. AB - In this communication, we report on a solvent free chemical oxidative polymerization route for the monomers based on 3,4-propylenedioxythiophenes wherein the process is applicable to both solid as well as liquid monomers and results in the bulk synthesis of ultra high molecular weight polymers. PMID- 22498913 TI - Common extensor tendon thickness measurements at the radiocapitellar region in diagnosis of lateral elbow tendinopathy. AB - PURPOSE: The aim of this study was to determine the value of measuring common extensor tendon (CET) thickness at the radiocapitellar and capitellar regions with qualitative ultrasonographic findings in the diagnosis of lateral elbow tendinopathy. MATERIALS AND METHODS: The study included 164 lateral elbow tendinopathy patients (84 bilateral, 80 unilateral) matched by age, gender, and body mass index with 80 normal subjects. CET was examined using gray-scale and Doppler ultrasonography for tendinopathy, and tendon thickness was measured at two landmark locations: capitellar and radiocapitellar. RESULTS: In tendinopathy, tendon thickness including the dominant capitellar region, increased in every measured location. In the capitellar region of the dominant elbow, the cut-off thickness was 5.15 mm, and in the radiocapitellar region, this value was 4.05 mm. For the non-dominant elbow, the cut-off thickness was 4.61 mm, whereas in the radiocapitellar region, this value was 3.51 mm. The greatest risk of tendinopathy was at the radiocapitellar region on the dominant side. The overall sensitivity and specificity of gray-scale findings were 54% and 88%, respectively, and the addition of Doppler readings did not alter these values. When capitellar measurements were added, the values increased to 79% and 80% for sensitivity and specificity, respectively. These values further increased to 93% and 91%, respectively, when radiocapitellar measurements were included. CONCLUSION: A second tendon thickness measurement at the radiocapitellar region of CET in addition to the capitellar region is recommended on the grounds that combined qualitative and quantitative evaluation of CET increases the diagnostic per- formance of ultrasonography in lateral elbow tendinopathy. PMID- 22498914 TI - Structural, elastic, magnetic and electronic properties of 4d perovskite CaTcO3: a DFT+U investigation. AB - The structural, elastic, magnetic and electronic properties of 4d high Neel temperature perovskite (Pv) CaTcO(3) have been studied using density functional theory plus the Hubbard U (DFT+U) method. The degree of correlations of CaTcO(3) is determined with a reasonable value of U. The compound is found to be an indirect band gap semiconductor with G-type antiferromagnetic ordering and large superexchange interactions. Large anisotropic compression behavior is found that is much alike the case of Pv CaIrO(3) reported by recent high pressure experiment. The b and c axes decrease linearly with pressure whereas the a axis nearly keeps constant and even slightly expands after ~23 GPa. Finally, we predict the single crystal elastic constants and investigate the polycrystalline elastic properties. PMID- 22498915 TI - Palladium-catalyzed monoselective C-H borylation of acetanilides under acidic conditions. AB - A practical Pd-catalyzed reaction was developed to achieve C-H activation/C-B cross-coupling of acetanilides under acidic conditions. The new reaction shows a good functional group tolerance and an exclusive mono-selectivity. This C-H borylation method may provide a generally applicable route for the conversion of C-H moieties into many other types of bonds. PMID- 22498916 TI - Deceased-donor kidney perfusate and urine biomarkers for kidney allograft outcomes: a systematic review. AB - BACKGROUND: Accurate and reliable assessment of kidney quality before transplantation is needed to predict recipient outcomes and to optimize management and allocation of the allograft. The aim of this study was to systematically review the published literature on biomarkers in two mediums (the perfusate from deceased-donor kidneys receiving machine perfusion and deceased donor urine) that were evaluated for their possible association with outcomes after kidney transplantation. METHODS: We searched the Ovid Medline and Scopus databases using broad keywords related to deceased-donor biomarkers in kidney transplantation (limited to humans and the English language). Studies were included if they involved deceased-donor kidneys, measured perfusate or urine biomarkers and studied a possible relationship between biomarker concentrations and kidney allograft outcomes. Each included article was assessed for methodological quality. RESULTS: Of 1430 abstracts screened, 29 studies met the inclusion criteria. Of these, 23 were studies of perfusate (16 biomarkers examined) and 6 were studies of urine (18 biomarkers examined). Only 3 studies (two perfusate) met the criteria of 'good' quality and only 12 were published since 2000. Perfusate lactate dehydrogenase, glutathione-S-transferase (GST) and aspartate transaminase were all found to be significantly associated with delayed graft function in a majority of their respective studies (6/9, 4/6 and 2/2 studies, respectively). Urine neutrophil gelatinase-associated lipocalin, GST, Trolox-equivalent antioxidant capacity and kidney injury molecule-1 were found to be significantly associated with allograft outcomes in single studies that examined diverse end points. CONCLUSION: Higher quality studies are needed to investigate modern kidney injury biomarkers, to validate novel biomarkers in larger donor populations and to determine the incremental predictive value of biomarkers over traditional clinical variables. PMID- 22498917 TI - Population screening for chronic kidney disease: a survey involving 38,721 Brazilians. AB - BACKGROUND: It is known that chronic kidney disease (CKD) is continuously increasing all over the world, but the available numbers of affected subjects are mostly collected from renal replacement therapy services and they correspond to individuals with end-stage renal disease. The aim of the present study was to diagnose CKD in its earliest stages in the general population based on detection of proteinuria. METHODS: In public prevention campaigns, from 2005 to 2010, 38 721 inhabitants were evaluated in the state of Sao Paulo (Brazil). Screening procedures included a dipstick test, blood pressure measurement and application of a medical questionnaire. RESULTS: In the whole population, urine samples of 37 771 individuals (mean age: 44.59 + 21.70, 55.74% females) were evaluated, 7.3% presented proteinuria (1+ or more) in the screening test and 85.5% of them had no previous knowledge of this urinary abnormality. Those individuals were referred for further clinical evaluation in order to confirm the detected alterations. Considering being diabetic and/or hypertensive as important risk factors for CKD, it was observed that they corresponded to 9.7 and 28.4% of the population screened for proteinuria, respectively. Newly detected cases of possible CKD, diabetes and hypertension corresponded to 6.2, 0.3 and 6.5%, respectively. CONCLUSIONS: This initiative provided information on proteinuria and possible cases of CKD based on a large sampling of the Brazilian population. Proteinuria was detected in 7.3% of these individuals, and such prevalence is similar to that previously described in developed countries. PMID- 22498918 TI - Twist overexpression promoted epithelial-to-mesenchymal transition of human peritoneal mesothelial cells under high glucose. AB - BACKGROUND: Long-term peritoneal dialysis (PD) results in functional and structural alterations of the peritoneal membrane. Previous studies have suggested that high glucose (HG) could induce transdifferentiation of peritoneal mesothelial cells into myofibroblasts, but the molecular mechanisms of HG-induced epithelial-to-mesenchymal transition (EMT) of human peritoneal mesothelial cells (HPMCs) are unclear. This study was undertaken to elucidate the effects and mechanisms of Twist on HG-induced EMT of HPMCs. METHODS: HPMCs were exposed to 5.6 mM glucose [normal glucose (NG)], 50 mM glucose (HG) or 50 mM glucose with Si Twist or pcDNA3.1-Twist. Western blot and immuocytochemistry were performed to determine Twist, E-cadherin and alpha-smooth muscle actin (alpha-SMA) protein expression. MMP2 and MMP9 were detected by zymography. Rats were daily instilled with PD fluid and lipopolysaccharide (LPS) or sodium chloride during 6 weeks. Histological analyses were carried out in parietal peritoneum. Twist was detected by western blotting. RESULTS: Twist and alpha-SMA protein and immuocytochemistry were significantly increased in HG-conditioned media compared to NG media. E cadherin protein was lower in pcDNA3.1-Twist-transfected HPMCs compared to pcDNA3.1 cells. Twist protein was upregulated 12 h after HG stimulation. MMP9 was increased in pcDNA3.1-Twist-transfected HPMCs compared to pcDNA3.1 cells. Exposure of rat peritoneum to PD fluid and LPS resulted in an increase of extracellular matrix deposition. Twist and alpha-SMA were stained in the PD fluid group and compared to the control group. Twist protein was significantly increased in the PD group. CONCLUSIONS: In conclusion, HG-induced Twist expression might contribute to EMT of HPMCs. Twist may control EMT of HPMCs by regulating MMP9. PMID- 22498919 TI - Novel Au/La2O3 and Au/La2O2SO4 catalysts for the water-gas shift reaction prepared via an anion adsorption method. AB - An anion-adsorption technique in which [Au(OH)(4)](-) is preferentially adsorbed onto La(2)O(3) and La(2)O(2)SO(4) surfaces is used to prepare two catalysts active for the low-temperature water-gas shift reaction. PMID- 22498920 TI - Simultaneous enhanced photon capture and carrier generation in Si solar cells using Ge quantum dot photonic nanocrystals. AB - We propose a novel solar cell structure with photonic nanocrystals coupled to quantum dots (QDs) for advanced management of photons and carriers. The photonic nanocrystals at the surface create an extra interaction between the photons and the QDs, which promotes light trapping. Photo-generated carriers can be efficiently transported by preparing vertically aligned QDs with electronic coupling. Implementation of the proposed structure was realized in crystalline Si solar cells with Ge QDs by development of a simple and practical formation method based on a wet chemical process without any lithography techniques. The wet process utilizes a periodically modulated etching rate induced by self-organized Ge QDs. The effectiveness of the proposed solar cell was demonstrated by the marked increase of the absolute conversion efficiency when compared with the control crystalline Si solar cells. It is found that light trapping by the photonic nanocrystals has a larger contribution to the efficiency improvement than the contributions from the carrier transport of the vertically aligned QDs. PMID- 22498921 TI - Three-dimensional nano-foam of few-layer graphene grown by CVD for DSSC. AB - We report a robust and direct route to fabricate a three-dimensional nano-foam of few-layer graphene (3D-NFG) with large area coverage via a chemical vapor deposition (CVD) technique. Pyrolysis of polymer/nickel precursor film under a hydrogen environment, simply prepared by spin-coating, leads to the creation of nano-foam in the film and the reduction process of nickel ions. Carbonized-C and the nickel nano-frame formed from the pyrolysis are used as a solid carbon source and as a catalyst for the growth of graphene under CVD conditions, respectively. We investigate the use of 3D-NFG, with the advantage of large surface area and high conductivity, as an alternative to the Pt counter electrode material in dye sensitized solar cells. The excellent properties of 3D-NFG, fabricated in this simple and direct manner, suggest a great potential for interconnected graphene networks in electronic devices and photocatalytic sensors as well as in energy related materials. PMID- 22498922 TI - A novel strategy for deciphering dynamic conservation of gene expression relationship. PMID- 22498923 TI - Real-time moment-to-moment emotional responses to narrative and informational breast cancer videos in African American women. AB - In a randomized experiment using moment-to-moment audience analysis methods, we compared women's emotional responses with a narrative versus informational breast cancer video. Both videos communicated three key messages about breast cancer: (i) understand your breast cancer risk, (ii) talk openly about breast cancer and (iii) get regular mammograms. A community-based convenience sample of African American women (n = 59) used a hand-held audience response device to report the intensity of their emotional reaction while watching one of the two videos. Strong emotions were more likely to correspond to contextual information about characters in the video and less likely to correspond to health content among women who watched the narrative video compared with those who watched the informational video (P < 0.05). Women who watched the narrative video were more likely to report feeling attentive (41 versus 28%, respectively), inspired (54 versus 34%) and proud (30 versus 18%) and less likely to feel upset (8 versus 16%) (all P < 0.05). Women in the narrative group were more likely to mention women's personal stories than health information in open-ended recall questions, but this did not detract from obtaining health information. Findings suggest that stories can be used to communicate health information without distracting from core health content. PMID- 22498924 TI - Efficacy and acceptability of an Internet platform to improve the learning of nutritional knowledge in children: the ETIOBE Mates. AB - Possessing sufficient nutritional knowledge is a necessary component in the prevention and treatment of obesity. A solid understanding of nutrition can help people make appropriate food selections and can also help correct irrational ideas or myths people may believe about food. It is a challenge to provide this information to children in ways that are exciting. Thus, we propose an online video game platform to deliver the information. The objective of this study was to study the efficacy and acceptability of an online game called 'ETIOBE Mates' that was designed to improve children's nutritional knowledge; furthermore, we compare it with the traditional paper-pencil mode of information delivery. A sample of 228 children participated in the study. Participants were divided into two groups: an experimental group (who used ETIOBE Mates) and a control group (who were given a pamphlet). Both groups increased their scores for nutritional knowledge. The interaction between group * time was also statistically significant; it indicated that acquisition of nutritional knowledge was superior in the experimental group. The children considered the serious games platform to be a useful medium for improving their nutritional knowledge. Online games can be an effective method of delivery for preventive and treatment tasks that are otherwise tedious for children. PMID- 22498925 TI - Development of an efficient method for genotyping at the gd locus in NC/Sgn mice based on PCR-RFLP analysis. AB - Growth deficit (gd) is a recessive mutation that occurs spontaneously in the inbred NC/Sgn mouse strain. Because homozygotes (gd/gd) of both sexes are sterile, they must be produced by mating putative heterozygous carriers (+/gd) whose phenotypes are essentially the same as those of wild-type +/+ mice. The objectives of this study were to develop an efficient method that distinguished a gd allele from a wild-type allele and, if possible, to identify nucleotide substitutions responsible for the gd mutation. The location of the gd locus was estimated to be at 58.3 Mbp on chromosome 4, over which Musk is located. An A-to G base substitution, which resulted in an M826V amino acid exchange, was identified within a tyrosine kinase domain of Musk. This base substitution disrupted a recognition site for NlaIII; this allowed for discriminating the gd allele from the wild-type allele using PCR-RFLP analysis. When 130 (C57BL/6J * NC/Sgn-gd) F(2) mice were genotyped by PCR-RFLP analysis, all 32 growth-retarded F(2) mice were judged to have the gd/gd genotype. Musk mutations are known to cause congenital myasthenia, which is accompanied by growth retardation, postnatal lethality, and development of a hunchback. These were the typical phenotypes of gd/gd mutants. Although we cannot rule out the possibility that the neighboring genes around the Musk locus are related to the gd phenotype, gd could possibly be classified as a mutant allele of Musk. PMID- 22498926 TI - Efficacy of omeprazole paste in the prevention of gastric ulcers in 2 years old Thoroughbreds. AB - Prevalence of equine gastric ulcer syndrome in 85 young Thoroughbreds was investigated. The presence of gastric ulcers was confirmed in 27.1% (23/85) of the horses by endoscopic examination. Sixty-two horses without gastric ulcers were allocated randomly to either the treated group (31 horses) or sham-dosed control group (31 horses) in order to investigate the efficacy of omeprazole oral paste in the prevention of gastric ulcers. At the second endoscopic examination conducted after 28 days of administration, only 1 horse in the treated group developed gastric ulcers, while 12 horses developed gastric ulcers in the control group. Based on these data, the efficacy of omeprazole in prevention of equine gastric ulcers in young Thoroughbreds during the training period was confirmed. PMID- 22498927 TI - Spironolactone, but not eplerenone, impairs glucose tolerance in a rat model of metabolic syndrome. AB - Although some clinical studies have suggested that spironolactone (SPL), a mineralocorticoid receptor (MR) antagonist, appears to increase the blood glucose levels, experimental studies have not supported this notion. Here, we investigated the effect of SPL on blood glucose levels in SHR/NDmcr-cp(cp/cp) (ND) rats, an animal model of metabolic syndrome, in comparison with that of eplerenone (EPL), another MR antagonist. At the same dose of 100 mg/kg, SPL and EPL increased the urinary sodium-to-potassium ratio to a comparable extent, indicating that both agents have similar renal MR antagonistic efficacy in ND rats. Interestingly, SPL but not EPL significantly increased the level of blood glucose. The oral glucose tolerance test revealed that treatment with SPL led to glucose intolerance. The levels of serum insulin and adiponectin, regulators of the blood glucose level, were virtually unaffected by treatment with SPL. On the other hand, SPL induced a marked increase in the blood level of aldosterone, known to be a risk factor for insulin resistance. These results demonstrate that in comparison with EPL, SPL characteristically impairs glucose tolerance in an animal model of metabolic syndrome, in association with a higher blood level of aldosterone. PMID- 22498928 TI - Rapid identification of Mycoplasma pulmonis isolated from laboratory mice and rats using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. AB - Mycoplasma species identification is based on biochemical, immunological, and molecular methods that require several days for accurate identification. Matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a novel method for identification of bacteria and has recently been introduced into the clinical microbiology laboratory as a rapid and accurate technique. This method allows a characteristic mass spectral fingerprint to be obtained from whole inactivated mycoplasmal cells. In this study, we evaluated the performance of the MALDI-TOF MS for the identification of Mycoplasma by comparison with standard sequence analysis of 16S rRNA. We developed the first database of MALDI-TOF MS profiles of Mycoplasma species, containing Mycoplasma pulmonis, M. arthritidis, and M. neurolyticum, which are the most common pathogens in mice and/or rats, and species-specific spectra were recorded. Using the database, 6 clinical isolates were identified. Six tracheal swabs from 4 mice and 2 rats were cultured on PPLO agar for 4 to 7 days, and the colonies were directly applied to analyze the protein profiles. Five strains were identified as M. pulmonis, and 1 strain from a mouse was identified as M. neurolyticum (spectral scores were >2.00); the results were consistent with the results of the 16S rRNA gene sequence analysis (homologies>97.0%). These data indicate that MALDI-TOF MS can be used as a clearly rapid, accurate, and cost-effective method for the identification of M. pulmonis isolates, and this system may represent a serious alternative for clinical laboratories to identify Mycoplasma species. PMID- 22498929 TI - Augmented activity of the pelvic nerve afferent mediated by TRP channels in dextran sulfate sodium (DSS)-induced colitis of rats. AB - Enteritis has been recognized as a major symptom in domestic animals and human patients suffering from feed and food poisonings. The aim of the present study was to clarify the excitatory mechanism of the pelvic nerve afferent which may influence the occurrence of enteritis in response to nociceptive chemical stimuli of the colon in normal and abnormal rats with colitis induced by dextran sulfate sodium (DSS). The pelvic nerve afferent activity was markedly increased by colonic instillation of solution (0.5 ml) of acetic acid (5-25%) and capsaicin (100 MUg/ml). The nerve activity was augmented by colonic instillation of capsaicin to a greater extent in rats with DSS-induced colitis than in normal control rats. This augmented activity by capsaicin was more prominent at one day (DSS-1) than at 8 day (DSS-8) after the administration of DSS. The increased nerve activity caused by capsaicin in DSS-1 and DSS-8 was significantly inhibited by pretreatment with ruthenium red, which is a nonselective inhibitor of TRP channels of unmyelinated C-fibers (nociceptors). In conclusion, it was elucidated that the nociceptive function of the pelvic nerve was largely elevated at one day after DSS-induced colitis and such increased function was mostly mediated by TRP channels. PMID- 22498930 TI - Selective apoptotic effect of Zelkova serrata twig extract on mouth epidermoid carcinoma through p53 activation. AB - Apoptosis or programmed cell death plays an essential role in chemotherapy induced tumor cell killing, and inducers of apoptosis are commonly used in cancer therapy. Treatment with Zelkova serrata extracts was performed in human gingival fibroblast (HGF), mouth epidermoid carcinoma cell (KB), lower gingival squamous cancer cell (YD38) and tongue mucoepidermoid carcinoma cells (YD15). We observed that extract prepared from Zelkova serrata twig selectively inhibited proliferation of various oral cancer cells, but not normal gingival fibroblasts, in a dose-dependent manner. Caspase-8-mediated apoptosis was induced by treatment with the extract only in mouth epidermoid carcinoma and not in other types of cancer cells, including lower gingival squamous cell carcinoma. The selective apoptotic effect of Zelkova serrata twig extract in mouth epidermoid carcinoma was dependent on normal p53 status. Apoptosis was not remarkably induced by treatment with the extract in either lower gingival squamous or tongue mucoepidermoid carcinoma cells, both of which contain abnormalities of p53. Upon treatment with Zelkova serrata twig extract, mouth epidermoid carcinoma cells accumulated in S phase by activation of p21. These data indicate that Zelkova serrata twig extract exerted a cancer type-specific, p53-dependent apoptotic effect and disturbed the cell cycle, which suggests that herbal medicine could be a treatment for specific types of cancers. PMID- 22498931 TI - Sensor specific imaging of proteomic Zn2+ with zinquin and TSQ after cellular exposure to N-ethylmaleimide. AB - The impact of the thiol binding reagent N-ethylmaleimide (NEM) on proteomic Zn(2+) availability was investigated in rat glioma cells. Zinquin (ZQ) or TSQ, two related fluorescent sensors, were used to observe reactive Zn(2+). Control cells contained proteomic Zn(2+) but no detectable low molecular weight (LMW) Zn(2+). With either sensor, basal cellular fluorescence emission centered near 470 nm, indicative of sensor-Zn-proteins. ZQ sequestered 13% of proteomic Zn(2+) as Zn(ZQ)(2); TSQ reacted only with the Zn-proteome. NEM (100 MUM) abolished LMW thiols, including glutathione (GSH) and lowered proteomic sulfhydryl content about 30%. In ZQ-treated cells, NEM exposure enhanced fluorescent intensity and the formation of Zn(ZQ)(2) (lambda(MAX), 492 nm). Cells incubated with TSQ and NEM also displayed increased fluorescence without a spectral shift in wavelength maximum, consistent with increased formation of TSQ-Zn-protein adducts but not Zn(TSQ)(2). In neither experiment was Zn(2+) lost from cells. NEM altered Zn(2+) accessibility to sensors in membrane-nuclear and cytosolic fractions, but Zn(ZQ)(2) was only generated in the cytosol. Similar results were obtained when cell supernatant replaced cells. In contrast, when isolated proteome was reacted with ZQ and 100 MUM NEM in the absence of GSH, 70% of the proteomic thiols underwent reaction. As a consequence, most of the ZQ-Zn-protein adducts were converted to Zn(ZQ)(2). Substituting TSQ for ZQ, only increased TSQ-Zn-proteins were observed. Evidently, the results of imaging cells with Zn(2+) sensors are dependent upon the specific chemical properties of the sensors and can only be understood after detailed chemical analysis. PMID- 22498933 TI - Crystal structure of DeSI-1, a novel deSUMOylase belonging to a putative isopeptidase superfamily. AB - Post-translational modification by small ubiquitin-like modifier (SUMO) can be reversed by sentrin/SUMO-specific proteases (SENPs), the first known class of deSUMOylase. Recently, we identified a new deSUMOylating enzyme DeSI-1, which is distinct from SENPs and belongs to the putative deubiquitinating isopeptidase PPPDE superfamily. Herein, we report the crystal structure of DeSI-1, revealing that this enzyme forms a homodimer and that the groove between the two subunits is the active site harboring two absolutely conserved cysteine and histidine residues that form a catalytic dyad. We also show that DeSI-1 exhibits an extremely low endopeptidase activity toward precursor forms of SUMO-1 and SUMO-2, unlike SENPs. PMID- 22498934 TI - Blue-shifting the monomer and excimer phosphorescence of tridentate cyclometallated platinum(II) complexes for optimal white-light OLEDs. AB - By using a tridentate N^C^N-coordinating ligand, the luminescence of a cyclometallated Pt(II) complex can be shifted into the blue region, without the problematic drop-off in quantum yield observed for bidentate analogues. The combination of blue-shifted monomer and excimer allows white-emitting OLEDs with high colour rendering index to be produced. PMID- 22498935 TI - Molecular characterization of endometrial cancer: a correlative study assessing microsatellite instability, MLH1 hypermethylation, DNA mismatch repair protein expression, and PTEN, PIK3CA, KRAS, and BRAF mutation analysis. AB - Endometrial cancer is associated with numeric and structural chromosomal abnormalities, microsatellite instability (MSI), and alterations that activate oncogenes and inactivate tumor suppressor genes. The aim of this study was to characterize a set of endometrial cancers using multiple molecular genetic and immunohistochemical techniques. Ninety-six cases were examined for genomic alterations by MSI, MLH1 promoter hypermethylation, p53 and mismatch repair protein expression (MLH1, MSH2, MSH6, PMS2), and PTEN, PIK3CA, KRAS, and BRAF mutation analysis. At least 1 alteration was identified in 48 of 87 (55%) specimens tested for PTEN, making it the most common abnormality in this study. A PIK3CA alteration was observed in 16 (17%) specimens. Twenty-nine of 94 (31%) MSI tested tumors exhibited an MSI-H phenotype. Of the 29 MSI-H cases, 24 (83%) were positive for methylation of the MLH1 promoter region. Twenty-three (82%) of the 28 MSI-H cases with immunohistochemistry results showed loss of expression of MLH1/PMS2 (n=19), MSH2/MSH6 (n=2), or MSH6 only (n=2). Of the 19 MSI-H cases with loss of MLH1/PMS2 on immunohistochemistry, 18 were positive, and 1 was equivocal for MLH1 promoter hypermethylation. Twelve of 94 cases (13%) analyzed for KRAS mutations were found to have a mutation. No BRAF V600E mutations were indentified. This study provides a comprehensive molecular genetic analysis of commonly analyzed targets in a large cohort of endometrial cancers. PMID- 22498936 TI - Papillary syncytial metaplasia associated with endometrial breakdown exhibits an immunophenotype that overlaps with uterine serous carcinoma. AB - Uterine serous carcinoma (USC) is an aggressive variant of Type 2 endometrial carcinoma, which in most cases exhibits, at least focally, a papillary architecture. Occasionally, especially in small biopsy specimens, it may be difficult to distinguish between USC and a variety of metaplastic or reactive processes. In particular, papillary syncytial metaplasia (PSM), as a result of endometrial breakdown, may be confused with USC or its precursor serous endometrial intraepithelial carcinoma. In such cases, immunohistochemistry is often undertaken, the panel of markers usually including estrogen receptor (ER), p53, p16, and MIB1. The expected immunoprofile of USC is ER negative, p53 and p16 positive, and a high MIB1 proliferation index, although studies have shown that significant numbers of cases deviate from this immunophenotype. With regard to the aforementioned markers, PSM has not been studied extensively, but intuitively, the expected immunophenotype would be ER positive, p53 and p16 negative, and a low MIB1 proliferation index. After 2 index cases in which breaking down menstrual endometrium with florid PSM was misdiagnosed on an endometrial biopsy as USC or suspected USC, in part due to the observed immunophenotype, we studied the expression of ER, p53, p16, MIB1, and HMGA2 (a recently described useful marker of USC) in 10 further cases of PSM associated with endometrial breakdown. We illustrate that compared with a nonbreaking down endometrium, PSM is characterized by a decreased expression of ER and an increased expression of p53 (although still wild-type staining) and p16, the latter marker typically being diffusely positive. HMGA2 is negative, and there is a low MIB1 proliferation index. In cases of PSM, which are morphologically problematic, the immunophenotype may further heighten the suspicion of serous malignancy and potentially result in a misdiagnosis. PMID- 22498938 TI - The value of additional pathology comments indicating suspicion of adenocarcinoma among women diagnosed preoperatively with complex atypical endometrial hyperplasia. AB - Over 40% of women with a preoperative diagnosis of complex atypical hyperplasia (CAH) will have endometrial cancer at hysterectomy. CAH diagnoses are often qualified by comments indicating suspicion of cancer. We examine whether these comments correlate with cancer found at hysterectomy. Pathology reports for 824 women with CAH diagnoses who underwent hysterectomy were reviewed to identify those qualified by comments indicating concern for cancer. The rate of cancer, severity of disease, and effects of endometrial sampling method and age were determined. Comments indicating suspicion of cancer qualified 219 of 824 (27%) CAH diagnoses and were associated with a significantly higher cancer rate at hysterectomy (69% versus 40%; P<0.0001), regardless of whether sampling consisted of curettage or biopsy. Cancer severity correlated independently with age. Comments indicating concern for underlying cancer frequently qualify CAH diagnoses and are associated with a high likelihood of cancer and with more extensive disease, especially for older women. PMID- 22498937 TI - HER2/neu as a potential target for immunotherapy in gynecologic carcinosarcomas. AB - Carcinosarcomas of the female genital tract are rare tumors with an aggressive clinical behavior. Trastuzumab, a humanized monoclonal antibody, acts by binding to HER2/neu extracellular domain and exhibits therapeutic efficacy in HER2/neu overexpressing cancers. Two uterine carcinosarcomas (UMMT-ARK-1, UMMT-ARK-2) and 2 ovarian carcinosarcomas (OMMT-ARK-1, OMMT-ARK-2) were established as primary tumor cell lines in vitro and evaluated for HER2/neu expression by immunohistochemistry, fluorescent in situ hybridization analysis, quantitative real-time polymerase chain reaction, and for membrane-bound complement regulatory proteins CD46, CD55, and CD59 by flow cytometry. Sensitivity to trastuzumab dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity was studied in 5-hr chromium release assays. HER2/neu expression was demonstrated in OMMT-ARK-1 and OMMT-ARK-2. OMMT-ARK-2 demonstrated an amplification of the c erbB2 gene by fluorescent in situ hybridization analysis and a high sensitivity to ADCC (mean killing, 45.6%; range, 32.3%-72.6%). A lower level of killing was detected against the fluorescent in situ hybridization analysis-negative OMMT-ARK 1 cell line (mean, 26.5%; range, 21.0%-31.8%). CD46, CD55, and CD59 membrane bound complement regulatory proteins were expressed at high levels in all primary mixed mullerian tumor cell lines, and all these tumors were found to be highly resistant to complement-dependent cytotoxicity with or without trastuzumab. Addition of untreated and heat-inactivated plasma did not significantly decrease ADCC against OMMT-ARK-2 cell line, suggesting that while the cell line is highly resistant to complement, irrelevant IgG does not significantly alter the ability of trastuzumab to mediate ADCC. Our results suggest that HER2/neu may represent a novel target for the immunotherapy of a subset of human carcinosarcomas refractory to salvage chemotherapy. PMID- 22498939 TI - Expression of angiotensin II receptor-like 1 in the placentas of pregnancy induced hypertension. AB - Angiotensin II receptor-like 1 (APJ), a G protein-coupled receptor that was identified as a homologue of angiotensin II type 1 (AT1) receptor, exerts antagonistic effects on AT1-mediated vasoconstriction. Studies on pregnancy induced hypertension (PIH) revealed aberrant activation of AT1 downstream signaling. In contrast, little is known about APJ in the pathophysiology of human pregnancy. In this study, we investigated APJ expression in normal human and PIH placentas. mRNAs were extracted from 50 placental villous tissues of 18 cases with severe PIH (8 late-onset, 4 early-onset, and 6 superimposed PIH) and 32 control pregnancies (including 6 preterm cases). Histopathologic studies were conducted using paraffin-embedded placental tissues from 12 control placentas (from 23 to 39 wk) and 23 PIH placentas (from 24 to 41 wk). Reverse transcriptase polymerase chain reaction showed that APJ was cooperatively expressed with its ligand apelin and AT1 in controls and in late-onset PIH placentas but was significantly downregulated in early-onset PIH placentas with poor fetal growth. Quantitative reverse transcriptase-polymerase chain reaction analysis revealed upregulated APJ in late-onset PIH placentas but significantly downregulated APJ in early-onset PIH. In immunohistochemical staining, APJ was detected strongly in villous capillary endothelial cells and trophoblasts of late-onset PIH placentas. In contrast, APJ was poorly stained in endothelial cells of hypoplastic villi of early-onset PIH placentas. Collective data indicate that the apelin-APJ system is involved in fetoplacental circulation during human pregnancy. Impaired APJ expression in early-onset PIH placentas may reflect an aggravated placental condition with poor fetal growth. PMID- 22498940 TI - An unusual uterine tumor with signet ring cell features. AB - In 2004, a 56-year-old woman was diagnosed with Stage IA follicular lymphoma in a cervical lymph node biopsy. The patient experienced total remission after local radiation therapy. In 2009, a control computed tomography scan evidenced a pelvic mass, prompting total hysterectomy. The latter harbored a 4.8-cm intramural uterine tumor corresponding to a mostly diffuse and focally nodular proliferation of medium to large cells, with extensive, periodic acid-Schiff negative, signet ring cell changes, and a pan-keratin negative, CD20+, CD10+, Bcl2+, Bcl6+ immunophenotype. Molecular genetic studies showed the same clonal IGH gene rearrangement in the lymph node and the uterus, establishing the uterine tumor as a relapse of the preceding follicular lymphoma, although no signet ring cells were evidenced at presentation. Uterine localization of lymphomas is rare, and lymphomas with signet ring cell features are uncommon. This exceptional case exemplifies a diagnostically challenging situation and expands the differential diagnosis of uterine neoplasms displaying signet ring cell morphology. PMID- 22498941 TI - Re: "Forde GK et al. A quality process of lymph node evaluation in endometrial cancer. Int J Gyn Pathol 2011;30(4):335-339". PMID- 22498942 TI - Validation of an algorithm for the diagnosis of serous tubal intraepithelial carcinoma. AB - It has been reported that the diagnosis of serous tubal intraepithelial carcinoma (STIC) is not optimally reproducible on the basis of only histologic assessment. Recently, we reported that the use of a diagnostic algorithm that combines histologic features and coordinate immunohistochemical expression of p53 and Ki 67 substantially improves reproducibility of the diagnosis. The goal of the current study was to validate this algorithm by testing a group of 6 gynecologic pathologists who had not participated in the development of the algorithm (3 faculty and 3 fellows) but who were trained in its use by referring to a website designed for the purpose. They then reviewed a set of microscopic slides, which contained 41 mucosal lesions of the fallopian tube. Overall consensus (>=4 of 6 pathologists) for the 4 categories of STIC, serous tubal intraepithelial lesion (our atypical intermediate category), p53 signature, and normal/reactive was achieved in 76% of the lesions, with no consensus in 24%. Combining diagnoses into 2 categories (STIC versus non-STIC) resulted in an overall consensus of 93% and no consensus in 7%. The kappa value for STIC versus non-STIC among all 6 observers was also high at 0.67 and did not significantly differ, whether for faculty (kappa=0.66) or fellows (kappa=0.60). These findings confirm the reproducibility of this algorithm by a group of gynecologic pathologists who were trained on a website for that purpose. Accordingly, we recommend its use in research studies. Before applying it to routine clinical practice, the algorithm should be evaluated by general surgical pathologists in a community setting. PMID- 22498943 TI - Aberrant expression of the mammalian target of rapamycin, hypoxia-inducible factor-1alpha, and glucose transporter 1 in the development of ovarian clear-cell adenocarcinoma. AB - Ovarian clear-cell adenocarcinoma (CCA) is known to be a type of cancer in humans with a high frequency of expression of the mammalian target of rapamycin (mTOR), hypoxia-inducible factor-1 (HIF-1), and glucose transporter 1 (Glut1). In this study, we aimed to determine how these alterations contribute to tumor development of CCAs. Immunohistochemical expressions of phosphorylated-mTOR (p mTOR), HIF-1alpha, and Glut1 were analyzed in 36 CCAs and 60 coexistent putative precursor lesions: 19 nonatypical and 16 atypical endometriotic lesions, and 11 benign and 14 borderline clear-cell adenofibroma (CCAF) components. Twenty-one cases with solitary endometriosis were also examined. The frequencies of immunopositivity for p-mTOR (in cytoplasm or nucleus), HIF-1alpha (in nucleus), and Glut1 increased in accordance with higher cytological atypia in the putative precursors: 58%, 5%, and 16% in the nonatypical endometriosis; 63%, 37%, and 50% in the atypical endometriosis; 77%, 95%, and 95% in the endometriosis-associated CCAs; 27%, 0%, and 0% in the benign-CCAF components; 64%, 79%, and 43% in the borderline CCAF components; and 71%, 100%, and 93% in the CCAF-associated CCAs, respectively. p-mTOR, HIF-1alpha (in the nucleus), and Glut1 were positive in 10%, 5%, and 19% of the solitary endometriosis, respectively. In the putative precursor lesions coexisting with CCA, a strong correlation in the expression between p-mTOR and HIF-1alpha and between HIF-1alpha and Glut1 was identified. Expressions of p-mTOR, HIF-1alpha, and Glut1 have already been evident in the putative precursor lesions of CCA, and these alterations cumulatively occur in the development of ovarian CCA. PMID- 22498944 TI - A low-grade ovarian carcinoma case with coincident LOH of PTCH1 and BRCA1, and a mutation in BRCA1. AB - We report a case of a 53-year-old woman with Grade 1 serous cystadenocarcinoma on her left ovary and metastatic serous adenocarcinoma on her right ovary. Serous carcinoma is the most common type of ovarian cancer, representing approximately half of all cases. Because of positive family history, the patient was referred for BRCA1/2 screening. Germline BRCA1 mutation c.676delT (p.C226VfsX8) was found, and in tumor tissue the normal allele was lost. Tumor tissue also had loss of heterozygosity in the PTCH1 gene, one of the major members of the Hedgehog-Gli (Hh-Gli) pathway. Gene expression analysis showed upregulation of the Hh-Gli pathway in both ovaries compared with healthy ovarian tissue. Primary cell culture was developed from the patient's tissue and showed downregulation of gene expression in response to cyclopamine, a Hh-Gli pathway inhibitor. The Hh-Gli signaling pathway may play a role in malignant transformation and metastasis of ovarian cancer. PMID- 22498945 TI - Squamous cell carcinoma arising within a mature cystic teratoma with invasion into the adjacent small intestine: a case report. AB - Malignant transformation in a mature cystic teratoma (MCT) is rare, with a reported incidence of approximately 1% to 3%. To our knowledge, no case has been reported previously with the invasion of malignant tumor of MCT into the adjacent small intestine. We report a case of squamous cell carcinoma arising within a MCT and invading into the adjacent small bowel. The patient is a 73-yr-old African American woman who noted the presence of a relatively asymptomatic abdominal mass over the past 40 yr. The mass had become more symptomatic over the past several months, with right-sided abdominal pain and constipation. She underwent an exploratory laparatomy, which demonstrated a cystic abdominal mass measuring 24 cm in diameter and weighing 8 kg. The mass contained necrotic debris, a cloudy fluid, hair, and cartilage. It was adherent to the small intestine in an area associated with focal thickening of the cystic wall of the mass. Histologically, the mass demonstrated a MCT within which arose a well-differentiated squamous cell carcinoma. At the point of attachment to the small intestine, histologic sections demonstrated a transmural invasion of the squamous cell carcinoma into the attached segment of the small intestine through the muscularis propria and the submucosa reaching the mucosal surface. Thirteen regional lymph nodes were isolated near the portion of the small intestine involved with the tumor; however, none of them exhibited metastatic carcinoma. PMID- 22498946 TI - High-grade sarcoma masquerading as growing teratoma syndrome after resection of ovarian immature teratoma: report of a case. AB - SUMMARY: A thorough literature search revealed no previous reports of this entity, and we are the first to describe a case of a high-grade sarcoma arising from a recurrent immature teratoma misdiagnosed as growing teratoma syndrome. The patient was a 23-yr-old female, diagnosed at the age of 20 with a Stage IIIB immature ovarian teratoma. After surgery and chemotherapy, the patient developed multiple liver and pelvic masses that were diagnosed as mature teratomas based on small samples obtained by computed tomography-guided core biopsy. Three years after diagnosis the patient presented with severe respiratory difficulty and following resection, the final pathology revealed multiple tumors with foci of high grade sarcoma compatible with primitive neuroectodermal tumor/extraskeletal Ewing sarcoma based on morphology and immunohistochemistry (CD99, CD56). However, on the basis of further immunostaining and fluorescent in situ hybridization studies negative for rearrangement of EWSR1, the final pathologic diagnosis was high-grade unspecified (undifferentiated) sarcoma. This case illustrates the pitfalls of biopsying 1 site in a patient with recurrence of a heterogeneous tumor such as immature ovarian teratoma, especially when rendering a benign diagnosis such as growing teratoma syndrome. It is of utmost importance to adequately sample large-volume recurrent teratomas, and we suggest biopsying several different sites, to increase the likelihood of detecting a malignant component. PMID- 22498947 TI - Genomic amplification of hTERC in paraffin-embedded tissues of cervical intraepithelial neoplasia and invasive cancer. AB - Cervical lesions and invasive cervical carcinomas are frequently associated with the amplification of chromosome 3q, which harbors the human telomerase gene hTERC. The differential diagnosis between low-grade and high-grade cervical lesions has been a clinical challenge in cytopathology. In the current study, we evaluated hTERC amplification by fluorescence in situ hybridization in cervical lesions with distinct histopathological changes and assessed the potential application of this technology in diagnosis. We showed that the frequency of genomic amplification of hTERC increased with the severity of the disease, with no marked difference between disease-free cervical squamous epithelium and Grade I cervical intraepithelial neoplasia(CIN)1, but that there were significant differences between these 2 stages and the CIN2, CIN3, and squamous cell carcinoma lesions. The difference between CIN1 and CIN2 would be of great importance for differential diagnosis in the clinic. In addition, hTERC amplification status exhibited a sensitivity of 59.42%, a specificity of 85.29%, an accuracy of 67.96%, a positive prediction value of 89.13%, and a negative prediction value of 68.42% in distinguishing CIN1 from CIN2/3 lesions. Therefore, hTERC amplification within cervical lesions can be accurately assessed by fluorescence in situ hybridization analysis on paraffin tissue microarrays. This technique may be clinically applied to differentiate between CIN1 and CIN2/3 lesions in paraffin-embedded biopsy tissues. PMID- 22498948 TI - HIV-associated hypertrophic herpes simplex genitalis with concomitant early invasive squamous cell carcinoma mimicking advanced genital cancer: case report and literature review. AB - Hypertrophic herpes simplex genitalis (HHSG) is an uncommon anogenital manifestation of herpes simplex virus (HSV) infection in immunocompromised patients. To date, 24 cases of HHSG have been reported; 23 of them were affected human immune deficiency virus (HIV) type 1-positive patients. We describe the case of a 44-year-old African HIV-1-positive woman who presented with painful ulcerated nodular lesions of the vulva and perianal area measuring up to 7 cm in diameter. Macroscopically, the lesions were highly suspicious of widely invasive cancer. The histologic workup of the resection specimen revealed patchy high grade vulvar intraepithelial neoplasia Grade 3 (VIN 3) and 2 microscopic foci of superficially invasive squamous cell carcinoma. The nodular lesions were caused by massive tumefactive plasma cell-rich inflammatory infiltrates extending into the subcutis. Multinucleated herpes simplex virus 1 and herpes simplex virus 2 positive epithelial cells with glassy intranuclear inclusions were detected at the borders of the ulcerations, consistent with HHSG. Despite repeated surgery and medical treatment, the patient had 3 recurrences of HHSG within 18 months. The presence of intraepithelial neoplasia in HHSG lesions is relatively rare and has been described in 6 of 18 resected HHSG lesions in the literature so far. With regard to invasive malignancy, the present case is the first report of a superficially invasive squamous cell carcinoma associated with HHSG. Awareness of this condition is necessary to avoid misinterpretation of HHSG as widely invasive squamous cell carcinoma with the hazard of surgical and oncological overtreatment. PMID- 22498949 TI - Clear cell adenosquamous carcinoma of the cervix: a case report with discussion of the differential diagnosis. AB - Clear cell adenosquamous carcinoma is an extremely rare and recently described variant of adenosquamous carcinoma of the cervix. It has a unique histologic appearance and has been shown to be associated with human papillomavirus-18. Its significance lies in the fact that it is associated with an aggressive clinical course and has to be differentiated microscopically from clear cell carcinoma and glassy cell carcinoma. PMID- 22498950 TI - Family therapy for schizophrenia: co-occurring psychotic and substance use disorders. AB - People with schizophrenia have a high prevalence of co-occurring substance use disorders, which is related to a worse course of psychiatric illness, more frequent relapses, and increased depression and suicide, compared with those with schizophrenia alone. The Family Intervention for Dual Diagnosis (FIDD) program, which includes psychoeducation and goal setting and focuses on building communication and problem-solving skills within the family, can aid in decreasing the stress related to having a close relationship with someone with a dual disorder. Here, the case of a young man with psychosis and marijuana dependence is examined. This article describes how the FIDD intervention helped him with his problematic substance use, as well as to build skills within his relationship for increased empathy and reduced interpersonal stress. PMID- 22498951 TI - Study on the electronic structure and hydrogen adsorption by transition metal decorated single wall carbon nanotubes. AB - The ground state geometry and electronic structure of various 4d transition metal (TM) atom (Y, Zr, Nb and Mo) decorated single wall carbon nanotubes (SWCNTs) are obtained using density functional theory and the projector augmented wave (PAW) method. We found a systematic change in the adsorption site of the transition metal atom with increasing number of d electrons. We also predicted that Y and Zr decorated SWCNTs are metallic whereas Nb and Mo decorated SWCNTs are semiconducting. From detailed electronic structure and Bader charge analysis we found that the systematic variation of the adsorption site with the number of d electrons is related to the decreasing amount of charge transfer from the TM atom to the SWCNT along the 4d series. We have also studied the hydrogen adsorption capabilities of these decorated SWCNTs to understand the role of transition metal d electrons in binding the hydrogen molecules to the system. We found that metallic SWCNT + TM systems are better hydrogen adsorbers. We showed that the hydrogen adsorption by a TM decorated SWCNT will be maximum when all the adsorptions are physisorption and that the retention of magnetism by the system is crucial for physisorption. PMID- 22498952 TI - Photochemical Norrish type I reaction as a tool for metal nanoparticle synthesis: importance of proton coupled electron transfer. AB - The Norrish type I photocleavage is an excellent source of strongly reducing free radicals that can be used to convert soluble metal ions into their atomic state that proceed to form nanoparticles. Proton coupled electron transfer (PCeT) is a useful tool to interpret the mechanism for metal ion reduction, a process that in these systems involves multisite PCeT, with proton and electron having separate receiving substrates. PMID- 22498953 TI - Simultaneous tonsillectomy and nasal surgery in adult obstructive sleep apnea: a pilot study. AB - OBJECTIVE: Although adenotonsillectomy is the accepted treatment for obstructive sleep apnea (OSA) in the pediatric population, tonsillectomy has not been widely adopted in adults, and its success in this group has not been well reported. Despite the lack of current evidence, there may be an important role for tonsillectomy in selected adult cases, and further study is required. This is a pilot study from a larger group of subjects currently enrolled and awaiting surgery and repeat polysomnography. STUDY DESIGN: Retrospective series with chart review. SETTING: Tertiary referral teaching hospitals. SUBJECTS AND METHODS: Thirteen consecutive eligible subjects with tonsillar hypertrophy and OSA were identified after treatment. These patients had undergone pre- and postoperative polysomnography for assessment of the severity of sleep-disordered breathing. Post hoc analysis of key parameters was performed by Wilcoxon signed rank and paired t tests. Tonsillectomy was performed on all subjects, using the diathermy dissection technique. Nasal surgery was performed simultaneously in 11 subjects for symptomatic nasal blockage unresponsive to medical treatment. RESULTS: There was a statistically significant improvement in the severity of OSA after surgery. The total Respiratory Disturbance Index (RDI) was significantly decreased from median values of 31.7 to 5.5 (P = .0002). The RDI in rapid eye movement and non rapid eye movement sleep and the arousal index were also significantly decreased. CONCLUSION: In selected adult subjects, tonsillectomy with intercurrent nasal surgery should be considered an effective treatment for OSA and may reduce the requirement for continuous positive airway pressure, oral appliances, or further therapeutic intervention. PMID- 22498954 TI - Developing a strategy for the management of rare diseases. PMID- 22498955 TI - A woman with generalised weakness, hypokalaemia, and metabolic acidosis. PMID- 22498956 TI - Care of IBD patients compromised by poor communication between primary and secondary care. PMID- 22498957 TI - Special support is offered to dementia sufferers in Scotland. PMID- 22498974 TI - miRNA-34c regulates Notch signaling during bone development. AB - During bone homeostasis, osteoblast and osteoclast differentiation is coupled and regulated by multiple signaling pathways and their downstream transcription factors. Here, we show that microRNA 34 (miR-34) is significantly induced by BMP2 during osteoblast differentiation. In vivo, osteoblast-specific gain of miR-34c in mice leads to an age-dependent osteoporosis due to the defective mineralization and proliferation of osteoblasts and increased osteoclastogenesis. In osteoblasts, miR-34c targets multiple components of the Notch signaling pathway, including Notch1, Notch2 and Jag1 in a direct manner, and influences osteoclast differentiation in a non-cell-autonomous fashion. Taken together, our results demonstrate that miR-34c is critical during osteoblastogenesis in part by regulating Notch signaling in bone homeostasis. Furthermore, miR-34c-mediated post-transcriptional regulation of Notch signaling in osteoblasts is one possible mechanism to modulate the proliferative effect of Notch in the committed osteoblast progenitors which may be important in the pathogenesis of osteosarcomas. Therefore, understanding the functional interaction of miR-34 and Notch signaling in normal bone development and in bone cancer could potentially lead to therapies modulating miR-34 signaling. PMID- 22498958 TI - Mass spectrometry-based proteomics: existing capabilities and future directions. AB - Mass spectrometry (MS)-based proteomics is emerging as a broadly effective means for identification, characterization, and quantification of proteins that are integral components of the processes essential for life. Characterization of proteins at the proteome and sub-proteome (e.g., the phosphoproteome, proteoglycome, or degradome/peptidome) levels provides a foundation for understanding fundamental aspects of biology. Emerging technologies such as ion mobility separations coupled with MS and microchip-based-proteome measurements combined with MS instrumentation and chromatographic separation techniques, such as nanoscale reversed phase liquid chromatography and capillary electrophoresis, show great promise for both broad undirected and targeted highly sensitive measurements. MS-based proteomics increasingly contribute to our understanding of the dynamics, interactions, and roles that proteins and peptides play, advancing our understanding of biology on a systems wide level for a wide range of applications including investigations of microbial communities, bioremediation, and human health. PMID- 22498975 TI - Insights from the sea: structural biology of marine polyketide synthases. AB - The world's oceans are a rich source of natural products with extremely interesting chemistry. Biosynthetic pathways have been worked out for a few, and the story is being enriched with crystal structures of interesting pathway enzymes. By far, the greatest number of structural insights from marine biosynthetic pathways has originated with studies of curacin A, a poster child for interesting marine chemistry with its cyclopropane and thiazoline rings, internal cis double bond, and terminal alkene. Using the curacin A pathway as a model, structural details are now available for a novel loading enzyme with remarkable dual decarboxylase and acetyltransferase activities, an Fe(2+)/alpha ketoglutarate-dependent halogenase that dictates substrate binding order through conformational changes, a decarboxylase that establishes regiochemistry for cyclopropane formation, and a thioesterase with specificity for beta-sulfated substrates that lead to terminal alkene offloading. The four curacin A pathway dehydratases reveal an intrinsic flexibility that may accommodate bulky or stiff polyketide intermediates. In the salinosporamide A pathway, active site volume determines the halide specificity of a halogenase that catalyzes for the synthesis of a halogenated building block. Structures of a number of putative polyketide cyclases may help in understanding reaction mechanisms and substrate specificities although their substrates are presently unknown. PMID- 22498976 TI - A novel nano-nonwoven fabric with three-dimensionally dispersed nanofibers: entrapment of carbon nanofibers within nonwovens using the wet-lay process. AB - This study demonstrates, for the first time, the manufacturing of novel nano nonwovens that are comprised of three-dimensionally distributed carbon nanofibers within the matrices of traditional wet-laid nonwovens. The preparation of these nano-nonwovens involves dispersing and flocking carbon nanofibers, and optimizing colloidal chemistry during wet-lay formation. The distribution of nanofibers within the nano-nonwoven was verified using polydispersed aerosol filtration testing, air permeability, low surface tension liquid capillary porometry, SEM and cyclic voltammetry. All these characterization techniques indicated that nanofiber flocks did not behave as large solid clumps, but retained the 'nanoporous' structure expected from nanofibers. These nano-nonwovens showed significant enhancements in aerosol filtration performance. The reduction oxidation reactions of the functional groups on nanofibers and the linear variation of electric double-layer capacitance with nanofiber loading were measured using cyclic voltammetry. More than 65 m2 (700 ft2) of the composite were made during the demonstration of process scalability using a Fourdrinier type continuous pilot papermaking machine. The scalability of the process with the control over pore size distribution makes these composites very promising for filtration and other nonwoven applications. PMID- 22498978 TI - Initiatives by the government and physician groups to improve awareness of medical ethics: Challenges in Japan. AB - Physicians have been required to possess high ethical standards, as medical practice is directly involved with patients' lives. Although ethics arise out of an individual's consciousness, ethical regulations imposed by the nation/government together with self-regulation by physician groups are important in the practice of ethics, for which reason countries around the world undertake various initiatives. This paper investigates physician licensure, organizations governing physician status, the role of physician groups, and the actual conditions of lifelong learning and ethics education in developed countries worldwide, in contrast with which it throws problems in the situation in Japan into relief. Organizations governing physician status, the form of medical associations, and the improvement of lifelong learning are pointed out as critical issues especially in Japan. PMID- 22498977 TI - A world of sphingolipids and glycolipids in the brain--novel functions of simple lipids modified with glucose. AB - Glycosphingolipids (GSLs) are present on cell surface membranes and are particularly abundant in the brain. Since over 300-400 GSLs are synthesized from glucosylceramide (GlcCer), GlcCer is believed to only serve as the source of most GSLs, including sialic acid-containing GSLs or gangliosides, in the brain. Recent studies, however, suggest that GlcCer itself plays a role in the heat stress response, as it functions as a glucose donor for the synthesis of cholesterylglucoside, a lipid mediator in heat stress responses in animals. GlcCer in adipose tissues is also thought to be involved in mechanisms that regulate energy (sugar and lipid) metabolism. Our extensive structural study revealed an additional novel glucosylated membrane lipid, called phosphatidylglucoside, in developing rodent brains and human neutrophils. These lipids, all modified with glucose, are enriched in lipid rafts and play important roles in basic cellular processes. Here, I summarize the recent progress regarding these glucosylated lipids and their biosynthesis and regulation in the central nervous system (CNS). PMID- 22498980 TI - Cause of deep venous thrombosis and pulmonary embolism in young patients from India as compared with other ethnic groups. AB - Venous thromboembolism (VTE), which consists of deep vein thrombosis (DVT) and pulmonary embolism, is a potentially fatal disease. The existing Asian literature has shown a wide variation in the prevalence of VTE, with very limited data from India. In the present study, the risk factors for VTE in Indian patients were compared with Caucasians and Blacks. We used data prospectively collected from total of 1396 Indian patients (716 males, 680 females) enrolled over a decade and compared with White (n = 2002) and Black (n = 395) patients objectively diagnosed with VTE. When compared with females, males had significantly higher episodes of pulmonary embolism and VTE (P = 0.0001). Amongst the known thrombophilia markers, only homocysteine was found to be significantly higher in males as compared with females (P = 0.006). Males had a higher proportion of rheumatic heart disease (RHD) and ischaemic heart disease (IHD) as compared with females. The prevalence of DVT amongst Indians was significantly higher as compared with Whites and Blacks. However, the rate of pulmonary embolism and VTE was lower in Indians as compared with both the races. Amongst the baseline characteristics identified as risk factors for VTE, Indians had a higher prevalence of infection as compared to both Whites and Blacks, but lower HIV infection as compared to Blacks. As compared to Whites, Indians had lower prevalence of idiopathic VTE (but similar to blacks) and had higher prevalence of idiopathic pulmonary embolism (P < 0.0001). This can be explained by different inherited and environment risk factors between these three populations. PMID- 22498979 TI - Antimicrobial peptide defensin: identification of novel isoforms and the characterization of their physiological roles and their significance in the pathogenesis of diseases. AB - Defensins comprise a family of cationic antimicrobial peptides containing a specific six-cysteine motif. Their contribution to the host defense against microbial invasion and the control of normal flora have been previously described. Some of the beta-defensin isoforms are predominantly expressed in the epididymis and showed a region-specific expression pattern in the epididymis, which thus suggested that these isoforms may possess epididymis-specific functions in addition to antimicrobial activities. A sequence variant of the beta defensin 126 gene has been shown to be associated with reductions in the human sperm function, thus supporting this hypothesis. Furthermore, defensins have the capacity to chemoattract immune cells and induce the secretion of inflammatory cytokines. Mice expressing human neutrophil alpha-defensin showed more severe lung injuries after the aspiration of acidic contents than did control mice. Recent investigations regarding copy number variations of human defensin genes also suggest the significance of defensin in the pathogenesis or the worsening of chronic obstructive pulmonary diseases, sepsis and psoriasis. PMID- 22498981 TI - Rituximab as prophylaxis in chronic relapsing thrombotic thrombocytopenic purpura: a case report and review of the literature. AB - Thrombotic thrombocytopenic purpura (TTP) is a rare disorder that most often arises from inhibition of the enzyme ADAMTS13 by autoantibodies. This provides the rationale for the use of rituximab, an anti-CD20 monoclonal antibody, as an effective treatment. Multiple reports have indicated success employing it in patients with TTP, but only a few have reported its use during remission as a prophylaxis to prevent a relapse. Herein, we report the case of a patient with chronic relapsing TTP who was successfully treated with prophylactic rituximab. We also provide a review of the literature on this topic. PMID- 22498982 TI - The in-vitro effect of fibrinogen, factor XIII and thrombin-activatable fibrinolysis inhibitor on clot formation and susceptibility to tissue plasminogen activator-induced fibrinolysis in hemodilution model. AB - Patients suffering major traumatic or surgical bleeding are often exposed to hemodilution resulting in dilutional coagulopathy. The aim of this study was to evaluate in vitro the effects of fibrinogen, factor XIII and thrombin-activatable fibrinolysis inhibitor (TAFI) on clot formation and resistance to fibrinolysis in hemodilution conditions. Citrated whole blood from 36 healthy volunteers was diluted to 30 and 60% with lactated Ringer's solution. Blood samples were subsequently supplemented with fibrinogen, FXIII, TAFI or their combinations. Rotation thromboelastometry (ROTEM) in whole blood and thrombin generation in plasma were performed in the presence of CaCl2 and tissue factor/EXTEM reagent, and fibrinolysis was induced by tissue plasminogen activator (tPA). Hemodilution was expressed by decrease of peak height in thrombin generation and alpha-angle and maximum clot firmness (MCF) in ROTEM. Fibrinogen, FXIII or TAFI did not correct the decrease in thrombin generation peak height. In ROTEM, spiking of diluted blood with fibrinogen stimulated clot propagation. In tPA-treated blood fibrinogen, FXIII and TAFI increased clot firmness and inhibited fibrinolysis. Stronger protection against fibrinolysis was achieved combining FXIII with TAFI. Hemodilution was associated with inhibition of thrombin generation; however, this effect was not sensitive to blood spiking with fibrinogen, FXIII and TAFI. In ROTEM, these hemostasis agents improved clot strength and decreased clot susceptibility to tPA in nondiluted and to more extent in diluted blood. The maximal protection against fibrinolysis was caused by TAFI. Combining FXIII with TAFI exerted synergistic inhibitory effect on fibrinolysis. PMID- 22498983 TI - Antithrombin Krakow II (c.624+1 G > T): a novel mutation leading to type 1 antithrombin deficiency. AB - Hereditary antithrombin (AT) deficiency is a rare autosomal disease. More than 200 mutations have been described in the AT gene leading to its deficiency. We describe here a case of type I AT deficiency in a 26-year-old Polish man who experienced proximal deep vein thrombosis and pulmonary embolism associated with a transient thrombotic risk factor, the right ankle trauma, despite the use of low-molecular-weight heparin prophylaxis. The family history was negative for venous thromboembolism. The AT activity was initially 47% and on repeated analysis 53%, and the antigen level, 0.15 g/l. The analysis of AT gene revealed the presence at the heterozygous state of a substitution G more than T located at the first nucleotide 3' of exon 3a (c.624 + 1 G > T, Human Genome Variation Society numbering system). The substitution might be detrimental taking account for its position in a donor splice site. To the best of our knowledge this mutation has not been previously described, so it was named antithrombin Krakow II. PMID- 22498984 TI - New drug update: 2011. AB - Five new drugs that are used for medical problems often encountered in the elderly have been selected for consideration in this review. The uses and most important properties of these agents are considered, and a rating for each new drug is determined using the New Drug Comparison Rating (NDCR) system developed by the author. In the NDCR system, a rating from 1 to 5 (5 being the highest rating) is assigned for each new drug. The rating is based on a comparison of the new drug with related drugs already marketed. Advantages, disadvantages, and other important information regarding the new drug are identified and used as the basis for determining the rating. PMID- 22498985 TI - Healthy aging: programs that make a difference-part 1. AB - Health promotion and disease prevention programs are critical elements in helping older Americans remain healthy and independent. Over the past decade, the efforts of the Administration on Aging and other agencies around the country have focused on ensuring that older adults have access to community-based health promotion and disease prevention ("healthy aging") programs that can make a noticeable difference in the health and well-being of older adults. Community-based organizations and agencies that provide these healthy aging programs provide ideal partners for senior care pharmacists. Many healthy aging programs target the prevention and management of chronic conditions in which medication management plays a key role. Pharmacists who desire to work with aging service providers and serve community-dwelling older adults should be aware of these programs that are growing in importance within the aging network. This series describes several healthy aging, evidence-based programs and discusses collaborative opportunities for senior care pharmacists. Part 2 will review the concepts behind and research basis for chronic disease self-management programs for older adults and provide practice advice for pharmacists who want to collaborate with organizations that have implemented healthy aging programs. PMID- 22498986 TI - Impact of final short-fill rule on Medicare Part D costs and long-term care pharmacy dispensing. AB - OBJECTIVE: To evaluate the impact of the final Centers for Medicare & Medicaid Services' (CMS) "short-fill" rule regarding the appropriate dispensing of prescription drugs in long-term care facilities. DESIGN: A prospective study to determine rates of unconsumed medication and the net-cost impact on Medicare Part D prescription drug plans based on the proposed and final CMS rule and other scenarios under consideration by CMS. SETTING: Four hundred twenty-five long-term care facilities in six states. PATIENTS: Residents covered by Medicare Part D. MAIN OUTCOME MEASURES: Rates of unconsumed medication, average dispensing fees, potential reduction in unconsumed medication, incremental fills, incremental dispensing fees, net cost or savings to Medicare Part D plans, and percentage increase in fills. RESULTS: Total estimates of the cost of unconsumed medication charged to Medicare Part D plans for residents in long-term care facilities are $87 million for brand products and $39 million for generics annually. Based on current dispensing fees, it is likely that implementation of the final rule will result in incremental costs to CMS plans in the range of $30 million annually. The number of Medicare Part D prescription fills will increase by about 20%. A seven-day fill requirement on brand products would raise incremental costs to more than $150 million annually, and inclusion of generic products in a seven-day fill requirement would result in incremental costs in the range of $850 million annually. CONCLUSION: The final CMS rule on short-fills is unlikely to result in savings to Medicare Part D plans. Shorter fill times and inclusion of generic products would significantly raise costs to these plans. PMID- 22498987 TI - Treatment and management of chronic lymphocytic leukemia in the elderly: what the pharmacist clinician should know. AB - OBJECTIVE: To review the literature for current treatment options and supportive care management for elderly patients with chronic lymphocytic leukemia (CLL). DATA SOURCES: PubMed searches using the terms chronic lymphocytic leukemia, elderly, practice guidelines, and controlled clinical trials were performed from 1949 through August 2011. Reference lists from relevant articles were examined for additional studies, review articles, and guidelines. STUDY SELECTION AND DATA EXTRACTION: Eighty-three articles were generated and abstracted articles were chosen based on trial results that changed clinical practice, resulted in approval of new drugs for CLL by the Food and Drug Administration and/or had clinical relevance to the elderly population. DATA SYNTHESIS: Fit elderly CLL patients have more treatment options than frail elderly. Most studies include patients younger than 65 years of age, and recent advances in treatment may not prove beneficial for all ages. Clinicians should use available evidence and clinical judgment when treating and monitoring elderly CLL patients. CONCLUSION: Treatment armamentarium has improved over the last decade, yet clinical trials research should include more elderly cohorts as new agents are developed. Increased awareness of supportive care issues improves quality of life for a population with multiple disease complications. PMID- 22498988 TI - Correcting vitamin D deficiency using over-the-counter supplements. AB - A patient was seen in a mass-merchandiser community pharmacy for medication therapy management services. The patient was taking over-the-counter vitamin D3 for the treatment of deficiency. Her therapy had increased her vitamin D serum levels, but not sufficiently. The literature was evaluated to establish that she is indicated for supplementation, to determine what an appropriate vitamin D level would be for this patient, and appropriately select a therapeutic regimen. This patient had several risk factors for low vitamin D levels including her race, weight, and age. After reviewing the recommendations for vitamin D supplementation, it was determined that an appropriate vitamin D serum level for this patient would be between 30 ng/dL and 40 ng/dL. Her original serum level of 10.2 ng/dL indicated that she was a candidate for supplementation. Generally, 1,000 IU daily of vitamin D will produce an increase of 10 ng/dL. This proved to be true with our patient, who had a level of 22.1 ng/dL after four months of treatment. She therefore needed an increase to 2,000 IU daily to further raise her levels and put her within her target goal. After working with the physician, the patient was started on 2,000 IU of vitamin D3 daily. A vitamin D serum concentration obtained after three months showed the patient reached her goal with a level of 35.4 ng/dL. The patient was put on a maintenance dosage of 800 IU daily and will receive periodic follow-up. PMID- 22498989 TI - Financial oversight of medication use: an expanded role for consultant pharmacists. AB - Many consultant pharmacists are moving beyond their federally defined role of reviewing resident charts in nursing facilities. They are taking on an expanded role, not only to provide the best possible care, but also to ensure that the spending for medications supports these efforts. This is increasingly important, given the 11% cut in Medicare effective October 1, 2011, which is forcing nursing facilities to operate even more efficiently and effectively. Involvement of the consultant pharmacist in medication finances requires knowledge in several new areas that include the dialysis-medication bundling, vaccine coverage, and responsibility for off-label use of medications. While the financial management of medications is an opportunity for the consultant pharmacist, it is only the first of many. Additional opportunities for consultant pharmacists will develop as nursing facilities become accountable for clinical outcomes-including readmissions-that will impact both hospital referrals to nursing facilities and Medicare payments. Appreciating these opportunities and gaining knowledge and expertise is critical to consultant pharmacists playing a lead role in the nursing facility. Consultant pharmacists need financial management expertise to become able to deal with ongoing changes. PMID- 22498990 TI - Extrusion of expandable stacked interbody device for lumbar fusion: case report of a complication. AB - STUDY DESIGN: A case report. OBJECTIVE: We report on the device failure of a polyetherether-ketone expandable cage device with posterior migration of one of its components. SUMMARY OF BACKGROUND DATA: Posterior migration of transforaminal lumbar interbody fusion cage devices has been reported with static devices, and ours is the first report of an expandable TLIF device failure and posterior migration of one of its components. METHODS: The patient is a 30-year-old man who had previously failed 3 lumbar surgical procedures and presented for L5-S1 lumbar fusion with pedicle screws and transforaminal interbody fusion. RESULTS: Postoperative imaging demonstrated posterior migration of one of the failed expandable interbody components with eventual revision surgery and placement of static transforaminal lumbar interbody fusion cages. CONCLUSION: This is the first case report to describe such complication, and caution must be warranted when using these devices. PMID- 22498991 TI - Rates and causes of mortality associated with spine surgery based on 108,419 procedures: a review of the Scoliosis Research Society Morbidity and Mortality Database. AB - STUDY DESIGN: A retrospective review of a prospectively collected database. OBJECTIVE: To assess rates and causes of mortality associated with spine surgery. SUMMARY OF BACKGROUND DATA: Despite the best of care, all surgical procedures have inherent risks of complications, including mortality. Defining these risks is important for patient counseling and quality improvement. METHODS: The Scoliosis Research Society Morbidity and Mortality database was queried for spinal surgery cases complicated by death from 2004 to 2007, including pediatric (younger than 21 yr) and adult (21 yr or older) patients. Deaths occurring within 60 days and complications within 60 days of surgery that resulted in death were assessed. RESULTS: A total of 197 mortalities were reported among 108,419 patients (1.8 deaths per 1000 patients). Based on age, rates of death per 1000 patients for adult and pediatric patients were 2.0 and 1.3, respectively. Based on primary diagnosis (available for 107,996 patients), rates of death per 1000 patients were as follows: 0.9 for degenerative (n = 47,393), 1.8 for scoliosis (n = 26,421), 0.9 for spondylolisthesis (n = 11,421), 5.7 for fracture (n = 6706), 4.4 for kyphosis (n = 3600), and 3.3 for other (n = 12,455). The most common causes of mortality included: respiratory/pulmonary causes (n = 83), cardiac causes (n = 41), sepsis (n = 35), stroke (n = 15), and intraoperative blood loss (n = 8). Death occurred prior to hospital discharge for 109 (79%) of 138 deaths for which this information was reported. The specific postoperative day (POD) of death was reported for 94 (48%) patients and included POD 0 (n = 23), POD 1-3 (n = 17), POD 4-14 (n = 30), and POD >14 (n = 24). Increased mortality rates were associated with higher American Society of Anesthesiologists score, spinal fusion, and implants (P < 0.001). Mortality rates increased with age, ranging from 0.9 per 1000 to 34.3 per 1000 for patients aged 20 to 39 years and 90 years or older, respectively. CONCLUSION: This study provides rates and causes of mortality associated with spine surgery for a broad range of diagnoses and includes assessments for adult and pediatric patients. These findings may prove valuable for patient counseling and efforts to improve the safety of patient care. PMID- 22498992 TI - Polymer-on-metal or metal-on-polymer total disc arthroplasty: does it make a difference? AB - STUDY DESIGN: Mechanical testing of total disc arthroplasty (TDA). OBJECTIVE: To compare the friction between a polymer socket-on-metal ball and metal socket-on polymer ball TDA. SUMMARY OF BACKGROUND DATA: A degenerate intervertebral disc can be replaced by TDA. The most common designs have a ball and socket articulation; the contact between the surfaces leads to friction. Friction needs to be minimized to prevent loosening and wear. One of the common material combinations in disc arthroplasty devices is the articulation of a metal socket on polymer ball. However, the combination of a polymer socket on metal ball (which is used in hip arthroplasty) has not been investigated for TDA. METHODS: TDA models with either a polymer socket/metal ball or a metal socket/polymer ball were manufactured with ball radii of 10 and 14 mm, each with a radial clearance of 0.35 mm. Samples were tested using a spine simulator with a lubricant of diluted newborn calf serum. Each sample was subjected to an axial load of 1200 N; motions of flexion-extension, lateral bending, and axial rotation were then applied at frequencies of 0.25 to 2 Hz. Frictional torque was measured to compare the performance of the TDAs. RESULTS: The frictional torque was found to be significantly higher for a disc with a metal socket/polymer ball than for a disc with a polymer socket/metal ball for both 10 and 14 mm radii in axial rotation, lateral bend, and extension. The frictional torque in flexion (0 degrees -6 degrees ) was not found to be significantly different between the 2 different material combinations. However, when the flexion motion was reduced to 0 degrees to 2 degrees , frictional torque in the metal socket/polymer ball was found to be significantly higher than the polymer socket/metal ball. CONCLUSION: TDA with a combination of a polymer socket/metal ball has lower friction than the conventional TDA with metal socket/polymer ball. This conclusion has implications in the design of TDA. PMID- 22498993 TI - Lumbar modic changes-a comparison between findings at low- and high-field magnetic resonance imaging. AB - STUDY DESIGN: A cross-sectional observational study. OBJECTIVE: To investigate whether there is a difference in findings of lumbar Modic changes in low-field (0.3 T) magnetic resonance imaging (MRI) compared with high-field (1.5 T). SUMMARY OF BACKGROUND DATA: It is a challenge to give patients with low back pain a specific diagnosis. Modic changes as seen on MRI have been reported to be a possible source of pain. However, it is unclear whether the diagnosis is independent on the field strength. METHODS: Twenty patients with Modic changes, 11 women and 9 men (mean age, 53.6 yr; range, 29-81 yr), with or without sciatica, seen in a Danish outpatient low back pain clinic were included. All patients obtained MRI scans on both a high-field and a low-field MRI scanner. Two radiologists evaluated all lumbar endplates independently, using a standardized evaluation protocol. Kappa statistics were used to analyze the interobserver reproducibility. We used paired t test to analyze the difference between low- and high-field MRI. RESULTS: The total number of Modic changes diagnosed with high field MRI was significantly higher than that with low-field MRI. However, 3 to 4 times as many Modic type 1 changes were found with low-field MRI compared with high-field MRI. Contrarily, with high-field MRI type 2 changes were diagnosed twice as often. CONCLUSION: There was a significant difference between low- and high-field MRI regarding the overall prevalence of any Modic change, but this had opposite directions for types 1 and 2: type 2 dominated in high field and conversely in high field [corrected]. The type of MRI unit should be taken into consideration when diagnosing patients with Modic changes PMID- 22498994 TI - Effect of magnetic resonance imaging field strength on delineation and signal intensity of alar ligaments in healthy volunteers. AB - STUDY DESIGN: A prospective study of healthy volunteers. OBJECTIVE: To evaluate the influence of magnetic resonance imaging (MRI) field strength on the delineation and signal intensity of alar ligaments (AL) in healthy volunteers. SUMMARY OF BACKGROUND DATA: The fact that AL physiologically show morphologic variabilities is well established. However, presence and etiology of high-signal intensities within the AL as well as the influence of the MRI field strength on the signal characteristics of AL are still not completely understood. METHODS.: Coronal and sagittal 2-mm proton-density weighted sequences were acquired in 50 healthy volunteers using different MRI field strengths (1 T, 1.5 T, 3 T). Delineation and signal characteristics of AL were evaluated by 2 neuroradiologists independently. Differences concerning delineation and signal intensity between the MRI scanners, inter rater reliability between the 2 readers, and intrarater reliability at different time points were calculated. RESULTS: Delineation of AL was significantly better both on 3 T and 1.5 T than on 1 T (P = 0.05) in sagittal as well as in coronal view. In coronal view delineation was significantly better on 3 T than on 1.5 T, whereas in sagittal view no significant difference was evident when comparing 1.5 T and 3 T. Concerning signal intensity of AL in sagittal view, there was no significant difference between the 3 different field strengths. Inter-rater and intrarater agreements were fair to moderate with respect to delineation as well as signal intensity of AL. CONCLUSION: 1.5 T and 3 T significantly improve the delineation of AL when compared with lower field strength (1 T), but signal intensity of the AL in healthy volunteers is not influenced by the field strength. Increased signal is present in asymptomatic subjects on both low- and high-field magnetic resonance systems. Accordingly, the pathologic relevance of increased signal intensity of the AL, regardless of field strength, may not be indicative of traumatic AL injury. PMID- 22498995 TI - Secondary curve behavior in Lenke type 1C adolescent idiopathic scoliosis after thoracoscopic selective anterior thoracic fusion. AB - STUDY DESIGN: Analysis of a case series of 24 patients with Lenke 1C adolescent idiopathic scoliosis (AIS) receiving selective thoracoscopic anterior scoliosis correction. OBJECTIVE: To report the behavior of the compensatory lumbar curve in a group of patients with Lenke IC AIS after thoracoscopic anterior scoliosis correction and to compare the results of this study with previously published data. SUMMARY OF BACKGROUND DATA: Several prior studies have reported spontaneous lumbar curve correction for both anterior and posterior selective fusions in patients with Lenke 1C/King-Moe 2; however, to our knowledge no previous studies have reported outcomes of thoracoscopic anterior correction for this curve type. METHODS: All patients with AIS with a curve classification of Lenke 1C and a minimum of 24-month follow-up were obtained from a consecutive series of 190 patients with AIS who underwent thoracoscopic anterior instrumented fusion. Cobb angles of the major curve, instrumented levels, compensatory lumbar curve, and T5 T12 kyphosis were recorded, as well as coronal spinal balance, T1 tilt angle, and shoulder balance. All radiographical parameters were measured before surgery and at 2, 6, 12, and 24 months after surgery. RESULTS: Twenty-four female patients with right thoracic curves had a mean thoracic Cobb angle of 53.0 degrees before surgery, decreasing to 24.9 degrees 2 years after surgery. The mean lumbar compensatory Cobb angle was 43.5 degrees before surgery, spontaneously correcting to 25.4 degrees 2 years after surgery, indicating balance between the thoracic and lumbar scoliotic curves. The lumbar correction achieved (41.8%) compares favorably to previous studies. CONCLUSION: Selective thoracoscopic anterior fusion allows spontaneous lumbar curve correction and achieves coronal balance of main thoracic and compensatory lumbar curves, good cosmesis, and patient satisfaction. Correction and balance are maintained 24 months after surgery. PMID- 22498996 TI - Adaptive servo ventilation reduces central sleep apnea in chronic heart failure patients: beneficial effects on autonomic modulation of heart rate. AB - AIM: Adaptive servo ventilation (ASV) is a method of ventilator support aimed to treat central sleep apnea (CSA). We investigated the effects of an acute use of ASV in chronic heart failure (CHF) patients with CSA and the potential influence on sympathetic nerve activity. METHODS: Patients were studied with ambulatory cardio-respiratory 24 Holter (Somte) recording of air flow, ECG and oxygen saturation. Comparison before and after ASV treatment was made for apnea index (AI), apnea-hypopnea index (AHI), pulse oxygen saturation, desaturation related to apnea, heart rate (HR) and heart rate variability (HRV). RESULTS: Seventeen patients were enrolled. At baseline, apnea index and apnea-hypopnea index were, respectively, 16.92 +/- 7.8 and 41.37 +/- 17.5. During ASV, they significantly decreased to 0.06 +/- 0.0 (P < 0.001) and 2.84 +/- 1.1 (P < 0.001). The mean and minimal oxygen saturation (%) increased from 94 +/- 1 and 86.5 +/- 4 to 95 +/- 2 (P = 0.04) and 91 +/- 2 (P = 0.008). Mean HR decreased from 68 +/- 10 to 62 +/- 7 beats/min (P < 0.003). In 11 out of 17 patients, HRV was calculated, documenting a significant improvement of the standard deviation of the average of NN - normal sinus to normal sinus (SDANN), standard deviation of NN intervals (SDNN) and SDNN index (respectively, 71.5 +/- 31.1 vs. 80.4 +/- 36.1, P = 0.008; 99.7 +/- 31.3 vs. 112.7 +/- 37.5, P = 0.003; 57.8 +/- 20.7 vs. 69.3 +/- 30.8, P = 0.03). CONCLUSION: The acute use of ASV is effective on CSA by increasing oxygen saturation and reducing HR. Moreover, the significant improvement of HRV highlights ASV's benefit in moderating the sympathetic adrenergic tone. PMID- 22498997 TI - Natriuretic peptide fragments as possible biochemical markers of hypertension in the elderly. AB - AIMS: To study the relationship between C-type natriuretic peptide (NT-proCNP) and other natriuretic peptides, such as pro-atrial natriuretic peptide [proANP(1 98)] and N-terminal pro-brain natriuretic peptide (NT-proBNP), in the elderly, investigating also their correlation with other traditional clinical markers of the hypertensive condition. METHODS: NT-proCNP, NT-proBNP and proANP(1-98) were measured in 57 elderly patients. They were hypertensive patients (n = 36) and normotensive controls (n = 21). Their anthropometric parameters, including Winsor's index and total and high-density lipoprotein cholesterol, were determined. RESULTS: A diagnostic role of NT-proBNP in hypertensive patients was detected by a model of logistic regression, which gave a significant result [odds ratio (OR) 1.0115, P = 0.0184]. By this model the area (AUC) under the receiver operating characteristic (ROC) curve was 0.69 +/- 0.071 (P = 0.0075). On the basis of the ROC curve, the calculated serum NT-proBNP cut-off for the prediction of hypertension was greater than 164 pmol/l - the value being provided with a sensitivity of 89% coupled with a specificity of 55%. NT-proCNP and proANP(1-98) did not predict the hypertensive condition, although significant correlations were detected with serum lipid profile and creatinine levels. CONCLUSIONS: By using the logistic regression analysis, NT-proBNP was identified as a significant predictor of hypertension, whereas NT-proCNP and proANP circulating levels were not shown to reliably predict the hypertensive condition. Further validation by means of larger cohort studies is undoubtedly needed to assess the use of all three peptides to increase the performance of a possible test for the prediction of the hypertensive condition in humans. PMID- 22498998 TI - Relationship of fragmented QRS complexes with inadequate coronary collaterals in patients with chronic total occlusion. AB - BACKGROUND: Fragmented QRS (fQRS) complexes are defined as various RSR' patterns (>=1 R' or notching of S wave or R wave) in two contiguous leads corresponding to a major coronary artery territory. In previous studies, fQRS has been associated with increased morbidity and mortality, sudden cardiac death and recurrent cardiovascular events (CVEs). The causative relationship between fQRS and cardiac fibrosis has been shown in prior studies. The association between inadequate (poor) coronary collaterals and presence of fQRS has not comprehensively been studied in patients with chronic total occlusion (CTO) until now. We tested the hypothesis that the presence of fQRS is associated with inadequate coronary collateral growth. METHODS: This study had a cross-sectional observational design. The study population consisted of patients who underwent coronary angiography with the suspicion of coronary artery disease at our institution in an outpatient manner. Patients who had CTO in at least one major epicardial coronary artery were included. Coronary angiograms of 148 eligible patients from our database were analyzed again. Ninety-three patients had good and 55 had poor collateral development according to the Cohen-Rentrop method. RESULTS: Patients with poor collateral development had higher plasma glucose (130 +/- 54 vs. 116 +/ 33 mg/dl, P = 0.047) and an older age (65 +/- 10 vs. 61 +/- 10 years, P = 0.042) in comparison to patients with good collateral growth. The presence and number of fQRS were higher in the poor collateral group than the good collateral group (64 vs. 32%, P < 0.001 and 2.3 +/- 2.4 vs. 1.2 +/- 2.0, P = 0.002, respectively). Left ventricular ejection fraction was significantly lower in the poor collateral group than the good collateral group (45 +/- 11 vs. 51 +/- 13, P = 0.014). There was a significant correlation between number of fQRSs and the echocardiographic wall-motion abnormality score (r = 0.662, P < 0.001). In multivariate analysis, only the presence of fQRS was independently related to poor collateral development (odds ratio, 3.559; 95% confidence interval, 1.708 7.415, P = 0.001). CONCLUSION: We found that fQRS was independently related to inadequate coronary collaterals in patients with CTO. fQRS, which may be derived from the effects of myocardial ischemia or scar on myocardial electricity at the cellular level, can represent inadequate coronary collateral development in patients with CTO. PMID- 22498999 TI - Cardiac remodeling and heart failure after a first anterior myocardial infarction in patients with diabetes mellitus. AB - AIMS: The mechanisms underlying the higher risk of heart failure after myocardial infarction (MI) in diabetic patients remain incompletely understood. Our aim was to investigate cardiac remodeling after MI according to diabetic status. METHODS: Data from 512 patients with a first anterior MI included in two prospective cohorts on left-ventricular remodeling were analyzed. Echocardiographic studies were performed before discharge, at 3 months and at 1 year. Clinical follow-up was performed after 3 years. RESULTS: There were 60 (23%) diabetic patients in cohort 1 and 51 (21%) in cohort 2. Therapeutic strategies, infarct size and residual left-ventricular ejection fraction did not differ between diabetic and nondiabetic patients. In both cohorts, there was a significant increase in left ventricular volumes and a recovery in left-ventricular systolic function from baseline to 1 year; these parameters did not differ according to diabetic status at any of the three time points. Diastolic function was analyzed in cohort 2: the E/Ea ratio was higher in diabetic patients at baseline and during follow-up. Diabetes mellitus was an independent predictor of cardiovascular death or rehospitalization for heart failure in cohort 1 [relative risk (RR) 2.62 (1.35 5.11)] and in cohort 2 [RR 4.99 (2.06-12.21)]. CONCLUSIONS: In patients with a modern treatment of MI, diabetes mellitus remains a major and independent predictor of subsequent heart failure. This higher risk is not associated with a decreased left-ventricular systolic function or with increased left-ventricular remodeling. The evidence of higher left-ventricular filling pressures suggests left-ventricular diastolic dysfunction as a potential mechanism. PMID- 22499000 TI - Apical hypertrophic cardiomyopathy with apical aneurysm in an African-American male. PMID- 22499001 TI - Postsurgical aortic false aneurysm: pathogenesis, clinical presentation and surgical strategy. AB - Postsurgical aortic false aneurysm occurs in less than 0.5% of all cardiac surgical cases and its management is a challenge in terms of preoperative evaluation and surgical approach. Although infections are well recognized as risk factors, technical aspects of a previous operation may have a role in pseudoaneurysm formation. The risk factors and clinical presentation of pseudoaneurysms and the surgical strategy are revisited in this article. PMID- 22499002 TI - Changing of SYNTAX score performing fractional flow reserve in multivessel coronary artery disease. AB - OBJECTIVES: To investigate the relationship between classic SYNTAX and functional SYNTAX score guided by fractional flow reserve (FFR). BACKGROUND: SYNTAX score predicts clinical outcome after percutaneous coronary intervention in patients with multivessel coronary artery disease (CAD), based on data from angiography alone. However, in the clinical setting, decision-making on myocardial revascularization should be guided by reliable demonstration of inducible ischemia, as detected by FFR. METHODS: FFR was collected in all 50-90% angiographic stenoses of 39 consecutive patients with stable multivessel CAD. SYNTAX score was calculated as usually described in SYNTAX group's reports. A functional SYNTAX (F-SYNTAX) score was determined by only considering ischemia producing lesions (FFR <= 0.80). The two scores were compared with correlation, Bland-Altman and agreement tests. RESULTS: FFR was measured in 97 lesions, with a median value of 0.82+/-0.10. In the 50-70% and 70-90% category stenoses, FFR was greater than 0.80 in 68 and 16% of cases, respectively. F-SYNTAX was systematically inferior to SYNTAX score, with a median difference of 8.4+/-7.4 (P<0.05). The correlation between the two methods was globally weak (r=0.621, rho=0.563; P<0.001). After determining F-SYNTAX score, more than 30% of the patients moved to a lower-risk tertile group (P=0.003). No clinical and angiographic differences were found between patients whether or not reclassified in lower-risk tertiles with F-SYNTAX score. CONCLUSIONS: In patients with multivessel CAD, implementation of SYNTAX score with FFR seems to be a more rational approach for revascularization. F-SYNTAX score reclassifies a significant proportion of patients to a lower-risk profile, thus leading to a possible change of therapeutic strategy. PMID- 22499003 TI - Percutaneous hepatic pseudoaneurysm exclusion using a pericardium covered stent. AB - Visceral artery pseudoaneurysms (PA) are a rare complication of abdominal surgery. Their natural history is generally unknown and unpredictable, so a repair is recommended. We report the case of a 77-year-old male with a huge PA of the hepatic artery diagnosed by computed tomography (CT) and treated successfully with percutaneous exclusion using a pericardium-covered stent. A staged CT confirmed the good result of the procedure. PMID- 22499004 TI - Extensive abdominal aortitis in a patient with Crohn's disease. AB - A 36-year-old woman with past medical history of Crohn's disease presented to our hospital with fever and back pain. Initial computed tomography (CT) demonstrated extensive abdominal aortitis. Here, we discuss the very rare association between Crohn's disease and aortitis, in addition to clinical and radiographic follow-up for our patient. PMID- 22499005 TI - Study of CD4+CD8+ double positive T-lymphocyte phenotype and function in Indian patients infected with HIV-1. AB - CD4+CD8+ double positive T cells represent a minor peripheral blood lymphocyte population. CD4+ expression on CD8+ T cells is induced following cellular activation, and as chronic HIV-1 infection is associated with generalized immune activation, double positive T cells studies have become necessary to understand the immunopathology of human immunodeficiency virus (HIV). The frequency of double positive T cells in persons infected with HIV was studied in comparison to uninfected controls. Further, the expression of CD38, HLA-DR, and programmed death (PD)-1 on these cells were ascertained. HIV-1 specific double positive T cells were also studied for their cytokine secretory ability and phenotype. A significantly higher double positive cell population was observed in the patients with advanced HIV disease (CD4+ T cell counts below 200 cells/ul), as compared to patients with CD4+ T cell counts above 500 cells/ul. Double positive T cells from patients with symptomatic HIV disease had a significantly increased activation and exhaustion levels, compared to asymptomatic subjects and to single positive T cells from the same subjects. HIV-1 specific double positive T cells showed further increase in CD38 and PD-1 expression levels. The proportion of CD38 and PD-1 expressing total and HIV-1 specific double positive T cells correlated positively with HIV-1 plasma viremia and negatively with CD4+ T cell counts. HIV infection results in a marked increase of double positive T cell population, and this cell population shows higher level of activation and exhaustion (increased PD-1 expression) compared to the single positive CD4+ and CD8+ T cells. PMID- 22499006 TI - Clinical and virological characteristics of hepatitis B or C virus co-infection with HIV in Indonesian patients. AB - Hepatitis virus-related liver disease increases substantially the mortality rate of patients with HIV on highly active antiretroviral therapy (HAART). Therefore, early diagnosis of hepatitis B virus (HBV) and hepatitis C virus (HCV) is important. However, the prevalence of HBV and HCV infection in Indonesian patients infected with HIV is unknown. Therefore, this study examined the molecular and clinical characteristics of HBV and HCV in 126 patients infected with HIV, mostly on HAART, at Dr. Sardjito Hospital, Yogyakarta, Indonesia. The rates of triple infection, HIV/HCV co-infection, HIV/HBV co-infection, and mono infection were 4.8%, 34.1%, 3.2%, and 57.9%, respectively. Seven HCV genotypes were detected, with genotypes 1a, 1b, 1c, 3a, 3k, 4a, and 6n found in 23 (52%), 1 (2%), 4 (9%), 5 (11%), 7 (16%), 3 (6%), and 1 (2%) patients, respectively, indicating multiple modes of transmission. HBV-DNA was detected in 2/10 patients with hepatitis B surface antigen; both patients were HAART naive. Univariate analysis revealed that male sex, higher education level, injection drug use, sexual contact, alanine aminotransferase >=40 IU/L, and aspartate aminotransferase-to-platelet ratio index > 0.5 were associated with HCV co infection. In multivariate analysis, injection drug use (OR: 26.52; 95% CI: 3.52 199.54) and alanine aminotransferase >=40 IU/L (OR: 6.36; 95% CI: 1.23-32.89) were independently associated with HCV co-infection. HCV co-infection was common among Indonesian patients infected with HIV, particularly among injecting drug users, and was a risk factor for disease progression of HIV. PMID- 22499007 TI - Hepatitis B virus with a proposed genotype I was found in Sichuan Province, China. AB - To date, eight hepatitis B virus (HBV) genotypes, A-H, have been designated, and two additional genotypes, I and J, have also been proposed. A serological survey targeting children in difficult-to-reach vaccination areas was carried out in remote counties of Sichuan Province, China. HBV genotypes and serotypes were also determined from HBsAg-positive serum samples by direct sequencing. Phylogenetic analysis showed two strains isolated from the Yi ethnic children clustered with the proposed genotype I. The pairwise genome genetic distance was 7.5% between genotypes I and C, and ranged from 8.4% to 15.2% between genotype I and other genotypes, except genotype C. Grouping Scan analyses of the two strains revealed apparent recombination events between an unknown genotype and genotype C. Two out of four HBV strains isolated from the Yi ethnic children were confirmed to be genotype I, suggesting widespread circulation and common infection with genotype I HBV in the local Yi population. High prevalence of HBsAg and low hepatitis B vaccination coverage indicated that additional efforts are needed to control HBV infection in those areas. PMID- 22499008 TI - Hepatitis B virus X protein blocks filamentous actin bundles by interaction with eukaryotic translation elongat ion factor 1 alpha 1. AB - Hepatitis B virus (HBV)-encoded X protein (HBx protein) is a multi-functional regulatory protein. It functions by protein-protein interaction and plays a pivotal role in the pathogenesis of HBV-related diseases. However, the partners in hepatocytes interacting with HBx protein are far from understood fully. In this study, immunoprecipitation was employed to screen for binding partners for the HBx protein from huh-7 hepatoma cells infected with recombinant adenovirus expressing HBx protein, and five cellular proteins including eukaryotic translation elongation factor 1 alpha 1 (eEF1A1), were identified. The interaction between HBx protein and eEF1A1 was confirmed further using a GST pull down assay and co-immunoprecipitation, respectively. In Huh-7 hepatoma cells, the HBx protein inhibits dimer formation of eEF1A1, hence blocks filamentous actin bundling. These findings provide new insights into the molecular mechanisms involved in the functions of the HBx protein. PMID- 22499009 TI - Prevalence of hepatitis B virus infection in a highly endemic area of southern China after catch-up immunization. AB - The Chinese national goals for control of hepatitis B virus (HBV) infection were to achieve a prevalence of HBsAg below 7% for the entire population, and 1% for children under 5-year old, by 2010. To determine whether Guangxi, a multi minority province with a low socio-economic status and a very high prevalence of HBV, achieved this goal, a seroepidemiological survey of HBV infection was carried out using stratified, random cluster sampling. The results show that the overall prevalence of HBsAg is 9.16% [95% confidence interval (CI) = 8.32-10%]. The prevalence in males (10.96%, 95% CI = 9.64-12.28%) is significantly higher than in females (7.71%, 95% CI = 6.64-8.78%; chi(2) = 10.5923, P < 0.05). The prevalence in children under 5-year old is 3.62% (95% CI = 0.60-6.64%) and increases with age. The prevalence of HBsAg in non-immunized individuals is significantly higher than in those immunized completely, although not within 24 hr of birth (chi(2) = 31.426, P < 0.05); a significant difference was found in those below the age of 20 years but not in older persons. Gender, age, immunization history, and familial HBsAg carriers are risk factors for infection. In conclusion, this study indicates that Guangxi has not reached the goal for the control of HBV infection. Catch-up HBV immunization may not protect adults effectively against infection in highly endemic regions. PMID- 22499010 TI - Assessing risk of a short-term antiretroviral therapy discontinuation as a read out of viral control in immune-based therapy. AB - Although analytical treatment interruption is used as a strategy to test immunotherapeutic agents in HIV-infection, it may pose a risk for study participants. The potential risks of short-term interruption of antiretroviral therapy (ART) during treatment with an autologous dendritic cell immune-based therapy (AGS-004-001) were assessed using data from a subgroup of subjects in the strategies for management of antiretroviral therapy (SMART) study with matched eligibility criteria. A retrospective subgroup analysis of the SMART study population using the eligibility criteria and treatment stopping rules of AGS-004 001 study was analyzed. Key inclusion criteria for AGS-004-001 study were applied to the data collected from participants of the SMART study. There were 440 of 2,720 on the drug conservation arm and 436 of 2,752 on the viral suppression arm that matched the AGS-004-001 inclusion criteria and were used in the SMART subgroup analysis. In the first 16 weeks following randomization into the SMART study there were no deaths in either subgroup. There were two AIDS-related events in the drug conservation subgroup and one in the viral suppression subgroup, making the overall risk of AIDS-related events 2 per 100 person years (0.005%) and 1 per 100 person years (0.002%) in the two subgroups, respectively. There were 6/440 subjects (1.4%) in the drug conservation subgroup and 4/436 subjects (0.92%) in the viral suppression subgroup who experienced Grade 2 adverse events. These results demonstrated that analytical treatment interruption within the context of highly selective, closely monitored studies assessing the antiviral activity of immune-based agents should be an acceptable strategy for at least 16 weeks. PMID- 22499011 TI - Improved quantitative PCR protocols for adenovirus and CMV with an internal inhibition control system and automated nucleic acid isolation. AB - With the establishment of routine virus load (DNAemia) screening for Human adenovirus (HAdV) and Cytomegalovirus (CMV) in post-transplant care quality standards for quantitative PCR-assays are increasing. Established real-time PCR assays were improved with a fully automated DNA-extraction and with a competitive internal control DNA packaged into a lambda phage which serves as an extraction and amplification control in each sample. HAdV and CMV DNA were detected and quantified simultaneously in various types of diagnostic samples like blood, feces or respiratory tract materials. Inhibition was observed in 0.33-0.66% of over 14,000 diagnostic samples, an infrequent but nevertheless not negligible event, which is observed mainly in stool samples. CMV viral load in broncho alveolar lavage fluid (BALF) ranged between positive but below the quantitation limit of 1,000 copies/ml up to 1.8 * 10(7) copies/ml with a median of 6.0 * 10(3) copies/ml. Forty-one (4.7%) BALF samples had a viral load above 5.0 * 10(5) copies/ml, which was proposed as a threshold for the diagnosis of pneumonia. HAdV viral loads ranged between positive but below the quantitation limit of 1,000 copies/ml to a very high concentration of 1.3 * 10(11) copies/ml in stool and BALF samples. A HAdV-DNAemia of >10(4) copies/ml was found only in patients with stool viral load of above 10(5) copies/ml. These data support the hypothesis that quantitation in diagnostic materials other than blood may give valuable diagnostic information and that further evaluation of this approach is reasonable. PMID- 22499012 TI - Case report: risk of virus infection after accidental blood inoculation from a multi-infected AIDS patient. AB - Infections caused by blood-borne viruses such as hepatitis B and C and the human immunodeficiency virus (HIV) are associated commonly with needlestick injuries, especially in a hospital setting. A prospective investigation was conducted on a medical doctor who suffered an accidental needlestick injury during blood collection from a patient with AIDS. The patient's blood contained 195,000 copies of HIV RNA, 1 * 10(6) IU hepatitis C virus (HCV) RNA, and >10(7) copies of parvovirus B19 DNA per 1 ml plasma. It was positive for cytomegalovirus virus and evidence of a resolved hepatitis B virus (HBV) infection was found. HCV viremia was detected in the physician 15 days later and was not resolved by seroconversion after 57 days. HIV infection was not transmitted, possibly because of the immediate use of anti-HIV prophylactic drugs after exposure. Parvovirus B19 infection was presumably prevented by pre-existing specific antibodies in the patient. Considering that many HIV carriers are coinfected with hepatitis B and C viruses, this case report support the knowledge that the risk of HCV transmission from a patient with AIDS is greater than that of HIV. PMID- 22499013 TI - Detection of human bocavirus 1 and 2 from children with acute gastroenteritis in Japan. AB - This study reports the detection and the genetic characterization of HBoV, a new member in the Parvoviridae family. Among 177 fecal specimens collected from children with diarrhea younger than 5 years in Japan, 11 (6.2%) were positive for HBoV. Co-infection with other enteric viruses (norovirus and adenovirus) was found in nine (81.8%) pediatric patients, while monoinfection by HBoV alone was detected in two (18.2%) cases. Nucleotide sequence analysis of 11 Japanese HBoV strains revealed that seven HBoV sequences were most closely related to other HBoV 1 reference strains, while the other four strains were similar to HBoV 2A. These results indicated that HBoV was one of the viral agents found in stool specimens collected from children with acute gastroenteritis and HBoV 1 and 2A circulated in Japan between 2009 and 2010 epidemic season. PMID- 22499014 TI - Prospective evaluation of a new automated nucleic acid extraction system using routine clinical respiratory specimens. AB - The aim of the study was to evaluate the MagNA Pure 96TM nucleic acid extraction system using clinical respiratory specimens for identifying viruses by qualitative real-time PCR assays. Three extraction methods were tested, that is, the MagNA Pure LCTM, the COBAS AmpliprepTM, and the MagNA Pure 96TM with 10-fold dilutions of an influenza A(H1N1)pdm09 sample. Two hundred thirty-nine respiratory specimens, 35 throat swabs, 164 nasopharyngeal specimens, and 40 broncho-alveolar fluids, were extracted with the MagNA Pure 96TM and the COBAS AmpliprepTM instruments. Forty COBAS AmpliprepTM positive samples were also tested. Real-time PCRs were used to identify influenza A and influenza A(H1N1)pdm09, rhinovirus, enterovirus, adenovirus, varicella zoster virus, cytomegalovirus, and herpes simplex virus. Similar results were obtained on RNA extracted from dilutions of influenza A(H1N1)pdm09 with the three systems: the MagNA Pure LCTM, the COBAS AmpliprepTM, and the MagNA Pure 96TM. Data from clinical respiratory specimens extracted with the MagNA Pure 96TM and COBAS AmpliprepTM instruments were in 98.5% in agreement (P < 0.0001) for influenza A and influenza A(H1N1)pdm09. Data for rhinovirus were in 97.3% agreement (P < 0.0001) and in 96.8% agreement for enterovirus. They were in 100% agreement for adenovirus. Data for cytomegalovirus and HSV1-2 were in 95.2% agreement (P < 0.0001). The MagNA Pure 96TM instrument is easy-to-use, reliable, and has a high throughput for extracting total nucleic acid from respiratory specimens. These extracts are suitable for molecular diagnosis with any type of real-time PCR assay. PMID- 22499015 TI - Role of mutations identified in ORFs M27, M36, m139, m141, and m143 in the temperature-sensitive phenotype of murine cytomegalovirus mutant tsm5. AB - A mutant of murine cytomegalovirus (MCMV), tsm5, which is temperature-sensitive for replication in murine embryo fibroblasts at 40 degrees C, failed to replicate to detectable levels in mice. A total of 18 non-synonymous mutations have been identified in tsm5. In a previous study, a mutation (C890Y) identified in the M70 primase gene, when introduced into the wt M70 primase, resulted in a mutant with reduced viral replication at 40 degrees C in vitro and which was severely attenuated in vivo. Five other previously identified mutations may also contribute to the tsm5 phenotype: (1) an A658S mutation in a protein expressed by the M27 ORF; (2) a V54I mutation in M36; (3) a Y565* mutation in m139; (4) a V195M mutation in m141; and (5) an M232I mutation in m143. In the present study, the above-mentioned mutations were introduced individually (M27, M36, m139, m141, m143) or together (M27/M36) into the MCMV K181 (Perth) variant bacterial artificial chromosome (BAC) using RecE/T homologous recombination. Growth in culture revealed that, apart from the double mutant (M27 and M36) and the m139 mutant, the introduced mutations in the above-mentioned genes did not show a temperature-sensitive phenotype in MEF or Raw 264.7 macrophage cells compared to their revertants or the wt virus. In contrast, replication of the M27/M36 double mutant was drastically reduced in MEFs at 40 degrees C and in macrophages at 37 degrees C. Replication of the m139 mutant was reduced in MEF cells at 40 degrees C but not in macrophages. Thus, at least three further mutations contribute to the tsm5 phenotype. PMID- 22499016 TI - Early human enterovirus infections in healthy Swedish children participating in the PRODIA pilot study. AB - Human enteroviruses (HEV) are common, especially in childhood and during the enterovirus season, causing mainly asymptomatic infections but also mild and severe illnesses. Numerous studies have shown the association between HEV infections and type 1 diabetes. Here, the prevalence of HEV infections was studied in healthy Swedish children with increased HLA-associated risk for type 1 diabetes participating in the PRODIA pilot study in which children were randomized to receive probiotics or placebo during the first 6 months of life. Stool specimens collected from 197 children in every 3 months from the age of 3 to 24 months were screened for HEV using traditional viral culturing method and identified with reverse transcriptase polymerase chain reaction (RT-PCR) and sequencing of the partial VP1 coding part of the viral genome. Altogether 4.8% (52/1,094) of the specimens were HEV-positive and 22.3% (44/197) of the children excreted HEV during the follow-up. HEV-A and HEV-B were present in 2.1 and 2.7% of the specimens, respectively. HEV-C and HEV-D viruses were not detected. In total, 17 different HEV serotypes were detected and the most common findings were CV-A9 (13.5%), CV-A16 (11.5%), and CV-A2 (9.6%). The majority of the infections (92.3%) were during the enterovirus season extending from July to December. Probiotic treatment did not affect significantly the risk of HEV infections during the 2-year follow-up although a trend for transient decrease for HEV positivity (HEV-A and/or HEV-B) by the age of 12 months was observed in children who received probiotics [OR 0.40; 95% confidence interval 0.15 to 1.08; P-value 0.071, generalized estimating (GEE) analysis]. According to the results, HEV-A findings were nearly as common as HEV-B findings among the healthy children participating in this study. Also it was shown that serotypes belonging to HEV-A species can be detected by means of viral culturing. PMID- 22499017 TI - Genetic characterization of enterovirus 71 isolated from patients with severe disease by comparative analysis of complete genomes. AB - Enterovirus 71 (EV71) which causes mild illness in children is also associated with severe neurological complications. This study analyzed the complete genomes of EV71 strains derived from mild and severe diseases in order to determine whether the differences of EV71 genomes were responsible for different clinical presentations. Compared to complete genomes of EV71 strains derived from mild cases (less virulent strains), nucleotide differences in EV71 strains isolated from severe cases (more virulent strains) were observed primarily in the internal ribosomal entry site (IRES) of the 5'-untranslated region (UTR), which is vital for the cap-independent translation of viral proteins. In the protein-coding region, an E-Q substitution at amino acid position 145 of structural protein VP1 that occurred in more than one of more virulent strains was observed. This site is known to be related functionally to receptor binding and virulence in mice. Overall, strains (Group III) isolated from patients with fatal or severe sequelae outcomes had greater sequence substitutions in the 5'-UTR and/or protein-coding region and exhibited a relatively low-average homology to less virulent strains across the entire genome, indicating the possibility of significant genomic diversity in the most virulent EV71 strains. Further studies of EV71 pathogenesis should examine the significance of genomic diversity and the effects of multiple mutations in a viral population. PMID- 22499019 TI - Genotyping of 11 human papillomaviruses by multiplex PCR with a GeXP analyzer. AB - A new, rapid, and high-throughput method was developed for simultaneous detection of 11 human papillomavirus (HPV) genotypes including nine high-risk types (HPV16, 18, 31, 33, 35, 39, 52, 58, and 66) and two low-risk types (HPV6 and 11) in a single tube by multiplex PCR based on a GenomeLab Gene Expression Profiler (GeXP) analyzer (GeXP-PCR). Eleven sets of chimeric primers were used to initiate the PCR, and one pair of universal primers was used for the subsequent cycles of the PCR. The specificity of GeXP-PCR for each HPV type was examined with clinical samples of single type HPV infection tested previously. The sensitivity of GeXP PCR was evaluated by performing the assay on serial 10-fold dilutions of cloned PCR products. The GeXP-PCR achieved a sensitivity of 100 copies when all of the 11 pre-mixed plasmids containing HPV targets were present. Analyses of 124 clinical specimens using the GeXP-PCR demonstrated that the GeXP-PCR assay had comparable sensitivity and specificity to those of reported multiple PCR assay and an increased detection of HPV 11 in samples with mixed infections. In conclusion, the GeXP-PCR is a fast, sensitive, and high throughput method for the detection of multiple HPV infections. PMID- 22499020 TI - Two years outcome of women infected with high risk HPV having normal colposcopy following low-grade or equivocal cytological abnormalities: are HPV16 and 18 viral load clinically useful predictive markers? AB - Management of patients infected with high-risk HPV (hrHPV) despite normal colposcopy following abnormal cytology remains a clinical challenge. The aim of this study was to evaluate if, in that specific population, initial HPV 16 and HPV 18 viral loads are predictive of infection clearance over a 24-month follow up. A total of 67 women infected with hrHPV having normal colposcopy following equivocal or low-grade cytological abnormalities were recruited and attended regular follow-ups based on repeat colposcopies and HPV testing. HPV16 and HPV18 infection were diagnosed in 36 (53.7%) and 7 (10.4%) cases, respectively. Viral load was quantified using the quantitative duplex real-time PCR method. Although this was not observed for HPV 18, initial HPV 16 viral load was highly associated to HPV 16 infection outcome (receiver operating characteristic curve analysis, area under curve: 0.90). Thus, women who had cleared their HPV 16 infection had significantly lower median initial HPV 16 viral load than those with persistent HPV 16 infection: 1.5 * 10(3) copies per million cells (CPMC) versus 3.8 * 10(6) CPMC, respectively (P = 0.006). The best prediction of HPV 16 clearance was obtained with an initial HPV 16 viral load of <7.5 * 10(4) CPMC: 86.7% specificity and 85.7% sensitivity. Finally, six patients were diagnosed with grade 2 or 3 cervical or vaginal intraepithelial neoplasia. Although all had a persistent hrHPV infection, neither HPV 16 nor 18 viral loads were found to be predictive of the risk of cervical or vaginal intraepithelial neoplasia. HPV16 viral load quantitation could represent a clinically useful marker in that very specific population. PMID- 22499018 TI - Prevalence and genotype distribution of human papillomavirus infection of the cervix in Spain: the CLEOPATRE study. AB - Human papillomavirus (HPV) infection is a necessary cause of cervical cancer. The aim of this study was to estimate the prevalence of cervical HPV infection and HPV type-specific distribution among women attending cervical cancer screening in Spain during 2007 and 2008. Women aged 18-65 years were recruited according to an age-stratified sampling method. Liquid-based cervical samples were collected and analyzed for cytology, HPV detection, and genotyping. HPV genotyping was determined using the INNO-LiPA HPV Genotyping Extra Reverse Hybridization Line Probe Assay. Prevalence estimates were age-standardized using 2001 Spanish census data. The present study included 3,261 women. Age-standardized HC2-based HPV prevalence was 14.3% (95% CI, 13.1-15.5) among women aged 18-65 years, and 28.8% (26.6-31.1) among women aged 18-25 years. High-risk HPV types were detected in 12.2% (95% CI, 11.1-13.4) of HPV-tested women, representing 84.0% of HPV-positive samples. Multiple infections were present in 4.1% (95% CI, 3.4-4.8) of HPV-tested women (25.0% of HPV-positive samples). The most common high-risk HPV-types among HPV-tested women were 16 (2.9%), 52 (1.8%), 51 (1.6%), 31 (1.3%), and 66 (1.2%). HPV-type 16 was present in 16.9% of HPV-positive samples. One or more of the HPV vaccine types 6/11/16/18 were detected in 3.8% of HPV-tested women (22.1% of HPV positive samples). Though not a true population-based survey, this study provides valuable baseline data for future assessment of the impact of current HPV vaccination programs in Spain. The high prevalence of HPV infection among young women may reflect recent changes in sexual behavior. PMID- 22499021 TI - Human parvovirus B19 surveillance in patients with rash and fever from Belarus. AB - Human parvovirus B19 (B19V) infection in immunocompetent patients usually has a mild clinical course, but during pregnancy it can cause serious and even fatal complications in the fetus. The most common clinical presentation of B19V infection is erythema infectiosum and in this case laboratory confirmation is required for differentiation from other exanthematous diseases. Measles and rubella negative sera collected in Belarus between 2005 and 2008 from 906 patients with a rash and fever were screened for B19V infection by ELISA. More than 35% of the samples (322/906) were positive for B19V. The proportion ranged from 10.1% in 2008 to 53.2% in 2006 when an outbreak took place in Minsk city. All B19V outbreaks and cluster cases occurred during the winter-spring period, but sporadic cases were recorded basically throughout the year. The majority of the cases (56.5%) occurred among the 2 till 10 year old children, and 27.3% of the cases were observed in adults between 19 and 53 years. All 104 B19V strains sequenced in the NS1/VP1u region belonged to genotype 1 with a maximal genetic distance of 1.75%. The two phylogenetic clusters reflected the geographic origins of the viruses within the country. Forty-two unique nucleotide mutations as compared to sequences downloaded from GenBank were found in the VP1u and NS1 regions; most of these changes were nonsynonymous. This report highlights the importance of B19V infection in patients with a rash and fever in Belarus. PMID- 22499022 TI - Broad respiratory virus detection in infants hospitalized for bronchiolitis by use of a multiplex RT-PCR DNA microarray system. AB - Newly available molecular tools allow a sensitive detection of a broad panel of viruses in respiratory tract specimens. In the present study, the application of a multiplex RT-PCR DNA microarray in diagnosis and epidemiological survey of viral infections in infants hospitalized for bronchiolitis was assessed. One hundred and thirty-eight nasopharyngeal aspirates collected from October 2007 to September 2008 were tested by direct immunofluorescence and viral culture, a combination of referenced RT-PCRs and the DNA microarray. One or more viruses were detected in 96, 126 and 126 of the specimens by direct immunofluorescence and viral culture, RT-PCRs and DNA microarray, respectively (70 vs. 91 vs. 91%, P < 10(-3)). The RT-PCRs and the DNA microarray yielded concordant results for 99% of specimens and identified mixed viral infections in 85 (62%). The most common associations were: human bocavirus and respiratory syncytial virus (32%), adenovirus and respiratory syncytial virus (30%), and parainfluenza virus type 3 and respiratory syncytial virus (23%). None of the bronchiolitis severity parameters including intensive care unit admission, O(2) supply, O(2) saturation percentage, O(2) length and length of stay at the hospital appeared to be significantly increased in multiple viral infections compared to single viral infections (P > 0.1). In conclusion, the use of this DNA microarray in clinical virology practice allows rapid and accurate identification of common and uncommon viral respiratory pathogens in infants hospitalized for bronchiolitis. It should improve the clinical management, the epidemiological survey, and the prevention of the nosocomial transmission of respiratory viruses in pediatric wards. PMID- 22499023 TI - Correlation between serum matrix metalloproteinase and antigenemia levels in patients infected with rotavirus. AB - Rotavirus (RV) antigenemia has been reported in patients with gastroenteritis; however, the exact mechanism remains unclear. In order to elucidate the mechanism of RV antigenemia, an association between RV antigenemia and matrix metalloproteinase (MMP) were analyzed. The object of this study was to elucidate the role of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in the pathogenesis of RV antigenemia. Forty children admitted to hospital with RV gastroenteritis were enrolled in this study. Paired serum samples were collected at the time of admission and discharge. Enzyme-linked immunosorbent assays (ELISA) were used to detect serum concentrations of viral antigens, MMP-1, -2, 9, -13, TIMP -1, and -2. Cytokines were measured using flow cytometric beads array. RV antigens were significantly higher in serum collected at the time of admission than discharge (P < 0.001). MMP-9 concentrations were significantly higher in serum collected at the time of admission than discharge (P < 0.001). MMP-2 concentrations were significantly lower in serum collected at the time of admission than discharge (P < 0.001). A weak but a significantly positive association (P = 0.034) was observed between RV antigen and MMP-9 in serum collected at the time of admission, and inverse association was observed between RV antigen and MMP-2. In addition, a weak but significantly positive association (P = 0.002) was observed between IL-6 and MMP-9. These data suggest that MMPs may contribute to the pathogenesis of RV antigenemia. PMID- 22499024 TI - Sodium intake and blood pressure in renal transplant recipients. AB - BACKGROUND: Hypertension is common among renal transplant recipients (RTR) and a risk factor for graft failure and mortality. Sodium intake is a well-established determinant of blood pressure (BP) in the general population. However, data in RTR are limited. International guidelines recommend a maximum daily sodium intake of 70 mmol. We investigated sodium intake in RTR as compared to healthy controls and its association with BP. METHODS: We included 660 RTR (age 53 +/- 13 years, 58% male) and 201 healthy controls (age 54 +/- 11 years, 46% male). Sodium intake was assessed from 24-h urine collections. The morning after completion of urine collection, BP was measured according to a strict protocol. RESULTS: Urinary sodium excretion was 156 +/- 62 mmol/24 h in RTR and 195 +/- 75 in controls (difference: P < 0.001), and 95% of RTR had a urinary sodium excretion >70 mmol/24 h. Systolic BP (SBP) and diastolic BP (DBP) were 136 +/- 18 and 82 +/- 11 mmHg, respectively. Sodium intake was positively associated with SBP (beta = 0.042 mmHg/mmol/24 h, P = 0.002) and DBP (beta = 0.023 mmHg/mmol/24 h, P = 0.007), independent of potential confounders. CONCLUSIONS: Although RTR had a lower sodium intake than healthy controls, their intake still exceeded current guidelines. Reduction of sodium intake to recommended amounts could reduce SBP by 4-5 mmHg. Better control of sodium intake may help to prevent graft failure and mortality due to hypertension among RTR. PMID- 22499025 TI - Association of pre-transplant erythropoiesis-stimulating agent responsiveness with post-transplant outcomes. AB - BACKGROUND: The role of pre-transplant erythropoiesis-stimulating agent (ESA) responsiveness in affecting post-transplant outcomes is not clear. METHODS: Linking the 5-year patient data of a large dialysis organization to the 'Scientific Registry of Transplant Recipients', we identified 8795 hemodialyzed patients who underwent first kidney transplantation. Mortality or graft failure, delayed graft function (DGF) and acute rejection risks were estimated by Cox regression [hazard ratio (HR)] and logistic regression, respectively. RESULTS: Patients were 48 +/- 14 years old and included 38% women and 36% diabetics. Compared to renal allograft recipients who were in the first quartile of pre transplant ESA responsiveness index (ERI), i.e. ESA dose divided by hemoglobin and weight, recipients in second, third and fourth quartiles had higher adjusted graft-censored death HR (and 95% confidence intervals) of 1.7 (1.0-2.7), 1.8 (1.1 2.9) and 2.3 (1.4-3.9) and higher death-censored graft failure HR of 1.6 (1.0 2.5), 2.0 (1.2-3.1) and 1.6 (0.9-2.6), respectively. No significant association between pre-transplant ERI and post-transplant DGF or acute rejection was detected. CONCLUSIONS: Higher pre-transplant ERI during the hemodialysis treatment period was associated with worse post-transplant long-term outcomes including increased all-cause death and higher risk of graft failure. PMID- 22499026 TI - Slope analysis of blood volume and calf bioimpedance monitoring in hemodialysis patients. AB - BACKGROUND: Continuous intradialytic bioelectrical impedance spectroscopy of the calf (cBIS) monitors changes in calf extracellular fluid volume (cECV), thus allowing estimation of hydration in end-stage renal disease patients. Blood volume monitoring (BVM) during hemodialysis (HD) provides information about relative changes in intravascular volume, which indirectly reflects plasma refilling. We hypothesize that the rate of plasma refilling changes when cBIS determined dry weight (BIS-DW) is reached. METHODS: Post-HD weight was reduced from baseline (BL) in 15 patients until dry weight was reached according to cBIS criteria (BIS-DW). The slopes of cBIS and BVM curves were analysed during the first 30 and last 20 min in 31 BL treatments, which were compared to the slopes during 31 treatments when BIS-DW was reached. RESULTS: During BL treatments, BVM slopes did not differ between the first 30 and last 20 min (-0.112 +/- 0.157%/min versus -0.089 +/- 0.036, P = n.s.), while cBIS slopes were generally steeper at the beginning than at the end of HD (-0.184 +/- 0.139%/min versus 0.10 +/- 0.127, P < 0.01). During BIS-DW treatments, BVM and cBIS slopes were steeper at the beginning than at the end (BVM: -0.131 +/- 0.122 versus -0.064 +/- 0.051, P < 0.01; cBIS: -0.192 +/- 0.129 versus -0.035 +/- 0.012, P < 0.001) and the cBIS slopes were steeper than BVM slopes at the beginning of HD. This relationship is inverted at the end of HD, when BIS-DW is reached (beginning: -0.192 +/- 0.129 versus -0.131 +/- 0.122, P < 0.05, end: -0.035 +/- 0.012 versus -0.064 +/- 0.051, P = 0.05). CONCLUSIONS: This study demonstrates that cECV changes faster at the beginning than at the end of HD. A reversal steepness of the cBIS slope in relation to BVM slope is observed at the time when BIS-DW is reached. Therefore, combined analysis of cBIS and BVM aiming at clinical end points may be useful to assess the relationship between plasma refilling and tissue hydration during dialysis. PMID- 22499028 TI - Building bridges. PMID- 22499027 TI - Combined prospective and retrospective correction to reduce motion-induced image misalignment and geometric distortions in EPI. AB - Despite rigid-body realignment to compensate for head motion during an echo planar imaging time-series scan, nonrigid image deformations remain due to changes in the effective shim within the brain as the head moves through the B(0) field. The current work presents a combined prospective/retrospective solution to reduce both rigid and nonrigid components of this motion-related image misalignment. Prospective rigid-body correction, where the scan-plane orientation is dynamically updated to track with the subject's head, is performed using an active marker setup. Retrospective distortion correction is then applied to unwarp the remaining nonrigid image deformations caused by motion-induced field changes. Distortion correction relative to a reference time-frame does not require any additional field mapping scans or models, but rather uses the phase information from the echo-planar imaging time-series itself. This combined method is applied to compensate echo-planar imaging scans of volunteers performing in plane and through-plane head motions, resulting in increased image stability beyond what either prospective or retrospective rigid-body correction alone can achieve. The combined method is also assessed in a blood oxygen level dependent functional MRI task, resulting in improved Z-score statistics. PMID- 22499029 TI - Reducing death from melanoma and standards of evidence. PMID- 22499033 TI - Second chances for skin: correcting genetic mutations. PMID- 22499034 TI - Montagna Symposium 2011: 60th Anniversary--Advances in Science and Medicine Catalyzed by Pioneering Skin Research. PMID- 22499035 TI - New activators and inhibitors in the hair cycle clock: targeting stem cells' state of competence. AB - The timing mechanism of the hair cycle remains poorly understood. However, it has become increasingly clear that the telogen-to-anagen transition is controlled jointly by at least the bone morphogenic protein (BMP), WNT, fibroblast growth factor (FGF), and transforming growth factor (TGF)-beta signaling pathways. New research shows that Fgf18 signaling in hair follicle stem cells synergizes BMP mediated refractivity, whereas Tgf-beta2 signaling counterbalances it. Loss of Fgf18 signaling markedly accelerates anagen initiation, whereas loss of Tgf-beta2 signaling significantly delays it, supporting key roles for these pathways in hair cycle timekeeping. PMID- 22499036 TI - Building models for keratin disorders. AB - Palmoplantar keratoderma is a hallmark of pachyonychia congenita (PC) and focal non-epidermolytic palmoplantar keratoderma (FNEPPK). By generating keratin 16 (Krt16)-deficient mice, Lessard and Coulombe, as described in this issue, have generated a mouse model to replicate these palmoplantar lesions. Studies using this model may provide novel insights into the molecular mechanisms responsible for the formation of palmoplantar lesions in PC and FNEPPK patients. PMID- 22499037 TI - IL-33: a novel danger signal system in atopic dermatitis. AB - IL-33 is a newly recognized cytokine of the IL-1 cytokine family that has recently been attributed to the epithelial "alarmin" defense system. IL-33 is released by the epithelial cells in various tissues and organs, including keratinocytes, endothelial cells, and immune cells. Recent reports have suggested that IL-33 might be a critical part of the innate immunity, although its precise role is as yet poorly understood. In several organs, IL-33 appears to drive T helper type 2 (Th2) responses, suggesting roles in allergic and atopic diseases, as well as in fibrosis. IL-33 exerts its effects by activating the ST2 (suppression of tumorigenicity 2)/IL-1 aR receptor on different types of cells, including mast cells and Th2 cells. The ST2 receptor is either expressed on the cell surface or shed from these cells (soluble ST2, sST2), thereby functioning as a "decoy" receptor. After binding to its receptor, IL-33 activates NF-kappaB, suggesting that it regulates the outcome of diseases such as atopic dermatitis. On the other hand, several studies have reported on the inhibitory effects of sST2 in inflammatory and fibrotic diseases, suggesting that IL-33/ST2 is a unique cytokine with potential pro- and anti-inflammatory effects. PMID- 22499038 TI - Toward personalized medicine in scleroderma: classification of scleroderma patients into stable "inflammatory" and "fibrotic" subgroups. AB - There is no universally agreed-upon treatment for the fibrosis of scleroderma. Recently, much information has been generated relating to the fundamental mechanisms underlying this disease. Partly based on these observations, both anti inflammatory and anti-fibrotic agents have been considered as possible therapies. However, this information has not been successfully translated into clinical practice. In this issue, Pendergrass et al. use genome-wide expression profiling to provide valuable insights into scleroderma. Previously, the authors showed that morphea and "limited" scleroderma patients and a small subset of diffuse scleroderma (dSSc) patients express an "inflammatory" profile, whereas the majority of dSSc patients express a "fibroproliferative" profile. In the current study, the investigators show that the gene expression profile of these patients is fixed over time; i.e., in contrast to a previously held belief, the inflammatory patients do not go on to become fibrotic, and vice versa. These data suggest that expression profiling might be used to design clinical trials for scleroderma. The inflammatory patients might be treated with anti-inflammatory agents, whereas fibroproliferative patients might be treated with antifibrotic agents. PMID- 22499039 TI - Saddles, twists, and curls: shape transitions in freestanding nanoribbons. AB - Efforts to modulate the electronic properties of atomically thin crystalline nanoribbons requires precise control over their morphology. Here, we perform atomistic simulations on freestanding graphene nanoribbons (GNRs) to first identify the minimal shapes as a function of ribbon width, and then develop a core-edge framework based on classical plate theory to explore the effect of size and ribbon elasticity in more general systems. The elastic edge-edge interactions are central to stabilization of the flat phase in ultra-narrow ribbons, and their bifurcation to twisted and bent shapes at critical widths that vary inversely with edge stress. In the case of compressive edge stress, we uncover hitherto ignored saddle shapes that are energetically indistinguishable with twisted shapes in the vicinity of the bifurcation yet dominate the morphological space with increasing width. At much larger widths with negligible edge-edge interactions, rippling instabilities set in, i.e. edge ripples and midline dimples for compressive and tensile edge stresses, respectively. Simulations of tapering GNRs reveal the dynamics of these shape transitions. Our results capture the interplay between geometry and mechanics that sets the morphology of crystalline nanoribbons and also highlight the utility of the core-edge framework in developing a unified understanding of the interplay. PMID- 22499041 TI - United we stand: emotionally focused therapy for couples in the treatment of posttraumatic stress disorder. AB - We present emotionally focused therapy (EFT) for couples as a viable treatment option for posttraumatic stress disorder (PTSD). We outline the empirical evidence of a link between interpersonal relationships and posttraumatic stress, with an emphasis on social support as a buffer for the development of PTSD symptoms. This leads into a discussion of the usefulness of attachment theory in the conceptualization and treatment of PTSD, followed by a description of the EFT approach and its empirical evidence. We present a clinical case with excerpts from EFT couple therapy sessions in which one partner was diagnosed with PTSD. The article concludes with clinical recommendations for helping people confront and overcome the pain and the fear that PTSD provokes. PMID- 22499042 TI - A method for generating single crystals that rely on internal fluid dynamics of microdroplets. AB - The single crystallization method by focusing on the characteristic internal fluid dynamics of the microdroplets was explored. Also the theoretical background was discussed, and the droplet size for obtaining only a single crystal within a microdroplet was estimated. PMID- 22499043 TI - Is incident drug-resistance of childhood-onset epilepsy reversible? A long-term follow-up study. AB - Given the grave morbidity and mortality of drug-resistant epilepsy, it is of great clinical interest to determine how often prior proven drug-resistant epilepsy is reversible without surgery and whether remission can be predicted by clinical features in children with incident drug-resistant epilepsy. We determined the likelihood of 1-, 2- and 5-year seizure remission and terminal 5 year seizure remission after the first adequate drug regimen in a population based cohort of 102 medically treated patients with incident, i.e. first-ever occurrence of drug-resistant epilepsy, as defined by the International League against Epilepsy. Among the 102 patients, 98 had focal seizures (68 symptomatic and 30 idiopathic/cryptogenic), one had generalized convulsive seizures and three had unclassified seizures. At the end of the 40.5-year median follow-up from the onset of adequate medication before the age of 16 years, 84 (82%) of 102 patients with incident drug-resistant epilepsy eventually entered one or more 1-year remissions, 81 (79%) one or more 2-year remissions, 70 (69%) one or more 5-year remissions and 52 (51%) of 102 5-year terminal remissions. In contrast, 18 (18%) of 102 patients with incident drug-resistant epilepsy never entered any 1-year remission, 21 (21%) 2-year remission, 32 (31%) 5-year remission and 50 (49%) of 102 any 5-year terminal remission. On multivariate analysis of clinical features, in every remission category, idiopathic or cryptogenic aetiology was the only significant predictor of entering remission. Incident drug-resistant epilepsy is eventually reversible in 49-79% of patients with mostly focal epilepsy, resulting in long-term remission of variable duration. Idiopathic or cryptogenic aetiology is a clinical predictor of reversible drug-resistant epilepsy. PMID- 22499044 TI - [Genome-wide analysis of GATA transcription factor in hematopoietic cells]. PMID- 22499045 TI - [Regulation of erythropoiesis by microbial nucleic acid]. PMID- 22499046 TI - [Retrospective analysis of progression to multiple myeloma or related disorders in 114 patients with monoclonal gammopathy of undetermined significance in a single institute]. AB - In 114 patients with monoclonal gammopathy of undetermined significance (MGUS) followed-up in Tachikawa Sougo hospital, we retrospectively analyzed progression of their disease to multiple myeloma (MM) or related disorders. The analysis was based on a total of 1,170 person-years of follow-up in a cohort with a median age at diagnosis of MGUS of 68 years 3 months, and with a median follow-up period of 9 years 5 months. Of these 114 patients, 13 (11%) showed progression to MM or related disorders with a median time to progression of 9 years 4 months; and the median age of these 13 patients was 78 years 8 months. The cumulative hazard ratio of progression at 5, 10, 15, and 20 years after diagnosis was 3.0%, 9.0%, 11.4%, and 32.1%, respectively. The risk of progression of MGUS to MM or related disorders in Japanese patients was as high as in Western patients studied previously, demonstrating that MGUS should be carefully monitored as a preneoplastic condition. PMID- 22499047 TI - [Cost-effectiveness analysis of azacitidine for myelodysplastic syndromes in Japan]. AB - The aim of this study was to assess the cost-effectiveness of azacitidine therapy for patients with myelodysplastic syndromes. A Markov model was developed to estimate the total additional direct cost and quality adjusted life years (QALYs) gained with azacitidine therapy versus best-supportive care in patients with high risk MDS. The cost-effectiveness of azacitidine was evaluated with incremental cost-effectiveness ratio, which represents the additional cost per QALY gained from the more effective treatment. Azacitidine therapy was 1.83 million yen more costly per patient but yielded an additional 0.353 QALYs. The ICER (Increment of Cost-effectiveness Ratio) was 5.18 million yen per QALY. In conclusion, because the ICER was less than the threshold for acceptable cost-effectiveness in Japan, azacitidine therapy for MDS patient was assumed to be cost-effective. PMID- 22499048 TI - [Allogeneic hematopoietic stem cell transplantation with fludarabine, melphalan, and total body irradiation as a conditioning for elderly patients with myeloid malignancies]. AB - A variety of reduced-intensity conditionings have been used in the reported studies of allogeneic hematopoietic stem cell transplantation (HSCT) for elderly patients with myeloid hematological malignancies. This study retrospectively analyzed the outcome of allogeneic HSCT for 10 patients aged 50 years or older with myeloid hematological malignancies after conditioning with fludarabine (125 mg/m(2)), melphalan (140 mg/m(2)) and total body irradiation (TBI; 8 Gy). Median age of the patients was 56.5 years, and diagnoses included acute myelogenous leukemia, advance myelodysplastic syndrome, and secondary myelofibrosis. Sources of stem cells were bone marrow from sibling (n=4) or unrelated donor (n=6). Both overall and disease-free survival rates were 40.0% (95% CI: 10.6~69.4%). Causes of death were relapse (n=2), fungal infection (n=2), and secondary malignancies (n=2). Because of a high incidence of transplant-related mortality, further refinement of this conditioning is required. PMID- 22499049 TI - [Clinical outcomes of allogeneic hematopoietic stem cell transplantation for adult primary myelofibrosis: retrospective analysis by Fukuoka BMT group]. AB - We retrospectively analyzed outcomes of eight evaluable patients with primary myelofibrosis (PMF) who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), using different graft sources; four patients received peripheral blood stem cells, three bone marrow, and one umbilical cord blood. The median age was 48 years (range, 43~64 years). Seven patients had an intermediate or high Dupriez score. Three patients underwent myeloablative conditioning, whereas five underwent reduced-intensity conditioning regimens. Engraftment was obtained in all of these recipients. The median days to reach a neutrophil count above 0.5*10(9)/l and platelet count above 20*10(9)/l were 20 and 35 days, respectively. No treatment-related deaths were observed within 100 days after allo-HSCT. Two patients died of sepsis or late-onset non-infectious pulmonary complications. Four patients developed grade I to II acute GVHD, and six patients developed chronic GVHD. The estimated 3-year overall survival was 75% with a median follow up time of 43 months (range, 6~127). Four of 5 patients who were transfusion-dependent became free from transfusion after allo-HSCT. In six of seven patients, a regression of fibrosis was confirmed by bone marrow biopsy. Despite the small number of cases, our results suggested that allo-HSCT is an encouraging curative strategy for treating PMF. PMID- 22499050 TI - [Retrospective survey on the clinical features of non-Hodgkin lymphomas in Gunma Prefecture, Japan]. AB - We retrospectively investigated pathological types, clinical backgrounds, treatments and prognoses in 726 adult patients with newly diagnosed malignant lymphoma in Gunma Prefecture. They consisted of 679 patients with non-Hodgkin lymphoma (B-cell type, 603; T- and NK-cell type, 76) of which 376 patients had diffuse large B-cell lymphoma (DLBCL) and 47 patients with Hodgkin lymphoma. When comparing the prognosis of DLBCL between patients receiving rituximab (R-CHOP group; n=212) and not using rituximab (CHOP group; n=126), both 3-year overall survival (73.5% vs 61.7%, p=0.010) and 3-year progression-free survival (65.1% vs 45.8%, p<0.001) were statistically better in the R-CHOP group compared to the CHOP group. Our results suggest that more than half of patients were DLBCL and the rituximab-containing regimen results in an improved prognosis for DLBCL patients. PMID- 22499051 TI - [Monitoring of Epstein-Barr virus-infected cells by flow cytometer permits early diagnosis and evaluation of disease progression in EBV-associated hemophagocytic lymphohistiocytosis]. AB - Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is characterized by clonal expansion of EBV-infected CD8(+)T-cells. We have recently demonstrated that detection of a clonally expanded population of EBV-infected CD8(+)T-cells with CD5 down-regulation was a useful tool to distinguish EBV-HLH from EBV-related disorders such as severe infectious mononucleosis. A 5-year-old girl who presented with fever, pancytopenia and liver dysfunction was diagnosed by this method in addition to conventional diagnostic tests. Further, EBV infected cells were identified as CD5(-)HLA-DR(+) TCR V beta3(+) CD8(+)T cells, an increase or decrease of which over time reflected the disease severity in this patient. Treatment of patients with EBV-HLH varies from steroid alone to intensive chemotherapy or hematopoietic stem cell transplantation. Easy monitoring of EBV-infected cells by using flow cytometry over time may provide useful information to choose an appropriate treatment for each individual patient with EBV-HLH. PMID- 22499052 TI - [Effective treatment with rituximab for primary thrombotic thrombocytopenic purpura complicated with multiple cerebral infarctions]. AB - A 22-year-old woman was diagnosed with thrombotic thrombocytopenic purpura (TTP). She had a high fever and disorientation without renal dysfunction. She immediately underwent plasma exchange and prednisolone treatment, but they proved ineffective. She subsequently suffered from left major cerebral infarction with right-side hemiplegia. Therefore, 375 mg/m(2) of rituximab was administered weekly from day 14 with informed consent. Immediate improvements were noted in not only the hematological and biochemical parameters such as platelet count, hemoglobin level, rate of fragmented red cells, and serum LDH level but also the neurological symptoms and MRI findings. The universal histopathologic findings of TTP are characterized by hyaline thrombi formed by the aggregation of platelets, mostly in small arterioles and capillaries. Therefore, abnormal findings are rarely detected by imaging modalities such as CT and MRI. Moreover, TTP with major stroke is an extremely rare occurrence. In conclusion, we present a patient with refractory TTP with major cerebral infarction, who was effectively treated with rituximab. PMID- 22499053 TI - [Additional chromosomal abnormality of inv(16)(p13q22) to del(7)(q32) in a patient with acute myelomonocytic leukemia]. AB - We report a 54-year-old man with acute myeloid leukemia (AML) carrying del(7)(q32) and inv(16)(p13q22). He was diagnosed as having AML M4Eo according to the FAB classification. RT-PCR for CBFbeta/MYH11 gene was positive. Karyotype analysis revealed the primary chromosomal abnormality to be del(7)(q32) and inv(16)(p13q22) developed as a secondary abnormality. He achieved complete remission after one course of induction chemotherapy and remained in remission after several courses of consolidation therapy. del(7q) is classified into an intermediate risk group or an adverse risk group, while inv(16)/t(16;16) is classified into a favorable risk group. Some AML cases with inv(16)/t(16;16) exhibit del(7q) as an additional chromosomal abnormality. It was reported that such cases showed good prognosis despite the presence of del(7q). However, AML cases with del(7q) and inv(16)/t(16;16) as secondary chromosomal abnormalities are rare. Further study is needed to clarify the clinical manifestations of such cases. PMID- 22499054 TI - [Complication of pernicious anemia during interferon-beta treatment for type C chronic hepatitis]. AB - A 62-year-old man with chronic hepatitis C underwent interferon (IFN)-beta therapy. After treatment for a period comprising 29 months and 2 weeks, hematological results showed a decrease in white blood cell, hemoglobin, and platelet counts (WBC 2,300/ul, Hb 7.2 g/dl, PLT 4.7*10(4)/ul), and IFN therapy was stopped. Despite therapy discontinuation, the pancytopenia continued to progress with elevation of LDH (LDH 4,898 IU/l), and the patient was admitted to our hospital with suspected hematological disease. The patient underwent clinical screening, and pernicious anemia caused by vitamin B12 deficiency was diagnosed. The anemia rapidly improved with vitamin B12 treatment. Interferon is the mainstay of treatment for patients with viral hepatitis. While the adverse effects of interferon therapy are widely recognized, only a few reports have documented pernicious anemia developing during IFN-therapy. We recommend that particular attention be paid to such clinical and laboratory conditions as megaloblastic anemia when administering IFN. We also recommend checking the vitamin B12 level, as a deficiency of this vitamin may lead to the development of megaloblastic anemia. PMID- 22499055 TI - [Significant decrease in factor VII activity by tissue thromboplastin derived from rabbit brain in a patient with congenital factor VII deficiency (FVII Padua)]. AB - Congenital factor VII (FVII) deficiency is a bleeding disorder that requires optimal hemostatic management for each case due to its wide variety of bleeding symptoms. We experienced a patient with inherited FVII deficiency who demonstrated different FVII activities depending on tissue thromboplastins used for assays. An 82-year-old woman without any episodes of abnormal bleeding was found to have different FVII activities of 1.4% and 32% when assayed using thromboplastins from rabbit brain and human placenta, respectively. DNA sequencing analysis revealed a homozygous missense mutation of G10828A (FVII Padua) that caused an amino acid substitution of Arg304 to Gln (R304Q). Carriers of 304Q alleles are usually clinically asymptomatic and do not require FVII replacement therapies even in cases of homozygotes. In case a prolonged prothrombin time or reduced FVII activity is detected, re-examination using thromboplastins of other sources can be helpful for preliminary diagnosis of R304Q, in order to prevent unnecessary FVII replacement therapies. PMID- 22499056 TI - [Effective infliximab treatment for a recurrent type of acute intestinal graft versus-host disease accompanied by steroid-induced depression]. AB - A 22-year-old man with chronic active Epstein-Barr virus infection underwent allogeneic bone marrow transplantation (allo-BMT) from an HLA two allele mismatched unrelated donor. Ten months after allo-BMT, he developed protein losing enteropathy following a respiratory syncytial virus infection. A diagnosis of a recurrent type of acute graft-versus-host disease (GVHD) was made based on the histopathological findings, such as the infiltration of T lymphocytes into the superficial epithelium and crypts, and apoptotic bodies in crypts. Although methylprednisolone (mPSL: 10 mg/kg) administration for two consecutive days improved gastrointestinal symptoms, acute pancreatitis and severe depression developed in association with corticosteroid treatment. Reduction of mPSL and administration of infliximab (5 mg/kg/dose, 3 times) resulted in rapid improvement of depression and pancreatitis without aggravating intestinal GVHD. Recent studies have demonstrated that tumor-necrosis-factor (TNF)-alpha is associated with not only GVHD but also depression and acute pancreatitis. In the present case, anti-TNF-alpha treatment enabled us to reduce corticosteroid dose without aggravating GVHD, which suggests that this approach might be effective for the treatment of depression and acute pancreatitis. PMID- 22499057 TI - Highly interconnected ordered mesoporous carbon-carbon nanotube nanocomposites: Pt-free, highly efficient, and durable counter electrodes for dye-sensitized solar cells. AB - We report the preparation of highly interconnected ordered mesoporous carbon carbon nanotube nanocomposites which show Pt-like dye-sensitized solar cell (DSSC) efficiency and remarkable long-term durability as DSSC counter electrodes. PMID- 22499058 TI - Central venous saturation is not an alternative to mixed venous saturation during cardiopulmonary bypass in coronary artery surgery patients. AB - BACKGROUND: To evaluate the correlation and agreement between central venous saturation (ScvO(2)) and mixed venous saturation (SvO(2)) during cardiopulmonary bypass. METHODS: Twenty-two consecutive patients scheduled for coronary artery surgery were prospectively included. Paired measurements of ScvO(2) and SvO(2) were performed 5 minutes after aortic cross-clamping, after each cardioplegia dose and after de-clamping of the aortic cross-clamp. ScvO(2) and SvO(2) were measured, respectively, by a fibreoptic catheter in the superior vena cava and on blood samples from the venous return line of the extracorporeal circuit, using a blood gas analyser RESULTS: Ninety-five paired measurements of venous saturation were obtained. Correlation between the measurements was associated with an r = 0.55. The mean bias was 2.2 [Limits of agreement: -13.6%, +18%]. Changes in oxygen saturation over time showed an r = 0.4 and a mean bias of 0.2 [Limits of agreement: -17.9%, +18.3%]. Multivariate analysis identified the oxygen consumption index as the only factor explaining this variability. CONCLUSIONS: Although mean biases between the measurements were low, limits of agreement were too large to provide a clinically acceptable estimation of SvO(2) by ScvO(2) in these conditions. Variations in regional oxygen consumption seem to be the main factor worsening the relationship. PMID- 22499059 TI - The reductive reaction mechanism of tobacco nitrite reductase derived from a combination of crystal structures and ultraviolet-visible microspectroscopy. AB - Assimilatory nitrite reductase (aNiR) reduces nitrite to an ammonium ion and has siroheme and a [Fe(4)S(4)] cluster as prosthetic groups. A reaction mechanism for Nii3, an aNiR from tobacco, is proposed based on high resolution X-ray structures and UV-Vis (ultraviolet-visible) microspectroscopy of Nii3-ligand complexes. Analysis of UV-Vis spectral changes in Nii3 crystals with increasing X-ray exposure showed prosthetic group reductions. In Nii3-NO2(-) structures, X-ray irradiation enhanced the progress of the reduction reaction, and cleavage of the N-O bond was observed when X-ray doses were increased. Crystal structures of Nii3 with other bound ligands, such as Nii3-NO and Nii3-NH(2)OH, were also determined. Further, by combining information from these Nii3 ligand-bound structures, including that of Nii3-NO2(-), with UV-Vis microspectral data obtained using different X-ray doses, a reaction mechanism for aNiR was suggested. Cleavage of the two N-O bonds of nitrite was envisaged as a two-step process: first, the N-O bond close to Lys224 was cleaved, followed by cleavage of the N-O bond close to Arg109. X-ray structures also indicated that aNiR-catalyzed nitrite reduction proceeded without the need for conformation changes in active site residues. Geometrical changes in the ligand molecules and the placement of neighboring water molecules appeared to be important to the stability of the active site residue interactions (Arg109, Arg179, and Lys224) and the ligand molecule. These interactions may contribute to the efficiency of aNiR reduction reactions. PMID- 22499060 TI - Distal pancreatectomy with en bloc celiac resection for locally advanced pancreas carcinoma. AB - In locally advanced pancreatic body cancers, cancer infiltrates major vessels such as the celiac axis, common hepatic artery and superior mesenteric artery or vein, which is the borderline of resectability. Patients also suffer severe abdominal pain. Kondo and Hirano et al. developed a radical operation called "distal pancreatectomy with en bloc celiac resection (DP-CAR)" for such cases. We applied this procedure three times in two patients with pancreatic body carcinomas, in which combined vascular resection was necessary. Radical operation was eventually achieved. PMID- 22499061 TI - Fluorescence imaging visualizes three sets of regional lymph nodes in patients with lower rectal cancer. AB - BACKGROUND/AIMS: To demonstrate the usefulness of a fluorescence imager (photodynamic eye; PDE) for observation of lymph flow in lower rectal cancer (LRC). METHODOLOGY: Between October 2006 and January 2010, PDE observations were performed in 14 patients with LRC. After induction of general anesthesia, a total of 2mL of indocyanine green (ICG) (2.5mg/mL) was injected into the submucosal layer on the dentate line or the anal margin of the LRC. RESULTS: Preoperative PDE observation was able to demonstrate several lymph flows running to the bilateral inguinal areas from the perianal area immediately after ICG injection in 13 of the patients (92.9%). Although these flows were pooled in the bilateral inguinal areas, there was no pooling of such lymph flows in the perianal area. Intraoperative PDE observation was able to demonstrate not only mesenteric lymph nodes in all patients but also bilateral lateral lymph nodes in 13 patients (92.9%). Although 6 patients had undergone sphincter-preserving surgery (SPS), no local recurrence was observed in such patients during the observation period. CONCLUSIONS: PDE is able to visualize three sets of regional lymph nodes in patients with LRC, suggesting that it would be useful for determining the effectiveness of SPS for such patients. PMID- 22499062 TI - Selecting patients with ankylosing spondylitis for TNF inhibitor therapy: comparison of ASDAS and BASDAI eligibility criteria. AB - OBJECTIVE: To compare Ankylosing Spondylitis Disease Activity Score (ASDAS) >=2.1 with BASDAI >4 as an eligibility criterion for initiation of TNF inhibitor (TNFi) treatment in AS, and to investigate if ASDAS performs satisfactorily in patients without elevated CRP or without peripheral joint swelling. METHODS: Two hundred and eighty-nine patients starting their first TNFi were identified from a longitudinal observational study (NOR-DMARD) and grouped according to the fulfilment of ASDAS and BASDAI TNFi eligibility criteria. The 3-month responses were compared across several response measures. Patients were also grouped according to CRP level and the presence or absence of swollen joints, and responses were compared. RESULTS: The majority of patients (n = 212) fulfilled both eligibility criteria, and this group had the best response. Very few patients (n = 4) fulfilled only the BASDAI criterion. Patients fulfilling only the ASDAS criterion (n = 48) had a reasonable response. Patients with an elevated vs not elevated CRP at baseline had better responses according to all response measures, but patients without elevated CRP also responded. We also observed trends towards better responses in patients with vs without peripheral joint swelling. CONCLUSION: More patients were eligible for TNFi using the ASDAS than the BASDAI eligibility criterion (n = 260 vs n = 216). Fulfilment of both criteria gave the greatest likelihood of improvement, but the patients who only fulfilled the ASDAS criterion also improved. ASDAS was found to be applicable also in subgroups without elevated CRP and without peripheral joint swelling. PMID- 22499063 TI - Thermal conductivity and secondary porosity of single anatase TiO2 nanowire. AB - Single anatase TiO2 nanowire is synthesized using the electrospinning technique with the sol-gel method and is suspended over a pre-processed 100 um-wide TEM grid for further characterization. The diameters of the nanowires fall in the range of 250-400 nm. The transient electrothermal (TET) method is adopted to acquire the voltage-time (U-t) profile of the Ir-coated nanowire under step Joule heating. The intrinsic thermal diffusivity of single anatase TiO2 nanowires varies from 1.3 to 4.6 * 10-6 m2 s-1, and the thermal conductivity changes distinctly from 1.3 to 5.6 W m-1 K-1, much lower than the value of the bulk counterpart: 8.5 W m-1 K-1. The density and thermal conductivity increase significantly with the diameter, largely because at larger diameters less secondary porosity is left by decomposition of organic composites and their escape from the wire during calcination. The density of TiO2 nanowires is found to be much lower than that of the bulk counterpart. This is supported by the SEM image of the secondary porous surface. High secondary porosity is observed for TiO2 nanowires, ranging from 18% to 63%. This very high secondary porosity confirms that the decomposition of PVP content may distort the fibrous matrix and leave vacancies. In addition, the transition from amorphous to anatase phase could also create a porous state due to crystal particle aggregation. PMID- 22499064 TI - Charge and orbital order in frustrated Pb3Mn7O15. AB - The candidate magnetoelectric Pb(3)Mn(7)O(15) has a structure consisting of one third filled kagome layers linked by ribbons of edge sharing octahedra in the stacking direction. Previous reports have indicated a complex hexagonal orthorhombic structural transition upon cooling through ~335 K, although its origins are uncertain. Here both structures are revisited using a combination of neutron and synchrotron x-ray diffraction data. Large shifts of oxygen positions are detected, which show that the interlayer sites and those which occupy voids in the kagome lattice are trivially charge ordered in both phases. The symmetry breaking is found to occur due to Mn(3+) orbital ordering on the ribbon sites and charge ordering of the subset of layer sites which make up a kagome network. PMID- 22499067 TI - Enantioselective recognition by a highly ordered porphyrin-assembly on a chiral molecular gel. AB - Enantioselective recognition of amino acids was achieved by using a highly ordered chiral assembly of achiral porphyrin on a chiral molecular gel. Exceptionally high enantioselectivity was observed for histidine derivatives by monitoring the CD patterns and fluorescence quenching, K(SV) (l): 26.3 * 10(3) M( 1); K(SV)(D)-enantiomer: 7.03 * 10(3) M(-1). PMID- 22499068 TI - Valence-induced assembly of Cu(I)-Cu(II) ions into different discrete coordination architectures by a disk-shaped polypyridyl ligand. AB - The valences of metal ions were found to play key roles in controlling the formation and structures of discrete coordination architectures in a copper and disk-shaped hexa-monodentate ligand system. When Cu(I) and Cu(II) ions react with a polydentate ligand HPDQ, a hexanuclear "double-decker" like discrete "LM(3)M(3)L" coordination architecture (CuI)(6)(HPDQ)(2)(CHCl(3))(8) (complex 1), and a "LM(3)L + LM(3)" composite structure complex (Cu(NO(3))(2))(6)(HPDQ)(3) (complex 2) are formed, respectively. PMID- 22499070 TI - Do poor "hand offs" between the proximal and distal esophagus cause peristaltic "fumbles"? PMID- 22499071 TI - A global perspective on irritable bowel syndrome: a consensus statement of the World Gastroenterology Organisation Summit Task Force on irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is common in western Europe and North America, and many aspects of its epidemiology, risk factors, and natural history have been described in these regions. Recent data suggest, however, that IBS is also common in the rest of the world and there has been some evidence to suggest some differences in demographics and presenting features between IBS in the west and as it is experienced elsewhere. The World Gastroenterology Organization, therefore, established a Task Force comprising experts on the topic from all parts of the world to examine IBS from a global perspective. IBS does, indeed, seem to be common worldwide though with some significant variations in prevalence rates between regions and countries and there may well be some potentially interesting variations in presenting symptoms and sex distribution. The global map of IBS is far from complete; community-based prevalence data is not available from many areas. Furthermore, while some general trends are evident in terms of IBS impact and demographics, international comparisons are hampered by differences in diagnostic criteria, study location and methodology; several important unanswered questions have been identified that should form the basis for future collaborative research and have the potential to shed light on this challenging disorder. PMID- 22499072 TI - Diagnostic accuracy of probe-based confocal laser endomicroscopy and narrow band imaging in detection of dysplasia in duodenal polyps. AB - GOALS: To estimate the accuracy of probe-based confocal laser endomicroscopy (pCLE) and narrow band imaging (NBI), individually and in combination, for classification of duodenal polyps. BACKGROUND: Ex vivo pathologic diagnosis of duodenal polyps causes time delay, requiring separate procedures for diagnosis and therapy. It also involves small risk of pancreatitis in ampullary adenomas and can make subsequent endoscopic mucosal resection more difficult by "tacking down" mucosa. In vivo diagnosis with pCLE and NBI may avoid these complications and may guide immediate therapy. STUDY: During high-definition white light endoscopy, 1 endoscopist (M.B.W.) performed NBI and then, pCLE of duodenal sites. Matched tissue sampling or endoscopic mucosal resection was performed. Confocal videos were recorded, de-identified, and reviewed by same endoscopist, blinded to histopathology, 1 month later. Confocal features of dysplasia in Barrett esophagus were applied for detection of duodenal dysplasia. RESULTS: Of 65 sites from 36 participants, 24 lesions showed dysplasia, whereas 41 polyps and control sites were nondysplastic on histopathology, used as standard reference. The accuracy, sensitivity, and specificity of pCLE were 83%, 92%, and 78%, whereas that of NBI were 80%, 83%, and 78%, respectively. In subset of 49 lesions with similar pCLE and NBI diagnosis, the accuracy, sensitivity, and specificity, improved significantly and was found to be 92%, 95%, and 90%, respectively. CONCLUSIONS: Our study suggests that pCLE has superior sensitivity as compared with NBI for detection of dysplasia in duodenal polyps. Combined accuracy of pCLE and NBI approaches that of ex vivo pathology, which may help in avoiding biopsy sampling. PMID- 22499073 TI - Prevalence of fibromyalgia among patients with chronic hepatitis C infection: relationship to viral characteristics and quality of life. AB - OBJECTIVES: We determined the prevalence of fibromyalgia syndrome (FMS) in a cohort of subjects with chronic hepatitis C virus (HCV), and the relationship to subject demographics, viral characteristics, and quality of life. METHODS: In a cross-sectional study of a cohort of HCV-infected individuals, all subjects underwent a standard assessment including history, clinical examination, and functional assessments for pain and disability. RESULTS: A total of 185 subjects met the inclusion criteria. Median age was 48.7 years, and 110 (59%) were women. A total of 106 (57%) of the subjects met criteria for the presence of FMS. Widespread pain and >=11 tender points were present in all of the subjects with FMS, fatigue in 98 (92%), and depression in 60 (57%). Among those with FMS, mean pain score was 70+/-11.78 and 36% reported some functional impairment on (HAQ DI>0), with 17% reporting moderate-to-severe functional impairment (HAQ-DI>=1.5). CONCLUSIONS: This study reveals a high prevalence of FMS (57%) among subjects with chronic HCV infection, one third of whom reported some degree of functional impairment. Recognition and management of this condition in such patients will help improve their quality of life. PMID- 22499074 TI - Relationship of HLA-DRB1 alleles with hepatocellular carcinoma development in chronic hepatitis B patients. AB - GOALS: We intended to analyze the relationship between specific human leukocyte antigen (HLA)-DRB1 alleles and development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. STUDY: A database of 468 consecutive CHB patients who received lamivudine for more than 12 months between July 1996 and February 2011 was retrospectively analyzed. Sera and buffy coats samples were obtained between April 2008 and April 2010. Six-digit HLA-DRB1 genotyping was performed with sequence-based typing. Serum alpha fetoprotein levels and ultrasonography or computed tomography image studies were assessed every 3 to 6 months for surveillance of HCC. RESULTS: At baseline, median age was 43 years (range, 16 to 71) [male: 359 (76.7%); HBeAg positivity: 385 (82.3%)]. Among the 27 HLA-DRB1 alleles identified, HLA-DRB1*090102, *080302, and *070101 were the most frequent (>10%). HCC was diagnosed in 36 (7.7%) patients during the median follow-up of 69 months. The frequency of the HLA-DRB1*140101 allele was 9.0% and significantly higher in patients of the HCC group than those of the non-HCC group (19.4 vs. 8.1%, P=0.014). The 2-year, 4-year, and 6-year cumulative rates of HCC development were markedly higher in patients with HLA-DRB1*140101 than those without HLA-DRB1*140101 (2.4, 8.2, and 25.1% vs. 1.9, 4.7, and 7.4%, respectively, P=0.011). No other HLA-DRB1 alleles were associated with HCC development. Baseline clinical characteristics did not differ between patients with and without HLA-DRB1*140101. CONCLUSIONS: The HLA-DRB1*140101 allele may be potentially associated with increased risk of HCC development in CHB patients, irrespective of the replicative activity of hepatitis B virus and antiviral responsiveness. PMID- 22499075 TI - Transient celiac autoimmunity or just temporary fluctuation? PMID- 22499078 TI - Spectrally selective 3D TSE imaging of phosphocreatine in the human calf muscle at 3 T. AB - Quantitative information about concentrations of several metabolites in human skeletal muscle can be obtained through localized (31)P magnetic resonance spectroscopy methods. However, these methods have shortcomings: long acquisition times, limited volume coverage, and coarse resolution. Significantly higher spatial and temporal resolution of imaging of single metabolites can be achieved through spectrally selective three-dimensional imaging methods. This study reports the implementation of a three-dimensional spectrally selective turbo spin echo sequence, on a 3T clinical system, to map the concentration of phosphocreatine in the human calf muscle with significantly increased spatial resolution and in a clinically feasible scan time. Absolute phosphocreatine quantification was performed with the use of external phantoms after relaxation and flip angle correction of the turbo spin-echo voxel signal. The mean +/- standard deviation of the phosphocreatine concentration measured in five healthy volunteers was 29.4 +/- 2.5 mM with signal-to-noise ratio of 14:1 and voxel size of 0.52 mL. PMID- 22499079 TI - Tobacco use treatment at the U.S. National Cancer Institute's designated Cancer Centers. AB - INTRODUCTION: Tobacco use is a leading cause of cancer, and continued use after cancer diagnosis puts patients at greater risk for adverse health outcomes, including increased risk for cancer recurrence. This study surveyed National Cancer Institute (NCI)-designated Cancer Centers to assess the availability of tobacco use treatment (TUT) services. METHODS: Directors and oncology providers of 58 NCI-designated Cancer Centers received invitations to participate in an online survey. The questionnaire asked about attitudes, awareness, policies, and practices related to TUT; barriers to treatment provision; and factors likely to increase services. RESULTS: All 58 Cancer Centers participated. Twelve (20.7%) Centers reported no TUT services for their patients. Of the remainder, 34 (58.6%) reported a TUT program within their Center and 12 (20.7%) reported external TUT services in their health care system or affiliated university. Only 62% of Centers reported routinely providing tobacco education materials to patients, just over half reported effective identification of patient tobacco use, and less than half reported an employee dedicated to providing TUT services or a clear commitment to providing TUT services from Center leadership. The 34 centers with internal TUT programs reported significantly greater services and administration support for TUT Services. CONCLUSIONS: These data demonstrate a national need for Cancer Centers to embrace and incorporate recommended standards for TUT. Tying TUT services to NCI recognition and providing stable funding for TUT services in Cancer Centers could lead to better health outcomes, treatment efficacy, and satisfaction for all U.S. Cancer Centers and their patients. PMID- 22499080 TI - Novel D-pi-A structured Zn(II)-porphyrin dyes containing a bis(3,3 dimethylfluorenyl)amine moiety for dye-sensitised solar cells. AB - A high solar-to-electricity conversion efficiency of 7.22% was achieved with a short circuit current (J(sc)) of 15.30 mA cm(-2), an open circuit voltage (V(oc)) of 669 mV and a fill factor (FF) of 0.71 for the 2Flu-ZnP-CN-COOH dye with a multi-functional co-adsorbent, under 100 mW cm(-2) AM 1.5 G simulated light. PMID- 22499081 TI - Distinguishing true coagulase-negative Staphylococcus infections from contaminants in the neonatal intensive care unit. AB - OBJECTIVE: To characterize true coagulase-negative Staphylococcus (CoNS) infections in infants receiving neonatal intensive care. STUDY DESIGN: Retrospective cohort study of neonatal intensive care unit (NICU) infants with clinical sepsis and CoNS isolated from >= 2 blood cultures (BCs) or one BC and a sterile site (proved infection) or CoNS isolated from one BC and deemed significant after blinded data review (probable infection). RESULT: In all, 98% of 40 proved and 96% of 55 probable infections occurred in infants with birth weight (BW) <2000 g and gestation <34 weeks. Total central lines (CLs) placed, but not CL duration or presence in situ, predicted proved (odds ratio (OR) 3.5, 95% confidence interval (CI) 1.4 to 8.3; P=0.005) and probable infection (OR 2.7, 95% CI 1.3 to 5.6; P=0.007) by multivariate analysis as did lethargy and gastric residuals. CONCLUSION: True CoNS infection is unlikely in infants with BW >2000 g and gestation >34 weeks. Total CL required for care, lethargy and gastric residuals predicted true CoNS infection. PMID- 22499083 TI - Increased cord blood angiotensin II concentration is associated with decreased insulin sensitivity in the offspring of mothers with gestational diabetes mellitus. AB - OBJECTIVE: To determine cord blood angiotensin II (Ang II) concentration and assess its relationship to fetal insulin sensitivity in the offspring of mothers with gestational diabetes mellitus (GDM) at birth. STUDY DESIGN: Thirty women with GDM and 30 healthy women were evaluated at elective cesarean delivery. Cord blood was obtained for measurement of Ang II, glucose and insulin. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated and used to estimate fetal insulin sensitivity. RESULT: The offspring of mothers with GDM had higher ponderal index (PI), HOMA-IR and cord Ang II and insulin concentrations than the offspring of healthy mothers. Cord insulin concentration and HOMA-IR were positively associated with PI in all the offspring. Cord Ang II concentration was positively associated with HOMA-IR in the offspring of mothers with GDM. CONCLUSION: Increased cord Ang II concentration is associated with decreased insulin sensitivity in the offspring of mothers with GDM. PMID- 22499084 TI - Early echocardiographic prediction of ductal closure in neonates <= 30 weeks gestation. AB - OBJECTIVE: To determine the accuracy of the patent ductus arteriosus:left pulmonary artery ratio (PDA:LPA) on echocardiogram (ECHO) at 3-day postnatal in predicting spontaneous PDA closure in neonates <= 30 weeks gestational age (GA). STUDY DESIGN: ECHOs were performed at 72 h to characterize PDA size as closed-to small (PDA:LPA <0.5) or moderate-to-large (PDA:LPA >= 0.5) and at 10 days to determine spontaneous closure (defined as closed-to-small in the absence of medical and/or surgical treatment). Caretakers were blinded to results; treatment was based on standard care. Neonates were prospectively enrolled and stratified: <27 weeks (n=31) and 27 to 30 weeks (n=65). RESULT: Neonates <27 weeks with closed-to-small PDAs had 60% spontaneous closure vs 9% when moderate-to-large (positive predictive value (PPV) 60%, negative predictive value (NPV) 91%). Neonates 27 to 30 weeks had 95% spontaneous closure vs 27%, respectively (PPV 95%, NPV 73%). Inter-observer variability for the initial ECHO was 0.84. CONCLUSION: PDA size defined by PDA:LPA at 3 days postnatal in combination with GA predicts spontaneous PDA closure. PMID- 22499082 TI - Efficacy of phototherapy devices and outcomes among extremely low birth weight infants: multi-center observational study. AB - OBJECTIVE: Evaluate the efficacy of phototherapy (PT) devices and the outcomes of extremely premature infants treated with those devices. STUDY DESIGN: This substudy of the National Institute of Child Health and Human Development Neonatal Research Network PT trial included 1404 infants treated with a single type of PT device during the first 24+/-12 h of treatment. The absolute (primary outcome) and relative decrease in total serum bilirubin (TSB) and other measures were evaluated. For infants treated with one PT type during the 2-week intervention period (n=1223), adjusted outcomes at discharge and 18 to 22 months corrected age were determined. RESULT: In the first 24 h, the adjusted absolute (mean (+/ s.d.)) and relative (%) decrease in TSB (mg dl(-1)) were: light-emitting diodes (LEDs) -2.2 (+/-3), -22%; Spotlights -1.7 (+/-2), -19%; Banks -1.3 (+/-3), -8%; Blankets -0.8 (+/-3), -1%; (P<0.0002). Some findings at 18 to 22 months differed between groups. CONCLUSION: LEDs achieved the greatest initial absolute reduction in TSB but were similar to Spots in the other performance measures. Long-term effects of PT devices in extremely premature infants deserve rigorous evaluation. PMID- 22499085 TI - Couple therapy for depression. AB - Relationship problems and depression often influence one another in a bidirectional, recursive fashion. Results from several clinical trials have demonstrated that couple therapy is effective in improving depression and reducing relationship problems. In this article, we describe an approach to working with depression in partnered individuals who are also unhappy in their relationship. This cognitive-behavior approach strives to (a) eliminate major stressors and reestablish positive activities in the relationship, (b) improve communication and problem solving in the relationship, and (c) solidify gains made in therapy and prevent relapse. The typical course of therapy is described and demonstrated in a case illustration. Couple therapy is a promising treatment for depressed individuals in distressed relationships. PMID- 22499086 TI - The true utility and indication for hand-held nerve conduction devices. PMID- 22499088 TI - Hand-held nerve conduction device in carpal tunnel syndrome: a prospective study. AB - INTRODUCTION: We assessed the clinical impact of replacing standard neurophysiologic testing with a hand-held device (Mediracer) for diagnosis of carpal tunnel syndrome (CTS). METHODS: One hundred patients (200 hands) with suspected CTS were studied by blinded assessors [Hand-therapist (HT)1 and Consultant Neurophysiologist] using the Mediracer, followed by standard neurophysiologic testing. To simulate testing by personnel without neurological training, Mediracer recordings were analyzed separately by an assessor who had not seen the patients (HT2). RESULTS: Correlation of the CTS grades was 0.94 for the results obtained by HT1, and 0.87 for HT2. The sensitivity and specificity of the Mediracer was 0.85 and 0.9, respectively, by HT1, and 0.84 and 0.89 for HT2. Nine patients had conditions other than CTS, and 35 patients were judged to require further investigation. CONCLUSIONS: The Mediracer should only be used in patients with typical CTS symptoms and signs and no muscle wasting who have had careful neurological assessment. PMID- 22499089 TI - Electrical impedance myography in spinal muscular atrophy: a longitudinal study. AB - INTRODUCTION: New approaches for assessing disease progression in spinal muscular atrophy (SMA) are needed. In this study, we evaluate whether electrical impedance myography (EIM) can detect disease progression in SMA compared with a group of healthy children of similar age. METHODS: Twenty-eight children with SMA and 20 normal children underwent repeated EIM testing in four muscles at regular intervals for up to 3 years. An average rate of change of EIM was calculated for each subject and normalized to subcutaneous fat thickness and muscle girth. RESULTS: Multiple EIM parameters showed a change in normal subjects over a mean of 16.7 months; however, no change was found in SMA patients over this period. CONCLUSIONS: EIM could detect non-mass-dependent muscle maturation in healthy children. In contrast, the muscle in children with SMA, as measured by EIM, was virtually static, showing no evidence of growth or active deterioration. PMID- 22499087 TI - Autoimmune stiff person syndrome and related myelopathies: understanding of electrophysiological and immunological processes. AB - Stiff person syndrome (SPS) is a disabling autoimmune central nervous system disorder characterized by progressive muscle rigidity and gait impairment with superimposed painful spasms that involve axial and limb musculature, triggered by heightened sensitivity to external stimuli. Impaired synaptic GABAergic inhibition resulting from intrathecal B-cell-mediated clonal synthesis of autoantibodies against various presynaptic and synaptic proteins in the inhibitory neurons of the brain and spinal cord is believed to be an underlying pathogenic mechanism. SPS is most often idiopathic, but it can occur as a paraneoplastic condition. Despite evidence that anti-GAD and related autoantibodies impair GABA synthesis, the exact pathogenic mechanism of SPS is not fully elucidated. The strong association with several MHC-II alleles and improvement of symptoms with immune-modulating therapies support an autoimmune etiology of SPS. In this review, we discuss the clinical spectrum, neurophysiological mechanisms, and therapeutic options, including a rationale for agents that modulate B-cell function in SPS. PMID- 22499090 TI - Predictors of response to immunomodulation in patients with myasthenia gravis. AB - INTRODUCTION: Factors determining response to intravenous immunoglobulin (IVIg) and plasmapheresis in myasthenia gravis (MG) have not been evaluated systematically. METHODS: This study included patients treated with IVIg (n = 63) or plasmapheresis (n = 42) from two trials evaluating IVIg vs. placebo or plasmapheresis in MG. Response was defined as improvement in the quantitative myasthenia gravis score (QMGS) of >=3.5 points at day 14. Baseline clinical, electrophysiological, and immunological factors were analyzed as predictors. RESULTS: Baseline QMGS, acetylcholine receptor antibody (AChRAb) positivity, single-fiber electromyography (SFEMG) jitter, and percent abnormal pairs and percent blocking pairs were higher in responders than in non-responders. Using multivariate logistic regression, the odds ratio for response was 13.0 (1.01 381.5) in QMGS 11-17 and 15.3 (1.34-414.3) in QMGS >17 compared with QMGS <11. CONCLUSIONS: Baseline QMGS, AChRAb positivity, and SFEMG parameters were more abnormal in patients who responded to treatment. Using multivariate regression, baseline QMGS remained as the only significant independent predictor of response. PMID- 22499091 TI - Agreement between clinical screening procedures for neuropathy in the feet. AB - INTRODUCTION: The correlation between monofilament testing, symptom surveys, and electrodiagnostic studies for the diagnosis of axonal polyneuropathy has not been well studied. This investigation was done to assess the agreement between these procedures in a non-random sample of volunteers. METHODS: The procedures evaluated included electrodiagnostic tests of the sural nerve, monofilament testing of the great toe, a symptom survey, and a body diagram. Kappa coefficients and sensitivity and specificity, using nerve conduction as a "gold standard," were used to determine the agreement between various combinations of procedures. RESULTS: Poor agreement (kappa values -0.12-0.44) and sensitivity (sensitivity <30%) were found for all combinations of symptoms and monofilament results in comparison with sural peak latency and amplitude. CONCLUSIONS: Overall, the results demonstrated a low discriminatory power for the screening procedures for identifying persons with impaired sural nerve function. The results highlight the need for further development and evaluation of screening methods for distal neuropathy in population-based studies. PMID- 22499092 TI - Muscle magnetic resonance imaging sensitivity does not decrease in chronic, mild, or proximal lower limb neuropathies. AB - INTRODUCTION: Muscle magnetic resonance imaging (MRI) is an innovative tool for exploring focal neuropathies. However, its usefulness in mild, proximal, or chronic lesions, when electromyography (EMG), the current "gold standard" sensitivity is inadequate, has yet to be studied. METHODS: Clinical, MRI, and EMG examinations were performed in 113 muscles of 17 consecutive patients with clinically diagnosed lower limb focal neuropathies. The sensitivity and specificity of MRI and EMG were evaluated in relation to disease duration, severity, and anatomical location. RESULTS: Muscle MRI was highly sensitive for the detection of denervated muscle, and, unlike EMG, its sensitivity did not decrease regardless of the anatomical location, duration, or severity of the neuropathy. Five MRI false positives were noted, including three in the thigh muscles. CONCLUSIONS: Muscle MRI is an alternative tool to EMG in proximal, mild, or chronic clinical diagnoses of lower limb focal neuropathies. However, it also seems prone to false-positive results, particularly in proximal muscles. PMID- 22499093 TI - Protective effect of scFv-DAF fusion protein on the complement attack to acetylcholine receptor: a possible option for treatment of myasthenia gravis. AB - INTRODUCTION: Autoantibody-induced complement activation, which causes disruption of the postsynaptic membrane, is recognized as a key pathogenic factor in myasthenia gravis (MG). Therefore, specific targeting of complement inhibitors to the site of complement activation is a potential therapeutic strategy for treatment of MG. METHODS: We assessed expression of single-chain antibody fragment-decay accelerating factor (scFv-DAF), comprising a single-chain fragment scFv1956 based on the rat complement inhibitor DAF in prokaryotic systems, and studied its inhibitory effect on complement deposition in vitro. RESULTS: The recombinant conjugate scFv-DAF completely retained the wild-type binding activity of scFv1956 to AChR and inhibited complement activation of DAF in vitro. CONCLUSIONS: We found that scFv-DAF could bind specifically to TE671 cells, and it is significantly more potent at inhibiting complement deposition than the untargeted parent molecule DAF. scFv-DAF may be a candidate for in vivo protection of the AChR in MG. PMID- 22499094 TI - Epidemiology of adult idiopathic inflammatory myopathies in a U.S. managed care plan. AB - INTRODUCTION: Idiopathic inflammatory myopathies have a reported incidence of 0.1 to 1 per 100,000 person-years and prevalence of 0.55 to 6 per 100,000 in the United States. METHODS: We retrospectively examined medical claims for adults aged >=18 years with myositis (International Classification of Diseases, Ninth Revision, Clinical Modification codes 710.3 [dermatomyositis], 710.4 [polymyositis], and 728.81 [interstitial myositis]) from 2003 to 2008 in a large US managed care database. RESULTS: The incidence and prevalence cohorts comprised 1,941 and 3,112 subjects, respectively. From 2003 to 2008, the adjusted annual incidence of myositis ranged from 5.8 to 7.9 per 100,000 person-years, and the annual prevalence of myositis ranged from 14.0 to 17.4 per 100,000. CONCLUSIONS: The incidence and prevalence of idiopathic inflammatory myopathies in the managed care plan studied was higher than previously reported in the United States. Because of the limitations inherent in claims analysis, additional research is needed to substantiate these results. PMID- 22499095 TI - Influence of botulinum toxin on rabbit jaw muscle activity and anatomy. AB - INTRODUCTION: Muscles can adapt their fiber properties to accommodate to new conditions. We investigated the extent to which a decrease in muscle activation can cause an adaptation of fiber properties in synergistic and antagonistic jaw muscles. METHODS: Three months after the injection of botulinum toxin type A in one masseter (anterior or posterior) muscle changes in fiber type composition and fiber cross-sectional areas in jaw muscles were studied at the microscopic level. RESULTS: The injected masseter showed a steep increase in myosin type IIX fibers, whereas fast fibers decreased by about 50% in size. Depending on the injection site, both synergistic and antagonistic muscles showed a significant increase in the size of their fast IIA fibers, sometimes combined with an increased number of IIX fibers. CONCLUSION: Silencing the activity in the masseter not only causes changes in the fibers of the injected muscle but also leads to changes in other jaw muscles. PMID- 22499097 TI - Myostatin deficiency is associated with an increase in number of total axons and motor axons innervating mouse tibialis anterior muscle. AB - INTRODUCTION: Myostatin (Mstn) is a secreted protein that acts as a negative regulator of skeletal muscle mass. However, a critical evaluation of neuromuscular aspects of hypertrophied muscles induced by Mstn deficiency has not been done. METHODS: We compared the tibialis anterior muscle-nerve interrelationships in wild-type and Mstn-null mice of both genders by immunohistochemical analyses, which allowed us to count the number of total axons and motor axons and estimate the size of motor units and the innervation ratio of the tibialis anterior muscle (TAm). RESULTS: There was an increase in the number of total axons and motor axons, and higher values in both the motor unit size and the innervation ratio of Mstn-null TAm compared with those of wild-type TAm. CONCLUSIONS: We found that myostatin is involved either directly in the control of neuromuscular interrelationships or indirectly through its effect on muscle size. PMID- 22499096 TI - The convergence of facial nerve branches providing whisker pad motor supply in rats: implications for facial reanimation study. AB - INTRODUCTION: Rodent whisking behavior is supported by the buccal and mandibular branches of the facial nerve, but a description of how these branches converge and contribute to whisker movement is lacking. METHODS: Eight rats underwent isolated transection of either the buccal or mandibular branch and subsequent opposite branch transection. Whisking function was analyzed after both transections. Anatomical measurements, and video recording of stimulation to individual branches, were taken from both facial nerves in 10 rats. RESULTS: Normal to near-normal whisking was demonstrated after isolated branch transection. Whisking was eliminated after transection of both branches. The buccal and mandibular branches form a convergence just proximal to the whisker pad, herein called "distal pes." Distal to this convergence, we identified consistent anatomy that demonstrated cross-innervation. CONCLUSION: The overlap of efferent supply to the whisker pad must be considered when studying facial nerve regeneration in the rat facial nerve model. PMID- 22499098 TI - Experimental muscle injury: correlation between ultrasound and histological findings. AB - INTRODUCTION: In this study we correlated ultrasound findings with histological changes taking place during experimentally induced degeneration-regeneration in rat skeletal muscle. METHODS: Gastrocnemius muscles were injected with mepivacaine, and the progress of the muscle injury was monitored by ultrasound from day 1 to day 20. Muscles were extracted on the same days for histological examination. RESULTS: The degenerative phase was characterized by increased echogenicity in the injured area; thereafter, echogenicity gradually diminished during the regenerative phase, attaining normal levels by 20 days postinjection. By this stage, histological examination revealed that regeneration was complete. The heteroechoic texture observed from day 4 to day 10 appeared to reflect the coexistence of degenerative and regenerative processes. CONCLUSIONS: The results suggest that the degenerative and regenerative phases of muscle injury may be distinguished sonographically through differences in echogenicity and echotexture and, using Doppler ultrasound, differences in the degree of vascularization. PMID- 22499099 TI - Myosin heavy chain isoform expression in human extraocular muscles: longitudinal variation and patterns of expression in global and orbital layers. AB - INTRODUCTION: We investigated the distribution of myosin heavy chain (MyHC) isoforms along the length of the global and orbital layers of human extraocular muscles (EOMs). METHODS: Whole muscle tissue extracts of human EOMs were cross sectioned consecutively and separated into orbital and global layers. The extracts from these layers were subjected to electrophoretic analysis, followed by quantification with scanning densitometry. RESULTS: MyHC isoforms displayed different distributions along the lengths of EOMs. In the orbital and global layers of all EOMs except for the superior oblique muscle, MyHCeom was enriched in the central regions. MyHCIIa and MyHCI were most abundant in the proximal and distal ends. CONCLUSIONS: A variation in MyHC isoform expression was apparent along the lengths of human EOMs. These results provide a basis for understanding the molecular mechanisms underlying the functional diversity of EOMs. PMID- 22499100 TI - Ultrasonographic assessment of longitudinal median nerve and hand flexor tendon dynamics in carpal tunnel syndrome. AB - INTRODUCTION: Changes in subsynovial connective tissue (SSCT) in carpal tunnel syndrome (CTS) patients may result in altered dynamics; consequently, quantification of these dynamics might support objective diagnosis of CTS. METHODS: We measured and compared longitudinal excursion of the flexor digitorum superficialis and profundus tendons, the median nerve, and the SSCT between the most and least affected hands of 51 CTS patients during extension-to-fist motion. RESULTS: Median nerve and flexor digitorum superficialis tendon excursions in the most affected hands were smaller than in the least affected hands of the same patients, whereas the excursions of the flexor digitorum profundus were larger. Based on these excursions, logistic regression models classified between 67% and 86% of the hands correctly as having CTS. CONCLUSIONS: The altered hand dynamics in CTS patients may have implications for the pathophysiology and clinical evaluation of CTS, and ultrasound-based classification models may further support the diagnosis of CTS. PMID- 22499102 TI - Zoster-associated mononeuropathies (ZAMs): a retrospective series. AB - INTRODUCTION: Zoster-associated limb paresis is an uncommon complication of herpes zoster (HZ) and one whose precise pathophysiologic mechanism is poorly understood. Occasionally, the paresis results from a zoster-associated mononeuropathy (ZAM). METHODS: Mayo Clinic records between 1996 and 2010 were reviewed for patients with ZAM whose clinical, electrophysiologic, and radiographic features were then abstracted. RESULTS: Ulnar (2), median (3), femoral (1), and sciatic (2) mononeuropathies were identified. Most patients had moderate to severe weakness in affected muscles, and most had post-herpetic neuralgia (88% at 1 month and 71% at 4 months). The minimum duration of weakness was prolonged (mean, 281.9 days; range, 45-1242 days). Nerve magnetic resonance imaging (MRI) was abnormal, demonstrating nerve enlargement (4/4 cases), T2 signal hypertintensity (2/4 cases), or enhancement (1/4 cases). CONCLUSIONS: While ZAM is an uncommon occurrence following cutaneous HZ, it is associated with significant weakness, high rates of post-herpetic neuralgia, and prolonged morbidity. PMID- 22499101 TI - Intra- and internerve cross-sectional area variability: new ultrasound measures. AB - INTRODUCTION: Nerve involvement in immune-related neuropathies is non homogeneous, and therefore characterization of ultrasound (US) abnormalities is difficult. We developed two measures to quantify US abnormalities in immune related neuropathies. METHODS: Intranerve cross-sectional area (CSA) variability for each nerve was calculated as: maximal CSA/minimal CSA. Internerve CSA variability for each patient was calculated as: maximal intranerve CSA variability/minimal intranerve CSA variability. Six patients underwent US evaluation of the median, ulnar, and fibular nerves, and the abnormalities were scored with our newly developed measures. RESULTS: The new measures were applicable to all nerves and patients. The highest degree of intra- and internerve CSA variability was observed in multifocal motor neuropathy, consistent with the asymmetric characteristics of this neuropathy. CONCLUSIONS: The application of intra- and internerve CSA variability measures allows us to quantify the heterogeneity of nerves and nerve segments and identify different US patterns in diverse immune-related neuropathies. PMID- 22499103 TI - Novel ANO5 mutations causing hyper-CK-emia, limb girdle muscular weakness and Miyoshi type of muscular dystrophy. AB - INTRODUCTION: Mutations in the anoctamin 5 gene (ANO5) have been recently identified.They cause limb girdle muscular dystrophy (LGMD2L) and Miyoshi muscular dystrophy. METHODS: Clinical findings of four unrelated patients are reviewed. Mutation detection was performed by direct sequencing of the ANO5 exons. RESULTS: We identified four novel mutations in the ANO5 gene. In one patient, a novel homozygous mutation (c.1965G>C). In three patients, the recurrent heterozygous exon 5 c.191dupA mutation is combined with other variants to form a compound heterozygous state: in two cases, novel splice site mutations in intron 5 (c.295-1G>A) and in intron 14 (c.1407+5G>A), and in one case, a novel missense mutation in exon 4 (c.172C>T). CONCLUSIONS: The cases reported here should help to better understand the important role of mutation screening in the ANO5 gene in patients with adult onset muscular dystrophy and very high CK levels. PMID- 22499104 TI - Sample size considerations in human muscle architecture studies. AB - INTRODUCTION: This report is a meta-analysis of the human muscle architecture literature that analyzes the number of muscles, number of subjects, and muscle fiber length coefficient of variation (CV) by body region. METHODS: Muscle fiber length data are used to make recommendations for dissection-based architectural study sample sizes. RESULTS: An average of 9 +/- 10 (mean +/- SD) muscles and an average of 9 +/- 5 subjects were reported in the 26 studies considered. Across all studies, average fiber length CV was highly variable (18% +/- 5%). This shows that sample sizes required to achieve adequate power varies by anatomical region. CONCLUSIONS: Studies involving muscle architecture should consider regional variability and effect size and determine sample size accordingly. PMID- 22499105 TI - Exercise and Duchenne muscular dystrophy: where we have been and where we need to go. PMID- 22499106 TI - Milder phenotype of congenital muscular dystrophy in a novel POMT1 mutation. AB - INTRODUCTION: Congenital muscular dystrophies (CMD) with hypoglycosylated alpha dystroglycan due to POMT1 mutations are associated with clinical phenotypes that vary in severity. METHODS: We describe a patient with congenital hypotonia, generalized weakness, elevated creatine kinase (CK), and normal brain imaging. RESULTS: Histochemical analysis of the index case's muscle showed deficiency of glycosylated alpha-dystroglycan and secondary merosin deficiency. Genetic testing revealed a novel mutation in exon 20 of the POMT1 gene. CONCLUSIONS: Our patient's milder form of CMD adds to the emerging evidence of an expanding phenotype caused by POMT1 mutations. The histopathological findings of the muscle biopsy in this case support the need for careful clinical, genetic, and histochemical diagnostic interpretation. PMID- 22499108 TI - Chronic inflammatory demyelinating polyneuropathy associated with alopecia totalis and Sjogren syndrome. PMID- 22499107 TI - Expanding the spectrum of monoclonal light chain deposition disease in muscle. AB - INTRODUCTION: The diagnosis of amyloid myopathy is delayed when monoclonal gammopathies are not detected on initial testing and muscle biopsies are nondiagnostic, and the EMG and symptoms can mimic an inflammatory myopathy. METHODS: Case report of a patient presenting with severe progressive muscle weakness of unclear etiology despite an extensive workup including two nondiagnostic muscle biopsies. RESULTS: Directed by MRI, a third biopsy revealed amyloid angiopathy and noncongophilic kappa light chain deposition in scattered subsarcolemmal rings and perimysial regions. A serum free light chain (FLC) assay revealed a kappa monoclonal gammopathy, which was not detected by multiple immunofixations. CONCLUSIONS: The spectrum of immunoglobulin deposition in muscle is similar to other organs. It comprises a continuum that includes parenchymal amyloid deposition, amyloid angiopathy, and noncongophilic Light Chain Deposition Disease (LCDD). We recommend including the FLC assay in the routine investigation for monoclonal gammopathies. This case also highlights the value of MRI-guided muscle biopsy. PMID- 22499109 TI - Successful steroid treatment for recurrent Miller Fisher syndrome. PMID- 22499110 TI - An unusual case of Miller Fisher syndrome presenting with proptosis and chemosis. PMID- 22499111 TI - Goya and a possible first visual representation of Charcot-Marie-Tooth disease. PMID- 22499112 TI - MRC sum-score in the ICU: good reliability does not necessarily reflect "true reliability". PMID- 22499119 TI - Hydrogen sulfide protects cardiomyocytes from myocardial ischemia-reperfusion injury by enhancing phosphorylation of apoptosis repressor with caspase recruitment domain. AB - Hydrogen sulfide (H(2)S) displays an anti-apoptotic activity against myocardial ischemia reperfusion (MIR). Apoptosis repressor with caspase recruitment domain (ARC) is constitutively expressed in the heart and inhibits cell apoptosis when it is phosphorylated. Here, we investigated whether H(2)S could inhibit apoptosis by affecting ARC phosphorylation using cultured rat cardiomyocytes and a rat model of MIR. Primary cardiomyocytes were prepared from hearts of newborn rats and were pre-incubated with NaHS, a donor of H(2)S, for 60 min. Cardiomyocytes were subjected to hypoxia for 4 h, followed by reoxygenation for 2 h. The hypoxia and subsequent reoxygenation (H/R) significantly induced cell apoptosis, increased expression levels of Fas and FasL proteins, enhanced release of cytochrome c from mitochondria, and elevated caspase-3 activity, while H/R reduced ARC phosphorylation and increased the activity of calcineurin that dephosphorylates ARC. Pre-incubation with NaHS significantly attenuated the above effects through promoting ARC phosphorylation by reducing calcineurin activity and by increasing the activity of protein kinase casein kinase II (CK2) that phosphorylates ARC. In fact, TBB, a specific inhibitor of CK2, abolished the effects of NaHS. In rats undergoing MIR, NaHS significantly reduced the myocardial infarct size, cell apoptosis, calcineurin activity, and the expression levels of Fas, FasL and cleaved caspase-3 proteins, while NaHS increased ARC phosphorylation. In contrast, DL-propargylglycine, an inhibitor of cystathionine gamma-lyase, the main enzyme for H(2)S production in hearts, showed opposite effects to NaHS. The results indicate that H(2)S inhibits apoptosis of cardiomyocytes induced by MIR through enhancing ARC phosphorylation. PMID- 22499120 TI - Increased prevalence of high anti-Cladosporium antibody titers in interstitial lung diseases. AB - Interstitial lung diseases (ILDs) represent a large group of different diseases, with a large part comprising idiopathic interstitial pneumonias. Differentiating hypersensitivity pneumonitis (HP), especially its chronic form and other ILDs, is difficult because of similarities in radiological manifestation and clinical course, and the difficulty of identifying causative antigens. We recently experienced a patient with Cladosporium-induced chronic HP that developed in a household environment, but the cause had been misdiagnosed as idiopathic interstitial pneumonia for several years. This case highlighted the need for measures differentiating HP from idiopathic interstitial pneumonia. In this study, we examined fungal exposure in ILDs using an antibody titer in serum to identify possible fungus-related HP. We measured the antibody titer to Cladosporium spp. in 34 patients with various ILDs, 17 patients with bronchial asthma, and 21 control subjects using an immunofluorescence assay. ILDs included HP (5 patients), idiopathic interstitial pneumonias (21 patients), and ILDs with collagen vascular diseases (8 patients). Results showed a significantly higher tendency for high anti-Cladosporium antibody titers in ILD groups (12 patients out of 34 patients), compared to patients with bronchial asthma (0/17) or control subjects (0/21). This increase in antibody titers was observed not only in patients with HP, but also in those with idiopathic interstitial pneumonias and those exhibiting collagen vascular diseases with ILDs. This report highlights the pathogenic role of fungal antigens in various ILDs. In conclusion, fungi commonly observed in our living environment such as Cladosporium could be involved in the development of ILDs. PMID- 22499121 TI - The H63D mutation of the hemochromatosis gene is associated with sustained virological response in chronic hepatitis C patients treated with interferon based therapy: a meta-analysis. AB - The hemochromatosis (HFE) gene encodes the HFE protein that regulates iron absorption. HFE mutations lead to the hemochromatosis disease of excessive iron absorption. HFE mutations may also influence the sustained virologic response (SVR, long-term virus suppression) in chronic hepatitis C patients treated with interferon-based antiviral therapy. We performed a meta-analysis of all English and Chinese language studies of HFE mutations and SVR in interferon-treated chronic hepatitis C patients indexed in the Medline, PubMed, Embase, and China National Knowledge Infrastructure databases to November 2011. Seven studies involving 605 patients with HFE mutations (homozygous or heterozygous mutation of C282Y, H63D or S65C) and 1279 with wild-type HFE (no mutation of C282Y, H63D or S65C for both alleles) were analyzed. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated with the fixed- or random-effect models. HFE mutations were associated with significantly higher SVR rate (vs. wild-type: OR = 1.56, 95% CI: 1.23-1.97, P < 0.001), indicating that mutation carriers were likely to achieve SVR in response to interferon-based antiviral therapy. Stratification analysis by HFE mutation type revealed that the H63D mutation was associated with a significantly higher SVR rate (OR = 1.60, 95% CI: 1.09-2.34, P = 0.020), while the C282Y mutation was not (OR = 1.19, 95% CI: 0.71-1.98, P = 0.510). Our meta-analysis results indicate that the H63D mutation in HFE is associated with a higher SVR rate in chronic hepatitis C patients treated with interferon-based antiviral therapy. PMID- 22499122 TI - Identification of distinct gene expression profiles between esophageal squamous cell carcinoma and adjacent normal epithelial tissues. AB - Esophageal squamous cell carcinoma (ESCC) is a predominant type of esophageal cancer, which is a malignant tumor originating from the esophageal mucosa or gland and is aggressive with poor prognosis. Identification of new gene expression patterns would be helpful for providing new targets for the early detection and treatment of ESCC patients. In the present study, we employed cDNA array technology to compare gene expression profiles between ESCC tissues and adjacent normal epithelial tissues from ESCC patients. There was at least a 4 fold change in the expression levels of 72 genes that were significantly increased and 107 genes that were decreased in ESCC compared with normal esophageal epithelium. Among them, genes known to be involved in ESCC were found, including matrix metalloproteinases, transcription factors SOX-4 and SOX 17, the Wingless-type MMTV integration site family member 2, and cell cycle regulators. Moreover, we have newly identified the two genes that are down regulated in ESCC: monoamine oxidase A, an enzyme that catalyzes monoamines oxidation and 15-hydroxyprostaglandin dehydrogenase [NAD+], a prostaglandin synthesizing enzyme that physiologically antagonizes COX-2. Likewise, we found the three genes that are up-regulated in ESCC: CD7, a cell surface glycoprotein member of the immunoglobulin superfamily, LIM-domain kinase 1, a small subfamily with an unique combination of two N-terminal LIM motifs and a C-terminal protein kinase domain, and TTK protein kinase, a previously unidentified member of the kinase family. These newly identified genes may be involved in the progression of the tumor and/or represent properties specific to ESCC. PMID- 22499123 TI - Glissonean pedicle approach in major liver resections. AB - BACKGROUND/AIMS: Liver resections are still one of the most challenging operations. The aim of this study was to analyze the efficiency and safety of the intrahepatic Glissonean pedicle approach vs. classical Hilar dissection in major hepatectomies. METHODOLOGY: Thirty-four patients were assigned to the Glissonean approach (GA, n=34), while the Hilar dissection were assessed as historical control, matched for the age, gender, comorbidities and Child-Pugh score (HD, n=34). RESULTS: The GA was associated with significantly shorter surgery duration (191.18+/-41.10 vs. 246.62+/- 56.55), transection time (38.94+/-14.56 vs. 56.32+/ 19.40) and ischemic duration (26.03+/-11.27 vs. 41.18+/-12.80) than HD (p<0.001 for all). The amount of blood loss was significantly lower in GA (245.59+/-169.39 vs. 344.71+/-166.25; p=0.018). The amount of blood transfusion was significantly lower in GA during surgery (322.86+/-102.07 vs. 414.76+/-135.48) as well as postoperatively than HD (246.67+/-5.77 vs. 336.67+/-120.55) (p=0.038 and p=0.026. respectively). CONCLUSIONS: Major hepatectomy can be performed more easily using the Glissonean pedicle approach than by hilar dissection. En-masse transection of pedicles, as well as hepatic veins, using endo-GIA vascular stapler could be performed safely. Liver surgeons should know the Glissonean pedicle approach. PMID- 22499126 TI - Spirally configured cis-stilbene/fluorene hybrids as bipolar, organic sensitizers for solar cell applications. AB - Hybrids based on a dibenzosuberene core bearing a spiro-fluorene junction at the C-5 position and with amino donor and beta-thiophenyl-alpha-cyanoacrylic acid acceptor groups at C-3 and C-7, respectively, serve as new organic sensitizer materials for solar cell applications. Solar cell devices based on these materials show a conversion efficiency (eta) of up to 6.1% (V(oc) = 697 mV, J(sc) = 12.2 mA cm(-2), FF = 0.72) under AM 1.5 G conditions. The best IPCE values exceed 75% within the 450-550 nm absorption range. PMID- 22499125 TI - Digital clocks: simple Boolean models can quantitatively describe circadian systems. AB - The gene networks that comprise the circadian clock modulate biological function across a range of scales, from gene expression to performance and adaptive behaviour. The clock functions by generating endogenous rhythms that can be entrained to the external 24-h day-night cycle, enabling organisms to optimally time biochemical processes relative to dawn and dusk. In recent years, computational models based on differential equations have become useful tools for dissecting and quantifying the complex regulatory relationships underlying the clock's oscillatory dynamics. However, optimizing the large parameter sets characteristic of these models places intense demands on both computational and experimental resources, limiting the scope of in silico studies. Here, we develop an approach based on Boolean logic that dramatically reduces the parametrization, making the state and parameter spaces finite and tractable. We introduce efficient methods for fitting Boolean models to molecular data, successfully demonstrating their application to synthetic time courses generated by a number of established clock models, as well as experimental expression levels measured using luciferase imaging. Our results indicate that despite their relative simplicity, logic models can (i) simulate circadian oscillations with the correct, experimentally observed phase relationships among genes and (ii) flexibly entrain to light stimuli, reproducing the complex responses to variations in daylength generated by more detailed differential equation formulations. Our work also demonstrates that logic models have sufficient predictive power to identify optimal regulatory structures from experimental data. By presenting the first Boolean models of circadian circuits together with general techniques for their optimization, we hope to establish a new framework for the systematic modelling of more complex clocks, as well as other circuits with different qualitative dynamics. In particular, we anticipate that the ability of logic models to provide a computationally efficient representation of system behaviour could greatly facilitate the reverse-engineering of large-scale biochemical networks. PMID- 22499127 TI - Marker-free registration for the accurate integration of CT images and the subject's anatomy during navigation surgery of the maxillary sinus. AB - OBJECTIVE: This study compared three marker-free registration methods that are applicable to a navigation system that can be used for maxillary sinus surgery, and evaluated the associated errors, with the aim of determining which registration method is the most applicable for operations that require accurate navigation. METHODS: The CT digital imaging and communications in medicine (DICOM) data of ten maxillary models in DICOM files were converted into stereolithography file format. All of the ten maxillofacial models were scanned three dimensionally using a light-based three-dimensional scanner. The methods applied for registration of the maxillofacial models utilized the tooth cusp, bony landmarks and maxillary sinus anterior wall area. The errors during registration were compared between the groups. RESULTS: There were differences between the three registration methods in the zygoma, sinus posterior wall, molar alveolar, premolar alveolar, lateral nasal aperture and the infraorbital areas. The error was smallest using the overlay method for the anterior wall of the maxillary sinus, and the difference was statistically significant. CONCLUSION: The navigation error can be minimized by conducting registration using the anterior wall of the maxillary sinus during image-guided surgery of the maxillary sinus. PMID- 22499128 TI - Radiofrequency heating and magnetically induced displacement of dental magnetic attachments during 3.0 T MRI. AB - OBJECTIVE: The aim of this study was to estimate the risk of injury from dental magnetic attachments due to their radiofrequency (RF) heating and magnetically induced displacement during 3.0 T MRI. METHODS: To examine the magnetic attachments, we adopted the American Society for Testing and Materials F2182-02a and F2052-06 standards in two MRI systems (Achieva 3.0 T Nova Dual; Philips, Tokyo, Japan, and Signa HDxt 3.0 T; GE Healthcare, Milwaukee, WI). The temperature change was measured in a cylindrical keeper (GIGAUSS D600; GC, Tokyo, Japan) with coping of the casting alloy and a keeper with a dental implant at the maximum specific absorption rate (SAR) for 20 min. To measure the magnetically induced displacement force, three sizes of keepers (GIGAUSS D400, D600 and D1000) were used in deflection angle tests conducted at the point of the maximum magnetic field strength. RESULTS: Temperature elevations of both coping and implant were higher in the Signa system than in the Achieva system. The highest temperature changes in the keeper with implant and keeper with coping were 0.6 degrees C and 0.8 degrees C in the Signa system, respectively. The temperature increase did not exceed 1.0 degrees C at any location. The deflection angle (alpha) was not measurable because it exceeded 90 degrees . GIGAUSS D400 required an extra 3.0 g load to constrain the deflection angle to less than 45 degrees ; GIGAUSS D600 and D1000 required 5.0 and 9.0 g loads, respectively. CONCLUSIONS: Dental magnetic attachments pose no risk due to RF heating and magnetically induced displacement at 3.0 T MRI. However, it is necessary to confirm that these keepers are securely attached to the prosthesis before imaging. PMID- 22499129 TI - Is pneumatization of middle turbinates compensatory or congenital? AB - OBJECTIVE: To determine the frequency of concha bullosa (CB) and the association between the degree of pneumatization and the severity of septum deviation in both paediatric and adult groups by CT evaluation and to investigate whether the pneumatization of middle turbinates is compensatory or congenital. METHOD: We retrospectively reviewed digitally stored paranasal sinus CT images of 86 paediatric and 204 adult patients. The severity of the deviation and cross sectional area of the pneumatized area of the CB were determined using tomography images. The septums were divided into three groups according to the severity of deviation. The cross-sectional area of the contralateral side divided by the cross-sectional area of the deviation was calculated and described as the interturbinate ratio. RESULTS: When bilateral CB was found, the pneumatization of the CB was more prominent on the contralateral side than on the deviation side in both the paediatric and the adult groups. However, we found that the interturbinate ratios were not statistically different between the paediatric and adult groups. Also, the interturbinate ratios were independent degrees of deviation in children and adults. The frequency of CB was low in the adult group compared with the paediatric group. CONCLUSION: Interturbinate ratios were not statistically different between paediatric and adult groups and were independent of the severity of deviation. These findings suggest that the pneumatization process is not compensatory. PMID- 22499130 TI - Detection and characterization of the mandibular accessory buccal foramen using CT. AB - OBJECTIVE: To investigate the frequency and characteristics of the mandibular accessory buccal foramen (ABF) with CT. METHODS: A retrospective study was carried out using the CT records of 504 patients referred to the Erciyes University Medical School (Kayseri, Turkey) between 2007 and 2010. Presence, location, diameter, area and number of ABFs and their continuity with mandibular canal and distance to the mental foramen were evaluated using axial, sagittal and three-dimensional CT images. Statistical analysis was performed using SPSS(r) v. 15 (SPSS Inc., Chicago, IL), and t-tests were used for statistical analysis. RESULTS: 14 ABFs were observed in 10 (2%) of 504 patients. The frequency of ABFs was found to be 2.6% in males and 1% in females. The mean distance between the ABF and the mental foramen was 5.0 mm [standard deviation (SD) +/- 2.48]. The mean long axis of the ABFs was 1.4 mm (SD +/- 0.4) and the mean area of them was 1.5 mm(2) (SD +/- 0.8). The mean area of the mental foramen on the side with the ABF was 4.1 mm(2) (SD +/- 2.71). CONCLUSIONS: This study presents a relatively lower frequency of ABFs than that in the literature. These foramina could have more complex neurovascular structures than was previously thought. Thus, in special cases where a direct surgical exploration during the planned surgery is not indicated, CT or cone beam CT examination to determine the possible presence of ABFs may be indicated. PMID- 22499131 TI - Variation in costs of cone beam CT examinations among healthcare systems. AB - OBJECTIVES: To analyse the costs of cone beam CT (CBCT) in different healthcare systems for patients with different clinical conditions. METHODS: Costs were calculated for CBCT performed in Cluj (Romania), Leuven (Belgium), Malmo (Sweden) and Vilnius (Lithuania) on patients with (i) a maxillary canine with eruption disturbance, (ii) an area with tooth loss prior to implant treatment or (iii) a lower wisdom tooth planned for removal. The costs were calculated using an approach based on the identification, measurement and valuation of all resources used in the delivery of the service that combined direct costs (capital equipment, accommodation, labour) with indirect costs (patients' and accompanying persons' time, "out of pocket" costs for examination fee and visits). RESULTS: The estimates for direct and indirect costs varied among the healthcare systems, being highest in Malmo and lowest in Leuven. Variation in direct costs was mainly owing to different capital costs for the CBCT equipment arising from differences in purchase prices (range ?148 000-227 000). Variation in indirect costs were mainly owing to examination fees (range ?0-102.02). CONCLUSIONS: Cost analysis provides an important input for economic evaluations of diagnostic methods in different healthcare systems and for planning of service delivery. Additionally, it enables decision-makers to separate variations in costs between systems into those due to external influences and those due to policy decisions. A cost evaluation of a dental radiographic method cannot be generalized from one healthcare system to another, but must take into account these specific circumstances. PMID- 22499132 TI - Effect of electric potential and current on mandibular linear measurements in cone beam CT. AB - OBJECTIVES: The purpose of this study was to compare mandibular linear distances measured from cone beam CT (CBCT) images produced by different radiographic parameter settings (peak kilovoltage and milliampere value). METHODS: 20 cadaver hemimandibles with edentulous ridges posterior to the mental foramen were embedded in clear resin blocks and scanned by a CBCT machine (CB MercuRay(TM); Hitachi Medico Technology Corp., Chiba-ken, Japan). The radiographic parameters comprised four peak kilovoltage settings (60 kVp, 80 kVp, 100 kVp and 120 kVp) and two milliampere settings (10 mA and 15 mA). A 102.4 mm field of view was chosen. Each hemimandible was scanned 8 times with 8 different parameter combinations resulting in 160 CBCT data sets. On the cross-sectional images, six linear distances were measured. To assess the intraobserver variation, the 160 data sets were remeasured after 2 weeks. The measurement precision was calculated using Dahlberg's formula. With the same peak kilovoltage, the measurements yielded by different milliampere values were compared using the paired t-test. With the same milliampere value, the measurements yielded by different peak kilovoltage were compared using analysis of variance. A significant difference was considered when p < 0.05. RESULTS: Measurement precision varied from 0.03 mm to 0.28 mm. No significant differences in the distances were found among the different radiographic parameter combinations. CONCLUSIONS: Based upon the specific machine in the present study, low peak kilovoltage and milliampere value might be used for linear measurements in the posterior mandible. PMID- 22499133 TI - A clinicoradiological study of odontogenic carcinomas and their impact on clinical diagnosis. AB - OBJECTIVES: To investigate the clinical and radiological characteristics of odontogenic carcinomas (OCs) and evaluate their impact on early clinical diagnosis. METHODS: The clinical and radiological features of all patients with OCs in our pathology record from January 1988 to December 2009 were retrospectively reviewed. The impact on a tentative diagnosis before final histological examination of clinical, panoramic and CT features was investigated. RESULTS: Of 474 cases with malignant jaw tumours, 417 (88%) were gingival squamous cell carcinomas (SCCs) and 27 (6%) were OCs. The average age of the patients with OCs was significantly lower than that of those with gingival SCCs. 20 OCs were in the mandible and 7 were in the maxilla. 22 OC patients (81%) had pain and/or swelling as an initial symptom of the disease. Although the majority of OCs showed irregularly contoured radiolucency, one-third of the cases showed cyst-like radiolucency totally or partially surrounded by a sclerotic rim on panoramic radiography. Permeative or gross cortical bone destruction and mass extension outside the jaw bone were found on CT and a diagnosis of malignant tumour was more common. Mass extension outside the cortex had a significant influence on malignant diagnosis. However, 22% of the patients were still clinically diagnosed as having osteomyelitis after CT. CONCLUSIONS: Although CT was useful to obtain a diagnosis of malignant tumour in OC patients, 22% of patients were clinically diagnosed as having osteomyelitis even after CT. When an osteomyelitis case is resistant to conventional therapy and gross bone destruction and/or mass extension is found on CT, a histopathological examination should be done. PMID- 22499135 TI - Room temperature L10 phase transformation in binary CoPt nanostructures prepared by focused-electron-beam-induced deposition. AB - CoPt-C binary alloys have been fabricated by focused-electron-beam-induced deposition by the simultaneous use of Co2(CO)8 and (CH3)3CH3C5H4Pt as precursor gases. The alloys are made of CoPt nanoparticles embedded in a carbonaceous matrix. TEM investigations show that as-grown samples are in an amorphous phase. By means of a room temperature low-energy electron irradiation treatment the CoPt nanoparticles transform into face-centered tetragonal L10 nanocrystallites. In parallel, the system undergoes a transition from a superparamagnetic to a ferromagnetic state at room temperature. By variation of the post-growth irradiation dose the electrical and magneto-transport properties of the alloy can be continuously tuned. PMID- 22499138 TI - Kim-1/Tim-1 and immune cells: shifting sands. AB - Kim-1/Tim-1 is an apoptotic-cell phagocytosis and scavenger receptor that is most highly upregulated in proximal tubular epithelium in acute and chronic kidney injury. While Kim-1/Tim-1 has been proposed to be a costimulatory molecule for immune cells, its potential immunological role has been controversial. In the presence of very high epithelial cell expression, understanding the influence of immune cell Kim-1/Tim-1 expression in kidney injury relies on a better definition of its functional significance in immune cells and better characterization of antibodies used to probe function. PMID- 22499139 TI - Can we cure HIV-1-associated nephropathy in transgenic mice? AB - HIV-1-associated nephropathy (HIVAN) is a rapidly progressive form of focal segmental glomerulosclerosis. HIV transgenic mice can develop a HIVAN-like renal disease. Zhong et al. show that the oral administration of a cyclic nucleotide phosphodiesterase 4 inhibitor and a retinoic acid receptor-alpha agonist can prevent the development of HIVAN in transgenic mice, acting through a cAMP dependent mechanism that is independent of HIV-1 genes. These findings suggest that endogenous host factors play a critical role in HIVAN. PMID- 22499140 TI - The fetal environment: a critical phase that determines future renal outcomes in autosomal dominant polycystic kidney disease. AB - Orskov and colleagues demonstrate the impact of birth weight on the mean age of end-stage renal disease (ESRD) in a large Danish ADPKD cohort. Each kilogram of birth weight extended the mean age of ESRD onset by 1.7 years. Placental insufficiency, activation of the renin-angiotensin-aldosterone system, increased fetal vasopressin levels, compensatory increases in insulin like growth factor-I, and a reduction in total nephron number may all contribute to this observation. Collectively, these changes result in an accelerated pace of cyst formation and expansion, and an inability to maintain glomerular hyperfiltration during kidney expansion which results in a more rapid progression to ESRD. Therefore the intrauterine environment may play a critical role in disease severity in ADPKD. PMID- 22499141 TI - Arteriovenous fistula between the posterior tibial artery and great saphenous vein. PMID- 22499142 TI - The case ? proteinuria and low platelet count. PMID- 22499143 TI - Oral immunotherapy for cow's milk allergy. AB - PURPOSE OF REVIEW: Cow's milk allergy (CMA) is common in children and may lead to severe systemic reactions. Avoidance of the ingestion of cow milk is the only effective approach, but this does not exclude the inadvertent or accidental ingestion, or the assumption of milk hidden in other foods. As no pharmacological treatment is available, specific desensitization has been considered an attractive strategy. RECENT FINDINGS: In the last years, several trials of oral desensitization to cow milk, with different protocols, were published. Overall the results were favourable and demonstrated the achievement of a full tolerance in a high percentage of children. Mild side effects that can be easily managed by slowing the desensitization were reported frequently. The discontinuation of the procedure was necessary in less than 20% of children, on average, due to severe side effects. SUMMARY: Oral immunotherapy (oral desensitization) seems to be a promising treatment strategy for cow milk allergy in children that can be applied also to other foods such as eggs or peanuts. PMID- 22499144 TI - Guideline fever: an overview of DRACMA, US NIAID and UK NICE guidelines. AB - PURPOSE OF REVIEW: It is well known that many aspects of food allergy are lacking sufficient research and publication. Practising evidence-based medicine in this field is, therefore, a particular challenge. Internationally, there is considerable variation in practices and no agreed treatment pathways. The time was right to review the evidence and seek the views of experts in the field, industry and food allergic individuals to develop guidance for clinical practice and to plan future research. The purpose of this review was to summarize points of agreement and discrepancy in the recently published Diagnosis and Rationale for Action against Cow's Milk Allergy, US NIAID and UK NICE guidelines. RECENT FINDINGS: The publication of the three guideline documents on food allergies gives clinicians, scientists, industry, governments and patients the opportunity to review the information in a concise format and appreciate the role of clinical expertise in decision making. The guidelines covered all aspects of food allergy: prevalence and natural history, diagnosis, management and treatment and other aspects such as vaccinations. SUMMARY: The guidelines summarized not only our current evidence base but also gaps in our knowledge. Use of these guidelines would facilitate high quality standardized care and indicate the direction of future research. PMID- 22499145 TI - Comparability of subcutaneous and sublingual immunotherapy outcomes in allergic rhinitis clinical trials. AB - PURPOSE OF REVIEW: To conduct a qualitative comparison between the primary and secondary outcomes used in clinical trials of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) for allergic rhinitis. RECENT FINDINGS: Studies of SCIT and SLIT for allergic rhinitis published up to January 2012 were included in this systematic review. Different ways of defining primary and secondary outcome parameters in studies investigating specific immunotherapy are described. Whereas older studies often use the total symptom score and the total medication score individually for the primary efficacy analysis, more recent studies follow current international recommendations of applying the total combined score as primary outcome measure. Even wider is the range of secondary outcomes in clinical trials with few being validated or standardized. SUMMARY: As already recognized as a major concern in recent literature, standardized and validated primary endpoints are of paramount importance in order to improve the comparability of study results. The lack of consistency in the selection of primary outcome parameters represents a major problem when comparing the same therapeutic intervention. A main point of concern is the absence of validation data for those primary and secondary outcomes selected. In conclusion, the qualitative analysis of well powered studies confirms an urgent call from academics, regulatory agencies and the pharmaceutical industry for validated primary outcome parameters and standardized definitions. PMID- 22499146 TI - Food allergy from an avoidance to a proactive approach: a bridge too far? PMID- 22499147 TI - Beyond the patient: couple and family therapy for individual problems. AB - We introduce the Journal of Clinical Psychology: In Session issue on couple and family therapies for adult psychological problems and health-compromising behaviors. The 8 articles, each with an extensive case study, represent different theoretical orientations (cognitive-behavioral, psychoeducational, systemic strategic, experiential) and address problems with depression, anxiety, severe mental illness, substance use disorders, and dysfunctional coping with chronic illness. We identify points of consensus and divergence among the different therapies and consider implications for training psychotherapists. PMID- 22499149 TI - Myoblast sheet can prevent the impairment of cardiac diastolic function and late remodeling after left ventricular restoration in ischemic cardiomyopathy. AB - BACKGROUND: Impairment of diastolic function and late remodeling are concerns after left ventricular restoration (LVR) for ischemic cardiomyopathy. This study aims to evaluate the effects of combined surgery of myoblast sheets (MS) implantation and LVR. METHODS: Rat myocardial infarction model was established 2 weeks after left anterior descending artery ligation. They were divided into three groups: sham operation (n=15; group sham), LVR by plicating the infracted area (n=15; group LVR), and MS implantation with LVR (n=15; group LVR+MS). RESULTS: Serial echocardiographic study revealed significant LV redilatation and decrease of ejection fraction 4 weeks after LVR in group LVR. MS implantation combined with LVR prevented those later deteriorations of LV function in group LVR+MS. Four weeks after the operation, a hemodynamic assessment using a pressure volume loop showed significantly preserved diastolic function in group LVR+MS; end-diastolic pressure (LVR vs. LVR+MS: 9.0+/-6.6 mm Hg vs. 2.0+/-1.0 mm Hg, P<0.05), end-diastolic pressure-volume relationship (LVR vs. LVR+MS 42+/-23 vs. 13+/-6, P<0.05). Histological examination revealed cellular hypertrophy and LV fibrosis were significantly less and vascular density was significantly higher in group LVR+MS than in the other two groups. Reverse transcription polymerase chain reaction demonstrated significantly suppressed expression of transforming growth factor-beta, Smad2, and reversion-inducing cysteine-rich protein with Kazal motifs in group LVR+MS. CONCLUSIONS: MS implantation decreased cardiac fibrosis by suppressing the profibrotic gene expression and attenuated the impairment of diastolic function and the late remodeling after LVR. It is suggesting that MS implantation may improve long-term outcome of LVR for ischemic heart disease. PMID- 22499150 TI - Enantioselective bromolactonization of cis-1,2-disubstituted olefinic acids using an amino-thiocarbamate catalyst. AB - A facile, highly regio- and enantioselective amino-thiocarbamate-catalyzed bromolactonization of cis-1,2-disubstituted olefinic acids has been developed. The use of the enantio-enriched lactones in the synthesis of chiral synthetic intermediates is also demonstrated. PMID- 22499148 TI - Podocyte foot process effacement in postreperfusion allograft biopsies correlates with early recurrence of proteinuria in focal segmental glomerulosclerosis. AB - BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a relatively prevalent glomerular disorder that often progresses to end-stage renal disease. Thirty to 80% of kidney transplant (KT) recipients with FSGS will experience recurrence characterized by proteinuria and podocyte damage. We hypothesized that the degree of podocyte foot process (FP) effacement in postreperfusion transplant biopsies can be used to predict the development of clinical recurrence of FSGS. METHOD: Nineteen pairs of pre- and postreperfusion biopsy specimens were studied. We evaluated the degree of FP effacement in postreperfusion KT biopsies by counting the number of widened FP per capillary loop. Early recurrence of FSGS was defined as development of nephrotic range proteinuria between days 3 and 30 posttransplant. RESULTS: Early recurrence occurred in 7 of 19 grafts (36.8%) at a mean of 4.29+/-1.89 days. The mean score of FP effacement in postreperfusion allograft biopsies was 0.72+/-0.31 and 1.35+/-0.63 in the nonrecurrent and recurrent group, respectively (P=0.039). There was an association between FP effacement and proteinuria (P = 0.04). The FP effacement score predicts early recurrence with a sensitivity of 71.4% and specificity of 91.7%. CONCLUSION: FP effacement can be observed within minutes after reperfusion in renal transplantation of recipients with FSGS that will ultimately develop recurrent FSGS. This suggests a key role for the podocyte injury in the pathogenesis of recurrent FSGS and further supports the presence of circulating factors causing FP effacement. The FP effacement score in the postreperfusion KT biopsy may become a useful predictive test if validated in larger studies. PMID- 22499151 TI - Combined nuclear magnetic resonance spectroscopy and molecular dynamics study of growth hormone releasing hexapeptide GHRP-6 and a cyclic analogue. AB - The Growth Hormone Releasing Hexapeptide, GHRP-6 was the first of a family of synthetic peptides that enhance the release of the Growth Hormone by the pituitary gland in a dose-dependent manner. Since its discovery, it has been used as a benchmark and starting point in numerous researches aiming to obtain new drugs. Complete resonance assignment of GHRP-6 NMR spectra in both open and cyclic forms are reported, showing some differences to random coil chemical shifts. Connectivities observed in the ROESY spectra indicate spatial proximity between the aromatic residues side-chains in both molecules, as well as between residues DPhe5 and Lys6 sidechains. An ensemble of 10 structures was generated for each one of the molecules, showing RMSD values indicative of nonrandom structures. Molecular Dynamics simulations, both with and without explicit solvent, were carried out for GHRP-6 and its cyclic analogue. Conformational analysis performed on the trajectories showed a nonrandom structure with a well preserved backbone. The presence of geometrical patterns resembling those typical of pi-pi interactions in both peptides, suggest that this kind of interactions may be relevant for the biological activity of GHRP-6. Same conclusion can be drawn from the spatial proximity of residues DPhe5 and Lys6 sidechains. PMID- 22499152 TI - Adapting the ITK Registration Framework to Fit Parametric Image Models. AB - The image registration framework in the Insight Tookit offers a powerful body of code for finding the optimal spatial transform that registers one image with another. However, ITK currently lacks a way to fit parametric models of image pixel values to an input image. Such a capability is necessary in certain applications such as sub-resolution localization of molecules in fluorescence microscopy. This document describes new classes that enable the use of the registration framework to provide this capability. We describe a new base class, itk::ParametricImageSource, that defines an interface for parametric image sources. An adapter class itk::ImageToParametricImageSourceMetric that enables itk::ParametricImageSources to be hooked into the registration framework is also described. An example adapter class that enables the existing itk::GaussianImageSource to be used for image fitting is presented, and we demonstrate use of the classes by fitting a 2D Gaussian function to an image generated by the itk::GaussianImageSource class. PMID- 22499154 TI - Functionalization, re-functionalization and rejuvenation of ssDNA nanotemplates. AB - Single-stranded DNA (ssDNA) with repetitive sequence was demonstrated to be a versatile nanotemplate for introducing biological activity in a self-assembled manner. Re-functionalization and rejuvenation of the ssDNA nanotemplate were achieved under mild biological conditions without using high temperature and strong alkaline treatment to denature DNA. PMID- 22499153 TI - ATP signaling is deficient in cultured Pannexin1-null mouse astrocytes. AB - Pannexins (Panx1, 2, and 3) comprise a group of proteins expressed in vertebrates that share weak yet significant sequence homology with the invertebrate gap junction proteins, the innexins. In contrast to the other vertebrate gap junction protein family (connexin), pannexins do not form intercellular channels, but at least Panx1 forms nonjunctional plasma membrane channels. Panx1 is ubiquitously expressed and has been shown to form large conductance (500 pS) channels that are voltage dependent, mechanosensitive, and permeable to relatively large molecules such as ATP. Pharmacological and knockdown approaches have indicated that Panx1 is the molecular substrate for the so-called "hemichannel" originally attributed to connexin43 and that Panx1 is the pore-forming unit of the P2X(7) receptor. Here, we describe, for the first time, conductance and permeability properties of Panx1-null astrocytes. The electrophysiological and fluorescence imaging analyses performed on these cells fully support our previous pharmacological and Panx1 knockdown studies that showed profoundly lower dye uptake and ATP release than wild-type untreated astrocytes. As a consequence of decreased ATP paracrine signaling, intercellular calcium wave spread is altered in Panx1-null astrocytes. Moreover, we found that in astrocytes as in Panx1-expressing oocytes, elevated extracellular K(+) activates Panx1 channels independently of membrane potential. Thus, on the basis of our present findings and our previous report, we propose that Panx1 channels serve as K(+) sensors for changes in the extracellular milieu such as those occurring under pathological conditions. PMID- 22499155 TI - Cardiac sarcoid: a clinician's review on how to approach the patient with cardiac sarcoid. AB - Cardiac sarcoid is an infiltrative, granulomatous disease of the myocardium. It is more prevalent entity than once believed, especially subclinical disease. It affects heart mechanics causing ventricular failure, and disrupts the cardiac electrical system leading to third degree heart block, malignant ventricular arrhythmias, and sudden cardiac death. This makes early diagnosis and treatment of this devastating disease essential. Based on reviewed literature this paper proposes step-wise diagnostic and therapeutic algorithms for patients with suspected cardiac sarcoidoisis who do or do not have prior history of systemic sarcoidosis. PMID- 22499157 TI - Organocatalytic asymmetric conjugate addition of 3-monosubstituted oxindoles to (E)-1,4-diaryl-2-buten-1,4-diones: a strategy for the indirect enantioselective furanylation and pyrrolylation of 3-alkyloxindoles. AB - An asymmetric conjugate addition of 3-monosubstituted oxindoles to a range of (E) 1,4-diaryl-2-buten-1,4-diones, catalyzed by commercially available cinchonine, is described. This organocatalytic asymmetric reaction affords a broad range of 3,3' disubstituted oxindoles that contain a 1,4-dicarbonyl moiety and vicinal quaternary and tertiary stereogenic centers in high-to-excellent yields (up to 98%), with excellent diastereomeric and moderate-to-high enantiomeric ratios (up to 99:1 and 95:5, respectively). Subsequently, cyclization of the 1,4-dicarbonyl moiety in the resultant Michael adducts under different Paal-Knorr conditions results in two new kinds of 3,3'-disubstituted oxindoles--3-furanyl- and 3 pyrrolyl-3-alkyl-oxindoles--in high yields and good enantioselectivities. Notably, the studies presented here sufficiently confirm that this two-step strategy of sequential conjugate addition/Paal-Knorr cyclization is not only an attractive method for the indirect enantioselective heteroarylation of 3 alkyloxindoles, but also opens up new avenues toward asymmetric synthesis of structurally diverse 3,3'-disubstituted oxindole derivatives. PMID- 22499160 TI - Magnetic order in hybrid frustrated magnets Gd(2-x)Tb(x)Ti2O7 (x = 0.2 and 0.5). AB - We report on the specific heat, magnetization and ac susceptibility measurements of single crystals of hybrid frustrated magnets Gd(1.8)Tb(0.2)Ti(2)O(7) and Gd(1.5)Tb(0.5)Ti(2)O(7). The analysis of experimental data revealed that, although partial replacing of the Gd(3+) ions by the Tb(3+) ions in the Gd(2)Ti(2)O(7) host lattice slightly enhances antiferromagnetic coupling, as inferred from the evolution of the paramagnetic Curie-Weiss temperature, the ordering temperature gradually decreases. Paramagnetic correlations introduced by the Tb(3+) ions cause this perturbation, altering the effective further neighbor interactions and destabilizing the ground state in Gd(2)Ti(2)O(7). In addition, the low-energy states of Gd(2-x)Tb(x)Ti(2)O(7) are suggested to possess a nature different from those in parent members Tb(2)Ti(2)O(7) and Gd(2)Ti(2)O(7). Finally, the frequency-dependent magnetic susceptibility behavior in Gd(1.5)Tb(0.5)Ti(2)O(7) is consistent with the formation of a spin-glass-like state indicating a pronounced slowing down of the dynamical response of the studied hybrid magnets. PMID- 22499158 TI - Attenuation of kidney injuries maintains serum sulfatide levels dependent on hepatic synthetic ability: a possible involvement of oxidative stress. AB - Serum sulfatides are the major glycosphingolipids in lipoproteins. Although serum sulfatides are mainly synthesized and secreted by the liver, they are significantly decreased when the kidneys are impaired. Our recent experimental study using a murine protein-overload nephropathy model suggested a hypothetical mechanism whereby serum sulfatides were reduced due to kidney dysfunction. This was the result of decreased hepatic expression of a sulfatide synthetic enzyme, cerebroside sulfotransferase (CST), which is associated with systemic enhancement of oxidative stress. However, there is a possibility that the experimental process, protein-overload itself, directly affected the sulfatide metabolism and oxidative stress in the liver. To determine whether kidney dysfunction actually reduces the hepatic synthesis of sulfatides via oxidative stress, we examined sulfatide levels, the hepatic content of metabolic sulfatide enzymes, and the degree of oxidative stress in protein-overload mice subjected to renoprotective therapy using clofibrate, a representative hypolipidemic medicine. Protein overload mice exhibited marked kidney injuries, enhancement of hepatic oxidative stress, decreased levels of serum and hepatic sulfatides, and decreased expression of hepatic CST. The clofibrate treatment attenuated kidney damage and hepatic oxidative stress while maintaining serum/hepatic sulfatide levels and hepatic CST content in the mice. Because clofibrate monotherapy without protein overload treatment only minimally affected these hepatic parameters, the hepatic synthesis of sulfatides appeared to be strongly influenced by kidney dysfunction and subsequent oxidative stress. This study suggests that the crosstalk between kidney dysfunction and hepatic sulfatide metabolism is mediated by oxidative stress. These results should help to understand the phenomenon in patients with end-stage kidney disease. PMID- 22499162 TI - A child with a difficult airway: what do I do next? AB - PURPOSE OF REVIEW: Difficulties in pediatric airway management are common and continue to result in significant morbidity and mortality. This review reports on current concepts in approaching a child with a difficult airway. RECENT FINDINGS: Routine airway management in healthy children with normal airways is simple in experienced hands. Mask ventilation (oxygenation) is always possible and tracheal intubation normally simple. However, transient hypoxia is common in these children usually due to unexpected anatomical and functional airway problems or failure to ventilate during rapid sequence induction. Anatomical airway problems (upper airway collapse and adenoid hypertrophy) and functional airway problems (laryngospasm, bronchospasm, insufficient depth of anesthesia and muscle rigidity, gastric hyperinflation, and alveolar collapse) require urgent recognition and treatment algorithms due to insufficient oxygen reserves. Early muscle paralysis and epinephrine administration aids resolution of these functional airway obstructions. Children with an 'impaired' normal (foreign body, allergy, and inflammation) or an expected difficult (scars, tumors, and congenital) airway require careful planning and expertise. Training in the recognition and management of these different situations as well as a suitably equipped anesthesia workstation and trained personnel are essential. SUMMARY: The healthy child with an unexpected airway problem requires clear strategies. The 'impaired' normal pediatric airway may be handled by anesthetists experienced with children, whereas the expected difficult pediatric airway requires dedicated pediatric anesthesia specialist care and should only be managed in specialized centers. PMID- 22499161 TI - Biodegradable, multi-layered coatings for controlled release of small molecules. AB - Incorporation of orthogonal functional groups into biodegradable polymers permits the fabrication of multi-layered thin films with improved adhesion and tunable degradation profiles. The bi-layer structure also allows for accurate control over small molecule release. PMID- 22499163 TI - Anesthesia in children with a cold. AB - PURPOSE OF REVIEW: Common colds are infections of mostly viral origin that frequently occur in childhood. The overall anesthetic risk in children with respiratory tract infections is increased because of the increased incidence of perioperative respiratory adverse events (PRAEs). Although the morbidity and mortality of PRAE are low when managed by experienced anesthesiologists, careful preoperative assessment and perioperative anesthetic care are indispensable. RECENT FINDINGS: This review summarizes recent studies to give a brief overview and background information with regard to the pathophysiological mechanisms of upper respiratory tract infections, risk factors for PRAE in children with a cold, management of anesthesia and prevention and treatment of frequently observed adverse events as well as a proposal for a decision algorithm. SUMMARY: Children with a cold can be safely anesthetized under certain circumstances; however, anesthesia in children with symptomatic infections with wheezing, purulent secretion, fever and reduced general condition should be postponed for at least 2 weeks. Anesthetic treatment options for children with infection of the upper airway with a runny nose and cough include preoperative inhalational therapy with salbutamol, avoidance of endotracheal intubation whenever possible, use of a face mask or laryngeal mask, intravenous induction with propofol and avoidance of desflurane. Prevention, early recognition and immediate treatment of complications by an experienced anesthesiologist are crucial. PMID- 22499164 TI - Effects of bile salts on gastrointestinal absorption of pravastatin. AB - This study aimed to examine the effects of bile salts and formulations on the absorption through gastrointestinal tract of pravastatin, which has low bioavailability. Pravastatin sodium physical mixtures and solid dispersions were prepared using various bile salts. The physicochemical characteristics and permeation profiles were investigated using pravastatin sodium-bile salt physical mixtures and solid dispersions. Pravastatin in the physical mixture did not achieve amorphous state, whereas that in the solid dispersion was completely converted to amorphous state. The permeation enhancement factors ranged between 1.13 and 11.9 with the addition of bile salts, and the permeation flux of pravastatin sodium greatly increased as the sodium cholate (NaC) concentration increased from 5 to 10 mM. Pravastatin sodium permeation fluxes [ug/(cm(2) h)] from solid dispersions (drug-NaC = 1:49) (20.8 +/- 2.7) were much higher than those from physical mixtures (4.7 +/- 3.1) and commercial tablets (3.5 +/- 1.2) (p < 0.05). The dissolution rates of pravastatin sodium from solid dispersions in pH 1.2 were much lower than those from physical mixtures and commercial products, whereas more than 97% of pravastatin sodium was dissolved at 5 min in pH 6.8. On the basis of the results, it was concluded that pravastatin sodium solid dispersions containing bile salts could enhance drug absorption. PMID- 22499165 TI - Shifting atomic patterns: on the origin of the different atomic-scale patterns of graphite as observed using scanning tunnelling microscopy. AB - We present an in-depth study of the myriad atomically resolved patterns observed on graphite using the scanning tunnelling microscope (STM) over the past three decades. Through the use of highly resolved atomic resolution images, we demonstrate how the interactions between the different graphene layers comprising graphite affect the local surface atomic charge density and its resulting symmetry orientation, with particular emphasis on interactions that are thermodynamically unstable. Moreover, the interlayer graphene coupling is controlled experimentally by varying the tip-surface interaction, leading to associated changes in the atomic patterns. The images are corroborated by first principles calculations, further validating our claim that surface graphene displacement, coming both from lateral and vertical displacement of the top graphene layer, forms the basis of the rich variety of atomic patterns observed in STM experiments on graphite. PMID- 22499167 TI - Cell type-specific protein and transcription profiles implicate periarbuscular membrane synthesis as an important carbon sink in the mycorrhizal symbiosis. AB - The development of an arbuscular mycorrhizal (AM) symbiosis is a non-synchronous process with typical mycorrhizal root containing different symbiotic stages at one time. Methods providing cell type-specific resolution are therefore required to separate these stages and analyze each particular structure independently from each other. We established an experimental system for analyzing specific proteomic changes in arbuscule-containing cells of Glomus intraradices colonized Medicago truncatula roots. The combination of laser capture microdissection (LCM) and liquid chromatography-tandem mass chromatography (LC-MS/MS) allowed the identification of proteins with specific or increased expression in arbuscule containing cells. Consistent with previous transcriptome data, the proteome of arbuscule-containing cells showed an increased number of proteins involved in lipid metabolism, most likely related to the synthesis of the periarbuscular membrane. In addition, transcriptome data of non-colonized cells of mycorrhizal roots suggest mobilization of carbon resources and their symplastic transport toward arbuscule-containing cells for the synthesis of periarbuscular membranes. This highlights the periarbuscular membrane as important carbon sink in the mycorrhizal symbiosis. PMID- 22499166 TI - ICV-transplanted human glial precursor cells are short-lived yet exert immunomodulatory effects in mice with EAE. AB - Human glial precursor cells (hGPs) have potential for remyelinating lesions and are an attractive cell source for cell therapy of multiple sclerosis (MS). To investigate whether transplanted hGPs can affect the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we evaluated the therapeutic effects of transplanted hGPs together with the in vivo fate of these cells using magnetic resonance imaging (MRI) and bioluminescence imaging (BLI). At 14 days post-EAE induction, mice (n = 19) were intracerebroventricularly (ICV) injected with 5 * 10(5) hGPs that were magnetically labeled with superparamagnetic iron oxide (SPIO) particles as MR contrast agent and transduced with firefly luciferase for BLI of cell survival. Control mice (n = 18) received phosphate buffered saline (PBS) vehicle only. The severity of EAE clinical disability in the hGP-transplanted group was significantly suppressed (P < 0.05) with concomitant inhibition of ConA and MOG-specific T cell proliferation in the spleen. Astrogliosis was reduced and a lower activity of macrophages and/or microglia was observed in the spinal cord (P < 0.05). On MRI, SPIO signal was detected within the lateral ventricle from 1 day post-transplantation and remained there for up to 34 days. BLI indicated that most cells did not survive beyond 5-10 days, consistent with the lack of detectable migration into the brain parenchyma and the histological presence of an abundance of apoptotic cells. Transplanted hGPs could not be detected in the spleen. We conclude that ICV transplantation of short-lived hGPs can have a remote therapeutic effect through immunomodulation from within the ventricle, without cells directly participating in remyelination. PMID- 22499168 TI - Insight into plant annexin function: from shoot to root signaling. AB - The multifunctionality of plant annexins and their importance for coordinating development and responses to biotic and abiotic environment have been largely reviewed. We recently described a tobacco annexin, named Ntann12, which is mainly localized in the nucleus of root cells when the plant is grown under light conditions. We also found that auxin and polar auxin transport are essential for Ntann12 accumulation in root cells. Under dark condition, Ntann12 is no longer detected in the root system. In the present addendum, light, regulating auxin signaling, is evidenced as an essential determinant for the synchronization of growth and development between the shoot and the root during light/dark cycle. A speculative model for Ntann12 is described and discussed with regards to relevant literature data. PMID- 22499169 TI - Overexpression of Rab16A gene in indica rice variety for generating enhanced salt tolerance. AB - We report here the overexpression of Rab16A full length gene (promoter + ORF), from the salt-tolerant indica rice Pokkali, in the salt-susceptible indica rice variety Khitish, via particle bombardment. Molecular analysis of the transgenics revealed stable integration of the transgene upto T2 generation. High level of expression of the transgene (driven by its own stress-inducible promoter), as well as the protein, was detectable in the leaves under simulated salinity stress (250 mM NaCl, 24 h); the expression level being higher than wild type (WT) plants. The Rab16A transcript also increased gradually with seed maturity, with its maximal accumulation at 30 d after pollination (DAP) i.e., fully matured seeds, explaining the protective role of Rab16A gene during seed maturation. Enhanced tolerance to salinity was observed in the plants transformed with Rab16A. The superior physiological performances of the transgenics under salt treatment were also reflected in lesser shoot or root length inhibition, reduced chlorophyll damages, lesser accumulation of Na(+) and reduced loss of K(+), increased proline content as compared with the WT plants. All these results indicated that the overproduction of RAB16A protein in the transgenics enable them to display enhanced tolerance to salinity stress with improved physiological traits. Our work demonstrates the profound potential of Group 2 LEA proteins (to which RAB16A belongs to) in conferring stress tolerance in crop plants through their genetic manipulation. PMID- 22499170 TI - Ethylene response pathway is essential for ARABIDOPSIS A-FIFTEEN function in floral induction and leaf senescence. AB - ARABIDOPSIS A-FIFTEEN (AAF) encodes a plastid protein and was originally identified as a SENESCENCE-ASSOCIATED GENE. Previously, we found that overexpression of AAF (AAF-OX) in Arabidopsis led to accumulated reactive oxygen species and promoted leaf senescence induced by oxidative stress, which was suppressed by a null mutant, ein2-5, in ethylene response pathway. Whether AAF function is involved in ethylene biosynthesis and/or the response pathway remained unknown. Here we show that neither overexpression (AAF-OX) nor a null mutant (aaf-KO) of AAF generates a higher level of ethylene than the wild type and display a typical triple-response phenotype in etiolated seedlings treated with 1-aminocyclopropane-1-carboxylic acid (ACC). Nevertheless, ein2-5 suppresses the phenotypes of early flowering and age-dependent leaf senescence in AAF-OX plants. We reveal that a functional ethylene response is essential for AAF function in leaf senescence and floral induction, but AAF is unlikely a regulatory component integral to the ethylene pathway. PMID- 22499171 TI - Does diacylglycerol serve as a signaling molecule in plants? AB - Diacylglycerol (DAG) is an important signaling phospholipid in animals, specifically binding to the C1 domain of proteins such as protein kinase C. In most plant species, however, DAG is present at low abundance, and no interacting proteins have yet been identified. As a result, it has been proposed that the signaling function of DAG has been discarded by plants during their evolution. In this mini-review, we summarize the accumulating experimental evidence which supports that notion that changes in DAG content in response to particular cues are a feature of plant cells. This behavior suggests that DAG does indeed act as a signaling molecule during plant development and in response to certain environmental stimuli. PMID- 22499172 TI - Function of Arabidopsis SWAP70 GEF in immune response. AB - In animals, major classes of Rho guanine nucleotide exchange factors (GEFs) possess a Dbl (diffuse B-cell lymphoma)- homology (DH) domain that functions as a GEF-catalytic domain. However, no GEFs with the DH domain had been identified in plants. Recently, we found that the rice homolog of human SWAP70, Oryza sative (Os) SWAP70, containing the DH domain, exhibited GEF activity toward the rice Rho GTPase OsRac1, and regulates chitin-induced production of reactive oxygen species and defense gene expression in rice. ( 1) Arabidopsis contains a single SWAP70 gene. A T-DNA insertion mutant of Arabidopsis SWAP70 was morphologically wild type. Measurement of in planta growth of Pseudomonas syringae DC3000 hrcC, a mutant incapable of type III effector delivery, revealed enhanced growth of the pathogen in the atswap70 mutant, indicating that AtSWAP70 is required for PAMP triggered immunity. In addition, the atswap70 mutation reduced the RPM1-mediated hypersensitive response. These results suggested that AtSWAP70 plays a role in both PAMP- and effector-triggered immunity in Arabidopsis. PMID- 22499173 TI - Investigation of copper homeostasis in plant cells by fluorescence lifetime imaging microscopy. AB - Copper ions play a fundamental role in plant metabolism where its uptake and distribution within the organism is highly regulated, allowing the cells to sustain an adequate concentration. Shortage or excess of Cu can cause severe damage to the organisms endangering their survival. We recently reported a non invasive method to follow the intracellular uptake of bivalent copper ion concentration by fluorescence lifetime microscopy of green fluorescent protein within plant cells. Measuring the fluorescence lifetime has the advantage of being independent on the fluorophore concentration and the excitation intensity. The use of GFP is beneficial because the protein can be introduced nondestructively. Here, we discuss the benefits of this approach as well as the possibility of applying this concept for the investigation of Cu redistribution and storage at the subcellular level. The fluorescence lifetime-encoded microscopic images are envisioned to map the copper distribution within plant cells not only qualitatively but even quantitatively. Time-lapse microscopy enables the following of cellular processes and the study of relevant transport mechanisms of copper in plant cells. Perspectives and necessary improvements are discussed. PMID- 22499174 TI - Ecological role of transgenerational resistance against biotic threats. AB - Plants in their natural environments are constantly subjected to biotic stress. In addition to possessing physical barriers and anti-nutritive toxins, plants can be primed to respond more efficiently against future attack via faster and stronger gene activation. Here we discuss recent findings showing that plants can pass signatures of attack to the next generation, thus rendering the progeny more resistant against insect and pathogen attack. A combination of phytohormone signaling, small RNA-mediated gene silencing and DNA methylation are involved in transgenerational induced resistance. Epiallelic variation against biotic threats should be under positive selection in populations of plants where the environment is predictable over time. Similarly, in very genetically homogenous populations, such as during range expansion, epigenome reorganization is a likely mechanism for faster plant adaptation to novel biotic attack. Further research is needed to understand the relative role of the genome vs. the epigenome for the evolution of increased plant resistance. PMID- 22499175 TI - Multivesicular bodies in developing tobacco seed and mung bean are functionally equivalent. AB - Protein storage vacuoles (PSVs) are the primarily storage organelles in cotyledon cells for protein preservation in seeds. Storage proteins are transported from the endoplasmic reticulum (ER) to the Golgi apparatus for subsequent delivery to PSVs via presumably Golgi-derived dense vesicles (DVs). However, recent studies demonstrated that storage proteins in early stage of developing cotyledon of mung beans reached the multivesicular bodies (MVBs) prior to the detection of DVs, indicating the possible involvement of MVBs in mediating transport of storage proteins during the early stage of seed development. Here, we further show that the MVBs in developing tobacco seeds are functionally and biochemically equivalent to those in developing mung beans. Thus, MVBs in developing tobacco seeds are structurally distinct from DVs, contain both vacuolar sorting receptors (VSRs) and storage proteins, and they are insensitive to treatments of wortmannin and brefeldin A (BFA). PMID- 22499177 TI - Architectural plasticity in a Mediterranean winter annual. AB - Size variability in plants may be underlain by overlooked components of architectural plasticity. In annual plants, organ sizes are expected to depend on the availability and reliability of resources and developmental time. Given sufficient resources and developmental time, plants are expected to develop a greater number of large branches, which would maximize fitness in the long run. However, under restrictive growth conditions and environmental reliability, developing large branches might be risky and smaller branches are expected to foster higher final fitness. Growth and architecture of Trifolium purpureum (Papilionaceae) plants from both Mediterranean (MED) and semi-arid (SAR) origins were studied, when plants were subjected to variable water availability, photoperiod cues and germination timing. Although no clear architectural plasticity could be found in response to water availability, plants subjected to photoperiod cuing typical to late spring developed fewer basal branches. Furthermore, plants that germinated late were significantly smaller, with fewer basal branches, compared with plants which grew for the same time, starting at the beginning of the growing season. The results demonstrate an intricate interplay between size and architectural plasticities, whereby size modifications are readily induced by environmental factors related to prevalent resource availability but architectural plasticity is only elicited following the perception of reliable anticipatory cues. PMID- 22499176 TI - Nitric oxide counters ethylene effects on ripening fruits. AB - Ethylene plays a key role in promoting fruit ripening, so altering its biosynthesis/signaling could be an important means to delay this process. Nitric oxide (NO)-generated signals are now being shown to regulate ethylene pathways. NO signals have been shown to transcriptionally repress the expression of genes involved in ethylene biosynthesis enzymes and post-translationally modify methionine adenosyl transferase (MAT) activity through S-nitrosylation to reduce the availably of methyl groups required to produce ethylene. Additionally, NO cross-talks with plant hormones and other signal molecules and act to orchestrate the suppression of ethylene effects by modulating enzymes/proteins that are generally triggered by ethylene signaling at post-climacteric stage. Thus, medication of endogenous NO production is suggested as a strategy to postpone the climacteric stage of many tropical fruits. PMID- 22499178 TI - Membrane microdomain may be a platform for immune signaling. AB - Arabidopsis RPS2 is a typical disease resistance (R) protein with nucleotide binding leucine-rich repeats (NB-LRR). Previously, we reported that RPS2 is physically associated with some Arabidopsis hypersensitive induced reaction (AtHIR) proteins, which are enriched in membrane microdomains. Biochemical and genetic analyses suggested that members of the AtHIR gene family have a function in RPS2-mediated immune signaling. Here, we provide evidence that the pattern recognition receptor (PRR) FLS2 is also physically associated with AtHIR2 in a N. benthamiana transient expression system. We thus speculate that PM microdomains provide a platform for both types of immune receptors, R proteins and PRRs, and that the activation of the receptors is facilitated by AtHIR proteins. PMID- 22499179 TI - Rice transgenic plants with suppressed expression of the beta subunit of the heterotrimeric G protein. AB - The deficient mutant for the rice heterotrimeric G protein alpha subunit gene (RGA1), d1, showed dwarfism and set small seed due to a reduced cell number. Mutants for the rice heterotrimeric G protein beta subunit gene (RGB1) have not been isolated. To determine the functions of RGB1, transgenic rice plants with suppressed expression of RGB1 were studied using the RNAi method. RGB1 knock-down lines showed browning of the lamina joint regions and nodes and reduced fertility, but these abnormality were not observed in d1. Transgenic plants in which the G protein beta subunit was greatly decreased were not obtained, suggesting that the complete suppression of RGB1 mRNA may be lethal. In contrast, the d1 mutants, with complete loss of the G protein alpha subunit, were fertile and half the size of the WT. These studies suggest that RGB1 has different functions than RGA1. PMID- 22499180 TI - Salt stress triggers enhanced cycling of Arabidopsis root plasma-membrane aquaporins. AB - Aquaporins of the plasma membrane intrinsic protein (PIP) subfamily are channels which facilitate the diffusion of water across the plant plasma membrane (PM). Although PIPs have been considered as canonical protein markers of this compartment, their endomembrane trafficking is still not well documented. We recently obtained insights into the constitutive cycling of PIPs in Arabidopsis root cells by means of fluorescence recovery after photobleaching (FRAP). This work also uncovered the behavior of the model isoform AtPIP2;1 in response to NaCl. The present addendum connects these findings to another recent work which describes the dynamic properties of AtPIP2;1 in the PM in normal and salt stress conditions by means of single particle tracking (SPT) and fluorescence correlation spectroscopy (FCS). The results suggest that membrane rafts play an important role in the partitioning of AtPIP2;1 in normal conditions and that clathrin-mediated endocytosis is predominant. In salt stress conditions, the rate of AtPIP2;1 cycling was enhanced and endocytosis was cooperated by a membrane raft-associated salt-induced pathway and a clathrin-dependent pathway. PMID- 22499181 TI - Blue light regulated shade avoidance. AB - Most plants grow in dense vegetation with the risk of being out-competed by neighboring plants. These neighbors can be detected not only through the depletion in light quantity that they cause, but also through the change in light quality, which plants perceive using specific photoreceptors. Both the reduction of the red:far-red ratio and the depletion of blue light are signals that induce a set of phenotypic traits, such as shoot elongation and leaf hyponasty, which increase the likelihood of light capture in dense plant stands. This set of phenotypic responses are part of the so called shade avoidance syndrome (SAS). This addendum discusses recent findings on the regulation of the SAS of Arabidopsis thaliana upon blue light depletion. Keller et al. and Keuskamp et al. show that the low blue light attenuation induced shade avoidance response of seedling and rosette-stage A. thaliana plants differ in their hormonal regulation. These studies also show there is a regulatory overlap with the R:FR regulated SAS. PMID- 22499182 TI - Branching of the PIF3 regulatory network in Arabidopsis: roles of PIF3-regulated MIDAs in seedling development in the dark and in response to light. AB - Plants need to accurately adjust their development after germination in the underground darkness to ensure survival of the seedling, both in the dark and in the light upon reaching the soil surface. Recent studies have established that the photoreceptors phytochromes and the bHLH phytochrome interacting factors PIFs regulate seedling development to adjust it to the prevailing light environment during post-germinative growth. However, complete understanding of the downstream regulatory network implementing these developmental responses is still lacking. In a recent work, published in The Plant Cell, we report a subset of PIF3 regulated genes in dark-grown seedlings that we have named MIDAs (MISREGULATED IN DARK). Analysis of their functional relevance using mutants showed that four of them present phenotypic alterations in the dark, and that each affected a particular facet of seedling development, suggesting organ-specific branching in the signal that PIF3 relays downstream. Furthermore, our results also showed an altered response to light in seedlings with an impaired PIF3/MIDA regulatory network, indicating that these factors might also be essential to initiate and optimize the developmental adjustment of the seedling to the light environment. PMID- 22499183 TI - microRNAs responsive to ozone-induced oxidative stress in Arabidopsis thaliana. AB - Ozone is a model abiotic elicitor of reactive oxygen species (ROS). ROS are important oxidative signaling molecules coordinating plant development and responses to biotic and abiotic stresses. Recently, microRNAs have been described as important players in regulating stress responses in plants. In this research we examined the miRNAs that are differentially expressed early in response to ozone in the Arabidopsis thaliana ecotype Col-0 that is tolerant to this oxidant. We used a plant miRNA array to identify 22 miRNA families that are differentially expressed within one hour of ozone fumigation. Majority of these miRNAs were also reported in response to UV-B stress. Analysis of the miRNA target genes showed a strong negative correlation to the miRNA expression. In silico promoter analysis of miRNA genes identified several stress responsive cis-elements that were enriched in the promoters of ozone responsive genes. Majority of the target genes of ozone responsive miRNAs were associated with developmental processes. Based on these results we suggest that post-transcriptional gene regulation via miRNAs may aid in resource allocation by downregulating developmental processes to cater to the oxidative stress demands on plants. PMID- 22499184 TI - Interactions between nitric oxide and plant hormones in aluminum tolerance. AB - Nitric oxide (NO) is involved, together with plant hormones, in the adaptation to Al stress in plants. However, the mechanism by which NO and plant hormones interplay to improve Al tolerance are still unclear. We have recently shown that patterns of plant hormones alteration differ between rye and wheat under Al stress. NO may enhance Al tolerance by regulating hormonal equilibrium in plants, as a regulator of plant hormones signaling. In this paper, some unsolved issues are discussed based on recent studies and the complex network of NO and plant hormones in inducing Al tolerance of plants are proposed. PMID- 22499185 TI - A model for combinatorial regulation of the petunia R2R3-MYB transcription factor ODORANT1. AB - The emission of floral volatiles requires coordinated expression of biosynthetic genes. In the regulatory network of the volatile benzenoid/phenylpropanoid pathway in Petunia hybrida two master regulators of the pathway have been identified. The R2R3-MYB transcription factor EMISSION OF BENZENOIDS II (EOBII) utilizes a specific MYB binding site to activate the expression of the R2R3-MYB ODORANT1 (ODO1). However, because EOBII is expressed early in flower development, when ODO1 is not, there must be other factors that play a role in regulating expression of ODO1. Through functional analyses of ODO1 promoter fragments from fragrant and non-fragrant flowers, we provide evidence for additional players and present a model for combinatorial regulation of ODO1 expression in Petunia. PMID- 22499187 TI - Prenatal management and thoracoamniotic shunting in primary fetal pleural effusions: a single centre experience. AB - OBJECTIVE: Primary fetal pleural effusions are rare. If severe, thoracoamniotic shunting is needed. Our objective was to study the management and outcomes of pleural effusions in our unit. METHODS: Retrospective analysis of primary fetal hydrothorax between 1991 and 2010. RESULTS: Of 41 cases, 23 (56%) were hydropic, and 27 (66%) required shunting. Overall, 2 (4.8%) were diagnosed with a chromosomal condition and 4 (9.6%) with a congenital condition (3 Noonan syndrome, 1 mild structural cardiac defect). There were 5 terminations of pregnancy (TOP), 3 in utero deaths and 33 liveborn neonates (80%). Intact survival rate was 44% (12/27) among those shunted, 56% (23/41) among all cases and 70% (23/33) among all liveborn neonates. Most (87.5%) neonatal deaths occurred in newborns delivered before 34 weeks of gestation. The survival rate was higher in nonhydropic compared with hydropic fetuses (85% vs 47%). There were no procedure-related fetal losses. One in utero death was complicated by fatal maternal amniotic embolism. CONCLUSION: Fetuses with pleural effusions should undergo expert prenatal workup. Hydropic fetuses and those with massive effusions are candidates for thoracoamniotic shunting. PMID- 22499188 TI - Honey: a novel antioxidant. AB - The global prevalence of chronic diseases such as diabetes mellitus, hypertension, atherosclerosis, cancer and Alzheimer's disease is on the rise. These diseases, which constitute the major causes of death globally, are associated with oxidative stress. Oxidative stress is defined as an "imbalance between oxidants and antioxidants in favor of the oxidants, potentially leading to damage". Individuals with chronic diseases are more susceptible to oxidative stress and damage because they have elevated levels of oxidants and/or reduced antioxidants. This, therefore, necessitates supplementation with antioxidants so as to delay, prevent or remove oxidative damage. Honey is a natural substance with many medicinal effects such as antibacterial, hepatoprotective, hypoglycemic, reproductive, antihypertensive and antioxidant effects. This review presents findings that indicate honey may ameliorate oxidative stress in the gastrointestinal tract (GIT), liver, pancreas, kidney, reproductive organs and plasma/serum. Besides, the review highlights data that demonstrate the synergistic antioxidant effect of honey and antidiabetic drugs in the pancreas, kidney and serum of diabetic rats. These data suggest that honey, administered alone or in combination with conventional therapy, might be a novel antioxidant in the management of chronic diseases commonly associated with oxidative stress. In view of the fact that the majority of these data emanate from animal studies, there is an urgent need to investigate this antioxidant effect of honey in human subjects with chronic or degenerative diseases. PMID- 22499189 TI - Assessment of worldwide genetic diversity of Siberian wild rye (Elymus sibiricus L.) germplasm based on gliadin analysis. AB - E. sibiricus L., the type species of the genus Elymus, is a perennial, self pollinating and allotetraploid grass indigenous to Northern Asia, which in some countries can be cultivated as an important forage grass. In the present study, eighty-six Elymus sibiricus accessions, mostly from different parts of Asia, were assayed by gliadin markers based on Acid Polyacrylamide Gel Electrophoresis to differentiate and explore their genetic relationships. The genetic similarity matrix was calculated by 47 polymorphic bands, which ranged from 0.108 to 0.952 with an average of 0.373. The total Shannon diversity index (H(o)) and the Simpson index (H(e)) was 0.460 and 0.302, respectively. Cluster analysis showed a clear demarcation between accessions from Qinghai-Tibetan Plateau, China and the others as separate groups. The clustering pattern was probably dependent on geographic origin and ecological adaptability of the accessions. The population structure analysis based on Shannon indices showed that the proportion of variance within and among the five geographic regions of the Northern Hemisphere was 55.9 and 44.1%, respectively, or 63.4 and 36.6% within and among six Chinese provinces. This distinct geographical divergence was perhaps depended on ecogeographical conditions such as climate difference and mountain distribution. The results of gladin analysis in this study are useful for the collection and preservation of E. sibiricus germplasm resources. PMID- 22499190 TI - Investigation on the protective effects of cranberry against the DNA damage induced by benzo[a]pyrene. AB - There are few reports that demonstrate the antigenotoxic potential of cranberries. Although the types of berry fruits consumed worldwide are many, this paper focuses on cranberries that are commonly consumed in Mexico (Vaccinium macrocarpon species). The purpose of the present study is to determine whether cranberry ethanolic extract (CEE) can prevent the DNA damage produced by benzo[a]pyrene (B[a]P) using an in vivo mouse peripheral blood micronucleus assay. The experimental groups were organized as follows: a negative control group (without treatment), a positive group treated with B[a]P (200 mg/kg), a group administered with 800 mg/kg of CEE, and three groups treated with B[a]P and CEE (200, 400, and 800 mg/kg) respectively. The CEE and benzo[a]pyrene were administered orally for a week, on a daily basis. During this period the body weight, the feed intake, and the determination of antigenotoxic potential were quantified. At the end of this period, we continued with the same determinations for one week more (recovery period) but anymore administration of the substances. The animals treated with B[a]P showed a weight increase after the first week of administration. The same phenomenon was observed in the lots combined with B[a]P and CEE (low and medium doses). The dose of 800 mg/kg of CEE showed similar values to the control group at the end of the treatment period. In the second part of the assay, when the substances were not administered, these experimental groups regained their normal weight. The dose of CEE (800 mg/kg) was not genotoxic nor cytotoxic. On the contrary, the B[a]P increases the frequency of micronucleated normochromatic erythrocytes (MNNE) and reduces the rate of polychromatic erythrocytes (PE) at the end of the treatment period. With respect to the combined lots, a significant decrease in the MN rate was observed from the sixth to the eighth day of treatment with the two high doses applied; the highest protection (60%) was obtained with 800 mg/kg of CEE. The same dose showed an anticytotoxic effect which corresponded to an improvement of 62.5% in relation to the animals administered with the B[a]P. In the second period, all groups reached values that have been seen in the control group animals. Our results suggest that the inhibition of clastogenicity of the cranberry ethanolic extract against B[a]P is related to the antioxidant capacity of the combination of phytochemicals present in its chemical composition. PMID- 22499191 TI - Determination of isotopic labeling of proteins by precursor ion scanning liquid chromatography/tandem mass spectrometry of derivatized amino acids applied to nuclear magnetic resonance studies. AB - RATIONALE: A method has been developed for the quantitation of isotopic labeling of proteins using liquid chromatography/tandem mass spectrometry (LC/MS/MS) for the application of protein nuclear magnetic resonance (NMR) studies. NMR relies on specific isotopic nuclei, such as (13)C and (15)N, for detection and, therefore, isotopic labeling is an important sample preparation step prior to in depth structural characterization of proteins. The goal of this study was to develop a robust quantitative assay for assessing isotopic labeling in proteins while retaining information on the extent of labeling for individual amino acids. METHODS: Complete digestion of proteins by acid hydrolysis was followed by derivatization of free amino acids with 6-aminoquinolyl N-hydroxysuccinimidyl carbamate (AQC) forming derivatives having identical MS/MS fragmentation behavior. Precursor ion scanning on a hybrid quadrupole-linear ion trap platform was used for amino acid analysis and determining isotopic labeling of proteins. RESULTS: Using a set of isotope-labeled amino acid standards mixed with their unlabeled counterparts, the method was validated for accurately measuring % isotopic contribution. We then applied the method for determining the (13)C isotopic content of algal proteins during a feeding study using (13)C(6)-glucose- or (13)C-bicarbonate-supplemented culture media as well as the level of labeling in mussel byssal threads obtained after feeding with labeled algae. CONCLUSIONS: This method is ideally suited for assessing the extent of protein labeling prior to NMR studies, where the isotopic labeling is a determining factor in the quality of resulting protein spectra, and can be applied to a multitude of different biological samples. PMID- 22499192 TI - Determination of low-level (sub-microgram) sulfur concentrations by isotope dilution multi-collector inductively couple plasma mass spectrometry using a 33S spike and internal normalization for mass bias correction. AB - RATIONALE: The certification of sulfur (S) in Standard Reference MaterialsTM by the National Institute of Standards and Technology (NIST) has been exclusively performed using isotope dilution thermal ionization mass spectrometry (ID-TIMS). The ID-TIMS measurement method is limited in its capability for low concentration measurements (<1 ug/g) due to the blank associated with the chemical reduction procedure (~0.2 S ug). Newly developed materials and applications, such as biofuels made from soy and nanomedicine, pose a challenge to the ID-TIMS technique because of their very low concentrations (<<1 ug/g) of S. As described here, a measurement technique with low S blanks is essential for low-level S measurements. METHODS: An isotope dilution (ID) multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS) method combined with an internal normalization approach for mass bias correction has been used to determine low level S concentrations in synthetically prepared mixtures using a (33)S-enriched spike material. Dilute sulfur solutions (1 ug S/g) were prepared from NIST SRM 3154 (Sulfate Spectrometric Solution) to test the capability of this technique for measuring very low-level S concentrations. RESULTS: The concentration results for each solution were 0.983 +/- 0.004 ug/g (95% CI, n = 2, k = 2), 1.006 +/- 0.005 ug/g (95% CI, n = 2, k = 2), and 0.999 +/- 0.003 ug/g (95% CI, n = 2, k = 2), in excellent agreement with the gravimetric determination, deviating less than 0.35% and suggesting the technique can yield unbiased and accurate results. The blanks averaged 13 +/- 0.0017 ng S (1s). CONCLUSIONS: The data results provide a clear indication that the ID-MC-ICP-MS method for the determination of low-level S concentrations is feasible. The more than one order of magnitude reduction of the blanks suggests that it is a better alternative to the ID-TIMS method for very low S materials such as are encountered in biofuels and some biochemical species. Published 2012. This article is a US Government work and is in the public domain in the USA. PMID- 22499193 TI - Traveling-wave ion mobility mass spectrometry of protein complexes: accurate calibrated collision cross-sections of human insulin oligomers. AB - RATIONALE: The collision cross-section (Omega) of a protein or protein complex ion can be measured using traveling-wave (T-wave) ion mobility (IM) mass spectrometry (MS) via calibration with compounds of known Omega. The T-wave Omega values depend strongly on instrument parameters and calibrant selection. Optimization of instrument parameters and calibration standards are crucial for obtaining accurate T-wave Omega-values. METHODS: Human insulin and the fast acting insulin aspart under native-like conditions (ammonium acetate, physiological pH) were analyzed on Waters SYNAPT G1 and G2 HDMS instruments. The calibrated T-wave Omega-values of insulin monomer, dimer, and hexamer ions were measured using many different combinations of denatured and native-like calibrants (masses between 2.85 and 256 kDa) and T-wave conditions. Drift-tube Omega-values were obtained on a modified SYNAPT G1. RESULTS: Insulin T-wave Omega values were measured at 26 combinations of T-wave velocity and amplitude. Optimal sets of calibrants were identified that yield Omega-values with minimal dependence on T-wave conditions and calibration plots with high R(2)-values. The T-wave Omega-values determined under conditions satisfying these criteria had absolute errors <2%. Structural differences between human insulin and fast-acting insulin aspart were probed with IM-MS. Insulin aspart monomers have increased flexibility, while hexamers are more compact than human insulin. CONCLUSIONS: Accurate T-wave Omega-values that are indistinguishable from drift-tube values are obtained when using (1) native-like calibrants with masses that closely bracket that of the analyte, (2) T-wave velocities that maximize the R(2) of the calibration plot for those calibrants, and (3) at least three replicates at T wave velocities that yield calibration plots with high R(2). PMID- 22499194 TI - Confined direct analysis in real time ion source and its applications in analysis of volatile organic compounds of Citrus limon (lemon) and Allium cepa (onion). AB - The DART (direct analysis in real time) ion source is a novel atmospheric pressure ionization technique that enables efficient ionization of gases, liquids and solids with high throughput. A major limit to its wider application in the analysis of gases is its poor detection sensitivity caused by open-air sampling. In this study, a confined interface between the DART ion source outlet and mass spectrometer sampling orifice was developed, where the plasma generated by the atmospheric pressure glow discharge collides and ionizes gas-phase molecules in a Tee-shaped flow tube instead of in open air. It leads to significant increase of collision reaction probability between high energy metastable molecules and analytes. The experimental results show that the ionization efficiency was increased at least by two orders of magnitude. This technique was then applied in the real time analysis of volatile organic compounds (VOCs) of Citrus Limon (lemon) and wounded Allium Cepa (onion). The confined DART ion source was proved to be a powerful tool for the studies of plant metabolomics. PMID- 22499195 TI - Secondary ion mass spectrometry of powdered explosive compounds for forensic evidence analysis. AB - RATIONALE: Residual quantities of explosives deposited on, or absorbed in, nearby surfaces can be of forensic value in post-blast analysis. As secondary ion mass spectrometry (SIMS) may be a suitable analytical approach for the screening of such residues, its performance was evaluated. METHODS: The analyses were carried out in a SIMS instrument fitted with a quadrupole analyzer. The sample was sputtered at a 45o incidence angle with a 100 um primary Ar(+) beam (3 keV, 500 nA). Surface sample compensation was performed with low-energy electrons (500 eV, 0.75 mA). RESULTS: TNT, RDX, PETN and cloratite were deposited in powdered form on double-sided tape and introduced into the mass spectrometer, without further handling, for SIMS analysis. The analysis conditions including compensation were optimized. A mixture of energetic compounds commonly used for explosive preparation was also analyzed, proving the potential of SIMS in forensic analysis. CONCLUSIONS: This study demonstrated the possibility of detecting explosives by SIMS making use of a simple sampling procedure consisting of sticking the sample in powdered form (compatible with the collection performed in forensic post-blast analysis) onto double-sided tape without handling or preparation. PMID- 22499196 TI - The use of a membrane filtration device to form dried plasma spots for the quantitative determination of guanfacine in whole blood. AB - RATIONALE: A two-layered polymeric membrane is employed for the formation of separated dried plasma spots from whole blood as an alternative to the direct analysis of whole dried blood spots (DBS). This dried plasma spot (DPS) analysis procedure precludes potential issues of hematocrit differences in whole blood samples while providing pharmokinetic data from plasma rather than whole blood. The described procedure is also semi-automated thus providing a simpler work flow for LC/MS/MS bioanalysis procedures. METHODS: Molecular filtration of red blood cells (RBC) from applied microsamples of whole blood fortified with guanfacine and its stable isotope internal standard was accomplished with a two-layer polymeric membrane substrate. The lower membrane surface containing the separated plasma spot was physically separated from the upper membrane followed by semi automated direct elution of the sample to an online solid-phase extraction (SPE) cartridge followed by liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). RESULTS: A two-layer membrane sample preparation substrate produced plasma from whole blood without centrifugation which could be directly eluted for semi-automated LC/MS/MS bioanalysis. Standard curves were constructed by plotting peak area ratios between the analyte and the stable isotope labeled internal standard (SIL-IS) versus the nominal concentration in whole blood. A weighted 1/x(2) linear regression was applied to the data from DPS samples. Standard curves were linear over the range 0.25-250 ng/mL human whole blood. The representative regression equation was y = 0.0142x + 0.00248 (R(2) = 0.995) for the described DPS assay. CONCLUSIONS: The described work demonstrates proof-of principle using membrane sample preparation techniques to form DPS samples from whole blood for subsequent bioanalysis by LC/MS/MS. This approach has the potential to eliminate the hematocrit issues from the current controversy surrounding validation of DBS assays. PMID- 22499197 TI - Surface-activated chemical ionization-electrospray ionization source improves biomarker discovery with mass spectrometry. AB - RATIONALE: Mass spectrometry (MS) is increasingly employed for the discovery of clinical biomarkers. However, due to sensitivity limitations related to in-source ionization yield, many potential biomarkers are not detected by standard mass spectrometers. Therefore, more efficient ion-source technologies are needed to improve MS applications in biomarker discovery. METHODS: Among novel ion-source technologies, Surface-Activated Chemical Ionization (SACI), although endowed with high sensitivity linked to its ability to reduce chemical noise in mass spectra, has seen limited application in biomarker discovery to date, due to its selectivity for highly polar compounds. However, in combination with an Electrospray Ionization (ESI) source, SACI selectivity can be enlarged in the range of less polar compounds. To validate the new SACI-ESI approach in biomarker discovery, we applied it to a translational setting in oncology. We performed MS profiles of 101 human serum samples from a male population, aged 40 or older, coming to the clinic for prostate cancer evaluation based on multiple PSA exams, digital rectal examination and echography. The SACI-ESI MS spectra were analyzed and classified with an innovative bioinformatic approach based on the MS-search freeware developed in house. RESULTS: Here we demonstrate that the SACI-ESI combination can produce MS spectra with greater sensitivity and lower noise than those obtained with the common ESI alone. We found that the SACI-ESI combination increased the number of detectable compounds and produced better quality of profiles in liquid chromatography (LC) coupled with MS (LC/MS) analysis of human serum samples, improving disease prediction potential. CONCLUSIONS: SACI-ESI can facilitate MS-based discovery of potential biomarkers in human serum. Combined with the proposed bioinformatic approach (based on XCMS and NIST data elaboration) for the analysis of the MS spectra obtained, the potential for developing biomarkers with diagnostic capabilities are demonstrated in a prostate cancer diagnosis clinical setting. PMID- 22499198 TI - Measurement of the 17O-excess (Delta17O) of tropospheric ozone using a nitrite coated filter. AB - RATIONALE: The (17)O-excess (Delta(17)O) of tropospheric ozone (O(3)) serves as a useful marker in studies of atmospheric oxidation pathways; however, due to the complexity and expense of currently available analytical techniques, no systematic sampling campaign has yet been undertaken and natural variations in Delta(17)O(O(3)) are therefore not well constrained. METHODS: The nitrite-coated filter method is a new technique for O(3) isotope analysis that employs the aqueous phase NO(2)(-) + O(3) -> NO(3)(-) + O(2) reaction to obtain quantitative information on O(3) via the oxygen atom transfer to nitrate (NO(3)(-)). The triple-oxygen isotope analysis of the NO(3)(-) produced during this reaction, achieved in this study using the bacterial denitrifier method followed by isotope ratio mass spectrometry (IRMS), directly yields the Delta(17)O value transferred from O(3). This isotope transfer process was investigated in a series of vacuum line experiments, which were conducted by exposing coated filters to O(3) of various known Delta(17)O values and then determining the isotopic composition of the NO(3)(-) produced on the filter. RESULTS: The isotope transfer experiments revealed a strong linear correlation between the Delta(17)O of the O(3) produced and that of the oxygen atom transferred to NO(3)(-), with a slope of 1.55 for samples with bulk Delta(17)O(O(3)) values in the atmospheric range (20-400/00). This finding is in agreement with theoretical postulates that place the (17) O excess on only the terminal oxygen atoms of ozone. Ambient measurements yield average Delta(17)O(O(3))(bulk) values in agreement with previous studies (22.9 +/ 1.90/00). CONCLUSIONS: The nitrite-coated filter technique is a sufficiently robust, field-deployable method for the determination of the triple-oxygen isotopic composition of tropospheric O(3). Further ambient measurements will undoubtedly lead to an improved quantitative view of natural Delta(17)O(O(3)) variation and transfer in the atmosphere. PMID- 22499199 TI - Isotope effects associated with the preparation and methylation of fatty acids by boron trifluoride in methanol for compound-specific stable hydrogen isotope analysis via gas chromatography/thermal conversion/isotope ratio mass spectrometry. AB - RATIONALE: Compound-specific stable hydrogen isotope analysis of fatty acids is being used increasingly as a means of deriving information from a diverse range of materials of archaeological, geological and environmental interest. Preparative steps required prior to isotope ratio mass spectrometry (IRMS) analysis have the potential to alter determined deltaD values and hence must be accounted for if accurate deltaD values for target compounds are to be obtained. METHODS: Myristic, palmitic, stearic, arachidic and behenic saturated fatty acids were derivatised to their respective fatty acid methyl esters (FAMEs), using 14% (w/v) boron trifluoride in methanol then analysed by gas chromatography/thermal conversion/IRMS (GC/TC/IRMS). FAMEs generated from fatty acid sodium salts of unknown deltaD values were then used to test a correction factor determined for this method of derivatisation. RESULTS: Derivatisation was found to alter the hydrogen isotopic composition of FAMEs although this effect was reproducible and can be accounted for. The difference between the mean corrected and mean bulk deltaD values was always less than 6.7 0/00. Extraction of saturated fatty acids and acyl lipids from samples, subsequent hydrolysis, then separation on a solid phase extraction cartridge, was found to alter the determined deltaD values by less than one standard deviation. CONCLUSIONS: Overall, it has been shown that for natural abundance hydrogen isotope determinations, the isolation and derivatisation of extracted fatty acids alters the determined deltaD values only by a numerical increment comparable with the experimental error. This supports the use of the described analytical protocol as an effective means of determining fatty acid deltaD values by GC/TC/IRMS. PMID- 22499200 TI - A new calibrant for matrix-assisted laser desorption/ionization time-of-flight time-of-flight post-source decay tandem mass spectrometry of non-digested proteins for top-down proteomic analysis. AB - RATIONALE: Matrix-assisted laser desorption/ionization (MALDI) time-of-flight time-of-flight (TOF-TOF) post-source decay (PSD) tandem mass spectrometry (MS/MS) has seen increasing use for analysis of non-digested protein ions for top-down proteomic identification. However, there is no commonly accepted calibrant for this purpose beyond the use of peptide calibrants whose fragment ions span a lower mass-to-charge (m/z) range. METHODS: We have used the PSD-generated fragment ions of disulfide-reduced/alkylated thioredoxin (AlkTrx) for TOF-TOF calibration in reflectron mode for the purpose of PSD-MS/MS analysis. The average m/z values of AlkTrx fragment ions were used for calibration. The quality of the calibration was assessed from the observed fragment ion mass error of MS/MS of the YahO protein from an unfractionated bacterial cell lysate of Escherichia coli O157:H7 as well as from MS/MS of bovine ubiquitin. The fragment ion mass errors of these two analytes were also used to assess instrument calibration using the monoisotopic fragment ions of [Glu(1)]-fibrinopeptide B (GluFib). RESULTS: A general improvement in fragment ion mass accuracy was observed using the AlkTrx calibration compared to the GluFib calibration which resulted in a more significant top-down proteomic identification of these analyte proteins. CONCLUSIONS: Our results suggest that AlkTrx may be useful as a calibrant for MALDI-TOF-TOF-PSD-MS/MS of small and modest-sized protein ions. The uniform fragmentation efficiency of YahO across its sequence suggests that it may be useful as a post-calibration standard to assess PSD-MS/MS instrument performance as well as establishing appropriate top-down proteomic fragment ion tolerances. PMID- 22499201 TI - A ultra-pressure liquid chromatography/triple quadrupole tandem mass spectrometry method for the analysis of 13 eicosanoids in human urine and quantitative 24 hour values in healthy volunteers in a controlled constant diet. AB - RATIONALE: Isoprostanes (IsoPs) are a series of prostaglandin (PG)-like compounds formed non-enzymatically through free-radical-induced peroxidation of arachidonic acid. They are considered as 'gold-standard' biomarkers for oxidative stress, in general, and lipid peroxidation, in particular. METHODS: A new qualitative and quantitative analytical method for the determination of 13 eicosanoids in human urine using solid-phase extraction (SPE) and ultra-pressure liquid chromatography coupled to tandem mass spectrometry (UPLC/MS/MS) has been developed. The SPE was optimized by comparison of the extraction efficiency and recoveries of three distinct cartridges: Strata X-AW, C18 Sep-Pak, and Oasis HLB. The UPLC/MS/MS approach in the multiple reaction monitoring (MRM) mode was developed using negative electrospray ionization (ESI). RESULTS: The validated method provides a high-throughput assay with an adequate linearity from 0.16 to 330 ng mL(-1). The limit of detection (LOD) and limit of quantification (LOQ) for each analyte showed low intervals (0.021-0.64 ng mL(-1) and 0.042-1.28 ng mL(-1), respectively). Urinary IsoPs were determined in 24 healthy volunteers and ranged from 685 to 3480 ng 24 h(-1) and from 864 to 7511 ng 24 h(-1) in urine from women and men, respectively. CONCLUSIONS: This analytical method could constitute a useful tool for the determination of oxidative stress biomarkers in clinical studies in which IsoPs may evidence early pathological conditions, as suggested by the determination of the baseline IsoPs content in human urine, since it improves upon the detection capacity of previously described methods. The quantity of IsoPs excreted in urine was higher than that found in previous reports due to the total hydrolysis of the conjugated forms. PMID- 22499202 TI - The THO/TREX complex functions in disease resistance in Arabidopsis. AB - Powdery mildew pathogens are biotrophic fungi that infect large number of plant species. EDR1 (ENHANCED DISEASE RESISTANCE 1) is a negative regulator of plant disease resistance, and loss-of-function in the EDR1 gene confers enhanced disease resistance to powdery mildew pathogen Golovinomyces cichoracearum. In an edr1 suppressor screen, we recently found that a mutation in HPR1, a component of the THO/TREX complex, suppresses edr1-mediated disease resistance, however the hpr1 mutation enhances the ethylene-induced senescence in edr1. The hpr1 single mutant displays enhanced susceptibility, indicating that HPR1 is involved in plant defense responses. THO/TREX is a conserved protein complex that functions in pre-mRNA processing and mRNA export. Several components of THO/TREX complex in Arabidopsis have been identified. By searching Arabidopsis database, we found that Arabidopsis (Columbia-0) has two copies of UAP56, another component of the THO/TREX complex, and the UAP56 proteins are highly conserved. Similar to human UAP56 protein, Arabidopsis UAP56 also localizes to the nucleus, showing a pattern similar to the splicing speckles. Further characterization of the components of THO/TREX in Arabidopsis will provide new insights into the role of THO/TREX in defense responses in plants. PMID- 22499203 TI - Cadmium toxicity: effects on cytoskeleton, vesicular trafficking and cell wall construction. AB - Cadmium is a well-known environmental pollutant with distinctly toxic effects on plants. It can displace certain essential metals from a wealth of metalloproteins, and thus disturb many normal physiological processes and cause severe developmental aberrant. The harmful effects of cadmium stress include, but are not limited to: reactive oxygen species overproduction, higher lipid hydroperoxide contents, and chloroplast structure change, which may lead to cell death. Plants have developed diverse mechanisms to alleviate environmental cadmium stress, e.g., cadmium pump and transporting cadmium into the leaf vacuoles. This mini-review focuses on the current research into understanding the cellular mechanisms of cadmium toxicity on cytoskeleton, vesicular trafficking and cell wall formation in plants. PMID- 22499204 TI - How to hierarchize the main physiological processes responsible for phenotypic differences in large-scale screening studies? AB - One difficulty when analyzing the determinants at the origin of plant phenotypic differences is that measured plant traits are frequently integrative: they result from the integration of a large number of physiological processes under the control of genetic and environmental factors. In a previous report, we demonstrated that dissecting integrative traits into simpler components using a simple crop physiology model was a valuable method for detecting quantitative trait loci (QTL) related to the nitrogen nutrition for a recombinant inbred lines population of Medicago truncatula. Here, using the same data set, we demonstrate the relevance of decomposing integrative traits for understanding biological differences among phenotypes, independently of QTL detection. Two examples are given to demonstrate that the dissection of integrative traits (i.e., plant leaf area and nitrogen nutrition index) into variables representing the efficiency of the plant to extract and valorize (carbon and nitrogen) resources is an effective method to determine the stream of physiological events that leads to the final phenotype. PMID- 22499205 TI - A molecular insight into Darwin's "plant brain hypothesis" through expression pattern study of the MKRN gene in plant embryo compared with mouse embryo. AB - MKRN gene family encodes zinc ring finger proteins characterized by a unique array of motifs (C3H, RING and a characteristic cys-his motif) in eukaryotes. To elucidate the function of the MKRN gene and to draw an analogy between plant root apical meristem and animal brain, we compared the gene expression pattern of MKRN in plant seeds with that of mouse embryo. The spatio-temporal expression of MKRN in seeds of pea and rice was performed using non radioactive mRNA in situ hybridization (NRISH) with DIG and BIOTIN labeled probes for pea and rice embryos respectively. Images of MKRN1 expression in e10.5 whole mount mouse embryo, hybridized with DIG labeled probes, were obtained from the Mouse Genome Database (MGD). MKRN transcripts were expressed in the vascular bundle, root apical meristem (RAM) and shoot apical meristem (SAM) in pea and rice embryos. The spatial annotation of the MKRN1 NRISH of whole mount mouse embryo shows prominent localization of MKRN1 in the brain, and its possible expression in spinal cord and the genital ridge. Localization of MKRN in the anterior and posterior ends of pea and rice embryo suggests to the probable role it may have in sculpting the pea and rice plants. The expression of MKRN in RAM may give a molecular insight into the hypothesis that plants have their brains seated in the root. The expression of MKRN is similar in functionally and anatomically analogous regions of plant and animal embryos, including the vascular bundle (spinal cord), the RAM (brain), and SAM (genital ridge) thus paving way for further inter-kingdom comparison studies. PMID- 22499207 TI - Aspects of plant plasmalemma charging induced by external electric field pulses. AB - The charging of the plasmalemma is a necessary condition for permeabilization of the plasma membrane (electroporation) in response to external electric field exposure. Common theories explain this permeabilization by formation of pores in the lipid bilayer. Using pulsed laser fluorescence microscopy, we measured the charging process of the membrane during the application of an external electric field with a temporal resolution of 5 ns. Visualization of the charging process of protoplasts plasma membrane (Nicotiana tabacum Bright Yellow 2) was achieved by staining of the plasma membrane with the voltage-sensitive fluorescent dye ANNINE-6. Measurements on membranes exhibiting negligible membrane permeabilization confirm the sine-shaped azimuthal distribution of the membrane voltage predicted by the relation of Cole. At higher membrane voltages, enhanced pore formation allows for the exchange of charge carriers, leading to deviations from the sine-shaped curve progression, i.e., a saturation of the membrane voltage at membrane segments facing the electrodes. Additionally, measurements on protoplasts exposed to multiple successive pulses indicate that the recovery of the membrane seems to be a fast process, occurring within seconds after termination of the external electric field pulse. PMID- 22499206 TI - To close or not to close: plasmodesmata in defense. AB - Cell death is a biological process that occurs during differentiation and maturation of certain cell types, during senescence, or as part of a defense mechanism against microbial pathogens. Intercellular coordination is thought to be necessary to restrict the spread of death signals, although little is known about how cell death is controlled at the tissue level. The recent characterization of a plasmodesmal protein, PDLP5, has revealed an important role for plasmodesmal control during salicylic acid-mediated cell death responses. Here, we discuss molecular factors that are potentially involved in PDLP5 expression, and explore possible signaling networks that PDLP5 interacts with during basal defense responses. PMID- 22499208 TI - ROS production during symbiotic infection suppresses pathogenesis-related gene expression. AB - Leguminous plants have exclusive ability to form symbiotic relationship with soil bacteria of the genus Rhizobium. Symbiosis is a complex process that involves multiple molecular signaling activities, such as calcium fluxes, production of reactive oxygen species (ROS) and synthesis of nodulation genes. We analyzed the role of ROS in defense gene expression in Medicago truncatula during symbiosis and pathogenesis. Studies in Arabidopsis thaliana showed that the induction of pathogenesis-related (PR) genes during systemic acquired resistance (SAR) is regulated by NPR1 protein, which resides in the cytoplasm as an oligomer. After oxidative burst and return of reducing conditions, the NPR1 undergoes monomerization and becomes translocated to the nucleus, where it functions in PR genes induction. We show that ROS production is both stronger and longer during symbiotic interactions than during interactions with pathogenic, nonhost or common nonpathogenic soil bacteria. Moreover, root cells inoculated with Sinorhizobium meliloti accumulated ROS in the cytosol but not in vacuoles, as opposed to Pseudomonas putida inoculation or salt stress treatment. Furthermore, increased ROS accumulation by addition of H2O2 reduced the PR gene expression, while catalase had an opposite effect, establishing that the PR gene expression is opposite to the level of cytoplasmic ROS. In addition, we show that salicylic acid pretreatment significantly reduced ROS production in root cells during symbiotic interaction. PMID- 22499209 TI - In vivo role of nitric oxide in plant response to abiotic and biotic stress. AB - Over the past few years, nitric oxide (NO) has emerged as an important regulator in many physiological events, especially in response to abiotic and biotic stress. However, the roles of NO were mostly derived from pharmacological studies or the mutants impaired NO synthesis unspecifically. In our recent study, we highlighted a novel strategy by expressing the rat neuronal NO synthase (nNOS) in Arabidopsis to explore the in vivo role of NO. Our results suggested that plants were able to perform well in the constitutive presence of nNOS, and provided a new class of plant experimental system with specific in vivo NO release. Furthermore, our findings also confirmed that the in vivo NO is essential for most of environmental abiotic stresses and disease resistance against pathogen infection. Proper level of NO may be necessary and beneficial, not only in plant response to the environmental abiotic stress, but also to biotic stress. PMID- 22499211 TI - Inclusion of human intravenous study data in new drug applications-impact of the Japanese guidance. AB - Human pharmacokinetic study after intravenous (i.v.) administration is inevitable in calculating basic pharmacokinetic parameters such as bioavailability, clearance, and distribution volume. However, i.v. data are not always included in the dossier, although the regulatory guidance recommends the inclusion of i.v. studies for Japanese new drug applications. We investigated the adherence to this guidance on the inclusion of i.v. data along with various factors. Logistic regression analyses were carried out on 117 new oral drugs approved in Japan between 1999 and 2009. Inclusion of i.v. data conspicuously increased after the issuance of the guidance for self-originated drugs developed by Japanese firms [odds ratio (OR) = 30-41). Moreover, drugs exhibiting large interindividual variations in pharmacokinetics showed a positive association (OR = 4.1-8.2), whereas solubility did not show notable association (OR = 1.0) with inclusion of i.v. data. Inclusion of i.v. data was not associated with physicochemical feasibility, but the developer's willingness to comply with the guidance seems to be involved. PMID- 22499210 TI - OsTRXh1 regulates the redox state of the apoplast and influences stress responses in rice. AB - The plant cell apoplast is the compartment beyond the cell plasmalemma, including the cell wall and intercellular space. Many environmental elements can trigger reactive oxygen species (ROS) burst at the plasma membrane which then alters the redox state of the apoplast. Recently, h-type thioredoxin (Trx), OsTRXh1, was identified to be involved in apoplastic redox state regulation in rice. OsTRXh1 is conserved redox-active Trx and can be secreted into the extracellular regions. Through transgenic rice plant, we found that OsTRXh1 regulated ROS accumulation in apoplast and influenced plant development and stress responses. This provides new insights into apoplastic redox state regulation pathway and expands our understanding of h-type Trxs function. PMID- 22499212 TI - Stereocontrolled access to optically-enriched oxabispidines. AB - A range of chiral, optically-enriched bicyclic oxabispidines were prepared from (S)-(-)-2,3-epoxypropylphthalimide using an efficient sequence featuring a stereocontrolled intramolecular Mannich reaction as the key transformation. PMID- 22499213 TI - Lipocalin 2 is a novel immune mediator of experimental autoimmune encephalomyelitis pathogenesis and is modulated in multiple sclerosis. AB - Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model of multiple sclerosis (MS), an inflammatory, demyelinating disease of the central nervous system (CNS). EAE pathogenesis involves various cell types, cytokines, chemokines, and adhesion molecules. Given the complexity of the inflammatory response in EAE, it is likely that many immune mediators still remain to be discovered. To identify novel immune mediators of EAE pathogenesis, we performed an Affymetrix gene array screen on the spinal cords of mice at the onset stage of disease. This screening identified the gene encoding lipocalin 2 (Lcn2) as being significantly upregulated. Lcn2 is a multi-functional protein that plays a role in glial activation, matrix metalloproteinase (MMP) stabilization, and cellular iron flux. As many of these processes have been implicated in EAE, we characterized the expression and role of Lcn2 in this disease in C57BL/6 mice. We show that Lcn2 is significantly upregulated in the spinal cord throughout EAE and is expressed predominantly by monocytes and reactive astrocytes. The Lcn2 receptor, 24p3R, is also expressed on monocytes, macrophages/microglia, and astrocytes in EAE. In addition, we show that EAE severity is increased in Lcn2(-/ ) mice as compared with wild-type controls. Finally, we demonstrate that elevated levels of Lcn2 are detected in the plasma and cerebrospinal fluid (CSF) in MS and in immune cells in CNS lesions in MS tissue sections. These data indicate that Lcn2 is a modulator of EAE pathogenesis and suggest that it may also play a role in MS. PMID- 22499214 TI - Anharmonic transitions in nearly dry L-cysteine I. AB - Two special dynamical transitions of universal character have recently been observed in macromolecules (lysozyme, myoglobin, bacteriorhodopsin, DNA and RNA) at T* ~100-150 K and T(D) ~180-220 K. The underlying mechanisms governing these transitions have been the subject of debate. In the present work, a survey is reported on the temperature dependence of structural, vibrational and thermodynamical properties of a nearly anhydrous amino acid (orthorhombic polymorph of the amino acid l-cysteine at a hydration level of 3.5%). The temperature dependence of x-ray powder diffraction patterns, Raman spectra and specific heat revealed these two transitions at T* = 70 K and T(D) = 230 K for this sample. The data were analyzed considering amino acid-amino acid, amino acid water, water-water phonon-phonon interactions and molecular rotor activation. Our results indicated that the two referred temperatures define the triggering of very simple and particular events that govern all the interactions of the biomolecular: activation of CH(2) rigid rotors (T < T* ), phonon-phonon interactions between specific amino acid and water dimer vibrational modes (T* < T < T(D)), and water rotational barriers surpassing (T > T(D)). PMID- 22499215 TI - Solid-state 11B and 13C NMR, IR, and X-ray crystallographic characterization of selected arylboronic acids and their catechol cyclic esters. AB - Nine arylboronic acids, seven arylboronic catechol cyclic esters, and two trimeric arylboronic anhydrides (boroxines) are investigated using (11)B solid state NMR spectroscopy at three different magnetic field strengths (9.4, 11.7, and 21.1 T). Through the analysis of spectra of static and magic-angle spinning samples, the (11)B electric field gradient and chemical shift tensors are determined. The effects of relaxation anisotropy and nutation field strength on the (11)B NMR line shapes are investigated. Infrared spectroscopy was also used to help identify peaks in the NMR spectra as being due to the anhydride form in some of the arylboronic acid samples. Seven new X-ray crystallographic structures are reported. Calculations of the (11)B NMR parameters are performed using cluster model and periodic gauge-including projector-augmented wave (GIPAW) density functional theory (DFT) approaches, and the results are compared with the experimental values. Carbon-13 solid-state NMR experiments and spectral simulations are applied to determine the chemical shifts of the ipso carbons of the samples. One bond indirect (13)C-(11)B spin-spin (J) coupling constants are also measured experimentally and compared with calculated values. The (11)B/(10)B isotope effect on the (13)C chemical shift of the ipso carbons of arylboronic acids and their catechol esters, as well as residual dipolar coupling, is discussed. Overall, this combined X-ray, NMR, IR, and computational study provides valuable new insights into the relationship between NMR parameters and the structure of boronic acids and esters. PMID- 22499216 TI - Chiral guanidine-catalyzed asymmetric direct vinylogous Michael reaction of alpha,beta-unsaturated gamma-butyrolactams with alkylidene malonates. AB - The asymmetric direct vinylogous Michael reaction of alpha,beta-unsaturated gamma butyrolactams with alkylidene malonates has been developed. Various 5-substituted 3-pyrrolidin-2-ones were obtained in high yields (up to 93%) with excellent stereoselectivities (up to 94% ee, 95 : 5 dr), using a novel bifunctional C(1) symmetric guanidine organocatalyst embodied a secondary amine subunit. PMID- 22499217 TI - Outcomes of congenital diaphragmatic hernia: a 12-year experience. AB - OBJECTIVE: To determine outcomes for babies with congenital diaphragmatic hernia (CDH) diagnosed prenatally and postnatally presenting to a tertiary unit. METHOD: Fetal medicine database and neonatal surgical unit admission books were reviewed to identify cases of CDH over a 12-year period (Jan 1998- Dec 2009). RESULTS: A total of 132 cases of CDH were diagnosed prenatally and 39 cases diagnosed postnatally. Mean gestation at diagnosis was 22 weeks (range 13-37 weeks). Karyotyping was abnormal in 15.9%; abnormal karyotype in 3.6% of fetuses without other structural anomalies compared with 38.9% when other anomalies were identified. In 45 cases (34.1%) pregnancy was terminated. Two stillbirths occurred (2.3% of ongoing pregnancies). One hundred twenty-four babies were live born, of whom 98 babies underwent surgery. Survival to discharge of all live born babies was 72.6%; survival following surgery was 91.8%. Birthweight had a significant effect on survival (odds ratio 0.22, 95% confidence intervals 0.08 0.66). Survival for live born babies prenatally diagnosed was significantly lower (65.9%) than those diagnosed postnatally (92.3%). CONCLUSION: Abnormal karyotype was more common when CDH was associated with other anomalies. In multivariate analysis, lower birthweight and prenatal diagnosis had a significant impact on survival. Only prenatally diagnosed CDH survival figures should be utilised in prenatal counselling. PMID- 22499218 TI - Role of mineralocorticoid receptor in insulin resistance. AB - PURPOSE OF REVIEW: Recent data suggest that mineralocorticoid receptor activation can affect insulin resistance independent of its effects on blood pressure. This review discusses new evidence linking mineralocorticoid receptor to insulin resistance and the underlying mechanisms of these effects. RECENT FINDINGS: Observational studies have shown mineralocorticoid activity to be associated with insulin resistance irrespective of race, blood pressure or body weight. Increased mineralocorticoid activity may be the common link between obesity, hypertension, dyslipidemia and insulin resistance, features that make up the metabolic syndrome. Treatment of primary aldosteronism is associated with a decrease in insulin resistance and provides one of the most convincing evidences in favor of the contribution of mineralocorticoid receptor to insulin resistance. Dietary salt restriction, which increases aldosterone levels, is also associated with an increase in insulin resistance. Potential mechanisms by which mineralocorticoid receptor may contribute to insulin resistance include a decreased transcription of the insulin receptor gene, increased degradation of insulin receptor substrates, interference with insulin signaling mechanisms, decreased adiponectin production and increased oxidative stress and inflammation. Advantages of mineralocorticoid receptor antagonists on insulin resistance have been demonstrated in animal models. SUMMARY: There may be a benefit of mineralocorticoid receptor antagonists in human insulin resistance states, but more clinical research is needed to explore these possibilities. PMID- 22499220 TI - Nonclassic congenital adrenal hyperplasia. AB - PURPOSE OF REVIEW: Late-onset or nonclassic congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive disorders. Reported prevalence ranges from 1 in 30 to 1 in 1000. Affected individuals typically present due to signs and symptoms of androgen excess. The purpose of this review is to provide current information regarding the pathophysiology, molecular genetics, and management of this common disorder. RECENT FINDINGS: Subfertility and the consequences of elevated progesterone concentrations have been increasingly documented for women with NCAH. Although testicular adrenal rest tumors (TARTs) are more common in men with classical congenital adrenal hyperplasia, oligospermia and TARTs have been described in men with NCAH. The phenotypic spectrum of defects in other components of the steroidogenic pathway such as P450 oxidoreductase and steroidogenic acute regulatory protein has been expanded to include milder forms. SUMMARY: Treatment needs to be directed toward the symptoms. Goals of treatment include normal linear growth velocity, normal rate of skeletal maturation, 'on-time' puberty, regular menstrual cycles, prevention of or limited progression of hirsutism and acne, and fertility. Treatment needs to be individualized and should not be initiated merely to decrease abnormally elevated hormone concentrations. PMID- 22499219 TI - Pharmacogenetics of follicle-stimulating hormone action. AB - PURPOSE OF REVIEW: To review the current knowledge of genetic variants in the two genes affecting the individual responsiveness to follicle-stimulating hormone (FSH) action-the FSH beta-subunit (FSHB) and the FSH receptor (FSHR), as well as the pharmacogenetic ramifications of the findings. RECENT FINDINGS: Four common variants in the FSHB and the FSHR genes were shown to exhibit significant effect on FSH action: linked FSHR variants Thr307Ala and Asn680Ser determining common receptor isoforms, and gene expression affecting polymorphisms FSHR -29G/A and FSHB -211G/T. In women, the FSHR Thr307Ala/Asn680Ser polymorphisms show consistent predictive value for estimating the most optimal recombinant FSH dosage in controlled ovarian hyperstimulation (COH). The same variants exhibit a potential for the pharmacogenetic assessment of the treatment of polycystic ovarian syndrome. The FSHR -29G/A variant was also shown to contribute to ovarian response to COH. Pilot studies have suggested the FSHB -211 TT homozygous oligozoospermic men with genetically determined low concentration of FSH, as potentially the best responders to FSH treatment; furthermore, modulation of this response by FSHR polymorphisms is possible. SUMMARY: Genetic variants in FSHB and FSHR exhibit a potential for pharmacogenetic applications in selecting appropriate treatment options (timing and dosage) in male and female conditions requiring or benefiting from FSH therapy. PMID- 22499221 TI - The physiology and timing of male puberty. AB - PURPOSE OF REVIEW: To describe available markers of male puberty, discuss associations between adiposity and pubertal timing and to review recent evidence of a possible secular trend in male pubertal timing. RECENT FINDINGS: An expert panel reviewing existing American pubertal data from boys in 2005 could not confirm a secular trend in male pubertal timing. National Health and Nutrition Examination Survey III findings have been confirmed by the National Institute of Child Health and Human Development study reporting a mean age of 10.4 years for Caucasian boys entering Tanner stage G2. Furthermore, the Copenhagen Puberty Study reported a 3 months decline in pubertal onset during a 15-year period (from 11.92 years in 1991 to 11.66 years in 2008).A negative association between obesity and early puberty was found in the National Institute of Child Health and Human Development study, in contrast to the positive association found in a Danish study. Other studies have not been able to document an association between prepubertal BMI and age at pubertal onset. SUMMARY: Evaluation of Tanner stage and especially assessment of testicular volume should both be used in epidemiological studies. We speculate that the association between fat mass and pubertal timing may be nonlinear and recent studies may indicate a small decline in age at pubertal onset in boys. PMID- 22499222 TI - Long-term outcome of idiopathic hypogonadotropic hypogonadism. AB - PURPOSE OF REVIEW: This review focuses on the presentation, treatment and long term outcomes of men with idiopathic hypogonadotropic hypogonadism (IHH). RECENT FINDINGS: The traditional view that IHH is a simple monogenic disorder has now been revised, with some cases having an oliogenic basis involving mutations in more than one locus in each affected individual. The majority of IHH men respond well to induction of spermatogenesis with gonadotropins or pulsatile gonadotropin releasing hormone. Favourable prognostic factors include larger testicular size, prior gonadotropin therapy, no previous androgen therapy, absence of cryptorchidism and pretreatment inhibin B levels more than 60 pg/ml. Genetic factors influence response to therapy and patients with KAL1 mutations tend to have less favourable outcomes as they may have defects in multiple levels of the hypothalamic-pituitary-gonadal axis.Androgen replacement is warranted in all IHH patients after usual chronological age of puberty, and poor treatment compliance is associated with lower bone mineral density and higher fat mass. However, 10% of patients display sustained reversal so a brief treatment interruption should be considered. SUMMARY: IHH is a heterogeneous disorder. The complex genetics and interaction with environmental factors likely underlie the variable expressivity of the reproductive and nonreproductive phenotypes. The demonstration of reversibility, the impact of inadequate testosterone replacement and the good response to induction of spermatogenesis confirm the need for specialist care and long-term follow-up. PMID- 22499223 TI - Prenatal exposure to smoking and male reproductive health. AB - PURPOSE OF REVIEW: To assess whether prenatal exposure to smoking is associated with impaired reproductive health in exposed men. RECENT FINDINGS: Men who have been exposed to maternal smoking in utero have smaller testes and impaired semen quality as compared to nonexposed men, suggesting toxic effects on Sertoli and/or germ cells. According to meta-analyses there is only a weak or no association with fetal exposure to smoking and the incidence of testicular germ cell cancer, cryptorchidism, or hypospadias. SUMMARY: Adverse effect of maternal smoking on sperm production capacity of their son is yet another good reason for women to quit smoking before pregnancy. PMID- 22499224 TI - The clinical spectrum of adrenocortical hyperplasia. AB - PURPOSE OF REVIEW: To describe the significance of a common adrenal radiological finding on computed tomography or MRI. RECENT FINDINGS: Bilateral adrenocortical hyperplasia is the common expression of a variety of adrenal disorders, and its cause needs to be properly assessed in order to institute appropriate management. SUMMARY: Behind the radiological finding of bilateral adrenal enlargement, there is a spectrum of diseases that require diagnostic evaluation and management. Many cases are benign and not associated with abnormalities of endocrine function. However, these abnormalities may develop years after the initial diagnosis has been made. PMID- 22499225 TI - Editorial overview: the adrenal cortex. PMID- 22499228 TI - Investigation of spin-flip reactions of Nb + CH3CN by relativistic density functional theory. AB - In order to explore the details of the reaction mechanisms of Nb atoms with acetonitrile molecules, the sextet, quartet, and doublet spin state potential energy surfaces have been investigated. Density functional theory (DFT) with the relativistic zero-order regular approximation at the PW91/TZ2P level has been applied. The complicated minimum energy reaction path involves four transition states (TS), stationary states (1) to (5) and two intersystem crossings from spin sextets to quartets to doublets (indicated by =>): (6)Nb + NCCH3->(6)Nb eta(1) NCCH3 ((6)1) ->(6)TS1/2=>(4)Nb eta(2)-(NC)CH3 ((4)2) ->(4)TS2/3->(4)NbH eta(3) (NCCH2) ((4)3) ->(4)TS3/4-> CNNbCH3 ((4)4) =>(2)TS4/5-> CN(NbH)CH2 ((2)5). The minimum energy crossing points were determined with the help of the DFT fractional-occupation-number approach. The first spin inversion leads from the sextet to an energetically low intermediate quartet ((4)2) with final insertion of Nb into the C-C bond. The second one from the quartet to the doublet state facilitates the activation of a C-H bond, lowering the rearrangement-barrier by 44 kJ mol(-1). The overall reaction is calculated to be exothermic by about 170 180 kJ mol(-1). All intermediate and product species were frequency and NBO analyzed. The species can be rationalized with the help of Lewis type formulas. PMID- 22499229 TI - Stereospecific carbene polymerization with oxygenated Rh(diene) species. PMID- 22499226 TI - A grading system combining architectural features and mitotic count predicts recurrence in stage I lung adenocarcinoma. AB - The International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) has recently proposed a new lung adenocarcinoma classification. We investigated whether nuclear features can stratify prognostic subsets. Slides of 485 stage I lung adenocarcinoma patients were reviewed. We evaluated nuclear diameter, nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, prominence of nucleoli, intranuclear inclusions, mitotic count/10 high-power fields (HPFs) or 2.4 mm(2), and atypical mitoses. Tumors were classified into histologic subtypes according to the IASLC/ATS/ERS classification and grouped by architectural grade into low (adenocarcinoma in situ, minimally invasive adenocarcinoma, or lepidic predominant), intermediate (papillary or acinar), and high (micropapillary or solid). Log-rank tests and Cox regression models evaluated the ability of clinicopathologic factors to predict recurrence-free probability. In univariate analyses, nuclear diameter (P=0.007), nuclear atypia (P=0.006), mitotic count (P<0.001), and atypical mitoses (P<0.001) were significant predictors of recurrence. The recurrence-free probability of patients with high mitotic count (>=5/10 HPF: n=175) was the lowest (5-year recurrence-free probability=73%), followed by intermediate (2-4/10 HPF: n=106, 80%), and low (0-1/10 HPF: n=204, 91%, P<0.001). Combined architectural/mitotic grading system stratified patient outcomes (P<0.001): low grade (low architectural grade with any mitotic count and intermediate architectural grade with low mitotic count: n=201, 5-year recurrence free probability=92%), intermediate grade (intermediate architectural grade with intermediate-high mitotic counts: n=206, 78%), and high grade (high architectural grade with any mitotic count: n=78, 68%). The advantage of adding mitotic count to architectural grade is in stratifying patients with intermediate architectural grade into two prognostically distinct categories (P=0.001). After adjusting for clinicopathologic factors including sex, stage, pleural/lymphovascular invasion, and necrosis, mitotic count was not an independent predictor of recurrence (P=0.178). However, patients with the high architectural/mitotic grade remained at significantly increased risk of recurrence (high vs low: P=0.005) after adjusting for clinical factors. We proposed this combined architectural/mitotic grade for lung adenocarcinoma as a practical method that can be applied in routine practice. PMID- 22499230 TI - Inducing hysteretic spin crossover in solution. AB - A hysteretic spin transition is induced in a solution assembly of a mononuclear Fe(III) amphiphilic complex which exhibits only gradual spin crossover in the solid state. The hysteretic behavior is dependent on dynamic solution assembly and removal of solvent causes reversion to the original bulk solid magnetic response. PMID- 22499231 TI - Impact of six fruits--banana, guava, mangosteen, pineapple, ripe mango and ripe papaya--on murine hepatic cytochrome P450 activities. AB - The effects of six Thai fruits, namely banana, guava, mangosteen, pineapple, ripe mango and ripe papaya, on cytochrome P450 (P450) activities were investigated. The median inhibitory concentrations (IC(50) ) of each of the fruit juices on CYP1A1, CYP1A2, CYP2E1 and CYP3A11 activities were determined. Pineapple juice showed the strongest inhibitory effect against all the evaluated P450 isozyme activities in mouse hepatic microsomes, followed by mangosteen, guava, ripe mango, ripe papaya and banana. The study was further performed in male ICR mice given pineapple juice intragastrically at doses of 10, 20 and 40 mg kg(-1) per day for 7 or 28 days. In a concentration-dependent fashion, the pineapple juice raised ethoxyresorufin O-deethylase, aniline hydroxylase and erythromycin N demethylase activities, which are marker enzymatic reactions responsible for CYP1A1, CYP2E1 and CYP3A11, respectively. The effect of pineapple juice on the expression of CYP1A1, CYP2E1 and CYP3A11 mRNAs corresponded to their enzymatic activities. However, the pineapple juice significantly decreased methoxyresorufin O-demethylase activity. These observations supported that the six Thai fruits were a feasible cause of food-drug interaction or adverse drug effects owing to their potential to modify several essential P450 activities. Individuals consuming large quantities of pineapple for long periods of time should be cautioned of these potential adverse effects. PMID- 22499232 TI - Free-standing 3D polyaniline-CNT/Ni-fiber hybrid electrodes for high-performance supercapacitors. AB - Free-standing 3D macroscopic polyaniline (PANi)-carbon nanotube (CNT)-nickel fiber hybrids have been developed, and they deliver high specific capacitance (725 F g(-1) at 0.5 A g(-1)) and high energy density at high rates (~22 W h kg( 1) at 2000 W kg(-1), based on total electrode mass) with good cyclability. PMID- 22499233 TI - Ivacaftor (Kalydeco) for cystic fibrosis. PMID- 22499234 TI - Transcatheter aortic-valve replacement. PMID- 22499235 TI - Tafluprost (Zioptan) - a new topical prostaglandin for glaucoma. PMID- 22499236 TI - In brief: asparaginase Erwinia chrysanthemi (Erwinaze) for ALL. PMID- 22499237 TI - Cu(I)-catalyzed annulation for the synthesis of substituted naphthalenes using o bromobenzaldehydes and beta-ketoesters as substrates. AB - Cu(I)-catalyzed reaction of o-bromobenzaldehydes with beta-ketoesters using Cs(2)CO(3) as a base and 2-picolinic acid as an additive proceeds under mild conditions and gives access to substituted naphthalenes in a single step with yields ranging from 71 to 86%. The new annulation process relies on a domino Knoevenagel condensation/C-arylation/1,2-addition/carboxylic acid cleavage. The annulation can also be achieved with o-iodobenzaldehyde. PMID- 22499238 TI - Adsorption of heavy metals on kaolinite and montmorillonite: a review. AB - The process of adsorption is considered to be one of the best water treatment technologies around the world. Different heavy metals, due to their toxic and hazardous nature, are possibly the most widespread groundwater contaminants imposing a serious threat to human health. In this review, an attempt has been made to discuss the use of two common clay materials, namely kaolinite and montmorillonite, along with their modified forms for heavy metal removal on the basis of published reports (2008 onwards). The modifications of clays have been attempted by the process of pillaring, intercalation, acid/base activation, functionalization, etc. The adsorption of toxic metals, viz., As, Cd, Cr, Co, Cu, Fe, Pb, Mn, Ni, Zn, etc., has been studied predominantly. Montmorillonite and its modified forms have much higher metal adsorption capacity compared to that of kaolinite as well as modified-kaolinite. The modification often boosted the adsorption capacities of the clays, however, reverse trends are also reported in some cases. PMID- 22499239 TI - A near-infrared mechano responsive polymer system. AB - A new type of crosslinked polyarylamide based film with a fibrillar morphology that is photomechanically responsive has been created. Without any additive or need of pre-alignment, these films can actuate under NIR stimulation. By constructing the photoresponsive film on top of a piezoelectric poly(vinylidene difluoride) film, electrical energy can be generated under NIR excitation. This is the first polymer system that exhibits NIR response without any conventional photosensitive moieties. PMID- 22499240 TI - Structural phase transition in LiFeSi2O6 from ab initio calculations. AB - The changes in crystal structure of LiFeSi(2)O(6) induced by the phase transition between the high-temperature C2/c and low-temperature P2(1)/c phase are studied using the density functional theory. For both monoclinic phases, the phonon dispersion curves and phonon density of states are calculated. The infrared absorption coefficients are obtained and analyzed in both structural phases of LiFeSi(2)O(6). The soft mode inducing the phase transition is revealed at the Z point of the Brillouin zone of the high-symmetry C2/c phase. The pressure dependence of the soft mode is studied and the mechanism of the structural phase transition in LiFeSi(2)O(6) is discussed. PMID- 22499241 TI - Body piercings and posttraumatic stress disorder symptoms in young adults. AB - Body piercing, which is prevalent in young adults, has been suggested to be associated with features usually related to posttraumatic stress disorder (PTSD) such as high-risk behaviours and psychopathological symptoms and might be motivated by a wish to deal with prior traumatic experiences. However, to date, no research has investigated the relationship between this practice and PTSD symptoms. The present research aims to investigate the possible relationship between body piercing and PTSD symptoms in French-speaking young adults. According to our results, having two or more body piercings was associated with a twofold increased risk for scoring above the cut-off score for PTSD on the PTSD checklist. Our findings suggest that two or more body piercings might serve as an identifiable marker for PTSD symptoms and may have important implications for clinical screening. PMID- 22499242 TI - Validation of a multiparameter flow cytometry method for the determination of phosphorylated extracellular-signal-regulated kinase and DNA in circulating tumor cells. AB - A simple, selective, and sensitive multiparameter fluorescence activated cell sorting method utilizing density gradient centrifugation and magnetic antibody cell sorting was developed and validated for the determination of phosphorylated extracellular-signal-regulated kinase (pERK) and DNA in circulating tumor cells (CTCs). Cell preparation tubes (CPT) were used for peripheral blood collection and density gradient centrifugation, followed by phosphorylation of ERK with epidermal growth factor (EGF). After fixation with formaldehyde and methanol, magnetic anti epithelial cell adhesion molecule (EpCAM) micro-beads were used for the selective isolation of CTCs from the background, consisting of peripheral blood mononuclear cells and platelets. Subsequently, samples were stained with Hoechst 33342, and fluorescent antibodies against EpCAM, CD45, and pERK. Flow cytometry was used for identification and enumeration of CTCs and determination of their pERK and DNA content. The validation parameters included specificity, recovery, linearity, precision, sensitivity, and stability. The lower limit of quantification was two CTCs per 8 ml peripheral blood. Samples were stable for 4 months in storage at -80 degrees C. The applicability of the method was demonstrated by successful enumeration of CTCs, and the determination of DNA, and pERK before and after stimulation with EGF in 8 ml peripheral blood samples from patients with metastatic cancer. PMID- 22499244 TI - Enantioselective organocatalytic reductive amination of aliphatic ketones by benzothiazoline as hydrogen donor. AB - The chiral phosphoric acid-catalyzed enantioselective reductive amination of aliphatic ketones with aromatic amines was successfully achieved by the use of benzothiazoline as the hydrogen donor. Corresponding chiral aliphatic amines were obtained with excellent enantioselectivities. PMID- 22499245 TI - A case-crossover study of laceration injuries in pork processing. AB - OBJECTIVES: The authors estimated the associations between transient risk factors and laceration injuries in workers at two meatpacking plants in the Midwest. METHODS: The case-crossover design was used to collect within-subject transient work task and personal-level exposure information. RRs of laceration injuries were estimated by comparing exposures during the 'hazard' period (just before the laceration injury) with exposures in the 'control' period (the previous workweek). Stratified analyses were utilised to estimate the effects of gender, ethnicity, training and the number of adjacent coworkers on each transient risk factor. RESULTS: The authors interviewed 295 meatpacking workers with laceration injuries (mean age 36.6 years, SD 11.2, 75% men, 48% Hispanic). Recent tool sharpening (RR 5.3, 95% CI 3.8 to 7.4) and equipment malfunction (RR 5.3, 95% CI 3.9 to 7.3) were associated with the highest RR for laceration injury, followed by using an unusual work method to accomplish a task (RR 4.1, 95% CI 2.6 to 6.4) and performing an unusual task (RR 2.3, 95% CI 1.8 to 3.0). Rushing and being distracted were not significantly associated with an elevated RR of a laceration injury. In stratified analyses, there were a number of significant differences in laceration risk factors by gender, ethnicity, training, and number of workers on the line. CONCLUSIONS: Sharpening tools, equipment malfunction, using an unusual work method to accomplish a task and performing an unusual task were all associated with increased risk of lacerations. Expanded training in atypical work circumstances and evaluation of tool sharpening procedures are intervention areas in meatpacking that need examination. PMID- 22499243 TI - Transporter-targeted lipid prodrugs of cyclic cidofovir: a potential approach for the treatment of cytomegalovirus retinitis. AB - Cidofovir (CDF) and its cyclic analogue (cCDF) have shown potential in vitro and in vivo antiviral activity against cytomegalovirus (CMV) retinitis. However, hydrophilic nature of CDF may affect cell permeation across lipophilic epithelium and thus limit its effectiveness in the treatment of CMV retinitis. In the present study, we have tested a novel hypothesis, which involves chemical derivatization of cCDF into lipophilic transporter-targeted prodrug [via conjugation with different carbon chain length of lipid raft and targeting moiety (biotin) for sodium-dependent multivitamin transporter (SMVT)]. We have synthesized and characterized three derivatives of cCDF including biotin B-C2 cCDF, B-C6-cCDF, and B-C12-cCDF. Physicochemical properties such as solubility, partition coefficient (n-octanol/water and ocular tissue), bioreversion kinetics, and interaction with SMVT transporter have been determined. Among these novel conjugates, B-C12-cCDF has shown higher interaction to SMVT transporter with lowest half maximal inhibitory concentration value, higher cellular accumulation, and high tissue partitioning. Improvement in physicochemical properties, lipophilicity, and interaction with transporter was observed in the trend of increasing the lipid chain length, that is, B-C12-cCDF > B-C6-cCDF > B-C2-cCDF. These results indicate that transporter-targeted lipid analogue of cCDF exhibits improved cellular accumulation along with higher transporter affinity and hence could be a viable strategy for the treatment of CMV retinitis. PMID- 22499246 TI - Should we share ideas or measurement data? PMID- 22499247 TI - Emergency response technical work at Fukushima Dai-ichi nuclear power plant: occupational health challenges posed by the nuclear disaster. PMID- 22499249 TI - A biologically inspired Cu(I)/topaquinone-like co-catalytic system for the highly atom-economical aerobic oxidation of primary amines to imines. PMID- 22499248 TI - Alimentary 'green' proteins as electrospun scaffolds for skin regenerative engineering. AB - As a potential alternative to currently available skin substitutes and wound dressings, we explored the use of bioactive scaffolds made of plant-derived proteins. We hypothesized that 'green' materials, derived from renewable and biodegradable natural sources, may confer bioactive properties to enhance wound healing and tissue regeneration. We optimized and characterized fibrous scaffolds electrospun from soy protein isolate (SPI) with addition of 0.05% poly(ethylene oxide) (PEO) dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol, and from corn zein dissolved in glacial acetic acid. Fibrous mats electrospun from either of these plant proteins remained intact without further cross-linking, possessing a skin like pliability. Soy-derived scaffolds supported the adhesion and proliferation of cultured primary human dermal fibroblasts. Using targeted PCR arrays and qPCR validation, we found similar gene expression profiles of fibroblasts cultured for 2 and 24 h on SPI substrates and on collagen type I at both time points. On both substrates there was a pronounced time-dependent upregulation of several genes related to ECM deposition remodelling, including MMP-10, MMP-1, collagen VII, integrin-alpha2 and laminin-beta3, indicating that both plant- and animal-derived materials induce similar responses from the cells after initial adhesion, degrading substrate proteins and depositing extracellular matrix in a 'normal' remodelling process. These results suggest that 'green' proteins, such as soy and zein, are promising as a platform for organotypic skin equivalent culture, as well as implantable scaffolds for skin regeneration. Future studies will determine specific mechanisms of their interaction with skin cells and their efficacy in wound-healing applications. PMID- 22499250 TI - Why does the immune system of Atlantic cod lack MHC II? AB - MHC II, a major feature of the adaptive immune system, is lacking in Atlantic cod, and there are different scenarios (metabolic cost hypothesis or functional shift hypothesis) that might explain this loss. The lack of MHC II coincides with an increased number of genes for MHC I and Toll-like receptors (TLRs). PMID- 22499251 TI - Electrophilic substitution of the nido-dicarbaborate anion 7,8-nido-C2B9H12- with sulfenyl chlorides. AB - Sulfenyl chlorides RSCl (R = p-C(6)H(4)OMe, Ph, p-C(6)H(4)NO(2), CN or 2 C(5)H(4)N) react with 7,8-nido-C(2)B(9)H(12)(-) with asymmetric substitution on the pentagonal C(2)B(3) face to give 9-RS-7,8-nido-C(2)B(9)H(11)(-) (R = p C(6)H(4)OMe (3), Ph (4), p-C(6)H(4)NO(2) (5), CN (6)) and the zwitterion 9-(S-2 C(5)H(4)NH)-7,8-nido-C(2)B(9)H(11) (7), respectively, in high yield, while tBuSCl did not react and S(2)Cl(2) led to decomposition. Further reaction of 5-7 with iodine gave the corresponding iodo derivatives NMe(4) [9-I-11-RS-7,8-nido C(2)B(9)H(10)] (R = p-C(6)H(4)NO(2) (8), CN (9)) and the zwitterion 9-I-11-(S-2 C(5)H(4)NH)-7,8-nido-C(2)B(9)H(11) (10), respectively. Compounds 3-10 were fully characterised by (1)H, (11)B, (11)B{(1)H}, (13)C{(1)H} spectroscopy, IR spectroscopy, mass spectrometry and elemental analysis, 3-7 also by (11)B (11)B{(1)H} COSY NMR spectroscopy and 8-10 by X-ray structure determination. PMID- 22499252 TI - Amphiphilic dynamic NDI and PDI probes: imaging microdomains in giant unilamellar vesicles. AB - Dynamic amphiphiles provide access to transmembrane ion transport, differential sensing and cellular uptake. In this report, we introduce dynamic amphiphiles with fluorescent tails. Core-substituted naphthalenediimides (cNDIs) and perylenediimides (cPDIs) are tested. Whereas the latter suffer from poor partitioning, dynamic cNDI amphiphiles are found to be purifiable by RP-HPLC, to partition selectively into liquid-disordered (Ld) microdomains of mixed lipid bilayers and to activate DNA as transporters. Importantly, fluorescence properties, partitioning and activity can be modulated by changes in the structure of mixed amphiphiles. These results confirm the potential of dynamic fluorescent amphiphiles to selectively label extra- and intracellular membrane domains and visualize biological function. PMID- 22499253 TI - Ability of tetraploid rat blastocysts to support fetal development after complementation with embryonic stem cells. AB - This study was undertaken to generate rat offspring via tetraploid blastocyst complementation with embryonic stem (ES) cells. Tetraploid blastocysts were prepared by electrofusion of blastomeres from two-cell stage embryos, and subsequent in vivo culture for 4 days. Microinjection into the tetraploid blastocoel of an inner cell mass isolated by immunosurgery resulted in the generation of rat offspring, suggesting the successful contribution of tetraploid blastocysts to their placenta. Tetraploid blastocyst complementation was attempted with a total of 4 ES cell lines (2 lines of female karyotype and 2 lines of male karyotype). In the rESWIv-3i-5 (XX) cell line, normal-sized fetuses with heartbeats were harvested on E11.5 (12.1%), E12.5 (9.5%), and E13.5 (9.1%), but no viable fetuses were detected on E14.5. Similarly, use of the rESWIv-3i-1 (XX) cell line resulted in no viable fetus production on E14.5. Using the rESBLK2i-1 (XY) cell line, viable fetuses were harvested not only on E11.5-E13.5 (2.6-5.5%), but also on E14.5 (3.0%). The transfer of a total of 487 tetraploid blastocysts complemented with rESBLK2i-1 cells resulted in 256 implantation sites (52.6%) on E21.5, but no viable offspring was detected. Use of the rESBLK2i 1/huKO (XY) cell line also resulted in no viable offspring production on E21.5. Analyses of the methylation pattern in differentially methylated regions and transcript level of genes that are imprinted in mice (H19, Meg3, Igf2r, Peg5, and Peg10) in the E14.5 conceptuses indicated a marked difference between the ES cell derived and control normal fetuses, but not between the tetraploid and control diploid placenta. PMID- 22499254 TI - Visible-NIR photodetectors based on CdTe nanoribbons. AB - Zinc blende-structured CdTe nanoribbons (NRs) were synthesized for the first time via a two-step process. The electronic, transport, and photoconductive properties of the CdTe NRs were studied systematically. It was revealed that the CdTe NRs showed p-type conductivity, and presented significant photoresponses to visible NIR (400-800 nm) irradiation with high responsivity and gain. The contribution of the factors such as surface states of NRs, channel length, light intensity, and working bias voltage to the photoresponse characteristics of CdTe NR photodetectors were discussed. Moreover, single CdTe NR-based visible-NIR photodetectors were also demonstrated to have high stability and reliability. PMID- 22499255 TI - Reaction dynamics of CN radicals with tetrahydrofuran in liquid solutions. AB - Transient, broadband infra-red absorption spectroscopy with picosecond time resolution has been used to study the dynamics of reactions of CN radicals with tetrahydrofuran (THF) and d(8)-THF in liquid solutions ranging from neat THF to 0.5 M THF in chlorinated solvents (CDCl(3) and CD(2)Cl(2)). HCN and DCN products were monitored via their v(1) (C=N stretching) and v(3) (C-H(D) stretching) vibrational absorption bands. Transient spectral features indicate formation of vibrationally excited HCN and DCN, and the onsets of absorption via the fundamental bands of HCN and DCN show short (5-15 ps) delays consistent with vibrational relaxation within the nascent reaction products. This interpretation is confirmed by non-equilibrium molecular dynamics simulations employing a newly derived analytic potential energy surface for the reaction in explicit THF solvent. The rate coefficient for reactive formation of HCN (as determined from measurements on both the 1(1)(0) and 3(1)(0) fundamental bands) decreases with increasing dilution of the THF in CDCl(3) or CD(2)Cl(2), showing pseudo-first order kinetic behaviour for THF concentrations in the range 0.5-4.5 M, and a bimolecular rate coefficient of (1.57 +/- 0.12) * 10(10) M(-1) s(-1) is derived. Simultaneous analysis of time-dependent HCN 1(1)(0) and 3(1)(0) band intensities following reaction of CN with THF (3.0 M) in CD(2)Cl(2) suggests that C-H stretching mode excitation is favoured, and this deduction is supported by the computer simulations. The results extend our recent demonstration of nascent vibrational excitation of the products of bimolecular reactions in liquid solution to a different, and more strongly interacting class of organic solvents. They serve to reinforce the finding that dynamics (and thus the topology of the reactive potential energy surface) play an important role in determining the nascent product state distributions in condensed phase reactions. PMID- 22499256 TI - Reconstructing the orientation distribution of actin filaments in the lamellipodium of migrating keratocytes from electron microscopy tomography data. AB - Migration of motile cells on flat substrates is usually driven by the polymerization of a flat actin filament network. Theoretical models have made different predictions regarding the distribution of the filament orientation in the lamellipodium with respect to the direction of motion. Here we show how one can automatically reconstruct the orientation distribution of actin filaments in the lamellipodium of migrating keratocytes from electron microscopy tomography data. We use two different image analysis methods, an algorithm which explicitly extracts an abstract network representation and an analysis of the gray scale information based on the structure tensor. We show that the two approaches give similar results, both for simulated data and for electron microscopy tomography data from migrating keratocytes. For the lamellipodium at the leading edge of fast moving cells, we find an orientation distribution that is peaked at +35/-35 degrees. For the lamellipodium at the leading edge of slow moving cells as well as for the lamellipodium at the flanks of fast moving cells, one broad peak around 0 degree dominates the distribution. PMID- 22499257 TI - Reproductive toxicity assessment of sunitinib, a multitargeted receptor tyrosine kinase inhibitor, in male and female rats. AB - BACKGROUND: Sunitinib (SUTENT, Pfizer Inc., New York, NY) is a multitargeted inhibitor of selected receptor tyrosine kinases, which produces an antiproliferative and antiangiogenic effect by blocking pathways fundamental to tumor growth and survival. We investigated the effects of sunitinib on male and female fertility and early embryonic development in the rat. METHODS: In the female fertility and early embryonic development phase, untreated males were paired with treated females dosed at 0 (control), 0.5, 1.5, and 5 mg/kg/day from 14 days premating, through mating, to gestation day 7. In the male fertility phase, the same males were then treated 58 days at doses of 0 (control), 1, 3, and 10 mg/kg/day, mated with untreated females, with continued daily dosing for a total of 74 days. RESULTS: There was no systemic toxicity- or treatment-related effects on fertility in female rats. Females exposed at 5 mg/kg/day had an increase in the number of early resorptions with associated decrease in viable embryos. In the males, body weight and food consumption were decreased at 10 mg/kg/day compared to the controls. Male reproductive capacity, as assessed by copulation, fertility, and conception indices, was not impacted at any dose level. Sperm morphology, concentration, and motility were also unaffected by treatment. CONCLUSIONS: There were no effects on male reproduction. An increase in corpora lutea and an increase in early resorptions with associated reduction in viable embryos was noted in the females dosed 5 mg/kg/day. Sunitinib at doses up to 1.5 and 10 mg/kg/day had no effects on female and male reproduction, respectively. PMID- 22499258 TI - A multicomponent formal [1+2+1+2]-cycloaddition for the synthesis of dihydropyridines. AB - Reaction of methoxyvinylmethylketone with different amines and aldehydes under Lewis-acid catalysed conditions results in a novel, formal, step-wise [1+2+1+2] cycloaddition to give dihydropyridine products. PMID- 22499259 TI - Geochemistry of intertidal sediment pore waters from the industrialized Santos Cubatao Estuarine System, SE Brazil. AB - The geochemical composition of sediment pore water was investigated in comparison with the composition of sediment particles and surface water in an estuary within one of the most industrialized areas in Latin America (Santos-Cubatao estuarine system, SE Brazil). Pore and surface waters presented anomalously high levels of F(-), NH4(+), Fe, Mn and P due to two industrial point sources. In the summer, when SO(4)(2-)/Cl(-) ratios suggested an enhanced sulfate reduction, the higher dissolved levels observed in pore waters for some metals (e.g., Cu and Ni) were attributed to reductive dissolution of oxidized phases. Results evidenced that the risks of surface water concentration increase due to diffusion or advection from pore water are probably dependent on coupled influences of tidal pumping and groundwater inputs. PMID- 22499260 TI - Reproductive success of South American terns (Sterna hirundinacea) from Cardos Islands, Florianopolis, SC, Brazil. AB - Sterna hirundinacea (Lesson, 1831) is a migratory seabird that breeds in the Pacific Coast (from Peru to Chile) and along the Atlantic coast of South America from Espirito Santo (Brazil) to Terra del Fuego (Argentina). This paper describes the reproductive success of South American Terns on Cardos Island, Florianopolis, Brazil in the breeding seasons of 2003, 2005 and 2006. The colony was formed in mid-May in 2003 and early April in other years, with the total number of nests ranging from 1,852 in 2006 to 2,486 in 2005. Hatching success was estimated at 76.39% in 2006, 62.73% in 2003 and 41.1% in 2005, the lowest value that could be attributed to predation by hawks Caracara plancus, lizards Tupinambis merianae and black vulture Coragyps atratus. The chicks hatched in July in 2003, and in June 2005 and 2006, and fledging success was 50.94%, 35.96 and 53.47% respectively. Cardos Island has been constantly used as a breeding site by South American Terns, and therefore represents an important area for conservation of this species. This success could be attributed to low pressure of Kelp gulls (Larus dominicanus), the main predator of seabirds along the Brazilian coast. PMID- 22499261 TI - Microfossils in micrites from Serra da Bodoquena (MS), Brazil: taxonomy and paleoenvironmental implications. AB - Microfossils present in Quaternary micrites from Serra da Bodoquena, Mato Grosso do Sul State, Brazil, are here described for the first time. The studied taxa are: a) ostracods: Candona sp., Candonopsis sp., Cyclocypris sp., Cypria sp., Cypridopsis sp., Notodromas sp., Ilyocypris sp., Cyprideis sp., Wolburgiopsis cf. chinamuertensis (Musacchio 1970), Darwinula sp. and 5 morphotypes; b) microgastropod Acrobis sp., and c) Characeae remains and gyrogonites Chara sp.. The presence of these microfossils suggests clear-water shallow lacustrine paleoenvironments and the presence of aquatic vegetation. Similarities between microfossils and the living taxa suggest possible Holocene ages for these deposits, which is in accordance with previous C(14) dates. PMID- 22499262 TI - High mobility, air stable, organic single crystal transistors of an n-type diperylene bisimide. PMID- 22499263 TI - Determination of solid-state acidity of chitin-metal silicates and their effect on the degradation of cephalosporin antibiotics. AB - It was of interest to determine the solid-state acidity of chitin-metal silicate coprocessed excipients and to correlate this acidity to the chemical stability of cefotaxime sodium in the presence of the aforementioned excipients. The solid state acidities of chitin aluminum silicate, chitin magnesium silicate, and chitin calcium silicate were determined by reflectance spectroscopy using structurally different dye molecules. The chemical stability of cefotaxime sodium was assessed at 50 degrees C in a 4% (w/v) slurry system in the pH range 6.6 10.5 and in the solid-state in the Hammett acidity range 6.1-7.8. The solid-state acidity was found to be reproducible because one or more structurally different dye molecules gave reliable solid-state acidity values. A significant discrepancy in pH stability profile of cefotaxime sodium between the solid-state and the slurry system was observed. Furthermore, chitin aluminum silicate showed minimum drug stability in the solid-state, close to where the maximum drug stability in the slurry was observed. This unexpected effect might be ascribed to the catalytic properties of chitin aluminum silicate. The slurry method was not able to predict efficiently the solid-state surface acidity and stability of cefotaxime sodium. Moreover, the solid-state chemical stability might be influenced by factors other than the solid-state acidity. PMID- 22499264 TI - Development of multilayer constructs for tissue engineering. AB - The rapidly developing field of tissue engineering produces living substitutes that restore, maintain or improve the function of tissues or organs. In contrast to standard therapies, the engineered products become integrated within the patient, affording a potentially permanent and specific cure of the disease, injury or impairment. Despite the great progress in the field, development of clinically relevantly sized tissues with complex architecture remains a great challenge. This is mostly due to limitations of nutrient and oxygen delivery to the cells and limited availability of scaffolds that can mimic the complex tissue architecture. This study presents the development of a multilayer tissue construct by rolling pre-seeded electrospun sheets [(prepared from poly (l-lactic acid) (PLLA) seeded with C2C12 pre-myoblast cells)] around a porous multibore hollow fibre (HF) membrane and its testing using a bioreactor. Important elements of this study are: 1) the medium permeating through the porous walls of multibore HF acts as an additional source of nutrients and oxygen to the cells, which exerts low shear stress (controllable by trans membrane pressure); 2) application of dynamic perfusion through the HF lumen and around the 3D construct to achieve high cell proliferation and homogenous cell distribution across the layers, and 3) cell migration occurs within the multilayer construct (shown using pre-labeled C2C12 cells), illustrating the potential of using this concept for developing thick and more complex tissues. PMID- 22499265 TI - Nonnatural amino acid synthesis by using carbon-hydrogen bond functionalization methodology. PMID- 22499266 TI - C- and D-class MADS-box genes from Phalaenopsis equestris (Orchidaceae) display functions in gynostemium and ovule development. AB - Gynostemium and ovule development in orchid are unique developmental processes in the plant kingdom. Characterization of C- and D-class MADS-box genes could help reveal the molecular mechanisms underlying gynostemium and ovule development in orchids. In this study, we isolated and characterized a C- and a D-class gene, PeMADS1 and PeMADS7, respectively, from Phalaenopsis equestris. These two genes showed parallel spatial and temporal expression profiles, which suggests their cooperation in gynostemium and ovule development. Furthermore, only PeMADS1 was ectopically expressed in the petals of the gylp (gynostemium-like petal) mutant, whose petals were transformed into gynostemium-like structures. Protein-protein interaction analyses revealed that neither PeMADS1 and PeMADS7 could form a homodimer or a heterodimer. An E-class protein was needed to bridge the interaction between these two proteins. A complementation test revealed that PeMADS1 could rescue the phenotype of the AG mutant. Overexpression of PeMADS7 in Arabidopsis caused typical phenotypes of the D-class gene family. Together, these results indicated that both C-class PeMADS1 and D-class PeMADS7 play important roles in orchid gynostemium and ovule development. PMID- 22499267 TI - Painful shoulder--moving deltoid syndrome. PMID- 22499268 TI - The investigation of irrigation with wastewater on trees (Populus deltoids L.). AB - The urban green space and environment should be considered to be among the most fundamental elements of the sustainability of natural and human life in the new citizenship. To investigate the effect of irrigation on northern Mashad municipal effluent treatment plant effluent on the chemical properties of soil and accumulation of nutrient in poplar trees, a study was carried out using a random systematic pattern. To investigate soil as well as accumulation of nutrients and cadmium in leaves, samples of soil (0-20, 20-40 and 40-60 cm) and leaves were taken from each plot in four replications. The measurements carried out in the laboratory showed that the cadmium of the samples of leaf and soil in the compound irrigated with waste water was significantly more than the compound irrigated with well water. The results of the present research suggest that urban waste water can be used as a source of irrigation whereas muck can be employed in forestation and irrigation with precise and particular supervision and control. PMID- 22499269 TI - Cement dust pollution induces toxicity or deficiency of some essential elements in wild plants growing around a cement factory. AB - In the present study, it was aimed to determine the effects of cement dust pollution on contents of some significant essential elements (P, S, K, Ca, Fe and Cl) in wild plants (Medigago varia, Anchusa leptophylla, Euphorbia orientalis, Lactuca serriola, Artemisia spicigera, Crambe orientalis, Convolvulus sepium and Senecio vernalis) using wavelength-dispersive spectrometer X-ray fluorescence technique. Plant samples were collected from different locations around a cement factory which is located at Askale about 50 km from Erzurum (Turkey). The element contents in the plant specimens that existed in both 0-100 m (dense dusted) and 2000 m (undusted) areas were compared. P, S, K and Cl contents were found to be high in the plants growing in areas 0-100 m from the cement factory, compared to same plants at 2000 m far from the factory. However, Ca and Fe contents were determined to be low in plants growing in 0-100 m area from the factory. Results of the study can contribute to understand how mineral deficiency and toxicity lead to detrimental effects on plant growth and development in the fields contaminated by cement dust. PMID- 22499270 TI - The synergistic effect of benzo[a]pyrene and lead on learning and memory of mice. AB - In the present study, the single and combined neurotoxic effects of benzo[a]pyrene ([BaP] 0.0, 0.5, and 5.0 mg/kg body weight; intragastric administration) and lead acetate (0.0, 5.4, and 54.0 mg/L; by drinking water) were examined on KunMing mice. In the Morris water maze, results showed that BaP and lead induced synergistic effects on the escape latency and the time spent in the target quadrant but also showed an additive effect on the number of times animal crossing the original platform. Also, BaP and lead induced a synergistic effect on DNA damage in the single-cell gel electrophoresis. However, BaP plus lead showed additive effects on the levels of malondialdehyde, superoxide dismutase, and glutathione. These results suggested that the combination of BaP and lead can lead to a synergistic effect on spatial learning and memory impairments, and the mechanisms of the synergistic effects on behavioral deficits may be due to the oxidative stress injury. PMID- 22499271 TI - Molecular determination of genotoxic effects of cobalt and nickel on maize (Zea mays L.) by RAPD and protein analyses. AB - Assessment of DNA damages stemming from toxic chemicals is an important issue in terms of genotoxicology. In this study, maize (Zea mays L.) seedlings were used for screening the genotoxic effects of cobalt (Co) and nickel (Ni) treatments at various concentrations (5 mM, 10 mM, 20 mM and 40 mM). For this purpose, randomly amplified polymorphic DNA (RAPD) technique was applied to genomic DNA extracted from metal-exposed and unexposed plant materials. Besides, changes in total protein contents were screened by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. For RAPD analysis, 16 RAPD primers were found to produce unique polymorphic band profiles on different concentrations of Co-/Ni-treated maize seedlings. Increased polymorphism resulting from the appearance of new bands or disappearance of normal bands was observed with increasing concentration of Co and Ni treatments. Genomic template stability, a qualitative measurement of changes in RAPD patterns of genomic DNA, decreased with increasing metal concentration. In SDS-PAGE analysis, it was observed that the total soluble protein content decreased by Co treatment, while it increased by Ni treatment. The results obtained from this study revealed that RAPD profiles and total soluble protein levels can be applied to detect genotoxicity, and these analyses can offer useful biomarker assays for the evaluation of genotoxic effects on Co- and Ni-polluted plants. PMID- 22499273 TI - Complexes of Cu(I) supported by a tris(ketimine) tripod. AB - Arylation of tris(2-benzylnitrile)amine with PhLi, followed by aqueous work-up, results in the formation of a tripodal tris(ketimine) scaffold, N(ArCNHPh)(3). N(ArCNHPh)(3) readily coordinates a number of Cu(I) salts, generating complexes that exhibit trigonal pyramidal geometries in the solid-state. PMID- 22499272 TI - Antihyperglycemic and antihyperlipidemic activities of ethanolic extract of Zygophyllum album in streptozotocin-induced diabetic mice. AB - Zygophyllum album has been mentioned in Tunisian system of folk medicine to be of value in the treatment of diabetes mellitus. The present study was designed to investigate the possible antihyperglycemic effects of ethanolic extracts of the whole plant of Z. album on blood glucose, plasma insulin, serum lipids and hepatic glycogen and metabolism enzymes of carbohydrate in streptozotocin (STZ) induced diabetic mice. Administration of the ethanolic extract from plant (100 and 300 mg/kg body weight) for 14 days resulted in significant reduction in plasma glucose, cholesterol, triglycerides, low-density lipoprotein, very-low density liprotein, hepatic glucokinase and glycogen in STZ diabetic mice. In addition to that, significant increase in plasma high-density lipoprotein, hepatic phosphofructokinase and glucose-6 phosphate dehydrogenase was observed in STZ diabetic mice. After administration of the ethanolic extract, the increased level of plasma insulin is not significant in diabetic mice. In conclusion, the present results showed that the ethanolic extract of Z. album possesses significant antihyperglycemic and antihyperlipidemic effects in experimental model of diabetes mellitus. PMID- 22499276 TI - "MR Physics for Clinicians" series: enhancement for the JMRI CME program. PMID- 22499274 TI - Synthetic UDP-galactofuranose analogs reveal critical enzyme-substrate interactions in GlfT2-catalyzed mycobacterial galactan assembly. AB - Mycobacterial cell wall galactan, composed of alternating beta-(1->5) and beta-(1 >6) galactofuranosyl residues, is assembled by the action of two bifunctional galactofuranosyltransferases, GlfT1 and GlfT2, which use UDP-galactofuranose (UDP Galf) as the donor substrate. Kinetic analysis of synthetic UDP-Galf analogs identified critical interactions involved in donor substrate recognition by GlfT2, a processive polymerizing glycosyltransferase. Testing of methylated UDP Galf analogs showed the donor substrate-binding pocket is sterically crowded. Evaluation of deoxy UDP-Galf analogs revealed that the C-6 hydroxyl group is not essential for substrate activity, and that interactions with the UDP-Galf C-3 hydroxyl group orient the substrate for turnover but appears to play no role in substrate recognition, making the 3-deoxy-analog a moderate competitive inhibitor of the enzyme. Moreover, the addition of a Galf residue deoxygenated at C-5 or C 6, or an l-arabinofuranose residue, to the growing galactan chain resulted in "dead end" reaction products, which no longer act as an acceptor for the enzyme. This finding shows dual recognition of both the terminal C-5 and C-6 hydroxyl groups of the acceptor substrate are required for GlfT2 activity, which is consistent with a recent model developed based upon a crystal structure of the enzyme. These observations provide insight into specific protein-carbohydrate interactions in the GlfT2 active site and may facilitate the design of future inhibitors. PMID- 22499277 TI - Imaging of prion diseases. AB - Prion diseases are caused by self-replicating proteins that induce lethal neurodegenerative disorders. In the last decade, the understanding of the different clinical, pathological, and neuroimaging phenotypes of this group of disorders has evolved paralleling the advances in prion molecular biology. From an imaging standpoint, the implementation of diffusion-weighted imaging in routine practice has markedly facilitated the detection of prion diseases, especially Creutzfeldt-Jakob. Less frequent prion-related disorders, including genetic diseases, may also benefit from progresses in the field of quantitative diffusion-weighted imaging, MR spectroscopy or molecular imaging. Herein, we present a review of the neuroimaging features of the prion disorders known to affect humans emphasizing the important contribution of MRI in the diagnosis of this group of disorders. PMID- 22499278 TI - Magnetic resonance imaging of the postoperative hip. AB - Magnetic resonance imaging (MRI) is ideally suited to imaging the patient with painful hip arthroplasty due to its superior soft tissue contrast, multiplanar capabilities, and lack of ionizing radiation. MRI is the most accurate imaging modality in the assessment of periprosthetic osteolysis and wear-induced synovitis, and can also assess regional tendons and neurovascular structures. This article discusses the technical aspects of MRI around metallic implants as well as the appearance of potential complications following hip arthroplasty, including osteolysis, wear-induced synovitis, infection, hemarthrosis, fracture, loosening, component displacement, heterotopic ossification, tendinopathy, and neurovascular impingement. The specific complication of metal hypersensitivity following metal-on-metal prostheses is reviewed. PMID- 22499281 TI - Theoretical investigations of sp-sp2 hybridized zero-dimensional fullerenynes. AB - Widely recognized as the quintessential material, sp(2) hybridized carbon material with low dimensions, such as zero-dimensional fullerene, one-dimensional carbon nanotube and two-dimensional graphene, has already compiled an impressive list of superlatives. Quite recently, one-dimensional sp-sp(2) hybridized carbon tubular arrays with a wall thickness of about 40 nm and two-dimensional carbon films with the average thickness of 970 nm have been synthesized successfully. Thus, we expect that the existence of a sp-sp(2) hybridized zero-dimensional carbon allotrope is possible. A novel and stable zero-dimensional carbon allotrope (fullerenyne) with sp-sp(2) hybridization is introduced by means of density functional theory calculation and molecular dynamics confirmation. Unique porous characteristic C(96) fullernenyne with an O(h) symmetry group exhibits exceptionally high stability. We hope that the present study will lead to a further development of a broad new class of carbon materials. PMID- 22499279 TI - Physics of MRI: a primer. AB - This article is based on an introductory lecture given for the past many years during the "MR Physics and Techniques for Clinicians" course at the Annual Meeting of the ISMRM. This introduction is not intended to be a comprehensive overview of the field, as the subject of magnetic resonance imaging (MRI) physics is large and complex. Rather, it is intended to lay a conceptual foundation by which magnetic resonance image formation can be understood from an intuitive perspective. The presentation is nonmathematical, relying on simple models that take the reader progressively from the basic spin physics of nuclei, through descriptions of how the magnetic resonance signal is generated and detected in an MRI scanner, the foundations of nuclear magnetic resonance (NMR) relaxation, and a discussion of the Fourier transform and its relation to MR image formation. The article continues with a discussion of how magnetic field gradients are used to facilitate spatial encoding and concludes with a development of basic pulse sequences and the factors defining image contrast. PMID- 22499282 TI - Observation of ultrafast NH3 (A) state relaxation dynamics using a combination of time-resolved photoelectron spectroscopy and photoproduct detection. AB - The ultrafast excited state relaxation of ammonia is investigated by resonantly exciting specific vibrational modes of the electronically excited NH(3) (A) state using three complementary femtosecond (fs) pump-probe techniques: time-resolved photoelectron, ion-yield and photofragment translational spectroscopy. Ammonia can be seen as a prototypical system for studying non-adiabatic dynamics and therefore offers a benchmark species for demonstrating the advantages of combining the aforementioned techniques to probe excited state dynamics, whilst simultaneously illuminating new aspects of ammonia's photochemistry. Time resolved photoelectron spectroscopy (TRPES) provides direct spectroscopic evidence of sigma* mediated relaxation of the NH(3) (A) state which manifests itself as coupling of the umbrella (nu(2)) and symmetric N-H stretch (nu(1)) modes in the photoelectron spectra. Time-resolved ion yield (TRIY) and time resolved photofragment translation spectroscopy (TRPTS) grant a measure of the dissociation dynamics through analysis of the H and NH(2) photodissociation co fragments. Initial vibrational level dependent TRIY measurements reveal photoproduct formation times of between 190 and 230 fs. Measurement of H-atom photoproduct kinetic energies enables investigation into the competition between adiabatic and non-adiabatic dissociation channels at the NH(3) (A)/NH(3) (X) conical intersection and has shown that upon non-adiabatic dissociation into NH(2) (X) + H, the NH(2) (X[combining tilde]) fragment is predominantly generated with significant fractions of internal vibrational energy. PMID- 22499283 TI - A novel multiparameter flow cytometric assay for inosine triphosphatase expression analysis in leukocytes. AB - The aim of this study was to assess inosine triphosphate (ITPase) expression in the different leukocyte populations present in peripheral blood samples of a nonimmune compromised control group. For this purpose, a multiparameter flow cytometric assay was developed and performed to study ITPase expression in peripheral leukocyte subpopulations of healthy volunteers (n = 20). Qualitative ITPase expression was assessed by determining the percentage of ITPase-positive cells. Quantitative data were obtained by measuring the median fluorescent intensity (MFI). Subcellular localization of ITPase was analyzed using immunocytochemistry. Immunocytochemistry showed that ITPase is present in all leukocytes and localized intracellular. Based on this finding, a multiparameter flow cytometric assay was developed using a Fix & Perm strategy. Qualitative and quantitative ITPase expression remained stable (variation, <10%) for at least 48 h after blood sampling. MFI values showed that activated monocytes contained significantly more ITPase when compared to the total monocyte fraction (P < 0.0001), which subsequently had a higher amount of expression than granulocytes (P < 0.0001). In addition, the phagocyte subpopulations ([activated] monocytes and granulocytes) contained significantly higher levels of ITPase when compared to lymphocytes (P < 0.0001). Within the lymphocyte fraction, it appeared that T helper cells contained significantly higher ITPase levels when compared to cytotoxic T cells, B lymphocytes, and natural killer cells (P < 0.0001). Our study is the first which describes a flow cytometry assay to analyze ITPase expression in leukocytes qualitatively as well as quantitatively and visualizes the intracellular localization of ITPase in leukocytes. (c) 2012 International Society for Advancement of Cytometry. PMID- 22499284 TI - Comparing intermediate range order for alkyl- vs. ether-substituted cations in ionic liquids. AB - X-ray scattering data from four pairs of ionic liquids (ILs) are compared. The alkyl-substituted cations show a first sharp diffraction peak between 3 and 4 nm( 1) that is not observed for ILs having cations with ether- or hydroxy substitutions. These observations indicate a significant difference in the intermediate range order for these liquids. PMID- 22499285 TI - Development of a biodegradable bone cement for craniofacial applications. AB - This study investigated the formulation of a two-component biodegradable bone cement comprising the unsaturated linear polyester macromer poly(propylene fumarate) (PPF) and crosslinked PPF microparticles for use in craniofacial bone repair applications. A full factorial design was employed to evaluate the effects of formulation parameters such as particle weight percentage, particle size, and accelerator concentration on the setting and mechanical properties of crosslinked composites. It was found that the addition of crosslinked microparticles to PPF macromer significantly reduced the temperature rise upon crosslinking from 100.3 degrees C +/- 21.6 degrees C to 102.7 degrees C +/- 49.3 degrees C for formulations without microparticles to 28.0 degrees C +/- 2.0 degrees C to 65.3 degrees C +/- 17.5 degrees C for formulations with microparticles. The main effects of increasing the particle weight percentage from 25 to 50% were to significantly increase the compressive modulus by 37.7 +/- 16.3 MPa, increase the compressive strength by 2.2 +/- 0.5 MPa, decrease the maximum temperature by 9.5 degrees C +/- 3.7 degrees C, and increase the setting time by 0.7 +/- 0.3 min. Additionally, the main effects of increasing the particle size range from 0-150 MUm to 150-300 MUm were to significantly increase the compressive modulus by 31.2 +/- 16.3 MPa and the compressive strength by 1.3 +/- 0.5 MPa. However, the particle size range did not have a significant effect on the maximum temperature and setting time. Overall, the composites tested in this study were found to have properties suitable for further consideration in craniofacial bone repair applications. PMID- 22499287 TI - Random composites of nickel networks supported by porous alumina toward double negative materials. AB - Random composites with nickel networks hosted randomly in porous alumina are proposed to realize double negative materials. The random composite for DNMs (RC DNMs) can be prepared by typical processing of material, which makes it possible to explore new DNMs and potential applications, and to feasibly tune their electromagnetic parameters by controlling their composition and microstructure. Hopefully, various new RC-DNMs with improved performance will be proposed in the future. PMID- 22499286 TI - 6''-Thioether tobramycin analogues: towards selective targeting of bacterial membranes. PMID- 22499288 TI - Losartan versus atenolol-based antihypertensive treatment reduces cardiovascular events especially well in elderly patients: the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. AB - BACKGROUND: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study has previously demonstrated a beneficial effect of losartan compared to atenolol-based antihypertensive treatment in patients with essential hypertension and left-ventricular hypertrophy (LVH). However, patient age often influences the choice of antihypertensive drugs. Therefore, we investigated the influence of age on the effects of losartan versus atenolol-based antihypertensive treatment. METHODS: A total of 9193 hypertensive patients with LVH aged 45-83 years were followed for a mean of 4.8 years. Blood pressure, high density lipoprotein cholesterol (HDL-C), Sokolow-Lyon voltage, Cornell voltage duration product and urine albumin-creatinine ratio (UACR) were measured yearly throughout the study. Patients were divided into two age groups according to the median age of 67 years and the effects of losartan versus atenolol-based antihypertensive treatment on the primary composite endpoint (CEP) consisting of cardiovascular death, nonfatal stroke or nonfatal myocardial infarction were investigated. RESULTS: The beneficial effect of losartan versus atenolol-based treatment was greater in the group of patients older than 67 years [hazard ratio 0.79 (0.69-0.91), P = 0.001] compared to the group of patients younger than 67 years [hazard ratio 1.03 (0.82-1.28), P = 0809], P = 0.045 for interaction. The beneficial effects of losartan versus atenolol-based antihypertensive treatment on pulse pressure, HDL-C, UACR, and Cornell and Sokolow-Lyon voltage were not more pronounced in patients older than 67 years compared to patients younger than 67 years. All five risk factors considered as time-varying covariates predicted CEP independently (P < 0.01) with the exception of pulse pressure (P = 0.37) and the interaction between age and treatment on outcome remained significant (P = 0.042). CONCLUSIONS: We showed a greater beneficial effect of losartan versus atenolol-based antihypertensive treatment in the group of patients older than 67 years compared to the group of patients younger than 67 years. This difference was not explained by a more pronounced effect of losartan-based treatment on any of the cardiovascular risk factors demonstrated to have independent prognostic importance. PMID- 22499289 TI - Home versus ambulatory and office blood pressure in predicting target organ damage in hypertension: a systematic review and meta-analysis. AB - OBJECTIVE: Studies have shown that ambulatory blood pressure (BP) is more closely related to preclinical target organ damage than office measurements. A review and meta-analysis of studies investigating the association of home BP measurements with target organ damage was performed. METHODS: A PubMed and Cochrane Library search (1950-2011) revealed 23 studies reporting comparative data of home BP versus ambulatory and/or office measurements in terms of their association with several indices of target organ damage. Correlation coefficients were pooled by random-effects model meta-analysis. RESULTS: Fourteen studies (n = 2485) assessing echocardiographic left ventricular mass index (LVMI) showed similar correlations with home (coefficients r = 0.46/0.28, systolic/diastolic) as with ambulatory BP (0.37/0.26, P = NS for difference versus home BP), and superior to office measurements (r = 0.23/0.19, P < 0.001/0.009 for difference versus home BP). Four methodologically heterogeneous studies assessing the glomerular filtration rate (n = 609) could not be pooled or lead to a concrete result. Four studies assessing carotid intima-media thickness (n = 1222), three assessing pulse wave velocity (n = 720) and two assessing urinary protein excretion (n = 156) showed no difference in pooled correlation coefficients with home versus office BP measurements. With all the measurement methods SBP was more closely associated with target organ damage than DBP. CONCLUSION: These data suggest that home BP is as good as ambulatory monitoring and superior to office measurements in regard to their association with preclinical organ damage assessed by echocardiographic LVMI. More research is required to evaluate the relationship of home BP with other indices of target organ damage. PMID- 22499290 TI - Persistence and adherence to antihypertensive treatment in relation to initial prescription: diuretics versus other classes of antihypertensive drugs. AB - BACKGROUND: The use of thiazide diuretics in the treatment of hypertension is widely considered as a first-line treatment, given the efficacy and low cost of this class of drugs. This indication is not unanimous, because thiazides can cause metabolic alterations, and other side effects that reduce compliance and persistence on treatment. OBJECTIVES: In a multicentre, open-label randomized study we compared adherence and persistence to therapy of chlortalidone versus other treatments, as a first-line antihypertensive therapy. METHODS: Ninety-two general practitioners (GPs) recruited 2409 hypertensive patients with indication to antihypertensive therapy, who were randomized in two arms to start treatment with chlortalidone (12.5-25 mg daily) or any other single medications (excluding thiazides). The patients have been followed for at least 2 years. RESULT: Patients receiving diuretic therapy as first-line antihypertensive treatment, modified antihypertensive treatment regimen more often than the others (79.1 versus 43.9%; chi (2)< 0.0001). Patients starting with diuretics received greater number of drugs, compared to patients starting with different antihypertensive therapy (1.55 versus 1.4 antihypertensive drugs; P < 0.0001), but achieved the same blood pressure (BP) control during the follow-up. No differences were observed in persistence and adherence to treatment between the two groups. CONCLUSION: Our results demonstrate that the recommendation to start antihypertensive therapy with diuretics, when no compelling indications are present, is not supported by the evidence that this strategy produces more rapid and better control of BP. PMID- 22499291 TI - Visit-to-visit blood pressure variability in the European Lacidipine Study on Atherosclerosis: methodological aspects and effects of antihypertensive treatment. AB - BACKGROUND: Recent studies have reported that in patients under antihypertensive treatment visit-to-visit (or long-term) variability of clinic BP within a given patient has an independent prognostic significance. Partly based on between patient dispersion of BP values during treatment (interindividual variability) it has also been reported that long-term clinic BP variability is greater for beta blocker than for calcium antagonist and other types of treatment. GOALS: To measure visit-to-visit intraindividual variations of both clinic and 24-h mean BP in the hypertensive patients of the European Lacidipine Study on Atherosclerosis (ELSA) trial treated for 4 years with either atenolol or lacidipine, and to check whether interindividual clinic and 24-h BP variabilities during treatment can really be considered a surrogate of intraindividual variabilities in exploring differences between beta-blocker and calcium antagonist treatments. METHODS: Long term intraindividual BP variability was defined as the coefficient of variation of the average systolic or diastolic values of clinic and 24-h BP measured at each visit throughout the treatment period. Patients in whom at least seven clinic (6-month intervals) or at least three (yearly intervals) 24-h values were available from the end of the drug titration phase to the end of the study were considered. RESULTS: Visit-to-visit 24-h SBP/DBP variabilities were 20-25% smaller than, and loosely correlated with clinic BP variability (r(2) < 0.022). There was also a very limited relationship (r (2)< 0.026) between visit-to-visit and within 24-h ambulatory BP variabilities, the latter being two to three times greater than the former. Visit-to-visit intraindividual clinic SBP variability was only slightly lower on calcium antagonist than on beta-blocker treatment but little or no between-treatment difference was found for visit-to-visit clinic DBP and ambulatory SBP/DBP particularly in patients under monotherapy throughout the study. Interindividual BP variability was markedly greater than the intra individiual one of which it did not precisely reflect the treatment-induced changes. CONCLUSION: In mild-to-moderate hypertensive patients, visit-to-visit BP variability does not differ substantially between beta-blocker and calcium antagonist treatment. Major discrepancies exist between visit-to-visit BP variability as quantified by 24-h vs. clinic BP, making investigation of which of these indices is clinically more relevant important. Interindividual BP variability during treatment shows marked quantitative differences with intraindividual BP variability questioning whether its use can accurately reflect individual BP variations from one visit to another. PMID- 22499292 TI - Predictors of lowering SBP to assigned targets at 12 months in the Secondary Prevention of Small Subcortical Strokes study. AB - OBJECTIVE: Lowering blood pressure for secondary stroke prevention remains a challenge. These analyses were conducted to identify factors predicting achievement of SBP targets in the Secondary Prevention of Small Subcortical Strokes (SPS3) study. METHODS: SPS3 is a randomized trial assigning patients with lacunar stroke to two targets of SBP control (130-149 mmHg or <130 mmHg). Logistic regression models were used to identify patient and SPS3 site characteristics predictive of lowering SBP to target at the 12-month study visit. RESULTS: Of those above target at baseline (n = 1041), 69% were within their assigned target at 12 months. In the model with baseline characteristics only, those receiving treatment for hypertension at baseline were 68% less likely to achieve target [odds ratio (OR) = 0.32; 95% confidence interval (CI) = 0.17 0.60], whereas those of Hispanic ethnicity were 1.49 times more likely (95% CI = 1.09-2.03) to achieve SBP target. When clinical site characteristics were added to the model, only treated hypertension at baseline remained significant. In addition, management at a larger site (OR = 1.51; 95% CI = 1.03-2.20), SBP in target at 6 months (OR = 2.39; 95% CI = 1.79-3.19), and medication adherence (OR = 2.73; 95% CI = 1.51-4.95) were positively associated with achieving target SBP. Missed appointments (OR = 0.55; 95% CI = 0.41-0.73) were negatively associated with lowering SBP to target at 12 months. CONCLUSION: These results demonstrate that it is feasible to achieve targets of SBP control in this multiethnic stroke cohort across multiple sites and countries. The results highlight the important variables reflecting clinical site management. PMID- 22499293 TI - Lymphomas of the gastro-intestinal tract - pathophysiology, pathology, and differential diagnosis. AB - The gastrointestinal tract (GIT) is the most commonly involved site of extranodal lymphomas. The close association between chronic inflammation and specific GIT lymphomas not only provide interesting insights into the pathobiology of lymphomas but also poses unique diagnostic challenges. A clear understanding of marginal zone and mucosa associated lymphoid tissue (MALT) in health and disease is helpful to place GIT lymphomas in proper context. A wide variety of lymphomas besides MALT lymphomas occur in various parts of the GIT. The characteristic pathological, immunophenotypic, and genetic features of different GIT lymphomas categorized according to World Health Organization (WHO) classification are presented. The epidemiological, clinical, and pathological features of lymphomas occurring in each part of the GIT are summarized and the key points regarding lymphomas at each site are emphasized. A tabular summary of the important differential diagnostic considerations at each site is given and suggestions for a minimal diagnostic work up are provided. PMID- 22499294 TI - Placental morphology in pre-eclampsia and eclampsia and the likely role of NK cells. AB - BACKGROUND: Placenta has long been a neglected organ as far as its pathology is concerned. This study is an attempt to observe the morphological features of placentae both gross and microscopic in normal pregnancy, preeclampsia, and eclampsia. MATERIALS AND METHODS: A total of 150 placentae were collected; of these, 50 belonged to normal pregnancy, 50 belonged to pre-eclamptic women, and 50 were from patients of eclampsia. RESULTS: Placental trimmed weight was seen to be decreased in patients of preeclampsia and eclampsia. Placental infarcts were more commonly seen in the diseased group and they were more centrally located. Hypertrophy of the spiral arterioles was observed in the decidual portion found in placental disc and membranes. Distal villous hypoplasia was also frequently seen in the diseased group. Fetal membranes were thickened and showed infarcts in preeclampsia and eclampsia. CONCLUSIONS: Morphological features seen in eclamptic placentae were similar but exaggerated compared to preeclampsia. In conclusion, the pathological changes were found to be more severe and frequent in preeclampsia and eclampsia, but more so in eclamptic placentae as compared with placenta of normal pregnancy. CD56 immunomarker was also used to identify NK cells. They were found to be present only in the diseased group and were located in the decidual portion of the basal plate, implicating their role in the development of the disease. PMID- 22499295 TI - Histological and immunohistochemical features in fatal acute fulminant hepatitis E. AB - BACKGROUND: Hepatitis E is being increasingly recognized as an emerging infection in developed countries. Data on histological findings and nature of inflammatory cell infiltrate in liver in this disease are quite sparse. AIMS: This study was planned to study the histological features and the type of inflammatory infiltrate in liver biopsies of patients with acute fulminant hepatitis E. MATERIALS AND METHODS: We retrieved postmortem liver biopsies of 11 Indian patients with fulminant hepatitis E, and compared these with biopsies from seven patients with fulminant hepatitis B. RESULTS: Biopsies from acute fulminant hepatitis E showed varying degrees of hepatocyte necrosis, mixed portal and lobular inflammation, accompanied by bile ductular proliferation, lymphocytic cholangitis, Kupffer cell prominence, cholestasis, apoptotic bodies, pseudo rosette formation, steatosis, and presence of plasma cells in portal tracts. Interface hepatitis was more frequent in acute hepatitis B than in acute hepatitis E (100% vs 20%; P<0.05). These findings differ from those reported in cases with autochthonous hepatitis E in Europe. On immunohistochemistry, lymphocyte infiltrate consisted predominantly of CD3 + T cells in both hepatitis E and hepatitis B; these cells contained a predominant cytotoxic (CD8 + ) cell subpopulation in 81.8% of cases with hepatitis E and in 50% of cases with hepatitis B. CONCLUSION: Our findings suggest that histological changes in HEV infection may vary with geographical location because of prevalent HEV genotypes, and that CD8 + lymphocytes play a role in HEV-induced liver injury. PMID- 22499296 TI - Renal histology in pauci-immune rapidly progressive glomerulonephritis: 8-year retrospective study. AB - CONTEXT: The need to perform reporting of renal biopsies of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides in a more uniform manner required relook at our eight-year data. AIMS: To document detailed renal histopathology of pauci-immune rapidly progressive glomerulonephritis (RPGN) and also to seek any significant differences in renal histology of C-ANCA-positive, P ANCA-positive, and ANCA-negative patients. MATERIALS AND METHODS: A detailed analysis of the histopathologic features of renal biopsies of 48 patients in whom a diagnosis of pauci-immune glomerulonephritis was concluded on renal biopsy and who presented clinically as rapidly progressive renal failure was done. STATISTICAL ANALYSIS USED: One-way ANOVA and Pearson Chi square tests. RESULTS: Compared with ANCA +ve patients, the ANCA -ve patients were much younger (46.85 +/- 16.12 years vs 34.28+/-15.94 years). No significant differences were found between renal lesions of C-ANCA, P-ANCA, and ANCA-negative patients, except for diffuse tubular atrophy which was more severe and more frequently present with P ANCA positivity (P value=0.013). CONCLUSIONS: Pauci-immune RPGN (irrespective of ANCA status) is a relatively rare disorder in patients who are undergoing the renal biopsy at our institute, constituting 2% of all renal biopsies submitted. It is mandatory to have ANCA serology status during reporting of a kidney biopsy showing pauci-immune crescentic or necrotizing glomerulonephritis. Also, if a uniform reporting strategy is followed throughout the country, the studies from this vast country will be comparable. PMID- 22499297 TI - The expression of immunohistochemical markers estrogen receptor, progesterone receptor, Her-2-neu, p53 and Ki-67 in epithelial ovarian tumors and its correlation with clinicopathologic variables. AB - BACKGROUND: This study aims to evaluate the expression of estrogen receptor alpha (ER alpha), progesterone receptor A (PRA), Her-2-neu, p53, and Ki-67 in epithelial ovarian tumors and their correlation with various clinicopathologic variables. MATERIALS AND METHODS: This study included 60 consecutive cases of epithelial ovarian tumors. Sections of 4 MUm were taken from paraffin embedded tissue blocks for immunohistochemistry (IHC). Statistical analysis was done using Chi square test, ANOVA. RESULTS: ER alpha had lower expression in benign (29%) and PRA higher expression in malignant (63.6%) tumors. ERalpha, PRA had higher expression in serous (72.72%, 57.14%), postmenopausal (81.8%, 71.42%), advanced stage (63.63%, 52.38%), grade 3 (45.45%, 38.09%), and tumors with ascites (90.90%, 85.7%). Her-2-neu, p53 were negative in benign and higher in malignant (21%, 57.6%), serous (71.42%, 57.89%), grade 3 (57.14%, 31.57%), and tumors with ascites (85.7%, 84.21%). Ki-67 had a significant higher expression in malignant (48.6 +/- 26.76), serous (55.43 +/- 27.85), and grade 3 tumors (68 +/- 22). CA 125 levels were significantly higher in malignant, serous, advanced stage, grade 3 and ER alpha, Her-2-neu and p53 positive tumors. CONCLUSION: ERalpha, PRA expression in tumors with adverse prognostic factors support the mitogenic role of estrogen and estrogenic regulation of PR. Her-2-neu and p53 expression only in malignant tumors suggest their carcinogenic role and aid in the differentiation of borderline and malignant tumors. Higher Ki-67 in tumors with adverse prognostic factors would help in prognostication and differentiation. Lack of co expression of markers proves the extreme heterogeneity of ovarian tumors. These markers may aid in differentiation and prognostication of ovarian tumors. PMID- 22499298 TI - Are we achieving the benchmark of retrieving 12 lymph nodes in colorectal carcinoma specimens? Experience from a tertiary referral center in India and review of literature. AB - INTRODUCTION: The number of lymph nodes (LNs) retrieved from a specimen of colorectal carcinoma may vary. Factors that can possibly affect LN yield are age of the patient, obesity, location of the tumor, neoadjuvant therapy, surgical technique and pathologist's handling of the specimen. AIM: The aim of our study is to look at lymph node retrieval from colorectal cancer (CRC) specimens in our hands and review the literature. MATERIALS AND METHODS: From May 2010 to January 2011, a total of 170 colorectal carcinoma cases were operated in our institute. Type of the surgeries, lymph node yield was looked at. RESULTS: There were 103 (60.6%) males and 67 (39.4%) females. The commonest age group was 50-59 years (30.6%). The surgeries included 107 surgeries for rectal carcinoma (63%) and 63 surgeries for colonic carcinoma (37%). Sixty six (38.8%) cases had received preoperative chemoradiotherapy, whereas 104 (61.2%) cases were without adjuvant therapy. The total lymph node positivity (metastatic disease) was 44.7% .The overall mean lymph node yield was 12.68 (range 0-63; median 11). The mean lymph node harvest in the age group < 39 was 15.76 whereas, the lymph node harvest in the group more than 39 years old was 11.90. ( statistically significant; P=0.03). The mean lymph node yield from specimens of rectal cancers (10.30) was lower than the mean lymph node yield from specimens for colonic cancers (16.71);( statistically significant, P<0.01). There was also statistically significant difference between the mean LN yield in chemoradionaiive cases (14.63) and in the cases where neoadjuvant therapy was received, (9.59); P<0.01. CONCLUSION: Pathologist while assessing a specimen of CRC should aim to retrieve a minimum of 12 LN. Surgical expertise and diligence of the pathologists remain two main alterable factors that can improve this yield. Neoadjuvant or preoperative radiotherapy can yield in less number of nodes. PMID- 22499299 TI - Molecular phenotypes of ductal carcinoma-in-situ and invasive ductal carcinoma: a comparative study. AB - AIMS AND OBJECTIVES: This study was aimed at analyzing the prevalence of molecular phenotypes in invasive ductal carcinoma (IDC) and coexisting ductal carcinoma-in-situ (DCIS) and to correlate with clinicopathological features. MATERIALS AND METHODS: In this study, 75 cases of IDC with coexisting DCIS were included. Molecular phenotype was determined using expression of estrogen receptor, progesterone receptor, HER2/neu, and cytokeratin 5/6. Statistical analysis was performed for correlation between molecular phenotypes and clinicopathologic parameters. RESULTS: Of the 75 cases, the invasive component in all cases was IDC--not otherwise specified. About one-third of our patients were post-menopausal. The most common molecular phenotype was luminal A (45.3%) followed by HER2-expressing type (24%). In all cases, the molecular phenotype was identical in DCIS and the invasive component. HER2-expressing tumors were found to be larger in size with frequent nodal involvement. On statistical analysis, tumor size and grade were found to correlate with the molecular phenotype. CONCLUSION: In conclusion, the molecular phenotype in DCIS correlates well with that of coexisting IDC, suggesting that DCIS is a precursor lesion in these tumors. This correlation of molecular phenotype can be utilized in prediction of phenotype of the invasive component in a case with in-situ carcinoma. PMID- 22499300 TI - Preliminary comparative analysis of antibacterial effects of activated and non activated of expired platelet concentrate by disc diffusion method. AB - BACKGROUND: Platelets release more than 30 cytokines to provide primary hemostatic function. In addition, platelets are also known to release antimicrobial peptides upon activation by thrombin. MATERIALS AND METHODS: In this study, comparative analysis of antibacterial activity of activated and non activated expired platelet concentrate was determined against Gram-positive and Gram-negative bacteria by Kirby-Bauer disk diffusion method. Thrombin was used to prepare activated platelet concentrate. Gram-positive bacteria tested in this study were S.aureus and S.pyogenes and Gram-negative bacteria were E.coli and K.oxytoca. All the bacteria used in this study were sensitive strains from clinical isolates. Activated and non-activated platelet showed no zone of inhibition against S.pyogenes and E.coli. RESULTS: Activated platelet showed antibacterial activity against S.aureus and K.oxytoca with the zone of inhibition of 8.3 +/- 0.6 mm and 7.7 +/- 0.2 mm, respectively. Zone of inhibition observed in non-activated platelet against S.aureus and K.oxytoca were 7.8 +/- 0.4 mm and 7.5 +/- 0.3 mm, respectively. CONCLUSIONS: These findings showed that no significant differences in antibacterial activity produced by activated and non activated platelet. However, zone of inhibition observed in activated and non activated platelet indicate the presence of antibacterial property in expired platelet. PMID- 22499301 TI - Evaluation of cervical cytological abnormalities in Turkish population. AB - INTRODUCTION: Cervical cancer is one of the most common female malignancy with high mortality rates in developing countries. Our purpose was to determine the prevalence of cervical cytologic abnormalities in population (strict Islamic religious area) and the detection rate of epithelial abnormalities by cervical cytology (CC). MATERIALS AND METHODS: A total of 32,026 conventional pap smear tests collected between January 2006 and January 2010 from three hospitals are retrospectively analyzed. RESULTS: Total of 900 (2.8%) cases had epithelial abnormalities. The numbers and rates of epithelial abnormalities were as the followings: Atypical squamous cell of undetermined significance (ASCUS; n=615 [1.9%]); atypical squamous cell suspicious for high-grade squamous intraepithelial lesion (ASC-H; n=27 [0.1%]); atypical glandular cell of undetermined significance (AGUS; n=73 [0.2%]); low- grade squamous intraepitelial lesion (LSIL; n=147 [0.5%]); high- grade squamous intraepithelial lesion (HSIL; n=35 [0.1%]); and squamous cell carinoma (SCC; n=3 [0.0%]). CONCLUSION: The prevalence of cervical cytological abnormality in our study was 2.8%. Recently, some conflicting results from the same population were published. More prospective studies with larger numbers are needed. PMID- 22499302 TI - Immunohistochemical study of osteopontin, Ki-67, and CD34 of psoriasis in Mansoura, Egypt. AB - BACKGROUND AND OBJECTIVE: Psoriasis is a chronic inflammatory skin disease characterized by hyper-proliferation, abnormal differentiation, and inflammatory infiltration in epidermis and dermis. We planned this study to analyze probable associations between Osteopontin (OPN), Ki-67, CD34, and histopathological features in psoriasis. MATERIALS AND METHODS: We studied OPN expression and its correlation with Ki-67 and CD34 expression in lesional, non-lesional skin, and normal skin. Immunoreactivity for OPN and Ki-67 was based on the level of epidermal staining. CD34 expression was scored as mild, moderate, and strong, according to the number of stained dermal capillaries. RESULTS: Our results showed statistically significant differences in the expression of OPN, Ki-67, and CD34 between lesional and non-lesional skin as well as between non-lesional skin and control group (P <= 0.001). In addition, there was a significant difference in the expression of OPN, Ki-67, and CD34 between control and lesional group (P=0.02, P=0.02, and P=0.04, respectively). CONCLUSIONS: OPN expression seems to be related to Ki-67 (proliferation index) and CD34 expression (angiogenesis marker) confirming its role in the pathogenesis of psoriasis. Then "anti- OPN and anti-angiogenesis" may eventually become a useful therapeutic approach in psoriasis. PMID- 22499303 TI - Clinico-pathological profile of Hairy cell leukemia: critical insights gained at a tertiary care cancer hospital. AB - CONTEXT: Hairy cell leukemia (HCL) is a rare, low grade, B-cell neoplasm with a characteristic morphologic and immunophenotypic profile. It has to be distinguished from chronic lymphoproliferative disorders because of different treatment protocol and clinical course. AIMS: To evaluate clinicopathological features including immunophenotypic analysis of cases diagnosed as HCL. MATERIALS AND METHODS: The present study included 28 cases diagnosed over a period of nine years (2002-2010). Clinical presentation, complete blood count, bone marrow aspirate, and flow cytometric analysis of cases were reviewed. Treatment and follow-up details (ranging from 3-90 months) were noted. RESULTS: This study revealed 28 cases (referrals-7, indoor-21), aged 26-69 years with a median age of 47 years, with a male predominance (M:F=6:1). The presenting complaints were weakness (80%) followed by fever (56%) and abdominal pain. Physical examination revealed splenomegaly in most patients (92%) and hepatomegaly in a minority (28%). The common laboratory features were anemia in 23 cases, pancytopenia in 14 cases, while two patients had leukocytosis and three patients had normal WBC count. Dry tap was observed in 84% of the cases where hairy cells constituted 16 97% of non-erythroid nucleated cells. Tartarte resistant acid phosphate staining was positive in all the eight cases where it was done. CD5 was negative in all the cases, while CD10 was expressed in three cases (13%) and CD23 in five cases (19%). CONCLUSIONS: Though pancytopenia is common, occasional patient can present with normal blood counts or leukocytosis. Few unusual findings include presence of lymphadenopathy, absence of palpable splenomegaly, and expression of CD23 and CD10 by the leukemic cells. PMID- 22499304 TI - Morphological spectrum of leukemic mantle cell lymphoma. AB - BACKGROUND: Leukemic involvement in mantle cell lymphoma (MCL) is common, and can be secondary to nodal or extranodal disease or can be de-novo. There is paucity of literature that describes the morphological spectrum. AIM: This study was aimed at studying the morphological spectrum of leukemic MCL and to correlate the morphology with other features. MATERIALS AND METHODS: Twenty six such cases diagnosed over a period of four years were studied. Peripheral blood and bone marrow aspiration smears stained with Wrights stain were examined by three hematopathologists. Immunophenotyping was done using multicolor flow cytometry. Fluorescence in situ hybridization (FISH) done in 12 cases showed t(11;14)(q13:q32). RESULTS: Six cases had de-novo leukemic involvement; while 20 cases had secondary involvement. Morphologically, the cells were small (less than twice the size of red blood cell) or large. Small cell morphology in turn showed irregular nuclear border (n=13) or round nuclear contour (n=6). Large cells had blastic morphology (n=5) or had central prominent nucleoli resembling prolymhphocytes (n=2). Twenty cases showed characteristic immunophenotype of CD5+/CD19+/CD20+/FMC7+/CD10-/CD23- and light chain restrictions. Three cases expressed CD23 and two cases were negative for FMC7. Five out of 12 cases, where FISH was done, showed cytogenetic abnormalities in addition to t(11;14)(q13;q32). CONCLUSION: Morphological spectrum of leukemic MCL ranges from small cells resembling chronic lymphocytic leukemia (CLL) or follicular lymphoma (FL) to large cell mimicking prolymphocytic leukemia (PLL) or acute leukemia. Large cell morphology was associated with more frequent additional cytogenetic abnormality as well as a poorer outcome. PMID- 22499305 TI - Antifungal susceptibility testing of Candida tropicalis biofilms against fluconazole using calorimetric indicator resazurin. AB - BACKGROUND: C.tropicalis is an important cause of nosocomial infections particularly in immunocompromised patients. Infections caused by Candida spp. are often associated with biofilm formation on implanted medical devices or on epithelial cell surfaces. Phenotypic characteristics of sessile cells in biofilms are known to be different from those of their free-living, planktonic counterparts. Biofilm forming strains often show increased resistance to antimicrobial agents. MATERIALS AND METHODS: We measured susceptibility to fluconazole of fifty C.tropicalis isolates from immunocompromised (29) and immunocompetent (21) patients by minimum inhibitory concentration (MIC) and minimum biofilm inhibitory concentration (MBIC) assays. MBIC was done using the calorimetric indicator resazurin, to measure the metabolically active cells. RESULTS: Biofilm forming cells showed increased resistance to fluconazole. CONCLUSION: The resazurin dye test was found to be a good method for determining MBIC. PMID- 22499306 TI - Role of C-erbB2 expression in gallbladder cancer. AB - BACKGROUND: Gallbladder cancer (GBC) is a lethal malignancy presenting at an advanced stage. The pathogenesis is not well categorized, and surgery is the only treatment available at the early stage of the disease. There have been few reports on role of growth factor receptors in GBC. C-erbB2 is one such receptor whose over-expression is being explored in GBC as one of the factors involved in carcinogenesis and possible target for therapy. MATERIALS AND METHODS: One hundred and four consecutive cases of GBC were retrospectively studied with regard to clinical features, histological type, grade and stage of tumor. Immunohistochemistry for C-erbB2 was done and expression was correlated with different clinic-pathological parameters and survival. RESULTS: C-erbB2 overexpression was seen in 9.4% cases with complete staining and both complete and incomplete staining (2+ and 3+) was seen in 13.4% cases. Eighty percent of the C-erbB2 over-expressed cases were well differentiated and in stage II to stage IV disease. Dysplasia adjacent to carcinoma did not show any expression. No correlation was found with tumor grade, stage, gall stones, and patient survival. Xanthogranulomatous inflammation was inversely correlated with C-erbB2 over expression. Median survival was 30 months in C-erbB2 over-expressed cases, and 12 months in C-erbB2 negative cases. CONCLUSION: We found complete membranous staining of C-erbB2 in 9.4% of GBC which was frequent in well differentiated and stage II to stage IV tumors. C-erbB2 tumors had longer median survival than C erbB2 negative tumors. C-erbB2 is not involved early in the carcinogenetic process as none of the dysplasia showed expression. C-erbB2 over-expression may be considered as target for therapy in advanced stage of GBC. PMID- 22499307 TI - Multicentric extraskeletal myxoid chondrosarcoma of uterine adnexa in a young female: an unusual presentation. AB - Extraskeletal myxoid chondrosarcoma is a rare soft-tissue sarcoma, mostly occurring in the proximal extremities and limb girdle. Majority of the patients are in fifth and sixth decades of life with male preponderance. We report here a case of primary extraskeletal myxoid chondrosarcoma of the uterine adnexa involving the broad ligament and fallopian tube synchronously without any evidence of uterine/ovarian involvement in a young multiparous female of 27 years. After the histopathological diagnosis, re-excision of the tumor bed with wide local margins was recommended. Since the tumor has an aggressive course, with propensity for late recurrence and metastases to lungs, the patient must be considered for long-term follow-up. PMID- 22499308 TI - Leiomyosarcoma of inferior vena cava: a case series of four cases. AB - Vascular leiomyosarcomas are rare tumors, arising most frequently from inferior vena cava (IVC). They are mostly seen in sixth decade, with a female predominance. Their diagnosis is often challenging, as patients may present with non-specific complaints such as dyspnea, malaise, weight loss, abdominal pain, or back pain, preceding the diagnosis by several years. Leiomyosarcoma of the IVC most frequently occurs in the middle segment. The final diagnosis can be made by an ultrasound or computed tomography guided biopsy. Because of limited experience with this disease, optimal management of IVC leiomyosarcoma is unknown. Curative surgical resection remains the current treatment of choice for primary leiomyosarcoma of IVC. Neoadjuvant therapy may be given to downsize the tumor and increase resectability rates. Nonetheless, when complete resection is not possible, debulking combined with radiation therapy still provides good palliation. We, hereby, report four cases of this rare entity with emphasis on management. PMID- 22499309 TI - Melanoma metastatic to a ruptured silicone breast implant capsule. AB - Metastasis to the breast is rare and most commonly represents spread from a contra-lateral primary mammary carcinoma. Metastasis of solid non-mammary carcinoma is very rare and melanoma and neuro-endocrine bronchogenic carcinoma are the more common primary neoplasms implicated. In up to half of affected individuals, there may be no prior diagnosis of malignancy. Breast metastasis by melanoma to our knowledge has never been described to an augmented breast, moreover, to a ruptured implant capsule. PMID- 22499310 TI - Epithelioid malignant mesothelioma of tunica vaginalis with deciduoid features: an unusual malignancy clinically masquerading an inguinal hernia. AB - Paratesticular/scrotal and inguinal canal mass lesions in elderly patients may pose a diagnostic challenge to both the surgeon as well as the pathologist. In most cases, these represent hernial sacs with their contents, and true neoplasms like lipomas, rhabdomyosarcomas, and fibrous pseudotumors are infrequent. Malignant mesotheliomas arising from the tunica layers are rare cause of inguinal and paratesticular tumors. Herein, we report a case of an elderly patient who presented with an inguinal hernia which pathologically had features of deciduoid malignant mesothelioma. PMID- 22499311 TI - HTLV 1 associated adult T cell lymphoma/leukemia a clinicopathologic, immunophenotypic tale of three cases from non-endemic region of south India. AB - Adult T cell lymphoma/leukemia is a peripheral T-cell neoplasm caused by human T cell lymphotrophic virus-1, affects mostly adults with systemic involvement and poor prognosis. Diagnosis of adult T-Cell leukemia/Lymphoma is challenging. The clinico-pathologic and immuno-phenotypic features of the three cases will be presented. PMID- 22499312 TI - Creutzfeldt-Jacob disease: an autopsy case report in tertiary care hospital. AB - Sporadic Creutzfeldt-Jakob disease (CJD) is the most common prion disease. It is a rare, fatal neurodegenerative disease caused by an infectious protein called prion. The diagnosis can be confirmed only by histological examination of brain tissue. Because of the transmissible nature of the disease, autopsy or brain biopsy cannot be performed at many institutions. Histology shows spongiform changes, neuronal loss, reactive astrocytic proliferation, accumulation of pathologic protein occurring in three general forms: Sporadic, familial, and acquired form, including a variant form of CJD. It clinically presents as predominantly progressive dementia with a rapid onset, myoclonus, cerebellar, pyramidal, extra pyramidal and visual signs. Occurrence of periodical spikes in electro-encephalogram, observation of cortical signal alterations in magnetic resonance imaging (MRI) studies, and detection of protein 14-3-3 in cerebrospinal fluid substantiate diagnosis. Autopsy case is presented of a 50 year old woman with progressive dementia, typical neurological symptoms, MRI findings and confirmation of CJD on histology and immunostaining. PMID- 22499313 TI - Pallister-Hall syndrome presenting as an intrauterine fetal demise at 39 weeks' gestation. AB - Pallister-Hall syndrome (PHS) is a pleiotropic autosomal-dominant malformation syndrome rarely presenting with genitourinary malformations. Literature has recorded 14 cases of PHS with genitourinary findings out of which only six have been females presenting with hydrometrocolpos and/or vaginal atresia. Fetal autopsy findings on a 39 weeks' gestation including demonstration of corticotroph deficiency in the pituitary, along with the review of literature is being presented here. None of the earlier literature pertaining to PHS with hydrometrocolpos and/or vaginal atresia describes an intrauterine fetal demise due to corticotroph deficiency. PMID- 22499314 TI - Plasmablastic extramedullary plasmacytoma. AB - Extramedullary plasmactyoma is the solitary, soft tissue form of plasma cell neoplasm but lack the defining features of medullary or multiple myeloma. The diagnosis is difficult to make in routine practice setting due to the morphological and immunohistochemical overlap with plasmablastic lymphoma. We report a case of plasmablastic extramedullary plasmacytoma in a 52-year-old in the mandibular lingual gingiva and discuss its differential from plasmablastic lymphoma. The gingival mass regressed with primary radiotherapy. PMID- 22499315 TI - Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum) as a component of Cowden syndrome. PMID- 22499316 TI - Littoral cell angioma of spleen in a patient with obstructive jaundice. PMID- 22499317 TI - Unusual manifestations of pleuro-pulmonary hydatidosis. PMID- 22499318 TI - Brunner's gland hamartoma. PMID- 22499319 TI - Masquerade in rosettes. PMID- 22499320 TI - Meningioangiomatosis: a report on a rare case, masquerading as schwannoma. PMID- 22499321 TI - Macrolithiasis in pulmonary tuberculosis: an autopsy report with review of literature. PMID- 22499322 TI - Myoid (muscular) hamartoma of the breast with chondroid metaplasia. PMID- 22499323 TI - Hodgkin's lymphoma presenting as an abscess in thyroid gland. PMID- 22499324 TI - Hemophagocytic syndrome associated with concomitant Klebsiella and Parvovirus B 19 infection. PMID- 22499325 TI - Nodular histiocytic proliferation in hernial sac: a potential diagnostic pitfall. PMID- 22499326 TI - Immunoglobulin M nephropathy in adults and adolescents in India: a single center study of natural history. PMID- 22499327 TI - Dementia, peripheral neuropathy, and chronic meningitis in Neurobrucellosis. PMID- 22499329 TI - Neonatal candidemia: a changing trend. PMID- 22499328 TI - Seemingly insignificant, but crucial morphological leads in the diagnosis of non secretory multiple myeloma in an adolescent. PMID- 22499330 TI - Toxoplasma lymphadenitis diagnosed by fine needle aspiration cytology: a rare finding. PMID- 22499331 TI - References in the Indian Journal of Pathology and Microbiology: are they accurate? PMID- 22499332 TI - Estimation of crystallinity of trehalose dihydrate microspheres by usage of terahertz time-domain spectroscopy. AB - Crystalline state of pharmaceutical materials is of great importance in the preparation of pharmaceutics because their physicochemical properties affect bioavailability, quality of products, therapeutic level, and manufacturing process. In this study, we have estimated the crystallinity of trehalose dihydrate microspheres by measuring terahertz (THz) spectroscopy. The commercially available trehalose dihydrate takes in general a crystalline state, but trehalose dihydrate microspheres prepared by using spray-drying method are in an amorphous state. We have prepared amorphous anhydrous trehalose by using melt quenched method from crystalline trehalose dihydrate. We have measured the absorbance of trehalose dihydrate containing amorphous anhydrous trehalose (0%, 25%, 50%, 75%, and 100%) using THz time-domain spectroscopy (THz-TDS) to prepare calibration curves. Using the calibration curves, we have estimated the crystallinity of trehalose dihydrate microspheres prepared by using spray-drying method. Our results suggest that THz-TDS is well suited to distinguish crystallinity differences in pharmaceutical compounds. PMID- 22499333 TI - Beta1-adrenergic receptor polymorphisms associated with atrial fibrillation in systolic heart failure. AB - BACKGROUND: The sympathetic nervous system is of great importance in the pathogenesis of atrial fibrillation in systolic heart failure. The identification of polymorphisms in the beta1-adrenergic receptor gene (ADBR1) represents an important step in understanding this pathogenesis. OBJECTIVE: This study assessed the association between the two functional polymorphisms of the beta1-adrenergic receptor gene (ADBR1), Ser49Gly and Arg389Gly, and the presence of atrial fibrillation in patients with systolic heart failure. METHODS: Case-control study with 144 patients with systolic heart failure, including 24 with atrial fibrillation (cases) and 120 without atrial fibrillation (controls). Genomic DNA was extracted from peripheral blood leukocytes and the genotypes of Ser49Gly and Arg389Gly polymorphisms were identified in all individuals by PCR/RFLP (polymerase chain reaction / restriction fragment length polymorphism). RESULTS: Mean age was 59 +/- 13 years, 70% of patients were males, 42% had ischemic causes and 74% had hypertension. Genotypes Ser49Ser and Arg389Arg were significantly associated with atrial fibrillation (p = 0.005 and p = 0.01, respectively). After logistic regression, both adjusted for left atrial size and age, the significant association persisted (Arg389Arg - odds ratios: 2.78, 95% confidence interval = 1.02 to 7.56 and Ser49Ser - odds ratios: 8.02, 95% confidence interval = 1.02 to 63.82). CONCLUSION: Both genotypes were associated with atrial fibrillation in patients; however, only Ser49Gly polymorphism was is in Hardy-Weinberg equilibrium. PMID- 22499334 TI - Morphology and contractility in cardiomyocytes of rats with low exercise performance. AB - BACKGROUND: Aerobic capacity is essential to physical performance, and low aerobic capacity is related to the triggering of various cardiovascular diseases. OBJECTIVE: To compare the morphology and contractility of isolated rat cardiomyocytes with low performance and standard performance for exercise. METHODS: Wistar rats with 10 weeks of age underwent a protocol of treadmill running to fatigue, and were divided into two groups: Low Performance (LP) and Standard Performance (SP). Then, the animals were sacrificed, the heart was quickly removed and, by means of enzymatic dissociation, left ventricular cardiomyocytes were isolated. The cell and sarcomeres length and width of cardiomyocytes were measured using an edge detection system. The isolated cardiomyocytes were electrically stimulated at 1 and 3 Hz and cell contraction was measured by registering the change of their length. RESULTS: The cell length was shorter in the LP group (157.2 +/- 1.3 um; p < 0.05) compared to SP (161.4 +/ 1.3 um), and the same result was observed for the volume of cardiomyocytes (LP, 25.5 +/- 0.4 vs. SP, 26.8 +/- 0.4 pL; p < 0.05). The time to peak contraction (LP, 116 +/- 1 vs. SP 111 +/- 2 ms) and total relaxation (LP, 143 +/- 3 vs. SP 232 +/- 3 ms) were higher in the LP group. CONCLUSION: We conclude that left ventricular myocytes of animals with low performance for exercise are smaller than animals with standard performance. In addition to that, they present losses in contractile capacity. PMID- 22499335 TI - Clinical usefulness of coronary angiography in patients with left ventricular dysfunction. AB - BACKGROUND: Performing a coronary angiography in patients with heart failure of unknown etiology is often justified by the diagnostic assessment of ischemic heart disease. However, the clinical benefit of this strategy is not known. OBJECTIVE: To evaluate the prevalence of ischemic heart disease by angiographic criteria in patients with heart failure and reduced ejection fraction of unknown etiology, as well as its impact on therapy decisions. METHODS: Consecutive outpatients with heart failure and systolic dysfunction, who had an indication for coronary angiography to clarify the etiology of heart disease were assessed from 1 January 2009 to December 31, 2010. Patients diagnosed with coronary artery disease, positive serology for Chagas disease, congenital heart disease, valve disease or patients undergoing cardiac transplantation were excluded from the analysis. The sample was divided into two groups according to the indication for catheterization. Group-1: Symptomatic due to angina or heart failure. Group-2: Presence of > 2 risk factors for coronary artery disease RESULTS: One hundred and seven patients were included in the analysis, with 51 (47.7%) patients in Group 1 and 56 (52.3%) in Group 2. The prevalence of ischemic heart disease was 9.3% (10 patients), and all belonged to Group 1 (p = 0.0001). During follow-up, only 4 (3.7%) were referred for CABG; 3 (2.8%) patients had procedure-related complications. CONCLUSION: In our study, coronary angiography in patients with heart failure and systolic dysfunction of unknown etiology, although supported by current guidelines, did not show benefits when performed only due to the presence of risk factors for coronary artery disease. PMID- 22499336 TI - From ritual sword duel to electrophysiology: hyperactive facial motor nucleus in hemifacial spasm. PMID- 22499337 TI - Facilitative functionalization of cyanine dye by an on-off-on fluorescent switch for imaging of H2O2 oxidative stress and thiols reducing repair in cells and tissues. AB - We presented the design, synthesis, spectroscopy, and biological applications of DA-Cy, an on-off-on fluorescent probe to monitor H(2)O(2) oxidative stress and thiols reducing repair in living cells and tissues simply and directly. PMID- 22499338 TI - Glycosaminoglycans enhance osteoblast differentiation of bone marrow derived human mesenchymal stem cells. AB - Extracellular matrix plays an important role in regulating cell growth and differentiation. The biomimetic approach of cell-based tissue engineering is based on mirroring this in vivo micro environment for developing a functional tissue engineered construct. In this study, we treated normal tissue culture plates with selected extracellular matrix components consisting of glycosaminoglycans such as chondroitin-4-sulphate, dermatan sulphate, chondroitin 6-sulphate, heparin and hyaluronic acid. Mesenchymal stem cells isolated from adult human bone marrow were cultured on the glycosaminoglycan treated culture plates to evaluate their regulatory role in cell growth and osteoblast differentiation. Although no significant improvement on human mesenchymal stem cell adhesion and proliferation was observed on the glycosaminoglycan-treated tissue culture plates, there was selective osteoblast differentiation, indicating its potential role in differentiation rather than proliferation. Osteoblast differentiation studies showed high osteogenic potential for all tested glycosaminoglycans except chondroitin-4-sulphate. Osteoblast differentiation associated genes such as osterix, osteocalcin, integrin binding sialoprotein, osteonectin and collagen, type 1, alpha 1 showed significant upregulation. We identified osterix as the key transcription factor responsible for the enhanced bone matrix deposition observed on hyaluronic acid, heparin and chondroitin-6 sulphate. Hyaluronic acid provided the most favourable condition for osteoblast differentiation and bone matrix synthesis. Our results confirm and emphasise the significant role of extracellular matrix in regulating cell differentiation. To summarise, glycosaminoglycans of extracellular matrix played a significant role in regulating osteoblast differentiation and could be exploited in the biomimetic approach of fabricating or functionalizing scaffolds for stem cell based bone tissue engineering. PMID- 22499339 TI - An SNX10 mutation causes malignant osteopetrosis of infancy. AB - BACKGROUND: Osteopetrosis is a life-threatening, rare disorder typically resulting from osteoclast dysfunction and infrequently from failure to commitment to osteoclast lineage. Patients commonly present in infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, and bone marrow failure. In ~70% of the patients there is a molecularly defined failure to maintain an acid pH at the osteoclast-bone interface (the ruffled border) which is necessary for the bone resorptive activity. METHODS AND RESULTS: In eight patients with infantile osteopetrosis which could be cured by bone marrow transplantation, the study identified by homozygosity mapping in distantly related consanguineous pedigrees a missense mutation in a highly conserved residue in the SNX10 gene. The mutation segregated with the disease in the families and was carried by one of 211 anonymous individuals of the same ethnicity. In the patients' osteoclasts, the mutant SNX10 protein was abnormally abundant and its distribution altered. The patients' osteoclasts were fewer and smaller than control cells, their resorptive capacity was markedly deranged, and the endosomal pathway was perturbed as evidenced by the distribution of internalised dextran. CONCLUSIONS: SNX10 was recently shown to interact with vacuolar type H(+)-ATPase (V-ATPase) which pumps protons at the osteoclast-bone interface. Mutations in TCIRG1, the gene encoding a subunit of the V-ATPase complex, account for the majority of cases of osteopetrosis. It is speculated that SNX10 is responsible for the vesicular sorting of V-ATPase from Golgi or for its targeting to the ruffled border. A mutation in SNX10 may therefore result in 'secondary V-ATPase deficiency' with a failure to acidify the resorption lacuna. Determination of the sequence of the SNX10 gene is warranted in molecularly undefined patients with recessive 'pure' osteopetrosis of infancy. PMID- 22499340 TI - NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases. AB - BACKGROUND: The lethal short rib polydactyly syndromes (SRP type I-IV) are characterised by notably short ribs, short limbs, polydactyly, multiple anomalies of major organs, and autosomal recessive mode of inheritance. Among them, SRP type II (Majewski; MIM 263520) is characterised by short ovoid tibiae or tibial agenesis and is radiographically closely related to SRP type IV (Beemer-Langer; MIM 269860) which is distinguished by bowed radii and ulnae and relatively well tubulated tibiae. NEK1 mutations have been recently identified in SRP type II. Double heterozygosity for mutations in both NEK1 and DYNC2H1 in one SRP type II case supported possible digenic diallelic inheritance. METHODS: The aim of this study was to screen DYNC2H1 and NEK1 in 13 SRP type II cases and seven SRP type IV cases. It was not possible to screen DYNC2H1 in two patients due to insufficient amount of DNA. RESULTS: The study identified homozygous NEK1 mutations in 5/13 SRP type II and compound heterozygous DYNC2H1 mutations in 4/12 cases. Finally, NEK1 and DYNC2H1 were excluded in 3/12 SRP type II and in all SRP type IV cases. The main difference between the mutation positive SRP type II group and the mutation negative SRP type II group was the presence of holoprosencephaly and polymycrogyria in the mutation negative group. CONCLUSION: This study confirms that NEK1 is one gene causing SRP type II but also reports mutations in DYNC2H1, expanding the phenotypic spectrum of DYNC2H1 mutations. The exclusion of NEK1 and DYNC2H1 in 3/12 SRP type II and in all SRP type IV cases further support genetic heterogeneity. PMID- 22499341 TI - Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes. AB - OBJECTIVE: To investigate the utility of autozygome analysis and exome sequencing in a cohort of patients with suspected or confirmed mitochondrial encephalomyopathy. METHODS: Autozygome was used to highlight candidate genes for direct sequencing in 10 probands, all born to consanguineous parents. Autozygome was also used to filter the variants from exome sequencing of four probands. RESULTS: In addition to revealing mutations in known mitochondrial genes, the analysis revealed the identification of two novel candidate disease genes: MFF and FARS2, encoding the mitochondrial fission factor and phenylalanyl-tRNA synthetase, respectively. INTERPRETATION: These findings expand the repertoire of genes that are mutated in patients with mitochondrial disorders and highlight the value of integrating genomic approaches in the evaluation of these patients. PMID- 22499342 TI - Recessive mutations in MCM4/PRKDC cause a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair. AB - BACKGROUND: A study is presented of 10 children with a novel syndrome born to consanguineous parents from the Irish Traveller population. The syndrome is characterised by a natural killer (NK) cell deficiency, evidence of an atypical Fanconi's type DNA breakage disorder, and features of familial glucocorticoid deficiency (FGD). The NK cell deficiency probably accounts for the patients' recurrent viral illnesses. Molecular tests support a diagnosis of mosaic Fanconi's anaemia, but the patients do not present with any of the expected clinical features of the disorder. The symptomatic presentation of FGD was delayed in onset and may be a secondary phenotype. As all three phenotypes segregate together, the authors postulated that the NK cell deficiency, DNA repair disorder and FGD were caused by a single recessive genetic event. METHODS: Single-nucleotide polymorphism homozygosity mapping and targeted next-generation sequencing of 10 patients and 16 unaffected relatives. RESULTS: A locus for the syndrome was identified at 8p11.21-q11.22. Targeted resequencing of the candidate region revealed a homozygous mutation in MCM4/PRKDC in all 10 affected individuals. Consistent with the observed DNA breakage disorder, MCM4 and PRKDC are both involved in the ATM/ATR (ataxia-telangiectasia-mutated/ATM-Rad 3 related) DNA repair pathway, which is defective in patients with Fanconi's anaemia. Deficiency of PRKDC in mice has been shown to result in an abnormal NK cell physiology similar to that observed in these patients. CONCLUSION: Mutations in MCM4/PRKDC represent a novel cause of DNA breakage and NK cell deficiency. These findings suggest that clinicians should consider this disorder in patients with failure to thrive who develop pigmentation or who have recurrent infections. PMID- 22499343 TI - A recessive form of Marshall syndrome is caused by a mutation in the COL11A1 gene. PMID- 22499344 TI - Keratinocytic epidermal nevi are associated with mosaic RAS mutations. AB - BACKGROUND: Activating RAS mutations in the germline cause rare developmental disorders such as Costello syndrome. Somatic RAS mutations are found in approximately 30% of human cancers. Keratinocytic epidermal nevi (KEN) represent benign congenital skin lesions arranged along Blaschko's lines. A subgroup of KEN is caused by hotspot oncogenic FGFR3 and PIK3CA mutations in mosaicism, but the majority lack these mutations. METHODS: This study screened 72 KEN for activating mutations in RAS genes and other oncogenes. RESULTS: Activating RAS mutations were identified in 28/72 (39%) of KEN. HRAS was the most commonly affected oncogene (86%), with the HRAS p.G13R substitution representing a new hotspot mutation. CONCLUSION: These results indicate that activating RAS somatic mutations leading to mosaicism result in benign KEN of the skin. Given the prevalence of KEN, mosaic HRAS mutations appear to be more common in patients than germline ones. These findings identify KEN as a mosaic RASopathy and lend further support to the notion that genetic mosaicism is an important contributor to disease. PMID- 22499345 TI - Identification of YAP1 as a novel susceptibility gene for polycystic ovary syndrome. AB - BACKGROUND: A previously reported genome-wide association study (GWAS) of polycystic ovary syndrome (PCOS) in Han Chinese found that several loci of p value around 10e-5 warrant investigation. Replication of the GWAS was applied in this study to determine whether gene YAP1 (yeast associated protein 1) is associated with PCOS. METHODS: An independent set of 1115 PCOS patients and 1137 controls were recruited; single nucleotide polymorphisms (SNPs) rs11225138, rs11225161, and rs11225166 from YAP1 were selected for the replication study. Real-time quantitative PCR was applied for genotyping by TaqMan-MGB probe assay. RESULTS: Meta-analysis showed that the allele frequency of rs11225161 (A/G) was significantly different between PCOS and controls at a GWA significance (Pmeta =3.98e-09). Genotype-phenotype correlation study found 30 min and 60 min glucose of the oral glucose tolerance test were higher in PCOS patients with rs11225161 risk allele A. The G allele of SNP rs11225138 (G/C) was a further risk factor for higher luteinising hormone level in PCOS patients (p=0.041). CONCLUSION: YAP1 appears to be a new susceptibility gene for PCOS in Han Chinese women. PMID- 22499346 TI - Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes. AB - BACKGROUND: Expanded GGGGCC hexanucleotide repeats in the promoter of the C9ORF72 gene have recently been identified in frontotemporal dementia (FTD), Amyotrophic Lateral Sclerosis (ALS) and ALS-FTD and appear as the most common genetic cause of familial (FALS) and sporadic (SALS) forms of ALS. METHODS: We searched for the C9ORF72 repeat expansion in 950 French ALS patients (225 FALS and 725 SALS) and 580 control subjects and performed genotype-phenotype correlations. RESULTS: The repeat expansion was present in 46% of FALS, 8% of SALS and 0% of controls. Phenotype comparisons were made between FALS patients with expanded C9ORF72 repeats and patients carrying another ALS-related gene (SOD1, TARDBP, FUS) or a yet unidentified genetic defect. SALS patients with and without C9ORF72 repeat expansions were also compared. The C9ORF72 group presented more frequent bulbar onset both in FALS (p<0.0001 vs SOD1, p=0.002 vs TARDBP, p=0.011 vs FUS, p=0.0153 vs other FALS) and SALS (p=0.047). FALS patients with C9ORF72 expansions had more frequent association with FTD than the other FALS patients (p<0.0001 vs SOD1, p=0.04 vs TARDBP, p=0.004 vs FUS, p=0.03 vs other FALS). C9ORF72-linked FALS patients presented an older age of onset than SOD1 (p=0.0139) or FUS mutation (p<0.0001) carriers. Disease duration was shorter for C9ORF72 expansion carriers than for SOD1 (p<0.0001) and TARDBP (p=0.0242) carriers, other FALS (p<0.0001) and C9ORF72-negative SALS (p=0.0006). CONCLUSIONS: Our results confirm the major role of expanded repeats in C9ORF72 as causative for ALS and provide evidence for specific phenotypic aspects compared to patients with other ALS-related genes. PMID- 22499349 TI - The Human Variome Project Beijing meeting. AB - The Human Variome Project Beijing Meeting, a joint meeting of the Human Variome Project Consortium and the Human Variome Project Chinese Node, was held in Beijing, 8th-12th of December, 2011. The aim of the Human Variome Project is to ensure that all information on genetic variation can be collected, curated, interpreted and shared freely and openly. The meeting officially welcomed the Human Variome Project Chinese Node as a partner of the Human Variome Project and focused on those areas where collaborations between China and the global Human Variome Project Consortium are required to develop and extend the coverage of international gene/disease specific databases. PMID- 22499347 TI - Genome-wide linkage and copy number variation analysis reveals 710 kb duplication on chromosome 1p31.3 responsible for autosomal dominant omphalocele. AB - BACKGROUND: Omphalocele is a congenital birth defect characterised by the presence of internal organs located outside of the ventral abdominal wall. The purpose of this study was to identify the underlying genetic mechanisms of a large autosomal dominant Caucasian family with omphalocele. METHODS AND FINDINGS: A genetic linkage study was conducted in a large family with an autosomal dominant transmission of an omphalocele using a genome-wide single nucleotide polymorphism (SNP) array. The analysis revealed significant evidence of linkage (non-parametric NPL = 6.93, p=0.0001; parametric logarithm of odds (LOD) = 2.70 under a fully penetrant dominant model) at chromosome band 1p31.3. Haplotype analysis narrowed the locus to a 2.74 Mb region between markers rs2886770 (63014807 bp) and rs1343981 (65757349 bp). Molecular characterisation of this interval using array comparative genomic hybridisation followed by quantitative microsphere hybridisation analysis revealed a 710 kb duplication located at 63.5 64.2 Mb. All affected individuals who had an omphalocele and shared the haplotype were positive for this duplicated region, while the duplication was absent from all normal individuals of this family. Multipoint linkage analysis using the duplication as a marker yielded a maximum LOD score of 3.2 at 1p31.3 under a dominant model. The 710 kb duplication at 1p31.3 band contains seven known genes including FOXD3, ALG6, ITGB3BP, KIAA1799, DLEU2L, PGM1, and the proximal portion of ROR1. Importantly, this duplication is absent from the database of genomic variants. CONCLUSIONS: The present study suggests that development of an omphalocele in this family is controlled by overexpression of one or more genes in the duplicated region. To the authors' knowledge, this is the first reported association of an inherited omphalocele condition with a chromosomal rearrangement. PMID- 22499348 TI - Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. AB - BACKGROUND: Next generation sequencing has become the core technology for gene discovery in rare inherited disorders. However, the interpretation of the numerous sequence variants identified remains challenging. We assessed the application of exome sequencing for diagnostics in complex I deficiency, a disease with vast genetic heterogeneity. METHODS: Ten unrelated individuals with complex I deficiency were selected for exome sequencing and sequential bioinformatic filtering. Cellular rescue experiments were performed to verify pathogenicity of novel disease alleles. RESULTS: The first filter criterion was 'Presence of known pathogenic complex I deficiency variants'. This revealed homozygous mutations in NDUFS3 and ACAD9 in two individuals. A second criterion was 'Presence of two novel potentially pathogenic variants in a structural gene of complex I', which discovered rare variants in NDUFS8 in two unrelated individuals and in NDUFB3 in a third. Expression of wild-type cDNA in mutant cell lines rescued complex I activity and assembly, thus providing a functional validation of their pathogenicity. Using the third criterion 'Presence of two potentially pathogenic variants in a gene encoding a mitochondrial protein', loss of-function mutations in MTFMT were discovered in two patients. In three patients the molecular genetic correlate remained unclear and follow-up analysis is ongoing. CONCLUSION: Appropriate in silico filtering of exome sequencing data, coupled with functional validation of new disease alleles, is effective in rapidly identifying disease-causative variants in known and new complex I associated disease genes. PMID- 22499350 TI - A novel decanuclear Co(II) cluster with adamantane-like metallic skeleton supported by 8-hydroxyquinoline and in situ formed CO3(2-) anions. AB - A novel decanuclear Co(II) cluster, [Co(10)(Q)(12)(MU(6)-CO(3))(4)].2.5DMF (1) (Q = 8-hydroxyquinoline), has been synthesized under solvothermal conditions and characterized by powder XRD, TGA and IR spectroscopy. Single-crystal X-ray diffraction analysis shows that 1 represents a new type of decanuclear cobalt cluster with an approximate supertruncated tetrahedral shape coordinated with coexisted Q ligands and in situ formed MU(6)-bridging CO(3)(2-) anions. Meanwhile, 1 is the largest aggregate in metal-Q coordination chemistry. Another distinguishing feature of 1 is the adamantane-like metallic skeleton with point symbol {6(3)}(2){6}(3), which is observed in the polynuclear metal complexes for the first time. Furthermore, it is considered that the in situ formed CO(3)(2-) anions have a crucial effect on the formation of the resultant unexpected polynuclear structures. The magnetic studies show that antiferromagnetic (AF) interactions exist within 1. PMID- 22499351 TI - One-step seeded growth of Au nanoparticles with widely tunable sizes. AB - A one-step seeded growth process has been developed for the synthesis of Au nanoparticles with tunable diameters from ~10 nm to ~200 nm. The delicately designed growth system suppresses self-nucleation by stabilizing a concentrated growth solution with strong coordinating ligands, leading to precise size control and convenient, scalable fabrication of Au nanoparticles. PMID- 22499352 TI - Ultrafast vibrational dynamics of SCN(-) and N3(-) in polar solvents studied by nonlinear infrared spectroscopy. AB - In this paper, we report on our investigation into the vibrational dynamics of the antisymmetric stretching modes of SCN(-) and N(3)(-) in several polar solvents. We used an infrared (IR) pump-probe method to study orientational relaxation processes. In two aprotic solvents (N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO)), the anisotropy decay shows a bimodal feature, whereas in other solvents the anisotropy decay can be fitted well by a single exponential function. We consider that the relative contribution of fast-decaying components is smaller in the other solvents than in DMF and DMSO. We discuss the possible origins of the different anisotropy decay behavior in different solvents. From the three-pulse IR photon echo measurements for SCN(-) and N(3)(-), we found that the time-correlation functions (TCFs) of vibrational frequency fluctuations decay on two different time scales, one of which is less than 100 fs and the other is approximately 3-6 ps. In aprotic solvents, the fast-decaying components of the TCFs on a <100 fs time scale play an important role in the vibrational frequency fluctuation, although the contribution of collective solvent reorganization in aprotic solvents was clearly observed to have small amplitudes. On the other hand, we found that the amplitude of components that decay in a few picoseconds and/or the constant offset of the TCF in protic solvents is relatively large compared with that in aprotic solvents. With the formation and dissociation of hydrogen bonds between ion solute and solvent molecules, the spectra of different solvated species are exchanged with each other and merged into one band. We considered that this exchange may be an origin of slow-decaying components of the TCFs and that the decay of the TCFs corresponds to the time scales of the exchange for protic solvents such as formamide. The mechanism of vibrational frequency fluctuations for the antisymmetric stretching modes of SCN(-) and N(3)( ) is discussed in terms of the difference between protic and aprotic solvents. PMID- 22499353 TI - Design, synthesis and biological evaluation of non-natural modulators of quorum sensing in Pseudomonas aeruginosa. AB - Many species of bacteria employ a mechanism of intercellular communication known as quorum sensing which is mediated by small diffusible signalling molecules termed autoinducers. The most common class of autoinducer used by Gram-negative bacteria are N-acylated-L-homoserine lactones (AHLs). Pseudomonas aeruginosa is a clinically important bacterium which is known to use AHL-mediated quorum sensing systems to regulate a variety of processes associated with virulence. Thus the selective disruption of AHL-based quorum sensing represents a strategy to attenuate the pathogenicity of this bacterium. Herein we describe the design, synthesis and biological evaluation of a collection of structurally novel AHL mimics. A number of new compounds capable of modulating the LasR-dependent quorum sensing system of P. aeruginosa were identified, which could have value as molecular tools to study and manipulate this signalling pathway. Worthy of particular note, this research has delivered novel potent quorum sensing antagonists, which strongly inhibit the production of virulence factors in a wild type strain of this pathogenic bacterium. PMID- 22499354 TI - Fabrication and characterization of novel nano hydroxyapatite/beta-tricalcium phosphate scaffolds in three different composition ratios. AB - The biphasic calcium phosphate (BCP) concept was introduced to overcome disadvantages of single phase biomaterials. Different composition ratios of BCP bioceramics have been studied, yet controversies regarding the effects of ratio on biomaterial behavior still exist. In this study, BCP scaffolds were prepared from nano hydroxyapatite (HA) and beta-tricalcium phosphate (beta-TCP) that were synthesized via a solid state reaction. Three different composition ratios of pure BCP and collagen-based BCP scaffolds (%HA/%beta-TCP; 30/70, 40/60, and 50/50) were produced using a polymeric sponge method. Physical and mechanical properties of all materials and scaffolds were investigated. SEM showed overall distribution of both macropores (80-200 MUm) and micropores (0.5-2 MUm) with high interconnected porosities. Total porosity of pure BCP (90% +/- 3%) was found to be higher than collagen-based BCP (85% +/- 2%). It was observed that following sintering process, dimensional shrinkage of large scaffolds (39% +/- 4%) was lower than small ones (42% +/- 5%) and scaffolds with high HA ratios (50%) experienced higher dimensional changes than those with higher beta-TCP (70%) ratios (45% +/- 3% and 36% +/- 1%, respectively). Compressive strength of both groups was less than 0.1 MPa and collagen coating had almost no influence on mechanical behavior. Further studies may improve the physical properties of these scaffolds and investigate their exact biological behaviors. PMID- 22499355 TI - Cost accounting method for cytometry facilities. PMID- 22499356 TI - Metal oxide thin film phototransistor for remote touch interactive displays. PMID- 22499357 TI - Hyperpolarized binding pocket nuclear Overhauser effect for determination of competitive ligand binding. PMID- 22499358 TI - p-Sulfonated calix[6]arene modified graphene as a 'turn on' fluorescent probe for L-carnitine in living cells. AB - p-Sulfonated calix[6]arene modified graphene has been firstly synthesized and provided as a 'turn on' probe for L-carnitine through monitoring the fluorescence signal both in vitro and in living cells. PMID- 22499359 TI - Indacaterol: a novel long-acting beta(2) -agonist. AB - Bronchodilator drugs are the foundation for the treatment of chronic obstructive pulmonary disease. The principal inhaled bronchodilator treatments used are beta(2) -agonists and anticholinergics, either alone or in combination. Currently available beta(2) -agonists are of either short duration and used multiple times/day, or of long duration, which requires twice-daily administration. Indacaterol is considered an ultra-long-acting beta(2) -agonist and was recently approved for use in the United States. Its duration of action is approximately 24 hours, allowing for once-daily administration. Cough was the most commonly reported adverse effect with use of indacaterol. Cough usually occurred within 15 seconds of inhalation of the drug, lasted around 6 seconds, was not associated with bronchospasm, and did not cause discontinuation of the drug. Otherwise, the drug's safety profile was similar to that of other bronchodilators. Based on similar improvement in spirometric measurements compared with other bronchodilator drugs and the convenience of its once-daily dosing, indacaterol may be beneficial in the management of mild-to-moderate chronic obstructive pulmonary disease, either alone or in combination with anticholinergic drugs administered once/day. PMID- 22499360 TI - Calix[4]arene-based metal-organic frameworks: towards hierarchically porous materials. AB - An upper rim-functionalised calix[4]arene dicarboxylic acid (H(2)caldc) has been used to prepare four metal-organic frameworks, three of which have been structurally characterised and shown to form two- or three-dimensional network structures. Simulations suggest that such networks are likely to display interesting selectivity to guest molecules. PMID- 22499361 TI - Dermal absorption of finite doses of volatile compounds. AB - Laplace domain solutions to a previously published finite dose skin diffusion model are presented. The purpose of the current analysis is to derive a simple algebraic expression quantifying the total mass that is systemically absorbed at infinite time after exposure, relative to the applied mass. The resulting expression is a function of two dimensionless parameters: f, the fractional depth within the skin surface through which the permeant is initially deposited, and chi, the ratio of maximum evaporation flux to maximum dermal flux. The result may be useful for dermal risk assessment as well as in the evaluation of cosmetic and pharmaceutical product performance. PMID- 22499362 TI - Antibiotics: from use to abuse. PMID- 22499363 TI - Neck dissection in squamous cell carcinoma of the larynx: indication of elective contralateral neck dissection. AB - Unilateral or bilateral neck dissection must be considered in the treatment of laryngeal cancer AIM: To evaluate the prevalence of contralateral metastases in larynx cancer and distribution of these metastases according to lymph node levels in the neck. METHOD: Retrospective longitudinal study of 272 charts from patients with squamous cell cancer of the larynx treated between 1996 and 2004; and we selected 104 surgical cases submitted to neck dissection. We evaluated the incidence of bilateral or contralateral metastases, according to the location and extension of the primary tumor, considering the anatomical sub-sites and the midline. RESULTS: Contralateral metastases in lateral tumors were observed in 3.5% of glottic lesions and in 26% of supraglottic lesions. Contralateral metastases were uncommon in N0 patients. Lymph nodes levels IIa and III were the most commonly involved in the neck. CONCLUSION: In lateral glottic tumors there is no need for elective contralateral neck dissection. In supraglottic lesions without ipsilateral metastases, the incidence of hidden metastasis does not justify elective contralateral dissection. The midline is not a reliable indicator of the risk of contralateral laryngeal tumors. PMID- 22499364 TI - Result on speech perception after conversion from Spectra(r) to Freedom(r). AB - New technology in the Freedom(r) speech processor for cochlear implants was developed to improve how incoming acoustic sound is processed; this applies not only for new users, but also for previous generations of cochlear implants. AIM: To identify the contribution of this technology-- the Nucleus 22(r)--on speech perception tests in silence and in noise, and on audiometric thresholds. METHODS: A cross-sectional cohort study was undertaken. Seventeen patients were selected. The last map based on the Spectra(r) was revised and optimized before starting the tests. Troubleshooting was used to identify malfunction. To identify the contribution of the Freedom(r) technology for the Nucleus22(r), auditory thresholds and speech perception tests were performed in free field in sound proof booths. Recorded monosyllables and sentences in silence and in noise (SNR = 0dB) were presented at 60 dBSPL. The nonparametric Wilcoxon test for paired data was used to compare groups. RESULTS: Freedom(r) applied for the Nucleus22(r) showed a statistically significant difference in all speech perception tests and audiometric thresholds. CONCLUSION: The Freedom(r) technology improved the performance of speech perception and audiometric thresholds of patients with Nucleus 22(r). PMID- 22499365 TI - Traumatic bone cyst of the mandible: a review of 26 cases. AB - The traumatic bone cyst is characterized by the presence of an asymptomatic sinus devoid of epithelial lining, which is rarely found in the jaws. OBJECTIVE: To describe the clinical, surgical and radiographic findings of traumatic bone cysts. MATERIAL AND METHOD: A retrospective study was made of patients diagnosed with traumatic bone cysts at an oral pathology department from 1992 to 2007. Data on the clinical, radiographic and surgical complications were gathered. RESULTS: Twenty-six cases of traumatic bone cyst were diagnosed in 15 years; 17 were male and 09 were female. Most patients were within first two decades of life and had no pain or history of trauma in the affected area. The multilocular pattern was observed in only seven cases, its radiographic appearance suggests a tumor. Air was found inside the lesion in about 70% of cases; serous fluid with blood and blood only were uncommon within the lesions. CONCLUSION: A higher prevalence in young patients, absence of a history of trauma, and a small number of lesions containing serous fluid with blood reflects the need to discuss the true pathogenesis of traumatic bone cysts. PMID- 22499366 TI - Prognostic significance of the number of lymph nodes in elective neck dissection for tongue and mouth floor cancers. AB - The presence of metastatic lymph nodes is a relevant aspect in the treatment of head and neck cancer, bringing about a 50% reduction in survival. OBJECTIVE: To assess the number of lymph nodes removed in the neck dissection and their relationship with the prognosis. METHODS: A retrospective study involving 143 patients with tongue and mouth floor epidermoid carcinoma, which histological exam showed no lymph node metastases. Among those, 119 were males and 24 females, with mean age of 54 years. As to the primary tumor site, 65 were in the tongue and 78 in the mouth floor. T stage distribution was of four T1, 84 T2, 36 T3 and 19 T4. We carried out 176 neck dissections, unilateral in 110 cases and bilateral in 33. Of these, 78 were radical and 98 selective. The patients were broken down into three groups, according to the 33 and 66 percentiles of the number of lymph nodes resected. RESULTS: The mean number of resected lymph nodes was 27; 24 in selective dissections and 31 in the complete ones. We did not have statistically significant differences when associated to the T and N stages. CONCLUSIONS: The larger number of lymph nodes dissected in the neck dissection identifies the group of better prognoses among pN0 cases. PMID- 22499367 TI - Study of the prevalence of impaired hearing and its determinants in the city of Itajai, Santa Catarina State, Brazil. AB - The number of people with impaired hearing is increasing; knowing its magnitude is essential for public health. OBJECTIVE: To study the prevalence and determinants of impaired hearing in Itajai/SC. METHODS: A population-based survey based on a World Health Organization protocol. Field research was carried out from July 2008 to 2011. Procedures for evaluating hearing in households: questionnaire, measurement of noise, otoscopy, pure tone audiometry at 1000, 2000, and 4000 Hz, tympanometry, and acoustic reflexes: individuals above 4 years; children under 4 years: evoked otoacoustic emissions (OAE), cocleo palpebral reflex(CPR), tympanometry, and acoustic reflexes. In the elderly population a questionnaire of perception of hearing loss was applied. RESULTS: The study sample consisted of 379 individuals--45.38% were males and 54.62% were females. Age-range: 11.34% up to 10 years; 64.39% 10 to 60 years, 24.27% over 60 years. Evaluation of the best hearing ear showed that 74.1% of residents had normal hearing, 18.9% had mild hearing loss, 5.1% had moderate hearing loss, 1.9% had severe hearing loss. Disabling impaired hearing was detected in 26 subjects: one child (otitis media); four adults (one otitis, one noise-induced, two idiopathic); 21 elderlies (presbyacusis). Of eight children under 4 years all presented CPR, three were normal examinations, two had absent OAE bilaterally, one had absent OAE in the right ear and one in the left ear. CONCLUSION: The prevalence of disabling impaired hearing in Itajai was 7%; the highest prevalence was in the 50-year and above age group--the main cause was presbyacusis. PMID- 22499368 TI - Chronic rhinitis in HTLV-1 carriers: a histopathologic study. AB - The nasal histopathology of HTLV-1 carriers with chronic rhinitis is unknown. OBJECTIVE: To describe the histopathological features of HTLV-1 carriers with chronic rhinitis. MATERIALS AND METHODS: Biopsies of nasal mucosa of ten HTLV-1 carriers with chronic rhinitis (eight patients with allergic rhinitis and two patients with non-allergic rhinitis) were studied using a light microscope. Samples from ten patients with allergic rhinitis not infected with HTLV-1 were used as controls. RESULTS: Subepithelial fibrosis was more pronounced in patients with allergic rhinitis infected with HTLV-1 (p=0.01), while the basement membrane thickness was greater in controls (p=0.03). There was a trend towards less eosinophilia and edema among those infected with HTLV-1, without statistical significance (p=0.2). For the lymphocytic infiltrate, there was no difference between infected and not infected patients with allergic rhinitis (p=1.0). Subepithelial fibrosis associated to moderate or small number of lymphocytes were found in the two HTLV-1 carriers with non-allergic rhinitis. CONCLUSIONS: This study suggests HTLV-1 may modify the histopathology of allergic rhinitis, especially by promoting subepithelial fibrosis, and may be related to chronic non allergic rhinitis with lymphocytic infiltrate. PMID- 22499369 TI - Objective computerized evaluation of normal patterns of facial muscles contraction. AB - Different methods used to evaluate the movements of the face have many degrees of subjectivity and reliability. The authors discuss the ease of using these methods in clinical practice or their accuracy in scientific research. AIM: To obtain the standard for normal facial muscles movements using an objective method - the Vicon system. MATERIALS AND METHODS: Light reflective markers were placed at points of interest on the face of 12 normal subjects. The movements were captured by cameras that sent the images to a computer. The points' displacements were measured between rest and maximum muscle contraction; and we calculated the means and the standard deviations (SD) were calculated. RESULTS: When smiling, the variation of the oral commissures was between 6.45 and 12.11 mm, mean of 9.28 mm and SD od 2.83; for lifting the eyebrow, it is between 6.0 and 13.08 mm, mean of 10.57 mm and SD of 2.51; for eyelids movement there was a variation of 6.89 and 11.29 mm, with a mean value of 9.09 mm and SD of 2.20; for the movement of wrinkling the forehead, the results showed a variation of 4.16 and 10.85 mm, with a mean value of 7.56 and SD of 3.29. CONCLUSION: The authors obtained normal patterns for facial muscle contraction. PMID- 22499370 TI - Assessing cochlear evoked potentials after electrocautery-induced trauma to the utricle. AB - Utriculostomy is a new surgical alternative for Meniere's disease. The basis of this procedure is that the outcome of an electrocautery-induced utricular trauma does not affect cochlear function. However, a demonstration of the hypothesis that this approach to the utricle would preserve hearing is still pending. OBJECTIVE: To determine whether any changes would occur in the electrical potentials evoked in the cochlea and auditory nerve before, during, and 1 month after a surgical procedure in the utricule in an animal model. MATERIALS AND METHODS: An experimental study. Eight sheep underwent electrocautery-induced utricular trauma, and their cochlear function was assessed by electrocochleography--recording of electrical evoked potentials, in the preoperative, immediate postoperative and medium-term postoperative periods. The results were analyzed statistically. RESULTS: There were no statistically significant variations in amplitude (p = 0.099) and latency (p = 0.591) before and 1 month after the surgical procedure. There was a statistically significant change in the summation of the potential/action potential area ratio (p = 0.0122), a calculated loss of 11.8 dB. CONCLUSION: The intervention performed in this study enabled us to conclude that, taking into account the impaired electrophysiological responses observed during and 1 month after the surgical procedure, hearing was preserved in the operated sheep. PMID- 22499371 TI - Tinnitus in individuals without hearing loss and its relationship with temporomandibular dysfunction. AB - Research has shown that dysfunction of the temporomandibular joint is often associated with tinnitus. AIM: To characterize tinnitus in individuals with normal hearing and search for a possible relationship with Temporomandibular Disorders (TMD). STUDY DESIGN: prospective and cross-sectional. MATERIALS AND METHODS: The participants included 20 adults of both genders with tinnitus and normal hearing thresholds on audiometry. We studied tinnitus psychoacoustic characteristics and employed the checklist of TMD signs and symptoms from the Tinnitus Handicap Inventory (THI). RESULTS: The high pitch, continuous and bilateral tinnitus was the most frequent. Upon acuphenometry, the average tinnitus pitch reported by the subjects was 8.6 kHz and the average loudness was 14.1 dBSL. The degree of discomfort caused by tinnitus was mild. We observed that the higher the pitch, the lower was the loudness and the higher was the THI score. We found that 90% of the patients had at least one TMD sign or symptom. CONCLUSIONS: The most common was the high pitch, continuous and bilateral tinnitus; 90% of patients had at least one sign or symptom of TMD and there was no correlation between the tinnitus and acuphenometry, THI and the TMD checklist. PMID- 22499372 TI - Oral infection by the Human Papilloma Virus in women with cervical lesions at a prison in Sao Paulo, Brazil. AB - Carcinoma of the head and neck is the 6th cause of death by cancer in the world. In recent decades the human papillomavirus (HPV) has been implicated in the etiology of this disease. OBJECTIVE: To characterize the types of HPV detected in the oral mucosa in women with cytological abnormalities suggesting intraepithelial squamous lesions in the uterine cervix. METHODS: Four-hundred nine cervical-vaginal and oral pap-smears of women interned in a Female Prison in Sao Paulo were examined. The relationship between cervical and oral lesion was analyzed by PCR/RFLP and DNA sequencing. RESULTS: Of 27 (6.67%) specimens showing cervical cytological abnormalities suggesting LSIL and HSIL, 22 (81.48%) had oncogenic high-risk HPV infection, of which HPV 59 was the most prevalent. Three (11.1%) samples showed cytological changes suggesting mild dysplasia in the oral cavity. CONCLUSION: Our study suggests an association between carcinoma of the oral cavity and HPV infection, regardless of the virus type. PMID- 22499373 TI - The effectiveness of audiometric evaluation in drug treatment for otospongiosis. AB - Otospongiosis is a primary osteodystrophy of the otic capsule that affects genetically predisposed individuals and leads to a progressive hearing loss. AIM: To evaluate the applicability of audiometric evaluation during drug treatment for otospongiosis. MATERIALS AND METHODS: A prospective, randomized, controlled, double-blind study involving 26 patients with clinical, audiometric and CT scan image of otosclerosis. Patients eligible for the study were divided into three groups (A, B and C) and received treatment with alendronate sodium (B), sodium fluoride (C) and placebo (A) for 6 months. After this period they were submitted to new tests. RESULTS: There were not statistically significant differences between air and bone conduction (gap). We also found no differences in the speech recognition threshold (SRT) and speech discrimination (IRF) between before and after treatment. CONCLUSION: After six months of drug treatment the audiometric evaluation kept the same hearing thresholds, suggesting stabilization of the otospongiotic lesions. PMID- 22499374 TI - Mastoiditis and facial paralysis as initial manifestations of Wegener's Granulomatosis. AB - Wegener's Granulomatosis (WG) is characterized by necrotizing granulomas and vasculitis. If left untreated, the prognosis is poor--a 90% mortality rate within 2 years. Several authors have described the otologic manifestations of WG; these authors, however, have not mentioned the stage of the disease in which these findings present--whether as initial manifestations or subsequent to other findings. AIM: To describe three confirmed cases of WG with mastoiditis as the first manifestation, progressing to peripheral facial paralysis (PFP). MATERIAL AND METHOD: A clinical series study. Patients diagnosed with WG that initially presented with otologic findings are described. RESULTS: The three cases presented with unilateral otalgia, otorrhea, and hearing loss associated with ipsilateral PFP. None recovered in spite of the treatment; an investigation of associated diseases was therefore undertaken. Positive ANCA-C titers where detected in all patients, confirming the diagnosis of WG. Clinical improvement was seen after treatment of WG; the PFP regressed and hearing thresholds improved partially. CONCLUSION: Complications of otitis media (mastoiditis and PFP) that do not respond to the usual treatment require an investigation of associated diseases; WG should be included for an early diagnosis to change the prognosis in these patients. PMID- 22499375 TI - Cognitive processing and body balance in elderly subjects with vestibular dysfunction. AB - Abnormal body balance and cognitive dysfunction may develop in elderly patients with chronic vestibular dysfunction. AIM: To evaluate the relationship between cognitive processing and body balance in elderly patients with chronic peripheral vestibular disease. TYPE OF STUDY: Cross-sectional. METHODS: Seventy-six patients (> 60 years) with chronic peripheral vestibular dysfunction and dizziness for more than three months were enrolled. The tests for investigating body balance were: the Berg Balance Scale (BBS), Dynamic Gait Index (DGI), Timed Up and Go Test (TUGT) Timed Up and Go Test modified (TUGTm); the Mini Mental State Examination (MMSE), Test Clock (RT,) and Verbal Fluency Test (VF) were applied for assessing cognition. RESULTS: The mean age was 69.03 years (SD=6.21 years); most were female (82.9%). There was a significant negative correlation between the MMSE and the TUGT (rho=-0.312; p=0.01), MMSE and TUGTm (rho=-0.306; p=0.01), FV and TUGT (rho=-0.346; p=0.01), and FV and TUGTm (rho=-0.536; p=0.01); there was a significant positive correlation between the TR and BBS (rho=0.343; p=0.01), TR and DGI (rho=0.298; p=0.01), FV and BBS (rho=0.299; p=0.01), and FV and DGI (rho=0.306; p=0.01). CONCLUSION: Elderly patients with chronic peripheral vestibular disease and worse performance in body balance tests have functional impairment in cognitive skills. PMID- 22499376 TI - Assessment of quality of life after endoscopic sinus surgery for chronic rhinosinusitis. AB - Chronic rhinosinusitis is a disease of undefined etiology that significantly impacts the quality of life of its patients. Various studies carried out in countries other than Brazil have shown endoscopic sinus surgery as an effective means of treating this condition. OBJECTIVE: This study aims to analyze, with the aid of SNOT-20, the association between endoscopic sinus surgery and disease specific quality of life of Brazilian patients treated for chronic rhinosinusitis accompanied or not by nasal polyps. MATERIALS AND METHODS: This prospective study enrolled patients submitted to endoscopic sinus surgery after drug therapy failed to improve their symptoms. They were assessed based on questionnaire SNOT-20p before and 12 months after surgery. Improvement on total scores and on the five items deemed more important by each patient were assessed. The study also looked into the correlation between preoperative scores and postoperative improvement and if there were any gender-related improvement differences. RESULTS: Forty three patients aged 44 (19), md (IQR), 65% of whom (26/43) were males. Statistically significant improvement was seen on SNOT-20 and SNOT-20(5+) and a correlation was established between preoperative scores and postoperative improved scores (p<0.001). No gender-related differences were observed in quality of life. CONCLUSION: Endoscopic sinus surgery in patients with chronic rhinosinusitis is associated with statistically significant improvements in disease-specific quality of life. PMID- 22499377 TI - Cochlear implant in postlingual children: functional results 10 years after the surgery. AB - The benefits of cochlear implants (CI) for communication skills are obtained over the years. There are but a few studies regarding the long-term outcomes in postlingual deaf children who grew up using the electronic device. AIM: To assess the functional results in a group of postlingual children, 10 years after using a CI. METHODS: Ten postlingual deaf children, implanted before 18 years of age, participated in this study. We assessed: sentence recognition and speech intelligibility. We documented: device use and function and the patient's academic/occupational status. STUDY DESIGN: series. RESULTS: The mean scores were 73% for sentence recognition in silence and 40% in noise. The average write-down intelligibility score was 92% and the average rating-scale intelligibility score was 4.15. There were no cases of device failure. Regarding educational/vocational status, three subjects graduated from the University. Five quit education after completing high school. Eight subjects had a professional activity. CONCLUSION: This study showed that cochlear implantation is a safe and reliable procedure. The postlingual profoundly hearing-impaired children after 10 years of CI use developed satisfactory levels regarding speech perception and intelligibility, and completed at least high school and were inserted in the labor market. PMID- 22499378 TI - Study of craniofacial alterations and of the importance of the rapid maxillary expansion after tonsillectomy. AB - Obstructive hypertrophy of the tonsils and/or adenoids is associated with mouth breathing and can lead to facial imbalances. Adenotonsillectomy is not enough to treat the anatomic changes. Facial orthopedic techniques aid in morphological and functional recovery. This prospective longitudinal clinical study aimed to observe craniofacial changes after adenotonsillectomy and to verify the importance of linking rapid maxillary expansion to treatment. METHOD: Fifty-three children of both genders, aged 6 to 12 years, were allocated to: Group 1, 20 children with nasal breathing; and group 2, 33 children with obstructive hypertrophy of pharyngeal and/or palate undergoing adenotonsillectomy. After surgery, this group was subdivided into Group 2A, 16 patients not treated with rapid maxillary expansion; and Group 2B, 17 patients treated with maxillary rapid expansion. Frontal and lateral cephalometric measurements were made prior to surgery and after 14 months. Statistical analysis used the Kruskal-Wallis and Wilcoxon tests--significance level of 5%. RESULTS: Adenotonsillectomy balanced transversal, sagittal and vertical growth in both groups, and was more effective in the group undergoing combined treatment. CONCLUSIONS: Adenotonsillectomy improved the facial growth of children with obstructive hypertrophy, which was more evident when associated with rapid maxillary expansion. PMID- 22499379 TI - Transcanal cochleostomy in cochlear implant surgery: long-term results of a cohort study. AB - The combined approach technique (CAT) is a variation of the classical the mastoidectomy-posterior tympanotomy technique (MPTA) that combines a transcanal approach to cochleostomy with a reduced posterior tympanotomy for insertion of electrodes. AIM: To compare and evaluate long-term safety and effectiveness outcomes obtained with the CAT and with MPTA approach in patients submitted to cochlear implant (CI) surgery. DESIGN: series study. METHODS: Patients who underwent CI using CAT or MPTA at a Brazilian center were followed in a cohort study. Main outcomes were complications,audiometric performance and radiological evaluation of electrode position. RESULTS: Fourty-four patients were implanted using CAT and 31 MPTA. There were no cases of facial nerve paralysis, mastoiditis, cholesteatoma or cerebrospinal fluid leaks after 3.4+/-1.0 years. Radiological evaluation of electrode position revealed that the median number of electrodes outside the cochlea was 0 in CAT and 3 in MPTA groups (p < 0.001). There were no differences between both surgical approaches in terms of mean pure tone thresholds with CI at all frequencies. CONCLUSION: Long-term follow-up data showed that the transcanal route to cochleostomy, combined with a reduced posterior tympanotomy, is a safe alternative approach in cochlear implant surgery, with no related major complications and fewer cases of electrode migration when compared with the MPTA. These findings encourage the use of the transcanal route to cochleostomy as an alternative approach option. PMID- 22499380 TI - Post-lingual deafness: benefits of cochlear implants vs. conventional hearing aids. AB - The technological advances in cochlear implants and processing strategies have enabled subjects affected by severe to profound hearing loss to hear sounds and recognize speech in various different degrees. The variability of hearing outcomes in subjects with post-lingual deafness has been significant and cochlear implant indications have been extended to include an ever larger population. OBJECTIVE: This paper aims to look into the groups of post-lingual deafness patients to find where cochlear implants have yielded better outcomes than conventional hearing aids. MATERIALS AND METHODS: Review the literature available on databases SciELO, Cochrane, MEDLINE, and LILACS-BIREME. The publications selected for review were rated as A or B on evidence strength on the day of the review. Their authors analyzed and compared hearing aids and cochlear implants in populations of post-lingually deaf patients. STUDY DESIGN: Systematic review. RESULTS: Eleven out of the 2,169 papers searched were found to be pertinent to the topic and were rated B for evidence strength. Six studies were prospective cohort trials, four were cross-sectional studies and one was a clinical trial. CONCLUSION: The assessment done on the benefits yielded by post-lingually deaf subjects from cochlear implants showed that they are effective and provide for better results than conventional hearing aids. PMID- 22499381 TI - Research ethics in animal models. AB - The use of animals in scientific experiments has been described since the fifth century BC. A number of scientific advances in health are attributed to animal models. The issue of the moral status of animals has always been debated. OBJECTIVES: This article aims to review and to present a historical summary of the current laws, to guide researchers who wish to use animal models in otolaryngology research. MATERIAL AND METHODS: Research on the medline database. RESULTS: For many years there were no laws ruling the use of animals in scientific experimentation in Brazil. Standards set by national and international organizations were followed. Recently, Law No. 11.794/08 established procedures for the scientific use of animals. Studies in otolaryngology have used the larynxes of rabbits, pigs, dogs, guinea pigs (Cavia porcellus), and mice. There were also studies comparing rabbits, rats, and dogs, rhinoplasty on rabbits, and inner ear studies on rats and guinea pigs (albino). CONCLUSIONS: The researchers involved in scientific work with animals should know the principles of Law 11.794/08 and investigate what animals are appropriate for each area of study in their models. Otolaryngologists, especially those dedicated to research, need to be mindful of the ethical rules regarding the use of animals in their studies. PMID- 22499382 TI - Extranasal epistaxis: a diagnostic challenge. PMID- 22499383 TI - Mandibular simple bone cysts: a rare case of bilateral occurrence. PMID- 22499384 TI - A rare case of chronic stridor and dysphonia in an adult patient. PMID- 22499385 TI - Hemangiopericytoma of the tongue. PMID- 22499386 TI - Efficient transfection of MG-63 osteoblasts using magnetic nanoparticles and oscillating magnetic fields. AB - AIMS: To examine the potential of magnetic nanoparticles (MNPs) in transfecting human osteosarcoma fibroblasts (MG-63) and investigate the effects of a novel non viral oscillating nanomagnetic gene transfection system (magnefect-nanoTM) in enhancing transfection efficiency (TE). METHODS: MG-63 cells were transfected using MNPs coupled with a GFP-carrying plasmid. The magnefect-nano system was evaluated for transfection efficiency and potential associated effects on cell viability. RESULTS: MG-63 cells were efficiently transfected using MNPs and the magnefect-nano system significantly enhanced overall transfection efficiency. MNPs were not found to affect cell viability and/or function of the cells. CONCLUSION: Non-viral transfection using MNPs and the magnefect-nano system can be used to transfect MG-63 cells and assist reporter gene delivery on a single cell basis, highlighting the wide potential of nanomagnetic gene transfection in gene therapy. PMID- 22499387 TI - Air-bridged Ohmic contact on vertically aligned si nanowire arrays: application to molecule sensors. AB - A simple, cost-effective, and highly reliable method for constructing an air bridged electrical contact on large arrays of vertically aligned nanowires was developed. The present method may open up new opportunities for developing advanced nanowire-based devices for energy harvest and storage, power generation, and sensing applications. PMID- 22499388 TI - Caffeine in Parkinson's disease: comment on its importance and the dose proposal. PMID- 22499389 TI - Automated measurement of MIB-1 positive area as an alternative to counting in follicular lymphoma. AB - Manual counting of MIB-1 positive cells which has been suggested as an alternative to centroblast counting for the diagnostic grading of follicular lymphoma is a laborious task. In this study, the validity of automated measurement of the MIB-1 positive area is analyzed as an alternative approach. Archival MIB-1 stained tissue sections of 15 follicular lymphomas were assessed manually and automatically by three independent observers. Concordance correlation coefficients and coefficients of variation were calculated to study reproducibility and variability of both methods and to compare result from both methods. A good concordance was observed between the two methods. The reproducibility of the automated method was slightly better than the manual counting of positive nuclei. Measurement of MIB-1 positive surface area may be used as a simple and fast alternative to tedious manual counting of positive nuclei as a potential help in follicular lymphoma grading. PMID- 22499390 TI - Asymmetric organocascades involving the formation of two C-heteroatom bonds from two distinct heteroatoms. AB - In the vast and expanding world of enantioselective organocascades, the ones in which two C-heteroatom bonds are created from two distinct heteroatoms are rare. These fascinating domino processes constitutes real synthetic challenges and allow very convenient syntheses of diverse optically active heterocycles and also highly functionalised acyclic derivatives. PMID- 22499391 TI - Reactivity of surfaces determined by local electrochemical triggering: a bromo terminated self-assembled monolayer. PMID- 22499392 TI - The in vivo osteogenesis of Mg or Zr-modified silicate-based bioceramic spheres. AB - The use of bioactive microspheres as bone filling materials has received much attention due to their ability to fill the bone defects with irregular and complex shapes and sizes. Divalent Mg(2+) modified silicate-based diopside (DIOP: CaMgSi(2)O(6)) and tetravalent Zr(4+) modified silicate-based baghdadite (BAGD: Ca(3)ZrSi(2)O(9)) ceramics have shown excellent in vitro bioactivity for potential bone repair application. However, their in vivo osteogenesis has not been systematically investigated. The aim of this study is to prepare DIOP and BAGD ceramic microspheres and investigate their in vivo osteogenesis. DIOP and BAGD ceramic spheres with loose microstructure were successfully prepared. The dissolution ability of two silicate-based bioceramics was investigated by testing the release of SiO 44- ions after soaking them in phosphate buffered saline. The ceramic spheres were implanted into supracondylar site of the femur defects in Wistar rats and the degree of in vivo osteogenesis was evaluated by hematoxylin and eosin (H and E), Safranin O staining, tartrate-resistant acid phosphatase (TRAP) staining, and immunohistochemistry (type I collagen: Col I, osteopontin: OPN) analyses. The results have shown that BAGD spheres induced a higher rate of new bone formation in the defects than did DIOP and beta-tricalcium phosphate (beta-TCP) spheres. Immunohistochemical analysis showed greater expression of Col I and OPN in BAGD group compared to DIOP and beta-TCP groups. The study indicates different ion modification playing an important role to regulate the in vivo osteogenesis of silicate-based bioceramics. BAGD spheres are a promising bone filler material due to their significantly enhanced osteogenesis, compared to beta-TCP spheres. PMID- 22499393 TI - Structural variability in transition metal oxide clusters: gas phase vibrational spectroscopy of V3O(6-8)+. AB - We present gas phase vibrational spectra of the trinuclear vanadium oxide cations V(3)O(6)(+).He(1-4), V(3)O(7)(+).Ar(0,1), and V(3)O(8)(+).Ar(0,2) between 350 and 1200 cm(-1). Cluster structures are assigned based on a comparison of the experimental and simulated IR spectra. The latter are derived from B3LYP/TZVP calculations on energetically low-lying isomers identified in a rigorous search of the respective configurational space, using higher level calculations when necessary. V(3)O(7)(+) has a cage-like structure of C(3v) symmetry. Removal or addition of an O-atom results in a substantial increase in the number of energetically low-lying structural isomers. V(3)O(8)(+) also exhibits the cage motif, but with an O(2) unit replacing one of the vanadyl oxygen atoms. A chain isomer is found to be most stable for V(3)O(6)(+). The binding of the rare gas atoms to V(3)O(6-8)(+) clusters is found to be strong, up to 55 kJ/mol for Ar, and markedly isomer-dependent, resulting in two interesting effects. First, for V(3)O(7)(+).Ar and V(3)O(8)(+).Ar an energetic reordering of the isomers compared to the bare ion is observed, making the ring motif the most stable one. Second, different isomers bind different number of rare gas atoms. We demonstrate how both effects can be exploited to isolate and assign the contributions from multiple isomers to the vibrational spectrum. The present results exemplify the structural variability of vanadium oxide clusters, in particular, the sensitivity of their structure on small perturbations in their environment. PMID- 22499394 TI - Graphene oxide versus functionalized carbon nanotubes as a reinforcing agent in a PMMA/HA bone cement. AB - Graphene oxide (GO) and functionalized carbon nanotubes (f-CNTs) (each in the concentration range of 0.01-1.00 wt/wt%) were investigated as the reinforcing agent in a poly(methyl methacrylate) (PMMA)/hydroxyapatite (HA) bone cement. Mixed results were obtained for the changes in the mechanical properties determined (storage modulus, bending strength, and elastic modulus) for the reinforced cement relative to the unreinforced counterpart; that is, some property changes were increased while others were decreased. We postulate that this outcome is a consequence of the fact that each of the nanofillers hampered the polymerization process in the cement; specifically, the nanofiller acts as a scavenger of the radicals produced during polymerization reaction due to the delocalized pi-bonds. Results obtained from the chemical structure and polymer chain size distribution determined, respectively, by nuclear magnetic resonance and size exclusion chromatography analysis, on the polymer extracted from the specimens support the postulated mechanism. Furthermore, in the case of the 0.5 wt/wt% GO-reinforced cement, we showed that when the concentration of the radical species in the PMMA bone cement was doubled, mechanical properties markedly improved (relative to the value in the unreinforced cement), suggesting suppression of the aforementioned scavenger activity. PMID- 22499395 TI - Unprecedented synthesis of iron-NHC complexes by C-H activation of imidazolium salts. Mild catalysts for reduction of sulfoxides. AB - A direct synthesis of bidentate cyclopentadienyl-functionalised NHC-iron(II) complexes by using imidazolium salts and commercially available Fe(3)(CO)(12) is developed. These well-defined iron-NHC complexes efficiently catalyse the reduction of sulfoxides under mild conditions. Radical scavenging experiments indicate the presence of free radicals in the catalytic reaction. PMID- 22499396 TI - A novel quinoline-based two-photon fluorescent probe for detecting Cd2+ in vitro and in vivo. AB - A new two-photon fluorescent Cd(2+) probe APQ is developed by introducing a N(1),N(1)-dimethyl-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine binding group and a 4-methoxyphenylvinyl conjugation-enhancing group to the 2- and 6-positions of quinoline. This probe shows a large red shift and good emission enhancement under Cd(2+) binding. It also exhibits a high ion selectivity for Cd(2+) (especially over Zn(2+)) and a large two-photon absorption cross section at 710 nm. Two photon microscopy imaging studies reveal that the new probe is non-toxic and cell permeable and can be used to detect intracellular Cd(2+) under two-photon excitation. PMID- 22499397 TI - Immunoassay cross-reactivity of phenylephrine and methamphetamine. AB - Phenylephrine, an alpha(1) -adrenergic agonist, and methamphetamine, a prescription drug and substance of abuse, have similar chemical structures and thus have the potential to cross-react in qualitative screening tools such as a urine drug screening (UDS) performed by immunoassay. This cross-reactivity may yield a false-positive result that may affect the provision of care in certain patient populations and clinical situations. We describe a 36-year-old woman with confirmed brain death after a short hospital stay who had an initial UDS that was negative for methamphetamine. The patient was assessed for potential organ donation, which included obtaining a follow-up UDS. A urine sample was obtained after being hospitalized for 36 hours, which tested positive for methamphetamine, with no suspected ingestion of the target substance. Confirmatory laboratory testing indicated that intravenous phenylephrine and its metabolites were the likely cause of the false-positive UDS. However, the patient was not deemed to be a suitable candidate for organ donation, but clear documentation of the reason for denial of organ donation was not available in the patient's medical record. To our knowledge, this is the first case published in the English-language literature that describes the clinical occurrence of apparent immunoassay cross reactivity of methamphetamine and phenylephrine that resulted in a false-positive UDS for methamphetamine. In addition, this report describes the potential implications of this situation on clinical care, including organ donation acceptance. Toxicology screening in the emergency department and intensive care unit is a tool to assist in the diagnosis of medical conditions, but it may not always be reliable. Therefore, positive immunoassay results that may change the management of a patient's condition should be quickly verified with confirmatory testing to minimize unfavorable consequences. PMID- 22499398 TI - A highly enantioselective catalytic Strecker reaction of cyclic (Z)-aldimines. AB - A range of 3H-indoles and 2H-benzo[b][1,4]thiazines smoothly undergo asymmetric Strecker reaction with ethyl cyanoformate in the presence of a Cinchona alkaloid based thiourea catalyst at 10 degrees C to give structurally diverse nitrogen containing heterocycles in good to excellent yields and with excellent ee. PMID- 22499399 TI - Validation of the needs assessment for advanced lung cancer patients (NA-ALCP). AB - OBJECTIVE: The Needs Assessment for Advanced Cancer Patients (NA-ACP) is a 132 item self-report questionnaire designed to assess the seven needs domains of patients with advanced, incurable cancer. This study aimed to evaluate the short derivative form of that questionnaire with advanced lung cancer patients. METHODS: Item factor loadings, item test-retest data and response distributions were used to retain or reject items from the original NA-ACP scale. This resulted in 38 items being maintained, preserving the original subscales. The response scale was simplified following feedback from patients. 108 people with advanced lung cancer completed the shortened NA-ALCP along with measures of psychological distress (HADS, DT) and quality of life (EORTC QLQ-C30). A-priori predictions were made for divergent and convergent validity. RESULTS: Internal consistency coefficients were satisfactory for six of seven subscales, range 0.71-0.95. Correlations between NA-ALCP and HADS, DT and EORTC-QLQ-C30 provided support for 11 of the 22 divergent (r = 0.13-0.27) and convergent predictions (r = 0.45 0.71). CONCLUSIONS: Subscales of the NA-ALCP demonstrated internal reliability consistent with the original scale. Results provided supporting evidence for divergent and convergent validity. This study indicates that the NA-ALCP is psychometrically robust, easily understood and one-quarter the length of the original version. PMID- 22499401 TI - Evaluation of acute radiation effects on mandibular movements of patients with head and neck cancer. AB - OBJECTIVES: To evaluate radiotherapy effects (RT) on mandibular movements of patients with head and neck cancer (H&NC) and associate them to the variables: functional capacity, radiation field, disease staging, type of feeding, concomitant chemotherapy and total dose of RT. METHODS: Twenty-six patients with H&NC were followed up at the RT service. Physical examination was performed in 3 follow up time points: before the beginning of RT (T0), between 14th and 17th session of RT (T1) and after the last session of RT (T2). The physical examination consisted of the assessment of the following variables: mouth opening without pain (MO), maximum mouth opening (MMO), right lateral excursion (RLE), left lateral excursion (LLE) and protrusion (PR) of the jaw. The feeding type and the Karnofsky Performance Status Scale (KPS) were evaluated in each follow up time point. Data with regards to the tumor lesion and the RT were collected from the patient's clinical notes. RESULTS: There was a statistical significant reduction in the values of MO (p=0.006), MMO (p=0.001), LLE (p=0.006) and KPS (p=0.001). There was significant a statistical association among the reduction in KPS and decreased measure of MO (r=0.390, p=0.048) and MMO (r=0.435, p=0.026). The mouth and oropharynx radiation fields when combined showed a significant reduction for both the measure of MO (p=0.005) and for MMO (p=0.004). Patients who used nasoenteric tube feeding (NTF) had greater reduction in the measurement of MMO (p=0.031). The remaining variables showed no statistically significant difference. CONCLUSION: Patients with H&NC present reduction of the measures of MO and MMO during the RT, especially if they present reduced functional capacity, have radiation in the mouth and oropharynx fields and used NTF. PMID- 22499402 TI - Comparison of active and passive forces of the pelvic floor muscles in women with and without stress urinary incontinence. AB - BACKGROUND: The reduction of the pelvic floor muscles (PFM) strength is a major cause of stress urinary incontinence (SUI). OBJECTIVES: To compare active and passive forces, and vaginal cavity aperture in continent and stress urinary incontinent women. METHOD: The study included a total of thirty-two women, sixteen continent women (group 1--G1) and sixteen women with SUI (group 2--G2). To evaluate PFM passive and active forces in anteroposterior (sagittal plane) and left-right directions (frontal plane) a stainless steel specular dynamometer was used. RESULTS: The anteroposterior active strength for the continent women (mean+/-standard deviation) (0.3+/-0.2 N) was greater compared to the values found in the evaluation of incontinent women (0.1+/-0.1 N). The left-right active strength (G1=0.43+/-0.1 N; G2=0.40+/-0.1 N), the passive force (G1=1.1+/-0.2 N; G2=1.1+/-0.3 N) and the vaginal cavity aperture (G1=21+/-3 mm; G2=24+/-4 mm) did not differ between groups 1 and 2. CONCLUSION: The function evaluation of PFM showed that women with SUI had a lower anteroposterior active strength compared to continent women. PMID- 22499403 TI - Self-controlled feedback enhances learning in adults with Down syndrome. AB - BACKGROUND: One factor that has consistently been shown to enhance learning in typical participants is self-controlled practice. OBJECTIVES: The purpose of the present study was to examine whether the learning benefits of self-controlled feedback found previously in non-disabled adults would also be found in adults with Down syndrome. METHODS: Participants with Down syndrome practiced a linear positioning task. In the self-control group, learners were provided with feedback about the movement outcome at their request. Each participant in the yoked group received the same feedback schedule as their counterpart in the self-control group. RESULTS: Learning was assessed by a retention test, consisting of 10 trials without feedback, one day later. The self-control group demonstrated more effective learning of the task than the yoked group. CONCLUSION: Self-controlled feedback enhanced motor learning in participants with Down syndrome. PMID- 22499404 TI - Chest physical therapy is effective in reducing the clinical score in bronchiolitis: randomized controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of chest physical therapy (CP) in reducing the clinical score in infants with acute viral bronchiolitis (AVB). METHODS: Randomized controlled trial of 30 previously healthy infants (mean age 4.08 SD 3.0 months) with AVB and positive for respiratory syncytial virus (RSV), evaluated at three moments: at admission, then at 48 and 72 hours after admission. The procedures were conducted by blinded assessors to each of three groups: G1 - new Chest Physical therapy- nCPT (Prolonged slow expiration - PSE and Clearance rhinopharyngeal retrograde - CRR), G2 - conventional Chest Physical therapy- cCPT (modified postural drainage, expiratory compression, vibration and percussion) and G3 - aspiration of the upper airways. The outcomes of interest were the Wang's clinical score (CS) and its components: Retractions (RE), Respiratory Rate (RR), Wheezing (WH) and General Conditions (GC). RESULTS: The CS on admission was reduced in G1 (7.0-4.0) and G2 (7.5-5.5) but was unchanged in G3 (7.5-7.0). We observed a change 48 hours after hospitalization in G1 (5.5-3.0) and G2 (4.0-2.0) and in 72 hours, there was a change in G1 (2.0-1.0). CONCLUSION: The CP was effective in reducing the CS in infants with AVB compared with upper airway suction only. After 48 hours of admission, both techniques were effective and nCPT techniques were also effective in the 72 hours after hospitalization compared with cCPT techniques. PMID- 22499405 TI - A controlled clinical trial on the effects of exercise on neuropsychiatric disorders and instrumental activities in women with Alzheimer's disease. AB - OBJECTIVE: To analyze the influence of a six-month exercise program on neuropsychiatric disorders and on the performance of instrumental activities in elderly patients with Alzheimer's disease (AD). METHODS: The study included 20 patients with AD in the mild to moderate stages of the Clinical Dementia Rating (CDR) divided into two groups: the experimental group, composed of 10 women who participated in the six-month exercise program, and the control group, composed of the 10 remaining AD patients who did not take part in an exercise program during the same period. All participants were evaluated using the Mini-Mental State Exam for global cognitive function, the Neuropsychiatric Inventory Questionnaire for neuropsychiatric disorders, and the Pfeffer Functional Activities Questionnaire for the degree of functional impairment. RESULTS: The control group showed functional and neuropsychiatric deterioration in the comparisons between pre- and post-intervention times and between groups. CONCLUSION: The experimental group showed a propensity for less deterioration in neuropsychiatric disorders and performance of instrumental activities compared to the sedentary group. PMID- 22499406 TI - Strain rate imaging combined with wall motion analysis gives incremental value in direct quantification of myocardial infarct size. AB - BACKGROUND: The study aimed to evaluate the diagnostic accuracy of a new method for direct echocardiographic quantification of the myocardial infarct size, using late enhancement magnetic resonance imaging (LE-MRI) as a reference method. METHODS AND RESULTS: Echocardiography and LE-MRI were performed on average 31 days after first-time myocardial infarction in 58 patients. Echocardiography was also performed on 35 healthy controls. Direct echocardiographic quantification of the infarct size was based on automated selection and quantification of areas with hypokinesia and akinesia from colour-coded strain rate data, with manual correction based on visual wall motion analysis. The left ventricular (LV) ejection fraction, speckle-tracking-based longitudinal global strain, wall motion score index (WMSI), longitudinal systolic motion and velocity, and the ratio of early mitral inflow velocity to mitral annular early diastolic velocity were also measured by echocardiography. The area under the receiver-operating characteristic curves for the identification of the infarct size >12% by LE-MRI was 0.84, using the new method for direct echocardiographic quantification of the infarct size. The new method showed significantly a higher correlation with the infarct size by LE-MRI both at the global (r = 0.81) and segmental (r = 0.59) level compared with other indices of LV function. CONCLUSION: Direct quantification of the percentage infarct size by strain rate imaging combined with wall motion analysis yields high diagnostic accuracy and better correlation to LE-MRI compared with other echocardiographic indices of global LV function. Echocardiography performed ~1 month after myocardial infarction showed ability to identify the patients with the infarct size >12%. PMID- 22499407 TI - Direct comparison of the cognitive effects of acute alcohol with the morning after a normal night's drinking. AB - OBJECTIVE: The aim of this study was to compare performance measures after acute alcohol consumption (intoxication) with the performance the day after a normal night's drinking (hangover). METHODS: Eighty-four social drinkers took part in two studies that followed a counterbalanced repeated measure design. Fifteen men and 33 women were tested the morning (09:00, 11:00 or 13:00 h) following normal/usual alcohol consumption and the morning after no alcohol consumption; the order of testing was counterbalanced. In a second study, 36 participants (18 men and 18 women) were tested after receiving alcohol to attain a blood alcohol concentration of 0.08%, and after no alcohol administration, the order of testing was counterbalanced. In both studies, participants completed a task battery of memory, reaction time and attention tasks. RESULTS: Alcohol had no effect on the free recall task and the spatial attention task. Alcohol consumption, either acute or the next day, significantly affected reaction time, divided attention, selective attention and Stroop interference. The impairments during intoxication and hangover were of comparable magnitude. Performance on tasks of delayed recognition and irregular interstimulus reaction time was worse during hangover when compared with intoxication. CONCLUSION: It is evident that awareness needs to be raised that performance the morning after alcohol consumption is at the same level if not worse than when participants are at the legal limit for driving (0.08% blood alcohol concentration). PMID- 22499408 TI - A new method for the production of gelatin microparticles for controlled protein release from porous polymeric scaffolds. AB - Tissue engineering using scaffolds and growth factors is a crucial approach in bone regeneration and repair. The combination of bioactive agents carrying microparticles with porous scaffolds can be an efficient solution when controlled release of bio-signalling molecules is required. The present study was based on a recent approach using a biodegradable scaffold and protein-loaded microparticles produced in an innovative manner in which protein loss is minimized during the loading process. Bovine serum albumin (BSA)-loaded gelatin microparticles were obtained by grinding freeze-dried membranes of gelatin and BSA. Porous scaffolds (250-355 um pore size) produced from a polyactide (PLLA) and polycaprolactone (PCL) blend by salt leaching/supercritical CO2 methods were used for the experiments. Gelatin microparticles containing three different BSA amounts were incorporated into the porous scaffolds by using a surfactant. In vitro release profiles showed up to 90% protein loading efficiency. This novel method appears to be an effective approach for producing particles that can minimize protein loss during the loading process. PMID- 22499409 TI - Catalytic asymmetric total synthesis of chimonanthine, folicanthine, and calycanthine through double Michael reaction of bisoxindole. PMID- 22499410 TI - Bias stress effect in "air-gap" organic field-effect transistors. AB - The origin of the bias stress effect related only to semiconductor properties is investigated in "air-gap" organic field-effect transistors (OFETs) in the absence of a material gate dielectric. The effect becomes stronger as the density of trap states in the semiconductor increases. A theoretical model based on carrier trapping and relaxation in localized tail states is formulated. Polar molecular vapors in the gap of "air-gap" OFETs also have a significant impact on the bias stress effect via the formation of bound states between the charge carriers and molecular dipoles at the semiconductor surface. PMID- 22499411 TI - Possible correlation of sirolimus plasma concentration with sinusoidal obstructive syndrome of the liver in patients undergoing myeloablative allogeneic hematopoietic cell transplantation. AB - STUDY OBJECTIVES: To determine the frequency of sinusoidal obstructive syndrome (SOS) in patients undergoing allogeneic hematopoietic cell transplantation who received graft-versus-host disease (GVHD) prophylaxis with sirolimus and tacrolimus, and to assess whether the occurrence of SOS correlates with immunosuppressant levels. DESIGN: Retrospective cohort study. SETTING: Hematopoietic cell transplant unit at an academic medical center. PATIENTS: Fifty nine adults who received myeloablative preparative regimens for transplantation of any hematologic malignancy and received sirolimus and tacrolimus for GVHD prophylaxis between January 1, 2007, and May 1, 2009; all donors and transplant recipients were human leukocyte antigen (HLA) matched for at least HLA-A, -B, -C, and -DRB1. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the occurrence of SOS after hematopoietic cell transplantation. Plasma concentrations of sirolimus and tacrolimus and the summative levels of sirolimus and tacrolimus were then compared in patients who developed SOS with those who did not develop SOS. Trough levels were measured from blood samples collected 30-60 minutes before the morning doses of sirolimus and tacrolimus on days 0-35, or until the development of SOS. Of the 59 patients, 12 (20%) developed SOS. The mean sirolimus level was significantly higher in patients who developed SOS relative to those who did not develop SOS (10.5 vs 8.7 ng/ml, p=0.003). The mean summative trough level of sirolimus and tacrolimus was also significantly higher in those who developed SOS compared with those who did not (19.7 vs 17.1 ng/ml, p=0.003). The mean +/- SD time to the occurrence of SOS was 28 +/- 8.7 days. The median time to death was 101 days for patients who developed SOS compared with 433 days for patients who did not develop SOS (p=0.002). CONCLUSION: Sirolimus plasma concentration may correlate with the development of delayed SOS; however, further research is needed to prospectively evaluate the role of sirolimus exposure in the pathogenesis of SOS. PMID- 22499412 TI - A Gal4/UAS system for conditional transgene expression in rhombomere 4 of the zebrafish hindbrain. AB - BACKGROUND: The zebrafish is well established as a model organism for the study of vertebrate embryogenesis, but transgenic lines enabling restricted gene expression are still lacking for many tissues. RESULTS: We first generated the hoxb1a(beta-globin):eGFP(um8) line that expresses eGFP in hindbrain rhombomere 4 (r4), as well as in facial motor neurons migrating caudally from r4. Second, we generated the hoxb1a(beta-globin) Gal4VP16(um60) line to express the exogenous Gal4VP16 transcription factor in r4. Lastly, we prepared the UAS(beta actin):hoxa3a(um61) line where the hoxa3a gene, which is normally expressed in r5 and r6, is under control of Gal4-regulated UAS elements. Crossing the hoxb1a(beta globin):Gal4VP16(um60) line to the UAS(beta-actin):hoxa3a(um61) line drives robust hoxa3a expression in r4. We find that transgenic expression of hoxa3a in r4 does not affect hoxb1a expression, but has variable effects on migration of facial motorneurons and formation of Mauthner neurons. While cases of somatic transgene silencing have been reported in zebrafish, we have not observed such silencing to date, possibly because of our efforts to minimize repetitive sequences in the transgenic constructs. CONCLUSION: We have generated three transgenic lines that will be useful for future studies by permitting the labeling of r4-derived cells, as well as by enabling r4-specific expression of various transgenes. PMID- 22499413 TI - Innovative magnetic scaffolds for orthopedic tissue engineering. AB - The use of magnetism in tissue engineering is a very promising approach, in fact magnetic scaffolds are able not only to support tissue regeneration, but they can be activated and work like a magnet attracting functionalized magnetic nanoparticles (MNPs) injected close to the scaffold enhancing tissue regeneration. This study aimed to assess the in vivo biocompatibility and osteointegrative properties of novel magnetic scaffolds. Two hydroxyapatite/collagen (70/30 wt %) magnetic scaffolds were magnetized with two different techniques: direct nucleation of biomimetic phase and superparamagnetic nanoparticles (MNPs) on self-assembling collagen fibers (MAG-A) and scaffold impregnation in ferro-fluid solution (MAG-B). Magnetic scaffolds were implanted in rabbit distal femoral epiphysis and tibial mid-diaphysis. Histopathological screening showed no inflammatory reaction due to MNPs. Significantly higher bone healing rate (DeltaBHR) results were observed in MAG-A in comparison to MAG-B. Significant differences were also found between experimental times with an increase in DeltaBHR from 2 to 4 weeks for both scaffolds in trabecular bone, while only for MAG-B (23%, p < 0.05) in cortical bone. The proposed magnetic scaffolds seem to be promising for magnetic guiding in orthopedic tissue engineering applications and they will be suitable to treat also several pathologies in regenerative medicine area. PMID- 22499414 TI - Studies on the instability of chlorhexidine, part I: kinetics and mechanisms. AB - The objectives of the studies presented herein were to determine the pH-dependent chlorhexidine (CHD) degradation scheme, to determine the rate laws, and to propose reasonable mechanisms for CHD hydrolysis in aqueous solutions. A series of degradation kinetic studies was conducted at 90.0 degrees C using reaction mixtures containing 0.10 mM CHD prepared in the pH range of 0.5-9.0 using hydrochloric acid, sodium hydroxide, acetate, phosphate, or 4-(2-hydroxyethyl)-1 piperazineethanesulfonic acid buffers at a constant ionic strength of 0.500 M. Concentration-time profiles for all degradation products, intermediates, and substrates were determined by high-performance liquid chromatography (HPLC). Degradation products and intermediates were identified using a combination of liquid chromatography-mass spectrometry, kinetic analysis, and HPLC comparison with authentic compounds. pH-dependent degradation scheme and rate laws were parameterized using nonlinear regression. The direct formation of p-chloroaniline (PCA) from CHD is the major pathway in acidic conditions, whereas the indirect formation of PCA via the formation of p-chlorophenylurea is the main pathway in alkaline conditions. PMID- 22499415 TI - Interactive segmentation and tracking in optical microscopic images. PMID- 22499416 TI - Synergic catalytic effects in confined spaces. AB - Combining the merits of confined effects and synergic effects is a promising way to build efficient and versatile heterogeneous catalytic systems. Recently, heterogeneous bifunctional and even trifunctional catalysts have attracted more and more attention because the synergic catalysis between the multifunctional groups could be developed within confined spaces. Significantly, many incompatible functional groups have been successfully incorporated into one confined space and show superior catalytic performance. Understanding the synergic catalytic effects in confined spaces is of great significance for constructing sophisticated and efficient catalytic systems. This feature article summarizes the recent advances in synergic catalysis in confined spaces as well as the methods to build synergic catalysts. The confined spaces provided by the one- or three-dimensional rigid pores of mesoporous silicas or the two dimensional flexible interlayer regions of layered double hydroxides (LDHs) are mainly involved. An important reason for choosing mesoporous silica and LDH solids is that they additionally participate in synergic effects through their intrinsic active sites, the acidic hydroxyl groups on mesoporous silicas and acid base bifunctional sites on layered double hydroxides, for example. Visible enhancement of catalytic activity or enantioselectivity or both was observed in aldol, Michael, Friedel-Crafts and Henry reactions, cyanosilylation, hydrolytic kinetic resolution of epoxides, etc. PMID- 22499417 TI - Nephrotic syndrome associated with toxoplasmosis: report of seven cases. AB - The concomitance of nephrotic syndrome and acute infection by Toxoplasma gondii is a rare occurrence in humans. In this paper seven cases of children, ranging from 11 months to 7 year-old, with concomitant nephrotic syndrome and asymptomatic acute T. gondii infection are reported. In one of those patients only the administration of anti-Toxoplasma therapy was enough to control the clinical and laboratory manifestations of the disease. In the other patients it was necessary to introduce corticosteroids or other immunosuppressant drugs. Three patients had complete clinical and laboratory improvement and the remaining showed only a partial response. PMID- 22499418 TI - Parasites in stool samples in the environment of Ilha da Marambaia, Rio de Janeiro, Brazil: an approach in public health. AB - This research aimed to describe the frequency of parasites in stool samples in the environment of Ilha da Marambaia, Rio de Janeiro, Brazil. One hundred and five stool samples were collected and processed by the coproparasitological techniques ethyl acetate sedimentation and centrifuge-flotation using saturated sugar solution. Parasites were detected in 81.9% of the samples, hookworm being the most prevalent, followed by Trichuris vulpis. Ascaris sp. eggs were also found. A high level of evolutive forms of parasites with public health risk was found in stool samples of the environment studied. We propose that health education programs, allied to an improvement of human and animal health care, must be employed to reduce the environmental contamination. PMID- 22499419 TI - A ten-year follow-up of human leptospirosis in Uruguay: an unresolved health problem. AB - Leptospira spp. are delicate bacteria that cannot be studied by usual microbiological methods. They cause leptospirosis, a zoonotic disease transmitted to humans through infected urine of wild or domestic animals. We studied the incidence of this disease in the Uruguayan population, its epidemiologic and clinical features, and compared diagnostic techniques. After examining 6,778 suspect cases, we estimated that about 15 infections/100,000 inhabitants occurred yearly, affecting mainly young male rural workers. Awareness about leptospirosis has grown among health professionals, and its lethality has consequently decreased. Bovine infections were probably the principal source of human disease. Rainfall volumes and floods were major factors of varying incidence. Most patients had fever, asthenia, myalgias or cephalalgia, with at least one additional abnormal clinical feature. 30-40% of confirmed cases presented abdominal signs and symptoms, conjunctival suffusion and altered renal or urinary function. Jaundice was more frequent in patients aged > 40 years. Clinical infections followed an acute pattern and their usual outcome was complete recovery. Laboratory diagnosis was based on indirect micro-agglutination standard technique (MAT). Second serum samples were difficult to obtain, often impairing completion of diagnosis. Immunofluorescence was useful as a screening test and for early detection of probable infections. PMID- 22499420 TI - Pandemic influenza A/H1N1 vaccination coverage, adverse reactions, and reasons for vaccine refusal among medical students in Brazil. AB - The aim of this cross-sectional study was to determine, among medical students at a public university in Rio de Janeiro, Brazil, the acceptance of the pandemic influenza A/H1N1 vaccine during the 2010 mass immunization campaign and the vaccine safety in this group and, among unvaccinated students, the reasons for refusing vaccination. Of a total of 858 students, 678 (79%) participated in the study. Vaccination coverage was 60.4% among students aged 20 to 39 years (an age group targeted for vaccination) and 43.8% among those who did not belong to this age group. The most frequent adverse reactions to the vaccine were pain at the injection site (8.7%) and fever (7.9%). There were no serious adverse reactions. Among students aged 20 to 39 years, the most common reasons for refusing the vaccine were "lack of time" (42.4%), "fear of adverse reactions" (41.9%), and "difficult access to the vaccine" (11.5%). Other reasons for vaccine refusal were "uncertainties about vaccine safety and efficacy" and "vaccination was not needed". To increase the acceptance of the influenza vaccine, a comprehensive immunization program should be offered to these students. PMID- 22499421 TI - Temporal differences in blood meal detection from the midguts of Triatoma infestans. AB - We used genus/species specific PCRs to determine the temporal persistence of host DNA in Triatoma infestans experimentally fed on blood from six common vertebrate species: humans, domestic dogs, guinea pigs, chickens, mice, and pigs. Twenty third or fourth instar nymphs per animal group were allowed to feed to engorgement, followed by fasting-maintenance in the insectary. At 7, 14, 21, or 28 days post-feeding, the midgut contents from five triatomines per group were tested with the respective PCR assay. DNA from all vertebrate species was detected in at least four of five study nymphs at seven and 14 days post-feeding. DNA of humans, domestic dogs, guinea pigs, pigs, and chickens were more successfully detected (80-100%) through day 21, and less successfully (20-100%) at day 28. Findings demonstrate that species-specific PCRs can consistently identify feeding sources of T. infestans within two weeks, a biologically relevant time interval. PMID- 22499422 TI - Morphological changes in the digestive system of 93 human immunodeficiency virus positive patients: an autopsy study. AB - Involvement of the digestive system in patients with acquired immunodeficiency syndrome (AIDS) is frequent and many changes in these patients are diagnosed only at autopsy. There are few studies of autopsy with detailed analysis of this system and only one was conducted in Brazil. We evaluated each segment of the digestive system in 93 consecutive autopsies of patients infected with human immunodeficiency virus (HIV) and the importance of these lesions to death. Of these, 90 (96.8%) patients had AIDS. We reviewed medical records, autopsy reports and histological sections from tongue to rectum stained with hematoxylin-eosin. When necessary, we analyzed special stains and immunohistochemistry to investigate infections. There was damage to the digestive system in 73 (78.5%) cases. The most common infections were candidiasis (42%), cytomegalovirus (29%), histoplasmosis (11.8%), toxoplasmosis (9.7%) and mycobacterial infection (9.7%). Malignancies were rare, present in four (4.3%) cases (two Kaposi's sarcoma, one adenocarcinoma and one metastatic embryonal carcinoma). All segments showed lesions: tongue (48.6%), esophagus (44.8%), stomach (44.7%), colon (43.2%) and small intestine (28.9%). The lesions found were immediate cause of death in five (5.4%) cases. In another 36 (38.7%) cases the basic disease was systemic and also compromised the digestive system. PMID- 22499423 TI - Susceptibility of peritoneal macrophage from different species of neotropical primates to ex vivo Leishmania (L.) infantum chagasi-infection. AB - This study examined the susceptibility of peritoneal macrophage (PM) from the Neotropical primates: Callithrix jacchus, Callithrix penicillata, Saimiri sciureus, Aotus azarae infulatus and Callimico goeldii to ex vivo Leishmania (L.) infantum chagasi-infection, the etiological agent of American visceral leishmaniasis (AVL), as a screening assay for evaluating the potential of these non-human primates as experimental models for studying AVL. The PM-susceptibility to infection was accessed by the PM-infection index (PMI) at 24, 72 h and by the mean of these rates (FPMI), as well as by the TNF-alpha, IL-12 (Capture ELISA) and Nitric oxide (NO) responses (Griess method). At 24h, the PMI of A. azarae infulatus (128) was higher than those of C. penicillata (83), C. goeldii (78), S. sciureus (77) and C. jacchus (55). At 72h, there was a significant PMI decrease in four monkeys: A. azarae infulatus (128/37), C. penicillata (83/38), S. sciureus (77/38) and C. jacchus (55/12), with exception of C. goeldii (78/54). The FPMI of A. azarae infulatus (82.5) and C. goeldii (66) were higher than C. jacchus (33.5), but not higher than those of C. penicillata (60.5) and S. sciureus (57.5). The TNF-a response was more regular in those four primates which decreased their PMI at 24/72 h: C. jacchus (145/122 pg/mL), C. penicillata (154/130 pg/mL), S. sciureus (164/104 pg/mL) and A. azarae infulatus (154/104 pg/mL), with exception of C. goeldii (38/83 pg/mL). The IL-12 response was mainly prominent in A. infulatus and C. goeldii which presented the highest FPMI and, the NO response was higher in C. goeldii, mainly at 72 h. These findings strongly suggest that these New World primates have developed a resistant innate immune response mechanism capable of controlling the macrophage intracellular growth of L. (L.) i. chagasi-infection, which do not encourage their use as animal model for studying AVL. PMID- 22499424 TI - Apoptotic-like activity of staurosporine in axenic cultures of Trypanosoma evansi. AB - Trypanosoma evansi is a blood protozoan parasite of the genus Trypanosoma which is responsible for surra (Trypanosomosis) in domestic and wild animals. This study addressed apoptotic-like features in Trypanosoma evansi in vitro. The mechanism of parasite death was investigated using staurosporine as an inducing agent. We evaluated its effects through several cytoplasmic features of apoptosis, including cell shrinkage, phosphatidylserine exposure, maintenance of plasma membrane integrity, and mitochondrial trans-membrane potential. For access to these features we have used the flow cytometry and fluorescence microscopy with cultures in the stationary phase and adjusted to a density of 10(6) cells/mL. The apoptotic effect of staurosporine in T. evansi was evaluated at 20 nM final concentration. There was an increase of phosphatidylserine exposure, whereas mitochondrial potential was decreased. Moreover, no evidence of cell permeability increasing with staurosporine was observed in this study, suggesting the absence of a necrotic process. Additional studies are needed to elucidate the possible pathways associated with this form of cell death in this hemoparasite. PMID- 22499425 TI - Infection and immune-mediated meningococcal-associated arthritis: combination features in the same patient. AB - We present a case of a 16-year-old male patient with sudden-onset, rash, arthritis and meningitis by Neisseria meningitidis one week after an acute upper respiratory infection. On the 10th day of treatment followed by neurological and arthritis clinical improvement, he presented once again a tender and swollen left knee with a moderate effusion, and active and passive range of motion was severely limited secondary to pain, and when he was submitted to surgical drainage and synovial fluid analysis he showed inflammatory characteristics. A non-steroidal anti-inflammatory drug was taken for five days with complete improvement of symptoms. The case is notable for its combination of features of septic and immune-mediated arthritis, which has rarely been reported in the same patient. PMID- 22499426 TI - Resurgence of measles virus in Sao Paulo, Brazil. PMID- 22499427 TI - Evaluation of the "Symbiosys" immunoassay for the serological diagnosis of Chagas disease. PMID- 22499428 TI - Apropos "Evaluation of dengue NS1 antigen detection for diagnosis in public health laboratories, Sao Paulo State, 2009". PMID- 22499429 TI - Analogies in medicine: little thief in the skin. PMID- 22499430 TI - Metal substitution in a Lindqvist polyoxometalate leads to improved photocatalytic performance. AB - The photochemical properties of homo- and heterometallic molybdate-based Lindqvist polyoxometalate clusters are investigated in a comparative study and it is shown that vanadium substitution can be used as a facile synthetic tool to optimize the visible light absorption and photocatalytic activity of the cluster. The mono-vanadium substituted unit, [VMo(5)O(19)](3-) shows light absorption up to 480 nm whereas the light absorption of the molybdate analogue [Mo(6)O(19)](2-) is mainly in the UV region below 400 nm. The electronic absorption properties of both clusters are further investigated using TD-DFT calculations which show that vanadium incorporation leads to the formation of low-energy O -> V LMCT transitions. In comparative photochemical dye decomposition test reactions under UV and Vis irradiation, a higher reactivity is observed for [VMo(5)O(19)](3-) together with turnover numbers of more than 1600. In addition it is shown that under anaerobic conditions, the photoreaction proceeds faster than in the presence of oxygen, suggesting that oxygen acts as a quencher in one of the photoredox steps. PMID- 22499431 TI - Coumarin-based chiral fluorescence sensor incorporating a thiourea unit for highly enantioselective recognition of N-Boc-protected proline. AB - New coumarin-based chiral thiourea sensor 1 was found to be an enantioselective fluorescent chemosensor for N-Boc-protected proline. The chiral sensor shows lower background fluorescence, and higher fluorescence enhancement with 18 nm blue shifts. Job plot analysis result indicates that sensor 1 can form a 1 : 1 stoichiometric complex and it could be used as a fluorescence sensor for the determination of enantiomer composition of N-Boc-protected proline. PMID- 22499433 TI - Electron-donating tetrathienyl-substituted borole. PMID- 22499432 TI - Characterization and induction of cementoblast cell proliferation by bioactive glass nanoparticles. AB - Cementum is a mineralized tissue that lines the surface of the tooth root enabling attachment of the periodontal ligament to the root and surrounding alveolar bone. Studies examining the mechanisms involved in the formation of root cementum have been hindered by an inability to isolate and culture the cells required for cementum production (cementoblasts). This study isolated and characterized cementoblast cells derived from rat molar periodontal ligament. It was observed that the isolated cells expressed F-Spondin, a cementoblast marker, while F-Spondin expression was not observed in the cells of other tissues such as gingival fibroblasts and osteoblasts. As expected, the isolated cementoblast cells also expressed osteocalcin (OC), bone sialoprotein (BSP), alkaline phosphatase (ALP), and type I collagen, demonstrating the presence of mineralized tissues genes in cementoblast cells. These cells showed high ALP activity and calcified nodule formation in vitro. Since cementogenesis could be a critical event for regeneration of periodontal tissues, this study investigated whether bioactive glass particles could affect the proliferation of cementoblasts since they are known to enhance osteoblast proliferation. It was found that the ionic products from bioactive glass nanoparticles increased cementoblast viability, mitochondrial activity, and induced cell proliferation. Together, these results show the characterization of cementoblast cells from rat molar periodontal ligament. Additionally, it was shown that bioactive glass nanoparticles induced cementoblast to proliferate, indicating that they could be a potential material for use in cement regeneration through tissue engineering. PMID- 22499434 TI - SERINE proteinase like activity in apolipophorin III from the hemolymph of desert locust, Schistocerca gregaria. AB - Apolipophorin III (apoLp-III) has been known as a lipid transport protein of insects. Recent studies indicated the involvement of apoLp-III in immune reactions and in the control of cell destruction, but no enzymatic activity has so far been detected. In the present study, a protease from the hemolymph of Schistocerca gregaria was purified to homogeneity and its enzymatic activity was examined. Identity as chymotrypsin-like proteinase was established by its high affinity toward bulky aromatic substrates and its catalytic specificity for amide or ester bonds on the synthetic substrates, Suc-Ala-Ala-Pro-Xaa-AMC (where Xaa was Phe, Tyr, Trp, and Lys, and AMC is 7-amino-4-methyl-coumarin) and thiolbenzyl ester substrate Suc-Ala-Ala-Pro-Phe-SBzl. The sensitivity for serine protease and chymotrypsin-specific covalent inhibitors, PMSF, TPCK, and noncovalent inhibitors SGCI, showed that it is a chymotrypsin-like proteinase. It showed its maximum activity at pH 8.0 and 55 degrees C for the hydrolysis of Suc-Ala-Ala-Pro-Tyr AMC. According to similarities in the amino terminal sequence, molar mass (19 kDa) and retention on reversed-phase analytical high-performance liquid chromatography (HPLC) column, this protein is S. gregaria homologue of Locusta migratoria apoLp-III. Our data suggest that apoLp-III also has an inherent proteolytic activity. Results indicated that S. gregaria apoLp-III is a good catalyst and could be used as a biotechnological tool in food processing and in agricultural biotechnology. PMID- 22499435 TI - The physiologic impact of transnasal flexible endoscopy. AB - OBJECTIVES/HYPOTHESIS: Diagnostic transnasal flexible endoscopy (TNFE) is a commonly used office procedure in otolaryngology. Currently there is a paucity of data on the impact of TNFE on physiologic parameters. This is relevant with the advent of office-based endoscopic procedures. The goal of this study is to measure the impact of topical decongestion, anesthesia, and diagnostic TNFE on vital signs: systolic blood pressure (SBP) and diastolic blood pressure (DBP), heart rate (HR), and oxygenation (O(2) sat). STUDY DESIGN: Prospective case control study, in which the patient is his/her control. METHODS: Vital signs were obtained at baseline, immediately after the application of Neosynephrine, after the application of lidocaine, 5 minutes later, with the scope in the nasopharynx and hypopharynx, and upon completion of the procedure. RESULTS: Compared to the baseline data, there was a statistically significant increase in HR after the procedure (mean change, 4.06 +/- 10.15 bpm; range, -14 to 42 bpm, P = .01). There was also a change in O(2) sat (mean change, 0.42% +/- 1.36%; range -3% to 3%, P = .03) after the application of lidocaine. When comparing each data point to the preceding point, there was a statistically significant change in SBP with the scope in the nasopharynx (mean change, 5.34 +/- 10.65 mm Hg; range, -22 to 28 mm Hg, P = .001) and in HR with the scope in the hypopharynx (mean change, 3.76 +/- 6.41 bpm; range, -9 to 19 bpm, P = .0004). CONCLUSIONS: Diagnostic TNFE and topical lidocaine can have an impact on physiologic parameters; however, these changes are unlikely to be clinically significant. PMID- 22499436 TI - Evaluation of a method allowing preservation of fresh lymph nodes for flow cytometric immunophenotyping. AB - BACKGROUND: Flow cytometric immunophenotyping (FCI) of lymph nodes (LN) requires fresh unfixed tissue, with analysis being carried out within few hours post surgery. This study evaluated a novel method for fresh LN preservation, in order to allow histomorphology-based FCI. METHODS: This study was carried out prospectively on 30 LN with suspected involvement by haematolymphoid neoplasms (HLN). FCI was performed on each fresh and post cryopreserved LN cell suspension. Percentage positivities (PP) and mean fluorescent intensities (MFI) were calculated on both preparations for a combination of T and B-lymphoid antigens together with viability. RESULTS: The cryopreservation method applied in this study did not affect significantly PP and had minor impact on MFI of the tested antigens. Overall, there was minimal decrease in PP and MFI on the cryopreserved cells when compared with fresh cells, for most antigens with only a mild increase in apoptotic cells. However, these changes were not diagnostically significant, since both reactive processes and HLN present within analyzed LN could be identified and differentiated. Viability was more than 75% for all cryopreserved LN composed of haematolymphoid cells. CONCLUSION: The method presented in this study confers the possibility of storing fresh LN biopsies for later FCI, thus allowing a morphology-based immunophenotypic approach. This would allow a more sensitive, specific, and cost-effective management of LN specimens, whilst maintaining the important benefits provided by FCI. PMID- 22499437 TI - Perifosine-mediated Akt inhibition in neuroendocrine tumor cells: role of specific Akt isoforms. AB - The majority of neuroendocrine tumors (NETs) of the gastroenteropancreatic system show aberrant Akt activity. Several inhibitors of the phosphoinositide 3-kinase (PI(3)K)-Akt-mTOR signaling pathway are currently being evaluated in clinical phase II and III studies for the treatment of NETs with promising results. However, the molecular mechanisms and particularly the role of different Akt isoforms in NET signaling are not fully understood. In this study, we examine the effect of Akt inhibition on NET cells of heterogeneous origin. We show that the Akt inhibitor perifosine effectively inhibits Akt phosphorylation and cell viability in human pancreatic (BON1), bronchus (NCI-H727), and midgut (GOT1) NET cells. Perifosine treatment suppressed the phosphorylation of Akt downstream targets such as GSK3alpha/beta, MDM2, and p70S6K and induced apoptosis. To further investigate the role of individual Akt isoforms for NET cell function, we specifically blocked Akt1, Akt2, and Akt3 via siRNA transfection. In contrast to Akt2 knockdown, knockdown of Akt isoforms 1 and 3 decreased phosphorylation levels of GSK3alpha/beta, MDM2, and p70S6K and suppressed NET cell viability and colony-forming capacity. The inhibitory effect of simultaneous downregulation of Akt1 and Akt3 on tumor cell viability was significantly stronger than that caused by downregulation of all Akt isoforms, suggesting a particular role for Akt1 and Akt3 in NET signaling. Akt3 siRNA-induced apoptosis while all three isoform specific siRNAs impaired BON1 cell invasion. Together, our data demonstrate potent antitumor effects of the pan-Akt inhibitor perifosine on NET cells in vitro and suggest that selective targeting of Akt1 and/or Akt3 might improve the therapeutic potential of Akt inhibition in NET disease. PMID- 22499438 TI - The Fleagle factor: in life and publishing alike, the editor has the final say. PMID- 22499439 TI - The science behind pre-Columbian evidence of syphilis in Europe: research by documentary. AB - This article discusses the presentation of scientific findings by documentary, without the process of peer review. We use, as an example, PBS's "The Syphilis Enigma," in which researchers presented novel evidence concerning the origin of syphilis that had never been reviewed by other scientists. These "findings" then entered the world of peer-reviewed literature through citations of the documentary itself or material associated with it. Here, we demonstrate that the case for pre-Columbian syphilis in Europe that was made in the documentary does not withstand scientific scrutiny. We also situate this example from paleopathology within a larger trend of "science by documentary" or "science by press conference," in which researchers seek to bypass the peer review process by presenting unvetted findings directly to the public. PMID- 22499440 TI - The role of terrestriality in promoting primate technology. AB - "Complex technology" has often been considered a hallmark of human evolution. However, recent findings show that wild monkeys are also capable of habitual tool use. Here we suggest that terrestriality may have been of crucial importance for the innovation, acquisition, and maintenance of "complex" technological skills in primates. Here we define complex technological skills as tool-use variants that include at least two tool elements (for example, hammer and anvil), flexibility in manufacture or use (that is, tool properties are adjusted to the task at hand), and that skills are acquired in part by social learning. Four lines of evidence provide support for the terrestriality effect. First, the only monkey populations exhibiting habitual tool use seem to be particularly terrestrial. Second, semi-terrestrial chimpanzees have more complex tool variants in their repertoire than does their arboreal Asian relative, the orangutan. Third, tool variants of chimpanzees used in a terrestrial setting tend to be more complex than those used exclusively in arboreal contexts. Fourth, the higher frequency in tool use among captive versus wild primates of the same species may be attributed in part to a terrestriality effect. We conclude that whereas extractive foraging, intelligence, and social tolerance are necessary for the emergence of habitual tool use, terrestriality seems to be crucial for acquiring and maintaining complex tool variants, particularly expressions of cumulative technology, within a population. Hence, comparative evidence among primates supports the hypothesis that the terrestriality premium may have been a major pacemaker of hominin technological evolution. PMID- 22499441 TI - The pre-Natufian Epipaleolithic: long-term behavioral trends in the Levant. AB - Few cultural developments have taken on as much archeological significance as when people began living in villages and producing their own food. The economic, social, technological, and ideological transformations immediately preceding and following these changes were profound. Early models of culture change associated with pre-agricultural societies of the Levant focused on the sudden, late origin of settled farming villages triggered by climate change. Accompanying this new economic and living situation was durable stone-built architecture; intensified plant and animal use; a flourishing of art and decoration; new mortuary traditions, including marked graves and cemeteries; elaborate ritual and symbolic behavior-a new way of life. This new life style arguably had a slow start, but really took off during the Epipaleolithic period (EP), spanning more than 10,000 years of Levantine prehistory from c. 23,000-11,500 cal BP. The last EP phase, immediately preceding the Neolithic, is by far the best-studied in terms of its cultural and economic contributions to questions on the origins of agriculture.1 4 Recently, archeologists have considered the earlier parts of the EP to be more culturally dynamic and similar to the later phase (Natufian) than was previously thought.3-10 The earlier EP is increasingly seen as demonstrating the behavioral variability and innovations that help us to understand the economic, technological, and social changes associated with complex hunter-gatherers of the Natufian and farmers of the Neolithic. This paper traces the cultural and biological developments of the EP period leading up to the Natufian and considers the long-term trajectory of culture change, social complexity, and village life in the Near East. PMID- 22499442 TI - Nanomembrane quantum-light-emitting diodes integrated onto piezoelectric actuators. AB - We integrate resonant-cavity light-emitting diodes containing quantum dots onto substrates with giant piezoelectric response. Via strain, the energy of the photons emitted by the diode can be precisely controlled during electrical injection over a spectral range larger than 20 meV. Simultaneously, the exciton fine-structure-splitting and the biexciton binding energy can be tuned to the values required for entangled photon generation. PMID- 22499443 TI - Frailty and aging. PMID- 22499444 TI - New therapeutic targets in dermatoporosis. AB - Dermatoporosis is a novel term proposed to describe the chronic cutaneous insufficiency/fragility syndrome characterized by an extreme skin atrophy. Dermatoporosis is principally due to chronological aging and long-term and unprotected sun exposure, but it may also result from the chronic use of topical and systemic corticosteroids. We have recently proposed a membrane organelle, hyalurosome, composed of molecules involved in hyaluronate (HA) metabolism and cell signaling in the keratinocytes, such as principal HA receptor CD44, heparin binding epidermal growth factor (HB-EGF), HB-EGF receptor erbB1 and HA synthase 3 (HAS3), which is functionally defective in dermatoporosis and may be a target for intervention. Several lines of evidence suggest that hyalurosome is located in keratinocyte filopodia, thin, actin-rich plasma membrane protrusions implicated in cell motility. We have recently shown that keratinocyte filopodia are downregulated by corticosteroids in vitro. Intermediate size HA fragments (HAFi) inhibited the downregulation of filopodia induced by corticosteroids. Topical HAFi prevented the skin atrophy induced by topical corticosteroids in mice without interfering with their anti-inflammatory effect. Topical treatment with HAFi 1% of atrophic forearm skin of dermatoporosis patients for 1 month resulted in a significant clinical improvement and induced the expression of hyalurosome molecules. Topical retinaldehyde (RAL) and HAFi showed a synergy in HA production and pro-HB-EGF expression in mouse skin and in the correction of skin atrophy in dermatoporosis patients. Uncovering the molecular mechanisms implicating hyalurosome seems to be crucial to better understand the pathogenesis of dermatoporosis and to develop new therapeutic strategies. PMID- 22499445 TI - Serum carotenoids and pulmonary function in older community-dwelling women. AB - BACKGROUND AND OBJECTIVES: Deterioration in pulmonary function is associated with greater disability and mortality in older adults. Dietary antioxidants are implicated in lung health, but the relationship between major dietary antioxidants, such as serum carotenoids, and pulmonary function have not been well characterized. Serum carotenoids are considered the most reliable indicator of fruit and vegetable intake. SUBJECTS AND METHODS: We examined the relationship between serum alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, and lycopene with pulmonary function (forced expiratory volume in one second [FEV1] and forced vital capacity [FVC]) in a population-based sample of 631 moderately to severely disabled community-dwelling older women (Women's Health and Aging Study I) in Baltimore, Maryland, USA. RESULTS: Higher serum alpha-carotene and beta-carotene concentrations were positively associated with both FEV1 and FVC, respectively (all P < 0.05), in separate multivariate linear regression models adjusting for age, race, education, cognition, anemia, inflammation, and chronic diseases. Total serum carotenoids were associated with FEV1 (P = 0.08) and FVC (P = 0.06), respectively, in similar models. No association was found between beta-cryptoxanthin, lutein/zeaxanthin, and lycopene, and FEV1 or FVC. CONCLUSIONS: Higher serum alpha-carotene and beta carotene concentrations, which reflect greater intake of orange and dark green leafy fruits and vegetables, were associated with better pulmonary function among older community-dwelling women.function may lead to food avoidance and to a higher incidence of digestive complaints. PMID- 22499446 TI - Body mass index, life-style, and healthy status in free living elderly people in Menorca Island. AB - OBJECTIVES: To assess the BMI, life-style, and healthy status, and explore relationships between these parameters, among Menorca's free living elderly people. METHODS: A cross-sectional survey carried out in Menorca Island in 2009. A random sample (n=450) of the elderly population (>=65 years) was interviewed. Anthropometric measurements and a general questionnaire incorporating questions related to socio-demographic and life-style factors and health status were used. RESULTS: Approximately five per cent of elders were underweight and 60% overweight or obese. Underweight were positively and overweight and obesity negatively affected by age. The prevalence of central obesity, according to the WC cut-off points, was 66.8% in men and 85.1% in women. Low education, socioeconomic status and physical activity were risk factors for malnutrition and overweight/obesity. A possible cognitive impairment was found among elderly persons with BMI<22 kg/m2. A J-shaped association between BMI and hypertension, hypercholesterolemia, heart failure and other CV diseases, a U-shaped relation between BMI and diabetes mellitus, arthritis, and chronic bronchitis, and an inverted J-shape between BMI and gastric ulcer, osteoporosis and bone fractures, cancer, and prostatitis (in men) were found. CONCLUSIONS: Both low and high BMI are associated with a wide range of prevalent conditions and diseases in Menorca elderly men and women. PMID- 22499447 TI - Patterns of dietary supplement use among older men and women in the UK: findings from the Hertfordshire Cohort Study. AB - OBJECTIVES: To determine patterns of supplement use in a UK community-dwelling older population, and to investigate the extent to which supplement user groups differ, in terms of their sociodemographic and lifestyle characteristics, diet and morbidity. DESIGN: Cross-sectional cohort study. SETTING: Home interview and clinic visit. PARTICIPANTS: 3217 Hertfordshire Cohort Study participants, aged 59 to 73. MEASUREMENTS: Information was obtained on the participant's social and medical history by a trained research nurse. Diet over the preceding 3 months was assessed by Food Frequency Questionnaire; compliance with 'healthy' eating recommendations was defined using individual scores for a 'prudent' dietary pattern, identified using principal components analysis. Details of all dietary supplements taken in the preceding 3 months were recorded. Individual supplements were allocated to one of 10 types based on their nutrient composition. Cluster analysis was used to define groups of supplement users. RESULTS: 45.4% of men and 57.5% of women reported taking at least one dietary supplement in the previous 3 month period. There were 5 distinct clusters of supplement users; these were common to men and women. They were labelled according to the principal supplement taken; oils, glucosamine, single vitamins, vitamins and minerals, and herbal products. These groups differed in their social class and prudent diet score, but few other characteristics. With the exception of a difference in diagnosis of diabetes among the women, there were no differences in morbidity between the supplement groups in either men or women. CONCLUSIONS: Dietary supplement use is high in this population. There are distinct patterns of supplement use, which are related to sociodemographic and lifestyle characteristics including diet, though there were few clear differences in morbidity. PMID- 22499448 TI - Screening for frailty in elderly emergency department patients by using the Identification of Seniors At Risk (ISAR). AB - OBJECTIVES: Frail older adults are at an increased risk for adverse outcomes after an Emergency Department (ED) visit. Comprehensive geriatric assessment (CGA) has been proposed to screen for frailty in the ED, but it is difficult to carry out. We tested whether a CGA-based approach using the Identification of Seniors At Risk (ISAR) screening tool was associated with the brief deficit accumulation index (DAI) of frailty. DESIGN: Prospective observational study. SETTING: Two urban EDs in Italy. PARTICIPANTS: A cohort of 200 elderly (>=65 years) ED patients. MEASUREMENTS: Identifiers, triage, clinical and social data along with the administration of ISAR. CGA was performed using: Charlson Index, Short Portable Mental Status Questionnaire and Katz's ADL. Follow-up data at 30 and 180 days included: mortality, ED revisit, hospital admission, and functional decline. Frailty was defined according to a brief DAI. Logistic regression evaluated the consistency of the frailty definition; ROC curves evaluated ISAR ability in identifying frailty. RESULTS: Frailty was present in 117 (58.5%) subjects and predicted ED revisit and frequent ED return, hospitalization and 6 month mortality. ISAR had an AUC of 0.92 (95%CI 0.88-0.96, p<0.0001) in identifying frail elders in the ED and using a cut-off of 2 showed 94% sensitivity and 63% specificity. CONCLUSION: ISAR is a useful screening tool for frailty and identifies elderly patients at risk of adverse outcomes after an ED visit. ISAR can also be used to select high-risk patients more likely to benefit from a geriatric approach or intervention, independently of admission or discharge. PMID- 22499449 TI - Nutrition and vascular dementia. AB - OBJECTIVE: The objective of this review was to elucidate the relationship between VaD and various nutritional factors based on epidemiological studies. BACKGROUND: Vascular dementia (VaD) is the second most common type of dementia. The prevalence of VaD continues to increase as the US population continues to grow and age. Currently, control of potential risk factors is believed to be the most effective means of preventing VaD. Thus, identification of modifiable risk factors for VaD is crucial for development of effective treatment modalities. Nutrition is one of the main modifiable variables that may influence the development of VaD. METHODS: A systematic review of literature was conducted using the PubMed, Web of Science, and CINAHL Plus databases with search parameters inclusive of vascular dementia, nutrition, and vascular cognitive impairment (VCI). RESULTS: Fourteen articles were found that proposed a potential role of specific nutritional components in VaD. These components included antioxidants, lipids, homocysteine, folate, vitamin B12, and fish consumption. Antioxidants, specifically Vitamin E and C, and fatty fish intake were found to be protective against VaD risk. Fried fish, elevated homocysteine, and lower levels of folate and vitamin B12 were associated with increased VaD. Evidence for dietary lipids was inconsistent, although elevated midlife serum cholesterol may increase risk, while late-life elevated serum cholesterol may be associated with decreased risk of VaD. CONCLUSION: Currently, the most convincing evidence as to the relationship between VaD and nutrition exists for micronutrients, particularly Vitamin E and C. Exploration of nutrition at the macronutrient level and additional long term prospective cohort studies are warranted to better understand the role of nutrition in VaD disease development and progression. At present, challenges in this research include limitations in sample size, which was commonly cited. Also, a variety of diagnostic criteria for VaD were employed in the studies reviewed, indicating the need for constructing a correct nosological definition of VaD for consistency and conformity in future studies and accurate clinical diagnosis of VaD. PMID- 22499450 TI - Hydration and cognitive performance. AB - A clinical link exists between severe dehydration and cognitive performance. Using rapid and severe water loss induced either by intense exercise and/or heat stress, initial studies suggested there were alterations in short-term memory and cognitive function related to vision, but more recent studies have not all confirmed these data. Some studies argue that water loss is not responsible for the observations made, and studies compensating water losses have failed to prevent the symptoms. Studies in children have suggested that drinking extra water helps cognitive performance, but these data rely on a small number of children. In older adults (mean age around 60) the data are not strong enough to support a relationship between mild dehydration and cognitive function. Data on frail elderly and demented people are lacking. Methodological heterogeneity in these studies are such that the relationship between mild dehydration and cognitive performance cannot be supported. PMID- 22499451 TI - Recruitment, retention and other methodological issues related to clinical trials for Alzheimer's disease. PMID- 22499452 TI - Recruitment methods for United States Alzheimer disease prevention trials. AB - There are no substantially effective treatments or preventatives for Alzheimer disease. The few prevention trials that were undertaken did not shown efficacy for the drugs tested; but, nevertheless, advanced prevention trials methods. We review past recruitment methods and discuss areas for improvement. Improvements in recruitment methods can enhance the likelihood for accurately demonstrating the efficacy of an effective drug. Effective therapeutics to prevent AD await discovery and proof. PMID- 22499453 TI - Is there a rationale for including only patients already being treated with acetylcholinesterase inhibitors in a prodromal AD trial? AB - Prodromal AD clinical trial methodology is advancing rapidly. It is now possible to more accurately identify MCI patients with underlying AD pathology at an earlier stage of the disease through the use of amyloid imaging and CSF biomarkers. Measurement of decline in these early stage clinical trials using continuous clinical and cognitive outcome measures is conceptually more appealing and adds greater efficiency compared to the classical outcome of "conversion" to dementia used in prior MCI clinical trials. Nevertheless, the fact that many prodromal AD patients who are likely to be recruited to these early stage studies are not taking acetylcholinesterase inhibitors at the time of enrollment, but are poised to start taking them over a multi-year period of follow-up, is a potential confound that needs to be addressed. PMID- 22499455 TI - Are biomarkers harmful to recruitment and retention in Alzheimer's disease clinical trials? An international perspective. AB - Clinical trials in Alzheimer's disease (AD) do not only generate high costs but have also been of little success within recent years. The failure of several large phase III clinical trials on highly promising disease modifying compounds calls for a critical reflection on potential reasons and counter-measures. The recent introduction of new diagnostic criteria of AD and the development and validation of diagnostic and predictive AD biomarkers allows enriching study populations, reducing variance, and improving statistical power of trials while even opening the possibility to reduce total study costs. While CSF or extensive imaging biomarkers might adversely affect retention in clinical trials, their careful application will unlikely reduce adherence. Regulatory authorities are generally supportive of biomarker use in clinical trials but potential consequences of biomarker based patient selection on the generalizability of trial results need careful evaluation. PMID- 22499454 TI - Alzheimer's disease therapeutic trials: EU/US Task Force report on recruitment, retention, and methodology. AB - While we may not be able to find a cure for Alzheimer's disease (AD) in the near future, several drugs presently in trials have shown promise as possible modifiers of disease progression. However, we may not be able to demonstrate efficacy due to issues of recruitment, retention, site-to-site variability, and other methodological issues. It is thus incumbent on the scientific community to find solutions to these problems, particularly as the field moves toward preventing illness or treating the disease in its prodromal stages, where these methodological issues will become even more critical. We need to better understand why participants agree or refuse to enter drug trials, and why both primary care physicians and Alzheimer's specialists agree or refuse to involve their patients. We also need to quantify the impact of requiring imaging studies, extensive questionnaires, cognitive testing, and lumbar punctures on recruitment and retention. With these concerns in mind, an international task force meeting of experts from academia and industry in the United States, European Union, and Japan in San Diego, California on November 2, 2011 to focus on recruitment, retention and other methodological issues related to clinical trials for AD. Based on the recommendations of this Task force meeting, this Perspectives article critically reflects on the most critical and timely methodological issues related to recruitment and retention in prevention and therapeutic trials in AD, which are paralleled by a paradigm shift in the diagnostic conceptualization of this disease, as reflected by recently new proposed diagnostic criteria involving preclinical stages of the disease. PMID- 22499456 TI - Task force on Alzheimer's disease trial methodology: recruitment and retention, data management and analysis. The use of imaging in recruitment: maintenance and methodological issues in Alzheimer's trials. AB - Imaging has been used in clinical trials for decades and has proven a useful biomarker in many disease states. Although imaging is not widely used in clinical practice for AD patient care, many pharmaceutical and biotech companies have relied on this technique for eligibility, safety and efficacy roles in their trials. In this overview, issues with standardization, validation and regulations will be discussed in order to gain a better understanding of the benefits, risks and impact on study conduct of adding imaging to Alzheimer's disease clinical trials. PMID- 22499457 TI - Representations and practices of prevention in elderly populations: investigating acceptance to participate in and adhesion to an intervention study for the prevention of Alzheimer's disease (ACCEPT study)--the need for a multidisciplinary approach. AB - BACKGROUND: In the domain of Alzheimer's disease (AD) prevention, various potentially protective factors have been identified in epidemiological studies. Although the results of these observational studies have been relatively consistent, the results of intervention studies remain disappointing. Methodological problems could explain these negative results, like the selection of the population; a plausible assumption is that the older people who agree to take part in these intervention studies differ from those who refuse, and are those that are least likely to benefit from such programs. The aim of this study was (i) to study the determinants of participation in and adhesion to a prevention trial in a population of older individuals via a quantitative approach using a questionnaire, (ii) to study the representations and practices of prevention in this population using a qualitative approach using semi-structured interviews and focus groups. METHOD: The study population for the ACCEPT study was recruited at the time of inclusion of subjects in a prevention trial. The population was made up of persons aged 70 years or older, living at home and demonstrating some form of frailty, defined as a spontaneous memory complaint to their general practitioner or difficulties in carrying out instrumental activities of daily living. We used a quantitative approach based on the administration of a self-completed questionnaire sent to 1680 subjects having accepted to take part in the prevention trial, and to the sample of subjects meeting the inclusion criteria but having refused to take part. The qualitative approach, carried out at the moment of inclusion, involved subjects that having accepted to take part and subjects that having refused. Semi-structured interviews were carried out in order to understand the logic leading to refusal or acceptance. CONCLUSION: The analysis of the results will combine the viewpoints of the different disciplines. It will allow us to better understand the logic at work, to characterise the populations at risk of refusal, and perhaps to remove some of the barriers to participation in prevention programs. The identification of such barriers will provide feedback in terms of the conception and management of prevention measures. PMID- 22499458 TI - Recruitment strategies for preventive trials. The MAPT study (MultiDomain Alzheimer Preventive Trial). AB - 1680 participants were randomized over the recruitment period in MAPT study. A total of 1290 participants were recruited in the 7 University Hospital centers, and 390 participants in the 6 memory clinics around Toulouse Gerontopole / Alzheimer Disease research clinical center. The first randomization was on May 30, 2008, and the targeted number of randomized participants was reached on February 24, 2011; 2595 subjects were finally screened, of which 1680 fulfilled the eligibility criteria which represents 64.8%. Approximately, one quarter of screened people refused to participate after the detailed presentation of the study and 4.3% were still interested in participating but missed for unknown reasons the baseline visit even after repeated contacts. Of the 1810 subjects who signed the consent for participating to the study at the baseline visit, 130 (7.1%) were excluded because one of the eligibility criteria was not satisfied. Interestingly, the higher percentage of randomizations compared to screened participants is the personal contact source; almost 85 % of screened participants entered in the study. In an equivalent way, Medias and conferences are efficient recruiting sources to enrol volunteers in the study. Unexpectedly, only about 60% of screened participants from the hospital and GP sources were randomized and 33.2% from health care services. Almost a quarter of the randomized participants come from the hospital outpatients clinics and approximately 20% from public conferences. A total of 1128 contacts yielded to 556 screened volunteers and 345 randomized participants in the coordinating center of Toulouse. Thus, 30 % of contacts were recruited. PMID- 22499459 TI - Mixed model of repeated measures versus slope models in Alzheimer's disease clinical trials. AB - Randomized clinical trials of Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) typically assess intervention efficacy with measures of cognitive or functional assessments repeated every six months for one to two years. The Mixed Model of Repeated Measures (MMRM), which assumes an "unstructured mean" by treating time as categorical, is attractive because it makes no assumptions about the shape of the mean trajectory of the outcome over time. However, categorical time models may be over-parameterized and inefficient in detecting treatment effects relative to continuous time models of, say, the linear trend of the outcome over time. Mixed effects models can also be extended to model quadratic time effects, although it is questionable whether the duration and interval of observations in AD and MCI studies is sufficient to support such models. Furthermore, it is unknown which of these models are most robust to missing data, which plagues AD and MCI studies. We review the literature and compare estimates of treatment effects from four potential models fit to data from five AD Cooperative Study (ADCS) trials in MCI and AD. PMID- 22499460 TI - Glutamine preconditioning protects against local and systemic injury induced by orthopaedic surgery. AB - INTRODUCTION: Long bone surgery represents a significant surgical insults, and may cause severe local and systemic sequalae following both planned and emergent surgery. Glutamine offers pharmacological modulation of injury through clinically acceptable preconditioning. This effect has not been previously demonstrated in an orthopaedic model. AIMS: The aim of the study was to test the hypothesis that glutamine preconditioning protects against the local and systemic effects of long bone trauma in a rodent model. METHODS: Thirty two adult male Sprague-Dawley rats were randomised into four groups: Control group which received trauma without preconditioning; Normal Saline preconditioning 1 hour before trauma; Glutamine preconditioning 1 hour before trauma; Glutamine preconditioning 24 hours prior to trauma. Trauma consisted of bilateral femoral fracture following intramedullary instrumentation. Blood samples were taken before the insult, and at an interval four hours following this. Bronchioalveolar lavage (BAL) was performed, with skeletal muscle and lung harvested for evaluation. RESULTS: Glutamine pre-treated rats had lower Creatine Kinase levels, less creatinine elevation, and a significant reduction in neutrophil infiltration into BAL fluid. Glutamine pre treated rats showed less muscle and lung oedema. This effect was more pronounced for the group which received glutamine 24 hours before trauma. CONCLUSION: Preconditioning with a single bolus of intravenous glutamine prior to planned orthopaedic intervention affords loco-regional and distal organ protection. We believe these finding have significant implications for elective orthopaedic surgery where significant soft tissue and long bone manipulation is anticipated. PMID- 22499461 TI - Efficacy of a home-based intervention programme on the physical activity level and functional ability of older people using domestic services: a randomised study. AB - OBJECTIVE: Our main objective was to assess whether a home-based program supervised by home helpers (HH) during their normal working hours can prevent excessive sedentariness (mainly maximum walking time and distance) and preserve functional status in elderly people at risk for frailty or disability and using domestic services. DESIGN: A four-month, open label, randomised trial with two groups called "prevention" and "control". SETTING: In the homes of study participants. PARTICIPANTS: The participants were all over 78 years old, lived independently at home, and received the visits of HHs at least once a week. INTERVENTION: The intervention combined a self-administered exercise program, with 10 g amino-acid supplementation under the supervision of HHs. MEASUREMENTS: Main outcome measures included physical activity (the PASE questionnaire), functional tests, nutritional and autonomy scores, and compliance (50% or more was considered satisfactory). Non-parametric methods were used for comparisons between the two groups. A linear regression model was fitted to assess the effect of the intervention on the relative variation of outcomes, adjusted for unbalanced baseline co-variables. RESULTS: One hundred and two persons (prevention n=53, control n=49) with a median age of 85 years were included. Their median Activities of Daily Living and Instrumental Activities of Daily Living (IADL) scores were 6 and 7 respectively. Twenty-three (44%) were good compliers for both interventions. The maximum walking time remained stable while decreasing by 25% in the control group (p=0.0015); and fewer participants had a worsened IADL score in the prevention group (p=0.05). The baseline IADL Score was significantly associated with good compliance to the prevention program (p=0.0011). In good compliers, maximum walking distance and maximum walking time increased by 29.15% (0.0 to 66.7) and 33.3% (-20.0 to 50.0) respectively. CONCLUSION: This study confirms the feasibility of a prevention program supervised by HHs, and some benefit from the intervention and identifies predictors for better compliance. It will help in the design of prevention trials for elderly people at risk for frailty. PMID- 22499462 TI - A multifaceted intervention model can give a lasting improvement of older peoples' nutritional status. AB - OBJECTIVE: The purpose of this study was with a multifaceted intervention model improve the nutritional status of elderly people living in residential homes to increase their energy intake and to maintain improvements over time. SETTING: Three different municipal residential homes in the south-east of Sweden. PARTICIPANTS: The study population consisted of 67 elderly people. A within subjects design was used which means that the participants were their own controls. INTERVENTION: A multifaceted intervention model was chosen, which included education on both theoretical and practical issues, training and support for staff, and individualized snacks to the residents. MEASUREMENTS: Nutritional status was measured by Mini Nutritional Assessment (MNA), the consumption of food was recorded by the staff using a food record method for 3 consecutive days. The length of night-time fasting has been calculated from the food records. RESULTS: Nutritional status improved after 3 months of intervention and was maintained after 9 months. Weight increased during the whole study period. Night-time fasting decreased but not to the recommended level. CONCLUSION: This study shows that it is possible by a multifaceted intervention model to increase energy intake including expanding snacks and thereby improve and maintain nutritional status over a longer period in the elderly living in residential homes. This result was possible to achieve because staff received education and training in nutritional issues and by provision of support during a period when new routines were introduced. PMID- 22499463 TI - Prospective observational study of isoflavone and the risk of stroke recurrence: potential clinical implications beyond vascular function. AB - BACKGROUND: Whether isoflavone has any effect on recurrent cardiovascular events is unknown. OBJECTIVE: To investigate the relations between isoflavone intake and the risk of stroke recurrence. SUBJECTS AND METHODS: We recruited 127 consecutive patients with prior history of atherothrombotic/ hemorrhagic stroke (mean age: 67 +/- 11 years, 69% male) and prospectively followed up for a mean duration of 30 months. Stroke recurrence and major adverse cardiovascular events (MACE) were documented. Brachial flow-mediated dilatation (FMD) was measured using high resolution ultrasound. Isoflavone intake was estimated using a validated food frequency questionnaire. RESULTS: Median isoflavone intake was 6.9 (range: 2.1 - 14.5) mg/day. Isoflavone intake was independently associated with increased FMD (Pearson R=0.23, p=0.012). At 30 months, there were 10 stroke recurrence and 12 MACE. Kaplan-Meier analysis showed that patients with isoflavone intake higher than median value had significantly longer median stroke recurrence-free survival time (19.0 [range: 10.4 - 27.6] mth versus 5.0 [range: 4.1 - 5.9] mth, p=0.021) and MACE-free survival time (19.0 [range: 10.4 - 27.6] mth versus 4.0 [range: 2.4 - 5.6] mth, p=0.013). Using multivariate cox regression, higher isoflavone intake was an independent predictor for lower risk of stroke recurrence (hazards ratio 0.18 [95%CI: 0.03 - 0.95], risk reduction 82%, p=0.043) and MACE (hazards ratio 0.16 [95%CI: 0.03 - 0.84], risk reduction 84%, p=0.030). CONCLUSIONS: Higher isoflavone intake in stroke patients was associated with prolonged recurrence free survival, and reduced risk of stroke recurrence and MACE independent of baseline vascular function. Whether isoflavone may confer clinically significant secondary protection in stroke patients should be further investigated in a randomized controlled trial. PMID- 22499464 TI - Effects of genistein and daidzein on hippocampus neuronal cell proliferation and BDNF expression in H19-7 neural cell line. AB - OBJECTIVES: Estrogen replacement therapy (ERT) reduces the risk of Alzheimer's disease and symptoms in postmenopausal and elderly women. However, ERT is associated with increased risk of uterine and breast cancer. Dietary phytoestrogens have been suggested as a potential alternative to ERT, while little information is available regarding the effects and the underlying mechanisms of such treatment on central neuron function. The present study aimed to determine the effects of phytoestrogens including genistein and daidzein on the proliferation and survival of the hippocampus neural cells, which are of importance in learning and memory function. MEASUREMENTS: H19-7/IGF-IR neural cell line was cultured in DMEM absented of serum for 72 h, and treated with various concentrations of genistein, daidzein or 17beta-estradiol. Neuronal cell viability and proliferation were determined by MTT and BrdU assay, respectively Cell cycle analysis was performed using flow cytometry. The effects of genistein and daidzein on brain-derived neurotrophic factor (BDNF) mRNA and protein expression were determined by RT-PCR and ELISA, respectively. The effect of Trk receptors inhibitor on genistein and daidzein - induced hippocampus neuronal cell proliferation was also examined. RESULTS: 17beta-estradiol, genistein and daidzein ranged from 20 nM to 2000 nM significantly promoted hippocampus neuronal cell viability and proliferation. Similar to the effect of 17beta-estradiol, genistein and daidzein induced an increase in the percentage of cells in S phase. Genistein and daidzein significantly increased the expression of BDNF mRNA and protein levels. The effect of genistien and daidzein on hippocampus neuronal proliferation was blocked by K252a, a selective Trk receptors inhibitor. CONCLUSION: This study concluded that genistein and daidzein improved hippocampus neuronal cell viability and proliferation in vitro. These neuroprotective effects might be mediated by BDNF-Trk pathway. PMID- 22499465 TI - The effect of methionine supplementation of the AIN-93G semi-synthetic diet on the levels of homocysteine and lipids in experimental rats. AB - OBJECTIVES: The studies were carried out on 36 growing albino Wistar rats. PARTICIPANTS/MEASUREMENTS: The animals were randomly divided into six equinumerous groups (six rats per group), and were fed six different diets for 42 days. The control group (I) was fed with AIN-93G semi-synthetic diet, whereas groups II-VI were fed with AIN-93G semi-synthetic diet supplemented with: 2, 4, 8, 16 and 32 g of methionine/kg diet, respectively. There were assessed enzymatically, in rats' blood serum, the contents of homocysteine, total cholesterol, HDL fraction and triacyloglicerols. In addition, the LDL+VLDL cholesterol content was calculated. RESULTS: The methionine content of the diet was found to be highly positively correlated with the homocysteine content (r = 0.981) and negatively correlated with the triacylglycerols content (r = -0.916) of the experimental animals' blood serum. CONCLUSION: In the blood serum of rats fed the highest-methionine diet (32 g methionine/kg diet), the homocysteine content was significantly higher, as were the levels of total cholesterol and its HDL fraction, while the triacylglycerols content was lower as compared to the values obtained for rats fed other diet types. PMID- 22499466 TI - Probiotics in the gastrointestinal diseases of the elderly. AB - Changes of the gut microflora in elderly appear to involve a reduction in numbers of healthy bacteria (lactobacilli and bifidobacteria) and an increase in numbers of potentially pathogenic species. These changes are generally described as gastrointestinal disorders and infections. This review analyses benefits of probiotics in old people, with particular interesting for the latest researches relevant to elderly people, e.g. trials examining enteric infections, antibiotic associated diarrhea and Clostridium difficile associated diarrhea, functional bowel problems (constipation and irritable bowel syndrome), inflammatory bowel diseases, stimulation of the immune system and prevention of cancer. A growing number of researches indicates that some probiotic strains may help to maintain the health in old people, suggesting both health and cost-saving benefits in offering fermented dairy products. These benefits include: establishment of balanced intestinal microflora; improving colonization resistance and or prevention of diarrhea; reduction of fecal enzymes; reduction of serum cholesterol; reduction of potential mutagenes; reduction of lactose intolerance; synthesis of vitamins; predigestion of proteins. PMID- 22499469 TI - A method for accurate temperature measurement using infrared thermal camera. AB - The temperature distribution on a centre-holed thin foil of molybdenum, used as a sample and heated using a sample-heating holder for electron microscopy, was measured using an infrared thermal camera. The temperature on the heated foil area located near the heating stage of the heating holder is almost equal to the temperature on the heating stage. However, during the measurement of the temperature at the edge of the hole of the foil located farthest from the heating stage, a drop in temperature should be taken into consideration; however, so far, no method has been developed to locally measure the temperature distribution on the heated sample. In this study, a method for the accurate measurement of temperature distribution on heated samples for electron microscopy is discussed. PMID- 22499467 TI - Analyses of laboratory data and establishment of reference values and intervals for healthy elderly people. AB - OBJECTIVE: Protein-energy malnutrition is a common disorder in the elderly. Although serum albumin is commonly used as a nutritional marker, data is lacking on serum albumin levels in the elderly. The purpose of this study was to determine whether serum albumin levels decrease with advancing age and to establish reference value and interval of laboratory data for elderly people (75 years and over). PARTICIPANTS: Blood samples from 13821 healthy people, 42064 outpatients, and 15959 inpatients were collected during 2008. Blood from 127 of our nutrition support team (NST) patients was also collected during August 2006 and May 2009, and analyzed. MEASUREMENTS: Serum albumin, hemoglobin, total cholesterol levels and lymphocyte count were determined. We analyzed the change in each parameter in accordance with age, compared the data for elderly people with younger people, and established new reference values. Clinical outcomes were examined depending on the improved reference values. RESULTS: Albumin was lower in older persons than in younger persons. The estimated reference value and interval were 42 (48-36) g/l in older persons and was much lower in NST patients. Hemoglobin was decreased while cholesterol and lymphocyte count were not changed in older persons: all were markedly decreased in NST patients. Terms of hospital stay were significantly longer and mortality rates were significantly higher in older persons, comparing from above to below using a new reference value of albumin (36 g/l). CONCLUSIONS: The serum albumin level decreases with advancing age, but it was maintained to some extent in healthy older people. Serum albumin levels related to the clinical outcome. Hemoglobin and cholesterol levels and lymphocyte count were all lower in NST patients. These measurements may be valuable markers of nutritional status and can help in guiding the need for nutritional support. PMID- 22499468 TI - Walk on the sunny side of life--epidemiology of hypovitaminosis D and mental health in elderly nursing home residents. AB - OBJECTIVES: Old age is a well-known risk factor for both depression and hypovitaminosis D, and an association between both conditions has been postulated. We document the prevalence of vitamin D deficiency in nursing home residents, and we examine the link with self-reported depressive symptoms and pharmacotherapy for depression. DESIGN: Cross- sectional. SETTING: nursing homes in Antwerp, Belgium. PARTICIPANTS: Healthy elderly (n=589), with a mean age of 84 years. MEASUREMENTS: We detected depressive symptoms by means of SF-36, a validated quality of life assessment; we registered the use of antidepressants and anxiolytics, and we measured serum 25(OH)D concentrations in all participants. RESULTS: Almost our entire study population appeared to be vit D deficient. Comparison of the most severely and least deficient subgroups showed a consistent tendency towards more depressive symptoms and more use of antidepressants in the group with the lowest vit D level. CONCLUSION: Nursing home residents are particularly vulnerable to preventable vit D deficiency. The relevance of the association with depressive symptoms and the possibilities for treatment are critically reviewed in the discussion. PMID- 22499470 TI - Local symmetry breaking of a thin crystal structure of beta-Si3N4 as revealed by spherical aberration corrected high-resolution transmission electron microscopy images. AB - This report is an extension of the study for structural imaging of 5-6 nm thick beta-Si(3)N(4) [0001] crystal with a spherical aberration corrected transmission electron microscope by Zhang and Kaiser [2009. Structure imaging of beta Si(3)N(4) by spherical aberration-corrected high-resolution transmission electron microscopy. Ultramicroscopy 109, 1114-1120]. In this work, a local symmetry breaking with an uneven resolution of dumbbells in the six-membered rings revealed in the reported images in the study of Zhang and Kaiser has been analyzed in detail. It is found that this local asymmetry in the image basically is not relevant to a slight mistilt of the specimen and/or a beam tilt (coma). Rather the certain variation of the tetrahedral bond length of Si-N(4) in the crystal structure is found to be responsible for the uneven resolution with a local structural variation from region to region. This characteristic of the variation is also supposed to give a distorted lattice of apparently 2 degrees 2.5 degrees deviations from the perfect hexagonal unit cell as observed in the reported image in the work of Zhang and Kaiser. It is discussed that this variation may prevail only in a thin specimen with a thickness ranging ~<= 5-6 nm. At the same time, it is noted that the average of the bond length variation is close to the fixed length known in a bulk crystal of beta-Si(3)N(4). PMID- 22499471 TI - Synthesis, characterization of bridged bis(amidinate) lanthanide amides and their application as catalysts for addition of amines to nitriles for monosubstituted N arylamidines. AB - A series of lanthanide amide complexes supported by bridged bis(amidinate) ligand L, LLnNHAr(1)(DME) (L = [Me(3)SiNC(Ph)N(CH(2))(3)NC(Ph)NSiMe(3)], Ar(1) = 2,6 (i)Pr(2)C(6)H(3), DME = dimethoxyethane, Ln = Y (1), Pr (2), Nd (3), Gd (4), Yb (5)), [Yb(MU(2)-NHPh)](2)(MU(2)-L)(2) (6) and [LYb](2)(MU(2)-NHAr(2))(2) (7) (Ar(2) = (o-OMe)C(6)H(4)), were synthesized by reaction of LLnCl(THF)(2) with the corresponding lithium amide in good yields and structurally characterized by X ray crystal structure analyses. All complexes were found to be precatalysts for the catalytic addition of aromatic amines to aromatic nitriles to give monosubstituted N-arylamidines. The catalytic activity was influenced by lanthanide metals and the amido groups with the active sequence of Y (1) < Gd (4) < Nd (3) < Pr (2) ~ Yb (5) for the lanthanide metals and -NHAr(2) < -NHPh < NHAr(1) for the amido groups. The catalytic addition reaction with complex 5 showed a good scope of aromatic amines. Some key reaction intermediates were isolated and structurally characterized, including the amidinate complexes LLn[NPhCNAr(1)](PhCN) (Ln = Y (8), Ln = Yb (9)), LYb[NAr(2)CNAr(1)](Ar(2)CN) (10), and amide complex 5 prepared by protonation of 9 by Ar(1)NH(2). Reactivity studies of these complexes suggest that the present catalytic formation of monosubstituted N-arylamidines proceeds through nucleophilic addition of an amido species to a nitrile, followed by amine protonolysis of the resultant amidinate species. PMID- 22499472 TI - A sacred practice heralded in modern times: a personal perspective. PMID- 22499473 TI - Antimicrobial stewardship: the next big thing? PMID- 22499474 TI - Two strategies to intensify evidence-based medicine education of undergraduate students: a randomised controlled trial. AB - INTRODUCTION: Undergraduate evidence-based practice (EBP) is usually taught through standalone courses and workshops away from clinical practice. This study compared the effects of 2 clinically integrated educational strategies on final year medical students. MATERIALS AND METHODS: Final year medical students rotating to the general medicine service for a 2-week internship were randomly assigned to participate in a weekly EBP-structured case conference focusing on students' primary care patients (Group A, n = 47), or to receive a weekly didactic lecture about EBP (Group B, n = 47). The teaching effects of these 2 interventions were evaluated by a validated instrument for assessment of EBP related knowledge (EBP-K), attitude (EBP-A), personal application (EBP-P), and anticipated future use (EBP-F) on the first and last days of rotation. RESULTS: All scores improved significantly after the 2-week EBM-teaching for both groups. When compared to Group B, students in Group A had significantly higher post intervention scores of EBP-K (21.2 +/- 3.5 vs 19.0 +/- 4.6; ie. 57.8 +/- 72.9% vs 29.1 +/- 39.1%; P <0.01) and EBP-P (18.7 +/- 4.3 vs 15.3 +/- 3.9; ie. 28.5 +/- 25.5 % vs 14.1 +/- 18.7 %; P <0.001). In contrast, the scores of EBP-A and EBP-F were similar between the 2 groups. CONCLUSION: Structured case conference, when compared to the didactic lectures, significantly improved EBP-K and EBP-P for final year medical students. PMID- 22499475 TI - Surgical hand antisepsis-a pilot study comparing povidone iodine hand scrub and alcohol-based chlorhexidine gluconate hand rub. AB - INTRODUCTION: The surgeon uses different methods of surgical hand antisepsis with the aim of reducing surgical site infections. To date, there are no local studies comparing the efficacy of iodine hand scrub against newer alcohol-based hand rubs with active ingredients. Our pilot study compares a traditional aqueous hand scrub using 7.5% Povidone iodine (PVP-I) against a hand rub using Avagard: 61% ethyl alcohol, 1% chlorhexidine gluconate. The outcome measure is the number of Colony Forming Units (CFU) cultured from 10-digit fingertip imprints on agar plates. MATERIALS AND METHODS: Ten volunteers underwent 2 hand preparation protocols, with a 30-minute interval in between-Protocol A (3-minute of aqueous scrub using PVP-I) and Protocol B (3-minute of hand rub, until dry, using Avagard). In each protocol, fingertip imprints were obtained immediately after hand preparation (t(0)). The volunteers proceeded to don sterile gloves and performed specific tasks (suturing). At one hour, the gloves were removed and a second set of imprints was obtained (t(1)). RESULTS: Four sets of fingertip imprints were obtained. All 10 participants complied with the supervised hand preparation procedures for each protocol. CFUs of initial fingertip imprints (t(0)): The median CFU counts for initial imprint was significantly higher in the PVP-I treatment (median = 6, Inter Quartile Range (IQR) = 33) compared to the Avagard treatment (median = 0, IQR = 0, P <0.001). CFUs of fingertip imprint at 1 hour (t(1)): The median CFU counts for second imprint (t(1)) was significantly higher in the PVP-I treatment (median = 0.5, IQR = 11) compared to the Avagard treatment (median = 0, IQR = 0, P = 0.009). Our results suggest that the Avagard was more efficacious than aqueous PVP-I scrub at reducing baseline colony counts and sustaining this antisepsis effect. CONCLUSION: Alcohol hand rub with an active compound, demonstrated superior efficacy in CFU reduction. Based on our results, and those pooled from other authors, we suggest that alcohol-based hand rubs could be included in the operating theatre as an alternative to traditional surgical scrub for surgical hand antisepsis. PMID- 22499476 TI - Melanoma: differences between Asian and Caucasian patients. AB - INTRODUCTION: Cutaneous melanoma is rare in Asia and the clinical presentation and outcome of melanoma is not well described in Southeast Asia. In addition, it is unclear if ethnic variations exist between the various racial groups. The objective of our study is to present the clinical characteristics of melanoma in Singapore and to highlight ethnical differences between Asians and Caucasians living in Singapore. MATERIALS AND METHODS: Data were retrospectively collected from 48 patients with histological confirmation of melanoma who were seen in both the National Skin Centre and National Cancer Centre of Singapore. RESULTS: Acral lentiginous melanoma (ALM) was the most common subtype of melanoma in Singapore (50%). A higher proportion of non-ALM subtypes of melanoma compared to ALM were diagnosed at stage 1 (48% vs. 25%). The delay in diagnosis of ALM was 27 months compared to 12 months in other subtypes. Compared to Caucasians, there was a trend towards Asian patients being older, having a higher proportion of ALM and a longer delay to diagnosis. CONCLUSION: Geographical and ethnic variations in the clinical presentation of melanoma exist. Specially adapted programmes are necessary to increase awareness of the different clinical presentation of melanoma in Asia and to encourage examination of the palms and soles in order to reduce the delay in diagnosis. PMID- 22499477 TI - 2011 Young Surgeon's Award Winner: high endothelial venules: a novel prognostic marker in cancer metastasis and the missing link? AB - INTRODUCTION: The extent of lymph nodes (LNs) metastasis is a major determinant for the staging and the most reliable adverse prognostic factor. Primary tumours can induce lymphatics and vasculature reorganisations within sentinel LN before the arrival of cancer cells and these key blood vessels are identified as high endothelial venules (HEV). The alterations of HEV in the presence of cancer, coupled with the increased proliferation rate of the endothelial cells, results in a functional shift of HEV from immune response mediator to blood flow carrier. We aim to evaluate tumour-induced vascularisation in regional LN of cancer patients by studying the morphological and functional alterations of HEV and its correlation to clinico-pathological features. MATERIALS AND METHODS: This multi centre study with a prospective database identified 65 consecutive patients with tongue squamous cell carcinoma (SCC) who underwent primary surgical treatment from 2001 to 2005. Immunohistochemical staining for HEV and image analysis were performed and analysed with correlation to the patients' clinico-pathological features. RESULTS: The total number of HEV is significantly associated to disease free interval when controlling for the group (P = 0.022) as well as combining both groups as one cohort (P = 0.023). There is also a similar association comparing the HEV parameters to overall survival. CONCLUSION: Our results suggest that HEV possibly plays a key role in the pathogenesis of lymphatic and subsequent distant metastases and may provide the missing link in cancer metastasis. Confirmation of this hypothesis would offer a novel therapeutic approach to preventing metastasis by blocking the remodeling processes of HEV in LN. PMID- 22499478 TI - Guidelines for antimicrobial stewardship training and practice. PMID- 22499479 TI - A case of dermatopathic lymphadenopathy associated with hypereosinophilic syndrome. PMID- 22499480 TI - Lymph node metastases in malignant colonic polyp with favourable histology detected by PET CT. PMID- 22499481 TI - Ortner's syndrome secondary to aortic aneurysm. PMID- 22499482 TI - An intensely pruritic papular eruption - is there a distant cause? PMID- 22499483 TI - Gradient system characterization by impulse response measurements with a dynamic field camera. AB - This work demonstrates a fast, sensitive method of characterizing the dynamic performance of MR gradient systems. The accuracy of gradient time-courses is often compromised by field imperfections of various causes, including eddy currents and mechanical oscillations. Characterizing these perturbations is instrumental for corrections by pre-emphasis or post hoc signal processing. Herein, a gradient chain is treated as a linear time-invariant system, whose impulse response function is determined by measuring field responses to known gradient inputs. Triangular inputs are used to probe the system and response measurements are performed with a dynamic field camera consisting of NMR probes. In experiments on a whole-body MR system, it is shown that the proposed method yields impulse response functions of high temporal and spectral resolution. Besides basic properties such as bandwidth and delay, it also captures subtle features such as mechanically induced field oscillations. For validation, measured response functions were used to predict gradient field evolutions, which was achieved with an error below 0.2%. The field camera used records responses of various spatial orders simultaneously, rendering the method suitable also for studying cross-responses and dynamic shim systems. It thus holds promise for a range of applications, including pre-emphasis optimization, quality assurance, and image reconstruction. PMID- 22499485 TI - D. A. Leigh. PMID- 22499484 TI - Practical guidelines for the high-sensitivity detection and monitoring of paroxysmal nocturnal hemoglobinuria clones by flow cytometry. AB - BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a life-threatening disorder caused by an inability to make glyco-phosphatidyl-inositol (GPI) anchors. While flow cytometry is the method of choice to detect the loss of GPI linked proteins, the development and validation of sensitive, standardized, methodologies have been hampered by the rarity of this disease and by technical difficulties in the accurate identification of PNH cells. METHODS: Guidelines for the diagnosis and monitoring of PNH by flow cytometry were recently published by the International Clinical Cytometry Society (ICCS). However, specific reagent cocktails, and associated detailed analytic strategies were not directly addressed therein. In this supporting document based on the ICCS guidelines, we provide concise practical protocols for the high-sensitivity detection of PNH RBCs and WBCs (both granulocytes and monocytes). RESULTS: The CD235aFITC/CD59PE assay described was capable of detecting as few as 20 Type III PNH RBCs per million cells. Frequencies of Type III PNH cells in 10 normal samples were in the 0-6 per million RBCs. The high-resolution granulocyte/neutrophil assays described in this study could detect PNH phenotypes consistently at a level of 0.01% sensitivity. Frequencies of PNH phenotypes in normal individuals were in the 0-10 per million granulocytes/neutrophils range. CONCLUSIONS: The careful screening and selection of specific antibody conjugates has allowed the development of reagent cocktails suitable for high-sensitivity flow cytometric detection of PNH RBCs and PNH WBCs. The reagent cocktails described herein can be used on a variety of clinical flow cytometers equipped with four or more photo multiplier tubes. PMID- 22499486 TI - Cytotoxicity and cell imaging potentials of submicron color-tunable yttria particles. AB - Increased demand of environment protection encouraged scientists to design products and processes that minimize the use and generation of hazardous substances. This work presents comprehensive result of large-scale fabrication and investigation of red-to-green tunable submicron spherical yttria particles codoped with low concentrations of Eu(+3) and Tb(+3). The color emission of synthesized particles can be precisely tuned from red to green by simple variation of Tb/Eu ratio and excitation wavelength. The Tb/Eu-codoped Y(2)O(3) particles did not adversely affect the viability of L-929 fibroblastic cells at concentrations less than 62.5 ppm. Through internalization and wide distribution inside the cells, Tb/Eu codoped Y(2)O(3) particles with intense bright green or red fluorescence rendered cell imaging to be possible. The high brightness, excellent stability, low-toxicity, and imaging capability along with fine color tunability of synthesized particles enable to find promising application in various areas. PMID- 22499487 TI - Non-traditional flours: frontiers between ancestral heritage and innovation. AB - Renewed interest in under-utilized plant species that can be used for obtaining flour mainly arises from the finding and promotion of nutritionally relevant attributes. These products can also gain value as functional foods and ingredients. Although they are often presented as new crops and raw materials, they have been used by local populations in traditional ways for many centuries. Their innovation is rather related to the ways in which old and new uses are being readdressed. The present work summarizes recent information about production, chemical composition, nutritional and functional components and health benefits of non-traditional flours. Amongst the most representative groups, pseudocereals, roots and tubers, and leguminous flours are included. Since non-traditional flours or other derivatives could contain relatively high amounts of antinutritional factors that also have health implications, related information about this subject is included. PMID- 22499488 TI - Organ transplantation update, part I: liver, intestine, and pancreas. PMID- 22499489 TI - Long-term outcome after liver transplantation. AB - Liver transplantation is a life-saving therapy for patients with end-stage liver disease, acute liver failure, and liver tumors. Over the past 4 decades, improvements in surgical techniques, peritransplant intensive care, and immunosuppressive regimens have resulted in significant improvements in short term survival. Focus has now shifted to addressing long-term complications and improving quality of life in liver recipients. These include adverse effects of immunosuppression; recurrence of the primary liver disease; and management of diabetes, hypertension, dyslipidemia, obesity, metabolic syndrome, cardiovascular disease, renal dysfunction, osteoporosis, and de novo malignancy. Issues such as posttransplant depression, employment, sexual function, fertility, and pregnancy must not be overlooked, as they have a direct impact on the liver recipient's quality of life. This review summarizes the latest data in long-term outcome after liver transplantation. PMID- 22499490 TI - Recurrent hepatitis C after liver transplantation. AB - Infection with hepatitis C virus is the most common indication for liver transplantation in the United States. Although recurrence of hepatitis C virus infection is universal following transplantation, the natural history of posttransplantation hepatitis C varies. In general, however, posttransplant hepatitis C virus infection progresses relatively quickly, with 10%-20% of patients developing cirrhosis within 5 years. Risk factors for severe recurrent hepatitis C include donor age, female sex, treatment of rejection, preservation injury, and high viral load pretransplant or early posttransplant. Type of allograft, infection with cytomegalovirus, or type of calcineurin inhibitor used may not play a role. Treatment with interferon + ribavirin in recurrent hepatitis C virus shows mixed results. Sustained virologic response has been observed in only 8%-30% of patients, and side effects of these medications are considerable. Protease inhibitors are not yet approved for the posttransplant population, but clinical trials are under way. PMID- 22499491 TI - Current concepts in pediatric liver transplantation. AB - Liver transplantation is the definitive treatment for end-stage liver disease in both children and adults. Advances over the last 2 decades have resulted in excellent patient and graft survival rates in what were previously cases of fatal disorders. These developments have been due to innovations in surgical technique, increased surgical experience, refinements in immunosuppressive regimens, quality improvements in intraoperative anesthetic management, better understanding of the pathophysiology of the liver diseases, and better preoperative and postoperative care. Remarkably, the use of split-liver and living-related liver transplantation surgical techniques has helped mitigate the well-recognized national organ shortage. This review will discuss the major aspects of pediatric liver transplantation as it pertains to indication for transplantation, recipient selection and listing for orthotopic liver transplantation, pre-orthotopic liver transplantation care of children, optimal timing of orthotopic liver transplantation, surgical technical considerations, postoperative care and complications, and patient and graft survival outcomes. PMID- 22499492 TI - Living donor liver transplantation: ethical considerations. AB - Most solid-organ transplants performed in the Western world are from deceased donors. In the last decade, deceased donation rates have reached a plateau as the number of patients with end-stage organ disease has steadily increased, resulting in a large discrepancy between organ supply and demand. Living donor transplantation is one way to decrease this discrepancy. However, living donation is not universally accepted. For instance, living donation rates vary geographically (eg, living donation is more accepted in Asia than in the Western world) and depend on the organ donated (eg, kidney versus liver donation). In this article we will review the ethical principles guiding living donor liver transplantation, with emphasis on justification and safeguards that support the practice of adult-to-adult living donor liver transplantation, the most clinically and ethically challenging type of living organ donation. Our ethical justification will include a presentation of triangular or tripartite equipoise, a framework that aims to balance donor safety, expected recipient outcomes, and need. PMID- 22499493 TI - Surgical management of hepatocellular carcinoma. AB - Hepatocellular carcinoma is the sixth most common cancer worldwide and its incidence is rising in Western countries. Liver resection is the treatment of choice in noncirrhotic patients and in cirrhotic patients with well-preserved liver function. Postresection survival rates are in the range of 41-74% at 5 years. Predictors of recurrence include tumor grade, vascular invasion, tumor size, number of tumors, presence of satellites, alpha-fetoprotein level, transfusion, and positive surgical margin. Second hepatic resection for recurrent hepatocellular carcinoma is applicable in about 15% of patients with recurrence. Liver transplantation has become an important element of the therapeutic strategy for hepatocellular carcinoma. Liver transplantation provides excellent outcomes applying the Milan criteria with 5-year survival rates of 70% and low recurrence rates. Intention-to-treat analysis has shown that wide extended indications lead to 25% 5-year survival rates. Expansion of indications beyond the Milan Criteria and use of bridging/downstaging procedures, to convert intermediate advanced stages of hepatocellular cancer within the Milan criteria limits, are counterbalanced by graft shortage and increasing use of marginal donors. Living donor transplantation is an alternative that can eliminate the waiting time and the attendant risk of drop-out. PMID- 22499494 TI - Current management of cholangiocarcinoma. AB - Cholangiocarcinoma is the second most common primary hepatobiliary malignancy after hepatocellular carcinoma and remains among the most difficult management problems faced by surgeons. Curative surgery is achieved in only 25% to 30% of patients. Local tumor extent, such as portal vein invasion and hepatic lobar atrophy, does not preclude resection. Long-term survival has been seen only in patients who underwent extensive liver resections, suggesting that bile-duct excision alone is less effective. The majority of patients have unresectable disease, with 20% to 30% incidence of distant metastasis at presentation. Unresectable patients should be referred for nonsurgical biliary decompression, and in potential curative resection candidates the use of biliary stents should be reduced. Liver transplantation provides the option of wide resection margins, expanding the indication of surgical intervention for selected patients who otherwise are not surgical candidates due to lack of functional hepatic reserve. PMID- 22499495 TI - Intestinal transplantation outcomes. AB - Intestinal transplantation has evolved from being considered an experimental procedure into a clinically accepted therapy for patients with intestinal failure and parenteral nutrition life-threatening complications. Early referral, advances in immunosuppression therapy, standardization of surgical techniques, prophylactic therapy of infections, early diagnosis of rejection, and better posttransplant patient management are some of the changes that have allowed more patients to receive transplants, thus recovering intestinal sufficiency, and at the same time allowing the procedure to spread worldwide. Over the last 2 decades, transplant centers have focused on improving short-term patient survival, which has consequently increased by >20%. It is now clear that even though isolated intestinal-transplant recipients have lower mortality risk on the waiting list, they are at higher risk for long-term graft loss. Mortality is higher on the waiting list and early posttransplant in recipients whose intestinal transplants are associated with liver grafts; however, they have better long-term patient and graft survival. Nevertheless, 3-year actuarial patient survival has not changed over the same period of time, and therefore this is our challenge for the next decade. PMID- 22499496 TI - Intestinal rehabilitation and transplantation for intestinal failure. AB - The management of intestinal failure has evolved dramatically in the last decade. This evolution has been in equal part due to continued improvements in outcomes of intestinal transplantation and to recognition of the need for multidisciplinary management of the patient with intestinal failure. This has led to establishment of intestinal rehabilitation programs, centered only in some instances at institutions with established intestinal transplant programs. Alongside this, improved management of parenteral nutrition-associated liver disease is creating a paradigm shift in both intestinal-failure management and in the evolving indications for intestinal transplantation. Unsolved challenges remain: A persistent mortality on the waiting list, especially for patients awaiting combined liver-intestine transplant; late graft loss to chronic rejection, especially in isolated intestine transplant; the role of antibody mediated rejection; and transplantation in the highly sensitized patient continue to defy satisfactory solution. Notwithstanding these challenges, overall outcomes for patients with intestinal failure are vastly improved today and are approaching those for patients with end-stage renal and liver disease. This review will focus on a comprehensive approach to the patient with intestinal failure, including an overview of intestinal rehabilitation and transplantation. Transplantation outcomes and transplantation of the patient with liver disease are covered elsewhere. PMID- 22499497 TI - Curing diabetes with transplantation? AB - Type 1 diabetes affects >1 million people in the United States, where it accounts for up to 10% of all diabetes cases. Glycemic control via the use of exogenous insulin injections in diabetic patients is incomplete, resulting in multiple long term complications such as retinopathy, neuropathy, vasculopathy, and nephropathy. The goal of beta-cell replacement by whole-pancreas or islet transplantation is to achieve long-term insulin independence, and the proposed benefits are improved quality of life, prevention of recurrent diabetic nephropathy, stabilization or improvement in secondary complications, and improved mortality. No other regimen of insulin delivery can achieve this level of physiologic regulation. PMID- 22499498 TI - Geriatric vision loss due to cataracts, macular degeneration, and glaucoma. AB - The major causes of impaired vision in the elderly population of the United States are cataracts, macular degeneration, and open-angle glaucoma. Cataracts and macular degeneration usually reduce central vision, especially reading and near activities, whereas chronic glaucoma characteristically attacks peripheral vision in a silent way, impacting balance, walking, and driving. Untreated, these visual problems lead to issues with regard to taking medications, keeping track of finances and personal information, walking, watching television, and attending the theater, and often create social isolation. Thus, visually impaired individuals enter nursing homes 3 years earlier, have twice the risk of falling, and have 4* the risk of hip fracture. Consequently, many elderly with low vision exercise greater demands on community services. With the prospect of little improvement and sustained visual loss, in the face of poor tolerance of low vision services and not accepting magnification as the only way to read, clinical depression is common. In many instances, however, early and accurate diagnosis can result in timely treatment and can preserve quality of life. This review will look at current diagnostic and therapeutic considerations. Currently, about 20.5 million people in the United States have cataracts. The number will reach 30 million by 2020. About 1.75 million Americans currently have some form of macular degeneration, and the number is estimated to increase to 2.95 million in 2020. Approximately 2.2 million Americans have glaucoma, and by 2020 that number is estimated to be close to 3.4 million people. It is projected that by 2030 there will be 72.1 million seniors. With some overlap of the above 3 groups conservatively estimated (if you add the 2030 cataract group to the macular degeneration and glaucoma groups), then about 1 in 2 senior individuals by 2030 may have some significant ocular disease, which could account for about 50% of the healthcare budget for the elderly. PMID- 22499499 TI - Automated analysis of coronary artery disease by computed tomography. AB - Computer-assisted detection systems are widely used in many areas of radiology. Coronary computed tomography angiography is a growing area of clinical cardiology and computer-assisted detection systems play an integral part in analysis. Truly automated systems are still in clinical-trial stages, but manually assisted programs are in clinical use today for calcium scoring as well as plaque burden, composition, and stenosis analysis. They are being used as a tool for confirmation more than for diagnosis. Accurate plaque-composition analysis would be a critical tool for better understanding the mechanisms and effectiveness of novel therapies for coronary atherosclerosis. A need for a complete quick, safe, noninvasive plaque analysis is the goal of automated coronary stenosis detection systems; however, their potential clinical benefit remains unknown. PMID- 22499500 TI - Sulfur-bridged annulene-TCNQ co-crystal: a self-assembled ''molecular level heterojunction'' with air stable ambipolar charge transport behavior. PMID- 22499501 TI - Vitamin D-related genetic variation, plasma vitamin D, and risk of lethal prostate cancer: a prospective nested case-control study. AB - BACKGROUND: The association of vitamin D status with prostate cancer is controversial; no association has been observed for overall incidence, but there is a potential link with lethal disease. METHODS: We assessed prediagnostic 25 hydroxyvitamin D [25(OH)D] levels in plasma, variation in vitamin D-related genes, and risk of lethal prostate cancer using a prospective case-control study nested within the Health Professionals Follow-up Study. We included 1260 men who were diagnosed with prostate cancer after providing a blood sample in 1993-1995 and 1331 control subjects. Men with prostate cancer were followed through March 2011 for lethal outcomes (n = 114). We selected 97 single-nucleotide polymorphisms (SNPs) in genomic regions with high linkage disequilibrium (tagSNPs) to represent common genetic variation among seven vitamin D-related genes (CYP27A1, CYP2R1, CYP27B1, GC, CYP24A1, RXRA, and VDR). We used a logistic kernel machine test to assess whether multimarker SNP sets in seven vitamin D pathway-related genes were collectively associated with prostate cancer. Tests for statistical significance were two-sided. RESULTS: Higher 25(OH)D levels were associated with a 57% reduction in the risk of lethal prostate cancer (highest vs lowest quartile: odds ratio = 0.43, 95% confidence interval = 0.24 to 0.76). This finding did not vary by time from blood collection to diagnosis. We found no statistically significant association of plasma 25(OH)D levels with overall prostate cancer. Pathway analyses found that the set of SNPs that included all seven genes (P = .008) as well as sets of SNPs that included VDR (P = .01) and CYP27A1 (P = .02) were associated with risk of lethal prostate cancer. CONCLUSION: In this prospective study, plasma 25(OH)D levels and common variation among several vitamin D-related genes were associated with lethal prostate cancer risk, suggesting that vitamin D is relevant for lethal prostate cancer. PMID- 22499502 TI - The controlled release of vancomycin in gelatin/beta-TCP composite scaffolds. AB - Osteomyelitis remains a difficult infection to treat for orthopaedic surgeons regardless of the continuous advances in surgical techniques and antimicrobial agents. The controlled release of vancomycin from local delivery system is a promising method for eliminating infection. In this study, biodegradable gelatin sponge containing different contents of beta-tricalcium phosphate ceramic (beta TCP) was prepared for the controlled-release of vancomycin. We aimed to confirm the composite scaffolds could be used as a vancomycin sustained-release system. Examinations of scanning electron microscopy, Fourier transform infrared spectroscopy, mechanical properties, and in vivo drug release were performed. The results showed that the composite scaffolds could achieve local therapeutic drug levels over an extended duration. Taking consideration of porosity, interconnection, mechanical properties, and controlled release performance, the composite gelatin scaffold containing 30% beta-TCP granules may be a good candidate for the controlled release of vancomycin in the treatment of chronic osteomyelitis. PMID- 22499504 TI - Electrochemically induced surface-initiated atom-transfer radical polymerization. PMID- 22499503 TI - NOrmalized MAgnetization Ratio (NOMAR) filtering for creation of tissue selective contrast maps. AB - An MRI segmentation technique based on collecting two additional saturation transfer images is proposed as an aid for improved detection of chemical exchange saturation transfer agents. In this approach, the additional images are acquired at saturation frequencies of -12.5 and -50 ppm. Use of the ratio of these images allows differentiation of voxels with low magnetization transfer contrast (such as fat, cerebrospinal fluid, edema, or blood) from target tissue voxels using a global threshold determined by histogram analysis. We demonstrate that this technique can reduce artifacts, in vitro, in a phantom containing tubes with chemical exchange saturation transfer contrast agent embedded in either crosslinked bovine serum albumin or buffer, and in vivo for detecting diamagnetic CEST (DIACEST) liposomes injected into mice. PMID- 22499505 TI - Probing the role of mesenchymal stem cells in salivary gland cancer on biomimetic microdevices. AB - Mesenchymal stem cells (MSCs) are the progenitors of stromal cells, which have been found to interact with cancer cells and represent an important target for cancer therapies. Salivary gland cancer is an aggressive malignant epithelial tumor and can easily disseminate to distant sites in vivo. In this work, we probed the role of MSCs in salivary gland cancer in an in vivo like tumor microenvironment by using a series of functional microfluidic devices for 2D and 3D assays. The results demonstrated that MSCs could be recruited by salivary gland cancer cells (ACC-M) and this effect was potentially mediated by TGF-beta secreted by cancer cells. In addition, MSCs exhibited the ability to squeeze into ACC-M spheroids by dispersing the cell-cell connection and reducing the expression of E-cadherin in cancer cells. In particular, MSCs exhibited the ability to enhance the invasion of salivary cancer under a chemokine CXCL12 gradient, indicating the involvement of a CXCL12-CXCR4 pathway and the tumor promoting properties of MSCs in cancer progression. This study recreated an in vivo-like tumor microenvironment by constructing a series of functional microdevices and explored the role of MSCs in ACC invasion for the first time. It provides a unique platform to open up new options to target stromal cells for cancer therapy and also analyzed the potential risk of using MSCs as drug delivery carriers for therapeutic purposes in carcinoma treatment. PMID- 22499507 TI - [Maternal deprivation-induced stress responses in female rats]. AB - OBJECTIVE: To investigate the effect of maternal deprivation on the activity of hypothalamo-pituitary-adrenal (HPA) axis, acute stress response and the sex hormone receptors expression in hypothalamic paraventricular nucleus (PVN) in female rats. METHODS: Maternal deprivation model was induced in female Sprague Dawley (SD) rats. Foot shock was given at different stages of estrus cycle during the adulthood. Plasma estradiol, testosterone and adrenocorticotropin (ACTH) levels were determined by radioimmunoassay; and plasma corticosterone level was measured by enzyme linked immunosorbent assay. The expression of androgen receptor (AR) and estrogen receptor (ER-beta) in the hypothalamic PVN was detected by immunohistochemistry. RESULTS: Decreased plasma ACTH and corticosterone levels were found in the proestrus of female rats with maternal deprivation (P=0.012 and P=0.019, respectively). A significant down-regulation (P=0.008) of PVN-AR, but not PVN-ER-beta expression was found in female rats with maternal deprivation. CONCLUSION: Maternal deprivation may reduce the HPA axis activity in female SD rats, which is closely correlated with the fluctuation of the circulating sex hormones. The androgen in the hypothalamus seems to play a more important role than the estrogen in this procedure. PMID- 22499508 TI - [Alterations of plasma aspartic acid, glycine and asparagine levels in patients with major depressive disorder]. AB - OBJECTIVE: To evaluate the changes of plasma levels of the excitatory amino acid neurotransmitter aspartic acid (Asp), inhibitory neurotransmitter glycine (Gly) and asparagine (Asn) in patients with major depressive disorder (MDD). METHODS: Plasma samples were collected from 15 MDD patients (9 males and 6 females, aged 32-64 y) and 14 healthy subjects (7 males and 7 females, aged 30-65 y); and also collected from 7 MDD patients (5 males and 2 females) 2 months after antidepressant treatment. The plasma levels of amino acids were determined by high performance liquid chromatography with fluorescence detection method. RESULTS: Plasma Asp and Gly levels were significantly lower in MDD patients than those in controls (P<0.04). There were positive correlations between plasma levels of Gly and Asp, and between Gly and Asn (P<0.005) in the control group; while in MDD patients, a significant positive correlation was found only between plasma levels of Gly and of Asp (P<0.001). MDD patients did not show significant changes in plasma Asp, Asn and Gly levels after antidepressant treatment compared to those before treatment. CONCLUSION: The reduced plasma Asp and Gly levels may serve as a clinical biomarker for MDD. PMID- 22499506 TI - Lentiviral vectors encoding short hairpin RNAs efficiently transduce and knockdown LINGO-1 but induce an interferon response and cytotoxicity in central nervous system neurones. AB - BACKGROUND: Knocking down neuronal LINGO-1 using short hairpin RNAs (shRNAs) might enhance axon regeneration in the central nervous system (CNS). Integration deficient lentiviral vectors have great potential as a therapeutic delivery system for CNS injuries. However, recent studies have revealed that shRNAs can induce an interferon response resulting in off-target effects and cytotoxicity. METHODS: CNS neurones were transduced with integration-deficient lentiviral vectors in vitro. The transcriptional effect of shRNA expression was analysed using quantitative real time-polymerase chain reaction and northern blots were used to assess shRNA production. RESULTS: Integration-deficient lentiviral vectors efficiently transduced CNS neurones and knocked down LINGO-1 mRNA in vitro. However, an increase in cell death was observed when lentiviral vectors encoding an shRNA were applied or when high vector concentrations were used. We demonstrate that high doses of vector or the use of vectors encoding shRNAs can induce an up-regulation of interferon-stimulated genes (2',5'-oligoadenylate synthase 1 and protein kinase R although not myxovirus resistance 1) and a down regulation of off-target genes (including p75(NTR) and Nogo receptor 1). Furthermore, the northern blot demonstrated that these negative consequences occur even when lentiviral vectors express low levels of shRNAs. Taken together, these results may explain why neurite outgrowth was not enhanced on an inhibitory substrate following transduction with lentiviral vectors encoding an shRNA targeting LINGO-1. CONCLUSIONS: These findings highlight the importance of including appropriate controls to verify silencing specificity and the requirement to check for an interferon response when conducting RNA interference experiments. However, the potential benefits that RNA interference and viral vectors offer to gene-based therapies to CNS injuries cannot be overlooked and demand further investigation. PMID- 22499509 TI - [Cysteinyl leukotriene receptor 1 is involved in rotenone-induced injury of PC12 cells]. AB - OBJECTIVE: To investigate whether cysteinyl leukotriene receptor 1 (CysLT1 receptor) is involved in rotenone-induced injury of PC12 cells. METHODS: After 24 h treatment with rotenone or with rotenone and the CysLT1 receptor antagonist montelukast, PC12 cell viability was determined by the colorimetric MTT reduction assay. After PC12 cells were treated with various concentrations of rotenone for 24 h or with 3 MUmol/L rotenone for various durations, the expression of CysLT(1) receptor was determined by Western blotting, and its intracellular distribution was detected by immunocytochemistry. RESULTS: Rotenone (0.3-30 MUmol/L) induced PC12 cell injury; this injury was significantly attenuated by montelukast at 1 and 5 MUmol/L.The expression of CysLT(1) receptor increased after rotenone treatment at 1-10 MUmol/L, or at 3 MUmol/L for 3 and 24 h. Rotenone caused concentration-and time-dependent translocation of CysLT1 receptor from the nucleus to the cytosol. CONCLUSION: Cysteinyl leukotriene receptor 1 is involved in rotenone-induced injury of PC12 cells. PMID- 22499510 TI - [Protective effect of nicotinamide in a mouse Parkinson's disease model]. AB - OBJECTIVE: To examine the protective effect of nicotinamide on 1-methyl-4-phenyl 1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) in mouse model and its mechanisms. METHODS: Parkinson's disease was induced by injection of MPTP in adult male C57BL/6 mice, nicotinamide (500 mg/kg,i.p.) was given prior to subacute (30 mg/kg/d * 5 d,i.p.) MPTP administration. Locomotor activities, striatal dopamine levels, lactate dehydrogenase (LDH) and NO synthase (NOS) activities of whole brains and striatum were analyzed at d5 after last MPTP injections. RESULTS: Pretreatment with nicotinamide significantly improved the locomotor activity in the open-field test (P<0.01), but not in the swimming test and grip & climbing test. Nicotinamide administration resulted in sparing striatal dopamine levels from MPTP-induced dopamine depletion. There was no significant difference in LDH and NOS activities in the whole brains among the groups; but the activities in the striatum were drastically elevated after MPTP treatment. Nicotinamide pretreatment markedly inhibited MPTP-induced LDH and NOS activities (P<0.01) and showed no significant difference compared to controls (P>0.05). CONCLUSION: Nicotinamide protects dopaminergic neurons against MPTP induced neurodegeneration,which suggests that the neuroprotective effects be associated with the inhibition of cell injuries and NOS activities. PMID- 22499511 TI - [K83 site affects PICK1 PDZ binding ability]. AB - OBJECTIVE: To investigate the role of 83 site in interaction of GluR2 C-terminal and PICK1 PDZ domain. METHODS: Docking structure of PICK1 PDZ domain with GluR2 C terminal PDZ binding motif was built with computer software. After K83 site was substituted by other amino acid, the structure and binding energy were recalculated; meanwhile, site specific mutants were constructed using wild type full length cDNA as template. Mutants were co-transfected with GluR2 into HEK293T cells. After staining, the distribution of PICK1 and GluR2 were observed under confocal microscope. RESULTS: Wild type PICK1 and GluR2 formed many co-clusters in HEK293T cells as reported by other research groups; but different K83 mutant had different distribution in HEK293T cells. CONCLUSION: The K83 site in PDZ domain of PICK1 is important for the interaction between PICK1 and GluR2. Altering lysine will probably change the hydrophobic interactions, the hydrogen bonds or the electrostatic interactions formed between PICK1 PDZ domain and GluR2 C terminal; accordingly, that will change the binding capacity between PICK1 and GluR2 in varying degrees. PMID- 22499512 TI - [GAD67-GFP expression and co-localization with bNOS in main olfactory bulb of GAD67-GFP knock-in mouse]. AB - OBJECTIVE: To investigate the distribution of GAD67 and the co-localization with bNOS in the main olfactory bulb of GAD67-GFP knock-in mouse. METHODS: Polymerase chain reaction was applied to identify the genotype of GAD67-GFP knock-in mouse, the animals were sacrificed and frozen sections of olfactory bulb were prepared. The Nissl-staining was performed to show an framework of the neuron in the olfactory bulb. The distribution of GAD67 and co-localization with bNOS were detected by immunofluorescence technique. RESULTS: The proportion of GAD67 positive cells among DAPI-positive cells were (42.98 +/- 0.92)% in glomerular layer, (23.64 +/- 0.84)% in mitral cell layer and (77.75 +/- 0.84)% in granule cell layer; the bNOS-positive cells mainly existed in glomerular layer and mitral cell layer, very few in granule cell layer. No co-localization of GAD67 and bNOS in granule cell layer and mitral cell layer was found, but there was dispersed distribution in glomerular layer. CONCLUSION: GAD67-positive neurons mainly appear in glomerular layer and granule cell layer, and the bNOS is mostly expressed in glomerular layer and mitral cell layer; while the co-localization of GAD67 and bNOS only occurs in glomerular layer of olfactory bulb. PMID- 22499513 TI - [Comparison of mannitol and hypertonic saline in treatment of intracranial hypertension of rabbits]. AB - OBJECTIVE: To compare the effects of mannitol and hypertonic saline (HS) in treatment of intracranial hypertension (ICH) of rabbits. METHODS: The animal mode of ICH was established by perfusing artificial cerebrospinal fluids (aCSF) with controlled pressure into the cerebral ventricles of rabbits. The mean arterial pressure, respiratory rate, tidal volume, perfusion rate of aCSF and water content of cerebrum were investigated in rabbits with ICH after a single bolus of 20% mannitol (5 ml/kg), 7.5% HS (2.2 ml/kg) or 23.4% HS (2.2 ml/kg). RESULTS: After the intracranial pressure was elevated from 15 cmH2O to 75 cmH2O, the mean arterial pressure was increased and the tidal volume was decreased. After treatment by 20% mannitol, 7.5% HS or 23.4% HS, the increased percentage of mean arterial pressure and the decreased percentage of tidal volume were similar to the changes in control group. However, the perfusion rate of CSF was increased and water content of cerebrum was decreased after treatment by either 20% mannitol or 23.4% HS, but not by 7.5% HS. No different effects were found between 20% mannitol and 23.4% HS. CONCLUSION: With the similar osmotic burden, 20% mannitol is more effective in treating ICH than 7.5% HS. With higher osmotic load, the efficacy of HS is enhanced, and 23.4% HS may be used as an alternative to mannitol in treatment of ICH. PMID- 22499514 TI - [Determination of nine penicillin residues in milk by high-performance liquid chromatography-mass spectrometry]. AB - OBJECTIVE: To establish a high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method for detection of nine penicillin residues in milk. METHODS: The samples were precipitated with acetonitrile and degreased with n-hexane for pre-processing. The chromatography was performed by reversed-phase HPLC in a C18 column and eluted gradiently on line for 11 min. The mobile phases were water with formic acid (pH 3.1) and acetonitrile-water with formic acid (pH 3.1). By optimizing the mass condition, the method was operated by multiple reaction monitoring (MRM) and quantitated by external standard calibration. RESULTS: The standard curves were linear in concentration range of 0.4 approximately 400 MUg/L and all nine penicillins showed a good linear relationship in the milk matrix (r>0.990). The detection limit of the method was from 0.1 to 0.8 MUg/L while the limit of quantification was from 0.3 to 2.6 MUg/L. The average recoveries were higher than 80%. The within-day precisions were less than 8.5%. CONCLUSION: The established method is convenient, rapid and accurate and meets the requirement of monitoring penicillin residues in milk. PMID- 22499515 TI - [Influence of isoliensinine on activity of CYP3A in rats]. AB - OBJECTIVE: To investigate the influence of isoliensinine (IL) on CYP3A enzyme activity. METHODS: A mixture metabolic system of liver microsome enzymes in vitro was developed. A HPLC method to test the metabolic activity of CYP3A was established with testosterone as a probe. The activities of CYP3A enzymes were measured with different IL concentrations and incubation time with testosterone. RESULTS: In mixture metabolic system of liver microsome enzymes, the best incubation concentration of testosterone was 200 MUmol/L, the best incubation time was 210 min, in this condition the IC50 of IL for CYP3A inhibition was >1 000 MUmol/L. CONCLUSION: No significant interaction between IL and CYP3A is detected, which indicates that IL might be used with CYP 3A enzyme substrates. PMID- 22499516 TI - [201TI and (99m)Tc-MIBI scintigraphy in evaluation of neoadjuvant chemotherapy for osteosarcoma]. AB - OBJECTIVE: To evaluate the application of 201TI and (99m)Tc-MIBI scintigraphy in assessment of neoadjuvant chemotherapy for osteosarcoma. METHODS: Twenty-two patients with osteosarcoma underwent both 201TI and (99m)Tc-MIBI scintigraphy. According to tumor necrosis rate (TNR), 22 patients were classified into three groups: Group 1(necrosis less than 50%), Group 2(50% ? 89% necrosis) and Group 3(necrosis greater than 90%). The uptake ratio(UR) was obtained in images before and after chemotherapy. The alteration ratio(AR) and tumor necrosis ratio (TNR) were calculated. RESULTS: In 201Tl images,UR(pre) and UR(post) (mean +/- s.d.) of Group 1 were 2.14 +/- 0.67, 2.07 +/- 0.71 (P>0.05); UR(pre) and UR(post)of Group 2 were 3.45 +/- 1.57 and 2.02 +/- 0.97 (P<0.01); UR(pre) and UR(post) of Group 3 were 3.57 +/- 0.67 and 1.36 +/- 0.20 (P<0.01). In (99m)Tc-MIBI images, UR(pre)and UR(post) of Group 1 were 1.66 +/- 0.42 and 1.85 +/- 0.70 (P>0.05); UR(pre) and UR(post) of Group 2 were 2.39 +/- 1.41 and 1.68 +/- 0.72 (P<0.05);UR(pre) and UR(post) of Group 3 were 2.56 +/- 0.60 and 1.19 +/- 0.14 (P<0.01). The AR value in (201)Tl scintigraphy was -0.03-0.72, the liner regression analysis of AR versus TNR showed a highly significant positive correlation (r=0.95). The AR value in (99m)Tc-MIBI scintigraphy was -1.21-0.64, the liner regression analysis of AR versus TNR showed a highly significant positive correlation (r=0.71). The liner regression analysis of AR in 201TI scintigraphy versus AR in (99m)Tc-MIBI scintigraphy showed a highly significant positive correlation (r=0.70). CONCLUSION: The AR changes significantly after neoadjuvant chemotherapy and is positively correlated with TNR, which indicates that 201TI- and (99m)Tc-MIBI scintigraphy can be used for evaluation of neoadjuvant chemotherapy. PMID- 22499517 TI - [Determination of hydroxyproline in rat kidney tissue by HPLC with pre-column derivatization]. AB - OBJECTIVE: To establish a pre-column derivatization HPLC method for quantitation of hydroxyproline (Hyp) in rat kidney tissue by reversed-phase assay. METHODS: Rat kidney samples were hydrolyzed in 6 mol x L-1 HCl under 110 degree for 24 h, then 9-fluorenylmethyl chloroformate (FMOC) was added for the pre-column reaction. The HPLC analysis was performed on a Phenomenex C18 column using sodium acetate buffer, methanol and acetonitrile as mobile phase with a flow rate of 1.0 ml min-1 and UV detective wavelength 265 nm at 40 degree. RESULTS: Linear range was 15.30-612.00 mg x L-1 (correlation coefficient was 0.9999). Recovery rate was 97.4%-103.9%. CONCLUSION: The established method is simple, accurate and sensitive to analyze Hyp content in rat kidney tissue. PMID- 22499518 TI - [Plasma gamma-glutamyl transpeptidase level as a cardiovascular risk factor in elderly patients with hypertension or hypertension with diabetes mellitus]. AB - OBJECTIVE: To investigate plasma gamma-glutamyl transpeptidase (gamma-GGT) level as a cardiovascular risk factor in elderly patients with hypertension or hypertension with diabetes mellitus. METHODS: Forty-nine elderly patients of hypertension and 42 elderly patients of hypertension with diabetes mellitus and 39 healthy elderly subjects were enrolled in the study. The height, weight and blood pressure of patients were measured, serum C reactive protein and other biochemical indicators were detected. The relation between plasma gamma-GGT and cardiovascular risk factors in three groups were analyzed. RESULTS: There was no significant difference in plasma gamma-GGT levels among three groups. There was a positive correlation of plasma gamma-GGT levels with systolic pressure, pulse pressure, hemoglobin A1c and CRP in control group. While in hypertension with diabetes mellitus group, plasma gamma-GGT levels were correlated with systolic pressure, mean arterial pressure, fasting blood sugar and cystatin. CONCLUSION: Plasma gamma-GGT might be a risk factor for cardiovascular diseases, and may be used as a predictive indicator for kidney injury in early patients with hypertension with diabetes mellitus. PMID- 22499519 TI - [Impact of prior percutaneous coronary intervention on outcome of coronary artery bypass graft surgery]. AB - OBJECTIVE: To determine the impact of prior percutaneous coronary intervention (PCI) on outcome of coronary artery bypass graft (CABG) surgery. METHODS: Perioperative data were collected from 1306 patients undergoing CABG from January 2002 to November 2010, including 117 patients with prior PCI and 1 189 patients without prior PCI. Among 117 patients with prior PCI, 99 patients had a single PCI procedure and 18 had multiple PCI procedures. The surgical outcomes including in-hospital mortality and major adverse cardiac events were compared between two groups. RESULTS: Patients with prior PCI were younger, less likely to have triple vessel and left main stem disease, and less recent myocardial infarction. Interval time between PCI and CABG was (13.39 +/- 13.81) months. There were no significant difference in in-hospital mortality (1.7% compared with 0.5 % P=0.156) and major adverse cardiac events (including postoperative myocardial infarction, stroke, and in-hospital death,2.6% compared with 1.1% P=0.167) between two groups. CONCLUSION: There was no association between prior PCI and isolated CABG. Good outcomes can be obtained in the group of patients undergoing CABG who have had previous PCI. PMID- 22499520 TI - [Arthroscopic glenoid labrum repair by anchor fixation for recurrent anterior shoulder dislocation]. AB - OBJECTIVE: To investigate the curative effect of arthroscopic glenoid labrum repair by biodegradable anchor fixation for recurrent anterior shoulder dislocation. METHODS: Twenty-one patients of recurrent anterior shoulder dislocation with the average UCLA function score of 22.3 +/- 4.1 were treated with arthroscopic glenoid labrum repair by biodegradable anchor fixation. The shoulder was fixed by shoulder-elbow elastic band for 4-6 weeks and canonical exercise of shoulder joint was taken postoperatively. RESULTS: The patients were followed up for 3-18(mean 8) months; and the average UCLA score was 32.3 +/- 2.6 postoperatively. The excellent results (34-35) were obtained in 11 patients, good (28-33) in 7 patients and fair (21-27) in 3 patients. The activity of shoulder joint was normal in all patients with an excellent subjective degree of satisfaction. CONCLUSION: Arthroscopic glenoid labrum repair by anchor fixation for recurrent anterior shoulder dislocation has the advantages of less invasiveness, simpler procedure, reliable fixation, less complications and rapid functional recovery. PMID- 22499521 TI - [Effect of metoclopramide on capsule endoscopy examination: a randomized study]. AB - OBJECTIVE: To investigate the effect of metoclopramide on capsule endoscopy (CE) examination. METHODS: Total 116 patients referred for CE were randomized into two groups with 58 patients in each group. In treatment group patients received 10 mg metoclopramide intramuscular injection after swallowing the capsule and in control group no metoclopramide was administered. The gastric transit time, small bowel transit time, complete endoscopy rate were observed in both groups. RESULTS: The CE examination was completed in 51 patients of treatment group (87.9%) and 48 of control group (84.2%). Mean gastric transit time was (32.45 +/- 29.63) min in treatment group and (45.81 +/- 40.01)min in control group, there was significant difference between two groups (P<0.05). Mean small bowel transit time was (252.69 +/- 113.29) min in treatment group and (258.75 +/- 83.83) min in control group, there was no significant difference between two groups (P>0.05). CONCLUSION: Metoclopramide may reduces gastric transit time, but not effect small bowel transit time,which suggests that it might increase the likelihood of complete small-bowel examination in patients undergoing capsule endoscopy. PMID- 22499522 TI - [Role of microglial activation induced by alpha-synuclein in pathogenesis of Parkinson's disease]. AB - Parkinson's disease (PD), a progressive neurodegenerative disorder, is pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of deposits of aggregated alpha-synuclein in intracellular inclusions known as Lewy bodies (LB). A highly localized inflammatory response mediated by reactive microglia is prominent in PD brains, but the mechanisms underlying the microglial activation are poorly understood. Recently some lines of evidences have shown that monomeric, or aggregated alpha-synuclein can activate microglia, the toxic factors released from activated microglia may lead to the cell death of dopaminergic neurons. This review is to summarize the recent progress on the role of alpha-synuclein induced microglia activation on the PD pathogenesis and progression, and to discuss the possible mechanisms involved. PMID- 22499523 TI - [Advances on Golgi glycoprotein 73 and its association with diseases]. AB - Golgi glycoprotein 73(GP73) is a transmembrane glycoprotein residing in the cis Golgi complex, which is strongly expressed in hepatocellular carcinoma (HCC) and secreted into the blood. It has been regarded as a promising serum tumor marker for the detection of HCC with higher sensitivity and specificity than AFP. GP73 is also significantly elevated in kidney cancer, prostate cancer, lung adenocarcinoma, esophageal cancer and seminomas; therefore, it would be helpful for the diagnosis of these diseases. However, the function of GP73 and the regulatory mechanism for its expression are unclear. In this article, the physical-chemical properties, the regulation of its expression, the relation with various cancers and the clinical applications of GP73 are reviewed. PMID- 22499524 TI - [Molecular mechanisms of TRP channels in mechano-sensory transduction]. AB - Channels from the TRP superfamily have essential roles in a wide variety of sensory transductions, especially in mechano-sensation, such as hearing, touch and mechanical pain. TRP channels are also implicated in major channelopathies, including deafness, chronic pain, autosomal dominant polycystic kidney disease (ADPKD) and ventricular hypertrophy. As the leading candidates for mechano sensitive channels, some TRP channels appear to be mechano-receptor, which can be activated by mechanical forces directly, such as C. elegans TRPN homolog TRP-4; whereas others may act as signal modulators, receiving and amplifying signals indirectly. This review is to introduce the function of TRPs in mechano-sensory transduction and to discuss the underlying molecular mechanisms. PMID- 22499525 TI - Hierarchical TiO2 nanospheres with dominant {001} facets: facile synthesis, growth mechanism, and photocatalytic activity. AB - Hierarchical TiO(2) nanospheres with controlled surface morphologies and dominant {001} facets were directly synthesized from Ti powder by a facile, one pot, hydrothermal method. The obtained hierarchical TiO(2) nanospheres have a uniform size of 400-500 nm and remarkable 78 % fraction of {001} facets. The influence of the reaction temperature, amount of HF, and reaction time on the morphology and the exposed facets was systematically studied. A possible growth mechanism speculates that Ti powder first dissolves in HF solution, and then flowerlike TiO(2) nanostructures are formed by assembly of TiO(2) nanocrystals. Because of the high concentration of HF in the early stage, these TiO(2) nanostructures were etched, and hollow structures formed on the surface. After the F(-) ions were effectively absorbed on the crystal surfaces, {001} facets appear and grow steadily. At the same time, the {101} facets also grow and meet the {101} facets from adjacent truncated tetragonal pyramids, causing coalescence of these facets and formation of nanospheres with dominant {001} facets. With further extension of the reaction time, single-crystal {001} facets of hierarchical TiO(2) nanospheres are dissolved and TiO(2) nanospheres with dominant {101} facets are obtained. The photocatalytic activities of the hierarchical TiO(2) nanospheres were evaluated and found to be closely related to the exposed {001} facets. Owing to the special hierarchical architecture and high percentage of exposed {001} facets, the TiO(2) nanospheres exhibit much enhanced photocatalytic efficiency (almost fourfold) compared to P25 TiO(2) as a benchmark material. This study provides new insight into crystal-facet engineering of anatase TiO(2) nanostructures with high percentage of {001} facets as well as opportunities for controllable synthesis of 3D hierarchical nanostructures. PMID- 22499526 TI - Nosology and epidemiology in autism: classification counts. AB - Since its initial description by Kanner in 1943, the criteria by which a diagnosis of autism or autism-like disorders was made--and their alleged etiologies portrayed--have undergone manifold changes, from a psychiatric disorder engendered by "refridgerator" parents to a neurodevelopmental disability produced in the main by genetic abnormalities. In addition, the behavioral characterization of autism has also entered the public consciousness and professional domains increasingly in the past 30 years, the effects of which we are continually coming to terms. A diagnosis of autism that once seemed quite unusual is now considered almost epidemic. Increasing numbers of individuals diagnosed with autism and related pervasive developmental disabilities will, in turn, affect the calculated prevalence of the disorder. In this essay, I attempt to account for the increasing prevalence of autism and autism-related disorders by examining its changing criteria, the individuals and instruments used to make the diagnosis, the reliability and validity of same, and the sample sizes and other aspects of the methodology needed to make an accurate estimate of its prevalence. PMID- 22499527 TI - Tuning the critical temperature of cuprate superconductor films with self assembled organic layers. AB - Control over the T(c) value of high-T(c) superconductors by self-assembled monolayers is demonstrated (T(c) = critical temperature). Molecular control was achieved by adsorption of polar molecules on the superconductor surface (see scheme) that change its carrier concentration through charge transport or light induced polarization. PMID- 22499528 TI - A novel approach to attenuate proliferative vitreoretinopathy using ultrasound targeted microbubble destruction and recombinant adeno-associated virus-mediated RNA interference targeting transforming growth factor-beta2 and platelet-derived growth factor-B. AB - BACKGROUND: To date, with the exception of surgery, there are no satisfactory treatments available for proliferative vitreoretinopathy (PVR). Ultrasound targeted microbubble destruction (UTMD) represents a new approach for the gene therapy of eye diseases. The present study aimed to investigate the feasibility of the attenuation of PVR by a combinatorial use of UTMD and recombinant adeno associated virus (rAAV)-mediated RNA interference (RNAi) targeting transforming growth factor (TGF)-beta2 and platelet-derived growth factor (PDGF)-B. METHODS: One hundred and eighty rats of the PVR model were averagely divided into six groups (G). The left eyes, respectively, received an intravitreal injection as follows: normal saline (G1), rAAV2-control small interfering RNA (siRNA) (G2), rAAV2-TGF-beta2-siRNA (G3), rAAV2-PDGF-B-siRNA (G4), rAAV2-TGF-beta2-siRNA and rAAV2-PDGF-B-siRNA (G5, G6) on day 3 after PVR induction. In G6, a condition of UTMD was used additionally. On days 14 and 28, pathological changes of eye fundus were assessed by ophthalmoscopic and histopathologic examination, and the protein and mRNA levels of TGF-beta2 and PDGF-B expression were tested using enzyme linked immunosorbent assay and a reverse transcriptase-polymerase chain reaction, respectively. RESULTS: The average grade scales of proliferation and the protein and mRNA expression levels of TGF-beta2 and PDGF-B in G6 were all lower than that in G5 on day 28 (p<0.05, unpaired t-test). They were all lower in G5 and G6 than in G1, G2, G3 and G4 on day 28 (p<0.05, one-way analysis of variance), although the protein and mRNA expression levels of PDGF-B in G6 did not differ from that in G1, G2, G3, G4 and G5 on day 14. CONCLUSIONS: The combinatorial use of UTMD and rAAV2-mediated RNAi targeting TGF-beta2 and PDGF-B can serve as a novel approach to attenuate PVR. PMID- 22499529 TI - Naphthalene and anthracene complexes sandwiched by two {(Cp*)Fe(I)} fragments: strong electronic coupling between the Fe(I) centers. AB - The reactions of the half-sandwich iron(II) complex [FeCl(Cp*)(tmeda)] (1; Cp*=eta(5)-C(5)Me(5), TMEDA=N,N,N',N'-tetramethylethylenediamine) with potassium naphthalenide or potassium anthracenide gave the diamagnetic complexes [(Cp*)Fe(MU-polyarene)Fe(Cp*)] (polyarene=naphthalene (2), anthracene (3a)), which have two {(Cp*)Fe} units bound to opposite faces of the polyarene. One of two {(Cp*)Fe} units in 3a is located over the central ring of anthracene while the other is positioned over an outer ring. The {(Cp*)Fe} unit bound to the central ring of 3a migrates to the outer ring upon heating in the solid state to give the isomer 3b. The electrochemical potential separations between successive one-electron redox events for complexes 2 and 3b are large. The mixed valence complexes [2](+) and [3b](+) were synthesized by chemical oxidation. The mixed valence complex [3b](+) is charge delocalized on the Mossbauer timescale at 78 K, and its absorption spectrum shows an intervalence charge-transfer band. Complex [2](+) exhibits two absorption bands in the near-IR region and a slightly broadened doublet in the Mossbauer spectrum. DFT calculations were carried out to examine the electronic structures of these dinuclear iron(I) complexes to elucidate the factors responsible for their diamagnetism and to determine the degree of charge delocalization in the mixed-valence complexes. PMID- 22499530 TI - Assessing the reconstruction of macromolecular assemblies with toleranced models. AB - We introduce toleranced models (TOMs), a generic and versatile framework meant to handle models of macromolecular assemblies featuring uncertainties on the shapes and the positions of proteins. A TOM being a continuum of nested shapes, the inner (resp. outer) ones representing high (low) confidence regions, we present topological and geometric statistics assessing features of this continuum at multiple scales. While the topological statistics qualify contacts between instances of protein types and complexes involving prescribed protein types, the geometric statistics scale the geometric accuracy of these complexes. We validate the TOM framework on recent average models of the entire nuclear pore complex (NPC) obtained from reconstruction by data integration, and confront our quantitative analysis against experimental findings related to complexes of the NPC, namely the Y-complex, the T-complex, and the Nsp1-Nup82-Nup159 complex. In the three cases, our analysis bridges the gap between global qualitative models of the entire NPC, and atomic resolution models or putative models of the aforementioned complexes. In a broader perspective, the quantitative assessments provided by the TOM framework should prove instrumental to implement a virtuous loop "model reconstruction-model selection", in the context of reconstruction by data integration. PMID- 22499531 TI - Working up autism: the practical role of medical genetics. AB - The autism spectrum disorders (ASD) comprise a group of neurobehavioral phenotypes of heterogeneous etiology. In spite of a worldwide extensive research effort to unravel the genetic mystery of autism, medical geneticists are still facing an embarrassing lack of knowledge in dealing with the diagnosis, and consequently prognosis, of a child with autism. However, some lessons can be learned from accumulating experience in the clinical and molecular genetic evaluation of children with this condition. Patient evaluation, indications for molecular testing and counseling are the three aspects that will be discussed in this review. PMID- 22499532 TI - Palladium(II)-catalyzed intramolecular diamination of alkynes under aerobic oxidative conditions: catalytic turnover of an iodide ion. PMID- 22499533 TI - Photoswitchable dynamic magnetic relaxation in a well-isolated {Fe2Co} double zigzag chain. PMID- 22499534 TI - Fluorescent silver nanoclusters as effective probes for highly selective detection of mercury(II) at parts-per-billion levels. AB - Facile preparation of water-soluble and fluorescent Ag nanoclusters (NCs) stabilized by glutathione at room temperature is described. Although the glutathione layer was introduced to prevent the silver nanoparticles from decomposition and increase their water solubility, this simple surface optimization resulted in surprisingly high efficiency of selective Hg(2+) sensing, where the limit of detection (LOD) was as low as 10(-10) M (0.02 ppb, 0.1 nM). This result revealed a simple and practical strategy for Hg(2+) detection using fluorescent Ag NCs as sensor probe, with the lowest detecting limits reported to date. PMID- 22499537 TI - Design of a water-soluble hybrid nanocomposite of CdTe quantum dots and an iridium complex for photoinduced charge transfer. AB - We report the use of an organo-iridium dye conjugated with a water-soluble copolyethylenimine polymer, allowing the hybrid material to be used in combination with thioacid-coated CdTe quantum dots in an aqueous medium. When they are combined, hot carrier cooling observed in the pure quantum-dot case is heavily suppressed indicating fast (ps) electron transfer on a timescale that competes with non-radiative (Auger) relaxation. PMID- 22499538 TI - [Efficacy, evidence and additional patient benefit--update to the assessment of new methods of treatment in Germany using the example of Dupuytrens contracture]. PMID- 22499539 TI - Distorted arene core allows room-temperature columnar liquid-crystal glass with minimal side chains. PMID- 22499536 TI - The genetic variability and commonality of neurodevelopmental disease. AB - Despite detailed clinical definition and refinement of neurodevelopmental disorders and neuropsychiatric conditions, the underlying genetic etiology has proved elusive. Recent genetic studies have revealed some common themes: considerable locus heterogeneity, variable expressivity for the same mutation, and a role for multiple disruptive events in the same individual affecting genes in common pathways. Recurrent copy number variation (CNV), in particular, has emphasized the importance of either de novo or essentially private mutations creating imbalances for multiple genes. CNVs have foreshadowed a model where the distinction between milder neuropsychiatric conditions from those of severe developmental impairment may be a consequence of increased mutational burden affecting more genes. PMID- 22499540 TI - Four-dimensional imaging of murine subpleural alveoli using high-speed optical coherence tomography. AB - The investigation of lung dynamics on alveolar scale is crucial for the understanding and treatment of lung diseases, such as acute lung injury and ventilator induced lung injury, and to promote the development of protective ventilation strategies. One approach to this is the establishment of numerical simulations of lung tissue mechanics where detailed knowledge about three dimensional alveolar structure changes during the ventilation cycle is required. We suggest four-dimensional optical coherence tomography (OCT) imaging as a promising modality for visualizing the structural dynamics of single alveoli in subpleural lung tissue with high temporal resolution using a mouse model. A high speed OCT setup based on Fourier domain mode locked laser technology facilitated the acquisition of alveolar structures without noticeable motion artifacts at a rate of 17 three-dimensional stacks per ventilation cycle. The four-dimensional information, acquired in one single ventilation cycle, allowed calculating the volume-pressure curve and the alveolar compliance for single alveoli. PMID- 22499541 TI - Reversible autism and intellectual disability in children. AB - Studies on young children with reversible autism and intellectual disability are discussed. Present evidence suggests a clear cause in a minority of cases including early institutionalization, Landau and Kleffner syndrome, and other early onset epilepsies, intrauterine rubella, and blindness. The majority of cases have normal laboratory results and some have early onset Tourette syndrome. Preliminary data of a follow-up study of this last group are reported in 15 patients suggesting the possibility of two subgroups, one represented by early onset Tourette syndrome phenotype, characterized by a positive family history, and by its appearance at the same time as regression and persistence into adolescence while the other of a different nature. Genetic studies could be of help to clarify this issue and support a diagnosis of favorable outcome in young children. PMID- 22499542 TI - Adherence of heart failure patients to exercise: barriers and possible solutions: a position statement of the Study Group on Exercise Training in Heart Failure of the Heart Failure Association of the European Society of Cardiology. AB - The practical management of heart failure remains a challenge. Not only are heart failure patients expected to adhere to a complicated pharmacological regimen, they are also asked to follow salt and fluid restriction, and to cope with various procedures and devices. Furthermore, physical training, whose benefits have been demonstrated, is highly recommended by the recent guidelines issued by the European Society of Cardiology, but it is still severely underutilized in this particular patient population. This position paper addresses the problem of non-adherence, currently recognized as a main obstacle to a wide implementation of physical training. Since the management of chronic heart failure and, even more, of training programmes is a multidisciplinary effort, the current manuscript intends to reach cardiologists, nurses, physiotherapists, as well as psychologists working in the field. PMID- 22499543 TI - Management and outcomes following an acute coronary event in patients with chronic heart failure 1999-2007. AB - AIM: The outcome of patients with chronic heart failure (CHF) following an ischaemic event is poorly understood. We evaluated the management and outcomes of CHF patients presenting with an acute coronary syndrome (ACS) and explored changes in outcomes over time. METHOD AND RESULTS: A total of 5556 patients enrolled in the Australia-New Zealand population of the Global Registry of Acute Coronary Events (GRACE) between 1999 and 2007 were included. Patients with CHF (n = 609) were compared with those without CHF (n = 4947). Patients with CHF were on average 10 years older, were more likely to be female, had more co-morbidities and cardiac risk factors, and were more likely to have a prior history of angina, myocardial infarction, and revascularization by coronary artery bypass graft (CABG) when compared with those without CHF. CHF was associated with a substantial increase in in-hospital renal failure [odds ratio (OR) 1.76, 95% confidence interval (CI) 1.15-2.71], readmission post-discharge (OR 1.47, 95% CI 1.17-1.90), and 6-month mortality (OR 2.25, 95% CI 1.55-3.27). Over the 9 year study period, in-hospital and 6 month mortality in those with CHF declined by absolute rates of 7.5% and 14%, respectively. This was temporally associated with an increase in prescription of thienopyridines, beta-blockers, statins, and angiotensin II receptor blockers, increased rates of coronary angiography, and 31.8% absolute increase in referral rates for cardiac rehabilitation. CONCLUSIONS: Acute coronary syndrome patients with pre-existing CHF are a very high risk group and carry a disproportionate mortality burden. Encouragingly, there was a marked temporal improvement in outcomes over a 9 year period with an increase in evidence-based treatments and secondary preventative measures. PMID- 22499544 TI - Reading between the Lyme: is Borrelia burgdorferi a cause of dilated cardiomyopathy? The debate continues. PMID- 22499545 TI - Leads for cardiac resynchronization therapy: where and how many? PMID- 22499546 TI - Feasibility/eligibility of T-wave alternans testing in patients with heart failure: should we rethink our current modus operandi? PMID- 22499549 TI - A microporous binol-derived phosphoric acid. PMID- 22499548 TI - Metabolic effects of a stabilizing peptide fusion protein of leptin in normal mice. AB - Leptin is a protein hormone produced by adipocytes. It is secreted into the blood stream and plays a key role in regulating body energy homeostasis by inhibiting feeding behavior followed by decreased body weight. Because protein aggregation is a major problem in therapeutic proteins, we previously demonstrated that a stabilizing peptide (SP) fusion protein of leptin (SP-leptin) appeared to resist aggregation induced by agitation, freezing/thawing, or heat stress. In this study, we fused mouse leptin with the stabilizing peptide and compared the biological activities of leptin and SP-leptin in vivo using a male C57Bl mouse model and ex vivo using MCF7 breast cancer cell lines. Each group of mice was treated with saline, leptin, and SP-leptin for 20 days and the differences in body weight, food intake, abdominal fat contents, and TG concentration were measured. The SP-leptin appeared to decrease the body weight and food intake in male C57Bl mice more significantly than wild type leptin, and the SP-leptin treated MCF7 cells displayed better cell proliferation than leptin. As a consequence of decreased body weight, the SP-leptin treated mouse group showed decreased abdominal fat contents and low triglyceride (TG) concentration. Moreover, the SP-leptin treated mouse group had fewer lipid droplets in liver and reduced lipid droplet size when analyzed by Oil red O and H & E staining. These results demonstrated that SP-leptin is more effective than wild type leptin in normal mice in lowering their body weight and fat contents in the abdominal region, the serum, and the liver. PMID- 22499550 TI - Genotoxicity of dicrotophos, an organophosphorous pesticide, assessed with different assays in vitro. AB - Dicrotophos is a systemic insecticide with a wide range of applications. We investigated the genotoxicity of dicrotophos using the Ames test, the chromosome aberration test in CHO-K1 cells, and the comet assay in the Hep G2 cells, while this chemicals' toxicity to both the cell lines was evaluated with the MTT assay. Results showed that dicrotophos did not show any cytotoxicity to CHO-K1 cells, whereas it was cytotoxic to HepG2 cells incubated for 24 h but not for 2 h. For genotoxicity of dicrotophos, a significant change in the numbers of bacterial reveratnts using Salmomella typhimurium TA97a, TA98, TA100, TA102, and TA1535 as the tester strains, an increase in the frequencies of chromosome aberration in CHO-K1 cells, and an induced DNA damage in HepG2 cells were observed, indicating that dicrotophos was genotoxic in these three performed assays. From this study, we provide further evidence towards of genotoxic effects of dicrotophos. PMID- 22499551 TI - Oxidative stress and cell-cycle change induced by coexposed PCB126 and benzo(a) pyrene to human hepatoma (HepG2) cells. AB - Benzo(a)pyrene (BaP) never exists in the environment as a single compound but always coexists with other chemicals. These chemicals may affect the toxicity of BaP. Our previous study confirmed that polychlorinated biphenyls (PCBs), which were recently found coexisting with BaP in various environmental media, dramatically enhanced the genotoxicity of BaP. But the known mechanisms associated with this phenomenon are limited. Because BaP's genotoxicity is highly associated with its ability to induce the oxidative stress, we propose that the coexistence of PCBs may enhance BaP's genotoxicity by affecting BaP-induced oxidative stress. In this study, the HepG2 cells were treated with either BaP (50 MUM), 3,3',4,4',5-pentachlorobiphenyl (PCB126) (0.01, 0.1, 1, and 10 nM), or pretreated with PCB126 followed by a coexposure to BaP and PCB126. We found that the exposure to BaP alone effectively increased the level of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and the percentage of cells in G0/G1 phase, but decreased the percentage of S-phase cells. Compared to BaP alone, coexposure to both BaP and PCB126 effectively enhanced the levels of ROS and MDA as well as the percentage of cells in S phase, but decreased the levels of GSH and percentage of cells in G0/G1 phase. Our findings suggest that increasing oxidative stress and impairing the normal cell-cycle control may be mechanisms by which PCB126 enhances the genotoxity of BaP exposure. PMID- 22499552 TI - Autism and intellectual disability: two sides of the same coin. PMID- 22499553 TI - Catalytic air oxidation of biomass-derived carbohydrates to formic acid. AB - An efficient catalytic system for biomass oxidation to form formic acid was developed. The conversion of glucose to formic acid can reach up to 52% yield within 3 h when catalyzed by 5 mol% of H(5)PV(2)Mo(10)O(40) at only 373 K using air as the oxidant. Furthermore, the heteropolyacid can be used as a bifunctional catalyst in the conversion of cellulose to formic acid (yield=35%) with air as the oxidant. PMID- 22499554 TI - Comparison of histopathological findings with duplex sonography of the temporal arteries in suspected giant cell arteritis. AB - INTRODUCTION: In clinical practice the temporal artery biopsy (TAB) in suspected giant cell arteritis (GCA) is still believed to be the "gold standard". The purpose of this study was to compare the histopathological findings of the TAB with duplex sonography of the temporal artery. PATIENTS AND METHODS: In our retrospective study we analysed 85 consecutive patients (52 female, mean age 71.5, range 55 - 91 years; 33 male, mean age 71.6, range 44 - 91 years) with suspected GCA who underwent TAB in our clinic between January 1999 - February 2011. All patients received a preoperative duplex sonography, 57 patients including description of the temporal arteries. RESULTS: 38 of 85 (44.7 %) of the artery biopsies were proven positive for GCA by histopathology. Interpretation of the duplex sonography was congruent of histopathological interpretation of the biopsy in 39 patients (68.4 %) and incongruent in 18 patients (31.6 %). Sensitivity of duplex-sonography was 44.4 %, specificity 90 %, positive predictive value 80 %. DISCUSSION: Duplex sonography is a non-invasive and very helpful diagnostic tool to guide the clinician in cases of suspected GCA but needs considerable skills. It shows a good specificity and relatively high positive predictive value as there are only few false positive results. A negative report however does not rule out GCA, so that in our opinion the TAB - at least in those cases - should still be performed. PMID- 22499555 TI - [Preoperative sizing of the TICL (Toric Implantable Collamer Lens): the largest was too small!]. PMID- 22499556 TI - Assessing the effects of three potential chemical repellents to prevent bird damage to corn seeds and seedlings. AB - BACKGROUND: Bird damage to seeds and seedlings of maize (Zea mays) and other crops is widespread, especially in organic farming, because no adequate seed protection is available. In this study, the effect of seed treatments with three substances likely to affect bird feeding behaviour (anthraquinone, pulegone and methyl anthranilate) was tested. Their repellent effect was tested in food and seedling choice (treated versus untreated) experiments with feral pigeons (Columba livia f. domestica) in aviaries. Most efficient variants were additionally tested in the field, where wild birds had unlimited access. RESULTS: In aviaries, untreated seeds were clearly preferred over treated seeds by pigeons. The highest feeding deterrence effect occurred with the treatment variants pulegone 1.4 mL kg(-1) and methyl anthranilate 0.085 mL kg(-1). In contrast, there was no repellent effect if seedlings were offered to the pigeons in aviaries. The same applies to the number of maize seeds and seedlings grown from treated and untreated seeds, which were damaged in the field mainly by pheasants (Phasianus colchicus). CONCLUSION: The study shows that the chemicals failed to repel feeding by birds in Germany. Further studies should concentrate on alternative, systemic effective substances possibly based on plant secondary metabolites to yield a bird repellent usable in organic farming. PMID- 22499557 TI - Ventricular tachycardia with different QRS morphologies arising from single origin. PMID- 22499558 TI - Network- and attribute-based classifiers can prioritize genes and pathways for autism spectrum disorders and intellectual disability. AB - Autism spectrum disorders (ASD) are a group of related neurodevelopmental disorders with significant combined prevalence (~1%) and high heritability. Dozens of individually rare genes and loci associated with high-risk for ASD have been identified, which overlap extensively with genes for intellectual disability (ID). However, studies indicate that there may be hundreds of genes that remain to be identified. The advent of inexpensive massively parallel nucleotide sequencing can reveal the genetic underpinnings of heritable complex diseases, including ASD and ID. However, whole exome sequencing (WES) and whole genome sequencing (WGS) provides an embarrassment of riches, where many candidate variants emerge. It has been argued that genetic variation for ASD and ID will cluster in genes involved in distinct pathways and protein complexes. For this reason, computational methods that prioritize candidate genes based on additional functional information such as protein-protein interactions or association with specific canonical or empirical pathways, or other attributes, can be useful. In this study we applied several supervised learning approaches to prioritize ASD or ID disease gene candidates based on curated lists of known ASD and ID disease genes. We implemented two network-based classifiers and one attribute-based classifier to show that we can rank and classify known, and predict new, genes for these neurodevelopmental disorders. We also show that ID and ASD share common pathways that perturb an overlapping synaptic regulatory subnetwork. We also show that features relating to neuronal phenotypes in mouse knockouts can help in classifying neurodevelopmental genes. Our methods can be applied broadly to other diseases helping in prioritizing newly identified genetic variation that emerge from disease gene discovery based on WES and WGS. PMID- 22499559 TI - Synergy study of the inhibitory potential of red wine polyphenols on vascular smooth muscle cell proliferation. AB - Vascular smooth muscle cell (VSMC) proliferation contributes to the development of atherosclerosis. Red wine consumption due to the polyphenol content has been reported to counteract atherosclerosis progression possibly through inhibition of VSMC proliferation, among other mechanisms. In this study we investigate the antiproliferative activity of four wine polyphenols: resveratrol, quercetin, ethyl gallate, and (+)-catechin in rat aortic VSMC. All four polyphenols inhibited serum-induced VSMC proliferation when applied as a single treatment. To further address a potential synergistic action of the investigated polyphenols, the antiproliferative effect of different combinations in equimolar, as well as equipotent ratios were quantified. The IC50 values of single polyphenols regarding the inhibition of VSMC proliferation ranged from 49.58 uM to 86.06 uM. However, apparent inhibitory efficacy of each compound increased by a factor of 10.4 in the quadruple equipotent mixture, as calculated from the dose-reduction index. Thus, the effective IC50 values of each of the four mixture constituents ranged from 4.76 uM to 8.27 uM. The calculated combination index (CI, where CI <, =, or > 1 indicate synergy, additivity, or antagonism, respectively) values of equimolar combinations of the polyphenols indeed indicated mainly synergy (CI ranging from 0.24 +/- 0.01 to 1.51 +/- 0.13). Optimized equipotent mixture showed enhanced synergy (CI ranging from 0.18 +/- 0.04 to 1.36 +/- 0.26). In conclusion, we show for the first time that four major polyphenols from wine synergistically inhibit VSMC proliferation. PMID- 22499560 TI - Plasma pharmacokinetics and tissue distribution of arctiin and its main metabolite in rats by HPLC-UV and LC-MS. AB - The pharmacokinetic profile of arctiin, the major active lignan in fruits of Arctium lappa L., was investigated. Its main meta"bolite arctigenin was identified by an LC-MS method, and an HPLC-UV technique was developed for the simultaneous quantification of the metabolite and arctiin in plasma and organs. Chromatographic separation was performed on an AgilentTM C18 HPLC column with acetonitrile and water by linear gradient elution. Arctiin and arctigenin were identified on-line by LC-MS. The pharmacokinetics and tissue distribution of arctiin and arctigenin were determined for the first time by using a simple, selective, and accurate HPLC method. The AUC0-t values of arctigenin were larger compared with arctiin after oral administration of arctiin. The concentration of the metabolite was significantly higher than the concentration of arctiin in the stomach and small intestine in rats after oral administration of arctiin, indicating that the stomach and small intestine were the major organs of arctiin metabolism. These findings could provide support for the clinical studies conducted with Fructus Arctii. PMID- 22499561 TI - Lignans from Schisandra propinqua with inhibitory effects on lymphocyte proliferation. AB - Seven new dibenzocyclooctadiene lignans, named propinquain E-K, together with 11 known lignans were isolated from the ethanol extract of the roots of Schisandra propinqua subsp. sinensis. The structures of the new compounds were elucidated by spectroscopic methods, including 1H- and 13C-NMR, 2D-NMR, HR ESI-MS, and CD spectra. Two dibenzocyclooctadienes revealed inhibitory effects on lymphocyte proliferation. PMID- 22499562 TI - What is the best strategy for preclinical testing of botanicals? A critical perspective. AB - The development of a new drug is generally marked by a number of preclinical investigations in a sequential order with regard to contents and logic. However, ethnopharmacology often uses the "reverse pharmacology" approach, which is based on anecdotal therapeutic effects of plants in ancient texts or based on the empirical knowledge of traditional healers. While this approach could successfully lead to new therapeutic applications by using sophisticated techniques and appropriate bioassays in a logical order, unfortunately there is an exponentially increasing number of reports of pharmacological effects of botanical extracts with insignificant bioactivities obtained in often irrelevant in vitro bioassays. The interpretation based on in vitro data can only be misleading since the pharmacokinetic properties of a compound are ignored, unacceptable high dosages of extracts are tested, or metabolism to inactive metabolites is not considered. Further, many natural products are prodrugs that need to be metabolized in vivo by the intestinal microflora or by mammalian phase I/II metabolism. Frequently, attempts are made to master poor pharmacokinetics by administering the extract intraperitoneally or intravenously, clearly moving away from the traditional oral application. In this review article, it is proposed that preclinical testing strategies of botanicals should start with the in vivo examination of extracts in relevant animal models to substantiate the ethnopharmacological/ethnopharmaceutical use, followed by bioguided fractionation processes using an adequate in vitro model, further followed by pharmacokinetic studies and final in vivo testing of isolated compounds. With our article we would like to encourage authors, reviewers and editors to implement this strategy for the design of experiments and for the reviewing and editing process of manuscripts. PMID- 22499563 TI - Orthoquinone and naphthalenone derivatives from Berrya ammonilla and their anti inflammatory activity. AB - A new orthoquinone, berryammone A (1), and four new naphthalenone derivatives, berryammone B (2), berryammone C (3), 6-O-methylberryammone C (4), and 4-O methylberryammone C (5), have been isolated from the stem of Berrya ammonilla, together with eleven known compounds (6-16). The structures of these new compounds were determined through spectroscopic and MS analyses. Among the isolates, compounds 1-3, 5, (+)-pinoresinol (6), and betulinic acid (12) exhibited inhibition (IC50 <= 4.41 uM) of superoxide anion generation by human neutrophils in response to formyl-L-methionyl-L-leucyl-L phenylalanine/cytochalasin B (fMLP/CB). Compounds 1, 2, and 5 also inhibited fMLP/CB-induced elastase release with IC50 values <= 3.95 uM. PMID- 22499564 TI - Engineering tendon and ligament tissues: present developments towards successful clinical products. AB - Musculoskeletal diseases are one of the leading causes of disability worldwide. Among them, tendon and ligament injuries represent an important aspect to consider in both athletes and active working people. Tendon and ligament damage is an important cause of joint instability, and progresses into early onset of osteoarthritis, pain, disability and eventually the need for joint replacement surgery. The social and economical burden associated with these medical conditions presents a compelling argument for greater understanding and expanding research on this issue. The particular physiology of tendons and ligaments (avascular, hypocellular and overall structural mechanical features) makes it difficult for currently available treatments to reach a complete and long-term functional repair of the damaged tissue, especially when complete tear occurs. Despite the effort, the treatment modalities for tendon and ligament are suboptimal, which have led to the development of alternative therapies, such as the delivery of growth factors, development of engineered scaffolds or the application of stem cells, which have been approached in this review. PMID- 22499565 TI - 3D kinematic of bunched, medium and elongated sprint start. AB - The aim of this study was to test the influence of 3 different horizontal distances between the blocks (bunched, medium and elongated) on the velocity of the centre of mass (VCM) and the kinetic energy (KE) of the body segments and of the whole body. 9 well-trained sprinters performed 4 maximal 10 m sprints. An opto-electronic Motion Analysis(r) system (12 digital cameras 250 Hz) was used to collect the 3D trajectories of 63 markers during the starting block phase. The results demonstrated that the elongated start, compared to the bunched or medium start, induced an increase of VCM at block clearing (2.89+/-0.13; 2.76+/-0.11; 2.84+/-0.14 m.s - 1) and a decrease of the performance at 5 and 10 m. Both results were explained by a greater pushing time on the blocks in the elongated condition. During the starting block phase, the KE of the whole body was greater in the elongated start (324.3+/-48.0 J vs. 317.4+/-57.2 J, bunched and 302.1+/ 53.2 J, medium). This greater KE of the whole body was mainly explained by the KE of the head-trunk segments. Thus, to improve the efficiency of the starting block phase, the athlete must produce greater KE of the head and trunk segments in the shortest time. PMID- 22499566 TI - Skeletal muscle strength and endurance are maintained during moderate dehydration. AB - This study investigated the effects of moderate dehydration (~2.5% body weight) on muscle strength and endurance using percutaneous electrical stimulation to quantify central and peripheral fatigue, and isolate the combined effects of exercise-heat stress and dehydration, vs. the effect of dehydration alone. Force production and voluntary activation were calculated in 10 males during 1 brief and 15 repeated maximal voluntary isometric contractions performed prior to (control) walking in the heat (35 degrees C), immediately following exercise, and the next morning (dehydration). The protocol was also performed in a euhydrated state. During the brief contractions, force production and voluntary activation were maintained in all trials. In contrast, force production decreased throughout the repeated contractions, regardless of hydration status (P<0.001). The decline in force was greater immediately following exercise-heat stress dehydration compared with control and euhydration (P<0.001). When dehydration was isolated from acute post-exercise dehydration, force production was maintained similarly to control and euhydration. Despite the progressive decline in force production and the increased fatigability observed during the repeated contractions, voluntary activation remained elevated throughout each muscle function test. Therefore, moderate dehydration, isolated from acute exercise-heat stress, does not appear to influence strength during a single contraction or enhance fatigability. PMID- 22499567 TI - Modelling developmental changes in repeated-sprint ability by chronological and skeletal ages in young soccer players. AB - This study investigated the influence of chronological (CA) and skeletal ages (SA), anthropometry, aerobic endurance and lower limb explosive strength on developmental changes in repeated-sprint ability (RSA) in soccer players aged 11 17 years. Participants were annually followed over 5 years, resulting in 366 measurements. Multilevel regression modelling analysed longitudinal data aligned by CA and SA (Model 1 and 2, respectively). After diagnosing for multicollinearity, it was possible to predict RSA with 2-level hierarchical models [Model 1 (CA as Level 2 predictor): Log-Likelihood=1,515.29, p<0.01; Model 2 (SA as Level 2 predictor): Log-Likelihood=1,513.89, p<0.01]. Estimating sum of sprints for young soccer players are given by equations: sum of sprints=84.47 - 1.82 * CA + 0.03 * CA2 - 0.05 * aerobic endurance - 0.10 * lower limb explosive strength -0.09 * fat-free mass + 0.13 * fat mass (Model 1); 73.58 - 0.43 * SA - 0.05 * aerobic endurance - 0.10 * lower limb explosive strength - 0.08 * fat-free mass - 0.45 * training experience + 0.13 * fat mass (Model 2). The models produced performance curves that may be used to estimate individual performance across adolescent years. Finally, the validity of each model was confirmed based on corresponding measurements taken on an independent cross-sectional sample. PMID- 22499568 TI - Leg strength is associated with ventilatory efficiency in older women. AB - The aim of the present study was to determine if leg function is associated with ventilatory efficiency during exercise in healthy older adults. 24 women and 18 men aged 60-80 years performed treadmill exercise to fatigue for calculation of ventilatory efficiency using the ratio of ventilation to carbon dioxide at the anaerobic threshold (VE/VCO2@AT). On a separate day, participants performed leg strength testing and graded single-leg knee extension exercise. The VE/VCO2@AT was higher in women than men (33+/-3 vs. 30+/-3; p=0.03). After adjustment for age and VO(2max), leg strength (knee extensor isometric force) was inversely associated with VE/VCO2@AT in women (r= - 0.44, p=0.03) while no relationships were found for men. Strength-matched women and men had similar VE/VCO2@AT indicating that the correlation between leg strength and VE/VCO2@AT was strength- but not sex-specific. During knee extensor exercise, women with lower leg strength had increased VE/VCO2 slope across 0-15 W as compared to higher strength women (38+/-8 vs. 31+/-3; p<0.05), while no differences were found for men. These results find leg strength to be associated with ventilatory responses to exercise in healthy older women, a finding that might be related to lower leg strength in women than men. PMID- 22499569 TI - The C allele in NOS3 -786 T/C polymorphism is associated with elite soccer player's status. AB - The NOS3-786 T/C polymorphism (rs2070744) is a candidate to explain individual variations in sports related phenotypes. We determined the genotype and allele frequency of NOS3-786 T/C in a group of 60 male professional elite soccer players. Their results were compared with those of 100 world-class endurance athletes, 53 elite power athletes, and 100 sedentary, healthy men (controls) of the same Caucasian (Spanish) origin. There were significant differences in genotype frequencies between soccer players, controls, endurance and power elite athletes (all P <= 0.02). These results were confirmed when we analysed allelic frequencies (all P<0.01). The likelihood of having the C allele was higher in soccer players compared with (i) controls [odds ratio (OR), 2.165, 95% confidence interval (CI): 1.362-3.441], (ii) endurance athletes (OR: 1.879, 95%CI: 1.184 2.984), and (iii) power athletes (OR: 4.032, 95%CI: 2.307-7.047). In conclusion, the -786C allele is associated with the status of being an elite soccer player, compared with non-athletic controls and also with elite endurance and power athletes. More research is needed in other groups of elite soccer players in order to replicate the results of the present study. PMID- 22499570 TI - Effect of caffeine on LT, VT and HRVT. AB - Caffeine has many diverse physiological effects including central nervous system stimulation. Ventilatory threshold and a recently described heart rate variability threshold both have a relationship with autonomic control that could be altered by caffeine consumption. The purpose of this investigation was to determine the influence of caffeine on lactate, ventilatory, and heart rate variability thresholds during progressive exercise. Using a randomized placebo controlled, double-blind study design, 10 adults performed 2 graded maximal cycle ergometry tests with and without caffeine (5 mg.kg-1). Respiratory gas exchange, blood lactate concentrations, and heart rate variability data were obtained at baseline and throughout exercise. RESULTS: At rest, caffeine (p<0.05) increased blood lactate, oxygen consumption, carbon dioxide production, and minute ventilation. For indices of heart rate variability at rest, caffeine increased (p<0.05) the coefficient of variation, while standard deviation, and mean successive difference displayed non-significant increases. During progressive exercise, minute ventilation volumes were higher in caffeine trials but no other parameters were significantly different compared to placebo tests. CONCLUSION: These data demonstrate the robustness of the lactate, ventilatory and heart rate variability thresholds when challenged by a physiological dose of caffeine. PMID- 22499571 TI - Deficits 10-years after Achilles tendon repair. AB - The purpose of this study was to determine the long-term impact of surgical repair and subsequent 6-week immobilization of an Achilles tendon rupture on muscle strength, muscle strength endurance and muscle activity. 63 patients participated in this study on average 10.8 +/- 3.4 years after surgically repaired Achilles tendon rupture and short-term immobilization. Clinical function was assessed and muscle strength, strength endurance and muscle activity were measured using a dynamometer and electromyography. Ankle ROM, heel height during heel-raise tests and calf circumference were smaller on the injured than on the contralateral side. Ankle torques during the concentric dorsiflexion tasks at 60 degrees /sec and 180 degrees /sec and ankle torques during the eccentric plantarflexion task and during the concentric plantarflexion task at 60 degrees /sec for the injured leg were significantly lower than those for the contralateral leg. The total work during a plantarflexion exercise at 180 degrees /sec was 14.9% lower in the injured compared to the contralateral leg (p < 0.001). Muscle activity for the gastrocnemius muscle during dorsiflexion tasks was significantly higher in the injured than in the contralateral limb. Limited ankle joint ROM and increased muscle activity in the injured leg suggest compensatory mechanisms to account for differences in muscle morphology and physiology caused by the injury. PMID- 22499572 TI - Leg stiffness changes in athletes with Achilles tendinopathy. AB - Overuse injuries of the Achilles tendon cause impairment in lower leg muscle tendon function. The purpose of this study was to evaluate leg stiffness in patients suffering unilateral Achilles tendinopathy. 51 athletes with unilateral Achilles tendinopathy underwent leg stiffness testing by modeling the vertical ground reaction force in a contact mat, measuring flight and contact time during hopping. Clinical status was estimated with a pain VAS and a validated questionnaire (VISA-A). The 'leg stiffness ratio' (LSR=stiffness of injured leg/stiffness of healthy leg) was calculated to determine the relative patient affectation and for intra-group comparison. 84 percent of subjects showed lower leg stiffness in the affected side during hopping. Leg stiffness was significantly lower in the limb affected by Achilles tendinopathy than in the healthy side (14.07+/-3.74 kN/m vs. 15.61+/-4.01 kN/m, p=0.047); overall LSR was 0.90+/-0.09. Intra-group comparison did not show significant differences related to patients' age, gender, sport level, and site of tendon injury (midportion or insertional). Leg stiffness was significantly reduced in patients with unilateral Achilles tendinopathy probably related to increasing ankle compliance. Regular leg stiffness assessment would be beneficial for athletes suffering Achilles tendon problems in terms of quantifying performance capabilities and providing objective data for a safer return to sport activity. PMID- 22499573 TI - Resistance training and glycogen content in ovariectomized rats. AB - The aim of the present study was to investigate the effects of resistance training on glycogen content and muscle cross-sectional area (CSA) in ovariectomized rats. Wistar rats were divided into: sedentary; ovariectomized sedentary; resistance trained; and ovariectomized resistance trained. In the 12 week resistance training, the animals climbed a 1.1 m vertical ladder, 3 days per week, with 4-8 climbs. Cardiac, liver and muscle glycogen content was determined. After the 12-week resistance training period there was a higher hepatic and muscle glycogen content in the resistance training group compared with the other groups (p<0.01). CSA was higher in soleus for the resistance trained, ovariectomized resistance trained and sedentary compared with ovariectomized sedentary (p<0.05). Ovariectomy attenuated the increase in liver and muscle glycogen content, while soleus muscle cross-sectional area increased with resistance training, even in ovariectomized rats. Resistance training could be an important exercise to increase muscle function in situations of reduced estrogen and progesterone. PMID- 22499574 TI - Doppler ultrasound signal in Achilles tendinopathy reduces immediately after activity. AB - BACKGROUND: A relationship has been identified between vascularization on Doppler ultrasound (Doppler signal) and Achilles tendon pain. Doppler signal may increase minutes after prolonged activity, but the immediate effect is unknown. The aim of the study was to investigate the immediate effect of short term activity on Achilles tendon Doppler signal. Achilles tendinopathy patients (7 patients, 10 tendons) and asymptomatic controls (6 controls, 12 tendons) performed 2 activity tasks; a 2 minute continuous step task and one minute continuous calf raise task. Doppler signal was measured at rest and within a minute after each activity. The presence of Doppler signal was quantified using both semi quantitative (modified Ohberg scale; 0=no signal, 5 = > 90% of pathological area contains Doppler signal) and quantitative methods (pixel number). Doppler signal was present in 90% of symptomatic individuals and in none of the asymptomatic controls. The modified Ohberg scale and pixel number reduced significantly after both activity tasks and heart rate increased significantly (p < 0.05). Doppler signal in Achilles tendinopathy may decrease immediately after activities that load the calf muscle and increase heart rate, suggesting that this activity should be avoided prior to imaging to avoid false negative results. PMID- 22499575 TI - Measuring energy expenditure after stroke: validation of a portable device. AB - BACKGROUND AND PURPOSE: Current means of assessing physical activity and energy expenditure have restrictions in stroke, limiting our understanding of its role in therapeutic management. This study validates a portable multisensor array for measuring free-living total energy expenditure compared with a gold standard method (doubly labeled water) in individuals with stroke. METHODS: Daily energy expenditure was measured in 9 participants with stroke (73 +/- 8 years) over a 10 day period with 2 techniques: a portable multisensor array and doubly labeled water. RESULTS: Bland-Altman analysis revealed a mean difference of 94 kcal/day (3.8%) in total energy expenditure measures given by the multisensor array in comparison to doubly labeled water with lower and upper limits of agreement of 276 to 463.8 kcal/day (2473 +/- 468 versus 2380 +/- 551, P=0.167). There was strong agreement between the multisensor array and labeled water methods of capturing total daily energy expenditure (r=0.850, P=0.004). CONCLUSIONS: The multisensor array is a portable and accurate method of capturing daily energy expenditure and may assist in understanding how stroke influences free-living energy expenditure and aid in clinical management. PMID- 22499576 TI - Dietary sodium and risk of stroke in the Northern Manhattan study. AB - BACKGROUND AND PURPOSE: The American Heart Association recommends limiting sodium intake to <= 1500 mg/day for ideal cardiovascular health. Although sodium intake has been linked to vascular disease by direct relationship with hypertension, few studies have supported an association with stroke risk. METHODS: Participants were from the Northern Manhattan Study (mean age 69 +/- 10 years, 64% women, 21% white, 53% Hispanic, 24% black), a population-based cohort study of stroke incidence. Sodium intake was assessed with a food frequency questionnaire at baseline and evaluated continuously and categorically: <= 1500 mg/day (12%), 1501 to 2300 mg/day (24%), 2301 to 3999 mg/day (43%), and >= 4000 mg/day (21%). Over a mean follow-up of 10 years, we examined the association between sodium consumption and 235 strokes using Cox models adjusting for sociodemographics, diet, behavioral/lifestyle, and vascular risk factors. RESULTS: Of 2657 participants with dietary data, the mean sodium intake was 3031 +/- 1470 mg/day (median, 2787; interquartile range, 1966-3815 mg/day). Participants who consumed >= 4000 mg/day sodium had an increased risk of stroke (hazard ratio, 2.59; 95% CI, 1.27-5.28) versus those who consumed <= 1500 mg/day with a 17% increased risk of stroke for each 500-mg/day increase (95% CI, 1.07-1.27). CONCLUSIONS: High sodium intake was prevalent and associated with an increased risk of stroke independent of vascular risk factors. The new American Heart Association dietary sodium goals will help reduce stroke risk. PMID- 22499577 TI - Less salt and less risk of stroke: further support to action. PMID- 22499578 TI - Letter by Kasivisvanathan et al regarding article, "stenting versus surgery in patients with carotid stenosis after previous cervical radiation therapy: systematic review and meta-analysis". PMID- 22499579 TI - Moving beyond a single perfusion threshold to define penumbra: a novel probabilistic mismatch definition. AB - BACKGROUND AND PURPOSE: The mismatch lesion volumes defined by perfusion-weighted imaging exceeding diffusion-weighted imaging have been used as a marker of ischemic penumbral tissue. Defining the perfusion lesion by thresholding has shown promise as a practical tool; several positron emission tomography studies have indicated a more probabilistic relationship between perfusion and infarction. Here, we used a randomized controlled trial dataset of tissue-type plasminogen activator 3 to 6 hours after stroke to: (1) quantify the relationship between severity of hypoperfusion (measured by Tmax) and risk of infarction; (2) exploit this relationship to present a novel definition of mismatch based on infarct probabilities rather than dichotomies; and (3) examine the treatment response in the subgroup of patients with mismatch by the new definition. METHODS: Patients from the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) were included. Baseline perfusion-weighted imaging and 90-day T2 weighted imaging were coregistered. Perfusion-weighted imaging lesion volumes were divided into 10 Tmax delay strata, and infarct risk was defined as the fraction of the tissue at a given Tmax strata that progressed to infarction by day 90. RESULTS: Sixty-two patients were studied. Infarct risk was an increasing function of Tmax for all subgroups, including the whole cohort. The probabilistic approach outperformed all Tmax thresholds, with exception of the Tmax >= 10 threshold, for which it was only favored by a trend. CONCLUSIONS: Infarct risk and treatment effect increased with severity of perfusion abnormalities. This suggests that a severity-weighted mismatch definition may define penumbral tissue more accurately. PMID- 22499580 TI - Mode of action of pulegone on the urinary bladder of F344 rats. AB - Essential oils from mint plants, including peppermint and pennyroyal oils, are used at low levels as flavoring agents in various foods and beverages. Pulegone is a component of these oils. In a 2-year bioassay, oral administration of pulegone slightly increased the urothelial tumor incidence in female rats. We hypothesized that its mode of action (MOA) involved urothelial cytotoxicity and increased cell proliferation, ultimately leading to tumors. Pulegone was administered by gavage at 0, 75, or 150 mg/kg body weight to female rats for 4 and 6 weeks. Fresh void urine and 18-h urine were collected for crystal and metabolite analyses. Urinary bladders were evaluated by light microscopy and scanning electron microscopy (SEM) and bromodeoxyuridine (BrdU) labeling index. Pulegone and its metabolites, piperitenone, piperitone, menthofuran, and menthone, were tested for cytotoxicity in rat (MYP3) and human (1T1) urothelial cells by the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. No abnormal urinary crystals were observed by light microscopy. Urine samples (18 h) showed the presence of pulegone, piperitone, piperitenone, and menthofuran in both treated groups. By SEM, bladders from treated rats showed superficial necrosis and exfoliation. There was a significant increase in the BrdU labeling index in the high-dose group. In vitro studies indicated that pulegone and its metabolites, especially piperitenone, are excreted and concentrated in the urine at cytotoxic levels when pulegone is administered at high doses to female rats. The present study supports the hypothesis that cytotoxicity followed by regenerative cell proliferation is the MOA for pulegone-induced urothelial tumors in female rats. PMID- 22499582 TI - Duplicated Kiss1 receptor genes in zebrafish: distinct gene expression patterns, different ligand selectivity, and a novel nuclear isoform with transactivating activity. AB - The kisspeptin (Kiss1) and Kiss1 receptor (Kiss1r) pathway plays a central role in the neuroendocrine control of reproduction. In contrast to humans and mammals that have a single Kiss1 gene and a single Kiss1r gene, multiple Kiss ligand and receptor genes are found in nonmammalian vertebrates. Their functional relationship, however, is poorly understood. Here, we report that the duplicated zebrafish kiss1r genes have evolved a distinct gene expression pattern, different ligand selectivity, and novel nuclear isoforms. While a single kiss1ra mRNA was detected exclusively in the brain, 5 kiss1rb transcripts were found in many peripheral tissues. Functional assays showed that kiss1ra encodes a receptor activated by both Kiss1 and Kiss2, while kiss1rb encodes a receptor that has a preference for Kiss1. The four alternatively spliced kiss1rb mRNAs encoded 4 truncated isoforms, denoted kiss1rb-derived protein (KRBDP)1-4. When their subcellular localization was examined, KRBDP3 and KRBDP4 were found in the nucleus in cultured mammalian cells and in zebrafish embryos. One-hybrid transcription activation assays revealed that KRBDP3, but not KRBDP4, possesses ligand-independent transactivation activity. These findings highlight how the duplication of Kiss1r genes may facilitate their adaptation of specialized functions. The discovery of a nuclear Kiss1r isoform raises the possibility of novel function of Kiss1r in the nucleus. PMID- 22499581 TI - Eicosanoid receptor subtype-mediated opposing regulation of TLR-stimulated expression of astrocyte glial-derived neurotrophic factor. AB - A major therapeutic target for Parkinson's disease (PD) is providing increased glial-derived neurotrophic factor (GDNF) to dopaminergic neurons. We tested the hypothesis that innate immune activation increases astrocyte GDNF production and that this is regulated by specific eicosanoid receptors. Innate immune-activated primary murine astrocytes were assayed for GDNF expression and secretion. Controls were agent vehicle exposure and wild-type mice. Rank order for up to 10 fold selectively increased GDNF expression was activators of TLR3 > TLR2 or TLR4 > TLR9. TLR3 activator-stimulated GDNF expression was selectively JNK-dependent, followed cyclooxygenase (COX)-2, was coincident with membranous PGE(2) synthase, and was not significantly altered by a nonspecific COX- or a COX-2-selective inhibitor. Specific eicosanoid receptors had opposing effects on TLR3 activator induced GDNF expression: ~60% enhancement by blocking or ablating of PGE(2) receptor subtype 1 (EP1), ~30% enhancement by activating PGF(2alpha) receptor or thromboxane receptor, or ~15% enhancement by activating EP4. These results demonstrate functionally antagonistic eicosanoid receptor subtype regulation of innate immunity-induced astrocyte GDNF expression and suggest that selective inhibition of EP1 signaling might be a means to augment astrocyte GDNF secretion in the context of innate immune activation in diseased regions of brain in PD. PMID- 22499583 TI - The role of vascular smooth muscle cell apoptosis and migration during uterine spiral artery remodeling in normal human pregnancy. AB - During human uterine spiral artery (SpA) remodeling, vascular smooth muscle cells (VSMCs) are lost and replaced by fibrinoid, incorporating extravillous trophoblast (EVT) cells. The aim of the current study was to determine the relative contributions of apoptosis and migration to VSMC loss during SpA remodeling. Immunohistochemistry (Apoptag, active caspase 3, lamin) of placental bed biopsies (8-20 wk gestation) demonstrated apoptotic cells in all samples; double immunolabeling identified these as trophoblasts, leukocytes, and endothelial cells. In total, 294 SpAs were studied, and only one apoptotic VSMC was identified. H-caldesmon-immunopositive VSMCs were observed surrounding and separate from SpA walls in partially remodeled vessels; the highest level of VSMC migration was observed in vessels with associated EVT cells (number of migrated cells 6.4 +/- 1.2; distance migrated 3.5 +/- 0.3 pixels) compared with those without (number of migrated cells 3.6 +/- 0.5, P<0.001; distance migrated 2.8 +/- 0.1 pixels, P<0.0001). VEGF-A, VEGF-C, TGF-beta1, and Ang-2 all stimulated human aorta VSMC invasion in vitro, although EVT cell culture supernatants did not. In summary, apoptosis is unlikely to play a major role in loss of VSMCs from SpAs during remodeling in normal pregnancy, but VSMCs appear to migrate away from the wall of the SpA, an effect enhanced by the presence of EVT cells. PMID- 22499584 TI - Glomerular VEGF resistance induced by PKCdelta/SHP-1 activation and contribution to diabetic nephropathy. AB - This study characterizes the effect of glucose-induced activation of protein kinase Cdelta (PKCdelta) and Src homology-2 domain-containing phosphatase-1 (SHP 1) expression on vascular endothelial growth factor (VEGF) actions in glomerular podocytes in cultures and in glomeruli of diabetic rodents. Elevation of glucose levels induced PKCdelta and p38 mitogen-activated protein kinase (p38 MAPK) to increase SHP-1 expression, increased podocyte apoptosis, and inhibited VEGF activation in podocytes and glomerular endothelial cells. The adverse effects of high glucose levels can be negated by molecular inhibitors of PKCdelta, p38MAPK, and SHP-1 and only partially reduced by antioxidants and nuclear factor-kappaB (NF-kappaB) inhibitor. Increased PKCdelta activation and SHP-1 expression correlated with loss of VEGF signaling and podocyte numbers in the glomeruli of diabetic rats and mice. In contrast, diabetic PKCdelta-knockout (Prkcd(-/-)) mice did not exhibit activation of p38 MAPK and SHP-1 or inhibition of VEGF signaling in renal glomeruli. Functionally, diabetic Prkcd(-/-) mice had decreased expressions of TGFbeta, VEGF, and extracellular matrix and less albuminuria than diabetic Prkcd(+/+) mice. Hyperglycemia and diabetes can cause glomerular podocyte apoptosis and endothelial dysfunction partly due to increased PKCdelta/p38 MAPK activation and the expression of SHP-1 to cause VEGF resistance, independent of NF-kappaB activation. PMID- 22499585 TI - Activated pericytes and the inhibition of renal vascular stability: obstacles for kidney repair. PMID- 22499586 TI - GFR estimation in adolescents and young adults. AB - The performance of creatinine-based equations to obtain the estimated GFR in adolescents and young adults is poorly understood. We assessed creatinine-based GFR estimating equations in a cross-section of 751 adolescents and young adults (1054 measurements), using inulin clearance (measured GFR [mGFR]) as the reference method. We evaluated the following: Cockcroft-Gault, four-variable Modified Diet in Renal Disease, and the Chronic Kidney Disease Epidemiology Collaboration equations for adult participants, as well as the Schwartz 2009 and Schwartz-Lyon equations for pediatric age groups. Participants ranged in age from 10 to 26 years (mean 16.8 years); we divided the population into four groups according to age (10-12 years, 13-17 years, 18-21 years, and 21-25 years). Evaluation of the agreement between these formulas and mGFR (e.g., correlation, Bland-Altman plots, bias, and accuracy) showed that there was a good correlation between mGFR and both pediatric formulas in all age groups, whereas the adult formulas substantially overestimated mGFR. In conclusion, we recommend the use of pediatric equations to estimate GFR from childhood to early adulthood. PMID- 22499587 TI - microRNA-induced IgA nephropathy. PMID- 22499588 TI - Yes, AKI truly leads to CKD. PMID- 22499589 TI - The impact of renal function on outcomes of bariatric surgery. PMID- 22499590 TI - New observational data demonstrate that mortality is lower in patients receiving more frequent dialysis. PMID- 22499591 TI - Polycomb function during oogenesis is required for mouse embryonic development. AB - In mammals, totipotent embryos are formed by fusion of highly differentiated gametes. Acquisition of totipotency concurs with chromatin remodeling of parental genomes, changes in the maternal transcriptome and proteome, and zygotic genome activation (ZGA). The inefficiency of reprogramming somatic nuclei in reproductive cloning suggests that intergenerational inheritance of germline chromatin contributes to developmental proficiency after natural conception. Here we show that Ring1 and Rnf2, components of Polycomb-repressive complex 1 (PRC1), serve redundant transcriptional functions during oogenesis that are essential for proper ZGA, replication and cell cycle progression in early embryos, and development beyond the two-cell stage. Exchange of chromosomes between control and Ring1/Rnf2-deficient metaphase II oocytes reveal cytoplasmic and chromosome based contributions by PRC1 to embryonic development. Our results strongly support a model in which Polycomb acts in the female germline to establish developmental competence for the following generation by silencing differentiation-inducing genes and defining appropriate chromatin states. PMID- 22499593 TI - HOT regions function as patterned developmental enhancers and have a distinct cis regulatory signature. AB - HOT (highly occupied target) regions bound by many transcription factors are considered to be one of the most intriguing findings of the recent modENCODE reports, yet their functions have remained unclear. We tested 108 Drosophila melanogaster HOT regions in transgenic embryos with site-specifically integrated transcriptional reporters. In contrast to prior expectations, we found 102 (94%) to be active enhancers during embryogenesis and to display diverse spatial and temporal patterns, reminiscent of expression patterns for important developmental genes. Remarkably, HOT regions strongly activate nearby genes and are required for endogenous gene expression, as we show using bacterial artificial chromosome (BAC) transgenesis. HOT enhancers have a distinct cis-regulatory signature with enriched sequence motifs for the global activators Vielfaltig, also known as Zelda, and Trithorax-like, also known as GAGA. This signature allows the prediction of HOT versus control regions from the DNA sequence alone. PMID- 22499592 TI - Drosophila Neto is essential for clustering glutamate receptors at the neuromuscular junction. AB - Neurotransmitter receptor recruitment at postsynaptic specializations is key in synaptogenesis, since this step confers functionality to the nascent synapse. The Drosophila neuromuscular junction (NMJ) is a glutamatergic synapse, similar in composition and function to mammalian central synapses. Various mechanisms regulating the extent of postsynaptic ionotropic glutamate receptor (iGluR) clustering have been described, but none are known to be essential for the initial localization and clustering of iGluRs at postsynaptic densities (PSDs). We identified and characterized the Drosophila neto (neuropilin and tolloid-like) as an essential gene required for clustering of iGluRs at the NMJ. Neto colocalizes with the iGluRs at the PSDs in puncta juxtaposing the active zones. neto loss-of-function phenotypes parallel the loss-of-function defects described for iGluRs. The defects in neto mutants are effectively rescued by muscle specific expression of neto transgenes. Neto clustering at the Drosophila NMJ coincides with and is dependent on iGluRs. Our studies reveal that Drosophila Neto is a novel, essential component of the iGluR complexes and is required for iGluR clustering, organization of PSDs, and synapse functionality. PMID- 22499594 TI - Physiological response to drought in radiata pine: phytohormone implication at leaf level. AB - Pinus radiata D. Don is one of the most abundant species in the north of Spain. Knowledge of drought response mechanisms is essential to guarantee plantation survival under reduced water supply as predicted in the future. Tolerance mechanisms are being studied in breeding programs, because information on such mechanisms can be used for genotype selection. In this paper, we analyze the changes of leaf water potential, hydraulic conductance (K(leaf)), stomatal conductance and phytohormones under drought in P. radiata breeds (O1, O2, O3, O4, O5 and O6) from different climatology areas, hypothesizing that they could show variable drought tolerance. As a primary signal, drought decreased cytokinin (zeatin and zeatin riboside-Z + ZR) levels in needles parallel to K(leaf) and gas exchange. When Z + ZR decreased by 65%, indole-3-acetic acid (IAA) and abscisic acid (ABA) accumulation started as a second signal and increments were higher for IAA than for ABA. When plants decreased by 80%, Z + ZR and K(leaf) doubled their ABA and IAA levels, the photosystem II yield decreased and the electrolyte leakage increased. At the end of the drought period, less tolerant breeds increased IAA over 10-fold compared with controls. External damage also induced jasmonic acid accumulation in all breeds except in O5 (P. radiata var. radiata * var. cedrosensis), which accumulated salicylic acid as a defense mechanism. After rewatering, only the most tolerant plants recovered their K(leaf,) perhaps due to an IAA decrease and 1-aminocyclopropane-1-carboxylic acid maintenance. From all phytohormones, IAA was the most representative 'water deficit signal' in P. radiata. PMID- 22499595 TI - Determinants of drought effects on crown condition and their relationship with depletion of carbon reserves in a Mediterranean holm oak forest. AB - Severe droughts may increase physiological stress on long-lived woody vegetation, occasionally leading to rapid defoliation and progressive increase in mortality of overstorey trees. Over the last few years, episodes of drought-induced tree dieback have been documented in a variety of woodlands and forests around the world. However, the factors determining tree survival and subsequent recovery are still poorly understood, especially in resprouter species. We have studied the effects of a single drought episode on crown condition in a holm oak (Quercus ilex L.) forest located in NE Spain 7 years after the drought event. Generalized linear models were used to study the environmental correlates of forest crown condition 7 years after the drought event. Additionally, we evaluated the association between crown condition and the carbon and nutrient reserves stored in lignotubers 7 years after the drought. Our study reveals the multifactor nature of a drought-driven forest dieback in which soil depth and the characteristics of individual trees, particularly their number of stems, determined a complex spatial pattern of tree-level responses. This dieback was associated with a depletion of the carbon reserves in lignotubers 7 years after the episode, representing a reduction of up to 60% in highly drought-damaged trees. Interestingly, in the absence of new acute droughts, successive surveys in 2007-11 showed a direct association between carbon reserves depletion and further deterioration of crown condition. More frequent droughts, as predicted by climate change projections, may lead to a progressive depletion of carbon reserves and to a loss of resilience in Mediterranean resprouter species. PMID- 22499596 TI - Recovery of diurnal depression of leaf hydraulic conductance in a subtropical woody bamboo species: embolism refilling by nocturnal root pressure. AB - Despite considerable investigations of diurnal water use characteristics in different plant functional groups, the research on daily water use strategies of woody bamboo grasses remains lacking. We studied the daily water use and gas exchange of Sinarundinaria nitida (Mitford) Nakai, an abundant subtropical bamboo species in Southwest China. We found that the stem relative water content (RWC) and stem hydraulic conductivity (K(s)) of this bamboo species did not decrease significantly during the day, whereas the leaf RWC and leaf hydraulic conductance (K(leaf)) showed a distinct decrease at midday, compared with the predawn values. Diurnal loss of K(leaf) was coupled with a midday decline in stomatal conductance (g(s)) and CO(2) assimilation. The positive root pressures in the different habitats were of sufficient magnitude to refill the embolisms in leaves. We concluded that (i) the studied bamboo species does not use stem water storage for daily transpiration; (ii) diurnal down-regulation in K(leaf) and gs has the function to slow down potential water loss in stems and protect the stem hydraulic pathway from cavitation; (iii) since K(leaf) did not recover during late afternoon, refilling of embolism in bamboo leaves probably fully depends on nocturnal root pressure. The embolism refilling mechanism by root pressure could be helpful for the growth and persistence of this woody monocot species. PMID- 22499597 TI - Foliar anatomical and morphological variation in Nothofagus pumilio seedlings under controlled irradiance and soil moisture levels. AB - Foliar anatomy and morphology are strongly related to physiological performance; therefore, phenotypic plasticity in leaves to variations in environmental conditions, such as irradiance and soil moisture availability, can be related to growth rate and survivorship, mainly during critical growth phases, such as establishment. The aim of this work was to analyze changes in the foliar internal anatomy (tissue proportions and cell dimensions) and external morphology (leaf length, width and area) of Nothofagus pumilio (Poepp. et Endl.) Krasser seedlings growing in a greenhouse under controlled irradiance (three levels) and soil moisture (two levels) during one growing season (measured three times), and to relate them to physiological traits. Three irradiance levels (4, 26 and 64% of the natural incident light) and two soil moisture levels (40 and 80% soil capacity) were evaluated during November, January and March. Internal foliar anatomy of seedlings was analyzed using digital photographs of histological cuttings, while leaf gross morphology was measured using digital calipers and image analysis software. Most internal anatomical variables presented significant differences under different irradiance levels during the growing season, but differences were not detected between soil moisture levels. Palisade parenchyma was the tissue most sensitive to irradiance levels, and high irradiance levels (64% natural incident light) produced greater values in most of the internal anatomical variables than lower irradiance levels (4-24% natural incident light). Complementarily, larger leaves were observed in medium and low irradiance levels, as well as under low soil moisture levels (40% soil capacity). The relationship of main results with some eco-physiological traits was discussed. Foliar internal anatomical and external morphological plasticity allows quick acclimation of seedlings to environmental changes (e.g., during harvesting). These results can be used to propose new forest practices that consider soil moisture and light availability changes to maintain high physiological performance of seedlings. PMID- 22499598 TI - Pioneer, entrepreneur or originator? PMID- 22499600 TI - Brigadier General James Stevens Simmons (1890-1954), Medical Corps, United States Army: a career in preventive medicine. AB - James Simmons began his career in the US Army as a laboratory officer and his assignments progressed into tropical medicine research. His interests and work evolved into preventive medicine (PM, as the Army termed public health), and he took both a PhD and a Doctorate in Public Health. As the Army's leading PM officer he was appointed head of PM in 1940 and guided the Army's PM effort through World War II. His responsibility ran from gas masks through healthy nutrition and occupational health to an enormous variety of diseases; by the war's end, the breadth and importance of PM was reflected in the Preventive Medicine Division, having fully one-sixth of all military personnel at the Surgeon General's Office. Simmons used his strong professional credentials to tap into civilian medicine for expertise the Army lacked and he established organizations that survive to this day. After retirement, he sought to expand the field of public health and raise another generation of public health physicians. PMID- 22499601 TI - Frederick William Pavy (1829-1911), forgotten pioneer. PMID- 22499602 TI - Louis Jurine (1751-1819): chirurgien et naturaliste. PMID- 22499603 TI - A glimpse of David Lyall (1817-95). PMID- 22499604 TI - The role of Edward Harrison's (1766-1838) disciples, Thomas Engall, John and George Epps, Charles Hoyland, John Evans Riadore, John Robinson and John Baptiste de Serney in the treatment of spinal deformity in the Victorian medical world. AB - Edward Harrison was a distinguished and innovative physician, an educationalist who had a profound influence on the treatment of spinal deformities. He founded the first infirmary for the treatment of spinal diseases in London in 1837. Little is known of this institution but much of Harrison's legacy rests with his disciples who followed Harrison's principles of treatment to treat spinal deformity. Like Harrison they were unconventional individuals, influenced by religious beliefs and liberal political and social ideologies. After his death, initially they followed his methods of treatment but subsequently they were not afraid to pursue new forms of treatment including homeopathy at a time when traditional medicine had little to offer. PMID- 22499605 TI - Victor Horsley (1857-1916) and the temperance movement. AB - For nearly all of his life Victor Horsley campaigned against the evils of alcohol. This led him into direct conflict with politicians, brewers, publicans and the army. His views are of interest today when the subject of excessive consumption of alcohol is the subject of great public concern. PMID- 22499606 TI - Ludwig Rehn (1849-1930): the German surgeon who performed the worldwide first successful cardiac operation. AB - Ludwig Rehn, a German surgeon, performed the worldwide first successful cardiac operation in 1896 when he repaired a stab wound to the heart by direct suture. When he presented his work one year later at a surgical conference this pioneering operation evoked considerable ethical discussion. Rehn's surgical contributions also include carrying out the first thyroidectomy in 1880 and clarifying the causes of cancer in workers in the local aniline factories. PMID- 22499607 TI - Else Steinert nee Loewenheim (1879-1948): one of Germany's first female specialist ophthalmologists. AB - This study of Else Steinert presents one of the first women in Germany to specialize as an ophthalmologist. Merely tolerated as a guest listener, she conducted most of her studies in Leipzig (1900-1905) and acquired her doctor's licence there. During World War I she worked as assistant at the Ophthalmology Clinic at Leipzig University under Hubert Sattler (1844-1928), but soon thereafter was displaced by her male colleagues returning from the War. Between 1920 and 1937 the young widow and mother of three had a private practice, first in Leipzig and then in Idar-Oberstein, which was one of the first ophthalmology practices to be opened by a female doctor on a national scale. After the Nazis had seized power and she had thus been declared a Jew, her doctor's licence was withdrawn and in this manner she was deprived of her livelihood. To escape being deported to a concentration camp she fled and survived World War II in the countryside of Bavaria. Her MD thesis of 1920, of which only an eight-page abridged version has survived, is a contribution to the debate on the indication and prognosis of Elliot's trepanation for the treatment of glaucoma. Based on her investigations she strongly recommended this operation for all patients with severe glaucoma. PMID- 22499608 TI - Sir George Shuckburgh Evelyn (1751-1804): precision in thermometry. AB - The universal clinical procedure of recording a patient's temperature depends upon the accuracy of thermometers. This in turn depends upon the accuracy of two fixed datum points (the freezing and boiling points of water) and subsequently on the fine calibration of the etched scale between them. Anders Celsius (1701-44) defined the boiling point of water as the upper fixed point of the thermometric scale, originally designated as 0 degrees C but inverted by Carl Linnaeus (1707 78) to read 100 degrees C. In 1724 Gabriel Fahrenheit (1686-1736) had observed that the upper fixed point, that of boiling water, varied with changes in atmospheric pressure. An English scientist, Sir George Shuckburgh (after 1794 known as Sir George Shuckburgh Evelyn), addressed this problem and over the period 1774-79 he defined the relationship of the temperature of boiling water to barometric pressure. This latter variable changed both with the ambient meteorological conditions of the moment and the height above sea level at which the calibrations were made. Clinical thermometry depends on an accuracy of 0.1 degrees C in both the baseline and the tracking of a patient's temperature but Shuckburgh's experiments showed that the upper fixed point of reference, that of boiling water, could change by up to 10 degrees C. He demonstrated that these variables must be measured and controlled in the manufacture and calibration of thermometers. Sir George Shuckburgh Evelyn published his results in the Philosophical Transactions of The Royal Society (1777-79) and made possible the accuracy of thermometry on which patient care depends. PMID- 22499609 TI - Doctors and the Victoria Cross. PMID- 22499610 TI - Heroism is only for the expendable. PMID- 22499611 TI - Development of separated elastic stockings. AB - OBJECTIVES: To investigate the acceptability of newly developed separated elastic stockings, which are divided into two portions at the ankle. METHODS: The difficulty in putting on and taking off stockings was compared between the original or modified separated stockings with various techniques in order to reduce the shift of the stockings and current non-separated stockings in healthy volunteers and patients with lymphoedema by applying both stockings alternately. In the modified model, the shift during daily activities was measured in healthy volunteers and patients with lymphoedema. RESULTS: The two items, 'easier compared with non-separated stockings' and 'much easier', were chosen at rates of 75% and 81% for putting on and taking off stockings for the original separated stockings and 75% and 75% for the modified separated stockings, respectively. Complaints during daily activities with the modified type to the stockings decreased as compared with the original type. The shift of stockings after an average 11-hour application was 1.6 +/- 3.0 SD mm (range: 0-10 mm). CONCLUSIONS: Modified separated elastic stockings are easier to put on and take off compared with current non-separated stockings, and they can be used safely because of their low-level shift during daily activities. PMID- 22499612 TI - PET imaging-based evaluation of hepatobiliary transport in humans with (15R)-11C TIC-Me. AB - It is well accepted that drug transporters play a pivotal role in hepatobiliary excretion of anionic drugs, in which drug-drug interactions and genetic polymorphisms are known to cause variations. However, PET probes for in vivo functional characterization of these transporters have not been established yet. We used PET to investigate hepatic uptake and subsequent canalicular efflux of (11)C-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester [(15R)-(11)C-TIC-Me)] in healthy subjects. METHODS: Serial PET scans of the abdominal region in healthy male subjects were obtained with or without the organic anion-transporting polypeptide (OATP) inhibitor rifampicin after intravenous injection of (15R)-(11)C-TIC-Me as a radiotracer. Venous blood samples and PET images were obtained at frequent intervals up to 30 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots of data collected for 2-10 min and for 10-30 min after tracer administration for the determination of tissue uptake clearance and biliary efflux clearance, respectively. RESULTS: After rapid hydrolysis in blood, the acid form-(11)C-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin [(15R)-(11)C-TIC]-accumulated in the liver (37% of the dose by 17 min), and the radioactivity was then excreted into the bile (6.2% by 30 min). Rifampicin (600 mg by mouth), a potent OATP inhibitor, significantly reduced the radioactivity excreted into the bile (by 44%) by inhibiting both uptake (by 45%) and subsequent canalicular efflux (by 62%). (15R)-(11)C-TIC is an in vitro substrate of OATP1B1 and OATP1B3, and clinically relevant concentrations of rifampicin inhibited uptake by OATP1B1 and OATP1B3. These results demonstrated that in humans, (15R) (11)C-TIC-associated radioactivity is excreted into the bile by organic anion transport systems. CONCLUSION: We demonstrated that PET image analysis with (15R) (11)C-TIC-Me is useful for investigating variations in OATP function in the human hepatobiliary transport system. PMID- 22499614 TI - N-(4-18F-fluorobenzoyl)interleukin-2 for PET of human-activated T lymphocytes. AB - Interleukin-2 (IL2) binds with high affinity to the IL2 receptors overexpressed on activated T lymphocytes in various pathologic conditions. Radiolabeling of IL2 with a positron-emitting isotope could provide a tool for noninvasive PET of activated T cells in immune-mediated diseases. We report the labeling of IL2 with N-succinimidyl 4-(18)F-fluorobenzoate ((18)F-SFB) for the synthesis of N-(4-(18)F fluorobenzoyl)interleukin-2 ((18)F-FB-IL2) and the in vitro and in vivo evaluation of this novel radiopharmaceutical for the detection of IL2 receptor positive cells by PET. METHODS: (18)F-SFB was efficiently prepared using a 3-step radiochemical pathway. Purified (18)F-SFB was incubated with IL2 in borate buffer (pH 8.5) and ethanol at 50 degrees C for 10 min. (18)F-FB-IL2 was purified by reversed-phase high-performance liquid chromatography. As in vitro quality controls, a biologic binding assay, sodium dodecyl sulfate polyacrylamide gel electrophoresis, mass spectrometry, and 3-chloroacetic acid precipitation stability tests were performed. Biodistribution studies were performed in BALB/c mice to evaluate the distribution of the tracer in healthy animals. PET experiments were performed in severe combined immunodeficiency disease mice inoculated with phytohemoagglutinin-activated human peripheral blood mononuclear cells (hPBMc). Whole-body images were acquired 30 min after injection of 5-15 MBq of (18)F-FB-IL2. RESULTS: (18)F-SFB was produced with a 34%-38% radiochemical yield. The radiochemical purity after solid-phase extraction purification ranged from 93% to 96%. Conjugation of (18)F-SFB to IL2 yielded (18)F-FB-IL2 as the major product. The radiochemical yield of (18)F-FB-IL2 after high-performance liquid chromatography purification was 25%-35% based on (18)F-SFB. (18)F-FB-IL2 was stable in plasma at 37 degrees C and capable of stimulating T cells to an extent similar to native IL2. A biodistribution study showed highest tracer uptake in the kidneys and bladder due to rapid renal clearance of the tracer. Small-animal PET images showed binding of (18)F-FB-IL2 to activated hPBMc proportional to the number of injected cells. CONCLUSION: We report the successful labeling of IL2 with (18)F for PET of activated T lymphocytes. (18)F FB-IL2 is stable, is biologically active, and allows in vivo detection of activated T lymphocytes. PMID- 22499613 TI - Biodistribution and radiation dosimetry of the integrin marker 18F-RGD-K5 determined from whole-body PET/CT in monkeys and humans. AB - 2-((2S,5R,8S,11S)-5-benzyl-8-(4-((2S,3R,4R,5R,6S)-6-((2-(4-(3-(18)F-fluoropropyl) 1H-1,2,3-triazol-1-yl)acetamido)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2 carboxamido)butyl)-11-(3-guanidinopropyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13 pentaazacyclopentadecan-2-yl)acetic acid ((18)F-RGD-K5) has been developed as an alpha(v)beta(3) integrin marker for PET. The purpose of this study was to determine the biodistribution and estimate the radiation dose from (18)F-RGD-K5 using whole-body PET/CT scans in monkeys and humans. METHODS: Successive whole body PET/CT scans were obtained after intravenous injection of (18)F-RGD-K5 in 3 rhesus monkeys (167 +/- 19 MBq) and 4 healthy humans (583 +/- 78 MBq). In humans, blood samples were collected between the PET/CT scans, and stability of (18)F-RGD K5 was assessed. Urine was also collected between the scans, to determine the total activity excreted in urine. The PET scans were analyzed to determine the radiotracer uptake in different organs. OLINDA/EXM software was used to calculate human radiation doses based on human and monkey biodistributions. RESULTS: (18)F RGD-K5 was metabolically stable in human blood up to 90 min after injection, and it cleared rapidly from the blood pool, with a 12-min half-time. For both monkeys and humans, increased (18)F-RGD-K5 uptake was observed in the kidneys, bladder, liver, and gallbladder, with mean standardized uptake values at 1 h after injection for humans being approximately 20, 50, 4, and 10, respectively. For human biodistribution data, the calculated effective dose was 31 +/- 1 MUSv/MBq, and the urinary bladder wall had the highest absorbed dose at 376 +/- 19 MUGy/MBq using the 4.8-h bladder-voiding model. With the 1-h voiding model, these doses reduced to 15 +/- 1 MUSv/MBq for the effective dose and 103 +/- 4 MUGy/MBq for the absorbed dose in the urinary bladder wall. For a typical injected activity of 555 MBq, the effective dose would be 17.2 +/- 0.6 mSv for the 4.8-h model, reducing to 8.3 +/- 0.4 mSv for the 1-h model. For monkey biodistribution data, the effective dose to humans would be 22.2 +/- 2.4 mSv for the 4.8-h model and 12.8 +/- 0.2 mSv for the 1-h model. CONCLUSION: The biodistribution profile of (18)F-RGD-K5 in monkeys and humans was similar, with increased uptake in the bladder, liver, and kidneys. There was rapid clearance of (18)F-RGD-K5 through the renal system. The urinary bladder wall received the highest radiation dose and was deemed the critical organ. Both whole-body effective dose and bladder dose can be reduced by more frequent voiding. (18)F-RGD-K5 can be used safely for imaging alpha(v)beta(3) integrin expression in humans. PMID- 22499615 TI - 99mTc-3PRGD2 for integrin receptor imaging of lung cancer: a multicenter study. AB - (99m)Tc-3PRGD2 is a new SPECT tracer targeting integrin alpha(V)beta(3) receptor for detecting tumors, imaging angiogenesis, and evaluating tumor response to therapy. A multicenter study was designed to investigate the efficacy of (99m)Tc 3PRGD2 for the evaluation of patients with lung cancer. METHODS: Seventy patients (51 men, 19 women; mean age +/- SD, 63 +/- 9 y) with a suspected lung lesion and for whom definite pathologic diagnosis was finally obtained (malignant, n = 58; benign, n = 12) were recruited from 6 centers. Whole-body planar scanning and chest SPECT were performed at 1 and 4 h, respectively, after intravenous injection of 11.1 MBq/kg (0.3 mCi/kg) of (99m)Tc-3PRGD2. The images were read in consensus by 6 experienced nuclear medicine physicians masked to the source, history, and pathologic diagnosis. The tumor-to-background (T/B) ratios were calculated for semiquantitative analysis. A Student t test was used for statistical analysis, and a P value less than 0.05 was considered significant. RESULTS: With low (99m)Tc-3PRGD2 background in the lungs and mediastinum, most lung malignancies were prominent on the 1-h images (T/B ratio, 1.65 +/- 0.47 for the planar imaging and 2.78 +/- 1.52 for SPECT). The T/B ratios were significantly lower in the benign lesions (P < 0.05). The sensitivity was 88% for semiquantitative analysis and could reach 93%-97% in visual analysis when considering the volume effect, necrosis, and metastasis. However, the specificity was only 58%-67%. Most lymph node and bone metastases could also be detected. CONCLUSION: (99m)Tc-3PRGD2 imaging at 1 h is sensitive for the detection of lung cancer, meriting further investigation of (99m)Tc-3PRGD2 as a novel clinical tracer for integrin receptor imaging. PMID- 22499616 TI - Leiomyosarcoma of the external iliac vein. AB - Leiomyosarcoma of the iliac vein is an uncommon tumor. We report a case of a 63 year-old Japanese woman with leiomyosarcoma of the right external iliac vein. The patient complained of right inguinal pain and swelling. Computed tomography demonstrated a mass surrounding the right external iliac artery and vein. Metastases in the lungs and liver were found. Complete resection of the tumor along with the involved vessels was performed. Polytetrafluoroethylene grafts were used to reconstruct the vessels. Pathological examination revealed leiomyosarcoma of the external iliac vein. Although the prognosis of leiomyosarcoma is poor, en bloc tumor resection is the treatment of choice. PMID- 22499617 TI - A Convergence Theorem for the Fuzzy ISODATA Clustering Algorithms. AB - In this paper the convergence of a class of clustering procedures, popularly known as the fuzzy ISODATA algorithms, is established. The theory of Zangwill is used to prove that arbitrary sequences generated by these (Picard iteration) procedures always terminates at a local minimum, or at worst, always contains a subsequence which converges to a local minimum of the generalized least squares objective functional which defines the problem. PMID- 22499618 TI - Area segmentation of images using edge points. AB - A new method for segmenting images using abrupt changes in intensity (edge points) to separate regions of smoothly varying intensity is discussed. Region segmentation using edge points has not been very successful in the past because small gaps would allow merging of dissimilar regions. The present method uses an expansion-contraction technique in which the edge regions are first expanded to close gaps and then contracted after the separate uniform regions have been identified. In order to preserve small uniform regions, the process is performed iteratively from small to large expansions with no expansion for edge regions that separate different uniform regions. The final result is a set of uniform intensity regions (usually less than 100) and a set of edge boundary regions. The program has successfully segmented scenes with industrial parts, landscapes, and integrated circuit chips. PMID- 22499619 TI - Extracting and labeling boundary segments in natural scenes. AB - This paper describes a set of algorithms used to perform segmentation of natural scenes through boundary analysis. The techniques include preprocessing, differentiation using a very simple operator, relaxation using case analysis, and postprocessing. The system extracts line segments as connected sets of edges, labels them, and computes features for them such as length and confidence. PMID- 22499620 TI - On a method of binary-picture representation and its application to data compression. AB - A method of representing a binary pictorial pattern is developed. Its original idea comes from a sequence of terminal symbols of a context-free grammar. It is a promising technique of data compression for ordinary binary-valued pictures such as texts, documents, charts, etc. Fundamental notions like complexity, primitives, simplifications, and other items about binary-valued pictures are introduced at the beginning. A simple context-free grammar G is also introduced. It is shown that every binary-valued picture is interpretable as a terminal sequence of that G. The DF-expression is defined as the reduced terminal sequence of G. It represents the original picture in every detail and contains no surplus data for reproducing it. A quantitative discussion about the total data of a DF expression leads to the conclusion that any binary-valued picture with complexity less than 0.47 is expressed by the DF-expression with fewer data than the original ones. The coding algorithm of original data into the DF-expression is developed. It is very simple and recursively executable. Experiments were carried out using a PDS (photo digitizing system), where test pictures were texts, charts, diagrams, etc. with 20 cm * 20 cm size. Data compression techniques in facsimile were also simulated on the same test pictures. Throughout these studies it was made clear that the DF-expression is a very effective technique as a data compression for binary pictorial patterns not only because it yields high data compression but also because its coding and decoding algorithms are very feasible. PMID- 22499621 TI - A theoretical development for the computer generation and display of piecewise polynomial surfaces. AB - Two algorithms for parametric piecewise polynomial evaluation and generation are described. The mathematical development of these algorithms is shown to generalize to new algorithms for obtaining curve and surface intersections and for the computer display of parametric curves and surfaces. PMID- 22499622 TI - A real-time video tracking system. AB - Object identification and tracking applications of pattern recognition at video rates is a problem of wide interest, with previous attempts limited to very simple threshold or correlation (restricted window) methods. New high-speed algorithms together with fast digital hardware have produced a system for missile and aircraft identification and tracking that possesses a degree of ''intelligence'' not previously implemented in a real-time tracking system. Adaptive statistical clustering and projection-based classification algorithms are applied in real time to identify and track objects that change in appearance through complex and nonstationary background/foreground situations. Fast estimation and prediction algorithms combine linear and quadratic estimators to provide speed and sensitivity. Weights are determined to provide a measure of confidence in the data and resulting decisions. Strategies based on maximizing the probability of maintaining track are developed. This paper emphasizes the theoretical aspects of the system and discusses the techniques used to achieve real-time implementation. PMID- 22499623 TI - On the sensitivity of the probability of error rule for feature selection. AB - The low sensitivity of the probability of error rule (Pe rule) for feature selection is demonstrated and discussed. It is shown that under certain conditions features with significantly different discrimination power are considered as equivalent by the Pe rule. The main reason for this phenomenon lies in the fact that, directly, the Pe rule depends only on the most probable class and that, under the stated condition, the prior most probable class remains the posterior most probable class regardless of the result for the observed feature. A rule for breaking ties is suggested to refine the feature ordering induced by the Pe rule. By this tie-breaking rule, when two features have the same value for the expected probability of error, the feature with the higher variance for the probability of error is preferred. PMID- 22499624 TI - A decision theory approach to the approximation of discrete probability densities. AB - The problem of approximating a probability density function by a simpler one is considered from a decision theory viewpoint. Among the family of candidate approximating densities, we seek the one that is most difficult to discriminate from the original. This formulation leads naturaliy to the density at the smallest Bhattacharyya distance. The resulting optimization problem is analyzed in detail. PMID- 22499625 TI - Nosing around the neighborhood: a new system structure and classification rule for recognition in partially exposed environments. AB - The scope of the classical k-NN classification techniques is enlarged under this study to cover partially exposed environments. The modified classification system structure required for successful operation in environments, wherein all the inherent pattern classes are not exposed to the system prior to deployment, is developed and illustrated with the aid of a specific classification rule-the neighborhood census rule (NCR). Admittedly, alternative rules can be visualized to fit this modified structure. However, this study concentrates on the use of NCR to bring out the underlying philosophy and develops optimum thresholds for admittance of unknown samples into the set of presently known classes. These thresholds are learned from the available training samples of these classes. This learning represents a new dimensionality of the learning system structure in that estimates of the domains of the known classes are developed in addition to learning of the discrimination among these classes. This facilitates identification of samples belonging to the classes previously unexposed to the recognition system. Experimental results are also presented in support of the proposed concepts and methodology for operation in partially exposed environments. PMID- 22499626 TI - A relaxation method for multispectral pixel classification. AB - Three approaches to reducing errors in multispectral pixel classification were compared: 1) postprocessing (iterated reclassification based on comparison with the neighbors' classes); 2) preprocessing (iterated smoothing, by averaging with selected neighbors, prior to classification); and 3) relaxation (probabilistic classification followed by iterative probability adjustment). In experiments using a color image of a house, the relaxation approach gave markedly superior performance; relaxation eliminated 4-8 times as many errors as the other methods did. PMID- 22499627 TI - Three-dimensional skeletonization: principle and algorithm. AB - An algorithm is proposed for skeletonization of 3-D images. The criterion to preserve connectivity is given in two versions: global and local. The latter allows local decisions in the erosion process. A table of the decisions for all possible configurations is given in this paper. The algorithm using this table can be directly implemented both on general purpose computers and on dedicated machinery. PMID- 22499628 TI - A method for automating the visual inspection of printed wiring boards. AB - The application of pattern recognition techniques to manufacturing processes is a rapidly developing technology. Automatic verification of the quality of printed wiring boards (PWB's) using pattern recognition techniques is one potential application in this field. Qualitatively, this problem is finding small, irregular features in an environment of complicated, but larger and well-defined geometric features. In addition to the basic pattern recognition task, stringent performance requirements, both for throughput and accuracy, must be met if actual production usage is expected. The method employed in this study is based on characterizing 5 * 5 or 7 * 7 element binary patterns derived from the class of PWB's being inspected as good or defective. A database of 80 512 * 512 element images of PWB's was constructed and used to determine the number of unique patterns and their rates of occurrence. The major experimental result of this study is that less than 500 of the possible (15/16)224 5 * 5 patterns are needed to describe all the border containing patterns in the 80 images. It is also apparent that more patterns would be required if the training database was larger. The small number of patterns needed to represent virtually all of the normal border patterns suggests a two-stage inspection strategy. In the first stage, each border pattern from the PWB being inspected is compared to a previously prepared list. PMID- 22499629 TI - Symbolic gray code as a multikey hashing function. AB - In this paper, we extend the binary Gray code to symbolic Gray code. We then show that this symbolic Gray code can be used as a multikey hashing function for storing symbolic records. The record stored at location k and the record stored at location k + 1 will be nearest neighbors if this hashing function is used. Thus, this symbolic Gray code hashing function exhibits some kind of clustering property which will group similar records together. This property is a desirable property for designing nearest neighbor searching (also called best match searching) systems. There are many other interesting properties of this hashing function. For instance, there exists an address-to-key transformation which can be used to determine the record stored at certain location k if this hashing function is used. Besides, if there are totally M records, we only have to reserve exactly M locations; there are no collisions and wasting of memory storage. At the end of this paper, it is shown that the resulting file exhibits the multiple-attribute tree structure. PMID- 22499630 TI - Automated visual inspection: a survey. AB - This paper surveys publications, reports, and articles dealing with automated visual inspection for industry. The references are organized according to their contents: overview and discussions, rationales, components and design considerations, commercially available systems, applications. A number of applications and their inspection methodologies are discussed in detail: the inspection of printed circuit boards, photomasks, integrated circuit chips. Other inspection applications are listed as a bibliography. A list of selectively annotated references in commercially available visual inspection tools is also included. PMID- 22499631 TI - Attributed programmed graph grammars and their application to schematic diagram interpretation. AB - Attributed programmed graph grammars are introduced in this paper and their application to the interpretation of schematic diagrams is proposed. In contrast with most of the approaches to syntactic pattern recognition, where the grammar controls a parser, the grammar in our system is used as a generative tool. Two classes of diagrams are studied, namely circuit diagrams and flowcharts. The task is in either case to extract a description from an input diagram. PMID- 22499632 TI - A mathematical model for computer image tracking. AB - A mathematical model using an operator formulation for a moving object in a sequence of images is presented. Time-varying translation and rotation operators are derived to describe the motion. A variational estimation algorithm is developed to track the dynamic parameters of the operators. The occlusion problem is alleviated by using a predictive Kalman filter to keep the tracking on course during severe occlusion. The tracking algorithm (variational estimation in conjunction with Kalman filter) is implemented to track moving objects with occasional occlusion in computer-simulated binary images. PMID- 22499633 TI - Organization of relational models for scene analysis. AB - Relational models are commonly used in scene analysis systems. Most such systems are experimental and deal with only a small number of models. Unknown objects to be analyzed are usually sequentially compared to each model. In this paper, we present some ideas for organizing a large database of relational models. We define a simple relational distance measure, prove it is a metric, and using this measure, describe two organizational/access methods: clustering and binary search trees. We illustrate these methods with a set of randomly generated graphs. PMID- 22499634 TI - Stable matching between a hand structure and an object silhouette. AB - A method is proposed which determines the possible ways to grasp an object, defined by its silhouette. This method is quite general and versatile: the geometry of the object is arbitrary and a large class of grippers is allowed; no a priori information is needed, except the parameters of the gripper, and so the method applies, in particular, to all the automatic prehension problems when the object and/or its orientation are unknown. Suitable segmentation and parametrization of the silhouette yields an explicit solution and a very fast and simple algorithm. PMID- 22499635 TI - Convex digital solids. AB - A definition of convexity of digital solids is introduced. Then it is proved that a digital solid is convex if and only if it has the chordal triangle property. Other geometric properties which characterize convex digital regions are shown to be only necessary, but not sufficient, conditions for a digital solid to be convex. An efficient algorithm that determines whether or not a digital solid is convex is presented. PMID- 22499636 TI - Digital convexity, straightness, and convex polygons. AB - New schemes for digitizing regions and arcs are introduced. It is then shown that under these schemes, Sklansky's definition of digital convexity is equivalent to other definitions. Digital convex polygons of n vertices are defined and characterized in terms of geometric properties of digital line segments. Also, a linear time algorithm is presented that, given a digital convex region, determines the smallest integer n such that the region is a digital convex n-gon. PMID- 22499637 TI - An algebraic description of painted digital pictures. AB - An algebraic system for binary digital pictures has already been described, along with the definition of the four arithmetic rules. In this paper, an extension of the binary algebraic system to a 2n-valued one is first proposed. It then becomes evident that this extended algebraic system satisfies several properties including those of a ring. An example of a 2n-valued model, an eight-valued algebraic system, is introduced and applied to painted digital pictures. Pictorial operations such as multiple arrangement, enlargement, differentiation, integration, and color changes are then dealt with by the combinations of the four arithmetic rules. PMID- 22499638 TI - An algebraic approach to the generation and description of binary pictures. AB - An algebra is proposed for compactly generating and describing binary pictures such as textures and graphics. Four arithmetic operations, differentiation, and integration of such pictures are defined using pictorial constants and rational polynomials. Examples for these operations are illustrated. PMID- 22499639 TI - Shape measurement of curved objects using multiple slit-ray projections. AB - A method for the shape measurement of curved objects has been developed using multiple slit-ray projections and a turntable. The object is placed on a computer controlled turntable and irradiated by two directed slit-ray projectors. An ITV camera takes a line image of the reflection from the object, and a computer calculates the space coordinates of the object surface. By using multiple projections, the total shape measurement of the object surface is attained accurately. PMID- 22499640 TI - Some accuracy and resolution aspects of computer vision distance measurements. AB - The distance between an object and stereo vision sensors can be measured using image processing and known system parameters. A detailed distance measurement synthesis procedure to meet system specifications is presented and illustrated with an example. An error analysis shows that error is proportional to distance. System parameters such as separation between sensor elements, sensor focal length, and sensor array dimensions are related in the design and error equations presented. The main desired design goal is to establish the smallest image sensor array size which will meet system operating specifications. Minimum and maximum distance, object height, optic parameters, scene shift, and sensor array parameters are related. PMID- 22499641 TI - A geometrical approach to polygonal dissimilarity and shape matching. AB - Two geometrical measures have been proposed to quantify the dissimilarity between two irregular polygons. These measures capture the intuitive notion of the dissimilarity between shapes and are related to the minimum value of the intersecting area of the polygons on superposing one on the other in various configurations. A more easily computable measure of dissimilarity, referred to as the minimum integral square error between the polygons, has also been proposed, and using the latter measure pattern classification, has been performed. Experimental results involving the classification of the noisy boundaries of the four Great Lakes, Erie, Huron, Michigan, and Superior, using this measure, have been presented. PMID- 22499642 TI - A string correction algorithm for cursive script recognition. AB - This paper deals with a method of estimating a correct string X from its noisy version Y produced by a cursive script recognition system. An accurate channel model that allows for splitting, merging, and substitution of symbols is introduced. The best estimate X is obtained by using a dynamic programming search which combines a known search strategy (stack decoding) with a trie structure representation of a dictionary. The computational complexity of the algorithm is derived and compared with that of a method based on the generalized Levenshtein metric. Experimental results with the algorithm on English text based on a dictionary of the 1027 most commonly occurring words are described. PMID- 22499643 TI - A fast algorithm for nonparametric probability density estimation. AB - A fast algorithm for the well-known Parzen window method to estimate density functions from the samples is described. The computational efforts required by the conventional and straightforward implementation of this estimation procedure limit its practical application to data of low dimensionality. The proposed algorithm makes the computation of the same density estimates with a substantial reduction of computer time possible, especially for data of high dimensionality. Some simulation experiments are presented which demonstrate the efficiency of the method. They indicate the computational savings that may be achieved through the use of this fast algorithm for artificially generated sets of data. PMID- 22499644 TI - A species classifier of sea creatures compiled on the basis of their echo sounder signals. AB - Species recognition of sea creatures is very important and is still a difficult task in the assessment of oceanic biological resources by hydroacoustic methods and in optimum selective industrial fishing. Trials have shown that recognition by means of the subjective estimation of echo sounder records and sample hauls is not yet fully satisfactory [1]. In this correspondence a classifier of sea creature species is described. The essential efforts have been made to find efficient procedure of distinguishing features selection. As a result the classifier operates on the basis of an observation vector whose components have been developed in a special way. These components are the central moments of consecutive samples of a few realizations of echo signal envelopes. From the point of view of the observation vector, the classifier is based on simple linear theory. In practice the described classifier can be realized with the aid of the rather uncomplicated microprocessor-based circuits. The chosen distinguishing features concem to exceptional complicated nature of the biological targets. Obtained results indicate that the classifier may also be very useful in the recognition of objects belonging to many nonbiological classes. PMID- 22499645 TI - A method for computing the partial singular value decomposition. AB - A method for computing the partial singular value decomposition of a matrix is described. The method is appropriate to problems where the matrix is known to be of low rank and only the principal singular vectors are of interest. The technique is simple, easy to implement in integer arithmetic, and places modest memory requirements. The convergence properties of the algorithm are investigated analytically and by simulation. PMID- 22499646 TI - Augmented relaxation labeling and dynamic relaxation labeling. AB - Current implementations of relaxation labeling are homogeneous, where each pixel is in an identical relationship to a static neighbor set. These systems maintain the iterative probabilistic labeling but use a nonhomogeneous dynamic neighborhood to establish a local consistency. Neighborhoods are created at each iteration through the broadcasting and reception of label information according to semantically established broadcasting patterns for each label. Augmented relaxation labeling is a two stage process which contains a separate relaxation stage with a top-down direction capability for specific pixel label updating. Dynamic relaxation is a one step process where every pixel label is updated through the dynamic neighborhoods. Both labeling processes are demonstrated on simple line drawings. PMID- 22499647 TI - Maximum likelihood methods in vowel recognition: a comparative study. AB - Vowel classification accuracy is studied using a generalized maximum likelihood ratio method. It is shown that two simplifying assumptions can reduce computation times by as much as a factor of five while producing practically no change in recognition accuracy. The two simplifying assumptions remove cross correlation terms and produce an Euclidean distance discriminant function. The vowels are taken from 350 multisyllabic isolated words spoken by five male speakers. The vowels occur in a variety of preand postconsonantal contexts. The recognition scores obtained for vowels are 83 percent. The effect of grouping of similar vowels on recognition scores is found to be marginal. The high back and high front vowels show better recognition scores (92-94 percent). In general, recognition performance for individual vowels follows a definite trend with respect to. the vowel diagram. A reasonable similarity is observed between confusion matrix and the distribution of vowels in first and second formant frequency (F1 F2) plane. PMID- 22499648 TI - Fractal-based description of natural scenes. AB - This paper addresses the problems of 1) representing natural shapes such as mountains, trees, and clouds, and 2) computing their description from image data. To solve these problems, we must be able to relate natural surfaces to their images; this requires a good model of natural surface shapes. Fractal functions are a good choice for modeling 3-D natural surfaces because 1) many physical processes produce a fractal surface shape, 2) fractals are widely used as a graphics tool for generating natural-looking shapes, and 3) a survey of natural imagery has shown that the 3-D fractal surface model, transformed by the image formation process, furnishes an accurate description of both textured and shaded image regions. The 3-D fractal model provides a characterization of 3-D surfaces and their images for which the appropriateness of the model is verifiable. Furthermore, this characterization is stable over transformations of scale and linear transforms of intensity. The 3-D fractal model has been successfully applied to the problems of 1) texture segmentation and classification, 2) estimation of 3-D shape information, and 3) distinguishing between perceptually ''smooth'' and perceptually ''textured'' surfaces in the scene. PMID- 22499649 TI - Matching images using linear features. AB - We describe techniques for matching two images or an image and a map. This operation is basic for machine vision and is needed for the tasks of object recognition, change detection, map up-dating, passive navigation, and other tasks. Our system uses line-based descriptions, and matching is accomplished by a relaxation operation which computes most similar geometrical structures. A more efficient variation, called the ''kernel'' method, is also described. We give results on complex aerial images which contain many image differences, caused by varying sun position, different seasons, and imaging environments, and also structural changes caused by man-made alterations such as new construction. PMID- 22499650 TI - Matched filters for bin picking. AB - Currently, a major difficulty for the widespread use of robots in assembly and material handling comes from the necessity of feeding accurately positioned workpieces to robots. ''Bin picking'' techniques help reduce this constraint. This paper presents the application of matched filters for enabling robots with vision to acquire workpieces randomly stored in bins. This approach complements heuristic methods already reported. The concept of matched filter is an old one. Here, however, it is redefined to take into account robot end-effector features, in terms of geometry and mechanics. In particular, the proposed filters match local workpiece structures where the robot end-effector is likely to grasp successfully and hold workpieces. The local nature of the holdsites is very important as computation costs are shown to vary with the fifth power of structure size. In addition, the proposed filters tend to have a narrow angular bandwidth. An example, which features a parallel-jaw hand is developed in detail, using both statistical and Fourier models. Both approaches concur in requiring a very small number of filters (typically four), even if a good orientation accuracy is expected (two degrees). Success rates of about 90 percent in three or fewer attempts have been experimentally obtained on a system which includes a small minicomputer, a 128 * 128 pixel solidstate camera, a prototype Cartesian robot, and a ''universal'' parallel-jaw hand. PMID- 22499651 TI - Recognitive aspects of moment invariants. AB - Moment invariants are evaluated as a feature space for pattern recognition in terms of discrimination power and noise tolerance. The notion of complex moments is introduced as a simple and straightforward way to derive moment invariants. Through this relation, properties of complex moments are used to characterize moment invariants. Aspects of information loss, suppression, and redundancy encountered in moment invariants are investigated and significant results are derived. The behavior of moment invariants in the presence of additive noise is also described. PMID- 22499652 TI - Bayes smoothing algorithms for segmentation of binary images modeled by markov random fields. AB - A new image segmentation algorithm is presented, based on recursive Bayes smoothing of images modeled by Markov random fields and corrupted by independent additive noise. The Bayes smoothing algorithm yields the a posteriori distribution of the scene value at each pixel, given the total noisy image, in a recursive way. The a posteriori distribution together with a criterion of optimality then determine a Bayes estimate of the scene. The algorithm presented is an extension of a 1-D Bayes smoothing algorithm to 2-D and it gives the optimum Bayes estimate for the scene value at each pixel. Computational concerns in 2-D, however, necessitate certain simplifying assumptions on the model and approximations on the implementation of the algorithm. In particular, the scene (noiseless image) is modeled as a Markov mesh random field, a special class of Markov random fields, and the Bayes smoothing algorithm is applied on overlapping strips (horizontal/vertical) of the image consisting of several rows (columns). It is assumed that the signal (scene values) vector sequence along the strip is a vector Markov chain. Since signal correlation in one of the dimensions is not fully used along the edges of the strip, estimates are generated only along the middle sections of the strips. The overlapping strips are chosen such that the union of the middle sections of the strips gives the whole image. The Bayes smoothing algorithm presented here is valid for scene random fields consisting of multilevel (discrete) or continuous random variables. PMID- 22499653 TI - Stochastic relaxation, gibbs distributions, and the bayesian restoration of images. AB - We make an analogy between images and statistical mechanics systems. Pixel gray levels and the presence and orientation of edges are viewed as states of atoms or molecules in a lattice-like physical system. The assignment of an energy function in the physical system determines its Gibbs distribution. Because of the Gibbs distribution, Markov random field (MRF) equivalence, this assignment also determines an MRF image model. The energy function is a more convenient and natural mechanism for embodying picture attributes than are the local characteristics of the MRF. For a range of degradation mechanisms, including blurring, nonlinear deformations, and multiplicative or additive noise, the posterior distribution is an MRF with a structure akin to the image model. By the analogy, the posterior distribution defines another (imaginary) physical system. Gradual temperature reduction in the physical system isolates low energy states (''annealing''), or what is the same thing, the most probable states under the Gibbs distribution. The analogous operation under the posterior distribution yields the maximum a posteriori (MAP) estimate of the image given the degraded observations. The result is a highly parallel ''relaxation'' algorithm for MAP estimation. We establish convergence properties of the algorithm and we experiment with some simple pictures, for which good restorations are obtained at low signal-to-noise ratios. PMID- 22499654 TI - Local estimation of the uniform error threshold. AB - The theory behind selection of the ''uniform error'' threshold which equalizes the probability of misclassification in an image containing two classes is presented. It is shown how this threshold can be estimated using local operations. Some examples and possible extensions are considered. PMID- 22499655 TI - Progressive refinement of 3-d images using coded binary trees: algorithms and architecture. AB - An encoding/decoding technique and a computer architecture for progressive refinement of 3-D images is suggested. The method is based on a binary tree representation of grey-level images. A scheme to transform an N * N * N image array into a sequence of at most N * N * N elements is given. As more elements of the sequence are scanned finer resolution representations of the image are obtained. The proposed architecture, which is suitable for VLSI implementation, performs the transformations between the image and its encoding using O(log N) processors and in time and space proportional to the image size. PMID- 22499656 TI - The uncertainty principle in image processing. AB - The uncertainty principle is recognized as one of the fundamental results in signal processing. Its role in inference is, however, less well known outside of quantum mechanics. It is the aim of this paper to provide a unified approach to the problem of uncertainty in image processing. It is shown that uncertainty can be derived from the fundamental constraints on the process of vision-the requirements for class-defining operations which are both shift-invariant and insensitive to changes in illumination. It is thus shown that uncertainty plays a key role in the language of vision, since it affects the choice of both the alphabet, the elementary signals, and the syntax, the inferential structure, of vision. The report is concluded with a number of practical illustrations of these ideas, taken from such image processing tasks as enhancement, data compression, and segmentation. PMID- 22499657 TI - Parallel Branch-and-Bound Formulations for AND/OR Tree Search. AB - This paper discusses two general schemes for performing branch-and-bound (B&B) search in parallel. These schemes are applicable in principle to most of the problems which can be solved by B&B. The schemes are implemented for SSS*, a versatile algorithm having applications in game tree search, structural pattern analysis, and AND/OR graph search. The performance of parallel SSS* is studied in the context of AND/OR tree and game tree search. The paper concludes with comments on potential applications of these parallel implementations of SSS* in structural pattern analysis and game playing. PMID- 22499658 TI - Classification error for a very large number of classes. AB - Classification error is analyzed for a situation where the number of possible classes may be on the order of a hundred or more. The error associated with classifying to a single class is shown to depend mainly on average nearest neighbor distance between class means, noise level, and effective dimensionality of the class mean distribution and not much on other aspects of the distribution, noise correlation, or number of classes. Since single class error is large, separation of classes into groups is also explored. Group classification error has the same properties as single class error but the size of the error is moderated by the Bayes overlap between groups. Standard curves are provided to predict single class and group error. Also discussed are the effect of pattern blurring on classification error and the nearest-neighbor distance statistics throughout a distribution. PMID- 22499659 TI - The use of objects' faces in interpreting line drawings. AB - The two parts, which this paper is composed of, deal each with scene interpretation via gaining understanding of the faces of the objects in the scene. The first part extends the set of rules defined in a previous work regarding the assembling of all lines belonging to the same face. The set of rules, originally defined for curved object, can be extended if we confine ourselves to polyhedra. In the second part, a new concept is defined and developed, which leads to a new way of looking at polyhedral line drawings. It puts under the same roof almost all consistency checks known for polyhedra, in a natural and simple way. Geometric inconsistencies as well as interpretations inconsistencies are treated uniformly and in a straightforward manner. Through this concept a way is suggested for acquiring some understanding of back faces, and for suggesting plausible interpretation for them. The generality of this concept is demonstrated through the fact that previously known catalogs of labeled junctions can be derived directly from this concept. PMID- 22499660 TI - An iterative segmentation method based on a contextual color and shape criterion. AB - An iterative segmentation method is presented and illustrated on specific examples. Full control of each iteration step is obtained by combining local and global properties according to a model of the image structure. A consistent convergence criterion is derived from additional image structure properties and a test is proposed to evaluate adequacy of segmentation. PMID- 22499661 TI - Synthesis and estimation of random fields using long-correlation models. AB - Random field models have arisen in important applications in many diverse fields, including image synthesis and analysis. The automatic description and processing of images is limited by the types of underlying models that are hypothesized for the image. Hence, new random field models and associated techniques are developed. The new class of models includes the traditional simultaneous autoregressive and moving average models, but extends these to comprise a substantially larger new class. Thus, new image textures are representable with convenient small-order parameterizations. In particular, representations with significant correlations between distant locations are achieved. The algorithms for synthesis and estimation, however, require only about the same amount of time as the classical models. The development is facilitated by a new mathematical formulation suitable for problems involving high-dimensional transformations. PMID- 22499662 TI - Identification of metallic spheroids by classification of their electromagnetic induction responses. AB - An investigation into the feasibility of applying pattern recognition concepts to the classification of metallic objects by their electromagnetic induction responses was performed. The effect on the response of a limited set of steel spheroids due to various factors such as object shape, size, and orientation was examined and a pattern recognition scheme based on these results was proposed. Implementation of the scheme involved the development of a novel extension to the nearest mean vector type of classifier in which the concept of the class mean as a point in feature space was generalized to be a curve. The resultant pattern recognition scheme was tested on a representative test set which included 815 responses, corresponding to 104 variations in object and orientation. A success rate of greater than 96 percent was achieved. It is noted that the classifier extension developed provides a viable approach to classification of responses that very continuously with respect to a single parameter. PMID- 22499663 TI - Machine vision applied to vehicle guidance. AB - Research on the semiautonomous operation of mobile robots in typical pathways is described. The image of the pathway will consist of two nearly vertical lines bounding a region with little texture (the pathway) after correction for perspective. In order to identify pathway boundaries, regions in the image space are examined using an edge detection algorithm, edges between regions are determined by the algorithm, and those corresponding to straight or nearly straight lines with large slope (path boundaries) are identified by means of the Hough transform. Once the path boundaries are identified, the horizontal distance from camera to road edge is determined. Next, a method to detect cubics in the roadway (i.e., obstacles) is presented. The region of interest in the roadway (from the camera to some predetermined distance in front of it) is known from the path boundary algorithm. The interior of this region is examined for edges. If edges are detected, it means that obstacles or shadows are present. A method to separate obstacles from shadows using stere vision is then presented. PMID- 22499664 TI - Conceptual recurrence plots: revealing patterns in human discourse. AB - Human discourse contains a rich mixture of conceptual information. Visualization of the global and local patterns within this data stream is a complex and challenging problem. Recurrence plots are an information visualization technique that can reveal trends and features in complex time series data. The recurrence plot technique works by measuring the similarity of points in a time series to all other points in the same time series and plotting the results in two dimensions. Previous studies have applied recurrence plotting techniques to textual data; however, these approaches plot recurrence using term-based similarity rather than conceptual similarity of the text. We introduce conceptual recurrence plots, which use a model of language to measure similarity between pairs of text utterances, and the similarity of all utterances is measured and displayed. In this paper, we explore how the descriptive power of the recurrence plotting technique can be used to discover patterns of interaction across a series of conversation transcripts. The results suggest that the conceptual recurrence plotting technique is a useful tool for exploring the structure of human discourse. PMID- 22499665 TI - Reorganization of the host epigenome by a viral oncogene. AB - Adenovirus small e1a oncoprotein causes ~70% reduction in cellular levels of histone H3 lysine 18 acetylation (H3K18ac). It is unclear, however, where this dramatic reduction occurs genome-wide. ChIP-sequencing revealed that by 24 h after expression, e1a erases 95% of H3K18ac peaks in normal, contact-inhibited fibroblasts and replaces them with one-third as many at new genomic locations. The H3K18ac peaks at promoters and intergenic regions of genes with fibroblast related functions are eliminated after infection, and new H3K18ac peaks are established at promoters of highly induced genes that regulate cell cycling and at new putative enhancers. Strikingly, the regions bound by the retinoblastoma family of proteins in contact-inhibited fibroblasts gain new peaks of H3K18ac in the e1a-expressing cells, including 55% of RB1-bound loci. In contrast, over half of H3K9ac peaks are similarly distributed before and after infection, independently of RB1. The strategic redistribution of H3K18ac by e1a highlights the importance of this modification for transcriptional activation and cellular transformation as well as functional differences between the RB-family member proteins. PMID- 22499667 TI - Systematic identification of edited microRNAs in the human brain. AB - Adenosine-to-inosine (A-to-I) editing modifies RNA transcripts from their genomic blueprint. A prerequisite for this process is a double-stranded RNA (dsRNA) structure. Such dsRNAs are formed as part of the microRNA (miRNA) maturation process, and it is therefore expected that miRNAs are affected by A-to-I editing. Editing of miRNAs has the potential to add another layer of complexity to gene regulation pathways, especially if editing occurs within the miRNA-mRNA recognition site. Thus, it is of interest to study the extent of this phenomenon. Current reports in the literature disagree on its extent; while some reports claim that it may be widespread, others deem the reported events as rare. Utilizing a next-generation sequencing (NGS) approach supplemented by an extensive bioinformatic analysis, we were able to systematically identify A-to-I editing events in mature miRNAs derived from human brain tissues. Our algorithm successfully identified many of the known editing sites in mature miRNAs and revealed 17 novel human sites, 12 of which are in the recognition sites of the miRNAs. We confirmed most of the editing events using in vitro ADAR overexpression assays. The editing efficiency of most sites identified is very low. Similar results are obtained for publicly available data sets of mouse brain regions tissues. Thus, we find that A-to-I editing does alter several miRNAs, but it is not widespread. PMID- 22499666 TI - Disentangling the relationship between sex-biased gene expression and X-linkage. AB - X chromosomes are preferentially transmitted through females, which may favor the accumulation of X-linked alleles/genes with female-beneficial effects. Numerous studies have shown that genes with sex-biased expression are under- or over represented on the X chromosomes of a wide variety of organisms. The patterns, however, vary between different animal species, and the causes of these differences are unresolved. Additionally, genes with sex-biased expression tend to be narrowly expressed in a limited number of tissues, and narrowly expressed genes are also non-randomly X-linked in a taxon-specific manner. It is therefore unclear whether the unique gene content of the X chromosome is the result of selection on genes with sex-biased expression, narrowly expressed genes, or some combination of the two. To address this problem, we measured sex-biased expression in multiple Drosophila species and at different developmental time points. These data were combined with available expression measurements from Drosophila melanogaster and mouse to reconcile the inconsistencies in X chromosome content among taxa. Our results suggest that most of the differences between Drosophila and mammals are confounded by disparate data collection/analysis approaches as well as the correlation between sex bias and expression breadth. Both the Drosophila and mouse X chromosomes harbor an excess of genes with female-biased expression after controlling for the confounding factors, suggesting that the asymmetrical transmission of the X chromosome favors the accumulation of female-beneficial mutations in X-linked genes. However, some taxon-specific patterns remain, and we provide evidence that these are in part a consequence of constraints imposed by the dosage compensation mechanism in Drosophila. PMID- 22499668 TI - Genome-wide analysis of mutations in mutant lineages selected following fast neutron irradiation mutagenesis of Arabidopsis thaliana. AB - Ionizing radiation has long been known to induce heritable mutagenic change in DNA sequence. However, the genome-wide effect of radiation is not well understood. Here we report the molecular properties and frequency of mutations in phenotypically selected mutant lines isolated following exposure of the genetic model flowering plant Arabidopsis thaliana to fast neutrons (FNs). Previous studies suggested that FNs predominantly induce deletions longer than a kilobase in A. thaliana. However, we found a higher frequency of single base substitution than deletion mutations. While the overall frequency and molecular spectrum of fast-neutron (FN)-induced single base substitutions differed substantially from those of "background" mutations arising spontaneously in laboratory-grown plants, G:C>A:T transitions were favored in both. We found that FN-induced G:C>A:T transitions were concentrated at pyrimidine dinucleotide sites, suggesting that FNs promote the formation of mutational covalent linkages between adjacent pyrimidine residues. In addition, we found that FNs induced more single base than large deletions, and that these single base deletions were possibly caused by replication slippage. Our observations provide an initial picture of the genome wide molecular profile of mutations induced in A. thaliana by FN irradiation and are particularly informative of the nature and extent of genome-wide mutation in lines selected on the basis of mutant phenotypes from FN-mutagenized A. thaliana populations. PMID- 22499669 TI - Competition, collaboration and coordination--determining how cells bypass DNA damage. AB - Cells must overcome replication blocks that might otherwise lead to genomic instability or cell death. Classical genetic experiments have identified a series of mechanisms that cells use to replicate damaged DNA: translesion synthesis, template switching and homologous recombination. In translesion synthesis, DNA lesions are replicated directly by specialised DNA polymerases, a potentially error-prone approach. Template switching and homologous recombination use an alternative undamaged template to allow the replicative polymerases to bypass DNA lesions and, hence, are generally error free. Classically, these pathways have been viewed as alternatives, competing to ensure replication of damaged DNA templates is completed. However, this view of a series of static pathways has been blurred by recent work using a combination of genetic approaches and methodology for examining the physical intermediates of bypass reactions. These studies have revealed a much more dynamic interaction between the pathways than was initially appreciated. In this Commentary, I argue that it might be more helpful to start thinking of lesion-bypass mechanisms in terms of a series of dynamically assembled 'modules', often comprising factors from different classical pathways, whose deployment is crucially dependent on the context in which the bypass event takes place. PMID- 22499671 TI - The role of androgens in regulating emotional state and aggressive behavior. AB - This manuscript attempts to develop a new theory to explain both the pre- and post-encounter increase in testosterone levels and the varying dynamics of androgen levels in dominant and subordinate males. The new theory includes the following hypotheses: (i) The pre-encounter increase in testosterone levels is a result of the excitement that is caused by the anticipation of victory. Individuals who do not experience this kind of emotion before the encounter usually do not demonstrate an increased secretion of androgens. (ii) The post encounter increase in testosterone levels is related to the pleasure that results as a result of victory and the sharp decrease in emotional tension. Additionally, an increased secretion of testosterone acts as a positive reward for the type of behavior that has led to the victory. (iii) A high basal level of testosterone in dominant males is only present in those instances when dominating not only results in a profit that is related to the possession of resources, but is also associated with low emotional tension. PMID- 22499672 TI - Role of stem cells in the regeneration and repair of peripheral nerves. AB - Peripheral nerve regeneration is a complex process, with Wallerian degeneration the most elementary reaction and Schwann cells playing an important role. In recent years, stem cells have been widely used to repair injured peripheral nerves. The sources of these stem cells are widespread and their effectiveness in the treatment of peripheral nerve injury may lie in their ability to differentiate into Schwann cells, secrete neurotrophic factors, and assist in myelin formation. Stem cells have been used as seed cells in tissue-engineered nerve grafts. The understanding of stem cell homing, novel repair material, and the ability to mobilize endogenous stem cells to assist peripheral nerve regeneration constitute a research direction of great interest. PMID- 22499670 TI - CD98 at the crossroads of adaptive immunity and cancer. AB - Adaptive immunity, a vertebrate specialization, adds memory and exquisite specificity to the basic innate immune responses present in invertebrates while conserving metabolic resources. In adaptive immunity, antigenic challenge requires extremely rapid proliferation of rare antigen-specific lymphocytes to produce large, clonally expanded effector populations that neutralize pathogens. Rapid proliferation and resulting clonal expansion are dependent on CD98, a protein whose well-conserved orthologs appear restricted to vertebrates. Thus, CD98 supports lymphocyte clonal expansion to enable protective adaptive immunity, an advantage that could account for the presence of CD98 in vertebrates. CD98 supports lymphocyte clonal expansion by amplifying integrin signals that enable proliferation and prevent apoptosis. These integrin-dependent signals can also provoke cancer development and invasion, anchorage-independence and the rapid proliferation of tumor cells. CD98 is highly expressed in many cancers and contributes to formation of tumors in experimental models. Strikingly, vertebrates, which possess highly conserved CD98 proteins, CD98-binding integrins and adaptive immunity, also display propensity towards invasive and metastatic tumors. In this Commentary, we review the roles of CD98 in lymphocyte biology and cancer. We suggest that the CD98 amplification of integrin signaling in adaptive immunity provides survival benefits to vertebrates, which, in turn, bear the price of increased susceptibility to cancer. PMID- 22499673 TI - Interferon regulatory factor 1 regulation of oligodendrocyte injury and inflammatory demyelination. AB - Oligodendrocyte injury and inflammatory demyelination are key pathological abnormalities of multiple sclerosis (MS), and its animal model, i.e., the experimental autoimmune encephalomyelitis (EAE). Traditionally, they are viewed as destructive processes secondary to a dysregulated autoimmune reaction. New evidence emerged over the last decade indicating that oligodendrocytes are not merely immune targets but rather active participants in the neuroimmune network and, in fact, can regulate the events leading to inflammatory demyelination. In this review, we are discussing the role of interferon regulatory factor 1 (IRF-1) as a master transcription factor orchestrating oligodendrocyte injury and inflammatory demyelination in MS and EAE. We are also discussing the significance of IRF-1 signaling in the induction of oligodendrocyte pyroptosis, a Caspase 1 dependent pro-inflammatory cell death, as a disease-enhancing mechanism. Finally, we are drawing attention to IRF-1 as a potential therapeutic target in MS and to the importance of investigating other oligodendrocyte-dependent disease mechanisms. PMID- 22499675 TI - Glial hemichannels and their involvement in aging and neurodegenerative diseases. AB - During the last two decades, it became increasingly evident that glial cells accomplish a more important role in brain function than previously thought. Glial cells express pannexins and connexins, which are member subunits of two protein families that form membrane channels termed hemichannels. These channels communicate intra- and extracellular compartments and allow the release of autocrine/paracrine signaling molecules [e.g., adenosine triphosphate (ATP), glutamate, nicotinamide adenine dinucleotide, and prostaglandin E2] to the extracellular milieu, as well as the uptake of small molecules (e.g., glucose). An increasing body of evidence has situated glial hemichannels as potential regulators of the beginning and maintenance of homeostatic imbalances observed in diverse brain diseases. Here, we review and discuss the current evidence about the possible role of glial hemichannels on neurodegenerative diseases. A subthreshold pathological threatening condition leads to microglial activation, which keeps active defense and restores the normal function of the central nervous system. However, if the stimulus is deleterious, microglial cells and the endothelium become overactivated, both releasing bioactive molecules (e.g., glutamate, cytokines, prostaglandins, and ATP), which increase the activity of glial hemichannels, reducing the astroglial neuroprotective functions, and further reducing neuronal viability. Because ATP and glutamate are released via glial hemichannels in neurodegenerative conditions, it is expected that they contribute to neurotoxicity. More importantly, toxic molecules released via glial hemichannels could increase the Ca2+ entry in neurons also via neuronal hemichannels, leading to neuronal death. Therefore, blockade of hemichannels expressed by glial cells and/or neurons during neuroinflammation might prevent neurodegeneration. PMID- 22499676 TI - Diversity of presynaptic calcium channels displaying different synaptic properties. AB - Why mediate P-/Q-type and not N-type Ca2+ channels in cerebellar inhibitory interneurons? Neurotransmitter release relies most on P-/Q- and N-type Ca2+ channels in the vast majority of neurons, although all types of voltage-gated Ca2+ channels are competent in initiating exocytosis. Up to date, it remains unclear why a particular Ca2+ channel type mediates neurotransmission in certain axon terminals and another type of Ca2+ channel evokes neurotransmission in axon terminals of another region. Therefore, the present review analyzes the diversity of presynaptic Ca2+ channels displaying different synaptic properties and focuses on an analysis of distribution and function of presynaptic voltage-gated Ca2+ channels, as well as on developmental changes. PMID- 22499674 TI - Phosphoinositide 3-kinase enhancer (PIKE) in the brain: is it simply a phosphoinositide 3-kinase/Akt enhancer? AB - Since its discovery in 2000, phosphoinositide 3-kinase enhancer (PIKE) has been recognized as a class of GTPase that controls the enzymatic activities of phosphoinositide 3-kinase (PI3K) and Akt in the central nervous system (CNS). However, recent studies suggest that PIKEs are not only enhancers to PI3K/Akt but also modulators to other kinases including insulin receptor tyrosine kinase and focal adhesion kinases. Moreover, they regulate transcription factors such as signal transducer and activator of transcription and nuclear factor kappaB. Indeed, PIKE proteins participate in multiple cellular processes including control of cell survival, brain development, memory formation, gene transcription, and metabolism. In this review, we have summarized the functions of PIKE proteins in CNS and discussed their potential implications in various neurological disorders. PMID- 22499677 TI - alpha-Synuclein phosphorylation as a therapeutic target in Parkinson's disease. AB - Phosphorylation is a key post-translational modification necessary for normal cellular signaling and, therefore, lies at the heart of cellular function. In neurodegenerative disorders, abnormal hyperphosphorylation of pathogenic proteins is a common phenomenon that contributes in important ways to the disease process. A prototypical protein that is hyperphosphorylated in the brain is alpha synuclein (alpha-syn) - found in Lewy bodies and Lewy neurites - the pathological hallmarks of Parkinson's disease (PD) and other alpha-synucleinopathies. The genetic linkage of alpha-syn to PD as well as its pathological association in both genetic and sporadic cases have made it the primary protein of interest. In understanding how alpha-syn dysfunction occurs, increasing focus is being placed on its abnormal aggregation and the contribution of phosphorylation to this process. Studies of both the kinases and phosphatases that regulate alpha-syn phosphorylation are beginning to reveal the roles of this post-translational modification in disease pathogenesis. Modulation of alpha-syn phosphorylation may ultimately prove to be a viable strategy for disease-modifying therapeutic interventions. In this review, we explore mechanisms related to alpha-syn phosphorylation, its biophysical and functional consequences, and its role in neurodegeneration. PMID- 22499678 TI - A historical justification for and retrospective analysis of the systematic application of light therapy in Parkinson's disease. AB - For the past 40 years the primary purpose of therapeutics for Parkinson's disease (PD) has been to replace deficient dopamine (DA) in the nigrostriatal dopamine (NSD) system. Even in the presence of limited efficacy, abundant side effects and impoverished quality of life, the involvement of other systems in the aetiology and treatment of this disorder has been sorely neglected and the excessive use of DA replacement therapy (DART) continues on a global basis. Recent scientific work suggests that the retina plays a major role in NSD function and intimates light therapy in the management of PD. After a thorough review of historical evidence supporting this contention, a retrospective, open-label study on 129 PD patients, whereby they were monitored for a period extending for a few months to eight years, was carried out. Primary motor and non-motor symptoms were monitored using an objectified global rating scale and timed motor tests that were assessed at regular intervals for the duration of the study. Thirty-one patients with other neurological disorders (OND) served as controls to determine whether any therapeutic effects seen with light were generalizable across other conditions. Patients were classified as compliant (COM), semi-compliant (SCOM), or early quit (EQUIT; prematurely discontinued treatment). EQUIT patients showed deterioration, while the COM group improved on most parameters. The SCOM patients were not as good as the COM group. The OND group showed significant improvement in depression and insomnia, but exposure to light did not improve motor function. The total drug burden of PD patients maintained on light was less with fewer side effects than SCOM or EQUIT groups. These results confirm the value of the strategic application of light therapy with controlled doses of DART in PD and warrants further controlled investigation. That the symptomatic improvement continued as long patients remained in the program suggests that exposure to light, under a strict daily regimen, combined with controlled DART, actively slows or arrests the progressive degenerative process underlying PD. PMID- 22499679 TI - Optimality criteria for the design of 2-color microarray studies. AB - We discuss the definition and application of design criteria for evaluating the efficiency of 2-color microarray designs. First, we point out that design optimality criteria are defined differently for the regression and block design settings. This has caused some confusion in the literature and warrants clarification. Linear models for microarray data analysis have equivalent formulations as ANOVA or regression models. However, this equivalence does not extend to design criteria. We discuss optimality criterion, and argue against applying regression-style D-optimality to the microarray design problem. We further disfavor E- and D-optimality (as defined in block design) because they are not attuned to scientific questions of interest. PMID- 22499680 TI - A mixture-model approach for parallel testing for unequal variances. AB - Testing for unequal variances is usually performed in order to check the validity of the assumptions that underlie standard tests for differences between means (the t-test and anova). However, existing methods for testing for unequal variances (Levene's test and Bartlett's test) are notoriously non-robust to normality assumptions, especially for small sample sizes. Moreover, although these methods were designed to deal with one hypothesis at a time, modern applications (such as to microarrays and fMRI experiments) often involve parallel testing over a large number of levels (genes or voxels). Moreover, in these settings a shift in variance may be biologically relevant, perhaps even more so than a change in the mean. This paper proposes a parsimonious model for parallel testing of the equal variance hypothesis. It is designed to work well when the number of tests is large; typically much larger than the sample sizes. The tests are implemented using an empirical Bayes estimation procedure which 'borrows information' across levels. The method is shown to be quite robust to deviations from normality, and to substantially increase the power to detect differences in variance over the more traditional approaches even when the normality assumption is valid. PMID- 22499681 TI - A context dependent pair hidden Markov model for statistical alignment. AB - This article proposes a novel approach to statistical alignment of nucleotide sequences by introducing a context dependent structure on the substitution process in the underlying evolutionary model. We propose to estimate alignments and context dependent mutation rates relying on the observation of two homologous sequences. The procedure is based on a generalized pair-hidden Markov structure, where conditional on the alignment path, the nucleotide sequences follow a Markov distribution. We use a stochastic approximation expectation maximization (saem) algorithm to give accurate estimators of parameters and alignments. We provide results both on simulated data and vertebrate genomes, which are known to have a high mutation rate from CG dinucleotide. In particular, we establish that the method improves the accuracy of the alignment of a human pseudogene and its functional gene. PMID- 22499683 TI - Fast wavelet based functional models for transcriptome analysis with tiling arrays. AB - For a better understanding of the biology of an organism, a complete description is needed of all regions of the genome that are actively transcribed. Tiling arrays are used for this purpose. They allow for the discovery of novel transcripts and the assessment of differential expression between two or more experimental conditions such as genotype, treatment, tissue, etc. In tiling array literature, many efforts are devoted to transcript discovery, whereas more recent developments also focus on differential expression. To our knowledge, however, no methods for tiling arrays have been described that can simultaneously assess transcript discovery and identify differentially expressed transcripts. In this paper, we adopt wavelet based functional models to the context of tiling arrays. The high dimensionality of the data triggered us to avoid inference based on Bayesian MCMC methods. Instead, we introduce a fast empirical Bayes method that provides adaptive regularization of the functional effects. A simulation study and a case study illustrate that our approach is well suited for the simultaneous assessment of transcript discovery and differential expression in tiling array studies, and that it outperforms methods that accomplish only one of these tasks. PMID- 22499684 TI - Transcriptional network inference from functional similarity and expression data: a global supervised approach. AB - An important challenge in system biology is the inference of biological networks from postgenomic data. Among these biological networks, a gene transcriptional regulatory network focuses on interactions existing between transcription factors (TFs) and and their corresponding target genes. A large number of reverse engineering algorithms were proposed to infer such networks from gene expression profiles, but most current methods have relatively low predictive performances. In this paper, we introduce the novel TNIFSED method (Transcriptional Network Inference from Functional Similarity and Expression Data), that infers a transcriptional network from the integration of correlations and partial correlations of gene expression profiles and gene functional similarities through a supervised classifier. In the current work, TNIFSED was applied to predict the transcriptional network in Escherichia coli and in Saccharomyces cerevisiae, using datasets of 445 and 170 affymetrix arrays, respectively. Using the area under the curve of the receiver operating characteristics and the F-measure as indicators, we showed the predictive performance of TNIFSED to be better than unsupervised state-of-the-art methods. TNIFSED performed slightly worse than the supervised SIRENE algorithm for the target genes identification of the TF having a wide range of yet identified target genes but better for TF having only few identified target genes. Our results indicate that TNIFSED is complementary to the SIRENE algorithm, and particularly suitable to discover target genes of "orphan" TFs. PMID- 22499686 TI - MicroRNA transcription start site prediction with multi-objective feature selection. AB - MicroRNAs (miRNAs) are non-coding, short (21-23nt) regulators of protein-coding genes that are generally transcribed first into primary miRNA (pri-miR), followed by the generation of precursor miRNA (pre-miR). This finally leads to the production of the mature miRNA. A large amount of information is available on the pre- and mature miRNAs. However, very little is known about the pri-miRs, due to a lack of knowledge about their transcription start sites (TSSs). Based on the genomic loci, miRNAs can be categorized into two types --intragenic (intra-miR) and intergenic (inter-miR). While it is already an established fact that intra miRs are commonly transcribed in conjunction with their host genes, the transcription machinery of inter-miRs is poorly understood. Although it is assumed that miRNA promoters are similar in structure to gene promoters, since both are transcribed by RNA polymerase II (Pol II), computational validations exhibit poor performance of gene promoter prediction methods on miRNAs. In this paper, we concentrate on the problem of TSS prediction for miRNAs. The present study begins with the identification of positive and negative promoter samples from recently published data stemming from RNA-sequencing studies. From these samples of experimentally validated miRNA TSSs, a number of standard sequence features are extracted. Furthermore, to account for potential footprints related to promoter regulation by CpG dinucleotide targeted DNA methylation, a number of novel features are defined. We develop a support vector machine (SVM) with RBF kernel for the prediction of miRNA TSSs trained on human miRNA promoters. A novel feature reduction technique based on archived multi-objective simulated annealing (AMOSA) identifies the final set of features. The resulting model trained on miRNA promoters shows improved performance over the one trained on protein-coding gene promoters in terms of classification accuracy, sensitivity and specificity. Results are also reported for a completely independent biologically validated test set. In a part of the investigation, the proposed approach is used to predict protein-coding gene TSSs. It shows a significantly improved performance when compared to previously published gene TSS prediction methods. PMID- 22499685 TI - Stopping-time resampling and population genetic inference under coalescent models. AB - To extract full information from samples of DNA sequence data, it is necessary to use sophisticated model-based techniques such as importance sampling under the coalescent. However, these are limited in the size of datasets they can handle efficiently. Chen and Liu (2000) introduced the idea of stopping-time resampling and showed that it can dramatically improve the efficiency of importance sampling methods under a finite-alleles coalescent model. In this paper, a new framework is developed for designing stopping-time resampling schemes under more general models. It is implemented on data both from infinite sites and stepwise models of mutation, and extended to incorporate crossover recombination. A simulation study shows that this new framework offers a substantial improvement in the accuracy of likelihood estimation over a range of parameters, while a direct application of the scheme of Chen and Liu (2000) can actually diminish the estimate. The method imposes no additional computational burden and is robust to the choice of parameters. PMID- 22499687 TI - The inheritance procedure: multiple testing of tree-structured hypotheses. AB - Hypotheses tests in bioinformatics can often be set in a tree structure in a very natural way, e.g. when tests are performed at probe, gene, and chromosome level. Exploiting this graph structure in a multiple testing procedure may result in a gain in power or increased interpretability of the results.We present the inheritance procedure, a method of familywise error control for hypotheses structured in a tree. The method starts testing at the top of the tree, following up on those branches in which it finds significant results, and following up on leaf nodes in the neighborhood of those leaves. The method is a uniform improvement over a recently proposed method by Meinshausen. The inheritance procedure has been implemented in the globaltest package which is available on www.bioconductor.org. PMID- 22499688 TI - Improving Hidden Markov Models for classification of human immunodeficiency virus 1 subtypes through linear classifier learning. AB - Profile Hidden Markov Models (pHMMs) are widely used to model nucleotide or protein sequence families. In many applications, a sequence family classified into several subfamilies is given and each subfamily is modeled separately by one pHMM. A major drawback of this approach is the difficulty of coping with subfamilies composed of very few sequences.Correct subtyping of human immunodeficiency virus-1 (HIV-1) sequences is one of the most crucial bioinformatic tasks affected by this problem of small subfamilies, i.e., HIV-1 subtypes with a small number of known sequences. To deal with small samples for particular subfamilies of HIV-1, we employ a machine learning approach. More precisely, we make use of an existing HMM architecture and its associated inference engine, while replacing the unsupervised estimation of emission probabilities by a supervised method. For that purpose, we use regularized linear discriminant learning together with a balancing scheme to account for the widely varying sample size. After training the multiclass linear discriminants, the corresponding weights are transformed to valid probabilities using a softmax function.We apply this modified algorithm to classify HIV-1 sequence data (in the form of partial-length HIV-1 sequences and semi-artificial recombinants) and show that the performance of pHMMs can be significantly improved by the proposed technique. PMID- 22499682 TI - Fast identification of biological pathways associated with a quantitative trait using group lasso with overlaps. AB - Where causal SNPs (single nucleotide polymorphisms) tend to accumulate within biological pathways, the incorporation of prior pathways information into a statistical model is expected to increase the power to detect true associations in a genetic association study. Most existing pathways-based methods rely on marginal SNP statistics and do not fully exploit the dependence patterns among SNPs within pathways.We use a sparse regression model, with SNPs grouped into pathways, to identify causal pathways associated with a quantitative trait. Notable features of our "pathways group lasso with adaptive weights" (P-GLAW) algorithm include the incorporation of all pathways in a single regression model, an adaptive pathway weighting procedure that accounts for factors biasing pathway selection, and the use of a bootstrap sampling procedure for the ranking of important pathways. P-GLAW takes account of the presence of overlapping pathways and uses a novel combination of techniques to optimise model estimation, making it fast to run, even on whole genome datasets.In a comparison study with an alternative pathways method based on univariate SNP statistics, our method demonstrates high sensitivity and specificity for the detection of important pathways, showing the greatest relative gains in performance where marginal SNP effect sizes are small. PMID- 22499689 TI - Special issue on computational statistical methods for genomics and systems biology. AB - We provide a brief editorial introduction to a special issue of Statistical Applications in Genetics and Molecular Biology dedicated to the workshop on "Computational Statistical Methods for Genomics and Systems Biology", held at the Centre de recherches mathematiques in Montreal in April 2011. PMID- 22499690 TI - Querying genomic databases: refining the connectivity map. AB - The advent of high-throughput biotechnologies, which can efficiently measure gene expression on a global basis, has led to the creation and population of correspondingly rich databases and compendia. Such repositories have the potential to add enormous scientific value beyond that provided by individual studies which, due largely to cost considerations, are typified by small sample sizes. Accordingly, substantial effort has been invested in devising analysis schemes for utilizing gene-expression repositories. Here, we focus on one such scheme, the Connectivity Map (cmap), that was developed with the express purpose of identifying drugs with putative efficacy against a given disease, where the disease in question is characterized by a (differential) gene-expression signature. Initial claims surrounding cmap intimated that such tools might lead to new, previously unanticipated applications of existing drugs. However, further application suggests that its primary utility is in connecting a disease condition whose biology is largely unknown to a drug whose mechanisms of action are well understood, making cmap a tool for enhancing biological knowledge.The success of the Connectivity Map is belied by its simplicity. The aforementioned signature serves as an unordered query which is applied to a customized database of (differential) gene-expression experiments designed to elicit response to a wide range of drugs, across of spectrum of concentrations, durations, and cell lines. Such application is effected by computing a per experiment score that measures "closeness" between the signature and the experiment. Top-scoring experiments, and the attendant drug(s), are then deemed relevant to the disease underlying the query. Inference supporting such elicitations is pursued via re sampling. In this paper, we revisit two key aspects of the Connectivity Map implementation. Firstly, we develop new approaches to measuring closeness for the common scenario wherein the query constitutes an ordered list. These involve using metrics proposed for analyzing partially ranked data, these being of interest in their own right and not widely used. Secondly, we advance an alternate inferential approach based on generating empirical null distributions that exploit the scope, and capture dependencies, embodied by the database. Using these refinements we undertake a comprehensive re-evaluation of Connectivity Map findings that, in general terms, reveal that accommodating ordered queries is less critical than the mode of inference. PMID- 22499691 TI - Bayesian sparsity-path-analysis of genetic association signal using generalized t priors. AB - We explore the use of generalized t priors on regression coefficients to help understand the nature of association signal within "hit regions" of genome-wide association studies. The particular generalized t distribution we adopt is a Student distribution on the absolute value of its argument. For low degrees of freedom, we show that the generalized t exhibits "sparsity-prior" properties with some attractive features over other common forms of sparse priors and includes the well known double-exponential distribution as the degrees of freedom tends to infinity. We pay particular attention to graphical representations of posterior statistics obtained from sparsity-path-analysis (SPA) where we sweep over the setting of the scale (shrinkage/precision) parameter in the prior to explore the space of posterior models obtained over a range of complexities, from very sparse models with all coefficient distributions heavily concentrated around zero, to models with diffuse priors and coefficients distributed around their maximum likelihood estimates. The SPA plots are akin to LASSO plots of maximum a posteriori (MAP) estimates but they characterise the complete marginal posterior distributions of the coefficients plotted as a function of the precision of the prior. Generating posterior distributions over a range of prior precisions is computationally challenging but naturally amenable to sequential Monte Carlo (SMC) algorithms indexed on the scale parameter. We show how SMC simulation on graphic-processing-units (GPUs) provides very efficient inference for SPA. We also present a scale-mixture representation of the generalized t prior that leads to an expectation-maximization (EM) algorithm to obtain MAP estimates should only these be required. PMID- 22499692 TI - A model-based analysis to infer the functional content of a gene list. AB - An important challenge in statistical genomics concerns integrating experimental data with exogenous information about gene function. A number of statistical methods are available to address this challenge, but most do not accommodate complexities in the functional record. To infer activity of a functional category (e.g., a gene ontology term), most methods use gene-level data on that category, but do not use other functional properties of the same genes. Not doing so creates undue errors in inference. Recent developments in model-based category analysis aim to overcome this difficulty, but in attempting to do so they are faced with serious computational problems. This paper investigates statistical properties and the structure of posterior computation in one such model for the analysis of functional category data. We examine the graphical structures underlying posterior computation in the original parameterization and in a new parameterization aimed at leveraging elements of the model. We characterize identifiability of the underlying activation states, describe a new prior distribution, and introduce approximations that aim to support numerical methods for posterior inference. PMID- 22499693 TI - A family-based probabilistic method for capturing de novo mutations from high throughput short-read sequencing data. AB - Recent advances in high-throughput DNA sequencing technologies and associated statistical analyses have enabled in-depth analysis of whole-genome sequences. As this technology is applied to a growing number of individual human genomes, entire families are now being sequenced. Information contained within the pedigree of a sequenced family can be leveraged when inferring the donors' genotypes. The presence of a de novo mutation within the pedigree is indicated by a violation of Mendelian inheritance laws. Here, we present a method for probabilistically inferring genotypes across a pedigree using high-throughput sequencing data and producing the posterior probability of de novo mutation at each genomic site examined. This framework can be used to disentangle the effects of germline and somatic mutational processes and to simultaneously estimate the effect of sequencing error and the initial genetic variation in the population from which the founders of the pedigree arise. This approach is examined in detail through simulations and areas for method improvement are noted. By applying this method to data from members of a well-defined nuclear family with accurate pedigree information, the stage is set to make the most direct estimates of the human mutation rate to date. PMID- 22499694 TI - Gene filtering in the analysis of Illumina microarray experiments. AB - Illumina bead arrays are microarrays that contain a random number of technical replicates (beads) for every probe (bead type) within the same array. Typically around 30 beads are placed at random positions on the array surface, which opens unique opportunities for quality control. Most preprocessing methods for Illumina bead arrays are ported from the Affymetrix microarray platform and ignore the availability of the technical replicates. The large number of beads for a particular bead type on the same array, however, should be highly correlated, otherwise they just measure noise and can be removed from the downstream analysis. Hence, filtering bead types can be considered as an important step of the preprocessing procedure for Illumina platform. This paper proposes a filtering method for Illumina bead arrays, which builds upon the mixed model framework. Bead types are called informative/non-informative (I/NI) based on a trade-off between within and between array variabilities. The method is illustrated on a publicly available Illumina Spike-in data set (Dunning et al., 2008) and we also show that filtering results in a more powerful analysis of differentially expressed genes. PMID- 22499695 TI - Candidate pathway based analysis for cleft lip with or without cleft palate. AB - The objective of this research was to identify potential biological pathways associated with non-syndromic cleft lip with or without cleft palate (NSCL/P), and to explore the potential biological mechanisms underlying these associated pathways on risk of NSCL/P. This project was based on the dataset of a previously published genome-wide association (GWA) study on NSCL/P (Beaty et al. 2010). Case parent trios used here originated from an international consortium (The Gene, Environment Association Studies consortium, GENEVA) formed in 2007. A total of 5,742 individuals from 1,908 CL/P case-parents trios (1,591 complete trios and 317 incomplete trios where one parent was missing) were collected and genotyped using the Illumina Human610-Quad array. Candidate pathways were selected using a list of 356 genes that may be related to oral clefts. In total, 42 candidate pathways, which included 1,564 genes and 40,208 SNPs were tested. Using a pathway based analysis approach proposed by Wang et al (2007), we conducted a permutation based test to assess the statistical significance of the nominal p-values of 42 candidate pathways. The analysis revealed several pathways yielding nominally significant p-values. However, controlling for the family wise error rate, none of these pathways could retain statistical significance. Nominal p-values of these pathways were concentrated at the lower tail of the distribution, with more than expected low p-values. A permutation based test for examining this type of distribution pattern yielded an overall p-value of 0.029. Thus, while this pathway-based analysis did not yield a clear significant result for any particular pathway, we conclude that one or more of the genes and pathways considered here likely do play a role in oral clefting. PMID- 22499696 TI - Adjusting for spurious gene-by-environment interaction using case-parent triads. AB - In the case-parent trio design, unrelated children affected with a disease are genotyped along with their parents. Information may also be collected on environmental factors in the children. The design permits estimation and testing of genetic effects and gene-by-environment interaction. Recently, it has been demonstrated that when genotypes are measured at a non-causal test locus, population stratification can create spurious interaction. That is, the environmental factor can appear to modify the disease risk associated with genotypes at the test locus without modifying the disease risk of genotypes at the causal locus. One design-based approach that is robust to spurious interaction requires the environmental factor to also be available on an unaffected sibling of the affected child. We explore the source of spurious interaction and suggest an alternate approach that mitigates its effects using case-parent triads. Our approach is based on adjusting the risk model using ancestry informative markers or random markers measured on the affected child and does not require data on unaffected siblings. We apply an approach to generating case-parent data, implemented in a freely-available R package soon to be released on the Comprehensive R Archive Network (CRAN). PMID- 22499697 TI - A generalized hidden Markov model for determining sequence-based predictors of nucleosome positioning. AB - Chromatin structure, in terms of positioning of nucleosomes and nucleosome-free regions in the DNA, has been found to have an immense impact on various cell functions and processes, ranging from transcriptional regulation to growth and development. In spite of numerous experimental and computational approaches being developed in the past few years to determine the intrinsic relationship between chromatin structure (nucleosome positioning) and DNA sequence features, there is yet no universally accurate approach to predict nucleosome positioning from the underlying DNA sequence alone. We here propose an alternative approach to predicting nucleosome positioning from sequence, making use of characteristic sequence differences, and inherent dependencies in overlapping sequence features. Our nucleosomal positioning prediction algorithm, based on the idea of generalized hierarchical hidden Markov models (HGHMMs), was used to predict nucleosomal state based on the DNA sequence in yeast chromosome III, and compared with two other existing methods. The HGHMM method performed favorably among the three models in terms of specificity and sensitivity, and provided estimates that were largely consistent with predictions from the method of Yuan and Liu (2008). However, all the methods still give higher than desirable misclassification rates, indicating that sequence-based features may provide only limited information towards understanding positioning of nucleosomes. The method is implemented in the open-source statistical software R, and is freely available from the authors' website. PMID- 22499698 TI - Principal components of heritability for high dimension quantitative traits and general pedigrees. AB - For many complex disorders, genetically relevant disease definition is still unclear. For this reason, researchers tend to collect large numbers of items related directly or indirectly to the disease diagnostic. Since the measured traits may not be all influenced by genetic factors, researchers are faced with the problem of choosing which traits or combinations of traits to consider in linkage analysis. To combine items, one can subject the data to a principal component analysis. However, when family date are collected, principal component analysis does not take family structure into account. In order to deal with these issues, Ott & Rabinowitz (1999) introduced the principal components of heritability (PCH), which capture the familial information across traits by calculating linear combinations of traits that maximize heritability. The calculation of the PCHs is based on the estimation of the genetic and the environmental components of variance. In the genetic context, the standard estimators of the variance components are Lange's maximum likelihood estimators, which require complex numerical calculations. The objectives of this paper are the following: i) to review some standard strategies available in the literature to estimate variance components for unbalanced data in mixed models; ii) to propose an ANOVA method for a genetic random effect model to estimate the variance components, which can be applied to general pedigrees and high dimensional family data within the PCH framework; iii) to elucidate the connection between PCH analysis and Linear Discriminant Analysis. We use computer simulations to show that the proposed method has similar asymptotic properties as Lange's method when the number of traits is small, and we study the efficiency of our method when the number of traits is large. A data analysis involving schizophrenia and bipolar quantitative traits is finally presented to illustrate the PCH methodology. PMID- 22499699 TI - Improving pedigree-based linkage analysis by estimating coancestry among families. AB - We present a method for improving the power of linkage analysis by detecting chromosome segments shared identical by descent (IBD) by individuals not known to be related. Existing Markov chain Monte Carlo methods sample descent patterns on pedigrees conditional on observed marker data. These patterns can be stored as IBD graphs, which express shared ancestry only, rather than specific family relationships. A model for IBD between unrelated individuals allows the estimation of coancestry between individuals in different pedigrees. IBD graphs on separate pedigrees can then be combined using these estimates. We report results from analyses of three sets of simulated marker data on two different pedigrees. We show that when families share a gene for a trait due to shared ancestry on the order of tens of generations, our method can detect a linkage signal when independent analyses of the families do not. PMID- 22499700 TI - GENOVA: gene overlap analysis of GWAS results. AB - In many published genome-wide association studies (GWAS), the top few strongly associated variants are often located in or near known genes. This observation raises the more general hypothesis that variants nominally associated with a phenotype are more likely to overlap genes than those not associated with a phenotype. We developed a simple approach - named GENe OVerlap Analysis (GENOVA) to formally test this hypothesis. This approach includes two steps. First, we define largely independent groups of highly correlated SNPs (or "clumps") and classify each clump as intersecting a gene or not. Second, we determine how strongly associated each clump is with the phenotype and use logistic regression to formally test the hypothesis that clumps associated with the phenotype are more likely to intersect genes. Simulations suggest that the power of GENOVA is affected by at least three factors: GWAS sample size, the gene boundaries used to define gene-intersecting clumps and the P-value threshold used to define phenotype-associated clumps. We applied GENOVA to results from three recent GWAS meta-analyses of height, body mass index (BMI) and waist-hip ratio (WHR) conducted by the GIANT consortium. SNPs associated with variation in height were 1.44-fold more likely to be in or near genes than SNPs not associated with height (P = 5 x 10-28). A weaker association was observed for BMI (1.09-fold, P = 0.008) and WHR (1.09-fold, P = 0.014). GENOVA is implemented in C++ and is freely available at https://genepi.qimr.edu.au/staff/manuelF/genova/main.html. PMID- 22499701 TI - A new approach for the joint analysis of multiple ChIP-seq libraries with application to histone modification. AB - Most approaches for analyzing ChIP-Seq data are focused on inferring exact protein binding sites from a single library. However, frequently multiple ChIP Seq libraries derived from differing cell lines or tissue types from the same individual may be available. In such a situation, a separate analysis for each tissue or cell line may be inefficient. Here, we describe a novel method to analyze such data that intelligently uses the joint information from multiple related ChIP-Seq libraries. We present our method as a two-stage procedure. First, separate single cell line analysis is performed for each cell line. Here, we use a novel mixture regression approach to infer the subset of genes that are most likely to be involved in protein binding in each cell line. In the second step, we combine the separate single cell line analyses using an Empirical Bayes algorithm that implicitly incorporates inter-cell line correlation. We demonstrate the usefulness of our method using both simulated data, as well as real H3K4me3 and H3K27me3 histone methylation libraries. PMID- 22499702 TI - Combining multiple laser scans of spotted microarrays by means of a two-way ANOVA model. AB - MOTIVATION: Assessment of gene expression on spotted microarrays is based on measurement of fluorescence intensity emitted by hybridized spots. Unfortunately, quantifying fluorescence intensity from hybridized spots does not always correctly reflect gene expression level. Low gene expression levels produce low fluorescence intensities which tend to be confounded with the local background while high gene expression levels produce high fluorescence intensities which rapidly reach the saturation level. Most algorithms that combine data acquired at different voltages of the photomultiplier tube (PMT) assume that a change in scanner setting transforms the intensity measurements by a multiplicative constant. METHODS AND RESULTS: In this paper we introduce a new model of spot foreground intensity which integrates a PMT voltage independent scanner optical bias. This new model is used to implement a "Combining Multiple Scan using a Two way ANOVA" (CMS2A) method, which is based on a maximum likelihood estimation of the scanner optical bias. After having computed scanner bias, coefficients of the two-way ANOVA model are used for correcting the saturated spots intensities obtained at high PMT voltage by using their counterpart values at lower PMT voltages. The method was compared to state-of-the-art multiple scan algorithms, using data generated from the MAQC study. CMS2A produced fold-changes that were highly correlated with qPCR fold-changes. As the scanner optical bias is accurately estimated within CMS2A, this method allows also avoiding fold-change compression biases whatever the value of this optical bias. PMID- 22499703 TI - Non-iterative, regression-based estimation of haplotype associations with censored survival outcomes. AB - The general availability of reliable and affordable genotyping technology has enabled genetic association studies to move beyond small case-control studies to large prospective studies. For prospective studies, genetic information can be integrated into the analysis via haplotypes, with focus on their association with a censored survival outcome. We develop non-iterative, regression-based methods to estimate associations between common haplotypes and a censored survival outcome in large cohort studies. Our non-iterative methods--weighted estimation and weighted haplotype combination--are both based on the Cox regression model, but differ in how the imputed haplotypes are integrated into the model. Our approaches enable haplotype imputation to be performed once as a simple data processing step, and thus avoid implementation based on sophisticated algorithms that iterate between haplotype imputation and risk estimation. We show that non iterative weighted estimation and weighted haplotype combination provide valid tests for genetic associations and reliable estimates of moderate associations between common haplotypes and a censored survival outcome, and are straightforward to implement in standard statistical software. We apply the methods to an analysis of HSPB7-CLCNKA haplotypes and risk of adverse outcomes in a prospective cohort study of outpatients with chronic heart failure. PMID- 22499704 TI - Detection of differentially expressed gene sets in a partially paired microarray data set. AB - Partially paired data sets often occur in microarray experiments (Kim et al., 2005; Liu, Liang and Jang, 2006). Discussions of testing with partially paired data are found in the literature (Lin and Stivers 1974; Ekbohm, 1976; Bhoj, 1978). Bhoj (1978) initially proposed a test statistic that uses a convex combination of paired and unpaired t statistics. Kim et al. (2005) later proposed the t3 statistic, which is a linear combination of paired and unpaired t statistics, and then used it to detect differentially expressed (DE) genes in colorectal cancer (CRC) cDNA microarray data. In this paper, we extend Kim et al.'s t3 statistic to the Hotelling's T2 type statistic Tp for detecting DE gene sets of size p. We employ Efron's empirical null principle to incorporate inter gene correlation in the estimation of the false discovery rate. Then, the proposed Tp statistic is applied to Kim et al's CRC data to detect the DE gene sets of sizes p=2 and p=3. Our results show that for small p, particularly for p=2 and marginally for p=3, the proposed Tp statistic compliments the univariate procedure by detecting additional DE genes that were undetected in the univariate test procedure. We also conduct a simulation study to demonstrate that Efron's empirical null principle is robust to the departure from the normal assumption. PMID- 22499705 TI - Sample size calculations for designing clinical proteomic profiling studies using mass spectrometry. AB - In cancer clinical proteomics, MALDI and SELDI profiling are used to search for biomarkers of potentially curable early-stage disease. A given number of samples must be analysed in order to detect clinically relevant differences between cancers and controls, with adequate statistical power. From clinical proteomic profiling studies, expression data for each peak (protein or peptide) from two or more clinically defined groups of subjects are typically available. Typically, both exposure and confounder information on each subject are also available, and usually the samples are not from randomized subjects. Moreover, the data is usually available in replicate. At the design stage, however, covariates are not typically available and are often ignored in sample size calculations. This leads to the use of insufficient numbers of samples and reduced power when there are imbalances in the numbers of subjects between different phenotypic groups. A method is proposed for accommodating information on covariates, data imbalances and design-characteristics, such as the technical replication and the observational nature of these studies, in sample size calculations. It assumes knowledge of a joint distribution for the protein expression values and the covariates. When discretized covariates are considered, the effect of the covariates enters the calculations as a function of the proportions of subjects with specific attributes. This makes it relatively straightforward (even when pilot data on subject covariates is unavailable) to specify and to adjust for the effect of the expected heterogeneities. The new method suggests certain experimental designs which lead to the use of a smaller number of samples when planning a study. Analysis of data from the proteomic profiling of colorectal cancer reveals that fewer samples are needed when a study is balanced than when it is unbalanced, and when the IMAC30 chip-type is used. The method is implemented in the clippda package and is available in R at: http://www.bioconductor.org/help/bioc-views/release/bioc/html/clippda.html. PMID- 22499706 TI - Normalization, bias correction, and peak calling for ChIP-seq. AB - Next-generation sequencing is rapidly transforming our ability to profile the transcriptional, genetic, and epigenetic states of a cell. In particular, sequencing DNA from the immunoprecipitation of protein-DNA complexes (ChIP-seq) and methylated DNA (MeDIP-seq) can reveal the locations of protein binding sites and epigenetic modifications. These approaches contain numerous biases which may significantly influence the interpretation of the resulting data. Rigorous computational methods for detecting and removing such biases are still lacking. Also, multi-sample normalization still remains an important open problem. This theoretical paper systematically characterizes the biases and properties of ChIP seq data by comparing 62 separate publicly available datasets, using rigorous statistical models and signal processing techniques. Statistical methods for separating ChIP-seq signal from background noise, as well as correcting enrichment test statistics for sequence-dependent and sonication biases, are presented. Our method effectively separates reads into signal and background components prior to normalization, improving the signal-to-noise ratio. Moreover, most peak callers currently use a generic null model which suffers from low specificity at the sensitivity level requisite for detecting subtle, but true, ChIP enrichment. The proposed method of determining a cell type-specific null model, which accounts for cell type-specific biases, is shown to be capable of achieving a lower false discovery rate at a given significance threshold than current methods. PMID- 22499707 TI - Graph selection with GGMselect. AB - Applications on inference of biological networks have raised a strong interest in the problem of graph estimation in high-dimensional Gaussian graphical models. To handle this problem, we propose a two-stage procedure which first builds a family of candidate graphs from the data, and then selects one graph among this family according to a dedicated criterion. This estimation procedure is shown to be consistent in a high-dimensional setting, and its risk is controlled by a non asymptotic oracle-like inequality. The procedure is tested on a real data set concerning gene expression data, and its performances are assessed on the basis of a large numerical study. The procedure is implemented in the R-package GGMselect available on the CRAN. PMID- 22499708 TI - Empirical Bayes interval estimates that are conditionally equal to unadjusted confidence intervals or to default prior credibility intervals. AB - Problems involving thousands of null hypotheses have been addressed by estimating the local false discovery rate (LFDR). A previous LFDR approach to reporting point and interval estimates of an effect-size parameter uses an estimate of the prior distribution of the parameter conditional on the alternative hypothesis. That estimated prior is often unreliable, and yet strongly influences the posterior intervals and point estimates, causing the posterior intervals to differ from fixed-parameter confidence intervals, even for arbitrarily small estimates of the LFDR. That influence of the estimated prior manifests the failure of the conditional posterior intervals, given the truth of the alternative hypothesis, to match the confidence intervals. Those problems are overcome by changing the posterior distribution conditional on the alternative hypothesis from a Bayesian posterior to a confidence posterior. Unlike the Bayesian posterior, the confidence posterior equates the posterior probability that the parameter lies in a fixed interval with the coverage rate of the coinciding confidence interval. The resulting confidence-Bayes hybrid posterior supplies interval and point estimates that shrink toward the null hypothesis value. The confidence intervals tend to be much shorter than their fixed parameter counterparts, as illustrated with gene expression data. Simulations nonetheless confirm that the shrunken confidence intervals cover the parameter more frequently than stated. Generally applicable sufficient conditions for correct coverage are given. In addition to having those frequentist properties, the hybrid posterior can also be motivated from an objective Bayesian perspective by requiring coherence with some default prior conditional on the alternative hypothesis. That requirement generates a new class of approximate posteriors that supplement Bayes factors modified for improper priors and that dampen the influence of proper priors on the credibility intervals. While that class of posteriors intersects the class of confidence-Bayes posteriors, neither class is a subset of the other. In short, two first principles generate both classes of posteriors: a coherence principle and a relevance principle. The coherence principle requires that all effect size estimates comply with the same probability distribution. The relevance principle means effect size estimates given the truth of an alternative hypothesis cannot depend on whether that truth was known prior to observing the data or whether it was learned from the data. PMID- 22499709 TI - Implementing team based learning in large classes: nurse educators' experiences. AB - Team-based learning (TBL) is an interactive teaching method promoted as an alternative to traditional lectures. TBL was implemented in four large second year classes in a baccalaureate nursing program but the implementation process was found to require much more effort than indicated in the literature. A predominant theme during the implementation phase was the importance of collegial support. Faculty workload increased significantly and they were challenged by occasional student confrontations and technological difficulties. The benefits for students included reduced attrition, reading workloads, and enhanced preparedness for classes, which allowed for more time to be spent in class discussing complex realistic nursing problems. Although TBL was not enthusiastically embraced by all of the students, the majority indicated that they liked and valued TBL, hence commitment to continuing to teach using the TBL method remains. PMID- 22499710 TI - Bring the popcorn: using film to teach sexual and reproductive health. AB - The use of film as a teaching modality offers an opportunity for nursing students to explore the intersections of science, theory, and personal values prior to caring for clients with sexual and reproductive health (SRH) needs. Although the use of a broad range of arts and humanities modalities in the classroom is described in the literature, the use of film in relationship to teaching SRH has not been explored. Furthermore, there is a paucity of literature regarding the didactic or clinical teaching of SRH in nursing education. This article provides a framework for incorporating film as a teaching strategy into both case-based and problem-based teaching pedagogies. Reviews and discussion questions of films are provided. PMID- 22499711 TI - Educating leaders in nursing: faculty perspectives. AB - Recent changes in health care legislation have presented an unprecedented opportunity for nurses to engage as full partners in transforming health care (Institute of Medicine, 2010). According to diverse opinion leaders from insurance, corporate, health services, government, and higher education, nurses should have more influence than they do now on health policy, planning, and management (Robert Wood Johnson Foundation, 2010). More than ever before, nursing needs leaders, and nursing faculty are in a pivotal position to educate leaders in nursing. This article describes the findings of a descriptive study that surveyed nursing faculty teaching in all degree levels to ascertain how they prepare students to be leaders in nursing. Data were analyzed using qualitative methods. Findings demonstrate that faculty engage in self-development as leaders, promote student role development as leaders, and use multiple teaching-learning strategies to educate students to be leaders in nursing. PMID- 22499712 TI - A model of nursing student retention. AB - A model of nursing student retention was studied in nontraditional, associate degree nursing students. Student retention was defined as persistence, or choosing to continue in a nursing program, and successful academic performance, or meeting the necessary academic standards to continue in a nursing program. The model shows the interaction of background variables, internal psychological processes, and external supports, and their relationships to persistence and academic performance. Participants were 458 nontraditional associate degree nursing students. There were significant differences in background variables between students who persisted and those who withdrew voluntarily or failed academically. Perceived faculty support was related to both persistence and academic performance, such that students with higher perceived faculty support were more likely to continue in a nursing program until graduation and were more likely to be successful academically. Students with higher perceived faculty support also had higher outcome expectations of earning an associate degree in nursing. PMID- 22499713 TI - Surveying the orientation learning needs of clinical nursing instructors. AB - The purpose of this study was to describe the knowledge and skills nurses need to be successful clinical instructors. A formal learning needs assessment was conducted to measure the orientation learning needs of new part-time clinical nursing faculty at one university. An existing, validated learning needs instrument was modified and administered online. The respondents (n=44; 16.6%) unanimously identified five essential learning needs for nursing clinical instructors, thus providing sound justification upon which to base an instructor orientation program. From these results, essential content for an orientation workshop to be followed by an online orientation course is outlined. Future research is needed to evaluate the outcomes of clinical instructor orientation; that is, whether participants have acquired the knowledge and skills needed to competently facilitate student learning in the clinical setting. PMID- 22499714 TI - Self-efficacy and resilience in baccalaureate nursing students. AB - The attrition of admitted students from nursing programs has been attributed to the perceived stress of nursing school. Students who possess the characteristics of self-efficacy and resilience may be persistent and therefore academically successful as demonstrated by test scores over the course of their education. In this article, the authors report on a study that explored self efficacy and resilience in relation to test scores among 136 baccalaureate nursing students in multiple courses during one, 16 week semester. No statistically significant differences were found in perceived self-efficacy or resilience total scores between early semester and late semester measurements. Significant differences were found on the Resilience Scale subscales of Perseverence and Existential Aloneness. Test scores were weakly correlated with resilience and self-efficacy scores. PMID- 22499715 TI - Nursing students' perceptions of clinical teachers' use of empowering teaching behaviours: instrument psychometrics and application. AB - The authors present findings of 2nd year nursing students' (N = 352) perceptions of their clinical teachers' use of empowering teaching behaviours (ETB) and to highlight steps undertaken to establish psychometric properties of the Empowering Teaching Behaviours Questionnaire-Student (ETBQ-S). The authors identify a) the process involved in the adoption of the ETBQ-S, b) ETBQ-S validity procedures completed prior to instrument implementation, c) results of nursing students' responses to the ETBQ-S, d) criterion validity, and e) ETBQ-S confirmatory factor analysis findings conducted after study completion. The ETBQ-S reliably measures five facets of empowering actions that clinical teachers can employ with nursing students in practice to enhance their confidence, involve them in decision-making and goal setting, make learning meaningful, and help them to become more autonomous nurses. PMID- 22499716 TI - Integrating advanced writing content into a scholarly inquiry in nursing course. AB - Since there are few data examining methods to help students learn to write in a scholarly manner, the purposes of this project were to (1) evaluate students' learning of writing content integrated into a Scholarly Inquiry in Nursing course by examining differences in scores on a writing assessment taken at the beginning and end of the course; and (2) examine student confidence ratings relative to writing to see if it improved during the course. After obtaining IRB approval and informed consent, the CLIPS pre and post assessment mean scores of 82 students in a Scholarly Inquiry in Nursing course were compared using the Wilcoxon signed rank test. Confidence ratings in formal and informal writing were also obtained from a subsample of 47 students. Mean scores improved in 12 out of 26 assessment categories related to punctuation, correct usage of words, and sentence construction. Student mean confidence ratings increased each month. PMID- 22499717 TI - Pharmacological study of the effect of licorice alone and in combination with diclofenac sodium on hepatotoxicity-induced experimentally in rats. AB - The protective effect of licorice and diclofenac sodium in doses of 50 mg/kg bwt. and 5 mg/kg bwt. respectively against liver toxicity induced by CCl4 (1ml/kg bwt.) in olive oil [1:1 (v/v)] every other day for 8 weeks and by hepatic ischemia/reperfusion in adult male albino rats was studied. Different antioxidant and liver function parameters were reported to find the protective effect of both licorice and diclofenac sodium against hepatotoxicity. Results showed that licorice protected against CCl4-induced hepatotoxicity as well as ischemia/reperfusion-induced liver injury. On the other hand, diclofenac sodium caused deleterious effects, especially in presence of CCl4, where a high mortality rate was observed. PMID- 22499718 TI - Effects of Panax notoginseng (Chinese ginseng) and acute exercise on postprandial glycemia in non-diabetic adults. AB - The purpose of this study is to determine whether Panax Notoginseng (PNG) taken for 3 days and one 30-min cycling exercise can reduce postprandial hyperglycemia after ingesting a 75-mg oral glucose solution (OGTT) in untrained non-diabetic men, age 20-45 years. We randomly assigned 52 men to: 1) ginseng (G) + exercise (G+Ex, n=14), 2) ginseng (G, n=13), 3) placebo (C) + exercise (C+Ex, n=12), and 4) placebo control groups (C, n=13). The G and C groups took a daily 3g dose of PNG and cornstarch-placebo supplement for 3 days, respectively. The exercise groups also performed a 30-min cycling exercise on day 3 prior to OGTT. The daily 3g-dose of PNG supplementation significantly lowered postprandial plasma glucose (PG) concentration at 30 min post-OGTT in the G group, compared with C (mean Delta+/-SE: G vs. C = 26.3+/-11 mg/dl, p<0.05) and PG area under the curve (PG AUC0-90) in the G and G+Ex groups, relative to the C (G vs. C = 96.5+/-42 and G+Ex vs. C = 85.2+/-41 mg/dl, both p<0.05). We conclude that a daily 3g-dose of PNG taken for 3 days, not one acute bout of 30-min cycling exercise at 60% VO2max, lowered postprandial glycemia at 30-min post-OGTT and PG-AUC 0-90 min in non-diabetic men, age 20-45 years. PMID- 22499719 TI - A new generation of complementary medicine users? AB - OBJECTIVES: To determine regular use of alternative remedies amongst undergraduate students. DESIGN: Questionnaire covered use of alternative remedies as well as demographic details. SETTINGS/LOCATION: Online completion of the questionnaire. SUBJECTS: Sixty-nine participants (55 female, 14 male) aged between 18 to 30 years studying undergraduate psychology at Bournemouth University, Dorset, UK. INTERVENTIONS: Structured open and closed questions; all questions were given to all of the participants. OUTCOME MEASURES: Qualitative comments were captured as well as percentage of respondents according to answers collected. RESULTS: Most respondents had used remedies for exam "anxiety" and obtained these products from relatives or friends or relatives. CONCLUSIONS: Reasons of effect provided by participants were that they provided a genuine effect; a general effect; or a placebo effect. PMID- 22499720 TI - Contractile effect of radish and betel nut extracts on rabbit gallbladder. AB - Raphanus sativus (abbreviated in this paper as Rs.Cr) and Areca catechu (Ac.Cr), commonly known as radish and betel nut respectively, are traditionally used in South Asia for different gastrointestinal, gallbladder, and hepatic diseases. There has not been any study to see how they modulate gallbladder contractility. We selected isolated rabbit gallbladder tissue preparations, mounted them in tissue baths containing Krebs-Henseleit solution at 37 degrees C, and then recorded the changes in baseline tone of the tissues upon administration of Rs.Cr and Ac.Cr. Both the extracts exhibited concentration-dependent stimulant effect on the baseline tone of gallbladder tissues, similar to carbachol, a muscarinic receptor agonist. The stimulant effect of the extract, as well as that of carbachol, was completely blocked in the presence of atropine, a muscarinic antagonist, indicating similarity in the mechanism of action of the extracts with carbachol. The result shows potential of these extracts to contract the gallbladder and to subsequently increase bile secretion, but this remains to be investigated in detail. This study justifies the traditional use of radish and betel nut in different gastrointestinal disorders. PMID- 22499721 TI - Anti-inflammatory effects of shea butter through inhibition of iNOS, COX-2, and cytokines via the Nf-kappaB pathway in LPS-activated J774 macrophage cells. AB - Shea butter is traditionally used in Africa for its anti-inflammatory and analgesic effects. In this study we explored the anti-inflammatory activities of the methanolic extract of shea butter (SBE) using lipopolysaccharide (LPS) induced murine macrophage cell line J774. It was observed that SBE significantly reduced the levels of LPS-induced nitric oxide, Tumor necrosis factor-alpha (TNF alpha), interleukins, 1beta (IL-1beta), and -12 (IL-12) in the culture supernatants in a dose dependent manner. Expression of pro-inflammatory enzymes, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were also inhibited by SBE. These anti-inflammatory effects were due to an inhibitory action of SBE on LPS-induced iNOS, COX-2, TNF-alpha, IL-1beta, and IL-12 mRNA expressions. Moreover, SBE efficiently suppressed IkappaB phosphorylation and NF kappaB nuclear translocation induced by LPS. These findings explain the molecular bases of shea butter's bioactivity against various inflammatory conditions and substantiate it as a latent source of novel therapeutic agents. PMID- 22499722 TI - H. Spinosa T. Anders ameliorates diabetic neuropathy in Wistar albino rats. AB - Diabetic neuropathic pain, an important microvascular complication in diabetes, is recognised as one of the most difficult types of pain to treat. The development of tolerance, inadequate relief, and potential toxicity of classical antinociceptives warrant the investigation of the newer agents to relieve this pain. Reactive oxygen/nitrogen species, increased oxidative stress, cytokines, and apoptosis are implicated in the pathogenesis of diabetic neuropathy. The aim of the present study was to explore the effect of methanolic extract of aerial parts of H. spinosa (HSME) on alloxan induced diabetic neuropathy in Wistar rats. Diabetic rats developed neuropathy after the third week of diabetes induction. Chronic treatment with HSME (250, 500, and 750 mg/kg body weight; p.o.) for 6 weeks starting from the 3rd week of alloxan injection showed significant increase in the pain threshold levels as compared to diabetic rats. HSME treated diabetic animals showed significant decrease in blood glucose level and increase in body weight as compared to diabetic control animals. The changes in lipid peroxidation status and antioxidant enzymes levels observed in sciatic nerve of diabetic rats were significantly restored by HSME treatment. Thus, the results suggest therapeutic potential of H. spinosa in treatment of diabetic neuropathy. PMID- 22499723 TI - Efficacy of aphrodisiac plants towards improvement in semen quality and motility in infertile males. AB - Infertility is the inability to conceive after one year of unprotected intercourse. In the present study, herbal composition prepared by using medicinal plants having aphrodisiac potentials was administered orally to the albino rats for 40 days and to the oligospermic patients for 90 days in order to prove the efficacy of herbal composition. Herbal composition was the mixture (powder form) of the medicinal plants namely, Mucuna pruriens (Linn), Chlorophytum borivillianum (Sant and Fernand), and Eulophia campestris (Wall). In the neem oil treated albino rats, there was significant reduction in almost all the parameters viz. body weight, testes and epididymes weight, sperm density and motility, serum levels of testosterone, FSH, and LH compared with control rats. Treatment with said herbal composition for 40 days results significant increased in the body weight, testis, and epididymes weight in rats. Concomitantly the sperm motility and the sperm density were significantly increased. After 90 days of treatment with this herbal composition, sperm density vis-a-vis motility was increased in oligozoospermic patients as a result of elevation in serum testosterone levels. No side effects were noticed during the entire duration of the trial. PMID- 22499724 TI - Cut-off estimation and medical decision making based on a continuous prognostic factor: the prediction of kidney graft failure. AB - The determination of a cut-off value for a continuous prognostic test is an important problem, which is statistically challenging and practically important for risk assessment. We propose in this paper a method to estimate the optimal cut-off from this type of longitudinal data with censored failure times. The principle is to combine the prognostic error rates of false positives and false negatives with a cost function, which has the advantages to be statistically convenient and to be directly associated with the decision-making. Simulations were performed and the results demonstrate the interest of our approach compared to a reference method. The method is also illustrated by predicting the long-term survival of kidney transplant recipients from the 1-year creatinine clearance. PMID- 22499725 TI - Targeted maximum likelihood estimation of natural direct effects. AB - In many causal inference problems, one is interested in the direct causal effect of an exposure on an outcome of interest that is not mediated by certain intermediate variables. Robins and Greenland (1992) and Pearl (2001) formalized the definition of two types of direct effects (natural and controlled) under the counterfactual framework. The efficient scores (under a nonparametric model) for the various natural effect parameters and their general robustness conditions, as well as an estimating equation based estimator using the efficient score, are provided in Tchetgen Tchetgen and Shpitser (2011b). In this article, we apply the targeted maximum likelihood framework of van der Laan and Rubin (2006) and van der Laan and Rose (2011) to construct a semiparametric efficient, multiply robust, substitution estimator for the natural direct effect which satisfies the efficient score equation derived in Tchetgen Tchetgen and Shpitser (2011b). We note that the robustness conditions in Tchetgen Tchetgen and Shpitser (2011b) may be weakened, thereby placing less reliance on the estimation of the mediator density. More precisely, the proposed estimator is asymptotically unbiased if either one of the following holds: i) the conditional mean outcome given exposure, mediator, and confounders, and the mediated mean outcome difference are consistently estimated; (ii) the exposure mechanism given confounders, and the conditional mean outcome are consistently estimated; or (iii) the exposure mechanism and the mediator density, or the exposure mechanism and the conditional distribution of the exposure given confounders and mediator, are consistently estimated. If all three conditions hold, then the effect estimate is asymptotically efficient. Extensions to the natural indirect effect are also discussed. PMID- 22499726 TI - Estimation of the mean frequency function for recurrent events when ascertainment of events is delayed. AB - In many large clinical trials there are delays between the time at which events occur and the time at which they are reported. Estimators of the mean frequency function for recurrent events that are currently used are inconsistent in these circumstances. We propose two new estimators to be used when events are reported with delay. One method is a basic inverse probability of censoring weighting approach, while the other explicitly estimates the distribution of the reporting delays. The asymptotic properties of these estimators are discussed and variance estimators are given. We examine the results of simulations comparing the new estimators to each other and to existing estimators that do not properly account for the delays. We also calculate some of these quantities using data from TNT, a clinical trial in which there were delays and events of interest were recurrent. PMID- 22499727 TI - Designs combining instrumental variables with case-control: estimating principal strata causal effects. AB - The instrumental variables framework is commonly used for the estimation of causal effects from cohort samples. However, the combination of instrumental variables with more efficient designs such as case-control sampling requires new methodological consideration. For example, as the use of Mendelian randomization studies is increasing and the cost of genotyping and gene expression data can be high, the analysis of data gathered from more cost-effective sampling designs is of prime interest. We show that the standard instrumental variables analysis does not appropriately estimate the causal effects of interest when the instrumental variables design is combined with the case-control design. We also propose a method that can estimate the causal effects in such combined designs. We illustrate the method with a study in oncology. PMID- 22499728 TI - Evaluating a new marker for risk prediction using the test tradeoff: an update. AB - Most of the methodological literature on evaluating an additional marker for risk prediction involves purely statistical measures of classification performance. A disadvantage of a purely statistical measure is the difficulty in deciding the improvement in the measure that would make inclusion of the additional marker worthwhile. In contrast, a medical decision making approach can weigh the cost or harm of ascertaining an additional marker against the benefit of a higher true positive rate for a given false positive rate that may be associated with risk prediction involving the additional marker. An appealing form of the medical decision making approach involves the risk threshold, which is the risk at which the expected utility of treatment and no treatment is the same. In this framework, a readily interpretable evaluation of the net benefit of an additional marker is the test tradeoff corresponding to the risk threshold. The test tradeoff is the minimum number of tests for a new marker that need to be traded for a true positive to yield an increase in the net benefit of risk prediction with the additional marker. For a sensitivity analysis the test tradeoff is computed over multiple risk thresholds. This article updates the theory and estimation of the test tradeoff. An example is provided. PMID- 22499729 TI - Special issue on causal inference in health research. AB - We provide a brief editorial introduction to a special issue of The International Journal of Biostatistics dedicated to some of the papers presented at a workshop held at the Centre de recherches mathematiques in Montreal, Quebec, in May 2011. PMID- 22499730 TI - Double-robust estimators: slightly more Bayesian than meets the eye? AB - Consider the simple setting of point exposure, outcome and confounding variables, all of which are discrete. As is well known, parametric modeling of outcome given exposure and confounders and also exposure given confounders can yield a double robust estimator. This has the property of being consistent as long as at least one of the two specified models is correct. Such an estimator can also be cast as arising from a compromise between the parametric outcome model and a nonparametric or saturated outcome model. This brings to mind an alternate compromise based on Bayesian model averaging, and prompts comparisons between the double-robust method and the Bayesian method. PMID- 22499731 TI - Meta-analysis of observational studies with unmeasured confounders. AB - Meta-analysis of observational studies is an exciting new area of innovation in statistical science. Unlike randomized controlled trials, which are the gold standard for proving causation, observational studies are prone to biases including confounding. In this article, we describe a novel Bayesian procedure to control for a confounder that is missing across the sequence of studies in a meta-analysis. We motivate the discussion with the example of a meta-analysis of cohort, case-control and cross-sectional studies examining the relationship between oral contraceptives and endometriosis. An important unmeasured confounder is dysmennoreah, which is an indication for oral contraceptive use. To adjust for unmeasured confounding, we combine random effects models with probabilistic sensitivity analysis techniques. Information about the unmeasured confounder is incorporated into the analysis via prior distributions, and we use MCMC to sample from posterior. PMID- 22499732 TI - Causal inference for vaccine effects on infectiousness. AB - If a vaccine does not protect individuals completely against infection, it could still reduce infectiousness of infected vaccinated individuals to others. Typically, vaccine efficacy for infectiousness is estimated based on contrasts between the transmission risk to susceptible individuals from infected vaccinated individuals compared with that from infected unvaccinated individuals. Such estimates are problematic, however, because they are subject to selection bias and do not have a causal interpretation. Here, we develop causal estimands for vaccine efficacy for infectiousness for four different scenarios of populations of transmission units of size two. These causal estimands incorporate both principal stratification, based on the joint potential infection outcomes under vaccine and control, and interference between individuals within transmission units. In the most general scenario, both individuals can be exposed to infection outside the transmission unit and both can be assigned either vaccine or control. The three other scenarios are special cases of the general scenario where only one individual is exposed outside the transmission unit or can be assigned vaccine. The causal estimands for vaccine efficacy for infectiousness are well defined only within certain principal strata and, in general, are identifiable only with strong unverifiable assumptions. Nonetheless, the observed data do provide some information, and we derive large sample bounds on the causal vaccine efficacy for infectiousness estimands. An example of the type of data observed in a study to estimate vaccine efficacy for infectiousness is analyzed in the causal inference framework we developed. PMID- 22499733 TI - Bounds on the effect of vaccine induced immune response on outcome. AB - A major goal of vaccine development is the identification of immune responses that are responsible for vaccine efficacy. In theory, modest vaccines could be successfully improved by increasing such immune responses. And for a vaccine with a great benefit in one population, inducing such immune response in a different population could help one conclude the vaccine would have great benefit there. Such identification is tricky because the immune response to vaccination can only be measured in the vaccine group and thus immune responses might only be identifying individuals with a constitutional ability to remain uninfected, rather than being causal. Define the vaccine induced immune response as X(1). The value X(1) is a potential outcome; it is measured directly in vaccinees but unobserved in the placebo group. Our goal is to regress outcome on X(1) separately in the vaccine and placebo groups and to see if the vaccine effect varies with X(1). Put another way, our goal is to see if there is a vaccine by X(1) interaction. Regression of outcome on X(1) is easy to do in the vaccine group, but difficult in the placebo group as X(1) is not observed. In this paper we derive bounds on the regression curve in the placebo group. For a continuous endpoint these bounds can be unhelpful, or can help modestly temper our enthusiasm for a role of X(1) on the vaccine effect. For binary outcomes with 100% placebo infection the bound is very tight but unhelpful as 100% infection precludes identification of any covariate with a differential effect on placebo infection. We apply these methods to experiments of anthrax vaccine in rabbits with survival to challenge as the outcome and demonstrate how to extrapolate the model to humans. PMID- 22499734 TI - Bias analysis to guide new data collection. AB - Bias analysis serves multiple objectives in epidemiologic data analysis. The objectives most often emphasized are quantification of uncertainty due to systematic errors and reduction in overconfidence by specifying hypotheses that compete with the causal hypothesis. A third objective is the utility of bias analysis to identify strategies for new data collection that will be productive in evaluating the validity of an association. The authors illustrate the value of this objective using two examples. The first example examines the value of comprehensive CYP2D6 genotyping in a study of tamoxifen resistance. Tamoxifen is metabolized primarily by CYP2D6 to more active forms. More than thirty polymorphisms in the CYP2D6 gene reduce its function. We genotyped the most prevalent CYP2D6 polymorphism and found a null association between genotype and breast cancer recurrence in a Danish population. One possibility is that incomplete genotyping of the multiple functional polymorphisms introduced non differential misclassification and biased the association toward the null. We used bias analysis to evaluate the plausibility of this explanation and to guide a decision about devoting study resources toward more comprehensive genotyping of other polymorphisms in the CYP2D6 gene. The second example examines the association between vitamin K antagonist (VKA) therapy and the incidence of 24 site-specific cancers, using heart valve replacement as an instrumental variable. Earlier studies suggested a protective association between VKA anticoagulants and the incidence of cancer. We observed a null-centered distribution of associations, which may be due to non-differential misclassification of VKA therapy by the instrument. We used bias analysis to evaluate whether this misclassification was likely to explain the null-centered distribution of associations and to guide decisions about conducting a more expensive validation study. In the first example, the bias analysis showed that new data collection would be required to resolve the uncertainty, whereas the second example showed that new data collection was unlikely to be a productive use of scarce study resources. PMID- 22499735 TI - Dynamic transcriptional regulation of autocrine/paracrine igfbp1, 2, 3, 4, 5, and 6 in the skeletal muscle of the fine flounder during different nutritional statuses. AB - The IGF-binding proteins (IGFBPs) play a dual role in the regulation of the activity and bioavailability of IGFs in different tissues. Diverse evidence has shown that IGFBPs can inhibit and/or potentiate IGF actions. In this study, igfbp1, 2, 3, 4, 5, and 6 were isolated in the fine flounder, a flat fish species that shows slow growth and inherent Gh resistance in muscle. Subsequently, the expression of all igfbps was assessed in the skeletal muscle of flounder that underwent different nutritional statuses. igfbp1 was not expressed in muscle during any of the nutritional conditions, whereas igfbp3 and igfbp5 were the lowest and the highest igfbps expressed respectively. A dynamic expression pattern was found in all the igfbps expressed in skeletal muscle, which depended on the nutritional status and sampling period. During the fasting period, igfbp2, 4, and 5 were downregulated, whereas igfbp3 was upregulated during part of the fasting period. The restoration of food modulated the expression of the igfbps dynamically, showing significant changes during both the long- and short-term refeeding. igfbp3 and igfbp6 were downregulated during short-term refeeding, whereas igfbp5 was upregulated, and igfbp2 and igfbp4 remained stable. During long-term refeeding, the expression of igfbp2, 4, 5, and 6 increased, while igfbp3 remained unchanged. In conclusion, this study shows for the first time the isolation of all igfbps in a single fish species, in addition to describing a dynamic nutritional and time-dependent response in the expression of igfbps in the skeletal muscle of a nonmammalian species. PMID- 22499736 TI - Executive summary: The Virginia Commonwealth University pharmacy practice transformation conference. AB - Pharmacy practice transformation was the focus of an invitational conference held in June 2011 to address the current status of the practice of pharmacy in Virginia and elucidate the consensus on future directions from pharmacists across the commonwealth. The series of presentations provided visionary perspectives on the role that pharmacists can have in the collaborative management of patients with chronic disease states, the optimal pharmacy practice model for direct patient care delivery in acute care settings, and payment for pharmacists' cognitive services, such as medication therapy management (MTM). The discussion groups were structured to have conference participants first identify future goals for pharmacy practice and then consider strategies to achieve these goals. The conference concluded with a consensus development dialogue that revealed the priorities as well as the strategies that needed to be employed to move the profession toward its goals. PMID- 22499737 TI - Pharmacy practice in Virginia in 2011. AB - BACKGROUND: Opportunities for pharmacy practice reform exist at state and national levels. The Virginia Commonwealth University (VCU) School of Pharmacy created a working group to assess these opportunities with a mission to advance pharmacy practice in Virginia. OBJECTIVES: To assess the perceptions of chronic and acute care pharmacy practice and confidence in providing patient care and medication therapy management (MTM) activities and characterize current work activities of pharmacists in Virginia. METHODS: A cross-sectional, online survey was used. VCU School of Pharmacy pharmacist preceptors, students, and faculty members were eligible. The questionnaire contained items that assessed perceptions of chronic and acute care pharmacy practice and confidence in patient care and MTM activities. Demographic and practice site characteristics were also collected. RESULTS: A total of 974 preceptors, 515 students, and 78 faculty members were invited to participate, and 335 preceptors, 155 students, and 41 faculty members had usable responses, yielding response rates of 34%, 30%, and 53%, respectively. Preceptors, students, and faculty members favorably viewed direct patient care roles in the chronic and acute care settings. Pharmacists were very confident or confident in performing many patient care and MTM activities. They were least confident in considering genetic characteristics when adjusting medications and creating business plans for new services. Many pharmacists in chronic and acute care settings provided some type of patient care service, but few were regularly providing services. Inadequate time, staffing, and reimbursement, and lack of perceived value from patients and providers were most frequently cited as barriers to service provision. CONCLUSIONS: VCU preceptors, students, and faculty members overwhelmingly believe that pharmacists should provide direct patient care and MTM activities. To transform pharmacy practice, it will be important to define the pharmacist's role, responsibilities, and expected outcomes and to consider time, staffing, and compensation as well as to engage patients and providers. PMID- 22499738 TI - Health care reform 2011: opportunities for pharmacists. AB - The health reforms of the last several years at the federal and state levels have created many opportunities for pharmacists to become actively involved in the direct patient care provision. Indeed, the statutory language in some sections of the Affordable Care Act of 2010 creates expectations of pharmacists that will require practice transformation if we are to arise to accept the responsibilities associated with these expectations. These new opportunities open the door for pharmacists to benefit community-dwelling patients with chronic medical conditions, those with acute/emergent care needs, those experiencing a transition between chronic and acute care and vice versa, as well as others in long-term care settings. Although the profession has demonstrated value in many practice environments, our contributions to improved medication-related patient outcomes through medication therapy management (MTM) and the other pharmaceutical care services remain to be rigorously quantified. Incorporation of pharmacists either by their physical presence within the practice or through the design of effective community linkages, such as electronic health records, must be developed to meet the needs of rural and urban patients seen in a variety of practice settings. New business models that build upon cognitive and direct patient care services in addition to the provision of drug products will surely need to emerge for the profession to become a viable and vital component of the US health care system. PMID- 22499739 TI - Ontario pharmacists practicing in family health teams and the patient-centered medical home. AB - The patient-centered medical home (PCMH) approach continues to gather momentum in the United States and Canada as a broad approach to reform the delivery of the complete primary care system. The family health team (FHT) model implemented in Ontario, Canada, best mirrors the PCMH approach of the United States. The integration of pharmacists as key members of the health care team providing on site, in-office coordinated care to FHT patients was included from the start of planning the FHT model and represents a substantial opportunity for pharmacists to realize their professional vision. Several research projects in Canada and elsewhere have contributed to providing evidence to support the integration of pharmacists into primary care practice sites. Two major research programs, the Seniors Medication Assessment Research Trial (SMART) cluster randomized controlled trial and the Integrating Family Medicine and Pharmacy to Advance Primary Care Therapeutics (IMPACT) multipronged demonstration project made substantial contributions to evidence-informed policy decisions supporting the integration of pharmacists into FHTs. These projects can provide useful information to support the integration of pharmacists into the PCMH and to encourage further research to better measure the effect of the pharmacist from the holistic patient-centered perspective. PMID- 22499740 TI - The future of health-system pharmacy: opportunities and challenges in practice model change. AB - Key factors outside of health-system pharmacy that will shape this sector of the profession in the coming years are (1) the national economy, (2) national politics, (3) the debt of the federal government, (4) global megatrends (including terrorism and economic globalization), (5) health care reform, and (6) trends in the development and use of medicines. These factors will translate into payment cutbacks to hospitals, expanded mandates to improve the quality of health care, increased focus on patient-centered care, more team-based care, and a higher degree of integration across the range of health care settings and providers. In this environment, pharmacists in hospitals and other health systems will have rich opportunities to help improve patient care and institutional sustainability by continuing to move from order-fulfillment and product preparation functions toward team leadership of drug therapy management. The American Society of Health-System Pharmacists Pharmacy Practice Model Initiative (PPMI) was created to encourage hospital and health-system practice leaders to examine how they deploy their resources (ie, pharmacist time, technician time, and technology) to ensure that the efforts of the pharmacy department are aligned with the most urgent needs of patients and institutions. Key recommendations of the PPMI and evidence about gaps in the provision of drug therapy management services are presented. It is important for every pharmacist and pharmacy technician in health-system practice to understand the imperatives for changing the profession's practice model and to actively pursue appropriate changes in that model. PMID- 22499741 TI - Pharmaceutical care, MTM, & payment: the past, present, & future. AB - Central to any discussion of payment reform is the need for a rational scientific medication use system to ensure that drug-related morbidity and mortality are minimized. The care provision process is based on a comprehensive assessment of all of a patient's drug-related needs and it behooves pharmacists to conduct a comprehensive assessment as do all other health professions. This comprehensive assessment is the foundation of medication therapy management (MTM) services provided within the practice of pharmaceutical care. Care can be delivered in the community by clinically oriented pharmacists, although building a practice is hard work much different from the business of dispensing medications. The number of pharmacists needed to provide comprehensive MTM services for every American is projected to range from 30,000 to 100,000 based on data/experiences from Minnesota, Ontario, and elsewhere. These individuals may benefit from some type of provider recognition so that society can differentiate between pharmacists who provide comprehensive MTM services and those in drug distribution roles. Approaching the legislature and policymakers with cost savings data, partnering with the business community, and focusing on dual eligible patients and those with unmet mental health needs are important strategies to make this practice transformation a reality. PMID- 22499742 TI - The Virginia pharmacy practice transformation conference: outcomes and next steps. AB - Thought leaders in Virginia came together to achieve consensus on the pharmacy practice innovations required to advance the medication-related health outcomes of patients in the Commonwealth. The participants identified key elements and strategies needed for practice transformation and these became the foundation for practice change. The primary key elements included legislation and regulation modifications, payment reform, and business model development. The Virginia Pharmacy Congress, which represents key pharmacy stakeholders in the Commonwealth, became the home for the transformation movement and the development and implementation of a unified action plan for achieving the envisioned practice transformation. PMID- 22499744 TI - Perioperative medicine: the future of anaesthesia? PMID- 22499745 TI - Innovation, NICE, and CardioQ. PMID- 22499746 TI - Perioperative management of hereditary arrhythmogenic syndromes. AB - Patients with inherited cardiac channel disorders are at high risk of perioperative lethal arrhythmias. Preoperative control of symptoms and a multidisciplinary approach are required for a well-planned management. Good haemodynamic monitoring, adequate anaesthesia and analgesia, perioperative maintenance of normocarbia, normothermia, and normovolaemia are important. In congenital long QT syndrome, torsades de pointes should be prevented with magnesium sulphate infusion and avoidance of drugs such as droperidol, succinylcholine, ketamine, and ondansetron. Propofol and epidural anaesthesia represent safe choices, while caution is needed with volatile agents. In Brugada syndrome, beta-blockers, alpha-agonists, and cholinergic drugs should be avoided, while isoproterenol reverses the ECG changes. Propofol, thiopental, and volatiles have been used uneventfully. In congenital sick sinus syndrome, severe bradycardia resistant to atropine may require isoproterenol or epinephrine. Anaesthetics with vagolytic properties are preferable, while propofol and vecuronium should be given with caution due to risk of inducing bradyarrhythmias. Neuraxial anaesthesia should produce the least autonomic imbalance. Arrhythmogenic right ventricular dysplasia/cardiomyopathy induces ventricular tachyarrhythmias, which should be treated with beta-blockers. Generally, beta adrenergic stimulation and catecholamine release should be avoided. Halothane and pancuronium are contraindicated, while large doses of local anaesthetics and epinephrine should be avoided in neuraxial blocks. In catecholaminergic polymorphic ventricular tachycardia, beta-blocker treatment should be continued perioperatively. Catecholamine release and beta-agonists, such as isoproterenol, should be avoided. Propofol and remifentanil are probably safe, while halothane and pancuronium are contraindicated. Regional anaesthesia, without epinephrine, is relatively safe. In suspicious cardiac deaths, postmortem examination and familial screening are recommended. PMID- 22499747 TI - Controversies in the determination of death. PMID- 22499748 TI - Controversies in the determination of death. PMID- 22499750 TI - Goal-directed fluid therapy in patients undergoing colorectal surgery. PMID- 22499752 TI - Extending epidural analgesia for emergency Caesarean section. PMID- 22499754 TI - Management of patients with implantable cardioverter defibrillator needing radiation therapy for cancer. PMID- 22499756 TI - Titration of electroconvulsive therapy: the use of rocuronium and sugammadex with adjunctive laryngeal mask. PMID- 22499757 TI - Extended-release epidural morphine (DepoDurTM) as analgesia for rib fractures. PMID- 22499758 TI - Lack of humidification may harm the patient during continuous positive airway pressure. PMID- 22499759 TI - Intraspinal and intracranial subarachnoid haemorrhage with severe cerebral vasospasm after spinal anaesthesia for assisted delivery. PMID- 22499763 TI - Plasma beta amyloid level and depression in older adults. AB - BACKGROUND: Older adults with depression have an increased risk of developing dementia. Low plasma beta-amyloid 42 (Abeta42) and Abeta42/Abeta40 have emerged as promising biomarkers of dementia. The association between depression and plasma Abeta is unclear. METHODS: In this longitudinal study of 988 community dwelling elders from the Health Aging and Body Composition study, depression was assessed with the Center for Epidemiologic Studies-Depression Scale 10-item version. We determined the association between Abeta42 and Abeta42/Abeta40 tertile and depression at baseline and over 9 years. We also stratified the models to determine if apolipoprotein E e4 allele status modified the associations. RESULTS: Mean baseline age was 74.0 +/- 3.0 years, 51 (5.2%) participants had depression, 545 (55.2%) were women, 531 (53.7%) were black, and 286 (30.7%) had one or more apolipoprotein E e4 allele. At baseline, there was no association between Abeta42/Abeta40 or Abeta42 and depression. Over 9 years, 220 (23.5%) participants developed depression. In adjusted Cox proportional hazards models, among those with one or more e4 allele, low Abeta42/Abeta40 was associated with an increased risk of developing depression over time (low 10.8% vs high 3.2%, hazard ratio = 2.38, 95% confidence interval: 1.15-4.92). Among those with no e4 allele, there was no association between Abeta42/Abeta40 and risk of depression over time (13.3% vs 17.5%, hazard ratio = 0.80, 95% confidence interval: 0.52-1.23; p value for interaction = .003). CONCLUSIONS: The association between low plasma Abeta42/Abeta40 and increased risk of incident depression among those with one or more apolipoprotein E e4 allele implies a synergistic relationship similar to that found with dementia. Future work should investigate the interrelationships among plasma Abeta42/Abeta40, depression, and dementia. PMID- 22499764 TI - Genetics, life span, health span, and the aging process in Caenorhabditis elegans. AB - As a tool for measuring the aging process, life span has been invaluable in dissecting the genes that modulate longevity. Studies over the past few decades have identified several hundred genes that can modify life span in model organisms such as yeast, worms, and flies. Yet, despite this vast amount of research, we still do not fully understand how the genes that affect life span influence how an organism ages. How does modulation of the genes that affect life span contribute to the aging process? Does life-span extension result in extension of healthy aging? Here, we will focus primarily on the insulin/IGF-1 signaling pathway in Caenorhabditis elegans because members of this pathway have been shown to be associated with extended life span across phylogeny, from worms to humans. I discuss how this connects to the aging process, age-associated disease, and the potential to increase healthy aging in addition to lengthening life span. PMID- 22499765 TI - Testosterone improves the regeneration of old and young mouse skeletal muscle. AB - Aging is associated with loss of muscle mass and strength, reduced satellite cell number, and lower regenerative potential. Testosterone increases muscle mass, strength, and satellite cell number in humans; however, the effects of testosterone on the regenerative potential of skeletal muscle are unclear. Here, we investigated the effect of testosterone on the skeletal muscle regeneration of young (2-month-old) and aged (24-month-old) male mice. We show that testosterone increases the number of proliferating satellite cells in regenerating "tibialis anterior" muscle of young and aged castrated mice 2 and 4 days postinjury. Testosterone supplementation increases the number and the cross-sectional area of regenerating fibers in both classes of age 4 days postinjury. Testosterone increases satellite cell activation and proliferation and the regeneration of both young and aged mouse muscle. These data suggest prospective application of androgens to improve the regenerating potential of the aged human skeletal muscle. PMID- 22499767 TI - Continuous and minimally invasive cardiac output monitoring by long time interval analysis of a radial arterial pressure waveform: assessment using a large, public intensive care unit patient database. AB - BACKGROUND: A potential practical approach for continuous and minimally invasive cardiac output (CO) monitoring in intensive care unit (ICU) patients is to mathematically analyse an arterial pressure (AP) waveform using an existing radial artery line ('pulse contour analysis'). We recently proposed a technique to estimate the relative CO change by unique long time interval analysis (LTIA) of an AP waveform. We aimed to test this technique in an ICU patient population and compare its accuracy relative to other techniques. METHODS: We studied a public, electronic ICU patient database. We extracted 1482 pairs of radial AP waveforms and thermodilution CO measurements (via single bolus injections) from 169 patients. We applied the LTIA and previous pulse contour analysis techniques to the AP waveforms. We assessed the calibrated CO estimates against the thermodilution measurements. RESULTS: The overall root-mean-squared-error of the LTIA technique was 18.8%. This total level of accuracy was not better than the previous techniques. However, the average magnitude of the thermodilution changes was only 12.3% (9.9 sd). When the magnitude of the thermodilution change exceeded 30%, 50%, and 70%, the median squared-error differences between the LTIA technique and the most accurate previous technique were -45 (-322:69 quartiles) (P=0.005), -128 (-704:23) (P=0.006), and -862 (-2871:306)%(2) (P=0.055), respectively. The LTIA technique was therefore superior in detecting clinically important CO changes. CONCLUSIONS: The LTIA technique attained an overall accuracy that may be considered clinically acceptable after taking into account the known thermodilution error and became progressively more accurate than previous techniques with increasing CO changes. PMID- 22499766 TI - The search for longevity and healthy aging genes: insights from epidemiological studies and samples of long-lived individuals. AB - Genetic factors clearly contribute to exceptional longevity and healthy aging in humans, yet the identification of the underlying genes remains a challenge. Longevity is a complex phenotype with modest heritability. Age-related phenotypes with higher heritability may have greater success in gene discovery. Candidate gene and genome-wide association studies (GWAS) for longevity have had only limited success to date. The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium conducted a meta-analysis of GWAS data for longevity, defined as survival to age 90 years or older, that identified several interesting associations but none achieved genome-wide significance. A recent GWAS of longevity conducted in the Leiden Longevity Study identified the ApoE E4 isoform as deleterious to longevity that was confirmed in an independent GWAS of long lived individuals of German descent. Notably, no other genetic loci for longevity have been identified in these GWAS. To examine the conserved genetic mechanisms between the mouse and humans for life span, we mapped the top Cohorts for Heart and Aging Research in Genomic Epidemiology GWAS associations for longevity to the mouse chromosomal map and noted that eight of the ten top human associations were located within a previously reported mouse life-span quantitative trait loci. This work suggests that the mouse and human may share mechanisms leading to aging and that the mouse model may help speed the understanding of how genes identified in humans affect the biology of aging. We expect these ongoing collaborations and the translational work with basic scientists to accelerate the identification of genes that delay aging and promote a healthy life span. PMID- 22499768 TI - Quantitative phosphoproteomic analysis reveals a role for serine and threonine kinases in the cytoskeletal reorganization in early T cell receptor activation in human primary T cells. AB - Protein phosphorylation-dephosphorylation events play a primary role in regulation of almost all aspects of cell function including signal transduction, cell cycle, or apoptosis. Thus far, T cell phosphoproteomics have focused on analysis of phosphotyrosine residues, and little is known about the role of serine/threonine phosphorylation in early activation of the T cell receptor (TCR). Therefore, we performed a quantitative mass spectrometry-based analysis of the global phosphoproteome of human primary T cells in response to 5 min of TCR activation with anti-CD3 antibody. Combining immunoprecipitation with an antiphosphotyrosine antibody, titanium dioxide phosphopeptide enrichment, isobaric tag for the relative and absolute quantitation methodology, and strong cation exchange separation, we were able to identify 2814 phosphopeptides. These unique sites were employed to investigate the site-specific phosphorylation dynamics. Five hundred and seventeen phosphorylation sites showed TCR-responsive changes. We found that upon 5 min of stimulation of the TCR, specific serine and threonine kinase motifs are overrepresented in the set of responsive phosphorylation sites. These phosphorylation events targeted proteins with many different activities and are present in different subcellular locations. Many of these proteins are involved in intracellular signaling cascades related mainly to cytoskeletal reorganization and regulation of small GTPase-mediated signal transduction, probably involved in the formation of the immune synapse. PMID- 22499769 TI - Identification of targets of c-Src tyrosine kinase by chemical complementation and phosphoproteomics. AB - The cellular proto-oncogene c-Src is a nonreceptor tyrosine kinase involved in cell growth and cytoskeletal regulation. Despite being dysregulated in a variety of human cancers, its precise functions are not fully understood. Identification of the substrates of c-Src remains a major challenge, because there is no simple way to directly stimulate its activity. Here we combine the chemical rescue of mutant c-Src and global quantitative phosphoproteomics to obtain the first high resolution snapshot of the range of tyrosine phosphorylation events that occur in the cell immediately after specific c-Src stimulation. After enrichment by anti phosphotyrosine antibodies, we identified 29 potential novel c-Src substrate proteins. Tyrosine phosphopeptide mapping allowed the identification of 382 nonredundant tyrosine phosphopeptides on 213 phosphoproteins. Stable isotope labeling of amino acids in cell culture-based quantitation allowed the detection of 97 nonredundant tyrosine phosphopeptides whose level of phosphorylation is increased by c-Src. A large number of previously uncharacterized c-Src putative protein targets and phosphorylation sites are presented here, a majority of which play key roles in signaling and cytoskeletal networks, particularly in cell adhesion. Integrin signaling and focal adhesion kinase signaling pathway are two of the most altered pathways upon c-Src activation through chemical rescue. In this context, our study revealed the temporal connection between c-Src activation and the GTPase Rap1, known to stimulate integrin-dependent adhesion. Chemical rescue of c-Src provided a tool to dissect the spatiotemporal mechanism of activation of the Rap1 guanine exchange factor, C3G, one of the identified potential c-Src substrates that plays a role in focal adhesion signaling. In addition to unveiling the role of c-Src in the cell and, specifically, in the Crk C3G-Rap1 pathway, these results exemplify a strategy for obtaining a comprehensive understanding of the functions of nonreceptor tyrosine kinases with high specificity and kinetic resolution. PMID- 22499771 TI - Medical research data-sharing: the 'public good' and vulnerable groups. AB - One of the moral tests of governments is how they treat those in the twilight of life (the elderly). As such, it is important not only to take care of the needs of the elderly, but also to place their reality in the forefront of deliberations and actions. Now that we are in the so-called century of biology, we must ensure that the newly transformed and increasingly relied on biosciences not only respond to the needs of the elderly but also reflect the reality of the elderly. While many arguments can be made in support of increased data-sharing in biomedical research (and indeed within and across healthcare systems more generally), there are some persuasive age-based arguments that might serve to encourage science regulators, through both funding structures and the law, to fundamentally reshape the research environment so as to enhance its potential to achieve public goods such as improved health and more effective healthcare systems. In this paper, after noting the new research model arising from population genomics, with its intense data needs, we advance three age-based arguments, in favour of increased and improved data-sharing, and we conclude with some brief observations about how increased data-sharing might be achieved. PMID- 22499770 TI - Tumor proteomics by multivariate analysis on individual pathway data for characterization of vulvar cancer phenotypes. AB - Vulvar squamous cell carcinoma (VSCC) is the fourth most common gynecological cancer. Based on etiology VSCC is divided into two subtypes; one related to high risk human papilloma virus (HPV) and one HPV negative. The two subtypes are proposed to develop via separate intracellular signaling pathways. We investigated a suggested link between HPV infection and relapse risk in VSCC through in-depth protein profiling of 14 VSCC tumor specimens. The tumor proteomes were analyzed by liquid-chromatography tandem mass spectrometry. Relative protein quantification was performed by 8-plex isobaric tags for relative and absolute quantification. Labeled peptides were fractionated by high resolution isoelectric focusing prior to liquid-chromatography tandem mass spectrometry to reduce sample complexity. In total, 1579 proteins were regarded as accurately quantified and analyzed further. For classification of clinical groups, data analysis was performed by comparing protein level differences between tumors defined by HPV and/or relapse status. Further, we performed a biological analysis on individual tumor proteomes by matching data to known biological pathways. We here present a novel analysis approach that combines pathway alteration data on individual tumor level with multivariate statistics for HPV and relapse status comparisons. Four proteins (signal transducer and activator of transcription-1, myxovirus resistance protein 1, proteasome subunit alpha type-5 and legumain) identified as main classifiers of relapse status were validated by immunohistochemistry (IHC). Two of the proteins are interferon regulated and on mRNA level known to be repressed by HPV. By both liquid chromatography tandem mass spectrometry and immunohistochemistry data we could single out a subgroup of HPV negative/relapse-associated tumors. The pathway level data analysis confirmed three of the proteins, and further identified the ubiquitin-proteasome pathway as altered in the high risk subgroup. We show that pathway fingerprinting with resolution on individual tumor level adds biological information that strengthens a generalized protein analysis. PMID- 22499772 TI - Calcium-mediated cell death during myocardial reperfusion. AB - Reperfusion may induce additional cell death in patients with acute myocardial infarction receiving primary angioplasty or thrombolysis. Altered intracellular Ca(2+) handling was initially considered an essential mechanism of reperfusion induced cardiomyocyte death. However, more recent studies have demonstrated the importance of Ca(2+)-independent mechanisms that converge on mitochondrial permeability transition (MPT) and are shared by cardiomyocytes and other cell types. This article analyses the importance of Ca(2+)-dependent cell death in light of these new observations. Altered Ca(2+) handling includes increased cytosolic Ca(2+) levels, leading to activation of calpain-mediated proteolysis and sarcoplasmic reticulum-driven oscillations; this can induce hypercontracture, but also MPT due to the privileged Ca(2+) transfer between sarcoplasmic reticulum and mitochondria through cytosolic Ca(2+) microdomains. In the opposite direction, permeability transition can worsen altered Ca(2+) handling and favour hypercontracture. Ca(2+) appears to play an important role in cell death during the initial minutes of reperfusion, particularly after brief periods of ischaemia. Developing effective and safe treatments to prevent Ca(2+)-mediated cardiomyocyte death in patients with transient ischaemia, by targeting Ca(2+) influx, intracellular Ca(2+) handling, or Ca(2+)-induced cell death effectors, is an unmet challenge with important therapeutic implications and large potential clinical impact. PMID- 22499774 TI - Nitric oxide-donating statins: a new concept to boost the lipid-independent effects. PMID- 22499773 TI - Normal and abnormal development of the intrapericardial arterial trunks in humans and mice. AB - AIMS: The definitive cardiac outflow channels have three components: the intrapericardial arterial trunks; the arterial roots with valves; and the ventricular outflow tracts (OFTs). We studied the normal and abnormal development of the most distal of these, the arterial trunks, comparing findings in mice and humans. METHODS AND RESULTS: Using lineage tracing and three-dimensional visualization by episcopic reconstruction and scanning electron microscopy, we studied embryonic day 9.5-12.5 mouse hearts, clarifying the development of the OFTs distal to the primordia of the arterial valves. We characterize a transient aortopulmonary (AP) foramen, located between the leading edge of a protrusion from the dorsal wall of the aortic sac and the distal margins of the two outflow cushions. The foramen is closed by fusion of the protrusion, with its cap of neural crest cells (NCCs), with the NCC-filled cushions; the resulting structure then functioning transiently as an AP septum. Only subsequent to this closure is it possible to recognize, more proximally, the previously described AP septal complex. The adjacent walls of the intrapericardial trunks are derived from the protrusion and distal parts of the outflow cushions, whereas the lateral walls are formed from intrapericardial extensions of the pharyngeal mesenchyme derived from the second heart field. CONCLUSIONS: We provide, for the first time, objective evidence of the mechanisms of closure of an AP foramen that exists distally between the lumens of the developing intrapericardial arterial trunks. Our findings provide insights into the formation of AP windows and the variants of common arterial trunk. PMID- 22499775 TI - Pickled food and risk of gastric cancer--a systematic review and meta-analysis of English and Chinese literature. AB - BACKGROUND: Ecological and experimental studies have suggested an increased risk of gastric cancer in relation to consumption of pickled vegetables in East Asia. METHODS: We conducted a meta-analysis of epidemiologic observational studies to evaluate the existing evidence. Searching PubMed, Vip Chinese Periodical, and China National Knowledge Infrastructure databases, we found a total of 60 studies, 50 case-control, and 10 prospective. We compared gastric cancer risk in pickled vegetable/food users versus nonusers (11 studies) or versus those in the lowest reported category of use (49 studies). Pooled results were computed with random-effects models. RESULTS: Among case-control studies, 30 showed significant increased risk and one showed significant decreased risk. Among prospective studies, two showed a significant increased risk but none showed a significant decreased risk. The OR (95% CI) was 1.52 (1.37-1.68) for the overall association, 1.56 (1.39-1.75) for case-control, and 1.32 (1.10-1.59) for cohort studies. The OR (95% CI) was 1.89 (1.29-2.77) in Korean, 1.86 (1.61-2.15) in Chinese, and 1.16 (1.04-1.29) in Japanese studies, and 1.14 (0.96-1.35) in studies from other countries. There was high heterogeneity in overall and subgroup analyses. There was little evidence for publication bias. CONCLUSION: Our results suggest a potential 50% higher risk of gastric cancer associated with intake of pickled vegetables/foods and perhaps stronger associations in Korea and China. IMPACT: The results of this study may offer ways to reduce the risk of gastric cancer in highly populated areas with high incidence of gastric cancer. PMID- 22499776 TI - Role of ISAba1 and ISAba125 in governing the expression of blaADC in clinically relevant Acinetobacter baumannii strains resistant to cephalosporins. AB - Acinetobacter baumannii is a multi-resistant opportunistic nosocomial pathogen responsible for several outbreaks worldwide. It can cause several infections at various sites of the body. One of the main infections caused by this bacterium is ventilator-associated pneumonia in patients in intensive care units. Treating these infections is becoming difficult because of the high resistance to antimicrobial agents. This study compared the expression of the chromosomally encoded bla(ADC) gene in isolates having ISAba1, ISAba125 and no insertion upstream of the bla(ADC) gene in A. baumannii clinical isolates. It showed that the expression of bla(ADC) was six times greater when ISAba125 was present upstream of the gene in comparison with the constitutively expressed bla(ADC) gene with no insertion present upstream. The study indicated that ISAba125 has better promoters than ISAba1 and this is responsible for the overexpression of the bla(ADC) gene as they share considerable homology to the well-established Escherichia coli promoters. The -10 box of ISAba125 formed a fusion promoter with the -35 box of the bla(ADC) gene causing the bla(ADC) gene to be significantly overexpressed. The ability to upregulate the expression of bla(ADC) with the assistance of different insertion elements such as ISAba1 and ISAba125 has become an important factor in A. baumannii resistance to cephalosporins. PMID- 22499777 TI - Association between pneumococcal load and disease severity in adults with pneumonia. AB - Determination of pneumococcal load by quantitative PCR may be useful for diagnostic and prognostic purposes. We hypothesized that higher pneumococcal load would be associated with increased pneumonia severity. Therefore, we tested serum, sputum and urine specimens from 304 adults with community-acquired pneumonia by using a quantitative lytA pneumococcal real-time PCR assay. The association between pneumococcal load and disease severity was assessed using several markers of severity: CURBage score, PSI risk class, intensive care unit admission, in-hospital death and admission duration. For PCR-positive specimens, the bacterial loads were higher in sputum specimens [median 8.55*10(5) copies ml( 1); interquartile range (IQR) 4.70*10(4)-4.69*10(6) copies ml(-1)] than either serum (median 180 copies ml(-1); IQR 165-8970 copies ml(-1)) or urine (median 623 copies ml(-1); IQR 510-650 copies ml(-1)). Detection of pneumococcal DNA in serum was associated with severe disease, and there was evidence of a dose-response effect with increased bacterial load being associated with increased severity. The same observations were not observed for other specimen types. This study adds to an increasing body of evidence suggesting that determination of pneumococcal load has a clinical utility. Further work is needed to determine whether measuring pneumococcal load in respiratory specimens from adults will differentiate colonization from coincidental carriage. PMID- 22499778 TI - Nocardia harenae, an uncommon causative organism of mycetoma: report on two patients. AB - Mycetoma is the most frequently diagnosed deep mycosis in Mexico and is caused, in 86% of cases, by Nocardia brasiliensis. Worldwide, Nocardia harenae has not been previously reported as a causative agent of human mycetoma. Herein we report, to our knowledge, the first two human cases of mycetoma due to N. harenae in a clinical setting. The strains were identified by phenotypic and molecular techniques. Both cases were characterized by long-lasting mycetoma that had previously been failed to be cured and had shown resistance to therapy. However, in our hospital, a multidrug therapy proved to be effective in these cases. PMID- 22499779 TI - Is Helicobacter pylori resident or transient in the human oral cavity? AB - Helicobacter pylori colonizes the stomachs of at least half of the world's human population. The role of the oral cavity in this colonization is not clear and there are, to date, no comprehensive data that clearly demonstrate the isolation of this bacterium from the oral cavity. The aim of this study was to evaluate the prevalence of H. pylori in the oral cavity of 15 patients who tested positive for H. pylori. A comprehensive dental examination of all patients was conducted. Samples were taken from supragingival and subgingival plaque, saliva, periapical exudates and tongue swabs. All samples were taken before the application of antibiotics. A total of 163 oral samples were investigated by PCR using two different H. pylori-specific primer pairs. A PCR inhibition control using a modified plasmid was always included for the most specific primer pair. In addition, a culture technique was used to confirm PCR results. Despite a PCR detection limit of 10(2) bacteria ml(-1), out of 14 patients, H. pylori could not be detected in any of the samples taken. In one patient, H. pylori-positive PCR signals were obtained in two samples using only one primer pair. H. pylori could not be cultivated from these two PCR-positive samples; therefore, no correlation to oral colonization status could be established. This study challenges the misleading preconception that H. pylori resides in the human oral cavity and suggests that this bacterium should be considered transient and independent of the oral status. To date, positive PCR results for H. pylori in the oral cavity have been overestimated and not critically interpreted in literature. PMID- 22499780 TI - White matter development in adolescence: diffusion tensor imaging and meta analytic results. AB - BACKGROUND: In light of the evidence for brain white matter (WM) abnormalities in schizophrenia, study of normal WM maturation in adolescence may provide critical insights relevant to the neurodevelopment of the disorder. Voxel-wise diffusion tensor imaging (DTI) studies have consistently demonstrated increases in fractional anisotropy (FA), a putative measure of WM integrity, from childhood into adolescence. However, the WM tracts that show FA increases have been variable across studies. Here, we aimed to assess which WM tracts show the most pronounced changes across adolescence. METHODS: DTI was performed in 78 healthy subjects aged 8-21 years, and voxel-wise analysis conducted using tract-based spatial statistics (TBSS). In addition, we performed the first meta-analysis of TBSS studies on WM development in adolescence. RESULTS: In our sample, we observed bilateral increases in FA with age, which were most significant in the left superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and anterior thalamic radiation. These findings were confirmed by the meta-analysis, and FA increase in the bilateral SLF was the most consistent finding across studies. Moreover, in our sample, FA of the bilateral SLF showed a positive association with verbal working memory performance and partially mediated increases in verbal fluency as a function of increasing age. CONCLUSIONS: These data highlight increasing connectivity in the SLF during adolescence. In light of evidence for compromised SLF integrity in high-risk and first-episode patients, these data suggest that abnormal maturation of the SLF during adolescence may be a key target in the neurodevelopment of schizophrenia. PMID- 22499781 TI - Differences in cognitive and emotional processes between persecutory and grandiose delusions. AB - BACKGROUND: Cognitive models propose that cognitive and emotional processes, in the context of anomalies of experience, lead to and maintain delusions. No large scale studies have investigated whether persecutory and grandiose delusions reflect differing contributions of reasoning and affective processes. This is complicated by their frequent cooccurrence in schizophrenia. We hypothesized that persecutory and grandiose subtypes would differ significantly in their associations with psychological processes. METHODS: Participants were the 301 patients from the Psychological Prevention of Relapse in Psychosis Trial (ISRCTN83557988). Persecutory delusions were present in 192 participants, and grandiose delusions were present in 97, while 58 were rated as having delusions both of persecution and grandiosity. Measures of emotional and reasoning processes, at baseline only, were employed. RESULTS: A bivariate response model was used. Negative self-evaluations and depression and anxiety predicted a significantly increased chance of persecutory delusions whereas grandiose delusions were predicted by less negative self-evaluations and lower anxiety and depression, along with higher positive self and positive other evaluations. Reasoning biases were common in the whole group and in categorically defined subgroups with only persecutory delusions and only grandiose delusions; however, jumping to conclusions, and belief flexibility were significantly different in the 2 groups, the grandiose group having a higher likelihood of showing a reasoning bias than the persecutory group. CONCLUSION: The significant differences in the processes associated with these 2 delusion subtypes have implications for etiology and for the development of targeted treatment strategies. PMID- 22499782 TI - Brain vs behavior: an effect size comparison of neuroimaging and cognitive studies of genetic risk for schizophrenia. AB - Genetic variants associated with increased risk for schizophrenia (SZ) are hypothesized to be more penetrant at the level of brain structure and function than at the level of behavior. However, to date the relative sensitivity of imaging vs cognitive measures of these variants has not been quantified. We considered effect sizes associated with cognitive and imaging studies of 9 robust SZ risk genes (DAOA, DISC1, DTNBP1, NRG1, RGS4, NRGN, CACNA1C, TCF4, and ZNF804A) published between January 2005-November 2011. Summary data was used to calculate estimates of effect size for each significant finding. The mean effect size for each study was categorized as small, medium, or large and the relative frequency of each category was compared between modalities and across genes. Random effects meta-analysis was used to consider the impact of experimental methodology on effect size. Imaging studies reported mostly medium or large effects, whereas cognitive investigations commonly reported small effects. Meta-analysis confirmed that imaging studies were associated with larger effects. Effect size estimates were negatively correlated with sample size but did not differ as a function of gene nor imaging modality. These observations support the notion that SZ risk variants show larger effects, and hence greater penetrance, when characterized using indices of brain structure and function than when indexed by cognitive measures. However, it remains to be established whether this holds true for individual risk variants, imaging modalities, or cognitive functions, and how such effects may be mediated by a relationship with sample size and other aspects of experimental variability. PMID- 22499783 TI - The characteristic features of auditory verbal hallucinations in clinical and nonclinical groups: state-of-the-art overview and future directions. AB - Despite a growing interest in auditory verbal hallucinations (AVHs) in different clinical and nonclinical groups, the phenomenological characteristics of such experiences have not yet been reviewed and contrasted, limiting our understanding of these phenomena on multiple empirical, theoretical, and clinical levels. We look at some of the most prominent descriptive features of AVHs in schizophrenia (SZ). These are then examined in clinical conditions including substance abuse, Parkinson's disease, epilepsy, dementia, late-onset SZ, mood disorders, borderline personality disorder, hearing impairment, and dissociative disorders. The phenomenological changes linked to AVHs in prepsychotic stages are also outlined, together with a review of AVHs in healthy persons. A discussion of key issues and future research directions concludes the review. PMID- 22499784 TI - Probing the stability of nonglycosylated wild-type erythropoietin protein via reiterative alanine ligations. AB - Nonglycosylated erythropoietin bearing acetamidomethyl protecting groups at the cysteine residues has been synthesized via chemical methods. Alanine ligation was used to assemble four peptide fragments, themselves prepared by solid phase peptide synthesis. This work outlines a route for the synthesis of homogeneous glycosylated erythropoietin. PMID- 22499785 TI - On De Giorgi's conjecture and beyond. AB - We consider the problem of existence of entire solutions to the Allen-Cahn equation Deltau + u - u(3) = 0 in , usually regarded as a prototype for the modeling of phase transition phenomena. In particular, exploiting the link between the Allen-Cahn equation and minimal surface theory in dimensions N >= 9, we find a solution, u, with ?(x(N))u > 0, such that its level sets are close to a nonplanar, minimal, entire graph. This counterexample provides a negative answer to a celebrated question by Ennio de Giorgi [De Giorgi E (1979) Proceedings of the International Meeting on Recent Methods in Nonlinear Analysis (Rome, 1978), 131-188, Pitagora, Bologna]. Our results suggest parallels of De Giorgi's conjecture for finite Morse index solutions in two and three dimensions and suggest a possible program of classification of all entire solutions. PMID- 22499786 TI - Extending the timescale and range of ecosystem services through paleoenvironmental analyses, exemplified in the lower Yangtze basin. AB - In China, and elsewhere, long-term economic development and poverty alleviation need to be balanced against the likelihood of ecological failure. Here, we show how paleoenvironmental records can provide important multidecadal perspectives on ecosystem services (ES). More than 50 different paleoenvironmental proxy records can be mapped to a wide range of ES categories and subcategories. Lake sediments are particularly suitable for reconstructing records of regulating services, such as soil stability, sediment regulation, and water purification, which are often less well monitored. We demonstrate the approach using proxy records from two sets of lake sediment sequences in the lower Yangtze basin covering the period 1800-2006, combined with recent socioeconomic and climate records. We aggregate the proxy records into a regional regulating services index to show that rapid economic growth and population increases since the 1950s are strongly coupled to environmental degradation. Agricultural intensification from the 1980s onward has been the main driver for reducing rural poverty but has led to an accelerated loss of regulating services. In the case of water purification, there is strong evidence that a threshold has been transgressed within the last two decades. The current steep trajectory of the regulating services index implies that regional land management practices across a large agricultural tract of eastern China are critically unsustainable. PMID- 22499788 TI - Misuse of hierarchical linear models overstates the significance of a reported association between OXTR and prosociality. PMID- 22499787 TI - Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions. AB - Dengue is a mosquito-borne flavivirus that is spreading at an unprecedented rate and has developed into a major health and economic burden in over 50 countries. Even though infected individuals develop potent and long-lasting serotype specific neutralizing antibodies (Abs), the epitopes engaged by human neutralizing Abs have not been identified. Here, we demonstrate that the dengue virus (DENV)-specific serum Ab response in humans consists of a large fraction of cross-reactive, poorly neutralizing Abs and a small fraction of serotype specific, potently inhibitory Abs. Although many mouse-generated, strongly neutralizing monoclonal antibodies (mAbs) recognize epitopes that are present on recombinant DENV envelope (E) proteins, unexpectedly, the majority of neutralizing Abs in human immune sera bound to intact virions but not to the ectodomain of purified soluble E proteins. These conclusions with polyclonal Abs were confirmed with newly generated human mAbs derived from DENV-immune individuals. Two of three strongly neutralizing human mAbs bound to E protein epitopes that were preserved on the virion but not on recombinant E (rE) protein. We propose that humans produce Abs that neutralize DENV infection by binding a complex, quaternary structure epitope that is expressed only when E proteins are assembled on a virus particle. Mapping studies indicate that this epitope has a footprint that spans adjacent E protein dimers and includes residues at the hinge between domains I and II of E protein. These results have significant implications for the DENV Ab and vaccine field. PMID- 22499789 TI - Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes. AB - Type 2 diabetes (T2D) is a complex, polygenic disease affecting nearly 300 million people worldwide. T2D is primarily characterized by insulin resistance, and growing evidence has indicated the causative link between adipose tissue inflammation and the development of insulin resistance. Genetic association studies have successfully revealed a number of important genes consistently associated with T2D to date. However, these robust T2D-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. Here, we report an alternative approach, gene expression-based genome wide association study (eGWAS): searching for genes repeatedly implicated in functional microarray experiments (often publicly available). We performed an eGWAS across 130 independent experiments (totally 1,175 T2D case-control microarrays) to find additional genes implicated in the molecular pathogenesis of T2D and identified the immune-cell receptor CD44 as our top candidate (P = 8.5 * 10(-20)). We found CD44 deficiency in a diabetic mouse model ameliorates insulin resistance and adipose tissue inflammation and also found that anti-CD44 antibody treatment decreases blood glucose levels and adipose tissue macrophage accumulation in a high-fat, diet-fed mouse model. Further, in humans, we observed CD44 is expressed in inflammatory cells in obese adipose tissue and discovered serum CD44 levels were positively correlated with insulin resistance and glycemic control. CD44 likely plays a causative role in the development of adipose tissue inflammation and insulin resistance in rodents and humans. Genes repeatedly implicated in publicly available experimental data may have unique functionally important roles in T2D and other complex diseases. PMID- 22499790 TI - Bacteriophage T4 polynucleotide kinase triggers degradation of mRNAs. AB - The bacteriophage T4-encoded RegB endoribonuclease is produced during the early stage of phage development and targets mostly (but not exclusively) the Shine Dalgarno sequences of early genes. In this work, we show that the degradation of RegB-cleaved mRNAs depends on a functional T4 polynucleotide kinase/phosphatase (PNK). The 5'-OH produced by RegB cleavage is phosphorylated by the kinase activity of PNK. This modification allows host RNases G and E, with activity that is strongly stimulated by 5'-monophosphate termini, to attack mRNAs from the 5' end, causing their destabilization. The PNK-dependent pathway of degradation becomes effective 5 min postinfection, consistent with our finding that several minutes are required for PNK to accumulate after infection. Our work emphasizes the importance of the nature of the 5' terminus for mRNA stability and depicts a pathway of mRNA degradation with 5'- to 3'-polarity in cells devoid of 5'-3' exonucleases. It also ascribes a role for T4 PNK during normal phage development. PMID- 22499791 TI - Perfecting precision of predicting prion propensity. PMID- 22499792 TI - Roy J. Britten, 1919-2012: our early years at Caltech. PMID- 22499793 TI - A calorie is not necessarily a calorie: technical choice, nutrient bioaccessibility, and interspecies differences of edible plants. PMID- 22499794 TI - Cross-protective immunity against heterologous Streptococcus pneumoniae. PMID- 22499796 TI - Deletion of Ten-m3 induces the formation of eye dominance domains in mouse visual cortex. AB - The visual system is characterized by precise retinotopic mapping of each eye, together with exquisitely matched binocular projections. In many species, the inputs that represent the eyes are segregated into ocular dominance columns in primary visual cortex (V1), whereas in rodents, this does not occur. Ten-m3, a member of the Ten-m/Odz/Teneurin family, regulates axonal guidance in the retinogeniculate pathway. Significantly, ipsilateral projections are expanded in the dorsal lateral geniculate nucleus and are not aligned with contralateral projections in Ten-m3 knockout (KO) mice. Here, we demonstrate the impact of altered retinogeniculate mapping on the organization and function of V1. Transneuronal tracing and c-fos immunohistochemistry demonstrate that the subcortical expansion of ipsilateral input is conveyed to V1 in Ten-m3 KOs: Ipsilateral inputs are widely distributed across V1 and are interdigitated with contralateral inputs into eye dominance domains. Segregation is confirmed by optical imaging of intrinsic signals. Single-unit recording shows ipsilateral, and contralateral inputs are mismatched at the level of single V1 neurons, and binocular stimulation leads to functional suppression of these cells. These findings indicate that the medial expansion of the binocular zone together with an interocular mismatch is sufficient to induce novel structural features, such as eye dominance domains in rodent visual cortex. PMID- 22499797 TI - Finding and feeling the musical beat: striatal dissociations between detection and prediction of regularity. AB - Perception of temporal patterns is critical for speech, movement, and music. In the auditory domain, perception of a regular pulse, or beat, within a sequence of temporal intervals is associated with basal ganglia activity. Two alternative accounts of this striatal activity are possible: "searching" for temporal regularity in early stimulus processing stages or "prediction' of the timing of future tones after the beat is found (relying on continuation of an internally generated beat). To resolve between these accounts, we used functional magnetic resonance imaging (fMRI) to investigate different stages of beat perception. Participants heard a series of beat and nonbeat (irregular) monotone sequences. For each sequence, the preceding sequence provided a temporal beat context for the following sequence. Beat sequences were preceded by nonbeat sequences, requiring the beat to be found anew ("beat finding" condition), or by beat sequences with the same beat rate ("beat continuation"), or a different rate ("beat adjustment"). Detection of regularity is highest during beat finding, whereas generation and prediction are highest during beat continuation. We found the greatest striatal activity for beat continuation, less for beat adjustment, and the least for beat finding. Thus, the basal ganglia's response profile suggests a role in beat prediction, not in beat finding. PMID- 22499799 TI - Connectional heterogeneity of the ventral part of the macaque area 46. AB - We found that the ventral part of the prefrontal area 46 (46v) is connectionally heterogeneous. Specifically, the rostral part (46vr) displayed an almost exclusive and extensive intraprefrontal connectivity and extraprefrontal connections limited to area 24 and inferotemporal areas. In contrast, the caudal part (46vc) mostly displayed intraprefrontal connectivity with ventrolateral areas and robust connectivity with frontal and parietal sensorimotor areas. Based on a topographic organization of these connections, 3 fields were identified in area 46vc. A caudal field (caudal 46vc) was preferentially connected to oculomotor prearcuate (8/FEF, 45B, and 8r) and inferior parietal areas. The other 2, located more rostrally, in the bank of the principal sulcus (rostral 46vc/bank) and on the ventrolateral convexity cortex (rostral 46vc/convexity), respectively, were connected with hand/mouth-related (F5a, 44) ventral premotor areas, area SII, and the insula. However, rostral 46vc/convexity was also connected to the hand-related area AIP, whereas rostral 46vc/bank to hand/arm related areas PFG and PG, to PGop, and to areas 11 and 24. The present data suggest a differential role in executive functions of areas 46vr and 46vc and a differential involvement of different parts of area 46vc in higher level integration for oculomotor behavior and goal-directed arm, hand, and mouth actions. PMID- 22499798 TI - Dynamic neurovascular coupling and uncoupling during ictal onset, propagation, and termination revealed by simultaneous in vivo optical imaging of neural activity and local blood volume. AB - Traditional models of ictal propagation involve the concept of an initiation site and a progressive outward march of activation. The process of neurovascular coupling, whereby the brain supplies oxygenated blood to metabolically active neurons presumably results in a similar outward cascade of hyperemia. However, ictal neurovascular coupling has never been assessed in vivo using simultaneous measurements of membrane potential change and hyperemia with wide spatial sampling. In an acute rat ictal model, using simultaneous intrinsic optical signal (IOS) and voltage-sensitive dye (VSD) imaging of cerebral blood volume and membrane potential changes, we demonstrate that seizures consist of multiple dynamic multidirectional waves of membrane potential change with variable onset sites that spread through a widespread network. Local blood volume evolves on a much slower spatiotemporal scale. At seizure onset, the VSD waves extend beyond the IOS signal. During evolution, spatial correlation with hemodynamic signal only exists briefly at the maximal spread of the VSD signal. At termination, the IOS signal extends spatially and temporally beyond the VSD waves. Hence, vascular reactivity evolves in a separate but parallel fashion to membrane potential changes resulting in a mechanism of neurovascular coupling and uncoupling, which is as dynamic as the seizure itself. PMID- 22499801 TI - Surgical treatment for pulmonary aspergilloma: a 35-year experience in the Chinese population. AB - The surgical treatment of pulmonary aspergilloma is challenging and controversial. This study was designed to evaluate the clinical profile, indications and surgical outcomes of pulmonary aspergilloma operated on in our institute. A total of 256 patients with pulmonary aspergilloma underwent surgical treatment from 1975 to 2010. The patients were divided into two groups: Group A (simple aspergilloma, n = 96) and Group B (complex aspergilloma, n = 160). The principal underlying lung disease was tuberculosis (71.1%). The surgical procedures consisted of 212 lobectomies in both groups; eight cavernoplasties, 10 bilobectomies, 16 pneumonectomies and six thoracoplasties in Group B; four segmentectomies and six wedge resections in Group A. Postoperative complications occurred in 40 patients (15.6%). The major complications were residual pleural space (3.9%), prolonged air leak (3.1%), bronchopleural fistula (1.6%), excessive bleeding (1.6%), respiratory insufficiency (1.9%) and empyema (1.2%). No intraoperative deaths occurred. The overall mortality within 30 days post operation was 1.2%, occurring only in Group B. There was no statistically significant difference in the postoperative morbidity between Groups A and B (P = 0.27). With the good selection of patients, meticulous surgical techniques and good postoperative management, aggressive surgical treatment with anti-fungal therapy for pulmonary aspergilloma is safe and effective, and can achieve favourable outcomes. PMID- 22499800 TI - Chronic in vivo imaging shows no evidence of dendritic plasticity or functional remapping in the contralesional cortex after stroke. AB - Most stroke survivors exhibit a partial recovery from their deficits. This presumably occurs because of remapping of lost capabilities to functionally related brain areas. Functional brain imaging studies suggest that remapping in the contralateral uninjured cortex might represent a transient stage of compensatory plasticity. Some postmortem studies have also shown that cortical lesions, including stroke, can trigger dendritic plasticity in the contralateral hemisphere, but the data are controversial. We used longitudinal in vivo two photon microscopy in the contralateral homotopic cortex to record changes in dendritic spines of layer 5 pyramidal neurons in green fluorescent protein mice. We could not detect de novo growth of dendrites or changes in the density or turnover of spines for up to 4 weeks after stroke. We also used intrinsic optical signal imaging to investigate whether the forepaw (FP) sensory representation is remapped to the spared homotopic cortex after stroke. Stimulation of the contralateral FP reliably produced strong intrinsic signals in the spared hemisphere, but we could never detect a signal with ipsilateral FP stimulation after stroke. This lack of contralateral plasticity at the level of apical dendrites of layer 5 pyramidal neurons and FP sensory maps suggests that the contralesional cortex may not contribute to functional recovery after stroke and that, at least in mice, the peri-infarct cortex plays the dominant role in postischemic plasticity. PMID- 22499802 TI - Age and sex differences in perioperative myocardial infarction after cardiac surgery. AB - We investigate age and sex differences in acute myocardial infarction (AMI) after cardiac surgery in a prospective study of 2038 consecutive patients undergoing cardiac surgery with cardiopulmonary bypass. An age of >= 70 years implied changes in the type of AMI from the ST-segment elevation myocardial infarction (STEMI) to non-ST-segment elevation myocardial infarction (non-STEMI). Men were more likely than women to suffer from AMI after cardiac surgery (11.8% vs. 5.6%), as a result of the higher frequency of STEMI (6% of men vs. 1.8% of women; P < 0.001) in both age groups. A troponin-I (Tn-I) peak was significantly higher in patients >= 70 years old. In-hospital mortality was higher in patients >= 70 (7.3%) than in those < 70 years old (3.3%), because of the increased mortality observed in men with non-AMI (2.1% vs. 6.3%) and women with STEMI (0% vs. 28.6%) and non-STEMI (0% vs. 36.8%, P < 0.05). Old age was associated with a higher frequency of non-STEMI, Tn-I peak, mortality and length of stay in the intensive care unit (ICU). Regardless of age, men more often suffer from AMI (particularly STEMI). AMI in women had a notable impact on excess mortality and ICU stay observed in patients >= 70 years of age. Clinical and Tn-I peak differences are expected in relation to age and gender after AMI post-cardiac surgery. PMID- 22499803 TI - Wide sternal retraction may impede internal mammary artery graft flow and reduce myocardial function during off-pump coronary artery bypass grafting: presentation of two cases. AB - The internal mammary artery (IMA) is routinely used for grafting of the left anterior descending coronary artery (LAD), providing good flow to the anterior left ventricle (LV) wall. Impeded IMA-to-LAD flow may result in myocardial ischaemia and haemodynamic deterioration. From a study population, we describe two incidents where myocardial ischaemia was observed during off-pump coronary artery bypass surgery (CABG), with a confirmed reduction in the IMA-to-LAD flow in one patient. In patient no. 1, normal IMA flow was assessed by transit-time flow measurement after a complete IMA-to-LAD anastomosis. The anterior LV wall thickening was monitored continuously by epicardial ultrasonic transducers. Normal wall thickening was confirmed after IMA grafting. During a wide sternal opening for circumflex grafting the anterior wall motion displayed an ischaemic pattern, with reduced systolic and increased post-systolic wall thickening. IMA flow was reduced simultaneously. When easing the sternal opening, IMA flow normalized, as did the motion pattern in the anterior LV wall. In patient no. 2, similar changes in wall thickening occurred during a wide sternal opening after IMA-to-LAD grafting. When easing the retractor, the wall thickening normalized. It is important for the surgeon to be aware of this possible cause of myocardial ischaemia, with a risk of subsequent haemodynamic deterioration. This may not only be of great importance during off-pump CABG, but can also be significant for successful weaning from the cardiopulmonary bypass machine. PMID- 22499804 TI - Tropheryma whipplei endocarditis without gastrointestinal involvement. AB - Whipple's disease, caused by the bacterium Tropheryma whipplei, is a rare chronic multi-system illness commonly affecting the gastrointestinal (GI) tract and presenting with a triad of diarrhoea, weight loss and malabsorption. While 20-55% of patients with a diagnosis of Whipple's disease have clinically evident cardiac manifestations, the initial presentation with isolated valvular disease, without any GI symptoms, is rare. Whereas cardiac involvement usually involves a single valve, cases of double-valve involvement are extremely rare. We report the case of a patient with T. whipplei native aortic and mitral valvular endocarditis, without GI involvement, who presented with the new-onset cardiac failure and ventricular arrhythmias, which required urgent double-valve replacement. This case report is accompanied by a review of the relevant literature. PMID- 22499805 TI - Signatures of Majorana fermions in hybrid superconductor-semiconductor nanowire devices. AB - Majorana fermions are particles identical to their own antiparticles. They have been theoretically predicted to exist in topological superconductors. Here, we report electrical measurements on indium antimonide nanowires contacted with one normal (gold) and one superconducting (niobium titanium nitride) electrode. Gate voltages vary electron density and define a tunnel barrier between normal and superconducting contacts. In the presence of magnetic fields on the order of 100 millitesla, we observe bound, midgap states at zero bias voltage. These bound states remain fixed to zero bias, even when magnetic fields and gate voltages are changed over considerable ranges. Our observations support the hypothesis of Majorana fermions in nanowires coupled to superconductors. PMID- 22499806 TI - Growing microtubules push the oocyte nucleus to polarize the Drosophila dorsal ventral axis. AB - The Drosophila dorsal-ventral (DV) axis is polarized when the oocyte nucleus migrates from the posterior to the anterior margin of the oocyte. Prior work suggested that dynein pulls the nucleus to the anterior side along a polarized microtubule cytoskeleton, but this mechanism has not been tested. By imaging live oocytes, we find that the nucleus migrates with a posterior indentation that correlates with its direction of movement. Furthermore, both nuclear movement and the indentation depend on microtubule polymerization from centrosomes behind the nucleus. Thus, the nucleus is not pulled to the anterior but is pushed by the force exerted by growing microtubules. Nuclear migration and DV axis formation therefore depend on centrosome positioning early in oogenesis and are independent of anterior-posterior axis formation. PMID- 22499808 TI - Ocean science. A dive to Challenger Deep. PMID- 22499807 TI - Mechanical control of morphogenesis by Fat/Dachsous/Four-jointed planar cell polarity pathway. AB - During animal development, several planar cell polarity (PCP) pathways control tissue shape by coordinating collective cell behavior. Here, we characterize by means of multiscale imaging epithelium morphogenesis in the Drosophila dorsal thorax and show how the Fat/Dachsous/Four-jointed PCP pathway controls morphogenesis. We found that the proto-cadherin Dachsous is polarized within a domain of its tissue-wide expression gradient. Furthermore, Dachsous polarizes the myosin Dachs, which in turn promotes anisotropy of junction tension. By combining physical modeling with quantitative image analyses, we determined that this tension anisotropy defines the pattern of local tissue contraction that contributes to shaping the epithelium mainly via oriented cell rearrangements. Our results establish how tissue planar polarization coordinates the local changes of cell mechanical properties to control tissue morphogenesis. PMID- 22499809 TI - Differential diffusivity of Nodal and Lefty underlies a reaction-diffusion patterning system. AB - Biological systems involving short-range activators and long-range inhibitors can generate complex patterns. Reaction-diffusion models postulate that differences in signaling range are caused by differential diffusivity of inhibitor and activator. Other models suggest that differential clearance underlies different signaling ranges. To test these models, we measured the biophysical properties of the Nodal/Lefty activator/inhibitor system during zebrafish embryogenesis. Analysis of Nodal and Lefty gradients revealed that Nodals have a shorter range than Lefty proteins. Pulse-labeling analysis indicated that Nodals and Leftys have similar clearance kinetics, whereas fluorescence recovery assays revealed that Leftys have a higher effective diffusion coefficient than Nodals. These results indicate that differential diffusivity is the major determinant of the differences in Nodal/Lefty range and provide biophysical support for reaction diffusion models of activator/inhibitor-mediated patterning. PMID- 22499810 TI - Epigenomic enhancer profiling defines a signature of colon cancer. AB - Cancer is characterized by gene expression aberrations. Studies have largely focused on coding sequences and promoters, even though distal regulatory elements play a central role in controlling transcription patterns. We used the histone mark H3K4me1 to analyze gain and loss of enhancer activity genome-wide in primary colon cancer lines relative to normal colon crypts. We identified thousands of variant enhancer loci (VELs) that comprise a signature that is robustly predictive of the in vivo colon cancer transcriptome. Furthermore, VELs are enriched in haplotype blocks containing colon cancer genetic risk variants, implicating these genomic regions in colon cancer pathogenesis. We propose that reproducible changes in the epigenome at enhancer elements drive a specific transcriptional program to promote colon carcinogenesis. PMID- 22499811 TI - Canada's turbulent medical tourism industry. PMID- 22499812 TI - Not just more global health--smarter global health. PMID- 22499813 TI - Implications of a newer Framingham model. PMID- 22499814 TI - Identifying women who might benefit from higher doses of folic acid in pregnancy. AB - QUESTION: One of my epileptic patients who takes carbamazepine is planning to become pregnant. She told me that Motherisk advised her to take 5 mg of folic acid daily until the end of the first trimester. Are there other women who need more than the regular dose of folic acid included in prenatal vitamins? ANSWER: Women who are at high risk of having babies with neural tube defects and who would benefit from higher doses of folic acid include those with certain folate enzyme genotypes, previous pregnancies with neural tube defects, diabetes, malabsorption disorders, or obesity, or those who take antifolate medications or smoke. Such women should take 5 mg/d of folic acid for the 2 months before conception and during the first trimester. PMID- 22499816 TI - Dermacase. Can you identify this condition? Secondary syphilis. PMID- 22499815 TI - Cranberry juice for urinary tract infection in children. AB - QUESTION: Several children in my clinic are recovering from urinary tract infections (UTI). A mother of one of the children asked me if I recommended cranberry juice for children to prevent future episodes of UTI. She was given cranberry juice after she suffered from a UTI several months ago. ANSWER: Cranberry juice has been shown to be effective in preventing adhesion of bacteria such as Escherichia coli to the bladder epithelium. Current evidence supports the use of cranberry juice for prevention of UTI in adult women, but no such evidence exists at this time for the prevention of UTI in children. While cranberry juice is very safe for most children, its acidity reduces palatability among children. The dose of cranberry juice to prevent UTI in children has also yet to be determined. PMID- 22499817 TI - Ophthaproblem. Can you identify this condition? Primary congenital glaucoma. PMID- 22499818 TI - Too busy to relax? PMID- 22499820 TI - Challenging learning situations in medical education: innovative and structured tools for assessment, educational diagnosis, and intervention. Part 1: history or data gathering. PMID- 22499821 TI - QI: the times they are a-changin'. PMID- 22499823 TI - Access to advanced diagnostic services. PMID- 22499824 TI - Defining competency-based evaluation objectives in family medicine: communication skills. AB - OBJECTIVE: To provide a pragmatic approach to the evaluation of communication skills using observable behaviours, as part of a multiyear project to develop competency-based evaluation objectives for Certification in family medicine. DESIGN: A nominal group technique was used to develop themes and subthemes and to identify positive and negative observable behaviours that demonstrate competence in communication in family medicine. SETTING: The College of Family Physicians of Canada in Mississauga, Ont. PARTICIPANTS: An expert group of 7 family physicians and 1 educational consultant, all of whom had experience in assessing competence in family medicine. Group members represented the Canadian context with respect to region, sex, language, community type, and experience. METHODS: The group used the nominal group technique to derive a list of observable behaviours that would constitute a detailed operational definition of competence in communication skills; multiple iterations were used until saturation was achieved. The group met several times a year, and membership remained unchanged during the 4 years in which the work was conducted. The iterative process was undertaken twice--once for communication with patients and once for communication with colleagues. MAIN FINDINGS: Five themes, 5 subthemes, and 106 positive and negative observable behaviours were generated. The subtheme of charting skills was defined using a key-features analysis. CONCLUSION: Communication skills were defined in terms of themes and observable behaviours. These definitions were intended to help assess family physicians' competence at the start of independent practice. PMID- 22499825 TI - Effect of acupuncture on symptoms of anxiety in women undergoing in vitro fertilisation: a prospective randomised controlled study. AB - PURPOSE: To determine if acupuncture improves symptoms of anxiety in infertile women undergoing in vitro fertilisation (IVF) treatment. METHODS: A randomised clinical trial was performed in 43 patients undergoing IVF. The patients were randomised into two groups: test group (n=22) and control group (n=21). The anxiety level of each patient was analysed before and after treatment using the Hamilton Anxiety Rating Scale (HAS). Treatment sessions consisted of four weekly sessions. In the test group, needles were inserted at points HT7, PC6, CV17, GV20 and Yintang. In the control group, needles were inserted in areas near but not corresponding to acupuncture points. RESULTS: The mean HAS score after the 4-week experimental period was significantly lower in the test group than in the control group (19.4 +/- 3.2 vs 24.4 +/- 4.2; p=0.0008). CONCLUSIONS: The results indicate that acupuncture can reduce anxiety symptoms observed by the reduction of psychological parameters of women undergoing IVF. Further evidence should be sought as to whether acupuncture might be a complementary option for patients undergoing IVF. PMID- 22499826 TI - Sleep apnea and glucose metabolism: a long-term follow-up in a community-based sample. AB - BACKGROUND: It has been suggested that sleep-disordered breathing (SDB) is a risk factor for diabetes, but long-term follow-up studies are lacking. The aim of this community-based study was to analyze the influence of SDB on glucose metabolism after > 10 years. METHODS: Men without diabetes (N = 141; mean age, 57.5 years) were investigated at baseline, including whole-night respiratory monitoring. After a mean period of 11 years and 4 months, they were followed up with an interview, anthropometric measurements, and blood sampling. Insulin resistance was quantified using the homeostasis model assessment of insulin resistance (HOMA IR). DeltaHOMA-IR was calculated as (HOMA-IR at follow-up - HOMA-IR at baseline). An oral glucose tolerance test was performed on 113 men to calculate the insulin sensitivity index. RESULTS: The mean apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) at baseline were 4.7 and 3.3, respectively. At follow up, 23 men had diabetes. An ODI > 5 was a predictor of developing diabetes (OR, 4.4; 95% CI, 1.1-18.1, after adjusting for age, BMI, and hypertension at baseline and DeltaBMI and years with CPAP during follow-up). The ODI was inversely related to the insulin sensitivity index at follow-up (r = -0.27, P = .003). A deterioration in HOMA-IR was significantly related to all variables of SDB (AHI, AHI > 5; ODI, ODI > 5; minimum arterial oxygen saturation), even when adjusting for confounders. When excluding the variable years with CPAP from the multivariate model, all associations weakened. CONCLUSIONS: SDB is independently related to the development of insulin resistance and, thereby, the risk of manifest diabetes mellitus. PMID- 22499827 TI - Comparison of APACHE III, APACHE IV, SAPS 3, and MPM0III and influence of resuscitation status on model performance. AB - BACKGROUND: There are few comparisons among the most recent versions of the major adult ICU prognostic systems (APACHE [Acute Physiology and Chronic Health Evaluation] IV, Simplified Acute Physiology Score [SAPS] 3, Mortality Probability Model [MPM]0III). Only MPM0III includes resuscitation status as a predictor. METHODS: We assessed the discrimination, calibration, and overall performance of the models in 2,596 patients in three ICUs at our tertiary referral center in 2006. For APACHE and SAPS, the analyses were repeated with and without inclusion of resuscitation status as a predictor variable. RESULTS: Of the 2,596 patients studied, 283 (10.9%) died before hospital discharge. The areas under the curve (95% CI) of the models for prediction of hospital mortality were 0.868 (0.854 0.880), 0.861 (0.847-0.874), 0.801 (0.785-0.816), and 0.721 (0.704-0.738) for APACHE III, APACHE IV, SAPS 3, and MPM0III, respectively. The Hosmer-Lemeshow statistics for the models were 33.7, 31.0, 36.6, and 21.8 for APACHE III, APACHE IV, SAPS 3, and MPM0III, respectively. Each of the Hosmer-Lemeshow statistics generated P values < .05, indicating poor calibration. Brier scores for the models were 0.0771, 0.0749, 0.0890, and 0.0932, respectively. There were no significant differences between the discriminative ability or the calibration of APACHE or SAPS with and without "do not resuscitate" status. CONCLUSIONS: APACHE III and IV had similar discriminatory capability and both were better than SAPS 3, which was better than MPM0III. The calibrations of the models studied were poor. Overall, models with more predictor variables performed better than those with fewer. The addition of resuscitation status did not improve APACHE III or IV or SAPS 3 prediction. PMID- 22499829 TI - English as the universal language of science: opportunities and challenges. PMID- 22499828 TI - Rationale for treatment of metastatic squamous cell carcinoma of the lung using fibroblast growth factor receptor inhibitors. AB - BACKGROUND: We previously identified amplification of the fibroblast growth factor receptor 1 gene (FGFR1) as a potential therapeutic target for small molecule inhibitor therapy in squamous cell lung cancer (L-SCC). Currently, clinical phase I trials are underway to examine whether patients with FGFR1 amplified L-SCC benefit from a targeted therapy approach using small-molecule inhibitors. Because most patients with lung cancer present with metastatic disease, we investigated whether lymph node metastases in L-SCC share the FGFR1 amplification status of their corresponding primary tumor. METHODS: The study cohort consisted of 72 patients with L-SCC, 39 with regional lymph node metastases. Tissue microarrays were constructed from formalin-fixed, paraffin embedded tissue of the primary tumors and, where present, of the corresponding lymph node metastasis. A biotin-labeled target probe spanning the FGFR1 locus (8p11.22-23) was used to determine the FGFR1 amplification status by fluorescence in situ hybridization. RESULTS: FGFR1 amplification was detected in 16% (12 of 72) of all primary L-SCCs. In metastatic tumors, 18% (seven of 39) of the lymph node metastases displayed FGFR1 amplification with an exact correlation of FGFR1 amplification status between tumor and metastatic tissue. CONCLUSIONS: FGFR1 amplification is a common genetic event occurring at a frequency of 16% in L SCCs. Moreover, lymph node metastases derived from FGFR1-amplified L-SCCs also exhibit FGFR1 amplification. Therefore, we suggest that the FGFR1 amplification is a clonal event in tumor progression. Beyond this biologically relevant observation, the findings carry potential therapeutic implications in that small molecule inhibitors may be applicable to the treatment of a subset of patients with metastatic L-SCC. PMID- 22499834 TI - A pretreatment method for HPLC analysis of cypermethrin in microbial degradation systems. AB - In this paper, a pretreatment method for high-performance liquid chromatography (HPLC) determination of cypermethrin (CY) in microbial degradation systems was systemically studied, primarily to solve the problem of inaccurate determination of CY concentration caused by its uneven distribution in the systems. A suitable pretreatment method was established, including sampling, extraction and dehydration of CY. Partial sampling could be taken for bacterial and yeast systems in which CY was uniformly dispersed by an emulsifying agent, while total sampling was only suitable for mold systems with or without an emulsifying agent. CY could be fully extracted from the samples in which microbial cells were disrupted by ultrasonic treatment with acetonitrile under ultrasonic condition. The extract could be effectively dehydrated and purified by passing it through an anhydrous Na(2)SO(4) column followed by an elution with acetonitrile. The determination of CY in the pretreated sample by HPLC showed a high precision [relative standard deviation (RSD) = 1.14%, n = 5] and a good stability over a period of five days (RSD = 1.57%, n = 5). The recoveries of CY in microbial degradation systems at three different spiked levels ranged from 95.68 to 108.09% (RSD = 0.50-5.87%, n = 5). PMID- 22499835 TI - Detection of naphthalene sulfonates from highly saline brines with high performance liquid chromatography in conjunction with fluorescence detection and solid-phase extraction. AB - A procedure is developed for the simultaneous determination of 1-naphthalene sulfonate, 2-naphthalene sulfonate, 1,5-naphthalene disulfonate, 1,6-naphthalene disulfonate, 2,6-naphthalene disulfonate and 2,7-naphthalene disulfonate from highly saline geothermal brines using ion-pair high-performance liquid chromatography with fluorescence detection after solid-phase extraction. The substances are baseline separated within 33 min and recoveries in brines with salinities of up to 175 g/L NaCl are 100% (+/- 10) by solid-phase extraction. For the overall method, the method quantification limits of the analytes are between 0.05 and 0.4 ug/L. The method is also shown to be feasible for matrices encountered in deep geothermal reservoirs. PMID- 22499836 TI - Application of a fluorescent derivatization reagent 9-chloromethyl anthracene on determination of carboxylic acids by HPLC. AB - A simple and sensitive high-performance liquid chromatography (HPLC) method is proposed for the analysis of some carboxylic acids in food samples and the environment. The use of 9-chloromethyl anthracene as a fluorescence-labeling reagent has been investigated. The derivatization reagent reacts with unitary carboxylic acids and tetrabutylammonium bromide as a catalyst within 50 min in acetonitrile to give esters, which can be separated by HPLC employing fluorescence detection at lambda(ex) = 365 and lambda(em) = 410 nm. The optimum conditions for derivatization, fluorescence detection and chromatographic separation are established. The method shows good sensitivity, with a detection limit from 0.18 to 2.53 pmol, and good linearity between 1-250 nmol/mL of each analyte. The practical applicability of the method was demonstrated by analyzing samples that were spiked with the acid standards, environment and food samples. PMID- 22499838 TI - High burden of congenital toxoplasmosis in the United States: the strain hypothesis? PMID- 22499837 TI - Prematurity and severity are associated with Toxoplasma gondii alleles (NCCCTS, 1981-2009). AB - BACKGROUND: Congenital toxoplasmosis is a severe, life-altering disease in the United States. A recently developed enzyme-linked immunosorbent assay (ELISA) distinguishes Toxoplasma gondii parasite types (II and not exclusively II [NE II]) by detecting antibodies in human sera that recognize allelic peptide motifs of distinct parasite types. METHODS: ELISA determined parasite serotype for 193 congenitally infected infants and their mothers in the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS), 1981-2009. Associations of parasite serotype with demographics, manifestations at birth, and effects of treatment were determined. RESULTS: Serotypes II and NE-II occurred in the United States with similar proportions during 3 decades. For persons diagnosed before or at birth and treated in infancy, and persons diagnosed after 1 year of age who missed treatment in infancy, proportions were similar (P = .91). NE-II serotype was more common in hot, humid regions (P = .02) but was also present in other regions. NE-II serotype was associated with rural residence (P < .01), lower socioeconomic status (P < .001), and Hispanic ethnicity (P < .001). Prematurity (P = .03) and severe disease at birth (P < .01) were associated with NE-II serotype. Treatment with lower and higher doses of pyrimethamine with sulfadizine improved outcomes relative to those outcomes of persons in the literature who did not receive such treatment. CONCLUSIONS: Type II and NE-II parasites cause congenital toxoplasmosis in North America. NE-II serotype was more prevalent in certain demographics and associated with prematurity and severe disease at birth. Both type II and NE-II infections improved with treatment. CLINICAL TRIALS REGISTRATION: NCT00004317. PMID- 22499839 TI - Monitoring peri-therapeutic cerebral circulation time: a feasibility study using color-coded quantitative DSA in patients with steno-occlusive arterial disease. AB - BACKGROUND AND PURPOSE: Intracranial hemodynamics are important for management of SOAD. This study aimed to monitor peri-stent placement intracranial CirT of patients with SOAD. MATERIALS AND METHODS: Twenty-five patients received stent placement for extracranial ICA stenosis, and 34 patients with normal CirT were recruited as controls. Their color-coded DSAs were used to define the Tmax of selected intravascular ROI. A total of 20 ROIs of the ICA, OphA, ACA, MCA, FV, PV, OV, SSS, SS, IJV, and MCV were selected. rTmax was defined as the Tmax at the selected region of interest minus Tmax at the cervical segment of the ICA (I1 on AP view and IA on lateral view). rTmax of the PV was defined as intracranial CirT. Intergroup and intragroup longitudinal comparisons of rTmax were performed. RESULTS: rTmax values of the normal cohorts were as follows: ICA-AP, 0.12; ICA LAT, 0.10; A1, 0.28; A2, 0.53; A3, 0.81; M1, 0.40; M2, 0.80; M3, 0.95; OphA, 0.35; FV, 4.83; PV, 5.11; OV, 5.17; SSS, 6.16; SS, 6.51; IJV, 6.81; and MCV, 3.86 seconds. Before stent placement, the rTmax values of arterial ROIs, except A3 and M3, were prolonged compared with values from control subjects (P < .05). None of the rTmax of any venous ROIs in the stenotic group was prolonged with significance. After stent placement, the rTmax of all arterial ROIs shortened significantly, except A1and M3. Poststenting rTmax was not different from the control group. CONCLUSIONS: Without extra contrast medium and radiation dosages, color-coded quantitative DSA enables real-time monitoring of peri-therapeutic intracranial CirT in patients with SOAD . PMID- 22499840 TI - Progressive brain iron accumulation in neuroferritinopathy measured by the thalamic T2* relaxation rate. AB - Neuroferritinopathy is an autosomal dominant extrapyramidal movement disorder, caused by FTL gene mutations. Iron decreases the MR T2* decay time, therefore increasing the R2* (R2* = 1 /T2*), which correlates with brain tissue iron content. 3T structural and quantitative MR imaging assessment of R2* in 10 patients with neuroferritinopathy demonstrated a unique pattern of basal ganglia cavitation involving the substantia nigra in older patients and increasing thalamic R2* signal intensity detectable during 6 months. Increasing R2* signal intensity in the thalamus correlated with progression on a clinical rating scale measuring dystonia severity. Thalamic R2* signal intensity is a clinically useful method of objectively tracking disease progression in this form of neurodegeneration with brain iron accumulation. PMID- 22499841 TI - Computerized occlusion rating: a superior predictor of aneurysm rebleeding for ruptured embolized aneurysms. AB - BACKGROUND AND PURPOSE: The initial angiographic occlusion rate is the strongest predictor of later rebleeding in previously ruptured coil-embolized cerebral aneurysms. Angiographic estimations of aneurysmal occlusion rates are, however, subjective in nature and confounded by methodologic problems. COR has been developed, and its superiority has been experimentally established to overcome subjective bias. The purpose of this study was to assess the clinical value of COR as a more objective predictor of aneurysm rebleeding when compared with SOR as described in the Raymond Classification. MATERIALS AND METHODS: We applied COR in a consecutive series of 249 patients. Two DSA projections were selected independently by 2 blinded investigators. In cases of disagreement on the selected projections, a consensus decision was obtained. SOR were determined by 2 independent observers according to the Raymond classification. COR was measured by 2 blinded investigators. Interobserver variations were determined for SOR and COR. COR results were compared with SOR results and stratified as 100%, 99.9% 90%, 89.9%-70%, and <70% occlusion. SOR and COR were evaluated as predictors for aneurysm rebleeding. RESULTS: Seven aneurysms rebled (2.8%; follow-up, 59 +/- 35 months). In 20.9% of all cases, DSA selection was performed by consensus evaluations. Interobserver variations were statistically significant for SOR (P = .0030) but not for COR (P = .3517). Compared with COR, SOR overestimated the degree of aneurysmal occlusion in 81.9% of all cases. Only COR predicted rebleeding (P = .0162). CONCLUSIONS: Unacceptable interobserver variations were shown for the standard SOR estimations. COR substantially reduced the impact of subjective bias. COR may, therefore, serve as an easily applicable more objective predictor of aneurysm rerupture. The remaining bias of COR, caused by 2D image analysis, may be overcome by use of direct 3D measurements. PMID- 22499842 TI - Subcortical and cortical gray matter atrophy in a large sample of patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis. AB - BACKGROUND AND PURPOSE: Recent studies have shown that selective regional, but not global, GM atrophy occurs from clinical onset to conversion to clinically definite MS. Our aim was to investigate the difference in the extent of SDGM and cortical atrophy in a large sample of patients with CIS and early RRMS and to explore the relationship between SDGM and cortical atrophy and other MR imaging and clinical outcomes. MATERIALS AND METHODS: Two hundred twelve patients with CIS recruited at the first clinical event (mean age, 29.3 years; median EDSS, 1.5; median disease duration, 3 months) and 177 patients with early RRMS (mean age, 30.7 years; median EDSS, 2.0; median disease duration, 47 months) were imaged on a 1.5T scanner by using a high-resolution 3D T1 spoiled gradient recalled sequence. Volumetric data for SDGM structures were obtained by using FSL FIRST, while whole-brain, GM, white matter, cortical, and lateral ventricle volumes were estimated by using SIENAX software. Comparisons between the groups were adjusted for age and sex. RESULTS: Patients with early RRMS showed significantly lower SDGM but not cortical volumes compared with patients with CIS. The most apparent SDGM differences were evident in the caudate and thalamus (P < .0001), total SDGM (P = .0001), and globus pallidus (P = .01). Patients with CIS with a median T2 lesion volume >4.49 mL showed lower total SDGM, caudate, thalamus (P < .001), globus pallidus (P = .007), hippocampus (P = .004), and putamen (P = .01) volumes and higher lateral ventricle volume (P = .001) than those with a median T2 lesion volume <4.49 mL. Decreased thalamic volume showed the most consistent relationship with MR imaging outcomes (P < .0001) in patients with CIS. CONCLUSIONS: Significant SDGM, but not cortical, atrophy develops during the first 4 years of the RRMS. GM atrophy is relevant for disease progression from the earliest clinical stages. PMID- 22499843 TI - Tract-based spatial statistical analysis of diffusion tensor imaging in pediatric patients with mitochondrial disease: widespread reduction in fractional anisotropy of white matter tracts. AB - BACKGROUND AND PURPOSE: Often diagnosed at birth or in early childhood, mitochondrial disease presents with a variety of clinical symptoms, particularly in organs and tissues that require high energetic demand such as brain, heart, liver, and skeletal muscles. In a group of pediatric patients identified as having complex I or I/III deficits on muscle biopsy but with white matter tissue appearing qualitatively normal for age, we hypothesized that quantitative DTI analyses might unmask disturbance in microstructural integrity. MATERIALS AND METHODS: In a retrospective study, DTI and structural MR brain imaging data from 10 pediatric patients with confirmed mitochondrial disease and 10 clinical control subjects were matched for age, sex, scanning parameters, and date of examination. Paired TBSS was performed to evaluate differences in FA, MD, and the separate diffusion direction terms (lambdar and lambdaa). RESULTS: In patients with mitochondrial disease, significant widespread reductions in FA values were shown in white matter tracts. Mean diffusivity values were significantly increased in patients, having a sparser distribution of affected regions compared with FA. Separate diffusion maps showed significant increase in lambdar and no significant changes in lambdaa. CONCLUSIONS: Despite qualitatively normal appearing white matter tissues, patients with complex I or I/III deficiency have widespread microstructural changes measurable with quantitative DTI. PMID- 22499845 TI - Tapering of the cervical spinal canal in patients with scoliosis with and without the Chiari I malformation. AB - BACKGROUND: Cervical spinal canal tapering may increase CSF velocities and pressures. One report suggests that the cervical spinal canal tapers more steeply in patients with Chiari I than in healthy subjects. The goal of this study was to test the conclusion by measuring spinal canal tapering in another cohort of patients. MATERIALS AND METHODS: Consecutive patients with scoliosis and MR imaging were selected. The MR images were evaluated for tonsillar herniation and syringomyelia. On a midline T2-weighted MR image, the anteroposterior diameter of the spinal canal was measured at each cervical level, and a linear trend line was fit by least-squares regression. The slope of this line was recorded as the taper ratio in millimeters/level. Patients with >5 mm of tonsillar herniation (with or without syrinx) were compared with those without tonsillar herniation (with or without syrinx). Differences in taper ratios for the 2 groups were tested for significance by the Kruskal-Willis test with significance set at .05. RESULTS: Fifty-four patients with scoliosis were identified; 22 had a Chiari malformation and 32 did not. Syringomyelia was identified in 20 of the patients with Chiari and in 8 of the others. The taper ratios averaged -0.9 mm/level for the patients with a Chiari malformation (with or without a syrinx) and -0.4 mm/level for those without it, significant at P = .035. Syringomyelia did not substantially alter the taper ratio in either group. CONCLUSIONS: Patients with scoliosis with a Chiari malformation have more steeply tapering cervical spinal canals than those without it. PMID- 22499844 TI - Hemodynamic changes in patients with arteriovenous malformations assessed using high-resolution 3D radial phase-contrast MR angiography. AB - BACKGROUND AND PURPOSE: Arteriovenous malformations have a high lifetime risk of hemorrhage; however, treatment carries a significant risk of morbidity and mortality, including permanent neurologic sequelae. WSS and other hemodynamic parameters are altered in patients with symptomatic AVMs, and analysis of hemodynamics may have value in stratifying patients into different risk groups. In this study, we examined hemodynamic data from patients with stable symptoms and those who presented with acute symptoms to identify trends which may help in risk stratification. MATERIALS AND METHODS: Phase-contrast MRA using a radial readout (PC-VIPR) is a fast, high-resolution technique that can acquire whole brain velocity-encoded angiograms with scan times of approximately 5 minutes. Ten patients with AVMs were scanned using PC-VIPR; velocity, area, flow, and WSS in vessels feeding the AVMs and normal contralateral vessels were calculated using velocity data from the phase-contrast acquisition. RESULTS: Patients with an asymptomatic presentation or mild symptoms (n = 4) had no significant difference in WSS in feeding vessels compared with normal contralateral vessels, whereas patients presenting with hemorrhage, severe headaches/seizures, or focal neurologic deficits (n = 6) had significantly higher WSS in feeding vessels compared with contralateral vessels. CONCLUSIONS: In this study, we demonstrate that estimates of WSS and other hemodynamic parameters can be obtained noninvasively in patients with AVMs in clinically useful imaging times. Variation in WSS between feeders and normal vessels appears to relate to the clinical presentation of the patient. Further analysis of hemodynamic changes may improve characterization and staging of AVM patients, when combined with existing risk factors. PMID- 22499846 TI - Preliminary experience with the percutaneous embolization of juvenile angiofibromas using only ethylene-vinyl alcohol copolymer (Onyx) for preoperative devascularization prior to surgical resection. AB - BACKGROUND AND PURPOSE: Juvenile angiofibromas are hypervascular tumors that may benefit from preoperative devascularization to reduce intraoperative blood loss. Our purpose was to evaluate the extent of angiographic devascularization and intraoperative blood loss by using only Onyx for percutaneous juvenile angiofibroma tumor embolization. MATERIALS AND METHODS: We reviewed the clinical records and preoperative and postoperative imaging studies of a consecutive series of 9 patients with juvenile angiofibromas who were treated with preoperative embolization with direct percutaneous injection of Onyx followed by resection from a standard open surgical or endoscopic approach. RESULTS: Two Fisch type I, 1 Fisch type II, 5 Fisch type IIIa, and 1 Fisch type IVa tumor were treated. Complete devascularization was achieved in all cases percutaneously with only Onyx. There were no complications. The average intraoperative blood loss was 567.7 mL (range, 10-1700 mL). An average of 2.2 needles (range, 1-5 needles) was placed into the tumor. An average of 14.6 mL of Onyx (range, 2-25 mL) was injected into each tumor. Four Fisch type IIIa tumors were removed completely from only an ENE approach. CONCLUSIONS: Presurgical direct percutaneous embolization of a juvenile angiofibroma with only EVOH before surgical resection is safe and feasible. Our preliminary experience suggests that Onyx may offer a higher degree of devascularization compared with other embolic agents. This may facilitate an easier surgical resection with lower blood loss. PMID- 22499847 TI - Vertebral endplate changes are not associated with chronic low back pain among Southern European subjects: a case control study. AB - BACKGROUND AND PURPOSE: Data on the association between vertebral endplate changes and low back pain are contradictory. This study was designed to assess whether this association exists among Southern European subjects. MATERIALS AND METHODS: Patients in this study serving as cases were 35-50 years of age with low back pain lasting >90 days, for whom a lumbar MR imaging had been prescribed. Controls were subjects 35-50 years of age, having a cranial MR imaging for headache with normal findings, and no history of clinically relevant LBP. Two hundred forty cases and 64 controls were recruited consecutively in the radiology services across 6 cities in Spain. Imaging findings and subject characteristics were gathered through previously validated instruments. Radiologists who interpreted MRI were blinded to the subject characteristics. A multivariate logistic regression model was developed to assess the association of vertebral endplate changes with LBP, adjusting for sex, age, body mass index, lifetime exposure to smoking, physical activity, disk degeneration, and the interaction between disk degeneration and vertebral endplate changes. RESULTS: Vertebral endplate changes were found in 80.4% of the cases and in 87.5% of the controls. In the regression model, disk degeneration was the only variable showing a confounding effect. Results showed that after adjusting for disk degeneration, the presence of vertebral endplate changes is associated with the absence of chronic LBP (OR for LBP: 0.31; 95% CI, 0.10-0.95). CONCLUSIONS: In Southern European subjects, vertebral endplate changes are not associated with chronic LBP. PMID- 22499848 TI - High-resolution versus standard-resolution cardiovascular MR myocardial perfusion imaging for the detection of coronary artery disease. AB - BACKGROUND: Although accelerated high-spatial-resolution cardiovascular MR (CMR) myocardial perfusion imaging has been shown to be clinically feasible, there has not yet been a direct comparison with standard-resolution methods. We hypothesized that higher spatial resolution detects more subendocardial ischemia and leads to greater diagnostic accuracy for the detection coronary artery disease. This study compared the diagnostic accuracy of high-resolution and standard-resolution CMR myocardial perfusion imaging in patients with suspected coronary artery disease. METHODS AND RESULTS: A total of 111 patients were recruited to undergo 2 separate perfusion-CMR studies at 1.5 T, 1 with standard resolution (2.5*2.5 mm in-plane) and 1 with high-resolution (1.6*1.6 mm in-plane) acquisition. High-resolution acquisition was facilitated by 8-fold k-t broad linear speed-up technique acceleration. Two observers visually graded perfusion in each myocardial segment on a 4-point scale. Segmental scores were summed to produce a perfusion score for each patient. All patients underwent invasive coronary angiography and coronary artery disease was defined as stenosis >=50% luminal diameter (quantitative coronary angiography). CMR data were successfully obtained in 100 patients. In patients with coronary artery disease (n=70), more segments were determined to have subendocardial ischemia with high-resolution than with standard-resolution acquisition (279 versus 108; P<0.001). High resolution acquisition had a greater diagnostic accuracy than standard resolution for identifying single-vessel disease (area under the curve, 0.88 versus 0.73; P<0.001) or multivessel disease (area under the curve, 0.98 versus 0.91; P=0.002) and overall (area under the curve, 0.93 versus 0.83; P<0.001). CONCLUSIONS: High resolution perfusion-CMR has greater overall diagnostic accuracy than standard resolution acquisition for the detection of coronary artery disease in both single- and multivessel disease and detects more subendocardial ischemia. PMID- 22499849 TI - Trabeculated (noncompacted) and compact myocardium in adults: the multi-ethnic study of atherosclerosis. AB - BACKGROUND: A high degree of noncompacted (trabeculated) myocardium in relationship to compact myocardium (trabeculated to compact myocardium [T/M] ratio >2.3) has been associated with a diagnosis of left ventricular noncompaction (LVNC). The purpose of this study was to determine the normal range of the T/M ratio in a large population-based study and to examine the relationship to demographic and clinical parameters. METHODS AND RESULTS: The thickness of trabeculation and the compact myocardium were measured in 8 left ventricular regions on long axis cardiac MR steady-state free precession cine images in 1000 participants (551 women; 68.1+/-8.9 years) of the Multi-Ethnic Study of Atherosclerosis cohort. Of 323 participants without cardiac disease or hypertension and with all regions evaluable, 140 (43%) had a T/M ratio >2.3 in at least 1 region; in 20 of 323 (6%), T/M >2.3 was present in >2 regions. A multivariable linear regression model revealed no association of age, sex, ethnicity, height, and weight with maximum T/M ratio in participants without cardiac disease or hypertension (P>0.05). In the entire cohort (n=1000), left ventricular ejection fraction (beta=-0.02/%; P=0.015), left ventricular end diastolic volume (beta=0.01/mL; P<0.0001), and left ventricular end-systolic volume (beta=0.01/mL; P<0.001) were associated with maximum T/M ratio in adjusted models, whereas there was no association with hypertension or myocardial infarction (P>0.05). At the apical level, T/M ratios were significantly lower when obtained on short- compared with long-axis images (P=0.017). CONCLUSIONS: A ratio of T/M of >2.3 is common in a large population-based cohort. These results suggest re-evaluation of the current cardiac MR criteria for left ventricular noncompaction may be necessary. PMID- 22499850 TI - Intestinal epithelial CD98 synthesis specifically modulates expression of colonic microRNAs during colitis. AB - The transmembrane glycoprotein CD98 is known to be involved in intestinal inflammation. In the present study, we found that CD98 overexpression in intestinal epithelial cells does not normally affect the expression of colonic (epithelial and immune cell) microRNAs (miRNAs), small noncoding RNAs that posttranscriptionally regulate a wide variety of biological processes. However, upon dextran sulfate sodium (DSS) treatment, the expression of several colonic miRNAs, but not miRNAs from other tissues such as liver and spleen, were differentially regulated in mice overexpressing CD98 in epithelial cells compared with wild-type (WT) animals. For example, the level of colonic miRNA 132 was not affected by DSS treatment in WT animals but was upregulated in mice overexpressing CD98 in intestinal epithelial cells. Other colonic miRNAs, including colonic miRNA 23a and 23b, were downregulated in WT animals after DSS treatment but not in colonic epithelial cell CD98-overexpressing mice. Interestingly, the expression of potential miRNA target genes affected intestinal epithelial cells that overexpress CD98 and cell types that did not overexpress CD98 but were in close proximity to CD98-overexpressing intestinal epithelial cells. Taken together, these observations show that the combination of an inflammatory context and intestinal epithelial cell expression of CD98 affects the regulation of miRNA expression in colonic epithelial and immune cells. This is new evidence that protein expression modulates miRNA expression and suggests the existence of regulatory crosstalk between proteins and miRNAs in diseases such as colitis. PMID- 22499851 TI - Blockade of CD70-CD27 interaction inhibits induction of allergic lung inflammation in mice. AB - The interaction between the TNF receptor family member CD27 and its ligand CD70 provides a costimulatory signal for T-cell activation. In this study, we investigated the effects of neutralizing anti-CD70 monoclonal antibody (mAb) in a murine model of allergic lung inflammation to determine whether CD27 contributes to the development of pathogenic Th2 cells and pulmonary inflammation. BALB/c mice were immunized by an injection of ovalbumin (OVA) with alum adjuvant and challenged with aerosolized OVA in PBS. Some groups of mice were treated with anti-CD70 mAb or control rat IgG during the induction or effector phase. The administration of anti-CD70 mAb during the induction phase, but not the effector phase, reduced eosinophil infiltration in lung tissue compared with control IgG treated mice. Treatment with anti-CD70 mAb also resulted in the decreased production of Th2 cytokines (IL-4, IL-5, and IL-13) in the bronchoalveolar lavage fluid and draining lymph node cell cultures. We further revealed that antigen specific CD4 T cells were separated into CD27(+) and CD27(-) populations in the lymph nodes of OVA-immunized DO11.10/Rag-2(-/-) mice. The CD27(+) CD4 T cells produced a high concentration of IFN-gamma, representing Th1 cells. In contrast, CD27(-) CD4 T cells produced high concentrations of IL-4, IL-5, and IL-13, representing Th2 cells. Moreover, the population of CD27(-) Th2 cells was significantly reduced by the anti-CD70 mAb treatment. These results indicate an important role for CD27 in the development of pathogenic Th2 cells in a murine model of allergic lung inflammation. PMID- 22499852 TI - Pulmonary endothelial cell NOX. AB - Reactive oxygen species (ROS) have profound influences on cellular homeostasis. In excess, they can potentiate the oxidation of numerous molecules, including proteins, lipids, and nucleic acids, affecting function. Furthermore, ROS mediated oxidation of proteins can directly or indirectly modulate gene expression via effects on redox-sensitive transcription factors or via effects on phospho-relay-mediated signal transduction. In doing so, ROS impact numerous fundamental cellular processes, and have thus been implicated as critical mediators of both homeostasis and disease pathogenesis. Vascular reduced nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a major contributor of ROS within the lung. The generation of ROS in the pulmonary vasculature has a pivotal role in endothelial cell (EC) activation and function. Alterations in EC phenotype contribute to vascular tone, permeability, and inflammatory responses and, thus, have been implicated in numerous diseases of the lung, including pulmonary hypertension, ischemic-reperfusion injury, and adult respiratory distress syndrome. Thus, although a detailed understanding of NOX-derived ROS in pulmonary EC biology in the context of health and disease is nascent, there is mounting evidence implicating these enzymes as critical modifiers of diseases of the lung and pulmonary circulation. The purpose of this review is to focus specifically on known as well as putative roles for pulmonary EC NOX, with attention to studies on the intact lung. PMID- 22499853 TI - SPLUNC1 deficiency enhances airway eosinophilic inflammation in mice. AB - Short palate, lung and nasal epithelium clone 1 (SPLUNC1) is enriched in normal airway lining fluid, but is significantly reduced in airway epithelium exposed to a Th2 cytokine milieu. The role of SPLUNC1 in modulating airway allergic inflammation (e.g., eosinophils) remains unknown. We used SPLUNC1 knockout (KO) and littermate wild-type (C57BL/6 background) mice and recombinant SPLUNC1 protein to determine the impact of SPLUNC1 on airway allergic/eosinophilic inflammation, and to investigate the underlying mechanisms. An acute ovalbumin (OVA) sensitization and challenge protocol was used to induce murine airway allergic inflammation (e.g., eosinophils, eotaxin-2, and Th2 cytokines). Our results showed that SPLUNC1 in the bronchoalveolar lavage fluid of OVA-challenged wild-type mice was significantly reduced (P < 0.05), which was negatively correlated with levels of lung eosinophilic inflammation. Moreover, SPLUNC1 KO mice demonstrated significantly higher numbers of eosinophils in the lung after OVA challenges than did wild-type mice. Alveolar macrophages isolated from OVA challenged SPLUNC1 KO versus wild-type mice had higher concentrations of baseline eotaxin-2 that was amplified by LPS (a known risk factor for exacerbating asthma). Human recombinant SPLUNC1 protein was applied to alveolar macrophages to study the regulation of eotaxin-2 in the context of Th2 cytokine and LPS stimulation. Recombinant SPLUNC1 protein attenuated LPS-induced eotaxin-2 production in Th2 cytokine-pretreated murine macrophages. These findings demonstrate that SPLUNC1 inhibits airway eosinophilic inflammation in allergic mice, in part by reducing eotaxin-2 production in alveolar macrophages. PMID- 22499854 TI - Round and large: morphological and genetic consequences of artificial selection on the gourd tree Crescentia cujete by the Maya of the Yucatan Peninsula, Mexico. AB - BACKGROUND AND AIMS: Artificial selection, the main driving force of domestication, depends on human perception of intraspecific variation and operates through management practices that drive morphological and genetic divergences with respect to wild populations. This study analysed the recognition of varieties of Crescentia cujete by Maya people in relation to preferred plant characters and documents ongoing processes of artificial selection influencing differential chloroplast DNA haplotype distribution in sympatric wild and home garden populations. METHODS: Fifty-three home gardens in seven villages (93 trees) and two putative wild populations (43 trees) were sampled. Through semi structured interviews we documented the nomenclature of varieties, their distinctive characters, provenance, frequency and management. Phenotypic divergence of fruits was assessed with morphometric analyses. Genetic analyses were performed through five cpDNA microsatellites. KEY RESULTS: The Maya recognize two generic (wild/domesticated) and two specific domesticated (white/green) varieties of Crescentia cujete. In home gardens, most trees (68 %) were from domesticated varieties while some wild individuals (32 %) were tolerated. Cultivation involves mainly vegetative propagation (76 %). Domesticated fruits were significantly rounder, larger and with thicker pericarp than wild fruits. Haplotype A was dominant in home gardens (76 %) but absent in wild populations. Haplotypes B-F were found common in the wild but at low frequency (24 %) in home gardens. CONCLUSIONS: The gourd tree is managed through clonal and sexual propagules, fruit form and size being the main targets of artificial selection. Domesticated varieties belong to a lineage preserved by vegetative propagation but propagation by seeds and tolerance of spontaneous trees favour gene flow from wild populations. Five mutational steps between haplotypes A and D suggest that domesticated germplasm has been introduced to the region. The close relationship between Maya nomenclature and artificial selection has maintained the morphological and haplotypic identity (probably for centuries) of domesticated Crescentia despite gene flow from wild populations. PMID- 22499855 TI - Floral development of Hydrocera and Impatiens reveals evolutionary trends in the most early diverged lineages of the Balsaminaceae. AB - BACKGROUND AND AIMS: Balsaminaceae consist of two genera, the monospecific Hydrocera and its species-rich sister Impatiens. Although both genera are seemingly rather similar in overall appearance, they differ in ecology, distribution range, habitat preference and morphology. Because morphological support for the current molecular phylogenetic hypothesis of Impatiens is low, a developmental study is necessary in order to obtain better insights into the evolutionary history of the family. Therefore, the floral development of H. triflora and I. omeiana was investigated, representing the most early-diverged lineage of Impatiens, and the observations were compared with the literature. METHODS: Flowers at all developmental stages were examined using scanning electron microscopy and light microscopy. KEY RESULTS: In Hydrocera, two whorls of five free perianth primordia develop into a less zygomorphic perianth compared with its sister genus. The androecial cap originates from five individual stamen primordia. Post-genital fusion of the upper parts of the filaments result in a filament ring below the anthers. The anthers fuse forming connivent anther-like units. The gynoecium of Hydrocera is pentamerous; it is largely synascidiate in early development. Only then is a symplicate zone formed resulting in style and stigmas. In I. omeiana, the perianth is formed as in Hydrocera. Five individual stamen primordia develop into five stamens, of which the UPPER PART OF THE FILAMENTS CONVERGE WITH EACH OTHER. THE GYNOECIUM OF I. OMEIANA IS TETRAMEROUS; IT APPEARS ANNULAR IN EARLY DEVELOPMENT. CONCLUSIONS: Comparison of the present results with developmental data from the literature confirms the perianth morphocline hypothesis in which a congenital fusion of the parts of the perianth results in a shift from pentasepalous to trisepalous flowers. In addition, the development of the androecial cap and the gynoecium follows several distinct ontogenetic sequences within the family. PMID- 22499856 TI - Demonstration of osmotically dependent promotion of aerenchyma formation at different levels in the primary roots of rice using a 'sandwich' method and X-ray computed tomography. AB - BACKGROUND AND AIMS: The effect of environmental factors on the regulation of aerenchyma formation in rice roots has been discussed for a long time, because aerenchyma is constitutively formed under aerated conditions. To elucidate this problem, a unique method has been developed that enables sensitive detection of differences in the development of aerenchyma under two different environmental conditions. The method is tested to determine whether aerenchyma development in rice roots is affected by osmotic stress. METHODS: To examine aerenchyma formation both with and without mannitol treatment in the same root, germinating rice (Oryza sativa) caryopses were sandwiched between two agar slabs, one of which contained 270 mm of mannitol. The roots were grown touching both slabs and were thereby exposed unilaterally to osmotic stress. As a non-invasive approach, refraction contrast X-ray computed tomography (CT) using a third-generation synchrotron facility, SPring-8 (Super photon ring 8 GeV, Japan Synchrotron Radiation Research Institute), was used to visualize the three-dimensional (3-D) intact structure of aerenchyma and its formation in situ in rice roots. The effects of unilateral mannitol treatment on the development of aerenchyma were quantitatively examined using conventional light microscopy. KEY RESULTS: Structural continuity of aerenchyma was clearly visualized in 3-D in the primary root of rice and in situ using X-ray CT. Light microscopy and X-ray CT showed that the development of aerenchyma was promoted on the mannitol-treated side of the root. Detailed light microscopic analysis of cross-sections cut along the root axis from the tip to the basal region demonstrated that aerenchyma developed significantly closer to the root tip on the mannitol-treated side of the root. CONCLUSIONS: Continuity of the aerenchyma along the rice root axis was morphologically demonstrated using X-ray CT. By using this 'sandwich' method it was shown that mannitol promoted aerenchyma formation in the primary roots of rice. PMID- 22499857 TI - Wait or escape? Contrasting submergence tolerance strategies of Rorippa amphibia, Rorippa sylvestris and their hybrid. AB - BACKGROUND AND AIMS: Differential responses of closely related species to submergence can provide insight into the evolution and mechanisms of submergence tolerance. Several traits of two wetland species from habitats with contrasting flooding regimes, Rorippa amphibia and Rorippa sylvestris, as well as F(1) hybrid Rorippa * anceps were analysed to unravel mechanisms underlying submergence tolerance. METHODS: In the first submergence experiment (lasting 20 d) we analysed biomass, stem elongation and carbohydrate content. In the second submergence experiment (lasting 3 months) we analysed survival and the effect of re-establishment of air contact on biomass and carbohydrate content. In a separate experiment we analysed expression of two carbohydrate catabolism genes, ADH1 and SUS1, upon re-establishment of air contact following submergence. KEY RESULTS: All plants had low mortality even after 3 months of submergence. Rorippa sylvestris was characterized by 100 % survival and higher carbohydrate levels coupled with lower ADH1 gene expression as well as reduced growth compared with R. amphibia. Rorippa amphibia and the hybrid elongated their stems but this did not pay-off in higher survival when plants remained submerged. Only R. amphibia and the hybrid benefited in terms of increased biomass and carbohydrate accumulation upon re-establishing air contact. CONCLUSIONS: Results demonstrate contrasting 'escape' and 'quiescence' strategies between Rorippa species. Being a close relative of arabidopsis, Rorippa is an excellent model for future studies on the molecular mechanism(s) controlling these strategies. PMID- 22499858 TI - Long-term cosmetic changes after breast-conserving treatment of patients with stage I-II breast cancer and included in the EORTC 'boost versus no boost' trial. AB - BACKGROUND: In breast cancer treated with breast-conserving radiotherapy, the influence of the boost dose on cosmetic outcome after long-term follow-up is unknown. PATIENTS AND METHODS: We included 348 patients participating in the EORTC 'boost versus no boost' mega trial with a minimum follow-up of 6 years. Digitalised pictures were analysed using specific software, enabling quantification of seven relative asymmetry features associated with different aspects of fibrosis. RESULTS: After 3 years, we noted a statistically significantly poorer outcome for the boost patients for six features compared with those of the no boost patients. Up to 9 years of follow-up, results continued to worsen in the same magnitude for the both patient groups. We noted the following determinants for poorer outcome: (i) boost treatment, (ii) larger excision volumes, (iii) younger age, (iv) tumours located in the central lower quadrants of the breast and (v) a boost dose administered with photons. CONCLUSIONS: A boost dose worsens the change in breast appearance in the first 3 years. Moreover, the development of fibrosis associated with whole-breast irradiation, as estimated with the relative asymmetry features, is an ongoing process until (at least) 9 years after irradiation. PMID- 22499859 TI - Changes in 18F-FDG tumor metabolism after a first course of neoadjuvant chemotherapy in breast cancer: influence of tumor subtypes. AB - BACKGROUND: The aim of this study is to evaluate the impact of the different breast cancer subtypes on the tumor (18)F-FDG uptake at baseline and on its changes after the first course of neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: One hundred and fifteen women with newly diagnosed, large or locally advanced breast cancer undergoing NAC were included. Estrogen receptor (ER), progesterone receptor (PR) and HER2 status were used to define three major tumor subtypes: triple negative (TN) (ER-/PR-/HER2-), luminal (ER+ and/or PR+; HER2-) and HER2 positive (HER2+). Using Fluorine-18 fluorodeoxyglucose positron emission tomography, the tumoral standard uptake value (SUV) maximal index was measured at baseline and just before the second course of NAC. RESULTS: TN tumors presented the highest baseline SUV (11.3 +/- 8.5; P < 0.0001). The decrease of SUV after the first course of NAC (DeltaSUV) was significantly higher in TN and HER2 positive subtypes (-45% +/- 25% and -57% +/- 30%, respectively) than in luminal one (-19% +/- 35%; P < 0.0001). DeltaSUV was a predictive factor of the pathological complete response only in HER2-positive tumors (cut-off = -75%; P < 0.03) with an accuracy of 76%. CONCLUSION: The baseline (18)F-FDG tumoral uptake but also its early response to NAC is different according to the immunohistological subtypes of breast cancer. PMID- 22499860 TI - Phenotypic responses of chickens to long-term selection for high or low antibody titers to sheep red blood cells. AB - A long-term bidirectional selection experiment was conducted to study antibody response to SRBC. Lines, high antibody selection (HAS) and low antibody selection (LAS), originating from the same White Leghorn base population had undergone 37 generations of selection for either high or low antibody response 5 d after a single intravenous injection of 0.1 mL of a 0.25% suspension of SRBC antigen. Subpopulations, where selection was relaxed, were maintained as contemporaries with the selected lines from generations 16 to 24 [high antibody relaxed (HAR) and low antibody relaxed (LAR)] and 24 to 37. Body weights were obtained at 4, 24, and 38 wk of age and at the onset of lay (BW at first egg). Also measured were age in days to first egg, percentages of hen-day ovulations and normal egg production, and percentages of normal and defective eggs from total ovulation (PNE and PDE). Selection lead to a large divergence in antibody titers between the selected lines, with a plateau reached in line LAS. Line HAS and HAR females displayed higher antibody titers, lower BW4, and matured at older ages than those from LAS and LAR (P < 0.05). Correlations between BW at 4 wk and antibody titers were different between the selected lines, being positive in line LAS and negative in line HAS. Quadratic regression models fit well with antibody titers, BW4, and PNE, with limiting values for these traits calculated based on regression curves. For line HAS, plots showed that an increased tendency of antibody titers was followed by decreased BW4 and increased PNE. For line LAS, however, antibody titers and BW4 decreased in parallel while PNE increased. It appears that at the phenotypic level there was a resource balance between immune response, growth, and reproductive traits, which during long-term selection, individuals altered their dynamic of resource allocations to satisfy certain needs. PMID- 22499861 TI - Polymorphisms of Pit-1 gene and its association with growth traits in chicken. AB - The Pit-1 gene is involved in regulation of muscle growth through controlling the expression of growth hormone, prolactin, and transforming growth factor-beta genes in chicken. The objectives of the study were to explore polymorphisms of the Pit-1 gene and to estimate the effect of these polymorphisms on growth traits in PB-1 and control (broiler strain) and IWI (layer strain) chickens. Single stranded conformation polymorphism followed by sequencing was performed to reveal polymorphisms of the gene. In total, 10 haplotypes were found across the lines. The mRNA expression of Pit-1 varied among haplogroups and had a significant effect on BW and growth rates. The haplogroups showed a significant effect on BW in wk 7 in PB-1 chickens. In control chickens there was a significant effect at d 1 and in wk 2 and 7, and in IWI strains, there was a significant effect at d 1 and wk 6 and 7. The significant association of haplogroups and growth rate was found between 0 and 2 wk in control and between 0 and 2 and 6 and 7 wk in IWI strains. It was concluded that the Pit-1 gene is polymorphic and has a significant effect on growth traits in chickens. PMID- 22499862 TI - Feed efficiency in the laying duck: appropriate measurements and genetic parameters. AB - The objective of this study was to characterize residual feed intake (RFI) in common laying ducks by a) adjusting position and duration of the measurement period and b) estimating genetic parameters of RFI. The feed intake (FI), BW, and egg mass laid (EML) were recorded for 64 I444 common ducks at the beginning (-35 wk of age) and the middle (41-48 wk of age) of the laying curve. Much feed wastage was observed at the beginning of the laying curve and led to biased FI data. However, when laying was well-established, weekly and fortnightly FI measurements were well correlated phenotypically (Rp from 0.84 to 0.92 and from 0.91 to 0.94, respectively for weekly and fortnightly FI) with the measurements over the whole 2-mo period. Regarding egg mass laid, phenotypic correlations between the one-week measurements and the measurements over the whole 2-mo period were more variable than those for FI, ranging from 0.74 to 0.94, and similar to whatever was the period of measurement. The RFI was investigated in a second experiment based on 384 common female ducks, for which FI, EML, BW, and BW gain were recorded at 39 wk of age. The RFI was determined by multiple regression of FI on metabolic BW and EML. Heritability values of FI and RFI were 0.34 and 0.24, respectively. In addition, if the heritability values obtained for BW (0.65) and BW gain (0.09) were consistent with studies in chickens, the very low EML estimates (0.06) were unexpected. The RFI was strongly genetically linked to FI (Rg = +0.89) but appeared to be independent from BW. Selection based on RFI should therefore reduce the FI of animals without clearly modifying the other components. Moreover, the correlated responses on reproductive traits seem favorable because lower RFI values increase the number of eggs produced per year as well as the hatchability and fertility rates. PMID- 22499863 TI - Effect of intranasal immunization with inactivated avian influenza virus on local and systemic immune responses in ducks. AB - To evaluate the effects of co-administration of inactivated avian influenza H9N2 virus and adjuvants in waterfowls, 10-d-old ducks were immunized intranasally with inactivated avian influenza virus (IAIV) combined with CpG DNA and sodium cholate. Immunoglobulin A and IgG antibody levels in throat and tracheal tissues increased significantly, as did specific IgA and IgG antibody levels in the serum after intranasal immunization with IAIV combined with CpG DNA and sodium cholate, compared with immunization with IAIV only. Furthermore, enhanced hemagglutination inhibition titers were also detected in serum samples taken between the third and seventh weeks after immunization with IAIV and both adjuvants compared with IAIV alone. The expression of IL-2 and IL-6 in tracheal and lung tissues increased significantly in the early period after booster immunization. However, the enhancement induced by a single adjuvant was insignificant, and no significant change was detected in the antibody titers or cytokine levels between the ducks that received IAIV alone or saline. In the viral challenge study, prior administration of both CpG DNA and sodium cholate with IAIV reduced the viral titers in the oropharynx and cloaca swabs. Our study suggests that the combination of CpG DNA and sodium cholate could be beneficial to immunization with inactivated H9N2 virus by enhancing the local and systemic immune responses. PMID- 22499864 TI - Differential gene expression profiles of beta-defensins in the crop, intestine, and spleen using a necrotic enteritis model in 2 commercial broiler chicken lines. AB - Changes in the expression levels of avian beta-defensin (AvBD) mRNA were evaluated in necrotic enteritis (NE) disease model in 2 genetically disparate commercial broiler chicken lines: Ross and Cobb. The NE was initiated in the gut by a previously established co-infection model using oral Eimeria maxima infection followed by a Clostridium perfringens challenge. Among the 14 AvBD types examined, there was a tissue-specific expression of AvBD transcripts: AvBD1, AvBD7, and AvBD9 in the crop; AvBD8, AvBD10, and AvBD13; in the intestine and AvBD1 and AvBD7 in the spleen. The 2 different commercial broiler chicken lines showed differential gene expression patterns of AvBD transcripts following co-infection with E. maxima and C. perfringens, with R-line chickens generally showing higher expression levels than the C strain. Both chicken strains showed enhanced gene expression levels of proinflammatory cytokines, such as IL-1beta, IL-6, IL-17F, and TNFSF15 in spleen, and TNFSF15 in intestine, whereas IL-17F was significantly increased only in the intestine of R-line chickens following NE infection. Although the exact nature of interactions between defensins and cytokines in determining the outcome of host innate immune responses to the pathogens of NE remains to be investigated, the differences in gene expression levels of beta-defensins and proinflammatory cytokines in the intestine, crop, and spleen could explain the predisposed disease resistance and susceptibility to NE in the 2 commercial broiler chicken lines. PMID- 22499865 TI - The effects of a galactoglucomannan oligosaccharide-arabinoxylan (GGMO-AX) complex in broiler chicks challenged with Eimeria acervulina. AB - Fermentable carbohydrates may enhance the ability of the gastrointestinal tract to defend against pathogenic infection. We hypothesized that a mannose-rich, galactoglucomannan oligosaccharide-arabinoxylan (GGMO-AX) complex would positively impact immune status and prevent weight loss resulting from acute coccidiosis (Eimeria acervulina) infection of chicks. Using a completely randomized design, 1-d-old commercial broiler chicks (n = 160; 4 replications/treatment; 5 chicks/replication) were assigned to one of 4 corn soybean meal-based diets containing supplemental GGMO-AX (0, 1, 2, or 4%) that replaced dietary cellulose. On d 9 posthatch, an equal number of chicks on each diet were inoculated with either distilled water (sham control) or E. acervulina (1 * 10(6) oocysts). All birds were euthanized on d 7 postinoculation (PI) for collection of cecal contents and duodenal tissue. Overall, BW gain of chicks was not affected by diet PI, whereas infection decreased (P < 0.01) weight gain on d 0 to 7 PI. Feed intake was not affected by dietary treatment, but infection decreased (P < 0.01) feed intake on d 0 to 7 PI. Overall, infection, but not diet, decreased (P < 0.01) G:F on d 0 to 7 PI. Cecal propionate concentrations were independently affected by infection and diet, while butyrate concentrations were affected only by infection (P = 0.02). Cecal Bifidobacterium spp. populations were affected (P < 0.01) by diet, with the 2% GGMO-AX resulting in the highest cfu/g of cecal contents (on a DM basis). Messenger RNA expression of all duodenal cytokines evaluated was affected by infection status (P <= 0.02) but not by dietary treatment alone. Supplementing 4% GGMO-AX consistently resulted in the greatest fold change in proinflammatory cytokine expression, while inhibiting antiinflammatory cytokine expression, which indicates a more robust innate immune response. Despite decreasing performance, 4% dietary GGMO-AX improved select fermentation indices and the innate intestinal immune response to an acute E. acervulina infection. PMID- 22499866 TI - Character of chicken polymorphic major histocompatibility complex class II alleles of 3 Chinese local breeds. AB - To better understand the major histocompatibility complex (MHC) genetic character of domestic birds, we sequenced and analyzed chicken MHC II (B-L) genes of 3 local chicken breeds, derived from 3 separate areas in China. We amplified cDNA sequences from 105 individuals, accounting for 35 alleles. Some of the same B-LB alleles with a high frequency were found in all samples. The putative B-L alpha chain had few polymorphic sites, whereas the B-L beta-chain had several polymorphic sites. Most of the mutation positions were located in the B-LB beta1 domain encoded by exon 2, especially in the peptide-binding region. This indicated that the highly polymorphic peptide-binding region could potentiate binding diverse antigen epitopes. The comparison of 3-D molecule structures of chicken B-L and human HLA-DR1 revealed a distinctly structural similarity, but the chicken B-L molecule had more polymorphic sites than the human HLA-DR1 molecule, which presumably might be a mechanism to compensate for responding to a wider array of pathogens due to fewer loci for chicken. Moreover, some conserved sites in human and chicken MHC class II molecules reflected their common ancestry and similar functions. These results suggest that the chicken B-L gene showed more polymorphic sites and distinctly dominant trans-breed alleles, potentially to adapt to pathogens. PMID- 22499867 TI - Innate immune response to yeast-derived carbohydrates in broiler chickens fed organic diets and challenged with Clostridium perfringens. AB - Necrotic enteritis (NE) caused by Clostridium perfringens is a reemerging disease of economic importance in areas of the world where antibiotic growth promoters have been banned. The effect of mannan-oligosaccharide (MOS) supplementation in organic diets of broilers challenged with C. perfringens on performance, gut morphology, and innate immunity was investigated. Three hundred Ross-308 broilers were fed antibiotic-free certified organic starter and grower diets. On d 14, birds were orally challenged with 1 mL of C. perfringens culture at 3 * 10(10) cfu/bird. Treatments consisted of a control no-challenge (CO; 0 g/kg of MOS in the basal diet), control challenge (COC, 0 g/kg of MOS in the basal diet), and MOS challenge (2 g/kg of MOS in the basal diet). Challenge of birds resulted in decreased feed intake and BW gain (P = 0.048 and P = 0.026, respectively). Even though supplementation of diet with MOS improved feed intake (P = 0.985), BW gain and G:F were not improved compared with those of the CO group (P = 0.026 and P = <0.001, respectively). There was no significant difference among treatments in jejunal and ileal villus height, crypt depth, and goblet cells/mm(2) (P > 0.05). Quantitative real-time PCR showed that, in the ileum, the MOS diet resulted in an upregulation of toll-like receptor (TLR)2b, TLR4, interleukin (IL)-12p35, and interferon (IFN)-gamma compared with CO (P = 0.003, P = 0.018, and P = 0.024, respectively). In the cecal tonsil, challenging birds with C. perfringens resulted in an upregulation of TLR2b compared with CO (P = 0.036), and MOS resulted in an upregulation of TLR4 (P = 0.018). In conclusion, feeding a MOS supplemented diet to C. perfringens-challenged broiler chickens did not improve performance and gut morphology-associated responses. However, MOS was capable of altering TLR and cytokine profiles, where dual TLR2 and TLR4 pathways were associated with MOS supplementation with subsequent upregulation of ileal IL 12p35 and IFN-gamma, implying that MOS supplementation in C. perfringens challenged chickens supports a proinflammatory effect via T-helper cell-1 associated pathways. PMID- 22499868 TI - Outbreak of gizzard erosion associated with fowl adenovirus infection in Korea. AB - The pathogenicity of a fowl adenovirus serotype-1 (FAdV-1, K181 strain) isolated from a case of gizzard erosion in layer chickens was investigated in specific pathogen-free (SPF) chicks. One-week-old SPF chicks were inoculated orally or intramuscularly with the isolate of FAdV-1 and euthanized for necropsy at 7, 14, and 21 d postinoculation. Although there were no clinical signs after inoculation, gizzard erosions were observed grossly and the virus was recovered from the gizzards in the inoculated chickens. Histologically, in the chickens that were infected orally, the lesions found in the gizzard consisted of severe degeneration and necrosis of glandular epitheliums and eosinophilic inclusion bodies. These results indicate that the Korean FAdV-1 isolate could induce gizzard lesions in chickens. Moreover, the present investigation reproduced an outbreak of gizzard erosion caused by FAdV-1 infection and, for the first time, described the isolation of FAdV-1 from chickens in Korea. These findings provide important information on the epidemiology and pathogenesis of FAdV-1 infection in chickens. PMID- 22499869 TI - Effect of a novel phytase on growth performance, apparent metabolizable energy, and the availability of minerals and amino acids in a low-phosphorus corn-soybean meal diet for broilers. AB - The addition of microbial phytase to diets for broiler chickens has been shown to improve the availability of phytate P, total P, some other minerals, and amino acids. In this study, the effect of a novel microbial phytase expressed by synthetic genes in Aspergillus oryzae on amino acid and mineral availability was assessed. Phytase was incorporated (1,000 and 2,000 U/kg) into low-P corn-soybean meal-based diets for broilers. Broilers received the experimental diets for 3 wk, and excreta were collected from d 18 to 21 for the determination of AME and mineral retention. On the 22nd day, the broilers were killed and the left leg removed and ileal digesta collected. Ileal phytate P and total P absorption, ileal amino acid digestibility, as well as the bone mineral content and bone mineral density were determined. Ileal phytate P absorption and absorbed phytate P content of the low-P corn-soybean meal diet were significantly (P < 0.05) higher after dietary inclusion of the novel phytase (49-60% and 65-77% higher, respectively). Apparent ileal total P absorption and apparent total P retention was 12 to 16% and 14 to 19% higher (P < 0.05), respectively, after dietary inclusion of phytase. The bone mineral content and bone mineral density in the tibia were 32 to 35% and 19 to 21% higher (P < 0.05), respectively, after dietary phytase inclusion. The apparent ileal digestibility of threonine, tyrosine, and histidine increased significantly (P < 0.05) by 14, 9, and 7%, respectively, after dietary inclusion of microbial phytase. Overall, the inclusion of a novel microbial phytase into a low-P corn-soybean meal diet for broiler chickens greatly increased phytate P and total P absorption, bone mineral content and density, as well as the digestibility of some amino acids. PMID- 22499870 TI - Sodium levels for Japanese quail at initial phases. AB - The aim of this research was to determine the nutritional requirements of sodium for Japanese quail (Coturnix coturnix Japonica) during the periods of 1 to 21 d and 22 to 40 d of age, as well as to evaluate the residual effect on egg production and densitometry bone traits from 41 to 63 d. Two experiments were developed. Experiment 1: 360 Japanese quail were used, from 1 to 21 d of age. Treatments consisted of 5 sodium levels (0.06, 0.12, 0.18, 0.24, and 0.30%). Experiment 2: 240 Japanese quail were used, from 22 to 40 d. Treatments consisted of 5 sodium levels (0.04, 0.12, 0.20, 0.28, and 0.36%). In both experiments, weight gain, final weight, and feed conversion presented a quadratic trend, whereas water intake presented a linear trend. Treatments did not affect the densitometry of bone traits, although they presented a quadratic influence on tibia ash, calcium, and calcium:phosphorus ratio. Therefore, the nutritional requirement of sodium for Japanese quail from 1 to 21 d and from 22 to 40 d is 0.222% and 0.253%, respectively. PMID- 22499871 TI - High levels of vitamin E affect retinol binding protein but not CYP26A1 in liver and hepatocytes from laying hens. AB - This study was conducted to determine the influence of vitamin E on the retinol binding protein (RBP) and cytochrome p450 family 26 subfamily A polypeptide 1 (CYP26A1), which are specific transporters and catabolic enzymes of vitamin A, respectively. In the in vivo experiments, a total of 450 laying hens was fed 5 levels of vitamin E (0, 20, 80, 320, and 1,280 IU/kg of feed) supplementation. For the in vitro assays, hepatocytes from laying hens were cultured in 4 levels of alpha-tocopherol (0, 10, 50, and 100 MUM). High dietary vitamin E increased the concentration of vitamin A in liver (P < 0.05). The RBP and its mRNA expression in liver and hepatocytes were markedly inhibited by dietary vitamin E (320 and 1,280 IU/kg) and alpha-tocopherol (100 MUM) in culture medium (P < 0.05). However, CYP26A1 and its mRNA expression were not affected by vitamin E in both liver and hepatocytes (P > 0.05). The results indicate that excessive vitamin E could increase the concentration of vitamin A in liver by inhibiting RBP synthesis in hepatocytes. PMID- 22499872 TI - Evaluation of the compositional and nutritional values of phytase transgenic corn to conventional corn in roosters. AB - Three experiments were conducted to evaluate the compositional and nutritional values of corn grains [phytase transgenic corn (PTC) and isogenic conventional corn (CC)] and compare the efficacy of corn-based phytase and extraneous microbial phytase for enhancing the utilization of phytate phosphorus (P) in single corn or corn-soybean mixed meals (corn:soybean = 2.5:1, wt:wt) fed to roosters. Following a 48-h fasting period, 16 roosters were given 50 g of each sample via crop intubation and excreta were collected for 48 h. Nitrogen-free and phosphorus-free diets were used to evaluate endogenous amino acid and endogenous P losses, respectively. Chemical composition was not different between PTC and CC, whereas the phytase content for PTC was greater than CC (8,047 vs. 37 FTU/kg of corn, DM basis; P < 0.001). No difference was observed in the TME and true amino acid availability values between the PTC and CC in roosters. The true P utilization for PTC was greater than CC (37.92 vs. 55.85%; P < 0.001), and CC and PTC contained 0.13 and 0.19% available P (AP, DM basis; P < 0.001), respectively. There was no difference in P utilization (72.76 vs. 70.23%; P > 0.05) between roosters fed PTC and extraneous microbial phytase in equivalent FTU/kg of diets. The results of this study indicated that the chemical composition, TME, and true amino acid availability in PTC are essentially equivalent to that in CC, and the true P utilization for roosters is higher in PTC than in CC. Corn expressing phytase is as efficacious as equivalent microbial phytase when supplemented in corn-soybean diets for chickens. PMID- 22499873 TI - Effect of dietary adipic acid and corn dried distillers grains with solubles on laying hen performance and nitrogen loss from stored excreta with or without sodium bisulfate. AB - Effects of dietary adipic acid (0 vs. 1%) and corn dried distillers grains with solubles (DDGS; 0 vs. 20%) were evaluated on hen performance and egg characteristics from 26 to 34 wk of age. Four isocaloric and isonitrogenous diets were randomly assigned to blocks of 6 consecutive cages (36 cages per diet; 2 hens per cage). On wk 2 and 7 of the experiment, excreta were collected by cage block, mixed, and equally split into 2 containers. Sodium bisulfate (SBS) was spread (8.8 kg/100 m(2)) on the top surface of half of the containers. All containers were stored uncovered for 14 d at room temperature. Excreta pH, DM, and N content were measured on d 0, 7, and 14 of storage. Feed intake (112 g/d per hen), egg production (96.1%), and egg specific gravity (1.079 g/g) were not affected by diet. On excreta collection day, a synergy (P = 0.014) between dietary adipic acid and DDGS was detected, as the lowest excreta pH was obtained with the diet including both adipic acid and DDGS. On d 7 of storage, excreta pH was still reduced by dietary adipic acid (P = 0.046) and DDGS (P < 0.001), but a week later, only dietary DDGS decreased excreta pH (8.91 vs. 9.21; P < 0.001). Whereas dietary adipic acid had no influence on excreta N loss, excreta from hens fed 20% DDGS lost 19.7% more N (P = 0.039) during storage than hens not eating DDGS. Surface amendment of excreta with SBS increased excreta DM content, with the effect being even more marked on d 14 of storage (increase of 6.7 percentage units; P < 0.001), consistently decreased excreta pH during storage (P < 0.001) and reduced N loss by 26.1% for the 14 d of storage period. PMID- 22499874 TI - Characterization of 5-hydroxytryptamine-induced contraction and acetylcholine induced relaxation in isolated chicken basilar artery. AB - The aim of the present study was to clarify the responsiveness of the chicken basilar artery to 5-hydroxytryptamine (5-HT) and acetylcholine (ACh) and to characterize the related receptor subtypes in vitro. Basilar arteries were obtained from freshly slaughtered broiler chickens. The 5-HT induced concentration-dependent contraction of the arteries. The concentration-response curves for 5-HT were shifted 30-fold to the right by methiothepin (a 5-HT(1) and 5-HT(2) receptor antagonist) and 3-fold to the right by ketanserin (a 5-HT(2) receptor antagonist). In the presence of ketanserin, the concentration-response curve for 5-HT was shifted 10-fold to the right by methiothepin. The pA(2) value for methiothepin was 8.26. The ACh induced concentration-dependent relaxation under conditions of precontraction by 5-HT. The concentration-response curve for ACh was shifted to the right by atropine [a nonselective muscarinic (M) receptor antagonist] and hexahydro-sila-difenidol hydrochloride, a p-fluoroanalog (pFHHSiD, an M(3) receptor antagonist), but not by pirenzepine (an M(1) receptor antagonist) or methoctramine (an M(2) receptor antagonist). The pA(2) value for pFHHSiD was 7.55. Nomega-Nitro-l-arginine (a nitric oxide synthase inhibitor) inhibited ACh-induced relaxation by approximately 50%. These results suggest that 5-HT induces contraction via activation of 5-HT(1) and 5-HT(2) receptors and that ACh induces relaxation via activation of the M(3) receptor. The 5-HT(1) receptor might play a dominant role in 5-HT-induced contraction. One of the factors involved in ACh-induced relaxation is probably nitric oxide released from endothelial cells. PMID- 22499875 TI - Maternal hyperthyroidism is associated with a decreased incidence of cold-induced ascites in broiler chickens. AB - A hypothesis was tested that providing the breeder hens with exogenous thyroxine (T(4)) would help their offspring to better survive the ascites-inducing condition during the growing period. In total, 132 broiler breeder hens were randomly assigned to one of 3 treatments: control (CON), hypothyroid [HYPO; 6-N propyl-2-thiouracil (PTU)-treated], and hyperthyroid (HYPER; T(4)-treated). The hens were artificially inseminated, and the hatching eggs (n = 1,320) were incubated. No eggs in the HYPO group hatched. The 1-d-old male chicks (n = 288) from other groups were reared for 42 d under standard or low ambient temperature to induce ascites. Blood samples were drawn from the hens, embryos, and broilers for determination of T(4) and triiodothyronine (T(3)). The hematocrit was also determined in broilers. The PTU-treated hens had an increased BW along with lower plasma T(3) and T(4) concentrations. Plasma T(4) was higher in the HYPER hens compared with CON hens, but T(3) concentration was not different between these groups. The fertility rate was not affected by either hypo- or hyperthyroidism. The embryos in the HYPO group had lower plasma T(3) and T(4) concentrations at d 18 of embryonic development and internal pipping. Higher plasma T(4) was recorded in the HYPER birds at internal pipping, although plasma T(3) concentration was not affected at this stage. Maternal hyperthyroidism decreased the overall incidence of ascites in the cold-exposed chickens (10.0 vs. 33.4% for HYPER and CON groups, respectively). Although the effect of maternal PTU or T(4) treatment on plasma thyroid hormones and on the right ventricle-to-total ventricular weight ratio in the broilers was not significant, the cold-exposed healthy CON chicks showed higher hematocrit values, compared with the HYPER birds. It was concluded that maternal hyperthyroidism could decrease the incidence of cold-induced ascites in broiler chickens; however, probable causal mechanisms remain to be elucidated. PMID- 22499876 TI - Differences in the mucosal surface barrier formed by mucin in the lower oviductal segments between laying and molting hens. AB - The aim of this study was to determine the differences in the mucin expression that forms a mucosal surface barrier in the oviduct between laying and molting hens. The lower segments of oviducts (isthmus, uterus, and vagina) of White Leghorn laying and molting hens were collected. Localization and gene expression of mucosal mucin were analyzed by quantitative reverse-transcription PCR of mucin mRNA and mucin5AC immunohistochemistry. Sugar residues were localized by lectin (WGA or Jacalin) histochemistry. Expression of mucin mRNA was significantly declined in the lower oviductal segments in molting compared with laying hens. Immunoreactive-mucin5AC was localized in the mucosal epithelium and on the epithelial surface of laying hens, whereas it was reduced in molting hens. Substances positively stained by WGA and Jacalin were identified on the surface of the mucosal epithelium in the lower oviductal segments in laying and molting hens. These results suggest that mucin synthesis in the lower segments of the oviduct is reduced, although the existence of WGA- and Jacalin-positive sugars may be kept even in the molting phase. The reduction of mucin synthesis may result in a decline of mucosal barrier function in the molting phase. PMID- 22499877 TI - Antimicrobial resistance of 100 Salmonella strains isolated from Gallus gallus in 4 wilayas of Algeria. AB - This study aims at identifying serotypes and surveying the antimicrobial resistance and plasmid support of resistance of 100 Salmonella strains, which were isolated from 96 out of 506 (18.97%) samples taken from different production farms in the wilayas (i.e., Algerian states) of Tizi-Ouzou, Bouira, Bejaia, and Boumerdes in 2007. The highest percentage of Salmonella (48%) was recorded in Bouira. Thirteen serotypes were identified among the 100 Salmonella strains used in this study. The most prevalent ones were Salmonella Heidelberg (24%), Salmonella Enteritidis (20%), Salmonella Albany (16%), and Salmonella Typhimurium (9%). The strains showed resistance to 8 of the 34 antibiotics tested. Fifty three percent of strains were resistant to at least one antibiotic, among which 15.09% were multiresistant. The most frequently observed resistance was to quinolones (58.49%), with a contribution of 94.74% of Salmonella Heidelberg resistant strains. The plasmid transfer performed on 53 strains showed that only 11 exhibited one or more markers of resistance, the most frequent being ampicillin, followed by tetracycline, then cotrimoxazole, sulphonamides, and kanamycin, in that order. The tetracycline characteristics were present in 72.72% of transconjugants, those of the beta-lactams and sulphonamides in 27.27% each and those of the aminosides in 9.09%. The incompatibility groups of plasmids belong to the F1me and Com1 classes, and the molecular weight of the plasmid DNA was greater than 100 kb. The phenotypic and genotypic results indicate a clonal dissemination in the Gallus gallus species in this particular study; this phenomenon could generate resistant bacteria and transferable genes of resistance to humans. PMID- 22499878 TI - Sodium chloride concentration affects yield, quality, and sensory acceptability of vacuum-tumbled marinated broiler breast fillets. AB - The objective of this experiment was to determine the effect of sodium chloride concentration on yield, instrumental quality, and sensory acceptability of broiler breast meat that was vacuum tumbled with a 15% solution (over green weight) for 30 min. Different concentrations (0, 0.25, 0.50, 0.75, 1.00, 1.25, and 1.50%) of NaCl (salt) and 0.35% sodium tripolyphosphate were included in the marinade solution. After marinating, breast fillets were evaluated for marination yields, pH, surface color, cooking loss, tenderness, expressible moisture, proximate composition, purge loss, sodium content, and sensory acceptability. As salt concentration increased, CIE L* decreased linearly, with a concentration of 0.75% having lower (P < 0.05) CIE L* values when compared with the control, 0, and 0.25% NaCl treatments. In addition, there was a linear and quadratic decrease (P < 0.05) in shear force as salt concentration increased, with no further decrease (P < 0.05) when greater than 0.75% NaCl was used. Cooking yield increased (P < 0.05) as the salt concentration increased to 1.0%. All marinated treatments were preferred (P < 0.05) over the control treatment, and all treatments marinated with at least 0.50% sodium chloride had an average rating of like moderately. Cluster analysis indicated that consumer groups varied in their preference of broiler breast meat treatments and that samples that were marinated with between 0.5 to 1.0% NaCl were acceptable to the majority of consumers. Marination with 0.75% NaCl was sufficient to maximize yields and decrease lightness (L*) in vacuum-tumbled, marinated broiler breast that is sold raw, but 1.0% NaCl could be used in a precooked product because it minimizes cook loss. In addition, use of 0.50% NaCl had minimal effects on yields, color, and sensory acceptability when compared with products that were marinated with greater concentrations of NaCl. PMID- 22499879 TI - Prevalence of coliforms, Salmonella, Listeria, and Campylobacter associated with eggs and the environment of conventional cage and free-range egg production. AB - There is a desire by US consumers for eggs produced by hens in alternative production systems. As the retail shell-egg market offers these products to accommodate consumer demands, additional information is needed to ensure processing methodologies result in safe eggs from all egg sources. A study was conducted to determine if there were differences in the prevalence of coliforms, Salmonella, Listeria, and Campylobacter on and within eggs and in the environment of a sister flock of conventional cage and free-range laying hens. Microbial sampling occurred approximately every 6 wk between 20 and 79 wk of age. A random sampling of typical coliform colonies produced 371 viable isolates for biochemical identification. Twenty-nine genera or species of bacteria were identified. There was a significantly greater (P < 0.0001) prevalence of Campylobacter in the free-range nest box swabs compared with that in the free range grass and conventional cage swab samples (number of positives: 8 nest box, 1 grass, 0 cage). Seven isolates of Listeria innocua were detected with no significant difference in prevalence between the treatments. Isolates were associated with eggshells (2 free-range floor, 1 cage) and the free-range environment (2 nest box, 2 grass). There were 21 Salmonella isolates detected between all sample locations, with no significant difference in the prevalence of Salmonella detection between the treatments. Additional studies are needed to fully understand the effect of alternative production methods on the prevalence of pathogens and coliforms associated with nest-run eggs and the production environment. PMID- 22499880 TI - Postmortem aging and freezing and thawing storage enhance ability of early deboned chicken pectoralis major muscle to hold added salt water. AB - The effects of postdeboning aging and frozen storage on water-holding capacity (WHC) of chicken breast pectoralis major muscle were investigated. Broiler breast muscle was removed from carcasses either early postmortem (2 h) or later postmortem (24 h). Treatments included: no postdeboning aging; 1-d postdeboning aging at 2 degrees C, 7-d postdeboning aging (2-h deboned meat only), and 6-d storage at -20 degrees C plus 1-d thawing at 2 degrees C (freezing and thawing treatment, 2-h deboned meat only). The WHC was determined by cooking loss, drip loss, a filter paper press method (results were presented as expressible fluid), and a salt-induced swelling and centrifugation method (results were presented as percentage of salt-induced water gain). There were no differences for WHC estimated by cooking loss and expressible fluid between the treatments. Only the freezing and thawing treatment resulted in a significant increase in drip loss. The average percentage of salt-induced water gains by the 24-h deboned samples, postdeboning aged 2 h samples, and frozen 2 h sample, which did not differ from each other, were significantly higher than that by the 2-h deboned sample. These results indicate that regardless of method (carcass aging vs. postdeboning aging) and time (aging for 1 d vs. for 7 d), postmortem aging more than 1 d does not affect WHC of the early deboned samples measured by dripping, cooking, and pressing. However, postmortem carcass aging, postdeboning aging, and freezing and thawing storage can significantly enhance the ability of chicken breast meat to hold added salt water or WHC measured by the salt-induced swelling and centrifuge method. PMID- 22499881 TI - Effect of feeding fermented Ginkgo biloba leaves on growth performance, meat quality, and lipid metabolism in broilers. AB - Aspergillus niger-fermented Ginkgo biloba leaves (FR) and its comparative effect with vitamin E (VE) and nonfermented (NF) Ginkgo leaves on growth, lipid metabolism, antioxidant capacity, and meat quality of broiler chicks were investigated. In total, 360 one-day-old broiler chicks were randomly allocated into 6 dietary treatments, which were then denoted as control group (basal diet), VE group (containing respectively 15 and 30 IU/kg of all-rac-alpha-tocopherol acetate in the starter and grower phase), NF group (containing respectively 0.35% and 0.7% NF in the starter and grower phase), and FR1, FR2, and FR3 groups containing respectively 0.2, 0.35, and 0.5% FR in the starter and 0.4, 0.7, and 1.0% FR in the grower phase. The results on performance showed that a significant (P < 0.05) reduction of feed:gain ratio of birds in the FR2 group (22-42 d and 1 42 d) was observed when compared with that of the control and NF groups. With dietary FR increasing, the serum alpha-tocopherol concentration increased linearly (P = 0.001). Compared with the control, broilers had higher (P < 0.05) serum high-density lipoprotein concentration, total superoxide dismutase activities, and total antioxidant capacity when they were provided with the FR2 and FR3 diet. Whereas the low-density lipoprotein and triglyceride concentrations were lower (P < 0.05 or P < 0.01) in broilers from FR2 or FR3 groups. As the dietary FR increased, abdominal fat (P = 0.002) and muscle malondialdehyde (P = 0.001) concentrations decreased. Furthermore, 24-h pH, 24-h drip loss, and cooking loss were greatly improved (P < 0.05) as the levels of FR increased. Birds fed with FR had a lower (P < 0.05) C16:0 and C18:0 concentrations but a greater (P = 0.001) concentration of C18:2, C18:3, and C20:4 than that of the control. In conclusion, FR can improve the growth performance and lipid metabolism of broilers with decreased abdominal fat deposition. Also, the antioxidant capacity and meat quality improving effects observed in broilers fed FR products might result from the increased retention of alpha-tocopherol and reduction in lipid peroxidation, as evidenced by the decrease in malondialdehyde and the increase in total superoxide dismutase activities. PMID- 22499882 TI - Evaluation of selective enrichment broths and chromogenic media for Salmonella detection in highly contaminated chicken carcasses. AB - We evaluated the effectiveness of 2 selective enrichment broths, Rappaport Vassiliadis Soy (RVS) and Muller-Kauffmann tetrathionate with novobiocin (MKTTn), for the isolation of Salmonella from chicken carcasses obtained from 3 different types of retail markets. We also compared a chromogenic agar, chromID Salmonella agar (SM-ID 2), with a classic plating medium, xylose lysine deoxycholate agar (XLD). Salmonella were isolated from 118 of the 180 samples (65.5%). Salmonella were detected in 105 samples (88%) plated on XLD and 111 samples (94%) plated on SM-ID 2 when RVS broth was used for enrichment, and 43 samples (36.4%) plated on XLD and 67 samples (56.8%) plated on SM-ID 2 when the MKTTn broth was used. The highest sensitivity was found in the RVS-XLD combination (0.99), followed by RVS SM-ID 2 (0.97). The specificity of the RVS-SM-ID 2 combination was the highest (0.89), but that of the MKTTn-XLD combination was zero. The results of this study indicate that the selective enrichment broths had a great effect on the sensitivity and specificity of plating media, and our study confirms that the RVS broth is the most suitable enrichment for the investigation of Salmonella in chicken carcasses. This observation suggests that use of RVS broth for selective enrichment and SM-ID 2 for selective isolation may be the best combination to determine the presence of Salmonella in chicken carcasses. PMID- 22499883 TI - Comparison of growth performance, carcass components, and meat quality between Mos rooster (Galician indigenous breed) and Sasso T-44 line slaughtered at 10 months. AB - The aim of this research was to make a full study of the meat from Mos-breed roosters (Spanish indigenous chicken). To achieve this purpose, the type of breed (Mos vs. a hybrid line, Sasso T-44) and the effect of finishing treatment in the last month (corn vs. commercial fodder) on growth performance, carcass and meat quality (physicochemical and textural traits), fatty and amino acid profile, and sensorial description were studied. The finishing feeding effect did not modify the growth, but the differences between genotypes were statistically significant (P < 0.05), in where Sasso T-44 was the genotype that generated the best growths and associated parameters. With regard to carcass characteristics, no significant influences of finishing feeding treatment (P > 0.05) were found, and carcass weight clearly differed between genotypes due to the lower growth rate of Mos roosters. Drumstick, thigh, and wing percentages were greater in Mos breed than in Sasso T-44 birds, whereas breast (15.2%), that is the most highly valued piece of the chicken, was similar for both genotypes. Significant differences in pH, protein, and ash content between genotypes have been found, whereas finishing feeding treatment had an effect on myoglobin and redness index (P < 0.01), showing meat from roosters fed with corn had a higher luminosity. Despite the fact of the slaughtered age of birds, values of shear force were slightly higher than 2 kg (2.11 kg) for both genotypes, thus it can be classified as very tender meat. Mos breed showed a higher percentage of polyunsaturated fatty acids (25.90 vs. 22.74; P < 0.001) and a lower percentage of monounsaturated fatty acids (35.14 vs. 38.95; P < 0.001) than Sasso T-44 chicken muscles. Surprisingly, birds finishing with the corn diet (2 times higher in linolenic acid than fodder) did not increase their polyunsaturated fatty acid level in the breast, obtaining in the Mos breed a polyunsaturated to saturated fatty acid ratio of 0.69. The amino acid profile of the indigenous-breed breast was not similar to that of the commercial-strain breast; besides, finishing feeding treatment had more of an effect on amino acid profile, affecting the majority of amino acids, with the exception of phenylalanine and threonine. PMID- 22499884 TI - Consumer acceptance of visual appearance of broiler breast meat with varying degrees of white striping. AB - White striping is a condition associated with heavier broiler breast fillets and is observed grossly as white striations seen parallel to the direction of the muscle fibers. The present study was intended to assess the consumer acceptance of broiler fillets with different degrees of white striping condition. High resolution digital images of fillets, representative of varying degrees of white striping, were shown to 75 consumers in a blind study. Individual images were presented using a completely randomized design. There were 4 replicates of individual fillets within each white striping category (normal = NORM, moderate = MOD, and severe = SEV) and one picture of tray pack (3 fillets) for each category. The consumers were asked to express their overall liking for appearance with a 9-point hedonic scale (9 = like extremely; 1 = dislike extremely) and purchase intent using a 5-point scale (5 = definitely would buy; 1 = definitely would not buy). An open-ended comments section was also included. The results showed that NORM fillets had a significantly higher hedonic score (6.9) than the MOD fillets (6.1), which was also significantly higher than the SEV fillets (4.5), indicating that as severity of white striping increased, the consumer acceptance decreased. From the distribution of the responses, 10.7, 22.4, and 56.7% of the consumers disliked the NORM, MOD, and SEV fillets, respectively. Furthermore, the average purchase intent score for the NORM fillets (3.6) was significantly higher than those with 2 degrees of white striping (2.4 and 2.5, respectively), suggesting that the consumers were more likely to buy NORM fillets. Over 50% of the consumers indicated that they would probably not or definitely not buy MOD or SEV fillets. The correspondence analysis of open-ended comments revealed the major reasons for the dislike of the white-striped meat was that the fillets had a more fatty or marbled appearance. The results of the study suggest that the white striping does affect the consumer acceptance based on the appearance of the fillets. PMID- 22499885 TI - Transfer of flubendazole and tylosin at cross contamination levels in the feed to egg matrices and distribution between egg yolk and egg white. AB - Chemical residues may be present in eggs from laying hens' exposure to drugs or contaminants. These residues may pose risks to human health. In this study, laying hens received experimental feed containing flubendazole or tylosin at cross contamination levels of 2.5, 5, and 10% of the therapeutic dose. Eggs were collected daily and analysis of the whole egg, egg white, and egg yolk was performed using liquid chromatography tandem mass spectrometry. Highest concentrations of the parent molecule flubendazole, as well as the hydrolyzed and the reduced metabolite, were detected in egg yolk. Residue concentrations of the parent molecule were higher compared with those of the metabolites in all egg matrices. No tylosin residue concentrations were detected above the limit of quantification for all concentration groups and in all egg matrices. Neither molecule exceeded the set maximum residue limits. PMID- 22499886 TI - Phase feeding in a big-bird production scenario: effect on growth performance, yield, and fillet dimension. AB - Phase feeding (PF) has been effective at maintaining broiler growth while reducing production cost, but the effect on different broiler strains and sex has not been assessed. An experiment was conducted using 4 commercial broiler strains grown up to 63 d of age (n = 1,440), comparing a PF approach to an industry-type diet. At d 17, birds began either the industry or PF regimen. The industry regimen consisted of average industry nutrient levels with periods from 17 to 32 d, 32 to 40 d, 40 to 49 d, and 49 d to the end of trial. For PF, diets were prepared that contained Lys, sulfur amino acids, and Thr levels matching the predicted requirements for birds at the beginning (high nutrient density) and end (low nutrient density) of PF. Pelleted high and low nutrient density diets were blended to produce rations containing amino acid levels that matched the predicted PF requirements over 2-d intervals. Weight gain, feed intake, and feed efficiency were calculated through d 58. Birds were commercially processed at 59, 61, or 63 d; yield and fillet dimensions were measured. Phase feeding did not effect weight gain or feed intake of broilers during the overall growth period (17-58 d). For most strains, PF did not effect final BW, yield, or fillet dimensions. However, strain and sex had greater effects on growth performance, yields, and fillet dimensions. Strains B and D had greater breast yield than strains A and C. Reduced feed costs ($0.01 to $0.04 per kilogram of gain, depending on strain) were observed for all strains with PF for the overall growth period (17-58 d). Therefore, potential savings on feed costs are possible for all strains used in this study with the incorporation of the PF regimen. PMID- 22499887 TI - Phase feeding in a small-bird production scenario: effect on growth performance, yield, and fillet dimension. AB - Phase feeding (PF) has been effective at maintaining broiler growth while reducing production cost, but the effect on different broiler strains grown in a small-bird production scenario has not been assessed. Three strains of commercial broilers were fed a diet containing average industry nutrient levels from 0 to 18 d. From 18 to 32 d, birds were fed either diets with average industry nutrient levels or diets with phased levels of amino acids. For PF, diets were prepared that contained Lys, sulfur amino acids, and Thr levels matching the predicted requirements for birds at the beginning (high nutrient density) and end (low nutrient density) of PF. Pelleted high and low nutrient-density diets were blended to produce rations containing amino acid levels that matched the predicted PF requirements over 2-d intervals, and diets were switched every other day during PF. Treatments were replicated in 6 pens; each pen contained 15 males and 15 females. Weight gain, feed intake, and feed efficiency were calculated. All birds were commercially processed; yield and fillet dimensions were calculated. Differences among strain BW were noted on d 0, 18, 32, and at processing. Males weighed more than females on d 18 (excluding strain C), 32, and the day of processing. Weight gain was affected by strain (P < 0.05) but not by feeding regimen in the overall growth period (18-39 d). Feed efficiency was improved by PF in strains B and C during the overall growth period. Fillet yield was improved with PF for strain B, and there were no significant differences between PF and industry fillet yields for the other 2 strains. Phase feeding had no effect on fillet dimensions, and there was little effect of strain. These results suggest that different strains may vary in their response to PF, although performance was similar or better in PF birds compared with birds fed the industry diet, regardless of strain. PMID- 22499888 TI - Interaction of hen production type, age, and temperature on laying pattern and egg quality. AB - The effect of production type (layer vs. broiler breeder), age (onset and end of laying cycle), and temperature (20 and 28 degrees C) on various aspects of the egg production process and quality was evaluated. Highly significant differences were detected between laying hens and broiler breeders (P <= 0.001) in all production parameters. Similarly, age significantly affected rate of lay (P <= 0.001; 75.4% for young vs. 62.6% for old), mean sequence length (P <= 0.001; 7.7 d for young vs. 2.6 d for old), and time of oviposition (P <= 0.001). However, there was no effect of temperature on rate of lay, sequence length, or feed intake. Significant interactions between hen type and age were apparent in rate of lay (P <= 0.001), sequence length (P <= 0.001), and time of oviposition (P <= 0.001). A significant interaction between production type and age (P <= 0.015) was evident in egg weight, but egg component proportions were dependent only on hen type. Egg shape index was significantly affected by age (P <= 0.004), by temperature (P <= 0.028), and an interaction between type and age (P <= 0.001). Specific gravity declined with age (P <= 0.035) and increasing temperature (P <= 0.013). PMID- 22499891 TI - Patient-centered integrated motor imagery delivered in the home with telerehabilitation to improve walking after stroke. AB - BACKGROUND AND PURPOSE: This case report describes the clinical reasoning process used to examine a person after stroke and intervene with a novel integrated motor imagery treatment designed for the rehabilitation of walking and delivered in the home through telerehabilitation. The integrated motor imagery treatment consisted of patient-centered goal setting and physical practice combined with motor and motivational imagery. CASE DESCRIPTION: The patient was a 38-year-old woman who had had a diffuse left subarachnoid hemorrhagic stroke 10 years earlier. She lived independently in an assisted living complex and carried a straight cane during long walks or in unfamiliar environments. Examination revealed a slow gait speed, reduced walking endurance, and decreased balance confidence. Although she was in the chronic phase, patient-centered integrated motor imagery was predicted to improve her community mobility. Treatment sessions of 45 to 60 minutes were held 3 times per week for 4 weeks. The practiced tasks included transitioning from sitting to standing, obstacle clearance, and navigation in interior and exterior environments; these tasks were first executed and then imagined at ratios of 1:5. Task execution allowed the creation of a scene based on movement observation. Imagery scenarios were customized to address the patient's goals and observed movement problems. Motivational elements of arousal, problem solving, and reward were embedded in the imagery scenarios. Half of the sessions were provided on site, and the remaining sessions were delivered remotely. Seven sessions were delivered by the clinician in the home, and 5 sessions were delivered using telerehabilitation. OUTCOMES: Improvements in motor imagery ability, gait parameters, and balance were observed after training. Most gains were retained at the 3-month follow-up. Compared with on-site delivery, the telerehabilitation sessions resulted in less therapist travel time and cost, as well as shorter therapy sessions. DISCUSSION: The delivery of integrated motor imagery practice for walking recovery was feasible both on site and remotely. PMID- 22499892 TI - Severe autoimmune insulin resistance--a case report. PMID- 22499893 TI - Osmotic stress and cryoinjury of koala sperm: an integrative study of the plasma membrane, chromatin stability and mitochondrial function. AB - This study investigated whether cryopreservation-induced injury to koala spermatozoa could be explained using an experimental model that mimics the structural and physiological effects of osmotic flux. DNA labelling after in situ nick translation of thawed cryopreserved spermatozoa revealed a positive correlation (r=0.573; P<0.001; n=50) between the area of relaxed chromatin in the nucleus and the degree of nucleotide labelling. While the chromatin of some spermatozoa increased more than eight times its normal size, not all sperm nuclei with relaxed chromatin showed evidence of nucleotide incorporation. Preferential staining associated with sperm DNA fragmentation (SDF) was typically located in the peri-acrosomal and peripheral regions of the sperm head and at the base of the spermatozoa where it appear to be 'hot spots' of DNA damage following cryopreservation. Results of the comparative effects of anisotonic media and cryopreservation on the integrity of koala spermatozoa revealed that injury induced by exposure to osmotic flux, essentially imitated the results found following cryopreservation. Plasma membrane integrity, chromatin relaxation and SDF appeared particularly susceptible to extreme hypotonic environments. Mitochondrial membrane potential (MMP), while susceptible to extreme hypo- and hypertonic environments, showed an ability to rebound from hypertonic stress when returned to isotonic conditions. Koala spermatozoa exposed to 64 mOsm/kg media showed an equivalent, or more severe, degree of structural and physiological injury to that of frozen-thawed spermatozoa, supporting the hypothesis that cryoinjury is principally associated with a hypo-osmotic effect. A direct comparison of SDF of thawed cryopreserved spermatozoa and those exposed to a 64 mOsm/kg excursion showed a significant correlation (r=0.878; P<0.05; n=5); however, no correlation was found when the percentage of sperm with relaxed chromatin was compared. While a cryo-induced osmotic injury model appears to explain post-thaw changes in koala SDF, the mechanisms resulting in relaxed chromatin require further study. A lack of correlation between the percentage of sperm with relaxed chromatin and SDF suggests that the timing of these pathologies are asynchronous. We propose an integrative model of cryo-induced osmotic injury that involves a combination of structural damage (rupture of membrane) and oxidative stress that first leads to the reduction of MMP and the relaxation of chromatin, which is then ultimately followed by an increase in DNA fragmentation. PMID- 22499894 TI - Neutrophils in atherosclerosis: alarmin evidence of a hit and run? PMID- 22499895 TI - Epigenetic mechanisms of metabolic memory in diabetes. PMID- 22499896 TI - Estrogen-related receptor-gamma: conductor of muscle angiogenesis through conversion of fast- to slow-twitch fibers? PMID- 22499897 TI - You can't run from inflammation: lower extremity ischemia, hypoxia signaling, and macrophage subtypes. PMID- 22499898 TI - Changing the diet to make more mitochondria and protect the heart. PMID- 22499899 TI - The secret life of fat suggests new therapeutic targets. PMID- 22499900 TI - The intersection between aging and cardiovascular disease. AB - The average lifespan of humans is increasing, and with it the percentage of people entering the 65 and older age group is growing rapidly and will continue to do so in the next 20 years. Within this age group, cardiovascular disease will remain the leading cause of death, and the cost associated with treatment will continue to increase. Aging is an inevitable part of life and unfortunately poses the largest risk factor for cardiovascular disease. Although numerous studies in the cardiovascular field have considered both young and aged humans, there are still many unanswered questions as to how the genetic pathways that regulate aging in model organisms influence cardiovascular aging. Likewise, in the molecular biology of aging field, few studies fully assess the role of these aging pathways in cardiovascular health. Fortunately, this gap is beginning to close, and these two fields are merging together. We provide an overview of some of the key genes involved in regulating lifespan and health span, including sirtuins, AMP-activated protein kinase, mammalian target of rapamycin, and insulin-like growth factor 1 and their roles regulating cardiovascular health. We then discuss a series of review articles that will appear in succession and provide a more comprehensive analysis of studies carried out linking genes of aging and cardiovascular health, and perspectives of future directions of these two intimately linked fields. PMID- 22499901 TI - Mitochondria and cardiovascular aging. AB - Old age is a major risk factor for cardiovascular diseases. Several lines of evidence in experimental animal models have indicated the central role of mitochondria both in lifespan determination and in cardiovascular aging. In this article we review the evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and biogenesis as well as the crosstalk between mitochondria and cellular signaling in cardiac and vascular aging. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans (left ventricular hypertrophy, fibrosis and diastolic dysfunction), while the phenotype of vascular aging include endothelial dysfunction, reduced vascular elasticity, and chronic vascular inflammation. Both cardiac and vascular aging involve neurohormonal signaling (eg, renin angiotensin, adrenergic, insulin-IGF1 signaling) and cell-autonomous mechanisms. The potential therapeutic strategies to improve mitochondrial function in aging and cardiovascular diseases are also discussed, with a focus on mitochondrial targeted antioxidants, calorie restriction, calorie restriction mimetics, and exercise training. PMID- 22499904 TI - Creativity at the interface. PMID- 22499909 TI - European debt crisis. Research cuts will cause 'exodus' from Spain. PMID- 22499910 TI - European debt crisis. Greece eyes CERN, ESA cuts to plug budget gap. PMID- 22499902 TI - Contribution of impaired mitochondrial autophagy to cardiac aging: mechanisms and therapeutic opportunities. AB - The prevalence of cardiovascular disease increases with advancing age. Although long-term exposure to cardiovascular risk factors plays a major role in the etiopathogenesis of cardiovascular disease, intrinsic cardiac aging enhances the susceptibility to developing heart pathologies in late life. The progressive decline of cardiomyocyte mitochondrial function is considered a major mechanism underlying heart senescence. Damaged mitochondria not only produce less ATP but also generate increased amounts of reactive oxygen species and display a greater propensity to trigger apoptosis. Given the postmitotic nature of cardiomyocytes, the efficient removal of dysfunctional mitochondria is critical for the maintenance of cell homeostasis, because damaged organelles cannot be diluted by cell proliferation. The only known mechanism whereby mitochondria are turned over is through macroautophagy. The efficiency of this process declines with advancing age, which may play a critical role in heart senescence and age-related cardiovascular disease. The present review illustrates the putative mechanisms whereby alterations in the autophagic removal of damaged mitochondria intervene in the process of cardiac aging and in the pathogenesis of specific heart diseases that are especially prevalent in late life (eg, left ventricular hypertrophy, ischemic heart disease, heart failure, and diabetic cardiomyopathy). Interventions proposed to counteract cardiac aging through improvements in macroautophagy (eg, calorie restriction and calorie restriction mimetics) are also presented. PMID- 22499911 TI - Marine science. Ocean's deep, dark trenches to get their moment in the spotlight. PMID- 22499912 TI - Circadian rhythms. Sleep study suggests triggers for diabetes and obesity. PMID- 22499903 TI - Growth factors, nutrient signaling, and cardiovascular aging. AB - Growth factors regulated by specific macronutrients have been shown to promote aging and accelerate mortality in the majority of the organisms studied. In particular, the enzymes activated by growth hormone, insulin, and insulin-like growth factor-1 in mammals and their orthologs in simple model organisms represent perhaps the best-understood proteins involved in the aging process. Dietary restriction, which reduces the level of insulin-like growth factor-1 and of other growth factors, has been associated with protection from diabetes, cancer, and cardiovascular diseases, and deficiencies in growth hormone signaling and insulin-like growth factor-1 are strongly associated with protection from cancer and diabetes in both mice and humans; however, their role in cardiac function and cardiovascular diseases is controversial. Here, we review the link between growth factors, cardiac function, and heart disease with focus on the cardioprotective and sensitizing effect of growth factors in both model organisms and humans. PMID- 22499914 TI - Physics. Sparks fly over shoestring test of 'holographic principle'. PMID- 22499913 TI - Tropical Diseases. Mystery disease haunts region. PMID- 22499915 TI - Lunar and planetary science conference. Icy-hot Mercury's water pinned down in the dark. PMID- 22499916 TI - Lunar and planetary science conference. Tougher times for any life on an early Mars? PMID- 22499917 TI - Lunar and planetary science conference. Snapshots from the meeting. PMID- 22499918 TI - Lunar and planetary science conference. The young solar system took a one-two punch? PMID- 22499919 TI - Outsourced psychiatry: remote support. PMID- 22499920 TI - Outsourced psychiatry: experts still relevant. PMID- 22499921 TI - Sound and fury, clarified. PMID- 22499925 TI - Science statesmanship. PMID- 22499924 TI - Cultural diversity in a global society. PMID- 22499926 TI - Research priorities. Shining light into black boxes. PMID- 22499927 TI - Neuroscience. Revitalizing remyelination--the answer is circulating. PMID- 22499928 TI - Planetary science. The strangest terrestrial planet. PMID- 22499929 TI - Computer science. Beyond Turing's machines. PMID- 22499930 TI - Computer science. Dusting off the Turing test. PMID- 22499931 TI - Cell biology. ESCRTing DNA at the cleavage site during cytokinesis. PMID- 22499932 TI - Neuroscience. Wiping drug memories. PMID- 22499933 TI - Psychology. Monkey see, monkey read. PMID- 22499934 TI - Retrospective. F. Sherwood Rowland (1927-2012). PMID- 22499935 TI - Computational biology. Does it compute? Introduction. PMID- 22499936 TI - Computational biology. Virtual hot spots. PMID- 22499937 TI - Cell polarity: quantitative modeling as a tool in cell biology. AB - Among a number of innovative approaches that have modernized cell biology, modeling has a prominent yet unusual place. One popular view is that we progress linearly, from conceptual to ever more detailed models. We review recent discoveries of cell polarity mechanisms, in which modeling played an important role, to demonstrate that the experiment-theory feedback loop requires diverse models characterized by varying levels of biological detail and mathematical complexity. We argue that a quantitative model is a tool that has to fit an experimental study, and the model's value should be judged not by how complex and detailed it is, but by what could be learned from it. PMID- 22499938 TI - Integrating genomes. AB - As genomic sequencing projects attempt ever more ambitious integration of genetic, molecular, and phenotypic information, a specialization of genomics has emerged, embodied in the subdiscipline of computational genomics. Models inherited from population genetics, phylogenetics, and human disease genetics merge with those from graph theory, statistics, signal processing, and computer science to provide a rich quantitative foundation for genomics that can only be realized with the aid of a computer. Unleashed on a rapidly increasing sample of the planet's 10(30) organisms, these analyses will have an impact on diverse fields of science while providing an extraordinary new window into the story of life. PMID- 22499940 TI - Computational approaches to developmental patterning. AB - Computational approaches are breaking new ground in understanding how embryos form. Here, we discuss recent studies that couple precise measurements in the embryo with appropriately matched modeling and computational methods to investigate classic embryonic patterning strategies. We include signaling gradients, activator-inhibitor systems, and coupled oscillators, as well as emerging paradigms such as tissue deformation. Parallel progress in theory and experiment will play an increasingly central role in deciphering developmental patterning. PMID- 22499939 TI - Using gene expression noise to understand gene regulation. AB - Phenotypic variation is ubiquitous in biology and is often traceable to underlying genetic and environmental variation. However, even genetically identical cells in identical environments display variable phenotypes. Stochastic gene expression, or gene expression "noise," has been suggested as a major source of this variability, and its physiological consequences have been topics of intense research for the last decade. Several recent studies have measured variability in protein and messenger RNA levels, and they have discovered strong connections between noise and gene regulation mechanisms. When integrated with discrete stochastic models, measurements of cell-to-cell variability provide a sensitive "fingerprint" with which to explore fundamental questions of gene regulation. In this review, we highlight several studies that used gene expression variability to develop a quantitative understanding of the mechanisms and dynamics of gene regulation. PMID- 22499941 TI - Observation of skyrmions in a multiferroic material. AB - A magnetic skyrmion is a topologically stable particle-like object that appears as a vortex-like spin texture at the nanometer scale in a chiral-lattice magnet. Skyrmions have been observed in metallic materials, where they are controllable by electric currents. Here, we report the experimental discovery of magnetoelectric skyrmions in an insulating chiral-lattice magnet Cu(2)OSeO(3) through Lorentz transmission electron microscopy and magnetic susceptibility measurements. We find that the skyrmion can magnetically induce electric polarization. The observed magnetoelectric coupling may potentially enable the manipulation of the skyrmion by an external electric field without losses due to joule heating. PMID- 22499942 TI - Demonstration of entanglement of electrostatically coupled singlet-triplet qubits. AB - Quantum computers have the potential to solve certain problems faster than classical computers. To exploit their power, it is necessary to perform interqubit operations and generate entangled states. Spin qubits are a promising candidate for implementing a quantum processor because of their potential for scalability and miniaturization. However, their weak interactions with the environment, which lead to their long coherence times, make interqubit operations challenging. We performed a controlled two-qubit operation between singlet triplet qubits using a dynamically decoupled sequence that maintains the two qubit coupling while decoupling each qubit from its fluctuating environment. Using state tomography, we measured the full density matrix of the system and determined the concurrence and the fidelity of the generated state, providing proof of entanglement. PMID- 22499943 TI - Topological transitions in metamaterials. AB - Light-matter interactions can be controlled by manipulating the photonic environment. We uncovered an optical topological transition in strongly anisotropic metamaterials that results in a dramatic increase in the photon density of states-an effect that can be used to engineer this interaction. We describe a transition in the topology of the iso-frequency surface from a closed ellipsoid to an open hyperboloid by use of artificially nanostructured metamaterials. We show that this topological transition manifests itself in increased rates of spontaneous emission of emitters positioned near the metamaterial. Altering the topology of the iso-frequency surface by using metamaterials provides a fundamentally new route to manipulating light-matter interactions. PMID- 22499944 TI - Ferroelectric columnar liquid crystal featuring confined polar groups within core shell architecture. AB - Ferroelectric liquid crystals are materials that have a remnant and electrically invertible polar order. Columnar liquid crystals with a ferroelectric nature have potential use in ultrahigh-density memory devices, if electrical polarization occurs along the columnar axis. However, columnar liquid crystals having an axial nonzero polarization at zero electric field and its electrical invertibility have not been demonstrated. Here, we report a ferroelectric response for a columnar liquid crystal adopting a core-shell architecture that accommodates an array of polar cyano groups confined by a hydrogen-bonded amide network with an optimal strength. Under an applied electric field, both columns and core cyano groups align unidirectionally, thereby developing an extremely large macroscopic remnant polarization. PMID- 22499945 TI - Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress. AB - Withdrawal of nutrients triggers an exit from the cell division cycle, the induction of autophagy, and eventually the activation of cell death pathways. The relation, if any, among these events is not well characterized. We found that starved mouse embryonic fibroblasts lacking the essential autophagy gene product Atg7 failed to undergo cell cycle arrest. Independent of its E1-like enzymatic activity, Atg7 could bind to the tumor suppressor p53 to regulate the transcription of the gene encoding the cell cycle inhibitor p21(CDKN1A). With prolonged metabolic stress, the absence of Atg7 resulted in augmented DNA damage with increased p53-dependent apoptosis. Inhibition of the DNA damage response by deletion of the protein kinase Chk2 partially rescued postnatal lethality in Atg7(-/-) mice. Thus, when nutrients are limited, Atg7 regulates p53-dependent cell cycle and cell death pathways. PMID- 22499946 TI - Mechanism of voltage gating in potassium channels. AB - The mechanism of ion channel voltage gating-how channels open and close in response to voltage changes-has been debated since Hodgkin and Huxley's seminal discovery that the crux of nerve conduction is ion flow across cellular membranes. Using all-atom molecular dynamics simulations, we show how a voltage gated potassium channel (KV) switches between activated and deactivated states. On deactivation, pore hydrophobic collapse rapidly halts ion flow. Subsequent voltage-sensing domain (VSD) relaxation, including inward, 15-angstrom S4-helix motion, completes the transition. On activation, outward S4 motion tightens the VSD-pore linker, perturbing linker-S6-helix packing. Fluctuations allow water, then potassium ions, to reenter the pore; linker-S6 repacking stabilizes the open pore. We propose a mechanistic model for the sodium/potassium/calcium voltage gated ion channel superfamily that reconciles apparently conflicting experimental data. PMID- 22499947 TI - miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay. AB - microRNAs (miRNAs) regulate gene expression through translational repression and/or messenger RNA (mRNA) deadenylation and decay. Because translation, deadenylation, and decay are closely linked processes, it is important to establish their ordering and thus to define the molecular mechanism of silencing. We have investigated the kinetics of these events in miRNA-mediated gene silencing by using a Drosophila S2 cell-based controllable expression system and show that mRNAs with both natural and engineered 3' untranslated regions with miRNA target sites are first subject to translational inhibition, followed by effects on deadenylation and decay. We next used a natural translational elongation stall to show that miRNA-mediated silencing inhibits translation at an early step, potentially translation initiation. PMID- 22499948 TI - A memory retrieval-extinction procedure to prevent drug craving and relapse. AB - Drug use and relapse involve learned associations between drug-associated environmental cues and drug effects. Extinction procedures in the clinic can suppress conditioned responses to drug cues, but the extinguished responses typically reemerge after exposure to the drug itself (reinstatement), the drug associated environment (renewal), or the passage of time (spontaneous recovery). We describe a memory retrieval-extinction procedure that decreases conditioned drug effects and drug seeking in rat models of relapse, and drug craving in abstinent heroin addicts. In rats, daily retrieval of drug-associated memories 10 minutes or 1 hour but not 6 hours before extinction sessions attenuated drug induced reinstatement, spontaneous recovery, and renewal of conditioned drug effects and drug seeking. In heroin addicts, retrieval of drug-associated memories 10 minutes before extinction sessions attenuated cue-induced heroin craving 1, 30, and 180 days later. The memory retrieval-extinction procedure is a promising nonpharmacological method for decreasing drug craving and relapse during abstinence. PMID- 22499949 TI - Orthographic processing in baboons (Papio papio). AB - Skilled readers use information about which letters are where in a word (orthographic information) in order to access the sounds and meanings of printed words. We asked whether efficient processing of orthographic information could be achieved in the absence of prior language knowledge. To do so, we trained baboons to discriminate English words from nonsense combinations of letters that resembled real words. The results revealed that the baboons were using orthographic information in order to efficiently discriminate words from letter strings that were not words. Our results demonstrate that basic orthographic processing skills can be acquired in the absence of preexisting linguistic representations. PMID- 22499951 TI - Impact of genetic diagnosis on clinical management of patients with congenital heart disease: cilia point the way. PMID- 22499952 TI - Relationship between high-sensitivity C-reactive protein and risk factors in patients with peripheral arterial disease--a cross-sectional study. AB - We investigated whether patients with peripheral arterial disease (PAD) with various serum levels of high-sensitivity C-reactive protein (hsCRP) differ in the frequency of atherosclerotic risk factors. Among 388 patients, hsCRP levels were (1) low, <1 mg/L, in 41 (10.6%) participants; (2) medium, from 1 to 3 mg/L, in 152 (39.2%) participants, and (3) high, >3 mg/L, in 195 (50.2%) individuals. According to multivariate logistic regression analysis, in comparison with patients with hsCRP level <=3.0 mg/L, those with higher hsCRP levels had more frequently a severe form of PAD (gangrene, P ranged from .045 to <.001; ankle brachial index <=.40, P = .059) and had more frequently some of atherosclerotic risk factors (metabolic syndrome, P = .007; hypertension, P = .013; abdominal obesity, P = .007; high levels of uric acid, P = .022; high level of fibrinogen, P < .001; and depression, P = .015). PMID- 22499950 TI - High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. AB - BACKGROUND: Patients with congenital heart disease (CHD) and heterotaxy show high postsurgical morbidity/mortality, with some developing respiratory complications. Although this finding is often attributed to the CHD, airway clearance and left right patterning both require motile cilia function. Thus, airway ciliary dysfunction (CD) similar to that of primary ciliary dyskinesia (PCD) may contribute to increased respiratory complications in heterotaxy patients. METHODS AND RESULTS: We assessed 43 CHD patients with heterotaxy for airway CD. Videomicrocopy was used to examine ciliary motion in nasal tissue, and nasal nitric oxide (nNO) was measured; nNO level is typically low with PCD. Eighteen patients exhibited CD characterized by abnormal ciliary motion and nNO levels below or near the PCD cutoff values. Patients with CD aged >6 years show increased respiratory symptoms similar to those seen in PCD. Sequencing of all 14 known PCD genes in 13 heterotaxy patients with CD, 12 without CD, 10 PCD disease controls, and 13 healthy controls yielded 0.769, 0.417, 1.0, and 0.077 novel variants per patient, respectively. One heterotaxy patient with CD had the PCD causing DNAI1 founder mutation. Another with hyperkinetic ciliary beat had 2 mutations in DNAH11, the only PCD gene known to cause hyperkinetic beat. Among PCD patients, 2 had known PCD causing CCDC39 and CCDC40 mutations. CONCLUSIONS: Our studies show that CHD patients with heterotaxy have substantial risk for CD and increased respiratory disease. Heterotaxy patients with CD were enriched for mutations in PCD genes. Future studies are needed to assess the potential benefit of prescreening and prophylactically treating heterotaxy patients for CD. PMID- 22499954 TI - Multiple potential regulatory sites of TLR4 activation induced by LPS as revealed by novel inhibitory human TLR4 mAbs. AB - Recognition of LPS by the toll-like receptor 4 (TLR4)/MD-2 complex is a trigger of innate immune defense against bacterial invasion. However, excessive immune activation by this receptor complex causes septic shock and autoimmunity. Manipulation of TLR4 signaling represents a potential therapy that would avoid the detrimental consequences of unnecessary immune responses. In this study, we established two novel mAbs that inhibit LPS-induced human TLR4 activation. HT52 and HT4 mAbs inhibited LPS-induced nuclear factor-kappaB activation in TLR4/MD-2 expressing Ba/F3-transfected cells and cytokine production and up-regulation of CD86 in the human cell line U373 and PBMCs. These inhibitory activities were stronger than that of HTA125 mAb, which we previously reported. Immunofluorescent and biochemical studies using TLR4 deletion mutants revealed that HT52 and HT4 recognized spatially distinct regions on TLR4 irrespective of MD-2 association. The HT52 and HTA125 epitopes were localized within aa 50-190, while the HT4 epitope was formed only by the full length of TLR4. In addition, we demonstrated that HT52 and HT4 failed to compete with LPS for binding to TLR4/MD-2 but inhibited LPS-induced TLR4 internalization. Inhibitory activities were not due to the interaction with the Fcgamma receptor CD32. Our finding that binding of mAbs to at least two distinct regions on TLR4 inhibits LPS-dependent activation provides a novel method for manipulating TLR4 activation and also a rationale for designing drugs targeted to TLR4. PMID- 22499955 TI - Open vertical vein in non-obstructed supracardiac TAPVC: merits and fate. AB - Data of 18 patients who underwent surgical repair of non-obstructed supracardiac total anomalous pulmonary venous connection between January 2007 and March 2011 were reviewed. The vertical vein was left patent in all patients as an elective surgical strategy. There was no operative mortality in patients with or without preoperative pulmonary infection, but there were significant differences in postoperative airway pressures, ventilation time, intensive care unit and hospital stay between the 2 groups. None of the patients demonstrated any flow in the vertical vein over a 30-day follow-up period. One patient had a mild anastomotic stricture and pulmonary venous hypoplasia. Operative repair of supracardiac total anomalous pulmonary venous connection can be carried out successfully without ligation of the vertical vein, and this strategy possibly reduces early postoperative morbidity and mortality, with no adverse effects detected in the short to midterm follow-up. PMID- 22499956 TI - Factor VII for excessive bleeding following congenital heart disease surgery. AB - Recombinant activated factor VII may be effective in patients with severe bleeding following congenital heart disease surgery requiring cardiopulmonary bypass. From August 2009 through June 2011, 13 patients (median age, 5 months) were given recombinant activated factor VII for severe bleeding after open heart surgery, preventing sternal closure 2 h after completion of cardiopulmonary bypass, or chest tube drainage >10 mL . kg(-1) . h(-1) for 2 h. The median dose was 75 MUg . kg(-1). The response was positive if postoperative bleeding decreased, permitting sternal closure in the operating room, or if there was >50% decrease in chest tube drainage. The 3 patients who received factor VIIa in the operating room had successful sternal closure within 1 h. Of the 10 patients who received factor VIIa in the intensive care unit, drainage decreased to <50% in 1 h in 6 cases, and a second dose was required in 4. None required surgical reexploration. There were 4 deaths, none was related to bleeding. Nine patients were discharged (median hospital stay, 29 days) and were doing well after 3 months. There were no thrombotic complications. Recombinant activated factor VII may be an effective rescue therapy for severe postoperative hemorrhage. PMID- 22499957 TI - Short crossclamp heart transplantation: a modified technique. AB - Prolongation of the ischemic time in heart transplantation adversely affects the performance of the donor heart. We compared the impact of ischemic time in 30 patients who had the conventional bicaval method with declamping just after the last anastomosis (group A) and 28 who had a modified short crossclamp technique with declamping after left atrial stump, aorta, and inferior vena caval anastomosis (group B). In the operating room, 4 (13.3%) group A patients need one inotropic and 26 (86.6%) need 2 or more; one (3.3%) needed intraaortic balloon pumping. In group B, one inotropic was used in 7 (25%) patients, 4 (14.2%) need 2 or more, and 17 (60.7%) needed no inotropic. Mean crossclamp time was 80.5 +/- 4.7 min in group A and 62.4 +/- 5.8 min in group B. Weaning from bypass was faster in group B. Transesophageal echocardiography at the end of the operation showed more complete de-airing in group B. There were no significant differences in intensive care unit stay or the incidence of postoperative neurologic complications between the 2 groups. Easier separation from bypass, even without a hot shot, and better echocardiographic systolic parameters postoperatively are the advantages of this modified technique. PMID- 22499958 TI - Quantification of diagnostic accuracy using nitrate enhanced Tc-99m sestamibi gated myocardial SPECT in assessing myocardial viability: prospective analysis. AB - The aim of this prospective study was to assess myocardial viability with nitrate enhanced Tc-99m sestamibi gated single-photon emission computed tomography in patients with known coronary artery disease. We enrolled 48 consecutive patients (39 men, 9 women) aged 24-82 years, with coronary artery disease and history of myocardial infarction. A Tc-99m sestamibi study was conducted at rest as baseline, followed by a nitrate-enhanced study the next day. Of 960 segments analyzed, 244 of 480 in the left anterior descending coronary artery territory showed viability on the baseline study, and 276 were viable according to the nitrate-enhanced study. Similarly, of 192 right coronary segments analyzed, 148 showed viability on the baseline study compared to 153 on the nitrate study. Of 288 left circumflex territory segments analyzed, 206 showed viability on the baseline study compared to 241 on the nitrate study. The overall improvement of viability with the nitrate study was 12.04%. On the gated studies, the overall improvement with nitrate was 2.02%. The gated study also allowed grading of wall motion and thickness. It was concluded that nitrate-augmented Tc-99m sestamibi myocardial imaging significantly improved the detection of hibernating myocardium, with gated images further improving the accuracy of detection in borderline cases. PMID- 22499959 TI - Clinical outcomes of open heart surgery in patients with atopic dermatitis. AB - Atopic dermatitis is a skin condition often complicated by colonization with Staphylococcus aureus, which increases the risk of infective endocarditis, skin cellulitis and osteomyelitis. Positive cultures for Staphylococcus aureus are obtained from 70% to 80% of wounds in patients with mediastinitis. Thus sternotomy carries increased risk of mediastinitis in patients with atopic dermatitis. We retrospectively reviewed 25 patients with atopic dermatitis who underwent cardiac surgery via a median sternotomy or thoracotomy from January 1997 to September 2010 at our institution. Postoperative mediastinitis due to methicillin-resistant Staphylococcus aureus was found in 3 patients who had a median sternotomy. They were ultimately discharged in good condition. No mediastinitis occurred in patients undergoing thoracotomy. Mediastinitis may occur due to direct exposure of the bone marrow to methicillin-resistant Staphylococcus aureus in patients with atopic dermatitis whose skin is colonized with such bacteria. Thoracotomy may be a better surgical approach in patients with atopic dermatitis who require thoracic surgery. PMID- 22499960 TI - Beating heart as an alternative for closure of secundum atrial septal defect. AB - We repaired secundum atrial septal defect in 135 consecutive patients from February 2003 to December 2010. There were 98 females and 37 males, with a mean age of 22.92 +/- 17.46 years (range, 3-55 years). To prevent myocardial dysfunction and systemic embolism caused by the conventional technique, the operation was performed with a beating heart under cardiopulmonary bypass in 63 cases, and compared the data retrospectively with cases treated under aortic crossclamping, to determine the safety of the beating-heart technique and to evaluate risk factors for embolism in stroke patients. Patient age and size of defect were similar in both groups. There was no death and no residual shunt in either group. The mean cardiopulmonary bypass time was 36.84 +/- 9.8 min in the beating-heart group and 43.13 +/- 16.7 min in the crossclamp group. The ejection fraction and the incidence of postoperative arrhythmia were similar in both groups. There were no differences in blood products transfused, intensive care unit stay, hospital stay, or perioperative morbidity. In our experience, the results of the beating-heart technique were not different from the conventional technique. PMID- 22499961 TI - Preoperative intra-aortic balloon pump in high-risk coronary bypass grafting. AB - Prophylactic intra-aortic balloon pumping prior to coronary artery bypass grafting is employed variably despite some evidence to support its use. The aim of this study was to describe the characteristics, preoperative balloon pump utilization, and outcomes of high-risk patients undergoing coronary artery bypass. The study cohort included all patients in the Australian National Cardiac Surgery Database over an 8 year period. The primary outcome was 30-day mortality adjusted for preoperative illness severity. Coronary artery bypass was performed in 18,662 patients including 2,348 (12.6%) identified as high-risk. Of these high risk patients, 359 (15.3%) received a balloon pump preoperatively. For high-risk patients, 30-day mortality was significantly higher in those with a preoperative balloon pump than in those who did not receive a preoperative balloon pump (15.3% vs. 4.9%). After adjusting for preoperative illness severity, there was no significant association between preoperative balloon pumping and 30-day mortality. High-risk patients represent a significant proportion of those undergoing coronary artery bypass grafting. Despite their increased risk of postoperative mortality, only a small minority currently receive a preoperative balloon pump. After adjusting for illness severity, there was no significant association between preoperative balloon pumping and 30-day mortality, although we could not rule out a 20% reduction in mortality. PMID- 22499962 TI - Assessment of the standard pediatric unfractionated heparin dosing protocol. AB - Current dosing guidelines for unfractionated heparin therapy in pediatric patients are based on recommendations of only one study that evaluated a weight based dosing nomogram. To test the hypothesis that adhering to a strict weight based nomogram yields better therapeutic results in pediatric patients, we prospectively monitored 25 consecutive pediatric patients who received unfractionated heparin based on the nomogram, and compared them to control patients whose treatment did not follow the standard nomogram. The mean time needed to achieve the target activated partial thromboplastin time was significantly shorter in the study group than the control group (18.32 +/- 9.98 vs. 43.8 +/- 30 h). A higher proportion of the study group reached the target activated partial thromboplastin time at 12, 24, and 36 h, compared to controls: 44% vs. 6%, 72% vs. 28%, 100% vs. 58%, respectively. Within the study group, patients under 1 year of age needed more time to achieve the target activated partial thromboplastin time than those over 1-year old. The performance of the standard dosing nomogram was excellent with regard to early anticoagulation target achievement, without increasing the risk of bleeding. Further studies are warranted to refine this nomogram for pediatric patients who are less than 1-year old. PMID- 22499963 TI - Repair of acute type A aortic dissection: results in 100 patients. AB - To determine short- and long-term outcomes after repair of type A aortic dissection, we reviewed data of 100 consecutive patients (64 men; mean age, 63 +/ 12.2 years) who underwent acute type A aortic dissection repair between January 2000 and June 2008. They were divided into group A, open anastomosis (circulatory arrest; n = 59) and group B, closed anastomosis (no circulatory arrest; n = 41). Aortic valve re-suspension or replacement was performed in 77 patients, aortic root replacement in 29, and aortic arch procedures in 31. The median follow-up was 2.8 years (range, 0-8.6 years). The 30-day mortality was 14%; 16.9% in group A and 9.8% in group B. None of the 23 variables analyzed to determine predictors of death or stroke was significant on multivariate analysis. Postoperatively, there was no difference between the 2 groups with respect to stroke, sepsis, renal failure, multiorgan failure, or reoperation. Overall actuarial survival at 1, 3, 5, and 8 years was not significantly different between the 2 groups. Considerable morbidity is still associated with repair of type A aortic dissection, despite a significant improvement in mortality. PMID- 22499964 TI - Coronary artery bypass and carotid endarterectomy with mild hypothermia. AB - The approach to treatment in patients with both coronary artery disease and major carotid disease is controversial. We analyzed our results of concomitant coronary artery bypass and carotid endarterectomy. Twenty-three patients aged 58 years or older underwent elective concomitant coronary artery bypass and carotid endarterectomy with mild hypothermia (32 degrees C). Demographic characteristics and preoperative risk factors were recorded prospectively. Data were collected during a mean follow-up of 22 +/- 9 months. The mean age of the patients was 71 +/- 7 years. Twenty-one patients were in New York Heart Association class I to II, and 2 were in class III. Early mortality was 8.6%. There was no early postoperative stroke. Mean intensive care unit stay was 64.5 +/- 30.5 h. One (4.3%) patient had a stroke one year later. One- and 2-year survival rates were estimated to be 86.9% and 73.9%, respectively. Although concomitant coronary and carotid artery surgery remains controversial, cooling to 32 degrees C provided good results in this challenging group of patients managed by one team. PMID- 22499965 TI - Nutritional status of patients undergoing chemoradiotherapy for lung cancer. AB - Impaired nutrition is an important predictor of perioperative complications in lung cancer patients, and preoperative chemoradiotherapy increases the risk of such complications. The goal of this study was to assess the effect of an immune enhancing diet on nutritional status in patients undergoing lung resection after chemoradiotherapy. We compared the preoperative nutritional status in 15 patients with lung cancer undergoing lung resection without chemoradiotherapy and 15 who had chemoradiotherapy. Body mass index and lymphocyte counts were lower in patients who had chemoradiotherapy. Although there was no difference in the rate of postoperative morbidity between groups, the chemoradiotherapy patients were more likely to have severe complications postoperatively. After chemoradiotherapy in 12 patients, 6 received oral Impact for 5 days, and 6 had a conventional diet before surgery. Oral intake of Impact for 5 days before surgery modified the decrease in transferrin and lymphocytes after the operation. Preoperative immunonutrition may improve the perioperative nutritional status after induction chemoradiotherapy in patients undergoing lung cancer surgery, and reduce the severity of postoperative complications. These potential benefits need to be confirmed in a randomized controlled trial. PMID- 22499966 TI - Management of complicated parapneumonic effusion and empyema using different treatment modalities. AB - To evaluate the efficacy of the 3 treatment modalities (intrapleural instillation of streptokinase, video-assisted thoracoscopic surgery, thoracotomy and decortication) in the management of complicated parapneumonic effusion and empyema, a prospective study was conducted between January 2008 and June 2010. The 69 patients (52 men and 17 women, aged 18-50 years) were divided into 3 groups: 20 patients underwent intrapleural administration of streptokinase, 25 underwent video-assisted thoracoscopic surgery, and 24 had thoracotomy and decortication. Perioperative variables, mortality, and procedure success were compared among groups. In all groups, preoperative variables were well matched for age, sex, and clinical stage according to Light's classification. No allergic or hemorrhagic complication occurred. Operative time was significantly shorter in patients undergoing video-assisted thoracoscopic surgery. There was no intraoperative complication in the 2 surgically treated groups. Length of hospital stay and duration of chest drainage were significantly shorter after video-assisted thoracoscopic surgery. Procedure success was 50% after streptokinase, 92% after video-assisted thoracoscopic surgery, and 100% after thoracotomy and decortication. There was no perioperative mortality in any group. Video-assisted thoracoscopic surgery is a safe and effective treatment modality for complicated parapneumonic effusion and pleural empyema. Earlier intervention with video-assisted thoracoscopic surgery may produce better clinical results. PMID- 22499967 TI - Thoracic surgery mortality and morbidity in a university hospital. AB - This study was undertaken to determine the mortality and morbidity of lung resection surgery in the 2,415-bed Siriraj University Hospital, Thailand, and compare them to rates in similar facilities (benchmarking). Demographic and clinical data as well as perioperative outcome variables of patients who underwent elective thoracic surgery from January 2006 to May 2010 were reviewed retrospectively. There were 558 cases of lung resection. Mortality was 0.9% and perioperative morbidity was 8.2%. Univariate analysis identified age >75 years, history of pulmonary disease, preoperative rehabilitation consultation, and operative time >2 h as predictors of mortality and morbidity. With less statistical power, hypertension, cancer, peripheral vascular disease, and thoracotomy also contributed to perioperative outcome. Comparisons with data from the current literature place our results in the range of good quality. Following benchmarking criteria, perioperative outcomes after lung resection surgery in our hospital are good. To further improve quality, we will pay special attention to patients with advanced age and history of pulmonary disease. PMID- 22499968 TI - Percutaneous iatrogenic coronary fistula closure in heart transplant recipient. AB - A 61-year-old man with ischemic cardiomyopathy underwent orthotopic heart transplantation. On routine coronary angiography 1 year later, a huge fistula was seen between the left anterior descending coronary artery and the right ventricle. When the patient developed symptoms of ischemia 8 years later, the fistula was successfully closed percutaneously, using a covered stent. PMID- 22499969 TI - Coronary surgery in a hemophiliac with continuous factor VIII replacement. AB - In the past, hemophiliacs rarely underwent cardiac surgery because of limited lifespan. As blood transfusions have become safer, hemophiliacs are living longer and becoming more susceptible to diseases that afflict the elderly, such as coronary atherosclerosis. We describe the hematologic management of a patient with hemophilia A who underwent coronary artery bypass surgery. PMID- 22499970 TI - Aortic root replacement for Valsalva sinus aneurysm with lupus erythematosus. AB - A 76-year-old man with systemic lupus erythematosus was found to have an aneurysm of the right sinus of Valsalva. Aortic root replacement with a stentless bioprosthesis, using a full root technique, was successfully performed. The pathological findings of the excised aortic valve were not secondary to atherosclerosis, inflammatory or infectious disease, but seemed to be compatible with those previously reported in a case of systemic lupus erythematosus. PMID- 22499971 TI - Fracture-dislocation of humeral head with intrathoracic displacement. AB - Intrathoracic displacement of fractured head of the humerus is a very rare injury. We describe a case of such injury in a 48-old-year lady who presented after a simple fall. She required chest drainage and a thoracotomy to remove the head of the humerus. She subsequently had shoulder hemiarthroplasty with a good outcome. PMID- 22499972 TI - Severe bronchoconstriction due to sarcoid-like reaction to lung cancer. AB - Chest radiography in a 59-year-old woman with recurrent pneumonia showed infiltrates in her left upper lung field. Fiberoptic bronchoscopy and chest computed tomography revealed severe constriction in the upper bronchus and a nodule in the left upper lobe. After lobectomy, adenocarcinoma was confirmed, with multiple non-caseating granulomas in the lung parenchyma and lymph nodes. Bronchial constriction was thought to be due to a sarcoid-like reaction secondary to lung cancer, leading to granuloma formation. PMID- 22499973 TI - Successful removal of expandable metallic stent in a patient with lung cancer. AB - A 64-year-old man, who had received chemoradiation therapy for stage IIIB non small-cell lung cancer, underwent stent insertion with a covered expandable metallic stent for post-radiation bronchial stenosis. Stenosis due to formation of granulation tissue at the distal stent site resulted in critical respiratory failure. The stent was removed after 43 months, using rigid bronchoscopy. PMID- 22499974 TI - Catamenial pneumothorax with multiple transdiaphragmatic hepatic herniations. PMID- 22499975 TI - Pulmonary artery dissection: a potential pitfall of multi-detector tomography. PMID- 22499976 TI - Primary cardiac lymphoma. PMID- 22499977 TI - Thickened ascending aortic wall mimicking intramural hematoma. PMID- 22499978 TI - Response to heart failure therapy: ventricular volume changes vs. shape changes. AB - The prolate ellipsoid left ventricular geometry is crucial for its unique contraction and relaxation patterns. Perturbations in optimal cardiac function preceding overt heart failure ensue when this ellipsoid shape assumes a more spherical configuration; this is the stage when therapy should be intensified. The dynamic shape changes during the cardiac cycle in valvular regurgitation, when ventricular volumes are within the normal range, have proved that shape changes are clearly dissociated from volume changes in the early stages. In advanced heart failure, several therapeutic interventions to decrease the ventricular equator and hence the volume, have been tried with variable success. However, the ventricular shape may still be spherical, leading to suboptimal function. The aim in any therapy for heart failure should therefore be to achieve near normal left ventricular anatomy and physiology, with shape assessment as the surrogate marker of therapeutic success. PMID- 22499979 TI - Double-line closure of anterior postinfarction ventricular septal perforation. AB - We describe a modified patch closure technique for repairing subacute anterior ventricular septal perforation. Through a left ventriculotomy, a larger double layered planar patch is secured with double suture lines to close the defect and cover the ventricular septum. This modification is simple and easy, and may help to avoid a residual shunt. PMID- 22499980 TI - Mitral approach in prosthetic endocarditis with calcified annulus and abscess. AB - Abscess resection and prosthesis reimplantation is the only effective treatment for mitral prosthesis endocarditis with extensive annular abscess, but it has high morbidity and mortality when associated with severe mitral annular calcification in the atrial and ventricular walls. We describe a technique that allows repair of the abscess cavity, reconstruction of the annulus, and implantation of a new mitral prosthesis when there is severe adjacent myocardial calcification, so decreasing the reoperation risk. PMID- 22499981 TI - Repair of total anomalous pulmonary venous return to the coronary sinus. AB - An alternative technique for channeling the pulmonary venous return towards the left atrium in patients with total anomalous pulmonary venous return to the coronary sinus is described. The advantages of this technique, which avoids the use of patch material and prevents arrhythmias, are discussed. PMID- 22499982 TI - Radiation-induced constrictive pericarditis and waffle procedure. PMID- 22499983 TI - Inter-examiner reliability in meibomian gland dysfunction assessment. AB - PURPOSE: We evaluated inter-examiner reliability in grading of clinical variables associated with meibomian gland dysfunction (MGD) in real-time examination versus a graded digital image. METHODS: Meibography grading of meibomian gland atrophy and acini appearance, and slit-lamp grading of lid debris and telangiectasias were conducted on 410 post-menopausal women. Meibography and slit-lamp photos were captured digitally and saved for analysis by a masked examiner. Gland atrophy was graded as a proportion of partial glands in the lower lid, and acini appearance by the presence/absence of grape-like clusters. Lid debris and telangiectasias were graded based on severity and quantity from the same image, respectively. Observed agreement and weighted kappas (kappa(w)) with 95% confidence intervals (CI) determined the degree of inter-examiner reliability between grading of these clinical variables in real-time examination and digital photographs using a multiple-point categorical scale. RESULTS: Observed agreement was determined for telangiectasias (40.6%), lid debris (50.9%), gland dropout (42.8%), and acini appearance (54.5%). Inter-examiner reliability for the four clinical outcomes ranged from fair agreement for acini appearance (kappa(w) = 0.23, 95% CI = 0.14-0.32) and lid debris (kappa(w) = 0.24, 0.16-0.32) to moderate agreement for gland dropout (kappa(w) = 0.50, 0.40-0.59) and telangiectasias (kappa(w) = 0.47, 0.39-0.55). Conclusions. Gland dropout and potentially lid telangiectasia grading from a photograph are more representative of grading in a real-time examination compared to acini appearance and lid debris. Alternative grading scales and/or clinical variables associated with MGD should be addressed in future studies. PMID- 22499984 TI - Spectral-domain optical coherence tomography as a noninvasive method to assess damaged and regenerating adult zebrafish retinas. AB - PURPOSE: These experiments assessed the ability of spectral-domain optical coherence tomography (SD-OCT) to accurately represent the structural organization of the adult zebrafish retina and reveal the dynamic morphologic changes during either light-induced damage and regeneration of photoreceptors or ouabain-induced inner retinal damage. METHODS: Retinas of control dark-adapted adult albino zebrafish were compared with retinas subjected to 24 hours of constant intense light and recovered for up to 8 weeks or ouabain-damaged retinas that recovered for up to 3 weeks. Images were captured and the measurements of retinal morphology were made by SD-OCT, and then compared with those obtained by histology of the same eyes. RESULTS: Measurements between SD-OCT and histology were very similar for the undamaged, damaged, and regenerating retinas. Axial measurements of SD-OCT also revealed vitreal morphology that was not readily visualized by histology. CONCLUSIONS: SD-OCT accurately represented retinal lamination and photoreceptor loss and recovery during light-induced damage and subsequent regeneration. SD-OCT was less accurate at detecting the inner nuclear layer in ouabain-damaged retinas, but accurately detected the undamaged outer nuclear layer. Thus, SD-OCT provides a noninvasive and quantitative method to assess the morphology and the extent of damage and repair in the zebrafish retina. PMID- 22499985 TI - Differential optical density of subretinal spaces. AB - PURPOSE: We investigated the optical density characteristics of 3subretinal spaces in neovascular age-related macular degeneration (AMD), diabetic retinopathy (DR), rhegmatogenous retinal detachment (RRD), central serous retinopathy (CSR), retinoschisis (RS), and pseudophakic cystoids macular edema (PCME). METHODS: Patients in whom subretinal fluid (SRF) was detected by optical coherence tomography (OCT), and whose earliest OCT scans showed sufficient SRF for sampling that did not include tissue edges, were chosen for study. The highest quality B-scan containing SRF (as graded by the OCT image acquisition software) was analyzed. Optical density measurements were obtained using ImageJ, an open code Java-based image processing software. RESULTS: The diagnoses of the 71 patients who met the inclusion criteria were AMD in 17, DR in 7, RRD in 18, CSR in 17, RS in 8, and PCME in 4. Optical density ratios (ODRs) were calculated as SRF OD divided by vitreous OD. ODRs were significantly higher in patients with AMD, DR, CSR, and PCME than in those with RRD and RS. No significant difference in vitreous reflectivity was detected between the former and latter patients. CONCLUSIONS: The finding that disease states produce significant changes in optical density ratios calls for further investigation of the possible usefulness of the parameter in differentiating between disease states, determining the outcome of various retinal diseases, and designing therapies aimed at treating the disease by correcting the abnormal density. PMID- 22499986 TI - Agreement of retinal nerve fiber layer color codes between Stratus and Cirrus OCT according to glaucoma severity. AB - PURPOSE: We assessed the agreement of retinal nerve fiber layer (RNFL) color codes between Stratus and Cirrus optical coherence tomography (OCT) according to the glaucoma severity. METHODS: We analyzed 184 eyes from 144 subjects with glaucoma and 40 normal subjects. Glaucoma was categorized into three subgroups according to mean deviation of visual field. The agreement of RNFL color code according to the glaucoma severity was assessed using Cohen's kappa value. Red or yellow color codes were defined as abnormal results, while green or white were defined as normal. Disagreement frequency of abnormal color code displayed by 2 OCTs was evaluated. RESULTS: The agreement of RNFL color code was fair to good in all subgroups (kappa 0.288-0.887) except for the nasal quadrant, 1 to 4, and the 9 o'clock sectors. In all severity groups, the frequency of disagreement was less than 10% for average, temporal, and inferior sectors. However, Stratus OCT displayed abnormal results, while Cirrus showed normal results for nasal sectors with considerable disagreement proportion (severe 22.5%, moderate 13.2%, and early 13.6%). The disagreement tended to be pronounced in severe glaucoma. On the other hand, Cirrus OCT displayed abnormal results, while Stratus showed normal results for superior sectors (severe 10.0%, moderate 10.5%, and early 15.2%). The frequency was higher in early glaucoma. CONCLUSIONS: Considerable color code disagreements were observed in nasal and superior sectors, and the proportion was different according to the glaucoma severity. Color codes of two OCTs could not be considered interchangeable. PMID- 22499987 TI - Morphometric analysis of aqueous humor outflow structures with spectral-domain optical coherence tomography. AB - PURPOSE: To describe morphometric details of the human aqueous humor (AH) outflow microvasculature visualized with 360-degree virtual castings during active AH outflow in cadaver eyes and to compare these structures with corrosion casting studies. METHODS: The conventional AH outflow pathways of donor eyes (n = 7) and eyes in vivo (n = 3) were imaged with spectral-domain optical coherence tomography (SD-OCT) and wide-bandwidth superluminescent diode array during active AH outflow. Digital image contrast was adjusted to isolate AH microvasculature, and images were viewed in a 3D viewer. Additional eyes (n = 3) were perfused with mock AH containing fluorescent tracer microspheres to compare microvasculature patterns. RESULTS: Observations revealed components of the conventional outflow pathway from Schlemm's canal (SC) to the superficial intrascleral venous plexus (ISVP). The superficial ISVP in both our study and corrosion casts were composed of interconnected venules (10-50 MUm) forming a hexagonal meshwork. Larger radial arcades (50-100 MUm) drained the region nearest SC and converged with larger tortuous vessels (>100 MUm). A 360-degree virtual casting closely approximated corrosion casting studies. Tracer studies corroborated our findings. Tracer decorated several larger vessels (50-100 MUm) extending posteriorly from the limbus in both raw and contrast-enhanced fluorescence images. Smaller tracer labeled vessels (30-40 MUm) were seen branching between larger vessels and exhibited a similar hexagonal network pattern. CONCLUSIONS: SD-OCT is capable of detailed morphometric analysis of the conventional outflow pathway in vivo or ex vivo with details comparable to corrosion casting techniques. PMID- 22499988 TI - Fas ligand-Fas signaling participates in light-induced apoptotic death in photoreceptor cells. AB - PURPOSE: We investigated the function of Fas in photoreceptors. METHODS: Postmortem human eyes and mouse-derived photoreceptor cells (661W) were examined for Fas expression by in situ hybridization and immunofluorescence. 661W cells were treated with FasL or Fas agonistic antibody, or exposed to light with/without pharmacological manipulation of Fas signaling, followed by apoptosis detection by TUNEL, immunofluorescence and fluorescence activated cell scanning (FACS). Fractionated cellular extracts were used to detect protein expression or protein phosphorylation after immunoprecipitation by Western blot. RESULTS: Fas was expressed in the photoreceptor layer of human retina. Fas and a cleaved form of FasL were found on the cell surface of 661W cells. Treatment with FasL or Fas agonistic antibody induced apoptosis in 661W cells. Blocking the activity of FasL or administration of caspase-8 inhibitor z-IETD inhibited light-induced apoptosis. However, it simultaneously caused induction of necroptosis, which could be blocked by the receptor-interacting protein 1 (RIP1) inhibitor, necrostatin-1. Light exposure in the presence of z-IETD caused hyper phosphorylation of RIP1. Light exposure did not elevate the expression of Fas, FasL, or the Fas-associated death domain adaptor protein (FADD). Cells or conditioned medium after light exposure induced apoptosis in dark-adapted cells, which could be attenuated by blockade of Fas. CONCLUSIONS: Fas has a pro apoptotic role in photoreceptors. Under light stress, soluble and membrane-bound FasL can bind to Fas, inducing apoptosis via a paracrine mechanism. Although blocking Fas signaling inhibits apoptosis, it does not improve the overall photoreceptor survival due to a compensatory activation of necroptosis. Hence, prevention of photoreceptor loss from retinal photo-oxidative stress should target Fas and RIP1. PMID- 22499989 TI - A leukocyte-mimetic magnetic resonance imaging contrast agent homes rapidly to activated endothelium and tracks with atherosclerotic lesion macrophage content. AB - OBJECTIVE: Endothelial cell activation is an important mediator of monocyte recruitment to sites of vascular inflammation. We hypothesized that high-affinity dual-ligand microparticles of iron oxide (MPIO), targeted to P-selectin and vascular cell adhesion molecule-1 (PV-MPIO), would identify activated endothelial cells during atherosclerosis progression. METHODS AND RESULTS: In vivo magnetic resonance imaging in apolipoprotein E-deficient mice showed rapid binding of PV MPIO to the aortic root, which was maximal 30 minutes post-MPIO injection and maintained at 60 minutes. Minimal binding was observed for control IgG-MPIO. Intensely low magnetic resonance signal areas, corresponding to PV-MPIO binding, were detected early (14 weeks), during foam cell formation. Contrast effects increased at 20 weeks during fibrofatty lesion development (P<0.05), but reduced by 30 weeks (P<0.01). Across all lesion severities, magnetic resonance imaging contrast effects correlated with lesion macrophage area quantified by immunohistochemistry (R=0.53; P<0.01). Near-infrared fluorescently labeled PV MPIO were shown, by flow cytometry, to bind only activated endothelial cells and not to macrophages. Using en face immunofluorescence, we further demonstrate selective PV-MPIO accumulation at atherosclerosis-susceptible sites, with minimal binding to atherosclerosis-spared regions. CONCLUSIONS: This high-affinity leukocyte-mimetic magnetic resonance imaging agent reveals endothelial activation. PV-MPIO demonstrate exceptionally rapid in vivo steady state accumulation, providing conspicuous magnetic resonance contrast effects that can be objectively quantified. In atherosclerosis progression, PV-MPIO tracked closely with the burden and distribution of plaque macrophages, not merely plaque size. On a biocompatible platform, this approach has potential for quantitative magnetic resonance imaging of inflammatory disease activity. PMID- 22499990 TI - Resolvin D1 limits polymorphonuclear leukocyte recruitment to inflammatory loci: receptor-dependent actions. AB - OBJECTIVE: Resolvin D1 (RvD1) limits neutrophil recruitment during acute inflammation and is derived from omega-3 docosahexaenoic acid to promote catabasis. The contribution of its specific receptors, the lipoxin A(4)/Annexin A1 receptor formyl-peptide receptor 2 (FPR2/ALX) and the orphan receptor G protein-coupled receptor 32 (GPR32) are of considerable interest. METHODS AND RESULTS: RvD1 reduced human polymorphonuclear leukocytes recruitment to endothelial cells under shear conditions as quantified using a flow chamber system. Receptor-specific antibodies blocked these anti-inflammatory actions of RvD1, with low (1 nmol/L) concentrations sensitive to GPR32 blockade, while the higher (10 nmol/L) concentration appeared FPR2/ALX-specific. Interestingly, polymorphonuclear leukocytes surface expression of FPR2/ALX but not GPR32 increased following activation with pro-inflammatory stimuli, corresponding with secretory vesicle mobilization. Lipid mediator metabololipidomics carried out with 24-hour exudates revealed that RvD1 in vivo gave a significant reduction in the levels of a number of pro-inflammatory mediators including prostaglandins and leukotriene B(4). These actions of RvD1 were abolished in fpr2 null mice. CONCLUSIONS: Pro-resolving lipid mediators and their receptors, such as RvD1 and the 2 G-protein-coupled receptors, studied here regulate resolution and may provide new therapeutic strategies for diseases with a vascular inflammatory component. PMID- 22499992 TI - Inhibition of development of abdominal aortic aneurysm by glycolysis restriction. AB - OBJECTIVE: The mechanisms underlying abdominal aortic aneurysm development remain unknown. We hypothesized that acceleration of glucose metabolism with the upregulation of glucose transporters is associated with abdominal aortic aneurysm development. METHODS AND RESULTS: Enhanced accumulation of the modified glucose analogue 18 fluoro-deoxyglucose by positron emission tomography imaging in the human abdominal aortic aneurysm was associated with protein expressions of glucose transporters-1 and -3, assessed by Western blot. The magnitude of glucose transporter-3 expression was correlated with zymographic matrix metalloproteinase 9 activity. Intraperitoneal administration of glycolysis inhibitor with 2 deoxyglucose significantly attenuated the dilatation of abdominal aorta induced by periaortic application of CaCl(2) in C57BL/6J male mice or reduced the aneurysmal formation in angiotensin II-infused apolipoprotein E knockout male mice. In monocytic cell line induced by phorbol 12-myristate 13-acetate or ex vivo culture obtained from human aneurysmal tissues, 2-deoxyglucose abrogated the matrix metalloproteinase-9 activity and interleukin-6 expression in these cells/tissues. Moreover, 2-deoxyglucose attenuated the survival/proliferation of monocytes and the adherence of them to vascular endothelial cells. CONCLUSIONS: This study suggests that the enhanced glycolytic activity in aortic wall contributes to the pathogenesis of aneurysm development. In addition, pharmacological intervention in glycolytic activity might be a potential therapeutic target for the disorder. PMID- 22499991 TI - Downregulation of endothelial microRNA-200b supports cutaneous wound angiogenesis by desilencing GATA binding protein 2 and vascular endothelial growth factor receptor 2. AB - OBJECTIVE: MicroRNAs (miRs) regulate angiogenesis by posttranscriptional silencing of target genes. The significance of angiostatic miR-200b in switching on skin wound angiogenesis was tested. METHODS AND RESULTS: Wounding caused imminent and transient downregulation of miR-200b in dermal wound-edge endothelial cells. Derailing this injury response by lentiviral delivery of miR 200b in vivo impaired wound angiogenesis. Computational prediction, target reporter luciferase assay, and Western blot analysis provided first evidence that miR-200b targets globin transcription factor binding protein 2 (GATA2) and vascular endothelial growth factor receptor 2 (VEGFR2). Overexpression of GATA2 or VEGFR2 in endothelial cells rescued the angiostatic effect of miR-200b in vitro. Downregulation of miR-200b derepressed GATA2 and VEGFR2 expression to switch on wound angiogenesis, which was disrupted in diabetic wounds. Treatment of endothelial cells with tumor necrosis factor-alpha, a proinflammatory cytokine abundant in diabetic wounds, induced miR-200b expression, silenced GATA2 and VEGFR2, and suppressed angiogenesis. These outcomes were attenuated using anti miR-200b strategy. Neutralization of tumor necrosis factor-alpha in the diabetic wounds improved wound angiogenesis and closure, which was accompanied by downregulation of miR-200b expression and desilencing of GATA2 and VEGFR2. CONCLUSIONS: Injury-induced repression of miR-200b turned on wound angiogenesis. In mice with diabetes mellitus,excessive tumor necrosis factor-alpha induced miR 200b blunting proangiogenic functions of GATA2 and VEGFR2. PMID- 22499993 TI - Evidence supporting a key role of Lp-PLA2-generated lysophosphatidylcholine in human atherosclerotic plaque inflammation. AB - OBJECTIVE: To determine whether the level of lysophosphatidylcholine (lysoPC) generated by lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with severity of inflammation in human atherosclerotic plaques. Elevated plasma Lp PLA2 is associated with increased cardiovascular risk. Lp-PLA2 inhibition reduces atherosclerosis. Lp-PLA2 hydrolyzes low-density lipoprotein-oxidized phospholipids generating lysoPCs. According to in vitro studies, lysoPCs are proinflammatory but the association between their generation and plaque inflammation remains unknown. METHODS AND RESULTS: Inflammatory activity in carotid plaques (162 patients) was determined immunohistochemically and by analyzing cytokines in homogenates (multiplex immunoassay). LysoPCs were quantified using mass spectrometry and Lp-PLA2 and the lysoPC metabolite lysophosphatidic acid (LPA) by ELISA. There was a strong correlation among lysoPC 16:0, 18:0, 18:1, LPA, and Lp-PLA2 in plaques. LysoPC 16:0, 18:0, 18:1, LPA, and Lp-PLA2 correlated with interleukin-1beta, interleukin-6, monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta, regulated on activation normal T-cell expressed and secreted, and tumor necrosis factor-alpha in plaques. High lysoPC and Lp-PLA2 correlated with increased plaque macrophages and lipids and with low content of smooth muscle cells, whereas LPA only correlated with plaque macrophages. Lp-PLA2, lysoPC 16:0, 18:0, and 18:1, but not LPA were higher in symptomatic than in asymptomatic plaques. CONCLUSIONS: The associations among Lp-PLA2, lysoPCs, LPA, and proinflammatory cytokines in human plaques suggest that lysoPCs play a key role in plaque inflammation and vulnerability. Our findings support Lp-PLA2 inhibition as a possible strategy for the prevention of cardiovascular disease. PMID- 22499994 TI - Red blood cells play a role in reverse cholesterol transport. AB - OBJECTIVE: Reverse cholesterol transport (RCT) involves the removal of cholesterol from peripheral tissue for excretion in the feces. Here, we determined whether red blood cells (RBCs) can contribute to RCT. METHODS AND RESULTS: We performed a series of studies in apolipoprotein AI-deficient mice where the high-density lipoprotein-mediated pathway of RCT is greatly diminished. RBCs carried a higher fraction of whole blood cholesterol than plasma in apolipoprotein AI-deficient mice, and as least as much of the labeled cholesterol derived from injected foam cells appeared in RBCs compared with plasma. To determine whether RBCs mediate RCT to the fecal compartment, we measured RCT in anemic and control apolipoprotein AI-deficient mice and found that anemia decreased RCT to the feces by over 35% after correcting for fecal mass. Transfusion of [(3)H]cholesterol-labeled RBCs led to robust delivery of the labeled cholesterol to the feces in apolipoprotein AI-deficient hosts. In wild type mice, the majority of the blood cholesterol mass, as well as [(3)H]cholesterol derived from the injected foam cells, was found in plasma, and anemia did not significantly alter RCT to the feces after correction for fecal mass. CONCLUSIONS: The RBC cholesterol pool is dynamic and facilitates RCT of peripheral cholesterol to the feces, particularly in the low high-density lipoprotein state. PMID- 22499995 TI - Comparison of two carbapenem-resistant Klebsiella pneumoniae clones: from a contained outbreak in a paediatric population and from a national epidemic. AB - OBJECTIVES: A refractory epidemic of carbapenem-resistant Klebsiella pneumoniae (CRKP) emerged in the adult population at our hospital in 2005, as in most Israeli hospitals. Contemporaneously, a different clone of CRKP caused an easily contained outbreak in a paediatric long-term care facility (LTCF) in Jerusalem. While previously identified host-related risk factors for colonization by these organisms undoubtedly contributed to these outbreaks, it is very likely that bacterial factors might be crucial in explaining the striking differences in transmissibility between the implicated strains. We therefore sought bacterial factors associated with these different epidemiological behaviours. METHODS: Seven CRKP isolated at our hospital and the LTCF during 2008-09 were examined by antimicrobial susceptibility testing and PFGE, and further analyses of these two clones was done using multilocus sequence typing and competition experiments. Plasmids were analysed by conjugation, restriction mapping, PCR and sequencing. RESULTS: Both clones were multidrug resistant and harboured identical plasmids carrying the bla(KPC-3) gene. The hyper-transmissible epidemic clone carried additional antibiotic resistance genes and hosted an additional plasmid. The clone from the LTCF did not demonstrate hyper-transmissible properties despite its presence in an institution of a type commonly plagued by the epidemic clone. Competition assays showed the more easily contained strain to be fitter. CONCLUSIONS: These findings suggest that neither the presence of the plasmid carrying the bla(KPC-3) gene nor relative survival fitness account for the hyper transmissibility of the epidemic strain. The role of patient age in susceptibility to colonization by the epidemic strain should be investigated. PMID- 22499996 TI - OXA-48-like carbapenemases: the phantom menace. AB - OXA-48-type carbapenem-hydrolysing class D beta-lactamases are increasingly reported in enterobacterial species. To date, six OXA-48-like variants have been identified, with OXA-48 being the most widespread. They differ by a few amino acid substitutions or deletions (one to five amino acids). The enzymes hydrolyse penicillins at a high level and carbapenems at a low level, sparing broad spectrum cephalosporins, and are not susceptible to beta-lactamase inhibitors. When combining permeability defects, OXA-48-like producers may exhibit a high level of resistance to carbapenems. OXA-163 is an exception, hydrolysing broad spectrum cephalosporins but carbapenems at a very low level, and being susceptible to beta-lactamase inhibitors. The bla(OXA-48)-type genes are always plasmid-borne and have been identified in association with insertion sequences involved in their acquisition and expression. The current spread of the bla(OXA 48) gene is mostly linked to the dissemination of a single IncL/M-type self transferable plasmid of 62 kb that does not carry any additional resistance gene. OXA-48-type carbapenemases have been identified mainly from North African countries, the Middle East, Turkey and India, those areas constituting the most important reservoirs; however, occurrence of OXA-48 producers in European countries is now well documented, with some reported hospital outbreaks. Since many OXA-48-like producers do not exhibit resistance to broad-spectrum cephalosporins, or only decreased susceptibility to carbapenems, their recognition and detection can be challenging. Adequate screening and detection methods are therefore required to prevent and control their dissemination. PMID- 22499997 TI - Pharmacokinetics, tissue distribution and immunomodulatory effect of intralipid formulation of nystatin in mice. AB - OBJECTIVES: We developed a novel lipid formulation of nystatin suitable for parenteral administration, nystatin-intralipid (NYT-IL), with antifungal activity and reduced toxicity in mice. We investigated the pharmacokinetics, tissue distribution and immunomodulatory effect of NYT-IL in mice. METHODS: Nystatin levels in serum and organs were determined using HPLC after NYT-IL or nystatin administration in mice. The levels of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) and the anti inflammatory cytokine interleukin 10 (IL-10) produced by splenocytes from mice injected with NYT-IL or nystatin were evaluated by an ELISA assay. RESULTS: Injection of NYT-IL resulted in similar levels and similar kinetics of nystatin in serum, higher concentrations in the liver and lower concentrations in the kidneys, in comparison with nystatin injection. Injection of mice with NYT-IL yielded higher levels of IL-10 than that of nystatin, whereas the levels of TNF alpha and IFN-gamma induced by NYT-IL were lower than those elicited by nystatin. CONCLUSIONS: Since polyene treatment is associated with nephrotoxicity, lower levels of nystatin in the kidneys following NYT-IL injection suggest the possibility of reduced toxicity. As the acute infusion-related adverse effects associated with polyene treatment are considered to be induced by pro inflammatory cytokines, a higher level of anti-inflammatory and lower levels of pro-inflammatory cytokines elicited by NYT-IL administration suggest the possibility of amelioration of such effects. In summary, the altered pharmacokinetics, tissue distribution and immune response due to the use of this intralipid formulation of nystatin merit further research towards the development of a therapeutic agent against invasive mycoses. PMID- 22499998 TI - Piperacillin/tazobactam (TazocinTM) seems to be no longer responsible for false positive results of the galactomannan assay. AB - OBJECTIVES: Galactomannan (GM) testing is extremely useful for diagnosing invasive aspergillosis in high-risk patients, but false-positive results have been reported in patients treated with piperacillin/tazobactam. The aims of this study are to test if the recent piperacillin/tazobactam (TazocinTM; Pfizer) preparation still contains GM, and if serum GM positivity in haematopoietic stem cell transplant (HSCT) recipients receiving piperacillin/tazobactam can be attributed to this treatment. PATIENTS AND METHODS: Serum samples obtained from 1 October 2009 to 31 October 2010 from HSCT recipients for GM testing were analysed. The difference in the rate of positive results (defined as GM >= 0.5) in patients receiving and not receiving piperacillin/tazobactam was evaluated. Piperacillin/tazobactam vials from randomly selected batches were tested. RESULTS: Of 1606 samples drawn in the absence of piperacillin/tazobactam therapy, 25 (1.6%) tested positive for GM versus 10 of 394 samples (2.5%) drawn while on piperacillin/tazobactam (P = 0.18). The median GM result of samples drawn on piperacillin/tazobactam was slightly higher than that of samples drawn in the absence of piperacillin/tazobactam (0.141 versus 0.122; P < 0.001). All 90 piperacillin/tazobactam vials from 30 randomly selected batches tested negative for GM, with a median GM value of 0.057 (range: 0.011-0.320). CONCLUSIONS: Although some residual GM might still be present in piperacillin/tazobactam, currently available brand piperacillin/tazobactam preparations seem no longer responsible for false-positive GM results. PMID- 22499999 TI - A novel multidrug resistance plasmid isolated from an Escherichia coli strain resistant to aminoglycosides. AB - OBJECTIVES: Previous studies have reported several different plasmids that confer multidrug resistance (MDR) including resistance to aminoglycosides. In this study, we investigated the aminoglycoside resistance patterns for 224 Escherichia coli isolates from diseased chickens and ducks in China, characterized a novel MDR plasmid, and collected prevalence data on similar resistance plasmids. METHODS: Antibiotic susceptibilities were determined using disc diffusion and the microdilution method. The plasmid pXZ was analysed by restriction fragment length polymorphism (RFLP) with EcoRI and SalI, and sequenced. The prevalence of similar resistance plasmids was assessed by multiplex PCR and by RFLP analysis. RESULTS: Among the 224 E. coli isolates, 189 (84.4%) were resistant to streptomycin, 125 (55.8%) were resistant to kanamycin, 116 (51.8%) were resistant to gentamicin, 106 (47.3%) were resistant to neomycin and 98 (43.8%) were resistant to amikacin. Among the 224 E. coli isolates, 17 contained a plasmid with the MDR-encoding region of pXZ, which showed high-level resistance to aminoglycosides (MICs of gentamicin and amikacin >= 512 mg/L). The plasmid pXZ was digested into five fragments by EcoRI and six fragments by SalI. The plasmid pXZ was a circular DNA molecule of 76635 bp with a 51.65% guanine + cytosine content and included four resistance genes (rmtB, fosA3, bla(TEM-1) and bla(CTX-M-24)). CONCLUSIONS: A novel MDR plasmid, pXZ, harbouring four resistance genes (rmtB, fosA3, bla(TEM-1) and bla(CTX-M)) was identified. To our knowledge, this is the first report of an aminoglycoside resistance plasmid harbouring the fosA3 gene. PMID- 22500000 TI - ChemSpot: a hybrid system for chemical named entity recognition. AB - MOTIVATION: The accurate identification of chemicals in text is important for many applications, including computer-assisted reconstruction of metabolic networks or retrieval of information about substances in drug development. But due to the diversity of naming conventions and traditions for such molecules, this task is highly complex and should be supported by computational tools. RESULTS: We present ChemSpot, a named entity recognition (NER) tool for identifying mentions of chemicals in natural language texts, including trivial names, drugs, abbreviations, molecular formulas and International Union of Pure and Applied Chemistry entities. Since the different classes of relevant entities have rather different naming characteristics, ChemSpot uses a hybrid approach combining a Conditional Random Field with a dictionary. It achieves an F(1) measure of 68.1% on the SCAI corpus, outperforming the only other freely available chemical NER tool, OSCAR4, by 10.8 percentage points. AVAILABILITY: ChemSpot is freely available at: http://www.informatik.hu berlin.de/wbi/resources. PMID- 22500002 TI - Bpipe: a tool for running and managing bioinformatics pipelines. AB - SUMMARY: Bpipe is a simple, dedicated programming language for defining and executing bioinformatics pipelines. It specializes in enabling users to turn existing pipelines based on shell scripts or command line tools into highly flexible, adaptable and maintainable workflows with a minimum of effort. Bpipe ensures that pipelines execute in a controlled and repeatable fashion and keeps audit trails and logs to ensure that experimental results are reproducible. Requiring only Java as a dependency, Bpipe is fully self-contained and cross platform, making it very easy to adopt and deploy into existing environments. AVAILABILITY AND IMPLEMENTATION: Bpipe is freely available from http://bpipe.org under a BSD License. PMID- 22500001 TI - optiCall: a robust genotype-calling algorithm for rare, low-frequency and common variants. AB - MOTIVATION: Existing microarray genotype-calling algorithms adopt either SNP-by SNP (SNP-wise) or sample-by-sample (sample-wise) approaches to calling. We have developed a novel genotype-calling algorithm for the Illumina platform, optiCall, that uses both SNP-wise and sample-wise calling to more accurately ascertain genotypes at rare, low-frequency and common variants. RESULTS: Using data from 4537 individuals from the 1958 British Birth Cohort genotyped on the Immunochip, we estimate the proportion of SNPs lost to downstream analysis due to false quality control failures, and rare variants misclassified as monomorphic, is only 1.38% with optiCall, in comparison to 3.87, 7.85 and 4.09% for Illuminus, GenoSNP and GenCall, respectively. We show that optiCall accurately captures rare variants and can correctly account for SNPs where probe intensity clouds are shifted from their expected positions. AVAILABILITY AND IMPLEMENTATION: optiCall is implemented in C++ for use on UNIX operating systems and is available for download at http://www.sanger.ac.uk/resources/software/opticall/. PMID- 22500003 TI - Effects of nasal continuous positive-airway pressure on nutritive swallowing in lambs. AB - Current knowledge suggests that, to be successful, oral feeding in preterm infants should be initiated as soon as possible, often at an age where immature respiration still requires ventilatory support in the form of nasal continuous positive airway pressure (nCPAP). While some neonatologist teams claim great success with initiation of oral feeding in immature infants with nCPAP, others strictly wait for this ventilatory support to be no longer necessary before any attempt at oral feeding, fearing laryngeal penetration and tracheal aspiration. Therefore, the aim of the present study was to provide a first assessment of the effect of various levels of nCPAP on bottle-feeding in a neonatal ovine model, including feeding safety, feeding efficiency, and nutritive swallowing-breathing coordination. Eight lambs born at term were surgically instrumented 48 h after birth to collect recordings of electrical activity of laryngeal constrictor muscle, electrocardiography, and arterial blood gases. Two days after surgery, lambs were bottle-fed under five randomized nCPAP conditions, including without any nCPAP or nasal mask and nCPAP of 0, 4, 7, and 10 cmH(2)O. Results revealed that application of nCPAP in the full-term lamb had no deleterious effect on feeding safety and efficiency or on nutritive swallowing-breathing coordination. The present study provides a first and unique insight on the effect of nCPAP on oral feeding, demonstrating its safety in newborn lambs born at term. These results open the way for further research in preterm lambs to better mimic the problems encountered in neonatology. PMID- 22500004 TI - Endothelial nitric oxide synthase mediates cutaneous vasodilation during local heating and is attenuated in middle-aged human skin. AB - Local skin heating is used to assess microvascular function in clinical populations because NO is required for full expression of the response; however, controversy exists as to the precise NO synthase (NOS) isoform producing NO. Human aging is associated with attenuated cutaneous vasodilation but little is known about the middle aged, an age cohort used for comparison with clinical populations. We hypothesized that endothelial NOS (eNOS) is the primary isoform mediating NO production during local heating, and eNOS-dependent vasodilation would be reduced in middle-aged skin. Vasodilation was induced by local heating (42 degrees C) and during acetylcholine dose-response (ACh-DR: 0.01, 0.1, 1.0, 5.0, 10.0, 50.0, 100.0 mmol/l) protocols. Four microdialysis fibers were placed in the skin of 24 men and women; age cohorts were 12 middle-aged (53 +/- 1 yr) and 12 young (23 +/- 1 yr). Sites served as control, nonselective NOS inhibited [N(G)-nitro-l-arginine methyl ester (l-NAME)], inducible NOS (iNOS) inhibited (1400W), and neuronal NOS (nNOS) inhibited (N(omega)-propyl-l-arginine). After full expression of the local heating response, l-NAME was perfused at all sites. Cutaneous vascular conductance was measured and normalized to maximum (%CVC(max): Nitropress). l-NAME reduced %CVCmax at baseline, all phases of the local heating response, and at all ACh concentrations compared with all other sites. iNOS inhibition reduced the initial peak (53 +/- 2 vs. 60 +/- 2%CVC(max); P < 0.001); however, there were no other differences between control, nNOS-, and iNOS inhibited sites during the phases of local heating or ACh-DR. When age cohorts were compared, NO-dependent vasodilation during local heating (52 +/- 6 vs. 68 +/ 4%CVC(max); P = 0.013) and ACh perfusion (50 mmol/l: 83 +/- 3 vs. 93 +/- 2%CVC(max); 100 mmol/l: 83 +/- 4 vs. 92 +/- 3%CVC(max); both P = 0.03) were reduced in middle-aged skin. There were no differences in NOS isoform expression obtained from skin biopsy samples between groups (all P > 0.05). These data suggest that eNOS mediates the production of NO during local heating and that cutaneous vasodilation is attenuated in middle-aged skin. PMID- 22500005 TI - Hypoxic intensity: a determinant for the contribution of ATP and adenosine to the genesis of carotid body chemosensory activity. AB - Excitatory effects of adenosine and ATP on carotid body (CB) chemoreception have been previously described. Our hypothesis is that both ATP and adenosine are the key neurotransmitters responsible for the hypoxic chemotransmission in the CB sensory synapse, their relative contribution depending on the intensity of hypoxic challenge. To test this hypothesis we measured carotid sinus nerve (CSN) activity in response to moderate and intense hypoxic stimuli (7 and 0% O(2)) in the absence and in the presence of adenosine and ATP receptor antagonists. Additionally, we quantified the release of adenosine and ATP in normoxia (21% O(2)) and in response to hypoxias of different intensities (10, 5, and 2% O(2)) to study the release pathways. We found that ZM241385, an A(2) antagonist, decreased the CSN discharges evoked by 0 and 7% O(2) by 30.8 and 72.5%, respectively. Suramin, a P(2)X antagonist, decreased the CSN discharges evoked by 0 and 7% O(2) by 64.3 and 17.1%, respectively. Simultaneous application of both antagonists strongly inhibited CSN discharges elicited by both hypoxic intensities. ATP release by CB increased in parallel to hypoxia intensity while adenosine release increased preferably in response to mild hypoxia. We have also found that the lower the O(2) levels are, the higher is the percentage of adenosine produced from extracellular catabolism of ATP. Our results demonstrate that ATP and adenosine are key neurotransmitters involved in hypoxic CB chemotransduction, with a more relevant contribution of adenosine during mild hypoxia, while vesicular ATP release constitutes the preferential origin of extracellular adenosine in high-intensity hypoxia. PMID- 22500006 TI - Continuum vs. spring network models of airway-parenchymal interdependence. AB - The outward tethering forces exerted by the lung parenchyma on the airways embedded within it are potent modulators of the ability of the airway smooth muscle to shorten. Much of our understanding of these tethering forces is based on treating the parenchyma as an elastic continuum; yet, on a small enough scale, the lung parenchyma in two dimensions would seem to be more appropriately described as a discrete spring network. We therefore compared how the forces and displacements in the parenchyma surrounding a contracting airway are predicted to differ depending on whether the parenchyma is modeled as an elastic continuum or as a spring network. When the springs were arranged hexagonally to represent alveolar walls, the predicted parenchymal stresses and displacements propagated substantially farther away from the airway than when the springs were arranged in a triangular pattern or when the parenchyma was modeled as a continuum. Thus, to the extent that the parenchyma in vivo behaves as a hexagonal spring network, our results suggest that the range of interdependence forces due to airway contraction may have a greater influence than was previously thought. PMID- 22500007 TI - Central command contributes to increased blood flow in the noncontracting muscle at the start of one-legged dynamic exercise in humans. AB - Whether neurogenic vasodilatation contributes to exercise hyperemia is still controversial. Blood flow to noncontracting muscle, however, is chiefly regulated by a neural mechanism. Although vasodilatation in the nonexercising limb was shown at the onset of exercise, it was unclear whether central command or muscle mechanoreflex is responsible for the vasodilatation. To clarify this, using voluntary one-legged cycling with the right leg in humans, we measured the relative changes in concentrations of oxygenated-hemoglobin (Oxy-Hb) of the noncontracting vastus lateralis (VL) muscle with near-infrared spectroscopy as an index of tissue blood flow and femoral blood flow to the nonexercising leg. Oxy Hb in the noncontracting VL and femoral blood flow increased (P < 0.05) at the start period of voluntary one-legged cycling without accompanying a rise in arterial blood pressure. In contrast, no increases in Oxy-Hb and femoral blood flow were detected at the start period of passive one-legged cycling, suggesting that muscle mechanoreflex cannot explain the initial vasodilatation of the noncontracting muscle during voluntary one-legged cycling. Motor imagery of the voluntary one-legged cycling increased Oxy-Hb of not only the right but also the left VL. Furthermore, an increase in Oxy-Hb of the contracting VL, which was observed at the start period of voluntary one-legged cycling, had the same time course and magnitude as the increase in Oxy-Hb of the noncontracting muscle. Thus it is concluded that the centrally induced vasodilator signal is equally transmitted to the bilateral VL muscles, not only during imagery of exercise but also at the start period of voluntary exercise in humans. PMID- 22500008 TI - Effect of incremental exercise on airway and systemic inflammation in patients with COPD. AB - Airway and systemic inflammation are features of chronic obstructive pulmonary disease (COPD), and there is growing interest in clarifying the inflammatory processes. Strenuous exercise induces an intensified systemic inflammatory response in patients with COPD, but no study has investigated the airway inflammatory and anti-inflammatory responses to exercise. Twenty steroid-naive, ex-smokers with diagnosed COPD (forced expired volume in 1 s = 66 +/- 12%) underwent baseline collection of venous blood and induced sputum followed by an incremental exercise test to symptom limitation 48 h later. Additional venous blood samples were collected following exercise at 0, 2, and 24 h, while induced sputum was collected 2 and 24 h after exercise. Sputum and blood samples were analyzed for differential cell count, CD4(+) and CD8(+) T lymphocytes (serum only), interleukin (IL)-6, IL-8, IL-10, chemokine (C-C motif) ligand 5 (CCL5), and high sensitivity C-reactive protein (serum only). There was an increase in the number of sputum eosinophils (cells/gram, P = 0.012) and a reduction in sputum IL-6 (P = 0.01) 24 h postexercise. Sputum IL-8 and CCL5 were also persistently decreased after exercise (P = 0.0098 and P = 0.0012, respectively), but sputum IL-10 did not change. There was a decrease in serum eosinophils 2 h after exercise (P = 0.0014) and a reduction in serum CCL5 immediately following and 2 h postexercise (P < 0.0001). Both serum eosinophils and CCL5 returned to baseline levels within 24 h. An acute bout of exercise resulted in a significant increase in the number of sputum eosinophils, which may be mediated by serum CCL5. However, there was also a reduction in sputum proinflammatory cytokines, suggesting some anti-inflammatory effect of exercise in the lungs of steroid naive patients with COPD. PMID- 22500009 TI - Dental management of antiplatelet-receiving patients: is uninterrupted antiplatelet therapy safe? PMID- 22500010 TI - Socioeconomic inequalities in common mental disorders and psychotherapy treatment in the UK between 1991 and 2009. AB - BACKGROUND: Inequality in health and treatment of disease across socioeconomic status groups is a major public health issue. AIMS: To examine differences in socioeconomic status in common mental disorders and use of psychotherapy provided by the public and private sector in the UK between 1991 and 2009. METHOD: During these years, 28 054 men and women responded to annual surveys by the nationally representative, population-based British Household Panel Survey (on average 7 measurements per participant; 207 545 person-observations). In each year, common mental disorders were assessed with the self-reported 12-item General Health Questionnaire and socioeconomic status was assessed on the basis of household income, occupational status and education. RESULTS: Higher socioeconomic status was associated with lower odds of common mental disorder (highest v. lowest household income quintile odds ratio (OR) 0.88, 95% CI 0.82-0.94) and of being treated by publicly provided psychotherapy (OR = 0.43, 95% CI 0.34-0.55), but higher odds of being a client of private psychotherapy (OR = 3.33, 95% CI 2.36 4.71). The status difference in publicly provided psychotherapy treatment was more pronounced at the end of follow-up (OR = 0.36, 95% CI 0.23-0.56, in 2005 2009) than at the beginning of the follow-up period (OR = 0.96, 95% CI 0.66-1.39, in 1991-1994; time interaction P<0.001). The findings for occupational status and education were similar to those for household income. CONCLUSIONS: The use of publicly provided psychotherapy has improved between 1991 and 2009 among those with low socioeconomic status, although social inequalities in common mental disorders remain. PMID- 22500011 TI - Clinicopathological significance of psychotic experiences in non-psychotic young people: evidence from four population-based studies. AB - BACKGROUND: Epidemiological research has shown that hallucinations and delusions, the classic symptoms of psychosis, are far more prevalent in the population than actual psychotic disorder. These symptoms are especially prevalent in childhood and adolescence. Longitudinal research has demonstrated that psychotic symptoms in adolescence increase the risk of psychotic disorder in adulthood. There has been a lack of research, however, on the immediate clinicopathological significance of psychotic symptoms in adolescence. AIMS: To investigate the relationship between psychotic symptoms and non-psychotic psychopathology in community samples of adolescents in terms of prevalence, co-occurring disorders, comorbid (multiple) psychopathology and variation across early v. middle adolescence. METHOD: Data from four population studies were used: two early adolescence studies (ages 11-13 years) and two mid-adolescence studies (ages 13 16 years). Studies 1 and 2 involved school-based surveys of 2243 children aged 11 16 years for psychotic symptoms and for emotional and behavioural symptoms of psychopathology. Studies 3 and 4 involved in-depth diagnostic interview assessments of psychotic symptoms and lifetime psychiatric disorders in community samples of 423 children aged 11-15 years. RESULTS: Younger adolescents had a higher prevalence (21-23%) of psychotic symptoms than older adolescents (7%). In both age groups the majority of adolescents who reported psychotic symptoms had at least one diagnosable non-psychotic psychiatric disorder, although associations with psychopathology increased with age: nearly 80% of the mid adolescence sample who reported psychotic symptoms had at least one diagnosis, compared with 57% of the early adolescence sample. Adolescents who reported psychotic symptoms were at particularly high risk of having multiple co-occurring diagnoses. CONCLUSIONS: Psychotic symptoms are important risk markers for a wide range of non-psychotic psychopathological disorders, in particular for severe psychopathology characterised by multiple co-occurring diagnoses. These symptoms should be carefully assessed in all patients. PMID- 22500012 TI - The extreme male brain revisited: gender coherence in adults with autism spectrum disorder. AB - BACKGROUND: The 'extreme male brain' theory suggests that autism spectrum disorder (ASD) is an extreme variant of male intelligence. However, somewhat paradoxically, many individuals with ASD display androgynous physical features regardless of gender. AIMS: To assess physical measures, supposedly related to androgen influence, in adults with and without ASD. METHOD: Serum hormone levels, anthropometry, the ratio of 2nd to 4th digit length (2D:4D) and psychiatric symptomatology were measured in 50 adults with high-functioning ASD and age- and gender-matched neurotypical controls. Photographs of face and body, as well as voice recordings, were obtained and assessed with respect to gender coherence, blindly and independently, by eight assessors. RESULTS: Women with ASD had higher total and bioactive testosterone levels, less feminine facial features and a larger head circumference than female controls. Men in the ASD group were assessed as having less masculine body characteristics and voice quality, and displayed higher (i.e. less masculine) 2D:4D ratios, but similar testosterone levels to controls. Androgynous facial features correlated strongly and positively with autistic traits measured with the Autism-Spectrum Quotient in the total sample. In males and females with ASD dehydroepiandrosterone sulfate did not decrease with age, in contrast to the control group. CONCLUSIONS: Women with ASD had elevated testosterone levels and several masculinised characteristics compared with controls, whereas men with ASD displayed several feminised characteristics. Our findings suggest that ASD, rather than being characterised by masculinisation in both genders, may constitute a gender defiant disorder. PMID- 22500013 TI - Health anxiety in Australia: prevalence, comorbidity, disability and service use. AB - BACKGROUND: Health anxiety is associated with high distress, disability and increased health service utilisation. However, there are relatively few epidemiological studies examining the extent of health anxiety or the associated sociodemographic and health risk factors in the general population. AIMS: To provide epidemiological data on health anxiety in the Australian population. METHOD: Lifetime and current prevalence estimates, associations between comorbid disorders, psychological distress, impairment, disability and mental health service utilisation were generated using the Australian 2007 National Survey of Mental Health and Wellbeing. RESULTS: Health anxiety affects approximately 5.7% of the Australian population across the lifespan and 3.4% met criteria for health anxiety at the time of the interview. Age, employment status, smoking status and comorbid physical conditions were significantly related to health anxiety symptoms. Health anxiety was associated with significantly more distress, impairment, disability and health service utilisation than that found in respondents without health anxiety. CONCLUSIONS: Health anxiety is non-trivial; it affects a significant proportion of the population and further research and clinical investigation of health anxiety is required. PMID- 22500014 TI - Visual cortex in dementia with Lewy bodies: magnetic resonance imaging study. AB - BACKGROUND: Visual hallucinations and visuoperceptual deficits are common in dementia with Lewy bodies, suggesting that cortical visual function may be abnormal. AIMS: To investigate: (1) cortical visual function using functional magnetic resonance imaging (fMRI); and (2) the nature and severity of perfusion deficits in visual areas using arterial spin labelling (ASL)-MRI. METHOD: In total, 17 participants with dementia with Lewy bodies (DLB group) and 19 similarly aged controls were presented with simple visual stimuli (checkerboard, moving dots, and objects) during fMRI and subsequently underwent ASL-MRI (DLB group n = 15, control group n = 19). RESULTS: Functional activations were evident in visual areas in both the DLB and control groups in response to checkerboard and objects stimuli but reduced visual area V5/MT (middle temporal) activation occurred in the DLB group in response to motion stimuli. Posterior cortical perfusion deficits occurred in the DLB group, particularly in higher visual areas. CONCLUSIONS: Higher visual areas, particularly occipito-parietal, appear abnormal in dementia with Lewy bodies, while there is a preservation of function in lower visual areas (V1 and V2/3). PMID- 22500015 TI - Reducing child conduct problems and promoting social skills in a middle-income country: cluster randomised controlled trial. AB - BACKGROUND: There is an urgent need for effective, affordable interventions to prevent child mental health problems in low- and middle-income countries. AIMS: To determine the effects of a universal pre-school-based intervention on child conduct problems and social skills at school and at home. METHOD: In a cluster randomised design, 24 community pre-schools in inner-city areas of Kingston, Jamaica, were randomly assigned to receive the Incredible Years Teacher Training intervention (n = 12) or to a control group (n = 12). Three children from each class with the highest levels of teacher-reported conduct problems were selected for evaluation, giving 225 children aged 3-6 years. The primary outcome was observed child behaviour at school. Secondary outcomes were child behaviour by parent and teacher report, child attendance and parents' attitude to school. The study is registered as ISRCTN35476268. RESULTS: Children in intervention schools showed significantly reduced conduct problems (effect size (ES) = 0.42) and increased friendship skills (ES = 0.74) through observation, significant reductions to teacher-reported (ES = 0.47) and parent-reported (ES = 0.22) behaviour difficulties and increases in teacher-reported social skills (ES = 0.59) and child attendance (ES = 0.30). Benefits to parents' attitude to school were not significant. CONCLUSIONS: A low-cost, school-based intervention in a middle-income country substantially reduces child conduct problems and increases child social skills at home and at school. PMID- 22500016 TI - Acute activation of beta2-adrenergic receptor regulates focal adhesions through betaArrestin2- and p115RhoGEF protein-mediated activation of RhoA. AB - beta(2)-Adrenergic receptors (beta(2)ARs) regulate cellular functions through G protein-transduced and betaArrestin-transduced signals. beta(2)ARs have been shown to regulate cancer cell migration, but the underlying mechanisms are not well understood. Here, we report that beta(2)AR regulates formation of focal adhesions, whose dynamic remodeling is critical for directed cell migration. beta(2)ARs induce activation of RhoA, which is dependent on betaArrestin2 but not G(s). betaArrestin2 forms a complex with p115RhoGEF, a guanine nucleotide exchange factor for RhoA that is well known to be activated by G(12/13)-coupled receptors. Our results show that betaArrestin2 forms a complex with p115RhoGEF in the cytosol in resting cells. Upon beta(2)AR activation, both betaArrestin2 and p115RhoGEF translocate to the plasma membrane, with concomitant activation of RhoA and formation of focal adhesions and stress fibers. Activation of RhoA and focal adhesion remodeling may explain, at least in part, the role of beta(2)ARs in cell migration. These results suggest that betaArrestin2 may serve as a convergence point for non-G(12/13) and non-G(q) protein-coupled receptors to activate RhoA. PMID- 22500017 TI - Lecithin:cholesterol acyltransferase deficiency protects against cholesterol induced hepatic endoplasmic reticulum stress in mice. AB - We recently reported that lecithin:cholesterol acyltransferase (LCAT) knock-out mice, particularly in the LDL receptor knock-out background, are hypersensitive to insulin and resistant to high fat diet-induced insulin resistance (IR) and obesity. We demonstrated that chow-fed Ldlr-/-xLcat+/+ mice have elevated hepatic endoplasmic reticulum (ER) stress, which promotes IR, compared with wild-type controls, and this effect is normalized in Ldlr-/-xLcat-/- mice. In the present study, we tested the hypothesis that hepatic ER cholesterol metabolism differentially regulates ER stress using these models. We observed that the Ldlr /-xLcat+/+ mice accumulate excess hepatic total and ER cholesterol primarily attributed to increased reuptake of biliary cholesterol as we observed reduced biliary cholesterol in conjunction with decreased hepatic Abcg5/g8 mRNA, increased Npc1l1 mRNA, and decreased Hmgr mRNA and nuclear SREBP2 protein. Intestinal NPC1L1 protein was induced. Expression of these genes was reversed in the Ldlr-/-xLcat-/- mice, accounting for the normalization of total and ER cholesterol and ER stress. Upon feeding a 2% high cholesterol diet (HCD), Ldlr-/ xLcat-/- mice accumulated a similar amount of total hepatic cholesterol compared with the Ldlr-/-xLcat+/+ mice, but the hepatic ER cholesterol levels remained low in conjunction with being protected from HCD-induced ER stress and IR. Hepatic ER stress correlates strongly with hepatic ER free cholesterol but poorly with hepatic tissue free cholesterol. The unexpectedly low ER cholesterol seen in HCD fed Ldlr-/-xLcat-/- mice was attributable to a coordinated marked up-regulation of ACAT2 and suppressed SREBP2 processing. Thus, factors influencing the accumulation of ER cholesterol may be important for the development of hepatic insulin resistance. PMID- 22500018 TI - Membrane potential regulates nicotinic acid adenine dinucleotide phosphate (NAADP) dependence of the pH- and Ca2+-sensitive organellar two-pore channel TPC1. AB - Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent second messenger that mobilizes Ca(2+) from the acidic endolysosomes by activation of the two-pore channels TPC1 and TPC2. The channel properties of human TPC1 have not been studied before, and its cellular function is not known. In the present study, we characterized TPC1 incorporated into lipid bilayers. The native and recombinant TPC1 channels are activated by NAADP. TPC1 activity requires acidic luminal pH and high luminal Ca(2+). With Ba(2+) as the permeable ion, luminal Ca(2+) activates TPC1 with an apparent K(m) of 180 MUm. TPC1 operates in two tightly coupled conductance states of 47 +/- 8 and 200 +/- 9 picosiemens. Importantly, opening of the large conductance markedly increases the small conductance mean open time. Changes in membrane potential from 0 to -60 mV increased linearly both the small and the large conductances and NP(o), indicating that TPC1 is regulated by voltage. Intriguingly, the apparent affinity for activation of TPC1 by its ligand NAADP is not constant. Rather, hyperpolarization increases the apparent affinity of TPC1 for NAADP by 10 nm/mV. The concerted regulation of TPC1 activity by luminal Ca(2+) and by membrane potential thus provides a potential mechanism to explain NAADP-induced Ca(2+) oscillations. These findings reveal unique properties of TPC1 to explain its role in Ca(2+) oscillations and cell function. PMID- 22500019 TI - Amyloid beta (Abeta) peptide directly activates amylin-3 receptor subtype by triggering multiple intracellular signaling pathways. AB - The two age-prevalent diseases Alzheimer disease and type 2 diabetes mellitus share many common features including the deposition of amyloidogenic proteins, amyloid beta protein (Abeta) and amylin (islet amyloid polypeptide), respectively. Recent evidence suggests that both Abeta and amylin may express their effects through the amylin receptor, although the precise mechanisms for this interaction at a cellular level are unknown. Here, we studied this by generating HEK293 cells with stable expression of an isoform of the amylin receptor family, amylin receptor-3 (AMY3). Abeta1-42 and human amylin (hAmylin) increase cytosolic cAMP and Ca(2+), trigger multiple pathways involving the signal transduction mediators protein kinase A, MAPK, Akt, and cFos. Abeta1-42 and hAmylin also induce cell death during exposure for 24-48 h at low micromolar concentrations. In the presence of hAmylin, Abeta1-42 effects on HEK293-AMY3 expressing cells are occluded, suggesting a shared mechanism of action between the two peptides. Amylin receptor antagonist AC253 blocks increases in intracellular Ca(2+), activation of protein kinase A, MAPK, Akt, cFos, and cell death, which occur upon AMY3 activation with hAmylin, Abeta1-42, or their co application. Our data suggest that AMY3 plays an important role by serving as a receptor target for actions Abeta and thus may represent a novel therapeutic target for development of compounds to treat neurodegenerative conditions such as Alzheimer disease. PMID- 22500020 TI - DNA repair and replication fork helicases are differentially affected by alkyl phosphotriester lesion. AB - DNA helicases are directly responsible for catalytically unwinding duplex DNA in an ATP-dependent and directionally specific manner and play essential roles in cellular nucleic acid metabolism. It has been conventionally thought that DNA helicases are inhibited by bulky covalent DNA adducts in a strand-specific manner. However, the effects of highly stable alkyl phosphotriester (PTE) lesions that are induced by chemical mutagens and refractory to DNA repair have not been previously studied for their effects on helicases. In this study, DNA repair and replication helicases were examined for unwinding a forked duplex DNA substrate harboring a single isopropyl PTE specifically positioned in the helicase translocating or -nontranslocating strand within the double-stranded region. A comparison of SF2 helicases (RecQ, RECQ1, WRN, BLM, FANCJ, and ChlR1) with a SF1 DNA repair helicase (UvrD) and two replicative helicases (MCM and DnaB) demonstrates unique differences in the effect of the PTE on the DNA unwinding reactions catalyzed by these enzymes. All of the SF2 helicases tested were inhibited by the PTE lesion, whereas UvrD and the replication fork helicases were fully tolerant of the isopropyl backbone modification, irrespective of strand. Sequestration studies demonstrated that RECQ1 helicase was trapped by the PTE lesion only when it resided in the helicase-translocating strand. Our results are discussed in light of the current models for DNA unwinding by helicases that are likely to encounter sugar phosphate backbone damage during biological DNA transactions. PMID- 22500022 TI - Role of conserved glycine in zinc-dependent medium chain dehydrogenase/reductase superfamily. AB - The medium-chain dehydrogenase/reductase (MDR) superfamily consists of a large group of enzymes with a broad range of activities. Members of this superfamily are currently the subject of intensive investigation, but many aspects, including the zinc dependence of MDR superfamily proteins, have not yet have been adequately investigated. Using a density functional theory-based screening strategy, we have identified a strictly conserved glycine residue (Gly) in the zinc-dependent MDR superfamily. To elucidate the role of this conserved Gly in MDR, we carried out a comprehensive structural, functional, and computational analysis of four MDR enzymes through a series of studies including site-directed mutagenesis, isothermal titration calorimetry, electron paramagnetic resonance (EPR), quantum mechanics, and molecular mechanics analysis. Gly substitution by other amino acids posed a significant threat to the metal binding affinity and activity of MDR superfamily enzymes. Mutagenesis at the conserved Gly resulted in alterations in the coordination of the catalytic zinc ion, with concomitant changes in metal-ligand bond length, bond angle, and the affinity (K(d)) toward the zinc ion. The Gly mutants also showed different spectroscopic properties in EPR compared with those of the wild type, indicating that the binding geometries of the zinc to the zinc binding ligands were changed by the mutation. The present results demonstrate that the conserved Gly in the GHE motif plays a role in maintaining the metal binding affinity and the electronic state of the catalytic zinc ion during catalysis of the MDR superfamily enzymes. PMID- 22500021 TI - A 43-nucleotide U-rich element in 3'-untranslated region of large number of Trypanosoma cruzi transcripts is important for mRNA abundance in intracellular amastigotes. AB - Trypanosoma cruzi, the agent of Chagas disease, does not seem to control gene expression through regulation of transcription initiation and makes use of post transcriptional mechanisms. We report here a 43-nt U-rich RNA element located in the 3'-untranslated region (3'-UTR) of a large number of T. cruzi mRNAs that is important for mRNA abundance in the intracellular amastigote stage of the parasite. Whole genome scan analysis, differential display RT-PCR, Northern blot, and RT-PCR analyses were used to determine the transcript levels of more than 900 U-rich-containing mRNAs of large gene families as well as single and low copy number genes. Our results indicate that the 43-nt U-rich mRNA element is preferentially present in amastigotes. The cis-element of a protein kinase 3'-UTR but not its mutated version promoted the expression of the green fluorescent protein reporter gene in amastigotes. The regulatory cis-element, but not its mutated version, was also shown to interact with the trypanosome-specific RNA binding protein (RBP) TcUBP1 but not with other related RBPs. Co immunoprecipitation experiments of TcUBP1-containing ribonucleoprotein complexes formed in vivo validated the interaction with representative endogenous RNAs having the element. These results suggest that this 43-nt U-rich element together with other yet unidentified sequences might be involved in the modulation of abundance and/or translation of subsets of transcripts in the amastigote stage. PMID- 22500023 TI - Crystal structure of C5b-6 suggests structural basis for priming assembly of the membrane attack complex. AB - The complement membrane attack complex (MAC) forms transmembrane pores in pathogen membranes. The first step in MAC assembly is cleavage of C5 to generate metastable C5b, which forms a stable complex with C6, termed C5b-6. C5b-6 initiates pore formation via the sequential recruitment of homologous proteins: C7, C8, and 12-18 copies of C9, each of which comprises a central MAC-perforin domain flanked by auxiliary domains. We recently proposed a model of pore assembly, in which the auxiliary domains play key roles, both in stabilizing the closed conformation of the protomers and in driving the sequential opening of the MAC-perforin beta-sheet of each new recruit to the growing pore. Here, we describe an atomic model of C5b-6 at 4.2 A resolution. We show that C5b provides four interfaces for the auxiliary domains of C6. The largest interface is created by the insertion of an interdomain linker from C6 into a hydrophobic groove created by a major reorganization of the alpha-helical domain of C5b. In combination with the rigid body docking of N-terminal elements of both proteins, C5b becomes locked into a stable conformation. Both C6 auxiliary domains flanking the linker pack tightly against C5b. The net effect is to induce the clockwise rigid body rotation of four auxiliary domains, as well as the opening/twisting of the central beta-sheet of C6, in the directions predicted by our model to activate or prime C6 for the subsequent steps in MAC assembly. The complex also suggests novel small molecule strategies for modulating pathological MAC assembly. PMID- 22500024 TI - Nrf1 CNC-bZIP protein promotes cell survival and nucleotide excision repair through maintaining glutathione homeostasis. AB - Skin cancer is the most common cancer in the United States. Its major environmental risk factor is UVB radiation in sunlight. In response to UVB damage, epidermal keratinocytes activate a specific repair pathway, i.e. nucleotide excision repair, to remove UVB-induced DNA lesions. However, the regulation of UVB response is not fully understood. Here we show that the long isoform of the nuclear factor erythroid 2-related factor 1 (Nrf1, also called NFE2L1), a cytoprotective transcription factor critical for the expression of multiple antioxidant response element-dependent genes, plays an important role in the response of keratinocytes to UVB. Nrf1 loss sensitized keratinocytes to UVB induced apoptosis by up-regulating the expression of the proapoptotic Bcl-2 family member Bik through reducing glutathione levels. Knocking down Bik reduced UVB-induced apoptosis in Nrf1-inhibited cells. In UVB-irradiated surviving cells, however, disruption of Nrf1 impaired nucleotide excision repair through suppressing the transcription of xeroderma pigmentosum C (XPC), a factor essential for initiating the global genome nucleotide excision repair by recognizing the DNA lesion and recruiting downstream factors. Nrf1 enhanced XPC expression by increasing glutathione availability but was independent of the transcription repressor of XPC. Adding XPC or glutathione restored the DNA repair capacity in Nrf1-inhibited cells. Finally, we demonstrate that Nrf1 levels are significantly reduced by UVB radiation in mouse skin and are lower in human skin tumors than in normal skin. These results indicate a novel role of Nrf1 in UVB induced DNA damage repair and suggest Nrf1 as a tumor suppressor in the skin. PMID- 22500025 TI - Borrelia burgdorferi, a pathogen that lacks iron, encodes manganese-dependent superoxide dismutase essential for resistance to streptonigrin. AB - Borrelia burgdorferi, the causative agent of Lyme disease, exists in nature through a complex life cycle involving ticks of the Ixodes genus and mammalian hosts. During its life cycle, B. burgdorferi experiences fluctuations in oxygen tension and may encounter reactive oxygen species (ROS). The key metalloenzyme to degrade ROS in B. burgdorferi is SodA. Although previous work suggests that B. burgdorferi SodA is an iron-dependent superoxide dismutase (SOD), later work demonstrates that B. burgdorferi is unable to transport iron and contains an extremely low intracellular concentration of iron. Consequently, the metal cofactor for SodA has been postulated to be manganese. However, experimental evidence to support this hypothesis remains lacking. In this study, we provide biochemical and genetic data showing that SodA is a manganese-dependent enzyme. First, B. burgdorferi contained SOD activity that is resistant to H(2)O(2) and NaCN, characteristics associated with Mn-SODs. Second, the addition of manganese to the Chelex-treated BSK-II enhanced SodA expression. Third, disruption of the manganese transporter gene bmtA, which significantly lowers the intracellular manganese, greatly reduced SOD activity and SodA expression, suggesting that manganese regulates the level of SodA. In addition, we show that B. burgdorferi is resistant to streptonigrin, a metal-dependent redox cycling compound that produces ROS, and that SodA plays a protective role against the streptonigrin. Taken together, our data demonstrate the Lyme disease spirochete encodes a manganese-dependent SOD that contributes to B. burgdorferi defense against intracellular superoxide. PMID- 22500026 TI - Low-density lipoprotein receptor deficiency causes impaired osteoclastogenesis and increased bone mass in mice because of defect in osteoclastic cell-cell fusion. AB - Osteoporosis is associated with both atherosclerosis and vascular calcification attributed to hyperlipidemia. However, the cellular and molecular mechanisms explaining the parallel progression of these diseases remain unclear. Here, we used low-density lipoprotein receptor knockout (LDLR(-/-)) mice to elucidate the role of LDLR in regulating the differentiation of osteoclasts, which are responsible for bone resorption. Culturing wild-type osteoclast precursors in medium containing LDL-depleted serum decreased receptor activator of NF-kappaB ligand (RANKL)-induced osteoclast formation, and this defect was additively rescued by simultaneous treatment with native and oxidized LDLs. Osteoclast precursors constitutively expressed LDLR in a RANKL-independent manner. Osteoclast formation from LDLR(-/-) osteoclast precursors was delayed, and the multinucleated cells formed in culture were smaller and contained fewer nuclei than wild-type cells, implying impaired cell-cell fusion. Despite these findings, RANK signaling, including the activation of Erk and Akt, was normal in LDLR(-/-) preosteoclasts, and RANKL-induced expression of NFATc1 (a master regulator of osteoclastogenesis), cathepsin K, and tartrate-resistant acid phosphatase was equivalent in LDLR-null and wild-type cells. In contrast, the amounts of the osteoclast fusion-related proteins v-ATPase V(0) subunit d2 and dendritic cell specific transmembrane protein in LDLR(-/-) plasma membranes were reduced when compared with the wild type, suggesting a correlation with impaired cell-cell fusion, which occurs on the plasma membrane. LDLR(-/-) mice consistently exhibited increased bone mass in vivo. This change was accompanied by decreases in bone resorption parameters, with no changes in bone formation parameters. These findings provide a novel mechanism for osteoclast differentiation and improve the understanding of the correlation between osteoclast formation and lipids. PMID- 22500027 TI - Intrinsic protein-protein interaction-mediated and chaperonin-assisted sequential assembly of stable bardet-biedl syndrome protein complex, the BBSome. AB - The pleiotropic features of obesity, retinal degeneration, polydactyly, kidney abnormalities, cognitive impairment, hypertension, and diabetes found in Bardet Biedl syndrome (BBS) make this disorder an important model disorder for identifying molecular mechanisms involved in common human diseases. To date, 16 BBS genes have been reported, seven of which (BBS1, 2, 4, 5, 7, 8, and 9) code for proteins that form a complex known as the BBSome. The function of the BBSome involves ciliary membrane biogenesis. Three additional BBS genes (BBS6, BBS10, and BBS12) have homology to type II chaperonins and interact with CCT/TRiC proteins and BBS7 to form a complex termed the BBS-chaperonin complex. This complex is required for BBSome assembly. Little is known about the process and the regulation of BBSome formation. We utilized point mutations and null alleles of BBS proteins to disrupt assembly of the BBSome leading to the accumulation of BBSome assembly intermediates. By characterizing BBSome assembly intermediates, we show that the BBS-chaperonin complex plays a role in BBS7 stability. BBS7 interacts with BBS2 and becomes part of a BBS7-BBS2-BBS9 assembly intermediate referred to as the BBSome core complex because it forms the core of the BBSome. BBS1, BBS5, BBS8, and finally BBS4 are added to the BBSome core to form the complete BBSome. PMID- 22500028 TI - Unraveling unique structure and biosynthesis pathway of N-linked glycans in human fungal pathogen Cryptococcus neoformans by glycomics analysis. AB - The encapsulated fungal pathogen Cryptococcus neoformans causes cryptococcosis in immunocompromised individuals. Although cell surface mannoproteins have been implicated in C. neoformans pathogenicity, the structure of N-linked glycans assembled on mannoproteins has not yet been elucidated. By analyzing oligosaccharide profiles combined with exoglycosidase treatment, we report here that C. neoformans has serotype-specific high mannose-type N-glycans with or without a beta1,2-xylose residue, which is attached to the trimannosyl core of N glycans. Interestingly, the neutral N-glycans of serotypes A and D were shown to contain a xylose residue, whereas those of serotype B appeared to be much shorter and devoid of a xylose residue. Moreover, analysis of the C. neoformans uxs1Delta mutant demonstrated that UDP-xylose is utilized as a donor sugar in N-glycan biosynthesis. We also constructed and analyzed a set of C. neoformans mutant strains lacking genes putatively assigned to the reconstructed N-glycan biosynthesis pathway. It was shown that the outer chain of N-glycan is initiated by CnOch1p with addition of an alpha1,6-mannose residue and then subsequently extended by CnMnn2p with multiple additions of alpha1,2-mannose residues. Finally, comparative analysis of acidic N-glycans from wild-type, Cnoch1Delta, Cnmnn2Delta, and Cnuxs1Delta strains strongly indicated the presence of xylose phosphate attached to mannose residues in the core and outer region of N-glycans. Our data present the first report on the unique structure and biosynthesis pathway of N-glycans in C. neoformans. PMID- 22500030 TI - Determinants of community capacity influencing residents' health status in Seoul, South Korea. AB - The effect of community capacity on health was evaluated by assessing the community via a questionnaire that included a capacity index in the social capital scale. The impact of the length of residence and the size and solidarity of networking on community capacity was also explored. The authors used logistic regression models controlling for sociodemographic factors and health behaviors among 1019 residents. The results indicate that lower community identity and social trust all led to statistically poor health levels. The manner in which members perceive their community was determined by cohesion, participation, length of residence, and the extent and strength of a member's network. Partnerships among and the subsequent organization of public resources by community members helped solidify the sense of community. With enhanced levels of sense of community, the collective level of health among residents can be readily and effectively improved. PMID- 22500029 TI - Unusual spectroscopic and ligand binding properties of the cytochrome P450 flavodoxin fusion enzyme XplA. AB - The Rhodococcus rhodochrous strain 11Y XplA enzyme is an unusual cytochrome P450 flavodoxin fusion enzyme that catalyzes reductive denitration of the explosive hexahydro-1,3,5-trinitro-1,3,5-triazene (RDX). We show by light scattering that XplA is a monomeric enzyme. XplA has high affinity for imidazole (K(d) = 1.6 MUM), explaining previous reports of a red-shifted XplA Soret band in pure enzyme. The true Soret maximum of XplA is at 417 nm. Similarly, unusually weak XplA flavodoxin FMN binding (K(d) = 1.09 MUM) necessitates its purification in the presence of the cofactor to produce hallmark flavin contributions absent in previously reported spectra. Structural and ligand-binding data reveal a constricted active site able to accommodate RDX and small inhibitory ligands (e.g. 4-phenylimidazole and morpholine) while discriminating against larger azole drugs. The crystal structure also identifies a high affinity imidazole binding site, consistent with its low K(d), and shows active site penetration by PEG, perhaps indicative of an evolutionary lipid-metabolizing function for XplA. EPR studies indicate heterogeneity in binding mode for RDX and other ligands. The substrate analog trinitrobenzene does not induce a substrate-like type I optical shift but creates a unique low spin EPR spectrum due to influence on structure around the distal water heme ligand. The substrate-free heme iron potential (-268 mV versus NHE) is positive for a low spin P450, and the elevated potential of the FMN semiquinone/hydroquinone couple (-172 mV) is also an adaptation that may reflect (along with the absence of a key Thr/Ser residue conserved in oxygen activating P450s) the evolution of XplA as a specialized RDX reductase catalyst. PMID- 22500031 TI - Multifactorial analysis of factors affecting recurrence of stroke in Japan. AB - Data on factors affecting stroke recurrence are relatively limited. The authors examined potential factors affecting stroke recurrence, retrospectively. The study participants were 1087 patients who were admitted to stroke centers suffering from first-ever ischemic stroke and returned questionnaires with usable information after discharge. The authors analyzed the association between clinical parameters of the patients and their prognosis. Recurrence rate of during an average of 2 years after discharge was 21.3%, and there were differences among stroke subtypes. It was found that the disability level of the patients after discharge correlated well with the level at discharge (r s = 0.66). Multivariate logistic regression analysis of the data shows that modified Rankin Scale score, National Institute of Health Stroke Scale score, gender, age, and family history had statistically significant impacts on stroke recurrence, and the impact was different depending on subtypes. These findings suggest that aggressive and persistent health education for poststroke patients and management of risk factors are essential to reduce stroke recurrence. PMID- 22500032 TI - Factors associated with poor hospital mortality rates after the National Health Insurance program. AB - The study examined whether hospital mortality rates have improved since National Health Insurance (NHI) in Taiwan and what factors affect the hospital mortality rates. The related hospital data were collected from databases belonging to the NHI Annual Statistics Information. In addition, panel data analysis and stepwise regression are used to indicate the determinants of hospital mortality rates from 1995 to 2008. The evidence shows that mortality rates have not improved since the NHI; competition, the elderly, family income, the poor, the number of clinical departments, length of stay, new technology, public hospitals and family medical expenses-all affect mortality rates. Moreover, longer length of stay, increase in the number of elderly and low-income families, and inequality of resource allocation have led to high mortality rates. Policy makers first have to realize what drives them to change and then set the benchmarks for their improvement. PMID- 22500033 TI - Temporal trend of anemia among reproductive-aged women in India. AB - BACKGROUND: Anemia is one of the major leading nutritional deficiencies in India, and the most vulnerable groups are preschool and adolescent children and pregnant and lactating women. AIM: The main objective of the study is to determine the temporal trend of anemia among reproductive-aged women of age 15-49 years. METHODOLOGY: The study uses data from second and third rounds of the National Family Health Surveys (NFHS-2, 1998-1999, and NFHS-3, 2005-2006), conducted by the International Institute for Population Sciences. The dependent variable was the status of anemia of women. The determining variables were type of residence, age group, religion and castes, educational status, marital status, and household standard of living index. RESULTS: Anemia was most prevalent in the east zone for both the periods. The changes at the all India level were not much, but the north east zone improved very well, whereas the south zone deteriorated drastically. The occurrence of severely anemic women in India varied between 1% and 2%. The highest prevalence rates were observed among women who were 15 to 24 years of age, illiterate, from non-Christian scheduled tribes (STs), unmarried, and whose standard of living was low. Rates of anemia have increased over time except in the case of Buddhists, Parsees, Jains, and the STs. CONCLUSION: From the viewpoint of our study, illiteracy and low standard of living may be the main causes of anemia among women in India. It is also necessary to take appropriate steps to curb anemia in women in their early adulthood. PMID- 22500034 TI - Mother-daughter correlation of central obesity and other noncommunicable disease risk factors: Tehran Lipid and Glucose Study. AB - This study aimed to investigate the mother-daughter correlation for central obesity and other noncommunicable disease risk factors. The authors used metabolic and anthropometric data from the Tehran Lipid and Glucose Study, enrolling 1041 mother-daughter pairs for the current study. Three age strata were defined: 3 to 9 years for childhood (146 mother-daughter pairs), 10 to 17 years for adolescence (395 mother-daughter pairs), and 18 to 25 years for early adulthood (500 mother-daughter pairs). Familial associations for central obesity and other noncommunicable disease risk factors were assessed. The prevalence of central obesity was 44.7% in mothers and 11.2% in daughters (6.2% in the 3-9, 19.2% in the 10-17, and 6.4% in the 18-25 years groups). Mothers with central obesity were more likely than nonobese mothers to have daughters with central obesity (10.5% and 1.7%, respectively; P = .0001). Central obesity indices among daughters were positively correlated with those of their mothers in all 3 age strata. Correlations for other noncommunicable disease risk factors were analyzed before and after adjusting the risk factor levels for mothers' and daughters' waist circumferences (WCs) within each group to determine whether risk factor correlations were, in part, a result of the central obesity correlations. After the non-communicable disease risk factor levels of participants were adjusted for their WCs, the mother-daughter correlations remained significant. The consistent association of central obesity between mothers and daughters may indicate the key role that could be played by the mother in the primary prevention of central obesity, particularly in high-risk families. PMID- 22500035 TI - Levels of satisfaction and factors influencing satisfaction for medical premarital examinations in Hubei, Middle China. AB - BACKGROUND: When the mandatory premarital examination requirement in China was cancelled in 2003, the rate of participation dropped sharply. This study examined the levels of exam satisfaction and the factors influencing satisfaction in the Hubei Province. METHODS: Graduate students administered 650 questionnaires, and 633 questionnaires were returned. Regression analysis was used to analyze satisfaction. RESULTS: The study found high levels of satisfaction, even though the exam participation rate was only 34.8%. A regression model for satisfaction showed that the most important objective factors were female sex (P < .05), specific city (P < .05), and level of education (P < .01); 2 important subjective variables were the level of understanding of the premarital examination (P < .01) and satisfaction with medical services of the premarital examination (P < .01). CONCLUSIONS: Satisfaction with the premarital examination might be increased by efforts to increase the level of understanding of the premarital examination and to improve medical services. PMID- 22500036 TI - Validation of the Educational Stress Scale for Adolescents (ESSA) in Vietnam. AB - INTRODUCTION: To date, there has been little systematic, quantitative research on the links between academic pressure and mental health among adolescents in Asia, and none in Vietnam. In part, this is because of a lack of appropriate tools to measure this complex phenomenon. This study was to validate the Educational Stress Scale for Adolescents (ESSA), developed and tested in China, with the aim of fostering further research in Asia. METHODS: A total of 1283 students were recruited in 3 secondary schools and 3 high schools in Ho Chi Minh City, Vietnam. Anonymous, self-report questionnaires included the ESSA and previously validated measures of mental health. RESULTS: Among the 1226 questionnaires available, 54% of respondents were female. The mean age was 15.3 years. Students reported substantial study burden. The ESSA had good internal consistency, and factorial validity and concurrent validity were established. CONCLUSION: The ESSA is a suitable measure for school-based mental health research in Asia. PMID- 22500037 TI - Access to environmental resources and physical activity levels of adults in Hawaii. AB - PURPOSE: Examine associations between physical activity (PA) and spatial accessibility to environmental PA resources in Hawaii. METHODS: Metabolic equivalents (METs) of mild, moderate, and strenuous PA were compared for accessibility with environmental PA resources within a population-based sample of Hawaiian adults (n = 381). Multiple linear regression estimated differences in PA levels for residing further from a PA resource or residing in an area with a greater number of resources. RESULTS: No associations were found in the total sample. Analyses within subsamples stratified by ethnicity revealed that greater spatial accessibility to a PA resource was positively associated with strenuous PA among Caucasians (P = .04) but negatively associated with moderate PA among Native Hawaiians (P = .00). CONCLUSION: The lack of association in the total sample may be a consequence of Hawaii's unique environment. Results of stratified sample analyses are unique, providing groundwork for future examinations within parallel environments and among similar ethnic groups. PMID- 22500039 TI - Relationship between duration of type 2 diabetes and self-reported participation in diabetes education in Korea. AB - The increasing prevalence of diabetes is a pressing issue in Korea. The aim of this study was to determine the relationship between duration of diabetes and self-reported participation in diabetes education among diabetic patients in Korea. This study used data from the Korean National Health and Nutrition Examination Survey in 2005. A total of 1405 respondents older than 19 years and having diabetes were included in the analyses. The relationship between these variables was assessed using logistic regression after adjusting for age, sex, and socioeconomic status. The authors observed that duration of diabetes was associated with having never attended diabetes education programs (odds ratio = 0.95; 95% confidence interval = 0.93-0.96; P < .001), with the greatest risk of not attending seen in recently diagnosed patients. In addition, having lower educational attainment and living in non-Metro Seoul regions were independent factors for never attending diabetes education programs among diabetic patients in Korea. This finding suggests the need for developing effective education programs to encourage diabetic patients, particularly recently diagnosed patients, to participate. Such programs could help deliver appropriate information for diabetes management to all diabetic patients in Korea. PMID- 22500040 TI - The optimal scaling combination of age and body mass index as an index of metabolic syndrome for postmenopausal Taiwanese women. AB - The aim of this study was to combine as a new index age with an anthropometric indicator of obesity that is more closely associated with metabolic syndrome (MS) risk than other anthropometric indicators for postmenopausal Taiwanese women. In this cross-sectional study, data were collected from 1128 postmenopausal women volunteers during the period from September 2008 to December 2009. Receiver operating characteristic (ROC) curves for assessing the risk of MS for postmenopausal Taiwanese women were computed for the optimal scaling combination (OSC) and anthropometric indicator of obesity. The area under the ROC curves of the OSC was significantly larger than those of the anthropometric indicator. OSC >= 4.98 was found to be the most prevalent cutoff point. The present investigation suggests that the OSC could be used in clinical practice as a simple parameter for the identification of postmenopausal Taiwanese women at risk of MS. PMID- 22500038 TI - Various adiposity measures show similar positive associations with type 2 diabetes in Caucasians, native Hawaiians, and Japanese Americans: the multiethnic cohort. AB - The authors evaluated the association of body mass index (BMI), waist circumference (WC) and hip circumference (HC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) with diabetes in Caucasians, Native Hawaiians, and Japanese Americans aged 45 to 75 years in the Multiethnic Cohort. Diabetes cases were obtained from self-reports and by linkages with health insurance plans. The authors estimated adjusted prevalence odds ratios (PORs) and compared the area under the receiver operating characteristic curves (AUC). All measures were positively associated with diabetes prevalence; the PORs were 1.25 to 1.64 in men and 1.52 to 1.83 in women. In all 3 ethnic groups, the AUCs in men were greater for BMI than for the other measures, whereas in women, the AUCs were greater for combined models than for BMI alone, but the differences were small and not clinically significant. It does not appear that one anthropometric measure best reflects diabetes prevalence or performs better in one ethnic group than in another. PMID- 22500041 TI - Risk of HIV infection among men having sex with men in Kathmandu Valley, Nepal. AB - Despite extensive distribution of free condoms and lubricants to prevent HIV transmission among men having sex with men (MSM) in Nepal, the prevalence of HIV and risky sexual behaviors remain high. The influence of individual-level, social capital, and social-structural factors on HIV risk has been insufficiently explored in MSM. The authors assessed association of these factors with HIV risk among 150 MSM enrolled using snowball sampling in the Kathmandu Valley. HIV risk was calculated on the basis of number and type of sexual partners and condom use during anal sex. Multivariate analysis showed a high risk of HIV infection was significantly associated with being involved in sex work, having no knowledge of male sexually transmitted infection (STI) symptoms, and having a history of STI symptoms. HIV prevention could be made more effective by targeting MSM who are involved in sex work and by improving their knowledge of male STI symptoms and early diagnosis and treatment. PMID- 22500042 TI - Prevalence of undernutrition, its determinants, and seasonal variation among tribal preschool children of Odisha state, India. AB - A community-based cross-sectional study was undertaken in the tribal areas of Odisha state, India, covering 1951 preschool children to assess their nutritional status in terms of underweight, stunting, and wasting; its correlates; and seasonal variation in nutritional status. chi(2) Test, one-way analysis of variance, and unadjusted and adjusted odds ratios were used for data analysis. The prevalence of underweight, stunting, and wasting was 58%, 65%, and 20%, respectively. The risk of underweight and stunting was, respectively, 1.9 and 2.4 times higher among children of illiterate mothers, whereas underweight and wasting was 1.4 times higher among children who had morbidities during the preceding fortnight. The prevalence of undernutrition was significantly (P < .01) higher during monsoon as compared with winter season. Undernutrition is an important public health problem and is associated with literacy of mother, morbidity, and season. Thus, improving socioeconomic condition, literacy, and sanitation along with insuring food security during monsoon season might improve nutritional status. PMID- 22500043 TI - Assembly and dynamics of Gp59-Gp32-single-stranded DNA (ssDNA), a DNA helicase loading complex required for recombination-dependent replication in bacteriophage T4. AB - The Gp59 protein of bacteriophage T4 plays critical roles in recombination dependent DNA replication and repair by correctly loading the replicative helicase, Gp41, onto recombination intermediates. Previous work demonstrated that Gp59 is required to load helicase onto single-stranded DNA that is saturated with Gp32, the T4 single-stranded DNA (ssDNA)-binding protein. Gp59 and Gp32 bind simultaneously to ssDNA, forming a Gp59-Gp32-ssDNA complex that is a key intermediate in helicase loading. Here we characterize the assembly and dynamics of this helicase loading complex (HLC) through changes in the fluorescent states of Gp32F, a fluorescein-Gp32 conjugate. Results show that HLC formation requires a minimum Gp32-ssDNA cluster size and that Gp59 co-localizes with Gp32-ssDNA clusters in the presence of excess free ssDNA. These and other results indicate that Gp59 targets helicase assembly onto Gp32-ssDNA clusters that form on the displaced strand of D-loops, which suggests a mechanism for the rapid initiation of recombination-dependent DNA replication. Helicase loading at the HLC requires ATP binding (not hydrolysis) by Gp41 and results in local remodeling of Gp32 within the HLC. Subsequent ATPase-driven translocation of Gp41 progressively disrupts Gp32-ssDNA interactions. Evidence suggests that Gp59 from the HLC is recycled to promote multiple rounds of helicase assembly on Gp32-ssDNA, a capability that could be important for the restart of stalled replication forks. PMID- 22500045 TI - Nephrotic syndrome in an African American female. PMID- 22500044 TI - Clinical implication of highly sensitive detection of the BRAF V600E mutation in fine-needle aspirations of thyroid nodules: a comparative analysis of three molecular assays in 4585 consecutive cases in a BRAF V600E mutation-prevalent area. AB - CONTEXT: Detection of the BRAF V600E mutation in fine-needle aspiration cytology (FNAC) specimens may increase the value of FNAC. OBJECTIVE: The objectives of the study was to compare the diagnostic performance of BRAF assays that differ in sensitivity and to examine the associations between the BRAF V600E mutation status and the clinicopathological features in papillary thyroid carcinoma (PTC). DESIGN AND SETTING: Three molecular assays were performed in all subjects and compared with regard to FNAC and histology results. PARTICIPANTS: We evaluated 4585 consecutive patients who were found to have malignant or indeterminate thyroid nodules by ultrasonography. OUTCOME MEASURES: All FNAC samples were tested for the BRAF V600E mutation using conventional Sanger sequencing, dual priming oligonucleotide-PCR, and mutant enrichment with 3'-modified oligonucleotide (MEMO) sequencing. RESULTS: The detection sensitivities of the three molecular assays for the BRAF V600E mutation were 20, 2, and 0.1%, respectively. Compared with conventional Sanger sequencing (n = 673), dual priming oligonucleotide-PCR and MEMO sequencing detected more tumors with the BRAF V600E mutation (n = 919 and n = 1044, respectively), especially tumors with a benign, indeterminate, or nondiagnostic cytology. All BRAF-positive tumors that were histologically examined were shown to be PTC, regardless of cytology results. The clinical sensitivities of the three assays for detecting PTC were 54.8, 74.4, and 79.7%, respectively. BRAF V600E mutations in microcarcinomas (<= 10 mm) were detected more efficiently as the detection sensitivity of the assay increased (P < 0.001). Tumor size correlated significantly with multifocality, extrathyroidal extension, and lymph node metastasis (P = 0.003, P < 0.001 and P < 0.001, respectively), but the BRAF V600E mutation status was not associated with any of those features. CONCLUSION: Highly sensitive and specific molecular assays such as MEMO sequencing are optimal for detecting the BRAF mutations in thyroid FNAC because these techniques can detect PTC that might be missed by cytology or less sensitive molecular assays. PMID- 22500046 TI - Severe metabolic acidosis in a newborn with an abnormal newborn screen. PMID- 22500047 TI - A loss of naivete. AB - Monogenic disorders leading to primary immunodeficiency have fascinated scientists and clinicians alike by their capacity to reveal the complexities of intracellular signaling pathways. Two articles in this issue of Blood by Abdollahpour et al and Nehme et al illustrate this point vividly, describing for the first time the clinical and immunologic phenotype associated with genetic mutations in STK4, manifested largely by a loss of T-cell naivete. PMID- 22500048 TI - Turning Tregs into class I suppressors. AB - In this issue of Blood, Plesa et al demonstrate that human Foxp3(+) regulatory T cells can be redirected using MHC class I-restricted T-cell receptors (TCRs), showing a surprising lack of correlation of TCR affinity and their suppressive potency. PMID- 22500049 TI - Advancing the STATus of MPN pathogenesis. AB - In this issue of Blood, Yan et al and Walz et al exploit mouse genetics to investigate the contribution of signal transducer and activator of transcription 5 (STAT5) to the abnormal in vivo growth of hematopoietic cells expressing JAK2(V617F) or BCR-ABL. Eliminating STAT5 expression had dramatic effects in both contexts, and this new work and other recent studies support the therapeutic potential of targeting pathways regulated by this important signaling molecule in patients with myeloproliferative neoplasms (MPNs). PMID- 22500050 TI - ALDH marks leukemia stem cell. AB - In this issue of Blood,Gerber et al use aldehyde dehydrogenase (ALDH) activity to further subdivide the CD34(+)CD38(-) compartment in the bone marrow of acute myeloid leukemia (AML) patients. They identify a unique population with intermediate ALDH activity (ALDH(int)) that contains leukemia stem cells (LSCs). Moreover, persistence of this population after therapy is a marker of clinically significant minimal residual disease. PMID- 22500051 TI - Overcoming "aspirin resistance" in MPN. AB - In this issue of Blood, Pascale and colleagues show that biochemical resistance to aspirin in patients with essential thrombocythemia (ET) can be reversed by twice daily dosing. PMID- 22500052 TI - New approaches for measurement of platelet reactivity. AB - In a highly interesting, intricate, and novel paper in this issue of Blood, Fung and colleagues have extended their previous pioneering studies and now reveal that molecules such as ATP can promote platelet activation through the P2X1 receptor. PMID- 22500053 TI - TAFI made stickier. AB - Bleeding in hemophilia is the result of factor VIII/IX deficiency with corresponding reduced thrombin production and enhanced fibrinolysis secondary to lower thrombin activatable fibrinolysis inhibitor (TAFI) production. Factor replacement is the cornerstone of hemophilia treatment but is often not possible in developing countries. PMID- 22500055 TI - Correction to Context-Dependent Effects of Asparagine Glycosylation on Pin WW Folding Kinetics and Thermodynamics. PMID- 22500056 TI - THE EFFECT OF TAX PREFERENCES ON HEALTH SPENDING. AB - In this paper, we estimate the effect of the tax preference for health insurance on health care spending using data from the Medical Expenditure Panel Surveys from 1996-2005. We use the fact that Social Security taxes are only levied on earnings below a statutory threshold to identify the impact of the tax preference. Because employer-sponsored health insurance premiums are excluded from Social Security payroll taxes, workers who earn just below the Social Security tax threshold receive a larger tax preference for health insurance than workers who earn just above it. We find a significant effect of the tax preference, consistent with previous research. PMID- 22500057 TI - Health Costs of Wealth Gains: Labor Migration and Perceptions of HIV/AIDS Risks in Mozambique. AB - The study employs survey data from rural Mozambique to examine how men's labor migration affects their non-migrating wives' perceptions of HIV/AIDS risks. Using a conceptual framework centered on tradeoffs between economic security and health risks that men's migration entails for their left-behind wives, it compares women married to migrants and those married to non-migrants while also distinguishing between economically successful and unsuccessful migration. The analysis finds that the economic success of men's migration, rather than migration itself, significantly predicts women's worries about getting infected by their husbands or their own extramarital partners, and their husbands' stance on condom use. These findings are situated within a broader context of socio-economic, gender, and marital dynamics and vulnerabilities produced or amplified by male labor migration in sub-Saharan and similar developing settings. PMID- 22500058 TI - Concise epoxide-based synthesis of the C14-C25 bafilomycin A(1) polypropionate chain. AB - An efficient non-aldol convergent synthesis of the C14-C25 polyketide fragment of bafilomycin A(1) was completed in 16% overall yield and 8 steps in its longest linear sequence. This synthesis highlights the formation of the key fragments using a three-step sequence of epoxide cleavage, alkyne reduction, and epoxidation developed in our laboratory; starting from suitably protected enantiomeric epoxides of trans-2,3-epoxybutanol. This chemistry represents a quick asymmetric and diastereoselective construction of the polyketide chain of bafilomycin A(1), in which every stereogenic center was constructed using solely epoxide chemistry. PMID- 22500059 TI - Investigating the Life Situations and Development of Teenage Mothers' Children: Evidence from the ECLS-B. PMID- 22500061 TI - Italian cross-cultural adaptation and validation of three different scales for the evaluation of shoulder pain and dysfunction after neck dissection: University of California - Los Angeles (UCLA) Shoulder Scale, Shoulder Pain and Disability Index (SPADI) and Simple Shoulder Test (SST). AB - Shoulder syndrome after neck dissection is a well known entity, but its incidence and prognostic factors influencing recovery have not been clearly assessed due to the heterogeneity of possible evaluations. The University of California - Los Angeles (UCLA) Shoulder Scale, the Shoulder Pain and Disability Index (SPADI) and the Simple Shoulder Test (SST) are three English-language questionnaires commonly used to test shoulder impairment. An Italian version of these scales is not available. The aim of the present study was to translate, culturally adapt and validate an Italian version of UCLA Shoulder Scale, SPADI and SST. Translation and cross-cultural adaptation of the SPADI, the UCLA shoulder scale and the SST was performed according to the international guidelines. Sixty-six patients treated with neck dissection for head and neck cancer were called to draw up these scales. Forty patients completed the same questionnaires a second time one week after the first to test the reproducibility of the Italian versions. All the English-speaking Italian patients (n = 11) were asked to complete both the English and the Italian versions of the three questionnaires to validate the scales. No major problems regarding the content or the language were found during the translation of the 3 questionnaires. For all three scales, Cronbach's alpha was > 0.89. The Pearson correlation coefficient was r > 0.91. With respect to validity, there was a significant correlation between the Italian and the English versions of all three scales. This study shows that the Italian versions of UCLA Shoulder Scale, SPADI and SST are valid instruments for the evaluation of shoulder dysfunction after neck dissection in Italian patients. PMID- 22500062 TI - Sentinel lymph node biopsy in squamous cell carcinoma of the head and neck: 10 years of experience. AB - Sentinel node (SN) biopsy of head and neck cancer is still considered investigational, and agreement on the width of the surgical sampling has not yet been reached. From May 1999 to Dec 2009, 209 consecutive patients entered a prospective study: 61.7% had primary tumour of the oral cavity and 23.9% of the oropharynx. SN was not found in 26 patients. Based on these data and definitive histopathological analysis, we proposed six hypothetic scenarios to understand the percentage of neck recurrences following different treatments Among patients with identified SN, 54 cases were pN+: 47 in SN and 7 in a different node. Considering the six hypothetic scenarios: "only SN removal", "SN level dissection", "neck dissection from the tumour site to SN level", "selective neck dissection of three levels (SND)", "dissection from level I to IV" and "comprehensive I-V dissection", neck recurrences could be expected in 6.5%, 3.8%, 2.18%, 2.73%, 1.09% and 1.09% of cases, respectively. SN biopsy can be considered a useful tool to personalize the surgical approach to a N0 carcinoma. The minimum treatment of the neck is probably dissection of the levels between the primary tumour and the level containing the SN(s). Outside the framework of a clinical study, the best treatment can still be considered SND. PMID- 22500060 TI - A review of genetic epidemiology of head and neck cancer related to polymorphisms in metabolic genes, cell cycle control and alcohol metabolism. AB - The purpose of this report is to review the relationship between genetic polymorphisms involved in carcinogen metabolism, alcohol metabolism and cell cycle control with the risk of head and neck cancer. The review was performed on available studies on genetic polymorphisms and head and neck cancer (HNC) published in PubMed up to September 2011. 246 primary articles and 7 meta analyses were published. Among these, a statistically significant association was reported for glutathione S-transferases (GSTM1), glutathione S-transferases (GSTT1) and human microsomal epoxide hydrolase (EPHX1) genes. An increased risk for HNC was also associated reported for P53 codon 72 Pro/Pro, ALDH2 and three variants of the ADH gene: ADH1B (rs1229984), ADH7 (rs1573496) and ADH1C (rs698). PMID- 22500063 TI - Alternative treatment for otitis media with effusion: eustachian tube rehabilitation. AB - In this study, we evaluated the effectiveness of eustachian tube rehabilitation (ETR) as treatment for otitis media with effusion (OME). Thirty-five children with persistent OME were enrolled. Patients were divided into three groups: group I (isolated OME); group II (OME and atypical swallowing); group II (OME, habitual mouth breathing and atypical swallowing). All children underwent ETR. Otomicroscopy and tympanograms were performed before treatment, and at one and three months following ETR. Considering the overall patient population after ETR (one and three months later), the prevalence of type A tympanogram increased significantly compared to before therapy (p < 0.005), while the prevalence of type B tympanogram decreased significantly (p < 0.005). We found significant differences between pre- and both post-therapy control in groups I and II. However, children in group II experienced significant improvement of middle ear conditions only three months after the end of therapy (p < 0.005). On the basis of the physiopathologic knowledge of OME and the underlying principles of ETR, we conclude that ETR can be considered a useful therapy in management of OME. PMID- 22500064 TI - An evaluation of the effects of hypertension during pregnancy on postpartum hearing as measured by transient-evoked otoacoustic emissions. AB - The aim of this study was to compare the ratio of hearing loss evaluated with transient evoked otoacoustic emission (TEOAEs) testing in normal and hypertensive pregnant women during the first week after delivery. This was a prospective, case control study. The hypertensive pregnancy group included 96 women with gestational hypertension preeclampsia, eclampsia, or HELLP syndrome, while the normal pregnancy group included age-matched 107 women with normal pregnancy. Postpartum first week, pure tone hearing threshold levels of all women were measured at 0.25, 1, 2, 4 and 6 kHz. TEOAEs testing results were also recorded. All subjects also underwent a detailed ear noise and throat examination. Hearing loss with TEOAE during the first postpartum week was detected in seven (7.3%) women in the hypertensive pregnancy group and in three (2.8%) women in normal pregnancy group. Mean hearing thresholds and individual thresholds at each of the examined frequencies (0.25-6 kHz) were similar in the two groups. Bone and air conduction pure tone average and TEOAE results were not statistically significantly different in the hypertensive pregnancy and normal pregnancy groups. Lastly, the ratios of hearing loss with TEOAE were significantly higher in women with HELLP syndrome compared to women with severe and mild preeclampsia. PMID- 22500065 TI - Body dysmorphic factors and mental health problems in people seeking rhinoplastic surgery. AB - There has been increasing number of requests for cosmetic rhinoplastic surgery among Iranian people in different age groups in recent years. One risk for people who undergo such plastic operations is the presence of body dysmorphic disorder (BDD), which can complicate the result and decrease the rate of satisfaction from surgery. This study aimed to investigate mental health problems in people seeking rhinoplastic surgery. In this case-control study, the scores of General Health Questionnaire (GHQ) and DCQ (Dysmorphic Concerns Questionnaire) were obtained from 50 individuals who were candidates for rhinoplasty, and the results were compared with a normal control group. The total GHQ score and scores in anxiety, depression, and social dysfunction sub-scales were higher among the study group. This was the same for the DCQ score. However, the scores of somatization sub scale of GHQ were not significantly different between the two groups. Psychiatric evaluation of candidates for rhinoplasty seems necessary for prevention of unnecessary and repetitive surgical operations. PMID- 22500067 TI - High mobility group box 1 (HMGB 1): a new protein in the pathogenesis of ENT inflammatory and infectious diseases. PMID- 22500066 TI - Ocular vestibular-evoked myogenic potential (oVEMP) to test utricular function: neural and oculomotor evidence. AB - A new test for utricular function has recently been introduced and validated, namely the ocular vestibular-evoked myogenic potential (oVEMP), which refers to the myogenic potentials recorded by surface EMG electrodes beneath both eyes in response to bone conducted vibration (BCV) of the head or air conducted sound (ACS). The oVEMP test differs from another vestibular-evoked myogenic potential recorded by surface EMG electrodes over the sternocleidomastoid muscles in that the cervical vestibular-evoked myogenic potential (cVEMP) due to saccular activation is measured. oVEMP is a reliable clinical test that relies on extensive physiological evidence from studies on guinea pigs, and in particular on recording the vestibular primary afferent responses to BCV, demonstrating that the same BCV causes similar eye movements in both guinea pigs and humans. This review briefly integrates the most recent physiological and behavioural evidence that substantiates the clinical use of oVEMP. PMID- 22500068 TI - The velo-uvulo-pharyngeal lift or "roman blinds" technique for treatment of snoring: a preliminary report. AB - Snoring is caused by vibrating anatomical structures in the upper aerodigestive tract. It can be treated surgically and non-surgically, although resective procedures are associated with high postoperative morbidity and failure rate. We describe a new non-resective surgical procedure called the velo-uvulo-pharyngeal lift in which the soft palate is lifted, shortened, advanced and stiffened by means of permanent threads anchored to fibro-osseous attachments at the level of the posterior nasal spine and both pterygoid hamuli. Four adult patients (median age 44.5 years; range 42-65) affected by snoring and mild obstructive sleep apnoea-hypopnoea syndrome (apneoa-hypopnoea index, AHI < 20) requiring septal surgery under general anesthesia also underwent velo-uvulo-pharyngeal lift. There were no significant intra- or post-operative complications, and all of the patients reported immediate snoring relief. The main complaints were slight pain and a sensation of local fullness, both of which spontaneously disappeared within two days. The subjective clinical improvement in snoring was confirmed during post-operative follow-up (median 15.5 months; range 6-25), as was the stable reshaping of the soft velo-uvulo-pharyngeal tissues and enlargement of the mesopharyngeal space. There was also a decrease in daytime sleepiness. Our preliminary results suggest that velo-uvulo-pharyngeal lift is a simple, cost effective and minimally invasive means of widening the mesopharyngeal space in snoring patients with or without mild sleep apnoea-hypopnoea syndrome. The widening of the mesopharyngeal space prevents contact-induced wall vibrations and its inspiratory obstruction causing hypopnoea and apnoea. It can also be combined with other procedures if indicated. PMID- 22500069 TI - Cavernous haemangioma of the external auditory canal: clinical case and review of the literature. AB - Although benign vascular lesions are frequent in the head and the neck region, clinical evidence of cavernous haemangioma of the external auditory canal is extremely rare; when present, the lesion invades the middle ear space. Herein, a rare case of a soft mass filling the external auditory canal, not involving the tympanic membrane, in a symptomatic 59-year-old male is described. Clinical and audiological characteristics, imaging studies and surgical treatment with histological evaluation are reported, which led to a diagnosis of a cavernous haemangioma. This is only the seventh case described in the literature, to date, not involving the tympanic membrane and the middle ear space. In addition, a review has been made of the relevant literature with respect to epidemiology, presentation, evaluation, pathology, and management options for haemangiomas arising in the external auditory canal. PMID- 22500070 TI - Internal laryngopyocele as a cause of acute airway obstruction: an extremely rare case and review of the literature. AB - The laryngocele is an abnormal cystic dilatation of the saccule or appendix of the laryngeal ventricle, filled with air and communicating with the lumen of the larynx. When the neck of the laryngocele is obstructed, it becomes filled with mucus of the glandular secretion and is changed to a laryngomucocele. When this lesion becomes infected, a laryngopyocele is formed. The laryngocele is fairly rare and laryngopyocele occurs even more rarely. Overall, 39 cases of laryngopyocele have been reported in the world literature. Only in 4 cases was a laryngopyocele reported to have caused acute airway obstruction and only one case of internal laryngopyocele causing acute airway obstruction has been reported until now. This is the first case reported in the literature of an internal laryngopyocele in a female patient in a septic condition, which caused almost 100% obstruction of the airway. An emergency tracheotomy was performed in order to secure the airway. Computed tomography of neck was performed which revealed a cystic 29 mm hypodense mass extending from the right false vocal cord to the level of the epiglottis, narrowing the laryngeal cavity and causing an almost 100% airway obstruction. Laryngopyoceles may present with a rapid and alarming obstruction of the airway and, therefore, an urgent tracheotomy may be inevitable. It is an emergency case, in the field of otolaryngology, and should be included in the differential diagnosis of acute airway obstruction, especially when hoarseness, stridor and fever are present. Diagnosis requires a high index of suspicion for these lesions and scrupulous clinical and radiological evaluation. A computed tomography scan is critical in determining the nature and site of the lesion. The recommended treatment of laryngopyocele is immediate endoscopic drainage. Definitive management of laryngopyoceles is surgical excision which can be performed immediately after endoscopic drainage or some time thereafter. PMID- 22500071 TI - Protein acetylation and the physiological role of HDACs. PMID- 22500072 TI - MOfinder: a novel algorithm for detecting overlapping modules from protein protein interaction network. AB - Since organism development and many critical cell biology processes are organized in modular patterns, many algorithms have been proposed to detect modules. In this study, a new method, MOfinder, was developed to detect overlapping modules in a protein-protein interaction (PPI) network. We demonstrate that our method is more accurate than other 5 methods. Then, we applied MOfinder to yeast and human PPI network and explored the overlapping information. Using the overlapping modules of human PPI network, we constructed the module-module communication network. Functional annotation showed that the immune-related and cancer-related proteins were always together and present in the same modules, which offer some clues for immune therapy for cancer. Our study around overlapping modules suggests a new perspective on the analysis of PPI network and improves our understanding of disease. PMID- 22500073 TI - Physiologically based pharmacokinetic modeling in pediatric drug development: a clinician's request for a more integrated approach. PMID- 22500074 TI - Cytotoxicity of selected medicinal and nonmedicinal plant extracts to microbial and cervical cancer cells. AB - This study investigated the cytotoxicity of 55 species of plants. Each plant was rated as medicinal, or nonmedicinal based on the existing literature. About 79% of the medicinal plants showed some cytotoxicity, while 75% of the nonmedicinal plants showed bioactivity. It appears that Asteraceae, Labiatae, Pinaceae, and Chenopodiaceae were particularly active against human cervical cancer cells. Based on the literature, only three of the 55 plants have been significantly investigated for cytotoxicity. It is clear that there is much toxicological work yet to be done with both medicinal and nonmedicinal plants. PMID- 22500075 TI - Predicting protein interactions by Brownian dynamics simulations. AB - We present a newly adapted Brownian-Dynamics (BD)-based protein docking method for predicting native protein complexes. The approach includes global BD conformational sampling, compact complex selection, and local energy minimization. In order to reduce the computational costs for energy evaluations, a shell-based grid force field was developed to represent the receptor protein and solvation effects. The performance of this BD protein docking approach has been evaluated on a test set of 24 crystal protein complexes. Reproduction of experimental structures in the test set indicates the adequate conformational sampling and accurate scoring of this BD protein docking approach. Furthermore, we have developed an approach to account for the flexibility of proteins, which has been successfully applied to reproduce the experimental complex structure from the structure of two unbounded proteins. These results indicate that this adapted BD protein docking approach can be useful for the prediction of protein protein interactions. PMID- 22500076 TI - Human L-ficolin (ficolin-2) and its clinical significance. AB - Human L-ficolin (P35, ficolin-2) is synthesised in the liver and secreted into the bloodstream where it is one of the major pattern recognition molecules of plasma/serum. Like other ficolins, it consists of a collagen-like tail region linked to a fibrinogen-related globular head; a basic triplet subunit arises via a collagen-like triple helix, and this then forms higher multimers (typically a 12-mer, Mr 400K). Unlike other ficolins, it has a complex set of binding sites arranged within an internal cleft enabling it to recognise a variety of molecular patterns including acetylated sugars and certain 1,3-beta-glucans. It is one of the few molecules known to activate the lectin pathway of complement. Recently, some disease association studies (at either the DNA or protein level) have implicated L-ficolin in innate immunity, where it might cooperate with pentraxins and collectins. Emerging lines of evidence point to a role for L-ficolin in respiratory immunity, where its affinity for Pseudomonas aeruginosa could be significant. PMID- 22500077 TI - Fenretinide (4-HPR): a preventive chance for women at genetic and familial risk? AB - The incidence and mortality of breast cancer have been recently influenced by several new therapeutic strategies. In particular our knowledge on cancer precursors, risk biomarkers, and genetics has considerably increased, and prevention strategies are being successfully explored. Since their discovery, retinoids, the natural and synthetic derivatives of vitamin A, have been known to play a crucial role in cell and tissue differentiation and their ability to inhibit carcinogenesis has made them the ideal chemopreventive agents studied in several preclinical and clinical trials. Fenretinide (4-HPR) is the most studied retinoid in breast cancer chemoprevention clinical trials due to its selective accumulation in breast tissue and its favorable toxicological profile. This agent showed a significative reduction of the incidence of second breast tumors in premenopausal women confirmed after 15-year followups. Considering Fenretinide protective action, a similar trend on ovarian cancer, this drug warrants reevaluations as a preventive agent for high-risk young women, such as BRCA-1 and 2 mutation carriers or with a high familial risk. This favorable effect therefore provides a strong rationale for a primary prevention trial in these unaffected cohort of women. PMID- 22500078 TI - Electric-field-directed self-assembly of active enzyme-nanoparticle structures. AB - A method is presented for the electric-field-directed self-assembly of higher order structures composed of alternating layers of biotin nanoparticles and streptavidin-/avidin-conjugated enzymes carried out on a microelectrode array device. Enzymes included in the study were glucose oxidase (GOx), horseradish peroxidase (HRP), and alkaline phosphatase (AP); all of which could be used to form a light-emitting microscale glucose sensor. Directed assembly included fabricating multilayer structures with 200 nm or 40 nm GOx-avidin-biotin nanoparticles, with AP-streptavidin-biotin nanoparticles, and with HRP streptavidin-biotin nanoparticles. Multilayered structures were also fabricated with alternate layering of HRP-streptavidin-biotin nanoparticles and GOx-avidin biotin nanoparticles. Results showed that enzymatic activity was retained after the assembly process, indicating that substrates could still diffuse into the structures and that the electric-field-based fabrication process itself did not cause any significant loss of enzyme activity. These methods provide a solution to overcome the cumbersome passive layer-by-layer assembly methods to efficiently fabricate higher-order active biological and chemical hybrid structures that can be useful for creating novel biosensors and drug delivery nanostructures, as well as for diagnostic applications. PMID- 22500079 TI - Topical application effect of the isolectin hydrogel (Cramoll 1,4) on second degree burns: experimental model. AB - This study aimed at evaluating the use of hydrogel isolectin in the treatment of second-degree burns. Twenty male rats were randomly divided into two groups (G1 = treatment with hydrogel containing 100 MUg/mL Cramoll 1,4 and G2 = Control, hydrogel). After 7, 14, 21, 28, and 35 days, animals were euthanized. On the 7th day, G1 showed intense exudates, necrosis and edema. On the 14th day, G1 showed tissue reepithelialization and moderate autolysis. On the 21st day, G1 showed intense fibroblastic proliferation, presence of dense collagen, and moderate fibrosis. On the 28th day, G1 showed complete tissue epithelialization. On the 35th day, G1 showed modeled dense collagen. The significant wound contraction was initiated from day, 14 in the G1. There were no significant differences in biochemical and hematological parameters analyzed. These results extend the potential of therapeutic applications for Cramoll 1,4 in the treatment of thermal burns. PMID- 22500080 TI - Advances in BAC-based physical mapping and map integration strategies in plants. AB - In the advent of next-generation sequencing (NGS) platforms, map-based sequencing strategy has been recently suppressed being too expensive and laborious. The detailed studies on NGS drafts alone indicated these assemblies remain far from gold standard reference quality, especially when applied on complex genomes. In this context the conventional BAC-based physical mapping has been identified as an important intermediate layer in current hybrid sequencing strategy. BAC-based physical map construction and its integration with high-density genetic maps have benefited from NGS and high-throughput array platforms. This paper addresses the current advancements of BAC-based physical mapping and high-throughput map integration strategies to obtain densely anchored well-ordered physical maps. The resulted maps are of immediate utility while providing a template to harness the maximum benefits of the current NGS platforms. PMID- 22500082 TI - Muscle contractility and cell motility. PMID- 22500081 TI - The anticaries effect of a food extract (shiitake) in a short-term clinical study. AB - The main objective was to investigate whether low-molecular-weight fraction of edible mushroom shiitake extract (Lentinus edodes) possesses caries-preventive properties. The study was designed as a double-blind, three-leg, cross-over, randomized, controlled clinical trial carried out on two series of volunteers at the University of Gothenburg, and the Academic Centre for Dentistry Amsterdam. Volunteers rinsed twice daily with a solution containing low-molecular-weight fraction of edible mushroom, placebo (negative control without active ingredients), or Meridol (positive control, AmF-SnF(2)) for two weeks, with a two week washout period between each rinsing period. Changes in the acidogenicity of dental plaque before and after a sucrose challenge, shifts in microbial composition, and plaque scores were determined. Frequent rinses with shiitake reduced the metabolic activity of dental plaque. No reduction of plaque scores and no inhibition of the production of organic acids in plaque was found. Minor differences in microbial composition between test sessions were found. To conclude, the results indicate that shiitake extract has anticariogenic potential, but not to the same extent as the positive control. PMID- 22500083 TI - Are basophils important mediators for helminth-induced Th2 immune responses? A debate. AB - Helminth parasites induce Th2 immune responses. Immunological mechanisms leading to Th2 induction are mainly dependent on IL-4. However, early source of IL-4 has not been precisely identified. Noticeably, basophils seem to be important mediators for inducing and maintaining the Th2 response probably because they secrete IL-4 and exert functions similar to APCs. Nevertheless, recent experimental evidence points that DCs could be also significant participants during this process. The involvement of basophils during memory responses is also discussed. PMID- 22500084 TI - Effects of saponins against clinical E. coli strains and eukaryotic cell line. AB - Saponins are detergent-like substances showing antibacterial as well as anticancer potential. In this study, the effects of saponins from Quillaja saponaria were analyzed against prokaryotic and eukaryotic cells. Multidrug resistant clinical E. coli strains were isolated from human urine. As eukaryotic cells, the CHO-K1 cell lines were applied. Antibacterial effect of ampicillin, streptomycin, and ciprofloxacin in the presence of saponins was measured by cultivation methods. Properties of saponins against CHO-K1 cells were measured by the MTT test, hemolysis assay and flow cytometry. Saponin from Quillaja saponaria has a cytotoxic effect at concentrations higher than 25 MUg/mL and in the range of 12-50 MUg/mL significantly increases the level of early apoptotic cells. Saponin at dose of 12 MUg/mL enhances the six E. coli strains growth. We postulate that saponins increase the influx of nutrients from the medium into E. coli cells. Saponins do not have synergetic effects on antibacterial action of tested antibiotics. In contrary, in the presence of saponins and antibiotics, more CFU/mL E. coli cells were observed. This effect was similar to saponins action alone towards E. coli cells. In conclusion, saponins was cytotoxic against CHO-K1 cells, whereas against E. coli cells this effect was not observed. PMID- 22500085 TI - Studying interactions by molecular dynamics simulations at high concentration. AB - Molecular dynamics simulations have been used to study molecular encounters and recognition. In recent works, simulations using high concentration of interacting molecules have been performed. In this paper, we consider the practical problems for setting up the simulation and to analyse the results of the simulation. The simulation of beta 2-microglobulin association and the simulation of the binding of hydrogen peroxide by glutathione peroxidase are provided as examples. PMID- 22500086 TI - Effective silencing of Sry gene with RNA interference in developing mouse embryos resulted in feminization of XY gonad. AB - Delivering siRNA or shRNA into the developing embryos is still a main challenge to use of RNAi in mammalian systems. Here we analyze several factors influencing RNAi-mediated silencing of Sry gene, which is a tightly controlled spatiotemporal expressed gene and only shortly expressed in developing mouse embryo gonad. A Sry gene-specific shRNAs expression vector (pSilencer4.1/Sry565) was constructed. The shRNA constructs were mixed with polyethylenimines (PEIs) to form a complex and then injected into pregnant mice though tail vein. Our results showed that Sry gene was downregulated significantly in developing embryos. Further study revealed that knocking-down of Sry expression resulted in feminization of gonad development in mouse embryos and the expression level of Sox9 and Wt1 gene was also significantly changed by downregulation of Sry. The transfection efficiency is associated with the amount of plasmid DNA injection, injection time, injection speed, and volume. Our studies suggest that transplacental RNAi could be implemented by tail vein injection of plasmid vector into pregnant mice. PMID- 22500088 TI - In vivo testing of microRNA-mediated gene knockdown in zebrafish. AB - The zebrafish (Danio rerio) has become an attractive model for human disease modeling as there are a large number of orthologous genes that encode similar proteins to those found in humans. The number of tools available to manipulate the zebrafish genome is limited and many currently used techniques are only effective during early development (such as morpholino-based antisense technology) or it is phenotypically driven and does not offer targeted gene knockdown (such as chemical mutagenesis). The use of RNA interference has been met with controversy as off-target effects can make interpreting phenotypic outcomes difficult; however, this has been resolved by creating zebrafish lines that contain stably integrated miRNA constructs that target the desired gene of interest. In this study, we show that a commercially available miRNA vector system with a mouse-derived miRNA backbone is functional in zebrafish and is effective in causing eGFP knockdown in a transient in vivo eGFP sensor assay system. We chose to apply this system to the knockdown of transcripts that are implicated in the human cardiac disorder, Long QT syndrome. PMID- 22500087 TI - Roles of pro- and anti-inflammatory cytokines in the pathogenesis of SLE. AB - SLE is an autoimmune inflammatory disease in which various pro- and anti inflammatory cytokines, including TGF-beta, IL-10, BAFF, IL-6, IFN-alpha, IFN gamma, IL-17, and IL-23, play crucial pathogenic roles. Virtually, all these cytokines can be generated by both innate and adaptive immune cells and exert different effects depending on specific local microenvironment. They can also interact with each other, forming a complex network to maintain delicate immune homeostasis. In this paper, we elaborate on the abnormal secretion and functions of these cytokines in SLE, analyze their potential pathogenic roles, and probe into the possibility of them being utilized as targets for therapy. PMID- 22500089 TI - Use of recombination-mediated genetic engineering for construction of rescue human cytomegalovirus bacterial artificial chromosome clones. AB - Bacterial artificial chromosome (BAC) technology has contributed immensely to manipulation of larger genomes in many organisms including large DNA viruses like human cytomegalovirus (HCMV). The HCMV BAC clone propagated and maintained inside E. coli allows for accurate recombinant virus generation. Using this system, we have generated a panel of HCMV deletion mutants and their rescue clones. In this paper, we describe the construction of HCMV BAC mutants using a homologous recombination system. A gene capture method, or gap repair cloning, to seize large fragments of DNA from the virus BAC in order to generate rescue viruses, is described in detail. Construction of rescue clones using gap repair cloning is highly efficient and provides a novel use of the homologous recombination-based method in E. coli for molecular cloning, known colloquially as recombineering, when rescuing large BAC deletions. This method of excising large fragments of DNA provides important prospects for in vitro homologous recombination for genetic cloning. PMID- 22500090 TI - Human umbilical cord blood-derived mesenchymal stem cell therapy promotes functional recovery of contused rat spinal cord through enhancement of endogenous cell proliferation and oligogenesis. AB - Numerous studies have shown the benefits of mesenchymal stem cells (MSCs) on the repair of spinal cord injury (SCI) model and on behavioral improvement, but the underlying mechanisms remain unclear. In this study, to investigate possible mechanisms by which MSCs contribute to the alleviation of neurologic deficits, we examined the potential effect of human umbilical cord blood-derived MSCs (hUCB MSCs) on the endogenous cell proliferation and oligogenesis after SCI. SCI was injured by contusion using a weight-drop impactor and hUCB-MSCs were transplanted into the boundary zone of the injured site. Animals received a daily injection of bromodeoxyuridine (BrdU) for 7 days after treatment to identity newly synthesized cells of ependymal and periependymal cells that immunohistochemically resembled stem/progenitor cells was evident. Behavior analysis revealed that locomotor functions of hUCB-MSCs group were restored significantly and the cavity volume was smaller in the MSCs-transplanted rats compared to the control group. In MSCs transplanted group, TUNEL-positive cells were decreased and BrdU-positive cells were significantly increased rats compared with control group. In addition, more of BrdU-positive cells expressed neural stem/progenitor cell nestin and oligo lineage cell such as NG2, CNPase, MBP and glial fibrillary acidic protein typical of astrocytes in the MSC-transplanted rats. Thus, endogenous cell proliferation and oligogenesis contribute to MSC-promoted functional recovery following SCI. PMID- 22500091 TI - Asbestos-induced cellular and molecular alteration of immunocompetent cells and their relationship with chronic inflammation and carcinogenesis. AB - Asbestos causes lung fibrosis known as asbestosis as well as cancers such as malignant mesothelioma and lung cancer. Asbestos is a mineral silicate containing iron, magnesium, and calcium with a core of SiO(2). The immunological effect of silica, SiO(2), involves the dysregulation of autoimmunity because of the complications of autoimmune diseases found in silicosis. Asbestos can therefore cause alteration of immunocompetent cells to result in a decline of tumor immunity. Additionally, due to its physical characteristics, asbestos fibers remain in the lung, regional lymph nodes, and the pleural cavity, particularly at the opening sites of lymphatic vessels. Asbestos can induce chronic inflammation in these areas due to the production of reactive oxygen/nitrogen species. As a consequence, immunocompetent cells can have their cellular and molecular features altered by chronic and recurrent encounters with asbestos fibers, and there may be modification by the surrounding inflammation, all of which eventually lead to decreased tumor immunity. In this paper, the brief results of our investigation regarding reduction of tumor immunity of immunocompetent cells exposed to asbestos in vitro are discussed, as are our findings concerned with an investigation of chronic inflammation and analyses of peripheral blood samples derived from patients with pleural plaque and mesothelioma that have been exposed to asbestos. PMID- 22500092 TI - The safety of cruciferous plants in humans: a systematic review. AB - Some cruciferous plants may serve as preventive treatments for several medical conditions; our objective was to systematically investigate their safety in humans. Four electronic databases were searched, and, of 10,831 references identified, 50 were included. Data were extracted by two independent reviewers, whereafter the association between interventions and adverse events was assessed. Adverse events in 53 subjects were identified through clinical trials; of these, altered drug metabolism was rated as certainly/likely caused by cruciferous plants. Adverse events in 1247 subjects were identified through observational studies, of which none received high causality ratings. Adverse events in 35 subjects were identified through case reports, of which allergies and warfarin resistance were rated as certainly/likely caused by cruciferous plants. We conclude that cruciferous plants are safe in humans, with the exception of allergies. Individuals treated with warfarin should consult their physician. Further investigation of uses of cruciferous plants in preventative medicine is warranted. PMID- 22500093 TI - Troglitazone induces extracellular matrix and cytoskeleton remodeling in mouse collecting duct cells. AB - Peroxisome proliferator-activated receptor (PPARgamma) has been shown to have a protective role in the nephron through its ability to inhibit a transforming growth factor- (TGF-beta) mediated fibrotic response. In contrast, PPARgamma was also shown to induce a mesenchymal transformation in epithelial intestinal cells. A fibrotic response in the collecting duct has only recently been established; however, the entire collecting duct has not been fully examined. Inner medullary collecting duct cells (IMCD-K2) and mouse cortical collecting duct cells (M1), representing the cortical and medullary collecting duct, were exposed to 5-10 MUM troglitazone for 24 hours. Troglitazone resulted in an elongated morphology, 60% decreases in E-cadherin and beta-catenin, a 35% decrease in alpha-catenin, and a 1.5-fold increase in fibronectin. These effects were not reversed with PPARgamma antagonists or affected with PPARgamma overexpression. Our results indicate that troglitazone induced a mesenchymal-like transformation in M1 and IMCD-K2 epithelial cells independently of PPARgamma. PMID- 22500094 TI - Evaluation of plant and fungal extracts for their potential antigingivitis and anticaries activity. AB - The link between diet and health has lead to the promotion of functional foods which can enhance health. In this study, the oral health benefits of a number of food homogenates and high molecular mass and low molecular mass fractions were investigated. A comprehensive range of assays were performed to assess the action of these foods on the development of gingivitis and caries using bacterial species associated with these diseases. Both antigingivitis and anticaries effects were investigated by assays examining the prevention of biofilm formation and coaggregation, disruption of preexisting biofilms, and the foods' antibacterial effects. Assays investigating interactions with gingival epithelial cells and cytokine production were carried out to assess the foods' anti- gingivitis properties. Anti-caries properties such as interactions with hydroxyapatite, disruption of signal transduction, and the inhibition of acid production were investigated. The mushroom and chicory homogenates and low molecular mass fractions show promise as anti-caries and anti-gingivitis agents, and further testing and clinical trials will need to be performed to evaluate their true effectiveness in humans. PMID- 22500095 TI - Quantitative proteomic study of human lung squamous carcinoma and normal bronchial epithelial acquired by laser capture microdissection. AB - OBJECTIVE: To investigate the differential protein profile of human lung squamous carcinoma (HLSC) and normal bronchial epithelium (NBE) and provide preliminary results for further study to explore the carcinogenic mechanism of HLSC. METHODS: Laser capture microdissection (LCM) was used to purify the target cells from 10 pairs of HLSC tissues and their matched NHBE, respectively. A stable-isotope labeled strategy using iTRAQ, followed by 2D-LC/Q-STAR mass spectrometry, was performed to separate and identify the differential expression proteins. RESULTS: A total of 96 differential expression proteins in the LCM-purified HLSC and NBE were identified. Compared with NBE, 49 proteins were upregulated and 47 proteins were downregulated in HLSC. Furthermore, the expression levels of the differential proteins including HSPB1, CKB, SCCA1, S100A8, as well as S100A9 were confirmed by western blot and tissue microarray and were consistent with the results of quantitative proteomics. CONCLUSION: The different expression proteins in HLSC will provide scientific foundation for further study to explore the carcinogenic mechanism of HLSC. PMID- 22500096 TI - CD24 expression as a marker for predicting clinical outcome in human gliomas. AB - CD24 is overexpressed in glioma cells in vitro and in vivo. However, the correlation of its expression with clinicopathological parameters of gliomas and its prognostic significance in this tumor remain largely unknown. To address this problem, 151 glioma specimens and 10 nonneoplastic brain tissues were collected. Quantitative real-time PCR, immunochemistry assay, and Western blot analysis were carried out to investigate the expression of CD24. As per the results, CD24 was overexpressed in gliomas. Its expression levels in glioma tissues with higher grade (P < 0.001) and lower KPS (P < 0.001) were significantly higher than those with lower grade and higher KPS, respectively. Cox multifactor analysis showed that CD24 (P = 0.02) was an independent prognosis factor for human glioma. Our data provides convincing evidence for the first time that the overexpression of CD24 at gene and protein levels is correlated with advanced clinicopathological parameters and poor prognosis in patients with glioma. PMID- 22500097 TI - A novel antihepatitis drug, bicyclol, prevents liver carcinogenesis in diethylnitrosamine-initiated and phenobarbital-promoted mice tumor model. AB - Bicyclol, an antihepatitis drug developed by Chinese scientists, has been shown to prevent the malignant transformation induced by 3-methylcholanthrene and 12-O tetradecanoylphorbol-13-acetate in WB-F344 rat liver epithelial cells. This study provides further evidence on its role as a chemopreventive agent in experimental mice with diethylnitrosamine- (DEN-) initiated and phenobarbital- (PB-) promoted liver carcinoma. Liver tissue and serum were collected. In the two-stage model of hepatocarcinogenesis in mice, oral administration of bicyclol (100, 200 mg/kg) before DEN injection showed significant reduction in the incidence of hepatocellular foci, nodules, or carcinoma. Histopathological examination revealed that there was no hepatocellular carcinoma (HCC) and hepatoma formation in the mice pretreated with bicyclol (200 mg/kg) at week 20, while the mice treated with DEN/PB developed 33.3% HCC and 55.6% hepatoma. Furthermore, the serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), and alpha-fetal protein (AFP) in serum significantly increased in the DEN/PB model group in comparison with the control group. Pretreatment with bicyclol showed a marked reduction in the above condition. Bicyclol also decreased the expression of AFP and proliferating cell nuclear antigen level in the liver tissue and attenuated the decrease in body weight. In this study, we also found that 10 weeks after stopping the administration of PB and drugs, the control and bicyclol treated (200 mg/kg) animals showed no HCC and hepatoma formation at the time of termination whereas DEN/PB-induced mice developed 100% hepatoma and 50% HCC. These results further indicate that bicyclol has the chemopreventive potential for liver carcinogenesis induced by carcinogens. PMID- 22500098 TI - Effects of IRF5 lupus risk haplotype on pathways predicted to influence B cell functions. AB - Both genetic and environmental interactions affect systemic lupus erythematosus (SLE) development and pathogenesis. One known genetic factor associated with lupus is a haplotype of the interferon regulatory factor 5 (IRF5) gene. Analysis of global gene expression microarray data using gene set enrichment analysis identified multiple interferon- and inflammation-related gene sets significantly overrepresented in cells with the risk haplotype. Pathway analysis using expressed genes from the significant gene sets impacted by the IRF5 risk haplotype confirmed significant correlation with the interferon pathway, Toll like receptor pathway, and the B-cell receptor pathway. SLE patients with the IRF5 risk haplotype have a heightened interferon signature, even in an unstimulated state (P = 0.011), while patients with the IRF5 protective haplotype have a B cell interferon signature similar to that of controls. These results identify multiple genes in functionally significant pathways which are affected by IRF5 genotype. They also establish the IRF5 risk haplotype as a key determinant of not only the interferon response, but also other B-cell pathways involved in SLE. PMID- 22500100 TI - Functional foods: towards improving oral health. PMID- 22500099 TI - Human blood-vessel-derived stem cells for tissue repair and regeneration. AB - Multipotent stem/progenitor cells with similar developmental potentials have been independently identified from diverse human tissue/organ cultures. The increasing recognition of the vascular/perivascular origin of mesenchymal precursors suggested blood vessels being a systemic source of adult stem/progenitor cells. Our group and other laboratories recently isolated multiple stem/progenitor cell subsets from blood vessels of adult human tissues. Each of the three structural layers of blood vessels: intima, media, and adventitia has been found to include at least one precursor population, that is, myogenic endothelial cells (MECs), pericytes, and adventitial cells (ACs), respectively. MECs and pericytes efficiently regenerate myofibers in injured and dystrophic skeletal muscles as well as improve cardiac function after myocardial infarction. The applications of ACs in vascular remodeling and angiogenesis/vasculogenesis have been examined. Our recent finding that MECs and pericytes can be purified from cryogenically banked human primary muscle cell culture further indicates their potential applications in personalized regenerative medicine. PMID- 22500101 TI - Triiodothyronine represses MUC5AC expression by antagonizing Sp1 binding to its promoter in human bronchial epithelial HBE16 cells. AB - Mucus hypersecretion is a distinguished feature of chronic inflammatory airway diseases. Interestingly, in this condition thyroid function is impaired with decreased level of triiodothyronine (T3), indicating potential link between low level of T3 and mucus hypersecretion. But the underlying mechanisms are poorly understood. In this study we aimed to elucidate the effect of T3 on MUC5AC secretion in human bronchial epithelial HBE16 cells and further investigate how T3 regulates MUC5AC gene expression at transcriptional level. By RT-PCR and ELISA we showed that T3 inhibited MUC5AC mRNA expression and protein secretion in HBE16 cells. Furthermore, luciferase assay and site-directed mutagenesis analysis demonstrated that T3 repressed MUC5AC expression at transcriptional level and the mechanism might partly lie in the specific inhibition of Sp1 binding to the promoter. Our results suggest that decreased T3 level leads to the release of repression of MUC5AC expression and thus contributes to mucus hypersecretion. PMID- 22500102 TI - Micromechanical thermal assays of Ca2+-regulated thin-filament function and modulation by hypertrophic cardiomyopathy mutants of human cardiac troponin. AB - Microfabricated thermoelectric controllers can be employed to investigate mechanisms underlying myosin-driven sliding of Ca(2+)-regulated actin and disease associated mutations in myofilament proteins. Specifically, we examined actin filament sliding-with or without human cardiac troponin (Tn) and alpha tropomyosin (Tm)-propelled by rabbit skeletal heavy meromyosin, when temperature was varied continuously over a wide range (~20-63 degrees C). At the upper end of this temperature range, reversible dysregulation of thin filaments occurred at pCa 9 and 5; actomyosin function was unaffected. Tn-Tm enhanced sliding speed at pCa 5 and increased a transition temperature (T(t)) between a high activation energy (E(a)) but low temperature regime and a low E(a) but high temperature regime. This was modulated by factors that alter cross-bridge number and kinetics. Three familial hypertrophic cardiomyopathy (FHC) mutations, cTnI R145G, cTnI K206Q, and cTnT R278C, cause dysregulation at temperatures ~5-8 degrees C lower; the latter two increased speed at pCa 5 at all temperatures. PMID- 22500104 TI - Sesquiterpene lactones isolated from Elephantopus scaber L. inhibits human lymphocyte proliferation and the growth of tumour cell lines and induces apoptosis in vitro. AB - This study was designed to isolate the compounds responsible for the cytotoxic properties of South Indian Elephantopus scaber L. and further investigate their effects on quiescent and proliferating cells. Bioassay-guided isolation of the whole plant of chloroform extract of South Indian Elephantopus scaber afforded the known sesquiterpene lactone, deoxyelephantopin, and isodeoxyelephantopin whose structures were determined by spectroscopic methods. These compounds caused a dose dependent reduction in the viability of L-929 tumour cells in 72 h culture (IC(50) value of 2.7 MUg/mL and 3.3 MUg/mL) by the cell viability assay. Both the compounds act selectively on quiescent and PHA-stimulated proliferating human lymphocytes and inhibited tritiated thymidine incorporation into cellular DNA of DLA tumour cells. The compound deoxyelephantopin at a concentration of 3 MUg/mL caused maximum apoptotic cells. It also exhibited significant in vivo antitumour efficacy against DLA tumour cells. The results, therefore, indicate that the antiproliferative property of deoxyelephantopin and isodeoxyelephantopin could be used in regimens for treating tumors with extensive proliferative potencies. PMID- 22500103 TI - EhADH112 is a Bro1 domain-containing protein involved in the Entamoeba histolytica multivesicular bodies pathway. AB - EhADH112 is an Entamoeba histolytica Bro1 domain-containing protein, structurally related to mammalian ALIX and yeast BRO1, both involved in the Endosomal Sorting Complexes Required for Transport (ESCRT)-mediated multivesicular bodies (MVB) biogenesis. Here, we investigated an alternative role for EhADH112 in the MVB protein trafficking pathway by overexpressing 166 amino acids of its N-terminal Bro1 domain in trophozoites. Trophozoites displayed diminished phagocytosis rates and accumulated exogenous Bro1 at cytoplasmic vesicles which aggregated into aberrant complexes at late stages of phagocytosis, probably preventing EhADH112 function. Additionally, the existence of a putative E. histolytica ESCRT-III subunit (EhVps32) presumably interacting with EhADH112, led us to perform pull down experiments with GST-EhVps32 and [(35)S]-labeled EhADH112 or EhADH112 derivatives, confirming EhVps32 binding to EhADH112 through its Bro1 domain. Our overall results define EhADH112 as a novel member of ESCRT-accessory proteins transiently present at cellular surface and endosomal compartments, probably contributing to MVB formation during phagocytosis. PMID- 22500105 TI - AngiotensinII preconditioning promotes angiogenesis in vitro via ERKs phosphorylation. AB - AngiotensinII (AngII) is involved in not only the formation of cardiac hypertrophy but also the development of cardiac remodeling both of which are associated with myocardial angiogenesis. This study was therefore performed to clarify the effects of AngII on the formation of vasculatures by cultured cardiac microvascular endothelial cells (CMVECs) after a long-period stimulation with or without the AngII preconditioning. Incubation with AngII for 18 hrs significantly impaired the formation of capillary-like tubes comparing to that without AngII. CMVECs with AngII pretreatment for 5 and 10 min formed more capillary-like tubes than those without AngII pretreatment, suggesting that preconditioning with AngII at a lower dose for a short period could prevent the further damage of CMVECs by a higher concentration of AngII. Moreover, AngII (10(-7) M) stimulation for 5 and 10 min significantly induced the increase in extracellular signal-regulated protein kinases (ERKs) phosphorylation, and an ERKs inhibitor, PD98059, abrogated the increase in the formation of capillary-like tubes induced by the AngII pretreatment. In conclusion, preconditioning with a lower concentration of AngII for a short period prevents the subsequent impairment of CMVECs by a higher dose of AngII, at least in part, through the increase in ERKs phosphorylation. PMID- 22500106 TI - Urinary neutrophil gelatinase-associated lipocalin is a potential biomarker for renal damage in patients with systemic lupus erythematosus. AB - Neutrophil gelatinase-associated lipocalin (NGAL) has been demonstrated to be a novel biomarker in acute and chronic kidney disease. We hypothesized that 24-hour urinary NGAL excretion may be a predictor for renal damage in patients with systemic lupus erythematosus (SLE). Thirty-four SLE patients with renal involvement (SLE-renal group), 8 SLE patients without renal involvement (SLE nonrenal group), 14 patients with non-SLE autoimmune diseases (disease control or DC group), and 12 healthy volunteers (normal control or NC group) were compared for 24-hour urinary excretion of NGAL and different cytokines. We found that the 24-hour urinary NGAL excretion in the SLE-renal group was higher than that in the SLE-non-renal, DC, and NC groups. However, the excretion of interleukin-10, transforming growth factor-beta1, and tumor necrosis factor-alpha was not different between the SLE-renal and SLE-non-renal groups. Furthermore, NGAL excretion in the SLE-renal group was correlated with serum creatinine levels and creatinine clearance, but not with the SLE Disease Activity Index score. Multivariate logistic regression analysis and receiver operating characteristic curve analysis revealed that 24-hour urinary NGAL excretion is a potential biomarker for renal damage in SLE patients, with higher sensitivity and specificity than anti-dsDNA antibody titers. PMID- 22500107 TI - Molecular modeling of the M3 acetylcholine muscarinic receptor and its binding site. AB - The present study reports the results of a combined computational and site mutagenesis study designed to provide new insights into the orthosteric binding site of the human M3 muscarinic acetylcholine receptor. For this purpose a three dimensional structure of the receptor at atomic resolution was built by homology modeling, using the crystallographic structure of bovine rhodopsin as a template. Then, the antagonist N-methylscopolamine was docked in the model and subsequently embedded in a lipid bilayer for its refinement using molecular dynamics simulations. Two different lipid bilayer compositions were studied: one component palmitoyl-oleyl phosphatidylcholine (POPC) and two-component palmitoyl-oleyl phosphatidylcholine/palmitoyl-oleyl phosphatidylserine (POPC-POPS). Analysis of the results suggested that residues F222 and T235 may contribute to the ligand receptor recognition. Accordingly, alanine mutants at positions 222 and 235 were constructed, expressed, and their binding properties determined. The results confirmed the role of these residues in modulating the binding affinity of the ligand. PMID- 22500108 TI - Interaction between pheromone and its receptor of the fission yeast Schizosaccharomyces pombe examined by a force spectroscopy study. AB - Interaction between P-factor, a peptide pheromone composed of 23 amino acid residues, and its pheromone receptor, Mam2, on the cell surface of the fission yeast Schizosaccharomyces pombe was examined by an atomic force microscope (AFM). An AFM tip was modified with P-factor derivatives to perform force curve measurements. The specific interaction force between P-factor and Mam2 was calculated to be around 120 pN at a probe speed of 1.74 MUm/s. When the AFM tip was modified with truncated P-factor derivative lacking C-terminal Leu, the specific interaction between the tip and the cell surface was not observed. These results were also confirmed with an assay system using a green fluorescent protein (GFP) reporter gene to monitor the activation level of signal transduction following the interaction of Mam2 with P-factor. PMID- 22500109 TI - The immunogenicity of the tumor-associated antigen alpha-fetoprotein is enhanced by a fusion with a transmembrane domain. AB - AIM: To investigate the ability of recombinant modified vaccinia virus Ankara (rMVA) vector to induce an immune response against a well-tolerated self-antigen. METHODS: rMVA vectors expressing different form of alpha-fetoprotein (AFP) were produced and characterized. Naive mice were vaccinated with MVA vectors expressing the AFP antigen in either a secreted, or a membrane-bound, or an intracellular form. The immune response was monitored by an IFNGamma ELISpot assay and antibody detection. RESULTS: Vaccination with the membrane-associated form of AFP induced a stronger CD8(+) T-cell response compared to the ones obtained with the MVA encoding the secreted or the intracellular forms of AFP. Moreover, the vaccination with the membrane-bound AFP elicited the production of AFP-specific antibodies. CONCLUSIONS: The AFP transmembrane form is more immunogenic. Expressing a membrane-bound form in the context of an MVA vaccination could enhance the immunogenicity of a self-antigen. PMID- 22500110 TI - Acid-base disorders in patients with chronic obstructive pulmonary disease: a pathophysiological review. AB - The authors describe the pathophysiological mechanisms leading to development of acidosis in patients with chronic obstructive pulmonary disease and its deleterious effects on outcome and mortality rate. Renal compensatory adjustments consequent to acidosis are also described in detail with emphasis on differences between acute and chronic respiratory acidosis. Mixed acid-base disturbances due to comorbidity and side effects of some drugs in these patients are also examined, and practical considerations for a correct diagnosis are provided. PMID- 22500112 TI - Characterization, tissue expression, and imprinting analysis of the porcine CDKN1C and NAP1L4 genes. AB - CDKN1C and NAP1L4 in human CDKN1C/KCNQ1OT1 imprinted domain are two key candidate genes responsible for BWS (Beckwith-Wiedemann syndrome) and cancer. In order to increase understanding of these genes in pigs, their cDNAs are characterized in this paper. By the IMpRH panel, porcine CDKN1C and NAP1L4 genes were assigned to porcine chromosome 2, closely linked with IMpRH06175 and with LOD of 15.78 and 17.94, respectively. By real-time quantitative RT-PCR and polymorphism-based method, tissue and allelic expression of both genes were determined using F1 pigs of Rongchang and Landrace reciprocal crosses. The transcription levels of porcine CDKN1C and NAP1L4 were significantly higher in placenta than in other neonatal tissues (P < 0.01) although both genes showed the highest expression levels in the lung and kidney of one-month pigs (P < 0.01). Imprinting analysis demonstrated that in pigs, CDKN1C was maternally expressed in neonatal heart, tongue, bladder, ovary, spleen, liver, skeletal muscle, stomach, small intestine, and placenta and biallelically expressed in lung and kidney, while NAP1L4 was biallelically expressed in the 12 neonatal tissues examined. It is concluded that imprinting of CDKN1C is conservative in mammals but has tissue specificity in pigs, and imprinting of NAP1L4 is controversial in mammalian species. PMID- 22500111 TI - Targeting costimulatory molecules to improve antitumor immunity. AB - The full activation of T cells necessitates the concomitant activation of two signals, the engagement of T-cell receptor by peptide/major histocompatibility complex II and an additional signal delivered by costimulatory molecules. The best characterized costimulatory molecules belong to B7/CD28 and TNF/TNFR families and play crucial roles in the modulation of immune response and improvement of antitumor immunity. Unfortunately, tumors often generate an immunosuppressive microenvironment, where T-cell response is attenuated by the lack of costimulatory molecules on the surface of cancer cells. Thus, targeting costimulatory pathways represent an attractive therapeutic strategy to enhance the antitumor immunity in several human cancers. Here, latest therapeutic approaches targeting costimulatory molecules will be described. PMID- 22500113 TI - Localization and regulation of the N terminal splice variant of PGC-1alpha in adult skeletal muscle fibers. AB - The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) regulates expression of genes for metabolism and muscle fiber type. Recently, a novel splice variant of PGC-1alpha (NT-PGC-1alpha, amino acids 1-270) was cloned and found to be expressed in muscle. Here we use Flag-tagged NT-PGC-1alpha to examine the subcellular localization and regulation of NT-PGC-1alpha in skeletal muscle fibers. Flag-NT-PGC-1alpha is located predominantly in the myoplasm. Nuclear NT-PGC-1alpha can be increased by activation of protein kinase A. Activation of p38 MAPK by muscle activity or of AMPK had no effect on the subcellular distribution of NT-PGC-1alpha. Inhibition of CRM1-mediated export only caused relatively slow nuclear accumulation of NT PGC-1alpha, indicating that nuclear export of NT-PGC-1alpha may be mediated by both CRM1-dependent and -independent pathways. Together these results suggest that the regulation of NT-PGC-1alpha in muscle fibers may be very different from that of the full-length PGC-1alpha, which is exclusively nuclear. PMID- 22500114 TI - Stem cell-mediated osteogenesis: therapeutic potential for bone tissue engineering. AB - Intervertebral disc degeneration often requires bony spinal fusion for long-term relief. Current arthrodesis procedures use bone grafts from autogenous bone, allogenic backed bone, or synthetic materials. Autogenous bone grafts can result in donor site morbidity and pain at the donor site, while allogenic backed bone and synthetic materials have variable effectiveness. Given these limitations, researchers have focused on new treatments that will allow for safe and successful bone repair and regeneration. Mesenchymal stem cells have received attention for their ability to differentiate into osteoblasts, cells that synthesize new bone. With the recent advances in scaffold and biomaterial technology as well as stem cell manipulation and transplantation, stem cells and their scaffolds are uniquely positioned to bring about significant improvements in the treatment and outcomes of spinal fusion and other injuries. PMID- 22500115 TI - Role of vandetanib in the management of medullary thyroid cancer. AB - Traditionally available treatments, like cytotoxic chemotherapy and external-beam radiation therapy, are limited and essentially ineffective for metastatic medullary thyroid carcinoma (MTC). In the last decade, small-molecule tyrosine kinase inhibitors (TKI) have been introduced in the field of thyroid cancer, after having been shown effective in a wide variety of other tumors. This review focuses on vandetanib (ZD6474, ZactimaTM; AstraZeneca) and its role in the treatment of MTC. Vandetanib is an oral TKI that targets VEGF receptors 2 and 3, RET, and at higher concentrations, the epidermal growth factor (EGF) receptor. This drug has been tested in two important phase II studies which demonstrated that both the 100 and 300 mg/day dosage of vandetanib have antitumor activity on advanced MTC. A phase III trial (ZETA trial) evaluating vandetanib in 331 patients with locally advanced or metastatic MTC showed a significant prolongation of PFS for patients receiving vandetanib compared with placebo. Toxicity surveillance in all studies reported high rates of adverse effects with diarrhea, rash, fatigue and nausea being the most commonly experienced by patients. Vandetanib is currently approved in the United States for unresectable locally advanced or metastatic MTC and has become a new standard of care in this rare and indolent pathology. PMID- 22500116 TI - Role and clinical utility of pramipexole extended release in the treatment of early Parkinson's disease. AB - The aim of this article is to provide a short review of the most relevant pharmacological and clinical data on pramipexole extended release (ER) as well as to address the clinical utility and potential advantages of a once-daily formulation especially in the treatment of early Parkinson's disease (PD). Pramipexole is widely established as a symptomatic treatment in early as well as advanced PD. The development of an ER formulation, with stable pramipexole plasma concentration over 24 hours, now offers a bioequivalent once-daily alternative. Double-blind randomized controlled trials in early and advanced PD, have established noninferiority of pramipexole ER compared with immediate release as well as superiority of both formulations over placebo. The overnight switch from the standard to the once-daily formulation was shown to be successful in >80% of patients without requiring any dose adjustments. Potential benefits of the prolonged-release design, which have not yet been formally demonstrated in the pivotal trial program, include improved compliance and a potential for better symptomatic control, particularly in patients with early disease that can be managed with monotherapy. PMID- 22500117 TI - Clinical utility of ultrasound guidance for intra-articular knee injections: a review. AB - Intra-articular corticosteroid and hyaluronic acid injections provide short-term symptom amelioration for arthritic conditions involving structural damage or degenerative changes in the knee. Conventional palpation-guided anatomical injections frequently result in inaccurate needle placement into extra-articular tissue and adjacent structures. The purpose of this review was to determine the effect of ultrasound guidance on the accuracy of needle placement, clinical outcomes, and cost-effectiveness in comparison with anatomical landmark-guided intra-articular large joint injections, with particular emphasis on the knee. A total of 13 relevant studies were identified; five studied the knee, seven studied the shoulder, one used both the knee and shoulder, and none studied the hip. Ultrasound was used in seven studies; the remaining studies utilized air arthrography, fluoroscopy, magnetic resonance arthrography, or magnetic resonance imaging. Across all studies (using all imaging modalities and all joints), needle placement accuracy ranged from 63% to 100% with ultrasound and from 39% to 100% with conventional anatomical guidance. Imaging guidance improved the accuracy of intra-articular injections of the knee (96.7% versus 81.0%, P < 0.001) and shoulder (97.3% versus 65.4%, P < 0.001). In particular, ultrasound guidance of knee injections resulted in better accuracy than anatomical guidance (95.8% versus 77.8%, P < 0.001), yielding an odds ratio of 6.4 (95% confidence interval 2.9-14). Ultrasound guidance notably improves injection accuracy in the target intra-articular joint space of large joints including the knee. The enhanced injection accuracy achieved with ultrasound needle guidance directly improves patient-reported clinical outcomes and cost-effectiveness. PMID- 22500118 TI - Relationships between respiratory and airway resistances and activity-related dyspnea in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: The aims of the study were: (1) to compare numerical parameters of specific airway resistance (total, sRaw(tot), effective, sRaw(eff) and at 0.5 L . s(-1), sRaw(0.5)) and indices obtained from the forced oscillation technique (FOT: resistance extrapolated at 0 Hz [Rrs(0 Hz)], mean resistance [Rrs(mean)], and resistance/frequency slope [Rrs(slope)]) and (2) to assess their relationships with dyspnea in chronic obstructive pulmonary disease (COPD). METHODS: A specific statistical approach, principal component analysis that also allows graphic representation of all correlations between functional parameters was used. A total of 108 patients (mean +/- SD age: 65 +/- 9 years, 31 women; GOLD stages: I, 14; II, 47; III, 39 and IV, 8) underwent spirometry, body plethysmography, FOT, and Medical Research Council (MRC) scale assessments. RESULTS: Principal component analysis determined that the functional parameters were described by three independent dimensions (airway caliber, lung volumes and their combination, specific resistance) and that resistance parameters of the two techniques were not equivalent, obviously. Correlative analyses further showed that Raw(tot) and Raw(eff) (and their specific resistances) can be considered as equivalent and correlated with indices that are considered to explore peripheral airways (residual volume (RV), RV/ total lung capacity (TLC), Rrs(slope)), while Rrs(mean) and Raw(0.5) explored more central airways. Only specific resistances taking into account the specific resistance loop area (sRaw(tot) and sRaw(eff)) and Rrs(slope) were statistically linked to dyspnea. CONCLUSION: Parameters obtained from both body plethysmography and FOT can explore peripheral airways, and some of these parameters (sRaw(tot), sRaw(eff,) and Rrs(slope)) are linked to activity-related dyspnea in moderate to severe COPD patients. PMID- 22500119 TI - Cost-effectiveness of available treatment options for patients suffering from severe COPD in the UK: a fully incremental analysis. AB - PURPOSE: Frequent exacerbations which are both costly and potentially life threatening are a major concern to patients with chronic obstructive pulmonary disease (COPD), despite the availability of several treatment options. This study aimed to assess the lifetime costs and outcomes associated with alternative treatment regimens for patients with severe COPD in the UK setting. PATIENTS AND METHODS: A Markov cohort model was developed to predict lifetime costs, outcomes, and cost-effectiveness of various combinations of a long-acting muscarinic antagonist (LAMA), a long-acting beta agonist (LABA), an inhaled corticosteroid (ICS), and roflumilast in a fully incremental analysis. Patients willing and able to take ICS, and those refusing or intolerant to ICS were analyzed separately. Efficacy was expressed as relative rate ratios of COPD exacerbation associated with alternative treatment regimens, taken from a mixed treatment comparison. The analysis was conducted from the UK National Health Service (NHS) perspective. Parameter uncertainty was explored using one-way and probabilistic sensitivity analysis. RESULTS: Based on the results of the fully incremental analysis a cost effectiveness frontier was determined, indicating those treatment regimens which represent the most cost-effective use of NHS resources. For ICS-tolerant patients the cost-effectiveness frontier suggested LAMA as initial treatment. Where patients continue to exacerbate and additional therapy is required, LAMA + LABA/ICS can be a cost-effective option, followed by LAMA + LABA/ICS + roflumilast (incremental cost-effectiveness ratio [ICER] versus LAMA + LABA/ICS: L16,566 per quality-adjusted life-year [QALY] gained). The ICER in ICS-intolerant patients, comparing LAMA + LABA + roflumilast versus LAMA + LABA, was L13,764/QALY gained. The relative rate ratio of exacerbations was identified as the primary driver of cost-effectiveness. CONCLUSION: The treatment algorithm recommended in UK clinical practice represents a cost-effective approach for the management of COPD. The addition of roflumilast to the standard of care regimens is a clinical and cost-effective treatment option for patients with severe COPD, who continue to exacerbate despite existing bronchodilator therapy. PMID- 22500120 TI - Adherence to current guidelines for chronic obstructive pulmonary disease (COPD) among patients treated with combination of long-acting bronchodilators or inhaled corticosteroids. AB - BACKGROUND: To estimate the potential cost savings by following the current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline recommendations in patients being treated for chronic obstructive pulmonary disease (COPD) with the combination of long-acting beta(2)-agonist (LABA), long acting muscarinic antagonist (LAMA) or inhaled corticosteroids (ICS). METHODS: The Geisinger Health System (GHS) database was utilized to identify subjects between January 1, 2004 to March 12, 2007. The index date was based on the first prescription of a LAMA plus LABA, LAMA plus LABA/ICS, or LABA plus ICS. Patients were included in the study if they: had a COPD diagnosis; had data representative of treatment 12 months prior to and 12 months post index date; were 40 years of age or over; had no prior diagnosis for asthma; and had pulmonary function test (PFT) data. We examined the baseline characteristics of these patients along with their healthcare resource utilization. Based on PFT data within 30 days of the index date, a subgroup was classified as adhering or non-adhering to GOLD guidelines. RESULTS: A total of 364 subjects could be classified as adhering or non-adherent to current GOLD guidelines based on their PFT results. The adherent subgroup received COPD medications consistent with current GOLD guidelines. Of the LAMA plus LABA cohort, 25 patients adhered and 39 patients were non-adherent to current GOLD guidelines. In the cohort of LABA plus ICS, 74 patients were adherent and 180 patients non-adherent to current GOLD guidelines. In the cohort of LAMA plus LABA/ICS, 21 patients were adherent and 25 patients non-adherent to current GOLD guidelines. GOLD adherence was associated with mean total cost of all services savings of $5,889 for LAMA plus LABA, $3,330 for LABA + ICS, and $10,217 for LAMA plus LABA/ICS cohorts. CONCLUSION: Staging of COPD with a PFT and adherence to current GOLD guidelines was associated with lower costs in subjects with moderate to severe COPD. Appropriate use of LAMA plus LABA, LABA plus ICS, and LAMA plus LABA/ICS has economic as well as clinical benefits for patients and payers. PMID- 22500121 TI - The burden of chronic obstructive pulmonary disease among employed adults. AB - OBJECTIVE: To examine quality of life, work productivity, and health care resource use among employed adults ages 40-64 years with chronic obstructive pulmonary disease (COPD) in the United States. METHODS: Data from the 2009 National Health and Wellness Survey were used. All employed adults ages 40-64 years with or without a self-reported diagnosis of COPD were included in the study. Impact on quality of life (using the mental and physical component summary scores and health utilities from the Short Form-12v2), work productivity and activity impairment (using the Work Productivity and Activity Impairment questionnaire), and resource use were analyzed using regression modeling. RESULTS: There were 1112 employed adults with COPD versus 18,912 employed adults without COPD. After adjusting for demographics and patient characteristics, adults with COPD reported significantly lower mean levels of mental component summary (46.8 vs 48.5), physical component summary (45.6 vs 49.2), and health utilities (0.71 vs 0.75) than adults without COPD. Workers with COPD reported significantly greater presenteeism (18.9% vs 14.3%), overall work impairment (20.5% vs 16.3%), and impairment in daily activities (23.5% vs 17.9%) than adults without COPD. Employed adults with COPD also reported more mean emergency room visits (0.21 vs 0.12) and more mean hospitalizations (0.10 vs 0.06) in the previous 6 months than employed adults without COPD. All of the above differences were significant at two-sided P < 0.05. CONCLUSION: After adjusting for various confounders, employed adults with COPD reported significantly lower quality of life and work productivity, and increased health care resource utilization than employed adults without COPD. These results highlight the substantial impact and burden of COPD in the United States workforce. PMID- 22500122 TI - Clinical and economic outcomes in an observational study of COPD maintenance therapies: multivariable regression versus propensity score matching. AB - PURPOSE: To investigate equivalency of results from multivariable regression (MR) and propensity score matching (PSM) models, observational research methods used to mitigate bias stemming from non-randomization (and consequently unbalanced groups at baseline), using, as an example, a large study of chronic obstructive pulmonary disease (COPD) initial maintenance therapy. METHODS: Patients were 32,338 health plan members, age >=40 years, with COPD initially treated with fluticasone propionate/salmeterol combination (FSC), tiotropium (TIO), or ipratropium (IPR) alone or in combination with albuterol. Using MR and PSM methods, the proportion of patients with COPD-related health care utilization, mean costs, odds ratios (ORs), and incidence rate ratios (IRRs) for utilization events were calculated for the 12 months following therapy initiation. RESULTS: Of 12,595 FSC, 9126 TIO, and 10,617 IPR patients meeting MR inclusion criteria, 89.1% (8135) of TIO and 80.2% (8514) of IPR patients were matched to FSC patients for the PSM analysis. Methods produced substantially similar findings for mean cost comparisons, ORs, and IRRs for most utilization events. In contrast to MR, for TIO compared to FSC, PSM did not produce statistically significant ORs for hospitalization or outpatient visit with antibiotic or significant IRRs for hospitalization or outpatient visit with oral corticosteroid. As in the MR analysis, compared to FSC, ORs and IRRs for all other utilization events, as well as mean costs, were less favorable for IPR and TIO. CONCLUSION: In this example of an observational study of maintenance therapy for COPD, more than 80% of the original treatment groups used in the MR analysis were matched to comparison treatment groups for the PSM analysis. While some sample size was lost in the PSM analysis, results from both methods were similar in direction and statistical significance, suggesting that MR and PSM were equivalent methods for mitigating bias. PMID- 22500123 TI - Alveolar fractal box dimension inversely correlates with mean linear intercept in mice with elastase-induced emphysema. AB - RATIONALE: A widely applicable model of emphysema that allows efficient and sensitive quantification of injury is needed to compare potential therapies. OBJECTIVES: To establish such a model, we studied the relationship between elastase dose and the severity of emphysema in female C57BL/6J mice. We compared alveolar fractal box dimension (D(B)), a new measure which is an assessment of the complexity of the tissue, with mean linear intercept (L(m)), which is commonly used to estimate airspace size, for sensitivity and efficiency of measurement. METHODS: Emphysema was induced in female C57BL/6J mice by administering increasing intratracheal doses of porcine pancreatic elastase (PPE). Changes in morphology and static lung compliance (C(L)) were examined 21 days later. Correlation of D(B) with L(m) was determined in histological sections of lungs exposed to PPE. The inverse relationship between D(B) and L(m) was supported by examining similar morphological sections from another experiment where the development of emphysema was studied 1 to 3 weeks after instillation of human neutrophil elastase (HNE). RESULTS: L(m) increased with PPE dose in a sigmoidal curve. C(L) increased after 80 or 120 U/kg body weight (P < 0.05), but not after 40 U/kg, compared with the control. D(B) progressively declined from 1.66 +/- 0.002 (standard error of the mean) in controls, to 1.47 +/- 0.006 after 120 U PPE/kg (P < 0.0001). After PPE or HNE instillation, D(B) was inversely related to L(m) (R = -0.95, P < 0.0001 and R = -0.84, P = 0.01, respectively), with a more negative slope of the relationship using HNE (P < 0.0001). CONCLUSION: Intratracheal instillation of increasing doses of PPE yields a scale of progression from mild to severe emphysema. D(B) correlates inversely with L(m) after instillation of either PPE or HNE and yields a rapid, sensitive measure of emphysema after elastase instillation. PMID- 22500124 TI - Hedgehog pathway as a drug target: Smoothened inhibitors in development. AB - Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh) represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely regulates self-renewal and terminal differentiation in embryonic development, but is typically silenced in adult tissues, with reactivation usually only during tissue repair. Aberrant Hh pathway signaling has been implicated in the pathogenesis, self-renewal, and chemotherapy resistance of a growing number of solid and hematologic malignancies. Major components of the Hh pathway include the Hh ligands (Sonic, Desert, and Indian), the transmembrane receptor Patched, the signal transducer Smoothened (Smo), and transcription factors Gli1-3 which regulate the transcription of Hh target genes. Mutations in Hh pathway genes, increased Hh signaling in tumor stroma, and Hh overexpression in self-renewing cells (cancer stem cells) have been described, and these different modes of Hh signaling have implications for the design of Hh pathway inhibitors and their integration into conventional treatment regimens. Discovery of a naturally-occurring Smo inhibitor, cyclopamine, and the identification of Hh pathway mutations and over expression in cancer cells prompted the development of several cyclopamine derivatives. Encouraging laboratory and in vivo data has resulted in Phase I and II clinical trials of Smo inhibitors. In this review, we will discuss the current understanding of Hh pathway signaling in malignancy and Smo antagonists in development. Recent data with these agents shows that they are well-tolerated and may be effective for subsets of patients. Challenges remain for appropriate patient selection and the optimal combination and sequence of these targeted therapies into current treatment paradigms. PMID- 22500125 TI - Costs and clinical consequences of suboptimal atrial fibrillation management. AB - Atrial fibrillation (AF) places a considerable burden on the US health care system, society, and individual patients due to its associated morbidity, mortality, and reduced health-related quality of life. AF increases the risk of stroke, which often results in lengthy hospital stays, increased disability, and long-term care, all of which impact medical costs. An expected increase in the prevalence of AF and incidence of AF-related stroke underscores the need for optimal management of this disorder. Although AF treatment strategies have been proven effective in clinical trials, data show that patients still receive suboptimal treatment. Adherence to AF treatment guidelines will help to optimize treatment and reduce costs due to AF-associated events; new treatments for AF show promise for future reductions in disease and cost burden due to improved tolerability profiles. Additional research is necessary to compare treatment costs and outcomes of new versus existing agents; an immediate effort to optimize treatment based on existing evidence and guidelines is critical to reducing the burden of AF. PMID- 22500126 TI - Economic comparison of capecitabine + oxaliplatin and 5-fluorouracil + oxaliplatin in the adjuvant treatment of colon cancer. AB - BACKGROUND: Colorectal cancer is one of the most frequent and lethal cancers. The aim of this study was to analyze the costs relating to treatment of colorectal cancer between Xelox and Folfox-4 at a regional level according to the clinical experience at an Italian hospital in Lombardy. METHODS: A cost analysis was carried out regarding resource consumption by patients suffering from colorectal cancer based on data collected over a 12-month period between 2010 and 2011. The analysis involved 40 patients who attended the Department of Medical Oncology and Hematology at Carlo Poma Hospital to undergo adjuvant therapy for colorectal cancer. A chart was created for each patient containing their medical history, their pharmacological therapy indicating the number and duration of chemotherapy cycles, dose in mg administered for each cycle, number of day hospital visits for each cycle, number of days spent in hospital to position the central vein catheter, type of infusion pump used, any subsequent supportive therapy, and any side effects and outpatient visits connected with side effects. RESULTS: The cost analysis shows the savings involved in using Xelox for a single cycle of treatment, ie, approximately ?1414.00 per patient (53% compared with Folfox-4). For each single cycle of treatment, the savings generated by using capecitabine compared with 5-FU can be attributed mostly to the fact that oral administration of chemotherapy requires fewer resources and does not require use of a central vein catheter (approximately 70% of overall cost) which amply compensates for the higher cost of capecitabine compared with 5-FU-LV. Sensibility analysis confirms the results of the base-case scenario. CONCLUSION: The results of our study indicate that infusion via a central vein catheter represents a significant cost, and that substitution with an oral therapy, even when associated with drugs administered intravenously, represents a consistent saving of hospital resources. PMID- 22500127 TI - Chronic infections in hip arthroplasties: comparing risk of reinfection following one-stage and two-stage revision: a systematic review and meta-analysis. AB - BACKGROUND: Two-stage revision is regarded by many as the best treatment of chronic infection in hip arthroplasties. Some international reports, however, have advocated one-stage revision. No systematic review or meta-analysis has ever compared the risk of reinfection following one-stage and two-stage revisions for chronic infection in hip arthroplasties. METHODS: The review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analysis. Relevant studies were identified using PubMed and Embase. We assessed studies that included patients with a chronic infection of a hip arthroplasty treated with either one-stage or two-stage revision and with available data on occurrence of reinfections. We performed a meta-analysis estimating absolute risk of reinfection using a random-effects model. RESULTS: We identified 36 studies eligible for inclusion. None were randomized controlled trials or comparative studies. The patients in these studies had received either one-stage revision (n = 375) or two-stage revision (n = 929). Reinfection occurred with an estimated absolute risk of 13.1% (95% confidence interval: 10.0%-17.1%) in the one-stage cohort and 10.4% (95% confidence interval: 8.5%-12.7%) in the two-stage cohort. The methodological quality of most included studies was considered low, with insufficient data to evaluate confounding factors. CONCLUSIONS: Our results may indicate three additional reinfections per 100 reimplanted patients when performing a one-stage versus two-stage revision. However, the risk estimates were statistically imprecise and the quality of underlying data low, demonstrating the lack of clear evidence that two-stage revision is superior to one-stage revision among patients with chronically infected hip arthroplasties. This systematic review underscores the need for improvement in reporting and collection of high-quality data and for large comparative prospective studies on this issue. PMID- 22500128 TI - Smoking cessation. PMID- 22500131 TI - Dengue, Urbanization and Globalization: The Unholy Trinity of the 21(st) Century. AB - Dengue is the most important arboviral disease of humans with over half of the world's population living in areas of risk. The frequency and magnitude of epidemic dengue have increased dramatically in the past 40 years as the viruses and the mosquito vectors have both expanded geographically in the tropical regions of the world. There are many factors that have contributed to this emergence of epidemic dengue, but only three have been the principal drivers: 1) urbanization, 2) globalization and 3) lack of effective mosquito control. The dengue viruses have fully adapted to a human-Aedes aegypti-human transmission cycle, in the large urban centers of the tropics, where crowded human populations live in intimate association with equally large mosquito populations. This setting provides the ideal home for maintenance of the viruses and the periodic generation of epidemic strains. These cities all have modern airports through which 10s of millions of passengers pass each year, providing the ideal mechanism for transportation of viruses to new cities, regions and continents where there is little or no effective mosquito control. The result is epidemic dengue. This paper discusses this unholy trinity of drivers, along with disease burden, prevention and control and prospects for the future. PMID- 22500132 TI - Imported dengue fever/dengue hemorrhagic fever cases in Japan. AB - Several dengue outbreaks occurred in Japan from 1942 to 1945. Dengue fever emerged in Nagasaki in August 1942 and soon spread to other cities such as Sasebo, Hiroshima, Kobe and Osaka, recurring every summer until 1945 and constituting the greatest outbreak in the temperate zone. Domestic outbreaks have not been reported in Japan since then. However, the number of imported dengue cases has increased year by year: 868 imported cases were reported in Japan between 1999 and 2010 according to the Infectious Diseases Control Law. Moreover, 406 imported cases were confirmed to be dengue virus infection among 768 dengue suspected cases received at NIID from 2003 to 2010. A total of 142 cases (35.6%), 103 cases (25.8%) and 62 cases (15.5%) were noted in the 20-29, 30-39 and 40-49 age groups, respectively. Infecting dengue virus serotypes were determined for 280 of the 406 cases. The number of cases infected with each of the 4 serotypes was 98 (35%) with type 1, 78 (28%) with type 3, 72 (26%) with type 2, and 32 (11%) with type 4. Sixty percent of dengue cases were imported from July to October, the summer vacation season in Japan. PMID- 22500133 TI - Dengue Vectors and their Spatial Distribution. AB - The distribution of dengue vectors, Ae. aegypti and Ae. albopictus, is affected by climatic factors. In addition, since their life cycles are well adapted to the human environment, environmental changes resulting from human activity such as urbanization exert a great impact on vector distribution. The different responses of Ae. aegypti and Ae albopictus to various environments result in a difference in spatial distribution along north-south and urban-rural gradients, and between the indoors and outdoors. In the north-south gradient, climate associated with survival is an important factor in spatial distribution. In the urban-rural gradient, different distribution reflects a difference in adult niches and is modified by geographic and human factors. The direct response of the two species to the environment around houses is related to different spatial distribution indoors and outdoors. Dengue viruses circulate mainly between human and vector mosquitoes, and the vector presence is a limiting factor of transmission. Therefore, spatial distribution of dengue vectors is a significant concern in the epidemiology of the disease.Current technologies such as GIS, satellite imagery and statistical models allow researchers to predict the spatial distribution of vectors in the changing environment. Although it is difficult to confirm the actual effect of environmental and climate changes on vector abundance and vector borne diseases, environmental changes caused by humans and human behavioral changes due to climate change can be expected to exert an impact on dengue vectors. Longitudinal monitoring of dengue vectors and viruses is therefore necessary. PMID- 22500134 TI - Quasispecies of dengue virus. AB - Pathogenic viruses have RNA genomes that cause acute and chronic infections. These viruses replicate with high mutation rates and exhibit significant genetic diversity, so-called viral quasispecies. Viral quasispecies play an important role in chronic infectious diseases, but little is known about their involvement in acute infectious diseases such as dengue virus (DENV) infection. DENV, the most important human arbovirus, is a causative agent of dengue fever (DF) and dengue hemorrhagic fever (DHF). Accumulating observations suggest that DENV exists as an extremely diverse virus population, but its biological significance is unclear. In other virus diseases, quasispecies affect the therapeutic strategies using drugs and vaccines. Here, I describe the quasispecies of DENV and discuss the possible role of quasispecies in the pathogenesis of and therapeutic strategy against DENV infection in comparison with other viruses such as Hepatitis C virus, human immunodeficiency virus type 1, and poliovirus. PMID- 22500135 TI - Dengue virus receptor. AB - Dengue virus is an arthropod-borne virus transmitted by Aedes mosquitoes. Dengue virus causes fever and hemorrhagic disorders in humans and non-human primates. Direct interaction of the virus introduced by a mosquito bite with host receptor molecule(s) is crucial for virus propagation and the pathological progression of dengue diseases. Therefore, elucidation of the molecular mechanisms underlying the interaction between dengue virus and its receptor(s) in both humans and mosquitoes is essential for an understanding of dengue pathology. In addition, understanding the molecular mechanism(s) of virus entry is crucial for the development of effective new therapies to treat dengue patients. Binding of dengue virus to its receptor molecules is mediated through a viral envelope glycoprotein, termed E protein. We present a summary and describe the structures, binding properties, and pathological relevance of dengue virus receptor molecules proposed to date. In mammalian cells, there are many candidate molecules that may act as receptors, such as sulfated glycosaminoglycans (GAGs), lectins that recognize carbohydrates, glycosphingolipid (GSL), proteins with chaperone activity, laminin-binding proteins, and other uncharacterized proteins. There are also several lines of evidence for receptor molecules such as GSLs, proteins with chaperone activity, laminin-binding proteins, and other uncharacterized proteins in mosquito cells and organs. This review focuses on several molecules involved in carbohydrate-dependent binding of the virus. PMID- 22500136 TI - T-cell responses to dengue virus in humans. AB - Dengue virus (DENV) is a leading cause of morbidity and mortality in most tropical and subtropical areas of the world. Dengue virus infection induces specific CD4+CD8- and CD8+CD4- T cells in humans. In primary infection, T-cell responses to DENV are serotype cross-reactive, but the highest response is to the serotype that caused the infection. The epitopes recognized by DENV-specific T cells are located in most of the structural and non-structural proteins, but NS3 is the protein that is most dominantly recognized. In patients with dengue hemorrhagic fever (DHF) caused by secondary DENV infection, T cells are highly activated in vivo. These highly activated T cells are DENV-specific and oligoclonal. Multiple kinds of lymphokines are produced by the activated T cells, and it has been hypothesized that these lymphokines are responsible for induction of plasma leakage, one of the most characteristic features of DHF. Thus, T-cells play important roles in the pathogenesis of DHF and in the recovery from DENV infection. PMID- 22500137 TI - Dengue and soluble mediators of the innate immune system. AB - Huge emphasis has been placed on the role of the adaptive immune system in dengue pathogenesis. Yet there is increasing evidence for the importance of the innate immune system in regulating dengue infection and possibly influencing the disease. This review focuses on the interplay between the innate immune system and dengue and highlights the role of soluble immunological mediators. Type I and type II interferons of the innate immune system demonstrate non-overlapping roles in dengue infection. Furthermore, while some IFN responses to dengue are protective, others may exert disease-related effects on the host. But aside from interferons, a number of cytokines have also been implicated in dengue pathogenesis. Our expanding knowledge of cytokines indicates that these soluble mediators act upon a complicated network of events to provoke the disease. This cytokine storm is generally attributed to massive T cell activation as an outcome of secondary infection. However, there is reason to believe that innate immune response-derived cytokines also have contributory effects, especially in the context of severe cases of primary dengue infection. Another less popular but interesting perspective on dengue pathogenesis is the effect of mosquito feeding on host immune responses and viral infection. Various studies have shown that soluble factors from vector saliva have the capacity to alter immune reactions and thereby influence pathogen transmission and establishment. Hence, modulation of the innate immune system at various levels of infection is a critical component of dengue disease. In the absence of an approved drug or vaccine for dengue, soluble mediators of the innate immune system could be a strategic foothold for developing anti-viral therapeutics and improving clinical management. PMID- 22500138 TI - Issues related to recent dengue vaccine development. AB - Dengue fever (DF) and dengue hemorrhagic fever (DHF) are mosquito-transmitted diseases of global importance. Despite significant research efforts, no approved vaccines or antiviral drugs against these diseases are currently available. This brief article reviews the status of dengue vaccine development, with particular emphasis on the vaccine strategies in more advanced stages of evaluation; these include traditional attenuation, chimerization and engineered attenuation. Several aspects of these vaccine design strategies, including concerns about vaccine candidates inducing infection-enhancing antibodies, are also presented. PMID- 22500139 TI - Host genetic susceptibility to severe dengue infection. AB - Epidemiological evidence indicates that host genetic factors are relevant and predispose DHF/DSS development. Here, we review the host genetic studies concerning human leucocyte antigens, antibody receptors, immune/inflammatory mediators, attachment molecules, cytokines and other factors exerting an immunoregulatory effect as well as the current genome-wide association studies. We also discuss some viewpoints on future challenges related to the design of safe and effective prevention and treatment options. PMID- 22500140 TI - Clinical Manifestations and Management of Dengue/DHF/DSS. AB - Dengue is one of the most important mosquito-borne viral illnesses. The first DHF outbreak was reported from the Philippines in 1953. Initially it was endemic only in Southeast Asia and the Western Pacific regions. After about 50 years from the first outbreak, it spread globally to almost every continent including North and South America, Australia and Africa. The majority of cases during the 50s to 80s were children, but today the disease affects both children and adults of all age groups. The disease is caused by dengue viruses that have four serotypes: dengue 1, dengue 2, dengue 3 and dengue 4. Primary infection usually results in milder illness, while more severe disease occurs in cases of repeated infection with different serotypes. In this paper clinical manifestations and management of dengue/DHF/DSS are summarized. PMID- 22500141 TI - The Catholic Church, moral doctrine, and HIV prevention in Recife, Brazil: Negotiating the contradictions between religious belief and the realities of everyday life. AB - Religious beliefs have had a key role in shaping local responses to HIV and AIDS. As the world's largest Catholic country, Brazil is no exception. Yet little research has been conducted to document how the religious doctrine is enacted in practice among its lay leaders and followers. In this article, we present ethnographic research from Recife, Brazil, conducted to understand the way in which religious doctrines are interpreted on a local level. Contextualized within the sociology of contemporary Brazilian Catholicism, we draw on interviews with clergy members, lay leaders and parishioners in order to discuss how the Catholic Church's vision of sexuality translates into the everyday lives of its followers by. We explore the disjuncture between the Catholic ideals of fidelity and delaying sex until marriage with the everyday reality of the Church's followers, highlighting the role that gender plays in defining sexual roles and expectations. We conclude posing questions for future research and HIV prevention strategies considering the formal institutional response of the Brazilian Catholic Church to AIDS on one hand, and the social and cultural contexts in which Catholics live their daily lives on the other. PMID- 22500142 TI - Quality of life in menopausal women: a Brazilian Portuguese version of the Cervantes Scale. AB - We present the translation, cultural adaptation and validation of the Cervantes Scale to Brazilian Portuguese. The Cervantes Scale (CS) was originally described in Spanish, and is a tool to measure health-related quality of life in perimenopausal and menopausal women. A cross-sectional study was carried out with 180 women aged 45 to 64 years. In addition to the CS, the following questionnaires were applied: Women's Health Questionnaire (WHQ) and abbreviated version of the World Health Organization's Quality of Life Questionnaire (Abbreviated WHOQOL-bref). In conclusion, the Brazilian Portuguese version of the CS is easy to apply and understand. The evaluation of its psychometric properties was satisfactory, and it can be applied to assess health-related QoL in Brazilian perimenopausal and menopausal women. PMID- 22500144 TI - Molecular detection and characterization of goat isolate of Taenia hydatigena in Turkey. AB - The aim of this study was to provide molecular detection and characterization of the goat isolate of Taenia hydatigena from Ankara province of Turkey. For this purpose, PCR amplification of small subunit ribosomal RNA (rrnS) and partial sequencing of mitochondrial cytochrome c oxidase subunit 1 (mt-CO1) genes were performed in a one-month-old dead goat. According to rrnS-PCR results, parasites were identified as Taenia spp., and partial sequence of mt-CO1 gene was corresponding to T. hydatigena. At the end of the study, we concluded that molecular tools can be used to define species of parasites in cases where the key morphologic features cannot be detected. Nucleotide sequence data of Turkish goat isolate of T. hydatigena was submitted to GenBank for other researchers interested in this subject. By this study, molecular detection and characterization of T. hydatigena was done for the first time in Turkey. PMID- 22500145 TI - Teaching and Assessing the Responsible Conduct of Research: A Delphi Consensus Panel Report. AB - In an effort to foster research integrity, the National Institutes of Health and the National Science Foundation mandate education of all trainees in the responsible conduct of research (RCR). Nevertheless, recent studies suggest that rates of questionable research practices and scientific misconduct are both high and considerably underreported. In part, this may be due to the fact that some ethical norms (e.g., authorship assignment) are far from clear and researchers are unsure how to respond to perceived misconduct. With funding from the U.S. Office of Research Integrity (ORI), we convened four panels of experts to develop a consensus on the overarching goals and teaching content of RCR instruction. Our panelists recommended nine overarching objectives for RCR instruction that require us to rethink common modes of instruction, and they identified issues and standards that should be covered within controversial areas such as authorship assignment and whistle-blowing. Additionally, our experts recommended two new core areas for RCR instruction: The social responsibilities of scientists and current topics in RCR. PMID- 22500143 TI - Mechanisms underlying the osteo- and adipo-differentiation of human mesenchymal stem cells. AB - Human mesenchymal stem cells (hMSCs) are considered a promising cell source for regenerative medicine, because they have the potential to differentiate into a variety of lineages among which the mesoderm-derived lineages such adipo- or osteogenesis are investigated best. Human MSCs can be harvested in reasonable to large amounts from several parts of the patient's body and due to this possible autologous origin, allorecognition can be avoided. In addition, even in allogenic origin-derived donor cells, hMSCs generate a local immunosuppressive microenvironment, causing only a weak immune reaction. There is an increasing need for bone replacement in patients from all ages, due to a variety of reasons such as a new recreational behavior in young adults or age-related diseases. Adipogenic differentiation is another interesting lineage, because fat tissue is considered to be a major factor triggering atherosclerosis that ultimately leads to cardiovascular diseases, the main cause of death in industrialized countries. However, understanding the differentiation process in detail is obligatory to achieve a tight control of the process for future clinical applications to avoid undesired side effects. In this review, the current findings for adipo- and osteo differentiation are summarized together with a brief statement on first clinical trials. PMID- 22500146 TI - Lapatinib: the evidence for its therapeutic value in metastatic breast cancer. AB - INTRODUCTION: Breast cancer is the most common cancer affecting women. Many patients ultimately progress to metastatic disease and optimal management of this disease remains a significant therapeutic challenge. Lapatinib, a dual tyrosine kinase inhibitor, is in clinical development for treatment of this disease. AIMS: The objective of this article is to review the published evidence for the treatment of metastatic breast cancer with lapatinib, and assess its therapeutic potential. EVIDENCE REVIEW: Most evidence has appeared in meeting abstract reports of phase I and II studies in healthy volunteers and cancer patients. Four studies have included patients with exclusively breast cancer. Complete and partial responses and stable disease has been reported in some patients. Emerging evidence indicates that complete and partial responses can be achieved in some patients with metastatic breast cancer. Lapatinib appears to be well tolerated in cancer patients and the maximum tolerated dose is in the region of 1800 mg/day. In addition, it has been used in combination with other cancer treatments. Five ongoing or planned phase II monotherapy and three phase III combination-therapy studies with lapatinib have been identified. OUTCOMES SUMMARY: The phase I and II studies reported to date have provided safety data and preliminary indications regarding efficacy. There is preliminary evidence that lapatinib can achieve objective response rates of 10-38% in patients with metastatic breast cancer. Patients with tumors overexpressing ErbB1 and/or ErbB2 are likely to benefit from lapatinib treatment. PMID- 22500147 TI - Exubera((r)) (inhaled insulin): an evidence-based review of its effectiveness in the management of diabetes. AB - INTRODUCTION: Inadequate glycemic control contributes to the development and progression of complications, which are associated with a significant economic burden on healthcare systems. However, optimal glycemic control is difficult to sustain with oral antidiabetic agents and adherence to intensive insulin regimens is compromised by patient compliance to multiple daily injections. Therefore, alternative delivery systems are required to improve the acceptability of insulin therapy. AIMS: This review assesses the evidence for the therapeutic value of inhaled insulin (Exubera((r))) in the management of type 1 and type 2 diabetes. EVIDENCE REVIEW: Evidence indicates that glycemic control, as measured by plasma HbA(1c) levels, with Exubera is as effective as subcutaneous insulin in patients with type 1 or type 2 diabetes. There is also good evidence that Exubera provides improved patient satisfaction and ease of use compared with subcutaneous insulin. However, the cost effectiveness of Exubera and its place in therapy compared with other inhaled insulin delivery systems currently in development remain to be determined. OUTCOMES SUMMARY: Exubera is an alternative treatment option for the management of diabetes which provides effective glycemic control with improved patient satisfaction. PMID- 22500148 TI - Topiramate: the evidence for its therapeutic value in the prevention of migraine. AB - INTRODUCTION: Preventive therapy is recommended in patients with migraines frequent and/or severe enough to interfere with daily life, and/or with an inadequate response to acute therapy (26-43% of patients with migraine in a recent US survey). Preventive treatments include beta blockers, amitriptyline, and antiepileptics (sodium valproate, gabapentin), but these may have significant adverse effects and are contraindicated in some patients. Topiramate is an antiepileptic recently approved for prevention of migraine. AIMS: To assess the evidence on the therapeutic value of topiramate as preventive treatment for migraine in adults. EVIDENCE REVIEW: All identified outcomes were patient oriented. Strong evidence shows that topiramate 100 or 200 mg/day is more effective than placebo in reducing mean monthly migraine frequency, and further evidence shows better effectiveness than placebo on responder rate, rescue medication use, migraine severity, and migraine duration. The 100 mg/day dose appears generally better tolerated than 200 mg/day. Evidence shows that topiramate is associated with weight loss rather than weight gain. Limited evidence suggests that topiramate can improve health-related quality of life and reduce days with disability. Uncontrolled studies indicate effectiveness in refractory migraine. Limited evidence indicates broadly similar efficacy and tolerability for topiramate 100 mg/day and propranolol 160 mg/day, though more comparative trials are required. There is insufficient economic evidence to assess the cost effectiveness of topiramate. PLACE IN THERAPY: Topiramate 100 mg/day is the dose with the best balance between efficacy and tolerability, and offers therapeutic value in patients in whom propranolol or other preventive migraine therapies are contraindicated, poorly tolerated, or ineffective. PMID- 22500149 TI - Eplerenone: the evidence for its place in the treatment of heart failure after myocardial infarction. AB - INTRODUCTION: Heart failure is a frequent complication after acute myocardial infarction (MI) and carries a poor prognosis. Current treatments inhibit the renin-angiotensin-aldosterone system but suppression of aldosterone may be incomplete. The aldosterone antagonist spironolactone has been shown to improve survival in patients with chronic, severe heart failure. Eplerenone is a selective aldosterone antagonist expected to have a lower incidence of hormonal side effects than spironolactone. AIMS: To assess the evidence on the therapeutic value of eplerenone for treatment of heart failure in adults. EVIDENCE REVIEW: The evidence base consists of one large double-blind placebo-controlled multicenter randomized trial in over 6000 patients with postmyocardial infarction (MI) heart failure, comparing eplerenone plus standard therapy with placebo plus standard therapy. All the main outcomes were patient-oriented. Evidence from this trial shows that eplerenone improves survival and reduces cardiovascular hospitalization/mortality, compared with standard treatment alone. The incidence of hormonal side effects is no greater than with placebo. The risk of hyperkalemia is significantly increased, especially in patients with low creatinine clearance. Eplerenone was both more effective and more costly than standard treatment alone. The cost-effectiveness ratio has been estimated at $US10 402-21 876 per life-year gained. PLACE IN THERAPY: Eplerenone reduces mortality compared with current treatment alone in patients with post-MI heart failure, at additional cost. Direct comparative evidence is needed to assess its efficacy versus spironolactone. It may be valuable in patients who are intolerant to the hormonal side effects of spironolactone. PMID- 22500150 TI - Dutasteride: an evidence-based review of its clinical impact in the treatment of benign prostatic hyperplasia. AB - INTRODUCTION: Benign prostatic hyperplasia (BPH) is a common condition affecting older men. Bothersome symptoms can progress to serious complications such as acute urinary retention (AUR) requiring surgical intervention. Dutasteride, a dual 5-alfa-reductase (5AR) inhibitor (5ARI), is a recently introduced therapy for the treatment of BPH. AIMS: The objective of this article is to review the evidence for the treatment of BPH with dutasteride. EVIDENCE REVIEW: Evidence from large clinical studies shows that men with an enlarged prostate achieve a measurable decrease in prostate volume by up to 26% after 4 years of treatment with dutasteride and urinary symptoms improve after 6 months of treatment. This is achieved by rapid suppression (through inhibition of 5AR) of the principal androgen (dihydrotestosterone or DHT) responsible for stimulating prostatic growth. Evidence suggests that dutasteride treatment results in a reduction in risk (rather than delay) of the most serious complications including episodes of AUR and the need for BPH-related surgery. Early symptom relief has been achieved with the combination of an alfa blocker and dutasteride. There is good evidence that dutasteride is well tolerated; side effects limited to sexual dysfunction (reduced libido, impotence, and gynecomastia) are more common compared with placebo but occur with a similar incidence to finasteride, another 5ARI. No pharmacoeconomic evidence from studies with dutasteride has so far been published. CLINICAL VALUE: In conclusion, dutasteride is a valuable treatment option in men with moderate to severe BPH. Reductions in prostate volume lead to symptom relief and serious complications appear to be reduced. PMID- 22500151 TI - FTY720 in multiple sclerosis: the emerging evidence of its therapeutic value. AB - INTRODUCTION: Multiple sclerosis is a demyelinating disease of the central nervous system which can cause severe disability and has profound effects on patients' quality of life over several decades. Although there is no cure for the disease, recently developed disease-modifying agents have modest effects on the impact of disease progression. There is therefore a need for a new, effective, and well-tolerated treatment for multiple sclerosis and FTY720 (an orally administered immunomodulatory compound with a novel mechanism of action) is one of a number of agents being evaluated for the treatment of this disease. AIMS: The objective of this article is to assess the therapeutic potential for FTY720, now in phase II clinical trials, for the treatment of multiple sclerosis through a review of the published evidence. EMERGING EVIDENCE: There is good evidence that FTY720 achieves immunomodulation as shown by a reversible redistribution of peripheral blood lymphocytes after oral administration. Two meeting abstracts have been published showing results obtained with FTY720 in a 12-month phase II clinical trial in patients with active relapsing multiple sclerosis. There is modest evidence that FTY720 significantly improves both patient-oriented (relapse rate) and disease-oriented outcomes (inflammatory disease activity). There is good evidence that FTY720 is well tolerated. PROFILE: Based on these early results from the clinical development program, FTY720 has the potential to be an effective disease-modifying agent for the treatment of multiple sclerosis. Further results from ongoing multinational phase III studies are awaited. PMID- 22500152 TI - K-111: the emerging evidence for its potential in the treatment of the metabolic syndrome. AB - INTRODUCTION: Prevalence of the metabolic syndrome has increased dramatically in recent years. Optimal patient care demands a multifaceted approach, with many individuals requiring several therapies to minimize the significant associated cardiovascular burden. The need for novel agents in the management of the metabolic syndrome is emphasized by the current lack of drugs to treat insulin resistance, one of the major components of the metabolic syndrome that has several deleterious consequences. AIMS: The objective of this review is to assess the emerging evidence for the potential use of K-111 in treatment of the metabolic syndrome. EMERGING EVIDENCE: K-111 is a peroxisome proliferator activated receptor (PPAR)-alfa agonist that, in preclinical studies, has shown efficacy in improving insulin resistance, reducing bodyweight, and ameliorating atherogenic dyslipidemia. Preliminary evidence suggests that toxicity and adverse events are low. PROFILE: The improvements in obesity and insulin resistance, together with other beneficial effects following activation of PPAR alfa by K-111 in preclinical models, are encouraging and offer several potential advantages over currently available therapies for patients with the metabolic syndrome. However, K-111 is at an early stage of development and establishment of its role will require full analysis of clinical trials carefully designed to determine its overall benefits in this increasingly important disease area. PMID- 22500153 TI - Tigecycline: an evidence-based review of its antibacterial activity and effectiveness in complicated skin and soft tissue and intraabdominal infections. AB - INTRODUCTION: There is an urgent need for novel agents to manage serious bacterial infections, particularly those contracted in healthcare facilities. Tigecycline is a novel broad-spectrum glycylcycline with good activity against Gram-positive, many Gram-negative, anaerobic, and some atypical pathogens that has been developed to address this need. AIMS: To review the evidence for the use of tigecycline in serious and complicated skin and soft tissue and intraabdominal infections. EVIDENCE REVIEW: There is substantial evidence that tigecycline is as effective as vancomycin plus aztreonam in complicated skin and skin structure infections (SSSIs) and as effective as imipenem plus cilastatin in intraabdominal infections. Limited evidence shows effectiveness in patients with resistant Acinetobacter infection in an intensive care unit, and the possibility that the use of tigecycline may reduce length of hospital stay. The drug is well tolerated, with nausea and vomiting as the major adverse effects. OUTCOMES SUMMARY: The introduction of tigecycline should be beneficial at a time of increasing problems with bacterial resistance, and evidence to date has been sufficient for regulatory approval for complicated SSSIs and intraabdominal infections. Research into tigecycline's efficacy in other infectious diseases (notably pneumonia and bacteremia) is ongoing. Further good quality studies and ongoing surveillance for any emerging bacterial resistance will be needed to determine outcomes with tigecycline relative to other novel antibacterial agents, and to explore the economic implications of its adoption. PMID- 22500155 TI - Present status and problems on molecular targeted therapy of cancer. AB - Numerous clinical trials of molecular targeted drugs for cancer have been conducted, with remarkable results for certain drugs and accumulation of "negative data" causing a hitch in the development plan for some other compounds. Five recent issues and problems of molecular targeted therapies were discussed critically. Drug discovery and effects against driver mutations (activating mutations) and problems: possibility for circumventing inherent and acquired resistance with the aim of achieving radical cure. Synthetic lethality: reasonable patient selection in individualized treatment strategy. Response rate and progression-free survival improvement with or without overall survival benefit and enhancement of toxicity in bevacizumab therapy: best endpoints for the evaluation of effect of antiangiogenic therapy. Negative data on small molecule targeted therapy, primarily vascular endothelial growth factor tyrosine kinase inhibitors: loose GO or NO-GO decision criteria for further development of new compounds in early clinical trials. Effect of immunotherapy: difficulty to verify by proof of principle study. We are faced to many questions for the development of efficient personalized therapy. Accumulation of scientific global preclinical and clinical evidences is essential to use these new therapeutic modalities for the improvement of oncologic health care. PMID- 22500154 TI - Donepezil in Alzheimer's disease: an evidence-based review of its impact on clinical and economic outcomes. AB - INTRODUCTION: Donepezil is indicated for the symptomatic treatment of mild to moderate Alzheimer's disease. It is a specific and reversible inhibitor of acetylcholinesterase (AChE); by increasing levels of available acetylcholine, donepezil may compensate for the loss of functioning cholinergic brain cells. AIMS: This review evaluates the clinical impact of donepezil by assessing randomized controlled and open-label naturalistic trials, as well as observational studies. A broad perspective is gained of its effectiveness on various outcomes. EVIDENCE REVIEW: There is strong evidence that donepezil has efficacy against the three major domains of Alzheimer's disease symptoms, namely functional ability, behavior, and cognition. The strongest evidence is for improvement or less deterioration in global outcomes and cognition in the short to medium term. There is limited evidence that improved global outcomes are maintained in the long term and clear evidence to support long-term maintenance of cognitive benefits. Also, donepezil appears to maintain function in the long term and there is some level 1 and 2 evidence of improved or limited deterioration in behavior or mood in the short to medium term. Despite donepezil's effects on major symptoms of Alzheimer's disease, its impact on patients' quality of life has not been consistently demonstrated, perhaps reflecting the difficulty of assessing this aspect in this patient population. Donepezil may also lessen caregiver burden. Donepezil has some effect on markers of brain function, but more data are needed to confirm a neuroprotective effect. There is limited and conflicting evidence that long-term donepezil treatment delays time to institutionalization. There is some evidence that donepezil may be cost effective, especially when unpaid caregiver costs are considered. Donepezil is generally safe and well tolerated. CLINICAL VALUE: AChE inhibitors are the only agents recommended for the treatment of cognitive decline in patients with mild to moderate Alzheimer's disease. Donepezil is more effective than placebo and is well tolerated in improving the major symptoms of this disease. Improvements are usually modest, although stabilization of cognitive and functional symptoms with donepezil can also be considered an important clinical outcome. Donepezil may lessen caregiver burden. Donepezil may also be cost effective, especially when unpaid caregiver costs are considered. More data are required from randomized controlled trials with long-term follow-up to confirm its cost effectiveness and impact on quality of life, disease progression, and time to institutionalization. PMID- 22500156 TI - Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2009. AB - PURPOSE: This study overviews nationwide cancer statistics, including incidence, mortality, survival, and prevalence, and their trends in Korea based on 2009 cancer incidence data. MATERIALS AND METHODS: Incidence data from 1993-2009 were obtained from the Korea National Cancer Incidence Database, and vital status was followed through 31 December 2010. Mortality data from 1983-2009 were obtained from Statistics Korea. Crude rates and age-standardized rates for incidence, mortality, and prevalence; and relative survival were calculated. RESULTS: In total, 192,561 cancer cases and 69,780 cancer deaths were observed during 2009, and 808,503 10-year cancer prevalent cases occurred in Korea as of 1 January 2010. The incidence rate for all cancers combined showed an annual increase of 3.3% from 1999 to 2009. CONCLUSION: Stomach, liver and cervical cancers have been decreasing and thyroid, breast and colorectal cancers have been increasing at large. In particular, in 2009, colorectal cancer became the third most common cancer in females and for the first time ranked higher than stomach cancer, which had been the long-standing common cancer in Korea. While overall cancer incidence has been rapidly increasing in Korea, age-standardized cancer mortality rates have been declining since 2002, and cancer survival has been improving. PMID- 22500157 TI - Prediction of cancer incidence and mortality in Korea, 2012. AB - PURPOSE: To estimate the current cancer burden in Korea, cancer incidence and mortality rates were projected for the year 2012. MATERIALS AND METHODS: The cancer incidence data from 1999 to 2009 were obtained from the Korea National Cancer Incidence Database, and the cancer mortality data from 1993 to 2010 were obtained from Statistics Korea. Cancer incidence in 2012 was projected by fitting a linear regression model on observed age-specific cancer incidence rates against observed years, then multiplying the projected age-specific rates by the age specific population. For cancer mortality, a similar procedure was applied, except that a Joinpoint regression model was used to determine at which year the linear trend significantly changed. RESULTS: A total of 234,727 new cancer cases and 73,313 cancer deaths are projected to occur in Korea in 2012. For all sites combined, the crude incidence rates are projected to be 465.6 and 459.7, and the age-standardized incidences to be 345.1 and 300.9 per 100,000 respectively for males and females. CONCLUSION: Cancer has become an important public health concern in Korea, and as the Korean population ages, the cancer burden will continue to increase. PMID- 22500158 TI - Prognostic Impact of Polymorphisms in the CASPASE Genes on Survival of Patients with Colorectal Cancer. AB - PURPOSE: This study analyzed potentially functional polymorphisms in CASPASE (CASP) genes and their impact on the prognosis for Korean colorectal cancer patients. MATERIALS AND METHODS: A total of 397 consecutive patients with curatively resected colorectal adenocarcinoma were enrolled in this study. Genomic DNA from these patients was extracted from fresh colorectal tissue, and the 10 polymorphisms in the CASP3, CASP6, CASP7, CASP8, CASP9, and CASP10 genes were determined using a reverse transcription polymerase chain reaction genotyping assay. RESULTS: The median patient age was 63 years, and 218 (54.9%) patients had colon cancer, while 179 (45.1%) patients had rectal cancer. Univariate and multivariate survival analysis including pathologic stage, patient age, differentiation, and carcinoembryonic antigen level demonstrated that these polymorphisms were not associated with either disease-free or overall survival. CONCLUSION: None of the 10 polymorphisms in the CASP genes investigated in this study was found to be an independent prognostic marker for Korean patients with curatively resected colorectal cancer. PMID- 22500159 TI - Chemotherapy in Patients Older than or Equal to 75 Years with Advanced Non-small Cell Lung Cancer. AB - PURPOSE: As the number of elderly patients diagnosed with non-small cell lung carcinoma (NSCLC) increases, the number of these patients receiving chemotherapy also increases. However, limited data exists regarding the use of chemotherapy in advanced NSCLC patients who are 75 years of age or older. MATERIALS AND METHODS: Between May 2002 and October 2008, data for 48 advanced NSCLC patients who were 75 years of age or older who had been treated with chemotherapy were retrospectively analyzed. RESULTS: The median age of study participants at the time of first line chemotherapy was 76 years (range, 75 to 87 years) and their median Charlson comorbidity index was 2 (range, 1 to 4). Of the total 48 patients, 43 patients (90%) were treated by platinum-based doublet as a first line chemotherapy regimen. Median progression free survival for first line chemotherapy was 5.7 months (95% confidence interval [CI], 4.93 to 6.47 months) with an overall response rate of 33.3%. After first line chemotherapy, only 14 of the 48 patients (29.2%) received second line chemotherapy. The median overall survival (OS) for these patients was 8.2 months (95% CI, 4.44 to 11.96 months). Multivariate analysis results indicated that female gender and having received second-line or more chemotherapy were independent prognostic factors for increased OS for all 48 patients. Charlson Index was not a significant independent prognostic factor for survival. There were 9 treatment related deaths due to infectious causes (18.8%). CONCLUSION: Patients 75 years of age or older with advanced NSCLC may obtain clinical benefit from the administration of platinum-based doublet or single agent chemotherapy. However, oncologists must consider the aspect of safety in relation to the clinical benefits when managing this patient group. PMID- 22500160 TI - Weekly gemcitabine and docetaxel in refractory soft tissue sarcoma: a retrospective analysis. AB - PURPOSE: The combination of gemcitabine and docetaxel (GD) is used to effectively treat patients with soft tissue sarcoma (STS). It is widely considered that the conventional doses used are too high for long term use and many patients must discontinue GD treatment due to its toxicity. Therefore, to determine the appropriate dose meeting acceptable efficacy results, while minimizing toxic side effects, we treated patients with a weekly infusion of GD (weekly GD). MATERIALS AND METHODS: A total of 22 patients presenting a variety of STSs were treated at Yonsei Cancer Center. All patients had metastatic or recurrent cancer and had previously received doxorubicin and ifosfamide combination chemotherapy. In all cases, gemcitabine (1,000 mg/m(2)) and docetaxel (35 mg/m(2)) were administered intravenously on days 1 and 8 of a 21-day cycle. We retrospectively reviewed the medical records of these patients. RESULTS: The response rate was 4.5%, with one patient diagnosed with leiomyosarcoma having a partial response, and the disease control rate was 40.9%. The median progression-free survival (PFS) duration was 2.7 months and the PFS was correlated with the treatment response to a weekly GD. The median overall survival (OS) duration was 7.8 months and the OS was correlated with histology. There was no significant difference in OS between patients who received weekly GD as a 2nd line chemotherapy and those who received 3rd line or more. Treatment was generally well tolerated. CONCLUSION: Weekly GD was well tolerated and showed moderate efficacy, indicating that this could be a reasonable option as a salvage treatment for metastatic STS. PMID- 22500161 TI - Correlation of AR, EGFR, and HER2 Expression Levels in Prostate Cancer: Immunohistochemical Analysis and Chromogenic In Situ Hybridization. AB - PURPOSE: The androgen receptor (AR) plays a central role in prostate cancer. Evidence from several groups indicates that epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) may enhance AR activity in prostate cancer cell lines. This study was designed to investigate the protein expression of AR, EGFR, and HER2 and to determine whether the EGFR and HER2 genes are amplified in prostate cancer tissues. MATERIALS AND METHODS: The protein expression levels of AR, EGFR, and HER2 in a tissue microarray block of 66 prostate cancer samples were investigated by immunohistochemical analysis and chromogenic in situ hybridization was used to determine whether the EGFR and HER2 genes were amplified in these tissues. RESULTS: The AR and EGFR proteins were expressed in 59.1% and 40.9% of prostate cancers, respectively, but their expression levels were not significantly associated with clinicopathologic factors. Of the cases in which tissues were negative for EGFR protein expression, 69.2% were positive for AR protein expression; however, AR protein expression was significantly reduced (44.4%) in tissues in which EGFR protein was expressed. HER2 expression was detected in only 1 case (1.5%). No amplification of the EGFR or HER2 genes was found in prostate cancer specimens. CONCLUSION: This study was limited by small number of subjects, but it can still be inferred that the expression levels of the AR and EGFR proteins are inversely correlated in prostate cancer patients. The potential utility of EGFR and HER2 as prognostic factors or therapeutic targets warrants further study. PMID- 22500162 TI - Immunohistochemical Expression of DCUN1D1 in Non-small Cell Lung Carcinoma: Its Relation to Brain Metastasis. AB - PURPOSE: Non-small cell lung carcinoma (NSCLC) comprises 75-85% of all lung cancers, and approximately 25% of all NSCLC patients develop brain metastasis. There are no reliable markers for predicting in which patients this metastasis will occur. DCUN1D1, also known as squamous cell carcinoma-related oncogene, is associated with tumor progression and poor outcomes in NSCLC. The objective of this study was to investigate the role of DCUN1D1 expression in cases of brain metastasis due to NSCLC. MATERIALS AND METHODS: Primary tumor samples from a total of 71 cases of NSCLC, either with (n=40) or without (n=31) brain metastasis, were evaluated for DCUN1D1 expression by immunohistochemistry analysis. RESULTS: DCUN1D1 expression was detected in 16 patients (23%) and tended to correlate with T classification (15% of T1-2 tumors vs. 30% of T3-4 tumors, p=0.083). DCUN1D1 expression was significantly associated with tumor stage. It was observed in none of the patients with stage I disease, 10% of those with stage II disease, and 29% with stage III disease (p=0.009). In addition, 14 of 16 DCUN1D1-positive patients resulted in brain metastasis (p=0.01). The odds ratio of brain metastasis for patients with DCUN1D1 expression was 3.112 (p=0.009). CONCLUSION: DCUN1D1 expression may play a role in tumor progression and development of brain metastasis in patients with NSCLC. Evaluation of DCUN1D1 expression may provide assistance in identifying those patients who are at higher risk for brain metastasis. PMID- 22500163 TI - Five cases report of solid tumor synchronously with hematologic malignancy. AB - The reported incidence of synchronous multiple primary cancer (SMPC) is rare, and it is even less common to observe synchronous solid tumor with a hematological malignancy. We report five cases of solid tumor presented synchronously with hematological malignancy, all observed within a 2 year period at the oncology department of a university hospital in Shanghai, China. These individual cases included lung adenocarcinoma with chronic myelogenous leukemia, colon cancer with solitary plasmocytoma, gastric adenocarcinoma with diffuse large B cell non Hodgkin's lymphoma, lung adenocarcinoma with multiple myeloma, and colon cancer with diffuse large B cell non-Hodgkin's lymphoma. It is challenging to therapeutically control the biological behavior of concurrent multiple primary tumors, and there is no standard treatment for such rare conditions. In this paper we discuss these five cases of SMPC and their treatments. PMID- 22500164 TI - A Case of Non-Hodgkin's Lymphoma in Patient with Coombs' Negative Hemolytic Anemia and Idiopathic Thrombocytopenic Purpura. AB - Coombs' negative autoimmune hemolytic anemia (AIHA) is a rare disease which shares similar clinical and hematological features with Coombs' positive AIHA, but its exact frequency remains unknown. There have been few reports of idiopathic thrombocytopenic purpura (ITP) and Coombs' negative AIHA associated with other lymphoproliferative disorders (LPDs). Since there is a well known association between LPDs and autoimmune phenomena, it is important to investigate the possibility of an underlying malignancy. We report a case of ITP and Coombs' negative AIHA associated with diffuse large B-cell lymphoma. PMID- 22500165 TI - Chromosomal Location of HCA1 and HCA2, Hybrid Chlorosis Genes in Rice. AB - MANY POSTZYGOTIC REPRODUCTIVE BARRIER FORMS HAVE BEEN REPORTED IN PLANTS: hybrid weakness, hybrid necrosis, and hybrid chlorosis. In this study, linkage analysis of the genes causing hybrid chlorosis in F(2) generation in rice, HCA1 and HCA2, was performed. HCA1 and HCA2 are located respectively on the distal regions of the short arms of chromosomes 12 and 11. These regions are known to be highly conserved as a duplicated chromosomal segment. The molecular mechanism causing F(2) chlorosis deduced from the location of the two genes was discussed. The possibility of the introgression of the chromosomal segments encompassing HCA1 and/or HCA2 was also discussed from the viewpoint of Indica-Japonica differentiation. PMID- 22500166 TI - Development of an antimicrobial stewardship intervention using a model of actionable feedback. AB - We describe the development of an audit and feedback intervention to improve antibiotic prescribing in the neonatal intensive care unit (NICU) using a theoretical framework. Participants included attending physicians, neonatal fellows, pediatric residents, and nurse practitioners. The intervention was based on the "model of actionable feedback" which emphasizes that feedback should be timely, individualized, nonpunitive, and customized to be effective. We found that real-time feedback could not be provided for the parameters established in this study, as we had to collect and analyze numerous data elements to assess appropriate initiation and continuation of antibiotics and required longer intervals to examine trends in antibiotic use. We learned during focus groups that NICU clinicians strongly resisted assigning individual responsibility for antibiotic prescribing as they viewed this as a shared responsibility informed by each patient's laboratory data and clinical course. We were able to create a non punitive atmosphere thanks to written informed consent from NICU attendings and assurance from leadership that prescribing practices would not be used to assess job performance. We provided customized, meaningful feedback integrating input from the participants. Adapting the principles of the "model of actionable feedback" to provide feedback for antimicrobial prescribing practices proved challenging in the NICU setting. PMID- 22500167 TI - Analysis of insulin in human breast milk in mothers with type 1 and type 2 diabetes mellitus. AB - Despite the important role that insulin plays in the human body, very little is known about its presence in human milk. Levels rapidly decrease during the first few days of lactation and then, unlike other serum proteins of similar size, achieve comparable levels to those in serum. Despite this, current guides for medical treatment suggest that insulin does not pass into milk, raising the question of where the insulin in milk originates. Five mothers without diabetes, 4 mothers with type 1, and 5 mothers with type 2 diabetes collected milk samples over a 24-hour period. Samples were analysed for total and endogenous insulin content and for c-peptide content. All of the insulin present in the milk of type 1 mothers was artificial, and c-peptide levels were 100x lower than in serum. This demonstrates that insulin is transported into human milk at comparable concentration to serum, suggesting an active transport mechanism. The role of insulin in milk is yet to be determined; however, there are a number of potential implications for the infant of the presence of artificial insulins in milk. PMID- 22500168 TI - Advances in Virus-Directed Therapeutics against Epstein-Barr Virus-Associated Malignancies. AB - Epstein-Barr virus (EBV) is the causal agent in the etiology of Burkitt's lymphoma and nasopharyngeal carcinoma and is also associated with multiple human malignancies, including Hodgkin's and non-Hodgkin's lymphoma, and posttransplantation lymphoproliferative disease, as well as sporadic cancers of other tissues. A causal relationship of EBV to these latter malignancies remains controversial, although the episomic EBV genome in most of these cancers is clonal, suggesting infection very early in the development of the tumor and a possible role for EBV in the genesis of these diseases. Furthermore, the prognosis of these tumors is invariably poor when EBV is present, compared to their EBV-negative counterparts. The physical presence of EBV in these tumors represents a potential "tumor-specific" target for therapeutic approaches. While treatment options for other types of herpesvirus infections have evolved and improved over the last two decades, however, therapies directed at EBV have lagged. A major constraint to pharmacological intervention is the shift from lytic infection to a latent pattern of gene expression, which persists in those tumors associated with the virus. In this paper we provide a brief account of new virus-targeted therapeutic approaches against EBV-associated malignancies. PMID- 22500170 TI - New directions in cariology research 2011. PMID- 22500169 TI - Protein Kinase C: One Pathway towards the Eradication of Latent HIV-1 Reservoirs. AB - An effective means to eradicate latent reservoirs in HIV-1-infected individuals remains elusive. Attempts to purge these reservoirs were undertaken over a decade ago without success. The subsequent lapse in further clinical attempts since may have been justified as our knowledge of the mechanisms which underpin the latent state still evolves. Although additional novel molecular antagonists of HIV-1 latency have subsequently been reported, these candidate agents have not been tested in human trials for reservoir ablation. This review provides an overview of the protein kinase C (PKC) pathway which can be modulated by small molecular agents to induce the expression of latent HIV-1 from within infected reservoir cells. Some of these agents have been tested against select cancers with seemingly tolerable side effects. As such, modulation of the PKC pathway may yet be a viable mechanism toward HIV-1 reservoir eradication. PMID- 22500171 TI - Rapid Heterotrophic Ossification with Cryopreserved Poly(ethylene glycol-) Microencapsulated BMP2-Expressing MSCs. AB - Autologous bone grafting is the most effective treatment for long-bone nonunions, but it poses considerable risks to donors, necessitating the development of alternative therapeutics. Poly(ethylene glycol) (PEG) microencapsulation and BMP2 transgene delivery are being developed together to induce rapid bone formation. However, methods to make these treatments available for clinical applications are presently lacking. In this study we used mesenchymal stem cells (MSCs) due to their ease of harvest, replication potential, and immunomodulatory capabilities. MSCs were from sheep and pig due to their appeal as large animal models for bone nonunion. We demonstrated that cryopreservation of these microencapsulated MSCs did not affect their cell viability, adenoviral BMP2 production, or ability to initiate bone formation. Additionally, microspheres showed no appreciable damage from cryopreservation when examined with light and electron microscopy. These results validate the use of cryopreservation in preserving the viability and functionality of PEG-encapsulated BMP2-transduced MSCs. PMID- 22500172 TI - Unraveling the determinants of protrusion formation. AB - A COMPUTERIZED MORPHOMETRIC CLASSIFICATION TECHNIQUE BASED ON LATENT FACTORS REVEALS MAJOR PROTRUSION CLASSES: factors 4, 5, and 7. Previous work showed that factor 4 represented filopodia, 5 the distribution of lamellar cytoplasm, and 7 a blunt protrusion. We explore the relationship of focal contact (FC) characteristics and their integrated actin cables to factors values. The results show that FC maturation/cytoskeletal integration affects factor 5, because FC elongation/integration was correlated with its values. On the contrary, 7 values decreased with maturation, so cable or FC size or their integration must be restricted to form these protrusions. Where integration did occur, the cables showed distinctive size and orientation, as indicated by correlation of 7 values with FC shape. Results obtained with myosin inhibitors support the interpretation that a central, isometric, contractile network puts constraints on both factor 5 and 7 protrusions. We conclude that cells establish functional domains by rearranging the cytoskeleton. PMID- 22500173 TI - Distribution of cytoskeletal components in endothelial cells in the Guinea pig renal artery. AB - The cytoskeletal components of endothelial cells in the renal artery were examined by analysis of en face preparations under confocal laser scanning microscopy. Renal arterial endothelial cells were shown to be elongated along the direction of blood flow, while stress fibers ran perpendicular to the flow in the basal portion. Focal adhesions were observed along the stress fibers in dot-like configurations. On the other hand, stress fibers in the apical portion of cells ran along the direction of flow. The localizations of stress fibers and focal adhesions in endothelial cells in the renal artery differed from those of unperturbed aortic and venous endothelial cells. Tyrosine-phosphorylated proteins were mainly detected at the sites of cell-to-cell apposition, but not in focal adhesions. Pulsatile pressure and fluid shear stress applied over endothelial cells in the renal artery induce stress fiber organization and localization of focal adhesions. These observations suggest that the morphological alignment of endothelial cells along the direction of blood flow and the organization of cytoskeletal components are independently regulated. PMID- 22500174 TI - Nasopharyngeal carcinoma signaling pathway: an update on molecular biomarkers. AB - Nasopharyngeal carcinoma (NPC) is an uncommon cancer, which has a distinctive ethnic and geographic distribution. Etiology of NPC is considered to be related with a complex interaction of environmental and genetic factors as well as Epstein-Barr virus infection. Since NPC is located in the silent painless area, the disease is usually therefore diagnosed at the advanced stages; hence early detection of NPC is difficult. Furthermore, understanding in molecular pathogenesis is still lacking, pondering the identification of effective prognostic and diagnostic biomarkers. Dysregulation of signaling molecules in intracellular signal transduction, which regulate cell proliferation, apoptosis, and adhesion, underlines the basis of NPC pathogenesis. In this paper, the molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression. The important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis. PMID- 22500175 TI - Coleopteran antimicrobial peptides: prospects for clinical applications. AB - Antimicrobial peptides (AMPs) are activated in response to septic injury and have important roles in vertebrate and invertebrate immune systems. AMPs act directly against pathogens and have both wound healing and antitumor activities. Although coleopterans comprise the largest and most diverse order of eukaryotes and occupy an earlier branch than Drosophila in the holometabolous lineage of insects, their immune system has not been studied extensively. Initial research reports, however, indicate that coleopterans possess unique immune response mechanisms, and studies of these novel mechanisms may help to further elucidate innate immunity. Recently, the complete genome sequence of Tribolium was published, boosting research on coleopteran immunity and leading to the identification of Tribolium AMPs that are shared by Drosophila and mammals, as well as other AMPs that are unique. AMPs have potential applicability in the development of vaccines. Here, we review coleopteran AMPs, their potential impact on clinical medicine, and the molecular basis of immune defense. PMID- 22500176 TI - Risk of orthopedic surgical site infections in patients with rheumatoid arthritis treated with antitumor necrosis factor alfa therapy. AB - Introduction. International guidelines recommend interruption of anti-TNF medications in the perioperative period, but there are no randomized trials to support such recommendation. Objectives. To study literature evidence assessing the risk of surgical site infections in orthopedic surgery patients with RA using anti-TNF drugs, compared to untreated patients or those using conventional DMARD. Methods. Systematic review of cohort studies is concerning surgical site infections in orthopedic procedures in patients with RA. Results. Three studies were selected. Only one was considered of high-quality, albeit with low statistical power. The review resulted in inconclusive data, since the best quality study showed no significant differences between groups, while others showed increased risk of infections in patients using anti-TNF medications. Conclusion. It is unclear whether patients with RA using anti-TNF medications are at increased risk of surgical site infections. Randomized controlled trials or new high quality observational studies are needed to clarify the issue. PMID- 22500177 TI - Biological therapy in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a prototypic inflammatory autoimmune disorder characterized by multisystem involvement and fluctuating disease activity. Symptoms range from rather mild manifestations such as rash or arthritis to life-threatening end-organ manifestations. Despite new and improved therapy having positively impacted the prognosis of SLE, a subgroup of patients do not respond to conventional therapy. Moreover, the risk of fatal outcomes and the damaging side effects of immunosuppressive therapies in SLE call for an improvement in the current therapeutic management. New therapeutic approaches are focused on B-cell targets, T-cell downregulation and costimulatory blockade, cytokine inhibition, and the modulation of complement. Several biological agents have been developed, but this encouraging news is associated with several disappointments in trials and provide a timely moment to reflect on biologic therapy in SLE. PMID- 22500178 TI - Molecular Cloning and Sequence Analysis of the cDNAs Encoding Toxin-Like Peptides from the Venom Glands of Tarantula Grammostola rosea. AB - Tarantula venom glands produce a large variety of bioactive peptides. Here we present the identification of venom components obtained by sequencing clones isolated from a cDNA library prepared from the venom glands of the Chilean common tarantula, Grammostola rosea. The cDNA sequences of about 1500 clones out of 4000 clones were analyzed after selection using several criteria. Forty-eight novel toxin-like peptides (GTx1 to GTx7, and GTx-TCTP and GTx-CRISP) were predicted from the nucleotide sequences. Among these peptides, twenty-four toxins are ICK motif peptides, eleven peptides are MIT1-like peptides, and seven are ESTX-like peptides. Peptides similar to JZTX-64, aptotoxin, CRISP, or TCTP are also obtained. GTx3 series possess a cysteine framework that is conserved among vertebrate MIT1, Bv8, prokineticins, and invertebrate astakines. GTx-CRISP is the first CRISP-like protein identified from the arthropod venom. Real-time PCR revealed that the transcripts for TCTP-like peptide are expressed in both the pereopodal muscle and the venom gland. Furthermore, a unique peptide GTx7-1, whose signal and prepro sequences are essentially identical to those of HaTx1, was obtained. PMID- 22500179 TI - Angiotensinogen gene transcription in pulmonary fibrosis. AB - An established body of literature supports the hypothesis that activation of a local tissue angiotensin (ANG) system in the extravascular tissue compartment of the lungs is required for lung fibrogenesis. Transcriptional activation of the angiotensinogen (AGT) gene is believed to be a critical and necessary step in this activation. This paper summarizes the data in support of this theory and discusses transcriptional regulation of AGT, with an emphasis on lung AGT synthesis as a determinant of fibrosis severity. Genetic data linking AGT polymorphisms to the severity of disease in Idiopathic Pulmonary Fibrosis are also discussed. PMID- 22500180 TI - How can microarrays unlock asthma? AB - Asthma is a complex disease regulated by the interplay of a large number of underlying mechanisms which contribute to the overall pathology. Despite various breakthroughs identifying genes related to asthma, our understanding of the importance of the genetic background remains limited. Although current therapies for asthma are relatively effective, subpopulations of asthmatics do not respond to these regimens. By unlocking the role of these underlying mechanisms, a source of novel and more effective treatments may be identified. In the new age of high throughput technologies, gene-expression microarrays provide a quick and effective method of identifying novel genes and pathways, which would be impossible to discover using an individual gene screening approach. In this review we follow the history of expression microarray technologies and describe their contributions to advancing our current knowledge and understanding of asthma pathology. PMID- 22500181 TI - Quality of life improvement with sublingual immunotherapy: a prospective study of efficacy. AB - Due to its excellent safety profile, ease of administration, and economic considerations, sublingual immunotherapy (SLIT) is becoming a preferred form of allergen specific immunotherapy. The efficacy of SLIT is still debated. The purpose of this act of practice trial is to evaluate quality of life outcomes in patients treated with SLIT. Fifty one patients with allergic rhinoconjunctivitis demonstrated by skin testing completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) at initiation, at four months and at 10-12 months of SLIT. Significant improvement (P < 0.05) on six of seven domain categories of the RQLQ questionnaire was noted. Total RQLQ scores also showed significant improvement. This study supports SLIT as a modality effective in controlling allergic symptoms. PMID- 22500182 TI - Cyclin D1 in ASM Cells from Asthmatics Is Insensitive to Corticosteroid Inhibition. AB - Hyperplasia of airway smooth muscle (ASM) is a feature of the remodelled airway in asthmatics. We examined the antiproliferative effectiveness of the corticosteroid dexamethasone on expression of the key regulator of G(1) cell cycle progression-cyclin D1-in ASM cells from nonasthmatics and asthmatics stimulated with the mitogen platelet-derived growth factor BB. While cyclin D1 mRNA and protein expression were repressed in cells from nonasthmatics in contrast, cyclin D1 expression in asthmatics was resistant to inhibition by dexamethasone. This was independent of a repressive effect on glucocorticoid receptor translocation. Our results corroborate evidence demonstrating that corticosteroids inhibit mitogen-induced proliferation only in ASM cells from subjects without asthma and suggest that there are corticosteroid-insensitive proliferative pathways in asthmatics. PMID- 22500183 TI - Role of the Arylhydrocarbon Receptor (AhR) in the Pathology of Asthma and COPD. AB - The dioxins and dioxin-like compounds in cigarette smoke and environmental pollutants modulate immunological responses. These environmental toxicants are known to cause lung cancer but have also recently been implicated in allergic and inflammatory diseases such as bronchitis, asthma, and chronic obstructive pulmonary disease (COPD). In a novel pathway of this response, the activation of a nuclear receptor, arylhydrocarbon receptor (AhR), mediates the effects of these toxins through the arachidonic acid cascade, cell differentiation, cell-cell adhesion interactions, cytokine expression, and mucin production that are implicated in the pathogenesis and exacerbation of asthma/COPD. We have previously reported that human bronchial epithelial cells express AhR, and AhR activation induces mucin production through reactive oxygen species. This review discusses the role of AhR in asthma and COPD, focusing in particular on inflammatory and resident cells in the lung. We describe the important impact that AhR activation may have on the inflammation phase in the pathology of asthma and COPD. In addition, crosstalk of AhR signaling with other ligand-activated transcription factors such as peroxisome proliferator-activated receptors (PPARs) has been well documented. PMID- 22500184 TI - Therapeutic effects and biomarkers in sublingual immunotherapy: a review. AB - Immunotherapy is considered to be the only curative treatment for allergic diseases such as pollinosis, perennial rhinitis, asthma, and food allergy. The sublingual route is widely applied for immunotherapy for allergy, instead of the conventional administration by subcutaneous route. A recent meta-analysis of sublingual immunotherapy (SLIT) has shown that this approach is safe, has positive clinical effects, and provides prolonged therapeutic effects after discontinuation of treatment. However, the mechanism of SLIT and associated biomarkers are not fully understood. Biomarkers that change after or during SLIT have been reported and may be useful for response monitoring or as prognostic indicators for SLIT. In this review, we focus on the safety, therapeutic effects, including prolonged effects after treatment, and new methods of SLIT. We also discuss response monitoring and prognostic biomarkers for SLIT. Finally, we discuss immunological mechanisms of SLIT with a focus on oral dendritic cells and facilitated antigen presentation. PMID- 22500185 TI - Combined Beta-agonists and corticosteroids do not inhibit extracellular matrix protein production in vitro. AB - Background. Persistent asthma is characterized by airway remodeling. Whereas we have previously shown that neither beta(2)-agonists nor corticosteroids inhibit extracellular matrix (ECM) protein release from airway smooth muscle (ASM) cells, the effect of their combination is unknown and this forms the rationale for the present study. Methods. ASM cells from people with and without asthma were stimulated with TGFbeta1 (1 ng/ml) with or without budesonide (10(-8) M) and formoterol (10(-10) and 10(-8) M), and fibronectin expression and IL-6 release were measured by ELISA. Bronchial rings from nonasthmatic individuals were incubated with TGFbeta1 (1 ng/ml) with or without the drugs, and fibronectin expression was measured using immunohistochemistry. Results. Budesonide stimulated fibronectin deposition, in the presence or absence of TGFbeta1, and this was partially reversed by formoterol (10(-8) M) in both asthmatic and nonasthmatic cells. Budesonide and formoterol in combination failed to inhibit TGFbeta-induced fibronectin in either cell type. A similar pattern of expression of fibronectin was seen in bronchial rings. TGFbeta1-induced IL-6 release was inhibited by the combination of drugs. Conclusion. Current combination asthma therapies are unable to prevent or reverse remodeling events regulated by ASM cells. PMID- 22500186 TI - Calreticulin is a negative regulator of bronchial smooth muscle cell proliferation. AB - Background. Calreticulin controls the C/EBPalphap42/p30 at the translational level trough a cis-regulatory CNG rich loop in the CEBPA mRNA. We determined the effects of steroids and long-acting beta-agonists on the p42/p30 ratio and on calreticulin expression in primary human bronchial smooth muscle (BSM) cells. Methods. The effects of budesonide (10(-8) M) and formoterol (10(-8) M) were studied in BSM cells pre-treated with siRNA targeting calreticulin. The expression of C/EBPalpha and calreticulin was determined by immuno-blotting. Automated cell counts were performed to measure proliferation. Results. All tested BSM cell lines (n = 5) expressed C/EBPalpha and calreticulin. In the presence of 5% FBS, the p42/p30 ratio significantly decreased (n = 3, P < 0.05) and coincided with BSM cell proliferation. High levels of calreticulin were associated with a decreased p42/p30 isoform ratio. FBS induced the expression of calreticulin (n = 3, P < 0.05), which was further increased by formoterol. siRNA targeting calreticulin increased the p42/p30 ratio in non-stimulated BSM cells and significantly inhibited the proliferation of PDGF-BB-stimulated BSM cells (n = 5, P < 0.05). Neither budesonide nor formoterol restored the p42 isoform expression. Conclusions. Our data show calreticulin is a negative regulator of C/EBPalpha protein expression in BSM cells. Modulation of calreticulin levels may provide a novel target to reduce BSM remodeling. PMID- 22500187 TI - A review of psychosocial risk factors for pediatric atopy. AB - Pediatric atopy is increasing in prevalence and creates a significant financial and quality of life burden for children and families (e.g., frequent clinic visits, academic, and social challenges). Thus, it is important to understand modifiable risk factors related to disease onset or exacerbation in young children. The existing research base suggests that while a genetic link has been identified, specific family psychological factors (e.g., parent stress) also appear to play a significant role in the development of pediatric atopy. The function of psychological stress in the clinical expression and exacerbation of allergic diseases in young children is hypothesized to be due to neuroendocrine and immunologic systems. Specifically, stress-related activation of the sympathetic and adrenomedullary (SAM) system as well as the hypothalamic pituitary-adrenocortical (HPA) axis from both the intrauterine environment and early childhood experiences may increase risk of childhood atopy above and beyond genetic risk. Consequently, prevention and intervention strategies aimed at reducing children's early exposure to stress and psychological difficulties in parents may prove beneficial in preventing or reducing the likelihood that their children will develop atopy. PMID- 22500188 TI - Evaluation of a Novel Rapid Test System for the Detection of Specific IgE to Hymenoptera Venoms. AB - Background. The Allergy Lateral Flow Assay (ALFA) is a novel rapid assay for the detection of sIgE to allergens. The objective of this study is the evaluation of ALFA for the detection of sIgE to bee venom (BV) and wasp venom (WV) in insect venom allergic patients. Methods. Specific IgE to BV and WV was analyzed by ALFA, ALLERG-O-LIQ, and ImmunoCAP in 80 insect venom allergic patients and 60 control sera. Sensitivity and specificity of ALFA and correlation of ALFA and ImmunoCAP results were calculated. Results. The sensitivity/specificity of ALFA to the diagnosis was 100%/83% for BV and 82%/97% for WV. For insect venom allergic patients, the Spearman correlation coefficient for ALFA versus ImmunoCAP was 0.79 for BV and 0.80 for WV. However, significant differences in the negative control groups were observed. Conclusion. ALFA represents a simple, robust, and reliable tool for the rapid detection of sIgE to insect venoms. PMID- 22500189 TI - Evaluation of a parental questionnaire to identify atopic dermatitis in infants and preschool children. AB - Aim. To develop and validate a questionnaire for detecting atopic dermatitis in infants and small children from the age of 2 months. Methods. Parents to 60 children answered a written questionnaire prior to a physical examination and individual semistructured interview. Qualitative and quantitative analyses of validity, sensitivity, specificity, and predictive values of the questionnaire were performed. Results. A total of 27 girls and 33 boys, aged 2 to 71 months, 35 with and 25 without physician-diagnosed eczema, participated. Validation of the questionnaire by comparisons with physicians' diagnoses showed a sensitivity of 0.91 (95% CI 0.77-0.98) and a specificity of 1 (95% CI 0.86-1). Conclusions. Three questions in a parental questionnaire were sufficient for diagnosing eczema in infants and small children. PMID- 22500190 TI - Reticular Basement Membrane Vessels Are Increased in COPD Bronchial Mucosa by Both Factor VIII and Collagen IV Immunostaining and Are Hyperpermeable. AB - Background and Objective. Using Collagen IV staining, we have previously reported that the reticular basement membrane (Rbm) is hypervascular and the lamina propria (LP) is hypovascular in COPD airways. This study compared Collagen IV staining with vessels marked with anti-Factor VIII and examined vessel permeability in bronchial biopsies from COPD and normal subjects using albumin staining. Results. Anti-Collagen IV antibody detected more vessels in the Rbm (P = 0.002) and larger vessels in both Rbm (P < 0.001) and LP (P = 0.003) compared to Factor VIII. COPD airways had more vessels (with greater permeability) in the Rbm (P = 0.01) and fewer vessels (with normal permeability) in the LP compared to controls with both Collagen IV and Factor VIII antibodies (P = 0.04 and P = 0.01). Conclusion. Rbm vessels were increased in number and were hyperpermeable in COPD airways. Anti-Collagen IV and anti-Factor VIII antibodies did not uniformly detect the same vessel populations; the first is likely to reflect larger and older vessels with the latter reflecting smaller, younger vessels. PMID- 22500191 TI - Helicobacter pylori: Eradication or Preservation. AB - Helicobacter pylori infects about 50% of the world's population and inevitably results in the development of gastritis. Of those infected, about 10% develop peptic ulcer disease and roughly 1% develop gastric cancer. Conversely, some take the view that H. pylori infection provides some protection against gastro esophageal reflux disease and possibly asthma. This review aims to explore the case for and against eradication of the bacterium using a "test and treat" approach amongst the general population. PMID- 22500192 TI - Telomeres in disease. AB - Telomeres and telomere repair are basic molecular features of cells possessing linear DNA chromosomes and defects in them result in various diseases. This review examines recent advances in understanding these diseases, particularly at a molecular level, and in relating telomere dysfunction to clinical diseases. We also discuss the potential role of telomere elongation as a therapy in diseases, and more controversially, the prevention/reversal of aging. PMID- 22500193 TI - The Protein Structure Initiative: achievements and visions for the future. AB - The Protein Structure Initiative (PSI) was established in 2000 by the National Institutes of General Medical Sciences with the long-term goal of providing 3D (three-dimensional) structural information for most proteins in nature. As advances in genomic sequencing, bioinformatics, homology modelling, and methods for rapid determination of 3D structures of proteins by X-ray crystallography and nuclear magnetic resonance (NMR) converged, it was proposed that our understanding of the biology of protein structure and evolution could be greatly enabled by 'genomic-scale' protein structure determination. Over the past 12 years, the PSI has evolved from a testing bed for new methods of sample and structure production to a core component of a wide range of biology programs. PMID- 22500194 TI - The context of gene expression regulation. AB - Recent advances in sequencing technologies have uncovered a world of RNAs that do not code for proteins, known as non-protein coding RNAs, that play important roles in gene regulation. Along with histone modifications and transcription factors, non-coding RNA is part of a layer of transcriptional control on top of the DNA code. This layer of components and their interactions specifically enables (or disables) the modulation of three-dimensional folding of chromatin to create a context for transcriptional regulation that underlies cell-specific transcription. In this perspective, we propose a structural and functional hierarchy, in which the DNA code, proteins and non-coding RNAs act as context creators to fold chromosomes and regulate genes. PMID- 22500195 TI - An Open Trial of Sustained Release Bupropion for Attention-Deficit/Hyperactivity Disorder in Adults with ADHD plus Substance Use Disorders. AB - OBJECTIVE: To evaluate the effectiveness and tolerability of bupropion in adults with Attention-Deficit/Hyperactivity Disorder (ADHD) and comorbid active Substance Use Disorders (SUD). METHODS: This was a six-week open trial of sustained-release (SR) bupropion in adults aged 18 to 55 years diagnosed with both ADHD and SUD. Bupropion-SR was initiated at 100 mg SR and increased weekly to a target dose of 200 mg SR twice daily. Subjects were assessed on multiple outcomes including ADHD, SUD, and adverse effects. All analyses were intent to treat, with last observation carried forward. RESULTS: Thirty-two subjects were treated with bupropion, with nineteen subjects completing the entire protocol (59%). At end point there were clinically significant reductions in the ADHD RS (34.1+/-8.2 to 19.4+/-11.4, -43%, t=6.49, p<0.0001) and the Clinical Global Impression (CGI) of ADHD severity (baseline=5.0, endpoint=3.8, -24%, t=6.16, p<0.0001). In contrast, there were clinically negligible effects on the self report of substance use (p's >0.05) and on the overall CGI of SUD severity (-23%, t=4.95, p<0.0001). CONCLUSIONS: Results from this open trial suggest that in adults with ADHD and SUD, treatment with bupropion-SR is associated with clinically significant reductions in ADHD, but not SUD. PMID- 22500196 TI - Identification of surgeon-individual treatment profiles to support the provision of an optimum treatment service for cataract patients. AB - One objective of ophthalmological departments is the optimization of patient treatment services. A strategy for optimization is the identification of individual potential for advanced training of surgeons based on their daily working results. The objective of this feasibility study was the presentation and evaluation of a strategy for the computation of surgeon-individual treatment profiles (SiTPs). We observed experienced surgeons during their standard daily performance of cataract procedures in the Ophthalmological Department of the University Medical Center Leipzig, Germany. One hundred five cases of cataract procedures were measured as Surgical Process Models (SPMs) with a detailed-to-the second resolution. The procedures were performed by three different surgeons during their daily work. Subsequently, SiTPs were computed and analyzed from the SPMs as statistical 'mean' treatment strategies for each of the surgeons. The feasibility study demonstrated that it is possible to identify differences in surgeon-individual treatment profiles beyond the resolution of cut-suture times. Surgeon-individual workflows, activity frequencies and average performance durations of surgical activities during cataract procedures were analyzed. Highly significant (p < 0.001) workflow differences were found between the treatment profiles of the three surgeons. Conclusively, the generation of SiTPs is a convenient strategy to identify surgeon-individual training potentials in cataract surgery. Concrete recommendations for further education can be derived from the profiles. PMID- 22500197 TI - Intra-arterial thrombolysis using double devices: mechanicomechanical or chemicomechanical techniques. AB - OBJECTIVE: To optimize the recanalization of acute cerebral stroke that were not effectively resolved by conventional intraarterial thrombolysis (IAT), we designed a double device technique to allow for rapid and effective reopening. In this article, we describe the feasibility and efficacy of this technique. METHODS: From January 2008 to September 2009, twenty patients with acute cerebral arterial occlusion (middle cerebral artery : n=12; internal carotid artery terminus : n=5; basilar artery : n=3) were treated by the double device technique. This technique was applied when conventional thrombolytic methods using drug, microwires, microcatheters and balloons did not result in recanalization. In the double device technique, two devices are simultaneously placed at the lesion (for example, one microcatheter and one balloon or two microcatheters). Chemicomechanical or mechanicomechanical thrombolysis was performed simultaneously using various combinations of two devices. Recanalization rates, procedural time, complications, and clinical outcomes were analyzed. RESULTS: The initial median National Institute of Health Stroke Scale (NIHSS) was 16 (range 5-26). The double device technique was applied after conventional IAT methods failed. Recanalization was achieved in 18 patients (90%). Among them, 55% (11 cases) were complete (thrombolysis in cerebral infarction 2B, 3). The median thrombolytic procedural time including the conventional technique was 135+/-83.7 minutes (range 75-427). Major symptomatic hemorrhages (neurological deterioration >=4 points in NIHSS) developed in two patients (10%). Good long term outcomes (modified Rankin Scale <=2 at 90 days) occurred in 25% (n=5) of the cases. Mortality within 90 days developed in two cases (10%). CONCLUSION: The double device technique is a feasible and effective technical option for large vessel occlusion refractory to conventional thrombolysis. PMID- 22500198 TI - The effect of body mass index on intra-abdominal pressure and blood loss in lumbar spine surgery. AB - OBJECTIVE: The purpose of this prospective study was to evaluate the effects of body mass index (BMI) on intra-abdominal pressure (IAP) and intraoperative blood loss (IBL) during lumbar spinal surgery. METHODS: Thirty patients scheduled for single level posterior lumbar interbody fusion were allocated equally to a normal group (Group 1, BMI;18.5-22.9 kg/m(2)), an overweight group (Group 2, BMI; 23 24.9 kg/m(2)), and an obese group (Group 3, BMI; 25.0-29.9 kg/m(2)) according to BMI. IAP was measured using a urinary bladder catheter; 1) supine after anesthesia induction, 2) prone at skin incision, 3) prone at the end of surgery. In addition, IBL was also measured in the three groups. RESULTS: IAP in the supine position was not significantly different in groups 1, 2, and 3 (2.7 mm Hg, 3.0 mm Hg, and 4.2 mm Hg, respectively) (p=0.258), and IAP in the prone position at incision increased to 7.8 mm Hg, 8.2 mm Hg, and 10.4 mm Hg, respectively, in the three groups, and these intergroup differences were significant, especially for Group 3 (p=0.000). IAP at the end of surgery was slightly lower (7.0 mm Hg, 7.7 mm Hg, and 9.2 mm Hg, respectively). IBLs were not significantly different between the three groups. However, IBLs were found to increase with IAP in the prone position (p=0.022) and BMI (p<0.05). CONCLUSION: These results show that BMI affects IAP in the prone position more than in the supine position during lumbar spinal surgery. In addition, IBLs were found to increase with IAP in the prone position and with BMI. Thus, IBLs can be expected to be higher in morbidly obese patients due to an increased IAP. PMID- 22500199 TI - Decompressive hemicraniectomy and duroplasty in toddlers and preschool children with refractory intracranial hypertension after unilateral hemispheric stroke. AB - OBJECTIVE: Life-threatening hemispheric stroke is associated with a high mortality and morbidity. Decompressive hemicraniectomy has been regarded as an effective treatment option for refractory intracranial hypertension. Here, we reported the clinical course of 5 children with decompressive craniectomy and duroplasty after non-traumatic refractory intracranial hypertension. METHODS: Four toddlers and one preschool-girl were included in this study; there were 3 boys and 2 girls with a mean age of 34.6 months (range 17-80). Decompressive craniectomy including duroplasty was performed in cases of dilatation of pupil size after intensified standard medical therapy had proven insufficient. All children had a Pediatric Glasgow Coma Scale score <8 at pre-operation state. The mean time-point of craniectomy after stroke attack was 12 hours (range 4-19). RESULTS: During the long-term follow-up period (mean 47.6 months), no children died. One year later, when we checked their Glasgow Outcome Scale scores, only one toddler received a score of 4 (moderate disability). But the others had good recoveries although they had minor physical or mental deficits. According to the Pediatric Cerebral Performance Category Scale, 4 children received a score of 2 (mild disability). CONCLUSION: Despite our small cases, we suggest that decompressive hemicraniectomy and duroplasty is an acceptable and life-saving treatment for refractory intracranial hypertension after unilateral hemispheric stroke in toddlers and preschool children. PMID- 22500200 TI - Acute spontaneous subdural hematoma of arterial origin. AB - Acute spontaneous subdural hematoma (SDH) of arterial origin is very rare. We report a case of acute spontaneous SDH that showed contrast media extravasation from cortical artery on angiograms. A 58-year-old male patient developed sudden onset headache and right hemiparesis. Brain CT scan demonstrated acute SDH at left convexity. The patient was drowsy mentality on admission. He had no history of head trauma. Cerebral angiography was performed and revealed a localized extravasation of the contrast media from distal cortical MCA branch. After angiography, the patient deteriorated to comatose mentality. Decompressive craniectomy for removal of SDH was performed. We verified the arterial origin of the bleeding and coagulated the bleeding focus. The histological diagnosis was aneurysmal artery. He recovered after surgery with mild disability. In a case of acute spontaneous SDH, the possibility of a cortical artery origin should be considered. PMID- 22500201 TI - A case of pituitary metastasis from breast cancer that presented as left visual disturbance. AB - Tumors that metastasize to the pituitary gland are unusual, and are typically seen in elderly patients with diffuse malignant disease. The most common metastases to the pituitary are from primary breast and lung cancers. We report a 65-year-old woman with pituitary metastasis from breast cancer who presented with recent-onset left progressive deterioration of visual acuity and visual field. The clinical diagnosis was made after brain and sellar magnetic resonance imaging showed a large sellar mass compressing the optic chiasm and invading the pituitary stalk. An otorhinolaryngology and neurosurgery team removed the tumor via a transsphenoidal approach, and this procedure obtained symptomatic relief. Postoperatively, metastasis from breast invasive ductal adenocarcinoma was confirmed histologically. We report this unusual case with a review of the relevant literature. PMID- 22500202 TI - Glioblastoma following radiosurgery for meningioma. AB - We report a patient who underwent gamma knife radiosurgery to treat recurrent meningioma after microsurgery and thereafter developed secondary malignancy adjacent to the original tumor. A 47-year-old woman had underwent resection of the olfactory groove meningioma. Then radiosurgery was done three times over 4 year period for the recurrent tumor. After 58 months from the initial radiosurgery, she presented with headache and progressive mental dullness. Huge tumor in bifrontal location was revealed in MRI. Subsequent operation and pathological examination confirmed diagnosis of glioblastoma. This case fits the criteria of radiation-induced tumor and the clinical implication of the issue is discussed. PMID- 22500203 TI - Paradoxical transtentorial herniation caused by lumbar puncture after decompressive craniectomy. AB - Although decompressive craniectomy is an effective treatment for various situations of increased intracranial pressure, it may be accompanied by several complications. Paradoxical herniation is known as a rare complication of lumbar puncture in patients with decompressive craniectomy. A 38-year-old man underwent decompressive craniectomy for severe brain swelling. He remained neurologically stable for five weeks, but then showed mental deterioration right after a lumbar puncture which was performed to rule out meningitis. A brain computed tomographic scan revealed a marked midline shift. The patient responded to the Trendelenburg position and intravenous fluids, and he achieved full neurologic recovery after successive cranioplasty. The authors discuss the possible mechanism of this rare case with a review of the literature. PMID- 22500204 TI - Giant cauda equina schwannoma with dystrophic calcifications : case report and review of the literature. AB - Giant spinal schwannoma of the cauda equine involving many nerve roots is rare, and ossification is usually not observed in the schwannoma. A 21-year-old man presented with a 12-month history of urinary dysfunction and numbness below the buttocks. Plain radiography showed scalloping of the posterior surface of the vertebral bodies from L4 to the sacrum, and magnetic resonance imaging and computed tomography revealed a giant cauda equina tumor with dystrophic calcification. The tumor was completely removed, with intraoperative neurophysiologic monitoring. Histopathologic examination showed that the tumor was a schwannoma. The patient's postoperative course was uneventful, with urinary function and numbness gradually improving. Although a giant schwannoma accompanied by dystrophic calcification is extremely rare, such a tumor can be removed safely and completely by meticulous dissection and careful neuromonitoring of the cauda equina spinal nerves involved in the tumor. PMID- 22500205 TI - Leptomeningeal Dissemination of a Low-Grade Brainstem Glioma without Local Recurrence. AB - It is rare for low-grade gliomas to disseminate to the leptomeninges. However, low-grade gliomas with dissemination to the leptomeninges have been occasionally reported in children, and have generally been associated with local recurrence. A 16-year-old boy sought evaluation for diplopia and gait disturbance. A brain magnetic resonance imaging (MRI) revealed pontine mass, which was proved to be fibrillary astrocytoma on biopsy, later. Radiation therapy (5400 cGy) was given and the patient's symptoms were improved. He was followed-up radiologically for brain lesion. Seven months after diagnosis he complained of back pain and gait disturbance. A brain MRI showed a newly-developed lesion at the left cerebellopontine angle without an interval change in the primary lesion. A spinal MRI demonstrated leptomeningeal dissemination of the entire spine. Radiation therapy (3750 cGy) to the spine, and adjuvant chemotherapy with a carboplatin plus vincristine regimen were administered. However, he had a progressive course with tumoral hemorrhage and expired 13 months after diagnosis. We report an unusual case of a low-grade brainstem glioma with spinal dissemination, but without local recurrence, and a progressive course associated with hemorrhage. PMID- 22500206 TI - Aneurysmal bone cyst of the orbit : a case report with literature review. AB - Aneurysmal bone cyst (ABC) is benign vascular lesion destructing the cortical bone by the expansion of the vascular channel in the diploic space that usually involve long bone and spine. Orbital ABC is rare and the clinical symptoms deteriorate rapidly after initial slow-progression period for a few months. A 12 year-old female patient visited ophthalmologist due to proptosis and upward gaze limitation of the right eye, and orbital mass was noted in the upper part of right eye on orbital MRI. Five months later, exophthalmos was worsened rapidly with other features of ophthalmoplegia. Orbital mass was enlarged on MRI with intracranial extension. Surgery was done through frontal craniotomy and intracranial portion of the tumor was removed. Destructed orbital roof and mass in the orbit was also removed, and surrounding bone which was suspected to have lesion was resected as much as possible. Histopathological diagnosis was aneurysmal bone cyst. Postoperative course was satisfactory and the patient's eye symptoms improved. Authors report a rare case of orbital ABC with review of the literature. Exact diagnosis by imaging studies is important and it is recommended to perform surgical resection before rapid-progressing period and to resect the mass completely to prevent recurrence. PMID- 22500207 TI - Reperfusion injury after autologous cranioplasty in a patient with sinking skin flap syndrome. AB - The sinking skin flap syndrome is a rare complication after a large craniectomy. It consists of a sunken skin above the bone defect with neurological symptoms such as severe headache, mental changes, focal deficits, or seizures. In patient with sinking skin flap syndrome, cerebral blood flow and cerebral metabolism are decreased by sinking skin flap syndrome, and it may cause the deterioration of autoregulation of brain. We report a case of a patient with sinking skin flap syndrome who suffered from reperfusion injury after cranioplasty with review of pertinent literature. PMID- 22500208 TI - Preliminary report of three-dimensional reconstructive intraoperative C-arm in percutaneous vertebroplasty. AB - OBJECTIVE: Percutaneous vertebroplasty (PVP) is usually carried out under three dimensional (2D) fluoroscopic guidance. However, operative complications or bone cement distribution might be difficult to assess on the basis of only 2D radiographic projection images. We evaluated the feasibility of performing an intraoperative and postoperative examination in patients undergoing PVP by using three-dimensional (3D) reconstructive C-arm. METHODS: Standard PVP procedures were performed on 14 consecutive patients by using a Siremobil Iso-C(3D) and a multidetector computed tomography machine. Post-processing of acquired volumetric datasets included multiplanar reconstruction (MPR) and surface shaded display (SSD). We analyzed intraoperative and immediate postoperative evaluation of the needle trajectory and bone cement distribution. RESULTS: THE MALE : female ratio was 2 : 12; mean age of patients, 70 (range, 77-54) years; and mean T score, 3.4. The mean operation time was 52.14 min, but the time required to perform and post-process the rotational acquisitions was 7.76 min. The detection of bone cement distribution and leakage after PVP by using MPR and SSD was possible in all patients. However, detection of the safe trajectory for needle insertion was not possible. CONCLUSION: 3D rotational image acquisition can enable intra- or post-procedural assessment of vertebroplasty procedures for the detection of bone cement distribution and leakage. However, it is difficult to assess the safe trajectory for needle insertion. PMID- 22500209 TI - Winding up superfluid in a torus via Bose Einstein condensation. AB - Phase transitions are usually treated as equilibrium phenomena, which yields telltale universality classes with scaling behavior of relaxation time and healing length. However, in second-order phase transitions relaxation time diverges near the critical point ("critical slowing down"). Therefore, every such transition traversed at a finite rate is a non-equilibrium process. Kibble-Zurek mechanism (KZM) captures this basic physics, predicting sizes of domains - fragments of broken symmetry - and the density of topological defects, long-lived relics of symmetry breaking that can survive long after the transition. To test KZM we simulate Bose-Einstein condensation in a ring using stochastic Gross Pitaevskii equation and show that BEC formation can spontaneously generate quantized circulation of the newborn condensate. The magnitude of the resulting winding numbers and the time-lag of BEC density growth - both experimentally measurable - follow scalings predicted by KZM. Our results may also facilitate measuring the dynamical critical exponent for the BEC transition. PMID- 22500210 TI - Delivery of subunit influenza vaccine to skin with microneedles improves immunogenicity and long-lived protection. AB - Influenza infection represents a major socio-economic burden worldwide. Novel delivery methods can render influenza vaccination easier and more acceptable by the public, and importantly confer protection equal or superior to that induced by conventional systemic administration. An attractive target for vaccine delivery is the skin. Recent studies have demonstrated improved immune responses after transdermal delivery of inactivated influenza virus with microneedle patches. Here we show that immunization with a licensed influenza subunit vaccine coated on metal microneedles can activate both humoral and cellular arms of the immune response and confer improved long-term protection in the mouse model when compared to the conventional systemic route of delivery. These results demonstrate the promising potential of microneedle delivery of licensed influenza subunit vaccines, that could be beneficial in increasing vaccine coverage and protection and reducing influenza-related mortality worldwide. PMID- 22500211 TI - Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. AB - The anti-cancer effects of metformin, the most widely used drug for type 2 diabetes, alone or in combination with ionizing radiation were studied with MCF-7 human breast cancer cells and FSaII mouse fibrosarcoma cells. Clinically achievable concentrations of metformin caused significant clonogenic death in cancer cells. Importantly, metformin was preferentially cytotoxic to cancer stem cells relative to non-cancer stem cells. Metformin increased the radiosensitivity of cancer cells in vitro, and significantly enhanced the radiation-induced growth delay of FSaII tumors (s.c.) in the legs of C3H mice. Both metformin and ionizing radiation activated AMPK leading to inactivation of mTOR and suppression of its downstream effectors such as S6K1 and 4EBP1, a crucial signaling pathway for proliferation and survival of cancer cells, in vitro as well as in the in vivo tumors. CONCLUSION: Metformin kills and radiosensitizes cancer cells and eradicates radioresistant cancer stem cells by activating AMPK and suppressing mTOR. PMID- 22500212 TI - Elucidation of the Rotavirus NSP4-Caveolin-1 and -Cholesterol Interactions Using Synthetic Peptides. AB - Rotavirus (RV) NSP4, the first described viral enterotoxin, is a multifunctional glycoprotein that contributes to viral pathogenesis, morphogenesis, and replication. NSP4 binds both termini of caveolin-1 and is isolated from caveolae fractions that are rich in anionic phospholipids and cholesterol. These interactions indicate that cholesterol/caveolin-1 plays a role in NSP4 transport to the cell surface, which is essential to its enterotoxic activity. Synthetic peptides were utilized to identify target(s) of intervention by exploring the NSP4-caveolin-1 and -cholesterol interactions. NSP4(112-140) that overlaps the caveolin-1 binding domain and a cholesterol recognition amino acid consensus (CRAC) motif and both termini of caveolin-1 (N-caveolin-1(2-20), (19-40) and C caveolin-1(161-180)) were synthesized. Direct fluorescence-binding assays were employed to determine binding affinities of the NSP4-caveolin-1 peptides and cholesterol. Intracellular cholesterol alteration revealed a redistribution of NSP4 and disintegration of viroplasms. These data further imply interruption of NSP4(112-140)-N-caveolin-1(19-40) and cholesterol interactions may block NSP4 intracellular transport, hence enterotoxicity. PMID- 22500215 TI - Role of HO/CO in the Control of Peripheral Circulation in Humans. AB - Experimental studies show that the heme oxygenase/carbon monoxide system (HO/CO) plays an important role in the homeostasis of circulation and in the pathophysiology of hypertension. No data are available on its role in the control of peripheral circulation in humans. We evaluated the effects of inhibition of HO with stannous mesoporphyrin IX (SnMP) (200 MUM) locally administered by iontophoresis, on human skin blood flow, evaluated by laser-Doppler flowmetry, in the presence and absence of nitric oxide synthase (NOS) inhibition with L-NG Nitroarginine methyl ester (L-NAME) (100 MUM). We also evaluated the effect of HO inhibition on vasodilatation induced by acetylcholine (ACh) and vasoconstriction caused by noradrenaline (NA). SnMP and L-NAME caused a similar 20-25% decrease in skin flow. After nitric oxide (NO) inhibition with L-NAME, HO inhibition with SnMP caused a further 20% decrease in skin perfusion. SnMP decreased vasodilatation induced by ACh by about 70%, while it did not affect vasoconstriction to NA. In conclusion, HO/CO participates in the control of peripheral circulation, independently from NO, and is involved in vasodilatation to ACh. PMID- 22500216 TI - Influence of Angiotensin II Subtype 2 Receptor (AT(2)R) Antagonist, PD123319, on Cardiovascular Remodelling of Aged Spontaneously Hypertensive Rats during Chronic Angiotensin II Subtype 1 Receptor (AT(1)R) Blockade. AB - Cardiac AT(2)R expression is upregulated in the normal process of aging. In this study we determined the contribution of AT(2)R to chronic antihypertensive and remodelling effects of AT(1)R blockade in aged hypertensive rats. Adult (20 weeks) and senescent (20 months) spontaneously hypertensive rats (SHRs) were treated with either the AT(1)R antagonist, candesartan cilexetil (2 mg/kg/day), the AT(2)R antagonist, PD123319 (10 mg/kg/day), or a combination of the 2 compounds. Mean arterial pressure (MAP) and left ventricular volume were markedly decreased by candesartan cilexetil, however, simultaneous treatment with PD123319 had no additional effect on either parameter. Perivascular fibrosis was significantly reduced by candesartan cilexetil in aged animals only, and this effect was reversed by concomitant PD123319 administration. Vascular hypertrophy was reduced by candesartan cilexetil, and these effects were reversed by simultaneous PD123319. These results suggest that AT(2)R stimulation does not significantly influence the antihypertensive effect of chronic AT(1)R blockade, but plays a role in the regulation of vascular structure. The severe degree of cardiac perivascular fibrosis in senescent animals was regressed by AT(1)R blockade and this effect was reversed by simultaneous AT(2)R inhibition, demonstrating an antifibrotic role of AT(2)R stimulation in the aging hypertensive heart. PMID- 22500214 TI - Real-Time Analysis of Specific Protein-DNA Interactions with Surface Plasmon Resonance. AB - Several proteins, like transcription factors, bind to certain DNA sequences, thereby regulating biochemical pathways that determine the fate of the corresponding cell. Due to these key positions, it is indispensable to analyze protein-DNA interactions and to identify their mode of action. Surface plasmon resonance is a label-free method that facilitates the elucidation of real-time kinetics of biomolecular interactions. In this article, we focus on this biosensor-based method and provide a detailed guide how SPR can be utilized to study binding of proteins to oligonucleotides. After a description of the physical phenomenon and the instrumental realization including fiber-optic-based SPR and SPR imaging, we will continue with a survey of immobilization methods. Subsequently, we will focus on the optimization of the experiment, expose pitfalls, and introduce how data should be analyzed and published. Finally, we summarize several interesting publications of the last decades dealing with protein-DNA and RNA interaction analysis by SPR. PMID- 22500213 TI - Glutathione homeostasis and functions: potential targets for medical interventions. AB - Glutathione (GSH) is a tripeptide, which has many biological roles including protection against reactive oxygen and nitrogen species. The primary goal of this paper is to characterize the principal mechanisms of the protective role of GSH against reactive species and electrophiles. The ancillary goals are to provide up to-date knowledge of GSH biosynthesis, hydrolysis, and utilization; intracellular compartmentalization and interorgan transfer; elimination of endogenously produced toxicants; involvement in metal homeostasis; glutathione-related enzymes and their regulation; glutathionylation of sulfhydryls. Individual sections are devoted to the relationships between GSH homeostasis and pathologies as well as to developed research tools and pharmacological approaches to manipulating GSH levels. Special attention is paid to compounds mainly of a natural origin (phytochemicals) which affect GSH-related processes. The paper provides starting points for development of novel tools and provides a hypothesis for investigation of the physiology and biochemistry of glutathione with a focus on human and animal health. PMID- 22500217 TI - Cardiovascular disease risk factor patterns and their implications for intervention strategies in Vietnam. AB - Background. Data on cardiovascular disease risk factors (CVDRFs) in Vietnam are limited. This study explores the prevalence of each CVDRF and how they cluster to evaluate CVDRF burdens and potential prevention strategies. Methods. A cross sectional survey in 2009 (2,130 adults) was done to collect data on behavioural CVDRF, anthropometry and blood pressure, lipidaemia profiles, and oral glucose tolerance tests. Four metabolic CVDRFs (hypertension, dyslipidaemia, diabetes, and obesity) and five behavioural CVDRFs (smoking, excessive alcohol intake, unhealthy diet, physical inactivity, and stress) were analysed to identify their prevalence, cluster patterns, and social predictors. Framingham scores were applied to estimate the global 10-year CVD risks and potential benefits of CVD prevention strategies. Results. The age-standardised prevalence of having at least 2/4 metabolic, 2/5 behavioural, or 4/9 major CVDRF was 28%, 27%, 13% in women and 32%, 62%, 34% in men. Within-individual clustering of metabolic factors was more common among older women and in urban areas. High overall CVD risk (>=20% over 10 years) identified 20% of men and 5% of women-especially at higher ages-who had coexisting CVDRF. Conclusion. Multiple CVDRFs were common in Vietnamese adults with different clustering patterns across sex/age groups. Tackling any single risk factor would not be efficient. PMID- 22500218 TI - Nevirapine-Based Antiretroviral Therapy Impacts Artesunate and Dihydroartemisinin Disposition in HIV-Infected Nigerian Adults. AB - Background. Nevirapine- (NVP-) based antiretroviral therapy (ART) and artesunate amodiaquine are frequently coprescribed in areas of HIV and malaria endemicity. We explored the impact of this practice on artesunate and dihydroartemisinin pharmacokinetics. Methods. We conducted a parallel-group pharmacokinetic comparison between HIV-infected patients receiving NVP-based ART (n = 10) and ART naive controls (n = 11). Artesunate-amodiaquine 200/600 mg was given daily for three days. Measurement of drug concentrations occurred between 0 and 96 hours after the final dose. Pharmacokinetic parameters were determined using noncompartmental analysis. Results. Comparing the NVP group to controls, clearance of artesunate was reduced 50% (1950 versus 2995 L/h; P = 0.03), resulting in a 45% increase in the AUC(0-96) (105 versus 69 ug(*)hr/L; P = 0.02). The half-life of dihydroartemisinin was shorter in the NVP group (1.6 versuss 3.2 h; P = 0.004), but other dihydroartemisinin pharmacokinetic parameters were unchanged. A lower conversion of artesunate to dihydroartemisinin was observed in the NVP group (dihydroartemisinin: artesunate AUC(0-96) = 5.6 versuss 8.5 in NVP and control groups, respectively, P = 0.008). Conclusion. Although NVP-containing ART impacted some pharmacokinetic parameters of artesunate and dihydroartemisinin, overall exposure was similar or better in the NVP group. PMID- 22500219 TI - Altered neurochemical ingredient of hippocampus in patients with bipolar depression. AB - Background. In a number of investigations, hippocampal neurochemicals were evaluated in the patients with bipolar disorder who were on their first episode or euthymic periods. However, we did not meet any investigation in which only patients with bipolar depression were examined. As a consequence, the objective of the present study was to examine both sides of hippocampus of patients with bipolar disorder in depressive episode and healthy controls using (1)H-MRS. Methods. Thirteen patients with DSM-IV bipolar I disorder, most recent episode depressed, were recruited from the Department of Psychiatry at Firat University School of Medicine. We also studied 13 healthy comparison subjects who were without any DSM-IV Axis I disorders recruited from the hospital staff. The patients and controls underwent proton magnetic resonance spectroscopy ((1)H-MRS) of their hippocampus. NAA, CHO, and CRE values were measured. Results. No significant effect of diagnosis was observed for NAA/CRE ratio. For the NAA/CHO ratio, the ANCOVA with age, gender, and whole brain volume as covariates revealed that the patients with bipolar depression had significantly lower ratio compared to healthy control subjects for right and for left side. As for the CHO/CRE ratio, the difference was statistically significant for right side, with an effect diagnosis of F = 4.763, P = 0.038, and was very nearly significant for left side, with an effect diagnosis of F = 3.732, P = 0.064. Conclusions. We found that the patients with bipolar depression had lower NAA/CHO and higher CHO/CRE ratios compared to those of healthy control subjects. The findings of the present study also suggest that there may be a degenerative process concerning the hippocampus morphology in the patients with bipolar depression. PMID- 22500220 TI - Extramammary Paget's Disease: 20 Years of Experience in Chinese Population. AB - Background. To examine the results of treatment of Extramammary Paget's disease (EMPD) in ethnic Chinese. Method. Between 1990 and 2010, patients treated for EMPD were reviewed. Data were analyzed retrospectively. Results. Forty-eight patients were treated by surgical resection. Local recurrence rate was 14.6%. The postresection defects were repaired by primary closure (8.3%), partial thickness skin graft (72.9%), or local/regional flaps (18.8%). Dermal invasion was found in 9 patients (18.8%). Seven patients (14.6%) developed regional lymph node metastasis (concurrent with surgery, n = 1; subsequent to surgery, n = 6), and 3 patients (6.3%) had systemic metastasis after surgery. The presence of dermal invasion was associated with significantly higher incidence of regional lymph nodes and systemic metastasis. The incidence of associated internal malignancy was 8.3%. Conclusion. The mainstay of treatment for EMPD is surgery. Pathological dermal invasion increases the chance of regional lymph node as well as systemic metastasis. The association with internal malignancy warrants preoperative endoscopic examination in all patients. PMID- 22500221 TI - A simple and safe anastomosis for pancreatogastrostomy using one binding purse string and two transfixing mattress sutures. AB - Pancreatic anastomotic leakage remains a persistent problem after pancreaticoduodenectomy (PD), especially in the presence of a soft, nonfibrotic pancreas. A modified technique for pancreatogastrostomy was devised, which combines one binding purse-string and two transfixing mattress sutures between the pancreatic stump and the posterior gastric wall. This technique was applied in 35 patients after PD for malignant and benign diseases of whom 10 (28.6%) had a soft pancreas. Median time for the anastomosis was 18 minutes. Operative mortality was zero, and morbidity was 34.3%. Three (8.6%) patients developed a pancreatic fistula (2 type A, 1 type B) as classified according to the International Study Group on pancreatic fistula. All fistulas resolved without further intervention. The described technique is a simple and safe reconstruction procedure after PD that warrants further evaluation. PMID- 22500222 TI - Proteomic and bioinformatics analyses of mouse liver microsomes. AB - Microsomes are derived mostly from endoplasmic reticulum and are an ideal target to investigate compound metabolism, membrane-bound enzyme functions, lipid protein interactions, and drug-drug interactions. To better understand the molecular mechanisms of the liver and its diseases, mouse liver microsomes were isolated and enriched with differential centrifugation and sucrose gradient centrifugation, and microsome membrane proteins were further extracted from isolated microsomal fractions by the carbonate method. The enriched microsome proteins were arrayed with two-dimensional gel electrophoresis (2DE) and carbonate-extracted microsome membrane proteins with one-dimensional gel electrophoresis (1DE). A total of 183 2DE-arrayed proteins and 99 1DE-separated proteins were identified with tandem mass spectrometry. A total of 259 nonredundant microsomal proteins were obtained and represent the proteomic profile of mouse liver microsomes, including 62 definite microsome membrane proteins. The comprehensive bioinformatics analyses revealed the functional categories of those microsome proteins and provided clues into biological functions of the liver. The systematic analyses of the proteomic profile of mouse liver microsomes not only reveal essential, valuable information about the biological function of the liver, but they also provide important reference data to analyze liver disease-related microsome proteins for biomarker discovery and mechanism clarification of liver disease. PMID- 22500223 TI - White matter changes: new perspectives on imaging, clinical aspects, and intervention. PMID- 22500224 TI - Alternative Exercise Technologies to Fight against Sarcopenia at Old Age: A Series of Studies and Review. AB - The most effective physiologic mean to prevent sarcopenia and related muscle malfunction is a physically active lifestyle, or even better, physical exercise. However, due to time constraints, lack of motivation, or physical limitations, a large number of elderly subjects are either unwilling or unable to perform conventional workouts. In this context, two new exercise technologies, whole-body vibration (WBV) and whole-body electromyostimulation (WB-EMS), may exhibit a save, autonomous, and efficient alternative to increase or maintain muscle mass and function. Regarding WB-EMS, the few recent studies indeed demonstrated highly relevant effects of this technology on muscle mass, strength, and power parameters at least in the elderly, with equal or even higher effects compared with conventional resistance exercise. On the contrary, although the majority of studies with elderly subjects confirmed the positive effect of WBV on strength and power parameters, a corresponding relevant effect on muscle mass was not reported. However, well-designed studies with adequate statistical power should focus more intensely on this issue. PMID- 22500226 TI - Novel intriguing strategies attenuating to sarcopenia. AB - Sarcopenia, the age-related loss of skeletal muscle mass, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, increased risk of fall-related injury, and, often, frailty. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for drug discovery. Resistance training combined with amino acid containing supplements is often utilized to prevent age-related muscle wasting and weakness. In this review, we summarize more recent therapeutic strategies (myostatin or proteasome inhibition, supplementation with eicosapentaenoic acid (EPA) or ursolic acid, etc.) for counteracting sarcopenia. Myostatin inhibitor is the most advanced research with a Phase I/II trial in muscular dystrophy but does not try the possibility for attenuating sarcopenia. EPA and ursolic acid seem to be effective as therapeutic agents, because they attenuate the degenerative symptoms of muscular dystrophy and cachexic muscle. The activation of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) in skeletal muscle by exercise and/or unknown supplementation would be an intriguing approach to attenuating sarcopenia. In contrast, muscle loss with age may not be influenced positively by treatment with a proteasome inhibitor or antioxidant. PMID- 22500225 TI - Aging-shifted prostaglandin profile in endothelium as a factor in cardiovascular disorders. AB - Age-associated endothelium dysfunction is a major risk factor for the development of cardiovascular diseases. Endothelium-synthesized prostaglandins and thromboxane are local hormones, which mediate vasodilation and vasoconstriction and critically maintain vascular homeostasis. Accumulating evidence indicates that the age-related changes in endothelial eicosanoids contribute to decline in endothelium function and are associated with pathological dysfunction. In this review we summarize currently available information on aging-shifted prostaglandin profiles in endothelium and how these shifts are associated with cardiovascular disorders, providing one molecular mechanism of age-associated endothelium dysfunction and cardiovascular diseases. PMID- 22500227 TI - Rumination and age: some things get better. AB - Rumination has been defined as a mode of responding to distress that involves passively focusing one's attention on symptoms of distress without taking action. This dysfunctional response style intensifies depressed mood, impairs interpersonal problem solving, and leads to more pessimistic future perspectives and less social support. As most of these results were obtained from younger people, it remains unclear how age affects ruminative thinking. Three hundred members of the general public ranging in age from 15 to 87 years were asked about their ruminative styles using the Response Styles Questionnaire (RSQ), depression and satisfaction with life. A Mokken Scale analysis confirmed the two-factor structure of the RSQ with brooding and reflective pondering as subcomponents of rumination. Older participants (63 years and older) reported less ruminative thinking than other age groups. Life satisfaction was associated with brooding and highest for the earlier and latest life stages investigated in this study. PMID- 22500229 TI - Effects of high-speed power training on muscle performance and braking speed in older adults. AB - We examined whether high-speed power training (HSPT) improved muscle performance and braking speed using a driving simulator. 72 older adults (22 m, 50 f; age = 70.6 +/- 7.3 yrs) were randomized to HSPT at 40% one-repetition maximum (1RM) (HSPT: n = 25; 3 sets of 12-14 repetitions), slow-speed strength training at 80%1RM (SSST: n = 25; 3 sets of 8-10 repetitions), or control (CON: n = 22; stretching) 3 times/week for 12 weeks. Leg press and knee extension peak power, peak power velocity, peak power force/torque, and braking speed were obtained at baseline and 12 weeks. HSPT increased peak power and peak power velocity across a range of external resistances (40-90% 1RM; P < 0.05) and improved braking speed (P < 0.05). Work was similar between groups, but perceived exertion was lower in HSPT (P < 0.05). Thus, the less strenuous HSPT exerted a broader training effect and improved braking speed compared to SSST. PMID- 22500231 TI - Intramuscular adipose tissue, sarcopenia, and mobility function in older individuals. AB - Objective. Intramuscular adipose tissue (IMAT) and sarcopenia may adversely impact mobility function and physical activity. This study determined the association of locomotor muscle structure and function with mobility function in older adults. Method. 109 older adults with a variety of comorbid disease conditions were examined for thigh muscle composition via MRI, knee extensor strength via isometric dynamometry, and mobility function. The contribution of strength, quadriceps lean tissue, and IMAT to explaining the variability in mobility function was examined using multivariate linear regression models. Results. The predictors as a group contributed 27-45% of the variance in all outcome measures; however, IMAT contributed between 8-15% of the variance in all four mobility variables, while lean explained only 5% variance in only one mobility measure. Conclusions. Thigh IMAT, a newly identified muscle impairment appears to be a potent muscle variable related to the ability of older adults to move about in their community. PMID- 22500230 TI - Apathy as marker of frail status. AB - Frailty is a complex and dynamic condition associated with aging. This condition is characterised by the difficult adaptation of an old subject to new challenges occurring during life. Frailty is supposed to be due to the progressive decrease of physiological reserves and multiorgan and multisystem change. It coincides with a reduced or absent resilience. In general comorbidities like hypertension, heart disease, inflammation and infectious diseases are potential risk factors for and psychophysical decline. The aim of this work is to highlight the importance of impaired cognition as factor predisposing to frailty. The authors are convinced and suggest that the presence of neurobehavioral disturbance like apathy associated to impaired executive function could be the major predisposing factor for frailty and unsuccessful aging. Unfortunately available literature largely underestimates the presence of these factors. Thus to better identify markers of frailty, a good neuropsychological assessment and the evaluation of behavioural disturbances are suggested. PMID- 22500232 TI - Caveolin 3, flotillin 1 and influenza virus hemagglutinin reside in distinct domains on the sarcolemma of skeletal myofibers. AB - We examined the distribution of selected raft proteins on the sarcolemma of skeletal myofibers and the role of cholesterol environment in the distribution. Immunofluorescence staining showed that flotillin-1 and influenza hemagglutinin exhibited rafts that located in the domains deficient of the dystrophin glycoprotein complex, but the distribution patterns of the two proteins were different. Cholesterol depletion from the sarcolemma by means of methyl-beta cyclodextrin resulted in distorted caveolar morphology and redistribution of the caveolin 3 protein. Concomitantly, the water permeability of the sarcolemma increased significantly. However, cholesterol depletion did not reshuffle flotillin 1 or hemagglutinin. Furthermore, a hemagglutinin variant that lacked a raft-targeting signals exhibited a similar distribution pattern as the native raft protein. These findings indicate that each raft protein exhibits a strictly defined distribution in the sarcolemma. Only the distribution of caveolin 3 that binds cholesterol was exclusively dependent on cholesterol environment. PMID- 22500228 TI - Insulin in central nervous system: more than just a peripheral hormone. AB - Insulin signaling in central nervous system (CNS) has emerged as a novel field of research since decreased brain insulin levels and/or signaling were associated to impaired learning, memory, and age-related neurodegenerative diseases. Thus, besides its well-known role in longevity, insulin may constitute a promising therapy against diabetes- and age-related neurodegenerative disorders. More interestingly, insulin has been also faced as the potential missing link between diabetes and aging in CNS, with Alzheimer's disease (AD) considered as the "brain type diabetes." In fact, brain insulin has been shown to regulate both peripheral and central glucose metabolism, neurotransmission, learning, and memory and to be neuroprotective. And a future challenge will be to unravel the complex interactions between aging and diabetes, which, we believe, will allow the development of efficient preventive and therapeutic strategies to overcome age related diseases and to prolong human "healthy" longevity. Herewith, we aim to integrate the metabolic, neuromodulatory, and neuroprotective roles of insulin in two age-related pathologies: diabetes and AD, both in terms of intracellular signaling and potential therapeutic approach. PMID- 22500233 TI - Differential expression of matrix metalloproteases in human fibroblasts with different origins. AB - Fibroblasts are widely distributed cells and are responsible for the deposition of extracellular matrix (ECM) components but also secrete ECM-degrading matrix metalloproteases. A finely balanced equilibrium between deposition and degradation of ECM is essential for structural integrity of tissues. In the past, fibroblasts have typically been understood as a uniform cell population with comparable functions regardless of their origin. Here, we determined growth curves of fibroblasts derived from heart, skin, and lung and clearly show the lowest proliferation rate for cardiac fibroblasts. Furthermore, we examined basal expression levels of collagen and different MMPs in these three types of fibroblasts and compared these concerning their site of origin. Interestingly, we found major differences in basal mRNA expression especially for MMP1 and MMP3. Moreover, we treated fibroblasts with TNF-alpha and observed different alterations under these proinflammatory conditions. In conclusion, fibroblasts show different properties in proliferation and MMP expression regarding their originated tissue. PMID- 22500234 TI - Management of Patients Presenting with Acute Subdural Hematoma due to Ruptured Intracranial Aneurysm. AB - Acute subdural hematoma is a rare presentation of ruptured aneurysms. The rarity of the disease makes it difficult to establish reliable clinical guidelines. Many patients present comatose and differential diagnosis is complicated due to aneurysm rupture results in or mimics traumatic brain injury. Fast decision making is required to treat this life-threatening condition. Determining initial diagnostic studies, as well as making treatment decisions, can be complicated by rapid deterioration of the patient, and the mixture of symptoms due to the subarachnoid hemorrhage or mass effect of the hematoma. This paper reviews initial clinical and radiological findings, diagnostic approaches, treatment modalities, and outcome of patients presenting with aneurysmal subarachnoid hemorrhage complicated by acute subdural hematoma. Clinical strategies used by several authors over the past 20 years are discussed and summarized in a proposed treatment flowchart. PMID- 22500235 TI - Permanent pacing in patients with recurrence of symptoms and relapse of left ventricular obstruction at midcavity level after alcohol septal ablation. AB - Treatment of symptom recurrence after initially successful alcohol septal ablation (ASA) in hypertrophic obstructive cardiomyopathy (HOCM) when accompanied by relapse of intracavitary left ventricular pressure gradient (LVG) is guided by the underlying mechanism. We describe our experience with permanent pacing in three patients with relapse of both LVG and symptoms 7 to 12 months after successful ASA. Even though pressure gradient recurrence was observed at midventricular level, we were able to achieve symptomatic improvement and LVG reduction after right ventricular apex pacing in all three cases. The effect on symptoms was long lasting-the 6-month followup echo-stress tests confirmed good exercise capacity and lack of provocable LVG. We found pacing to be a safe and effective treatment option in this clinical scenario. Based on our overall observations, we propose pacing as a niche treatment for patients with recurrence of LVG at midventricular level after ASA. PMID- 22500236 TI - The natural history and treatment options for unruptured intracranial aneurysms. AB - Recent advances in angiographic technique have raised our awareness of the presence of unruptured intracranial aneurysms (UIAs). However, the appropriate management for these lesions remains controversial. To optimize patient outcomes, the physician must weigh aneurysmal rupture risk associated with observation against the complication risks associated with intervention. In the case that treatment is chosen, the two available options are surgical clipping and endovascular coiling. Our paper summarizes the current body of literature in regards to the natural history of UIAs, the evolution of the lesion if it progresses uninterrupted, as well as the safety and efficacy of both treatment options. The risks and benefits of treatment and conservative management need to be evaluated on an individual basis and are greatly effected by both patient specific and aneurysm-specific factors, which are presented in this paper. Ultimately, this body of data has led to multiple sets of treatment guidelines, which we have summated and presented in this paper. PMID- 22500237 TI - Evaluation of the EndoPAT as a Tool to Assess Endothelial Function. AB - Endothelial dysfunction is a potential target for (pharmaceutical) intervention of several systemic pathological conditions. We investigated the feasibility of the EndoPAT to evaluate acute changes in endothelial function with repeated noninvasive measurements and assessed its discriminating power in different populations. Endothelial function was stable over a longer period of time in renally impaired patients (coefficient of variation 13%). Endothelial function in renally impaired and type 2 diabetic patients was not decreased compared to healthy volunteers (2.9 +/- 1.4 and 1.8 +/- 0.3, resp., versus 1.8 +/- 0.5, P > 0.05). The EndoPAT did not detect an effect of robust interventions on endothelial function in healthy volunteers (glucose load: change from baseline 0.08 +/- 0.50, 95% confidence interval -0.44 to 0.60; smoking: change from baseline 0.49 +/- 0.92, 95% confidence interval -0.47 to 1.46). This suggests that at present the EndoPAT might not be suitable to assess (changes in) endothelial function in early-phase clinical pharmacology studies. Endothelial function as measured by the EndoPAT could be physiologically different from endothelial function as measured by conventional techniques. This should be investigated carefully before the EndoPAT can be considered a useful tool in drug development or clinical practice. PMID- 22500238 TI - Carotid atherosclerosis, endothelial disfunction, and arterial stiffness in young and middle-aged men with coronary artery disease. AB - Background. To assess structural and functional status of the arteries in young and middle-aged men with recently developed CAD. Methods and Results. A total of 78 men aged 28 to 50 years underwent carotid ultrasound, endothelial function, and arterial stiffness measurements. Angiographically proven CAD was present in 49 patients. Carotid plaques were present in 45 (91.8%) patients with CAD and in 8 (27.6%) men without CAD (P < 0.001). Patients with CAD more often had multiple plaques (86.7% versus 13.8%, P < 0.001). The prevalence of carotid intima-media thickness (IMT) >=0.9 mm and of abnormal brachial artery flow-mediated dilatation (FMD) was not differing in both groups. The mean aortic pulse wave velocity (PWV) was 6.8 +/- 1.3 m/s for patients with CAD and 5.8 +/- 0.9 m/s for subjects without CAD (P < 0.001). Aortic PWV above the 75th percentile of the "normal" samples was found in 26 (53.1%) patients with CAD and in 7 (24.1%) subjects without CAD (P = 0.02). Aortic PWV was related to the severity of CAD. Conclusions. Carotid plaques and increased aortic PWV may be more powerful predictors of the occurrence of CAD in young and middle-aged men, than the presence of increased carotid IMT and abnormal brachial artery FMD. PMID- 22500239 TI - A Literature Review on Care at the End-of-Life in the Emergency Department. AB - The hospitalisation and management of patients at the end-of-life by emergency medical services is presenting a challenge to our society as the majority of people approaching death explicitly state that they want to die at home and the transition from acute care to palliation is difficult. In addition, the escalating costs of providing care at the end-of-life in acute hospitals are unsustainable. Hospitals in general and emergency departments in particular cannot always provide the best care for patients approaching end-of-life. The main objectives of this paper are to review the existing literature in order to assess the evidence for managing patients dying in the emergency department, and to identify areas of improvement such as supporting different models of care and evaluating those models with health services research. The paper identified six main areas where there is lack of research and/or suboptimal policy implementation. These include uncertainty of treatment in the emergency department; quality of life issues, costs, ethical and social issues, interaction between ED and other health services, and strategies for out of hospital care. The paper concludes with some areas for policy development and future research. PMID- 22500240 TI - PKCalpha and ERbeta Are Associated with Triple-Negative Breast Cancers in African American and Caucasian Patients. AB - Although the incidence of breast cancer in the United States is higher in Caucasian women compared with African American women, African-American patients have more aggressive disease as characterized by a higher percentage of triple negative breast cancers (TNBCs), high-grade tumors, and a higher mortality rate. PKCalpha is a biomarker associated with endocrine resistance and poor prognosis and ERbeta is emerging as a protective biomarker. Immunohistochemical analysis of ERbeta and PKCalpha expression was performed on 198 formalin-fixed paraffin embedded primary infiltrating ductal carcinomas from 105 African-American and 93 Caucasian patients. PKCalpha is positively correlated with TNBC in patients of both races and with high tumor grade in African-American patients. Patients with TNBC express less nuclear ERbeta compared with all other subtypes. We find no difference in frequency or intensity of PKCalpha or ERbeta expression between African-American and Caucasian patients. PKCalpha and ERbeta are discussed as potential therapeutic targets for the treatment of patients with TNBC. PMID- 22500241 TI - Oxidative stress and inflammation: essential partners in alcoholic liver disease. AB - Alcoholic liver disease (ALD) is a multifaceted disease that is characterized by hepatic steatosis or fat deposition and hepatitis or inflammation. Over the past decade, multiple lines of evidence have emerged on the mechanisms associated with ALD. The key mechanisms identified so far are sensitization to gut-derived endotoxin/lipopolysaccharide resulting in proinflammatory cytokine production and cellular stress due to oxidative processes, contributing to the development and progression of disease. While oxidative stress and inflammatory responses are studied independently in ALD, mechanisms linking these two processes play a major role in pathogenesis of disease. Here we review major players of oxidative stress and inflammation and highlight signaling intermediates regulated by oxidative stress that provokes proinflammatory responses in alcoholic liver disease. PMID- 22500242 TI - Intrasellar chondroid chordoma: a case report. AB - Chordomas are tumors derived from cells that are remnants of the notochord, particularly from its proximal and distal extremes, they are mainly midline and represent approximately 1% of all malignant bone tumors and 0.1 to 0.2% of intracranial neoplasms. Chordomas involving the sellar region are rare. Herein, we describe a 57-year-old male patient presenting with a history of retro-orbital headache, progressive loss of vision, and clinical features of hypopituitarism, for over 2 months. During evaluation, the CT scan revealed a large contrast enhancing intrasellar tumor with a 3.6-cm largest diameter. The patient underwent transsphenoidal partial resection of the tumor, and histological examination was consistent with the diagnosis of chondroid chordoma. Although chordomas are rare, they may be considered to constitute a differential diagnostic of pituitary adenomas, especially if a calcified intrasellar tumor with bone erosion is diagnosed. PMID- 22500243 TI - Antioxidant Activity of beta-Glucan. AB - beta-Glucans extracted from barley, which mainly contains beta-(1,3-1,4)-D glucan, are used extensively as supplements and food additives due to their wide biologic activities, including a reduction in blood lipid level. In this study, the antioxidant activity of beta-glucan was examined to assess potential new benefits associated with beta-glucan, because oxidative stress is considered one of the primary causal factors for various diseases and aging. beta-Glucan extracted from barley was found to possess significant antioxidant activity. The amount of antioxidant activity was influenced by different physiologic properties (e.g., structure and molecular size) of beta-glucan, which varied depending on the source and extraction method used. The antioxidant activity of beta-glucan was significantly higher than that of various polymers that are used as food additives. These results indicate that beta-glucan has promise as a polymeric excipient for supplement and food additive with antioxidant and other benefits, which may contribute to enhancing health and beauty. PMID- 22500244 TI - Development and stability studies of novel liposomal vancomycin formulations. AB - A promising strategy to improve the therapeutic efficiency of antimicrobial agents is targeted therapy. Although vancomycin has been considered a gold standard for the therapy of MRSA pneumonia, clinical failure rates have also been reported owing to its slow, time-dependent bactericidal activity, variable lung tissue penetration and poor intracellular penetration into macrophages. Liposomal encapsulation has been established as an alternative for antimicrobial delivery to infected tissue macrophages and offers enhanced pharmacodynamics, pharmacokinetics and decreased toxicity compared to standard preparations. The aim of the present work is to prepare vancomycin in two different liposomal formulations, conventional and PEGylated liposomes using different methods. The prepared formulations were optimized for their particle size, encapsulation efficiency and physical stability. The dehydration-rehydration was found to be the best preparation method. Both the conventional and PEGylated liposomal formulations were successfully formulated with a narrow particle size and size distribution and % encapsulation efficiency of 9 +/- 2 and 12 +/- 3, respectively. Both the formulations were stable at 4 degrees C for 3 months. These formulations were successfully used to evaluate for their intracellular killing of MRSA and in vivo pharmacokinetic and bio-distribution studies. PMID- 22500245 TI - Effects of anosognosia on perceived stress and cortisol levels in Alzheimer's disease. AB - Anosognosia, or unawareness of one's own cognitive deficits, may cause issues when measuring perceived stress and cortisol levels in Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). The goal of this study was to examine the effects of anosognosia on perceived stress and salivary cortisol levels in normal elderly (NE) adults, MCI individuals, newly diagnosed AD patients, and long lasting AD patients, suspected to show more anosognosia. An anosognosia index for perceived stress was computed by subtracting the score on the Perceived Stress Scale measured in the participants and their relative. Cortisol levels were measured four times a day over two nonconsecutive days. Greater anosognosia for dementia correlated with greater anosognosia for perceived stress in the group as a whole. However, no correlation between cortisol levels and either anosognosia for dementia or perceived stress was observed. Our results suggest that measuring perceived stress in AD patients may be influenced by anosognosia. PMID- 22500246 TI - Genome Signature Difference between Deinococcus radiodurans and Thermus thermophilus. AB - The extremely radioresistant bacteria of the genus Deinococcus and the extremely thermophilic bacteria of the genus Thermus belong to a common taxonomic group. Considering the distinct living environments of Deinococcus and Thermus, different genes would have been acquired through horizontal gene transfer after their divergence from a common ancestor. Their guanine-cytosine (GC) contents are similar; however, we hypothesized that their genomic signatures would be different. Our findings indicated that the genomes of Deinococcus radiodurans and Thermus thermophilus have different tetranucleotide frequencies. This analysis showed that the genome signature of D. radiodurans is most similar to that of Pseudomonas aeruginosa, whereas the genome signature of T. thermophilus is most similar to that of Thermanaerovibrio acidaminovorans. This difference in genome signatures may be related to the different evolutionary backgrounds of the 2 genera after their divergence from a common ancestor. PMID- 22500247 TI - A New Turnaround on the Urologist's Stance over the Inflammatory Signals. PMID- 22500249 TI - Effects of Tamsulosin on Urinary Bladder Function and Neuronal Activity in the Voiding Centers of Rats with Cyclophosphamide-induced Overactive Bladder. AB - PURPOSE: The overactive bladder (OAB) syndrome is characterized by urgency usually with frequency and nocturia. Tamsulosin, alpha(1)-adrenergic receptor antagonist, is widely used to reduce symptoms of urinary obstruction and prostatic hyperplasia. Tamsulosin can across the blood-brain barrier. We investigated the effects of tamsulosin on the symptoms of OAB in relation to neuronal activity using rats. METHODS: Adult female Sprague-Dawley rats, weighing 250+/-10 g (9 weeks old), were used in this study. The animals were divided into five groups (n=8 in each group): control group, OAB-induced group, OAB-induced and 0.01 mg/kg tamsulosin-treated group, OAB-induced and 0.1 mg/kg tamsulosin treated group, and OAB-induced and 1 mg/kg tamsulosin-treated group. OAB was induced by intraperitoneal injection of cyclophosphamide (75 mg/kg) every third day for 10 days. The rats in the tamsulosin-treated groups orally received tamsulosin once a day for 14 consecutive days at the respective dose of the groups, starting 1 day after the induction of OAB. Cystometry for bladder pressure determination, immunohistochemistry for c-Fos, nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry for nitric oxide synthase (NOS) in the neuronal voiding centers and western blot for inducible NOS in the bladder were conducted. RESULTS: Cyclophosphamide injection enhanced contraction pressure and time, representing the induction of OAB. Contraction pressure and time were significantly suppressed by tamsulosin treatment. c-Fos and NOS expressions in the neuronal voiding centers were enhanced by induction of OAB. OAB-induced c-Fos and NOS expressions were suppressed by tamsulosin treatment. CONCLUSIONS: Tamsulosin exerts inhibitory effect on neuronal activation in the neuronal voiding centers of OAB. The present results suggest the possibility that tamsulosin is effective therapeutic modality for ameliorating the symptoms of OAB. PMID- 22500250 TI - Socioeconomic costs of overactive bladder and stress urinary incontinence in Korea. AB - PURPOSE: We quantified and described the economic burden of overactive bladder and stress urinary incontinence in Korea. We calculated direct costs by identifying public and private data sources that contain population-based data on resource utilization by patients with stress urinary incontinence and overactive bladder. METHODS: For estimating indirect costs (productivity loss), the human capital approach was applied. Data were collected from several institutes, including the Health Insurance Review Agency. RESULTS: The estimated total economic cost in treating overactive bladder was 117 billion Korean Won (KRW, the currency of South Koea) in 2006 and 145 billion KRW in 2007. The estimated total cost in treating stress urinary incontinence was 122 billion KRW in 2006 and 59 billion KRW in 2007. CONCLUSIONS: By quantifying the total economic costs of overactive bladder and stress urinary incontinence, this study provides an important perspective in Korea. Because the average age of the Korean population is rapidly increasing, this study provides important information on the direct and indirect costs of overactive bladder and stress urinary incontinence for an aging society. PMID- 22500248 TI - The Role of NLR-related Protein 3 Inflammasome in Host Defense and Inflammatory Diseases. AB - Among a number of innate receptors, the nucleotide-binding domain leucine-rich repeat containing (NLR) nucleotide oligomerization domain (NOD)-like receptor families are involved in the recognition of cytosolic pathogen- or danger associated molecules. Activation of these specific sets of receptors leads to the assembly of a multiprotein complex, the inflammasome, leading to the activation of caspase-1 and maturation of the cytokines interleukin (IL)-1beta, IL-18, and IL-33. Among NLRs, NLR-related protein 3 (NLRP3) is one of the best-characterized receptors that activates the inflammasome. There is no doubt that NLRP3 inflammasome activation is important for host defense and effective pathogen clearance against fungal, bacterial, and viral infection. In addition, mounting evidence indicates that the NLRP3 inflammasome plays a role in a variety of inflammatory diseases, including gout, atherosclerosis, and type II diabetes, as well as under conditions of cellular stress or injury. Here, we review recent advances in our understanding of the role of the NLRP3 inflammasome in host defense and various inflammatory diseases. PMID- 22500251 TI - Predictors of Voiding Dysfunction after Mid-urethral Sling Surgery for Stress Urinary Incontinence. AB - PURPOSE: Postoperative voiding dysfunction is a bothersome complication after mid urethral sling surgery. The current study presents multiple repeated postoperative voiding trials against a urine load of preoperative functional bladder capacity, as estimated by a preoperative frequency volume chart, to identify the relevance of preoperative and immediate factors to the outcome. METHODS: A total of 180 patients were enrolled from August 2008 to August 2011. Patients received mid-urethral sling surgery with a transobturator tape, with or without concomitant cystocele repair. Patients reported relevant medical histories and a 3-day frequency volume chart and underwent urodynamic studies. After surgery, patients were filled to their maximum bladder capacity as dictated by their frequency volume chart and performed the first voiding trial. Two subsequent voiding trials were performed after natural filling. Failure of any single voiding trial was considered failure. Patients who failed the final voiding trial received intermittent catheterization to follow-up. After screening for relevant factors with the use of univariate analyses, preoperative, surgical, and postoperative factors predicting outcome were estimated by logistic regression analysis. RESULTS: The urine load at the voiding trial and the peak flow rate immediately preceding the voiding trial predicted voiding trial success in the multivariate analysis. Urine load and previous trial peak flow rate were relevant when tested against each individual voiding trial. Preoperative and surgical factors, such as age, parity, and concomitant cystocele repair, showed significance in the univariate analysis. Overall, 16.1% of patients who passed the first voiding trial failed on subsequent trials, whereas 36.8% of patients who failed the first voiding trial succeeded. CONCLUSIONS: Postoperative voiding dysfunction is transient and is associated with the immediate voiding conditions following surgery. Close observation against urine overload in the bladder is important when weaning patients back to normal voiding conditions. PMID- 22500252 TI - The Relations between Enuresis in Childhood and Nocturnal Polyuria Syndrome in Adult Life. AB - PURPOSE: The aim of this study, to investigate whether there is any association between enuresis in childhood and nocturnal polyuria syndrome (NPS) in adult life. METHODS: The study consisted of thirty five patients with nocturnal polyuria, and thirty five healthy people without nocturnal polyuria in adult life, were asked to assess their enuresis in childhood. RESULTS: There was a history of enuresis in childhood in 18 (51.42%) of 35 of men with nocturnal polyuria and in 4 (11.42%) of 35 without nocturnal polyuria. Enuresis in childhood was significantly more common in men with nocturnal polyuria than without nocturnal polyuria. The difference was significant (P<0.0001). The prevalence of enuresis in the nocturnal polyuria (51.42%) was more than two-fold higher than reported prevalence in general populations. CONCLUSIONS: The results of this study suggest that the history of enuresis in childhood seems to increase the risk of having NPS in adult life. This relationship should be taken into account in the evaluation of men with complaints from NPS in adult life and the possible common pathophysiology should be considered in the treatment planning. PMID- 22500253 TI - Effects of combination treatment of intravesical resiniferatoxin instillation and hydrodistention in patients with refractory painful bladder syndrome/interstitial cystitis: a pilot study. AB - PURPOSE: Painful bladder syndrome/interstitial cystitis (PBS/IC) is a disabling disease of the urinary bladder, and its etiology and treatment are not yet established. Current medications used in the treatment of PBS/IC have shown limited efficacy. This prospective study investigated the efficacy of intravesical resiniferatoxin (RTX) in PBS/IC refractory to medical treatment. METHODS: Patients with proven PBS/IC refractory to traditional medical treatment were enrolled. By randomized trial, a total of 18 consecutive patients were divided into two groups: treatment with hydrodistention and intravesical RTX (group 1) or treatment with hydrodistension only (group 2). We assessed bladder pain by use of a visual analogue pain scale, the maximal urine flow rate, post void residual urine volume, and a voiding diary before and 3 months after treatment. RESULTS: The median age of the 18 patients was 55.8+/-6.9 years, and the median duration of symptoms before diagnosis was 3.6+/-1.6 years. Frequency, functional bladder capacity, and score on a 5-point pain scale were significantly improved at 3-month after treatment in both groups. Intravesical RTX instillation plus hydrodistention, compared with hydrodistention only, did not have a significant effect on the voiding symptoms or uroflowmetry of the patients but significantly improved scores on the pain scale. CONCLUSIONS: Intravesical RTX instillation plus hydrodistention was effective in relieving pain but was not effective in improving lower urinary tract symptoms. Further larger studies are needed to clarify the efficacy of combination treatment of intravesical RTX instillation and hydrodistention. PMID- 22500254 TI - Long-term Outcomes of Tension-free Vaginal Tape Procedure for Treatment of Female Stress Urinary Incontinence with Intrinsic Sphincter Deficiency. AB - PURPOSE: To assess the long-term outcomes of tension-free vaginal tape (TVT) for stress urinary incontinence (SUI) with intrinsic sphincter deficiency (ISD) and to identify influencing factors for failure in these cases. METHODS: A total of 136 women who underwent TVT procedures with minimum follow-up duration of 3 years were included in the study. Patients were divided into two groups (non-ISD and ISD groups) based on preoperative urodynamic studies. Patient outcomes were assessed from retrospective chart review and telephone research. Cure was defined as the subjective resolution of SUI in any circumstances. Improvement was defined as the subjective improvement of SUI without complete resolution. Failure was defined as the subjective lack of improvement of SUI. Patients in ISD group were subdivided into two subgroups (cure and non-cure groups) and were compared to identify influencing factors for TVT procedure failure. RESULTS: Eighty-nine patients were in non-ISD group, and 47 in ISD group. The mean follow-up durations were 50.3+/-9.2 and 49.7+/-9.7 months, respectively. Subjective cure rate was 75.3% for non-ISD group, and 76.7% for ISD group (P>0.05). Improvement rate was 6.7% for non-ISD group, and 2.1% for ISD group (P>0.05). Satisfaction scores was 3.8+/-1.2 points in the non-ISD group, and 3.5+/-1.2 points in ISD group (P>0.05). In ISD subgroups, VLPP was 41.9+/-12.0 cmH(2)O for non-cure group, and 50.5+/-8.6 cmH(2)O for cure group, and was the only factor that showed significant statistical difference between the two subgroups (P=0.011). CONCLUSIONS: With our long-term results, TVT is an effective treatment even in women with ISD. However, ISD patients with low VLPP should be counseled carefully about TVT outcome. PMID- 22500256 TI - The future of sentinel node oriented tailored approach in patients with early gastric cancer. PMID- 22500255 TI - Persistent genital swelling after hydrocele ligation in a patient receiving continuous ambulatory peritoneal dialysis. AB - We report a case of genital swelling in a patient receiving continuous ambulatory peritoneal dialysis. A physical examination did not identify any defect. Ultrasonography revealed a large hydrocele, and surgical repair brought resolution of the genital swelling. Two months later, however, the genital swelling had recurred and was not improved until peritoneal dialysis was replaced by hemodialysis 3 months later. PMID- 22500257 TI - Update of adjuvant chemotherapy for resected gastric cancer. AB - Gastric cancer is the second cause of cancer that is related to death and the fourth most common cancer, worldwide. Complete resection of cancer is the only curative treatment for gastric cancer. However, even if complete resection is possible, recurrence is frequently observed in Gastric patients. Therefore, adjuvant treatment modality for resectable gastric cancer is needed to increase the survival of patients. This study wants to describe the role of adjuvant chemotherapy for resectable gastric cancer, with updated data of recent studies. Several meta-analysis studies demonstrated a benefit of adjuvant chemotherapy for resectable gastric cancer. Due to the heterogeneity of the population and regimens, there is no consensus regarding the adjuvant chemotherapy. Recently published, well designed phase III studies demonstrated the statistically significance of adjuvant chemotherapy for the resectable gastric cancer, with the extended lymph node dissection. Further phase III trials, to determine the best regimen and schedule of adjuvant chemotherapy, was suggested to use the fluoropyrimidine based regimen as control group. PMID- 22500258 TI - What is the problem in clinical application of sentinel node concept to gastric cancer surgery? AB - More than ten years have passed since the sentinel node (SN) concept for gastric cancer surgery was first discussed. Less invasive modified surgical approaches based on the SN concept have already been put into practice for malignant melanoma and breast cancer, however the SN concept is not yet placed in a standard position in gastric cancer surgery even after two multi-institutional prospective clinical trials, the Japan Clinical Oncology Group trial (JCOG0302) and the Japanese Society for Sentinel Node Navigation Surgery (SNNS) trial. What is the problem in the clinical application of the SN concept to gastric cancer surgery? There is no doubt that we need reliable indicator(s) to determine with certainty the absence of metastasis in the lymph nodes in order to avoid unnecessary lymphadenectomy. There are several matters of debate in performing the actual procedure, such as the type of tracer, the site of injection, how to detect and harvest, how to detect metastases of SNs, and learning period. These issues have to be addressed further to establish the most suitable procedure. Novel technologies such as indocyanine green (ICG) fluorescence imaging and one step nucleic acid amplification (OSNA) may overcome the current difficulties. Once we know what the problems are and how to tackle them, we can pursue the goal. PMID- 22500259 TI - History of minimally invasive surgery for gastric cancer in Korea. AB - Laparoscopic gastrectomy was begun in 1995 in Korea. But, there was 4 years gap to reactivate in 1999. High incidence of gastric cancer and increasing proportion of early cancer through national screening program along with huge effort and enthusiasm of laparoscopic gastric surgeon, and active academic exchange with Japanese doctors contributed development of laparoscopic gastrectomy in Korea. Study group activity of Korean Laparoscopic Gastrointestinal Surgery Study (KLASS) group and Collaborative Action for Gastric Cancer (COACT) group were paramount to evoke large scale multicenter clinical study and various well performed clinical studies. This review encompasses mainly international publications about this area so far in Korea. PMID- 22500260 TI - Long-term outcomes and feasibility with laparoscopy-assisted gastrectomy for gastric cancer. AB - PURPOSE: Recently, laparoscopy-assisted gastrectomy (LAG) has been widely accepted modality for early gastric cancer in Korea. The indication of LAG may be extended in an experienced institution. In our institution, the first case of laparoscopy-assisted gastrectomy (LAG) for gastric cancer was performed in May 1998. We retrospectively reviewed the long-term oncologic outcomes over 12 years to clarify the feasibility of LAG for gastric cancer. MATERIALS AND METHODS: The authors retrospectively analyzed 753 patients who underwent LAG for gastric cancer, from May 1998 to August 2010. We reviewed clinicopathological features, postoperative outcomes, mortality and morbidity, recurrence, and survival of LAG for gastric cancer. RESULTS: During the time period, 3,039 operations for gastric cancer were performed. Among them, 753 cases were done by LAG (24.8%). There were 69 cases of total gastrectomy, 682 subtotal gastrectomies, and 2 proximal gastrectomies. According to TNM stage, 8 patients were in stage 0, 619 in stage I, 88 in stage II, and 38 in stage III. The operation-related complications occurred in 77 cases (10.2%). Median follow-up period was 56.2 months (range 0.7~165.6 months). Twenty-five patients (3.3%) developed recurrence, during the follow-up period. The overall 5-year and disease free survival rates were 97.1% and 96.3%, respectively. CONCLUSIONS: The number of postoperative complications and survival rates of our series were comparable to the results from that of other reports. The authors consider LAG to be a feasible alternative for the treatment of early gastric cancer. However, rationale for laparoscopic surgery in advanced gastric cancer has yet to be determined. PMID- 22500261 TI - Analysis of risk factors for postoperative morbidity in perforated peptic ulcer. AB - PURPOSE: Emergency operations for perforated peptic ulcer are associated with a high incidence of postoperative complications. While several studies have investigated the impact of perioperative risk factors and underlying diseases on the postoperative morbidity after abdominal surgery, only a few have analyzed their role in perforated peptic ulcer disease. The purpose of this study was to determine any possible associations between postoperative morbidity and comorbid disease or perioperative risk factors in perforated peptic ulcer. MATERIALS AND METHODS: In total, 142 consecutive patients, who underwent surgery for perforated peptic ulcer, at a single institution, between January 2005 and October 2010 were included in this study. The clinical data concerning the patient characteristics, operative methods, and complications were collected retrospectively. RESULTS: The postoperative morbidity rate associated with perforated peptic ulcer operations was 36.6% (52/142). Univariate analysis revealed that a long operating time, the open surgical method, age (>=60), sex (female), high American Society of Anesthesiologists (ASA) score and presence of preoperative shock were significant perioperative risk factors for postoperative morbidity. Significant comorbid risk factors included hypertension, diabetes mellitus and pulmonary disease. Multivariate analysis revealed a long operating time, the open surgical method, high ASA score and the presence of preoperative shock were all independent risk factors for the postoperative morbidity in perforated peptic ulcer. CONCLUSIONS: A high ASA score, preoperative shock, open surgery and long operating time of more than 150 minutes are high risk factors for morbidity. However, there is no association between postoperative morbidity and comorbid disease in patients with a perforated peptic ulcer. PMID- 22500262 TI - Outcomes of Abdominal Total Gastrectomy for Type II and III Gastroesophageal Junction Tumors: Single Center's Experience in Korea. AB - PURPOSE: The aim of this study was to evaluate the surgical outcomes of abdominal total gastrectomy, without mediastinal lymph node dissection for type II and III gastroesophageal junction (GEJ) cancers. MATERIALS AND METHODS: We retrospectively reviewed surgical outcomes in 67 consecutive patients with type II and III GEJ cancers that were treated by the surgical resection between 2004 and 2008. RESULTS: Thirty (45%) patients had type II and 37 (55%) had type III tumor. Among the 65 (97%) patients with curative surgery, 21 (31%) patients underwent the extended total gastrectomy with trans-hiatal distal esophageal resection, and in 44 (66%) patients, abdominal total gastrectomy alone was done. Palliative gastrectomy was performed in two patients due to the accompanying peritoneal metastasis. The postoperative morbidity and mortality rates were 21.4% and 1.5%, respectively. After a median follow up of 36 months, the overall 3 years was 68%, without any differences between the Siewert types or the operative approaches (transhiatal approach vs. abdominal approach alone). On the univariate analysis, the T stage, N stage and R0 resection were found to be associated with the survival, and multivariate analysis revealed that the N stage was a poor independent prognostic factor for survival. CONCLUSIONS: Type II and III GEJ cancers may successfully be treated with the abdominal total gastrectomy, without mediastinal lymph node dissection in the Korean population. PMID- 22500263 TI - Mesenteric pseudocyst of the small bowel in gastric cancer patient: a case report. AB - Mesenteric pseudocyst is rare. This term is used to describe the abdominal cystic mass, without the origin of abdominal organ. We presented a case of mesenteric pseudocyst of the small bowel in a 70-year-old man. Esophago-gastro-duodenoscopy showed a 3.5 cm sized excavated lesion on the posterior wall of angle. Endocopic biopsy confirmed a histologic diagnosis of the poorly differentiated adenocarcinoma, which includes the signet ring cell component. Abdominal computed tomography scan showed a focal mucosal enhancement in the posterior wall of angle of the stomach, a 2.4 cm sized enhancing mass on the distal small bowel loop, without distant metastases or ascites in rectal shelf, and multiple gallbladder stones. The patient underwent subtotal gastrectomy with gastroduodenostomy, segmental resection of the small bowel, and cholecystectomy. The final pathological diagnosis was mesenteric pseudocyst. This is the first case report describing incidentally detected mesenteric pseudocyst of the small bowel in gastric cancer patients. PMID- 22500264 TI - Diagnosis of a trocar site mass as omental herniation after laparoscopic gastrectomy. AB - A trocar site hernia is a rare complication. We report a patient who had an abdominal wall mass at a previous trocar site after laparoscopic distal gastrectomy. It was diagnosed as omental herniation and fat necrosis. We conclude that patients with trocar site masses exhibiting fat density on a computed tomography scan could be followed up without surgery, and that fascial defects located at 10-mm or larger trocar sites should be closed whenever possible to prevent hernia formation. PMID- 22500265 TI - Late onset iatrogenic diaphragmatic hernia after laparoscopy-assisted total gastrectomy for gastric cancer. AB - Through the advent of surgical techniques and the improvement of laparoscopic tools including the ultrasonic activated scissor, laparoscopic gastrectomy has been increasingly used in far more cases of benign or malignant gastric lesions for the benefit of patients without compromising therapeutic outcomes. Even though possible complications provoked by the ultrasonic activated scissor can be prevented during the procedure with increasing advanced laparoscopic experience and supervision, unexpected late complications after the operations rarely occur. An extremely rare case of left incarcerated diaphragmatic hernia of the transverse colon developed in an 81-year-old female patient as a late complication, 8 months after laparoscopy-assisted total gastrectomy for gastric cancer, with laparoscopy successfully resumed and without the need to sacrifice any portion of the bowel. PMID- 22500267 TI - Aging Successfully: a Research and Public Health Priority for the 21(st) Century. PMID- 22500268 TI - Successful aging as a continuum of functional independence: lessons from physical disability models of aging. AB - Successful aging is a multidimensional construct that could be viewed as a continuum of achievement. Based on the disability model proposed by the WHO International Classification of Functioning, Disability and Health, successful aging includes not only the presence or absence of disease, but also aspects of mobility and social participation. Here we review definitions of successful aging and discuss relevance of the disability model in the evaluation of successful aging and frailty. In particular, we summarize evidences that highlight the importance of measures of mobility (ability to walk and perform activities of daily living), and social participation in identifying and locating older adults across the range of the successful aging continuum. Lastly, we discuss the role of inflammation in age-related decline and in frailty. Future research directions are proposed, including identifying causal pathways among inflammatory markers, disability, and frailty. A better understanding of immunological functioning in late life may help unlock novel ways to promote successful aging. PMID- 22500269 TI - Maintaining brain health by monitoring inflammatory processes: a mechanism to promote successful aging. AB - Maintaining brain health promotes successful aging. The main determinants of brain health are the preservation of cognitive function and remaining free from structural and metabolic abnormalities, including loss of neuronal synapses, atrophy, small vessel disease and focal amyloid deposits visible by neuroimaging. Promising studies indicate that these determinants are to some extent modifiable, even among adults seventy years and older. Converging animal and human evidence further suggests that inflammation is a shared mechanism, contributing to both cognitive decline and abnormalities in brain structure and metabolism. Thus, inflammation may provide a target for intervention. Specifically, circulating inflammatory markers have been associated with declines in cognitive function and worsening of brain structural and metabolic characteristics. Additionally, it has been proposed that older brains are characterized by a sensitization to neuroinflammatory responses, even in the absence of overt disease. This increased propensity to central inflammation may contribute to poor brain health and premature brain aging. Still unknown is whether and how peripheral inflammatory factors directly contribute to decline of brain health. Human research is limited by the challenges of directly measuring neuroinflammation in vivo. This review assesses the role that inflammation may play in the brain changes that often accompany aging, focusing on relationships between peripheral inflammatory markers and brain health among well-functioning, community-dwelling adults seventy years and older. We propose that monitoring and maintaining lower levels of systemic and central inflammation among older adults could help preserve brain health and support successful aging. Hence, we also identify plausible ways and novel experimental study designs of maintaining brain health late in age through interventions that target the immune system. PMID- 22500270 TI - Integration of immunity with physical and cognitive function in definitions of successful aging. AB - Studies comparing chronologically "young" versus "old" humans document age related decline of classical immunological functions. However, older adults aged >=65 years have very heterogeneous health phenotypes. A significant number of them are functionally independent and are surviving well into their 8(th)-11(th) decade life, observations indicating that aging or old age is not synonymous with immune incompetence. While there are dramatic age-related changes in the immune system, not all of these changes may be considered detrimental. Here, we review evidences for novel immunologic processes that become elaborated with advancing age that complement preserved classical immune functions and promote immune homeostasis later in life. We propose that elaboration such of late life immunologic properties is indicative of beneficial immune remodeling that is an integral component of successful aging, an emerging physiologic construct associated with similar age-related physiologic adaptations underlying maintenance of physical and cognitive function. We suggest that a systems approach integrating immune, physical, and cognitive functions, rather than a strict immunodeficiency-minded approach, will be key towards innovations in clinical interventions to better promote protective immunity and functional independence among the elderly. PMID- 22500271 TI - Immune Responses to pneumococcal vaccines in children and adults: Rationale for age-specific vaccination. AB - Streptococcus pneumoniae is a significant human pathogen and currently available pneumococcal vaccines are designed to elicit anti-capsule antibodies. The 23 valent polysaccharide vaccine has been used in older adults for many years whereas 7-, 10-, and 13-valent pneumococcal conjugate vaccines have only been used commonly for young children in the last decade. In addition to their high protective efficacy among children, the use of conjugate vaccines in young children has had a number of additional effects, including production of a serotype shift and providing new herd immunity to adults. The immunogenicity of both of these types of vaccines can be determined by using an ELISA assay to measure antibody levels or an opsonophagocytosis assay to assess opsonic function. As these assays have improved over time, awareness of the analytical limitations of older studies has grown. While the 23-valent vaccine is effective among young adults, it is less effective among elderly adults. Aging-associated ineffectiveness may be due to aging-dependent changes in the antibody repertoire and/or a reduction in IgM antibody production associated with aging-dependent changes in B cell subpopulations. The immunologic basis of aging-associated immune defects thus remains an active area of research. PMID- 22500275 TI - The effect of distal aortic pressure on spinal cord perfusion in rats. AB - BACKGROUND: Aortic cross clamping is associated with spinal cord ischemia. This study used a rat spinal cord ischemia model to investigate the effect of distal aortic pressure on spinal cord perfusion. MATERIALS AND METHODS: Male Sprague Dawley rats (n=12) were divided into three groups. In group A (n=4), the aorta was not occluded. In groups B (n=4) and C (n=4), the aorta was occluded. In group B the distal aortic pressures dropped to around 20 mmHg. In group C, the distal aortic pressure was decreased to near zero. The carotid artery and tail artery were cannulated to monitor the proximal aortic pressure and the distal aortic pressure. Fluorescent microspheres were used to measure the regional blood flow in the spinal cord. RESULTS: After aortic occlusion, blood flow to the cervical spinal cord showed no significant difference among the three groups. In groups B and C, the thoracic and lumbar spinal cord and renal blood flow decreased. No microspheres were detected in the thoracic and lumbar spinal cord of group C. CONCLUSION: The spinal cord blood flow is dependent on the distal aortic pressure after thoracic aortic occlusion. PMID- 22500274 TI - Exercise, inflammation and aging. AB - Aging results in chronic low grade inflammation that is associated with increased risk for disease, poor physical functioning and mortality. Strategies that reduce age-related inflammation may improve the quality of life in older adults. Regular exercise is recommended for older people for a variety of reasons including increasing muscle mass and reducing risk for chronic diseases of the heart and metabolic systems. Only recently has exercise been examined in the context of inflammation. This review will highlight key randomized clinical trial evidence regarding the influence of exercise training on inflammatory biomarkers in the elderly. Potential mechanisms will be presented that might explain why exercise may exert an anti-inflammatory effect. PMID- 22500276 TI - Minimally invasive approaches versus conventional sternotomy for aortic valve replacement: a propensity score matching study. AB - BACKGROUND: The aim of this study is to evaluate our institutional results of the aortic valve replacement through minimally invasive approaches compared with conventional sternotomy. MATERIALS AND METHODS: From August 1997 to July 2010, 838 patients underwent primary isolated aortic valve replacement. Of them, 73 patients underwent surgery through minimally invasive approaches (MIAS group) whereas 765 patients underwent surgery through the conventional sternotomy (CONV group). Clinical outcomes were compared using a propensity score matching design. RESULTS: Propensity score matching yielded 73 pairs of patients in which there were no significant differences in baseline profiles between the two groups. Patients in the MIAS group had longer aortic cross clamp than those in the CONV group (74.9+/-27.9 vs.. 66.2+/-27.3, p=0.058). In the MIAS group, conversion to full sternotomy was needed in 2 patients (2.7%). There were no significant differences in the rates of low cardiac output syndrome (4 vs. 8, p=0.37), reoperation due to bleeding (7 vs. 6, p=0.77), wound infection (2 vs. 4, p=0.68), or requirements for dialysis (2 vs. 1, p=0.55) between the two groups. Postoperative pain was significantly less in the MIAS group than the conventional group (pain score, 3.79+/-1.67 vs. 4.32+/-1.56; p=0.04). CONCLUSION: Both minimally invasive approaches and conventional sternotomy had comparable early clinical outcomes in patients undergoing primary isolated aortic valve replacement. Minimally invasive approaches significantly decrease postoperative pain. PMID- 22500278 TI - Outcomes of venovenous extracorporeal membrane oxygenation support for acute respiratory distress syndrome in adults. AB - BACKGROUND: Despite improved managements for acute respiratory distress syndrome (ARDS), its mortality remains high. Extracorporeal membrane oxygenation (ECMO) has emerged as the final option for the treatment of ARDS unresponsive to conventional measures. This study describes our experiences of venovenous ECMO support for the treatment of ARDS. MATERIALS AND METHODS: Between 2007 and 2010, 56 patients (aged 56.6+/-13.4 years, 43 males) received venovenous ECMO for the treatment of ARDS. The detailed clinical records were retrospectively reviewed. RESULTS: Before the institution of ECMO support, 35 patients (55.4%) required nitric oxide inhalation, 35 patients (55.4%) received continuous renal replacement therapy, and 20 patients (35.7%) were in shock status. The median duration of ECMO support was 164 hours (range, 5 to 1,413 hours). 27 (48%) patients could be successfully weaned from ECMO. Of them, 7 (13%) survived to discharge. On logistic regression analysis, a requirement for higher inspiratory pressure before ECMO support was the only significant factor that could predict ECMO weaning failure. CONCLUSION: The outcome of venovenous ECMO support for the treatment of ARDS was suboptimal. Further improvements in outcomes should be made through the accumulation of experience and establishment of a standardized protocol for the management of ECMO. PMID- 22500272 TI - Immunosenescence and Challenges of Vaccination against Influenza in the Aging Population. AB - Influenza is an important contributor to morbidity and mortality worldwide. Accumulation of genetic mutations termed antigenic drift, allows influenza viruses to inflict yearly epidemics that may result in 250,000 to 500,000 deaths annually. Over 90% of influenza-related deaths occur in the older adult population. This is at least in part a result of increasing dysregulation of the immune system with age, termed immunosenescence. This dysregulation results in reduced capacity to cope with infections and decreased responsiveness to vaccination. The older adult population is in dire need of improved vaccines capable of eliciting protective responses in the face of a waning immune system. This review focuses on the status of immunity, responses to influenza vaccination, and strategies that are currently being explored to elicit enhanced immune responses in this high risk population. PMID- 22500277 TI - Comparison of the Outcomes between Axillary and Femoral Artery Cannulation for Acute Type A Aortic Dissection. AB - BACKGROUND: At present, many surgeons prefer axillary artery cannulation because it facilitates antegrade cerebral perfusion and may diminish the risk of cerebral embolization. However, axillary artery cannulation has not been established as a routine procedure because there is controversy about its clinical advantage. MATERIALS AND METHODS: We examined 111 patients diagnosed with acute type A aortic dissection between January 2000 and December 2009. The right axillary artery was cannulated in 58 patients (group A) and the femoral artery was cannulated in 53 (group F). The postoperative outcomes were retrospectively reviewed and compared between the two groups. RESULTS: There were 46 male and 65 female patients with a mean age of 58.9+/-13.1 years (range, 26 to 84 years). The extent of aortic replacement in both groups did not differ. There were 8 early deaths (7.2%) and 2 late deaths (1.8%). The mean follow-up duration was 46.0+/ 32.6 months (range, 1 month to 10 years). Transient neurologic dysfunction was observed in 11 patients (19.0%) in group A and 14 patients (26.4%) in group F. A total of 11 patients (9.9%) suffered from a permanent neurologic dysfunction. Early and delayed stroke were observed in 6 patients (10.3%) and 2 patients (3.4%), respectively, in group A as well as 2 patients (3.8%) and 1 patient (1.9%), respectively, in group F. There were no statistical differences in the cannulation-related complications between both groups (3 in group A vs. 0 in group F). CONCLUSION: There were no differences in postoperative neurologic outcomes and cannulation-related complications according to the cannulation sites. The cannulation site in an aortic dissection should be carefully chosen on a case-by-case basis. It is important to also pay attention to the possibility of intraoperative malperfusion syndrome occurring and the subsequent need to change the cannulation site. PMID- 22500273 TI - The role of nutrition in enhancing immunity in aging. AB - Aging is associated with declined immune function, particularly T cell-mediated activity, which contributes to increased morbidity and mortality from infectious disease and cancer in the elderly. Studies have shown that nutritional intervention may be a promising approach to reversing impaired immune function and diminished resistance to infection with aging. However, controversy exists concerning every nutritional regimen tested to date. In this article, we will review the progress of research in this field with a focus on nutrition factor information that is relatively abundant in the literature. While vitamin E deficiency is rare, intake above recommended levels can enhance T cell function in aged animals and humans. This effect is believed to contribute toward increased resistance to influenza infection in animals and reduced incidence of upper respiratory infection in the elderly. Zinc deficiency, common in the elderly, is linked to impaired immune function and increased risk for acquiring infection, which can be rectified by zinc supplementation. However, higher than recommended upper limits of zinc may adversely affect immune function. Probiotics are increasingly being recognized as an effective, immune-modulating nutritional factor. However, to be effective, they require an adequate supplementation period; additionally, their effects are strain-specific and among certain strains, a synergistic effect is observed. Increased intake of fish or n-3 PUFA may be beneficial to inflammatory and autoimmune disorders as well as to several age-related diseases. Conversely, the immunosuppressive effect of fish oils on T cell-mediated function has raised concerns regarding their impact on resistance to infection. Caloric restriction (CR) is shown to delay immunosenescence in animals, but this effect needs to be verified in humans. Timing for CR initiation may be important to determine whether CR is effective or even beneficial at all. Recent studies have suggested that CR, which is effective at improving the immune response of unchallenged animals, might compromise the host's defense against pathogenic infection and result in higher morbidity and mortality. The studies published thus far describe a critical role for nutrition in maintaining the immune response of the aged, but they also indicate the need for a more in-depth, wholestic approach to determining the optimal nutritional strategies that would maintain a healthy immune system in the elderly and promote their resistance to infection and other immune-related diseases. PMID- 22500279 TI - Routine Shunting is Safe and Reliable for Cerebral Perfusion during Carotid Endarterectomy in Symptomatic Carotid Stenosis. AB - BACKGROUND: The purpose of this report is to describe the perioperative outcomes of standard carotid endarterectomy (CEA) with general anesthesia, routine shunting, and tissue patching in symptomatic carotid stenoses. MATERIALS AND METHODS: Between October 2007 and July 2011, 22 patients with symptomatic carotid stenosis (male/female, 19/3; mean age, 67.2+/-9.4 years) underwent a combined total of 23 CEAs using a standardized technique. The strict surgical protocol included general anesthesia and standard carotid bifurcation endarterectomy with routine shunting. The 8-French Pruitt-Inahara shunt was used in all the patients. RESULTS: During the ischemic time, the shunts were inserted within 2.5 minutes, and 5 patients (22.7%) revealed ischemic cerebral signals (flat wave) in electroencephalographic monitoring but recovered soon after insertion of the shunt. The mean shunting time for CEA was 59.1+/-10.3 minutes. There was no perioperative mortality or even minor stroke. All patients woke up in the operating room or the operative care room before being moved to the ward. One patient had difficulty swallowing due to hypoglossal nerve palsy, but had completely recovered by 1 month postsurgery. CONCLUSION: Routine shunting is suggested to be a safe and reliable method of brain perfusion and protection during CEA in symptomatic carotid stenoses. PMID- 22500280 TI - Poor Prognostic Factors in Surgically Resected Stage I Non-small Cell Lung Cancer: Histopathologic and Immunohistochemical Analysis. AB - BACKGROUND: A better understanding of the histopathology and molecular biology of lung cancer might improve our capability to predict the outcome for any individual patient. The purpose of this study was to evaluate several histopathologic and molecular markers in order to assess their prognostic value in stage I non-small cell lung cancer. MATERIALS AND METHODS: One hundred ten patients at the Kyungpook National University Hospital were enrolled in the study. Histopathologic factors and molecular markers were selected. RESULTS: Univariate analysis showed that the T stage, differentiation, visceral pleural invasion, and survivin expression were significantly associated with recurrence. Multivariate analysis demonstrated that differentiation and survivin overexpression emerged as independent prognostic factors of recurrence. CONCLUSION: In resected stage I non-small cell lung cancer, poor differentiation and survivin overexpression have been identified as independent predictors of poor disease-free survival. PMID- 22500281 TI - Early and Long-term Outcomes of Pneumonectomy for Treating Sequelae of Pulmonary Tuberculosis. AB - BACKGROUND: Pneumonectomy remains the ultimate curative treatment modality for destroyed lung caused by tuberculosis despite multiple risks involved in the procedure. We retrospectively evaluated patients who underwent pneumonectomy for treatment of sequelae of pulmonary tuberculosis to determine the risk factors of early and long-term outcomes. MATERIALS AND METHODS: Between January 1980 and December 2008, pneumonectomy or pleuropneumonectomy was performed in 73 consecutive patients with destroyed lung caused by tuberculosis. There were 48 patients with empyema (12 with bronchopleural fistula [BPF]), 11 with aspergilloma and 7 with multidrug resistant tuberculosis. RESULTS: There were 5 operative mortalities (6.8%). One patient had intraoperative uncontrolled arrhythmia, one had a postoperative cardiac arrest, and three had postoperative respiratory failure. A total of 29 patients (39.7%) suffered from postoperative complications. Twelve patients (16.7%) were found to have postpneumonectomy empyema (PPE), 4 patients had wound infections (5.6%), and 7 patients required re exploration due to postoperative bleeding (9.7%). The prevalence of PPE increased in patients with preoperative empyema (p=0.019). There were five patients with postoperative BPF, four of which occurred in right-side operation. The only risk factor for BPF was the right-side operation (p=0.023). The 5- and 10-year survival rates were 88.9% and 76.2%, respectively. The risk factors for late deaths were old age (>=50 years, p=0.02) and low predicted postoperative forced expiratory volume in one second (FEV1) (<1.2 L, p=0.02). CONCLUSION: Although PPE increases in patients with preoperative empyema and postoperative BPF increases in right-side operation, the mortality rates and long-term survival rates were found to be satisfactory. However, the follow-up care for patients with low predicted postoperative FEV1 should continue for prevention and early detection of pulmonary complication related to impaired pulmonary function. PMID- 22500282 TI - Bridge to transplantation with a left ventricular assist device. AB - A 61-year-old female patient was diagnosed with dilated cardiomyopathy with severe left ventricle dysfunction. Two days after admission, continuous renal replacement therapy was performed due to oliguria and lactic acidosis. On the fifth day, an intra-aortic balloon pump was inserted due to low cardiac output syndrome. Beginning 4 days after admission, she was supported for 15 days thereafter with an extracorporeal left ventricular assist device (LVAD) because of heart failure with multi-organ failure. A heart transplant was performed while the patient was stabilized with the LVAD. She developed several complications after the surgery, such as cytomegalovirus pneumonia, pulmonary tuberculosis, wound dehiscence, and H1N1 infection. On postoperative day 19, she was discharged from the hospital with close follow-up and treatment for infection. She received follow-up care for 10 months without any immune rejection reaction. PMID- 22500283 TI - Cardiac angiosarcoma on the right atrium: two cases. AB - We detected two cases of right atrial angiosarcoma that had a similar appearance on imaging studies. Although the surgical findings were similar for the two patients, one had a clear resection margin, while the other had tumor cells in the resection margin on frozen biopsy. We suggest that preoperative data on magnetic resonance imaging and computed tomography in patients with angiosarcomas may not predict the exact extent of surgical resection or prognostic outcomes. PMID- 22500284 TI - Axillofemoral Bypass to Treat Severe Heart Failure Caused by Takayasu's Arteritis. AB - Takayasu's arteritis is an inflammatory vasculitis that primarily affects the aorta and its major branches. Involvement of the thoracic and abdominal aortas, although rare, causes marked hypertension and may lead to severe heart failure. We report the improvement of cardiac function after axillofemoral bypass grafting in a 59-year-old woman who had this condition. PMID- 22500285 TI - Titanium plate fixation for a dehisced sternum following coronary artery bypass grafting: a case report. AB - Sternal dehiscence is one of the most troublesome complications following cardiac surgery. Treatment failure and consequent lethal results are very common, even with all the efforts to resolve sternal dehiscence such as removal of infectious tissue, muscle flap interposition, and sternal rewiring. We report on a case of sternal osteomyelitis following coronary artery bypass grafting that was successfully treated with wide sternal resection, titanium plate fixation, and pectoralis muscle flap interposition. PMID- 22500286 TI - Ectopic pancreas with hemorrhagic cystic change in the anterior mediastinum. AB - A 31-year-old female was referred from other hospital due to migrating chest pain, mild cough, and blood-tinged sputum for three days before admission. Laboratory tests were unremarkable. Chest computed tomography revealed an elliptical necrotic mass at the left anterior mediastinum, measuring 7*3*4 cm. With the impression of mediastinal abscess or loculated empyema, thoracoscopic resection was performed. There was severe pleural adhesion around the mass. The mass could be resected by the wedge resection of the adhesed upper lobe tissue of left lung around the mass. Final pathologic diagnosis was ectopic pancreas. PMID- 22500287 TI - Fluid-filled Giant Bulla Treated with Percutaneous Drainage and Talc Sclerotherapy: A Modified Brompton Technique. AB - A 75-year-old man who was diagnosed as having a fluid-filled giant bulla was treated with a modified Brompton technique due to his poor performance status. Percutaneous drainage, suction, and talc sclerotherapy through a Foley catheter can be good treatment options for patients with conditions that are too poor to allow surgical intervention, especially if there is adhesion between a giant bulla and parietal pleura. Talc can also be used safely when mixed with normal saline as a sclerosant. PMID- 22500288 TI - Intercostal lung hernia after pectus bar removal. PMID- 22500289 TI - Determination of chlorothalonil in difficult-to-analyse vegetable matrices using various multiresidue methods. AB - The molecular characteristics of chlorothalonil can cause particular determination difficulties in some vegetable commodities such as leek or garlic. These difficulties are mainly related to the low recoveries obtained using common multi-residue methods (MRMs)--a consequence of the very high interaction level with natural components in the matrix. These shortcomings were pointed out in the last European Proficiency Test for Pesticide Residues on Fruits and Vegetables, where false negatives for chlorothalonil in leek were observed at around 50%. In this study we have evaluated the ethyl acetate, the Dutch mini-Luke and the QuEChERS MRMs to compare their capabilities for chlorothalonil determination using GC-MS/MS in both the electron impact ionization (EI) and negative chemical ionization (NCI) modes. Best recoveries (in the range of 100-120%, with an RSD below 20%) were obtained using the Dutch mini-Luke method. Lower values (52-70%) were obtained for ethyl acetate whereas no recovery was obtained when the QuEChERS method was applied. Furthermore, tomato matrix was also included in the experiments in order to facilitate the comparability of results. Two ionization modes, electron impact ionization (EI) and negative chemical ionization (NCI) in GC-MS/MS, were applied to evaluate their respective advantages and disadvantages for quantification and identification. As expected, NCI showed limits of detection (LODs) 5 to 10 times lower than EI. However, in both cases, the LODs were still below 10 MUg kg(-1). The proposed optimal method was applied for chlorothalonil determination in leek and garlic with good results--in accordance with the European Union (EU) Analytical Quality Control (AQC) Guidelines for pesticides analysis. PMID- 22500291 TI - Acaricidal activities of the active component of Lycopus lucidus oil and its derivatives against house dust and stored food mites (Arachnida: Acari). AB - BACKGROUND: Recent studies have focused on materials derived from plant extracts as mite control products against house dust and stored food mites because repeated use of synthetic acaricides had led to resistance and unwanted activities on non-target organisms. The aim of this study was to evaluate the acaricidal activity of materials derived from Lycopus lucidus against Dermatophagoides farinae, D. pteronyssinus and Tyrophagus putrescentiae. RESULTS: The LD50 values of L. lucidus oil were 2.19, 2.25 and 8.45 ug cm(-2) against D. farinae, D. pteronyssinus and T. putrescentiae. The acaricidal constituent of L. lucidus was isolated by chromatographic techniques and identified as 1-octen-3 ol. In a fumigant method against D. farinae, the acaricidal activity of 1-octen-3 ol (0.25 ug cm(-2)) was more toxic than N,N-diethyl-m-toluamide (DEET) (36.84 ug cm(-2)), followed by 3,7-dimethyl-1-octen-3-ol (0.29 ug cm(-2)), 1-octen-3-yl butyrate (2.32 ug cm(-2)), 1-octen-3-yl acetate (2.42 ug cm(-2)), 3,7-dimethyl-1 octene (9.34 ug cm(-2)) and benzyl benzoate (10.02 ug cm(-2)). In a filter paper bioassay against D. farinae, 1-octen-3-ol (0.63 ug cm(-2)) was more effective than DEET (20.64 ug cm(-2)), followed by 3,7-dimethyl-1-octen-3-ol (1.09 ug cm( 2)). CONCLUSION: 1-Octen-3-ol and 3,7-dimethyl-1-octen-3-ol could be useful as natural agents for the management of three mite species. PMID- 22500292 TI - Use of a potentiometric vital dye to determine the effect of the herbicide bromoxynil octanoate on mitochondrial bioenenergetics in Chlamydomonas reinhardtii. AB - BACKGROUND: The aims of the present study were to validate a vital mitochondrial potentiometric staining method in Chlamydomonas reinhardtii and to utilise this method to examine the effect of the herbicide bromoxynil octanoate on mitochondrial potential in this species. A range of stains was investigated, including Rhodamine 123, DASPMI, Mitotracker Green, Mitotracker Orange and JC-1. RESULTS: Rhodamine 123 (R123) had the highest utility of several candidate stains. Incubation with both 5 and 10 uM carbonyl cyanide 3-chlorophenylhydrazone caused significant fluorescence collapse [Dunn's post test (40.00, P < 0.01) and (45.49, P < 0.01) respectively], demonstrating that the R123 fluorescence reported mitochondrial potential. The effect of the herbicide bromoxynil octanoate was examined. Exposure to 0.1 mM of bromoxynil resulted in a significant increased mitochondrial fluorescence compared with the baseline (Mann Whitney U = 222, P < 0.002), while concentrations of 1 mM and greater resulted in significant, almost complete loss of mitochondrial potential [mean fluorescence ratio = 1.193-1.289 (where a ratio of 1 represents total potential loss), Mann Whitney U = 0.0, P < 0.001 (1 mM), 0.0, P < 0.0001 (2 mM), 0.0, P < 0.0001 (5 mM)]. EC50 of the collapse in mitochondrial potential owing to bromoxynil incubation occurred at 0.72 mM, and the mean t50 of bromoxynil octanoate action was 93 s. CONCLUSIONS: R123 is a sensitive potentiometric dye in C. reinhardtii that may find further use in investigations of both mitochondrial bioenergetics in plants and environmental toxicology. PMID- 22500293 TI - Validation of RNA interference in western corn rootworm Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae) adults. AB - BACKGROUND: RNA interference (RNAi) is commonly used in insect functional genomics studies and usually involves direct injection of double-stranded RNA (dsRNA). Only a few studies have involved exposure to dsRNAs through feeding. For western corn rootworm (Diabrotica virgifera virgifera) larvae, ingestion of dsRNA designed from the housekeeping gene, vacuolar ATPase (vATPase) triggers RNAi causing growth inhibition and mortality; however, the effect of dsRNA feeding on adults has not been examined. In this research, WCR adults were fed with vATPase dsRNA-treated artificial diet containing a cucurbitacin bait, which is a proven feeding stimulant for chrysomelid beetles of the subtribe Diabroticina to which rootworms belong. RESULTS: Real-time PCR confirmed suppression of vATPase expression and western blot analysis indicated reduced signal of a protein that cross-reacted with a vATPase polyclonal antiserum in WCR adults exposed to artificial diet treated with dsRNA and cucurbitacin bait. Continuous feeding on cucurbitacin and dsRNA-treated artificial diet resulted in more than 95% adult mortality within 2 weeks while mortality in control treatments never exceeded 20%. CONCLUSIONS: This research clearly demonstrates the effect of RNAi on WCR adults that have been exposed to dsRNA by feeding and establishes a tool to screen dsRNAs of potential target genes in adults. This technique may serve as an alternative to target screening of larvae which are difficult to maintain on artificial diets. PMID- 22500294 TI - Application of the constraint on instantaneous dose rate in the UK Approved Code of Practice 249 is inappropriate for radiology. PMID- 22500295 TI - Comment on 'severe deterministic effects of external exposure and intake of radioactive material: basis for emergency response criteria'. PMID- 22500296 TI - [Too high price of rotavirus vaccination!]. PMID- 22500298 TI - [Pitfalls. A new rubric in Der Pathologe]. PMID- 22500299 TI - [Declining infant mortality in China]. PMID- 22500300 TI - [Diagnosis of tuberculosis in low and middle income countries]. PMID- 22500301 TI - Comment on "An unusual presentation of bee sting: subarachnoid hemorrhagia". PMID- 22500302 TI - Prediction of dynamic behavior of mutant strains from limited wild-type data. AB - Metabolic engineering is the field of introducing genetic changes in organisms so as to modify their function towards synthesizing new products of high impact to society. However, engineered cells frequently have impaired growth rates thus seriously limiting the rate at which such products are made. The problem is attributable to inadequate understanding of how a metabolic network functions in a dynamic sense. Predictions of mutant strain behavior in the past have been based on steady state theories such as flux balance analysis (FBA), minimization of metabolic adjustment (MOMA), and regulatory on/off minimization (ROOM). Such predictions are restricted to product yields and cannot address productivity, which is of focal interest to applications. We demonstrate that our framework ( [Song and Ramkrishna, 2010] and [Song and Ramkrishna, 2011]), based on a "cybernetic" view of metabolic systems, makes predictions of the dynamic behavior of mutant strains of Escherichia coli from a limited amount of data obtained from the wild-type. Dynamic frameworks must necessarily address the issue of metabolic regulation, which the cybernetic approach does by postulating that metabolism is an optimal dynamic response of the organism to the environment in driving reactions towards ensuring survival. The predictions made in this paper are without parallel in the literature and lay the foundation for rational metabolic engineering. PMID- 22500303 TI - Fighting infections. PMID- 22500304 TI - Plasmablasts evolving from low-grade lymphoma. PMID- 22500305 TI - [Mixed affective states in the juvenile age (historical aspects, current state of the problem, psychopathology)]. AB - The author analyzed the problem in historical, diagnostic and psychopathological aspects and presented the results of his own study. The aim was to study the structure and dynamics of endogenous juvenile mixed states in order to work out the psychopathological typology and to clarify the criteria of diagnosis, differential treatment and clinical-social prognosis. The study included 174 patients, 118 men and 56 women, aged from 17 to 25 years (mean age 20, 4 years). Depressive states were found in 65%, mania in 16% and mixed in 19% of patients. The clinical differentiation of mixed states was carried out basing on the dominating pole of affective disorders and the following types were singled out and described: mania type (dysphoria-like mania)--34%, depressive type (association-driven depression)--38%; alternating type of mixed states--28%. The preference of the formation of alternating and atypical variants of mixed states in the juvenile age demonstrated in the study may reflect the pathogenetic and pathoplastic effect of biological features characteristic of this age--lability and polymorphism of clinical presentations as well as immaturity of emotional and cognitive spheres. PMID- 22500306 TI - [Post stroke affective disorders]. AB - We have studied 198 patients with first-ever stroke. The spectrum of affective disorders included depressions, generalized anxiety disorder, phobias. The study has demonstrated that mentioned post stroke affective disorders have different risk and pathogenetic factors. In stroke patients, affective disorders were caused by the damage of different brain areas. Depression was associated with the damage of left frontal/temporal cortical areas and left subcortical structures. On the contrary, anxiety disorders were associated with the damage of these structures in the right hemisphere. PMID- 22500307 TI - [Structural-functional characteristics of the brain in juvenile patients in remission after first-episode of endogenous psychosis]. AB - The structural MRI and auditory evoked potentials (odd-ball paradigm) were analyzed in juvenile patients at the remission stage after the first episode of endogenous psychosis. Eleven male patients and 11 male controls, aged 18-25, years were examined. There were no statistically significant between-group differences by averaged volume of grey matter in superior and middle frontal gyri, anterior cingulate gyrus, hippocampus, and superior temporal gyrus in both hemispheres as well by P300 amplitude and latency. It can be assumed that the certain normalization of neurobiological processes can be seen at the studied stage of the disease. PMID- 22500308 TI - [The state of nociceptive and antinociceptive brain systems in patients with the pain form of diabetic polyneuropathy]. AB - We studied 48 patients with the pain form of distal symmetric sensorimotor diabetic polyneuropathy (DPN) before and after polytherapy and 17 sex- and age matched healthy people. Clinical/neurological, psychometric and neurophysiologic (recording of nociceptive flexor reflex (NFR) and exteroceptive suppression of involuntary muscle activity) methods were used. Lower NFR thresholds and coefficients pain threshold/reflex threshold (Pt/Rt) as well as the presence of moderately-severe depression and high anxiety level were found in patients with DPN. This reflects a lack of supraspinal and antinociceptive effects and a significant role of psychological factors in the formation of chronic neuropathic pain. The significant reduction of pain, increase of NFR thresholds and Pt/Rt coefficients were seen after the treatment with antidepressants (venlafaxine or pipofezine) in the combination with carbamazepine that suggests the strengthening of supraspinal and antinociceptive systems activity. Measuring of NFR parameters has a practical value for the assessment of the state of antinociceptive brain systems, intensity of pain syndrome, severity of comorbid anxiety-depression disorders and for the objectification of treatment efficacy in patients with DPN. PMID- 22500309 TI - [Attention-deficit hyperactivity disorder: determination of the optimal medical treatment duration]. AB - Thirty-two patients with attention-deficit hyperactivity disorder (ADHD), 23 boys and 9 girls, aged 6-12 years, were examined in two months intervals during the long-term treatment (up to 6-8 months) with pantogam (homopantothenic acid) in daily dosages of 500-1000 mg. The treatment results were evaluated by the ADHD Rating Scale-DSM-IV and The Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P). While the core symptoms of ADHD were according ADHD-DSM-IV diminished after 2 months, the improvement of WFIRS-P parameters required the longer duration of medical treatment. Only after 4 months of treatment, the improvement was achieved in selfesteem and social activities, and after 6 months in learning and behavior at school as well as in the level of life skills along with the decrease of risky activities. Thus, getting over psychosocial adaptation problems needs the longer treatment duration than the decrease of ADHD core symptoms. PMID- 22500310 TI - [The retrospective study of efficacy and safety of levetiracetam as an add-on treatment of epilepsy in children]. AB - The objective was to retrospectively study the efficacy and safety of levetiracetam (keppra) as an add-on treatment of pharmacoresistant forms of epilepsy in children. We have analyzed medical histories of 192 patients with pharmacoresistant epilepsy admitted to a neurological department of the Research and Treatment Center of Children's Medical Care over the period of 2008-2011. The patient's age varied in the range from 6 months to 19 years (mean age 5.7 years). The results of the study revealed the high efficacy of levetiracetam as an add-on treatment of pharmacoresistant epilepsy in children. The efficacy of > 50%, including patients in the remission, was found in 60.2%, the remission of more than 6 months was observed in 20.3% of patients. The efficacy of levetiracetam was higher in the treatment of the following variants of pharmacoresistant epilepsy: seizures caused by brain defects (the efficacy of > 50% was seen in 66.7% of patients), atypical rolandic epilepsy (the efficacy of > 50% was seen in 100% of patients). The efficacy of levetiracetam was not correlated with the priority of prescription of the drug that might be explained by the unique mechanism of the action of this anticonvulsant. Levetiracetam is well tolerated in the children age. Side-effects that were not life threatening were noted only in 6.2% of patients and the retention rate was 75.5%. The aggravation of seizures and EEG abnormalities, regardless of the epilepsy form, type of seizure, drug dose or the combination of anticonvulsants were seen in 5.7% of patients. PMID- 22500311 TI - [The "cost-benefit" analysis of new antiepileptic drugs]. AB - The objective was to optimize the pharmaceutical treatment of epileptic patients and to evaluate the clinical-economical effectiveness of new antiepileptic drugs (AED)--levetiracetam, lamotrigine, topiramate and oxcarbazepine. The study included 134 patients with different types of seizures who received earlier antiepileptics with the addition of new AED as mono- or polytherapy. The cost of treatment and pharmacoeconomic "cost-benefit" index were calculated before and after the treatment optimization. After one year of the treatment with "news" AED, the decrease in seizure frequency was 75-92%. The "cost-benefit" ratio was significantly (p < 0.05) decreased by 2-3 times in all types of seizures despite the increase of direst costs of the treatment. The significant (p < 0.05) decrease in the cost of treatment of epilepsy was noted in all groups studied. In conclusion, the rational treatment using "new" AED allows to reduce both the total cost of treatment and ccost-benefits ratio. PMID- 22500312 TI - [Noopept in the treatment of mild cognitive impairment in patients with stroke]. AB - Noopept is a neuroprotector and nootropics. Literature data revealed the treatment effect of noopept on mild cognitive impairment in patients with discirculatory encephalopathy. The present open prospective study included 60 patients with stroke treated with noopept during 12 months. Cognitive functions were assessed before and after treatment using neuropsychological tests. An analysis of MMSE scores and lateral and categorical associations revealed the significant improvement of cognitive functions after 2 months in patients of the main group compared to the controls. The global assessment of efficacy revealed the mild improvement in the main group while no changes were found in the control group. The results have demonstrated that noopept, used in dose 20 mg daily during 2 months, improves cognitive functions in stroke patients and has a high level of safety. PMID- 22500313 TI - [Comparison of efficacy of different neurometabolic and vasoactive medicines in ischemic stroke patients's rehabilitation]. AB - The aim of present investigation is research of influence of vasoactive and neurometabolic medicines in stroke patients's rehabilitation. We had analysed 280 stroke patients. The degree of rehabilitation had been defined with the help of Barthel and Lindmark scales. The degree of cognitive functions's rehabilitation had been defined with the help of MMSE scale. For every medicine coefficients of efficiency were calculated. As the result of the present investigation the medicine's efficiency was found out. The most efficient medicines in ischaemic stroke patients's rehabilitation among the investigated ones are the medicines which activate the neuronal metabolism, first of all,--ceraxon (citicoline). PMID- 22500314 TI - [Features of fractal dynamics EEG of alpha-rhythm in patients with neurotic and neurosis-like disorders]. AB - Fifty-five patients with neurotic and neurosis-like disorders and 20 healthy controls, aged 17-64 years, have been examined. The basic research method was electroencephalography (EEG) with the fractal analysis of alpha power fluctuations. In patients, the changes in the fractal structure were of the same direction: the decrease of fractal indexes of low-frequency fluctuations and the increase of fractal indexes of mid-frequency fluctuations. Patients with neurosis like disorders, in comparison to those with neurotic disorders, were characterized by more expressed (quantitative) changes in fractal structures of more extended character. It suggests the presence of deeper pathological changes in patients with neurosis-like disorders. PMID- 22500315 TI - [Neurophysiological assessment of afferent-efferent interaction in the trigeminal cervical system in patients with secondary headaches]. AB - We carried out the neurophysiological assessment of functional state of the trigeminal-cervical system and studied peculiarities of afferent-efferent interaction in patients with the most frequent variants of secondary headaches: chronic posttraumatic headaches, cervicogenic headaches, vascular headaches and painful dysfunction of temporomandibular articulation. According to the results of neurophysiological studies (somatosensory, trigeminal evoked potentials, blink reflex and stimulation EMG of masticatory muscles), the functional activity of the trigeminal system in patients with secondary headaches changes less significantly compared to patients with primary headaches. In most secondary headaches, the reflex activity of the trigeminal system and the EMG activity of masticatory muscles are determined by the functional state of spinal and brainstem structures. PMID- 22500316 TI - [The morphometric analysis of serotonin granules of platelets in migraine]. AB - The serotonin hypothesis of migraine attack is based on a phenomenon of fast and significant decreasing of serotonin granules in blood platelets. The morphometric analysis was used to study area, diameter, length and wideness of platelet serotonin granules in 20 migraine patients during a headache attack and in an interparoxysmal period. We found that the area of serotonin granule surface in platelets was 0.231 +/- 0.595 mcm during the migraine attack that was significantly higher than that during the interparoxysmal period (0.205 +/- 0.037 mcm) and in the platelets of healthy controls (0.190 +/- 0.028 mcm) (n = 10). The study has shown that during migraine attack serotonin granules are undergone also structural changes. PMID- 22500317 TI - [Mapping genes of major recurrent depression in genetic isolates]. AB - We conducted a genome-wide linkage scan in two extended pedigrees ascertained from two Dagestan genetic isolates (N(o)6007 and 6008) with high aggregation of early onset major depressive disorders (MDD). The first pedigree included in total 22 cases of MDD (15 available) and 11 suicides; the second pedigree contained 29 MDD cases (23 available) and 12 suicides. Five linked regions in our study are consistent with previous findings in association and/or linkage studies with MDD: 11p15, 12q23-24, 13q11-32, 18q22 and 22q11-13. We found two novel for early onset MDD genomic regions with significant linkages in N(o)6007 with Lods = 3.1-3.4 at 2p13.2-p11.2 (and some weak signal in the same region for N(o)6008) and at 14q31.12-q32.13. We also obtained suggestive level linkages at 9q33.3 q34.2 (N(o)6008), 13q31.1-q31.2 (N(o)6007), 11p15 (N(o)6008), 17q25.3 (N(o)6007) and 19q13.31-q13.33 (N(o)6008). Six linked regions (1p36.1-p35.2, 2p13.2 p11.2,13q31, 17q25.3, 18q22 and 22q12.3) were consistent across the two isolates' pedigrees while all other linkage regions (5q14.1-q14.3, 9q33.3-q34.2, 13q31.1 q32.1, 14q31.12-q32.13, 20p13) demonstrated population-specific genetic heterogeneity of MDD. Our results suggest that genetic mapping of complex diseases, including MDD, across genetically homogeneous isolates can enrich the harvest of linkage signals and expedite the search for susceptibility genes. PMID- 22500318 TI - [The use of vasobral in patients with chronic cerebrovascular disorders]. PMID- 22500319 TI - [The contribution of professor E.L. Venderovich to the Russian neurology (130 anniversary of birthday)]. PMID- 22500320 TI - [Idiopathic relapsing multiple cranial neuropathy]. PMID- 22500321 TI - [A case of poliovirus infection caused by a wild strain in the adult patient]. PMID- 22500322 TI - [Virtual reality in treatment of pain syndromes]. PMID- 22500323 TI - [Thioctic (alpha-lipoic) acid-spectrum of clinical use]. PMID- 22500324 TI - [Classification of antipsychotics and it is importance for the choice of treatment (to 60 anniversary of the introduction of neuroleptics)]. PMID- 22500325 TI - [Bekhterev's choreic epilepsy: a myth or a reality? (A history of the problem)]. PMID- 22500326 TI - ["Comprehensive Epileptology" International Conference (St. Petersburg, May 23 25, 2011)]. PMID- 22500327 TI - [Magnetic-resonance tomography in the diagnosis of hystogically verified epileptogenic lesions]. AB - The aim of the study was to reveal MRI features of focal cortical dysplasia and sclerosis of the hippocampus in patients with symptomatic epilepsy. Twenty-four patients who underwent the surgery with symptomatic epilepsy were studied. The results of pre-surgical MRI and histological studies of the removed cortex were compared. The signs of focal cortical dysplasia in the lesion area were found in patients with oncologic and non-oncologic lesions. In patients with sclerosis of the hippocampus, such specific sign as the T2-signal elevation was not seen in all cases. Though MRI is a highly sensitive method for detecting cortical dysplasia, it does not allow to differentiate significantly different types of this pathology. Even in the presence of typical signs of focal cortical dysplasia, its real boundaries may spread beyond the clearly visualized lesion. In the absence of typical signs of focal cortical dysplasia, one should take into account non-specific signs in the comparison with clinical and neurophysiologic data. In sclerosis of the hippocampus, the changes in the signal intensity were not constantly seen and the decrease in the volume of the structure was a main diagnostic sign. In the cases of so-called "medial temporal epilepsy", any changes in hippocampus volume may be diagnostically important. PMID- 22500328 TI - [Serotoninergic mediator system in the pathogenesis and treatment of idiopathic generalized epilepsy]. AB - Psychoemotional status and blood serotonin level were investigated in 69 patients with different forms of idiopathic epilepsy during the seizures and interictal period. Twenty-two patients with juvenile myoclonic epilepsy, 22 patients with absence forms and 22 patients with generalized convulsive seizures, aged 10-47 years, were included in the study. We found the significant decrease in blood serotonin levels during the interictal period, with the lower levels seen after generalized convulsive and myoclonic seizures. After the treatment with antidepressant fluvoxamine as add-on treatment, 16 patients revealed improved psychoemotional well-being and quality of life as well as a decreased number of generalized convulsive seizures along with the increasing of blood serotonin level. PMID- 22500329 TI - [Epileptic leukoencephalopathy and its significance in the pathogenesis of epilepsy]. AB - A role of the white matter pathology in the pathogenesis of epilepsy is discussed. Results of the neurohistological study of the removed material of patients who were operated for pharmacoresistant temporal epilepsy are presented. The experimental study of animals that allowed to follow-up morphological changes in the cortex and underlying white matter during the formation of an epileptic focus has been conducted. The attempt has been made to evaluate in-vivo noninvasively the white matter in patients with local cryptogenic epilepsy using different functional neuroimaging methods. PMID- 22500330 TI - [The study of quality of life of epileptic children with the special questionnaire QOLCE]. AB - The objective was to create a Russian version of the special quality of life (QOL) questionnaire QOLCE for children with epilepsy and to use it to study QOL. The language and cultural adaptation of the questionnaire has been carried out. The final pilot version was administered to 50 mothers of children with epilepsy. The age of patients was from 4 to 16 years (mean 8.94 +/- 4.21), mean age at disease-onset was 5.30 +/- 3.33 years (from 1 month to 12 years), mean duration of epilepsy was 4.36 +/- 3.48 years, mean duration of treatment was 3.28 +/- 2.58 years. Idiopathic epilepsy was diagnosed in 17 (34%) children, symptomatic - in 13 (26%), cryptogenic - in 20 (40%). The QOLCE was acceptable for all parents. For the majority of items, the mean percentage of missing answers was 3.09%; for Social activity and Stigma subscales the values were 15%. The lowest scores were shown on subscales Physical Restrictions (49.16 +/- 20.31), Cognitive Function (55.78 +/- 23.36), General Health (59.90 +/- 26.16). The highest scores were on the subscale Social Activity (78.08 +/- 26.88). The authors believe that the further testing of the Russian version of the QOLCE is needed. PMID- 22500331 TI - [Main factors determining the choice of antiepileptic drugs in a polytherapy regime in adult patients and specifics of the treatment of focal epilepsy with some new medications]. PMID- 22500332 TI - [Side-effects of antiepileptic treatment: the current state of the problem]. AB - The current treatment of epilepsy is directed not only at the control of seizures and comorbid states but at the improvement of quality of life and destigmatization that is the key strategic direction. The basis of treatment of epilepsy is a long-term regular taking of antiepileptic drugs (AED). However, it has been shown that quality of life of patients depends not only on clinical presentations of the disease, including seizures and higher mental functions, but on the tolerability of AED. The safety of these drugs becomes the most important component of the treatment even compared to the control of seizures. Therefore, tolerability and compliance (a patient's adherence to a recommended course of treatment, common understanding between a doctor and a patient as well as his/her relatives) receive special attention. The timed detection and correction of side effects is an integral component of treatment of epilepsy. In some cases, the presence of rare seizures with minimal clinical presentations and even more frequent seizures that are not danger for a patient seems to be more appropriate than the increase in the number and doses of AED reducing quality of life. The balance between therapeutic and toxic effects of AED is a key issue of treatment of epilepsy. PMID- 22500333 TI - [New drugs in the treatment of adult patients with refractery epilepsy]. PMID- 22500334 TI - [Expert opinion on topamax]. PMID- 22500335 TI - [Migraine and epilepsy: clinical features and common pathogenetic mechanisms]. PMID- 22500336 TI - [Transitory cognitive dysfunction in rolandic epilepsy]. AB - Forty-four patients with rolandic epilepsy (32 boys, 12 girls), aged from 5 to 14 years, were examined in the prospective study during 5 years. Before the antiepileptic treatment, most of patients had transitory cognitive disturbances. There were the impairment of verbal functions, especially verbal intellect, while non-verbal intellect remained intact; dyspraxia, impairment of auditory-speech memory, disturbances of arbitrary regulation and optical-motor coordination. The cognitive impairment was not severe and did not impact on learning of school program. No significant correlations were found between the lateralization of regional EEG changes and the character of cognitive dysfunction though the age related lateralization of the focal epileptiform activity was shown: the right side localization of central-temporal EEG spikes predominated in children at the age of 6.29 +/- 0.9 years, the left-side localization - in children at the age of 8.4 +/- 1.4 years. The clinical remission was achieved 4-5 years earlier than the recovery of cognitive functions. Valproates used as monotherapy or in the combination with ethosuximidum and levetiracetam were drugs of choice. PMID- 22500337 TI - [Psychogenic nonepileptic seizures and epilepsy]. AB - We studied 1100 patients with suspected epilepsy. The study included evaluation of anamnesis, clinical and neurological examination, routine EEG and/or video-EEG monitoring, MRT of the brain. Psychogenic nonepileptic seizures (PNES) were diagnosed in 68 cases. Algorithms of diagnostic and treatment of PNES were described and analyzed. PMID- 22500338 TI - [Neurotic disorders in epileptic patients]. PMID- 22500339 TI - [Cultural differences in quality of life in patients with epilepsy according to QOLIE-31 data]. AB - The study's objectives were to assess the quality of life in Russian patients with epilepsy using the special QOLIE-31 questionnaire and to compare the findings obtained with those of similar foreign studies. Two hundreds and eight patients with epilepsy at the age 18-74 years (average duration of disease - 12.05 +/- 9.89 years) completed the QOLIE-31. In whole, QOL scores for the Russian population were lower than in the European countries, the USA and Brazil. The greatest differences have been noted on the overall QOL, emotional well being, cognitive and social functioning. The scores on a subscale "medication effect" corresponded to the data published by European and USA researchers but were higher than the Brazilian data. In the Russian population, the scores on the cognitive and social functioning were also higher compared to the Brazilian population. In conclusion, the considerable decrease in QOL scores in the Russian population indicate current problems on medical, psychological and social support of patients with epilepsy demanding special attention and further research. PMID- 22500340 TI - [Statistical analysis of the occurrence of relapse in epilepsy]. AB - For obtaining of reliability data it is important to use adequate statistical techniques. We have analysed probability of occurrence of relapse at a long current of an epilepsy by means of the survival analysis on Kaplan-Meyer, risk factors of relapse by means of Cox regression. CONCLUSIONS: relapse occurrence at an epilepsy equiprobably at any stage of a current of disease, and a major factor of risk for relapse is a disease current. PMID- 22500341 TI - [Rare form of epilepsy]. AB - The author describes 7 clinical cases of epilepsy with the presence of sinusitis and one case with chronic otitis. Sphenoiditis was noted in all cases. In tree cases, epileptic seizures disappeared after the sanation of sinuses and after the radical surgery intervention in one patient as well. To exclude respiratory origin of epilepsy, CT and MRT of paranasal sinuses in all cases of epilepsy are recommended. PMID- 22500344 TI - Perception of insecurity in French poor neighbourhoods: racial proxy or pure discrimination hypotheses? AB - Many poor neighbourhoods, home to both socially disadvantaged populations and to foreigners, are characterised by a strong perception of insecurity. The purpose of this article is determine the origin of this perception. To do so, two possible causes are dissociated: racial prejudice and racial proxy (the ethnic minorities are perceived in terms of the negative social characteristics that are often associated with them). More specifically, it is shown that the 'ethnic' variable captures the effects of an overconcentration of poverty, approximated here by the concentration of unemployment, but that these two variables act separately. This result should be taken into account in the policies implemented by public authorities and local actors. In this study, an original methodology is applied based simultaneously on individual geocoded data, the proportion of foreigners, the unemployment rate at the neighbourhood level and an indirect indicator of perceived insecurity. PMID- 22500343 TI - Labour mobility and housing: the impact of housing tenure and housing affordability on labour migration in the Czech Republic. AB - This article examines whether housing tenure and regional differences in housing affordability have an impact on labour mobility. This relationship is important for understanding the sources of structural unemployment and impediments to economic growth. Using two sample surveys from the Czech Republic, this research reveals that at the individual level housing tenure is the most powerful factor determining willingness to change residence for employment reasons. A time-series regression analysis reveals that the impact of housing affordability on observed interregional migration patterns is relatively weak and that this effect is concentrated among the highly educated seeking employment in the capital, Prague. These results demonstrate that housing tenure has a significant impact on labour migration plans in case of unemployment and that the dynamic impact of regional differences in housing affordability on labour mobility is concentrated within the most highly skilled segment of the labour force. PMID- 22500345 TI - Urban policy engagement with social sustainability in metro Vancouver. AB - This article presents an analysis of social sustainability in comparative theoretical context and as a challenge to the post-political interpretation of sustainability in policy practice at the urban and regional scales. Metro Vancouver provides a case study for improving our understanding of the meaning of social sustainability as a framework for social policy in that it is among the handful of cities around the world currently working to define and enact social sustainability in governance terms. Results of this participant research provide evidence that some cities are politically engaging alternative development pathways using the concept of social sustainability. For sustainable development to retain its promise as an alternative policy framework for cities, social sustainability must be at the forefront. PMID- 22500346 TI - Metropolitan fragmentation and neo-localism in the periphery: revisiting the case of Curitiba. AB - In this paper, the Curitiba-centred narrative on the success of its urban planning experience will be qualified in light of the complexities of its metropolitan development trajectory. It will be claimed that the institutional vacuum that surrounds Brazilian metropolitan areas in general, and Greater Curitiba in particular, has been intensified by the emergence of a competitive and decentralised state spatial regime, which has consolidated a fragmented and neo-localist system of governance. Preliminary empirical evidence will be provided on the challenges that are being faced within the new regime in articulating socio-spatial, economic and environmental strategies in the direction of a more sustainable metropolitan future. PMID- 22500349 TI - CFTC/CFDT attitudes towards immigration in the Parisian region: making immigrant workers' condition a cause. AB - This paper, which is based on the detailed analysis of the post-war archives of the French Christian union Confederation Francaise des Travailleurs Chretiens (CFTC), which became the Confederation Francaise Democratique du Travail (CFDT) in 1964, highlights the difficulties, both from a practical and ideological point of view, for a militant organisation to embrace the cause of immigrant workers and to give them a voice. The CFDT had to 'construct' immigrant workers as a group they could represent, which means as a group that relates to French workers, despite possible xenophobia. A key moment was the denunciation of their housing conditions that make immigrant workers not competitors in the job market but victims of injustice. The union had to reinvent its engagement frames in order to include the specific problems faced by the immigrant workforce. The study shows that the urban dimension was essential in this process as Paris slums made visible an important plight of migrants and provided the opportunity to change public opinion. PMID- 22500350 TI - The boy who changed the world: Ohio and the Crippled Children's Movement. PMID- 22500351 TI - Toledo dentist Charles Betts and the health crusade against aluminum. PMID- 22500353 TI - Should I prefer chest pain over leg pain? PMID- 22500354 TI - Bleeding umbilical nodule. PMID- 22500355 TI - [FTO gene and his role in genetic determination of obesity]. PMID- 22500356 TI - Combining Martha and Mary: gender and work in seventeenth-century English cloisters. PMID- 22500357 TI - Memorializing motherhood: literary women and modernity. PMID- 22500358 TI - Chronic kidney disease in the developing countries! Are we really so different? PMID- 22500359 TI - The importance of class III overcorrection. PMID- 22500360 TI - Early Alt-RAMEC and facial mask protocol in class III malocclusion. PMID- 22500361 TI - "Reverse" indirect bonding: a protocol for temporary debonding. PMID- 22500362 TI - Self-ligating brackets. PMID- 22500363 TI - 2011 JCO orthodontic practice study. Part 2 net income. PMID- 22500364 TI - Palatal-implant anchorage in an adult class II patient. PMID- 22500365 TI - A guide to ranking above your competition in Google search results. PMID- 22500366 TI - The big anniversary--200 years of the New England Journal of Medicine. PMID- 22500367 TI - [Determination of morphine, codeine and 6-monoacetylmorphine in saliva of substance-abuse patients using HPLC/MS methods]. AB - BACKGROUND/AIM: Saliva represents an alternative specimen for substances abuse determination in toxicology. Hence, the aim of this study was to optimize a method for saliva specimen preparation for heroin metabolites, morphine and 6 monoacetylmorphine (6-mam), and codeine determination by liquid chromatography mass spectrometry (LC/MS), and to apply this method on saliva samples taken from the patients. METHODS: Saliva specimen was prepared using liqiud/liquid extraction of morphine, codeine and 6-mam by mixture of chloroform and isopropanol (9 : 1; v/v). Extracts were analysed by HPLC/MS technique: separation column Waters Spherisorb 5 microm, ODS2, 4.6 x 100 mm; mobile phase: ammonium acetate : acetonitile (80 : 20; v/v), mobile phase flow rate 0.3 mL/min; mass detection range: 100-400 m/z. Regression and correlation analyses were performed with the probalility level of 0.05. Concentrations of morphine, codeine and 6-mam were determined in saliva samples of the patients with "opiates" in urine identified by the test strips. RESULTS: Calibration for each analysed substance was done in the concentration range from 0.1 to 1 mg/L and the coefficient of correlation was R2 > 0.99. We obtained following calibration curves: y = 385531x + 14584; y = 398036x + 31542; and y = 524162x - 27105, for morphine, codeine and 6-mam, respectively. Recovery for morphine and codeine determination was 99%, while for 6-mam it was 94%. Limits of detection and quantification of a proposed method were 0.01 mg/L and 0.05 mg/L, respectively. Concentration of morphine in the saliva of the heroin users ranged between 0.54 and 5.82 mg/L, concentration of codeine between 0.05 and 5.33, and 6-mam between 0.01 and 0.68 mg/L. A statistically significant correlation between codeine and 6-mam concentrations was obtained. CONCLUSION: A proposed HPLC/MS method for morphine, codeine and 6 mam determination in saliva is accurate, simple, cheap and suitable for routine analysis and monitoring of heroin abuse. PMID- 22500368 TI - Glycosaminoglycans in the urinary bladder mucosa, tumor tissue and mucosal tissue around tumor. AB - INTRODUCTION/AIM: Glycosaminoglycans (GAG) are one of the main constituents of the connective tissue and cellular membrane. Their presence has been evidenced in mucosa and muscular tissue of the urinary bladder of both healthy individuals and those affected by carcinoma. This suggest their potential role in the onset of bladder carcinoma and follow-up of those patients. The aim of the study was to determine GAG levels in tumor tissue and the surrounding bladder mucosa in patients with bladder tumor, as well as in the bladder mucosa in patients with bladder carcinoma, and to compare the results according to the grade and stage of tumor and relapse. METHODS: Tissue samples were taken in 61 patients (48 males and 13 females), mean age 61.5 years, range 40-92 years, obtained by transurethral resection (TUR) of bladder tumor, and 8 healthy persons. Determination of a total GAG content in the tissue samples was done by the Whiteman's method and then compared regarding the tumor grade and stage. RESULTS: Tumor grade and stage directly correlated with the levels of GAG. The GAG levels were significantly higher in tumor samples as compared to healthy mucosa. CONCLUSION: Higher GAG levels were recorded in all the patients with bladder tumors comparing to samples obtained from healthy individuals. GAG levels do not predict tumor relapse. PMID- 22500369 TI - Tumor necrosis factor-alfa and interleukin-4 in cerbrospinal fluid and plasma in different clinical forms of multiple sclerosis. AB - BACKGROUND/AIM: Multiple sclerosis (MS) is an immune-mediated central nervous system disease characterized by inflammation, demyelination and axonal degeneration. Cytokines are proven mediators of immunological process in MS. The aim of this study was to investigate whether there is a difference in the production of the tumor necrosis factor alpha (TNF-alpha) and interleukin-4 (IL 4) in cerebrospinal fluid (CSF) and plasma in the MS patients and the controls (other neurological non-inflammatory diseases) and to determine a possible difference in these cytokines in plasma and CSF in different clinical forms of MS. METHODS: This study involved 60 consecutive MS patients--48 patients with relapsing-remitting MS (RRMS) and 12 patients with secondary progressive MS (SPMS). The control group consisted of 20, age and sex matched, non immunological, neurological patients. According to the clinical presentation of MS at the time of this investigation, 34 (56.7%) patients had relapse (RRMS), 14 (23.3%) were in remission (RRMS), while the rest of the patients, 12 (20.0%), were SPMS. TNF-alpha and IL-4 concentrations were measured in the same time in CSF and plasma in the MS patients and the controls. Extended disability status score (EDSS), albumin ratio and IgG index were determined in all MS patients. RESULTS: The MS patients had significantly higher CSF and plasma levels of TNF alpha than the controls (p < 0.001 for both samples). IL-4 CSF levels were significantly lower in the MS patients than in the controls (p < 0.001), however plasma levels were similar. The patients in relapse (RRMS) and with progressive disease (SPMS) had higher concentrations of CSF TNF-alpha levels than the patients in remission (p < 0.001). IL-4 CSF levels in relapse (RRMS) and SPMS groups were lower than in the patients in remission. The patients in remission had an unmeasurable plasma TNF-alpha level and the patients with SPMS had significantly lower IL-4 levels in plasma than the patients in relapse and remission (p < 0.001). The only significant correlation between cytokine level with either EDSS, or albumin ratio, or IgG index, was found between CSF TNF-alpha levels and albumin ratio in the patients with relapse (R square = 0.431, p < 0.001). CONCLUSION: According to the obtained data MS relapse was characterized by high concentrations of TNF-alpha in CSF and plasma and low concentrations of IL-4 in CSF. Remission was characterized by high concentrations of IL-4 and low concentrations of TNF-alpha both in CSF and plasma. SPMS was characterized with lower concentrations of TNF-alpha and IL-4 compared to relapse, both in CSF and plasma. PMID- 22500371 TI - Frequency and changes in trends of leading risk factors of coronary heart disease in women in the city of Novi Sad during a 20-year period. AB - BACKROUND/AIM: From 1984 to 2004 the city of Novi Sad participated through its Health Center "Novi Sad" in the international Multinational MONItoring of Trends and Determinants in CArdiovascular Disease (MONICA) project, as one of the 38 research centers in 21 countries around the world. The aim of this study was to determine frequency and changes of trends in leading risk factors of coronary heart disease (CHD) and to analyze the previous trend of movement of coronary event in women in Novi Sad during a 20-year period. METHODS: In 2004, the fourth survey within MONICA project was conducted in the city of Novi Sad. The representative sample included 1,041 women between the age of 25 and 74. The prevalence of risk factors in CHD such as smoking, high blood pressure, elevated blood cholesterol, elevated blood glucose and obesity was determined. Also, indicators of risk factors and rates of coronary events in women were compared with the results from MONICA project obtained in previous three screens, as well as with the results from other research centres. chi2-test, linear trend and correlartion coefficient were used in statistical analysis of results obtained. RESULTS: It was observed that during a 20-year period covered by the study, the prevalence of the leading risk factors for the development of CHD in the surveyed women was significantly increasing and in positive correlation with the values of linear trend. Also, the increase of morbidity rates and mortality rates of coronary event were in positive correlation. The decrease was only recorded in the period from 1985-1989 (the implementation of the intervention programme). CONCLUSION: Upon analysing the increase in prevalence of leading risk factors of CHD and significant increase in the rates of coronary event, we can conclude that health status of women in Novi Sad during a 20-year period was deteriorating. PMID- 22500370 TI - 123I-FP-CIT brain SPECT (DaTSCAN) imaging in the diagnosis of patients with movement disorders--first results. AB - BACKGROUND/AIM: 123I-FP-CIT brain single-photon emission computed tomography (SPECT), DaTSCAN imaging, offers a possibility to study structural and biochemical integrity of presinaptic dopaminergic neurotransmitter system. The aim of this study was to evaluate the usefulness of 123I-FP-CIT brain SPECT scintigraphy in patients with extrapyramidal diseases. METHODS: Fifteen patients (8 males and 7 females), aged 26-81 years, presenting with extrapyramidal symptoms entered the study. Out of them, 7 patients were diagnosed with definite clinical form of idiopathic Parkinson's disease (PD) or clinical probable for PD clinical stage 2-4 using the Hoehn & Yahr scale (H & Y); 6 patients were with atypical parkinsonism (AP), 1 patient with essential, and 1 with psychogenic tremor. SPECT was performed 180 min after injection of 185 MBq 123I FP-CIT using a dual head Gamma camera. Sixty four one minutes' frames were acquired using a noncircular rotation mode into a 128 x 128 image matrix. Transverse slices were reconstructed using a 0.6 order Butterworth filter. Visual interpretation was based on striatal uptake, left to right asymmetry and substructures most affected. The ratio of binding for the entire striatum, caudate and putamen to nonspecific binding in occipital cortex was calculated. SPECT findings were categorized as normal and abnormal (incipient, moderate and severe presinaptic deficit). RESULTS: 123I-FP-CIT uptake was reduced in the striatum of 6/7 patients with PD and 5/6 patients with AP. Two patients with PD and AP showed a negative finding. The remaining 2 negative results were obtained in the patients diagnosed with essential tremor and psychogenic tremor. The mean striato-occipital ratio (SDR) of the most affected side was lower in the patients with PD. CONCLUSION: Our first results confirm the usefulness of 123I-FP-CIT brain SPECT in differential diagnosis of extrapyramidal diseases. PMID- 22500373 TI - [Applicability of a Serbian version of the "Oral Impacts on Daily Performance (OIDP)" index--assessment of oral health-related quality of life]. AB - BACKGROUND/AIM: The Oral Impacts on Daily Performance (OIDP) is a well-known psychometric test used internationally to assess the oral health-related quality of life. The interview and self-administrated questionnaire both assess the degree to which oral health problems have affected the life of the participants over the previous 6 months. The aim of this study was to translate the OIDP index into Serbian and to assess its reliability in practice as its initial verification in the Serbian speaking area. METHODS: Following an internationally established methods, the OIDP scale was translated using standardized methodology that consisted of forward translation, pilot study and backward translation. RESULTS: A pilot study was carried out with 44 respondents (24 males i 20 females) using a preliminar Serbian version of the OIDP index. All patients were aged over 65 years. A total of 68.2% of the participants replied that they had at least one OIDP impact on daily life in the past 6 months. These troubles were most prominent during eating (47.7%) and speaking (36.4%), but there is a little impact of troubles in the domain of psychosocial sphere. The corrected item-total correlation coefficients for all items were above the minimum recommended level of 0.20 for including an item in a scale. The standardized Cronbach's alpha coefficient was 0.75. CONCLUSION: Based on these results, we can conclude that this index is suitable for use in everyday practice in Serbian speaking area providing useful information required to assess oral health-related quality of life. PMID- 22500372 TI - [Efficacy of TNF-alpha antagonist and other immunomodulators in the treatment of patients with ophthalmologic manifestations of Behcet's disease and HLA B51 positive vasculitis]. AB - BACKGROUND/AIM: Behcet's disease is genetically conditioned, immune-mediated multisystem occlusive vasculitis of small blood vessels, espesially venules, of unknown etiology. The aim of this study was to analyze the clinical features, disease activity and therapy of the patients with ophthalmologic manifestation of Behcet's disease. METHODS: In this study symptoms and signs of the disease were analyzed both prospectively and retrospectively during the active manifestation of the disease. The diagnosis was reached according to the International Criteria for Behcet's Disease (2006). The treatment effects were evaluated based on the presence of the best corrected visual acuity and the inflammation of the vitreous humour before and after the application of our therapeutic method. The applied therapeutic modality consisted of the primary application of corticosteroid therapy in the active stage of the disease complemented with the choice of drugs from the immunosuppressive group. In this study there drugs were cyclosporine or methotrexate. A treatment refractory patients with poor vision prognosis were treated with a third drug, the biological preparation infliximab, a tumor necrosis factor-alpha (TNF-alpha) antagonist. RESULTS: The mean age of 11 patients with ophthalmologic manifestation of Behcet's disease was 50.6 years. HLA B-5 (51) was positive in 81% of the patients while 36% of the patients had positive pathergy test. Changes in affected eyes included vitritis (100%), posterior uveitis (45%), panuveitis (54%), retinal vasculitis (54%), cystoid macular edema (54%), and cystoid degeneration (18%). Increased intraocular pressure was observed in 27% of the patients. There was no statistically significant variation in disease activity parameters in any of the patients (p > 0.05). A statistically significant improvement in visual acuity (p < 0.05) and a high statistically significant decrease of inflammation of the worst affected eyes (p = 0.001) were detected. CONCLUSION: Our therapeutic method is useful for producing the optimal therapeutic plan for the acute--chronic stage of the difficult ophtamological manifestation of Behcet's desease as well as the prevention of relapse. However the high cost of the therapy and the potential complications should be taken into consideration when prescribing this therapy, especially a TNF-alpha antagonist. PMID- 22500374 TI - [Immediate implant loading with fixed dental restorations--an animal model study]. AB - BACKGROUND/AIM: Immediate loading is considered to be the most innovative technique in contemporary implant dentistry. Recent clinical and experimental findings have demonstrated that only implants with high primary stability can be subjected to immediate loading protocol with predictable results. It is generally accepted that the most important prerequsite for successful osseointegration is achievement and maintenance of implant stability. The aim of this in vivo study was to investigate the possibility for successful application of immediate loading protocol in implant systems with different surface properties. METHODS: In the experimental study 2 mongrel dogs were edentulated bilaterally in the mandibular and maxillary premolar areas. After 3 months implants were placed in a pattern 4 different commercially available implants per quadrant (n = 32): Mk III TiUnite (Nobel Biocare, Sweden), ITI TPS (Straumann, Switzerland), 31-Osseotite (Implant Innovation, USA) and XiVE Cell-Plus (Friadent, Germany). Implants were subjected to immediate loading with 4 unit gold cast bridges, 2 days post implantation. The assessment of implant stability and immediate loading possibilities were done by performing Resonance frequency analysis (RFA). RESULTS: After a 6-month loading period all bridges were in function and all implants occurred well osseointegrated. When summarizing the Implant Stability Quotient (ISQ) values, it was noted that resonance frequency was significantly higher for mandibular implants. The results of this experimental setting showed that all evaluated surfaces achieved good implant stability. Increase of ISQ values was found for all implants in the mandible and partially decrease of ISQ values for maxillary implants after 6 months of functional loading with 4 unit bridges. CONCLUSIONS: Investigated endooseal implants did not show different degree of osseointegration, because there was not statisticaly significant difference among observed parameters (ISQh i ISQp) between implant systems. PMID- 22500375 TI - Prognostic significance of tympanosclerotic plaques localization and their morphological and histological characteristics for the outcome of surgical treatment. AB - BACKGROUND/AIM: Tympanosclerosis is a sequela of inflammation of the middle ear usually causing conductive hearing loss. The aim of the study was to determine the significance of tympanosclerotic plaques localization in the middle ear and their morphological and histological characteristics for surgical treatment outcome. METHODS: This retrospective study included a total of 73 patients operated on for tympanosclerosis in the Clinic for Otorhinolaryngology, Military Medical Academy (MMA) in a period 1996-2010. The results of surgical treatment as well as the last audiometry findings were analyzed considering follow-up periods of 6 months to 8 years. The patients were divided into 4 groups according to tympanosclerotic plaques localization in the middle ear and the classification suggested by Wieling and Kerr. The patients were also divided based on intraoperatively noticed morphological characteristics of tympanosclerotic plaques, while the third division was done as per histological findings. Surgical success was assessed using the suggestions of the Japan Otological Society. RESULTS: The analyzed results showed the surgical success especially in the group II according to Wieling and Kerr, while histological findings had no impact on the outcome of the surgery. CONCLUSION: Surgical treatment has good results especially in patients with the mobile stapes. Results are satisfactory in other localizations, while various morphological and histological characteristics do not have impact on the surgery outcome. PMID- 22500376 TI - Should we prescribe "vasodilating" beta-blockers in Marfan syndrome to prevent aortic aneurysm and dissection? PMID- 22500377 TI - Depressive symptoms as a side effect of the sustained release form of methylphenidate in a 7-year-old boy with attention-deficit hyperactivity disorder. AB - INTRODUCTION: Hyperkinetic disorder or attention-deficit hyperactivity disorder (ADHD) is a clinical entity consisting of a cluster of symptoms including hyperactivity, attention disorder and impulse control disorder group. In the context of ADHD etiology we may say that genetic, clinical and imaging studies point out a disruption of the brain dopamine system, which is corroborated by the clinical effectiveness of stimulant drugs, which increase extracellular dopamine in the brain. Basically, it is a biological and not psychological disorder, which is important both for the comprehension and therapeutical approach to this problem. Today, the best recommended approach regarding children with ADHD is a combination of two therapeutic modalities: pharmacotherapy and behavioral treatment. The first-choice drugs for this disorder belong to the group of sympathomimetics--psychostimulants and atomoxetine (more recently). As the first choice therapy, methylphenydate in sustained release form has numerous advantages. Like all drugs, methylphenidate has its unwanted side effects. Most common are: loss of appetite, weight loss, sleeping disorders, irritability, headache. These side effects are well-known and documented in the literature. By analysing the available literature we have found cases of psychiatric side effects such as: psychosis, mania, visual hallucinations, agitation, suicidal ideas. We have not found examples of ADHD in children who use increased dosage of sustained release of methylphenidate leading to depressive symptomatology. On the other side, methylphenidate may be prescribed for off-label use in treatment resistant cases of depression. CASE REPORT: The case of a 7-year-old boy diagnosed with ADHD was on a minimal dose of sustained release form of methylphenidate. After initial titration of the drug, i.e. after raising the dose to the next level the boy developed clinical signs of depression. The treatment was ceased and depressive symptoms were withdrawed. CONCLUSION: Manifestation of depressive symptomatology after dose increasement of sustained release form of methylphenidate in a 7-year-old boy with ADHD represents an uncommon side effect. Precise drug activity mechanisms responsible for the appearance of these symptoms remains to be explained. PMID- 22500378 TI - Reversal deterioration of renal function accompanied with primary hypothyrodism. AB - INTRODUCTION: Hypothyroidism is often accompanied with decline of kidney function, or inability to maintain electrolyte balance. These changes are usually overlooked in everyday practice. Early recognition of this association eliminates unnecessary diagnostic procedures that postpone the adequate treatment. CASE REPORT: Two patients with elevated serum creatinine levels due to primary autoimmune hypothyroidism, with complete recovery of creatinine clearance after thyroid hormone substitution therapy are presented. The first patient was a young male whose laboratory tests suggested acute renal failure, and the delicate clinical presentation of reduced thyroid function. The second patient was an elderly woman with a history of a long-term signs and symptoms attributed to ageing, including the deterioration of renal function, with consequently delayed diagnosis of hypothyroidism. CONCLUSION: Serum thyrotropin and thyroxin levels measurement should be done in all cases of renal failure with undefined renal desease, even if the typical clinical presentation of hypothyroidism is absent. Thyroid hormone assays sholud also be performed in all patients with chronic kidney disease whose kidney function is rapidly worsening. PMID- 22500379 TI - Multiple myeloma invasion of the central nervous system. AB - INTRODUCTION: Multiple myeloma (MM) is characterized by the presence of neoplastic proliferating plasma cells. The tumor is generally restricted to the bone marrow. The most common complications include renal insufficiency, hypercalcemia, anemia and reccurent infections. The spectrum of MM neurological complications is diverse, however, involvement of MM in the cerebrospinal fluid (CSF) and leptomeningeal infiltration are rare considered. In about 1% of the cases, the disease affects the central nervous system (CNS) and presents itself in the form of localized intraparenchymal lesions, solitary cerebral plasmocytoma or CNS myelomatosis (LMM). CASE REPORT: We presented the clinical course of a 55 year-old man with MM and LMM proven by malignant plasma cells in the CSF, hospitalized with the pain in the thoracic spine. His medical history was uneventful. There had been no evidence of mental or neurological impairment prior to the seizures. Physical examination showed no abnormalities. After a complete staging, the diagnosis of MM type biclonal gammopathia IgG lambda and free lambda light chains in the stage III was confirmed. The treatment started with systemic chemotherapy (with vincristine, doxorubicin plus high-dose dexamethasone--VAD protocol), radiotherapy and bisphosphonate. The patient developed weakness, nausea, febrility, dispnea, bilateral bronchopneumonia, acute renal insufficiency, confusions, headaches and soon thereafter sensomotor aphasias and right hemiparesis. The patient was treated with the adequate therapy including one hemodyalisis. His neurological status was deteriorated, so Multislice Computed Tomography (MSCT) of the head was performed and the findings were normal. Analysis of CSF showed pleocytosis, 26 elements/mL and increased concentrations of proteins. Cytological analysis revealed an increased number of plasma cells (29%). Electrophoretic analysis of proteins disclosed the existance of monoclonal components in the serum, urine and CSF. Immunofixation electrophoretic and quantitative nephelometric tests confirmed Biclonal multiple myeloma of IgG lambda and light chain lambda isotypes. Analysis of neurothropic viruses with ELISA methods was negative. Once the presence of LMM was confirmed, the patient received intrathecal chemotherapy with methotrexate, cytosine arabinoside, dexamethasone three times a week, and systemic high doses of dexamethasone iv like a single agent without craniospinale irradiations. Despite the treatment, the patient died one month after the diagnosis. Autopsy was not performed. CONCLUSION: Presented patient, as well as most other patients with MM progressing to CN Sinfiltration was in the stage III. In addition to the detailed clinical examination, and all investigations required for MM diagnosis and staging of the disease, we introduced the additional CSF examination and calculation of kappa lambda ratio, that helped us make an early diagnosis and prognosis of MM with LMM. Although LMM had a low prevalence, it could be more frequent than expected especially in patients with high risk. CSF examination with positive plasma cells and abnormal morphology remains the hallmark for diag nosing CNS infiltration. PMID- 22500380 TI - [A speech at the National Conference on Integrative Medicine Development Strategies and the 30-year anniversary conference for the founding of Chinese Association of Integrative Medicine]. PMID- 22500381 TI - [Effects of Shen invigorating and Chong-channel regulating method on anti Mullerian hormone and oocyte quality in polycystic ovarian syndrome patients]. AB - OBJECTIVE: To study the effects of Shen invigorating and Chong-channel Regulating Method (SCRM) on anti-Mullerian hormone (AMH) and its correlation with oocyte quality in the serum and the follicular fluid of infertile patients with polycystic ovarian syndrome (PCOS) who received in vitro fertilization (IVF), thus studying the mechanism of SCRM on the oocyte quality of PCOS patients. METHODS: Sixty infertile patients with PCOS undergo ing in vitro fertilization and embryo transfer (IVF-ET) were randomly assigned to two groups, 30 in each. Erzhi Tiangui Granule combined with Western medicine was given to patients in the treatment group, while Western medicine was given to those in the control group. The single oocyte estradiol (E2) level, the resistive Index ( RI), the pulsatility index (PI) of the follicular membrane, the number of harvested oocytes, the high quality oocyte rate, the fertilization rate, the cleavage rate, the high quality embryo rate, and the difference of AMH in the serum and the follicular fluid were observed between the two groups. The correlation tests were performed between the levels of AMH in the serum and the follicular fluid and te uli rates of high quality oocyte and high quality embryo. Meanwhile, the correlation analysis of the AMH level between the serum and the follicular fluid was also conducted. RESULTS: (1) The single oocyte E2 level, the high quality oocyte rate, the fertilization rate, the cleavage rate, the high quality embryo rate were significantly higher in the treatment group than in the control group (P < 0.05). (2) The RI and the PI of the follicular membrane both significantly more decreased in the treatment group than in the control group (P < 0.05). (3) The levels of AMH in the serum and the follicular fluid were obviously lower in the treatment group than in the control group (P < 0.01). The AMH levels in the serum and the follicle fluid were positively correlated. The level of AMH in the follicular fluid was obviously negatively correlated with the high quality oocyte rate and the high quality embryo rate. CONCLUSIONS: SCRM could improve the oocyte quality of PCOS patients. Its mechanisms were correlated with regulating the AMH levels in the serum and the follicular fluid, adjusting the androgen level, improving the pathophysiological changes of PCOS patients, and activating the ovarian microenvironment. It is necessary to carry out further studies. PMID- 22500382 TI - [Analysis of the perinatal outcome of the early severe preeclampsia women treated with Compound Danshen Injection and low molecular weight heparin]. AB - OBJECTIVE: To study the effects of using Compound Danshen Injection (CDI) and low molecular weight heparin (LMWH) on early severe preeclampsia women. METHODS: Retrospective analysis was carried out in 95 patients with early severe preeclampsia from October 2008 to January 2011. They were assigned to 3 groups based on anticoagulant drugs. The routine therapy of magnesium sulfate (MgSO4) was given to the MgSO4 group (40 cases); the MgSO4 + CDI was given to those in the CDI group (23 cases), the MgSO4 + LMWH group was given to those in the LMWH group (32 cases). The general data of all patients were collected to analyze their effects on labor, postpartum hemorrhage, reasons for terminating the pregnancy, and maternal complications. RESULTS: (1) The average gestational week (weeks) of terminating the pregnancy was 31.7 +/- 1.9 in the MgSO4 group, 33.0 +/ 1.8 in the CDI group, and 32.8 +/- 1.7 in the LMWH group. The average weight of newborn babies (g) was 1 450.5 +/- 402.3 in the MgSO4 group, 1 582.2 +/- 332.5 in the CDI group, and 1 590.0 +/- 340.1 in the LMWH group. There was no obviously difference in the average gestational weeks or the average weight of newborn babies among the three groups. (2) The way of terminating the pregnancy was uterine-incision delivery. The main reasons for operation were sequenced as maternal complications, unsatisfied control of the blood pressure, and fetal distress. (3) The maternal complications in the three groups were sequenced as renal failure (12 cases), placental abruption (9 cases), hemolysis, increased liver enzymes and low platelet (HELLP) syndrome (8 cases). Sixteen (40.0%) had complications in the MgSO4 group, 12 (52.2%) in the CDI group, and 15 (46.9%) in the LMWH group. No statistic difference existed among the 3 groups. CONCLUSIONS: LMWH and CDI were helpful to improving the therapeutic effects of severe preeclampsia patients. They did not increase adverse drug reactions. They seemingly had effects on prolonging the gestational week. PMID- 22500383 TI - [Effects of Guilin Watermelon Frost on the mRNA expressions of basic fibroblast growth factor in patients with uterine cervical columnar ectopy]. AB - OBJECTIVE: To study the molecular biological effects of Guilin Watermelon Frost (GWF) on the mRNA expressions of basic fibroblast growth factor (bFGF) in patients with uterine uterine cervical columnar ectopy. METHODS: One hundred and sixty patients with uterine cervical columnar ectopy were assigned to two groups by the random digit table. Patients in the treatment group were treated with local spray of GWF, while those in the control group were local applied with bFGF collagen sponge. The mRNA expressions of bFGF of the uterine tissue were detected in the two groups before and after treatment using RT-PCR. RESULTS: Before treatment the mRNA expression of bFGF in the uterine cervical columnar ectopy was 0.55 +/- 0.10 in the treatment group and 0.58 +/- 0.13 in the control group, without insignificant difference (P > 0.05). After treatment it significantly increased in the two groups, being 0.82 +/- 0.17 and 0.78 +/- 0.15 respectively, showing statistical difference from before treatment (P < 0.01). But no statistical difference existed between the two groups after treatment (P > 0.05). CONCLUSION: GWF showed enhancement on the mRNA expressions of bFGF in patients with uterine cervical columnar ectopy. PMID- 22500384 TI - [Effects of Fuzheng Huayu Capsule on the ratio of TGF-beta1/BMP-7 of chronic viral hepatitis B fibrosis patients of Gan-Shen insufficiency blood-stasis obstruction syndrome]. AB - OBJECTIVE: To observe the effects of Fuzheng Huayu Capsule (FHC) on the liver function, HBV DNA quantization, the ratio of transforming growth factor beta1/bone morphogenetic protein-7 (TGF-beta1/ BMP-7) of peripheral blood mononuclear cells (PBMCs), HBV DNA YMDD variation, and the liver tissue pathology of chronic viral hepatitis B fibrosis patients of Gan-Shen insufficiency blood stasis obstruction syndrome (GSIBSOS) on the basis of antiviral treatment by lamivudine. METHODS: Eighty chronic viral hepatitis B fibrosis patients of GSBSOS were randomly assigned to two groups. Patients in the control group (43 cases) were treated with lamivudine alone, while those in the treatment group (37 cases) were treated with lamivudine + FHC. The treatment period lasted for 6 months. By the end of treatment lamivudine was continually given to all patients, and patients were followed up for 6 months. Before and after treatment, liver tissue pathology was examined by liver biopsy. The serum HBV DNA quantization, the ratio of TGF-beta1/BMP-7 were determined by fluorescence quantitative polymerase chain reaction (PCR). HBV DNA YMDD variation was tested by the end of follow-ups. RESULTS: Better effects were obtained in decreasing the levels of ALT, AST, and HBV DNA after 6 months of treatment in the two groups, with statistical difference when compared with before treatment in the same group, but with no statistical difference between the two groups. At the end of the 6th month follow up, YMDD variation occurred in 9 cases of the control group and in 5 cases of the treatment group, with statistical difference between the two groups (P < 0.05). FHC could significantly reduce the ratio of TGF-beta1/BMP-7, significantly lower in the treatment group (0.09 vs 0.25, P < 0.05). In the aspect of liver tissue pathological changes, the rates of inflammatory activity over G3 and fibrosis degree S3 in the treatment group were significantly lower than those in the control group (P < 0.05). CONCLUSIONS: On the basis antiviral treatment of lamivudine for chronic viral hepatitis B fibrosis patients of BSOS, additional application of FHC could lower the HBV DNA YMDD variation, improve the hepatic inflammation and fibrosis, and exert anti-fibrosis by decreasing the ratio of TGF beta1/BMP-7. PMID- 22500385 TI - [Effects of Jinhuang Yidan Granule on the bile compositions of primary bile duct pigment calculus patients]. AB - OBJECTIVE: To study the effects of Jinhuang Yidan Granule (JYD) on the bile compositions of primary bile duct pigment calculus patients. METHODS: Sixty-six patients with primary bile duct pigment calculus were randomly assigned to the control group (who took no Chinese medicine) and the JYD group (who took JYD). The bile from T-tube during the operation, 3, 10, and 40 days after medication were examined. The contents of bile acids, bilirubin (conjugated bilirubin, mono conjugated bilirubin), glucoprotein, calcium ion, beta-glucuronidase, superoxide radical anion, and other components were detected and compared. RESULTS: Three days after taking JYD, the total bile acids increased, the total bilirubin and beta-glucuronidase decreased, showing statistical significance when compared with the control group (P < 0.05). In the JYD group, the total bile acid increased, the total bilirubin, the conjugated bilirubin, the mono-conjugated bilirubin, glucoprotein, calcium ion, beta-glucuronidase, superoxide radical anions decreased 10 and 40 days after medication, showing statistical significance when compared with the control group (P < 0.05, P < 0.01). The level of the total bile acid increased, the levels of the total bilirubin, the conjugated bilirubin, the mono-conjugated bilirubin, glucoprotein, calcium ion, beta-glucuronidase, superoxide radical anions decreased after 40-day medication in the two groups, showing statistical significance when compared with the peri-operative indices of the same group (P < 0 05, P < 0.01). CONCLUSIONS: JYD could significantly improve the pathologic bile compositions of the bile duct calculus, improve the environment of the biliary tract, showing certain preventive and therapeutic effects on bile pigment calculus of the primary bile duct calculus. Better effects may be obtained by long-term taking. PMID- 22500386 TI - [Clinical study of Qinggan Huatan Huoxue Recipe on the treatment of non-alcoholic steatohepatitis]. AB - OBJECTIVE: To observe the therapeutic effects of Qinggan Huatan Huoxue Recipe (QHHR) on patients with non-alcoholic steatohepatitis (NASH). METHODS: One hundred and fifty NASH patients were randomly assigned to the treatment group (78 cases) and the control group (72 cases). QHHR was given to patients in the treatment groups, while Danning Tablet was given to those in the control group. The therapeutic course for all was three months. Before and after treatment changes of clinical symptoms and physical signs, liver imageology, liver functions, blood lipids, and insulin resistance index (IRI) were observed. RESULTS: Compared with before treatment, obvious improvement of clinical symptoms, weight, body mass index (BMI), liver functions, blood lipids, and integral of liver ultrasound B was obtained in the two groups (P < 0.05). The IRI of the treatment group was significantly reduced after treatment (P < 0.05). Better effects were obtained in lowering the body weight, BMI, alanine aminotransferase (ALT), gamma glutamyltransferase (gamma-GT), triglyceride (TG), total cholesterol (TC), integral of liver ultrasound B, and the total effective rate (P < 0.05). CONCLUSIONS: QHHR had definite effects on NASH. Its therapeutic effects were better than Danning Tablet. PMID- 22500387 TI - [Clinical study of Fuzheng Yiliu Recipe combined with microwave ablation on hepatocellular carcinoma]. AB - OBJECTIVE: To explore the clinical value of Fuzheng Yiliu Recipe (FYR) combined with microwave ablation on hepatocellular carcinoma. METHODS: Sixty patients with hepatocellular carcinoma were randomly assigned to the control group and the treatment group according to the random digit table, 30 in each group. Patients in the control group received microwave ablation therapy, while those in the treatment group received FYR three days after microwave ablation. The therapeutic course was 6 months. By the end of the treatment, the short-term objective therapeutic efficacy, the liver function, the hepatic fibrosis index, the cellular immune function were statistically analyzed between the two groups. RESULTS: The indices of the liver function, the hepatic fibrosis, and the cellular immune function were more significantly improved in the treatment group than in the control group (P < 0.05). The CD4+ level and the ratio of CD4+/CD8+ of the treatment group were remarkably higher than those of the control group (40.38 +/- 12.47 vs 28. 19 +/- 6.59, 1.49 +/- 0.41 vs 1.22 +/- 0.31). The tubercle recurrence rate of the treatment group (14.0%, 7/50) was significantly lower than that of the control group (33.3%, 15/45) after 6 months of treatment (P < 0.05). CONCLUSION: FYR combined with microwave ablation could elevate the therapeutic efficacy, enhance the patients' immunity, improve the liver function and the hepatic fibrosis degree. PMID- 22500388 TI - [Clinical observation of treating early diabetic nephropathy by qi supplementing, yin nourishing, blood stasis dispersing, collateral dredging recipe]. AB - OBJECTIVE: To observe therapeutic effects of qi supplementing, yin nourishing, blood stasis dispersing, collateral dredging recipe (QYBCR) on early diabetic nephropathy (DN). METHODS: Seventy-eight early DN patients were randomly assigned to the treatment group (39 cases, treated by QYBCR) and the control group (39 cases, treated by irbesartan). The changes of the therapeutic efficacy, Chinese medicine syndrome scores, urine albumin excretion rate (UAER), serum creatinine (SCr), blood urine nitrogen (BUN), fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), and the occurrence of end-point events were observed after one-year treatment. RESULTS: The total effective rate in treatment group was 83.8% (31/37 cases), which was obviously higher than that in control group (60.5%, 23/38 cases) (P < 0.05). After treatment the Chinese medicine syndrome scores were reduced significantly in the treatment group (P < 0.05, P < 0.01), and showed significant difference when compared with those in the control group (P < 0.05, P < 0.01). Levels of UAER, SCr, BUN, FBG, TC, and TG were (65. 78 +/- 9.67) microg/min, (93.20 +/- 12.99) micromol/L, (5.69 +/- 1.21) mmol/L, (6.14 +/- 1.47) mmol/L, (4. 85 +/- 0. 83) mmol/L, (1.46 +/- 0.81) mmol/L after treatment in treatment group. All of them decreased more significantly than before treatment [(161.03 +/- 20.01) microg/min, (101.11 +/- 14.33) micromol/L, (6.54 +/- 1.12) mmol/L, (9.27 +/- 2.32) mmol/L, (6. 19 +/- 2.13) mmol/L, (2. 70 +/- 1.86) mmol/L] (P < 0.05, P < 0.01). The aforesaid indices were also improved in the control group after treatment (P < 0.05, P < 0.01). The reduction of TC and TG after treatment in the treatment group was more significant [(5.58 +/- 1.57) mmol/L, (1.99 +/- 1.22) mmol/L] (P < 0.05). Besides, the incidence rate of end-point events (5.4%, 2/37) (1 year after the development of clinical DN) of the treatment group was slightly lower than that of the control group (10.5%, 4/38), but with no statistical difference. CONCLUSION: QYBCR combined with Western medicine-based treatment showed better therapeutic efficacy on early DN. PMID- 22500389 TI - [A cohort study on delaying the progress of chronic renal failure mainly with Modified Shenqi Dihuang Decoction]. AB - OBJECTIVE: To assess the therapeutic effects of Chinese medicine (CM) treatment mainly by Modified Shenqi Dihuang Decoction (MSDD) in delaying the progress of chronic renal failure (CRF). METHODS: A prospective cohort method was employed. CRF patients with serum creatinine (SCr) ranging between 133 and 442 micromol/L were recruited. Those in the CM treatment group (61 cases) were treated with MSDD as well as basic treatment of Western medicine, while those in the control group (57 cases) were treated with basic treatment of Western medicine alone. A 2-year follow-up study was carried out. The effects on postponing the progression of CRF were observed mainly from the levels of hemoglobin (HB), plasma albumin (ALB), SCr, estimated glomerular filtration rate (eGFR), reciprocal slope of serum creatinine (b value), and endpoint events, etc. RESULTS: (1) The progression of the renal function: After 24 months of treatment, better therapeutic effects were shown in the CM treatment group than in the control group (P < 0.05), which could be illustrated by decreased SCr levels, increased eGFR levels, and the positive reciprocal slope of SCr (1/SCr) to the time linear regression slope (b value). There were 40 cases (65.57%) with a reciprocal slope of SCr (b value) > or = 0 (34.43%) and 21 cases with b < 0 in the CM treatment group. However, there were 7 cases (12.28%) with b > or = 0 and 50 cases (87.72%) with b < 0 in the control group. The difference was statistically significant (P < 0.05). (2) There was no significant difference in HB or ALB between the two groups after 12 months and 24 months of treatment (P > 0.05). (3) Twenty-four months later, there were 6 endpoint events (9.84%) in the CM treatment group and 9 (15.79%) in the control group, with insignificant difference (P > 0.05). CONCLUSION: MSDD plus basic treatment of Western medicine could delay the progression of CRF patients. PMID- 22500390 TI - [Effects of Busui Shengxue Granule on bFGF and bFGFR in bone marrow derived stroma cells of chronic aplastic anemia patients]. AB - OBJECTIVE: To observe the therapeutic effects of Busui Shengxue Granule (BSSXG) on chronic aplastic anemia (CAA) patients and its effects on bone marrow derived stroma cells (BMDSCs) correlated cytokines. METHODS: One hundred and twenty-four patients with CAA were randomly assigned to two groups according to the random digit table. Patients in the test group (61 cases) were treated with BSSXG, while those in the control group (63 cases) were treated with Zaizao Shengxue Tablet (ZST). The therapeutic course was 6 months for all. Besides, 10 healthy subjects were recruited as the normal control group. Changes of the symptom integral, therapeutic efficacy judgment, and changes of peripheral hemogram of patients were observed. The mRNA expression of b-fibroblast growth factors (bFGF) and b fibroblast growth factors receptor (bFGFR) were detected by reverse transcription PCR. RESULTS: The total effective rate of the test group was 75.0% (45/61), higher than that of the control group (58.7%, 37/63). Its symptom integral and peripheral hemogram were obviously improved, better than those of the control group (P < 0.05, P < 0.01). The mRNA expressions of bFGF and bFGFR of the test group were obviously lower than those of the normal control group (P < 0.05, P < 0.01). They were somewhat improved after treatment in the two groups, with better results obtained in the test group. CONCLUSIONS: BSSXG showed better clinical effects. It could improve the symptom integral and peripheral hemogram of CAA patients, improve the clinical efficacy, and regulate the expression levels of bFGF and bFGFR. It improved the hematopoietic microenvironment and promoted the hematopoiesis of the bone marrow through regulating the proliferation and oriental differentiation of stroma cells, and promoting the bone marrow angiogenesis. PMID- 22500391 TI - [A crossover control study of prophylactic treatment of chemotherapy-induced constipation by senna extract]. AB - OBJECTIVE: To observe the prophylactic effects of senna extract 40 mg/kg on chemotherapy-induced constipation. METHODS: Eighty-two patients suffering from constipation after chemotherapy were assigned to Group AB and Group BA. Group AB referred to patients who first took senna extract in the 1st chemotherapeutic course and the crude fiber diet in the 2nd chemotherapeutic course. But the sequence was just the opposite in Group BA. The effective rates of relieving chemotherapy-induced constipation by senna extract and by the crude fiber diet were observed. The differences of the digestive tract reaction and the hematotoxicity reaction were compared. The conditions of patients' abdominal pain and stool properties were observed after they took senna extract. RESULTS: The effective rate of constipation by taking senna extract was 92.68% and that by the crude fiber diet was 10.93%, with statistical difference shown (P < 0.01). There was no statistic difference in adverse reaction rate such as decreased neutrophils over degree II, decreased hemoglobin, decreased platelet, nausea, vomit, etc. (P > 0.05). The occurrence rate of abdominal pain over degree II after taking senna was 8.54%. In the distribution of stool properties, the rate of loose stool was 35.53%. CONCLUSION: Senna extract 40 mg/kg was effective and safe in treating chemotherapy-induced constipation. PMID- 22500392 TI - [Analysis of the toll-like receptor 2 Arg753Gln gene polymorphisms of acne patients of Gan-depression induced qi stagnation syndrome and damp-heat in the interior syndrome]. AB - OBJECTIVE: To study the toll-like receptor 2 (TLR2) Arg753Gln gene polymorphisms of acne patients of Gan-depression induced qi stagnation syndrome and damp-heat in the interior syndrome, thus laying the foundation for genetics studies on its occurrence. METHODS: The distribution and the frequency of allelic genes were studied in 75 acne patients of damp-heat in the interior syndrome, and 87 acne patients with Gan-depression induced qi stagnation syndrome, as well as 70 healthy subjects (as the normal control group) using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: There was significant difference in the frequency of the genotype Arg/Gln + Gln/Gln in the TLR2 Arg753Gln genetic polymorphisms [26. 44% (23/87) in Gan-depression induced qi stagnation syndrome, 41.33% (31/75) in damp-heat in the interior syndrome, and 12.86% (9/70) in the normal control group] (P < 0.05). CONCLUSION: The existence of 753Gln allele in the Arg753Gln of TLR2 increased the onset risk of acne patients of Gan-depression induced qi stagnation syndrome and damp-heat in the interior syndrome. PMID- 22500393 TI - [Effects of Yangling Zhongyu Decoction on the secretion of ovarian granule cells in polycystic ovarian syndrome rat model]. AB - OBJECTIVE: To observe the effects of Yangjing Zhongyu Decoction (YJZYD) on the serum estradiol (E2), testosterone (T), 17-hydroxyprogesterone (17-OHP), ovarian follicle stimulating hormone receptor (FSHR), insulin-like growth factor I (IGF 1), steroid hormone acute regulator protein (StAR) mRNA expressions in female rats. METHODS: Fifty PCOS rats were equally divided into 5 groups, i. e., the control group (C, normal PNA rats), the model group (M), the low dose YJZYD group (Y1), the medium dose YJZYD group (Y2), and the high dose YJZYD group (Y3), 10 in each. The levels of serum hormones were detected using radioimmunoassay. The morphological changes of the ovary were observed using HE method. The expressions of FSHR, IGF-1, and StAR mRNA were detected using RT PCR. RESULTS: Compared with Group C, serum T and 17-OHP significantly increased (P < 0.01), E2 significantly decreased (P < 0.01), the expressions of FSHR, IGF-1, and StAR mRNA significantly decreased in Group M (P < 0.01). Compared with Group M, the serum T level significantly decreased (P < 0.01), 17-OHP decreased (P < 0.05), and E2 significantly increased in Group Y3 (P < 0.01). The expressions of FSHR, IGF-1, and StAR mRNA increased in Group Y1, Y2, and Y3. The increase was most obvious in Group Y3 (P < 0.01). CONCLUSIONS: YJZYD could lower the hyperandrogenemia of PCOS rats. It also could increase the ovarian expressions of FSHR, IGF-1, and StAR mRNA, improve the ovarian functions, and promote the follicular development. PMID- 22500394 TI - [Effects of Modified Wenjing Decoction on the ovarian oxidative damage of cold coagulation blood stasis model rats]. AB - OBJECTIVE: To observe the effects of Modified Wenjing Decoction (MWJD) on the ovarian oxidative damage of cold coagulation blood stasis (CCBS) model rats, thus consummating the action mechanisms of MWJD for treating gynecopathy of CCBS syndrome. METHODS: Female SD rats were randomly divided into the normal group, the model group, and the treatment group. Rats in the model group and the treatment group were placed in the ice water (0 -1 degrees C) to establish the rat model of CCBS syndrome. Meanwhile, MWJD was given by gastrogavage to rats in the treatment group for 2 weeks. Rats were decapitated during the oestrous cycle. The serum levels of estradiol (E2), progestone (P), testosterone (T) were detected. The bilateral ovarian tissues were taken out and operated on ice. The total bilirubin (TBIL), superoxide dismutase (SOD), malondialdehyde (MDA), total antioxygen capacity (T-AOC) were detected after homogenate. RESULTS: Compared with the normal group, serum levels of E2, P, T, and ovarian levels of TBIL, SOD, T-AOC all obviously decreased in the model group, and the ovarian MDA level increased, showing statistical difference (P <0. 05, P <0.01). After treated by MWJD, when compared with the model group, serum levels of E2, P, T, and ovarian levels of TBIL, SOD, T-AOC increased, the ovarian MDA level decreased, showing statistical difference (P <0.05, P <0.01). All indices except serum T level and the ovarian MDA content restored to the normal levels (all P>0.05). CONCLUSIONS: The ovarian functions are abnormal in CCBS model rats. MWJD could restore the ovarian functions by improving the ovarian oxidative damage state, thus treating gynecopathy of CCBS syndrome. PMID- 22500395 TI - [Effects of high dose glycosides of Tripterygium wilfordii Hook. f on the fertility of young rats]. AB - OBJECTIVE: To explore the effects of high dose glycosides of Tripterygium wilfordii Hook. f (GTW) on the fertility of young rats. METHODS: Fifty female SD young rats and 50 male SD young rats were randomly divided into the blank group and the GTW group, 25 in each. GTW was given at the daily dose of 9 mg/kg. After 12 weeks of medication, the male rats were caged together with healthy adult female rats in the ratio of 1:1. The female rats were caged together with healthy adult male rats in the ratio of 2:1. The cage process lasted for two weeks, totally for three times. The pregnant rate of female rats and the survival rate of baby rats were then observed. RESULTS: There was no significant difference in the pregnant rate or the survival rate of baby rats in the GTW group. CONCLUSION: High dose GTW showed no obvious effects on the fertility of adult rats or the growth and development of new born rats. PMID- 22500396 TI - [Comparison of in vitro anti-oxidative activities among Siwu Decoction Serial Recipes, their composed crude herbs, and main aromatic acids, as well as their dose-effect correlation]. AB - OBJECTIVE: To assess and compare the in vitro anti-oxidative activities among Siwu Decoction Serial Recipes, their composed crude herbs, and main aromatic acids they contained. METHODS: Their anti-oxidative activities (including Siwu Decoction and correlated recipes such as Taohong Siwu Decoction, Xiangfu Siwu Decoction, Shaofu Zhuyu Decoction, and Xiongqiong Decoction, 16 kinds of crude herbs, and main aromatic acids they contained) were determined using 2,2-diphenyl 1-picrylhydrazyl (DPPH) free radical clearance method. RESULTS: The selected five decoctions showed obvious activities of scavenging free radicals. Siwu Decoction was better than other decoctions in scavenging free radicals and Xiongqiong Decoction was the least. Among the 16 kinds of crude herbs, red peony root, white peony root, safflower, ligustici chuanxiong, common aucklandia root showed the strongest activities, while peach seed showed the poorest activities. Among aromatic acids, gallic acid, protocatechuic acid, vanillic acid, caffeic acid, chlorogenic acid, p-coumaric acid, and ferulic acid showed obvious anti-oxidative activities in scavenging free radicals, showing obvious dose-effect correlation. p-hydroxybenzoic acid, benzoic acid, and cinnamic acid showed no activities on scavenging free radicals (P > 0.05). CONCLUSION: Siwu Decoction and aromatic acids contained in correlated decoctions played significant roles in anti oxidative activities. PMID- 22500397 TI - [Effects of interferon-alpha combined with saikosaponin on serum T lymphocyte subgroups and hepatic cytokines in mice with immune hepatic injury]. AB - OBJECTIVE: To observe the effects of interferon-alpha combined with saikosaponin on serum T lymphocyte subgroups and hepatic cytokines in mice with immune hepatic injury. METHODS: The mice were randomly divided into five groups, i. e., the normal control group, the model group, the interferon group, the saikosaponin group, and the interferon combined saikosaponin group. Corresponding medication was given to mice in respective groups for two days. Peripheral blood was collected 8 and 24 h after concanavalin A (Con A) was injected. Serum lymphocyte subgroups, tumor necrosis factor alpha (TNF-alpha), levels of interleukin 18 (IL 18) and IL-10, activities of alanine aminotransferase (ALT) and aspartate transaminase (AST) were detected. Pathological changes of the liver tissue were observed. RESULTS: (1) Compared with the normal control group, serious inflammation and necrosis was significant in the liver tissue of the model group. The serum levels of ALT and AST obviously increased. Meanwhile, the 24-h peripheral blood CD4+ T cell and CD8+ T cell ratios and the hepatic IL-10 level obviously decreased (P < 0.01). The levels of IL-18 and TNF-alpha significantly increased (P < 0.05, P < 0.01). (2) Compared with the model group, dot and lamellar necrosis was dispersedly seen in the liver tissue in the three medication groups. The serum activities of ALT and AST significantly decreased (P < 0.01). Meanwhile, the peripheral blood CD4+ T cell and CD8+ T cell ratios, as well as the hepatic IL-10 level obviously increased (P < 0.01, P < 0.05). The levels of IL-18 and TNF-alpha significantly decreased (P < 0.05, P < 0.01). (3) In the interferon combined saikosaponin group, the 24-h peripheral blood CD4+ T cell and CD8+ T cell ratios increased more obviously than those of the interferon group. The 8- and 24-h IL-18 levels were obviously lower than those of the interferon group, while the 24-h TNF-alpha level significantly decreased more than that of the interferon group (P < 0.05). CONCLUSION: Interferon-alpha combined saikosaponin could effectively play a role in fighting against the immune hepatic injury. PMID- 22500398 TI - [Effects of extract of Buddleja officinalis eye drops on androgen receptors of lacrimal gland cells of castrated rats with dry eye]. AB - OBJECTIVE: To observe the effects of the extract of Buddleja officinalis eye drops (EBOED) on basic tears secretory volume, tear film stability, and expressions of androgen receptors (AR) in castrated rats with dry eye, and to investigate the mechanism of EBOED on dry eye caused by decreased anti-androgen levels. METHODS: Forty-five male Wistar rats were randomly divided into the blank group, the model group, and the treatment group (treated by EBOED), respectively. Rats in each group were further divided into three sub-groups (fed for one month, two months, and three months, respectively). There were totally nine groups, with five in each. The dry eye model was established with orchiectomy of rats in the model group and the treatment group. EBOED was given to rats in the treatment group for one successive month. Schirmer I test (SIT) and breakup time of tear film (BUT) were determined in all experimental rats. Expressions of AR was analyzed by flow cytometer. RESULTS: Ths SIT value, BUT, and AR positive rate in the model group at the 1st, 2nd, 3rd month were lower than those in the blank group of the same time points (P < 0.01). There was statistical difference in SIT value, BUT, and AR positive rate between the model group and the treatment group at the three time points (P < 0.01). Take the three-month subgroup as an example, the SIT value in the treatment group was (12.667 +/- 5.221) mm, obviously higher than that in the model group (2.676 +/- 1.987) mm. The BUT in the treatment group was (11.758 +/- 4.415) s, obviously longer than that of the model group (4.667 +/ 2.108) s. The AR positive rate in the treatment group was 49.33% +/- 3.44%, obviously higher than that of the model group (33.32% +/- 7.12%, all P < 0.01). CONCLUSIONS: The main components of EBOED was the flavonoids which could significantly inhibit the occurrence of dry eye in rats with decreased androgen levels. Its mechanism might possibly be similar to androgen. PMID- 22500399 TI - [Effects of ecdysterone on the expression of NF-kappaB p65 in H2O2 induced oxidative damage of human lens epithelial cells]. AB - OBJECTIVE: To study the effects of ecdysterone (ECR) on the expression of nuclear factor (NF)-kappaB in H2O2 induced oxidative damage of human lens epithelial cells (HLECs). METHODS: The cultured HLECs were divided into 5 groups, i.e., the control group, the H2O2 group, the beta-estradiol (E2) group, the ECR group, and the pyrrolidine dithiocarbamate group (PDTC) group. The expression rate of NF kappaB p65 in the HLECs were detected by flow cytometer (FCM). RESULTS: The expression of NF-kappaB p65 occurred in normal HLECs (9. 53%). The expression rate of NF-kappaB p65 in the H2O2 group obviously increased (39.87%, P < 0.01). The expression rate of NF-kappaB p65 in the PDTC group obviously decreased (5.90%, P < 0.01). The expression rates of NF-kappaB p65 in the ECR group (13.99%) and the E2 group (25.18%) ranged between the control group and the H2O2 group, but still lower than that of the H2O2 group (P < 0.01). CONCLUSIONS: The activation of NF-kappaB in the HLECs could be induced by H2O2 ECR with the estrogenic activity could effectively inhibit the activation of NF-kappaB. PMID- 22500400 TI - [Effects of scorpion and centipede on IL-2, IL-4, and IL-10 in the small intestinal mucosa and joint injury of rats with collagen induced arthritis]. AB - OBJECTIVE: To observe the effects of scorpion and centipede on interleukin (IL) 2, IL-4, IL-10 in the small intestinal mucosa and joint injury of rats with collagen induced arthritis (CIA). METHODS: Sixty Wistar rats were randomly divided into 6 groups: the normal control group, the model group, the low dose scorpion and centipede group, the middle dose scorpion and centipede group, the high dose scorpion and centipede group, and the type II collagen treatment group. The joints' volume was measured 40 days after type II collagen (CII) induced rheumatoid arthritis model was established. The joint injury was observed by naked eyes. The expression levels of IL-2, IL-4, and IL-10 in the small intestine tissue homogenate were detected by enzyme linked immunosorbent assay (ELISA). RESULTS: The joint injury score and volume of two hind limbs were obviously higher in the model group than in the normal control group since the 23rd day (P < 0.01). Rats were accompanied with red, swollen, and deformed foot toes and ankle joints. Walking was even affected. Meanwhile, the joint injury score and volume of two hind limbs were obviously lowered by medicated with 0.4, 0.2, 0.1 g/kg scorpion and centipede, as well as CII on the 32nd day after medication (P <0.05, P < 0.01). The expression levels of IL-2, IL-4, and IL-10 in the small intestine tissue homogenate were obviously lower in the model group than in the normal control group (P < 0.05, P < 0.01). Compared with the model group, only the expression levels of IL-2 and IL-4 in the small intestine tissue homogenate of the high dose scorpion and centipede group and the type II collagen treatment group significantly increased. The expression level of IL-10 significantly increased in the high and middle dose scorpion and centipede groups, as well as the type II collagen treatment group, showing statistical difference (P < 0.05, P < 0.01). CONCLUSIONS: Scorpion and centipede could effectively release the joint injury of rats with CIA. Its mechanism might be correlated with increased expression levels of IL-2, IL-4, and IL-10 in the small intestine mucosa. PMID- 22500401 TI - [Study on the mechanism of akebia saponin D for leukemia]. AB - OBJECTIVE: To investigate the mechanism of akebia saponin D (ASD) for fight against leukemia cells. METHODS: The human acute leukemia cell strain U937 and human acute promyelocytic leukemia cell strain HL-60 were treated with ASD at different doses (10, 30, 50, and 100 microg/mL). The proliferation inhibition of ASD was observed using MTT assay. Apoptosis was detected by Annexin-V staining. The expressions of correlated genes were detected by PCR. Changes of p53 were detected using Western blot. The nitrite content, as the metabolite of nitric oxide (NO) was detected by Griess spectrophotometry. RESULTS: 50 microg/mL ASD could obviously inhibit the growth of U937 and HL-60 cells in a dose-dependent manner, accompanied with the down-regulation of bcl-2 mRNA expression. Results of Western blot showed that the P53 expression increased along with the dose of ASD. Besides, ASD could elevate the content of NO in U937 and HL-60 cells (P < 0.05). CONCLUSIONS: ASD could inhibit the proliferation and induce the apoptosis of U937 and HL-60 cells. The mechanism might be correlated with down-regulating the bcl-2 expression, up-regulating the p53 expression, and increasing the NO content in U937 and HL-60 cells. PMID- 22500402 TI - [Effect of Shengxue Zengbai Decoction on the cell cycle and apoptosis in mice after bone marrow transplantation]. AB - OBJECTIVE: To explore the effect of Shengxue Zengbai Decoction on the cell cycle and apoptosis in hematopoietic rebuilding in mice after bone marrow transplantation (BMT). METHODS: The experimental animals were randomly divided into 5 groups: the normal group (with no treatment), the model group, the granulocyte-colony stimulating factor (G-CSF) group, the Shengxue group, and the Shengxue + G-CSF group. BMT mouse model was established. Shengxue Zengbai Decoction concentrated decoction was given by gastrogavage to mice in the Shengxue group and the Shengxue + G-CSF group. On Day 9, 14, and 24 after BMT, the apoptotic rates of myelomonocytes were detected using flow cytometry. Changes of the cell cycle were analyzed. Peripheral blood cells and myelomonocyte were counted. Histological observation was performed. RESULTS: On Day 14 after BMT the level of hemoglobin in the peripheral blood cells was higher in the Shengxue group than in the model group and the G-CSF group (P < 0.05). The level of hemoglobin in the Shengxue +G-CSF group was higher than that in the model group (P < 0.05). On Day 24 after BMT the level of white blood cells in the peripheral blood cells in the Shengxue group was higher than that in the model group (P < 0.05). On Day 24 after BMT the myelomonocyte count in the G-CSF group, the Shengxue group, and the Shengxue + G-CSF group was higher than in the model group (P < 0. 01). The cell apoptotic rate on Day 24 after BMT was lower in the Shengxue group than in the G-CSF group and the model group of the same period. CONCLUSION: Shengxue Zengbai Decoction could promote the proliferation and differentiation of bone marrow hematopoietic cells, inhibit the apoptosis of bone marrow cells, which might be one of the mechanisms for hematopoietic rebuilding of Shengxue Zengbai Decoction. PMID- 22500403 TI - [Effects of angelica polysaccharides on the proliferation of mouse skeletal muscle satellite cells and the expression of stem cell factor receptor protein]. AB - OBJECTIVE: To observe the effects of angelica polysaccharides (APS) on the proliferation of mouse skeletal muscle satellite cells (MSCs) and c-kit expression in different in vitro hematopoietic microenvironments. METHODS: MSCs were primarily cultured. The desmin protein was examined by immunohistochemical assay five days later. The MSCs were randomly divided into 8 groups, i. e., the control group, the supernatant from cultured bone marrow stroma cells group, 100, 200, 300 microg/mL APS added in the DMEM/F12 medium experimental groups, and 100, 200, 300 microg/mL APS intervened medium groups. The effects of the proliferation activities of MSCs were detected using MTT method. The c-kit protein of the MSCs was stained by immunohistochemistry. RESULTS: The desmin protein was positive in the isolated cultured MSCs. Results of MTT method showed the proliferation of MSCs in APS intervened medium groups was significant. The strong positive c-kit immunoreactivity existed in APS intervened medium groups. The strong positive c kit immunoreactivity was present in the cytoplasmic of the MSCs in the DMEM/F12 medium experimental groups and the APS intervened medium groups. CONCLUSIONS: The APS intervened MSC medium could effectively change the growth properties of MSCs, obviously promote the proliferation of MSCs and c-kit expression. The c-kit protein might play some regulative roles in the proliferation of the MSCs. PMID- 22500404 TI - [Effects of moxibustion on the expressions of hippocampal VEGF, flt-1, bFGF, and bFGF-r in vascular dementia rats]. AB - OBJECTIVE: To observe the expression levels of hippocampal vascular endothelial growth factor (VEGF), fms-like tyrosine kinase-1 (flt-1), basic fibroblast growth factor (bFGF), and basic fibroblast growth factor receptor (bFGF-r) in vascular dementia (VD) rats, thus studying the angiogenesis mechanism of moxibustion in VD. METHODS: Sixty male elderly Wistar rats were selected. The VD rat model was prepared by bilateral carotid artery occlusion and reperfusion of sodium nitroprusside injection. The model rats were divided into 3 groups by the random digit table, i. e., the moxibustion group, the Western medicine group, and the model group. A sham-operation control group was also set up. In the moxibustion group rats was acupunctured at Baihui (GV20), Shenting (GV14), and Dazhui (GV24). Aniracetam was given to rats in the Western medicine group by gastrogavage for 2 therapeutic courses, 15 days as one course. The learning and memory results were observed by the neuroethological score in combination of step-down avoidance test before treatment and by the end of the 2nd course respectively. The expression levels of hippocampal VEGF, flt-1, bFGF, and bFGF-r of all rats were detected using immunohistochemical assay. RESULTS: After 2 courses of treatment, statistical difference existed in the latent period, the error times, and the neuroethological score in the moxibustion group and the Western medicine group when compared with the model group (P < 0.01, P < 0.05). Statistical difference existed in the latent period and the neuroethological score between the moxibustion group and the Western medicine group (P < 0.05), which indicated that moxibustion and Western medicine showed significant effects in improving the latent period, decreasing the error times and the neuroethological score. Better results were obtained in the moxibustion group than in the Western medicine group (P < 0.01, P < 0.05). Statistical difference of the average grey level (AGL) of hippocampal VEGF, flt-1, and bFGF existed in the moxibustion group and the Western medicine group when compared with the model group. Statistical difference of the bFGF-r expression existed only between the moxibustion group and the model group. Statistical difference of the VEGF and flt-1 expressions existed between the moxibustion group and the Western medicine group (P < 0.05). CONCLUSIONS: Moxibustion showed confirmative effects in improving the behavioral score and memory performance in VD rats. Its mechanisms might lie in that moxibustion regulated and controlled the expression levels of hippocampal VEGF, flt-1, bFGF, and bFGF-r in VD rats. Particularly it up-regulated the expression levels of key factors VEGF and flt-1, promoted the angiogenesis in the vital parts, and ultimately stimulated the repairing mechanisms of cerebral nerve injury. PMID- 22500405 TI - [Understanding of diabetic kidney disease and reflecting of the current clinical research situation of Chinese medicine]. AB - Along with the development of clinical and pathological studies, and the wide spreading of the concepts or ideas of chronic kidney disease (CKD) and diabetic kidney disease (DKD), the clinical research of DKD has entered a new stage, which has brought new requirements for Chinese medicine treatment of DKD. It is necessary to carry out good design, have reasonable inclusion and exclusion criteria, select appropriate biomarkers capable of reflecting the pathophysiology of DKD, choose convincible hard endpoints capable of reflecting the prognosis of DKD, and conduct observations of enough long therapeutic course. This is the main trend of conducting clinical trials of DKD and scientifically assessing the efficacy of Chinese medicine treatment of DKD. PMID- 22500406 TI - [Analyzing the Chinese medicine pathogenesis of stroke]. AB - Both ischemic and hemorrhage stroke pertain to the category of wind stroke in Chinese medicine (CM). Up to date, it is deemed that the etiology and pathogenesis of wind stroke are wind, fire, sputum, qi, stasis, and deficiency. Among them, it is regarded that wind and fire are the key factors triggering wind stroke. By analyzing the time order and causality, it is found that wind stroke is prior to the onset of wind and fire, wind and fire are the secondary outcomes of wind stroke. By parallel comparing stroke with thromboembolism and hemorrhagic diseases in other Zang-organs, it can be comprehended that the reason why wind symptoms appear in stroke is due to its physiological feature of brain itself. Based on Neijing, the pathogenesis of wind stroke is proposed as follows. Tunnels of viscera (vessels) get lesions. The old pathogenic factors of sputum and stasis or the stasis formed by bleeding inside viscera consume qi, and blood of viscera and damage the spirits hidden in them. The damage of Gan-spirit causes symptoms of stroke, such as hemiplegia, deviation of eyes and mouth, and so on. Wind and fire symptoms are caused by the injury of Gan blood and yin, and/or the stagnation of fire in pericardium (the pathway organ) due to obstruction by old pathogenic factors and stasis (formed by bleeding). PMID- 22500407 TI - [The reliance and significance of stability as a new way to reveal the essence of syndrome in Chinese medicine]. AB - Stability is the important feature of the control system. Stability exists extensively in the biological systems such as different cell types during the process of individual development, new biological properties formed under the environment and/or diet factors, drug addition, long-term memory formation, and so on. The underlying mechanisms generally include epigenetically modification, the emergence of certain substance with long half life, the formation of positive feedback loop, and the activation of stem cells. Introduction of stability into researches of Chinese medicine syndrome is essentially to explore the mechanisms of quantitative changes into the qualitative alternation. It is also helpful for us to choose an appropriate time window of animal models for Chinese syndrome and to consider what are the core effects of Chinese materia medica in improving syndrome. The stability not only meets the features of Chinese medicine theories, but also agrees with the progress of modern systems theory and biology. We hope it could promote studies on Chinese medicine syndrome. PMID- 22500408 TI - [Clinical practice and challenges of integrative medicine in hospitals]. AB - The clinical practice of China's integrative medicine (IM) and international integrative medicine was reviewed. As for the existent problems, we raised some personal ideas from the aspects of policies and regulations, safety, efficacy, and educational training, etc. PMID- 22500409 TI - [An investigation of the statistical power of the effect size in randomized controlled trials for the treatment of patients with type 2 diabetes mellitus using Chinese medicine]. AB - OBJECTIVE: To investigate whether the power of the effect size was based on adequate sample size in randomized controlled trials (RCTs) for the treatment of patients with type 2 diabetes mellitus (T2DM) using Chinese medicine. METHODS: China Knowledge Resource Integrated Database (CNKI), VIP Database for Chinese Technical Periodicals (VIP), Chinese Biomedical Database (CBM), and Wangfang Data were systematically recruited using terms like "Xiaoke" or diabetes, Chinese herbal medicine, patent medicine, traditional Chinese medicine, randomized, controlled, blinded, and placebo-controlled. Limitation was set on the intervention course > or = 3 months in order to identify the information of outcome assessement and the sample size. Data collection forms were made according to the checking lists found in the CONSORT statement. Independent double data extractions were performed on all included trials. The statistical power of the effects size for each RCT study was assessed using sample size calculation equations. RESULTS: (1) A total of 207 RCTs were included, including 111 superiority trials and 96 non-inferiority trials. (2) Among the 111 superiority trials, fasting plasma glucose (FPG) and glycosylated hemoglobin HbA1c (HbA1c) outcome measure were reported in 9% and 12% of the RCTs respectively with the sample size > 150 in each trial. For the outcome of HbA1c, only 10% of the RCTs had more than 80% power. For FPG, 23% of the RCTs had more than 80% power. (3) In the 96 non-inferiority trials, the outcomes FPG and HbA1c were reported as 31% and 36% respectively. These RCTs had a samples size > 150. For HbA1c only 36% of the RCTs had more than 80% power. For FPG, only 27% of the studies had more than 80% power. CONCLUSIONS: The sample size for statistical analysis was distressingly low and most RCTs did not achieve 80% power. In order to obtain a sufficient statistic power, it is recommended that clinical trials should establish clear research objective and hypothesis first, and choose scientific and evidence-based study design and outcome measurements. At the same time, calculate required sample size to ensure a precise research conclusion. PMID- 22500410 TI - [Case analysis of adverse reaction induced by overdose of safflower injection]. PMID- 22500411 TI - [Mechanism and research progress of Chinese medicine induced ovarian cancer apoptosis]. PMID- 22500412 TI - [Progress of tongue figures correlated molecular mechanisms in Chinese medicine]. PMID- 22500413 TI - [The performance of agronomic traits in F1 crossing combinations derived from male sterile line of Platycodon grandiflorum]. AB - OBJECTIVE: To determine the possibility of heterosis utilization by male sterility in Platycodon grandiflorum. METHODS: The analysis of variance, heterosis over standard and correlation on 12 agronomic in 18 crossing combinations were carried out. RESULTS: Except the dry weight of upground part of plant, the length of main root and the diameter of middle part of the main root, all other agricultural traits were different significantly among the 18 F1 combinations. The diameter of middle part of the main root had the highest coefficient of variation and the ratio of fresh weight of main root and total root had the lowest coefficient of variation,which was 85.42% and 3.66%, respectively. For the traits related to the yield of root,average heterosis over standard in fresh main root and total root was 42.35% and 45.50%, respectively; For the traits related to the form of root, the diameter of up part and middle part of main root had a middle heterosis over standard, which was 12.38% and 29.97%, respectively. The shoot growth was significantly related to its root growth in combination (0.651). The number of nodes on main stem was significantly related to five out of six traits of root in hybrids. CONCLUSION: Variation of agricultural traits in crossing combination is rich, heterosis of traits in root is evident,and F1 hybrids with good yield and the forms could be selected from these combinations. The Platycodon grandiflorum of crossing combinations have reasonable morphological characteristics, and the number of nodes of main stem could be taken as the selected index. All show us that the heterosis by the male sterility could be utilized in the breeding of Platycodon grandiflorum. PMID- 22500414 TI - [Culture in vitro and plant regeneration of Panax japonicus]. AB - OBJECTIVE: To study the condition of culture in vitro and plant regeneration of Panax japonicus. METHODS: Embryos, stems and leaves of P. japonicus were used as explants, effects of different hormones for callus induction and plant regeneration were studied and optimized. RESULTS: The optimal way to obtain sterile explant for seeds was sterilized in 75% ethyl alcohol for 60 s then 0.1% HgCL2 for 12 min; Stems and leaves were sterilized in 75% ethyl alcohol for 15 s then 5% NaClO for 5 min. Used MS as basic medium, the optimal hormones combination for callus induction of embryos, stems and leaves were MS + 1.5 mg/L NAA + 1.5 mg/L 2, 4-D + 0.1 mg/L KT; MS + 1.5 mg/L NAA + 1.0 mg/L 2,4-D + 0.1 mg/L KT; MS + 1.5 mg/L NAA + 1.0 mg/L 2,4-D + 0.2 mg/L KT respectindy under the illumination. But under the darkness,the optimal callus induction hormones combination for embryos leaves were MS + 1.0 mg/L NAA + 1.5 mg/L 2,4-D +0.2 mg/L KT; 1.5 mg/L NAA + 1.5 mg/L 2,4-D + 0.1 mg/L KT; MS + 1.5 mg/L NAA + 1.0 mg/L 2,4 D + 0.1 mg/L KT respectivety. The optimal medium for germination was MS + 3.0 mg/L 6-BA + 1.0 mg/L GA3. The optimal medium for roots generation was MS + 1.0 mg/L 6-BA + 3.0 mg/L IBA. CONCLUSION: We establish the system of culture in vitro and plant regeneration for P. japonicus. PMID- 22500415 TI - [Study on effect of heavy metal cadmium ions on the ultramicrostructure damage of Pheretima aspergillum gastrointestinal epithelial cells]. AB - OBJECTIVE: To study the effect of cadmium ions of different concentrations on gastrointestinal epithelial cells structure of Pheretima aspegillum (PA). METHODS: PA were contaminated with cadmium ions of different concentrations,and the structure of the body skin was observed, under light microscope and transmission electron microscope. RESULTS: With the increasing of cadmium ions concentration, a large number of lysosomal hyperplasia could be seen in the PA intestinal epithelial cells, the Golgi complex distributed around, and some Golgi complex hyperplasiaed, extended to a large bubble, microvilli, cilia arranged in irregular, disordered. While in the group contaminated with the high concentration cadmium ions, such as 30 mg/kg, the microvilli of the PA intestinal epithelial cells contracted, necrotic ulcer lesions occurred in the ciliated cells. CONCLUSION: The ultrastructure damage extent of PA gastrointestinal epithelial cells is dependent on the amount of the heavy metal contamination. PA with lower concentration Cd contamination shows mainly lysosomal proliferation, indicating heavy metal accumulation in lysosomes to eliminate toxic substances as a responsible reaction, this kind of damage is reversible. However, PA with higher concentration Cd contamination shows mainly microvilli and mitochondrial damage, nuclear membrane disintegration, nucleoplasm spillover, leading to necrosis, irreversible damage, indicating heavy metal accumulation of PA is related to this trait of intestinal epithelial cells. PMID- 22500416 TI - [Determination of metal elements in Achyranthis bidentatae radix from various habitats]. AB - OBJECTIVE: To establish an atomic absorption spectrometry method for determination of the contents of metal elements in Achyranthis Bidentatae Radix and analyze 21 batches of samples from different areas. METHODS: Fe, Mn, Ca, Mg, K, Zn and Cu were detected by atomic absorption spectrometry with hydrogen flame detector, Pb, As and Cd were detected by graphite furnace atomic absorption, Hg was detected by cold atomic absorption. RESULTS: The heavy metal contents met the requirement of Chinese Pharmacopoeia. The contents of K, Mg, Cu and Mn in the samples of geo-authentic areas were higher,while the contents of Fe, Zn, Hg and Pb in the samples of non-authentic areas were higher. CONCLUSION: This method is sample, accurate, repeatable and could be used to evaluate the quality of Achyranthis Bidentatae Radix. PMID- 22500417 TI - [Determination of 6 kinds of pesticides residue in Dioscoreae rhizoma slices by GC-MS]. AB - OBJECTIVE: To determine the 6 residues including organophosphorus, organochlorinated and pyrethroid pesticides simultaneously in crude yam slices, yam slices stir-fried with bran and sulfur fumigation yam. METHODS: The compounds were ready for GC-MS analysis after being extracted with acetonitrile and purified. Determinations were performed with selected ion monitoring mode and external standard method was adopted in the quantificaticon. RESULTS: The contents of 6 kinds pesticides residue had good linear correlation with the peak area in the rang of 0.01-0.5 microg/mL. The average recoveries of 6 kinds pesticides residue were 87.5%-95.5%. The method detection limits ranged from 0.002-0.005 microg/g. Organochlorine and pyrethroid pesticides were detected in the three samples except the parathion residue. CONCLUSION: Stir-fried with bran and sulphur fumigation had nearly no effects on the pesticides residue in yam. The method is sensitive and accurate and can be used in determination of multiresidual pesticides residue in yam. PMID- 22500418 TI - [Study on quality standards of decoction pieces of Indian stringbush root with sweat]. AB - OBJECTIVE: To study quality standards of 10 batches of Indian of stringbush root decoction pieces with sweat processing and build up the quality standard. METHODS: 10 batches of indian stringbush root decoction pieces with sweat were investigated with TLC. Moisture content, total ash, acid-insoluble ash and extractum were explored. The content of daphnoretin was determined by HPLC. RESULTS: Indian stringbush root decoction pieces with sweat,the moisture content should not pass 14.5%, total ash should not pass 3.5%, acid-insoluble ash should not pass 1.0%, alcohol-soluble extractive should not lower than 9.0%, the content of daphnoretin should not lower than 0.2%. CONCLUSION: Quality control quantization evaluation system of Indian stringbush root decoction pieces with sweat is establishment initial. PMID- 22500419 TI - [HPLC fingerprint spectrum of xinjiang uyghur medicine Nigella glandulifera seed]. AB - OBJECTIVE: To establish the HPLC fingerprint spectrum of Nigella glandulifera seed identification. METHODS: The chromatographic system consisted of a Shim-pack ODS C18 column (150 mm x 4.6 mm, 5 microm) and a mobile phase of acetonitrile 0.1% formic acid in condition of gradient elution,The detection wavelength was 280 nm. The column temperature was 30 degrees C. RESULTS: Detected the HPLC fingerprint spectrum of 10 batches samples Nigella glandulifera seed from Xinjiang; Calibrated 18 characteristic peaks. The result was in accordance with the technical requirement of fingerprint spectrum. The similarity calculation software showed that the similarity was higher than 0. 95. CONCLUSION: The HPLC fingerprint spectrum of Nigella glandulifera seed can be used as an identification method. It may provide the basis for quality control of Nigella glandulifera seed. PMID- 22500420 TI - [Study on fingerprint of semen cassiae, ultramicro powder and powder particle]. AB - OBJECTIVE: To establish HPLC fingerprint of Semen Cassiae. METHODS: Analysis on a Phenomenex C18 (4.6 mm x 250 mm, 5 microm) column eluted with phases containing acetonitrile and 0.1% phosphoric acid in water in gradient mode. The flow rate was 0.8 mL/min and the detection wavelength was 280 nm. The temperature of column was 30 degrees C. Data of 12 batches of Semen Cassiae, ultramicro powder and powder particle from different sources were analysed by "similarity evaluation for chromatographic Fingerprint of Traditional Chinese Medicine" software, and the similarity of them was compared. RESULTS: Twenty-seven common peaks were identified in the chromatograms,and all the common peaks were separated effectively. Fingerprint of ultramicro powder and Semen Cassiae was basic similar, but fingerprint of powder particle and Semen Cassiae was obviously different. CONCLUSION: The method is precise, repeatabe and stable. It can be used to identity and evaluate the quality of Semen Cassiae, and provide important theoretical foundation for clinical applications of Semen Cassiae. PMID- 22500421 TI - [Study on the secondary metabolites from the marine sponge Phakellia fusca fungi PF18]. AB - OBJECTIVE: To study the secondary metabolites from the marine sponge Phakellia fusca epiphytic fungi. METHODS: The compounds were isolated by column chromatography over silica gel and purified by Sephadex LH-20 column chromatography and preparative TLC. The structures were elucidated by means of physiochemical properties and spectroscopic analyses. RESULTS: Four compounds were separated and identified as: cyclo-(L-Val-L-Pro) (1), cyclo-(L-Phe-L-Pro) (2), cyclo-(L-Tyr-L-Pro) (3), cyclo-(3-hydroxy-4-methyldecanoyl-Gly-L-Val-D-Leu-L Ala-L-Phe) (4). CONCLUSION: Compounds 1-4 are obtained from the marine sponge Phakellia fusca epiphytic fungi for the first time. PMID- 22500422 TI - [Study on the chemical constituents from Fructus Toosendan (III)]. AB - OBJECTIVE: To study the chemical constituents from Fructus Toosendan. METHODS: Isolation and identification were carried out by using various chromatography techniques and spectral methods. RESULTS: Ten compounds were isolated and identified as n-Hentriacontane (I), Octacosyl alcohol (II), Stearic acid (III), Linoleic acid (IV), Isovanillin (V), Vanillin (VI), Vanillic acid (VII), Ohchinal (VIII), Succinic acid (IX) and Homoeriodictyol (X). CONCLUSION: Compounds V, VII, IX, X are isolated from this genus and compounds I, II, III are obtained from this plant for the first time. PMID- 22500423 TI - [Study on the chemical constituents from the ethyl acetate extracts of Cremastra appendiculata]. AB - OBJECTIVE: To study the chemical constituents from the ethyl acetate extracts of Cremastra appendiculata. METHODS: The compounds from the ethyl acetate extracts were isolated by the silica gel column and Sephadex LH-20 column chromatography, their structures were elucidated by the spectral analysis and chemical evidence. RESULTS: Seven componds were separated and identified as fumaric acid (1), dimethylhexyl phthalate (2), L-pyroglutamic acid (3), 2-furoic acid (4), vanillic acid (5), p-coumaric acid (6), protocatechuic acid (7). CONCLUSIONS: Compounds 1 to 6 are obtained from this plant for the first time. PMID- 22500424 TI - [Study on the chemical composition of triterpenoid from the fruit of Buddleja lindleyana and their neuroprotective activitiy]. AB - OBJECTIVE: To study the chemical composition of triterpenoid from the fruit of Buddleja lindleyana. METHODS: The chemical components were isolated by chromatography. The structures were identified by spectral data. The neuroprotective activity of these compounds were evaluated by using MPP+ induced injury in PC12 cells. RESULTS: 3 compounds were separated and identified as oleanane, alpha-L-msnnopyranoside derive (1), 13, 28-epoxy-3beta,23-dihydroxy-11 oleanene (2), 3, 23, 28-trihydroxyolean-11,13 (18)-diene (3). Compounds 1-3 showed obviously neuroprotective activity. CONCLUSION: The data of compound (1) is reported for the first time. The neuroprotective activities of compounds 1, 2, 3 are reported for the first time. PMID- 22500425 TI - [Analysis of essential oil extracted from Lactuca sativa seeds growing in Xinjiang by GC-MS]. AB - OBJECTIVE: To analyze the components of essential oil from Lactuca sativa seeds growing in Xinjiang. METHODS: The components of essential oil from Lactuca sativa seeds were analyzed by gas chromatography-mass spectrometry (GC-MS). RESULTS: 62 components were identified from 71 separated peaks,amounting to total mass fraction 95.07%. The dominant compounds were n-Hexanol (36.31%), n-Hexanal (13.71%), trans-2-Octen-l-ol (8.09%) and 2-n-Pentylfuran (4.41%). CONCLUSION: The research provides a theoretical basis for the exploitation and use of Lactuca sativa seeds resource. PMID- 22500426 TI - [Determination of content changes of three diester-diterpenoid alkaloids in compatibility of radix aconiti laterlis preparata and Rhizoma pinelliae, Fructus trichosanthis, Bulbus fritillariae, Radix ampelopsis, Rhizoma bletillae by HPLC]. AB - OBJECTIVE: To analyze the three diester-alkaloids content in the decoctions before and after Radix aconiti lateralis preparata combined with Rhizoma pinelliae, Fructus trichosanthis, Bulbus fritillariae, Radix ampelopsis, Rhizoma bletillae, respectively. METHODS: HPLC analysis was performed on a Agilent Extend C18 column,eluted with a mobile phase consisted of acetonitrile/methanol - 35 mmol/L ammonium acetate and gradient elution,with a flow rate of 0.6 ml/min and the detection wavelength of 235 nm. RESULTS: The contents of three diester alkaloids in the co-decoctions of Radix aconiti laterlis preparata combined with Rhizoma pinelliae, Fructus trichosanthis, Bulbus fritillariae, Rhizoma bletillae were more than that of single Radix aconiti laterlis preparata decoction, expect the Bulbus fritillariae cirrhosae,Radix ampelopsis and Rhizoma pinelliae praeparatum. From the result,we can found that the content of three diester alkaloids in decoctions was correlated with the decoction pH. CONCLUSION: The pH of decoction is one of the most important factors to relate the three diester alkaloids content in the decoctions. PMID- 22500427 TI - [Study on fat-soluble components in different parts of miao ethnomedicine Pileostegia viburnoides by the herbal blitzkrieg extractor]. AB - OBJECTIVE: To study the fat-soluble components in different parts of Pileostegia viburnoides. METHODS: The fat-soluble components in different parts of Pileostegia viburnoides were extracted by Herbal Blitzkrieg Extractor (HBE), and its constituents were analyzed by GC-MS. RESULTS: 37 compounds from the stems, 14 compounds from the leaves were separated and identified. The ratios of identification of total compounds were 90. 63% and 81.61%, respectively. CONCLUSION: This result provides the scientific basis for ex-ploiting resources of Miao ethnomedicine Pileostegia viburnoides. PMID- 22500428 TI - [Analysis on the compositions of volatile oil of Alpinia henryi with GC-MS method]. AB - OBJECTIVE: To study the components of volatile oil of Alpinia henryi. METHODS: The volatile oil was extracted by steam distillation method,used gaseous phase mass spectrum combination method (GC-MS) to analyze the components of volatile oil. RESULTS: 58 kinds of components were isolated, among them 42 were identified and determined the relative content. CONCLUSION: This study provides a basis for the development and utilization of Alpinia henryi. PMID- 22500429 TI - Study on the interference of rat feed to pharmacokinetics of flavonoids. AB - OBJECTIVE: To investigate the interference of rat feed to pharmacokinetic of flavonoids. METHODS: Flavonoids in rat feed and plasma samples were separated by rapid resolution reversed-phase HPLC and characterized by LC-ESI-MS/MS analysis with an electrospray ionization source (ESI) and a triple quadrupole analyzer by fragmentation pattern. RESULTS: Five Citrus flavonoids (naringin, naringenin, quercetin, hesperidin and hesperetin) and two soybean isoflavonoids (daizin,daidzein) were identified in common formula rat feed. The presence of these flavonoids in plasma from rats receiving the feed was also confirmed. CONCLUSION: The results showed the flavonoids in animal food might interfere with pharmacological and pharmacokinetic study of foreign natural compounds. This paper could be taken as a reference to pharmacological and pharmacokinetic studies of all the related substances. PMID- 22500430 TI - [Pharmacokinetics and tissue distribution of Schisandra chinensis extract in mice]. AB - OBJECTIVE: To investigate the pharmacokinetics and tissue distribution of Schisandra chinensis in mice. METHODS: Schisandrin in mice plasma and tissues including heart, liver, spleen, lung and kidney was quantitatively determined by HPLC. RESULTS: The concentration-time curve of Schisandra chinensis extract was described by a single compartment model, Cmax was (2.17 +/- 0.27) mg/ mL, t(max) was (1.00 +/- 0.32) h, AUC0-->infinity, was (4.07 +/- 0.62) mg x h/mL. The sequence of distribution of schisandrin in mice body was as follows: liver > plasma > kidney > lung > heart > spleen. CONCLUSION: The distribution of extract in the body is abroad. Liver has relative high concentration of schisandrin, which is beneficial to the treatment of hepatic disease. PMID- 22500431 TI - [Discussion of protective mechanism of Lyceum barbarum polysaccharides on ovarian tissue in female senile rats]. AB - OBJECTIVE: To study the protective mechanism of Lyceum barbarum polysaccharides (LBP) on ovarian tissue in female senile rat. METHODS: Senile rats of 14 months old were divided randomly into model group, positive drug group, LBP low dosage group, LBP medium dosage group and LBP high dosage group. SD female rats of 4 months old formed a youth group. 30 days after administration,rat blood was taken, radioimmunoassay was employed to determine the levels of estrone and progesterone and enzyme immunoassay was used to determine the levels of IGF-I. Then ovarian tissue was taken to determine the levels of IGFBP-1 and IGFR. RESULTS: Daily oral LBP(60,40,20 mg/kg body weight) for 30 days significantly recovered uterine atrophy and restored serum IGF-I level, estrone and progesterone levels that were decreased in elder rats, reduced the expressing of IGFBP-1 in ovarian tissue that were increased in elder rats. CONCLUSION: LBP has a notable protection on rat ovarian system. PMID- 22500432 TI - [Mechanism of Dahuang Zhechong pill against atherosclerosis induced by balloon angioplasty in rabbits]. AB - OBJECTIVE: To study the mechanism of Dahuang Zhechong pill (DHZCP) against atherosclerosis induced by balloon angioplasty in rabbits. METHODS: Atherosclerosis model was established by the combination of balloon angioplasty induced endothelial injury and high cholesterol feeding in rabbit. Male New Zealand rabbits were divided into six groups randomly: normal control, sham, model, positive control and two doses of DHZCP-treated groups. Rabbits in DHZCP treated groups were intragastrically administered 0.9 and 1.8 g/kg DHZCP for 60 days respectively,and rabbits in positive control group were given 0.5 g/kg Danshen. MDA, NO levels and SOD activity in serum, and MPO activity in the vascular wall were determined with spectrophotometry. Expressions of proliferating cell nuclear antigen (PCNA) and BCL-2 in the vascular wall were detected by SP immuohistochemical technique. RESULTS: Compared with the model group, DHZCP significantly reduced serum MDA level and MPO activity in the vascular wall, increased serum NO level and SOD activity,and inhibited PCNA and BCL-2 expressions in the vascular wall. CONCLUSION: DHZCP inhibits the formation and development of atherosclerosis through anti-oxidative action, protecting endothelium from injury,inhibiting proliferation and promoting apoptosis of vascular smooth muscle cells. PMID- 22500433 TI - [Purification of salidroside in Rhodiola crenulata with macroporous resin]. AB - OBJECTIVE: To select the appropriate macroporous resin and optimize the process parameters for purifying salidroside in Rhodiola crenulata. METHODS: The static adsorption and desorption capacities of salidroside on 21 macroporous resins were investigated. Several important parameters influencing purification efficiency including sample concentration, sample volume, adsorption rate, type and dosage of eluent were optimized. RESULTS: LSA-30 showed good separation efficiency with adsorption and desorption rate of 63.8% and 82.39%, respectively. The optimum conditions for purifying process were as follows: the sample concentration was that 1 mL was equal to 0.4 g raw material. The ratio of sample volume (mL) to resin weight (g) was 4:1. The adsorption rate was 1-2 mL/min. 30% ethanol with 10 times of the bed volume was adopted as the eluent. Under the optimal conditions,the purity and yield rate of the obtained salidroside was 10.7% and 70.6%, respectively. CONCLUSION: The optimized process provides guidance for the industrial production of salidroside. PMID- 22500434 TI - [Study on the extraction technology of total flavonoids from Selaginella uncinata]. AB - OBJECTIVE: To optimize the extraction technology of total flavonoids and improve the extraction ratio of total flavonoids from Selaginella uncinata. METHODS: Using the content of flavonoids as the index determined by UV spectrophotometry, chose single factor experiment to investigate the total flavonoids content influenced by four factor ethanol concentration, extracting time, extraction times and solvent content on the influence of extraction efficiency. And on the basis, L9 (3(4)) orthogonal experiment was carried out. RESULTS: The ethanol reflux extraction conditions were as tollows: extracted in 60% ethanol (solid liquid rate at 1: 35) for 3 times and heated for 1.5 hours per time. CONCLUSION: The optimum extraction by the orthogonal design method is rational and feasible, provides experimental basis for improving the content of the total flavonoids and further scientific theoretical basis for industrial production of the total flavonoids from Selaginella uncinata. PMID- 22500435 TI - [Effect on elimination of pyrogen and effectual components of Panax notoginseng saponins by ultrafiltration membranes of different cut-off molecular weight and different materials]. AB - OBJECTIVE: To study the elimination effect of bacterial endotoxins and the transmittance of Panax notoginseng saponins by ultrafiltration membranes of different cut-off molecular weight and different materials. METHODS: The kinetic turbidimetric method was used to determine the content of bacterial endotoxins in Panax notoginseng saponins solution before and after using the ultrafiltration. The change of the contents of active components was examined by HPLC,using notoginsennoside R1, ginsennoside Rg1, ginsennoside Rb1 and ginsennoside Rd as the mark components. RESULTS: The removal rate of bacterial endotoxin fell along with the increasing of membrane aperture. The removal rate was 20. 69% by ultrafiltration membranes of 100 KDa with polysulfone material,less than those of other ultrafiltration membranes with polysulfone material. But the removal rate of bacterial endotoxin by E membranes of blend materials was higher than those of other ultrafiltration membranes with polysulfone material. The contents of active components filtered by E membranes of blend materials was more than that of ultrafiltration membranes of 100 KDa with polysulfone material. CONCLUSION: The applicability of ultrafiltration membranes of large cut-off molecular weight and blend materials of effectual component in Panax notoginseng saponins and elimination of pyrogen is good. PMID- 22500436 TI - [Quadratic regression-orthogonal design optimization ethanol extraction craft of baicalin]. AB - OBJECTIVE: To optimize the extraction process of baicalin using the quadratic regression-orthogonal design. METHODS: The influential factors were ethanol doses, ethanol concentration and extract time. Used the high level statistical method to design experiment parameter and forecast analysis results. RESULTS: The optimization conditions of extraction was 64% ethanol, 115 min for extract time,volume of use 11. 6 times and it's extraction rate was 85.21%. CONCLUSION: It shows that the optimum model is simple,highly precision and highly predictive. PMID- 22500437 TI - [The purification and characterization of polysaccharides isolated from Ginkgo biloba and their in vitro antioxidant activities]. AB - OBJECTIVE: To isolate and identify the polysaccharides of Ginkgo biloba and determine their antioxidant activities in vitro. METHODS: Used hot extraction and alcohol precipitation to get the crude polysaccharides, removed protein with Sevag method, further purify by column chromatography packed with DEAE-52 and DEAE-Sepharose Fast Flow. The homogeneity and molecular weights were evaluated, configuration and monosaccharide composition were measured by IR and high performance ion chromatography analysis, the scavenging activities of GBPB-S on hydroxyl radical and DPPH were measured. RESULTS: The molecular weights of GBPB-W and GBPB-S were 26 300 and 19 100, and both of them were composed of rhamnose, arabinose, galactose, glucose and mannose with the ratios of (3.48: 8.47:3.73: 1.76: 1) and (5.34: 5.37: 5.27: 1:1.68). GBPB-S had certain scavenging effect on hydroxyl radical and DPPH. CONCLUSION: The polysaccharide isolated from Ginkgo biloba has a direct antioxidant activities in vitro. PMID- 22500438 TI - [Simultaneous determination of nine preservatives and sweeteners in yellow wine and wine by ultrafast liquid chromatography-tandem mass spectrometry]. AB - A sensitive and selective analytical method based on ultrafast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) was developed for the simultaneous determination of nine preservatives and sweeteners in yellow wine and wine. After the sample was diluted by pure water, the UFLC separation was performed on a Shim-pack XR-ODS II column (100 mm x 2.0 mm, 2.2 microm) with a linear gradient elution program of acetonitrile-ammonium acetate (AmAc, 2.5 mmol/L)-trifluoroacetic acid (TFA, 0.01%, v/v) aqueous solution as the mobile phase. Electrospray ionization was applied and operated in the negative multiple reaction monitoring (MRM) mode. The results showed that the limits of detection (LODs, S/N > 3) for the nine analytes were in the range of 0.03 - 15.0 microg/L, and the limits of quantitation (LOQs, S/N > 10) were in the range of 0.1 - 50.0 microg/L. The calibration curves showed good linearity for the nine analytes in their detection ranges, and the correlation coefficients (r2) were larger than 0.998. The recoveries were between 96.2% and 100.5% with the relative standard deviations (RSDs) of 0.6% - 5.4% for yellow wine, and between 96.0% and 104.0% with the RSDs of 0.7% - 4.8% for wine. Additionally, the mass spectral characterizations of the nine food additives were studied and the fragmentation pathways were speculated. The method is sensitive, reproducible and adaptable to the simultaneous rapid determination of the nine food additives in different yellow wine and wine samples. PMID- 22500439 TI - [Determination of aflatoxins in cashew by high performance liquid chromatography tandem mass spectrometry]. AB - A method for the determination of four aflatoxins in cashew using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was developed. The sample was extracted with methanol-water (8: 2, v/v) solution, followed by a cleanup procedure with Florisil column. The target compounds were eluted using 5 mL acetone-water-formic acid (96: 3.5:0.5, v/v/v) solution. The eluate was dried under N2, then dissolved in 1 mL methanol. Four aflatoxins were separated in MG C18 column (100 mm x 3.0 mm, 3 microm) adopting a gradient program within 15 min. A triple quadrupole mass spectrometry equipped with an electrospray ionization source operated in the positive ion mode was used to detect the aflatoxins. The good correlation coefficients (r2 > 0.997) of the four aflatoxins were obtained within their respective linear ranges. The limits of detection (S/N = 3) were between 0.009 microg/kg and 0.04 microg/kg, and the limits of quantification (S/N = 10) were between 0.03 microg/kg and 0.12 microg/kg. The recoveries were in a range of 63.0% -78.5% with the relative standard deviations (RSDs) varied from 2.8% to 9.1%. The validation results meet the requirements of trace assay. Matrix effects were estimated and the signal suppression/enhancement ranged from 88.8% to 99.4%. The results indicate that the developed method is simple, fast, accurate, and can be applied for the determination of fours aflatoxins in cashew. PMID- 22500440 TI - [Determination of alkylphenol and alkylphenolpolyethoxylates in brine by solid phase extraction and high performance liquid chromatography-mass spectrometry]. AB - A simple method based on solid phase extraction (SPE) coupled with high performance liquid chromatography-mass spectrometry (HPLC-MS) was developed for the determination of octylphenol (OP), nonylphenol (NP), octylphenol ethoxylates (OPEOs) and nonylphenol ethoxylates (NPEOs) in brine. The extraction and cleanup of brine samples were performed on C18 solid-phase extraction cartridges. The complete separation among OP, NP, OPEOs and NPEOs was achieved on a Hypersil GOLD analytical column with methanol-water as the mobile phase. The determination was achieved using HPLC-MS with electrospray ionization (ESI) in selected ion monitoring mode. The results showed that the average recoveries of target compounds were 59.6% - 104.4% and the corresponding relative standard deviations (RSDs, n = 3) were 1.0% - 13.5%. The instrumental limits of detection for the compounds were 0.08 - 3 microg/L. This method was applied to the analysis of the samples of seawater near Dalian coast. The results showed that both NP and NPEOs were detected in all samples and their concentrations in seaport and oil port were much higher than those in other sampling sites. PMID- 22500441 TI - [Determination of three brominated flame retardants in human serum using solid phase extraction coupled with ultra-performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry]. AB - A solid-phase extraction (SPE) method for the simultaneous extraction of hexabromocyclododecanes (HBCDs)/tetrabromobisphenol A (TBBPA) and polybrominated diphenyl ethers (PBDEs) in human serum was developed. The extracts of HBCDs/TBBPA and PBDEs were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and gas chromatography-negative chemical ionization/mass spectrometry (GC-NCI/MS), respectively. The samples with the spiked internal standards, 13C(12)-HBCD, 13C(12)-TBBPA, 3, 3', 4, 4' tetrabromodiphenyl ether (BDE-77) and 13C(12)-decabromodiphenyl ether (BDE-209), were extracted using the mixture of methyl tert-butyl ether (MTBE) and hexane (1:1, v/v). Then the co-extracted lipid was removed by sulfuric acid treatment. The newly obtained extract was purified using SPE with an LC-Si column and two fractions of HBCDs/TBBPA and PBDEs were finally got. The determination of HBCDs/TBBPA was performed on a 50 mm BEH C18 column in the multi-reaction monitoring (MRM) mode and the determination of PBDEs was on a 15 m capillary column in the selected ion-monitoring (SIM) mode. The limits of detection (LODs, S/N = 3) ranged from 1.81 to 42.16 pg/g. The average recoveries were from 80.3% to 108.8% at two spiked levels of 0.5 and 5 ng/g for HBCDs, 0.05 and 0.5 ng/g for TBBPA and BDE-209 with the relative standard deviations between 1.02% and 11.42% (n = 5). The developed method has been successfully applied to the determination of the 12 analytes in 42 pooled human serum samples. The levels of TBBPA in the samples ranged from < LOD to 6.58 ng/g, that of alpha-HBCD diastereoisomer ranged from < LOD to 7.22 ng/g, which was the most abundant isomer comparing with beta- and gamma-HBCD. The total PBDEs found ranged from 2.90 to 89.69 ng/g. This method was validated to be accurate and sensitive for the analysis of HBCDs, TBBPA and PBDEs in serum samples. PMID- 22500442 TI - [Determination of polycyclic aromatic hydrocarbons in thermoplastic elastomer by gas chromatography-mass spectrometry]. AB - A simple and accurate method for the determination of 16 polycyclic aromatic hydrocarbons (PAHs) in thermoplastic elastomer by gas chromatography-mass spectrometry (GC-MS) has been developed. The effects of various operational parameters (e. g. sample pretreatment, extraction solvent, extraction method, extraction temperature, extraction time, etc) on the extraction efficiency were carefully investigated by analyzing different kinds of positive PAHs thermoplastic elastomer samples made by the manufacturer. The samples were extracted ultrasonically with toluene, concentrated to about 1 mL and then redissolved by cyclohexane. After being purified by dimethyl sulfoxide liquid liquid extraction, 16 PAHs in the sample were analyzed by GC-MS and quantified by internal standard method. Different kinds of thermoplastic elastomer materials and products were analyzed by this method with the recoveries ranged from 70% to 117% and the relative standard derivations between 0.2% and 10.8%. The method is acceptable for the determination of PAHs in thermoplastic elastomer materials and products. PMID- 22500443 TI - [Determination of residual acrylate monomers in adhesives by headspace gas chromatography-mass spectrometry]. AB - A method was developed for the determination of methyl acrylate, ethyl acrylate, butyl acrylate, methyl methacrylate, ethyl methacrylate and butyl methacrylate in adhesives by headspace gas chromatography-mass spectrometry (HS-GC-MS). The samples were treated at 100 degrees C for 30 min, then separated on a DB-WAX column (30 m x 0.25 mm x 0.25 microm) and determined by MS under selected ion monitoring mode and quantified by internal standard method. The established method showed good separation with the limits of detection (LODs, S/N = 3) of 0.069 - 0.096 mg/kg and the limits of quantification (LOQs, S/N = 10) of 0.23 - 0.32 mg/kg. The recoveries for acrylate monomers were in the range from 96.0% to 104.6% with the relative standard deviations less than 7.2%. The method is simple, accurate, rapid and highly sensitive. It can be applied to analyze the residual acrylates and methyl acrylates in adhesives. PMID- 22500444 TI - [Analysis of aliphatic aldehydes and ketones in water-based adhesive by direct derivatization-ionic liquid gathering coupled with high performance liquid chromatography]. AB - A novel method was developed for trace analysis of aliphatic aldehydes and ketones in water-based adhesive based on 2,4-dinitrophenylhydrazine (DNPH) direct derivatization-1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM] PF6) preconcentration coupled with high performance liquid chromatography (HPLC). The dispersive water-based adhesive emulsion directly reacted with 80 mg/L DNPH solution containing 0.44 mol/L phosphoric acid at 40 degrees C for 18 min. After centrifuging, 0.5 mL [BMIM] PF6 was added to extract the derivatives at 30 degrees C. The ionic liquid (IL) phase was filtered and then analyzed by HPLC. The separation was achieved by using a Dionex Acclaim Explosive E2 column (250 mm x 4.6 mm, 5 microm) under the gradient elution with acetonitrile and water as mobile phases at the flow rate of 1.2 mL/min. The column temperature was 35 degrees C, and the detection wavelength was 365 nm. The results showed that the limits of detection (LODs) were 0.022 -0.221 mg/kg, and the limits of quantification (LOQs) were 0.073 - 0.738 mg/kg. The relative standard deviations (RSDs) were in the range of 3.5% - 7.3%, and the recoveries were 84.0% - 102.5% for 8 aliphatic aldehydes and ketones. Compared with solvent extraction, the established method has the advantages of lower LOD and LOQ, and is more stable and precise. This method is practical for the determination of aliphatic aldehydes and ketones in water-based adhesives. PMID- 22500445 TI - [Effects of trace water in mobile phase on enantioseparation of alpha-propionate derivatives in normal phase chromatography]. AB - Trace water was added as a modifier of the mobile phase to achieve enantioseparation of alpha-propionate pollutants and their degradation products in normal phase high performance liquid chromatography (HPLC). A Chiralcel OJ-H column (25 cm x 4.6 mm, 5 microm) was used with hexane-isopropanol-acetic acid as the mobile phase. The flow rate of the mobile phase was 0.8 mL/min. The results indicated that the addition of trace water differentially improved enantiomeric resolution of chiral alpha-propionate compounds, depending on the amount of water added and chemical structure of the analytes. It is primarily ascribed to the fact that trace water bound to chiral stationary phase and competed with the analytes. Moreover, trace water affected pH values of the mobile phase and the dissociation of free acids, thereby induced the variation in resolution efficiency. Additionally, the free acids were more sensitive to trace water than their neutral analogues (i. e., amides and carboxylic esters), in terms of the different roles of enthalpy and entropy terms. PMID- 22500446 TI - [A method for the analysis of overlapped peaks in the high performance liquid chromatogram based on spectrum analysis]. AB - A method was established to analyse the overlapped chromatographic peaks based on the chromatographic-spectra data detected by the diode-array ultraviolet detector. In the method, the three-dimensional data were de-noised and normalized firstly; secondly the differences and clustering analysis of the spectra at different time points were calculated; then the purity of the whole chromatographic peak were analysed and the region were sought out in which the spectra of different time points were stable. The feature spectra were extracted from the spectrum-stable region as the basic foundation. The nonnegative least square method was chosen to separate the overlapped peaks and get the flow curve which was based on the feature spectrum. The three-dimensional divided chromatographic-spectrum peak could be gained by the matrix operations of the feature spectra with the flow curve. The results displayed that this method could separate the overlapped peaks. PMID- 22500447 TI - [Determination of seven phenoxyacid herbicides in environmental water by high performance liquid chromatography coupled with three phase hollow fiber liquid phase microextraction]. AB - A novel method for the simultaneous determination of seven phenoxyacid herbicides such as dicamba, fluroxypyr, 4-chlorophenoxyacetic acid (4-CPA), 2-methyl-4 chlorophenoxyacetic acid (MCPA), 2, 4-dichlorophenoxyacetic acid (2,4-D), 2,4 dichlorophenoxybutyric acid (2,4-DB) and 4-(2-methyl-4-chlorophenoxy) butyric acid (MCPB) in environmental water by three phase hollow fiber liquid phase microextraction (HF-LPME) coupled with high performance liquid chromatography (HPLC) was developed. In order to optimize the experimental conditions, the orthogonal test has been used. The effects of extraction solvent, pH of the donor phase and acceptor phase, extraction time, stirring speed and salt concentration on the detection were investigated. The optimal experimental conditions were as follows: octanol as organic solvent, pH 3 of donor phase, pH 12 of acceptor phase, extraction time of 30 min, stirring speed of 400 r/min. The results showed that the proposed method provided a wide linear range for 7 phenoxyacid herbicides with correlation coefficients of 0.995 3 - 0.998 8. The detection limits ranged from 0.2 to 1.0 microg/L. The enrichment factors were in the range of 76.7 - 121. The recoveries were in the range of 68% - 104% and the relative standard deviations (RSDs) were less than 8.1% for the environmental water samples. The method has the advantages of sensitivity, simplicity, fastness and the use of very small amounts of organic solvent. The method can meet the requirements of the determination of trace phenoxyacid herbicides in the environmental water samples, and the study provided a useful method for the analysis of trace substances in water samples. PMID- 22500448 TI - [Rapid determination of propranolol enantiomers in rat plasma by column-switching high performance liquid chromatography]. AB - A high performance liquid chromatographic (HPLC) method with column-switching was developed and validated for rapid determination of two propranolol enantiomers in rat plasma. The column of restricted-access media was used as a pre-treatment column and a Chiralcel OD-RH was used as analytical column. The plasma samples were injected directly into the pretreatment column to remove plasma protein and endogenous constituents as well as to retent the propranolol enantiomers in the column using the mobile phase of borate buffer (pH 8.5)-methanol (95:5, v/v) at the flow rate of 1.0 mL/min. Then the propranolol enantiomers were transferred to the Chiralcel OD-RH column using the mobile phase of isopropanol-ethanol-0.2 mmol/L borate buffer (pH 8.5) (30: 30: 40, v/v/v) at a flow rate of 0.8 mL/min by column-switching technology. The column-switching time was 3.0 min, the used wavelength was 293 nm and the column temperature was set at 25 degrees C. The calibration curve showed excellent linear relationship (r = 0.999 5) in the concentration range from 25 mg/L to 500 mg/L for propranolol enantiomers in plasma. The intra-day and inter-day assay precisions and accuracies were well and the relative standard deviations (RSDs) were less than 5%. The average recoveries (n = 6) of the two enantiomers at 3 spiked levels were from 97.89% to 101.56%. All the values of the method validation were within the generally accepted criteria for biological sample analysis. The results show that the method is convenient, quick, sensitive and accurate. The method was successfully applied in the determination of propranolol enantiomers in rat blood pharmacokinetics study. PMID- 22500449 TI - [Stability evaluation of chemical compositions of Rhizoma gastrodiae with 60Co gamma irradiation by high performance liquid chromatography]. AB - The main chromatographic fingerprint peaks of Rhizoma gastrodiae were established for evaluating the stability of chemical compositions of Rhizoma gastrodiae with 60Co-gamma irradiation to control the dosage of 60Co-gamma irradiation sterilization by high performance liquid chromatography (HPLC). Eight Rhizoma gastrodiae samples were analyzed. The chromatographic fingerprints of Rhizoma gastrodiae were constructed with 14 common fingerprint peaks, and its 10 main peaks were identified using the similarity evaluation system of chromatographic fingerprints of traditional Chinese medicine (version 2004 A) recommended by State Food and Drug Administration of China. The relative standard deviations of the peak areas of the 10 main peaks were used to evaluate the stability of corresponding chemical compositions of Rhizoma gastrodiae with 60Co-gamma irradiation. The results showed that the compositions of 3 of the 10 main peaks were influenced and a good relationship was obtained between the influence and 60Co-gamma irradiation doses for the eight Rhizoma gastrodiae samples. Some chemical components of Rhizoma gastrodiae weren't steady after 60Co-gamma irradiation, so a low dosage should be selected for 60Co-gamma irradiation sterilization. PMID- 22500450 TI - [An embedded peak recognition algorithm design for chromatography data in portable gas chromatographic instrument]. AB - The evaluation and validation of an embedded peak recognition algorithm design for chromatography data analysis are presented. This portable gas chromatographic (GC) system can easily generate the measurement results directly without computer (PC) connecting in the field. In this research project, we demonstrated the sequential mapping as the peak recognition method to distinguish each part of the chromatographic peak. The new recognition algorithm not only reduces the dependence on the slope threshold, but also improves the relativity and accuracy of the data analysis process. The practice showed that the embedded analysis system can detect all the components even in the complex cases. Its output result was proven to be comparable to the Chemstation software data processing result. This portable GC design meets the analysis demand in the field and improves the convenience for its quick time response. PMID- 22500451 TI - [Preparation of chiral monolithic column with covalently bonded cellulose and their application to rapid enantioseparation]. AB - A chiral monolithic capillary column for rapid enantioseparation was prepared by covalently bonding of cellulose tris(4-methylbenzoate) (CTMB) on N acryloxysuccinimide-based monolith. The preparation and derivatization conditions of the monolithic column were optimized. The successful grafting of CTMB was confirmed on the characterizations of the infrared spectrum and the cathodic electroosmotic flow (EOF). The effects of acetic acid concentration and methanol content on the enantioseparation were studied. The solvent resistance, reproducibility and stability of the monolithic column have also been investigated. The rapid enantioseparation of the five solutes (phenylalanine, tyrosine, tryptophan, propranolol and phenylethanol) with resolution (R(s)) values up to 1.31 was achieved within 1.2 min on the prepared chiral capillary monolithic column by capillary electrochromatography. PMID- 22500452 TI - [Determination of baclofen using micellar electrokinetic chromatography with laser induced fluorescence detection]. AB - A novel micellar electrokinetic chromatographic method with laser induced fluorescence detection after derivatization with 4-chloro-7-nitrobenzo-2-oxa-1,3 diazole (NBD-Cl) was developed for the determination of muscle relaxant drug baclofen (BAL). After optimization, baseline separation of the derivatives of BAL and gabapentin (internal standard) was obtained within 7 min in a running buffer (pH 9.75) composed of 15 mmol/L sodium borate, 20 mmol/L sodium dodecyl sulfate and 10% (v/v) acetonitrile. The separation voltage was 17.5 kV. The column temperature was 25 degrees C. The samples were injected by a pressure of 3.45 kPa (0.5 psi) for 3 s. The method has a linear range of 0.025 - 25 mg/L for BAL with the correlation coefficient of 0.999 9. The limit of detection (LOD, S/N = 3) and the limit of quantification (LOQ, S/N = 10) were 0.90 microg/L and 6.25 microg/L, respectively. The developed method was used for the analysis of BAL pharmaceutical preparation and urine samples spiked with BAL standard. The ranges of recovery were 101.6% - 107.9% for BAL preparation and 107.0% - 109.6% for urine samples. This method can be applied to the quality assessment of baclofen drug products, and provide supplementary means for the drug metabolism research of baclofen. PMID- 22500453 TI - [Determination of phthalate plasticizers in foods by high performance liquid chromatography with gel permeation chromatographic clean-up]. AB - A method of gel permeation chromatography-high performance liquid chromatography (GPC-HPLC) was established for the simultaneous determination of 5 main phthalate plasticizers in foods (edible oil, instant noodles, fried pastries, Saqima, etc.). The samples were extracted with petroleum ether in an ultrasonator, purified by a GPC column, and analyzed by HPLC. The chromatographic separation was achieved on a Labtech-C18 column (250 mm x 4.6 mm, 5 microm) using acetonitrile and water mixture as the mobile phases in a gradient elution mode. The developed method exhibited a linear correlation coefficient of more than 0.997 and the detection limits of 3.25 - 13.4 microg/L. The spike recoveries were between 70.4% and 113.6% with the relative standard deviations (RSDs, n = 3) of 0.3% - 5.8% at the spiked level of 50 mg/L. This method is simple, rapid and practical, and can be used for the simultaneous determination of PAEs in grease food samples. PMID- 22500454 TI - [Determination of chlorfluazuron residue in foods by high performance liquid chromatography]. AB - A method for the determination of chlorfluazuron residue in foods by high performance liquid chromatography (HPLC) was developed. The samples were extracted with hexane or acetonitrile. After cleaned up with Florisil-solid phase extraction (SPE), the samples were analyzed by the separation on a C18 chromatographic column with an acetonitrile and water (85 : 15, v/v) mixed solution as the mobile phase and the determination with an ultraviolet detector at 260 nm. The linear range was 0.05 - 2.0 mg/L, the correlation coefficient was 0.999 8 and the limit of quantification (S/N = 10) was 0.05 mg/kg. The recoveries were 82.1% - 102.5% with the relative standard deviations (n = 10) of 3.00% - 6.25% at the three different spiked levels of 0.05, 0.1 and 1 mg/kg. The method is easy, fast, accurate and consuming less sample and organic solvents. It can be applied in the determination of chlorfluazuron in foods. PMID- 22500455 TI - [Separation and purification of flavones from Nelumbo nucifera Gaertn. by silica gel chromatography and high-speed counter-current chromatography]. AB - Three flavones were isolated and purified from Nelumbo nucifera Gaertn. by the combination of silica gel chromatography and high-speed counter-current chromatography (HSCCC). The crude extract of N. nucifera was separated by silica gel chromatography and the fraction containing flavones was obtained. Then, the fraction was separated by HSCCC with two phase solvent systems composed of ethyl acetate-ethanol-water-acetic acid (4: 1 : 5:0.025, v/v/v/v). The upper phase was as the stationary phase and the lower phase as the mobile phase. Under the conditions of a flow rate of 2.0 mL/min, while the apparatus rotated at 800 r/min and the detection wavelength was at 254 nm, 6.1 mg of quercetin-3-O-beta-D glucuronide, 14.8 mg of myricetin-3-O-beta-D-glucopyranoside and 20. 2 mg of astragalin were obtained from 150 mg of the crude sample in one step. The purities determined by high performance liquid chromatography (HPLC) were 97.0%, 95.4% and 96.3%, respectively. The structures of the target compounds were identified by electrospray ionisation mass spectrometry (ESI-MS), 1H-nuclear magnetic resonance (1H-NMR) and 13C-nuclear magnetic resonance (13C-NMR). This method that has practical value not only saves solvent but also is convenient. It is effective in the separation of flavones from N. nucifera, and provides theoretical foundation for the further development and use of N. nucifera resources. PMID- 22500456 TI - [Analysis of prognostic factors of primary mucosal melanoma in nasal and oral cavity]. AB - OBJECTIVE: Primary mucosal melanoma of nasal and oral cavity is a rare tumor with a poor prognosis. This study aims to summarize the clinical features and survival status and then to evaluate the prognostic factors. METHOD: Clinical data of 66 patients with mucosal melanoma in nasal and oral cavity treated from Jan. 1980 to Jan. 2005, were retrospectively reviewed. All patients received the surgery. The following parameters: gender, age, primary location, tumor size, presence of ulcer, presence of pigment aggravation, lymph node metastasis, treatment mode and initially treatment outcome were investigated to evaluate their potential impact on survival. Kaplan-Meier method and Log-rank test were used for survival analysis. Cox proportional hazards regression was used for multivariate analysis. RESULT: The primary locations were nasal cavity (34 cases), oral cavity (23 cases) and paranasal sinuses (9 cases). All patients received surgery. Thirty seven patients received post-operative adjuvant treatments. Of which, 12 received adjuvant chemotherapy. 8 received adjuvant immunotherapy, 5 received adjuvant chemotherapy and immunotherapy, 8 received adjuvant radiotherapy and 4 received adjuvant radiotherapy and chemotherapy. Local recurrence, lymph node metastasis or distant metastasis appeared in 15 patients at 6 months after the primary treatment. The distant metastasis rate was 15.2% (10/66). The average survival time was 77.9 months, the median survival time was 33.7 months. The 3-year and 5 year overall survival rates were 41.4% and 31.1% respectively. Multivariate analysis showed that tumor size, lymph node metastasis and initially treatment outcome were significant prognostic factors for overall survival. CONCLUSION: The prognosis of mucosal melanoma in nasal and oral cavity is poor. Tumor size, lymph node metastasis, initially treatment outcome are independent prognostic factors for overall survival. The effect of post-operative adjuvant treatments is not clear, and further studies are needed. PMID- 22500457 TI - [Role of TGF-beta, IL-10 and IL-17 in allergic rhinitis patients with specific immunotherapy]. AB - OBJECTIVE: To detect the level of TGF-beta, IL-10 and IL-17 in the allergic rhinitis(AR) patients pre- and post-specific immunotherapy (SIT). METHOD: The level of TGF-beta, IL-10 and IL-17 in serum of 48 AR patients were detected by enzyme-linked immunosorbent assay before SIT. and the nasal symptom score (NSS) was evaluated in the first and second year after SIT. At the same time. 35 healthy persons were made as normal. RESULT: (1) The level of TGF-beta and IL-10 in serum of AR patients were lower than that of normal group (P < 0.05). The level of TGF-beta and IL-10 in AR patients taken SIT for two years was lower than that of patients with one year SIT (P < 0.05), but it was higher than that of patients pre-immunotherapy (P < 0.05). However, The level of TGF-beta and IL-10 in the group that taken SIT for two years was still lower than that of normal group (P < 0.05). (2) The level of IL-17 in serum of AR patients pre- immunotherapy was higher than that of normal group (P < 0.05). The level of IL-17 continuously declined after taking SIT, However it was higher than that of normal group two years later (P < 0.05). (3) In AR patients pre-immunotherapy and post- immunotherapy for 2 years, the level of IL-10 and TGF-beta showed negative correlation with NSS respectively, the level of IL-17 was positive related to NSS respectively (P < 0.05). But the level of IL-10, TGF-beta and IL-17 showed no correlation with NSS respectively (P > 0.05) when SIT was taken for one year. CONCLUSION: IL-10 and TGF-beta were fluctuated in AR patients taking SIT, which raised first and then dropped. but the level of IL-10 and TGF-beta was higher than that of pre- immunotherapy. However, the level of IL-17 continuously declined in the whole process. It showed that the level change of IL-10, TGF-beta and IL-17 correlate with patients' symptom only two years after SIT,so the level change of IL-10, TGF-beta and IL-17 can be used as an index for evaluating the treatment effectiveness of SIT at that time. PMID- 22500458 TI - [Efficacy and compliance of specific immunotherapy in allergic rhinitis]. AB - OBJECTIVE: To evaluate the efficacy, safety and compliance of specific immunotherapy in allergic rhinitis. METHOD: Two hundred and eighty cases with allergic rhinitis were undertaken immunotherapy, and then were observed its symptoms, signs and treatment by graded score. RESULT: Total effective rate was 86.8%, 70.4%, 62.5% at 16 week, 6 months and 1 year after treatment. Of 280 patients treated, 74 patients stopped treatment after one year, compliance rate was 73.6%. CONCLUSION: Specific immunotherapy is a safe and effective treatment methods for allergic rhinitis and worthy of attention and promotion, while strengthening the health education is needed to improve treatment compliance of patients. PMID- 22500459 TI - [Research on misdiagnosis of space occupying lesions in unilateral nasal sinus]. AB - OBJECTIVE: By nearly 3-year retrospective analysis of cases with space-occupying lesions in unilateral nasal sinus in Guizhou Province People's Hospital, clinical diagnostic and misdiagnosis of such lesions were explored to provide references for clinicians in diagnosis and treatment of such diseases. METHOD: Combining related literatures in recent years, 213 patients with space-occupying lesions in unilateral nasal sinus were selected. The patients misdiagnosed were reviewed for its clinical manifestations, of patients had been misdiagnosed, imaging features and and pathology. RESULT: Of 213 patients, 116 cases located in the left nasal sinus and 97 in right, 65 patients were nasal polyps, 66 were sinus cyst, 20 were fungal sinusitis, 31 were benign tumor, 28 were malignant tumor and 3 were nasal foreign body. Misdiagnosis were as follow: 12 patients with malignant tumor were misdiagnosed as nasal polyps and the misdiagnosis rate 5.63%. Nasal foreign bodies were misdiagnosed as sinusitis in 2 cases and the misdiagnosis rate 0. 94%. Inserted papilloma misdiagnosed as nasal polyps in 6 cases and the misdiagnosis rate 8.45%. Fungal sinusitis misdiagnosed as purulent sinusitis in 5 cases and the misdiagnosis rate 2.35%. Sinus cyst misdiagnosed as sinusitis in 8 cases and the misdiagnosis rate 3.75%. CONCLUSION: Enquiry history, carefully specialized examination including nasal endoscopy, three-dimensional image and biopsy are crucial on the accurate diagnosis and reducing the misdiagnosis. PMID- 22500460 TI - [Comparative analysis on data of nasal sinus between helicopter and(strike) fighter pilots under physical examination for change to new-type aircraft]. AB - OBJECTIVE: To comparatively analyze the disease data of nasal sinus between helicopter and (strike) fighter pilots under flying qualification, and then to provide references for aeromedical support as a significant part of new logistics service union in army, METHOD: The CT data of nasal sinus in 138 pilots who accepted physical examination for change to new-type aircraft, were collected included 46 cases of helicopter pilots and 92 cases of (strike)fighter pilots). The incidence of chronic sinusitis and cyst of nasal sinus were computed respectively in helicopter pilots and (strike)fighter pilots. RESULT: (1) Fourteen cases suffered from chronic sinusitis (6 cases of maxillary sinusitis, 4 cases of ethmoiditis and 4 cases of maxillary sinusitis and ethmoiditis) in helicopter pilots whose incidence rate of chronic sinusitis was 30.4% (14/46). Of which, 3 cases of antracele were treated. Twelve cases suffered from chronic sinusitis (8 cases of maxillary sinusitis, 1 case of ethmoiditis, 3 cases of maxillary sinusitis and ethmoiditis) in (strike)fighter pilots whose incidence of chronic sinusitis was 13.0% (12/92). Of which, 1 case of antracele was treated. The incidence of chronic sinusitis was higher in helicopter pilots than (strike) fighters pilots (Chi2 = 6.07, P < 0.05). (2) Four cases suffered from unilateral mucosa cysts in maxillary sinus in helicopter pilots whose incidence of cyst of nasal sinus was 8.7% (4/46). Ten cases suffered from mucosa cysts in maxillary sinus (unilateral 8 cases and bilateral 2 cases) in (strike) fighters pilots whose incidence of cyst of nasal sinus was 10.87% (10/92). The difference of the incidence of cyst of nasal sinus was not statistically significant between the helicopter pilots and(strike)fighters pilots. The cysts of nasal sinus did not need treatment in 14 cases of this group data. CONCLUSION: The incidence of symptomless chronic sinusitis and cyst of nasal sinus are high in pilots. It is related with repeatedly changes of atmosphere pressure during flying. But most chronic sinusitis and cyst of nasal sinus do not need treatment. The incidence of chronic sinusitis is higher in helicopter pilots than(strike)fighter pilots. It may be related with the environment of helicopter which have unclosed cockpit and load other aircrew. PMID- 22500461 TI - [Fluctuation of symptomatic VAS score during immunotherapy on allergic rhinitis]. AB - OBJECTIVE: To understand the fluctuation of symptomatic visual analogue scale(VAS)score and its reasons during the allergic rhinitis patients treated with single-mite antigen immunotherapy. METHOD: Three hundred and seventy six patients with allergic rhinitis were treated with single-mite antigen immunotherapy and their symptoms were evaluated by VAS score and chart, the relative factors which could affect the symptom were followed up. RESULT: During the allergic rhinitis patients treated with single-mite antigen immunotherapy, the symptomatic VAS score appeared fluctuation from the 8th to 34th time of therapy. The VAS score increased at the 8 th, 18 th, 22 th, 25 th, 29 th, and 34 th time. Afterwards, it generally decreased to a lowest level of the whole treatment process in the last. The comprehensive analysis implied that the factors resulting in VAS score fluctuation were patients expectation, emotion, socio-economic conditions, living environment, re-contact of allergen and children's unclear complain. CONCLUSION: Patients' expectation, emotion, socio economic conditions, living environment, re-contact of allergen and children's unclear complain can result in symptomatic VAS score fluctuation. It prompts that health education be necessary before the treatment of allergic rhinitis with single-mite antigen immunotherapy. PMID- 22500462 TI - [Inflammatory myofibroblastic tumor in the maxillary sinus: a case report and review of literature]. AB - OBJECTIVE: To investigate the clinical feature, diagnostic and therapeutic methods of inflammatory myofibroblastic tumor(IMT). METHOD: One case of IMT was reported and the relevant literatures were reviewed. RESULT: The computed tomography scan showed irregular soft tissue density shade and aggressive bone destruction with unclear boundary. Pathological findings showed variable numbers of inflammatory cells and myofibroblastic spindle cells. Tumor cells were immunoreactive for vimentin and smooth muscle actin, but negative for desmin et al. CONCLUSION: IMT of the maxillary sinus is very rare. The diagnosis of IMT base on histopathology and immunohistochemistry. The genesis and development of IMT result from chromosomal translocations that often cause an overexpression of anaplastic lymphoma kinase. IMT are clinical and pathological distinct entities and its biological behavior is still uncertain. PMID- 22500463 TI - [Observation on morphology and nerve growth factor expression in nasal mucosal of depression rats]. AB - OBJECTIVE: To establish the rat model of depression and observe its morphological changes and nerve growth factor (NGF) expression in nasal mucosal. METHOD: Thirty SD rats were divided into depression model group and normal controls with 15 rats in each group. The rat depression model were made by application of chronic unforeseeable medium stress stimulating. Behavior change were observed with open box experiment(open field) and humoral consumption-experiments (sucrose consumption), After being sacrificed, the nasal mucosal were taken for HE and NGF immunohistochemical study. The difference of nasal mucosal NGF protein between two groups were examined with medical digital image analysis technology. RESULT: There were no swelling and inflammatory cells infiltrating in nasal mucosal of normal group, but 53% nasal mucosal of depression model were observed such morphological changes. Th NGF immunohistochemical staining were negative in normal group but positive in 53% depression model group. There were significant differences between two groups (P < 0.01). CONCLUSION: Depression rats may appear rhinitis symptoms under long-term stress stimulating. NGF may exert immunoregulatory effects, stimulate the immune cell proliferation and gathering, induce various media release, increase the sensitivity of nerve fibers itself and the producing of neuropeptide, promote the formation of nerve source inflammation and increase the reactivity of nasal mucosa. PMID- 22500464 TI - [The effect of intranasal steroid on nasal mucosa in rat model of allergic rhinitis]. AB - OBJECTIVE: To investigate the effects of intranasal steroid on nasal mucosa in rat model of allergic rhinitis (AR). METHOD: Thirty-six SD rats were randomly divided into three groups (each included 12 rats): the intranasal steroid group(group A),the allergic rhinitis group(group B) and the normal control group(group C). AR model was reproduced by ovalbumin in group A and B. The control group was allergized by NS instead of ovalbumin. Group A was used steroid spray in nasal and Group B and C was used normal saline. Then ,after the last provocation,the allergic symptoms were evaluated,the number of eosinophil (EOS) of the rats' nasal mucosa was counted under hematoxylineosin staining and the goblet cells was counted under alcian blue-periodic acid-Schiff staining. The morphological changes of the rats' nasal mucosa were observed by scanning electron microscope. RESULT: Compared with group B,the inhibition of nasal symptoms was found after used of steroid spray in group A. The EOS and the goblet cells in group A was significantly different with that in Group B (P < 0.05), but no significant differences compared with group C (P > 0.05). Observed by scanning electron microscope, the cilia of the epithelium in group B were significantly lodging, disoriented, winding and secreting,while the cilia of the epithelium in Group A and C had similar appearance. CONCLUSION: Intranasal steroid spray can relieve symptoms and inflammatory conditions of nasal mucosa in allergic rhinitis, and can repair injured nasal mucosa cilia. PMID- 22500465 TI - Wettability and antifouling behavior on the surfaces of superhydrophilic polymer brushes. AB - The surface wettabilities of polymer brushes with hydrophobic and hydrophilic functional groups were discussed on the basis of conventional static and dynamic contact angle measurements of water and hexadecane in air and captive bubble measurements in water. Various types of high-density polymer brushes with nonionic and ionic functional groups were prepared on a silicon wafer by surface initiated atom-transfer radical polymerization. The surface free energies of the brushes were estimated by Owens-Wendt equation using the contact angles of various probe liquids with different polarities. The decrease in the water contact angle corresponded to the polarity of fluoroalkyl, hydroxy, ethylene oxide, amino, carboxylic acid, ammonium salt, sulfonate, carboxybetaine, sulfobetaine, and phosphobetaine functional groups. The poly(2 perfluorooctylethyl acrylate) brush had a low surface free energy of approximately 8.7 mN/m, but the polyelectrolyte brushes revealed much higher surface free energies of 70-74 mN/m, close to the value for water. Polyelectrolyte brushes repelled both air bubbles and hexadecane in water. Even when the silicone oil was spread on the polyelectrolyte brush surfaces in air, once they were immersed in water, the oil quickly rolled up and detached from the brush surface. The oil detachment behavior observed on the superhydrophilic polyelectrolyte brush in water was explained by the low adhesion force between the brush and the oil, which could contribute to its excellent antifouling and self-cleaning properties. PMID- 22500466 TI - Sodium titanate nanotubes as negative electrode materials for sodium-ion capacitors. AB - The lithium-based energy storage technology is currently being considered for electric automotive industry and even electric grid storage. However, the hungry demand for vast energy sources in the modern society will conflict with the shortage of lithium resources on the earth. The first alternative choice may be sodium-related materials. Herein, we propose an electric energy storage system (sodium-ion capacitor) based on porous carbon and sodium titanate nanotubes (Na TNT, Na(+)-insertion compounds) as positive and negative electrode materials, respectively, in conjunction with Na(+)-containing non-aqueous electrolytes. As a low-voltage (0.1-2 V) sodium insertion nanomaterial, Na-TNT was synthesized via a simple hydrothermal reaction. Compared with bulk sodium titanate, the predominance of Na-TNT is the excellent rate performance, which exactly caters to the need for electrochemical capacitors. The sodium-ion capacitors exhibited desirable energy density and power density (34 Wh kg(-1), 889 W kg(-1)). Furthermore, the sodium-ion capacitors had long cycling life (1000 cycles) and high coulombic efficiency (~ 98 % after the second cycle). More importantly, the conception of sodium-ion capacitor has been put forward. PMID- 22500467 TI - Immunoreagent generation and competitive assay development for cyprodinil analysis. AB - Cyprodinil is an anilinopyrimidine fungicide applied worldwide for the prevention and treatment of highly destructive plant diseases in a large variety of crops, including cereals, fruits, and vegetables. This paper describes the development of the first reported immunoassays for cyprodinil. Two original haptens have been synthesized and conjugated to different carrier proteins, and polyclonal antibodies have been produced. Moreover, competitive enzyme-linked immunosorbent assays have been developed and characterized for the analysis of this widely used pesticide. The influence of organic solvents and buffer conditions over the assay analytical parameters was studied. The IC(50) values of the optimized immunoassays were 1.6 and 2.8 ng/mL for the direct and indirect formats, respectively. Quantitative recoveries were found using spiked apple and grape juice samples after a simple direct dilution, and a limit of quantification of 20 ng/mL for both fruit matrices was achieved. These immunoreagents could be very valuable for the sensitive, straightforward, and rapid monitoring of cyprodinil residues in foodstuffs. PMID- 22500470 TI - A review on decision support for massive transfusion: understanding human factors to support the implementation of complex interventions in trauma. AB - BACKGROUND: Critically bleeding trauma patients require coordinated and efficient decision-making processes to ensure optimal management of their massive transfusion (MT) requirements. Human factors (HFs) is a discipline that investigates factors influencing work processes from the organizational, group, and individual levels. Given the complexity of trauma resuscitation, implementing any intervention for decision support in MT is challenging and may benefit from a HFs-assisted approach. STUDY DESIGN AND METHODS: A systematic review was performed to identify reports of the introduction of any type of decision support for the provision of MT in critically bleeding adult trauma patients. Crucial contributions reported to influence design and uptake of the intervention were categorized into four HFs categories (environment, human, machine, and task). Extracted information was supplemented by surveying the contact authors. Evidence of clinical practice changes resulting from the intervention was also considered. RESULTS: We identified nine studies that had reported an intervention implementing new practice guidelines or a MT protocol. All were before-and-after comparative cohort studies and used historical controls as the preintervention cohort. CONCLUSION: Based on the identified reports, this review provides a HFs assisted approach to aid clinicians and policy makers with the implementation of decision support for MT in the trauma care setting. PMID- 22500468 TI - Iron transport in cancer cell culture suspensions measured by cell magnetophoresis. AB - Cell motion in a magnetic field reveals the presence of intracellular paramagnetic elements, such as iron or manganese. Under controlled field and liquid media composition, such motion previously allowed us to compare the paramagnetic contribution to cell magnetic susceptibility in erythrocytes differing in the spin state of heme associated with hemoglobin. The method is now tested on cells with less obvious paramagnetic properties: cell cultures derived from human cancers to determine if the magnetophoretic mobility (MM) measurement is sufficiently sensitive to the dysregulation of the intracellular iron metabolism as suggested by reports on loss of iron homeostasis in cancer. The cell lines included hepatocellular carcinoma (Hep 3B 2.1-7 and Hep G2), promyelocytic (HL-60) and chronic myelogenous (K-562) leukemias, histiocytic lymphoma (U-937), tongue (CAL 27) and pharyngeal (Detroit 562) carcinomas, and epitheloid carcinoma (HeLa), whose MM was measured in complete media with standard and elevated soluble iron (ferric nitrate and ferric ammonium citrate), against oxy- and met-hemoglobin erythrocytes used as controls. Different cell lines responded differently to the magnetic field and the soluble iron concentrations in culture media establishing the possibility of single cell elemental analysis by magnetophoresis and magnetic cell separation based upon differences in intracellular iron concentration. PMID- 22500472 TI - Commentary: towards a cardiac safe prokinetic. PMID- 22500475 TI - Palliative care consultations as American football: full contact, or just touch? PMID- 22500473 TI - Maternal, fetal, and neonatal care in open fetal surgery for myelomeningocele. AB - Fetal myelomeningocele closure (fMMC) was demonstrated in a randomized, prospective clinical trial to improve outcomes for children diagnosed prenatally. Complex care of the maternal/fetal dyad undergoing fetal surgery requires a well coordinated multidisciplinary team. Nurses in many roles are essential members of the team that cares for these women across the continuum. In this article we discuss the care of the woman, fetus, and family from initial contact through the discharge of the neonate. PMID- 22500476 TI - Development of a content valid tool for assessing end-of-life communication in acute care settings. AB - BACKGROUND: Current recommendations throughout the literature require that physicians demonstrate proficiency in handling end-of-life care issues. However, current training and assessment tools are not easily translated to acutely decompensating emergency department patients with whom the practitioner is not familiar. Without these tools, robust assessment of physician performance cannot occur. OBJECTIVE: To develop a content valid instrument to measure the critical care communication skills of emergency physicians in order to facilitate education and assessment of end-of-life communication skills in a time-sensitive acute care setting. METHODS: A two-step modified Delphi methodology with emergency medicine palliative care subject matter experts was used. First, an extensive review of the literature was conducted to elucidate broad communication domains important to end-of-life care. Next, subject matter experts were asked open-ended questions to ascertain critical skills and behaviors that characterized these broad domains. Finally, both questions and domains were ranked as to their importance and relevance to end-of-life communication in an emergency department setting. RESULTS: Literature review identified five domains of end-of-life care: (1) seek information, (2) assess life values, (3) educate family, (4) extend care in a consistent manner, and (5) respond to family questions and concerns. Within each domain, the expert panel identified subdomains with related behavioral examples that were consistently rated as important to end-of-life care for emergency practitioners. CONCLUSION: The resulting assessment tool provides a list of skill domains with specific descriptors and clear behavioral examples that can be used as both a teaching and assessment tool. This represents an essential first step that will allow further validation of the assessment tool, ultimately producing a valid and reliable measure of physician skill in emergency medicine end-of-life care. PMID- 22500477 TI - Preliminary analysis of midlevel practitioners on pain and health-related quality of life and function for a palliative care service at a comprehensive cancer center. PMID- 22500478 TI - Balancing evidence-based medicine, justice in health care, and the technological imperative: a unique role for the palliative medicine clinician. PMID- 22500479 TI - Validity of the end-of-life professional caregiver survey to assess for multidisciplinary educational needs. AB - The National Consensus Project for Quality Palliative Care (NCP) has put forth eight domains of clinical practice guidelines that address the multidisciplinary nature of palliative and end-of-life (EOL) care. Extant surveys to assess education needs of palliative and EOL workers, however, have been constructed for individual professions. Thus we developed the End-of-life Professional Caregiver Survey (EPCS) as an instrument for assessing the palliative and EOL care-specific educational needs of multidisciplinary professionals. PMID- 22500480 TI - Nurses' attitudes and experiences surrounding palliative sedation: components for developing policy for nursing professionals. AB - BACKGROUND: Nurses play an integral role in providing care for patients with end of life (EOL) symptoms refractory to conventional treatments and that may necessitate palliative sedation (PS). A paucity of research on nurses' attitudes, knowledge, and experience with PS exists, despite nurses being instrumental in evaluating its appropriateness and carrying out the care plan. OBJECTIVE: The objective of the study was to elicit nurses' perspectives and conceptualizations of knowledge and skills needed to administer PS in order to inform development of a hospital policy that addresses identified concerns. METHODS: Four focus groups were conducted with nurses likely to have had exposure to PS (oncology, intensive care, and hospice) at an academic medical center. Focus groups were audiotaped, transcribed verbatim, and coded for salient themes. Grounded theory principles were used for the analysis. RESULTS: Among the four focus groups (n=31), 87% were female, 58% between the ages of 36 and 55, and more than 40% reported 10-plus years of providing patient care. Five domains emerged as important in developing a PS policy: 1) ability to define PS; 2) criterion for using PS; 3) skill set for administering PS; 4) policy and procedural guidelines; and 5) education on PS and EOL care. CONCLUSIONS: Nurses identified knowledge, skills, and guidelines as key considerations for implementing PS. Comprehensive policies along with adequate training are needed to expand the availability of PS in acute care hospitals and hospice programs. PMID- 22500481 TI - End-of-life quality-of-care measures for nursing homes: place of death and hospice. AB - OBJECTIVE: The Centers for Medicare and Medicaid Services (CMS) publishes a web based quality report card for nursing homes. The quality measures (QMs) do not assess quality of end-of-life (EOL) care, which affects a large proportion of residents. This study developed prototype EOL QMs that can be calculated from data sources available for all nursing homes nationally. METHODS: The study included approximately 1.5 million decedents residing in 16,000 nursing homes during 2003-2007, nationally. Minimum Data Set (MDS) data were linked to Medicare enrollment files, hospital claims, and hospice claims. Random effect logistic models were estimated to develop risk-adjustment models predicting two outcome measures (place of death [POD] and hospice enrollment), which were then used to construct two EOL QMs. The distributional properties of the QMs were investigated. RESULTS: The QMs exhibited moderate stability over time. They were more stable in identifying quality outliers among the larger nursing homes and in identifying poor-quality outliers than high-quality outliers. CONCLUSIONS: This study offers two QMs specialized to EOL care in nursing homes that can be calculated from data that are readily available and could be incorporated in the Nursing Home Compare (NHC) report card. Further work to validate the QMs is required. PMID- 22500482 TI - Staff perceptions of end-of-life care following implementation of the liverpool care pathway for the dying patient in the acute care setting: a New Zealand perspective. AB - BACKGROUND AND METHODS: Ensuring appropriate palliative and end-of-life (EOL) care in the acute environment is complex and challenging. The Liverpool Care Pathway (LCP) aims to support staff to provide holistic EOL care utilizing a structured framework to prompt and guide care. We report on the post implementation findings of a mixed methodology (survey and focus group [FG] forums) study into staff perceptions of EOL care following the pilot implementation of the LCP into two acute wards. RESULTS AND CONCLUSIONS: Study results suggest that within acute settings staff perceive that the LCP improves EOL care overall, assists interdisciplinary communication around death and dying, and that is a useful tool to positively influence decision making and care delivery. Further research into aspects of staff communication, diagnosing dying, changing direction of care, and the physical environment is warranted. PMID- 22500483 TI - Ketamine for pain: an update of uses in palliative care. AB - Ketamine is a lipophilic, general anesthetic. When given at subanesthetic doses, it also has been found to be an effective analgesic, with efficacy in cancer associated neuropathic pain, ischemic pain, and regional pain syndromes. It can be administered orally, intravenously, subcutaneously, and topically, and interacts with several receptors important in pain management, most importantly the N-methyl-D aspartate (NMDA) receptor. Blockade of the NMDA receptor is associated with reversal of opioid tolerance. Ketamine is metabolized via cytochrome P450 3A4, although no significant interactions have been reported. Ketamine is considered one of the World Health Organization (WHO) essential drugs for the management of refractory pain. PMID- 22500484 TI - Counseling patients on side effects and driving when starting opioids #248. PMID- 22500485 TI - Borderline personality disorder in palliative care #252. PMID- 22500486 TI - A wanting. PMID- 22500487 TI - Why not DNR? PMID- 22500488 TI - Speechless. PMID- 22500489 TI - Music has charms .... PMID- 22500492 TI - Mathematical explanation of the predictive power of the X-level approach reaction noise estimator method. AB - The X-level Approach Reaction Noise Estimator (XARNES) method has been developed previously to study reaction noise in well mixed reaction volumes. The method is a typical moment closure method and it works by closing the infinite hierarchy of equations that describe moments of the particle number distribution function. This is done by using correlation forms which describe correlation effects in a strict mathematical way. The variable X is used to specify which correlation effects (forms) are included in the description. Previously, it was argued, in a rather informal way, that the method should work well in situations where the particle number distribution function is Poisson-like. Numerical tests confirmed this. It was shown that the predictive power of the method increases, i.e. the agreement between the theory and simulations improves, if X is increased. In here, these features of the method are explained by using rigorous mathematical reasoning. Three derivative matching theoremsare proven which show that the observed numerical behavior is generic to the method. PMID- 22500493 TI - Predictors of early mortality after radical nephrectomy with renal vein or inferior vena cava thrombectomy - a population-based study. AB - Study Type - Prognosis (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Surgical volume has been well established as a predictor of outcomes for several complex surgical procedures, yet few studies have evaluated this relationship with regards to radical nephrectomy with either renal vein or inferior vena cava thrombectomy. In addition, most published literature consists of single-institution series from centres of excellence. We performed a population-level analysis and identified surgeon volume as a significant predictor of short-term mortality for this procedure. Such findings have potential implications regarding future policy and regionalization of care. OBJECTIVE: * To study the short-term mortality associated with radical nephrectomy with renal vein or inferior vena cava thrombectomy and the variables associated with this adverse outcome. METHODS: * Using the Ontario Cancer Registry, we identified 433 patients in the province of Ontario, Canada undergoing radical nephrectomy with venous thrombectomy between 1995 and 2004. * We determined mortality rates at postoperative days 30 and 90. * Other variables analysed include pathological tumour characteristics, surgeon graduation year, hospital/surgeon academic status, surgery year and hospital/surgeon volume. * We used multivariable logistic regression to assess outcomes. RESULTS: * Overall mortality was 2.8% (30-day) and 5.8% (90-day). * Surgeons performing a single nephrectomy with venous thrombectomy performed 14% of the cases and had the highest 30-day (6.7%) and 90-day (10%) mortality. The mortality rate for surgeons performing more than one surgery was 2.1% (30-day) and 5.1% (90-day). * In recent years, this procedure was performed more commonly by the highest volume surgeons 67% of cases in 2004 vs 40% in 1995. * Significant predictors of 30-day mortality included procedure year and low surgeon volume. * Significant predictors of 90-day mortality included procedure year, low surgeon volume, left sided tumour and increasing hospital volume. CONCLUSIONS: * For radical nephrectomy with venous thrombectomy, surgeon volume predicts short-term mortality, emphasizing the importance of experience in patient outcome. * Despite a shift towards high-volume surgeons, 13.8% of cases continued to be performed by low-volume providers. * If these results are confirmed in other jurisdictions, radical nephrectomy with venous thrombectomy should be regionalized and performed by surgeons who manage these cases regularly. PMID- 22500495 TI - Optimal approach to immunization in pediatric solid organ transplantation. PMID- 22500496 TI - Empirical research in medical ethics: how conceptual accounts on normative empirical collaboration may improve research practice. AB - BACKGROUND: The methodology of medical ethics during the last few decades has shifted from a predominant use of normative-philosophical analyses to an increasing involvement of empirical methods. The articles which have been published in the course of this so-called 'empirical turn' can be divided into conceptual accounts of empirical-normative collaboration and studies which use socio-empirical methods to investigate ethically relevant issues in concrete social contexts. DISCUSSION: A considered reference to normative research questions can be expected from good quality empirical research in medical ethics. However, a significant proportion of empirical studies currently published in medical ethics lacks such linkage between the empirical research and the normative analysis. In the first part of this paper, we will outline two typical shortcomings of empirical studies in medical ethics with regard to a link between normative questions and empirical data: (1) The complete lack of normative analysis, and (2) cryptonormativity and a missing account with regard to the relationship between 'is' and 'ought' statements. Subsequently, two selected concepts of empirical-normative collaboration will be presented and how these concepts may contribute to improve the linkage between normative and empirical aspects of empirical research in medical ethics will be demonstrated. Based on our analysis, as well as our own practical experience with empirical research in medical ethics, we conclude with a sketch of concrete suggestions for the conduct of empirical research in medical ethics. SUMMARY: High quality empirical research in medical ethics is in need of a considered reference to normative analysis. In this paper, we demonstrate how conceptual approaches of empirical-normative collaboration can enhance empirical research in medical ethics with regard to the link between empirical research and normative analysis. PMID- 22500494 TI - Allergen-specific immunotherapy provides immediate, long-term and preventive clinical effects in children and adults: the effects of immunotherapy can be categorised by level of benefit -the centenary of allergen specific subcutaneous immunotherapy. AB - Allergen Specific Immunotherapy (SIT) for respiratory allergic diseases is able to significantly improve symptoms as well as reduce the need for symptomatic medication, but SIT also has the capacity for long-term clinical effects and plays a protective role against the development of further allergies and symptoms. The treatment acts on basic immunological mechanisms, and has the potential to change the pathological allergic immune response. In this paper we discuss some of the most important achievements in the documentation of the benefits of immunotherapy, over the last 2 decades, which have marked a period of extensive research on the clinical effects and immunological background of the mechanisms involved. The outcome of immunotherapy is described as different levels of benefit from early reduction in symptoms over progressive clinical effects during treatment to long-term effects after discontinuation of the treatment and prevention of asthma. The efficacy of SIT increases the longer it is continued and immunological changes lead to potential long-term benefits. SIT alone and not the symptomatic treatment nor other avoidance measures has so far been documented as the therapy with long-term or preventive potential. The allergic condition is driven by a subset of T-helper lymphocytes (Th2), which are characterised by the production of cytokines like IL-4, and IL-5. Immunological changes following SIT lead to potential curative effects. One mechanism whereby immunotherapy suppresses the allergic response is through increased production of IgG4 antibodies. Induction of specific IgG4 is able to influence the allergic response in different ways and is related to immunological effector mechanisms, also responsible for the reduced late phase hyperreactivity and ongoing allergic inflammation. SIT is the only treatment which interferes with the basic pathophysiological mechanisms of the allergic disease, thereby creating the potential for changes in the long-term prognosis of respiratory allergy. SIT should not only be recognised as first-line therapeutic treatment for allergic rhinoconjunctivitis but also as secondary preventive treatment for respiratory allergic diseases. PMID- 22500497 TI - Molecular pathogenesis of vestibular schwannomas: insights for the development of novel medical therapies. AB - Vestibular schwannomas (VS), benign intracranial tumors originating from the vestibulocochlear nerve, usually present with hearing loss, tinnitus, and balance dysfunction. Rarely, however, if untreated, these neoplasms can cause significant patient compromise - resulting in facial paralysis, brainstem compression, and even death. Those with vestibular schwannomas currently choose between surgery and stereotactic radiation therapy as available treatment options. Unfortunately, no medical therapies are presently U.S. Food & Drug Administration approved, representing an urgent and unmet clinical need. Recent breakthroughs in research have discovered key cell surface receptors and intracellular signaling pathways that drive vestibular schwannoma tumorigenesis, proliferation, and survival. A number of promising inhibitors targeting these signaling molecules have also now shown efficacy in preclinical VS cell culture models and animal experiments, with some recently entering human clinical trials. In this review, we summarize ErbB receptor signaling, PDGF receptors, MAP kinase signaling, AKT, p21-activated kinase signaling, mTOR, and VEGF signaling in the context of vestibular schwannoma drug development efforts worldwide. Today, it is truly an exciting time as our specialty stands on the verge of major breakthroughs in the development of medical therapies for VS. PMID- 22500498 TI - [Craniofacial resection for tumors of paranasal sinuses involving the anterior skull base]. AB - INTRODUCTION: Craniofacial resection is a treatment of choice for paranasal malignant and benign tumors invading the skull base. THE AIM OF THE STUDY: In this article the authors present the experience in craniofacial resection for malignant tumors invading the anterior skull base. MATERIALS AND METHODS: The material consisted of four patients operated in the Department of Otolaryngology and Laryngology Oncology CM UMK between 2007 and 2010. The patients were treated for malignant neoplasms of the paranasal sinuses with anterior skull base involvement. THe age range of the group were between 60 and 75 years. Of these patients three were females and one male. RESULTS: We performed a lateral rhinotomy for laryngological acces for the tumor. The neurosurgeon performed anterior skull base osteotomy at and appropriate site above. The patients recovered uneventfully. The follow up period ranged between 13 and 42 months. The overall 3-year survival for all patients in our series was 66,6%. CONCLUSIONS: Combined craniofacial resection of tumors of the anterior skull base is an effective approach for the management of these pathologies. This type of approach in elderly patients over 70 years old could be associated with increased mortality and complications leading to poorer outcome. PMID- 22500499 TI - [The quality of voice in coal-miners after burn/inhalation injury due to methane explosion]. AB - The job as a coal-miner exposes to the greatest risk. One of the most dangerous health hazard is a burn/inhalation injury during the methane explosion. The victims undergo physical trauma, effect of high temperature and inhalation of toxic gases and products of incomplete combustion, As a result of inhalation injury both, upper and lower airways are affected. The aim of the study was to analyse the relationship between burn/inhalation injury and quality of voice in affected coal-miners. A group of 23 patients (men) in age from 28 to 59 (mean 38.5) 3 years after burn/inhalation injury participated in this study. The voice evaluation based on ENT examination, videlaryngostroboscopy, acoustic analysis, MPT parameter and GRBAS analysis was performed. The special control group of coal miners served as a control. On the basis of the subjective evaluation and the objective acoustic analysis, aerodynamic parameter and videlaryngostroboscopy the worse quality of voice in the group of injured coalminers was shown in comparison to the control group. No substantial correlation between the acoustic parameters, MPT parameter and ventilating rates was found. PMID- 22500500 TI - [Usefulness of laser arytenoidectomy and laterofixation in treatment of bilateral vocal cord paralysis]. AB - INTRODUCTION: Bilateral vocal cord paralysis is caused by the damage of both recurrent laryngeal nerves. Such a pathology is not commonplace in the ordinary medical practice. It most often occurs as a complication after the thyroid gland surgery or thyroid re-surgery. In the case of bilateral vocal cord paralysis the treatment of the patient includes performing immediate tracheotomy or one of the surgeries aiming at widening the glottis because of dyspnea caused by the upper respiratory tract obstruction on the glottis level. AIM: The comparison of efficacy and usefulness of two surgical techniques performed to widen the glottis - laser arytenoidectomy with posterior cordectomy and laterofixation. MATERIAL AND METHODS: The research was carried out on the group of 57 patients suffering from bilateral vocal cord paralysis who, in the period of 1997-2009, underwent treatment in ENT Department in Zabrze Medical University of Silesia in Katowice. The first group included 36 patients who underwent laser arytenoidectomy with posterior chordectomy. The second group included 21 patients who underwent laterofixation. All of the patients treated with the laser arytenoidectomy with posterior cordectomy and laterofixation were subjected to respiratory system ventilation examinations before the procedure of widening the glottis and after the healing, at least 4 months after the surgery. Making self-evaluation, each of the patients answered a question concerning the improvement of their breathing comfort after the surgery. The patients from both groups underwent the vocal apparatus examination which included: subjective perceptive voice analysis according to GRBAS scale, videolaryngostroboscopy, evaluation of the maximum phonation time, self-evaluation survey of the post-surgical voice quality. RESULTS: Among 57 patients suffering from bilateral vocal cord paralysis and operated by arytenoidectomy with posterior cordectomy (group I) and laterofixation (group II), a subjective improvement of the comfort of living was achieved which resulted in the possibility of making more physical activities. From the first group, 35 out of 36 patients were decannulated. In the second group, both patients who had previously undergone tracheotomy were successfully decannulated. There were no statistically significant differences in the increase of selected ventilation markers between the patients who underwent laser arytenoidectomy and those who underwent laterofixation. There were no substantial discrepancies in the perceptive voice analysis in GRBAS scale between the patients after laser arytenoidectomy and those treated with the technique of laterofixation. When asked about their post-surgical voice quality, the patients of the first and the second group rated their voice as worse than before the surgery. CONCLUSION: Both surgical techniques, laser arytenoidectomy with posterior cordectomy and laterofixation, are efficient and useful in widening the glottis in the case of bilateral vocal cord paralysis. The improvement of the ventilation markers allows the growth in the comfort of living, restoration of the physiological respiratory tract and decannulation of the patients who had undergone tracheotomy. The deterioration of the voice quality is characteristic of both surgical techniques. PMID- 22500501 TI - [Cochlea development in infants with central nervous system impairment occurring as an effect of perinatal asphyxia]. AB - Asphyxia in neonates with inadequate blood-inner ear barrier function causes damage to the inner ear included the degeneration of outer hair cells of the organ of Corti and oedematous changes in stria vascularis. The major consequences in the central nervous system (CNS) are found to be hypoxic-ischemic encephalopathy (HIE) in term newborns, peri- (PVH) or intraventricular hemorrhages (IVH) and periventricular leucomalacia (PVL) in preterm neonates. THE AIM OF THE STUDY: was to carry out the objective assessment of the cochlea development using CEOAEs in infants with CNS impairment occurring as an effect of perinatal asphyxia, imaged during trans-fontanel ultrasonography. MATERIAL AND METHODS: To the investigation 36 infants with HIE, IVH or PVL were included, the control group encompassed 32 born at term, health children. In all children three times otoscopic examination and CEOAEs recordings were performed: after birth, in 3rd and in 6th month of life using Otodynamics Otoacoustic Analyser ILO-88 in Quick Screen version. Perinatal anamnesis, general pediatric status, results of trans-fontanel ultrasonography and biochemical test results were taken into account in statistical analyses. RESULTS: The mean amplitudes of CEOAEs in the first days of life were significantly reduced in InvG comparing to control babies. In half-octave frequency bandwidth analysis significant reduction of S/N Ratio at 1,5-4 kHz in InvG was observed. 3 and 6 months later the recorded responses significantly increased, they didn't reach values of CG but no statistical differences between groups were observed. CONCLUSION: In conclusion, the outer hair cells activity in first days of life is reduced in newborns with CNS impairment and perinatal asphyxia in anamnesis comparing to health children. The maturation of the cochlea is intensive during first 3 months of life, later only subtle changes in CEOAEs are observed. PMID- 22500502 TI - [The comparison of the influence of various types of anaesthesia on perioperative bleeding control in endoscopic paranasal sinus surgery]. AB - INTRODUCTION: The study aimed at evaluating the influence of targeted hypotension with three types of anaesthetics on the amount of blood loss in extensive endoscopic operations of polyps of the nose and paranasal sinuses. MATERIAL AND METHODS: Ninety patients, including 30 women aged 31-73 and 60 men aged 21-79, who were operated within the period of 2008-2010 at Department of Otolaryngology and Laryngological Oncology Military Medical Academy University Clinical Hospital in Lodz, were qualified for the study. The bilateral removal of nasal polyps, bilateral ethmoidectomy, and surgery or revision of the maxillary, sphenoid and temporal sinuses in endoscopy were conducted in each patient. Due to the type of general anaesthesia the patients were divided into three groups, 30 patients each: I - sevoflurane inhalation (sedation) and fentanyl I.V., II - sevoflurane inhalation (sedation) and remifentanil I.V. (analgesia), III - TIVA, propofol sedation and remifentanil analgesia. The drugs were administered via the infusion pomp TCI. RESULTS: In group I the mean anaesthesia time was 108.67+/-20.80 min., group II - 112.63+/-22.17 min., group III - 103.67+/-17.47 min. The surgery time in the studied groups was as follows: I - 71.33+/-16.71 min, II - 78.83+/-24.24 min, III - 66.5+/-15.49 min. During the operation the mean blood loss was: group I - 365+/-176.2 ml, group II - 340+/-150.5 ml, group III - 225+/-91.7 ml. During the operation the mean rate of blood loss was: group I - 5.118+/-2.38 ml/min, II 4.507+/-2.215 ml/min, group III - 3.416+/-1.059 ml/min. CONCLUSIONS: In TIVA the advanced technologically control of a drug dose allows for a better control of hypotension, which, finally, results in lower haemorrhage within the operation area, a favourable condition for both a patient and a physician. Perioperative bleeding was independent on sex in every type of anaesthesia. PMID- 22500503 TI - [The methodology of measurements of ossicular chain movability during tympanoplasty using Laser Doppler vibrometry]. AB - INTRODUCTION: Laser Doppler vibrometry can potentially be applied in the measurement of the acoustic conductivity of the middle ear during tympanoplasty. Its usefulness in estimating the accuracy of ossiculoplasty requires experimentally verified. AIM: The article presents the test procedure developed at the Department of Otolaryngology, Medical University of Warsaw for the displacement measurement of the conductive elements of the middle ear. MATERIALS AND METHOD: In the study were used 14 fresh-frozen temporal bones. In the initial stage was performed antrotomy with posterior tympanotomy. During the measurements, ER-2 speakers generated a signal with a frequency of 1000 Hz, 2000 Hz, 4000 Hz, 8000 Hz. Acoustic conductivity of the middle ear was measured on the back branch of the stapes, round window. Laser Doppler Vibrometer was used to measure velocity of each selected elements of the ear. In four experiments were assessed the intraoperative availability of measurement points, the impact of laser beam angle changes and the presence of reflective tape on the amplitude of vibration measured point, intra- and interindividual variability of the method. RESULTS: For all measured frequencies intra-individual differences were no statistically significant. There were observed large differences between the velocity values in various temporal bones. Changing the angle of the laser beam does not significantly affect the results. Mucosal surface of the tympanic cavity does not reflect the laser beam. CONCLUSION: Laser Doppler vibrometry can be used to measure motion of the middle ear sound conductivity with very good repeatability of measurements. Changing the angle of the laser beam should not vary amplitude of measurement during surgery. To maintain the sensitivity of response, it is necessary to use part of reflective tape. PMID- 22500504 TI - [Coping strategies in postlingually deafened adult cochlear implant users in comparison to the hearing population]. AB - OBJECTIVE: The research question was: what coping strategies are used by the postlingually deafened adult cochlear implant (CI) users, in comparison to the hearing population, taking into account their gender and CI experience. MATERIAL AND METHODS: In the assessment of the coping strategies we used the C.S. Carver's Brief COPE questionnaire in Polish adaptation. The questionnaire and information form have been sent to the adult patients implanted in the Institute of Physiology and Pathology of Hearing in the years 2005 and 2009. The response ratio was 59.5% (n = 78). The control group (n = 77) comprised hearing persons selected at random, allowing for age. RESULTS: The stress coping strategies are different in the postlingually deafened adults and hearing ones. The postlingually deaf more seldom use the effective strategies, such as the active coping, planning and humour, and more often the denial. Also, they significantly more seldom turn to the self-blame and the substance use. People with longer CI experience significantly more often use the denial, more seldom they adopt the substance use and the self-distraction compared with those with shorter CI experience. Female postlingually deafened CI users are significantly less active in coping with stress and more seldom turn to the substance use, but more often, compared with the hearing women in the same age-group, use the denial. Male postlingually deafened CI users differ significantly from the hearing men only in more seldom turning to the self-blame and the substance use. CONCLUSIONS: Postlingually deafened CI patients more often use the ineffective coping strategies. This tendency becomes stronger with the time lapse from the cochlear implantation and is more frequent in women, which corresponds with the data on both the considerably worse mental health of the postlingually deafened people compared to the general population and the deterioration of the mental, social and physical functioning with the lapse of time from the implantation. The standing availability of the psychological support for these patients is essential, as well as the awareness of their problems. PMID- 22500505 TI - [Routine follow-up in patients treated of head and neck cancer]. AB - OBJECTIVE: To evaluate the usefulness of routine follow-up in group of patients with head and neck cancer and to present the recommended schedule taking into consideration the oncological safety and costefectivness. AIM: Retrospective cohort study with follow-up of 3 years for all patients. RESULTS: In Outpatient Department in 2010 there were examined 3012 patients treated of head and neck cancer. The biggest group comprised patients with larynx and oral cavity cancer. During routine ENT examination 70% of recurrences was detected. CONCLUSION: In patients with head and neck cancer routine follow up is indispensable. Introduced modern schedules make the monitoring work-up shorter and more sensible, although the benefit in improving patients survival is doubtful. PMID- 22500506 TI - Nasolacrimal duct obstruction after toxic epidermal necrolysis. AB - Toxic epidermal necrolysis also known as Lyell's syndrome is acute dermatomyositis as an adverse drug reactions. It is characterized by erosions of skin over 30% of total body surface area and is associated with significant mortality of 25%-50% of cases. The conjunctival mucosa involvement could result in cornea erosion and ulceration. Other ocular complications are: purulent conjunctivitis with pseudomembrane formation, entropion, symblefaron and synechiae with nasolacrimal duct obstruction or punctual stenosis. The authors present a very rare complication of nasolacrimal duct obstruction after toxic epidermal necrolysis in young girl. The endoscopic dacricystorhinostomy with one lacrimal point intubation was performed. Early ophthalmic assessment and frequent follow-up could be helpful to avoid metaplasia of epithelium, vascular neoplasia in conjunctiva and cornea. This will protect from dysfunction of tears secretion causing nasolacrimal duct or lacrimal point obliteration. If there is a permanent epiphora the endoscopic dacriocystorhinostomy, with silicone tube intubation could be the method of choice. A satisfactory results are also obtained after opening a passage of only one occluded lacrimal point. PMID- 22500507 TI - [Mucoepidermoid cancer of parotid gland in 14-years-old girl--case report]. AB - INTRODUCTION: Malignant tumors of salivary glands are rare, especially in children. MATERIAL AND METHOD: We present a case report of 14-years-old girl affected by mucoepidermoid cancer of parotid gland. RESULTS: Patient was admitted to our Department in May 2007 due to small, hard, moveable tumor localized in right mandibular angle. The VII nerve function was normal. Fine needle aspiration revealed inflammatory cells without atypical cytologic features. Intraoperative tumor was hard, with irregular surface, surrounded by capsule, connected with the main trunk of facial nerve and cartilaginous part of external auditory meatus. Tumor was excised together with superficial part of parotid gland and surrounding lymph nodes. After operation no signs of facial nerve damage were observed. Postoperative histopathological examination revealed mucoepidermoid cancer, in 2 out of 6 specimens neoplasmatic cells were seen in border of excised tissue. In June 2007 the second operation was performed. Remain part of parotid gland was removed with right facial nerve and conservative lymph node resection. Facial nerve and its branches were reconstructed with sural and great auricular nerve as donor grafts. The symptoms of nerve damage were observed in early postoperative days adequate to 5th degree of House-Brackman scale (HB5). 4 years after operation function of facial nerve is estimated on HB3. The girl is under regular oncological and laryngological control free of neoplasm recurrence. CONCLUSIONS: Diagnostics and treatment of malignant parotid tumors in children are difficult and clinical picture must be always taken into consideration as the most important factor. PMID- 22500509 TI - Molecular profiling of individual tumor cells by hyperspectral microscopic imaging. AB - We developed a hyperspectral microscopic imaging (HMI) platform that can precisely identify and quantify 10 molecular markers in individual cancer cells in a single pass. The exploitation of an improved separation of circulating tumor cells and the application of HMI provided an opportunity (1) to identify molecular changes in these cells, (2) to recognize the coexpression of these markers, (3) to pose an important opportunity for noninvasive diagnosis, and (4) to use targeted therapy. We balanced the intensity of 10 fluorochromes bound to 10 different antibodies, each specific to a particular tumor marker, so that the intensity of each fluorochrome can be discerned from overlapping emissions. Using 2 touch preps from each primary breast cancer, the average molecular marker intensities of 25 tumor cells gave a representative molecular signature for the tumor despite some cellular heterogeneity. The intensities determined by the HMI correlate well with the conventional 0-3+ analysis by experts in cellular pathology. Because additional multiplexes can be developed using the same fluorochromes but different antibodies, this analysis allows quantification of many molecular markers on a population of tumor cells. HMI can be automated completely, and eventually, it could allow the standardization of protein biomarkers and improve reproducibility among clinical pathology laboratories. PMID- 22500510 TI - Genetic analysis of the promoter region of the GATA4 gene in patients with ventricular septal defects. AB - Ventricular septal defects (VSDs) are the most common type of congenital heart diseases (CHDs). To date, the genetic causes for sporadic VSDs remain largely unknown. GATA transcription factor 4 (GATA4) is a zinc-finger transcription factor that is expressed in developing heart and adult cardiomyocytes. Mutations in the coding region of the GATA4 gene have been identified in CHD patients, including VSD. As the GATA4 factor is a dosage-sensitive regulator, we hypothesized that the promoter region variants of the GATA4 gene may be genetic causes of VSD. In this study, we analyzed the promoter region of the GATA4 gene by bidirectional sequencing in 172 VSD patients and 171 healthy controls. The results showed that 5 heterozygous sequence variants (NG_008177:g.4071T>C, NG_008177:g.4148C>A, NG_008177:g.4566C>T, NG_008177:g.4653G>T, and NG_008177:g.4690G>deletion) within the promoter region of the GATA gene were identified in 5 VSD patients, but in none of controls. One heterozygous sequence variant (g.4762C>A) was found only in one control, which may have no functional significance. A functional analysis revealed that the transcriptional activity of variant NG_008177:g.4566C>T was reduced significantly, whereas the transcriptional activities of the variants (NG_008177:g.4071T>C, NG_008177:g.4148C>A, NG_008177:g.4653G>T, and NG_008177:g.4690G>deletion) were increased significantly compared with the wild-type GATA4 gene promoter. As GATA4 is a dosage-sensitive regulator during development, our data suggest that these sequence variants within the promoter region of the GATA4 gene may contribute to the VSD etiology by altering its gene expression. Additional studies in experimental animals will deepen our understanding of the genetic basis of VSD and shed light on designing novel molecular therapies for adult VSD patients carrying these variants. PMID- 22500508 TI - Role of advanced glycation endproducts and glyoxalase I in diabetic peripheral sensory neuropathy. AB - Diabetic neuropathy is the most common and debilitating complication of diabetes mellitus with more than half of all patients developing altered sensation as a result of damage to peripheral sensory neurons. Hyperglycemia results in altered nerve conduction velocities, loss of epidermal innervation, and development of painful or painless signs and symptoms in the feet and hands. Current research has been unable to determine whether a patient will develop insensate or painful neuropathy or be protected from peripheral nerve damage all together. One mechanism that has been recognized to have a role in the pathogenesis of sensory neuron damage is the process of reactive dicarbonyls forming advanced glycation endproducts (AGEs) as a direct result of hyperglycemia. The glyoxalase system, composed of the enzymes glyoxalase I (GLO1) and glyoxalase II, is the main detoxification pathway involved in breaking down toxic reactive dicarbonyls before producing carbonyl stress and forming AGEs on proteins, lipids, or nucleic acids. This review discusses AGEs, GLO1, their role in diabetic neuropathy, and potential therapeutic targets of the AGE pathway. PMID- 22500512 TI - Chronic kidney disease as a risk factor for acute coronary syndromes in patients presenting to the emergency room with chest pain. AB - We sought to determine whether persons with intermediate risk factors for cardiovascular disease presenting to an emergency department with chest pain and chronic kidney disease (CKD) were triaged effectively by chest pain units (CPUs). CPUs evaluate patients with intermediate risk and acute chest pain effectively. CKD is a risk factor for poor outcomes once cardiovascular disease has developed. However, current algorithms to risk stratify patients with acute chest pain do not include renal function. A total of 408 patients enrolled previously in the CHEER study of intermediate risk patients with chest pain, assigned randomly to hospitalization or observation in a CPU where an estimated glomerular filtration rate (GFR) was available, were included. No difference was found in short-term outcomes of patients including in-hospital death, myocardial infarction, or coronary revascularization based on renal function. For the 205 patients randomized to the CPU, the rate of admission to the hospital was significantly higher in the group with CKD compared with the group with normal renal function (68.2 vs 48.2%, P=0.007). In a multivariate analysis, decreased renal function was not associated with adverse short-term outcomes. On 5 years follow-up, the overall long-term mortality was significantly higher in the group with CKD (14.1% vs 5.5%, P=0.003). We concluded that CKD is a strong predictor of hospitalization and overall long-term mortality in patients presenting with chest pain to the emergency department. Current risk factor stratification scoring systems should consider CKD as a predictor of increased risk in patients with chest pain. PMID- 22500511 TI - Uncoupling protein-2 expression and effects on mitochondrial membrane potential and oxidant stress in heart tissue. AB - Myocardial uncoupling protein (UCP)-2 is increased with chronic peroxisome proliferator-activated receptor gamma (PPARgamma) stimulation, but the effect on membrane potential and superoxide is unclear. Wild-type (WT) and UCP-2 knockout (KO) mice were given a 3-week diet of control (C) or the PPARgamma agonist pioglitazone (PIO; 50 MUg/g-chow per day). In isolated mitochondria, UCP-2 content by Western blots, membrane potential (DeltaPsim) by tetraphenylphosphonium (TPP), and relative superoxide levels by dihydroethidium (DHE) were measured. Oxygen respiration was determined at baseline and after 10 min anoxia-reoxygenation. PIO induced a 2-fold increase in UCP-2 and nuclear bound PGC1alpha in WT mice with no UCP-2 expression in KO mice. Mitochondrial DeltaPsim from WT mice on C and PIO diets was -166+/-4 mV and -147+/-6 mV, respectively (P<0.05). These values were lower than in UCP-2 KO mice on C and PIO (-180+/-4 mV and -180+/-4 mV, respectively; P<0.05). Maximal complex III inhibitable superoxide from WT mice on C and PIO diets was 22.5+/-1.3 and 17.8+/ 1.1 AU, respectively (P<0.05), and were lower than UCP-2 KO on C and PIO (32.9+/ 2.3 and 29.2+/-1.9 AU, respectively; P<0.05). Postanoxia, the respiratory control index (RCI) in mitochondria from WT mice with and without PIO was 2.5+/-0.3 and 2.4+/-0.2, respectively, and exceeded that of UCP-2 KO mice on C and PIO (1.2+/ 0.1 and 1.4+/-0.1, respectively; P<0.05). In summary, chronic PPARgamma stimulation leads to depolarization of the inner membrane and reduced superoxide of isolated heart mitochondria, which was critically dependent on increased expression of UCP-2. Thus, UCP-2 expression affords resistance to brief anoxia reoxygenation. PMID- 22500513 TI - Genetic and immune predictors for hypersensitivity syndrome to antiepileptic drugs. AB - Hypersensitivity syndrome reactions (HSR) to antiepileptic drugs (AED) are associated with severe clinical cutaneous adverse reactions (SCAR). We aimed (1) to assess HSRs to AEDs using the in vitro lymphocyte toxicity assay (LTA) in patients who manifested HSRs clinically; (2) to correlate LTA results with the clinical syndrome; (3) to correlate LTA results with the human leukocyte antigen (HLA) allele B*1502 (HLA-B*1502) positivity in a Han Chinese-Canadian population; and (4) to determine the cytokine network in this population. Patients that developed fever and cutaneous eruptions in the presence or absence of organ involvement within 8 weeks of exposure to carbamazepine (CBZ), phenytoin (PHY), or lamotrigine (LTG) were enrolled. Control patients received AEDs without presenting HSR. We investigated 10 CBZ-HSR patients (4 with Stevens-Johnson syndrome [SJS]), 24 CBZ-controls, 10 PHY-HSR patients (4 with drug-induced liver injury [DILI]), 24 PHY-controls,6 LTG-HSR patients (1 with SJS and 1 with DILI), and 24 LTG-controls. There were 30 Han Chinese individuals (14 HSR patients and 16 controls) in our cohort. LTA toxicity greater than 12.5%+/-2.5% was considered positive. Differences among groups were determined by analysis of variance. In addition, we measured cytokine secretion in the patient sera between 1 month and 3 years after the event. All Han Chinese individuals and 30% of Caucasians were genotyped for HLA-B*1502. A perfect correlation (r=0.92) was observed between positive LTA and clinical diagnosis of DILI and SJS/toxic epidermal necrolysis (TEN). HLA-B*1502 positivity in Han Chinese is a predictor of CBZ-HSR and PHY HSR. HLA-B*1502-negative Han Chinese receiving only CBZ or a combination of CBZ and PHY tolerated the drug(s) clinically, presenting negative CBZ-LTA and PHY LTA. However, 3 patients presenting negative CBZ-LTA and PHY-LTA, as well as negative HLA-B*1502, showed positive LTG-LTA (38%, 28%, and 25%, respectively), implying that they should not be prescribed LTG. Three patients had LTA positive to both PHY and CBZ, and 3 others had LTA positive to both PHY and LTG. Clinically, all 6 patients presented HSR to both drugs that they tested positive to (cross-reactivity). Patients were grouped based on the clinical presentation of their symptoms as only rash and fever or as a triad of rash, fever and DILI or SJS/TEN that characterizes "true" HSR. Levels of proinflammatory cytokines were significantly higher in patient sera compared with control sera. More specifically, the highest levels of tumor necrosis factor-alpha have been measured in patients presenting "true" HSR, as were the apoptotic markers Fas, caspase 8 activity, and M30. The LTA is sensitive for DILI and SJS/TEN regardless of drug or patient ethnicity. HSR prediction will prevent AED-induced morbidity. In Han Chinese, HLA-B*1502 positivity is a predictor for CBZ-HSR and PHY-HSR. Its negativity does not predict a negative LTG-HSR. There is cross-reactivity between AEDs. Additionally, T-cell cytokines and chemokines control the pathogenesis of SJS/TEN and DILI, contributing to apoptotic processes in the liver and in the skin. PMID- 22500514 TI - Dopamine receptor D1 mediates the inhibition of dopamine on the distal colonic motility. AB - The motility of distal colon could be inhibited by dopamine (DA), yet, the involved receptor is controversial according to the published reports. The goal of present study was to investigate DA receptor(s) mediated inhibition of DA on the colonic motility in rat. The contraction of isolated colon strips was assessed through isometric force transducer. The expressions of DA receptors in distal colon were detected through immunofluorescence and Western blot. DA concentration in colonic smooth muscle was measured by liquid chromatography/mass spectrometry. The results showed that DA inhibited the spontaneous motility of distal colon in a dose-dependent manner with EC50 8.3 MUM. Tetrodotoxin increased colonic contractive frequency, but failed to affect the inhibition of DA on the colonic motility. Pretreatment with SCH-23390, an antagonist of dopaminergic receptor D1, shifted the dose-response curve to the right with EC50 of DA 37 MUM. However, blocking dopaminergic receptor D2 with sulpiride, had no effect. The immunoreactivity of D1 and D2 were detected in the distal colon including myenteric plexus and smooth muscle. Acute cold-restraint stress (CRS) enhanced spontaneous contraction of rat distal colon, which was more sensitive to DA compared with control. Moreover, DA content and D1 expression in smooth muscle layer were increased under CRS condition. In conclusion, D1 in the smooth muscle is mediated DA inhibition on the spontaneous contraction of rat distal colon. The increased DA content and D1 receptor expression in the smooth muscle layer could be a compensatory effect under CRS condition to balance the enhanced colonic motility. PMID- 22500515 TI - Intracardiac T-wave alternans, ischemia, and arrhythmias, in a canine model. PMID- 22500516 TI - Functional characterization of UvrD helicases from Haemophilus influenzae and Helicobacter pylori. AB - Haemophilus influenzae and Helicobacter pylori are major bacterial pathogens that face high levels of genotoxic stress within their host. UvrD, a ubiquitous bacterial helicase that plays important roles in multiple DNA metabolic pathways, is essential for genome stability and might, therefore, be crucial in bacterial physiology and pathogenesis. In this study, the functional characterization of UvrD helicase from Haemophilus influenzae and Helicobacter pylori is reported. UvrD from Haemophilus influenzae (HiUvrD) and Helicobacter pylori (HpUvrD) exhibit strong single-stranded DNA-specific ATPase and 3'-5' helicase activities. Mutation of highly conserved arginine (R288) in HiUvrD and glutamate (E206) in HpUvrD abrogated their activities. Both the proteins were able to bind and unwind a variety of DNA structures including duplexes with strand discontinuities and branches, three- and four-way junctions that underpin their role in DNA replication, repair and recombination. HiUvrD required a minimum of 12 nucleotides, whereas HpUvrD preferred 20 or more nucleotides of 3'-single stranded DNA tail for efficient unwinding of duplex DNA. Interestingly, HpUvrD was able to hydrolyze and utilize GTP for its helicase activity although not as effectively as ATP, which has not been reported to date for UvrD characterized from other organisms. HiUvrD and HpUvrD were found to exist predominantly as monomers in solution together with multimeric forms. Noticeably, deletion of distal C-terminal 48 amino acid residues disrupted the oligomerization of HiUvrD, whereas deletion of 63 amino acids from C-terminus of HpUvrD had no effect on its oligomerization. This study presents the characteristic features and comparative analysis of Haemophilus influenzae and Helicobacter pylori UvrD, and constitutes the basis for understanding the role of UvrD in the biology and virulence of these pathogens. PMID- 22500517 TI - Endoscopic assessment of inflammatory bowel disease: colonoscopy/esophagogastroduodenoscopy. AB - Endoscopy plays an important role in the initial diagnosis of IBD, including the evaluation of disease severity, activity, and extent. The implications of complete mucosal healing further confirm the function of endoscopy in the follow up of IBD patients. The use of therapeutic endoscopy, for example stricture dilatation, can avoid the need for bowel resection. Modalities such as capsule endoscopy, EUS, NBI, CE, and other emerging techniques are likely to have an increasing role in the management of IBD, particularly in the area of dysplasia surveillance and treatment. PMID- 22500518 TI - Chromoendoscopy in inflammatory bowel disease. AB - Chromoendoscopy with methylene blue or indigo carmine significantly increases the diagnostic yield of finding intraepithelial neoplasia in patients with longstanding colitis. The number needed to treat is 14 for panchromoendoscopy to identify 1 additional patient with dysplasia. Chromoendoscopy can greatly facilitate the identification of flat lesions harboring intraepithelial neoplasia. Chromoendoscopy can guide biopsies and clearly reduces the amount of biopsies that are needed per patient. Magnifying endoscopy or CLE are additional techniques, which can be used in conjunction with chromoendoscopy to further reduce the amount of biopsies and to further increase the diagnostic yield. Chromoendoscopy is an established clinical procedure and recommended by many gastroenterological societies for surveillance of patients with longstanding ulcerative colitis. Thus, intravital staining should be an essential part of the diagnostic armamentarium of every colonoscopist. PMID- 22500519 TI - Evaluation for postoperative recurrence of Crohn disease. AB - Disease recurrence following resective surgery for Crohn disease remains a challenging clinical problem, and more studies are needed to better define risk stratification and treatment recommendations in the postoperative setting. Endoscopy remains the gold standard for the assessment of postoperative disease recurrence, and all Crohn disease patients who undergo surgery should undergo ileocolonoscopy within 6 to 12 months of surgery. The degree of endoscopic recurrence in the neoterminal ileum during this procedure provides prognostic information regarding the severity of the future disease course. WCE, MRE, and SICUS are all promising noninvasive modalities to assess for postoperative Crohn disease activity. However, further studies are needed to better define scoring systems, operating characteristics and variability, and prognostic data for each of these modalities. In patients at risk for early disease recurrence, more aggressive prophylactic therapy should be considered, in hopes of delivering true "top-down" therapy that may offer maximum impact in altering the natural history of Crohn disease. PMID- 22500520 TI - The role of capsule endoscopy in evaluating inflammatory bowel disease. AB - Capsule endoscopy is a relatively new technology available in the investigation of IBD. Its place in the algorithm of evaluating IBD is being refined. Capsule endoscopy has the ability to visualize the entire SB with very few complications. It is a sensitive test for the diagnosis of mucosal changes, but should be viewed as complementary to other radiologic evaluations, such as CTE and MRE. Capsule endoscopy is nonspecific and its findings have to be interpreted with caution and in the right clinical setting, because up to one fifth of normal individuals may have subtle changes in the small intestine. Care should also be taken to exclude NSAID use because it mimics findings seen in CD. Capsule endoscopy is an exciting technology that opened the possibility of the evaluation of the SB in the era of "deep remission." It is best applied in patients with a high clinical suspicion for IBD after unremarkable colonoscopy with terminal ileal intubation and radiologic investigation. PMID- 22500521 TI - Health maintenance in the inflammatory bowel disease patient. AB - Gastroenterologists are in a unique position to make very positive differences in the lives of their IBD patients. We understand that IBD patients do not receive preventive services at the same rate as general medical patients. Because these individuals are at increased risk for complications from preventable diseases, we have a valuable opportunity to protect this population (Table 1). Establishing a close working relationship with PCPs can facilitate delivering quality care, but it is important to note that some of these patients rely solely on their GI clinician for the majority of their care. In such a vulnerable population, it is important to be aggressive with vaccine recommendations, monitoring for depression, tobacco cessation, and in performing the appropriate cancer screening examinations. As professional societies and health care system increase their focus on quality measures, incorporating these important issues into routine practice will ultimately result in addressing quality standards; perhaps more important, it should provide our patients with the best individual care possible. PMID- 22500522 TI - Detecting and treating Clostridium difficile infections in patients with inflammatory bowel disease. AB - The prevalence of CDI in patients with IBD has increased over the last decade. The excess morbidity and mortality associated with CDI appears to be greater in patients with IBD than in those without preexisting bowel disease. The risk factors for CDI in IBD and non-IBD populations appear similar; unique IBD-related risk factors are use of maintenance immunosuppression and extent and severity of prior colitis. Nevertheless, a significant proportion of CDI-IBD patients may have the disease without traditional risk factors (ie, antibiotic use, recent hospitalization). The absence of such risk factors must not preclude considering CDI in the differential diagnosis of IBD patients presenting with a disease flare. Vancomycin and metronidazole appear to have similar efficacy with vancomycin being the preferred agent for severe disease. Early surgical consultation is key for improving outcomes of patients with severe disease. Several gaps in research exist; prospective multicenter cohorts of CDI-IBD are essential to improve our understanding of the impact of CDI on IBD patients and define appropriate therapeutic regimens to improve patient outcomes. PMID- 22500523 TI - Evaluating pouch problems. AB - IPAA is a technically demanding procedure that requires appropriate skills and expertise. Adverse sequelae of IPAA are common. Accurate diagnosis and classification of pouch disorders and associated complications are important for proper management and prognosis. Based on presenting symptoms, appropriate and combined diagnostic modalities should apply. A multidisciplinary approach involving gastroenterologists, colorectal surgeons, gastrointestinal pathologists, and gastrointestinal radiologists is advocated for diagnosis and treatment of pouch disorders. PMID- 22500524 TI - The evaluation and treatment of Crohn perianal fistulae: EUA, EUS, MRI, and other imaging modalities. AB - Perianal fistulizing disease is a common complication of CD that requires a multidisciplinary collaboration between gastroenterology, surgery, and radiology professionals for successful assessment and treatment. Optimal success comes from a combined medical and surgical approach to treat the fistulizing disease (see Fig. 1). Unfortunately, even with a variety of surgical options, a subset of patients require permanent fecal diversion and/or proctectomy to successfully treat their disease. Further studies (likely requiring large, multicenter trials) of novel medical and surgical treatments are still warranted to formulate optimal management of this complex condition. PMID- 22500525 TI - Optimizing immunomodulators and anti-TNF agents in the therapy of Crohn disease. AB - Randomized trials support the use of the thiopurines and anti-TNF monoclonal antibodies in treating Crohn disease. New therapeutic approaches and laboratory assays have helped optimize the use of these agents. Thiopurine methyltransferase activity should always be determined to avoid thiopurines in individuals with absent enzyme activity. The role of metabolite-adjusted dosing when initiating thiopurines is not settled. Measuring metabolites helps guide management in patients failing therapy. Loss of response to anti-TNF therapy is mitigated by maintenance therapy and concomitant immunomodulators. When loss of response to infliximab occurs, management is guided by the serum concentrations of infliximab and antibodies to infliximab. PMID- 22500527 TI - Disability in inflammatory bowel disease. AB - Disability can include different aspects of patient's quality of life from physical to psychosocial to employment. Disability in IBD patients contributes to loss of workplace personnel, increased sick leave, and other indirect costs to society. Considerations for more expensive treatment regimens should include their potential to reduce indirect costs to the individual patients and to society in general. The recently developed tool could help establish specific criteria in a set of these diseases that have varied effects and severity. PMID- 22500526 TI - Patient-specific approach to combination versus monotherapy with the use of antitumor necrosis factor alpha agents for inflammatory bowel disease. AB - It is likely that the debate surrounding combination versus monotherapy will continue for the foreseeable future, because there will always be a risk-benefit ratio that must be taken into account with IBD therapy. However, because more studies now include a thoughtful approach with respect to concomitant IS therapy with inclusion of objective end points such as mucosal healing and drug pharmacokinetics, it is anticipated that this issue will become clearer over time, which will benefit patients and practitioners. The BRIDGe approach described in this review is a useful tool but must be taken in the context of the subjectivity of much of the analyzed data and the individual perspectives that influenced the results. It cannot in any way be interpreted as a clinical practice guideline or standard of care, but rather a tool that seeks to interpret and incorporate the available literature and, it is hoped, aid clinicians in making sense of the conflicting data in this area. The decision regarding the risks and benefits of combination therapy must be carefully weighed in each individual patient. PMID- 22500528 TI - Clinical predictors of aggressive/disabling disease: ulcerative colitis and crohn disease. AB - Many clinical factors predict the aggressive course of CD. Younger age at initial diagnosis, the presence of perianal lesions, ileal involvement, smoking, and the need for therapy with corticosteroids are the major predictors of disabling disease or change of behavior to a more aggressive disease. On the other hand, treatment with azathioprine and biologic agents and colonic localization of disease are the major factors that are predictive of less aggressive CD course. The problem we face with determining the factors that increase the risk of disabling disease is that there is no standardized and consistent definition of disabling or aggressive disease. Only two studies analyzed predictors using the same definition of aggressive disease. Only Beaugerie and colleagues developed the score predictive of disabling disease based on three independent factors associated with disabling course that were present at the time of initial diagnosis of CD (requirement of corticosteroids, age less than 40 years, and presence of perianal disease). This score ranged from 0 to 3 points based on the presence of given parameters. The positive predictive value was 0.91 and 0.93 in patients having two or three risk factors, 0.61 for no factors present, and 0.67 for one factor present. In order to determine factors predictive of disabling CD there is a need to establish consistent definition of disabling disease with subsequent future studies on large group of patients to validate such definition and determine factors that may predict the aggressive course. PMID- 22500529 TI - The promise and pitfalls of serologic testing in inflammatory bowel disease. AB - The role of IBD serologies is still evolving. However, as that evolution progresses, it will continue to provide important insights into the etiology of IBD and help define individualized treatment strategies for patients. The presence of multiple IBD antimicrobial antibodies and increased reactivity form a useful heuristic model to understand the evolution of CD. The role of ANCAs and autoantibodies in pathogenesis of UC is an area that requires further investigation. Although IBD serologies exhibit considerable diagnostic accuracy, it is unclear whether they will supplant simpler and more direct evaluations in making an initial diagnosis of UC or Crohn (Table 3). The utility of panels of IBD serologies to stratify and predict the course of CD has been an arena of fertile investigation. Developing individual treatment strategies based on the probability of developing complicated aggressive disease would be a significant advance in medical management of CD. However, if major clinical decisions are to be made based on these serologies, we will need more prospective critical studies from the time of diagnosis to define their clinical applicability and to demonstrate a true difference in outcomes. PMID- 22500530 TI - Fecal markers: calprotectin and lactoferrin. AB - Overall, fecal markers have been found to be more accurate than serum markers. However, fecal markers are not specific for IBD and may be elevated in a range of organic conditions. Fecal calprotectin and lactoferrin can still differentiate inflammatory disease from functional bowel disorders. Comparison studies have found an overall diagnostic accuracy in IBD of 80% to 100% for both calprotectin and lactoferrin. Elevated levels are found in both CD and UC making it difficult to distinguish between these 2 diagnoses from these biomarkers alone. Both markers correlated well to mucosal healing and histologic improvement. Hence, they may be useful in monitoring response to treatment and predicting endoscopic and clinical relapse. Overall, patients with elevated markers were at higher risk of postoperative recurrence than those with normal levels. Fecal markers are useful in predicting pouchitis as well. Fecal markers are helpful as an adjunctive tool in overall evaluation of patients with nonspecific symptoms and as a management tool in those with inflammatory disease to monitor disease activity and possibility of relapse. They are less invasive than colonoscopy and can help guide management in a more cost-effective manner. PMID- 22500531 TI - Imaging for luminal disease and complications: CT enterography, MR enterography, small-bowel follow-through, and ultrasound. AB - The advent of cross-sectional enterography has revolutionized small-bowel imaging, providing comprehensive, reproducible evaluation of CD and its complications. Continued collaboration between radiologists and gastroenterologists is critical to ensure further progress toward the common goals of classifying disease activity, predicting response to treatment, and appropriate triage to medical versus surgical therapy. PMID- 22500532 TI - Genetics in diagnosing and managing inflammatory bowel disease. AB - We believe the future clinical application of genomic information in IBD will lie in the use of a combination of "gene-chips" designed specifically for variation relevant to IBD and ultimately in the cataloging of an individual's entire collection of genomic variation through whole-genome sequencing. In the short term, the expansion of pharmacogenomic tests and biomarker assessments are likely to have the most significant influence on prescribed IBD treatment therapies and disease management. Moreover, these pharmacogenomic and biomarker data are likely to benefit greatly from the ongoing genomic analyses, as they can begin to put these data in the proper genetic context as they relate to monitoring and assessing these effects across different ethnic and racial populations. Although mentioned only briefly in this review, a clearer understanding of environmental triggers of IBD will be of utmost importance to furthering our understanding of the genetic factors and the complex interactions that are likely to exist between genes and environment. The successful identification of genetic factors influencing IBD risk has been accelerating over the last few years and is likely to continue. Currently, these genetic factors provide no direct bearing on clinical treatments or therapies. Instead, these findings aid in our understanding of disease pathogenesis and indirectly to potential for development of novel therapeutics. In the near term, they may be able to provide some additional utility in distinguishing CD cases from UC cases. Future use of genomic information and its role in diagnosing and managing IBD patients is promising but not yet mature. The search for the so-called missing heritability in IBD will undoubtedly continue to uncover novel genes, biological pathways, and the likely interplay between genetic variation and environmental factors. The creation of a customized gene-chip (allowing for the creation of a patient specific cataloging of IBD relevant genetic information), for use in clinical practice, is an almost certainty. Although this information will likely provide significant aid to diagnostics and treatment, it is doubtful that it could ever fully stand alone. It must be accompanied by thorough clinical evaluation and data, a more complete characterization of a patient's potential environmental triggers, and integration with other known pharmacogenomic and molecular biomarker information. PMID- 22500533 TI - Evaluation of inflammatory bowel disease. PMID- 22500534 TI - Neutrophil gelatinase-associated lipocalin protects renal tubular epithelial cell in ischemic/reperfusion injury rats via apoptosis-regulating proteins. AB - We investigated the role of neutrophil gelatinase-associated lipocalin (NGAL) on renal tubular epithelial cell in the renal ischemia/reperfusion injury (IRI) rats. Male Sprague-Dawley rats were randomly assigned to three groups. The control group (n = 5) underwent left nephrectomy. The ischemia/reperfusion (I/R) + normal saline (NS) (n = 5) and I/R + NGAL groups (n = 5) were subjected to 45 min right renal ischemia followed by 48 h of reperfusion after left nephrectomy. The pathological changes of kidney tissues were investigated using hematoxylin eosin staining; renal tubular epithelial cell apoptosis was detected using terminal dUTP nick-labeling method; expression of apoptosis-regulating protein Fas and Bcl-2 was measured using real-time polymerase chain reaction, Western blot, and immunohistochemical staining. Compared with I/R + NS group, kidney tissues from I/R + NGAL group revealed reduced histological damage and a decreased number of renal tubular epithelial cell apoptosis (9.2 +/- 2.53 nuclei or 4.0 +/- 0.7 per high-power field vs. 20.3 +/- 3.7 nuclei or 8.1 +/- 0.3 per high-power field); rats with NGAL showed downregulated fas mRNA (2.34 +/- 0.51 vs. 6.84 +/- 2.34), fas protein (0.65 +/- 0.05 vs. 0.95 +/- 0.08), and upregulated bcl-2 protein (0.33 +/- 0.05 vs. 0.24 +/- 0.03). The results had statistical significance (p < 0.05). We think NGAL could protect against renal IRI and might be related to decreasing tubular epithelial cell apoptosis via adjusting the expression of apoptosis-regulating proteins. PMID- 22500535 TI - A potential role for nilotinib in KIT-mutated melanoma. AB - INTRODUCTION: The advent of effective immunotherapy and targeted therapy, such as ipilimumab (anti-CTLA-4 monoclonal antibody) and vemurafenib (BRAF inhibitor), are changing the treatment paradigm for metastatic melanoma. One of the most readily recognized targets in metastatic melanoma is the oncogenic 'driver' mutations KIT, which is thought to be an important driver mutation in up to 3% of melanomas. AREAS COVERED: We review the current state of development of KIT targeted agents in melanoma with KIT mutations. The pharmacokinetic and pharmacodynamic profiles of nilotinib are presented, as well its safety clinical activity data. Finally, we present the knowledge learned from the experience of nilotinib in chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST) to guide its development for melanoma. EXPERT OPINION: Given its favorable safety and efficacy profile in CML and imatinib-resistant GISTs, nilotinib, a second-generation tyrosine kinase inhibitor with greater potency than imatinib, emerges as a promising agent in the treatment of metastatic melanoma harboring the KIT mutation and warrants clinical investigation in this setting. PMID- 22500536 TI - Factors leading to excessive polypharmacy. AB - There are numerous risk factors for patients to develop excessive polypharmacy. The most prominent risk factors are associated with sociodemographics and the patients' conditions. Risk factors associated with patient behavior, such as patient's self medication with all types of medications, have not been observed to the same extent but might be at the same level of importance for patients developing excessive polypharmacy. Risk factors related to physicians, and the interaction between patient and physician, are studied to a much lesser extent. The few studies conducted regarding the large variation in physicians' individual prescribing practices, in terms of polypharmacy, add another perspective to the complexity of the area. Interventions aiming to improve communication between GP and hospital specialist, to create support systems for medical reviews that include all patients' medications, and to improve the knowledge of multiple prescribing might have the largest potential to better manage excessive polypharmacy. PMID- 22500537 TI - Polypharmacy, adverse drug reactions, and geriatric syndromes. AB - The elderly are at risk for polypharmacy, which is associated with significant consequences such as adverse effects, medication nonadherence, drug-drug and drug disease interactions, and increased risk of geriatric syndromes. Providers should evaluate all existing medications at each patient visit for appropriateness and weigh the risks and benefits of starting new medications to minimize polypharmacy. PMID- 22500538 TI - Clinical practice guidelines for chronic diseases--understanding and managing their contribution to polypharmacy. PMID- 22500539 TI - Factors associated with polypharmacy in nursing home residents. AB - The prevalence of polypharmacy is very high in the nursing home setting. In this comprehensive review, we describe the many demographic, functional status, chronic disease, and healthcare financing factors associated with polypharmacy in nursing home patients. Recognition of the factors associated with polypharmacy is the first step for practitioners. A quality improvement intervention study previously conducted by the authors of this paper demonstrated that polypharmacy can be reduced in the nursing setting as a result of systematic review of medications by physicians. PMID- 22500540 TI - Outcomes of polypharmacy in nursing home residents. AB - This article provides a comprehensive review of the outcomes of polypharmacy in nursing homes. Our review had some limitations. First, we only included studies beginning in 1990, and significant earlier studies are not included. Only English language articles were included. We only researched studies from MEDLINE, and may have missed studies based on our search terms and search tools. There are many definitions of polypharmacy in the literature, including number of medications or inappropriate medications. In this review, we defined polypharmacy as a high number of medications, but not inappropriate medications. It was not surprising that polypharmacy was consistently associated with an increased number of potentially inappropriate drugs. The majority of studies were viewed showed that polypharmacy was associated with increased ADEs, increased DDIs, and increased hospitalizations. We were surprised that polypharmacy was not consistently linked with falls, fractures, and mortality. For the mortality studies, it has been postulated that perhaps some patients receiving 10 or more medications may have been moribund or receiving end-of-life or hospice care. It is possible that the number of medications is not as important as the number of potentially in appropriate drugs. There need to be more studies on these outcomes, using different definitions of polypharmacy. Polypharmacy was associated with increased costs. The drug-related morbidity and mortality, including those resulting from inappropriate medications and increased staff time, led to increased costs. Use of consultant pharmacists has been shown to decrease polypharmacy costs. PMID- 22500541 TI - Deprescribing trials: methods to reduce polypharmacy and the impact on prescribing and clinical outcomes. AB - Different styles of interventions can reduce medication exposure in older adults. However, the evidence for their clinical effectiveness and sustainability is conflicting and lacking. There are some data to guide clinicians on which medicines are more likely to be inappropriate in older people, which medicines are more likely to cause ADWEs, and which medicines should be tapered slowly rather than stopped. To reduce the likelihood of clinically significant adverse events, clinicians should undertake a step-wise approach to discontinuing medications and do so under appropriate supervision. Further research to determine the most effective ways to discontinue medications, and to provide a better understanding of the clinical benefits of various interventions is required. Large RCTs evaluating multidisciplinary interventions and clinical outcomes of changes in medicines regimen across different settings are required to confirm the findings of the studies performed so far. PMID- 22500542 TI - Ethical framework for medication discontinuation in nursing home residents with limited life expectancy. AB - A recent editorial by health economist Victor Fuchs summarized the current challenges with health care delivery in this way: "Most physicians want to deliver 'appropriate' care. Most want to practice 'ethically', but it is difficult to know what is 'appropriate' and what is 'ethical'. This characterization is particularly true for medication use and deprescribing in elderly NH residents with limited life expectancy. Medical ethics sets 4 key principles (beneficence, nonmaleficence, patient autonomy, and justice) to guide practice. However, decisional conflicts will continue between providers and patients, and physicians will continue to struggle with the dilemma of balancing the primacy of patient welfare, values, and beliefs against the desire for promising, but often minimally beneficial and harmful, medications that threaten limited clinical resources. Despite these challenges, physicians should be able to perform systematic medication reviews and monitor discontinuation trials in their NH patients for whom this is consistent with their goals of care. PMID- 22500543 TI - Pharmacokinetics and pharmacodynamic changes associated with aging and implications for drug therapy. AB - The population of older adults continues to increase, and polypharmacy in this population is more the rule than the exception. Physiologic changes that occur with aging result in multiple alterations to the pharmacokinetics and pharmacodynamics of drugs, which, in turn, increase the risk of adverse drug reactions. Consideration of initial dose adjustment, along with frequent medication reconciliation and analysis of the medication list, are keys to providing optimal pharmaceutical care for elderly patients. PMID- 22500544 TI - Medication adherence to multidrug regimens. AB - Despite the fact that medication adherence has been extensively described in the literature over the last several decades, a quote by Becker and Maiman from over 35 years ago best captures the current state of our understanding: "Patient compliance[sic adherence] has become the best documented, but least understood, health behavior." Future research is greatly needed to identify and translate safe and effective interventions into routine clinical practice to improve adherence. Only then can we begin to make significant improvements to the medication use process and, in turn, the health of older adults. PMID- 22500545 TI - Electronic prescribing and other forms of technology to reduce inappropriate medication use and polypharmacy in older people: a review of current evidence. AB - This review provided an overview of the current evidence in relation to the use of e-prescribing and other forms of technology, such as CDSS, to reduce inappropriate prescribing in older people. The evidence indicates that various types of e-prescribing and CDSS interventions have the potential to reduce inappropriate prescribing and polypharmacy in older people, but the magnitude of their effect varies according to study design and setting. There was significant heterogeneity in the studies reported in terms of study designs, intervention design, patient settings, and outcome measures with patient outcomes seldom reported. Widespread diffusion of these interventions has not occurred in any of the health care settings examined. Overall, health care providers report being satisfied with e-prescribing systems and see the systems as having a positive impact on the safety of their prescribing practices, yet the problem of overriding or ignoring alerts persists. The problem of large numbers of inaccurate and insignificant alerts and this issue, along with the other barriers that have been identified, warrant further investigation. PMID- 22500546 TI - Tools to reduce polypharmacy. AB - The reduction in polypharmacy and avoidance of inappropriate medications is a common goal in the care of older persons, regardless of setting. While multidisciplinary teams and regular medication reconciliation and review can identify and reduce medication-related problems, tools to decrease the use of high-risk/low benefit medications can help the individual clinician to improve prescribing. Numerous criteria, tools, algorithms, and scoring systems have been developed for use in a wide range of areas from long-term care to the outpatient setting, and some may not be applicable to individual situations. Not all medication review instruments have been adequately validated, and the tools we have presented have varying levels of evidence to support their use. Clinicians also need to be aware of regulatory, policy, and guideline issues that may impact the use of certain criteria for optimum prescribing. Ultimately, optimizing prescribing by reducing polypharmacy and avoiding inappropriate medications is a highly individualized process for each patient, and clinicians will have to use extensive clinical judgment in using the tools presented here. PMID- 22500547 TI - Polypharmacy. PMID- 22500548 TI - Isolation, structure characterization, and immunomodulating activity of a hyperbranched polysaccharide from the fruiting bodies of Ganoderma sinense. AB - A polysaccharide (GSP-6B) with a molecular mass of 1.86 * 106 Da was isolated from the fruiting bodies of Ganoderma sinense . Chemical composition analysis, methylation analysis, infrared spectroscopy, and nuclear magnetic resonance spectroscopy were conducted to elucidate its structure. GSP-6B contains a backbone of (1->6)-linked-beta-D-glucopyranosyl residues, bearing branches at the O-3 position of every two sugar residues along the backbone. The side chains contain (1->4)-linked-beta-D-glucopyranosyl residues, (1->3)-linked-beta-D glucopyranosyl residues, and nonreducing end beta-D-glucopyranosyl residues. An in vitro immunomodulating activity assay revealed that GSP-6B could significantly induce the release of IL-1beta and TNF-alpha in human peripheral blood mononuclear cell (PBMC) and showed no toxicity to either PBMC or a human macrophage cell line THP-1. GSP-6B could also activate dendritic cells (DC) by stimulating the secretion of IL-12 and IL-10 from DC. PMID- 22500549 TI - Modification of the zonal elution method for detection of transient protein protein interactions involving ligand exchange. AB - A new affinity chromatography method was developed by modifying a zonal elution method. The new method targets transient protein-protein interactions, such as those encountered during direct ligand transfer between the ligand transporter and its cognate receptor. A ligand-loaded transport protein is immobilized on the solid support, and a plug containing a putative receptor is flowed through the column. Elution profiles of proteins not interacting with the immobilized transporter can be approximated with a simple Gaussian curve, while the elution profiles of cognate receptors show significant delay and exhibit complex shape. Ligand transfer from the immobilized transporter molecules to the receptors is verified by both UV absorbance measurements and mass spectrometry. The sensitivity of the method is demonstrated using retinoic acid (RA) transfer from various isoforms of cellular RA binding proteins (CRABPs) and RA receptor gamma (RARgamma). Although these interactions have been hypothesized long ago to proceed via direct mechanism (i.e., via transient docking of the receptor and the transporter), the existing biophysical techniques failed to detect the presence of the transporter-receptor complexes. However, the modified zonal elution method provides unequivocal evidence of direct interaction between RARgamma and one of the CRABP isoforms (CRABP II) during the ligand transfer to the receptor. PMID- 22500550 TI - Moisture-insensitive polycarbosilane films with superior mechanical properties. AB - We report cross-linked polycarbosilane (CLPCS) films with superior mechanical properties and insensitivity to moisture. CLPCS are prepared by spin-coating and thermal curing of hexylene-bridged disilacyclobutane (DSCB) rings. The resulting films are siloxane-free and hydrophobic, and present good thermal stability and a low dielectric constant of k = 2.5 without the presence of supermicropores and mesopores. The elastic stiffness and fracture resistance of the films substantially exceed those of traditional porous organosilicate glasses because of their unique molecular structure. Moreover, the films show a remarkable insensitivity to moisture attack, which cannot be achieved by traditional organosilicate glasses containing siloxane bonds. These advantages make the films promising candidates for replacing traditional organosilicate glasses currently used in numerous applications, and for use in emerging nanoscience and energy applications that need protection from moisture and harsh environments. PMID- 22500551 TI - Inotuzumab ozogamicin in the treatment of B-cell acute lymphoblastic leukemia. AB - INTRODUCTION: Inotuzumab ozogamicin (CMC-544) is a humanized anti-CD22 monoclonal antibody conjugated with calicheamicin. Preclinical data indicate activity against B-cell tumors and early results from clinical trials indicate activity against B-cell lineage acute lymphoblastic leukemia (ALL). AREAS COVERED: This paper reviews the design, pharmacokinetic and pharmacodynamic characteristics, and preclinical and clinical experience of inotuzumab ozogamicin in adult ALL. EXPERT OPINION: Inotuzumab ozogamicin appears as an effective salvage therapy in patients with advanced ALL, allowing more patients to receive stem cell transplant (SCT) with encouraging response rates. This agent should provide a unique opportunity to treat selected ALL patient subpopulations. PMID- 22500552 TI - Maternal risk factors for peripartum transfusion. AB - BACKGROUND: Postpartum hemorrhage remains one of the most significant maternal complications of childbirth in the United States, with peripartum transfusion the most commonly identified morbidity. METHODS: We completed a retrospective cohort study of women delivering at 20+ weeks at a large regional obstetric hospital between 2000 and 2008. Data were extracted from the institutional data warehouse; women with a potential coagulopathy were excluded. The association of maternal and obstetric factors with odds of transfusion was explored using univariate and multivariable logistic regression. RESULTS: We identified 59,282 deliveries and 614 cases of transfusion, an incidence rate of 10.4/1,000 deliveries. Rates were highest for black (14.1/1,000 deliveries) and lowest for white (8.4/1,000 deliveries) women. Increased odds of perinatal transfusion were seen for women with anemia at entry to labor and delivery (odds ratio [OR] 3.03, 95% confidence interval [CI] 2.43-3.79 for hemoglobin (Hgb) 9.5-10.5 g/dL; OR 12.65, 95% CI 10.35-15.46 for Hgb<9.5 g/dL) and those undergoing a cesarean delivery (OR 4.28, 95% CI 3.62-5.05). The excess risk associated with black race was eliminated after adjusting for anemia and other covariates. A synergistic effect of anemia with delivery method was observed. Anemia was estimated to account for 31.7% of transfusions. CONCLUSIONS: Potentially modifiable factors most strongly associated with risk for transfusion were antenatal anemia and cesarean delivery, and their co-occurrence was synergistic. Anemia is an easily identified and treatable risk factor and warrants focus as part of preconception and interconception care in childbearing women. PMID- 22500554 TI - Poor prognosis of Hodgkin variant of Richter transformation in chronic lymphocytic leukemia treated with cladribine. PMID- 22500553 TI - Cyclin A1 is essential for setting the pluripotent state and reducing tumorigenicity of induced pluripotent stem cells. AB - The proper differentiation and threat of cancer rising from the application of induced pluripotent stem (iPS) cells are major bottlenecks in the field and are thought to be inherently linked to the pluripotent nature of iPS cells. To address this question, we have compared iPS cells to embryonic stem cells (ESCs), the gold standard of ground state pluripotency, in search for proteins that may improve pluripotency of iPS cells. We have found that when reprogramming somatic cells toward pluripotency, 1%-5% of proteins of 5 important cell functions are not set to the correct expression levels compared to ESCs, including mainly cell cycle proteins. We have shown that resetting cyclin A(1) protein expression of early-passage iPS cells closer to the ground state pluripotent state of mouse ESCs improves the pluripotency and reduces the threat of cancer of iPS cells. This work is a proof of principle that reveals that setting expression of certain proteins correctly during reprogramming is essential for achieving ESC-state pluripotency. This finding would be of immediate help to those researchers in different fields of iPS cell work that specializes in cell cycle, apoptosis, cell adhesion, cell signaling, and cytoskeleton. PMID- 22500555 TI - Role of the registered nurse in the care of the pregnant woman receiving analgesia and anesthesia by catheter techniques. PMID- 22500556 TI - How do we want to grow old? Anti-ageing-medicine and the scope of public healthcare in liberal democracies. AB - Healthcare counts as a morally relevant good whose distribution should neither be left to the free market nor be simply imposed by governmental decisions without further justification. This problem is particularly prevalent in the current boom of anti-ageing medicine. While the public demand for medical interventions which promise a longer, healthier and more active and attractive life has been increasing, public healthcare systems usually do not cover these products and services, thus leaving their allocation to the mechanisms of supply and demand on the free market. This situation raises the question on which basis the underlying preferences for and claims to a longer, healthier life should be evaluated. What makes anti-ageing medicine eligible for public funding? In this article, we discuss the role of anti-ageing medicine with regard to the scope and limits of public healthcare. We will first briefly sketch the basic problem of justifying a particular healthcare scheme within the framework of a modern liberal democracy, focusing on the challenge anti-ageing interventions pose in this regard. In the next section, we will present and discuss three possible solutions to the problem, essentialistic, transcendental, and procedural strategies of defining the scope of public healthcare. We will suggest a procedural solution adopting essentialistic and transcendental elements and discuss its theoretical and practical implications with regard to anti-ageing medicine. PMID- 22500557 TI - Role of magnetic resonance imaging in bladder cancer: current status and emerging techniques. AB - OBJECTIVES: To evaluate the current status of magnetic resonance imaging (MR) as a staging tool for bladder cancer. To investigate the role of MR in assessing chemotherapeutic response in bladder cancer patients. PATIENTS AND METHODS: A Pubmed/MEDLINE search was conducted to identify original articles, review articles, and editorials regarding the use of MR in bladder cancer. RESULTS: Contrast-enhanced MR and diffusion weighted MR (DW-MRI) can likely distinguish between non-muscle invasive bladder cancer and muscle invasive cancer with >80% accuracy. Some advantages of DW-MRI are the differentiation of benign versus malignant tissue involvement without the need for intravenous contrast, and the possibility of obtaining information on histologic grade and T stage. Traditional MR sequence have low sensitivity for identifying small lymph node metastases but MR lymphography (MRL) using ultra-small paramagnetic iron oxide (USPIO) may enhance their detectin. There may be a role for DW-MRI in the evaluation of chemotherapeutic response in bladder cancer patients. CONCLUSION: To date, sample sizes and study designs are insufficient to clearly establish the role of MR in bladder cancer management, and to this end, well designed prospective trials are needed. PMID- 22500558 TI - Cardiac antibody-mediated rejection. AB - Many factors limit short- and long-term survival after pediatric heart transplantation. Historically, attention had been directed toward T-cell responses and acute cellular rejection. Presence of pretransplant antibodies against HLA is associated with increased donor wait times and poor post transplant outcomes. Therapies aimed to mitigate circulating antibodies include plasmapheresis, protein A immunoadsorption columns, intravenous immune globulin, rituximab, and bortezomib. The negative effects of B cells, HLA antibodies, and AMR and potential interventions are the focus of this review article. PMID- 22500559 TI - Simultaneous determination of 16 nucleosides and nucleobases by hydrophilic interaction chromatography and its application to the quality evaluation of Ganoderma. AB - In order to develop a simple, efficient, and sensitive method for comprehensive analysis of the nucleosides and nucleobases in natural products, a zwitterionic hydrophilic interaction chromatography (ZIC-HILIC) method for the simultaneous determination of 16 nucleosides and nucleobases has been studied. A mechanistic study confirmed that ZIC-HILIC separation showed a mixed-mode effect of both hydrophilic and electrostatic interactions. This method was validated to be precise, accurate, and sensitive with overall precision (intra- and interday) less than 1.8% (RSD), and LOD and LOQ was in the range of 0.005-0.029 MUg/mL and 0.018-0.096 MUg/mL, respectively. With this method, the nucleosides and nucleobases in Ganoderma of different species (G. atrum, G. lucidum, and G. sinense) and origins were quantified. The results showed that the contents varied with the species and origins. With the aid of hierarchical cluster analysis (HCA), cultivated Ganoderma from different origins and species were successfully discriminated. It is for the first time that the content of nucleosides and nucleobases in G. atrum is reported and compared. Our data showed that HILIC had advantages as a useful and potential tool for the study of the bioactive components in Ganoderma as well as their quality control, and could therefore be used for the determination of the analytes in other natural products. PMID- 22500560 TI - Evaluating the impact of patients' online access to doctors' visit notes: designing and executing the OpenNotes project. AB - BACKGROUND: Providers and policymakers are pursuing strategies to increase patient engagement in health care. Increasingly, online sections of medical records are viewable by patients though seldom are clinicians' visit notes included. We designed a one-year multi-site trial of online patient accessible office visit notes, OpenNotes. We hypothesized that patients and primary care physicians (PCPs) would want it to continue and that OpenNotes would not lead to significant disruptions to doctors' practices. METHODS/DESIGN: Using a mixed methods approach, we designed a quasi-experimental study in 3 diverse healthcare systems in Boston, Pennsylvania, and Seattle. Two sites had existing patient internet portals; the third used an experimental portal. We targeted 3 key areas where we hypothesized the greatest impacts: beliefs and attitudes about OpenNotes, use of the patient internet portals, and patient-doctor communication. PCPs in the 3 sites were invited to participate in the intervention. Patients who were registered portal users of participating PCPs were given access to their PCPs' visit notes for one year. PCPs who declined participation in the intervention and their patients served as the comparison groups for the study. We applied the RE-AIM framework to our design in order to capture as comprehensive a picture as possible of the impact of OpenNotes. We developed pre- and post intervention surveys for online administration addressing attitudes and experiences based on interviews and focus groups with patients and doctors. In addition, we tracked use of the internet portals before and during the intervention. RESULTS: PCP participation varied from 19% to 87% across the 3 sites; a total of 114 PCPs enrolled in the intervention with their 22,000 patients who were registered portal users. Approximately 40% of intervention and non-intervention patients at the 3 sites responded to the online survey, yielding a total of approximately 38,000 patient surveys. DISCUSSION: Many primary care physicians were willing to participate in this "real world" experiment testing the impact of OpenNotes on their patients and their practices. Results from this trial will inform providers, policy makers, and patients who contemplate such changes at a time of exploding interest in transparency, patient safety, and improving the quality of care. PMID- 22500561 TI - Pathways of ion-molecular interactions of nucleogenic phenyl cations with the nucleophilic centers of picolines. AB - BACKGROUND: The nuclear-chemical method brought unique opportunity for synthesis of unknown and hardly available organic compounds. Presence of tritium labeling allows one-step preparation of radioactive markers for the investigation of chemical and biological processes. METHODS: The ion-molecular reactions of nucleogenic phenyl cations with 4-picoline have been carried out. The phenyl cations were generated by spontaneous tritium beta-decay within the tritium labeled benzene. Both additions to the nitrogen and substitutions about the aromatic ring were able to be studied simultaneously. RESULTS: Unusual substitutions on both the alpha- and beta-positions of the ring system have been revealed. CONCLUSION: By unknown direct phenylation of nitrogen atom tritium labeled N-phenylpicolinium derivatives, perspective biological markers have been synthesized. PMID- 22500563 TI - Chrominance to dimension: a real-time method for measuring the size of single gold nanoparticles. AB - Noble metal nanoparticles have excellent optical and chemical properties and are widely used in optics, sensors, and biomedicines. The inherent characteristics of metal nanoparticles, particularly their size, play important roles in their applications. The ability to readily measure the size of single nanomaterials on site is crucial to the rapid development of single-particle sensors. In this study, we developed a facile and real-time method for estimating the diameter of single gold nanoparticles (GNPs) that range from 35 to 110 nm in diameter; this technique uses the chrominance of the GNP's plasmon resonance scattering light that is captured by a dark-field microscope (DFM). The RGB (three primary colors, red, green, and blue) chrominance information from the dark-field image can be directly converted into the diameters of the GNPs using the relationship between the particle size and the scattering light peak wavelength; this conversion was carried out using Matlab program based on an RGB-To-Wavelength (RTW) process. This approach is more convenient, less time-consuming, and enables observation under arbitrary conditions compared to the scanning electron microscopy (SEM) technique. The differences between the diameters of the GNPs that were calculated using this method and those that were measured using SEM were less than 5 nm. The RTW method has also been applied in the monitoring of the refractive index of the media surrounding the GNPs, and their dynamic acting within cells in real-time. PMID- 22500562 TI - West Nile virus: characterization and diagnostic applications of monoclonal antibodies. AB - BACKGROUND: Diagnosis of West Nile virus (WNV) infections is often difficult due to the extensive antigenic cross-reactivity among flaviviruses, especially in geographic regions where two or more of these viruses are present causing sequential infections. The purpose of this study was to characterize a panel of monoclonal antibodies (MAbs) produced against WNV to verify their applicability in WNV diagnosis and in mapping epitope targets of neutralizing MAbs. METHODS: Six MAbs were produced and characterized by isotyping, virus-neutralization, western blotting and MAb-epitope competition. The MAb reactivity against various WNVs belonging to lineage 1 and 2 and other related flaviviruses was also evaluated. The molecular basis of epitopes recognized by neutralizing MAbs was defined through the selection and sequencing of MAb escape mutants. Competitive binding assays between MAbs and experimental equine and chicken sera were designed to identify specific MAb reaction to epitopes with high immunogenicity. RESULTS: All MAbs showed stronger reactivity with all WNVs tested and good competition for antigen binding in ELISA tests with WNV-positive equine and chicken sera. Four MAbs (3B2, 3D6, 4D3, 1C3) resulted specific for WNV, while two MAbs (2A8, 4G9) showed cross-reaction with Usutu virus. Three MAbs (3B2, 3D6, 4D3) showed neutralizing activity. Sequence analysis of 3B2 and 3D6 escape mutants showed an amino acid change at E307 (Lys -> Glu) in the E protein gene, whereas 4D3 variants identified mutations encoding amino acid changed at E276 (Ser -> Ile) or E278 (Thr -> Ile). 3B2 and 3D6 mapped to a region on the lateral surface of domain III of E protein, which is known to be a specific and strong neutralizing epitope for WNV, while MAb 4D3 recognized a novel specific neutralizing epitope on domain II of E protein that has not previously been described with WNV MAbs. CONCLUSIONS: MAbs generated in this study can be applied to various analytical methods for virological and serological WNV diagnosis. A novel WNV-specific and neutralizing MAb (4D3) directed against the unknown epitope on domain II of E protein can be useful to better understand the role of E protein epitopes involved in the mechanism of WNV neutralization. PMID- 22500564 TI - Progress in the treatment of bone metastases in cancer patients. AB - INTRODUCTION: Bone metastases are a frequent complication of cancer, occurring in up to 70% of patients with advanced breast or prostate cancer. Skeletal-related events involving pathological fractures, spinal cord compression and a need for surgery/radiotherapy, which are frequently observed in cancer patients with bone metastases have a detrimental effect on patients' survival and quality of life. Therefore, prevention of skeletal-related events is a crucial element in cancer treatment. AREAS COVERED: The aim of this article was to summarize data on bone modifying agents used for treatment of cancer patients with bone metastases. We searched PubMed, EMBASE, and abstracts from ASCO, AUA, ESMO, AACR congresses for clinical studies evaluating bone-modulating agents in the treatment of patients with bone metastases. EXPERT OPINION: In breast cancer patients with bone metastasis, several bisphosphonates and denosumab demonstrated clinical efficacy. On the other hand, in patients with bone metastases from prostate cancer or other solid tumors only zoledronic acid and denosumab were clinically active. However, neither bisphosphonates nor denosumab have any positive impact on survival of patients with bone metastases. In a recent interim analysis of a Phase III clinical study, a novel bone-modulating agent - radium-223 chloride (alpharadin), a bone-seeking alpha emitter, has been demonstrated to significantly improve median overall survival of prostate cancer patients with bone metastases compared with placebo. PMID- 22500565 TI - Moderate red wine drinking does not help cut women's breast cancer risk. PMID- 22500566 TI - Morphological and morphometric study of the opossum's dorsal root ganglia neurons. AB - The ultrastructural characteristics and the morphometric evaluation of the different types of neurons present in the dorsal root ganglia (DRG) of the South American opossum (Didelphis albiventris) were studied. Four adult male animals were used and the neurons from cervical and lumbar DRG were removed and processed for histological and transmission electron microscopy observations. The morphometric data were obtained from serial sections stained by H/E and Masson's trichrome. The number of neurons in cervical and lumbar DRG was 22 300 and 31 000, respectively. About 68% of the cervical neurons and 62.5% of the lumbar neurons presented areas up to 1300 um(2) and were considered as the small neurons of the DRG. The ultrastructural observations revealed two morphological types of neurons: clear large neurons and dark small neurons. The nuclei of both cell types are spherical and the chromatin is disperse and rarefected. The cytoplasm of the dark small neuron is more electron dense and shows a regular distribution of small mitochondria and many rough reticulum cisterns in the periphery. A small Golgi apparatus was close to the nucleus and many disperse neurofilaments occupy most parts of the cytoplasm. Smooth reticulum cisterns are rare and lipofucsin like inclusions are present at some points. In the clear large neurons, the organelles are homogenously scattered through the cytoplasm. The neurofilaments are close packed forming bundles and small mitochondria and rough reticulum cisterns are disperse. Lipofucsin-like inclusions are more frequent in these cells. PMID- 22500567 TI - High-resolution inventory of Japanese anthropogenic mercury emissions. AB - Heavy metals like mercury that are emitted into the environment remain there indefinitely, posing a long-term threat to both the environment and human health. Elemental mercury is volatile and is in gaseous form, and because of the long residence time, transported over long distances. Comprehensive control of mercury emissions therefore remains an important international issue. The crucial steps for designing effective approaches for such control include the quantification of mercury emissions by sources and the identification of geographical characteristics of the emissions. In this study a detailed, high-resolution inventory of Japanese mercury emissions in 2005 was developed to improve understanding of their geographical distribution. Proceeding from a national emissions inventory per source category, emissions were spatially allocated with increasing geographical resolution in a stepwise procedure using statistics from geographic information resources, yielding mercury emissions per prefecture, per municipality and per grid cell of approximately 1 * 1 km. The five prefectures with the highest emissions were Fukuoka, Yamaguchi, Hyogo, Oita, and Hokkaido, accounting for 35.2% of all emissions. In each prefecture a small number of municipalities account for a major share of emissions. Distribution by grid cell is characterized by a concentration of 50% of all emissions in a mere 32 of the 255 954 grid cells over which emissions are distributed in this study. It was also quantitatively confirmed that use of larger grid cells leads to greater uncertainty in emissions distribution. Problems with data collection are clarified and measures to improve the accuracy of future estimation are proposed. PMID- 22500568 TI - Cardiopulmonary bypass assisted resection of mediastinal masses. AB - We report a recurrent solitary fibrous tumor of the mediastinum that was encircling the right pulmonary artery. The resection of the tumor with the involved right pulmonary artery segment and sequential graft reconstruction of the vessel was facilitated by the use of cardiopulmonary bypass. We review the indications, management, and outcomes of cardiopulmonary bypass for the resection of mediastinal masses. PMID- 22500569 TI - Stable unstable reliability theory. AB - Classical reliability theory assumes that individuals have identical true scores on both testing occasions, a condition described as stable. If some individuals' true scores are different on different testing occasions, described as unstable, the estimated reliability can be misleading. A model called stable unstable reliability theory (SURT) frames stability or instability as an empirically testable question. SURT assumes a mixed population of stable and unstable individuals in unknown proportions, with w(i) the probability that individual i is stable. w(i) becomes i's test score weight which is used to form a weighted correlation coefficient r(w) which is reliability under SURT. If all w(i) = 1 then r(w) is the classical reliability coefficient; thus classical theory is a special case of SURT. Typically r(w) is larger than the conventional reliability r, and confidence intervals on true scores are typically shorter than conventional intervals. r(w) is computed with routines in a publicly available R package. PMID- 22500570 TI - Angoff's delta method revisited: improving DIF detection under small samples. AB - Most methods for detecting differential item functioning (DIF) are suitable when the sample sizes are sufficiently large to validate the null statistical distributions. There is no guarantee, however, that they will still perform adequately when there are few respondents in the focal group or in both the reference and the focal group. Angoff's delta plot is a potentially useful alternative for small-sample DIF investigation, but it suffers from an improper DIF flagging criterion. The purpose of this paper is to improve this classification rule under mild statistical assumptions. This improvement yields a modified delta plot with an adjusted DIF flagging criterion for small samples. A simulation study was conducted to compare the modified delta plot with both the classical delta plot approach and the Mantel-Haenszel method. It is concluded that the modified delta plot is consistently less conservative and more powerful than the usual delta plot, and is also less conservative and more powerful than the Mantel-Haenszel method as long as at least one group of respondents is small. PMID- 22500571 TI - Telecare, remote monitoring and care. AB - Telecare is often regarded as a win/win solution to the growing problem of meeting the care needs of an ageing population. In this paper we call attention to some of the ways in which telecare is not a win/win solution but rather aggravates many of the long-standing ethical tensions that surround the care of the elderly. It may reduce the call on carers' time and energy by automating some aspects of care, particularly daily monitoring. This can release carers for other caring activities. On the other hand, remote and impersonal monitoring seems to fall short of providing care. Monitoring may be used to help elderly users retain independence. But it may also increase the amount of information which flows from users to carers, which can result in a form of function-creep that actually undermines independence. PMID- 22500572 TI - Bipolar tissue sealant device decreases hemoglobin loss in multilevel spine surgery. AB - BACKGROUND: Traditional techniques for obtaining hemostasis during orthopedic surgery, such as conventional electrocautery and sealants, have limited clinical effectiveness in reducing hemoglobin (Hb) loss and requirement for transfusion. The bipolar tissue sealant device studied in this trial combines radiofrequency energy with saline irrigation to hemostatically seal both cut bone and soft tissue, potentially aiding hemostasis. STUDY DESIGN AND METHODS: Sixty patients undergoing multilevel posterior lumbar instrumentation and fusion were randomly assigned to unipolar cautery alone (control group) or unipolar cautery plus use of the bipolar tissue sealant device (treatment group). Hb loss from the surgical field was measured (rather than estimated) and compared between the two groups. The primary hypothesis was that the treatment group would lose significantly less Hb than the control group. RESULTS: The control group experienced a mean Hb loss of 102.4 g while the treatment group showed a significantly lower mean Hb loss of 66.2 g (p = 0.0004). No significant difference was found between groups with respect to secondary endpoints including length of surgery, number of red blood cell units transfused, number of total blood component units transfused, transfusion avoidance, length of stay, or serious adverse events. CONCLUSION: Use of a bipolar tissue sealant device in addition to unipolar cautery significantly decreased Hb loss during multilevel, posterior lumbar spinal instrumentation and fusion when compared with unipolar cautery alone. PMID- 22500573 TI - Use of Solovov-Badenoch principle in treating severe and recurrent vesico urethral anastomosis stricture after radical retropubic prostatectomy: technique and long-term results. AB - What's known on the subject? and What does the study add? Many different approaches have been used to treat bladder neck strictures and urinary incontinence after radical prostatectomy in the past. Most techniques are highly invasive and carry a high risk of complications. The present study describes the use of the Solovov-Badenoch 'pull-through urethroplasty' as well as artificial urinary sphincter implantation. OBJECTIVE: * To report our experience in the management of patients with combined urinary incontinence and stricture after radical prostatectomy with a two-step approach: urethroplasty with a 'pull through' technique after the Solovov-Badenoch principle; and artificial urinary sphincter (AUS) insertion after 8-10 months. PATIENTS AND METHODS: * We retrospectively evaluated a cohort of 11 patients treated between September 2001 and January 2010. RESULTS: * There were no intraoperative complications in either procedure. * After urethroplasty one patient was unable to empty the bladder with complete urine retention without urethral stricture (treatment failure). * At 6 months after the urethroplasty 10 patients were completely incontinent and received AUS. * One previously irradiated patient developed urethral erosion 6 months after AUS implantation and underwent complete removal of the device. * After a mean (range) follow-up of 65 (19-119) months, nine patients (81.8%) were continent with no post-void residual urine and a perfectly functioning AUS. CONCLUSION: * Our experience with a two-step approach (combined suprapubic/transperineal redo anastomosis and AUS placement) shows that redo vesico-urethral anastomosis is easier than pure transperineal approaches with good results in restoring patency and that the transperineal step provides a dedicated operative field for AUS implantation with reduced risks of perioperative complications. PMID- 22500574 TI - The limonoids and their antitobacco mosaic virus (TMV) activities from Munronia unifoliolata Oliv. AB - Five new limonoids, named munronoids K-O (1-5), together with three known limonoids were isolated from Munronia unifoliola Oliv. These limonoids were involved in the skeletons of evodulone, gedunin, and peieurianin types of limonoids, and their structures were established on the basis of spectroscopic data. Compound 5 featuring a gamma-lactone ring instead of the beta-substituted furan ring was found in the peieurianin type for the first time. The antitobacco mosaic virus (anti-TMV) activities of compounds 1-8 were also evaluated with half leaf, enzyme-linked immunosorbent assay, and Western blot methods, and limonoids 1, 5, and 8 showed stronger anti-TMV treatment activities than the positive control ningnanmycin. Six compounds (1-5 and 8) exhibited infection inhibition activities against TMV. PMID- 22500575 TI - Supramolecular interaction of coumarin 1 dye with cucurbit[7]uril as host: combined experimental and theoretical study. AB - Molecules of the coumarin family have fluorescence characteristics that are highly sensitive to their environment, and thus, they have been used as fluorescent sensors in chemical and biological systems. However, the very poor fluorescence yield of most coumarin dyes in aqueous media limits their applications. We have adopted a supramolecular strategy to improve the fluorescence intensity of coumarin dye through its interaction with the relatively new host cucurbit[7]uril (CB[7]). The virtually nonfluorescent coumarin 1 (Phi(f) = 0.04) was converted into a highly fluorescent (Phi(f) = 0.52) entity in water upon addition of the nonfluorescent host CB[7]. Various spectroscopy techniques, namely, UV-vis absorption and steady-state and time resolved fluorescence spectroscopies, established the formation of a strong 1:1 dye-CB[7] inclusion complex with a high binding constant of (1.2 +/- 0.1) * 10(5) M(-1) for the dye. The stable inclusion complex of the neutral molecule was supported by density-functional-theory- (DFT-) based quantum chemical calculations. Energy decomposition analysis of various interaction factors in the host-guest complex revealed that key components providing stability to the complex were electrostatic, polarization, and charge-transfer energies. These new results on the formation of a strong inclusion complex of the versatile fluorophore coumarin 1 with the nontoxic host CB[7] could lead to the design of efficient molecular-scale biological probes, sensors, and photostable aqueous UV dye lasers. PMID- 22500576 TI - The epidemiology of postpartum malaria: a systematic review. AB - Pregnant women are more susceptible to malaria than their non-pregnant counterparts. Less is known about the risk of malaria in the postpartum period. The epidemiology of postpartum malaria was systematically reviewed. Eleven articles fitted the inclusion criteria. Of the 10 studies that compared malaria data from the postpartum period with pregnancy data, nine studies suggested that the risk for malaria infection decreased after delivery. All three studies that compared postpartum data with non-pregnant non-postpartum women concluded that the risk did not return to pre-pregnancy levels immediately after delivery. The results of this review have to be carefully interpreted, as the majority of studies were not designed to study postpartum malaria, and there was large variability in study designs and reported outcomes. Current evidence suggests an effort should be made to detect and radically cure malaria during pregnancy so that women do not enter the postpartum period with residual parasites. PMID- 22500577 TI - Hepatitis B surface antigen variants in voluntary blood donors in Nanjing, China. AB - BACKGROUND: Hepatitis B virus (HBV) is still one of the serious infectious risks for the blood transfusion safety in China. One plausible reason is the emergence of the variants in the major antigenic alpha determinant within the major hydrophilic region (MHR) of hepatitis B surface antigen (HBsAg), which have been assumed to evade the immune surveillance and pose a challenge to the disease diagnosis. It is well documented that some commercial ELISA kits could detect the wild-type but not the mutant viruses. The high prevalence of HBV in China also impaired the application of nucleic acid testing (NAT) in the improvement of blood security. Molecular epidemiological study of HBsAg variations in China is still limited. This study was designed to identify the prevalence of mutations in the HBsAg in voluntary blood donors in Nanjing, China. METHODS: A total of 20,326 blood units were enrolled in this study, 39 donors were positive for HBV S gene in the nested-PCR. Mutations in the major hydrophilic region (MHR; aa 99-169) were identified by direct sequencing of S region. RESULTS: Among of 20,326 blood units in the Red Cross Transfusion Center of Nanjing from October 2008 to April 2009, 296 samples (1.46%, 296/20,326) were HBsAg positive in the 2 successive rounds of the ELISA test. In these HBsAg positive units, HBV S gene could be successfully amplified from 39 donors (13.18%, 39/296) in the nested-PCR. Sequence analysis revealed that 32 strains (82.1%, 32/39) belong to genotype B, 7 strains (17.9%, 7/39) to genotype C. Besides well known G145R, widely dispersed variations in the MHR of S region, were observed in 20 samples of all the strains sequenced. CONCLUSIONS: HBV/B and HBV/C are dominant in Nanjing, China. The mutations in the MHR of HBsAg associated with disease diagnosis are common. PMID- 22500578 TI - Pharyngeal airway space, hyoid bone position and head posture after orthognathic surgery in Class III patients. AB - OBJECTIVE: To determine the effect of orthognathic surgery on pharyngeal airway in Class III patients and to (1) compare the results of different surgical techniques, (2) determine the change at the position of the hyoid bone, and (3) evaluate the craniocervical posture changes related to pharyngeal airway change. MATERIALS AND METHODS: Forty-eight Class III adult patients were included in the study to assess airway space after orthognathic surgery. Nine patients were treated with maxillary advancement, seven patients were treated with mandibular set back, and 32 patients were treated with bimaxillary surgery. Cephalometric records were taken before treatment, after surgery, and about 1 year after surgery (at the end of the treatment). RESULTS: No differences were determined at the position of hyoid bone and craniocervical posture. Nasopharyngeal area was significantly increased in all groups (P < .05). Oropharyngeal area and SPSS and IPS parameters were significantly decreased after mandibular set back operation (P < .05). In bimaxillary and maxillary advancement groups, PPS parameter was significantly increased (P < .01), and IPS parameter was significantly decreased (P < .05). No differences were detected at oropharyngeal and hypopharyngeal areas in bimaxillary and maxillary advancement groups. CONCLUSION: Different surgical procedures have different effects on pharyngeal airway space. PMID- 22500580 TI - Access and regioselective transformations of 6-substituted 4-aryl-2,8 dichloropyrido[3,2-d]pyrimidine compounds. AB - We report herein an efficient route for the synthesis of 2,4,8 trichloropyrido[3,2-d]pyrimidines 1 with R(1) substituents at C-6. The potential of such scaffolds was demonstrated by the possibility to displace regioselectively each aromatic chloride to introduce diversity. Sequential sulfur nucleophilic addition followed by Liebeskind-Srogl cross-coupling reaction yielded unprecedented aryl introduction at C-4 on a trichloropyrido[3,2 d]pyrimidine derivative. The reactivity difference of the remaining two chlorides toward S(N)Ar reactions was investigated. Amination yielded high C-2 regioselectivity, while thiolation was influenced by C-6 substituents, resulting in medium to high C-2 versus C-8 regioselectivity. The last chloride was efficiently displaced by S(N)Ar, Suzuki-Miyaura cross-coupling reaction, or reduction. C-2 arylation as a final step was also possible by Liebeskind-Srogl cross-coupling reaction on the previously introduced C-2 thioether. A concise and highly divergent synthetic use of 1 was developed, thereby providing an efficient approach to explore the structure-activity relationship of pyrido[3,2 d]pyrimidine derivatives such as 9, 10, 15, and 16. PMID- 22500579 TI - Shotgun lipidomics analysis of 4-hydroxyalkenal species directly from lipid extracts after one-step in situ derivatization. AB - 4-Hydroxyalkenal species are a class of peroxidative products of polyunsaturated fatty acids, which serve as "toxic second messengers" in cellular systems. Investigation of their cellular role is hindered due to the lack of sensitive, reliable, robust method for identification and quantification of these metastable metabolites. Herein, we explored the facile Michael adduct of carnosine with 4 hydroxyalkenal species and developed a sensitive, facile, shotgun lipidomics based method for quantification of these compounds directly from organic solvent lipid extracts of biological samples. In the study, we extensively examined the factors that may affect the accurate quantification of 4-hydroxyalkenal species and found that this method possessed high reproducibility (<8%) and nearly 3 orders of linear dynamic range with a limit of quantification at lower than 0.56 fmol/MUL. Mass levels of 4-hydroxyalkenal species in various biological samples, including mouse heart, kidney, liver, and skeletal muscle, were determined by this developing method. In addition, the effects of sample collection methods and sample storage time on 4-hydroxyalkenal mass levels were also determined. We believe that development of this novel methodology should provide a powerful tool for us to better understand the role of 4-hydroxyalkenal species in biological processes. PMID- 22500581 TI - Design and evaluation of a crystalline hybrid of molecular conductors and molecular rotors. AB - Combining recent concepts from the fields of molecular conductivity and molecular machinery we set out to design a crystalline molecular conductor that also possesses a molecular rotor. We report on the structures, electronic and physical properties, and dynamics of two solids with a common 1,4 bis(carboxyethynyl)bicyclo[2.2.2]octane (BABCO) functional rotor. One, [nBu(4)N(+)](2)[BABCO][BABCO(-)](2), is a colorless insulator where the dicarboxylic acid cocrystallizes with two of its monoanionic conjugated bases. The other is self-assembled by electrocrystallization in the form of black, shiny needles, with highly conducting molecular slabs of (EDT-TTF-CONH(2))(2)(+) (EDT TTF = ethylenedithiotetrathiafulvalene) and anionic [BABCO(-)] rotors. Using variable-temperature (5-300 K) proton spin-lattice relaxation, (1)H T(1)(-1), we were able to assign two types of Brownian rotators in [nBu(4)N(+)](2)[BABCO][BABCO(-)](2). We showed that neutral BABCO groups have a rotational frequency of 120 GHz at 300 K with a rotational barrier of 2.03 kcal mol(-1). Rotors on the BABCO(-) sites experience stochastic 32 GHz jumps at the same temperature over a rotational barrier of 2.72 kcal mol(-1). In contrast, the BABCO(-) rotors within the highly conducting crystals of (EDT-TTF CONH(2))(2)(+)[BABCO(-)] are essentially "braked" at room temperature. Notably, these crystals possess a conductivity of 5 S cm(-1) at 1 bar, which increases rapidly with pressure up to 50 S cm(-1) at 11.5 kbar. Two regimes with different activation energies E(a) for the resistivity (180 K above 50 and 400 K below) are observed at ambient pressure; a metallic state is stabilized at ca. 8 kbar, and an insulating ground state remains below 50 K at all pressures. We discuss two likely channels by which the motion of the rotors might become slowed down in the highly conducting solid. One is defined as a low-velocity viscous regime inherent to a noncovalent, physical coupling induced by the cooperativity between five C(sp3)-H...O hydrogen bonds engaging any rotor and five BABCO units in its environment. The rotational barrier calculated with the effect of this set of hydrogen bonds amounts to 7.3 kcal mol(-1). Another is quantum dissipation, a phenomenon addressing the difference of dynamics of the rotors in the two solids with different electrical properties, by which the large number of degrees of freedom of the low dimensional electron gas may serve as a bath for the dissipation of the energy of the rotor motion, the two systems being coupled by the Coulomb interaction between the charges of the rotors (local moments and induced dipoles) and the charges of the carriers. PMID- 22500582 TI - Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation. AB - INTRODUCTION: The possible oncostatic properties of melatonin on different types of neoplasias have been studied especially in hormone-dependent adenocarcinomas. Despite the promising results of these experimental investigations, the use of melatonin in breast cancer treatment in humans is still uncommon. AREAS COVERED: This article reviews the usefulness of this indoleamine for specific aspects of breast cancer management, particularly in reference to melatonin's antiestrogenic and antioxidant properties: i) treatments oriented to breast cancer prevention, especially when the risk factors are obesity, steroid hormone treatment or chronodisruption by exposure to light at night (LAN); ii) treatment of the side effects associated with chemo- or radiotherapy. EXPERT OPINION: The clinical utility of melatonin depends on the appropriate identification of its actions. Because of its SERM (selective estrogen receptor modulators) and SEEM (selective estrogen enzyme modulators) properties, and its virtual absence of contraindications, melatonin could be an excellent adjuvant with the drugs currently used for breast cancer prevention (antiestrogens and antiaromatases). The antioxidant actions also make melatonin a suitable treatment to reduce oxidative stress associated with chemotherapy, especially with anthracyclines, and radiotherapy. PMID- 22500583 TI - Using bacteria to treat diseases. AB - INTRODUCTION: Mosquito-borne diseases such as malaria and dengue fever result in significant morbidity and mortality in developing countries. Vector control is often the most effective strategy to prevent disease transmission and novel methods are required to complement existing insecticide-based strategies. Biological control uses natural predators or pathogens to kill mosquitoes or reduce their capacity to transmit disease. Bacteria such as Wolbachia have been proposed to have the potential to provide effective biological control of mosquitoes. AREAS COVERED: A review of the potential role of bacteria in the control of mosquito-borne diseases highlighting the advantages and disadvantages of each strategy. In particular, a comprehensive summary of the progress made using the bacterial endosymbiont Wolbachia for dengue control. EXPERT OPINION: Pathogenic bacteria such as Bti can be used to kill mosquito larvae and several endosymbiotic bacteria such as Asaia could be genetically transformed to alter the mosquito's ability to transmit pathogens. The endosymbiotic bacterium Wolbachia has been successfully introduced into the principal vector of dengue, Aedes aegypti, and induces a variety of phenotypic effects that are predicted to reduce dengue transmission. The release of Wolbachia-infected mosquitoes has been undertaken as part of preliminary trials to determine the applied use of this bacterium for mosquito-borne disease control. PMID- 22500584 TI - Reconstruction versus no reconstruction of iliac crest defects following harvest for spinal fusion: a systematic review: A review. AB - OBJECT: Autologous bone from the iliac crest is commonly used for spinal fusion. However, its use is associated with significant donor site morbidity, especially pain. Reconstructive procedures of the iatrogenic defect have been investigated as a technique to alleviate these symptoms. The goal of this study was to assess the effects of reconstruction versus no reconstruction following iliac crest harvest in adults undergoing spine surgery. METHODS: The authors searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2011, Issue 4); MEDLINE (1948-Oct 2011); EMBASE (1947-Oct 2011); and the reference lists of articles. Randomized controlled trials (RCTs) or nonrandomized controlled trials (NRCTs) were included in the study. Two independent reviewers selected the studies, extracted data using a standardized collection form, and assessed for risk of bias. RESULTS: Three RCTs (96 patients) and 2 NRCTs (82 patients) were included. These had a moderate to high risk of bias. The results suggest that iliac crest reconstruction may be useful in reducing postoperative pain, minimizing functional disability, and improving cosmesis. No pattern of other clinical, radiological, or resource outcomes was identified. CONCLUSIONS: Although the available evidence is suboptimal, this systematic review supports the notion that iliac crest reconstruction following harvest for spinal fusion may reduce postoperative pain, minimize functional disability, and improve cosmesis. PMID- 22500585 TI - Beyond altruistic and commercial contract motherhood: the professional model. AB - It has become common to distinguish between altruistic and commercial contract motherhood (or 'surrogacy'). Altruistic arrangements are based on the 'gift relationship': a woman is motivated by altruism to have a baby for an infertile couple, who are free to reciprocate as they see fit. By contrast, in commercial arrangements both parties are motivated by personal gain to enter a legally enforceable agreement, which stipulates that the contract mother or 'surrogate' is to bear a child for the intending parents in exchange for a fee. She is required to undergo medical examinations and to refrain from behaviour that could harm the foetus. The intending parents are the child's legal parents from the outset. The parties to the contract can, but are not expected to, maintain contact after the transaction is completed. We argue that contract motherhood should not be organized according to the norms of the gift relationship, and that contract mothers should be compensated for their labour. However, we accept that there are good reasons for rejecting the commercial model as a suitable framework for contract pregnancy, and argue, instead, in favour of viewing it as a profession. PMID- 22500586 TI - Coastal projects in China: from reclamation to restoration. PMID- 22500587 TI - Impact of storage temperature and processing delays on cord blood quality: discrepancy between functional in vitro and in vivo assays. AB - BACKGROUND: Optimal conditions of cord blood (CB) storage, processing, cryopreservation, and thawing are critical for banking and transplantation. Nevertheless, standardized procedures are still awaited. STUDY DESIGN AND METHODS: We evaluated the impact of preprocessing storage and temperature on recovery, viability, and functional differentiation capacities of hematopoietic progenitor cells. We compared units stored at room temperature (RT) or at 4 degrees C for 72 hours before cryopreservation to units processed shortly after collection (<12 hr). RESULTS: Postthaw results showed similar in vitro characteristics between immediate processing and 4 degrees C storage for cell recovery and viability, both significantly higher than RT storage. Surprisingly, we demonstrated that storage of CB units at RT before processing and cryopreservation profoundly altered in vivo hematopoietic reconstitution in mice, although in vitro hematopoietic colony-forming unit potential was unaltered. CONCLUSION: Our findings challenge current CB storage practices and suggest standard in vitro quality assessments may not always be indicative of CB engraftment potential. PMID- 22500588 TI - Surveillance guidelines based on recurrence patterns after radical cystectomy for bladder cancer: the Canadian Bladder Cancer Network experience. AB - Study Type - Prognosis (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Radical cystectomy with pelvic lymph node dissection is recognized as the standard of care for carcinoma invading bladder muscle and for refractory non-muscle-invasive bladder cancer. Owing to high recurrence and progression rates, a two-pronged strict surveillance regimen, consisting of both functional and oncological follow-up, has been advocated. It is also well recognized that more aggressive tumours with extravesical disease and node-positive disease recur more frequently and have worse outcomes. This study adds to the scant body of literature available regarding surveillance strategies after radical cystectomy for bladder cancer. In the absence of any solid evidence supporting the role of strict surveillance regimens, this extensive examination of recurrence patterns in a large multi-institutional project lends further support to the continued use of risk-stratified follow-up and emphasizes the need for earlier strict surveillance in patients with extravesical and node-positive disease. OBJECTIVES: * To review our data on recurrence patterns after radical cystectomy (RC) for bladder cancer (BC). * To establish appropriate surveillance protocols. PATIENTS AND METHODS: * We collected and pooled data from a database of 2287 patients who had undergone RC for BC between 1998 and 2008 in eight different Canadian academic centres. * Of the 2287 patients, 1890 had complete recurrence information and form the basis of the present study. RESULTS: * A total of 825 patients (43.6%) developed recurrence. * According to location, 48.6% of recurrent tumours were distant, 25.2% pelvic, 14.5% retroperitoneal and 11.8% to multiple regions such as pelvic and retroperitoneal or pelvic and distant. * The median (range) time to recurrence for the entire population was 10.1 (1-192) months with 90 and 97% of all recurrences within 2 and 5 years of RC, respectively. * According to stage, pTxN+ tumours were more likely to recur than >=pT3N0 tumours and <=pT2N0 tumours (5-yr RFS 25% vs. 44% vs. 66% respectively, P < 0.001). Similarly, pTxN+ tumours had a shorter median time to recurrence (9 months, range 1-72 months) than >=pT3N0 tumours (10 months, range 1-70 months) or <=pT2N0 tumours (14 months, range 1-192 months, P < 0.001). CONCLUSIONS: * Differences in recurrence patterns after RC suggest the need for varied follow-up protocols for each group. * We propose a stage-based protocol for surveillance of patients with BC treated with RC that captures most recurrences while limiting over-investigation. PMID- 22500589 TI - Mental health education programmes for generalist health professionals: an integrative review. AB - Mainstreaming of mental health services has led to an increase in the presentation and care of mental health patients in generalist health settings. The lack of adequate mental health educational preparation of general health professionals (GHP) has been identified as a major barrier to meeting the health care needs of mental health patients. This study aimed to review and synthesize research evidence on mental health education programmes (MHEP) that have been designed to develop the knowledge, skills, and attitudes of GHP. An integrative literature review was conducted following a search of key electronic databases and hand searching of references of relevant papers, and 25 papers met the study inclusion criteria. Knowledge, skill, and attitudinal improvements in GHP post MHEP were shown in most studies. MHEP that included supervised clinical experience, role play, and case scenarios were reported as being more effective. Issues such as patient participation in education, interprofessional education models, and the willingness, interest and, motivation for GHP to be involved in MHEP warrant further research. PMID- 22500590 TI - Temperature- and pressure-dependent densities, self-diffusion coefficients, and phase behavior of monoacid saturated triacylglycerides: toward molecular-level insights into processing. AB - Using molecular-dynamics (MD) simulations the densities and self-diffusion coefficients of a range of liquid monoacid triacylglycerides (TAGs) have been studied as a function of temperature and, for the first time, pressure. While offset by their ambient properties, the response of the TAGs to temperature and pressure is qualitatively similar. Application of pressure was found to significantly increase densities and reduce diffusion of the TAG molecules, suggesting that it may have as much a role in processing and crystallizing TAGs as supercooling does. A solution of glycerol tripalmitate and glycerol trihexanoate was also studied, showing that application of pressure should lead to a significant decrease in the saturation point of the solution, which is an important consideration for processing TAGs. Different solid/liquid interfaces of glycerol tripalmitate have also been investigated. Although crystal growth could not be observed, dissolution of one interface was seen in the MD simulations. The results suggest that over moderate distances the melting of TAGs may be cooperative in nature, rather than involving dissolution of individual TAG molecules. PMID- 22500591 TI - Intertwined aligned carbon nanotube fiber based dye-sensitized solar cells. AB - Metal wires suffer from corrosion in fiber-shaped dye-sensitized solar cells (DSSCs). We report herein that stable, ultrastrong, and highly flexible aligned carbon nanotube fibers can be used not only as catalytic counter electrodes but also as conductive materials to support dye-loaded TiO(2) nanoparticles in DSSCs. The power conversion efficiency of this fiber solar cell can achieve 2.94%. These solar power fibers, exhibiting power conversion efficiency independent of incident light angle and cell length, can be woven into textiles via a convenient weaving technology. PMID- 22500592 TI - Noncitrus alkaline fruit: a dietary alternative for the treatment of hypocitraturic stone formers. AB - BACKGROUND AND PURPOSE: Fruits and vegetables are natural suppliers of potassium, bicarbonate, or bicarbonate precursors such as citrate, malate and others-hence, possessing potential effects on citraturia. We aimed to compare the acute effects of a noncitrus (melon) fruit vs citric ones (orange and lime) on citraturia and other lithogenic parameters. PATIENTS AND METHODS: Two-hour urine samples were collected from 30 hypocitraturic stone-forming patients after an overnight fast and 2, 4, and 6 hours after the consumption of 385 mL (13 oz) of either freshly squeezed orange juice (n=10), freshly blended melon juice (n=10), or freshly squeezed lime juice (n=10). Urinary citrate, potassium, pH, and other lithogenic parameters were determined and net gastrointestinal alkali absorption (NGIA) was calculated. Potential renal acid load (PRAL) and pH from juices were determined. RESULTS: Significant and comparable increases of mean urinary citrate were observed in all groups, whereas mean urinary potassium, pH, and NGIA were significantly increased only after consumption of melon and orange juices. The pH of melon juice was higher and the PRAL value was more negative compared with orange juice, indicating a higher alkalinity. CONCLUSIONS: These findings suggested that melon, a noncitrus source of potassium, citrate, and malate, yielded an increase in urinary citrate excretion equivalent to that provided by orange, and hence represents another dietary alternative for the treatment of hypocitraturic stone-formers. Despite its low potassium content, lime also produced comparable increases in citraturia possibly because of its high citric acid content. PMID- 22500593 TI - The use of a tailored surgical technique for minimally invasive esophagectomy. AB - OBJECTIVE: Uncertainty exists among surgeons as to whether minimally invasive esophagectomy (MIE) is a comparable operation to open esophagectomy (OE). The surgical technique and oncologic dissection should not be degraded when using a minimally invasive approach. METHODS: We reviewed a single hospital's experience with both OE and MIE. From 2000 to 2010, 257 patients underwent esophagectomy by 1 of 3 surgical techniques: transhiatal, Ivor Lewis, or 3-hole. RESULTS: Of the 257 patients (median age, 67 years; range, 58-74), 92 underwent MIE. Both groups were comparable in terms of gender, age, comorbidities, surgical technique, and induction chemotherapy and radiotherapy. The overall median follow-up was 29.5 months (range, 9.9-61.5). The MIE group had a significantly shorter operative time (MIE vs OE, 330 vs 365 minutes, P = .04), length of stay (MIE vs OE, 9 vs 12 days, P < .01), intensive care unit admission rate (MIE vs OE, 55% vs 81%, P < .01), intensive care unit length of stay (MIE vs OE, 1 vs 2 days, P < .01), and estimated blood loss (MIE vs OE, 100 vs 400 mL, P < .01). More lymph nodes were harvested in the MIE group than in the OE group (17 vs 11 nodes, P < .01). There were insignificant differences in 30-day mortality (MIE vs OE, 2.2% vs 3.0%; P = .93) and overall survival (P = .19), as well as in the rates of all complications, except pneumonia (MIE vs OE, 2% vs 13%; P = .01). CONCLUSIONS: A thoracic surgeon can safely tailor the MIE to a patient's anatomy and oncologic demands while maintaining equivalent survival. PMID- 22500594 TI - Outcomes after transplantation for "failed" Fontan: a single-institution experience. AB - OBJECTIVE: Despite the excellent outcomes in the current era after the Fontan procedure, it continues to have an inherent risk of failure. Cardiac transplantation provides 1 option for treating these patients; however, the indications for, timing of, and outcomes after, transplantation remain undefined. We examined our own institutional experience with transplantation for failed Fontan. METHODS: The records of 155 patients transplanted for congenital heart disease at a single institution from June 1984 to September 2007 were reviewed. Of these patients, 43 had undergone a previous Fontan procedure (25 male, 15 female; median age, 14.5 years; range, 1-47; 23 classic Fontan, 13 lateral tunnel, 4 extracardiac conduit, and 3 revised to shunt). The predictors of short- and long-term survival were evaluated, and the Fontan patients were compared with all other patients with congenital heart disease (n = 129, 78 male, 51 female). RESULTS: The most common indications for transplantation included protein-losing enteropathy (PLE) (39.5%), chronic heart failure (41.8%), and acute post-Fontan failure (9.3%). The transplants performed in Fontan patients were more likely to require pulmonary artery reconstruction (85.4% vs 42.9%; P < .0001) and had longer cardiopulmonary bypass times (278 vs 179 minutes; P < .0001). The 90-day mortality rate was greater in the Fontan group (35.0% vs 20.0%; P = .055). No correlation was observed between the interval from Fontan to transplantation and morality; however, renal failure was a strong predictor of early mortality (odds ratio, 10.8; 95% confidence interval, 1.5-75.7). CONCLUSIONS: Transplantation is an acceptable treatment for patients with a failed Fontan. Clinical factors (instead of the indication for transplantation) appear to have the greatest correlation with early mortality. PMID- 22500596 TI - Open versus endovascular repair for acute traumatic thoracic aortic rupture. PMID- 22500597 TI - Does anastomosis device or epiaortic ultrasonography reduce the risk of postoperative stroke after coronary artery bypass grafting? PMID- 22500598 TI - Simulation of thoracoscopic surgery using 3-dimensional tailor-made virtual lung. PMID- 22500600 TI - Re: simplified perfusion strategy for removing retroperitoneal tumors with extensive cavoatrial involvement. PMID- 22500601 TI - Guiding the molecular diagnosis of hypertrophic cardiomyopathy. PMID- 22500602 TI - Methotrexate and risk of cardiovascular disease. PMID- 22500603 TI - Effect of timing of chronic preoperative aspirin discontinuation on morbidity and mortality in patients having combined coronary artery bypass grafting and valve surgery. PMID- 22500604 TI - Deactivation of implantable cardioverter-defibrillators in terminal illness and end-of-life care. PMID- 22500606 TI - Asymmetric phase-transfer-catalyzed conjugate addition of glycine imine to exocyclic alpha,beta-unsaturated ketones: construction of polycyclic imines containing three stereocenters. AB - We developed a facile, one-pot, multistep transformation between glycine imine and exocyclic alpha,beta-unsaturated ketones in reactions catalyzed by chiral phase-transfer catalysts (PTC). A series of polycyclic imines containing three adjacent stereocenters were obtained in good to high yields with high diastereo- and enantioselectivities. Further transformation of the imines could afford N fused polycyclic compounds with four adjacent stereocenters. PMID- 22500605 TI - Construct validity of a figure rating scale for Brazilian adolescents. AB - BACKGROUND: Figure rating scales were developed as a tool to determine body dissatisfaction in women, men, and children. However, it lacks in the literature the validation of the scale for body silhouettes previously adapted. We aimed to obtain evidence for construct validity of a figure rating scale for Brazilian adolescents. METHODS: The study was carried out with adolescent students attending three public schools in an urban region of the municipality of Florianopolis in the State of Santa Catarina (SC). The sample comprised 232 10-19 year-old students, 106 of whom are boys and 126 girls, from the 5th "series" (i.e. year) of Primary School to the 3rd year of Secondary School. Data-gathering involved the application of an instrument containing 8 body figure drawings representing a range of children's and adolescents' body shapes, ranging from very slim (contour 1) to obese (contour 8). Weights and heights were also collected, and body mass index (BMI) was calculated later. BMI was analyzed as a continuous variable, using z-scores, and as a dichotomous categorical variable, representing a diagnosis of nutritional status (normal and overweight including obesity). RESULTS: Results showed that both males and females with larger BMI z scores chose larger body contours. Girls with higher BMI z-scores also show higher values of body image dissatisfaction. CONCLUSION: We provided the first evidence of validity for a figure rating scale for Brazilian adolescents. PMID- 22500607 TI - Supramolecular displacement-mediated activation of a silent fluorescence probe for label-free ligand screening. AB - We report a new approach for the rapid screening of analyte binding affinities for a target protein. We demonstrate that a molecular probe, with a pro fluorophore substrate and ligand moieties, can be hindered from enzymatic access when bound to the target protein. When analytes displace the probe from the protein's binding pocket, a fluorescence profile is generated. This profile is used to discriminate analytes based on their relative binding affinities. PMID- 22500609 TI - Vibrational and electronic circular dichroism of dimethyl mesobilirubins XIIIalpha. AB - The vibrational circular dichroism (VCD) spectra of (alphaR,alpha'R)-, (alphaS,alpha'S)-, (betaR,beta'R)-, and (betaS,beta'S)-dimethylmesobilirubin XIIIalpha have been recorded in the range of 1800-900 cm(-1) in CDCl3 solution and in mixed DMSO-d6/CDCl3 solutions. Ab initio density functional theory (DFT) calculations predict IR vibrational absorption (VA) and VCD spectra in excellent to good correspondence with observed data. The same calculations confirmed the ridge-tile conformation that has been known for a long time. Assignment of vibrational normal modes (NMs) sheds light on the relative importance of local moieties and groups in determining conformational properties of the molecules, as well as their interaction with solvent molecules. Time-dependent DFT (TDDFT) calculations were also performed to provide an understanding of electronic circular dichroism (ECD) spectra and confirm the well-known interpretation based on the exciton model. PMID- 22500608 TI - Serotonin-induced hypersensitivity via inhibition of catechol O-methyltransferase activity. AB - The subcutaneous and systemic injection of serotonin reduces cutaneous and visceral pain thresholds and increases responses to noxious stimuli. Different subtypes of 5-hydroxytryptamine (5-HT) receptors are suggested to be associated with different types of pain responses. Here we show that serotonin also inhibits catechol O-methyltransferase (COMT), an enzyme that contributes to modultion the perception of pain, via non-competitive binding to the site bound by catechol substrates with a binding affinity comparable to the binding affinity of catechol itself (K(i) = 44 MUM). Using computational modeling, biochemical tests and cellular assays we show that serotonin actively competes with the methyl donor S adenosyl-L-methionine (SAM) within the catalytic site. Binding of serotonin to the catalytic site inhibits the access of SAM, thus preventing methylation of COMT substrates. The results of in vivo animal studies show that serotonin induced pain hypersensitivity in mice is reduced by either SAM pretreatment or by the combined administration of selective antagonists for beta(2)- and beta(3) adrenergic receptors, which have been previously shown to mediate COMT-dependent pain signaling. Our results suggest that inhibition of COMT via serotonin binding contributes to pain hypersensitivity, providing additional strategies for the treatment of clinical pain conditions. PMID- 22500610 TI - Detection of paralytic shellfish toxins by a solid-phase inhibition immunoassay using a microsphere-flow cytometry system. AB - Paralytic shellfish poisoning is a toxic syndrome described in humans following the ingestion of seafood contaminated with saxitoxin and/or its derivatives. The presence of these toxins in shellfish is considered an important health threat and their levels in seafood destined to human consumption are regulated in many countries, as well as the levels of other chemically unrelated toxins. We studied the feasibility of immunodetection of saxitoxin and its analogs using a solid phase microsphere assay coupled to flow cytometry detection in a Luminex 200 system. The technique consists of a competition assay where the toxins in solution compete with bead-bound saxitoxin for binding to an antigonyautoxin 2/3 monoclonal antibody (GT-13A). The assay allowed the detection of saxitoxin both in buffer and mussel extracts in the range of 2.2-19.7 ng/mL (IC(20)-IC(80)). Moreover, the assay cross-reactivity with other toxins of the group is similar to previously published immunoassays, with adequate detection of most analogs except N-1 hydroxy analogs. The recovery rate of the assay for saxitoxin was close to 100%. This microsphere-based immunoassay is suitable to be used as a screening method, detecting saxitoxin from 260 to 2360 MUg/kg. This microsphere/flow cytometry system provided similar sensitivities to previously published immunoassays and provides a solid background for the development of easy, flexible multiplexing of toxin detection in one sample. PMID- 22500611 TI - Myocyte-depleted engineered cardiac tissues support therapeutic potential of mesenchymal stem cells. AB - The therapeutic potential of mesenchymal stem cells (MSCs) for restoring cardiac function after cardiomyocyte loss remains controversial. Engineered cardiac tissues (ECTs) offer a simplified three-dimensional in vitro model system to evaluate stem cell therapies. We hypothesized that contractile properties of dysfunctional ECTs would be enhanced by MSC treatment. ECTs were created from neonatal rat cardiomyocytes with and without bone marrow-derived adult rat MSCs in a type-I collagen and Matrigel scaffold using custom elastomer molds with integrated cantilever force sensors. Three experimental groups included the following: (1) baseline condition ECT consisting only of myocytes, (2) 50% myocyte-depleted ECT, modeling a dysfunctional state, and (3) 50% myocyte depleted ECT plus 10% MSC, modeling dysfunctional myocardium with intervention. Developed stress (DS) and pacing threshold voltage (VT) were measured using 2-Hz field stimulation at 37 degrees C on culture days 5, 10, 15, and 20. By day 5, DS of myocyte-depleted ECTs was significantly lower than baseline, and VT was elevated. In MSC-supplemented ECTs, DS and VT were significantly better than myocyte-depleted values, approaching baseline ECTs. Findings were similar through culture day 15, but lost significance at day 20. Trends in DS were partly explained by changes in the cell number and alignment with time. Thus, supplementing myocyte-depleted ECTs with MSCs transiently improved contractile function and compensated for a 50% loss of cardiomyocytes, mimicking recent animal studies and clinical trials and supporting the potential of MSCs for myocardial therapy. PMID- 22500612 TI - Peripheral blood stem cell collection in allogeneic donors: impact of venous access. AB - BACKGROUND: Peripheral blood stem cell (PBSC) collection is accepted as a routine procedure in related and unrelated healthy donors worldwide. Venous access can be accomplished by peripheral veins or a central venous catheter (CVC). STUDY DESING AND METHODS: We compared efficacy and tolerability of 40 PBSC collections via CVC with 6267 PBSC collections via peripheral veins in healthy allogeneic donors. Results of the leukapheresis procedures and side effects in the donors were evaluated. RESULTS: The median CD34+ cell counts on Day 5 and the results of the stem cell collection were not significantly different between the two groups of allogeneic donors. Pain or problems at the site of puncture or catheter insertion occurred in 58.6% of the donors with a CVC versus 37.8% of the donors with peripheral venous access (p = 0.03). The incidence and severity of paresthesia during the leukapheresis was not significantly different in both groups of donors (p = 0.09). During follow-up no major adverse events related to CVC were reported. CONCLUSION: Central femoral lines proved to be safe and tolerable in healthy allogeneic donors but peripheral venous access should be preferred, whenever possible. PMID- 22500613 TI - Psychopathological outcome of extratemporal lobe surgery: the need for international collaboration on data collection. PMID- 22500614 TI - Cell-free and cell-bound circulating nucleic acid complexes: mechanisms of generation, concentration and content. AB - INTRODUCTION: Extracellular nucleic acids are found in human blood and cell culture medium as cell-free or being adsorbed at cell surface. In the last years, the circulating extracellular nucleic acids in blood were shown to be associated with certain diseases. Attempts are made to develop non-invasive methods of early tumor diagnostics based on analysis of circulating DNA and RNA. AREAS COVERED: This article reviews accumulating data regarding cell-free and cell-surface-bound extracellular nucleic acid nature and generation mechanisms. Their existence as a constituent of the naturally occurring complexes with proteins or membrane bearing particles is discussed with regard to their homeostatic concentration and distribution in healthy donor blood which are significantly altered in cancer patients. Gene-target and whole-genome studies reveal significant differences in gene representation between extracellular DNA and genome DNA. Overrepresentation of regions with high transcription activity has led to proposal that extracellular DNA generation is strongly dependent on the parent genome functionality, which is associated with chromosome packaging and DNA methylation levels. EXPERT OPINION: Recent studies provide evidence of the circulating nucleome organization complexity indicating that discovery of extracellular DNA generation and circulation patterns in healthy condition and cancer is essential to enable the development of proper approaches for the selection of valid diagnostic markers. PMID- 22500615 TI - A high-throughput screen to identify inhibitors of ATP homeostasis in non replicating Mycobacterium tuberculosis. AB - Growing evidence suggests that the presence of a subpopulation of hypoxic non replicating, phenotypically drug-tolerant mycobacteria is responsible for the prolonged duration of tuberculosis treatment. The discovery of new antitubercular agents active against this subpopulation may help in developing new strategies to shorten the time of tuberculosis therapy. Recently, the maintenance of a low level of bacterial respiration was shown to be a point of metabolic vulnerability in Mycobacterium tuberculosis. Here, we describe the development of a hypoxic model to identify compounds targeting mycobacterial respiratory functions and ATP homeostasis in whole mycobacteria. The model was adapted to 1,536-well plate format and successfully used to screen over 600,000 compounds. Approximately 800 compounds were confirmed to reduce intracellular ATP levels in a dose-dependent manner in Mycobacterium bovis BCG. One hundred and forty non-cytotoxic compounds with activity against hypoxic non-replicating M. tuberculosis were further validated. The resulting collection of compounds that disrupt ATP homeostasis in M. tuberculosis represents a valuable resource to decipher the biology of persistent mycobacteria. PMID- 22500616 TI - Do proteomics analyses provide insights into reduced oxidative stress in the brain of an Alzheimer disease transgenic mouse model with an M631L amyloid precursor protein substitution and thereby the importance of amyloid-beta resident methionine 35 in Alzheimer disease pathogenesis? AB - The single methionine (Met/M) residue of amyloid-beta (Abeta) peptide, at position 35 of the 42-mer, has important relevance for Abeta-induced oxidative stress and neurotoxicity. Recent in vivo brain studies in a transgenic (Tg) Alzheimer disease (AD) mouse model with Swedish and Indiana familial AD mutations in human amyloid precursor protein (APP) (referred to as the J20 Tg mouse) demonstrated increased levels of oxidative stress. However, the substitution of the Met631 residue of APP to leucine (Leu/L) (M631L in human APP numbering, referred to as M631L Tg and corresponding to residue 35 of Abeta1-42) resulted in no significant in vivo oxidative stress levels, thereby supporting the hypothesis that Met-35 of Abeta contributes to oxidative insult in the AD brain. It is conceivable that oxidative stress mediated by Met-35 of Abeta is important in regulating numerous downstream effects, leading to differential levels of relevant biochemical pathways in AD. Therefore, in the current study using proteomics, we tested the hypothesis that several brain proteins involved in pathways such as energy and metabolism, antioxidant activity, proteasome degradation, and pH regulation are altered in J20Tg versus M631L Tg AD mice. PMID- 22500617 TI - Broadening the scope of debates around stem cell research. AB - Over the last decade, stem cell research has generated an enormous amount of public, political and bioethical debate. These debates have overwhelmingly tended to focus on two moral issues: the moral status of human embryos and the duty to care for the sick and vulnerable. This preoccupation, especially on the question of moral status, has not only dichotomized the debate around two fundamentally incommensurable positions, it has come at the cost of other important issues largely being ignored. In highlighting some of the bioethical and regulatory deficiencies of this fixation, we draw on recent developments in the experimental use of autologous adult stem cells to argue for a more inclusive approach to the ethical issues surrounding stem cell research. PMID- 22500618 TI - Aorto-pulmonary artery disruption following acute type-A aortic dissection repair with the use of BioGlue(r). AB - We report an extremely rare complication of a delayed aorto-pulmonary artery wall disruption with false aneurysm formation after repair of acute type-A aortic dissection with BioGlue(r). The potential role of BioGlue(r) in this complication is the subject of this report. PMID- 22500619 TI - Improving the quality of environmental measurements on short chain chlorinated paraffins to support global regulatory efforts. PMID- 22500620 TI - Rise of multi-resistant urinary tract infections. PMID- 22500621 TI - Concentrations and allelopathic effects of benzoxazinoid compounds in soil treated with rye (Secale cereale) cover crop. AB - The concentration of benzoxazinoids (BX) was measured in field soils at selected intervals after rye residue was either incorporated or left on the soil surface. The spectrum of compounds arising in the soil persisted approximately two weeks and was dominated by methoxy containing BX compounds, which were only minor components of the rye foliage. Growth assays with lettuce and smooth pigweed species showed inhibition when treated soils were tested during the first two weeks after rye applications; however, there were no sufficient concentrations of any one BX compound in the soil to explain these affects. Solution applications of two pure BX compounds, benzoxazolin-2(3H)-one (BOA) and 6-methoxy-benzoxazolin 2(3H)-one (MBOA), to the surface of soils revealed that movement into the soil column was minimal (greater than 70% BOA and 97% MBOA remained in the top 1-cm of soil profiles) and that the time course for their complete dissipation was less than 24 h. PMID- 22500622 TI - Fragile X syndrome therapeutics S(C)TEP through the developmental window. AB - Treatment for fragile X syndrome and related autism spectrum disorders has long been thought to be effective only during a narrow window early in development. In this issue of Neuron, Michalon et al. (2012) dispel this myth. PMID- 22500623 TI - Axonally translated SMADs link up BDNF and retrograde BMP signaling. AB - Axonal target-derived BMP and neurotrophin signaling are both known to regulate neuronal gene expression, differentiation, and axon growth. In this issue of Neuron, Ji and Jaffrey (2012) discovered that BMP-signaling endosomes depend on BDNF-induced axonal synthesis of SMADs to retrogradely regulate transcription in developing trigeminal neurons, providing a mechanism of integrating the two target-derived signals. PMID- 22500624 TI - Cysteine string protein alpha: a new role in vesicle recycling. AB - Zhang et al. (2012) and Rozas et al. (2012) in this issue of Neuron find that cysteine string protein alpha, a protein involved in neurodegeneration, regulates vesicle endocytosis via interaction with dynamin 1, which may participate in regulating synaptic transmission and possibly in maintaining synapses. PMID- 22500625 TI - Familiarity breeds plasticity: distinct effects of experience on putative excitatory and inhibitory neurons in inferior temporal cortex. AB - Primates have a remarkable capacity to recognize a vast array of visual objects, an ability that depends on experience. In this issue of Neuron, Woloszyn and Sheinberg (2012) report that putative excitatory and inhibitory neurons in inferior temporal cortex exhibit distinct influences long-term visual experience. PMID- 22500627 TI - Not noisy, just wrong: the role of suboptimal inference in behavioral variability. AB - Behavior varies from trial to trial even when the stimulus is maintained as constant as possible. In many models, this variability is attributed to noise in the brain. Here, we propose that there is another major source of variability: suboptimal inference. Importantly, we argue that in most tasks of interest, and particularly complex ones, suboptimal inference is likely to be the dominant component of behavioral variability. This perspective explains a variety of intriguing observations, including why variability appears to be larger on the sensory than on the motor side, and why our sensors are sometimes surprisingly unreliable. PMID- 22500626 TI - Toward a unified theory of visual area V4. AB - Visual area V4 is a midtier cortical area in the ventral visual pathway. It is crucial for visual object recognition and has been a focus of many studies on visual attention. However, there is no unifying view of V4's role in visual processing. Neither is there an understanding of how its role in feature processing interfaces with its role in visual attention. This review captures our current knowledge of V4, largely derived from electrophysiological and imaging studies in the macaque monkey. Based on recent discovery of functionally specific domains in V4, we propose that the unifying function of V4 circuitry is to enable selective extraction of specific functional domain-based networks, whether it be by bottom-up specification of object features or by top-down attentionally driven selection. PMID- 22500628 TI - Somatic activation of AKT3 causes hemispheric developmental brain malformations. AB - Hemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged, malformed cerebral hemisphere, typically causing epilepsy that requires surgical resection. We studied resected HMG tissue to test whether the condition might reflect somatic mutations affecting genes critical to brain development. We found that two out of eight HMG samples showed trisomy of chromosome 1q, which encompasses many genes, including AKT3, a gene known to regulate brain size. A third case showed a known activating mutation in AKT3 (c.49G->A, creating p.E17K) that was not present in the patient's blood cells. Remarkably, the E17K mutation in AKT3 is exactly paralogous to E17K mutations in AKT1 and AKT2 recently discovered in somatic overgrowth syndromes. We show that AKT3 is the most abundant AKT paralog in the brain during neurogenesis and that phosphorylated AKT is abundant in cortical progenitor cells. Our data suggest that somatic mutations limited to the brain could represent an important cause of complex neurogenetic disease. PMID- 22500629 TI - Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. AB - Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, but a crucial unanswered question is whether pharmacological mGlu5 inhibition is able to reverse an already established FXS phenotype in mammals. Here we have used the novel, potent, and selective mGlu5 inhibitor CTEP to address this issue in the Fmr1 knockout mouse. Acute CTEP treatment corrects elevated hippocampal long-term depression, protein synthesis, and audiogenic seizures. Chronic treatment that inhibits mGlu5 within a receptor occupancy range of 81% +/- 4% rescues cognitive deficits, auditory hypersensitivity, aberrant dendritic spine density, overactive ERK and mTOR signaling, and partially corrects macroorchidism. This study shows that a comprehensive phenotype correction in FXS is possible with pharmacological intervention starting in young adulthood, after development of the phenotype. It is of great interest how these findings may translate into ongoing clinical research testing mGlu5 inhibitors in FXS patients. PMID- 22500630 TI - Hub GABA neurons mediate gamma-frequency oscillations at ictal-like event onset in the immature hippocampus. AB - Gamma-frequency oscillations (GFOs, >40 Hz) are a general network signature at seizure onset at all stages of development, with possible deleterious consequences in the immature brain. At early developmental stages, the simultaneous occurrence of GFOs in different brain regions suggests the existence of a long-ranging synchronizing mechanism at seizure onset. Here, we show that hippocamposeptal (HS) neurons, which are GABA long-range projection neurons, are mandatory to drive the firing of hippocampal interneurons in a high-frequency regime at the onset of epileptiform discharges in the intact, immature septohippocampal formation. The synchronized firing of interneurons in turn produces GFOs, which are abolished after the elimination of a small number of HS neurons. Because they provide the necessary fast conduit for pacing large neuronal populations and display intra- and extrahippocampal long-range projections, HS neurons appear to belong to the class of hub cells that play a crucial role in the synchronization of developing networks. PMID- 22500631 TI - Intralineage directional Notch signaling regulates self-renewal and differentiation of asymmetrically dividing radial glia. AB - Asymmetric division of progenitor/stem cells generates both self-renewing and differentiating progeny and is fundamental to development and regeneration. How this process is regulated in the vertebrate brain remains incompletely understood. Here, we use time-lapse imaging to track radial glia progenitor behavior in the developing zebrafish brain. We find that asymmetric division invariably generates a basal self-renewing daughter and an apical differentiating sibling. Gene expression and genetic mosaic analysis further show that the apical daughter is the source of Notch ligand that is essential to maintain higher Notch activity in the basal daughter. Notably, establishment of this intralineage and directional Notch signaling requires the intrinsic polarity regulator Partitioning defective protein-3 (Par-3), which segregates the fate determinant Mind bomb unequally to the apical daughter, thereby restricting the self-renewal potential to the basal daughter. These findings reveal with single-cell resolution how self-renewal and differentiation become precisely segregated within asymmetrically dividing neural progenitor/stem lineages. PMID- 22500632 TI - Sox9 and NFIA coordinate a transcriptional regulatory cascade during the initiation of gliogenesis. AB - Transcriptional cascades that operate over the course of lineage development are fundamental mechanisms that control cellular differentiation. In the developing central nervous system (CNS), these mechanisms are well characterized during neurogenesis, but remain poorly defined during neural stem cell commitment to the glial lineage. NFIA is a transcription factor that plays a crucial role in the onset of gliogenesis; we found that its induction is regulated by the transcription factor Sox9 and that this relationship mediates the initiation of gliogenesis. Subsequently, Sox9 and NFIA form a complex and coregulate a set of genes induced after glial initiation. Functional studies revealed that a subset of these genes, Apcdd1 and Mmd2, perform key migratory and metabolic roles during astro-gliogenesis, respectively. In sum, these studies delineate a transcriptional regulatory cascade that operates during the initiation of gliogenesis and identifies a unique set of genes that regulate key aspects of astro-glial precursor physiology during development. PMID- 22500633 TI - Intra-axonal translation of SMAD1/5/8 mediates retrograde regulation of trigeminal ganglia subtype specification. AB - In many cases, neurons acquire distinct identities as their axons navigate toward target cells and encounter target-derived signaling molecules. These molecules generate retrograde signals that activate subtype-specific gene transcription. Mechanisms by which axons convert the complex milieu of signaling molecules into retrograde signals are not fully understood. Here, we examine retrograde signaling mechanisms that specify neuronal identity in the trigeminal ganglia, which relays sensory information from the face to the brain. We find that neuron specification requires the sequential action of two target-derived factors, BDNF and BMP4. BDNF induces the translation of axonally localized SMAD1/5/8 transcripts. Axon-derived SMAD1/5/8 is translocated to the cell body, where it is phosphorylated to a transcriptionally active form by BMP4-induced signaling endosomes and mediates the transcriptional effects of target-derived BDNF and BMP4. Thus, local translation functions as a mechanism by which coincident signals are converted into a retrograde signal that elicits a specific transcriptional response. PMID- 22500634 TI - 14-3-3epsilon couples protein kinase A to semaphorin signaling and silences plexin RasGAP-mediated axonal repulsion. AB - The biochemical means through which multiple signaling pathways are integrated in navigating axons is poorly understood. Semaphorins are among the largest families of axon guidance cues and utilize Plexin (Plex) receptors to exert repulsive effects on axon extension. However, Semaphorin repulsion can be silenced by other distinct cues and signaling cascades, raising questions of the logic underlying these events. We now uncover a simple biochemical switch that controls Semaphorin/Plexin repulsive guidance. Plexins are Ras/Rap family GTPase activating proteins (GAPs) and we find that the PlexA GAP domain is phosphorylated by the cAMP-dependent protein kinase (PKA). This PlexA phosphorylation generates a specific binding site for 14-3-3epsilon, a phospho binding protein that we find to be necessary for axon guidance. These PKA mediated Plexin-14-3-3epsilon interactions prevent PlexA from interacting with its Ras family GTPase substrate and antagonize Semaphorin repulsion. Our results indicate that these interactions switch repulsion to adhesion and identify a point of convergence for multiple guidance molecules. PMID- 22500635 TI - Calcium-dependent dephosphorylation of the histone chaperone DAXX regulates H3.3 loading and transcription upon neuronal activation. AB - Activity-dependent modifications of chromatin are believed to contribute to dramatic changes in neuronal circuitry. The mechanisms underlying these modifications are not fully understood. The histone variant H3.3 is incorporated in a replication-independent manner into different regions of the genome, including gene regulatory elements. It is presently unknown whether H3.3 deposition is involved in neuronal activity-dependent events. Here, we analyze the role of the histone chaperone DAXX in the regulation of H3.3 incorporation at activity-dependent gene loci. DAXX is found to be associated with regulatory regions of selected activity-regulated genes, where it promotes H3.3 loading upon membrane depolarization. DAXX loss not only affects H3.3 deposition but also impairs transcriptional induction of these genes. Calcineurin-mediated dephosphorylation of DAXX is a key molecular switch controlling its function upon neuronal activation. Overall, these findings implicate the H3.3 chaperone DAXX in the regulation of activity-dependent events, thus revealing a new mechanism underlying epigenetic modifications in neurons. PMID- 22500637 TI - Motorneurons require cysteine string protein-alpha to maintain the readily releasable vesicular pool and synaptic vesicle recycling. AB - Cysteine string protein-alpha (CSP-alpha) is a synaptic vesicle protein that prevents activity-dependent neurodegeneration by poorly understood mechanisms. We have studied the synaptic vesicle cycle at the motor nerve terminals of CSP-alpha knock-out mice expressing the synaptopHluorin transgene. Mutant nerve terminals fail to sustain prolonged release and the number of vesicles available to be released decreases. Strikingly, the SNARE protein SNAP-25 is dramatically reduced. In addition, endocytosis during the stimulus fails to maintain the size of the recycling synaptic vesicle pool during prolonged stimulation. Upon depolarization, the styryl dye FM 2-10 becomes trapped and poorly releasable. Consistently with the functional results, electron microscopy analysis revealed characteristic features of impaired synaptic vesicle recycling. The unexpected defect in vesicle recycling in CSP-alpha knock-out mice provides insights into understanding molecular mechanisms of degeneration in motor nerve terminals. PMID- 22500636 TI - Identification of CSPalpha clients reveals a role in dynamin 1 regulation. AB - Cysteine string protein alpha (CSPalpha), a presynaptic cochaperone for Hsc70, is required for synapse maintenance. Deletion of CSPalpha leads to neuronal dysfunction, synapse loss, and neurodegeneration. We utilized unbiased, systematic proteomics to identify putative CSPalpha protein clients. We found 22 such proteins whose levels are selectively decreased in CSPalpha knockout synapses. Of these putative CSPalpha protein clients, two directly bind to the CSPalpha chaperone complex and are bona fide clients. They are the t-SNARE SNAP 25 and the GTPase dynamin 1, which are necessary for synaptic vesicle fusion and fission, respectively. Using hippocampal cultures, we show that CSPalpha regulates the stability of client proteins and synaptic vesicle number. Our analysis of CSPalpha-dynamin 1 interactions reveals unexpectedly that CSPalpha regulates the polymerization of dynamin 1. CSPalpha, therefore, participates in synaptic vesicle endocytosis and may facilitate exo- and endocytic coupling. These findings advance the understanding of how synapses are functionally and structurally maintained. PMID- 22500638 TI - TOR is required for the retrograde regulation of synaptic homeostasis at the Drosophila neuromuscular junction. AB - Homeostatic mechanisms operate to stabilize synaptic function; however, we know little about how they are regulated. Exploiting Drosophila genetics, we have uncovered a critical role for the target of rapamycin (TOR) in the regulation of synaptic homeostasis at the Drosophila larval neuromuscular junction. Loss of postsynaptic TOR disrupts a retrograde compensatory enhancement in neurotransmitter release that is normally triggered by a reduction in postsynaptic glutamate receptor activity. Moreover, postsynaptic overexpression of TOR or a phosphomimetic form of S6 ribosomal protein kinase, a common target of TOR, can trigger a strong retrograde increase in neurotransmitter release. Interestingly, heterozygosity for eIF4E, a critical component of the cap-binding protein complex, blocks the retrograde signal in all these cases. Our findings suggest that cap-dependent translation under the control of TOR plays a critical role in establishing the activity dependent homeostatic response at the NMJ. PMID- 22500639 TI - Calcium-activated chloride channels (CaCCs) regulate action potential and synaptic response in hippocampal neurons. AB - Central neurons respond to synaptic inputs from other neurons by generating synaptic potentials. Once the summated synaptic potentials reach threshold for action potential firing, the signal propagates leading to transmitter release at the synapse. The calcium influx accompanying such signaling opens calcium activated ion channels for feedback regulation. Here, we report a mechanism for modulating hippocampal neuronal signaling that involves calcium-activated chloride channels (CaCCs). We present evidence that CaCCs reside in hippocampal neurons and are in close proximity of calcium channels and NMDA receptors to shorten action potential duration, dampen excitatory synaptic potentials, impede temporal summation, and raise the threshold for action potential generation by synaptic potential. Having recently identified TMEM16A and TMEM16B as CaCCs, we further show that TMEM16B but not TMEM16A is important for hippocampal CaCC, laying the groundwork for deciphering the dynamic CaCC modulation of neuronal signaling in neurons important for learning and memory. PMID- 22500640 TI - Effects of long-term visual experience on responses of distinct classes of single units in inferior temporal cortex. AB - Primates can learn to recognize a virtually limitless number of visual objects. A candidate neural substrate for this adult plasticity is the inferior temporal cortex (ITC). Using a large stimulus set, we explored the impact that long-term experience has on the response properties of two classes of neurons in ITC: broad spiking (putative excitatory) cells and narrow-spiking (putative inhibitory) cells. We found that experience increased maximum responses of putative excitatory neurons but had the opposite effect on maximum responses of putative inhibitory neurons, an observation that helps to reconcile contradictory reports regarding the presence and direction of this effect. In addition, we found that experience reduced the average stimulus-evoked response in both cell classes, but this decrease was much more pronounced in putative inhibitory units. This latter finding supports a potentially critical role of inhibitory neurons in detecting and initiating the cascade of events underlying adult neural plasticity in ITC. PMID- 22500641 TI - Hydrophobic substituent effects on proline catalysis of aldol reactions in water. AB - Derivatives of 4-hydroxyproline with a series of hydrophobic groups in well defined orientations have been tested as catalysts for the aldol reactions. All of the modified proline catalysts carry out the intermolecular aldol reaction in water and provide high diastereoselectivity and enantioselectivity. Modified prolines with aromatic groups syn to the carboxylic acid are better catalysts than those with small hydrophobic groups (1a is 43.5 times faster than 1f). Quantum mechanical calculations provide transition structures, TS-1a(water) and TS-1f(water), that support the hypothesis that a stabilizing hydrophobic interaction occurs with 1a. PMID- 22500642 TI - Decomposition pathways of Z-selective ruthenium metathesis catalysts. AB - The decomposition of a Z-selective ruthenium metathesis catalyst and structurally similar analogues has been investigated utilizing X-ray crystallography and density functional theory. Isolated X-ray crystal structures suggest that recently reported C-H activated catalysts undergo decomposition via insertion of the alkylidene moiety into the chelating ruthenium-carbon bond followed by hydride elimination, which is supported by theoretical calculations. The resulting ruthenium hydride intermediates have been implicated in previously observed olefin migration, and thus lead to unwanted byproducts in cross metathesis reactions. Preventing these decomposition modes will be essential in the design of more active and selective Z-selective catalysts. PMID- 22500643 TI - Clinical effect of pricking blood at neiyingxiang (ExHN 9) on non-allergic rhinopathy: study protocol for a randomized controlled trial. AB - BACKGROUND: Non-allergic rhinopathy (NAR), formerly known as vasomotor rhinitis, is a non-allergic and non-infectious chronic disease that is accompanied by nasal hyperemia, rhinorrhea, and no increase in the number of eosinophils. Although the medications for NAR, including intranasal corticosteroids and intranasal antihistamine, have been used in clinical practice, given the relative paucity of effective therapy with available medications, alternative non-pharmacologic treatments could play an important role in treating NAR. Acupuncture treatment is representative potential alternative therapy for the treatment of various diseases, including rhinitis. Therefore, the objective of this study was to evaluate the efficacy of pricking blood at Neiyingxiang (ExHN 9) relative to acupuncture treatment at Waiyingxiang (LI 20) in patients with NAR. METHODS/DESIGN: A randomized, parallel-group, controlled, assessor single blinded, trial will be conducted. Fifty participants with NAR will be randomized into one of two groups: either the control group with acpuncture treatment at LI 20 or the experimental group with pricking blood at ExHN 9. After randomization, a total of three sessions of treatment will be performed once a week in both groups. The total nasal symptom score (TNSS) and the Mini-Rhinoconjunctivitis Quality-of-Life Questionnaire (MiniRQLQ) at baseline and the end of the trial will be used to evaluate the efficacy of each treatment. DISCUSSION: This study will be the first randomized trial to evaluate the efficacy of pricking blood for the treatment of NAR. The results of this study will help establish an alternative approach for treating patients with NAR that do not respond to Western medication. PMID- 22500644 TI - Comparison of CD20 expression in B-cell lymphoma between newly diagnosed, untreated cases and those after rituximab treatment. AB - Few studies have statistically investigated reduced CD20 expression in B-cell lymphoma after rituximab therapy and genomic mutation of CD20 associated with reduction. We examined CD20-positive rate in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) by flow cytometry (FCM) and immunohistochemical staining (IHS), comparing 138 cases after rituximab therapy with 360 initial, not yet treated cases. Sequence analysis of exons 3 to 8 of CD20 was performed on 22 cases with low CD20-positive rate after rituximab treatment. The results showed a statistical correlation between CD20-positive rate in FCM and IHS. By FCM, the CD20-positive rate among post-rituximab cases was significantly lower than among initial cases in DLBCL, non-germinal center origin B-cell type (average values [avg] 57.8 and 87.9, respectively) (P < 0.0001), FL2 (avg, 93.9; 103.2) (P = 0.0083), and FL3A (avg, 90.6; 100.7) (P = 0.033). Stratified analyses of post rituximab cases showed significantly lower CD20-positive rate in cases that were resistant at the start of the treatment and cases with progressive disease during rituximab therapy before biopsy. Sequence analysis showed silent mutation of exon 4 (632 C/T) in seven cases, although this number was not statistically significant. These results suggest the influence of B-lymphoma subtype and a therapeutic effect before biopsy on CD20 expression at relapse and contribute to a better therapeutic approach for relapse cases after rituximab therapy. PMID- 22500645 TI - Race and region have independent and synergistic effects on dietary intakes in black and white women. AB - BACKGROUND: Few studies have examined the effects of race and region on dietary intakes and the evidence on racial and regional disparities among women is limited. We aimed to examine whether race and region were associated with nutrient intakes among black and white women living in the Stroke Belt, Stroke Buckle, and Other regions in the United States. We hypothesized that significant differences would be observed among population sub-groups and that the effects of race on dietary intakes would vary across regions. METHODS: This study included dietary data from 12,105 women from the Reasons for Geographic and Racial Differences in Stroke study (United States). Dietary data were collected using the Block 98 food frequency questionnaire. RESULTS: Blacks consumed 1.05% lower energy from saturated fat (95% CI: -0.95, -1.16), and intakes were also lower in the Buckle (beta = -0.20; 95% CI: -0.08, -0.32) and Belt (beta = -0.35; 95% CI: 0.24, -0.46) compared to the Other regions. Within each region, sodium, potassium, and magnesium intakes were all lower among black women compared to white women (P <0.05 for all); intakes were significantly lower among blacks living in the Belt and Buckle compared to those in the Other regions. Significant interactions between race and region were detected for trans fat, calcium, and cholesterol (P <0.05 for all), where black women in the Other regions consumed the lowest dietary cholesterol and calcium while black women in the Belt consumed the lowest trans fat. CONCLUSIONS: Race and region were significantly associated with nutrient intakes in a large study of black and non-Hispanic white women in the United States. Intakes of trans fat, calcium, and cholesterol among black and white women differed across regions. Race and region thus interact to impact dietary intakes, and their effects may be mediated by such factors as the broader food environment and food availability as well as food customs and culture. Race, region, and their correlates should therefore be considered together when examining diet and disease associations and planning dietary advice for population sub-groups. PMID- 22500646 TI - Treating pediatric migraine: an expert opinion. AB - INTRODUCTION: Headaches are common in children and adolescents and migraine affects almost 8% of this population. As revisions are made to the ICHD-II criteria to include additional characteristics of pediatric migraine, the diagnosis of migraine is expected to increase. Therefore, it is important to understand and apply successful treatment in acute migraine. Patients and families should be educated about the options for migraine treatment that includes both pharmacologic and conservative behavioral techniques in managing headaches. AREAS COVERED: This review examines the studies that have been performed in pediatric patients, in addition to exploring the treatment options commonly used in pediatrics and adolescents for migraine and their rationale for use. EXPERT OPINION: For the acute treatment of migraine, we recommend the use of ibuprofen or acetaminophen for mild, moderate or severe headache. For moderate to severe headache, or for headaches that fail to respond to over-the-counter medications, we recommend the use of a triptan or combination NSAID/triptan therapy. For preventative treament of migraine, cyproheptadine should be reserved for younger children unable to swallow tablets while amitriptyline is preferred due to its once daily dosing and minimal side effects. Topiramate and divalproate are considerable options depending on patient co-morbid profile and preference. PMID- 22500647 TI - A new non-invasive prenatal diagnosis of Down syndrome through epigenetic markers and real-time qPCR. AB - INTRODUCTION: Non-invasive prenatal diagnosis (NIPD) of Down syndrome is rapidly evolving. Currently, two applications for NIPD of Down syndrome have been developed with potential and have displayed positive results; the NIPD using next generation sequencing technologies and the NIPD using the methylated DNA immunoprecipitation (MeDIP) real-time quantitative polymerase chain reaction (qPCR). AREAS COVERED: The MeDIP real-time qPCR approach is based on the identification of differentially methylated regions (DMRs) and their use for discriminating normal from Down syndrome cases. DMRs were identified using high resolution oligo-arrays. A subgroup of DMRs was selected for further investigation. Through the design of a discriminant equation which combines the results obtained from different DMRs, normal and abnormal cases are correctly classified indicating 100% sensitivity and specificity. EXPERT OPINION: Previous studies have also identified DMRs between non-pregnant female blood and placental DNA. However, these methods have been associated with a number of limitations including the low sensitivity and/or specificity of the assays, the limited number of identified DMRs or methylation sensitive sites and SNPs located on DMRs. These limitations have been overawed by the development of the MeDIP real time qPCR-based methodology. PMID- 22500648 TI - Ion mobility spectrometry: a comprehensive and versatile tool for occupational pharmaceutical exposure assessment. AB - The qualitative and quantitative capabilities of ion mobility spectrometry (IMS) as a comprehensive and powerful tool in workplace air monitoring have been demonstrated on the example of a Spanish pharmaceutical company. The developed IMS based procedure is capable of detecting and determining in air samples the active pharmaceutical ingredients (APIs) manipulated and/or produced in this pharmaceutical industry. Sensitivity, in the ng-pg range, selectivity, possibly to provide results in near real time, and reduction of analysis costs are the most important properties that ratify IMS as a serious alternative in occupational exposure assessment. The possibility of false positives by drift time interferences and false negatives by competitive ionization and also desorption process interferences has been deeply evaluated. Moreover, chemometric strategies based on self-modeling curve resolution (SMCR) have been applied to obtain qualitative and quantitative individual component information from overlapped peaks. The IMS procedure has been successfully applied to evaluate the concentration of APIs (nimesulide, dexketoprofen, deflazacort) handled by the pharmaceutical company employees in the making of tablets and granulates, and control measures have been suggested in accordance. PMID- 22500649 TI - Risk perception and behaviors: anticipating and responding to crises. PMID- 22500650 TI - The dynamics of evolving beliefs, concerns emotions, and behavioral avoidance following 9/11: a longitudinal analysis of representative archival samples. AB - September 11 created a natural experiment that enables us to track the psychological effects of a large-scale terror event over time. The archival data came from 8,070 participants of 10 ABC and CBS News polls collected from September 2001 until September 2006. Six questions investigated emotional, behavioral, and cognitive responses to the events of September 11 over a five year period. We found that heightened responses after September 11 dissipated and reached a plateau at various points in time over a five-year period. We also found that emotional, cognitive, and behavioral reactions were moderated by age, sex, political affiliation, and proximity to the attack. Both emotional and behavioral responses returned to a normal state after one year, whereas cognitively-based perceptions of risk were still diminishing as late as September 2006. These results provide insight into how individuals will perceive and respond to future similar attacks. PMID- 22500651 TI - Pseudomonas aeruginosa-derived rhamnolipids subvert the host innate immune response through manipulation of the human beta-defensin-2 expression. AB - Pseudomonas aeruginosa is a well-known cause of infections especially in compromised patients. To neutralize this pathogen, the expression of antimicrobial factors in epithelial cells is crucial. In particular the human beta-defensin hBD-2 is especially active against P. aeruginosa. In this study, we identified rhamnolipids in P. aeruginosa culture supernatants that are able to prevent the pathogen-induced hBD-2 response in keratinocytes. The presence of rhamnolipids within the host cells and inhibition assays suggest that calcium regulated pathways and protein kinase C activation are impaired by rhamnolipids. In consequence, the induction of hBD-2 in keratinocytes by P. aeruginosa-derived flagellin as well as the host's own hBD-2 mediator interleukin IL-1beta is inhibited. Strikingly, rhamnolipids did not affect the release of the proinflammatory mediator interleukin IL-8 by flagellin. Thus, in addition to their function in establishment and persistence of P. aeruginosa infections, rhamnolipids can be engaged by P. aeruginosa for a targeted attenuation of the innate immunity to manage its survival and colonization on compromised epithelia. PMID- 22500652 TI - Direct nanoscale observations of CO2 sequestration during brucite [Mg(OH)2] dissolution. AB - The dissolution and carbonation of brucite on (001) cleavage surfaces was investigated in a series of in situ and ex situ atomic force microscopy (AFM) experiments at varying pH (2-12), temperature (23-40 degrees C), aqueous NaHCO(3) concentration (10(-5)-1 M), and PCO(2) (0-1 atm). Dissolution rates increased with decreasing pH and increasing NaHCO(3) concentration. Simultaneously with dissolution of brucite, the growth of a Mg-carbonate phase (probably dypingite) was directly observed. In NaHCO(3) solutions (pH 7.2-9.3,), precipitation of Mg-carbonates was limited. Enhanced precipitation was, however, observed in acidified NaHCO(3) solutions (pH 5, DIC ~ 25.5 mM) and in solutions that were equilibrated under a CO(2) atmosphere (pH 4, DIC ~ 25.2 mM). Nucleation predominantly occurred in areas of high dissolution such as deep step edges suggesting that the carbonation reaction is locally diffusion-transport controlled. More extensive particle growth was also observed after ex situ experiments lasting for several hours. This AFM study contributes to an improved understanding of the mechanism of aqueous brucite carbonation at low temperature and pressure conditions and has implications for carbonation reactions in general. PMID- 22500653 TI - Psychopathology in children before and after surgery for extratemporal lobe epilepsy. AB - AIM: To establish the rates and types of psychiatric disorder in children before and after surgery for extratemporal epilepsy. Relationships between psychiatric morbidity and demographic/clinical variables were examined. METHOD: A retrospective case note review of 71 children undergoing extratemporal focal resection for drug resistant epilepsy in a specialist epilepsy surgery programme between 1997 and 2008. Psychiatric diagnoses were derived from pre- and postoperative assessments according to DSM-IV criteria. RESULTS: Seventy-one children (38 males, 33 females) were eligible for this study. Mean age (SD) at surgery was 9 (5) years. Frontal resections were performed in 73% of the children, parietal in 17%, and occipital in 10%. Mental health problems were present in 37 of 71 (52%) children pre- and/or postoperatively. A similar proportion of children had psychiatric diagnoses pre- and postoperatively: 31 of 71 (44%) and 32 of 71 (45%) respectively. INTERPRETATION: Psychopathology is common in children with extratemporal epilepsy. In this sample, the impact of surgery on psychiatric symptoms was not predictable: some children were unchanged, others improved, and others acquired new psychiatric diagnoses postoperatively. Given the high rates of psychiatric disorder in this group of patients, detection and treatment of mental health needs may be important. PMID- 22500654 TI - Tissue engineering for total meniscal substitution: animal study in sheep model- results at 12 months. AB - The aim of the study was to investigate the use of a hyaluronic acid/polycaprolactone material for meniscal tissue engineering and to evaluate the tissue regeneration after the augmentation of the implant with expanded autologous chondrocytes. Eighteen skeletally mature sheep were treated. The animals were divided into three groups: cell-free scaffold, scaffold seeded with autologous chondrocytes, and meniscectomy alone. The implant was sutured to the capsule and to the meniscal ligament. At a 12-month gross assessment, histology and histomorphometry were used to assess the meniscus implant, knee joint, and osteoarthritis development. All implants showed excellent capsular ingrowth at the periphery. The implant gross assessment showed significant differences between cell-seeded and cell-free groups (p=0.011). The histological analysis indicated a cellular colonization throughout the implanted constructs. Avascular cartilaginous tissue formation was significantly more frequent in the cell-seeded constructs. Joint gross assessment showed that sheep treated with scaffold implantation achieved a significant higher score than those underwent meniscectomy (p<0.0005), and the Osteoarthritis Research Society International score showed that osteoarthritic changes were significantly less in the cell seeded group than in the meniscectomy group (p=0.047), even though results were not significantly superior to those of the cell-free scaffold. Seeding of the scaffold with autologous chondrocytes increases its tissue regeneration capacity, providing a better fibrocartilaginous tissue formation. The study suggests the potential of the novel hyaluronic acid/polycaprolactone scaffold for total meniscal substitution, although this approach has to be further improved before being applied into clinical practice. PMID- 22500655 TI - High insulin-like growth factor mRNA-binding protein 3 (IMP3) protein expression is associated with poor survival in muscle-invasive bladder cancer. AB - What's known on the subject? and What does the study add? Insulin-like growth factor mRNA-binding protein 3 (IMP3) is an oncofetal protein found to be re expressed in a series of human cancers including bladder cancer. In vitro analyses showed an invasion and proliferation promoting effect for IMP3. Further in vitro studies suggested that IMP3 is able to bind to the mRNAs of CD44 and insulin-like growth factor 2 (IGF2), enhancing their stability and expression. However, this molecular interaction has not yet been analysed in tumour samples. In the present study, we identified for the first time high IMP3 tissue protein expression as an independent predictor of poor patients' survival in muscle invasive bladder cancer. Furthermore, there was no correlation between IMP3 and its molecular targets in bladder carcinoma specimens and concluded that the tumour-promoting effect of IMP3 is not related to its regulatory action on IGF2 and CD44. OBJECTIVE: To assess the prognostic value and molecular actions of the oncofetal protein insulin-like growth factor mRNA-binding protein 3 (IMP3) in muscle-invasive bladder cancer (BC). PATIENTS AND METHODS: IMP3 expression was analysed by immunohistochemistry, real-time polymerase chain reaction and Western blot analysis in 224 patients with BC. The molecular targets of IMP3; CD44, insulin-like growth factor 2 (IGF2) and its receptor the IGF1 receptor (IGF1-R) were also investigated. Expression levels were correlated with clinical follow-up data by using both univariate and multivariate Cox regression analyses. RESULTS: IMP3 mRNA and protein levels were significantly elevated in high-stage and high grade muscle-invasive BC. In muscle-invasive BC IMP3 protein but not gene expression proved to be an independent predictor of disease-specific (hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.28-4.56, P = 0.004) and overall survival (HR 2.07, 95% CI 1.12-3.82, P = 0.020). The expression levels of IGF2 and CD44 showed no correlation with that of IMP3. CONCLUSIONS: High IMP3 protein levels may identify patients with BC at high risk of disease progression and may therefore select patients for a more intensive therapy or for a strict follow-up. Its high expression in high-grade bladder carcinoma cells makes IMP3 for an attractive target for therapy. The tumour promoting effect of IMP3 is independent from its regulatory action on IGF2 and CD44 expression. PMID- 22500656 TI - Microwave-assisted extraction of bound phenolic acids in bran and flour fractions from sorghum and maize cultivars varying in hardness. AB - To release bound phenolic acids, a microwave-assisted extraction procedure was applied to bran and flour fractions obtained from eight sorghum and eight maize cultivars varying in hardness. The procedure was followed by HPLC analysis, and the identities of phenolic acids were confirmed by MS/MS spectra. The extraction of sorghum and maize bound phenolic acids was done for 90 s in 2 M NaOH to release ferulic acid and p-coumaric acid from bran and flour. Two diferulic acids, 8-O-4'- and 8-5'-benzofuran form, were identified and quantitated in sorghum bran, and only the former was found in maize bran. The contents of ferulic acid and diferulic acids in sorghum bran were 416-827 and 25-179 MUg/g, respectively, compared to 2193-4779 and 271-819 MUg/g in maize. Phenolic acid levels of sorghum were similar between hard and soft cultivars, whereas those of maize differed significantly (p < 0.05) except for ferulic acid in flour. Sorghum phenolic acids were not correlated with grain hardness as measured using a tangential abrasive decortication device. Maize ferulic acid (r = -0.601, p < 0.01), p-coumaric acid (r = -0.668, p < 0.01), and 8-O-4'-diferulic acid (r = 0.629, p < 0.01) were significantly correlated with hardness. PMID- 22500657 TI - Replication protein A unfolds G-quadruplex structures with varying degrees of efficiency. AB - Replication protein A (RPA) is known to interact with guanine- (G-) rich sequences that adopt G-quadruplex (GQ) structures. Most studies reported in the literature were performed on GQ formed by homogeneous sequences, such as the human telomeric repeat, and RPA's ability to unfold GQ structures of differing stability is not known. We compared the thermal stability of three potential GQ forming DNA sequences (PQSs) to their stability against RPA-mediated unfolding using single-molecule fluorescence resonance energy transfer (FRET) and bulk biophysical and biochemical experiments. One of these sequences is the human telomeric repeat and the other two, located in the promoter region of tyrosine hydroxylase gene, are highly heterogeneous sequences that better represent PQSs in the genome. The three GQ constructs have thermal stabilities that differ significantly. Our measurements showed that the most thermally stable structure (Tm = 86 degrees C) was also the most stable against RPA-mediated unfolding, although the least thermally stable structure (Tm = 69 degrees C) had at least an order-of-magnitude higher stability against RPA-mediated unfolding than the structure with intermediate thermal stability (Tm = 78 degrees C). The significance of this observation becomes more evident when considered within the context of the cellular environment where protein-DNA interactions can be an important determinant of GQ viability. Considering these results, we conclude that thermal stability is not necessarily an adequate criterion for predicting the physiological viability of GQ structures. Finally, we measured the time it takes for an RPA molecule to unfold a GQ from a fully folded to a fully unfolded conformation using a single-molecule stopped-flow method. All three GQ structures were unfolded within Deltat ~ 0.30 +/- 0.10 s, a surprising result considering that the unfolding time does not correlate with thermal stability or stability against RPA-mediated unfolding. These results suggest that the limiting step in G quadruplex unfolding by RPA is simply the accessibility of the structure to the RPA protein. PMID- 22500658 TI - The incidence of hepatitis C in patients with thalassemia after screening in blood transfusion centers: a fourteen-year study. AB - BACKGROUND: Blood safety is important in all transfusion centers. The aim has always been to try to guarantee the recipient's safety through careful screening and examination of donors' blood samples. In Iran the hepatitis C virus (HCV) screening test became mandatory for blood donations from 1996. We decided to determine the incidence of new cases of HCV in patients with thalassemia, after screening of blood bags was initiated. STUDY DESIGN AND METHODS: The study was done on patients with complete files for anti-HCV test results. Only cases that had a confirmed positive anti-HCV result after a negative result were considered as new cases. The incidence rate was estimated and expressed in person-years (PY). Also, for increased accuracy and comparison of incidence in recent years, the incidence rate was calculated at two 7-year intervals (1996-2002 and 2003 2009). RESULTS: A total of 395 files were studied with a mean age of 27.5 years (SD +/- 7.99 years). We had 109 (27.5%) anti-HCV positive, of which 21 (19.2% of positive cases) were exposed after 1996 and considered as new cases. The incidence of HCV cases in 14 years (1996-2009) was 4.2/1000 PY. The incidence in the first 7-year period (1996-2002) was 6.2/1000 PY and 1.3/1000 PY in the second 7-year period (2003-2009). CONCLUSION: The incidence of HCV is on the decline in Iran, both in blood donors and in recipients. We owe this to the improved blood safety in our transfusion center that has taken up better strategies. Even though the residual risk will never reach zero and we may still have new cases of HCV, it will definitely be with a lower rate. The fact that we have had no new cases among our patients with thalassemia since 2005 bears witness to this matter. PMID- 22500659 TI - A comprehensive yoga programs improves pain, anxiety and depression in chronic low back pain patients more than exercise: an RCT. AB - INTRODUCTION: Previously, outpatient Yoga programs for patients with chronic low back pain (CLBP) lasting several months have been found to reduce pain, analgesic requirement and disability, and improve spinal mobility. This study evaluated changes in pain, anxiety, depression and spinal mobility for CLBP patients on short-term, residential Yoga and physical exercise programs, including comprehensive yoga lifestyle modifications. METHODS: A seven day randomized control single blind active study in an residential Holistic Health Centre in Bangalore, India, assigned 80 patients (37 female, 43 male) with CLBP to yoga and physical exercise groups. The Yoga program consisted of specific asanas and pranayamas for back pain, meditation, yogic counselling, and lectures on yoga philosophy. The control group program included physical therapy exercises for back pain, and matching counselling and education sessions. RESULTS: Group*time interactions (p<0.05) and between group differences (p<0.05) were significant in all variables. Both groups' scores on the numerical rating scale for pain reduced significantly, 49% in Yoga (p<0.001, ES=1.62), 17.5% in controls (p=0.005, ES=0.67). State anxiety (STAI) reduced 20.4% (p<0.001, ES=0.72) and trait anxiety 16% (p<0.001, ES=1.09) in the yoga group. Depression (BDI) decreased in both groups, 47% in yoga (p<0.001, ES=0.96,) and 19.9% in controls (p<0.001, ES=0.59). Spinal mobility ('Sit and Reach' instrument) improved in both groups, 50%, in yoga (p<0.001, ES=2.99) and 34.6% in controls (p<0.001, ES=0.81). CONCLUSION: Seven days intensive residential Yoga program reduces pain, anxiety, and depression, and improves spinal mobility in patients with CLBP more effectively than physiotherapy exercises. PMID- 22500660 TI - Dietary selenium and major depression: a nested case-control study. AB - OBJECTIVES AND METHODS: Alterations in redox biology are established in depression; however, there are no prospective epidemiological data on redox active selenium in depression. We aimed to determine if low levels of dietary selenium are associated with an increased risk for de novo major depressive disorder (MDD). In this nested case-control study, women aged 20 years or more were identified from a randomly selected cohort being followed prospectively for the Geelong Osteoporosis Study. Cases were individuals with incident MDD, identified using the Structured Clinical Interview for DSM-IV-TR (SCID-I/NP); controls had no such history. Dietary selenium intake was measured using a food frequency questionnaire at baseline, together with anthropometric and lifestyle measures. RESULTS: Eighteen women who developed de novo MDD were classified as cases; there were 298 controls. Low dietary selenium intakes increased the likelihood of developing MDD; OR 2.74 (95%CI 0.95-7.89). After adjusting for age and SES, compared with a high selenium intake, a low intake (<8.9 MUg/MJ/day) was associated with an approximate trebling of the likelihood for developing de novo MDD; OR 2.95 (95%CI 1.00-8.72). Smoking, alcohol consumption and physical activity did not confound the association. CONCLUSION: These data suggest that lower dietary selenium intakes are associated with an increased risk of subsequent de novo MDD. We propose that selenium's function as an antioxidant, and as a constituent of selenoproteins that are important in redox homeostasis, warrants further investigation as a risk factor for depression, and suggest a potentially novel modifiable factor in the primary prevention and management of depression. PMID- 22500661 TI - Effect of collagen hydrolysate in articular pain: a 6-month randomized, double blind, placebo controlled study. AB - OBJECTIVE: Evaluation of the efficacy and safety of a food supplement made of collagen hydrolysate 1200 mg/day versus placebo during 6 months, in subjects with joint pain at the lower or upper limbs or at the lumbar spine. DESIGN: Comparative double-blind randomized multicenter study in parallel groups. SETTING: 200 patients of both genders of at least 50 years old with joint pain assessed as >=30 mm on a visual analogical scale (VAS). INTERVENTION: Collagen hydrolysate 1200 mg/day or placebo during 6 months. MAIN OUTCOME MEASURE: Comparison of the percentage of clinical responder between the active collagen hydrolysate group and the placebo group after 6 months of study. A responder subject was defined as a subject experiencing a clinically significant improvement (i.e. by 20% or more) in the most painful joint using the VAS score. All analyses were performed using an intent-to-treat procedure. RESULTS: At 6 months, the proportion of clinical responders to the treatment, according to VAS scores, was significantly higher in the collagen hydrolysate (CH) group 51.6%, compared to the placebo group 36.5% (p<0.05). However, there was no significant difference between groups at 3 months (44.1% vs. 39.6%, p=0.53). No significant difference in terms of security and tolerability was observed between the two groups. CONCLUSIONS: This study suggests that collagen hydrolysate 1200 mg/day could increase the number of clinical responders (i.e. improvement of at least 20% on the VAS) compared to placebo. More studies are needed to confirm the clinical interest of this food supplement. PMID- 22500662 TI - Acupuncture for symptoms of Gaucher disease. AB - OBJECTIVE: The purpose of this study was to examine the effect of acupuncture on bone/joint pain, headache and fatigue, as well as quality of life in patients with Gaucher disease (GD), within the framework of an integrated treatment programme. METHODS: Patients with GD suffering from any of the above symptoms were offered a series of 10-12 weekly acupuncture treatment sessions. Prior to initiation of treatment, participants were asked to score the severity of pain, as well as to complete the Functional Assessment of Chronic Illness Therapy Fatigue measure (FACIT-F) and the Medical Outcomes Study (MOS) Short-Form (SF) questionnaire. These tools were evaluated again at the end of the treatment period. RESULTS: A total of 12 patients were evaluated. While the only pain outcome reduced by acupuncture was knee pain, a significant improvement was observed with respect to nearly all FACIT-Fatigue measures, including the Physical Well Being (PWB) subscales and the SF-12 Physical Composite Score (PCS), though not for the Mental Composite Score (MCS). Patients reported satisfaction with the treatment process, and no significant side effects were reported. CONCLUSION: Acupuncture may play a beneficial role for patients with GD when used in conjunction with conventional therapy, reducing fatigue and improving physical function. The preliminary finding of this observational study should encourage further research. PMID- 22500663 TI - Health services use among young Australian women with allergies, hayfever and sinusitis: a longitudinal analysis. AB - OBJECTIVES: The existing knowledge base on the use of complementary and alternative medicine among patients with allergies is built upon findings of cross-sectional surveys and there is a lack of longitudinal data. There is also a lack of studies that examine both the use of conventional medicine and complementary and alternative medicine among allergy patients. DESIGN AND SETTING: This paper reports the findings of the first ever longitudinal study of the use of conventional providers, practitioners of complementary and alternative medicine, and self-prescribed modalities amongst women with allergies, hayfever and sinusitis from a large nationally representative sample. MAIN OUTCOME MEASURES: Analysis focused upon data from 7538 women from the younger cohort of the Australian Longitudinal Study on Women's Health collected between 1996 and 2006. Chi-square tests were employed to compare the groups across consultations and self-prescribed treatments and one-way analysis of variance was used to compare the groups across health status. A modified Bonferroni test was used to correct for multiple comparisons. RESULTS: The study identified that women who sought help for their allergic disorder were more likely to consult a range of practitioners and self-prescribed complementary and alternative medicine than women who either did not seek help or did not have allergic disorders. The analysis shows that many women with allergic disorders use complementary and alternative medicine alongside or as a complement to conventional healthcare services. CONCLUSIONS: The frequent use of a range of conventional providers and practitioner-based and self-prescribed complementary and alternative medicine amongst women with allergic disorders warrants further investigation. PMID- 22500664 TI - Clinical efficacy and safety of Chinese herbal medicine for Wilson's disease: a systematic review of 9 randomized controlled trials. AB - Wilson's disease is an autosomal recessive disorder of copper metabolism. Despite being treatable, there is no universally accepted treatment regimen. Currently, various Chinese herbal medicines (CHMs) are widely used in the treatment of Wilson's disease in China, but there is a lack of reliable scientific evidence for the effectiveness of such therapies. The objective of this systematic review is to assess the clinical efficacy and safety of CHM as an alternative or/and adjuvant therapy for Wilson's disease. A systematic literature search in different medical databases was performed to identify randomized controlled trials comparing CHM as monotherapy or CHM as adjuvant therapy with western conventional medical therapy in the treatment of Wilson's disease. A total of 687 participants were included in nine eligible studies. The main findings are that CHM as monotherapy or adjuvant therapy for Wilson's disease may be able to improve the clinical symptoms, to promote the urinary copper excretion, to ameliorate liver function and/or liver cirrhosis, and has fewer adverse effects in comparison with western conventional medication. Furthermore, CHM generally appeared to be safe and well tolerated in patients with Wilson's disease. However, the evidence presented in this review are insufficient to warrant a clinical recommendation due to the generally low methodological quality of the included studies. In conclusion, CHM seems to be beneficial and safe for Wilson's disease, but high-quality evidences are still needed to further evaluate this therapy. Therefore, additional well-designed, randomized, placebo-controlled clinical trials are needed. PMID- 22500665 TI - Could ginseng-based medicines be better than nitrates in treating ischemic heart disease? A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Ginseng-based medicines and nitrates are commonly used in treating ischemic heart disease (IHD) angina pectoris in China. Hundreds of randomized controlled trials (RCTs) reported in Chinese language claimed that ginseng-based medicines can relieve the symptoms of IHD. This study provides the first PRISMA compliant systematic review with sensitivity and subgroup analyses to evaluate the RCTs comparing the efficacies of ginseng-based medicines and nitrates in treating ischemic heart disease, particularly angina pectoris. METHODS: Past RCTs published up to 2010 on ginseng versus nitrates in treating IHD for 14 or more days were retrieved from major English and Chinese databases, including PubMed, Science Direct, Cochrane Library, WangFang Data, and Chinese National Knowledge Infrastructure. The qualities of included RCTs were assessed with Jadad scale, a refined Jadad scale called M scale, CONSORT 2010 checklist, and Cochrane risk of bias tool. Meta-analysis was performed on the primary outcomes including the improvement of symptoms and electrocardiography (ECG). Subgroup analysis, sensitivity analysis, and meta-regression were performed to evaluate the effects of study characteristics of RCTs, including quality, follow-up periods, and efficacy definitions on the overall effect size of ginseng. RESULTS: Eighteen RCTs with 1549 participants were included. Overall odds ratios for comparing ginseng-based medicines with nitrates were 3.00 (95% CI: 2.27-3.96) in symptom improvement (n=18) and 1.61 (95% CI: 1.20-2.15) in ECG improvement (n=10). Subgroup analysis, sensitivity analysis, and meta-regression found no significant difference in overall effects among all study characteristics, indicating that the overall effects were stable. CONCLUSION: The meta-analysis of 18 eligible RCTs demonstrates moderate evidence that ginseng is more effective than nitrates for treating angina pectoris. However, further RCTs for higher quality, longer follow-up periods, lager sample size, multi-center/country, and are still required to verify the efficacy. PMID- 22500668 TI - Can old observations explain the pathogenesis of SMA? PMID- 22500666 TI - Mid-term results of tricuspid annuloplasty with a three-dimensional remodelling ring. AB - OBJECTIVE: To assess the results of tricuspid annuloplasty performed with the Edwards MC3 remodeling ring. METHODS: From 2005 to 2007, 140 patients with tricuspid regurgitation (TR) secondary to left-sided valve disease (mean age 63.8 +/- 11.6, permanent pacemaker in 7.8%, LVEF 56.4 +/- 10.1%, LVEDD 54.1 +/- 8 mm, SPAP 52.5 +/- 14.4 mmHg) underwent tricuspid annuloplasty using the MC3 ring. Dilatation of the tricuspid annulus was present in all patients. Other concomitant mechanisms of TR (moderate leaflet prolapse, pacemaker wires, leaflets' retraction) were documented in 21 cases (15%). All patients underwent concomitant left-sided valve surgery. Ring size was between 28 and 32 in 84.3% of patients. RESULTS: Hospital mortality was 3.5% and actuarial survival at 3 years 94.8 +/- 2.1%. Mean follow-up of the 135 hospital survivors was 22 +/- 9.5 months (median 23 months). Echocardiography at hospital discharge documented no or mild TR in 119 patients (87%), moderate TR (2+/4+) in 15 (11%) and moderate-to-severe (3+/4+) in 1 patient (0.7%). At echocardiographic follow-up moderate TR was present in 14 patients (10.3%) and moderate-to-severe TR in 2 (1.4%). At 3 years freedom from TR >= 2+ was 88.1 +/- 2.78% and freedom from TR >= 3+ was 94.3 +/- 4.89. Predictors of TR >= 2+ at hospital discharge and at follow-up were preoperative LVEF (OR:0.8; p = 0.001 at discharge; HR:0.9; p = 0.003 at follow up) and the presence of other mechanisms of TR besides annular dilatation (OR:10.8; p = 0.007 at discharge; HR:6.1; p = 0.003 at follow-up). CONCLUSION: Tricuspid annuloplasty with the MC3 ring provides satisfactory early results which remain stable at mid-term follow-up. The presence of other mechanisms besides annular dilatation leads to residual valve insufficiency after ring annuloplasty alone. PMID- 22500669 TI - Formation of HO2 radicals from the 248 nm two-photon excitation of different aromatic hydrocarbons in the presence of O2. AB - The excitation energy dependence of HO(2) radical formation from the 248 nm irradiation of four different aromatic hydrocarbons (benzene, toluene, o-xylene, and mesitylene) in the presence of O(2) has been studied. HO(2) has been monitored at 6638.20 cm(-1) by cw-CRDS, and the formation of a short-lived, unidentified species, showing broad-band absorption around the HO(2) absorption line, has been observed. For all four hydrocarbons, the same HO(2) formation pattern has been observed: HO(2) is formed immediately on our time scale after the excitation pulse, followed by a formation of more HO(2) on a much longer time scale. Taking into account the absorption of the short-lived species, the yields of both types of HO(2) radicals are in agreement with a formation following 2 photon absorption by the aromatic hydrocarbons. The yields do not much depend on the nature of the aromatic hydrocarbon. For practical use in past and future experiments on aromatic hydrocarbons, an empirical value is given, allowing the estimation of the total concentration of HO(2) radicals formed at 40 Torr He in the presence of around [O(2)] = 1 * 10(17)cm(-3) as a function of the 248 nm excitation energy: [HO(2)]/[aromatic hydrocarbon] ~ 2 * 10(-6) * E(2) (with E in mJ cm(-2)). PMID- 22500672 TI - Contemporary issues in rural surgery. PMID- 22500673 TI - Lessons to be learned from the clinical management of a MEN 2A patient bearing a novel 634/640/700 mutation of the RET proto-oncogene. PMID- 22500674 TI - Primary progressive apraxia of speech (AOS) in a patient with Pick's disease with Pick bodies: a neuropsychological and anatomical study and review of literatures. AB - A 56-year-old right-handed man suffered from progressive apraxia of speech (AOS), characterized by agrammatism and buccofacial apraxia. He also became mute at the later stages of the disease progression. At autopsy, the left precentral gyrus, pars opercularis, and hippocampus showed severe atrophy. Pick bodies and Pick cells were observed. In this report, we also review previous case reports of AOS. Pick's disease is among the most commonly associated of the major diseases. Brain lesions associated with AOS may be found in regions such as the precentral gyrus and the pars opercularis in the left hemisphere. PMID- 22500675 TI - Risk and causes of death in children with a seizure disorder. AB - AIM: To describe the frequency and causes of death in children with epilepsy, ascertain the contribution of seizure disorder to cause of death, and compare with rates of sudden unexplained death in children without epilepsy. METHOD: This study was a retrospective review of clinical and death certificate records. It examined two UK population-based samples of deaths in children with epilepsy from 1 month to 18 years, together comprising the largest reported series of deaths in children with epilepsy (n=265). RESULTS: In approximately two-thirds, the death was not due to the seizure disorder. Rates of unexplained death were similar in the two samples at 7.3% and 9.7%: all were in children with symptomatic or presumed symptomatic epilepsy. There were no unexplained deaths in the children with idiopathic epilepsy. Four per cent of the deaths were of children experiencing acute symptomatic seizures as part of their final illness. The risk of unexpected, unexplained death in children with idiopathic epilepsy is not more than 65 per 100,000 child-years. INTERPRETATION: Epilepsy is associated with an increased risk of death in childhood but this risk is almost entirely confined to those with an associated neurodevelopmental disorder. The risk of unexpected, unexplained death in children with idiopathic epilepsy is extremely small. PMID- 22500676 TI - Meso-structured platinum thin films: active and stable electrocatalysts for the oxygen reduction reaction. AB - Improving both the activity and the stability of the cathode catalyst in platinum based polymer electrolyte fuel cells is a key technical challenge. Here, we synthesize a high surface area meso-structured Pt thin film that exhibits higher specific activity for the oxygen reduction reaction (ORR) than commercial carbon supported Pt nanoparticles (Pt/C). An accelerated stability test demonstrates that the meso-structured Pt thin film also displays significantly enhanced stability as compared to the commercial Pt/C catalyst. Our study reveals the origin of the high turnover frequency (TOF), and excellent durability is attributed to the meso-structure, which yields a morphology with fewer undercoordinated Pt sites than Pt/C nanoparticles, a key difference with substantial impact to the surface chemistry. The improved catalyst activity and stability could enable the development of a high-performance gas diffusion electrode that is resistant to corrosion even under the harsh conditions of start up, shut-down, and/or hydrogen starvation. PMID- 22500677 TI - Virtual reality surgical simulation in training. PMID- 22500678 TI - Brain metastases from non-small-cell lung cancer: is there room for improvement? PMID- 22500680 TI - The role of abiraterone in the management of metastatic castration-resistant prostate cancer. AB - Prostate cancer is the most common solid-organ cancer affecting the male population. Men with metastatic prostate cancer treated with androgen ablation therapy often respond rapidly, with improvement in bone pain and decreases in serum prostate-specific antigen. However, almost all patients progress to the castrate-resistant state and until recently chemotherapy was the only treatment available with proven survival benefit. Abiraterone is a new class of anti androgen with proven survival benefit post-chemotherapy. In this review we discuss the characteristics of abiraterone and the clinical trials that led to its approval for the treatment of patients with prostate cancer. PMID- 22500681 TI - Epidermal growth factor vaccine in non-small-cell lung cancer. AB - After many years of uncertainty regarding the role of immunotherapy in cancer, we finally have vaccines approved for the treatment of some malignancies (e.g., prostate cancer and melanoma). In non-small-cell lung cancer, several vaccines are being studied in randomized Phase III clinical trials due to their promising results seen in the clinic, such as BLP-25 and melanoma-associated antigen A3. Traditionally, non-small-cell lung cancer has not been considered a good target for immunotherapy due to lack of immunogenicity and the strong presence of regulatory T cells, which do not allow an adequate immune response in the host. EGF vaccination is a novel area of immunotherapy for this disease. Thus far, there has been success in generating immune and clinical responses with this vaccine in several clinical trials, and we will review in depth the efficacy and toxicity of this novel agent. PMID- 22500682 TI - ROS1 as a 'druggable' receptor tyrosine kinase: lessons learned from inhibiting the ALK pathway. AB - ROS1 is one of 58 receptor tyrosine kinases, and one of two orphan receptor tyrosine kinases where its ligand is unknown. ROS1 is evolutionarily related to ALK. ROS1 rearrangement was discovered in glioblastoma in 1987, in non-small-cell lung cancer (NSCLC) in 2007, and in cholangiocarcinoma in 2011. While the clinicopathologic characteristics of ROS1-rearranged glioblastoma and cholangiocarcinoma patients remain to be defined, the clinicopathologic characteristics of ROS1-rearranged NSCLC patients have recently been described. Although ROS1 shares only 49% amino acid sequence homology with ALK in the kinase domains, several ALK inhibitors have demonstrated in vitro inhibitory activity against ROS1. With the recent US approval of crizotinib, a multi-targeted ALK/MET kinase inhibitor, for the treatment of ALK-rearranged NSCLC, attention has turned to ROS1-rearranged tumors, especially NSCLC. The next few years should witness a rapid pace of clinical research in ROS1-rearranged tumors utilizing available ALK inhibitors. PMID- 22500683 TI - New targeted approaches against the ubiquitin-proteasome system in gastrointestinal malignancies. AB - The ubiquitin-proteasome system plays a role in a broad range of cellular functions, including cell growth and proliferation. The dysregulation of the ubiquitination process may lead to tumor development. Bortezomib was the first proteasome inhibitor demonstrating activity either as a single agent or in combination with cytotoxic drugs in a wide spectrum of hematological and solid malignancies. A deeper knowledge of the intrinsic molecular mechanisms that govern the ubiquitin system will uncover more opportunities for therapeutic intervention. In this sense, there are a number of compounds under clinical development that target the E3-ubiquitin ligase family, the deubiquitinating enzymes or the enzymatic machinery of the proteasome. In this article we review the rationale for the use of novel ubiquitin-proteasome system inhibitors in gastrointestinal malignancies. PMID- 22500685 TI - Multimodal treatment strategies for locally advanced rectal cancer. AB - This review outlines the important multimodal treatment issues associated with locally advanced rectal cancer. Changes to chemotherapy and radiation schema, as well as modern surgical approaches, have led to a revolution in the management of this disease but the morbidity and mortality remains high. Adequate treatment is dependent on precise preoperative staging modalities. Advances in staging via endorectal ultrasound, computed tomography, MRI and PET have improved pretreatment triage and management. Important prognostic factors and their impact for this disease are under investigation. Here we discuss the different treatment options including modern tumor-related surgical approaches, neoadjuvant as well as adjuvant therapies. Further clinical progress will largely depend on the broader implementation of multidisciplinary treatment strategies following the principles of evidence-based medicine. PMID- 22500686 TI - Colorectal cancer and thoracic surgeons: close encounters of the third kind. AB - Resection of lung metastases from colorectal cancer (CRC) is increasingly performed with a curative intent. This strategy was made possible in the 1990s by the development of new chemotherapeutic approaches, improved surgical techniques and better imaging modalities. However, evidence-based data showing clinical benefits of lung metastasectomy in this setting are nonexistent, and there are no prospective randomized trials to support the routine performance of these procedures for stage IV CRC. Current evidence suggests that resection of pulmonary metastases in combination with new cytotoxic agents, such as oxaliplatin, irinotecan and bevacizumab, may result in prolonged survival for many, and cure for a small minority of CRC patients who experienced tumor spread beyond the limits of the abdomen. This review focuses on the results of surgical management of CRC patients with lung metastases: we report the outcome of published series according to the presence or the absence of liver metastasis (and hepatic resection) prior to lung resection. PMID- 22500687 TI - Prophylactic cranial irradiation for small-cell lung cancer: how, when and for whom? AB - Prophylactic cranial irradiation (PCI) reduces the incidence of brain metastases and improves overall survival in both limited disease (LD) and extensive disease (ED) small-cell lung cancer (SCLC), in complete and good responders to initial chemo(radio)therapy. In LD-SCLC, a standard dose of 25 Gy given in ten fractions is recommended, whereas in ED-SCLC a shorter schedule of 20 Gy in five fractions could be used. The issues of acute neurotoxicity (NT) and the potential impact of PCI on quality of life are of particular concern in ED-SCLC patients, as their expected survival is short. In LD-SCLC late neurologic sequelae may worsen quality-adjusted life expectancy for long-term survivors, as the pronounced effect of NT becomes apparent after several years. Some novel potential approaches to reduce the PCI-related late NT have recently been investigated. Despite the growing incidence of lung cancer in elderly people, there are no established standards of treatment for this subset of the population. PMID- 22500684 TI - The role of chemoradiation for patients with resectable or potentially resectable pancreatic cancer. AB - Conflicting data and substantial controversy exist regarding optimal adjuvant treatment for those patients with resectable or potentially resectable adenocarcinoma of the pancreas. Despite improvements in short-term surgical outcomes, the use of newer chemotherapeutic agents, development of targeted agents and more precise delivery of radiation, the 5-year survival rates for early-stage patients remains less than 25%. This article critically reviews the existing data for various adjuvant treatment approaches for patients with surgically resectable pancreatic cancer. Our review confirms that despite several randomized clinical trials, the optimal adjuvant treatment approach for these patients remains unclear. PMID- 22500688 TI - Targeting the Met pathway in lung cancer. AB - Dysregulation of Met signaling has been implicated in the initiation, progression and metastasis of human cancers, and therefore represents an attractive target for anticancer drug development. Met is overexpressed in non-small-cell lung cancer and its lack of staining in normal lung tissue makes it an attractive target. To date, erlotinib and gefitinib have established themselves as first line therapy for non-small-cell lung cancer patients whose tumors harbor an EGF receptor gene mutation, and hence, it is crucial that we identify mechanisms of resistance that could be targeted by novel agents, while keeping an acceptable toxicity profile at the same time; something very important when we develop these new drugs. Inhibitors of the Met pathway represent a therapeutic alternative in this setting. In this review, we discuss the early clinical studies reported using two Met inhibitors, a monoclonal antibody (MetMAb) and a small molecule tyrosine kinase inhibitor (MGCD265). PMID- 22500689 TI - Maintenance therapy for advanced non-small-cell lung cancer: ready for clinical practice? AB - The treatment paradigm for advanced non-small-cell lung cancer has changed in recent years with the importance of histological subtyping for the choice of chemotherapy, and the use of molecular markers to select patients for targeted therapy. Maintenance therapy (MT) is another focus of interest. The potential benefit of MT for the patient is that it prolongs tumor control reached with first-line chemotherapy in order to improve overall survival with little added toxicity. Historical studies have never reached this goal, as the agents used for MT were too poorly tolerated. We review the data of the two types of recent MT studies, 'continuation' and 'switch' or 'consolidation' MT. We comment on how the benefits demonstrated in these studies may change clinical practice and reflect on factors that may identify subgroups of patients who derive the greatest benefit from MT in general, as this will help in a rational use of MT. PMID- 22500691 TI - Additional treatment of wastewater reduces endocrine disruption in wild fish--a comparative study of tertiary and advanced treatments. AB - Steroid estrogens are thought to be the major cause of feminization (intersex) in wild fish. Widely used wastewater treatment technologies are not effective at removing these contaminants to concentrations thought to be required to protect aquatic wildlife. A number of advanced treatment processes have been proposed to reduce the concentrations of estrogens entering the environment. Before investment is made in such processes, it is imperative that we compare their efficacy in terms of removal of steroid estrogens and their feminizing effects with other treatment options. This study assessed both steroid removal and intersex induction in adult and early life stage fish (roach, Rutilus rutilus). Roach were exposed directly to either secondary (activated sludge process (ASP)), tertiary (sand filtrated (SF)), or advanced (chlorine dioxide (ClO(2)), granular activated charcoal (GAC)) treated effluents for six months. Surprisingly, both the advanced GAC and tertiary SF treatments (but not the ClO(2) treatment) significantly removed the intersex induction associated with the ASP effluent; this was not predicted by the steroid estrogen measurements, which were higher in the tertiary SF than either the GAC or the ClO(2). Therefore our study highlights the importance of using both biological and chemical analysis when assessing new treatment technologies. PMID- 22500693 TI - Surveillance guidelines based on recurrence patterns after radical cystectomy for bladder cancer: the Canadian Bladder Cancer Network experience. PMID- 22500692 TI - Transfer entropy estimation and directional coupling change detection in biomedical time series. AB - BACKGROUND: The detection of change in magnitude of directional coupling between two non-linear time series is a common subject of interest in the biomedical domain, including studies involving the respiratory chemoreflex system. Although transfer entropy is a useful tool in this avenue, no study to date has investigated how different transfer entropy estimation methods perform in typical biomedical applications featuring small sample size and presence of outliers. METHODS: With respect to detection of increased coupling strength, we compared three transfer entropy estimation techniques using both simulated time series and respiratory recordings from lambs. The following estimation methods were analyzed: fixed-binning with ranking, kernel density estimation (KDE), and the Darbellay-Vajda (D-V) adaptive partitioning algorithm extended to three dimensions. In the simulated experiment, sample size was varied from 50 to 200, while coupling strength was increased. In order to introduce outliers, the heavy tailed Laplace distribution was utilized. In the lamb experiment, the objective was to detect increased respiratory-related chemosensitivity to O2 and CO2 induced by a drug, domperidone. Specifically, the separate influence of end-tidal PO2 and PCO2 on minute ventilation (VE) before and after administration of domperidone was analyzed. RESULTS: In the simulation, KDE detected increased coupling strength at the lowest SNR among the three methods. In the lamb experiment, D-V partitioning resulted in the statistically strongest increase in transfer entropy post-domperidone for PO2 -> VE. In addition, D-V partitioning was the only method that could detect an increase in transfer entropy for PCO2 -> VE, in agreement with experimental findings. CONCLUSIONS: Transfer entropy is capable of detecting directional coupling changes in non-linear biomedical time series analysis featuring a small number of observations and presence of outliers. The results of this study suggest that fixed-binning, even with ranking, is too primitive, and although there is no clear winner between KDE and D-V partitioning, the reader should note that KDE requires more computational time and extensive parameter selection than D-V partitioning. We hope this study provides a guideline for selection of an appropriate transfer entropy estimation method. PMID- 22500694 TI - Genomic amplification patterns of human telomerase RNA gene and C-MYC in liquid based cytological specimens used for the detection of high-grade cervical intraepithelial neoplasia. AB - BACKGROUND: The amplification of oncogenes initiated by high-risk human papillomavirus (HPV) infection is an early event in cervical carcinogenesis and can be used for cervical lesion diagnosis. We measured the genomic amplification rates and the patterns of human telomerase RNA gene (TERC) and C-MYC in the liquid-based cytological specimens to evaluate the diagnostic characteristics for the detection of high-grade cervical lesions. METHODS: Two hundred and forty three residual cytological specimens were obtained from outpatients aged 25 to 64 years at Qilu Hospital, Shandong University. The specimens were evaluated by fluorescence in situ hybridization (FISH) using chromosome probes to TERC (3q26) and C-MYC (8q24). All of the patients underwent colposcopic examination and histological evaluation. A Chi-square test was used for categorical data analysis. RESULTS: In the normal, cervical intraepithelial neoplasia grade 1 (CIN1), grade 2 (CIN2), grade 3 (CIN3) and squamous cervical cancer (SCC) cases, the TERC positive rates were 9.2%, 17.2%, 76.2%, 100.0% and 100.0%, respectively; the C-MYC positive rates were 20.7%, 31.0%, 71.4%, 81.8% and 100.0%, respectively. The TERC and C-MYC positive rates were higher in the CIN2+ (CIN2, CIN3 and SCC) cases than in the normal and CIN1 cases (p < 0.01). Compared with cytological analysis, the TERC test showed higher sensitivity (90.0% vs. 84.0%) and higher specificity (89.6% vs. 64.3%). The C-MYC test showed lower sensitivity (80.0% vs. 84.0%) and higher specificity (77.7% vs. 64.3%). Using a cut-off value of 5% or more aberrant cells, the TERC test showed the highest combination of sensitivity and specificity. The CIN2+ group showed more high-level TERC gene copy number (GCN) cells than did the normal/CIN1 group (p < 0.05). For C-MYC, no significant difference between the two histological categories was detected (p > 0.05). CONCLUSIONS: The TERC test is highly sensitive and is therefore suitable for cervical cancer screening. The C-MYC test is not suitable for cancer screening because of its lower sensitivity. The amplification patterns of TERC become more diverse and complex as the severity of cervical diseases increases, whereas for C-MYC, the amplification patterns are similar between the normal/CIN1 and CIN2+ groups. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1308004512669913. PMID- 22500695 TI - Comparison of phenolic acids profile and antioxidant potential of six varieties of spelt (Triticum spelta L.). AB - Phenolic acids profile and antioxidant activity of six diverse varieties of spelt are reported. Antioxidant activity was assessed using eight methods based on different mechanism of action. Phenolic acids composition of spelt differed significantly between varieties and ranged from 506.6 to 1257.4 MUg/g DW. Ferulic and sinapinic acids were the predominant phenolic acids found in spelt. Total ferulic acid content ranged from 144.2 to 691.5 MUg/g DW. All analyzed spelt varieties possessed high antioxidant potential. In spite of the fact that bound phenolic acids possessed higher antioxidant activities, analysis of antioxidant potential and their relationship with phenolic acid content showed that free phenolics were more effective. Eight antioxidant methods were integrated to obtain a total antioxidant capacity index that may be used for comparison of total antioxidant capacity of spelt varieties. Total antioxidant potential of spelt cultivars were ordered as follows: Ceralio > Spelt INZ ~ Ostro > Oberkulmer Rotkorn > Schwabenspelz > Schwabenkorn. PMID- 22500696 TI - Adipose-derived stem cells combined with a demineralized cancellous bone substrate for bone regeneration. AB - Mesenchymal stem cells (MSCs) isolated from cadaveric adipose tissue can be obtained in large quantities, and have been reported in the literature to be capable of inducing bone formation in vivo and ex vivo.( 1-6 ) The hypothesis tested whether a demineralized cancellous bone matrix (DCBM) can provide an effective substrate for selection and retention of stem cells derived from the stromal vascular fraction (SVF) of adipose. Human cadaveric adipose tissue was recovered from a donor and digested. The resulting SVF-containing MSCs were seeded onto the demineralized bone allografts, after which the nonadherent cells were washed off. The MSCs were characterized using a flow cytometer and tri lineage differentiation (osteogenesis, chondrogenesis, and adipogenesis) in vitro. The stem cell-seeded allografts were also characterized for cell number, adherence to the DCBM, osteogenic activity (alkaline phosphatase and Alizarin Red staining), and bone morphorgenic protein (BMP) quantity. Flow cytometry identified a mean total of 7.2% MSCs in SVF and 87.2% MSCs after culture. The stem cells showed the capability of differentiating into bone, cartilage, and fat. On the 21 stem cell-seeded bone allografts, there were consistent, attached, viable cells (100,744+/-22,762 cells/cube). An assessment of donor age, gender, and body mass index revealed no significant differences in cell numbers. Enzyme linked immunosorbent assay revealed the presence of BMP-2 and BMP-7. In conclusion, this bone graft contains three key elements for bone regeneration: adhered osteogenic stem cells, 3D osteoconductive bone scaffold, and osteoinductive BMP signal. It therefore has the potential to be effective for bone regeneration. PMID- 22500697 TI - Extraocular lymphoma in the horse. AB - OBJECTIVE: To describe the clinical findings and prognosis for extraocular lymphoma in the horse. PROCEDURES: Retrospective medical records study of horses diagnosed with third eyelid, corneoscleral, conjunctival, and/or eyelid lymphoma from multiple academic and private veterinary institutions. Data collected from the medical records included signalment, clinical descriptions of the extraocular lesions, treatment, and treatment outcomes. Nonparametric statistical analysis was performed with Fischer's exact tests. RESULTS: Extraocular lymphoma involving the eyelid, third eyelid, cornea, sclera, and/or conjunctiva was diagnosed in 26 horses. Differences in signalment, unilateral vs. bilateral extraocular involvement, and single vs. multiple extraocular lesion locations held no significance in terms of outcome. ANIMALS STUDIED: Horses with lesions localized to the eyelid or other nonextraocular cutaneous locations had a significantly higher chance of negative outcome when compared to the horses with no eyelid or cutaneous involvement (P = 0.019). Lesions to the third eyelid, corneosclera, and conjunctiva were either nodular or diffuse in nature. Nodular lesions when compared to diffuse lesions were associated with a higher chance of a positive outcome (P = 0.007). Surgical resection of the extraocular lesions as part of the treatment produced a statistically higher chance of a positive outcome when compared to horses where resection was not performed (P = 0.03). CONCLUSIONS: The prognosis for clinical remission in horses with extraocular lymphoma is generally fair to good, as long as the affected tissues are completely excised, and there is no eyelid or cutaneous involvement. Horses diagnosed with the nodular form of extraocular lymphoma seem to have the best prognosis with complete excision. PMID- 22500698 TI - [Towards a new approach of neurophysiology in clinical psychiatry: functional magnetic resonance imaging neurofeedback applied to emotional dysfunctions]. AB - Emotions color in a singular way our everyday life and constitute important determinants of human cognition and behavior. Emotional regulation is an essential process involved in neuropathophysiology and therapeutic efficacy in many psychiatric disorders. Yet, traditional psychiatric therapeutic has focused on symptomatic rather than neurophysiological criteria. Therefore, it was proposed to teach patients to modify their own brain activity directly, in order to obtain a therapeutic effect. These techniques, which are named neurofeedback, were originally developed using electroencephalography. Recent technical advances in fMRI enable real-time acquisition, and open opportunities to its utilization in neurofeedback. This seems particularly interesting in emotion regulation, which, at a neurofunctional level, lies on cortico-limbic pathways that, in great parts, were previously identified by traditional fMRI paradigms. This emotion regulation plays a central role in the etiopathogeny psychiatric, especially depressive and anxious, disorders. It is possible to devise new therapeutic strategies and research approach for addressing directly the neurophysiological processes of emotion regulation by integrating the neurofunctional activities of a subject. These prospects seem to be in line with the neurophenomenology project, which proposes to establish a link between subjective experiences and objective neurophysiological measures. PMID- 22500699 TI - Navigated rTMS for the treatment of tinnitus: a pilot study with assessment by fMRI and AEPs. AB - OBJECTIVE: Repeated transcranial magnetic stimulation (rTMS) of auditory cortex has been proposed to treat refractory chronic tinnitus, but the involved mechanisms of action remain largely unknown. The purpose of this pilot study was to evaluate the impact of rTMS on auditory cortex activity in a series of tinnitus patients, using for the first time both functional magnetic resonance imaging (fMRI) of the brain and auditory evoked potentials (AEPs). METHOD: In six patients with chronic, lateralized refractory tinnitus, we performed five sessions of neuronavigated rTMS delivered at 1Hz over the secondary auditory cortex (defined on morphological MRI), contralateral to tinnitus side. The effects of rTMS were assessed on clinical scales, fMRI, and AEPs (N1 and P2 components). RESULTS: The clinical impact of rTMS on tinnitus was good for three patients (25-50% improvement of tinnitus severity compared to baseline), moderate for two patients (15% improvement), and null for one patient who had the most severe tinnitus at baseline. The changes induced by rTMS on fMRI data varied with the baseline level of auditory cortex activation before rTMS. This baseline level of activation was itself related to the severity of tinnitus. Thus, cortical stimulation increased auditory cortex activation in patients who had less severe tinnitus and low level of activation before rTMS, whereas it decreased auditory cortex activation in patients who had more severe tinnitus and higher level of activation before rTMS. Regarding AEPs, rTMS decreased N1 amplitude in all patients, except in the patient who had the most severe tinnitus at baseline and showed no improvement after rTMS. Conversely, P2 amplitude decreased after rTMS only in patients with severe tinnitus, at least for auditory stimulation contralateral to tinnitus, but increased in patients with less severe tinnitus. CONCLUSIONS: The changes produced by rTMS in auditory cortex activity, as assessed by fMRI and AEPs, appeared to depend on a process of disease-related homeostatic cortical plasticity, regardless of the therapeutic impact of rTMS on tinnitus. PMID- 22500700 TI - Therapeutic effects of peripheral magnetic stimulation on traumatic brachial plexopathy: clinical and neurophysiological study. AB - OBJECTIVE: To evaluate the therapeutic effects of peripheral repetitive magnetic stimulation (rMS) on recovery of traumatic brachial plexopathy. PATIENTS AND METHODS: Thirty-four patients with traumatic brachial plexopathy were studied. Strength of different muscles of upper limbs was evaluated neurologically. Nerve conduction studies (NCS), upper limb F-waves and visual analogue scales (VAS) for shoulder pain were obtained for all patients. These were randomly assigned into two groups with a ratio of 2:1; each patient received conventional physical therapy modalities and active exercises as well as real or sham rMS applied over the superior trapezius muscle of the affected limb daily for 10 sessions. Patients were reassessed with the same parameters after the 5th and the 10th session, and 1 month after rMS treatment. RESULTS: No significant between-group differences were recorded at baseline assessment. Significant improvement was observed (time X groups) after real rMS in comparison to the sham group (P=0.0001 for muscle strength and 0.01 for VAS of shoulder pain). These improvements were still present at 1 month after the end of treatment. In accordance with the clinical improvement, a significant improvement was recorded in the neurophysiological parameters in the real vs the sham group. CONCLUSIONS: We demonstrate that peripheral rMS for 10 sessions may have positive therapeutic effects on motor recovery and pain relief in patients with traumatic brachial plexopathy. Therefore, it is a useful adjuvant in the therapy of these patients. PMID- 22500701 TI - Cervical vestibular evoked myogenic potentials to air-conducted sound in early amyotrophic lateral sclerosis. AB - OBJECTIVES: Cervical vestibular evoked myogenic potentials (cVEMPs) provide assessment of lower-brainstem lesions affecting their neuronal pathways. We aimed to determine whether cVEMPs to air-conducted sound (ACS) are also abnormal in patients with early stages of amyotrophic lateral sclerosis (ALS), with or without bulbar involvement. METHODS: cVEMPs were recorded in 22 ALS patients and 23 age- and sex-matched healthy volunteers. Their latencies and amplitudes were compared between the ALS patients and the control group. RESULTS: cVEMPs were obtained in all ALS patients and controls. P(13) and N(23) latencies and P(13) N(23) amplitudes did not significantly differ between controls and ALS patients, either with or without bulbar involvement. CONCLUSIONS: We postulate that the ACS cVEMP neural pathway is not affected in patients with early stages of ALS, even with clinical findings of bulbar involvement. Therefore, ACS-cVEMP is not a sensitive diagnostic tool for early detection of brainstem involvement in patients with ALS. PMID- 22500702 TI - Sympathetic skin response in Parkinson's disease before and after mental stress. AB - OBJECTIVES: This study aims to evaluate sympathetic sudomotor activity in Parkinson's disease (PD) by means of the sympathetic skin response (SSR) and explore its possible changes due to mental stress. METHODS: Sudomotor function was evaluated using SSR in 29 patients with PD (Hoehn and Yahr stage I-IV) without any clinical evidence of autonomic dysfunction. Twenty-seven healthy matched controls were also evaluated. SSR was elicited by electrical stimulation of the right median nerve and simultaneously recorded on the palms of both hands. Arithmetic mental stress was evoked by means of the WAIS-R arithmetic subscale. Latency and amplitude of SSR were evaluated before and after arithmetic mental stress. RESULTS: The SSR was obtained in all patients and controls. There were no significant differences in its mean latency and amplitude between patients and controls. SSR parameters were significantly correlated with disease duration, UPDRS score, and disease stage. There were also significant correlations with rigidity and bradykinesia, but not with tremor. Mental stress had no effect on SSR parameters in any group. CONCLUSIONS: SSR parameters in PD without autonomic dysfunction were comparable to matched controls. Although PD patients are sensitive to mental stress, the arithmetic task had no effect on SSR parameters. Consequently, SSR as a method of evaluation of sympathetic sudomotor function is not sufficient for exploration of subclinical autonomic dysfunction in PD, but should be combined with other tests of autonomous nervous system. PMID- 22500703 TI - Could home be an appropriate location for performing posturographic assessments in elderly subjects? AB - INTRODUCTION: Posturographic measurements are often performed in hospital in the context of assessing fall risks in elderly subjects. These hospital visits may generate different kinds of stimuli that could influence test outcomes. STUDY AIM: The aim was to investigate whether posturographic measurements performed both at home and in hospital in a randomized order provide similar data. METHODS: Thirty-five healthy elderly subjects (average age 72.5 +/- 3.7 years) were assigned to two postural evaluations performed in a random order: one at home and one at the hospital. Before the first evaluation, subject's levels of anxiety, depression and stress were assessed. Then, the area of body sway, velocity and medial-lateral and antero-posterior amplitudes were recorded twice, first with the subject's eyes opened and then with eyes closed. RESULTS AND DISCUSSION: The posturographic data obtained in hospital and at home were quite similar. However, when the group that was first evaluated in hospital was compared with the group first evaluated at home, the medio-lateral amplitude was observed to significantly decrease in the second evaluation compared with the data obtained in the first trial (P<0.05), and this decrease was significantly higher in the first group (P<0.05). For the eyes-opened condition, we found significant correlations between anxiety and the area of body sway, stress and the area of body sway, and anxiety and the medial-lateral amplitude. CONCLUSIONS: Psychological factors may influence some posturographic data, and carrying out posturographic evaluations at home for elderly subjects could be a reasonable strategy. PMID- 22500704 TI - Degradation of superparamagnetic iron oxide nanoparticle-induced ferritin by lysosomal cathepsins and related immune response. AB - AIM: To examine the physiological impact of superparamagnetic iron oxide nanoparticles (SPIONs) on cell function and its interaction with oxysterol laden cells. MATERIALS & METHODS: Intracellular iron was determined by Prussian blue staining. Cellular ferritin, cathepsin L and ferroportin were analyzed by flow cytometry and fluorescence microscopy. Cytokine secretion was determined by ELISA and immunoblotting. RESULTS: In U937 and THP 1 cells, we did not detect any loss of cell viability on SPION loading. Desferrioxamine prevents induction of both ferritin and cathepsin L by SPIONs. Inhibition of lysosomal cathepsins upregulates both endogenous- and SPION-induced ferritin. SPION loading induces membranous ferroportin and incites secretion of ferritin, TNF-alpha and IL-10. 7beta-hydroxycholesterol exposure reduces SPION uptake by cells. CONCLUSION: SPION loading results in upregulation of lysosomal cathepsin, membranous ferroportin and ferritin degradation, which is associated with secretion of both pro- and anti-inflammatory cytokines. A reduced SPION uptake by oxysterol-laden cells may lead to a compromised MRI with elevated cathepsins and ferritin. PMID- 22500705 TI - An integrated framework for high angular resolution diffusion imaging-based investigation of structural connectivity. AB - Structural connectivity models hold great promise for expanding what is known about the ways information travels throughout the brain. The physiologic interpretability of structural connectivity models depends heavily on how the connections between regions are quantified. This article presents an integrated structural connectivity framework designed around such an interpretation. The framework provides three measures to characterize the structural connectivity of a subject: (1) the structural connectivity matrix describing the proportion of connections between pairs of nodes, (2) the nodal connection distribution (nCD) characterizing the proportion of connections that terminate in each node, and (3) the connection density image, which presents the density of connections as they traverse through white matter (WM). Individually, each possesses different information concerning the structural connectivity of the individual and could potentially be useful for a variety of tasks, ranging from characterizing and localizing group differences to identifying novel parcellations of the cortex. The efficiency of the proposed framework allows the determination of large structural connectivity networks, consisting of many small nodal regions, providing a more detailed description of a subject's connectivity. The nCD provides a gray matter contrast that can potentially aid in investigating local cytoarchitecture and connectivity. Similarly, the connection density images offer insight into the WM pathways, potentially identifying focal differences that affect a number of pathways. The reliability of these measures was established through a test/retest paradigm performed on nine subjects, while the utility of the method was evaluated through its applications to 20 diffusion datasets acquired from typically developing adolescents. PMID- 22500706 TI - The European directive on traditional herbal medicinal products: friend or foe for plant-based therapies? PMID- 22500707 TI - High-tech acupuncture made in Austria--cerebral circulation. AB - It is little known that Austria has tradition in research in Chinese integrative medicine, especially traditional Chinese medicine. For more than 15 years, the research concerning high-tech acupuncture has been playing an important role at the Medical University of Graz, Austria. Within this review article, a short summary concerning high-tech acupuncture and cerebral circulation, and transcranial Doppler (TCD) sonography is presented. TCD has been extensively used in various basic and clinical situations, and in the last decade has established its role also as a tool of investigating the effects of various acupuncture methods. Based on the Doppler principle, it uses ultrasound waves to insonate the blood vessels supplying the brain and to obtain stimulation-induced changes of hemodynamic information. The purpose of this review is to present the basic concepts of TCD technique in relation to acupuncture research, and the specific effects on cerebral hemodynamics caused by acupuncture stimulation. PMID- 22500708 TI - [Connotations and extensions of comparative effectiveness research and feasibility analysis for clinical evaluation in traditional Chinese medicine]. AB - Comparative effectiveness research (CER) is well developed in international medical research. This article analyzes the basic connotations of CER from five aspects, including selection of objective, positioning of target population, comparison of intervention scheme, identification of contrast condition and analysis of therapeutic effects. The inclusiveness and advanced nature of CER were revealed by comparing with modern medical research methods, such as evidence based medicine, patient-important outcome and randomized controlled trials. Based on the superiority of CER, the feasibility of applying CER in clinical evaluation of traditional Chinese medicine is explored. CER should be combined with the holistic concept, syndrome differentiation and individuality-concerned treatment so as to facilitate its development in research of traditional Chinese medicine in China. PMID- 22500709 TI - [Approaches for developing a system model for health evaluation based on body constitutions of traditional Chinese medicine and order parameters]. AB - From the point of view of systems science, human body can be considered as a complex system, and the human health system is a subsystem of it. Systems science conducts investigation in a holistic manner. As a theoretical method, it deals with the operation and evolution of systems from the macroscopic perspective, so this theory is similar to phenomenological theory of traditional Chinese medicine (TCM) in methodology. Naturally, numerous theories of systems science can be used in research of the human health systems of TCM. In this paper, the authors introduced synergetic, a theory of modern systems science, and its slaving principle, and in particular, analyzed the concept of order parameters related to the slaving principle and the relationship between body constitutions of TCM and order parameters. The body constitution of TCM can be treated as a slow variable in the human health systems. By using synergetic, the authors established a model of the human health system based on body constitutions of TCM. As an application of the model, the authors illustrated the argumentation in the theory of constitution being separable, the theory of a relationship between constitution and disease, and the theory of a recuperable constitution. To some extent, this work has made links between the TCM theory of body constitution and modern systems science, and it will offer a new thought for modeling the human health system. PMID- 22500710 TI - Estimation of sample size and testing power (part 7). AB - Two-factor factorial design refers to the research involving two experimental factors and the number of the experimental groups equals to the product of the levels of the two experimental factors. In other words, it is the complete combination of the levels of the two experimental factors. The research subjects are randomly divided into the experimental groups. The two experimental factors are performed on the subjects at the same time, meaning that there is no order. The two experimental factors are equal during statistical analysis, that is to say, there is no primary or secondary distinction, nor nested relation. This article introduces estimation of sample size and testing power of quantitative data with two-factor factorial design. PMID- 22500711 TI - External Chinese medical therapy for pain associated with hyperplastic disease of the breast: study protocol of a randomized, double-blind, multicenter, controlled trial. AB - BACKGROUND: Hyperplastic disease of the breast (HDB) is caused by a hormone imbalance experienced among women at a certain age. Slight breast pain is common in women before menstruation without need of treatment; however, if the pain becomes severe, it can cause physical and mental suffering. Therefore, it is of great clinical significance to control this disease. METHODS AND DESIGN: This study will follow the principle of evidence-based medicine and adopt various design methods, being conducted as a randomized, controlled, double-blind and multicenter trial based on the cause of HDB defined in Chinese and Western medicine. According to the cause of HDB in Chinese and Western medicine and its pathogenesis and prognosis, this study will conduct syndrome differentiation, adopt external therapy of Chinese medicine by using Sanjie Zhitong plaster as the intervention, take placebo as the control method and aim at relieving pain. The effectiveness and safety of Chinese medicine therapy will be evaluated. During the design process, some confounding factors will be taken into consideration and prevented with corresponding measures. We will also discuss the side effects of the medicine used and corresponding countermeasures to be taken. DISCUSSION: On the basis of traditional Chinese medicine (TCM) theory, Sanjie Zhitong plaster takes the advantage of external therapy of TCM. According to the main etiology and pathogenesis of HDB, the treatment principles of warming the meridians and activating blood, smoothing circulation and relieving pain, and removing swelling and dissipating stagnation are put forward. The medicine exerts its effects directly on the lesion site by permeating into the skin and stimulating the meridians, thus improving blood supply to the breast and relieving pain. PMID- 22500712 TI - Effects of Chinese medicine for tonifying the kidney and resolving phlegm and blood stasis in treating patients with amnestic mild cognitive impairment: a randomized, double-blind and parallel-controlled trial. AB - BACKGROUND: It is important to detect and prevent Alzheimer disease (AD) at its early stage. Constituting the early stage sign of AD, amnestic mild cognitive impairment (aMCI) has drawn much attention. Studies have shown that donepezil could reduce the AD assessment scale-cognitive subscale (ADAS-Cog) score in MCI patients and improve the patient's attention and speed of response; however, it also has many side effects. Therefore, the authors aim to explore the effects of Chinese herbal medicine for treating aMCI. OBJECTIVE: To explore the clinical efficacy and safety of Chinese medicine for tonifying the kidney, and resolving phlegm and blood stasis in the treatment of aMCI. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This clinical trial used randomized, double-blind, double dummy and parallel-controlled design. According to the randomized, double-blind principle, some aMCI patients were randomly divided into Chinese medicine group and donepezil group. Other patients who did not receive any treatment were enrolled as the control. Patients in the Chinese medicine group received oral administration of Chinese medicine, 1 bag/dose, two doses per day, while patients in the donepezil group received donepezil hydrochloride, 5mg/day. Twelve weeks were allocated as the trial period. MAIN OUTCOME MEASURES: After 12 weeks, the Chinese medicine group patients, the donepezil group patients and those patients who did not receive any treatment were accessed using the scores of ADAS-Cog and mini-mental status examination (MMSE). RESULTS: The ADAS-Cog and MMSE scores of the Chinese medicine group and the donepezil group were both improved from baseline (P=0.001, P=0.000), but the non-treatment group showed no change from baseline (P=0.151, P=0.125); furthermore, there was no significant difference between the Chinese medicine group and the donepezil group. The attention function of the Chinese medicine group was better than baseline (P=0.015), but no change was seen in the donepezil group (P=0.085) at the 12th week. Safety data showed that the occurrence of insomnia, nausea and diarrhea was greater in the donepezil group than in the Chinese medicine group (P=0.002, P=0.005, P=0.000), and both treatments had no influence in participants' vital signs and laboratory examination results. CONCLUSION: Both Chinese medicine and donepezil can improve global cognition in patients with aMCI after 12 weeks of treatment. Chinese medicine can also improve attention function and some clinical symptoms in patients with aMCI. Furthermore, Chinese medicine is safe for aMCI patients. Further study is necessary to explore the long-term effect of Chinese medicine for aMCI. PMID- 22500713 TI - [Weighting coefficients of symptoms and signs in the diagnosis of corresponding TCM syndrome elements of ulcerative colitis based on expert questionnaire investigation]. AB - OBJECTIVE: To define the weighting coefficients of the symptoms and signs in the diagnosis of corresponding traditional Chinese medicine (TCM) syndrome elements of ulcerative colitis based on expert questionnaire investigation. METHODS: The questionnaire included eight syndrome elements of location and 11 syndrome elements relating to disease characteristics. Experts who answered the questionnaire were titled as associate chief physician or above, and had been practicing as professionals in general practice of medicine of digestive system for a long time. They came from 15 third-grade class-A hospitals (6 provinces and Beijing) in China. The weighting coefficients of the symptoms and signs in the diagnosis of corresponding TCM syndrome elements of ulcerative colitis were identified preliminarily based on consent degree of the experts (mean value and variation coefficient). RESULTS: There were 9, 6, 14, 5, 9, 8, 12 and 2 symptoms and signs corresponding to 8 TCM syndrome elements related to disease location and the ranges of weighting coefficients were listed as follows: liver, from 7.49 to 4.18; heart, from 6.90 to 5.51; spleen, from 7.96 to 5.55; lung, from 6.30 to 5.27; kidney, from 7.82 to 5.71; stomach, from 7.53 to 6.15; large intestine, from 8.40 to 6.70; bowel collaterals, from 8.49 to 6.41. Numbers of symptoms and signs corresponding to 11 TCM syndrome elements related to disease nature were 13, 8, 17, 18, 17, 18, 6, 11, 2, 10 and 11 and the ranges of weighting coefficients were listed as follows: qi deficiency, from 7.44 to 5.60; blood deficiency, from 7.90 to 5.59; yin deficiency, from 6.88 to 4.91; yang deficiency, from 7.54 to 5.57; dampness, from 7.91 to 4.96; excess heat (fire), from 7.13 to 5.69; excess cold, from 7.51 to 6.14; qi stagnation, from 7.38 to 5.88; qi sinking, from 7.65 to 7.43; blood stasis, from 7.60 to 5.79; fluid retention, from 7.08 to 4.46. CONCLUSION: On the basis of previous document research and clinical research in ulcerative colitis, the expert questionnaire can collect consensus opinions of experts. The weighting coefficients of the symptoms and signs in the diagnosis of corresponding TCM syndrome elements of ulcerative colitis are defined preliminarily. Thereby it will lay the foundation for establishing differentiation criteria of ulcerative colitis based on TCM syndrome elements. PMID- 22500714 TI - [Characteristic genomics of peripheral blood mononuclear cells of hepatocellular carcinoma patients with liver-kidney yin deficiency syndrome]. AB - OBJECTIVE: To explore the characteristic genomics of syndrome of liver-kidney yin deficiency in peripheral blood mononuclear cells of hepatocellular carcinoma (HCC) patients. METHODS: HCC patients with or without syndrome of liver-kidney yin deficiency were enrolled into the experimental group and the control group, respectively; their gene expression profiles were evaluated by a whole-genome Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. The differentially expressed mRNAs were then selected by Gene Ontology (GO) and pathway analyses, respectively. Based on the results of GO and pathway analyses, gene coexpression networks were built according to the normalized signal intensity of specifically expressed genes. Finally, the results from microarray were confirmed by real-time fluorescence quantitative polymerase chain reaction and Western blot methods. RESULTS: The results showed that a set of 615 mRNAs were differentially expressed in the HCC patients with syndrome of liver-kidney yin deficiency. By GO enrichment analysis, the genes for anti-apoptosis, regulation of cell cycle, transmembrane transport, etc. were up-regulated or down-regulated in the experimental group. Another functional analysis of mRNAs by KEGG revealed that 10 signal transduction pathways were up-regulated and 16 were down-regulated, such as antigen processing and presentation, cell cycle, and protein export. Based on the above results, we constructed coexpression networks to determine which genes may play pivotal role in HCC patients with syndrome of liver-kidney yin deficiency. Some critical genes, including SEC62 (SEC62 homolog (S. cerevisiae)), CCNB1 (cyclin B1) and BIRC3 (baculoviral IAP repeat-containing 3), which rank the top 3 in |delta normalized degree| were chosen. Of another 60 samples, we found that the mRNA expressions of SEC62, CCNB1 and BIRC3 were significantly lower in HCC patients with syndrome of liver-kidney yin deficiency than those without syndrome of liver-kidney yin deficiency (P<0.01). Also, the protein expressions of SEC62, CCNB1 and BIRC3 were significantly lower (P<0.01). CONCLUSION: Gene chip technique allows rapid and high-throughput screening for different gene expression in HCC patients with or without liver-kidney yin deficiency syndrome. The results of this study further confirm the hypothesis on the essence of syndrome, namely, a kind of deviation from the normal state in multigene style on the levels of both mRNA and protein. PMID- 22500715 TI - Effects of electroacupuncture on expression of c-fos protein and N-methyl-D aspartate receptor 1 in the rostral ventromedial medulla of rats with chronic visceral hyperalgesia. AB - OBJECTIVE: Acupuncture has been clinically proved to be effective in treating abdominal pain in patients with irritable bowel syndrome (IBS). However, its neurobiological mechanism remains largely unexplored. The aim of this study was to investigate the effect of electroacupuncture (EA) in relieving chronic visceral hyperalgesia and the possible involvement of N-methyl-D-aspartate receptor 1 (NR1) in rostral ventromedial medulla (RVM) of the brain in an IBS rat model. METHODS: To establish the IBS rat model, male Sprague-Dawley neonatal rats received colon mechanical irritation on a daily basis from the 9th to the 22nd day after their birth. After a resting period of another two to four weeks, behavioral tests of pain threshold pressure (PTP) and abdominal withdrawal reflex (AWR) responding to colorectal distention (CRD) stimuli were conducted to judge the colorectal sensitive situation. Then administration of EA at acupoints of Zusanli (ST36) and Shangjuxu (ST37) bilaterally in the hind limbs was repeated four times every other day, while sham-EA was done by inserting needles at similar acupoints without electrical stimulation. Immunohistochemical method was used to display the expression of proto-oncogene protein c-fos and NR1 in RVM of rats. RESULTS: The results demonstrated that the PTP values and AWR scores, in response to the CRD stimuli, significantly decreased and increased, respectively (P<0.01, P<0.01), while the number of immunoreactive neurons of c-fos protein and NR1 significantly increased in nucleus reticularis gigantocellularis (Gi), nucleus lateralis paragigantocellularis (LPGi), nucleus reticularis gigantocellularis pars alpha (GiA) and nucleus raphe magnus (NRM) of RVM in IBS model rats compared with the normal rats (P<0.05). After EA treatment, PTP values and AWR scores significantly increased and decreased, respectively (P<0.01, P<0.05); the number of immunoreactive neurons of c-fos and NR1 significantly decreased respectively in Gi, LPGi and GiA and in Gi, LPGi, GiA and NRM (P<0.05). No such effects on PTP values, AWR scores and the number of immunoreactive neurons of c-fos and NR1 were observed after sham-EA treatment. CONCLUSION: These data provide the evidence that EA can relieve chronic visceral hyperalgesia in rats with IBS, and such an effect may be correlated with inhibitory modulation of hyperactivity of neurons by means of down-regulating the high expression of NR1 in RVM of IBS model rats. PMID- 22500716 TI - Effects of valerian consumption during pregnancy on cortical volume and the levels of zinc and copper in the brain tissue of mouse fetus. AB - OBJECTIVE: The aim of the present study was to determine the effects of valerian (Valeriana officinalis) consumption in pregnancy on cortical volume and the levels of zinc and copper, two essential elements that affect brain development and function, in the brain tissues of mouse fetuses. METHODS: Pregnant female mice were treated with either saline or 1.2 g/kg body weight valerian extract intraperitoneally daily on gestation days (GD) 7 to 17. On GD 20, mice were sacrificed and their fetuses were collected. Fetal brains were dissected, weighed and processed for histological analysis. The volume of cerebral cortex was estimated by the Cavalieri principle. The levels of zinc and copper in the brain tissues were measured by atomic absorption spectroscopy. RESULTS: The results indicated that valerian consumption in pregnancy had no significant effect on brain weight, cerebral cortex volume and copper level in fetal brain. However,it significantly decreased the level of zinc in the brain (P<0.05). CONCLUSION: Using valerian during midgestation do not have an adverse effect on cerebral cortex; however,it caused a significant decrease in zinc level in the fetal brain. This suggests that valerian use should be limited during pregnancy. PMID- 22500717 TI - Antitumor activity of ethanol extract of Gracilaria edulis (Gmelin) Silva on Ehrlich ascites carcinoma-bearing mice. AB - OBJECTIVE: To evaluate antitumor activity of Gracilaria edulis in Swiss albino mice with Ehrlich ascites carcinoma (EAC). METHODS: Tumors were induced in mice by intraperitoneal injection of EAC cells. Ethanol extract of Gracilaria edulis (EEGE) was administered to the experimental animals in different doses after 24 h of tumor inoculation. The antitumor effect of the EEGE was evaluated by assessing in vitro cytotoxicity, survival time, biochemical parameters and hepatic enzyme levels. RESULTS: EEGE increased the life span of EAC-bearing mice compared with that of the model control mice (P<0.05 or P<0.01). EEGE treatment also converted the changes of biochemical parameters and hepatic enzyme levels in the EAC bearing mice (P<0.05 or P<0.01). EEGE induced inhibition of tumor formation in EAC-bearing mice compared with that of the model control group (P<0.05 or P<0.01). CONCLUSION: The present study scientifically proved the antitumor activity of marine algae G. edulis and the effect can be correlated with doses. PMID- 22500718 TI - [Chinese herbal decoction Shiquan Dabu Tang inhibits tumor growth and angiogenesis of metastasis after primary tumor surgical removal in mice]. AB - OBJECTIVE: This study aimed to investigate the effects of Shiquan Dabu Tang (SDT) on growth and angiogenesis of subcutaneously implanted tumors, hepatic metastases, and incision-implanted tumors after surgical removal of primary colon tumor in mice. METHODS: Three experimental models were built after surgical removal of primary colon tumor and the mice were randomly divided into three groups: primary tumor resection (TR) group, primary tumor-preserved (TP) group and SDT group. After resection of the primary tumor and SDT treatment for 10 d, levels of vascular endothelial growth factor (VEGF), angiostatin (AS) and endostatin (ES) were examined by enzyme-linked immunosorbent assay (ELISA); microvascular density (MVD) and cell proliferation of metastasis were detected by streptavidin-peroxidase immunohistochemical staining; tumor cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) assay. RESULTS: In the subcutaneously implanted tumor model, the average volume of metastases of the SDT group was significantly lower than that of the TR group (P<0.01); the incidence rate of metastases was 50%. In the hepatic metastases model, the average number of hepatic metastases nodules of the SDT group was significantly lower than that of the TR group (P<0.01); the incidence rate of metastases was 40%. In the incision-implanted tumor model, the average volume of metastases of the SDT group was significantly lower than that of the TR group; the incidence rate of metastases was 30%. MVD was significantly inhibited by SDT and Ki67 expression of the SDT group was significantly lower than that of the TR group (P<0.01). TUNEL apoptotic index of tumor of the SDT group was higher than that of the TR group (P<0.01). ELISA showed that the serum VEGF level was significantly decreased and the serum ES level was significantly increased in the SDT group compared with those in the TR group (P<0.01). CONCLUSION: Resection of primary tumor in mice causes imbalance of VEGF, AS and ES, thus promoting angiogenesis and metastasis of tumors. SDT can inhibit growth, angiogenesis and cell proliferation of the metastatic tumor and promote cell apoptosis after surgical removal of the primary tumors. PMID- 22500719 TI - [Effects of Chinese herbal medicine Feiyanning decoction on expressions of nucleosome conformation-regulating factors H3-K56, Rtt109, Asf1 and E2F1 in Lewis bearing mice]. AB - OBJECTIVE: Malignant tumor cells were found with an abnormal cell cycle. Previous in vivo experiment had confirmed the Feiyanning's intervention effect on checkpoint signaling of G1/S in the cell cycle. This study was to further observe the expressions of nucleosome conformation-regulating factors intervened by Feiyanning decoction in S phase. METHODS: Lewis lung carcinoma models of C57BL/6 mice were established. Sixty mice were randomly divided into four groups: normal control group, model control group, Feiyanning group, and cisplatin group. There were 15 mice in each group. Tumor weight and tumor inhibition rate were observed. In addition, the cell cycle distribution was detected by flow cytometry and the proliferation index was calculated. Furthermore, mRNA and protein expressions of H3-K56, regulator of Ty1 transposition 109 (Rtt109), antisilencing function 1 (Asf1) and E2F1 were analyzed by real-time polymerase chain reaction and Western blot methods, respectively. RESULTS: The tumor weights of mice in the Feiyanning group and the cisplatin group were lower than those in the model group (P<0.01), with tumor inhibition rates of 27.92% and 42.50%, respectively. Cancer cell proliferation index and proportion of cancer cell population in S phase in the Feiyanning group were significantly lower than those in the cisplatin group (P<0.01). The mRNA and protein levels of H3-K56, Rtt109, Asf1, E2F1 in the Feiyanning group were lower than those in the model group (P<0.05). CONCLUSION: Feiyanning plays a role in intervening in the abnormal cell cycle by nucleosome conformation-regulating factors and thus inhibits the lung cancer cell proliferation. PMID- 22500720 TI - [Salvianolic acid B inhibits ERK signal transduction pathway activated by transforming growth factor-beta1 in rat hepatic stellate cells]. AB - OBJECTIVE: To investigate the effects of salvianolic acid B (SA-B) on extracellular signal-regulated kinase (ERK) signal transduction pathway activated by transforming growth factor-beta1 (TGF-beta1) in rat hepatic stellate cells (HSCs). METHODS: HSCs were isolated from male Sprague-Dawley rats by in situ perfusion and Nycodenz density-gradient centrifugation method. TGF-beta1 and SA-B were directly added to the serum-free medium of HSCs. Total and phosphorylated ERK, MEK, Raf and alpha-smooth muscle actin (alpha-SMA) and type I collagen were assayed by Western blotting. RESULTS: Phosphorylation of MEK in HSCs with or without TGF-beta1 was inhibited by SA-B; however, phosphorylation of Raf in HSCs with or without TGF-beta1 was not inhibited by SA-B. Expression of alpha-SMA in HSCs with TGF-beta1 was inhibited by SA-B. Combination of SA-B and the inhibitors of ERK (PD98059) can effectively inhibit the expression of alpha-SMA. SA-B also inhibited synthesization of type I collagen in HSCs with or without TGF-beta1. CONCLUSION: The action point of SA-B inhibiting ERK signaling induced by TGF beta1 in HSCs is the inhibition of the phosphorylation of MEK. SA-B reduces the increase of expression of alpha-SMA and protein synthesization of type I collagen induced by TGF-beta1 by means of inhibiting ERK signaling in activated HSCs of rats. PMID- 22500721 TI - Phenotypic evidence of ultra-highly diluted homeopathic remedies acting at gene expression level: a novel probe on experimental phage infectivity in bacteria. AB - OBJECTIVE: To explore if some ultra-highly diluted homeopathic remedies claimed to have antiviral effects can demonstrate any discernible action in the bacteria Escherichia coli through modulating infectivity potentials of the bacteriophage phiX174 DNA. METHODS: phiX174 was selected because of its known host specificity to E. coli and its constitutive expression of lytic gene E when inside the bacterial host. We deployed the "bacteriophage assay system" by "top layer agar plating" method of plaque-counting for evaluation of efficacy of the homeopathic remedies in rendering the bacteria's protective ability against the attack of phiX174. The plaque number in the agar-plated Petri dishes, either containing the phage-bacteria mixture subjected to one of the diluted homeopathic drugs under test (1% volume ratio; Belladonna 30C, Rhus Tox 30C, Arnica 30C) or the succussed 1% "alcoholic vehicle" of the drug was recorded. The plaques represented the bacterial colony actually infected and lysed by phiX174. Conversely, we subjected phiX174 to the homeopathic drug treatment before allowing them to interact with the bacteria to ascertain if the drug itself had any direct effect on the infective potential of the phage DNA entering into the bacterial cell. RESULTS: Each homeopathic remedy showed a significant decrease in plaque number on pretreated bacteria (1 h prior to infection) with respect to untreated and placebo-treated controls; there was only an insignificant change in the plaque number when phiX174 was pretreated with the drugs. As phiX174 starts lytic cycle when inside the bacterial cell, the loss of plaque number would mean that either the lytic gene E in many was repressed or the entire phage DNA was annihilated by the bacterial gene product (restriction enzymes) known to be regulated by a cluster of genes. CONCLUSION: This provides phenotypic evidence for the ability of ultra-highly diluted homeopathic remedies to regulate expression of certain gene(s) depending on need of the organism. PMID- 22500722 TI - Comparative study on WHO Western Pacific Region and World Federation of Chinese Medicine Societies international standard terminologies on traditional medicine: Diseases in Internal Medicine (part 1). PMID- 22500723 TI - Early and late outcomes of coronary artery bypass surgery versus percutaneous coronary intervention with drug-eluting stents for dialysis patients. AB - BACKGROUND: Advances in percutaneous coronary intervention (PCI) using drug eluting stents (DES) have impacted clinical practice. However, the efficacy of DES for dialysis patients still remains controversial. This study compares the early and long-term clinical outcomes of coronary artery bypass grafting (CABG) and PCI with DES in dialysis patients. METHODS: A retrospective review was performed in 125 dialysis patients treated between 2004 and 2007. Fifty-eight patients underwent CABG and 67 underwent PCI with DES. The overall death, cardiac death, and cardiac-related event rates were analyzed using the Kaplan-Meier method. For the risk-adjusted comparisons, multivariable logistic and Cox regression analyses were used. RESULTS: The preoperative characteristics of the patients were similar except for the ejection fraction (p = 0.002) and the number of diseased vessels (p < 0.001). The 30-day mortality was 0 in both groups. The overall survival rates at one, three, and five years were 84.2%, 64.7%, and 56.2% in CABG group and 88.2%, 75.5%, and 61.7% in DES group, respectively (p = 0.202). The rates of freedom from cardiac-related events at one, three, and five years were 76.6%, 68.1%, and 48.6%, and 63.0%, 31.4%, and 0% in CABG and DES groups (p < 0.001), respectively, including seven (10%) late thromboses in the DES group. Although the risk-adjusted analysis showed no significant difference for overall and cardiac death rates, the rates of cardiac-related events and graft/stent failure were significantly higher in the DES group. CONCLUSIONS: CABG is superior for revascularization in dialysis patients compared with PCI using DES in terms of freedom from cardiac-related events. PMID- 22500724 TI - Current patch test results with the European baseline series and extensions to it from the 'European Surveillance System on Contact Allergy' network, 2007-2008. AB - BACKGROUND: The pattern of contact sensitization to the supposedly most important allergens assembled in the baseline series differs between countries, presumably at least partly because of exposure differences. Objectives. To describe the prevalence of contact sensitization to allergens tested in consecutive patients in the years 2007 and 2008, and to discuss possible differences. METHODS: Data from the 39 departments in 11 European countries comprising the European Surveillance System on Contact Allergy network (www.essca-dc.org) in this period have been pooled and analysed according to common standards. RESULTS: Patch test results with the European baseline series, and country-specific or department specific additions to it, obtained in 25 181 patients, showed marked international variation. Metals and fragrances are still the most frequent allergens across Europe. Some allergens tested nationally may be useful future additions to the European baseline series, for example methylisothiazolinone, whereas a few long-term components of the European baseline series, namely primin and clioquinol, no longer warrant routine testing. CONCLUSIONS: The present analysis points to 'excess' prevalences of specific contact sensitization in some countries, although interpretation must be cautious if only few, and possibly specialized, centres are representing one country. A comparison as presented may help to target in-depth research into possible causes of 'excess' exposure, and/or consideration of methodological issues, including modifications to the baseline series. PMID- 22500725 TI - Psychotropic medication use and association with physical and psychosocial outcomes in nursing home residents. AB - Psychotropic medications are commonly prescribed for older adults living in long term care settings. Use of these medications has been associated with negative functional outcomes. The purpose of this study was to describe the prevalence of psychotropic medication use among nursing home residents, and to explore the relationship of psychotropic medication use on physical and psychosocial outcomes. A secondary data analysis was done using baseline measures from the Res Care Intervention Study. The sample included 419 residents from 12 nursing homes. There were 288 participants (69%) who were prescribed at least one psychotropic medication, with 81 participants (19%) receiving antipsychotics, 248 (59%) receiving antidepressants, 50 (12%) receiving anxiolytics and 37 (9%) receiving sedative/hypnotics. Controlling for gender, age and cognition, physical outcomes were significantly lower in residents receiving psychotropic medications (F= 3.2, P= 0.01) compared to those not receiving psychotropic medications. Psychosocial outcomes were significantly lower in those residents receiving psychotropic mediations (F= 2.0, P= 0.04). The findings from this study provide additional support for the prevalence of psychotropic medication use among nursing home residents and suggest that residents receiving psychotropic medications may be less likely to engage in functional activities and experience decreased quality of life. PMID- 22500726 TI - Hyperbranched glycopolymers for blood biocompatibility. AB - Carbohydrate-based drug and gene delivery carriers are becoming extremely popular for in vitro and in vivo applications. These carriers are found to be nontoxic and can play a significant role in targeted delivery. However, the interactions of these carriers with blood cells and plasma components are not well explored. To the best of our knowledge, there are currently no reports that explore the role of carbohydrate based carriers for blood biocompatibility. Hyperbranched glycopolymers of varying molecular weights are synthesized by reversible addition fragmentation chain transfer polymerization (RAFT) and are studied in detail for their biocompatibility, including hemocompatibility and cytotoxicity against different cell lines in vitro. The hemocompatibility studies (such as hemolysis and platelet activation) indicate that hyperbranched glycopolymers of varying molecular weights produced are highly hemocompatible and do not induce clot formation, red blood cell aggregation, and immune response. Hence, it can be concluded that glycopolymers functionalized carriers can serve as an excellent candidate for various biomedical applications. In addition, cytotoxicity of these hyperbranched polymers is studied in primary and malignant cell lines at varying concentrations using cell viability assay. PMID- 22500727 TI - Is obesity an adaptative response to inflammation? PMID- 22500728 TI - Osteopontin predicts adverse right ventricular remodelling and dysfunction in pulmonary hypertension. AB - BACKGROUND: Osteopontin (OPN) was found upregulated in several heart failure models and appears to play an important role in myocardial remodelling. As we have previously demonstrated that OPN predicts mortality in patients with pulmonary hypertension (PH), we now evaluated whether OPN also predicts adverse right ventricular (RV) remodelling and dysfunction in PH. METHODS: We prospectively included 71 patients with PH of different etiology in this study. OPN plasma level were determined by ELISA and assessed for correlation with RV dilatation and dysfunction determined by echocardiography. RESULTS: OPN plasma values significantly correlated with RV end-diastolic diameter, Tricuspid Annular Plane Systolic Excursion (TAPSE) and Tricuspid Annular Systolic Velocity (TASV) (r = 0.43, P = 0.0002; r = -0.46, P = 0.0006; r = -0.31, P = 0.02). Furthermore, stratification of our study population according to RV end-diastolic diameter and RV dysfunction revealed that patients with enlarged and functionally impaired RV's display higher OPN levels (956 ng/mL vs. 628 ng/mL, P = 0.0005; 1108 ng/mL vs. 792 ng/mL; P = 0.02). Next, we determined OPN cut-off values for the detection of RV remodelling and dysfunction by receiver operating curve analyses and further stratified these parameters in a multivariate analysis. Here, OPN emerged as an independent predictor of RV dilatation and dysfunction. Finally, we demonstrate synergism of OPN and NT-proBNP in the prediction of RV dilatation and dysfunction by calculation of the Rothman Synergy Index. CONCLUSION: In summary, OPN predicts adverse RV remodelling and dysfunction in PH. Together with our previously published data regarding OPN's value for the prognostication of death in PH, we believe that OPN can improve risk stratification in patients with PH beyond current assessment standards. PMID- 22500729 TI - Sex differences in transcriptional expression of FABPs in zebrafish liver after chronic perfluorononanoic acid exposure. AB - Perfluorononanoic acid (PFNA), a nine carbon backbone of perfluorinated acids (PFAAs), has wide production applications and is found in environmental matrices as a contaminant. To understand the adverse effects of PFNA, adult male and female zebrafish were exposed to differing PFNA dosages (0, 0.01, 0.1, and 1.0 mg/L) for 180 days using a flow-through exposure system. Results showed body weight, body length, and hepatosomatic index (HSI) decreased in both sexes. The HPLC-MS/MS analysis found that PFNA concentrations were higher in male livers than in female livers with increasing significance in a dose-dependent manner. Total cholesterol levels increased in the livers of both sexes, whereas triglyceride (TG) levels increased in males and decreased in females. With the exception of FABP1b, the transcriptional expression levels of fatty acid binding proteins (FABPs) were up-regulated in males and down-regulated in females. A similar trend between sexes occurred for peroxisome proliferator-activated receptors (PPARs) and Ccaat-enhancer-binding proteins (C/EBPs), which may be the upstream regulatory elements of FABPs. The results indicated that PFNA exposure caused opposite adverse effects on liver TG levels between the sexes in zebrafish possibly due to the opposite expression of FABPs and its upstream genes. PMID- 22500730 TI - Mechanism of radiation-induced reactions in aqueous solution of coumarin-3 carboxylic acid: effects of concentration, gas and additive on fluorescent product yield. AB - The radiation-induced reactions of a water-soluble coumarin derivative, coumarin 3-carboxyl acid (C3CA), have been investigated in aqueous solutions by pulse radiolysis with a 35 MeV electron beam, final product analysis following (60)Co gamma-irradiations and deterministic model simulations. Pulse radiolysis revealed that C3CA reacted with both hydroxyl radicals ((*)OH) and hydrated electrons (e( ) (aq)) with near diffusion-controlled rate constants of 6.8 * 10(9) and 2.1 * 10(10) M(-1) s(-1), respectively. The reactivity of C3CA towards O(2)(* -) was not confirmed by pulse radiolysis. Production of the fluorescent molecule, 7 hydroxy-coumarin-3-carboxylic acid (7OH-C3CA), was confirmed by final product analysis with a fluorescence spectrometer coupled to a high performance liquid chromatography (HPLC) system. Production yields of 7OH-C3CA following (60)Co gamma-irradiations depended on the irradiation conditions and ranged from 0.025 to 0.18 (100 eV) (-1). Yield varied with saturating gas, additive and C3CA concentration, implying the presence of at least two pathways capable of providing 7OH-C3CA as a stable product following the scavenging reaction of C3CA with (*)OH, including a peroxidation/elimination sequence and a disproportionation pathway. A reaction mechanism for the two pathways was proposed and incorporated into a deterministic simulation, showing that the mechanism can explain experimentally measured 7OH-C3CA yields with a constant conversion factor of 4.7% from (*)OH scavenging to 7OH-C3CA production, unless t BuOH was added. PMID- 22500731 TI - Information needs associated with changes to sexual well-being after breast cancer. AB - AIMS: This article is the report of a study of sexual information needs, experiences of obtaining such information, and patient communication about sexuality with health professionals, after breast cancer. BACKGROUND: Changes to sexuality after breast cancer can significantly affect quality of life. However, information needs associated with such changes are little understood, resulting in the absence of a knowledge base to guide information provision aimed at preventing or ameliorating distress. DESIGN: This study employs a mixed method analysis, integrating qualitative and quantitative responses to an online survey. METHOD: Participants were 1965 individuals with breast cancer (98.8% female) drawn from the membership of a national Australian breast cancer organization. The data were collected over 2 weeks in December 2010. RESULTS: Eighty-five per cent of participants reported changes to sexual well-being after breast cancer, with 68% wanting information on such changes, primarily in a written form. Information on physical changes, sexual response, relationship issues, psychological consequences, and body image or identity, were rated as very important by a substantial proportion of participants. Only 41% had obtained such information; however, 65% had spoken about sexual changes, to partner (76%), G.P. (49%), friend/relative (47%), oncologist (39%), or breast-care nurse (21%). Ratings of satisfaction with the discussion were highest for breast-care nurses (60%) and lowest for oncologists (34%). CONCLUSION: These findings provide clinicians and cancer organizations with specific suggestions about sexual information needs after breast cancer and the modalities which are preferred, to prevent and ameliorate distress. PMID- 22500732 TI - Horizontal transmission of malignancy by cell-cell fusion. AB - INTRODUCTION: The crosstalk between tumor and stromal cells has become an increasing important subject of the biology of oncogenesis, also involving new therapy paradigms for treating tumor-reactive host cells and vasculature. AREAS COVERED: This article describes the long-term propagation in hamsters of a human glioblastoma which was derived from the in-vivo fusion of the human tumor cells with hamster stromal cells. The hybrid tumor cells retained at least seven human genes, of which three were able to translate their protein products during serial passages in vitro and in vivo, as well as features of the original tumor's histological appearance. This heterospecific fusion of cancer and normal host stromal cells is discussed as a mechanism for the horizontal transmission of malignancy, which may be a more common phenomenon in human cancer than appreciated previously. EXPERT OPINION: Cell-cell fusion in vivo is one of several mechanisms by which genetic information can be transmitted from tumor to host cells, resulting in new and different (more aggressive) tumor cell populations. PMID- 22500733 TI - H3K56me1 marks a spot for PCNA. AB - In the current issue of Molecular Cell, Yu et al. (2012) establish H3K56 monomethylation (H3K56me1) as a new mammalian chromatin mark, imposed by the G9a methyltransferase and recognized by the replication clamp PCNA. PMID- 22500734 TI - An arresting development in transcription. AB - In this issue of Molecular Cell, Walmacq et al. (2012) show that bypass of UV photodimers by RNA polymerase II during transcription unexpectedly contributes to survival following UV irradiation; this process may clear the way for transcription-coupled repair of DNA damage. PMID- 22500735 TI - Hijacking leucyl-tRNA synthetase for amino acid-dependent regulation of TORC1. AB - TORC1 activity in all eukaryotes is dependent on amino acid availability. However, the mechanism through which TORC1 senses amino acids is still a mystery. In the current issues of Molecular Cell and Cell, Bonfils et al. (2012) and Han et al. (2012) implicate leucyl-tRNA synthetase in this evolving story. PMID- 22500736 TI - BLM helicase ortholog Sgs1 is a central regulator of meiotic recombination intermediate metabolism. AB - The BLM helicase has been shown to maintain genome stability by preventing accumulation of aberrant recombination intermediates. We show here that the Saccharomyces cerevisiae BLM ortholog, Sgs1, plays an integral role in normal meiotic recombination, beyond its documented activity limiting aberrant recombination intermediates. In wild-type meiosis, temporally and mechanistically distinct pathways produce crossover and noncrossover recombinants. Crossovers form late in meiosis I prophase, by polo kinase-triggered resolution of Holliday junction (HJ) intermediates. Noncrossovers form earlier, via processes that do not involve stable HJ intermediates. In contrast, sgs1 mutants abolish early noncrossover formation. Instead, both noncrossovers and crossovers form by late HJ intermediate resolution, using an alternate pathway requiring the overlapping activities of Mus81-Mms4, Yen1, and Slx1-Slx4, nucleases with minor roles in wild type meiosis. We conclude that Sgs1 is a primary regulator of recombination pathway choice during meiosis and suggest a similar function in the mitotic cell cycle. PMID- 22500737 TI - Molecular model of the human 26S proteasome. AB - The 26S proteasome plays a fundamental role in eukaryotic homeostasis by undertaking the highly controlled degradation of a wide range of proteins, including key cellular regulators such as those controlling cell-cycle progression and apoptosis. Here we report the structure of the human 26S proteasome determined by cryo-electron microscopy and single-particle analysis, with secondary structure elements identified both in the 20S proteolytic core region and in the 19S regulatory particle. We have used this information together with crystal structures, homology models, and other biochemical information to construct a molecular model of the complete 26S proteasome. This model allows for a detailed description of the 20S core within the 26S proteasome and redefines the overall assignment of subunits within the 19S regulatory particle. The information presented here provides a strong basis for a mechanistic understanding of the 26S proteasome. PMID- 22500738 TI - Structure-activity relationship of citrus polymethoxylated flavones and their inhibitory effects on Aspergillus niger. AB - Citrus peels are rich in polymethoxylated flavones (PMFs) and are potential sources of natural preservatives. Six PMFs extracts, isolated and purified from the peels of three mandarins (Citrus reticulata) and three sweet oranges (Citrus sinensis), were identified and quantitated. Their inhibitory effects on Aspergillus niger were evaluated using a microbroth dilution assay. The Red tangerine variety exhibited the greatest antifungal activity (MIC = 0.2 mg/mL), while Jincheng showed the lowest activity (MIC = 1.8 mg/mL). An analysis of principal components was applied to the results in order to elucidate the structure-activity relationships of the citrus PMFs. The structure-activity relationship analysis revealed that, for good inhibitory effect, the 5-OH, 3 OCH3, and 8-OCH3 functionalities were essential, while the presence of 3-OH and 3'-OCH3 greatly reduced inhibition. The findings of this study provide important information for the exploitation and utilization of citrus PMFs as natural biopreservatives. PMID- 22500739 TI - Regiocontrolled Cu(I)-catalyzed borylation of propargylic-functionalized internal alkynes. AB - Good to excellent reactivity and regiocontrol have been achieved in the Cu(I) catalyzed borylation of dialkyl internal alkynes with bis(pinacolato)diboron. The presence of a propargylic polar group (OH, OR, SAr, SO(2)Ar, or NHTs), in combination with PCy(3) as ligand, allowed maximizing the reactivity and site selectivity (beta to the propargylic function). DFT calculations suggest a subtle orbitalic influence from the propargylic group, matched with ligand and substrate size effects, as key factors involved in the high beta-selectivity. The vinylboronates allowed the stereoselective synthesis of trisubstituted olefins, while allylic substitution of the SO(2)Py group without affecting the boronate group provided access to formal hydroboration products of unbiased dialkylalkynes. PMID- 22500740 TI - Wireless medical sensor networks: design requirements and enabling technologies. AB - This article analyzes wireless communication protocols that could be used in healthcare environments (e.g., hospitals and small clinics) to transfer real-time medical information obtained from noninvasive sensors. For this purpose the features of the three currently most widely used protocols-namely, Bluetooth((r)) (IEEE 802.15.1), ZigBee (IEEE 802.15.4), and Wi-Fi (IEEE 802.11)-are evaluated and compared. The important features under consideration include data bandwidth, frequency band, maximum transmission distance, encryption and authentication methods, power consumption, and current applications. In addition, an overview of network requirements with respect to medical sensor features, patient safety and patient data privacy, quality of service, and interoperability between other sensors is briefly presented. Sensor power consumption is also discussed because it is considered one of the main obstacles for wider adoption of wireless networks in medical applications. The outcome of this assessment will be a useful tool in the hands of biomedical engineering researchers. It will provide parameters to select the most effective combination of protocols to implement a specific wireless network of noninvasive medical sensors to monitor patients remotely in the hospital or at home. PMID- 22500741 TI - The Sankara Nethralaya mobile teleophthalmology model for comprehensive eye care delivery in rural India. AB - BACKGROUND: Teleophthalmology holds great potential to overcome barriers and improve quality, access, and affordability in eye care. We introduced mobile units for comprehensive eye care delivery and have successfully conducted eye camps over the past 1.5 years. METHODS: Here we describe the current process and review results of conducting comprehensive eye camps with the aid of teleophthalmology mobile units and determine major causes of avoidable blindness in central and south India. Retrospective chart reviews of all the camps were done as a part of the rural teleophthalmology project of Sankara Nethralaya during the period of April 2009-September 2010. Speciality consultation was achieved by means of teleophthalmology during which images were converted to Digital Imaging and Communications in Medicine standard and transferred to the base hospital by a satellite link using a very small aperture terminal at 256-384 kilobits per second with store-and-forward technology as well as real-time videoconferencing when possible. In addition to comprehensive examination, schoolteachers were trained to assess visual acuity, and various public awareness activities were undertaken. RESULTS: Over the 1.5-year study period, 54,751 patients underwent evaluation at 872 camps across four states in India. Among these, uncorrected refractive error was the commonest cause of avoidable blindness (59%), followed by cataract (30%). Retinal diseases, mainly diabetic retinopathy, contributed 3.3% of avoidable blindness, and corneal diseases accounted for another 1%. CONCLUSIONS: Comprehensive eye camps utilizing a mobile teleophthalmology unit appears to be a very useful tool to improve eye care delivery in the developing world. PMID- 22500742 TI - Stress and fitness monitoring embedded on a modern telematics platform. AB - Lack of regular physical activity and high stress levels are the leading causes of several illnesses. There is thus a real need for a personal low-cost and mobile monitoring solution over extended periods to prevent health risks. Based on the above fact, this article presents a system capable of estimating and monitoring both stress and fitness levels without a physical consultation of a medical specialist. The system consists of three main subcomponents: a mobile real-time acquisition of physiological as well as subjective data, an expert model for stress and fitness estimations based on physiological signals collected from wireless vital sensors, and a secure and scalable telematics platform on which the entire system is embedded. Features and tasks performed by the telematics platform will be presented. The experimental part of the work involved a representative number of subjects. Results for 110 subjects whose fitness levels were assessed at different periods of the year and 50 individuals whose stress scores were assessed at different times of the day showed a high correlation of the estimated values with the true ones. The application of such a low-cost monitoring system will improve the quality of service in preventive medicine. PMID- 22500743 TI - Total hip arthroplasty in HIV-infected patients: a retrospective, controlled study. AB - BACKGROUND: Although HIV-infected patients are at greater risk of presenting with ischaemic necrosis of the femoral head, there have been concerns about whether total hip arthroplasty (THA) may have worse outcomes than expected. METHODS: From the Orthopedic and Trauma Surgery database we identified all patients who had undergone THA because of ischaemic necrosis of the femoral head from January 2001 until March 2010. Patient's diagnosis of HIV infection was confirmed at the time of arthroplasty by cross-matching with the HIV unit database. For every THA in HIV-infected patients, two THAs in patients not known to be HIV-infected, with the same diagnosis of ischaemic necrosis of the femoral head and having undergone surgery over the same period, were randomly selected. THAs were compared in HIV- and non-HIV-infected patients for surgical procedure, in-patient stay and long term prognosis. RESULTS: There were 18 THAs in 13 HIV-infected patients and 36 THAs in 27 non-HIV-infected patients. No significant differences were observed in the mean time spent in surgery (106 vs. 109 minutes, respectively; P = 0.66), the need for red cell transfusion (1 vs. 4, respectively; P = 0.48) or the mean duration of hospitalization (7.8 vs. 9.4 days, respectively; P = 0.48). The two groups showed similar postoperative functional results, which were maintained until the end of the follow-up period (median 3.3 years in the HIV-positive group and 5.8 years in the HIV-negative group). CONCLUSION: Our study suggests that the outcome of THA in HIV-positive patients is not worse than that of HIV-negative patients, although future research on larger numbers of patients is required to confirm this. PMID- 22500744 TI - 'How to know what you need to do': a cross-country comparison of maternal health guidelines in Burkina Faso, Ghana and Tanzania. AB - BACKGROUND: Initiatives to raise the quality of care provided to mothers need to be given priority in Sub Saharan Africa (SSA). The promotion of clinical practice guidelines (CPGs) is a common strategy, but their implementation is often challenging, limiting their potential impact. Through a cross-country perspective, this study explored CPGs for maternal health in Burkina Faso, Ghana, and Tanzania. The objectives were to compare factors related to CPG use including their content compared with World Health Organization (WHO) guidelines, their format, and their development processes. Perceptions of their availability and use in practice were also explored. The overall purpose was to further the understanding of how to increase CPGs' potential to improve quality of care for mothers in SSA. METHODS: The study was a multiple case study design consisting of cross-country comparisons using document review and key informant interviews. A conceptual framework to aid analysis and discussion of results was developed, including selected domains related to guidelines' implementability and use by health workers in practice in terms of usability, applicability, and adaptability. RESULTS: The study revealed few significant differences in content between the national guidelines for maternal health and WHO recommendations. There were, however, marked variations in the format of CPGs between the three countries. Apart from the Ghanaian and one of the Tanzanian CPGs, the levels of both usability and applicability were assessed as low or medium. In all three countries, the use of CPGs by health workers in practice was perceived to be limited. CONCLUSION: Our cross-country study suggests that it is not poor quality of content or lack of evidence base that constitute the major barrier for CPGs to positively impact on quality improvement in maternal care in SSA. It rather emphasises the need to prioritise the format of guidelines to increase their usability and applicability and to consider these attributes together with implementation strategies as integral to their development processes. PMID- 22500745 TI - A proposed confinement modulated gap nanowire transistor based on a metal (tin). AB - Energy bandgaps are observed to increase with decreasing diameter due to quantum confinement in quasi-one-dimensional semiconductor nanostructures or nanowires. A similar effect is observed in semimetal nanowires for sufficiently small wire diameters: A bandgap is induced, and the semimetal nanowire becomes a semiconductor. We demonstrate that on the length scale on which the semimetal semiconductor transition occurs, this enables the use of bandgap engineering to form a field-effect transistor near atomic dimensions and eliminates the need for doping in the transistor's source, channel, or drain. By removing the requirement to supply free carriers by introducing dopant impurities, quantum confinement allows for a materials engineering to overcome the primary obstacle to fabricating sub-5 nm transistors, enabling aggressive scaling to near atomic limits. PMID- 22500747 TI - Mechanisms by which cytoplasmic calcium wave propagation and alternans are generated in cardiac atrial myocytes lacking T-tubules-insights from a simulation study. AB - This study investigated the mechanisms underlying the propagation of cytoplasmic calcium waves and the genesis of systolic Ca(2+) alternans in cardiac myocytes lacking transverse tubules (t-tubules). These correspond to atrial cells of either small mammals or large mammals that have lost their t-tubules due to disease-induced structural remodeling (e.g., atrial fibrillation). A mathematical model was developed for a cluster of ryanodine receptors distributed on the cross section of a cell that was divided into 13 elements with a spatial resolution of 2 MUm. Due to the absence of t-tubules, L-type Ca(2+) channels were only located in the peripheral elements close to the cell-membrane surface and produced Ca(2+) signals that propagated toward central elements by triggering successive Ca(2+) induced Ca(2+) release (CICR) via Ca(2+) diffusion between adjacent elements. Under control conditions, the Ca(2+) signals did not fully propagate to the central region of the cell. However, with modulation of several factors responsible for Ca(2+) handling, such as the L-type Ca(2+) channels (Ca(2+) influx), SERCA pumps (sarcoplasmic reticulum (SR) Ca(2+) uptake), and ryanodine receptors (SR Ca(2+) release), Ca(2+) wave propagation to the center of the cell could occur. These simulation results are consistent with previous experimental data from atrial cells of small mammals. The model further reveals that spatially functional heterogeneity in Ca(2+) diffusion within the cell produced a steep relationship between the SR Ca(2+) content and the cytoplasmic Ca(2+) concentration. This played an important role in the genesis of Ca(2+) alternans that were more obvious in central than in peripheral elements. Possible association between the occurrence of Ca(2+) alternans and the model parameters of Ca(2+) handling was comprehensively explored in a wide range of one- and two parameter spaces. In addition, the model revealed a spontaneous second Ca(2+) release in response to a single voltage stimulus pulse with SR Ca(2+) overloading and augmented Ca(2+) influx. This study provides what to our knowledge are new insights into the genesis of Ca(2+) alternans and spontaneous second Ca(2+) release in cardiac myocytes that lack t-tubules. PMID- 22500748 TI - Mass transfer enhancement in moving biofilm structures. AB - Biofilms are layers of microbial cells growing on an interface and they can form highly complex structures adapted to a wide variety of environmental conditions. Biofilm streamers have a small immobile base attached to the support and a flexible tail elongated in the flow direction, which can vibrate in fast flows. Herein we report numerical results for the role of the periodical movement of biofilm streamers on the nutrient uptake and in general on the solute mass transfer enhancement due to flow-induced oscillations. We developed what to our knowledge is a novel two-dimensional fluid-structure interaction model coupled to unsteady solute mass transport and solved the model using the finite element method with a moving mesh. Results demonstrate that the oscillatory movement of the biofilm tail significantly increases the substrate uptake. The mass transfer coefficient is the highest in regions close to the streamer tip. The reason for substrate transfer enhancement is the increase in speed of tip movement relative to the surrounding liquid, thereby reducing the thickness of the mass transfer boundary layer. In addition, we show that the relative mass transfer enhancement in unsteady conditions compared with the rigid static structure is larger at higher flow velocities, and this relative increase favors a more flexible structure. PMID- 22500749 TI - Excitable actin dynamics in lamellipodial protrusion and retraction. AB - Many animal cells initiate crawling by protruding lamellipodia, consisting of a dense network of actin filaments, at their leading edge. We imaged XTC cells that exhibit flat lamellipodia on poly-L-lysine-coated coverslips. Using active contours, we tracked the leading edge and measured the total amount of F-actin by summing the pixel intensities within a 5-MUm band. We observed protrusion and retraction with period 130-200 s and local wavelike features. Positive (negative) velocities correlated with minimum (maximum) integrated actin concentration. Approximately constant retrograde flow indicated that protrusions and retractions were driven by fluctuations of the actin polymerization rate. We present a model of these actin dynamics as an excitable system in which a diffusive, autocatalytic activator causes actin polymerization; F-actin accumulation in turn inhibits further activator accumulation. Simulations of the model reproduced the pattern of actin polymerization seen in experiments. To explore the model's assumption of an autocatalytic activation mechanism, we imaged cells expressing markers for both F-actin and the p21 subunit of the Arp2/3 complex. We found that integrated Arp2/3-complex concentrations spike several seconds before spikes of F actin concentration. This suggests that the Arp2/3 complex participates in an activation mechanism that includes additional diffuse components. Response of cells to stimulation by fetal calf serum could be reproduced by the model, further supporting the proposed dynamical picture. PMID- 22500750 TI - Membrane tension, myosin force, and actin turnover maintain actin treadmill in the nerve growth cone. AB - A growth cone is a motile structure at the tips of axons that is driven by the actin network and guides axon extension. Low actin adhesion to the substrate creates a stationary actin treadmill that allows leading-edge protrusion when adhesion increases in response to guidance cues. We use experimental measurements in the Aplysia bag growth cone to develop and constrain a simple mechanical model of the actin treadmill. We show that actin retrograde flow is primarily generated by myosin contractile forces, but when myosin is inhibited, leading-edge membrane tension increases and drives the flow. By comparing predictions of the model with previous experimental measurements, we demonstrate that lamellipodial and filopodial filament breaking contribute equally to the resistance to the flow. The fully constrained model clarifies the role of actin turnover in the mechanical balance driving the actin treadmill and reproduces the recent experimental observation that inhibition of actin depolymerization causes retrograde flow to slow exponentially with time. We estimate forces in the actin treadmill, and we demonstrate that measured G-actin distributions are consistent with the existence of a forward-directed fluid flow that transports G-actin to the leading edge. PMID- 22500751 TI - Direct upstream motility in Escherichia coli. AB - We provide an experimental demonstration of positive rheotaxis (rapid and continuous upstream motility) in wild-type Escherichia coli freely swimming over a surface. This hydrodynamic phenomenon is dominant below a critical shear rate and robust against Brownian motion and cell tumbling. We deduce that individual bacteria entering a flow system can rapidly migrate upstream (>20 MUm/s) much faster than a gradually advancing biofilm. Given a bacterial population with a distribution of sizes and swim speeds, local shear rate near the surface determines the dominant hydrodynamic mode for motility, i.e., circular or random trajectories for low shear rates, positive rheotaxis for moderate flow, and sideways swimming at higher shear rates. Faster swimmers can move upstream more rapidly and at higher shear rates, as expected. Interestingly, we also find on average that both swim speed and upstream motility are independent of cell aspect ratio. PMID- 22500752 TI - Membrane dynamics correlate with formation of signaling clusters during cell spreading. AB - The morphology and duration of contacts between cells and adhesive surfaces play a key role in several biological processes, such as cell migration, cell differentiation, and the immune response. The interaction of receptors on the cell membrane with ligands on the adhesive surface leads to triggering of signaling pathways, which allow cytoskeletal rearrangement, and large-scale deformation of the cell membrane, which allows the cell to spread over the substrate. Despite numerous studies of cell spreading, the nanometer-scale dynamics of the membrane during formation of contacts, spreading, and initiation of signaling are not well understood. Using interference reflection microscopy, we study the kinetics of cell spreading at the micron scale, as well as the topography and fluctuations of the membrane at the nanometer scale during spreading of Jurkat T cells on antibody-coated substrates. We observed two modes of spreading, which were characterized by dramatic differences in membrane dynamics and topography. Formation of signaling clusters was closely related to the movement and morphology of the membrane in contact with the activating surface. Our results suggest that cell membrane morphology may be a critical constraint on signaling at the cell-substrate interface. PMID- 22500754 TI - Lifetime of major histocompatibility complex class-I membrane clusters is controlled by the actin cytoskeleton. AB - Lateral heterogeneity of cell membranes has been demonstrated in numerous studies showing anomalous diffusion of membrane proteins; it has been explained by models and experiments suggesting dynamic barriers to free diffusion, that temporarily confine membrane proteins into microscopic patches. This picture, however, comes short of explaining a steady-state patchy distribution of proteins, in face of the transient opening of the barriers. In our previous work we directly imaged persistent clusters of MHC-I, a type I transmembrane protein, and proposed a model of a dynamic equilibrium between proteins newly delivered to the cell surface by vesicle traffic, temporary confinement by dynamic barriers to lateral diffusion, and dispersion of the clusters by diffusion over the dynamic barriers. Our model predicted that the clusters are dynamic, appearing when an exocytic vesicle fuses with the plasma membrane and dispersing with a typical lifetime that depends on lateral diffusion and the dynamics of barriers. In a subsequent work, we showed this to be the case. Here we test another prediction of the model, and show that changing the stability of actin barriers to lateral diffusion changes cluster lifetimes. We also develop a model for the distribution of cluster lifetimes, consistent with the function of barriers to lateral diffusion in maintaining MHC-I clusters. PMID- 22500753 TI - Super-resolution imaging of C-type lectin and influenza hemagglutinin nanodomains on plasma membranes using blink microscopy. AB - Dendritic cells express DC-SIGN, a C-type lectin (CTL) that binds a variety of pathogens and facilitates their uptake for subsequent antigen presentation. DC SIGN forms remarkably stable microdomains on the plasma membrane. However, inner leaflet lipid markers are able to diffuse through these microdomains suggesting that, rather than being densely packed with DC-SIGN proteins, an elemental substructure exists. Therefore, a super-resolution imaging technique, Blink Microscopy (Blink), was applied to further investigate the lateral distribution of DC-SIGN. Blink indicates that DC-SIGN, another CTL (CD206), and influenza hemagglutinin (HA) are all localized in small (~80 nm in diameter) nanodomains. DC-SIGN and CD206 nanodomains are randomly distributed on the plasma membrane, whereas HA nanodomains cluster on length scales up to several microns. We estimate, as a lower limit, that DC-SIGN and HA nanodomains contain on average two tetramers or two trimers, respectively, whereas CD206 is often nonoligomerized. Two-color Blink determined that different CTLs rarely occupy the same nanodomain, although they appear colocalized using wide-field microscopy. What to our knowledge is a novel domain structure emerges in which elemental nanodomains, potentially capable of binding viruses, are organized in a random fashion; evidently, these nanodomains can be clustered into larger microdomains that act as receptor platforms for larger pathogens like yeasts. PMID- 22500755 TI - Influence of hydrophobic mismatch on structures and dynamics of gramicidin a and lipid bilayers. AB - Gramicidin A (gA) is a 15-amino-acid antibiotic peptide with an alternating L-D sequence, which forms (dimeric) bilayer-spanning, monovalent cation channels in biological membranes and synthetic bilayers. We performed molecular dynamics simulations of gA dimers and monomers in all-atom, explicit dilauroylphosphatidylcholine (DLPC), dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), and 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayers. The variation in acyl chain length among these different phospholipids provides a way to alter gA-bilayer interactions by varying the bilayer hydrophobic thickness, and to determine the influence of hydrophobic mismatch on the structure and dynamics of both gA channels (and monomeric subunits) and the host bilayers. The simulations show that the channel structure varied little with changes in hydrophobic mismatch, and that the lipid bilayer adapts to the bilayer-spanning channel to minimize the exposure of hydrophobic residues. The bilayer thickness, however, did not vary monotonically as a function of radial distance from the channel. In all simulations, there was an initial decrease in thickness within 4-5 A from the channel, which was followed by an increase in DOPC and POPC or a further decrease in DLPC and DMPC bilayers. The bilayer thickness varied little in the monomer simulations-except one of three independent simulations for DMPC and all three DLPC simulations, where the bilayer thinned to allow a single subunit to form a bilayer-spanning water permeable pore. The radial dependence of local lipid area and bilayer compressibility is also nonmonotonic in the first shell around gA dimers due to gA-phospholipid interactions and the hydrophobic mismatch. Order parameters, acyl chain dynamics, and diffusion constants also differ between the lipids in the first shell and the bulk. The lipid behaviors in the first shell around gA dimers are more complex than predicted from a simple mismatch model, which has implications for understanding the energetics of membrane protein-lipid interactions. PMID- 22500756 TI - Differential effect of cholesterol and its biosynthetic precursors on membrane dipole potential. AB - Dipole potential is the potential difference within the membrane bilayer, which originates due to the nonrandom arrangement of lipid dipoles and water molecules at the membrane interface. Cholesterol, a representative sterol in higher eukaryotic membranes, is known to increase membrane dipole potential. In this work, we explored the effects of immediate (7-DHC and desmosterol) and evolutionary (ergosterol) precursors of cholesterol on membrane dipole potential, monitored by the dual wavelength ratiometric approach utilizing the probe di-8 ANEPPS. Our results show that the effect of these precursors on membrane dipole potential is very different from that observed with cholesterol, although the structural differences among them are subtle. These results assume relevance, since accumulation of cholesterol precursors due to defective cholesterol biosynthesis has been reported to result in several inherited metabolic disorders such as the Smith-Lemli-Opitz syndrome. Interestingly, cholesterol (and its precursors) has a negligible effect on dipole potential in polyunsaturated membranes. We interpret these results in terms of noncanonical orientation of cholesterol in these membranes. Our results constitute the first report on the effect of biosynthetic and evolutionary precursors of cholesterol on dipole potential, and imply that a subtle change in sterol structure can significantly alter the dipolar field at the membrane interface. PMID- 22500757 TI - pH-responsive titratable inotropic performance of histidine-modified cardiac troponin I. AB - Cardiac troponin I (cTnI) functions as the molecular switch of the thin filament. Studies have shown that a histidine button engineered into cTnI (cTnI A164H) specifically enhances inotropic function in the context of numerous pathophysiological challenges. To gain mechanistic insight into the basis of this finding, we analyzed histidine ionization states in vitro by studying the myofilament biophysics of amino acid substitutions that act as constitutive chemical mimetics of altered histidine ionization. We also assessed the role of histidine-modified cTnI in silico by means of molecular dynamics simulations. A functional in vitro analysis of myocytes at baseline (pH 7.4) indicated similar cellular contractile function and myofilament calcium sensitivity between myocytes expressing wild-type (WT) cTnI and cTnI A164H, whereas the A164R variant showed increased myofilament calcium sensitivity. Under acidic conditions, compared with WT myocytes, the myocytes expressing cTnI A164H maintained a contractile performance similar to that observed for the constitutively protonated cTnI A164R variant. Molecular dynamics simulations showed similar intermolecular atomic contacts between the WT and the deprotonated cTnI A164H variant. In contrast, simulations of protonated cTnI A164H showed various potential structural configurations, one of which included a salt bridge between His-164 of cTnI and Glu-19 of cTnC. This salt bridge was recapitulated in simulations of the cTnI A164R variant. These data suggest that differential histidine ionization may be necessary for cTnI A164H to act as a molecular sensor capable of modulating sarcomere performance in response to changes in the cytosolic milieu. PMID- 22500758 TI - A genetic network that balances two outcomes utilizes asymmetric recognition of operator sites. AB - Stability and induction of the lysogenic state of bacteriophage lambda are balanced by a complex regulatory network. A key feature of this network is the mutually exclusive cooperative binding of a repressor dimer (CI) to one of two pairs of binding sites, O(R)1-O(R)2 or O(R)2-O(R)3. The structural features that underpin the mutually exclusive binding mode are not well understood. Recent studies have demonstrated that CI is an asymmetric dimer. The functional importance of the asymmetry is not fully clear. Due to the asymmetric nature of the CI dimer as well as its binding sites, there are two possible bound orientations. By fluorescence resonance energy transfer measurements we showed that CI prefers one bound orientation. We also demonstrated that the relative configuration of the binding sites is important for CI dimer-dimer interactions and consequent cooperative binding. We proposed that the operator configuration dictates the orientations of the bound CI molecules, which in turn dictates CI cooperative interaction between the O(R)1-O(R)2 or O(R)2-O(R)3, but not both. Modeling suggests that the relative orientation of the C- and N-terminal domains may play an important role in the mutually exclusive nature of the cooperative binding. This work correlates unique structural features of a transcription regulatory protein with the functional properties of a gene regulatory network. PMID- 22500759 TI - Thermodynamic coupling of protonation and conformational equilibria in proteins: theory and simulation. AB - Ionization-coupled conformational phenomena are ubiquitous in biology. However, quantitative characterization of the underlying thermodynamic cycle comprised of protonation and conformational equilibria has remained an elusive goal. Here we use theory and continuous constant pH molecular dynamics (CpHMD) simulations to provide a thermodynamic description for the coupling of proton titration and conformational exchange between two distinct states of a protein. CpHMD simulations with a hybrid-solvent scheme and the pH-based replica-exchange (REX) protocol are applied to obtain the equilibrium constants and atomic details of the ionization-coupled conformational exchange between open and closed states of an engineered mutant of staphylococcal nuclease. Although the coupling of protonation and conformational equilibria is not exact in the simulation, the results are encouraging. They demonstrate that REX-CpHMD simulations can be used to study thermodynamics of ionization-coupled conformational processes--which has not possible using present experimental techniques or traditional simulations based on fixed protonation states. PMID- 22500760 TI - Imaging nanometer-sized alpha-synuclein aggregates by superresolution fluorescence localization microscopy. AB - The morphological features of alpha-synuclein (AS) amyloid aggregation in vitro and in cells were elucidated at the nanoscale by far-field subdiffraction fluorescence localization microscopy. Labeling AS with rhodamine spiroamide probes allowed us to image AS fibrillar structures by fluorescence stochastic nanoscopy with an enhanced resolution at least 10-fold higher than that achieved with conventional, diffraction-limited techniques. The implementation of dual color detection, combined with atomic force microscopy, revealed the propagation of individual fibrils in vitro. In cells, labeled protein appeared as amyloid aggregates of spheroidal morphology and subdiffraction sizes compatible with in vitro supramolecular intermediates perceived independently by atomic force microscopy and cryo-electron tomography. We estimated the number of monomeric protein units present in these minute structures. This approach is ideally suited for the investigation of the molecular mechanisms of amyloid formation both in vitro and in the cellular milieu. PMID- 22500761 TI - Solution model of the intrinsically disordered polyglutamine tract-binding protein-1. AB - Polyglutamine tract-binding protein-1 (PQBP-1) is a 265-residue nuclear protein that is involved in transcriptional regulation. In addition to its role in the molecular pathology of the polyglutamine expansion diseases, mutations of the protein are associated with X-linked mental retardation. PQBP-1 binds specifically to glutamine repeat sequences and proline-rich regions, and interacts with RNA polymerase II and the spliceosomal protein U5-15kD. In this work, we obtained a biophysical characterization of this protein by employing complementary structural methods. PQBP-1 is shown to be a moderately compact but largely disordered molecule with an elongated shape, having a Stokes radius of 3.7 nm and a maximum molecular dimension of 13 nm. The protein is monomeric in solution, has residual beta-structure, and is in a premolten globule state that is unaffected by natural osmolytes. Using small-angle x-ray scattering data, we were able to generate a low-resolution, three-dimensional model of PQBP-1. PMID- 22500762 TI - End-to-end self-assembly of RADA 16-I nanofibrils in aqueous solutions. AB - RADARADARADARADA (RADA 16-I) is a synthetic amphiphilic peptide designed to self assemble in a controlled way into fibrils and higher ordered structures depending on pH. In this work, we use various techniques to investigate the state of the peptide dispersed in water under dilute conditions at different pH and in the presence of trifluoroacetic acid or hydrochloric acid. We have identified stable RADA 16-I fibrils at pH 2.0-4.5, which have a length of ~200-400 nm and diameter of 10 nm. The fibrils have the characteristic antiparallel beta-sheet structure of amyloid fibrils, as measured by circular dichroism and Fourier transform infrared spectrometry. During incubation at pH 2.0-4.5, the fibrils elongate very slowly via an end-to-end fibril-fibril aggregation mechanism, without changing their diameter, and the kinetics of such aggregation depends on pH and anion type. At pH 2.0, we also observed a substantial amount of monomers in the system, which do not participate in the fibril elongation and degrade to fragments. The fibril-fibril elongation kinetics has been simulated using the Smoluchowski kinetic model, population balance equations, and the simulation results are in good agreement with the experimental data. It is also found that the aggregation process is not limited by diffusion but rather is an activated process with energy barrier in the order of 20 kcal/mol. PMID- 22500763 TI - Is a malleable protein necessarily highly dynamic? The hydrophobic core of the nuclear coactivator binding domain is well ordered. AB - The nuclear coactivator binding domain of CREB binding protein folds into remarkably different structures in complex with different ligands. To understand the mechanism of the structural adaptability in the nuclear coactivator binding domain (NCBD), we have compared the dynamics of the hydrophobic core of NCBD in the ligand-free state and in a well-folded complex with the ligand activator for thyroid hormone and retinoid receptors using multiple NMR methods including methyl chemical shifts, coupling constants, and methyl order parameters. From all NMR measures, the aliphatic side chains in the hydrophobic core are slightly more dynamic in the free protein than in the complex, but have mobility comparable to the hydrophobic cores of average folded proteins. Urea titration monitored by NMR reveals that all parts of the protein, including the side-chain packing in the hydrophobic core, denatures in a single cooperative process. The molten globule characteristics of NCBD are thus restricted to a slowly fluctuating tertiary structure. Consequently, the conformational plasticity of the protein is most likely related to its low overall stability rather than an intrinsically flexible protein structure. The well-defined structure supports a model of molecular recognition dominated by conformational selection, whereas only minor structural adjustments are necessary after the association. PMID- 22500764 TI - Highly perturbed pKa values in the unfolded state of hen egg white lysozyme. AB - The majority of pK(a) values in protein unfolded states are close to the amino acid model pK(a) values, thus reflecting the weak intramolecular interactions present in the unfolded ensemble of most proteins. We have carried out thermal denaturation measurements on the WT and eight mutants of HEWL from pH 1.5 to pH 11.0 to examine the unfolded state pK(a) values and the pH dependence of protein stability for this enzyme. The availability of accurate pK(a) values for the folded state of HEWL and separate measurements of mutant-induced effects on the folded state pK(a) values, allows us to estimate the pK(a) values of seven acidic residues in the unfolded state of HEWL. Asp-48 and Asp-66 display pK(a) values of 2.9 and 3.1 in our analysis, thus representing the most depressed unfolded state pK(a) values observed to date. We observe a strong correlation between the folded state pK(a) values and the unfolded state pK(a) values of HEWL, thus suggesting that the unfolded state of HEWL possesses a large degree of native state characteristics. PMID- 22500766 TI - Minimizing the impact of photoswitching of fluorescent proteins on FRAP analysis. AB - Fluorescence recovery after photobleaching (FRAP) is a widely used imaging technique for measuring the mobility of fluorescently tagged proteins in living cells. Although FRAP presumes that high-intensity illumination causes only irreversible photobleaching, reversible photoswitching of many fluorescent molecules, including GFP, can also occur. Here, we show that this photoswitching is likely to contaminate many FRAPs of GFP, and worse, the size of its contribution can be up to 60% under different experimental conditions, making it difficult to compare FRAPs from different studies. We develop a procedure to correct FRAPs for photoswitching and apply it to FRAPs of the GFP-tagged histone H2B, which, depending on the precise photobleaching conditions exhibits apparent fast components ranging from 9-36% before correction and ~1% after correction. We demonstrate how this ~1% fast component of H2B-GFP can be used as a benchmark both to estimate the role of photoswitching in previous FRAP studies of TATA binding proteins (TBP) and also as a tool to minimize the contribution of photoswitching to tolerable levels in future FRAP experiments. In sum, we show how the impact of photoswitching on FRAP can be identified, minimized, and corrected. PMID- 22500767 TI - Label-free imaging of lipid-droplet intracellular motion in early Drosophila embryos using femtosecond-stimulated Raman loss microscopy. AB - Lipid droplets are complex organelles that exhibit highly dynamic behavior in early Drosophila embryo development. Imaging lipid droplet motion provides a robust platform for the investigation of shuttling by kinesin and dynein motors, but methods for imaging are either destructive or deficient in resolution and penetration to study large populations of droplets in an individual embryo. Here we report real-time imaging and quantification of droplet motion in live embryos using a recently developed technique termed "femtosecond-stimulated Raman loss" microscopy. We captured long-duration time-lapse images of the developing embryo, tracked single droplet motion within large populations of droplets, and measured the velocity and turning frequency of each particle at different apical-to-basal depths and stages of development. To determine whether the quantities for speed and turning rate measured for individual droplets are sufficient to predict the population distributions of droplet density, we simulated droplet motion using a velocity-jump model. This model yielded droplet density distributions that agreed well with experimental observations without any model optimization or unknown parameter estimation, demonstrating the sufficiency of a velocity-jump process for droplet trafficking dynamics in blastoderm embryos. PMID- 22500765 TI - Two different binding modes of alpha-synuclein to lipid vesicles depending on its aggregation state. AB - Aggregation of alpha-synuclein is involved in the pathogenesis of Parkinson's disease (PD). Studies of in vitro aggregation of alpha-synuclein are rendered complex because of the formation of a heterogeneous population of oligomers. With the use of confocal single-molecule fluorescence techniques, we demonstrate that small aggregates (oligomers) of alpha-synuclein formed from unbound monomeric species in the presence of organic solvent (DMSO) and iron (Fe(3+)) ions have a high affinity to bind to model membranes, regardless of the lipid-composition or membrane curvature. This binding mode contrasts with the well-established membrane binding of alpha-synuclein monomers, which is accompanied with alpha helix formation and requires membranes with high curvature, defects in the lipid packing, and/or negatively charged lipids. Additionally, we demonstrate that membrane-bound alpha-synuclein monomers are protected from aggregation. Finally, we identified compounds that potently dissolved vesicle-bound alpha-synuclein oligomers into monomers, leaving the lipid vesicles intact. As it is commonly believed that formation of oligomers is related PD progression, such compounds may provide a promising strategy for the design of novel therapeutic drugs in Parkinson's disease. PMID- 22500768 TI - Structure, stability, and aggregation of beta-2 microglobulin mutants: insights from a Fourier transform infrared study in solution and in the crystalline state. AB - beta-2 microglobulin (beta2m) is an amyloidogenic protein involved in dialysis related amyloidosis. We report here the study of the structural properties of the protein in solution and in the form of single crystals by Fourier transform infrared (FTIR) spectroscopy and microspectroscopy. The investigation has been extended to four beta2m mutants previously characterized by x-ray crystallography: Asp(53)Pro, Asp(59)Pro, Trp(60)Gly, and Trp(60)Val. These variants displayed very similar three-dimensional structures but different thermal stability and aggregation propensity, investigated here by FTIR spectroscopy. For each variant, appreciable spectral differences were found between the protein in solution and in single crystals, consisting in a downshift of the main beta-sheet band and in better resolved turn and loop bands, indicative of reduced protein secondary structure dynamics in the crystalline state. Notably, the well-resolved spectra of the beta2m crystalline variants enabled us to identify structural differences induced by the single amino acid mutations. Such differences encompass turn and loop structures that might affect the stability and aggregation propensity of the investigated beta2m variants. This study highlights the potential of FTIR microspectroscopy to acquire useful structural information on protein crystals, complementary to the crystallographic analyses. PMID- 22500769 TI - Single-image diffusion coefficient measurements of proteins in free solution. AB - Diffusion coefficient measurements are important for many biological and material investigations, such as studies of particle dynamics and kinetics, and size determinations. Among current measurement methods, single particle tracking (SPT) offers the unique ability to simultaneously obtain location and diffusion information about a molecule while using only femtomoles of sample. However, the temporal resolution of SPT is limited to seconds for single-color-labeled samples. By directly imaging three-dimensional diffusing fluorescent proteins and studying the widths of their intensity profiles, we were able to determine the proteins' diffusion coefficients using single protein images of submillisecond exposure times. This simple method improves the temporal resolution of diffusion coefficient measurements to submilliseconds, and can be readily applied to a range of particle sizes in SPT investigations and applications in which diffusion coefficient measurements are needed, such as reaction kinetics and particle size determinations. PMID- 22500770 TI - Picosecond kinetics of light harvesting and photoprotective quenching in wild type and mutant phycobilisomes isolated from the cyanobacterium Synechocystis PCC 6803. AB - In high light conditions, cyanobacteria dissipate excess absorbed energy as heat in the light-harvesting phycobilisomes (PBs) to protect the photosynthetic system against photodamage. This process requires the binding of the red active form of the Orange Carotenoid Protein (OCP(r)), which can effectively quench the excited state of one of the allophycocyanin bilins. Recently, an in vitro reconstitution system was developed using isolated OCP and isolated PBs from Synechocystis PCC 6803. Here we have used spectrally resolved picosecond fluorescence to study wild type and two mutated PBs. The results demonstrate that the quenching for all types of PBs takes place on an allophycocyanin bilin emitting at 660 nm (APC(Q)(660)) with a molecular quenching rate that is faster than (1 ps)(-1). Moreover, it is concluded that both the mechanism and the site of quenching are the same in vitro and in vivo. Thus, utilization of the in vitro system should make it possible in the future to elucidate whether the quenching is caused by charge transfer between APC(Q)(660) and OCP or by excitation energy transfer from APC(Q)(660) to the S(1) state of the carotenoid--a distinction that is very hard, if not impossible, to make in vivo. PMID- 22500771 TI - NMR observable-based structure refinement of DAP12-NKG2C activating immunoreceptor complex in explicit membranes. AB - NMR observables, such as NOE-based distance measurements, are increasingly being used to characterize membrane protein structures. However, challenges in membrane protein NMR studies often yield a relatively small number of such restraints that can create ambiguities in defining critical side chain-side chain interactions. In the recent solution NMR structure of the DAP12-NKG2C immunoreceptor transmembrane helix complex, five functionally required interfacial residues (two Asps and two Thrs in the DAP12 dimer and one Lys in NKG2C) display a surprising arrangement in which one Asp side chain faces the membrane hydrophobic core. To explore whether these side-chain interactions are energetically optimal, we used the published distance restraints for molecular dynamics simulations in explicit micelles and bilayers. The structures refined by this protocol are globally similar to the published structure, but the side chains of those five residues form a stable network of salt bridges and hydrogen bonds, leaving the Asp side chain shielded from the hydrophobic core, which is also consistent with available experimental observations. Moreover, the simulations show similar short-range interactions between the transmembrane complex and lipid/detergent molecules in micelles and bilayers, respectively. This study illustrates the efficacy of NMR membrane protein structure refinements in explicit membrane systems. PMID- 22500772 TI - Reliability and validity of the Chinese version of the Psoriasis Disability Index (PDI) in Chinese patients with psoriasis. AB - BACKGROUND: The Psoriasis Disability Index (PDI) is a widely used instrument to measure the impact of psoriasis on patients. There has not been psychometric evaluation of the Chinese version of PDI. The aim of this study was to evaluate its reliability and validity among Chinese patients with psoriasis. METHODS: A multi-center, cross-sectional study was conducted at 9 hospitals including patients aged 18 years and over. Reliability was determined by internal consistency using Cronbach's alpha. Validity was assessed through convergent validity and known groups validity. Dimensionality of the PDI was examined by exploratory factor analysis in working patients and nonworking patients respectively. RESULTS: In all, 831 patients were studied. Internal consistency of the PDI was satisfactory. Cronbach's alpha coefficient was 0.91 for the total score and over 0.70 for each subscale of the PDI. Evidence of convergent validity of the PDI was proved by excellent and moderate to good correlations with the Dermatology Life Quality Index (DLQI) and four subscales of the Short Form-36 (SF 36) (role-physical, bodily pain, social functioning, and role-emotional): r = 0.51-0.78. Known groups validity was confirmed that the PDI score discriminated well among patients with different severity of psoriasis. The dimensionality of the PDI was determined by the presence of two-factor structure for working patients and three-factor structure for nonworking patients which accounted for 57.3% and 62.3% of the variance respectively. CONCLUSION: The Chinese version of the PDI is a reliable and valid instrument to assess the impact of psoriasis on patients' lives and could be used in future quality of life assessment of Chinese patients with psoriasis. PMID- 22500773 TI - Altered structural brain connectivity in healthy carriers of the autism risk gene, CNTNAP2. AB - Recently, carriers of a common variant in the autism risk gene, CNTNAP2, were found to have altered functional brain connectivity using functional MRI. Here, we scanned 328 young adults with high-field (4-Tesla) diffusion imaging, to test the hypothesis that carriers of this gene variant would have altered structural brain connectivity. All participants (209 women, 119 men, age: 23.4+/-2.17 SD years) were scanned with 105-gradient high-angular-resolution diffusion imaging (HARDI) at 4 Tesla. After performing a whole-brain fiber tractography using the full angular resolution of the diffusion scans, 70 cortical surface-based regions of interest were created from each individual's co-registered anatomical data to compute graph metrics for all pairs of cortical regions. In graph theory analyses, subjects homozygous for the risk allele (CC) had lower characteristic path length, greater small-worldness and global efficiency in whole-brain analyses, and lower [corrected] eccentricity (maximum path length) in 60 of the 70 nodes in regional analyses. These results were not reducible to differences in more commonly studied traits such as fiber density or fractional anisotropy. This is the first study that links graph theory metrics of brain structural connectivity to a common genetic variant linked with autism and will help us understand the neurobiology of the circuits implicated in the risk for autism. PMID- 22500774 TI - Diffuse abnormality of low to moderately organized white matter in schizophrenia. AB - Increasing evidence suggests that abnormal white matter is central to the pathophysiology and, potentially, the pathogenesis of schizophrenia (SCZ). The spatial distribution of observed abnormalities and the type of white matter involved remain to be elucidated. Seventeen chronically ill individuals with SCZ and 17 age- and gender-matched controls were studied using a 3T magnetic resonance imaging diffusion tensor imaging protocol designed to examine the abnormalities of white matter by region and by level of architectural infrastructure as assessed by fractional anisotropy (FA) in native space. After assessing whole-brain FA, FA was divided into quartiles, capturing all brain regions with FA values from 0 to 0.25, 0.25 to 0.5, 0.5 to 0.75, and 0.75 to 1.0. Mean whole-brain FA was 4.6% smaller in the SCZ group than in healthy controls. This difference was largely accounted for by FA values from the second quartile (between 0.25 and 0.5). Second quartile FA was decreased in all 130 brain regions of the template in the SCZ group, with the difference reaching statistical significance in 41 regions. Correspondingly, the amount of brain tissue with an FA of ~0.4 was significantly reduced in the SCZ group, while the amount of brain tissue falling in the lowest quartile of FA was increased. These findings strongly imply a diffuse loss of white matter integrity in SCZ. Our finding that the loss of integrity disproportionately involves white matter of low to moderate organization suggests an approach to the specificity of white matter abnormalities in SCZ based on microstructure rather than spatial distribution. PMID- 22500775 TI - Comparative study of workflows optimized for in-gel, in-solution, and on-filter proteolysis in the analysis of plasma membrane proteins. AB - Proteomic studies of plasma membrane proteins are challenged by the limited solubility of these proteins and the limited activity of proteolytic enzymes in solubilizing agents such as SDS. In this work, we have evaluated three bottom-up workflows to obtain tryptic peptides from plasma membrane proteins solubilized with 2% SDS. The workflows are in-gel digestion, in-solution digestion, and on filter digestion. The efficiencies of these strategies, optimized to employ different matrices for trypsin cleavage, were compared using a plasma membrane sample enriched from multiple myeloma cells using a nanoparticle pellicle. On the basis of the number of proteins identified, number of transmembrane proteins identified, hydrophobicity, and spectral count per protein, the workflow that uses in-gel digestion is the most advantageous approach for analysis of plasma membrane proteins. PMID- 22500776 TI - Polyphosphate scores a hat trick in regulating host defense mechanisms. PMID- 22500777 TI - Mortality, health care utilization and associated diagnoses in hospitalized patients with haemophilia in the United States: first reported nationwide estimates. AB - To describe the in-hospital epidemiology of haemophilia A and B in the US we analysed the National Inpatient Sample (NIS), a stratified probability sample of 20% of all hospital discharges in the US for the year 2007. We applied sampling weights to represent all hospital discharges for haemophilia A and B identified using ICD-9 codes 286.0 and 286.1, respectively. Haemophilia (A or B) was one of all the listed diagnoses in 9737 discharges and principal diagnosis in 1684 discharges. The most common associated diagnoses in discharges with Haemophilia in adults and children were hypertension (28.1 +/- 1.6%) and central line infections (15.2 +/- 1.8%) respectively. No Hepatitis C or HIV was reported in children. Among 212 deaths, associated diagnoses included sepsis (37.9%), heart failure (30.2%), respiratory failure (28.3%), pneumonia (24.5%), HIV (14.2%), hepatic coma (5.2%) and intracranial haemorrhage (2.3%). All fifteen reported paediatric deaths occurred on day zero of life, the commonest associated diagnoses being Intraventricular haemorrhage and newborn haemorrhage-NOS (33% each). Median age of in-hospital mortality for diagnosis of Haemophilia was 68.3 years as compared to 72.3 years for all males for all hospitalizations in NIS combined. Mean hospital charges for haemophilia of $76823 +/- 5530 were significantly higher than those from all causes of hospitalization of $26,120 +/- 562. In-hospital mortality is rare in children with haemophilia beyond the neonatal period and age of mortality in adults is approaching that of the general male population. Hospitalization in children is most often due to central line infections and hospitalization and death in adults is primarily due to age related illnesses. PMID- 22500778 TI - Evaluation and optimization of nucleic acid extraction methods for the molecular analysis of bacterial communities associated with corroded carbon steel. AB - Different DNA and RNA extraction approaches were evaluated and protocols optimized on in situ corrosion products from carbon steel in marine environments. Protocols adapted from the PowerSoil DNA/RNA Isolation methods resulted in the best nucleic acid (NA) extraction performances (ie combining high NA yield, quality, purity, representativeness of microbial community and processing time efficiency). The PowerSoil RNA Isolation Kit was the only method which resulted in amplifiable RNA of good quality (ie intact 16S/23S rRNA). Sample homogenization and hot chemical (SDS) cell lysis combined with mechanical (bead beating) lysis in presence of a DNA competitor (skim milk) contributed to improving substantially (around 23 times) the DNA yield of the PowerSoil DNA Isolation Kit. Apart from presenting NA extraction strategies for optimizing extraction parameters with corrosion samples from carbon steel, this study proposes DNA and RNA extraction procedures suited for comparative molecular analysis of total and active fractions of bacterial communities associated with carbon steel corrosion events, thereby contributing to improved MIC diagnosis and control. PMID- 22500779 TI - Role of morphological growth state and gene expression in Desulfovibrio africanus strain Walvis Bay mercury methylation. AB - The biogeochemical transformations of mercury are a complex process, with the production of methylmercury, a potent human neurotoxin, repeatedly demonstrated in sulfate- and Fe(III)-reducing as well as methanogenic bacteria. However, little is known regarding the morphology, genes, or proteins involved in methylmercury generation. Desulfovibrio africanus strain Walvis Bay is a Hg methylating delta-proteobacterium with a sequenced genome and has unusual pleomorphic forms. In this study, a relationship between the pleomorphism and Hg methylation was investigated. Proportional increases in the sigmoidal (regular) cell form corresponded with increased net MeHg production but decreased when the pinched cocci (persister) form became the major morphotype. D. africanus microarrays indicated that the ferrous iron transport genes (feoAB), as well as ribosomal genes and several genes whose products are predicted to have metal binding domains (CxxC), were up-regulated during exposure to Hg in the exponential phase. Whereas no specific methylation pathways were identified, the finding that Hg may interfere with iron transport and the correlation of growth phase-dependent morphology with MeHg production are notable. The identification of these relationships between differential gene expression, morphology, and the growth-phase dependence of Hg transformations suggests that actively growing cells are primarily responsible for methylation, and so areas with ample carbon and electron-acceptor concentrations may also generate a higher proportion of methylmercury than more oligotrophic environments. The observation of increased iron transporter expression also suggests that Hg methylation may interfere with iron biogeochemical cycles. PMID- 22500780 TI - High HIV prevalence in a southern semi-rural area of Mozambique: a community based survey. AB - BACKGROUND: Southern African countries have borne the brunt of the HIV/AIDS pandemic. Monitoring epidemiological dynamics is critical to identify the populations at greatest risk of infection and to guide control strategies. METHODS: A cross-sectional community-based study to determine age- and sex specific HIV prevalence among individuals aged 18-47 years was carried out in Manhica, southern Mozambique. Participants were randomly selected from the demographic surveillance system in place in the area and voluntary HIV counselling and testing were offered at home. In addition, HIV prevalence estimates from the antenatal clinic (ANC) were collected prospectively. RESULTS: A total of 839 individuals were invited to participate in the study. Of these, 722 were recruited (50.7% women). The overall HIV prevalence in the community was 39.9% [95% confidence interval (CI) 35.9-43.8%]. By age, the prevalence was 23.2% (95% CI 17.9-28.6%) in individuals aged 18-27 years, 41.2% (95% CI 35.6-48.3%) in those aged 28-37 years and 44.8% (95% CI 38.4-51.2%) in those aged 38-47 years. HIV prevalence was higher among women than men in all age groups. The overall HIV prevalence estimate for women in the community (43.1%; 95% CI 37.6-48.5%) was 1.4 times higher than that for those attending the ANC (29.4%; 95% CI 26.7-32.0%). CONCLUSIONS: The high HIV prevalence found in this region suggests that the epidemic is in a mature stable phase. The lower rates in the ANC than in the community suggest that ANC evaluations may underestimate community HIV prevalence. Resources to monitor HIV infection dynamics are needed to guide targeted control strategies in countries in which the epidemic exacts the greatest toll. PMID- 22500781 TI - A review of augmentation therapy for alpha-1 antitrypsin deficiency. AB - INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a relatively common, but under-recognized condition which manifests commonly with liver cirrhosis and emphysema. Specific therapy for lung-affected individuals with AATD is augmentation therapy, which consists of intravenous infusion of purified human plasma-derived alpha-1 antitrypsin (AAT). Augmentation therapy was first approved by the United States Food and Drug Administration (FDA) in 1987 for emphysema associated with severe AATD and today, six augmentation therapy preparations, all of which derive from pooled human plasma, have received FDA approval. AREAS COVERED: This paper reviews augmentation therapy for AATD, including the various available commercial preparations, their processing and biochemical differences, evidence regarding biochemical and clinical efficacy, patterns of clinical use, adverse effect profiles, cost-effectiveness and potential uses in conditions other than emphysema associated with AATD. Novel and emerging strategies for treating AATD are briefly discussed next, including alternative dosing and administration strategies, recombinant preparations, small molecule inhibitors of neutrophil elastase and of AAT polymerization, autophagy-enhancing drugs and gene therapy approaches. EXPERT OPINION: We conclude with a discussion of our approach to managing patients with AATD and use of augmentation therapy. PMID- 22500782 TI - Single-wall carbon nanotubes induce oxidative stress in rat aortic endothelial cells. AB - Oxidative stress is a major factor contributing to endothelial cell damage. Single-wall carbon nanotubes (SWCNTs) have oxidative properties; however, the oxidative effects of SWCNTs on endothelial cells are not fully understood. In the present study, we investigated the effects of oxidative stress induced by SWCNTs on rat aortic endothelial cells (RAECs). Various markers of cellular damage were assessed, such as biochemical and ES immunity indexes, and DNA and protein damage. Our findings suggest that RAEC endured oxidative damage following SWCNT exposure. Specifically, after SWCNTs exposure, non-enzymatic antioxidant glutathione was activated prior to superoxide dismutase activation in order to defend against oxidative stress. Additionally, it was found that as SWCNT concentration increased, so did the stress protein, heme oxygenase-1 (HO-1), expression levels. These changes may induce RAEC damage, and result in many serious diseases. PMID- 22500783 TI - Serum alkaline phosphatase isoenzymes in SD rats detected by polyacrylamide-gel disk electrophoresis. AB - Serum alkaline phosphatase (ALP) activity is frequently measured in toxicity studies. In the present study, we assessed the usefulness of a commercially available polyacrylamide-gel disk electrophoresis kit used in humans (AlkPhor System, Jokoh Co. Ltd., Tokyo, Japan) for identifying serum ALP isoenzymes in rats of the Sprague-Dawley strain (SD rats), which are commonly used in toxicity studies. We also examined age-related changes in serum ALP isoenzymes in SD rats. In order to identify the origin of each ALP isoenzyme, tissue ALP extracts from the liver, bone and small intestine (SI) and serum samples were treated with neuraminidase, antiintestinal ALP antibody, ALP inhibitor levamisole, and/or wheat germ agglutinin. It became clear that pretreatment of serum with neuraminidase is necessary for rat serum ALP isoenzyme analysis. The kit revealed that the main serum ALP isoenzymes in fasted 8-week-old intact rats were bone- and SI-derived and they tended to decrease with age. Serum liver-derived isoenzyme was slightly detected in both sexes of all ages examined, but it greatly increased in cholestasis model rats with bile-duct ligation, and rats of this model also had large molecular ALP detected in the stacking gel, suggesting hepatic damage. High-molecular intestinal ALP isoenzyme was slightly observed at the most cathodal side of the resolving gel. These results suggest that the present method is a useful tool for detecting serum ALP isoenzymes in SD rats and that concomitant levamisole inhibition with another gel is applicable for the evaluation of organ toxicity. PMID- 22500784 TI - Thermoelectrics with earth abundant elements: high performance p-type PbS nanostructured with SrS and CaS. AB - We report high thermoelectric performance in nanostructured p-type PbS, a material consisting of highly earth abundant and inexpensive elements. The high level of Na doping switched intrinsic n-type PbS to p-type and substantially raised the power factor maximum for pure PbS to ~9.0 MUW cm(-1) K(-2) at >723 K using 2.5 at. % Na as the hole dopant. Contrary to that of PbTe, no enhancement in the Hall coefficient occurs at high temperature for heavily doped p-type PbS, indicating a single band model and no heavy hole band. We also report that the lattice thermal conductivity of PbS can be greatly reduced by adding SrS or CaS, which form a combination of a nanostructured/solid solution material as determined by transmission electron microscopy. We find that both nanoscale precipitates and point defects play an important role in reducing the lattice thermal conductivity, but the contribution from nanoscale precipitates of SrS is greater than that of CaS, whereas the contribution from point defects in the case of CaS is greater than that of SrS. Theoretical calculations of the lattice thermal conductivity based on the modified Callaway model reveal that both nanostructures and point defects (solid solution) effectively scatter phonons in this system. The lattice thermal conductivity at 723 K can be reduced by ~50% by introducing up to 4.0 at. % of either SrS or CaS. As a consequence, ZT values as high as 1.22 and 1.12 at 923 K can be achieved for nominal Pb(0.975)Na(0.025)S with 3.0 at. % SrS and CaS, respectively. No deterioration was observed after a 15 d annealing treatment of the samples, indicating the excellent thermal stability for these high performance thermoelectrics. The promising thermoelectric properties of nanostructured PbS point to a robust low cost alternative to other high performance thermoelectric materials. PMID- 22500785 TI - Autoimmune pancreatitis: a novel disease? PMID- 22500786 TI - Is obesity an indicator of complications and mortality in acute pancreatitis? An updated meta-analysis. AB - OBJECTIVE: To provide a meta-analyisis on whether obesity could be a prognostic indicator on the severity, development of complications and mortality of acute pancreatitis (AP). METHODS: Eligible articles were retrieved using electronic databases. Clinical studies evaluating the association between obesity and disease course of patients with AP were included. Weighted mean difference (WMD) and 95% confidence interval (CI) were estimated and pooled using RevMan 4.2.8. RESULTS: In all, 12 clinical studies with a total of 1483 patients were included in the analysis. Obese patients had a significantly increased risk of severe acute pancreatitis (SAP; RR=2.20, 95% CI 1.82-2.66, P<0.05), local complication (RR=2.68, 95% CI 2.09-3.43, P<0.05), systemic complication (RR=2.14, 95% CI 1.42 3.21, P<0.05) and in-hospital mortality (RR=2.59, 95% CI 1.66-4.03, P<0.05) compared with non-obese patients. CONCLUSIONS: Obesity is a definite risk factor of morbidity and in-hospital mortality for AP and may serve as a prognostic indicator. PMID- 22500787 TI - Anxiety and depression in various functional gastrointestinal disorders: do differences exist? AB - OBJECTIVE: To examine the differences in the prevalence and severity of anxiety and depression in patients with functional dyspepsia (FD), nonerosive reflux disease (NERD), irritable bowel syndrome (IBS) and healthy controls. METHODS: Consecutive patients undergoing an index endoscopic examination for various symptoms were interviewed. All the three functional gastrointestinal disorders (FGIDs) were diagnosed according to the Rome III criteria. Anxiety and depression were diagnosed using a locally validated version of the hospital anxiety and depression scale. RESULTS: A total of 248 patients were recruited (62 in FD, NERD, IBS and control groups each) with no differences in the basic characteristics. There was a higher prevalence of anxiety and depression in FD, NERD and IBS groups than that in the control group (43.5%, 45.2% and 67.7% vs 14.5%, P<0.001; and 22.6%, 33.9% and 38.7% vs 6.5%, P<0.0001). Using the cut-off score (>8) for anxiety or depression, IBS patients had a higher rate of anxiety than FD (P=0.01) and NERD (P=0.02), while no significant differences in depression rates were observed among all three groups. CONCLUSION: [corrected] Anxiety is more common in patients with IBS than in those with FD and NERD, indicating a possible causal link in the former. PMID- 22500788 TI - Clinical outcomes of palliative self-expanding metallic stents in patients with malignant colorectal obstruction. AB - OBJECTIVE: Self-expanding metallic stents (SEMS) are useful palliative option and a bridge to surgery in malignant colorectal obstruction. The aim of this study was to evaluate the clinical outcomes of SEMS to palliate colorectal malignant obstruction. METHODS: Malignant colorectal obstructive patients who underwent SEMS insertion at the National Cancer Center, Korea from January 2004 to June 2008 were enrolled in the study. Patients' clinical characteristics, outcomes and complications for palliative SEMS insertion were retrospectively analyzed. RESULTS: A total of 54 patients were enrolled in the palliative SEMS group and 48 patients with obstructive CRC were included in the SEMS as the bridge to surgery group. Obstruction of the left colon occurred in 52 patients of the palliative SEMS group and all patients in SEMS as bridge to surgery group. For primary SEMS insertion, the technical success (TS) rate was 87.0% and the clinical success (CS) rate 89.4%, while the rates of early and late complications were 24.1% and 23.4%, respectively. There was no procedure-related mortality. Stent migration rate was higher in the cases treated with small diameter and covered type of stents. Median time to reobstruction and migration were 85 and 101 days, respectively. TS and CS rates for SEMS reinsertion were comparable to those for primary SEMS insertion. CONCLUSIONS: Palliative SEMS are effective and favorable procedures for malignant colorectal obstruction but with some complications. Stent migration is associated with covered type and small diameter stents while other factors including length of stent and chemotherapy do not affect stent complications in the present study. PMID- 22500789 TI - Differentiation of autoimmune pancreatitis with pancreatic carcinoma remains a challenge to physicians. AB - OBJECTIVE: The aim of this study was to summarize the clinical features of autoimmune pancreatitis (AIP) and review the advances in the differential diagnosis with pancreatic carcinoma, thus help to make a correct diagnosis and avoid unnecessary surgery in clinical practice. METHODS: Five patients diagnosed as AIP in accordance with the HISORt criteria in Zhongshan Hospital, Fudan University from 2008 to 2010 were enrolled in the study. Clinical features were analyzed and related literature was reviewed. RESULTS: Progressive jaundice and abdominal pain were the most frequent symptoms, as well as weight loss, together with serological changes such as elevation of alkaline phosphatase, gamma glutamyl-transpeptidase and serum bilirubin. Two of them showed high serum immunoglobulin G4 (IgG4) levels. Both focal and diffuse changes were found on computed tomography and magnetic resonance imaging. Two of our patients underwent operation because of a high suspicion of malignant tumor, and steroid therapy was administered to the other three patients diagnosed as AIP. No relapse was observed during the follow-up duration of all the patients. CONCLUSIONS: Although some recent advances have been made to help the diagnosis of AIP, the differentiation between AIP and pancreatic carcinoma is still a challenge. Clinicians must remember to exclude AIP before making a diagnosis of pancreatic carcinoma. PMID- 22500790 TI - Relationship between pancreatic and/or extrapancreatic lesions and serum IgG and IgG4 levels in IgG4-related diseases. AB - OBJECTIVE: We aimed to investigate the relationship between the number of involved organs or regions and serum immunoglobulin G (IgG) and immunoglobulin G4 (IgG4) levels. METHODS: The number of pancreatic and/or extrapancreatic lesions and serum IgG and IgG4 levels were examined by groups in 46 patients with IgG4 related diseases at diagnosis prior to the initiation of steroid treatment: group A (one region involved, n=7), group B (two regions involved, n=11), group C (three regions involved, n=12), group D (four regions involved, n=9) and group E (five to seven regions involved, n=7). RESULTS: Both serum IgG and IgG4 levels increased with the number of inflamed regions. Mean serum IgG levels were 15.11, 18.65, 20.92, 23.29 and 30.98 g/L while the mean IgG4 levels were 3.99, 4.70, 4.70, 9.86 and 16.49 g/L in group A, B, C, D and E, respectively. Regression analysis also suggested that IgG4 was positively correlated with the number of regions involved. Additionally, serum IgG4 was higher in patients with multiple lesions when accompanied by sclerosing sialadenitis. CONCLUSION: Patients having IgG4-related disease with high serum IgG and IgG4 levels should be systematically examined for involved lesions. PMID- 22500791 TI - IgG4-related sclerosing cholangitis with autoimmune pancreatitis and periaortitis: case report and review of the literature. PMID- 22500792 TI - Pancreatic carcinoma mimicking diffuse-type autoimmune pancreatitis: important diagnostic role of pancreatic juice cytology using endoscopic naso-pancreatic drainage. PMID- 22500793 TI - Breathe in and straighten your back: hypoxia, notch, and scoliosis. AB - In this issue of Cell, Sparrow et al. propose a new mechanism for sporadically occurring congenital scoliosis in which Notch signaling and hypoxia converge in the embryo on somite patterning via the segmentation clock. This interaction between hypoxia and a predisposed genetic background might underlie other birth defects with incomplete penetrance. PMID- 22500794 TI - Sgs1--the maestro of recombination. AB - The Sgs1 DNA helicase and its mammalian homolog BLM control crossover formation in mitotic cells. Zakharyevich et al. and De Muyt et al. now uncover a key role for Sgs1 in meiotic crossover regulation, which in turn reveals a joint molecule resolution pathway that produces the majority of crossovers in budding yeast. PMID- 22500795 TI - Growing cells push back under pressure. AB - In both plants and animals, the interplay between mechanical force generation and mechanical sensing plays a stabilizing role in many developmental processes. Uyttewaal et al. now demonstrate that cells in the Arabidopsis shoot apical meristem respond to local mechanical stresses by reorienting their growth, thereby guiding morphogenesis. Notably, the mechanism underlying such guidance is amplification--not suppression--of growth-rate heterogeneity. PMID- 22500796 TI - Role of the biomolecular energy gap in protein design, structure, and evolution. AB - The folding of natural biopolymers into unique three-dimensional structures that determine their function is remarkable considering the vast number of alternative states and requires a large gap in the energy of the functional state compared to the many alternatives. This Perspective explores the implications of this energy gap for computing the structures of naturally occurring biopolymers, designing proteins with new structures and functions, and optimally integrating experiment and computation in these endeavors. Possible parallels between the generation of functional molecules in computational design and natural evolution are highlighted. PMID- 22500799 TI - Negative feedback enhances robustness in the yeast polarity establishment circuit. AB - Many cells undergo symmetry-breaking polarization toward a randomly oriented "front" in the absence of spatial cues. In budding yeast, such polarization involves a positive feedback loop that enables amplification of stochastically arising clusters of polarity factors. Previous mathematical modeling suggested that, if more than one cluster were amplified, the clusters would compete for limiting resources and the largest would "win," explaining why yeast cells always make one and only one bud. Here, using imaging with improved spatiotemporal resolution, we show the transient coexistence of multiple clusters during polarity establishment, as predicted by the model. Unexpectedly, we also find that initial polarity factor clustering is oscillatory, revealing the presence of a negative feedback loop that disperses the factors. Mathematical modeling predicts that negative feedback would confer robustness to the polarity circuit and make the kinetics of competition between polarity factor clusters relatively insensitive to polarity factor concentration. These predictions are confirmed experimentally. PMID- 22500798 TI - Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. AB - Kinase inhibitors have limited success in cancer treatment because tumors circumvent their action. Using a quantitative proteomics approach, we assessed kinome activity in response to MEK inhibition in triple-negative breast cancer (TNBC) cells and genetically engineered mice (GEMMs). MEK inhibition caused acute ERK activity loss, resulting in rapid c-Myc degradation that induced expression and activation of several receptor tyrosine kinases (RTKs). RNAi knockdown of ERK or c-Myc mimicked RTK induction by MEK inhibitors, and prevention of proteasomal c-Myc degradation blocked kinome reprogramming. MEK inhibitor-induced RTK stimulation overcame MEK2 inhibition, but not MEK1 inhibition, reactivating ERK and producing drug resistance. The C3Tag GEMM for TNBC similarly induced RTKs in response to MEK inhibition. The inhibitor-induced RTK profile suggested a kinase inhibitor combination therapy that produced GEMM tumor apoptosis and regression where single agents were ineffective. This approach defines mechanisms of drug resistance, allowing rational design of combination therapies for cancer. PMID- 22500797 TI - mTOR signaling in growth control and disease. AB - The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation. PMID- 22500800 TI - Delineation of joint molecule resolution pathways in meiosis identifies a crossover-specific resolvase. AB - At the final step of homologous recombination, Holliday junction-containing joint molecules (JMs) are resolved to form crossover or noncrossover products. The enzymes responsible for JM resolution in vivo remain uncertain, but three distinct endonucleases capable of resolving JMs in vitro have been identified: Mus81-Mms4(EME1), Slx1-Slx4(BTBD12), and Yen1(GEN1). Using physical monitoring of recombination during budding yeast meiosis, we show that all three endonucleases are capable of promoting JM resolution in vivo. However, in mms4 slx4 yen1 triple mutants, JM resolution and crossing over occur efficiently. Paradoxically, crossing over in this background is strongly dependent on the Blooms helicase ortholog Sgs1, a component of a well-characterized anticrossover activity. Sgs1 dependent crossing over, but not JM resolution per se, also requires XPG family nuclease Exo1 and the MutLgamma complex Mlh1-Mlh3. Thus, Sgs1, Exo1, and MutLgamma together define a previously undescribed meiotic JM resolution pathway that produces the majority of crossovers in budding yeast and, by inference, in mammals. PMID- 22500801 TI - Cooperative tertiary interaction network guides RNA folding. AB - Noncoding RNAs form unique 3D structures, which perform many regulatory functions. To understand how RNAs fold uniquely despite a small number of tertiary interaction motifs, we mutated the major tertiary interactions in a group I ribozyme by single-base substitutions. The resulting perturbations to the folding energy landscape were measured using SAXS, ribozyme activity, hydroxyl radical footprinting, and native PAGE. Double- and triple-mutant cycles show that most tertiary interactions have a small effect on the stability of the native state. Instead, the formation of core and peripheral structural motifs is cooperatively linked in near-native folding intermediates, and this cooperativity depends on the native helix orientation. The emergence of a cooperative interaction network at an early stage of folding suppresses nonnative structures and guides the search for the native state. We suggest that cooperativity in noncoding RNAs arose from natural selection of architectures conducive to forming a unique, stable fold. PMID- 22500802 TI - Coordinated regulation of accessory genetic elements produces cyclic di nucleotides for V. cholerae virulence. AB - The function of the Vibrio 7(th) pandemic island-1 (VSP-1) in cholera pathogenesis has remained obscure. Utilizing chromatin immunoprecipitation sequencing and RNA sequencing to map the regulon of the master virulence regulator ToxT, we identify a TCP island-encoded small RNA that reduces the expression of a previously unrecognized VSP-1-encoded transcription factor termed VspR. VspR modulates the expression of several VSP-1 genes including one that encodes a novel class of di-nucleotide cyclase (DncV), which preferentially synthesizes a previously undescribed hybrid cyclic AMP-GMP molecule. We show that DncV is required for efficient intestinal colonization and downregulates V. cholerae chemotaxis, a phenotype previously associated with hyperinfectivity. This pathway couples the actions of previously disparate genomic islands, defines VSP-1 as a pathogenicity island in V. cholerae, and implicates its occurrence in 7(th) pandemic strains as a benefit for host adaptation through the production of a regulatory cyclic di-nucleotide. PMID- 22500803 TI - EBs recognize a nucleotide-dependent structural cap at growing microtubule ends. AB - Growing microtubule ends serve as transient binding platforms for essential proteins that regulate microtubule dynamics and their interactions with cellular substructures. End-binding proteins (EBs) autonomously recognize an extended region at growing microtubule ends with unknown structural characteristics and then recruit other factors to the dynamic end structure. Using cryo-electron microscopy, subnanometer single-particle reconstruction, and fluorescence imaging, we present a pseudoatomic model of how the calponin homology (CH) domain of the fission yeast EB Mal3 binds to the end regions of growing microtubules. The Mal3 CH domain bridges protofilaments except at the microtubule seam. By binding close to the exchangeable GTP-binding site, the CH domain is ideally positioned to sense the microtubule's nucleotide state. The same microtubule-end region is also a stabilizing structural cap protecting the microtubule from depolymerization. This insight supports a common structural link between two important biological phenomena, microtubule dynamic instability and end tracking. PMID- 22500804 TI - A PLETHORA-auxin transcription module controls cell division plane rotation through MAP65 and CLASP. AB - Despite their pivotal role in plant development, control mechanisms for oriented cell divisions have remained elusive. Here, we describe how a precisely regulated cell division orientation switch in an Arabidopsis stem cell is controlled by upstream patterning factors. We show that the stem cell regulatory PLETHORA transcription factors induce division plane reorientation by local activation of auxin signaling, culminating in enhanced expression of the microtubule-associated MAP65 proteins. MAP65 upregulation is sufficient to reorient the cortical microtubular array through a CLASP microtubule-cell cortex interaction mediator dependent mechanism. CLASP differentially localizes to cell faces in a microtubule- and MAP65-dependent manner. Computational simulations clarify how precise 90 degrees switches in cell division planes can follow self-organizing properties of the microtubule array in combination with biases in CLASP localization. Our work demonstrates how transcription factor-mediated processes regulate the cellular machinery to control orientation of formative cell divisions in plants. PMID- 22500805 TI - Biochemically distinct vesicles from the endoplasmic reticulum fuse to form peroxisomes. AB - As a rule, organelles in eukaryotic cells can derive only from pre-existing organelles. Peroxisomes are unique because they acquire their lipids and membrane proteins from the endoplasmic reticulum (ER), whereas they import their matrix proteins directly from the cytosol. We have discovered that peroxisomes are formed via heterotypic fusion of at least two biochemically distinct preperoxisomal vesicle pools that arise from the ER. These vesicles each carry half a peroxisomal translocon complex. Their fusion initiates assembly of the full peroxisomal translocon and subsequent uptake of enzymes from the cytosol. Our findings demonstrate a remarkable mechanism to maintain biochemical identity of organelles by transporting crucial components via different routes to their final destination. PMID- 22500806 TI - Mechanical stress acts via katanin to amplify differences in growth rate between adjacent cells in Arabidopsis. AB - The presence of diffuse morphogen gradients in tissues supports a view in which growth is locally homogenous. Here we challenge this view: we used a high resolution quantitative approach to reveal significant growth variability among neighboring cells in the shoot apical meristem, the plant stem cell niche. This variability was strongly decreased in a mutant impaired in the microtubule severing protein katanin. Major shape defects in the mutant could be related to a local decrease in growth heterogeneity. We show that katanin is required for the cell's competence to respond to the mechanical forces generated by growth. This provides the basis for a model in which microtubule dynamics allow the cell to respond efficiently to mechanical forces. This in turn can amplify local growth rate gradients, yielding more heterogeneous growth and supporting morphogenesis. PMID- 22500807 TI - Inactivation of conserved C. elegans genes engages pathogen- and xenobiotic associated defenses. AB - The nematode C. elegans is attracted to nutritious bacteria and is repelled by pathogens and toxins. Here we show that RNAi and toxin-mediated disruption of core cellular activities, including translation, respiration, and protein turnover, stimulate behavioral avoidance of normally attractive bacteria. RNAi of these and other essential processes induces expression of detoxification and innate immune effectors, even in the absence of toxins or pathogens. Disruption of core processes in non-neuronal tissues was sufficient to stimulate aversion behavior, revealing a neuroendocrine axis of control that additionally required serotonergic and Jnk kinase signaling pathways. We propose that surveillance pathways overseeing core cellular activities allow animals to detect invading pathogens that deploy toxins and virulence factors to undermine vital host functions. Variation in cellular surveillance and endocrine pathways controlling behavior, detoxification, and immunity selected by past toxin or microbial interactions could underlie aberrant responses to foods, medicines, and microbes. PMID- 22500808 TI - Dynamic transformations of genome-wide epigenetic marking and transcriptional control establish T cell identity. AB - T cell development comprises a stepwise process of commitment from a multipotent precursor. To define molecular mechanisms controlling this progression, we probed five stages spanning the commitment process using RNA-seq and ChIP-seq to track genome-wide shifts in transcription, cohorts of active transcription factor genes, histone modifications at diverse classes of cis-regulatory elements, and binding repertoire of GATA-3 and PU.1, transcription factors with complementary roles in T cell development. The results highlight potential promoter-distal cis regulatory elements in play and reveal both activation sites and diverse mechanisms of repression that silence genes used in alternative lineages. Histone marking is dynamic and reversible, and though permissive marks anticipate, repressive marks often lag behind changes in transcription. In vivo binding of PU.1 and GATA-3 relative to epigenetic marking reveals distinctive factor specific rules for recruitment of these crucial transcription factors to different subsets of their potential sites, dependent on dose and developmental context. PMID- 22500810 TI - SnapShot: Histone lysine methylase complexes. PMID- 22500811 TI - Kinetic (T = 201-298 K) and equilibrium (T = 320-420 K) measurements of the C3H5 + O2 ? C3H5O2 reaction. AB - The kinetics and equilibrium of the allyl radical reaction with molecular oxygen have been studied in direct measurements using temperature-controlled tubular flow reactor coupled to a laser photolysis/photoionization mass spectrometer. In low-temperature experiments (T = 201-298 K), association kinetics were observed, and the measured time-resolved C(3)H(5) radical signals decayed exponentially to the signal background. In this range, the determined rate coefficients exhibited a negative temperature dependence and were observed to depend on the carrier-gas (He) pressure {p = 0.4-36 Torr, [He] = (1.7-118.0) * 10(16) cm(-3)}. The bimolecular rate coefficients obtained vary in the range (0.88-11.6) * 10(-13) cm(3) s(-1). In higher-temperature experiments (T = 320-420 K), the C(3)H(5) radical signal did not decay to the signal background, indicating equilibration of the reaction. By measuring the radical decay rate under these conditions as a function of temperature and following typical second- and third-law procedures, plotting the resulting ln K(p) values versus 1/T in a modified van't Hoff plot, the thermochemical parameters of the reaction were extracted. The second-law treatment resulted in values of DeltaH(298) degrees = -78.3 +/- 1.1 kJ mol(-1) and DeltaS(298) degrees = -129.9 +/- 3.1 J mol(-1) K(-1), with the uncertainties given as one standard error. When results from a previous investigation were taken into account and the third-law method was applied, the reaction enthalpy was determined as DeltaH(298) degrees = -75.6 +/- 2.3 kJ mol(-1). PMID- 22500809 TI - Large-scale cellular-resolution gene profiling in human neocortex reveals species specific molecular signatures. AB - Although there have been major advances in elucidating the functional biology of the human brain, relatively little is known of its cellular and molecular organization. Here we report a large-scale characterization of the expression of ~1,000 genes important for neural functions by in situ hybridization at a cellular resolution in visual and temporal cortices of adult human brains. These data reveal diverse gene expression patterns and remarkable conservation of each individual gene's expression among individuals (95%), cortical areas (84%), and between human and mouse (79%). A small but substantial number of genes (21%) exhibited species-differential expression. Distinct molecular signatures, comprised of genes both common between species and unique to each, were identified for each major cortical cell type. The data suggest that gene expression profile changes may contribute to differential cortical function across species, and in particular, a shift from corticosubcortical to more predominant corticocortical communications in the human brain. PMID- 22500812 TI - Quasi-ohmic single molecule charge transport through highly conjugated meso-to meso ethyne-bridged porphyrin wires. AB - Understanding and controlling electron transport through functional molecules are of primary importance to the development of molecular scale devices. In this work, the single molecule resistances of meso-to-meso ethyne-bridged (porphinato)zinc(II) structures (PZn(n) compounds), connected to gold electrodes via (4'-thiophenyl)ethynyl termini, are determined using scanning tunneling microscopy-based break junction methods. These experiments show that each alpha,omega-di[(4'-thiophenyl)ethynyl]-terminated PZn(n) compound (dithiol PZn(n)) manifests a dual molecular conductance. In both the high and low conductance regimes, the measured resistance across these metal-dithiol-PZn(n) metal junctions increases in a near linear fashion with molecule length. These results signal that meso-to-meso ethyne-bridged porphyrin wires afford the lowest beta value (beta = 0.034 A(-1)) yet determined for thiol-terminated single molecules that manifest a quasi-ohmic resistance dependence across metal-dithiol PZn(n)-metal junctions. PMID- 22500813 TI - Exaggerated vasopressor response to exercise and cerebral blood flow velocity. AB - We studied 10 young adults, normotensive at rest, comprising a control group (n = 5) with normal blood pressure responsiveness to exercise and an experimental group exhibiting greater percentage of body fat and body mass index (BMI) than the controls, with exaggerated blood pressure (vasopressor) responsiveness to exercise (EEBPR) (n = 5). Lower absolute and varying oxygen consumption/body weight normalized units of middle cerebral arterial blood flow velocity (MCAV) were found during exercise in the experimental group (P < .01). These findings support the hypothesis that the combination of EEBPR and high BMI is associated with low MCAV that may put such individuals at risk for cerebral hypoperfusion and cognitive deficits. PMID- 22500814 TI - A comparative analysis of toluidine blue with frozen section in oral squamous cell carcinoma. AB - BACKGROUND: Surgical excision of the primary tumor with safe margins remains the mainstay of treatment for oral cavity squamous cell carcinoma (OSCC). The standard of care for assessment of intraoperative margins is frozen section histopathology. Unfortunately the facility is not available at most centers in limited resource countries. Toluidine blue, a metachromatic dye, has been well described in clinical identification of malignant and premalignant lesion in the oral cavity. Considering this we decided to explore intraoperative use of toluidine blue staining, in comparison with frozen sections, for the assessment of tumor-free margins. METHODS: After obtaining clearance from the in-house ethical review committee, a prospective study was conducted at Aga Khan University Hospital, Karachi, from August 15, 2009 to March 14, 2010. A sample of 56 consenting patients with biopsy-proven OSCC were included in the study, giving us 280 tumor margins. Margins were analyzed using toluidine blue staining and frozen section histopathology. A receiver operator curve (ROC) was then applied to compare assessment of margin status by toluidine blue and frozen section. RESULTS: Of the 280 examined margins 11 stained positive with toluidine blue, three were positive on frozen section biopsy, and three were positive on final histopathology. Toluidine blue staining had sensitivity and specificity of 100% and 97%, respectively. The diagnostic accuracy of toluidine blue was found to be 97.1% with a positive predictive value (PPV) of 27.2% and a negative predictive value (NPV) of 100%. CONCLUSIONS: Toluidine blue can be used as an effective screening modality for the assessment of intraoperative margins in resource limited environments and reducing the number of frozen section biopsies performed. Further by providing real-time clinical information within minutes it can reduce indirect costs such as operating room time. It may also be used as an ad hoc for frozen section biopsies where frozen section facilities are available. PMID- 22500815 TI - Contact allergy to epoxy resin: risk occupations and consequences. AB - BACKGROUND: Epoxy resin monomers are strong skin sensitizers that are widely used in industrial sectors. In Denmark, the law stipulates that workers must undergo a course on safe handling of epoxy resins prior to occupational exposure, but the effectiveness of this initiative is largely unknown. OBJECTIVES: To evaluate the prevalence of contact allergy to epoxy resin monomer (diglycidyl ether of bisphenol A; MW 340) among patients with suspected contact dermatitis and relate this to occupation and work-related consequences. PATIENTS/METHODS: The dataset comprised 20 808 consecutive dermatitis patients patch tested during 2005-2009. All patients with an epoxy resin-positive patch test were sent a questionnaire. RESULTS: A positive patch test reaction to epoxy resin was found in 275 patients (1.3%), with a higher proportion in men (1.9%) than in women (1.0%). The prevalence of sensitization to epoxy resin remained stable over the study period. Of the patients with an epoxy resin-positive patch test, 71% returned a questionnaire; 95 patients had worked with epoxy resin in the occupational setting, and, of these, one-third did not use protective gloves and only 50.5% (48) had participated in an educational programme. CONCLUSION: The 1% prevalence of epoxy resin contact allergy is equivalent to reports from other countries. The high occurrence of epoxy resin exposure at work, and the limited use of protective measures, indicate that reinforcement of the law is required. PMID- 22500816 TI - Controlling assembly of mixed thiol monolayers on silver nanoparticles to tune their surface properties. AB - Modifying the surfaces of metal nanoparticles with self-assembled monolayers of functionalized thiols provides a simple and direct method to alter their surface properties. Mixed self-assembled monolayers can extend this approach since, in principle, the surfaces can be tuned by altering the proportion of each modifier that is adsorbed. However, this works best if the composition and microstructure of the monolayers can be controlled. Here, we have modified preprepared silver colloids with binary mixtures of thiols at varying concentrations and modifier ratios. Surface-enhanced Raman spectroscopy was then used to determine the effect of altering these parameters on the composition of the resulting mixed monolayers. The data could be explained using a new model based on a modified competitive Langmuir approach. It was found that the composition of the mixed monolayer only reflected the ratio of modifiers in the feedstock when the total amount of modifier was sufficient for approximately one monolayer coverage. At higher modifier concentrations the thermodynamically favored modifier dominated, but working at near monolayer concentrations allowed the surface composition to be controlled by changing the ratios of modifiers. Finally, a positively charged porphyrin probe molecule was used to investigate the microstructure of the mixed monolayers, i.e., homogeneous versus domains. In this case the modifier domains were found to be <2 nm. PMID- 22500817 TI - Enhanced Brownian ratchet molecular separation using a self-spreading lipid bilayer. AB - A new approach is proposed for two-dimensional molecular separation based on the Brownian ratchet mechanism by use of a self-spreading lipid bilayer as both a molecular transport and separation medium. In addition to conventional diffusivity-dependence on the ratchet separation efficiency, the difference in the intermolecular interactions between the target molecules and the lipid bilayer is also incorporated as a new separation factor in the present self spreading ratchet system. Spreading at the gap between two ratchet obstacles causes a local change in the lipid density at the gap. This effect produces an additional opportunity for a molecule to be deflected at the ratchet obstacle and thus causes an additional angle shift. This enables the separation of molecules with the same diffusivity but with different intermolecular interaction between the target molecule and surrounding lipid molecules. Here we demonstrate this aspect by using cholera toxin subunit B (CTB)-ganglioside GM1 (GM1) complexes with different configurations. The present results will unlock a new strategy for two-dimensional molecular manipulation with ultrasmall devices. PMID- 22500819 TI - HLA-Bw4 identifies a population of HIV-infected patients with an increased capacity to control viral replication after structured treatment interruption. AB - OBJECTIVES: After structured treatment interruption (STI) of treatment for HIV-1, a fraction of patients maintain suppressed viral loads. Prospective identification of such patients might improve HIV-1 treatment, if selected patients are offered STI. METHODS: We analysed the effect of previously identified genetic modulators of HIV-1 disease progression on patients' ability to suppress viral replication after STI. Polymorphisms in the genes killer cell immunoglobulin-like receptor 3DLI (KIR3DL1)/KIR3DS1, human leucocyte antigen B (HLA-B) and HLA Complex P5 (HCP5), and a polymorphism affecting HLA-C surface expression were analysed in 130 Swiss HIV Cohort Study patients undergoing STI. Genotypes were correlated with viral load levels after STI. RESULTS: We observed a statistically significant reduction in viral load after STI in carriers of HLA B alleles containing either the Bw480Thr or the Bw480Ile epitope (mean adjusted effect on post-STI viral load: -0.82 log HIV-1 RNA copies/ml, P < 0.001; and 1.12 log copies/ml, P < 0.001, respectively). No significant effects were detected for the other polymorphisms analysed. The likelihood of being able to control HIV-1 replication using a prespecified cut-off (viral load increase < 1000 copies/ml) increased from 39% in Bw4-negative patients to 53% in patients carrying Bw4-80Thr, and to 65% in patients carrying Bw4-80Ile (P = 0.02). CONCLUSIONS: These data establish a significant impact of HLA-Bw4 on the control of viral replication after STI. PMID- 22500820 TI - A sensitive venous bleeding model in haemophilia A mice: effects of two recombinant FVIII products (N8 and Advate((r))). AB - Haemostatic effect of compounds for treating haemophilia can be evaluated in various bleeding models in haemophilic mice. However, the doses of factor VIII (FVIII) for normalizing bleeding used in some of these models are reported to be relatively high. The aim of this study was to establish a sensitive venous bleeding model in FVIII knock out (F8-KO) mice, with the ability to detect effect on bleeding at low plasma FVIII concentrations. We studied the effect of two recombinant FVIII products, N8 and Advate((r)), after injury to the saphenous vein. We found that F8-KO mice treated with increasing doses of either N8 or Advate((r)) showed a dose-dependent increase in the number of clot formations and a reduction in both average and maximum bleeding time, as well as in average blood loss. For both compounds, significant effect was found at doses as low as 5 IU kg(-1) when compared with vehicle-treated F8-KO mice. Normalization of maximum bleeding time was found at doses equal to or above 10 IU kg(-1) N8 or Advate((r)), corresponding to plasma concentrations of approximately 10% of the level in wild type mice. The present study adds a new model to the armamentarium of bleeding models used for evaluation of pro-coagulant compounds for treatment of haemophilia. Interestingly, the vena saphena model proved to be sensitive towards FVIII in plasma levels that approach the levels preventing bleeding in haemophilia patients, and may, thus, in particular be valuable for testing of new long-acting variants of e.g. FVIII that are intended for prophylaxis. PMID- 22500821 TI - A phase 1 ascending dose study of a subcutaneously administered factor IXa inhibitor and its active control agent. AB - BACKGROUND: The REG2 anticoagulation system consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous control agent, anivamersen. OBJECTIVES: To assess the safety, tolerability and pharmacokinetic and pharmacodynamic responses of REG2. PATIENTS/METHODS: In this phase 1a study, 36 healthy volunteers were enrolled into five cohorts and given one dose of pegnivacogin. Cohorts 1 (n = 6) and 1A (n = 4) received 0.5 mg kg( 1); cohort 2 (n = 6) received 1.0 mg kg(-1); cohort 3 (n = 6) received 3.0 mg kg( 1); and cohort 4 (n = 8) received 2.0 mg kg(-1) . In cohorts 1-3, two subjects were randomized to placebo. Cohort 4 subjects were subsequently randomized to single-dose (n = 4) or multidose (n = 4) anivamersen. RESULTS: The mean maximum observed concentrations of pegnivacogin in cohorts 1, 1A, 2 and 3 at median time were 5.16 MUg mL(-1) at 84 h, 5.19 MUg mL(-1) at 72 h, 9.32 MUg mL(-1) at 90 h, and 32.5 MUg mL(-1) at 84 h, respectively. The maximum relative activated partial thromboplastin time and time needed to achieve this were 1.18 at 2 days, 1.16 at 2 days, 1.27 at 3 days, and 1.85 at 2 days, respectively. The calculated mean half-life and mean residence times of pegnivacogin were 6.12 days and 9.6 days, respectively. There was rapid reversal with intravenous anivamersen, although subsequent reaccumulation of pegnivacogin was observed. CONCLUSIONS: In our first in-human study, REG2 was well tolerated and provided dose-proportional anticoagulation for several days after a single subcutaneous dose, with complete, although transient, reversal by its control agent. This study demonstrates the first application of a subcutaneously administered aptamer, and represents a potential advance in aptamer therapeutics. PMID- 22500822 TI - Light-induced Ostwald ripening of organic nanodots to rods. AB - Ostwald ripening allows the synthesis of 1D nanorods of metal and semiconductor nanoparticles. However, this phenomenon is unsuccessful with organic pi-systems due to their spontaneous self-assembly to elongated fibers or tapes. Here we demonstrate the uses of light as a versatile tool to control the ripening of amorphous organic nanodots (ca. 15 nm) of an azobenzene-derived molecular assembly to micrometer-sized supramolecular rods. A surface-confined dipole variation associated with a low-yield (13-14%) trans-cis isomerization of the azobenzene moiety and the consequent dipole-dipole interaction in a nonpolar solvent is believed to be the driving force for the ripening of the nanodots to rods. PMID- 22500823 TI - Treatment of Gorlin syndrome (nevoid basal cell carcinoma syndrome) with methylaminolevulinate photodynamic therapy in seven patients, including two children: interest of tumescent anesthesia for pain control in children. AB - OBJECTIVE: To report our experience of methylaminolevulinate photodynamic therapy (MAL-PDT) in the treatment of multiple basal cell carcinoma (BCC) in adults and children with Gorlin syndrome (GS). DESIGN: Report of cases. SETTING: University of Montpellier, Department of Dermatology. PATIENTS: Seven Gorlin patients (41 superficial or nodular carcinomas), including two children. INTERVENTIONS: Prior superficial curettage for superficial BBCs or debulking for nodular BCCs was systematically performed. Methylaminolevulinic acid was applied topically to lesions 3 h before illumination with 635 nm red light for 10 min (37 J/cm(2)). To prevent treatment discomfort, analgesics and/or cooling by sprayed water were most often provided, and occasionally 1% lidocaine local anesthesia. A ropivacaine-lidocaine tumescent anesthesia was performed on the youngest patient. MAIN OUTCOME MEASURES: The initial response rate; tolerance, particularly in children; cosmetic outcome. RESULTS: Overall clearance in patients was 60% after one session of MAL-PDT and 78% after three sessions. Resolution of the lesions was accompanied by an excellent cosmetic outcome in all patients. Treatments were well tolerated in adults with moderate pain sensation during illumination. In a child, tumescent anesthesia assured excellent tolerance in all treatment stages. CONCLUSION: We add our experience to previous articles that consider PDT as an interesting option in the treatment of GS. To our knowledge, this study is the first report of MAL-PDT in GS children using tumescent anesthesia. Specific guidelines for adult and pediatric patients remain to be established. PMID- 22500825 TI - Enhanced transport of 2,2',5,5'-polychlorinated biphenyl by natural organic matter (NOM) and surfactant-modified fullerene nanoparticles (nC60). AB - Stable colloidal suspensions of buckminsterfullerene (nC(60)) in aqueous environments can significantly affect the fate and transport of hydrophobic organic contaminants by serving as a contaminant carrier. In this study, we examined enhanced transport of 2,2',5,5'-polychlorinated biphenyl (PCB) in saturated sandy soil columns by a variety of nC(60) samples, including an nC(60) sample prepared by the typical solvent exchange method, as well as eight natural organic matter (NOM) or surfactant-modified nC(60) samples, prepared by phase transferring C(60) from toluene to an NOM or a surfactant solution. Whereas the NOM- and surfactant-modified nC(60) samples have mobility similar to the unmodified nC(60), their contaminant-mobilizing capabilities are significantly greater: breakthrough of PCB increases by 47.2 to 227% with the surfactant modified nC(60) samples and by 233 to 370% with the NOM-modified nC(60) samples. The significantly enhanced contaminant-mobilizing capability of the modified nC(60) is likely due to a combined effect of increased adsorption affinities and increased tendency of desorption nonequilibrium, likely caused by the changes of nC(60) aggregation properties induced by the presence of NOM or surfactant. Findings in this study indicate that nC(60) formed in different processes might have vastly different effects on contaminant fate and transport. PMID- 22500826 TI - Stem cells combined with bone graft substitutes in skeletal tissue engineering. AB - INTRODUCTION: Bone grafting is used to repair large bone defects and autograft is recognised as producing the best clinical outcome, which is partly due to its cellular component. When autograft is unavailable, allograft and bone graft substitutes can be used; however, they rely on the host bed to provide cellular osteogenic activity. AREAS COVERED: Bone graft substitutes have the potential to benefit from the addition of stem cells aimed at enhancing the rate and quality of defect repair. Mesenchymal stem cells (MSCs) can be isolated from bone marrow or periosteum and culture expanded. Other sources of primary cells include muscle, adipose tissue, human umbilical cord and the pluripotent embryonic stem cells (ESCs). EXPERT OPINION: MSCs isolated from bone marrow have been the best characterised approach for osteogenic differentiation. Their use with synthetic scaffolds such as hydroxyapatite and tricalcium phosphate has produced promising clinical results. MSCs derived from adipose tissue, muscle or human umbilical cord cells combined with various scaffolds are an attractive option. Further in vivo and clinical investigation of their potential is required. Pluripotent ESCs have a theoretical advantage over MSCs; however, purification, cell-specific differentiation, effective delivery vehicles-scaffolds and teratogenesis control are still under in vitro and in vivo evaluation. PMID- 22500827 TI - Germinal centers. PMID- 22500828 TI - Affinity-based selection and the germinal center response. AB - Interactions between B-cell antigen receptors (BCRs) and their ligands have a complexity and variability that is unparalleled within known biology. Each developing B cell undergoes gene rearrangements to generate a BCR encoded by a unique pair of immunoglobulin (Ig) variable region genes, which serves to make the antigen-binding capabilities of primary BCRs incredibly diverse. Further diversification of the BCR repertoire takes place when antigen-activated B cells enter the germinal center (GC) response and undergo somatic hypermutation (SHM) of their Ig variable region genes. To develop optimal antibody responses against foreign antigens, the key B-cell survival and differentiation decisions made in the GC are based primarily on the affinity of the BCR (and therefore subsequent antibodies) for foreign antigen. However, the secondary diversification of BCRs by SHM also carries the risk of generating new self-reactive specificities and thus autoantibody production. Herein, we review the role of antigen affinity/avidity in controlling pivotal events both leading up to and during the GC response. The emergence of self-reactivity during the GC response is also examined, with particular focus on the threat posed by cross-reactive GC B cells that bind both self and foreign antigen. PMID- 22500829 TI - From SAP-less T cells to helpless B cells and back: dynamic T-B cell interactions underlie germinal center development and function. AB - Operation of the immune system critically depends on intercellular communication among multiple cell types, frequently in the form of physical cell-cell interactions. Germinal centers (GCs) are highly organized tissue microdomains in which high affinity, class-switched, antibody-producing cells and humoral immune memory are generated. Critical underlying cell-cell interaction events include at the minimum binary interactions between CD4(+) T-helper cells and antigen presenting dendritic cells (DCs), which ensure proper T-cell activation and acquisition of effecter potentials, and those between T-helper cells and antigen activated B cells whereby the latter cells receive helper signals (e.g. CD40L) important for their proliferation, survival, and differentiation. How these critical cellular interaction events are molecularly regulated and dynamically orchestrated to support GC formation and function is still a study in progress. Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) has recently been defined as a pivotal molecule that controls cognate T-B interactions and GC formation. Detailed analysis of interaction and migration dynamics of SAP-deficient T cells has raised the interesting possibility that T cell:antigen-presenting cell interactions underlying GC development and function are regulated in a cell type- and spatiotemporal stage-specific manner. This has important implications for our understanding of synapse formation, helper signal delivery to B cells, follicular helper T-cell differentiation, and quality control of the GC reaction in general. A model of selective T-B interactions involving bi-directional feedback and feed-forward logic is proposed to underlie GC development and function. PMID- 22500831 TI - Germinal center selection and the development of memory B and plasma cells. AB - A hallmark of adaptive immune responses is the generation of long-lived protection after primary exposure to a pathogen. In humoral responses, this protection stems from a combination of sustained antibody titers and long-lived memory B cells (MBCs), with the former deriving from long-lived plasma cells (PCs). Both types of cell are thought to primarily derive from the germinal center (GC), a unique structure that forms during the immune response to many types of antigenic stimuli. GCs are seeded by antigen-specific B and T cells that were previously activated in the early stages of the response. The GC does not directly or immediately generate effector function; rather, it is a site of intense B-cell proliferation and cell death. GC B cells undergo both somatic hypermutation and isotype switch, and a Darwinian process very efficiently selects B cells with higher fitness for survival and expansion. GC B cells adopt a unique activation and transcriptional state, and the cells become poised to differentiate to either MBCs or PCs. Despite this general understanding of the events in the GC, the mechanisms that control both affinity selection as well as differentiation have not been well worked out. In this review, we address what is known about what determines whether GC B cells become MBCs or PCs. This is discussed in the broader context of the origins of both cell types, whether from the GC or potentially other sources. We present a model encompassing recent data from several laboratories including our own that suggests that the GC undergoes a temporal switch that alters the nature of its output from MBCs to PCs as the response progresses. We will discuss B-cell receptor signaling in the GC as it relates to potential mechanisms for affinity-based selection during the reaction. PMID- 22500830 TI - S1PR2 links germinal center confinement and growth regulation. AB - Germinal centers (GCs) are sites of rapid B-cell proliferation and somatic mutation. These ovoid structures develop within the center of follicles and grow to a stereotypic size. The cell migration and interaction dynamics underlying GC B-cell selection events are currently under intense scrutiny. In recent study, we identified a role for a migration inhibitory receptor, S1PR2, in promoting GC B cell confinement to GCs. S1PR2 also dampens Akt activation and deficiency in S1PR2 or components of its signaling pathway result in a loss of growth control in chronically stimulated mucosal GCs. Herein, we detail present understanding of S1PR2 and S1P biology as it pertains to GC B cells and place this information in the context of a current model of GC function. PMID- 22500833 TI - The diverse roles of IRF4 in late germinal center B-cell differentiation. AB - Interferon regulatory factor 4 (IRF4) is a member of the IRF family of transcription factors and is expressed in most cell types of the immune system. Within the B-cell lineage, IRF4 is expressed in all developmental stages except during the germinal center (GC) reaction. IRF4 expression, however, is upregulated during exit from the GC reaction and has been demonstrated to have critical functions in at least three key developmental processes: the termination of the GC B-cell transcriptional program, immunoglobulin (Ig) class switch recombination (CSR), and plasma cell development. Herein, we attempt to reconcile the often contradictory findings regarding IRF4 into a model to explain the role of IRF4 in the transcription factor networks that operate within exiting GC B cells. In addition, a deregulation of the biological programs controlled by IRF4 has recently been implicated in the pathogenesis of various B-cell-derived malignancies. Determining the specific functions of IRF4 in the markedly diverse developmental processes that coordinate B-cell development is therefore likely to have important implications for understanding these malignancies and devising therapeutic interventions. PMID- 22500832 TI - Contribution of Toll-like receptor signaling to germinal center antibody responses. AB - Toll-like receptors (TLRs) have emerged as one of the most important families of innate immune receptors for initiating inflammation and also for promoting adaptive immune responses. Recent studies have examined the ability of TLRs to promote antibody responses, including T-cell-dependent antibody responses. Initial study suggested that TLR stimulation promotes primarily an extrafollicular antibody response, which rapidly produces moderate affinity antibodies made by short-lived plasma cells. Recent studies, however, have shown that TLRs can also enhance the germinal center response, which produces high affinity class-switched antibody made by long-lived plasma cells. TLR stimulation can increase the magnitude of the latter response and also enhance selection for high affinity IgG. This review summarizes recent advances in understanding the roles of TLRs in B cells and also in other cell types for enhancement of antibody responses, with an emphasis on T-cell-dependent and germinal center antibody responses. PMID- 22500834 TI - Through a glass less darkly: apoptosis and the germinal center response to antigen. AB - The regulation of cell death is crucial for normal immune responses. Apoptosis is required for appropriate affinity-based recruitment of B cells into an immune response, for the normal expansion, contraction--and thereby selection--of B cells within germinal centers, and also for the normal expansion, contraction, and persistence of plasma cells, both extrafollicular and germinal center derived. In this review, we focus on the intrinsic pathway of apoptosis, which is mediated by the interaction of pro- and anti-apoptotic members of the Bcl-2 family of proteins. Early, relatively crude studies using transgene-mediated over expression of pro-survival proteins or germline-encoded loss of pro-apoptotic proteins demonstrated clearly the consequences of dysregulation of this apoptosis pathway on immunity. More recent studies have both been more targeted and extensive, meaning that a large number of Bcl-2 family members have been assessed for roles in immune regulation in a relatively precise manner. These studies are revealing a level of specialization in the use of the pro-survival proteins during immune responses, with several showing what appear to be stage-specific contributions. Lastly, we consider the involvement of Bcl-2 family proteins in the transformation of B cells at distinct stages of the response to antigen, comparing this involvement with that in the normal processes. PMID- 22500836 TI - Differentiation of germinal center B cells and follicular helper T cells as viewed by tracking Bcl6 expression dynamics. AB - Development of germinal center (GC) B cells and follicular helper T (Tfh) cells requires the transcription factor B-cell lymphoma 6 (Bcl6). Expression of Bcl6 in B cells and helper T cells is regulated by complex signals including those generated through their antigen-specific interactions, which take place in various microenvironments depending on their activation/differentiation states. In the last several years, it has become possible to detect Bcl6 protein in individual B cells and T cells by intracellular staining with the newly developed antibodies or by using the reporter mice. Experiments using these reagents have started to clarify microanatomical location of early Bcl6 upregulation in B cells and T cells, and contributed to reveal the dispensability and indispensability of B cells in the early and late phase of Tfh differentiation. They also started to reveal the diversity, plasticity, and/or instability of Tfh cells. We summarize the recent findings made by tracking Bcl6 expression together with the updated knowledge about dynamics of antigen-engaged B cells and helper T cells and discuss them in relation to possible signaling requirements for the development of GC B cells and Tfh cells. PMID- 22500835 TI - POK/ZBTB proteins: an emerging family of proteins that regulate lymphoid development and function. AB - The germinal center (GC) is a unique histological structure found in peripheral lymphoid organs. GCs provide an important source of humoral immunity by generating high affinity antibodies against a pathogen. The GC response is tightly regulated during clonal expansion, immunoglobulin modification, and affinity maturation, whereas its deregulation has a detrimental effect on immune function, leading to development of diseases, such as lymphoma and autoimmunity. LRF (lymphoma/leukemia-related factor), encoded by the ZBTB7A gene, is a transcriptional repressor belonging to the POK (POZ and Kruppel)/ZBTB (zing finger and BTB) protein family. LRF was originally identified as a PLZF (promyelocytic leukemia zinc finger) homolog that physically interacts with BCL6 (B-cell lymphoma 6), whose expression is required for GC formation and associated with non-Hodgkin's lymphoma. Recently, our group demonstrated that LRF plays critical roles in regulating lymphoid lineage commitment, mature B-cell development, and the GC response via distinct mechanisms. Herein, we review POK/ZBTB protein function in lymphoid development, with particular emphasis on the role of LRF in GC B cells. PMID- 22500837 TI - The 1-1-1 fallacy. AB - T-cell help to B cells is a fundamental aspect of adaptive immunity and the generation of B-cell memory (memory B cells and plasma cells). Follicular helper CD4(+) T (Tfh) cells are the specialized providers of B-cell help, and Tfh cells depend on Bcl6 for their differentiation. This review discusses Tfh cell functions, transcription factors, and induction signals, with particular focus on the richness of the underlying biology and assessing the simplicity or complexity of each of these processes. PMID- 22500838 TI - T-follicular helper cell differentiation and the co-option of this pathway by non helper cells. AB - Human and mouse studies performed over the last decade have established that follicular helper T (Tfh) cells are a CD4(+) helper subset specialized in the provision of help to B cells. Tfh differentiation is driven by expression of the transcriptional repressor B-cell lymphoma-6 (Bcl-6), which turns on a program that guides T cells close to B-cell areas where Tfh cells first provide help to B cells. Sustained Bcl-6 expression promotes the entry of Tfh cells into follicles and modulates their cytokine expression profile so they can support and select germinal center B cells that have acquired affinity-enhancing mutations in their immunoglobulin genes. Forkhead box 3 protein (Foxp3)(+) regulatory T cells and invariant natural killer T (NKT) cells can also co-opt the Bcl-6-dependent follicular differentiation pathway to migrate into B-cell follicles and regulate antibody responses. The resulting NKT follicular helper cells drive a distinctive type of T-dependent B-cell response to lipid-containing antigens, whereas FoxP3(+) follicular regulatory (Tfr) cells exert a suppressive function on germinal centers. Elucidating how Tfr cells are functionally and numerically regulated and the factors that control the balance between Tfh and Tfr cells is likely to be critical for improved understanding of the pathogenesis and progression of autoimmunity and lymphomas of germinal center origin, and generation of effective vaccines. PMID- 22500840 TI - Roles of BCL6 in normal and transformed germinal center B cells. AB - BCL6 is a transcriptional repressor required in mature B cells during the germinal center (GC) reaction. Multiple mechanisms act coordinately to timely modulate BCL6 expression at transcriptional and post-transcriptional levels. BCL6 prevents premature activation and differentiation of GC B cells and provides an environment tolerant of the DNA breaks associated with immunoglobulin gene remodeling mechanisms involved in the production of high-affinity antibodies of different isotypes. The critical functions exerted by BCL6 during normal B-cell development can be hijacked by the malignant transformation process. Indeed, BCL6 is targeted by genetic aberrations and acts as an oncogene in GC-derived lymphomas. The aberrations affecting BCL6 interfere with the multiple levels of regulation that grant a fine tuning of BCL6 expression and activity in physiologic conditions. This review summarizes the current knowledge on BCL6 function and its role in lymphomagenesis. PMID- 22500841 TI - Investigating complementary and alternative medicine in maternity care: the need for further public health/health services research. PMID- 22500839 TI - T cells that promote B-Cell maturation in systemic autoimmunity. AB - Follicular helper T (Tfh) cells play an essential role in helping B cells generate antibodies upon pathogen encounters. Such T-cell help classically occurs in germinal centers (GCs) located in B-cell follicles of secondary lymphoid organs, a site of immunoglobulin affinity maturation and isotype switching. B cell maturation also occurs extrafollicularly, in the red pulp of the spleen and medullary cords in lymph nodes, with plasma cell formation and antibody production. Development of extrafollicular foci (EF) in T-cell-dependent (TD) immune responses is reliant upon CD4(+) T cells with characteristics of Tfh cells. Pathogenic autoantibodies, arising from self-reactive B cells having undergone somatic hypermutation with affinity selection and class switching within GCs and EF, are major contributors to the end-organ injury in systemic autoimmunity. B cells maturing to produce autoantibodies in systemic autoimmune diseases, like those in normal immune responses, largely require T-helper cells. This review highlights Tfh cell development as an introduction to a more in-depth discussion of human Tfh cells and blood borne cells with similar features and the role of these cells in promotion of systemic autoimmunity. PMID- 22500842 TI - Availability of complementary and alternative medicine for people with cancer in the British National Health Service: results of a national survey. AB - This study assessed access to Complementary and Alternative Medicine (CAM) therapies for people with cancer within the British National Health Service. CAM units were identified through an internet search in 2009. A total of 142 units, providing 62 different therapies, were identified: 105 (74.0%) England; 23 (16.2%) Scotland; 7 (4.9%) each in Wales and Northern Ireland. Most units provide a small number of therapies (median 4, range 1-20), and focus on complementary, rather than alternative approaches. Counselling is the most widely provided therapy (available at 82.4% of identified units), followed by reflexology (62.0%), aromatherapy (59.1%), reiki (43.0%), massage (42.2%). CAM units per million of the population varied between countries (England: 2.2; Wales: 2.3; Scotland: 4.8; Northern Ireland: 5.0), and within countries. Better publicity for CAM units, greater integration of units in conventional cancer treatment centres may help improve access to CAMs. PMID- 22500843 TI - Short- and long-term effects of a lactose-restricted diet and probiotics in children with chronic abdominal pain: a retrospective study. AB - OBJECTIVE: To determine the short- and long-term effect of treatment in children with chronic abdominal pain (CAP). METHODS: A database with the results of H(2) breath test of children with CAP was created. All children with an abnormal test result were included and classified as small intestinal bacterial overgrowth (SIBO) or lactose intolerant (LTI). SIBO was treated with probiotics and LTI with a lactose-restricted diet. CAP was evaluated 5 months and 15 months after the test. RESULTS: 37 children (41%) were included. 17 LTI children (94%) improved after 5 months and 11 children (61%) after 15 months (P<0.05). Seven SIBO children improved after 5 months and 4 children after 15 months. In the combination group all 4 children improved after 5 months and 3 children after 15 months. CONCLUSION: Children with CAP caused by LTI or SIBO had less CAP after 5 months. This positive effect persists only in half of the children. PMID- 22500844 TI - Therapeutic effects of calcium & vitamin D supplementation in women with PCOS. AB - OBJECTIVE: To evaluate the efficacy of calcium & vitamin D supplementation in infertile women suffering from polycystic ovary syndrome (PCOS), and to assess levels of 25-hydroxy vitamin D in these patients. METHODS: In a case control study, 100 infertile PCOS women based on a randomly divided into two groups. Group I (n = 50) were treated with metformin 1500 mg/day, and group II (n = 50) treated with metformin 1500 mg/day plus Calcium 1000 mg/day and Vitamin D 100000 IU/month for 6 months. Patients were followed by transvaginal sonography at first, 3 and 6 months later for evaluating dominant follicle. BMI, menstrual regularity, follicle diameter, pregnancy, serum 25-OH-vitamin D level were matured and compared in two groups. RESULTS: BMI decreased almost significantly (25.49 +/- 1.88 vs 26.28 +/- 2.15, p: 0.054) in group II. A better improvement was gained in regulating menstrual abnormalities (70% vs 58%, p: 0.211), follicle maturation (28% vs 22%, p: 0.698), and infertility (18% vs 12%, p: 0.401) in group II compared with group I, but these results were not statistically significant. Eighty three percent of all the PCOS patients showed vitamin D deficiency while 35% were severely deficient. The serum 25-OH-vitamin D mean levels were 13.38 +/- 6.48 ng/ml. Vitamin D deficiency was recompensed in 74% of the PCOS patients who had taken calcium & vitamin D supplementation. There was no correlation between BMI and 25-OH-VD before and after the treatment (p >= 0.01). CONCLUSION: This study showed the positive effects of calcium & vitamin D supplementation on weight loss, follicle maturation, menstrual regularity, and improvement of hyperandrogenism, in infertile women with PCOS. PMID- 22500845 TI - The chiropractic care of a child with extremity tremors concomitant with a medical diagnosis of conversion disorder. AB - OBJECTIVE: To describe the care of a patient with spinal and cranial dysfunctions and medically diagnosed with conversion disorder. CLINICAL FEATURES: The patient was an 11-yr-old girl presented by her parents with complaints of uncontrollable tremors of both arms and right leg. Conversion disorder was diagnosed following negative examination findings for an organic etiology. Prior to institutionalization, her parents requested a "second opinion" from a clinical psychologist that eventually led to chiropractic referral. INTERVENTION AND OUTCOME: Care was provided using spinal manipulation to sites of spinal and cranial dysfunctions. With subsequent visit, the patient's tremors improved. Following 12 chiropractic visits, the patient's symptoms resolved. Long-term follow-up revealed continued resolution of the symptoms of tremors. CONCLUSION: This case report provides supporting evidence that patients with ballistic tremors of possible unknown organic etiology may benefit from chiropractic care. We support further research in this field. PMID- 22500846 TI - The effects of deep breathing on 'tension-anxiety' and fatigue in cancer patients undergoing adjuvant chemotherapy. AB - AIMS: We investigated the effect of deep breathing intervention on 'tension anxiety' and fatigue in Japanese women with gynaecological cancer undergoing adjuvant chemotherapy. SETTING: A total of 23 patients were randomly allocated to intervention (n = 11) and control (n = 12) groups. INTERVENTION: Deep breathing was practised in the intervention group, but not in the control group. Deep breathing comprised a 10-min breathing program comprising abdominal breathing, thoracic breathing and breathing with arms raised. Using the Profile of Mood States-Short Form (Japanese version) and the Cancer Fatigue Scale, the effects were assessed pre- and post-chemotherapy. RESULTS: 'Tension-anxiety' and fatigue of the intervention group were relieved more than those of the control group. CONCLUSIONS: The findings indicated that deep breathing intervention is likely to ameliorate the 'tension-anxiety' and fatigue in patients with gynaecological cancer undergoing adjuvant chemotherapy. PMID- 22500847 TI - How Natural Therapists enhance positive expectations of patients. AB - OBJECTIVE: To examine if Natural Therapists purposely enhance patient expectations, and if so which strategies are used in clinical practice. METHOD: Interviews were conducted with ten experienced Australian Natural Therapists using semi-structured questionnaires. Data was analysed using grounded theory. RESULTS: The Natural Therapists in the present study reported that they spent considerable time and effort to deliberately enhance positive expectations. Strategies included an enthusiastic delivery of the therapeutic scope of the practitioner's modality and the practitioner's capacity to diagnose and treat disease based upon their training and experience, and confidence in patients' self-efficacy, with an emphasis on personal strengths and positive aspects of patients' health. The therapists claimed to be optimistic, but at the same time realistic, cautioning against false hope, particularly in serious or terminal diseases. In order to enhance patient expectation greater emphasis should be placed on these strategies in the training of Natural Therapists. PMID- 22500848 TI - Guided visualization interventions on perceived stress, dyadic satisfaction and psychological symptoms in highly stressed couples. AB - This study focused on the effect of a brief CBT-based relaxation/guided visualization intervention on perceived stress, dyadic satisfaction and psychological symptoms. This study also tested the hypothesis that indicators of global orientation including Sense of Coherence and Differentiation of Self would mediate between perceived stress and symptoms of physical, psychological and relational distress. A three session intervention used guided visualization scripts which incorporated relaxation and controlled breathing techniques as well as a CBT approach that focused on stress management and internal locus of control. Results indicated that after the intervention, participants showed lower levels of perceived stress and lower levels of dyadic distress, as well as lower psychological and physical complaints as reported with the Symptom Checklist-90 R. Both Sense of Coherence and Differentiation of Self were mediators for the effect of perceived stress on the number of endorsed symptoms. PMID- 22500849 TI - Complementary and Alternative Medicine (CAM) use by Malaysian oncology patients. AB - The current study sought to evaluate Malaysian oncology patients' decision making about the use of Complementary and Alternative Medicine (CAM) for the management of their care. Patients were interviewed across three major Malaysian ethnic groups, Malay, Chinese and Indian. Thematic content analysis identified four central themes: Conceptualizing CAM, the decision making process; rationale given for selecting or rejecting CAM and barriers to CAM use. Participants generally used the term 'traditional medicine', referred to locally as 'ubat kampung', meaning medicine derived from 'local traditions'. Mixed reactions were shown concerning the effectiveness of CAM to cure cancer and the slow progression of CAM results and treatment costs were cited as major barriers to CAM use. Concerns regarding safety and efficacy of CAM in ameliorating cancer as well as potential interactions with conventional therapies highlighted the importance of patients' knowledge about cancer treatments. PMID- 22500850 TI - Complementary alternative medicine use among a sample of Muslim Jordanian oncology patients. AB - PURPOSE: The purpose of this study was to assess the frequency of use of Complementary and Alternative Medicine (CAM) therapies among a sample of Muslim Jordanian patients diagnosed with cancer. METHOD: Interviews using a modified structured questionnaire from Lengacher et al. survey with a convenient sample of 123 patients diagnosed with cancer. RESULT: Of 123 participants, 54.5% were men, with a mean age of 44.5 years (26.8%) had some college education and 82.9% were living in urban areas. The mean number of the therapies used was 6.6 (SD = 4.3, R = 0-17). There was a significant positive moderate correlation between the time since diagnosis and the number of CAM therapies used (r = 0.3, P < 0.05). There was a positive correlation between chemotherapy as a treatment modality and the number of CAM therapies used (r = 0.4, P < 0.05). The highest usage of dietary and nutritional supplements occurred with honey, olive oil, black seeds, and dates. The highest stress reducing CAM techniques included reading the Holy Qur'an, praying, and Ruqya. Other CAM treatments involved ZamZam water, cinnamon, black seeds oil, and the use of a plant called Zaamtoot (primrose). CONCLUSION: Even though a range of CAM therapies are used by Jordanian oncology patients it is suggested that both patients and medical staff be educated about the possible benefits or harmful effects of using these treatments. PMID- 22500851 TI - Psychometric testing of the Chinese evidence-based practice scales. AB - AIM: This article is a report of the psychometric testing of the Chinese version of Evidence-Based Practice Implementation and Beliefs, and Barriers to, and Facilitators of Research Utilization scales. BACKGROUND: Investigations into the effect of evidence-based practice on clinical care could be facilitated by instruments for measuring the levels of evidence-based practice implementation; the strength of beliefs in evidence-based practice; the barriers to, and the facilitators of research utilization. An English version of the scales measuring the above constructs has been tested whereas the Chinese one has not. DESIGN: Instrument development. METHODS: Psychometric analyses of the four evidence-based scales were conducted on a sample of 361 nurses from a medical centre in Taiwan. Both the internal consistency and squared multiple correlation coefficients were used to examine reliability. The validity testing for the four scales was estimated by examining their construct and concurrent validity. Data were collected between December 2008-January 2009. FINDINGS: Internal consistencies exist for the Chinese Evidence-Based Practice Implementation, Beliefs, and Barriers to, and Facilitator of Research Utilization scales (>=0.85); some were greater than 0.9, which may indicate redundancy in items. Construct validity of the four scales was supported by hypotheses testing. Concurrent validity of the four scales was supported by known-group analysis, in which experienced nursing researchers had higher scores compared with clinical nurses. CONCLUSION: These scales may have value in discrimination between implementation of EBP and perception of barriers to, and facilitators of research utilization among nurses with different education levels, research experiences or working years in clinical setting. PMID- 22500852 TI - GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer (IVF/ET). AB - Several protocols are actually available for in Vitro Fertilization and Embryo Transfer. The review summarizes the main differences and the clinic characteristics of the protocols in use with GnRH agonists and GnRH antagonists by emphasizing the major outcomes and hormonal changes associated with each protocol. The majority of randomized clinical trials clearly shows that in "in Vitro" Fertilization and Embryo Transfer, the combination of exogenous Gonadotropin plus a Gonadotropin Releasing Hormone (GnRH) agonist, which is able to suppress pituitary FSH and LH secretion, is associated with increased pregnancy rate as compared with the use of gonadotropins without a GnRH agonist. Protocols with GnRH antagonists are effective in preventing a premature rise of LH and induce a shorter and more cost-effective ovarian stimulation compared to the long agonist protocol. However, a different synchronization of follicular recruitment and growth occurs with GnRH agonists than with GnRH antagonists. Future developments have to be focused on timing of the administration of GnRH antagonists, by giving a great attention to new strategies of stimulation in patients in which radio-chemotherapy cycles are needed. PMID- 22500853 TI - Developmental and evolutionary significance of the mandibular arch and prechordal/premandibular cranium in vertebrates: revising the heterotopy scenario of gnathostome jaw evolution. AB - The cephalic neural crest produces streams of migrating cells that populate pharyngeal arches and a more rostral, premandibular domain, to give rise to an extensive ectomesenchyme in the embryonic vertebrate head. The crest cells forming the trigeminal stream are the major source of the craniofacial skeleton; however, there is no clear distinction between the mandibular arch and the premandibular domain in this ectomesenchyme. The question regarding the evolution of the gnathostome jaw is, in part, a question about the differentiation of the mandibular arch, the rostralmost component of the pharynx, and in part a question about the developmental fate of the premandibular domain. We address the developmental definition of the mandibular arch in connection with the developmental origin of the trabeculae, paired cartilaginous elements generally believed to develop in the premandibular domain, and also of enigmatic cartilaginous elements called polar cartilages. Based on comparative embryology, we propose that the mandibular arch ectomesenchyme in gnathostomes can be defined as a Dlx1-positive domain, and that the polar cartilages, which develop from the Dlx1-negative premandibular ectomesenchyme, would represent merely posterior parts of the trabeculae. We also show, in the lamprey embryo, early migration of mandibular arch mesenchyme into the premandibular domain, and propose an updated version of the heterotopy theory on the origin of the jaw. PMID- 22500854 TI - Rhodium-catalyzed synthesis of branched amines by direct addition of benzamides to imines. AB - Rhodium-catalyzed addition of benzamide C-H bonds to a range of aromatic N sulfonyl aldimines has been developed and proceeds with high functional group compatibility. The synthetic utility of the resulting branched amine products has also been demonstrated by the preparation of isoindoline and isoindolinone frameworks. PMID- 22500855 TI - Prospective clinical trial to compare standard colon-reflecting with transmesocolic laparoscopic pyeloplasty. AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Laparoscopic pyeloplasty has replaced open pyeloplasty as the new standard of care and we, among others, have even proven its applicability to redo surgery. The focus is now on limiting morbidity. One technical modification to this end is transmesocolic (TM) exposure of the PUJ. This randomized study pinpoints the objective benefits of TM exposure of the PUJ compared with standard colon reflection, and its results showed a 23% conservation in operating time. OBJECTIVE: * To compare the efficacy and safety of colon-reflecting (CR) and transmesocolic (TM) laparoscopic pyeloplasty approaches in a prospective randomized non-selective setting. PATIENTS AND METHODS: * Excluding only those patients with a history of abdominal surgery, all consenting patients scheduled for laparoscopic pyeloplasty of left-sided pelvi ureteric junction (PUJ) obstruction between December 2004 and November 2007 were randomized into one of two groups: laparoscopic pyeloplasty using the standard CR approach or laparoscopic pyeloplasty through the TM aperture. * All patients underwent dismembered repair by a single expert and were followed by diuretic renogram and urography at 4 months postoperatively and by annual diuretic renogram thereafter. * Four discrete task phases were timed for comparison: trochar to PUJ, dismembering and spatulation, stenting and anastomosis. RESULTS: * Sixty-four patients were randomized into two groups, TM or CR, with 32 patients in each. * The groups were similar, with no significant difference in sex, age, initial renal function or body mass index. Forty-seven patients were <= 15 years old. * The mean (sd) operating time was 23% shorter in the TM group, owing mostly to the much shorter trochar to PUJ phase (5.0 [3.2] min in the TM group vs 35.8 [10.3] in the CR group; P < 0.001). The mean hospitalization time was shorter in the TM group than in the CR group (2.9 vs 3.6 days; P < 0.001). * Thirty-one of 32 patients in each group (96.9%) achieved a durable cure. CONCLUSION: * Transmesocolic exposure of left-sided PUJ obstruction is superior to standard CR exposure, in that it saves anaesthesia time, hospitalization time and has lower morbidity with no compromise in efficiency, and could be considered as the new standard approach. PMID- 22500856 TI - The fuzzy quantum proton in the hydrogen chloride hydrates. AB - The motion of the excess proton is understood as a process involving interconversion between two limiting states, namely, the Eigen and Zundel cations. Nuclear quantum effects (NQE) and the organization of the surrounding solvent play a significant role in this process. However, little is known about how these factors can change the limiting state in molecular systems and the physicochemical properties of its surrounding hydrogen-bond environment. In this work we use state of the art ab initio molecular dynamics simulations to examine the role of NQE on the nature of the proton in four hydrogen chloride hydrates. We demonstrate that NQE significantly alter the phase space properties of the proton and that the local electronic structure of the proton is an exquisitely sensitive indicator of the limiting state in each of the crystals. We evaluate both the proton momentum distribution and the proton chemical shifts and demonstrate that deep inelastic neutron scattering and solid-state nuclear magnetic resonance experiments can serve as complementary techniques for probing the quantum nature of the proton in hydrogen-bonding systems. We believe that the rich and insightful information we obtain for these acid hydrates provides a motivation for new experimental studies. PMID- 22500857 TI - Association of factor XII gene C46T polymorphism with cerebral venous thrombosis in the south Indian population. PMID- 22500858 TI - How we manage prostate biopsy and prostate cancer therapy in men with haemophilia. AB - A 56-year-old African American male with severe haemophilia A [baseline factor VIII (FVIII) activity <1%] and chronic hepatitis C virus infection started annual serial monitoring of prostate-specific antigen (PSA) at age 40 because of a family history of prostate cancer (his father died from the disease at age 63). His most recent PSA level was 4.4 ng L (-1); previous values were <3 ng L(-1 . Digital rectal examination was unrevealing. PMID- 22500860 TI - Theoretical exploration of hydrogen loss from Al3H9. AB - The Al(3)H(9) and Al(3)H(7) potential energy surfaces were explored using quantum chemistry calculations to investigate the H(2) loss mechanism from Al(3)H(9), which provide new insights into hydrogen production from bulk alane, [AlH(3)](x), a possible energy storage material. We present results of B3LYP/6-311++G(d,p) calculations for the various Al(3)H(9) and Al(3)H(7) optimized local minima and transition state structures along with some reaction pathways for their interconversion. We find the energy for Al(3)H(9) decomposition into Al(2)H(6) and AlH(3) is slightly lower than that for H(2) loss and Al(3)H(7) formation, but the calculations show that H(2) loss from Al(3)H(9) is a lower energy process than for losing hydrogen from either Al(2)H(6) or AlH(3). We found four transition state structures and reaction pathways for Al(3)H(9) -> Al(3)H(7) + H(2), where the lowest energy activation barrier is around 25-73 kJ/mol greater than the experimental value for H(2) loss from bulk alane. Intrinsic reaction coordinate calculations show that the H(2) loss pathway involves considerable rearrangement of the H atom positions around a single Al center. Three of the pathways start with the formation of an AlH(3) moiety, which then enables a terminal H on the AlH(3) to get within 1.1 to 1.2 A of a nearby bridging H atom. The bridging and terminal H atoms eventually combine to form H(2) and leave Al(3)H(9). One implication of these H(2) loss reaction pathways is that, since the H atoms in bulk alanes are all at bridging positions, if a similar H(2) loss mechanism were to apply to bulk alane, then H(2) loss would most likely occur on the bulk alane surface or at a defect site where there should be more terminal H atoms available for reaction with nearby bridging H atoms. PMID- 22500861 TI - Ipilimumab in the treatment of melanoma. AB - INTRODUCTION: Recent advances in the understanding of the complex cellular mechanisms regulating cancer immunity have led to new strategies in the development of cancer immunotherapy. Targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), a key negative regulator of immune activity, with the monoclonal antibody ipilimumab has shown promising clinical benefit in patients with advanced or metastatic melanoma. AREAS COVERED: This review illustrates the pharmacology of ipilimumab and highlights the clinical evidence regarding its efficacy and safety in patients with advanced or metastatic melanoma. The unique clinical response pattern and class-specific immune-related toxicity profile associated with this biologic agent are also characterized. A literature search using PubMed database was undertaken using search words ipilimumab, anti cytotoxic T-lymphocyte-associated antigen 4, melanoma and tumor immunity barrier. EXPERT OPINION: Ipilimumab, approved by the FDA for patients with advanced or metastatic melanoma based on the overall survival benefit when compared with a peptide vaccine, is a major breakthrough in the treatment of melanoma. While clinicians are embracing this innovative biologic agent, special attentions in patient selection, class-specific immune-related toxicities and their management as well as treatment response evaluation are needed. PMID- 22500859 TI - What have we learned from brucellosis in the mouse model? AB - Brucellosis is a zoonosis caused by Brucella species. Brucellosis research in natural hosts is often precluded by practical, economical and ethical reasons and mice are widely used. However, mice are not natural Brucella hosts and the course of murine brucellosis depends on bacterial strain virulence, dose and inoculation route as well as breed, genetic background, age, sex and physiological statu of mice. Therefore, meaningful experiments require a definition of these variables. Brucella spleen replication profiles are highly reproducible and course in four phases: i), onset or spleen colonization (first 48 h); ii), acute phase, from the third day to the time when bacteria reach maximal numbers; iii), chronic steady phase, where bacterial numbers plateaus; and iv), chronic declining phase, during which brucellae are eliminated. This pattern displays clear physiopathological signs and is sensitive to small virulence variations, making possible to assess attenuation when fully virulent bacteria are used as controls. Similarly, immunity studies using mice with known defects are possible. Mutations affecting INF-gamma, TLR9, Myd88, Tgammadelta and TNF-beta favor Brucella replication; whereas IL-1beta, IL-18, TLR4, TLR5, TLR2, NOD1, NOD2, GM-CSF, IL/17r, Rip2, TRIF, NK or Nramp1 deficiencies have no noticeable effects. Splenomegaly development is also useful: it correlates with IFN-gamma and IL-12 levels and with Brucella strain virulence. The genetic background is also important: Brucella-resistant mice (C57BL) yield lower splenic bacterial replication and less splenomegaly than susceptible breeds. When inoculum is increased, a saturating dose above which bacterial numbers per organ do not augment, is reached. Unlike many gram-negative bacteria, lethal doses are large (>= 108 bacteria/mouse) and normally higher than the saturating dose. Persistence is a useful virulence/attenuation index and is used in vaccine (Residual Virulence) quality control. Vaccine candidates are also often tested in mice by determining splenic Brucella numbers after challenging with appropriate virulent brucellae doses at precise post-vaccination times. Since most live or killed Brucella vaccines provide some protection in mice, controls immunized with reference vaccines (S19 or Rev1) are critical. Finally, mice have been successfully used to evaluate brucellosis therapies. It is concluded that, when used properly, the mouse is a valuable brucellosis model. PMID- 22500863 TI - Making haemophilia a global priority. PMID- 22500862 TI - South Africa's AIDS response: the next 5 years. PMID- 22500864 TI - Obesity and cancer outcome. PMID- 22500865 TI - A new resolution for global mental health. PMID- 22500867 TI - Stefan Willich: conductor and cardiologist. PMID- 22500868 TI - Serotype replacement after pneumococcal vaccination. PMID- 22500869 TI - Serotype replacement after pneumococcal vaccination. PMID- 22500870 TI - Serotype replacement after pneumococcal vaccination. PMID- 22500872 TI - QASC trial: swallow surveillance rates comparable with international data. PMID- 22500873 TI - Team-building intervention to improve acute stroke care. PMID- 22500874 TI - Breast and cervical cancer in 187 countries between 1980 and 2010. PMID- 22500876 TI - Breast and cervical cancer in 187 countries between 1980 and 2010. PMID- 22500878 TI - Bilateral anterior lens dislocation: the genetic perspective. PMID- 22500879 TI - Fooled by the heart. PMID- 22500880 TI - Concerns about the Jikei Heart Study. PMID- 22500881 TI - Pharmacokinetics of tildipirosin in porcine plasma, lung tissue, and bronchial fluid and effects of test conditions on in vitro activity against reference strains and field isolates of Actinobacillus pleuropneumoniae. AB - The pharmacokinetics of tildipirosin (Zuprevo((r)) 40 mg/mL solution for injection for pigs), a novel 16-membered-ring macrolide for the treatment for swine respiratory disease (SRD), was investigated in studies collecting blood plasma and postmortem samples of lung tissue and bronchial fluid (BF) from swine. In view of factors influencing the in vitro activity of macrolides, and for the interpretation of tildipirosin pharmacokinetics in relation to minimum inhibitory concentrations (MIC), additional experiments were conducted to study the effects of pH, carbon dioxide-enriched atmosphere, buffers, and serum on tildipirosin MICs for various reference strains and Actinobacillus (A.) pleuropneumoniae field isolates. After single intramuscular (i.m.) injection at 4 mg/kg body weight, maximum plasma concentration (Cmax) was 0.9 MUg/mL observed within 23 min (Tmax ). Mean residence time from the time of dosing to the time of last measurable concentration (MRTlast) and terminal half-life (T1/2) both were about 4 days. A dose-response relationship with no significant sex effect is observed for area under the plasma concentration-time curve from time 0 to the last sampling time with a quantifiable drug concentration (AUClast) over the range of doses up to 6 mg/kg. However, linear dose proportionality could not be proven with statistical methods. The time-concentration profile of tildipirosin in BF and lung far exceeded that in blood plasma. In lung, tildipirosin concentrations reached 3.1 MUg/g at 2 h, peaked at 4.3 MUg/g at day 1, and slowly declined to 0.8 MUg/g at day 17. In BF, tildipirosin levels were 14.3, 7.0, and 6.5 MUg/g at days 5, 10, and 14. T1/2 in lung was ~7 days. Tildipirosin is rapidly and extensively distributed to the respiratory tract followed by slow elimination. Culture media pH and carbon dioxide-enriched atmosphere (CO2 -EA) had a marked impact on in vitro activity of tildipirosin in reference strains of various rapidly growing aerobic and fastidious bacteria including Histophilus (H.) somni ATCC 700025 and A. pleuropneumoniae ATCC 27090. For A. pleuropneumoniae ATCC 27090 testing conditions without CO2 -EA resulted in reduced acidification of culture media pH and a reduction in the minimum inhibitory concentrations compared to standard in vitro test conditions by 2 log2 dilution steps (4-fold) from 8 to 2 MUg/mL. Supplementary buffering of standard culture media resulted in a reduction in the A. pleuropneumoniae (n = 8) MIC range by 4 log2 dilution steps (16-fold) from 8 16 to 0.5-1 MUg/mL. Incremental supplementation of culture media with 50% serum resulted in noticeable shifts to lower minimum or maximum MICs by at least 2 log2 dilution steps (>=4-fold) in all aerobic and fastidious reference strains tested except for Pasteurella (P.) multocida. The MIC of A. pleuropneumoniae ATCC 27090 decreased by 2-4 log2 dilution steps (4 to 16-fold) from 8 to 0.5-2 MUg/mL when 50% serum was added to the standard assay. Considering a higher presence of serum and the rather neutral pH conditions maintained in vivo, it is suggested to take the influence of these factors on in vitro activity into account when interpreting tildipirosin MICs for A. pleuropneumoniae in relation to pharmacokinetics. PMID- 22500882 TI - Individual, social and environmental factors influencing physical activity levels and behaviours of multiethnic socio-economically disadvantaged urban mothers in Canada: a mixed methods approach. AB - BACKGROUND: Existing data provide little insight into the physical activity context of multiethnic socio-economically disadvantaged mothers in Canada. Our primary objectives were: (1) to use focus group methodology to develop tools to identify the individual, social, and environmental factors influencing utilitarian and leisure time physical activities (LTPA) of multiethnic SED mothers; and (2) to use a women specific physical activity survey tool to assess psychosocial barriers and supports and to quantify individual physical activity (PA) levels of multi-ethnic SED mothers in Canada. METHODS: Qualitative focus group sessions were conducted in West, Central and Eastern Canada with multiethnic SED mothers (n = 6 focus groups; n = 42 SED mothers) and with health and recreation professionals (HRPs) (n = 5 focus groups; n = 25 HRPs) involved in community PA programming for multiethnic SED mothers. Administration of the women specific Kaiser Physical Activity Survey (KPAS) tool was completed by consenting SED mothers (n = 59). RESULTS: More than half of SED mothers were employed and had higher total PA scores with occupation included than unemployed mothers. However, nearly 60% of both groups were overweight or obese. Barriers to LTPA included the lack of available, affordable and accessible LTPA programs that responded to cultural and social needs. Concerns for safety, nonsupportive cultural and social norms and the winter climate were identified as key barriers to both utilitarian and LTPA. CONCLUSIONS: Findings show that multiethnic SED mothers experience many barriers to utilitarian and LTPA opportunities within their communities. The varying LTPA levels among these multi-ethnic SED mothers and the occurrence of overweight and obesity suggests that current LTPA programs are likely insufficient to maintain healthy body weights. PMID- 22500883 TI - The use of thallium diethyldithiocarbamate for mapping CNS potassium metabolism and neuronal activity: Tl+ -redistribution, Tl+ -kinetics and Tl+ -equilibrium distribution. AB - The potassium (K(+)) analogue thallium (Tl(+)) can be used as a tracer for mapping neuronal activity. However, because of the poor blood-brain barrier (BBB) K(+) -permeability, only minute amounts of Tl(+) enter the brain after systemic injection of Tl(+) -salts like thallium acetate (TlAc). We have recently shown that it is possible to overcome this limitation by injecting animals with the lipophilic chelate complex thallium diethyldithiocarbamate (TlDDC), that crosses the BBB and releases Tl(+) prior to neuronal or glial uptake. TlDDC can thus be used for mapping CNS K(+) metabolism and neuronal activity. Here, we analyze Tl(+) -kinetics in the rodent brain both experimentally and using simple mathematical models. We systemically injected animals either with TlAc or with TlDDC. Using an autometallographic method we mapped the brain Tl(+) -distribution at various time points after injection. We show that the patterns and kinetics of Tl(+) -redistribution in the brain are essentially the same irrespective of whether animals have been injected with TlAc or TlDDC. Data from modeling and experiments indicate that transmembrane Tl(+) -fluxes in cells within the CNS in vivo equilibrate at similar rates as K(+) -fluxes in vitro. This equilibration is much faster than and largely independent of the equilibration of Tl(+) -fluxes across the BBB. The study provides further proof-of-concept for the use of TlDDC for mapping neuronal activity and CNS K(+) -metabolism. A theoretical guideline is given for the use of K(+) -analogues for imaging neuronal activity with general implications for the use of metal ions in neuroimaging. PMID- 22500884 TI - Androgen deprivation therapy for volume reduction, lower urinary tract symptom relief and quality of life improvement in patients with prostate cancer: degarelix vs goserelin plus bicalutamide. AB - Study Type--Therapy (RCT) Level of Evidence 1b. What's known on the subject? and What does the study add? Androgen deprivation therapy (ADT) is commonly used as a primary treatment for patients with prostate cancer (PCa) who are not eligible for radical treatment options. ADT is also used in patients with PCa as neo adjuvant hormone therapy to reduce prostate volume and down-stage the disease before radiotherapy with curative intent. The present study showed that ADT with the gonadotropin hormone-releasing hormone (GhRH) antagonist degarelix is non inferior to combined treatment with the LHRH agonist goserelin and bicalutamide in terms of reducing prostate volume during the treatment period of 3 months. Degarelix treatment evokes, however, significantly better relief of lower urinary tract symptoms in patients having moderate and severe voiding problems. OBJECTIVE: * To assess the efficacy of monthly degarelix treatment for reduction of total prostate volume (TPV), relief of lower urinary tract symptoms (LUTS) and improvement of quality of life (QoL) in patients with prostate cancer (PCa) using monthly goserelin as active control. METHODS: * This was a randomized, parallel arm, active-controlled, open-label, multicentre trial on 182 patients treated with either monthly degarelix (240/80 mg) or goserelin (3.6 mg) for 12 weeks. * For flare protection, goserelin-treated patients also received daily bicalutamide (50 mg) during the initial 28 days. * Key trial variables monitored monthly were TPV (primary endpoint), serum testosterone, prostate-specific antigen (PSA), the International Prostate Symptom Score (IPSS) and the Benign Prostate Hyperplasia Impact Index. RESULTS: * In all, 175 patients completed the trial (96.1%). * At week 12, changes in TPV for degarelix and goserelin were similar (-37.2% vs 39.0%) and met the predefined non-inferiority criterion. * Decreases in IPSS were greater in degarelix than in goserelin-treated patients, differences being statistically significant in patients with baseline IPSS > 13 (-6.7 +/- 1.8 vs 4.0 +/- 1.0; P = 0.02). * The number of patients with an IPSS change of >= 3 over baseline was also significantly higher in patients treated with degarelix (61.0 vs 44.3%, P = 0.02). * Both treatments were safe and well tolerated. CONCLUSIONS: * Medical castration reduces TPV and could also improve LUTS in patients with PCa. * While the short-term efficacy of degarelix and goserelin + bicalutamide was the same in terms of TPV reduction, degarelix showed superiority in LUTS relief in symptomatic patients, which could highlight the different actions of these drugs on extrapituitary gonadotrophin-releasing hormone (GnRH) receptors in the bladder and/or the prostate. PMID- 22500885 TI - Telocytes in human skin--are they involved in skin regeneration? AB - Telocytes (TCs), a particular interstitial cell type, have been recently described in a wide variety of mammalian organs (www.telocytes.com). The TCs are identified morphologically by a small cell body and extremely long (tens to hundreds of MUm), thin prolongations (less than 100 nm in diameter, below the resolving power of light microscopy) called telopodes. Here, we demonstrated with electron microscopy and immunofluorescence that TCs were present in human dermis. In particular, TCs were found in the reticular dermis, around blood vessels, in the perifollicular sheath, outside the glassy membrane and surrounding sebaceous glands, arrector pili muscles and both the secretory and excretory portions of eccrine sweat glands. Immunofluorescence screening and laser scanning confocal microscopy showed two subpopulations of dermal TCs; one expressed c-kit/CD117 and the other was positive for CD34. Both subpopulations were also positive for vimentin. The TCs were connected to each other by homocellular junctions, and they formed an interstitial 3D network. We also found TCs adjoined to stem cells in the bulge region of hair follicles. Moreover, TCs established atypical heterocellular junctions with stem cells (clusters of undifferentiated cells). Given the frequency of allergic skin pathologies, we would like to emphasize the finding that close, planar junctions were frequently observed between TCs and mast cells. In conclusion, based on TC distribution and intercellular connections, our results suggested that TCs might be involved in skin homeostasis, skin remodelling, skin regeneration and skin repair. PMID- 22500886 TI - 'Being in it together': living with a partner receiving deep brain stimulation for advanced Parkinson's disease--a hermeneutic phenomenological study. AB - AIM: This article is a report of an exploration of the lived experience of being a spouse to a person living with advanced Parkinson's disease, before and during the first year of deep brain stimulation. BACKGROUND: Parkinson's disease is a chronic progressive neurodegenerative disease. It has a profound impact on the everyday life for patients and spouses. Deep brain stimulation is offered with the aim of reducing symptoms of Parkinson's disease. The treatment is known to improve quality of life for patients, but little is known of how spouses experience life following their partners' treatment. DESIGN: A longitudinal interview study with a hermeneutic phenomenological approach. METHOD: Ten spouses were included in the study. Data were gathered in 2007-2008, through qualitative in-depth interviews with spouses once before and three times during the first year of their partners' treatment with Deep Brain Stimulation. Data collection and data analysis were influenced by the hermeneutic phenomenological methodology of van Manen. FINDINGS: The uniting theme 'Solidarity - the base for joined responsibility and concern' was the foundation for the relationship between spouses and their partners. Before treatment, the theme 'Living in partnership' was dominant. After treatment two dichotomous courses were described 'A sense of freedom embracing life' and 'The challenge of changes and constraint'. CONCLUSION: Spouses are deeply involved in their partners' illness and their experience of life is highly affected by their partners' illness, both before and after deep brain stimulation. The relationship is founded on solidarity and responsibility, which emphasizes spouses' need to be informed and involved in the process following Deep Brain Stimulation. PMID- 22500887 TI - Molecular dynamics studies of the STAT3 homodimer:DNA complex: relationships between STAT3 mutations and protein-DNA recognition. AB - Signal Transducers and Activators of Transcription (STAT) proteins are a group of latent cytoplasmic transcription factors involved in cytokine signaling. STAT3 is a member of the STAT family and is expressed at elevated levels in a large number of diverse human cancers and is now a validated target for anticancer drug discovery.. Understanding the dynamics of the STAT3 dimer interface, accounting for both protein-DNA and protein-protein interactions, with respect to the dynamics of the latent unphosphorylated STAT3 monomer, is important for designing potential small-molecule inhibitors of the activated dimer. Molecular dynamics (MD) simulations have been used to study the activated STAT3 homodimer:DNA complex and the latent unphosphorylated STAT3 monomer in an explicit water environment. Analysis of the data obtained from MD simulations over a 50 ns time frame has suggested how the transcription factor interacts with DNA, the nature of the conformational changes, and ways in which function may be affected. Examination of the dimer interface, focusing on the protein-DNA interactions, including involvement of water molecules, has revealed the key residues contributing to the recognition events involved in STAT3 protein-DNA interactions. This has shown that the majority of mutations in the DNA-binding domain are found at the protein-DNA interface. These mutations have been mapped in detail and related to specific protein-DNA contacts. Their structural stability is described, together with an analysis of the model as a starting point for the discovery of novel small-molecule STAT3 inhibitors. PMID- 22500889 TI - Cytokine-induced killer (CIK) cells as feasible and effective adoptive immunotherapy for the treatment of solid tumors. AB - INTRODUCTION: Cytokine-induced killer (CIK) cells are heterogeneous ex vivo expanded T lymphocytes with mixed T-NK phenotype and endowed with a wide MHC unrestricted antitumor activity. CIK cells can be expanded from peripheral blood mononuclear cells (PBMC) cultured with the timed addition of IFN-gamma, Ab anti CD3 and IL2. A consistent subset of mature CIK cells presents a CD3(+)CD56(+) phenotype. The CD3(+)CD56(+) cellular subset is the main responsible for the tumor-killing activity, mostly mediated by the interaction of NKG2D receptor with MHC-unrestricted ligands (MIC A/B; ULBPs) on tumor cells. AREAS COVERED: In the present work, we described the biologic characteristics of CIK cells, focusing on those aspects that may favor their clinical translation. We reviewed preclinical data and analyzed reports from clinical trials. A specific paragraph is dedicated to future research perspectives in the field. EXPERT OPINION: CIK cells represent a realistic new option in the field of cancer immunotherapy. Crucial issues, favoring their clinical translation, are the easy availability of large amounts of expanded CIK cells and their MHC-unrestricted tumor killing, potentially effective against many tumor types. Intriguing future perspectives and open challenges are the investigation of synergisms with other immunotherapy approaches, targeted therapies or even conventional chemotherapy. PMID- 22500888 TI - Describing the structural robustness landscape of bacterial small RNAs. AB - BACKGROUND: The potential role of RNA molecules as gene expression regulators has led to a new perspective on the intracellular control and genome organization. Because secondary structures are crucial for their regulatory role, we sought to investigate their robustness to mutations and environmental changes. RESULTS: Here, we dissected the structural robustness landscape of the small non-coding RNAs (sncRNAs) encoded in the genome of the bacterium Escherichia coli. We found that bacterial sncRNAs are not significantly robust to both mutational and environmental perturbations when compared against artificial, unbiased sequences. However, we found that, on average, bacterial sncRNAs tend to be significantly plastic, and that mutational and environmental robustness strongly correlate. We further found that, on average, epistasis in bacterial sncRNAs is significantly antagonistic, and positively correlates with plasticity. Moreover, the evolution of robustness is likely dependent upon the environmental stability of the cell, with more fluctuating environments leading to the emergence and fixation of more robust molecules. Mutational robustness also appears to be correlated with structural functionality and complexity. CONCLUSION: Our study provides a deep characterization of the structural robustness landscape of bacterial sncRNAs, suggesting that evolvability could be evolved as a consequence of selection for more plastic molecules. It also supports that environmental fluctuations could promote mutational robustness. As a result, plasticity emerges to link robustness, functionality and evolvability. PMID- 22500890 TI - A flu by any other name: why the World Health Organization should adopt the World Meteorological Association's storm naming system as a model for naming emerging infectious diseases. AB - This article explores the factors that contributed to the use of different names for H1N1 by diverse actors in the early stages of the pandemic of 2009 and discusses the implications of inconsistent naming practices for the public's understanding of the virus and the credibility of scientists and health authorities. The authors propose a naming protocol for novel variants modeled after the World Meteorological Association's practice for naming weather events, a model that would enable accurate transmission of technical information among experts and provide a stable name for public use, even in the context of incomplete or changing scientific understanding of the nature of the pathogen. PMID- 22500891 TI - A retrospective cohort study of cancer incidence among patients treated with radiosynoviorthesis. AB - Radiosynoviorthesis (RS) is an intra-articular injection of a radioactive colloid for the treatment of synovitis administered most often to patients with rheumatoid arthritis or haemophilia. Although highly cost-effective in comparison with surgical or arthroscopic synovectomy, the risk of cancer associated with this treatment is not well known. We evaluated the incidence of cancer in a group of patients treated with RS. A cohort of 2412 adult patients with a variety of underlying conditions (mainly rheumatoid arthritis) and treated with at least one RS between January 1976 and December 2001, was recruited from two centres in Montreal. Cancer incidence and mortality data for cohort members over that time period were obtained from regulatory agencies using linkage. Background rates for all and specific types of cancer were obtained for the provincial (Quebec) and national (Canada) population according to age, gender and calendar period categories. Category-specific rates in the cohort were compared with rates in similar categories from the general population generating standardized incidence ratios (SIR). The effects of specific isotope doses and of number of RS treatments were analysed using a Cox-regression model. No increase in the risk of cancer was observed (SIR 0.96; 95% confidence interval 0.82-1.12). There was no dose-response relationship with the amount of radioisotope administered or number of RS treatments. The study provides some indication for the safety of the procedure but homogenous diagnostic groups of younger patients (such as haemophilic patients) receiving RS will need more evaluation. PMID- 22500892 TI - Laccase- and chloroperoxidase-nanotube paint composites with bactericidal and sporicidal activity. AB - Laccase and chloroperoxidase (CPO) were separately immobilized onto multi-walled carbon nanotubes (MWNTs) and subsequently mixed with a commercial eco-friendly paint to generate biocatalytic coatings. The laccase-nanotube based paints showed >99% bactericidal activity against Escherichia coli and Staphylococcus aureus (both challenged with 106 CFU/mL) within 30 min and >98% sporicidal activity against Bacillus cereus and Bacillus anthracis-DeltaSterne (initially challenged with 104 CFU/mL) within 120 min. The CPO-nanotube based paints also showed >99% antimicrobial activity within 30 min against E. coli and S. aureus (both challenged with 106 CFU/mL). These enzyme-nanotube based formulations provide an eco-friendly route to generate biocidal compounds, which can prevent the growth of a broad spectrum of bacterial pathogens, including spores. These enzyme containing paints may be envisioned to be applied as self-decontaminating coatings onto a wide range of surfaces, such as hospital infrastructure, medical devices and equipment, food processing and packaging, etc.; in all cases effective killing of a variety of infectious organisms is critical. PMID- 22500893 TI - The direct repeat sequence upstream of Bacillus chitinase genes is cis-acting elements that negatively regulate heterologous expression in E. coli. AB - To explore the influence of the direct repeat sequence (DRS) in Bacillus chitinase genes on heterogonous expression in Escherichia coli, we cloned and sequenced the entire open reading frame (ORF) and upstream sequences of the chitinase B (chiB) and chitinase MY75 (chiMY75) from Bacillus thuringiensis and Bacillus licheniformis. A pair of 8-bp DRS was found upstream of each chi gene. Chi ORFs with a series of truncated DRS were cloned and transformed into E. coli XL-Blue. The activity of the transformants without the DRS were significantly higher in chitinase assays than transformants containing the DRS. SDS-PAGE showed that part and full deletion of the DRS increased chi gene expression by approximately 1.7 and 3.8-fold, respectively. Northern blotting revealed deletion of the DRS regions increased chiB and chiMY75 mRNA expression. Specific binding of DNA-binding factors in the E. coli cell lyaste was observed to both the chiB and chiMY75 promoter regions and DRS elements. This is the first investigation to demonstrate that heterologous expression of Bacillus chi genes in E. coli is negatively regulated by their upstream DRS regions, which act as cis-acting elements. PMID- 22500894 TI - Bostrycin, a novel coupling agent for protein immobilization and prevention of biomaterial-centered infection produced by Nigrospora sp. No. 407. AB - Bostrycin, a red antibacterial agent with tetrahydroanthraquinone structure, has been isolated from Nigrospora sp. No. 407. This study investigated the potential antibacterial and multifunctional properties of matrixes through immobilization of bostrycin on their surface for immobilization of protein and prevention of bacterial growth. Bostrycin was immobilized on nonwoven polypropylene (PP) fabric by a technique using glutaraldehyde and polyethyleneimine for the activation of the surface. Glucose oxidase immobilized on bostrycin-treated nonwoven PP fabric showed high activity. The immobilization process improved thermal stability of the enzymes. During repeated assay for 30 cycles, the enzyme activity dropped to only 70% of the initial activity. Both bostrycin-treated nonwoven PP fabric sample and subsequently immobilized glucose oxidase sample on the surface also still exhibited a bacteriostatic effect. This is the first study to show that bostrycin is a promising coupling agent for surface modification on matrix and its potential applications in protein immobilization and biomaterial-centered infection. PMID- 22500895 TI - Incremental truncation of PHA synthases results in altered product specificity. AB - PHA synthase is the key enzyme involved in the biosynthesis of microbial polymers, polyhydroxyalkanoates (PHA). In this study, we created a hybrid library of PHA synthase gene with different crossover points by an incremental truncation method between the C-terminal fragments of the phaC(Cn) (phaC from Cupriavidus necator) and the N-terminal fragments of the phaC1(Pa) (phaC from Pseudomonas aeruginosa). As the truncation of the hybrid enzyme increased, the in vivo PHB synthesis ability of the hybrids declined gradually. PHA synthase PhaC(Cn) with a deletion on N-terminal up to 83 amino acid residues showed no synthase activity. While with the removal of up to 270 amino acids from the N-terminus, the activity of the truncated PhaC(Cn) could be complemented by the N-terminus of PhaC1(Pa). Three of the hybrid enzymes W188, W235 and W272 (named by the deleted nucleic acid number) were found to have altered product specificities. PMID- 22500896 TI - Application of anoxia with glucose addition for the enhanced production of hCTLA4Ig in transgenic rice suspension cell cultures. AB - To enhance the production of hCTLA4Ig in transgenic rice suspension cell cultures, anoxic conditions were applied during the production phase. Under the anoxic conditions in sugar-depleted media, cell viability was reduced rapidly and protease activity increased compared to aerobic conditions. However, the maximum production level of hCTLA4Ig with sugar-depleted anoxic conditions was the same as that in aerobic conditions. In addition, the production of hCTLA4Ig under anoxic conditions reached a peak 2 days earlier than that in aerobic conditions. Addition of 30 mM glucose at the production phase under anoxic conditions markedly improved cell viability. A viability level over 65% could be maintained for more than 30 days. Repression of the RAmy3D promoter by residual sugar in the production of hCTLA4Ig was not observed under anoxic conditions with 30 mM glucose. In addition, the production periods of hCTLA4Ig was extended up to 30 days and the maximum production level of hCTLA4Ig under anoxic conditions was 2.1 fold higher. Therefore, anoxic conditions could be used for the enhanced production of hCTLA4Ig in transgenic rice cell cultures. PMID- 22500897 TI - Hydrolytic potential of Trichoderma sp. strains evaluated by microplate-based screening followed by switchgrass saccharification. AB - Bioconversion of lignocellulosic biomass to fuel requires a hydrolysis step to obtain fermentable sugars, generally accomplished by fungal enzymes. Large-scale screening of different microbial strains would provide optimal enzyme cocktails for any target feedstock. The aim of this study was to screen a large collection of Trichoderma sp. strains for the hydrolytic potential towards switchgrass (Panicum virgatum L.). Strains were cultivated in a small-scale system and assayed in micro-plates for xylanase and cellulase activities. The population distributions of these traits are reported after growth on switchgrass in comparison with cellulose. The distribution profiles suggest that the growth on switchgrass strongly promotes xylanase production. The IK4 strain displayed the highest xylanase activity after growth on switchgrass (133U/mL). Enzymes (10FPU/g substrate) from IK4 were compared with those from 2 cellulolytic Trichoderma strains and a commercial enzyme in saccharification time-course experiments on untreated and pretreated switchgrass and on an artificial substrate. Samples were analysed by DNS assay and by an oxygraphic method for sugar equivalent or glucose concentration. On the untreated substrate, IK4 enzymes even outperformed a 5-fold load of commercial enzyme, suggesting that xylanase or accessory enzymes are a limiting factor on this type of recalcitrant substrate. On the other substrates, IK4 preparations showed intermediate behaviour if compared with the commercial enzyme at 10FPU/g substrate and at 5-fold load. IK4 also nearly halved the time to release 50% of the hydrolysable sugar equivalents (T(50%)), with respect to the other preparations at the same enzymatic load. DNS assay and oxygraphic method gave highly correlated results for the 3 saccharified substrates. The study suggests that accessory enzymes like xylanase play a key role in improving the performance of cellulase preparations on herbaceous lignocellulosic feedstocks like switchgrass. PMID- 22500898 TI - Promoting pellet growth of Trichoderma reesei Rut C30 by surfactants for easy separation and enhanced cellulase production. AB - It is desirable to modify the normally filamentous Trichoderma reesei Rut C-30 to a pellet form, for easy biomass separation from the fermentation medium containing soluble products (e.g., cellulase). It was found in this study that this morphological modification could be successfully achieved by addition of the biosurfactant rhamnolipid (at >= 0.3g/L) and the synthetic Triton X-100 (at >= 0.1g/L) to the fermentation broth before the cells started to grow actively. Thirteen other surfactants tested were not as effective. Furthermore, the added rhamnolipid and Triton X-100 increased the maximum cellulase activity (Filter Paper Units) produced in the fungal fermentation; the increase was 68 +/- 7.8% for rhamnolipid and 73 +/- 12% for Triton X-100. At the concentrations required for pellet formation, rhamnolipid had negative effect on the cell growth: with increasing rhamnolipid concentrations, the growth rate decreased and the lag phase duration increased linearly. Triton X-100 caused no significant differences in growth rate or lag phase. PMID- 22500899 TI - Oxytetracycline biosynthesis improvement in Streptomyces rimosus following duplication of minimal PKS genes. AB - Oxytetracycline (OTC) is a widely used antibiotic, which is commercially produced by Streptomyces rimosus. The type II minimal polyketide synthases (minimal PKS) genes of the oxytetracycline biosynthesis cluster in S. rimosus, consisting of oxyA, oxyB and oxyC, are involved in catalyzing 19-C chain building by the condensation of eight malonyl-CoA groups to form the starting polyketide. This study aimed to investigate the effects of overexpression of the minimal PKS gene in a model S. rimosus strain (M4018) and in an industrial overproducer (SR16) by introduction of a second copy of the gene into the chromosome. Increased levels of oxyA, oxyB and oxyC gene transcription were monitored using reverse transcription quantitative real-time PCR. Overexpression of the minimal PKS gene elicited retardation of cell growth and a significant improvement in OTC production in corresponding mutants (approximately 51.2% and 32.9% in M4018 and SR16 mutants respectively). These data indicate that the minimal PKS plays an important role in carbon flux redirection from cell growth pathways to OTC biosynthesis pathways. PMID- 22500900 TI - High-throughput screening of B factor saturation mutated Rhizomucor miehei lipase thermostability based on synthetic reaction. AB - Conventional lipase screening methods are mostly based on hydrolytic activity, which may not always be the best method to assess the enzyme activity, especially for evaluating synthetic activity. Here we developed a high throughput and visual method to screen clones with high synthetic activity and used it to assess lipases thermostability. All mutants' lipase synthetic activity were identified through esterification of caprylic acid and ethanol with methyl red as the pH indicator adding in the substrates on according to the color change halo around the colony on culture plates since synthetic reaction was often accompanied with a rise in pH. After two rounds operation with the pH indicator screening method, we obtained a double mutant Asn120Lys/Lys131Phe from the Rhizomucor miehei lipase saturation mutated library based on amino acid residue B factors. The mutant's initial synthetic activity was a little higher than wild type and its thermostability in synthetic reaction was enhanced, which remained 63.1% residual activity after being heated at 70 degrees C for 5h comparing to 51.0% of wild type. The double mutant with the two residue replacements balanced well between stability and activity. Yeast surface display technology and the pH indicator method, combined with colony screening were shown to facilitate high-throughput screening for lipase synthetic activity. PMID- 22500901 TI - Immobilisation and characterisation of biocatalytic co-factor recycling enzymes, glucose dehydrogenase and NADH oxidase, on aldehyde functional ReSynTM polymer microspheres. AB - The use of enzymes in industrial applications is limited by their instability, cost and difficulty in their recovery and re-use. Immobilisation is a technique which has been shown to alleviate these limitations in biocatalysis. Here we describe the immobilisation of two biocatalytically relevant co-factor recycling enzymes, glucose dehydrogenase (GDH) and NADH oxidase (NOD) on aldehyde functional ReSynTM polymer microspheres with varying functional group densities. The successful immobilisation of the enzymes on this new high capacity microsphere technology resulted in the maintenance of activity of ~40% for GDH and a maximum of 15.4% for NOD. The microsphere variant with highest functional group density of ~3500 MUmol g-1 displayed the highest specific activity for the immobilisation of both enzymes at 33.22 U mg-1 and 6.75 U mg-1 for GDH and NOD with respective loading capacities of 51% (0.51 mg mg-1) and 129% (1.29 mg mg-1). The immobilised GDH further displayed improved activity in the acidic pH range. Both enzymes displayed improved pH and thermal stability with the most pronounced thermal stability for GDH displayed on ReSynTM A during temperature incubation at 65 degrees C with a 13.59 fold increase, and NOD with a 2.25-fold improvement at 45 degrees C on the same microsphere variant. An important finding is the suitability of the microspheres for stabilisation of the multimeric protein GDH. PMID- 22500902 TI - Enhancing the value of nitrogen from rapeseed meal for microbial oil production. AB - Rapeseed meal, a major byproduct of biodiesel production, has been used as a low cost raw material for the production of a generic microbial feedstock through a consolidated bioconversion process. Various strategies were tested for the production of a novel fermentation medium, rich in free amino nitrogen (FAN): commercial enzymes (CEs) (2.7 mg g-1 dry meal), liquid state fungal pre-treatment (LSF) using Aspergillus oryzae (4.6 mg g-1), liquid state fungal pre-treatment followed by fungal autolysis (LSFA) (9.13 mg g-1), liquid state pre-treatment using fungal enzymatic broth (EB) (2.1 mg g-1), but the best strategy was a solid state fungal pre-treatment followed by fungal autolysis (34.5 mg g-1). The bioavailability of the nitrogen sources in the novel medium was confirmed in fed batch bioreactor studies, in which 82.3g dry cell L-1 of the oleaginous yeast Rhodosporidium toruloides Y4 was obtained with a lipid content of 48%. The dry cell weight obtained was higher than that obtained using conventional yeast extract, due to a higher total nitrogen content in the novel biomedium. The fatty acids obtained from the microbial oil were similar to those derived from rapeseed oil. PMID- 22500903 TI - Repeated fermentation from raw starch using Saccharomyces cerevisiae displaying both glucoamylase and alpha-amylase. AB - A diploid yeast strain displaying both alpha-amylase and glucoamylase was developed for repeated fermentation from raw starch. First, the construct of alpha-amylase was optimized for cell surface display, as there have been no reports of alpha-amylase-displaying yeast. The modified yeast displaying both glucoamylase and alpha-amylase produced 46.5 g/l of ethanol from 200 g/l of raw corn starch after 120 h of fermentation, and this was 1.5-fold higher when compared to native alpha-amylase-displaying yeast. Using the glucoamylase and modified alpha-amylase co-displaying diploid strain, we repeated fermentation from 100g/l of raw starch for 23 cycles without the loss of alpha-amylase or glucoamylase activity. The average ethanol productivity and yield during repeated fermentation were 1.61 g/l/h and 76.6% of the theoretical yield, respectively. This novel yeast may be useful for reducing the cost of bio-ethanol production and may be suitable for industrial-scale bio-ethanol production. PMID- 22500904 TI - Delivery of growth factors for tissue regeneration and wound healing. AB - Growth factors are soluble secreted proteins capable of affecting a variety of cellular processes important for tissue regeneration. Consequently, the self healing capacity of patients can be augmented by artificially enhancing one or more processes important for healing through the application of growth factors. However, their application in clinics remains limited due to lack of robust delivery systems and biomaterial carriers. Interestingly, all clinically approved therapies involving growth factors utilize some sort of a biomaterial carrier for growth factor delivery. This suggests that biomaterial delivery systems are extremely important for successful usage of growth factors in regenerative medicine. This review outlines the role of growth factors in tissue regeneration, and their application in both pre-clinical animal models of regeneration and clinical trials is discussed. Additionally, current status of biomaterial substrates and sophisticated delivery systems such as nanoparticles for delivery of exogenous growth factors and peptides in humans are reviewed. Finally, issues and possible future research directions for growth factor therapy in regenerative medicine are discussed. PMID- 22500905 TI - Discogenic low back pain - is there an ideal treatment strategy? PMID- 22500906 TI - Preoperative anxiety in surgical patients - experience of a single unit. AB - OBJECTIVES: Preoperative anxiety has a significant effect on the outcome of anesthesia and surgery. At present, there is no published data on the preoperative anxiety levels in Sri Lankan patients. In the West, several validated questionnaires such as The Amsterdam Preoperative Anxiety and Information Scale (APAIS) and State Trait Anxiety Inventory (STAI) are used. To measure the preoperative anxiety levels in patients using APAIS and to analyze the factors affecting anxiety and the role played by the anesthetist in allaying anxiety. METHODS: One hundred patients scheduled for elective surgery were prospectively studied using the APAIS. The internal consistency was checked using Cronbach's alpha. RESULTS: The ages varied 25 to 72 years (mean=48.7 years, SD=13.6). Reliability of the APAIS was high; Cronbach's alpha=0.864 in the overall component and 0.84, 0.73 and 0.97 in the anxiety related to surgery, anesthesia and in the information desire components, respectively. Females were more anxious than males (p=0.02) and those who had never sustained surgery were more anxious than those who previously had surgery (p=0.05). An anesthetist's visit and premedication reduced total anxiety scores (Z=-3.07, p=0.002) and anesthesia related anxiety scores (Z=-3.45, p=0.001). CONCLUSIONS: The prevalence of anxiety is high among Sri Lankan patients. Females are more anxious than males and those who have never had surgery are more anxious than those who have had surgery. The anesthetist's visit could reduce anxiety. Sinhala version of the APAIS is highly reliable in assessing the preoperative anxiety levels. PMID- 22500907 TI - Direct endotracheal intubation using a novel detachable optic probe (Sunscope) by emergency medical technicians with various training backgrounds. AB - OBJECTIVE: Effective airway management requires both proper technique and the appropriate devices. With the widespread implementation of advanced life-support techniques in emergency medical services (EMS), orotracheal intubation is now performed not only by professional practitioners but, in many occasions, nonprofessionals. With extensively diversified skill equipped, we tested whether the Sunscope, a patented tracheal intubation device with a digital display, is able to facilitate tracheal intubation by naive EMS personnel with various training backgrounds. METHODS: We conducted a study to determine rate of success and time required to insert an orotracheal tube into a mannequin using Sunscope. The participants were placed into the professional group (i.e., anesthesiologists and emergency medical paramedics; EMT-P) or the nonprofessional group (i.e., emergency medical technicians; EMT). Intubation required three steps: equipment preparation, vocal cord exposure, and tube insertion. The time required for each step was recorded by a senior staff member, and the data were analyzed by nonparametric statistics. RESULTS: Each consecutive step in the operating procedure was significantly shorter for the professional group in comparison with the nonprofessional group during the first trial: equipment preparation, 10.5 +/- 2.1 vs. 11.9 +/- 4.1 seconds; vocal cord exposure, 7.4 +/- 7.7 vs. 12.2 +/- 7.7 seconds; tube insertion, 8.8 +/- 4.8 vs. 17.6 +/- 9.4 seconds; and total time required for intubation, 26.7 +/- 8.8 vs. 35.8 +/- 19.6 seconds. The professional practitioners showed no significant improvement, in terms of time reduction, on the following three trials. On the other hand, the nonprofessional practitioners showed no significant differences, in terms of time required to expose the vocal cords and total operation time, following the third trial in comparison with the professional practitioners. CONCLUSION: Our research demonstrates that professional practitioners are able to use the Sunscope on their first attempt. Despite a lack of training in conventional endotracheal intubation, emergency medical technicians (EMT-I and -II) were able to complete intubation on their first attempt; a significant reduction in the time required to intubate was noted after repeated practice. All levels of naive EMTs were able to readily visualize the vocal cords through Sunscope and, thereby, reliably insert the endotracheal tube in less than 1 minute, regardless of their skills before testing. PMID- 22500908 TI - Poincare plot indexes of heart rate variability detect dynamic autonomic modulation during general anesthesia induction. AB - PURPOSE: Beat-to-beat heart rate variability (HRV) is caused by the fluctuating balance of sympathetic and parasympathetic tone. The Poincare plot has been used to evaluate HRV. In this study, we validate that this new method may qualitatively and quantitatively assess the sympathovagal fluctuation in patients during induction of anesthesia with sevoflurane. METHODS: Twenty-eight young patients were allocated for the study. The patients received a tilt test and on the next day they sustained anesthesia induced with inhaled anesthetics. Electrocardiography signals from the patients were relayed to an analogue-digital converter. The Poincare plot is quantified by measuring SD1, SD2, and SD1/SD2. Power spectral analyses were performed and LF, HF and HF/LF were calculated. RESULTS: The LF power and the SD2 of the Poincare plot increased while subjects were tilt-up from the supine position. Additionally, a significant correlation were found between LF and SD2, HF and SD1 (p < 0.05), and LF/HF and SD2/SD1 (p < 0.01). Sevoflurane inhalation for 10 minutes had no effect on heart rate, but diminished LF, total power and SD1, SD2 of the Poincare plot respectively. However, the LF, SD2 and LF/HF increased; the HF, SD1 and SD1/SD2 ratio decreased after intubation stimulation. CONCLUSION: Poincare plot and power spectral analysis of HRV during tilt test and sevoflurane induction significantly correlate. Poincare plot analysis is easier and more sensitive at evaluating the sympathovagal balance and observing the beat-to-beat HRV. PMID- 22500909 TI - Comparison of postoperative analgesic effect of intrathecal magnesium and fentanyl added to bupivacaine in patients undergoing lower limb orthopedic surgery. AB - OBJECTIVE: To compare the analgesic efficacy and side effects of magnesium and fentanyl as an additive to intrathecal bupivacaine. METHODS: Ninety adult patients scheduled for femur surgery under spinal anesthesia were randomly allocated to one of the following three groups to receive intrathecally: bupivacaine 15 mg combined with 0.5 mL magnesium 10%; bupivacaine 15 mg combined with 0.5 mL fentanyl; or bupivacaine 15 mg combined with 0.5 mL distilled water (control). The time to first analgesic request, sensory and motor blockade onset time, duration of sensory and motor blockade, analgesic requirement in the first 12 hours after surgery, and the incidences of hypotension, bradycardia, hypoxemia and ephedrine were recorded. RESULTS: Magnesium caused a significant delay in the onset of both sensory and motor blockade compared with the fentanyl (95% CI 3 to 4; p < 0.001) and control (95% CI 3.5-5; p < 0.001) groups. The duration of spinal analgesia in group F (fentanyl) was significantly greater than in group C (control) (95% CI 365-513; p < 0.001) and group M (magnesium) (95% CI 385-523; p < 0.001). The total amount of methadone consumption over 12 hours was significantly lower in the magnesium and fentanyl groups than in the control group (5 mg vs. 5.666 +/- 1.728 mg; p = 0.04). CONCLUSION: Addition of intrathecal magnesium sulfate to spinal anesthesia induced by bupivacaine significantly prolonged the onset of both sensory and motor blockade compared with fentanyl. Although magnesium failed to prolong the time to first analgesic requirement as seen with fentanyl, it reduced the total consumption of opioids in the first 12 hours postoperatively compared with the control group. PMID- 22500910 TI - Percutaneous intradiscal treatments for discogenic pain. AB - Severe discogenic pain including axial or radicular pain is not easy to treat properly. Although mechanical correction was made possible to some extent, the high incidence of failed back surgery syndrome frustrates both patients and physicians. For discogenic pain, like other disorders, pain management is the discipline of intervention, principally with the application of certain techniques, such as intradiscal electrothermal therapy, nucleoplasty, Dekompressor and targeted disc decompression (TDD). These techniques are simple to use, have low complication rates and seem to be effective. The goals of interventional pain management include decrease the frequency and intensity of the pain, increase daily activities, quality of life, enhancement of coping skills and lowering narcotic use and/or other pain medications. PMID- 22500911 TI - Review of interscalene block for postoperative analgesia after shoulder surgery in obese patients. AB - In recent years, the prevalence of obesity has significantly increased in developed countries, a trend that has been just as apparent in France as elsewhere. Obesity may predispose to osteoarthritis, which may subject a high percentage of patients to shoulder surgery. Interscalene block remains one of the most efficient technique for postoperative analgesia after shoulder surgery. However, there are no specific guidelines or discussions in the literature about the use and management of interscalene block for obese patients. No study has yet specifically assessed obesity relative to interscalene block. Regional anesthesia offers certain advantages in obese patients: minimal airway intervention, improved postoperative analgesia, and decreased opioid consumption. In obese patients undergoing shoulder surgery, the goal of postoperative pain management is to provide comfort, early mobilization, and improved respiratory function without the worry of inadequate sedation and respiratory compromise. The ongoing debate on the relevance of obesity, for example in terms of obstructive sleep apnea syndrome, obesity hypoventilation syndrome, and other related respiratory disturbances, in relation to the choice of analgesic techniques, especially interscalene block, patient-controlled intravenous analgesia and patient monitoring, demands large-scale, well-designed studies to resolve it. Nevertheless, obesity per se should not dissuade patients from undergoing shoulder surgery under interscalene block. PMID- 22500912 TI - Anesthetic breathing circuit obstruction mimicking severe bronchospasm: an unusual manufacturing defect. AB - We report an unexpected ventilation difficulty with an anesthetic breathing circuit in a pediatric patient receiving left herniorrhaphy. A manufacturing defect in a limb of the anesthetic breathing circuit caused this problem. This defect induced a high-pitched, wheezing-like sound, which was difficult to differentiate from a hyper-reactive airway, commonly seen in pediatric patients with recent upper respiratory tract infection. We recommend that the patency of the anesthetic breathing circuit should routinely be examined before connecting it to the anesthesia machine. PMID- 22500913 TI - Early recognition of an entrapped pulmonary artery catheter by blood leaking into the syringe and thermistor connector during cardiac surgery. AB - An 84-year-old male was scheduled for coronary artery bypass graft surgery under general anesthesia. During cardiopulmonary bypass, the leakage of blood into the syringe being used for balloon inflation and the thermistor connector of the pulmonary artery catheter (PAC) was detected. Resistance was encountered when trying to withdraw the PAC. A surgical suture of the right atrium cannulation was stitched to PAC and was immediately released. Early detection of surgical damage to PAC and recognition of the entrapped PAC by gently withdrawing it avoided possible life-threatening complications, including pulmonary air embolism, and the inevitable of resternotomy. Transesophageal echocardiography, chest radiography, and fluoroscopy can help confirm any postoperative surgical damage following closure of the sternum or while in the intensive care unit. PMID- 22500914 TI - Development of acute ischemic stroke in a patient with acute respiratory distress syndrome (ARDS) resulting from H1N1 pneumonia. AB - Pneumonia due to H1N1 infection is now very common. We report a case of ischemic stroke which arose subsequently to H1N1 influenza. The patient was a female who developed acute respiratory distress syndrome (ARDS) after H1N1 influenza, was ventilated as per standard protocol and started treatment with oseltamivir. When sedation was stopped during weaning from the ventilator, she was found to have left hemiparesis resulting from multiple infarctions in the brain. Contrary to thrombocytosis usually seen in acute influenza, the platelet counts in our patient actually dropped. We suspected that increased interleukin release or stickiness of the platelets might have caused this ischemic stroke. In the course of time, she had acceptable neurological recovery following treatment with aspirin and neuro-rehabilitation. This case report provides evidence that a rare, debilitating complication like stroke can occur in H1N1 infection. A high index of suspicion of the probability of a cerebrovascular event should be borne in mind and regular neurological assessment should be done in such cases. PMID- 22500915 TI - Fitness of three Fusarium pathogens of wheat. AB - Crown rot and head blight of wheat are caused by the same Fusarium species. To better understand their biology, this study has compared 30 isolates of the three dominant species using 13 pathogenic and saprophytic fitness measures including aggressiveness for the two diseases, saprophytic growth and fecundity and deoxynivalenol (DON) production from saprophytic colonization of grain and straw. Pathogenic fitness was generally linked to DON production in infected tissue. The superior crown rot fitness of Fusarium pseudograminearum was linked to high DON production in the stem base tissue, while Fusarium culmorum and Fusarium graminearum had superior head blight fitness with high DON production in grains. Within each species, some isolates had similar aggressiveness for both diseases but differed in DON production in infected tissue to indicate that more than one mechanism controlled aggressiveness. All three species produced more DON when infecting living host tissue compared with saprophytic colonization of grain or straw, but there were significant links between these saprophytic fitness components and aggressiveness. As necrotrophic pathogens spend a part of their life cycle on dead organic matter, saprophytic fitness is an important component of their overall fitness. Any management strategy must target weaknesses in both pathogenic fitness and saprophytic fitness. PMID- 22500916 TI - A medium-controlled fluorescence dual-responsive probe for Cu2+ and Hg2+ in aqueous solutions. AB - In this study, we report a histidine-based fluorescence probe for Cu(2+) and Hg(2+), in which the amino group and imino group were modified by two common protective groups, 9-fluorenylmethoxycarbonyl and trityl group, respectively. In a water/methanol mixed solution, the probe displayed a selective fluorescence "turn-off" response to Cu(2+) when the ratio of CH(3)OH/H(2)O was higher than 1:1. Specifically, when the solvent is changed to 1:1 methanol/water, the 304 nm fluorescence peak is enhanced, while the 317 nm peak is weakened, upon addition of either Cu(2+) or Hg(2+) ions. The mechanism for such distinct responses of the probe to Cu(2+) and Hg(2+) was further clarified by using NMR and molecular simulation. The experiment results indicated that the polarity of solvent could influence the coordination mode of 1 with Cu(2+) and Hg(2+), and control the fluorescence response as a "turn-off" or ratiometric probe. PMID- 22500917 TI - Engaging basic scientists in translational research: identifying opportunities, overcoming obstacles. AB - This report is based on the Federation of American Societies for Experimental Biology's symposium, "Engaging basic Scientists in Translational Research: Identifying Opportunities, Overcoming Obstacles," held in Chevy Chase, MD, March 24-25, 2011. Meeting participants examined the benefits of engaging basic scientists in translational research, the challenges to their participation in translational research, and the roles that research institutions, funding organizations, professional societies, and scientific publishers can play to address these challenges. PMID- 22500918 TI - A novel method to delivery stem cells to the injured heart: spatially focused magnetic targeting strategy. PMID- 22500919 TI - A contingency perspective on team learning and innovation in nursing. AB - AIMS: To report a correlational study of the relation between team learning activities and implementation-effectiveness of innovations in nursing teams. BACKGROUND: Non-compliance to implementation of innovations is a problem in nursing teams. In the literature, team learning is proposed as a facilitator for change. Still, studies reporting the effects of team learning activities on the implementation of innovations in nursing teams are scarce. To address this gap in the literature, this study explored the influence of team learning on the implementation of two innovations. DESIGN: A cross-sectional survey. METHODS: The survey was conducted in 2008-2009 with a sample of 469 nurses, representing 30 nursing teams from The Netherlands and Belgium. The relationship between variables representing team learning and the use and the knowledge of an incremental (n = 14) or a radical innovation (n = 16) was examined by correlation and multiple regression analyses. RESULTS: Correlation analyses revealed positive relationships between the team learning activities handling production-oriented information and implementation-effectiveness of an incremental innovation. In addition, team learning activities about development-oriented information positively affected the implementation of a radical innovation. Multiple regression yielded models that explain 83% of the variance on the use of an incremental variable, 73% on knowledge of a radical innovation, and 80% on use of a radical innovation. CONCLUSION: In nursing teams, team learning activities that relate to the production of nursing care affect the implementation of an incremental innovation. The implementation of a radical innovation is effected by team learning activities that relate to the development of the provided nursing care. PMID- 22500920 TI - Comparative pharmacokinetic study of two mycophenolate mofetil formulations in stable kidney transplant recipients. AB - We compared steady-state pharmacokinetics of mycophenolate mofetil (MMF) - Myfenax((r)) (Teva) and CellCept((r)) (Roche) - in stable kidney transplant recipients (KTRs). This was an international, multi-centre, randomized, open label, two-treatment, two-sequence crossover study with a 3-month follow-up. We included KTRs at least 12 months post-transplantation with stable renal graft function for at least 3 months. The maintenance treatment consisted of MMF in combination with tacrolimus with or without steroids. At the end of the two treatment periods, 6-h or 12-h PK studies of mycophenolic acid (MPA) were performed. A total of 43 patients (mean age: 50.7 +/- 13.5 years; 19 females, 24 males) were randomized. Estimates of test to reference ratios (90% CIs) were 0.959 (0.899; 1.023) h*MUg/ml for AUC((0-tau)) and 0.873 (0.787; 0.968) MUg/ml for C(max). Estimates for AUC((0-6h)) were 0.923 (0.865; 0.984) h*MUg/ml and 0.985 (0.877; 1.106) MUg/ml for C(min). Thus, AUC((0-tau)), AUC((0-6h)), and C(min) of MPA were within the predefined margins. C(max) was somewhat outside of these margins in this set of patients. The numbers and types of adverse events were not different between the two treatments. The steady-state pharmacokinetics of MPA as well as adverse events are comparable for Myfenax((r)) and CellCept((r)) in tacrolimus-treated stable KTRs. PMID- 22500921 TI - Marketing HIV prevention for heterosexually identified Latino men who have sex with men and women: the Hombres Sanos campaign. AB - This article describes the development process of Hombres Sanos, a social marketing campaign to promote HIV testing and condom use for heterosexually identified Latino men who have sex with men and women. The steps included qualitative formative research and a social marketing analytic framework to understand our target audience better, identify incentives and barriers to risk reduction, guide product development, define an optimal promotional campaign, and inform the selection of campaign platforms. A better grasp of the authors' target beneficiaries' needs and values led to an innovative dual strategy for audience segmentation and targeting. The campaign had consumer-centered, culturally sensitive, and theory-driven communication materials. The authors found communication materials and events to be appealing and effective. The campaign was well received among the wider community, and evaluation showed promising results among Latino men in general and among heterosexually identified Latino men who have sex with men and women in particular. The authors provide a step-by step overview of the project's formative research, including research methods and findings, and how these were translated into a social marketing campaign. In addition, the authors discuss the challenges encountered in this process and the potential of social marketing to reduce HIV risk among Latinos. PMID- 22500922 TI - The evolution of Dscam genes across the arthropods. AB - BACKGROUND: One way of creating phenotypic diversity is through alternative splicing of precursor mRNAs. A gene that has evolved a hypervariable form is Down syndrome cell adhesion molecule (Dscam-hv), which in Drosophila melanogaster can produce thousands of isoforms via mutually exclusive alternative splicing. The extracellular region of this protein is encoded by three variable exon clusters, each containing multiple exon variants. The protein is vital for neuronal wiring where the extreme variability at the somatic level is required for axonal guidance, and it plays a role in immunity where the variability has been hypothesised to relate to recognition of different antigens. Dscam-hv has been found across the Pancrustacea. Additionally, three paralogous non-hypervariable Dscam-like genes have also been described for D. melanogaster. Here we took a bioinformatics approach, building profile Hidden Markov Models to search across species for putative orthologs to the Dscam genes and for hypervariable alternatively spliced exons, and inferring the phylogenetic relationships among them. Our aims were to examine whether Dscam orthologs exist outside the Bilateria, whether the origin of Dscam-hv could lie outside the Pancrustacea, when the Dscam-like orthologs arose, how many alternatively spliced exons of each exon cluster were present in the most common recent ancestor, and how these clusters evolved. RESULTS: Our results suggest that the origin of Dscam genes may lie after the split between the Cnidaria and the Bilateria and supports the hypothesis that Dscam-hv originated in the common ancestor of the Pancrustacea. Our phylogeny of Dscam gene family members shows six well-supported clades: five containing Dscam-like genes and one containing all the Dscam-hv genes, a seventh clade contains arachnid putative Dscam genes. Furthermore, the exon clusters appear to have experienced different evolutionary histories. CONCLUSIONS: Dscam genes have undergone independent duplication events in the insects and in an arachnid genome, which adds to the more well-known tandem duplications that have taken place within Dscam-hv genes. Therefore, two forms of gene expansion seem to be active within this gene family. The evolutionary history of this dynamic gene family will be further unfolded as genomes of species from more disparate groups become available. PMID- 22500923 TI - Genetic and environmental influences of white and gray matter signal contrast: a new phenotype for imaging genetics? AB - The estimation of cortical thickness is in part dependent on the degree of contrast in T1 signal intensity between white matter and gray matter along the cortical mantle. The ratio of white matter to gray matter signal (WM/GM contrast) has been found to vary as a function of age and Alzheimer's disease status, suggesting a biological component to what might otherwise be labeled as a nuisance variable. The aim of the present study was to determine if measures of WM/GM contrast are genetically influenced, as well as the degree to which this phenotype may be related to the genetic and environment determinants of cortical thickness. Participants were 514 male twins (130 monozygotic, 97 dizygotic pairs, and 60 unpaired individuals) from the Vietnam Era Twin Study of Aging. Ages ranged from 51 to 59 years. Measures of WM/GM contrast and cortical thickness were derived for 66 cortical regions of interest (ROI) using FreeSurfer-based methods. Univariate and bivariate twin analyses were used in order to estimate the heritability of WM/GM contrast, as well as the degree of shared genetic and environmental variance between WM/GM contrast and cortical thickness. WM/GM contrast was found to be significantly heritable in the majority of ROIs. The average heritability across individual ROIs was highest in the occipital lobe (.50), and lowest in the cingulate cortex (.24). Significant phenotypic correlations between WM/GM contrast and cortical thickness were observed for most of the ROIs. The majority of the phenotypic correlations were negative, ranging from ?.11 to ?.54. Of the 66 associations, only 17 significant genetic correlations were found, ranging from ?.16 to ?.34, indicating small amounts of shared genetic variance. The majority of the phenotypic correlations were accounted for by small unique environmental effects common between WM/GM contrast and cortical thickness. These findings demonstrate that like cortical thickness, WM/GM contrast is a genetically influenced brain structure phenotype. The lack of significant genetic correlations with cortical thickness suggests that this measure potentially represents a unique source of genetic variance, one that has yet to be explored by the field of imaging genetics. PMID- 22500924 TI - Multi-atlas multi-shape segmentation of fetal brain MRI for volumetric and morphometric analysis of ventriculomegaly. AB - The recent development of motion robust super-resolution fetal brain MRI holds out the potential for dramatic new advances in volumetric and morphometric analysis. Volumetric analysis based on volumetric and morphometric biomarkers of the developing fetal brain must include segmentation. Automatic segmentation of fetal brain MRI is challenging, however, due to the highly variable size and shape of the developing brain; possible structural abnormalities; and the relatively poor resolution of fetal MRI scans. To overcome these limitations, we present a novel, constrained, multi-atlas, multi-shape automatic segmentation method that specifically addresses the challenge of segmenting multiple structures with similar intensity values in subjects with strong anatomic variability. Accordingly, we have applied this method to shape segmentation of normal, dilated, or fused lateral ventricles for quantitative analysis of ventriculomegaly (VM), which is a pivotal finding in the earliest stages of fetal brain development, and warrants further investigation. Utilizing these innovative techniques, we introduce novel volumetric and morphometric biomarkers of VM comparing these values to those that are generated by standard methods of VM analysis, i.e., by measuring the ventricular atrial diameter (AD) on manually selected sections of 2D ultrasound or 2D MRI. To this end, we studied 25 normal and abnormal fetuses in the gestation age (GA) range of 19 to 39 weeks (mean=28.26, stdev=6.56). This heterogeneous dataset was essentially used to 1) validate our segmentation method for normal and abnormal ventricles; and 2) show that the proposed biomarkers may provide improved detection of VM as compared to the AD measurement. PMID- 22500925 TI - Multiple imputation of missing fMRI data in whole brain analysis. AB - Whole brain fMRI analyses rarely include the entire brain because of missing data that result from data acquisition limits and susceptibility artifact, in particular. This missing data problem is typically addressed by omitting voxels from analysis, which may exclude brain regions that are of theoretical interest and increase the potential for Type II error at cortical boundaries or Type I error when spatial thresholds are used to establish significance. Imputation could significantly expand statistical map coverage, increase power, and enhance interpretations of fMRI results. We examined multiple imputation for group level analyses of missing fMRI data using methods that leverage the spatial information in fMRI datasets for both real and simulated data. Available case analysis, neighbor replacement, and regression based imputation approaches were compared in a general linear model framework to determine the extent to which these methods quantitatively (effect size) and qualitatively (spatial coverage) increased the sensitivity of group analyses. In both real and simulated data analysis, multiple imputation provided 1) variance that was most similar to estimates for voxels with no missing data, 2) fewer false positive errors in comparison to mean replacement, and 3) fewer false negative errors in comparison to available case analysis. Compared to the standard analysis approach of omitting voxels with missing data, imputation methods increased brain coverage in this study by 35% (from 33,323 to 45,071 voxels). In addition, multiple imputation increased the size of significant clusters by 58% and number of significant clusters across statistical thresholds, compared to the standard voxel omission approach. While neighbor replacement produced similar results, we recommend multiple imputation because it uses an informed sampling distribution to deal with missing data across subjects that can include neighbor values and other predictors. Multiple imputation is anticipated to be particularly useful for 1) large fMRI data sets with inconsistent missing voxels across subjects and 2) addressing the problem of increased artifact at ultra-high field, which significantly limit the extent of whole brain coverage and interpretations of results. PMID- 22500927 TI - CIK cells--current status, clinical perspectives and future prospects--the good news. PMID- 22500928 TI - A theoretical reassessment of microbial maintenance and implications for microbial ecology modeling. AB - We attempted to reconcile three microbial maintenance models (Herbert, Pirt, and Compromise) through a theoretical reassessment. We provided a rigorous proof that the true growth yield coefficient (Y(G)) is the ratio of the specific maintenance rate (a in Herbert) to the maintenance coefficient (m in Pirt). Other findings from this study include: (1) the Compromise model is identical to the Herbert for computing microbial growth and substrate consumption, but it expresses the dependence of maintenance on both microbial biomass and substrate; (2) the maximum specific growth rate in the Herbert (MU(max,H)) is higher than those in the other two models (MU(max,P) and MU(max,C)), and the difference is the physiological maintenance factor (m(q) = a); and (3) the overall maintenance coefficient (m(T)) is more sensitive to m(q) than to the specific growth rate (MU(G)) and Y(G). Our critical reassessment of microbial maintenance provides a new approach for quantifying some important components in soil microbial ecology models. PMID- 22500926 TI - Deficits in axonal transport in hippocampal-based circuitry and the visual pathway in APP knock-out animals witnessed by manganese enhanced MRI. AB - Mounting evidence implicates axonal transport defects, typified by the presence of axonal varicosities with aberrant accumulations of cargo, as an early event in Alzheimer's disease (AD) pathogenesis. Work identifying amyloid precursor protein (APP) as a vesicular motor receptor for anterograde axonal transport further implicates axonal transport in AD. Manganese-enhanced MRI (MEMRI) detects axonal transport dynamics in preclinical studies. Here we pursue an understanding of the role of APP in axonal transport in the central nervous system by applying MEMRI to hippocampal circuitry and to the visual pathway in living mice homozygous for either wild type or a deletion in the APP gene (n=12 for each genotype). Following intra-ocular or stereotaxic hippocampal injection, we performed time lapse MRI to detect Mn(2+) transport. Three dimensional whole brain datasets were compared on a voxel-wise basis using within-group pair-wise analysis. Quantification of transport to structures connected to injection sites via axonal fiber tracts was also performed. Histology confirmed consistent placement of hippocampal injections and no observable difference in glial-response to the injections. APP-/- mice had significantly reduced transport from the hippocampus to the septal nuclei and amygdala after 7h and reduced transport to the contralateral hippocampus after 25 h; axonal transport deficits in the APP-/- animals were also identified in the visual pathway. These data support a system wide role for APP in axonal transport within the central nervous system and demonstrate the power of MEMRI for assessing neuronal circuitry involved in memory and learning. PMID- 22500929 TI - Asymptomatic intracardiac mass in a 14-year-old girl with granulomatosis with polyangiitis: Case report. AB - Granulomatosis with polyangiitis (GPA; Wegener's granulomatosis) is a systemic necrotizing vasculitis of unknown etiology that commonly involves the upper airways, lungs, and kidneys. Cardiac involvement with an intracardiac mass is an exceedingly rare manifestation of this disease, especially in the pediatric population where, to our knowledge, only one article exists to date that has described such a finding. In this report, we present the case of an adolescent female who initially presented with renal failure and an intracardiac mass. Subsequent work-up led to a diagnosis of granulomatosis with polyangiitis (GPA). Cardiac manifestations in pediatric GPA are not common; however, they may be more prevalent than reported given recent adult literature and concern for clinically silent abnormalities. PMID- 22500930 TI - Methyl effects on protein-ligand binding. AB - The effects of addition of a methyl group to a lead compound on biological activity are examined. A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is found with an 8% frequency, and a 100 fold boost is a 1 in 200 event. Four cases in the latter category are analyzed in depth to elucidate any unusual aspects of the protein-ligand binding, distribution of water molecules, and changes in conformational energetics. The analyses include Monte Carlo/free-energy perturbation (MC/FEP) calculations for methyl replacements in inhibitor series for p38alpha MAP kinase, ACK1, PTP1B, and thrombin. Methyl substitutions ortho to an aryl ring can be particularly effective at improving activity by inducing a propitious conformational change. The greatest improvements in activity arise from coupling the conformational gain with the burial of the methyl group in a hydrophobic region of the protein. PMID- 22500931 TI - Uncontrolled donation after cardiac death: potential for future. PMID- 22500932 TI - Characterization of Malassezia microbiota in the human external auditory canal and on the sole of the foot. AB - Of the fungal skin microbiota, the lipophilic yeast genus Malassezia predominates at all body sites. Of the members of this genus, M. globosa, M. restricta, and M. sympodialis are the most common on the face, limbs, and trunk. In the present study, the Malassezia microbiotas in the external auditory canal and on the sole of the foot were characterized. M. slooffiae was the most common species in both the external auditory canal and on the sole of the foot, followed by M. restricta. Principal component analysis further revealed that the Malassezia microbiota in the external auditory canal and on the sole of the foot constitute a different cluster from those on the scalp and cheek and in the nasal cavity. Additionally, five new Malassezia phylotypes were detected on the sole of the foot and in the external auditory canal. Our results suggest that a distinctive Malassezia microbiota is present in the external auditory canal and on the sole of the foot, although the clinical significance of this finding remains unknown. PMID- 22500933 TI - Genetic analysis of multiple antimicrobial resistance in Salmonella isolated from diseased broilers in Egypt. AB - To date, no information has been available on the molecular bases of antimicrobial resistance in Salmonella spp. from poultry in Egypt or even in Africa. Therefore, the objective of this study was to analyze, at the molecular level, the mechanisms of multidrug-resistance in isolates of Salmonella recovered from diseased broilers in Egypt. Twenty-one Salmonella isolates were identified; 13 of these isolates were Salmonella enterica serovar Enteritidis and eight Salmonella enterica serovar Typhimurium. 17 (81%). Salmonella isolates displayed multidrug resistance phenotypes, particularly against ampicillin, streptomycin, spectinomycin, kanamycin, tetracycline, chloramphenicol, and trimethoprim/sulfamethoxazole. PCR and DNA sequencing identified class 1 integrons in nine (42.9%) isolates and class 2 integrons in three (14.3%) isolates. The identified resistance genes within class 1 integrons were aminoglycoside adenyltransferase type A, aadA1, aadA2 and aadA5 and dihydrofolate reductase type A, dfrA1, dfrA5, dfrA12, dfrA15 and dfrA17. The beta-lactamase encoding genes bla(TEM-1) and bla(CMY-2) and florfenicol resistance gene floR were also identified. Furthermore, the tetracycline resistance gene tet(A) was identified in 14 (66.7%) Salmonella isolates. To the best of our knowledge, this is the first report of the molecular basis of antimicrobial resistance in Salmonella spp. isolated from poultry in Africa. PMID- 22500934 TI - Phylogenetic analyses of pandemic influenza A (H1N1) virus in university students at Tobetsu, Hokkaido, Japan. AB - Pandemic influenza H1N1 virus (A[H1N1]pdm09) emerged in 2009. To determine the phylogeography of A(H1N1)pdm09 in a single population, 70 strains of the virus were isolated from university students or trainee doctors at Tobetsu, Hokkaido, Japan, between September and December 2009. The nucleotide sequences of the HA1 region of the HA genes and described phylogenetic relationships of the strains circulating among them were analyzed. It was found that the 70 isolates could be phylogenetically separated into three groups and that two epidemics were caused by different groups of the virus. The three groups were also distinguishable from each other by three amino acid changes: A197T, S203T and Q293H. The substitution of S203T, which is located in the antigenic site, suggests antigenic drift of the virus. PMID- 22500935 TI - The vomeronasal chemosensory pathway: a potential route for neuroinvasion by neurotropic microbes. PMID- 22500940 TI - A Gaijin-like miniature inverted repeat transposable element is mobilized in rice during cell differentiation. AB - BACKGROUND: Miniature inverted repeat transposable element (MITE) is one type of transposable element (TE), which is largely found in eukaryotic genomes and involved in a wide variety of biological events. However, only few MITEs were proved to be currently active and their physiological function remains largely unknown. RESULTS: We found that the amplicon discrepancy of a gene locus LOC_Os01g0420 in different rice cultivar genomes was resulted from the existence of a member of Gaijin-like MITEs (mGing). This result indicated that mGing transposition was occurred at this gene locus. By using a modified transposon display (TD) analysis, the active transpositions of mGing were detected in rice Jiahua No. 1 genome under three conditions: in seedlings germinated from the seeds received a high dose gamma-ray irradiation, in plantlets regenerated from anther-derived calli and from scutellum-derived calli, and were confirmed by PCR validation and sequencing. Sequence analysis revealed that single nucleotide polymorphisms (SNPs) or short additional DNA sequences at transposition sites post mGing transposition. It suggested that sequence modification was possibly taken place during mGing transposition. Furthermore, cell re-differentiation experiment showed that active transpositions of both mGing and mPing (another well studied MITE) were identified only in regenerated plantlets. CONCLUSIONS: It is for the first time that mGing active transposition was demonstrated under gamma-ray irradiation or in cell re-differentiation process in rice. This newly identified active MITE will provide a foundation for further analysis of the roles of MITEs in biological process. PMID- 22500941 TI - Airborne isocyanate exposures in the collision repair industry and a comparison to occupational exposure limits. AB - Isocyanate exposure was evaluated in 33 spray painters from 25 Washington State autobody shops. Personal breathing zone samples (n = 228) were analyzed for isophorone diisocyanate (IPDI) monomer, 1,6-hexamethylene diisocyanate (HDI) monomer, IPDI polyisocyanate, and three polyisocyanate forms of HDI. The objective was to describe exposures to isocyanates while spray painting, compare them with short-term exposure limits (STELs), and describe the isocyanate composition in the samples. The composition of polyisocyanates (IPDI and HDI) in the samples varied greatly, with maximum amounts ranging from up to 58% for HDI biuret to 96% for HDI isocyanurate. There was a significant inverse relationship between the percentage composition of HDI isocyanurate to IPDI and to HDI uretdione. Two 15-min STELs were compared: (1) Oregon's Occupational Safety and Health Administration (OR-OSHA) STEL of 1000 MUg/m(3) for HDI polyisocyanate, and (2) the United Kingdom's Health and Safety Executive (UK-HSE) STEL of 70 MUg NCO/m(3) for all isocyanates. Eighty percent of samples containing HDI polyisocyanate exceeded the OR-OSHA STEL while 98% of samples exceeded the UK-HSE STEL. The majority of painters (67%) wore half-face air-purifying respirators while spray painting. Using the OR-OSHA and the UK-HSE STELs as benchmarks, 21% and 67% of painters, respectively, had at least one exposure that exceeded the respirator's OSHA-assigned protection factor. A critical review of the STELs revealed the following limitations: (1) the OR-OSHA STEL does not include all polyisocyanates, and (2) the UK-HSE STEL is derived from monomeric isocyanates, whereas the species present in typical spray coatings are polyisocyanates. In conclusion, the variable mixtures of isocyanates used by autobody painters suggest that an occupational exposure limit is required that includes all polyisocyanates. Despite the limitations of the STELs, we determined that a respirator with an assigned protection factor of 25 or greater is required to protect against isocyanate exposures during spray painting. Consequently, half face air-purifying respirators, which are most commonly used and have an assigned protection factor of 10, do not afford adequate respiratory protection. PMID- 22500942 TI - Association of OPRD1 polymorphisms with heroin dependence in a large case-control series. AB - Genes encoding the opioid receptors (OPRM1, OPRD1 and OPRK1) are obvious candidates for involvement in risk for heroin dependence. Prior association studies commonly had samples of modest size, included limited single nucleotide polymorphism (SNP) coverage of these genes and yielded inconsistent results. Participants for the current investigation included 1459 heroin-dependent cases ascertained from maintenance clinics in New South Wales, Australia, 1495 unrelated individuals selected from an Australian sample of twins and siblings as not meeting DSM-IV criteria for lifetime alcohol or illicit drug dependence (non dependent controls) and 531 controls ascertained from economically disadvantaged neighborhoods in proximity to the maintenance clinics. A total of 136 OPRM1, OPRD1 and OPRK1 SNPs were genotyped in this sample. After controlling for admixture with principal components analysis, our comparison of cases to non dependent controls found four OPRD1 SNPs in fairly high linkage disequilibrium for which adjusted P values remained significant (e.g. rs2236857; OR 1.25; P=2.95*10(-4) ) replicating a previously reported association. A post hoc analysis revealed that the two SNP (rs2236857 and rs581111) GA haplotype in OPRD1 is associated with greater risk (OR 1.68; P=1.41*10(-5) ). No OPRM1 or OPRK1 SNPs reached more than nominal significance. Comparisons of cases to neighborhood controls reached only nominal significance. Our results replicate a prior report providing strong evidence implicating OPRD1 SNPs and, in particular, the two SNP (rs2236857 and rs581111) GA haplotype in liability for heroin dependence. Support was not found for similar association involving either OPRM1 or OPRK1 SNPs. PMID- 22500944 TI - Diverse and highly active diazotrophic assemblages inhabit ephemerally wetted soils of the Antarctic Dry Valleys. AB - Eolian transport of biomass from ephemerally wetted soils, associated with summer glacial meltwater runoffs and lake edges, to low-productivity areas of the Antarctic Dry Valleys (DV) has been postulated to be an important source of organic matter (fixed nitrogen and fixed carbon) to the entire DV ecosystem. However, descriptions and identification of the microbial members responsible for N(2) fixation within these wetted sites are limited. In this study, N(2) fixers from wetted soils were identified by direct nifH gene sequencing and their in situ N(2) fixation activities documented via acetylene reduction and RNA-based quantitative PCR assays. Shannon-index nifH diversity levels ranged between 1.8 and 2.6 and included the expected cyanobacterial signatures and a large number of phylotypes related to the gamma-, beta-, alpha-, and delta-proteobacteria. N(2) fixation rates ranged between approximately 0.5 and 6 nmol N cm(-3) h(-1) with measurements indicating that approximately 50% of this activity was linked with sulfate reduction at some sites. Comparisons with proximal dry soils also suggested that these communities are not ubiquitously distributed, and conditions unrelated to moisture content may define the composition, diversity, or habitat suitability of the microbial communities within wetted soils of the DVs. PMID- 22500945 TI - Implementing noninvasive prenatal fetal sex determination using cell-free fetal DNA in the United Kingdom. AB - INTRODUCTION: Fetal sex determination has traditionally been performed in pregnancies at risk of sex-linked genetic conditions by analysis of chorionic villi or amniocytes following invasive tests. The development of noninvasive prenatal diagnosis (NIPD) using cell-free fetal DNA in maternal plasma has allowed women to have accurate information about fetal sex early in pregnancy without the risk of miscarriage. AREAS COVERED: In the UK, NIPD for fetal sex determination has been offered on a research basis since 2003. Formal approval and regulation through national bodies is essential to ensure standardized laboratory services, appropriate funding and equity of access for service users. Here we describe the process of formal commissioning that has been supported by a multifaceted approach to service evaluation, including appraisal of analytical and clinical validity, clinical utility and economic costs together with an exploration of service users' and providers' attitudes, preferences and information needs. EXPERT OPINION: Implementation strategies that reach beyond the assessment of laboratory test parameters to consider psychosocial and economic issues have been crucial in bringing NIPD for fetal sex determination into routine practice. Ongoing audit and monitoring of service delivery will ensure a high standard of care is maintained. PMID- 22500943 TI - Shedding light on bioluminescence regulation in Vibrio fischeri. AB - The bioluminescence emitted by the marine bacterium Vibrio fischeri is a particularly striking result of individual microbial cells co-ordinating a group behaviour. The genes responsible for light production are principally regulated by the LuxR-LuxI quorum-sensing system. In addition to LuxR-LuxI, numerous other genetic elements and environmental conditions control bioluminescence production. Efforts to mathematically model the LuxR-LuxI system are providing insight into the dynamics of this autoinduction behaviour. The Hawaiian squid Euprymna scolopes forms a natural symbiosis with V. fischeri, and utilizes the symbiont derived bioluminescence for certain nocturnal behaviours, such as counterillumination. Recent work suggests that the tissue with which V. fischeri associates not only can detect bioluminescence but may also use this light to monitor the V. fischeri population. PMID- 22500946 TI - Shape effect on nanoparticle solvation: a comparison of morphometric thermodynamics and microscopic theories. AB - Conventional wisdom for controlling the nanoparticle size and shape during synthesis is that particle growth favors the direction of a facet with the highest surface energy. However, the particle solvation free energy, which dictates the particle stability and growth, depends not only on the surface area and surface free energy but also on other geometric measures such as the solvent excluded volume and the surface curvature and their affiliated thermodynamic properties. In this work, we study the geometrical effects on the solvation free energies of nonspherical nanoparticles using morphometric thermodynamics and density functional theories. For idealized systems that account for only molecular excluded-volume interactions, morphometric thermodynamics yields a reliable solvation free energy when the particle size is significantly larger than the solvent correlation length. However, noticeable deviations can be identified in comparison to the microscopic theories for predicting the solvation free energies of small nanoparticles. This conclusion also holds for predicting the potential of mean force underlying the colloidal "key-and-lock" interactions. Complementary to the microscopic theories, morphometric thermodynamics requires negligible computational cost, therefore making it very appealing for a broad range of practical applications. PMID- 22500947 TI - Graphene-supported SnO2 nanoparticles prepared by a solvothermal approach for an enhanced electrochemical performance in lithium-ion batteries. AB - SnO2 nanoparticles were dispersed on graphene nanosheets through a solvothermal approach using ethylene glycol as the solvent. The uniform distribution of SnO2 nanoparticles on graphene nanosheets has been confirmed by scanning electron microscopy and transmission electron microscopy. The particle size of SnO2 was determined to be around 5 nm. The as-synthesized SnO2/graphene nanocomposite exhibited an enhanced electrochemical performance in lithium-ion batteries, compared with bare graphene nanosheets and bare SnO2 nanoparticles. The SnO2/graphene nanocomposite electrode delivered a reversible lithium storage capacity of 830 mAh g-1 and a stable cyclability up to 100 cycles. The excellent electrochemical properties of this graphene-supported nanocomposite could be attributed to the insertion of nanoparticles between graphene nanolayers and the optimized nanoparticles distribution on graphene nanosheets. PMID- 22500948 TI - Consistency of extended-release niacin/laropiprant effects on Lp(a), ApoB, non HDL-C, Apo A1, and ApoB/ApoA1 ratio across patient subgroups. AB - BACKGROUND: According to prior analyses, extended-release niacin/laropiprant (ERN/LRPT) consistently reduces low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) and increases high-density lipoprotein cholesterol (HDL-C) levels across a wide range of dyslipidemic patient subgroups. OBJECTIVES: This analysis examined ERN/LRPT's consistency across four phase III, randomized, double-blind trials in improving other lipid/lipoprotein parameters associated with cardiovascular risk, across several key dyslipidemic patient subgroups. METHODS: In three of the studies, the randomized population included patients with primary hypercholesterolemia or mixed hyperlipidemia; in the remaining study, the population included patients with type 2 diabetes mellitus. The lipid altering consistency of ERN/LRPT's efficacy was evaluated versus the pre-defined comparator (placebo or active control) among key subgroups of sex, race (White, non-White), region (US, ex-US), baseline age (<65 years, >=65 years), use of statin therapy (yes, no), coronary heart disease (yes, no), risk status (low, multiple, high), and type of hyperlipidemia (primary hypercholesterolemia, mixed dyslipidemia), as well as across baseline LDL-C, HDL-C, and TG levels. The consistency of the treatment effects on lipoprotein(a).[Lp(a)], apolipoprotein B (ApoB), non-HDL-C, ApoA1, and ApoB/ApoA1 ratio was evaluated by examining treatment difference estimates of the percentage change from baseline with 95% confidence intervals. RESULTS: Treatment with ERN/LRPT produced significantly greater improvements in Lp(a), ApoB, non-HDL-C, ApoA1, and ApoB/ApoA1 ratio compared with placebo/active comparator in each study. These effects were generally consistent across key subgroups within each study. CONCLUSION: ERN/LRPT produced lipid-altering efficacy on the parameters evaluated in four controlled studies; these effects were generally consistent across all examined subgroups. ERN/LRPT represents an effective and reliable therapeutic option for the treatment of dyslipidemia in a wide range of patient types. CLINICAL TRIAL REGISTRATION: Registered as Clinicaltrials.gov NCT00269204, NCT00269217, NCT00479388, and NCT00485758. PMID- 22500949 TI - Quantitative analysis of diagnostic guidelines for HER2-status assessment. AB - Human epidermal growth factor receptor 2 (HER2, alias ERBB2)-targeted therapy in breast and gastric cancers depends on the reliable assessment of HER2 protein expression and (in equivocal cases) the quantitative evaluation of HER2 gene amplification. Typically, HER2 and centromere 17 gene copy numbers are evaluated using in situ hybridization (ISH) to calculate ratios for which cutoff values dividing nonamplified and amplified cases have been proposed. Although several studies have investigated how laboratory procedures affect diagnostics, a rigorous quantitative assessment of the diagnostic guidelines for data analysis is still missing. Here, we analyze the dependence of the diagnosed HER2/chromosome 17 ratios on i) sample size (evaluated cells), ii) gene/chromosome signal distributions, and iii) the approach used for quotient calculation using Monte Carlo simulations. Our data show that the current recommendation may lead to statistical HER2/CHR17 ratio variations of up to 0.94 and may therefore lead to incorrect HER2 status diagnoses, given the ratio threshold of 2.0 defined by the Food and Drug Administration. Moreover, borderline cases may receive different amplification diagnoses, depending on the ratio calculation approach: Brightfield-silver ISH with aggregated signal counts may underestimate the HER2/CHR17 ratio compared with two-color fluorescence ISH. Our results provide a basis for quantitative rationales behind HER2 diagnostic guidelines that call for increased numbers of evaluated cells and emphasize the importance of well-designed data analysis methods in diagnostic pathology, especially for predictive clinical application. PMID- 22500950 TI - Dendritic cell therapies in transplantation revisited: deletion of recipient DCs deters the effect of therapeutic DCs. AB - A critical goal in transplantation is the achievement of donor-specific tolerance, minimizing the use of immunosuppressants. Dendritic cells (DCs) are antigen (Ag) presenting cells (APCs) with capability to promote immunity or tolerance. The immune-regulatory properties of DCs have been exploited for generation of tolerogenic/immunosuppressive (IS) DCs that, when transfer systemically, prolong allograft survival in murine models. Surprisingly, the in vivo mechanisms of therapies based on (donor- or recipient-derived) ISDCs in transplantation remain unknown, given that previous studies investigated their effects in vitro, or ex vivo after transplantation. Since once injected, ISDCs are short-lived and transfer Ag to recipient APCs, we assessed the role of recipient DCs by depleting them at the time of ISDC-therapy in a mouse model of cardiac transplantation. The results indicate that, contrary to the accepted paradigm, systemically administered ISDCs reduce the alloresponse and prolong allograft survival, not by themselves, but through conventional DCs (cDCs) of the recipient. These findings raise doubts on the advantages of the currently used ISDC-therapies, since the immune-regulatory properties of the injected ISDC do not seem to be functionally relevant in vivo, and the quiescent/pro-tolerogenic status of cDCs may be compromised in patients with end-stage diseases that require transplantation. PMID- 22500951 TI - Submicron particle monitoring of paving and related road construction operations. AB - This study identified activities and sources that contribute to ultrafine and other submicron particle exposure that could trigger respiratory symptoms in highway repair workers. Submicron particle monitoring was conducted for paving, milling, and pothole repair operations in a major metropolitan area where several highway repair workers were identified as symptomatic for respiratory illness following exposures at the 2001 World Trade Center disaster site. Exposure assessments were conducted for eight trades involved in road construction using a TSI P-Trak portable condensation particle counter. Direct readings near the workers' breathing zones and observations of activities and potential sources were logged on 7 days on 27 workers using four different models of pavers and two types of millers. Average worker exposure levels ranged from 2 to 3 times background during paving and from 1 to 4 times background during milling. During asphalt paving, average personal exposures to submicron particulates were 25,000 60,000, 28,000-70,000, and 23,000-37,000 particles/ cm(3) for paver operators, screed operators, and rakers, respectively. Average personal exposures during milling were 19,000-111,000, 28,000-81,000, and 19,000 particles/cm(3) for the large miller operators, miller screed operators, and raker, respectively. Personal peak exposures were measured up to 467,000 and 455,000 particles/cm(3) in paving and milling, respectively. Several sources of submicron particles were identified. These included the diesel and electric fired screed heaters; engine exhaust from diesel powered construction vehicles passing by or idling; raking, dumping, and paving of asphalt; exhaust from the hotbox heater; pavement dust or fumes from milling operations, especially when the large miller started and stopped; and secondhand cigarette smoke. To reduce the potential for health effects in workers, over 40 recommendations were made to control exposures, including improved maintenance of paver ventilation systems; diesel fume engineering controls; reduced idling; provision of cabs for the operators; and improved dust suppression systems on the milling machine. PMID- 22500952 TI - Gibbsiella dentisursi sp. nov., isolated from the bear oral cavity. AB - A Gram-negative, rod-shaped, non-spore forming and non-motile bacterium, designated strain NUM 1720(T) , was isolated from the oral cavity of bears. Based on 16S rRNA gene sequence similarity, strain NUM 1720(T) was shown to be related to Gibbsiella quercinecans (99.4%). The gyrB and rpoB gene sequences of strain NUM 1720T showed 98.0% and 98.2% similarity with those of G. quercinecans. The DNA-DNA hybridization value of strain NUM 1720(T) with G. quercinecans was 63.8%. The G + C content of the genomic DNA of the isolates was 55.0 mol%. Fatty acid analysis data supported the affiliation of strain NUM 1720(T) to the genus Gibbsiella. The major menaquinone and ubiquinone were MK-8 and Q-8, respectively. Strain NUM 1720(T) can be differed from G. quercinecans by the reactions to acetoin, inositol and D-arabinose. Strain NUM 1720(T) therefore represents a novel species, for which the name Gibbsiella dentisursi sp. nov. is proposed, with type strain NUM 1720(T) (= JCM 17201(T) = DSM 23818(T)). PMID- 22500953 TI - Understanding mechanisms of vitiligo development in Smyth line of chickens by transcriptomic microarray analysis of evolving autoimmune lesions. AB - BACKGROUND: The Smyth line (SL) of chicken is an excellent avian model for human autoimmune vitiligo. The etiology of vitiligo is complicated and far from clear. In order to better understand critical components leading to vitiligo development, cDNA microarray technology was used to compare gene expression profiles in the target tissue (the growing feather) of SL chickens at different vitiligo (SLV) states. RESULTS: Compared to the reference sample, which was from Brown line chickens (the parental control), 395, 522, 524 and 526 out of the 44 k genes were differentially expressed (DE) (P <= 0.05) in feather samples collected from SL chickens that never developed SLV (NV), from SLV chickens prior to SLV onset (EV), during active loss of pigmentation (AV), and after complete loss of melanocytes (CV). Comparisons of gene expression levels within SL samples (NV, EV, AV and CV) revealed 206 DE genes, which could be categorized into immune system-, melanocyte-, stress-, and apoptosis-related genes based on the biological functions of their corresponding proteins. The autoimmune nature of SLV was supported by predominant presence of immune system related DE genes and their remarkably elevated expression in AV samples compared to NV, EV and/or CV samples. Melanocyte loss was confirmed by decreased expression of genes for melanocyte related proteins in AV and CV samples compared to NV and EV samples. In addition, SLV development was also accompanied by altered expression of genes associated with disturbed redox status and apoptosis. Ingenuity Pathway Analysis of DE genes provided functional interpretations involving but not limited to innate and adaptive immune response, oxidative stress and cell death. CONCLUSIONS: The microarray results provided comprehensive information at the transcriptome level supporting the multifactorial etiology of vitiligo, where together with apparent inflammatory/innate immune activity and oxidative stress, the adaptive immune response plays a predominant role in melanocyte loss. PMID- 22500954 TI - Discovery of novel 1,2,4-thiadiazole derivatives as potent, orally active agonists of sphingosine 1-phosphate receptor subtype 1 (S1P(1)). AB - A novel series of 1,2,4-thiadiazole compounds was discovered as selective S1P(1) agonists. The extensive structure-activity relationship studies for these analogues were reported. Among them, 17g was identified to show high in vitro potency with reasonable free unbound fraction in plasma (F(u) > 0.5%), good brain penetration (BBR > 0.5), and desirable pharmacokinetic properties in mouse and rat. Oral administration of 1 mg/kg 17g resulted in significant peripheral lymphocytes reduction at 4 h after dose and rapid lymphocytes recovery at 24 h. 17g showed a transient lymphopenia profile in the repeated dose study in mouse. In addition, 17g also demonstrated efficacy comparable to that of FTY720 (1) in the mouse EAE model of MS. PMID- 22500956 TI - [Herbal medicine may only be a scientific medicine]. PMID- 22500955 TI - Binge-like ethanol consumption increases corticosterone levels and neurodegneration whereas occupancy of type II glucocorticoid receptors with mifepristone is neuroprotective. AB - Excessive ethanol (EtOH) use leads to impaired memory and cognition. Using a rat model of binge-like intoxication, we tested whether elevated corticosterone (Cort) levels contribute to the neurotoxic consequences of EtOH exposure. Rats were adrenalectomized (Adx) and implanted with cholesterol pellets, or cholesterol pellets containing Cort in order to achieve basal, medium, or high blood concentrations of Cort. Intragastric EtOH or an isocaloric control solution was given three times daily for 4 days to achieve blood alcohol levels ranging between 200 and 350 mg/dl. Mean 24-hour plasma levels of Cort were ~110 and ~40 ng/ml in intact EtOH-treated and intact control animals, respectively. Basal Cort replacement concentrations in EtOH-treated Adx animals did not exacerbate alcohol induced neurodegeneration in the hippocampal dentate gyrus (DG) or the entorhinal cortex (EC) as observed by amino-cupric silver staining. In contrast, Cort replacement pellets resulting in plasma Cort levels twofold higher (medium) than normal, or greater than twofold higher (high) in Adx-Cort-EtOH animals increased neurodegeneration. In separate experiments, pharmacological blockade of the Type II glucocorticoid (GC) receptor was initiated with mifepristone (RU38486; 0, 5, 15 mg/kg/day, i.p.). At the higher dose, mifepristone decreased the number of degenerating hippocampal DG cells in binge-EtOH-treated intact animals, whereas, only a trend for reduction was observed in 15 mg/kg/day mifepristone-treated animals in the EC, as determined by fluoro-jade B staining. These results suggest that elevated circulating Cort in part mediates EtOH-induced neurotoxicity in the brain through activation of Type II GC receptors. PMID- 22500957 TI - [Opportunities for medication errors and pharmacist's interventions in the context of computerized prescription order entry: a review of data published by French hospital pharmacists]. AB - INTRODUCTION: Computerized prescription order entry (CPOE) is accelerating in France. CPOE has been shown to reduce the occurrence of some medication errors, but evidence of a beneficial effect on clinical outcomes remains limited. In some cases, new error types have arisen with its use. The aim of this study was to investigate the French data on the nature and frequency of medication errors opportunities generated by the computer use, which led pharmacists to alert prescribers. METHODS: We performed a search on PubMed and CAT-INIST databases completed by a manual one. RESULTS: Ten publications, 11 abstracts and three personal communications were analysed. As part of the analysis of computerized prescriptions, the rate of pharmaceutical interventions due to CPOE ranges from 5.9 to 35% depending on the study. Duplicate orders, unit errors, the use of free text, parameterization flaws and poor usability of software are probably the root of many prescribing errors. Errors generated by the tool can have serious potential consequences. DISCUSSION: Pharmacist's interventions due to CPOE are common. It is not known whether variability of the percentage of pharmacist's interventions is due to software used or to conditions by witch studies were carried out. With implementation of CPOE in hospital, pharmacists must acquire new knowledge and new skills in order to prevent prescription errors generated by these tools and its misuse. CONCLUSION: Studies are urgently needed in order to identify the safest tools and to discard the most dangerous. PMID- 22500958 TI - [Stable iodine as a prophylaxis therapy following exposure to radioactive iodines: pharmacological and pharmaceutical characteristics]. AB - More or less rapid radio-induction of thyroidian cancers is the main pathological consequence of an accidental exposure to ingested or inhaled radioactive iodines following a nuclear power plant accident. The prophylactic administration of potassium iodine in a single oral dose has to be practiced as soon as possible after the nuclear accident. The efficacy of this therapy depends on pharmacokinetics of radioidines. Iodines are rapidly and completely absorbed as iodides. The radioactive iodines, mainly iodine 131, concentrate in the thyroid gland because of a carrier-mediated transport by the Na-I symporter. Administration of stable iodine results in the symporter blockade, which limits the uptake of radioactive iodines by the thyroid and the duration of the internal irradiation. This irradiation will never exceed 3days if the therapy is started between 6h before the accidental exposure and 1h after. The pharmacist asked to dispense the tablets of stable iodine has a important place because, besides his advices on the optimal modalities of taking stable iodine and the risks of unwanted effects, he extend these advices to information on the radioactive risk and on measures of civil and sanitary protection. PMID- 22500959 TI - The development and implementation of pharmaceutical care across borders. AB - The community pharmacist is an essential professional for a high standard healthcare delivery system. However, many indicators, at the EU level or national level, suggest that the tasks entrusted to him, since the beginning of the 20th century, must ensure a safe and efficient treatment to patient. In several member states, the legislation has recently been changed and community pharmacists in Europe have redefined their role in the healthcare delivery system in order to focus more on patients' care. In France, the new reform concerning hospitals and the report on community pharmacy, written by social inspectors for the government, in some aspects, contains propositions similar to those adopted in Canada. PMID- 22500960 TI - Stability study of amiodarone hydrochloride in capsules for paediatric patients using a high-performance liquid chromatography method. AB - Amiodarone hydrochloride, a class III antiarrhythmic agent, shows beta blocker like and potassium channel blocker-like actions on the sinuatrial and atrioventricular nodes. It is given by mouth in the treatment of all forms of atrial, junctional and ventricular arrhythmias. Capsules for paediatric patients are not commercially available and must be prepared in the pharmacy department. The aim of the study was to evaluate the stability of amiodarone hydrochloride at different dosages, 10, 60 and 100 mg, in capsules for paediatric patients stored in three packages under dark conditions and at room temperatures over one year. At different intervals during the storage period, amiodarone hydrochloride concentration was tested using a high-performance liquid chromatography (HPLC) method. Amiodarone hydrochloride content remained greater than 95% of the initial concentration in all capsules at all dosages. The 10, 60 and 100 mg amiodarone paediatric capsules were stable for one year when stored in the three packages at ambient temperature and under dark conditions. PMID- 22500961 TI - [Prioritization of healthcare programs by pharmacy students from France and from Quebec, according to the perceived impact of a decentralized pharmacist]. AB - INTRODUCTION: Healthcare decision makers need to establish priorities and their decisions must be justified. However, few data is available on the prioritization process of the healthcare programs that should benefit from decentralized pharmacists. PATIENTS AND METHODS: The main objective was to prioritize healthcare programs according to the perceived impact of a decentralized pharmacist for outpatient and inpatient clienteles. The secondary objective was to compare the prioritization made by pharmacy students from two Quebec universities and from one French university. Two different approaches were developed (perceived impact according to three indicators and according to the global impact). RESULTS: The majority of healthcare programs with a high evidence based literature quality score (5/6 outpatient programs and 5/8 inpatient programs) were highly prioritized by at least two out of three cohorts. The median rank that was attributed for each healthcare program was significantly different between the three cohorts for 8/17 (47%) of outpatient programs and for 10/18 (56%) of inpatient programs. DISCUSSION: A higher rank was attributed to healthcare programs when the evidence based literature quality score was high. The prioritization was also influenced by the difference in pharmaceutical practice between France and Quebec (e.g. sterilization and medical devices in France). CONCLUSIONS: This study presented two approaches for the prioritization of healthcare programs that should benefit from a decentralized pharmacist, according to students from France and from Quebec. PMID- 22500962 TI - [Physical and chemical stability of fortified ophtalmic ready-to-use solutions: review of literature]. AB - INTRODUCTION: Ophtalmic infections and inflammations are often encountered during hospitalization. They require the preparation of "fortified" ophtalmic solutions, i.e. pharmaceutical ophtalmic solutions which are hyperconcentrated in active substance. The data of physicochemical stabilities are modified and it is therefore essential to gather the results of the various publications devoted to this subject. METHOD: In 2006, an initial literature review was undertaken to identify the molecules mostly used in the preparation of fortified ophtalmic solutions in hospital. A second review of the literature in 2010 has enriched the knowledge about it. RESULTS: Two new drugs have entered the summary table: amikacin and ticarcillin disodium. Date on 12 molecules already known in 2006 were updated to improve clinical practices. A review of the literature was undertaken in order to collect the results of the molecules mostly used for the preparation of the fortified ophtalmic solutions in hospitals. A summary table, indicating the active substance, its concentration, the assay method, the storage temperature and physicochemical modifications, presents all the results. CONCLUSION: This review of literature makes it possible to match stability and validity period to these preparations. PMID- 22500963 TI - [Anti-inflammatory activity of aqueous and ethanolic extracts of Zygophyllum gaetulum]. AB - Zygophylle or Zygophyllum gaetulum Emberger and. Maire is a Moroccan medicinal plant which has been used as an anti-inflammatory, antidiabetic, antispasmodic and antidiarrheic. The present study was carried out to study and compare the anti-inflammatory effect of ethanolic extract with aqueous extract of Z. gaetulum. Organic extract of Z. gaetulum was obtained in soxhlet apparatus. Aqueous extract was obtained by infusion. The Wistar albinos rats of either sex weighing 200-300 g aged 2-3 months were used for this experiment. The rats were housed under standard environmental conditions. The anti-inflammatory activity was estimated by measuring the oedema induced by carragenin according to the method of Winter and al. Ethanolic extract of Z. gaetulum reduced the increase of the paw volume with a percentage of inhibition of 46% (p<0.01), this percentage was 47.48% (p<0.01) with aqueous extract. The inhibition decrease in time, it arrived to 39% (p<0.01) at the sixth hour while the activity of aqueous extract decrease a lot. In conclusion, Z. gaetulum is an interesting plant which the aqueous and ethanolic extracts could be used scientifically in the treatment of inflammation. PMID- 22500966 TI - Reprogramming of carbon metabolism by the transcriptional activators AcuK and AcuM in Aspergillus nidulans. AB - The ability of fungi to use carbon sources metabolized via the TCA cycle requires gluconeogenesis. In Aspergillus nidulans the AcuK and AcuM transcription factors regulate the expression of the gluconeogenic genes acuF, encoding phosphoenolpyruvate carboxykinase, and acuG, encoding fructose-1,6 bisphosphatase. Expressed proteins containing the AcuK/AcuM N-terminal DNA binding domains bind together in vitro to motifs containing repeats of CGG separated by seven bases (CCGN7CCG) and the functionality of these sequences was verified in vivo by acuF-lacZ reporter studies. Chromatin immunoprecipitation analysis showed inter-dependent DNA binding of the proteins to the promoters of gluconeogenic genes in vivo independent of the carbon source. Deletion of the mdhC gene encoding a cytoplasmic/peroxisomal malate dehydrogenase showed that this activity is not essential for gluconeogenesis and indicated that induction of AcuK/AcuM regulated genes might result from malate accumulation. Deletion of the gene for the alternative oxidase did not affect growth on gluconeogenic carbon sources; however, expression was absolutely dependent on AcuK and AcuM. Orthologues of AcuK and AcuM, are present in a wide range of fungal taxa and the CCGN7CCG motif is present in the 5' of many genes involved in gluconeogenesis indicating a fundamental role for these transcription factors in reprogramming fungal carbon metabolism. PMID- 22500967 TI - Facile synthesis of superhydrophobic surface of ZnO nanoflakes: chemical coating and UV-induced wettability conversion. AB - This work reports an oriented growth process of two-dimensional (2D) ZnO nanoflakes on aluminum substrate through a low temperature hydrothermal technique and proposes the preliminary growth mechanism. A bionic superhydrophobic surface with excellent corrosion protection over a wide pH range in both acidic and alkaline solutions was constructed by a chemical coating treatment with stearic acid (SA) molecules on ZnO nanoflakes. It is found that the superhydrophobic surface of ZnO nanoflake arrays shows a maximum water contact angle (CA) of 157 degrees and a low sliding angle of 8 degrees , and it can be reversibly switched to its initial superhydrophilic state under ultraviolet (UV) irradiation, which is due to the UV-induced decomposition of the coated SA molecules. This study is significant for simple and inexpensive building of large-scale 2D ZnO nanoflake arrays with special wettability which can extend the applications of ZnO films to many other important fields. PMID- 22500968 TI - Plasmonic enhancement of the two photon absorption cross section of an organic chromophore using polyelectrolyte-coated gold nanorods. AB - The effect of plasmonic enhancement on the two-photon absorption cross section of organic chromophores attached to polyelectrolyte-coated gold nanorods was investigated. The magnitudes of such enhancements were confirmed using single and two photon excitations of the chromophore molecules bound to polyelectrolyte coated gold nanorods. By synthesizing two-, four-, six-, and eight polyelectrolyte layer coated nanorods of a particular aspect ratio, the distance dependence of the evanescent electromagnetic field on molecular two-photon absorption was observed. Enhancements of 40-fold were observed for the chromophores nearest to the surface. PMID- 22500969 TI - Temporary auxiliary partial orthotopic liver transplantation using a small graft for familial amyloid polyneuropathy. AB - Donor shortage is a major issue in liver transplantation. We have successfully performed temporary auxiliary partial orthotopic liver transplantation (APOLT) using a small volume graft procured from a living donor for recipients with familial amyloid polyneuropathy (FAP). The aim of this study was to evaluate this procedure by comparing it with standard living donor liver transplantation (LDLT). We compared 13 recipients undergoing this procedure with 23 recipients undergoing a standard LDLT for the treatment of FAP. The estimated donor graft volume and the graft volume/recipient's standard liver volume ratio were significantly smaller in the temporary APOLT group than in the standard LDLT group. Postoperative complications were comparable, although the hospital stay was longer in the temporary APOLT group. All the patients safely underwent a remnant native liver resection about 2 months after their first operation in the temporary APOLT group. No symptoms related to FAP developed before the remnant liver resection, and no significant differences in graft and patient survival were observed between the two groups. We successfully performed temporary APOLT using a small volume liver graft without postoperative liver failure for FAP. Temporary APOLT for FAP might be a useful alternative procedure for expanding the donor pool for LDLT. PMID- 22500971 TI - Non-invasive prenatal diagnosis of fetal aneuploidies using massively parallel sequencing-by-ligation and evidence that cell-free fetal DNA in the maternal plasma originates from cytotrophoblastic cells. AB - Blood plasma of pregnant women contains circulating cell-free fetal DNA (ccffDNA), originating from the placenta. The use of this DNA for non-invasive detection of fetal aneuploidies using massively parallel sequencing (MPS)-by synthesis has been proven previously. Sequence performance may, however, depend on the MPS platform and therefore we have explored the possibility for multiplex MPS-by-ligation, using the Applied Biosystems SOLiD(TM) 4 system. DNA isolated from plasma samples from 52 pregnant women, carrying normal or aneuploid fetuses, was sequenced in multiplex runs of 4, 8 or 16 samples simultaneously. The sequence reads were mapped to the human reference genome and quantified according to their genomic location. In case of a fetal aneuploidy, the number of reads of the aberrant chromosome is expected to be higher or lower than in normal reference samples. To statistically determine this, Z-scores per chromosome were calculated as described previously, with thresholds for aneuploidies set at > +3.0 and < -3.0 for chromosomal over- or underrepresentation, respectively. All samples from fetal aneuploidies yielded Z-scores outside the thresholds for the aberrant chromosomes, with no false negative or positive results. Full-blown fetal aneuploidies can thus be reliably detected in maternal plasma using a multiplex MPS-by-ligation approach. Furthermore, the results obtained with a sample from a pregnancy with 45,X in the cytotrophoblastic cell layer and 46,XX in the mesenchymal core cells show that ccffDNA originates from the cytotrophoblastic cell layer. Discrepancies between the genetic constitution of this cell layer and the fetus itself are well known, and therefore, care should be taken when translating results to the fetus itself. PMID- 22500972 TI - CRT 2012 welcomed former President Bill Clinton. PMID- 22500970 TI - Does lithium prevent Alzheimer's disease? AB - Lithium salts have a well-established role in the treatment of major affective disorders. More recently, experimental and clinical studies have provided evidence that lithium may also exert neuroprotective effects. In animal and cell culture models, lithium has been shown to increase neuronal viability through a combination of mechanisms that includes the inhibition of apoptosis, regulation of autophagy, increased mitochondrial function, and synthesis of neurotrophic factors. In humans, lithium treatment has been associated with humoral and structural evidence of neuroprotection, such as increased expression of anti apoptotic genes, inhibition of cellular oxidative stress, synthesis of brain derived neurotrophic factor (BDNF), cortical thickening, increased grey matter density, and hippocampal enlargement. Recent studies addressing the inhibition of glycogen synthase kinase-3 beta (GSK3B) by lithium have further suggested the modification of biological cascades that pertain to the pathophysiology of Alzheimer's disease (AD). A recent placebo-controlled clinical trial in patients with amnestic mild cognitive impairment (MCI) showed that long-term lithium treatment may actually slow the progression of cognitive and functional deficits, and also attenuate Tau hyperphosphorylation in the MCI-AD continuum. Therefore, lithium treatment may yield disease-modifying effects in AD, both by the specific modification of its pathophysiology via inhibition of overactive GSK3B, and by the unspecific provision of neurotrophic and neuroprotective support. Although the clinical evidence available so far is promising, further experimentation and replication of the evidence in large scale clinical trials is still required to assess the benefit of lithium in the treatment or prevention of cognitive decline in the elderly. PMID- 22500973 TI - Coronary stenting using the radial approach in two women with situs viscerum inversus and acute myocardial infarction. AB - A situs inversus with dextrocardia (DC) is a rare condition in adults. Usually, patients have structurally normal hearts and normal life expectancy. The incidence of coronary artery disease in this setting is similar to that in the general population. Coronary revascularization may present potential difficulties related to the unusual anatomy. Although the radial artery is a safe and effective site of access for coronary interventions, some anatomical variations may make this procedure more complicated. We describe two cases of patients with situs viscerum inversus and acute myocardial infarction who underwent successful transradial percutaneous coronary intervention (PCI). We will show that coronary angioplasty with stent application via the radial approach in patients with DC is feasible and effective also in emergency and urgent care. PMID- 22500974 TI - Evaluation of portable single-gas monitors for the detection of low levels of hydrogen sulfide and sulfur dioxide in petroleum industry environments. AB - Many portable single-gas monitors are used for the detection of low concentrations of hydrogen sulfide (H(2)S) and sulfur dioxide (SO(2)) in the workplace. With the recent lowering of the H(2)S and SO(2) ACGIH(r) threshold limit value (TLV(r)) the ability of these devices to selectively respond to these new lower levels is not well documented in petroleum industry environments, which often have potential interfering gases and vapors present as well as varying environmental conditions. Tests were carried out to measure the ability of various monitors with their respective sensors to correctly quantify and respond to H(2)S and SO(2) in a simulated petroleum industry environment. This included the identification of selected interference effects and estimation of the reliable lower limit of detection for real workplace environments. None of the H(2)S monitors responded at 0.1 times the new TLV (0.1 ppm), only some of them responded at the new TLV concentration (1 ppm), and all the monitors exposed to five times the new TLV (5 ppm) responded with reasonable accuracy. There was generally little effect of interferent gases and vapors on the H(2)S monitors. None of the SO(2) monitors responded at 0.1 and 1 times the new TLV (0.025 ppm and 0.25 ppm) concentrations, and all but one of them exposed to five times the new TLV (1.25 ppm) responded. There was much greater cross-sensitivity to interferents at the tested concentrations with the SO(2) monitors, which responded to six out of eight of the interferents tested. Results demonstrate that these monitors cannot reliably alarm and measure H(2)S or SO(2) concentrations at the new TLVs with an acceptable degree of accuracy. However, these monitors are designed to alarm as a safety device; these results do not change this important function. PMID- 22500975 TI - The biogeochemical role of Actinobacteria in Altamira Cave, Spain. AB - The walls and ceiling of Altamira Cave, northern Spain, are coated with different coloured spots (yellow, white and grey). Electron microscopy revealed that the grey spots are composed of bacteria and bioinduced CaCO(3) crystals. The morphology of the spots revealed a dense network of microorganisms organized in well-defined radial and dendritic divergent branches from the central area towards the exterior of the spot, which is coated with overlying spheroidal elements of CaCO(3) and CaCO(3) nest-like aggregates. Molecular analysis indicated that the grey spots were mainly formed by an unrecognized species of the genus Actinobacteria. CO(2) efflux measurements in rocks heavily covered by grey spots confirmed that bacteria-forming spots promoted uptake of the gas, which is abundant in the cave. The bacteria can use the captured CO(2) to dissolve the rock and subsequently generate crystals of CaCO(3) in periods of lower humidity and/or CO(2). A tentative model for the formation of these grey spots, supported by scanning electron microscopy and transmission electron microscopy data, is proposed. PMID- 22500976 TI - Cancer-associated fibroblasts from human NSCLC survive ablative doses of radiation but their invasive capacity is reduced. AB - BACKGROUND: Cancer-Associated Fibroblasts (CAFs) are significant components of solid malignancies and play central roles in cancer sustainability, invasion and metastasis. In this study we have investigated the invasive capacity and matrix remodelling properties of human lung CAFs after exposure to ablative doses of ionizing radiation (AIR), equivalent to single fractions delivered by stereotactic ablative radiotherapy (SART) for medically inoperable stage-I/II non small-cell lung cancers. METHODS: CAFs were isolated from lung tumour specimens from 16 donors. Initially, intrinsic radiosensitivity was evaluated by checking viability and extent of DNA-damage response (DDR) at different radiation doses. The migrative and invasive capacities of CAFs were thereafter determined after a sub-lethal single radiation dose of 18 Gy. To ascertain the mechanisms behind the altered invasive capacity of cells, expression of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) were measured in the conditioned media several days post-irradiation, along with expression of cell surface integrins and dynamics of focal contacts by vinculin-staining. RESULTS: Exposing CAFs to 1 * 18 Gy resulted in a potent induction of multiple nuclear DDR foci (> 9/cell) with little resolution after 120 h, induced premature cellular senescence and inhibition of the proliferative, migrative and invasive capacity. AIR promoted MMP-3 and inhibited MMP-1 appearance to some extent, but did not affect expression of other major MMPs. Furthermore, surface expression of integrins alpha2, beta1 and alpha5 was consistently enhanced, and a dramatic augmentation and redistribution of focal contacts was observed. CONCLUSIONS: Our data indicate that ablative doses of radiation exert advantageous inhibitory effects on the proliferative, migratory and invasive capacity of lung CAFs. The reduced motility of irradiated CAFs might be a consequence of stabilized focal contacts via integrins. PMID- 22500977 TI - De novo peptide design with C3a receptor agonist and antagonist activities: theoretical predictions and experimental validation. AB - Targeting the complement component 3a receptor (C3aR) with selective agonists or antagonists is believed to be a viable therapeutic option for several diseases such as stroke, heart attack, reperfusion injuries, and rheumatoid arthritis. We designed a number of agonists, partial agonists, and antagonists of C3aR using our two-stage de novo protein design framework. Of the peptides tested using a degranulation assay in C3aR-transfected rat basophilic leukemia cells, two were prominent agonists (EC(50) values of 25.3 and 66.2 nM) and two others were partial agonists (IC(50) values of 15.4 and 26.1 nM). Further testing of these lead compounds in a calcium flux assay in U937 cells yielded similar results although with reduced potencies compared to transfected cells. The partial agonists also displayed full antagonist activity when tested in a C3aR inhibition assay. In addition, the electrostatic potential profile was shown to potentially discriminate between full agonists and partial agonists. PMID- 22500978 TI - Effects of cocaine self-administration and extinction on D2 -like and A2A receptor recognition and D2 -like/Gi protein coupling in rat striatum. AB - Striatal adenosine (A)2 -dopamine (D)2 receptor (R) heteromers exist with antagonistic interactions. We have studied these Rs and their interactions during cocaine self-administration and extinction using a 'yoked' protocol to understand the role of motivational mechanisms behind the adaptive observed. In the ventral striatum, a significant increase in the A2A R density was observed in rats that received 'yoked' cocaine during maintenance phase and following its extinction while this significant increase was only observed after extinction from cocaine self-administration. In the dorsal striatum, a significant increase in the affinity of A2A Rs was determined in the two groups of rats that received cocaine during maintenance. D2 -like Rs were significantly increased in the dorsal striatum of animals that received 'yoked' cocaine during maintenance. In the rat dorsal, but not the ventral, striatum significant reductions in the EC50 values for dopamine and increases in the guanosine5'-([gamma]-thio)triphosphate (GTPgammaS) accumulation were observed following active and passive cocaine injections during maintenance. After 10-day extinction, a significant reduction of the Bmax value of GTPgammaS accumulation was demonstrated in the dorsal striatum of rats previously self-administered cocaine, while a significant reduction of the EC50 value for dopamine in the ventral striatum was found in the 'yoked' cocaine group. By comparing the cocaine self-administration group with the 'yoked' cocaine group, evidence for the existence of motivational mechanisms that guide adaptive changes in the A2A R and D2 R and in the D2 -Gi coupling differentially developed in the ventral and dorsal striatum during cocaine maintenance and its extinction has been demonstrated. PMID- 22500979 TI - Prevalence of oral mucosal lesions in an elderly population in the city of Valparaiso, Chile. AB - OBJECTIVE: Chilean population is ageing, which means an increase in the prevalence of multiple pathologies, including those located in the oral cavity. AIM: To measure the prevalence and distribution of oral mucosal lesions and to identify associated risk factors in elderly patients in the city of Valparaiso. MATERIAL AND METHODS: This study includes 126 patients over 60 years. The sample was calculated with a sampling error of 3.7% from a population size of 6000 file cards. Frequency and contingency tables were made together with odds ratios, with a confidence interval of 95%. Finally, we built a predictive model based on a binary logistic regression. RESULTS: From the whole sample, 85 patients (67.5%) had some oral mucosal lesion. The most frequent lesions were denture-induced stomatitis (37.1%). It was noted that there is a statistically significant association between the use of denture and the presence of oral candidiasis. The consumption of drugs and the use of denture increase the likelihood of having oral mucosal lesions. CONCLUSION: There is a high prevalence of oral lesions in the elderly patients of Valparaiso. The use of drugs and /or denture increases significantly the likelihood that a person over 60 years presents lesions in the oral mucosa. PMID- 22500981 TI - Portion size estimation aids for Asian foods. AB - BACKGROUND: Portion size estimation is fundamental to the accuracy of dietary recall, as well as interventions in obesity. Data on portion size estimation aids (PSEA) for Asian foods are limited. PSEA for Asian foods were developed and their accuracy and precision were tested for inclusion in a food atlas. METHODS: Sixteen food items were selected to represent all food groups. Small and life size photographs were developed, and line diagrams were drawn. These, together with household utensils, were tested among a random sample of 80 schoolchildren (aged 10-16 years). A total of 3180 estimations were made: 876 for small photographs (n = 11 foods), 558 for life size photographs (n = 7 foods), 1271 for line diagrams (n = 16 foods) and 475 for household utensils (n = 6 foods). RESULTS: Line diagrams had a high percentage (63.9%) of correct estimations and a low percentage of over estimations (18.0%) and under estimations (18.1%), whereas household utensils performed poorly with 0.6% correct estimations. Greater accuracy and precision were obtained for amorphous foods with small photographs and for non-amorphous foods with line diagrams. The combination of small photographs (for vegetables) and line diagrams (for other foods) achieved a high correlation (r = 0.959, P <= 0.001), percentage correct estimations (68.3%) and low under estimations (19.9%) and over estimations (11.8%). Food texture, but not age or sex, was associated with correct estimations in all of the PSEA, except household utensils. CONCLUSIONS: Accuracy and precision of a combination PSEA is convincing, enabling inclusion into an Asian food atlas for dietary assessment and intervention. PMID- 22500982 TI - Synthesis of monodisperse, highly cross-linked, fluorescent PMMA particles by dispersion polymerization. AB - We describe a facile method to synthesize sterically stabilized monodisperse fluorescent poly(methyl methacrylate) (PMMA) colloids in the polar solvent mixture water/methanol with either a core-shell or a homogeneously cross-linked structure by dispersion polymerization. The particles were sterically stabilized by the polymer poly(vinylpyrrolidone) (PVP). The morphology of the particles was controlled by varying the moment at which the gradual addition of cross-linker and dye was started. The absence of these extra agents at a time when the particle nuclei formed reduced the negative effects on this important process to a minimum and produced a core-shell structure, whereas an essentially homogeneously cross-linked fluorescent polymer colloid structure could be obtained by reducing the starting time of the addition of dye and cross-linker to zero. Three different dyes were chemically incorporated into the polymer network. Such dyes are important for the use of the particles in confocal scanning laser microscopy studies aimed at characterizing concentrated dispersions quantitatively in real space. A series of PMMA particles with different sizes were obtained through the variation of the weight ratio of solvents and the content of cross-linker. Furthermore, the swelling properties of the cross-linked PMMA particles in a good solvent (tetrahydrofuran) were investigated. The particles were stable in polar solvents (water and formamide) but could also successfully be transferred to apolar solvents such as decahydronaphthalene (decalin). The PVP stabilizer also allowed the particles to be permanently bonded in flexible strings by the application of an external electric field. PMID- 22500980 TI - High glucose concentrations induce TNF-alpha production through the down regulation of CD33 in primary human monocytes. AB - BACKGROUND: CD33 is a membrane receptor containing a lectin domain and a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM) that is able to inhibit cytokine production. CD33 is expressed by monocytes, and reduced expression of CD33 correlates with augmented production of inflammatory cytokines, such as IL-1beta, TNF-alpha, and IL-8. However, the role of CD33 in the inflammation associated with hyperglycemia and diabetes is unknown. Therefore, we studied CD33 expression and inflammatory cytokine secretion in freshly isolated monocytes from patients with type 2 diabetes. To evaluate the effects of hyperglycemia, monocytes from healthy donors were cultured with different glucose concentrations (15-50 mmol/l D-glucose), and CD33 expression and inflammatory cytokine production were assessed. The expression of suppressor of cytokine signaling protein-3 (SOCS-3) and the generation of reactive oxygen species (ROS) were also evaluated to address the cellular mechanisms involved in the down-regulation of CD33. RESULTS: CD33 expression was significantly decreased in monocytes from patients with type 2 diabetes, and higher levels of TNF-alpha, IL-8 and IL-12p70 were detected in the plasma of patients compared to healthy donors. Under high glucose conditions, CD33 protein and mRNA expression was significantly decreased, whereas spontaneous TNF-alpha secretion and SOCS-3 mRNA expression were increased in monocytes from healthy donors. Furthermore, the down regulation of CD33 and increase in TNF-alpha production were prevented when monocytes were treated with the antioxidant alpha-tocopherol and cultured under high glucose conditions. CONCLUSION: Our results suggest that hyperglycemia down regulates CD33 expression and triggers the spontaneous secretion of TNF-alpha by peripheral monocytes. This phenomenon involves the generation of ROS and the up regulation of SOCS-3. These observations support the importance of blood glucose control for maintaining innate immune function and suggest the participation of CD33 in the inflammatory profile associated with type 2 diabetes. PMID- 22500984 TI - Low-dose rapamycin treatment increases the ability of human regulatory T cells to inhibit transplant arteriosclerosis in vivo. AB - Regulatory T cells (T(reg)) are currently being tested in clinical trials as a potential therapy in cell and solid organ transplantation. The immunosuppressive drug rapamycin has been shown to preferentially promote T(reg) expansion. Here, we hypothesized that adjunctive rapamycin therapy might potentiate the ability of ex vivo expanded human T(reg) to inhibit vascular allograft rejection in a humanized mouse model of arterial transplantation. We studied the influence of combined treatment with low-dose rapamycin and subtherapeutic T(reg) numbers on the development of transplant arteriosclerosis (TA) in human arterial grafts transplanted into immunodeficient BALB/cRag2(-/-) Il2rg(-/-) mice reconstituted with allogeneic human peripheral blood mononuclear cell. In addition, we assessed the effects of the treatment on the proliferation and apoptosis of naive/effector T cells. The combined therapy efficiently suppressed T-cell proliferation in vivo and in vitro. Neointima formation in the human arterial allografts was potently inhibited compared with each treatment alone. Interestingly, CD4(+) but not CD8(+) T lymphocytes were sensitive to T(reg) and rapamycin-induced apoptosis in vitro. Our data support the concept that rapamycin can be used as an adjunctive therapy to improve efficacy of T(reg)-based immunosuppressive protocols in clinical practice. By inhibiting TA, T(reg) and rapamycin may prevent chronic transplant dysfunction and improve long-term allograft survival. PMID- 22500985 TI - Effects of acid on the microstructures and properties of three-dimensional TiO2 hierarchical structures by solvothermal method. AB - Three-dimensional (3D) TiO2 hierarchical structures with various microstructures have been successfully synthesized via a surfactant-free and single-step solvothermal route, in which hydrochloric acid (HCl), nitric acid (HNO3), and acetic acid (HAc) are employed as the acid medium, respectively. The effects of acid medium on the microstructures and properties of 3D TiO2 hierarchical structure have been studied. The results indicate that 3D dandelion-like microspheres assembled of radial rutile nanorods are obtained in the sample prepared with HCl. Both the fraction of rutile and the diameter of nanorod enhance with the increasing HCl concentration. For the products derived from either HNO3 or HAc, 3D spheres composed of anatase nanoparticles are present. The 3D dandelion-like TiO2 hierarchical structures show low reflectance and efficient light harvesting since this ordered rod geometry offers a light-transfer path for incident light as well as multiple reflective and scattering effects. Moreover, 3D TiO2 with this unique topology shows superior photocatalytic activity despite low surface area, which can be ascribed to the enhanced light harvesting, fast electron transport, and low electron/hole recombination loss. PMID- 22500986 TI - Pharmacoeconomics of bisphosphonates for skeletal-related event prevention in metastatic non-breast solid tumours. AB - Bisphosphonates reduce the risk of skeletal-related events (SREs; i.e. spinal cord compression, pathological fracture, radiation or surgery to the bone, and hypercalcaemia) in patients with metastatic cancer. A number of analyses have been conducted to assess the cost effectiveness of bisphosphonates in patients with bone metastases secondary to breast cancer, but few in other solid tumours. This is a review of cost-effectiveness analyses in patients with non-breast solid tumours and bone metastases. A literature search was conducted to identify cost effectiveness analyses reporting the cost per QALY gained of bisphosphonates in patients with metastatic bone disease secondary to non-breast solid tumours. Four analyses met inclusion criteria. These included two in prostate cancer (one of which used a global perspective but expressed results in $US, and the other reported from a multiple country perspective: France, Germany, Portugal and the Netherlands). The remaining analyses were in lung cancer (in the UK, France, Germany, Portugal and the Netherlands), and renal cell carcinoma (in the UK, France and Germany). In each analysis, the cost effectiveness of zoledronic acid versus placebo was analysed. Zoledronic acid was found to be cost effective in all European countries across all three indications but not in the sole global prostate cancer analysis. Across countries and indications, assumptions regarding patient survival, drug cost and baseline utility (i.e. patient utility with metastatic disease but without an SRE) were the most robust drivers of modelled estimates. Assumptions of SRE-related costs were most often the second strongest cost driver. Further review indicated that particular attention should be paid to the inclusion or exclusion of nonsignificant survival benefits, whether health state utilities were elicited from community or patient samples or author assumptions, delineation between symptomatic and asymptomatic SREs, and the methods with which SRE disutility was modelled over time. While the field of cost effectiveness analysis in solid tumours other than breast cancer is still evolving, outcomes will likely continue to be driven by drug cost and assumptions regarding treatment benefits. Although considerations such as adverse events and administration costs are important, they were not found to influence cost effectiveness estimates greatly. As zoledronic acid will lose patent protection in 2013 and subsequently be greatly reduced in price, it is likely that the field of cost effectiveness will change with regard to SRE-limiting agents. Meanwhile, research should be conducted to improve our understanding of the impact on quality of life and medical costs of preventing SREs. PMID- 22500988 TI - Targeting of eosinophils in asthma. AB - Severe asthma continues to be an important source of morbidity despite the availability of bronchodilators and corticosteroids. Although new treatments are needed, better identification of asthma phenotypes may improve treatment effectiveness. One phenotype that has emerged is eosinophilic asthma. Eosinophils in asthma have been studied for many years, and the evidence suggests they play a major role in some forms of asthma. Eosinophilic asthma can be diagnosed using peripheral blood, sputum eosinophil count or exhaled nitric oxide. Depletion of eosinophils can be achieved by corticosteroids, specific anti-interleukin 5 (IL 5) or anti-IL-5-receptor-alpha therapies, or anti-immunoglobulin E approaches. This editorial refers to the approaches that are being taken in eosinophilic asthma with emphasis on the new investigational anti-IL-5-receptor-alpha antibody, benralizumab. PMID- 22500989 TI - Characterization of nuclear import and export signals determining the subcellular localization of WD repeat-containing protein 42A (WDR42A). AB - WD repeat-containing protein 42A (WDR42A) is a member of the WD40-repeat proteins. Here, we investigated the localization pattern of WDR42A in living cells. By mutational analysis, a nuclear localization signal, 114PRRRVQRKR122, was for the first time determined. The dominant negative, co-immunoprecipitation and GST pull-down results further demonstrated that the nuclear import of WDR42A was mediated by karyopherin-alpha1/beta1 in conjunction with the GTPase Ran. Additionally, a nuclear export signal, 39IEVEASDLSLSL50, was verified to be a functional NES, which mediated the nuclear export through Chromosome Region Maintenance 1 dependent pathway. All these data suggest WDR42A is a nucleocytoplasmic shuttling protein. PMID- 22500990 TI - ROPGEF1 and ROPGEF4 are functional regulators of ROP11 GTPase in ABA-mediated stomatal closure in Arabidopsis. AB - ROPs constitute a family of plant-specific, RHO-like small GTPases that serve as molecular switches in a wide range of signaling pathways. The activities of ROPs are regulated by guanine nucleotide exchange factors (GEFs). ROP11, a member of the ROP GTPase family in Arabidopsis, is a negative regulator of multiple ABA responses. In this study, we show that ROPGEF1 and ROPGEF4 interact with ROP11 on plasma membranes in guard cells. Furthermore, our analyses of ROPGEF1/4 knockout mutants and overexpressing lines suggested that ROPGEF1 and ROPGEF4 are specific regulators of ROP11 function in ABA-mediated stomatal closure. PMID- 22500991 TI - Sun, sand, and citizenship: the marketing of gay tourism. AB - This article investigates trends in the marketing of gay and lesbian tourism. It reviews gay and lesbian travel guides from the 1960s to the 1990s before examining more recent travel materials including brochures and Web sites promoting specific American cities. These promotional materials are a valuable object of inquiry because they are uniquely situated at the intersection of discussions of sexuality, the market, representation, space, and citizenship. Through an aggregate semiotic analysis and ideological criticism, this article examines themes and concerns raised by the recent wave of gay tourism marketing, including questions of visibility, privacy, and assimilation. I argue that while marketers' recent attempts to lure gay and lesbian tourists to specific destinations may seem to suggest increased tolerance and societal inclusion, the specific strategies that they employ actually reveal the second-class citizen status still experienced by gays and lesbians within the rest of American society. PMID- 22500992 TI - Perceptions of lesbian and gay (LG) individuals as desecrators of Christianity as predictors of anti-LG attitudes. AB - This study applied religious coping theory to examine the relationship between participants' perceptions that lesbian and gay (LG) individuals desecrate Christian values (the stressor) and anti-LG attitudes (the response) and whether religious coping influences the relationship between these variables. Greater agreement with desecration messages was associated with higher levels of anti-LG attitudes. Positive religious coping was associated with lower levels of anti-LG attitudes while negative religious coping was associated with higher levels. Greater exposure to messages that LG individuals desecrate Christian values was associated with greater agreement with those messages. Longitudinal studies with more diverse samples are needed to examine causality and the generalizability of the findings. However, these results have implications for preventing and mitigating anti-LG attitudes. PMID- 22500993 TI - Homophobia as a barrier to comprehensive media coverage of the Ugandan anti homosexual bill. AB - The Ugandan Anti-Homosexuality Bill of October 2009 caused an international outcry and sparked intense debate in the local media. This article explores to what degree a discriminatory social environment manifests itself in the Ugandan print media and discusses the potential implications for media's coverage of contentious policy options such as the Anti-Homosexuality Bill. A content analysis of 115 items from two daily newspapers (the government-owned New Vision and the privately owned the Daily Monitor, between October and December 2009) indicates the existence of two separate house styles; this is in spite of the fact that both newspapers reproduce the surrounding society's homophobia, albeit with different frequency. Unlike the New Vision, the Daily Monitor includes coverage on homophobia and discrimination, as well as provides space for criticism of the Bill. By acknowledging discrimination and its negative impact, the newspaper de-legitimizes homophobia and problematizes the proposed Anti homosexuality Bill for their readers. PMID- 22500994 TI - Does the "marriage benefit" extend to same-sex union?: Evidence from a sample of married lesbian couples in Massachusetts. AB - This study investigated the relationship between wellbeing and marital quality in a married lesbian sample from Massachusetts. Two hundred twenty five (225) participants responded to this mailed survey study. Participants completed a demographic questionnaire, the Dyadic Adjustment Scale (DAS), and the World Health Organization Quality of Life-Brief Instrument (WHOQOL-Bref). DAS scores were a strong predictor of reported wellbeing in all quality of life domains including physical, psychological, and financial wellbeing. Results support the finding in the heterosexual marriage literature that healthy marriage is associated with distinct wellbeing benefits for lesbian couples. Implications of these findings are discussed. PMID- 22500995 TI - HIV disclosure and subsequent sexual behaviors among men who have sex with men who meet online. AB - To assess HIV disclosure discussions and related sexual behaviors among men who have sex with men (MSM) who meet sex partners online, 28 qualitative interviews with Seattle-area MSM were analyzed using grounded theory methods and themes and behavior patterns were identified. MSM found a greater ease in communicating and could prescreen partners through the Internet. However, no consistent relationship was found between HIV disclosure and subsequent behaviors: some were safer based on disclosure while perceived HIV status led others to risky behaviors. Interventions need to promote accurate disclosure while acknowledging its limitations and the need for men to self-protect. PMID- 22500996 TI - (In)visibility in lesbian and gay student organizing: the case of gay student services. AB - Drawing on newspaper, movement correspondence, and interview data, I examine the (in)visibility of a lesbian and gay student group, Gay Student Services (GSS), in a hostile university campus in Texas from the mid-1970s through the 1980s. GSS formed to create a safe space for sexual minorities at Texas A&M University (TAMU) and asked university officials to recognize the group officially. TAMU's resistance to their request forced GSS to file a lawsuit to achieve recognition. Using interviews with past members and archival data, such as newspapers and movement correspondence, I examine how GSS utilized (in)visibility to navigate the hostile environment. By controlling their (in)visibility, GSS members protected the organization from scrutiny and protect members' safety. PMID- 22500998 TI - A dragon rises. PMID- 22500999 TI - World Neurosurgery Neurosurgeon of the Year 2012: Liangfu Zhou. PMID- 22501000 TI - The neurosurgeon "Academician" in China. PMID- 22501001 TI - Liangfu Zhou: Clinical neurosurgeon, Academician, teacher, and friend. PMID- 22501015 TI - Preoperative planning for cerebral aneurysms based on in vitro experimentation: are we there yet? PMID- 22501016 TI - What is the best medical treatment for symptomatic intracranial stenosis? PMID- 22501017 TI - Glioma stem cells: their role in chemoresistance. PMID- 22501018 TI - Cerebral collateral circulation: integral to defining clinical outcome in acute cerebral ischemia. PMID- 22501019 TI - Treatment of ruptured aneurysms: earlier is better. PMID- 22501020 TI - Endoscopic endonasal compared with microscopic transsphenoidal and open transcranial resection of craniopharyngiomas. AB - OBJECTIVE: Craniopharyngiomas have traditionally represented a challenge for open transcranial or transsphenoidal microscopic neurosurgery because of their anatomical location and proximity to vital neurovascular structures. The extended endoscopic endonasal transsphenoidal approach has been more recently developed as a potentially surgically aggressive, yet minimal access, alternative. To gain a more comprehensive assessment of the benefits and limitations of the various approaches to resection of craniopharyngiomas, we performed a systematic review of the available published reports after endoscope-assisted endonasal approaches and compared their results with transsphenoidal purely microscope-based or transcranial microscope-based techniques. METHODS: We performed a MEDLINE search of the modern literature (1995-2010) to identify open and endoscopic surgical series for pediatric and adult craniopharyngiomas. Comparisons were made for patient and tumor characteristics as well as extent of resection, morbidity, and visual outcome. Statistical analyses of categorical variables were undertaken by the use of chi(2) and Fisher exact tests with post-hoc Bonferroni analysis to compare endoscopic, microsurgical transsphenoidal, and transcranial approaches. RESULTS: Eighty eight studies, involving 3470 patients, were included. The endoscopic cohort had a significantly greater rate of gross total resection (66.9% vs. 48.3%; P < 0.003) and improved visual outcome (56.2% vs. 33.1%; P < 0.003) compared with the open cohort. The transsphenoidal cohort had similar outcomes to the endoscopic group. The rate of cerebrospinal fluid leakage was greater in the endoscopic (18.4%) and transsphenoidal (9.0%) than in the transcranial group (2.6%; P < 0.003), but the transcranial group had a greater rate of seizure (8.5%), which did not occur in the endonasal or transsphenoidal groups (P < 0.003). CONCLUSIONS: The endoscopic endonasal approach is a safe and effective alternative for the treatment of certain craniopharyngiomas. Larger lesions with more lateral extension may be more suitable for an open approach, and further follow-up is needed to assess the long-term efficacy of this minimal access approach. PMID- 22501021 TI - Bypass or not? Adjustment of surgical strategies according to motor evoked potential changes in large middle cerebral artery aneurysm surgery. AB - OBJECTIVE: To report the use of neuroelectrophysiologic monitoring to alter the course in aneurysm surgery to minimize postoperative infarction and bypass related adverse events. METHODS: Two patients with large middle cerebral artery (MCA) aneurysms were admitted to the authors' hospital. Direct clipping seemed to be difficult, and postoperative paralysis was not rare in the authors' experience owing to prolonged temporal occlusion of the parent artery. Balloon test occlusion (BTO) was positive in one patient, who developed paralysis and aphasia 3 minutes after balloon occlusion of the feeding M1 artery. A bypass procedure seemed to be inevitable in both patients. Motor evoked potentials (MEPs) and sensory evoked potentials (SEPs) were used for monitoring during the operation. RESULTS: For the patient with a positive BTO result, MEP waves did not change until 17 minutes after temporary clip placement. The aneurysm was clipped, and the occlusion time was 24 minutes. MEP waves recovered quickly after reperfusion. In the other patient, there were early changes in MEP waves after temporary clipping. After bypass construction from the temporal artery to the inferior M2 trunk, the time window of safe occlusion was prolonged to 7-8 minutes. Both the aneurysm and the bypassed branch were obliterated, and the clip reconstruction was done to preserve the flow from M1 to the superior M2 trunk. Permanent postoperative disability did not occur in either patient. CONCLUSIONS: Intraoperative physiologic monitoring is a complementary method to preoperative BTO to evaluate the window of safe occlusion with high reliability. PMID- 22501023 TI - Human genetics. PMID- 22501022 TI - Treatment strategies for oesophageal cancer - time-trends and long term outcome data from a large tertiary referral centre. AB - BACKGROUND AND OBJECTIVES: Treatment options for oesophageal cancer have changed considerably over the last decades with the introduction of multimodal treatment concepts dominating the progress in the field. However, it remains unclear in how far the documented scientific progress influenced and changed the daily routine practice. Since most patients with oesophageal cancer generally suffer from reduced overall health conditions it is uncertain how high the proportion of aggressive treatments is and whether outcomes are improved substantially. In order to gain insight into this we performed a retrospective analysis of patients treated at a larger tertiary referral centre over time course of 25 years. PATIENTS AND METHODS: Data of all patients diagnosed with squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the oesophagus, treated between 1983 and 2007 in the department of radiation oncology of the LMU, were obtained. The primary endpoint of the data collection was overall survival (calculated from the date of diagnosis until death or last follow up). Changes in basic clinical characteristics, treatment approach and the effect on survival were analysed after dividing the cohort into five subsequent time periods (I-V) with 5 years each. In a second analysis any pattern of change regarding the use of radio(chemo)therapy (R(C)T) with and without surgery was determined. RESULTS: In total, 503 patients with SCC (78.5%) and AC (18.9%) of the oesophagus were identified. The average age was 60 years (range 35-91 years). 56.5% of the patients were diagnose with advanced UICC stages III-IV. R(C)T was applied to 353 (70.2%) patients; R(C)T+ surgery was performed in 134 (26.6%) patients, 63.8% of all received chemotherapy (platinum-based 5.8%, 5-fluorouracil (5-FU)12.1%, 42.3% 5-FU and mitomycin C (MMC)). The median follow-up period was 4.3 years. The median overall survival was 21.4 months. Over the time, patients were older, the formal tumour stage was more advanced, the incidence of AC was higher and the intensified treatment had a higher prevalence. However there was only a trend for an improved OS over the years with no difference between RCT with or without surgery (p = 0.09). The use of radiation doses over 54 Gy and the addition of chemotherapy (p = 0.002) were associated with improved OS. CONCLUSION: Although more complex treatment protocols were introduced into clinical routine, only a minor progress in OS rates was detectable. Main predictors of outcome in this cohort was the addition of chemotherapy. The addition of surgery to radio chemotherapy may only be of value for very limited patient groups. PMID- 22501024 TI - Novel phosphoramidate prodrugs of N-acetyl-(D)-glucosamine with antidegenerative activity on bovine and human cartilage explants. AB - (D)-Glucosamine and other nutritional supplements have emerged as safe alternative therapies for osteoarthritis (OA), a chronic and degenerative articular joint disease. In our preceding paper, a series of novel O-6 phosphate N-acetyl (d)-glucosamine prodrugs aimed at improving the oral bioavailability of N-acetyl-(d)-glucosamine as its putative bioactive phosphate form were shown to have greater chondroprotective activity in vitro when compared to the parent agent. In order to extend the SAR studies, this work focuses on the O-3 and O-4 phosphate prodrugs of N-acetyl-(d)-glucosamine bearing a 4-methoxy phenyl group and different amino acid esters on the phosphate moiety. Among the compounds, the (l)-proline amino acid-containing prodrugs proved to be the most active of the series, more effective than the prior O-6 compounds, and well processed in chondrocytes in vitro. Data on human cartilage support the notion that these novel O-3 and O-4 regioisomers may represent novel promising leads for drug discovery for osteoarthritis. PMID- 22501025 TI - GABRA2 markers moderate the subjective effects of alcohol. AB - Individual differences in subjective responses (SRs) to alcohol are moderated by genetic variants and may be risk factors for the development of alcohol use disorders. Variation in the GABA(A) alpha2 receptor subunit gene (GABRA2) has been associated with alcohol dependence (AD). Therefore, we examined whether individual differences in SRs, which reflect sensitivity to the effects of alcohol, are associated with variation in GABRA2. Sixty-nine healthy subjects (21 30 years) underwent a laboratory-based within-session cumulative oral alcohol dosing procedure, achieving a mean peak blood alcohol level of 100.4 mg/dl (standard error = 2.5). Subjective assessments were obtained throughout the session, including ascending and descending limbs of the alcohol curve. We genotyped single nucleotide polymorphisms (SNPs) across the chromosome 4 region spanning GABRA2 and analyzed the effect of genotype and haplotypes on subjective responses to alcohol. Population substructure was characterized through the use of ancestry informative markers. Individual SNP analysis demonstrated that carriers of the minor alleles for SNPs rs279858, rs279844, rs279845, rs279826, rs279828 and rs279836 had lower 'Negative' alcohol effects scores than individuals homozygous for the common allele at each SNP (P = 0.0060, P = 0.0035, P = 0.0045, P = 0.0043, P = 0.0037 and P = 0.0061, respectively). Haplotype effects of block 1 showed concordant results with SNPs in this block (P = 0.0492 and P = 0.0150 for haplotypes 1 and 4, respectively). The minor alleles for several of these SNPs have previously been associated with AD. Our findings provide further evidence that variation within GABRA2 is associated with attenuated negative responses to alcohol, a known risk factor for vulnerability to alcohol use disorders. PMID- 22501027 TI - Circadian waves of cytosolic calcium concentration and long-range network connections in rat suprachiasmatic nucleus. AB - The suprachiasmatic nucleus (SCN) is the master clock in mammals governing the daily physiological and behavioral rhythms. It is composed of thousands of clock cells with their own intrinsic periods varying over a wide range (20-28 h). Despite this heterogeneity, an intact SCN maintains a coherent 24 h periodic rhythm through some cell-to-cell coupling mechanisms. This study examined how the clock cells are connected to each other and how their phases are organized in space by monitoring the cytosolic free calcium ion concentration ([Ca(2+)](c)) of clock cells using the calcium-binding fluorescent protein, cameleon. Extensive analysis of 18 different organotypic slice cultures of the SCN showed that the SCN calcium dynamics is coordinated by phase-synchronizing networks of long-range neurites as well as by diffusively propagating phase waves. The networks appear quite extensive and far-reaching, and the clock cells connected by them exhibit heterogeneous responses in their amplitudes and periods of oscillation to tetrodotoxin treatments. Taken together, our study suggests that the network of long-range cellular connectivity has an important role for the SCN in achieving its phase and period coherence. PMID- 22501026 TI - Serum cortisol predicts death and critical disease independently of CRB-65 score in community-acquired pneumonia: a prospective observational cohort study. AB - BACKGROUND: Several biomarkers and prognostic scores have been evaluated to predict prognosis in community-acquired pneumonia (CAP). Optimal risk stratification remains to be evaluated. The aim of this study was to evaluate serum cortisol as biomarker for the prediction of adverse outcomes independently of the CRB-65 score und inflammatory biomarkers in a large cohort of hospitalised patients with CAP. METHODS: 984 hospitalised CAP-patients were included. Serum cortisol was measured and its prognostic accuracy compared to the CRB-65 score, leucocyte count and C-reactive protein. Predefined endpoints were 30-day mortality and the combined endpoint critical pneumonia, defined as presence of death occurring during antibiotic treatment, mechanical ventilation, catecholamine treatment or ICU admission. RESULTS: 64 patients died (6.5%) and 85 developed critical pneumonia (8.6%). Cortisol levels were significantly elevated in both adverse outcomes (p < 0.001) and predicted mortality (AUC 0.70, cut-off 795 nmol/L) and critical pneumonia (AUC 0.71) independently of all other measured variables after logistic regression analysis (p = 0.005 and 0.001, respectively). Prognostic accuracy of CRB-65 was significantly improved by adding cortisol levels (combined AUC 0.81 for both endpoints). In Kaplan-Meier analysis, cortisol predicted survival within different CRB-65 strata (p = 0.003). In subgroup analyses, cortisol independently predicted critical pneumonia when compared to procalcitonin, the CURB65 score and minor criteria for severe pneumonia according to the 2007 ATS/IDSA-guideline. CONCLUSION: Cortisol predicts mortality and critical disease in hospitalised CAP-patients independently of clinical scores and inflammatory biomarkers. It should be incorporated into trials assessing optimal combinations of clinical criteria and biomarkers to improve initial high risk prediction in CAP. PMID- 22501029 TI - High mobility flexible graphene field-effect transistors with self-healing gate dielectrics. AB - A high-mobility low-voltage graphene field-effect transistor (FET) array was fabricated on a flexible plastic substrate using high-capacitance natural aluminum oxide as a gate dielectric in a self-aligned device configuration. The high capacitance of the native aluminum oxide and the self-alignment, which minimizes access resistance, yield a high current on/off ratio and an operation voltage below 3 V, along with high electron and hole mobility of 230 and 300 cm(2)/V.s, respectively. Moreover, the native aluminum oxide is resistant to mechanical bending and exhibits self-healing upon electrical breakdown. These results indicate that self-aligned graphene FETs can provide remarkably improved device performance and stability for a range of applications in flexible electronics. PMID- 22501028 TI - Leiomyosarcoma of renal vein, initially resembling pheochromocytoma. AB - We report the case of a 43-year-old woman who presented with mild left-sided abdominal pain. Computed tomography and MRI findings revealed a 10.7 * 8.5 * 12 cm left-sided soft tissue mass on the renal vessels pushing away the left kidney. The combination of the patient's medical history (episodes of paroxysmal hypertension accompanied with dizziness and sweating) and radiological findings initially pointed toward the diagnosis of a paraganglioma or ectopic pheochromocytoma. Surgical removal of the tumor and left nephrectomy was performed. Histological findings were consistent with a renal vein leiomyosarcoma of a high malignancy grade. There is no evidence of local recurrence or metastatic disease for more than 2 years postoperatively, although the patient did not receive adjuvant chemotherapy or radiation therapy. PMID- 22501030 TI - Nitrogen under- and over-supply induces distinct protein responses in maize xylem sap. AB - Xylem sap primarily transports water and mineral nutrients such as nitrogen (N) from roots to shoots in vascular plants. However, it remains largely unknown how nitrogenous compounds, especially proteins in xylem sap, respond to N under- or over-supply. We found that reducing N supply increased amino-N percentage of total N in maize (Zea mays L.) xylem sap. Proteomic analysis showed that 23 proteins in the xylem sap of maize plants, including 12 newly identified ones, differentially accumulated in response to various N supplies. Fifteen of these 23 proteins were primarily involved in general abiotic or biotic stress responses, whereas the other five proteins appeared to respond largely to N under- or over supply, suggesting distinct protein responses in maize xylem upon N under- and over-supply. Furthermore, one putative xylanase inhibitor and two putative O glycosyl hydrolases had preferential gene expression in shoots. PMID- 22501031 TI - Au-Pd alloy and core-shell nanostructures: one-pot coreduction preparation, formation mechanism, and electrochemical properties. AB - It is a known fact that Pd-based bimetallic nanostructures possess unique properties and excellent catalytic performance. In this work, the Au-Pd alloy and core-shell nanostructures have been prepared by a simple one-pot hydrothermal coreduction route, and their formation process and mechanism are discussed in detail. A reducing capacity-induced controlled reducing mechanism is proposed for the formation process of Au-Pd bimetallic nanostructures. CTAB plays a key role in the formation of alloy Au-Pd nanostructures. When CTAB is absent, the products are typical core-shell nanostructures. Moreover, the as-prepared nanostructures exhibit excellent electrocatalytic ORR performance in alkaline media, especially for Au-Pd alloy nanostructures. The overpotential of oxygen reduction gets reduced significantly, and the peak potential is positive-shifted by 44 and 34 mV in comparison with the core-shell ones and Pd/C catalyst, respectively. Thus, the controllable preparation and excellent electrocatalytic properties will make them become a potentially cheaper Pd-based cathodic electrocatalyst for DAFCs in alkaline media. PMID- 22501032 TI - Novel optoelectronic devices based on single semiconductor nanowires (nanobelts). AB - Semiconductor nanowires (NWs) or nanobelts (NBs) have attracted more and more attention due to their potential application in novel optoelectronic devices. In this review, we present our recent work on novel NB photodetectors, where a three terminal metal-semiconductor field-effect transistor (MESFET) device structure was exploited. In contrast to the common two-terminal NB (NW) photodetectors, the MESFET-based photodetector can make a balance among overall performance parameters, which is desired for practical device applications. We also present our recent work on graphene nanoribbon/semiconductor NW (SNW) heterojunction light-emitting diodes (LEDs). Herein, by taking advantage of both graphene and SNWs, we have fabricated, for the first time, the graphene-based nano-LEDs. This achievement opens a new avenue for developing graphene-based nano electroluminescence devices. Moreover, the novel graphene/SNW hybrid devices can also find use in other applications, such as high-sensitivity sensor and transparent flexible devices in the future. PMID- 22501035 TI - Frequency discrimination under conditions of comodulation masking release (L). AB - Masked detection thresholds can often be improved by introducing coherent masker amplitude modulation across frequency, a phenomenon referred to as comodulation masking release (CMR). While CMR can be large for detection, it is smaller for supra-threshold tasks, such as intensity discrimination. In this experiment, frequency discrimination for a 1000-Hz tone near threshold was found to be poorer in an amplitude-modulated than a steady bandpass noise. These results parallel previous findings for intensity discrimination. Although this study examined the relatively simple task of frequency discrimination, the results may have implications for more complex tasks, such as speech recognition in fluctuating noise. PMID- 22501034 TI - Decreasing frequency of plasma exchange complications in patients treated for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 1996 to 2011. AB - BACKGROUND: Plasma exchange (PEX) treatment for patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) has risk for major complications. STUDY DESIGN AND METHODS: Data for PEX-related complications have been prospectively collected on all patients enrolled in the Oklahoma TTP-HUS Registry, 1996 to 2011. PEX-related complications have been defined as major or minor and as central venous catheter related or plasma related. RESULTS: During 15 years, 1996 to 2011, 72 (24%) of 302 consecutive patients had major PEX related complications. Analysis of five consecutive 3-year cohorts demonstrated that there has been a significant trend for decreasing frequency of all PEX related major complications (p = 0.014) and central venous catheter-related major complications (p = 0.021) but not for the less common plasma-related major complications (p = 0.380). ADAMTS13 activity was measured in 288 (95%) of the 302 patients. Analysis of the 66 patients with ADAMTS13 activity of less than 10% demonstrated a significant trend for decreasing frequency of PEX-related major complications (p = 0.036); the trend for the 222 patients with ADAMTS13 activity of at least 10% was not significant (p = 0.118). The decreased frequency of PEX related major complications among patients with ADAMTS13 activity of less than 10% may be related to a significant trend for decreasing duration of PEX treatment (p = 0.040) and decreasing frequency of requirement for more than one central venous catheter (p = 0.044). The decreased duration of PEX treatment may be related to increased use of adjunctive treatments: corticosteroids (p < 0.001) and rituximab (p < 0.001). CONCLUSIONS: The frequency of PEX-related major complications has decreased from 1996 to 2011, possibly related to increased use of corticosteroids and rituximab and the decreased duration of PEX required to achieve remission. PMID- 22501036 TI - Binaural temporal fine structure sensitivity, cognitive function, and spatial speech recognition of hearing-impaired listeners (L). AB - The relationships between spatial speech recognition (SSR; the ability to understand speech in complex spatial environments), binaural temporal fine structure (TFS) sensitivity, and three cognitive tasks were assessed for 17 hearing-impaired listeners. Correlations were observed between SSR, TFS sensitivity, and two of the three cognitive tasks, which became non-significant when age effects were controlled for, suggesting that reduced TFS sensitivity and certain cognitive deficits may share a common age-related cause. The third cognitive measure was also significantly correlated with SSR, but not with TFS sensitivity or age, suggesting an independent non-age-related cause. PMID- 22501037 TI - A note on the modal kurtosis and the concentration factor in reverberation rooms. AB - The effect known as "weak Anderson localization," "coherent backscattering," or "enhanced back-scattering" is a physical phenomenon that occurs in random systems, e.g., disordered media and linear wave systems, including reverberation rooms: The mean square response is increased at the drive point. In a reverberation room, this means that one can expect an increase of the reverberant sound field at the position of the source that generates the sound field. This affects the sound power output of the source and is therefore of practical concern. The relative increase of reverberant energy is described by the concentration factor, which is usually assumed to be 2. However, because of the stronger direct sound field at the source position, it is obviously very difficult to measure this quantity directly under steady-state conditions. A related parameter of crucial importance for the ensemble statistics of responses in rooms is the modal kurtosis, which is usually assumed to be 3. The modal kurtosis is also very difficult to measure directly. This paper presents the results of an indirect experimental estimation of the two parameters. PMID- 22501038 TI - Scattering of time-harmonic elastic waves by an elastic inclusion with quadratic nonlinearity. AB - This paper considers the scattering of a plane, time-harmonic wave by an inclusion with heterogeneous nonlinear elastic properties embedded in an otherwise homogeneous linear elastic solid. When the inclusion and the surrounding matrix are both isotropic, the scattered second harmonic fields are obtained in terms of the Green's function of the surrounding medium. It is found that the second harmonic fields depend on two independent acoustic nonlinearity parameters related to the third order elastic constants. Solutions are also obtained when these two acoustic nonlinearity parameters are given as spatially random functions. An inverse procedure is developed to obtain the statistics of these two random functions from the measured forward and backscattered second harmonic fields. PMID- 22501039 TI - Adaptive control of contrast agent microbubbles for shell parameter identification. AB - An adaptive controller design is proposed and simulated for parameter identification and oscillation control in microbubble systems. Lyapunov's direct method and a Lyapunov-like analysis are used to show stability and convergence of trajectory tracking and parameter adaptation. The method allows for the determination of microbubble contrast agent shell thickness or material parameters in a nondestructive manner. PMID- 22501040 TI - Horizontal refraction of propagating sound due to seafloor scours over a range dependent layered bottom on the New Jersey shelf. AB - Three-dimensional propagation effects of low frequency sound from 100 to 400 Hz caused by seafloor topography and range-dependent bottom structure over a 20 km range along the New Jersey shelf are investigated using a hybrid modeling approach. Normal modes are used in the vertical dimension, and a parabolic equation approximate model is applied to solve the horizontal refraction equation. Examination of modal amplitudes demonstrates the effect of environmental range dependence on modes trapped in the water column, modes interacting with the bottom, and modes trapped in the bottom. Using normal mode ray tracing, topographic features responsible for three-dimensional effects of horizontal refraction and focusing are identified. These effects are observed in the measurements from the Shallow Water 2006 experiment. Specifically, signals from a pair of fixed sources recorded on a horizontal line array sitting on the seafloor show an intensification caused by horizontal focusing due to the seabed topography of 4 dB along the array. PMID- 22501041 TI - Blind deconvolution for robust signal estimation and approximate source localization. AB - Synthetic time reversal (STR) is a technique for blind deconvolution in an unknown multipath environment that relies on generic features (rays or modes) of multipath sound propagation. This paper describes how ray-based STR signal estimates may be improved and how ray-based STR sound-channel impulse-response estimates may be exploited for approximate source localization in underwater environments. Findings are based on simulations and underwater experiments involving source-array ranges from 100 m to 1 km in 60 -m-deep water and chirp signals with a bandwidth of 1.5-4.0 kHz. Signal estimation performance is quantified by the correlation coefficient between the source-broadcast and the STR-estimated signals for a variable number N of array elements, 2 <= N <= 32, and a range of signal-to-noise ratio (SNR), -5 dB <= SNR <= 30 dB. At high SNR, STR-estimated signals are found to have cross-correlation coefficients of ~90% with as few as four array elements, and similar performance may be achieved at a SNR of nearly 0 dB with 32 array elements. When the broadband STR-estimated impulse response is used for source localization via a simple ray-based backpropagation scheme, the results are less ambiguous than those obtained from conventional broadband matched field processing. PMID- 22501042 TI - Low frequency seabed scattering at low grazing angles. AB - Low-frequency (LF) seabed scattering at low grazing angles (LGA) is almost impossible to directly measure in shallow water (SW), except through inversion from reverberation. The energy flux method for SW reverberation is briefly introduced in this paper. The closed-form expressions of reverberation in an isovelocity waveguide, derived from this method, indicate that in the three halves law range interval multimode/ray sea bottom scattering with different incident and scattering angles in forming the reverberation may equivalently be represented by the bottom backscattering at a single range-dependent angle. This equivalent relationship is used to derive the bottom backscattering strength (BBS) as a function of angle and frequency. The LF&LGA BBS is derived in a frequency band of 200-2500 Hz and in a grazing angle range of 1.1 degrees -14.0 degrees from reverberation measurements at three sites with sandy bottoms. This is based on three previous works: (1) The closed-form expressions of SW reverberation [Zhou, (Chinese) Acta Acustica 5, 86-99 (1980)]; (2) the effective geo-acoustic model of sandy bottoms that follows the Biot model [Zhou et al., J. Acoust. Soc. Am. 125, 2847-2866 (2009)] and (3) A quality database of wideband reverberation level normalized to source level [Zhou and Zhang, IEEE J. Oceanic Eng. 30, 832-842 (2005)]. PMID- 22501043 TI - Anechoic coatings obtained from two- and three-dimensional monopole resonance diffraction gratings. AB - Underwater sound reflections can be reduced in magnitude by a rubber coating including three-dimensional (3-D) cavities forming a doubly periodic diffraction grating. A monopole resonance for sphere-like cavities enhances absorption in the surrounding rubber solid. A corresponding resonance for an infinite cylinder is studied in the present paper. Appearing at a considerably lower frequency than for a sphere with the same radius, it suggests the possibility of much thinner anechoic coatings including cylindrical cavities, with axes in a lateral direction, forming a diffraction grating with a single period. This is effectively a 2-D case, because of invariance in the axial direction. Subsequent coating design computations, using the layer-multiple-scattering method and including cavities of different sizes, show improved reflection reduction with coatings only about one third as thick. Still accounting for multiple scattering among the cavities and capturing the essential physics, the monopole approximation is applied to advance the analytic study of the reflection reduction. An energy decomposition relation is derived and used to quantify the absorption of the incident sound energy by cavities of different sizes. Coatings based on filled inclusions and other resonance effects are briefly considered. Again, the 2-D alternative with cylinders of mixed sizes gives thinner coatings. PMID- 22501044 TI - A single-scattering correction for the seismo-acoustic parabolic equation. AB - An efficient single-scattering correction that does not require iterations is derived and tested for the seismo-acoustic parabolic equation. The approach is applicable to problems involving gradual range dependence in a waveguide with fluid and solid layers, including the key case of a sloping fluid-solid interface. The single-scattering correction is asymptotically equivalent to a special case of a single-scattering correction for problems that only have solid layers [Kusel et al., J. Acoust. Soc. Am. 121, 808-813 (2007)]. The single scattering correction has a simple interpretation (conservation of interface conditions in an average sense) that facilitated its generalization to problems involving fluid layers. Promising results are obtained for problems in which the ocean bottom interface has a small slope. PMID- 22501045 TI - Cross-correlation in band-limited ocean ambient noise fields. AB - Observations of ambient noise in the ocean are generally band limited, because of the natural spectral shape of the noise or the restricted bandwidth of the detection system. Either way, the noise may be regarded as white noise to which a band-limiting filter has been applied. An analysis of the two-point cross correlation function of such filtered noise is presented for two cases, isotropic and surface-generated noise. The most pronounced effects occur with high-pass and bandpass filters when the low-frequency cut-off falls well above the first few zeros in the coherence function. In this situation, the sensor separation is very many times the longest acoustic wavelength (associated with the lowest frequency) in the passband. The filtering then produces sharp pulses at correlation delays equal to the numerical value of the acoustic travel time between the sensors. Although these pulses are narrow, they have a finite width, within which a fine structure appears in the form of multiple rapid oscillations, due to the differentiating action of the filter. The number of such oscillations increases as the low-frequency roll-off of the filter becomes steeper. This fine structure is evident in several recently published experimental determinations of the cross correlation function of band-limited ocean ambient noise. PMID- 22501046 TI - Bayesian geoacoustic inversion using wind-driven ambient noise. AB - This paper applies Bayesian inversion to bottom-loss data derived from wind driven ambient noise measurements from a vertical line array to quantify the information content constraining seabed geoacoustic parameters. The inversion utilizes a previously proposed ray-based representation of the ambient noise field as a forward model for fast computations of bottom loss data for a layered seabed. This model considers the effect of the array's finite aperture in the estimation of bottom loss and is extended to include the wind speed as the driving mechanism for the ambient noise field. The strength of this field relative to other unwanted noise mechanisms defines a signal-to-noise ratio, which is included in the inversion as a frequency-dependent parameter. The wind speed is found to have a strong impact on the resolution of seabed geoacoustic parameters as quantified by marginal probability distributions from Bayesian inversion of simulated data. The inversion method is also applied to experimental data collected at a moored vertical array during the MAPEX 2000 experiment, and the results are compared to those from previous active-source inversions and to core measurements at a nearby site. PMID- 22501047 TI - Sequential Bayesian geoacoustic inversion for mobile and compact source-receiver configuration. AB - Geoacoustic characterization of wide areas through inversion requires easily deployable configurations including free-drifting platforms, underwater gliders and autonomous vehicles, typically performing repeated transmissions during their course. In this paper, the inverse problem is formulated as sequential Bayesian filtering to take advantage of repeated transmission measurements. Nonlinear Kalman filters implement a random-walk model for geometry and environment and an acoustic propagation code in the measurement model. Data from MREA/BP07 sea trials are tested consisting of multitone and frequency-modulated signals (bands: 0.25-0.8 and 0.8-1.6 kHz) received on a shallow vertical array of four hydrophones 5-m spaced drifting over 0.7-1.6 km range. Space- and time-coherent processing are applied to the respective signal types. Kalman filter outputs are compared to a sequence of global optimizations performed independently on each received signal. For both signal types, the sequential approach is more accurate but also more efficient. Due to frequency diversity, the processing of modulated signals produces a more stable tracking. Although an extended Kalman filter provides comparable estimates of the tracked parameters, the ensemble Kalman filter is necessary to properly assess uncertainty. In spite of mild range dependence and simplified bottom model, all tracked geoacoustic parameters are consistent with high-resolution seismic profiling, core logging P-wave velocity, and previous inversion results with fixed geometries. PMID- 22501048 TI - A generalized power-law detection algorithm for humpback whale vocalizations. AB - Conventional detection of humpback vocalizations is often based on frequency summation of band-limited spectrograms under the assumption that energy (square of the Fourier amplitude) is the appropriate metric. Power-law detectors allow for a higher power of the Fourier amplitude, appropriate when the signal occupies a limited but unknown subset of these frequencies. Shipping noise is non stationary and colored and problematic for many marine mammal detection algorithms. Modifications to the standard power-law form are introduced to minimize the effects of this noise. These same modifications also allow for a fixed detection threshold, applicable to broadly varying ocean acoustic environments. The detection algorithm is general enough to detect all types of humpback vocalizations. Tests presented in this paper show this algorithm matches human detection performance with an acceptably small probability of false alarms (P(FA) < 6%) for even the noisiest environments. The detector outperforms energy detection techniques, providing a probability of detection P(D) = 95% for P(FA) < 5% for three acoustic deployments, compared to P(FA) > 40% for two energy-based techniques. The generalized power-law detector also can be used for basic parameter estimation and can be adapted for other types of transient sounds. PMID- 22501049 TI - Relationship between visual counts and call detection rates of gray whales (Eschrichtius robustus) in Laguna San Ignacio, Mexico. AB - Daily acoustic calling rates of Eastern North Pacific (ENP) gray whales were measured on 6 days during 1 mo of their 2008 breeding season in the sheltered coastal lagoon of Laguna San Ignacio in Baja California, Mexico. Visual counts of whales determined that the numbers of single animals in the lower lagoon more than tripled over the observation period. All call types showed production peaks in the early morning and evening with minimum rates generally detected in the early afternoon. For four of the five observation days, the daily number of "S1" type calls increased roughly as the square of the number of the animals in the lower lagoon during both daytime and nighttime. This relationship persisted when raw call counts were adjusted for variations in background noise level, using a simple propagation law derived from empirical measurements. The one observation day that did not fit the square-law relationship occurred during a week when the group size in the lagoon increased rapidly. These results suggest that passive acoustic monitoring does not measure gray whale group size directly but monitors the number of connections in the social network, which rises as roughly M(2)/2 for a group size M. PMID- 22501050 TI - Mode separation of Lamb waves based on dispersion compensation method. AB - Ultrasonic Lamb modes typically propagate as a combination of multiple dispersive wave packets. Frequency components of each mode distribute widely in time domain due to dispersion and it is very challenging to separate individual modes by traditional signal processing methods. In the present study, a method of dispersion compensation is proposed for the purpose of mode separation. This numerical method compensates, i.e., compresses, the individual dispersive waveforms into temporal pulses, which thereby become nearly un-overlapped in time and frequency and can thus be extracted individually by rectangular time windows. It was further illustrated that the dispersion compensation also provided a method for predicting the plate thickness. Finally, based on reversibility of the numerical compensation method, an artificial dispersion technique was used to restore the original waveform of each mode from the separated compensated pulse. Performances of the compensation separation techniques were evaluated by processing synthetic and experimental signals which consisted of multiple Lamb modes with high dispersion. Individual modes were extracted with good accordance with the original waveforms and theoretical predictions. PMID- 22501052 TI - Spatial impulse response of a rectangular double curved transducer. AB - Calculation of the pressure field from transducers with both a convex and a concave surface geometry is a complicated assignment that often is accomplished by subdividing the transducer surface into smaller flat elements of which the spatial impulse response is known. This method is often applied to curved transducers because an analytical solution is unknown. In this work a semi analytical algorithm for the exact solution to a first order in diffraction effect of the spatial impulse response of rectangular-shaped double curved transducers is presented. The solution and an approximation to it are investigated. The approximation reformulates the solution to an analytically integrable expression, which is computationally efficient to solve. Simulation results are compared to FIELD II simulations. Calculating the response from 200 different points yields a mean error for the different approximations ranging from 0.03% to 0.8% relative to a numerical solution for the spatial impulse response. It is also shown that the presented algorithm gives consistent results with FIELD II for a linear flat, a linear focused, and a convex nonfocused element. The solution involved a three-point Taylor expansion and gave an accuracy of 0.01%. PMID- 22501051 TI - Development of a theoretical model describing sonoporation activity of cells exposed to ultrasound in the presence of contrast agents. AB - Sonoporation uses ultrasound, with the aid of ultrasound contrast agents (UCAs), to enhance cell permeabilization, thereby allowing delivery of therapeutic compounds noninvasively into specific target cells. The objective of this study was to determine if a computational model describing shear stress on a cell membrane due to microstreaming would successfully reflect sonoporation activity with respect to the peak rarefactional pressure. The theoretical models were compared to the sonoporation results from Chinese hamster ovary cells using Definity((r)) at 0.9, 3.15, and 5.6 MHz and were found to accurately describe the maximum sonoporation activity, the pressure where a decrease in sonoporation activity occurs, and relative differences between maximum activity and the activity after that decrease. Therefore, the model supports the experimental findings that shear stress on cell membranes secondary to oscillating UCAs results in sonoporation. PMID- 22501053 TI - Stabilization of time domain acoustic boundary element method for the interior problem with impedance boundary conditions. AB - The time domain boundary element method (BEM) is associated with numerical instability that typically stems from the time marching scheme. In this work, a formulation of time domain BEM is derived to deal with all types of boundary conditions adopting a multi-input, multi-output, infinite impulse response structure. The fitted frequency domain impedance data are converted into a time domain expression as a form of an infinite impulse response filter, which can also invoke a modeling error. In the calculation, the response at each time step is projected onto the wave vector space of natural radiation modes, which can be obtained from the eigensolutions of the single iterative matrix. To stabilize the computation, unstable oscillatory modes are nullified, and the same decay rate is used for two nonoscillatory modes. As a test example, a transient sound field within a partially lined, parallelepiped box is used, within which a point source is excited by an octave band impulse. In comparison with the results of the inverse Fourier transform of a frequency domain BEM, the average of relative difference norm in the stabilized time response is found to be 4.4%. PMID- 22501054 TI - Audience noise in concert halls during musical performances. AB - Noise generated by the audience during musical performances is audible and sometimes disturbing. In this study, an attempt to estimate such audience noise was carried out. From the recordings of performances in five performance spaces (four concert halls and one opera house), probability density functions of the sound pressure levels were obtained in octave bands, which were fitted with three Gaussian distribution curves. The Gaussian distribution curve with the lowest mean value corresponds to a mixture of the technical background noise and audience generated noise, which is named the mixed background noise. Finally, the audience noise distribution is extracted by energy subtraction of the technical background noise levels measured in an empty condition from the mixed background noise levels. As a single index, L(90) of the audience noise distribution is named the audience noise level. Empirical prediction models were made using the four orchestra concert halls, revealing that the audience noise level is significantly correlated with the technical background noise level. It is therefore concluded that a relaxation of the current background noise recommendations for concert halls is not recommended. PMID- 22501055 TI - Perception of urban park soundscape. AB - A number of studies have been initiated to explore how to improve the soundscape quality in urban parks. However, good soundscape quality in parks cannot be provided without a thorough understanding of the complex relationships among sound, environment, and individuals. As acoustic comfort is considered to be an important outcome of soundscape quality, this study investigates the relative impacts of the factors influencing acoustic comfort evaluation by formulating a multivariate ordered logit model. This study also explores the inter relationships among acoustic comfort evaluation, acceptability of the environment, and preference to stay in a park using a path model. A total of 595 valid responses were obtained from interview surveys administered in four parks in Hong Kong while objective sound measurements were carried out at the survey spots concurrently. The findings unveil that acoustic comfort evaluation, besides visual comfort evaluation of landscape, also plays an important role on users' acceptability of the urban park environment. Compared with all the studied acoustic related factors, acoustic comfort evaluation serves as a better proxy for park users' preference to stay in urban parks. Hearing the breeze will significantly increase the likelihood of individuals in giving high acoustic comfort evaluation. Conversely, hearing the sounds from heavy vehicles or sounds from bikes will significantly reduce the likelihood in giving a high acoustic evaluation. PMID- 22501056 TI - Role of community tolerance level (CTL) in predicting the prevalence of the annoyance of road and rail noise. AB - Fidell et al. [(2011), J. Acoust. Soc. Am. 130(2), 791-806] have shown (1) that the rate of growth of annoyance with noise exposure reported in attitudinal surveys of the annoyance of aircraft noise closely resembles the exponential rate of change of loudness with sound level, and (2) that the proportion of a community highly annoyed and the variability in annoyance prevalence rates in communities are well accounted for by a simple model with a single free parameter: a community tolerance level (abbreviated CTL, and represented symbolically in mathematical expressions as L(ct)), expressed in units of DNL. The current study applies the same modeling approach to predicting the prevalence of annoyance of road traffic and rail noise. The prevalence of noise-induced annoyance of all forms of transportation noise is well accounted for by a simple, loudness-like exponential function with community-specific offsets. The model fits all of the road traffic findings well, but the prevalence of annoyance due to rail noise is more accurately predicted separately for interviewing sites with and without high levels of vibration and/or rattle. PMID- 22501057 TI - Audiometric thresholds among a Canadian sample of 10 to 17 year old students. AB - A total of 237 students, 10 to 17 years of age, from 14 schools underwent hearing evaluations. Otoscopic examination, tympanometry and air-conduction pure tone audiometry was conducted at low (0.5, 1, 2 kHz) and high (4 and 8 kHz) frequencies. In all schools, hearing thresholds were measured with headphones in a portable audiometric booth. Socio-demographic information from students and their parents were collected using questionnaires. Overall, the prevalence of any hearing loss greater than 15 dB was 22.3% for low or high frequency pure tone averages. Self-reported symptoms of hearing loss, such as tinnitus, difficulty following a conversation with background noise, and having to turn up the TV/radio more than in the past, were associated with audiometric thresholds, most notably at 4 kHz. These study findings are among the first to provide a detailed characterization of hearing status in a sample of youth in a Canadian demographic. PMID- 22501058 TI - Vibro-acoustic analysis of a rectangular cavity bounded by a flexible panel with elastically restrained edges. AB - A coupled system consisting of an acoustic cavity and an elastic panel is a classical problem in structural acoustics and is typically analyzed using modal approaches based on in vacuo structural modes and the rigidly walled acoustic modes which are pre-determined based on separate component models. Such modeling techniques, however, tend to suffer the following drawbacks or limitations: (a) a panel is only subjected to ideal boundary conditions such as the simply supported, (b) the coupling between the cavity and panel is considered weak, and (c) the particle velocity cannot be correctly predicted from the pressure gradient on the contacting interface, to name a few. Motivated by removing these restrictions, this paper presents a general method for the vibro-acoustic analysis of a three-dimensional (3D) acoustic cavity bounded by a flexible panel with general elastically restrained boundary conditions. The displacement of the plate and the sound pressure in the cavity are constructed in the forms of standard two-dimensional and 3D Fourier cosine series supplemented by several terms introduced to ensure and accelerate the convergence of the series expansions. The unknown expansions coefficients are treated as the generalized coordinates and determined using the Rayleigh-Ritz procedure based on the energy expressions for the coupled structural acoustic system. The accuracy and effectiveness of the proposed method are demonstrated through numerical examples and comparisons with the results available in the literature. PMID- 22501059 TI - A blind algorithm for reverberation-time estimation using subband decomposition of speech signals. AB - An algorithm for blind estimation of reverberation time (RT) in speech signals is proposed. Analysis is restricted to the free-decaying regions of the signal, where the reverberation effect dominates, yielding a more accurate RT estimate at a reduced computational cost. A spectral decomposition is performed on the reverberant signal and partial RT estimates are determined in all signal subbands, providing more data to the statistical-analysis stage of the algorithm, which yields the final RT estimate. Algorithm performance is assessed using two distinct speech databases, achieving 91% and 97% correlation with the RTs measured by a standard nonblind method, indicating that the proposed method blindly estimates the RT in a reliable and consistent manner. PMID- 22501060 TI - Investigations into vocal doses and parameters pertaining to primary school teachers in classrooms. AB - Investigations into vocal doses and parameters were carried out on 40 primary school teachers (36 females and 4 males) in six schools in Italy, divided into two groups of three, A and B, on the basis of the type of building and the mid frequency reverberation time in the classrooms, which was 1.13 and 0.79 s, respectively. A total of 73 working-day samples were collected (66 for females and 7 for males), from which 54 traditional lessons were analyzed separately. The average value over the working days of the mean sound pressure level of the voiced speech at 1 m from the teacher's mouth was 62.1 dB for the females and 57.7 dB for the males, while the voicing time percentage was 25.9 and 25.1 %, respectively. Even though the vocal doses and parameters did not differ for the two school groups, the differences in the subjective scores were significant, with enhanced scores in group B. A 0.72 dB increase in speech level per 1 dB increase in background noise level, L(A90), was found during traditional lessons, as well as an increase in the mean value of the fundamental frequency with an increase in L(A90), at a rate of 1.0 Hz/dB. PMID- 22501061 TI - Localization of distinct reflections in rooms using spherical microphone array eigenbeam processing. AB - This paper presents an experimental and comparative study of several spherical microphone array eigenbeam (EB) processing techniques for localization of early reflections in room acoustic environments, which is a relevant research topic in both audio signal processing and room acoustics. This paper focuses on steered beamformer-based and subspace-based localization techniques implemented in the spherical EB domain, including the plane-wave decomposition, eigenbeam delay and sum, eigenbeam minimum variance distortionless response, eigenbeam multiple signal classification (EB-MUSIC), and eigenbeam estimation of signal parameters via rotational invariance techniques (EB-ESPRIT) methods. The directions of arrival of the original sound source and the associated reflection signals in acoustic environments are estimated from acoustic maps of the rooms, which are obtained using a spherical microphone array. The EB-domain-based frequency smoothing and white noise gain control techniques are derived and employed to improve the performance and robustness of reflection localization. The applicability of the presented methods in practice is confirmed by experiments carried out in real rooms. PMID- 22501062 TI - Comparison of methods for processing acoustic intensity from orthogonal multimicrophone probes. AB - One design for three-dimensional multimicrophone probes is the four-microphone orthogonal design consisting of one microphone at an origin position with the other three microphones equally spaced along the three coordinate axes. Several distinct processing methods have been suggested for the estimation of active acoustic intensity with the orthogonal probe; however, the relative merits of each method have not been thoroughly studied. This comparative study is an investigation of the errors associated with each method. Considered are orthogonal probes consisting of matched point sensor microphones both freely suspended and embedded on the surface of a rigid sphere. Results are given for propagating plane-wave fields for all angles of incidence. It is shown that the lowest error for intensity magnitude results from having the microphones in a sphere and using just one microphone for the pressure estimate. For intensity direction, the lowest error results from having the microphones in a sphere and using Taylor approximations to estimate the particle velocity and pressure. PMID- 22501063 TI - The seismic noise wavefield is not diffuse. AB - Passive seismology is burgeoning under the apparent theoretical support of diffuse acoustics. However, basic physical arguments suggest that this theory may not be applicable to seismic noise. A procedure is developed to establish the applicability of the diffuse field paradigm to a wavefield, based on testing the latter for azimuthal isotropy and spatial homogeneity. This procedure is then applied to the seismic noise recorded at 65 sites covering a wide variety of environmental and subsoil conditions. Considering the instantaneous oscillation vector measured at single triaxial stations, the hypothesis of azimuthal isotropy is rejected in all cases with high confidence, which makes the spatial homogeneity test unnecessary and leads directly to conclude that the seismic noise wavefield is not diffuse. However, such a conclusion has no practical effect on passive imaging, which is also possible in non-diffuse wavefields. PMID- 22501064 TI - An acoustic system for the individual recognition of insects. AB - Research into acoustic recognition systems for insects has focused on species identification rather than individual identification. In this paper, the feasibility of applying pattern recognition techniques to construct an acoustic system capable of automatic individual recognition for insects is investigated analytically and experimentally across two species of Orthoptera. Mel-frequency cepstral coefficients serve as the acoustic feature, and alpha-Gaussian mixture models were selected as the classification models. The performance of the proposed acoustic system is promising and displays high accuracy. The results suggest that the acoustic feature and classifier method developed here have potential for individual animal recognition and can be applied to other species of interest. PMID- 22501065 TI - Energy streamlines for qualitative inverse scattering in fluids and solids. AB - In time-harmonic acoustic fields, energy streamlines are defined as the integral curves of the power-flux density vector, averaged over a period. They provide a tool to visualize the details of propagation of energy. After reviewing the role of energy streamlines in the linear sampling method for acoustic inverse scattering, this work formulates a physical interpretation of the same qualitative method in the case of an isotropic homogeneous solid matrix. Specifically, it is shown that the linear sampling method results from conservation of energy along streamline tubes of energy flow associated with elastic waves. PMID- 22501066 TI - A Bayesian approach to sound source reconstruction: optimal basis, regularization, and focusing. AB - The reconstruction of acoustical sources from discrete field measurements is a difficult inverse problem that has been approached in different ways. Classical methods (beamforming, near-field acoustical holography, inverse boundary elements, wave superposition, equivalent sources, etc.) all consist--implicitly or explicitly--in interpolating the measurements onto some spatial functions whose propagation are known and in reconstructing the source field by retropropagation. This raises the fundamental question as whether, for a given source topology and array geometry, there exists an optimal interpolation basis which minimizes the reconstruction error. This paper provides a general answer to this question, by proceeding from a Bayesian formulation that is ideally suited to combining information of physical and probabilistic natures. The main findings are the followings: (1) The optimal basis functions are the M eigen-functions of a specific continuous-discrete propagation operator, with M being the number of microphones in the array. (2) The a priori inclusion of spatial information on the source field causes super-resolution according to a phenomenon coined "Bayesian focusing." (3) The approach is naturally endowed with an internal regularization mechanism and results in a robust regularization criterion with no more than one minimum. (4) It admits classical methods as particular cases. PMID- 22501067 TI - Transient-evoked otoacoustic emission generators in a nonlinear cochlea. AB - This study focuses on the theoretical prediction and experimental evaluation of the latency of transient-evoked otoacoustic emissions. Response components with different delay have been identified in several studies. The main generator of the transient response is assumed to be coherent reflection from cochlear roughness near the resonant place. Additional components of different latency can be generated by different mechanisms. Experimental data are re-analyzed in this study to evaluate the dependence of the latency on stimulus level, for each component of the response, showing that previous estimates of the otoacoustic emission latency were affected by systematic errors. The latency of the emission from each generator changes very little with stimulus level, whereas their different growth rate causes sharp changes of the single-valued latency, estimated as the time of the absolute maximum of the bandpass filtered response. Results of passive linear models, in which gain and bandwidth of the cochlear amplifier are strictly related, are incompatible with the observations. Although active linear models including delayed stiffness terms do predict much slower dependence of latency on the stimulus level, a suitable nonlinear model should be designed, capable of decoupling more effectively the dependence on stimulus level of amplitude and phase of the otoacoustic response. PMID- 22501068 TI - Channel selection in the modulation domain for improved speech intelligibility in noise. AB - Background noise reduces the depth of the low-frequency envelope modulations known to be important for speech intelligibility. The relative strength of the target and masker envelope modulations can be quantified using a modulation signal-to-noise ratio, (S/N)(mod), measure. Such a measure can be used in noise suppression algorithms to extract target-relevant modulations from the corrupted (target + masker) envelopes for potential improvement in speech intelligibility. In the present study, envelopes are decomposed in the modulation spectral domain into a number of channels spanning the range of 0-30 Hz. Target-dominant modulations are identified and retained in each channel based on the (S/N)(mod) selection criterion, while modulations which potentially interfere with perception of the target (i.e., those dominated by the masker) are discarded. The impact of modulation-selective processing on the speech-reception threshold for sentences in noise is assessed with normal-hearing listeners. Results indicate that the intelligibility of noise-masked speech can be improved by as much as 13 dB when preserving target-dominant modulations, present up to a modulation frequency of 18 Hz, while discarding masker-dominant modulations from the mixture envelopes. PMID- 22501069 TI - Informational masking of speech produced by speech-like sounds without linguistic content. AB - This study investigated whether speech-like maskers without linguistic content produce informational masking of speech. The target stimuli were nonsense Chinese Mandarin sentences. In experiment I, the masker contained harmonics the fundamental frequency (F0) of which was sinusoidally modulated and the mean F0 of which was varied. The magnitude of informational masking was evaluated by measuring the change in intelligibility (releasing effect) produced by inducing a perceived spatial separation of the target speech and masker via the precedence effect. The releasing effect was small and was only clear when the target and masker had the same mean F0, suggesting that informational masking was small. Performance with the harmonic maskers was better than with a steady speech-shaped noise (SSN) masker. In experiments II and III, the maskers were speech-like synthesized signals, alternating between segments with harmonic structure and segments composed of SSN. Performance was much worse than for experiment I, and worse than when an SSN masker was used, suggesting that substantial informational masking occurred. The similarity of the F0 contours of the target and masker had little effect. The informational masking effect was not influenced by whether or not the noise-like segments of the masker were synchronous with the unvoiced segments of the target speech. PMID- 22501070 TI - Effects of pulsing of a target tone on the ability to hear it out in different types of complex sounds. AB - Judgments of whether a sinusoidal probe is higher or lower in frequency than the closest partial ("target") in a multi-partial complex are improved when the target is pulsed on and off. These experiments explored the contribution of reduction in perceptual confusion and recovery from adaptation to this effect. In experiment 1, all partials except the target were replaced by noise to reduce perceptual confusion. Performance was much better than when the background was composed of multiple partials. When the level of the target was reduced to avoid ceiling effects, no effect of pulsing the target occurred. In experiment 2, the target and background partials were irregularly and independently amplitude modulated. This gave a large effect of pulsing the target, suggesting that if recovery from adaptation contributes to the effect, amplitude fluctuations do not prevent this. In experiment 3, the background was composed of multiple steady partials, but the target was irregularly amplitude modulated. This gave better performance than when the target was unmodulated and a moderate effect of pulsing the target. It is argued that when the target and background are steady tones, pulsing the target may result both in reduction of perceptual confusion and recovery from adaptation. PMID- 22501071 TI - Sensitivity of school-aged children to pitch-related cues. AB - Two experiments investigated the ability of 17 school-aged children to process purely temporal and spectro-temporal cues that signal changes in pitch. Percentage correct was measured for the discrimination of sinusoidal amplitude modulation rate (AMR) of broadband noise in experiment 1 and for the discrimination of fundamental frequency (F0) of broadband sine-phase harmonic complexes in experiment 2. The reference AMR was 100 Hz as was the reference F0. A child-friendly interface helped listeners to remain attentive to the task. Data were fitted using a maximum-likelihood technique that extracted threshold, slope, and lapse rate. All thresholds were subsequently standardized to a common d' value equal to 0.77. There were relatively large individual differences across listeners: eight had relatively adult-like thresholds in both tasks and nine had higher thresholds. However, these individual differences did not vary systematically with age, over the span of 6-16 yr. Thresholds were correlated across the two tasks and were about nine times finer for F0 discrimination than for AMR discrimination as has been previously observed in adults. PMID- 22501072 TI - Rapid head-related transfer function adaptation using a virtual auditory environment. AB - The paper reports on the ability of people to rapidly adapt in localizing virtual sound sources in both azimuth and elevation when listening to sounds synthesized using non-individualized head-related transfer functions (HRTFs). Participants were placed within an audio-kinesthetic Virtual Auditory Environment (VAE) platform that allows association of the physical position of a virtual sound source with an alternate set of acoustic spectral cues through the use of a tracked physical ball manipulated by the subject. This set-up offers a natural perception-action coupling, which is not limited to the visual field of view. The experiment consisted of three sessions: an initial localization test to evaluate participants' performance, an adaptation session, and a subsequent localization test. A reference control group was included using individual measured HRTFs. Results show significant improvement in localization performance. Relative to the control group, participants using non-individual HRTFs reduced localization errors in elevation by 10 degrees with three sessions of 12 min. No significant improvement was found for azimuthal errors or for single session adaptation. PMID- 22501074 TI - Relating binaural pitch perception to the individual listener's auditory profile. AB - The ability of eight normal-hearing listeners and fourteen listeners with sensorineural hearing loss to detect and identify pitch contours was measured for binaural-pitch stimuli and salience-matched monaurally detectable pitches. In an effort to determine whether impaired binaural pitch perception was linked to a specific deficit, the auditory profiles of the individual listeners were characterized using measures of loudness perception, cognitive ability, binaural processing, temporal fine structure processing, and frequency selectivity, in addition to common audiometric measures. Two of the listeners were found not to perceive binaural pitch at all, despite a clear detection of monaural pitch. While both binaural and monaural pitches were detectable by all other listeners, identification scores were significantly lower for binaural than for monaural pitch. A total absence of binaural pitch sensation coexisted with a loss of a binaural signal-detection advantage in noise, without implying reduced cognitive function. Auditory filter bandwidths did not correlate with the difference in pitch identification scores between binaural and monaural pitches. However, subjects with impaired binaural pitch perception showed deficits in temporal fine structure processing. Whether the observed deficits stemmed from peripheral or central mechanisms could not be resolved here, but the present findings may be useful for hearing loss characterization. PMID- 22501073 TI - The effect of an additional reflection in a precedence effect experiment. AB - Studies on the precedence effect typically utilize a two-source paradigm, which is not realistic relative to real world situations where multiple reflections exist. A step closer to multiple-reflection situations was studied using a three source paradigm. Discrimination of interaural time differences (ITDs) was measured for one-, two-, and three-source stimuli, using clicks presented over headphones. The ITD was varied in either the first, second, or the third source. The inter-source intervals ranged from 0-130 ms. A perceptual weighting model was extended to incorporate the three-source stimuli and used to interpret the data. The effect of adding a third source could mostly, but not entirely, be understood by the interaction of effects observed in the precedence effect with two sources. Specifically, for delays between 1 and 8 ms, the ITD information of prior sources was typically weighted more heavily than subsequent sources. For delays greater than 8 ms, subsequent sources were typically weighted slightly more heavily than prior sources. However, there were specific conditions that showed a more complex interaction between the sources. These findings suggest that the two-source paradigm provides a strong basis for understanding how the auditory system processes reflections in spatial hearing tasks. PMID- 22501075 TI - Effect of enhancement of spectral changes on speech intelligibility and clarity preferences for the hearing impaired. AB - Most information in speech is carried in spectral changes over time, rather than in static spectral shape per se. A form of signal processing aimed at enhancing spectral changes over time was developed and evaluated using hearing-impaired listeners. The signal processing was based on the overlap-add method, and the degree and type of enhancement could be manipulated via four parameters. Two experiments were conducted to assess speech intelligibility and clarity preferences. Three sets of parameter values (one corresponding to a control condition), two types of masker (steady speech-spectrum noise and two-talker speech) and two signal-to-masker ratios (SMRs) were used for each masker type. Generally, the effects of the processing were small, although intelligibility was improved by about 8 percentage points relative to the control condition for one set of parameter values using the steady noise masker at -6 dB SMR. The processed signals were not preferred over those for the control condition, except for the steady noise masker at -6 dB SMR. Further work is needed to determine whether tailoring the processing to the characteristics of the individual hearing impaired listener is beneficial. PMID- 22501076 TI - Source-tract interaction with prescribed vocal fold motion. AB - An equation describing the time-evolution of glottal volume velocity with specified vocal fold motion is derived when the sub- and supra-glottal vocal tracts are present. The derivation of this Fant equation employs a property explicated in Howe and McGowan [(2011) J. Fluid Mech. 672, 428-450] that the Fant equation is the adjoint to the equation characterizing the matching conditions of sub- and supra-glottal Green's functions segments with the glottal segment. The present aeroacoustic development shows that measurable quantities such as input impedances at the glottis, provide the coefficients for the Fant equation when source-tract interaction is included in the development. Explicit expressions for the Green's function are not required. With the poles and zeros of the input impedance functions specified, the Fant equation can be solved. After the general derivation of the Fant equation, the specific cases where plane wave acoustic propagation is described either by a Sturm-Liouville problem or concatenated cylindrical tubes is considered. Simulations show the expected skewing of the glottal volume velocity pulses depending on whether the fundamental frequency is below or above a sub- or supra-glottal formant. More complex glottal wave forms result when both the first supra-glottal fundamental frequencies are high and close to the first sub-glottal formant. PMID- 22501077 TI - A study of high front vowels with articulatory data and acoustic simulations. AB - The purpose of this study is to test a methodology for describing the articulation of vowels. High front vowels are a test case because some theories suggest that high front vowels have little cross-linguistic variation. Acoustic studies appear to show counterexamples to these predictions, but purely acoustic studies are difficult to interpret because of the many-to-one relation between articulation and acoustics. In this study, vocal tract dimensions, including constriction degree and position, are measured from cineradiographic and x-ray data on high front vowels from three different languages (North American English, French, and Mandarin Chinese). Statistical comparisons find several significant articulatory differences between North American English /i/ and Mandarin Chinese and French /i/. In particular, differences in constriction degree were found, but not constriction position. Articulatory synthesis is used to model the acoustic consequences of some of the significant articulatory differences, finding that the articulatory differences may have the acoustic consequences of making the latter languages' /i/ perceptually sharper by shifting the frequencies of F(2) and F(3) upwards. In addition, the vowel /y/ has specific articulations that differ from those for /i/, including a wider tongue constriction, and substantially different acoustic sensitivity functions for F(2) and F(3). PMID- 22501078 TI - The development of acoustic cues to coda contrasts in young children learning American English. AB - Research on children's speech perception and production suggests that consonant voicing and place contrasts may be acquired early in life, at least in word-onset position. However, little is known about the development of the acoustic correlates of later-acquired, word-final coda contrasts. This is of particular interest in languages like English where many grammatical morphemes are realized as codas. This study therefore examined how various non-spectral acoustic cues vary as a function of stop coda voicing (voiced vs. voiceless) and place (alveolar vs. velar) in the spontaneous speech of 6 American-English-speaking mother-child dyads. The results indicate that children as young as 1;6 exhibited many adult-like acoustic cues to voicing and place contrasts, including longer vowels and more frequent use of voice bar with voiced codas, and a greater number of bursts and longer post-release noise for velar codas. However, 1;6-year-olds overall exhibited longer durations and more frequent occurrence of these cues compared to mothers, with decreasing values by 2;6. Thus, English-speaking 1;6 year-olds already exhibit adult-like use of some of the cues to coda voicing and place, though implementation is not yet fully adult-like. Physiological and contextual correlates of these findings are discussed. PMID- 22501079 TI - The influence of stop consonants' perceptual features on the Articulation Index model. AB - Studies on consonant perception under noise conditions typically describe the average consonant error as exponential in the Articulation Index (AI). While this AI formula nicely fits the average error over all consonants, it does not fit the error for any consonant at the utterance level. This study analyzes the error patterns of six stop consonants /p, t, k, b, d, g/ with four vowels (/alpha/, /epsilon/, /I/, /ae/), at the individual consonant (i.e., utterance) level. The findings include that the utterance error is essentially zero for signal to noise ratios (SNRs) at least -2 dB, for >78% of the stop consonant utterances. For these utterances, the error is essentially a step function in the SNR at the utterance's detection threshold. This binary error dependence is consistent with the audibility of a single binary defining acoustic feature, having zero error above the feature's detection threshold. Also 11% of the sounds have high error, defined as >= 20% for SNRs greater than or equal to -2 dB. A grand average across many such sounds, having a natural distribution in thresholds, results in the error being exponential in the AI measure, as observed. A detailed analysis of the variance from the AI error is provided along with a Bernoulli-trials analysis of the statistical significance. PMID- 22501081 TI - The interrelation between acoustic context effects and available response categories in speech sound categorization. AB - In an investigation of contextual influences on sound categorization, 64 Peruvian Spanish listeners categorized vowels on an /i/ to /e/ continuum. First, to measure the influence of the stimulus range (broad acoustic context) and the preceding stimuli (local acoustic context), listeners were presented with different subsets of the Spanish /i/-/e/ continuum in separate blocks. Second, the influence of the number of response categories was measured by presenting half of the participants with /i/ and /e/ as responses, and the other half with /i/, /e/, /a/, /o/, and /u/. The results showed that the perceptual category boundary between /i/ and /e/ shifted depending on the stimulus range and that the formant values of locally preceding items had a contrastive influence. Categorization was less susceptible to broad and local acoustic context effects, however, when listeners were presented with five rather than two response options. Vowel categorization depends not only on the acoustic properties of the target stimulus, but also on its broad and local acoustic context. The influence of such context is in turn affected by the number of internal referents that are available to the listener in a task. PMID- 22501080 TI - Talker-identification training using simulations of binaurally combined electric and acoustic hearing: generalization to speech and emotion recognition. AB - Understanding speech in background noise, talker identification, and vocal emotion recognition are challenging for cochlear implant (CI) users due to poor spectral resolution and limited pitch cues with the CI. Recent studies have shown that bimodal CI users, that is, those CI users who wear a hearing aid (HA) in their non-implanted ear, receive benefit for understanding speech both in quiet and in noise. This study compared the efficacy of talker-identification training in two groups of young normal-hearing adults, listening to either acoustic simulations of unilateral CI or bimodal (CI+HA) hearing. Training resulted in improved identification of talkers for both groups with better overall performance for simulated bimodal hearing. Generalization of learning to sentence and emotion recognition also was assessed in both subject groups. Sentence recognition in quiet and in noise improved for both groups, no matter if the talkers had been heard during training or not. Generalization to improvements in emotion recognition for two unfamiliar talkers also was noted for both groups with the simulated bimodal-hearing group showing better overall emotion recognition performance. Improvements in sentence recognition were retained a month after training in both groups. These results have potential implications for aural rehabilitation of conventional and bimodal CI users. PMID- 22501082 TI - Dialect experience and perceptual integrality in phonological registers: fundamental frequency, voice quality and the first formant in Cham. AB - The perceptual integrality of f0, F1 and voice quality is investigated by looking at register, a phonological contrast that relies on these three properties in three dialects of Cham, an Austronesian language of Mainland Southeast Asia. The results of a Garner classification experiment confirm that the three acoustic properties integrate perceptually and that their patterns of integrality are similar in the three dialects. Moreover, they show that dialect-specific sensitivity to acoustic properties can cause salient dimensions to override weaker ones. Finally, the patterns of integrality found in Cham suggest that auditory integrality is not limited to acoustically similar properties. PMID- 22501083 TI - The influence of non-spatial factors on measures of spatial release from masking. AB - This study tested the hypothesis that the reduction in spatial release from masking (SRM) resulting from sensorineural hearing loss in competing speech mixtures is influenced by the characteristics of the interfering speech. A frontal speech target was presented simultaneously with two intelligible or two time-reversed (unintelligible) speech maskers that were either colocated with the target or were symmetrically separated from the target in the horizontal plane. The difference in SRM between listeners with hearing impairment and listeners with normal hearing was substantially larger for the forward maskers (deficit of 5.8 dB) than for the reversed maskers (deficit of 1.6 dB). This was driven by the fact that all listeners, regardless of hearing abilities, performed similarly (and poorly) in the colocated condition with intelligible maskers. The same conditions were then tested in listeners with normal hearing using headphone stimuli that were degraded by noise vocoding. Reducing the number of available spectral channels systematically reduced the measured SRM, and again, more so for forward (reduction of 3.8 dB) than for reversed speech maskers (reduction of 1.8 dB). The results suggest that non-spatial factors can strongly influence both the magnitude of SRM and the apparent deficit in SRM for listeners with impaired hearing. PMID- 22501084 TI - Sentence recognition in noise promoting or suppressing masking release by normal hearing and cochlear-implant listeners. AB - Normal-hearing (NH) listeners maintain robust speech understanding in modulated noise by "glimpsing" portions of speech from a partially masked waveform--a phenomenon known as masking release (MR). Cochlear implant (CI) users, however, generally lack such resiliency. In previous studies, temporal masking of speech by noise occurred randomly, obscuring to what degree MR is attributable to the temporal overlap of speech and masker. In the present study, masker conditions were constructed to either promote (+MR) or suppress (-MR) masking release by controlling the degree of temporal overlap. Sentence recognition was measured in 14 CI subjects and 22 young-adult NH subjects. Normal-hearing subjects showed large amounts of masking release in the +MR condition and a marked difference between +MR and -MR conditions. In contrast, CI subjects demonstrated less effect of MR overall, and some displayed modulation interference as reflected by poorer performance in modulated maskers. These results suggest that the poor performance of typical CI users in noise might be accounted for by factors that extend beyond peripheral masking, such as reduced segmental boundaries between syllables or words. Encouragingly, the best CI users tested here could take advantage of masker fluctuations to better segregate the speech from the background. PMID- 22501085 TI - The role of stimulus cross-splicing in an event-related potentials study. Misleading formant transitions hinder automatic phonological processing. AB - The mental organization of linguistic knowledge and its involvement in speech processing can be investigated using the mismatch negativity (MMN) component of the auditory event-related potential. A contradiction arises, however, between the technical need for strict control of acoustic stimulus properties and the quest for naturalness and acoustic variability of the stimuli. Here, two methods of preparing speech stimulus material were compared. Focussing on the automatic processing of a phonotactic restriction in German, two corresponding sets of various vowel-fricative syllables were used as stimuli. The former syllables were naturally spoken while the latter ones were created by means of cross-splicing. Phonetically, natural and spliced syllables differed with respect to the appropriateness of coarticulatory information about the forthcoming fricative within the vowels. Spliced syllables containing clearly misleading phonetic information were found to elicit larger N2 responses compared to their natural counterparts. Furthermore, MMN results found for the natural syllables could not be replicated with these spliced stimuli. These findings indicate that the automatic processing of the stimuli was considerably affected by the stimulus preparation method. Thus, in spite of its unquestioned benefits for MMN experiments, the splicing technique may lead to interference effects on the linguistic factors under investigation. PMID- 22501086 TI - Acoustic analysis of trill sounds. AB - In this paper, the acoustic-phonetic characteristics of steady apical trills- trill sounds produced by the periodic vibration of the apex of the tongue--are studied. Signal processing methods, namely, zero-frequency filtering and zero time liftering of speech signals, are used to analyze the excitation source and the resonance characteristics of the vocal tract system, respectively. Although it is natural to expect the effect of trilling on the resonances of the vocal tract system, it is interesting to note that trilling influences the glottal source of excitation as well. The excitation characteristics derived using zero frequency filtering of speech signals are glottal epochs, strength of impulses at the glottal epochs, and instantaneous fundamental frequency of the glottal vibration. Analysis based on zero-time liftering of speech signals is used to study the dynamic resonance characteristics of vocal tract system during the production of trill sounds. Qualitative analysis of trill sounds in different vowel contexts, and the acoustic cues that may help spotting trills in continuous speech are discussed. PMID- 22501087 TI - Characterization of woodwind instrument toneholes with the finite element method. AB - A method is proposed to determine the transfer matrix parameters of a discontinuity in a waveguide with the finite element method (FEM). This is used to characterize open and closed woodwind instrument toneholes and develop expressions for the shunt and series equivalent lengths. Two types of toneholes are characterized: Unflanged toneholes made of thin material, such as found on saxophones and concert flutes, and toneholes drilled through a thick material, such as found on most instruments made of wood. The results are compared with previous tonehole models from the literature. In general, the proposed expressions provide a better fit across a wide range of frequencies and tonehole sizes than previous results. For tall toneholes, the results are in general agreement with previous models. For shorter tonehole heights, some discrepancies from previous results are found that are most important for larger diameter toneholes. Finally, the impact of a main bore taper (conicity) on the characterization of toneholes was investigated and found to be negligible for taper angles common in musical instruments. PMID- 22501088 TI - Rapid crystallization from acoustically levitated droplets. AB - This paper reports on an ultrasonic levitation system developed for crystallization from solution in a containerless condition. The system has been proven to be able to levitate droplets stably and grow crystals rapidly and freely from a levitated droplet. Crystals of four samples, including NaCl, NH(4)Cl, lysozyme, and proteinase K, were obtained successfully utilizing the system. The studies showed that the crystals obtained from the acoustically levitated droplets all exhibited higher growth rates, larger sizes, better shapes, fewer crystals, as well as fewer twins and shards, compared with the control on a vessel wall. The results indicated that containerless ultrasonic levitation could play a key role in improving the crystallization of both inorganic salts and proteins. The ultrasonic levitation system could be used as a ground-based microgravity simulation platform, which could swiftly perform crystallization and screening of crystallization conditions for space crystallization and other ground-based containerless techniques. Moreover, the approach could also be conveniently applied to researching the dynamics and mechanism of crystallization. In addition, the device could be used for the preparation of high-purity materials, analysis of minute or poisonous samples, study of living cells, environmental monitoring, and so on. PMID- 22501089 TI - Characteristics of gunshot sound displays by North Atlantic right whales in the Bay of Fundy. AB - North Atlantic right whales (Eubalaena glacialis) produce a loud, broadband signal referred to as the gunshot sound. These distinctive sounds may be suitable for passive acoustic monitoring and detection of right whales; however, little is known about the prevalence of these sounds in important right whale habitats, such as the Bay of Fundy. This study investigates the timing and distribution of gunshot sound production on the summer feeding grounds using an array of five marine acoustic recording units deployed in the Bay of Fundy, Canada in mid summer 2004 and 2005. Gunshot sounds were common, detected on 37 of 38 recording days. Stereotyped gunshot bouts averaged 1.5 h, with some bouts exceeding 7 h in duration with up to seven individuals producing gunshots at any one time. Bouts were more commonly detected in the late afternoon and evening than during the morning hours. Locations of gunshots in bouts indicated that whales producing the sounds were either stationary or showed directional travel, suggesting gunshots have different communication functions depending on behavioral context. These results indicate that gunshots are a common right whale sound produced during the summer months and are an important component in the acoustic communication system of this endangered species. PMID- 22502482 TI - Time reversal acoustic communication for multiband transmission. AB - In this letter, multiband acoustic communication is proposed to access a relatively wide frequency band. The entire frequency band is divided into multiple separated sub-bands, each of which is several kilohertz in width. Time reversal decision feedback equalizers are used to compensate for inter-symbol interference at each sub-band. The communication scheme was demonstrated in a shallow water acoustic experiment conducted in Kauai, Hawaii during the summer of 2011. Using quadrature phase-shift keying signaling at four sub-bands over the frequency band of 10-32 kHz, a data rate of 32 k bits/s was achieved over a 3 km communication range. PMID- 22502483 TI - Characterization of circumferential guided waves in a cylindrical cortical bone mimicking phantom. AB - The femoral neck cortical shell was recently demonstrated to act like a waveguide for circumferential waves. Femoral neck assessment with ultrasound could be enhanced by guided waves measurement. In this study, the decomposition of the time reversal operator (DORT) method is used to measure the phase velocities of circumferential guided modes in a circular tube with dimensions characteristic of femoral neck. The tube is made of a bone-mimicking material. Five guided modes are obtained and compared to theoretical predictions. The work substantiates the feasibility of measuring guided waves in a relatively thick tube of attenuating material with the DORT method. PMID- 22502484 TI - High-frequency modulated signals of killer whales (Orcinus orca) in the North Pacific. AB - Killer whales in the North Pacific, similar to Atlantic populations, produce high frequency modulated signals, based on acoustic recordings from ship-based hydrophone arrays and autonomous recorders at multiple locations. The median peak frequency of these signals ranged from 19.6-36.1 kHz and median duration ranged from 50-163 ms. Source levels were 185-193 dB peak-to-peak re: 1 MUPa at 1 m. These uniform, repetitive, down-swept signals are similar to bat echolocation signals and possibly could have echolocation functionality. A large geographic range of occurrence suggests that different killer whale ecotypes may utilize these signals. PMID- 22502485 TI - Modeling interface roughness scattering in a layered seabed for normal-incident chirp sonar signals. AB - Downward looking sonar, such as the chirp sonar, is widely used as a sediment survey tool in shallow water environments. Inversion of geo-acoustic parameters from such sonar data precedes the availability of forward models. An exact numerical model is developed to initiate the simulation of the acoustic field produced by such a sonar in the presence of multiple rough interfaces. The sediment layers are assumed to be fluid layers with non-intercepting rough interfaces. PMID- 22502486 TI - Extracting the Green's function from measurements of the energy flux. AB - Existing methods for Green's function extraction give the Green's function from the correlation of field fluctuations recorded at those points. In this work it is shown that the Green's function for acoustic waves can be retrieved from measurements of the integrated energy flux through a closed surface taken from three experiments where two time-harmonic sources first operate separately, and then simultaneously. This makes it possible to infer the Green's function in acoustics from measurements of the energy flux through an arbitrary closed surface surrounding both sources. The theory is also applicable to quantum mechanics where the Green's function can be retrieved from measurement of the flux of scattered particles through a closed surface. PMID- 22502487 TI - Acoustic performance of a duct loaded with identical resonators. AB - This paper presents a theoretical study of a duct loaded with identical side branch resonators. The Bloch wave theory and the transfer matrix method are used to investigate wave propagation in the duct. It is found that this duct-resonator system has a unique attenuation characteristic brought about by structural periodicity. Three types of stop-bands are discussed and their bandwidths are predicted. All of the results predicted by the theory fit well with a computer simulation using a three-dimensional finite element method. Compared to a single resonator, this structure may have a potential application in broadband noise control. PMID- 22502488 TI - Individual and level-dependent differences in masking for adults with normal and impaired hearing. AB - Simultaneous, on-frequency masking is commonly assumed to be linear with increasing noise intensity. However, some evidence suggests that, expressed in terms of signal-to-noise ratio changes with background level changes, masking slopes can vary from 0 dB/dB. These results and evidence from a large sample of subjects with normal and impaired hearing demonstrate level-dependent changes in masking, large individual differences in masking among subjects with similar thresholds in quiet, and significant correlations of masking slope with other estimates of auditory function measured in the same backgrounds. PMID- 22502489 TI - Axial radiation force exerted by general non-diffracting beams. AB - The axial radiation force exerted by a general non-diffracting beam on an object of arbitrary shape in lossless medium is analyzed. The object may be on or off the beam's axis. The analysis is based on the plane-wave representation of the beam using an azimuthal function and conical angle. The analytical expression relates the force to axial projections of the extracted and scattered momentum. Using an extended optical theorem, the extinction is related to the scattering at the forward direction of the beam's plane wave components. The axial force is expressed using the scattering amplitude and known angular functions. PMID- 22502490 TI - Effects of repeated production on vowel distinctiveness within nonwords. AB - In the present study acoustic distinctiveness of vowels within nonwords with repeated production was investigated. Participants were 9 males and 15 females divided into two groups. Participants repeated 6 nonwords varying in phonemic composition. The mean Euclidean distance (MED) of the vowels from each production of a nonword from the center of the F1/F2 space was calculated. The changes in MED with repeated production were analyzed using linear mixed effects regression. Results revealed an increase in MED, indicating greater vowel dispersion, for the three-syllable nonwords and a significant decrease, i.e., greater reduction, in vowel dispersion for the six-syllable nonwords. Findings support the dynamic influence of sublexical processes on phonetic realization in speech production. PMID- 22502491 TI - Bidirectional equalization for underwater acoustic communication. AB - The bidirectional decision feedback equalizer (BiDFE) that combines the outputs of a conventional decision feedback equalizer (DFE) and backward DFE can improve the performance of the conventional DFE by up to 1-2 dB based on simulations. In this letter, the BiDFE concept is extended to multichannel time reversal communications involving a DFE as a post-processor. Experimental data collected in shallow water (10-20 kHz) show that the performance can be enhanced by 0.4-1.8 dB in terms of output signal-to-noise ratio. In particular, a larger improvement (e.g., 1.8 dB) is achieved for time-varying channels where the channel diversity in opposite directions is more profound. PMID- 22502492 TI - Presence detection under optimum fusion in an ultrasonic sensor system. AB - Reliable presence detection is a requirement in energy-efficient occupancy adaptive indoor lighting systems. A system of multiple ultrasonic sensors is considered for presence detection, and the performance gain from optimum fusion is studied. Two cases are considered wherein an individual sensor determines presence based on (i) local detection by processing echoes at its receiver, and (ii) the optimum Chair-Varshney fusion rule using multiple sensor detection results. The performance gains of using optimum fusion over local detection are characterized under different sensor system configurations and it is shown that improved detection sensitivity is obtained over a larger detection coverage region. PMID- 22502493 TI - Communication: Competition between pi...pi interaction and halogen bond in solution: a combined 13C NMR and density functional theory study. AB - Competition between pi...pi interaction and halogen bond in solution has been investigated by using carbon nuclear magnetic resonance spectroscopy ((13)C NMR) combined with density functional theory calculation. Both experimental and theoretical results clearly show that there are no C-Cl...pi or C-Br...pi halogen bonds and only the pi...pi interactions exist in the binary liquid mixtures of C(6)D(6) with C(6)F(5)Cl and C(6)F(5)Br, respectively. The case is totally different for the binary liquid mixtures of C(6)D(6) with C(6)F(5)I in which the C-I...pi halogen bonds not the pi...pi interactions are present. The important role of entropy in the competition between pi...pi interaction and halogen bond in solution was also discussed. PMID- 22502494 TI - Communication: Scanning tunneling microscopy study of the reaction of octanethiolate self-assembled monolayers with atomic chlorine. AB - Scanning tunneling microscopy was used to investigate the reaction of octanethiolate self-assembled monolayers (SAMs) with atomic chlorine. We have found that exposing a SAM to low fluxes of radical Cl results primarily in the formation of new defects in areas with close-packed alkanethiolates, but has little to no effect on the domain boundaries of the SAM. Dosing high quantities of atomic chlorine results in the near-complete loss of surface order at room temperature, but not the complete removal of the thiolate monolayer. These observations are in stark contrast to the results of previous measurements of the reaction of atomic hydrogen with alkanethiolate SAMs. PMID- 22502495 TI - On the evaluation of the non-interacting kinetic energy in density functional theory. AB - The utility of both an orbital-free and a single-orbital expression for computing the non-interacting kinetic energy in density functional theory is investigated for simple atomic systems. The accuracy of both expressions is governed by the extent to which the Kohn-Sham equation is solved for the given exchange correlation functional and so special attention is paid to the influence of finite Gaussian basis sets. The orbital-free expression is a statement of the virial theorem and its accuracy is quantified. The accuracy of the single-orbital expression is sensitive to the choice of Kohn-Sham orbital. The use of particularly compact orbitals is problematic because the failure to solve the Kohn-Sham equation exactly in regions where the orbital has decayed to near-zero leads to unphysical behaviour in regions that contribute to the kinetic energy, rendering it inaccurate. This problem is particularly severe for core orbitals, which would otherwise appear attractive due to their formally nodeless nature. The most accurate results from the single-orbital expression are obtained using the relatively diffuse, highest occupied orbitals, although special care is required at orbital nodes. PMID- 22502496 TI - Theory of binless multi-state free energy estimation with applications to protein ligand binding. AB - The weighted histogram analysis method (WHAM) is routinely used for computing free energies and expectations from multiple ensembles. Existing derivations of WHAM require observations to be discretized into a finite number of bins. Yet, WHAM formulas seem to hold even if the bin sizes are made arbitrarily small. The purpose of this article is to demonstrate both the validity and value of the multi-state Bennet acceptance ratio (MBAR) method seen as a binless extension of WHAM. We discuss two statistical arguments to derive the MBAR equations, in parallel to the self-consistency and maximum likelihood derivations already known for WHAM. We show that the binless method, like WHAM, can be used not only to estimate free energies and equilibrium expectations, but also to estimate equilibrium distributions. We also provide a number of useful results from the statistical literature, including the determination of MBAR estimators by minimization of a convex function. This leads to an approach to the computation of MBAR free energies by optimization algorithms, which can be more effective than existing algorithms. The advantages of MBAR are illustrated numerically for the calculation of absolute protein-ligand binding free energies by alchemical transformations with and without soft-core potentials. We show that binless statistical analysis can accurately treat sparsely distributed interaction energy samples as obtained from unmodified interaction potentials that cannot be properly analyzed using standard binning methods. This suggests that binless multi-state analysis of binding free energy simulations with unmodified potentials offers a straightforward alternative to the use of soft-core potentials for these alchemical transformations. PMID- 22502497 TI - Nonadiabatic Ehrenfest molecular dynamics within the projector augmented-wave method. AB - We derive equations for nonadiabatic Ehrenfest molecular dynamics within the projector augmented-wave (PAW) formalism. The discretization of the electrons is time-dependent as the augmentation functions depend on the positions of the nuclei. We describe the implementation of the Ehrenfest molecular dynamics equations within the real-space PAW method. We demonstrate the applicability of our method by studying the vibration of NaCl, the torsional rotation of H(2)C=NH(2)(+) in both the adiabatic and the nonadiabatic regimes, and the hydrogen bombardment of C(40)H(16). PMID- 22502498 TI - Combining active-space coupled-cluster methods with moment energy corrections via the CC(P;Q) methodology, with benchmark calculations for biradical transition states. AB - We have recently suggested the CC(P;Q) methodology that can correct energies obtained in the active-space coupled-cluster (CC) or equation-of-motion (EOM) CC calculations, which recover much of the nondynamical and some dynamical electron correlation effects, for the higher-order, mostly dynamical, correlations missing in the active-space CC/EOMCC considerations. It is shown that one can greatly improve the description of biradical transition states, both in terms of the resulting energy barriers and total energies, by combining the CC approach with singles, doubles, and active-space triples, termed CCSDt, with the CC(P;Q)-style correction due to missing triple excitations defining the CC(t;3) approximation. PMID- 22502499 TI - The orbital-specific-virtual local coupled cluster singles and doubles method. AB - We extend the orbital-specific-virtual tensor factorization, introduced for local Moller-Plesset perturbation theory in Ref. [J. Yang, Y. Kurashige, F. R. Manby and G. K. L. Chan, J. Chem. Phys. 134, 044123 (2011)], to local coupled cluster singles and doubles theory (OSV-LCCSD). The method is implemented by modifying an efficient projected-atomic-orbital local coupled cluster program (PAO-LCCSD) described recently, [H.-J. Werner and M. Schutz, J. Chem. Phys. 135, 144116 (2011)]. By comparison of both methods we find that the compact representation of the amplitudes in the OSV approach affords various advantages, including smaller computational time requirements (for comparable accuracy), as well as a more systematic control of the error through a single energy threshold. Overall, the OSV-LCCSD approach together with an MP2 correction yields small domain errors in practical calculations. The applicability of the OSV-LCCSD is demonstrated for molecules with up to 73 atoms and realistic basis sets (up to 2334 basis functions). PMID- 22502500 TI - Analytical solution for the depolarization of hyperpolarized nuclei by chemical exchange saturation transfer between free and encapsulated xenon (HyperCEST). AB - We present an analytical solution of the Bloch-McConnell equations for the case of chemical exchange saturation transfer between hyperpolarized nuclei in cavities and in solvent (HyperCEST experiment). This allows quantitative investigation of host-guest interactions by means of nuclear magnetic resonance spectroscopy and, due to the strong HyperCEST signal enhancement, even NMR imaging. Hosts of interest can be hydrophobic cavities in macromolecules or artificial cages like cryptophane-A which was proposed as a targeted biosensor. Relevant system parameters as exchange rate and host concentration can be obtained from the monoexponential depolarization process which is shown to be governed by the smallest eigenvalue in modulus. For this dominant eigenvalue we present a useful approximation leading to the depolarization rate for the case of on- and off-resonant irradiation. It is shown that this rate is a generalization of the longitudinal relaxation rate in the rotating frame. We demonstrate for the free and cryptophane-A-encapsulated xenon system, by comparison with numerical simulations, that HyperCEST experiments are precisely described in the valid range of this widely applicable analytical approximation. Altogether, the proposed analytical solution allows optimization and quantitative analysis of HyperCEST experiments but also characterization and optimal design of possible biosensors. PMID- 22502501 TI - Distance-dependent Schwarz-based integral estimates for two-electron integrals: reliable tightness vs. rigorous upper bounds. AB - A new integral estimate for four-center two-electron integrals is introduced that accounts for distance information between the bra- and ket-charge distributions describing the two electrons. The screening is denoted as QQR and combines the most important features of the conventional Schwarz screening by Haser and Ahlrichs published in 1989 [J. Comput. Chem. 10, 104 (1989)] and our multipole based integral estimates (MBIE) introduced in 2005 [D. S. Lambrecht and C. Ochsenfeld, J. Chem. Phys. 123, 184101 (2005)]. At the same time the estimates are not only tighter but also much easier to implement, so that we recommend them instead of our MBIE bounds introduced first for accounting for charge-distance information. The inclusion of distance dependence between charge distributions is not only useful at the SCF level but is particularly important for describing electron-correlation effects, e.g., within AO-MP2 theory, where the decay behavior is at least 1/R(4) or even 1/R(6). In our present work, we focus on studying the efficiency of our QQR estimates within SCF theory and demonstrate the performance for a benchmark set of 44 medium to large molecules, where savings of up to a factor of 2 for exchange integrals are observed for larger systems. Based on the results of the benchmark set we show that reliable tightness of integral estimates is more important for the screening performance than rigorous upper bound properties. PMID- 22502503 TI - Incorporating a completely renormalized coupled cluster approach into a composite method for thermodynamic properties and reaction paths. AB - The correlation consistent composite approach (ccCA), using the S4 complete basis set two-point extrapolation scheme (ccCA-S4), has been modified to incorporate the left-eigenstate completely renormalized coupled cluster method, including singles, doubles, and non-iterative triples (CR-CC(2,3)) as the highest level component. The new ccCA-CC(2,3) method predicts thermodynamic properties with an accuracy that is similar to that of the original ccCA-S4 method. At the same time, the inclusion of the single-reference CR-CC(2,3) approach provides a ccCA scheme that can correctly treat reaction pathways that contain certain classes of multi-reference species such as diradicals, which would normally need to be treated by more computationally demanding multi-reference methods. The new ccCA CC(2,3) method produces a mean absolute deviation of 1.7 kcal/mol for predicted heats of formation at 298 K, based on calibration with the G2/97 set of 148 molecules, which is comparable to that of 1.0 kcal/mol obtained using the ccCA-S4 method, while significantly improving the performance of the ccCA-S4 approach in calculations involving more demanding radical and diradical species. Both the ccCA-CC(2,3) and ccCA-S4 composite methods are used to characterize the conrotatory and disrotatory isomerization pathways of bicyclo[1.1.0]butane to trans-1,3-butadiene, for which conventional coupled cluster methods, such as the CCSD(T) approach used in the ccCA-S4 model and, in consequence, the ccCA-S4 method itself might fail by incorrectly placing the disrotatory pathway below the conrotatory one. The ccCA-CC(2,3) scheme provides correct pathway ordering while providing an accurate description of the activation and reaction energies characterizing the lowest-energy conrotatory pathway. The ccCA-CC(2,3) method is thus a viable method for the analyses of reaction mechanisms that have significant multi-reference character, and presents a generally less computationally intensive alternative to true multi-reference methods, with computer costs and ease of use that are similar to those that characterize the more established, CCSD(T)-based, ccCA-S4 methodology. PMID- 22502502 TI - Improved delay-leaping simulation algorithm for biochemical reaction systems with delays. AB - In biochemical reaction systems dominated by delays, the simulation speed of the stochastic simulation algorithm depends on the size of the wait queue. As a result, it is important to control the size of the wait queue to improve the efficiency of the simulation. An improved accelerated delay stochastic simulation algorithm for biochemical reaction systems with delays, termed the improved delay leaping algorithm, is proposed in this paper. The update method for the wait queue is effective in reducing the size of the queue as well as shortening the storage and access time, thereby accelerating the simulation speed. Numerical simulation on two examples indicates that this method not only obtains a more significant efficiency compared with the existing methods, but also can be widely applied in biochemical reaction systems with delays. PMID- 22502504 TI - Analytical evaluation of Fukui functions and real-space linear response function. AB - Many useful concepts developed within density functional theory provide much insight for the understanding and prediction of chemical reactivity, one of the main aims in the field of conceptual density functional theory. While approximate evaluations of such concepts exist, the analytical and efficient evaluation is, however, challenging, because such concepts are usually expressed in terms of functional derivatives with respect to the electron density, or partial derivatives with respect to the number of electrons, complicating the connection to the computational variables of the Kohn-Sham one-electron orbitals. Only recently, the analytical expressions for the chemical potential, one of the key concepts, have been derived by Cohen, Mori-Sanchez, and Yang, based on the potential functional theory formalism. In the present work, we obtain the analytical expressions for the real-space linear response function using the coupled perturbed Kohn-Sham and generalized Kohn-Sham equations, and the Fukui functions using the previous analytical expressions for chemical potentials of Cohen, Mori-Sanchez, and Yang. The analytical expressions are exact within the given exchange-correlation functional. They are applicable to all commonly used approximate functionals, such as local density approximation (LDA), generalized gradient approximation (GGA), and hybrid functionals. The analytical expressions obtained here for Fukui function and linear response functions, along with that for the chemical potential by Cohen, Mori-Sanchez, and Yang, provide the rigorous and efficient evaluation of the key quantities in conceptual density functional theory within the computational framework of the Kohn-Sham and generalized Kohn Sham approaches. Furthermore, the obtained analytical expressions for Fukui functions, in conjunction with the linearity condition of the ground state energy as a function of the fractional charges, also lead to new local conditions on the exact functionals, expressed in terms of the second-order functional derivatives. We implemented the expressions and demonstrate the efficacy with some atomic and molecular calculations, highlighting the importance of relaxation effects. PMID- 22502505 TI - Rejection-free Monte Carlo scheme for anisotropic particles. AB - We extend the geometric cluster algorithm [J. Liu and E. Luijten, Phys. Rev. Lett. 92, 035504 (2004)], a highly efficient, rejection-free Monte Carlo scheme for fluids and colloidal suspensions, to the case of anisotropic particles. This is made possible by adopting hyperspherical boundary conditions. A detailed derivation of the algorithm is presented, along with extensive implementation details as well as benchmark results. We describe how the quaternion notation is particularly suitable for the four-dimensional geometric operations employed in the algorithm. We present results for asymmetric Lennard-Jones dimers and for the Yukawa one-component plasma in hyperspherical geometry. The efficiency gain that can be achieved compared to conventional, Metropolis-type Monte Carlo simulations is investigated for rod-sphere mixtures as a function of rod aspect ratio, rod sphere diameter ratio, and rod concentration. The effect of curved geometry on physical properties is addressed. PMID- 22502506 TI - The splitting of atomic orbitals with a common principal quantum number revisited: np vs. ns. AB - Atomic orbitals with a common principal quantum number are degenerate, as in the hydrogen atom, in the absence of interelectronic repulsion. Due to the virial theorem, electrons in such orbitals experience equal nuclear attractions. Comparing states of several-electron atoms that differ by the occupation of orbitals with a common principal quantum number, such as 1s(2) 2s vs. 1s(2) 2p, we find that although the difference in energies, DeltaE, is due to the interelectronic repulsion term in the Hamiltonian, the difference between the interelectronic repulsions, DeltaC, makes a smaller contribution to DeltaE than the corresponding difference between the nuclear attractions, DeltaL. Analysis of spectroscopic data for atomic isoelectronic sequences allows an extensive investigation of these issues. In the low nuclear charge range of pertinent isoelectronic sequences, i.e., for neutral atoms and mildly positively charged ions, it is found that DeltaC actually reverses its sign. About 96% of the nuclear attraction difference between the 6p (2)P and the 6s (2)S states of the Cs atom is cancelled by the corresponding interelectronic repulsion difference. From the monotonic increase of DeltaE with Z it follows (via the Hellmann-Feynman theorem) that DeltaL > 0. Upon increasing the nuclear charge along an atomic isoelectronic sequence with a single electron outside a closed shell from Z(c), the critical charge below which the outmost electron is not bound, to infinity, the ratio DeltaC/DeltaL increases monotonically from lim(Z >Z(c)(+))DeltaC/DeltaL=-1 to lim(Z->infinity)DeltaC/DeltaL=1. These results should allow for a more nuanced discussion than is usually encountered of the crude electronic structure of many-electron atoms and the structure of the periodic table. PMID- 22502507 TI - Coupled-monomers in molecular assemblies: theory and application to the water tetramer, pentamer, and ring hexamer. AB - We present extensions to the local-monomer (LMon) Model, a general quantum method to describe coupled intramolecular vibrational modes of a molecular cluster consisting of a set of monomers [Y. Wang and J. M. Bowman, J. Chem. Phys. 134, 154510 (2011)], to incorporate monomer-monomer coupling. A central aspect of the LMon model is a local normal-mode analysis, done for each monomer, perturbed by all other mononers. Monomer-monomer coupling is described by several approaches based on these normal-mode analyses. Two are Huckel-type models, where coupling constants for each intramolecular mode are determined non-empirically from normal mode analyses. One model, the simple one, is limited to nearest-neighbor interactions. The second and more general one determines monomer-monomer couplings from the full and local-monomer Hessians, with no further assumptions. The simple approach is applied to the water tetramer, pentamer and ring hexamer. For the tetramer and ring hexamer cases, artificial degeneracies of the intramolecular energies in the LMon model, owing to the high symmetry of the cluster, are correctly lifted. The general approach to obtain coupling constants is illustrated for the ring hexamer, where new fundamental energies are reported. Other, more rigorous approaches are suggested but not implemented. PMID- 22502508 TI - Optimal coherent control of coherent anti-Stokes Raman scattering: signal enhancement and background elimination. AB - The ability to enhance resonant signals and eliminate the non-resonant background is analyzed for coherent anti-Stokes Raman scattering (CARS). The analysis is done at a specific frequency as well as for broadband excitation using femtosecond pulse-shaping techniques. An appropriate objective functional is employed to balance resonant signal enhancement against non-resonant background suppression. Optimal enhancement of the signal and minimization of the background can be achieved by shaping the probe pulse alone while keeping the pump and Stokes pulses unshaped. In some cases analytical forms for the probe pulse can be found, and numerical simulations are carried out for other circumstances. It is found that a good approximate optimal solution for resonant signal enhancement in two-pulse CARS is a superposition of linear and arctangent-type phases for the pump. The well-known probe delay method is shown to be a quasi-optimal scheme for broadband background suppression. The results should provide a basis to improve the performance of CARS spectroscopy and microscopy. PMID- 22502509 TI - Improved constraint satisfaction in a simple generalized gradient approximation exchange functional. AB - Though there is fevered effort on orbital-dependent approximate exchange correlation functionals, generalized gradient approximations, especially the Perdew-Burke-Ernzerhof (PBE) form, remain the overwhelming choice in calculations. A simple generalized gradient approximation (GGA) exchange functional [A. Vela, V. Medel, and S. B. Trickey, J. Chem. Phys. 130, 244103 (2009)] was developed that improves substantially over PBE in energetics (on a typical test set) while being almost as simple in form. The improvement came from constraining the exchange enhancement factor to be below the Lieb-Oxford bound for all but one value of the exchange dimensionless gradient, s, and to go to the uniform electron gas limit at both s = 0 and s -> infinity. Here we discuss the issue of asymptotic constraints for GGAs and show that imposition of the large s constraint, lim(s->infinity)s(1/2)F(xc)(n,s) 0 and r(12) -> 0 do not commute, DPT is doomed to fail due to incorrect descriptions of the small-small component Psi(SS) of the DC wave function for r(12) < R(c). Another deduction from the possible divergence of Psi(SS) at r(12) = R(c) is that the DC Hamiltonian has no bound electronic states, although the last word cannot be said. These findings enrich our understandings of relativistic wave functions. On the practical side, it is shown that, under the no-pair approximation, relativistic explicitly correlated wave function methods can be made completely parallel to the nonrelativistic counterparts, as demonstrated explicitly for MP2-F12. Yet, this can only be achieved by using an extended no-pair projector. PMID- 22502512 TI - Quantum Monte Carlo for the x-ray absorption spectrum of pyrrole at the nitrogen K-edge. AB - Fixed-node diffusion Monte Carlo (FNDMC) is used to simulate the x-ray absorption spectrum of a gas-phase pyrrole molecule at the nitrogen K-edge. Trial wave functions for core-excited states are constructed from ground-state Kohn-Sham determinants substituted with singly occupied natural orbitals from configuration interaction with single excitations calculations of the five lowest valence excited triplet states. The FNDMC ionization potential (IP) is found to lie within 0.3 eV of the experimental value of 406.1 +/- 0.1 eV. The transition energies to anti-bonding virtual orbitals match the experimental spectrum after alignment of IP values and agree with the existing assignments. PMID- 22502513 TI - Time-dependent wave packet theory for state-to-state differential cross sections of four-atom reactions in full dimensions: application to the HD + OH -> H2O + D reaction. AB - Time-dependent wave packet method has been developed to calculate differential cross section for four-atom reactions in full dimension, utilizing an improved version of reactant-product-decoupling scheme. Differential cross sections for the title reaction were calculated for collision energy up to 0.4 eV. It is found that the differential cross sections for the reaction are all peaked in the backward direction. The majority of H(2)O is produced in the first stretch excited state, with a large fraction of available energy for the reaction going into H(2)O internal motion. As compared in a previous report by Xiao et al. [Science 333, 440 (2011)], the differential cross section at E(c) = 0.3 eV and the differential cross section at the backward direction as a function of collision energy agree with experiment very well, indicating it is possible now to calculate complete dynamical information for some simple four-atom reactions, as have been done for three-atom reactions in the past decades. PMID- 22502514 TI - Quasi-classical trajectories study of Ne2Br2(B) vibrational predissociation: kinetics and product distributions. AB - The vibrational predissociation of the Ne(2)Br(2)(B) van der Waals complex has been investigated using the quasi-classical trajectory method (QCT), in the range of vibrational levels v(') = 16-23. Extensive comparison is made with the most recent experimental observations [Pio et al., J. Chem. Phys. 133, 014305 (2010)], molecular dynamics with quantum transitions simulations [Miguel et al., Faraday Discuss. 118, 257 (2001)], and preliminary results from 24-dimensional Cartesian coupled coherent state (CCCS) calculations. A sequential mechanism is found to accurately describe the theoretical dynamical evolution of intermediate and final product populations, and both QCT and CCCS provide very good estimates for the dissociation lifetimes. The capabilities of QCT in the description of the fragmentation kinetics are analyzed in detail by using reduced-dimensionality models of the complexes and concepts from phase-space transport theory. The problem of fast decoupling of the different coherent states in CCCS simulations, resulting from the high dimensionality of phase space, is tackled using a re expansion scheme. QCT ro-vibrational product state distributions are reported. Due to the weakness of the van der Waals couplings and the low density of vibrational states, QCT predicts a larger than observed propensity for Deltav' = 1 and -2 channels for the respective dissociation of the first and second Ne atoms. PMID- 22502515 TI - Auger spectrum of a water molecule after single and double core ionization. AB - The high intensity of free electron lasers opens up the possibility to perform single-shot molecule scattering experiments. However, even for small molecules, radiation damage induced by absorption of high intense x-ray radiation is not yet fully understood. One of the striking effects which occurs under intense x-ray illumination is the creation of double core ionized molecules in considerable quantity. To provide insight into this process, we have studied the dynamics of water molecules in single and double core ionized states by means of electronic transition rate calculations and ab initio molecular dynamics (MD) simulations. From the MD trajectories, photoionization and Auger transition rates were computed based on electronic continuum wavefunctions obtained by explicit integration of the coupled radial Schrodinger equations. These rates served to solve the master equations for the populations of the relevant electronic states. To account for the nuclear dynamics during the core hole lifetime, the calculated electron emission spectra for different molecular geometries were incoherently accumulated according to the obtained time-dependent populations, thus neglecting possible interference effects between different decay pathways. We find that, in contrast to the single core ionized water molecule, the nuclear dynamics for the double core ionized water molecule during the core hole lifetime leaves a clear fingerprint in the resulting electron emission spectra. The lifetime of the double core ionized water was found to be significantly shorter than half of the single core hole lifetime. PMID- 22502517 TI - An orbital and electron density analysis of weak interactions in ethanol-water, methanol-water, ethanol and methanol small clusters. AB - A computational study of (ethanol)(n)-water, n = 1 to 5 heteroclusters was carried out employing the B3LYP/6-31+G(d) approach. The molecular (MO) and atomic (AO) orbital analysis and the topological study of the electron density provided results that were successfully correlated. Results were compared with those obtained for (ethanol)(n), (methanol)(n), n = 1 to 6 clusters and (methanol)(n) water, n = 1 to 5 heteroclusters. These systems showed the same trends observed in the (ethanol)(n)-water, n = 1 to 5 heteroclusters such as an O---O distance of 5 A to which the O-H---O hydrogen bonds (HBs) can have significant influence on the constituent monomers. The HOMO of the hetero(clusters) is less stable than the HOMO of the isolated alcohol monomer as the hetero(cluster) size increases, that destabilization is higher for linear geometries than for cyclic geometries. Changes of the occupancy and energy of the AO are correlated with the strength of O-H---O and C-H---O HBs as well as with the proton donor and/or acceptor character of the involved molecules. In summary, the current MO and AO analysis provides alternative ways to characterize HBs. However, this analysis cannot be applied to the study of H---H interactions observed in the molecular graphs. PMID- 22502516 TI - Strength of hydrogen bonds of water depends on local environment. AB - In-depth knowledge of water-water potential is important for devising and evaluating simple water models if they are to accurately describe water properties and reflect various solvation phenomena. Water-water potential depends upon inter-molecular distance, relative orientation of water molecules, and also local environment. When placed at a favorable distance in a favorable orientation, water molecules exhibit a particularly strong attractive interaction called hydrogen bond. Although hydrogen bond is very important for its effects on the elements of life, industrial applications, and bulk water properties, there is no scientific consensus on its true nature and origin. Using quantum mechanical methods, hydrogen bond strength was calculated in different local environments. A simple empirical linear relationship was discovered between maximum hydrogen bond strength and the number of water molecules in the local environment. The local environment effect was shown to be considerable even on the second coordination shell. Additionally, a negative linear correlation was found between maximum hydrogen bond strength and the distance, at which it was observed. These results provide novel insights into the nature of hydrogen bonding. PMID- 22502518 TI - Core level (S 2p) excitation and fragmentation of the dimethyl sulfide and dimethyldisulfide molecules. AB - Electronic excitation and ionic dissociation of dimethylsulfide (DMS) and dimethyldisulfide (DMDS) have been studied around the S 2p edge using synchrotron radiation and time-of-flight mass spectrometry techniques. Mass spectra were obtained for both molecules, below, on and above the well defined resonances observed in the S 2p photoabsorption spectrum and centered at approximately 166 eV photon energy. Ab initio IS-CASSCF calculations were performed for a better understanding of the photoabsorption spectra. Similar calculations were also performed for the H(2)S molecule, in order to establish a bench mark. For both molecules, a higher fragmentation degree is observed with increasing photon energy. In the DMDS case, selective fragmentation was observed in the formation of the [CH(n)S](+) ions at the first S 2p resonance (corresponding to excitation to a sigma*SS state) and in the formation of the [S(2)](+) and [S](+) ions at the third S 2p resonance (corresponding to excitation to a sigma*CS state). Previously unreported doubly charged ([S](2+), [CH(3)](2+)) are observed for DMS and DMDS. PMID- 22502519 TI - Resonances in rotationally inelastic scattering of OH(X2Pi) with helium and neon. AB - We present detailed calculations on resonances in rotationally and spin-orbit inelastic scattering of OH (X(2)Pi, j = 3/2, F(1), f) radicals with He and Ne atoms. We calculate new ab initio potential energy surfaces for OH-He, and the cross sections derived from these surfaces compare well with the recent crossed beam scattering experiment of Kirste et al. [Phys. Rev. A 82, 042717 (2010)]. We identify both shape and Feshbach resonances in the integral and differential state-to-state scattering cross sections, and we discuss the prospects for experimentally observing scattering resonances using Stark decelerated beams of OH radicals. PMID- 22502520 TI - Influence of collision energy and reagent rotation on the cross sections and product polarizations of the reaction F + HCl. AB - Quasiclassical trajectory calculations have been carried out for the F+HCl reaction in three dimensions on a recent DHSN PES of the ground 1(2)A' electronic state [M. P. Deskevich, M. Y. Hayes, K. Takahashi, R. T. Skodje, and D. J. Nesbitt, J. Chem. Phys. 124, 224303 (2006)]. The effects of the collision energy and the reagent initial rotational excitation on the cross sections and product polarization are studied for the v = 0 and j <= 10 states of HCl over a wide collision energy range. It has been found that either the collision energy or the HCl rotational excitation increase remarkably reaction cross sections. The QCT calculated integral cross sections are in good agreement with previous QM results. A detailed study on product polarization for the title reaction is also performed. The calculated results show that the product rotational angular momentum j' is not only aligned, but also oriented along the direction perpendicular to the scattering plane. The orientation of the HF product rotational angular momentum vector j' depends very sensitively on the collision energy and also affected by the reagent rotation. The theoretical findings and especially the roles of the collision energy and initial rotational momentum on the product polarization are discussed and reasonably explained by the HLH mass combination, the property of the PES, as well as the reactive mechanism. PMID- 22502521 TI - Elastic and inelastic cross sections for low-energy electron collisions with pyrimidine. AB - We present theoretical elastic and electronic excitation cross sections and experimental electronic excitation cross sections for electron collisions with pyrimidine. We use the R-matrix method to determine elastic integral and differential cross sections and integral inelastic cross sections for energies up to 15 eV. The experimental inelastic cross sections have been determined in the 15-50 eV impact energy range. Typically, there is quite reasonable agreement between the theoretical and experimental integral inelastic cross sections. Calculated elastic cross sections agree very well with prior results. PMID- 22502522 TI - Nuclear dynamics and spectator effects in resonant inelastic soft x-ray scattering of gas-phase water molecules. AB - The electronic structure of gas-phase H(2)O and D(2)O molecules has been investigated using resonant inelastic soft x-ray scattering (RIXS). We observe spectator shifts for all valence orbitals when exciting into the lowest three absorption resonances. Strong changes of the relative valence orbital emission intensities are found when exciting into the different absorption resonances, which can be related to the angular anisotropy of the RIXS process. Furthermore, excitation into the 4a(1) resonance leads to nuclear dynamics on the time scale of the RIXS process; we find evidence for vibrational coupling and molecular dissociation in both, the spectator and the participant emission. PMID- 22502523 TI - The microwave and millimeter rotational spectra of the PCN radical (X3Sigma-). AB - The pure rotational spectrum of the PCN radical (X(3)Sigma(-)) has been measured for the first time using a combination of millimeter/submillimeter direct absorption and Fourier transform microwave (FTMW) spectroscopy. In the millimeter instrument, PCN was created by the reaction of phosphorus vapor and cyanogen in the presence of an ac discharge. A pulsed dc discharge of a dilute mixture of PCl(3) vapor and cyanogen in argon was the synthetic method employed in the FTMW machine. Twenty-seven rotational transitions of PCN and six of P(13)CN in the ground vibrational state were recorded from 19 to 415 GHz, all which exhibited fine structure arising from the two unpaired electrons in this radical. Phosphorus and nitrogen hyperfine splittings were also resolved in the FTMW data. Rotational satellite lines from excited vibrational states with v(2) = 1-3 and v(1) = 1 were additionally measured in the submillimeter range. The data were analyzed with a Hund's case (b) effective Hamiltonian and rotational, fine structure, and hyperfine constants were determined. From the rotational parameters of both carbon isotopologues, the geometry of PCN was established to be linear, with a P-C single bond and a C-N triple bond, structurally comparable to other non-metal main group heteroatom cyanides. Analysis of the hyperfine constants suggests that the two unpaired electrons reside almost exclusively on the phosphorus atom in a pi(2) configuration, with little interaction with the nitrogen nucleus. The fine structure splittings in the vibrational satellite lines differ significantly from the pattern of the ground state, with the effect most noticeable with increasing v(2) quantum number. These deviations likely result from spin-orbit vibronic perturbations from a nearby (1)Sigma(+) state, suggested by the data to lie ~12,000 cm(-1) above the ground state. PMID- 22502524 TI - Franck-Condon simulation of vibrationally resolved optical spectra for zinc complexes of phthalocyanine and tetrabenzoporphyrin including the Duschinsky and Herzberg-Teller effects. AB - High resolved absorption and fluorescence spectra of zinc complexes of phthalocyanine (ZnPc) and tetrabenzoporphyrin (ZnTBP) in the region of Q states were reported. Few theoretical investigations were performed to simulate the well resolved spectra and assigned the vibrational bands of the large molecules, especially for high symmetrical characteristic molecules, on account of the difficulties to optimize the excited states and analyze a large number of final vibrational-normal modes. In the present work, the S(0) <-> S(1) absorption and fluorescence spectra (that is, the Q band) of ZnPc and ZnTBP were simulated using time-dependent density functional theory with the inclusions of Duschinsky and Herzberg-Teller contributions to the electronic transition dipole moments. The theoretical results provide a good description of the optical spectra and are proved to be in excellent agreement with experimental spectra in inert-gas matrices or in supersonic expansion. This study focused attentions on the optical spectral similarities and contrasts between ZnPc and ZnTBP, in particular the noticeable Duschinsky and Herzberg-Teller effects on the high-resolved absorption and fluorescence spectra were considered. Substitution of meso-tetraaza on the porphyrin macrocycle framework could affect the ground state geometry and alter the electron density distributions, the orbital energies that accessible in the Q band region of the spectrum. The results were used to help interpret both the nature of the electronic transitions in Q band region, and the spectral discrepancies between phthalocyanine and porphyrin systems. PMID- 22502525 TI - Chemi-luminescence measurements of hyperthermal Xe+/Xe2+ + NH3 reactions. AB - Luminescence spectra are recorded for the reactions of Xe(+) + NH(3) and Xe(2+) + NH(3) at energies ranging from 11.5 to 206 eV in the center-of-mass (E(cm)) frame. Intense features of the luminescence spectra are attributed to the NH (A (3)Pi(i)-X (3)Sigma(-)), hydrogen Balmer series, and Xe I emission observable for both primary ions. Evidence for charge transfer products is only found through Xe I emission for both primary ions and NH(+) emission for Xe(2+) primary ions. For both primary ions, the absolute NH (A-X) cross section increases with collision energy before leveling off at a constant value, approximately 9 * 10(-18) cm(2), at about 50 eV while H-alpha emission increases linearly with collision energy. The nascent NH (A) populations derived from the spectral analysis are found to be independent of collision energy and have a constant rotational temperature of 4200 K. PMID- 22502526 TI - The generalized block-localized wavefunction method: a case study on the conformational preference and C-O rotational barrier of formic acid. AB - A Lewis structure corresponding to the most stable electron-localized state is often used as a reference for the measure of electron delocalization effect in the valence bond (VB) theory. As the simplest variant of ab initio VB theory, the generalized block-localized wavefunction (BLW) method defines the wavefunction for an electron-localized state with block-localized orbitals without the orthogonalization constraint on different blocks. The validity of the method can be critically examined with experimental evidences. Here the BLW method has been applied to the investigation of the roles of both the pi conjugation and sigma hyperconjugation effects in the conformational preference of formic acid for the trans (Z) conformer over the cis (E) conformer. On one hand, our computations showed that the deactivation of the pi conjugation or sigma hyperconjugation has little impact on the Z-E energy gap, thus neither is decisive and instead the local dipole-dipole electrostatic interaction between the carbonyl and hydroxyl groups is the key factor determining the Z-E energy gap. On the other hand, the present study supported the conventional view that pi conjugation is largely responsible for the C-O rotation barrier in formic acid, though the existence of hyperconjugative interactions in the perpendicular structure lowers the barrier considerably. PMID- 22502527 TI - Electronic coherence dynamics in trans-polyacetylene oligomers. AB - Electronic coherence dynamics in trans-polyacetylene oligomers are considered by explicitly computing the time dependent molecular polarization from the coupled dynamics of electronic and vibrational degrees of freedom in a mean-field mixed quantum-classical approximation. The oligomers are described by the Su-Schrieffer Heeger Hamiltonian and the effect of decoherence is incorporated by propagating an ensemble of quantum-classical trajectories with initial conditions obtained by sampling the Wigner distribution of the nuclear degrees of freedom. The electronic coherence of superpositions between the ground and excited and between pairs of excited states is examined for chains of different length, and the dynamics is discussed in terms of the nuclear overlap function that appears in the off-diagonal elements of the electronic reduced density matrix. For long oligomers the loss of coherence occurs in tens of femtoseconds. This time scale is determined by the decay of population into other electronic states through vibronic interactions, and is relatively insensitive to the type and class of superposition considered. By contrast, for smaller oligomers the decoherence time scale depends strongly on the initially selected superposition, with superpositions that can decay as fast as 50 fs and as slow as 250 fs. The long lived superpositions are such that little population is transferred to other electronic states and for which the vibronic dynamics is relatively harmonic. PMID- 22502528 TI - The critical behavior of the refractive index near liquid-liquid critical points. AB - The nature of the critical behavior in the refractive index n is revisited in the framework of the complete scaling formulation. A comparison is made with the critical behavior of n as derived from the Lorentz-Lorenz equation. Analogue anomalies to those predicted for the dielectric constant epsilon, namely, a leading |t|(2beta) singularity in the coexistence-curve diameter in the two-phase region and a |t|(1-alpha) along the critical isopleth in the one phase region, are expected in both cases. However, significant differences as regards the amplitudes of both singularities are obtained from the two approaches. Analysis of some literature data along coexistence in the two-phase region and along the critical isopleth in the one-phase region provide evidence of an intrinsic effect, independent of the density, in the critical anomalies of n. This effect is governed by the shift of the critical temperature with an electric field, which is supposed to take smaller values at optical frequencies than at low frequencies in the Hz to MHz range. PMID- 22502529 TI - Intramolecular vibrational coupling contribution to temperature dependence of vibrational mode frequencies. AB - High-frequency vibrational modes in molecules in solution are sensitive to temperature and shift either to lower or higher frequencies with the temperature increase. These frequency shifts are often attributed to specific interactions of the molecule and to the solvent polarization effect. We found that a substantial and often dominant contribution to sensitivity of vibrational high-frequency modes to temperature originates from anharmonic interactions with other modes in the molecule. The temperature dependencies were measured for several modes in ortho-, meta-, and para-isomers of acetylbenzonitrile in solution and in a solid matrix and compared to the theoretical predictions originated from the intramolecular vibrational coupling (IVC) evaluated using anharmonic density functional theory calculations. It is found that the IVC contribution is essential for temperature dependencies of all high-frequency vibrational modes and is dominant for many modes. As such, the IVC contribution alone permits predicting the main trend in the temperature dependencies, especially for vibrational modes with smaller transition dipoles. In addition, an Onsager reaction field theory was used to describe the solvent contribution to the temperature dependencies. PMID- 22502530 TI - Localization transition of instantaneous normal modes and liquid diffusion. AB - We analyze the structure of instantaneous normal modes (INM) associated with the Hessian matrix of a liquid. Utilizing a scaling theory developed in the framework of Anderson localization studies, we unambiguously identify the crossover point in the INM spectrum between extended and localized modes. We establish a relation between the unstable, delocalized INMs and the liquid diffusion coefficient that appears valid over a large temperature range, covering both Arrhenius and non Arrhenius regimes of temperature dependence. These results suggest a possible route to theoretically relate dynamics to thermodynamical properties of the liquid via the tomography of the INMs. PMID- 22502531 TI - Dependence of diffusivity on density and solute diameter in liquid phase: a molecular dynamics study of Lennard-Jones system. AB - Investigations into the variation of self-diffusivity with solute radius, density, and degree of disorder of the host medium is explored. The system consists of a binary mixture of a relatively smaller sized solute, whose size is varied and a larger sized solvent interacting via Lennard-Jones potential. Calculations have been performed at three different reduced densities of 0.7, 0.8, and 0.933. These simulations show that diffusivity exhibits a maximum for some intermediate size of the solute when the solute diameter is varied. The maximum is found at the same size of the solute at all densities which is at variance with the prediction of the levitation effect. In order to understand this anomaly, additional simulations were carried out in which the degree of disorder has been varied while keeping the density constant. The results show that the diffusivity maximum gradually disappears with increase in disorder. Disorder has been characterized by means of the minimal spanning tree. Simulations have also been carried out in which the degree of disorder is constant and only the density is altered. The results from these simulations show that the maximum in diffusivity now shifts to larger distances with decrease in density. This is in agreement with the changes in void and neck distribution with density of the host medium. These results are in excellent agreement with the predictions of the levitation effect. They suggest that the effect of disorder is to shift the maximum in diffusivity towards smaller solute radius while that of the decrease in density is to shift it towards larger solute radius. Thus, in real systems where the degree of disorder is lower at higher density and vice versa, the effect due to density and disorder have opposing influences. These are confirmed by the changes seen in the velocity autocorrelation function, self part of the intermediate scattering function and activation energy. PMID- 22502532 TI - Freezing of parallel hard cubes with rounded edges. AB - The freezing transition in a classical three-dimensional system of rounded hard cubes with fixed, equal orientations is studied by computer simulation and fundamental-measure density functional theory. By switching the rounding parameter s from zero to one, one can smoothly interpolate between cubes with sharp edges and hard spheres. The equilibrium phase diagram of rounded parallel hard cubes is computed as a function of their volume fraction and the rounding parameter s. The second order freezing transition known for oriented cubes at s = 0 is found to be persistent up to s = 0.65. The fluid freezes into a simple-cubic crystal which exhibits a large vacancy concentration. Upon a further increase of s, the continuous freezing is replaced by a first-order transition into either a sheared simple cubic lattice or a deformed face-centered cubic lattice with two possible unit cells: body-centered orthorhombic or base-centered monoclinic. In principle, a system of parallel cubes could be realized in experiments on colloids using advanced synthesis techniques and a combination of external fields. PMID- 22502533 TI - Relating composition, structural order, entropy and transport in multi-component molten salts. AB - Molecular dynamics simulations of the LiF-BeF(2) molten salt mixture are used to establish relationships between composition, structural order, entropy, and transport properties of multi-component ionic liquids. A sharp rise in tetrahedral order associated with formation of the fluoroberyllate network occurs for compositions with BeF(2) concentrations greater than that of the Li(2)BeF(4) BeF(2) eutectic. The excess entropy of the liquid in this regime, within the pair correlation approximation, is strongly correlated with the local tetrahedral order. The different degree of participation of beryllium, fluorine, and lithium ions in the cooperative dynamics of the fluoroberyllate network can be related to the degree of deviation from Rosenfeld-type excess entropy scaling, with the lithium ions remaining essentially unaffected by the liquid state network. We demonstrate that the deviations from Nernst-Einstein and Stokes-Einstein behaviour emerge only in temperature-composition regimes where tetrahedral order strongly correlates with the pair entropy. Implications for understanding structure-property relationships in other ionic liquids, such as molten salts, oxide melts, and RTILs are considered. PMID- 22502534 TI - Absolute Helmholtz free energy of highly anharmonic crystals: theory vs Monte Carlo. AB - We discuss the problem of the quantitative theoretical prediction of the absolute free energy for classical highly anharmonic solids. Helmholtz free energy of the Lennard-Jones (LJ) crystal is calculated accurately while accounting for both the anharmonicity of atomic vibrations and the pair and triple correlations in displacements of the atoms from their lattice sites. The comparison with most precise computer simulation data on sublimation and melting lines revealed that theoretical predictions are in excellent agreement with Monte Carlo simulation data in the whole range of temperatures and densities studied. PMID- 22502535 TI - Using heavy atom rare gas matrix to control the reactivity of 4 methoxybenzaldehyde: a comparison with benzaldehyde. AB - Different patterns of photochemical behavior were observed for 4 methoxybenzaldehyde (p-anisaldehyde) isolated in xenon and in argon matrices. Monomers of the compound isolated in solid Xe decarbonylate upon middle ultraviolet irradiation, yielding methoxybenzene (anisole), and CO. On the other hand, p-anisaldehyde isolated in an Ar matrix and subjected to identical irradiation, predominantly isomerizes to the closed-ring isomeric ketene (4 methoxycyclohexa-2,4-dien-1-ylidene) methanone. Experimental detection of a closed-ring ketene photoproduct, generated from an aromatic aldehyde, constitutes a rare observation. The difference between the patterns of photochemical transformations of p-anisaldehyde isolated in argon and xenon environments can be attributed to the external heavy-atom effect, where xenon enhances the rate of intersystem crossing from the singlet to the triplet manifold in which decarbonylation (via p-methoxybenzoyl radical) takes place. The parent compound, benzaldehyde, decarbonylates (to benzene + CO) when subjected to middle ultraviolet irradiation in both argon and xenon matrices. This demonstrates the role of the methoxy p-anisaldehyde substituent in activation of the reaction channel leading to the formation of the ketene photoproduct. PMID- 22502536 TI - Theoretical study on ionization process in aqueous solution. AB - Ionization potential (ionization energy) is a fundamental quantity characterizing electronic structure of a molecule. It is known that the energy in solution phase is significantly different from that in the gas phase. In this report, vertical and adiabatic ionization processes in aqueous solution are studied based on a hybrid method of quantum chemistry and statistical mechanics called reference interaction site model-SCF-spacial electron density distribution method. A role of solvation effect is elucidated through molecular level information, i.e., solvent distribution function around solute molecule. By utilizing the linear response regime, a simple expression to evaluate the spectral width from the distribution function is proposed and compared with experimental data. PMID- 22502537 TI - Spectrum of position fluctuations of a Brownian particle bound in a harmonic trap near a plane wall. AB - The spectrum of position fluctuations of a Brownian particle bound in a harmonic trap near a plane wall is calculated from an approximate result for the Fourier transform of the velocity autocorrelation function. Both a no-slip and a perfect slip boundary condition at the wall are considered. In both cases at low frequency the calculated spectrum differs markedly from recent experimental data. It is suggested that a partial slip boundary condition with a frequency-dependent slip coefficient may explain the experimental results. PMID- 22502538 TI - Phase behavior of mixed submonolayer films of krypton and xenon on graphite. AB - Using the results of extensive Monte Carlo simulations in the canonical and grand canonical ensembles, we discuss the phase behavior of mixed submonolayer films of krypton and xenon adsorbed on the graphite basal plane. The calculations have been performed using two- and three-dimensional models of the systems studied. It has been demonstrated that out-of-plane motion does not affect the properties of the films as long as the total density is well below the monolayer completion and at moderate temperatures. For the total densities close to the monolayer completion, the promotion of particles to the second layer considerably affects the film properties. Our results are in a reasonable agreement with the available experimental data. The melting point of submonolayer films has been shown to exhibit non-monotonous changes with the film composition, and reaches minimum for the xenon concentration of about 50%. At the temperatures below the melting point, the structure of solid phases depends upon the film composition and the temperature; one can also distinguish commensurate and incommensurate phases. Two dimensional calculations have demonstrated that for the xenon concentration between about 15% and 65% the adsorbed film exhibits the formation of a superstructure, in which each Xe atom is surrounded by six Kr atoms. This superstructure is stable only at very low temperatures and transforms into the mixed commensurate (?3*?3)R30 degrees phase upon the increase of temperature. Such a superstructure does not appear when a three-dimensional model is used. Grand canonical ensemble calculations allowed us to show that for the xenon concentration of about 3% the phase diagram topology of monolayer films changes from the krypton-like (with incipient triple point) to the xenon-like (with ordinary triple point). PMID- 22502539 TI - Adsorption dynamics of ethylene on Si(001). AB - The dynamics of ethylene adsorption on the Si(001) surface was investigated by means of molecular beam techniques. A constant decrease of initial sticking probability s(0) was observed with increasing kinetic energy indicating a non activated adsorption channel. With increasing surface temperature, s(0) decreases as well, pointing towards adsorption via a precursor state. Quantitative evaluation of the temperature dependence of s(0) via the Kisliuk model was possible for surface temperatures above 250 K; below that value, the temperature dependence is dominated by the adsorption dynamics into the precursor state. Maximum surface coverage was found to be reduced with increasing surface temperature, which is discussed on the basis of a long lifetime of the precursor state at low temperatures. PMID- 22502540 TI - The theory of surface-enhanced Raman scattering. AB - By considering the molecule and metal to form a conjoined system, we derive an expression for the observed Raman spectrum in surface-enhanced Raman scattering. The metal levels are considered to consist of a continuum with levels filled up to the Fermi level, and empty above, while the molecule has discrete levels filled up to the highest occupied orbital, and empty above that. It is presumed that the Fermi level of the metal lies between the highest filled and the lowest unfilled level of the molecule. The molecule levels are then coupled to the metal continuum both in the filled and unfilled levels, and using the solutions to this problem provided by Fano, we derive an expression for the transition amplitude between the ground stationary state and some excited stationary state of the molecule-metal system. It is shown that three resonances contribute to the overall enhancement; namely, the surface plasmon resonance, the molecular resonances, as well as charge-transfer resonances between the molecule and metal. Furthermore, these resonances are linked by terms in the numerator, which result in SERS selection rules. These linked resonances cannot be separated, accounting for many of the observed SERS phenomena. The molecule-metal coupling is interpreted in terms of a deformation potential which is compared to the Herzberg Teller vibronic coupling constant. We show that one term in the sum involves coupling between the surface plasmon transition dipole and the molecular transition dipole. They are coupled through the deformation potential connecting to charge-transfer states. Another term is shown to involve coupling between the charge-transfer transition and the molecular transition dipoles. These are coupled by the deformation potential connecting to plasmon resonance states. By applying the selection rules to the cases of dimer and trimer nanoparticles we show that the SERS spectrum can vary considerably with excitation wavelength, depending on which plasmon and/or charge-transfer resonance is excited. PMID- 22502541 TI - Dynamics of the sputtering of water from ice films by collisions with energetic xenon atoms. AB - The flow of energy from the impact site of a heavy, translationally energetic xenon atom on an ice surface leads to several non-equilibrium events. The central focus of this paper is on the collision-induced desorption (sputtering) of water molecules into the gas-phase from the ice surface. Sputtering is strongly activated with respect to xenon translational energy, and a threshold for desorption was observed. To best understand these results, we discuss our findings in the context of other sputtering studies of molecular solids. The sputtering yield is quite small; differential measurements of the energy of xenon scattered from ice surfaces show that the ice efficiently accommodates the collisional energy. These results are important as they quantitatively elucidate the dynamics of such sputtering events, with implications for energetic non equilibrium processes at interfaces. PMID- 22502542 TI - Sheet-like assemblies of spherical particles with point-symmetrical patches. AB - We report a computational study on the spontaneous self-assembly of spherical particles into two-dimensional crystals. The experimental observation of such structures stabilized by spherical objects appeared paradoxical so far. We implement patchy interactions with the patches point-symmetrically (icosahedral and cubic) arranged on the surface of the particle. In these conditions, preference for self-assembly into sheet-like structures is observed. We explain our findings in terms of the inherent symmetry of the patches and the competition between binding energy and vibrational entropy. The simulation results explain why hollow spherical shells observed in some Keplerate-type polyoxometalates (POM) appear. Our results also provide an explanation for the experimentally observed layer-by-layer growth of apoferritin--a quasi-spherical protein. PMID- 22502543 TI - Structures and orientations of cobalt phthalocyanine adsorbed on Sb(111). AB - The structures and orientations of cobalt phthalocyanine (CoPc) adsorbed on Sb(111) were investigated by low-temperature scanning tunneling microscope. We found that at the initial coverage molecular domains formed both on the terraces and at the vicinity of step edges that were saturated by molecular chains in advance. With the increasing of molecular coverage, the alternately arranged molecular rows of CoPc adsorbed on the bridge sites of Sb(111) and the orientations of them were rotated by 14 degrees +/- 2 degrees with respect to the [-101] direction. At the coverage above one monolayer, the molecules of the second layer were assembled along the directions of the underlying molecular rows and showed similar configurations. Consequently, the second-layer CoPc molecules interacted with neighboring molecules via pi orbitals, resulting in the observation of overlapped molecular orbitals. PMID- 22502544 TI - Structured water in polyelectrolyte dendrimers: understanding small angle neutron scattering results through atomistic simulation. AB - Based on atomistic molecular dynamics (MD) simulations, the small angle neutron scattering (SANS) intensity behavior of a single generation-4 polyelectrolyte polyamidoamine starburst dendrimer is investigated at different levels of molecular protonation. The SANS form factor, P(Q), and Debye autocorrelation function, gamma(r), are calculated from the equilibrium MD trajectory based on a mathematical approach proposed in this work. The consistency found in comparison against previously published experimental findings (W.-R. Chen, L. Porcar, Y. Liu, P. D. Butler, and L. J. Magid, Macromolecules 40, 5887 (2007)) leads to a link between the neutron scattering experiment and MD computation, and fresh perspectives. The simulations enable scattering calculations of not only the hydrocarbons but also the contribution from the scattering length density fluctuations caused by structured, confined water within the dendrimer. Based on our computational results, we explore the validity of using radius of gyration R(G) for microstructure characterization of a polyelectrolyte dendrimer from the scattering perspective. PMID- 22502545 TI - Isotropic to smectic-C phase transition in liquid-crystalline elastomers. AB - A phenomenological model is developed to describe the isotropic-smectic-C phase transition in liquid-crystalline side-chain elastomers. We analyze the influence of external mechanical stress on the isotropic-smectic-C phase transition. While this phase transition is first order in low-molecular-weight materials, we show here that the order of this transition does not change in liquid-crystalline elastomers. The temperature dependence of the heat capacity and the nonlinear dielectric effect in the isotropic phase above the isotropic-smectic-C phase transition in liquid crystalline elastomers are calculated. The theoretical results are found to be in good agreement with experiment. PMID- 22502546 TI - A highly coarse-grained model to simulate entangled polymer melts. AB - We introduce a highly coarse-grained model to simulate the entangled polymer melts. In this model, a polymer chain is taken as a single coarse-grained particle, and the creation and annihilation of entanglements are regarded as stochastic events in proper time intervals according to certain rules and possibilities. We build the relationship between the probability of appearance of an entanglement between any pair of neighboring chains at a given time interval and the rate of variation of entanglements which describes the concurrence of birth and death of entanglements. The probability of disappearance of entanglements is tuned to keep the total entanglement number around the target value. This useful model can reflect many characteristics of entanglements and macroscopic properties of polymer melts. As an illustration, we apply this model to simulate the polyethylene melt of C(1000)H(2002) at 450 K and further validate this model by comparing to experimental data and other simulation results. PMID- 22502547 TI - Exploring the inter-molecular interactions in amyloid-beta protofibril with molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area free energy calculations. AB - Aggregation of amyloid-beta (Abeta) peptides correlates with the pathology of Alzheimer's disease. However, the inter-molecular interactions between Abeta protofibril remain elusive. Herein, molecular mechanics Poisson-Boltzmann surface area analysis based on all-atom molecular dynamics simulations was performed to study the inter-molecular interactions in Abeta(17-42) protofibril. It is found that the nonpolar interactions are the important forces to stabilize the Abeta(17 42) protofibril, while electrostatic interactions play a minor role. Through free energy decomposition, 18 residues of the Abeta(17-42) are identified to provide interaction energy lower than -2.5 kcal/mol. The nonpolar interactions are mainly provided by the main chain of the peptide and the side chains of nine hydrophobic residues (Leu17, Phe19, Phe20, Leu32, Leu34, Met35, Val36, Val40, and Ile41). However, the electrostatic interactions are mainly supplied by the main chains of six hydrophobic residues (Phe19, Phe20, Val24, Met35, Val36, and Val40) and the side chains of the charged residues (Glu22, Asp23, and Lys28). In the electrostatic interactions, the overwhelming majority of hydrogen bonds involve the main chains of Abeta as well as the guanidinium group of the charged side chain of Lys28. The work has thus elucidated the molecular mechanism of the inter molecular interactions between Abeta monomers in Abeta(17-42) protofibril, and the findings are considered critical for exploring effective agents for the inhibition of Abeta aggregation. PMID- 22502548 TI - Tensegrity and motor-driven effective interactions in a model cytoskeleton. AB - Actomyosin networks are major structural components of the cell. They provide mechanical integrity and allow dynamic remodeling of eukaryotic cells, self organizing into the diverse patterns essential for development. We provide a theoretical framework to investigate the intricate interplay between local force generation, network connectivity, and collective action of molecular motors. This framework is capable of accommodating both regular and heterogeneous pattern formation, arrested coarsening and macroscopic contraction in a unified manner. We model the actomyosin system as a motorized cat's cradle consisting of a crosslinked network of nonlinear elastic filaments subjected to spatially anti correlated motor kicks acting on motorized (fibril) crosslinks. The phase diagram suggests there can be arrested phase separation which provides a natural explanation for the aggregation and coalescence of actomyosin condensates. Simulation studies confirm the theoretical picture that a nonequilibrium many body system driven by correlated motor kicks can behave as if it were at an effective equilibrium, but with modified interactions that account for the correlation of the motor driven motions of the actively bonded nodes. Regular aster patterns are observed both in Brownian dynamics simulations at effective equilibrium and in the complete stochastic simulations. The results show that large-scale contraction requires correlated kicking. PMID- 22502550 TI - Erratum: "Multipole-based integral estimates for the rigorous description of distance dependence in two-electron integrals" [J. Chem. Phys. 123, 184101 (2005)]. PMID- 22502549 TI - High-pressure effect on the dynamics of solvated peptides. AB - The dynamics of peptides has a direct connection to how quickly proteins can alter their conformations. The speed of exploring the free energy landscape depend on many factors, including the physical parameters of the environment, such as pressure and temperature. We performed a series of molecular dynamics simulations to investigate the pressure-temperature effects on peptide dynamics, especially on the torsional angle and peptide-water hydrogen bonding (H-bonding) dynamics. Here, we show that the dynamics of the omega angle and the H-bonding dynamics between water and the peptide are affected by pressure. At high temperature (500 K), both the dynamics of the torsional angle omega and H-bonding slow down significantly with increasing pressure, interestingly, at approximately the same rate. However, at a lower temperature of 300 K, the observed trend on H bonding dynamics as a function of pressure reverses, i.e., higher pressure speeds up H-bonding dynamics. PMID- 22502551 TI - Erratum: "Rigorous integral screening for electron correlation methods" [J. Chem. Phys. 123, 184102 (2005)]. PMID- 22502552 TI - Modified Wiener estimation of diffuse reflectance spectra from RGB values by the synthesis of new colors for tissue measurements. AB - We present a new method for the accurate estimation of diffuse reflectance spectra from RGB values based on Wiener estimation. In the proposed method, a system matrix obtained from the original RGB values is combined with a set of synthetic optical filters to generate another three values corresponding to new colors. A modified Wiener matrix can then be created with the original RGB values and the new color values, which will yield a more accurate estimation because of the new color information that has been incorporated. This method was tested on in vivo color measurements from 200 skin sites in 10 volunteers. The results show that the proposed method is able to improve the estimation accuracy significantly compared with the traditional Wiener estimation method. The fast speed of this method may enable the estimation of diffuse reflectance spectra at multiple tissue locations from color images in real time, which provides a cost-effective alternative to spectral imaging with the additional advantage of high spectral resolution. PMID- 22502553 TI - Optical coherence photoacoustic microscopy: accomplishing optical coherence tomography and photoacoustic microscopy with a single light source. AB - We developed optical coherence photoacoustic microscopy (OC-PAM) to demonstrate that the functions of optical coherence tomography (OCT) and photoacoustic microscopy (PAM) can be achieved simultaneously by using a single illuminating light source. We used a pulsed broadband laser centered at 580 nm and detected the absorbed photons through photoacoustic detection and the back-scattered photons with an interferometer. In OC-PAM, each laser pulse generates both one OCT A-line and one PAM A-line simultaneously; as a result, the two imaging modalities are intrinsically co-registered in the lateral directions. In vivo images of the mouse ear were acquired to demonstrate the capabilities of OC-PAM. PMID- 22502554 TI - Photoacoustic section imaging using an elliptical acoustic mirror and optical detection. AB - A method is proposed that utilizes the advantages of optical ultrasound detection in two-dimensional photoacoustic section imaging, combining an optical interferometer with an acoustic mirror. The concave mirror has the shape of an elliptical cylinder and concentrates the acoustic wave generated around one focal line in the other one, where an optical beam probes the temporal evolution of acoustic pressure. This yields line projections of the acoustic sources at distances corresponding to the time of flight, which, after rotating the sample about an axis perpendicular to the optical detector, allows reconstruction of a section using the inverse Radon transform. A resolution of 120 [micro sign]m within and 1.5 mm between the sections can be obtained with the setup. Compared to a bare optical probe beam, the signal-to-noise ratio (SNR) is seven times higher with the mirror. Furthermore, the imaging system is tested on a biological sample. PMID- 22502555 TI - Polarization-sensitive optical coherence tomography using continuous polarization modulation with arbitrary phase modulation amplitude. AB - We demonstrate theoretically and experimentally that the phase retardance and relative optic-axis orientation of a sample can be calculated without prior knowledge of the actual value of the phase modulation amplitude when using a polarization-sensitive optical coherence tomography system based on continuous polarization modulation (CPM-PS-OCT). We also demonstrate that the sample Jones matrix can be calculated at any values of the phase modulation amplitude in a reasonable range depending on the system effective signal-to-noise ratio. This has fundamental importance for the development of clinical systems by simplifying the polarization modulator drive instrumentation and eliminating its calibration procedure. This was validated on measurements of a three-quarter waveplate and an equine tendon sample by a fiber-based swept-source CPM-PS-OCT system. PMID- 22502556 TI - Addressable multiregional and multifocal multiphoton microscopy based on a spatial light modulator. AB - Through a combination of a deflective phase-only diffractive spatial light modulator (SLM) and galvo scanners, an addressable multiregional and multifocal multiphoton microscope (AM-MMM) is developed. The SLM shapes an incoming mode locked, near-infrared Ti:sapphire laser beam into multiple beamlet arrays with addressable shapes and sizes that match the regions of interest on the sample. Compared with conventional multifocal multiphoton microscope (MMM), AM-MMM achieves the effective use of the laser power with an increase of imaging rate and a decrease of photodamage without sacrifice of resolution. PMID- 22502558 TI - Analytic evaluation of diffuse fluence error in multilayer scattering media with discontinuous refractive index. AB - A simple analytic method of estimating the error involved in using an approximate boundary condition for diffuse radiation in two adjoining scattering media with differing refractive indices is presented. The method is based on asymptotic planar fluences and enables the relative error to be readily evaluated without recourse to Monte Carlo simulation. Three examples of its application are considered: (1) evaluating the error in calculating the diffuse fluences at a boundary between two media with differing refractive index and dissimilar scattering properties, (2) the dependence of the relative error in a multilayer medium with discontinuous refractive index on the ratio of the reduced scattering coefficient to the absorption coefficient MU(s)'/MU(a), and (3) the parametric dependence of the error in the radiant flux J(s) at the surface of a three-layer medium. The error is significant for strongly forward-biased scattering media with non-negligible absorption and is cumulative in multilayered media with refractive index increments between layers. PMID- 22502557 TI - Time-reversed ultrasonically encoded optical focusing in biological tissue. AB - We report an experimental investigation of time-reversed ultrasonically encoded optical focusing in biological tissue. This technology combines the concepts of optical phase conjugation and ultrasound modulation of diffused coherent light. The ultrasonically encoded (or tagged) diffused light from a tissue sample is collected in reflection mode and interferes with a reference light in a photorefractive crystal (used as a phase conjugation mirror) to form a hologram. Then a time-reversed copy of the tagged light is generated and traces back the original trajectories to the ultrasonic focus inside the tissue sample. With our current setup, we can achieve a maximum penetration depth of 5 mm in a chicken breast sample and image optical contrasts within a tissue sample with a spatial resolution approximately equaling 1/?2 of the ultrasound focal diameter. PMID- 22502559 TI - Investigation of three home-applied bleaching agents on enamel structure and mechanical properties: an in situ study. AB - The safety of at-home tooth bleaching, based upon carbamide peroxide (CP) or hydrogen peroxide (HP) as the active agent, has been questioned. The aim of the present study was to investigate the effects of three differently concentrated home-applied bleaching agents on human enamel under in situ conditions. Sixty specimens were divided randomly into four groups and treated with 10% CP, 15% CP, 20% CP, and distilled water, respectively. Raman spectroscopy, attenuated total reflectance-infrared (ATR-IR) spectroscopy, atomic force microscopy (AFM), microhardness, and fracture toughness (FT) measurements were conducted to determine variations on enamel structure and mechanical properties before and after the bleaching process. Raman revealed little variation of Raman relative intensity after treatment with CP, which was consistent with the results of ATR IR, AFM, and microhardness analyses. In addition, laser-induced fluorescence (LIF) intensity, and FT showed significant decreases on CP-treated specimens. These findings suggested there were minimal demineralization effects of the three at-home bleaching agents on enamel in situ. However, the decrease of LIF intensity and FT on enamel seemed to be inevitable. PMID- 22502560 TI - Polarization-interferometry-based wavelength-interrogation surface plasmon resonance imager for analysis of microarrays. AB - Polarization interferometry (PI) techniques, which are able to improve surface plasmon resonance (SPR) sensing performance and reduce restrictions on allowable parameters of SPR-supporting metal films, have been experimentally realized only in SPR sensors using monochromatic light as a source. Wavelength-interrogation SPR sensors modulated by PI techniques have not been reported due to the wavelength-sensitive characterization of PI phase compensators. In this work we develop a specially designed rhombic prism for phase compensating which is totally insensitive to wavelength. For the first time we successfully apply PI technique to a wavelength-interrogation SPR imager. This imager is able to offer two-dimensional imaging of the whole array plane. As a result of PI modulation, resolutions of 1.3*10(-6) refractive index unit (RIU) under the normal condition and 3.9*10(-7) RIU under a more time-consuming condition are acquired. The application of this imager was demonstrated by reading microarrays for identification of bacteria, and SPR results were confirmed by means of fluorescence imaging. PMID- 22502561 TI - Wide-field spectral imaging of human ovary autofluorescence and oncologic diagnosis via previously collected probe data. AB - With no sufficient screening test for ovarian cancer, a method to evaluate the ovarian disease state quickly and nondestructively is needed. The authors have applied a wide-field spectral imager to freshly resected ovaries of 30 human patients in a study believed to be the first of its magnitude. Endogenous fluorescence was excited with 365-nm light and imaged in eight emission bands collectively covering the 400- to 640-nm range. Linear discriminant analysis was used to classify all image pixels and generate diagnostic maps of the ovaries. Training the classifier with previously collected single-point autofluorescence measurements of a spectroscopic probe enabled this novel classification. The process by which probe-collected spectra were transformed for comparison with imager spectra is described. Sensitivity of 100% and specificity of 51% were obtained in classifying normal and cancerous ovaries using autofluorescence data alone. Specificity increased to 69% when autofluorescence data were divided by green reflectance data to correct for spatial variation in tissue absorption properties. Benign neoplasm ovaries were also found to classify as nonmalignant using the same algorithm. Although applied ex vivo, the method described here appears useful for quick assessment of cancer presence in the human ovary. PMID- 22502562 TI - Laser 3-D measuring system and real-time visual feedback for teaching and correcting breathing. AB - We present a novel method for real-time 3-D body-shape measurement during breathing based on the laser multiple-line triangulation principle. The laser projector illuminates the measured surface with a pattern of 33 equally inclined light planes. Simultaneously, the camera records the distorted light pattern from a different viewpoint. The acquired images are transferred to a personal computer, where the 3-D surface reconstruction, shape analysis, and display are performed in real time. The measured surface displacements are displayed with a color palette, which enables visual feedback to the patient while breathing is being taught. The measuring range is approximately 400*600*500 mm in width, height, and depth, respectively, and the accuracy of the calibrated apparatus is +/-0.7 mm. The system was evaluated by means of its capability to distinguish between different breathing patterns. The accuracy of the measured volumes of chest-wall deformation during breathing was verified using standard methods of volume measurements. The results show that the presented 3-D measuring system with visual feedback has great potential as a diagnostic and training assistance tool when monitoring and evaluating the breathing pattern, because it offers a simple and effective method of graphical communication with the patient. PMID- 22502563 TI - Approach to quantify human dermal skin aging using multiphoton laser scanning microscopy. AB - Extracellular skin structures in human skin are impaired during intrinsic and extrinsic aging. Assessment of these dermal changes is conducted by subjective clinical evaluation and histological and molecular analysis. We aimed to develop a new parameter for the noninvasive quantitative determination of dermal skin alterations utilizing the high-resolution three-dimensional multiphoton laser scanning microscopy (MPLSM) technique. To quantify structural differences between chronically sun-exposed and sun-protected human skin, the respective collagen specific second harmonic generation and the elastin-specific autofluorescence signals were recorded in young and elderly volunteers using the MPLSM technique. After image processing, the elastin-to-collagen ratio (ELCOR) was calculated. Results show that the ELCOR parameter of volar forearm skin significantly increases with age. For elderly volunteers, the ELCOR value calculated for the chronically sun-exposed temple area is significantly augmented compared to the sun-protected upper arm area. Based on the MPLSM technology, we introduce the ELCOR parameter as a new means to quantify accurately age-associated alterations in the extracellular matrix. PMID- 22502564 TI - Performance of laser fluorescence devices and visual examination for the detection of occlusal caries in permanent molars. AB - The aim of this study was to evaluate the diagnostic capabilities of a laser fluorescence tool DIAGNOdent (KaVo, Biberach, Germany) and two light-emitting diode fluorescence tools-Spectra Caries Detection Aid (AIR TECHNIQUES, Melville, NY), and SOPROLIFE light-induced fluorescence evaluator in daylight and blue florescence mode (SOPRO, ACTEON Group, La Ciotat, France)-in comparison to the caries detection and assessment system (ICDAS-II) in detection of caries lesions. In 100 subjects (age 23.4+/-10.6 years), 433 posterior permanent unrestored teeth were examined. On the occlusal surfaces, up to 1066 data points for each assessment method were available for statistical evaluation, including 1034 ICDAS scores (intra-examiner kappa=0.884). For the SOPROLIFE tool, a new caries-scoring system was developed. Per assessment tool each average score for one given ICDAS code was significantly different from the one for another ICDAS code. Normalized data linear regression revealed that both SOPROLIFE assessment tools allowed for best caries score discrimination followed by DIAGNOdent and Spectra Caries Detection Aid. The area under the receiver operating characteristics curve calculations showed the same grading sequence when cutoff point ICDAS codes 0-1-2 were grouped together. Sensitivity and specificity values at the same cutoff were calculated (DIAGNOdent 87/66, Spectra Caries Detection Aid 93/37, SOPROLIFE 93/63, SOPROLIFE blue fluorescence 95/55.). PMID- 22502565 TI - Cardiac-phase filtering in intracardiac particle image velocimetry. AB - The ability to accurately measure velocity within the embryonic zebrafish heart, at high spatial and temporal resolution, enables further insight into the effects of hemodynamics on heart development. Unfortunately, currently available techniques are unable to provide the required resolution, both spatial and temporal, for detailed analysis. Advances in imaging hardware are allowing bright field imaging combined with particle image velocimetry to become a viable technique for the broader community at the required spatial and temporal resolutions. While bright field imaging offers the necessary temporal resolution, this approach introduces heart wall artifacts that interfere with accurate velocity measurement. This study presents a technique for cardiac-phase filtering of bright field images to remove the heart wall and improve velocimetry measurements. Velocity measurements were acquired for zebrafish embryos ranging from 3 to 6 days postfertilization. Removal of the heart wall was seen to correct a severe (3-fold) underestimation in velocity measurements obtained without filtering. Additionally, velocimetry measurements were used to quantitatively detect developmental changes in cardiac performance in vivo, investigating both changes in contractile period and maximum velocities present through the ventricular-bulbar valve. PMID- 22502566 TI - Autofocus evaluation for brightfield microscopy pathology. AB - An essential and indispensable component of automated microscopy framework is the automatic focusing system, which determines the in-focus position of a given field of view by searching the maximum value of a focusing function over a range of z-axis positions. The focus function and its computation time are crucial to the accuracy and efficiency of the system. Sixteen focusing algorithms were analyzed for histological and histopathological images. In terms of accuracy, results have shown an overall high performance by most of the methods. However, we included in the evaluation study other criteria such as computational cost and focusing curve shape which are crucial for real-time applications and were used to highlight the best practices. PMID- 22502568 TI - Qualitative investigation of fresh human scalp hair with full-field optical coherence tomography. AB - We have investigated depth-resolved cellular structures of unmodified fresh human scalp hairs with ultrahigh-resolution full-field optical coherence tomography (FF OCT). The Linnik-type white light interference microscope has been home implemented to observe the micro-internal layers of human hairs in their natural environment. In hair shafts, FF-OCT has qualitatively revealed the cellular hair compartments of cuticle and cortex layers involved in keratin filaments and melanin granules. No significant difference between black and white hair shafts was observed except for absence of only the melanin granules in the white hair, reflecting that the density of the melanin granules directly affects the hair color. Anatomical description of plucked hair bulbs was also obtained with the FF OCT in three-dimensions. We expect this approach will be useful for evaluating cellular alteration of natural hairs on cosmetic assessment or diagnosis of hair diseases. PMID- 22502567 TI - Dual-wavelength multifrequency photothermal wave imaging combined with optical coherence tomography for macrophage and lipid detection in atherosclerotic plaques using gold nanoparticles. AB - The objective of this study was to assess the ability of combined photothermal wave (PTW) imaging and optical coherence tomography (OCT) to detect, and further characterize the distribution of macrophages (having taken up plasmonic gold nanorose as a contrast agent) and lipid deposits in atherosclerotic plaques. Aortas with atherosclerotic plaques were harvested from nine male New Zealand white rabbits divided into nanorose- and saline-injected groups and were imaged by dual-wavelength (800 and 1210 nm) multifrequency (0.1, 1 and 4 Hz) PTW imaging in combination with OCT. Amplitude PTW images suggest that lateral and depth distribution of nanorose-loaded macrophages (confirmed by two-photon luminescence microscopy and RAM-11 macrophage stain) and lipid deposits can be identified at selected modulation frequencies. Radiometric temperature increase and modulation amplitude of superficial nanoroses in response to 4 Hz laser irradiation (800 nm) were significantly higher than native plaque (P<0.001). Amplitude PTW images (4 Hz) were merged into a coregistered OCT image, suggesting that superficial nanorose-loaded macrophages are distributed at shoulders on the upstream side of atherosclerotic plaques (P<0.001) at edges of lipid deposits. Results suggest that combined PTW-OCT imaging can simultaneously reveal plaque structure and composition, permitting characterization of nanorose-loaded macrophages and lipid deposits in atherosclerotic plaques. PMID- 22502569 TI - In vivo testing of a prototype system providing simultaneous white light and near infrared autofluorescence image acquisition for detection of bladder cancer. AB - A prototype instrument developed to provide simultaneously ordinary visual endoscopy together with near infrared (NIR) autofluorescence imaging via parallel image acquisition is demonstrated. The two images are recorded concurrently and the instrument interfaces with any ordinary endoscope. Preliminary results of a pilot study focused on imaging of bladder tumors in vivo using this instrumentation are presented. The experimental results demonstrate the capabilities of this instrumentation design, imaging methodology, and define the current limitation for further development of the system. PMID- 22502570 TI - Blood oxygen flux estimation with a combined photoacoustic and high-frequency ultrasound microscopy system: a phantom study. AB - The metabolic rate of oxygen consumption, an important indicator of tissue metabolism, can be expressed as the change of net blood oxygen flux into and out of a tissue region per 100 g of tissue. In this work, we propose a photoacoustic and Doppler ultrasound method for imaging local blood oxygen flux of a single vessel. An imaging system for combined photoacoustic and high-frequency ultrasound microscopy is presented. This system uses a swept-scan 25-MHz ultrasound transducer with confocal dark-field laser illumination optics. A pulse sequencer enables ultrasonic and laser pulses to be interlaced so that photoacoustic and Doppler ultrasound images are co-registered. Since the mean flow speed can be measured by color Doppler ultrasound, the vessel cross sectional area can be measured by power Doppler or structural photoacoustic imaging, and multi-wavelength photoacoustic methods can be used to estimate oxygen saturation (sO(2)) and total concentration of haemoglobin (C(Hb)), all of the parameters necessary for oxygen flux estimation can be provided. The accuracy of the flow speed and sO(2) estimation has been investigated. In vitro sheep blood phantom experiments have been performed at different sO(2) levels and mean flow speeds. Blood oxygen flux has been estimated, and the uncertainty of the measurement has been quantified. PMID- 22502571 TI - Influence of absorption and scattering on the quantification of fluorescence diffuse optical tomography using normalized data. AB - Reconstruction algorithms for imaging fluorescence in near infrared ranges usually normalize fluorescence light with respect to excitation light. Using this approach, we investigated the influence of absorption and scattering heterogeneities on quantification accuracy when assuming a homogeneous model and explored possible reconstruction improvements by using a heterogeneous model. To do so, we created several computer-simulated phantoms: a homogeneous slab phantom (P1), slab phantoms including a region with a two- to six-fold increase in scattering (P2) and in absorption (P3), and an atlas-based mouse phantom that modeled different liver and lung scattering (P4). For P1, reconstruction with the wrong optical properties yielded quantification errors that increased almost linearly with the scattering coefficient while they were mostly negligible regarding the absorption coefficient. This observation agreed with the theoretical results. Taking the quantification of a homogeneous phantom as a reference, relative quantification errors obtained when wrongly assuming homogeneous media were in the range +41 to +94% (P2), 0.1 to -7% (P3), and -39 to +44% (P4). Using a heterogeneous model, the overall error ranged from -7 to 7%. In conclusion, this work demonstrates that assuming homogeneous media leads to noticeable quantification errors that can be improved by adopting heterogeneous models. PMID- 22502572 TI - Multiphoton microscopy and microspectroscopy for diagnostics of inflammatory and neoplastic lung. AB - Limitations of current medical procedures for detecting early lung cancers inspire the need for new diagnostic imaging modalities for the direct microscopic visualization of lung nodules. Multiphoton microscopy (MPM) provides for subcellular resolution imaging of intrinsic fluorescence from unprocessed tissue with minimal optical attenuation and photodamage. We demonstrate that MPM detects morphological and spectral features of lung tissue and differentiates between normal, inflammatory and neoplastic lung. Ex vivo MPM imaging of intrinsic two photon excited fluorescence was performed on mouse and canine neoplastic, inflammatory and tumor-free lung sites. Results showed that MPM detected microanatomical differences between tumor-free and neoplastic lung tissue similar to standard histopathology but without the need for tissue processing. Furthermore, inflammatory sites displayed a distinct red-shifted fluorescence compared to neoplasms in both mouse and canine lung, and adenocarcinomas displayed a less pronounced fluorescence emission in the 500 to 550 nm region compared to adenomas in mouse models of lung cancer. These spectral distinctions were also confirmed by two-photon excited fluorescence microspectroscopy. We demonstrate the feasibility of applying MPM imaging of intrinsic fluorescence for the differentiation of lung neoplasms, inflammatory and tumor-free lung, which motivates the application of multiphoton endoscopy for the in situ imaging of lung nodules. PMID- 22502573 TI - Instrument for fluorescence sensing of circulating cells with diffuse light in mice in vivo. AB - Accurate quantification of circulating cell populations in mice is important in many areas of preclinical biomedical research. Normally, this is done either by extraction and analysis of small blood samples or, more recently, by using microscopy-based in vivo fluorescence flow cytometry. We describe a new technological approach to this problem using detection of diffuse fluorescent light from relatively large blood vessels in vivo. The diffuse fluorescence flow cytometer (DFFC) uses a laser to illuminate a mouse limb and an array of optical fibers coupled to a high-sensitivity photomultiplier tube array operating in photon counting mode to detect weak fluorescence signals from cells. We first demonstrate that the DFFC instrument is capable of detecting fluorescent microspheres and Vybrant-DiD-labeled cells in a custom-made optical flow phantom with similar size, optical properties, linear flow rates, and autofluorescence as a mouse limb. We also present preliminary data demonstrating that the DFFC is capable of detecting circulating cells in nude mice in vivo. In principle, this device would allow interrogation of the whole blood volume of a mouse in minutes, with sensitivity improvement by several orders of magnitude compared to current approaches. PMID- 22502574 TI - Design of refractive index sensors based on the wavelength-selective resonant coupling phenomenon in dual-core photonic crystal fibers. AB - Design strategies for high-sensitivity refractive index sensors based on the principle of wavelength-selective resonant coupling in dual-core photonic crystal fibers are presented. Phase matching at a single wavelength can be achieved between an analyte-filled microstructured core and a small core with a down-doped rod or one small air hole in the center, thus enabling selectively directional resonant-coupling between the two cores. The transmission spectra of the output light presents a notch at the index-matched wavelength, yielding a resonant wavelength depending on the refractive index of the analyte. Numerical simulations demonstrate that both of the two proposed sensors can be used for highly sensitive detection of low-index analyte. In particular, the configuration realized by introducing the fiber with a small air hole in one core can be used to the detection of the analyte index around 1.33 and the sensitivity reach to 1.2*10(4) nm per refractive index unit (RIU). In addition, the detection limit is as low as 2.5*10(-7) RIU at n(a)=1.33. PMID- 22502575 TI - Spectral analysis of human saliva for detection of lung cancer using surface enhanced Raman spectroscopy. AB - Surface-enhanced Raman spectroscopy (SERS) has been shown to be able to detect low-concentration biofluids. Saliva SERS readings of 21 lung cancer patients and 20 normal people were measured and differentiated. Most of the Raman peak intensities decrease for lung cancer patients compared with that of normal people. Those peaks were assigned to proteins and nucleic acids, which indicate a corresponding decrease of those substances in saliva. Principal component analysis (PCA) and linear discriminant analysis (LDA) were used to reduce and discriminate between the two groups of data, and the study resulted in accuracy, sensitivity, and specificity being 80%, 78%, and 83%, respectively. In conclusion, SERS of saliva showed the ability to predict lung cancer in our experiment. PMID- 22502576 TI - Evanescent field-fiber loop ringdown glucose sensor. AB - Evanescent field-fiber loop ringdown (EF-FLRD) is a relatively new hybrid sensing technique which combines a versatile sensing mechanism with a sensitivity enhanced ringdown detection scheme. An array of low cost, fast response, and high sensitivity biosensors based on the EF-FLRD technique can be developed. In this work, new fiber loop ringdown glucose sensors using refractive index-difference evanescent field attenuation effect as a sensing mechanism are described. The sensor head consists of either a section of partially-etched bare single mode fiber or a section of the etched fiber with glucose oxidase (GOD) immobilized on the etched fiber surface. Effects of the sensor head, with and without the immobilized GOD, on the sensor's performance are comparatively examined. The sensors' responses to standard glucose solutions and synthetic urines in different glucose concentrations ranging from 50 mg/dl to 10 g/dl are studied. The sensors, with or without the immobilized GOD, showed a linear response to glucose concentrations in the range of 100 mg/dl to 1 g/dl, but a nonlinear response in the higher glucose concentration ranging from 1 to 10 g/dl. The detection sensitivities of the sensors for the glucose solutions and artificial urine samples are 75 and 50 mg/dl respectively, and the sampling rate of the sensors is 10 to 100 Hz. Estimated theoretical detection sensitivity of the EF FLRD glucose sensors is 10 mg/dl, which is approximately 17 times lower than the glucose renal threshold concentration. PMID- 22502577 TI - Use of ambient light in remote photoplethysmographic systems: comparison between a high-performance camera and a low-cost webcam. AB - Imaging photoplethysmography (PPG) is able to capture useful physiological data remotely from a wide range of anatomical locations. Recent imaging PPG studies have concentrated on two broad research directions involving either high performance cameras and or webcam-based systems. However, little has been reported about the difference between these two techniques, particularly in terms of their performance under illumination with ambient light. We explore these two imaging PPG approaches through the simultaneous measurement of the cardiac pulse acquired from the face of 10 male subjects and the spectral characteristics of ambient light. Measurements are made before and after a period of cycling exercise. The physiological pulse waves extracted from both imaging PPG systems using the smoothed pseudo-Wigner-Ville distribution yield functional characteristics comparable to those acquired using gold standard contact PPG sensors. The influence of ambient light intensity on the physiological information is considered, where results reveal an independent relationship between the ambient light intensity and the normalized plethysmographic signals. This provides further support for imaging PPG as a means for practical noncontact physiological assessment with clear applications in several domains, including telemedicine and homecare. PMID- 22502578 TI - Microstructured optical fiber interferometric breathing sensor. AB - In this paper a simple photonic crystal fiber (PCF) interferometric breathing sensor is introduced. The interferometer consists of a section of PCF fusion spliced at the distal end of a standard telecommunications optical fiber. Two collapsed regions in the PCF caused by the splicing process allow the excitation and recombination of a core and a cladding PCF mode. As a result, the reflection spectrum of the device exhibits a sinusoidal interference pattern that instantly shifts when water molecules, present in exhaled air, are adsorbed on or desorbed from the PCF surface. The device can be used to monitor a person's breathing whatever the respiration rate. The device here proposed could be particularly important in applications where electronic sensors fail or are not recommended. It may also be useful in the evaluation of a person's health and even in the diagnosis and study of the progression of serious illnesses such as sleep apnea syndrome. PMID- 22502579 TI - Validation of diffuse correlation spectroscopic measurement of cerebral blood flow using phase-encoded velocity mapping magnetic resonance imaging. AB - Diffuse correlation spectroscopy (DCS) is a novel optical technique that appears to be an excellent tool for assessing cerebral blood flow in a continuous and non invasive manner at the bedside. We present new clinical validation of the DCS methodology by demonstrating strong agreement between DCS indices of relative cerebral blood flow and indices based on phase-encoded velocity mapping magnetic resonance imaging (VENC MRI) of relative blood flow in the jugular veins and superior vena cava. Data were acquired from 46 children with single ventricle cardiac lesions during a hypercapnia intervention. Significant increases in cerebral blood flow, measured both by DCS and by VENC MRI, as well as significant increases in oxyhemoglobin concentration, and total hemoglobin concentration, were observed during hypercapnia. Comparison of blood flow changes measured by VENC MRI in the jugular veins and by DCS revealed a strong linear relationship, R=0.88, p<0.001, slope=0.91+/-0.07. Similar correlations were observed between DCS and VENC MRI in the superior vena cava, R=0.77, slope=0.99+/-0.12, p<0.001. The relationship between VENC MRI in the aorta and DCS, a negative control, was weakly correlated, R=0.46, slope=1.77+/-0.45, p<0.001. PMID- 22502581 TI - Broadband absorption spectroscopy of turbid media using a dual step steady-state method. AB - We present a method for the determination of the absorption coefficient of turbid media in a broad wavelength range with high spectral resolution using a dual step method. First, the reduced scattering coefficient is determined for a few wavelengths with spatially resolved reflectance measurements. The reduced scattering coefficient for the intermediate wavelengths is interpolated by fitting a power law. Second, the absorption coefficient is obtained from measurements of the total reflectance using the a priori knowledge of the reduced scattering coefficient. By applying a white light source and a spectrometer to measure the total reflectance, the absorption coefficient is determined with a high spectral resolution. The methodology is verified by comparing the absorption coefficients determined by the spatially resolved reflectance measurements with those obtained by the dual step method. The influence of an unknown refractive index and phase function on the determination of the optical properties is investigated. In addition, the optical properties of Intralipid/ink phantoms and the fat layer of porcine rind were determined. The absorption coefficient of the investigated phantoms varying by four orders of magnitude could be determined with an average error of less than 10%. PMID- 22502580 TI - Method for physiologic phenotype characterization at the single-cell level in non interacting and interacting cells. AB - Intercellular heterogeneity is a key factor in a variety of core cellular processes including proliferation, stimulus response, carcinogenesis, and drug resistance. However, cell-to-cell variability studies at the single-cell level have been hampered by the lack of enabling experimental techniques. We present a measurement platform that features the capability to quantify oxygen consumption rates of individual, non-interacting and interacting cells under normoxic and hypoxic conditions. It is based on real-time concentration measurements of metabolites of interest by means of extracellular optical sensors in cell isolating microwells of subnanoliter volume. We present the results of a series of measurements of oxygen consumption rates (OCRs) of individual non-interacting and interacting human epithelial cells. We measured the effects of cell-to-cell interactions by using the system's capability to isolate two and three cells in a single well. The major advantages of the approach are: 1. ratiometric, intensity based characterization of the metabolic phenotype at the single-cell level, 2. minimal invasiveness due to the distant positioning of sensors, and 3. ability to study the effects of cell-cell interactions on cellular respiration rates. PMID- 22502582 TI - Development of a new illumination procedure for photodynamic therapy of the abdominal cavity. AB - A homogeneous illumination of intra-abdominal organs is essential for successful photodynamic therapy of the abdominal cavity. Considering the current lack of outstanding light-delivery systems, a new illumination procedure was assessed. A rat model of peritoneal carcinomatosis was used. Four hours after intraperitoneal injection of hexaminolevulinate, a square illuminating panel connected to a 635 nm laser source was inserted vertically into the abdominal cavity. The abdominal incision was sutured and a pneumoperitoneum created prior to illumination. Light dosimetry was based on the calculation of the peritoneal surface by MRI. The rats were treated with a light dose of 20, 10, 5 or 2.5 J/cm(2) administered continuously with an irradiance of 7 mW/cm(2). The homogeneity of the cavity illumination was assessed by quantification of the photobleaching of the tumor lesions according to their localization and by scoring of that of the liver and of the bowel immediately after treatment. Photobleaching quantification for tumor lesions relied on the calculation of the fluorescence intensity ratio (after/before treatment) after recording of the lesions during blue-light laparoscopy and determination of their fluorescence intensity with Sigmascan Pro software. The procedure led to a homogeneous treatment of the abdominal cavity. No statistical difference was observed for the photobleaching values according to the localization of the lesions on the peritoneum (p=0.59) and photobleaching of the liver and of the intestine was homogeneous. We conclude that this procedure can successfully treat the major sites involved in peritoneal carcinomatosis. PMID- 22502583 TI - Towards endoscopic ultrafast laser microsurgery of vocal folds. AB - Vocal fold scarring is a predominant cause of voice disorders yet lacks a reliable treatment method. The injection of soft biomaterials to improve mechanical compliance of the vocal folds has emerged as a promising treatment. Here, we study the use of precise femtosecond laser microsurgery to ablate subsurface voids, with a goal of eventually creating a plane in dense subepithelial scar tissue into which biomaterials can be injected for their improved localization. Specifically, we demonstrate the ablation of small subepithelial voids in porcine vocal fold tissue up to 120 [micro sign]m below the surface such that larger voids in the active area of vocal fold mucosa (~3*10 mm(2)) can eventually be ablated in about 3 min. We use sub-MUJ, 776-nm pulses from a compact femtosecond fiber laser system operating at a 500-kHz repetition rate. The use of relatively high repetition rates, with a small number of overlapping pulses, is critical to achieving ablation in a very short time while still avoiding significant heat deposition. Additionally, we use the same laser for nonlinear optical imaging to provide visual feedback of tissue structure and to confirm successful ablation. The ablation parameters, including pulse duration, pulse energy, spot size, and scanning speed, are comparable to the specifications in our recently developed miniaturized femtosecond laser surgery probes, illustrating the feasibility of developing an ultrafast laser surgical instrument. PMID- 22502584 TI - Influence of water layer thickness on hard tissue ablation with pulsed CO2 laser. AB - The theory of hard tissue ablation reported for IR lasers is based on a process of thermomechanical interaction, which is explained by the absorption of the radiation in the water component of the tissue. The microexplosion of the water is the cause of tissue fragments being blasted from hard tissue. The aim of this study is to evaluate the influence of the interdependence of water layer thickness and incident radiant exposure on ablation performance. A total of 282 specimens of bovine shank bone were irradiated with a pulse CO(2) laser. Irradiation was carried out in groups: without a water layer and with a static water layer of thickness ranging from 0.2 to 1.2 mm. Each group was subdivided into five subgroups for different radiant exposures ranging from 18 to 84 J/cm(2), respectively. The incision geometry, surface morphology, and microstructure of the cut walls as well as thermal injury were examined as a function of the water layer thickness at different radiant exposures. Our results demonstrate that the additional water layer is actually a mediator of laser tissue interaction. There exists a critical thickness of water layer for a given radiant exposure, at which the additional water layer plays multiple roles, not only acting as a cleaner to produce a clean cut but also as a coolant to prevent bone heating and reduce thermal injury, but also helping to improve the regularity of the cut shape, smooth the cut surface, and enhance ablation rate and efficiency. The results suggest that desired ablation results depend on optimal selection of both water layer thickness and radiant exposure. PMID- 22502586 TI - Discrepancies in identification of Vibrio cholerae strains as members of Aeromonadaceae and Enterobacteriaceae by automated microbial identification system. AB - AIMS: Incidental observation of a discrepancy in identification of Vibrio cholerae prompted a study to understand the ability of an automated microbial identification system to identify this important pathogen. METHODS AND RESULTS: Twenty clinical isolates of V. cholerae showing difference in genetic profiles by random amplified polymorphic DNA (RAPD) fingerprinting, serologically confirmed as O1, and showing presence of ctxA and tcpA genes in PCR were subjected to analysis by Vitek 2 Compact automated identification system for identification. Vitek 2 Compact detected 10 of 20 isolates correctly, whereas the remaining 10 were identified as various members of Aeromonadaceae and Enterobacteriaceae. CONCLUSIONS: Our results indicate that Vitek 2 Compact automated microbial system does not always identify V. cholerae strains correctly. SIGNIFICANCE AND IMPACT OF STUDY: These observations should create awareness among end users about possible misidentifications by automated systems and encourage simultaneous use of serology and/or PCR for correct identification at least for V. cholerae, which is one of the most important enteric pathogens. PMID- 22502587 TI - A novel recombinant Leishmania donovani p45, a partial coding region of methionine aminopeptidase, generates protective immunity by inducing a Th1 stimulatory response against experimental visceral leishmaniasis. AB - The development of a vaccine against visceral leishmaniasis (VL) conferring long lasting immunity remains a challenge. Identification and proteomic characterization of parasite proteins led to the detection of p45, a member of the methionine aminopeptidase family. To our knowledge the present study is the first known report that describes the molecular and immunological characterization of p45. Recombinant Leishmania donovani p45 (rLdp45) induced cellular responses in cured hamsters and generated Th1-type cytokines from peripheral blood mononuclear cells of cured/endemic VL patients. Immunization with rLdp45 exerted considerable prophylactic efficacy (~85%) supported by an increase in mRNA expression of iNOS, IFN-gamma, TNF-alpha and IL-12 and decrease in TGF-beta and IL-4, indicating its potential as a vaccine candidate against VL. PMID- 22502588 TI - Computing evolutionary distinctiveness indices in large scale analysis. AB - We present optimal linear time algorithms for computing the Shapley values and 'heightened evolutionary distinctiveness' (HED) scores for the set of taxa in a phylogenetic tree. We demonstrate the efficiency of these new algorithms by applying them to a set of 10,000 reasonable 5139-species mammal trees. This is the first time these indices have been computed on such a large taxon and we contrast our finding with an ad-hoc index for mammals, fair proportion (FP), used by the Zoological Society of London's EDGE programme. Our empirical results follow expectations. In particular, the Shapley values are very strongly correlated with the FP scores, but provide a higher weight to the few monotremes that comprise the sister to all other mammals. We also find that the HED score, which measures a species' unique contribution to future subsets as function of the probability that close relatives will go extinct, is very sensitive to the estimated probabilities. When they are low, HED scores are less than FP scores, and approach the simple measure of a species' age. Deviations (like the Solendon genus of the West Indies) occur when sister species are both at high risk of extinction and their clade roots deep in the tree. Conversely, when endangered species have higher probabilities of being lost, HED scores can be greater than FP scores and species like the African elephant Loxondonta africana, the two solendons and the thumbless bat Furipterus horrens can move up the rankings. We suggest that conservation attention be applied to such species that carry genetic responsibility for imperiled close relatives. We also briefly discuss extensions of Shapley values and HED scores that are possible with the algorithms presented here. PMID- 22502589 TI - Ku protein as the main cellular target of cell-surface-bound circulating DNA. AB - OBJECTIVE: An immunomodulatory activity of circulating DNA (cirDNA) is implemented via the interactions of cirDNA with the targets exposed on the cell membrane and/or intracellular targets. The goal of this work was to identify the cellular targets of immunoinhibiting cell-surface-bound cirDNA (csbDNA) using its oligodeoxyribonucleotide (ODN) analogs containing the nucleotide motifs frequently found in csbDNA and displaying the same effects. MATERIALS AND METHODS: The binding of [(32)P]-labeled single- and double-stranded ODNs (ss- and ds-ODNs) with membrane-cytosolic (MC) extracts and living human umbilical vein endothelial cells (HUVEC) was studied by electromobility shift assay (EMSA). Complexes of biotinylated ODNs with target proteins were affinity isolated using streptavidin Sepharose with subsequent SDS-PAGE and identified by MALDI-TOF mass spectrometry. RESULTS AND CONCLUSIONS: Both ss- and ds-ODNs form strong ODN protein complexes with similar electrophoretic mobilities after incubation with the MC extracts of HUVEC either when added extracellularly or lipofected into cells. The ODN-binding proteins were identified as the DNA-binding components of DNA-dependent protein kinase (DNA-PK), namely, Ku70 and Ku80 proteins. Diverse cellular localizations and functions of the Ku proteins demand further clarification of Ku70/80 role as a mediator of the csbDNA immunoinhibiting effects. PMID- 22502590 TI - Fungal origins of the bicyclo[2.2.2]diazaoctane ring system of prenylated indole alkaloids. AB - Over eight different families of natural products consisting of nearly 70 secondary metabolites that contain the bicyclo[2.2.2]diazaoctane ring system have been isolated from various Aspergillus, Penicillium, and Malbranchea species. Since 1968, these secondary metabolites have been the focus of numerous biogenetic, synthetic, taxonomic, and biological studies and, as such, have made a lasting impact across multiple scientific disciplines. This review covers the isolation, biosynthesis, and biological activity of these unique secondary metabolites containing the bridging bicyclo[2.2.2]diazaoctane ring system. Furthermore, the diverse fungal origin of these natural products is closely examined and, in many cases, updated to reflect the currently accepted fungal taxonomy. PMID- 22502591 TI - Spatial distribution of submarine groundwater discharge and associated nutrients within a local coastal area. AB - To understand the local-scale distribution of submarine groundwater discharge (SGD) and dissolved nutrients, a multiple-detector (222)Rn monitoring survey was undertaken along the Mt. Chokai volcanic coast in northern Japan. The surveys revealed that the highest SGD (calculated to be 6.2 * 10(4) m(3) d(-1), within an area of 2 * 10(4) m(2)) with the greatest nutrient fluxes (sum of NO(3)(-), NO(2)(-), and NH(4)(+) (DIN): 9.2 * 10(2) mol d(-1); PO(4)(3-) (DIP): 56 mol d( 1)) is present at the edge of the youngest volcanic lava flow in the area. Recharged groundwater transports nutrients through porous volcanic flows and discharges as SGD near shore. Our results demonstrate that the spatial distribution of SGD in the study area is closely regulated by the local geology and topography. Furthermore, we show that continuous (222)Rn monitoring with a multidetector system at boat speeds of 1-2 knots provides details at a scale one order of magnitude greater than has been reported previously. In addition, the results of our study suggest that SGD-borne DIP may play an important role in the important local oyster production. PMID- 22502593 TI - Development of a behavioural marker system for scrub practitioners' non-technical skills (SPLINTS system). AB - RATIONALE, AIMS AND OBJECTIVES: Adverse events still occur despite ongoing efforts to reduce harm to patients. Contributory factors to adverse events are often due to limitations in clinicians' non-technical skills (e.g. communication, situation awareness), rather than deficiencies in technical competence. We developed a behavioural rating system to provide a structured means for teaching and assessing scrub practitioners' (i.e. nurse, technician, operating department practitioner) non-technical skills. METHOD: Psychologists facilitated focus groups (n = 4) with experienced scrub practitioners (n = 16; 4 in each group) to develop a preliminary taxonomy. Focus groups reviewed lists of non-technical skill-related behaviours that were extracted from an interview study. The focus groups labelled skill categories and elements and also provided examples of good and poor behaviours for those skills. An expert panel (n = 2 psychologists; n = 1 expert nurse) then used an iterative process to individually and collaboratively review and refine those data to produce a prototype skills taxonomy. RESULTS: A preliminary taxonomy containing eight non-technical skill categories with 28 underlying elements was produced. The expert panel reduced this to three categories (situation awareness, communication and teamwork, task management), each with three underlying elements. The system was called the Scrub Practitioners' List of Intraoperative Non-Technical Skills system. A scoring system and a user handbook were also developed. CONCLUSION: A prototype behavioural rating system for scrub practitioners' non-technical skills was developed, to aid in teaching and providing formative assessment. This important aspect of performance is not currently explicitly addressed in any educational route to qualify as a scrub practitioner. PMID- 22502594 TI - Effect of hypertension on coronary remodeling patterns in angiographically normal or minimally atherosclerotic coronary arteries: an intravascular ultrasound study. AB - Whether there is any particular role of hypertension in remodeling process has not been completely understood yet. The aim of this study was to assess the association between hypertension and remodeling patterns in normal or minimally atherosclerotic coronary arteries. Seventy-nine patients who were free of significant coronary atherosclerosis were divided into two groups according to the absence (n = 39) or presence (n = 40) of hypertension; and standard intravascular ultrasound examination was performed in 145 segments. To determine the remodeling pattern in early atherosclerotic process, patients were also analyzed according to the level of plaque burden at the lesion site after the analysis of remodeling patterns. Positive remodeling was more prevalent in the hypertensive group (52.5% vs. 12.8%; P < .001) whereas negative remodeling was more common in diabetic patients (53.6% vs. 27.4%; P = .03). Mean remodeling index was 1.04 for hypertensives and 0.96 for normotensives (P = .03). There were no correlations between remodeling patterns and other risk factors such as age, family history, and hypercholesterolemia. Early atherosclerotic lesions (< 30%) exhibited more negative remodeling characteristics while intermediate pattern was observed more frequently in patients with high plaque burden (P = .006 and .02, respectively). Positive remodeling showed no association in this context (P = .07). This study demonstrated that minimal atherosclerotic lesions in hypertensives had a tendency for compensatory arterial enlargement. Positive remodeling may result from local adaptive processes within vessel wall or hemodynamic effects of blood pressure itself. PMID- 22502592 TI - Definition of the binding mode of a new class of phosphoinositide 3-kinase alpha selective inhibitors using in vitro mutagenesis of non-conserved amino acids and kinetic analysis. AB - The binding mechanism of a new class of lipid-competitive, ATP non-competitive, p110alpha isoform-selective PI3K (phosphoinositide 3-kinase) inhibitors has been elucidated. Using the novel technique of isoform reciprocal mutagenesis of non conserved amino acids in the p110alpha and p110beta isoforms, we have identified three unique binding mechanisms for the p110alpha-selective inhibitors PIK-75, A 66S and J-32. Each of the inhibitor's p110alpha-isoform-selective binding was found to be due to interactions with different amino acids within p110. The PIK 75 interaction bound the non-conserved region 2 amino acid p110alpha Ser(773), A 66S bound the region 1 non-conserved amino acid p110alpha Gln(859), and J-32 binding had an indirect interaction with Lys(776) and Ile(771). The isoform reciprocal mutagenesis technique is shown to be an important analytical tool for the rational design of isoform-selective inhibitors. PMID- 22502595 TI - Prevention and treatment of postpartum hemorrhage in low-resource settings. PMID- 22502596 TI - The fetus as patient. PMID- 22502597 TI - A novel single nucleotide polymorphism within the NOD2 gene is associated with pulmonary tuberculosis in the Chinese Han, Uygur and Kazak populations. AB - BACKGROUND: The present study aimed to investigate the genetic polymorphisms in exon 4 of the NOD2 gene in tuberculosis patients and healthy controls, in order to clarify whether polymorphisms in the NOD2 gene is associated with tuberculosis. METHODS: A case-control study was performed on the Chinese Han, Uygur and Kazak populations. Exon 4 of the NOD2 gene was sequenced in 425 TB patients and 380 healthy controls to identify SNPs. RESULTS: The frequency of T/G genotypes for the Arg587Arg (CGT -> CGG) single nucleotide polymorphism (SNP) in NOD2 was found to be significantly higher in the Uygur (34.9%) and Kazak (37.1%) populations than the Han population (18.6%). Also, the frequency of G/G genotypes for the Arg587Arg SNP was significantly higher in the Uyghur (8.3%) and Kazak (5.4%) populations than the Han population (0.9%). Meanwhile, no significant difference was found in the Arg587Arg polymorphism between the tuberculosis patients and healthy controls in the Uyghur and Kazak populations (P > 0.05) whereas, a significant difference was observed in the Arg587Arg polymorphism between the tuberculosis patients and healthy controls in the Han population (P < 0.01). The odd ratio of 2.16 (95% CI = 1.31-3.58; P < 0.01) indicated that the Arg587Arg SNP in NOD2 may be associated with susceptibility to tuberculosis in the Chinese Han population. CONCLUSIONS: Our study is the first to demonstrate that the Arg587Arg SNP in NOD2 is a new possible risk factor for tuberculosis in the Chinese Han population, but not in the Uyghur and Kazak populations. Our results may reflect racial differences in genetic susceptibility to tuberculosis. PMID- 22502598 TI - An injectable hybrid nanoparticle-in-oil-in-water submicron emulsion for improved delivery of poorly soluble drugs. AB - Poor drugability problems are commonly seen in a class of chemical entities with poor solubility in water and oil, and moreover, physicochemical instability of these compounds poses extra challenges in design of dosage forms. Such problems contribute a significant high failure rate in new drug development. A hybrid nanoparicle-in-oil-in-water (N/O/W) submicron emulsion was proposed for improved delivery of poorly soluble and unstable drugs (e.g., dihydroartemisinin (DHA)). DHA is known for its potent antimalarial effect and antitumor activity. However, its insolubility and instability impose big challenges for formulations, and so far, no injectable dosage forms are clinically available yet. Therefore, an injectable DHA N/O/W system was developed. Unlike other widely-explored systems (e.g., liposomes, micelles, and emulsions), in which low drug load and only short term storage are often found, the hybrid submicron emulsion possesses three-fold higher drug-loading capacity than the conventional O/W emulsion. Of note, it can be manufactured into a freeze-drying form and can render its storage up to 6 months even in room temperature. The in vivo studies demonstrated that the PK profiles were significantly improved, and this injectable system was effective in suppressing tumor growth. The strategy provides a useful solution to effective delivery of such a class of drugs. PMID- 22502599 TI - Hollow mesoporous aluminosilica spheres with perpendicular pore channels as catalytic nanoreactors. AB - The design and synthesis of hollow/yolk-shell mesoporous structures with catalytically active ordered mesoporous shells can infuse new vitality into the applications of these attractive structures. In this study, we report that hollow/yolk-shell structures with catalytically active ordered mesoporous aluminosilica shells can be easily prepared by using silica spheres as the silica precursors. By simply treating with a hot alkaline solution in the presence of sodium aluminate (NaAlO(2)) and cetyltrimethylammonium bromide (CTAB), solid silica spheres can be directly converted into high-quality hollow mesoporous aluminosilica spheres with perpendicular pore channels. On the basis of the proposed formation mechanism of etching followed by co-assembly, the synthesis strategy developed in this work can be extended as a general strategy to prepare ordered mesoporous yolk-shell structures with diverse compositions and morphologies simply by replacing solid silica spheres with silica-coated nanocomposites. The reduction of 4-nitrophenol with yolk-shell structured Au@ordered mesoporous aluminosilica as the catalyst has clearly demonstrated that the highly permeable perpendicular pore channels of mesoporous aluminosilica can effectively prevent the catalytically active yolk from aggregating. Furthermore, with accessible acidity, the yolk-shell structured ordered mesoporous aluminosilica spheres containing Pd yolk exhibit high catalytic activity and recyclability in a one-pot two-step synthesis involving an acid catalysis and subsequent catalytic hydrogenation for desired benzimidazole derivative, which makes the proposed hollow ordered aluminosilica spheres a versatile and practicable scaffold for advanced catalytic nanoreactor systems. PMID- 22502600 TI - Defects in oxygen-depleted titanate nanostructures. AB - The identification of defects and their controlled generation in titanate nanostructures is a key to their successful application in photoelectronic devices. We comprehensively explored the effect of vacuum annealing on morphology and composition of Na(2)Ti(3)O(7) nanowires and protonated H(2)Ti(3)O(7) nanoscrolls using a combination of scanning electron microscopy, Auger and Fourier-transform infrared (FT-IR) spectroscopy, as well as ab initio density functional theory (DFT) calculations. The observation that H(2)Ti(3)O(7) nanoscrolls are more susceptible to electronic reduction and annealing-induced n type doping than Na(2)Ti(3)O(7) nanowires is attributed to the position of the conduction band minimum. It is close to the vacuum level and, thus, favors the Fermi level-induced compensation of donor states by cation vacancies. In agreement with theoretical predictions that suggest similar formation energies for oxygen and sodium vacancies, we experimentally observed the annealing induced depletion of sodium from the surface of the nanowires. PMID- 22502601 TI - A randomized study of sodium hypochlorite versus formocresol pulpotomy in primary molar teeth. AB - BACKGROUND: Alternatives to vital pulpotomy treatment in primary teeth are being sought because of the high formaldehyde content of traditional formocresol (FC) pulpotomy medicaments. AIM: The aim was to compare the clinical and radiographic success of vital pulpotomy treatment in primary molars using 3% sodium hypochlorite (NaOCl) versus a 1:5 dilution of Buckley's FC. DESIGN: Pulpotomies were performed in primary molars of healthy children between 3 and 10 years old. Sixty-five primary teeth were randomized into two groups that were evaluated for treatment outcomes. Following treatment, the pulp chamber was filled with zinc oxide eugenol (ZnOE) and restored with a stainless steel crown cemented with glass ionomer cement. Clinical and radiographic outcomes were recorded at 6 and 12 months. RESULTS: The control (FC) and experimental (NaOCl) groups demonstrated 100% clinical success at 6 and 12 months. The NaOCl group had 86% (19/22) radiographic success at 6 months and 80% (12/15) at 12 months. The FC group had 84% (21/25) radiographic success at 6 months and 90% (9/10) at 12 months. No significant differences were found in the radiographic outcomes between the two groups at 6 and 12 months (Fisher's exact test; P=0.574 and P=0.468, respectively). CONCLUSION: NaOCl demonstrated clinical and radiographic success comparable to FC. PMID- 22502602 TI - Identification of bitterness-masking compounds from cheese. AB - Bitterness-masking compounds were identified in a natural white mold cheese. The oily fraction of the cheese was extracted and further fractionated by using silica gel column chromatography. The four fractions obtained were characterized by thin-layer chromatography and nuclear magnetic resonance spectroscopy. The fatty acid-containing fraction was found to have the highest bitterness-masking activity against quinine hydrochloride. Bitterness-masking activity was quantitated using a method based on subjective equivalents. At 0.5 mM, the fatty acid mixture, which had a composition similar to that of cheese, suppressed the bitterness of 0.008% quinine hydrochloride to be equivalent to that of 0.0049 0.0060% and 0.5 mM oleic acid to that of 0.0032-0.0038% solution. The binding potential between oleic acid and the bitter compounds was estimated by isothermal titration calorimetry. These results suggest that oleic acid masked bitterness by forming a complex with the bitter compounds. PMID- 22502603 TI - Prostate-specific antigen concentration in young men: new estimates and review of the literature. AB - Study Type--Diagnostic (cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? Although non-recommended PSA testing has been reported in men younger than 40 years of age, there are few recognized data on PSA in younger American men, particularly younger African-American men, to provide age- and race-specific references. Using data from an existing large study of young, male members of the US military, aged 28-36 years, the present study provides PSA reference distributions for young Caucasian-American men (median = 0.56, 95th percentile = 1.42, range: <0.01-3.34 ng/mL) and African American men (median = 0.64, 95th percentile = 1.89, range: 0.12-6.45 ng/mL). Previous estimates from the literature are also summarized. OBJECTIVE: * To provide race-specific prostate-specific antigen (PSA) reference distributions for young men less than 40 years of age who might have undergone non-recommended PSA testing because of their family history of prostate cancer or inadvertently as part of a standard panel of tests. MATERIALS AND METHODS: * We used data from a large existing study of young, male Caucasian- and African-American members of the US military with stored serum in the Department of Defense serum repository. * As part of this previous study, we selected a random sample of 373 Caucasian- and 366 African-American men aged 28-36 years with an archived serum specimen collected for standard military purposes from 2004 to 2006. * We measured serum total PSA concentration in this specimen using the Beckman Coulter Access Hybritech PSA assay. RESULTS: * The PSA level ranged from <0.01 to 3.34 ng/mL among Caucasian-American men, with a median of 0.56 ng/mL and a 95th percentile of 1.42 ng/mL. * The PSA level ranged from 0.12 to 6.45 ng/mL among African American men, with a median of 0.64 ng/mL and 95th percentile of 1.89 ng/mL. * The PSA level was significantly higher in African- than in Caucasian-American men (P= 0.001). CONCLUSION: * The PSA estimates, together with those summarized from the literature, provide age- and race-specific PSA reference distributions for young men who might have undergone non-recommended PSA testing. * Comparisons by race could also begin to inform the timing of divergence of prostate cancer risk by race. PMID- 22502604 TI - Mouse models of neuronal ceroid lipofuscinoses: useful pre-clinical tools to delineate disease pathophysiology and validate therapeutics. AB - The neuronal ceroid lipofuscinoses (NCL, also known as Batten disease) is a devastating neurodegenerative diseases caused by mutations in either soluble enzymes or membrane-associated structural proteins that result in lysosome dysfunction. Different forms of NCL were defined initially by age of onset, affected population and/or type of storage material but collectively represent the most prevalent pediatric hereditary neurovisceral storage disorder. Specific gene mutations are now known for each subclass of NCL in humans that now largely define the disease: cathepsin D (CTSD) for congenital (CLN10 form); palmitoyl protein thioesterase 1 (PPT1) for infantile (CLN1 form); tripeptidyl peptidase 1 (TPP1) for classic late infantile (CLN2 form); variant late infantile-CLN5, CLN6 or CLN8 for variant late infantile forms; and CLN3 for juvenile (CLN3 form). Several mouse models of NCL have been developed, or in some cases exist sporadically, that exhibit mutations producing a progressive neurodegenerative phenotype similar to that observed in human NCL. The study of these mouse models of NCL has dramatically advanced our knowledge of NCL pathophysiology and in some cases has helped delineate the function of proteins mutated in human NCL. In addition, NCL mutant mice have been tested for several different therapeutic approaches and as such they have become important pre-clinical models for validating treatment options. In this review we will assess the current state of mouse models of NCL with regards to their unique pathophysiology and how these mice have helped investigators achieve a better understanding of human NCL disease and therapy. PMID- 22502605 TI - Molecular diversity of CTX prophage in Vibrio cholerae. AB - AIMS: The objective of this study was to investigate the molecular diversity of CTX genetic element within toxigenic Vibrio cholerae genomes and to determine the genetic diversity of V. cholerae population collected in a 6-year period (2004 2009) in Iran. METHODS AND RESULTS: The results of mismatch amplification mutation assay (MAMA)-PCR and sequencing showed cytosine nucleotide in positions 203 and 115 in all 50 El Tor V. cholerae strains, which is the same as classical ctxB sequence. One strain yielded amplicons with both El Tor and classical biotype primers in MAMA-PCR indicative of presence of two copies of CTX phages with different genotypes (rstR(ET) ctxB(class) and rstR(ET) ctxB(ET)) integrated within the genome of this isolate, which suggested the integration of two different CTX phages at different occasions or point mutation in one copy of CTX. Sequencing and PCR analysis indicated the presence of hybrid CTX genotype (rstR(ET) ctx(class)) in 70.6% of the isolates; however, only El Tor RS1 phage has been integrated in flanking to the CTX phages with different genotypes. CONCLUSIONS: Enterobacterial repetitive intergenic consensus-PCR (ERIC-PCR) and ribosomal gene spacer-PCR (RS-PCR) showed a relatively homogenous population in different years. Our findings indicate that sequence analysis of RS and ctxB regions has more discriminative power than restriction-based methods. SIGNIFICANCE AND IMPACT OF THE STUDY: Investigating the molecular diversity of CTX prophage among V. cholerae strains helps to establish a new valuable database of genetic information about isolates, which is of great importance for epidemiologic studies in Iran and other countries encountering cholera epidemics. PMID- 22502606 TI - Sample introduction techniques for microchip electrophoresis: a review. AB - The number of applications of microfluidic analysis systems continues to increase, along with the variety of substrate materials and complexity of the devices themselves. One of the most common features of these devices that has remained relatively unchanged, however, is the introduction of a sample mixture into a separation channel so that individual components can be separated by electrophoresis. Whether a relatively simple mixture of amino acids or a more complex sample of DNA fragments extracted and amplified on-chip, the ability to reliably and reproducibly inject a representative sample is arguably the most significant requirement for an electrophoretic micro total analysis system (MUTAS). This review will focus on the different methods reported for sample introduction in microchip electrophoresis, highlighting both pressure-driven and electrokinetic techniques, with an emphasis on the methods employed in MUTAS applications. PMID- 22502607 TI - A density-based segmentation for 3D images, an application for X-ray micro tomography. AB - Density-based spatial clustering of applications with noise (DBSCAN) is an unsupervised classification algorithm which has been widely used in many areas with its simplicity and its ability to deal with hidden clusters of different sizes and shapes and with noise. However, the computational issue of the distance table and the non-stability in detecting the boundaries of adjacent clusters limit the application of the original algorithm to large datasets such as images. In this paper, the DBSCAN algorithm was revised and improved for image clustering and segmentation. The proposed clustering algorithm presents two major advantages over the original one. Firstly, the revised DBSCAN algorithm made it applicable for large 3D image dataset (often with millions of pixels) by using the coordinate system of the image data. Secondly, the revised algorithm solved the non-stability issue of boundary detection in the original DBSCAN. For broader applications, the image dataset can be ordinary 3D images or in general, it can also be a classification result of other type of image data e.g. a multivariate image. PMID- 22502608 TI - Evolving chemometric models for predicting dynamic process parameters in viscose production. AB - In viscose production, it is important to monitor three process parameters in order to assure a high quality of the final product: the concentrations of H(2)SO(4), Na(2)SO(4) and Z(n)SO(4). During on-line production these process parameters usually show a quite high dynamics depending on the fiber type that is produced. Thus, conventional chemometric models, which are trained based on collected calibration spectra from Fourier transform near infrared (FT-NIR) measurements and kept fixed during the whole life-time of the on-line process, show a quite imprecise and unreliable behavior when predicting the concentrations of new on-line data. In this paper, we are demonstrating evolving chemometric models which are able to adapt automatically to varying process dynamics by updating their inner structures and parameters in a single-pass incremental manner. These models exploit the Takagi-Sugeno fuzzy model architecture, being able to model flexibly different degrees of non-linearities implicitly contained in the mapping between near infrared spectra (NIR) and reference values. Updating the inner structures is achieved by moving the position of already existing local regions and by evolving (increasing non-linearity) or merging (decreasing non linearity) new local linear predictors on demand, which are guided by distance based and similarity criteria. Gradual forgetting mechanisms may be integrated in order to out-date older learned relations and to account for more flexibility of the models. The results show that our approach is able to overcome the huge prediction errors produced by various state-of-the-art chemometric models. It achieves a high correlation between observed and predicted target values in the range of [0.95,0.98] over a 3 months period while keeping the relative error below the reference error value of 3%. In contrast, the off-line techniques achieved correlations below 0.5, ten times higher error rates and the more deteriorate, the more time passes by. PMID- 22502609 TI - Ultrasensitive aptamer-based bio bar code immunomagnetic separation and electrochemiluminescence method for the detection of protein. AB - An ultrasensitive aptamer-based bio bar code immunomagnetic separation and electrochemiluminescence (IM-ECL) method for the detection of protein is developed. The target protein is captured by biotin-labeled aptamer (biotin probe) and [Ru(bpy)(3)](2+) (TBR)-Au bio bar code-labeled aptamer (ECL nanoprobe), to form a double aptamer-protein sandwich complex. The complex is then immobilized on the streptavidin microbeads through biotin-streptavidin linkage and detected by ECL assay. The ECL signal of the target protein is amplified by the TBR-bio bar code DNAs. As an example, platelet-derived growth factor B-chain homodimer (PDGF-BB) was detected by the method. Experimental results show that the detection limit of the assay is 1 pM of PDGF-BB. A calibration curve with a linearity range from 1 pM to 10 nM is established, thus, make quantitative analysis possible. The method has been used to detect PDGF-BB in fetal calf serum with minimum background interference. Due to the wide availability of aptamer for numerous proteins, this aptamer-based bio bar code IM ECL method holds great promise in protein detection. PMID- 22502610 TI - Separation and electrochemical detection of paracetamol and 4-aminophenol in a paper-based microfluidic device. AB - The present work describes the construction and application of a simple, low cost and sensitive microfluidic paper-based device with electrochemical detection for the detection of paracetamol and 4-aminophenol. The separation channels of a width of 2.0 mm were created on paper using a wax printing process to define the regions of the device. A baseline separation level of the analytes can be obtained in 0.1 mol L(-1) acetate buffer solution at pH 4.5 and by injecting 500 nL of the standard solutions at 12 mm from the working electrode. The electrochemical detection system was created at the end of the channels through a process known as sputtering. The previously separated analytes were detected at the end of the hydrophilic separation channel by applying a potential of 400 mV vs. pseudo Au on the working electrode. Experimental variables such as type of paper (cation exchanger and n1), pH, sample volume, applied potential and distance of sample injection were evaluated and, under the conditions of higher response, it was possible to obtain detection limits of 25.0 and 10.0 MUmol L(-1) for paracetamol and 4-aminophenol, respectively. PMID- 22502611 TI - Electromembrane extraction combined with gas chromatography for quantification of tricyclic antidepressants in human body fluids. AB - Recent advances in electromembrane extraction (EME) methodology calls for effective and accessible detection methods. Using imipramine and clomipramine as model therapeutics, this proof-of-principle work combines EME with gas chromatography analysis employing a flame ionization detector (FID). The drugs were extracted from acidic aqueous sample solutions, through a supported liquid membrane (SLM) consisting of 2-nitrophenyl octyl ether (NPOE) impregnated on the walls of the hollow fiber. EME parameters, such as SLM composition, type of ion carrier, pH and the composition of donor and acceptor solutions, agitation speed, extraction voltage, and extraction time were studied in detail. Under optimized conditions, the therapeutics were effectively extracted from different matrices with recoveries ranging from 90 to 95%. The samples were preconcentrated 270-280 times prior to GC analysis. Reliable linearity was also achieved for calibration curves with a regression coefficient of at least 0.995. Detection limits and intra-day precision (n=3) were less than 0.7 ng mL(-1) and 8.5%, respectively. Finally, method was applied to determination and quantification of drugs in human plasma and urine samples and satisfactory results were achieved. PMID- 22502612 TI - Quantification of retinoid concentrations in human serum and brain tumor tissues. AB - Retinoic acid signaling is essential for central nervous system (CNS) differentiation and appears to be impaired in tumors. Thus far, there are no established methods to quantify relevant retinoids (all-trans-retinoic acid, 9 cis-retinoic acid, 13-cis retinoic acid, and retinol) in human brain tumors. We developed a single step extraction and quantification procedure for polar and apolar retinoids in normal tissue, lipid-rich brain tumor tissues, and serum. This quantification procedure is based on high performance liquid chromatography (HPLC) with diode-array detection (DAD) using all-trans-acitretin as an internal standard and extraction by liquid-liquid partition with ethyl acetate and borate buffer at pH 9. Recovery with this extraction procedure was higher than earlier (two-step) liquid-liquid extraction procedures based on hexane, NaOH, and HCl. The overall quantification procedure was validated according to Food and Drug Administration (FDA) guidelines and fulfilled all criteria of accuracy, precision, selectivity, recovery, and stability. The overall method accuracy varied between -5.6% and +5.4% for serum and -3.8% and +6.2% for tissues, and overall precision ranged from 3.1% to 6.9% for serum and 2.1% to 8.3% for tissues (%CV batch-to-batch). The lower limit of quantification for all compounds in tumor tissue (and serum) was 3.9 ng g(-1) (ng mL(-1)). Using this assay, photodegradation of the retinoids was evaluated and endogenous polar and apolar retinoids were quantified in sera and brain tumor tissues of patients and compared with serum and tonsil tissue concentrations of controls. It may thus serve as a suitable method for the characterization of retinoid uptake and metabolism in the respective compartments. PMID- 22502613 TI - Fluorescence-quenching-based homogeneous caspase-3 activity assay using photon upconversion. AB - Caspase proteases are key mediators in apoptosis and thus of great interest in pharmaceutical industry. Enzyme-activity assays are commonly employed in the screening of protease inhibitors that are potential drug candidates. Conventional homogeneous fluorescence-based assays are susceptible to autofluorescence originating from biological material. This background autofluorescence can be eliminated by using upconverting phosphors (UCPs) that emit visible light upon excitation at near-infrared. In the assay energy was transferred from a UCP-donor to a conventional fluorophore acceptor that resided at one end of a caspase-3 specific substrate peptide. Attached to the other end was a quencher molecule that was used to attenuate the acceptor emission through intramolecular energy transfer in an intact peptide. In non-inhibitory conditions the enzyme reaction separated the fluorophore from the quencher and the emission of the fluorophore was recovered. The method was applied for the detection and characterization of a known caspase-3 inhibitor Z-DEVD-FMK, and the assay gave IC(50) values of approximately 13 nM for this inhibitor. We have demonstrated the applicability of UCPs on a fluorescence-quenching-based homogeneous enzyme-activity assay for the detection of caspase-3 inhibitors. The use of near-infrared excitable UCPs enables inexpensive instrumentation and total elimination of autofluorescence, while the use of an internally quenched substrate molecule diminishes the background resulting from radiatively excited acceptor molecules. The reduction of autofluorescence and radiative background result in high signal-to-background ratios (ratios of approximately 100 were obtained). By further utilizing assay miniaturization and signal enhancement in a white microtitration plate, a significant reduction in the reagent consumption can be achieved rendering the assay applicable for high-throughput screening. PMID- 22502614 TI - Development of an electrochemical membrane-based nanobiosensor for ultrasensitive detection of dengue virus. AB - A sensitive membrane-based electrochemical nanobiosensor is developed for the detection of dengue type 2 virus (DENV-2) using nanoporous alumina-modified platinum electrode. Its sensing mechanism relies on the monitoring of electrode's Faradaic current response toward redox probe, ferrocenemethanol, which is sensitive toward the formation of immune complexes within the alumina nanochannels. Anti-DENV-2 monoclonal antibody (clone 3H5, isotype IgG) is used as the biorecognition element in this work. The stepwise additions of antibody, bovine serum albumin (BSA) and DENV-2 are characterized by differential pulse voltammetry (DPV). A low detection limit of 1 pfu mL(-1) with linear range from 1 to 10(3) pfu mL(-1) (R(2)=0.98) can be achieved by the nanobiosensor. The nanobiosensor is selective toward DENV-2 with insignificant cross reaction with non-specific viruses, Chikungunya virus, West Nile virus and dengue type 3 virus (DENV-3). Relative standard deviation (RSD) for triplicate analysis of 5.9% indicates an acceptable level of reproducibility. The first direct quantitation of DENV-2 concentration in whole mosquito vector is demonstrated using this electrochemical nanobiosensor. PMID- 22502615 TI - Modified mesoporous silica materials for on-line separation and preconcentration of hexavalent chromium using a microcolumn coupled with flame atomic absorption spectrometry. AB - A modified SBA-15 mesoporous silica material NH(2)-SBA-15 was synthesized successfully by grafting gamma-aminopropyl-triethoxysilane. The material was characterized using transmission electron microscopy (TEM) and Fourier transform infrared/Raman (FT-IR/Raman) spectroscopy, and used for the first time in a flow injection on-line solid phase extraction (SPE) coupled with flame atomic absorption spectrometry (FAAS) to detect trace Cr (VI). Effective sorption of Cr (VI) was achieved at pH 2.0 with no interference from Cr (III) and other ions and 0.5 mol L(-1) NH(3).H(2)O solution was found optimal for the complete elution of Cr (VI). An enrichment factor of 44 and was achieved under optimized experimental conditions at a sample loading of 2.0 mL min(-1) sample loading (300 s) and an elution flow rate of 2.0 mL min(-1) (24s). The precision of the 11 replicate Cr (VI) measurements was 2.1% at the 100 MUg L(-1) level with a detection limit of 0.2 MUg L(-1) (3s, n=10) using the FAAS. The developed method was successfully applied to trace chromium determination in waste water. The accuracy was validated using a certified reference material of riverine water (GBW08607). PMID- 22502616 TI - Effect of temperature and solvent composition on acid dissociation equilibria, I: Sequenced (s)(s)pKa determination of compounds commonly used as buffers in high performance liquid chromatography coupled to mass spectroscopy detection. AB - A new automated and rapid potentiometric method for determining the effect of organic-solvent composition on pK(a) has been developed. It is based on the measurements of pH values of buffer solutions of variable solvent compositions using a combined glass electrode. Additions of small volumes of one precisely thermostated solution into another, both containing exactly the same analytical concentrations of the buffer components, can produce continuous changes in the solvent composition. Two sequences of potential measurements, one of increasing and the other of decreasing solvent content, are sufficient to obtain the pK(a) values of the acidic compound within the complete solvent-composition range in about 2h. The experimental design, procedures, and calculations needed to convert the measured pH into the thermodynamic pK(a) values are thoroughly discussed. This rapid and automated method allows the systematic study of the effect of solvent compositions and temperatures on the pK(a). It has been applied to study the dissociation constants of two monoprotic acids: formic acid and triethylamine:HCl in acetonitrile/water mixtures within the range from 0 to 90% (v/v) at temperatures between 20 degrees C and 60 degrees C. These volatile compounds are frequently used to control the pH of the mobile phase in HPLC, especially in methods coupled to mass-spectrometry detection. The obtained pK(a) values are in excellent agreement with those previously reported. The results were fitted to empirical functions between pK(a) and temperature and composition. These equations, which can be used to estimate the pK(a) of these substances at any composition and temperature, would be highly useful in practical work during chromatographic method development. PMID- 22502617 TI - Atlas shrugged (kind of). PMID- 22502618 TI - Editorial: Are you concerned about the practice called "dry labbing" in the dietary supplement industry? PMID- 22502619 TI - Do environmental toxicants contribute to allergy and asthma? AB - The rates of asthma and allergy (Type 1 hypersensitivity disorders) have been increasing worldwide for the last few decades. Various theories have been proposed to account for this alarming trend. One of these is the impact of environmental toxicants. Epidemiological research has correlated exposure to environmental chemicals (such as pesticides, solvents, and air pollutants) with increasing rates of both asthma and allergies. Research has documented chemicals as causal agents capable of producing immune system imbalances characteristic of type 1 hypersensitivity. In vitro studies and in vivo animal models have demonstrated that many of the environmental chemicals and pollutants that have been epidemiologically associated with increased allergic tendency have been shown to enhance Type 2 helper T cell (Th2) dominance, which is consistent with the T-helper cell pattern found in asthma, allergic rhinitis, and other Type 1 hypersensitivity disorders. Depletion of glutathione is one possible mechanism for this T-helper cell imbalance. Preliminary evidence suggests the possibility that repletion of glutathione levels (with oral supplementation of N acetylcysteine), and enhancement of glutathione transferase function (using sulforaphanes), might be therapeutic options for countering type 1 hypersensitivity disorders caused by environmental chemicals. PMID- 22502620 TI - The effects of yoga on anxiety and stress. AB - Stress and anxiety have been implicated as contributors to many chronic diseases and to decreased quality of life, even with pharmacologic treatment. Efforts are underway to find non-pharmacologic therapies to relieve stress and anxiety, and yoga is one option for which results are promising. The focus of this review is on the results of human trials assessing the role of yoga in improving the signs and symptoms of stress and anxiety. Of 35 trials addressing the effects of yoga on anxiety and stress, 25 noted a significant decrease in stress and/or anxiety symptoms when a yoga regimen was implemented; however, many of the studies were also hindered by limitations, such as small study populations, lack of randomization, and lack of a control group. Fourteen of the 35 studies reported biochemical and physiological markers of stress and anxiety, but yielded inconsistent support of yoga for relief of stress and anxiety. Evaluation of the current primary literature is suggestive of benefits of yoga in relieving stress and anxiety, but further investigation into this relationship using large, well defined populations, adequate controls, randomization and long duration should be explored before recommending yoga as a treatment option. PMID- 22502621 TI - Use of a standardized extract from Echinacea angustifolia (Polinacea) for the prevention of respiratory tract infections. AB - Echinacea preparations are extensively used for the prevention and the management of the common cold. Despite this popularity, the clinical studies on Echinacea have produced mixed results, possibly in part because of the poor characterization of the extracts investigated and the use of different species and/or plant parts for the preparations investigated in the various trials. To address this issue, Polinacea, a highly standardized extract from a well-defined botanical source (roots of Echinacea angustifolia) with a specific phytochemical profile (presence of the complex polysaccharide IDN5405, the phenylethanoid echinacoside, and substantial lack of alkamides) was developed. We have studied whether Polinacea could enhance the immune response subsequent to the influenza vaccination, and whether the use of this preparation could translate into a decreased morbidity from influenza. The preliminary results were encouraging, and suggest that Polinacea could be used for improving the immune response to influenza vaccine. PMID- 22502622 TI - Nutritional supplement therapy improves oxidative stress, immune response, pulmonary function, and quality of life in allergic asthma patients: an open label pilot study. AB - OBJECTIVE: To examine the effects of nutritional supplement therapy on oxidant antioxidant status, inflammation and immune system responses, pulmonary function, and health-related quality of life in patients with mild to moderate allergic asthma. METHODS: Adult asthma patients (n=30) received daily multiple nutrient supplements for two months. Age- and gender-matched healthy controls (n=30) did not receive any supplements. Enzymatic and non-enzymatic antioxidant status, malondialdehyde (MDA), high-sensitivity C-reactive protein (hs-CRP), immunoglobulin E (IgE) and T-lymphocyte subsets, pulmonary function indices, as well as scores for asthma control and quality of life, were assessed at baseline, at one month of treatment, and at two months of treatment, which was also the end of the study. RESULTS: At baseline, asthma patients had significantly higher IgE, MDA, copper (Cu), hs-CRP, and CD19 and CD4/CD8 lymphocyte ratios, and decreased selenium (Se), zinc (Zn), beta-carotene, vitamins C and E, and catalase, glutathione peroxidase (GPx) and glutathione reductase (GR) activities compared to healthy controls (p < 0.05). During the study period, asthmatics showed non significantly increased pulmonary function and a trend toward lower IgE levels, markedly reduced MDA, Cu, hs-CRP, and CD19 and CD4/CD8 ratios, and increases in levels of Se, Zn, beta-carotene, vitamins C and E, and enzymatic antioxidant activities. Also, their asthma control and health-related quality-of-life scores increased significantly by the end of the study. CONCLUSION: Our results indicate that nutritional supplement therapy may improve dysregulated oxidant and antioxidant status, inflammation and immune responses, pulmonary function, and health-related quality of life in patients with mild to moderate allergic asthma. PMID- 22502623 TI - A randomized controlled trial of a multifaceted integrated complementary alternative therapy for chronic herpes zoster-related pain. AB - INTRODUCTION: Our objective was to determine whether a three-week complementary and alternative medicine (CAM) approach integrating several therapies from Traditional Chinese Medicine (TCM) along with neural therapy (injection of 1% procaine as local anesthesia) reduces the level of unresolved pain associated with herpes zoster. METHODS: The design was a randomized controlled clinical trial in a community-based primary care clinic in Toronto, Ontario. We studied individuals 18 years of age and older with a confirmed diagnosis of herpes zoster of at least 30 days duration and with at least moderate postherpetic neuralgia pain (>=4) on a 10-point Likert scale. The CAM therapies used were acupuncture, neural therapy (1% procaine injection as a local anesthetic), cupping and bleeding, and TCM herbs. An immediate treatment group (n=32) received the CAM intervention once daily, five days per week, for three weeks. A wait-list (delayed treatment) group (n=27) was used as a control and received the same treatment starting three weeks after randomization. This three-week time period, when one group was receiving active CAM treatment and the other was not, was used as basis of comparison for treatment effects between groups. Pain, quality of life, and depression were measured at baseline, and three, six, and nine weeks post-randomization. Patients were followed for up to two years. RESULTS: Participants had a mean age of 69.8 years (SD=11.1) and had had herpes zoster related pain for a median of 4.8 months (range: 1 month to 15 years). The immediate treatment and control groups had similar pain levels at baseline (treatment = 7.5; control = 7.8; p=0.5; scores based on the 10-point Likert pain scale). At three weeks post-randomization (i.e., after the immediate treatment group completed treatment) pain scores differed significantly (treatment = 2.3; control = 7.2; p<0.001). The observed reduction in pain in the immediate treatment group was maintained at nine weeks and at long-term follow-up (one to two years later). The delayed treatment (control) group also had significant reductions in pain after their integrated CAM treatment was completed. CONCLUSION: The described CAM protocol was associated with significantly reduced sub-acute and chronic post-herpes zoster neuralgia pain within three weeks of initiating treatment. Improvements persisted for up to two years. PMID- 22502624 TI - Application of the essential oil from copaiba (Copaifera langsdori Desf.) for acne vulgaris: a double-blind, placebo-controlled clinical trial. AB - Copaiba oil-resin is widely used in traditional medicine due to its anti inflammatory, healing, and antiseptic activities. This research aims to extract and evaluate the qualitative and quantitative composition of copaiba essential oil from the oil-resin, and test its effects, after incorporation in a gel applied in volunteers with acne, in a double-blind placebo controlled clinical trial. The essential oil was extracted by steam distillation, and purified by freezing to remove the residual remnant water. The density of the essential oil was gravimetrically determined by weighing 1 mL of liquid at 20 degree C. The identification of the essential oil components was carried out through high resolution gas chromatography analysis, coupled with mass spectrometry. The essential oil has a density of 0.9175 mg/mL and was composed of 48 substances, 14 of which were the major components representing 95.80% of total essential oil composition. Cis-thujopsene was the main component (46.96% of total essential oil composition). The surface affected with acne decreased when treated with placebo (F = 13.931, p = 0.001, r = 0.518; r2 = 0.268), but the linear model could explain only 26.8% of total variance in original data matrix. There was a highly significant decrease in the surface affected with acne in the areas treated with the 1.0% copaiba essential oil preparation (F = 86.494, p = 0.000, r = 0.834; r2 = 0.695). PMID- 22502625 TI - Bacillus coagulans: Monograph. PMID- 22502626 TI - Lost papers (4). PMID- 22502627 TI - Studies of the protein and the energy metabolism in man during a wintering in Antarctica. AB - During the 29th Soviet Antarctic Expedition in Novolazarevskaya from March 1984 to March 1985, the protein and energy metabolisms were studied in six expeditioners from the German Democratic Republic. The investigations were carried out at the beginning of the expedition (May), during the polar night (July) and during the polar day (December). The effect of a special stress situation (sledge trek in April 1984) was investigated in one subject. The stable nitrogen isotope (15)N was used to study the protein metabolism. The assessment of the energy metabolism was based on the oxygen consumption, which was determined by means of a spirograph. In addition, the vital capacity, the breath minute volume, the blood pressure, etc. were measured. The following results were obtained: During the polar night, the utilisation of the dietary proteins and the whole body protein synthesis calculated by means of the (15)N excretion of the total nitrogen in urine were greater (73.6+/-0.9 % and 3.48+/-0.17 g protein d( 1) kg(-1), n=3) than the respective values during the polar day (69.7+/-1.2, p<0.05, n=3 and 3.05+/-0.07, p<0.05, n=3) and at the beginning of the expedition (69.6+/-1.4, p<0.02, n=5 and 2.81+/-0.09, p<0.01, n=5). The lowest values (58.0 % and 2.43 g protein d(-1) kg(-1)) were obtained in the subject after the trek. The resting metabolic rate (in kJ d(-1) m(-2)) was decreased during the polar night (45.6+/-5.0, n=4) in comparison with the polar day (61.5+/-11.3, n=3) and the beginning of the expedition (52.3+/-9.6, n=4) with p<0.01 in both cases. PMID- 22502628 TI - Tracer kinetics and metabolic models in medicine. AB - In the present paper, a survey of methods applied to the interpretation and evaluation of tracer kinetic data is given. For their mathematical description, both compartmental and non-compartmental models, such as the modified model of Sprinson and Rittenberg, the San Pietro-Rittenberg model, two models of the albumin metabolism and a 10-pool model of the N and protein metabolism were used. By means of single or multiple pulse, infusion and priming techniques, the N and protein metabolism in various metabolic states (e.g. healthy man, pathological and stress conditions, therapeutic treatments) were studied. PMID- 22502629 TI - Pharmacists' awareness and attitude toward blood pressure measurement at home and in the pharmacy in Japan. AB - The aim of this study is to investigate the status of Japanese pharmacists' awareness and attitude toward blood pressure (BP) measurement at home (HBP) and in the pharmacy. Of the 708 community pharmacists and the 117 hospital pharmacists, more than 90% of pharmacists answered that HBP was equally important to or more important than clinic BP, 71.9% (community) and 48.7% (hospital) recommended HBP measurement to the hypertensive patients, and about 15% correctly recognized the reference values of HBP hypertension. Among community pharmacists, 54.0% answered that BP-measuring devices were available in their pharmacy. More aggressive promotion of HBP measurement among pharmacists is warranted. PMID- 22502632 TI - Development of environmental fate models for engineered nanoparticles--a case study of TiO2 nanoparticles in the Rhine River. AB - For a proactive risk assessment of engineered nanoparticles (ENPs) it is imperative to derive predicted environmental concentration (PEC) values for ENPs in different environmental compartments; PECs can then be compared to effect thresholds. From the basis of established multimedia environmental fate models for organic pollutants, we develop a new concept of environmental fate modeling for ENPs with process descriptions based on the specific properties of ENPs. Our new fate modeling framework is highly flexible and can be adjusted to different ENPs and various environmental settings. As a first case study, the fate and transport of TiO(2) NPs in the Rhine River is investigated. Predicted TiO(2) NP concentrations lie in the ng/L range in the water compartment and mg/kg in the sediment, which represents the main reservoir for the nanoparticles. We also find that a significant downstream transport of ENPs is possible. A fundamental process, the heteroaggregation between TiO(2) NPs and suspended particulate matter (SPM), is analyzed in more detail. Our modeling results demonstrate the importance of both the SPM properties (concentration, size, density) as well as the affinity of TiO(2) NPs and SPM, characterized by the attachment efficiency, alpha(het-agg), on the transport potential of ENPs in a surface water system. PMID- 22502631 TI - Selective cerebral perfusion with 4-branch graft total aortic arch replacement: outcomes in 12 patients. AB - BACKGROUND: Aortic arch reconstruction is associated with high neurological morbidity. Our purpose is to describe our experience using a 4-branched graft and selective antegrade brain perfusion (SABP) for total aortic arch replacement (TAR). METHODS: We retrospectively reviewed the medical records of 12 patients who received TAR, with or without ascending aorta replacement, with a 4-branched graft for Stanford type A dissection (n = 9) or aortic arch aneurysm (n = 3). In all patients surgery was performed with deep hypothermic circulatory arrest (DHCA) with or without retrograde brain perfusion, and selective antegrade brain perfusion (SABP) via the subclavian artery or axillary artery. RESULTS: There were 8 males and 4 females with an average age of 63.14 years. Emergent operations were performed in 9 patients with acute type A aortic dissections. Of all 12 patients, 2 deaths occurred and 1 patient experienced lower extremity paraplegia resulting in an in-hospital mortality rate of 16.6% and a permanent neurological deficit rate of 8.3%. CONCLUSIONS: The use of a 4-branched graft, hypothermic circulatory arrest, and SABP is a useful operative method for aortic arch replacement with acceptable morbidity and mortality. PMID- 22502633 TI - Suppressing of gamma-crystal formation in metallocene-based isotactic polypropylene during isothermal crystallization under shear flow. AB - The effect of shear flow on isothermal crystallization behavior of gamma-crystals in metallocene-based isotactic polypropylene melt was investigated by in situ synchrotron wide-angle X-ray diffraction (WAXD). In the sample under weak shear (at strain of 300% for 30 s duration), simultaneous evolution of alpha- and gamma crystals occurred, and the final fraction of gamma-crystals (fgamma) was 0.66, which was identical to the undeformed sample (PP-Static). In this scenario, alpha crystals probably served as effective seeds for nucleation of gamma-crystals. In the samples under strong shear (at strain of 500% for 30 s duration or long-time continuous shear at strains of 100% and 500%), the sequential emergence of alpha- and gamma-crystals was observed. In this case, molten polymer chains were probably constrained by the surrounding crystals after intense short-time shear and/or maintained their extended chain conformation after long-time shear. These oriented chains had little chance to form the gamma-crystals directly, behaving very differently from the relaxed chains. Under strong shear fields, the emergence of gamma-crystals was delayed or inhibited, whereas the fgamma value was also decreased rapidly. A simple model for the possible pathway of gamma crystal formation in the strong shear environment was proposed. PMID- 22502635 TI - Biphasic clearance of incompatible red blood cells through a novel mechanism requiring neither complement nor Fcgamma receptors in a murine model. AB - BACKGROUND: Antibody binding to red blood cells (RBCs) can induce potentially fatal outcomes, including hemolytic transfusion reactions (HTRs), hemolytic disease of the fetus and newborn, and autoimmune hemolytic anemia. The mechanism(s) of RBC destruction following antibody binding is typically thought to require complement activation and/or the involvement of Fcgamma receptors (FcgammaRs). In the current report, we analyzed mechanisms of HTRs during incompatible transfusions of murine RBCs expressing human glycophorin A (hGPA) into mice with anti-hGPA. STUDY DESIGN AND METHODS: C3 and Fcgamma receptor knockout, splenectomized, Fcgamma receptor blocking antibody-treated, and clodronate-treated mice were passively immunized with anti-hGPA (10F7 or 6A7) and transfused with RBCs expressing the hGPA antigen. Posttransfusion blood and serum were collected and analyzed via flow cytometry and confocal microscopy. RESULTS: This HTR model results in both rapid clearance and cytokine storm. Neither complement nor FcgammaRs were required for RBC clearance; in contrast, FcgammaRs were required for cytokine storm. Circulating aggregates of hGPA RBCs were visible during the HTR. Splenectomy and phagocyte depletion by clodronate had no effect on acute RBC clearance; however, incompatible RBCs reentered over 24 hours in clodronate-treated mice. CONCLUSION: These data demonstrate a biphasic HTR, the first phase involving sequestration of incompatible hGPA RBCs and the second phase involving phagocytosis of sequestered RBCs. However, the mechanism(s) of phagocytosis in the second phase required neither C3 nor FcgammaRs. These findings demonstrate novel mechanistic biology of HTRs. PMID- 22502634 TI - Towards an evaluation framework for information quality management (IQM) practices for health information systems--evaluation criteria for effective IQM practices. AB - RATIONALE, AIMS AND OBJECTIVES: Poor information quality (IQ) must be understood as a business problem rather than systems problem. In health care organization, what is required is an effective quality management that continuously manages and reviews the factors influencing IQ in health information systems (HIS) so as to achieve the desired outcomes. Hence, in order to understand the issues of information quality management (IQM) practices in health care organizations, a more holistic evaluation study should be undertaken to investigate the IQM practices in health care organizations. It is the aim of this paper to identify the significant evaluation criteria that influence the production of good IQ in HIS. METHODS: Six selected frameworks and best practices both from health informatics and information systems literature have been reviewed to identify the evaluation criteria from the perspective of human, organizational and technological factors. RESULTS: From the review, it was found that human and organization factors are of greater significance in influencing HIS IQ. Our review depicts that there is still shortage in finding a comprehensive IQM evaluation framework. Thus, the criteria from the frameworks reviewed can be used in combination for more comprehensive evaluation criteria. Integrated IQM evaluation criteria for HIS are then proposed in this study. CONCLUSIONS: Poor IQ is the result of complex interdependency within sociotechnical factors in health care organization and lack of formal and structured IQM practices. Thus, a feedback mechanism such as evaluation is needed to understand the issues in depth in the future. PMID- 22502636 TI - Colloidal nanocube supercrystals stabilized by multipolar Coulombic coupling. AB - We explore microscopic principles governing the self-assembly of colloidal octylamine-coated platinum nanocubes solvated in toluene. Our experiments show that regular nanocubes with an edge length of l(RC) = 5.5 nm form supercrystals with simple cubic packing, while slightly truncated nanocubes with an edge length of l(TC) = 4.7 nm tend to arrange in fcc packing. We model by averaged force fields and atomistic molecular dynamics simulations the coupling forces between these nanocrystals. Our detailed analysis shows that the fcc packing, which for cubes has a lower density than simple cubic packing, is favored by the truncated nanocubes due to their Coulombic coupling by multipolar electrostatic fields, formed during charge transfer between the octylamine ligands and the Pt cores. PMID- 22502637 TI - Population size and major valleys explain microsatellite variation better than taxonomic units for caribou in western Canada. AB - Identifying conservation units below the species level is becoming increasingly important, particularly when limited resources necessitate prioritization for conservation among such units. This problem is exemplified with caribou, a mammal with a circum-Arctic distribution that is exposed to a broad spectrum of ecological conditions, but is also declining in many parts of its range. We used microsatellite markers to evaluate the suitability of existing intra-specific taxonomic designations to act as population units for conservation and contrasted this with landscape features that were independent of taxonomy. We also quantified the relationship between genetic differentiation and subpopulation size, a factor that has been under-represented in landscape genetic research. Our data set included three subspecies and three ecotypes of caribou that varied in population size by five orders of magnitude. Our results indicated that genetic structure did not correspond to existing taxonomic designation, particularly at the level of ecotype. Instead, we found that major valleys and population size were the strongest factors associated with substructure. There was a negative exponential relationship between population size and F(ST) between pairs of adjacent subpopulations, suggesting that genetic drift was the mechanism causing the structure among the smallest subpopulations. A genetic assignment test revealed that movement among subpopulations was a fraction of the level needed to stabilize smaller subpopulations, indicating little chance for demographic rescue. Such results may be broadly applicable to landscape genetic studies, because population size and corresponding rates of drift have the potential to confound interpretations of landscape effects on population structure. PMID- 22502638 TI - Adsorption of sterically stabilized latex particles at liquid surfaces: effects of steric stabilizer surface coverage, particle size, and chain length on particle wettability. AB - A series of five near-monodisperse sterically stabilized polystyrene (PS) latexes were synthesized using three well-defined poly(glycerol monomethacrylate) (PGMA) macromonomers with mean degrees of polymerization (DP) of 30, 50, or 70. The surface coverage and grafting density of the PGMA chains on the particle surface were determined using XPS and (1)H NMR spectroscopy, respectively. The wettability of individual latex particles adsorbed at the air-water and n dodecane-water interfaces was studied using both the gel trapping technique and the film calliper method. The particle equilibrium contact angle at both interfaces is relatively insensitive to the mean DP of the PGMA stabilizer chains. For a fixed stabilizer DP of 30, particle contact angles were only weakly dependent on the particle size. The results are consistent with a model of compact hydrated layers of PGMA stabilizer chains at the particle surface over a wide range of grafting densities. Our approach could be utilized for studying the adsorption behavior of a broader range of sterically stabilized inorganic and polymeric particles of practical importance. PMID- 22502639 TI - Growth of catalyst-free high-quality ZnO nanowires by thermal evaporation under air ambient. AB - ZnO nanowires have been successfully fabricated on Si substrate by simple thermal evaporation of Zn powder under air ambient without any catalyst. Morphology and structure analyses indicated that ZnO nanowires had high purity and perfect crystallinity. The diameter of ZnO nanowires was 40 to 100 nm, and the length was about several tens of micrometers. The prepared ZnO nanowires exhibited a hexagonal wurtzite crystal structure. The growth of the ZnO nanostructure was explained by the vapor-solid mechanism. The simplicity, low cost and fewer necessary apparatuses of the process would suit the high throughput fabrication of ZnO nanowires. The ZnO nanowires fabricated on Si substrate are compatible with state-of-the-art semiconductor industry. They are expected to have potential applications in functional nanodevices. PMID- 22502640 TI - Women's and care providers' perspectives of quality prenatal care: a qualitative descriptive study. AB - BACKGROUND: Much attention has been given to the adequacy of prenatal care use in promoting healthy outcomes for women and their infants. Adequacy of use takes into account the timing of initiation of prenatal care and the number of visits. However, there is emerging evidence that the quality of prenatal care may be more important than adequacy of use. The purpose of our study was to explore women's and care providers' perspectives of quality prenatal care to inform the development of items for a new instrument, the Quality of Prenatal Care Questionnaire. We report on the derivation of themes resulting from this first step of questionnaire development. METHODS: A qualitative descriptive approach was used. Semi-structured interviews were conducted with 40 pregnant women and 40 prenatal care providers recruited from five urban centres across Canada. Data were analyzed using inductive open and then pattern coding. The final step of analysis used a deductive approach to assign the emergent themes to broader categories reflective of the study's conceptual framework. RESULTS: The three main categories informed by Donabedian's model of quality health care were structure of care, clinical care processes, and interpersonal care processes. Structure of care themes included access, physical setting, and staff and care provider characteristics. Themes under clinical care processes were health promotion and illness prevention, screening and assessment, information sharing, continuity of care, non-medicalization of pregnancy, and women-centredness. Interpersonal care processes themes were respectful attitude, emotional support, approachable interaction style, and taking time. A recurrent theme woven throughout the data reflected the importance of a meaningful relationship between a woman and her prenatal care provider that was characterized by trust. CONCLUSIONS: While certain aspects of structure of care were identified as being key dimensions of quality prenatal care, clinical and interpersonal care processes emerged as being most essential to quality care. These processes are important as they have a role in mitigating adverse outcomes, promoting involvement of women in their own care, and keeping women engaged in care. The findings suggest key considerations for the planning, delivery, and evaluation of prenatal care. Most notably, care should be woman-centred and embrace shared decision making as an essential element. PMID- 22502641 TI - Practice-setting and surgeon characteristics heavily influence the decision to perform partial nephrectomy among American Urologic Association surgeons. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There is great variability in the utilization of partial nephrectomy, but the causes of these variations are not well understood. The present study underscores the already observed phenomenon of surgical volume influencing surgical planning and outcomes, but it gets at why this might be so. We observe that high-volume renal surgeons have different thresholds of 'technical feasibility'. OBJECTIVE: To investigate why there continues to be wide variability in the application of partial nephrectomy (PN) for treating small renal masses despite guidelines in the US and Europe stating that a PN is a standard of care for a patient with a T1 renal mass. PATIENTS AND METHODS: In June 2009, 764 surgeon-members of the American Urologic Association (AUA) participated in a survey evaluating the management of renal masses. Renal mass complexity was graded by nephrometry score (NS). Multivariable logistic regression models with generalized estimating equations were constructed to evaluate how tumour, surgeon and practice-setting characteristics influence the use of PN. RESULTS: The survey response rate was 19%. Each urological surgeon responded to eight scenarios, providing 6112 evaluable cases. Tumour NS ranged from 4 to 10, and each unit increase in NS was associated with 59% increased likelihood of a surgeon offering RN on multivariable analysis (odds ratio [OR] = 1.59; 95% CI: 1.52-1.64). When holding patient and tumour characteristics constant, the following surgeon and practice setting characteristics significantly increased the odds of offering a PN: increasing renal case volume (OR = 1.57; 95% CI: 1.27-1.95), academic practice (OR = 1.80; 95% CI: 1.42-2.29), increasing PN % volume (OR = 3.7; 95% CI: 2.46 5.55) and younger surgeon age (<= 40 vs >50 years) (OR = 1.64; 95% CI: 1.35 1.96). CONCLUSION: The characteristics of a surgeon and the setting in which he or she practices influence the utilization of PN, the adherence to professional guidelines, and the threshold of tumour complexity at which a surgeon stops offering PN. PMID- 22502642 TI - Adenosine A2A receptor activation and hyaluronan fragment inhibition reduce inflammation in mouse articular chondrocytes stimulated with interleukin-1beta. AB - Small hyaluronan (HA) fragments produced from native HA during inflammation contribute greatly to cell injury in many pathologies. HA oligosaccharides increase proinflammatory cytokine levels by activating both CD44 and toll-like receptor (TLR)-4. Stimulation of CD44 and TLR-4 then activates nuclear factor kappaB, which induces the production of proinflammatory cytokines. The adenosine 2A receptor (A(2A)R) is also involved in several inflammation pathologies, and the nucleoside adenosine acts as a potent endogenous inhibitor of inflammation in various tissues by interacting with this receptor. The aim of this study was to investigate the effects of an HA-blocking peptide that inhibits the proinflammatory action of HA oligosaccharides produced during inflammation, together with a specific A(2A)R agonist in a model of normal mouse articular chondrocytes stimulated with interleukin (IL)-1beta. IL-1beta stimulation significantly increased mRNA expression and the related protein production of TLR 4, TLR-2, CD44 and A(2A)R in articular chondrocytes. The induced nuclear factor kappaB activation was also associated with increased levels of inflammatory cytokines, including tumor necrosis factor-alpha and IL-6, and other inflammatory mediators, such as matrix metalloprotease-13 and inducible nitric oxide synthase. Treatment of chondrocytes with the HA-blocking peptide Pep-1 and/or a specific A(2A)R agonist (CGS-21680) significantly reduced all of the inflammatory parameters upregulated by IL-1beta. These results suggest that the inflammatory response may be reduced either by blocking oligosaccharides from HA degradation or by A(2A)R stimulation. PMID- 22502643 TI - Structural analysis of a new cytotoxic demethylated analogue of neo-N methylsansalvamide with a different peptide sequence produced by Fusarium solani isolated from potato. AB - A novel cytotoxic cyclic pentadepsipeptide, neosansalvamide, was produced by Fusarium solani KCCM90040 isolated from Fusarium -contaminated potato in Korea. The molecular formula of neosansalvamide was analyzed as C32H50N4O6 by electrospray ionization tandem mass spectrometry and combined structural analysis. The one- and two-dimensional nuclear magnetic resonance and absolute configuration of amino acid spectral data allowed for the resolution of cyclic five subunits linked in the following order: (S)-leucic acid, two L-leucine, L valine, and L-phenylalanine, and this sequence shows a molecular structure as a new demethylated analogue of neo-N-methylsansalvamide but having a different peptide sequence. The cytotoxic effects of neosansalvamide were investigated by sulforhodamine B bioassay on four human cancer cell lines. The IC50 value of neosansalvamide required to inhibit cell growth in vitro by 50% for A549 (lung cancer), SK-OV-3 (ovarian cancer), SK-MEL-2 (skin melanoma), and MES-SA (uterine sarcoma) cell lines were 11.70 +/- 0.55, 10.38 +/- 0.64, 13.99 +/- 1.32, and 11.75 +/- 0.13 MUM, respectively (mean +/- standard error). PMID- 22502644 TI - Detection of quantitative trait loci for resistance to gastrointestinal nematode infections in Creole goats. AB - This study aimed to identify regions of the genome affecting resistance to gastrointestinal nematodes in a Creole goat population naturally exposed to a mixed nematode infection (Haemonchus contortus, Trichostrongylus colubriformis and Oesophagostomum columbianum) by grazing on irrigated pasture. A genome-wide quantitative trait loci (QTL) scan was performed on 383 offspring from 12 half sib families. A total of 101 microsatellite markers were genotyped. Traits analysed were faecal egg count (FEC), packed cell volume (PCV), eosinophil count and bodyweight (BW) at 7 and 11 months of age. Levels of activity of immunoglobulin A (IgA) and activity of immunoglobulin E (IgE) anti-Haemonchus contortus L3 crude extracts and adult excretion/secretion products (ESPs) were also analysed. Using interval mapping, this study identified 13 QTL for parasite resistance. Two QTL linked with FEC were found on chromosomes 22 and 26. Three QTL were detected on chromosomes 7, 8 and 14 for eosinophil counts. Three QTL linked with PCV were identified on chromosomes 5, 9 and 21. A QTL for BW at 7 months of age was found on chromosome 6. Lastly, two QTL detected on chromosomes 3 and 10 were associated with IgE anti-L3, and IgE anti-ESP was linked with two QTL on chromosomes 1 and 26. This study is the first to have identified regions of the genome linked with nematode resistance in a goat population using a genome scan. These results provide useful tools for the understanding of parasite resistance in small ruminants. PMID- 22502645 TI - Measurement of whole blood thrombus formation using parallel-plate flow chambers a practical guide. AB - Custom-made and commercial parallel-plate flow chambers are widely used for studies of platelet activation and thrombus formation in whole blood at defined shear rates. When used in a reproducible way, such flow chamber devices give valuable information on the thrombogenic potential of human, mouse, or rat blood. This article aims to provide a practical guide for the use of parallel-plate flow chambers in combination with routine microscopic imaging techniques. The following methodological aspects are addressed: preparation of surface coatings, calculation of blood flow and shear rate, control of pre-analytical variables, protocols for routine performing of flow chamber tests with non-coagulating or coagulating blood, and procedures for real-time and end-point analysis of thrombus formation. Frequently encountered experimental problems and artifacts are discussed, as well as possibilities for using flow chamber devices as a diagnostic tool to test antithrombotic medication. PMID- 22502646 TI - Small heat shock protein expression and functions during development. AB - The expression of small heat shock proteins is tightly regulated during development in multiple organisms. As housekeeping proteins, small heat shock proteins help protect cells from apoptosis, stabilize the cytoskeleton and contribute to proteostasis. Consistently, depletion of one small heat shock protein is usually not detrimental due to a certain level of redundancy between the functions of each small heat shock protein. However, while their stress induced expression is regulated by heat shock factors, their constitutive expression is under the control of other specific transcription factors, suggesting the existence of very specialized functions. This review focuses on the expression patterns and functions of small heat shock proteins in various organisms during development. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology. PMID- 22502647 TI - New furostanol saponins from the rhizomes of Tupistra chinensis. AB - Three new furostanol saponins (1-3), including a polyhydroxyl saponin, were isolated from the rhizomes of Tupistra chinensis. The structures of these compounds were identified by NMR, MS spectral data and chemical methods. PMID- 22502648 TI - VDAC structure, function, and regulation of mitochondrial and cellular metabolism. PMID- 22502649 TI - Prostate cancer and metabolic syndrome: is there a link? AB - Metabolic syndrome has become quite prevalent within our society. Over the past two decades, the prevalence of metabolic syndrome has sharply increased worldwide and it has become a major public health problem in several countries. It is associated with the global epidemic of obesity and diabetes mellitus and imposes numerous cardiovascular risks. Prostate cancer is the second most common cancer among men, surpassed only by non-melanoma skin cancer. A considerable body of evidence exists suggesting that some components of the metabolic syndrome have been associated with the risk of prostate cancer. These components include obesity, an abdominal fat distribution, and hyperinsulinemia. Androgen deprivation therapy (ADT) is the most widely used therapeutic modality in prostate cancer. It changed the body composition and lipid profile of men with prostate cancer. Androgen deficiency is associated with increased levels of total cholesterol, low-density lipoprotein (LDL)- cholesterol, increased production of proinflammatory factors, and increased thickness of the arterial wall and contributes to endothelial dysfunction. The aim of this review is to evaluate the association between metabolic syndrome and prostate cancer and to discuss the implications of androgen deficiency in men with cardiovascular risk factors. A comprehensive literature search was carried out with the use of PubMed from 1980 through 2012, and relevant articles pertinent to metabolic syndrome and prostate cancer are evaluated and discussed. PMID- 22502650 TI - Neoadjuvant chemotherapy for resectable esophageal carcinoma: a meta-analysis of randomized clinical trials. AB - Neoadjuvant chemotherapy for resectable esophageal carcinoma has been a focus of study, but no agreement has been reached on clinical randomized controlled trials and relevant systematic evaluation. The purpose of this study was to perform a meta-analysis on published randomized controlled trials (RCTs) that compared neoadjuvant chemotherapy and surgery with surgery alone for resectable esophageal carcinoma. Medline and manual searches was conducted in PubMed, ASCO (American Society of Clinical Oncology) meeting summary, Embase, the Cochrane Library (up to October 2010), Chinese Biomedical Literature Database, China National Knowledge Infrastructure, VIP Database, Wanfang Database. The selection contents were to identify all published and unpublished RCTs that compared neoadjuvant chemotherapy and surgery with surgery alone for resectable esophageal carcinoma. Sixteen RCTs which included 2,594 patients were selected. The risk ratio (RR) (95% confidence interval [CI]; P value), expressed as neoadjuvant chemotherapy and surgery versus surgery alone (treatment versus control), was 1.02 (0.95, 1.10; P=0.54) for 1-year survival, 1.29 (1.13, 1.47; P=0.0001) for 3-year survival, 1.31 (1.13, 1.51; P=0.0003) for 5-year survival, 1.00 (0.95, 1.04; P= 0.85) for rate of resection and 0.89 (0.64, 1.23; P=0.48) for operative mortality. The results showed that neoadjuvant chemotherapy for resectable esophageal carcinoma can raise the overall survival rate of patients with esophageal carcinoma, but it does not affect treatment-related mortality. PMID- 22502651 TI - XRCC1-77T>C polymorphism and cancer risk: a meta- analysis. AB - Variants of X-ray repair cross-complementing group 1 (XRCC1) are involved in the development of cancer, but studies investigating the association of XRCC1-77T>C polymorphism with cancer risk have reported conflicting results. To clarify the effect of the XRCC1 -77T>C polymorphism on cancer risk, we performed a meta analysis by conducting searches of the published literature in PubMed, Embase and CBM databases. Finally, 13 studies were included into our meta-analysis, involving a total of 11, 678 individuals. Subgroup analyses were performed by ethnicity and cancer type. The results of this meta-analysis showed that there was significant association between the C variant of XRCC1-77T>C polymorphism and cancer risk in all four genetic comparison models (ORC vs. T =1.19, 95%CI 1.07 1.31, P = 0.001; OR homozygote model =1.28, 95%CI 1.07-1.52, P = 0.007; OR recessive genetic model =1.22, 95%CI 1.04-1.44, P = 0.015; OR dominant model =1.21, 95% CI 1.07-1.35, P = 0.001). In the subgroup analyses based on ethnicity, the association was still significant in the Asian population (all p values<0.001), but not in the Caucasian population (all p values > 0.05). Thus, the XRCC1 -77T>C polymorphism is associated with cancer risk, and individuals with XRCC1 -77C variant have a significantly higher cancer risk, particularly in the Asian population. PMID- 22502652 TI - Antitumor effects of hyperthermic CO2 pneumoperitoneum on human gastric cancer cells. AB - AIM: To elucidate the effects of hyperthermic CO2 pneumoperitoneum on human gastric AGS cells. METHODS: Based on a newly devised in vitro study model, we evaluated the anti-cancer effects of HT-CO2 (42-44 degrees C for 2-4h) on human gastric cancer cells, and also the corresponding mechanisms. RESULTS: HT-CO2 (42 44 degrees C for 2-4h) severely inhibited cell proliferation as assessed by Cell Counting Kit-8 assay, while inducing apoptosis in a temperature- and time dependent manner demonstrated by annexin-V/PI flow cytometry and morphological analysis (Hoechst/PI fluorescence). In addition, it was found that HT-CO2 (42-44 degrees C for 2-4h) promoted the up-regulation of Bax by western blotting. Significantly, it could also suppress gastric cancer cell invasion and metastasis by in vitro invasion and motility assay. CONCLUSION: In conclusion, HT-CO2 had an efficacious cytotoxic effect on gastric cancer cells through Bax-induced mitochondrial apoptotic signaling. Our studies indicate that it may serve as a potential therapy for peritoneal carcinomatosis of gastric cancer. Further investigations in vivo using animal models are now urgently needed. PMID- 22502653 TI - Awareness and practice of breast self-examination among Korean women: results from a nationwide survey. AB - PURPOSE: The purpose of this study was to identify the current status of the awareness and practice of breast self-examination (BSE) among Korean women. MATERIALS AND METHODS: The study population was derived from the 2007 Korea National Cancer Screening Survey (KNCSS), an annual cross-sectional survey that uses a nationally representative random sample to investigate cancer-screening rates and related factors. A total of 1,255 Korean women aged >= 30 years participated in this study. RESULTS: Of all participants, 88.0% reported that they had heard of BSE. The most common source of information on BSE was the media such as TV, radio and newspapers (87.0%). Recommendations from medical staff reached only 17.2%. The overall proportions of regular and irregular BSE were 13.2% and 16.1%, respectively. The main reason for not performing BSE was lack of knowledge about how to conduct the exam (31.7%). CONCLUSION: Despite a high level of awareness about BSE, only a small minority of women examine their breasts regularly in Korea. PMID- 22502654 TI - Study on the health-related quality of life in patients after surgery for malignant bone tumors. AB - AIM: We conducted a study in China to assess the health-related quality of life (HRQoL) in patients treated on for malignant bone tumors after surgery, and investigate the possible determinants. METHODS: The subjects were 120 patients surgically treated by amputation and limb-salvage for bone tumors during the period of June 2008 to June 2010. The Medical Outcomes Study Short Form 36 (SF 36) was employed to measure the HRQoL of all the patients before and after surgery. RESULTS: With regard to the results of the general quality of life tool (SF-36), we observed a significant improvement of all the indexes of HRQoL after 6 months (p<0.05). PF, RP and BP scores showed significant increase between surgery after 6 and 12 months (p<0.05). The means of the HRQoL of bone tumor patients in our study were still much lower than those of general population in every domain, even 12 months after surgery. Logistic regression showed that female patients were found to have lower scores in physical component summary (PCS) than males (OR=0.64, 95% CI=0.35-0.89). Patients older than 15 years had lower scores in mental component summary (MCS) (OR=0.60, 95% CI=0.32-0.86). Ablative surgery was related to both lower MCS and PCS scores (For MCS, OR=0.54, 95% CI=0.31-0.83; for PCS, OR=0.43, 95% CI=0.25-0.73). CONCLUSION: Our study showed the treatment for bone tumor could greatly alter the HRQoL of patients. Age, sex and type of surgery were associated with physical or mental HRQoL after surgery. PMID- 22502655 TI - ABO blood group and risk of pancreatic cancer in a Turkish population in Western Blacksea region. AB - BACKGROUND: We aimed to investigate the relationship between blood groups and pancreatic cancer in a Turkish population in Western Blacksea region. METHODS: This is a retrospective study. Zonguldak Karaelmas University outpatient oncology clinic records were screened for the period between 2004 and 2011. RESULTS: The median age of patients were 56 (+/- 16) and 132 of 633 study population had pancreatic cancer. Pancreatic cancer patients had significantly higher rates of blood group A compared to controls (OR 1.8, 95%CI, p 0.005). Rates of blood group AB was significantly lower than the control group (OR 0.37, 95% CI, p 0.04). The median survival (IR) time in subjects having the blood groups A, B, AB and O were 7.0 (1-28), 7.0 (2-38), 10 (2-36) and 9.0 (2-48) months respectively; the blood group 0 had significantly higher overall survival (OS) compared to the non-0 groups (p 0.04). CONCLUSIONS: Pancreatic cancer patients had more common blood group A in our population. Moreover, blood group AB appeared to be a protective factor against pancreatic cancer in our population. Blood group 0 had a significantly longer survival compared to non-0, regardless of prognostic factors. PMID- 22502656 TI - Apoptin induces apoptosis in human bladder cancer EJ and BIU-87 cells. AB - OBJECTIVE: To investigate whether apoptin is a apoptosis-inducing protein with a potential for bladder cancer therapy. METHODS: We constructed a PCDNA3/Apoptin eukaryotic expression vector, and transfected this vector into bladder cancer cell lines BIU-87 and EJ, then observed the results by RT-PCR, transmission electron microscopy, MTT assay and the flow cytometry (TUNEL method). RESULTS: PCDNA3/Apoptin successfully induced a high level apoptosis in both bladder cancer cell lines, compared with the controls (p<0.05). CONCLUSIONS: Apoptin can induce high level apoptosis in human bladder cancer EJ and BIU-87 cells, which suggests a potential for human bladder cancer therapy. PMID- 22502657 TI - Diabetes, overweight and risk of postmenopausal breast cancer: a case-control study in Uruguay. AB - Obese postmenopausal women increase their risk of developing breast cancer (BC), in particular if they display an android-type pattern of adiposity, which is also associated to increased risks of diabetes mellitus, hypertension and cardiovascular disease. In order to explore the associations among anthropometry (body mass index, body composition, somatotype), some specific items of medical history (diabetes, hypertension, dislypidemias, hyperuricemia) and the risk of BC in Uruguayan women, a case-control study was carried out between 2004-2009 at our Oncology Unit. 912 women of ages between 23-69 years (367 new BC cases and 545 non hospitalized, age-matched controls with a normal mammography) were interviewed. Twenty body measurements were taken in order to calculate body composition and somatotype. Patients were queried on socio-demographics, reproductive history, family history of cancer, a brief food frequency questionnaire and on personal history of diabetes, dislypidemias, hyperuricemia, hypertension and gallbladder stones. Uni- and multivariate analyses were done, generating odds ratios (ORs) as an expression of relative risks. A personal history of diabetes was positively associated to BC risk (OR=1.64, 95% CI 1.00 2.69), being higher among postmenopausal women (OR=1.92, 95% CI 1.04-3.52). The risks of BC for diabetes in postmenopausal women with overweight combined with dislypidemia (OR=9.33, 95% CI 2.10-41.5) and high fat/muscle ratio (OR=7.81, 95% CI 2.01-30.3) were significantly high. As a conclusion, a personal history of diabetes and overweight was strongly associated to BC. The studied sample had a subset of high-risk of BC featured by postmenopausal overweight and diabetic women, who also had a personal history of hypertension and/or dyslipidemia. The present results could contribute to define new high risk groups and individuals for primary as well as for secondary prevention, since this pattern linked to the metabolic syndrome is usually not considered for BC prevention. PMID- 22502658 TI - Breast screening and breast cancer survival in Aboriginal and Torres Strait Islander women of Australia. AB - Aboriginal and Torres Strait Islander people comprise about 2.5% of the Australian population. Cancer registry data indicate that their breast cancer survivals are lower than for other women but the completeness and accuracy of Indigenous descriptors on registries are uncertain. We followed women receiving mammography screening in BreastScreen to determine differences in screening experiences and survivals from breast cancer by Aboriginal and Torres Strait Islander status, as recorded by BreastScreen. This status is self-reported and used in BreastScreen accreditation, and is considered to be more accurate. The study included breast cancers diagnosed during the period of screening and after leaving the screening program. DESIGN: Least square regression models were used to compare screening experiences and outcomes adjusted for age, geographic remoteness, socio-economic disadvantage, screening period and round during 1996 2005. Survival of breast cancer patients from all causes and from breast cancer specifically was compared for the 1991-2006 diagnostic period using linked cancer registry data. Cox proportional hazards regression was used to adjust for socio demographic differences, screening period, and where available, tumour size, nodal status and proximity of diagnosis to time of screen. RESULTS: After adjustment for socio-demographic differences and screening period, Aboriginal and Torres Strait Islander women participated less frequently than other women in screening and re-screening although this difference appeared to be diminishing; were less likely to attend post-screening assessment within the recommended 28 days if recalled for assessment; had an elevated ductal carcinoma in situ but not invasive cancer detection rate; had larger breast cancers; and were more likely than other women to be treated by mastectomy than complete local excision. Linked cancer registry data indicated that five-year year survivals of breast cancer cases from all causes of death were 81% for Aboriginal and Torres Strait Islander women, compared with 90% for other women, and that the former had larger breast cancers that were more likely to have nodal spread at diagnosis. After adjusting for socio-demographic factors, tumour size, nodal spread and time from last screen to diagnosis, Aboriginal and Torres Strait Islander women had approximately twice the risk of death from breast cancer as other women. CONCLUSIONS: Aboriginal and Torres Strait Islander women have less favourable screening experiences and those diagnosed with breast cancer (either during the screening period or after leaving the screening program) have lower survivals that persist after adjustment for socio-demographic differences, tumour size and nodal status. PMID- 22502659 TI - Male breast carcinoma: epidemiology, risk factors and current therapeutic approaches. AB - Male breast cancer is a very rare disease with an incidence of about 0.5-1% comparing with the one of female breast cancer but relatively little is known about its cause. Treatment strategies for breast cancer in males are derived from studies performed among females. The probable reasons behind the frequent, late diagnoses presented at stages III or IV might be the lack of awareness. The rarity of the disease precludes large prospective randomized clinical trials. This study reviews male breast cancer and its risk factors, recommendations for diagnosis and the management of patients with male breast cancer. PMID- 22502660 TI - An updated pooled analysis of glutathione S-transferase genotype polymorphisms and risk of adult gliomas. AB - OBJECTIVE: Glutathione S-transferases (GSTs) are multifunctional enzymes that play a crucial role in the detoxification of both the endogenous products of oxidative stress and exogenous carcinogens. Recent studies investigating the association between genetic polymorphisms in GSTs and the risk of adult brain tumors have reported conflicting results. The rationale of this pooled analysis was to determine whether the presence of a GST variant increases adult glioma susceptibility by combining data from multiple studies. METHODS: In our meta analysis, 12 studies were identified by a search of the MEDLINE, HIGHWIRE, SCIENCEDIRECT and EMBASE databases. Of those 12, 11 evaluated GSTM1, nine evaluated GSTT1 and seven evaluated GSTP1 Ile105Val. Between-study heterogeneity was assessed using chi2-based Q statistic and the I2 statistic. Crude odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to estimate the association between GSTM1, GSTT1 and GSTP1 polymorphisms and the risk of adult gliomas. RESULTS: The quantitative synthesis showed no significant evidence to indicate an association exists between the presence of a GSTM1, GSTT1 or GSTP1 Ile105Val haplotype polymorphism and the risk of adult gliomas (OR, 1.008, 1.246, 1.061 respectively; 95% CI, 0.901-1.129, 0.963-1.611, 0.653-1.724 respectively). CONCLUSIONS: Overall, this study did not suggest any strong relationship between GST variants or related enzyme polymorphisms and an increased risk of adult gliomas. Some caveats include absence of specific raw information on ethnic groups or smoking history on glioma cases in published articles; therefore, well designed studies with a clear stratified analysis on potential confounding factors are needed to confirm these results. PMID- 22502661 TI - Awareness and knowledge of oral cancer among university students in Malaysia. AB - OBJECTIVES: This study aimed to assess the level of knowledge of oral cancer and its associated factors among university students in Malaysia. METHODS: A cross sectional study was conducted among 200 university students in Malaysia. A self administered questionnaire was used to collect data. It included questions on socio- demographic data, awareness and knowledge of oral cancer. RESULTS: Mean age of the respondents was 21.5 +/- 2.5 and the age ranged from 18 to 27 years. The majority of the respondents were aware of oral cancer (92.0%) and recognized the followings as signs and symptoms of oral cancer: ulcer and oral bleeding (71.0%), followed by swelling (61.5%). A satisfactory knowledge was observed on the following risk factors; smoking (95.5%), poor oral hygiene (90.5%), family history (90.0%), alcohol (84.5%) and poor fitting dentures (83.0%). However, unsatisfactory knowledge was observed about hot/spicy food (46.5%), obesity (36.0%), old age (31.5%), dietary factor (29.0%) and smokeless tobacco (25.5%). Knowledge of oral cancer was associated significantly with age (p<0.01), year of study (p<0.01) and course of study (p<0.01). CONCLUSION: Instead of satisfactory awareness and knowledge of oral cancer and its clinical presentations, inadequate knowledge was observed about its risk factors. There is a need to introduce oral cancer education among university students. PMID- 22502662 TI - Comparisons of curative and side effects of chemoradiotherapy among Xinjiang Han, Uigur and Kazakh esophageal carcinoma patients. AB - OBJECTIVE: This study aimed to explore the differences in the curative and side effects of chemoradiotherapy on esophageal cancer (EC) among Xinjiang Han, Uigur and Kazakh patients. METHODS: 170 patients with IIA stage-IV of esophageal squamous cell carcinoma were analyzed retrospectively. Based on different nationalities, they were divided into the Han, Uigur and Kazakh groups. The 1-, 2 and 3-year survival rates, incidence of the side effects (including hematological toxicities, radioactive esophagitis and percutaneous reactions) and application of antibiotics and harmonics were compared among the groups. There was no significant difference in the short-term curative effects among the Han, Uigur and Kazakh groups. The 1- 2- and 3-year survival rates of the three groups were 84%, 40%, 26%; 78%, 27%, 18%; and 60%, 21%, 12% (x2=14.497, P<0.05). The incidence rate of hamatological toxicity >= Grade 2 in the Kazakh group was significantly lower than that in the Han or Uigur group. RESULTS: The incidence rates of radioactive esophagitis and percutaneous reactions Grade 2 in the Han group were significantly higher than those in the Uigur or Kazakh group. There was no significant difference in the types of applied antibiotics among the groups, but there were significant differences in the days of antibiotic application and proportion of patients receiving harmonics between the Hans and either of other groups. CONCLUSION: Chemoradiotherapy shows a better effect in the long-term survival rate among Han EC patients compared with Uigur or Kazakh EC patients. Uigur and Kazakh patients show a better tolerance to the side effects of chemoradiotherapy compared with Hans. PMID- 22502663 TI - Factors associated with success or failure of quit attempts: a clinical approach for lung cancer prevention. AB - The objective of the study is to investigate the success rate of quit attempts and identify factors associated with success or failure of quit attempts in a quit smoking clinic. A cohort study was conducted with 495 smokers who enrolled in a quit smoking clinic from 2005 to 2008. The factors leading to quit smoking successfully were "being Malay", "having high blood pressure" "type of Nicotine Replacement Therapy" and "duration of follow up". In contrast, clerical staff had negative association to quit smoking. People who started smoking in their teenage years had a high risk of relapse. Integration of active follow up and tailor-made support programmes for quitters appear necessary in order to maintain their non smoking status and encourage them to be permanent quitters. Integration of quit smoking clinics and primary care clinics could be another potential step for the success of quit smoking programmes. PMID- 22502664 TI - Association between p16, hMLH1 and E-cadherin promoter hypermethylation and intake of local hot salted tea and sun-dried foods in Kashmiris with gastric tumors. AB - The aim of this study was to evaluate the methylation status of three important cancer related genes viz. p16, E-cadherin and hMLH1 promoters and to associate the findings with specific dietary habits in Kashmiris, a culturally distinct population in India, with gastric cancer. The study subjects were divided into three age groups viz. 0-30 yrs (1st), 31-60 yrs (2nd) and 61-90 yrs (3rd). A highly significant association between the intake of local hot salted tea in 2nd (p=0.001) and 3rd (p=0.009) age groups was observed with the promoter hypermethylation of E cadherin. Again a highly significant association between the aberrant methylation of hMLH1 (p=0.000) and p16 (p=0.000) promoters and the intake of local hot salted tea was observed in the 2nd age group of gastric cancer patients. The intake of sun-dried food was also significantly associated with the promoter hypermethylation of E cadherin (p=0.003) and p16 (p=0.015) genes in 3rd age group. The results of the present study suggest a close association between the aberrant methylation of p16, E-cadherin and hMLH1 promoters and the intake of local hot salted tea and sun-dried foods in Kashmiri population. PMID- 22502665 TI - Chronic heavy metal exposure and gallbladder cancer risk in India, a comparative study with Japan. AB - BACKGROUND: High incidence of gallbladder cancer (GBC) is reported from North India, with elevated concentrations of heavy metals in water and soil. This Indo Japan collaborative study compared presence of heavy metals in gallbladder tissues. METHODS: Heavy metal concentrations were estimated in Indian GBC and cholecystitis tissues and compared with Japanese GBC and cholecystitis tissues. Spectrophotometry was done for 13 Indian gallbladder tissues (8 GBC, 5 cholecystitis) and 9 Japanese (5 GBC, 4 cholecystitis). Transmission electron microscopy (TEM) thin foil element analysis was done in 10 Indian samples (6 GBC, 4 cholecystitis). RESULTS: Chromium, lead, arsenic and zinc were significantly high in Indian GBC compared with Japanese GBC. Chromium, lead and arsenic were significantly high in the Indian cholecystitis tissues compared to the Japanese. TEM of Indian tissues demonstrated electron dense deposits in GBC. CONCLUSION: Heavy metals- chromium, lead, arsenic and zinc are potential carcinogens in Indian GBC from endemic areas. This preliminary study links presence of heavy metals in gallbladder cancer tissues in endemic areas. PMID- 22502666 TI - Evaluation of DNA repair gene XRCC1 polymorphism in prediction and prognosis of hepatocellular carcinoma risk. AB - We conducted a case-control study in China to clarify the association between XRCC1-Arg399Gln polymorphism and HCC risk. A total of 150 cases and 158 controls were selected from the the Affiliated Hospital of Qingdao University from May 2008 to May 2010. XRCC1-Arg399Gln polymorphism was based upon duplex polymerase chain-reaction with the confronting-two-pair primer (PCR-CTPP) method. All analyses were performed using the STATA statistical package. A significantly increased risk was associated with the Arg/Gln genotype (adjusted OR 1.78, 95%CI=1.13-2.79) compared with genotype Arg/Arg. In contrast, the Gln/Gln genotype had non-significant increased risk of HCC with adjusted OR (95%CI) of 1.69 (0.93-2.66). A significant association was found between positive HBsAg and Arg/Gln, with an OR of 3.43 (95% CI=1.45-8.13). Patients carrying Gln/Gln genotypes showed significantly lower median survival than Arg/Arg genotypes (HR=1.38, 95% CI=1.04-1.84). Further Kaplan-Meier analysis showed decreased median survival in Arg/Gln+Gln/Gln genotype carriers in comparison to Arg/Arg carriers (HR=1.33, 95% CI=1.02-1.76). In conclusion, we observed that XRCC1 Arg399Cln polymorphism is associated with susceptibility to HCC, and XRCC1 Gln allele genotype showed significant prognostic associations. PMID- 22502667 TI - Public awareness of colorectal cancer in a Turkish population: importance of fecal occult blood testing. AB - To date, there was no controlled-study regarding awareness and knowledge of colorectal cancer in the Turkish population. We therefore designed a questionnaire consisting of items related to socio-demographic parameters, medical and family history and questions of awareness and knowledge about colorectal cancer for use in a descriptive cross-sectional study. An interviewer administered technique was applied and 450 subjects were interviewed in the outpatient clinics at Near East University Hospital. Among all subjects, 337 were found to be eligible for the study group. Exclusion criteria were age below 18 years, any cancer history, family history of colorectal cancer, current colorectal problems, history of any diagnostic or therapeutic interventions for colorectal diseases.All participants stated that they heard about colorectal cancer. When asked about the lifetime risk of colorectal carcinoma, only 25.4% of women and 37.9% of men estimated correctly. Univariate analysis revealed that the total awareness score was significantly correlated with age, marital status, parenthood and fecal occult blood testing history. On multivariate analysis of independent predictors for awareness of colorectal cancer were found to be history of fecal occult blood testing, age and marital status were found to be the most important determinants. As a conclusion, opportunistic screening with fecal occult blood test by physicians from non-gastrointestinal specialties not only helps to reduce the mortality but also increases the awareness of colorectal cancer. PMID- 22502668 TI - Prognostic significance of CYFRA21-1, CEA and hemoglobin in patients with esophageal squamous cancer undergoing concurrent chemoradiotherapy. AB - PURPOSE: To evaluate the prognostic value of serum CYFRA21-1, CEA and hemoglobin levels regarding long-term survival of patients with esophageal squamous cell carcinoma (ESCC) treated with concurrent chemoradiotherapy (CRT). METHODS: Age, gender, Karnofsky Performance Status (KPS), tumor location, tumor length, T stage, N stage and serum hemoglobin, and CYFRA21-1 and CEA levels before concurrent CRT were retrospectively investigated and related to outcome in 113 patients receiving 5-fluorouracil and cisplatin combined with radiotherapy for ESCC. The Kaplan-Meier method was used to analyze prognosis, the log-rank to compare groups, the Cox proportional hazards model for multivariate analysis, and ROC curve analysis for assessment of predictive performance of biologic markers. RESULTS: The median survival time was 20.1 months and the 1-, 2-, 3-, 5- year overall survival rates were 66.4%, 43.4%, 31.9% and 15.0%, respectively. Univariate analysis showed that factors associated with prognosis were KPS, tumor length, T-stage, N-stage, hemoglobin, CYFRA21-1 and CEA level. Multivariate analysis showed T-stage, N-stage, hemoglobin, CYFRA21-1 and CEA level were independent predictors of prognosis. By ROC curve, CYFRA21-1 and hemoglobin showed better predictive performance for OS than CEA (AUC= 0.791, 0.704, 0.545; P=0.000, 0.000, 0.409). CONCLUSIONS: Of all clinicopathological and molecular factors, T stage, N stage, hemoglobin, CYFRA21-1 and CEA level were independent predictors of prognosis for patients with ESCC treated with concurrent CRT. Among biomarkers, CYFRA21-1 and hemoglobin may have a better predictive potential than CEA for long-term outcomes. PMID- 22502670 TI - Complementary and alternative medicine use by gynecologic oncology patients in Turkey. AB - The use of complementary and alternative medicines (CAM) among women with gynecologic cancer is becoming increasingly popular. Therefore, it is important to gain insight into the prevalence and factors related to the use of CAM. The aim of this study was to assess the use of CAM in women with gynecologic cancer. This is a descriptive cross-sectional study. Data were obtained from 67 gynecological cancer patients at gynecologic oncology clinic of a hospital in Turkey between October 2009 to December 2010 using a questionnaire developed specifically for this study. The instrument included questions on socio demographic information, disease specifics and complementary and alternative medicine usage. On the basis of women's responses, all participants were divided into 2 groups: CAM users and nonusers. The findings indicated that 61.2% of the women reported the use of 1 or more CAM therapies. There were no significant differences in the sociodemographic and clinical characteristics between CAM users and nonusers (P <0.05). The most frequently used CAM method was herbal therapy (90.2%) and the second was prayer (41.5%). The main sources of information about CAM were informal (friends/ family members). A considerable proportion (56.1%) of CAM users had discussed their CAM use with their physicians or nurses. Turkish women with gynecologic cancer frequently use CAM in addition to standard medical therapy. Nurses/ oncologists caring for women with gynecologic cancer should initiate a dialogue about usage of CAM, discussing the potential adverse effects of CAM and the patient's therapeutic goals. PMID- 22502669 TI - Paris polyphylla Smith extract induces apoptosis and activates cancer suppressor gene connexin26 expression. AB - BACKGROUND: The inhibition of tumor cell growth without toxicity to normal cells is an important target in cancer therapy. One possible way to increase the efficacy of anticancer drugs and to decrease toxicity or side effects is to develop traditional natural products, especially from medicinal plants. Paris polyphylla Smith has shown anti-tumour effects by inhibition of tumor promotion and inducement of tumor cell apoptosis, but mechanisms are still not well understood. The present study was to explore the effect of Paris polyphylla Smith extract (PPSE) on connexin26 and growth control in human esophageal cancer ECA109 cells. METHODS: The effects of PPSE on Connexin26 were examined by RT-PCR, western blot and immunofluorescence; cell growth and proliferation were examined by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay. RESULTS: PPSE inhibited the growth and proliferation on esophageal cancer ECA109 cells, while increasing the expression of connexin26 mRNA and protein; conversely, PPSE decreased Bcl-2 and increased Bad. CONCLUSION: This study firstly shows that PPSE can increase connexin26 expression at mRNA and protein level, exerting anti-tumour effects on esophageal cacner ECA109 cells via inhibiting cell proliferation and inducing cell apoptosis. PMID- 22502671 TI - Patients' profile, clinical presentations and histopathological features of colo rectal cancer in Al Hassa region, Saudi Arabia. AB - BACKGROUND: Patients' demographics, presenting clinical and histopathological features for colo-rectal cancer (CRC) are important factors for patients' outcome and disease prognosis. This study aimed to describe the pattern of CRC in terms of patients' demographics, main presenting symptoms and histopathological features in Al Hassa region of Saudi Arabia. SUBJECTS AND METHODS: A retrospective hospital records-based study which included reviewing of patients' records diagnosed with CRC at three general hospitals in Al Hassa region, Saudi Arabia. A compilation form was designed to collect information regarding socio demographics, age at diagnosis; referral sites and the main presentations at CRC diagnosis. sites and the main presentations at CRC diagnosis. Histopathological reports were reviewed to delineate the main cytopathologic features, prominent cytological characteristics, the presence of predisposing pathology, and disease stage. RESULTS: Of the 142 cases with CRC, 15.5% and 33.1% were affected before 40 and 50 years of age respectively. Emergency rooms were main referral sites for CRC cases (31.0%). Right colon was affected in 16.9% while left colonic lesions accounted for 62.7%. Intestinal obstruction was the main presentations (41.5%), and 26.1% presented with symptoms indicating distant metastatic lesions. Adenocarcinoma was the predominant pathological lesions (86.6%). Metastatic CRC was diagnosed in 62.7%. Duke's staging showed that 22.5% and 40.1% of lesions were classified into C and D categories respectively. CONCLUSION: Saudi patients with CRC present late with distant metastasis, and advanced disease stage. A sizeable proportion of patients developed the lesions at relatively young age. Screening recommendations should be enacted and revised in response to current change with younger age of affection. PMID- 22502672 TI - Tobacco related habits among first degree relatives of patients undergoing surgery for advanced head and neck malignancies in India. AB - This prospective study records the tobacco related habits among the relatives of patients with advanced head and neck cancers who underwent both surgery and chemotherapy as part of their treatment from September 2009 to March 2010. A total of 200 relatives were interviewed (148 males and 52 females). 198 (99%) were aware of the fact that tobacco use can lead to cancer and 168 (84%) had any one of the habits. Smoking alone was reported in 36 (18%) individuals, pan chewing alone in 66 (33%) and multiple habits in 64 (32%). Alcohol and tobacco chewing alone was reported in one case each. There were change in habits following diagnosis of head and neck cancers among the relatives, 33 (16.5%) stopped their habits and smoking was reduced by 25% in 72 (36%)and by 50% in 63 (31.2%) individuals. However, 135 continued the habit even after the diagnosis of cancer in their relatives. Of note, 15 out of the 33 who quit the habit did it because of health advice given to them during the hospital visit. PMID- 22502673 TI - Elevated level of prostate specific antigen among prostate cancer patients and high prevalence in the Gangetic zone of Bihar, India. AB - Prostate cancer (CaP) is a common reproductive cancer among men. This study was conducted to correlate the cancer incidence with Gangetic zone and to correlate the tumor marker prostate specific antigen (PSA) level in serum with different age groups and stage of malignancy. Patients suffering from CaP in the pathology unit of Mahavir Cancer Sansthan (Hospital and Research Centre), Patna, Bihar, India were studied from June 2009 to May 2010. PSA level in the serum of CaP patients was estimated by ELISA method. CaP incidence was highly recorded in Gangetic zone than the non-Gangetic zone. Maximum patients were in the 56 - 75 years age group with a marked predominance. Results of PSA examination showed that serum PSA level was not correlating with the age of patient and stage of malignancy. Significantly, elevated level of more than 10 ng/ml of PSA was recorded among the studied cancer patients. In this study, it is concluded that Gangetic zone habitat have high risk of CaP and elevated level of PSA was marked in Bihar, India. PMID- 22502674 TI - Sex-related differences in DNA copy number alterations in hepatitis B virus associated hepatocellular carcinoma. AB - BACKGROUND: Males have a higher prevalence of hepatocellular carcinoma (HCC) than females in general, but the reasons for the sex disparity are still obscure. DNA copy number alteration (CNA) is a major feature of solid tumors including HCC, but whether CNA plays a role in sex-related differences in HCC development has never been evaluated. METHODS: High-resolution array comparative genomic hybridization (CGH) was used to examine 17 female and 46 male HCC patients with chronic hepatitis B virus (HBV) infection in Shanghai, China. Two-tailed Fisher's exact or chi2 tests was used to compare CNAs between females and males. RESULTS: The overall frequencies and patterns of CNAs in female and male cases were similar. However, female HCC tumors presented more copy number gains compared to those in males on 1q21.3-q22 (76.5% vs. 37.0%, P = 0.009), 11q11 (35.3% vs. 0.0%, P = 0.0002) and 19q13.31-q13.32 (23.5% vs. 0.0%, P = 0.004), and loss on 16p11.2 (35.3% vs. 6.5%, P = 0.009). Relative to females, male cases had greater copy number loss on 11q11 (63.0% vs. 17.6%, P = 0.002). Further analyses showed that 11q11 gain correlated with 19q13.31-q13.32 gain (P = 0.042), 11q11 loss (P = 0.011) and 16p11.2 loss (P = 0.033), while 1q21.3-q22 gain correlated with 19q13.31-q13.32 gain (P = 0.046). CONCLUSIONS: These findings suggest that CNAs may play a role in sex-related differences in HBV-associated HCC development. PMID- 22502675 TI - Nutrient-derived dietary patterns and risk of colorectal cancer: a factor analysis in Uruguay. AB - In order to explore the role of nutrients and bioactive related substances in colorectal cancer, we conducted a case-control in Uruguay, which is the country with the highest production of beef in the world. Six hundred and eleven (611) cases afflicted with colorectal cancer and 1,362 controls drawn from the same hospitals in the same time period were analyzed through unconditional multiple logistic regression. This base population was submitted to a principal components factor analysis and three factors were retained. They were labeled as the meat based, plant-based, and carbohydrates patterns. They were rotated using orthogonal varimax method. The highest risk was positively associated with the meat-based pattern (OR for the highest quartile versus the lowest one 1.63, 95 % CI 1.22-2.18, P value for trend = 0.001), whereas the plant-based pattern was strongly protective (OR 0.60, 95 % CI 0.45-0.81, P value for trend <0.0001. The carbohydrates pattern was only positively associated with colon cancer risk (OR 1.46, 95 % CI 1.02-2.09). The meat-based pattern was rich in saturated fat, animal protein, cholesterol, and phosphorus, nutrients originated in red meat. Since herocyclic amines are formed in the well-done red meat through the action of amino acids and creatine, it is suggestive that this pattern could be an important etiologic agent for colorectal cancer. PMID- 22502676 TI - Screening for colorectal neoplasias with fecal occult blood tests: false-positive impact of non-dietary restriction. AB - OBJECTIVE: Screening for colorectal cancer using guaiac-based fecal occult blood tests (gFOBT) is well established in Western populations, but is hampered by poor patient compliance due to the imposed dietary restrictions. Fecal immunochemical tests (FIT) do not require dietary restriction, but are more expensive than gFOBT and therefore restrict its use in developing countries in Asia. However, Asian diets being low in meat content may not require diet restriction for gFOBT to achieve equivalent results. The objective of this study was to evaluate and compare the validity and suitability of gFOBT and FIT or a combination of the two in screening for colorectal neoplasias without prior dietary restriction in an Asian population. METHODS: Patients referred to the Endoscopic Unit for colonoscopy were recruited for the study. Stool samples were collected prior to bowel preparation, and tested for occult blood with both gFOBT and FIT. Dietary restriction was not imposed. To assess the validity of either tests or in combination to detect a neoplasm or cancer in the colon, their false positive rates, their sensitivity (true positive rate) and the specificity (true negative rate) were analyzed and compared. RESULTS: One hundred and three patients were analysed. The sensitivity for picking up any neoplasia was 53% for FIT, 40% for gFOBT and 23.3% for the combination. The sensitivities for picking up only carcinoma were 77.8% , 66.7% and 55.5%, respectively. The specificity for excluding any neoplasia was 91.7% for FIT, 74% for gFOBT and 94.5% for a combination, whereas for excluding only carcinomas they were 84%, 73.4% and 93.6%. Of the 69 with normal colonoscopic findings, FOBT was positive in 4.3%, 23.2 %and 2.9% for FIT, gFOBT, or combination of tests respectively. CONCLUSION: FIT is the recommended method if we are to dispense with dietary restriction in our patients because of its relatively low-false positivity and better sensitivity and specificity rates. PMID- 22502677 TI - Perceptions and opinions about male breast cancer and male breast self examination: a qualitative study. AB - OBJECTIVE: While the relatively common nature of female breast cancer has resulted in a high level of general awareness, male breast cancer is still comparatively unknown to the general public and to healthcare professionals. The objective of this study is to explore the perceptions and opinions about male breast cancer and male breast self-examination among male university students. METHODOLOGY: In-depth interviews were conducted among 36 male university students from the Management and Science University, Malaysia, selected by simple random sampling. The themes of the interview were: knowledge of male breast cancer and male breast self-examination, sources of knowledge and attitudes towards male BSE. The data obtained were classified into various categories and analyzed manually. RESULTS: The majority of participants mentioned that there is a low possibility for males to get breast cancer. They also believed that the cause of breast cancer among men is due to the carcinogens from cigarettes. The majority of participants mentioned that they know about breast self-examination from the mass media and that the presence of a lump in the breast is the main symptom of breast cancer in men. The majority of participants mentioned that they encourage their family members to practice breast self-examination but considered that BSE is not important for men because they have a low probability of getting breast cancer. CONCLUSIONS: Misconceptions regarding male breast cancer and breast self examination among men still exist among male university students. Therefore special attention should be given to educate men about male breast cancer and male BSE. PMID- 22502678 TI - Expression of CDX2 and villin in gastric cardiac intestinal metaplasia and the relation with gastric cardiac carcinogenesis. AB - OBJECTIVE: To determine whether CDX2 and villin protein expression are associated with intestinal metaplasia (IM) in gastric cardiac mucosa and to explore the relationship with evolution of gastric cardiac adenocarcinoma (GCA). METHODS: We studied 143 gastric cardiac biopsy or resection specimens from Henan province China, including 25 cardiac gastritis specimens with IM, 65 dysplasia specimens with IM and 35 gastric cardiac adenocarcinoma specimens and stained them for CDX2 and villin by the immunohistochemical SP method. 15 normal gastric cardiac biopsy specimens were also collected as control. RESULTS: (1) Normal gastric mucosa presented no CDX2 and villin expression. The positive rates of CDX2 protein in cardiac gastritis with IM, dysplasia with IM, and carcinoma tissues were 84.0% (21/25), 66.7% (32/48) and 36.4% (20/55), respectively. While the positive rates of villin protein in cardiac gastritis with IM, dysplasia with IM, and carcinoma tissues were 76.0% (19/25), 70.8% (34/48) and 45.5% (25/55), respectively.There were significant differences among the three groups for both CDX2 and villin (P<0.01). Spearman's rank correlation coefficient(rho) showed a close correlation between the two proteins (r=0.843, P<0.01) and both were positively related with tumor differentiation (both P<0.05), but not associated with age, sex, invasion and metastasis of lymph node (P>0.05). CONCLUSION: Our results suggest that ectopic expression of CDX2 and villin may be involved in early-stage IM and tumorigenesis in gastric cardia and the expression of villin may be regulated by CDX2. PMID- 22502679 TI - Factors influencing axillary lymph node metastasis in invasive breast cancer. AB - PURPOSE: To explore the relationship between auxiliary lymph node metastasis and clinical features, and to identify the factors that affect metastasis occurrence. METHODS: A total of 164 cases of primary breast cancer were selected to investigate features such as age, concomitant chronic disease and pathologic diagnosis. Immunohistochemistry was used to detect the expression of the estrogen receptor (ER) and CerbB-2. Logistic regression was employed to analyze the factors that affect the incidence of lymph node metastases. RESULTS: The incidence of lymph node metastases was 46.3% among elderly patients with breast cancer. Based on logistic regression, chronic disease, scale of tumor, age, and ER expression affected the occurrence of lymph node metastases; the ORs were 3.05, 2.18, 0.34, and 3.83, respectively. Between different pathologic diagnoses and the risk factors, the OR scores were 12.7 and 8.02, respectively, for aggressive ductal carcinoma and aggressive lobular carcinoma auxiliary lymph node metastases. CONCLUSION: The incidence of lymph node metastases is affected by chronic disease, scale of tumor, age, ER expression and pathologic diagnosis. PMID- 22502680 TI - MicroRNA-214 regulates the acquired resistance to gefitinib via the PTEN/AKT pathway in EGFR-mutant cell lines. AB - Patients with non-small cell lung cancer (NSCLC) who have activating epidermal growth factor receptor (EGFR) mutations derive clinical benefit from treatment with EGFR-tyrosine kinase inhibitors ((EGFR-TKIs)- namely gefitinib and erlotinib. However, these patients eventually develop resistance to EGFR-TKIs. Despite the fact that this acquired resistance may be the result of a secondary mutation in the EGFR gene, such as T790M or amplification of the MET proto oncogene, there are other mechanisms which need to be explored. MicroRNAs (miRs) are a class of small non-coding RNAs that play pivotal roles in tumorigenesis, tumor progression and chemo-resistance. In this study, we firstly successfully established a gefitinib resistant cell line-HCC827/GR, by exposing normal HCC827 cells (an NSCLC cell line with a 746E-750A in-frame deletion of EGFR gene) to increasing concentrations of gefitinib. Then, we found that miR-214 was significantly up-regulated in HCC827/ GR. We also showed that miR-214 and PTEN were inversely expressed in HCC827/GR. Knockdown of miR-214 altered the expression of PTEN and p-AKT and re-sensitized HCC827/GR to gefitinib. Taken together, miR-214 may regulate the acquired resistance to gefitinib in HCC827 via PTEN/AKT signaling pathway. Suppression of miR-214 may thus reverse the acquired resistance to EGFR-TKIs therapy. PMID- 22502681 TI - Predictive value of thymidylate synthase expression in gastric cancer: a systematic review with meta-analysis. AB - PURPOSE: The relationship between thymidylate synthase (TS) expression and outcomes in gastric cancer (GC) patients remains controversial, although most studies reported poor survival and reduced response to fluoropyrimidine were related to high TS in tumors. We carried out a systematic review of the literature with meta-analysis to estimate the predictive value of TS expression from published studies. METHODS: We identified 24 studies analysing the outcome data in gastric cancer stratified by TS expression. Effect measures of outcome were hazard ratios (HRs) for overall survival (OS) and event-free survival (EFS), or the odds ratio (OR) for overall response rate (ORR). HRs and ORs from these eligible studies were pooled using random-effects meta- analysis. RESULTS: Fifteen studies investigated outcomes in a total of 844 patients with advanced GC, and nine studies investigated outcomes in a total of 1,235 patients with localized GC undergoing adjuvant therapy. Meta- analysis of estimates showed high TS expression was significantly associated with poor OS in the advanced setting (HR: 1.43, 95%CI: 1.08 - 1.90), and poor EFS in the adjuvant setting (HR: 1.53, 95%CI: 1.01 - 2.32). Subgroup analysis demonstrated TS expression to have even greater value in predicting OS, EFS and ORR in advanced GC patients treated with fluoropyrimidine monotherapy (HR for OS: 2.32, 95%CI: 1.53 - 3.50; HR for EFS: 1.76, 95%CI: 1.19 - 2.60; OR for ORR: 0.32, 95%CI: 0.11 - 0.95). CONCLUSION: High levels of TS expression were associated with a poorer OS for advanced GC patients compared with low levels. In the adjuvant setting, high TS expression was also associated with a worse EFS. Additional studies with consistent methodology are needed to define the precise predictive value of TS. PMID- 22502682 TI - Prevalence and determinants of high-risk human papillomavirus infection in women with high socioeconomic status in Seoul, Republic of Korea. AB - We aimed to estimate the prevalence of high-risk human papillomavirus (HPV) infections in women of high socioeconomic status (SES) in Seoul, Republic of Korea and to identify risk factors. This study included 13,386 women visiting a prestigious healthcare center located in Seoul between 2003 and 2008. High-risk HPV infections were detected in 994 (7%) and the age-standardized prevalence was 8%. Abnormal Pap smear results >= atypical squamous cells of unknown significance (ASCUS) were observed in 280 of 12,080 women (2%). Based on univariate analysis, age, level of education and number of children were associated with high-risk HPV infections. Based on multivariate analysis, age and high-risk HPV infections had an inverse relationship. In women with high SES in Seoul, the prevalence of high risk HPV infection was 7% and the age-standardized prevalence was 8%. Age was a strong determinant of high-risk HPV infection. PMID- 22502683 TI - Expression of VEGF-C/VEGFR-3 in human laryngeal squamous cell carcinomas and its significance for lymphatic metastasis. AB - OBJECTIVES: Expression of vascular endothelial growth factor C (VEGF-C)and vascular endothelial growth factor receptor-3 (VEGFR-3) in laryngeal squamous carcinoma and its relationship to lymph node metastasis were investigated. METHODS: VEGF-C and VEGFR-3 gene expression in 30 cases of normal laryngeal mucosa tissue (NLM), primary laryngeal carcinoma cell carcinomas (PLC) and cervical lymph nodes (CLN) was examined by reverse transcription polymerase chain reaction (RT-PCR). Protein levels of VEGF-C expression were determined by immunohistochemical staining in 60 cases of PLC. RESULTS: Expression of VEGF-C and VEGFR-3 different among NLM, PLC and CLN in the same patient. In PLC, expression was significantly higher in lymph node positive group than in the lymph node negative group and associated with histological grade of differentiation; Expression of VEGF-C and VEGFR-3 was not linked with age, sex, site or T stage. CONCLUSIONS: A close correlation was found between VEGF-C/VEGFR 3 expression and lymph node metastasis in PLC, suggesting a role in metastasis of laryngeal carcinomas. PMID- 22502684 TI - Efficacy of carcinogenic embryonic antigen in differential diagnosis of diseases of pancreas and liver--a comparative study in a tertiary care hospital of Western Nepal. AB - OBJECTIVE: The objective of our present study was to assess the efficacy of carcinoembryonic antigen (CEA) for differentiating and diagnosis of pancreatic and liver diseases in Pokhara valley. MATERIALS AND METHODS: A hospital based retrospective study was carried out using data retrieved from the register maintained in the Department of Biochemistry of the Manipal Teaching Hospital, Pokhara, Nepal between 1st January, 2011 and 31st October, 2011. Estimation of CEA was performed by ELISA reader for all cases. Approval for the study was obtained from the institutional research ethical committee. RESULTS: Of the 771 subjects, 208 (27%), 60(7.8%), 240(31.1%), 54(7.0%) , 75(9.7%), 59(7.7%), 75(9.7%) cases were of active chronic hepatitis , cryptogenic cirrhosis, alcoholic cirrhosis, primary biliary cirrhosis, hepatoma, acute or chronic pancreatitis, carcinoma of pancreas respectively. The majority of cases (104) of active chronic hepatitis had CEA levels <5 ng/ml(50%). CEA levels were found to be increased in cases of alcoholic cirrhosis with maximum number of cases (106) in range of 10 to 20 ng/ml (44%). There were no cases having more than 20 ng/ml of CEA in primary biliary cirrhosis and acute or chronic pancreatitis. In cases of pancreatic cancer, maximum number of cases (35) were having CEA >20 ng/ml(47%). CONCLUSION: High levels of CEA are associated with advanced stage of disease. CEA can thus provide an important improvement in the diagnosis by differentiating pancreatic cancer especially from chronic pancreatitis when there is a high suspicion of malignancy. Increased CEA levels may also signify progression from benign to malignant transformation in the liver. PMID- 22502685 TI - Anatomical distribution of colorectal carcinoma in Iran: a retrospective 15-yr study to evaluate rightward shift. AB - BACKGROUND: Although more than two third of colorectal cancers are localized on the left side, recent studies suggest a right ward shift in anatomical distribution with increase in proximal colon cancers. The aim of the present study was to determine the anatomical distribution of colorectal cancer in a referral center over a 15 year period. METHOD: Records of patients who underwent colectomy in the Cancer Institute of Iran from 1994 to 2009 were retrieved. Data including anatomical localization, year of diagnosis, patient age and gender, tumor histology and differentiation, and disease stage were extracted. Tumors located from the cecum to the distal transverse colon were classified as right side and those occurring from the splenic flexure to the descending colon as left sided. Cancer of rectum and recto-sigmoid junction were considered as rectal cancers. RESULTS: A total of 442 patients including 220 (49/8%) men and 222 (50/2%) women with mean age 53 were included. Most patients were in stages II and III (47.1% and 33% respectively). There were 157 (35.5 %) colon cancers and 285 (64.5%) rectal cancers. 43.3% of the colon cancers were right sided and 56.7% were left sided. There was no statistically significant increase in right sided cancer during the period of the study. There were no significant differences in age at diagnosis, gender, grade and stage of tumor between the right and the left sided cancers. CONCLUSION: No proximal shift over time was identified in our study. PMID- 22502686 TI - Breast and colorectal cancer screening and associated correlates among Chinese older women. AB - OBJECTIVE: To explore the participation rates for breast and colorectal cancer screening and identify associated correlates among elderly women. METHODS: Logistic regressions were conducted using data collected in 2006 from 1,533 elderly women aged 60 years or above who had completed a screening instrument, the Minimum Data Set-Home Care, while applying for long-term care services at the first time in Hong Kong. RESULTS: The participation rates for breast and colorectal cancer screening among frail older Chinese women were 3.7% and 10.8% respectively. Cognitive status was inversely associated with the likelihood of participation in screening (breast: OR = 0.66, 95%CI = 0.47-0.94; colon: OR = 0.81, 95%CI = 0.66-0.99), as was educational level with the likelihood of participation in breast cancer screening (no formal education: OR = 0.20, 95%CI = 0.06-0.61, some primary education: OR = 0.31, 95%CI = 0.10-1.00). CONCLUSION: The delivery of cancer preventive health services to frail older women is less than ideal. Cognitive status and educational level were important factors in cancer screening behaviour. Tailor-made strategic promotion programmes targeting older women with low cognitive status and educational levels are needed to enhance awareness and acceptance within this vulnerable group. PMID- 22502687 TI - Antifibrotic effect of curcumin in TGF-beta 1-induced myofibroblasts from human oral mucosa. AB - BACKGROUND: Myofibroblasts play an important role in the development of oral submucous fibrosis (OSF). In the current study, we investigate the effect of curcumin on growth and apoptosis of myofibroblasts derived from human oral mucosa. METHODS: Myofibroblasts were generated by incubating fibroblasts, obtained from human oral mucosa, with transforming growth factor-beta 1 (TGF-beta 1). MTT, PI staining, and FACS assays were used to investigate curcumin's effect on proliferation and cell cycle of fibroblasts and myofibroblasts. Annexin V/PI binding and FACS assays were used to examine apoptosis of myofibroblasts, Western blotting to determine the levels of Bcl-2 and Bax, and enzyme-linked immunosorbant assay was employed to examine the levels of collagen type I and III in the supernatants of myofibroblasts. RESULTS: Curcumin inhibits proliferation of fibroblasts and myofibroblasts; it also disturbs the cell cycle, induces apoptosis and decreases the generation of collagen type I and III in myofibroblasts, which are more sensitive to its effects than fibroblasts. Curcumin induces apoptosis in myofibroblasts by down-regulating the Bcl-2/ Bax ratio. CONCLUSION: Our results demonstrate the antifibrotic effect of curcumin in vitro. It may therefore be a candidate for the treatment of OSF. PMID- 22502688 TI - The effects of educational level on breast cancer awareness: a cross-sectional study in Turkey. AB - Breast self-examination (BSE) is important for early diagnosis of breast cancer (BC). However, the majority of Turkish women do not perform regular BSE. We aimed to evaluate the effects of education level on the attitudes and behaviors of women towards BSE. A descriptive cross-sectional study was conducted on 413 women (20-59 years), divided into university graduates (Group I, n = 224) and high school or lower graduates (Group II, n = 189). They completed a 22-item scale assessing the knowledge level, attitudes and behaviors regarding BSE, and the Turkish version of the Champion's Revised Health Belief Model. A significantly higher number of women in Group II did not believe in early diagnosis of BC. A significantly higher number of Group I had conducted BSE at least once, and their BSE frequency was also significantly high. Moreover, a significantly lower number of Group I women considered themselves to not be at risk for BC and the scores for "perceived susceptibility" and "perceived barriers" were significantly higher. Logistic regression analysis identified the university graduate group to have a higher likelihood of performing BSE, by 1.8 times. Higher educational levels were positively associated with BSE performance. Overall, the results suggest that Turkish women, regardless of their education level, need better education on BSE. Consideration of the education level in women will help clinicians develop more effective educational programs, resulting in more regular practice and better use of BSE. PMID- 22502690 TI - Health and economic burden of HPV-related diseases in Singapore. AB - OBJECTIVE: To assess the health and economic burden of human papillomavirus (HPV) related diseases (cervical cancer, cervical intraepithelial neoplasia (CIN) 1/2/3, and genital warts) in Singapore over a period of 25 years beginning in 2008. METHODS: Incidence-based modeling was used to estimate the incidence cases and associated economic burden, with the assumption that age-stratified incidence rates will remain the same throughout the period of 25 years. The incidence rates in 2008 were projected based on data obtained from the National Cancer Registry for cervical cancer, and from a combination of published data and hospital registry review for CIN1/2/3 and genital warts. The population growth rate was factored into the projection of incidence cases over time. Direct cost data per cervical cancer and per CIN1/2/3 case were obtained from the financial database of large local hospitals while cost data for genital warts were obtained from the National Skin Center; these costs were multiplied by the number of incidence cases to produce an aggregate estimate of the economic burden over the 25-year period (in 2008 Singapore dollars) using a 3% discount rate. RESULTS: The total number of incidence cases of HPV-disease over 25 years beginning in 2008 was estimated to be 60,183, including 8,078 for cervical cancer, 11,685 for CIN 2/3, 8,849 for CIN1, and 31,572 for genital warts. The estimated total direct cost was 83.2 million Singapore Dollars over 25 years: 57.6 million attributable to cervical cancer, 13.0 million to CIN2/3, 6.83 million to CIN1, and 5.70 million to genital warts. CONCLUSION: HPV-related diseases are expected to impose significant health and economic burden on the Singapore healthcare resources in the next 25 years. PMID- 22502689 TI - Clinical application of serum tumor associated material (TAM) from non-small cell lung cancer patients. AB - OBJECTIVE: To explore the associations of serum tumor associated material (TAM) with other common tumor markers like carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), carbohydrate antigen19-9 (CA19-9) and its clinical application in non-small cell lung cancer (NSCLC) patients. METHODS: A total of 87 patients were enrolled into this study, all with histologically or cytologically confirmed NSCLC. With the method of chemical colorimetry, the level of TAM was determined and compared, while chemiluminescence was used to measure the levels of common tumor markers. RESULTS: The level of TAM decreased after chemotherapy compared with before chemotherapy when CT or MRI scans showed disease control. Furthermore, it increased when disease progressed and there was no statistically significant difference in monitoring of TAM and common tumor markers (P>0.05). CONCLUSIONS: Detecting TAM in NSCLC patients has a higher sensitivity and specificity, so it can be used as an indicator for clinical monitoring of lung cancer chemotherapy. PMID- 22502691 TI - Factors associated with psychological characteristics in patients with hepatic malignancy before interventional procedures. AB - OBJECTIVE: To investigate the psychological characteristics of hepatic malignancy patients before interventional procedures and assess associations with related factors. METHODS: Two hundred and thirteen patients requiring interventional procedure for hepatic malignancy were asked to complete a survey of health knowledge and psychological symptom on health knowledge questionnaire and SCL-90 before interventional procedure. Logistic regression analysis was employed to determine the association of various demographic, clinical and health knowledge factors with the presence of psychological symptoms in patients. RESULTS: Eight psychological symptom scores, i.e. somatization, obsessive-compulsive tendencies, depression, anxiety, hostility, phobia, paranoid ideations and psychotic states, were significantly higher than the normal range (P< 0.001). Of 213 cases in the study, 49 families (23.00%) concealed the diagnoses of hepatic carcinoma from patients; 135 patients (63.38%) described the prognosis of the disease correctly. It was demonstrated that the correlations between psychological symptoms and related factors, i.e. age, gender, education, interventional procedure times and health knowledge, were statistically significant (P< 0.05). CONCLUSION: Psychological distress is severe in hepatic malignancy patients before interventional procedures. Age, gender, education, interventional procedure times and health knowledge are associated with psychological symptoms which are significant different from the normal range in Chinese. PMID- 22502692 TI - Cyclooxygenase-2 expression is not a marker of poor survival in lung cancer. AB - OBJECTIVE: Cyclooxygenase-2 (COX-2) has been claimed to play role in carcinogenesis and be related to a bad prognosis in tumours. The aim of this study was to investigate the relationship between COX-2 expression and clinical and pathological parameters in early and advanced stage lung cancer patients. MATERIALS AND METHODS: A total of 73 patients with lung cancer (27 adenocarcinomas, 33 squamous cell carcinomas, 4 large cell carcinomas and 9 small cell cancer) were analysed retrospectively. COX-2 expression was evaluated by immunohistochemistry in resection materials or lung biopsies. Tumor cells demonstrating more intense staining than smooth muscle and endothelial cells were recorded as COX-2 positive. We investigated the correlation between increased COX 2 expression and histological type of the tumor, the stage of the disease and survival. RESULTS: COX-2 expression was observed in 55% of the adenocarcinomas, 45% of the squamous cell carcinomas and 22% of the small cell carcinomas. No correlation was apparent between COX-2 expression and disease stage, histological type and the survival. CONCLUSION: The results of this study do not support COX-2 expression as an independent prognostic factor in lung cancer. However, since results of the literature are different, further studies made in larger series are needed. PMID- 22502693 TI - Feasibility of shrinking field radiation therapy through 18F-FDG PET/CT after 40 Gy for stage III non-small cell lung cancers. AB - OBJECTIVE: To explore the feasibility of shrinking field technique after 40 Gy radiation through 18F-FDG PET/ CT during treatment for patients with stage III non-small cell lung cancer (NSCLC). METHODS: In 66 consecutive patients with local-advanced NSCLC, 18F-FDG PET/CT scanning was performed prior to treatment and repeated after 40 Gy. Conventionally fractionated IMRT or CRT plans to a median total dose of 66 Gy (range, 60-78 Gy) were generated. The target volumes were delineated in composite images of CT and PET. Plan 1 was designed for 40 Gy to the initial planning target volume (PTV) with a subsequent 20-28 Gy-boost to the shrunken PTV. Plan 2 was delivering the same dose to the initial PTV without shrinking field. Accumulated doses of normal tissues were calculated using deformable image registration during the treatment course. RESULTS: The median GTV and PTV reduction were 35% and 30% after 40 Gy treatment. Target volume reduction was correlated with chemotherapy and sex. In plan 2, delivering the same dose to the initial PTV could have only been achieved in 10 (15.2%) patients. Significant differences (p<0.05) were observed regarding doses to the lung, spinal cord, esophagus and heart. CONCLUSIONS: Radiotherapy adaptive to tumor shrinkage determined by repeated 18F-FDG PET/CT after 40 Gy during treatment course might be feasible to spare more normal tissues, and has the potential to allow dose escalation and increased local control. PMID- 22502694 TI - Lack of association between GSTM1 and GSTT1 polymorphisms and brain tumour risk. AB - OBJECTIVE: Glutathione S-transferases (GSTs) are important enzymes that are involved in detoxification of environmental carcinogens. Molecular epidemiological studies have been conducted to investigate the association between GSTM1 and GSTT1 homozygous deletion polymorphisms and brain tumours but results have been conflicting. The aim of this study was to clarify this problem using a meta-analysis. METHODS: A total of 9 records were identified by searching the PubMed and Embase databases. Fixed- and random-effects models were performed to estimate the pooled odds ratios. RESULTS: No significant association was found between the GSTM1 and GSTT1 homozygous deletion polymorphisms and risk of brain tumours, including glioma and meningioma. Similar negative results were also observed in both population-based and hospital-based studies. CONCLUSION: These findings indicate that the GSTM1 and GSTT1 polymorphisms may not be related to the development of brain tumours. PMID- 22502695 TI - Efficacy of primed in situ labelling in determination of HER-2 gene amplification and CEN-17 status in breast cancer tissue. AB - Considerable attention has been given to the accuracy of HER-2 testing and the correlation between the results of different testing methods. This interest reflects the growing importance of HER-2 status in the management of patients with breast cancer. In this study the detection of HER-2 gene and centromere 17 status was evaluated using dual-colour primed in situ labelling (PRINS) in comparison with fluorescence in situ hybridization (FISH). These two methods were evaluated on a series of 27 formalin fixed paraffin embedded breast carcinoma tumours, previously tested for protein overexpression by HercepTest (grouped into Hercep 1+/0, 2+ and 3+). HER-2 gene amplification (ratio >= 2.2) by PRINS was found in 3:3, 6:21 and 0:3 in IHC 3+, 2+ and 1+/0 cases, respectively. Comparing FISH and IHC (immunohistochemistry), showed the same results as for PRINS and IHC. Chromosome 17 aneusomy was found in 10 of 21 IHC 2+ cases (47.6%), of which 1 (10%) showed hypodisomy (chromosome 17 copy number per cell <= 1.75), 7 (70%) showed low polysomy (chromosome 17 copy number per cell=2.26 - 3.75) and 2 (20%) showed high polysomy (chromosome 17 copy number per cell >= 3.76). The overall concordance of detection of HER-2 gene amplification by FISH and PRINS was 100% (27:27). Furthermore, both the level of HER-2 amplification and copy number of CEN17 analysis results correlated well between the two methods. In conclusion, PRINS is a reliable, reproducible technique and in our opinion can be used as an additional test to determine HER-2 status in breast tumours. PMID- 22502696 TI - Abortions and breast cancer risk in premenopausal and postmenopausal women in Jiangsu Province of China. AB - To evaluate the relationship between abortions and risk of breast cancer, we conducted a case-control study with 669 cases and 682 population-based controls in Jiangsu Province of China. A structured questionnaire was used to elicit detailed information. Unconditional logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). The results have revealed that induced abortion was related to increased risk of breast cancer. Premenopausal women who had >= 3 times of induced abortion were at increased crude OR (2.41, 95%CI: 1.09-5.42) and adjusted-OR (1.55, 95%CI: 1.15-5.68). Postmenopausal women with a previous induced abortion were at increased crude OR (2.04, 95%CI: 1.48-2.81) and adjusted-OR (1.82, 95%CI: 1.30-2.54), and there was a significant increase trend in OR with number of induced abortions (p for trend: 0.0001). Overall, spontaneous abortion did not significantly alter the risk of breast cancer, but postmenopausal women who had history of spontaneous abortion were at increased OR. These results suggested that relationship between breast cancer and abortions may depend on menopausal status and induced abortion may played an important role in the development of breast cancer in Jiangsu' women of China. PMID- 22502697 TI - Lack of association between herpes simplex virus type 2 infection and cervical cancer--Taq Man realtime PCR assay findings. AB - BACKGROUND: About one third of the human population suffer cancer during their lifetime and more than 20% of total morbidity is related to neoplasia. Cervical cancer is generally the most common cancer in developing countries and the second most common in women globally. The role of human papilloma viruses viruses in its induction is clear. However, the involvement of herpes simplex virus type 2 (HSV 2) is controversial. Therefore a survey was conducted of the prevalence of HSV-2 in patients with cervical cancer and also healthy people with sensitive and quantitative Taq Man real-time PCR assay. MATERIALS AND METHODS: Seventy six formaldehyde fixed paraffin embedded tissue specimens from patients with histologically proven history of cervical cancer as well as 150 control blocks were sectioned for deparaffinization and DNA extraction. RESULTS: There was no HSV-2 DNA in our patient specimens but four control samples were positive, all with a history of hysterectomy. CONCLUSION: Considering the absence of any positive viral HSV-2 DNA in our patients and also the presence of four positive specimens among our controls, we did not find any relationship between the presence of HSV-2 DNA and cervical cancer. PMID- 22502698 TI - Heaviness of smoking index, number of cigarettes smoked and the Fagerstrom test for nicotine dependence among adult male Malaysians. AB - Two methods of identifying smokers with high nicotine dependence, the heaviness of smoking index (HSI) and number of cigarettes per day (CPD) were compared with the Fagerstrom test for nicotine dependence (FTND). The HSI, CPD and the FTND were administered to 316 adult Malaysian male, daily smokers aged between 25-64 years old in the Malaysian NCD Surveillance-1 Survey using a two-stage stratified random sampling of enumeration blocks and living quarters, via an interview based on a validated questionnaire. The cut-off point for classification of high nicotine dependence on the HSI was a score of four or higher, and for the heavy smoking category, smoking more than 20 cigarettes per day. Classification using each method was compared with classification by the FTND (score of six or more) as the reference standard. Sensitivity, specificity and kappa statistics for concordance between both measures and the FTND were evaluated. The HSI gave a similar prevalence rate of high nicotine dependence as the FTND. There was substantial agreement between the HSI and the FTND (kappa=0.63.), with moderate sensitivity (69.8%) and high specificity (92.5%). However, prevalence of high nicotine dependence using the CPD was 7% lower than the FTND. The heavy smoking category also showed fair agreement with the FTND (kappa=0.45) and moderate sensitivity (67.0%), but specificity was high (86.9%). The findings indicate that the HSI can be used as an alternative to the FTND in screening for high nicotine dependence among daily smokers in large population-based studies, while CPD may not be a suitable alternative to the FTND. PMID- 22502699 TI - TP53 codon 72 polymorphism and risk of acute leukemia. AB - TP53 is the mostly commonly mutated gene in many cancers and the P53 tumor suppressor protein is involved in multiple cellular processes, including transcription, DNA repair, genomic stability, senescence, cell cycle control and apoptosis. A common single nucleotide polymorphism located within the proline rich region of TP53 gene at codon 72 in exon 4 encodes either proline or arginine. TP53 Arg 72 is more active than TP53 Pro 72 in inducing apoptosis. The aim of this study was to understand the association of the 72 codon polymorphism with acute leukemia development and prognosis. A total of 288 acute leukemia cases comprising 147 acute lymphocytic leukemia (ALL) and 141 acute myeloid leukemia (AML), as well as 245 controls were recruited for analysis of the TP53 72 polymorphism using PCR-RFLP method. Significant association of homozygous arginine genotype with AML was observed (chi2- 133.53; df-2, p < 0.001. When data were analyzed with respect to clinical variables, elevation in mean WBC, blast %, LDH levels and slight reduction in DFS in ALL cases with the arginine genotype was observed. In contrast, AML patients with Pro/Pro had elevated WBC, Blast%, LDH levels with slightly reduced DFS. Our study indicates that Arg/Arg genotype might confer increased risk to development of acute myeloid leukemia. PMID- 22502700 TI - Leisure time physical activity in Saudi Arabia: prevalence, pattern and determining factors. AB - BACKGROUND: Identification of reliable predictors of leisure time physical activity (LTPA) will enable healthcare providers to intervene and change the patterns of LTPA in the population to improve community health. OBJECTIVES: The objectives of this study were to determine prevalence and pattern of LTPA among adult Saudis aged 18-65 years, and to define the socio-demographic determinants that correlate with LTPA in Al-Hassa, Saudi Arabia. SUBJECTS AND METHODS: A cross sectional study of 2176 adult Saudis attending urban and rural primary health care centers were selected using a multistage proportionate sampling method. Participants were personally interviewed to gather information regarding socio demographics, physical activity pattern using the Global Physical Activity Questionnaire (GPAQ). Physical activity (PA) in each domain was expressed in metabolic equivalents (METs). RESULTS: The median total METs minutes/week for LTPA for both genders was 256, higher for men (636 METs minutes/week) compared to women (249 METs minutes/week). Overall, only 19.8% of the total PA was derived from LTPA. Of the sampled population 50.0% reported doing no leisure activity. Using the cut off of 600 METs-minutes/day or 150 minutes of moderate intensity over 5 or more days/week, only 21.0% of the included sample were considered as being sufficiently active and 10.4% were in the high active category with beneficial health effects. Multivariate regression analysis showed that male, younger age (<35 years), absence of chronic disease conditions and moderate level of total PA were significant predictors for being active in the LTPA domain. CONCLUSION: The prevalence and intensity of LTPA among the included sample demonstrated low levels. Nearly 80% of the included sample population did not achieve the recommended LTPA level with beneficial health effects. Female gender, urban residence and associated chronic diseases correlated with a low LTPA. PMID- 22502701 TI - Expression of beta-tubulin III and survivin in advance stage breast cancer correlates with chemotherapeutic effects of docetaxel. AB - AIMS: To investigate the relationship between the expression of beta-tubulin III and survivin in advanced breast cancers and chemotherapeutic effects of docetaxel. METHODS: Clinical pathological data of 74 patients with advanced breast cancer were retrospectively analyzed after docetaxel chemotherapy. Expression of beta-tubulin III and survivin was assessed by immunohistochemistry and analyzed with reference to therapeutical and adverse effects of docetaxel. RESULTS: The positive expression rate of beta-tubulin III was 38.1% (32/84), while that of survivin was 76.2% (64/84). The effective rate (complete response + partial response) was 52.4%. That for patients with the positive expression of beta-tubulin III or/and survivin was significantly lower than for those with negative expression (P<0.05). There were significant differences in the non progression of median diseases, 1-year and 2-year survival rates of between the patients with positive and negative expression (P<0.05). The main side effects were myelosuppression, alimentary canal response and alopecia, no differences being observed between groups. CONCLUSIONS: The combined detection of beta tubulin III and survivin is a predictive index for chemotherapy effects of docetaxel in metastatic breast cancer. PMID- 22502702 TI - Increased trend of breast cancer mortality in Iran. AB - BACKGROUND: Breast cancer is the most commonly diagnosed cancer in women worldwide In Iran, it ranks first among cancers diagnosed in women and is the fifth most common cause of death. The aim of this study was to present the mortality trends from breast cancer for Iranian women during a period of almost a decade, in order to provide update information regarding the likely future. METHODS: We analyzed National death Statistic reported by the Iranian Ministry of Health and Medical Education from 1995 to 2004 to generate annual mortality rates/100,000, overall, by age group (<15, 15-49 and >= 50 years of age) and age standardized rate (ASR). RESULTS: The age standardized mortality rate of breast cancer increased dramatically during these years from 1.40 to 3.52 per 100,000 and its mortality was increasing 151.4% for Iranian women, although it seemed that the rate leveled off from 2002 to 2004. Moreover the increasing rate was higher for those aged between 15-49 compared to age > 50 years old. CONCLUSION: There is an increasing trend for breast cancer mortality in Iran. Thus, health education programs to rectify the lack of women awareness about breast cancer signs and effective screening are urgently needed. PMID- 22502703 TI - Prevalence of cervical human papilloma virus infection among married women in Vietnam, 2011. AB - The burden of cervical cancer is increasing in Vietnam in the recent years, infection with high risk HPV being the cause. This study aimed to examine the prevalence of HPV and the distribution of HPV specific types among the general population in 5 big cities in Vietnam. Totals of 1500 women in round 1 and 3000 in round 2 were interviewed and underwent gynecological examination. HPV infection status, and HPV genotyping test were performed for all participants. Results indicated that the prevalence of HPV infection in 5 cities ranged from 6.1% to 10.2% with Can Tho having highest prevalence. The most common HPV types in all 5 cities were HPV 16, 18 and 58. Most of the positive cases were infected with high risk HPV, especially in Hanoi and Can Tho where more than 90% positive cases were high risk HPV. Furthermore, in Can Tho more than 60% of women were infected with multiple HPV types. The information from this study can be used to provide updated data for planning preventive activities for cervical cancer in the studied cities. PMID- 22502704 TI - 5'-CpG island promoter hypermethylation of the CAV-1 gene in breast cancer patients of Kashmir. AB - BACKGROUND: Caveolin-1 (CAV-1), encoding the structural component of cellular caveolae, is a suggested tumor suppressor gene involved in cell signalling. Aberrant promoter methylation of CAV-1 is associated with inactivation of expression. We previously observed CAV-1 mutations in breast cancers and therefore devised this study to examine the hypermethylation status of the promoter region of CAV-1 with reference to breast cancer progression and development. METHODS: Hypermethylation status of CAV-1 was analyzed by methylation specific PCR. Loss of expression of the CAV-1 gene was further evaluated by semi-quantitative rt-PCR. RESULTS: 28/130 (21.5%) breast cancer cases showed promoter hypermethylation with reduced CAV-1 expression levels when compared with adjacent normal breast tissue. CAV-1 gene hypermethylation was significantly related to menopausal status, histopathological grade and age. CONCLUSION: The rationale of our study is that CAV-1 gene is transcriptionally repressed in breast cancer cells due to hypermethylation. Our results reveal that promoter hypermethylation and loss of expression of the CAV-1 gene is an important alternative mechanism for inactivation of CAV-1 leading to complete gene silencing. PMID- 22502705 TI - Screening peptides binding specifically to colorectal cancer cells from a phage random peptide library. AB - The aim of this study was to screen for polypeptides binding specifically to LoVo human colorectal cancer cells using a phage-displayed peptide library as a targeting vector for colorectal cancer therapy. Human normal colorectal mucous epithelial cells were applied as absorber cells for subtraction biopanning with a c7c phage display peptide library. Positive phage clones were identified by enzyme-linked immunosorbent assay and immunofluorescence detection; amino acid sequences were deduced by DNA sequencing. After 3 rounds of screening, 5 of 20 phage clones screened positive, showing specific binding to LoVo cells and a conserved RPM motif. Specific peptides against colorectal cancer cells could be obtained from a phage display peptide library and may be used as potential vectors for targeting therapy for colorectal cancer. PMID- 22502706 TI - Lymphoproliferative disorders in multiple primary cancers. AB - BACKGROUND: Cancer survivors are at increased risk of second cancers. Lymphoproliferative disorders (LPD) are common neoplasms that are primary or subsequent cancers in cases of multiple primary cancer. We here analyzed metachronous or synchronous LPD in multiple primary cancers. METHODS: Between 2001 and 2010, LPD were assessed retrospectively in 242 multiple primary cancers patients. RESULTS: Forty nine (20.2%) patients with LPD were detected. Six patients had two LPD where one patient had three LPD. The median age of patients was 60.5 years (range: 28-81). LPD were diagnosed in 29 patients as primary cancer, in 23 patients as second cancer, and in three patients as third cancer in multiple primary cancers. Primary tumor median age was 56 (range: 20-79). Diffuse large B cell lymphoma (n=16), breast cancer (n=9), and lung cancer (n=6) were detected as subsequent cancers. Alklylating agents were used in 19 patients (43.2%) and 20 patients (45.5%) had received radiotherapy for primary cancer treatment. The median follow-up was 70 months (range: 7-284). Second malignancies were detected after a median of 51 months (range: 7-278), and third malignancies with a median of 18 months (range: 6-72). CONCLUSIONS: In this study, although breast and lung cancer were the most frequent detected solid cancers in LPD survivors, diffuse large B cell lymphoma was the most frequent detected LPD in multiple primary cancers. PMID- 22502707 TI - Resistant gestational trophoblastic neoplasia patients treated with 5 fluorouracil plus actinomycin D. AB - A combination of 5-fluorouracil plus actinomycin D (5FU plus Act D) is the regimen that has been commonly administered to Chinese and Japanese gestational trophoblastic neoplasia patients as the first or second line of treatment with an excellent outcome. However, the efficacy of this regimen in a salvage setting was unclear. To evaluate the efficacy and safety of the 5 FU plus Act D regimen utilized in this condition, all GTN patients resistant to at least three previous chemotherapy regimens who received the 5 FU plus Act D regimen between August 2009 and January 2011 at Chiang Mai University Hospital were reviewed. There were five cases who met the criteria. Four of those patients were in FIGO stage III to IV with a WHO scoring of more than 12. The median number of cycles for each patient was two and only one case achieved remission while four of the cases were unresponsive. The toxicity was evaluated in 12 cycles. Common complications were uncomplicated myelosuppression and mucositis. In conclusion, this regimen revealed modest efficacy in a salvage setting with manageable toxicity. PMID- 22502708 TI - Depression and survival in Chinese patients with gastric cancer: a prospective study. AB - AIM: Depression is thought to be a predictor of poor survival among cancer patients. In our study, we aimed to investigate the association between depression and survival in patients with gastric cancer. METHODS: The subjects were a total of 300 patients aged 20-75 years who had histological confirmed diagnosis of gastric cancer from January 2004 to May 2006. Three months after patients diagnosis, depression was scored using by the Depression Status Inventory (DSI) designed by Willian WK Zung. The follow-up period consisted of a total of 13,643 person-months. A Cox's regression analysis was used to assess the association between depression and survival. RESULTS: The percentage of subjects with depression according to the DSI depression criteria was 31%. Tumor stage and treatment methods were significantly associated with depression of patients. Age (60 years or older), annual income, tumor stage, lymph nodes metastasis and treatment were significantly associated with increased hazard ratio (HR) for gastric cancer survival. The adjusted HR for mortality risk in gastric cancer patients with depression tended to be high (HR=3.34, 95% CI=1.23-5.49) and a significant trend was found (P<0.05). CONCLUSION: The data obtained in this prospective study in Chinese support the hypothesis that depression is associated with poor survival among gastric cancer patients. Further studies with a large sample and longer term follow-up period are needed. PMID- 22502709 TI - Associations between adiponectin and two different cancers: breast and colon. AB - OBJECTIVES: Breast and colon cancer are neoplasms well known to be related to obesity. Adiponectin, a protein that increases in obesity, seems to be involved in the relationship but clinical data are limited. METHODS: In this study, we therefore evaluated the serum adiponectin levels in 87 breast and 27 colon cancer patients and assessed the relation with BMI, menopausal status, receptor status and stage of disease. RESULTS: Serum adiponectin levels were lower in cancer cases (8583 +/- 2095 ng/ml for breast cancer, 9513 +/- 2276 for colon cancer) than in controls (13905 +/- 3263). CONCLUSION: A low serum adiponectin level may be associated with both breast and colon cancer, and that this association is not statistically significant for either receptor or menopausal status in breast cancer groups. PMID- 22502710 TI - Bufalin, a traditional oriental medicine, induces apoptosis in human cancer cells. AB - Bufalin is a traditional oriental medicines which induces apoptosis in some lines of human tumor cells. It constitutes the major digoxin-like immunoreactive component of Chan Su, obtained from the skin and parotid venom glands of toads. Bufalin is cardioactive C-24 steroids that exhibits a variety of biological activities, such as cardiotonic, anaesthetic, blood pressure stimulatory, respiratory and antineoplastic effects. In terms of its anti-tumor activity, bufalin has been demonstrated to inhibit the growth of tumors, such as endometrial and ovarian cancers. This commentary introduces biologic and therapeutic effects of bufalin in treating some cancers. The compound is able to mediate inhibition of cell growth, cell cycle arrest, apoptosis, and expression of genes related to the malignant phenotype in human cancer cells. PMID- 22502711 TI - Use of mobile phones and cancer risk. AB - Mobile phones work by transmitting and receiving radio frequency microwave radiation. The radio frequency (RF) emitted by mobile phones is stronger than FM radio signal which are known to cause cancer. Though research and evidence available on the risk of cancer by mobile phones does not provide a clear and direct support that mobile phones cause cancers. Evidence does not also support an association between exposure to radio frequency and microwave radiation from mobile phones and direct effects on health. It is however clear that lack of available evidence of cancer as regards the use of mobile phone should not be interpreted as proof of absence of cancer risk, so that excessive use of mobile phones should be taken very seriously and with caution to prevent cancer. PMID- 22502712 TI - Prostate stem cell antigen single nucleotide polymorphisms influence risk of estrogen receptor negative breast cancer in Korean females. AB - INTRODUCTION: Breast cancer is the second leading cancer in Korean women. To assess potential genetic associations between the prostate stem cell antigen (PSCA) gene in the chromosome 8q24 locus and breast cancer risk in Korean women, 13 SNPs were selected and associations with breast cancer risk were analyzed with reference to hormone receptor (HR) and menopausal status. METHODS: We analyzed DNA extracted from buffy coat from 456 patients and 461 control samples, using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) based upon region-specific PCR followed by allele- specific single base primer extension reactions. Risks associated with PSCA genotypes and haplotypes were estimated with chi-square test (chi2 -test), and polytomous logistic regression models using odds ratios (OR) and 95% confidence intervals (CIs), by HR and menopausal status. RESULTS: In case-control analysis, odds ratios (OR) of rs2294009, rs2294008, rs2978981, rs2920298, rs2976395, and rs2976396 were statistically significant only among women with estrogen receptor (ER) negative cancers, and those of rs2294008, rs2978981, rs2294010, rs2920298, rs2976394, rs10216533, and rs2976396 were statistically significant only in pre menopausal women, and not in postmenopausal women. Risk with the TTGGCAA haplotype was significantly elevated in ER (-) status (OR= 1.48, 95% CI= 1.03~2.12, p<0.05). Especially risk of allele T of rs2294008 is significantly low in pre-menopausal breast cancer patients and AA genotype of rs2976395 in ER (-) status represents the increase of OR value. CONCLUSION: This report indicated for the first time that associations exist between PSCA SNPs and breast cancer susceptibility in Korean women, particularly those who are pre-menopausal with an estrogen receptor negative tumor status. PMID- 22502713 TI - Psychosocial factors and health behavior among Korean adults: a cross-sectional study. AB - OBJECTIVE: This study was an attempt to identify associations between health behavior, such as smoking, alcohol consumption, healthy diet, and physical activity, and psychosocial factors. METHODS: This cross- sectional study was conducted among 1,500 participants aged between 30 and 69 years, selected from a population-based database in October 2009 through multiple-stratified random sampling. Information was collected about the participants' smoking and drinking habits, dietary behavior, level of physical activity, stress, coping strategies, impulsiveness, personality, social support, sense of coherence, self-efficacy, health communication, and sociodemographics. RESULTS: Agreeableness, as a personality trait, was negatively associated with smoking and a healthy diet, while extraversion was positively associated with drinking. The tendency to consume a healthy diet decreased in individuals with perceived higher stress, whereas it increased in individuals who had access to greater social support. Self-efficacy was found to be a strong predictor of all health behaviors. Provider-patient communication and physical environment were important factors in promoting positive healthy behavior, such as consumption of a healthy diet and taking regular exercise. CONCLUSIONS: Psychosocial factors influence individuals' smoking and drinking habits, dietary intake, and exercise patterns. PMID- 22502714 TI - Inhibition of the NEDD8 conjugation pathway by shRNA to UBA3, the subunit of the NEDD8-activating enzyme, suppresses the growth of melanoma cells. AB - Neural precursor cell-expressed developmentally down-regulated 8 (NEDD8), a ubiquitin-like protein, mainly functions through covalent ligation to cullin proteins. Conjugation of NEDD8 with cullins can promote ubiquitination, which plays a critical role in the degradation of many proteins. UBA3 is the subunit of NEDD8- activating enzyme which is one of the keys for NEDD8 linkage to cullin proteins. Previous research showed NEDD8 conjugation to be up-regulated in highly proliferative cell lines. In the present study, up-regulated NEDD8 conjugation was observed in melanoma cell lines by Western blot analysis. After down regulation with a RNAi to UBA3, proliferation of M14 was suppressed in vitro and in vivo. In conclusion, up-regulated NEDD8 conjugation may be involved in the development of melanoma. Interference in this pathway might offera promising method for melanoma therapy. PMID- 22502715 TI - Satisfaction in the National Cancer Screening Program for breast cancer with and without clinical breast examination. AB - The purpose of this study was to evaluate whether screening by clinical breast examination (CBE) in addition to mammography affected participant satisfaction in the National Cancer Screening Program (NCSP). Data were derived from the Quality Evaluation of National Cancer Screening satisfaction survey. This population based nationwide telephone survey included participants who had been screened by the NCSP for breast cancer between June and August 2010 (n=2,370), and collected information on satisfaction with screening and screening service use. Five multiple regression models were used to determine satisfaction according to screening method, and according to each of five satisfaction measures (pre- screening information transfer, staff interpersonal skills, physical surroundings, reporting of results and general satisfaction). A total of 1,858 (78.4%) participants were screened by mammography alone and 512 (21.6%) by both mammography and CBE. Satisfaction was significantly higher in subjects screened by both mammography and CBE compared with those screened by mammography alone. PMID- 22502716 TI - Polymorphic variation in glutathione-S-transferase genes and risk of chronic myeloid leukaemia in the Kashmiri population. AB - Cancer is a complex disease and the genetic susceptibility to it could be an outcome of the inherited difference in the capacity of xenobiotic metabolizing enzymes. Glutathione-S-transferases (GSTs) are phase II metabolizing enzymes whose various genotypes have been associated with increased risk of different types of cancer. Null mutations caused by the deletion of the entire gene result in the absence of the enzymatic activity and increase in the risk of developing cancer including chronic myeloid leukaemia (CML). In the present case-control study we evaluated the effect of null mutations in GSTM1 and GSTT1 genes on the risk of developing CML. The study included 75 CML patients (43 males and 32 females; age (mean +/- S.D) 42.3 +/- 13.4 years) and unrelated non-malignant controls (76 male and 48 females; age (mean +/- S.D) 41.5 +/- 12.9). The distribution of GSTM1 and GSTT1 genotypes in CML patients and controls was assessed by multiplex-PCR method. Logistic regression was used to assess the relationship between GSTM1 and GSTT1 genotypes and risk of CML. Chi-square test was used to evaluate the trend in modulating the risk to CML by one or more potential high risk genotype. Although GSTM1 null genotype frequency was higher in CML patients (41%) than in the controls (35%), it did not reached a statistical significance (OD = 1.32, 95% CI: 0.73-2.40; P value = 0.4295). The frequency of GSTT1 null genotypes was higher in the CML patients (36%) than in the controls (21%) and the difference was found to be statistically significant (OD = 2.12, 95% CI: 1.12-4.02; P value = 0.0308). This suggests that the presence of GSTT1 genotype may have protective role against the CML. We found a statistically significant (OD = 3.09, 95% CI: 1.122-8.528; P value = 0.0472) interaction between the GSTM1 and GSTT1 null genotypes and thus individuals carrying null genotypes of both GSTM1 and GSTT1 genes are at elevated risk of CML. PMID- 22502717 TI - Quality of life and radiotherapy complications of Chinese nasopharyngeal carcinoma patients at different 3DCRT. AB - PURPOSE: the study aimed to compare the quality of life (QOL) and radiotherapy complications among Chinese nasopharyngeal carcinoma (NPC) patients at different 3-dimensional conformal radiotherapy (3DCRT) stages adjusting for other variables. METHODS: 511 NPC patients at different 3DCRT stages were enrolled. They were interviewed regarding SF-36, complications and socio-demographic variables and cancer- or treatment- related variables. Analysis of covariance (ANCOVA) based on SF-36, complications scores as dependent variables, 3DCRT stages as independent variables, and other variables as covariate were established. RESULTS: The influencing factors of PCS included 3DCRT stages and age group. The influencing factors of MCS included 3DCRT stages and income. Most QOL scores of NPC patients were significantly associated with 3DCRT stage, after accounting for other variables. QOL scores of the patients receiving 3DCRT were the lowest, QOL scores of people after 3DCRT gradually increased. PCS scores of people greater than 5 years after 3DCRT was improved to or even better than the level before 3DCRT. The complications with significantly different scores of patients at different 3DCRT status included xerostomia, throat ache, hypogeusia, caries, hearing loss, snuffles. CONCLUSIONS: Clinicians should pay more attention to older NPC patients and patients with lower income. When patients receive 3DCRT, measures should be taken to reduce radiation injury to improve the patients' QOL. PMID- 22502718 TI - Induction of apoptosis by a combination of paclitaxel and carboplatin in the presence of hyperthermia. AB - PURPOSE: To study enhancing effects of paclitaxel in the thermochemotherapy of osteosarcoma cell lines and related mechanisms. MATERIALS AND METHODS: Paclitaxel and carboplatin were used alone or jointly on OS732 cell lines in the presence of hyperthermia. Inhibition of proliferation was measured by MTT assay and cellular changes were assessed with inverted phase contrast and fluorescence microscopy. Apoptosis was analyzed with flow cytometry (FCM) and Fas expression by immunocytochemistry. RESULTS: At 43 degrees C, one hour after the application of 10 MUg/ml paclitaxel and 5 MUg/ml carboplatin on OS732 cells jointly, the survival rate was 15.8% which was significantly lower than with 10 MUg/ml paclitaxel (45.8%) and 5 MUg/ml carboplatin (47.7%) respectively (P<0.01). Moreover, changes of morphology and apoptotic rates indicated that the apoptosis inducing effect of combined application was also much enhanced, as evident also regarding Fas expression. CONCLUSION: Paclitaxel is conducive to thermochemotherapy of osteosarcoma cell lines, possibly accomplished by up regulation of Fas expression with induction of apoptosis. PMID- 22502719 TI - Ultrasonography as a tool for monitoring the development and progression of cholangiocarcinoma in Opisthorchis viverrini/ dimethylnitrosamine-induced hamsters. AB - Cholangiocarcinoma (CCA) is the most common cancer in northeastern Thailand. At present, effective diagnosis of CCA either in humans or animals is not available. Monitoring the development and progression of CCA in animal models is essential for research and development of new promising chemotherapeutics. Ultrasonography has been widely used for screening of bile duct obstruction in CCA patients. In this study, we preliminarily investigated the applicability of ultrasonography to monitor the development and progression of CCA in Syrian golden hamsters (n=8) induced by Opisthorchis viverrini (OV)/dimethylnitrosamine (DMN) administration. Ultrasonography and histopathological examination of hamsters was performed at week 0, 20, 24 and 28 of OV infection or at the start of water/Tween-80 administration to controls. The ultrasonographic images of liver parenchyma and gallbladders of OV/DMN-induced CCA hamsters showed sediments in gallbladder, thickening of gallbladder wall, and hypoechogenicity of liver parenchyma cells. The ultrasonographic images of liver tissues were found to correlate well with histopathological examination. Although ultrasonography does not directly detect the occurrence of CCA, it reflects the thickening of bile ducts and abnormality of liver tissues. It may be applied as a reliable tool for monitoring the development and progression of CCA in animal models in research and development of new promising chemotherapeutics for CCA. PMID- 22502721 TI - Prediction of length of ICU stay using data-mining techniques: an example of old critically Ill postoperative gastric cancer patients. AB - OBJECTIVE: With the background of aging population in China and advances in clinical medicine, the amount of operations on old patients increases correspondingly, which imposes increasing challenges to critical care medicine and geriatrics. The study was designed to describe information on the length of ICU stay from a single institution experience of old critically ill gastric cancer patients after surgery and the framework of incorporating data-mining techniques into the prediction. METHODS: A retrospective design was adopted to collect the consecutive data about patients aged 60 or over with a gastric cancer diagnosis after surgery in an adult intensive care unit in a medical university hospital in Shenyang, China, from January 2010 to March 2011. Characteristics of patients and the length their ICU stay were gathered for analysis by univariate and multivariate Cox regression to examine the relationship with potential candidate factors. A regression tree was constructed to predict the length of ICU stay and explore the important indicators. RESULTS: Multivariate Cox analysis found that shock and nutrition support need were statistically significant risk factors for prolonged length of ICU stay. Altogether, seven variables entered the regression model, including age, APACHE II score, SOFA score, shock, respiratory system dysfunction, circulation system dysfunction, diabetes and nutrition support need. The regression tree indicated comorbidity of two or more kinds of shock as the most important factor for prolonged length of ICU stay in the studied sample. CONCLUSIONS: Comorbidity of two or more kinds of shock is the most important factor of length of ICU stay in the studied sample. Since there are differences of ICU patient characteristics between wards and hospitals, consideration of the data-mining technique should be given by the intensivists as a length of ICU stay prediction tool. PMID- 22502720 TI - HPV prevalence and cervical intraepithelial neoplasia among HIV-infected women in Yunnan Province, China: a pilot study. AB - OBJECTIVES: To determine the prevalence of HPV and cervical neoplasia among HIV infected women in southwestern China. METHODS: Cervical cytology, HPV detection by Hybrid Capture-2TM assay, and diagnostic colposcopy were followed by cervical biopsy if indicated. Logistic regression analysis was used to analyze associations between HPV co-infection and cervical intraepithelial neoplasia (CIN), and HIV-related clinical and laboratory parameters. RESULTS: Colposcopic histopathologically proven CIN2+ lesions were present in 7/83 (8.4%) HIV-infected women. Nearly half (41/83, 43%) were co-infected with carcinogenic HPV genotypes. HPV co-infection was higher in women with colposcopic-histopathologically proven CIN2+ lesions than women with 2 was 0.76 and 0.72 (P = 0.23). Negative predictive value for cirrhosis using this cut-off was high for both techniques (HVTT, 88%; HTT, 92%), suggesting utility for exclusion of cirrhosis. Inter-observer reliability for HTT and HVTT were 0.92 and 0.94, respectively. Intra-observer reliability for HTT and HVTT were 0.98 and 0.99. CONCLUSION: In this cohort, reliability exceeded 90% while diagnostic accuracy was in keeping with previous studies of microbubble transit time analysis. Despite higher numerical diagnostic accuracy for HTT, no significant difference was demonstrated between the techniques, suggesting that both methods can be used reliably. PMID- 22502743 TI - Integration of pro-inflammatory cytokines, 12-lipoxygenase and NOX-1 in pancreatic islet beta cell dysfunction. AB - Elevated cellular reactive species, which can be produced by diabetic serum conditions such as elevated inflammatory cytokines, lipotoxicity or glucotoxicity contribute to islet beta cell dysfunction and cell death. Cellular pathways that result in beta cell oxidative stress are poorly resolved. In this study, stimulation of human donor islets, primary mouse islets or homogeneous beta cell lines with a cocktail of inflammatory cytokines (TNFalpha, IL-1beta, and INFgamma) significantly induced NADPH oxidase-1 (NOX-1) gene expression (p<0.05). This pro-inflammatory cytokine cocktail concomitantly induced loss of islet glucose stimulated insulin response (p<0.05), elevated expression of MCP-1 (p<0.01), increased cellular reactive oxygen species (ROS) and induced cell death. Inhibitors of NADPH oxidase, apocynin and diphenyleneiodonium, and a dual selective NOX1/4 inhibitor, blocked ROS generation (p<0.01) and induction of MCP 1 (p<0.05) by pro-inflammatory cytokines in beta cells. It has previously been reported that pro-inflammatory cytokine stimulation induces 12-lipoxygenase (12 LO) expression in human islets. 12-Hydroxyeicosatetraenoic acid (12-HETE), a product of 12-LO activity, stimulated NOX-1 expression in human islets (p<0.05). A novel selective inhibitor of 12-LO blocked induction of NOX-1, production of ROS and pro-caspase 3 cleavage by pro-inflammatory cytokines in INS-1 beta cells (p<0.01). Inhibition was not seen with a structurally related but inactive analog. Importantly, islets from human type 2 diabetic donors have an elevated expression of NOX-1 (p<0.05). This study describes an integrated pathway in beta cells that links beta cell dysfunction induced by pro-inflammatory cytokines with 12-lipoxygenase and NADPH oxidase (NOX-1) activation. Inhibitors of this pathway may provide a new therapeutic strategy to preserve beta cell mass in diabetes. PMID- 22502746 TI - Evaluating environmental exposures and potential mechanisms of a leukemia cluster: Churchill County, NV case study. PMID- 22502747 TI - An overview of surgical techniques, research trials, and future directions of fetal therapy. AB - During the latter part of the 20(th) century, the fetus became recognized as a patient separate from the mother. Powerful imaging and sampling techniques provided insight into normal fetal development and the opportunity to detect anomalies. In this overview of the rapidly evolving fetal surgery field, we describe the evolution of surgical techniques, clinical trials, and emerging research. We hope to ignite interest among professionals in this growing area of patient care. PMID- 22502748 TI - Effect of zinc supplementation on lipid peroxidation and lactate levels in rats with diabetes induced by streptozotocin and subjected to acute swimming exercise. AB - OBJECTIVE: The present study aims to explore the effect of zinc supplementation on lipid peroxidation and lactate levels in rats having diabetes induced by streptozotocin and subjected to acute swimming exercise. METHOD: A total of 80 adult male rats of Sprague-Dawley type were equally allocated to 8 groups: Group 1, general control. Group 2, zinc-supplemented group. Group 3, zinc-supplemented, diabetic group. Group 4, swimming control group. Group 5, zinc-supplemented swimming group. Group 6, zinc-supplemented diabetic swimming group. Group 7, diabetic swimming group. Group 8, diabetic group. At the end of the 4-week study, blood samples were collected to determine MDA, GSH, GPx, SOD, lactate and zinc levels. RESULTS: The highest MDA values were found in group 7 and 8 (p<0.001). GSH values in groups 5 and 6 were higher (p<0.001). The highest GPx values were established in groups 2, 5 and 6 (p<0.001). SOD values were the highest in groups 5 and 6 (p<0.001) and lowest in groups 2, 3 and 8 (p<0.001). The highest plasma lactate levels were found in group 7 (p<0.001). The highest zinc levels were obtained in groups 1, 2 and 5 (p<0.001), and the lowest zinc levels were found in groups 7 and 8 (p<0.001). CONCLUSION: Results of the study reveal that zinc supplementation prevents the increase of free radical formation, suppression of antioxidant activity and muscle exhaustion, all of which result from diabetes and acute exercise. Zinc supplementation may contribute to health performance in diabetes and acute exercise (Tab. 2, Fig. 1 Ref. 47). Full Text in PDF www.elis.sk. PMID- 22502749 TI - Bacterial translocation and intestinal injury in experimental necrotizing enterocolitis model. AB - OBJECTIVE: To study the occurrence of bacterial translocation and to assess the impact of breastfeeding on bacterial translocation in the animal model of necrotizing enterocolitis. METHODS: A total of 20 neonate Sprague-Dawley rats were enrolled in the study. Rats were randomly allocated into either control or study group just after birth. Ten newborn rats in the control group were left with their mother to be breast-fed. In contrary, necrotizing enterocolitis group consisted of neonates that were separated from their mothers, housed in an incubator and were gavaged with a special rodent formula three times daily. Survival rates, weight changes, and morphologic scoring obtained after microscopic evaluation were determined as microbiologic evaluation criteria. RESULTS: All the rats in the control group survived, while 1 (10 %) rat died in the necrotizing enterocolitis group. Mortality rates of the two groups were similar. All the formula-fed animals in the necrotizing enterocolitis group had significant weight loss compared to the breast milk-fed rats in the control group (p<0.05). A total of 7 (70 %) and 2 (20 %) E. coli growths were identified in the bowel lumen, liver, and spleen of necrotizing enterocolitis and control groups, respectively. This difference was statistically significant. In peritoneal smear cultures, a total of 3 (30 %) growths were detected in the necrotizing enterocolitis group and 1 (10 %) growth in the control group. CONCLUSION: As the result of a disturbance in the intestinal flora and impairment of the intestinal barrier in necrotizing enterocolitis, microrganisms in the bowel pass through the intestinal barrier and reach the liver and the spleen via the hematogenous route. This condition is closely related to the impairment of physiological and functional features of the intestinal barrier and is independent from the degree of intestinal injury. Bacterial translocation should be remembered in cases suspected of necrotizing enterocolitis, and a rapid and effective treatment algorithm should be applied in such circumstances (Tab. 3, Fig. 3, Ref. 21). Full Text in PDF www.elis.sk. PMID- 22502750 TI - The evaluation of effects of lornoxicam on blood flow and erythrocyte deformability in comparison with iv paracetamol in rats. AB - BACKGROUND: Lornoxicam and iv paracetamol are commonly preferred to be used for postoperative analgesia. Although Aspirin is a well known non-steroid anti inflammatory drug that decreases the erythrocyte deformability, there is no study comparing lornoxicam and iv paracetamol regarding their effects on erythrocyte deformability recorded in literature. The aim of this study was to compare the effects of lornoxicam and IV paracetamol on blood perfusion and erythrocyte deformability on rats. METHODS: Twenty male Wistar Albino rats were randomly divided into three groups as Lornoxicam group (Group L), IV paracetamol group (Group P), and control group (Group C). Intraperitoneal administrations were done in all groups except Group C. Liver and renal blood flows were conducted by laser Doppler and euthanasia was performed via intraabdominal blood uptake. Erythrocyte deformability was measured using a constant flow filtrometer system. RESULTS: Lornoxicam increased the relative resistance which shows the erythrocyte deformability in rats (p<0.05). The comparison of Groups C and P revealed no statistically different results (p=0.731) while Group L revealed statistically higher results than Group C (p=0.022). No statistically significant differences were found between groups L and P (p=0.073). Liver and renal blood flow values in Group L were just numerically decreased not statistically whilst no statistically significant difference was found between the three groups. CONCLUSIONS: Lornoxicam have lead to functional disorders related to tissue perfusion as a result of both decreased blood flow and erythrocyte deformability (Fig. 3, Ref. 21). Full Text in PDF www.elis.sk. PMID- 22502751 TI - Iron-rich complexes in human spleen in hereditary spherocytosis. AB - OBJECTIVE: Tissue iron plays an important role in the development of certain diseases. Although it is one of biogenic elements, its excess induces the reactive oxygen species (ROS) formation. The aim of the present work is to examine the protection against free or loosely bound iron from the view of morphology and chemical composition of iron-rich complexes in human spleen tissues with hereditary spherocytosis (HS) by scanning and transmission electron microscope with energy-dispersive microanalysis (EDX). RESULTS: The examination of human spleen tissues by scanning and transmission electron microscope showed covering of iron-rich particles. EDX revealed many iron-rich complexes of multi element composition in HS samples with sulphur and phosphorus as the major elements. Detection was negative in the reference samples. CONCLUSION: The covering of iron-rich particles can be explained by elimination and isolation of ferritin/iron complexes from surrounding environment to prevent the ROS formation. Sulphur, phosphorus and their compounds are probably the most significant elements that influence the ROS formation (Fig. 5, Ref. 16). Full Text in PDF www.elis.sk. PMID- 22502752 TI - Coronary atherosclerosis -- a postmortem histopathological study. AB - Cardiovascular disease in general and coronary heart disease in particular remains the leading cause of morbidity and mortality in developed countries. The aim of this study was to look at the prevalence of coronary atherosclerosis, its severity and site of involvement in postmortem hearts. The hearts of 30-60 yrs old, fifty dead victims were considered who died from various natural and unnatural deaths. After autopsy, coronary arteries were inspected grossly and microscopically. Out of all these cases, 10 cases (20 %) showed no pathological lesions. Total distribution of lesions in the coronaries are as follows; 34 (68 %) atheromatous lesions in Left Anterior Descending Artery, 25 (50 %) lesions in the Right Coronary Artery, 18 (36 %) lesions in Left Circumflex. Proximal involvement was more common except in the right coronary artery, which was involved distally. The overall prevalence of coronary atherosclerosis in the present study was comparable with that noted by other investigators in autopsy studied. There is a higher prevalence of atherosclerosis in Indians, which may be due to changes in life-styles and other risks factors (Tab. 1, Ref. 14). Full Text in PDF www.elis.sk. PMID- 22502753 TI - Intracoronary injection of autologous bone marrow-derived mononuclear cells in patients with large anterior acute myocardial infarction and left ventricular dysfunction: a 24- month follow up study. AB - OBJECTIVE AND BACKGROUND: Despite the use of reperfusion therapies, outcomes in patients with large myocardial infarction (MI), late reperfusion and left ventricular (LV) dysfunction are poor. We investigated long-term safety and efficacy of intracoronary injections of autologous bone marrow-derived mononuclear cells (BMNCs). METHODS: 27 patients with anterior MI (age 59+/-12 years, mean baseline LV ejection fraction (LVEF) 39+/-5 %), who underwent percutaneous coronary intervention 4-24 hours after the onset of symptoms, were randomly assigned either to intracoronary BMNCs injection (n=17, BMNCs group, out of which 14 underwent long-term follow-up), or to standard therapy (n=10, Control group). The LVEF, the LV end-diastolic and end-systolic volumes (LVEDV, LVESV) were assessed by echocardiography at discharge, Month 4 and 24. Myocardial perfusion was assessed using SPECT at baseline and Month 4. RESULTS: At 24-month, there was no difference in rates of serious clinical events (36 % vs 50 %, p=0.54). At Month 4 LVEF improved to similar extent in both groups (absolute change +5.8 % vs +7.6 %, p=0.75), with similar infarct size reductions (-10.9 % vs -12.2 %, p=0.47). However, at Month 24, LVEF further improved in BMNCs patients (+12 % vs +8.5 %, p=0.03). This effect resulted from a more pronounced reduction in LVESV (-2.6 ml vs -1.8 ml, p=0.26) and a smaller increase in LVEDV (+16.7 ml vs +17.9 ml, p=0.27) suggesting beneficial long-term effects on LV remodeling. CONCLUSIONS: BMNCs injections in patients with MI and LV dysfunction were associated with a significant improvement of global LVEF during long term follow-up compared to standard therapy (Tab. 3, Fig. 1, Ref. 50). Full Text in PDF www.elis.sk. PMID- 22502754 TI - Current therapy for retinal vein occlusion. AB - Retinal vein occlusion is a common retinal vascular disorder causing visual deterioration in the elderly. Vision-threatening complications include macular ischemia, neovascularisations, and vitreous hemorrhages. There are central and branch retinal vein occlusions as well as their ischemic and nonischemic subtypes. Branch occlusion and nonischemic cases are associated with better prognosis, often with good recovery of visual acuity. There have been various modes of therapy used for this disease but with little or poor effect. Due to the lack of effective monotherapy for retinal vein occlusions, there is probably a need to combine the therapy approaches (Fig. 4, Ref. 24). Full Text in PDF www.elis.sk. PMID- 22502755 TI - Gastrointestinal stromal tumour (GIST) from the point of view of a general surgeon. AB - Authors present the current knowledge about pathology of gastrointestinal stromal tumours (GISTs), their symptoms and diagnostics. They present data about surgical and biological therapy of GISTs and relation between them based on literature. This work is supplemented with the own group of 16 patients with GISTs, treated on their surgical ward in years 2003-2008. General surgeon meets GISTs in unclear diagnosed tumours and when encountering their complications. Recurrent and metastatic tumours should be treated in centres (Tab. 6, Fig. 1, Ref. 24). Full Text in PDF www.elis.sk. PMID- 22502756 TI - Catheter ablations of supraventricular tachycardias. AB - BACKGROUND: Supraventricular tachycardias (SVT) occur at all ages. Their spectrum as well as tolerance change with increasing age. OBJECTIVES: The aim of our study was to assess the course of SVT catheter ablations in elderly patients when compared to younger population. METHODS: The course of the SVT radiofrequency catheter ablation (RFCA) in the group of 288 patients, who underwent catheter ablation at our department during 24 months was retrospectively evaluated. Patients were divided into two subgroups according to age. In the first group 142 patients younger than 65 years were included and 146 patients aged 65 years or more in the second group. In both groups, the occurrence of heart rhythm disorders, fluoroscopy time and the incidence of complications with varying severity were observed. RESULTS: Life-threatening complications were observed only in three patients from the first group (one pulmonary embolism and two unintended complete atrioventricular blocks). Serious complications included a haemopericardium requiring a pericardial drainage in two cases and an arterial venous fistula in one patient in the first group, and one retroperitoneal heamatoma in the second group. Minor complications represented by one heamatoma larger than 5x5cm occurred in one patient from each group. The occurrence of complications as well as average fluoroscopy time were not correlated between the groups. CONCLUSION: Based on our experience, radiofrequency catheter ablation of SVT in elderly patients is a safe procedure when indicated correctly. Taking into account the physical status of patients in this age group it is advisable to simplify and thus shorten the procedure (Tab. 1, Ref. 13). Full Text in PDF www.elis.sk. PMID- 22502757 TI - Root-end resection. AB - AIM: The aim of the retrospective clinical study was to analyse a complex of patients who underwent a root end resection in the Department of Dentistry and Maxillofacial Surgery, Comenius University, St. Elisabeth Hospital, Bratislava, Slovakia between January 2006 and December 2009 on the small surgery court. PATIENTS: A total number of 285 patients who underwent root end resection. METHODS: Factors examined include sex, patients age structure, total number of resected teeth and their position in upper or lower jaw and the 10 most resected teeth. RESULTS: From 285 patients 103 (36.14 %) were males and 182 (63.86 %) were females. A total number of 378 root end resections was performed, 55 (14.55 %) in the lower jaw and 323 (85.45 %) in the upper jaw. The most resected teeth are from the first and second quadrant. CONCLUSION: There is a decrease trend by the number of patients who underwent root end resection and teeth which were resected in the timeline between 2006-2009. This process is positive and matches the worldwide trend, by making better and successfull endodontic treatment which results in healing of periapical pathology without the need of root end resection (Tab. 2, Fig. 2, Ref. 20). Full Text in PDF www.elis.sk. PMID- 22502758 TI - Traumatic haemarthrosis of the knee -- indication to acute arthroscopy. AB - BACKGROUND AND AIMS: The most common mechanisms of the knee injuries are distortions and contusions. Fairly often they will result in hemarthrosis. The purpose of this study was to evaluate the findings in patients with acute traumatic hemarthrosis of the knee and based on these findings estimate the necessity of acute artroscopic examination with therapeutic procedure. MATERIAL AND METHODS: In the years 2007 and 2009 a total of 266 patients underwent acute arthroscopic examination in Department of Traumatology the Faculty Hospital Brno after the acute knee trauma. Patients with other intraarticular bone fractures were excluded. RESULTS: The ruptures of the ACL were the most common findings (52 %), meniscal tear (27 %), dislocation of the patella (11 %) and chondral or subchondral fractures were (13 %). In 224 (84 %) cases was performed artroscopic therapeutic procedure and in only 43 (16 %) case was performed routine arthroscopic examination. CONCLUSIONS: Based on our findings we believe that arthroscopic examination is necessary in patients with acute traumatic haemarthrosis of the knee and it is better methods like NMR examination because is provided to execute therapeutic procedure (Tab. 1, Fig. 2, Ref. 8). Full Text in PDF www.elis.sk. PMID- 22502759 TI - Anogenital squamous cell carcinoma in neglected patient. AB - Skin squamous cell carcinomas (SCCs) are arguably the second most common carcinoma of the skin and are responsible for the majority of non-melanoma skin cancer deaths. Gynecologist treated a Caucasian 56-years old female patient for genital wart with podophyllotoxin cream. She did not achieve complete response and therefore she has interrupted the therapy and the collaboration with the gynecologist. At the time of evaluation the lesion had a size of man's palm in anogenital region and showed characteristic features of neoplasm. The regional lymph nodes have produced infiltrated painful bubo. PCR analysis for HPV proved negative. Histopathology revealed well-differentiated squamous cell keratinizing carcinoma from the tumor as well as from the regional lymph node packet. Staging computed tomography scans proved negative and pelvis scans disclosed regional lymphadenopathy underlying the tumor. Palliative radiation therapy (by linear accelerator) was administered for the oversized tumor to the total TD 50.0Gy. The patient died 6 months after diagnostic assessment from cardio-respiratory failure. Staging computed tomography before her death did not disclose distinct metastases in her inner organs. Well-differentiated squamous cell keratinizing carcinoma could be growing endophytically affecting the underlying adipose tissue and musculature, with spreading into the regional lymph nodes. The rate of metastases into inner organs seems to vary according to the aggressiveness and metastatic behavior of each SCC. The case report calls for attention to the importance of collaboration among various specialists assisting in the diagnosis and management of skin neoplasm (Fig. 5, Ref. 12). Full Text in PDF www.elis.sk. PMID- 22502760 TI - Successful radiotherapy treatment of lacrimal gland infiltration in patient with Sjogren?s syndrome. AB - OBJECTIVE: To present a single case report on successful radiotherapy treatment of lacrimal gland infiltration in patient with Sjogren?s syndrome. BACKGROUND: Radiotherapy is occasionally used for the treatment of benign disorders. There is no report on use of radiotherapy for local treatment of the Sjogren?s syndrome in the literature. METHODS: Female patient with lacrimal gland involvement as a part of Sjogren?s syndrome with diplopia and visus deterioration was treated by radiotherapy with eye shielding. RESULTS: Regression of the infiltration with full restoration of visus and minimal acute radiation reaction was achieved. CONCLUSION: A case report of successful use of local radiotherapy in the treatment of lacrimal gland affected by Sjogren?s syndrome is presented (Fig. 3, Ref. 6). Full Text in PDF www.elis.sk. PMID- 22502761 TI - Should routine screening for celiac disease be considered before starting interferon/ribavirin treatment in patients affected by chronic hepatitis C or not? PMID- 22502763 TI - Vertigo in childhood: a methodological approach. AB - Children complaints dizziness merit meticulous evaluation to differentially diagnose a vestibular disease. A syndrome mimicking certain classic signs and symptoms of adult vestibular disorders may be presents in children, such as benign paroxysmal positional vertigo, usually associated with aging. Benign paroxysmal vertigo, in which migraine is a manifestation, with sudden onset of dizziness is a rare peripheral vestibular disorder that is commonly ignored or misdiagnosed. This review covers the development of the diagnosis, evaluation and treatment approaches of vertigo of childhood, a valid support for physician that approach dizzy children (Ref. 25). Full Text in PDF www.elis.sk. PMID- 22502762 TI - The functional morphology of the thymus -- new views on this forgotten organ. PMID- 22502764 TI - Novel use of an exchange catheter to facilitate intubation with an Aintree catheter in a tall patient with a predicted difficult airway: a case report. AB - INTRODUCTION: The Aintree intubating catheter (Cook(r) Medical Inc., Bloomington, IN, USA) has been shown to successfully facilitate difficult intubations when other methods have failed. The Aintree intubating catheter (Cook(r) Medical Inc., Bloomington, IN, USA) has a fixed length of 56 cm, and it has been suggested in the literature that it may be too short for safe use in patients who are tall. CASE PRESENTATION: We present the case of a 32-year-old, 180 cm tall Caucasian woman with a predicted difficult airway who presented to our facility for an emergency cesarean section. After several failed intubation attempts via direct laryngoscopy, an airway was established with a laryngeal mask airway. After delivery of a healthy baby, our patient's condition necessitated tracheal intubation. A fiber-optic bronchoscope loaded with an Aintree intubating catheter (Cook(r) Medical Inc., Bloomington, IN, USA) was passed through the laryngeal mask airway into the trachea until just above the carina, but was too short to safely allow for the passage of an endotracheal tube. CONCLUSIONS: We present a novel technique in which the Aintree intubating catheter (Cook(r) Medical Inc., Bloomington, IN, USA) was replaced with a longer (100 cm) exchange catheter, over which an endotracheal tube was passed successfully into the trachea. PMID- 22502765 TI - Effects of clinical and laboratory variables at admission and of in-hospital treatment with cardiovascular drugs on short term prognosis of ischemic stroke. The GIFA study. AB - INTRODUCTION: No information exists, to our knowledge, about the possible role of cardiovascular drug administration in the acute phase of ischemic stroke and possible effects on stroke outcome. The aim of our study was to evaluate the relationship between in-hospital treatment with cardiovascular drugs in patients with acute ischemic stroke and some outcome indicators. METHODS AND RESULTS: 1096 subjects enrolled in the GIFA study, who had a main discharge diagnosis of ischemic stroke represent the final sample. Drugs considered for the analysis were the following: ACE-inhibitors (ACEI), angiotensin II receptor blockers (ARBs), statins, calcium-channel-blockers (CCBs), antiplatelet (APL) drugs, antivitamin-k (VKAs), and heparins. As outcome indicators we choose in-hospital mortality, cognitive function evaluated by Hodkinson Abbreviated Mental Test (HAMT), and functional status evaluated by activity daily living (ADL). Indicators of a good outcome were: no in-hospital mortality, HAMT >6 and 0 ADL impaired. Patients with a good outcome showed a higher rate of in-hospital treatment with ACE-inhibitors, calcium-channel blockers and a lower rate of pre treatment with heparin. CONCLUSIONS: Our study suggests that if a patient with acute ischemic stroke has higher SBP at admission, higher total cholesterol plasma levels, a lower Charlson index and is treated with ACE-inhibitors, calcium channel blockers and antiplatelet drugs, the short term outcome is better in terms of in-hospital mortality and functional indicators such as cognitive and functional performance at discharge. PMID- 22502766 TI - Nitrogen source and growth stage of Candida albicans influence expression level of vacuolar aspartic protease Apr1p and carboxypeptidase Cpy1p. AB - Vacuoles play an important role in the physiology of pathogenic Candida spp. However, information on Candida albicans vacuolar enzymes, their properties, and regulation is scarce. Expression of the genes APR1 and CPY1 encoding vacuolar aspartic protease and serine carboxypeptidase, respectively, was analyzed using a clinical isolate of C. albicans. The transcription of both APR1 and CPY1 was upregulated in midexponential phase, together with increasing size of the vacuoles, when C. albicans was cultivated in yeast extract-peptone-dextrose agar at 30 degrees C. However, simultaneous upregulation of protein synthesis occurred only for Cpy1p. Analysis of APR1 and CPY1 expression under nitrogen limited conditions revealed that the genes were regulated on both the transcriptional and translational levels and detectable amounts of Apr1p were synthesized only when C. albicans was grown in nitrogen-limited media. PMID- 22502767 TI - Evidence that an APOE epsilon4 'double whammy' increases risk for Alzheimer's disease. AB - Temporal lobe epilepsy (TLE) is associated with some of the same neuropathological features as those reported for early stages of typical Alzheimer's disease (AD). The APOE epsilon4 allele is associated with a gene-dose dependent increase in AD risk and in the severity of amyloid-beta (Abeta) pathology. In a study published in the current BMC Medicine, Sue Griffin and colleagues studied markers of brain resilience in the amputated temporal lobes of TLE patients. They discovered compelling evidence that the APOE epsilon3 isoform in TLE patients is apparently more neuroprotective from Abeta toxicity than is the APOE epsilon4 isoform, as shown by the reduced levels of neuronal damage, glial activation, and expression of IL-1alpha in the APOE epsilon3/epsilon3 brains. This result points to a new property of APOE isoforms: not only are APOE epsilon4 alleles associated with increased brain amyloid plaque burden, but these alleles are also apparently inferior to APOE epsilon3 alleles in conveying resistance to Abeta neurotoxicity. This 'double whammy' result opens up a new direction for studies aimed at elucidating the relevant neurobiological activities of APOE isoforms in the pathogenesis of AD. PMID- 22502768 TI - Duration of exposure to cranial vault surgery: associations with neurodevelopment among children with single-suture craniosynostosis. AB - OBJECTIVE: To evaluate associations between neurodevelopment and exposure to surgery and anesthetic agents in children with single-suture craniosynostosis (SSC). BACKGROUND: Young children with SSC have unexplained neurodevelopmental delays. The possible contributions of factors related to cranial vault surgery - including anesthesia - have not been previously examined. METHODS/MATERIALS: Two anesthesiologists reviewed the surgical records of 89 infants (70 had complete data). Primary exposures were duration of surgery and anesthesia and total duration of inhaled anesthesia (at age 6 months on average). Outcomes were the cognitive and motor scores from the Bayley Scales of Infant Development-II and language scores from the Preschool Language Scale, 3rd edition, given at age 36 months. Linear regression using robust standard error estimates was performed, adjusting for age at surgery and suture site. RESULTS: Anesthesia duration ranged from 155 to 547 min. For every 30-min increase in anesthesia duration, the estimated average decrease in developmental test scores ranged from 1.1 to 2.9 (P ranged from <0.001 to 0.30). Similar, but weaker findings were observed with surgery duration and total duration of inhaled anesthesia. Inverse relations between exposure amounts and neurodevelopment were stronger in children with nonsagittal synostosis. CONCLUSIONS: Average neurodevelopmental scores were lower among children experiencing longer surgeries and higher exposures to inhaled anesthesia. These associations may be due to anesthesia exposure, nonspecific effects of surgery, or unmeasured variables that correlate with surgery duration. Further study of potential causal mechanisms is warranted. PMID- 22502769 TI - Use of thiazolidinedione and cancer risk in Type 2 diabetes: the Hong Kong diabetes registry. AB - We examined possible anticancer effects of thiazolidinediones (TZDs) in 6074 Chinese with Type 2 diabetes free of cancer at enrolment. During a median follow up of 4.93 years, 270 patients developed cancer. Use of TZDs was associated with reduced risk of cancer in a dose-response manner in multivariable analysis. PMID- 22502770 TI - Patient-reported quality of life during radiation treatment for localized prostate cancer: results from a prospective phase II trial. AB - Study Type--Therapy (cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Patient-reported quality of life (QoL) in prostate cancer is recognized as an important outcome, and has been shown in multiple studies to capture the incidence and timing of patient symptoms more accurately than physician-graded toxicity reports. Although the long-term QoL after completing radiation therapy (RT) has been previously studied, patient experience during RT is not well described in the literature. The present study collected patient-reported QoL during RT in a prospective phase II clinical trial. The study describes in detail the time course and severity of gastrointestinal and genitourinary symptoms during radiation, providing clinically useful information for patients and physicians considering RT during the treatment decision-making process. OBJECTIVE: * To evaluate data collected from a phase II trial to describe the time course and trajectory of patient-reported acute urinary and bowel symptom development during radiation therapy (RT) for prostate cancer. PATIENTS AND METHODS: * In all, 100 patients with intermediate- or high-risk prostate cancer received 72 Gy of RT to the prostate and seminal vesicles, with 6 months of concurrent androgen deprivation therapy; a rectal balloon was used for prostate immobilization. * Patients completed the validated Prostate Cancer Symptom Indices questionnaire every 1-2 weeks, reporting urinary and bowel symptoms on a four- or five-point Likert scale. * A score of >= 3 in a symptom is associated with clinically meaningful distress. Cumulative incidence of each symptom is reported. Bonferroni corrections of P values were used to adjust for multiple comparisons. RESULTS: * Urinary symptoms were frequent at baseline and worsened during treatment. By the end of RT, 28-50% of patients developed clinically meaningful obstructive and irritative urinary symptoms. * Acute bowel symptoms were less frequent. Each bowel symptom increased in frequency by 9-26% from baseline to end of RT. * Urinary incontinence was rare. * Overall, symptom burden at the end of treatment was modest. CONCLUSIONS: * Urinary symptoms were common during RT, and bowel symptoms were less frequent. * These results inform patients and physicians during the decision-making process about potential patient quality of life experiences during RT, and also provide a benchmark for comparative effectiveness studies against newer treatments and technologies. PMID- 22502771 TI - Analgesic benefits of preincisional transversus abdominis plane block for abdominal aortic aneurysm repair. PMID- 22502772 TI - Spectral entropy monitoring reduces anesthetic dosage for patients undergoing off pump coronary artery bypass graft surgery. AB - OBJECTIVES: The measurement of the depth of anesthesia is of clinical interest for patients undergoing off-pump coronary artery bypass graft (OPCAB) surgery in order to avoid intraoperative awareness and cardiac depression. Entropy recently was introduced as a monitor of anesthetic depth. This study was conducted to investigate the feasibility of entropy monitoring during the conduct of OPCAB surgery and to find out whether it reduced the anesthetic dosage for patients undergoing OPCAB surgery. DESIGN: A prospective, randomized, single-blind, controlled study. SETTING: A teaching hospital. PARTICIPANTS: Seventy patients scheduled for OPCAB surgery were randomized to receive propofol-sufentanil anesthesia either with the entropy values visible (the entropy group, n = 35) or without the entropy values visible (the control group, n = 35). INTERVENTIONS: In the entropy group, propofol and sufentanil infusion rates were titrated to maintain a state entropy (SE) value of 45 to 55 and a response entropy (RE)-SE difference below 10 U. In the control group, patients were anesthetized to keep the heart rate and blood pressure within 25% of the baseline values. MEASUREMENTS AND MAIN RESULTS: The course of surgery, the consumption of anesthetics, and intraoperative recall were recorded. Plasma levels of adrenocorticotropic hormone (ACTH) and cortisol were measured. The average SE during anesthesia was 50 +/- 5 in the entropy group; the entropy values were lower in the control group (p < 0.05). Compared with the control group, propofol and sufentanil consumption were significantly less in the entropy group, which shortened the time to tracheal extubation (p < 0.05). Significantly, patients in the control group needed more phenylephrine to maintain arterial pressure than patients in the entropy group (p < 0.05). ACTH and cortisol release were prevented completely, and there was no intraoperative recall reported in the 2 groups. CONCLUSIONS: Entropy monitoring reduced propofol and sufentanil dosage for patients undergoing OPCAB surgery. PMID- 22502773 TI - Synthesizing specificity: multiple approaches to understanding the attack and defense of plants. PMID- 22502774 TI - Trying to make sense of retromer. AB - Retromer is a cytosolic protein complex which binds to post-Golgi organelles involved in the trafficking of proteins to the lytic compartment of the cell. In non-plant organisms, retromer mediates the recycling of acid hydrolase receptors from early endosomal (EE) compartments. In plants, retromer components are required for the targeting of vacuolar storage proteins, and for the recycling of endocytosed PIN proteins. However, there are contradictory reports as to the localization of the sorting nexins and the core subunit of retromer. There is also uncertainty as to the identity of the organelles from which vacuolar sorting receptors (VSRs) and endocytosed plasma membrane (PM) proteins are recycled. In this review we try to resolve some of these conflicting observations. PMID- 22502775 TI - Biosynthesis of amphetamine analogs in plants. AB - Amphetamine analogs are produced by plants in the genus Ephedra and by Catha edulis, and include the widely used decongestants and appetite suppressants pseudoephedrine and ephedrine. A combination of yeast (Candida utilis or Saccharomyces cerevisiae) fermentation and subsequent chemical modification is used for the commercial production of these compounds. The availability of certain plant biosynthetic genes would facilitate the engineering of yeast strains capable of de novo pseudoephedrine and ephedrine biosynthesis. Chemical synthesis has yielded amphetamine analogs with myriad functional group substitutions and diverse pharmacological properties. The isolation of enzymes with the serendipitous capacity to accept novel substrates could allow the production of substituted amphetamines in synthetic biosystems. Here, we review the biology, biochemistry and biotechnological potential of amphetamine analogs in plants. PMID- 22502776 TI - Aggregation and dissolution of silver nanoparticles in natural surface water. AB - This study investigated aggregation and silver release of silver nanoparticles suspended in natural water in the absence and presence of artificial sun light. The influence of the capping layer was investigated using uncoated particles and particles coated with citrate or Tween 80. The experiments were conducted over 15 days in batch mode using a river water matrix. Silver release was monitored over this time while the aggregation state and morphological changes of the silver nanoparticles were tracked using dynamic light scattering and transmission electron microscopy. Results indicate sterically dispersed particles coated with Tween released silver quicker than did bare- and citrate-coated particles, which rapidly aggregated. A dissolved silver concentration of 40 MUg/L was reached after just 6 h in the Tween-coated particle systems, accounting for ca. 3% of the total silver. Similar levels of dissolved silver were reached in the uncoated and citrate-coated systems at the end of the 15 days. Silver release was not significantly impacted by the artificial sun light; however, the light (and citrate) imparted significant morphological changes to the particles. Their impact was masked by aggregation, which seemed to be the controlling process in this study. PMID- 22502777 TI - Immune hemolytic anemia caused by drugs. AB - INTRODUCTION: Drug-induced immune hemolytic anemia (DIIHA) is a rare cytopenia; about 130 drugs have been incriminated. The antibodies causing DIIHA can be i) drug-independent (drug not needed to be present to detect antibodies in vitro) DIIHA caused by this type of antibody presents clinically and serologically as an autoimmune hemolytic anemia (AIHA) with red cell (RBC) autoantibodies in patients' sera and in eluates from their RBCs; or (2) drug-dependent (antibodies react in vitro with RBCs only in the presence of drug, on the RBC membrane or when added to the patient's plasma and RBCs). AREAS COVERED: Literature is reviewed regarding pathophysiology of DIIHA (mechanisms; incidence of drugs involved; the clinical, hematological, and serological characteristics of the most common antibodies causing DIIHA). EXPERT OPINION: DIIHA is often poorly investigated and many reports do not provide data to support the diagnosis (i.e., no serology to support an immune etiology). The three most common drugs currently causing DIIHA are piperacillin, cefotetan, and ceftriaxone. All three (especially piperacillin) can cause in vitro and in vivo effects mimicking AIHA, and in transfused patients, hemolytic transfusion reactions. It is important to exclude DIIHA in such patients as the only treatment needed is to discontinue the drug. PMID- 22502778 TI - Phytochemical studies and antioxidant activity of two South African medicinal plants traditionally used for the management of opportunistic fungal infections in HIV/AIDS patients. AB - BACKGROUND: It has been observed that perturbations in the antioxidant defense systems, and consequently redox imbalance, are present in many tissues of HIV infected patients. Hence, the exogenous supply of antioxidants, as natural compounds that scavenge free radicals, might represent an important additional strategy for the treatment of HIV infection. The aim of this study was therefore to analyse the phytochemical constituents and antioxidant potential of Gasteria bicolor Haw and Pittosporum viridiflorum Sims., two South African plants traditionally used for the management of opportunistic fungal infections (OFIs) in AIDS patients. METHODS: The in vitro antioxidant properties of the two plants were screened through DPPH (1,1-diphenyl-2-picrylhydrazyl), NO (nitric oxide), H2O2 (hydrogen peroxide) radical scavenging effects and reducing power assays. Phytochemical studies were done by spectrophotometric techniques. RESULTS: There were no significant differences in the flavonoid and proanthocyanidins contents between the leaves and bark extracts of Gasteria bicolor and Pittosporum viridiflorum respectively, while the total phenolic content of the bark extract of P. viridiflorum was significantly higher than that of G. bicolor leaf. The acetone extracts of both plants indicated strong antioxidant activities. CONCLUSION: The results from this study indicate that the leaves and stem extracts of Gasteria bicolor and Pittosporum viridiflorum respectively possess antioxidant properties and could serve as free radical inhibitors, acting possibly as primary antioxidants. Since reactive oxygen species are thought to be associated with the pathogenesis of AIDS, and HIV-infected individuals often have impaired antioxidant defenses, the inhibitory effect of the extracts on free radicals may partially justify the traditional use of these plants in the management of OFIs in HIV patients in South Africa. PMID- 22502779 TI - On the flexibility of letter position coding during lexical processing: evidence from eye movements when reading Thai. AB - Previous research supports the view that initial letter position has a privileged role in comparison to internal letters for visual-word recognition in Roman script. The current study examines whether this is the case for Thai. Thai is an alphabetic script in which ordering of the letters does not necessarily correspond to the ordering of a word's phonemes. Furthermore, Thai does not normally have interword spaces. We examined whether the position of transposed letters (internal, e.g., porblem, vs. initial, e.g., rpoblem) within a word influences how readily those words are processed when interword spacing and demarcation of word boundaries (using alternating bold text) is manipulated. The eye movements of 54 participants were recorded while they were reading sentences silently. There was no apparent difference in degree of disruption caused when reading initial and internal transposed-letter nonwords. These findings give support to the view that letter position encoding in Thai is relatively flexible and that actual identity of the letter is more critical than letter position. This flexible encoding strategy is in line with the characteristics of Thai--that is, the flexibility in the ordering of the letters and the lack of interword spaces, which creates a certain level of ambiguity in relation to the demarcation of word boundaries. These findings point to script-specific effects operating in letter encoding in visual-word recognition and reading. PMID- 22502781 TI - Clinical features of brain motor control and influence in upper motor neuron dysfunction. PMID- 22502780 TI - Prevalence and determinants of depression in Mexican patients with Parkinson's disease. AB - OBJECTIVE: To assess the prevalence and associated factors of depression in a Mexican Parkinson's disease (PD) population. BACKGROUND: Depressive symptoms are frequent in PD and have been recognized as a major determinant of quality of life. Only two previous studies have partially addressed depression in Mexican PD patients. METHODS: One hundred forty-seven non-demented PD patients were recruited at the movement disorder specialist clinic at the National Institute of Neurology and Neurosurgery, Mexico City. The following sociodemographic variables were collected: gender, age, age at onset, disease duration and disease severity in terms of Hoehn and Yahr stage. PDQ-8, NMSQuest and Beck Depression Inventory (BDI) were applied to all participants. RESULTS: One hundred forty-seven patients were included (49.7% female). The mean age of the sample was 62.1 +/- 11.7 years, the mean age at diagnosis was 55.8 +/- 12.3 and the mean duration of the disease was 6.3 +/- 5 years. A total of 49 (33.3%) patients were diagnosed with current depression. Depressed patients also scored higher in the NMSQuest even when depression/anxiety items were excluded. Differences were found in gender, UPDRS III score and HY stage, but after the logistic regression analysis was performed only the NMSQuest score and low education remained as statistically significant factors for depression in Mexican PD patients. CONCLUSIONS: Depression prevalence in PD Mexican patients is similar to other international reports. The main associated factor was the presence of non-motor symptoms. PMID- 22502782 TI - Symptomatic orthostatic tremor with progressive cognitive impairment in spinal cord lesions. PMID- 22502783 TI - Reduced percentage of neurocysticercosis cases among patients with late-onset epilepsy in the new millennium. AB - OBJECTIVE: To determine if the number of neurocysticercosis cases among patients with late-onset epilepsy has decreased over the past two decades. DESIGN: Retrospective cohort study of 431 consecutive patients with recurrent seizures starting after the age of 20 years evaluated at our Institution from 1990 to 2009. METHODS: Patients were classified according to the year in which they were first seen. Group I included 129 patients evaluated between 1990 and 1994, Group II included 108 patients evaluated between 1995 and 1999, Group III included 106 patients evaluated between 2000 and 2004, and Group IV included 88 patients evaluated between 2005 and 2009. We correlated the percentage of persons with cryptogenic and symptomatic epilepsy between the groups to determine if there was any change in the causes of late-onset epilepsy. RESULTS: One hundred seventy-one patients had cryptogenic and 260 had symptomatic epilepsy. Common causes of symptomatic epilepsy were neurocysticercosis in 120 cases, cerebrovascular disease in 68, and brain tumors in 40. We found a reduction in the number of patients with symptomatic epilepsy (p=0.0007) as well as a reduction in the number of neurocysticercosis cases (p=0.0004) over the study years. There was a reduction in the weight of neurocysticercosis as an etiological factor for symptomatic late-onset epilepsy related to a drop in the number of patients with this condition evaluated between 2005 and 2009 (p=0.0045). CONCLUSION: The number of neurocysticercosis cases among patients with late-onset epilepsy has changed over the years. This parasitic disease is no longer the most common cause of symptomatic late-onset epilepsy in our population. PMID- 22502784 TI - Simultaneous combined single stage removal of immature teratoma at anterior skull base: a case report. PMID- 22502785 TI - Decompressive craniectomy after intravenous tissue plasminogen activator administration for stroke. AB - OBJECTIVE: Intravenous tissue plasminogen activator (IV tPA) is an approved treatment for acute ischemic stroke. However, the effects of decompressive craniectomy (DC) after IV tPA administration for ischemic stroke are still largely unknown. The aim of this study was to investigate the safety and outcomes of DC after IV tPA administration. METHODS: We retrospectively reviewed patients who underwent DC for malignant hemispheric infarction. We compared 20 patients who underwent DC after IV tPA administration with another 20 patients who underwent DC without prior IV tPA administration. RESULTS: The patient characteristics did not differ between the DC patients with and without prior IV tPA administration. New intracranial bleeding or worsening of pre-existing ICH occurred in two patients (10%) in each group. Furthermore, the rates of an mRS score of 4-6, 5 or 6, and 6 did not differ significantly between the two groups. CONCLUSION: DC may be a safe and useful surgical procedure for space-occupying edema after IV tPA administration for acute stroke. PMID- 22502786 TI - Pontine and extrapontine myolinolysis associated with hypernatraemia. PMID- 22502788 TI - Restorative neurology and motor control. Preface. PMID- 22502787 TI - Myotonic dystrophy type 2 and multiple sclerosis: case report. PMID- 22502789 TI - Ventriculitis revealing Bing-Neel syndrome in a patient without Waldenstrom's macroglobulinemia. PMID- 22502790 TI - A randomized trial comparing tamoxifen therapy vs. tamoxifen prophylaxis in bicalutamide-induced gynecomastia. AB - BACKGROUND: Tamoxifen (TAM) has been shown to be active against the bicalutamide induced breast events (BEs) gynecomastia, and breast pain in patients with prostate cancer (PC). Optimal doses and schedules are not yet established. Debate still exists about whether prophylaxis with TAM is more effective than treatment of BEs when diagnosed. The results of a randomized study comparing TAM prophylaxis vs. TAM therapy are presented. METHODS: One hundred seventy-six patients with prostate cancer (PC) who were candidates for bicalutamide monotherapy were randomized to receive TAM 20 mg daily orally within 1 month from the onset of BEs (arm A) vs. TAM 10 mg daily starting simultaneously with bicalutamide (arm B). TAM was administered for up to 1 year. BEs were evaluated by a self-administered visual analogue scale. Neither ultrasonography nor calipers were used to measure the degree of gynecomastia. RESULTS: In arm A, BEs showed a prevalence, increasing with time up to 78.3%. After therapy with TAM they persisted in 27.7% of cases. Two patients (3%) interrupted TAM therapy because of dizziness, and 3 patients (4%) interrupted bicalutamide therapy because of painful gynecomastia. In arm B, the prevalence of BEs was 35% after 12 months of therapy. The difference in BEs between the 2 arms was statistically significant (P < .0001). The differences in prevalence of gynecomastia and breast pain between the 2 arms both favored TAM prophylaxis (P < .0001 and P < .001, respectively). Up to 35% of patients had BEs of low intensity, never requiring bicalutamide withdrawal. Two patients (3%) interrupted the treatment because of gastrointestinal intolerance. No difference emerged between the 2 arms in terms of prostate-specific antigen (PSA) response, plasma testosterone levels, and tumor progression. CONCLUSION: Bicalutamide-induced BEs can be prevented to a significant degree by prophylaxis with TAM 10 mg/day or effectively treated with TAM therapy 20 mg/day. Persisting BEs are of higher intensity after therapy than after prophylaxis. PMID- 22502791 TI - Theoretical considerations on mechanisms of harvesting cells cultured on thermoresponsive polymer brushes. AB - Poly (N-isopropylacrylamide) (PNIPAM) brushes and hydrogels serve as temperature responsive cell culture substrates. The cells adhere at 37 degrees C and are detached by cooling to below the lower critical solution temperature T(LCST) ~ 32 degrees C, an effect hitherto attributed to change in PNIPAM hydration. The article proposes a mechanism coupling the change of hydration to integrin mediated environmental sensing for cell culture on brushes and hydrogels in serum containing medium. Hydration is associated with swelling and higher osmotic pressure leading to two effects: (i) The lower osmotic pressure in the collapsed brush/hydrogel favors the adsorption of serum borne extracellular matrix (ECM) proteins enabling cell adhesion; (ii) Brush/hydrogel swelling at T < T(LCST) gives rise to a disjoining force f(cell) due to confinement by the ventral membrane of a cell adhering via integrin-ECM bonds. f(cell) places the integrin ECM bonds under tension thus accelerating their dissociation and promoting desorption of ECM proteins. Self consistent field theory of PNIPAM brushes quantifies the effect of the polymerization degree N, the area per chain Sigma, and the temperature, T on ECM adsorption, f(cell) and the dissociation rate of integrin-ECM bonds. It suggests guidelines for tuning Sigma and N to optimize adhesion at 37 degrees C and detachment at T < T(LCST). The mechanism rationalizes existing experimental results on the influence of the dry thickness and the RGD fraction on adhesion and detachment. PMID- 22502792 TI - Contrast enhanced breast MRI: spatial displacement from prone to supine patient's position. Preliminary results. AB - OBJECTIVE: To estimate the spatial displacement of breast lesions and nipples in MR images when the patient is moved from the standard prone to a supine position close to ultrasound (US) or surgical setting. MATERIALS AND METHODS: Eleven patients underwent breast MRI in prone position with dynamic 3D T1-weighted sequences using 0.1 mmol/kg gadobenate dimeglumine. Subsequently, the patient was repositioned in supine position and a 3D volumetric interpolated breathhold examination sequence was acquired using a thoracic surface coil. For both positions we measured the following minimal distances: (A) from lesion margin to the coronal plane passing through the anterior surface of the sternum, antero posterior, on native axial images; (B) from lesion margin to the medial sagittal plane, on native axial images, latero-medial; (C) from lesion margin to the axial plane passing through the tracheal bifurcation, cranio-caudal; (D) from lesion margin to the thoracic wall/pectoral muscle, on native axial images; (E) from lesion margin to the skin, on native axial images; (F) from lesion margin to the base of the nipple, on oblique reconstructions. Measurements from A to D were also obtained for each nipple. The prone-to-supine spatial displacement was calculated as the absolute difference between the measurement obtained in supine position and the same measurement obtained in prone position. Displacements were presented as mean +/- standard deviation and median in parenthesis. RESULTS: Lesion displacements were (mm): A = 60 +/- 38 (55); B = 40 +/- 26 (41); C = 41 +/ 33 (34); D = 32 +/- 31 (27); E = 6 +/- 5 (7); and F = 8 +/- 6 (7). Nipple displacements were (mm): A = 84 +/- 44 (91); B = 54 +/- 24 (56); C = 27 +/- 15 (24); and D = 48 +/- 20 (48). CONCLUSION: These preliminary results show that preoperative breast MRI in prone position implies a median lesion displacement of about 3-6 cm along the three orthogonal directions in comparison with supine MRI. Conversely, median lesion-to-skin and lesion-to-nipple displacements were less than 1cm, even though nipple displacements were similar to or larger than those of lesions. The lesion-to-nipple distance may be the most reliable measure to be used for second look breast US. Larger studies are warranted in order to define an optimized breast MRI protocol in the preoperative setting. PMID- 22502793 TI - Addition of intra-articular hyaluronate injection to physical therapy program produces no extra benefits in patients with adhesive capsulitis of the shoulder: a randomized controlled trial. AB - OBJECTIVE: To compare the efficacy of intra-articular hyaluronic acid (HA) injections plus physical therapy (PT) with that of PT alone for the treatment of adhesive capsulitis (AC) of the shoulder. DESIGN: Prospective, randomized controlled trial. SETTING: Rehabilitation and orthopedics department of a private teaching hospital. PARTICIPANTS: Patients (N=70) with AC of the shoulder were randomly placed into either of the following treatment groups: group 1, HA injections with PT (HAPT group); or group 2, PT alone (PT group). INTERVENTIONS: The patients in group 1 received intra-articular glenohumeral joint injections of HA, 20mg, once per week for 3 consecutive weeks and also participated in a PT program for 3 months. The patients in group 2 received PT alone. MAIN OUTCOME MEASURES: Active and passive range of motion (ROM) of the affected shoulder, pain, disability, and quality of life. RESULTS: Both groups experienced improvements in terms of pain, disability, and quality of life after the treatments; furthermore, the active and passive ROM improved linearly with increasing treatment duration. When the groups were compared, no significant group effect was found for any of the outcome measurements. CONCLUSIONS: Intra articular HA injections did not produce added benefits for patients with AC of the shoulder who were already receiving PT. Thus, the use of intra-articular HA injections for patients with AC of the shoulder should be carefully assessed to reduce unnecessary medical expenditures. PMID- 22502794 TI - Does diversity of environmental microbial exposure matter for the occurrence of allergy and asthma? AB - This review describes the recent literature on microbial exposures and protective effects for asthma and atopy. Certain microorganism-associated molecular patterns have been identified as agents that might influence the development of the immune system, which in turn leads to protective effects for asthma and atopy. Endotoxins from gram-negative bacteria were the first agents associated with a reduced risk for asthma and atopy. In later studies, beta(1->3)glucans, extracellular polysaccharides, and muramic acid from, respectively, molds and gram-positive bacteria were associated with a reduced risk of allergy and asthma separately in rural and urban populations. These results already suggested that not just one but several independent microbial signals from gram-negative and gram-positive bacteria, as well as molds, might play a role in explaining the protective effects. Recently, the diversity of microbial exposure has been associated with such a reduced risk in farmers' children. Surprisingly, the diversity of both fungal and bacterial exposure seemed to have protective effects. These results open new areas of research and create complex challenges. Methodological issues, such as environmental exposure characterization and assessment and elucidation of potential underlying mechanisms, are discussed because these aspects have a major influence on how microbial diversity can be studied in future studies in relation to protective effects for asthma and atopy. PMID- 22502795 TI - Patchy eosinophil distributions in an esophagectomy specimen from a patient with eosinophilic esophagitis: Implications for endoscopic biopsy. PMID- 22502796 TI - Effects of ultraviolet light on human serum 25-hydroxyvitamin D and systemic immune function. AB - BACKGROUND: Many immune-mediated diseases are associated with low levels of vitamin D and sunlight. UV light or supplementation with vitamin D can increase regulatory T-cell activity and prevent animal models of autoimmune disease. Increasing population vitamin D levels may therefore alleviate the burden of human immune-mediated disease. OBJECTIVE: To determine the responses of circulating 25-hydroxyvitamin D [25(OH)D] levels, regulatory T-cell numbers, and immune function to UV light exposure in patients being treated for skin disease. METHODS: Twenty-four subjects with skin disease from the North of Scotland were recruited between December and March. At baseline, and after 2 and 4 weeks of narrowband UV light exposure, we measured peripheral blood 25(OH)D level, numbers of regulatory T cells (CD4(+)CD25(hi)FoxP3(+)), and T-cell proliferative and cytokine responses to anti-CD3/CD28 stimulation. RESULTS: Median (interquartile range) narrowband UV-B received during the study was 39.1 (30.9) as standard erythema dose, comparable to a quarter of the median summer sunlight exposure received locally. This increased the 25(OH)D level from a mean +/- SD of 34 +/- 17 nmol/L to 58 +/- 16 nmol/L after 2 weeks and 78 +/- 19 nmol/L after 4 weeks. The mean proportion of circulating regulatory T cells increased from 0.5% to 1.6% CD3(+) cells, which significantly correlated with the increased 25(OH)D level. UV treatment was also followed by reduced proliferative and IL-10 responses to anti CD3/CD28 independent of the 25(OH)D level. CONCLUSION: Narrowband UV light reduces systemic immune responsiveness via the induction of regulatory T cells. Light and 25(OH)D levels may affect particular immune functions independently. The levels of serum 25(OH)D over which these effects are apparent should guide future interventions. PMID- 22502798 TI - Novel severe wheezy young children phenotypes: boys atopic multiple-trigger and girls nonatopic uncontrolled wheeze. AB - BACKGROUND: Recurrent wheezing during infancy is a heterogeneous disorder that has been associated with early-onset asthma. OBJECTIVE: To identify phenotypes of severe recurrent wheezing and therapeutic approaches. METHODS: We performed cluster analysis with 20 variables of 551 children with active asthma, younger than 36 months old, and enrolled in the Trousseau Asthma Program. RESULTS: We identified 3 independent clusters of children with wheezing. Cluster 1, mild episodic viral wheeze (n= 327), consisted of children with wheezing related only to colds (71%), mild disease (76%), and mainly normal chest x-ray results. Cluster 2, nonatopic uncontrolled wheeze (n = 157), was characterized by moderate to severe disease (91%), uncontrolled wheezing despite high doses of inhaled corticosteroids (55%), parents with asthma, and increased levels of ferritine. Cluster 3, atopic multiple-trigger wheeze (n = 67), included more children with multiple-trigger wheeze (68%) than did clusters 1 or 2; eczema (75%); a positive result from the Phadiatop Infant test (90%); increased levels of IgE, IgA, and IgG; and abnormal results from chest x-rays. In separate analysis, 1 parameter for boys (increased total level of IgE) and 2 parameters for girls (wheezing severity and increased total level of IgE) properly classified 90% of boys and 83% of girls in the appropriate cluster. Significant associations were found between overcrowding, molds and cockroaches at home, and atopic multiple-trigger wheeze and between day-care attendance and nonatopic uncontrolled wheeze in other parts. CONCLUSION: We identified different phenotypes of recurrent wheezing in young children by using cluster analysis with usual variables. These phenotypes require confirmation in longer, follow-up studies. PMID- 22502797 TI - Case-control admixture mapping in Latino populations enriches for known asthma associated genes. AB - BACKGROUND: Polymorphisms in more than 100 genes have been associated with asthma susceptibility, yet much of the heritability remains to be explained. Asthma disproportionately affects different racial and ethnic groups in the United States, suggesting that admixture mapping is a useful strategy to identify novel asthma-associated loci. OBJECTIVE: We sought to identify novel asthma-associated loci in Latino populations using case-control admixture mapping. METHODS: We performed genome-wide admixture mapping by comparing levels of local Native American, European, and African ancestry between children with asthma and nonasthmatic control subjects in Puerto Rican and Mexican populations. Within candidate peaks, we performed allelic tests of association, controlling for differences in local ancestry. RESULTS: Between the 2 populations, we identified a total of 62 admixture mapping peaks at a P value of less than 10(-3) that were significantly enriched for previously identified asthma-associated genes (P= .0051). One of the peaks was statistically significant based on 100 permutations in the Mexican sample (6q15); however, it was not significant in Puerto Rican subjects. Another peak was identified at nominal significance in both populations (8q12); however, the association was observed with different ancestries. CONCLUSION: Case-control admixture mapping is a promising strategy for identifying novel asthma-associated loci in Latino populations and implicates genetic variation at 6q15 and 8q12 regions with asthma susceptibility. This approach might be useful for identifying regions that contribute to both shared and population-specific differences in asthma susceptibility. PMID- 22502801 TI - Techno-economic evaluation of 2nd generation bioethanol production from sugar cane bagasse and leaves integrated with the sugar-based ethanol process. AB - BACKGROUND: Bioethanol produced from the lignocellulosic fractions of sugar cane (bagasse and leaves), i.e. second generation (2G) bioethanol, has a promising market potential as an automotive fuel; however, the process is still under investigation on pilot/demonstration scale. From a process perspective, improvements in plant design can lower the production cost, providing better profitability and competitiveness if the conversion of the whole sugar cane is considered. Simulations have been performed with AspenPlus to investigate how process integration can affect the minimum ethanol selling price of this 2G process (MESP-2G), as well as improve the plant energy efficiency. This is achieved by integrating the well-established sucrose-to-bioethanol process with the enzymatic process for lignocellulosic materials. Bagasse and leaves were steam pretreated using H3PO4 as catalyst and separately hydrolysed and fermented. RESULTS: The addition of a steam dryer, doubling of the enzyme dosage in enzymatic hydrolysis, including leaves as raw material in the 2G process, heat integration and the use of more energy-efficient equipment led to a 37 % reduction in MESP-2G compared to the Base case. Modelling showed that the MESP for 2G ethanol was 0.97 US$/L, while in the future it could be reduced to 0.78 US$/L. In this case the overall production cost of 1G + 2G ethanol would be about 0.40 US$/L with an output of 102 L/ton dry sugar cane including 50 % leaves. Sensitivity analysis of the future scenario showed that a 50 % decrease in the cost of enzymes, electricity or leaves would lower the MESP-2G by about 20%, 10% and 4.5%, respectively. CONCLUSIONS: According to the simulations, the production of 2G bioethanol from sugar cane bagasse and leaves in Brazil is already competitive (without subsidies) with 1G starch-based bioethanol production in Europe. Moreover 2G bioethanol could be produced at a lower cost if subsidies were used to compensate for the opportunity cost from the sale of excess electricity and if the cost of enzymes continues to fall. PMID- 22502799 TI - Mast cell TNF receptors regulate responses to Mycoplasma pneumoniae in surfactant protein A (SP-A)-/- mice. AB - BACKGROUND: Mycoplasma pneumoniae (Mp) frequently colonizes the airways of patients with chronic asthma and likely contributes to asthma exacerbations. We previously reported that mice lacking surfactant protein A (SP-A) have increased airway hyperresponsiveness (AHR) during M pneumoniae infection versus wild-type mice mediated by TNF-alpha. Mast cells (MCs) have been implicated in AHR in asthma models and produce and respond to TNF-alpha. OBJECTIVE: Determine the contribution of MC/TNF interactions to AHR in airways lacking functional SP-A during Mp infection. METHODS: Bronchoalveolar lavage fluid was collected from healthy and asthmatic subjects to examine TNF-alpha levels and M pneumoniae positivity. To determine how SP-A interactions with MCs regulate airway homeostasis, we generated mice lacking both SP-A and MCs (SP-A(-/-)Kit(W-sh/W sh)) and infected them with M pneumoniae. RESULTS: Our findings indicate that high TNF-alpha levels correlate with M pneumoniae positivity in human asthmatic patients and that human SP-A inhibits M pneumoniae-stimulated transcription and release of TNF-alpha by MCs, implicating a protective role for SP-A. MC numbers increase in M pneumoniae-infected lungs, and airway reactivity is dramatically attenuated when MCs are absent. Using SP-A(-/-)Kit(W-sh/W-sh) mice engrafted with TNF-alpha(-/-) or TNF receptor (TNF-R)(-/-) MCs, we found that TNF-alpha activation of MCs through the TNF-R, but not MC-derived TNF-alpha, leads to augmented AHR during M pneumoniae infection when SP-A is absent. Additionally, M pneumoniae-infected SP-A(-/-)Kit(W-sh/W-sh) mice engrafted with TNF-alpha(-/-) or TNF-R(-/-) MCs have decreased mucus production compared with that seen in mice engrafted with wild-type MCs, whereas burden was unaffected. CONCLUSION: Our data highlight a previously unappreciated but vital role for MCs as secondary responders to TNF-alpha during the host response to pathogen infection. PMID- 22502802 TI - Heterochronic shifts in the ossification sequences of surface- and subsurface dwelling skinks are correlated with the degree of limb reduction. AB - Scincid lizards exhibit a variety of limb anatomies which reflect the functional requirements of different modes of life. Besides surface dwellers which show neither body elongation nor limb reduction, there are numerous examples that can be arranged as increasingly serpentiform taxa moving in sand, humus or leaf litter. We explored the question of whether limb reduction and body elongation in skinks are linked to heterochronic shifts in the ossification sequences. The study material comprises skinks showing four different morphotypes: Liopholis whitii, Lerista bougainvillii, Hemiergis peronii and Saiphos equalis. Results showed that (i) scincid lizards with limb reductions exhibit an earlier onset of ossification in the cervical vertebrae, and (ii) ossification starts earlier in the pectoral girdle (scapula and coracoid) and pelvic girdle (ilium, ischium and pubis) relative to the timing of the onset in elements of the forelimbs and hind limbs. Furthermore, they show (iii) an earlier strengthening of the premaxilla, which first completes the anterior part of the dorsal cranial roof, and (iv) an earlier onset of ossification in the forelimb elements than in the equivalent elements of the hind limbs. The species showing the least limb reduction (L. bougainvillii) had the greatest developmental similarity to the normally proportioned surface-dwelling species (L. whitii). S. equalis, as the morphotype with the greatest deviation from the normally proportioned, pentadactyle form, varies the most from L. whitii. The heterochronic shifts in the ossification sequences are linked to a shift in the emphasis from limbed locomotion to trunk locomotion in the species with body elongation and/or limb reduction. PMID- 22502800 TI - Tolerance induction with T cell-dependent protein antigens induces regulatory sialylated IgGs. AB - BACKGROUND: Under inflammatory conditions, T cell-dependent (TD) protein antigens induce proinflammatory T- and B-cell responses. In contrast, tolerance induction by TD antigens without costimulation triggers the development of regulatory T cells. Under both conditions, IgG antibodies are generated, but whether they have different immunoregulatory functions remains elusive. OBJECTIVE: It was shown recently that proinflammatory or anti-inflammatory effector functions of IgG molecules are determined by different Fc N-linked glycosylation patterns. We sought to examine the Fc glycosylation and anti-inflammatory quality of IgG molecules formed on TD tolerance induction. METHODS: We administered chicken ovalbumin (OVA) with or without costimulus to mice and analyzed OVA-reactive IgG Fc glycosylation. The anti-inflammatory function of differentially glycosylated anti-OVA IgGs was further investigated in studies with dendritic cell cultures and in an in vivo model of allergic airway disease. Additionally, we analyzed the Fc glycosylation pattern of birch pollen-reactive serum IgGs after successful allergen-specific immunotherapy in patients. RESULTS: Stimulation with TD antigens under inflammatory conditions induces plasma cells expressing low levels of alpha2,6-sialyltransferase and producing desialylated IgGs. In contrast, plasma cells induced on tolerance induction did not downregulate alpha2,6 sialyltransferase expression and secreted immunosuppressive sialylated IgGs that were sufficient to block antigen-specific T- and B-cell responses, dendritic cell maturation, and allergic airway inflammation. Importantly, successful specific immunotherapy in allergic patients also induced sialylated allergen-specific IgGs. CONCLUSIONS: Our data show a novel antigen-specific immunoregulatory mechanism mediated by anti-inflammatory sialylated IgGs that are formed on TD tolerance induction. These findings might help to develop novel antigen-specific therapies for the treatment of allergy and autoimmunity. PMID- 22502803 TI - Passive mechanical properties of gastrocnemius muscles of people with ankle contracture after stroke. AB - OBJECTIVE: To investigate the mechanisms of contracture after stroke by comparing passive mechanical properties of gastrocnemius muscle-tendon units, muscle fascicles, and tendons in people with ankle contracture after stroke with control participants. DESIGN: Cross-sectional study. SETTING: Laboratory in a research institution. PARTICIPANTS: A convenience sample of people with ankle contracture after stroke (n=20) and able-bodied control subjects (n=30). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Stiffness and lengths of gastrocnemius muscle tendon units, lengths of muscle fascicles, and tendons at specific tensions. RESULTS: At a tension of 100N, the gastrocnemius muscle-tendon unit was significantly shorter in participants with stroke (mean, 436mm) than in able bodied control participants (mean, 444mm; difference, 8mm; 95% confidence interval [CI], 0.2-15mm; P=.04). Muscle fascicles were also shorter in the stroke group (mean, 44mm) than in the control group (mean, 50mm; difference, 6mm; 95% CI, 1-12mm; P=.03). There were no significant differences between groups in the mean stiffness or length of the muscle-tendon units and fascicles at low tension, or in the mean length of the tendons at any tension. CONCLUSIONS: People with ankle contracture after stroke have shorter gastrocnemius muscle-tendon units and muscle fascicles than control participants at high tension. This difference is not apparent at low tension. PMID- 22502804 TI - Balance and balance self-efficacy are associated with activity and participation after stroke: a cross-sectional study in people with chronic stroke. AB - OBJECTIVES: To (1) examine the relationships between multiple poststroke mobility variables (gait speed, walking capacity, balance, balance self-efficacy, and falls self-efficacy) and activity and participation; and (2) determine which poststroke mobility variables are independently associated with activity and participation. DESIGN: This is the primary analysis of a prospective cross sectional study completed to understand the impact of mobility on activity and participation in people with chronic stroke. SETTING: University-based research laboratory, hospitals, and stroke support groups. PARTICIPANTS: People (N=77) with stroke greater than 6 months ago were included in the study if they were referred to occupational or physical therapy for physical deficits as a result of the stroke, completed all stroke related inpatient rehabilitation, had residual functional disability, scored a >=4 out of 6 on the short, 6-item Mini-Mental State Examination, and were between the ages of 50 and 85. INTERVENTIONS: Not applicable, this is a cross-sectional data collection of 1 timepoint. MAIN OUTCOME MEASURES: We measured activity and participation with the validated International Classification of Functioning, Disability and Health Measure of Participation and Activities. Other variables included gait speed (10-meter walk), walking capacity (6-minute walk), balance (Berg Balance Scale), balance self-efficacy (Activities Specific Balance Confidence Scale), and falls self efficacy (Modified Falls Efficacy Scale). RESULTS: Only balance self-efficacy was found to be independently associated with poststroke activity (beta=-.430, P<.022, 95% confidence interval [CI], -.247 to -.021) and participation (beta= .439, P<.032, 95% CI, -.210 to -.010). CONCLUSIONS: Among people with chronic stroke, balance self-efficacy, not physical aspects of gait, was independently associated with activity and participation. While gait training continues to be important, this study indicates a need to further evaluate and address the psychological factors of balance and falls self-efficacy to obtain the best stroke recovery. PMID- 22502805 TI - Minimal detectable changes of the Berg Balance Scale, Fugl-Meyer Assessment Scale, Timed "Up & Go" Test, gait speeds, and 2-minute walk test in individuals with chronic stroke with different degrees of ankle plantarflexor tone. AB - OBJECTIVE: To determine test-retest reliability and absolute and relative minimal detectable changes at the 95% confidence level (MDC(95)) of measures to detect postural balance and lower limb movements in individuals with chronic stroke who were able to walk and had differences in ankle plantarflexor tone. DESIGN: Test retest study. Data were collected on 2 occasions, about 6 days apart. SETTING: Outpatient physical therapy clinics. PARTICIPANTS: Volunteers (N=61) with chronic stroke who were able to walk and had differences in ankle plantarflexor tone: no increase in ankle plantarflexor tone (n=12), a slight increase in ankle plantarflexor tone (n=32), and a marked increase in ankle plantarflexor tone (n=17). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Reliability and absolute and relative MDC(95) of the Berg Balance Scale (BBS), the lower limb subscale of Fugl-Meyer Assessment (FMA-LE), the Timed "Up & Go" test (TUG), the comfortable gait speed (CGS), the fast gait speed (FGS), and the 2-minute walk test (2MWT). RESULTS: Excellent reliability of the BBS, FMA-LE, TUG, CGS, FGS, and 2MWT for all the participants combined and for the subgroups was shown. All the participants combined showed the absolute and relative MDC(95) in the BBS of 5 points and 10%, FMA-LE of 4 points and 16%, TUG of 8 seconds and 28%, CGS of 0.2m/s and 34%, FGS of 0.1m/s and 21%, and 2MWT of 13m and 23%. The absolute and relative MDC(95) of the subgroups were varied based on ankle plantarflexor tone. CONCLUSIONS: The BBS, FMA-LE, TUG, CGS, FGS, and 2MWT are reliable measures to detect postural balance and lower limb movements in individuals with chronic stroke who have differences in ankle plantarflexor tone. The absolute and relative MDC(95) of each measure are dissimilar in those with differences in ankle plantarflexor tone. The relative MDC(95) seems more useful than the absolute MDC(95) because the relative value can be used for a single individual. PMID- 22502806 TI - A prospective study on employment outcome 3 years after moderate to severe traumatic brain injury. AB - OBJECTIVES: To evaluate the employment outcome in patients with moderate to severe traumatic brain injury (TBI) and to identify which patients are at risk of unemployment 3 years after injury. DESIGN: Prospective cohort study. SETTING: Patients with moderate and severe TBI discharged from the neurosurgery departments of 3 level 1 trauma centers in The Netherlands. PARTICIPANTS: Patients aged 18 to 65 years (N=113; mean age +/- SD, 33.2+/-13.1y; 73% men) who were hospitalized with moderate (26% of patients) to severe (74% of patients) TBI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The main outcome measure was employment status. Potential predictors included patient characteristics, injury severity factors, functional outcome measured at discharge from the acute hospital with the Glasgow Outcome Scale (GOS), Barthel Index (BI), and FIM, and cognitive functioning measured with the Functional Assessment Measure (FAM). RESULTS: Ninety-four patients (83%) completed the 3 year follow-up. The employment rate dropped from 80% preinjury to 15% at 3 months postinjury and gradually increased to 55% after 3 years. The employment rate significantly increased from 3 months up to 1 year, but it did not change significantly from 1 to 3 years postinjury. Age, length of hospital stay, discharge to a nursing home (vs home), psychiatric symptoms, and BI, GOS, FIM, and FAM scores were found to be significant univariate determinants for employment status. By using multiple logistic regression analysis, the FAM score (adjusted odds ratio 1.1; P<.000) and psychiatric symptoms (adjusted odds ratio .08; P<.019) were selected as independent predictors for employment status. A FAM cutoff score of less than 65 to identify patients at risk of long-term unemployment had a good diagnostic value. CONCLUSIONS: Patients with TBI with psychiatric symptoms and impaired cognitive functioning at hospital discharge are at the highest risk of long-term unemployment. These factors should be the focus of vocational rehabilitation. PMID- 22502807 TI - Is spastic muscle echo intensity related to the response to botulinum toxin type A in patients with stroke? A cohort study. AB - OBJECTIVE: To investigate the relationship between gastrocnemius muscle echo intensity and response to botulinum toxin type A (BoNT-A) in patients with spastic equinus foot resulting from stroke. DESIGN: Cohort study. SETTING: University hospital. PARTICIPANTS: Adult patients (N=56) with spastic equinus foot resulting from stroke scheduled to receive BoNT-A injection into the gastrocnemius muscle. INTERVENTIONS: All patients were injected with BoNT-A (abobotulinumtoxinA) into the gastrocnemius muscle with an ultrasonography guided, multisite injection technique. The toxin dose was 250U for the gastrocnemius medialis and 250U for the gastrocnemius lateralis (dilution 500U/2mL) in each patient. All patients were evaluated before and 4 weeks after BoNT-A injection. MAIN OUTCOME MEASURES: Spastic gastrocnemius muscle echo intensity visually graded with the Heckmatt scale. Clinical assessment of the spastic gastrocnemius with the Modified Ashworth Scale, Tardieu Scale, and ankle passive range of motion. RESULTS: Postintervention testing at 4 weeks showed overall significant improvements in the clinical assessment of the spastic gastrocnemius muscle. No significant change was observed in the echo muscle intensity of the spastic gastrocnemius after BoNT-A injection. Post hoc comparisons showed that all clinical outcomes were significantly better in those patients with echo muscle intensity of the spastic gastrocnemius graded II on the Heckmatt scale than those with grades III (P<.001) and IV (P<.001) after botulinum toxin injection. CONCLUSIONS: These findings support the hypothesis that patients with higher spastic muscle echo intensity have a reduced response to BoNT-A. PMID- 22502808 TI - Implications of sociodemographic factors and health examination rate for people with disabilities. AB - OBJECTIVES: To determine disparities in health examination rates between people with disabilities (PWD) and the general population (GP), and to investigate the sociodemographic factors influencing health examination rates in PWD. DESIGN: The study compared the health examination rates between PWD and the GP using data from 2 national surveys. SETTING: We used data from the Korean National Health and Nutrition Examination Survey of (KNHANES) 2008 and the National Survey on Persons with Disabilities (NSPD) in 2008. PARTICIPANTS: The study comprised data from the NSPD 2008 for PWD (n=6999) and data from the KNHANES 2008 for the GP (n=6582). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Health examination rates of 2 groups were assessed. Multiple logistic regression analysis was used to identify the related factors influencing health examination rates in PWD. RESULTS: Health examination rates for PWD were significantly lower than those for the GP (P<.001). The health examination rates for PWD were lowest when they were in the age group of 30 to 39 years, in the quartile 2 group of income level, had no "existing spouse," had chronic diseases, thought their health condition was very bad, and when they needed complete help from others to carry out activities of daily living. CONCLUSIONS: Health examination rates were reduced by the disability factor. To enhance the overall rate of health examinations, researchers should determine which groups of PWD have relatively low health examination rates and propose measures to increase their rates of health examination. PMID- 22502809 TI - Production of natural folates by lactic acid bacteria starter cultures isolated from artisanal Argentinean yogurts. AB - Folate is a B-group vitamin that cannot be synthesized by humans and must be obtained exogenously. Although some species of lactic acid bacteria (LAB) can produce folates, little is known about the production of this vitamin by yogurt starter cultures. Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus strains were isolated from artisanal Argentinean yogurts and were grown in folate-free culture medium (FACM) and nonfat milk after which intracellular and extracellular folate production were evaluated. From the initial 92 isolated LAB strains, 4 L. delbrueckii subsp. bulgaricus and 32 S. thermophilus were able to grow in the absence of folate. Lactobacillus delbrueckii subsp. bulgaricus CRL 863 and S. thermophilus CRL 415 and CRL 803 produced the highest extracellular folate levels (from 22.3 to 135 ug/L) in FACM. In nonfat milk, these strains were able to increase the initial folate concentrations by almost 190%. This is the first report where native strains of L. delbrueckii subsp. bulgaricus were shown to produce natural folate. The LAB strains identified in this study could be used in developing novel fermented products bio-enriched in natural folates that could in turn be used as an alternative to fortification with the controversial synthetic chemical folic acid. PMID- 22502810 TI - Changes in serial B-type natriuretic peptide level independently predict cardiac allograft rejection. AB - BACKGROUND: Despite positive associations with rejection, the clinical value of B type natriuretic peptide (BNP) monitoring in heart transplant recipients has not been established. We sought to determine the predictive value of changes in serial BNP level for identifying patients with acute allograft rejection. METHODS: BNP, hemodynamics and biopsies were obtained for 205 transplant recipients who underwent a total of 4,007 endomyocardial biopsy procedures. Samples analyzed were collected >= 180 days post-transplant, without evidence of rejection on the immediately preceding biopsy. Using a repeated-measures multivariate model, we assessed the association of change in BNP with Grade >= 3A (2R) rejection. We also determined predictive values of various cut-off thresholds of change in serial BNP levels to predict Grade >= 3A rejection. RESULTS: There were 47 episodes of Grade >= 3A rejection among the 1,350 samples analyzed. Median change in serial BNP (DeltaBNP) for those with Grade >= 3A rejection was 20 pg/ml (IQR -26 to 169 pg/ml) and among those with Grade <3A rejection was -4 pg/ml (IQR -34 to 22 pg/ml, p = 0.003). On multivariate analysis, DeltaBNP remained the most potent independent predictor of Grade >= 3A rejection (p = 0.001). DeltaBNP >100 pg/ml predicted increased risk of Grade >= 3A rejection (OR = 5.3, p < 0.001) with high specificity (93.3%) and positive predictive value (13.0%) and excellent negative predictive value (97.3%). CONCLUSIONS: Change in serial BNP level is an independent predictor of cardiac allograft rejection. With wide availability, rapid turnaround, low cost, favorable positive predictive value and excellent negative predictive value, serial BNP monitoring has several advantages for non-invasive monitoring of heart transplant recipients for acute cardiac allograft rejection. PMID- 22502811 TI - Mechanisms of pulmonary hypertension in chronic obstructive pulmonary disease: a pathophysiologic review. AB - Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity worldwide and is often complicated by the development of pulmonary hypertension (PHT). The presence of PHT in COPD subjects is associated with increased mortality, morbidity and use of health-care resources. Thus, there has been significant effort to treat PHT in COPD patients to achieve improved clinical outcomes, but with only minimal success. There is renewed interest in understanding the mechanisms contributing to PHT in COPD as the basis for exploring new therapeutic strategies. In this study we review the evidence supporting the postulated mechanisms contributing to PHT in COPD. Hypoxia plays a pivotal role in the development of COPD-associated PHT. However, other mechanisms are also likely involved in the pathogenesis of increased pulmonary vascular resistance in this cohort, including acidemia, dynamic pulmonary hyperinflation, parenchymal destruction, pulmonary vascular remodeling, endothelial dysfunction and inflammation. These mechanisms are interdependent, modulated by genetic factors, and may be confounded by comorbidities such as sleep-disordered breathing, left heart failure and pulmonary thromboembolism. Despite significant research in recent decades, there is surprisingly little evidence of a causal relationship between many of these factors and the development of COPD-associated PHT. The pathogenesis of PHT in COPD is complex and multifaceted. Ultimately, as we obtain better information on COPD phenotypes, we may be able to more precisely account for the varied pathologic mechanisms of PHT occurring in various COPD patients. This may ultimately enable targeted PHT therapy for each COPD phenotype. PMID- 22502812 TI - Diabetic cardiomyopathy and diastolic heart failure -- difficulties with relaxation. AB - Diabetic patients carry a four- to five-fold increased risk of heart failure. Hyperglycaemia plays a central role in the pathogenesis of diabetic cardiomyopathy. Diabetic cardiomyopathy represents a distinct structural and functional disorder of the myocardium characterized by cardiac hypertrophy and an increased myocardial stiffness. At an early stage, diabetic cardiomyopathy is manifested by diastolic heart failure with preserved ejection fraction. In some patients, diastolic dysfunction may progress to heart failure with reduced ejection fraction and result in overt systolic heart failure. Diastolic dysfunction can accurately be diagnosed by echocardiography and BNP measurement in daily clinical practice. Early treatment is prognostically important. Optimal control of blood glucose levels and blood pressure is beneficial. So far metformin is the only antidiabetic agent not associated with harm in diabetic patients with heart failure. Incretin-based therapies potentially provide cardiovascular benefits. ACE inhibitors, angiotensin-1 receptor antagonists and beta-blockers should be preferred in heart failure therapy. PMID- 22502813 TI - Adiponectin improves endothelial dysfunction caused by elevated FFAs levels, partially through cAMP-dependent pathway. AB - AIMS: To determine whether adiponectin can attenuate endothelial dysfunction caused by elevated free fatty acids (FFAs) concentration, and if so, to explore the underlying mechanism. METHODS: Male Sprague-Dawley rat thoracic aortas were isolated then cut into four vascular rings, incubated in organ bath containing Krebs-Henseleit buffer with different agents separately: 800 MUmol/L Palmic acid (FFA, n = 14), 800 MUmol/L Palmic acid + 2 MUg/mL adiponectin (FFA + gAd, n = 14), 800 MUmol/L Palmic acid + 2 MUg/mL adiponectin + 200 MUmol/L adenylate cyclase inhibitor dideoxyadenosine (FFA + gAd + ddAdo, n = 7), blank control (NC, n=10). The endothelial dependent vasodilatation (EDV) and endothelial independent vasodilatation (EIV) were assessed by acetylcholine (Ach) induced contraction of the aortas. Nuclear transcription factor kappa B (NF-kappaB) expression in rat aortic section was evaluated immunohistochemically. RESULTS: Ach caused a concentration dependent vascular relaxation in all pre-constricted aortic rings. PA treatment impaired the Ach induced EDV which was significantly attenuated by pretreatment with adiponectin. Dideoxyadenosine partly abolished the vascular protective effect of adiponectin. Sodium nitroprusside (SNP) had no significant effect on the vasodilatation among four groups. Increased NF-kappaB expression was noted in FFA group. Pretreatment with adiponectin partly decreased NF-kappaB expression when compared with FFA group. CONCLUSION: Adiponectin may independently mitigate endothelial dysfunction caused by elevated FFAs concentration through the cross talk between cAMP and NF-kappaB signaling pathway. PMID- 22502814 TI - Low level helium neon laser therapy for chemoradiotherapy induced oral mucositis in oral cancer patients - a randomized controlled trial. AB - BACKGROUND: Patients receiving chemoradiotherapy (CRT) for oral cancer (OC) often develop oral mucositis (OM). OM associated pain severely affects oral functions and nutrition of the patient, resulting in narcotic analgesic use and CRT interruption. Laser therapy has shown some promising results in preventing and treating OM caused by cancer therapies. So in this trial we used prophylactic Low Level Helium Neon (He-Ne) Laser for the prevention and treatment of CRT induced OM in OC patients. MATERIALS AND METHODS: This double blinded trial block randomized 121 primary OC patients scheduled to undergo CRT [RT dosage=66 Gray/33 fractions for 5 days/week and chemotherapy (3 weekly Cisplatin)] into laser (n=60) and placebo (n=61) group. Laser group received He-Ne Laser (lambda=632.8 nm, P=24 mW, ED=3.5 J/cm(2)) while placebo received sham treatment just before radiation for 6.5 weeks. OM (RTOG/EORTC Scale), its associated pain, and total parenteral nutrition (TPN), were assessed on every week by a blinded assessor. Also opioid analgesic use, weight loss and any CRT break were recorded. Data was analyzed using descriptive statistics, t-test and Man Whitney U test. Level of significance was set at p<0.05. RESULTS: Incidence of severe OM (29% vs. 89%, p<0.001) and its associated pain (18% vs. 71%, p<0.001), opioid analgesic use (7% vs. 21%, p<0.001)and TPN (30% vs. 39% p=0.039) was significantly less in laser than placebo group patients. Also duration of severe OM and pain experienced was less in laser than placebo group. CRT break required only for placebo group (9%) patients. CONCLUSION: Low Level He-Ne Laser decreased the incidence of CRT induced severe OM and its associated pain, opioid analgesics use and TPN. PMID- 22502815 TI - Global quality of life during the acute toxicity phase of multimodality treatment for patients with head and neck cancer: can we identify patients most at risk of profound quality of life decline? AB - PURPOSE: Treatment intensification has improved outcomes for patients with head and neck cancer (HNC), but little has been reported on health-related quality of life (QoL) consequences. We investigated changes in QoL after (chemo)radiotherapy to identify patient characteristics that predict those whose QoL deteriorates most profoundly in the acute post-treatment period. MATERIALS AND METHODS: Patients with locally advanced HNC treated with curative intent received intensity-modulated radiotherapy (60-70 Gy) in this prospective study. (Chemo)radiotherapy was either definitive or adjuvant. Induction chemotherapy consisted of three cycles of docetaxel, cisplatin, and 5-fluorouracil; responders received (chemo)radiotherapy; nonresponders underwent salvage surgery followed by (chemo)radiotherapy if appropriate. Patients completed the EORTC QLQ-C30 and HNC specific HN35 module before and at the end of (chemo)radiotherapy and 6-8 weeks after therapy completion. RESULTS: Ninety-five patients participated. At baseline, patients reported significantly lower Global health status, functioning, and symptom scale scores than a reference German population (all p<0.001). At the end of (chemo)radiotherapy, patients had significantly lower QoL scores vs. baseline on all functioning scales (p<0.05). Most symptom and HN35 scores worsened during (chemo)radiotherapy but many recovered 6-8 weeks post treatment. QoL deteriorated more in patients with high vs. low baseline QoL; no clinical or sociodemographic characteristics of patients most likely to experience a significant deterioration in QoL during treatment were identified. CONCLUSION: These standard QoL instruments did not predict patients at risk of profound global QoL impairments during acute treatment. Other than baseline QoL, no patient characteristics associated with significant QoL deterioration were identified. PMID- 22502816 TI - Intermittent hormonal therapy in the treatment of metastatic prostate cancer: a randomized trial. AB - Study Type - Therapy (RCT) Level of Evidence 1b. What's known on the subject? and What does the study add? Intermittent androgen deprivation therapy (ADT) involves cycling ADT, allowing hormonal recovery during off-treatment periods. This could lead to a better quality of life during off-treatment periods and could delay progression to castration resistance. Safety and feasibility of intermittent ADT have been shown but tolerability and health-related quality of life improvement have been suggested but questioned by others. Results from randomized trials, including relapsing or mixed populations, have suggested intermittent ADT to be as effective as continuous ADT. In this study of only metastatic patients, no statistical difference in either overall survival or progression-free survival was shown between intermittent and continuous ADT and suggests that intermittent might be as safe as continuous castration. It could be an option in highly responding and well-informed metastatic patients even if no clear benefit in health-related quality of life was shown. This intermittent modality could be of interest in metastatic patients with significant treatment-induced side-effects. OBJECTIVE: * To compare intermittent androgen deprivation therapy (ADT) and continuous ADT after 6 months of induction of ADT in patients with metastatic prostate cancer (PCa). PATIENTS AND METHODS: * This is an open-label randomized multi-centre study conducted in 58 centres in Europe. * Patients with metastatic PCa and prostate-specific antigen (PSA) level >20 ng/mL at selection were randomized after 6 months of induction of ADT (leuprorelin and flutamide) if PSA level had decreased below 4 ng/mL. * Patients received either continuous or intermittent ADT. All patients were treated until signs of disease progression under treatment or until study end with a monthly central PSA determination and follow-up visits were performed every 3 months. * The primary endpoint was overall survival. Secondary endpoints included progression-free survival, health related quality of life (QLQ C30 questionnaire) and safety criteria. RESULTS: * Of 383 selected patients, 173 had a PSA level below 4 ng/mL after 6 months of induction of ADT and were randomized. Median overall survival (52 vs 42 months, P= 0.75) and median progression-free survival (15.1 vs 20.7 months, P= 0.74) were not significantly different between continuous and intermittent ADT. * Although some differences in quality of life were observed, most of the functional and symptom scales showed no significant difference between the two groups. * Significantly fewer treatment-emergent adverse events occurred in the intermittent group (P= 0.042), with the incidence of headache and hot flushes also lower. CONCLUSIONS: * This first randomized trial comparing continuous with intermittent ADT in metastatic PCa suggests that intermittent ADT might be as safe as continuous ADT. * It could be an option in highly responding and well informed patients even if no clear benefit in health-related quality of life was shown. PMID- 22502817 TI - Effects of immunosuppression by cyclosporine A on allogenic uterine transplant in the rat. AB - OBJECTIVE(S): Research on uterine transplantation (UTx) is conducted in preparation for its introduction in the human as a treatment for absolute uterine factor infertility. A major area of research in experimental animals is to ascertain that immunosuppressants that will be used at UTx do not negatively affect the potential of the uterus to implant an embryo and to carry a pregnancy to term. This study investigates the effects on a uterine transplant in the rat of the calcineurin inhibitor, cyclosporine A (CsA), on uterine morphology and expression patterns of some mediators involved in implantation/inflammation. STUDY DESIGN: Donor rats were of Brown Norway strain and recipients were of Lewis strain. The uterus was transplanted to an orthotopic site by vascular anastomosis. The recipients were given CsA (10mg/kg) sc once daily or no CsA until they were sacrificed at postoperative day 7. Syngenic transplanted Lewis rats were used as controls. Uteri were analyzed regarding histology, immunohistochemistry against T-cells and mRNA levels of the implantation/inflammation-related markers leukaemia inhibitory factor (LIF), galectin-1, CD200, interleukin (IL)-1alpha, and IL-15. RESULT(S): There was pronounced inflammation with abundance of CD8-lymphocytes in uterine grafts of non-CsA-treated animals and only mild inflammation in treated animals. The uterine mRNA levels of IL-1alpha were decreased after CsA in comparison to uteri of non-treated transplanted animals. The mRNA levels of galectin-1 were decreased in the rejected uteri and were higher in the CsA-treated. The levels of mRNA of IL-15 were lower in the syngenic transplanted group compared to the CsA-treated transplanted. There was no difference between the groups concerning mRNA levels of CD200, or LIF, with wide variation of the levels of the two latter mediators in all groups. CONCLUSION(S): Cyclosporine A suppresses rejection of an allogenic rat uterine transplant, with normalization of mRNA levels of the proinflammatory cytokine IL-1alpha and the glycan-binding protein galectin-1. PMID- 22502818 TI - Context-specific control and the Stroop negative priming effect. AB - The present study highlights the utility of context-specific learning for different probe types in accounting for the commonly observed dependence of negative priming on probe selection. Using a Stroop priming procedure, Experiments 1a and 1b offered a demonstration that Stroop priming effects can differ qualitatively for selection and no-selection probes when probe selection is manipulated between subjects, but not when it is manipulated randomly from trial to trial within subject (see also Moore, 1994). In Experiments 2 and 3, selection and no-selection probes served as two contexts that varied randomly from trial to trial, but for which proportion repeated was manipulated separately. A context-specific proportion repeated effect was observed in Experiment 2, characterized by modest quantitative shifts in the repetition effects as a function of the context-specific proportion repeated manipulation. However, with a longer intertrial interval in Experiment 3, a context-specific proportion repeated manipulation that focused on the no-selection probes changed the repetition effect qualitatively, from negative priming when the proportion repeated was .25 to positive priming when the proportion repeated was .75. The results are discussed with reference to the role of rapid, context-specific learning processes in the integration of prior experiences with current perception and action. PMID- 22502819 TI - Vitamin D: evidence and controversies: comment on the article by Gilaberte et al. AB - Vitamin D deficiency is associated with increased risk of approximately 100 conditions and diseases. Ecological, observational, and cross-sectional studies as well as randomized controlled trials support these associations. Observational studies, with support from the other types, provide the data needed to determine how serum 25-hydroxyvitamin D [25(OH)D] concentration affects disease incidence and mortality rates. The findings for breast and colorectal cancer, respiratory infections, and all-cause mortality rates indicate that benefits increase as serum 25(OH)D concentrations increase to between 75 and 100nmol/L. Reaching those levels takes up to 5000IU of vitamin D per day, with considerable individual variation. The main sources of vitamin D that can help people reach those levels are UV-B irradiance and vitamin D(3) supplements. The skin characteristics-both in terms of pigmentation and ability to tan-of most inhabitants of Spain are ideally suited for regular moderate solar UV irradiance. In general, melanoma risk is low in southern Europe. Risk of nonmelanoma skin cancer is higher, but such cancers are seldom fatal, and a study in Denmark found a 9% reduction in 10 year all-cause mortality rate for patients diagnosed with basal cell carcinoma. PMID- 22502820 TI - Different serine and glycine metabolism in patients with schizophrenia receiving clozapine. AB - Dysfunction of the N-methyl-d-aspartate receptor, which is modulated by excitatory amino acids (EAA), is involved in the pathophysiology of schizophrenia. The effects of antipsychotics on EAA metabolism are uncertain. Positive clinical effects of treatment with antipsychotics were not always associated with changes in EAA serum levels in patients with schizophrenia in clinical trials. To examine EAA serum levels in relation to the intensity of psychotic symptoms and the type of medication received we compared these variables among patients with schizophrenia (n = 49) treated with first (FGA) or second (SGA) generation antipsychotics or clozapine. Glutamate, aspartate, glycine, total serine and d-serine serum levels were measured by High Performance Liquid Chromatography. The Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) were used to assess symptoms of schizophrenia. Lower average levels of glycine and total serine were found in the serum of patients receiving clozapine when compared to the groups of patients treated with FGA or SGA. There were no differences in serum glutamate, aspartate or d-serine levels or in the intensity of schizophrenic symptoms assessed by PANSS or SANS among the groups of patients treated with FGA or SGA or clozapine. Lower glycine and total serine serum levels could be caused by the particular characteristics of the population of patients receiving clozapine rather than as an effect of the clozapine. The results suggest selective deficiency of l-serine synthesis in the patients with resistance to non-clozapine treatment. It might be an unique biochemical and pathophysiological characteristic of the treatment resistance in schizophrenia. PMID- 22502821 TI - A wireless object location detector enabling people with developmental disabilities to control environmental stimulation through simple occupational activities with Nintendo Wii Balance Boards. AB - The latest researches have adopted software technology, turning the Nintendo Wii Balance Board into a high performance standing location detector with a newly developed standing location detection program (SLDP). This study extended SLDP functionality to assess whether two people with developmental disabilities would be able to actively perform simple occupational activities by controlling their favorite environmental stimulation using Nintendo Wii Balance Boards and SLDP software. An ABAB design was adopted in this study to perform the tests. The test results showed that, during the intervention phases, both participants significantly increased their target response (i.e. simple occupational activity) to activate the control system to produce environmental stimulation. The practical and developmental implications of the findings are discussed. PMID- 22502822 TI - Factors related to hysterectomy in women with physical and mobility disabilities. AB - This paper aims to identify self-report data for hysterectomy prevalence and to explore its correlated factors among women with physical and mobility disabilities in Taiwan. This paper was part of a larger study, "Survey on Preventive Health Utilizations of People with Physical and Mobility Disability in Taiwan", which is a cross-sectional survey conducted in 2009. We recruited 502 women aged ?15 years who were officially registered as having physical and mobility disabilities. The results show that 11.3% of women with physical and mobility disabilities accepted hysterectomy surgery and that hysterectomy prevalence was increasing by age: 7% (45-49 years), 9.7% (50-54 years), 26.3% (55 59 years), 31% (60-64 years) and 17.6% (?65 years). Multilevel logistic regression analyses revealed that being ?50 years or older (OR=4.65, 95% CI=1.79 12.064), having had cervical cancer (OR=17.2, 95% CI=3.5-84.47) and not having a Pap smear test within the last 3 years (OR=2.79, 95% CI=1.194-6.561) were more likely to accept a hysterectomy operation than their counterparts. This study suggests that future studies should analyze hospital data and assesses long-term changes to understand an area's hysterectomy profile and correlated factors for these types of vulnerable populations. PMID- 22502823 TI - Motor and cognitive performance differences between children with and without developmental coordination disorder (DCD). AB - The current study adopts the PASS theory of information processing to investigate the probable differences in specific motor and cognitive abilities between children with and without developmental coordination disorder (DCD). Participants were 108 5- and 6-year-old preschoolers (54 children with DCD and 54 children without DCD). The Movement Assessment Battery for Children assessed motor function. Running speed and agility were measured using the Bruininks-Oseretsky Test of Motor Proficiency. Finally, the Planning, Attention and Simultaneous Scales from the Das-Naglieri Cognitive Assessment System evaluated cognitive ability. Children with DCD differed significantly from those without DCD performing at a lower level on all motor and cognitive tasks. A correlation analysis revealed significant relationships between cognitive processes and motor skills. Simultaneous cognitive processing and manual dexterity were significantly correlated for both groups. Furthermore, a significant relationship was revealed between planning cognitive processing and balance for the non-DCD group. Thus, early assessment might identify specific cognitive-motor difficulties. Furthermore, early intervention might prevent some of the developmental comorbidities in the academic and everyday lives of children with movement difficulties. PMID- 22502824 TI - Can gymnastic teacher predict leisure activity preference among children with developmental coordination disorders (DCD)? AB - The aims of the study were to analyze: (1) whether significant differences exist between children with typical development and children with developmental coordination disorders (DCD) in their preference to participate in leisure activities (2) whether the teacher estimation of activity form (TEAF) evaluation predicts participation preference. Participants were 68 children, aged 6-9.83 years, 35 diagnosed as DCD by pediatrician and based on the Movement ABC (M-ABC) and 33 children with typical development. The controls were matched by age and gender to the DCD group. The children filled the preference for activities of children (PAC) and their sport teacher completed the TEAF. Significant differences were found between the groups in their participation preference based on the PAC items and subscales as well as in the TEAF scores. Significant correlations were found between the TEAF and PAC subscales. TEAF score significantly predicted children's preference to participate in leisure activities. Study results recommend using the TEAF for screening DCD and to further consider participation issues among children with DCD as a preventive aid for consequently socio-emotional implications of DCD. PMID- 22502825 TI - Persons with Alzheimer's disease make phone calls independently using a computer aided telephone system. AB - This study assessed whether four patients with a diagnosis of Alzheimer's disease could make independent phone calls via a computer-aided telephone system. The study was carried out according to a non-concurrent multiple baseline design across participants. All participants started with baseline during which the telephone system was not available, and continued with intervention in which such system was used. It involved a net-book computer provided with specific software, a global system for mobile communication modem (GSM), a microswitch, and photos of the persons available for the phone calls. All participants learned to use the system and made phone calls independently to a variety of partners such as family members, friends and staff personnel. The positive implications of the system were discussed in relation to previous data in this area and the possibility of helping persons with Alzheimer's disease restore an important, instrumental daily ability and engage in communication with distant partners. PMID- 22502826 TI - How do researchers define self-injurious behavior? AB - Self-injurious behavior is commonly observed among persons with intellectual disabilities. However, a second parallel use of this term is used in the general mental health field for self-mutilation. The authors describe these two disorders and how they differ. Characteristics of what we refer to as repetitive self injurious behavior among persons with intellectual disabilities and risk factors for these behaviors are discussed. We also describe different assessment/testing methods which aid in defining this phenomenon. The implications of these data for research and clinical practice are discussed. PMID- 22502827 TI - Behavioral problems in children with motor and intellectual disabilities: prevalence and associations with maladaptive personality and marital relationship. AB - Prevalence rates of behavioral problems in children with motor disabilities are commonly based on questionnaires developed for a general population (e.g., Child Behavior CheckList). These questionnaires do not take into account lower levels of intellectual functioning. The first aim of this study was to examine the prevalence of parent-reported and daily caretaker-reported behavioral problems in children with motor and intellectual disabilities (MID) using the Developmental Behavior Checklist. Second, we investigated whether behavioral problems were related to sex and age. Our third and fourth aim were to determine whether behavioral problems are related to maladaptive personality traits and to marital stress and conflict. Participants were 101 Flemish children with MID (mean age=14 years 6 months). For total behavioral problems, we found prevalence rates of 18% and 8% based on parent and daily caretaker reports, respectively. Based on parent reports, twenty seven percent of the children with MID exhibited anxiety problems. Behavioral problems were not related to sex. Older children showed fewer behavioral problems than younger children. Multiple hierarchical regression analyses revealed that lower scores on Compulsivity and higher scores on Emotional Instability and Disagreeableness were related to behavioral problems. In addition to personality traits, stress and conflict in the marital relationship was also positively associated with behavioral problems. Given the importance of behavioral problems in children with MID, this study is of theoretical and clinical interest and has the potential to inform targeted clinical interventions. PMID- 22502828 TI - Specific Language Impairment affects the early spelling process quantitatively but not qualitatively. AB - The present study investigated whether children with Specific Language Impairment (SLI) need a special spelling education program, by examining whether the early spelling of children with SLI is quantitatively and qualitatively different from the spelling of typically developing children. Two groups of first grade children participated: 39 children with a typical language development between the age of 73 and 88 months, and 59 children with SLI between the age of 71 and 97 months. The results indicated that children with SLI do have a quantitative delay in both grapheme knowledge and spelling during first grade. However, there was no qualitative difference between the early spelling of children with SLI and typically developing children. This indicated that children with SLI have the same spelling processes as typically developing children, although they develop slower. For clinical practice, this means that teachers of children with SLI can practice the same skills as with typically developing children, but they have to practice substantially more than typically developing children. PMID- 22502829 TI - Low physical fitness levels in older adults with ID: results of the HA-ID study. AB - Physical fitness is as important to aging adults with ID as in the general population, but to date, the physical fitness levels of this group are unknown. Comfortable walking speed, muscle strength (grip strength), muscle endurance (30s Chair stand) and cardiorespiratory endurance (10 m incremental shuttle walking test) were tested in a sample of 1050 older adults with ID, and results were compared with reference values from the general population. Across all age ranges, approximately two-third of the entire study population scored 'below average' or 'impaired'. Even the youngest age groups (50-59 or 50-54 years) in this sample achieve similar or worse results than age groups 20-30 years older in the general population. Low physical fitness levels in older adults with ID demonstrate that this group is prone to unnecessary premature loss of functioning and health problems, and maintaining physical fitness should have priority in practice and policy. PMID- 22502831 TI - The evaluation of a screening tool for children with an intellectual disability: the Child and Adolescent Intellectual Disability Screening Questionnaire. AB - The study outlines the evaluation of an intellectual disability screening tool, the Child and Adolescent Intellectual Disability Screening Questionnaire (CAIDS Q), with two age groups. A number of aspects of the reliability and validity of the CAIDS-Q were assessed for these two groups, including inter-rater reliability, convergent and discriminative validity. For both age groups, a significant positive relationship was found between full scale IQ and CAIDS-Q score, indicating convergent validity. Significant differences were found in the CAIDS-Q scores between those with and without an intellectual disability, with the former group scoring significantly lower. The sensitivity and specificity of the CAIDS-Q were above 96.7% and 85.5% respectively for the younger group and 90.9% and 94.9% respectively for the older group. Limitations and implications of the study are discussed. PMID- 22502830 TI - Perceptions of distress in young children with autism compared to typically developing children: a cultural comparison between Japan and Italy. AB - This study investigates how adults in two contrasting cultures (Italian and Japanese) perceive episodes of crying of typically developing (TD) children and children with Autism Disorder (AD). Although cries of children with AD have been reported to elicit more distress in Western cultures, it is not known whether similar findings hold in Eastern cultures. In Experiment 1, we artificially modified structural parameters (fundamental frequency, duration of pauses, waveform modulation) of cries and asked Italian and Japanese adults to judge levels of expressed and felt distress in the cries. In Experiment 2, we asked Italian and Japanese adults to report these levels of distress on hearing cries of AD and TD children. In both cultures, cries with higher fundamental frequency and shorter pause durations were judged more distressing and distressed and observers perceived cries of children with AD as more distressing and distressed than cries of TD children. The similar responses in adults from two contrasting societies constitute evidence that reactions to cries of children with AD might be universal. PMID- 22502832 TI - Moderating factors of video-modeling with other as model: a meta-analysis of single-case studies. AB - Video modeling with other as model (VMO) is a more practical method for implementing video-based modeling techniques, such as video self-modeling, which requires significantly more editing. Despite this, identification of contextual factors such as participant characteristics and targeted outcomes that moderate the effectiveness of VMO has not previously been explored. The purpose of this study was to meta-analytically evaluate the evidence base of VMO with individuals with disabilities to determine if participant characteristics and targeted outcomes moderate the effectiveness of the intervention. Findings indicate that VMO is highly effective for participants with autism spectrum disorder (IRD=.83) and moderately effective for participants with developmental disabilities (IRD=.68). However, differential effects are indicated across levels of moderators for diagnoses and targeted outcomes. Implications for practice and future research are discussed. PMID- 22502833 TI - Muscle strength enhancement following home-based virtual cycling training in ambulatory children with cerebral palsy. AB - This study is the first well-designed randomized controlled trial to assess the effects of a novel home-based virtual cycling training (hVCT) program for improving muscle strength in children with spastic cerebral palsy (CP). Twenty eight ambulatory children with spastic CP aged 6-12 years were randomly assigned to an hVCT group (n=13) or a control group (n=15). Outcome measures, including gross motor function of the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP) and muscle strength (isokinetic torque of knee extensor and flexor muscle), were administered before and immediately after the 12-week intervention. Analysis of covariance (ANCOVA) at post-treatment showed that, compared to the control group, the hVCT group had significantly higher isokinetic torque in the knee extensor and flexor muscles at 60 degrees /s and 120 degrees /s angular velocities (p<0.05). At post-treatment, the hVCT group also showed greater isokinetic strength improvement in the knee flexor than in the knee extensor at 60 degrees /s (knee flexor: 41%; knee extensor: 19%) and at 120 degrees /s (knee flexor: 36%; knee extensor: 30%). However, the BOTMP scores at post-treatment did not differ between the two groups. Although the proposed 12-week hVCT protocol does not improve gross motor function, it enhances knee muscle strength in children with CP. The protocol obtains larger gains in the knee flexor than in the knee extensor at different angular velocities. The study findings will help clinicians to provide more effective and efficient strategies for muscle strength training in children with CP. PMID- 22502834 TI - Problematic alcohol use and mild intellectual disability: standardization of pictorial stimuli for an alcohol cue reactivity task. AB - The present study focused on the first step in developing a cue reactivity task for studying cognitive biases in individuals with mild to borderline intellectual disability (ID) and alcohol use-related problems: the standardization of pictorial stimuli. Participants (N=40), both with and without a history of alcohol use-related problems and varying in IQ, were admitted to a forensic setting and were all abstinent. They were asked to rate familiarity, complexity, valence and attractiveness of pictures portraying both alcoholic and non alcoholic beverages. There was a tendency to rate non-alcoholic beverages as more pleasant and attractive than alcoholic beverages. In participants with mild to borderline ID, this difference reached statistical significance, even when controlling for alcohol use-related problems in the past. The overall result of the study is a large database of 255 pictures portraying both alcoholic and non alcoholic beverages that will be used to validate an implicit measure of cognitive biases for alcohol in individuals with mild to borderline ID. PMID- 22502835 TI - Life satisfaction in persons with intellectual disabilities. AB - We appraised life satisfaction using the Satisfaction with Life Scale (SWLS), and analysed its psychometric properties in persons with intellectual disability (ID). Ninety-nine persons with ID from four services in Spain participated. A battery of subjective assessments was used, including the SWLS, a Quality of Life measure (WHOQOL-BREF), and health status and sociodemographic information. Psychometric properties of the SWLS were investigated using standard psychometric methods. Overall, our results showed that persons with ID were satisfied with their life (SWLS score 25-29). Internal consistency (Cronbach's alpha) was .79. A factor analysis using principal components method, showed a one factor structure accounting for 55.7% of the variance. Associations, using Spearman's rho correlation coefficients, were confirmed between SWLS with the overall QoL, satisfaction with health and WHOQOL-BREF total score. Regarding 'known group' differences, persons living in residential institutions had lower life satisfaction compared to persons living in community facilities or living at home, though differences were not statistically significant. Student t-tests showed that SWLS scores significantly discriminated between healthy and unhealthy; and those reporting higher satisfaction with their relationships, home environment and their jobs compared to participants with lower satisfaction levels. To our best knowledge, this study is the first to report on the psychometrics properties of the SWLS in persons with ID, both in Spain and internationally. It might be a promising tool to use, with other outcome measures, in appraising persons with ID in different services and types of care; also, it might guide policymakers on the implementation of policies for persons with ID. PMID- 22502836 TI - The effects of developmental quotient and diagnostic criteria on challenging behaviors in toddlers with developmental disabilities. AB - Previous research has found that individuals with intellectual disability and/or autism spectrum disorder (ASD), and those with greater symptom severity within these diagnoses, show higher rates of aggressive/destructive behavior, stereotypic behavior, and self-injurious behavior. In this exploratory cross sectional study, toddlers at-risk for a developmental disorder (n=1509) ranging from 17 to 36 months fell into one of three diagnostic categories: Autistic Disorder, Pervasive Developmental Disorder-Not Otherwise Specified [PDD-NOS], and atypically developing - no ASD diagnosis. Mental health professionals from EarlySteps, Louisiana's Early Intervention System, interviewed parents and guardians using the Baby and Infant Screen for Children with aUtIsm Traits (BISCUIT) -Part 3 (Matson, Boisjoli, & Wilkins, 2007) to obtain measures of challenging behaviors and the Battelle Developmental Inventory, 2nd Edition (BDI 2) (Newborg, 2005) to obtain developmental quotients (DQ). Toddlers diagnosed with Autistic Disorder or PDD-NOS showed a positive relationship between total DQ and challenging behavior; whereas, atypically developing toddlers with no ASD diagnosis showed a more adaptive, negative relationship. The DQ domains that were most influential on challenging behaviors varied by diagnosis, with communication and motor domains playing greater roles for toddlers with Autistic Disorder or PDD-NOS, and personal-social and cognitive domains playing greater roles for atypically developing toddlers with no ASD diagnosis. PMID- 22502837 TI - The tell-tale: what do heart rate; skin temperature and skin conductance reveal about emotions of people with severe and profound intellectual disabilities? AB - Identifying emotions in people with severe and profound intellectual disabilities is a difficult challenge. Since self-reports are not available, behaviour is the most used source of information. Given the limitations and caveats associated with using behaviour as the sole source of information about their emotions, it is important to supplement behavioural information with information from another source. As it is accepted that emotions consist of language, behaviour and physiology, in this article we investigated if physiology could give information about the emotions of people with severe and profound intellectual disabilities. To this aim we tested hypotheses derived from the motivational model of Bradley, Codispoti, Cuthbert, and Lang (2001) about the relation between heart rate and the valence of emotions and between heart rate, skin conductance and skin temperature and behavioural expressions of emotions of people with severe and profound intellectual disability. We presented 27 participants with 4 staff selected negative and 4 staff-selected positive stimuli. The situations were videotaped and their heart rate, skin conductance and skin temperature was measured. Each behaviour of the participant was coded using the observational method developed by Petry and Maes (2006). As hypothesized, we found a lower heart rate when participants were presented with negative stimuli than when they were presented with positive stimuli in the first 6s of stimuli presentation. Their skin temperature was higher for the expression of low intensity negative emotions compared to the expression of low intensity positive emotions. The results suggest that, as with people without disability, heart rate and skin temperature can give information about the emotions of persons with severe and profound ID. PMID- 22502838 TI - Mathematical problems in children with developmental coordination disorder. AB - Developmental coordination disorder (DCD) is a heterogeneous disorder, which is often co-morbid with learning disabilities. However, mathematical problems have rarely been studied in DCD. The aim of this study was to investigate the mathematical problems in children with various degrees of motor problems. Specifically, this study explored if the development of mathematical skills in children with DCD is delayed or deficient. Children with DCD performed significantly worse for number fact retrieval and procedural calculation in comparison with age-matched control children. Moreover, children with mild DCD differed significantly from children with severe DCD on both number fact retrieval and procedural calculation. In addition, we found a developmental delay of 1 year for number fact retrieval in children with mild DCD and a developmental delay of 2 years in children with severe DCD. No evidence for a mathematical deficit was found. Diagnostic implications are discussed. PMID- 22502839 TI - Transcutaneous electrical acupoint stimulation in children with autism and its impact on plasma levels of arginine-vasopressin and oxytocin: a prospective single-blinded controlled study. AB - Acupuncture increases brain levels of arginine-vasopressin (AVP) and oxytocin (OXT), which are known to be involved in the modulation of mammalian social behavior. Transcutaneous electrical acupoint stimulation (TEAS) is often used clinically to produce a similar stimulation to that of acupuncture on the acupoints. In the present study, TEAS was applied to children with autism to assess its therapeutic efficacy. Seventy-six autistic children receiving rehabilitation training were divided into 2 groups: a treatment group receiving TEAS 30min per day, 5 days per week for 12 weeks (n=37) and a control group without TEAS treatment (n=39). A series of rating scales was used in outcome assessment. Plasma levels of AVP and OXT were determined by enzyme immunoassay (EIA) before and after treatment. The TEAS group showed a significant improvement over the control in their emotional response, fear or anxiety, level/consistency of intellective relations and general impressions on the Childhood Autism Rating Scale (CARS) as well as improvements in the sensory and related factors in the Autism Behavior Checklist (ABC). In addition, the varieties of accepted food increased after TEAS treatment. It appears that TEAS was effective in autistic children who showed passive and aloof behavior, but not in those who were active but odd. The plasma level of AVP was significantly higher in the TEAS group than in the control group after the intervention. In addition, the change in the plasma AVP level paralleled the improvement of some of the behavior factors in CARS, including adaptation to environmental change, listening response, perceptive response and fear or anxiety. It is concluded that TEAS is effective for the treatment of autistic children with a passive and aloof social interaction style. Changes in plasma levels of AVP and possibly OXT may be involved in mediating the therapeutic effect of TEAS. PMID- 22502840 TI - Substance abuse among individuals with intellectual disabilities. AB - Individuals with disabilities are a growing population that confronts multiple disadvantages from social and environmental determinants of health. In particular, the 7-8 million people in the U.S. with an intellectual disability (ID) suffer disproportionately from substance use problems, largely because of a lack of empirical evidence to inform prevention and treatment efforts for them. Although available research could inform future research efforts, studies are scattered across disciplines with the last review synthesizing findings written more than five years ago. To consider more recent findings with earlier works, PubMed, PsychINFO, and Google Scholar were searched and produced 37 peer-reviewed texts across multiple disciplines, 15 from 2006 or later. While the prevalence of alcohol and illicit drug use in this population are low, the risk of having a substance-related problem among ID substance users is comparatively high. Gaps in the research and population subgroups that warrant special attention are identified, such as individuals with borderline and mild ID, individuals with co occurring mental illness, and individuals who are incarcerated. Compared with substance abusers without ID, ID substance abusers are less likely to receive substance abuse treatment or remain in treatment. Research is needed to better gauge the magnitude of substance use problems, identify prevention strategies, and specify treatment components that meet the unique needs of individuals with ID. PMID- 22502842 TI - How executive functions are related to intelligence in Williams syndrome. AB - Williams syndrome is characterized by impairments in executive functions (EFs). However, it remains unknown how distinct types of EFs relate to intelligence in this syndrome. The present study analyzed performance on working memory, inhibiting and shifting, and its links to IQ in a sample of 17 individuals with WS, and compared them with a group of 17 typically developing individuals matched on chronological age and gender. In conclusion, our results suggest that working memory, inhibiting, and shifting relate differently to intelligence in WS as well as in typical development, with working memory being the EF most closely related to intelligence in both groups. Notably, the magnitude of the associations between the three EFs and IQ was substantially higher in the WS group than in the TD group, bringing further confirmation to the notion that frontal lobe impairments may produce a general compromise of several EFs. PMID- 22502843 TI - Relationships between respiratory muscle strength and daily living function in children with cerebral palsy. AB - Cerebral palsy (CP) is a common childhood disorder characterized by motor disability. Children with CP are at risk of developing significant respiratory problems associated with insufficient respiratory muscle strength. It is crucial to identify important factors which are associated with the limitations in daily living function in such children. Hence, the aim of this study was to investigate the relationship between respiratory muscle strength and daily living function in children with CP. The participants were 30 children with CP (M+/-SD age, 8.7+/ 2.1 years) and 30 children with typical development (M+/-SD age, 8.3+/-0.9 years). Respiratory muscle strength was measured by maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) for the both groups of children. Children with CP were also assessed on daily living function with the subscales of Pediatric Evaluation of Disability Inventory (PEDI), the Functional Skills Scales (PEDI-FSS) and the Caregiver Assistance Scale (PEDI-CAS). Results show that, compared to the children with typical development, the MIP and MEP in the CP group were significantly lower (p=.003 and p=.001, respectively). In the CP group, MIP and MEP were correlated to two of the three PEDI-FSS domain scores (r=.43-.53, p<.05) but not with the three PEDI-CAS domain scores. MET explained 19% of the variance in the self-care domain score of PEDI-FSS. MEP also explained 15% of the variance in the social domain score of PEDI-FSS. The results of this study demonstrate that respiratory muscle strength in children with CP is correlated positively to their capability levels of daily living self-care and social function, and we suggest this should be taken into account when planning intervention to improving ability of daily living function for children with CP. PMID- 22502841 TI - Symptoms of autism and schizophrenia spectrum disorders in clinically referred youth with oppositional defiant disorder. AB - Examined autism spectrum disorder (ASD) and schizophrenia spectrum disorder (SSD) symptoms in a clinically referred, non-ASD sample (N=1160; ages 6-18) with and without oppositional defiant disorder (ODD). Mothers and teachers completed DSM IV-referenced symptom checklists. Youth with ODD were subdivided into angry/irritable symptom (AIS) or noncompliant symptom (NS) subtypes. Two different classification strategies were used: within-informant (source-specific) and between-informant (source-exclusive). For the source-specific strategy, youth were classified AIS, NS, or Control (C) according to mothers' and teachers' ratings separately. A second set of analyses focused on youth classified AIS according to mother or teacher report but not both (source-exclusive) versus both mother and teacher (cross-informant) AIS. Results indicated the mother-defined source-specific AIS groups generally evidenced the most severe ASD and SSD symptoms (AIS>NS>C), but this was more pronounced among younger youth. Teacher defined source-specific ODD groups exhibited comparable levels of symptom severity (AIS, NS>C) with the exception of SSD (AIS>NS>C; younger youth). Source exclusive AIS groups were clearly differentiated from each other, but there was little evidence of differential symptom severity in cross-informant versus source exclusive AIS. These findings were largely dependent on the informant used to define the source-exclusive groups. AIS and NS groups differed in their associations with ASD and SSD symptoms. Informant discrepancy provides valuable information that can inform nosological and clinical concerns and has important implications for studies that use different strategies to configure clinical phenotypes. PMID- 22502844 TI - Kata techniques training consistently decreases stereotypy in children with autism spectrum disorder. AB - The effects of 14 weeks of Kata techniques training on stereotypic behaviors of children with autism spectrum disorders (ASD) were investigated. The study included 30 eligible (diagnosed ASD, school age) children with ages ranging from 5 to 16 years whom they assigned to an exercise (n=15) or a no-exercise control group (n=15). Participants of the exercise group received Kata techniques instruction four times per week for 14 weeks (56 sessions). Stereotypy was assessed at baseline (pre-intervention), week 14 (post-intervention), and at one month follow up in both groups. Results showed that Kata techniques training significantly reduced stereotypy in the exercise group. Following participation in Kata techniques training, stereotypy decreased from baseline levels by a M of 42.54% across participants. Interestingly, after 30 days of no practice, stereotypy in the exercise group remained significantly decreased compared to pre intervention time. The participants of the control group did not show significant changes in the stereotypy. Teaching martial arts techniques to children with ASD for a long period of time consistently decreased their stereotypic behaviors. PMID- 22502845 TI - Enabling people with developmental disabilities to actively perform designated occupational activities according to simple instructions with a Nintendo Wii Remote Controller by controlling environmental stimulation. AB - The latest researches have adopted software technology, turning the Nintendo Wii Remote Controller into a high performance three-dimensional object orientation detector. This study extended Wii Remote Controller functionality to assess whether two people with developmental disabilities would be able to actively perform designated simple occupational activities according to simple instructions by controlling their favorite environmental stimulation using a Nintendo Wii Remote Controller. This study was conducted using ABAB designs. The data showed that both participants significantly increased their target response (performing a designated occupational activity) by activating the control system to produce their preferred environmental stimulation during the intervention phases. PMID- 22502846 TI - A new screening programme for autism in a general population of Swedish toddlers. AB - The evidence from early intervention studies of autism has emphasised the need for early diagnosis. Insight into the early presentation of autism is crucial for early recognition, and routine screening can optimise the possibility for early diagnosis. General population screening was conducted for 2.5-year-old children at child health centres in Gothenburg, Sweden, and the efficacy of the screening instruments in predicting a clinical diagnosis of autism was studied. The tools used for autism screening comprised the Modified Checklist for Autism in Children (M-CHAT) and an observation made by trained nurses of the child's joint attention abilities (JA-OBS). From the new screening procedure a "definitive" suspicion of autism spectrum disorder (ASD) was raised in 64 individuals in the study population of 3999 young children. Fifty-four of these were clinically assessed in detail. Forty-eight children had a confirmed diagnosis of ASD, three had severe language disorder, and three (6%) were classified as having typical development. The Positive predictive Value (PPV) for the combination of M-CHAT and the JA-OBS was 90%. The combination of instruments used showed promise for early detection of autism as a routine in the developmental programme at child health centres. Trained medical staff is a basic requirement and enables earlier detection and the use of screening tools beyond routine population screening regardless of the age at which a suspicion of autism is raised. PMID- 22502847 TI - Preterm birth and leisure participation: a synthesis of the literature. AB - Leisure participation has been associated with happiness and well-being in children. Individuals born preterm are at greater risk for motor, cognitive and behavioral difficulties which may contribute to difficulties participating in leisure activities. This systematic review examined the current knowledge on participation in leisure activities in individuals born preterm throughout the lifespan as compared to term born controls. An electronic search of eight databases for articles published up to October 2011 was conducted. The quality of each study was assessed using a standardized checklist. Thirteen studies met the selection criteria. In school-age children, no significant differences were found in activity levels between children born prematurely and term born controls. In adolescents, leisure scores in social activities, hobbies and sports were statistically significantly lower compared to controls. In young adults, differences in frequency and intensity of physical activity were reported compared to term controls. Promoting participation in leisure activities should be encouraged at a young age and continued to adulthood by minimizing the gaps between capabilities and the demands of the tasks and the environment. PMID- 22502848 TI - Effects of an exercise programme on anxiety in adults with intellectual disabilities. AB - Although high anxiety is common in people with intellectual disabilities (ID) and the anxiolytic effects of exercise have been systematically recognised in clinical and non-clinical populations, research is scant concerning the role played by exercise on anxiety in people with ID. The purpose of this study was to investigate the effects of a 12-week exercise programme on anxiety states in a group of adults with ID. Twenty-seven individuals with mild to moderate ID were randomly assigned to an exercise group or a control group. The Zung Self-Rating Anxiety Scale adapted for individuals with ID and the State-Trait Anxiety Inventory form Y were used to assess trait and state anxiety. In comparison with the control group, the anxiety scores of people in the exercise group decreased significantly over time. PMID- 22502849 TI - Twenty weeks of computer-training improves sense of agency in children with spastic cerebral palsy. AB - Children with cerebral palsy (CP) show alteration of perceptual and cognitive abilities in addition to motor and sensory deficits, which may include altered sense of agency. The aim of this study was to evaluate whether 20 weeks of internet-based motor, perceptual and cognitive training enhances the ability of CP children to determine whether they or a computer are responsible for the movement of a visually observed object. 40 CP children (8-16 years) were divided into a training (n:20) and control group (n:20). The training group trained 30 min each day for 20 weeks. The ability of the children to judge whether they themselves or a computer were responsible for moving an object on a computer screen was tested before and after the 20-week period. Furthermore, we included a healthy age-matched group to determine a normal functional level of performance. Our results showed a significantly larger increase in the number of correct subjective reporting for the training group (p<0.001). In accordance with this, the training group was also less fooled by computer-induced movements given by a decreased curvature which indicated a compensatory motor strategy when drawing the line to hit the target following the training than the control group (p=0.018). These findings suggest that sense of agency may be altered, and that training of sense of agency may help to increase the outcome of training programmes in children with CP. PMID- 22502850 TI - Fundamental movement skills and physical activity among children with and without cerebral palsy. AB - Fundamental movement skills (FMS) proficiency is believed to influence children's physical activity (PA), with those more proficient tending to be more active. Children with cerebral palsy (CP), who represent the largest diagnostic group treated in pediatric rehabilitation, have been found to be less active than typically developing children. This study examined the association of FMS proficiency with PA in a group of children with CP, and compared the data with a group of typically developing children. Five FMS (run, jump, kick, throw, catch) were tested using process- and product-oriented measures, and accelerometers were used to monitor PA over a 7-day period. The results showed that children with CP spent less time in moderate to vigorous physical activity (MVPA), but more time in sedentary behavior than typically developing children. FMS proficiency was negatively associated with sedentary time and positively associated with time spent in MVPA in both groups of children. Process-oriented FMS measures (movement patterns) were found to have a stronger influence on PA in children with CP than in typically developing children. The findings provide evidence that FMS proficiency facilitates activity accrual among children with CP, suggesting that rehabilitation and physical education programs that support FMS development may contribute to PA-related health benefits. PMID- 22502851 TI - Construct validity of the Children's Hand-Skills ability Questionnaire (CHSQ) in children with disabilities: a Rasch analysis. AB - The Children's Hand-Skill ability Questionnaire (CHSQ) is a new parent-report questionnaire that assesses children's manual ability in three domains: leisure and play, school/education, and activities of daily living. The CHSQ can be used with children presenting with a range of disabilities and works as a companion assessment before detailed performance-based observations of hand skill are completed. This study further investigated the internal and external construct validity of the CHSQ. Participants included 53 Australian children and 70 Taiwanese children with known disabilities ranging age from 2 to 12 years. Rasch analysis results confirmed the appropriateness of the CHSQ's 3-level rating scale in this combined group of children. Twenty-one of the 22 items in the CHSQ formed three individual unidimensional scales representing with the domains of leisure and play, school/education, and activities of daily living. The CHSQ also exhibited sufficient person-response validity (all the three domains) and item difficulty range (all but one domain) when applied to children with disabilities. Less than half of the CHSQ items were found to exhibit differential item functioning with regards to gender (4 items) and cultural difference (7 items). In addition, moderate to high correlations (0.61 <= Pearson's r coefficients <= 0.76, p<0.01) were found with the assessments of self-care and hand skill performance. Therefore, the CHSQ exhibits preliminary evidence of construct validity for its clinical use in obtaining children's manual ability based on parent-report information. PMID- 22502852 TI - Social deficits in male children and adolescents with sex chromosome aneuploidy: a comparison of XXY, XYY, and XXYY syndromes. AB - We compare social skills in three groups of males with sex chromosome aneuploidies (SCAs) using the Social Responsiveness Scale (SRS). Participants included males with XXY (N=102, M=10.08 years), XYY (N=40, M=9.93 years), and XXYY (N=32, M=11.57 years). XXY had lower (better) SRS scores compared to XYY and XXYY. Scores were not significantly different between XYY and XXYY. In all groups, there were significantly more with SRS scores in the severe range compared to the SRS normative sample. All groups scored lowest (better) on Social Motivation. Relationships between SRS scores and demographic and clinical variables were examined. Results describe the social skills in males with SCA, and suggest that an additional Y chromosome may contribute to increased risk of autistic behaviors. PMID- 22502853 TI - Unsupervised Categorization in a sample of children with autism spectrum disorders. AB - Studies of supervised Categorization have demonstrated limited Categorization performance in participants with autism spectrum disorders (ASD), however little research has been conducted regarding unsupervised Categorization in this population. This study explored unsupervised Categorization using two stimulus sets that differed in their difficulty of Categorization according to the simplicity model. ASD participants displayed a greater tendency to categorise according to one dimension as compared with mental-aged matched participants in the easily categorised sets, but both ASD and Control groups became more prone to one-dimensional sorting as the difficulty of the Categorization task increased. These results are discussed in terms of the processes underlying over-selective responding. PMID- 22502854 TI - Quantifying morbidity burdens and medical utilization of children with intellectual disabilities in Taiwan: a nationwide study using the ACG case-mix adjustment system. AB - The purpose of this study was to quantify morbidity burdens of children with intellectual disability (ID) and to examine its association with total medical utilization and expenditure on a national basis in Taiwan. People under 18 years of age that had been continuously enrolled in the National Health Insurance (NHI) between year 2008 and 2010 were selected from one million randomly-sampled NHI beneficiaries. The Johns Hopkins Adjusted Clinical Group (ACG) System was applied to evaluate an individual's morbidity burden using 2008-2010 claims data, including age, sex, diagnosis, pharmacy, ambulatory, and inpatient utilization and expenditure (in New Taiwan Dollars, NTDs). The ID prevalence rate was 0.69% for people aged under 18. People with ID could be assigned to 20 mutually exclusive ACGs and to five simplified morbidity categories: healthy (0.1%), low (1.5%), moderate (31.9%), high (44.0%), and very high (22.4%). People with ID had more per capita visits (108.4 vs. 51.5, p<0.001), hospital admission (27.7% vs. 13.1%, p<0.001), pharmacy (NTD 21,069 vs. 4983, p<0.001) and total expenditure (NTD 144,962 vs. 29,764, p<0.001) than those without ID over 3 years. Those who assigned to the high-morbid categories cost more in ambulatory and inpatient services than those with low to moderate morbidities. In conclusion, the morbidity burdens of people with ID can be quantified by the ACG System based on readily available data. Regularly evaluating morbidity burdens and medical utilization has particular relevance for planning high-quality and efficient care. People's disabilities and comorbid illnesses shall be treated by integrated multidisciplinary teams. PMID- 22502855 TI - Survey and analysis of dental caries in students at a deaf-mute high school. AB - The present cross-sectional study was conducted to assess and compare the prevalence of dental caries of 229 deaf adolescents in a special senior high school and to identify factors related to dental caries, with a match group of 196 healthy adolescents in a normal senior high school, in Jiangsu province of East China. In this study the prevalence of dental caries was 55.9%, Decayed, Missing and Filled Teeth (DMFT) index in deaf students was 1.40+/-1.89; in healthy students was 13.8% and 1.36+/-1.72, respectively. Relatively lower proportion of awareness on dental health knowledge and lower proper practice of dental health behavior have been observed among deaf students compared with the control group. Multiple logistic regressions showed that the risk factors of dental caries in deaf students involved high frequency of consuming dessert and carbonated beverage. Poor oral health, lack of oral health knowledge and proper oral health practice could be found in deaf students. The dental treatment for the two groups was urgently needed. The dental health education concerning dietary behavior and prevention program to the deaf students and their parents should be reinforced; the supervision of oral health behavior for deaf and healthy students needs to be strengthened. PMID- 22502856 TI - Psychiatric disorders among children with cerebral palsy at school starting age. AB - The aim of the present population study was to estimate the prevalence of psychiatric disorders in children with cerebral palsy (CP), as well as the impact of comorbid conditions. A cohort of children with CP born 2001-2003, and living in the Western Health Region of Norway were evaluated at school starting age. Parents were interviewed with the diagnostic instrument Kiddie-SADS, to find the prevalence of psychiatric disorders. Sixty-seven children participated, 43 boys, with mean age 88 months (SD 6,8 months). Most children had spastic CP, Gross Motor Function Classification System (GMFCS) levels I and II were found in 2/3 of the group. We found the diagnostic instrument appropriate for GMFCS levels I-IV. Child psychiatric disorders were found in 57% of the children, including 28 children meeting criteria for an attention deficit disorder, which was the most common. Communication problem was significantly associated with having a psychiatric disorder, whereas intellectual disability, type of CP and functional level did not account for significant differences. Subthreshold symptoms were found in 33 children, and 42 children (75%) met criteria for either psychiatric disorder, or mental health symptoms. One in four (14 children) were considered well-functioning from a mental health point of view. We conclude with a recommendation for early psychiatric evaluation of all children with CP. PMID- 22502857 TI - Static standing balance in adolescents with Down syndrome. AB - AIM: To analyse static-standing-balance of adolescents with Down syndrome (DS). METHODS: Thirty-two adolescents with DS aged 10-19 years (DSG); 33 adolescents, age/sex-matched, without DS (CG). Static-standing-balance under four conditions (C1: open-eyes/fixed-foot-support; C2: closed-eyes/fixed-foot-support; C3: open eyes/compliant-foot-support; closed-eyes/compliant-foot-support) was examined by means of time and frequency Postural-Parameters (PPs). To evaluate the contribution of each sensory system influencing postural control ratios among the four conditions were calculated. Mean values of all PPs were higher in the DSG than in the CG. Mean values of time PPs were higher in both groups on compliant foot-support (with open and closed eyes) than on fixed-foot-support. Ratios C2/C1 were significantly lower in DSG than in CG; ratios C3/C1 presented higher values in DSG than in CG, with significant differences in length path and RMS-velocity; there were no differences in ratios C4/C1. CONCLUSIONS: In our group of DS adolescents the shift from visual to multimodal control of stance had occurred and they showed similar postural control patterns than non-DS. Even though, they presented worse static balance than their peers without DS and they had more problems with altered somasosensory input. An adequate rehabilitation program insisting on somatosensory input could be a useful measure to improve balance. PMID- 22502858 TI - Handwriting performance and underlying factors in children with Attention Deficit Hyperactivity Disorder. AB - Preliminary evidence suggests that handwriting difficulties are common to children with Attention Deficit Hyperactivity Disorder (ADHD). However, the nature of the task-specific impairments is needed to be clarified. The aim of this study was to describe handwriting capacity in ADHD children without DCD and identify underlying factors of performance by use of outcome-oriented assessments and a digitizing tablet. Twenty-one children with ADHD (8.59+/-1.25 years) and 21 match controls (8.5+/-1.08 years) were recruited. Children with ADHD scored lower than controls on Tseng Handwriting Problem Checklist and writing composite of Basic Reading and Writing Test, indicating the ADHD group wrote less legibly. The ADHD group spent more on-paper time to copy 50 Chinese characters and exhibited more writing time during the writing process. The ADHD group scored significantly lower on tasks demanding upper limb and eye-hand coordination and visual-motor integration compared with controls. Furthermore, motor skill and visual-motor integration were positively correlated with the legibility. Motor skill was negatively correlated with writing time, in-air time, and in-air trajectory. PMID- 22502859 TI - Prevalence, associated factors and treatment of sleep problems in adults with intellectual disability: a systematic review. AB - In people with intellectual disability (ID), impaired sleep is common. Life expectancy has increased in this group, and it is known that in general population sleep deteriorates with aging. Therefore the aims of this systematic review were to examine how sleep problems are defined in research among adults and older people with ID, and to collect information on the prevalence, associated factors and treatment of sleep problems in this population. PubMed, EMBase, PsycINFO and Web of Science were searched for studies published between January 1990 and August 2011. All empirical studies covering sleep problems in adults with ID were included, and assessed on quality (level of evidence), using a slightly modified version of the SIGN-50 methodology checklist for cohort studies. Of 50 studies that were included for systematic review, one was of high quality, 14 were well conducted, 14 were well conducted but with a high risk of bias, and 21 were non-analytical. The reported estimated prevalence rates of sleep problems in adults with ID ranged from 8.5% to 34.1%. A prevalence of 9.2% was reported for significant sleep problems. Sleep problems were associated with the following factors: challenging behavior; respiratory disease; visual impairment; psychiatric conditions; and using psychotropic, antiepileptic and/or antidepressant medication. Little information was found on older people specifically. Two studies reported treatment effects on sleep problems in larger populations; their findings suggest that non-pharmaceutical interventions are beneficial. Research on the prevalence, associated factors and treatment of sleep problems in adults and older people with ID has mainly focused on subjectively derived data. The definitions used to describe a sleep problem are not uniform, and associations are mainly described as correlations. In order to give recommendations for clinical practice further research is needed, involving objective measurements and multivariate analysis. PMID- 22502860 TI - Prevalence of self-reported asthma in urban and rural areas of Turkey. AB - BACKGROUND AND PURPOSE: The risk factors for asthma in rural and urban population of Turkey are not well known. In this study we examined the effects of risk factors on the prevalence of asthma in adults living in rural and urban areas using data from a representative sample. METHODS: Parents and grandparents of students from 20 randomly selected primary schools in urban and rural areas of Kirikkale, Turkey, were asked about respiratory diseases using the respiratory questionnaire, which were returned to us by their children. RESULTS: Out of 13,225 parents and grandparents of primary school students 12,270 returned the questionnaires, for an overall response rate of 92.7%. The prevalence of asthma was more common in adults living in rural areas than in urban areas (10.8% vs. 6.2%, p < .0001, respectively). Asthma was more prevalent in women exposed to biomass smoke than those who were not exposed to it in rural areas (14.8% vs. 6.6%, p = .0001, respectively). Frequent childhood respiratory infections were more common in adults living in rural areas than in urban areas (18.2% vs. 10.9%, p < .0001, respectively). Exposure to biomass smoke and frequent childhood respiratory infections were associated with an increased risk of asthma, after adjusting for possible confounding factors in the logistic model for rural subjects. Chronic rhinitis (p = .0001) and frequent childhood respiratory infections (p = .0001) were associated with an increased risk of asthma, after adjusting for possible confounding factors in the logistic model for urban subjects. CONCLUSIONS: The prevalence of asthma in adults living in the rural areas of the Kirikkale Region in Central Turkey was significantly higher than that in the urban population. Exposure to biomass smoke and childhood respiratory infections were more common in adults living in rural areas. The higher rate of asthma in adults living in rural areas may be due to a higher frequency of childhood respiratory infections and exposure to biomass smoke. PMID- 22502862 TI - Tips and tricks for high quality MAR-FISH preparations: focus on bacterioplankton analysis. AB - The combination of microautoradiography and fluorescence in situ hybridization (MAR-FISH) is a powerful technique for tracking the incorporation of radiolabelled compounds by specific bacterial populations at a single cell resolution. It has been widely applied in aquatic microbial ecology as a tool to unveil key ecophysiological features, shedding light on relevant ecological issues such as bacterial biomass production, the role of different bacterioplankton groups in the global carbon and sulphur cycle, and, at the same time, providing insights into the life styles and niche differentiation of cosmopolitan members of the aquatic microbial communities. Despite its great potential, its application has remained restricted to a few laboratories around the world, in part due to its reputation as a "difficult technique". Therefore, the objective of this minireview is to highlight the impact of MAR-FISH application on aquatic microbial ecology, and also to provide basic concepts, as well as practical tips, for processing MAR-FISH preparations, thus aiming to contribute to a more widespread application of this powerful method. PMID- 22502861 TI - Regulation of ATP production by mitochondrial Ca(2+). AB - Stimulation of mitochondrial oxidative metabolism by Ca(2+) is now generally recognised as important for the control of cellular ATP homeostasis. Here, we review the mechanisms through which Ca(2+) regulates mitochondrial ATP synthesis. We focus on cardiac myocytes and pancreatic beta-cells, where tight control of this process is likely to play an important role in the response to rapid changes in workload and to nutrient stimulation, respectively. We also describe a novel approach for imaging the Ca(2+)-dependent regulation of ATP levels dynamically in single cells. PMID- 22502863 TI - Activated cranial cervical cord neurons affect left ventricular infarct size and the potential for sudden cardiac death. AB - To evaluate whether cervical spinal neurons can influence cardiac indices and myocyte viability in the acutely ischemic heart, the hearts of anesthetized rabbits subjected to 30 min of LAD coronary arterial occlusion (CAO) were studied 3h after reperfusion. Control animals were compared to those exposed to pre emptive high cervical cord stimulation (SCS; the dorsal aspect of the C1-C2 spinal cord was stimulated electrically at 50 Hz; 0.2 ms; 90% of motor threshold, starting 15 min prior to and continuing throughout CAO). Four groups of animals were so tested: 1) neuroaxis intact; 2) prior cervical vagotomy; 3) prior transection of the dorsal spinal columns at C6; and 4) following pharmacological treatment [muscarinic (atropine) or adrenergic (atenolol, prazosin or yohimbine) receptor blockade]. Infarct size (IS) was measured by tetrazolium, expressed as percentage of risk zone. C1-C2 SCS reduced acute ischemia induced IS by 43%, without changing the incidence of sudden cardiac death (SCD). While SCS-induced reduction in IS was unaffected by vagotomy, it was no longer evident following transection of C6 dorsal columns or atropinization. Beta-adrenoceptor blockade eliminated ischemia induced SCD, while alpha-receptor blockade doubled its incidence. During SCS, myocardial ischemia induced SCD was eliminated following vagotomy while remaining unaffected by atropinization. These data indicate that, in contrast to thoracic spinal neurons, i) cranial cervical spinal neurons affect both adrenergic and cholinergic motor outflows to the heart such that ii) their activation modifies ventricular infarct size and lethal arrhythmogenesis. PMID- 22502864 TI - Treatment of seasonal allergic rhinoconjunctivitis with a once-daily SQ standardized grass allergy immunotherapy tablet. AB - OBJECTIVES: Specific immunotherapy with the grass allergy immunotherapy tablet (AIT) has been developed as an effective, well tolerated, and convenient treatment for grass pollen induced seasonal allergic rhinoconjunctivitis (ARC). Six phase II/III randomized, placebo-controlled trials with the duration of a single grass pollen season of treatment using the SQ-standardized grass AIT, Grazax (Phleum pratense, 75,000 SQ-T/2,800 BAU, ALK, Denmark), have been published previously. This review compares results from these trials. METHODS: As outcome measures and methods of assessing them were similar across the trials, we have summarized the main efficacy findings (Total Combined Score [TCS], average daily rhinoconjunctivitis symptom and medication scores, percentage of well days, quality of life scores) during a single season of treatment with grass AIT in adults and children with seasonal ARC. RESULTS: The results of the European and North American trials were similar. Compared with the placebo group, who received symptomatic medications only, treatment with grass AIT resulted in fewer rhinoconjunctivitis symptoms, a lower intake of symptomatic medication, better patient self-rated quality of life and a greater percentage of well days during the entire grass pollen season. The data indicate that grass AIT treatment is equally effective in adults and children; the measured effect varies with pollen exposure, but is comparable across regions and continents, with a consistent difference compared with placebo in TCS that was above 20% for all trials. Local adverse events were experienced by the majority of patients. These reactions were generally mild to moderate in severity and transient in duration. Systemic adverse events were rare. CONCLUSIONS: This review confirms SQ-standardized grass AIT as a suitable therapeutic option for seasonal use in patients aged 5 years or older with grass pollen induced ARC. PMID- 22502865 TI - Loss of PPARgamma expression by fibroblasts enhances dermal wound closure. AB - BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)gamma may be a key regulator of connective tissue deposition and remodeling in vivo. PPARgamma expression is reduced in dermal fibroblasts isolated from fibrotic areas of scleroderma patients; PPARgamma agonists suppress the persistent fibrotic phenotype of this cell type. Previously, we showed that loss of PPARgamma expression in fibroblasts resulted in enhanced bleomycin-induced skin fibrosis. However, whether loss of PPARgamma expression in skin fibroblasts affects cutaneous tissue repair or homeostasis is unknown. RESULTS: Mice deleted for PPARgamma in skin fibroblasts show an enhanced rate of dermal wound closure, concomitant with elevated phosphorylation of Smad3, Akt and ERK, and increased expression of proliferating cell nuclear antigen (PCNA), collagen, alpha-smooth muscle actin (alpha-SMA) and CCN2. Conversely, dermal homeostasis was not appreciably affected by loss of PPARgamma expression. CONCLUSION: PPARgamma expression by fibroblasts suppresses cutaneous tissue repair. In the future, direct PPARgamma antagonists and agonists might be of clinical benefit in controlling chronic wounds or scarring, respectively. PMID- 22502866 TI - The poly(A)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites. AB - Alternative cleavage and polyadenylation (APA) is emerging as an important layer of gene regulation. Factors controlling APA are largely unknown. We developed a reporter-based RNAi screen for APA and identified PABPN1 as a regulator of this process. Genome-wide analysis of APA in human cells showed that loss of PABPN1 resulted in extensive 3' untranslated region shortening. Messenger RNA transcription, stability analyses, and in vitro cleavage assays indicated enhanced usage of proximal cleavage sites (CSs) as the underlying mechanism. Using Cyclin D1 as a test case, we demonstrated that enhanced usage of proximal CSs compromises microRNA-mediated repression. Triplet-repeat expansion in PABPN1 (trePABPN1) causes autosomal-dominant oculopharyngeal muscular dystrophy (OPMD). The expression of trePABPN1 in both a mouse model of OPMD and human cells elicited broad induction of proximal CS usage, linked to binding to endogenous PABPN1 and its sequestration in nuclear aggregates. Our results elucidate a novel function for PABPN1 as a suppressor of APA. PMID- 22502867 TI - Atypical fibroxanthoma developing on a pacemaker pocket mimicking a pyogenic granuloma. AB - Malignant tumors at the site of implantation of a pacemaker generator, although rare, have been reported in the literature. We present a case of an 89-year-old man with atypical fibroxanthoma in a pacemaker pocket. The device had been implanted for more than 4 years. An exophytic tumor had developed in this place and was clinically interpreted as a pyogenic granuloma. An excisional biopsy revealed the nature of the tumor. To our knowledge, the association of atypical fibroxanthoma arising from a pacemaker pocket has not been previously reported. A review of the literature has revealed four malignant soft tissue tumors previously reported at the pacemaker site. Routine examination in all patients with implanted pacemaker generators should be practiced at follow-up visits. This would allow an early diagnosis of a malignant associated neoplasm. Pathologists should become familiar with this type of devices and their potential neoplastic complications. PMID- 22502868 TI - Cardiovascular risk and atherosclerosis prevention. AB - Until recently, coronary artery disease (CAD) was the leading cause of death in the developed countries. Its remarkable decline can be attributed to our knowledge of the major risk factors identified by several studies resulting in better prevention and treatment. Of the major risk factors, the ratio of apolipoprotein (apo) B/apo A1 followed by smoking, diabetes, and hypertension are the most important. A number of risk scores for men and women are now available to estimate the likelihood of development of CAD. However, because of the risk of CAD differs in various populations, some of the algorithms are more appropriate for some countries but not suitable for others. These risk assessment algorithms differ in the parameters they use. All the risk scores have some limitations such as different study populations; the age of the study is also different, and number of points awarded for age categories also differs among the various algorithms. In an effort to further improve the risk prediction, a number of biomarkers have been studied. In addition to plasma lipids, a lot of interest has focused on apo measurements; particularly of apo B. Another valuable biomarker is lipoprotein (a) [Lp(a)]. Lp(a) is not only atherogenic as low-density lipoprotein (LDL) but also prothrombotic, and several studies indicate that Lp(a) is an independent risk factor for CAD. The lipid profile provides a framework for appropriate management. This includes therapeutic lifestyle changes and medications. Lifestyle interventions are the cornerstone of CAD prevention strategies and are the first step in risk factor management. Of particular importance are smoking cessation, achievement and maintenance of ideal body weight, regular exercise, reduction in the intake of saturated fat and sugars, and decreasing level of stress. Of medications, lipid-lowering, anti hypertensive, and anti-coagulant can be effectively used. The current strategies for risk assessment and prevention have been very successful contributing to the more than 50% decrease in CAD mortality over the last 20 years. Thus, in Canada, cardiovascular disease is no longer the leading cause of death. PMID- 22502869 TI - CD4+CD25+ T regulatory cell-depleted splenocytes enhance chimerism in graft recipients. PMID- 22502870 TI - The expanding universe of bile acid physiology: delving into the mysteries of dark (green) matter. PMID- 22502871 TI - Cloning and biochemical analysis of beta-glucoside utilization (bgl) operon without phosphotransferase system in Pectobacterium carotovorum subsp. carotovorum LY34. AB - beta-Glucosidases are widespread in bacteria and involved in the metabolism of various carbohydrate substrates. Studying of beta-glucoside utilization (bgl) operons on operon of Pectobacterium carotovorum subsp. carotovorum LY34 (Pcc LY34) will help us understanding how beta-glucoside utilization (bgl) operon can cooperate with other systems in bacterium caused soft-rot disease. Pcc LY34 causes soft-rot disease in plants and expresses multiple enzymatic forms of beta glucosidases. To fully explore the beta-glucoside utilization system in Pcc LY34, we have isolated a bgl operon from a genomic library for screening of beta glucosidase activities. Sequence analysis of a 3050bp cloned DNA fragment (accession number AY870655) shows two open reading frames (bglY and bglK) that are predicted to encode proteins of 474 and 278 amino acid residues, respectively. Pair wise similarity analysis suggests BglY is a beta-glucosidase (a member of glycosyl hydrolase family 1) and BglK is a transcriptional antiterminator protein. bglY promoter region contains an inverted repeat sequence similar to transcriptional terminator. Different from other four beta-glucoside utilization operons of Pcc LY34 strain, BglY contains signal peptide sequences as extracellular beta-glucosidase. Comparisons of five beta-glucoside utilization operons of Pcc LY34 strain showed that bglYK operon does not have phosphotransferase system domain which are responsible for sugar transportation. BglY shares 33-44% identity with other four beta-glucosidases of Pcc LY34 strain. Enzyme assay showed that purified BglY enzyme hydrolyzed salicin, arbutin, pNPG, and MUG, and exhibited maximal activity at pH 7.0 and 40 degrees C. This activity was enhanced Mg(2+). Site-directed mutagenesis revealed E166 and E371 are critical of BglY's beta-glucosidase activity. PMID- 22502872 TI - Unique toxin profile of a Mediterranean Ostreopsis cf. ovata strain: HR LC-MS(n) characterization of ovatoxin-f, a new palytoxin congener. AB - Currently, the benthic dinoflagellate Ostreopsis cf. ovata represents a serious concern to human health in the whole Mediterranean basin due to the production of palytoxin congeners, a putative palytoxin and ovatoxins (ovatoxin-a, -b, -c, -d/ e), listed among the most potent marine toxins. High resolution liquid chromatography-mass spectrometry (HR LC-MS) based investigation of a North Western Adriatic strain of Ostreopsis cf. ovata collected at Portonovo (Italy) in 2008 is reported herein. Toxin profile was different from those previously reported for other O. cf. ovata, both qualitatively and quantitatively. For the first time, ovatoxin-a did not dominate the toxin profile, and a new palytoxin congener, here named ovatoxin-f, was detected. Ovatoxin-f and its elemental formula present C(2)H(4) more than ovatoxin-a. HR CID MS(n) experiments allowed us to restrict structural differences between ovatoxin-a and -f to the region between C-95 and C-102, a region not previously been described to be modified in other palytoxins. Ovatoxin-f represents the major component of the toxin profile of the analyzed strain accounting for 50% of the total toxin content, while ovatoxin-a, the dominant toxin in most of the Mediterranean O. cf. ovata strains we have analyzed so far, is the second major component of the toxin profile (23%). Thus, the presence of ovatoxin-f should be taken into account when monitoring programs for palytoxin-like compounds in microalgae and/or seawater are carried out. PMID- 22502875 TI - Rapid characterization of transgenic and non-transgenic soybean oils by chemometric methods using NIR spectroscopy. AB - Near infrared (NIR) spectroscopy and multivariate classification were applied to discriminate soybean oil samples into non-transgenic and transgenic. Principal Component Analysis (PCA) was applied to extract relevant features from the spectral data and to remove the anomalous samples. The best results were obtained when with Support Vectors Machine-Discriminant Analysis (SVM-DA) and Partial Least Squares-Discriminant Analysis (PLS-DA) after mean centering plus multiplicative scatter correction. For SVM-DA the percentage of successful classification was 100% for the training group and 100% and 90% in validation group for non transgenic and transgenic soybean oil samples respectively. For PLS DA the percentage of successful classification was 95% and 100% in training group for non transgenic and transgenic soybean oil samples respectively and 100% and 80% in validation group for non transgenic and transgenic respectively. The results demonstrate that NIR spectroscopy can provide a rapid, nondestructive and reliable method to distinguish non-transgenic and transgenic soybean oils. PMID- 22502873 TI - Prognostic role of tumour multifocality in renal cell carcinoma. AB - What's known on the subject? and What does the study add? In RCC about 5% of the patients presented multifocal disease. Prevalence of tumour multifocality was associated with a higher percentage of symptomatic RCC, higher pathological TNM stages, higher tumour grade and higher prevalence of tumour necrosis. Although in univariable analysis multifocal tumours had lower probability of CSS, tumour multifocality did not retain an independent predictive role in multivariable analysis. Patient age at surgery, gender, mode of presentation, pathological N stage and presence of metastases were independent predictors of CSS in multivariable analyses. OBJECTIVE: * To evaluate the prevalence and the prognostic role of multifocality in a large multi-institutional series of patients who underwent radical or partial nephrectomy for renal cell carcinoma (RCC). METHODS: * We retrospectively collected the data of 5378 patients who were surgically treated for RCC in 16 academic centres involved in the Surveillance and Treatment Update Renal Neoplasms (SATURN) project. * Univariable and multivariable Cox regression models addressed time to cancer-specific survival (CSS) after surgery. RESULTS: * Tumour multifocality was identified in 249 patients (5%). The median follow-up of the whole cohort was 42 months. At last follow-up, 786 (14.6%) were dead of cancer and 336 (6.2%) had experienced non cancer-related death. * The 5- and 10-year CSS estimates were 84.1% and 77.3%, respectively, in patients with monofocal RCC, compared with 71.1% and 63.6%, respectively, in patients with multifocal disease (P < 0.001). * In univariable Cox regression analysis, tumour multifocality was significantly associated with CSS (hazard ratio [HR]= 1.83; P < 0.001). * On multivariate Cox regression analysis adjusted for the effects of other covariates, tumour multifocality did not retain an independent predictive value (HR = 1.24; P= 0.291). CONCLUSIONS: * In the present multi-institutional collaboration, about 5% of the patients presented multifocal RCC. * The presence of multifocal cancer was associated with some unfavourable clinical and pathological features. * Although in univariable analysis multifocal tumours had lower CSS probabilities, tumour multifocality did not retain an independent predictive role in multivariable analysis, once adjusted for the effect of the other clinical and pathological covariates. PMID- 22502874 TI - The report of male gender and retinopathy status improves the current consensus guidelines for the screening of myocardial ischemia in asymptomatic type 2 diabetic patients. AB - BACKGROUND AND AIMS: American Diabetes Association (ADA), French-speaking Societies for diabetes & cardiology (ALFEDIAM-SFC) and Cardiac Radionuclide Imaging (CRI) have proposed guidelines for the screening of silent myocardial ischemia (SMI). The aim of the study was to evaluate their diagnostic values and how to improve them. METHODS AND RESULTS: 731 consecutive type 2 diabetic patients with >=1 additional risk factor were screened between 1992 and 2006 for SMI by stress myocardial scintigraphy and for silent coronary artery disease (CAD) by coronary angiography. A total of 215 (29.4%) patients had SMI, and 79 of them had CAD. ADA (Odds Ratio 1.7 [95% Confidence Interval: 1.2-2.5]; p < 0.05), ALFEDIAM-SFC (OR 1.5 [1.0-2.5], p < 0.05) and CRI criteria (OR 2.0 [1.4-2.8], p < 0.01) predicted SMI. Considering the presence of male gender and retinopathy added to the prediction of SMI allowed by ADA criteria (c statistic: area under the curve AROC 0.651 [0.605-0.697] versus 0.582 [0.534-0.630]), p < 0.01 and ALFEDIAM-SFC criteria (AROC 0.672 [0.620-0.719] versus 0.620 [0.571-0.670], p < 0.05). CRI prediction of SMI was improved by considering the presence of macroproteinuria and retinopathy (AROC 0.621 [0.575-0.667] versus 0.594 [0.548 0.641], p < 0.01). Severe retinopathy (OR 3.4 [1.2-9.4], p < 0.05), smoking habits (OR 2.1 [1.1-4.2], p < 0.05) and triglyceride levels (OR 1.3 [1.0-1.6], p < 0.05) were independent predictors of CAD in the patients with SMI. CONCLUSION: Current guidelines criteria are able to predict SMI but prediction may be improved by considering male gender and the presence of retinopathy. CAD is more frequent in the patients with SMI who are current smokers, have severe retinopathy and higher triglyceride levels. PMID- 22502876 TI - Tumour microenvironment and radiation response in sarcomas originating from tumourigenic human mesenchymal stem cells. AB - BACKGROUND: Resistance to radiation therapy remains a serious impediment to cancer therapy. We previously reported heterogeneity for clonogenic survival when testing in vitro radiation resistance among single-cell derived clones from a human mesenchymal cancer stem cell model (hMSC). Here we aimed to determine whether this heterogeneity persisted in tumours established from these clones, and whether the response to radiation treatment was principally governed by cell intrinsic qualities or by factors pertaining to the tumour microenvironment, such as the degree of hypoxia and vascularization. METHODS: Immune-deficient female mice were implanted on the backs with cells from one of the clones. The subsequent tumours were subjected to either radiation treatment or had the tumour microenvironment assayed, when they reached 400 mm3. Radiation was given as a single fraction of 0-15 Gy and the degree of tumour control and time to three times the treatment volume were noted. Tumours used for the microenvironmental assay had intratumoral hypoxia measured by the Eppendorf oxygen electrode and pimonidazole staining, and the extent of vascularization determined by a microvasculature density assay using endothelial-specific staining. RESULTS: All microenvironmental assays indicated a similar degree of hypoxia and vascularization for the selected clones. Nonetheless, the tumours responded differently to radiation treatment since the BB3 clone displayed tumour control at 5, 10 and 15 Gy, whereas tumour control was not seen below 15 Gy with the CE8 clone. CONCLUSION: For tumours that displayed similar degrees of oxygenation and vascularization, the clone-specific in vitro radiation resistance could predict the in vivo response to radiation treatment. These results favor the hypothesis that intrinsic genetic factors can govern radiation resistance in this cancer stem cell model. PMID- 22502877 TI - A method of evaluating the lower limit of cerebral autoregulation and its correlation with blood pressure by transcranial Doppler in rats. AB - The aim of present study was to validate the assessment of lower limit of cerebral autoregulation (LLCA) as derived from mean artery blood pressure (MABP) and cerebral zero flow pressure (ZFP) by means of transcranial Doppler (TCD) and to determine the accurate relationship between LLCA and MABP in stroke-prone renovascular hypertensive rats (RHRSP). We studied two groups of rats: RHRSP and normal controls. Blood flow velocity of middle cerebral artery was monitored by TCD and arterial blood pressure was recorded in right femoral artery to compute the ZFP. The value of LLCA was determined as the difference between MABP and ZFP and validated by the value determined by blood withdrawal-induced cerebral autoregulation. In normal rats, the LLCA derived from the new method was 69.8 +/- 8.7 mm Hg, from the change of blood velocity was 69.4 +/- 9.8 mmHg and from blood volume flow after blood withdrawal was 68.8 +/- 9.7 mmHg. In the RHRSP group, the corresponding values of LLCA were 109.1 +/- 17.2 mm Hg, 110.0 +/- 18.0 mm Hg and 109.0 +/- 19.3 mm Hg, respectively. In each group, there was no statistically significant difference among the three values. LLCA in RHRSP began to increase 6 weeks after hypertension-induced operation, significantly higher than controls (p < 0.05), and stabilized at 110 mm Hg, 10 weeks after operation. The increase of LLCA was positively correlated with MABP, following an "S" curve, demonstrating that the change of LLCA was more obvious in the middle range of MABP in RHRSP (R(2) = 0.8848, p < 0.05). In conclusion, TCD is a valid and noninvasive method for determination of LLCA compared with the classic method in rats. Our data demonstrated that the change of LLCA may be correlated with MABP, following an "S" curve relationship. PMID- 22502878 TI - Effect of albumin and dextrose concentration on ultrasound and microbubble mediated gene transfection in vivo. AB - Ultrasound and microbubble mediated gene transfection has great potential for site-selective, safe gene delivery. Albumin-based microbubbles have shown the greatest transfection efficiency but have not been optimised specifically for this purpose. Additionally, few studies have highlighted desirable properties for transfection specific microbubbles. In this article, microbubbles were made with 2% or 5% (w/v) albumin and 20% or 40% (w/v) dextrose solutions, yielding four distinct bubble types. These were acoustically characterised and their efficiency in transfecting a luciferase plasmid (pGL4.13) into female, CD1 mice myocardia was measured. For either albumin concentration, increasing the dextrose concentration increased scattering, attenuation and resistance to ultrasound, resulting in significantly increased transfection. A significant interaction was noted between albumin and dextrose; 2% albumin bubbles made with 20% dextrose showed the least transfection but the most transfection with 40% dextrose. This trend was seen for both nonlinear scattering and attenuation behaviour but not for resistance to ultrasound or total scatter. We have determined that the attenuation behaviour is an important microbubble characteristic for effective gene transfection using ultrasound. Microbubble behaviour can also be simply controlled by altering the initial ingredients used during manufacture. PMID- 22502879 TI - Experimental research of RB94 gene transfection into retinoblastoma cells using ultrasound-targeted microbubble destruction. AB - The purpose of this study was to explore the transfection of the recombinant expression plasmid pEGFP-C1/RB94 into human retinoblastoma cells (HXO-Rb44) using ultrasound-targeted microbubble destruction (UTMD). pEGFP-C1/RB94 was transfected into HXO-Rb44 in vitro by UTMD, with liposome as the positive control. After 24 to 72 h, the expression of the reporter gene enhanced green fluorescent protein (EGFP) was observed using fluorescent microscopy and flow cytometry. The cell viability of HXO-Rb44 was measured by a MTT assay. The mRNA and proteins of RB94, caspase-3 and Bax were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Moreover, the apoptosis rate and cell cycle progression of the cells were detected by flow cytometry. This study demonstrated that UTMD can enhance the transfection efficiency of RB94, which has an obvious impact on the inhibition of the growth process of retinoblastoma cells, suggesting that the combination of UTMD and RB94 compounds might be a useful tool for use in the gene therapy of retinoblastoma. PMID- 22502880 TI - Ultrasound-microbubble mediated cavitation of plant cells: effects on morphology and viability. AB - The interaction between ultrasound pulses and microbubbles is known to generate acoustic cavitation that may puncture biological cells. This work presents new experimental findings on the bioeffects of ultrasound-microbubble mediated cavitation in plant cells with emphasis on direct observations of morphological impact and analysis of viability trends in tobacco BY-2 cells that are widely studied in higher plant physiology. The tobacco cell suspensions were exposed to 1 MHz ultrasound pulses in the presence of 1% v/v microbubbles (10% duty cycle; 1 kHz pulse repetition frequency; 70 mm between probe and cells; 1-min exposure time). Few bioeffects were observed at low peak negative pressures (<0.4 MPa) where stable cavitation presumably occurred. In contrast, at 0.9 MPa peak negative pressure (with more inertial cavitation activities according to our passive cavitation detection results), random pores were found on tobacco cell wall (observed via scanning electron microscopy) and enhanced exogenous uptake into the cytoplasm was evident (noted in our fluorescein isothiocyanate dextran uptake analysis). Also, instant lysis was observed in 23.4% of cells (found using trypan blue staining) and programmed cell death was seen in 23.3% of population after 12 h (determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling [TUNEL]). These bioeffects generally correspond in trend with those for mammalian cells. This raises the possibility of developing ultrasound-microbubble mediated cavitation into a targeted gene transfection paradigm for plant cells and, conversely, adopting plant cells as experimental test-beds for sonoporation-based gene therapy in mammalian cells. PMID- 22502881 TI - The speed of sound and attenuation of an IEC agar-based tissue-mimicking material for high frequency ultrasound applications. AB - This study characterized the acoustic properties of an International Electromechanical Commission (IEC) agar-based tissue mimicking material (TMM) at ultrasound frequencies in the range 10-47 MHz. A broadband reflection substitution technique was employed using two independent systems at 21 degrees C +/- 1 degrees C. Using a commercially available preclinical ultrasound scanner and a scanning acoustic macroscope, the measured speeds of sound were 1547.4 +/- 1.4 m?s(-1) and 1548.0 +/- 6.1 m?s(-1), respectively, and were approximately constant over the frequency range. The measured attenuation (dB?cm(-1)) was found to vary with frequency f (MHz) as 0.40f + 0.0076f(2). Using this polynomial equation and extrapolating to lower frequencies give values comparable to those published at lower frequencies and can estimate the attenuation of this TMM in the frequency range up to 47 MHz. This characterisation enhances understanding in the use of this TMM as a tissue equivalent material for high frequency ultrasound applications. PMID- 22502882 TI - Ultrasound assessment of transverse carpal ligament thickness: a validity and reliability study. AB - The transverse carpal ligament (TCL) forms the palmar boundary of the carpal tunnel and plays an important role in carpal tunnel mechanics. TCL hypertrophy has been observed for individuals with carpal tunnel syndrome (CTS) and postulated as a potential etiologic factor. Ultrasound is particularly advantageous for TCL imaging because of its capability of detecting the interfaces between the TCL and other tissues. The purposes of this study were to develop an ultrasound based method to measure the TCL thickness and to test the validity and reliability of this method. Three operators conducted two sessions of ultrasound examination on eight cadaveric specimens and eight healthy volunteers. A custom script was used to calculate TCL thickness along the TCL length from the ultrasound images. The ultrasound based TCL thickness of the cadaveric specimens was compared with the dissection based TCL thickness for validation. The results showed Pearson's correlation coefficients of 0.867-0.928, intraclass correlation coefficient (ICC) values of 0.726-0.865, a standard error of measurement of 0.02-0.07 mm and a minimal detectable difference of 0.05-0.15 mm. The high correlation coefficients and small errors indicate that the ultrasound based method is valid for measuring TCL thickness. Furthermore, ultrasound measurements showed excellent intraoperator and interoperator reliability with ICC values as 0.826-0.933 and 0.840-0.882, respectively. The ultrasound based TCL thickness was in the range of 0.93-2.34 (1.54 +/- 0.33) mm and agreed well with previous studies. The ultrasound method developed in this study is a valuable tool to examine morphologic properties of healthy and pathologic TCLs. PMID- 22502883 TI - Atherosclerotic risk stratification strategy for carotid arteries using texture based features. AB - Plaques in the carotid artery result in stenosis, which is one of the main causes for stroke. Patients have to be carefully selected for stenosis treatments as they carry some risk. Since patients with symptomatic plaques have greater risk for strokes, an objective classification technique that classifies the plaques into symptomatic and asymptomatic classes is needed. We present a computer aided diagnostic (CAD) based ultrasound characterization methodology (a class of Atheromatic systems) that classifies the patient into symptomatic and asymptomatic classes using two kinds of datasets: (1) plaque regions in ultrasound carotids segmented semi-automatically and (2) far wall gray-scale intima-media thickness (IMT) regions along the common carotid artery segmented automatically. For both kinds of datasets, the protocol consists of estimating texture-based features in frameworks of local binary patterns (LBP) and Law's texture energy (LTE) and applying these features for obtaining the training parameters, which are then used for classification. Our database consists of 150 asymptomatic and 196 symptomatic plaque regions and 342 IMT wall regions. When using the Atheromatic-based system on semiautomatically determined plaque regions, support vector machine (SVM) classifier was adapted with highest accuracy of 83%. The accuracy registered was 89.5% on the far wall gray-scale IMT regions when using SVM, K-nearest neighbor (KNN) or radial basis probabilistic neural network (RBPNN) classifiers. LBP/LTE-based techniques on both kinds of carotid datasets are noninvasive, fast, objective and cost-effective for plaque characterization and, hence, will add more value to the existing carotid plaque diagnostics protocol. We have also proposed an index for each type of datasets: AtheromaticPi, for carotid plaque region, and AtheromaticWi, for IMT carotid wall region, based on the combination of the respective significant features. These indices show a separation between symptomatic and asymptomatic by 4.53 units and 4.42 units, respectively, thereby supporting the texture hypothesis classification. PMID- 22502884 TI - Determination of the augmentation effects of hyaluronic acid on different heel structures in amputated lower limbs of diabetic patients using ultrasound elastography. AB - This study measured tissue properties of different anatomies of heels in amputated lower limbs of diabetic patients before and after hyaluronic acid (HA) or normal saline (NS) injections. Seven amputated lower limbs from six diabetic patients constituted the experimental group and one amputated lower limb from a diabetic patient served as the control. The limbs were placed in a fixation platform. A 5-12 MHz linear-array ultrasound transducer controlled by a stepping motor was used to load and unload tested heels. The loading-unloading velocity was 6 mm/s and the maximum loading stress was 178 kPa. Loading-unloading tests were performed before and after 1 mL HA injections into heels in the experimental group. The control limb underwent the same test before and after 1 mL NS injection. The unloaded thickness and Young's modulus of the macrochambers, microchambers and heel pads were determined before and after the interventions. The unloaded thickness of the macrochambers and the heel pad increased significantly (p = 0.012) after HA injection. The Young's modulus of the macrochambers decreased nonsignificantly after HA injections. Similar thickness and tissue stiffness changes were observed in the control limb. The baseline heel pad energy dissipation ratio (EDR(hp)) was 81.3 +/- 1.3% and decreased significantly (p = 0.012) to 73.1 +/- 1.7% after HA injections. The EDR(hp) in the control increased after NS injection. Histologic examinations revealed localized HA accumulation in the macrochambers with an extension into the adjacent fibrous septa. Injection of HA can increase tissue thickness and enhance heel-pad tissue resilience. PMID- 22502885 TI - Methodological aspects of functional transcranial Doppler sonography and recommendations for simultaneous EEG recording. AB - The neurovascular coupling describes a vasoregulative principle of the brain that adapts local cerebral blood flow in accordance with the underlying neuronal activity. It is the basis of modern indirect brain imaging techniques. Because of its wide availability and high tolerability the functional transcranial Doppler has been often used to assess brain function in clinical conditions. In the present paper we will give an overview of the current understanding of the coupling, explain basic principles of the Doppler technique and summarize relevant findings of functional Doppler tests in the different vascular territories of the brain. Finally, the concept of a combined functional electroencephalogram and transcranial Doppler technique will be outlined, which allows simultaneous investigation of the neuronal and vascular responses of neurovascular coupling. PMID- 22502886 TI - Different patterns of longitudinal displacement of the common carotid artery wall in healthy humans are stable over a four-month period. AB - Using an in-house developed ultrasonic method, we have shown that there is distinct longitudinal multiphasic displacement of the human common carotid artery (CCA) wall during the cardiac cycle. Different subjects showed markedly different patterns of displacement. At present, it is not known if the pattern of displacement in an individual is stable over time. Therefore, in this study, we measured the longitudinal displacement of the right CCA in 10 healthy humans at two different occasions 4 months apart. The basic pattern of longitudinal displacement for an individual was highly stable, including intraclass correlation coefficient (ICC) of 0.88 for the ratio between the first antegrade and the retrograde displacement, and ICC of 0.76 for the magnitude of the first antegrade displacement. The stable basic pattern of displacement showed marked differences among subjects, also of the same age and gender. Further studies are needed to elucidate the underlying mechanisms, the physiologic, pathophysiologic and clinical implications of this phenomenon. PMID- 22502887 TI - Effects of active, passive and motor imagery paradigms on cerebral and peripheral hemodynamics in older volunteers: a functional TCD study. AB - This study aimed to compare the response of metabolic-induced cerebral hemodynamic changes measured using transcranial Doppler (TCD) ultrasonography during passive, active and motor imagery paradigms, and associated peripheral hemodynamic responses. Continuous recordings of bilateral cerebral blood flow velocity (CBFv), blood pressure, heart rate and end-tidal CO(2) were performed in 12 right-handed subjects (aged >=45 y) before, during and after 60 s of active, passive and mental-imagined paradigms. The results revealed no significant difference in CBFv responses between the paradigms and, furthermore, the temporal patterns of the hemodynamic responses showed some degree of similarity. Moreover, significant changes were seen in cerebral and peripheral hemodynamic responses for all paradigms. Our results suggest that active, passive and motor imagery paradigms can be used interchangeably to assess hemodynamic responses. This will enable more detailed noninvasive assessment in patients, where voluntary movement is not possible, but where abnormalities of cerebral hemodynamic control mechanisms can be anticipated. PMID- 22502888 TI - Relationship between plasmid size and shock wave-mediated bacterial transformation. AB - Bacterial transformation is a fundamental tool in molecular biology; nevertheless, there is still a lack of efficient methods for gene delivery. The use of shock waves has been proposed as an alternative. Recently, our group demonstrated that shock wave-induced transfer of deoxyribonucleic acid (DNA) into bacteria can be increased by enhancing acoustic cavitation; however, so far, little information exists about the effects of shock waves on DNA. The objective of this study was to identify the size regimes of plasmids (DNA molecules that are separate from the chromosomal DNA), which promote shock wave-induced transformation. The transformation efficiency of shock waves and the integrity of DNA were studied for six different plasmid sizes, using the parameters that led to the best results in our previous study. PMID- 22502889 TI - A practical method for ultrasonographically monitoring the day-to-day growth of individual ovarian follicles in women undergoing assisted reproduction. AB - The objective of this study was to validate the use of the nonidentity (NonID) method compared with the identity (ID) method for tracking the day-to-day growth of individual follicles in women undergoing ovarian stimulation for assisted reproduction. A retrospective observational study was conducted in 20 women during ovarian stimulation. Conventional 2-D transvaginal ultrasonography was used to monitor follicle growth every 2-3 days throughout stimulation. Video clips of both ovaries were obtained in sagittal and coronal planes at each visit. Standardized diameter measurements of all follicles >=4 mm were made retrospectively from video clips. The growth profiles of all follicles that developed to >=10 mm were determined using the ID and NonID methods. Using Lin's concordance statistics, we documented that agreement between methods was 91% for follicles <10 mm, 96% for follicles 10-15 mm and 99% for follicles >15 mm. Lin's concordance correlation coefficient between the two methods was 0.96 (standard error = 0.003). We concluded that the NonID method is a practical, effective tool for monitoring the day-to-day growth of individual ovarian follicles in women undergoing assisted reproduction. PMID- 22502890 TI - Using the gradient of human cortical bone properties to determine age-related bone changes via ultrasonic guided waves. AB - Bone fragility depends not only on bone mass but also on bone quality (structure and material). To accurately evaluate fracture risk or propose therapeutic treatment, clinicians need a criterion, which reflects the determinants of bone strength: geometry, structure and material. In human long bone, the changes due to aging, accentuated by osteoporosis are often revealed through the trabecularization of cortical bone, i.e., increased porosity of endosteal bone inducing a thinning of the cortex. Consequently, the intracortical porosity gradient corresponding to the spatial variation in porosity across the cortical thickness is representative of loss of mass, changes in geometry (thinning) and variations in structure (porosity). This article examines the gradient of material properties and its age-related evolution as a relevant parameter to assess bone geometry, structure and material. By applying a homogenization process, cortical bone can be considered as an anisotropic functionally graded material with variations in material properties. A semi-analytical method based on the sextic Stroh formalism is proposed to solve the wave equation in an anisotropic functionally graded waveguide for two geometries, a plate and a tube, without using a multilayered model to represent the structure. This method provides an analytical solution called the matricant and explicitly expressed under the Peano series expansion form. Our findings indicate that ultrasonic guided waves are sensitive to the age-related evolution of realistic gradients in human bone properties across the cortical thickness and have their place in a multimodal clinical protocol. PMID- 22502891 TI - A pilot study evaluating real-time shear wave ultrasound elastography of miscellaneous non-nodal neck masses in a routine head and neck ultrasound clinic. AB - A pilot study was performed to evaluate shear wave ultrasound elastography (SWE) for miscellaneous non-nodal/salivary/thyroid neck lesions. Forty-six lesions undergoing conventional sonography also underwent SWE. Elastic moduli from the stiffest areas in lesions were correlated with diagnosis. Forty lesions were benign (9 lipomas, 8 lymphatic/venous vascular malformations, 7 thyroglossal duct cysts, 4 branchial cleft cysts, 4 abscesses/phlegmons, 3 neurogenic tumors and 1 each of paraganglioma, sebaceous cyst, pseudotumor, hypertrophic scar, ranula) and 6 were malignant (1 malignant fibrous histiocytoma, 2 primary squamous cell carcinomas and 3 intramuscular metastases [2 squamous cell carcinomas, 1 malignant melanoma]).Median stiffness of malignant lesions (226.4 kPa, range 55.6 to 300.0) was higher than benign lesions (28.3 kPa, range 4.0 to 300.0) (p < 0.001). SWE cut-off with highest accuracy (174.4 kPa) achieved 83.3% sensitivity and 97.5% specificity, and the cut-off with 100% sensitivity (55.6 kPa) achieved 75% specificity. All malignant lesions were suspected on conventional sonography. The preliminary data indicate that SWE is feasible for miscellaneous neck lesions. SWE would not have altered management in terms of detecting undisclosed malignancies, although as a quantitative technique, it may increase the diagnostic confidence of less experienced operators performing head and neck ultrasound. PMID- 22502892 TI - The effect of preactivation vial temperature on the acoustic properties of DefinityTM. AB - DefinityTM is a widely available clinically approved ultrasound contrast agent. The manufacturer's instructions indicate that the refrigerated vial should be allowed to reach room temperature prior to its 45 s mechanical agitation activation process. Activation results in vial heating and it has been previously observed that "smaller" bubbles are formed later in this process (>10 s) when the vial temperature is elevated. The objective of this work was to examine the effects of preactivation vial temperature on the size distribution, frequency dependent attenuation (1.5-27 MHz) and nonlinear imaging performance of DefinityTM. Experiments were conducted with vials at refrigerator temperature (2 degrees C), room temperature (22 degrees C) or 37 degrees C at the outset of the activation procedure. The size distributions were found to be strongly dependent on preactivation vial temperature and the attenuation results indicated considerable differences in the frequency response of the agent, most notably the appearance of a peak at 4 MHz for the 2 degrees C case. Nonlinear imaging results performed using a 1-5 MHz transducer probe with a wall-less vessel phantom indicated that 2 degrees C vials produced a signal enhancement 5.1 dB greater than for 22 degrees C DefinityTM (p < 0.05). These results, therefore, indicate that not permitting the vial to reach room temperature has a considerable impact on the imaging performance of DefinityTM. Conversely, activating a cooled vial can provide a means by which to improve contrast enhancement when using low frequency clinical transducers. PMID- 22502893 TI - Ultrasound and cisplatin combined treatment of human melanoma cells A375--the study of sonodynamic therapy. AB - Sonodynamic therapy, an effect of low-power ultrasound field and the anticancer drug cisplatin, was studied in vitro on human melanoma cells A375. The viability of cells has been studied by standard 3-(4,5-dimethylthiazol-2-Yl)-2,5 diphenyltetrazolium bromide viability assay according to different modes of treatment: application of cisplatin alone, exposure of ultrasound field alone, exposure to ultrasound followed by cisplatin and application of cisplatin followed by exposure to ultrasound. Ultrasound was used at a therapeutic intensity of 1 W?cm(-2) for 10 min. Concentration of cisplatin in the cell suspension was always 2.3 MUM. The results show that sonodynamic therapy is one of the possibilities of how to intensify standard cytostatic therapy. This conclusion is supported by reducing the viability of studied cells, especially 72 h after the treatment. The time sequence of application of ultrasonic field and cytostatics appears to be a significant factor affecting the changes in cell viability. Maximum suppression of viability has been found when applying the experimental design involving application of cisplatin followed by exposure to ultrasound; the final value of viability of combined affected cells was more than 10% lower than for cisplatin treatment alone. PMID- 22502894 TI - The usefulness of ultrasound colour-Doppler twinkling artefact for detecting urolithiasis compared with low dose nonenhanced computerized tomography. AB - This prospective study evaluates the usefulness of the twinkling artefact (TA) seen on colour-Doppler ultrasound (US) in diagnosing urolithiasis. US and standard computed tomography (CT) were performed blinded on 105 patients. B-mode US and colour-Doppler used separately and in combination showed 55% sensitivity and 99% specificity (positive predictive value [PPV] 67% and negative predictive value [NPV] 98%). Of CT verified stones, 61% were <=3 mm. TAs were present in 74% of the B-mode stones (43% of all CT verified stones). Patients with CT verified stone disease had significantly more TAs in other foci than the stone(s) found on CT, suggestive of microlithiasis. In conclusion, colour-Doppler TA is a helpful supplement for detecting urolithiasis when CT is contraindicated. In addition, US can be valuable in monitoring stones left to pass without intervention if they have presented a TA. CT, US and US with colour-Doppler TA can be useful as complementary techniques for detecting stones. PMID- 22502895 TI - Phalangeal quantitative ultrasound measurements in chronic hemodialysis patients: a 4-year follow-up. AB - In the course of chronic kidney disease, bone metabolism disturbances occur and become aggravated simultaneously with the progression of renal disorder, worsening patients' quality of life. We conducted a 4-year follow-up to assess phalangeal quantitative ultrasound (QUS) measurements in 32 patients undergoing chronic hemodialysis (17 males and 15 females) whose mean ages were 56.3 +/- 15.2 years. The QUSs of hand phalanges were performed using DBM 1200 (IGEA, Carpi, Italy) and are expressed as amplitude-dependent speed of sound (Ad-SoS), Z scores, and T-scores. In comparison with the age-, sex-, and body mass index adjusted control group, QUS parameters were significantly decreased in all patients undergoing dialysis. During the 4-year follow-up, Ad-SoS and T-scores in all study groups sloped significantly with time. The significant negative relationships between follow-up Ad-SoS results and both baseline and follow-up parathormone values were demonstrated. Our results confirm a high prevalence of bone disturbances in patients undergoing chronic hemodialysis, and they do not improve during renal replacement therapy. The parathormone level seems to be an important agent in influencing bone status, but further studies are needed to understand the other risk factors in kidney-related bone disease. PMID- 22502896 TI - Room temperature synthesis and highly enhanced visible light photocatalytic activity of porous BiOI/BiOCl composites nanoplates microflowers. AB - This research represents a highly enhanced visible light photocatalytic removal of 450 ppb level of nitric oxide (NO) in air by utilizing flower-like hierarchical porous BiOI/BiOCl composites synthesized by a room temperature template free method for the first time. The facile synthesis method avoids high temperature treatment, use of organic precursors and production of undesirable organic byproducts during synthesis process. The result indicated that the as prepared BiOI/BiOCl composites samples were solid solution and were self assembled hierarchically with single-crystal nanoplates. The aggregation of the self-assembled nanoplates resulted in the formation of 3D hierarchical porous architecture containing tri-model mesopores. The coupling to BiOI with BiOCl led to down-lowered valence band (VB) and up-lifted conduction band (CB) in contrast to BiOI, making the composites suitable for visible light excitation. The BiOI/BiOCl composites samples exhibited highly enhanced visible light photocatalytic activity for removal of NO in air due to the large surface areas and pore volume, hierarchical structure and modified band structure, exceeding that of P25, BiOI, C-doped TiO(2) and Bi(2)WO(6). This research results could provide a cost-effective approach for the synthesis of porous hierarchical materials and enhancement of photocatalyst performance for environmental and energetic applications owing to its low cost and easy scaling up. PMID- 22502897 TI - Review of Pb availability and toxicity to plants in relation with metal speciation; role of synthetic and natural organic ligands. AB - Biogeochemical behavior of lead (Pb), a persistent hazardous pollutant of environmental concern, strongly depends on its chemical speciation. Therefore, in this review, link between Pb speciation: presence of organic ligands and its environmental behavior has been developed. Both, biogeochemical and ecotoxicological data are discussed in environmental risk assessment context and phytoremediation studies. Three kinds of organic ligands selected for this review include: (1) ethylene diamine tetra-acetic acid (EDTA), (2) low molecular weight organic acids (LMWOAs) and (3) humic substances (HSs). The review highlights the effect of Pb speciation on: (i) Pb fate and behavior in soil; (ii) Pb plant uptake and accumulation in different plant parts; and (iii) Pb-induced phyto toxicity. Effects of organic ligands on Pb speciation are compared: how they can change Pb speciation modifying accordingly its fate and biogeochemistry in soil plant system? EDTA forms soluble, stable and phytoavailable Pb-chelates due to high binding Pb affinity. LMWOAs can solubilize Pb in soil by decreasing soil pH or increasing soil organic contents, but have little effect on its translocation. Due to heterogeneous structure, HSs role is complex. In consequence Pb speciation knowledge is needed to discuss phyto-toxicity data and improved soil phytoremediation techniques. PMID- 22502898 TI - Cavitationally induced biodegradability enhancement of a distillery wastewater. AB - Hydrodynamic cavitation (HC) was evaluated as a pretreatment option for the complex/recalcitrant biomethanated distillery wastewater (B-DWW). The effect of various process parameters such as inlet pressure, dilution and reaction time on reduction of COD/TOC and enhancement of biodegradability index (BI:BOD(5):COD ratio) of the B-DWW was studied with an aim to maximize the biodegradability index and reducing the toxicity of the distillery wastewater. It was observed that higher operating pressure (13 bar) yielded the maximum BI whereas the lower pressure (5 bar) is suitable for the reduction in the toxicity of B-DWW. The toxicity of the distillery wastewater was analyzed by measuring the COD, TOC and color of the wastewater sample. The HC pretreatment under optimized conditions leads to a BI of 0.32, COD and TOC reduction of 32.24% and 31.43%, respectively along with a color reduction by 48%. These results indicate the potential of HC as a pretreatment option for enhancing the biodegradability index of the recalcitrant wastewater such as B-DWW along with reduced toxicity of wastewater as observed from COD, TOC and color reduction profile under optimized conditions. PMID- 22502899 TI - Enantioselective bioaccumulation of soil-associated fipronil enantiomers in Tubifex tubifex. AB - Enantioselective behavior of chiral pesticides in the aquatic environment has been a subject of growing interest. In this study, the enantioselective bioaccumulation of fipronil enantiomers in Tubifex tubifex (Oligochaeta, Tubificida) was detected in both spike-water and spike-soil systems, respectively. For the spike-water treatment, a 9-day exposure experiment was employed and the enantiomer fraction in tubifex tissue was maintained approximately at 0.58 during the experiment. In addition, a 14-day bioaccumulation period was chosen for the spike-soil treatment and a more significant deviation of enantiomer fraction from 0.5 in tubifex tissue was detected, with concentrations of the R-form higher than that of the S-form. Therefore, the bioaccumulation of fipronil was enantioselective in tubifex tissue for the two treatments and the magnitude of enantioselectivity may be influenced by different exposure conditions. For the spike-soil treatment, the concentrations of fipronil in verlying water and soil were also determined. With the presence of tubifex worms, higher concentrations of fipronil in overlying water and lower concentrations in soil were detected than that in the absence of tubifex treatment during the whole 14-day exposure period. This means that tubifex has positive functions in fipronil's diffusion from soil to overlying water and in the degradation of the soil-associated fipronil. PMID- 22502900 TI - Association of serum triiodothyronine with B-type natriuretic peptide and severe left ventricular diastolic dysfunction in heart failure with preserved ejection fraction. AB - There are well-documented changes in thyroid hormone metabolism that accompany heart failure (HF). However, the frequency of thyroid hormone abnormalities in HF with preserved ejection fraction (HFpEF) is unknown, and no studies have investigated the association between triiodothyronine (T(3)) and markers of HF severity (B-type natriuretic peptide [BNP] and diastolic dysfunction [DD]) in HFpEF. In this study, 89 consecutive patients with HFpEF, defined as symptomatic HF with a left ventricular ejection fraction >50% and a left ventricular end diastolic volume index <97 ml/m(2), were prospectively studied. Patients were dichotomized into 2 groups on the basis of median T(3) levels, and clinical, laboratory, and echocardiographic data were compared between groups. Univariate and multivariate linear regression analyses were performed to determine whether BNP and DD were independently associated with T(3) level. We found that 22% of patients with HFpEF had reduced T(3). Patients with lower T(3) levels were older, were more symptomatic, more frequently had hyperlipidemia and diabetes, and had higher BNP levels. Severe (grade 3) DD, higher mitral E velocity, shorter deceleration time, and higher pulse pressure/stroke volume ratio were all associated with lower T(3) levels. T(3) was inversely associated with log BNP (p = 0.004) and the severity of DD (p = 0.039). On multivariate analysis, T(3) was independently associated with log BNP (beta = -4.7 ng/dl, 95% confidence interval -9.0 to -0.41 ng/dl, p = 0.032) and severe DD (beta = -16.3 ng/dl, 95% confidence interval -30.1 to -2.5 ng/dl, p = 0.022). In conclusion, T(3) is inversely associated with markers of HFpEF severity (BNP and DD). Whether reduced T(3) contributes to or is a consequence of increased severity of HFpEF remains to be determined. PMID- 22502901 TI - Therapeutic ranges of serum digoxin concentrations in patients with heart failure. PMID- 22502902 TI - Resource utilization and costs following hospitalization of patients with chronic heart failure in the US. AB - BACKGROUND: Despite advances in its management and the identification of preventable risk factors, heart failure (HF) is a growing health problem in the US. The objective of this study was to describe treatment patterns, medical resource utilization and costs following hospitalization for chronic HF for patients stratified by age. METHODS: Patients with at least one hospitalization with chronic HF were identified in a US commercial insurance claims database from 2004-2008. Patients were followed from the 1st day of chronic HF hospitalization (index hospitalization) until disenrollment or end of data availability. Inpatient, outpatient and prescription drug utilization rates were calculated per person per month (PPPM). Costs included payments made by insurers and, where available, patient out-of-pocket payments and sick-leave costs were also calculated. Utilization rates and costs were stratified by patient age. RESULTS: There were 7814 patients included in the study. Index hospitalization was the most resource intensive and expensive ($31,023 age <65, $12,426 age >= 65). The rate of outpatient visits was the highest within 3 months following index hospitalization (3.6/PPPM age <65, 4.1/PPPM age >= 65). For the older age group, rate of re-hospitalizations was highest (0.06/PPPM) within 3-6 months following index hospitalization, while the younger group had its highest rate (0.08/PPPM) during the first 3 months following index hospitalization. Prescription dispensing rates were similar between age groups; average reimbursement PPPM for cardiovascular drugs did not exceed $92 (age <65) and $221 (age >= 65), which represents less than 3% of hospitalization costs for both groups. CONCLUSIONS: Treating chronic HF patients is resource intensive. The greatest burden occurs within 6 months after index hospitalization for both age groups; patients continue to be burdened after hospitalization by high inpatient and outpatient visit rates. Outpatient cardiovascular drug costs account for a small proportion of total healthcare costs. PMID- 22502903 TI - Systems biology approach to transplant immune tolerance. PMID- 22502904 TI - Chimeric acceleration by donor CD4+CD25+T-reg depleted fraction in splenocyte transplantation. AB - BACKGROUND: We have established a splenocytic chimera model that can induce donor specific tolerance and reconstitute the recipient immune system by donor splenocytes. AIM: To accelerate such reconstitution, we investigated the role of donor-derived CD4(+)CD25(+) regulatory T-cells (T-reg). METHODS: We established C3H/B6D2F1 mixed bone marrow chimeras in lethally irradiated C3H mice. We transplanted skin grafts from C57BL/6 mice 30 d later. After an additional 30 d, we transplanted the following types of splenocytes from B6C3F1 mice: total splenocytes (group A), CD4(+)CD25(+) T-reg depleted splenocytes (group B), CD8(+) depleted splenocytes (group C), and CD4(+)-depleted splenocytes (group D). We assessed class I major histocompatibility complex, percentage of chimeric cells in peripheral blood, and survival of skin grafts in each group. RESULTS: Group A and B mice switched to splenocytic chimeras, permitting the long-term survival of skin grafts. The proportions of H-2K(b+)H-2K(k-) cells in group B were significantly lower than those in group A on day 14 (0.47% +/- 0.68% versus 9.49% +/- 8.30%; P = .01) and day 21 (0.16% +/- 0.25% versus 3.35% +/- 2.78%; P = .01). The initial increase in the proportion of H-2K(b+)H-2K(k+) double-positive cells in group B was faster than that in group A (from 0.33% +/- 0.10% versus. 0.39% +/ 0.14% before splenocyte injection to 39.03% +/- 30.50% versus 10.73% +/- 11.54% on day 7; P = .02). The initial increase in the proportion of CD8(+) T-cells was faster in group B than in group A (from 2.72% +/- 0.52% versus 2.49% +/- 1.07% before splenocyte injection to 29.61% +/- 26.72% versus 4.92% +/- 1.56% on day 7; P = .04). CONCLUSIONS: The depletion of CD4(+)CD25(+) T-reg fraction in donor splenocytes can accelerate switching to splenocytic chimera. PMID- 22502905 TI - Understanding the causes of hyperglycemia in burn patients. PMID- 22502906 TI - Inhibitory CpG sequences reduced ischemia/reperfusion-induced hepatic metastases of liver tumor in a murine model. AB - BACKGROUND: It is reported that hepatic ischemia/reperfusion (I/R) during hepatectomy accelerates liver tumor growth. Hepatic I/R induces inflammation cytokines, which can accelerate the outgrowth of liver tumor. Inhibitory CpG sequence (iCpG) is an inhibitor of TLR9, which plays an important role in hepatic I/R. The aim of this study was to examine whether iCpG could prevent hepatic I/R induced metastases of the liver tumor. MATERIALS AND METHODS: A murine tumor model that underwent partial hepatic I/R or sham operation was treated with iCpG or control DNA sequence (Ctrl ODN). Tumor growth and metastases were observed on day 14 after surgery; Endothelial leukocyte adhesion molecules such as E-selectin and intracellular adhesion molecule-1 (ICAM-1) protein expression were measured 24 h after reperfusion by Western blotting; E-selectin and ICAM-1 mRNA expression in hepatic tissue was measured 2 h after reperfusion by RT-PCR; NF-kappaB activity in hepatic tissue was measured 2 h after reperfusion by electrophoretic gel mobility shift assay. RESULTS: The tumor growth in the mice subjected to hepatic I/R was remarkably stimulated when compared with the mice subjected to laparotomy alone. The iCpG had no significant inhibitory effect on tumor growth in sham-operated mice subjected to tumor. However, iCpG could reduce the tumor growth and inhibit the activation of NF-kappaB and downregulate the E-selectin and ICAM-1 mRNA and protein in the mice with tumor subjected to I/R. CONCLUSIONS: ICpG might reduce I/R-induced hepatic metastases of liver tumor cells by inhibiting NF-kappaB expression and downregulating the adhesive molecules, such as E-selectin and ICAM-1. PMID- 22502907 TI - Determination of carotenoids in Taraxacum formosanum by HPLC-DAD-APCI-MS and preparation by column chromatography. AB - The objectives of this study were to determine the variety and content of carotenoids in Taraxacum formosanum, a traditional Chinese herb possessing vital biological activities, by developing an HPLC-DAD-APCI-MS method and a preparative column chromatographic method for carotenoid isolation. A total of 25 carotenoids were resolved within 66 min by employing a YMC C30 column and a gradient mobile phase of methanol-acetonitrile-water (79:14:7, v/v/v) and methylene chloride (100%) with flow rate at 1.0 mL/min and detection at 450 nm. All-trans canthaxanthin was shown to be an appropriate internal standard for quantitation, with all-trans-beta-carotene and its cis isomers present in largest amount (413.6 MUg/g), followed by all-trans-violoxanthin and its cis isomers (209.5 MUg/g), all trans-lutein and its cis isomers (212.4 MUg/g), all-trans-neoxanthin and its cis isomers (134.6 MUg/g), antheraxanthin (16.5 MUg/g), all-trans-beta-cryptoxanthin and its cis isomers (5.8 MUg/g), all-trans-zeaxanthin (3.6 MUg/g) and neochrome (0.1 MUg/g). For preparative chromatography, with a glass column containing 52 g of magnesium oxide-diatomaceous earth (1:3, w/w) as adsorbent, the carotenoid fraction was eluted with 300 mL of ethyl acetate with flow rate at 10 mL/min. Some more epoxides and cis isomers of carotenoids were generated during preparative column chromatography. Nevertheless, the carotenoids isolated from T. formosanum may be used as raw material for possible production of health food in the future. PMID- 22502908 TI - Human recombinant beta-secretase immobilized enzyme reactor for fast hits' selection and characterization from a virtual screening library. AB - In the present work, a human recombinant BACE1 immobilized enzyme reactor (hrBACE1-IMER) has been applied for the sensitive fast screening of 38 compounds selected through a virtual screening approach. HrBACE1-IMER was inserted into a liquid chromatograph coupled with a fluorescent detector. A fluorogenic peptide substrate (M-2420), containing the beta-secretase site of the Swedish mutation of APP, was injected and cleaved in the on-line HPLC-hrBACE1-IMER system, giving rise to the fluorescent product. The compounds of the library were tested for their ability to inhibit BACE1 in the immobilized format and to reduce the area related to the chromatographic peak of the fluorescent enzymatic product. The results were validated in solution by using two different FRET methods. Due to the efficient virtual screening methodology, more than fifty percent of the selected compounds showed a measurable inhibitory activity. One of the most active compound (a bis-indanone derivative) was characterized in terms of IC(50) and K(i) determination on the hrBACE1-IMER. Thus, the hrBACE1-IMER has been confirmed as a valid tool for the throughput screening of different chemical entities with potency lower than 30MUM for the fast hits' selection and for mode of action determination. PMID- 22502909 TI - The metabonomics of combined dietary exposure to phthalates and polychlorinated biphenyls in mice. AB - Humans undergo simultaneous daily exposure to a multitude of endocrine-disrupting compounds (EDCs). In present study, after combined exposure to endocrine disruptors DEHP and Aroclor 1254 for 12 days, a liquid chromatography/time-of flight mass spectrometer method combining both reversed-phase (RP) and hydrophilic interaction chromatography (HILIC) separations was carried out to investigate the metabolic responses in mice. The metabolic profiles of endogenous metabolites could differentiate the dose and control groups in both RPLC and HILIC modes. Moreover, the male mice and female mice in different groups could be obviously clustered in their own regions with combined model. Fourteen lysoPCs, PC(18:4/18:1), lysoPE(18:2/0:0), phenylalanine and tryptophan were identified as potential biomarkers for the combined toxicity of DEHP and Aroclor 1254. Different change trends could be observed for the identified lysoPCs, due to their different levels of uptake and metabolism in mice. Moreover, gender specific differences in several lysoPCs (e.g. lysoPC(18:0), lysoPC(22:6), lysoPC(20:3), and PC(18:4/18:1)) were observed for treated mice. The metabonomic results indicated the combined exposure led to a disturbance of lipid metabolism. The mRNA expressions of PLA2, ACOX1, CPT1, FAS and SCD1 involved in lipid metabolism were investigated. Among them, significant increases of FAS and SCD1 expressions in the liver induced by the exposure could be observed for both male and female mice, contributing to the hepatic lipid accumulation in mice. Besides lipid metabolism, tryptophan metabolism and phenylalanine metabolism may also be involved with the toxic responses to these EDCs. The present study not only improves the understanding of the combined toxicity of phthalates and PCBs but also shows that the metabonomic approach may prove to be a promising technique for the toxicity research of EDCs. PMID- 22502910 TI - Stability-indicating UPLC method for determination of Imatinib Mesylate and their degradation products in active pharmaceutical ingredient and pharmaceutical dosage forms. AB - A simple, precise, accurate stability-indicating gradient reverse phase ultra performance liquid chromatographic (RP-UPLC) method was developed for quantitative determination of purity of Imatinib Mesylate (IMM) drug substance and drug products in the presence of its process related impurities, and degradation products. The proposed RP-UPLC method utilizes Acquity UPLC BEH 50 mm, 2.1mm and 1.7 MUm C-18 column at 30 degrees C, with a gradient program of 9.0 min at a flow rate of 0.3 mL/min. The compounds of interest were monitored at 237 nm. Resolution for Imatinib and eight related components was found to be greater than 1.5 for any pair of components. The correlation coefficients (r(2)>0.9990) obtained indicate clear correlations between the concentrations and their peak areas for the investigated compounds. RSD obtained for the repeatability and intermediate precision experiments, was less than 5.0%. Accuracy of the method was further ascertained by performing recovery studies through spiking experiments. The drug substance was subjected to hydrolytic, oxidative, photolytic and thermal stress conditions as per ICH. The developed method was validated according to the current ICH guidelines for specificity, limit of detection, limit of quantitation, linearity, accuracy, precision, ruggedness and robustness. The method is also suitable for the assay determination of IMM in pharmaceutical dosage forms. PMID- 22502911 TI - Characteristics of cavernomas of the brain and spine. AB - The incidence of cavernomas in the general population ranges from 0.3% to 0.5%. They frequently occur in young adults, usually being detected between the second and fifth decade of life, in both sporadic and familial forms. Patients with inherited cavernomas are typically affected by multiple lesions, whereas sporadic forms mostly present with a single lesion. Three genes responsible for development of cavernomas identified to date include CCM1, CCM2, and CCM3. The natural history of brain cavernomas is relatively benign and up to 21% of patients are asymptomatic. The most frequent manifestations of the disease are seizures, focal neurological deficits, and hemorrhage. We review the current literature data on the characteristics of brain and spinal cavernomas. PMID- 22502912 TI - Endovascular management of postoperative pseudoaneurysms of the external carotid artery. AB - Hemorrhage secondary to postoperative pseudoaneurysm is a rare event, but may complicate the clinical course of straightforward and common interventions such as sinonasal procedures, tonsillectomy, and maxillofacial and plastic surgeries. We report our experience with the endovascular management of iatrogenic pseudoaneurysm in eight patients who had undergone recent craniomaxillofacial surgery. Computed tomography (CT), including CT-angiography, detected only three of the eight lesions. In all patients, endovascular embolization achieved successful occlusion of the pseudoaneurysm without local or general procedure related complications. Immediate proximal arterial occlusion with detachable coils was performed in every case, and pseudoaneurysm coiling was performed in three cases presenting with active hemorrhage. Endovascular therapy proved to be safe and effective in the management of postoperative pseudoaneurysms. Surgeons involved in the craniomaxillofacial procedures should be aware of this complication and its management. PMID- 22502913 TI - Abnormalities of magnetic resonance spectroscopy and diffusion tensor imaging are correlated with executive dysfunction in patients with ischemic leukoaraiosis. AB - Abnormal diffusion tensor imaging (DTI) results have been observed in the periventricular white matter in patients with ischemic leukoaraiosis (ILA). However, the underlying pathological changes and their relationship to cognitive impairments are obscure. In addition, damage in the thalamus, an important structure in the executive function network, has been suggested in ILA, but is poorly understood. Twenty patients with ILA and 20 healthy volunteers with similar ages and educational histories underwent DTI, magnetic resonance spectroscopy (MRS) and a neuropsychological assessment. In patients with ILA, we observed an increased mean diffusivity (MD) and decreased levels of N acetylaspartate (NAA)/creatine (Cr) in the anterior and posterior periventricular region and the thalamus, as well as decreased fractional anisotropy (FA) in the anterior and posterior periventricular regions. MD and NAA/Cr levels in the anterior and posterior periventricular white matter and NAA/Cr levels in the thalamus were correlated with executive function. DTI and MRS abnormalities were consistent with axonal and/or neuronal loss and dysfunction in the anterior and posterior periventricular white matter and the thalamus. This study demonstrates that DTI and MRS techniques can be used to investigate pathological changes in the anterior and posterior periventricular white matter and the thalamus; these changes may be correlated with executive functional changes in patients with ILA. PMID- 22502914 TI - The association between two single nucleotide polymorphisms within the insulin degrading enzyme gene and Alzheimer's disease in a Chinese Han population. AB - Several previous studies on the relationship between the insulin-degrading enzyme (IDE) gene and Alzheimer's disease (AD) have connected certain genetic variants to late-onset AD, in the absence of the apolipoprotein E (APOE)epsilon4 allele. However, the conclusions of these studies remain controversial. We investigated the association between two polymorphisms of IDE with AD in the Chinese population and found that the T/A genotype of rs4646958 had an important role in AD (adjusted p=0.007, odds ratio [OR]=2.796, 95% confidence interval [CI]=1.330 5.878), under the co-dominant genetic model. The T/C genotype of rs1887922 was also significantly associated with AD compared to the T/T genotype (adjusted p=0.003, OR=2.644, 95% CI=1.407-4.970). The C allele of rs1887922 conferred a higher risk of AD under the dominant genetics model (adjusted p=0.001, OR=2.719, 95% CI=1.472-5.022). Compared with the two other variant genotypes, the T/T genotype showed a protective effect in both polymorphisms (adjusted p=0.007, OR=0. 358, 95% CI=0.170-0.752 for rs4646958; adjusted p=0.001, OR=0. 368, 95% CI=0.199-0.679 in rs1887922). In the context of APOEepsilon4-negative status, both variants were significantly associated with AD in some genetic models. PMID- 22502915 TI - Diabetic retinopathy: a new predictor in patients on regular hemodialysis. AB - BACKGROUND: Data evaluating the presence and impact of diabetic retinopathy (DR) in patients on regular hemodialysis (HD) are scarce. OBJECTIVE: To assess prevalence and outcomes of DR in HD patients. METHODS: Data were collected from 252 consecutive HD-dependent patients who underwent eye examination for detection of DR in 2007. Patients were divided into two groups (DR vs. no-DR) and followed up for 3 years. Demographic and clinical profiles were analyzed and compared. Multivariate logistic regression was used to find out the predictors of DR, morbidity and mortality. RESULTS: DR was diagnosed in 113 patients (45%). In comparison to no-DR, DR patients were older and more likely to have high prevalence of dyslipidemia, coronary artery disease and cerebrovascular accidents. Duration of DM was longer in DR patients (p = 0.02). There was significant correlation between DR and nephropathy (r = 0.38; p = 0.001) and PAD (r = 0.27; p = 0.001). Hemoglobin A1c, serum calcium and total cholesterol were higher while serum albumin and phosphorus were lower in DR in comparison to no-DR group. The rates of renal transplant, coronary artery disease and cerebrovascular accidents were comparable in the two groups. Peripheral arterial disease (PAD) was associated with 4-fold increase in the presence of DR (Adjusted OR 3.9; p = 0.009). DR was independent predictor for PAD (adjusted OR 2.2; p = 0.01). Age-sex adjusted DR was independent predictor of 3-year mortality (OR 2.04; p = 0.03). LIMITATIONS: The main issue with a cross-sectional study such as this, is differentiating cause and effect from simple association. Also, the current study did not specify the severity of DR. CONCLUSION: Prevalence of DR is high among HD patients and associated with high mortality. DR is an independent predictor for PAD and not for transplantation. Early detection of DR is highly recommended among HD population for risk-stratification and counseling. Further randomized controlled studies are needed to support our finding. PMID- 22502916 TI - Current evidence for the management of paediatric parapneumonic effusions. AB - BACKGROUND: Parapneumonic effusions (PPE) and empyema, secondary to bacterial pneumonia, are relatively uncommon but their prevalence is increasing lately. Even if their prognosis is generally good, they may still cause significant morbidity. The traditional treatment of PPE has been intravenous antibiotics and, when necessary, chest tube drainage. Open thoracotomy with decortication has usually been applied in case of failure of the traditional approach. Lately, the use of fibrinolysis and/or video-assisted thoracoscopic surgery (VATS) are utilized in the management of PPE; however, there is still little consensus on the most effective primary treatment. SCOPE: In this article our goal was to summarize, based on up-to-date evidence, all the management options for PPE available to physicians and weigh the benefits and risks of the most popular ones, in an effort to figure out which one is superior as a first-line approach in children. FINDINGS: A literature search of randomized and retrospective studies that pinpoint methods of evaluation and treatment of PPE was carried out in Medline and Scopus databases. Chest X-ray, ultrasound as well as microbiology and biochemical characteristics of the pleural fluid will facilitate decision making. Small uncomplicated effusions resolve with antibiotics alone, larger ones require small-bore chest tube drainage and in case of complicated loculated PPE, fibrinolysis or VATS should be considered. Both methods promote faster drainage, reduce hospital stay and obviate the need for further interventions when used as first-line approach. However, primary treatment with VATS is not advised by the majority of studies as a first choice intervention, unless medical treatment has failed. CONCLUSION: The main steps in treatment are diagnostic thoracocentesis and imaging, small percutaneous drainage, and considering fibrinolysis in complicated PPE. In case of failure, VATS should be the surgical method to be applied. PMID- 22502917 TI - Basic life support skills of high school students before and after cardiopulmonary resuscitation training: a longitudinal investigation. AB - BACKGROUND: Immediate bystander cardiopulmonary resuscitation (CPR) significantly improves survival after a sudden cardiopulmonary collapse. This study assessed the basic life support (BLS) knowledge and performance of high school students before and after CPR training. METHODS: This study included 132 teenagers (mean age 14.6 +/- 1.4 years). Students completed a two-hour training course that provided theoretical background on sudden cardiac death (SCD) and a hands-on CPR tutorial. They were asked to perform BLS on a manikin to simulate an SCD scenario before the training. Afterwards, participants encountered the same scenario and completed a questionnaire for self-assessment of their pre- and post-training confidence. Four months later, we assessed the knowledge retention rate of the participants with a BLS performance score. RESULTS: Before the training, 29.5% of students performed chest compressions as compared to 99.2% post-training (P < 0.05). At the four-month follow-up, 99% of students still performed correct chest compressions. The overall improvement, assessed by the BLS performance score, was also statistically significant (median of 4 and 10 pre- and post-training, respectively, P < 0.05). After the training, 99.2% stated that they felt confident about performing CPR, as compared to 26.9% (P < 0.05) before the training. CONCLUSIONS: BLS training in high school seems highly effective considering the minimal amount of previous knowledge the students possess. We observed significant improvement and a good retention rate four months after training. Increasing the number of trained students may minimize the reluctance to conduct bystander CPR and increase the number of positive outcomes after sudden cardiopulmonary collapse. PMID- 22502918 TI - Towards a need to a "biological Sokal risk" in the era of tyrosine kinase inhibitors in choosing front-line therapy in chronic myeloid leukemia. PMID- 22502919 TI - Leukemia Research welcomes a new co-editor-in-chief: Eric J. Feldman, M.D. PMID- 22502920 TI - Deferasirox exposure induces reactive oxygen species and reduces growth and viability of myelodysplastic hematopoietic progenitors. AB - We examined the effect of deferasirox (DFX) on CD34+ hematopoietic progenitors from MDS patients. Progressive, dose-dependent suppression of MDS progenitor proliferation in culture was observed with DFX concentrations ranging from 5 MUM to 20 MUM. This effect was more pronounced in MDS compared to CD34+ progenitors isolated from umbilical cord blood or normal peripheral blood. There was reduced viability of MDS progenitors but not normal progenitors at 20 MUM DFX which increased with duration of exposure. Exposure to 20 MUM DFX for 14 days markedly suppressed colony growth of MDS progenitors. Reactive oxygen species levels were elevated above control at concentrations of DFX above 5 MUM. We conclude that exposure to DFX results in dose-dependent inhibition of proliferation, and survival in MDS progenitors. PMID- 22502921 TI - New complex chromosome abnormalities in multiple myeloma associated with a poor prognosis: a case report. PMID- 22502922 TI - New public health services and systems research agenda: directions for the next decade. PMID- 22502923 TI - Public health workforce research in review: a 25-year retrospective. AB - CONTEXT: The Robert Wood Johnson Foundation commissioned a systematic review of public health workforce literature in fall 2010. This paper reviews public health workforce articles published from 1985 to 2010 that support development of a public health workforce research agenda, and address four public health workforce research themes: (1) diversity; (2) recruitment, retention, separation, and retirement; (3) education, training, and credentialing; and (4) pay, promotion, performance, and job satisfaction. EVIDENCE ACQUISITION: PubMed, ERIC, and Web of Science databases were used to search for articles; Google search engine was used to identify gray literature. The study used the following inclusion criteria: (1) articles written in English published in the U.S.; (2) the main theme(s) of the article relate to at least one of the four public health workforce research themes; and (3) the document focuses on the domestic public health workforce. EVIDENCE SYNTHESIS: The literature suggests that the U.S. public health workforce is facing several urgent priorities that should be addressed, including: (1) developing an ethnically/racially diverse membership to meet the needs of an increasingly diverse nation; (2) recruiting and retaining highly trained, well prepared employees, and succession planning to replace retirees; (3) building public health workforce infrastructure while also confronting a major shortage in the public health workforce, through increased education, training, and credentialing; and (4) ensuring competitive salaries, opportunities for career advancement, standards for workplace performance, and fostering organizational cultures which generate high levels of job satisfaction for effective delivery of services. CONCLUSIONS: Additional research is needed in all four thematic areas reviewed to develop well-informed, evidence-based strategies for effectively addressing critical issues facing the public health workforce. PMID- 22502924 TI - The structure and organization of local and state public health agencies in the U.S.: a systematic review. AB - CONTEXT: This systematic review provides a synthesis of the growing field of public health systems research related to the structure and organization of state and local governmental public health agencies. It includes an overview of research examining the influence of organizational characteristics on public health performance and health status and a summary of the strengths and gaps of the literature to date. EVIDENCE ACQUISITION: Data were retrieved through an iterative process, beginning with key word searches in three publication databases (PubMed, JSTOR, Web of Science). Gray literature was searched through the use of Google ScholarTM. Targeted searches on websites and key authors were also performed. Documents underwent an initial and secondary screening; they were retained if they contained information about local or state public health structure, organization, governance, and financing. EVIDENCE SYNTHESIS: 77 articles met the study criteria. Public health services are delivered by a mix of local, state, and tribal governmental and nongovernmental agencies and delivered through centralized (28%); decentralized (37%); or combined authority (35%). The majority of studies focused on organizational characteristics that are associated with public health performance based on the 10 Essential Public Health Services framework. Population size of jurisdiction served (>50,000); structure of authority (decentralized and mixed); per capita spending at the local level; some partnerships (academic, health services); and leadership of agency directors have been found to be related to public health performance. Fewer studies examined the relationship between organizational characteristics and health outcomes. Improvements in health outcomes are associated with an increase in local health department expenditures, FTEs per capita, and location of health department within local networks. CONCLUSIONS: Public health systems in the U.S. face a number of critical challenges, including limited organizational capacity and financial resources. Evidence on the relationship of public health organization, performance, and health outcomes is limited. Public health systems are difficult to characterize and categorize consistently for cross-jurisdictional studies. Progress has been made toward creating standard terminology. Multi-site studies that include a mix of system types (e.g., centralized, decentralized) and local or state characteristics (e.g., urban, rural) are needed to refine existing categorizations that can be used in examining studies of public health agency performance. PMID- 22502925 TI - Methods in public health services and systems research: a systematic review. AB - CONTEXT: Public Health Services and Systems Research (PHSSR) is concerned with evaluating the organization, financing, and delivery of public health services and their impact on public health. The strength of the current PHSSR evidence is somewhat dependent on the methods used to examine the field. Methods used in PHSSR articles, reports, and other documents were reviewed to assess their methodologic strengths and challenges in light of PHSSR goals. EVIDENCE ACQUISITION: A total of 364 documents from the PHSSR library met the inclusion criteria as empirical and based in the U.S. After additional exclusions, 327 of these were analyzed. EVIDENCE SYNTHESIS: A detailed codebook was used to classify articles in terms of (1) study design; (2) sampling; (3) instrumentation; (4) data collection; (5) data analysis; and (6) study validity. Inter-coder reliability was assessed for the codebook; once it was found reliable, the available empirical documents were coded. CONCLUSIONS: Although there has been a dramatic increase in the amount of published PHSSR recently, methods used remain primarily cross-sectional and descriptive. Moreover, although appropriate for exploratory and foundational work in a new field, these approaches are limiting progress toward some PHSSR goals. Recommendations are given to advance and strengthen the methods used in PHSSR to better meet the goals and challenges facing the field. PMID- 22502926 TI - Quality improvement interventions in public health systems: a systematic review. AB - CONTEXT: Public health leaders are making difficult decisions about how to maximize the effectiveness of public health services with diminishing funds. Quality improvement (QI) interventions seek to improve the efficiency and effectiveness of public health programs, services, or organizations. The purpose of this study was to review the literature to describe public health system QI interventions and their impact on public health practices and health outcomes. EVIDENCE ACQUISITION: A systematic review was conducted using PRISMA guidelines. Three databases were searched for peer-reviewed articles that included public health quality improvement-related terms in their abstracts. Articles published in 1990-2010 that described results from QI interventions conducted within the U.S. public health system were included. EVIDENCE SYNTHESIS: Fifteen studies were identified, reporting on 18 separate QI interventions. Studies fell naturally into three functional categories: organization-wide QI, program- or service specific QI, and administrative or management function QI. Few of the studies linked their improvements directly to a health outcome or predictors of health outcomes. Studies generally were implemented in state-level or large local public health departments. CONCLUSIONS: Formally published QI interventions may not be representative of typical, smaller-scale QI activities. Collection and distribution of QI results associated with proven, effective public health interventions and that quantify the benefits of QI practices in public health should be a goal. More research is needed to definitively "connect the dots" between QI efforts, resulting practice improvements, and actual (or predictors of) health outcome improvements. Future studies should examine QI in diverse public health systems. PMID- 22502927 TI - Building an effective workforce: a systematic review of public health workforce literature. AB - CONTEXT: The Robert Wood Johnson Foundation commissioned a systematic review of public health workforce literature in fall 2010. This paper reviews public health workforce articles published from 1985 to 2010 that support development of a public health workforce research agenda and address four public health workforce research themes: size and composition, effectiveness and health impact, demand, and policy. EVIDENCE ACQUISITION: PubMed, ERIC, and Web of Science databases were used to search for articles; Google search engine was used to identify gray literature. The study used the following inclusion criteria: (1) the document was published in the U.S.; (2) the main theme(s) of the article address public health workforce research or relate to at least one of the four workforce research themes; and (3) the article focuses on the domestic workforce. EVIDENCE SYNTHESIS: A total of 126 public health workforce articles and gray literature documents were analyzed in this review, including 34 related to effectiveness and health impact, 32 summary articles, 30 articles on size and composition, 20 articles about demand, and 10 policy articles. The primary sources for identifying articles were PubMed (66%); Google (28%); and Web of Science (6%). CONCLUSIONS: The majority of public health workforce articles are descriptive in nature; few empirical studies about the public health workforce have been published in the peer-reviewed literature. Future research should consider use of organizational theories to develop workforce capacity models for public health and development of quantifiable output measures on which to base models that incorporate workforce demand. PMID- 22502928 TI - A national research agenda for public health services and systems. AB - The field of public health services and systems research (PHSSR) has emerged over the past decade to produce the evidence needed to address critical uncertainties about how best to organize, finance, and deliver effective public health strategies to all Americans. To advance these efforts, a national PHSSR research agenda-setting process was used to identify a broad inventory of information needs and uncertainties that public health stakeholders face in the domains of public health workforce, public health system structure and performance, public health financing, and public health information and technology. This paper presents the results of an expert review process used to transform the identified information needs into a concise set of research questions that can be pursued through new scientific inquiry in PHSSR. Established research frameworks were used to specify the contexts, mechanisms of action, and outcomes within the public health system that require further study. A total of 72 research questions were developed from the 113 original items in the PHSSR inventory of information needs. The questions include both persistent problems and newly emerging needs in public health practice and policy. The resulting research agenda provides a starting point for mobilizing the public health scientific enterprise around contemporary, high-priority uncertainties identified by broad cross sections of public health stakeholders. Regular updates to this agenda will be required to achieve continuous improvements in both the science and practice of public health. PMID- 22502929 TI - Public health services and systems research: an agenda where research and practice matter to each other and to our nation's health. PMID- 22502930 TI - The value of public health services and systems research. PMID- 22502931 TI - Public health services and systems research: an afterword. PMID- 22502932 TI - Balancing economic freedom against social policy principles: EC competition law and national health systems. AB - EU Health policy exemplifies the philosophical tension between EC economic freedoms and social policy. EC competition law, like other internal market rules, could restrict national health policy options despite the subsidiarity principle. In particular, European health system reforms that incorporate elements of market competition may trigger the application of competition rules if non-economic gains in consumer welfare are not adequately accounted for. This article defines the policy and legal parameters of the debate between competition law and health policy. Using a sample of cases it analyses how the ECJ, national courts, and National Competition Authorities have applied competition laws to the health services sector in different circumstances and in different ways. It concludes by considering the implications of the convergence of recent trends in competition law enforcement and health system market reforms. PMID- 22502933 TI - Public support for smoke-free areas in Israel: a case for action. AB - OBJECTIVE: Secondhand smoke exposure (SHSe) harms adults and children. Though most governments are obliged by international health treaty to protect nonsmokers from SHSe, few adequately do so. Public opinion can provide a powerful mandate for smoke-free policies, but a representative public voice is often absent from the political discussion. For example, following Cabinet approval of a national tobacco control plan, Israel remains embroiled in stormy debate about smoke-free legislation. This debate has unfolded without benefit of current empirical evidence on nationwide public support. The present study reports and assesses public opinion regarding smoke-free places. METHODS: A nationally representative survey (n=505) was conducted in December, 2010. The response rate was 61%. RESULTS: Public opinion supports smoke-free air in many places. There was broad consensus among current, former, and never-smokers for smoke-free cars carrying children (94.4%), and smoke-free healthcare facility entrances (92.6%). A clear majority (67.0%) supported completely smoke-free bars and pubs. Nearly half (47.3%) supported eliminating school staff smoking rooms. CONCLUSIONS: These data strengthen the case for the recent government-approved tobacco control plan. Valid data regarding public opinion on tobacco control can facilitate passage and implementation of smoke-free legislation, thus speeding transition to smoke-free societies. PMID- 22502934 TI - New Zealand's post-2008 health system reforms: toward re-centralization of organizational arrangements. AB - The election of a centre-right government in 2008 has spawned a series of ongoing reforms to the structures for governing New Zealand's health system. These mainly involve creation of a series of new national agencies designed to stimulate national coordination and centralization of some planning and service delivery functions along with performance improvements in specific areas, namely quality, information technology, service efficiency, reduction of administrative costs, and comparative-effectiveness research. This brief article provides an overview of the post-2008 reforms. It notes that, while there appears to be agreement within the health system that the reforms are moving in the right direction, the new institutional arrangements are perhaps overly complicated. PMID- 22502935 TI - Responses to increasing cigarette prices in France: how did persistent smokers react? AB - OBJECTIVES: (1) To build a typology of persistent smokers' reactions to increasing cigarette prices (persistent smokers were defined as smokers who did not quit because of such increases) and (2) to investigate which factors were correlated with their reactions (we considered three categories: no reaction, trying to quit or smoking less, reducing the cost of smoking). METHODS: We used a French national telephone survey (n=2000; 621 smokers) that included questions about smokers' reactions to increasing cigarette prices, as well as questions about their socio-demographic background, personal time perspective, smoking behavior and reasons for smoking. We used logistic regressions to identify which of these factors were linked to smokers' reactions. RESULTS: In response to the increasing cigarette prices, 24% of persistent smokers did not change their smoking habits at all, 31% only reduced the cost of smoking (they neither reduced their consumption nor tried to quit) and 45% tried to give up smoking or reduced their consumption (they also frequently reduced the cost of smoking). Male and older smokers, the more educated ones and the wealthier ones more frequently reported no reaction at all, as did those who smoked to improve their concentration or keep their weight down. Younger and unemployed smokers more frequently opted for spending less on cigarettes, as did those who smoked to forget about their problems. Finally, present-oriented smokers were less prone to try to quit or to reduce their consumption. CONCLUSION: These findings show the need to increase the price of all tobacco products in cooperation with neighboring states. People's reasons for smoking and their personal time perspectives contribute to their reactions to price increases, and different preventive measures are required for each category of persistent smokers. PMID- 22502936 TI - Public procurement of health technologies in Greece in an era of economic crisis. AB - Public procurement is generally an important sector of the economy and, in most countries, is controlled by the introduction of regulatory and policy mechanisms. In the Greek healthcare sector, recent legislation redefined centralized procurement through the reestablishment of a state Health Procurement Committee (EPY), with an aim to formulate a plan to reduce procurement costs of medical devices and pharmaceuticals, improve payment time, make uniform medical requests, transfer redundant materials from one hospital to another and improve management of expired products. The efforts described in this paper began in early 2010, under the co-ordination of the Ministry of Health (MoH) and with the collaboration of senior staff from the International Monetary Fund (IMF), the European Commission (EC) and the European Central Bank (ECB). The procurement practices and policies set forth by EPY and the first measurable outcomes, in terms of cost savings, resulting from these policies are presented. The importance of these measures is discussed in light of the worst economic crisis faced by Greece since the restoration of democracy in 1974, as a result of both the world financial crisis and uncontrolled government spending. PMID- 22502937 TI - Diabetes mellitus in genetically isolated populations in Jordan: prevalence, awareness, glycemic control, and associated factors. AB - OBJECTIVES: Diabetes mellitus is one of the most common non-communicable diseases globally. This study seeks to estimate the prevalence of impaired fasting glycemia and type 2 diabetes mellitus in genetically isolated populations in Jordan: the Circassians and Chechans. RESEARCH DESIGN AND METHODS: Data were analyzed from a cross-sectional study that included a random sample of adult Circassians and Chechans. A subject was defined as affected by diabetes mellitus if diagnosis was known to patient or, according to the American Diabetes Association definition. Impaired fasting glucose was defined as a fasting serum glucose level of >=6.1 mmol/L (100 mg/dl) but <7 mmol/L. HbA(1c) >7% was defined as 'unsatisfactory' metabolic control. RESULTS: The prevalence of impaired fasting glycemia was 18.5% for Circassians and 14.6% for Chechans. Prevalence of diabetes was 9.6% for Circassians and 10.1% for Chechans. The prevalence of impaired fasting glycemia and diabetes were significantly higher in men, older age groups, married, subjects of lower educational level, past smokers, and subjects with obesity. Low high-density lipoprotein cholesterol was the most common abnormality in the two populations. CONCLUSIONS: The homogenous, genetically isolated Circassian and Chechan populations sharing the same environmental influences suggest a role for genetic risk factors for diabetes. Thus these two populations are suitable for additional genetics studies that may lead to the identification of novel risk factors for type 2 diabetes. In addition, more than half of patients with diabetes were with unsatisfactory control. Therefore, they are likely to benefit from programs encouraging healthy weight and physical activity. PMID- 22502938 TI - Time-course changes in nerve conduction velocity (NCV) in type 2 diabetes. AB - AIM: Changes in NCV were surveyed over 10 years in type 2 diabetes patients to clarify the time-course relationships between NCV and retinopathy stage and between NCV and HbA1c. In addition, the natural course of diabetic sensorimotor polyneuropathy (DSPN) was discussed based on the findings. METHODS: Using a simple NCV measurement device, NCV (MCV and SCV) was measured once a year over 10 years in 474 patients with type 2 diabetes. These patients were grouped based on the retinopathy stage and HbA1c level in the course to investigate the time course relationships between the retinopathy stage and NCV and between HbA1c and NCV. RESULTS: The retinopathy stage and NCV reduction were strongly correlated, and NCV decreased as retinopathy progressed. On comparison of time-course NCV among the retinopathy stages, continuity of NCV reduction along with the retinopathy progression was noted. Regarding the relationship between HbA1c and NCV, NCV reduction was moderate in the group maintaining HbA1c at a relatively favorable level, but morbid reduction of NCV could not be prevented even though favorable control was maintained. CONCLUSION: NCV reduction is strongly correlated with retinopathy progression from more than 10 years before its manifestation through reaching proliferative retinopathy. It was also suggested that NCV reduction can be attenuated by controlling blood glucose, but the reduction cannot be prevented completely. Based on these findings, DSPN is a progressive complication that starts from an early phase after onset of diabetes and steadily aggravates, keeping step with retinopathy aggravation, and it may be difficult to completely prevent the progression. PMID- 22502939 TI - Comparison of demographic factors and cardiovascular risk factor control among U.S. adults with type 2 diabetes by insulin treatment classification. AB - AIMS: Data on glucose and cardiovascular disease (CVD) risk factor control among persons with type 2 diabetes mellitus (DM) according to insulin treatment status are lacking. We examined DM control, risk factors, and comorbidities among U.S. persons according to insulin treatment status. METHODS: In the U.S. National Health and Nutrition Examination Surveys 2003-2006, we examined in 10,637 adults aged >=30 with type 2 DM the extent of control of A1c, LDL-C, HDL-C, triglycerides, and blood pressure (BP) and composite goal attainment by insulin use status. RESULTS: 6.6% (n=889, projected to 14.3 million) had type 2 DM; of these, 22.9% were insulin users and 57.2% were treated only by other diabetes medications. Overall, 58.2% had an A1c<7% (53 mmol/mol) (insulin users 33.1%, non insulin treated 66.1%, and 77.9% of those not on medication, p<0.0001). Overall, 44.2% were at a BP goal of <130/80 mmHg, 43.8% had an LDL-C<100 mg/dl (2.6 mmol/L), and 13.9% a BMI<25 kg/m(2). Only 10.2% were simultaneously at A1c, LDL, and BP goals (5.4% of those on insulin). CONCLUSIONS: U.S. adults with type 2 DM, especially those treated with insulin remain inadequately controlled for A1c and CVD risk factors and have a high prevalence of comorbidities. PMID- 22502940 TI - Yield and turnover of illicit indoor cannabis (Cannabis spp.) plantations in Belgium. AB - In prosecution, Belgian judiciary currently uses outdated yield figures (28.1g per plant, sold at ? 3/g at grower level) for fining illicit indoor cannabis plantations. Using state-of-the-art cultivation techniques, our growth experiments showed that yield is better expressed in g/m(2) cultivated surface area rather than in g per plant, and that yield varies significantly between different cannabis strains. It was found that the lower-bound of the one-sided 95% confidence interval of the yield of an indoor cannabis plantation can be set at 575 g/m(2). Prices and pricing mechanisms were investigated using interviews with respondents selected through snowball sampling. Results reveal that (i) the Belgian cannabis market chain is highly complex; (ii) unit prices are predominantly determined by transaction sizes; but also (iii) a set of product- and socially-related price-fixing mechanisms have an equally important role. At grower level, respondents reported prices for 1 g of dry cannabis buds to range ? 3.00-4.25. PMID- 22502941 TI - Characterisation of gunshot residue from three ammunition types using suppressed anion exchange chromatography. AB - Gunshot residue (GSR) is commonly analysed in forensic casework using either scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDX) or gas chromatography-mass spectrometry (GC-MS). Relatively little work has been reported on the post-discharge GSR content of non-metallic inorganic or low molecular weight organic anions to distinguish between different ammunition types. The development of an analytical method using suppressed micro-bore anion exchange chromatography (IC) is presented for the analysis of GSR. A hydroxide gradient was optimised for the separation of 19 forensically relevant organic and inorganic anions in <23min and sensitivities of the order of 0.12-3.52ng of anion detected for all species were achieved. Along with an optimised extraction procedure, this method was applied to the analysis of post-ignition residues from three selected ammunition types. By profiling and comparing the anionic content in each ammunition residue, the possibility to distinguish between each type using their anionic profiles and absolute weight is presented. The potential for interference is also discussed with respect to sample types which are typically problematic in the analysis of GSR using SEM-EDX and GC-MS. To the best of our knowledge this represents the first study on the analysis of inorganic anions in GSR using suppressed ion chromatography. PMID- 22502942 TI - Addition of radiotherapy to long-term androgen deprivation in locally advanced prostate cancer: an open randomised phase 3 trial. AB - BACKGROUND: Radiotherapy combined with androgen-deprivation therapy (ADT) is superior to radiotherapy alone in localised prostate cancer; however, data comparing ADT alone are somewhat limited. OBJECTIVE: To compare 3-yr ADT plus radiotherapy with ADT alone in locally advanced prostate cancer patients. DESIGN, SETTING, AND PARTICIPANTS: A multicentre randomised open controlled phase 3 trial in 264 histologically confirmed T3-4 or pT3N0M0 prostate cancer patients randomised from March 2000 to December 2003. INTERVENTION: ADT (11.25mg subcutaneous depot injection of leuprorelin every 3 mo for 3 yr) plus external beam radiotherapy or ADT alone. Flutamide (750 g/d) was administered for 1 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objective was 5 yr progression-free survival (PFS) according to clinical or biologic criteria, using the American Society for Therapeutic Radiology and Oncology (ASTRO) and the newer (Phoenix) definition (nadir plus 2 ng/ml), by intention to treat. Secondary objectives included time to locoregional recurrence and distant metastases, and overall and disease-specific survival. Our Analyses: intent-to-treat analysis, multivariate analyses using a Cox model with a 5% threshold from univariate analysis, and Kaplan-Meier estimates. RESULTS AND LIMITATIONS: ADT alone was administered to 130 patients and combined therapy to 133. With a median follow-up of 67 mo, 5-yr PFS was 60.9% for combined therapy versus 8.5% with ADT alone (ASTRO; p<0.0001), and 64.7% versus 15.4%, respectively, for Phoenix (p<0.0011). Locoregional progression was reported in 9.8% of combined-therapy patients versus 29.2% with ADT alone (p<0.0001) and metastatic progression in 3.0% versus 10.8%, respectively (p<0.018). Overall survival was 71.4% with combined therapy versus 71.5% with ADT alone; disease-specific survival was 93.2% versus 86.2%. Limitations included the relatively small population and a relatively short follow-up period. CONCLUSIONS: Combined therapy strongly favoured improved PFS, locoregional control, and metastasis-free survival. Longer follow-up is needed to assess the potential survival impact. PMID- 22502944 TI - Exome sequencing of prostate cancer supports the hypothesis of independent tumour origins. AB - BACKGROUND: Prostate cancer (PCa) is a clinically and pathologically heterogeneous disease. The rapid development of sequencing technology has the potential to deliver new biomarkers with emphasis on aggressive disease and to revolutionise personalised cancer treatment. However, a prostate harbouring cancer commonly contains multiple separate tumour foci, with the potential to aggravate tumour sampling. The level of intraprostatic tumour heterogeneity remains to be determined. OBJECTIVE: To determine the level of intraprostatic tumour heterogeneity through genome-wide, high-resolution profiling of multiple tumour samples from the same individual. DESIGN, SETTINGS, AND PARTICIPANTS: Multiple tumour samples were obtained from four individuals following radical prostatectomy. One individual (SWE-1) contained >70% cancer cells in all tumour samples, whereas the other three (SWE-2 to SWE-4) required the use of laser capture microdissection for tumour cell enrichment. Subsequently, DNA was extracted from all tissue samples, and exome sequencing was performed. All tumour foci of SWE-1 were also profiled using a high-resolution array for the identification of copy number alterations (CNA). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Shared somatic high-frequency single nucleotide variants (SNV) and CNAs were used to infer the level of intraprostatic tumour heterogeneity. RESULTS AND LIMITATIONS: No high-frequency mutations, common for the three tumour samples of SWE-1, were identified. Ten randomly chosen positions were validated with Sanger sequencing in all foci, which verified the exome data. The high level of intraprostatic heterogeneity was consistent in all individuals. In total, three out of four individuals harboured tumours without an apparent common somatic denominator. Although we cannot exclude the presence of common structural rearrangements, a high-density array was used for the detection of deletions and amplifications in SWE-1, which agreed with the exome data. CONCLUSIONS: We present evidence for the presence of somatically independent tumours within the same prostate. This finding will have implications for personalised cancer treatment and biomarker discovery. PMID- 22502945 TI - Unexpected bias in NIST 4pigamma ionization chamber measurements. AB - In January of 2010, it was discovered that the source holder used for calibrations in the NIST 4pigamma ionization chamber (IC) has not been stable. The positioning ring that determines the height of the sample in the reentrant tube of the IC has slowly shifted during 35 years of use. This has led to a slow change in the calibration factors for the various radionuclides measured by this instrument. The changes are dependent on gamma-ray energy and the time the IC was calibrated for a given radionuclide. A review of the historic data with regard to when the calibrations were done has enabled us to approximate the magnitude of the changes with time. This requires a number of assumptions, and corresponding uncertainty components, including whether the changes in height were gradual or in steps as will be shown in drawings of sample holder. For calibrations the changes in calibration factors have been most significant for low energy gamma emitters such as (133)Xe, (241)Am, (125)I and (85)Kr. The corrections to previous calibrations can be approximated and the results corrected with an increase in the overall uncertainty. At present we are recalibrating the IC based on new primary measurements of the radionuclides measured on the IC. Likewise we have been calibrating a new automated ionization-chamber system. A bigger problem is the significant number of half-life results NIST has published over the last 35 years that are based on IC measurements. The effect on half-life is largest for long-lived radionuclei, especially low-energy gamma-ray emitters. This presentation will review our results and recommend changes in values and/or uncertainties. Any recommendation for withdrawal of any results will also be undertaken. PMID- 22502946 TI - Revisiting cerebral thromboangiitis obliterans. AB - We describe a 56-year-old patient with progressive cognitive decline in the context of heavy tobacco use and migraine, and imaging evidence of an occlusive terminal cerebral vasculopathy. The results of brain biopsy recapitulated the pathological features described by Lindenberg and Spatz in their classic 1939 treatise on cerebral thromboangiitis obliterans, or cerebral Buerger's disease. Although the condition is associated with heavy smoking, the identification of a hypercoagulable state in our patient suggests a multifactorial pathogenesis. The diagnosis of cerebral thromboangiitis obliterans in life is facilitated by modern neuroimaging and should prompt immediate cessation of smoking and a search for an underlying prothrombotic tendency. PMID- 22502947 TI - Regulating a novel drug: an evaluation of changes in use of Salvia divinorum in the first year of Florida's ban. AB - BACKGROUND: A plant with dissociative and psychoactive properties began to attract the attention of the media and United States policymakers following a well-publicized suicide in 2006 and reports that the plant served as a 'legal high' and substitute for cannabis. As a result, Salvia divinorum and its active ingredient, salvinorin A, were classified as Schedule I substances by the Florida Legislature on July 1, 2008. As of yet, no research has explored the efficacy of this policy or similar policies in other jurisdictions. METHODS: Three self report studies collected from young adults both prior to and following the policy's implementation are employed to investigate the potential relationship between the policy and usage rates. In addition, law enforcement personnel from the state's most populated areas were interviewed to determine the extent to which they were encountering salvia in their work. RESULTS: It was indicated that less than two-thirds of those surveyed were aware of the drug's legal status. Lifetime prevalence of salvia use was largely unchanged. However, the rates of self-reported past year and past month use in Florida were significantly lower following the scheduling. Though use of Salvia divinorum appears to have decreased, perceptions of peer use increased markedly. Law enforcement officers and laboratories reported rarely, if ever, dealing with cases of salvia possession. CONCLUSIONS: Data suggests the classification of Salvia divinorum as a Schedule I drug was followed by a substantial reduction in recreational use. We caution that other factors may have influenced use, that the efficacy of scheduling novel substances is likely to vary by drug type, that such a reduction in reported use may only exist transiently until a sophisticated illicit market develops to replace the legitimate one, and that a state's success in regulating salvia may be related to their regulation of and enforcement of other drug prohibitions. PMID- 22502948 TI - Grading dermatologic adverse events of cancer treatments: the Common Terminology Criteria for Adverse Events Version 4.0. AB - Dermatologic adverse events to cancer therapies have become more prevalent and may to lead to dose modifications or discontinuation of life-saving or prolonging treatments. This has resulted in a new collaboration between oncologists and dermatologists, which requires accurate cataloging and grading of side effects. The Common Terminology Criteria for Adverse Events Version 4.0 is a descriptive terminology and grading system that can be used for uniform reporting of adverse events. A proper understanding of this standardized classification system is essential for dermatologists to properly communicate with all physicians caring for patients with cancer. PMID- 22502950 TI - Polarized micropores in a novel 3D metal-organic framework for selective adsorption properties. AB - A novel 3D porous metal-organic framework with 1D polarized channels was synthesized, and its adsorption properties for gas separation and chemical sensing were studied. The framework shows a preferential adsorption of CO(2) over N(2) with a selectivity of 22:1. It also exhibits a very good sensitivity to water with respect to most of the organic solvents in view of chemical sensing applications. PMID- 22502949 TI - Protein carbonylation in a murine model for early alcoholic liver disease. AB - Hepatic oxidative stress and subsequent lipid peroxidation are well-recognized consequences of sustained ethanol consumption. The covalent adduction of nucleophilic amino acid side-chains by lipid electrophiles is significantly increased in patients with alcoholic liver disease (ALD); a global assessment of in vivo protein targets and the consequences of these modifications, however, has not been conducted. In this article, we describe the identification of novel protein targets for covalent adduction in a 6-week murine model for ALD. Ethanol fed mice displayed a 2-fold increase in hepatic TBARS, while immunohistochemical analysis for the reactive aldehydes 4-hydroxynonenal (4-HNE), 4-oxononenal (4 ONE), acrolein (ACR), and malondialdehyde (MDA) revealed a marked increase in the staining of modified proteins in the ethanol-treated mice. Increased protein carbonyl content was confirmed utilizing subcellular fractionation of liver homogenates followed by biotin-tagging through hydrazide chemistry, where approximately a 2-fold increase in modified proteins was observed in microsomal and cytosolic fractions. To determine targets of protein carbonylation, a secondary hydrazide method coupled to a highly sensitive 2-dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS or MuDPIT) technique was utilized. Our results have identified 414 protein targets for modification by reactive aldehydes in ALD. The presence of novel in vivo sites of protein modification by 4-HNE (2), 4-ONE (4) and ACR (2) was also confirmed in our data set. While the precise impact of protein carbonylation in ALD remains unknown, a bioinformatic analysis of the data set has revealed key pathways associated with disease progression, including fatty acid metabolism, drug metabolism, oxidative phosphorylation, and the TCA cycle. These data suggest a major role for aldehyde adduction in the pathogenesis of ALD. PMID- 22502951 TI - Heartbeat evoked potentials: a new possible clinical biomarker for depression based on the somatic marker hypothesis. PMID- 22502952 TI - Impact of the CHA2DS2-VASc score on anticoagulation recommendations for atrial fibrillation. AB - BACKGROUND: The Congestive heart failure, Hypertension, Age >= 75 years, Diabetes mellitus, Stroke (CHADS(2)) score is used to predict the need for oral anticoagulation for stroke prophylaxis in patients with atrial fibrillation. The Congestive heart failure, Hypertension, Age >= 75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category (CHA(2)DS(2)-VASc) schema has been proposed as an improvement. Our objective is to determine how adoption of the CHA(2)DS(2)-VASc score alters anticoagulation recommendations. METHODS: Between 2004 and 2008, 1664 patients were seen at the University of Virginia Atrial Fibrillation Center. We calculated the CHADS(2) and CHA(2)DS(2)-VASc scores for each patient. The 2006 American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines for atrial fibrillation management were used to determine anticoagulation recommendations based on the CHADS(2) score, and the 2010 European Society of Cardiology guidelines were used to determine anticoagulation recommendations based on the CHA(2)DS(2)-VASc score. RESULTS: The average age was 62+/-13 years, and 34% were women. Average CHADS(2) and CHA(2)DS(2)-VASc scores were 1.1+/-1.1 and 1.8+/-1.5, respectively (P<.0001). The CHADS(2) score classified 33% as requiring oral anticoagulation. The CHA(2)DS(2)-VASc score classified 53% as requiring oral anticoagulation. For women, 31% had a CHADS(2) score >= 2, but 81% had a CHA(2)DS(2)-VASc score >= 2 (P = .0001). Also, 32% of women with a CHADS(2) score of zero had a CHA(2)DS(2) VASc score >= 2. For men, 25% had a CHADS(2) score >= 2, but 39% had a CHA(2)DS(2)-VASc score >= 2 (P<.0001). CONCLUSION: Compared with the CHADS(2) score, the CHA(2)DS(2)-VASc score more clearly defines anticoagulation recommendations. Many patients, particularly older women, are redistributed from the low- to high-risk categories. PMID- 22502953 TI - Paradoxical response to tuberculosis treatment in a patient receiving tumor necrosis factor-alpha antagonist. PMID- 22502954 TI - Transesophageal echocardiograms in patients with catheter-derived Staphylococcus aureus bacteremia. PMID- 22502955 TI - Rules of engagement: the principles of underserved global health volunteerism. PMID- 22502956 TI - Alternative smoking cessation aids: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Acupuncture, hypnotherapy, and aversive smoking are the most frequently studied alternative smoking cessation aids. These aids are often used as alternatives to pharmacotherapies for smoking cessation; however, their efficacy is unclear. METHODS: We carried out a random effect meta-analysis of randomized controlled trials to determine the efficacy of alternative smoking cessation aids. We systematically searched the Cochrane Library, EMBASE, Medline, and PsycINFO databases through December 2010. We only included trials that reported cessation outcomes as point prevalence or continuous abstinence at 6 or 12 months. RESULTS: Fourteen trials were identified; 6 investigated acupuncture (823 patients); 4 investigated hypnotherapy (273 patients); and 4 investigated aversive smoking (99 patients). The estimated mean treatment effects were acupuncture (odds ratio [OR], 3.53; 95% confidence interval [CI], 1.03-12.07), hypnotherapy (OR, 4.55; 95% CI, 0.98-21.01), and aversive smoking (OR, 4.26; 95% CI, 1.26-14.38). CONCLUSION: Our results suggest that acupuncture and hypnotherapy may help smokers quit. Aversive smoking also may help smokers quit; however, there are no recent trials investigating this intervention. More evidence is needed to determine whether alternative interventions are as efficacious as pharmacotherapies. PMID- 22502957 TI - Strange case of Dr Jekyll and Mr Hyde--and John Hunter. PMID- 22502958 TI - An unusual cause of jaundice. PMID- 22502959 TI - Performance of 2 commercial real-time polymerase chain reaction assays for the detection of Aspergillus and Pneumocystis DNA in bronchoalveolar lavage fluid samples from critical care patients. AB - This article investigates the performance of 2 commercial real-time polymerase chain reaction (PCR) assays, MycAssayTM Aspergillus (Myc(Asp)Assay) and MycAssayTM Pneumocystis (Myc(PCP)Assay), on the ABI 7300 platform for the detection of Aspergillus (Asp) or Pneumocystis jirovecii (Pj) DNA in bronchoalveolar lavage (BAL) samples from 20 patients. Operationally, patients enrolled were clustered into 3 groups: invasive aspergillosis group (IA, 7 patients), Pj pneumonia group (PCP, 8 patients), and negative control group (5 patients). All the IA patients were Myc(Asp)Assay positive, whereas 12 non-IA patients returned negative PCR results. Furthermore, 7 of 8 PCP patients were Myc(PCP)Assay positive, while 9 non-PCP patients were PCR negative. In conclusion, these data provide an early indication of the effectiveness of both the Myc(Asp)Assay and Myc(PCP)Assay on the ABI 7300 platform for the detection of either Asp or Pj DNA in BAL from patients with deep fungal infections. PMID- 22502960 TI - Optimized serodiagnosis of Mycoplasma pneumoniae infections. AB - Serologic methods are well established for the diagnosis of Mycoplasma pneumoniae infections in humans, but they are less sensitive than polymerase chain reaction (PCR). To improve their sensitivity, a new panel of antigens was tested. Compared with PCR results, up to 92% of PCR-positive patients were confirmed by our immunoblotting approach having a specificity between 92.6% and 100%. PMID- 22502962 TI - Lexical selectivity in danish toddlers with cleft palate. AB - Objective : To study if Danish children with cleft palate display lexical selectivity in their early lexicon at 18 months of age. Design : A cross sectional study. Participants : Thirty-four children with unilateral cleft lip and palate and 35 children without cleft palate, matched for gender and age. Methods : All participants were video recorded at 18 months of age during play interaction with a parent. The video recordings were transcribed according to the International Phonetic Alphabet and an individual consonant inventory was established for each participant. The video recordings were also analyzed with respect to word productions, establishing an observed productive vocabulary size for each participant. Results : At 18 months of age Danish children with cleft palate showed marked lexical selectivity in their early words. The distribution of consonant classes observed at 11 months of age in a previous study of the children with cleft palate was almost perfectly reflected in their early lexicon at 18 months. The early lexicon of children with cleft palate differed from the early lexicon of their noncleft peers. Conclusions and Implications : Danish toddlers with cleft palate display lexical selectivity in the early lexicon as it has been described for English-speaking toddlers with and without cleft palate, even though some qualitative differences were found. PMID- 22502961 TI - Hepatic mucormycosis with abscess formation. AB - We describe a case of hepatic mucormycosis with abscess, an uncommon presentation of mucormycetes infection. Our patient was initially treated with transcutaneous pigtail catheter placement, liposomal amphotericin B, and micafungin without improvement. The patient subsequently improved after hepatic segmentectomy and hemidiaphragm resection. PMID- 22502963 TI - Development of a cardiac surgery simulation curriculum: from needs assessment results to practical implementation. AB - OBJECTIVE: A paradigm shift in surgical training has led to national efforts to incorporate simulation-based learning into cardiothoracic residency programs. Our goal was to determine the feasibility of developing a cardiac surgery simulation curriculum using the formal steps of curriculum development. METHODS: Cardiothoracic surgery residents (n = 6) and faculty (n = 9) evaluated 54 common cardiac surgical procedures to determine their need for simulation. The highest scoring procedures were grouped into similarly themed monthly modules, each with specific learning objectives. Educational tools consisting of inanimate, animate, and cadaveric facilities and a newly created virtual operating room were used for curriculum implementation. Resident satisfaction was evaluated by way of a 5 point Likert scale. Perceived competency (scale of 1-10) and pre-/post-self confidence (scale of 1-5) scores were collected and analyzed using cumulative mean values and a paired t-test. RESULTS: Of the 23 highest scoring procedures (mean score, >= 4.0) on the needs assessment, 21 were used for curriculum development. These procedures were categorized into 12 monthly modules. The simulation curriculum was implemented using the optimal simulation tool available. Resident satisfaction (n = 57) showed an overwhelmingly positive response (mean score, >= 4.7). The perceived competency scores highlighted the procedures residents were uncomfortable performing independently. The pre-/post self-confidence scores increased throughout the modules, and the differences were statistically significant (P < .001). CONCLUSIONS: It is feasible to develop and implement a cardiac surgery simulation curriculum using a structured approach. High-fidelity, low-technology tools such as a fresh tissue cadaver laboratory and a virtual operating room could be important adjuncts. PMID- 22502964 TI - Healing process after total cricoidectomy and laryngotracheal reconstruction: endoscopic and histologic evaluation in a canine model. AB - OBJECTIVE: The surgical procedure for subglottic stenosis is technically challenging when the vocal cords are involved and concomitant management for glottic involvement is required. After total cricoidectomy and laryngotracheal anastomosis, T-tube placement for 3 to 6 months is recommended. Bone grafts might shorten this period. We report the histologic and endoscopic changes after total cricoidectomy with or without bone grafts in a canine model to suggest an appropriate period for T-tube placement and the necessity for bone grafts. METHODS: Ten dogs underwent total cricoidectomy and laryngotracheal anastomosis with or without bone grafts harvested from the ribs. Endoscopic examination was performed monthly, and 1 dog from both groups was humanely killed at 1, 2, 3, 6, and 12 months. The T-tube was removed before death in the dogs killed at 1, 2, and 3 months and at 3 and 6 months in those killed at 6 and 12 months, respectively. RESULTS: Endoscopically, the glottic opening was in good condition in all dogs, except for 1 that had glottic stenosis. Histologically, active lymphocyte infiltration was observed in dense collagen fibers at the anastomosis at 1 month. At 2 and 3 months, fibroblasts were evident, suggesting active collagen fiber production. At 6 and 12 months, the collagen fibers had become looser. The bone grafts were intact and did not influence the surrounding tissue. CONCLUSIONS: In the canine model, 6 months of T-tube placement is probably sufficient; however, 3 months of placement might not be. Additionally, no difference was found between the dogs with and without a bone graft. PMID- 22502965 TI - Left main coronary artery atresia with tetralogy of Fallot: a novel association. PMID- 22502966 TI - Educational program in crisis management for cardiac surgery teams including high realism simulation. AB - INTRODUCTION: Cardiac surgery demands effective teamwork for safe, high-quality care. The objective of this pilot study was to develop a comprehensive program to sharpen performance of experienced cardiac surgical teams in acute crisis management. METHODS: We developed and implemented an educational program for cardiac surgery based on high realism acute crisis simulation scenarios and interactive whole-unit workshop. The impact of these interventions was assessed with postintervention questionnaires, preintervention and 6-month postintervention surveys, and structured interviews. RESULTS: The realism of the acute crisis simulation scenarios gradually improved; most participants rated both the simulation and whole-unit workshop as very good or excellent. Repeat simulation training was recommended every 6 to 12 months by 82% of the participants. Participants of the interactive workshop identified 2 areas of highest priority: encouraging speaking up about critical information and interprofessional information sharing. They also stressed the importance of briefings, early communication of surgical plan, knowing members of the team, and continued simulation for practice. The pre/post survey response rates were 70% (55/79) and 66% (52/79), respectively. The concept of working as a team improved between surveys (P = .028), with a trend for improvement in gaining common understanding of the plan before a procedure (P = .075) and appropriate resolution of disagreements (P = .092). Interviewees reported that the training had a positive effect on their personal behaviors and patient care, including speaking up more readily and communicating more clearly. CONCLUSIONS: Comprehensive team training using simulation and a whole-unit interactive workshop can be successfully deployed for experienced cardiac surgery teams with demonstrable benefits in participant's perception of team performance. PMID- 22502967 TI - Adjuvant chemotherapy for surgically resected non-small cell lung cancer. AB - Despite surgical resection, patients with early-stage (I to IIIA) non-small cell lung cancer (NSCLC) are at considerable risk of recurrence and death from their lung cancer. In recent years, multiple, large, randomized trials assessing the efficacy of adjuvant chemotherapy for resected NSCLC have been reported. Three of 6 trials with 300 or more patients with early-stage NSCLC have demonstrated that adjuvant cisplatin-based chemotherapy can significantly improve 5-year survival in carefully selected patients with resected NSCLC. These benefits have been confirmed in a meta-analysis of modern cisplatin-based adjuvant trials. The most consistent benefit has been reported in patients with resected stage II and IIIA NSCLC. The benefit of adjuvant chemotherapy in patients with resected stage IB NSCLC is less concrete. Herein, we review the results of the major adjuvant chemotherapy trials and their implications for the treatment of patients with completely resected NSCLC. A future challenge will be to identify the subsets of patients who will derive the greatest benefit from adjuvant chemotherapy. Current trials are also underway to define the role of novel targeted therapies, such as inhibitors of the epidermal growth factor receptor and monoclonal antibodies, in adjuvant treatment strategies. PMID- 22502968 TI - Combined surgical and ablative cure for localized sternal compression-induced cardiomyopathy and ventricular tachyarrhythmia. PMID- 22502969 TI - Segmentectomy for selected cT1N0M0 non-small cell lung cancer: a prospective study at a single institute. AB - BACKGROUND: To examine whether segmentectomy is radical for cT1N0M0 non-small cell lung cancer (NSCLC), a prospective single-arm study was performed at a single institution. METHODS: The criteria for segmentectomy were as follows: (1) peripheral-type cT1N0M0 NSCLC; (2) intraoperative frozen sections of sentinel nodes identified with isotope showing no metastasis; (3) surgical margins greater than 2 cm; (4) patient choice for segmentectomy; and (5) exclusion of right middle lobe tumors. From 2005 to 2009, of 245 patients with cT1N0M0 NSCLC, 195 (80%) were enrolled in the present study. Of these 195 patients, 179 ultimately underwent segmentectomy with systematic lymph node dissection. Of these 179 patients, 134 (75%) had tumors 2 cm or smaller, and 45 (25%) had tumors 2.1 cm to 3 cm. The median follow-up period was 43 months. RESULTS: All 181 tumors from 179 patients were stage pN0. Of the 179 patients, 6 developed distant site recurrence and 3 local recurrence (ie, 1 developed pulmonary metastases within the same lobe 21 months after segmentectomy and 2 developed local recurrence at the surgical margin 60 and 62 months after segmentectomy, respectively). The 5-year overall survival was 94% for patients with tumors 2 cm or smaller and 81% for those with 2.1-cm to 3-cm tumors. Postoperative pulmonary function was preserved at 90% +/- 12% of preoperative levels. CONCLUSIONS: Segmentectomy with systematic lymph node dissection with a sufficient surgical margin could be a radical treatment for selected cT1N0M0/pN0 NSCLC while preserving pulmonary function. The surgical margin should be monitored for the development of local recurrence for a long period after segmentectomy. PMID- 22502971 TI - Penetrating injury to the right side of the heart without hemodynamic compromise. PMID- 22502973 TI - Management of postdissection thoracoabdominal aneurysm after previous frozen elephant trunk procedure with the E-vita Open Plus stent-graft. PMID- 22502972 TI - Extensive endarterectomy and reconstruction of the left anterior descending artery: early and late outcomes. AB - OBJECTIVES: Coronary endarterectomy has been shown to be an effective adjunctive technique of revascularization for diffuse coronary artery disease. A long arteriotomy and reconstruction of the left anterior descending artery (LAD) are occasionally required for complete extraction of the atherosclerotic plaque. The aim of this study was to examine early and late results of this technique and compare 2 different reconstruction methods. METHODS: We retrospectively reviewed 224 consecutive patients who underwent extensive LAD endarterectomy and reconstruction between January 1992 and March 2010. For reconstruction, 101 patients underwent saphenous vein patch and LAD grafting (group A) and 123 patients had left internal thoracic artery onlay patch grafting (group B). We compared early and late outcomes and assessed the association of the reconstruction method and long-term survival. RESULTS: The mean age was 66 and 67 years in groups A and B, respectively. Operative mortality was 3.0% and 4.1%, and the incidence of perioperative myocardial infarction in the LAD territory was 4.0% and 4.1% in groups A and B, respectively. There was no significant difference in early operative outcomes (P > .05). Actuarial 5-year survival was 78.6% and 87.1% and 10-year survival was 45.4% and 49.4% in groups A and B, respectively. Cox hazard proportional analysis showed that the reconstruction method did not have a significant impact on long-term survival. CONCLUSIONS: Extensive LAD endarterectomy and reconstruction is a safe and feasible technique of revascularization for diffuse coronary artery disease. The reconstruction method should be based on the availability of conduits and length of the arteriotomy. PMID- 22502974 TI - Aortopulmonary collateral flow volume affects early postoperative outcome after Fontan completion: a multimodality study. AB - OBJECTIVE: Aortopulmonary collaterals are a frequent phenomenon in patients after bidirectional cavopulmonary connection. The aortopulmonary collateral flow volume can be quantified using cardiac magnetic resonance imaging. However, the significance of aortopulmonary collateral flow for the postoperative outcome after total cavopulmonary connection is unclear and was sought to be determined. METHODS: The data from 33 patients were prospectively studied with cardiac magnetic resonance, echocardiography, and cardiac catheterization before the total cavopulmonary connection operation. The early postoperative outcomes after total cavopulmonary connection completion were recorded. RESULTS: Aortopulmonary collateral flow was 1.59 L/min/m(2) +/- 0.65 L/min/m(2) (range, 0.54 L/min/m(2) 3.34 L/min/m(2)), constituting 43% +/- 13% (range, 12-87%) of pulmonary blood flow and 35% +/- 12% (range, 11-62%) of the cardiac index, resulting in a pulmonary blood flow/systemic blood flow ratio of 1.06 +/- 0.17 (range, 0.79 1.55). The aortopulmonary collateral flow correlated with pulmonary blood flow/systemic blood flow ratio (r = 0.69, P < .0001), oxygen saturation (r = 0.42, P = .018), and cardiac index (r = 0.53, P = .002). Of the 36 patients, 24 underwent fenestrated total cavopulmonary connection during the study period. The aortopulmonary collateral flow, relative to the cardiac index, correlated with the duration of hospital stay (r = 0.48, P = .02) and pleural drainage (r = 0.45, P = .03). Patients whose pleural drainage lasted 1 week or less had less aortopulmonary collateral flow before the Fontan operation than those with a longer period until chest tube removal (1.23 L/min/m(2) +/- 0.38 L/min/m(2) vs 1.73 L/min/m(2) +/- 0.76 L/min/m(2); P = .03). Compared with a contemporary group of total cavopulmonary connection patients with fenestration in their extracardiac conduit who were studied prospectively, with a similar protocol, the bidirectional cavopulmonary connection had a greater amount of aortopulmonary collateral flow (1.59 L/min/m(2) +/- 0.65 L/min/m(2) vs 1.30 L/min/m(2) +/- 0.57 L/min/m(2), P = .04). CONCLUSIONS: Patients after bidirectional cavopulmonary connection routinely acquire a large amount of aortopulmonary collateral flow. The hemodynamic consequences of aortopulmonary collateral flow translate into adverse outcomes early after total cavopulmonary connection completion. PMID- 22502975 TI - Neural substrates activated by viewing others expressing fatigue: a magnetoencephalography study. AB - The neural substrates of the fatigue sensation have not been totally identified. Several lines of evidence demonstrate that seeing emotional changes in others activates brain regions involved in experiencing similar emotions. We hypothesized that there exists a mirror system regarding the fatigue sensation and that brain regions associated with the fatigue sensation may be activated by viewing other individuals expressing fatigue. In this study, we attempted to identify the neural substrates activated by viewing other fatigued individuals using magnetoencephalography (MEG). Twelve healthy participants were enrolled in our study after providing written informed consent. During MEG recordings, they viewed a set of pictures projected on a screen. The pictures, which were presented in a randomized order, were of a person with a fatigued or neutral facial expression. When participants viewed pictures of people with fatigued expressions, we were able to estimate equivalent current dipoles (ECDs) in the posterior cingulate cortex (PCC) in 9 of 12 participants approximately 300 ms after the onset of each picture presentation. When they viewed pictures of people with neutral expressions, we were not able to estimate corresponding ECDs for any participant. The PCC is the brain region activated by viewing others expressing fatigue, suggesting existence of the shared neural substrates of felt and observed fatigue. PMID- 22502976 TI - Activation lateralization in human core, belt, and parabelt auditory fields with unilateral deafness compared to normal hearing. AB - We studied activation magnitudes in core, belt, and parabelt auditory cortex in adults with normal hearing (NH) and unilateral hearing loss (UHL) using an interrupted, single-event design and monaural stimulation with random spectrographic sounds. NH patients had one ear blocked and received stimulation on the side matching the intact ear in UHL. The objective was to determine whether the side of deafness affected lateralization and magnitude of evoked blood oxygen level-dependent responses across different auditory cortical fields (ACFs). Regardless of ear of stimulation, NH showed larger contralateral responses in several ACFs. With right ear stimulation in UHL, ipsilateral responses were larger compared to NH in core and belt ACFs, indicating neuroplasticity in the right hemisphere. With left ear stimulation in UHL, only posterior core ACFs showed larger ipsilateral responses, suggesting that most ACFs in the left hemisphere had greater resilience against reduced crossed inputs from a deafferented right ear. Parabelt regions located posterolateral to core and belt auditory cortex showed reduced activation in UHL compared to NH irrespective of RE/LE stimulation and lateralization of inputs. Thus, the effect in UHL compared to NH differed by ACF and ear of deafness. PMID- 22502977 TI - Septal nuclei critically mediate the development of behavioral sensitization to a single morphine injection in rats. AB - Behavioral sensitization to a single morphine injection is a unique model to study the neuroanatomical substrates of long-lasting behavioral plasticity associated with opioid reward and abuse. Earlier observations have demonstrated that septal nuclei are critically involved in the processes of reward, learning and memory. In the present study, we investigated the effects of septal nuclei lesions on behavioral sensitization to a single morphine injection, morphine induced conditioned place preference and antinociception in rats. Behavioral sensitization was established by a single injection of 3-30 mg/kg morphine in rats. Bilateral electrical lesions of septal nuclei were carried out 7 days before morphine pretreatment. Acute morphine injection induced hyperactivity in the non-surgery control, sham surgery and septal nuclei-lesioned rats. Seven days later, the challenge injection with 3mg/kg morphine induced significant behavioral sensitization in rats with no surgery and sham surgery, but failed to induce behavioral sensitization in septal nuclei-lesioned rats. When the septal nuclei ablation was carried out after acute morphine pretreatment, the expression of behavioral sensitization was unaffected and not different among rats. In addition, septal nuclei lesions did not impact the rewarding and antinociceptive effects of 10 mg/kg morphine when the rats were tested in a conditioned place preference test and tail-flick test, respectively. Collectively, these results suggest that septal nuclei may be selectively involved in the initiation of behavioral sensitization to morphine, which is separable from the effects of morphine for exerting its rewarding and antinociceptive effects. PMID- 22502978 TI - Antagonist muscle co-activation during straight walking and its relation to kinematics: insight from young, elderly and Parkinson's disease. AB - Increased antagonist muscle co-activation of the lower limb during walking seems to be an adaptive process to the physiological changes of aging, in order to gain joint stability. In the healthy subjects this view seems to be reinforced by the fact that the co-activation index (CAI) increases when the gait is faster. The few reports on antagonist co-activation in Parkinson's disease (PD) patients indicate that they have larger co-activation than the healthy elderly, supporting the idea of the stabilization role of CAI during gait, as postural instability is a cardinal feature of PD. However it has also been reported that there is a reduction of the CAI when increasing velocity in PD or normal elderly. This questions the role of co-activation in stabilization during increased velocity. In this study we have analyzed the gait of healthy subjects (young and elderly), and PD patients (with and without freezing of gait, FOG) in order to better understand the relation between co-activation and gait kinematics, and to gain insight into the pathological changes associated with FOG in PD. We used Multiple Linear Regression models to study the relationship in shank muscles between CAI, velocity and cadence. Our results indicate that, for all groups of interest, the relationship between co-activation and the kinematics of gait is poor, due to the high degree of variability, questioning the explanatory value of the index. PMID- 22502979 TI - Lead induces dysregulation of iron regulatory protein 1 via the extracellular signal-regulated kinase pathway in human vascular endothelial cells. AB - Lead (Pb) can target the vascular system for both acute injury and disease promotion. Cellular iron (Fe) disruption may be implicated in Pb vascular toxicity. To investigate the potential involvement of iron response element 1 (IRP1) protein in the vascular endothelium during Pb exposure, human umbilical vein endothelial cells (HUVEC) were treated with different concentrations of lead nitrate, 30 MUM iron sulfate, or 100 MUM deferoxamine. PD98059, a specific inhibitor of the mitogen-activated protein kinase kinase (MEK) activator, was administered to block the ERK/MAPK pathway. Western blotting was used to detect the expression of IRP1 and p-ERK1/2, and microscopy, and co-immunoprecipitation was used to show the association between IRP1 and p-ERK1/2. In vitro measurements revealed a decrease in IRP1 and activated ERK1/2 in the membrane following Pb treatment. HUVEC treated with PD98059 enhanced the levels of membrane IRP1 and efficiently inhibited the effect of Pb on the levels of membrane IRP1. Partial IRP1 co-localization existed with p-ERK1/2 in the membrane, and Pb treatment produced an obvious decrease in the amount of IRP1 that co-localized with p ERK1/2. Co-immunoprecipitation further revealed a possible association between IRP-1 and p-ERK1/2. Collectively, Pb specifically induced the dysregulation of IRP1 protein by activating the ERK1/2 signaling pathway in the plasma membrane, indicating a novel role for IRP1 and the ERK/MAPK pathway in vascular endothelial functions. PMID- 22502980 TI - Effect of amitriptyline on glycinergic transmission in rat medullary dorsal horn neurons. AB - Amitriptyline, a representative tricyclic antidepressant, has been widely used for the treatment of neuropathic pain, such as post-herpetic and trigeminal neuralgia. In the present study, we investigated the effect of amitriptyline on glycinergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in acutely isolated medullary dorsal horn neurons by use of a conventional whole cell patch-clamp technique. Amitriptyline (30 MUM) significantly increased mIPSC frequency without affecting the current amplitude, suggesting that amitriptyline acts presynaptically to increase the probability of glycine release. Amitriptyline also directly inhibited the glycine receptor-mediated Cl(-) currents induced by lower concentrations of glycine. The amitriptyline-induced increase in mIPSC frequency was not affected either in the Na(+)-free external solutions or in the presence of Cd(2+), a general voltage-dependent Ca(2+) channel blocker, indicating that amitriptyline is unlikely to elicit a presynaptic depolarization. In addition, amitriptyline still increased mIPSC frequency even in the absence of extracellular Ca(2+). In contrast, the depletion of intracellular Ca(2+) stores with thapsigargin significantly reduced the extent of amitriptyline-induced increase in mIPSC frequency. These data suggest that amitriptyline increases spontaneous glycine release onto acutely isolated medullary dorsal neurons by increasing the intraterminal Ca(2+) concentration, which might be mediated by the Ca(2+) release from the Ca(2+) stores rather than the Ca(2+) influx from the extracellular space. The amitriptyline-induced modulation of glycinergic transmission could have a broad impact on the excitability of medullary dorsal neurons, and this mechanism would contribute, at least in part, to the anti-allodynic action of amitriptyline. PMID- 22502981 TI - The effects of maternal caffeine and chocolate intake on fetal heart rate. AB - OBJECTIVE: The aim of our study was to analyze the effects of caffeine and chocolate (70% cocoa) on fetal heart rate (FHR). STUDY DESIGN: Fifty pregnant women with uncomplicated gestation, matched for age and parity, underwent computerized FHR recording before and after the consumption of caffeine and then, after one week, before and after 70% cocoa chocolate intake. Computerized cardiotocography (cCTG) parameters were expressed as mean and SD. The differences were tested for statistical significance using the paired t-test, with significance at p < 0.05. RESULTS: The number of uterine contraction peaks, the number of small and large accelerations (10 and 15 beats per minute for 15 seconds), the duration of episodes of high variation and the short-term FHR variation were significantly higher (p < 0.001) after maternal coffee intake. The number of large accelerations, the duration of episodes of high variation and the short-term FHR variation were significantly higher (p < 0.001) after maternal consumption of chocolate, whilst no effect of cocoa was found during contractions. CONCLUSIONS: Our results suggest that maternal intake of both caffeine and 70% cocoa have a stimulating action on fetal reactivity. This finding is likely due to the pharmacological action of theobromine, a methilxanthine present in coffee and in chocolate. The correlation between maternal caffeine intake and increased uterine contraction peaks is likely due to the effect of caffeine on the uterine muscle. PMID- 22502982 TI - Combined 18F-fluorocholine and 18F-fluoride positron emission tomography/computed tomography imaging for staging of high-risk prostate cancer. AB - OBJECTIVE: To investigate how often positron emission tomography/computed tomography (PET/CT) scans, with both (18)F-fluorocholine and (18)F-fluoride as markers, add clinically relevant information for patients with prostate cancer who have high-risk tumours and a normal or inconclusive planar bone scan. PATIENTS AND METHODS: Patients with prostate cancer with prostate specific antigen (PSA) levels between 20 and 99 ng/mL and/or Gleason score 8-10 tumours, planned for treatment with curative intent based on routine staging with a negative or inconclusive bone scan, were further investigated with a (18)F fluorocholine and a (18)F-fluoride PET/CT. None of the patients received hormonal therapy before the staging procedures were completed. RESULTS: For 50 of the 90 included patients (56%) one or both PET/CT scans indicated metastases. (18)F fluorocholine PET/CT indicated lymph node metastases and/or bone metastases in 35 patients (39%). (18)F-fluoride PET/CT was suggestive for bone metastases in 37 patients (41%). In 18 patients (20%) the PET/CT scans indicated widespread metastases, leading to a change in therapy intent from curative to non-curative. Of the patients with positive scans, 74% had Gleason score 8-10 tumours. Of the patients with Gleason score 8-10 tumours, 64% had positive scans. CONCLUSIONS: PET/CT scans with (18)F-fluorocholine and (18)F-fluoride commonly detect metastases in patients with high-risk prostate cancer and a negative or inconclusive bone scan. For 20% of the patients the results of the PET/CT scans changed the treatment plan. PMID- 22502983 TI - An Actor-Critic based controller for glucose regulation in type 1 diabetes. AB - A novel adaptive approach for glucose control in individuals with type 1 diabetes under sensor-augmented pump therapy is proposed. The controller, is based on Actor-Critic (AC) learning and is inspired by the principles of reinforcement learning and optimal control theory. The main characteristics of the proposed controller are (i) simultaneous adjustment of both the insulin basal rate and the bolus dose, (ii) initialization based on clinical procedures, and (iii) real-time personalization. The effectiveness of the proposed algorithm in terms of glycemic control has been investigated in silico in adults, adolescents and children under open-loop and closed-loop approaches, using announced meals with uncertainties in the order of +/-25% in the estimation of carbohydrates. The results show that glucose regulation is efficient in all three groups of patients, even with uncertainties in the level of carbohydrates in the meal. The percentages in the A+B zones of the Control Variability Grid Analysis (CVGA) were 100% for adults, and 93% for both adolescents and children. The AC based controller seems to be a promising approach for the automatic adjustment of insulin infusion in order to improve glycemic control. After optimization of the algorithm, the controller will be tested in a clinical trial. PMID- 22502984 TI - A PC-based system for predicting movement from deep brain signals in Parkinson's disease. AB - There is much current interest in deep brain stimulation (DBS) of the subthalamic nucleus (STN) for the treatment of Parkinson's disease (PD). This type of surgery has enabled unprecedented access to deep brain signals in the awake human. In this paper we present an easy-to-use computer based system for recording, displaying, archiving, and processing electrophysiological signals from the STN. The system was developed for predicting self-paced hand-movements in real-time via the online processing of the electrophysiological activity of the STN. It is hoped that such a computerised system might have clinical and experimental applications. For example, those sites within the STN most relevant to the processing of voluntary movement could be identified through the predictive value of their activities with respect to the timing of future movement. PMID- 22502985 TI - The impact of the Solution Based Casework (SBC) practice model on federal outcomes in public child welfare. AB - OBJECTIVE: To test the effects of the Solution-Based Casework practice model on federal outcomes of safety, permanency and well-being. The Solution-Based Casework model combines family development theory, solution-focused skills and relapse prevention for the casework process in child protection. METHOD: 4,559 public child welfare cases were reviewed through a CQI case review process. RESULTS: This study found that cases with high levels of fidelity to the model demonstrated significantly better outcomes in the areas of child safety, permanency and well-being and exceeded federal standards, while cases with low fidelity to the model failed to meet federal standards. CONCLUSION: Components of the Solution-Based Casework were significant predictors of these federal outcomes and accounted for variance in these outcomes better than any other casework process factors. PMID- 22502986 TI - Common genetic variants and gene-expression changes associated with bipolar disorder are over-represented in brain signaling pathway genes. AB - BACKGROUND: Despite high heritability, the genetic variants influencing bipolar disorder (BD) susceptibility remain largely unknown. Low statistical power to detect the small effect-size alleles believed to underlie much of the genetic risk and possible heterogeneity between cohorts are an increasing concern. Integrative biology approaches might offer advantages over genetic analysis alone by combining different genomic datasets at the higher level of biological processes rather than the level of specific genetic variants or genes. We employed this strategy to identify biological processes involved in BD etiopathology. METHOD: Three genome-wide association studies and a brain gene expression study were combined with the Human Protein Reference Database protein protein interaction network data. We used bioinformatic analysis to search for biological networks with evidence of association on the basis of enrichment among both genetic and differential-expression associations with BD. RESULTS: We identified association with gene networks involved in transmission of nerve impulse, Wnt, and Notch signaling. Three features stand out among these genes: 1) they localized to the human postsynaptic density, which is crucial for neuronal function; 2) their mouse knockouts present altered behavioral phenotypes; and 3) some are known targets of the pharmacological treatments for BD. CONCLUSIONS: Genetic and gene-expression associations of BD cluster in discrete regions of the protein-protein interaction network. We found replicated evidence for association for networks involving several interlinked signaling pathways. These genes are promising candidates to generate animal models and pharmacological interventions. Our results demonstrate the potential advantage of integrative biology analyses of BD datasets. PMID- 22502989 TI - On the safety and benefits of repeated intravenous injections of ketamine for depression. PMID- 22502987 TI - Estrogen levels are associated with extinction deficits in women with posttraumatic stress disorder. AB - BACKGROUND: Women are twice as likely to develop posttraumatic stress disorder (PTSD) than men. As shown in our previous work, the inability to suppress fear responses in safe conditions may be a biomarker for PTSD. Low estrogen in naturally cycling women is associated with deficits in fear extinction. On the basis of these findings, we have now examined the influence of estrogen levels on fear extinction in women with and without PTSD. METHODS: We measured fear potentiated startle during fear conditioning and extinction in women. The study sample (N = 81) was recruited from an urban, highly traumatized civilian population at Grady Memorial Hospital in Atlanta, Georgia. We assayed serum estrogen levels and used a median split to divide the sample into high and low estradiol (E(2)) groups. Seventeen of 41 women (41.5%) in the low E(2) group and 15 of 40 women (37.5%) met criteria for PTSD in the high E(2) group. RESULTS: The results showed that all groups had equivalent levels of fear conditioning. However, we found significant interaction effects between high versus low E(2) groups and PTSD diagnosis [F(1,71) = 4.55, p < .05] on extinction. Among women with low estrogen levels, fear-potentiated startle was higher during extinction in the PTSD group compared with traumatized control women [F(1,38) = 5.04, p < .05]. This effect was absent in the High E(2) group. CONCLUSION: This study suggests that low estrogen may be a vulnerability factor for development of PTSD in women with trauma histories. Research on the role of estrogen in fear regulation may provide insight into novel treatment strategies for PTSD. PMID- 22502988 TI - Deficient inhibitory cortical networks in antipsychotic-naive subjects at risk of developing first-episode psychosis and first-episode schizophrenia patients: a cross-sectional study. AB - BACKGROUND: Impaired cortical inhibition is a well-established finding in schizophrenia patients and has been linked to dysfunctional gamma-aminobutyric acid (GABA)ergic transmission. However, there have been no previous studies investigating cortical excitability with particular regard to intracortical inhibitory networks in antipsychotic-naive subjects at risk of developing first episode psychosis. METHODS: A total of 18 subjects at risk, 18 first-episode schizophrenia patients, and 18 healthy control subjects were included in this study. Transcranial magnetic stimulation over the left primary motor cortex was used to determine short-latency intracortical inhibition, intracortical facilitation, and the contralateral silent period (CSP). Short-latency intracortical inhibition can be considered as a parameter of GABA type A (GABA(A))-mediated inhibition and it has been proposed that CSP can test GABA type B (GABA(B))-mediated inhibitory intracortical networks. RESULTS: Subjects at risk and first-episode patients showed a reduced short-latency intracortical inhibition compared with healthy control subjects, suggesting reduced GABA(A) mediated inhibition. First-episode patients had a prolonged CSP duration compared with the other two groups, implying a GABA(B) imbalance only in patients with full-blown psychosis. Analyses did not reveal group differences for intracortical facilitation. CONCLUSIONS: These results indicate specific alterations in inhibitory cortical networks in subjects at risk and in first-episode patients. It appears that there is already a cortical inhibitory deficit in at-risk individuals. These results suggest a possible GABA(A) dysfunction early in the disease course, whereas alterations in GABA(B) functionality seem to occur later in the disease's progression. Future longitudinal studies will be needed to clarify this inhibitory deficit and its relation to the transition to psychosis. PMID- 22502990 TI - Lesions of ventrolateral prefrontal or anterior orbitofrontal cortex in primates heighten negative emotion. AB - BACKGROUND: Heightened fear and anxiety are core symptoms of a variety of neuropsychiatric disorders. They are associated with structural and activity changes throughout neural circuitry that includes the ventral and medial prefrontal cortices (PFC), the amygdala, and hippocampus. Although the contributions of the medial PFC, amygdala, and hippocampus to fear and anxiety have been studied extensively with animal models, the selective roles of the ventral PFC-including the ventrolateral prefrontal cortex (vlPFC) and orbitofrontal cortex-are poorly understood. METHODS: We investigated the effects of selective excitotoxic lesions of either the vlPFC or anterior orbitofrontal cortex (antOFC) on anxious behavior and Pavlovian conditioned autonomic and behavioral fear responses in the New World primate, the common marmoset. RESULTS: Both vlPFC and antOFC lesions resulted in stronger, less adaptable conditioned fear responses. They also heightened the anxiety responses of a marmoset to a human intruder. In contrast, only a lesion of the vlPFC affected the coping style that a marmoset displayed in the presence of the human intruder, increasing the likelihood of proactive mobbing. CONCLUSIONS: These results suggest that both the antOFC and vlPFC can downregulate fear and anxiety and, together, provide necessary but independent contributions to the top-down control of negative emotion. PMID- 22502992 TI - Predictors of new findings on repeat head CT scan in blunt trauma patients with an initially negative head CT scan. AB - BACKGROUND: Our goal was to determine the need for a repeat head CT scan when the initial CT was negative. STUDY DESIGN: Data were collected from January 1, 2002 to December 31, 2008. There were 281 patients admitted to the trauma center with an initial negative head CT, who had a repeat CT during the same hospitalization. Repeat CTs were categorized into negative/negative (NNG) and negative/positive (NPG) groups. RESULTS: There were 281 patients who underwent a repeat head CT for changes in neurologic status, persistent symptoms, follow-up, decreased mental status, or suspected bleed. Of these, 241 patients remained negative (NNG) and new abnormal findings were noted in 40 patients (NPG). There were no differences in sex (NNG, 63% males vs NPG, 75% females; p = 0.14) or average age (NNG, 51.6 +/- 22.5 years vs NPG, 45.2 +/- 24.6 years; p = 0.07). There was no difference in positive toxicology (NNG, 29% vs NPG, 30%; p = 0.94) or mechanism of injury (NNG, 51% motor vehicle crash [MVC] vs NPG, 62% MVC; p = 0.18). There was a significant difference in Injury Severity Score (ISS) (NNG, 10.7 +/- 8.1 vs NPG, 17.9 +/- 11.0; p = 0.0002) and initial Glasgow Coma Scale (GCS) (NNG, 12.7 +/- 3.5 vs NPG, 10.9 +/- 4.2; p = 0.006). Patients with an ISS > 15 and who were intubated were associated with an increased odds of having a positive repeat CT scan (odds ratio [OR] 2.6; 95%CI 1.2, 5.5 and OR 3.5; 95% CI, 1.7, 7.3, respectively). CONCLUSIONS: Patients with a high ISS score and/or those who are intubated have significantly higher odds of having a positive repeat head CT when repeated for follow-up or when clinically warranted. PMID- 22502993 TI - Hospital costs associated with smoking in veterans undergoing general surgery. AB - BACKGROUND: Approximately 30% of patients undergoing elective general surgery smoke cigarettes. The association between smoking status and hospital costs in general surgery patients is unknown. The objectives of this study were to compare total inpatient costs in current smokers, former smokers, and never smokers undergoing general surgical procedures in Veterans Affairs (VA) hospitals; and to determine whether the relationship between smoking and cost is mediated by postoperative complications. STUDY DESIGN: Patients undergoing general surgery during the period of October 1, 2005 to September 30, 2006 were identified in the VA Surgical Quality Improvement Program (VASQIP) data set. Inpatient costs were extracted from the VA Decision Support System (DSS). Relative surgical costs (incurred during index hospitalization and within 30 days of operation) for current and former smokers relative to never smokers, and possible mediators of the association between smoking status and cost were estimated using generalized linear regression models. Models were adjusted for preoperative and operative variables, accounting for clustering of costs at the hospital level. RESULTS: Of the 14,853 general surgical patients, 34% were current smokers, 39% were former smokers, and 27% were never smokers. After controlling for patient covariates, current smokers had significantly higher costs compared with never smokers: relative cost was 1.04 (95% Cl 1.00 to 1.07; p = 0.04); relative costs for former smokers did not differ significantly from those of never smokers: 1.02 (95% Cl 0.99 to 1.06; p = 0.14). The relationship between smoking and hospital costs for current smokers was partially mediated by postoperative respiratory complications. CONCLUSIONS: These findings complement emerging evidence recommending effective smoking cessation programs in general surgical patients and provide an estimate of the potential savings that could be accrued during the preoperative period. PMID- 22502994 TI - The transport along membrane nanotubes driven by the spontaneous curvature of membrane components. AB - Intercellular membrane nanotubes (ICNs) serve as a very specific transport system between neighboring cells. The underlying mechanisms responsible for the transport of membrane components and vesicular dilations along the ICNs are not clearly understood. The present study investigated the spatial distribution of anisotropic membrane components of tubular shapes and isotropic membrane components of spherical shapes. Experimental results revealed the preferential distribution of CTB (cholera toxin B)-GM1 complexes mainly on the spherical cell membrane, and cholesterol-sphingomyelin at the membrane leading edge and ICNs. In agreement with previous studies, we here propose that the spatial distribution of CTB-GM1 complexes and cholesterol-sphingomyelin rafts were due to their isotropic and anisotropic shapes, respectively. To elucidate the relationship between a membrane component shape and its spatial distribution, a two-component computational model was constructed. The minimization of the membrane bending (free) energy revealed the enrichment of the anisotropic component along the ICN and the isotropic component in the parent cell membrane, which was due to the curvature mismatch between the ICN curvature and the spontaneous curvature of the isotropic component. The equations of motion, derived from the differentiation of the membrane free energy, revealed a curvature-dependent flux of the isotropic component and a curvature-dependent force exerted on a vesicular dilation along the ICN. Finally, the effects of possible changes in the orientational ordering of the anisotropic component attendant to the transport of the vesicular dilation were discussed with connection to the propagation of electrical and chemical signals. PMID- 22502995 TI - Shotgun blast to the face with unexpected consequences. PMID- 22502996 TI - The Pearl of the Antilles becomes a pearl of shared wisdom. PMID- 22502997 TI - Towards a more accurate annotation of tyrosine-based site-specific recombinases in bacterial genomes. AB - BACKGROUND: Tyrosine-based site-specific recombinases (TBSSRs) are DNA breaking rejoining enzymes. In bacterial genomes, they play a major role in the comings and goings of mobile genetic elements (MGEs), such as temperate phage genomes, integrated conjugative elements (ICEs) or integron cassettes. TBSSRs are also involved in the segregation of plasmids and chromosomes, the resolution of plasmid dimers and of co-integrates resulting from the replicative transposition of transposons. With the aim of improving the annotation of TBSSR genes in genomic sequences and databases, which so far is far from robust, we built a set of over 1,300 TBSSR protein sequences tagged with their genome of origin. We organized them in families to investigate: i) whether TBSSRs tend to be more conserved within than between classes of MGE types and ii) whether the (sub)families may help in understanding more about the function of TBSSRs associated in tandem or trios on plasmids and chromosomes. RESULTS: A total of 67% of the TBSSRs in our set are MGE type specific. We define a new class of actinobacterial transposons, related to Tn554, containing one abnormally long TBSSR and one of typical size, and we further characterize numerous TBSSRs trios present in plasmids and chromosomes of alpha- and beta-proteobacteria. CONCLUSIONS: The simple in silico procedure described here, which uses a set of reference TBSSRs from defined MGE types, could contribute to greatly improve the annotation of tyrosine-based site-specific recombinases in plasmid, (pro)phage and other integrated MGE genomes. It also reveals TBSSRs families whose distribution among bacterial taxa suggests they mediate lateral gene transfer. PMID- 22502998 TI - Expansion mutation in C9ORF72 does not influence plasma progranulin levels in frontotemporal dementia. AB - A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) gene has recently been described as a cause of familial and sporadic frontotemporal lobar degeneration. The aim of this study was to assess whether plasma progranulin (GRN) levels could be modulated by the presence of this repeat expansion. Sixty-five patients diagnosed with frontotemporal dementia and 10 family members with familial aggregation of disease were screened for the presence of the hexanucleotide repeat expansion in C9ORF72 gene, using a repeat primed polymerase chain reaction method. Plasma GRN levels were measured in all subjects through enzyme-linked immunosorbent assay. Seven individuals with the repeat expansion were identified. No differences were found between C9ORF72 repeat expansion carriers and noncarriers (116.4 +/- 21 ng/mL and 131.7 +/- 36 ng/mL, respectively, p = 0.3). Analysis of family members did not disclose any difference in plasma GRN levels between carriers and noncarriers. In conclusion, plasma GRN levels are not influenced by the hexanucleotide repeat expansion in C9ORF72 gene, and therefore, cannot be used as a reliable biomarker to detect mutation carriers. PMID- 22502999 TI - Frontal asymmetry in behavioral variant frontotemporal dementia: clinicoimaging and pathogenetic correlates. AB - We aimed to assess associations between clinical, imaging, pathologic, and genetic features and frontal lobe asymmetry in behavioral variant frontotemporal dementia (bvFTD). Volumes of the left and right dorsolateral, medial, and orbital frontal lobes were measured in 80 bvFTD subjects and subjects were classified into 3 groups according to the degree of asymmetry (asymmetric left, asymmetric right, symmetric) using cluster analysis. The majority of subjects were symmetric (65%), with 20% asymmetric left and 15% asymmetric right. There were no clinical differences across groups, although there was a trend for greater behavioral dyscontrol in right asymmetric compared with left asymmetric subjects. More widespread atrophy involving the parietal lobe was observed in the symmetric group. Genetic features differed across groups with symmetric frontal lobes associated with C9ORF72 and tau mutations, while asymmetric frontal lobes were associated with progranulin mutations. These findings therefore suggest that neuroanatomical patterns of frontal lobe atrophy in bvFTD are influenced by specific gene mutations. PMID- 22503000 TI - How can elderly apolipoprotein E epsilon4 carriers remain free from dementia? AB - Apolipoprotein E (APOE) epsilon4 is a major risk factor for Alzheimer's disease (AD) and dementia, but not all epsilon4 carriers develop dementia. We sought to identify factors that may play a role in modifying the risk of dementia due to epsilon4. A cognitively intact cohort (n = 932, age >= 75) was followed for 9 years to detect incident dementia cases. At baseline, information on education, leisure activities, and vascular risk factors was collected, and APOE was genotyped. During the follow-up, 324 subjects developed dementia, including 247 AD cases. The hazard ratio (HR, 95% confidence interval [95% CI]) of dementia related to the epsilon4 was 1.39 (1.11-1.76), while the risk was reduced when epsilon4 carriers had high education, no vascular risk factors, or high score of leisure activities. Among epsilon4 carriers, the multiadjusted HRs of dementia that were associated with high education, high level of leisure activities, and absence of vascular risk factors were 0.59 (0.40-0.87), 0.49 (0.29-0.85), and 0.61 (0.41-0.90), respectively. The epsilon4 carriers with these factors had about 1.2 years delayed time to dementia onset compared with those without these factors. High education, active leisure activities, or maintaining vascular health seems to reduce the risk of dementia related to APOE epsilon4. The epsilon4 carriers with these characteristics appear to have similar dementia-free survival time to non-epsilon4 carriers. PMID- 22503002 TI - O-linked beta-N-acetylglucosaminidase inhibitor attenuates beta-amyloid plaque and rescues memory impairment. AB - Deposition of beta-amyloid (Abeta) as senile plaques and disrupted glucose metabolism are two main characteristics of Alzheimer's disease (AD). It is unknown, however, how these two processes are related in AD. Here we examined the relationship between O-GlcNAcylation, which is a glucose level-dependent post translational modification that adds O-linked beta-N-acetylglucosamine (O-GlcNAc) to proteins, and Abeta production in a mouse model of AD carrying 5XFAD genes. We found that 1,2-dideoxy-2'-propyl-alpha-d-glucopyranoso-[2,1-D]-Delta2'-thiazoline (NButGT), a specific inhibitor of O-GlcNAcase, reduces Abeta production by lowering gamma-secretase activity both in vitro and in vivo. We also found that O GlcNAcylation takes place at the S708 residue of nicastrin, which is a component of gamma-secretase. Moreover, NButGT attenuated the accumulation of Abeta, neuroinflammation, and memory impairment in the 5XFAD mice. This is the first study to show the relationship between Abeta generation and O-GlcNAcylation in vivo. These results suggest that O-GlcNAcylation may be a suitable therapeutic target for the treatment of AD. PMID- 22503001 TI - Amyloid and metabolic positron emission tomography imaging of cognitively normal adults with Alzheimer's parents. AB - This study examines the relationship between fibrillar beta-amyloid (Abeta) deposition and reduced glucose metabolism, a proxy for neuronal dysfunction, in cognitively normal (NL) individuals with a parent affected by late-onset Alzheimer's disease (AD). Forty-seven 40-80-year-old NL received positron emission tomography (PET) with (11)C-Pittsburgh compound B (PiB) and 18F-fluoro-2 deoxy-d-glucose (FDG). These included 19 NL with a maternal history (MH), 12 NL with a paternal history (PH), and 16 NL with negative family history of AD (NH). Automated regions of interest, statistical parametric mapping, voxel-wise intermodality correlations, and logistic regressions were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. The MH group showed higher PiB retention and lower metabolism in AD regions compared with NH and PH, which were negatively correlated in posterior cingulate, frontal, and parieto-temporal regions (Pearson r <= -0.57, p <= 0.05). No correlations were observed in NH and PH. The combination of Abeta deposition and metabolism yielded accuracy >= 69% for MH vs. NH and >= 71% for MH vs. PH, with relative risk = 1.9-5.1 (p values < 0.005). NL individuals with AD-affected mothers show co-occurring Abeta increases and hypometabolism in AD-vulnerable regions, suggesting an increased risk for AD. PMID- 22503004 TI - Synthesis and photophysical properties of cyclometalated platinum(II) 1,2 benzenedithiolate complexes and heterometallic derivatives obtained from the addition of [Au(PCy3)]+ units. AB - The cyclometalated compounds [Pt(C^N)(HC^N)Cl] [HC^N = 2-phenylpyridine (Hppy; 1a), 1-(4-tert-butylphenyl)isoquinoline (Htbpiq; 1b)] react with 1,2 benzenedithiol, t-BuOK, and Bu(4)NCl in a 1:1:2:1 molar ratio in CH(2)Cl(2)/MeOH to give the complexes Bu(4)N[Pt(C^N)(bdt)] [bdt = 1,2-benzenedithiolate; C^N = ppy (Bu(4)N2a), tbpiq (Bu(4)N2b)]. In the absence of Bu(4)NCl, the same reactions afford solutions of K2a and K2b, which react with [AuCl(PCy(3))] to give the neutral heterometallic derivatives [Pt(C^N)(bdt){Au(PCy(3))}] [C^N = ppy (3a), tbpiq (3b)]. The cationic derivatives [Pt(C^N)(bdt){Au(PCy(3))}(2)]ClO(4) [C^N = ppy (4a), tbpiq (4b)] are obtained by reacting 3a and 3b with acetone solutions of [Au(OClO(3))(PCy(3))]. The crystal structures of 3b and 4b reveal the formation of short Pt...Au metallophilic contacts in the range 2.929-3.149 A. Complexes 3b, 4a, and 4b undergo dynamic processes in solution that involve the migration of the [Au(PCy(3))](+) units between the S atoms of the dithiolate. Complexes Bu(4)N2a and 2b display a moderately solvatochromic band in their electronic absorption spectra that can be ascribed to a transition of mixed ML'CT/LL'CT character (M= metal; L = bdt; L' = C^N; CT = charge transfer), while their emissions are assignable to transitions of the same orbital parentage but from triplet excited states. The successive addition of [Au(PCy(3))](+) units to the anions 2a and 2b results in an increase in the absorption and emission energies attributable to lower highest occupied molecular orbital energies. Additionally, the characteristics of the absorption and emission spectra of the heterometallic derivatives indicate a gradual loss of LL'CT character in the involved electronic transitions, with a concomitant increase of the L'C and ML'CT contributions. PMID- 22503003 TI - Age-related appearance of dendritic inclusions in catecholaminergic brainstem neurons. AB - We identified p62-immunoreactive inclusions in dendrites of catecholaminergic brainstem projection neurons using antibodies against p62, ubiquitin, alpha synuclein, hyperphosphorylated tau, and tyrosine hydroxylase in 100-MUm sections through the brainstem dorsal vagal area, locus coeruleus, and substantia nigra of 149 autopsy cases staged for intraneuronal Alzheimer's and Parkinson's disease associated lesions. The inclusions resembled Marinesco bodies within cell nuclei of catecholaminergic neurons as well as the dot-like structures previously described by Dickson in specific neuropil areas in humans. The p62-positive inclusions were confined to dendrites of catecholaminergic neurons, lacked neuromelanin granules, and were tau- and alpha-synuclein-negative. Their immunoreactivity for ubiquitin varied and their prevalence significantly increased with advancing age. The presence or absence of Alzheimer's and/or Parkinson's disease-associated pathology did not influence their existence. There was a strong association between the presence of p62-positive inclusions and Marinesco bodies (p < 0.0001). Our results reveal a hitherto unknown alteration within specific neuronal types of the human brainstem that may be independent of the sequestosome-ubiquitin-proteasomal pathway and unrelated to proteinaceous aggregate-formation of neurodegenerative diseases. PMID- 22503005 TI - Effect of added dead space on sleep disordered breathing at high altitude. AB - OBJECTIVE: Sleep disordered breathing with central apnea or hypopnea frequently occurs at high altitude and is thought to be caused by a decrease in blood CO(2) level. The aim of this study was to assess the effects of added respiratory dead space on sleep disordered breathing. METHODS: Full polysomnographies were performed on 12 unacclimatized swiss mountaineers (11 males, 1 female, mean age 39 +/- 12 y.o.) in Leh, Ladakh (3500 m). In random order, half of the night was spent with a 500 ml increase in dead space through a custom designed full face mask and the other half without it. RESULTS: Baseline data revealed two clearly distinct groups: one with severe sleep disordered breathing (n=5, AHI>30) and the other with moderate to no disordered breathing (n=7, AHI<30). DS markedly improved breathing in the first group (baseline vs DS): apnea hypopnea index (AHI) 70.3 +/- 25.8 vs 29.4 +/- 6.9 (p=0.013), oxygen desaturation index (ODI): 72.9 +/- 24.1/h vs 42.5 +/- 14.4 (p=0.031), whereas it had no significant effect in the second group or in the total population. Respiratory events were almost exclusively central apnea or hypopnea. Microarousal index, sleep efficiency, and sleep architecture remained unchanged with DS. A minor increase in mean PtcCO(2) (n=3) was observed with DS. CONCLUSION: A 500 ml increase in dead space through a fitted mask may improve nocturnal breathing in mountaineers with severe altitude induced sleep disordered breathing. PMID- 22503006 TI - Investigating the response to intravenous iron in restless legs syndrome: an observational study. AB - OBJECTIVE: To investigate the effect of intravenous (IV) iron (500 mg ferric carboxymaltose [FCM] as a single dose) on restless legs syndrome (RLS) severity on a day-to-day basis. METHODS: Twenty patients with RLS and absolute or functional iron deficiency or low normal serum ferritin (<45 MUg/l) were included. Change of RLS severity was evaluated using the International RLS severity scale (IRLS) and the RLS-severity diary (RLS-SD) which evaluates symptom severity over a 6-h period on an 11-point numerical Likert scale, four times a day. RESULTS: Twelve patients reported that IV FCM improved RLS ("responders"). IRLS score decreased from 30.1 (+/- 5.9) to 23.07 (+/- 9.5) (p=0.001) in the whole group and from 28.3 (+/- 6.1) to 18.3 (+/- 8.0) (p=0.002) in the responder group three weeks after IV FCM treatment. A clinically relevant effect of IV iron on RLS severity could be seen as early as day eight. The responder group differed from the non-responder group in tendency by being younger (p=0.064), having a lower serum ferritin level at baseline (p=0.097), and presenting a lower number of comorbid conditions. CONCLUSIONS: FCM led to a considerable improvement in RLS in the responder group within about one week. These findings are clinically relevant, especially for patients with severe RLS symptoms and iron deficiency, since a change or uptitration of RLS-specific medication can be avoided or postponed in these patients due to the rapid response to IV FCM treatment. PMID- 22503007 TI - Abdominopelvic ultrasound: a cost-effective way to diagnose solitary kidney. AB - PURPOSE: Solitary kidneys are detected on approximately 1 of 1,500 prenatal ultrasounds and during evaluation for other urological complaints. Although renal scintigraphy is currently the gold standard for confirming the diagnosis and ruling out renal ectopia, scintigraphy is associated with radiation exposure, placement of an intravenous line and sedation. We hypothesize that ultrasonography alone is sufficient to detect solitary kidneys and that confirmatory renal scintigraphy is unnecessary. MATERIALS AND METHODS: We reviewed the records of children with a solitary kidney who underwent ultrasound and nuclear scintigraphy at our institution from 2001 to 2010. Radiological findings were compared to assess the accuracy of ultrasound in diagnosing solitary kidneys. Costs were calculated based on 2011 Medicare global reimbursement. RESULTS: A total of 25 children met the inclusion criteria of undergoing ultrasound and renal scintigraphy (dimercapto-succinic acid or mercaptoacetyltriglycine scan). The majority of cases were male (16, 64%) and left sided (17, 68%). Median age was 9 days (range 1 day to 11.6 years) at first ultrasound and 4.4 months (3 weeks to 12 years) at first renal scintigraphy. In 24 patients ultrasound correctly diagnosed a solitary kidney as confirmed by nuclear scan. In 1 patient ultrasound suggested a pelvic kidney but repeat ultrasound was negative, as was dimercapto-succinic acid scan. The diagnostic accuracy of ultrasound was 96%. Medicare reimbursement for dimercapto-succinic acid scan (CPT 78700) is $460 to $720 ($222 plus $240 for radiotracer plus $260 for anesthesia, if used). CONCLUSIONS: Our findings suggest that ultrasonography alone is sufficient to make the diagnosis of solitary kidney. Omitting routine renal scintigraphy saves approximately $460 to $720 per case, and avoids radiation and discomfort without sacrificing diagnostic accuracy. PMID- 22503008 TI - Nonspecific granulomatous prostatitis. PMID- 22503009 TI - Urodynamic findings in patients with Currarino syndrome. AB - PURPOSE: Currarino syndrome is an inherited disorder consisting of a triad of anorectal anomaly, sacrococcygeal defect and presacral mass. We evaluated the urological issues in patients with Currarino syndrome and sought to determine whether spinal cord detethering improves urinary tract function. MATERIALS AND METHODS: We retrospectively reviewed 14 patients diagnosed with Currarino syndrome. We evaluated urinary signs/symptoms and urodynamic findings before and after spinal cord detethering. RESULTS: All patients with Currarino syndrome having a sacral defect and presacral mass were diagnosed between birth and 6 years. Of the patients 86% had a tethered spinal cord that was surgically detethered between 8 months and 6 years (average 3 years). Overall 10 of 12 children who underwent surgery had voiding complaints postoperatively, including urgency, frequency and incontinence. Five patients had recurrent urinary tract infections, of whom 3 had vesicoureteral reflux that resolved spontaneously. Three patients had mild unilateral hydronephrosis without reflux. Ten of 12 patients who underwent spinal cord detethering underwent comprehensive urodynamic evaluation. Of the 5 patients who underwent preoperative and postoperative urodynamic evaluation 3 showed improvement with resolution of detrusor overactivity or dyssynergia postoperatively, and 2 demonstrated no change. Of the 5 patients who underwent only postoperative urodynamic evaluation 4 had abnormal findings, including small capacity, poor compliance, detrusor overactivity, detrusor sphincter dyssynergia and/or high voiding pressure. No progressive denervation was seen on electromyography preoperatively or postoperatively. CONCLUSIONS: Currarino syndrome is a rare congenital disorder with few published reports regarding the long-term implications. Although no solid conclusions could be drawn regarding urodynamic improvement postoperatively due to our small sample size, spinal cord detethering did not lessen ongoing voiding complaints in the study patients. PMID- 22503010 TI - Editorial comment. PMID- 22503011 TI - Urethroplasty: a geographic disparity in care. AB - PURPOSE: Urethroplasty is the gold standard for urethral strictures but its geographic prevalence throughout the United States is unknown. We analyzed where and how often urethroplasty was being performed in the United States compared to other treatment modalities for urethral stricture. MATERIALS AND METHODS: De identified case logs from the American Board of Urology were collected from certifying/recertifying urologists from 2004 to 2009. Results were categorized by ZIP codes to determine the geographic distribution. RESULTS: Case logs from 3,877 urologists (2,533 recertifying and 1,344 certifying) were reviewed including 1,836 urethroplasties, 13,080 urethrotomies and 19,564 urethral dilations. The proportion of urethroplasty varied widely among states (range 0% to 17%). The ratio of urethroplasty-to-urethrotomy/dilation also varied widely from state to state, but overall 1 urethroplasty was performed for every 17 urethrotomies or dilations performed. Certifying urologists were 3 times as likely to perform urethroplasty as recertifying urologists (12% vs 4%, respectively, p<0.05). Urethroplasties were performed more commonly in states with residency programs (mean 5% vs 3%). Some states reported no urethroplasties during the observation period (Vermont, North Dakota, South Dakota, Maine and West Virginia). CONCLUSIONS: To our knowledge this is the first report on the geographic distribution of urethroplasty for urethral stricture disease. There are large variations in the rates of urethroplasty performed throughout the United States, indicating a disparity of care, especially for those regions in which few or no urethroplasties were reported. This disparity may decrease with time as younger certifying urologists are performing 3 times as many urethroplasties as older recertifying urologists. PMID- 22503012 TI - Complex repetitive discharges--a feature of the urethral continence mechanism or a pathological finding? AB - PURPOSE: We compared the proportion of women with complex repetitive discharges on urethral sphincter electromyography during filling cystometry among women with and without urinary disorders. MATERIALS AND METHODS: After receiving institutional review board approval we recruited community dwelling women without urinary symptoms and women who presented for urinary incontinence treatment. Participants completed the Pelvic Floor Distress Inventory. Women who responded affirmatively to an inventory item ("Do you have difficulty emptying your bladder?" or "Do you experience a feeling of incomplete bladder emptying?") were classified with voiding dysfunction. Women with post-void residual urine greater than 100 ml, active urinary tract infection, prolapse greater than stage II or neuromuscular disease were excluded from study. Participants underwent standardized multichannel urodynamics with continuous concentric needle electromyography of the urethral sphincter throughout filling cystometry. RESULTS: In the 31 controls and 56 incontinent participants mean+/-SD age was 48+/-15 years and median vaginal parity was 1 (range 0 to 2). The urodynamic diagnosis in the incontinent group included urodynamic stress incontinence in 31 (56%), detrusor overactivity with incontinence in 17 (30%) and mixed urodynamic stress incontinence with detrusor overactivity in 8 (14%). Of the women 26 (32%) met voiding dysfunction criteria with 96% reporting a feeling of incomplete bladder emptying and 53% reporting difficult bladder emptying. Controls were significantly more likely to have complex repetitive discharges than incontinent women (9 of 30 vs 2 of 56, p<0.002). CONCLUSIONS: Complex repetitive discharges occur in about a third of women without urinary symptoms. PMID- 22503013 TI - Selective management of the urethra at time of pelvic organ prolapse repair: an assessment of postoperative incontinence and patient satisfaction. AB - PURPOSE: Management of the urethra in women without stress urinary incontinence during pelvic organ prolapse repair can be approached selectively or with a prophylactic suburethral sling. We report on patient satisfaction and outcomes in patients who underwent selective urethral management during pelvic organ prolapse repair. MATERIALS AND METHODS: Patients undergoing repair of advanced apical and/or anterior compartment pelvic organ prolapse underwent prolapse reduction to screen for stress urinary incontinence. Patients with clinical, occult and urodynamic stress urinary incontinence underwent a sling procedure. Those without stress urinary incontinence did not undergo sling surgery. Patients completed responses to the UDI-6 (Urogenital Distress Inventory, PGI-I (Patient Global Impression of Improvement) and MESA (Medical, Epidemiological, and Social Aspects of Aging). Cost analysis of selective urethral management was completed. RESULTS: A total of 42 patients met the study inclusion criteria and 30 completed responses to all questionnaires. Patients were separated into prolapse repair only (14) and prolapse repair with sling (16) groups. In the prolapse repair only group 1 patient required a subsequent sling. Mean UDI-6, MESA urge and MESA stress scores were 3.71, 1.29 and 3.14 in the prolapse repair only group, and 2.31 (p=0.219), 2.69 (p=0.244) and 3.00 (p=0.918) in the prolapse repair with sling group, respectively. The PGI-I revealed no statistical difference between the groups. A total cost savings of $55,804 was achieved using selective urethral management. CONCLUSIONS: Patients undergoing prolapse repair only have continence and satisfaction outcomes that appear equivalent to those who underwent concomitant prolapse repair and sling. The decision to perform a concomitant sling at the time of prolapse repair should be tailored to the patient. PMID- 22503014 TI - Polysymptomatic, polysyndromic presentation of patients with urological chronic pelvic pain syndrome. AB - PURPOSE: Somatization disorder has been described in several comorbid functional syndromes of urological chronic pelvic pain syndrome, such as irritable bowel syndrome. We investigated whether a subset of patients with urological chronic pelvic pain syndrome may have the polysymptomatic, polysyndromic presentation pattern that is common in somatization disorder. MATERIALS AND METHODS: A total of 70 male and female patients with urological chronic pelvic pain syndrome and 35 age matched controls without the syndrome completed a 59-item symptom checklist to assess the classic polysymptomatic, polysyndromic symptom pattern. The 2 operational tools used were the Perley-Guze derived symptom checklist and the somatic symptom algorithm used for Diagnostic and Statistical Manual, 4th Edition, Text Revision somatization disorder criteria. RESULTS: Female patients with urological chronic pelvic pain syndrome (interstitial cystitis/bladder pain syndrome) reported significantly more nonpain symptoms and pain symptoms outside the pelvis than control female urology patients (p=0.0016 and 0.0018, respectively). Female patients with urological chronic pelvic pain syndrome were more likely to endorse a polysymptomatic, polysyndromic symptom pattern than female controls (27% vs 0%, p=0.0071). In contrast, male patients with urological chronic pelvic pain syndrome (interstitial cystitis/bladder pain syndrome and/or chronic prostatitis/chronic pelvic pain syndrome) did not report more extrapelvic pain than male controls (p=0.89). Male patients with urological chronic pelvic pain syndrome were not more likely than male controls to have a polysymptomatic, polysyndromic symptom pattern. CONCLUSIONS: A subset of female patients with urological chronic pelvic pain syndrome endorses numerous extrapelvic symptoms across multiple organ systems. The checklist may be valuable to assess patients for this polysymptomatic, polysyndromic symptom pattern, which is common in somatization disorder. Recognizing this polysymptomatic, polysyndromic presentation will prompt clinicians to investigate further to determine whether somatization disorder may be an underlying diagnosis in a small subset of patients with urological chronic pelvic pain syndrome who complain of numerous extrapelvic symptoms. PMID- 22503016 TI - Outcomes following artificial sphincter implantation after prior unsuccessful male sling. AB - PURPOSE: Despite the proven success and durability of the artificial urinary sphincter many patients elect an AdVance(r) sling as the initial treatment of male stress incontinence. We determined whether sling placement would change the outcome of an ensuing artificial urinary sphincter. MATERIALS AND METHODS: A total of 29 patients with stress urinary incontinence after failed sling placement were treated with an AMS 800(r) artificial urinary sphincter between January 2006 and May 2011. A control group of 136 men with a primary artificial urinary sphincter was used for comparison. Preoperative and postoperative evaluation included demographic variables, voiding diary, 24-hour pad weight, urodynamic characteristics, operative time, estimated blood loss, complication rate, followup and cuff selection. RESULTS: There was no statistical difference in urodynamic characteristics, operative variables or the complication rate. Pad use was reported as less than 1 pad daily in 96% of patients (28 of 29) with a secondary artificial urinary sphincter at 3-month followup. At 20.7 months 6.9% of patients (2 of 29) treated with an artificial urinary sphincter after the male sling required revision of the artificial urinary sphincter. The overall complication rate in the control group was 8.8% (12 of 136 patients) with a 2.2% infection rate (3 of 136). The overall complication rate in the artificial urinary sphincter plus male sling group was 6.9% (2 of 29 patients) with a 0% infection rate. CONCLUSIONS: Patients who require an artificial urinary sphincter after an initial male sling seem to fare as well as those who undergo primary artificial urinary sphincter implantation. PMID- 22503017 TI - Editorial comment. PMID- 22503015 TI - Randomized multicenter clinical trial of myofascial physical therapy in women with interstitial cystitis/painful bladder syndrome and pelvic floor tenderness. AB - PURPOSE: We determined the efficacy and safety of pelvic floor myofascial physical therapy compared to global therapeutic massage in women with newly symptomatic interstitial cystitis/painful bladder syndrome. MATERIALS AND METHODS: A randomized controlled trial of 10 scheduled treatments of myofascial physical therapy vs global therapeutic massage was performed at 11 clinical centers in North America. We recruited women with interstitial cystitis/painful bladder syndrome with demonstrable pelvic floor tenderness on physical examination and a limitation of no more than 3 years' symptom duration. The primary outcome was the proportion of responders defined as moderately improved or markedly improved in overall symptoms compared to baseline on a 7-point global response assessment scale. Secondary outcomes included ratings for pain, urgency and frequency, the O'Leary-Sant IC Symptom and Problem Index, and reports of adverse events. We compared response rates between treatment arms using the exact conditional version of the Mantel-Haenszel test to control for clustering by clinical center. For secondary efficacy outcomes cross-sectional descriptive statistics and changes from baseline were calculated. RESULTS: A total of 81 women randomized to the 2 treatment groups had similar symptoms at baseline. The global response assessment response rate was 26% in the global therapeutic massage group and 59% in the myofascial physical therapy group (p=0.0012). Pain, urgency and frequency ratings, and O'Leary-Sant IC Symptom and Problem Index decreased in both groups during followup, and were not significantly different between the groups. Pain was the most common adverse event, occurring at similar rates in both groups. No serious adverse events were reported. CONCLUSIONS: A significantly higher proportion of women with interstitial cystitis/painful bladder syndrome responded to treatment with myofascial physical therapy than to global therapeutic massage. Myofascial physical therapy may be a beneficial therapy in women with this syndrome. PMID- 22503019 TI - Renal primitive neuroectodermal tumor. PMID- 22503020 TI - Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. AB - PURPOSE: We assessed the efficacy, safety and effects on quality of life of onabotulinumtoxinA in patients with neurogenic detrusor overactivity. MATERIALS AND METHODS: In this 52-week, international, multicenter, double-blind, randomized, placebo controlled trial 416 patients with neurogenic detrusor overactivity and urinary incontinence (14 or more episodes per week) resulting from multiple sclerosis (227) and spinal cord injury (189) were treated with intradetrusor injections of onabotulinumtoxinA (200 or 300 U) or placebo. The primary end point was the change from baseline in the mean number of urinary incontinence episodes per week at week 6. Maximum cystometric capacity, maximum detrusor pressure during the first involuntary detrusor contraction and Incontinence Quality of Life total score were secondary end points. Adverse events were monitored. RESULTS: OnabotulinumtoxinA at a dose of 200 U in 135 patients and 300 U in 132 decreased mean urinary incontinence at week 6 by 21 and 23 episodes per week, respectively, vs 9 episodes per week in 149 on placebo (each dose p<0.001). Also, maximum cystometric capacity, maximum detrusor pressure during the first involuntary detrusor contraction and Incontinence Quality of Life score were significantly improved over values in the placebo group (each dose p<0.001). Median time to patient re-treatment request was greater for onabotulinumtoxinA 200 and 300 U than for placebo (256 and 254 days, respectively, vs 92). The most common adverse events were urinary tract infection and urinary retention. Of patients who did not catheterize at baseline 10% on placebo, 35% on 200 U and 42% on 300 U initiated catheterization due to urinary retention. CONCLUSIONS: OnabotulinumtoxinA significantly improved neurogenic detrusor overactivity symptoms vs placebo. Clean intermittent catheterization initiation due to urinary retention appeared to increase in a dose dependent fashion. No clinically relevant benefit in efficacy or duration was identified for the 300 U dose over the 200 U dose. PMID- 22503021 TI - Pediatric urinary stone composition in the United States. AB - PURPOSE: The incidence of urolithiasis in children is increasing. However, stone composition studies in this population are limited. We sought to determine the effects of age, gender and geographical location on urinary stone composition in the United States pediatric population. MATERIALS AND METHODS: We obtained composition analyses for all urinary stones submitted to a reference laboratory between 2000 and 2009. Stones were excluded if the patient was younger than 1 year or older than 18 years. Stone composition was determined by Fourier transform infrared spectroscopy. Logistic regression analysis was performed to determine associations between stone composition frequency and age, gender and geographical region. RESULTS: A total of 5,245 stones were included in our analysis. Calcium was found in 89.2% of stones. The percentage of stones containing calcium oxalate increased, while magnesium ammonium phosphate and ammonium acid urate containing stones decreased with age. Calcium oxalate and magnesium ammonium phosphate containing stones were more common in females, while uric acid stones were more common in males. Additionally, significant differences in stone composition frequency were noted between males and females in specific age groups and between age groups within the same gender. Geographical distribution was not significantly associated with stone composition. CONCLUSIONS: This series is the largest analysis to date of urinary stone composition in the pediatric population in the United States. Age and gender were significantly associated with stone composition, while geographical region was not significantly associated with stone composition. PMID- 22503022 TI - The influence of testosterone suppression and recovery on sexual function in men with prostate cancer: observations from a prospective study in men undergoing intermittent androgen suppression. AB - PURPOSE: We investigated the effects of testosterone change on the sexual function of men with prostate cancer undergoing intermittent maximal androgen deprivation therapy. MATERIALS AND METHODS: We conducted a phase II cohort study of 250 patients with prostate cancer undergoing intermittent maximal androgen deprivation therapy. Flutamide (Eulexin(r)) 250 mg 3 times daily and leuprolide (Lucrin(r)) 22.5 mg were given during a 9-month treatment phase (ONPhase). Therapy was ceased provided that prostate specific antigen was 4 ng/ml or less. Monitoring continued every 3 months for a further 2 years (OFFPhase) unless re treatment occurred. Sexual function was assessed with the QLQ-PR25 version 3.0 prostate module in conjunction with the QLQ-C30 questionnaire at baseline and every 3 months thereafter. RESULTS: At baseline 46% of patients reported sexual activity with almost half (43%) reporting mild or no erectile problems. Of the men 63% reported an interest in sex (libido), with 28% reporting moderate to high libido. In addition, 26% felt less masculine as a result of illness or treatment. By 3 months of ONPhase all parameters deteriorated, worsening to a low at 9 months. Only 13% of the men reported sexual activity and 10% reported moderate to high libido. The proportion of men feeling less masculine increased to 50%. During the OFFPhase recovery was observed. Of those previously sexually active men 52% resumed sexual activity. Of these patients all reported erectile function returning to baseline. Levels of libido, masculinity and sexual activity recovered but not to baseline levels. CONCLUSIONS: Libido, sexual activity and perceptions of masculinity deteriorate during ONPhase. Of the sexually active men at baseline half will resume sexual activity despite 9 months of androgen deprivation therapy. PMID- 22503023 TI - Intermittent androgen suppression--ready for prime time? PMID- 22503024 TI - The role of uroflowmetry in the diagnosis of lower urinary tract disorders in children. PMID- 22503025 TI - The quest for the perfect prostate biopsy continues. PMID- 22503026 TI - Simultaneous use of 2 different antimuscarinics to treat refractory urge urinary incontinence. Con. PMID- 22503027 TI - Simultaneous use of 2 different antimuscarinics to treat refractory urge urinary incontinence. Pro. PMID- 22503028 TI - Early aggressive treatment of lichen sclerosus may prevent disease progression. AB - PURPOSE: When not recognized and treated aggressively, lichen sclerosus may progress and cause debilitating symptoms. It also may result in significant morbidity in patients undergoing treatment for urethral strictures because unrecognized, it may result in rapid and severe recurrence after surgical treatment. We present our experience treating patients with lichen sclerosus in an equal access health care system. MATERIALS AND METHODS: We performed an institutional review board approved retrospective review of all adult men with lichen sclerosus treated at our institution during a 10-year period. We analyzed all patients diagnosed with lichen sclerosus, and recorded patient demographics and therapies. We recorded characteristics of the disease process including external and internal manifestations. We also recorded the various treatments, and whether the patients experienced recurrence. RESULTS: A total of 43 patients were diagnosed with lichen sclerosus during the review period. Of those patients presenting with more severe (urethral) involvement and undergoing 1 or 2-stage urethroplasties, we noted 7 with recurrence. In the remainder of patients presenting with less severe disease who were treated aggressively with clobetasol and/or minor procedures, no recurrences were noted on followup examination, and all of these patients had documented normal flow patterns on noninvasive urodynamics. CONCLUSIONS: Our data suggest that early aggressive topical therapy plus minimally invasive surgical therapy to relieve high pressure voiding may prevent the progression of lichen sclerosus in patients who present with limited disease involving the skin and meatus. PMID- 22503029 TI - Prospective blinded laboratory assessment of prophylactic antibiotic compliance in a pediatric outpatient setting. AB - PURPOSE: Prophylactic antibiotics are commonly used to prevent urinary tract infections in children with conditions such as vesicoureteral reflux. Patient compliance with antibiotics is salient, given the effects that noncompliance can have on development of antibiotic resistance and outcomes of clinical trials. Prior series have shown variable compliance (17% to 70%). However, no study has used objective methods. We hypothesized that direct measurement of urine antibiotic levels can reveal poor compliance. MATERIALS AND METHODS: During a pediatric urology clinic visit patients 0 to 18 years old taking trimethoprim prophylaxis for any urological diagnosis were invited to participate in the study. They were unaware of any potential urine testing before the visit. Urine was sent for chromatography to quantify trimethoprim levels. Parents also completed a compliance self-assessment. RESULTS: Of patients invited to participate 97% consented (54 patients). Of the patients 91% were compliant based on urine levels. Factors not associated with compliance included age, gender, self-report of compliance, duration of time on antibiotics, insurance status and history of breakthrough infection, surgery, pyelonephritis or hospitalization. CONCLUSIONS: This study demonstrates the highest compliance reported for children taking prophylactic antibiotics to prevent urinary tract infection. We attribute this unexpected result to the discussion by specialists of 1 problem for the duration of an office visit. All education in this study was part of clinical care. Thus, our results should be generalizable to nonstudy environments. Future studies should confirm whether this high level of compliance can be achieved by nephrologists and pediatricians. If such compliance cannot be achieved at nonsurgical clinics, then early referral to a pediatric urologist may be warranted. PMID- 22503030 TI - Can staccato and interrupted/fractionated uroflow patterns alone correctly identify the underlying lower urinary tract condition? AB - PURPOSE: Worldwide, uroflowmetry without simultaneous electromyography is often the only testing performed during the initial assessment of children with lower urinary tract symptoms. Various alterations in uroflow pattern are thought to indicate particular types of lower urinary tract conditions, specifically staccato uroflow indicating dysfunctional voiding and intermittent/fractionated uroflow indicating detrusor underactivity. We determined how reliable uroflow pattern alone is as a surrogate for simultaneously measured pelvic floor electromyography activity during voiding, and how well staccato and interrupted uroflow actually correlate with the diagnoses they are presumed to represent. MATERIALS AND METHODS: We reviewed uroflow/electromyography studies performed during the initial evaluation of 388 consecutive neurologically and anatomically normal patients with persistent lower urinary tract symptoms. We identified those with staccato, interrupted/fractionated and mixed uroflow based on current International Children's Continence Society guidelines. RESULTS: A total of 69 girls (58.5%) and 49 boys (41.5%) met inclusion criteria. Staccato uroflow was noted in 60 patients, interrupted/fractionated uroflow in 28 and a combination in 30. An active electromyography during voiding confirmed the diagnosis of dysfunctional voiding in 33.3% of patients with staccato, 46.4% with interrupted/fractionated and 50% with mixed uroflow patterns. CONCLUSIONS: Diagnoses based on uroflow pattern appearance without simultaneous electromyography to support them can be misleading, and reliance on uroflow pattern alone can lead to overdiagnoses of dysfunctional voiding and detrusor underactivity. When assessing patients with uroflow, an accompanying simultaneous pelvic floor electromyography is of utmost importance for improving diagnostic accuracy and thereby allowing for the most appropriate therapy. PMID- 22503031 TI - Piezoelectrically driven vertical cavity acoustic transducers for the convective transport and rapid detection of DNA and protein binding to DNA microarrays with SPR imaging--a parametric study. AB - Mixing within the microdomain is limited because convective mixing cannot be achieved since diffusion dominates as the main form of transport. Hence microassays can take on the order of 1 to 72 h, without the aid of a passive or active mixer to shorten the time of transport of a target molecule to a probe (Lai et al., 2004). Liu et al. (2002, 2003) developed a low cost cavitation microstreaming based mixer which is easy to implement and use, but no comprehensive study has been done to optimize such a mixer for various applications. We present a study of the effects of various frequencies and cavity parameters on mixing using dye and surface based assays with protein, DNA, and nanoparticles to obtain an optimum mixing frequency and configuration for a wide range of assay applications. We present a novel method to monitor real time binding using surface plasmon resonance imaging (SPRI) coupled with a vertical cavity acoustic transducer (VCAT) micromixer for various biomolecule surface assays. The combination of VCAT and SPRI allows assay signal saturation within one minute while conserving reagent volume. The kinetic rate constant for adsorption (k(a)) and desorption (k(d)) as well as the limit of detection (LOD) of 5 nM for the DNA duplex formation are reported using this VCAT micromixer. PMID- 22503032 TI - Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. AB - BACKGROUND: Fluorouracil-based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. We investigated the efficacy and safety of substituting fluorouracil with the oral prodrug capecitabine. METHODS: This randomised, open-label, multicentre, non-inferiority, phase 3 trial began in March, 2002, as an adjuvant trial comparing capecitabine based chemoradiotherapy with fluorouracil-based chemoradiotherapy, in patients aged 18 years or older with pathological stage II-III locally advanced rectal cancer from 35 German institutions. Patients in the capecitabine group were scheduled to receive two cycles of capecitabine (2500 mg/m(2) days 1-14, repeated day 22), followed by chemoradiotherapy (50.4 Gy plus capecitabine 1650 mg/m(2) days 1-38), then three cycles of capecitabine. Patients in the fluorouracil group received two cycles of bolus fluorouracil (500 mg/m(2) days 1-5, repeated day 29), followed by chemoradiotherapy (50.4 Gy plus infusional fluorouracil 225 mg/m(2) daily), then two cycles of bolus fluorouracil. The protocol was amended in March, 2005, to allow a neoadjuvant cohort in which patients in the capecitabine group received chemoradiotherapy (50.4 Gy plus capecitabine 1650 mg/m(2) daily) followed by radical surgery and five cycles of capecitabine (2500 mg/m(2) per day for 14 days) and patients in the fluorouracil group received chemoradiotherapy (50.4 Gy plus infusional fluorouracil 1000 mg/m(2) days 1-5 and 29-33) followed by radical surgery and four cycles of bolus fluorouracil (500 mg/m(2) for 5 days). Patients were randomly assigned to treatment group in a 1:1 ratio using permuted blocks, with stratification by centre and tumour stage. The primary endpoint was overall survival; analyses were done based on all patients with post-randomisation data. Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12.5% margin. This trial is registered with ClinicalTrials.gov, number NCT01500993. FINDINGS: Between March, 2002, and December, 2007, 401 patients were randomly allocated; 392 patients were evaluable (197 in the capecitabine group, 195 in the fluorouracil group), with a median follow-up of 52 months (IQR 41-72). 5-year overall survival in the capecitabine group was non-inferior to that in the fluorouracil group (76% [95% CI 67-82] vs 67% [58-74]; p=0.0004; post-hoc test for superiority p=0.05). 3-year disease-free survival was 75% (95% CI 68-81) in the capecitabine group and 67% (59-73) in the fluorouracil group (p=0.07). Similar numbers of patients had local recurrences in each group (12 [6%] in the capecitabine group vs 14 [7%] in the fluorouracil group, p=0.67), but fewer patients developed distant metastases in the capecitabine group (37 [19%] vs 54 [28%]; p=0.04). Diarrhoea was the most common adverse event in both groups (any grade: 104 [53%] patients in the capecitabine group vs 85 [44%] in the fluorouracil group; grade 3-4: 17 [9%] vs four [2%]). Patients in the capecitabine group had more hand-foot skin reactions (62 [31%] any grade, four [2%] grade 3-4 vs three [2%] any grade, no grade 3-4), fatigue (55 [28%] any grade, no grade 3-4 vs 29 [15%], two [1%] grade 3-4), and proctitis (31 [16%] any grade, one [<1%] grade 3-4 vs ten [5%], one [<1%] grade 3-4) than did those in the fluorouracil group, whereas leucopenia was more frequent with fluorouracil than with capecitabine (68 [35%] any grade, 16 [8%] grade 3-4 vs 50 [25%] any grade, three [2%] grade 3-4). INTERPRETATION: Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer. FUNDING: Roche Pharma AG (Grenzach Wyhlen, Germany). PMID- 22503033 TI - Protein detection based on small molecule-linked DNA. AB - Based on small molecule-linked DNA and the nicking endonuclease-assisted amplification (NEA) strategy, a novel electrochemical method for protein detection is proposed in this work. Specifically, the small molecule-linked DNA (probe 1) can be protected from exonuclease-catalyzed digestion upon binding to the protein target of the small molecule, so the DNA strand may hybridize with another DNA strand (probe 2) that is previously immobilized onto an electrode surface. Consequently, the NEA process is triggered, resulting in continuous removal of the DNA strands from the electrode surface, and the blocking effect against the electrochemical species [Fe(CN)(6)](3-/4-) becomes increasingly lower; thus, increased electrochemical waves can be achieved. Because the whole process is activated by the target protein, an electrochemical method for protein quantification is developed. Taking folate receptor (FR) as an example in this work, we can determine the protein in a linear range from 0.3 to 15 ng/mL with a detection limit of 0.19 ng/mL. Furthermore, because the method can be used for the assay of FR in serum samples and for the detection of other proteins such as streptavidin by simply changing the small molecule moiety of the DNA probes, this novel method is expected to have great potential applications in the future. PMID- 22503034 TI - Reducing the throughput time of the diagnostic track involving CT scanning with computer simulation. AB - INTRODUCTION: To examine the use of computer simulation to reduce the time between the CT request and the consult in which the CT report is discussed (diagnostic track) while restricting idle time and overtime. METHODS: After a pre implementation analysis in our case study hospital, by computer simulation three scenarios were evaluated on access time, overtime and idle time of the CT; after implementation these same aspects were evaluated again. Effects on throughput time were measured for outpatient short-term and urgent requests only. CONCLUSION: The pre implementation analysis showed an average CT access time of 9.8 operating days and an average diagnostic track of 14.5 operating days. Based on the outcomes of the simulation, management changed the capacity for the different patient groups to facilitate a diagnostic track of 10 operating days, with a CT access time of 7 days. After the implementation of changes, the average diagnostic track duration was 12.6 days with an average CT access time of 7.3 days. The fraction of patients with a total throughput time within 10 days increased from 29% to 44% while the utilization remained equal with 82%, the idle time increased by 11% and the overtime decreased by 82%. The fraction of patients that completed the diagnostic track within 10 days improved with 52%. Computer simulation proved useful for studying the effects of proposed scenarios in radiology management. Besides the tangible effects, the simulation increased the awareness that optimizing capacity allocation can reduce access times. PMID- 22503035 TI - Treg/Th17 functional disequilibrium in Chinese uremia on hemodialysis: a link between calcification and cardiovascular disease. AB - AIM: To investigate the correlation of the functional disequilibrium of regulatory T cells (Treg)/T-helper (Th17) cells with calcification and to explore the significance of their influence on the outcome of cardiovascular disease (CVD) in uremic patients after hemodialysis (HD). METHODS: Out of 66 uremia patients, 36 patients had CVD after HD (maintenance hemodialysis (MHD) group1) and 30 patients did not have CVD (MHD group2). Twenty healthy volunteers were selected as normal control group. Peripheral blood mononuclear cells were isolated and treated with recombinant human bone morphogenetic protein-2 (rhBMP 2). Treg and Th17 frequencies were measured by flow cytometry. Forkhead/winged helix transcription factor (Foxp3) and retinoic acid receptor-related orphan receptor-gammat (ROR-gammat) mRNA expressions were measured by real-time quantitative polymerase chain reaction. Levels of interleukin (IL)-10 and IL-17 were detected by enzyme-linked immunosorbent assay. RESULTS: When compared with controls, rhBMP-2 upregulates Treg/Th17 functional disequilibrium in uremia patients, displaying higher Treg and Th17 frequencies, Foxp3 and ROR-gammat expressions, and levels of cytokines (p < 0.05). These differences were also significant between MHD group1 and group2 (p < 0.05). It was also observed that Treg/Th17 functional disequilibrium was not only correlated with a calcification state but also consistent with the CVD. CONCLUSION: The Treg/Th17 cell function disequilibrium might act synergistically with calcification in the high incidence of CVD after HD. PMID- 22503036 TI - Diagnosis and treatment of coenurosis in sheep. AB - Coenurosis is a disease of the central nervous system in sheep, caused by Coenurus cerebralis, the larval stage of Taenia multiceps, a tapeworm, which infests the small intestine of carnivores. In 80-90% of cases, the cyst is located in one cerebral hemisphere, whilst in 5-10% of cases, it is localised in the cerebellum; rarely it involves two sites in the brain of the affected animal. Listeriosis, louping-ill, sarcocystosis and polioencephalomalacia and brain abscessation should be considered when formulating a diagnosis of acute coenurosis. In all cases, it is essential to carefully examine the animal and not simply rely on results of ancillary tests (mainly of cerebrospinal fluid examination), as disorders other than coenurosis can be responsible for changes in the results of these tests. Treatment is based on surgical removal of the coenurus cyst after general anaesthesia of the animal; the approach has a very good success rate, especially after accurate localisation of the lesion. Despite that, many farmers may choose to slaughter those sheep fit for marketing for economic reasons and euthanise those in poor condition. PMID- 22503037 TI - Special issue: Update on parasitic diseases of sheep. Preface. PMID- 22503038 TI - The bias, accuracy and precision of faecal egg count reduction test results in cattle using McMaster, Cornell-Wisconsin and FLOTAC egg counting methods. AB - The faecal egg count reduction test (FECRT) is the recommended method to monitor anthelmintic drug efficacy in cattle. There is a large variation in faecal egg count (FEC) methods applied to determine FECRT. However, it remains unclear whether FEC methods with an equal analytic sensitivity, but with different methodologies, result in equal FECRT results. We therefore, compared the bias, accuracy and precision of FECRT results for Cornell-Wisconsin (analytic sensitivity = 1 egg per gram faeces (EPG)), FLOTAC (analytic sensitivity = 1 EPG) and McMaster method (analytic sensitivity = 10 EPG) across four levels of egg excretion (1-49 EPG; 50-149 EPG; 150-299 EPG; 300-600 EPG). Finally, we assessed the sensitivity of the FEC methods to detect a truly reduced efficacy. To this end, two different criteria were used to define reduced efficacy based on FECR, including those described in the WAAVP guidelines (FECRT <95% and lower limit of 95%CI <90%) (Coles et al., 1992) and those proposed by El-Abdellati et al. (2010) (upper limit of 95%CI <95%). There was no significant difference in bias and accuracy of FECRT results across the three methods. FLOTAC provided the most precise FECRT results. Cornell-Wisconsin and McMaster gave similar imprecise results. FECRT were significantly underestimated when baseline FEC were low and drugs were more efficacious. For all FEC methods, precision and accuracy of the FECRT improved as egg excretion increased, this effect was greatest for McMaster and least for Cornell-Wisconsin. The sensitivity of the three methods to detect a truly reduced efficacy was high (>90%). Yet, the sensitivity of McMaster and Cornell-Wisconsin may drop when drugs only show sub-optimal efficacy. Overall, the study indicates that the precision of FECRT is affected by the methodology of FEC, and that the level of egg excretion should be considered in the final interpretation of the FECRT. However, more comprehensive studies are required to provide more insights into the complex interplay of factors inherent to study design (sample size and FEC method) and host-parasite interactions (level of egg excretion and aggregation across the host population). PMID- 22503039 TI - Anthelmintic resistance in sheep in Europe: a selected review. AB - Intensive use of anthelmintics to control gastrointestinal nematodes selects for anthelmintic resistance, which has become an important issue in many European countries. Presence of nematode strains resistant to benzimidazoles, imidazothiazoles and/or macrocyclic lactones has been repeatedly reported, particularly for the three most important genera, Haemonchus, Teladorsagia and Trichostrongylus. Additionally, multiple drug-resistant populations of these parasites have also been detected. Examples are given for the situation in European countries with differing climatic conditions and management systems of small ruminants. The widespread emergence of multi-resistant nematodes proves that the past intensive suppressive chemical control strategies may not be a successful approach any longer. Experience from the up to now development of anthelmintic resistance suggests that modern control schemes should not rely on sole use of anthelmintics, but employ other, more complex and sustainable recipes, combing chemical, environmental and immunological control. PMID- 22503040 TI - Urinary chemokines as noninvasive predictors of ulcerative interstitial cystitis. AB - PURPOSE: Based on basic research findings an increase in chemokines and cytokines (CXCL-1 and 10, nerve growth factor and interleukin-6) is considered responsible for inflammation and afferent sensitization. In this cross-sectional study we tested the hypothesis that select chemokines are increased in the urine of patients with ulcerative and nonulcerative interstitial cystitis/painful bladder syndrome. MATERIALS AND METHODS: Midstream urinary specimens were collected from 10 patients with ulcerative and nonulcerative interstitial cystitis/painful bladder syndrome, respectively, and from 10 asymptomatic controls. Urinary levels of 7 cytokines were measured by a human cytokine/chemokine assay. Nerve growth factor was measured by enzyme-linked immunosorbent assay. RESULTS: Urinary levels of most chemokines/cytokines were tenfold to 100-fold lower in asymptomatic controls vs patients with ulcerative and nonulcerative interstitial cystitis/painful bladder syndrome. Univariate comparison of 8 tested proteins in the ulcerative vs nonulcerative groups revealed a significant fivefold to twentyfold increase in CXCL-10 and 1, interleukin-6 and nerve growth factor (ANOVA p<0.001). CONCLUSIONS: Differential expression of chemokines in ulcerative and nonulcerative subtypes of interstitial cystitis/painful bladder syndrome suggests differences in paracrine signaling between the 2 entities. PMID- 22503041 TI - Nitric oxide signaling pathways involved in the inhibition of spontaneous activity in the guinea pig prostate. AB - PURPOSE: We investigated nitric oxide mediated inhibition of spontaneous activity recorded in young and aging guinea pig prostates. MATERIALS AND METHODS: Conventional intracellular microelectrode and tension recording techniques were used. RESULTS: The nitric oxide donor sodium nitroprusside (10 MUM) abolished spontaneous contractions and slow wave activity in 5 young and 5 aging prostates. Upon adding the nitric oxide synthase inhibitor L-NAME (10 MUM) the frequency of spontaneous contractile and electrical activity was significantly increased in each age group. This increase was significantly larger in 4 to 8 preparations of younger vs aging prostates (about 40% to 50% vs about 10% to 20%, 2-way ANOVA p<0.01). Other measured parameters, including the duration, amplitude and membrane potential of spontaneous electrical and contractile activity, were not altered from control values. The guanylate cyclase inhibitor ODQ (10 MUM) significantly increased the frequency of spontaneous activity by 10% to 30% in 6 young guinea pig prostates (Student paired t test p<0.05). However, it had no effect on aging prostates. The cGMP analogue 8-Br-GMP (1 MUM) and the PDE5 inhibitor dipyridamole (1 MUM) significantly decreased the frequency of contractile activity by about 70% in 4 to 9 young and older prostates (Student paired t test p<0.05). CONCLUSIONS: The decrease in the response to L-NAME in spontaneous contractile and slow wave activity in aging prostate tissue compared to that in young prostates suggests that with age there is a decrease in nitric oxide production. This may further explain the increase in prostatic smooth muscle tone observed in age related prostate specific conditions, such as benign prostatic hyperplasia. PMID- 22503044 TI - Re: Implications of pacemakers and implantable cardioverter defibrillators in urological practice: S. S. Ubee, V. S. Kasi, D. Bello and R. Manikandan J Urol 2011; 186: 1198-1205. PMID- 22503045 TI - Re: Baseline urodynamic predictors of treatment failure 1 year after mid urethral sling surgery: C. W. Nager, L. Sirls, H. J. Litman, H. Richter, I. Nygaard, T. Chai, S. Kraus, H. Zyczynski, K. Kenton, L. Huang, J. Kusek and G. Lemack for the urinary incontinence treatment network J Urol 2011; 186: 597-603. PMID- 22503046 TI - Serum neutrophil gelatinase associated lipocalin during the early postoperative period predicts the recovery of graft function after kidney transplantation from donors after cardiac death. AB - PURPOSE: Kidneys procured from donors after cardiac death hold great potential to expand the donor pool. However, they have not yet been fully used, in part due to the high incidence of delayed graft function. Although urine neutrophil gelatinase-associated lipocalin is a well-known early biomarker for renal injury after kidney transplantation, its usefulness is limited in cases with delayed graft function because of the unavailability of a urine sample. We evaluated serum neutrophil gelatinase-associated lipocalin as a potential biomarker to predict the functional recovery of kidneys transplanted from donors after cardiac death. MATERIALS AND METHODS: Consecutive patients transplanted with a kidney from a living related (39), brain dead (1) or post-cardiac death (27) donor were retrospectively enrolled in the study. Serum samples were collected serially before and after kidney transplantation. Serum neutrophil gelatinase-associated lipocalin was measured using the ARCHITECT(r) assay. RESULTS: Average serum neutrophil gelatinase-associated lipocalin was markedly high during the pre transplantation period. It decreased rapidly after transplantation. The slope of the decrease correlated well with the recovery period. By analyzing ROC curves we determined cutoffs to predict immediate, slow or delayed graft function requiring hemodialysis for longer than 1 week with high sensitivity and specificity. CONCLUSIONS: These data suggest that serial monitoring of serum neutrophil gelatinase-associated lipocalin may allow us to predict graft recovery and the need for hemodialysis after kidney transplantation from a donor after cardiac death. PMID- 22503047 TI - Bradeion (SEPT4) as a urinary marker of transitional cell bladder cancer: a real time polymerase chain reaction study of gene expression. AB - PURPOSE: We evaluated whether Bradeion/SEPT4 gene expression could be used as a potential urinary marker to diagnose bladder transitional cell carcinoma. MATERIALS AND METHODS: From 2005 to 2007 we collected urine samples from 58 individuals, 17 healthy controls and 41 patients in whom bladder tumors were previously diagnosed by cystoscopy. Urine was collected from all patients before transurethral resection of bladder tumor. We performed real-time reverse transcriptase-polymerase chain reaction to evaluate Bradeion/SEPT4 transcript levels using urine sample mRNA. Statistical analysis was done with the Mann Whitney test and ROC curves. RESULTS: Pathological examination of bladder tumor specimens revealed transitional cell bladder cancer. According to the 2002 TNM classification stage was Ta in 11 patients, T1 in 18 and T2/T3 in 12. All patients had G2 or G3 tumors according to the 1973 WHO grade classification. Relative quantification analysis of Bradeion transcript showed significantly increased levels compared to controls, namely 21.85 times higher in Ta stage tumors, 7.21 times higher in T1 tumors and 4.36 times higher in grade T2/T3 tumors. We compared each tumor stage group with the control group using the Mann Whitney test to verify the statistical significance of observed differences. The ROC curve built on the change in threshold cycle revealed that with this method we attained 92.68% sensitivity and 64.71% specificity (AUC 0.798, p=0.0001). CONCLUSIONS: Bradeion/SEPT4 transcript levels are significantly increased in patients with transitional cell bladder cancer compared to healthy controls. Our preliminary study supports the possible usefulness of Bradeion as a urinary marker of urothelial disease. PMID- 22503048 TI - Phase 2b study of the clinical efficacy and safety of collagenase Clostridium histolyticum in patients with Peyronie disease. AB - PURPOSE: Collagenase Clostridium histolyticum is an investigational nonsurgical treatment for Peyronie disease. In this phase 2b, double-blind, randomized, placebo controlled study we determined the safety and efficacy of collagenase C. histolyticum and assessed a patient reported outcome questionnaire. MATERIALS AND METHODS: A total of 147 subjects were randomized into 4 groups to receive collagenase C. histolyticum or placebo (3:1) with or without penile plaque modeling (1:1). Per treatment cycle 2 injections of collagenase C. histolyticum (0.58 mg) were given 24 to 72 hours apart. Subjects received up to 3 cycles at 6 week intervals. When designated, investigator modeling was done 24 to 72 hours after the second injection of each cycle. We evaluated penile curvature by goniometer measurement, patient reported outcomes and adverse event profiles. RESULTS: After collagenase C. histolyticum treatment significant improvements in penile curvature (29.7% vs 11.0%, p=0.001) and patient reported outcome symptom bother scores (p=0.05) were observed compared to placebo. In modeled subjects 32.4% improvement in penile curvature was observed in those on collagenase C. histolyticum compared to 2.5% worsening of curvature in those on placebo (p<0.001). Those treated with collagenase C. histolyticum who underwent modeling also showed improved Peyronie disease symptom bother scores (p=0.004). In subjects without modeling there were minimal differences between the active and placebo cohorts. Most adverse events in the collagenase C. histolyticum group occurred at the injection site and were mild or moderate in severity. No treatment related serious adverse events were reported. CONCLUSIONS: Collagenase C. histolyticum treatment was well tolerated. We noted significant improvement in penile curvature and patient reported outcome symptom bother scores, suggesting that this may be a safe, nonsurgical alternative for Peyronie disease. PMID- 22503049 TI - Protective effects of hydrogen rich saline solution on experimental testicular ischemia-reperfusion injury in rats. AB - PURPOSE: We examined the effectiveness of hydrogen rich saline solution on the prevention of testicular damage induced by ischemia/reperfusion in rats. MATERIALS AND METHODS: Male Sprague-Dawley(r) rats were divided randomly into 4 groups, including group 1-sham operated, group 2-torsion-detorsion, group 3 torsion-detorsion plus saline and group 4-torsion-detorsion plus hydrogen rich saline solution. Testicular torsion was performed by rotating the left testis 720 degrees clockwise for 4 hours. Reperfusion was allowed for 4 hours. Hydrogen rich saline solution (5 ml/kg) was injected intraperitoneally in rats in group 4 15 minutes before the start of detorsion. Rats were sacrificed after 4-hour initiation of detorsion. Left orchiectomy was done for histopathological examination and biochemical assay. RESULTS: The testicular injury score in groups 2 and 3 was significantly lower than in sham operated group 1 but higher in group 4 with hydrogen rich saline than in group 2 with torsion-detorsion. The apoptosis index was significantly increased in groups 2 and 3. Hydrogen rich saline solution treatment significantly decreased the apoptosis index. A significant increase in malondialdehyde and a decrease in superoxide dismutase activity were observed in groups 2 and 3. In group 4 malondialdehyde was significantly lowered and superoxide dismutase activity was significantly improved compared with groups 2 and 3. CONCLUSIONS: Results provide a biochemical and histopathological basis for the action of hydrogen rich saline solution as a therapeutic agent for testicular damage induced by ischemia/reperfusion injury. PMID- 22503050 TI - Anti-interleukin-10R1 monoclonal antibody enhances bacillus Calmette-Guerin induced T-helper type 1 immune responses and antitumor immunity in a mouse orthotopic model of bladder cancer. AB - PURPOSE: Proper induction of the T-helper type 1 immune response is required for effective bacillus Calmette-Guerin immunotherapy for bladder cancer. Interleukin 10 down-regulates the T-helper 1 response and is associated with bacillus Calmette-Guerin failure. We investigated whether blocking interleukin-10 receptor 1 would enhance the bacillus Calmette-Guerin induced T-helper type 1 immune response and anti-bladder cancer immunity in a mouse model. MATERIALS AND METHODS: Splenocytes were incubated with bacillus Calmette-Guerin or bacillus Calmette-Guerin plus control IgG1, anti-interleukin-10 receptor 1 mAb or anti interleukin-10 neutralizing mAb, followed by enzyme-linked immunosorbent assay of interferon-gamma production. Bladder RNA was extracted after intravesical bacillus Calmette-Guerin plus intraperitoneal IgG1 or anti-interleukin-10 receptor 1 mAb and analyzed by reverse transcriptase and/or quantitative polymerase chain reaction. Urine was collected and analyzed by enzyme-linked immunosorbent assay. Mice bearing a luciferase expressing MB49 orthotopic tumor were treated with intravesical bacillus Calmette-Guerin plus intraperitoneal IgG1 or anti-interleukin-10 receptor 1 mAb. Tumor response was assessed by bioluminescent imaging and bladder weight measurement. RESULTS: Bacillus Calmette Guerin plus anti-interleukin-10R1 mAb induced significantly higher interferon gamma production by splenocytes than bacillus Calmette-Guerin plus anti interleukin-10 mAb. Bacillus Calmette-Guerin plus anti-interleukin-10 receptor 1 mAb also induced significantly higher interferon-gamma mRNA and protein in bladder and urine, respectively, in a dose dependent manner. Treatment with phosphate buffered saline, bacillus Calmette-Guerin plus control IgG1 and bacillus Calmette-Guerin plus anti-interleukin-10 receptor 1 mAb showed a 0% tumor-free rate with a 20% death rate, a 20% tumor-free rate with a 20% death rate and a 40% tumor-free rate with a 0% death rate, respectively. Bladder weight also revealed the effect of anti-interleukin-10 receptor 1 mAb on the bacillus Calmette-Guerin induced bladder tumor response. CONCLUSIONS: Anti-interleukin-10 receptor 1 mAb enhanced the bacillus Calmette-Guerin induced T-helper type 1 immune response and anti-bladder cancer immunity. A humanized form of this mAb warrants future investigation for bacillus Calmette-Guerin treatment of bladder cancer. PMID- 22503055 TI - Establishment and characterization of primary cell lines of squamous cell carcinoma of the penis and its metastasis. AB - PURPOSE: We established cell lines from penile squamous cell carcinoma and its lymph node metastasis, and investigated the role of chemokines, chemokine receptors and podoplanin in cancer progression. MATERIALS AND METHODS: Tumor specimen of primary tumors, and lymph node and distant metastases were cultured in vitro and xenotransplanted in SCID beige mice. Specimens were analyzed by hematoxylin and eosin staining, and immunohistochemistry. Comparative screening for chemokines, chemokine receptors and podoplanin was done by polymerase chain reaction, fluorescence activated cell sorting and enzyme-linked immunosorbent assay. RESULTS: We established 2 cell lines from a primary tumor and its corresponding lymph node metastasis, respectively. Heterotopic xenotransplantation revealed reliable tumor growth in vivo. Morphological and immunohistological analysis showed comparable features for human tumors, cell lines in vitro and xenotransplanted tumors in mice regarding the primary tumor and metastasis. Comprehensive analysis of chemokines and chemokine receptors in the metastasis derived cell line and in the cell line originating from the primary tumor revealed the most pronounced changes for CXCL14. This pattern was confirmed on the protein level. Comparative analysis of podoplanin showed marked down-regulation in the metastatic variant on the mRNA and protein levels. CONCLUSIONS: To our knowledge we established the first pair of cell lines of a human primary penile tumor and the corresponding lymph node metastasis. These cell lines offer unique possibilities for further comparative functional investigations in in vitro and in vivo settings. They enable studies of new potential therapeutic agents and other assays to better understand the molecular mechanisms of penile cancer progression. PMID- 22503056 TI - Expression and role of HMGA1 in renal cell carcinoma. AB - PURPOSE: Although molecular targeted therapy has improved the clinical outcome of metastatic renal cell carcinoma, a complete response is rare and there are various side effects. Identifying novel target molecules is necessary to improve the clinical outcome of metastatic renal cell carcinoma. HMGA1 is over expressed in many types of cancer and it is associated with metastatic potential. It is expressed at low levels or not expressed in normal tissue. We examined HMGA1 expression and function in human renal cell carcinoma. MATERIALS AND METHODS: HMGA1 expression in surgical specimen from patients with renal cell carcinoma was examined by immunoblot. HMGA1 expression in 6 human renal cell carcinoma cell lines was examined by immunoblot and immunofluorescence. The molecular effects of siRNA mediated knockdown of HMGA1 were examined in ACHN and Caki-1 cells. RESULTS: Immunoblot using surgical specimen showed that HMGA1 was not expressed in normal kidney tissue but it was expressed in tumor tissue in 1 of 30 nonmetastatic (3%) and 6 of 18 metastatic (33%) cases (p=0.008). Immunoblot and immunofluorescence revealed significant nuclear expression of HMGA1 in ACHN and Caki-1 cells derived from metastatic sites. HMGA1 knockdown remarkably suppressed colony formation and induced significant apoptosis in ACHN and Caki-1 cells. HMGA1 knockdown significantly inhibited invasion and migration in vitro, and induced anoikis associated with P-Akt down-regulation in ACHN cells. CONCLUSIONS: HMGA1 is a potential target for novel therapeutic modalities for metastatic renal cell carcinoma. PMID- 22503057 TI - First results of the DEB-AMI (drug eluting balloon in acute ST-segment elevation myocardial infarction) trial: a multicenter randomized comparison of drug-eluting balloon plus bare-metal stent versus bare-metal stent versus drug-eluting stent in primary percutaneous coronary intervention with 6-month angiographic, intravascular, functional, and clinical outcomes. AB - OBJECTIVES: The goal of this study was to compare angiographic, intravascular imaging, and functional parameters, as well as the clinical outcomes of patients treated with drug-eluting balloon (DEB) plus bare-metal stent (BMS) versus BMS versus drug-eluting stent (DES) for ST-segment elevated acute myocardial infarction (STEMI). BACKGROUND: Concerns remain regarding the long-term safety of DES in STEMI. DEB could provide an attractive alternative in order to achieve potentially similar effectiveness but limiting the long-term hazards related to late-acquired stent malapposition and thus stent thrombosis. METHODS: In this randomized, international, 2-center, single-blinded, 3-arm study, STEMI patients were randomly assigned to group A: BMS; group B: DEB plus BMS; or group C: DES after successful thrombus aspiration. The primary endpoint was 6-month angiographic in-stent late-luminal loss. Secondary endpoints were in-stent binary restenosis, major adverse cardiac events (MACE: cardiac death, myocardial infarction, target vessel revascularization). In a subgroup of patients, stent (mal)apposition (by optical coherence tomography) and endothelial function (by acetylcholine infusion) was assessed. RESULTS: Overall, 150 patients were randomized. Procedural success was achieved in 96.7%. In groups A, B, and C, respectively, late-luminal loss was 0.74 +/- 0.57 mm, 0.64 +/- 0.56 mm, and 0.21 +/- 0.32 mm (p < 0.01); binary restenosis was 26.2%, 28.6%, and 4.7% (p = 0.01); and MACE rates were 23.5%, 20.0%, and 4.1% (p = 0.02), respectively. The median percentage [25th to 75th interquartile range] of uncovered and malapposed stent struts per lesion was 0 [0 to 0.35], 2.84 [0 to 6.63], and 5.21 [3.25 to 14.5] (p < 0.01). Significant paradoxical vasoconstriction was seen in groups B and C. CONCLUSIONS: In STEMI patients, DEB followed by BMS implantation failed to show angiographic superiority to BMS only. Angiographic results of DES were superior to both BMS and DEB. Moreover, DEB before implantation induced more uncovered and malapposed stent struts than BMS, but less than after DES. (Drug-Eluting Balloon in Acute Myocardial Infarction [DEB-AMI]; NCT00856765). PMID- 22503058 TI - Clinical outcomes after transcatheter aortic valve replacement using valve academic research consortium definitions: a weighted meta-analysis of 3,519 patients from 16 studies. AB - OBJECTIVES: This study sought to perform a weighted meta-analysis to determine the rates of major outcomes after transcatheter aortic valve replacement (TAVR) using Valve Academic Research Consortium (VARC) definitions and to evaluate their current use in the literature. BACKGROUND: Recently, the published VARC definitions have helped to add uniformity to reporting outcomes after TAVR. METHODS: A comprehensive search of multiple electronic databases from January 1, 2011, through October 12, 2011, was conducted using predefined criteria. We included studies reporting at least 1 outcome using VARC definitions. RESULTS: A total of 16 studies including 3,519 patients met inclusion criteria and were included in the analysis. The pooled estimate rates of outcomes were determined according to VARC's definitions: device success, 92.1% (95% confidence interval [CI]: 88.7% to 95.5%); all-cause 30-day mortality, 7.8% (95% CI: 5.5% to 11.1%); myocardial infarction, 1.1% (95% CI: 0.2% to 2.0%); acute kidney injury stage II/III, 7.5% (95% CI: 5.1% to 11.4%); life-threatening bleeding, 15.6% (95% CI: 11.7% to 20.7%); major vascular complications, 11.9% (95% CI: 8.6% to 16.4%); major stroke, 3.2% (95% CI: 2.1% to 4.8%); and new permanent pacemaker implantation, 13.9% (95% CI: 10.6% to 18.9%). Medtronic CoreValve prosthesis use was associated with a significant higher rate of new permanent pacemaker implantation compared with the Edwards prosthesis (28.9% [95% CI: 23.0% to 36.0%] vs. 4.9% [95% CI: 3.9% to 6.2%], p < 0.0001). The 30-day safety composite endpoint rate was 32.7% (95% CI: 27.5% to 38.8%) and the 1-year total mortality rate was 22.1% (95% CI: 17.9% to 26.9%). CONCLUSIONS: VARC definitions have already been used by the TAVR clinical research community, establishing a new standard for reporting clinical outcomes. Future revisions of the VARC definitions are needed based on evolving TAVR clinical experiences. PMID- 22503059 TI - Treatment of a large and symptomatic septum pellicidum cyst with endoscopic fenestration in a child--case report and review of the literature. PMID- 22503060 TI - Acute pure motor demyelinating neuropathy with hyperreflexia and anti-GalNAc-GD1a antibodies. PMID- 22503061 TI - FDG PET findings leading to diagnosis of neurosarcoidosis. PMID- 22503062 TI - Immunomodulatory activity of vardenafil on induced lung inflammation in cystic fibrosis mice. AB - BACKGROUND: We tested the hypothesis that vardenafil, a common drug used for improving erectile dysfunction and able to partially normalize transepithelial chloride transport in cystic fibrosis (CF), modulates CF lung inflammation. METHODS: Inflammatory markers in lungs of F508del-CF and wild-type mice were monitored in response to lipopolysaccharide from Pseudomonas aeruginosa (LPS). The effect of pretreatment with vardenafil (0.14 mg/kg) was evaluated. RESULTS: A latent inflammatory status, characterized by neutrophil infiltrate, mouse macrophage inflammatory protein (MIP)-2 and tumor necrosis factor (TNF)-alpha, was found in baseline conditions in F508del-CF mice. Inflammatory markers were increased after LPS with higher responses in CF. Vardenafil globally attenuated inflammatory responses in both genotypes however reduction of macrophage infiltration, macrophage chemoattractant chemokine and interleukin-1beta was observed in the CF group only. CONCLUSION: Vardenafil reduces lung inflammation with a more pronounced effect in F508del-CF mice, particularly on macrophage cell markers. PMID- 22503063 TI - Molecular analysis of the Noggin (NOG) gene in holoprosencephaly patients. AB - Holoprosencephaly (HPE) is the most common structural anomaly of the human forebrain. Various genetic and teratogenic causes have been implicated in its pathogenesis. A recent report in mice described Noggin (NOG) as a candidate gene involved in the etiogenesis of microform HPE. Here, we present for the first time genetic analysis of a large HPE cohort for sequence variations in NOG. On the basis of our study, we conclude that mutations in the coding region of NOG are rare, and play at most an uncommon role in human HPE. PMID- 22503064 TI - Are antioxidant and transcriptional responses useful for discriminating between chemo- and radiotoxicity of uranium in the crayfish Procambarus clarkii? AB - The main objectives of this study were to evaluate uranium (U) toxicity in the crayfish Procambarus clarkii at a low dose of exposure and to discriminate between the chemotoxicity and radiotoxicity of U. We conducted two sets of experiments using either 30 MUg L(-1) of depleted uranium (DU) or (233)U, which differ from each other only in their specific activity (DU=1.7*10(4)Bqg(-1), (233)U=3.57*10(8)Bqg(-1)). The endpoints were oxidative stress responses and mitochondrial functioning in the gills and hepatopancreas, which were measured in terms of enzyme activities and gene expression levels. U accumulation levels were measured in different organs (gills, hepatopancreas, stomach, intestine, green gland, muscles, and carapace), and internal dose rates in the hepatopancreas were compared after DU and (233)U exposures. Significant U accumulation occurred in the organs of P. clarkii, and mitochondrial damage and antioxidant responses were detected. Despite the huge difference (21,000*) in the specific activities of DU and (233)U, few significant differences in biological responses were detected in P. clarkii exposed to these two pollutants. This finding indicates that the radiotoxicity was low compared to the chemotoxicity under our exposure conditions. Finally, genes expression levels were more sensitive markers of U toxicity than enzyme activities. PMID- 22503066 TI - Limitations of preoperative biopsy in patients with metastatic renal cell carcinoma: comparison to surgical pathology in 405 cases. AB - Study Type--Diagnostic (cohort) Level of Evidence: 2b. What's known on the subject? and What does the study add? Although there have been many investigations of biopsy for small renal masses, there are scant data on the accuracy of biopsy in the setting of metastatic renal cell carcinoma (mRCC). We report a large series of biopsies and compare with nephrectomy pathology in patients with mRCC. The present study highlights the inaccuracy of biopsy in the setting of metastatic disease, which is related to sampling error because of heterogeneity within the tumour and among metastases. These limitations are important to realize when designing trials that depend on pathological findings from biopsy and not nephrectomy. In addition, we found that biopsy of primary tumours were more likely than biopsy of metastatic sites to be diagnostic of RCC. Future studies with multiquadrant biopsies of primary tumours could yield the most accurate pathological results for future studies. OBJECTIVE: * To evaluate the ability of preoperative biopsy to identify high-risk pathological features by comparing pathology from preoperative metastatic site and primary tumour biopsies with nephrectomy pathology in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: * We reviewed clinical and pathological data from patients who underwent biopsy before cytoreductive nephrectomy for mRCC at MD Anderson Cancer Center (MDACC) from 1991 to 2007. * Percutaneous biopsy techniques included fine-needle aspiration, core needle biopsy or a combination of both techniques. RESULTS: * The pathology of 405 preoperative biopsies (239 metastatic site, 166 primary tumour) from 378 patients was reviewed at MDACC before cytoreductive nephrectomy. * The biopsy and nephrectomy specimens had the same histological subtype in 96.0% of clear-cell renal cell carcinomas (RCCs) and 72.7% of non-clear-cell RCCs. * Of 76 nephrectomy specimens where sarcomatoid de differentiation was identified, only seven (9.2%) were able to be identified from the preoperative biopsy. * In 38.3% of patients, the same Fuhrman grade was identified in both the biopsy and nephrectomy specimens. * A definitive diagnosis of RCC was more likely to be reported in primary tumour biopsies than in metastatic site biopsies. (P < 0.001). CONCLUSIONS: * Preoperative biopsy has limited ability to identify non-clear-cell histological subtype, Fuhrman grade or sarcomatoid features. * When surgical pathology is not available, a biopsy obtaining multiple samples from different sites within the primary tumour should be recommended rather than limited metastatic site biopsy to identify patients for clinical trials. PMID- 22503065 TI - The obesity paradox, cardiorespiratory fitness, and coronary heart disease. AB - OBJECTIVE: To investigate associations of cardiorespiratory fitness (CRF) and different measures of adiposity with cardiovascular disease (CVD) and all-cause mortality in men with known or suspected coronary heart disease (CHD). PATIENTS AND METHODS: We analyzed data from 9563 men (mean age, 47.4 years) with documented or suspected CHD in the Aerobics Center Longitudinal Study (August 13, 1977, to December 30, 2002) using baseline body mass index (BMI) and CRF (quantified as the duration of a symptom-limited maximal treadmill exercise test). Waist circumference (WC) and percent body fat (BF) were measured using standard procedures. RESULTS: There were 733 deaths (348 of CVD) during a mean follow-up of 13.4 years. After adjustment for age, examination year, and multiple baseline risk factors, men with low fitness had a higher risk of all-cause mortality in the BMI categories of normal weight (hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.24-2.05), obese class I (HR, 1.38; 95% CI, 1.04 1.82), and obese class II/III (HR, 2.43; 95% CI, 1.55-3.80) but not overweight (HR, 1.09; 95% CI, 0.88-1.36) compared with the normal-weight and high-fitness reference group. We observed a similar pattern for WC and percent BF tertiles and for CVD mortality. Among men with high fitness, there were no significant differences in CVD and all-cause mortality risk across BMI, WC, and percent BF categories. CONCLUSION: In men with documented or suspected CHD, CRF greatly modifies the relation of adiposity to mortality. Using adiposity to assess mortality risk in patients with CHD may be misleading unless fitness is considered. PMID- 22503067 TI - Tonsillitis, peritonsillar and lateral pharyngeal abscesses. AB - Oral and maxillofacial surgeons are occasionally called on to diagnose, treat, and rule out peritonsillar abscesses. In this article, the anatomy of the peritonsillar area, its contents, surgical approaches, and possible complications are discussed. PMID- 22503068 TI - Allergic rhinitis and the unified airway: a therapeutic dilemma. AB - Inflammatory diseases of the upper and lower airways act not as individual entities but more as an integrated unit-the concept of the unified airway. This article focuses on the role of allergic rhinitis (AR) in the unified airway. An overview of AR and its association with upper and lower airway diseases is provided. AR is described in terms of its epidemiology, pathophysiology, and recent options for successful treatment. The recent use of immunotherapy and its future potential as a prophylactic method for the treatment of AR and concomitant diseases within the unified airway are emphasized. PMID- 22503069 TI - Epistaxis and hemostatic devices. AB - Epistaxis is a common medical problem that rarely requires surgical intervention. However, when medical or surgical intervention is required, epistaxis can sometimes be difficult to control. Knowledge of nasopharyngeal anatomy is absolutely essential to the proper management of epistaxis. This article begins with a discussion of the essential anatomy of the region and the basic epidemiology of epistaxis, followed by a review of initial treatment as well as devices and procedures specifically designed for the control of epistaxis. Advances and new devices for the control of epistaxis are described. PMID- 22503070 TI - Oroantral communication. AB - The practicing oral and maxillofacial surgeon treating patients with oroantral communication (OAC)/oroantral fistulas should be familiar and competent with the various treatment options available. Multiple techniques are available from purely soft tissue flaps, which have proved to be successful over time, to a combination of hard tissue grafts (autologous, alloplastic, or allograft), which can prove to be useful with the increased demand for implant restorations. Although different procedures have proved to be successful, all are premised on the treatment of any underlying sinusitis, which is associated with a higher risk of recurrent OAC. PMID- 22503071 TI - Bidirectional encroachment of collagen into the tunica media in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. AB - Arteries in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are susceptible to smooth muscle loss and fibrosis, but the molecular components underlying these dramatic vascular changes are not well characterized. The purpose of this study was to investigate the distribution of collagen isoforms in the cerebral vessels of North American CADASIL patients with classical NOTCH3 mutations. Expression of types I-VI collagen in brains obtained at autopsy from six CADASIL patients with cysteine altering mutations in NOTCH3 was compared to control brain expression. We identified a consistent increase of types I, III, IV, and VI collagen in CADASIL brains. Strong accumulation of types I, III, IV and VI collagen was noted in all calibers of vessels, including small and medium-sized leptomeningeal arteries, small penetrating white matter arteries, and capillaries. Within leptomeningeal arteries, where we could define the three tunicae of each vessel, we found distinct collagen subtype distribution patterns in CADASIL. Types I and III collagen were largely found in either adventitial/medial or transmural locations. Type IV collagen was strictly intimal/medial. Type VI collagen was adventitial or adventitial/medial. Within the thickened penetrating arteries of CADASIL patients, all four collagens extended through most of the arterial wall. We observed increased staining of capillaries in CADASIL for types I, IV, and VI collagen. In conclusion, brain vascular collagen subtypes are increased in CADASIL in multiple layers of all sizes of arteries, with disease-specific changes most prominent in the tunica media and thickened small penetrating vessels. In diseased arteries, types I, III, and VI collagen spreads from an external location (adventitia) into the vascular media, while type IV collagen accumulates in an internal pattern (intima and media). These observations are consistent with a pathological role for collagen accumulation in the vascular media in CADASIL. PMID- 22503072 TI - Direct protection of neurons and astrocytes by matrine via inhibition of the NF kappaB signaling pathway contributes to neuroprotection against focal cerebral ischemia. AB - Matrine (Mat) and oxymatrine are two major alkaloids of the Chinese herb Sophora flavescens Ait. (Leguminosae). Previous study has demonstrated that Mat reduces brain edema induced by focal cerebral ischemia. More recently, oxymatrine has been reported to produce neuroprotective effects against focal cerebral ischemia via inhibiting the activation of NF-kappaB in the ischemic brain tissue. In the current study, we investigated whether direct protection on neurons and astrocytes via inhibition of NF-kappaB signaling pathway is associated with Mat's neuroprotective effects against cerebral ischemia. In a model of permanent middle cerebral artery occlusion (pMCAO), Mat (12.5, 25 and 50 mg/kg) reduced the infarction volume and improved the neurological deficits in a dose-dependent manner, administered 10 min, 3h and even 6h following pMCAO. Mat 50 mg/kg also decreased the hemispheric water content. The number of GFAP-positive cells was markedly decreased in the ischemic cortex at 12h after ischemia. In contrast, Mat increased the number of GFAP-positive cells. Mat 50mg/kg has no effect on the cerebral blood flow (CBF). Primary neuron or astrocyte cultures were exposed to a paradigm of ischemic insult by using an oxygen-glucose deprivation (OGD), Mat (50 200 MUM) reduced LDH leakage and the number of neuronal and astrocytic apoptosis, and increased the number of MAP2-positive and GFAP-positive cells. Further observations revealed that Mat increased the protein levels of IkappaBalpha, and blocked the translocation of NF-kappaB p65 from the cytosol to the nucleus in the ischemic cortex and injured neurons and astrocytes induced by in vitro OGD. Moreover, Mat could down-regulate NF-kappaB p65 downstream pro-apoptotic gene p53 and/or c-Myc in the injured neurons and astrocytes induced by OGD. The present findings suggest that Mat, even when administrated 6h after ischemia, has neuroprotective effects against focal cerebral ischemia and directly protects neurons and astrocytes via inhibition of NF-kappaB signaling pathway, contributing to matrine's neuroprotection against focal cerebral ischemia. PMID- 22503073 TI - The effect of high temperature on the kinetics of lipopolysaccharide (LPS) induced human monocytes activity in vitro. AB - Human peripheral blood monocytes were stimulated with lipopolysaccharide at different temperatures (34, 37 and 40 degrees C) and TNF-alpha, IL-1beta and NO production was measured. Levels of TNF-alpha mRNA and IL-1beta mRNA were measured by RT-PCR. Phagocytic activity of LPS-stimulated monocytes in terms of bacterial uptake and intracellular bacterial killing was checked at different conditions in vitro. Early elevation of TNF-alpha, IL-1beta and NO production was found in LPS stimulated monocytes that incubated at 40 degrees C followed by cells that incubated at 37 degrees C and lowest level was detected at 34 degrees C. Similar results were observed in the phagocytic activity. Expression of TNF-alpha mRNA and IL-1beta mRNA was observed as early as 30 min post exposure to LPS in all studied temperatures and these, decreased sharply after 12 h post exposure to LPS in LPS-stimulated monocytes that incubated at 40 degrees C only. This report describes the striking effects of incubation temperature on activity of LPS stimulated monocytes. PMID- 22503074 TI - Lung disease with anti-CCP antibodies but not rheumatoid arthritis or connective tissue disease. AB - OBJECTIVE: We sought to characterize a novel cohort of patients with lung disease, anti-cyclic citrullinated peptide (CCP) antibody positivity, without rheumatoid arthritis (RA) or other connective tissue disease (CTD). METHODS: The study sample included 74 subjects with respiratory symptoms, evaluated January 2008-January 2010 and found to have a positive anti-CCP antibody but no evidence for RA or other CTD. Each underwent serologic testing, pulmonary physiology testing, and thoracic high-resolution computed tomography (HRCT) scan as part of routine clinical evaluation. RESULTS: The majority of subjects were women, and most were former cigarette smokers. Four distinct radiographic phenotypes were identified: isolated airways disease (54%), isolated interstitial lung disease (ILD) (14%), mixed airways disease and ILD (26%), and combined pulmonary fibrosis with emphysema (7%). This cohort had a predominance of airways disease, either in isolation or along with a usual interstitial pneumonia-pattern of ILD. Among subjects with high-titer anti-CCP positivity (n=33), three developed the articular manifestations of RA during a median follow-up of 449 days. CONCLUSION: We have described a unique cohort of patients with anti-CCP antibody positivity and lung disease in the absence of existing RA or other CTD. The lung phenotypic characteristics of this cohort resemble those of established RA and a few of these patients have developed articular RA within a short period of follow-up. The implications of a positive anti-CCP antibody among patients with lung disease but not RA are not yet known, but we believe requires further investigation. PMID- 22503075 TI - Black Hawk down? Establishing helicopter parenting as a distinct construct from other forms of parental control during emerging adulthood. AB - The purpose of the current study was to establish a measure of helicopter parenting that was distinct from other forms of parental control, and to examine parental and behavioral correlates of helicopter parenting. Participants included 438 undergraduate students from four universities in the United States (M(age) = 19.65, SD = 2.00, range = 18-29; 320 women, 118 men), and at least one of their parents. Analyses revealed that helicopter parenting loaded on a separate factor from both behavioral and psychological control, and that helicopter parenting was positively associated with behavioral and psychological control, but not at levels suggesting complete overlap. Results also revealed that helicopter parenting was positively associated with parental involvement and with other positive aspects of the parent-child relationship; but negatively associated with parental autonomy granting and school engagement. Discussion focuses on the implications of helicopter parenting for healthy development during emerging adulthood. PMID- 22503076 TI - Adolescent leisure dimensions, psychosocial adjustment, and gender effects. AB - Leisure provides the context for much of adolescent behaviour and development. While both theory and research point to the benefits of participation in leisure activities that are highly structured, the association between structured leisure and psychosocial adjustment is not uniformly high. This paper presents a model of adolescent leisure comprising three dimensions: structure, effort, and social contact. Adolescent adjustment is hypothesized to increase with participation in activities characterized by each of these attributes. Adjustment is also predicted to vary with gender, and with the interaction of gender and leisure participation. These propositions were tested in a questionnaire-based study of 433 Australian adolescents. Results revealed majority support for hypotheses pertaining to the positive effects of the leisure dimensions, and for gender differences in leisure participation and adjustment. Evidence was also obtained of gender-differentiated effects of leisure on adjustment, with social leisure predicting adjustment more strongly in females than males. PMID- 22503077 TI - Nonsense mediated decay of VWF mRNA subsequent to c.7674-7675insC mutation in type3 VWD patients. AB - Von Willebrand disease (VWD), the most common genetic bleeding disorder, is caused by defects in Von Willebrand factor (VWF). Quantitative deficiencies of the protein lead to either VWD type3, the severe form of the disease or VWD type1 with milder clinical manifestation. Null alleles are the most common mutations in VWF gene causing type3. However, some of these mutations are not translated into the protein and are selectively degraded at mRNA level by nonsense-mediated decay (NMD) pathway. Here, we have studied a large VWD type3 pedigree with a premature termination codon (PTC) causing insertion mutation (c.7674-7675insC) in VWF exon 45. We further investigated the impact of the mutation on the VWF mRNA expression using a quantitative Real-time PCR assay and cDNA sequencing. The relative expression of the gene was significantly decreased in the patients' platelets (Mean ratio=0.03 (0.01-0.05), p=0.001) compared to their normal relatives. The heterozygote carriers of the mutation had lower than normal VWF mRNA levels (Mean ratio=0.62 (0.29-0.91), p=0.006). Direct sequencing of exon 45 on the platelet derived cDNA in the carriers revealed only the wild-type allele confirming the decay of the mutation carrying allele. In conclusion, quantitative analysis of VWF gene expression showed that c.7674-7675insC mutation in VWF gene resulted in degradation of VWF mRNA via NMD. This pathway might play an important role in the pathogenesis of VWD characterized by quantitative deficiency of VWF due to reduced mRNA levels. PMID- 22503078 TI - Oxidative stress and vein graft failure: a focus on NADH oxidase, nitric oxide and eicosanoids. AB - Recent interest has focused on superoxide and the upregulation of NADPH oxidase expression in the aetiology of vein graft failure. Implantation of saphenous vein grafts promotes upregulation of NADPH oxidase through a number of distinct interrelated mechanisms: (a) endothelial denudation, (b) factors released by adherent platelets, monocytes and neutrophils, (c) hypoxia and (d) altered prostacyclin (PGI(2)) and enhanced isoprostane formation. These, in turn, impact on neointima (NI) formation (vascular smooth muscle cell [VSMC] replication and migration) and metalloproteinase (MMP) expression, key events in vein graft thickening. NADPH oxidase in the aetiology of vein graft failure will be discussed in this review with particular reference to nitric oxide and eicosanoids and related drugs that inhibit its activity and expression. PMID- 22503080 TI - Osteogenic potential of human umbilical cord-derived mesenchymal stromal cells cultured with umbilical cord blood-derived autoserum. AB - OBJECTIVE: Osteogenesis in the bone defect at the site of an alveolar cleft is important to enable patients with cleft lip and palate to acquire dental articulation. The presence of umbilical cord-derived mesenchymal stem cells has been reported. In this study, we used autoserum derived from the umbilical cord blood (UCB) of neonates in an attempt to examine the osteoblastic differentiation potential of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) in nude mice. MATERIALS AND METHODS: UCB, hydroxyapatite, and rhBMP were used as the supply source of autoserum, scaffold, and osteoinductive growth factor, respectively. MSCs, obtained from Wharton's jelly and cultured for 3-4weeks to induce their differentiation into osteoblasts, were implanted subcutaneously into the dorsum of male nude mice for 6weeks before the assessment by real-time reverse transcriptase chain reaction of osteoblast marker expression. RESULTS: UCB-derived autoserum was a viable source for the culture and implantation of UC MSCs. The osteoblastic differentiation potential of UC-MSCs was demonstrated in nude mice by performing immunohistochemical staining and by the presence of osteoblast marker expression. CONCLUSIONS: Our results confirm the osteogenic potential of UC-MSCs and provide basic evidence for the realization of regenerative medicine using autologous tissues. PMID- 22503081 TI - Application of custom-made bioresorbable raw particulate hydroxyapatite/poly-L lactide mesh tray with particulate cellular bone and marrow and platelet-rich plasma for a mandibular defect: evaluation of tray fit and bone quality in a dog model. AB - The purpose of this study was to evaluate tray fit and bone quality of particulate cancellous bone and marrow (PCBM) mandibular reconstruction using custom-made bioresorbable forged composites of a raw particulate hydroxyapatite/poly-L-lactide (HA/PLLA) tray in a dog model. Mesh sheets of HA/PLLA were formed in a tray shape according to the mandible stereolithographs of 14 beagle dogs. Platelet-rich plasma (PRP) was obtained from venous blood, and PCBM was harvested from the iliac crest. Bone defects were made bilaterally on the lower borders of the mandible. The PCBM and PRP were mixed and compressed into the defects and a custom-made HA/PLLA or a manually adopted titanium tray was fixed by screws. Tray fit and bone qualities were evaluated using computed tomography, microfocus computed tomography and confocal laser scanning microscopy. In buccal side, there is no significant difference with tray fit between the HA/PLLA and the titanium type, but in lingual side, it was better in the HA/PLLA type than that of the Ti type. Bone volume fraction (BV/TV) had markedly increased on the HA/PLLA side at 12 months. In conclusion, the custom made HA/PLLA tray was easily and accurately adapted to the mandible, and had achieved sufficient bone quality by 12 months. PMID- 22503082 TI - Segmental stability of resorbable P(L/DL)LA-TMC osteosynthesis versus titanium miniplates in orthognatic surgery. AB - After two decades of the use of resorbable miniplates, new polymer compositions for resorbable osteosynthesis are still being developed to make the handling and outcome of operations even more predictable and give higher stability to the repositioned segments. This study investigates a new resorbable osteosynthesis system in orthognathic patients. 50 patients were treated with P(L/DL)LA-TMC resorbable osteosynthesis and compared to a group of 50 patients treated with titanium miniplates. Segmental stability and relapse were measured comparing preoperative, postoperative and follow-up lateral cephalograms. Throughout this study, resorbables appeared to be as stable as titanium miniplates except in maxillary elongation and mandibular setback. Here, the titanium miniplates showed significantly higher stability than resorbable plates. P(L/DL)LA-TMC osteosynthesis seem to have less strength against compressive forces after maxillary elongation and they are less resistant to the forces the tongue exerts, pressing against the mandible after setback. It can therefore be concluded that the resorbable osteosynthesis can be used in the same situations as titanium miniplates except in maxillary elongation and mandibular setback. PMID- 22503083 TI - The treatment of mandibular condyle fractures: a meta-analysis. AB - BACKGROUND: The treatment for mandibular condyle fractures remains controversial. Conservative management (CM) and open reduction/internal fixation (ORIF) are both used, but the evidence to support superiority of one method over the other has not been assessed. METHODS: We performed a meta-analysis of studies comparing CM versus ORIF in patients with condyle fractures. The primary outcome was post treatment function; we looked at the status of the post-treatment occlusion, mouth opening, protrusion, facial height, pain and the presence of postoperative ankylosis. Furthermore, in studies evaluating ORIF, adverse effects such as facial nerve weakness and scarring, were also recorded. RESULTS: Twenty (20) studies enrolling 1596 patients were eligible. These included four randomized controlled trials (RCTs) and 16 non-randomized case series. Only 1186 of these patients were analyzed by the studies; the reasons for exclusion were rarely clarified. All four RCTs were prospective but the majority (69%) of the remaining studies were retrospective. The inclusion criteria were described in all four RCTs; however, this was not the case in half of the remaining studies (44%). Only four (20%) studies were blinded. Across all included studies, we recorded great variation between treatment protocols, follow-up periods, and outcomes measured. This precluded any quantitative synthesis. In nine studies (45%) the superiority of ORIF over CM reached statistical significance. The incidence of facial nerve weakness following ORIF averaged 6% and it was temporary for the majority of the patients. The identified RCTs were small (160 patients) and suffered from a number of methodological shortcomings. All of them reached statistically significant conclusions favoring ORIF over CM. CONCLUSION: The current meta analysis suggests that ORIF for condylar fractures may be as good or better than CM. The morbidity associated with the operation is low. However, the available evidence is of poor quality and not strong enough to change clinical practice. PMID- 22503084 TI - The phosphorus mass balance: identifying 'hotspots' in the food system as a roadmap to phosphorus security. AB - Phosphorus is a critical element on which all life depends. Global crop production depends on fertilisers derived from phosphate rock to maintain high crop yields. Population increase, changing dietary preferences towards more meat and dairy products, and the continuing intensification of global agriculture supporting this expansion will place increasing pressure on an uncertain, but finite supply of high-quality phosphate rock. Growing concern about phosphorus scarcity and security, coupled with the environmental impact of phosphorus pollution, has encouraged an increase in research exploring how phosphorus is used and lost in the food system-from mine to field to fork. An assessment of recent phosphorus flows analyses at different geographical scales identifies the key phosphorus 'hotspots', for example within the mining, agriculture or food processing sectors, where efficiency and reuse can be substantially improved through biotechnological approaches coupled with policy changes. PMID- 22503085 TI - Measurement of the activity of individual subunits of single molecules of the tetrameric enzyme beta-galactosidase. AB - Escherichia coli beta-galactosidase was incubated in the presence of the slow release inhibitor D-galactal for 30 min at a concentration of 70 times its K(i). The sample was then diluted 20000-fold into buffer containing the fluorogenic substrate 9H-(1,3-dichloro-9,9-dimethylacridin-2-on-7-yl) beta-D-galactoside, reducing the inhibitor concentration to K(i)/280. The sample was subjected to a capillary electrophoresis continuous flow single enzyme molecule assay. As the inhibitor dissociated while the enzyme traveled the length of the capillary, a fraction of molecules showed stepwise increases in activity. This was due to the activation of individual subunits within single molecules. The changes in activity can be largely explained in terms of each molecule containing subunits of indistinguishable activity. PMID- 22503086 TI - Transcript level responses of Plasmodium falciparum to antimycin A. AB - The mitochondrial electron transport chain is essential to Plasmodium and is the target of the antimalarial drug atovaquone. The mitochondrial genomes of Plasmodium sp. are the most reduced known, and the majority of mitochondrial proteins are encoded in the nucleus and imported into the mitochondrion post translationally. Many organisms have signalling pathways between the mitochondria and the nucleus to regulate the expression of nuclear-encoded mitochondrially targeted proteins, for example in response to mitochondrial dysfunction. We have studied the transcript profiles of synchronous Plasmodium falciparum treated with an LD(50) concentration of the complex III inhibitor antimycin A, to investigate whether such pathways exist in the parasite. There was a broad perturbation of gene expression. The differentially expressed genes were enriched for transcripts encoding proteins involved in invasion, stress response, nucleotide biosynthesis and respiration. Some effects were attributable to a delay in the gene expression phase of drug-treated parasites. However, our data indicated regulation of mitochondrial stress response genes and genes involved in pyrimidine biosynthesis, implying the existence of a signalling pathway from the mitochondrion to the nucleus. PMID- 22503087 TI - Detection of rectal cancer and response to concurrent chemoradiotherapy by proton magnetic resonance spectroscopy. AB - INTRODUCTION: To diagnose rectal cancer and monitor treatment response after preoperative concurrent chemoradiotherapy (CCRT) in rectal cancer patients using proton-1 magnetic resonance spectroscopy ((1)H-MRS). MATERIALS AND METHODS: We enrolled 134 rectal cancer patients before treatment, of whom 34 underwent preoperative CCRT and follow-up MR spectroscopy before surgery. (1)H-MRS was performed using a six-channel phased-array coil at 3.0 T. We evaluated the presence of a choline peak at 3.2 ppm, and lipid peaks at 0.9 and 1.3 ppm, and glutamine and glutamate peaks at 2.1-2.3 and 2.7 ppm seen at two TEs (40 and 135 ms). We divided MR spectra patterns into two groups (A and B). RESULTS: A choline peak at 3.2 ppm seen in both TEs was characteristic for rectal cancer before treatment. Of 103 patients, 55 (53%) showed an elevated choline peak before treatment (type A). Type A spectra were seen in 68% of patients (23/34) before preoperative CCRT. After CCRT, the choline peak disappeared, resulting in only the lipid peak at 1.3 ppm (type B) in 97% of patients (33/34). DISCUSSION: We optimized a localized in vivo(1)H-MRS method for detection of rectal adenocarcinoma and monitoring treatment response after preoperative CCRT. The method appears to be a promising and feasible noninvasive modality. PMID- 22503088 TI - Calibration-less multi-coil MR image reconstruction. AB - In parallel magnetic resonance imaging (MRI), the problem is to reconstruct an image given the partial K-space scans from all the receiver coils. Depending on its position within the scanner, each coil has a different sensitivity profile. All existing parallel MRI techniques require estimation of certain parameters pertaining to the sensitivity profile, e.g., the sensitivity map needs to be estimated for the SENSE and SMASH and the interpolation weights need to be calibrated for GRAPPA and SPIRiT. The assumption is that the estimated parameters are applicable at the operational stage. This assumption does not always hold, consequently the reconstruction accuracies of existing parallel MRI methods may suffer. We propose a reconstruction method called Calibration-Less Multi-coil (CaLM) MRI. As the name suggests, our method does not require estimation of any parameters related to the sensitivity maps and hence does not require a calibration stage. CaLM MRI is an image domain method that produces a sensitivity encoded image for each coil. These images are finally combined by the sum-of squares method to yield the final image. It is based on the theory of Compressed Sensing (CS). During reconstruction, the constraint that "all the coil images should appear similar" is introduced within the CS framework. This leads to a CS optimization problem that promotes group-sparsity. The results from our proposed method are comparable (at least for the data used in this work) with the best results that can be obtained from state-of-the-art methods. PMID- 22503089 TI - Ex vivo study of carotid endarterectomy specimens: quantitative relaxation times within atherosclerotic plaque tissues. AB - PURPOSE: Previous studies reporting relaxation times within atherosclerotic plaque have typically used dedicated small-bore high-field systems and small sample sizes. This study reports quantitative T(1), T(2) and T(2) relaxation times within plaque tissue at 1.5 T using spatially co-matched histology to determine tissue constituents. METHODS: Ten carotid endarterectomy specimens were removed from patients with advanced atherosclerosis. Imaging was performed on a 1.5-T whole-body scanner using a custom built 10-mm diameter receive-only solenoid coil. A protocol was defined to allow subsequent computation of T(1), T(2) and T(2) relaxation times using multi-flip angle spoiled gradient echo, multi-echo fast spin echo and multi-echo gradient echo sequences, respectively. The specimens were subsequently processed for histology and individually sectioned into 2-mm blocks to allow subsequent co-registration. Each imaging sequence was imported into in-house software and displayed alongside the digitized histology sections. Regions of interest were defined to demarcate fibrous cap, connective tissue and lipid/necrotic core at matched slice locations. Relaxation times were calculated using Levenberg-Marquardt's least squares curve fitting algorithm. A linear-mixed effect model was applied to account for multiple measurements from the same patient and establish if there was a statistically significant difference between the plaque tissue constituents. RESULTS: T(2) and T(2) relaxation times were statistically different between all plaque tissues (P=.026 and P=.002 respectively) [T(2): lipid/necrotic core was lower 47 +/- 13.7 ms than connective tissue (67 +/- 22.5 ms) and fibrous cap (60 +/- 13.2 ms); T(2): fibrous cap was higher (48 +/- 15.5 ms) than connective tissue (19 +/- 10.6 ms) and lipid/necrotic core (24 +/- 8.2 ms)]. T(1) relaxation times were not significantly different (P=.287) [T(1): Fibrous cap: 933 +/- 271.9 ms; connective tissue (1002 +/- 272.9 ms) and lipid/necrotic core (1044 +/- 304.0 ms)]. We were unable to demarcate hemorrhage and calcium following histology processing. CONCLUSIONS: This study demonstrates that there is a significant difference between qT(2) and qT(2) in plaque tissues types. Derivation of quantitative relaxation times shows promise for determining plaque tissue constituents. PMID- 22503090 TI - Multicontrast multiecho FLASH MRI for targeting the subthalamic nucleus. AB - The subthalamic nucleus (STN) is one of the most common stimulation targets for treating Parkinson's disease using deep brain stimulation (DBS). This procedure requires precise placement of the stimulating electrode. Common practice of DBS implantation utilizes microelectrode recording to locate the sites with the correct electrical response after an initial location estimate based on a universal human brain atlas that is linearly scaled to the patient's anatomy as seen on the preoperative images. However, this often results in prolonged surgical time and possible surgical complications since the small-sized STN is difficult to visualize on conventional magnetic resonance (MR) images and its intersubject variability is not sufficiently considered in the atlas customization. This paper proposes a multicontrast, multiecho MR imaging (MRI) method that directly delineates the STN and other basal ganglia structures through five co-registered image contrasts (T1-weighted navigation image, R2 map, susceptibility-weighted imaging (phase, magnitude and fusion image)) obtained within a clinically acceptable time. The image protocol was optimized through both simulation and in vivo experiments to obtain the best image quality. Taking advantage of the multiple echoes and high readout bandwidths, no interimage registration is required since all images are produced in one acquisition, and image distortion and chemical shift are reduced. This MRI protocol is expected to mitigate some of the shortcomings of the state-of-the-art DBS implantation methods. PMID- 22503091 TI - Cardiovascular magnetic resonance for the assessment of pulmonary arterial hypertension: toward a comprehensive CMR exam. AB - Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by abnormally increased blood pressure of the pulmonary circulation. The clinical course of the untreated PAH involves rapid progression to right ventricular (RV) failure and death. Right heart catheterization is the gold-standard method for confirming PAH. However, the technique's invasiveness and associated risks preclude its use on a regular basis. Different imaging techniques have been implemented for evaluating PAH, including echocardiography, computed tomography and nuclear medicine. However, these techniques have their own limitations. During the past decade, cardiovascular magnetic resonance (CMR) has been increasingly used for the evaluation of different cardiovascular diseases, including PAH, due to its high resolution, high tissue contrast, and the plethora of anatomical and physiological parameters that can be measured with this modality. This article presents an up-to-date review of the implementation of CMR for evaluating PAH. This is achieved by describing a comprehensive CMR protocol that includes several imaging sequences for assessing different cardiovascular parameters pertaining to PAH. In contrast to the previously published articles, the presented CMR protocol evaluates both RV function and pulmonary artery hemodynamics, which are both affected in PAH. Each imaging sequence is explained along with the image analysis steps required for deriving the cardiovascular parameters of interest. Then, based on an extensive literature review, the article illustrates the significance of the derived cardiovascular parameters and their association with PAH. The article concludes with a discussion of the advantages of the proposed CMR exam for better understanding of the disease pathophysiology and treatment planning. PMID- 22503092 TI - Pediatric primary and metastatic neuroblastoma: MRI findings: pictorial review. AB - Magnetic resonance imaging (MRI) has become one of the most valuable modalities for initial and follow-up imaging of suspected or known neuroblastoma (NBL) owing to its excellent inherent contrast, lack of ionizing radiation and multiplanar imaging capability. Importantly, NBL has a variable appearance on different imaging modalities, and this is particularly pertinent to MRI. MRI is a cornerstone for management of NBL, providing essential information at initial presentation regarding diagnosis, staging, resectability and relation to vital structures. It can also define the extent of residual disease after surgical resection or assess the efficacy of treatment. Follow-up MRI is frequently performed to ensure sustained complete remission or to monitor known residual disease. This pictorial review article aims to provide the reader with a concise, yet comprehensive, collection of MR images of primary and metastatic NBL lesions with relevant correlation with other imaging modalities. PMID- 22503093 TI - Signal displacement in spiral-in acquisitions: simulations and implications for imaging in SFG regions. AB - Susceptibility field gradients (SFGs) cause problems for functional magnetic resonance imaging (fMRI) in regions like the orbital frontal lobes, leading to signal loss and image artifacts (signal displacement and "pile-up"). Pulse sequences with spiral-in k-space trajectories are often used when acquiring fMRI in SFG regions such as inferior/medial temporal cortex because it is believed that they have improved signal recovery and decreased signal displacement properties. Previously postulated theories explain differing reasons why spiral in appears to perform better than spiral-out; however it is clear that multiple mechanisms are occurring in parallel. This study explores differences in spiral in and spiral-out images using human and phantom empirical data, as well as simulations consistent with the phantom model. Using image simulations, the displacement of signal was characterized using point spread functions (PSFs) and target maps, the latter of which are conceptually inverse PSFs describing which spatial locations contribute signal to a particular voxel. The magnitude of both PSFs and target maps was found to be identical for spiral-out and spiral-in acquisitions, with signal in target maps being displaced from distant regions in both cases. However, differences in the phase of the signal displacement patterns that consequently lead to changes in the intervoxel phase coherence were found to be a significant mechanism explaining differences between the spiral sequences. The results demonstrate that spiral-in trajectories do preserve more total signal in SFG regions than spiral-out; however, spiral-in does not in fact exhibit decreased signal displacement. Given that this signal can be displaced by significant distances, its recovery may not be preferable for all fMRI applications. PMID- 22503094 TI - Polynomial fitting of DT-MRI fiber tracts allows accurate estimation of muscle architectural parameters. AB - Fiber curvature is a functionally significant muscle structural property, but its estimation from diffusion-tensor magnetic resonance imaging fiber tracking data may be confounded by noise. The purpose of this study was to investigate the use of polynomial fitting of fiber tracts for improving the accuracy and precision of fiber curvature (kappa) measurements. Simulated image data sets were created in order to provide data with known values for kappa and pennation angle (theta). Simulations were designed to test the effects of increasing inherent fiber curvature (3.8, 7.9, 11.8 and 15.3 m(-1)), signal-to-noise ratio (50, 75, 100 and 150) and voxel geometry (13.8- and 27.0-mm(3) voxel volume with isotropic resolution; 13.5-mm(3) volume with an aspect ratio of 4.0) on kappa and theta measurements. In the originally reconstructed tracts, theta was estimated accurately under most curvature and all imaging conditions studied; however, the estimates of kappa were imprecise and inaccurate. Fitting the tracts to second order polynomial functions provided accurate and precise estimates of kappa for all conditions except very high curvature (kappa=15.3 m(-1)), while preserving the accuracy of the theta estimates. Similarly, polynomial fitting of in vivo fiber tracking data reduced the kappa values of fitted tracts from those of unfitted tracts and did not change the theta values. Polynomial fitting of fiber tracts allows accurate estimation of physiologically reasonable values of kappa, while preserving the accuracy of theta estimation. PMID- 22503095 TI - The relationship of visfatin levels with insulin resistance and left ventricular hypertrophy in peritoneal dialysis patients. AB - BACKGROUND/OBJECTIVES: Cardiovascular abnormalities are common in patients with chronic kidney disease. Visfatin influences lipid metabolism, insulin sensitivity, and cardiovascular health. The aim of this study was to explore the relation of serum visfatin to cardiovascular risk factors in nondiabetic peritoneal dialysis (PD) patients. PATIENTS AND METHODS: Eighty-seven nondiabetic patients (mean age 48 +/- 15 years, 39 males) under PD were enrolled. Weight, anthropometric measurements, blood pressure, biochemical parameters, and insulin resistance (homeostatic model assessment-insulin resistance-HOMA-IR) were measured. Visfatin was measured and left ventricular mass index (LVMI) was calculated by echocardiography. RESULTS: LVMI was correlated with body mass index (BMI; r = 0.47, p = 0.01), systolic blood pressure (SBP; r = 0.62, p = 0.04), and serum visfatin levels (r = 0.49, p = 0.03). According to HOMA-IR levels patients were grouped as insulin-resistant (IR) (HOMA-IR >=2.0, n = 35) and noninsulin resistant (non-IR) (HOMA-IR <2.0, n = 52) groups. The IR group had longer PD duration and higher BMI, total cholesterol, uric acid, and serum visfatin levels (p < 0.05). The study patients were divided into three groups according to their serum visfatin levels. Group 1 (<=34 ng/mL, n = 22) was considered as the lowest tertile of low visfatin and group 2 (35-42 ng/mL, n = 43) and group 3 (>=43 ng/mL, n = 22) in the upper tertile. Considering the visfatin groups, group 3 patients had significantly higher BMI (p = 0.00), total cholesterol (p = 0.03), C reactive protein (CRP) (p = 0.03), HOMA-IR (p = 0.03), and LVMI (p = 0.02). In regression analysis, SBP (beta = 0.19, p < 0.05) and serum visfatin levels (beta = 0.74, p < 0.05) were independent variables affecting LVMI. CONCLUSION: Serum visfatin might be a sensitive marker than HOMA-IR evaluations for cardiac performance in nondiabetic PD patients. PMID- 22503096 TI - Identification of basepairs within Tn5 termini that are critical sfor H-NS binding to the transpososome and regulation of Tn5 transposition. AB - BACKGROUND: The H-NS protein is a global regulator of gene expression in bacteria and can also bind transposition complexes (transpososomes). In Tn5 transposition H-NS promotes transpososome assembly in vitro and disruption of the hns gene causes a modest decrease in Tn5 transposition (three- to five-fold). This is consistent with H-NS acting as a positive regulator of Tn5 transposition. Molecular determinants for H-NS binding to the Tn5 transpososome have not been determined, nor has the strength of the interaction been established. There is also uncertainty as to whether H-NS regulates Tn5 transposition in vivo through an interaction with the transposition machinery as disruption of the hns gene has pleiotropic effects on Escherichia coli, the organism used in this study. RESULTS: In the current work we have further examined determinants for H-NS binding to the Tn5 transpososome through both mutational studies on Tn5 termini (or 'transposon ends') and protein-protein cross-linking analysis. We identify mutations in two different segments of the transposon ends that abrogate H-NS binding and characterize the affinity of H-NS for wild type transposon ends in the context of the transpososome. We also show that H-NS forms cross-links with the Tn5 transposase protein specifically in the transpososome, an observation consistent with the two proteins occupying overlapping binding sites in the transposon ends. Finally, we make use of the end mutations to test the idea that H-NS exerts its impact on Tn5 transposition in vivo by binding directly to the transpososome. Consistent with this possibility, we show that two different end mutations reduce the sensitivity of the Tn5 system to H-NS regulation. CONCLUSIONS: H-NS typically regulates cellular functions through its potent transcriptional repressor function. Work presented here provides support for an alternative mechanism of H-NS-based regulation, and adds to our understanding of how bacterial transposition can be regulated. PMID- 22503097 TI - Continuous production of drug nanoparticle suspensions via wet stirred media milling: a fresh look at the Rehbinder effect. AB - Nanoparticles of BCS Class II drugs are produced in wet stirred media mills operating in batch or recirculation mode with the goal of resolving the poor water-solubility issue. Scant information is available regarding the continuous production of drug nanoparticles via wet media milling. Griseofulvin and Naproxen were milled in both recirculation mode and multi-pass continuous mode to study the breakage dynamics and to determine the effects of suspension flow rate. The evolution of the median particle size was measured and described by an empirical breakage model. We found that these two operation modes could produce drug nanosuspensions with similar particle size distributions (PSDs). A reduced suspension flow rate slowed the breakage rate and led to a wider PSD and more differentiation between the two operation modes. The latter part of this study focused on the roles of stabilizers (hydroxypropyl cellulose and sodium lauryl sulfate) and elucidation of the so-called Rehbinder effect (reduction in particle strength due to adsorbed stabilizers such as polymers and surfactants). Milling the drugs in the absence of the stabilizers produced primary nanoparticles and their aggregates, while milling with the stabilizers produced smaller primary nanoparticles with minimal aggregation. Using laser diffraction, BET nitrogen adsorption, scanning electron microscopy imaging, and a microhydrodynamic analysis of milling, this study, for the first time, provides sufficient evidence for the existence of the Rehbinder effect during the milling of drugs. Not only do the polymers and surfactants allow proper stabilization of the nanoparticles in the suspensions, but they also do facilitate drug particle breakage. PMID- 22503098 TI - Evaluation of the influence of homopolymerization on the removal of water insoluble organics by grafted polypropylene fibers. AB - Lauryl acrylate (LA) grafted polypropylene (PP) fibers (PP-g-LA) were prepared via ultraviolet radiation and used to adsorb insoluble organics from aqueous solutions. The grafted fibers showed a maximum adsorption capacity of 18.85 g/g for benzene, while the adsorption capacity of the original PP fiber was only 8.21 g/g. However, graft polymerization is usually accompanied by the homopolymerization phenomenon, which is detrimental to practical applications of the grafted fiber. Homopolymerization negatively affected the adsorption capacities and the reusabilities of the grafted fibers, which decreased with increasing rates of homopolymerization. The adsorption capacity of grafted fiber with a homopolymerization rate of 18.40% was maintained above 85% of its initial adsorption capacity after being regenerated 10 times, while the adsorption capacity of the grafted fiber with a homopolymerization rate of 70.51% was approximately 40% of its initial capacity after 10 regenerations. PMID- 22503099 TI - Laser-assisted nasal decolonization of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus. AB - OBJECTIVES: Methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin resistant S aureus (MRSA) contribute to 25% of nosocomial infections, increasing complications, health care cost, and growing antibiotic resistance. Nasal decolonization (ND) can reduce the staphylococcal infection rate. A new method of laser therapy (LT) MRSA ND was tested. STUDY DESIGN: This is a prospective, nonrandomized study. METHODS: Following institutional review board approvals, 25 patients colonized with MSSA/MRSA were allocated to 4 treatment arms; low-power, dual-wavelength 870-/930-nm laser alone (GR1); low-power, dual-wavelength laser followed by erythromycin (E-mycin) cream (GR2); low-power, dual-wavelength laser followed by peroxide irrigation (GR3); and high-power 940-nm laser alone (GR4). Quantitative cultures were obtained before and after in all arms. Laser therapy was performed via a laser fiber diffuser, delivering 200 to 600 J/cm2 to each naris circumferentially. Patient's distribution was 3 in GR1, 14 in GR2, 4 in GR3, and 4 in GR4 (last 10 recruited to GR4). RESULTS: Nasal decolonization for GR1, GR2, GR3, and GR4 was 1 of 3, 13 of 14, 2 of 4, and 4 of 4, respectively. Because LT + E-mycin cleared all first 3 patients of MRSA and MSSA, all remaining patients were treated with LT + Er with over 90% of patients clearing. No adverse events or discomfort were reported. CONCLUSIONS: First human study using LT and topical E-mycin in ND is presented. Laser therapy can eradicate MRSA and potentially resensitization of bacteria to the antimicrobial effect of erythromycin. Although decolonization was maintained at 4 weeks posttreatment, further studies can determine the LT long-term effect. PMID- 22503100 TI - Traumatic gallbladder rupture. PMID- 22503101 TI - Cholangioscopy in a patient with Roux-en-Y limb via a gastric access loop. PMID- 22503102 TI - Staufen1-mediated mRNA decay functions in adipogenesis. AB - The double-stranded RNA binding protein Staufen1 (Stau1) is involved in diverse gene expression pathways. For Stau1-mediated mRNA decay (SMD) in mammals, Stau1 binds to the 3' untranslated region of target mRNA and recruits Upf1 to elicit rapid mRNA degradation. However, the events downstream of Upf1 recruitment and the biological importance of SMD remain unclear. Here we show that SMD involves PNRC2, decapping activity, and 5'-to-3' exonucleolytic activity. In particular, Upf1 serves as an adaptor protein for the association of PNRC2 and Stau1. During adipogenesis, Stau1 and PNRC2 increase in abundance, Upf1 becomes hyperphosphorylated, and consequently SMD efficiency is enhanced. Intriguingly, downregulation of SMD components attenuates adipogenesis in a way that is rescued by downregulation of an antiadipogenic factor, Kruppel-like factor 2 (KLF2), the mRNA of which is identified as a substrate of SMD. Our data thus identify a biological role for SMD in adipogenesis. PMID- 22503103 TI - A redox-regulated SUMO/acetylation switch of HIPK2 controls the survival threshold to oxidative stress. AB - Moderate concentrations of reactive oxygen species (ROS) serve as coregulatory signaling molecules, whereas exceedingly high concentrations trigger cell death. Here, we identify ROS-induced acetylation of the proapoptotic kinase HIPK2 as a molecular mechanism that controls the threshold discerning sensitivity from resistance toward ROS-mediated cell death. SUMOylation of HIPK2 at permissive ROS concentrations allows the constitutive association of HDAC3 and keeps HIPK2 in the nonacetylated state. Elevated ROS concentrations prevent SUMOylation of HIPK2 and, consequently, reduce association of HDAC3, thus leading to the acetylation of HIPK2. Reconstitution experiments showed that HIPK2-dependent genes cause decreased ROS levels. Although a nonacetylatable HIPK2 mutant enhanced ROS induced cell death, an acetylation-mimicking variant ensured cell survival even under conditions of high oxidative stress. PMID- 22503104 TI - Precursor microRNA-programmed silencing complex assembly pathways in mammals. AB - Assembly of microRNA ribonucleoproteins (miRNPs) or RNA-induced silencing complexes (RISCs) is essential for the function of miRNAs and initiates from processing of precursor miRNAs (pre-miRNAs) by Dicer or by Ago2. Here, we report an in vitro miRNP/RISC assembly assay programmed by pre-miRNAs from mammalian cell lysates. Combining in vivo studies in Dicer Knockout cells reconstituted with wild-type or catalytically inactive Dicer, we find that the miRNA loading complex (miRLC) is the primary machinery linking pre-miRNA processing to miRNA loading. We show that a miRNA precursor deposit complex (miPDC) plays a crucial role in Dicer-independent miRNA biogenesis and promotes miRNP assembly of certain Dicer-dependent miRNAs. Furthermore, we find that 5'-uridine, 3'-mid base pairing, and 5'-mid mismatches within pre-miRNAs promote their assembly into miPDC. Our studies provide a comprehensive view of miRNP/RISC assembly pathways in mammals, and our assay provides a versatile platform for further mechanistic dissection of such pathways in mammals. PMID- 22503106 TI - [Autoimmune hepatitis triggered by consumption of Goji berries]. PMID- 22503105 TI - Tacrolimus versus intravenous pulse cyclophosphamide therapy in Chinese adults with steroid-resistant idiopathic minimal change nephropathy: a multicenter, open label, nonrandomized cohort trial. AB - BACKGROUND: The treatment of steroid-resistant minimal change nephropathy (SR MCN) in adults remains a challenge to nephrologists. Although immunosuppressants such as cyclophosphamide (CTX), chlorambucil, and cyclosporin A have been used in these patients, their use has been limited by low remission rates and severe adverse effects. Alternative immunosuppressive treatments for SR-MCN are therefore needed. OBJECTIVE: The aim of this study was to compare the efficacy of tacrolimus (TAC) with that of intravenous (IV) pulse CTX therapy in the management of SR-MCN and to assess the tolerability of those treatments. METHODS: This was a nonrandomized, case-matched trial in Chinese adults with SR-MCN. Patients were self-assigned to either: (1) combination therapy with prednisone and oral TAC; or (2) combination therapy with prednisone and IV CTX. TAC was initiated at 0.05 mg/kg/d and was adjusted to maintain a trough blood level of 5 to 10 ng/mL for 1 year. CTX was initiated at 1 g/1.73 m(2) for a total dosage of 10 g/1.73 m(2) over 1 year. In both groups, oral prednisone was initiated at 0.5 mg/kg/d for 3 months but was tapered off to complete cessation by 6 months. RESULTS: A total of 37 patients were enrolled (21 in the TAC group; 16 in the CTX group), of whom 33 (19 in the TAC group; 14 in the CTX group) completed the study. There were no significant difference in baseline demographic characteristics between the two treatment groups (The TAC group-mean age at onset, 28.8 [11.3]; mean age at trial, 29.6 [11.0]; male, 63.16%; The CTX group mean age at onset, 34.4 [12.7]; mean age at trial, 35.9 [12.7]; male, 57.14%). The remission rates were 57.9%, 73.7%, and 78.9% in the TAC group and 14.3%, 42.9%, and 50.0% in the CTX group after 2, 4, and 6 months, respectively. The remission rate at 2 months was significantly higher in the TAC group than in the CTX group (P < 0.05). The remission rates during the 1-year therapy and the 1 year follow-up were higher in the TAC group than in the CTX group (Kaplan-Meier curve, log-rank test, P < 0.001). For patients who achieved remission, the mean (SD) time needed for remission was 48.7 (36.0) days in the TAC group and 85.3 (40.6) days in the CTX group (P < 0.05). During the 1-year therapy and 1-year follow-up periods, 6 of the 15 TAC-treated patients and 1 of the 7 CTX-treated patients relapsed (P = 0.35). CONCLUSIONS: These findings suggest that TAC therapy was effective compared with IV pulse CTX therapy in treating this select group of Chinese adults with SR-MCN. Both agents were well tolerated although TAC seemed to induce remission more rapidly than IV pulse CTX therapy. Australian New Zealand Clinical Trials Registry: study number ACTR 00362050. PMID- 22503107 TI - [Ipratropium bromide-induced anisocoria during non-invasive ventilation]. PMID- 22503108 TI - Measuring research influence on drug policy: a case example of two epidemiological monitoring systems. AB - BACKGROUND: Assessing the extent to which drug research influences and impacts upon policy decision-making needs to go beyond bibliometric analysis of academic citations. Policy makers do not necessarily access the academic literature, and policy processes are largely iterative and rely on interactions and relationships. Furthermore, media representation of research contributes to public opinion and can influence policy uptake. In this context, assessing research influence involves examining the extent to which a research project is taken up in policy documents, used within policy processes, and disseminated via the media. METHODS: This three component approach is demonstrated using a case example of two ongoing illicit drug monitoring systems: the Illicit Drug Reporting System (IDRS) and the Ecstasy and related Drugs Reporting System (EDRS). Systematic searches for reference to the IDRS and/or EDRS within policy documents, across multiple policy processes (such as parliamentary inquiries) and in the media, in conjunction with analysis of the types of mentions in these three sources, enables an analysis of policy influence. The context for the research is also described as the foundation for the approach. RESULTS: The application of the three component approach to the case study demonstrates a practical and systematic retrospective approach to measure drug research influence. For example, the ways in which the IDRS and EDRS were mentioned in policy documents demonstrated research utilisation. Policy processes were inclusive of IDRS and EDRS findings, while the media analysis revealed only a small contribution in the context of wider media reporting. CONCLUSION: Consistent with theories of policy processes, assessing the extent of research influence requires a systematic analysis of policy documents and processes. Development of such analyses and associated methods will better equip researchers to evaluate the impact of research. PMID- 22503109 TI - A water-soluble Pybox derivative and its highly luminescent lanthanide ion complexes. AB - A new water-soluble Pybox ligand, 1, has been synthesized and found to crystallize in the monoclinic P2(1)/n space group with unit cell parameters a = 6.0936(1) A, b = 20.5265(4) A, c = 12.0548(2) A, and beta = 90.614(1) degrees . In the crystal, a water molecule is bound through hydrogen-bonding interactions to the nitrogen atoms of the oxazoline rings. This ligand was used to complex a variety of lanthanide ions, opening up new avenues for luminescence and catalysis in aqueous environment. These complexes are highly luminescent in aqueous solutions, in acetonitrile, and in the solid state. Aqueous quantum yields are high at 30.4% for Eu(III), 26.4% for Tb(III), 0.32% for Yb(III), and 0.11% for Nd(III). Er(III) did not luminesce in water, but an emission efficiency of 0.20% could be measured in D(2)O. Aqueous emission lifetimes were also determined for the visible emitting lanthanide ions and are 1.61 ms for Eu(III) and 1.78 ms for Tb(III). Comparing emission lifetimes in deuterated and nondeuterated water indicates that no water molecules are coordinated to the metal ion. Speciation studies show that three species form successively in solution and the log beta values are 5.3, 9.6, and 13.8 for Eu(III) and 5.3, 9.2, and 12.7 for Tb(III) for 1:1, 2:1, and 3:1 ligand to metal ratios, respectively. PMID- 22503111 TI - Optogenetics and psychiatry: applications, challenges, and opportunities. PMID- 22503112 TI - [Cerebral aspergillosis in an human immunodeficiency virus infected patient]. PMID- 22503110 TI - Social dominance in female monkeys: dopamine receptor function and cocaine reinforcement. AB - BACKGROUND: Brain imaging and behavioral studies suggest an inverse relationship between dopamine (DA) D2/D3 receptors and vulnerability to cocaine abuse, although most research has used males. For example, male monkeys that become dominant in a social group have significant elevations in D2/D3 receptor availability and are less vulnerable to cocaine reinforcement. METHODS: DA D2/D3 receptor availability was assessed in female cynomolgus monkeys (n = 16) with positron emission tomography (PET) while they were individually housed, 3 months after stable social hierarchies had formed, and again when individually housed. In addition, PET was used to examine changes in dopamine transporter (DAT) availability after social hierarchy formation. After imaging studies were complete, monkeys received implantation with indwelling intravenous catheters and self-administered cocaine (.001-.1 mg/kg/injection) under a fixed-ratio 30 schedule of reinforcement. Acquisition of cocaine reinforcement occurred when response rates were significantly higher than when saline was self-administered. RESULTS: Neither DAT nor D2/D3 receptor availability in the caudate nucleus and putamen was predictive of social rank, but both significantly changed after formation of social hierarchies. DA D2/D3 receptor availability significantly increased in females that became dominant, whereas DAT availability decreased in subordinate females. Dominant female monkeys acquired cocaine reinforcement at significantly lower doses than subordinate monkeys. CONCLUSIONS: The relationship between D2/D3 receptor availability and vulnerability to cocaine reinforcement seems, on the basis of these findings, opposite in females and males. These data indicate that the social environment profoundly affects the DA system but does so in ways that have different functional consequences for females than for males. PMID- 22503113 TI - Rickettsia typhi. A new causative agent of round pneumonia in adults. PMID- 22503114 TI - [Acute hydrocephalus as a presentation form of disseminated aspergillosis]. PMID- 22503115 TI - Beyond alpha-synuclein transfer: pathology propagation in Parkinson's disease. AB - alpha-Synuclein (alpha-syn) is the most abundant protein found in Lewy bodies, a hallmark of Parkinson's disease (PD), and can aggregate to form toxic oligomers and fibrillar structures. Recent studies have shown that alpha-syn can be transmitted between neurons and can seed the formation of toxic aggregates in recipient neurons in a prion-like manner. In addition, it is known that Lewy body pathology may spread gradually and systematically from the peripheral or enteric nervous system or olfactory bulb to specific brain regions during progression of idiopathic PD. It is therefore conceivable that alpha-syn species could act as seeds that drive PD progression. Here, we review recent advances from studies of alpha-syn cell-to-cell transfer, the current understanding of alpha-syn toxicity, and how these relate to progression of PD pathology. PMID- 22503116 TI - MARCH1 down-regulation in IL-10-activated B cells increases MHC class II expression. AB - IL-10 is vastly studied for its anti-inflammatory properties on most immune cells. However, it has been reported that IL-10 activates B cells, up-regulates their MHC class II molecules and prevents apoptosis. As MARCH1 was shown to be responsible for the intracellular sequestration of MHC class II molecules in dendritic cells and monocytes in response to IL-10, we set out to clarify the role of this ubiquitin ligase in B cells. Here, we demonstrate in mice that splenic follicular B cells represent the major cell population that up-regulate MHC II molecules in the presence of IL-10. Activation of these cells through TLR4, CD40 or the IL-10 receptor caused the down-regulation of MARCH1 mRNA. Accordingly, B cells from MARCH1-deficient mice do not up-regulate I-A(b) in response to IL-10. In all, our results demonstrate that IL-10 can have opposite effects on MARCH1 regulation in different cell types. PMID- 22503117 TI - Amnesic disorders. AB - Memory disturbances frequently occur after brain damage, but can be associated with psychiatric illnesses as well. Amnesia--the most severe form of memory impairment--has several variants, including anterograde and retrograde amnesia, material-specific and modality-specific amnesia, and transient global amnesia. We searched databases to obtain an overview of amnesia research from the past 5 years. Research into amnesia has increased exponentially, probably because of the availability of modern brain-imaging techniques. In line with the view that memory is not a unity but is organised into several systems, amnesia is described as a multifaceted disease with a frequently poor prognosis. PMID- 22503118 TI - Bullying at Barts. PMID- 22503119 TI - Bullying at Barts. PMID- 22503120 TI - Magnetic resonance imaging and aneurysm clips. AB - The problem of implanted metals causing tissue damage by movement in patients exposed to MRI fields has produced a confusing welter of erroneous, pseudoscientific publications about magnetics, metals, medical equipment, and tissue compatibility. Quite simply, among the devices made for implantation, only those fabricated of stainless steel have the ferromagnetic properties capable of causing such accidents. The author, who introduced the basic design of the modern aneurysm clip in the late 1960s and then a cobalt nickel alloy as an improvement over steel, while chairing the neurosurgical committee assigned to the task of establishing neurosurgical standards at American Society for Testing and Materials, exposes this flawed information and offers clear guidelines for avoiding trouble. PMID- 22503121 TI - Tuberculum sellae. PMID- 22503122 TI - Occult tumors presenting with negative imaging: analysis of the literature. AB - OBJECT: Some patients presenting with neurological symptoms and normal findings on imaging studies may harbor occult brain tumors that are undetectable on initial imaging. The purpose of this study was to analyze the cases of occult brain tumors reported in the literature and to determine their modes of presentation and time to diagnosis on imaging studies. METHODS: A review of the literature was performed using PubMed. The authors found 15 articles reporting on a total of 60 patients with occult tumors (including the authors' illustrative case). RESULTS: Seizures were the mode of initial presentation in a majority (61.7%) of patients. The initial imaging was CT scanning in 55% and MRI in 45%. The mean time to diagnosis for occult brain tumors was 10.3 months (median 4 months). The time to diagnosis (mean 7.5 months, median 3.2 months) was shorter (p = 0.046) among patients with seizures. Glioblastoma multiforme (GBM) was found more frequently among patients with seizures (67.6% vs 34.8%, p = 0.013). The average time to diagnosis of GBM was shorter than the time to diagnosis of other tumors; the median time to diagnosis was 3.2 months for GBM and 6 months for other tumors (p = 0.04). There was no predilection for side or location of occult tumors. In adult patients, seizures may be predictive of left-sided tumors (p = 0.04). CONCLUSIONS: Based on the results of this study, the authors found that in patients with occult brain tumors, the time to diagnosis is shorter among patients with seizures and also among those with GBM. PMID- 22503124 TI - Natural history of neurofibromatosis Type 2 tumors. PMID- 22503123 TI - Long-term natural history of neurofibromatosis Type 2-associated intracranial tumors. AB - OBJECT: Neurofibromatosis Type 2 (NF2) is a heritable tumor predisposition syndrome that leads to the development of multiple intracranial tumors, including meningiomas and schwannomas. Because the natural history of these tumors has not been determined, their optimal management has not been established. To define the natural history of NF2-associated intracranial tumors and to optimize management strategies, the authors evaluated long-term clinical and radiographic data in patients with NF2. METHODS: Consecutive NF2 patients with a minimum of 4 years of serial clinical and MRI follow-up were analyzed. RESULTS: Seventeen patients, 9 males and 8 females, were included in this analysis (mean follow-up 9.5+/-4.8 years, range 4.0-20.7 years). The mean age at initial evaluation was 33.2+/-15.5 years (range 12.3-57.6 years). Patients harbored 182 intracranial neoplasms, 164 of which were assessable for growth rate analysis (18 vestibular schwannomas [VSs], 11 nonvestibular cranial nerve [CN] schwannomas, and 135 meningiomas) and 152 of which were assessable for growth pattern analysis (15 VSs, 9 nonvestibular CN schwannomas, and 128 meningiomas). New tumors developed in patients over the course of the imaging follow-up: 66 meningiomas, 2 VSs, and 2 nonvestibular CN schwannomas. Overall, 45 tumors (29.6%) exhibited linear growth, 17 tumors (11.2%) exhibited exponential growth, and 90 tumors (59.2%) displayed a saltatory growth pattern characterized by alternating periods of growth and quiescence (mean quiescent period 2.3+/-2.1 years, range 0.4-11.7 years). Further, the saltatory pattern was the most frequently identified growth pattern for each tumor type: meningiomas 60.9%, VSs 46.7%, and nonvestibular schwannoma 55.6%. A younger age at the onset of NF2-related symptoms (p=0.01) and female sex (p=0.05) were associated with an increased growth rate in meningiomas. The identification of saltatory growth in meningiomas increased with the duration of follow-up (p=0.01). CONCLUSIONS: Neurofibromatosis Type 2-associated intracranial tumors most frequently demonstrated a saltatory growth pattern. Because new tumors can develop in NF2 patients over their lifetime and because radiographic progression and symptom formation are unpredictable, resection may be best reserved for symptom-producing tumors. Moreover, establishing the efficacy of nonsurgical therapeutic interventions must be based on long-term follow-up (several years). PMID- 22503125 TI - Dual regeneration of muscle and nerve by intravenous administration of human amniotic fluid-derived mesenchymal stem cells regulated by stromal cell-derived factor-1alpha in a sciatic nerve injury model. AB - OBJECT: Human amniotic fluid-derived mesenchymal stem cells (AFMSCs) have been shown to promote peripheral nerve regeneration. The expression of stromal cell derived factor-1alpha (SDF-1alpha) in the injured nerve exerts a trophic effect by recruiting progenitor cells that promote nerve regeneration. In this study, the authors investigated the feasibility of intravenous administration of AFMSCs according to SDF-1alpha expression time profiles to facilitate neural regeneration in a sciatic nerve crush injury model. METHODS: Peripheral nerve injury was induced in 63 Sprague-Dawley rats by crushing the left sciatic nerve using a vessel clamp. The animals were randomized into 1 of 3 groups: Group I, crush injury as the control; Group II, crush injury and intravenous administration of AFMSCs (5 * 10(6) cells for 3 days) immediately after injury (early administration); and Group III, crush injury and intravenous administration of AFMSCs (5 * 10(6) cells for 3 days) 7 days after injury (late administration). Evaluation of neurobehavior, electrophysiological study, and assessment of regeneration markers were conducted every week after injury. The expression of SDF-1alpha and neurotrophic factors and the distribution of AFMSCs in various time profiles were also assessed. RESULTS: Stromal cell-derived factor 1alpha increased the migration and wound healing of AFMSCs in vitro, and the migration ability was dose dependent. Crush injury induced the expression of SDF 1alpha at a peak of 10-14 days either in nerve or muscle, and this increased expression paralleled the expression of its receptor, chemokine receptor type-4 (CXCR-4). Most AFMSCs were distributed to the lung during early or late administration. Significant deposition of AFMSCs in nerve and muscle only occurred in the late administration group. Significantly enhanced neurobehavior, electrophysiological function, nerve myelination, and expression of neurotrophic factors and acetylcholine receptor were demonstrated in the late administration group. CONCLUSIONS: Amniotic fluid-derived mesenchymal stem cells can be recruited by expression of SDF-1alpha in muscle and nerve after nerve crush injury. The increased deposition of AFMSCs paralleled the expression profiles of SDF-1alpha and its receptor CXCR-4 in either muscle or nerve. Administration of AFMSCs led to improvements in neurobehavior and expression of regeneration markers. Intravenous administration of AFMSCs may be a promising alternative treatment strategy in peripheral nerve disorder. PMID- 22503126 TI - The effect of warm-up on intermittent sprint performance and selected thermoregulatory parameters. AB - OBJECTIVES: To investigate the effect of various warm-up intensities based upon individual lactate thresholds on subsequent intermittent sprint performance, as well as to determine which temperature (muscle; T(mu), rectal; T(re) or body; T(b)) best correlated with performance (total work, work and power output of the first sprint, and % work decrement). DESIGN: Nine male team-sport participants performed five 10-min warm-up protocols consisting of different exercise intensities on five separate occasions, separated by a week. METHODS: Each warm up protocol was followed by a 6*4-s intermittent sprint test performed on a cycle ergometer with 21-s of recovery between sprints. T(mu), T(re) and T(b) were monitored throughout the test. RESULTS: There were no differences between warm-up conditions for total work (J kg-1; P=0.442), first sprint work (J kg-1; P=0.769), power output of the first sprint (W kg-1; P=0.189), or % work decrement (P=0.136), respectively. Moderate to large effect sizes (>0.5; Cohen's d) suggested a tendency for improvement in every performance variable assessed following a warm-up performed at an intensity midway between lactate inflection and lactate threshold. While T(mu), T(re), T(b), heart rate, ratings of perceived exertion and plasma lactate increased significantly during the exercise protocols (P<0.05), there were no significant correlations between T(mu), T(re), and T(b) assessed immediately after each warm-up condition and any performance variable assessed. CONCLUSIONS: Warm-up performed at an intensity midway between lactate inflection and lactate threshold resulted in optimal intermittent sprint performance. Significant increases in T(mu), T(re) and T(b) during the sprint test did not affect exercise performance between warm-up conditions. PMID- 22503127 TI - Type I punctate palmoplantar keratoderma (Buschke-Fisher-Brauer disease) in a family--a report of two cases. AB - BACKGROUND: Inherited palmoplantar keratoderma are a rare group of disorder affecting the palm and sole characterised by hyperkeratosis resulting in severe disability and deformities. OBJECTIVE: To report a rare case of punctate palmoplantar keratoderma. METHOD: A case attending our OPD is reported. RESULT: Case report. CONCLUSION: This case is reported for its unique presentation and rarity. PMID- 22503128 TI - [Consensus document on the management after hospital discharge of patient with hyperglycaemia]. AB - The present document intends to adapt the general recommendations set up in a consensus to elaborate the hospital discharge report in medical specialties to the specific needs of the hospitalized diabetic population. Diabetes is an illness with a very high health cost, being the global risk of death in people with diabetes almost double than in non-diabetes people, justifying the fact that diabetes constitutes one of the most frequent diagnoses in hospitalized patients and the growing interest upon hyperglycaemia management during hospitalization and at discharge. To set up an adequate treatment plan at discharge suitable for each patient, the most important elements to take into account are the etiology and prior hyperglycaemia treatment, the patient's clinical situation and the degree of glycaemia control. Due to instability of glycaemia control, it is also needed to anticipate the educational needs for each patient, as well as to set up the monitoring schedule and follow-up at discharge, and an adequate treatment plan at discharge. PMID- 22503129 TI - BioDoser: improved dose-estimation software for biological radiation dosimetry. AB - This paper introduces a software program that was developed with the aims to improve the efficiency and veracity of calibration curve fitting and data processing in radiation biological dosimetry and other biological experiments, and which is termed BioDoser. BioDoser uses least squares and loop testing of monotonicity method and algorithm of non-uniformed confidence interval. In addition, this program enables integration of multiple different biomarkers typically used in biological dosimetry. These include partial body exposure, minimum number of cells to be analyzed, G function correction modules that are helpful in dose estimation when using chromosome aberration frequencies, micronucleus rate, comet assay and other biological methods. The software is freely available at http://bit.ly/kKBSNR. PMID- 22503130 TI - Thermal stability of the prototypical Mn porphyrin-based superoxide dismutase mimic and potent oxidative-stress redox modulator Mn(III) meso-tetrakis(N ethylpyridinium-2-yl)porphyrin chloride, MnTE-2-PyP(5+). AB - Cationic Mn porphyrins are among the most potent catalytic antioxidants and/or cellular redox modulators. Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin chloride (MnTE-2-PyPCl(5)) is the Mn porphyrin most studied in vivo and has successfully rescued animal models of a variety of oxidative stress-related diseases. The stability of an authentic MnTE-2-PyPCl(5) sample was investigated hereon by thermogravimetric, derivative thermogravimetric, and differential thermal analyses (TG/DTG/DTA), under dynamic air, followed by studies at selected temperatures to evaluate the decomposition path and appropriate conditions for storage and handling of these materials. All residues were analyzed by thin-layer chromatography (TLC) and UV-vis spectroscopy. Three thermal processes were observed by TG/DTG. The first event (endothermic) corresponded to dehydration, and did not alter the MnTE-2-PyPCl(5) moiety. The second event (endothermic) corresponded to the loss of EtCl (dealkylation), which was characterized by gas chromatography-mass spectrometry. The residue at 279 degrees C had UV-vis and TLC data consistent with those of the authentic, completely dealkylated analog, MnT-2 PyPCl. The final, multi-step event corresponded to the loss of the remaining organic matter to yield Mn(3)O(4) which was characterized by IR spectroscopy. Isothermal treatment at 188 degrees C under static air for 3h yielded a mixture of partially dealkylated MnPs and traces of the free-base, dealkylated ligand, H(2)T-2-PyP, which reveals that dealkylation is accompanied by thermal demetallation under static air conditions. Dealkylation was not observed if the sample was heated as a solid or in aqueous solution up to ~100 degrees C. Whereas moderate heating changes sample composition by loss of H(2)O, the dehydrated sample is indistinguishable from the original sample upon dissolution in water, which indicates that catalytic activity (on Mn basis) remains unaltered. Evidently, dealkylation at high temperature compromises sample activity. PMID- 22503131 TI - Epigenetic regulation of PRAME in acute myeloid leukemia is different compared to CD34+ cells from healthy donors: effect of 5-AZA treatment. AB - PRAME is a tumor associated antigen (TAA) of particular interest since it is widely expressed by lymphoid and myeloid malignancies. Several studies have associated high PRAME RNA levels with good prognosis in acute myeloid leukemia (AML). PRAME expression is regulated at the epigenetic level. For this reason inhibitors of DNA methylation, such as 5-azacytidine, can modulate the expression of this TAAs. In the current study we analyzed the effect of 5-azaC on the expression of PRAME in blasts versus CD34+ cells from healthy donors in an attempt to increase its expression, thus inducing a potential target for therapeutic strategies. PMID- 22503133 TI - A pilot study on the use of geometrically accurate face models to replicate ex vivo N95 mask fit. AB - To test the feasibility of replicating a face mask seal in vitro, we created 5 geometrically accurate reconstructions of the head and neck of an adult human subject using different materials. Three breathing patterns were simulated with each replica and an attached N95 mask. Quantitative fit testing on the subject and the replicas showed that none of the 5 isotropic materials used allowed duplication of the ex vivo mask seal for the specific mask-face combination studied. PMID- 22503132 TI - Azacitidine differentially affects CD4(pos) T-cell polarization in vitro and in vivo in high risk myelodysplastic syndromes. AB - CD4(pos) T-cell subsets play a role in myelodysplastic syndromes (MDS) pathogenesis and may be affected upon 5-azacitidine (Aza) treatment. Aza enhanced human T(H)1 frequencies in vitro but not in vivo. The proportion of functional FoxP3(pos) regulatory T cells (Treg) was enhanced by Aza in vitro (p < 0.0002), and a modest, temporary increase was observed in vivo (p = 0.08). The overall number of T(H)17 was reduced both in vitro (p < 0.03) and in vivo (p < 0.006), indicating that Aza directly affects CD4(pos) polarization during activation in vitro. Upon in vivo treatment in high risk MDS patients, particularly the T(H)17 Treg axis is affected. PMID- 22503134 TI - Respiratory hygiene in emergency departments: compliance, beliefs, and perceptions. AB - BACKGROUND: Low respiratory hygiene compliance among health care workers of emergency departments has become a major concern in the spread of respiratory infections. Our objective was to determine the compliance with respiratory hygiene of triage nurses at 2 university hospital centers and to identify factors influencing compliance to the respiratory hygiene principles of emergency health care workers. METHODS: A 2-part, cross-sectional, descriptive study was conducted at 2 training centers. An anonymous observation of compliance with respiratory hygiene by triage emergency nurses was performed. A self-administered, voluntary questionnaire on attitudes, perceptions, and knowledge of respiratory hygiene guidelines was distributed to the health care workers at the emergency department of the 2 hospital sites. RESULTS: Median objective compliance with respiratory hygiene measures of triage nurses was 22% (interquartile range [IQR], 11%-33%). Median perceived compliance of the health care workers was 68% (IQR, 61%-79%). Median actual knowledge score was 75% (IQR, 75%-100%). Overall, 91.9% of respondents believed that the mask was an effective preventive measure. The main obstacles toward mask wearing by the health care worker were "tendency to forget" (37.8%) and "discomfort" (35.1%). CONCLUSION: The compliance rate at our institution is very low. We identified a few factors affecting adherence to respiratory hygiene measures that are of potential use in targeting groups and formulating recommendations. PMID- 22503135 TI - Hereditary diffuse leukoencephalopathy with axonal spheroids caused by R782H mutation in CSF1R: case report. AB - We report a biopsy-proven and genetically determined case with leukoencephalopathy showing autosomal dominant inheritance and pre-senile dementia. A 51-year old woman gradually developed a decline in cognitive functions with aphasia and epileptic seizures. Four of her family members were diagnosed as having dementia in their forties to sixties. Five years later she became apathetic and bed-ridden. Brain MRI initially showed fronto-temporal dominant cerebral atrophy with multiple small lacunar-like lesions in the deep white matter, but these white matter lesions became diffuse at an advanced stage. Such possibilities as hereditary vascular or fronto-temporal dementia were clinically suspected, but her family members requested a definitive diagnosis. Brain biopsy showed severe loss of myelin and axons in the white matter with relatively preserved cortical structure. The remaining axons disclosed irregular shapes with the formation of many spheroids, and these findings were consistent with a histopathological diagnosis of neuroaxonal dystrophy. DNA analysis disclosed a novel heterozygous c.2345G>A (p.782Arg>His) mutation in exon 18 of the colony stimulating factor 1 receptor gene (CSF1R). Hereditary diffuse leukoencephalopathy with axonal spheroids should be included in the differential diagnosis of familial occurrence of pre-senile dementia. PMID- 22503136 TI - Affective symptoms and cognitive functions in Parkinson's disease. AB - Patients with Parkinson's disease (PD) typically present with motor symptoms, but several non-motor symptoms, such as cognitive impairment, autonomic dysfunction and neuropsychiatric symptoms, are usually also present, when adequately looked for. The objective of this paper is to provide an up-to-date, comprehensive review of the influence of affective disorders, mainly depression and apathy, on cognitive functioning of PD patients. Reviewed empirical findings suggest that, although depression and apathy have differential neurobiological bases in PD, both are associated to an increased risk of cognitive impairment, especially of executive functions, in this clinical population. The potential influence of other affective disorders, as anxiety and alexithymia, on cognitive functioning of PD patients is actually almost unknown and needs further empirical investigation. The clinical implication of these findings is that the best assessment and management of PD patients should include both neuropsychological and neuropsychiatric evaluations and the presence of non-motor symptoms as cognitive disturbances and affective features should be investigated with patients and caregivers. PMID- 22503137 TI - A randomized open-label trial on the use of budesonide/formoterol (Symbicort(r)) as an alternative reliever medication for mild to moderate asthmatic attacks. AB - BACKGROUND: Conventionally, a nebulized short-acting beta-2 agonist like salbutamol is often used as the reliever in acute exacerbations of asthma. However, recent worldwide respiratory outbreaks discourage routine use of nebulization. Previous studies have shown that combined budesonide/formoterol (Symbicort(r), AstraZeneca) is effective as both a maintenance and reliever anti asthmatic medication. METHODS: We performed a randomized, open-label study from March until August 2011 to compare the bronchodilatory effects of Symbicort(r) vs. nebulized salbutamol in acute exacerbation of mild to moderate asthmatic attack in an emergency department. Initial objective parameters measured include the oxygen saturation, peak expiratory flow rate (PEFR) and respiratory rate. During clinical reassessment, subjective parameters [i.e., Visual Analog Scale (VAS) and 5-point Likert scale of breathlessness] and the second reading of the objective parameters were measured. For the 5-point Likert scale, the patients were asked to describe their symptom relief as 1, much worse; 2, a little worse; 3, no change; 4, a little better; 5, much better. RESULTS: Out of the total of 32 patients enrolled, 17 patients (53%) were randomized to receive nebulized salbutamol and 15 (47%) to receive Symbicort(r). For both treatment arms, by using paired t- and Wilcoxon signed rank tests, it was shown that there were statistically significant improvements in oxygen saturation, PEFR and respiratory rate within the individual treatment groups (pre- vs. post-treatment). Comparing the effects of Symbicort(r) vs. nebulized salbutamol, the average improvement of oxygen saturation was 1% in both treatment arms (p = 0.464), PEFR 78.67 l/min vs. 89.41 l/min, respectively (p = 0.507), and respiratory rate 2/min vs. 2/min (p = 0.890). For subjective evaluation, all patients reported improvement in the VAS (average 2.45 cm vs. 2.20 cm), respectively (p = 0.765). All patients in both treatment arms reported either "a little better" or "much better" on the 5-point Likert scale, with none reporting "no change" or getting worse. CONCLUSION: This study suggests that there is no statistical difference between using Symbicort(r) vs. nebulized salbutamol as the reliever for the first 15 min post-intervention. PMID- 22503138 TI - Glucocorticoid sensitivity of leukocytes predicts PTSD, depressive and fatigue symptoms after military deployment: A prospective study. AB - AIM: Posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and severe fatigue may develop in response to severe stress and trauma. These conditions have all been shown to be associated with altered sensitivity of leukocytes for regulation by glucocorticoids (GCs). However, it remains unknown whether sensitivity of leukocytes for GCs is a pre-existing vulnerability factor, or whether GC-sensitivity of leukocytes alters as a consequence of stress and stress-related conditions. Our aim was to investigate whether sensitivity of T cells and monocytes for regulation by GCs (i.e. dexamethasone: DEX) assessed before military deployment predicts high levels of PTSD, depressive, and/or fatigue symptoms 6 months after return from deployment. METHODS: We included 526 male military personnel before deployment to Afghanistan. Logistic regression analysis was performed to predict fatigue, depressive, and PTSD symptoms 6 months after deployment based on sensitivity of LPS-induced TNF-alpha production and PHA induced T-cell proliferation to DEX-inhibition before deployment. RESULTS: Severe fatigue 6 months after deployment was independently associated with low DEX sensitivity of monocyte TNF-alpha production before deployment. A high level of depressive symptoms after deployment was independently associated with a low DEX sensitivity of T-cell proliferation. In contrast, a high level of PTSD symptoms after deployment was independently associated with a high DEX-sensitivity of T cell proliferation before deployment, but only in individuals who reported PTSD symptoms without depressive symptoms. The predictive value of DEX-sensitivity was independent of childhood trauma and GR number, GR subtype and GR target gene mRNA expression in leukocytes. CONCLUSIONS: We present here for the first time that the sensitivity of leukocytes for GCs prior to deployment is a predictive factor for the development of PTSD, depressive and fatigue symptomatology in response to deployment. Notably, PTSD, depressive and fatigue symptoms were differentially associated with GC-sensitivity of monocytes and T-cells and therefore may have different biological underpinnings. PMID- 22503139 TI - Loneliness and stress-related inflammatory and neuroendocrine responses in older men and women. AB - Loneliness is a predictor of mortality and increased cardiovascular morbidity. Inflammation is a potential pathway through which loneliness might impact health. The aim of the study was to investigate the relationship between loneliness and inflammatory interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra) and monocyte chemotactic protein-1 (MCP-1) responses to standardized mental stress. A secondary purpose was to evaluate whether individual variations in cortisol responses influenced the hypothesised relationship between loneliness and inflammation. Saliva samples and blood were taken from 524 healthy middle-aged men and women from the Whitehall II cohort at baseline, immediately after the stress tasks and 45min later. Loneliness was measured using the revised UCLA loneliness scale. Greater loneliness was associated with larger IL-6 (p=0.044) and IL-1Ra (p=0.006) responses to psychological stress and higher MCP-1 (p<0.001) levels in women, independently of age, grade of employment, body mass index and smoking status. No associations were observed in men. Cortisol responsivity was inversely related to loneliness in women, with the odds of being a cortisol responder decreasing with increased loneliness independently of covariates (p=0.008). The impact of loneliness on health in women may be mediated in part through dysregulation of inflammatory and neuroendocrine systems. PMID- 22503140 TI - Glucocorticoid receptor number predicts increase in amygdala activity after severe stress. AB - INTRODUCTION: Individuals who are exposed to a traumatic event are at increased risk of developing psychiatric disorders such as posttraumatic stress disorder (PTSD). Studies have shown that increased amygdala activity is frequently found in patients with PTSD. In addition, pre-trauma glucocorticoid receptor (GR) number in peripheral blood mononuclear cells (PBMCs) has been found to be a significant predictor for the development of PTSD symptoms. Research in rodents has shown that the response of basolateral amygdala neurons to corticosterone is mediated by GR. However, to the best of our knowledge, no previous study has investigated GR number in PBMCs and amygdala function in humans. METHODS: To investigate whether peripheral GR number is related to amygdala functioning, we assessed GR number in PBMCs of healthy soldiers before their deployment to Afghanistan. Amygdala functioning was assessed with fMRI before and after deployment. RESULTS: We found that pre-deployment GR number was significantly negatively correlated to pre-deployment amygdala activity. More importantly, pre deployment GR number predicted the increase in amygdala activity by deployment. DISCUSSION: Our results demonstrate that peripheral GR number is associated with amygdala functioning and predicts the increase in amygdala activity following military deployment in healthy individuals who did not develop PTSD. It is uncertain how this relationship is mediated mechanistically, but future studies should examine the relation of GR and amygdala activity to determine whether this is part of a common pathway leading to increased vulnerability to stress-related disorders. PMID- 22503141 TI - Iron phthalocyanine/TiO2 nanofiber heterostructures with enhanced visible photocatalytic activity assisted with H2O2. AB - One-dimensional 2,9,16,23-tetra-nitrophthalocyanine iron(II) (TNFePc)/TiO(2) nanofiber heterostructures have been successfully obtained by a simple combination of electrospinning technique and solvothermal process. The as obtained products were characterized by field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray (EDX) spectroscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and IR spectrum. The results revealed that the TNFePc nanosheets were successfully grown on the primary TiO(2) nanofibers. And, the coverage density of the secondary TNFePc nanostructures could be controlled by adjusting the experimental parameters. Photocatalytic tests displayed that the H(2)O(2) assisted TNFePc/TiO(2) nanofiber heterostructures (TNFePc/TiO(2) H(2)O(2)) possessed a much higher degradation rate of methyl orange than the pure TiO(2) and TNFePc/TiO(2) nanofiber without H(2)O(2) under visible light. Moreover, the TNFePc/TiO(2) nanofiber heterostructures could be easily recycled without the decrease of the photocatalytic activity due to their one-dimensional nanostructural property of TiO(2) nanofibers. PMID- 22503142 TI - Molecular dissection of atrazine-responsive transcriptome and gene networks in rice by high-throughput sequencing. AB - The residue of atrazine (a herbicide) has become hazards in environments due to its intensive use. However, its molecular toxicity to on plants and human beings is not fully understood. In this study, we performed high-throughput sequencing of atrazine-exposed rice (Oryza sativa) to analyze global expression and complexity of genes in the crop. Four libraries were constructed from shoots and roots with or without atrazine exposure. We sequenced 5,751,861, 5,790,013, 5,375,999 and 6,039,618 clean tags that corresponded to 220,806, 111,301, 248,802 and 114,338 distinct tags for Root-Atr (root control, atrazine-free), Shoot-Atr (shoot control, atrazine-free), Root+Atr (root treated with atrazine) and Shoot+Atr (shoot treated with atrazine) libraries, respectively. Mapping the clean tags to gene databases generated 18,833-21,007 annotated genes for each library. Most of annotated genes were differentially expressed among the libraries. The most 40 differentially expressed genes were associated with resistance to environmental stress, degradation of xenobiotics and molecular metabolism. Validation of gene expression by quantitative RT-PCR confirmed the deep-sequencing results. The transcriptome sequences were further subjected to Gene Orthology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and showed modified biological functions and metabolic pathways. Our results not only highlight the transcriptional complexity in rice with atrazine but also represent a major improvement for analyzing transcriptional changes on a large scale in xenobiotics-responsive toxicology. PMID- 22503143 TI - Preliminary support for links between media body ideal insecurity and women's shoe and handbag purchases. AB - Two studies examined the relationship between women's insecurity-arousing comparisons with female models and shoe/handbag ownership. Idealized media images appear capable of threatening some women's sense of attractiveness and it may be that as a result, accessorizing becomes particularly appealing because it helps increase physical attractiveness without drawing attention to one's figure, the object of the threatening comparisons. In Study 1 (N=922), a correlational study, the more women reported that they feel insecure when they see attractive female models, the more shoes they tended to own. In Study 2 (N=286), we manipulated whether women saw images of attractive female models or not. The more women exhibited insecurity following exposure to the images of attractive models, the more shoes and handbags they tended to own. In both studies, these effects did not hold for ownership of trousers, an item of clothing that draws attention toward one's body. PMID- 22503144 TI - Peripheral neuropathy in children with type 1 diabetes. AB - Diabetic neuropathy (DN) is a major complication of type 1 diabetes mellitus (T1DM) with significant morbidity and mortality in adulthood. Clinical neuropathy is rarely seen in paediatric populations, whereas subclinical neuropathy is commonly seen, especially in adolescents. Peripheral DN involves impairment of the large and/or small nerve fibres, and can be diagnosed by various methods. Nerve conduction studies (NCS) are the gold-standard method for the detection of subclinical DN; however, it is invasive, difficult to perform and selectively detects large-fibre abnormalities. Vibration sensation thresholds (VSTs) and thermal discrimination thresholds (TDTs) are quicker and easier and, therefore, more suitable as screening tools. Poor glycaemic control is the most important risk factor for the development of DN. Maintaining near-normoglycaemia is the only way to prevent or reverse neural impairment, as the currently available treatments can only relieve the symptoms of DN. Early detection of children and adolescents with nervous system abnormalities is crucial to allow all appropriate measures to be taken to prevent the development of DN. PMID- 22503145 TI - The effect of combination treatment with trenbolone acetate and estradiol-17beta on skeletal muscle expression and plasma concentrations of oxytocin in sheep. AB - Implantation of trenbolone acetate (TBA) in conjunction with estradiol-17beta (E(2)) increases growth, feed conversion efficiency, and carcass leanness in cattle. Our previous study in Brahman steers suggested that the neuropeptide hormone oxytocin (OXT) may be involved in increasing muscle growth after TBA-E(2) treatment. The present study aimed to determine whether OXT mRNA expression in the longissimus muscle (LM) is also up-regulated in TBA-E(2-)implanted wethers as has been found in steers. Real-time quantitative PCR was used to measure the expression of the gene encoding the OXT precursor, three genes with increased expression in the LM muscle of TBA-E(2)-treated steers, MYOD1 (muscle transcription factor), GREB1 (growth regulation by estrogen in breast cancer 1), and WISP2 (Wnt-1 inducible signaling pathway protein 2), and two genes encoding IGF pathway proteins, IGF1, IGFR, in the LM of both untreated and TBA-E(2) treated wethers. The expression of OXT mRNA in wethers that received the TBA-E(2) treatment was increased ~4.4-fold (P = 0.01). TBA-E(2) treatment also induced a 2.3-fold increase in circulating OXT (P = 0.001). These data, together with the observation that untreated wethers had much higher baseline concentrations of circulating OXT than previously observed in steers, suggest that wethers and steers have quite different OXT hormone systems. TBA-E(2) treatment had no effect on the expression of IGF1, IGFR, and the muscle regulatory gene MYOD1 mRNA levels in wethers (P >= 0.15), but there was an increase in the expression of the two growth-related genes, GREB1 (P = 0.001) and WISP2 (P = 0.04). Both genes are common gene targets for both the estrogen and androgen signaling pathways. Consequently, their actions may contribute to the positive interaction between TBA and E(2) on additive improvements on muscle growth. PMID- 22503146 TI - Teaching patients how to talk with biomedical providers about their complementary and alternative medicine use. AB - OBJECTIVE: The goal was to examine the feasibility and impact of a face-to-face communication skills training intervention based on a current public health campaign to encourage patients to talk about complementary and alternative medicine (CAM) with their biomedical health providers. METHODS: Current CAM users were invited to complete a survey about current/past CAM use and communication with biomedical providers before beginning a communication skills training workshop. In the 6-month period following the training, participants were asked to record information on any CAM conversations with those providers. RESULTS: Of the 38 participants who received training, 32 finished the entire study. Over half of those participants reported discussing CAM in post-training visits with biomedical providers. Participants initiated the conversation in most cases, and were more likely to disclose CAM use than they were to ask questions about CAM. Participants who talked about CAM were significantly more likely to perceive CAM as relevant to their visit, compared with individuals who did not talk about CAM. CONCLUSIONS: Participants positively evaluated this patient communication workshop. Consistent with previous research, most CAM conversations were patient initiated. PRACTICE IMPLICATIONS: These findings reinforce the importance of patient education interventions for improving patient-provider communication in general, and CAM communication specifically. PMID- 22503147 TI - [Single incision laparoscopic surgery: analysis of the national register]. AB - INTRODUCTION: Laparoscopic surgery through a single incision is an innovative concept which is a challenge for surgeons to implement and develop. The interest aroused by these techniques in Spain led to the Endoscopy Section of the Spanish Association of Surgeons (AEC) to start a National Register for Single-Incision Surgery (RNCIU). The aim of this study was to collect the primary clinical data, techniques, and the possible complications of these techniques in Spain. MATERIAL AND METHODS: Data were gathered using a form available on the AEC website. The forms included in this study correspond to those received between June 2010 and June 2011. RESULTS: A total of 35 centers had taken part during the study period, with 1,198 forms being collected. The surgeries performed included 62.2% cholecystectomies, 22% appendectomies, and 7.8% colectomies. Procedures on solid organs (3.4%), bariatric surgery (2.7%), and various hernia repairs (1.9%), were also registered. The overall incidence of complications was 0.8%. The mortality rate in the series was 0.1%. CONCLUSIONS: Single incision laparoscopic surgery is a novel concept that is not beyond our scientific community. The results of the Register demonstrate the feasibility of numerous effective and safe procedures. Finally, the RNCIU is an important data source to be able to study sub-groups of diseases in detail, with the aim of advancing the knowledge of these techniques and generating scientific evidence. PMID- 22503148 TI - Production of cellulases from Aspergillus niger NS-2 in solid state fermentation on agricultural and kitchen waste residues. AB - Various agricultural and kitchen waste residues were assessed for their ability to support the production of a complete cellulase system by Aspergillus niger NS 2 in solid state fermentation. Untreated as well as acid and base-pretreated substrates including corn cobs, carrot peelings, composite, grass, leaves, orange peelings, pineapple peelings, potato peelings, rice husk, sugarcane bagasse, saw dust, wheat bran, wheat straw, simply moistened with water, were found to be well suited for the organism's growth, producing good amounts of cellulases after 96 h without the supplementation of additional nutritional sources. Yields of cellulases were higher in alkali treated substrates as compared to acid treated and untreated substrates except in wheat bran. Of all the substrates tested, wheat bran appeared to be the best suited substrate producing appreciable yields of CMCase, FPase and beta-glucosidase at the levels of 310, 17 and 33 U/g dry substrate respectively. An evaluation of various environmental parameters demonstrated that appreciable levels of cellulases could be produced over a wide range of temperatures (20-50 degrees C) and pH levels (3.0-8.0) with a 1:1.5 to 1:1.75 substrate to moisture ratio. PMID- 22503149 TI - Abnormal gray matter aging in chronic pain patients. AB - Widespread brain gray matter (GM) atrophy is a normal part of the aging process. However, recent studies indicate that age-related GM changes are not uniform across the brain and may vary according to health status. Therefore the aims of this study were to determine whether chronic pain in temporomandibular disorder (TMD) is associated with abnormal GM aging in focal cortical regions associated with nociceptive processes, and the degree to which the cumulative effects of pain contributes to age effects. We found that patients have accelerated whole brain GM atrophy, compared to pain-free controls. We also identified three aberrant patterns of GM aging in five focal brain regions: 1) in the thalamus, GM volume correlated with age in the TMD patients but not in the control group; 2) in the anterior mid- and pregenual cingulate cortex (aMCC/pgACC), the TMD patients showed age-related cortical thinning, whereas the controls had age related cortical thickening; and 3) in the dorsal striatum and the premotor cortex (PMC). Interestingly, the controls but not the patients showed age-related GM reductions. Finally, a result of particular note is that after accounting for the effects of TMD duration, age remained as a significant predictor of GM in the PMC and dorsal striatum. Thus, abnormal GM aging in TMD may be due to the progressive impact of TMD-related factors in pain-related regions, as well as inherent factors in motor regions, in patients with TMD. This study is the first to show that chronic pain is associated with abnormal GM aging in focal cortical regions associated with pain and motor processes. PMID- 22503150 TI - Defining principles for good practice: using case studies to inform health systems action on health inequalities. AB - This paper presents work using case studies as a source of data to see if we could extrapolate from the specific to the general particularly with regard to understanding what constitutes effective practice in taking action on SDHI and as a way of enabling policy makers to make better use of knowledge within the case studies and as a way of better understanding what works, in what context and why. Case studies are important to evaluators in that they are relatively straightforward to undertake and because those involved in implementing an intervention are usually keen to profile the intervention. A checklist described in this paper will enable policy advisers and evaluators to quickly review a case study and right away see if it contains enough information to assist in the development of policy options for reducing socially determined health inequalities. PMID- 22503151 TI - Prediction of prognosis after trimodal therapy in patients with locally advanced squamous cell carcinoma of the oesophagus. AB - BACKGROUND: Due to the poor prognosis of locally advanced oesophageal cancer, predictive markers are warranted to better select patients who may benefit from multimodal therapy. PATIENTS AND METHODS: Patients with oesophageal cancer from two multicentric prospective trials were selected for having received radiochemotherapy followed by macroscopic complete tumour resection. Several pretreatment and treatment related factors were retrospectively analysed for their ability to serve as predictive markers. RESULTS: Overall 107 patients with squamous cell carcinomas stage T3-4 N and M0 were included in the analysis. All of them had complete preoperative radiochemotherapy. Microscopic (n=96) or macroscopic (N=11) complete resection was achieved by transthoracic oesophagectomy. The median follow-up time exceeded 6 years. Local progression free and overall survival were significantly hampered in patients with residual tumour in their resected specimen (n=76) compared with patients who showed a pathohistologic complete tumour remission (n=31) (overall survival rate at 3 years 25.2% versus 65.6%; hazard ratio (HR)=3.50 (95%-confidence interval (CI) 1.91-6.44); p<0.0001). A multivariable analysis proved both resection status and pathohistologic results to be independent acting predictive factors for local progression free and overall survival after preoperative radiochemotherapy with surgery. CONCLUSIONS: From our study it appears that the pathohistologic results can be a valuable surrogate marker for predicting long term survival and local tumour control in patients with locally advanced squamous cell carcinoma (SCC) of the oesophagus after preoperative radiochemotherapy and surgery. Moreover, even after intensive preoperative therapy a complete tumour resection seems to be an important precondition for long term survival. PMID- 22503153 TI - Community-driven interventions can revolutionise control of neglected tropical diseases. AB - Whether global health interventions target diseases (vertical), systems (horizontal) or both (diagonal), they must address the challenge of delivering services in very remote areas of poor countries with inadequate infrastructure. The primacy of this challenge has been underscored by persistent service-delivery difficulties despite several large financial commitments - the latest, US $363 million in the January 2012 London Declaration. Community-driven approaches, pioneered in river blindness control, show that engaging communities can maximise access and performance. This experience should inform a paradigm shift in disease control whereby communities are empowered to extend health service access themselves. PMID- 22503152 TI - Variability in resource consumption in patients with spondyloarthritis in Spain. Preliminary descriptive data from the emAR II study. AB - OBJECTIVE: Our objective was to describe the variability in the management of spondyloarthritis (SA) in Spain in terms of healthcare resources and their use. METHODS: A review of 1168 medical files of patients seen in randomly selected Spanish hospital rheumatology departments. We analyzed demographic variables and variables related to the consumption of health resources. RESULTS: The total number of visits to rheumatology were 5,908 with a rate of 254 visits/100 patient years. The total number of visits to rheumatology specialty nurses was 775, with a rate of 39 visits/100 patient-years, and there were 446 hospitalizations, representing a rate of 22 per 100 patient-years. The number of admissions due to SA was 89, with a rate of 18 admissions/100 patient-years. Total visits to other specialists was 4,307 with a rate of 200/100 patient-years. The total number of orthopedic surgeries was 41, which leads to a rate of 1.8 surgeries/100 patient years. CONCLUSIONS: The data regarding visits to the rheumatologist and prosthetic surgery of patients with in Spain is similar to most studies published in our environment, however, other aspects concerning the use of health resources are different compared to other countries. This data may help to understand and improve organizational aspects of management of SA in Spanish hospitals. PMID- 22503154 TI - Application of dissolved air flotation on separation of waste plastics ABS and PS. AB - The aim of this research was to separate waste plastics acrylonitrile butadiene styrene (ABS) and polystyrene (PS) by dissolved air flotation in a self-designed dissolved air flotation apparatus. The effects of wetting agents, frother, conditioning time and flotation time on flotation behavior of waste plastics ABS (w-ABS) and PS (w-PS) were investigated and the optimized separation conditions were obtained. The results showed that when using 25 mgL(-1) tannic acid, 5 mgL( 1) terpineol, 15 min conditioning time and 15 min flotation time, mixtures of w ABS and w-PS were separated successfully by dissolved air flotation in two stages, the results revealed that the purity and recovery rate of w-PS in the floated products were 90.12% and 97.45%, respectively, and the purity and recovery rate of w-ABS in the depressed products were 97.24% and 89.38%, respectively. Based on the studies of wetting mechanism of plastic flotation, it is found that the electrostatic force and hydrophobic attraction cannot be the main factor of the interaction between wetting agent molecules and plastic particles, which can be completed through water molecules as a mesophase, and a hydrogen bonding adsorption model with hydration shell as a mesophase was proposed. PMID- 22503155 TI - An integrated multi criteria approach for landfill siting in a conflicting environmental, economical and socio-cultural area. AB - Landfill site selection is a complicated multi criteria land use planning that should convince all related stakeholders with different insights. This paper addresses an integrating approach for landfill siting based on conflicting opinions among environmental, economical and socio-cultural expertise. In order to gain optimized siting decision, the issue was investigated in different viewpoints. At first step based on opinion sampling and questionnaire results of 35 experts familiar with local situations, the national environmental legislations and international practices, 13 constraints and 15 factors were built in hierarchical structure. Factors divided into three environmental, economical and socio-cultural groups. In the next step, the GIS-database was developed based on the designated criteria. In the third stage, the criteria standardization and criteria weighting were accomplished. The relative importance weights of criteria and subcriteria were estimated, respectively, using analytical hierarchy process and rank ordering methods based on different experts opinions. Thereafter, by using simple additive weighting method, the suitability maps for landfill siting in Marvdasht, Iran, was evaluated in environmental, economical and socio-cultural visions. The importance of each group of criteria in its own vision was assigned to be higher than two other groups. In the fourth stage, the final suitability map was obtained after crossing three resulted maps in different visions and reported in five suitability classes for landfill construction. This map indicated that almost 1224 ha of the study area can be considered as best suitable class for landfill siting considering all visions. In the last stage, a comprehensive field visit was performed to verify the selected site obtained from the proposed model. This field inspection has confirmed the proposed integrating approach for the landfill siting. PMID- 22503156 TI - Municipal solid waste in rural areas of developing country: do we need special treatment mode? PMID- 22503158 TI - Docking and QSAR study on the binding interactions between polycyclic aromatic hydrocarbons and estrogen receptor. AB - Little is known about the estrogenic activities of polycyclic aromatic hydrocarbons (PAHs) and the underlying mechanisms on estrogenic activities are still unclear. Molecular docking and quantitative structure-activity relationship (QSAR) were used to understand the relationship between molecular structural features and estrogenic activity, and to predict the binding affinity of PAHs to estrogen receptor alpha (ERalpha). From molecular docking analysis, hydrogen bonding as well as hydrophobic and pi interactions were found between PAHs and ERalpha. Based on the docking results, appropriate molecular structural parameters were adopted to develop a QSAR model. Five descriptors were included in the QSAR model, which indicated that the estrogenic activity was related to molecular size, van der Waals volumes, shape profiles, polarizabilities and electropological states were significant parameters explaining the estrogenicity. Comparatively, the developed QSAR model had good robustness, predictive ability and mechanistic interpretability. Moreover, the applicability domain of the model was described. PMID- 22503157 TI - [Trend in lead exposure in the Spanish child population in the last 20 years. An unrecognized example of health in all policies?]. AB - OBJECTIVE: To describe the time trend in atmospheric lead concentrations in Spain, from before lead was banned as a gasoline additive to the present, and to determine the trend in lead body burden in the Spanish child population. METHODS: We obtained the annual average for atmospheric lead levels in several Spanish cities from the 1980s to the present. A literature search was conducted to identify published studies on lead concentrations in populations of Spanish children. RESULTS: Overall, atmospheric lead levels decreased, particularly between 1991 and 1999. This downward trend was related to a decrease in lead concentrations in Spanish children from 1989, the year in which the first study of childhood lead exposure was published, until the present. The decreased concentrations in both air and in children was most probably a result of legislative measures regulating the maximum amount of lead in gasoline in 1987 until a complete ban in August 2001. CONCLUSIONS: From a public health point of view, the banning of leaded gasoline has significantly increased health protection in the Spanish population. PMID- 22503159 TI - Metal contents in Centaurium erythraea and its biometry at various levels of environmental pollution. AB - In this investigation we focus on the influence of pollution on concentration of elements in the medicinal Centaurium erythraea. This herb is collected from wild populations and also provides important information as monitor of environmental quality. Concentrations of Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, N, Ni, P, Pb, V and Zn in Centaurium erythraea and in the soil in which this plant grew were measured together with biometrical features of the species from sites affected by various levels of pollution. C. erythraea from sites polluted by lignite mining and industrial combustion had the highest concentrations of Cd, Co and Zn (principal component and classification analysis, PCCA). C. erythraea from sites influenced by ferrous-chromium and thermal power plants had the highest concentrations of Cr and Fe as well as Cu, Mn and Ni and the highest length of shoots and number of leaves, shoots, nodes, flowers and flowers on the main shoot. These luxurious growth forms were probably related to the highest concentrations of N, P and Fe in the soil and concentrations of N and K accumulated by C. erythraea on these sites as revealed by the established models. Controlling the collection of C. erythraea for medicinal purposes is recommended as this species is able to accumulate increased levels of metals from polluted sites. The medical quality of C. erythraea may be negatively related to the degree and type of pollution of the environment and should not be based on the luxurious growth of individuals which may contain hazardous levels of metals. PMID- 22503160 TI - Estimating sample sizes for predementia Alzheimer's trials based on the Alzheimer's Disease Neuroimaging Initiative. AB - This study modeled predementia Alzheimer's disease clinical trials. Longitudinal data from cognitively normal (CN) and mild cognitive impairment (MCI) participants in the Alzheimer's Disease Neuroimaging Initiative were used to calculate sample size requirements for trials using outcome measures, including the Clinical Dementia Rating scale sum of boxes, Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-cognitive subscale with and without delayed recall, and the Rey Auditory Verbal Learning Task. We examined the impact on sample sizes of enrichment for genetic and biomarker criteria, including cerebrospinal fluid protein and neuroimaging analyses. We observed little cognitive decline in the CN population at 36 months, regardless of the enrichment strategy. Nonetheless, in CN subjects, using Rey Auditory Verbal Learning Task total as an outcome at 36 months required the fewest subjects across enrichment strategies, with apolipoprotein E genotype epsilon4 carrier status requiring the fewest (n = 499 per arm to demonstrate a 25% reduction in disease progression). In MCI, enrichment reduced the required sample sizes for trials, relative to estimates based on all subjects. For MCI, the Clinical Dementia Rating scale sum of boxes consistently required the smallest sample sizes. We conclude that predementia clinical trial conduct in Alzheimer's disease is enhanced by the use of biomarker inclusion criteria. PMID- 22503161 TI - Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. AB - In order to assess the frequency of mutations in the known Alzheimer's disease causative genes in Turkish dementia patients we screened amyloid precursor protein (APP), PSEN1 and PSEN2 for mutations in a cohort of 98 Turkish dementia families. Six families were found to carry PSEN1 mutations (p.H163R, p.P264L, and p.H214Y) or variants suggested to cause the disease (p.L134R, p.L262V, and p.A396T). In 4 other families, previously reported PSEN2 variants were identified (p.R62H, p.R71W, p.M174V (n = 2), and p.S130L). The phenotype of the carriers varied from rapid progressing Alzheimer's disease to frontotemporal dementia, with spasticity and seizures also observed. Here we report a frequency of 11.2% of mutations and variants in the known Alzheimer disease genes in the dementia cohort studied and 24% in the early onset subgroup of patients, suggesting that mutations in these genes are not uncommon in Turkey and are associated with various phenotypes. We thus believe that genetic analysis should become a standardized diagnostic implement, not only for the identification of the genetic disease, but also for appropriate genetic counseling. PMID- 22503162 TI - Safety profile and tolerability of up to 1 year of pregabalin treatment in 3 open label extension studies in patients with fibromyalgia. AB - BACKGROUND: Pain relief and an acceptable safety profile have been reported in randomized controlled trials (RCTs) of pregabalin in the treatment of fibromyalgia (FM) for up to 14 weeks. OBJECTIVE: To evaluate the safety profile and tolerability of pregabalin (75-300 mg BID) treatment for up to 1 year in patients with FM. METHODS: Twelve-week data were pooled from 3 open-label extension studies of pivotal RCTs. Study 1 was a 1-year extension of a 13-week RCT, and studies 2 and 3 were 12-week extensions of 14-week RCTs. The 1-year data were separately evaluated. The open-label data are summarized using descriptive statistics. RESULTS: Overall, 1206 patients (92.4% female) with a mean (SD) age of 48.8 (10.7) years received open-label extended pregabalin treatment. A total of 119 of 1206 patients (9.9%) permanently discontinued study participation due to treatment-emergent adverse events (all causality) at 12 weeks (pooled data) and 53 of 429 (12.4%) within 1 year. Consistent with previous RCTs, the most commonly reported treatment-emergent adverse events with open-label pregabalin treatment were dizziness, somnolence, headache, peripheral edema, and increased weight. The highest incidence rates in the pooled 12-week data were for dizziness (214 of 1206; 17.7%) and somnolence (96 of 1206; 8.0%). In ratings of severity (mild, moderate, severe), most were reported as mild to moderate. The mean (SD) change in patient-reported visual analog scale pain scores (0-100) from the open label baseline to the end of treatment was -21 (30.5) in study 1 (1 year), -26.7 (28.8) in study 2 (12 weeks), and -20.1 (26.8) in study 3 (12 weeks). CONCLUSIONS: The data from these extension studies suggest that the adverse event safety profile and tolerability of patients with FM treated with open-label pregabalin (75-300 mg BID) for up to 1 year were stable and were consistent with those of previous studies. ClinicalTrials.gov identifiers: NCT00151528 (A0081057 [study 1]), NCT00282997 (A0081078 [study 2]), and NCT00346034 (A0081101 [study 3]). PMID- 22503163 TI - Promoting only the consumption of healthy foods may be an alternative stategy for treating patients with the metabolic syndrome. AB - OBJECTIVE: To evaluate the effectiveness of two lifestyle, interventional approaches on metabolic abnormalities and eating habits of patients with metabolic syndrome. MATERIALS/METHODS: This is a randomized controlled trial, involving a 6-month lifestyle intervention. Eighty-eight metabolic syndrome patients were randomized to one of the three groups: (i) "Increase - Decrease" group, (ii) "Increase" group, and (iii) "Minimum intervention" group. All patients received dietary and physical activity advice at baseline; patients in the first two groups also participated in individual counseling sessions. In the "Increase - Decrease" group, all recommended dietary and physical activity goals were targeted, whereas in the "Increase" group, only goals proposing an increase in dietary intake or physical activity were included. Patients received nutrition counseling through seven, one-to-one sessions, conducted every two weeks for the first 2 months, every month for the following 4 months. All participants underwent a full medical and nutritional assessment at baseline and at the end of the intervention. RESULTS: At 6 months, BMI and waist circumference were improved in the "Increase" and the "Increase - Decrease" groups, compared to the "Minimum Intervention" group. Additionally, "Increase - Decrease" group reduced blood systolic (p=0.017), diastolic pressure (p=0.005) and glucose concentrations (p=0.015). Forty eight percent, 32%, and 19% of the patients in the "Increase - Decrease", "Increase" and "Minimum Intervention" groups, respectively, ceased to fulfill the criteria for the metabolic syndrome (p=0.031). CONCLUSIONS: Promoting only the increase of the intake of healthy foods did not result in better outcome values compared to a conventional all-food approach. PMID- 22503164 TI - Clinical characteristics and risk factors of ocular candidiasis. AB - Ocular candidiasis is a major complication of Candida bloodstream infection (BSI). This study was performed to reveal the clinical characteristics of ocular candidiasis. Of the 220 patients with Candida BSI, 204 cases received ophthalmology consultations between January 2005 and December 2011 at 2 teaching hospitals. Fifty-four (26.5%) cases had findings consistent with the diagnosis of ocular candidiasis. Of these 54 cases, 43 (79.6%) were diagnosed within 7 days after a positive blood culture. Among ocular candidiasis cases, more cases were due to Candida albicans (P =0.034 odds ratio [OR]; 3.68 95% confidence interval [CI] 1.11-12.2) and had higher beta-d-glucan values (P = 0.001 OR; 9.99 95% CI 2.60-21.3). We need to consider fundoscopic examination to be performed within the first 7 days of therapy, especially for those patients who have C. albicans BSIs and higher beta-d-glucan values. Additionally, follow-up fundoscopic examination should be considered before stopping therapy for high-risk patients. PMID- 22503165 TI - Pick your poison: stimuli selection in alcohol-related implicit measures. AB - It is common for people to report strong preferences for certain types of alcohol, often as a function of past positive or negative experiences with particular types of drinks. Despite this individual difference, implicit measures related to alcohol frequently use nomothetic approaches--i.e., use a standard set of alcohol beverage stimuli--which may not match individuals' actual drinking behavior. Moreover, this mismatch may account for some of the inconsistencies across studies using implicit measures. The present study used an idiographic variant of the Implicit Association Test (IAT) in which participants (N=300) selected alcohol images that matched their drinking behavior (non-drinkers selected what they were offered most often). Results were consistent with previous research on alcohol preference: women selected more liquor and wine images, men selected more beer images; heavy episodic drinkers selected more beer and liquor images and selected fewer wine images than lighter drinkers and non drinkers. In addition, IAT scores were sensitive to drinking levels in the expected direction and, importantly, were robust to stimuli selected. Thus, results provide initial validation of idiographic approaches to stimuli selection. PMID- 22503166 TI - Impairment of two types of circulating endothelial progenitor cells in patients with glucocorticoid-induced avascular osteonecrosis of the femoral head. AB - OBJECTIVES: This study examined whether abnormalities of early EPCs and endothelial colony forming cells (ECFCs) are present and compared their functions in glucocorticoid (GC)-induced avascular osteonecrosis of the femoral head (ANFH). METHODS: Early EPCs and endothelial colony forming cells (ECFCs) were obtained from 33 patients with glucocorticoid-induced ANFH and 33 age- and sex matched control subjects. Cells were isolated, in vitro cultured and studied by Flow Cytometry and Immunofluorescence. Colony-forming unit counts were observed from 33 patients and 33 healthy controls. Growth kinetics, migratory capacity to multiple chemo-attractants, in vitro tube formation capacity and cytokine (vascular endothelial growth factor and stromal cell-derived factor-1) levels in supernatants of two types of EPCs were assayed in ANFH patients and matched controls (n=4). RESULTS: Mean numbers of colonies formed by both types of EPCs were decreased in ANFH patients (Early EPCs: 2.42+/-1.46 versus 4.52+/-2.00, p<0.05; ECFCs: 0.62+/-0.55 versus 1.12+/-0.82, p<0.05). Early EPCs from ANFH patients showed impaired migratory capacity (63.8+/-11.7 versus 152.3+/-12.4, p<0.001) and VEGF secretion (50.8+/-7.2 pg/ml versus 62.8+/-10.1 pg/ml, p<0.05). ECFCs from ANFH patients showed decreased tube formation capacity (7.1+/-2.7 versus 23.8+/-4.3, p<0.001) and proliferation. DISCUSSION: Early EPCs and ECFCs were impaired in number and function in GC-induced ANFH, and their distinct reduced capacity profiles might reflect different roles they played in endothelial dysfunction of GC-induced ANFH. PMID- 22503167 TI - Destructive septic arthritis of the sternoclavicular joint due to Neisseria gonorrhoeae. PMID- 22503169 TI - Schaumann bodies in Crohn's disease: a case report and review of the literature. AB - Schaumann bodies are inclusion bodies, first described by Schaumann in 1941, typically seen in granulomatous diseases such as tuberculosis, sarcoidosis and chronic beryllium diseases. Williams WJ, in 1964, reported Schaumann bodies to occur in 10% of Crohn's disease (CD). We report a case of Crohn's disease, initially misdiagnosed as a schistosoma-related colitis for the presence of numerous calcified bodies resembling calcified ova and scattered granulomas. Subsequent biopsies showed more typical histological features and, in combination with a more complete clinical history, diagnosis of Crohn's disease was made. PMID- 22503168 TI - Clinical status, psychosocial impairments, medical treatment and health care costs for patients with inflammatory bowel disease (IBD) in Germany: an online IBD registry. AB - BACKGROUND: The aim of this cross-sectional study was to establish an online inflammatory bowel disease (IBD) registry for a first picture of the situation of IBD outpatients' treatment in Germany. METHODS: Between March 2006 and July 2007 IBD outpatients from 24 gastroenterological specialist practices and two hospitals in Germany were enrolled in an Internet-based registry to evaluate the outpatients' clinical status, psychological impairments, provided health care, as well as medical treatment and medication costs. RESULTS: 1032 IBD patients (ulcerative colitis/UC: 519; Crohn's disease/CD: 511; indeterminate colitis: 2) were enrolled in the study (age: 43 +/- 14 years/M +/- SD). Disease duration of all patients averaged 10 +/- 8.5 years. In 519 UC-patients (49% male; 33% pancolitis), 66% were in remission as were 55% of CD patients (37 % male; 41 % active smokers). Associated with higher rates of disease activity (CDAI >= 150; CAI>4) were corticosteroids (CD, UC), topical medication (UC), relevant reported depressive symptoms (15%; 6-31%) and impairments in sexuality (21%; 9-42%). Relevant medication groups prescribed were oral aminosalicylates (UC: 70%; CD: 47%); immunosuppressive therapy - mostly azathioprine/6 MP (CD: 47%; UC: 26%), and Infliximab (CD: 8%; UC: 3%). Strongly associated with their clinical disease activity in UC as well as CD patients, 15% (6-31%) reported relevant depressive symptoms and 21% (9-42%) relevant impairments in sexuality. CONCLUSIONS: The registry constitutes a large complemental database for the patient population in Germany. About one third of the IBD patients were not in clinical remission (CDAI >=150/CAI >4) (CD: 45%; UC: 27%), although high rates of immunosuppressive drugs (CD: 47%; UC 26%) were administered. This study shows a large burden of active disease associated with an unexpectedly high (co)morbidity and high psychosocial impairments, indicating a reduced health state in IBD patients. PMID- 22503170 TI - Type A aortic dissection diagnosed at coronary angiography. PMID- 22503171 TI - The use of computerised simulators for training of transthoracic and transoesophageal echocardiography. The future of echocardiographic training? AB - BACKGROUND: Echocardiography is the commonest form of non-invasive cardiac imaging but due to its methodology, it is operator dependent. Numerous advances in technology have resulted in the development of interactive programs and simulators to teach trainees the skills to perform particular procedures, including transthoracic and transoesophageal echocardiography. METHODS: Forty trainee sonographers assessed a computerised mannequin echocardiographic simulator and were taught how to obtain an apical two-chamber (A2C) view and image the superior vena cava (SVC). Forty-two attendees at a TOE simulator workshop assessed its utility and commented on perceived future use, using defined criteria. RESULTS: One hundred percent and 88% of sonographers found the simulator useful in obtaining the SVC or A2C view respectively. All users found it easy to use and the majority found it helped with image acquisition and interpretation. Attendees of the TOE training day assessed the simulator with 100% finding it easy to use, as well as the augmented reality graphics benefiting image acquisition. Ninety percent felt that it was realistic. CONCLUSIONS: This study revealed that both trainee sonographers and TOE proceduralists found the simulation process was realistic, helped in image acquisition and improved assessment of spatial relationships. Echocardiographic simulators may play an important role in the future training of echocardiographic skills. PMID- 22503172 TI - Assessment of platelet function in patients on antiplatelet therapy undergoing cardiac surgery: a review. AB - Increasing numbers of patients are undergoing cardiac surgery on dual antiplatelet therapy following previous percutaneous coronary intervention. The dilemma of stopping antiplatelet therapy prior to surgery with risk of stent thrombosis, versus continuation and risk of post-operative bleeding has received much debate. Currently, an accurate and standardised method of predicting antiplatelet drug efficacy has not yet been determined and significant inter individual variance has been shown. This review focuses on the most widely used laboratory and point of care assays currently available to measure platelet function and recent published data evaluating these methods. Further studies may enable predictive values to be defined, to guide the practicing clinician in balancing the risk of thrombosis versus haemorrhage. PMID- 22503173 TI - Surgical considerations for large asymptomatic cardiac fibromas in the context of fatal ventricular arrhythmias. AB - Cardiac fibromas are rare intracardiac neoplasms but represent the most common resectable tumours of childhood. They can remain asymptomatic for extended periods of time but a pertinent and unpredictable risk of sudden cardiac death and fatal ventricular arrhythmia always exists even in asymptomatic patients. We report a case of an asymptomatic two month-old with cardiac fibroma who presented with a ventricular tachycardia (VT) arrest. Here, we discuss management of cardiac fibroma in the context of occurrence of sudden VT. PMID- 22503174 TI - Calf muscle oxygen saturation and the effects of supervised exercise training for intermittent claudication. AB - OBJECTIVE: The mechanisms underlying the symptomatic improvement witnessed as a result of exercise training in intermittent claudication remain unclear. There is no reproducible evidence to support increased limb blood flow resulting from neovascularization. Changes in oxygenation of active muscles as a result of blood redistribution are hypothesized but unproven. This study sought evidence of improved gastrocnemius oxygenation resulting from exercise training. METHODS: The study recruited 42 individuals with claudication. After an initial control period of exercise advice, participants undertook a 3-month supervised exercise program. Spatially resolved near-infrared spectroscopy monitored calf muscle oxygen saturation (Sto(2)) during exercise and after a period of cuff-induced ischemia. Comparison was made with 14 individuals undergoing angioplasty for calf claudication. Clinical outcomes of claudication distance and maximum walking distance were measured by treadmill assessment. RESULTS: Significant increases occurred in mean [interquartile range] claudication disease (57 [38-78] to 119 [97-142] meters; P = .01) and maximum walking distance (124 [102-147] to 241 [193 265] meters; P = .02) after supervised exercise but not after the control period. No change occurred in resting Sto(2) at any interval. Angioplasty (27% [21-34] to 19% [13-29]; P = .02) but not exercise training (26% [21-32] vs 23% [20-31]; P > .20) resulted in a reduced Sto(2) desaturation in response to submaximal exercise and an increased hyperemic hemoglobin oxygen recovery rate after ischemia (0.48 [0.39-0.55] to 0.63 [0.52-0.69] s(-1); P = .01). However supervised exercise reduced the Sto(2) recovery half-time by 17% (82 [64-101] to 68 [55-89] seconds; P = .02). CONCLUSIONS: Supervised exercise training is not associated with increased gastrocnemius muscle oxygenation during exercise or increased hyperemic hemoglobin flow after a model of ischemia. This suggests that the symptomatic improvement witnessed is not the result of increased oxygen delivery to the active muscle. The enhanced recovery after exercise training therefore reflects a combination of enhanced metabolic economy and increased oxidative capacity, suggesting that exercise training helps reverse an acquired metabolic myopathy. PMID- 22503175 TI - Effect of cilostazol and pentoxifylline on gait biomechanics in rats with ischemic left hindlimb. AB - OBJECTIVE: The purpose of this study was to determine the impact of pharmacologic treatment with cilostazol and pentoxifylline on gait biomechanics of ischemic rat hindlimbs compared with nonischemic controls. METHODS: An experimental study was designed using 30 Wistar rats divided into five groups (n = 6): control (C); ischemia (I) - animals submitted to left common iliac artery interruption without pharmacologic treatment; pentoxifylline (Pen) - rats submitted to procedure and treated with pentoxifylline 3 mg/kg twice a day for 6 weeks; cilostazol (Cil) - animals submitted to procedure and treated with cilostazol 30 mg/kg twice a day for 6 weeks; and sham (S) - animals submitted to procedure without artery interruption. Gait analysis was performed using a computed treadmill. Time, number, and duration of each hindlimb contact were obtained. The total number of contacts (TNC) and the total duration of contacts (TDC) were compared between left and right hindlimb and among groups. Left hindlimb ischemic incapacitation index (LHII) was defined by the formula: LHII = (1-TNCleft x TDCleft / TNCright x TDCright) x 100. RESULTS: Left hindlimb TNC values were twofold lower in I, Pen, and Cil groups than in C and S groups (P < .01). In I, Pen, and Cil groups, TNC values for the left hindlimb were half of the right hindlimb ones (P < .01). Left hindlimb TDC values were lower in I and Pen groups than the other groups (P < .01). Cil group presented twofold increased values, not different from C and S groups (P = 0.16). Right hindlimb TNC values were greater for I group (P < .01). LHII was around zero in C and S groups and 82 in both I and Pen groups (P < .01). Cil group presented a LHII of 42; higher than C and S groups, but lower than I and Pen groups (P < .01). CONCLUSIONS: Cilostazol at a dose of 30 mg/kg twice a day promoted improvement in gait performance in rats submitted to chronic hindlimb ischemia. Pentoxifylline at a dose of 3 mg/kg twice a day did not show this effect. PMID- 22503176 TI - Revascularization for acute mesenteric ischemia. AB - OBJECTIVE: Acute mesenteric ischemia (AMI) remains difficult to diagnose, carries a high rate of complications, and is associated with significant mortality. We evaluated our experience with AMI over the last 2 decades to evaluate changes in management and assess current outcomes. METHODS: Data from consecutive patients who underwent arterial revascularization for AMI over a 20-year period (January 1990-January 2010) were retrospectively reviewed. Patient demographics, treatment modalities, and outcomes over the last decade (2000-2010) were compared with those of the preceding decade (1990-1999) previously reported. RESULTS: Over the last 2 decades, 93 patients with AMI underwent emergency arterial revascularization. Forty-five patients were treated during the 1990s and 48 during the 2000s. The majority of these patients were transferred from outside facilities. Patient demographics and risk factors were similar between the 2 decades with the exception that the more contemporary patients were significantly older (65.1 +/- 14 vs 71.3 +/- 14; P = .04). Etiology remained constant between the groups with in situ thrombosis being the most common followed by arterial embolus. The majority of patients were treated with open revascularization. Endovascular therapy alone or as a hybrid procedure was used in 11 total patients, eight of which were treated in the last 10 years. The use of second look laparotomy was much more liberal in the last decade (80% vs 48%; P = .003) Thirty-day mortality was 27% in the 1990s and 17% during the 2000s (P = 0.28). Major adverse events occurred in 47% of patients with no difference between decades. There was no significant difference in outcomes between open and endovascular revascularization. On univariate analysis, elevated SVS comorbidity score, congestive heart failure, and chronic kidney disease predicted early death, while a history of chronic mesenteric ischemia appeared protective. On multivariate analysis, no factor independently predicted perioperative mortality. Bowel resection and cerebrovascular disease predicted postoperative morbidity, while advanced age and connective tissue disease predicted long-term mortality. CONCLUSIONS: Morbidity and mortality from AMI continues to be high. Revascularization by endovascular means, although more frequent in the last decade, was still utilized in a minority of patients with severe AMI. Advanced ischemia with bowel infarction at presentation, and markers of generalized atherosclerosis are predictors of poor outcome, while history of chronic mesenteric ischemia is associated with better outcome. PMID- 22503177 TI - A comparison of total laparoscopic and open repair of abdominal aortic aneurysms. AB - OBJECTIVE: The feasibility of total laparoscopic abdominal aortic aneurysm (AAA) repair has been well established. In a previous case-control study, we showed that the postoperative courses of total laparoscopic and open AAA repairs were similar. The purpose of this study was to compare the long-term results of these techniques in the same cohort of patients. METHODS: Thirty patients with AAAs treated by total laparoscopic repair between July 2003 and December 2004 (group I) were matched in a case-control fashion by morphology and American Society of Anesthesiologists class with 30 patients who underwent open AAA repair between April 1997 and May 2004 (group II). Patients who survived the intervention were followed up during 5 years. Follow-up consisted of physical examination and duplex ultrasonography at 1 month and yearly thereafter. Group I patients had an additional control computed tomography scan within the first 3 months postoperatively. RESULTS: Five-year cumulative survival rates were similar (group I: 83% +/- 7% vs group II: 79% +/- 7%; log-rank test, P = .69). No late aneurysm related death occurred during the follow-up period. Incisional hernias were more likely to occur in group II patients (group I: 0% vs group II: 15.4%; P = .047). Incidence of postoperative sexual dysfunction was similar in both groups (group I: 22.2% vs group II: 25.0%; P = not significant [NS]). No late reintervention was recorded in group I, whereas 2 patients in group II had incisional hernia repair. At 5 years, no graft sepsis or anastomotic pseudoaneurysm was reported. CONCLUSIONS: This study suggests that total laparoscopic AAA repair provides good long-term results, comparable to those of open repair in terms of aneurysm related mortality and morbidity. It may reduce the incidence of laparotomy related complications. PMID- 22503179 TI - Evolution of treatment for traumatic thoracic aortic injuries. AB - OBJECTIVE: To review the evolution of traumatic thoracic aortic injury (TTAI) treatment at a single institution. METHODS: Retrospective analysis of all patients included in an institutional trauma registry and vascular surgery database who underwent treatment of TTAI between January 1999 and January 2011. RESULTS: Ninety-one patients (69 males) were treated for TTAI. The mean age was 38.5 years (range, 16-79 years). Forty-one patients underwent open repair (OR) and 50 thoracic endovascular repair (TEVAR), 37 with thoracic stent grafts (TSG) alone, 11 with infrarenal aortic extender cuffs (AEC), and two with a combination of TSG and AEC. OR was performed exclusively until 2004; the last one was performed in January 2007. All TTAIs have since been treated with TEVAR. The left subclavian artery (LSA) was fully covered in 10 patients (20%) and partially covered in eight patients, with revascularization in only two cases. The use of AEC and avoidance of LSA coverage increased after 2007. Baseline characteristics and injury severity scores were similar between groups. The mortality rate was higher in the OR group (19.5% vs 6.0%; P = .06), although it did not reach statistical significance. The overall incidence of morbidities was similar between the two groups (42% OR vs 50% TEVAR). Two patients developed paraplegia (4.4%) after OR compared with none after TEVAR. In the TEVAR group, a pseudoaneurysm, an iliac artery thrombosis, and a retroperitoneal hematoma developed in one patient each. Overall, eight patients (16%) developed stent graft-related complications (SRC), with two developing early (within 30 days) complications. All complications were related to poor apposition, requiring 10 reinterventions. Four patients underwent open conversions with no mortality. Nine out of 10 SRCs were associated with the use of thoracic stent graft malapposition. No patient treated with AEC had endoleaks or SRC. CONCLUSIONS: TEVAR for TTAI has superior survival outcomes and has replaced OR. SRC requiring reintervention is associated with malapposition and the use of TSG. Until TTAI specific endografts become available, use of AEC may minimize malapposition and reduce reinterventions. Routine overstenting of the LSA is not necessary and may increase SRC. PMID- 22503180 TI - Hybrid approach for removal of an errant intra-vascular pedicle spinal fixation screw in the thoracic aorta. AB - Late presentation of aortic injuries secondary to internal fixation hardware is uncommon and generally associated with pseudoaneurysm formation. We herein present a case of transmural migration of a pedicle screw into the descending thoracic aorta, which was revealed incidentally by computed tomography scan after almost 4 years of hardware implantation. Approximately 75% of the pedicle screw was exposed to the bloodstream, and was successfully removed using endovascular segmental exclusion to avoid aortic cross-clamping and an open approach via left thoracotomy. This case illustrates the successful repair of an iatrogenic aortic injury using a hybrid technique. PMID- 22503181 TI - Calcium channel blockers enhance sac shrinkage after endovascular aneurysm repair. AB - OBJECTIVE: Sac shrinkage is a surrogate marker of success after endovascular aneurysm repair (EVAR). We set out to determine if any common cardioprotective medications had a beneficial effect on sac shrinkage. METHODS: This retrospective observational study took place at Leeds Vascular Institute, a tertiary vascular unit in the Northern United Kingdom. The cohort comprised 149 patients undergoing EVAR between January 1, 2005, and December 31, 2008. Medication use was recorded at intervention (verified at study completion in 33 patients), and patients were monitored for 2 years. The main outcome measures were the effect of medication on sac shrinkage as determined by percentage change in maximal idealized cross sectional area of the aneurysm at 1 month, 6 months, 1 year, and 2 years by linear regression model, in addition to 2-year endoleak and death rates determined by a binary logistic regression model. RESULTS: After exclusions, 112 patients, who were a median age of 78 years (interquartile range, 78-83 years), remained for analysis. The median Glasgow Aneurysm Score was 85 (interquartile range, 79-92). At 2 years, mortality was 13.4%, endoleak developed in 37.5%, and significant endoleak developed in 14.3%. Patients taking a calcium channel blocker had enhanced sac shrinkage, compared with those not taking a calcium channel blocker, by 6.6% at 6 months (-3.0% to 16.3%, P = .09), 12.3% at 1 year (2.9% to 21.7%, P = .008), and 13.1% at 2 years (0.005% to 26.2%, P = .007) independent of other medication use, graft type, endoleak development, or death. CONCLUSIONS: Enhanced sac shrinkage occurred after EVAR in patients taking calcium channel blockers. This warrants further study in other centers and at the molecular level. PMID- 22503182 TI - Extensive congenital abdominal aortic aneurysm and renovascular disease in the neonate. AB - Primary congenital abdominal aortic aneurysm is an extremely rare entity, with only 15 patients reported in the literature. Options for repair are often limited secondary to branch vessel size and other anatomic limitations. We present a neonate diagnosed with an abdominal aortic aneurysm on prenatal ultrasound. A postpartum computed tomography angiogram revealed an extensive type IV thoracoabdominal aortic aneurysm extending to the aortic bifurcation and resulting in bilateral renal artery stenosis. The unique features of this patient and challenges in management are discussed. PMID- 22503183 TI - Delayed open conversions after endovascular abdominal aortic aneurysm repair. AB - OBJECTIVE: Secondary interventions after endovascular aneurysm repair (EVAR) remain a concern. Most are simple catheter-based procedures, but in some instances, open conversions (OCs) are required and carry a worse outcome. We reviewed our experience to characterize these OCs. METHODS: A retrospective review was conducted of all patients who underwent an OC after a previous EVAR for an aneurysm-related indication from 2001 to 2010. Clinical outcomes are reported. RESULTS: Data were reviewed for 44 patients (77% men) with a mean age of 74 years (range, 55-90 years). The average time from EVAR to the first OC was 45 months (range, 2-190 months). In six patients (14%), the initial EVAR was at another institution. The endografts used were Ancure in 16, Excluder in 13, AneuRx in eight, Zenith in three, Lifepath in one, Renu in one, and undetermined in two. Twenty-two patients had previously undergone a total of 32 endovascular reinterventions before their index OC. Indications for OC were aneurysm expansion in 28 (64%), rupture in 12 (27%), and infection in four (9%). The endograft was preserved in situ in 10 patients (23%). Explantation was partial in 18 (41%) or complete in 16 (36%). Endograft preservation was used for type II endoleak in all but one patient by selective ligation of the culprit arteries (lumbar in four, inferior mesenteric artery in five, and middle sacral in one). Proximal neck banding was performed in one type Ia endoleak. Overall morbidity was 55%, and mortality was 18%. No deaths occurred in a subgroup of patients who underwent endograft preservation with selective ligation of culprit vessels for type II endoleak. Intraoperative complications included bowel injury in two, bleeding in two, splenectomy in one, and ureteral injury in one. At a mean follow-up of 20 months, two patients underwent additional procedures after the index OC: one after endograft preservation and one after partial explantation. None of the patients who underwent elective OC with endograft preservation required subsequent endograft explantation. CONCLUSIONS: Most OCs after EVAR are associated with significant morbidity and mortality, except when electively treating an isolated type II endoleak with ligation of branches and preservation of the endograft. PMID- 22503184 TI - Bidirectional endovascular treatment for chronic total occlusive lesions of the femoropopliteal arterial segment using a hand-carried ultrasound device and a retrograde microcatheter. AB - BACKGROUND: Although endovascular therapy for complex lesions in the lower limbs has frequently achieved successful recanalization by improvement of techniques and devices, chronic total occlusion in the femoropopliteal arterial segment still remains a challenge for treatment by endovascular therapy. We investigated the efficacy and safety of endovascular therapy for chronic total occlusion in the femoropopliteal arterial segment guided by a hand-carried ultrasound (HCUS) device and supported by a retrograde microcatheter. METHODS: We attempted endovascular therapy for chronic total occlusion lesions in the femoropopliteal arterial segment using a protocol involving a dual-access procedure using the HCUS device and a retrograde 2.7F microcatheter from January 2008 to June 2010. We evaluated the success rate, complications, and clinical outcomes, including the ankle-brachial index (ABI) and primary and secondary patency. RESULTS: Success was achieved in 18 of 19 patients (95%), without major complications (only two small hematomas). The HCUS device was useful in reducing the personnel and space requirements, radiation exposure, and the required amount of contrast agent. The retrograde flexible 2.7F microcatheter was also useful in achieving successful recanalization and contributed to reducing puncture-related complications. The ABI was significantly improved, from 0.56 +/- 0.12 to 0.81 +/- 0.11 at 1 year (P < .01) and this effect remained stable. Primary and secondary patency was 63% and 89%, respectively, at 3 years. CONCLUSIONS: HCUS-guided and retrograde 2.7F microcatheter-supported endovascular therapy for chronic total occlusion lesions of the femoropopliteal arterial segment can achieve a favorable clinical outcome without major complications. PMID- 22503185 TI - Open surgical inferior vena cava filter retrieval for caval perforation and a novel technique for minimal cavotomy filter extraction. AB - Late complications of retrievable inferior vena cava (IVC) filters resulting from IVC perforation and erosion into adjacent structures is an increasingly frequent phenomena. We describe six cases of open filter explantation for IVC penetration and offer a novel technique for open filter removal without the need for an extensive cavotomy. All patients had radiographic evidence of filter erosion into pericaval structures requiring open surgical filter explant. Four of the six patients underwent minimal cavatomy filter extraction, eliminating the need for caval reconstruction. PMID- 22503186 TI - The surgical anatomy of the small saphenous vein and adjacent nerves in relation to endovenous thermal ablation. AB - BACKGROUND: Thermal damage to peripheral nerves is a known complication of endovenous thermal ablation (EVA) of the small saphenous vein (SSV). Therefore, the main objective of this anatomic study was to define a safe zone in the lower leg where EVA of the SSV can be performed safely. METHODS: The anatomy of the SSV and adjacent nerves was studied in 20 embalmed human specimens. The absolute distances between the SSV and the sural nerve (SN) (closest/nearest branch) were measured over the complete length of the leg (>120 data points per leg), and the presence of the interlaying deep fascia was mapped. The distance between the SSV and the tibial nerve (TN) and the common peroneal nerve was assessed. A new analysis method, computer-assisted surgical anatomy mapping, was used to visualize the gathered data. RESULTS: The distance between the SSV and the SN was highly variable. In the proximal one-third of the lower leg, the distance between the vein and the nerve was <5 mm in 70% of the legs. In 95%, the deep fascia was present between the SSV and the SN. In the distal two-thirds of the lower leg, the distance between the vein and the nerve was <5 mm in 90% of the legs. The deep fascia was present between both structures in 15%. In 19 legs, the SN partially ran beneath the deep fascia. In the saphenopopliteal region, the average shortest distance between the SSV and the TN was 4.4 mm. In 20%, the distance was <1 mm. The average, shortest distance between the SSV and the common peroneal nerve was 14.2 mm. The distance was <1 mm in one leg. CONCLUSIONS: At the saphenopopliteal region, the TN is at risk during EVA. In the distal two thirds of the lower leg, the SN is at risk for (thermal) damage due to the small distance to the SSV and the absence of the deep fascia between both structures. The proximal one-third of the lower leg is the optimal region for EVA of the SSV to avoid nerve damage; the fascia between the SSV and the SN is a natural barrier in this region that could preclude (thermal) damage to the nerve. PMID- 22503187 TI - Twenty-year review of abdominal aortic aneurysm screening in men in the county of Gloucestershire, United Kingdom. AB - OBJECTIVE: An ultrasound screening program for abdominal aortic aneurysms (AAAs) in men began in Gloucestershire in 1990 and has been running for 20 years. This report examines the workload and results. METHODS: We reviewed the screening database for attendance and outcome records from AAA surgery in Gloucestershire and postmortem and death certificate results looking for men who died from ruptured AAAs in the screening cohort. The setting was an AAA screening program in the county of Gloucestershire, UK. Men aged 65 were invited by year of birth to attend for an ultrasound screening for AAAs. Men with an aorta <2.6 cm were reassured and discharged; men with an aorta between 2.6 cm and 5.4 cm were offered follow-up surveillance; men with an aorta >5.4 cm were considered for intervention. We analyzed attendance rates, screening and surveillance outcomes, and intervention rates and outcomes over the 20 years of the study. RESULTS: Some 61,982 men were invited, and 52,690 attended for screening (85% attendance). At first scan, 50,130 men (95.14%) had an aortic diameter <2.6 cm in diameter and were reassured and discharged; 148 men (0.28%) had an AAA >5.4 cm in diameter and were referred for possible treatment; 2412 (4.57%) had an aortic diameter between 2.6 and 5.4 cm and entered a program of ultrasound surveillance. The overall mean aortic diameter on initial scan fell from 2.1 cm to 1.7 cm during the study (reduction 0.015 cm/y, 95% confidence interval [CI], 0.0144-0.0156 cm/y; P < .0001). Some 631 patients with AAAs had intervention treatment with a perioperative mortality rate of 3.9%; during the same interval, 372 AAAs detected incidentally were treated, with a mortality rate of 6.7%. The number of ruptured AAAs treated annually in Gloucestershire fell during the study (chi(2) for trend = 18.31, df = 1; P < .0001). CONCLUSIONS: Screening reduced the number of ruptured AAAs in Gloucestershire during the 20 years of the program. There has been a significant reduction of men with an abnormal aorta, as the mean aortic diameter of the 65-year-old male has reduced over 20 years. PMID- 22503188 TI - Challenges in the management of a patient with Cowden syndrome: case report and literature review. AB - We would like to present a patient with a classical phenotype of a rare disorder - Cowden syndrome, its diagnostics and management challenges. A breast surgeon has to be aware of this rare condition when treating a patient with breast manifestations of Cowden syndrome and has to refer the patient to a clinical geneticist for further evaluation. Sequencing of the PTEN gene showed the Asp24Gly mutation. According to the latest literature data, the lifetime risk of breast cancer for Cowden syndrome patients is 81% and surgery is a justified option to reduce the risk of breast cancer. Bilateral risk-reducing mastectomy with immediate reconstruction was performed to eliminate further risk of breast cancer. 3 years after the risk-reducing breast surgery the patient is satisfied with the outcome. This is to our best knowledge the first reported Cowden syndrome case with follow-up data after risk-reducing measures have been taken. PMID- 22503189 TI - Administration of botanicals with the diet regulates gene expression in peripheral blood cells of Sarda sheep during ACTH challenge. AB - The aim of the present research was to investigate the regulation of gene expression in ovine blood leukocytes during ACTH-induced cortisol release and the effect of dietary administration of botanicals to counteract the evoked response in polymorphonucleate cells (PMNCs). Thirty-six homogeneous Sarda sheep (age, 18+/-4.1 mo; BW, 38.7+/-1.3 kg) were allotted to six groups of six sheep each. One group was used as a negative control (Saline) and five groups were treated, every 12 h for 48 h, with 0.5 mL of ACTH agonist (250 MUg/mL of tetracosactrin). Before ACTH treatment, four of the five ACTH-treated groups were separated and fed for 22 d with a basal diet supplemented with extracts from Echinacea angustifolia roots (PO+ACTH), Echinacea angustifolia flowers (EA+ACTH), Andrographis paniculata (AP+ACTH), and the bark of Larix decidua milled (LB+ACTH). Control groups (Saline and ACTH) were fed with the same basal diet without botanicals. Total RNA was extracted from blood samples collected before (T0) and after 3 h (T3) and 51 h (T51) from the first ACTH injection, and transcriptome analysis was performed using a custom oligoarray, designed from 12,194 Ovis aries UniGenes on a CombiMatrix platform. At T3, treatment with ACTH caused down-regulation of transcripts (P<0.001) involved in "response to stress" (GADD45A, GADD45B, WRNIP1, and XRCC6) and in "innate immune response" (MAPK3 and NFkBIB). At T51, treatment with ACTH caused down-regulation (P<0.001) of genes involved in "immune response" (IFNG and IL2) and up-regulation (P<0.001) of NF kappaB1 and TP53. Each botanical produced a different (P<0.001) molecular signature for these genes at T3 and T51. The most active botanical in modulating transcriptome modifications in PMNCs after ACTH-induced cortisol release was Larix decidua Mill bark followed by Polinacea roots. These botanicals can be viewed as promising feed supplements in ruminants to cope with conditions associated with increased concentrations of plasma cortisol. PMID- 22503192 TI - Kinetic modeling of bioregeneration of chlorophenol-loaded granular activated carbon in simultaneous adsorption and biodegradation processes. AB - A kinetic model incorporating adsorption, desorption and biodegradation processes was developed to describe the bioregeneration of granular activated carbon (GAC) loaded with 4-chlorophenol (4-CP) and 2,4-dichlorophenol (2,4-DCP), respectively, in simultaneous adsorption and biodegradation processes. The model was numerically solved and the results showed that the kinetic model was well-fitted (R(2)>0.83) to the experimental data at different GAC dosages and at various initial 4-CP and 2,4-DCP concentrations. The rate of bioregeneration in simultaneous adsorption and biodegradation processes was influenced by the ratio of initial chlorophenol concentration to GAC dosage. Enhancement in the rate of bioregeneration was achieved by using the lowest ratio under either one of the following experimental conditions: (1) increasing initial chlorophenol concentration at constant GAC dosage and (2) increasing GAC dosage at constant initial chlorophenol concentration. It was found that the rate enhancement was more pronounced under the second experimental condition. PMID- 22503190 TI - A novel immunosensor based on an alternate strategy of electrodeposition and self assembly. AB - A novel amperometric immunosensor for the determination of carcinoembryonic antigens (CEA) was developed. Firstly, ordered multilayer films of Prussian blue (PB) and multiwalled-carbon nanotube/polyethylenimine/Au (MWNT-PEI-Au) nanocomposite were fabricated onto the surface of a glassy carbon electrode via alternate electrodeposition and self-assembly. Then a layer of chitosan mixed with gold nanoparticles was cast onto the surface of the electrode. Subsequently, the electrode was coated with antibody (Ab(1)) and blocked with BSA. The morphology of the MWNT-PEI-Au nanocomposite was characterized by transmission electron microscopy (TEM). The fabrication process of the ordered multilayer structure and immunosensor were characterized by scanning electron microscopy (SEM) and electrochemical measurements, respectively. The proposed fabrication strategy effectively ensured the stability of the Prussian blue as electron mediator. Under optimal conditions, the fabricated immunosensor exhibited a good response to CEA, with a detection range from 0.5 to 160 ng/mL and a detection limit of 0.08 ng/mL at 3delta. The current fabricated immunosensor exhibited good sensitivity, selectivity, and long-term stability. Furthermore, current study demonstrated the promising application of the alternate strategy based on electrodeposition and self-assembly for the construction of biosensor. PMID- 22503193 TI - Reduction of water and energy requirement of algae cultivation using an algae biofilm photobioreactor. AB - This paper reports the construction and performance of an algae biofilm photobioreactor that offers a significant reduction of the energy and water requirements of cultivation. The green alga Botryococcus braunii was cultivated as a biofilm. The system achieved a direct biomass harvest concentration of 96.4 kg/m(3) with a total lipid content 26.8% by dry weight and a productivity of 0.71 g/m(2) day, representing a light to biomass energy conversion efficiency of 2.02%. Moreover, it reduced the volume of water required to cultivate a kilogram of algal biomass by 45% and reduced the dewatering energy requirement by 99.7% compared to open ponds. Finally, the net energy ratio of the cultivation was 6.00 including dewatering. The current issues of this novel photobioreactor are also identified to further improve the system productivity and scaleup. PMID- 22503194 TI - Thermophilic anaerobic co-digestion of separated solids from acidified dairy cow manure. AB - This study examined the potential for partly substituting dairy cow manure (DCM) with solids from solid to liquid separation of acidified dairy cow manure (SFDCM) during thermophilic anaerobic digestion. Three different substituting levels with a maximum of 30% substitution were tested. All digesters substituting DCM with SFDCM showed a stable biogas production with low volatile fatty acid concentrations after a short transition period. An increased methane yield in terms of digester volume compared to DCM alone was obtained with increasing amount of SFDCM and about 50% more methane was achieved when 30% of DCM was substituted with SFDCM. The digestates were subsequently digested in a post digestion, during which the methane yield increased proportionally with increasing amounts of SFDCM. It can be concluded that SFDCM is a suitable biomass for co-digestion and can be used to increase methane yield in terms of digester volume at ratios up to at least 30%. PMID- 22503195 TI - Nitrite accumulation under constant temperature in anoxic denitrification process: The effects of carbon sources and COD/NO(3)-N. AB - Effects of external carbon sources and COD/NO(3)-N on nitrite accumulation through denitrification were studied at a temperature of 28+/-2.0 degrees C using mixed activated sludge. Nitrite accumulation was observed for each type of carbon source studied. Glucose resulted in the greatest nitrite accumulation and production rate, which were 14.51+/-2.41 mg/L and 0.121+/-0.013 g N/(g VSS d), respectively. Moreover, a higher COD/NO(3)-N ratio ranging from 1.0 to 15.0 increased accumulation to the maximum value of 0.34+/-0.03 g N/(g VSS d). It was assumed that the competition for electrons between nitrite reductase and nitrate reductase led to different reduction rates and finally caused the accumulation. In addition, it was reasonable to use the pH and ORP as proxies for monitoring the real endpoint of the denitrification process with the addition of carbon sources. PMID- 22503196 TI - Biosynthesis of long chain hydroxyfatty acids from glucose by engineered Escherichia coli. AB - This study devised a pathway in Escherichia coli for direct production of long chain hydroxyfatty acids (HFAs) from glucose. This is first report on the biosynthesis of HFAs from renewable sugar, without the need of exogenous fatty acids. By employing thioesterases BTE and 'TesA to tailor the composition of free fatty acids (FFAs) and using fatty acid hydroxylase P450(BM3) to convert FFAs to HFAs, high-specificity production of C12 and C14 HFAs was achieved. By further knocking out the endogenous fadD gene of E. coli, an engineered strain capable of producing 117.0 mg/L HFAs was finally obtained, representing a high HFA production in shake flask. This study indicated an attractive metabolic strategy for the biosynthesis of HFAs directly from renewable carbohydrates resources. PMID- 22503197 TI - Curriculum meeting points: a transcultural and transformative initiative in nursing education. AB - Following the Bologna initiative in the 1990s, schools of nursing across Europe began considering ways in which they might collaborate with each other in educating nurses in advanced/post-bachelor programs. There were various levels of success which led the writers to explore if such collaboration was possible with similar programs in the United States. Spearheaded by the Institute of Nursing at the Oslo and Akershus University College of Applied Sciences (HiOA), a consortium was established in 2010 to explore the possibilities of international collaborations in this area. In the process, recognition of subtle and more obvious barriers to such collaborations emerged. Consortium members agreed that there was a need to explore the origins and effects of these barriers and the assumptions which seemed to underpin them. The identified barriers were often caused by assumptions about the content of educational programs and about individual and collective approaches to teaching and learning. Several participants experienced a shift in consciousness about nursing education following the consortium's initial meeting in Oslo. For some, there was a feeling of finding 'like-minded thinkers' and for others it was like viewing a new landscape. This article details the evolution of the consortium and the philosophic underpinnings which guide its continued deliberations. PMID- 22503198 TI - The Medicine with Respect Project: a stakeholder focus group evaluation. AB - The administration of medicines is a role that fundamentally impacts on the wellbeing of the patient and has been described as one of the highest risk activities that a nurse undertakes. This article reports on the Medicine with Respect Project where collaborating organisations sought to improve the education and training of Mental Health Nurses toward safe and competence practice. Focus groups were used to evaluate stakeholders experiences and what emerged was overall satisfaction but with specific suggestions in how to improve the effectiveness of the project. All groups emphasised that all nurses in administering medicines should undergo a rigorous assessment of their medicines administration performance. This would make the ultimate aim of competent and safe practice more achievable. PMID- 22503199 TI - Is VAMLA/TEMLA the new standard of preresection staging of non-small cell lung cancer? AB - Accurate mediastinal staging is the hallmark of a good thoracic oncology program. Mediastinal lymph node staging is important for prognostication and to guide the administration of neoadjuvant and adjuvant therapy. In addition, accurate mediastinal staging is necessary for a fair comparison of different clinical studies. The most important surgical advance in mediastinal lymph node staging in the past few years is transcervical staging, by either sternal elevation or video assisted mediastinoscopy. The present report summarizes the existing published data evaluating such an approach. PMID- 22503200 TI - Surgical approaches to apical thoracic malignancies. AB - OBJECTIVE: Several surgical approaches have been described to access apical thoracic malignancies extending into the thoracic inlet. However, most publications have focused on a specific approach and considered the thoracic inlet as 1 entity. In the present analysis, we divided the thoracic inlet into 5 different zones requiring specific surgical considerations to identify the best approach for each zone. METHODS: A review of 22 consecutive patients undergoing surgery for apical thoracic malignancies extending into the thoracic inlet from January 2005 to November 2011 was performed. RESULTS: Different surgical approaches were used for each zone. The first (anterolateral) zone required a subclavicular approach to open the costoclavicular space and expose the subclavian vein with or without elevating or removing the clavicle (n = 4). The second (anterocentral) zone required a transverse supraclavicular approach with or without extension to a partial (trapdoor) or full sternotomy (n = 10). The third (posterosuperior) zone located between the top of the subclavian artery and the T1 vertebra along the posterior superior border of the first rib was the most difficult area to access (n = 5). The transclavicular approach was ideally suited to expose this zone in our experience. The fourth (posteroinferior) zone and fifth (inferolateral) zone located posteriorly and laterally along the inferior border of the first rib were accessed using a posterolateral and posterotransaxillary approach, respectively (n = 3). CONCLUSIONS: The thoracic inlet could be divided into 5 zones requiring specific surgical considerations and different approaches. Division of the thoracic inlet into these zones could provide more clarity and guidance for thoracic surgeons to select the correct surgical approach. PMID- 22503201 TI - Low-flow antegrade cerebral perfusion attenuates early renal and intestinal injury during neonatal aortic arch reconstruction. AB - OBJECTIVE: Deep hypothermic circulatory arrest (DHCA) and antegrade cerebral perfusion (ACP) are 2 cardiopulmonary bypass strategies mainly used in aortic arch reconstructions. It has been suggested that during ACP, abdominal organs are better protected than during DHCA owing to partial perfusion via collaterals. We tested this hypothesis using intraoperative near-infrared spectroscopy (NIRS), lactate measurements, and biomarkers for early abdominal injury in neonates undergoing complex aortic arch repair. METHODS: Neonates scheduled for aortic arch reconstruction via median sternotomy between 2009 and 2011 were randomized to either DHCA or ACP. During surgery, regional oxygen saturations of the abdomen were monitored using NIRS. Immediately aafter DHCA or ACP, lactate concentrations from the inferior vena cava were compared with those from the arterial cannula. Postoperatively, biomarkers for early abdominal organ injury were measured in urine. RESULTS: Twenty-five neonates were analyzed (DHCA, n = 12; ACP, n = 13). Procedures were performed at 18 degrees C, and ACP flow was set at 35 to 50 mL . kg(-1) . min(-1). Median abdominal NIRS value during DHCA was 31% (IQR, 28%-41%) whereas during ACP it was 56% (IQR, 34%-64%; P < .01 between groups). Immediately after DHCA, median lactate from the inferior vena cava was 4.2 mmol/L (IQR, 3.3 5.3 mmol/L) compared with 3.1 mmol/L (IQR, 2.9-4.4 mmol/L) after ACP (P = .03). Postoperatively, biomarkers for renal and intestinal damage (gluthatione s transferase and intestinal fatty acid binding protein, respectively) were higher in the DHCA group than for the ACP group (P = .03, P = .04, respectively). CONCLUSIONS: These results substantiate earlier suggestions that ACP provides more abdominal organ protection than DHCA in neonates undergoing aortic arch reconstruction. PMID- 22503202 TI - Prediction of the critical thermal zone during pulmonary cryoablation on computed tomography from correlated experimental and clinical findings. AB - OBJECTIVE: During cryoablation, cells are destroyed at temperatures less than -20 degrees C. The determining factors for local cancer control in pulmonary cryoablation were assessed using computed tomography (CT), isothermal curves, and histologic findings in pigs. Experimental findings were compared with clinical CT findings and were extrapolated to local cancer control outcomes. METHODS: Cryoablation was performed with thermal monitoring, and the ablated areas were divided into 3 zones: less than -20 degrees C, -20 degrees C to 0 degrees C, and greater than 0 degrees C and were compared with histologic findings. CT findings with multiplanar reconstruction in 36 nodules were compared with the porcine histologic findings. The relationship between CT findings and 3-year local cancer control was evaluated in 98 nodules. RESULTS: The 3 concentric thermal zones correlated with histologic findings as follows: less than -20 degrees C zone, complete tissue destruction (zone D); -20 degrees C to 0 degrees C zone (which surrounded zone D), hemorrhage with air trapping and maintenance of alveolar structures (zone H); and greater than 0 degrees C zone (outermost), edema with sustained alveolar structures (zone E). The CT findings in 36 nodules showed a central solid zone, a surrounding air-containing zone, and an outside solid zone, corresponding to zones D, H, and E, respectively. Local cancer control at 3 years in 80 nodules contained within the central solid zone was significantly greater compared with the 18 nodules that were not (82% vs 33%, P = .0002). CONCLUSIONS: Pulmonary cryoablation should be performed such that tumors are contained within the central solid zone on CT, which represents the less than -20 degrees C zone. PMID- 22503203 TI - Extracorporeal membrane oxygenation after stage 1 palliation for hypoplastic left heart syndrome. AB - OBJECTIVE: To report the outcomes from a large multicenter cohort of neonates requiring extracorporeal membrane oxygenation (ECMO) after stage 1 palliation for hypoplastic left heart syndrome. METHODS: Using data from the Extracorporeal Life Support Organization (2000-2009), we computed the survival to hospital discharge for neonates (age <=30 days) supported with ECMO after stage 1 palliation for hypoplastic left heart syndrome. The factors associated with mortality were evaluated using multivariate logistic regression analysis. RESULTS: Among 738 neonates, the survival rate was 31%. The median age at cannulation was 7 days (interquartile range, 4-11). Black race (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.2-3.6), mechanical ventilation before ECMO (>15-131 hours: OR, 1.6; 95% CI, 1.1-2.4; >131 hours: OR, 1.9; 95% CI, 1.3-2.9), use of positive end expiratory pressure (>6-8 cm H(2)O: OR, 1.7; 95% CI, 1.1-2.7; >8 cm H(2)O: OR, 1.9; 95% CI, 1.2-3.1), and longer ECMO duration (per day, OR, 1.2; 95% CI, 1.1 1.3) increased mortality. ECMO support for failure to wean from cardiopulmonary bypass (OR, 1.6; 95% CI, 1.02-2.4) also decreased survival. ECMO complications, including renal failure (OR, 1.9; 95% CI, 1.2-3.1), inotrope requirement (OR, 1.5; 95% CI, 1.1-2.1), myocardial stun (OR, 3.2; 95% CI, 1.3-7.7), metabolic acidosis (OR, 2.9; 95% CI, 1.3-6.7), and neurologic injury (OR, 1.7; 95% CI, 1.1 2.6), during support also increased mortality. CONCLUSIONS: Mortality for neonates with hypoplastic left heart syndrome supported with ECMO after stage 1 palliation is high. Longer ventilation before cannulation, longer support duration, and ECMO complications increased mortality. PMID- 22503204 TI - Warm beating heart with deep hypothermic circulatory arrest: a technique for an unclampable aorta with aortic valve regurgitation. PMID- 22503205 TI - Role of the sinuses of Valsalva on the opening of the aortic valve. AB - OBJECTIVE: The present in vitro study was designed to ascertain whether the presence of sinuses of Valsalva in the aortic root were able to regulate the valve effective orifice area and modulate the gradient across the valve independently from root compliance. METHODS: Four different root configurations were prepared. Of the 4, 2 were silicon configurations with the same compliance, 1 with and 1 without sinuses of Valsalva, in which a 25-mm Solo stentless aortic valve was sutured inside. The other 2 configurations were obtained by substituting the upper part of the root with a straight Dacron graft or with a Valsalva graft in a remodeling fashion to reproduce the surgical situation. All roots were mounted in a pulse duplicator to measure the pressure decrease across the valve and effective orifice area at different cardiac outputs. RESULTS: With increasing cardiac output up to 7 L/min, an increase in the pressure decrease across the valve was evident in both configurations without sinuses of Valsalva (7.90 +/- 1.7 and 11 mm Hg +/- 0.1 mm Hg, respectively) but not in those with sinuses (2.87 +/- 0.5 and 2.42 mm Hg +/- 0.5 mm Hg). Similarly, with increasing cardiac output, the effective orifice area increased significantly only in the roots with sinuses (5.13 +/- 0.5 and 5.47 +/- 0.5 vs 3.06 +/- 0.3 and 2.50 cm(2) +/- 0.02 cm(2), respectively). CONCLUSIONS: When the cardiac output is increased to greater than the resting physiologic values, the presence of sinuses of Valsalva, independently of root compliance, prevents an increase in the pressure decrease across the valve by way of an increase of the effective orifice area. PMID- 22503206 TI - Prevalence of risk factors for tail biting on commercial farms and intervention strategies. AB - A husbandry advisory tool (HAT) was devised to help pig producers and their advisors identify and minimise possible risk factors for tail biting in finishing pigs. The prevalence of 83 risk factors identified from the literature and expert opinion was recorded on 65 commercial pig farms in England between May 2007 and July 2009. Those considered most important were associated with atmosphere/environment, environmental enrichment, the provision of food/drink and animal health factors. Forty-six farms received advice on minimising these risks and, of these, 27 also received a financial incentive to encourage the uptake of advice. A reduction in risk factors was observed on 42/57 farms visited at the end of the study, with the greatest reduction occurring on the farms that had been incentivised. However, farms not receiving advice also had reduced risk factors associated with atmosphere/environment and stocking density over the course of the study. In conclusion, while some risk factors are structural and require substantial capital investment to change, a significant reduction in the risk of tail biting can be achieved on many farms through the systematic evaluation and modification of management practices. PMID- 22503207 TI - Imidazonaphthyridine systems (part 2): Functionalization of the phenyl ring linked to the pyridine pharmacophore and its replacement by a pyridinone ring produces intriguing differences in cytocidal activity. AB - We recently discovered that five- and pseudo-five-fused-ring derivatives in an imidazonaphthyridine series were promising hit compounds for the development of new DNA-intercalators. In this study, novel (dihydro)imidazo[1,6] and [1,7]naphthyridi(no)nes were prepared including pseudo-pentacycles. All the compounds synthesized were screened against four tumor cell lines. Compounds 3(b d) showed significant in vitro cytotoxicity, and DNA intercalation properties were demonstrated at 25 MUM. Imidazonaphthyridinones exhibited no DNA binding affinity despite significant growth inhibition activity. Interestingly, when a pyridinone pharmacophore was linked to the imidazo[1,2-a]pyridine scaffold, the geometric orientation of the link had a strong impact on the growth inhibition activity. From these results we conclude that the moderate cytotoxicity observed for these compounds is independent of their DNA-binding and topoisomerase inhibition activities. PMID- 22503208 TI - Synthesis, structure-activity relationship and in vitro anti-mycobacterial evaluation of 13-n-octylberberine derivatives. AB - Twenty-eight new 13-n-octylberberine derivatives were synthesized and evaluated for their activities against drug-susceptible Mycobacterium tuberculosis (M. tuberculosis) strain H(37)Rv. Among these compounds, compound 16e was the most effective anti-tubercular agent with a MIC value of 0.125 MUg/mL. Importantly, compound 16e exhibited more potent effect against rifampicin (RIF)- and isoniazid (INH)-resistant M. tuberculosis strains than both RIF and INH, suggesting a new mechanism of action. Therefore, it has been selected as a drug candidate for further investigation, or as a chemical probe for identifying protein target and studying tuberculosis biology. We consider 13-n-octylberberine analogs to be a promising novel class of antituberculars against multi-drug-resistant (MDR) strains of M. tuberculosis. PMID- 22503210 TI - Tumor PD-L1 co-stimulates primary human CD8(+) cytotoxic T cells modified to express a PD1:CD28 chimeric receptor. AB - Tumors exploit immunoregulatory checkpoints that serve to attenuate T cell responses as a means of circumventing immunologic rejection. Programmed death ligand 1 (PD-L1) is a negative regulator of T cell function and is frequently expressed by solid tumors. By engaging programmed death 1 (PD-1) on activated T cells, PD-L1(+) tumors directly render tumor-specific T cells, including adoptively transferred T cells, functionally exhausted. As a strategy to overcome tumor PD-L1 effects on adoptively transferred T cells, we sought to convert PD-1 to a T cell costimulatory receptor by exchanging its transmembrane and cytoplasmic tail with that of CD28. Rather than becoming exhausted upon engagement of PD-L1(+) tumors, we hypothesized that CD8(+) cytotoxic T lymphocytes (CTL) genetically modified to express this PD1:CD28 chimera would exhibit enhanced functional attributes. Here we show that cell surface expressed PD1:CD28 retains the capacity to bind PD-L1 resulting in T cell costimulation as evidenced by increased levels of ERK phosphorylation, augmentation of cytokine secretion, increased proliferative capacity, and enhanced expression of effector molecule Granzyme B. We provide evidence that this chimera could serve as a novel engineering strategy to overcome PD-L1 mediated immunosuppression. PMID- 22503209 TI - Magnetic beads-based enzymatic spectrofluorometric assay for rapid and sensitive detection of antibody against ApxIVA of Actinobacillus pleuropneumoniae. AB - In this paper, a simple, easily-operated and enzyme-amplified fluorescence immunoassay method using magnetic particles for the detection of antibody against Actinobacillus pleuropneumoniae (APP) has been presented. The A protein of APP Repeats-in-Toxin IV (ApxIVA) with high specificity to the APP species was immobilized onto the magnetic bead surfaces. Horseradish peroxidase (HRP), which can catalyze the substrate 4-hydroxyphenylacetic acid (p-HPA), generating fluorescent bi-p, p'-hydroxyphenylacetic acid (DBDA), was selected as an enzymatic-amplified tracer. The ApxIVA antibody was detected for the presence of APP infection by measuring the fluorescence intensity of DBDA. Under optimal conditions, the calibration plot obtained for standard positive serum was approximately linear within the dilution range 1:160-1:5120. The limit of detection (LOD) for the assay was 1:10240, considerably lower than that of ApxIVA ELISA (1:320) (S/N=3). A series of repeatability measurements of using 1:320-fold diluted standard positive serum gave reproducible results with a relative standard deviation (RSD) of 4.8% (n=11). The ability of the immunosensor to analyze clinical samples was tested on porcine sera. The immunosensor yielded an efficiency of 89.7%, sensitivity of 90.9% and specificity of 89.3% compared with ApxIVA-ELISA. PMID- 22503211 TI - [Invasive fungal infection in critically ill patients]. AB - The most common organism implicated in fungal infections in the critically ill patients is Candida spp. C. albicans continues to be the species that causes the largest number of invasive candidiasis. In critically ill patients, Candida spp. are frequently isolated in non-sterile sites. Candida colonization is documented in nearly 60% of non-neutropenic critically ill patients staying more than one week in the ICU. However, only 5% of colonized patients will develop invasive candidiasis. The diagnosis of invasive non-candidemic candidiasis remains elusive in the majority of the patients. Candida in a blood culture should never be viewed as a contaminant and should always prompt treatment initiation. Patients with multifocal colonization with a Candida score >3 should also receive antifungal therapy. Fluconazole is reserved for non-severely ill patients without recent exposure to azoles. The use of an echinocandin is recommended for hemodynamically unstable patients or with a history of recent fluconazole exposure. PMID- 22503212 TI - Pharmacokinetic and pharmacodynamic properties of the calcimimetic agent cinacalcet (KRN1493) in healthy male Korean subjects: a randomized, open-label, single ascending-dose, parallel-group study. AB - BACKGROUND: Cinacalcet (KRN1493) was developed to manage secondary hyperparathyroidism in patients with chronic kidney disease. The characteristics of cinacalcet have not been studied in the Korean population. OBJECTIVE: The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties and tolerability of single-dose cinacalcet 50 to 100 mg in healthy male Korean subjects for the purposes of a New Drug Application package for the Korean Food and Drug Administration. METHODS: A randomized, open-label, single ascending-dose, parallel-group study was conducted in healthy male Korean subjects. Subjects were randomly assigned to receive a single oral dose of cinacalcet 50, 75, or 100 mg. Serial blood samples for PK/PD analysis were taken for up to 96 hours after administration. Plasma cinacalcet concentrations were analyzed by HPLC-MS/MS. PK parameters were determined using noncompartmental methods. Plasma intact parathyroid hormone (iPTH) concentrations, albumin corrected serum calcium concentrations, and serum phosphorus concentrations were measured for PD evaluation. For the evaluation of tolerability, adverse events (AEs) were collected using investigators' questionnaires, subjects' spontaneous reports, clinical laboratory tests, ECG, and physical examinations including vital sign measurements. RESULTS: Sixteen subjects in the 50-mg group, 16 in the 75-mg group, and 6 in the 100-mg group completed the study and were included in the PK/PD analysis. The mean (SD) age, height, and weight of the study population were 4.3 (3.0) years, 174.8 (4.9) cm, and 68.2 (7.5) kg, respectively. The median T(max) value in each of the 3 dose groups was 6.0 hours. Mean C(max) values in the 50-, 75-, and 100-mg dose groups were 12.0 (5.5), 17.2 (14.9), and 43.1 (15.5) MUg/L; mean AUC(0-infinity) values were 126.6 (56.4), 184.3 (87.9), and 417.4 (169.9) MUg . h/L. Characteristics were not linear, based on the data over the dose range of 50 to 100 mg. Mean plasma iPTH concentrations in the 50-, 75-, and 100-mg dose groups were decreased from baseline by 64.0% (11.7%), 63.1% (14.6%), and 70.6% (6.3%). Albumin-corrected serum calcium concentrations displayed patterns similar to those of the plasma iPTH concentrations. Sixteen AEs were reported in 11 subjects. No clinically significant abnormalities were observed in the tolerability assessments. CONCLUSIONS: A single oral dose of cinacalcet was well-tolerated up to 100 mg in this small, selected population of healthy male Korean subjects. In addition, the PK characteristics of cinacalcet and its accompanying PD changes-the decreases in the concentrations of plasma iPTH and albumin corrected serum calcium-were demonstrated in the same population. ClinicalTrials.gov identifier: NCT00942773. PMID- 22503213 TI - Cancer incidence in patients with polyglutamine diseases: a population-based study in Sweden. AB - BACKGROUND: Polyglutamine (polyQ) diseases are characterised by the expansion of CAG triplet repeats in specific genes. The accumulated encoded proteins affect the transcription of numerous transcription factors. We investigated whether polyQ diseases reduce the risk of cancer development. METHODS: Data on patients with the polyQ diseases Huntington's disease (HD), spinobulbar muscular atrophy (SBMA), and hereditary ataxia (HA) in Sweden were linked to the Swedish Cancer Registry. We calculated standardised incidence ratios for cancers at specific sites or of specific types and the risks were compared with those in the general population. We also analysed risks in the unaffected parents of patients. FINDINGS: In the period January, 1969, to December, 2008, we identified 1510 patients with HD, 471 with SBMA, and 3425 with HA. Cancer was diagnosed in 91 (6.0%) HD patients, 34 (7.2%) SBMA patients, and 421 (12.3%) HA patients. The standardised incidence ratios were 0.47 (95% CI 0.38-0.58), 0.65 (0.45-0.91), and 0.77 (0.70-0.85), respectively. Before diagnosis of polyQ disease, the risk of cancer was even lower. Cancer incidence and risk in the unaffected parents of patients with polyQ diseases were similar to those in the general population. INTERPRETATION: The consistently decreased incidence of cancer in patients with polyQ diseases suggests that a common mechanism protects against the development of cancer. This feature could be related to the polyQ-tract expansion seen in these diseases. Further studies are warranted to investigate the underlying mechanisms linking cancer and polyQ diseases. FUNDING: Swedish Cancer Society, Swedish Council for Working Life and Social Research. PMID- 22503214 TI - Successful microcosm demonstration of a strategy for biodegradation of a mixture of carbon tetrachloride and perchloroethene harnessing sulfate reducing and dehalorespiring bacteria. AB - Carbon tetrachloride (CT) is known to inhibit the transformation of perchloroethene (PCE) to ethene by dehalorespiring bacteria, creating a challenge for the bioremediation of environments contaminated with both compounds. We report on the sequential use of sulfate reduction and dehalorespiration as a microbial strategy for the transformation of a mixture of CT (10 MUM) and PCE (14 MUM). Sulfide production in Desulfovibrio vulgaris cultures led to complete CT disappearance in as little as 12 days. The addition of amorphous ferric oxide decreased the proportion of chloroform (CF) produced from 65% to 30%. CT conversion rates were enhanced more than 13-fold where vitamin B(12) (5 MUM) was added. In vitamin B(12)-containing D. vulgaris cultures, no chlorinated products were detected and carbon disulfide was the major product of CT transformation. PCE concentrations were not impacted upon by D. vulgaris activity. The subsequent inoculation of a PCE-respiring enrichment culture resulted in microbial PCE dechlorination to ethene. PMID- 22503215 TI - Controlled expedient disposal of excess gun propellant. AB - The expedient field disposal of excess gun propellants on the ground is an integral part of live-fire training in many countries. However, burning excess propellant in the field will leave significant quantities of energetic residues and heavy metals in the environment. Compounds such as dinitrotoluene and nitroglycerin and metals such as lead will leach into the soil column, eventually migrating to groundwater. Contamination of the environment will lead to high remediation costs and the possible loss of the training facility. After investigating the contamination at several propellant disposal sites, a portable propellant burn pan was developed and tested. The pan was transported to training sites where excess propellant was loaded and burned in a controlled manner. Up to 120 kg of excess single-base propellant charges have been burned during two series of tests at a consumption rate of greater than 99.9%. Less than 0.03% of the energetic material was recovered outside the burn pan. Recovered lead is largely contained within the pan. The turnover rate for burns is 15 min. The residues can be collected following cool-down for proper disposal. PMID- 22503216 TI - Visible light CrO4(2-) reduction using the new CuAlO2/CdS hetero-system. AB - In this study, 64% of hexavalent chromium Cr(VI) reduction from the initial concentration (10(-4) M) is reported under visible light using the (CuAlO(2)/CdS) hetero-system. In this new hetero-system, low doped CuAlO(2) delafossite, synthesized by sol-gel works as an electrons reservoir with a wide space charge region (440 nm). In this case, the electron transfer to chromate is mediated via the hexagonal CdS variety, whose conduction band level is at -1.08 V with respect to the saturated calomel electrode which is more negative than the CrO(4)(2 )/Cr(3+) level. This high reduction rate is achieved under optimized pH and CuAlO(2) percentage. Moreover, salicylic acid gives the best performance among hole scavengers and CuAlO(2) approaches 100% photostability at pH 7.5. The photo catalytic process follows a pseudo first order kinetic with a half life of 2h. The reaction products are identified by UV-visible spectrophotometry and linear voltametry at a platinum rotating electrode. The results reveal the presence of Cr(3+) after irradiation. PMID- 22503217 TI - Selective recovery of soil-borne metal contaminants through integrated solubilization by biogenic sulfuric acid and precipitation by biogenic sulfide. AB - A hybrid process combining solubilization via sulfuric acid produced by sulfur oxidizing bacteria with precipitation via sulfide produced by sulfate-reducing bacteria was investigated to isolate soil-borne metal contaminants as purified metal-sulfides. The highly efficient two-step acidification process involved bioproduction of sulfuric acid in a culture medium containing 30% (v/v) of sludge filtrate (SF). Soil was added to the culture after maximum acid production. Solubilization efficiencies of 95% for Zn, 76% for Cu and 97% for Cd were achieved after 16 days. At pH 1.9, 3.0 and 4.0, 99% of Cu(2+), 96% of Cd(3+) and 93% of Zn(2+), respectively, were precipitated from the soil leachate by sulfide transported from sulfidogenic bioreactor via N(2) sparging, resulting in final effluent metal contents at the ppb-level. The introduction of SF did not affect the precipitation kinetics and purity of the recovered precipitates. Ultimately, 75% of Cu and 86% of Zn were recovered from the soil as pure CuS and ZnS (confirmed by SEM-EDS and XRD). These results demonstrate the potential of the integrated method for the selective production of valuable metals from metal contamination in soils. PMID- 22503218 TI - Potential benefit of surfactants in a hydrocarbon contaminated soil washing process: fluorescence spectroscopy based assessment. AB - Soil washing is an ex situ soil remediation treatment process. The purpose of soil washing is to clean the major gravel and sand fractions, concentrating contamination into the fine silt and clay fractions. The addition of surfactants can improve the efficiency of this method. Here we report the use of UV fluorescence spectroscopy to assess the hydrocarbon cleaning process as a rapid and cost effective alternative to gas chromatography. Three wash solutions were tested on a total petroleum hydrocarbon contaminated soil: water, Sea Power 101 (SP101) at 1% (v/v) and Tween80 at 0.5% (w/v). The most effective to wash the gravel and sand was SP101 (54 and 65% improvement over the water only wash, respectively) which moved contamination to the silt fraction (94% of contaminants). Tween80 appeared not to enhance TPH removal efficiency from the gravel and sand fractions but did concentrate TPH in the effluent (95% more than water wash). In addition to TPH removal from gravel and sand, SP101 also showed potential benefit in the soil washing sedimentation process, enhancing sludge/water volume separation by 10% over the water only wash. In summary, fluorescence spectroscopy proved an effective technique to compare TPH removal efficiencies as part of soil washing laboratory based treatability testing. PMID- 22503219 TI - Mechanisms-based assessment and treatment of pain: the art of fine dissection. PMID- 22503220 TI - The basis for medical therapy of fibromyalgia with growth hormone. PMID- 22503221 TI - Development and validation of shortened, restructured Treatment Outcomes in Pain Survey instrument (the S-TOPS) for assessment of individual pain patients' health related quality of life. AB - Chronic pain produces major functional disability and quality-of-life impairment. Monitoring of health-related quality of life (HRQoL) outcomes in chronic pain patients during treatment is of great importance. Nevertheless, monitoring individual chronic pain patients remains a challenge due to the lack of a validated and efficient HRQoL assessment instrument. The Treatment Outcomes in Pain Survey (TOPS) is a validated HRQoL tool with sufficient accuracy and sensitivity to monitor the overall pain experience of individual patients while receiving multidisciplinary chronic pain management. However, the amount of time required to complete the TOPS questionnaire limits routine clinical utility and patient compliance. The full 14 TOPS scales are not needed to monitor routine clinical outcomes. Therefore, we developed and initially validated a shortened and restructured instrument, the S-TOPS, for individual patient monitoring in multidisciplinary chronic pain treatment. The reliability and validity of the S TOPS were analyzed using data from 964 chronic pain patients who were treated in a single interdisciplinary pain clinic and completed >1 TOPS. The 7 scales of the S-TOPS have excellent construct validity, high reliabilities, and improved sensitivity to change for monitoring individual patient outcomes. Patients accepted the S-TOPS well, finding it brief enough for routine repeated administration. PMID- 22503222 TI - Opioid-independent mechanisms supporting offset analgesia and temporal sharpening of nociceptive information. AB - The mechanisms supporting temporal processing of pain remain poorly understood. To determine the involvement of opioid mechanisms in temporal processing of pain, responses to dynamic noxious thermal stimuli and offset analgesia were assessed after administration of naloxone, a MU-opioid antagonist, and on a separate day, during and after intravenous administration of remifentanil, a MU-opioid agonist, in 19 healthy human volunteers. Multiple end points were sampled from real-time computerized visual analog scale ratings (VAS, 1 to 10) to assess thermal sensitivity, magnitude and duration of offset analgesia, and painful after sensations. It was hypothesized that the magnitude of offset analgesia would be reduced by direct opioid antagonism and during states of acute opioid-induced hypersensitivity (OIH), as well as diminished by the presence of exogenous opioids. Surprisingly, the magnitude of offset analgesia was not altered after naloxone administration, during remifentanil infusion, or after the termination of remifentanil infusion. Because thermal hyperalgesia was observed after both drugs, 8 of the original 19 subjects returned for an additional session without drug administration. Thermal hyperalgesia and increased magnitude of offset analgesia were observed across conditions of remifentanil, naloxone, and no drug within this subset analysis, indicating that repeated heat testing induced thermal hyperalgesia, which potentiated the magnitude of offset analgesia. Thus, it is concluded that the mechanisms subserving temporal processing of nociceptive information are largely opioid-independent, but that offset analgesia may be potentiated by heat-induced thermal hyperalgesia in a proportion of individuals. PMID- 22503224 TI - Embolization for multicompartmental bleeding in patients in hemodynamically unstable condition: prognostic factors and outcome. AB - PURPOSE: To determine prognostic factors and evaluate outcomes of transcatheter arterial embolization in severely injured patients in hemodynamically unstable condition with multicompartmental bleeding. MATERIALS AND METHODS: Between June 2000 and May 2008, 36 consecutive patients treated with transcatheter arterial embolization for major retroperitoneal bleeding associated with at least one additional source of bleeding were retrospectively reviewed. Mean Injury Severity Score (ISS) was 49.4 +/- 15.8. Univariate and multivariate analyses were performed to identify parameters associated with failure of embolization, need for additional surgery to control bleeding, and fatal outcome at 30 d. RESULTS: Embolization was technically successful in 35 of 36 patients (97.2%) and resulted in immediate and sustained (> 24 h) hemodynamic improvement in 29 (80.5%). Additional hemostatic surgery was necessary after embolization in six patients (16.6%). Fifteen patients (41.6%) died within 30 d. Failure to restore hemodynamic stability was correlated with the rate of administration of packed red blood cells (P = .014), rate of administration of fresh frozen plasma (FFP; P = .031), and systolic blood pressure (SBP) immediately before embolization (P = .002). The need for additional surgery was correlated with FFP administration rate before embolization (P = .0002) and hemodynamic success (P = .003). Death was correlated with Glasgow Coma Scale score at admission (P = .001), ISS (P = .014), New Injury Severity Score (P = .016), number of injured sites (P = .012), SBP before embolization (P = .042), need for vasopressive drugs before embolization (P = .037), and hemodynamic success (P = .0004). CONCLUSIONS: In patients in hemodynamically unstable condition, transcatheter arterial embolization effectively controls bleeding and improves hemodynamic stability. Immediate survival is related to hemodynamic condition before embolization, and 30-d mortality is mainly related to associated brain trauma. PMID- 22503223 TI - Pain coping skills training and lifestyle behavioral weight management in patients with knee osteoarthritis: a randomized controlled study. AB - Overweight and obese patients with osteoarthritis (OA) experience more OA pain and disability than patients who are not overweight. This study examined the long term efficacy of a combined pain coping skills training (PCST) and lifestyle behavioral weight management (BWM) intervention in overweight and obese OA patients. Patients (n=232) were randomized to a 6-month program of: 1) PCST+BWM; 2) PCST-only; 3) BWM-only; or 4) standard care control. Assessments of pain, physical disability (Arthritis Impact Measurement Scales [AIMS] physical disability, stiffness, activity, and gait), psychological disability (AIMS psychological disability, pain catastrophizing, arthritis self-efficacy, weight self-efficacy), and body weight were collected at 4 time points (pretreatment, posttreatment, and 6 months and 12 months after the completion of treatment). Patients randomized to PCST+BWM demonstrated significantly better treatment outcomes (average of all 3 posttreatment values) in terms of pain, physical disability, stiffness, activity, weight self-efficacy, and weight when compared to the other 3 conditions (Ps<0.05). PCST+BWM also did significantly better than at least one of the other conditions (ie, PCST-only, BWM-only, or standard care) in terms of psychological disability, pain catastrophizing, and arthritis self efficacy. Interventions teaching overweight and obese OA patients pain coping skills and weight management simultaneously may provide the more comprehensive long-term benefits. PMID- 22503225 TI - Two-wavelength near-infrared fluorescence for the quantitation of drug antiplatelet effects in large animal model systems. AB - OBJECTIVE: Intraoperative imaging of intravascular thrombi is limited by the inability of visible light to penetrate thick-walled vessels. Near-infrared (NIR) light has relatively high tissue penetration and low autofluorescence and scatter, offering significant advantages. We hypothesized that the development of 700-nm NIR fluorophores for platelet labeling, in conjunction with existing 800 nm NIR fluorophores, would permit simultaneous and separable quantitation of intravascular thrombi and measurement of the antiplatelet effect of drugs. METHODS: We synthesized a series of lipophilic, cationic, polymethine indocyanine dyes (MHI-86, 94, 106, and 114) that emit at approximately 700 nm. Platelet uptake was optimized in vitro and the bioactivity and blood half-life of labeled platelets was characterized in vitro and in vivo. FeCl(3)-induced injury of the femoral arteries and intravascular thrombus formation was performed in 35-kg Yorkshire pigs. A combination of 700-nm and 800-nm NIR fluorophore-labeled platelets was used in conjunction with the fluorescence-assisted resection and exploration imaging system to image and quantify the antiplatelet effect of cilostazol and acetylsalicylic acid. RESULTS: MHI-114 was incorporated at nearly 4.1 * 10(6) molecules per platelet without affecting platelet function. When infused into pigs, the signal-to-background ratio of MHI-114-labeled platelets exhibited a blood half-life of 16.4 +/- 2.2 (mean +/- SEM; n = 3) minute and generated a signal-to-background ratio of 2.5 +/- 0.5 (mean +/- SEM; n = 3) at the site of thrombi. Using dual-NIR-labeled platelet populations, cilostazol and acetylsalicylic acid were found to cause a reduction in platelet incorporation into thrombi of 51 +/- 2% and 10 +/- 1% (mean +/- SEM; n = 3), respectively, relative to vehicle-only treated control thrombi. CONCLUSIONS: New platelet-avid 700-nm NIR fluorophores permit simultaneous two-wavelength NIR fluorescence imaging and quantitation of intravascular thrombi in intact vessels approaching the size of humans and can be used to study the antiplatelet effect of drugs. PMID- 22503226 TI - Murine ultrasound imaging for circumferential strain analyses in the angiotensin II abdominal aortic aneurysm model. AB - OBJECTIVE: The underlying causes of abdominal aortic aneurysms (AAAs) remain obscure, although research tools such as the angiotensin II (Ang II) apolipoprotein E-deficient (apoE(-/-)) mouse model have aided investigations. Longitudinal imaging and determination of biomechanical forces in this small scale model have been difficult. We hypothesized that high-frequency ultrasound biomicroscopy combined with speckle-tracking analytical strategies can be used to define the role of circumferential mechanical strain in AAA formation in the Ang II/apoE(-/-) mouse model of AAAs. We simultaneously examined dietary perturbations that might impact the biomechanical properties of the aortic wall, hypothesizing that the generalized inflammatory phenotype associated with diet induced obesity would be associated with accelerated loss of circumferential strain and aneurysmal aortic degeneration. METHODS: Receiving either a 60 kcal% fat Western diet or standard 10 kcal% fat normal chow, Ang II-treated apoE(-/-) mice (n = 34) underwent sequential aortic duplex ultrasound scan imaging (Vevo 2100 System; VisualSonics, Toronto, Ontario, Canada) of their entire aorta. Circumferential strains were calculated using speckle-tracking algorithms and a custom MatLab analysis. RESULTS: Decreased strains in all aortic locations after just 3 days of Ang II treatment were observed, and this effect progressed during the 4-week observation period. Anatomic segments along the aorta impacted wall strain (baseline highest in ascending aorta; P < .05), whereas diet did not. At 2 and 4 weeks, there was the largest progressive decrease in strain in the paravisceral/supraceliac aorta (P < .05), which was the segment most likely to be involved in aneurysm formation in this model. CONCLUSIONS: In the Ang II/apoE(-/ ) aneurysm model, the aorta significantly stiffens (with decreased strain) shortly after Ang II infusion, and this progressively continues through the next 4 weeks. High-fat feeding did not have an impact on wall strain. Delineation of biomechanical factors and AAA morphology via duplex scan and speckle-tracking algorithms in mouse models should accelerate insights into human AAAs. PMID- 22503227 TI - Acute type B aortic dissection in the absence of aortic dilatation. AB - BACKGROUND: Increasing aortic diameter is thought to be an important risk factor for acute type B aortic dissection (ABAD). However, some patients develop ABAD in the absence of aortic dilatation. In this report, we sought to characterize ABAD patients who presented with a descending thoracic aortic diameter <3.5 cm. METHODS: We categorized 613 ABAD patients enrolled in the International Registry of Acute Aortic Dissection from 1996 to 2009 according to the aortic diameter <3.5 cm (group 1) and >=3.5 cm (group 2). Demographics, clinical presentation, management, and outcomes of the two groups were compared. RESULTS: Overall, 21.2% (n = 130) had an aortic diameter <3.5 cm. Patients in group 1 were younger (60.5 vs 64.0 years; P = .015) and more frequently female (50.8% vs 28.6%; P < .001). They presented more often with diabetes (10.9% vs 5.9%; P = .050), history of catheterization (17.0% vs 6.7%; P = .001), and coronary artery bypass grafting (9.7% vs 3.4%; P = .004). Marfan syndrome was equally distributed in the two groups. The overall in-hospital mortality did not differ between groups 1 and 2 (7.6% vs 10.1%; P = .39). CONCLUSIONS: About one-fifth of patients with ABAD do not present with any aortic dilatation. These patients are more frequently females and younger, when compared with patients with aortic dilatation. This report is an initial investigation to clinically characterize this cohort, and further research is needed to identify risk factors for aortic dissection in the absence of aortic dilatation. PMID- 22503228 TI - [A 10,000 km long airborne medical evacuation of a patient under ECLS]. PMID- 22503229 TI - Detection and time to treatment of uveal melanoma in the United Kingdom: an evaluation of 2,384 patients. AB - PURPOSE: To determine the mode of detection of uveal melanoma and time to treatment in the United Kingdom. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 2384 patients diagnosed with uveal melanoma at the Liverpool Ocular Oncology Center between 1996 and early 2011. METHODS: A questionnaire was completed with every new patient, and the results were correlated with clinical features and treatment. MAIN OUTCOME MEASURES: Tumor detection, practitioner initiating referral, referral pathway, time to treatment, baseline clinical features, and primary ocular treatment. RESULTS: The referral process was initiated by an optometrist, family doctor, or ophthalmologist in 68.0%, 18.2%, and 13.8% of patients, respectively. On referral, 30.2% of patients were asymptomatic. Twenty-three percent of patients reported that their tumor was initially missed; these tended to have a more advanced tumor when they reached our center. The time from referral to treatment had a median of 49 days, exceeding 6 months in 19.8% of patients. This delay was longer in patients who reported that their tumor was missed (median, 92 vs. 40 days; Mann-Whitney, P<0.001). Ophthalmologists delayed the referral process by more than 6 months in 10.9% of patients. Primary enucleation was performed in 33.3% of patients and was more likely in those who reported that their tumor was missed (44.8% vs. 29.8%; chi-square, P<0.001). CONCLUSIONS: Many patients with uveal melanoma experience long delays in treatment because their tumor was missed or misdiagnosed. Such patients tend to have a more advanced tumor by the time they reach an oncology center and are more likely to require enucleation. PMID- 22503230 TI - Association of single nucleotide polymorphisms of interleukins-1beta, -6, and 12B with contact lens keratitis susceptibility and severity. AB - PURPOSE: To investigate whether single nucleotide polymorphisms (SNPs) in interleukin (IL)-1beta, IL-6, and IL-12beta are associated with the susceptibility and severity of contact lens-related keratitis. DESIGN: Retrospective, case control study. PARTICIPANTS: One hundred twelve cases of keratitis and 225 controls were recruited from studies conducted at Moorfields Eye Hospital and in Australia during 2003 through 2005. METHODS: Buccal swab samples were collected on Whatman FTA cards and were mailed by post for analysis. IL-1beta (-31), IL-6 (-174, -572, -597), and IL-12B (3'+1158) genotypes were analyzed with pyrosequencing and analyzed using a regression model for susceptibility (sterile, microbial keratitis, controls) and severity. Statistical significance was set at 0.05. MAIN OUTCOME MEASURES: The relative risk of developing contact lens-related keratitis and more severe forms of the disease based on allele, genotype, and haplotype associations. RESULTS: Carriers of IL-6 SNPs were more likely to experience moderate and severe events compared with those with nonmutated genotypes (-174 heterozygous: odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1-8.3; homozygous: OR, 6.4; 95% CI, 1.4-28.4; -174/ 597: OR, 4.1; 95% CI, 1.6-11.0). More severe keratitis and microbial keratitis were less likely to occur in wearers with the nonmutated IL-6 haplotype (severity OR, 0.4 [95% CI, 0.2-0.7]; microbial OR, 0.6 [95% CI, 0.4-0.9]). Wearers carrying an IL-12B SNP had an increased risk of sterile keratitis (OR, 9.7; 95% CI, 1.2 76.9) compared with controls. CONCLUSIONS: The IL-6 SNPs are known to reduce protein expression of this cytokine and thus ocular immune defense, and carriers of these SNPs were more likely to experience more severe and microbial keratitis, suggesting that IL-6 decreases the severity and susceptibility of contact lens related keratitis. Carriers of a functional SNP of IL-12B that is known to increase IL-12 expression and stability are more likely to experience sterile keratitis, suggesting that this is associated with the intense inflammatory reaction that occurs in this condition. PMID- 22503231 TI - Multipotent MAO and cholinesterase inhibitors for the treatment of Alzheimer's disease: synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amine. AB - The synthesis, pharmacological evaluation and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amines 1-7 of type I, and 9-12 of type II, designed as multipotent inhibitors able to simultaneously inhibit monoamine oxidases (MAO-A/B) as well as cholinesterase (AChE/BuChE) enzymes, as potential drugs for the treatment of Alzheimer's disease, are described. Indole derivatives 1-7 of type I are well known MAO inhibitors whose capacity to inhibit AChE and BuChE was here investigated for the first time. As a result, compound 7 was identified as a MAO-B inhibitor (IC(50) = 31 +/- 2 nM) and a moderately selective eqBuChE inhibitor (IC(50) = 4.7 +/- 0.2 MUM). Conversely, the new and readily available 5-amino-7-(prop-2-yn-1-yl)-6,7,8,9-tetrahydropyrido[2,3 b][1,6]naphthyridine derivatives 9-13 of type II are poor MAO inhibitors, but showed AChE selective inhibition, compound 12 being the most attractive as it acts as a non-competitive inhibitor on EeAChE (IC(50) = 25 +/- 3 nM, K(i) = 65 nM). The ability of this compound to interact with the AChE peripheral binding site was confirmed by kinetic studies and by molecular modeling investigation. Studies on human ChEs confirmed that 12 is a selective AChE inhibitor with inhibitory potency in the submicromolar range. Moreover, in agreement with its mode of action, 12 was shown to be able to inhibit Abeta aggregation induced by hAChE by 30.6%. PMID- 22503232 TI - Re: Alterations in connective tissue metabolism in stress incontinence and prolapse: B. Chen and J. Yeh J Urol 2011; 186: 1768-1772. PMID- 22503233 TI - Re: Increased risk of diabetes in patients with urinary calculi: a 5-year followup study: S.-D. Chung, Y.-K. Chen and H.-C. Lin J Urol 2011; 186: 1888 1893. PMID- 22503234 TI - Implementation and outcomes of a multidisciplinary high-risk breast cancer program: the William Beaumont Hospital experience. AB - Limited data are available on the implementation of a high-risk assessment program in the construct of a community clinical oncology program. The development of a high-risk breast cancer screening program at our institution identified 15%-20% of patients screened as high risk, with limited increases in structural or personnel requirements. Identification of patients as high risk could potentially improve outcomes by allowing for individualized prevention strategies and more appropriate high-risk surveillance. PURPOSE: The implementation of a program that incorporates a risk assessment questionnaire (RAQ) to identify high-risk patients in a community-based health system was evaluated. MATERIALS AND METHODS: Women with no history of breast cancer or ductal carcinoma in situ who were undergoing annual screening mammography were offered an RAQ. Cases determined to be high risk (Gail lifetime risk >=20% or as indicated through personal and/or family history) were offered referral to our High-risk Breast Cancer Program. A retrospective data review was conducted on completed questionnaires. RESULTS: A total of 5878 women underwent evaluation with the RAQ between September 2009 and August 2010. The mean age of the cohort was 55 years old, with 84.9% (4990) of participants being white, and 6.8% (400) African American. In the entire population, 45.7% (2446) had at least 1 first degree relative with breast cancer (BC), and 923 (17.2%) women were found to be high risk by the Gail model. Beyond the Gail model, 53 (0.9%) women had undergone prior chest radiation, 34 (0.6%) had a male relative with BC, 200 (3.4%), had 3 or more relatives with BC on one side of their family, 308 (5.2%) had a relative with breast and ovarian cancer on one side of the family, and 105 (1.8%) noted 2 relatives with BC with onset under age 50 years on the same side of the family. CONCLUSIONS: Our experience indicates that the identification of women at high risk for BC can be easily incorporated into an annual screening mammography visit. Identification of these patients as high risk can allow for individualized, more-appropriate surveillance and prevention. PMID- 22503235 TI - Intraglandular flap technique for tumors located in the upper outer quadrant of the breast. AB - We applied the intraglandular flap technique with racquet incision for tumors located in the upper outer quadrant of medium to small size breasts of 47 patients. It is an easy and safe technique with respect to cosmetic results, surgical margins, and complications. BACKGROUND: The intraglandular flap is a volume replacement technique in which glandular tissue is used to close the tissue defect. We applied the intraglandular flap technique with racquet incision for tumors located in the upper outer quadrant of medium to small size breasts of 47 patients. In this report, we present our preliminary results of this technique. PATIENTS AND METHODS: The intraglandular flap technique using a racquet incision was used on 47 consecutive breast cancer patients with T1 and T2 tumors, and analyzed prospectively. RESULTS: The median age of the patients was 46.5 (range, 24-63 years). The mean tumor size was 2.53 +/- 0.8 cm. The volume of the resected specimen was 185 +/- 29 cm(3). The mean length of incision was 9.68 +/- 1.8 cm. The mean distance from the tumor to the nearest surgical margin was 1.65 +/- 0.4 cm. Fat necrosis was evident in 8 patients (17%) and hematoma in 2 patients (4.2%). The other complications like seroma, glandular, and flap necrosis were not observed. DISCUSSION: Intraglandular flap technique with racquet incision used for tumors located in the upper outer quadrant of patients with medium and small breasts is an easy and safe technique with respect to cosmetic results, surgical margins and complications. The learning period of this technique is quite short. When used in patients with dense breasts the incidence of fat necrosis was found to be low. PMID- 22503236 TI - Pharmaceutical protein production by yeast: towards production of human blood proteins by microbial fermentation. AB - Since the approval of recombinant insulin from Escherichia coli for its clinical use in the early 1980s, the amount of recombinant pharmaceutical proteins obtained by microbial fermentations has significantly increased. The recent advances in genomics together with high throughput analysis techniques (the so called-omics approaches) and integrative approaches (systems biology) allow the development of novel microbial cell factories as valuable platforms for large scale production of therapeutic proteins. This review summarizes the main achievements and the current situation in the field of recombinant therapeutics using yeast Saccharomyces cerevisiae as a model platform, and discusses the future potential of this platform for production of blood proteins and substitutes. PMID- 22503237 TI - Minimal systems to study membrane-cytoskeleton interactions. AB - In the context of minimal systems design, there are two areas in which the reductionist approach has been particularly successful: studies of molecular motors on cytoskeletal filaments, and of protein-lipid interactions in model membranes. However, a minimal cortex, that is, the interface between membrane and cytoskeleton, has just begun to be functionally reconstituted. A key property of living cells is their ability to change their shape in response to extracellular and intracellular stimuli. Although studied in live cells since decades, the mutual dependence between cytoskeleton and membrane dynamics in these large-scale transformations is still poorly understood. Here we report on inspiring recent in vitro work in this direction, and the promises it holds for a better understanding of key cellular processes. PMID- 22503238 TI - [Diagnosis of hepatic iron overload]. PMID- 22503239 TI - [Why and how withdrawing treatment with proton pump inhibitor after long-term use?]. PMID- 22503240 TI - [Thrombophilia: which tests in 2012?]. PMID- 22503241 TI - Estimation of the duration after methamphetamine injection using a pharmacokinetic model in suspects who caused fatal traffic accidents. AB - When the population parameters of drug pharmacokinetics in the human body system are known, the time-course of a certain drug in an individual can generally be estimated by pharmacokinetics. In the present two cases where methamphetamine abusers were suspected to have inflicted mortalities in traffic accidents, the time-elapse or duration immediately after methamphetamine injection to the time when the accidents occurred became points of contention. In each case, we estimated the time-course of blood methamphetamine after the self-administration in the suspects using a 2-compartment pharmacokinetic model with known pharmacokinetic parameters from the literatures. If the injected amount can be determined to a certain extent, it is easy to calculate the average time-elapse after injection by referring to reference values. However, there is considerable individual variability in the elimination rate based on genetic polymorphism and a considerably large error range in the estimated time-elapse results. To minimize estimation errors in such cases, we also analyzed genotype of CYP2D6, which influenced methamphetamine metabolism. Estimation based on two time-point blood samples would usefully benefit legal authorities in passing ruling sentences in cases involving similar personalities and circumstances as those involved in the present study. PMID- 22503242 TI - Difference in molecular pathology of natriuretic peptides in the myocardium between acute asphyxial and cardiac deaths. AB - In investigating death due to mechanical asphyxiation and drowning, a cardiac attack is important for discriminating between possible causes of death and as a contributory factor in death processes; however, general pathologies involving visceral congestion are often similar. The present study compared terminal cardiac dysfunction in these fatalities using the molecular pathology of atrial and brain natriuretic peptides (ANP and BNP) in the myocardium as markers of cardiac strain. Both mechanical asphyxiation (n=27) and drowning (n=23) showed significantly lower ANP and BNP mRNA expressions in bilateral ventricular walls than sudden cardiac deaths (n=36). In addition, right atrial wall BNP mRNA expression was lower in asphyxiation; however, immunostaining did not demonstrate any difference among these fatalities. Differences among the subtypes of asphyxiation or between fresh- and saltwater drowning were insignificant. These observations suggest a difference between primary heart failure in sudden cardiac death and terminal cardiac dysfunction secondary to fatal asphyxiation or drowning. PMID- 22503243 TI - Replication study of the association of SNPs in the LHX3-QSOX2 and IGF1 loci with adult height in the Japanese population; wide-ranging comparison of each SNP genotype distribution. AB - Adult height is a highly heritable trait involving multiple genes. Recent genome wide association studies have identified that SNP rs12338076 in the LHX3-QSOX2 locus, and rs1457595 and rs17032362 in the IGF1 locus are associated with human height in the Japanese population (Okada et al. (2010)). We performed a replication study to examine the associations between these three SNPs and adult height in the Japanese population based on autopsy cases. However, it was not possible to confirm that all these SNPs influenced adult height in the study population. We first conducted a wide-ranging survey of these three SNPs in the above genes using nine different populations including Asians, Africans and Caucasians, and demonstrated that the genotypes of rs12338076 and rs17032362 were distributed in an ethnicity-dependent manner; even within Asian populations, the genotype distributions of the SNPs differed widely. Although there are differences in height distribution between different populations, possibly due to genetic factors and/or gene-environmental interactions, the contradictory results of the association study and ethnic differences in genotype distribution allow us to assume that these height-related SNPs in the genes may contribute to adult height to a slight extent, at least in the Japanese population. It is anticipated that the present information will be useful for developing a reliable tool for personal identification through elucidation of the genetic basis of human height. PMID- 22503244 TI - The relationship between adrenal gland morphometric changes and postmortem interval in rats: a stereological study. AB - The importance of determining time of death is crucial to forensic cases. The ability to use adrenal gland volume changes and adrenal medulla chromaffin cell counts to obtain the postmortem interval was examined in this study. A total of 15 rats were sacrificed by cervical dislocation and divided into three groups. The left adrenal glands were quickly excised in the first group at 0 h, in the second group at 12 h and in the third group at 24 h. Subsequently, the samples were fixed in 10% formalin solution and embedded in paraffin according to standard procedures. Ten to fifteen sections were obtained from each left adrenal gland by taking 30 MUm thick sections; then, the sections were stained with hematoxylin-eosin (HE). The adrenal cortex and medullar volumes were calculated by Cavalieri's principle, which is a stereological method. The adrenal medullary chromaffin cell count was evaluated by the optical fractionator method. The total volume of the adrenal gland was determined as 4.82+/-1 mm(3) at 0 h, 6.32+/-0.28 mm(3) at 12 h and 8.35+/-1.73 mm(3) at 24 h. Increases in the adrenal cortex, adrenal medulla and the total volume of the adrenal gland at 12 and 24 h postmortem compared with at 0 h were statistically significant (p<0.05). The difference between the groups in terms of the total number chromaffin cells was statistically significant (p<0.05). In this preliminary study, we evaluated the total volume of the adrenal gland and the number of chromaffin cells of the adrenal medulla. We concluded that these parameters could be used reliably in determining the postmortem interval. PMID- 22503245 TI - Practice of clinical forensic medicine in Sri Lanka: does it need a new era? AB - Clinical forensic medicine is a sub-specialty of forensic medicine and is intimately associated with the justice system of a country. Practice of clinical forensic medicine is evolving, but deviates from one jurisdiction to another. Most English-speaking countries practice clinical forensic medicine and forensic pathology separately while most non-English-speaking countries practice forensic medicine which includes clinical forensic medicine and forensic pathology. Unlike the practice of forensic pathology, several countries have informal arrangements to deal with forensic patients and there are no international standards of practice or training in this discipline. Besides, this is rarely a topic of discussion. In the adversarial justice system in Sri Lanka, the designated Government Medical Officers practice both clinical forensic medicine and forensic pathology. Practice of clinical forensic medicine, and its teaching and training in Sri Lanka depicts unique features. However, this system has not undergone a significant revision for many decades. In this communication, the existing legal framework, current procedure of practice, examination for drunkenness, investigations, structure of referrals, reports, subsequent legal procedures, undergraduate, in-service, and postgraduate training are discussed with suggestions for reforms. PMID- 22503246 TI - Long-acting peptidomimetics based DPP-IV inhibitors. AB - Pyrrolidine based peptidomimetics are reported as potent and selective DPP-IV inhibitors for the treatment of T2DM. Compounds 16c and 16d showed excellent in vitro potency and selectivity towards DPP-IV and the lead compound 16c showed sustained antihyperglycemic effects, along with improved pharmacokinetic profile. PMID- 22503247 TI - Identification of a selective small molecule inhibitor of breast cancer stem cells. AB - A high-throughput screen (HTS) with the National Institute of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) compound collection identified a class of acyl hydrazones to be selectively lethal to breast cancer stem cell (CSC) enriched populations. Medicinal chemistry efforts were undertaken to optimize potency and selectivity of this class of compounds. The optimized compound was declared as a probe (ML239) with the NIH Molecular Libraries Program and displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control line (HMLE_sh_GFP). PMID- 22503248 TI - Identification of a series of 1,3,4-oxadiazol-2-amines as potent alpha-7 agonists with efficacy in the novel object recognition model of cognition. AB - A series of alpha7 nicotinic acetylcholine receptor full-agonists with a 1,3,4 oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both alpha7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement. PMID- 22503249 TI - Modulation of thermo-transient receptor potential (thermo-TRP) channels by thymol based compounds. AB - A series of thirty-three thymol, p-cymene-3-carboxylic acid, and 3-amino-p-cymene derivatives was synthesized and tested on TRPA1, TRPM8, and TRPV3 channels. Most of them acted as strong modulators of TRPA1, TRPM8, and TRPV3 channels with EC(50) and/or IC(50) values distinctly lower than those of thymol and related monoterpenoids. Some of the compounds examined, that is, 3c, 4e, f, 6b, and 8b exhibited an appreciable subtype-selectivity. PMID- 22503250 TI - Synthesis and SAR studies of imidazo-[1,2-a]-pyrazine Aurora kinase inhibitors with improved off-target kinase selectivity. AB - The structure-activity relationships of new Aurora A/B kinase inhibitors derived from the previously identified kinase inhibitor 12 are described. Introduction of acetic acid amides onto the pyrazole of compound 12 was postulated to influence Aurora A/B selectivity and improve the profile against off-target kinases. The SAR of the acetic acid amides was explored and the effect of substitution on enzyme inhibition as well as mechanism-based cell activity was studied. Additionally, several of the more potent inhibitors were screened for their off target kinase selectivity. PMID- 22503251 TI - A feasible and effective lifestyle counseling program for obese children and adolescents. PMID- 22503252 TI - Ultrasound diagnosis of liver masses in children. PMID- 22503253 TI - Current status and future diagnostic trends of prenatal illicit drug exposure in the neonate. PMID- 22503254 TI - Strategies for the prevention of neonatal candidiasis. AB - Invasive fungal infections represent the third-leading cause of late-onset sepsis in very-low-birth-weight infants (VLBWI) and have a high rate of infection associated mortality. The infants at high risk for fungal sepsis are VLBWI with presence of additional risk factors that contribute to increased colonization and concentration of fungal organisms. Colonization with Candida spp. in neonates is secondary to either maternal vertical transmission or nosocomial acquisition in the nursery. Multiple sites may become colonized and a direct correlation between fungal colonization and subsequent progression to invasive candidemia was determined. Randomized, single and multiple-center, placebo-controlled trials found intravenous fluconazole prophylaxis to be effective in decreasing fungal colonization and sepsis for at-risk preterm infants <1500 g birth weight. The prophylactic use of fluconazole was found to be safe with no significant development of fungal resistance. Fluconazole prophylaxis administered to preterm neonates with birth weight <1000 g and/or 27 weeks' gestation or less has the potential of reducing and potentially eliminating invasive fungal infections and Candida-related mortality. PMID- 22503255 TI - Can a trial of motivational lifestyle counseling be effective for controlling childhood obesity and the associated cardiometabolic risk factors? AB - OBJECTIVES: This study was conducted to assess the effectiveness of a simple office-based program for encouraging healthy lifestyle on controlling childhood obesity and associated cardiometabolic risk factors. METHODS: This non-randomized 24-week lifestyle modification trial was conducted among 457 obese children and adolescents, aged 2-18 years, who had at least one cardiometabolic risk factor in addition to obesity. This trial included three components of exercise, diet education and behavior modification, with all recommendations provided by a pediatrician, two general physicians and a nurse. Instead of strict inhibitory recommendations, healthier lifestyle was encouraged. RESULTS: Overall 448 (98.04%) of enrolled children completed the trial with a mean age of 9.6 +/- 2.9 years. After the trial, the mean of anthropometric measures and cardiometabolic risk factors decreased significantly, the mean high-density lipoprotein cholesterol (HDL-C) increased significantly, and the prevalence of the metabolic syndrome decreased from 20.8% to 1.8%. Triglycerides, LDL-C, diastolic blood pressure and WC had the highest decrease in all age groups, with the most prominent changes in the 14-18-year age group. By each -1SD decline in BMI and WC, risk factors had significant improvement. CONCLUSION: Motivational office based counseling can be effective in treatment of childhood obesity and its associated cardio-metabolic risk factors. Such approach can be implemented in the primary health care system; and can be of special concern in low- and middle income countries with limited human and financial resources. We suggest that expanding the roles of non-physician clinicians such as nurse practitioners can help to increase the amount of time available for such services. PMID- 22503256 TI - Pitfalls in a sonographic diagnosis of liver abscess in children. AB - BACKGROUND: The purpose of this article is to identify the pitfalls of sonography in the diagnosis of liver abscesses, hematomas, and hepatic tumors, which appear similar and therefore are difficult to differentiate from each other. METHODS: Cases were collected at the China Medical University Hospital between January 2008 and January 2010. Liver abscesses were initially diagnosed by sonograph in selected patients who were younger than 18 years. RESULTS: There were 15 patients in whom a liver mass was diagnosed by ultrasound, but 6 of them were excluded from further study because of failure to meet any of the screening criteria. Nine patients with a mean age of 11.3 years (range 5-17 years) were initially suspected to have liver abscesses by ultrasound and were enrolled in the study. These nine patients were identified as follows: five with liver abscess, one with liver hematoma, one with hepatic lymphoma, one with perihepatic abscess, and one with undifferentiated liver sarcoma. Ultrasonography alone was sufficient for diagnosis in five patients. Four patients required abdominal CT scanning to confirm final diagnosis. CONCLUSION: Different liver lesions may present sonographic images similar to those of liver abscesses. Therefore, it is suggested that patients in whom liver abscesses were diagnosed by ultrasound undergo further evaluation if the clinical condition is less likely. PMID- 22503257 TI - A nationwide survey of risk factors for stillbirth in Taiwan, 2001-2004. AB - OBJECTIVE: The purpose of this study was to evaluate the nationwide stillbirth rate and explore the potential risk factors associated with stillbirths. PATIENTS AND METHODS: Data from vital registrations during the time period from January 1, 2001 through to December 31, 2004 in Taiwan were used. Stillbirth was defined as fetal death with more than 20 completed weeks' gestational age (GA) or with birth weight more than 500 g if the GA was not known. RESULTS: There were a total of 8481 stillbirths identified nationwide between January 1, 2001 and December 31, 2004. The stillbirth rate was nine per 1000 total births in the study period, and the proportionate decline was nearly 48.8% in the most recent decade. There was a significant increase in average maternal age during this period. Advanced maternal age and teenage pregnancy were independent significant risk factors for stillbirths even after accounting for the effects of medical conditions that were more likely to occur among these particular age groups. Those fetuses that had been exposed to cord prolapse, maternal cervical incompetence and oligohydramnios/polyhydramnios were especially vulnerable. By contrast, women who had foreign nationality, fetal ultrasound surveys, fetal heart beat monitoring and hastened parturition were less likely to have stillbirth. CONCLUSION: The stillbirth rate in Taiwan has remained high despite advancements in medical care. Prenatal evaluation of high risk women may decrease the adverse fetal outcomes. PMID- 22503258 TI - Perinatal effects of combined use of heroin, methadone, and amphetamine during pregnancy and quantitative measurement of metabolites in hair. AB - OBJECTIVE: There has been very limited research on the clinical features of newborns exposed to combined use of heroin, methadone, and amphetamine in the uterus. We describe a technique for the quantification of drug metabolites in neonatal hair samples. METHODS: In a tertiary neonatal care center in Taiwan, three neonates whose mothers self-reported heroin abuse with methadone treatment during pregnancy were studied. Involuntary exposure to amphetamine was not suspected before the births. To assess long-term illicit drug exposure during pregnancy, a quantifying technique of gas chromatography/mass spectrometry (GC/MS) for hair samples from neonates was developed to replace current methods for urine and blood specimens. RESULTS: All three mothers were addicted to heroin and prescribed oral methadone treatment during pregnancy. Two males and one female were born and then admitted to the neonatal intensive care unit because of apparent neonatal abstinence syndrome (NAS) after birth. Additional hypertonicity and cerebral dysfunction were also diagnosed by electroencephalography in one case. Supportive care was given to the neonates, unless special treatments were needed in responding to tachypnea, fetal distress, or withdrawal symptoms. During follow-up periods from 10 months to 15 months, the signs of NAS remained and delays in milestones of development were observed. Further follow-up on the infants' neurobehavioral development is necessary. Measurement results of neonates' hair samples revealed high levels of metabolites of heroin, methadone, and amphetamine, reflecting the amount of illicit drug exposure 2-3 months before delivery. CONCLUSION: The current study suggested the possibility of polydrug exposure, which was previously unknown in pregnant women in Taiwan. Measurement of neonatal hair samples could provide a basis for clinical evaluation and potential corresponding treatment. PMID- 22503259 TI - Auditory event-related potentials in children with attention deficit hyperactivity disorder. AB - BACKGROUND: Recording of event-related potentials (ERPs) from the scalp is a noninvasive technique reflecting the sensory and cognitive processes associated with attention tasks. Attention deficit hyperactivity disorder (ADHD) is a disorder involving deficits in attention and behavioral control. The aim of this study was to investigate the difference in ERPs between normal children and those with ADHD. METHODS: We examined 50 children with ADHD and 51 age-matched controls. All children with ADHD met the full criteria for ADHD according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). The auditory oddball paradigm was applied, and event-related long-latency components (N1, P2, N2 and P3) from Fz, Cz and Pz were measured in each test subject. RESULTS: Children with ADHD showed a significantly longer latency and a lower amplitude of P3 compared to normal control children (p < 0.01). Delayed N2 latency at the Pz electrode was shown in children with ADHD compared to normal controls (p < 0.01). No differences in other ERP indices were found between children with ADHD and controls. When divided into four age groups, the latency of P3 was significantly increased in all age groups and a significantly smaller amplitude in P3 over the central region was found in children with ADHD > 10 years of age (p < 0.05). CONCLUSION: We found that the endogenous ERPs (P3 and N2) were significantly affected in children with ADHD, compared to exogenous ERPs (N1 and P2). Increased latency of P3 suggests a slower processing speed, and decreased P3 amplitude is interpreted as disruption of inhibitory control in children with ADHD. These results indicate a neurocognitive abnormality in ADHD, as presented by a reduction in ERP response. PMID- 22503260 TI - Treatment with propranolol for infantile hemangioma in 13 Taiwanese newborns and young infants. AB - BACKGROUND: Hemangioma in infants has a benign self-limited course, but the 10% of cases with complications need further treatment. Successful treatment with propranolol in western countries has been reported over the past few years. We evaluated the efficacy of propranolol for treating infantile hemangioma in Taiwanese newborns and young infants. METHODS: Patients below 1 year of age treated with propanolol between November 2009 and March 2011 were enrolled. Demographic data, clinical features, imaging findings, treatment regimens of propranolol, and outcome were investigated. RESULTS: Thirteen patients were treated with propranolol at a dose of 2-3 mg/kg/day. Seven (53.8%) patients had solitary hemangioma and six had multiple ones. The indications for treatment were risk of local event in nine patients, functional risk in four, local complication in one, and life-threatening complication in one. The median age for starting propranolol was 4 months (range: 1-11 months). Responses to propranolol, such as decolorization, regression in tumor size, or improvement of hemangioma-associated complications were observed in all patients within 1-2 weeks after treatment. Propranolol-associated adverse effects occurred in two patients. One infant had occasional tachypnea, and the other had occasional pale-looking appearance. The symptoms resolved after dosage tapering. CONCLUSION: Propranolol may be a promising therapeutic modality for infantile hemangioma. Therapeutic strategies are needed to evaluate the optimal treatment protocol and long-term adverse effects. PMID- 22503261 TI - Clinical impacts of delayed diagnosis of Hirschsprung's disease in newborn infants. AB - BACKGROUND: Asian infants are at a higher risk of having Hirschsprung's disease (HD). Although HD is surgically correctable, serious and even lethal complications such as Hirschsprung's-associated enterocolitis (HAEC) can still occur. The aim of this study was to investigate the risk factors of HAEC, and the clinical impacts of delayed diagnosis of HD in newborn infants. PATIENTS AND METHODS: By review of medical charts in a medical center in Taiwan, 51 cases of neonates with HD between 2002 and 2009 were collected. Patients were divided into two groups based on the time of initial diagnosis: Group I, diagnosis made within 1 week after birth, and Group II after 1 week. Clinical features including demographic distribution, presenting features of HD, short-term and long-term complications related to HD were compared between the two groups of patients. RESULTS: There were 25 patients in Group I and 19 in Group II. Group II patients had more severe clinical signs and symptoms of HAEC than Group I patients. The incidence of preoperative HAEC was 12% in Group I and 63% in Group II (adjusted odds ratio = 12.81, confidence interval = 2.60-62.97). Patients with preoperative HAEC were more likely to develop adhesive bowel obstruction after operation (33% vs. 3%, p = 0.013) and failure to thrive (33% vs. 3%, p = 0.013). Also, patients with long-segment or total colonic aganglionosis were at risk of developing both postoperative HAEC (85% vs. 29%, p = 0.001) and failure to thrive (39% vs. 3%, p = 0.002). CONCLUSION: In our study, we found that delayed diagnosis of HD beyond 1 week after birth significantly increases the risk of serious complications in neonatal patients. Patients with long-segment or total colonic aganglionosis have higher risk of postoperative HAEC and failure to thrive. Patients with preoperative HAEC are more likely to have adhesive bowel obstruction and failure to thrive. PMID- 22503262 TI - Association of ABO incompatibility with red blood cell indices of cord blood unit. AB - BACKGROUND: Maternal-fetal ABO incompatibility is one of the causes of neonatal hyperbilirubinemia. We postulate that hemoglobin (Hb), hematocrit (Hct), and red blood cell (RBC) values for cord blood units (CBUs) are lower and erythroblast values higher for maternal-fetal ABO incompatible dyads than for compatible dyads. OBJECTIVE: We investigated the relationship between Hb, Hct, RBC, and erythroblast CBU values and maternal-fetal ABO blood type compatibility. METHODS: Mothers having blood group O who gave birth to infants with blood group A, B, or AB were classified as Group I. According to baby's blood group, the members of Group I were further divided into AO (baby group A, mother group O), BO (baby group B, mother group O), and ABO (baby group AB, mother group O) subgroups. Mothers having blood group A who gave birth to infants with blood group B or AB and mothers having blood group B who gave birth to infants with blood group A or AB were classified as Group II. All other maternal-fetal blood type pairs were considered ABO compatible and were classified as Group III. We compared mean Hb, Hct, RBC, and erythroblast values for the infants' CBUs among these three groups including the subgroups of Group I. RESULTS: Group I had lower mean Hb, Hct, and RBC values than Group II and Group III (both p < 0.001). Although the mean Hb, Hct, and RBC values for Group II were lower than for Group III, the difference was not statistically significant. Mean Hb and RBC for the AO group were higher and nucleated RBC (nRBC) ratios were lower than for the BO group; however, these differences were also not statistically significant. Interestingly, the mean Hct value of the BO group was significantly lower than that of the AO group (p = 0.04). CONCLUSION: Group A or B neonates with a group O mother have lower mean Hb, Hct, and RBC values for CBUs than other neonates. The role of RBC indices in predicting neonatal hemolytic hyperbilirubinemia remains unclear and further studies are needed to identify the possible clinical association. PMID- 22503263 TI - Hepatic subcapsular hematoma: two neonates with disparate presentations. AB - Subcapsular hematoma of the liver rarely occurs in neonates and the diagnosis is often missed or delayed. We report two babies who had this uncommon condition in the early neonatal period. In the first baby, the hematoma was associated with ventouse delivery and presented with abdominal distension and worsening jaundice. In contrast, the other baby was relatively well, with progressive pallor as the only clinical finding. The former had no other identifiable risk factors, whereas the latter was confirmed as having classical hemophilia. The literature is briefly reviewed with regards to incidence, etiology, diagnosis and management. Awareness of this unusual entity coupled with a high index of suspicion is essential for early identification and stabilization of such babies. PMID- 22503264 TI - Nager syndrome: a case report. AB - Nager syndrome (preaxial acrofacial dysostosis) is rare and mostly sporadic. We present a case of Nager syndrome in Taiwan. Craniofacial findings included micrognathia, malar hypoplasia, downslanting palpebral fissures, cleft palate, and ear anomalies. Radial defects consisted of hypoplastic thumb, short forearm, and proximal radioulnar synostosis. Patent ductus arteriosus, atrial septal defect, lower limb deformities, and uncommon flat nasal bridge were noted. Nasal endotube passing through a narrowing oropharynx region or oral airway is life saving before tracheostomy is performed on patients with Nager syndrome and restricted jaw opening and glossoptosis. PMID- 22503265 TI - Intestinal obstruction caused by potato bezoar in infancy: a report of three cases. AB - We present a report of three young infants with unusual intestinal obstruction caused by potato bezoar. They presented with vomiting, irritable crying, and abdominal distention. Barium gastrointestinal series clearly revealed intraluminal filling defect in the duodenum in two cases and ileum in one. Those bezoars in the pylorus and duodenal bulb were all successfully retrieved endoscopically. The patient's abdominal symptoms subsided after the bezoars were eliminated; no subsequent gastrointestinal events occurred in the following months. The authors believe that the occurrence of these cases suggest that feeding mashed potato to young infants (<=4 months) should be prohibited because it can result in bezoar formation. PMID- 22503266 TI - Egg-sharing, consent and exploitation: examining donors' and recipients' circumstances and retrospective reflections. AB - Egg-sharing schemes involve a woman sharing a portion of her eggs with another in exchange for free or reduced-cost fertility treatment and have been regulated in the UK since 1998. However, while being perceived as a unique anomaly (within the UK system) such schemes have caused considerable debate. Some critics have been concerned that the benefit-in-kind (i.e. fertility treatment) offered in exchange for donating eggs might compromise the consent of potential donors, particularly those who have no other means to access treatment, and lead to exploitation and the commodification of gametes. This article reports empirical findings that engage directly with these concerns. First, data on the demographic characteristics, circumstances and treatment outcomes of donors and recipients are presented, followed by data on egg sharers' own retrospective assessments of egg-sharing and their opinions regarding its ethics and regulation. This study shows that, contrary to some expectations, there are very few differences in the characteristics, experiences and opinions of egg-sharing donors and recipients, and also highlights the overwhelmingly positive assessment of egg-sharing by women who have taken part in such schemes. PMID- 22503267 TI - Consecutive repeat miscarriages are likely to occur in the same gestational period. AB - This is a retrospective, observational study to determine how often repeated consecutive miscarriages occur consistently in the same gestational period, including 1589 miscarriages among 543 women with recurrent miscarriage. In women who had two miscarriages only, 49.17% of both miscarriages occurred in the same gestational period, which was significantly higher than the expected probability of 34.54% (P<0.01). The proportions of all miscarriages occurring in the same gestational period in women with three, four and five or more miscarriages were 28.72%, 19.44% and 18.60%, compared with the expected probabilities of 14.36% (P<0.01), 6.57% (P<0.05) and <3.15% (P<0.05). The proportions of miscarriages occurring consistently in the same gestational period are higher than the theoretical probabilities calculated for the whole population. PMID- 22503268 TI - Intensive luteal-phase support with oestradiol and progesterone after GnRH agonist triggering: does it help? PMID- 22503269 TI - Successful delivery following ICSI with macrocephalic sperm head syndrome: a case report. AB - This article reports a case of macrocephalic sperm head syndrome, which is defined as the presence of a very high percentage of spermatozoa with enlarged heads and multiple flagellae, together with detailed morphological analysis. After a couple presented with infertility, sperm analysis showed severe teratozoospermia and almost all of the spermatozoa had macrocephaly with multiple tails. The morphological analysis revealed that most of the sperm heads contained several nuclei and had a similar number of tails as that of nuclei. However, detailed analysis revealed that there were a very few spermatozoa with an almost normal morphology. After genetic counselling, intracytoplasmic sperm injection was performed using a few spermatozoa that had an almost normal morphology, resulting in pregnancy and successful delivery. Even in macrocephalic sperm head syndrome, which may be caused by meiotic division failure, pregnancy is possible if some spermatozoa with almost normal morphology can be utilized, although there may be genetic risks. PMID- 22503270 TI - Forming a family with sperm donation: a survey of 244 non-biological parents. AB - There has been little research on the views and experiences of non-biological parents of sperm donor children. This paper reports the results of a survey of non-biological mothers and fathers. An online survey was designed and conducted by the Donor Sibling Registry, a US-based non-profit organization that supports those who have used donor conception. A total of 244 people responded (199 non biological mothers and 45 non-biological fathers). The survey aimed to understand the perspectives of the respondents who had used donor spermatozoa within heterosexual or same-sex relationships, by exploring their views on a number of key issues. Certain issues and concerns associated with not being genetically related to their offspring were experienced differently by men and women. However, there were many important areas of common ground: a concern for getting a healthy donor, the importance of matching the donor to the non-biological partner, and the amount of thought that went into selecting the donor. The implications of these results for policies concerning donor spermatozoa are discussed. PMID- 22503271 TI - Adjustment of cryoprotectant exposure time to counteract reduced cooling rates. PMID- 22503272 TI - Oocyte cryopreservation following failed testicular sperm extraction: a French case report with implications for the management of non-obstructive azoospermia. AB - The French law regulating assisted reproductive technologies forbids donor spermatozoa to be available in case of failed testicular sperm extraction (TESE) performed on the day of oocyte retrieval. This article reports the first French live birth after intracytoplasmic sperm injection of donated spermatozoa into frozen-thawed oocytes cryopreserved following failure of TESE. By reinforcing the relevance of TESE performed on the day of oocyte retrieval, oocyte cryopreservation in couples having beforehand consented to go to sperm donation will avoid cycle cancellation and potentially lead to successful live birth. Therefore, it could modify the French policy of management of patients suffering from non-obstructive azoospermia. PMID- 22503273 TI - Soluble BAFF-R produced by decidual stromal cells plays an inhibitory role in monocytes and macrophages. AB - A sophisticated immunological regulation between decidual stromal cells (DSC) and monocytes and macrophages is essential for the successful symbiosis of the mother and her fetus, but the mechanisms remain incompletely understood. The mRNA and proteins of B lymphocyte stimulator (BAFF, also known as BLys) and its receptor, BAFF-R (also known as BR3, CD268 or TNFRSF17), have been detected in both first trimester and term placentas, but whether BAFF or BAFF-R participates in the cross-talk between DSC and monocytes and macrophages in the first-trimester pregnancy has not been described. This study found that purified DSC extensively shed BAFF-R and that polyinosinic:polycytidylic acid (poly(I:C); a synthetic toll like receptor (TLR) 3 agonist) dramatically up-regulated BAFF-R secretion, suggesting that release of these soluble proteins was an inherent property of DSC and its induction might have relevance to TLR-3-mediated signal transduction. When monocytes were cultured with the supernatants of resting DSC or poly(I:C) treated DSC, the proliferation of CD14(+)HLA-DR(+) monocytes (P=0.025 and 0.045) and the secretion levels of tumour necrosis factor alpha (P=0.035 and 0.031) and interleukin 6 (P=0.021 and 0.035) were significantly increased after the BAFF-R was blocked. Soluble BAFF-R may play inhibitory roles in monocytes and macrophages. PMID- 22503275 TI - Validation of array comparative genome hybridization for diagnosis of translocations in preimplantation human embryos. AB - Fluorescent in-situ hybridization (FISH) for preimplantation genetic diagnosis (PGD) of structural chromosome abnormalities has limitations, including carrier testing, inconclusive results and limited aneuploidy screening. Array comparative genome hybridization (CGH) was used in PGD cases for translocations. Unbalances could be identified if three fragments were detectable. Smallest detectable fragments were ~6 Mbp and ~5 Mbp for blastomeres and trophectoderm, respectively. Cases in which three or more fragments were detectable by array CGH underwent PGD by FISH and concordance was obtained in 53/54 (98.1%). The error rate for array CGH was 1.9% (1/54). Of 402 embryos analysed, 81 were normal or balanced, 92 unbalanced but euploid, 123 unbalanced and aneuploid and 106 balanced but aneuploid. FISH with additional probes to detect other aneuploidies would have missed 28 abnormal embryos in the reciprocal group and 10 in the Robertsonian group. PGD cases (926) were retrospectively reviewed for reciprocal translocations performed by FISH to identify which could have been analysed by array CGH. This study validates array CGH in PGD for translocations and shows that it can identify all embryos with unbalanced reciprocal and Robertsonian translocations. Array CGH is a better approach than FISH since it allows simultaneous screening of all chromosomes for aneuploidy. PMID- 22503276 TI - The effects of letrozole on ovarian stimulation for fertility preservation in cancer-affected women. AB - Survival rates for fertile women with cancer have increased significantly, lending importance to considering the possibility of motherhood after cancer. This study was a retrospective analysis of a prospective database comparing two groups of patients who underwent fertility preservation after being diagnosed with either breast cancer or a non-hormone-dependent cancer between 2009 and 2011. Nineteen oncology patients were included in the study. The objective was to assess the efficacy of ovarian stimulation with aromatase inhibitors versus a standard antagonist protocol. This study sought to quantify oestradiol concentrations in patients receiving letrozole and to determine the length of time between diagnosis of malignancy and onset of fertility preservation. Number of mature oocytes retrieved in the non-hormone-dependent cancer group was comparable to that in the breast cancer group (15.4+/-8.19 versus 16.3+/-7.31). Oestradiol concentrations were higher for patients with non-hormone-dependent cancer (1666.4+/-739.42 pg/ml versus 829+/-551.11 pg/ml, P=0.006). There were no differences between the groups in the length of time between diagnosis and fertility preservation (17.4+/-4.93 versus 16.4+/-1.74 days). Oestradiol concentrations of breast cancer patients on the letrozole protocol remained much lower than those of patients on the antagonist protocol. PMID- 22503277 TI - Array CGH analysis shows that aneuploidy is not related to the number of embryos generated. AB - This study retrospectively analysed array comparative genomic hybridization (CGH) results of 7753 embryos from 990 patients to determine the frequency of embryonic euploidy and its relationship with the cohort size (i.e. the number of embryos available for biopsy and array CGH analysis). Linear regression analysis was performed to assess the effect of cohort size on euploidy rate adjusted for the effect of female age. While increasing female age was associated with a significant decrease in euploidy rate of day-3 and day-5 embryos (P<0.001 for both groups), cohort size was not significantly associated with euploidy rate. Logistic regression analysis was performed to assess the effect of cohort size, adjusted for maternal age, on the likelihood of having at least one euploid embryo available for transfer. The odds of having at least one euploid embryo in an assisted cycle was significantly decreased by increasing female age (P<0.01 for both day-3 and day-5 embryos) and was significantly increased by every additional embryo available for analysis (P<0.001 for both day-3 and day-5 embryos). PMID- 22503278 TI - Glycodelin suppresses endometrial cell migration and invasion but stimulates spheroid attachment. AB - Glycodelin contains four isoforms with diverse biological functions. Glycodelin-A is potentially a diagnostic marker for cancer patients and receptivity marker of the secretory endometrium. Yet, direct evidence for the role of glycodelin in the regulation of endometrial epithelial cell migration, invasion and attachment of trophoblastic spheroids (blastocyst surrogate) is lacking. In this study, the human glycodelin gene was stably transfected into human endometrial (HEC1-B) cells. Forced expression of glycodelin in HEC1-B cells did not affect cell proliferation, cell viability or cell-cycle progression, but significantly reduced migration and invasion of the stably transfected cells (both P<0.05). The migration rate returned to normal levels when the glycodelin-forced-expressing HEC1-B cells were treated with glycodelin RNAi. Furthermore, forced expression of glycodelin in HEC1-B cells significantly increased the attachment of trophoblastic spheroids onto the endometrial epithelial cells (P<0.05). In summary, glycodelin suppressed endometrial cell migration and invasion but enhanced spheroid attachment. PMID- 22503279 TI - Mutations in WNT4 are not responsible for Mullerian duct abnormalities in Chinese women. AB - The WNT4 gene plays a crucial role in sexual differentiation and female genital tract development. This study screened WNT4 for mutation in 189 Chinese women with Mullerian duct abnormalities (10 Mayer-Rokitansky-Kuster-Hauser syndrome, five Mullerian aplasia and 174 incomplete Mullerian fusion) and detected no perturbation that would indicate a major role for WNT4. Only one novel synonymous mutation (c.1091G>A) in exon 5 and one known single-nucleotide polymorphism (rs16826648) in exon 2 were found. The results suggest that WNT4 might not contribute to the aetiology of Mullerian duct abnormalities in Chinese women. PMID- 22503280 TI - Intra-cycle fluctuations of anti-Mullerian hormone in normal women with a regular cycle: a re-analysis. AB - Anti-Mullerian hormone (AMH) has emerged as an important marker of ovarian reserve. Its variation throughout the cycle, however, may still be a matter of debate. The objective of this study was to re-evaluate the intra-cycle fluctuations of AMH in individuals in a prospective clinical study with focus on the age-related effects on these fluctuations. Frequent blood samples were obtained from the mid-luteal phase of the first cycle to the mid-luteal phase of the second cycle in 44 healthy, regularly menstruating Caucasian women. Main outcome measures were individual fluctuations of AMH concentrations during the natural menstrual cycle. AMH concentrations exhibited large fluctuations throughout the cycle and did not follow a defined pattern. Female age was negatively correlated with mean AMH concentrations. The absolute intra-individual variation was also negatively associated with age, whereas the relative intra individual variation was positively associated with age. Although the fluctuation in relative intra-individual variation was higher in the older group, the absolute variation is very low and these fluctuations might therefore be of limited clinical relevance in this age group. These data show that in younger women caution should be exerted with the interpretation of a single randomly taken AMH measurement as a representative of ovarian reserve. PMID- 22503281 TI - Unveiling the mystery of deja vu: the structural anatomy of deja vu. AB - Deja vu (DV) is a widespread, fascinating and mysterious human experience. It occurs both in health and in disease, notably as an aura of temporal lobe epilepsy. This feeling of inappropriate familiarity has attracted interest from psychologists and neuroscientists for over a century, but still there is no widely agreed explanation for the phenomenon of non-pathological DV. Here we investigated differences in brain morphology between healthy subjects with and without DV using a novel multivariate neuroimaging technique, Source-Based Morphometry. The analysis revealed a set of cortical (predominantly mesiotemporal) and subcortical regions in which there was significantly less gray matter in subjects reporting DV. In these regions gray matter volume was inversely correlated with the frequency of DV. Our results demonstrate a structural correlate of DV in healthy individuals for the first time and support a neurological explanation for the phenomenon. We hypothesis that the observed local gray matter decrease in subjects experiencing DV reflects an alteration of hippocampal function and postnatal neurogenesis with resulting changes of volume in remote brain regions. PMID- 22503282 TI - Zoom-out attentional impairment in children with autism spectrum disorder. AB - Autism spectrum disorder (ASD) has long been associated with an inability to experience wholes without full attention to the constituent parts. A zoom-out attentional dysfunction might be partially responsible for this perceptual integration deficit in ASD. In the present study, the efficiency of attentional focusing mechanisms was investigated in children affected by ASD. We measured response latencies to a visual target onset displayed at three eccentricities from the fixation. Attentional resources were focused (zoom-in) or distributed (zoom-out) in the visual field presenting a small (containing only the nearest target eccentricity) or large (containing also the farthest target eccentricity) cue, 100 or 800 msec, before the target onset. Typically developing children, at the short cue-target interval, showed a gradient effect (i.e., latencies are slower at the farthest eccentricity) in the small focusing cue, but not in the large focusing cue condition. These results indicate an efficient zoom-in and zoom-out attentional mechanism. In contrast, children with ASD showed a gradient effect also in the large focusing cue condition, suggesting a specific zoom-out attentional impairment. In addition, the ASD group showed an atypical gradient effect at the long cue-target interval only in the small cue condition, suggesting a prolonged zoom-in and sluggish zoom-out attentional mechanism. This abnormal attentional focusing - probably linked to a dysfunctional top-down feedback from fronto-parietal network to the early visual areas - could contribute to the atypical visual perception associated to individuals with ASD which, in turn, could have consequences in their social-communicative development. PMID- 22503283 TI - Is delayed foveal feedback critical for extra-foveal perception? AB - Recent neuroimaging evidence suggests that visual inputs arising beyond the fovea can be 'fed back' to foveal visual cortex to construct a new retinotopic representation. However, whether these representations are critical for extra foveal perception remains unclear. Using transcranial magnetic stimulation we found that relatively late (350-400 msec) disruption of foveal retinotopic cortex impaired perceptual discrimination of objects in the periphery. These results are consistent with the hypothesis that feedback to the foveal retinotopic cortex is crucial for extra-foveal perception, and provide additional evidence for 'constructive' feedback in human vision. PMID- 22503284 TI - The 2 stromal compartments of the normal cervix with distinct immunophenotypic and histomorphologic features. AB - Cervical plasticity is partially attributed to subepithelial stromal cells. Knowing this population of cells in its variable physiologic states, with its immunophenotypic variations, will lead to better understanding of neoplastic processes related to these stromal cells. We reviewed slides of cervices from premenopausal, postmenopausal, and postpartum patients and used mesenchymal immunohistochemical stains. Results demonstrate 2 distinct subepithelial compartments, within the ectocervix and the endocervix/transformation zone. The endocervix/transformation zone has twice the number of stromal cells as the ectocervix, regardless of age. Ectocervical stromal cells are desmin+/smooth muscle actin (SMA)-, and endocervical stromal cells are desmin+/SMA-. In postpartum/premenopausal patients, the cervix has less desmin+ ectocervical and SMA- endocervical cells. In postmenopausal/prolapse patients, the cervix has no desmin+ ectocervical cells. Desmin+/SMA, calponin, caldesmon, myogenin, myoD1, CD34- cells could represent unusual myofibroblasts that should not be confused with a neoplastic process, especially if a mass is not present. PMID- 22503285 TI - Perineal and colonic metastases in two cases of malignant mesothelioma. AB - Two patients with rare sites of metastatic pleural mesothelioma are presented and the literature on similar cases is examined. One patient developed colonic metastases from a sarcomatoid mesothelioma. Another patient with epithelioid mesothelioma developed perineal metastases. PMID- 22503286 TI - 3rd line Erlotinib for lung cancer in Asia may be as cost-effective as in the Western world. PMID- 22503287 TI - Complete mitochondrial genome of Membranipora grandicella (Bryozoa: Cheilostomatida) determined with next-generation sequencing: the first representative of the suborder Malacostegina. AB - Next-generation sequencing (NGS) has proven a valuable platform for fast and easy obtaining of large numbers of sequences at relatively low cost. In this study we use shot-gun sequencing method on Illumina HiSeq 2000, to obtain enough sequences for the assembly of the bryozoan Membranipora grandicella (Bryozoa: Cheilostomatida) mitochondrial genome, which is the first representative of the suborder Malacostegina. The complete mitochondrial genome is 15,861 bp in length, which is relatively larger than other studied bryozoans. The mitochondrial genome contains 13 protein-coding genes, 2 ribosomal RNAs and 20 transfer RNAs. To investigate the phylogenetic position and the inner relationships of the phylum Bryozoa, phylogenetic trees were constructed with amino acid sequences of 11 PCGs from 30 metazoans. Two superclades of protostomes, namely Lophotrochozoa and Ecdysozoa, are recovered as monophyletic with strong support in both ML and Bayesian analyses. Somewhat to surprise, Bryozoa appears as the sister group of Chaetognatha with moderate or high support. The relationship among five bryozoans is Tubulipora flabellaris + (M. grandicella + (Flustrellidra hispida + (Bugula neritina + Watersipora subtorquata))), which supports for the view that Cheilostomatida is not a natural, monophyletic clade. NGS proved to be a quick and easy method for sequencing a complete mitochondrial genome. PMID- 22503288 TI - Metabolic insight into mechanisms of high-altitude adaptation in Tibetans. AB - Recent studies have identified genes involved in high-altitude adaptation in Tibetans. Genetic variants/haplotypes within regions containing three of these genes (EPAS1, EGLN1, and PPARA) are associated with relatively decreased hemoglobin levels observed in Tibetans at high altitude, providing corroborative evidence for genetic adaptation to this extreme environment. The mechanisms that afford adaptation to high-altitude hypoxia, however, remain unclear. Considering the strong metabolic demands imposed by hypoxia, we hypothesized that a shift in fuel preference to glucose oxidation and glycolysis at the expense of fatty acid oxidation would improve adaptation to decreased oxygen availability. Correlations between serum free fatty acid and lactate concentrations in Tibetan groups living at high altitude and putatively selected haplotypes provide insight into this hypothesis. An EPAS1 haplotype that exhibits a signal of positive selection is significantly associated with increased lactate concentration, the product of anaerobic glycolysis. Furthermore, the putatively advantageous PPARA haplotype is correlated with serum free fatty acid concentrations, suggesting a possible decrease in the activity of fatty acid oxidation. Although further studies are required to assess the molecular mechanisms underlying these patterns, these associations suggest that genetic adaptation to high altitude involves alteration in energy utilization pathways. PMID- 22503289 TI - A novel biochemically salvageable animal model of hyperammonemia devoid of N acetylglutamate synthase. AB - All knockout mouse models of urea cycle disorders die in the neonatal period or shortly thereafter. Since N-acetylglutamate synthase (NAGS) deficiency in humans can be effectively treated with N-carbamyl-l-glutamate (NCG), we sought to develop a mouse model of this disorder that could be rescued by biochemical intervention, reared to adulthood, reproduce, and become a novel animal model for hyperammonemia. Founder NAGS knockout heterozygous mice were obtained from the trans-NIH Knock-Out Mouse Project. Genotyping of the mice was performed by PCR and confirmed by Western blotting of liver and intestine. NCG and L-citrulline (Cit) were used to rescue the NAGS knockout homozygous (Nags(-/-)) pups and the rescued animals were characterized. We observed an 85% survival rate of Nags(-/-) mice when they were given intraperitoneal injections with NCG and Cit during the newborn period until weaning and supplemented subsequently with both compounds in their drinking water. This regimen has allowed for normal development, apparent health, and reproduction. Interruption of this rescue intervention resulted in the development of severe hyperammonemia and death within 48 h. In addition to hyperammonemia, interruption of rescue supplementation was associated with elevated plasma glutamine, glutamate, and lysine, and reduced citrulline, arginine, ornithine and proline levels. We conclude that NAGS deprived mouse model has been developed which can be rescued by NCG and Cit and reared to reproduction and beyond. This biochemically salvageable mouse model recapitulates the clinical phenotype of proximal urea cycle disorders and can be used as a reliable model of induced hyperammonemia by manipulating the administration of the rescue compounds. PMID- 22503290 TI - Small molecule drugs - optimizing DNA damaging agent-based therapeutics. AB - DNA-targeted chemotherapies remain fundamental in clinical management of both common solid tumours and hematologic malignancies. Recent studies indicate that novel combinations of cytotoxic chemotherapy may have significant activity even in tumours regarded as being resistant to conventional chemotherapy. In addition, the search for more selective and efficacious drugs that can deliver critical DNA damage with minimal side effects continues. Trabectedin, bendamustine and the pyrrolobenzodiazepine dimer SG2000 exemplify three different classes of DNA targeted agent undergoing clinical evaluation. Increasingly, DNA damaging drugs are being used in combination with novel agents such as small molecule inhibitors or antibodies targeting receptor tyrosine kinases. Understanding the mechanistic basis for interactions of these novel targeted agents with DNA-interactive drugs will inform design of optimal combinations for future studies and is critical to maximize benefit in the clinic. PMID- 22503291 TI - [Genomic revolution of rare disease diagnosis]. PMID- 22503292 TI - [The challenges of medicoeconomic assessment, benefit for the patient]. PMID- 22503293 TI - Isokinetic muscle strengthening after acquired cerebral damage: a literature review. AB - OBJECTIVE: Isokinetic strengthening is a rehabilitation technique rarely used in stroke patients. However, the potential benefits of force and endurance training in this population are strongly suspected. METHOD: This literature review synthesizes the results of clinical trials on this topic. The research was conducted on PubMed, using "Stroke", "rehabilitation", "isokinetic", "upper limb" and "training" as keywords. RESULTS: Seventeen studies focusing on the use of isokinetics in assessment or rehabilitation (six studies) following stroke were reviewed. For the lower limb, muscle strength and walking ability improved after isokinetic rehabilitation programs. For the upper limb, the only two studies found in the literature suggest improvement in the strength of the trained muscles, of grip force, of the Fugl-Meyer motor score and of global functional capacities. This review does not reveal any consensus on the protocols to be implemented: type of muscle contraction, velocities.... CONCLUSION: While isokinetic strengthening has not proven its efficiency in rehabilitation of the upper limb following stroke, its interest with regard to rehabilitation of the lower limbs has been recognized. Randomized controlled trials in this field are necessary to confirm its efficiency, especially concerning upper arm rehabilitation. PMID- 22503294 TI - Ethical concerns in the student/preceptor relationship: a need for change. AB - Nursing schools are required to ensure that the clinical and academic milieu prepares nurses not only to recognize but also to act on various ethical issues. As a result of our years teaching nursing ethics to undergraduate nursing students we have come to believe there is a disconnect between classroom teaching and students' experiences in practice. How then can nurse educators help nursing students not only to see the ethical components of their work but also to take the necessary steps to solve ethical dilemmas and challenge unethical practice? One such strategy is the use of preceptorship. In this paper, we set out to learn about nursing students' ethical encounters in the clinical area, specifically those within the preceptor/student relationship. To this end we conducted an integrative review and are weaving in Gesler's (1992) concepts who argued that ethical issues play out in our physical and social environments. We identified nine articles that describe students' perceptions of ethical problems in their relationships with preceptors. However, it was rare for the authors of these articles to label these as 'ethical' issues. The integrative review revealed first, that students describe ethical issues in their narratives, and second, their most common response to these issues is silence. We continue to be concerned that nursing students' classroom learning of ethics is disconnected from their everyday nursing practice. Further research and education implications are discussed and explored in this paper. PMID- 22503295 TI - Becoming a nurse in Italy: a multi-method study on expenditures by families and students. AB - Potential nursing students and their families are faced with difficult decisions regarding the amount of time and money required to complete the nursing programme and the availability of funds to cover the costs and this seems to have received little no attention to date. With the aim of describing the costs incurred by Italian nursing students and/or their families per academic year and compare cost trends incurred from 2004-05 to 2010-11, a multi-centre qualitative/quantitative study design was adopted. Italian Nursing students attending the first, second and third academic years in 2004-05 and those attending the first, second and third academic years in 2010-11 were eligible. Five hundred and six students were involved: 215 (out of 300 eligible, 71.6%) attended the bachelor's degree in nursing in 2004-05 and 291 (out of 383 eligible, 75.9%) in 2010-11. On an annual basis, the average annual expenditures increased by 12% for nursing education from 2004-05 to 2010-11. Given that qualification as a nurse requires at least three years, and considering inflation, for a student who matriculated in 2005 an average of 2485.7? per year (7457.0? in total) was required. Data suggest that students have modified their spending behaviour (limiting lunches at public bars, buying books and photocopies) in order to handle the rise of non-discretionary costs, such as tuition fees and the costs of attending lectures and hospital/district trainings. Policies supporting nursing education in general and for those students who are motivated but unable to undertake the course for economic reasons are urgently needed. PMID- 22503296 TI - Telehealth nurse practitioner student clinical experiences: an essential educational component for today's health care setting. AB - In order to meet the continuous changes and innovations within the health care system, nurse practitioner faculty must look to the future and prepare nurse practitioner graduates who deliver safe, quality patient care addressing the realities of a global society with a fast-paced expansion of technologies. Preparing nurse practitioner students for practice must include more than information technology knowledge in graduate nursing programs. Formal clinical experiences using various telehealth applications must be integrated into nurse practitioner training. Innovative strategies must be explored by nurse practitioner faculty to assure that graduates can meet the demanding technological demands of our current health care society. PMID- 22503297 TI - [Cardiac metastasis of bronchial squamous cell carcinoma]. AB - Secondary location of lung cancer are frequent but the location heart is rare and often diagnosed postmortem. We report a case of a patient of 67 years without disease history, individuals smoking outside a chronic carrier of bronchial squamous cell carcinoma and the staging of which finds a secondary location within the left atrial. Through this observation, the authors propose an update on this rare and exceptional location. PMID- 22503298 TI - Simultaneous onset of anterior and middle cerebral artery dissections with an old vertebral artery dissection. AB - Multiple arterial dissections in the anterior circulation with simultaneous onset are extremely rare. We report a patient with infarctions caused by simultaneous arterial dissections in the right anterior cerebral artery and the left middle cerebral artery and discuss the characteristic feature of this vascular disorder. A 53-year-old woman presented with a severe headache and a mild aphasia. Magnetic resonance imaging revealed multiple acute cerebral infarctions in the left temporal and right frontal lobes. The initial angiographic findings revealed arterial dissections of the anterior cerebral, left middle cerebral, and right vertebral arteries. The follow-up angiographic examination found improvement of the stenosis in both the anterior cerebral and middle cerebral arteries. We have concluded that the lesion of the vertebral artery was not in an acute stage, because no interval change was seen during the radiologic evaluation. She underwent conservative therapy, and her symptoms disappeared. Multiple arterial dissections are rare, especially those developing simultaneously in different arteries. This is the first case of multiple arterial dissections of the different arteries in the anterior circulation manifesting cerebral infarction simultaneously. PMID- 22503299 TI - Higher on-admission serum triglycerides predict less severe disability and lower all-cause mortality after acute ischemic stroke. AB - BACKGROUND: High(er) on-admission triglyceride (TG) levels have been suggested as an independent predictor of better outcomes of the acute ischemic stroke. Data regarding poststroke physical disabilities have been contradictory. We aimed to investigate the relationship between fasting on-admission TG and development of disability and all-cause mortality over a 2.5-year period. METHODS: This prospective observational study included 83 acute ischemic stroke patients (29 cardioembolic; 41% men; median age 76 years) followed-up for 28 to 30 months and assessed for physical disability using the Modified Rankin scale (mRS) at 1 week and 3, 12, and 24 months poststroke. TGs were considered as a continuous and a binary variable (<= 1.27 [n = 43] and >1.27 mmol/L [n = 43]). RESULTS: Higher TGs (continuous or binary) were independently (default adjustments: stroke type, severity at presentation, age, atrial fibrillation, preindex event antiplatelet use, infarct volume, postindex event antiplatelet, statin and angiotensin converting enzyme inhibitor use, on-admission fasting cholesterol, mean platelet volume, and glomerular filtration rate) were associated with: (1) higher odds of mRS 0 to 2 (none/mild disability) across the assessments (overall odds ratio [OR] 2.73 [95% confidence interval {CI} 1.15-6.38] and OR 3.57 [95% CI 1.04-12.3], respectively); (2) lower odds of mRS worsening between any 2 consecutive assessments (overall OR 0.44 [95% CI 0.20-0.96] and OR 0.35 [95% CI 0.16-0.77], respectively); (3) lower risk of all-cause mortality (hazard ratio 0.47 [95% CI 0.23-0.96] and hazard ratio 0.45 [95% CI 0.21-0.98], respectively). CONCLUSIONS: These data suggest that higher fasting TGs on-admission predict less severe disability, reduced disability progression, and all-cause mortality in patients with acute ischemic stroke. PMID- 22503300 TI - Prostate-specific antigen kinetics as a surrogate endpoint in clinical trials of metastatic castration-resistant prostate cancer: a review. AB - Prostate cancer is the most common cancer in men. Overall survival is considered the best endpoint for clinical trials, but it is difficult to use in phase-2 studies. Although the reduction of PSA after cytotoxic chemotherapy has been identified as a valid surrogate for overall survival, it has not proven reliable for the evaluation of many biologics. Moreover, the PSA progression-free survival at 3 months was validated only for cytotoxic drugs, and the various measures of progression/delay have not been confirmed by large studies. Ultimately, outside of overall survival, no measure has been validated as a surrogate endpoint after treatment with targeted therapies and vaccine therapy. The PSA levels have a great variability and, theoretically, the use of measures of cell kinetics and PSA may be the most reliable approach to estimate the behavior of metastatic disease. Some measures of PSA kinetics have been well developed in the clinical castration-resistant prostate cancer, the PSA doubling time and the growth rate constant. The studies about the kinetics of PSA measures are reviewed and discussed. To date, studies that consider the measures of PSA kinetics as surrogate endpoints are still very few. However in the near future, the drug evaluation can not proceed separately, with distinct endpoints between cytotoxic and non-cytotoxic agents. Therefore, extensive analysis and validation of measures of kinetics derived from PSA, and candidates for a role for surrogate endpoint, will be needed in phase-3 studies, in order to test their effectiveness in different disease scenarios. PMID- 22503301 TI - Cost-effectiveness analysis of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. AB - OBJECTIVE: Perform a cost-effectiveness analysis of the treatment of diabetic macular edema (DME) with ranibizumab plus prompt or deferred laser versus triamcinolone plus prompt laser. Data for the analysis were drawn from reports of the Diabetic Retinopathy Clinical Research Network (DRCRnet) Protocol I. DESIGN: Computer simulation based on Protocol I data. Analyses were conducted from the payor perspective. PARTICIPANTS: Simulated participants assigned characteristics reflecting those seen in Protocol I. METHODS: Markov models were constructed to replicate Protocol I's 104-week outcomes using a microsimulation approach to estimation. Baseline characteristics, visual acuity (VA), treatments, and complications were based on Protocol I data. Costs were identified by literature search. One-way sensitivity analysis was performed, and the results were validated against Protocol I data. MAIN OUTCOME MEASURES: Direct cost of care for 2 years, change in VA from baseline, and incremental cost-effectiveness ratio (ICER) measured as cost per additional letter gained from baseline (Early Treatment of Diabetic Retinopathy Study). RESULTS: For sham plus laser (S+L), ranibizumab plus prompt laser (R+pL), ranibizumab plus deferred laser (R+dL), and triamcinolone plus laser (T+L), effectiveness through 104 weeks was predicted to be 3.46, 7.07, 8.63, and 2.40 letters correct, respectively. The ICER values in terms of dollars per VA letter were $393 (S+L vs. T+L), $5943 (R+pL vs. S+L), and $20 (R+dL vs. R+pL). For pseudophakics, the ICER value for comparison triamcinolone with laser versus ranibizumab with deferred laser was $14 690 per letter gained. No clinically relevant changes in model variables altered outcomes. Internal validation demonstrated good similarity to Protocol I treatment patterns. CONCLUSIONS: In treatment of phakic patients with DME, ranibizumab with deferred laser provided an additional 6 letters correct compared with triamcinolone with laser at an additional cost of $19 216 over 2 years. That would indicate that if the gain in VA seen at 2 years is maintained in subsequent years, then the treatment of phakic patients with DME using ranibizumab may meet accepted standards of cost-effectiveness. For pseudophakic patients, first-line treatment with triamcinolone seems to be the most cost-effective option. PMID- 22503302 TI - Vitamins E and C and medical record-confirmed age-related macular degeneration in a randomized trial of male physicians. AB - PURPOSE: To test whether supplementation with alternate-day vitamin E or daily vitamin C affects the incidence of the diagnosis of age-related macular degeneration (AMD) in a large-scale randomized trial of male physicians. DESIGN: Randomized, double-masked, placebo-controlled trial. PARTICIPANTS: We included 14 236 apparently healthy United States male physicians aged >=50 years who did not report a diagnosis of AMD at baseline. METHODS: Participants were randomly assigned to receive 400 international units (IU) of vitamin E or placebo on alternate days, and 500 mg of vitamin C or placebo daily. Participants reported new diagnoses of AMD on annual questionnaires and medical record data were collected to confirm the reports. MAIN OUTCOME MEASURES: Incident diagnosis of AMD responsible for a reduction in best-corrected visual acuity to <=20/30. RESULTS: After 8 years of treatment and follow-up, a total of 193 incident cases of visually significant AMD were documented. There were 96 cases in the vitamin E group and 97 in the placebo group (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.78-1.37). For vitamin C, there were 97 cases in the active group and 96 in the placebo group (HR, 0.99; 95% CI, 0.75-1.31). CONCLUSIONS: In a large-scale, randomized trial of United States male physicians, alternate-day use of 400 IU of vitamin E and/or daily use of 500 mg of vitamin C for 8 years had no appreciable beneficial or harmful effect on risk of incident diagnosis of AMD. PMID- 22503303 TI - Proud osteochondral autograft versus synthetic plugs--contact pressures with cyclical loading in a bovine knee model. AB - PURPOSE: To determine whether proud synthetic and proud osteochondral plugs conform to native surrounding cartilage after cyclical loading and if there are differences in height and contact pressure after loading. METHODS: Sixteen bovine knees were used. Each received one osteochondral plug and one of two types of synthetic plugs (Smith & Nephew TruFit(r) BGS plug or Kensey Nash OsseoFit(r) plug). Plugs were placed in the center of each condyle's highest pressure area of articulation identified prior to defect creation (control). Static loads of 800N were applied and contact pressures measured with Tekscan sensors. RESULTS: Both types of synthetic grafts and the osteochondral grafts all subsided with cyclical loading (p<0.001). The OsseoFit(r) plug displayed a greater reduction in height than the TruFit(r) plug compared to osteochondral grafts. The OsseoFit(r) plugs had significantly lower height than osteochondral grafts after both periods of cyclical loading (p<0.001), while height of the TruFit(r) plugs was not significantly different than the heights of osteochondral grafts after either first (p=0.387) or second (p=0.261) periods of cyclical loading. Contact pressures for the OsseoFit(r) plugs were significantly lower than contact pressures for osteochondral grafts after both periods of cyclical loading (p<0.001 for both). There was no difference between the pressures of TruFit(r) and osteochondral plugs after the first (p=0.381) or second (p=0.292) periods of cyclical loading. CONCLUSIONS: Precision and accuracy are demanded to achieve flush osteochondral plug placement and OsseoFit synthetic plugs may subside more with less pressure than TruFit plugs if placed proud. PMID- 22503304 TI - Home therapy with subcutaneous immunoglobulins for patients with primary immunodeficiency diseases. AB - The most frequently encountered patients with primary immunodeficiency disease (PID) are those with antibody deficiencies. These patients require life-long immunoglobulin (IgG) replacement therapy to prevent severe and reoccurring infections. IgG is traditionally administered intravenously (IVIG) on an outpatient basis, although in some Scandinavian countries subcutaneous administration of IgG (SCIG) as home self-infusion has become the predominant mode of delivery. Compared with IVIG, SCIG therapy leads to a more physiologic IgG profile since the large variations between peak and trough levels of serum IgG are blunted by slow absorption and maintenance of closer equilibrium between intra- and extravascular compartments. SCIG therapy has been shown to be as effective as IVIG in preventing infections and has a better safety profile, with fewer systemic side effects. While local tissue reactions are common with SCIG, they are usually mild, tend to improve over time and typically do not interfere with therapy. Switching to SCIG therapy from IVIG can lead to significant improvements in health-related quality of life, appears to be more convenient for the patient, and can make it easier for the patient to travel. In those patients with difficult vascular access and intolerable side-effects with IVIG therapy, SCIG therapy may be the only treatment option. Selected patients can be expected to benefit greatly from SCIG therapy, although implementation of a successful home-treatment program requires proper education, training, and supportive care. PMID- 22503305 TI - Hemophilia management in transfusion medicine. AB - Hemophilia is an X-linked bleeding disorder caused by a deficiency of factor VIII or IX activity. We will review the use of blood products, including plasma derived and recombinant coagulation factor concentrates (CFCs), and other hemostatic agents central to the management of bleeding, surgical procedures, prophylaxis and inhibitors. However, management of hemophilia is more than just giving CFCs. Attention to the physical and psychosocial health of persons with hemophilia to improve their quality of life must be the goal. These goals can best be met by comprehensive care hemophilia (bleeding disorders) clinics designed to provide clinical service and education to persons with hemophilia and their families, and to conduct research to improve hemophilia care. PMID- 22503306 TI - A primer in pretransfusion testing. AB - Pretransfusion testing encompasses much more than testing a patient's sample in the laboratory. All aspects pertaining to this testing will be reviewed, from the clinician's order to the final step of when the blood product is ready to be issued to the clinical side from the laboratory. The importance of patient safety and positive outcomes will be stressed through discussion of positive patient identification and appropriate labelling in order to get the right product to the right patient at the right dose. Transfusion service does not stop in the laboratory; it is imperative that all who are involved in this service appreciate the significance of performing tasks accordingly to standards and regulations. PMID- 22503307 TI - Prothrombin complex concentrate for the urgent reversal of warfarin. Assessment of a standard dosing protocol. AB - BACKGROUND: Octaplex(r), a six factor prothrombin complex concentrate (PCC), has recently been approved for use in Canada. The optimal dose of Octaplex has yet to be established and our study was designed to monitor the efficacy of a low standard dose. STUDY DESIGN AND METHODS: Patients on warfarin treatment in need of urgent reversal for bleeding, invasive procedures or surgery were given a standard dose of 40 ml (1000 IU FIX, 14 IU/kg). We conducted a retrospective chart review of 231 patients. RESULTS: Patients given concurrent frozen plasma (FP) for reversal were eliminated from the study. Overall, 150 patients were reviewed and divided into three groups: (1) non-CNS bleeders, (2) CNS bleeders, and (3) non-bleeders. Correction of INR to 1.5 or less was achieved to the same extent in each group. Patients with active bleeding had the least successful bleeding cessation and patients with intracranial bleeding had the most dismal outcome compared to non-intracranial bleeders. CONCLUSIONS: Our data suggests that Octaplex, when given as a low standard dose is effective at INR reversal with 76% of our patients correcting to an INR of 1.5 or less. It appears that this dose is sufficient for non-bleeding patients. Bleeding patients may benefit most from a dose increase to achieve more complete reversal and patients with intracranial bleeding should achieve more complete reversal within 2h of presentation. PMID- 22503308 TI - Trimming the fat with an IVIG approval process. PMID- 22503309 TI - The Canadian Transfusion Surveillance System: what is it and how can the data be used? AB - Hemovigilance systems are important programs for: monitoring trends of known risks; evaluating effectiveness of steps taken to reduce risks; providing data to support recommendations for change and guideline development; and contributing overall to the safety of transfusion. The Transfusion Transmitted Injury Surveillance System is the hemovigilance system implemented in Canada. It evolved in 1999 as a pilot program and expanded across Canada in 2005. Each province reports their adverse reactions to the transfusion of blood products and plasma proteins to the Public Health Agency of Canada (PHAC) at predetermined intervals. PHAC reconciles, summarizes the data and publishes a report approximately 2 years after the data are collected. This is considered a passive reporting system but in spite of the delays, the program provides useful information to address a variety of questions. Examples include: assessing the impact of a provincial patient transfusion history registry in Quebec on reporting of hemolytic transfusion reactions; identifying trends of bacterial contamination of blood products and assessing the impact of interventions on these events; and the impact of male-only plasma on the incidence of Transfusion Related Acute Lung Injury. Although hemovigilance data has been successfully used to improve blood safety, we must continue to explore ways to utilize such data to improve and implement safe transfusion practices. PMID- 22503310 TI - Glutamate, GABA, and other cortical metabolite concentrations during early abstinence from alcohol and their associations with neurocognitive changes. AB - BACKGROUND: Little is known about the effects of alcohol dependence on cortical concentrations of glutamate (Glu) or gamma aminobutyric acid (GABA). We used proton magnetic resonance spectroscopy (MRS) to study cross-sectionally and longitudinally the concentrations of these in alcohol dependent individuals (ALC) during early abstinence from alcohol. METHODS: Twenty ALC were studied at about one week of abstinence from alcohol (baseline) and 36 ALC at five weeks of abstinence and compared to 16 light/non-drinking controls (LD). Eleven ALC were studied twice during abstinence. Participants underwent clinical interviewing, blood work, neuropsychological testing, structural imaging and single-volume proton MRS at 4Tesla. Absolute concentrations of Glu, GABA and those of other (1)H MRS-detectable metabolites were measured in the anterior cingulate (ACC), parieto-occipital cortex (POC) and dorso-lateral prefrontal cortex (DLPFC). Relationships of metabolite levels to drinking severity and neurocognition were also assessed. RESULTS: ALC at baseline had lower concentrations of Glu, N acetylaspartate (NAA), choline- (Cho) and creatine-containing metabolites (Cr) than LD in the ACC, but had normal GABA and myo-inositol (mI) levels. At five weeks of abstinence, metabolite concentrations were not significantly different between groups. Between one and five weeks of abstinence, Glu, NAA and Cho levels in the ACC increased significantly. Higher cortical mI concentrations in ALC related to worse neurocognitive outcome. CONCLUSION: These MRS data suggest compromised and regionally specific bioenergetics/metabolism in one-week abstinent ALC that largely normalizes over four weeks of sustained abstinence. The correlation between mI levels and neurocognition affirms the functional relevance of this putative astrocyte marker. PMID- 22503311 TI - The relationship between foot motion and lumbopelvic-hip function: a review of the literature. AB - Excessive pronation has been implicated in the development of numerous overuse injuries of the lower limb and is suggested to cause more proximal biomechanical dysfunction. Functional foot orthoses (FFO) are frequently prescribed for lower limb injury associated with excessive foot pronation and have been demonstrated to have efficacy with specific conditions. However, the mechanism of action of FFO is largely unknown. Research investigating the kinematic and kinetic changes associated with FFO use is inconclusive. Furthermore there is a growing body of evidence suggesting that changes to muscle activity patterns in response to FFO may be responsible for their therapeutic effect. Additionally, current research suggests dysfunction of musculature of the lumbopelvic-hip complex is involved in lower extremity functional changes and is related to the development some pathologies traditionally attributed to excessive foot pronation. Evidence of temporal coupling between the hip and the foot and changes in hip muscle activity associated with FFO use further suggest a relationship between proximal and distal lower limb function. The aim of this review is to discuss the association between foot and lumbopelvic-hip complex dysfunction and injury, assess the evidence for functional changes to lower limb and lumbopelvic-hip function with FFO use and finally to discuss the potential for changes to hip musculature activation with FFO use to influence distal mechanics and produce a therapeutic benefit. PMID- 22503312 TI - Dual perforator propeller internal mammary artery perforator (IMAP) flap for soft tissue defect of the contralateral clavicular area. AB - The internal mammary artery perforator (IMAP) flap represents the evolution from axially pedicled flaps (deltopectoral flap) to perforator flaps. Both flaps are typically used for neck and tracheostoma reconstruction in male patients. We present the case of a 68-year-old obese female patient with a right upper thoracic radionecrosis secondary to breast irradiation. Soft-tissue defect measured 12*18 cm. She also complained of left breast hypertrophy. Following radical debridement, a left IMAP flap extending from midline to the anterior axillary fold was raised, based on the second and fourth IMAP vessels. The flap was rotated 180 degrees on its second and fourth perforators to cover the defect and the left breast was reshaped. The flap survived entirely and wound healing was uneventful. Ptosis and breast hypertrophy were corrected at the same time. The IMAP flap can be harvested all the way to the anterior axillary fold and used as a large propeller flap, which makes this flap suitable for contralateral thoracic reconstructions, even in female patients. PMID- 22503313 TI - Extradural myelomeningocele reconstruction using local turnover fascial flaps and midline linear skin closure. AB - Myelomeningocele is the most common neural tube defect. Repair typically involves deep closure with regional muscle flaps (e.g. latissimus dorsi, gluteus maximus) and skin closure with rotation, bipedicle, or rhomboid flaps. We describe the reconstruction of large myelomeningocele defects using (1) local fascial turnover flaps with or without paraspinous muscle flaps for deep coverage of the dural repair followed by (2) linear, midline skin closure. PMID- 22503314 TI - Correction of breast contour deformities using polyurethane breast implant capsule in revisional breast surgery. AB - Surgeons are commonly confronted with breast contour deformities and defects that result from previous surgical interventions. These soft tissue deformities can be corrected by conventional reconstructive flap surgery using autologous tissue, but there can be donor site morbidity. Smaller volume replacement is possible using temporary fillers such as hyaluronic acid or polylactic acid, or by using 'permanent' fillers such as autologous fat, but large defects are notoriously difficult to fill and often the fillers resorb or migrate. The patient described in this case report had an exchange of polyurethane implant (PU) in the left breast and correction of a contralateral breast contour filling deformity. A left breast partial capsulectomy was performed after implant removal and the capsule graft was inserted into a predissected pocket where soft tissue augmentation was required. A biopsy from the PU capsule was reported to show a foreign body type giant cell reaction to PU material in a fibrous capsule, lined by synovial metaplasia. The post-operative result showed satisfactory soft tissue revolumisation. PU breast implant structured capsule has thus been used as filler to correct breast soft tissue deformity and contour defects. Clearly it may have a use in other anatomical sites. PMID- 22503315 TI - Time trends in educational differences in lung and upper aero digestive tract cancer mortality in France between 1990 and 2007. AB - BACKGROUND: We investigated the magnitude of educational differences in lung and upper aero digestive tract (UADT) cancer mortality in France from 1990 to 2007. METHODS: The analyses were based on census data from a representative sample of the French population. Educational level was used as the indicator for socioeconomic status. Educational differences in mortality from lung and UADT cancer were calculated among people aged 30-74 and by birth cohort. Two periods were compared: 1990-1998 and 1999-2007. Mortality rates, hazard ratios and relative indices of inequality (RII) were computed. RESULTS: We found higher lung and UADT cancer mortality among those with less education. Inequalities in male UADT cancer mortality remained stable over time (RII(1990-1998)=0.21 (95% confidence interval 0.15-0.29); RII(1999-2007)=0.17 (0.11-0.26)) whereas inequalities in lung cancer mortality increased among the younger men (RII(1990 1998)=0.48 (0.28-0.83); RII(1999-2007)=0.16 (0.09-0.31)). Among women, inequalities in lung cancer mortality became apparent during the second period with higher mortality among those with less education. This trend was exclusively driven by the younger women, among whom inequalities reached about the same magnitude as among younger men (RII(1999-2007)=0.21 (0.08-0.56)). CONCLUSION: UADT cancer mortality rates strongly decreased over time for every educational level. This implies that the burden of health associated with socioeconomic inequalities in UADT cancer mortality decreased substantially. Inequalities in lung cancer mortality are increasing among the younger generation and are expected to increase even more. Differences in magnitude of inequalities among men and women may disappear in the coming decades. PMID- 22503316 TI - A critical analysis of the American Joint Committee on Cancer (AJCC) staging system for differentiated thyroid carcinoma in young patients on the basis of the Surveillance, Epidemiology, and End Results (SEER) registry. AB - BACKGROUND: Differentiated thyroid carcinomas (DTC) are the only tumors for which age is a determinant of stage in the American Joint Committee on Cancer's (AJCC) staging protocol. In this study, we re-examined the relationship between age, extent of disease, and prognosis by using a large dataset with longer follow-up times. METHODS: We examined the Surveillance, Epidemiology, and End Results (SEER) registry data 1973 to 2005 for patients with DTC as their only known malignancy. We used Cox multivariate analyses to generate mortality hazard ratios, controlling for several variables, to evaluate the effects of age and disease extent. RESULTS: We identified 55,402 patients with DTC. Of these, 49,240 had sufficient data to generate a TNM stage on the basis of AJCC guidelines. Within stage II, younger patients (<45 years) have worse outcomes than older patients (P < .001). Younger patients had an 11-fold increase in mortality between stages I and II, whereas there was no difference for older patients. When we uniformly applied the 45-and-older staging protocol to all patients, we found that stages III-IVc had a significantly greater risk of mortality for all patients compared with stage I. CONCLUSION: The presence of regional and metastatic thyroid cancer bears prognostic significance for all ages. Under current AJCC guidelines, young patients with metastatic thyroid cancer may be understaged. PMID- 22503317 TI - Ki-67 predicts disease recurrence and poor prognosis in pancreatic neuroendocrine neoplasms. AB - BACKGROUND: Pancreatic neuroendocrine neoplasms are rare malignancies for which the ideal staging method remains controversial. Ki-67 is a cell proliferation marker that has been shown to have some utility in predicting prognosis in neuroendocrine neoplasms. We sought to test the predictive ability of Ki-67 staining for disease recurrence and overall survival (OS) in pancreatic neuroendocrine neoplasms. METHODS: The medical records of patients who underwent pancreatic resection for pancreatic neuroendocrine neoplasms at a tertiary referral hospital from 1994 to 2009 were reviewed. The pathologic specimens of all were stained for Ki-67 and recorded as percentage of cells staining positive per high-powered field. The 10-year disease-free and OSs were analyzed. RESULTS: We identified 140 patients. Gender and age were not associated with increased risk of disease recurrence. Patients with tumors >4 cm or with Ki-67 staining >9% were more likely to have disease recurrence (P = .0454 and .047) and have decreased OS (P < .0001 and .0007). CONCLUSION: Increasing tumor size and increasing Ki-67 staining both correlate with increased risk of disease recurrence and decreased OS. Designing a staging system that incorporates both of these clinical variables will enable better identification of patients at risk for recurrent pancreatic neuroendocrine neoplasms. PMID- 22503318 TI - Delivery of interferon alpha using a novel Cox2-controlled adenovirus for pancreatic cancer therapy. AB - BACKGROUND: Combination therapy with interferon alpha (IFN) is correlated with improved survival in patients with pancreatic ductal adenocarcinoma (PDAc) but frequently presents side effects. We designed a novel targeted adenovirus with replication restricted to cyclooxygenase 2 (Cox2)-overexpressing PDAcs and hypothesize that the locally delivered therapeutic gene IFN can augment oncolytic effects while minimizing systemic toxicity. METHODS: IFN-expressing vectors were tested in vitro with the use of 4 PDAc cell lines with cytocidal effect measured by crystal violet and colorimetrically and IFN production assayed by ELISA. Cox2 promoter activity was checked by a luciferase reporter assay. In vivo, subcutaneous tumor xenografts with 2 PDAc cell lines in nude mice were treated with a single intratumoral viral dose. RESULTS: All PDAc cell lines were Cox2 positive. Oncolysis from the novel Cox2-controlled virus was comparable or superior to Adwt, the wild-type virus without safety features. The absence of cytocidal effect in Cox2-negative cells with the novel virus indicated cancer specificity. In vivo, stronger tumor suppression from the novel virus was seen when compared with nonreplicating IFN-expressing vectors. CONCLUSION: We demonstrated the potent therapeutic effects of a novel tumor-specific conditionally replicative IFN-expressing adenovirus. With potential to locally deliver IFN and avoid systemic toxicity, this strategy may therefore expand the application of this robust and promising therapy. PMID- 22503319 TI - Prevalence of alcohol misuse among men and women undergoing major noncardiac surgery in the Veterans Affairs health care system. AB - BACKGROUND: Patients who screen positive for alcohol misuse on the Alcohol Use Disorder Identification Test Consumption Questionnaire (AUDIT-C >=5 points) have significantly increased postoperative complications. Severe alcohol misuse (AUDIT C >=9 points) is associated with increased postoperative health care use; however, little is known about the prevalence of alcohol misuse in demographic and clinical subgroups of surgical patients. METHODS: The prevalence of alcohol misuse was evaluated among 10,284 patients (9,771 men and 513 women) who underwent major noncardiac surgery in Veterans Affairs (VA) hospitals during the fiscal years 2004 to 2006 and completed the AUDIT-C. Sex-stratified analyses evaluated prevalence rates of alcohol misuse (AUDIT-C >=5) and severe misuse (AUDIT-C >=9) across demographic and clinical subgroups. RESULTS: Overall, 1,607 (16%) men and 24 (5%) women screened positive for alcohol misuse (AUDIT-C >=5) in the year before operation, with 4% and 2% screening positive for severe misuse (AUDIT-C >=9), respectively. Alcohol misuse was more common among men who were <60 years of age, divorced or separated, current smokers, or American Stoke Association class 1 or 2, and those with cirrhosis/hepatitis or substance use disorders. Among patients with alcohol misuse, 36% of men and 58% of women were American Society of Anesthesiologists class 1 or 2, and most did not have diagnoses that were commonly associated with alcohol misuse. CONCLUSION: Alcohol misuse is relatively common in male surgical patients. Moreover, surgical patients undergoing operation who screen positive for alcohol misuse are often relatively healthy, without health problems that might alert providers to their alcohol misuse in the absence of screening. PMID- 22503320 TI - Safety and feasibility of using low-dose perioperative intravenous steroids in inflammatory bowel disease patients undergoing major colorectal surgery: A pilot study. AB - BACKGROUND: High-dose perioperative corticosteroids are the standard of care for steroid-treated patients undergoing surgery. There is little evidence, however, to support this practice. We investigated the safety of perioperative low-dose steroids in patients with inflammatory bowel disease (IBD) undergoing major colorectal surgery. METHODS: Steroid-treated IBD patients undergoing major colorectal surgery were treated with the intravenous equivalent of their preoperative steroid dose in the perioperative period. Patients who were not taking steroids at the time of operation but who were treated with steroids within 1 year of surgery received no perioperative corticosteroids. Perioperative vital signs were analyzed. Hemodynamic instability was defined as heart rate >120 beats per minute, heart rate <60 beats per minute, or systolic blood pressure <90 mm Hg. RESULTS: Thirty-two procedures were performed on 10 patients on steroids at the time of operation and 22 patients had who stopped steroids within 1 year of surgery. Five patients (16%) developed tachycardia and 8 patients (25%) had bradycardia. Hypotension occurred in 5 (16%) patients. All cases of hemodynamic instability resolved with no intervention, fluid boluses, or blood transfusion. No patients required vasopressors or high-dose corticosteroids for adrenal insufficiency. CONCLUSION: In steroid-treated IBD patients undergoing major colorectal surgery, the use of low-dose perioperative corticosteroids seems safe. A prospective study assessing perioperative corticosteroid dosing is in progress. PMID- 22503321 TI - Safety skills training for surgeons: A half-day intervention improves knowledge, attitudes and awareness of patient safety. AB - BACKGROUND: Education and training of health care professionals is necessary to achieve sustainable improvements in patient safety. Despite its inherently risky nature, little training specifically in safety has been conducted in the surgical disciplines. In this study we explored the effects of a safety skills training program on surgical residents' knowledge, attitudes, and awareness of patient safety. METHODS: A half-day training program incorporating safety awareness, analysis, and improvement skills was delivered to surgical residents from 19 hospitals in London, United Kingdom. Participants were assessed in terms of safety knowledge (MCQs) and attitudes to safety (validated questionnaire; scale 1 to 5) before and after training. To determine long-term effects, 6 months after training participants identified and reported on observed safety events in their own workplace by using an observational form for data collection. RESULTS: A total of 27 surgeons participated in the training program. Knowledge of safety significantly improved after the course (mean pre = 45.26% vs mean post = 70.59%, P < .01) as did attitudes to error analysis and improving safety (mean pre 3.50 vs mean post 3.97, P < .001) and ability to influence safety (mean pre 3.22 vs mean post 3.49, P < .01). After the course, participants reported richer, detailed sets of observations demonstrating enhanced understanding, recognition, and analysis of patient safety issues in their workplace. CONCLUSION: Safety skills training with positive educational outcomes can be delivered in a half day. Such a course may allow patient safety to be integrated into any curriculum, thereby training the next generation of the healthcare workforce to maintain the safety momentum. PMID- 22503322 TI - Surgical resident participation in laparoscopic Roux-en-Y bypass: Is it safe? AB - BACKGROUND: The majority of bariatric surgeons use dedicated surgical assistants when performing laparoscopic Roux-en-Y gastric bypass (LGBP) because of the technical difficulty and steep learning curve involved in the operation. At our institution, either a senior surgical resident (SSR) or a physician assistant (PA) participates in LGBP cases. The PA's role is confined to assisting, whereas the SSR progressively acts as the operating surgeon. We were interested in evaluating patient outcomes to determine whether any differences existed between the LGBP operations in which either the PA or the SSR participated. METHODS: All patients undergoing LGBP between January 2007 and December 2009 in our prospectively collected bariatric database were reviewed. Demographics, baseline measures, intraoperative parameters, and outcomes were compared. RESULTS: A total of 711 patients were identified. The group involving PAs included 343 patients, and the group involving SSRs included 368 patients. Preoperative comorbidities, including diabetes, hypertension, coronary artery disease, asthma, sleep apnea, hyperlipidemia, musculoskeletal disability, and depression, were similar in both groups. Personal histories of venous thromboembolism were higher in the PA group (5.1% vs 2.5%; P = .075). The mean body-mass indexes (BMI) (53 +/- 9 vs 51 +/- 8 kg/m(2); P = .006) and weights (323 +/- 67 vs 306 +/- 59 lbs; P < .001) in the PA group were significantly higher than in the SSR group. The proportion of males was higher in the PA group (24% vs 16%; P = .008). The operative time was significantly shorter in the PA group (121 +/- 36 vs 164 +/- 30 minutes; P < .001). There was no significant difference between the groups in intraoperative complications, length of hospital stay, 30-day complications, or reoperations within 1 year. There were no mortalities in either group. The 1-year percent excess weight loss (64% vs 66%) was similar in the PA and SSR groups, respectively. CONCLUSION: SSR participation in LGBP prolongs operative time but does not increase complications, mortality rates, or length of stay. Therefore, SSR participation in LGBP is safe and produces outcomes comparable to those performed with PAs. PMID- 22503323 TI - Previous percutaneous coronary intervention increases morbidity after coronary artery bypass grafting. AB - BACKGROUND: We hypothesized that the incidence of previous percutaneous coronary intervention (PCI) is increasing and that prior PCI influences patient morbidity and mortality after coronary artery bypass grafting (CABG). METHODS: A total of 34,316 patients underwent isolated CABG operations at 16 different statewide, institutions from 2001 to 2008. Patients were stratified into prior PCI (n = 4346; 12.7%) and no prior PCI (n = 29,970). Patient risk factors, intraoperative variables, and outcomes were compared by univariate and multivariate analyses. RESULTS: The incidence of prior PCI in CABG has risen from <1% to 22.0% from 2001 to 2008 (P < .001). Prior PCI patients were younger (P < .001) and more commonly had previous myocardial infarction (P < .001), but less commonly had heart failure (P < .001). The operative mortality was similar between groups (2.3% vs 1.9%; P = .13). Prior PCI patients had more major complications (15.0% vs 12.0%; P < .001), longer hospitalization (P = .01), and higher readmission rates (P = .01). Importantly, by multivariate analyses, prior PCI was not associated with mortality, but was an independent predictor of major complications after CABG (odds ratio, 1.15; P = .01). CONCLUSION: The incidence of prior PCI in patients undergoing CABG is increasing. Previous PCI is associated with a higher risk of major complications, greater hospital length of stay, and higher readmission rates after CABG. PMID- 22503324 TI - Laparoscopic cholecystectomy: What is the price of conversion? AB - BACKGROUND: Laparoscopic cholecystectomy (LC) is the gold standard procedure for gallbladder removal. Conversion to an open procedure is sometimes deemed necessary, especially in complex cases in which a prolonged laparoscopic operative time is anticipated. A prolonged LC case is thought to be associated with increased complications and cost and therefore generally discouraged. The purpose of this study was to test this assumption, and compare outcomes and cost of converted and prolonged LC cases. METHODS: By using institutional National Surgical Quality Improvement Program and financial databases, we retrospectively reviewed and compared prolonged laparoscopic cases (Long-LC) with converted (CONV) procedures. Surgical times, length of stay (LOS), 30-day complications, operative room, and total hospital charges were compared between the 2 groups. RESULTS: A total of 101 Long-LC and 66 CONV cases met our inclusion criteria. Long-LC cases were 19 minutes longer than CONV cases (123 vs 104 min; P < .01). No differences in postoperative complications were found between the 2 groups (P > .05). When Poisson regression was used, we found that LOS was significantly shorter in the Long-LC compared with CONV group (1 day vs 4 days; P < .01). Long LC cases had greater operative charges ($15,278 vs $13,128; P < .01). However, hospital charges for Long-LC cases were 26% less than for CONV cases ($23,946 vs $32,446; P < .01). CONCLUSION: Conversion is associated with a 3-day increase in LOS. Long-LC cases have greater operative room charges, but overall hospital charges were 26% less than CONV cases. Our data suggest that decision making regarding conversion should focus on safety and not time considerations. PMID- 22503325 TI - Realizing neighbourhood potential? The role of the availability of health care services on contact with a primary care physician. AB - Access to health services research has traditionally focused on demographic, socioeconomic, and need-based factors, resulting in a relative lack of knowledge regarding place-based determinants. Further, much of what we know comes from international, national, and regional study. This study analyzes survey data (n=1635) to explore the relationship between neighbourhood-level potential access (i.e., availability) and realized access (i.e., use) in two Canadian cities. Controlling for predisposing, enabling and need factors, living in a well-served neighbourhood was a significant predictor of realized access, particularly in Saskatoon. This suggests that the relationship between potential and realized access may be modified by place-based factors. PMID- 22503326 TI - Evaluating the implementation of a quality improvement initiative: weekend gastrojejunostomy tube maintenance service in a tertiary pediatric center. PMID- 22503327 TI - Analysis of blood-based gene expression signature in first-episode psychosis. AB - Blood-based transcriptomic signature in psychosis is an alternative to a brain based signature. In this study, we profiled whole-blood RNA from 26 patients with first-episode psychosis, and 26 matching controls. We identified a 400-gene signature that classified patients from controls accurately and tested the robustness using other modelling methods. PMID- 22503328 TI - Patient factors predicting early dropout from psychiatric outpatient care for borderline personality disorder. AB - Despite obvious clinical need, factors underlying early treatment discontinuation among 'real world' borderline personality disorder (BPD) patients are still unknown. This study investigates individual characteristics that can predict early (http://www.ddtjournal.com/home) for the purpose of promoting research exchanges in the field of drug discovery and therapeutic. This year's JCMWDDT is the second workshop and focused particularly on novel development and technological innovation of anti-influenza agents. The workshop began with an announcement by the Japanese Co-chairperson, Dr. Sekimizu (Department of Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan; Editorin- Chief of Drug Discoveries & Therapeutics, DDT) followed by a speech by the Chinese Co-chairperson, Dr. Wenfang Xu (School of Pharmaceutical Sciences, Shandong University, Shandong, China; Editor in China Office of DDT), with additional speeches by Dr. Norio Matsuki (The University of Tokyo, Japan; Editor of DDT) and Dr. Guanhua Du (Chinese Academy of Medical Science, China; Editor of DDT). Fifty-nine titles were presented in 6 specialized sessions (Research Advances in Drug Discoveries and Therapeutics, Drug Synthesis/Clinical Therapeutics, Medicinal Chemistry/Natural Products, Anti influenza Drugs, Anti-infection/antiviral Drugs, Biochemistry/Molecular Biology /Pharmacology) and a poster session (Drug Discov Ther 2008; 2, Suppl; available at http://www.ddtjournal.com/Announce/index.htm). An annual outbreak of avian influenza in Asian countries including China and Japan has sparked fears that the virus will mutate and then cause an epidemic in humans. Therefore, Asian researchers need to work together to control this infection. This year's JCMWDDT helped provide an opportunity to reiterate the crucial role of medicinal chemistry in conquering influenza and created an environment for cooperative research in Asian countries. (reported on October 1st, with grateful thanks to all participants) Main program Session I. Research Advances in Drug Discoveries and Therapeutics ? Design, synthesis and preliminary activity assay of influenza virus neuraminidase inhibitors by Wenfang Xu (Shandong University, China) ? Infection disease models with silkworms to evaluate the therapeutic effects of drug candidates by Kazuhisa Sekimizu (The University of Tokyo, Japan) ? Japan's governmental approaches to facilitate drug development process by Makoto Shimoaraiso (Ministry of Foreign Affairs of Japan, Japan) ? Effective detection of the epidermal growth factor receptor mutation by the peptide nucleic acid-locked nucleic acid PCR Clamp by Sakuo Hoshi (The University of Tokyo Hospital, Japan) ? Design and synthesis of p53-MDM2 binding inhibitors by Yongzhou Hu (Zhejiang University, China) Session II. Drug Synthesis/Clinical Therapeutics ? Pharmacogenomics-based clinical studies using a novel fully-automated genotyping system by Setsuo Hasegawa (Sekino Clinical Pharmacology Clinic, Japan) ? Synthesis and biological evaluation of pentacyclic triterpenes as anti-tumor agents by Hongbin Sun (China Pharmaceutical University, China) ? Drug discovery and therapeutics using silkworm as experimental animal by Yasuyuki Ogata (The University of Tokyo, Japan) ? Novel selective estrogen recetpor modulators (SERMs) with unusual structure and biological activities by Haibing Zhou (Wuhan University, China) Session III. Medicinal Chemistry/Natural Products ? Synthesis and properties of isonucleosides incorporated oligonucleotides by Zhenjun Yang (Peking University, China) ? Isolation of antiviral compounds from plant resources using silkworm bioassay by Yutaka Orihara (The University of Tokyo, Japan) ? Synthesis and structural modifcation of tasiamide and the effect of these modifications on in vitro anticancer activity by Yingxia Li (Ocean University of China, China) ? Spirohexalines A and B, novel undecaprenyl pyrophosphate inhibitors produced by Penicillium sp. FKI-3368 by Junji Inokoshi (Kitasato University, Japan) ? Nosokomycins, novel anti-MRSA antibiotics, produced by Streptomyces sp. K04-0144 by OR. Uchida (Kitasato University, Japan) ? In vivo screening for antimicrobial activity of Thai Herbal Medicines using silkworm model by Santad Chanprapaph (Chulalongkorn University, Thailand) ? Novel electrochemical sensor of nitric oxide for screening anti-aging Traditional Chinese Medicine by Zilin Chen (Wuhan University, China) ? Polysacchride from green tea purified by silkworm muscle contraction assay induces innate immunity by increasing the expression of various inflammatory cytokine mRNA in human leukocytes by Saphala Dhital (The University of Tokyo, Japan) Session IV. Anti influenza Drugs ? Structure-activity relationship of flavonoids as influenza virus neuraminidase inhibitors and their in vitro anti-viral activities by Guanhua Du (Chinese Academy of Medical Sciences and Peking Union Medical College, China) ? Mechanisms and consequences of phagocytosis of influenza virus-infected cells by Yoshinobu Nakanishi (Kanazawa University, Japan) ? Nuclear export inhibitors; a possible target for novel anti-influenza viral drugs by Ken Watanabe (Nagasaki University, Japan) ? Catalytic asymmetric synthesis of oseltamivir phosphate directing toward its stable worldwide supply by Motomu Kanai (The University of Tokyo, Japan) ? Clinical effects of probiotic bifidobacterium in the prevention of influenza virus infections and allergic diseases by Jin-zhong Xiao (Morinaga Milk Industry Co., Ltd., Japan) ? Production of anti-influenza PR8-scFv using a phage display by Normaiza Zamri (Tokai University, Japan) Session V. Anti-infection/Antiviral Drugs ? Emerging infectious diseases and anti-viral drugs: Urgent need to develop effective drugs which cause less resistant virus by Nobuyuki Kobayashi (Nagasaki University, Japan) ? Design, synthesis and antiviral evaluation of novel heterocyclic compounds as HIV-1 NNRTIs by Xinyong Liu (Shandong University, China) ? Antiviral drug screening from microbial products by Eisaku Tsujii (Astellas Pharma Inc., Japan) ? Viral factors that determine the natural course of chronic hepatitis B viral infection by Hiroshi Yotsuyanagi (The University of Tokyo, Japan) ? Effect of andrographolide derivatives having alpha-glucosidase inhibition, on HBsAg, HBeAg secretion in HepG2 2.2.15 cells by Hongmin Liu (Zhengzhou University, China) ? Current and future antiviral therapy for influenza by Hideki Asanuma (Tokai University, Japan) ? Establishment of an HIV-based pseudotyping system as a safe model for screening inhibitors on bird flu H5N1 entry by Ying Guo (Peking Union Medical Collegee Chinese Academy of Medical Sciences, China) ? Strategy of discovery for novel antibiotics using silkworm infection model by Hiroshi Hamamoto (The University of Tokyo, Japan) ? Potent neuraminidase inhibitors and anti-inflammatory substances from Chaenomeles speciosa by Li Zhang (Chinese Academy of Medical Sciences and Peking Union Medical College, China) ? High-throughput screening assay for hepatitis C virus helicase inhibitors using fluorescence-quenching phenomenon by Hidenori Tani (Waseda University and National Institute of Advanced Industrial Science and Technology, Japan) Session VI. Biochemistry/Molecular Biology/Pharmacology ? A novel conjugate of low-molecular-weight heparin and Cu,Zn-superoxide dismutase: Study on its mechanism in preventing brain reperfusion injury after ischemia in gerbils by Fengshan Wang (Shandong University, China) ? A novel gene fudoh in SCCmec region regulates the colony spreading ability and virulence in Staphylococcus aureus by Chikara Kaito (The University of Tokyo, Japan) ? Water soluble fluorescent boronic acid sensors for tumor cell-surface saccharide by Hao Fang (Shandong Unviersity, China) ? Molecular characterization of the biosynthetic enzyme for the biotechnological production of tetrahydrocannabinol, the active constituent of marijuana by Futoshi Taura (Kyushu University, Japan) ? Galloyl cyclic-imide derivative CH1104I inhibits tumor invasion via suppressing matrix metalloproteinase activity by Xianjun Qu (Shandong University, China) ? Neuroprotection by inhibition of GAPDH-MAO B mediated cell death induced by ethanol by Xiao-Ming Ou (University of Mississippi Medical Center, USA). PMID- 22504719 TI - Pulmonary drug delivery: Implication for new strategy for pharmacotherapy for neurodegenerative disorders. AB - Innovative drug delivery in the treatment of brain neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD) has the potential to avoid many unwanted side effects over current medications. Advances in understanding of these diseases and their treatments have led to the search for novel modes of drug delivery. In this review, we have highlighted new strategies and future prospects for pulmonary delivery of drugs for the management of these important neurological disorders. The advancement of knowledge on pulmonary drug delivery will provide novel therapeutic formulations for better management of the PD and AD patients throughout the world. PMID- 22504720 TI - Effect of drug-polymer binary mixtures on the in-vitro release of ibuprofen from transdermal drug-in-adhesive layers. AB - We report on the formation of eutectic mixtures of ibuprofen using two different polymers together with investigations on the in-vitro release of ibuprofen from drug-in-adhesive layers. Ibuprofen, literature melting point (m.p.) = 73.5-76.5 degrees C, was tested together with Pluronic F127, literature m.p. = 54.4-60.5 degrees C, and polyethylene glycol 1000 (PEG 1000), literature m.p. = 37-40.9 degrees C, as second components in binary mixtures, incorporated into an acrylic adhesive, either as solid physical mixtures (PM) or molten mixtures (MM). Studies of how the type of mixture preparation (PM versus MM) and the ratio of components in binary mixtures affecting the in-vitro drug release of ibuprofen, compared with ibuprofen-adhesive layers without polymer addition were conducted. Ibuprofen release did not improve using the eutectic composition with Pluronic F127, possibly due to increased ibuprofen solubilisation in the adhesive and a subsequent decrease in the thermodynamic activity of the formulation. A significant increase in ibuprofen release (P < 0.05) was shown for compositions adjacent to the eutectic one, with ibuprofen: Pluronic F127 (40:60) and ibuprofen: PEG 1000 (20:80, 25:75, 30:70), from both PM- and MM-adhesive formulations, compared to the ibuprofen-adhesive formulations. PMID- 22504721 TI - Effect of benzyl-N-acetyl-alpha-galactosaminide on KL-6 mucin expression and invasive properties of a human pancreatic carcinoma cell line. AB - KL-6 mucin is a type of MUC1 mucin and its aberrant expression has been shown to be associated with aggressive metastasis and poor clinical outcome in tumors. The present study is to investigate the effects of benzyl-N-acetyl-alpha galactosaminide (GalNAc-O-bn), an O-glycosylation inhibitor, on KL-6 mucin expression and invasive properties of a human pancreatic carcinoma cell line, Suit-2 cells. Expression profiles of KL-6 mucin in the cells pretreated with or without 5 mM GalNAc-O-bn for 48 h were examined by Western blotting and immunocytochemical staining and invasive properties were examined by transwell chamber assay. Western blotting and immunocytochemical staining showed that the expression profiles of KL-6 mucin changed significantly after GalNAc-O-bn treatment. Meanwhile, the invasive ability of Suit-2 cells decreased significantly after GalNAc-O-bn treatment (p < 0.05). These results suggest that glycosylation of KL-6 mucin may be closely related to aggressive behaviors of pancreatic cancer cells like metastasis and invasion. PMID- 22504722 TI - Antioxidant activity of wild plants collected in Beni-Sueif governorate, Upper Egypt. AB - Antioxidant activity of a selection of commonly occurring wild plants growing in Beni-Sueif governorate, Upper Egypt, has been tested. The plants selected are Tamarix nilotica, Ambrosia maritima, Zygophyllum coccenium, Conyza dioscoridis, Chenopodium ambrosioides, and Calotropis procera. The in vitro antioxidant assays used in this study were 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging activity, superoxide anion scavenging activity and iron chelating activity. Extracts prepared from the leaves and flowers of Tamarix nilotica have shown the highest antioxidant activity in the three kinds of assay. PMID- 22504723 TI - Regulation of the nitric oxide synthesis pathway and cytokine balance contributes to the healing action of Myristica malabarica against indomethacin-induced gastric ulceration in mice. AB - The role of the ariginine-metabolism in the healing action of the methanol extract of Myristica malabarica (rampatri) (RM) and omeprazole (Omez) against indomethacin-induced stomach ulceration in mouse was investigated. Indomethacin (18 mg/kg) was found to induce maximum stomach ulceration in Swiss albino mice on the 3rd day of its administration, which was associated with reduced arginase activity (38.5%, p < 0.05), eNOS expression, along with increased iNOS expression, total NOS activity (5.37 fold, p < 0.001), NO generation (55.1%, p < 0.01), and ratio of pro-/anti-inflammatory cytokines. Besides providing comparable healing as Omez (3 mg/kg * 3 d), RM (40 mg/kg * 3 d, p.o.) shifted the iNOS/NO axis to the arginase/polyamine axis as revealed from the increased arginase activity (59.5%, p < 0.01), eNOS expression, and reduced iNOS expression, total NOS activity (73%, p < 0.001), and NO level (49.8%, p < 0.01). These could be attributed to a favourable anti/pro inflammatory cytokines ratio, generated by RM. The healing by Omez was however, not significantly associated with those parameters. PMID- 22504724 TI - High resolution single cell analytics to follow microbial community dynamics in anaerobic ecosystems. AB - Analyzing natural anaerobic microbial communities is a challenge and interpretation of the respective members' performances arduous. Strict anaerobes are often slow-growing and difficult to cultivate due to their unknown physiological capacities. Additionally, abiotic micro-environmental data are difficult to assess, limiting the information on the eco-chemical background in natural environments. This review describes how qualitative and quantitative data can be obtained on anaerobic microbial communities isolated from anoxic environments and treated under laboratory conditions. It gives information on how community composition ('phylogenetic fingerprint') and community structure ('cytometric fingerprint') can be described by PCR-based and single cell-based techniques, respectively. A cell sorting step combined both approaches and enabled quantitative and more precise community resolution. The community dynamics found were swift and strong, despite low and slow changes in measured abiotic parameters. Therefore, the community structure itself mirrored variation in the constructed long term (6 years) ecosystem in a most sensitive way and can be used as sensor for the ecosystems situation. New statistical tools are presented allowing suddenly changing performances of complex communities to be detected and community (in) stabilities to be monitored and/or predicted. PMID- 22504725 TI - The taxonomy and phylogenetics of the human and animal pathogen Rhinosporidium seeberi: a critical review. AB - Rhinosporidum seeberi is the etiologic agent of rhinosporidiosis, a disease of mucous membranes and infrequent of the skin and other tissues of humans and animals. Because it resists culture, for more than 100 years true taxonomic identity of R. seeberi has been controversial. Three hypotheses in a long list of related views have been recently introduced: 1) a prokaryote cyanobacterium in the genus Microcystis is the etiologic agent of rhinosporidiosis, 2) R. seeberi is a eukaryote pathogen in the Mesomycetozoa and 3) R. seeberi is a fungus. The reviewed literature on the electron microscopic, the histopathological and more recently the data from several molecular studies strongly support the view that R. seeberi is a eukaryote pathogen, but not a fungus. The suggested morphological resemblance of R. seeberi with the genera Microcystis (bacteria), Synchytrium and Colletotrichum (fungi) by different teams is merely hypothetical and lacked the scientific rigor needed to validate the proposed systems. A fundamental aspect against the prokaryote theory is the presence of nuclei reported by numerous authors and updated in this review. Moreover, Microcystis's and Synchytrium's ultra-structural and key cell cycle traits cannot be found in R. seeberi parasitic phase. The PCR amplification of a cyanobacteria 16S rDNA sequence from cases of rhinosporidiosis, while intriguing, will be viewed here as an anomaly due to contamination with environmental Microcystis or perhaps as an endosymbiotic acquisition of plastids from cyanobacteria ancestors. Thus, even if R. seeberi possesses prokaryote DNA, this does not prove that R. seeberi is a cyanobacterium. The placement of R. seeberi within the fungi is scientifically untenable. The isolation and the DNA analysis performed in a fungal strain, and the lack of appropriate controls are the main problems of this claim. Further studies are needed to validate R. seeberi's acquisition of prokaryote plastids and other issues that still need careful scrutiny. PMID- 22504726 TI - Cerebrovascular reserve: the link between fitness and cognitive function? AB - Better physical fitness in later life is associated positively with cognitive functioning. Novel data suggest that this association is mediated, in part, by increases in brain perfusion and the ability of cerebral blood vessels to respond to demand. This review presents evidence on the beneficial effects of exercise on cerebrovascular and cognitive health with aging and explores potential underlying vascular-related mechanisms. PMID- 22504727 TI - Sertraline treatment of patients with major depressive disorder who failed initial treatment with paroxetine or fluvoxamine. AB - This study was undertaken to examine the long-term effectiveness and safety of switching to sertraline from other selective serotonin reuptake inhibitors (SSRIs) in the treatment of non-remitted or treatment-intolerant major depressive disorder. The study included 25 patients with major depressive disorder according to DSM-IV-TR criteria. None had achieved remission with paroxetine or fluvoxamine, but each had been used in an adequate dose for an adequate time period or had been intolerant of these SSRIs. Most patients (n=22, 88%) were non remitters. Switching was accomplished by gradual cross-titration and tapering. We conducted assessments at baseline and at weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24. Outcomes were assessed using the Quick Inventory of Depressive Symptomatology Self-Report, Japanese version (QIDS-SRJ) score (primary outcome), the 17-item Hamilton Depression Rating Scale (HDRS), and the Clinical Global Impressions (CGI) scale. Mean QIDS-SRJ and HDRS scores improved significantly from baseline to week 8 and week 24. At the respective endpoints of weeks 8 and 24, remitters on QIDS-SRJ (<=5) were 2 of 25 (8%) and 4 of 25 (16%). At weeks 8 and 24, 11 of 25 (44%) were responders on QIDS-SRJ (>=50% reduction). Five patients (20%) terminated early, before week 8, because of side effects and/or lack of efficacy. These preliminary data suggest that the switching strategy from paroxetine or fluvoxamine to sertraline might be effective and well-tolerated in patients with non-remitted or treatment-intolerant major depressive disorder. PMID- 22504728 TI - Methylmercury in mosquitoes around a large coal-fired power plant in central Ohio. AB - Emissions from coal-fired power plants are the major anthropogenic source of mercury (Hg) in the environment. Because emitted Hg can be deposited near the source, concerns arise about the effects of coal-burning facilities on levels of toxic methylmercury (MeHg) in biota near such sources. We investigated the potential impact of a large Hg-emitting (450 kg in 2005) coal-fired power station in Conesville, Ohio, on MeHg levels in adult mosquitoes near the plant. In July 2010, mosquitoes were sampled at 23 locations within a 60-km radius of the plant and at three reference sites distant from major combustion sources of Hg. Nearly all of the Hg in mosquitoes appeared in the form of MeHg (mean=91%). Concentrations of MeHg in mosquitoes were unrelated to either distance or direction from the Conesville plant and did not differ from those at the three reference sites. Moreover, measured levels of MeHg in mosquitoes near Conesville are in good agreement with those predicted from an empirical relationship to wet atmospheric Hg fluxes alone. This suggests that either little of the Hg emitted from the Conesville plant is deposited locally or near-source deposition of Hg does not have a significant impact on MeHg in mosquitoes and, by extension, other insects with similar life histories in the local food web. PMID- 22504730 TI - Practical issues in relation to clinical trials in children in low-income countries: experience from the front line. AB - Clinical trials in children in resource-poor environments are essential for local health policy and practice to be relevant and evidence based. Research must be ethical, appropriate, relevant and of good quality. It should, where possible, benefit the subjects studied,the clinical, scientific and support staff involved, and the service and academic institutions of the host country. The challenge for researchers and their sponsors is to maximise such benefits while avoiding the many possible pitfalls. PMID- 22504729 TI - Intraductal papillary neoplasm of the bile duct: a biliary equivalent to intraductal papillary mucinous neoplasm of the pancreas? AB - Intraductal papillary neoplasm of the bile duct (IPNB) is a variant of bile duct carcinoma characterized by intraductal growth and better outcome compared with the more common nodular-sclerosing type. IPNB is a recognized precursor of invasive carcinoma, but its pathogenesis and natural history are ill-defined. This study examines the clinicopathologic features and outcomes of IPNB. A consecutive cohort of patients with bile duct cancer (hilar, intrahepatic, or distal) was reviewed, and those with papillary histologic features identified. Histopathologic findings and immunohistochemical staining for tumor markers and for cytokeratin and mucin proteins were used to classify IPNB into subtypes. Survival data were analyzed and correlated with clinical and pathologic parameters. Thirty-nine IPNBs were identified in hilar (23/144), intrahepatic (4/86), and distal (12/113) bile duct specimens between 1991 and 2010. Histopathologic examination revealed 27 pancreatobiliary, four gastric, two intestinal, and six oncocytic subtypes; results of cytokeratin and mucin staining were similar to those of intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Invasive carcinoma was seen in 29/39 (74%) IPNBs. Overall median survival was 62 months and was not different between IPNB locations or subtypes. Factors associated with a worse median survival included presence and depth of tumor invasion, margin-positive resection, and expression of MUC1 and CEA. CONCLUSION: IPNBs are an uncommon variant of bile duct cancer, representing approximately 10% of all resectable cases. They occur throughout the biliary tract, share some histologic and clinical features with IPMNs of the pancreas, and may represent a carcinogenesis pathway different from that of conventional bile duct carcinomas arising from flat dysplasia. Given their significant risk of harboring invasive carcinoma, they should be treated with complete resection. PMID- 22504731 TI - Percutaneous gastrojejunostomy in children: efficacy and safety. AB - Transgastric jejunal intubation via gastrostomy (GJ) can be indicated when enteral nutrition via gastrostomy is not possible. Between 2001 and 2008, the authors prospectively assessed the outcomes in 29 patients (median age, 10 months) after GJ. Indications for jejunal feeding were severe gastro-oesophageal reflux (n=27) and intestinal dysmotility (n=2). The GJ was successfully placed in 27/29 patients. Complications were: 31 tube dislodgements, 16 obstructions, 7 leakages around the tube, 6 internal balloon ruptures and 1 intussusception. The median lifetime of the tube was 3 months. 9/27 patients died during the study period, 11 patients required surgery, 2 required parenteral nutrition, gastric feeding became tolerated in 3 and the gastrojejunal feeding tube was kept in place in the remaining 2. A transgastric jejunal feeding tube may constitute a transitory alternative to antireflux surgery or prolonged parenteral nutrition. However, the high frequency of complications and tube replacement limits its use. PMID- 22504732 TI - Poor sensitivity of musculoskeletal history in children. AB - OBJECTIVES: To demonstrate the sensitivity of musculoskeletal (MSK) history taking. DESIGN: Prospective study: consecutive children attending outpatient clinics. SETTING AND PATIENTS: Paediatric rheumatology clinic (n=45; girls n=28; median age 12 years, range 3-18), acute general paediatric assessment unit (n=50; girls n=21; median age 8 years, range 3-16). INTERVENTION: Pro forma recording abnormal joint involvement from history taking and then following MSK examination completed by clinicians. MAIN OUTCOME MEASURES: Sensitivity of MSK history taking compared with clinical examination. RESULTS: Paediatric rheumatology clinic: 135 abnormal joints identified in 34 children; 53/135 (39%) by history alone, 82/135 (61%) detected on examination resulting in MSK history sensitivity 53%, specificity 98%. Acute paediatric unit: 29 abnormal joints identified in 17 children; 18/29 identified on history (sensitivity 62%). CONCLUSIONS: MSK history taking failed to identify a large number of abnormal joints which were detected on physical examination, emphasising the need for all joints to be examined as part of a screening examination as a minimum. PMID- 22504733 TI - Controlled reversible debundling of single-walled carbon nanotubes by photo switchable dendritic surfactants. AB - Stimulus responsive surfactants based on dendritic glycerol azobenzene conjugates were used to solubilize and debundle single-walled carbon nanotubes in aqueous media. Their debundling property as well as their reaggregation behavior upon irradiation with light was examined and light triggered reversible bundling and precipitation are shown. PMID- 22504734 TI - Filtering artifacts from lifetime distributions when maximizing entropy using a bootstrapped model. AB - The maximum entropy method (MEM) has been used in many studies to reliably recover effective lifetimes from kinetics, whether measured experimentally or simulated computationally. Here, recent claims made by Mulligan et al. regarding MEM analyses of kinetics (Anal. Biochem. 421 (2012) 181-190) are shown to be unfounded. Their assertion that their software allows "analysis of datasets too noisy to process by existing iterative search algorithms" is refuted with a MEM analysis of their triexponential test case with increased noise. In addition, it is shown that lifetime distributions recovered from noisy kinetics data with the MEM can be improved by using a simple filter when bootstrapping the prior model. When deriving the bootstrapped model from the lifetime distribution obtained using a uniform model, only the slower processes are represented as Gaussians in the bootstrapped model. Using this new approach, results are clearly superior to those of Mulligan et al. despite the presence of increased noise. In a second example, ambiguity in the interpretation of Poisson kinetics in the presence of scattered excitation light is resolved by filtering the prior model. PMID- 22504735 TI - Evaluation of genotoxicity of multi-walled carbon nanotubes in a battery of in vitro and in vivo assays. AB - The genotoxic potential of two products of multi-walled carbon nanotubes (coded as N-MWCNTs, diameter of 44 nm/BET surface area of 69 m2/g and MWNT-7, diameter of 70 nm/BET surface area of 23 m2/g) was evaluated using a battery of genotoxicity assays, comprising a bacterial reverse mutation test, an in vitro mammalian chromosomal aberration test, and a mammalian erythrocytes micronucleus test. Neither type exerted mutagenicity in Salmonella typhimurium TA98, TA100, TA1535, and TA1537, or in Escherichia coli WP2uvrA, in the absence or presence of metabolic activation. The products of MWCNTs did not increase the number of structural chromosomal aberrations either, regardless of metabolic activation, though they increased the number of numerical chromosomal aberrations, one slightly and the other distinctly, in the absence of metabolic activation. In ICR mice, the two products did not affect the proportion of immature erythrocytes, the total proportion of erythrocytes, or the number of micronuclei in immature erythrocytes. PMID- 22504736 TI - Personalised medicine in 2012: editorial to the special issue of New Biotechnology on "molecular diagnostics & personalised medicine". AB - This special issue of New Biotechnology is focused on molecular diagnostics and personalised medicine and appears at an epochal moment in the development of the field. The practice of medicine is taking a significant and irrevocable turn towards personalisation, due to the great progress in areas such as genomics, pharmacogenomics and molecular diagnosis. It becomes increasingly apparent that to deliver the promise of personalised treatments, more and more novel medicines discovered today will be presented together with innovative companion diagnostics. The contributions to this volume touch on many disciplines, ranging from cell biology to genetics, immunology, molecular diagnostics, pharmaceutics and economic issues. The contributions of clinicians and basic scientists are synergistically presented to underline better the wide spectrum of studies that can contribute to the new field of personalised medicine. The promising perspectives of individualised treatments are related not only to higher effectiveness, but also to increased efficiency. This is relevant not only for the individual patient, but even more so for the general public, within a wider economical perspective where resources are limited and it becomes more and more mandatory to close the gap between social costs and benefits. This approach follows the steps of a stratified and individualised medicine and finds its final goal in an individualised healthcare. PMID- 22504737 TI - From morphologic to molecular: established and emerging molecular diagnostics for breast carcinoma. AB - Diagnostics in the field of breast carcinoma are constantly evolving. The recent wave of molecular methodologies, both microscope and non-microscope based, have opened new ways to gain insight into this disease process and have moved clinical diagnostics closer to a 'personalized medicine' approach. In this review we highlight some of the advancements that laboratory medicine technology is making toward guiding the diagnosis, prognosis, and therapy selection for patients affected by breast carcinoma. The content of the article is largely structured by methodology, with a distinct emphasis on both microscope based and non-microscope based diagnostic formats. Where possible, we have attempted to emphasize the potential benefits as well as limitations to each of these technologies. Successful molecular diagnostics, applied in concert within the morphologic context of a patient's tumor, are what will lay the foundation for personalized therapy and allow a more sophisticated approach to clinical trial stratification. The future of breast cancer diagnostics looks challenging, but it is also a field of great opportunity. Never before have there been such a plethora of new tools available for disease investigation or candidate therapy selection. PMID- 22504738 TI - [Gorham's disease and intra-osseous vascular abnormalities]. AB - Gorham's disease is a rare condition of unknown etiology, which is characterized by intra-osseous vascular abnormalities leading to osteolysis and sometimes, extension to adjacent tissues. Although there is no histological evidence of malignancy, the lesions display an aggressive potential responsible of osteolysis with pathological fractures and respiratory failure. The extension of the disease varies from one location to multiple bone lesions throughout the skeleton and the clinical presentations depend on the sites of involvement. In the ISSVA (International Society for the Study of Vascular Abnormalities) classification, its affiliation to the group of vascular tumors or vascular malformations is still debated. To date, there is no standard treatment defined for this disease. The proposed treatments are inhibitors of bone resorption (bisphosphonates) and interferon alpha therapy or anti-angiogenic molecules. Radiation therapy and surgery may also have a place in the therapeutic strategy. PMID- 22504739 TI - DSM-5 status of psychotic disorders: 1 year prepublication. PMID- 22504741 TI - Role of multidrug resistance associated proteins in drug development. AB - The multidrug resistance associated proteins (MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, MRP8 and MRP9) belongs to the ATP-binding cassette superfamily (ABCC family) of transporters expressed differentially in the liver, kidney, intestine and blood-brain barrier. MRPs transport a structurally diverse array of endo- and xenobiotics and their metabolites (in particular conjugates) and are subject to induction and inhibition by a variety of compounds. An increased efflux of natural product anticancer drugs and other anticancer agents by MRPs in cancer cells is associated with tumor resistance. These transporting proteins play a role in the absorption, distribution and elimination of various compounds in the body. There are increased reports on the clinical impact of genetic mutations of genes encoding MRP1-9. Therefore, MRPs have an important role in drug development, and a better understanding of their function and regulating mechanism can help minimize and avoid drug toxicity, unfavourable drug-drug interactions, and to overcome drug resistance. PMID- 22504742 TI - Pharmacogenomics-based clinical studies using a novel, fully automated genotyping system. AB - Clinical investigations into single nucleotide polymorphisms (SNPs) in drug metabolism have already been set out for clinical trials in subject groups classified as extensive metabolizers or poor metabolizers. In particular, the frequency of CYP2C19 in poor metabolizers within the Japanese population is relatively high, and genetic variations result in differences in kinetics and pharmacological action, e.g. clinical response to proton pump inhibitors which are mainly metabolized by 2C19 in the liver. We introduced a novel, fully automated genotyping system and used it in the genotyping of CYP2C19. The completed system is based on the analysis of a melting curve of probe DNA which is bound to the target SNP site using a fluorescence quenching probe. The system enables automated and multiple SNP-genotyping from sample preparation. This fully automated system of analysis can be adapted to clinical studies, e.g. classification of genes related to pharmacokinetics and target receptors by genetic variations. PMID- 22504740 TI - Lecture: New light on the role of claudins in the kidney. AB - The physiology of paracellular permeation of ions and solutes in the kidney is pivotally important but poorly understood. Claudins are the key components of the paracellular pathway. Defects in claudin function result in a broad range of renal diseases, including hypomagnesemia, hypercalciuria and nephrolithiasis. This review describes recent findings on the physiological function of claudins underlying paracellular transport mechanisms with a focus on renal Ca(2+) handling. We have uncovered a molecular mechanism underlying paracellular Ca(2+) transport in the thick ascending limb of Henle (TAL) that involves the functional interplay of three important claudin genes: claudin-14, -16 and -19, all of which are associated with human kidney diseases with hypercalciuria, nephrolithiasis and bone mineral loss. The Ca(2+) sensing receptor (CaSR) signaling in the kidney has long been a mystery. By analyzing small non-coding RNA molecules in the kidney, we have uncovered a novel microRNA based signaling pathway downstream of CaSR that directly regulates claudin-14 gene expression and establishes the claudin-14 molecule as a key regulator for renal Ca(2+) homeostasis. The molecular cascade of CaSR-microRNAs-claudins forms a regulatory loop to maintain proper Ca(2+) homeostasis in the kidney. PMID- 22504743 TI - Apoptosis-inducing effect of cinobufacini, Bufo bufo gargarizans Cantor skin extract, on human hepatoma cell line BEL-7402. AB - Cinobufacini, a water-soluble preparation of Chinese medicine, is extracted from the skin of Bufo bufo gargarizans Cantor. The present study sought to investigate the effects of Cinobufacini on apoptosis of the hepatocellular carcinoma cell line BEL-7402. Cell viability was measured by methyl thiazolyl tetrazolium assay. Cell morphology was observed by Hoechst 33258 staining. Western blotting analysis was used to detect Bax and Bcl-2 expression. Results indicated that Cinobufacini inhibited the proliferation of BEL-7402 cells in a dose and time-dependent manner. Marked morphological changes indicative of apoptosis were observed after treatment with different concentrations of Cinobufacini. Western blot analysis showed that Bcl-2 expression was down-regulated while Bax expression was upregulated. Thus, Cinobufacini may have a significant apoptosis-inducing effect on BEL-7402 cells, and this could prove useful for further anti-cancer research. PMID- 22504744 TI - Part 2. Long term in vivo/in vitro evaluation of the Cholecystokinin antagonists: N-(5-methyl-3-oxo-1,2-diphenyl-2,3-dihydro-1H-pyrazol-4-yl)-N'-phenylurea MPP and carboxamide MPM. AB - The mixed CCK antagonist N-(3-oxo- 2,3-dihydro-1H-pyrazol-4-yl)-indole carboxamide MPP with a binding affinity of 25nM /20nM and the CCK1 selective 3 oxo-1,2-diphenyl-2,3-dihydro-1Hpyrazol- 4-yl)-N'-phenyl-urea MPM (IC50 = 25nM) represent the best two compounds of an amide and a urea pyrazoline series, which were previously evaluated in mice (Part 1) for their CNS activity. The long term in vivo and in vitro evaluation is described in this part. Stress was induced for a 4 week period daily. A dose of 0.5 mg/kg of MPP and MPM showed a significant antidepressant effect in the foced swim test in rats, which was in enhanced within a 4 week test period. The mixed CCK antagonist MPM only occurred anxiolytic properties in the elevated X-maze in rats at a 0.5 mg/kg dose. For the stress induced rats, the MPP and MPM treatment reversed the effects of stress on the dendritic atrophy in hippocampal CA3 pyramidal neurons. A reduction of organ weight was reversed for the adrenal gland, when the animals were treated with the CCK antagonists MPP and MPM over a period of 4 weeks. PMID- 22504745 TI - Pioglitazone attenuates tactile allodynia and microglial activation in mice with peripheral nerve injury. AB - To test the possibility of a peroxisome proliferator activated receptor (PPAR) gamma agonist to treat neuropathic pain, we examined the effects of pioglitazone, a PPARgamma agonist, on tactile allodynia and expression of activated microglia in the dorsal horn of spinal cord using neuropathic pain model. The unilateral sciatic nerve was partially ligated (PSL) in male ICR mice. Pioglitazone (1-25 mg/kg p.o.) was administrated to mice once daily for five days immediately after PSL. We stimulated the footpad of the hind paw of mice using a von Frey filament to estimate tactile allodynia on day 5 of PSL. The activated microglia in the lumbar spinal cord was observed by immunohistochemistry with anti-Iba1 antibody, a marker for activated microglia. The number of Iba1-immunoreactive cells was counted in the dorsal horn spinal cord. On day 5, significant allodynia was developed in PSL mice. Pioglitazone significantly attenuated the tactile allodynia in a dose of 1-25 mg/kg. However, these doses of pioglitazone did not affect nociceptive responses in sham mice. Moreover, on day 6, the number of activated microglia was significantly increased in the ipsilateral dorsal horn of mice. The increase in the number of activated microglia induced by PSL was significantly suppressed by pioglitazone (1-25 mg/kg p.o.). Pioglitazone did not affect the number of activated microglia in sham mice. These results suggest that PPARgamma activation inhibits the development of tactile allodynia and the expression of activated microglia in the dorsal horn of spinal cord in mice with PSLinduced peripheral nerve injury. PMID- 22504746 TI - Phenolphthalein treatment in pregnant women and congenital abnormalities in their offspring: A population-based case-control study. AB - Phenolphthalein is frequently used laxative drug since 1930s, but the possible teratogenic effect of phenolphthalein was not checked in casecontrol eptedmiological study. In addition US Food and Drug Administration (FDA) declared the mutagenic and carcinogenic effect of phenolphthalein in 1999, thus we decided to evaluate the birth outcomes particularly congenital abnormalities (CAs) of newborn infants born to women treated with phenolphthalein during pregnancy. Cases with CA and their matched controls without CA born to mothers with phenolphthalein use during pregnancy were compared in the population-based large data set of the Hungarian Case-Control Surveillance System of Congenital Abnormalities. Of 22,843 cases with CA, 191 (0.83%) while of 38,151 controls, 247 (0.64%) were born to mothers with phenolphthalein treatment (adjusted OR with 95% CI: 1.3, 1.0-1.5). The mean gestational week at delivery was somewhat longer in both the case (0.3 week) and control (0.2 week) groups while the mean birth weight was somewhat larger in cases (46 g) and controls (12 g) born to mothers with phenolphthalein treatment during the study pregnancy compared with mothers without phenolphthalein treatment. These differences were in agreement with the lower rate of preterm births and low birth weight in controls born to mothers with phenolphthalein treatment during pregnancy. The detailed analysis of different CA groups showed an association between maternal phenolphthalein treatment during pregnancy and a higher risk for Hirschsprung's disease (p = 0.01) based on 4 cases in the so-called other isolated CA-group. In conclusion phenolphthalein treatment in pregnant women associates with a higher risk for Hirschsprung's disease in their children, but this finding is only a signal which needs confirmation or rejection in other studies. PMID- 22504747 TI - Using patient-reported outcome measures to assess health-care quality. AB - The transparency of surgical outcomes data and the drive for quality has been highlighted since the public inquiry, led by Professor Ian Kennedy, into children's heart surgery at the Bristol Royal Infirmary. This was formalized in Lord Darzi's 2008 report High Quality Care for All, that proposed the NHS should: 'systematically measure and publish information about the quality of care'. Subsequently the NHS White paper, Equity and Excellence: Liberating the NHS (Department of Health, 2010), set out the ambitions and aims of the NHS and in particular that it should provide: '...a service that offers care that is safe and of the highest quality.' PMID- 22504748 TI - Exertional heat stroke. AB - The increasing popularity of mass participation endurance events necessitates that on-site medical teams be well versed in the management of both common and life-threatening conditions. Exertional heat stroke is one such condition, which if left untreated can be fatal. PMID- 22504749 TI - Hepatic encephalopathy. AB - Hepatic encephalopathy is a serious and potentially fatal complication of both acute and chronic liver disease, arising as a result of hepatocellular failure, cirrhosis and/or portal-systemic shunting (Ferenci et al, 2002). It reflects a broad spectrum of neuropsychiatric abnormalities, encompassing a range of defects in psychomotor, locomotive, cognitive, emotional and behavioural functions (Prakash and Mullen, 2010). Hepatic encephalopathy is either overt or minimal. While overt hepatic encephalopathy can be diagnosed using bedside clinical tests, minimal hepatic encephalopathy is clinically invisible and requires psychometric testing to diagnose. The rising prevalence of end-stage viral hepatitis-related liver disease, coupled with the growing problem of alcoholic and non-alcoholic fatty liver disease, has significantly increased the burden of disease from cirrhosis (Mooney et al, 2007; Fleming et al, 2008), so recognition and appropriate management of the manifestations of decompensating cirrhosis (including hepatic encephalopathy) is essential. Hepatic encephalopathy has a substantial societal burden because of its impact on survival, quality of life and daily functioning, including an impaired ability to drive, leaving patients especially vulnerable to road traffic accidents (Ferenci et al, 2002; Prakash and Mullen, 2010). PMID- 22504750 TI - Sudden sensorineural hearing loss. AB - Sudden onset sensorineural hearing loss is a medical emergency that continues to be poorly understood despite being recognized in the literature since 1944 (De Kleyn, 1944). A commonly used criterion to qualify for this diagnosis is a sensorineural hearing loss over three contiguous pure-tone frequencies of 30 dB or more that develops within 72 hours. The vast majority of cases are unilateral and the estimated annual incidence is 20 per 100 000 persons (Nosrati-Zarenoe et al, 2007). A cause for the hearing loss is only identified in up to 10% of cases but 50% of patients will improve spontaneously (Penido et al, 2009). PMID- 22504751 TI - Platelet-rich plasma in sports medicine: hot favourite or non-starter? AB - In the field of sports injury, musculoskeletal injuries require prompt treatment to allow a quick return to the pre-injury level of function. Ideally, any given treatment should, among other factors, be minimally invasive and highly effective, with minimal side effects. One emerging strategy to accelerate tissue healing is the use of platelet rich plasma. Platelet-rich plasma has been used in clinical practice since the 1980s, in dentistry, maxillofacial surgery and dermatology (Margolis et al, 2001). The treatment developed because platelet-rich plasma is seen as a preparation of growth factors which facilitate rapid healing of damaged tissue. There have been wide variations in agreeing a definition of platelet-rich plasma. PMID- 22504752 TI - Management of prostate cancer. AB - Prostate cancer is diagnosed in 37 000 new patients a year, and causes 10 000 deaths each year in the UK (Cancer Research UK, 2011). Diagnoses are increasingly the result of screening using measurement of prostate- specific antigen levels. The natural history of early disease is unclear. Autopsy studies before prostate specific antigen screening showed an actual latent prevalence (not diagnosed during life) of around 30% at the age of 50 years and 75% at the age of 80 years, and many of these demonstrated local invasion (Franks, 1954). One of the main current challenges in urology is distinguishing indolent prostate cancers from potentially lethal ones. The specificity of the prostate-specific antigen test for clinically significant disease remains disappointingly low and population screening is not encouraged (Ilic et al, 2011). However, prostate-specific antigen testing is often done in good faith, but pre-test counselling is essential. Thus, prostate-specific antigen testing should only be undertaken by the patient's GP or on the advice of a urologist. PMID- 22504753 TI - The future training of surgeons to manage patients with cleft lip and palate disorders. AB - The development of the face and the upper lip occurs during the fifth to ninth week of pregnancy. A cleft is a separation or split in either the upper lip or palate and sometimes both. Cleft lip and palate can occur on its own (nonsyndromic) or is sometimes part of a wider series of birth defects (syndromic). PMID- 22504754 TI - Acute rhabdomyolysis caused by combination therapy with atorvastatin and warfarin. AB - Atorvastatin and warfarin are commonly prescribed in combination. Acute rhabdomyolysis is a rare but recognized side effect of atorvastatin occurring within a few weeks of initiation. This article presents a case of a 69-year-old man, on stable atorvastatin therapy, who developed acute rhabdomyolysis following initiation of warfarin. Rising international normalized ratio is a well recognized feature of interaction between warfarin and various statins (fluvastatin, lovastatin and simva-statin). There has only been one previous similar case of acute rhabdomyolysis following the commencement of warfarin, reported in a patient on stable simvastatin therapy. To the authors' knowledge, no similar case has been reported with atorvastatin. PMID- 22504755 TI - Parathyroid cysts: a clinical and radiological challenge. AB - Parathyroid cysts are rare causes of neck swelling accounting for 0.6% of thyroid and parathyroid lesions. They may be functional, resulting in the release of parathyroid hormone, or non-functional. Non-functional cysts may be cosmetically unacceptable or cause dysphagia, dyspnoea or recurrent laryngeal nerve palsy as a result of compression. This article presents a young woman who was diagnosed with a thyroid cyst both on examination and imaging. However, the final histology confirmed this to be parathyroid in origin and this should be considered in the differential of such neck swellings. PMID- 22504756 TI - An unusual cause of spontaneous recurrent pneumothoraces. AB - Epithelioid sarcoma is a rare distinctive soft tissue neoplasm with a predilection for the distal parts of the extremities. While epithelioid sarcoma presenting as median nerve palsy or carpal tunnel syndrome has been described, epithelioid sarcoma presenting as cystic lung metastases has not been reported. This article reports a case of a man who presented with spontaneous recurrent pneumothoraces and was found to have bilateral cystic lung disease, which was ultimately diagnosed as epithelioid sarcoma with cystic lung metastases. He underwent left arm amputation, chemotherapy and radiation, but succumbed to his advanced disease. PMID- 22504757 TI - A large thumb mass. AB - A 31-year-old man presented with a 5-year history of a spontaneously occurring soft tissue mass on the palmar aspect of his left non dominant thumb. Over 5 months he was having progressive difficulty flexing at the interphalangeal joint. Magnetic resonance imaging demonstrated an heterogeneously enhancing soft tissue mass likely to be either a peripheral fibromatosis or giant cell tumour of the flexor tendon (Figure 1). Intraoperatively a large neuroma in continuity with the ulnar digital nerve was found and debulked (Figure 2). The diagnosis was confirmed histologically. PMID- 22504758 TI - An unusual complication of central line insertion: the left superior vena cava. AB - A Vascath dialysis line was inserted under direct ultrasound guidance into the left internal jugular vein for plasmapharesis to treat a 60-year-old woman admitted with a myasthenic crisis secondary to sepsis. A chest X-ray was arranged to check the position of the line and look for any complications, which revealed the presence of a left superior vena cava. Because of the uncertainty of the drainage of this vein a right-sided catheter was then inserted. The repeat chest X-ray (Figure 1) shows both lines, and the two vena cava. PMID- 22504759 TI - Gerhard Hansen: discoverer of the organism of leprosy. AB - This year marks the hundredth anniversary of the death, on 12 February 1912, of the Norwegian leprologist, Gerhard Hansen, who was the first to describe the Mycobacterium leprae (Hansen's bacillus). It was, in fact, only the second specific disease-causing organism to be discovered, the first being the bacillus of anthrax. PMID- 22504760 TI - Evaluation of jugular venous pressure in suspected heart failure: does it matter in 2012? AB - Even in the modern era documentation of raised jugular venous pressure enhances the evaluation of suspected cardiac failure, as shown by a prospective study of 721 adults of mean age 70.7 years in whom an elevated jugular venous pressure contributed 12 points towards the score of >54 needed to generate a >70% probability of heart failure (Kelder et al, 2011). The combination of three items from the clinical history plus six (including jugular venous pressure elevation) from the physical examination showed independent diagnostic value (c-statistic 0.83), which increased to a c-statistic of 0.86 with the addition of natriuretic peptide measurement to the diagnostic armamentarium. PMID- 22504761 TI - Making sense of the Hutton report. AB - Late last year, Health Secretary Andrew Lansley outlined the government's latest proposals for the NHS Pension Scheme following on from the Hutton report. Over the coming weeks and months negotiations will continue between the government and unions and while we can not yet be sure what the final outcome will be, it is certain there will be changes to your NHS pension. This article explains how some of the proposed changes will affect you. PMID- 22504763 TI - Angiotensin-converting enzyme inhibitors in the perioperative period. AB - Angiotensin-converting enzyme (ACE) inhibitors inhibit the enzyme that cleaves angiotensin I to form angiotensin II. They are potent vasodilators as they decrease concentrations of angiotensin II and noradrenaline and increase concentrations of bradykinin and nitric oxide. They reduce secretion of aldosterone and antidiuretic hormone, thus reducing salt and water reabsorption by the kidney (Groban and Butterworth, 2006). PMID- 22504764 TI - What does polarity inversion of extrastriate activity tell us about striate contributions to the early VEP? A comment on Ales et al. (2010). AB - Recently, a forward-model simulation study demonstrated that the upper and lower visual field projections to extrastriate visual cortical areas V2 and V3 have polarity-inverted electrical scalp projections, a property famously associated with potentials generated in primary visual cortex (V1) (Ales et al., 2010a). The authors use this finding, along with other findings from fMRI-constrained source modeling, to argue that the initial component "C1" of the human visual evoked potential may not be generated in V1 as has been widely believed, but may instead come from V2/V3. Here, we examine the validity of this claim with respect to the full set of anatomical and electrophysiological factors comprising the unabridged "cruciform" model linking C1 to V1. We find that the simulations in their current form do not present a valid test of the model, nor are their results inconsistent with it. We also review non-human primate neurophysiology findings that support the C1-V1 principle, and that can and should be taken into account in assessing the validity of constrained source models of human EEG in general. PMID- 22504765 TI - Cortical sulci asymmetries in chimpanzees and macaques: a new look at an old idea. AB - Functional and neuroanatomical asymmetries are an important characteristic of the human brain. The evolution of such specializations in the human cortex has provoked great interest in primate brain evolution. Most research on cortical sulci has revolved around linear measurements, which represent only one dimension of sulci organization. Here, we used a software program (BrainVISA) to quantify asymmetries in cortical depth and surface area from magnetic resonance images in a sample of 127 chimpanzees and 49 macaques. Population brain asymmetries were determined from 11 sulci in chimpanzees and seven sulci in macaques. Sulci were taken from the frontal, temporal, parietal, and occipital lobes. Population-level asymmetries were evident in chimpanzees for several sulci, including the fronto orbital, superior precentral, and sylvian fissure sulci. The macaque population did not reveal significant population-level asymmetries, except for surface area of the superior temporal sulcus. The overall results are discussed within the context of the evolution of higher order cognition and motor functions. PMID- 22504767 TI - Assessment of EGFR and K-ras mutations in fixed and fresh specimens from transesophageal ultrasound-guided fine needle aspiration in non-small cell lung cancer patients. AB - In non-small cell lung cancer (NSCLC) patients, somatic EGFR and K-ras mutations predict therapeutic effectiveness and resistance, respectively, to EGFR tyrosine kinase inhibitors (TKIs). Transesophageal ultrasound-guided fine needle aspiration (EUS-FNA) is a validated technique for diagnosis and staging of NSCLC. In the present study, we compared the feasibility and reliability of EGFR and K ras gene mutation analysis in fixed and fresh mediastinal lymph nodes and extra lymph nodal samples obtained by EUS-FNA in patients suspicious for NSCLC. Thirty six patients were enrolled into the study. For each patient, DNA was extracted from both fresh samples and fixed cytological smears. Exons 18-21 of EGFR and exon 2 of K-ras were amplified by PCR and mutation status was determined by direct sequencing and pyrosequencing. All cases were eligible for analysis. NSCLC was diagnosed in 32 patients (25 adenocarcinomas and 7 squamous cell carcinomas) and 4 patients were free of malignancy. Of the 25 patients with adenocarcinoma, EGFR mutations were detected in 2 (8%) fresh tumor samples and in 3 (12%) fixed cytological smears. K-ras mutations were detected in 8 (32%) fresh samples, and in 9 (36%) fixed cytological smears. Fixed and stained cytological samples seem to be more reliable than fresh material for molecular analysis. PMID- 22504766 TI - From a concept to a word in a syntactically complete sentence: an fMRI study on spontaneous language production in an overt picture description task. AB - Spontaneous language has rarely been subjected to neuroimaging studies. This study therefore introduces a newly developed method for the analysis of linguistic phenomena observed in continuous language production during fMRI. Most neuroimaging studies investigating language have so far focussed on single word or - to a smaller extent - sentence processing, mostly due to methodological considerations. Natural language production, however, is far more than the mere combination of words to larger units. Therefore, the present study aimed at relating brain activation to linguistic phenomena like word-finding difficulties or syntactic completeness in a continuous language fMRI paradigm. A picture description task with special constraints was used to provoke hesitation phenomena and speech errors. The transcribed speech sample was segmented into events of one second and each event was assigned to one category of a complex schema especially developed for this purpose. The main results were: conceptual planning engages bilateral activation of the precuneus. Successful lexical retrieval is accompanied - particularly in comparison to unsolved word-finding difficulties - by the left middle and superior temporal gyrus. Syntactic completeness is reflected in activation of the left inferior frontal gyrus (IFG) (area 44). In sum, the method has proven to be useful for investigating the neural correlates of lexical and syntactic phenomena in an overt picture description task. This opens up new prospects for the analysis of spontaneous language production during fMRI. PMID- 22504768 TI - Impacts of core-shell structures on properties of lanthanide-based nanocrystals: crystal phase, lattice strain, downconversion, upconversion and energy transfer. AB - This feature article highlights the new development and current status of rare earth (RE) based core-shell nanocrystals, which is one of the new classes of hybrid nanostructures. Attractive properties of rare-earth based nanomaterials include extremely narrow emission bands, long lifetimes, large Stoke's shifts, photostability and absence of blinking that can be exploited for biophotonic and photonic applications. Core-shell nanostructures have been attracting a great deal of interest to improve the luminescence efficiency by the elimination of deleterious cross-relaxation. The main focus of this feature article is to address the impacts of core-shell structures on the properties of lanthanide based nanocrystals including crystal phase, lattice strain, downconversion emission, upconversion emission and energy transfer. We describe general synthetic methodologies to design core-shell nanostructure materials. An interesting finding reported is that the local environment of an ion in the core shell structure significantly affects the modifications of radiative and nonradiative relaxation mechanisms. Finally, a tentative outlook on future developments of this research field is given. Here, we attempt to identify the critical parameters governing the design of luminescent lanthanide based core shell nanostructures. PMID- 22504770 TI - Newly diagnosed immune thrombozytopenia--German guideline concerning initial diagnosis and therapy. AB - Newly diagnosed immune thrombocytopenia occurs in 3-5/100 000 children < 14 y per year. Bleeding symptoms do not correlate with platelet count. Diagnostic approach includes history, clinical examination and analysis of blood count with blood smear by experienced hematologist. Additional investigations are only necessary in atypical cases and cases with additional symptoms or inadequate response to therapy. The decision to treat ITP should be made cautiously and not entirely be based on the platelet count. Decisions based on clinical symptoms and progress of the illness are more reasonable. There is no evidence, that therapy at the time of diagnosis influences the further course and can avoid intracerebral hemorrhage. PMID- 22504769 TI - Surgical aspects in the treatment of adrenocortical carcinomas in children: data of the GPOH-MET 97 trial. AB - Adrenocortical carcinomas (ACCs) are a rare entity, with an incidence of 1.5 per million population per year. The prognosis of ACC is poor. Complete surgical resection is essential for a curative approach and significantly determines overall prognosis. Tumor resection is sophisticated and complicated by the vulnerability of the tumor and its invasive growth. Chemotherapy and Mitotane are additional therapeutic approaches that are combined with surgery in an interdisciplinary strategy. In this study, 59 patients between 2 months and 18 years of age with histologically verified ACC were analyzed retrospectively with respect to oncosurgical aspects. Patients were registered in the GPOH-MET 97 trial of the Society of Pediatric Oncology and Haematology. Preoperative management, factors influencing surgical severity, and operative complications were assessed.The gender ratio was 1:2 (m:f). A total of 58 patients showed increased hormonal activity and associated clinical signs of hormonal excess. Tumor volume was >= 300 mL in 25 patients. These patients showed an increased rate of operative complications and a poorer overall survival (OS) rate (p<0.01). A total of 14 patients showed metastatic spread, particularly to the lungs and lymph nodes. Biopsy of the tumor was performed in 12 patients. Tumor rupture occurred in 11 patients. Preoperative biopsy and/or experienced tumor rupture were associated with poorer OS rate. R2 resection only was achievable in 5 patients, and surgery was not feasible in 3 patients.In conclusion, since most of the pediatric ACC are hormone active and can be diagnosed clinically, the need of a tumor biopsy has to be discussed critically. Thorough pre- and perioperative management is essential for oncosurgical success. PMID- 22504771 TI - Combined use of recombinant activated factor VII and ECMO in severe postoperative bleeding after cardiac surgery in a newborn: death due to ventricular dysfunction. PMID- 22504772 TI - A case of disseminated tuberculosis with psoas abscess in a 12-year-old girl with sickle cell trait. PMID- 22504774 TI - Stress and coping in parents of children and adolescents with spinal muscular atrophy. AB - BACKGROUND: Chronic illness and disability is not only associated with higher rates of behavioural problems in children, but also parental stress which requires active coping. The aim of the study was to analyse stress and coping, as well as their mediating variables, in parents of children and adolescents with Spinal Muscular Atrophy (SMA). METHOD: 96 children and adolescents with SMA aged 6;0 to 18;11 years were compared to 59 age, sex and SES matched controls. RESULTS: Parental stress was measured with the QRS, coping with the F-COPES and social support with the F-SOZU questionnaires.Parental stress was significantly higher in the SMA families for the total score and all subscales of the QRS. Stress was higher in families with severely affected SMA types I and II. The greatest percentage of variance contributing to stress could be explained by lack of social support, degree of disability and behavioural problems in the child. Although social support was reduced, the actual coping abilities of the families did not differ. CONCLUSION: Families with children and adolescents with SMA show high degrees of stress and strain which are associated with the severity of the disease, reduced social support and child behaviour. Despite these stresses they manage and cope no differently from families with healthy children. PMID- 22504773 TI - ['Do not worry, it hurts!'--psychological preparation for medical procedures in pediatric oncology]. AB - In the last decades the chances of surviving childhood cancer have increased. Nowadays psychological and psychosocial long term side effects become more spotlighted. Especially the posttraumatic stress disorder is focused at the moment as a possible side effect of childhood cancer. Cancer as a life threatening illness is unpredictable and associated with repeating loads, such as medical procedures or treatment. Most of the patients report anxiety, especially young children have an increased risk of making a traumatic experience while undergoing medical treatment. A psychological support before, meanwhile and after can ensure compliance as well as reducing emotional and behavioral disorders. Even preventive impact is conceivable. Therefore psychological support has become a standard in pediatric cancer treatment. The current case report of the 10 year old Tom is a practical example how to support has undergoing medical procedures. The interventions described have the aim of stabilizing the patient and reducing his anxiety and discomfort. They also show an effect on self-efficacy. PMID- 22504775 TI - Invasive aspergillosis in pediatric oncology patients: a rare event with poor prognosis--case analysis to plan better targeted prophylactic or therapeutic measurement. AB - Despite the implementation of new antifungal drugs, invasive aspergillosis (IA) still remains a considerable challenge in pediatric oncology with a severe mortality. Prophylactic and therapeutic measurement have to be evaluated in these rare but poor prognostic patients. Therefore the entire group of patients at risk of developing IA has to be defined before cooperative prospective trials. In a retrospective analysis including all our patients with malignancies we looked for patients with proven/probable IA. Cases of the period from 2003 to 2008 were analyzed in detail.In the period between 2003 to 2008 24 of 755 patients were affected by proven/ probable IA. Compared to former studies incidence increased from 1.3%in 1980 to 3.4% in 2008. AML patients with or without allogeneic/haploidentical stem cell transplantation were at highest risk (24% and 25% respectively, in comparison to 1% in ALL-patients). Survival after 2 years was 50% for patients with AML and IA. In patients with high risk to develop IA the effect of intensified, intravenous antimycotic prophylaxis has to be proven prospectively in a cooperative and randomized setting. PMID- 22504777 TI - Hypertension. Tackling challenges in the diagnosis and management of hypertension in 2012. PMID- 22504778 TI - Altered white matter integrity of forebrain in treatment-resistant depression: a diffusion tensor imaging study with tract-based spatial statistics. AB - BACKGROUND: The association between alterations of the white matter (WM) integrity in brain regions and mood dysregulation has been reported in major depressive disorder (MDD). However, there has never been a neuroimaging study in patients who have treatment-resistant depression (TRD) and are in a current treatment-resistant state. In the present study, we used diffusion tensor imaging (DTI) with tract-based spatial statistics (TBSS) method to investigate the WM integrity of different brain regions in patients who had TRD and were in a current treatment-resistant state. METHODS: Twenty-three patients with TRD and Hamilton Rating Scale total score of >=18 and 19 healthy controls matched with age, gender, and education level to patients were scanned with DTI. Thirty 4 mm thick, no gap, contiguous axial slices were acquired and fractional anisotropy (FA) images were generated for each participant. An automated TBSS approach was used to analyze the data. RESULTS: Voxel-wise statistics revealed that patients with TRD had lower FA values in the right anterior limb of internal capsule, the body of corpus callosum, and bilateral external capsule compared to healthy subjects. Patients with TRD did not have increased FA values in any brain regions compared to healthy subjects. There was no correlation between the FA values in any brain region and patients' demographics and the severity of illness. CONCLUSIONS: Our findings suggest the abnormalities of the WM integrity of neuronal tracts connecting cortical and subcortical nuclei and two brain hemispheres may play a key role in the pathogenesis of TRD. PMID- 22504776 TI - Squamous cell carcinomas of the head and neck in Fanconi anemia: risk, prevention, therapy, and the need for guidelines. AB - Fanconi anemia (FA) is a rare recessive DNA repair disorder that is clinically characterized by congenital malformations, progressive bone marrow failure, and increased incidence of malignancies, especially acute myeloid leukemia and squamous cell carcinomas of the head and neck (HNSCCs) and the anogenital regions. On a cellular level, typical features of the disorder are a high degree of genomic instability and an increased sensitivity to bi-functionally alkylating agents. So far, germ-line defects in 15 different FA genes have been identified. Some of these FA genes are also established as tumor susceptibility genes for familiar cancers.In recent years, the prevention and therapy of HNSCCs in FA patients has become more important as the percentage of patients surviving into adulthood is rising. HNSCCs appear in very young FA patients without common risk factors. Since cisplatin-based chemotherapy in combination with radiotherapy, essential parts of the standard treatment approach for sporadic HNSCCs, cannot be used in FA patients due to therapy-associated toxicities and mortalities even with reduced dosing, surgery is the most important treatment option for HNSCCs, in FA patients and requires an early and efficient detection of malignant lesions. So far, no uniform treatment protocol for the management of HNSCCs in FA patients exists. Therefore, we propose that the information on affected FA patients should be collected worldwide, practical therapeutic guidelines developed and national treatment centers established. PMID- 22504779 TI - Neural correlates of stress and favorite-food cue exposure in adolescents: a functional magnetic resonance imaging study. AB - Adolescence is a critical period of neurodevelopment for stress and appetitive processing, as well as a time of increased vulnerability to stress and engagement in risky behaviors. This study was conducted to examine brain activation patterns during stress and favorite-food-cue experiences relative to a neutral-relaxing condition in adolescents. Functional magnetic resonance imaging was employed using individualized script-driven guided imagery to compare brain responses with such experiences in 43 adolescents. Main effects of condition and gender were found, without a significant gender-by-condition interaction. Stress imagery, relative to neutral, was associated with activation in the caudate, thalamus, left hippocampus/parahippocampal gyrus, midbrain, left superior/middle temporal gyrus, and right posterior cerebellum. Appetitive imagery of favorite food was associated with caudate, thalamus, and midbrain activation compared with the neutral-relaxing condition. To understand neural correlates of anxiety and craving, subjective (self-reported) measures of stress-induced anxiety and favorite-food-cue-induced craving were correlated with brain activity during stress and appetitive food-cue conditions, respectively. High self-reported stress-induced anxiety was associated with hypoactivity in the striatum, thalamus, hippocampus, and midbrain. Self-reported favorite-food-cue-induced craving was associated with blunted activity in cortical-striatal regions, including the right dorsal and ventral striatum, medial prefrontal cortex, motor cortex, and left anterior cingulate cortex. These findings in adolescents indicate the activation of predominantly subcortical-striatal regions in the processing of stressful and appetitive experiences and link hypoactive striatal circuits to self-reported stress-induced anxiety and cue-induced favorite-food craving. PMID- 22504780 TI - Successful treatment of HER-2-positive metastatic apocrine carcinoma of the skin with lapatinib and capecitabine. PMID- 22504781 TI - A multicenter investigation of late adverse events in Japanese women treated with breast-conserving surgery plus conventional fractionated whole-breast radiation therapy. AB - OBJECTIVE: To investigate late adverse events in Japanese women treated with breast-conserving surgery plus conventional fractionated radiation therapy in 24 hospitals. METHODS: This is a prospective investigation into patients who have been followed for 3 years or more after the completion of radiation therapy. The women visited hospitals for routine medical follow-up between 1 March and 31 May 2008. All patients underwent interviews and visual/palpating examinations. Their clinical chart, past chest X-rays and laboratory findings were reviewed. Evaluation criteria for late adverse events and breast cosmetic outcome were based on the Common Terminology Criteria for Adverse Events v.3 and the European Organization for Research and Treatment of Cancer Global Cosmetic Rating System. RESULTS: Seven hundred and three women, including 448 treated with whole-breast irradiation and 255 treated with whole-breast and boost irradiation, were examined by radiation oncologists in 24 hospitals. The frequent adverse events were breast pain (Grade 1, 115; Grade 2, 2), breast fibrosis (Grade 1, 72; Grade 2, 8), chest wall pain (Grade 1, 67; Grade 2, 3), telangiectasia (Grade 1, 29; Grade 2, 5) and pneumonitis (Grade 1, 20; Grade 2, 6; Grade 3, 3). Adverse events of Grade 2 or 3 were found in 27 patients (3.8%); 3 presented with radiation pneumonitis of Grade 3. The percentage of patients with an excellent or good cosmetic outcome was 69.1%. CONCLUSIONS: In the first multicenter investigation for Japanese women after breast-conserving therapy, the evaluation of late adverse events and breast cosmetic outcome was similar to several other reports from clinical trials in North America and Europe. PMID- 22504782 TI - Dissociative stupor mimicking consciousness disorder in an advanced lung cancer patient. AB - Although there are three kinds of stupor in psychiatry, dissociative stupor is the most commonly recognized. In psychiatric clinics or emergency rooms, dissociative stupor is common, but in an oncology setting it is hardly known. Therefore, distinguishing dissociative stupor from consciousness disorder is occasionally difficult, especially in the advanced or terminal phase. We report an advanced lung cancer patient who presented dissociative stupor mimicking consciousness disorder. It is necessary to distinguish between consciousness disorder and dissociative stupor. In addition, consultation with a psychiatrist should be taken into consideration. PMID- 22504783 TI - Prins cyclization of bis(silyl) homoallylic alcohols to form 2,6-cis tetrahydropyrans containing a geometrically defined exocyclic vinylsilane: efficient synthesis of ring B of the bryostatins. PMID- 22504784 TI - An innovative approach to the safety evaluation of natural products: cranberry (Vaccinium macrocarpon Aiton) leaf aqueous extract as a case study. AB - Assessment of safety for a food or dietary ingredient requires determination of a safe level of ingestion compared to the estimated daily intake from its proposed uses. The nature of the assessment may require the use of different approaches, determined on a case-by-case basis. Natural products are chemically complex and challenging to characterize for the purpose of carrying out a safety evaluation. For example, a botanical extract contains numerous compounds, many of which vary across batches due to changes in environmental conditions and handling. Key components integral to the safety evaluation must be identified and their variability established to assure that specifications are representative of a commercial product over time and protective of the consumer; one can then extrapolate the results of safety studies on a single batch of product to other batches that are produced under similar conditions. Safety of a well characterized extract may be established based on the safety of its various components. When sufficient information is available from the public literature, additional toxicology testing is not necessary for a safety determination on the food or dietary ingredient. This approach is demonstrated in a case study of an aqueous extract of cranberry (Vaccinium macrocarpon Aiton) leaves. PMID- 22504787 TI - Bullying in schools: what is the problem, and how can educators solve it? AB - This chapter reviews recent research on bullying from an educator's perspective. It is well known that bullying, a serious issue in schools, can be prevented when educators intervene. But research has shown that it is difficult for educators to detect bullying situations in their school and intervene competently and effectively. This chapter examines how educators can detect bullying, how they can best tackle serious cases of bullying, and how they can best prevent bullying in the long run. PMID- 22504788 TI - The Bernese Program against Victimization in Kindergarten and Elementary School. AB - The Bernese Program against Victimization in Kindergarten and Elementary School was designed to be adaptable to the very different situations and needs encountered by teachers in kindergarten and elementary school. The basic principle of the program is to enhance teachers' ability to address bullying. The program consists of six modules, each corresponding to a specific topic. Teachers are urged to implement the tasks discussed during the meetings in their own classes during the time between the meetings. The program has been evaluated using a prevention-control pre- and posttest design. The informants were teachers as well as children. There was a significant interaction between time (pre- and posttest) and group (prevention and control) as to victimization. Changes in teachers' attitudes toward bullying and their ability to cope with such problems were also significant and in the expected direction. PMID- 22504789 TI - The Zero program. AB - Zero is a schoolwide antibullying program developed by the Centre for Behavioural Research at the University of Stavanger, Norway. It is based on three main principles: a zero vision of bullying, collective commitment among all employees at the school using the program, and continuing work. Based on these principles, the program aims to reduce student bullying by increasing the school's ability to uncover and stop bullying, and eventually to prevent it. The Zero program was launched in 2003, but the work that led to it goes back to the first national steps against bullying in 1983. The program extends over sixteen months as teachers develop their awareness of bullying and their competence in addressing it. Students and parents are involved in the program as well. The role of the school leadership is very important. More than 360 Norwegian schools have carried out the program. PMID- 22504790 TI - Making bullying prevention a priority in Finnish schools: the KiVa antibullying program. AB - The KiVa antibullying program has been widely implemented in Finnish comprehensive schools since 2009. The program is predicated on the idea that a positive change in the behaviors of classmates can reduce the rewards gained by the perpetrators of bullying and consequently their motivation to bully in the first place. KiVa involves both universal and bullying specific actions to prevent the emergence of new cases of bullying, stop ongoing bullying, and reduce the negative consequences of victimization. The program has been evaluated in a randomized controlled trial involving 234 Finnish schools and during broad dissemination across Finnish schools (the evaluation involving almost one thousand schools) with positive findings. The program content and the implementation model are presented in this article, and the findings from the evaluation studies are summarized. PMID- 22504791 TI - School-based prevention of bullying and relational aggression in adolescence: the fairplayer.manual. AB - The fairplayer.manual is a school-based program to prevent bullying. The program consists of fifteen to seventeen consecutive ninety-minute lessons using cognitive-behavioral methods, methods targeting group norms and group dynamics, and discussions on moral dilemmas. Following a two-day training session, teachers, together with skilled fairplayer.teamers, implement fairplayer.manual in the classroom during regular school lessons. This chapter offers a summary of the program's conception and underlying prevention theory and summarizes the results from two evaluation studies. Standardized questionnaires showed a positive impact of the intervention program on several outcome variables. PMID- 22504792 TI - ViSC Social Competence Program. AB - The ViSC Social Competence Program has been implemented in Austrian schools within the scope of a national strategy plan, Together Against Violence. The program is a primary preventive program designed for grades 5 to 8. The prevention of aggression and bullying is defined as a school development task, and the initial implementation of the program lasts one school year. The program consists of universal and specific actions that are implemented through in-school teacher training and a class project for students. The program was evaluated with a randomized intervention control group design. Data were collected from teachers and students. Results suggest that the program reduces aggression in schools. PMID- 22504793 TI - Risk and protective factors, longitudinal research, and bullying prevention. AB - This chapter presents the results from two systematic/meta-analytic reviews of longitudinal studies on the association of school bullying (perpetration and victimization) with adverse health and criminal outcomes later in life. Significant associations between the two predictors and the outcomes are found even after controlling for other major childhood risk factors that are measured before school bullying. The results indicate that effective antibullying programs should be encouraged. They could be viewed as a form of early crime prevention as well as an early form of public health promotion. The findings from a systematic/meta-analytic review on the effectiveness of antibullying programs are also presented. Overall, school-based antibullying programs are effective, leading to an average decrease in bullying of 20 to 23 percent and in victimization of 17 to 20 percent. The chapter emphasizes the lack of prospective longitudinal research in the area of school bullying, which does not allow examination of whether any given factor (individual, family,. or social) is a correlate, a predictor, or a possible cause for bullying. This has important implications for future antibullying initiatives, as well as implications for the refinement of theories of school bullying. It is necessary to extend the framework of the traditional risk-focused approach by incorporating the notion of resiliency and investigating possible protective factors against school bullying and its negative consequences. PMID- 22504795 TI - 2D-DIGE analysis of mango (Mangifera indica L.) fruit reveals major proteomic changes associated with ripening. AB - A comparative proteomic investigation between the pre-climacteric and climacteric mango fruits (cv. Keitt) was performed to identify protein species with variable abundance during ripening. Proteins were phenol-extracted from fruits, cyanine dye-labeled, and separated on 2D gels at pH 4-7. Total spot count of about 373 proteins spots was detected in each gel and forty-seven were consistently different between pre-climacteric and climacteric fruits and were subjected to LC MS/MS analysis. Functional classification revealed that protein species involved in carbon fixation and hormone biosynthesis decreased during ripening, whereas those related to catabolism and the stress-response, including oxidative stress and abiotic and pathogen defense factors, accumulated. In relation to fruit quality, protein species putatively involved in color development and pulp softening were also identified. This study on mango proteomics provides an overview of the biological processes that occur during ripening. PMID- 22504796 TI - The Silk Road, Marco Polo, a Bible and its proteome: a detective story. AB - Around the end of XIII century (at the time of young Marco Polo's first trip to China at the court of Khubilai Khan in Khan Baliq) a pocket Bible was delivered by a Franciscan friar to the Mogul Emperor, in the framework of the evangelization program of the Far East. Four centuries later, in 1685, this Bible was rediscovered by the Jesuit Philippe Couplet in the house of a rich Chinese in Nanchin and donated to Cosimo III, Grand Duke of Tuscany. This Bible was recently "unearthed" in the Biblioteca Medicea Laurenziana in Florence, wrapped up in a precious yellow silk cloth, in a rather ruined state. After two years of restoration, the Bible will return to China in 2012 for a celebration of its >700years of life and of its remarkable return trip on the Silk Road. On account of the thinness of the parchment (barely 80MUm thickness, the size of each foil being 16.5*11cm) it was widely held that the pages were produced from foetal lambskins. On tiny fragments of the margins of a foil, after several unsuccessful attempts at digesting the vellum, we were able to obtain a tryptic peptide mixture, which, upon mass spectrometry analysis, yielded the identity of 8 unique proteins, belonging to the genus Bos taurus, thus confirming the origin of the vellum from calfskins rather than from foetal lambskins. Our results prove that it is possible to obtain reliable protein extraction and IDs from ancient parchment documents. PMID- 22504797 TI - Quantitative immunoproteomics analysis reveals novel MHC class I presented peptides in cisplatin-resistant ovarian cancer cells. AB - Platinum-based chemotherapy is widely used to treat various cancers including ovarian cancer. However, the mortality rate for patients with ovarian cancer is extremely high, largely due to chemo-resistant progression in patients who respond initially to platinum based chemotherapy. Immunotherapy strategies, including antigen specific vaccines, are being tested to treat drug resistant ovarian cancer with variable results. The identification of drug resistant specific tumor antigens would potentially provide significant improvement in effectiveness when combined with current and emerging therapies. In this study, using an immunoproteomics method based on iTRAQ technology and an LC-MS platform, we identified 952 MHC class I presented peptides. Quantitative analysis of the iTRAQ labeled MHC peptides revealed that cisplatin-resistant ovarian cancer cells display increased levels of MHC peptides derived from proteins that are implicated in many important cancer pathways. In addition, selected differentially presented epitope specific CTL recognize cisplatin-resistant ovarian cancer cells significantly better than the sensitive cells. These over presented, drug resistance specific MHC class I associated peptide antigens could be potential targets for the development of immunotherapeutic strategies for the treatment of ovarian cancer including the drug resistant phenotype. PMID- 22504798 TI - Two-dimensional nanoarchitectures for lithium storage. AB - Two dimensional nanoarchitectures are of great interest in lithium storage for energy-storage devices, in particular lithium-ion batteries, due to its shortened paths for fast lithium ion diffusion and large exposed surface offering more lithium-insertion channels. Their competitive lithium-storage features provide huge potentials to develop next-generation high-performance lithium-ion batteries. This review is devoted to the recent progress in the fabrication of innovative 2D structures with various synthetic strategies and their applications for lithium storage in lithium-ion batteries. These 2D architectures are categorized into six styles, i.e., nanoporous nanosheets, ultrathin nanosheets, flower-like structures assembled by nanosheets, sandwich-like nanosheets, corrugated nanosheets, and nanosheets with specific facets. Based on the lithium storage manner, we further summerized their electrochemical performance for lithium storage with four classified themes including surface Li storage, zero or low-strain Li storage, volume-variation Li storage and synergic-effect Li storage. Finally, the outlook and perspective on 2D lithium-storage materials is concisely provided. PMID- 22504799 TI - Effect of bisphosphonates on bone mineral density and fracture prevention in gastric cancer patients after gastrectomy. AB - GOAL: To evaluate the effectiveness of bisphosphonates in preventing fractures in gastric cancer patients by increasing bone mineral density (BMD). BACKGROUND: The effectiveness of bisphosphonates is questionable in gastric cancer patients who have undergone gastrectomy, although they display a high prevalence of osteoporosis. STUDY: Forty-seven gastric cancer patients with osteoporosis were retrospectively analyzed. All patients were supplemented with calcium and vitamin D. Twenty-four patients were treated with bisphosphonate (bisphosphonate group) and 23 patients were untreated (control group). Fractures, severe bone pain, and adverse effects of bisphosphonates were monitored. BMD of the lumbar spine and femoral neck were measured before and 1-year treatment with bisphosphonates by dual-energy X-ray absorptiometry. RESULTS: During a 1-year follow-up, 7 of the 47 (15%) patients developed new fractures. The bisphosphonate-treated group had a significantly lower fracture rate than the control group (n=1 vs. 6, P<0.05). Lumbar spine BMD increased in both groups (0.047 +/- 0.03 vs. 0.021 +/- 0.03 g/cm2, respectively), whereas femoral neck BMD increased only in the bisphosphonate group (0.032 +/- 0.03 vs. -0.004 +/- 0.02 g/cm2, respectively). Furthermore, the bisphosphonate group showed greater increases in lumbar spine and femoral neck BMDs than the controls (P<0.05). No difference was found between alendronate and risedronate in terms of BMD at follow-up. CONCLUSIONS: Therapy using bisphosphonates might be effective at increasing BMD and reducing fracture risk in gastric cancer patients after gastrectomy. Further well-designed randomized controlled trials are needed for confirmation. PMID- 22504800 TI - Modified Cre-loxP recombination in Aspergillus oryzae by direct introduction of Cre recombinase for marker gene rescue. AB - Marker rescue is an important molecular technique that enables sequential gene deletions. The Cre-loxP recombination system has been used for marker gene rescue in various organisms, including aspergilli. However, this system requires many time-consuming steps, including construction of a Cre expression plasmid, introduction of the plasmid, and Cre expression in the transformant. To circumvent this laborious process, we investigated a method wherein Cre could be directly introduced into Aspergillus oryzae protoplasts on carrier DNA such as a fragment or plasmid. In this study, we define the carrier DNA (Cre carrier) as a carrier for the Cre enzyme. A mixture of commercial Cre and nucleic acids (e.g., pUG6 plasmid) was introduced into A. oryzae protoplasts using a modified protoplast-polyethylene glycol method, resulting in the deletion of a selectable marker gene flanked by loxP sites. By using this method, we readily constructed a marker gene-rescued strain lacking ligD to optimize homologous recombination. Furthermore, we succeeded in integrative recombination at a loxP site in A. oryzae. Thus, we developed a simple method to use the Cre-loxP recombination system in A. oryzae by direct introduction of Cre into protoplasts using DNA as a carrier for the enzyme. PMID- 22504801 TI - Determination of Wolbachia diversity in butterflies from Western Ghats, India, by a multigene approach. AB - Members of the genus Wolbachia are intracellular bacteria that are widespread in arthropods and establish diverse symbiotic associations with their hosts, ranging from mutualism to parasitism. Here we present the first detailed analyses of Wolbachia in butterflies from India with screening of 56 species. Twenty-nine species (52%) representing five families were positive for Wolbachia. This is the first report of Wolbachia infection in 27 of the 29 species; the other two were reported previously. This study also provides the first evidence of infection in the family Papilionidae. A striking diversity was observed among Wolbachia strains in butterfly hosts based on five multilocus sequence typing (MLST) genes, with 15 different sequence types (STs). Thirteen STs are new to the MLST database, whereas ST41 and ST125 were reported earlier. Some of the same host species from this study carried distinctly different Wolbachia strains, whereas the same or different butterfly hosts also harbored closely related Wolbachia strains. Butterfly-associated STs in the Indian sample originated by recombination and point mutation, further supporting the role of both processes in generating Wolbachia diversity. Recombination was detected only among the STs in this study and not in those from the MLST database. Most of the strains were remarkably similar in their wsp genotype, despite divergence in MLST. Only two wsp alleles were found among 25 individuals with complete hypervariable region (HVR) peptide profiles. Although both wsp and MLST show variability, MLST gives better separation between the strains. Completely different STs were characterized for the individuals sharing the same wsp alleles. PMID- 22504802 TI - Overexpression of genes encoding glycolytic enzymes in Corynebacterium glutamicum enhances glucose metabolism and alanine production under oxygen deprivation conditions. AB - We previously reported that Corynebacterium glutamicum strain DeltaldhADeltappc+alaD+gapA, overexpressing glyceraldehyde-3-phosphate dehydrogenase-encoding gapA, shows significantly improved glucose consumption and alanine formation under oxygen deprivation conditions (T. Jojima, M. Fujii, E. Mori, M. Inui, and H. Yukawa, Appl. Microbiol. Biotechnol. 87:159-165, 2010). In this study, we employ stepwise overexpression and chromosomal integration of a total of four genes encoding glycolytic enzymes (herein referred to as glycolytic genes) to demonstrate further successive improvements in C. glutamicum glucose metabolism under oxygen deprivation. In addition to gapA, overexpressing pyruvate kinase-encoding pyk and phosphofructokinase-encoding pfk enabled strain GLY2/pCRD500 to realize respective 13% and 20% improved rates of glucose consumption and alanine formation compared to GLY1/pCRD500. Subsequent overexpression of glucose-6-phosphate isomerase-encoding gpi in strain GLY3/pCRD500 further improved its glucose metabolism. Notably, both alanine productivity and yield increased after each overexpression step. After 48 h of incubation, GLY3/pCRD500 produced 2,430 mM alanine at a yield of 91.8%. This was 6.4-fold higher productivity than that of the wild-type strain. Intracellular metabolite analysis showed that gapA overexpression led to a decreased concentration of metabolites upstream of glyceraldehyde-3-phosphate dehydrogenase, suggesting that the overexpression resolved a bottleneck in glycolysis. Changing ratios of the extracellular metabolites by overexpression of glycolytic genes resulted in reduction of the intracellular NADH/NAD(+) ratio, which also plays an important role on the improvement of glucose consumption. Enhanced alanine dehydrogenase activity using a high-copy-number plasmid further accelerated the overall alanine productivity. Increase in glycolytic enzyme activities is a promising approach to make drastic progress in growth-arrested bioprocesses. PMID- 22504803 TI - High diversity and novel species of Pseudomonas aeruginosa bacteriophages. AB - The diversity of Pseudomonas aeruginosa bacteriophages was investigated using a collection of 68 phages isolated from Central Mexico. Most of the phages carried double-stranded DNA (dsDNA) genomes and were classified into 12 species. Comparison of the genomes of selected archetypal phages with extant sequences in GenBank resulted in the identification of six novel species. This finding increased the group diversity by ~30%. The great diversity of phage species could be related to the ubiquitous nature of P. aeruginosa. PMID- 22504805 TI - High-throughput screening for Streptomyces antibiotic biosynthesis activators. AB - A genomic cosmid library of Streptomyces clavuligerus was constructed and transferred efficiently by conjugation to Streptomyces lividans, and 12 distinct groups of overlapping cosmid clones that activated the silent actinorhodin biosynthesis gene cluster were identified. This generally applicable high throughput screening procedure greatly facilitates the identification of antibiotic biosynthesis activators. PMID- 22504804 TI - Abundance, distribution, and activity of Fe(II)-oxidizing and Fe(III)-reducing microorganisms in hypersaline sediments of Lake Kasin, southern Russia. AB - The extreme osmotic conditions prevailing in hypersaline environments result in decreasing metabolic diversity with increasing salinity. Various microbial metabolisms have been shown to occur even at high salinity, including photosynthesis as well as sulfate and nitrate reduction. However, information about anaerobic microbial iron metabolism in hypersaline environments is scarce. We studied the phylogenetic diversity, distribution, and metabolic activity of iron(II)-oxidizing and iron(III)-reducing Bacteria and Archaea in pH-neutral, iron-rich salt lake sediments (Lake Kasin, southern Russia; salinity, 348.6 g liter(-1)) using a combination of culture-dependent and -independent techniques. 16S rRNA gene clone libraries for Bacteria and Archaea revealed a microbial community composition typical for hypersaline sediments. Most-probable-number counts confirmed the presence of 4.26 * 10(2) to 8.32 * 10(3) iron(II)-oxidizing Bacteria and 4.16 * 10(2) to 2.13 * 10(3) iron(III)-reducing microorganisms per gram dry sediment. Microbial iron(III) reduction was detected in the presence of 5 M NaCl, extending the natural habitat boundaries for this important microbial process. Quantitative real-time PCR showed that 16S rRNA gene copy numbers of total Bacteria, total Archaea, and species dominating the iron(III)-reducing enrichment cultures (relatives of Halobaculum gomorrense, Desulfosporosinus lacus, and members of the Bacilli) were highest in an iron oxide-rich sediment layer. Combined with the presented geochemical and mineralogical data, our findings suggest the presence of an active microbial iron cycle at salt concentrations close to the solubility limit of NaCl. PMID- 22504806 TI - Novel clade of alphaproteobacterial endosymbionts associated with stinkbugs and other arthropods. AB - Here we report a novel clade of secondary endosymbionts associated with insects and other arthropods. Seed bugs of the genus Nysius (Hemiptera: Lygaeidae) harbor the primary gammaproteobacterial symbiont Schneideria nysicola within a pair of bacteriomes in the abdomen. Our survey of Nysius species for their facultative bacterial associates consistently yielded a novel type of alphaproteobacterial 16S rRNA gene sequence in addition to those of Wolbachia. Diagnostic PCR survey of 343 individuals representing 24 populations of four Nysius species revealed overall detection rates of the alphaproteobacteria at 77.6% in Nysius plebeius, 87.7% in Nysius sp. 1, 81.0% in Nysius sp. 2, and 100% in Nysius expressus. Further survey of diverse stinkbugs representing 24 families, 191 species, and 582 individuals detected the alphaproteobacteria from an additional 12 species representing six families. Molecular phylogenetic analysis showed that the alphaproteobacteria from the stinkbugs form a distinct and coherent monophyletic group in the order Rickettsiales together with several uncharacterized endosymbionts from fleas and ticks. The alphaproteobacterial symbiont clade was allied to bacterial clades such as the endosymbionts of acanthamoebae, the endosymbionts of cnidarians, and Midichloria spp., the mitochondrion-associated endosymbionts of ticks. In situ hybridization and electron microscopy identified small filamentous bacterial cells in various tissues of N. plebeius, including the bacteriome and ovary. The concentrated localization of the symbiont cells at the anterior pole of oocytes indicated its vertical transmission route through host insect generations. The designation "Candidatus Lariskella arthropodarum" is proposed for the endosymbiont clade. PMID- 22504807 TI - Isolation of Lactococcus lactis mutants simultaneously resistant to the cell wall active bacteriocin Lcn972, lysozyme, nisin, and bacteriophage c2. AB - Lactococcin 972 (Lcn972) is a nonlantibiotic bacteriocin that inhibits cell wall biosynthesis by binding to lipid II. In this work, two mutants resistant to Lcn972, Lactococcus lactis D1 and D1-20, with high (>320 arbitrary units [AU]/ml) and low (80 AU/ml) susceptibilities, respectively, have been isolated. Resistance to Lcn972 did not impose a burden to growth under laboratory conditions, nor did it substantially alter the physicochemical properties of the cell surface. However, the peptidoglycan of the mutants featured a higher content of muropeptides with tripeptide side chains than the wild-type strain, linking for the first time peptidoglycan remodelling to bacteriocin resistance. Moreover, L. lactis lacking a functional D,D-carboxypeptidase DacA (i.e., with a high content of pentapeptide side chain muropeptides) was shown to be more susceptible to Lcn972. Cross-resistance to lysozyme and nisin and enhanced susceptibility to penicillin G and bacitracin was also observed. Intriguingly, the Lcn972-resistant mutants were not infected by the lytic phage c2 and less efficiently infected by phage sk1. Lack of c2 infectivity was linked to a 22.6-kbp chromosomal deletion encompassing the phage receptor protein gene pip. The deletion also included maltose metabolic genes and the two-component system (TCS) F. However, a clear correlation between these genes and resistance to Lcn972 could not be clearly established, pointing to the presence of as-yet-unidentified mutations that account for Lcn972 resistance. PMID- 22504808 TI - Lactobacillus equigenerosi strain Le1 invades equine epithelial cells. AB - Lactobacillus equigenerosi strain Le1, a natural inhabitant of the equine gastrointestinal tract, survived pH 3.0 and incubation in the presence of 1.5% (wt/vol) bile salts for at least 2 h. Strain Le1 showed 8% cell surface hydrophobicity, 60% auto-aggregation, and 47% coaggregation with Clostridium difficile C6. Only 1% of the cells adhered to viable buccal epithelial cells and invaded the cells within 20 min after contact. Preincubation of strain Le1 in a buffer containing pronase prevented adhesion to viable epithelial cells. Preincubation in a pepsin buffer delayed invasion from 20 min to 1 h. Strain Le1 did not adhere to nonviable epithelial cells. Administration of L. equigenerosi Le1 (1 * 10(9) CFU per 50 kg body weight) to healthy horses did not increase white blood cell numbers. Differential white blood cell counts and aspartate aminotransferase levels remained constant. Glucose, lactate, cholesterol, and urea levels remained constant during administration with L. equigenerosi Le1 but decreased during the week after administration. PMID- 22504809 TI - Distribution of genetic marker concentrations for fecal indicator bacteria in sewage and animal feces. AB - Very little is known about the density and distribution of fecal indicator bacteria (FIB) genetic markers measured by quantitative real-time PCR (qPCR) in fecal pollution sources. Before qPCR-based FIB technologies can be applied to waste management and public health risk applications, it is vital to characterize the concentrations of these genetic markers in pollution sources (i.e., untreated wastewater and animal feces). We report the distribution of rRNA genetic markers for several general FIB groups, including Clostridium spp., Escherichia coli, enterococci, and Bacteroidales, as determined by qPCR on reference collections consisting of 54 primary influent sewage samples collected from treatment facilities across the United States and fecal samples representing 20 different animal species. Based on raw sewage sample collection data, individual FIB genetic markers exhibited a remarkable similarity in concentration estimates from locations across the United States ranging from Hawaii to Florida. However, there was no significant correlation between genetic markers for most FIB combinations (P > 0.05). In addition, large differences (up to 5 log(10) copies) in the abundance of FIB genetic markers were observed between animal species, emphasizing the importance of indicator microorganism selection and animal source contribution for future FIB applications. PMID- 22504810 TI - Characterization of the biosynthetic operon for the antibacterial peptide herbicolin in Pantoea vagans biocontrol strain C9-1 and incidence in Pantoea species. AB - Pantoea vagans C9-1 is a biocontrol strain that produces at least two antibiotics inhibiting the growth of Erwinia amylovora, the causal agent of fire blight disease of pear and apple. One antibiotic, herbicolin I, was purified from culture filtrates of P. vagans C9-1 and determined to be 2-amino-3-(oxirane-2,3 dicarboxamido)-propanoyl-valine, also known as N(beta)-epoxysuccinamoyl-DAP valine. A plasposon library was screened for mutants that had lost the ability to produce herbicolin I. It was shown that mutants had reduced biocontrol efficacy in immature pear assays. The biosynthetic gene cluster in P. vagans C9-1 was identified by sequencing the flanking regions of the plasposon insertion sites. The herbicolin I biosynthetic gene cluster consists of 10 coding sequences (CDS) and is located on the 166-kb plasmid pPag2. Sequence comparisons identified orthologous gene clusters in Pantoea agglomerans CU0119 and Serratia proteamaculans 568. A low incidence of detection of the biosynthetic cluster in a collection of 45 Pantoea spp. from biocontrol, environmental, and clinical origins showed that this is a rare trait among the tested strains. PMID- 22504811 TI - Complete sequence analysis of two methanotroph-specific repABC-containing plasmids from Methylocystis sp. strain SC2. AB - The complete nucleotide sequences of two large, low-copy-number plasmids of 229.6 kb (pBSC2-1) and 143.5 kb (pBSC2-2) were determined during assembly of the whole genome shotgun sequences of the methane-oxidizing bacterium Methylocystis sp. strain SC2. The physical existence of the two plasmids in strain SC2 was confirmed by pulsed-field gel electrophoresis followed by Southern hybridization. Both plasmids have a conserved replication module of the repABC system and carry genes involved in their faithful maintenance and conjugation. In addition, they contain genes that might be involved in essential metabolic processes. These include several heavy metal resistance genes and copper transport genes in pBSC2 1 and a complete nitrous oxide reductase operon and a pmoC singleton in pBSC2-2, the latter encoding the PmoC subunit of particulate methane monooxygenase. PMID- 22504812 TI - In vitro functional and immunomodulatory properties of the Lactobacillus helveticus MIMLh5-Streptococcus salivarius ST3 association that are relevant to the development of a pharyngeal probiotic product. AB - The use of proper bacterial strains as probiotics for the pharyngeal mucosa is a potential prophylactic strategy for upper respiratory tract infections. In this context, we characterized in vitro the functional and immunomodulatory properties of the strains Lactobacillus helveticus MIMLh5 and Streptococcus salivarius ST3 that were selected during previous investigations as promising pharyngeal probiotics. In this study, we demonstrated in vitro that strains MIMLh5 and ST3, alone and in combination, can efficiently adhere to pharyngeal epithelial cells, antagonize Streptococcus pyogenes, and modulate host innate immunity by inducing potentially protective effects. In particular, we found that the strains MIMLh5 and ST3 activate U937 human macrophages by significantly inducing the expression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha). Nonetheless, the induction of the anti-inflammatory interleukin-10 (IL-10) by MIMLh5 or ST3 was never lower than that of TNF-alpha, suggesting that these bacteria can potentially exert a regulatory rather than a proinflammatory effect. We also found that the strains MIMLh5 and ST3 induce cyclooxygenase 2 (COX-2) expression and demonstrated that toll-like receptor 2 (TLR-2) participates in the recognition of the strains MIMLh5 and ST3 by U937 cells. Finally, we observed that these microorganisms grow efficiently when cocultured in milk, suggesting that the preparation of a milk-based fermented product containing both MIMLh5 and ST3 can be a practical solution for the administration of these bacteria. In conclusion, we propose the combined use of L. helveticus MIMLh5 and S. salivarius ST3 for the preparation of novel products that display probiotic properties for the pharyngeal mucosa. PMID- 22504814 TI - Prevalence of Clostridium difficile in uncooked ground meat products from Pittsburgh, Pennsylvania. AB - The prevalence of Clostridium difficile in retail meat samples has varied widely. The food supply may be a source for C. difficile infections. A total of 102 ground meat and sausage samples from 3 grocers in Pittsburgh, PA, were cultured for C. difficile. Brand A pork sausages were resampled between May 2011 and January 2012. Two out of 102 (2.0%) meat products initially sampled were positive for C. difficile; both were pork sausage from brand A from the same processing facility (facility A). On subsequent sampling of brand A products, 10/19 samples from processing facility A and 1/10 samples from 3 other facilities were positive for C. difficile. The isolates recovered were inferred ribotype 078, comprising 6 genotypes. The prevalence of C. difficile in retail meat may not be as high as previously reported in North America. When contamination occurs, it may be related to events at processing facilities. PMID- 22504813 TI - Insights into the maturation of hyperthermophilic pyrolysin and the roles of its N-terminal propeptide and long C-terminal extension. AB - Pyrolysin-like proteases from hyperthermophiles are characterized by large insertions and long C-terminal extensions (CTEs). However, little is known about the roles of these extra structural elements or the maturation of these enzymes. Here, the recombinant proform of Pyrococcus furiosus pyrolysin (Pls) and several N- and C-terminal deletion mutants were successfully expressed in Escherichia coli. Pls was converted to mature enzyme (mPls) at high temperatures via autoprocessing of both the N-terminal propeptide and the C-terminal portion of the long CTE, indicating that the long CTE actually consists of the C-terminal propeptide and the C-terminal extension (CTEm), which remains attached to the catalytic domain in the mature enzyme. Although the N-terminal propeptide deletion mutant PlsDeltaN displayed weak activity, this mutant was highly susceptible to autoproteolysis and/or thermogenic hydrolysis. The N-terminal propeptide acts as an intramolecular chaperone to assist the folding of pyrolysin into its thermostable conformation. In contrast, the C-terminal propeptide deletion mutant PlsDeltaC199 was converted to a mature form (mPlsDeltaC199), which is the same size as but less stable than mPls, suggesting that the C terminal propeptide is not essential for folding but is important for pyrolysin hyperthermostability. Characterization of the full-length (mPls) and CTEm deletion (mPlsDeltaC740) mature forms demonstrated that CTEm not only confers additional stability to the enzyme but also improves its catalytic efficiency for both proteineous and small synthetic peptide substrates. Our results may provide important clues about the roles of propeptides and CTEs in the adaptation of hyperthermophilic proteases to hyperthermal environments. PMID- 22504815 TI - Characterization and identification of productivity-associated rhizobacteria in wheat. AB - The rhizosphere is populated by a numerous and diverse array of rhizobacteria, and many impact productivity in largely unknown ways. Here we characterize the rhizobacterial community in a wheat variety categorized according to shoot biomass using 16S rRNA pyrosequencing abundance data. Plants were grown in homogenized field soil under greenhouse conditions, and DNA was extracted and pyrosequenced, resulting in 29,007 quality sequences. Operational taxonomic units (OTUs) that were significantly associated with biomass productivity were identified using an exact test adjusted for the false-discovery rate. The productivity deviation expressed as a percentage of the total mean square for regression (PMSR) was determined for each OTU. Out of 719 OTUs, 42 showed significant positive associations and 39 showed significant negative associations (q value, <=0.05). OTUs with the greatest net positive associations, by genus, were as follows: Duganella, OTU 43 and OTU 3; Janthinobacterium, OTU 278; Pseudomonas, OTU 588; and Cellvibrio, OTU 1847. Those with negative associations were as follows: Bacteria, OTU 273; Chryseobacterium, OTU 508; Proteobacteria, OTU 249; and Enterobacter, OTU 357. Shoot biomass productivity was strongly correlated with the balance between the overall abundances of positive- and negative-productivity-associated OTUs. High-productivity rhizospheres contained 9.2 significant positives for every negatively associated rhizobacterium, while low-productivity rhizospheres showed 2.3 significant negatives for every positively associated rhizobacterium. Overall rhizobacterial community diversity as measured by the Chao1, Shannon, and Simpson indexes was nonlinearly related to productivity, closely fitting a wavelike cubic equation. We conclude that shoot biomass productivity is strongly related to the ratio of positive- to negative productivity-associated rhizobacteria in the rhizosphere. This study identifies significant OTUs composing the productive and unproductive rhizobacterial communities. PMID- 22504816 TI - Shiga toxin-producing Escherichia coli O104:H4: a new challenge for microbiology. AB - In 2011, Germany experienced the largest outbreak with a Shiga toxin-producing Escherichia coli (STEC) strain ever recorded. A series of environmental and trace back and trace-forward investigations linked sprout consumption with the disease, but fecal-oral transmission was also documented. The genome sequences of the pathogen revealed a clonal outbreak with enteroaggregative E. coli (EAEC). Some EAEC virulence factors are carried on the virulence plasmid pAA. From an unknown source, the epidemic strains acquired a lambdoid prophage carrying the gene for the Shiga toxin. The resulting strains therefore possess two different mobile elements, a phage and a plasmid, contributing essential virulence genes. Shiga toxin is released by decaying bacteria in the gut, migrates through the intestinal barrier, and is transported via the blood to target organs, like the kidney. In a mouse model, probiotic bifidobacteria interfered with transport of the toxin through the gut mucosa. Researchers explored bacteriophages, bacteriocins, and low-molecular-weight inhibitors against STEC. Randomized controlled clinical trials of enterohemorrhagic E. coli (EHEC)-associated hemolytic uremic syndrome (HUS) patients found none of the interventions superior to supportive therapy alone. Antibodies against one subtype of Shiga toxin protected pigs against fatal neurological infection, while treatment with a toxin receptor decoy showed no effect in a clinical trial. Likewise, a monoclonal antibody directed against a complement protein led to mixed results. Plasma exchange and IgG immunoadsoprtion ameliorated the condition in small uncontrolled trials. The epidemic O104:H4 strains were resistant to all penicillins and cephalosporins but susceptible to carbapenems, which were recommended for treatment. PMID- 22504817 TI - Diversity and partitioning of bacterial populations within the accessory nidamental gland of the squid Euprymna scolopes. AB - Microbial consortia confer important benefits to animal and plant hosts, and model associations are necessary to examine these types of host/microbe interactions. The accessory nidamental gland (ANG) is a female reproductive organ found among cephalopod mollusks that contains a consortium of bacteria, the exact function of which is unknown. To begin to understand the role of this organ, the bacterial consortium was characterized in the Hawaiian bobtail squid, Euprymna scolopes, a well-studied model organism for symbiosis research. Transmission electron microscopy (TEM) analysis of the ANG revealed dense bacterial assemblages of rod- and coccus-shaped cells segregated by morphology into separate, epithelium-lined tubules. The host epithelium was morphologically heterogeneous, containing ciliated and nonciliated cells with various brush border thicknesses. Hemocytes of the host's innate immune system were also found in close proximity to the bacteria within the tubules. A census of 16S rRNA genes suggested that Rhodobacterales, Rhizobiales, and Verrucomicrobia bacteria were prevalent, with members of the genus Phaeobacter dominating the consortium. Analysis of 454-shotgun sequencing data confirmed the presence of members of these taxa and revealed members of a fourth, Flavobacteria of the Bacteroidetes phylum. 16S rRNA fluorescent in situ hybridization (FISH) revealed that many ANG tubules were dominated by members of specific taxa, namely, Rhodobacterales, Verrucomicrobia, or Cytophaga-Flavobacteria-Bacteroidetes, suggesting symbiont partitioning to specific host tubules. In addition, FISH revealed that bacteria, including Phaeobacter species from the ANG, are likely deposited into the jelly coat of freshly laid eggs. This report establishes the ANG of the invertebrate E. scolopes as a model to examine interactions between a bacterial consortium and its host. PMID- 22504818 TI - Styrene oxide isomerase of Rhodococcus opacus 1CP, a highly stable and considerably active enzyme. AB - Styrene oxide isomerase (SOI) is involved in peripheral styrene catabolism of bacteria and converts styrene oxide to phenylacetaldehyde. Here, we report on the identification, enrichment, and biochemical characterization of a novel representative from the actinobacterium Rhodococcus opacus 1CP. The enzyme, which is strongly induced during growth on styrene, was shown to be membrane integrated, and a convenient procedure was developed to highly enrich the protein in active form from the wild-type host. A specific activity of about 370 U mg(-1) represents the highest activity reported for this enzyme class so far. This, in combination with a wide pH and temperature tolerance, the independence from cofactors, and the ability to convert a spectrum of substituted styrene oxides, makes a biocatalytic application imaginable. First, semipreparative conversions were performed from which up to 760 MUmol of the pure phenylacetaldehyde could be obtained from 130 U of enriched SOI. Product concentrations of up to 76 mM were achieved. However, due to the high chemical reactivity of the aldehyde function, SOI was shown to be the subject of an irreversible product inhibition. A half life of 15 min was determined at a phenylacetaldehyde concentration of about 55 mM, indicating substantial limitations of applicability and the need to modify the process. PMID- 22504819 TI - Dioxygenation of the biphenyl dioxygenation product. AB - Two biphenyl dioxygenases (BphAs) were shown to catalyze dioxygenation of biphenyldienediol in the nonoxidized ring to form the respective symmetrical biphenyl-bis-dienediol. This novel metabolite served as a growth substrate for both BphA source strains. Its catabolism through the upper bph pathway of Burkholderia xenovorans LB400 was analyzed. PMID- 22504820 TI - Diversity of Listeria species in urban and natural environments. AB - A total of 442 Listeria isolates, including 234 Listeria seeligeri, 80 L. monocytogenes, 74 L. welshimeri, 50 L. innocua, and 4 L. marthii isolates, were obtained from 1,805 soil, water, and other environmental samples collected over 2 years from four urban areas and four areas representing natural environments. Listeria spp. showed similar prevalences in samples from natural (23.4%) and urban (22.3%) environments. While L. seeligeri and L. welshimeri were significantly associated with natural environments (P <= 0.0001), L. innocua and L. monocytogenes were significantly associated with urban environments (P <= 0.0001). Sequencing of sigB for all isolates revealed 67 allelic types with a higher level of allelic diversity among isolates from urban environments. Some Listeria spp. and sigB allelic types showed significant associations with specific urban and natural areas. Nearest-neighbor analyses also showed that certain Listeria spp. and sigB allelic types were spatially clustered within both natural and urban environments, and there was evidence that these species and allelic types persisted over time in specific areas. Our data show that members of the genus Listeria not only are common in urban and natural environments but also show species- and subtype-specific associations with different environments and areas. This indicates that Listeria species and subtypes within these species may show distinct ecological preferences, which suggests (i) that molecular source-tracking approaches can be developed for Listeria and (ii) that detection of some Listeria species may not be a good indicator for L. monocytogenes. PMID- 22504821 TI - Identification of the promoter in the intergenic region between orf1 and cry8Ea1 controlled by sigma H factor. AB - Bacillus thuringiensis Cry8Ea toxin is specifically toxic to larvae of the Asian cockchafer, Holotrichia parallela. Here we investigated the mechanism of transcriptional regulation of the cry8Ea1 gene. Reverse transcription-PCR (RT PCR) results indicated that cry8Ea1 and an upstream gene (orf1) were cotranscribed. Transcriptional fusions with the lacZ gene demonstrated that transcription of the cry8Ea1 gene started from two promoters: P(orf1), which is located upstream of the orf1 gene, and P(cry8E), located in the intergenic region mapping between orf1 and cry8Ea1. Of the known, similar orf1-cry operons, this is the first report of the existence of a promoter in the intergenic region between the orf1 and cry genes. The transcriptional activity of P(orf1) was found during sporulation in B. thuringiensis subsp. kurstaki HD-73 and was almost abolished in the sigE mutant, while the transcriptional activity of P(cry8E) was detected after the end of the exponential phase in HD-73 and was considerably lower in the sigH mutant. The transcription start sites generated by the two cry8Ea1 promoters were determined by the 5' -SMARTer rapid amplification of cDNA ends (RACE) method. The -35 and -10 regions of P(orf1) and P(cry8E) showed high sequence similarity with the sigma(E) and sigma(H) promoters, respectively. These results indicated that P(orf1) is controlled by the sigma(E) factor and P(cry8E) by the sigma(H) factor. PMID- 22504822 TI - Historical and recent achievements in the field of microbial degradation of natural and synthetic rubber. AB - This review intends to provide an overview of historical and recent achievements in studies of microbial degradation of natural and synthetic rubber. The main scientific focus is on the key enzymes latex-clearing protein (Lcp) from the Gram positive Streptomyces sp. strain K30 and rubber oxygenase A (RoxA) from the Gram negative Xanthomonas sp. strain 35Y, which has been hitherto the only known rubber-degrading bacterium that does not belong to the actinomycetes. We also emphasize the importance of knowledge of biodegradation in industrial and environmental biotechnology for waste natural rubber disposal. PMID- 22504823 TI - Bactericidal antibiotics do not appear to cause oxidative stress in Listeria monocytogenes. AB - Oxidative stress can be an important contributor to the lethal effect of bactericidal antibiotics in some bacteria, such as Escherichia coli and Staphylococcus aureus. Thus, despite the different target-specific actions of bactericidal antibiotics, they have a common mechanism leading to bacterial self destruction by internal production of hydroxyl radicals. The purpose of the present study was to determine if a similar mechanism is involved in antibiotic killing of the infectious human pathogen, Listeria monocytogenes. We treated wild type L. monocytogenes and oxidative stress mutants (Deltasod and Deltafri) with three different bactericidal antibiotics and found no difference in killing kinetics. In contrast, wild-type E. coli and an oxidative stress mutant (DeltasodA DeltasodB) differed significantly in their sensitivity to bactericidal antibiotics. We conclude that bactericidal antibiotics did not appear to cause oxidative stress in L. monocytogenes and propose that this is caused by its noncyclic tricarboxylic acid (TCA) pathway. Hence, in this noncyclic metabolism, there is a decoupling between the antibiotic-mediated cellular requirement for NADH and the induction of TCA enzyme activity, which is believed to mediate the oxidative stress reaction. PMID- 22504824 TI - Increase in furfural tolerance in ethanologenic Escherichia coli LY180 by plasmid based expression of thyA. AB - Furfural is an inhibitory side product formed during the depolymerization of hemicellulose by mineral acids. Genomic libraries from three different bacteria (Bacillus subtilis YB886, Escherichia coli NC3, and Zymomonas mobilis CP4) were screened for genes that conferred furfural resistance on plates. Beneficial plasmids containing the thyA gene (coding for thymidylate synthase) were recovered from all three organisms. Expression of this key gene in the de novo pathway for dTMP biosynthesis improved furfural resistance on plates and during fermentation. A similar benefit was observed by supplementation with thymine, thymidine, or the combination of tetrahydrofolate and serine (precursors for 5,10 methylenetetrahydrofolate, the methyl donor for ThyA). Supplementation with deoxyuridine provided a small benefit, and deoxyribose was of no benefit for furfural tolerance. A combination of thymidine and plasmid expression of thyA was no more effective than either alone. Together, these results demonstrate that furfural tolerance is increased by approaches that increase the supply of pyrimidine deoxyribonucleotides. However, ThyA activity was not directly affected by the addition of furfural. Furfural has been previously shown to damage DNA in E. coli and to activate a cellular response to oxidative damage in yeast. The added burden of repairing furfural-damaged DNA in E. coli would be expected to increase the cellular requirement for dTMP. Increased expression of thyA (E. coli, B. subtilis, or Z. mobilis), supplementation of cultures with thymidine, and supplementation with precursors for 5,10-methylenetetrahydrofolate (methyl donor) are each proposed to increase furfural tolerance by increasing the availability of dTMP for DNA repair. PMID- 22504826 TI - Cortical thickness parameters for endoscopic browlift fixation. AB - BACKGROUND: Techniques for endoscopic browlift include bony fixation over the lateral frontal region and soft tissue fixation over the temporal region. Although bony fixation over the lateral frontal region is advocated universally, limited information exists about bicortical thickness in this area. OBJECTIVES: The authors provide bicortical thickness measurements between the frontal midline and the most inferior temporal region to assist surgeons in identifying appropriate fixation planes. METHODS: Bicortical thickness was measured in the hemicraniums of 13 female cadavers, along the coronal planes that travel through the anterior border of the mandibular condyles and at the junction of the posterior mandibular condyles and the external auditory meatuses. Measurements began at the midline and coursed laterally at 1-cm intervals. RESULTS: Average cranial thickness along the frontal region ranged from 8.9 +/- 2.4 mm to 6.4 +/- 2.8 mm over the anterior coronal line and 8.8 +/- 2.2 mm to 5.6 +/- 1.8 mm over the posterior line. Average thickness along the temporal region ranged from 5.6 +/- 2.8 mm to 2.8 mm +/- 1.4 mm over the anterior coronal line and 5.1 +/- 1.8 mm to 3.4 +/- 1.4 mm over the posterior line. Minimum thickness was 3.7 mm and 1.3 mm over the frontal and temporal regions, respectively. There was no significant difference between left and right hemicranial thickness. CONCLUSIONS: To avoid violation of the inner cortex during surgery, endoscopic browlift procedures should include measurement of cortical thickness at various fixation points. Bony fixation over the temporal region should be avoided. Minimal bicortical thickness was observed in the lateral frontal region. PMID- 22504825 TI - Semifield testing of a bioremediation tool for atrazine-contaminated soils: evaluating the efficacy on soil and aquatic compartments. AB - The present study evaluated the bioremediation efficacy of a cleanup tool for atrazine-contaminated soils (Pseudomonas sp. ADP plus citrate [P. ADP + CIT]) at a semifield scale, combining chemical and ecotoxicological information. Three experiments representing worst-case scenarios of atrazine contamination for soil, surface water (due to runoff), and groundwater (due to leaching) were performed in laboratory simulators (100 * 40 * 20 cm). For each experiment, three treatments were set up: bioremediated, nonbioremediated, and a control. In the first, the soil was sprayed with 10 times the recommended dose (RD) for corn of Atrazerba and with P. ADP + CIT at day 0 and a similar amount of P. ADP at day 2. The nonbioremediated treatment consisted of soil spraying with 10 times the RD of Atrazerba (day 0). After 7 d of treatment, samples of soil (and eluates), runoff, and leachate were collected for ecotoxicological tests with plants (Avena sativa and Brassica napus) and microalgae (Pseudokirchneriella subcapitata) species. In the nonbioremediated soils, atrazine was very toxic to both plants, with more pronounced effects on plant growth than on seed emergence. The bioremediation tool annulled atrazine toxicity to A. sativa (86 and 100% efficacy, respectively, for seed emergence and plant growth). For B. napus, results point to incomplete bioremediation. For the microalgae, eluate and runoff samples from the nonbioremediated soils were extremely toxic; a slight toxicity was registered for leachates. After only 7 d, the ecotoxicological risk for the aquatic compartments seemed to be diminished with the application of P. ADP + CIT. In aqueous samples obtained from the bioremediated soils, the microalgal growth was similar to the control for runoff samples and slightly lower than control (by 11%) for eluates. PMID- 22504827 TI - First trimester placental volume and three dimensional power doppler ultrasonography in type I diabetic pregnancies. AB - OBJECTIVE: This study aimed to investigate the placental volume and three dimensional (3D) power Doppler vascularization in type I diabetic pregnancies during the first trimester METHODS: 3D-power Doppler ultrasonography of the placenta was performed at 11+0-13+6 weeks in 32 pregnancies complicated by type I diabetes. Placental volume, vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were calculated using a standardized setting. RESULTS: In nine pregnancies, a poor first trimester glycemic control was present as expressed by HbA1c levels >= 7%, whereas in the remaining 23 mothers, the HbA1c concentrations were <7%. No differences were found in the placental volumes of diabetic mothers when compared with reference limits. 3D Doppler placental vascular indices were significantly higher in diabetic mothers (VI delta value 0.99, p=0.0012; FI delta value 0.64, p=0.0008; VFI delta value 1.28, p=0.0039) when compared with reference limits. Pregnancies with HbA1c >= 7% exhibited higher placental vascular indices when compared with diabetic mothers with better glycemic control. CONCLUSIONS: In type I diabetic mothers, placental vascular indices are increased and these modifications are more evident in pregnancies with poor first trimester glycemic control. PMID- 22504828 TI - Sustained telomere length in hepatocytes and cholangiocytes with increasing age in normal liver. AB - Telomeres, a validated biomarker of aging, comprise multiple nucleotide repeats capping chromosomes that shorten with each cell cycle until a critical length is achieved, precipitating cell senescence. Only two previous studies focused on the effect of aging in "normal" liver tissue, but these studies were compromised by small sample size, limited age range, tissue derived from individuals with an increased risk of senescence, and the use of liver homogenates. We developed a robust large-volume, four-color quantitative fluorescent in situ hybridization technique to measure telomere length in large numbers of hepatocytes, Kupffer cells, hepatic stellate cells, CD4-positive and CD8-positive lymphocytes, and cholangiocytes. Following validation against the gold standard (Southern blotting), the technique was applied to normal archived paraffin-embedded liver tissue obtained following reperfusion of implanted donor liver. We studied 73 highly selected donors aged 5-79 years with a short medical illness preceding death and no history of liver disease, reperfusion injury, or steatosis and normal graft function 1-year posttransplantation. Cholangiocytes had significantly longer telomeres compared with all other intrahepatic lineages over a wide age range (P < 0.05). Age-related telomere attrition was restricted to sinusoidal cells (i.e., Kupffer cells [P = 0.0054] and stellate cells [P = 0.0001]). Cholangiocytes and hepatocytes showed no age-related telomere shortening. CONCLUSION: In normal liver and over a broad age range, cholangiocytes have longer telomeres than all other intrahepatic lineages. Age related telomere length decline is restricted to Kupffer cells and stellate cells. PMID- 22504830 TI - Selective formation of twisted intramolecular charge transfer and excimer emissions on 2,7-bis(4-diethylaminophenyl)-fluorenone by choice of solvent. AB - We designed and synthesized a donor-acceptor-donor dye consisting of a 2,7 disubstituted fluorenone with diethylaminophenyl moieties present as strong electron donating groups. Switching between twisted intramolecular charge transfer (TICT) emission and excimer emission was achieved, with no ground state changes, by simply changing the solvent used. In a nonpolar solvent, excimer emission was observed; with increasing polarity, the emission gradually disappeared, and the TICT emission appeared. PMID- 22504829 TI - Dyslipidemia and changes in lipid profiles associated with rheumatoid arthritis and initiation of anti-tumor necrosis factor therapy. AB - OBJECTIVE: To investigate the frequency of lipid testing in clinical practice and to explore the relationship between rheumatoid arthritis (RA), dyslipidemia, and other cardiovascular (CV) risk factors with RA treatment. METHODS: Patients in this retrospective database study were ages >=18 years and had >=2 physician diagnoses for RA or osteoarthritis (OA; comparator group) between March 2004 and March 2008. Outcomes of interest included the percentage of RA and OA patients receiving lipid tests, lipid profiles (total cholesterol, low-density lipoprotein [LDL] cholesterol, and high-density lipoprotein [HDL] cholesterol) of RA versus OA patients, and lipid profiles of RA patients before and after initiation with a tumor necrosis factor (TNF) inhibitor. We used multivariable regression to control potential confounders between the cohorts. RESULTS: Over a median >=2 year followup, fewer RA patients than OA patients had >=1 lipid test (62.0% [95% confidence interval (95% CI) 61.5-62.5] versus 69.8% [95% CI 69.5-70.1]). Mean total cholesterol and LDL cholesterol were each 4 mg/dl lower in the RA cohort (P < 0.0001); HDL cholesterol was similar between the cohorts. Across the RA cohort, 25.2% of patients had suboptimal LDL cholesterol levels (>=130 mg/dl). Among RA patients not receiving lipid-lowering therapy who initiated TNF inhibitor therapy (n = 96), mean total cholesterol and LDL cholesterol increased by 5.4 and 4.0 mg/dl, respectively. CONCLUSION: Patients with RA were less likely to be tested for hyperlipidemia and had more favorable lipid profiles than patients with OA. TNF inhibitor therapy modestly increased all lipid parameters. Additional studies are needed to determine the effect of traditional CV risk factors and inflammation and the impact of biologic agents on CV outcomes in RA patients. PMID- 22504831 TI - Synthesis of 2RS,4RS-1-[2-phenyl-4-[2-(2-trifluromethoxy-phenoxy)-ethyl]-1,3 dioxolan-2-yl-methyl]-1H-1,2,4-triazole derivatives as potent inhibitors of brassinosteroid biosynthesis. AB - Brassinosteroids are important phytohormones that affect many aspects of plant growth and development. In order to manipulate brassinosteroid levels in plant tissues by using specific biosynthesis inhibitors, we have carried out a systemic search for specific inhibitors of brassinosteroid biosynthesis. Synthesis of triazole derivatives based on the ketoconazole scaffold revealed a series of novel brassinosteroid biosynthesis inhibitors (the YCZ series). To explore the structure-activity relationships of this synthetic series, we now report the synthesis of new triazole derivatives with different aromatic structures at position 2 of 1,3-dioxolane skeleton. We found that the variation of aromatic substituent significantly affect the inhibitory potency. Structure-activity relationships studies indicated that 4-chlorophenyl analogue is the most potent inhibitor of BR biosynthesis with an IC50 value approximately 0.12 +/- 0.04 uM, while a bulky biphenyl group exhibited a great negative effect on promoting the inhibitory potency with an IC50 larger than 10 uM. PMID- 22504832 TI - Antiangiogenic polyketides from Peperomia dindygulensis Miq. AB - Two new polyketides: 2Z-(heptadec-12-enyl)-4-hydroxy-3,4,7,8-tetrahydro-2H chromen-5(6H)-one (1) and 2-(heptadec-12-enyl)-5-hydroxy-5,6,7,8 tetrahydrochromen- 4-one (2), together with eleven known compounds: 4-hydroxy-2 [(3,4-methylenedioxy- phenyl)tridecanoyl] cyclohexane-1,3-dione (3), oleiferinone (4), 4-hydroxy-2-[(3,4- methylenedioxyphenyl)undecanoyl]cyclohexane-1,3-dione (5), 4-hydroxy-2-[(11-phenyl- undecanoyl)cyclohexane-1,3-dione (6), proctorione C (7), surinone C (8), 5-hydroxy- 7,8,4'-trimethoxyflavone (9), 5-hydroxy-7,8,3',4' tetramethoxyflavone (10), 5-hydroxy- 7,3',4'-trimethoxyflavone (11), 5,8 dihydroxy-7,3',4'-trimethoxyflavone (12) and cepharanone B (13) were isolated from the whole plant of Peperomia dindygulensis Miq. Their structures were elucidated by spectroscopic methods, including 2D-NMR techniques. Compounds 2, 3, 5 and 8 inhibited human umbilical vein endothelial cell (HUVEC) proliferation and compounds 5 and 8 sharply suppressed HUVEC tube formation. PMID- 22504833 TI - Natural chlorophyll-related porphyrins and chlorins for dye-sensitized solar cells. AB - Natural-chlorophyll-related porphyrins, including (2H, Zn, Cu)-protoporphyrin IX (Por-1) and Zn-mesoporphyrin IX (Por-2), and chlorins, including chlorin e6 (Chl 1), chlorin e4 (Chl-2), and rhodin G7 (Chl-3), have been used in dye-sensitized solar cells (DSSCs). For porphyrin sensitizers that have vinyl groups at the beta positions, zinc coordinated Por-1 gives the highest solar-energy-to-electricity conversion efficiency (h) of up to 2.9%. Replacing the vinyl groups of ZnPor-1 with ethyl groups increases the open-circuit voltage (V(oc)) from 0.61 V to 0.66 V, but decreases the short-circuit current (J(sc)) from 7.0 mA.cm-2 to 6.1 mA.cm 2 and the value of h to 2.8%. Density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations suggest that the higher J(sc) values of Zn-based porphyrin sensitizers result from the favorable electron injection from the LUMO at higher energy levels. In the case of the chlorin sensitizers, the number of carboxyl protons has a large effect on the photovoltaic performance. Chl-2 with two carboxyl protons gives much higher values of J(sc), V(oc), and h than does Chl-1 with three carboxyl protons. Replacing the protons of Chl-1 with sodium ions can substantially improve the photovoltaic performance of Chl-1-based solar cells. Furthermore, the sodium salt of Chl-3 with an aldehyde group at the C7 position shows poorer photovoltaic performance than does the sodium salt of Chl-1 with methyl groups at the C7 position. This is due to the low light-harvesting capability of Chl-3. PMID- 22504834 TI - Expression of multidrug resistance-associated proteins in paediatric soft tissue sarcomas before and after chemotherapy. AB - Expression of multidrug resistance (MDR) proteins is thought to significantly contribute to the different biological/clinical behaviour of soft tissue sarcomas (STS) of various histological types and clinicopathological stages, as they are responsible for active efflux of cytotoxic drugs from tumour cells. We investigated the expression of 3 MDR proteins, i.e., permeability glycoprotein 1 (P-gp), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance 3 (MDR3), in 43 STS specimens from newly-diagnosed paediatric patients, 31 with rhabdomyosarcoma (RMS) and 12 with non-RMS STS. To assess the influence of chemotherapy on STS drug resistance, the number of MDR-associated protein positive cells was determined in 15 patients on both primary lesions before chemotherapy and on residual tumour after chemotherapy. At least one of the MDR associated proteins tested was detected in 84% of primary untreated STS specimens. In these specimens, MRP1 was detected in a high percentage (70%) of the cases, followed by MDR3 in 58% and P-gp in 44%. Many specimens showed co expression of two different MDR proteins. Interestingly, MDR3 was significantly associated with the presence of PAX3/PAX7-FKHR transcripts in RMS (p<0.05). Moreover, expression of MRP1 and MDR3 was significantly more frequent in group III and IV tumours as compared with those of groups I and II (p<0.01). After chemotherapy MRP1, MDR3 and, to a lesser extent, P-gp expression was found to be increased in most of the samples. The frequent expression of these MDR-associated proteins in primary tumour cells before chemotherapy and the increase of their levels after chemotherapy, suggest that these proteins play a pivotal role in conferring drug resistance and in producing therapy-induced differentiation on STS. PMID- 22504835 TI - Protein farnesylation is requisite for mitochondrial fuel-induced insulin release: further evidence to link reactive oxygen species generation to insulin secretion in pancreatic beta-cells. AB - Several lines of recent evidence implicate regulatory roles for reactive oxygen species (ROS) in islet function and insulin secretion. The phagocyte-like NADPH oxidase (Nox2) has recently been shown to be one of the sources of ROS in the signaling events leading to glucose stimulated insulin secretion (GSIS). We recently reported inhibition of glucose- or mitochondrial fuel-induced Nox2 derived ROS by a specific inhibitor of protein farnesyl transferse (FTase; FTI 277), suggesting that activation of FTase might represent one of the upstream signaling events to Nox2 activation. Furthermore, FTase inhibitors (FTI-277 and FTI-2628) have also been shown to attenuate GSIS in INS 832/13 cells and normal rodent islets. Herein, we provide further evidence to suggest that inhibition of FTase either by pharmacological (e.g., FTI-277) or gene silencing (siRNA-FTase) approaches markedly attenuates mitochondrial fuel-stimulated insulin secretion (MSIS) in INS 832/13 cells. Together, our findings further establish a link between nutrient-induced Nox2 activation, ROS generation and insulin secretion in the pancreatic beta-cell. PMID- 22504836 TI - Nanoionic transport and electrochemical reactions in resistively switching silicon dioxide. AB - The mobility of copper ions and redox reactions of Cu at the interface with SiO(2) being directly attributed to the resistive switching effect have been studied by cyclic voltammetry (CV). The electrode kinetics of the Cu(z+)/Cu redox reactions were analyzed suggesting the formation of both Cu(+) and Cu(2+) species. The ion mobility shows an unexpected strong dependence on the ion concentration indicating ion-ion interactions typical for concentrated solution conditions. Based on the standard reduction potentials for Cu(z+)/Cu we identified partial electrochemical redox reactions during oxidation and reduction. The results contribute to a detailed understanding of the resistive switching effect in Cu/SiO(2)/Pt cells and provide insight into electrochemically assisted diffusion of metal cations in oxides in general. PMID- 22504837 TI - Immediate removal of posteriorly dislocated lens fragments through sclerocorneal incision during cataract surgery. AB - AIM: To describe a new method of removing dislocated nuclear fragments smaller than one-fourth the size of the lens nucleus through the sclerocorneal incision made for cataract surgery. METHODS: Dislocated lens nuclear fragments on the surface of the retina were removed from six eyes of six consecutive patients. An anterior vitreous cutter with a 27-gauge chandelier endoilluminator (Twinlight illumination) tied to its sleeve was inserted into the eye through the incision made for cataract surgery and used for core vitrectomy. A fragmatome with another 27-gauge chandelier endoilluminator (Twinlight illumination) fibre was used to grasp and move the larger dislocated nuclear fragments into the anterior chamber where they were divided and removed. RESULTS: All dislocated nuclear fragments were removed through the incision for cataract surgery, and a posterior chamber lens was implanted in each patient without major complications. CONCLUSIONS: The procedure can be used to remove dislocated lens nuclear fragments from the surface of the retina through the incision for cataract surgery. Neither a second surgery, which would require three ports, nor the body of instruments for vitreal surgery are needed with this procedure. PMID- 22504838 TI - Childhood blepharokeratoconjunctivitis: characterising a severe phenotype in white adolescents. AB - BACKGROUND: The syndrome of childhood blepharokeratoconjunctivitis (BKC) is frequently underestimated. While prevalent and aggressive among Indo Pakistani/Middle-Eastern populations, we observe a recalcitrant destructive phenotype in white children/adolescents that persists into early adulthood and may require systemic immunosuppression. METHODS: A cohort of 10 white patients (20 eyes), median age 15.2 (range 6-27) years were identified among 62 patients with BKC attending a tertiary referral centre. Clinical features were graded and lid/conjunctiva swabs were performed, before instituting a hierarchical therapeutic protocol comprising lid hygiene, topical/systemic antibiotics, intensive topical glucocorticoids and systemic immunosuppression. RESULTS: The median duration of symptoms prior to presentation was 4.3 (range 1.2-16.3) years, with 14 eyes (nine patients) demonstrating 360 degrees peripheral corneal vascularisation associated with encroachment/involvement of the visual axis in 10 eyes (six patients). Corneal perforation(s) occurred in three eyes (two patients). Intensive topical glucocorticoids enabled disease control in 10 eyes (seven patients). In six eyes (three patients), persistent active disease necessitated systemic immunosuppression (azathioprine (2), mycophenolate mofetil (1), prednisolone (1)) achieving disease remission within three months with no adverse events reported. CONCLUSIONS: Suboptimal treatment of BKC in white children may permit a progressively destructive sight-threatening phenotype, which may last into adulthood and require immunosuppression. Appropriate aggressive steroid-based and steroid-sparing strategies are vital for disease remission. PMID- 22504839 TI - [Jaffe-Lichtenstein syndrome with acute peripheral facial palsy?]. PMID- 22504840 TI - An algorithm to identify preterm infants in administrative claims data. AB - PURPOSE: To develop and validate an algorithm to identify preterm infants in the absence of birth certificates within Medicaid data. METHODS: Medicaid fee-for service claims data from Florida (FL) and Texas (TX) were linked to vital statistics data for infants who were continuously eligible during the first 3 months following birth or died within that period. Prematurity was defined as less than 34 weeks gestational age. Using FL as exploratory dataset and vital statistics birth data as gold standard, we developed a logistic regression model from diagnostic and procedure codes commonly associated with preterm care, creating a prematurity score for each infant. A score cutoff was selected that maximized sensitivity while maintaining a positive predictive value (PPV) >= 90%. Confirmatory analyses were conducted in the TX datasets. RESULTS: The prevalence of prematurity was 5.2% (95%CI: 5.1-5.2) and 4.5% (95%CI: 4.4-4.6) in FL and TX, respectively. Using only gestational age International Classification of Disease version 9, Clinical Modification (ICD-9-CM) codes (765.20-765.27) associated with inpatient claims achieved sensitivity of 25.7% (FL) and 12.5% (TX), specificity of 99.9% (FL) and (TX), and PPV of 91.7% (FL) and 84.8% (TX). The model had excellent discriminatory validity with a c-statistic of 0.928 (95%CI: 0.925 0.931). The selected cutoff point achieved sensitivity of 52.6%, specificity of 99.8%, and PPV of 91.7% in FL. In TX, sensitivity was 46.8%, specificity was 99.9%, and PPV was 82.2%. CONCLUSION: Identification of prematurity based on gestational age ICD-9-CM codes is not sensitive. The prematurity score has superior construct validity and allows more comprehensive identification of preterm infants in the absence of birth certificates. PMID- 22504842 TI - CD163+ adult xanthogranuloma arising from Merkel cell carcinoma treated with local radiotherapy. PMID- 22504843 TI - Hepatoprotective effects of dieckol-rich phlorotannins from Ecklonia cava, a brown seaweed, against ethanol induced liver damage in BALB/c mice. AB - Alcoholic liver disease, which is one of the most serious liver disorders, has been known to cause by ethanol intake. In the present study, in vivo hepatoprotective effects of dieckol-rich phlorotannins (DRP) from Ecklonia cava, a brown seaweed, on ethanol induced hepatic damage in BALB/c mice liver were investigated. After administration of 5 and 25mg/kg mouse of DRP and 4 g/kg mice ethanol, the body weights and survival rates were increased as compared to the control, which is ethanol-treated group without DRP. The glutamic oxaloacetic transaminase and glutamic pyruvic transaminase levels in the serum were lower than those of the control. DRP exhibited a reduction of the total cholesterol. The lower levels of SOD enzyme and a reduction of the formation of malondialdehyde were occurred in mice fed with 5 and 25mg/kg mouse of DRP. Finally the effect on improvement of fatty liver induced by ethanol was observed by taking out the liver immediately after dissecting the mouse. However, no significant difference was observed on hepatic histopathological changes. In conclusion, this study indicated that DRP could protect liver injury induced by ethanol in vivo. It suggested that DRP possesses the beneficial effect to human against ethanol-induced liver injury. PMID- 22504841 TI - Brain correlates of phasic autonomic response to acupuncture stimulation: an event-related fMRI study. AB - Autonomic nervous system (ANS) response to acupuncture has been investigated by multiple studies; however, the brain circuitry underlying this response is not well understood. We applied event-related fMRI (er-fMRI) in conjunction with ANS recording (heart rate, HR; skin conductance response, SCR). Brief manual acupuncture stimuli were delivered at acupoints ST36 and SP9, while sham stimuli were delivered at control location, SH1. Acupuncture produced activation in S2, insula, and mid-cingulate cortex, and deactivation in default mode network (DMN) areas. On average, HR deceleration (HR-) and SCR were noted following both real and sham acupuncture, though magnitude of response was greater following real acupuncture and inter-subject magnitude of response correlated with evoked sensation intensity. Acupuncture events with strong SCR also produced greater anterior insula activation than without SCR. Moreover, acupuncture at SP9, which produced greater SCR, also produced stronger sharp pain sensation, and greater anterior insula activation. Conversely, acupuncture-induced HR- was associated with greater DMN deactivation. Between-event correlation demonstrated that this association was strongest for ST36, which also produced more robust HR-. In fact, DMN deactivation was significantly more pronounced across acupuncture stimuli producing HR-, versus those events characterized by acceleration (HR+). Thus, differential brain response underlying acupuncture stimuli may be related to differential autonomic outflows and may result from heterogeneity in evoked sensations. Our er-fMRI approach suggests that ANS response to acupuncture, consistent with previously characterized orienting and startle/defense responses, arises from activity within distinct subregions of the more general brain circuitry responding to acupuncture stimuli. PMID- 22504844 TI - A rotaxane-based switchable organocatalyst. PMID- 22504845 TI - A first-principles model for prediction of product dose uniformity based on drug substance particle size distribution. AB - The unit dose uniformity (UDU) of low-dose drug products can be affected by active pharmaceutical ingredient (API) particle size. UDU relative standard deviation increases as the fraction of large API particles increases and/or as the unit dose decreases. Control of API particle size has traditionally been based on the empirical relationship of d(90) and/or d(50) statistics to drug product uniformity. Several articles have been written that have identified a theoretical relationship between these particle size statistics, dose, and the probability of meeting US Pharmacopeial UDU testing criteria (Huang CY, Ku S. 2010. Int J Pharm 383:70-80; Rohrs B, Amidon G, Meury R, Secreast P, King H, Skoug C. 2006. J Pharm Sci 95(5):1049-1059; Huang CY, Ku S. 2010. J Pharm Sci 99:4351-4362; Yalkowsky SH, Bolton S. 1990. Pharm Res 7(9):962-966). However, these theoretical relationships assume a fixed shape for the API particle size distribution (PSD, i.e., lognormal) and do not account for changes in the distribution shape. A more rigorous method for predicting the effect of a given PSD on UDU is to evaluate the contribution of individual particle size bins on UDU variability. The latter approach is taken in this work, and the derivation reveals that the individual contribution of particles size bins can be expressed completely in terms of a single-particle-size statistic, D[6,3]. D[6,3] is therefore a valid predictor of UDU, regardless of the shape of the PSD (e.g., multimodal) and can form the basis of a particle size control strategy for low dose drug products. PMID- 22504846 TI - Angiotensin II AT(2) receptor decreases AT(1) receptor expression and function via nitric oxide/cGMP/Sp1 in renal proximal tubule cells from Wistar-Kyoto rats. AB - BACKGROUND: The renin-angiotensin (Ang) system controls blood pressure, in part, by regulating renal tubular sodium transport. In the kidney, activation of the angiotensin II type 1 (AT(1)) receptor increases renal sodium reabsorption, whereas the angiotensin II type 2 (AT(2)) receptor produces the opposite effect. We hypothesized that the AT(2) receptor regulates AT(1) receptor expression and function in the kidney. METHODS AND RESULTS: In immortalized renal proximal tubule (RPT) cells from Wistar-Kyoto rats, CGP42112, an AT(2) receptor agonist, decreased AT(1) receptor mRNA and protein expression (P < 0.05), as assessed by reverse transcriptase-polymerase chain reaction and immunoblotting. The inhibitory effect of the AT(2) receptor on AT(1) receptor expression was blocked by the AT(2) receptor antagonist, PD123319 (10 (-6)mol/l), the nitric oxide synthase inhibitor N(w)-nitro-L-arginine methyl ester (10(-4) mol/l), or the nitric oxide-dependent soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (10(-5) mol/l), indicating that both nitric oxide and cyclic guanosine monophosphate (cGMP) were involved in the signaling pathway. Furthermore, CGP42112 decreased Sp1 serine phosphorylation and reduced the binding of Sp1 to AT(1) receptor DNA. Stimulation with Ang II (10(-11) mol/l per 30 min) enhanced Na(+)-K(+)-ATPase activity in RPT cells, which was prevented by pretreatment with CGP42112 (10(-7) mol/l per 24 h) (P < 0.05). The above mentioned results were confirmed in RPT cells from AT(2) receptor knockout mice; AT(1) receptor expression and Ang II-stimulated Na-K-ATPase activity were greater in these cells than in RPT cells from wild-type mice (P < 0.05). AT(1)/AT(2) receptors co-localized and co-immunoprecipitated in RPT cells; short-term CGP42112 (10 mol/l per 30 min) treatment increased AT(1)/AT(2) receptor co immunoprecipitation (P < 0.05). CONCLUSIONS: These results indicate that the renal AT(2) receptor, via nitric oxide/cGMP/Sp1 pathway, regulates AT(1 )receptor expression and function, which may be important in the regulation of sodium excretion and blood pressure. PMID- 22504847 TI - Relationship between media-to-lumen ratio of subcutaneous small arteries and wall to-lumen ratio of retinal arterioles evaluated noninvasively by scanning laser Doppler flowmetry. AB - BACKGROUND: Structural alterations of subcutaneous small resistance arteries, as indicated by an increased media-to-lumen ratio, are frequently present in hypertensive and/or diabetic patients, and may represent the earliest alteration observed. Furthermore, media-to-lumen ratio of small arteries evaluated by micromyography has a strong prognostic significance; however, its extensive evaluation is limited by the invasivity of the assessment, since a biopsy of subcutaneous fat is needed. Noninvasive measurement of wall-to-lumen of retinal arterioles using scanning laser Doppler flowmetry (SLDF) has recently been introduced. However, this new technique has not yet been compared to micromyographic measurement, generally considered the gold standard approach. METHODS AND RESULTS: We investigated 40 individuals and patients, 24 of them were hypertensive patients and 16 normotensive individuals. All patients underwent a biopsy of subcutaneous fat during an elective surgical intervention. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph, and media-to-lumen ratio was measured. In addition, an evaluation of wall-to-lumen ratio of retinal arterioles by SLDF was performed (Heidelberg Retina Flowmeter, Heidelberg Engineering). A close correlation was observed between media-to-lumen ratio of subcutaneous small arteries and wall-to-lumen ratio of retinal arterioles (r = 0.76, P < 0.001; P < 0.001, r(2) = 0.57). CONCLUSION: A noninvasive and easily repeatable procedure (intraobserver and interobserver variation coefficient <13%) such as an evaluation of the arterioles in the fundus oculi by SLDF may provide similar information regarding microvascular morphology compared with an invasive, accurate and prognostically relevant micromyographic measurement of media-to-lumen ratio of subcutaneous small arteries. PMID- 22504848 TI - Initial infectious dose dictates the innate, adaptive, and memory responses to influenza in the respiratory tract. AB - Factors from the virus and the host contribute to influenza virus pathogenicity and to the development of immunity. This study thoroughly examined the effects of an initial infectious dose of virus and unveiled new findings concerning the antiviral and inflammatory responses, innate and adaptive immunity, memory responses, and protection against secondary heterologous infection. Our results demonstrated that the initial infectious dose significantly affects the gene expression of antiviral (IFN-beta) and inflammatory (TNF-alpha, IL-6, IL-1beta) cytokines and of enzymes involved in nitrosative/oxidative stress (iNOS, HO-1, NQO1) early in the response to influenza. This response correlated with significantly increased recruitment of innate immune cells into the lungs of infected mice. We showed that this response also alters the subsequent accumulation of activated IFN-gamma(+) CD44(hi) CD62L(lo) influenza-specific CD8(+) T cells into the lungs of infected mice through increased T cell recruiting chemokine gene expression (CCL3, CCL4, CCL5, CXCL10). Furthermore, we demonstrated that the initial infectious dose determines the generation and the distribution of memory CD8(+) T cell subsets without affecting trafficking mechanisms. This impacted on immune protection against heterologous infection. Lastly, we showed that the effects on innate and adaptive immunity were not dependent on influenza strain or on the genetic background of the host. Collectively, our data show for the first time and in detail that the initial infectious dose of influenza determines the development of several aspects of antiviral immunity. This study provides new insights on virus-host interaction in the generation of the global immune response to influenza. PMID- 22504851 TI - Establishing consistency across all regions in a multi-regional clinical trial. AB - In recent years, global collaboration has become a conventional strategy for new drug development. To accelerate the development process and shorten approval time, the design of multi-regional clinical trials (MRCTs) incorporates subjects from many countries/regions around the world under the same protocol. After showing the overall efficacy of a drug in a global trial, one can also simultaneously evaluate the possibility of applying the overall trial results to all regions and subsequently support drug registration in each region. However, most of the recent approaches developed for the design and evaluation of MRCTs focus on establishing criteria to examine whether the overall results from the MRCT can be applied to a specific region. In this paper, we use the consistency criterion of Method 1 from the Japanese Ministry of Health, Labour and Welfare (MHLW) guidance to assess whether the overall results from the MRCT can be applied to all regions. Sample size determination for the MRCT is also provided to take all the consistency criteria from each individual region into account. Numerical examples are given to illustrate applications of the proposed approach. PMID- 22504852 TI - Primary biliary cirrhosis and cancer risk: a systematic review and meta-analysis. AB - Several studies have indicated that primary biliary cirrhosis (PBC) may be associated with increased risk of some cancers, but the results are controversial. We conducted a systematic review of studies to examine the association of PBC with cancer risk by meta-analysis. We searched the PubMed and EMBASE databases for English-language studies published before November 2011. Studies were included if they reported relative risk estimates with 95% confidence intervals (CIs) or related data for the association between PBC and cancer risk. Approximately 16,300 PBC patients from several countries were included in this analysis. Of the 3510 titles identified, 16 publications involving 17 studies meeting the inclusion criteria were included in the meta analysis. Compared with the general population, PBC patients had a significantly higher risk of overall cancer (pooled rate ratio [RR], 1.55; 95% CI, 1.28-1.83) and hepatocellular carcinoma (HCC) (pooled RR, 18.80; 95% CI, 10.81-26.79). For stomach and pancreas cancers, the results of one study that only examined male patients with PBC indicated that PBC patients had increased risk of stomach cancer and pancreatic cancer, whereas the results of other studies of mixed-sex patients showed no significant association. Therefore, despite inconsistent results, the meta-analysis could not be conducted for assessing the association. PBC was not significantly associated with increased risk of other cancers. CONCLUSION: The present systematic review and meta-analysis demonstrate that PBC is closely associated with a greater risk of overall cancer and HCC, but not with other cancers. The data regarding the association between PBC and risks of several cancers need to be further confirmed in future studies. PMID- 22504853 TI - Seasonal exposure of fish to neurotoxic pesticides in an intensive agricultural catchment, Uma-oya, Sri Lanka: linking contamination and acetylcholinesterase inhibition. AB - The annual cultivation pattern in the Uma-oya catchment in Sri Lanka is characterized by Yala and Maha rainfall periods and associated cropping. Two cultivation seasons were compared for pesticide residues: base flow, field drainage, and the runoff and supplementary sediment data for three sites in the catchment. Organophosphate and N-methyl carbamate pesticide analysis confirmed a higher concentration in the Yala season with low-flow conditions. Acetylcholinesterase (AChE) activity was measured by standard spectrometry in the brain, muscle, and eye tissues of three freshwater cyprinid fishes, Garra ceylonensis, Devario malabaricus, and Rasbora daniconius from three study sites during months overlapping two seasons in 2010 (December) and 2011 (July). Baseline AChE data were measured from fish samples from a forested reserve in the Knuckles. A 73% inhibition in muscle AChE activity in G. ceylonensis was associated with intense pesticide exposure months in the Yala season. The AChE inhibition more than 70% in G. ceylonensis eyes in both Yala (76%) and Maha (72.5%) seasons indicates particular sensitivity of eye tissue to inhibitors. The less dramatic AChE inhibition in the eye tissues in D. malabaricus and R. daniconius in both seasons indicates exemplary protective capacity of muscle AChE in fish. The highest inhibition of AChE (up to 60% in brain and up to 56% in muscle AChE activity in R. daniconius and up to 47.8% in brain and up to 64.6% in muscle AChE activity in D. malabaricus) occurred during the Yala season. Tissue AChE activity and physiological activity in fish were correlated. The results collectively indicate that AChE is a consistent biomarker for diffused contaminant exposure in agricultural catchments. PMID- 22504854 TI - When it hurts, a positive attitude may help: association of positive affect with daily walking in knee osteoarthritis. Results from a multicenter longitudinal cohort study. AB - OBJECTIVE: While depressive symptoms and knee pain are independently known to impede daily walking in older adults, it is unknown whether positive affect promotes daily walking. This study investigated this association among adults with knee osteoarthritis (OA) and examined whether knee pain modified this association. METHODS: This study is a cross-sectional analysis of the Multicenter Osteoarthritis Study. We included 1,018 participants (mean +/- SD age 63.1 +/- 7.8 years, 60% women) who had radiographic knee OA and had worn a StepWatch monitor to record their number of steps per day. High and low positive affect and depressive symptoms were based on the Center for Epidemiologic Studies Depression Scale. Knee pain was categorized as present in respondents who reported pain on most days at both a clinic visit and a telephone screening. RESULTS: Compared to respondents with low positive affect (27% of all respondents), those with high positive affect (63%) walked a similar number of steps per day, while those with depressive symptoms (10%) walked less (adjusted beta -32.6 [95% confidence interval (95% CI) -458.9, 393.8] and -579.1 [95% CI -1,274.9, 116.7], respectively). There was a statistically significant interaction of positive affect by knee pain (P = 0.0045). Among the respondents with knee pain (39%), those with high positive affect walked significantly more steps per day (adjusted beta 711.0 [95% CI 55.1, 1,366.9]) than those with low positive affect. CONCLUSION: High positive affect was associated with more daily walking among adults with painful knee OA. Positive affect may be an important psychological factor to consider for promoting physical activity among people with painful knee OA. PMID- 22504855 TI - Impact of simulator training and crew resource management training on final-year medical students' performance in sepsis resuscitation: a randomized trial. AB - BACKGROUND: We developed a 1.5 days crew resource management (CRM) course on situation awareness (SA) to improve the participants' ability to recognise critical situations in crisis scenarios. Objective of the study was to evaluate the influence of the CRM course on SA and medical performance in crisis scenarios and to compare the results with the effects of a purely clinical simulator training. METHODS: Sixty-one final-year medical students, randomized into three groups, took part in a pre-intervention test scenario of septic shock in a patient simulator setting. Medical performance and SA were assessed using a checklist and the Situation Awareness Global Assessment Tool (SAGAT), respectively. All students received a lecture about the sepsis guidelines. The simulator (SIM) group took part in a 1.5-day simulator training on sepsis resuscitation. The CRM group took part in a course on situation awareness. The control group (CG) did not obtain any training. All students accomplished a post intervention test scenario comparable to the pre-intervention scenario. RESULTS: The SAGAT score rose from 10.6+/-2.3 to 11.9+/-1.7 (preintervention vs. postintervention test, P=0.04) in the SIM group, whereas no significant changes could be shown in the CRM group and the control group, respectively. The clinical performance scores in the post-intervention test did not differ from those in the preintervention test. CONCLUSION: Neither the 1.5 days simulator training nor the 1.5 days CRM course did influence the clinical performance scores. SAGAT scores were higher after the simulator training, but not after the CRM training. PMID- 22504856 TI - Sensory evoked potentials and the search for the Holy Grail method to predict the outcome after hypoxic-ischemic coma. PMID- 22504857 TI - Bacterial physiology: From indolence to persistence. PMID- 22504858 TI - Cellular microbiology: Replication comes in all sizes. PMID- 22504859 TI - The first green revolution. AB - This month's Genome Watch describes how analysis of a basal member of the Plantae can inform us about the evolution of photosynthetic eukaryotes. PMID- 22504861 TI - Maternal anxiety and pain during prenatal diagnostic techniques: a prospective study. AB - OBJECTIVE: To explore anxiety and pain felt by women undergoing chorionic villus sampling (CVS) and amniocentesis (AC). METHOD: We prospectively questioned 254 women (67 undergoing CVS, 187 AC) before the procedure on their anxiety, after the procedure on their pain felt, and the support they received or desired. The medical team collected technical information concerning each procedure. RESULTS: The level of anxiety was significantly higher in women undergoing CVS than AC, in those who had received complete information before the procedure, and when indication for the procedure was fetal structural abnormalities. The level of pain was significantly higher in cases of anxious women, those undergoing a CVS rather than AC, those who had undergone invasive prenatal diagnostic procedures in previous pregnancies, in procedures deemed difficult by the operator, and with needle insertion in the lateral part of the uterus. About 30% of women undergoing CVS and 8% of those undergoing AC would have desired some form of pain prevention, mostly with nonpharmacologic therapy. CONCLUSION: Prenatal diagnosis is frequently associated with anxiety and pain. We identified factors that could exacerbate either one. When questioned, patients would desire a nonpharmacologic means for pain prevention. PMID- 22504860 TI - Mathematical models of pancreatic islet size distributions. AB - The islets of Langerhans, ranging in size from clusters of a few cells to several thousand cells, are scattered near large blood vessels. While the beta-cell mass in mammals is proportional to body weight, the size ranges of islets are similar between species with different body sizes, possibly reflecting an optimal functional size. The large range of islet sizes suggests a stochastic developmental process. It is not fully understood how islets develop to reach such size distributions, and how their sizes change under certain physiological and pathological conditions such as development, pregnancy, aging, obesity, and diabetes. The lack of a high-resolution in vivo imaging technique for pancreatic islets implies that the only data available to elucidate the dynamics of islet development are cross-sectional quantifications of islet size distributions. In this review, we infer biological processes affecting islet morphology in the large by examining changes of islet size distributions. Neonatal islet formation and growth is shown as a particular example of developing a mathematical model of islet size distribution. Application of this modeling to elucidate islet changes under other conditions is also discussed. PMID- 22504862 TI - Glucose decreases extracellular adenosine levels in isolated mouse and rat pancreatic islets. AB - The pancreatic islets of Langerhans are responsible for the regulated release of the endocrine hormones insulin and glucagon that participate in the control of glucose homeostasis. Abnormal regulation of these hormones can result in glucose intolerance and lead to the development of diabetes. Numerous efforts have been made to better understand the physiological regulators of insulin and glucagon secretion. One of these regulators is the purine nucleoside, adenosine. Though exogenous application of adenosine has been demonstrated to stimulate glucagon release and inhibit insulin release, the physiological significance of this pathway has been unclear. We used a novel 7 um enzyme-coated electrode biosensor to measure adenosine levels in isolated rodent islets. In the mouse islets, basal adenosine levels in the presence of 3 mM glucose were estimated to be 5.7 +/- 0.6 uM. As glucose was increased, extracellular adenosine diminished. A 10-fold increase of extracellular KCl increased adenosine levels to 16.4 +/- 2.0 uM. This release required extracellular Ca (2+) suggesting that it occurred via an exocytosis-dependent mechanism. We also found that while rat islets were able to convert exogenous ATP into adenosine, mouse islets were unable to do this. Our study demonstrates for the first time the basal levels of adenosine and its inverse relationship to extracellular glucose in pancreatic islets. PMID- 22504863 TI - Management of severe neuropathic cancer pain: an illustrative case and review. AB - Neuropathic cancer pain is common, very disabling and difficult to treat. It can be related to tumor invasion of neural structures and neuronal damage by surgery, chemotherapy and radiation therapy. Adjuvant analgesics are often used with opioids to control neuropathic pain in cancer patients. Methadone, a synthetic opioid with multiple mechanisms of action, is gaining increasing importance as an effective agent in the treatment of cancer related neuropathic pain. This case illustrates the challenges of managing severe pain in a patient with head and neck cancer while undergoing anti-tumor treatment. A review of the adjuvant analgesics and opioids, particularly methadone, in the management of neuropathic pain is also included. PMID- 22504864 TI - Subclinical bulimia predicts conduct disorder in middle adolescent girls. AB - This study investigates the comorbidity and longitudinal associations between self-reported conduct disorder and subclinical bulimia in a community-based sample of Finnish adolescents in a 2-year prospective follow-up study. There are 2070 adolescents who participated in the survey as ninth graders (mean age 15.5) and followed-up 2 years later. The Youth Self-Report Externalizing scale was used to measure conduct disorder and DSM-IV-based questionnaire to measure bulimia. Co occurrence of female conduct disorder and subclinical bulimia was found at ages 15 and 17. Subclinical bulimia among girls at age 15 was a risk factor for conduct disorder at age 17, but conduct disorder at age 15 was not predictive of subclinical bulimia at age 17. The pathway from bulimia to conduct disorder may be suggestive of an association with future borderline personality disorder among girls. PMID- 22504865 TI - Lipophilicity as a determinant of binding of procaine analogs to rat alpha3beta4 nicotinic acetylcholine receptor. AB - Nicotinic acetylcholine receptors (nAChRs) have been studied in detail with regard to their interaction with therapeutic and drug addiction-related compounds. Using a structure-activity approach, we have examined the relationship among the molecular features of a set of eight para-R-substituted N,N [(dimethylamino)ethyl] benzoate hydrochlorides, structurally related to procaine and their affinity for the alpha(3)beta(4) nAChR heterologously expressed in KXalpha3beta4R2 cells. Affinity values (log[1/IC50]) of these compounds for the alpha(3)beta(4) nAChR were determined by their competition with [(3)H]TCP binding. Log(1/IC50) values were analyzed considering different hydrophobic and electronic parameters and those related to molar refractivity. These have been experimentally determined or were taken from published literature. In accordance with literature observations, the generated cross-validated quantitative structure-activity relationship (QSAR) equations indicated a significant contribution of hydrophobic term to binding affinity of procaine analogs to the receptor and predicted affinity values for several local anesthetics (LAs) sets taken from the literature. The predicted values by using the QSAR model correlated well with the published values both for neuronal and for electroplaque nAChRs. Our work also reveals the general structure features of LAs that are important for interaction with nAChRs as well as the structural modifications that could be made to enhance binding affinity. PMID- 22504866 TI - The stereocontrolled total synthesis of spirastrellolide A methyl ester. Expedient construction of the key fragments. AB - Due to a combination of their promising anticancer properties, limited supply from the marine sponge source and their unprecedented molecular architecture, spirastrellolides represent attractive and challenging synthetic targets. A modular strategy for the synthesis of spirastrellolide A methyl ester, which allowed for the initial stereochemical uncertainties in the assigned structure was adopted, based on the envisaged sequential coupling of a series of suitably functionalised fragments; in this first paper, full details of the synthesis of these fragments are described. The pivotal C26-C40 DEF bis-spiroacetal was assembled by a double Sharpless asymmetric dihydroxylation/acetalisation cascade process on a linear diene intermediate, configuring the C31 and C35 acetal centres under suitably mild acidic conditions. A C1-C16 alkyne fragment was constructed by application of an oxy-Michael reaction to introduce the A-ring tetrahydropyran, a Sakurai allylation to install the C9 hydroxyl, and a 1,4-syn boron aldol/directed reduction sequence to establish the C11 and C13 stereocentres. Two different coupling strategies were investigated to elaborate the C26-C40 DEF fragment, involving either a C17-C25 sulfone or a C17-C24 vinyl iodide, each of which was prepared using an Evans glycolate aldol reaction. The remaining C43-C47 vinyl stannane fragment required for introduction of the unsaturated side chain was prepared from (R)-malic acid. PMID- 22504867 TI - Children's experiences of living with juvenile idiopathic arthritis: a thematic synthesis of qualitative studies. AB - OBJECTIVE: To describe the experiences and perspectives of children and adolescents living with juvenile idiopathic arthritis (JIA). METHODS: We conducted a systematic review of qualitative studies that explored the experiences of children living with JIA. We searched electronic databases (to week 2 of July 2011) and reference lists of relevant articles. RESULTS: Twenty seven studies that reported the experiences of more than 542 participants were included. Six major themes were identified: aversion to being different (unrelenting and unpredictable pain, disablement, internal disfigurement, differential treatment, and forced dependency on others); striving for normality (preserving social identity, resourcefulness, sense of community, focus on remission, and mastery over body and pain); stigma and misunderstanding (trivialization of disease, invisible pain, and discrimination); suspension in uncertainty (control versus powerlessness, hope versus disappointment); managing treatment (benefits of taking medicines, respect and involvement in health care, and motivation for physical therapy); and desire for knowledge (medical treatment and advances, lifestyle management). CONCLUSION: JIA disrupts a child's sense of normality and impairs his or her capacity for social participation. Children with JIA have a sense of being misunderstood and stigmatized, and they feel perpetually caught between having hope and control over their bodies and overwhelming pain and despair. To increase their confidence, the ability to manage pain, and their resourcefulness for self-management, children need ongoing information about treatments and lifestyle management, strong social support, community advocacy, and active involvement in their own health decision making. PMID- 22504868 TI - An association study of HFE gene mutation with idiopathic male infertility in the Chinese Han population. AB - Mutations in the haemochromatosis gene (HFE) influence iron status in the general population of Northern Europe, and excess iron is associated with the impairment of spermatogenesis. The aim of this study is to investigate the association between three mutations (C282Y, H63D and S65C) in the HFE gene with idiopathic male infertility in the Chinese Han population. Two groups of Chinese men were recruited: 444 infertile men (including 169 with idiopathic azoospermia) and 423 controls with proven fertility. The HFE gene was detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The experimental results demonstrated that no C282Y or S65C mutations were detected. Idiopathic male infertility was not significantly associated with heterozygous H63D mutation (odds ratio=0.801, 95% confidence interval=0.452-1.421, chi(2)=0.577, P=0.448). The H63D mutation frequency did not correlate significantly with the serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T) levels in infertile men (P=0.896, P=0.404 and P=0.05, respectively). Our data suggest that the HFE H63D mutation is not associated with idiopathic male reproductive dysfunction. PMID- 22504870 TI - The effects of long-term administration of tadalafil on STZ-induced diabetic rats with erectile dysfunction via a local antioxidative mechanism. AB - Type 5 phosphodiesterase inhibitors (PDE5Is) are well known being effective via the nitric oxide and cyclic guanosine monophosphate (NO-cGMP) pathway and are widely used in the treatment of diabetic erectile dysfunction (ED). However, it is unclear whether other pathways may be involved in the treatment of diabetic ED with PDE5Is. The purpose of this study was to clarify the role of antioxidants in diabetic ED treatment through the long-term administration of PDE5Is. Three groups of Sprague-Dawley rats were utilized: Group N, the normal control; Group D, streptozotocin (STZ)-induced diabetic rats as a control; and Group D+T, STZ induced diabetic rats who received oral administration of tadalafil for 8 weeks. Erectile function was assessed by intracavernous pressure (ICP) and mean arterial pressure (MAP) during electrical stimulation of the cavernous nerve before euthanasia. The levels of malondialdehyde (MDA), superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) of cavernous tissue were assessed by biochemical analysis. The morphology of mitochondria was observed by electron microscopy. The ICP/MAP ratio was higher in Group D+T than in Group D (P<0.05). The levels of MDA decreased and the activities of SOD increased in Group D+T in comparison with Group D (P<0.05). The mitochondrial membrane potential level of cavernous tissue in diabetic rats was partially recovered by tadalafil treatment for 8 weeks. The morphology changes of mitochondria were also remarkably ameliorated in Group D+T. Collectively, the long-term administration of tadalafil in diabetic rats partially reduced oxidative stress lesions of the penis via a local antioxidative stress pathway. Long-term dosages of tadalafil given once daily beginning soon after the onset of diabetes may aid in preventing rats from developing diabetic ED. PMID- 22504869 TI - Lifestyle and dietary factors in the prevention of lethal prostate cancer. AB - The prevention of lethal prostate cancer is a critical public health challenge that would improve health and reduce suffering from this disease. In this review, we discuss the evidence surrounding specific lifestyle and dietary factors in the prevention of lethal prostate cancer. We present a summary of evidence for the following selected behavioral risk factors: obesity and weight change, physical activity, smoking, antioxidant intake, vitamin D and calcium, and coffee intake. PMID- 22504871 TI - Small interfering RNA targeting HMGN5 induces apoptosis via modulation of a mitochondrial pathway and Bcl-2 family proteins in prostate cancer cells. AB - We investigated the importance of HMGN5, a nuclear protein that binds to nucleosomes, unfolds chromatin, and affects transcription, in the LNCaP prostate cancer cell line. We also examined the molecular mechanisms that promote apoptosis of LNCaP cells after infection with small interfering RNA (siRNA) targeting HMGN5 (siRNA-HMGN5). The androgen-dependent LNCaP human prostate cancer cells were infected with siRNA-HMGN5. Apoptosis was detected using the Annexin V PE/7-AAD double staining and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assays. Mitochondrial membrane potential was measured by JC-1 staining. HMGN5 and GAPDH mRNA expression were determined using real-time PCR. Bcl-2 and other apoptosis-related protein levels were determined by Western blot analysis. Caspase activity was measured by cleavage of the caspase substrate. Infection with siRNA targeting HMGN5 efficiently and specifically reduced the HMGN5 expression in LNCaP cells. The downregulation of HMGN5 induced remarkable apoptosis of LNCaP cells and resulted in the reduction of mitochondrial membrane potential. The induction of cell apoptosis was accompanied by the upregulation of Bax, the Bax/Bcl-2 ratio and the activation of caspase3. The HMGN5-targeted siRNA was effective in downregulating the expression of HMGN5 in androgen-dependent prostate cancer cells and inducing cell apoptosis via the regulation of a caspase-related mitochondrial pathway and Bcl-2 family proteins. This study suggests that HMGN5 may be a potential molecular target with therapeutic relevance for the treatment of prostate cancer. PMID- 22504872 TI - Clinical features and prognostic factors for patients with bone metastases from prostate cancer. AB - To identify the clinical features and independent predictors of survival in patients with bone metastases from prostate cancer (PCa). We retrospectively analysed 115 PCa patients with bone metastases between 1997 and 2009. The overall survival rate after bone metastases was calculated using the Kaplan-Meier method. The prognostic factors were identified by univariate analysis using a log-rank test and by multivariate analysis using Cox proportional hazards regression models. The follow-up rate was 100%, the follow-up cases during 1, 3 and 5 years were 103, 79 and 55, respectively. The 1-, 3- and 5-year survival rates were 89.1%, 60.9% and 49.8%, respectively, with a median survival time of 48.5 months for patients with bone metastases from PCa. In univariate analysis, age, Gleason score, clinical stage, the number of bone lesions, alkaline phosphatase (ALP) level, invasion of neighbouring organs and non-regional lymph node metastases were correlated with prognosis. By multivariate analysis using Cox regression, ALP level, Gleason score and non-regional lymph node metastases were independent prognostic factors. These prognostic factors will help us to determine the appropriate dose and fraction of radiotherapy for these patients. PMID- 22504873 TI - Active surveillance as a practical strategy to differentiate lethal and non lethal prostate cancer subtypes. AB - Differentiation between lethal and non-lethal prostate cancer subtypes has become a very important issue in avoiding excessive treatment in an era when prostate specific antigen (PSA) screening has reduced the rate of prostate cancer deaths by more than 20%. However, it is difficult to determine the patients who may or may not benefit from immediate treatment interventions at the time of the initial diagnosis. The selection of candidate patients who can postpone immediate treatment and undergo follow-ups with a specific surveillance program, or 'active surveillance,' is a practical way to minimize overtreatment. In this review, the benefits and risks of active surveillance are discussed. Future perspectives, including imaging and new biomarkers for improving the outcomes of active surveillance programs, are also discussed. PMID- 22504874 TI - ETS rearrangements in prostate cancer. AB - Prostate cancer is a clinically and molecularly heterogeneous disease. Understanding the biologic underpinning of prostate cancer is necessary to best determine how biology is associated with the risk of disease progression and how this understanding might provide insight into the development of novel therapeutic approaches. The focus of this review is on the recently identified common ETS and non-ETS gene rearrangements in prostate cancer. Although multiple molecular alterations have been detected in prostate cancer, a basic understanding of gene fusion prostate cancer should help explain the clinical and biologic diversity, providing a rationale for a molecular subclassification of the disease. PMID- 22504876 TI - Prostate cancer risk and aggressiveness associated with the CYP1B1 4326C/G (Leu432Val) polymorphism: a meta-analysis of 2788 cases and 2968 controls. AB - To derive a precise estimation of the associations between the cytochrome P450 1B1 (CYP1B1) 4326C/G variants and prostate cancer (PCa) risk or aggressiveness, a meta-analysis was performed using all eligible published studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association in seven literature studies with 2788 cases and 2968 controls. In the overall analysis, no significant association was found between the CYP1B1 4326C/G polymorphism and PCa risk, but ethnicity subgroup analyses and a case-source analysis revealed significant associations. The 4326G allele showed a significant association with increased PCa risk in Asians (OR=1.52, 95% CI: 1.20-1.92), and significant associations were also observed in a heterozygote comparison (OR=1.40, 95% CI: 1.03-1.89), a homozygote comparison (OR=2.38, 95% CI: 1.31 4.33) and in a dominant genetic model (OR=1.52, 95% CI: 1.14-2.01). Moreover, the 4326G allele was also significantly correlated with an increased risk of sporadic PCa (OR=1.13, 95% CI: 1.04-1.24), and significant associations were observed in a heterozygote comparison (OR=1.16, 95% CI: 1.02-1.33), a homozygote comparison (OR=1.24, 95% CI: 1.03-1.49) and a dominant genetic model (OR=1.19, 95% CI: 1.05 1.34). The overall analyses and all subgroup analyses showed no significant association between the 4326C/G polymorphism and PCa aggressiveness. Our meta analysis showed that CYP1B1 4326G allele is significantly associated with an increased PCa risk in Asians and in sporadic PCa cases. PMID- 22504875 TI - Nuclear morphometry, nucleomics and prostate cancer progression. AB - Prostate cancer (PCa) results from a multistep process. This process includes initiation, which occurs through various aging events and multiple insults (such as chronic infection, inflammation and genetic instability through reactive oxygen species causing DNA double-strand breaks), followed by a multistep process of progression. These steps include several genetic and epigenetic alterations, as well as alterations to the chromatin structure, which occur in response to the carcinogenic stress-related events that sustain proliferative signaling. Events such as evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis are readily observed. In addition, in conjunction with these critical drivers of carcinogenesis, other factors related to the etiopathogenesis of PCa, involving energy metabolism and evasion of the immune surveillance system, appear to be involved. In addition, when cancer spread and metastasis occur, the 'tumor microenvironment' in the bone of PCa patients may provide a way to sustain dormancy or senescence and eventually establish a 'seed and soil' site where PCa proliferation and growth may occur over time. When PCa is initiated and progression ensues, significant alterations in nuclear size, shape and heterochromatin (DNA transcription) organization are found, and key nuclear transcriptional and structural proteins, as well as multiple nuclear bodies can lead to precancerous and malignant changes. These series of cellular and tissue related malignancy-associated events can be quantified to assess disease progression and management. PMID- 22504878 TI - Pivaloylmetals (tBu-COM: M = Li, MgX, K) as equilibrium components. AB - Short-lived pivaloylmetals, (H(3)C)(3)C-COM, were established as the reactive intermediates arising through thermal heterolytic expulsion of O=CtBu(2) from the overcrowded metal alkoxides tBuC(=O)-C(-OM)tBu(2) (M = MgX, Li, K). In all three cases, this fission step is counteracted by a faster return process, as shown through the trapping of tBu-COM by O=C(tBu)-C(CD(3))(3) with formation of the deuterated starting alkoxides. If generated in the absence of trapping agents, all three tBu-COM species "dimerize" to give the enediolates MO-C(tBu)=C(tBu)-OM along with O=CtBu(2) (2 equiv). A common-component rate depression by surplus O=CtBu(2) proves the existence of some free tBu-COM (separated from O=CtBu(2)); but companion intermediates with the traits of an undissociated complex such as tBu-COM & O=CtBu(2) had to be postulated. The slow fission step generating tBu COMgX in THF levels the overall rates of dimerization, ketone addition, and deuterium incorporation. Formed by much faster fission steps, both tBu-COLi and tBu-COK add very rapidly to ketones and dimerize somewhat slower (but still fairly fast, as shown through trapping of the emerging O=CtBu(2) by H(3)CLi or PhCH(2)K, respectively). At first sight surprisingly, the rapid fission, return, and dimerization steps combine to very slow overall decay rates of the precursor Li and K alkoxides in the absence of trapping agents: A detailed study revealed that the fast fission step, generating tBu-COLi in THF, is followed by a kinetic partitioning that is heavily biased toward return and against the product-forming dimerization. Both tBu-COLi and tBu-COK form tBu-CH=O with HN(SiMe(3))(3), but only tBu-COK is basic enough for being protonated by the precursor acyloin tBuC(=O)-C(-OH)tBu(2) . PMID- 22504877 TI - Generation of male germ cells from induced pluripotent stem cells (iPS cells): an in vitro and in vivo study. AB - Recent studies have reported that induced pluripotent stem (iPS) cells from mice and humans can differentiate into primordial germ cells. However, whether iPS cells are capable of producing male germ cells is not known. The objective of this study was to investigate the differentiation potential of mouse iPS cells into spermatogonial stem cells and late-stage male germ cells. We used an approach that combines in vitro differentiation and in vivo transplantation. Embryoid bodies (EBs) were obtained from iPS cells using leukaemia inhibitor factor (LIF)-free medium. Quantitative PCR revealed a decrease in Oct4 expression and an increase in Stra8 and Vasa mRNA in the EBs derived from iPS cells. iPS cell-derived EBs were induced by retinoic acid to differentiate into spermatogonial stem cells (SSCs), as evidenced by their expression of VASA, as well as CDH1 and GFRalpha1, which are markers of SSCs. Furthermore, these germ cells derived from iPS cells were transplanted into recipient testes of mice that had been pre-treated with busulfan. Notably, iPS cell-derived SSCs were able to differentiate into male germ cells ranging from spermatogonia to round spermatids, as shown by VASA and SCP3 expression. This study demonstrates that iPS cells have the potential to differentiate into late-stage male germ cells. The derivation of male germ cells from iPS cells has potential applications in the treatment of male infertility and provides a model for uncovering the molecular mechanisms underlying male germ cell development. PMID- 22504879 TI - Stormwater input of pyrethroid insecticides to an urban river. AB - The American River flows for nearly 50 km through highly urbanized lands surrounding Sacramento, California, USA. Twenty-three streams, drainage canals, or pumping stations discharge urban runoff to the river, with the cumulative effect of nearly doubling the river's flow during rain events. During winter storms, the water column in the most downstream 13-km reach of the river exhibited toxicity to the standard testing species, Hyalella azteca, in 52% of samples, likely because of the pyrethroid insecticide bifenthrin. The compound is heavily used by professional pest controllers, either as a liquid perimeter treatment around homes or as granules broadcast over landscaped areas. It was found in 11 of 12 runoff sources examined, at concentrations averaging five times the H. azteca 96-h EC50. Quantified inputs of bifenthrin should have been sufficient to attain peak concentrations in the river twice those actually observed, suggesting loss by sedimentation of particulates and pesticide adsorption to the substrate and/or vegetation. Nevertheless, observed bifenthrin concentrations in the river were sufficient to cause water column toxicity, demonstrated during six storms studied over three successive winters. Toxicity and bifenthrin concentrations were greatest when river flow was low (<23 m(3) /s) but persisted even at atypically high flows (585 m(3) /s). PMID- 22504881 TI - [Pathological patella fracture]. PMID- 22504880 TI - The rate of charge tunneling through self-assembled monolayers is insensitive to many functional group substitutions. PMID- 22504883 TI - Structure of the c(10) ring of the yeast mitochondrial ATP synthase in the open conformation. AB - The proton pore of the F(1)F(o) ATP synthase consists of a ring of c subunits, which rotates, driven by downhill proton diffusion across the membrane. An essential carboxylate side chain in each subunit provides a proton-binding site. In all the structures of c-rings reported to date, these sites are in a closed, ion-locked state. Structures are here presented of the c(10) ring from Saccharomyces cerevisiae determined at pH 8.3, 6.1 and 5.5, at resolutions of 2.0 A, 2.5 A and 2.0 A, respectively. The overall structure of this mitochondrial c ring is similar to known homologs, except that the essential carboxylate, Glu59, adopts an open extended conformation. Molecular dynamics simulations reveal that opening of the essential carboxylate is a consequence of the amphiphilic nature of the crystallization buffer. We propose that this new structure represents the functionally open form of the c subunit, which facilitates proton loading and release. PMID- 22504882 TI - Antidiabetic phospholipid-nuclear receptor complex reveals the mechanism for phospholipid-driven gene regulation. AB - The human nuclear receptor liver receptor homolog-1 (LRH-1) has an important role in controlling lipid and cholesterol homeostasis and is a potential target for the treatment of diabetes and hepatic diseases. LRH-1 is known to bind phospholipids, but the role of phospholipids in controlling LRH-1 activation remains highly debated. Here we describe the structure of both apo LRH-1 and LRH 1 in complex with the antidiabetic phospholipid dilauroylphosphatidylcholine (DLPC). Together with hydrogen-deuterium exchange MS and functional data, our studies show that DLPC binding is a dynamic process that alters co-regulator selectivity. We show that the lipid-free receptor undergoes previously unrecognized structural fluctuations, allowing it to interact with widely expressed co-repressors. These observations enhance our understanding of LRH-1 regulation and highlight its importance as a new therapeutic target for controlling diabetes. PMID- 22504884 TI - Heterochromatin protein 1 forms distinct complexes to direct histone deacetylation and DNA methylation. AB - DNA methylation, methylation of histone H3 at Lys9 (H3K9me3) and hypoacetylated histones are common molecular features of heterochromatin. Important details of their functions and inter-relationships remain unclear, however. In Neurospora crassa, H3K9me3 directs DNA methylation through a complex containing heterochromatin protein 1 (HP1) and the DNA methyltransferase DIM-2. We identified a distinct HP1 complex, HP1, CDP-2, HDA-1 and CHAP (HCHC), and found that it is responsible for silencing independently of DNA methylation. HCHC defects cause hyperacetylation of centromeric histones, greater accessibility of DIM-2 and hypermethylation of centromeric DNA. Loss of HCHC also causes mislocalization of the DIM-5 H3K9 methyltransferase at a subset of interstitial methylated regions, leading to selective DNA hypomethylation. We demonstrate that HP1 forms distinct DNA methylation and histone deacetylation complexes that work in parallel to assemble silent chromatin in N. crassa. PMID- 22504885 TI - Benchmark selection considerations. AB - Benchmarking with other organizations is an important component in achieving best practice and the highest level of quality patient care. When more than 1 benchmark exists for the same metric, choosing which one to use can be challenging. Considerations are discussed for the selection of the best benchmark to use to ensure that an organization is striving for top performance. PMID- 22504886 TI - Deep phenotyping for precision medicine. AB - In medical contexts, the word "phenotype" is used to refer to some deviation from normal morphology, physiology, or behavior. The analysis of phenotype plays a key role in clinical practice and medical research, and yet phenotypic descriptions in clinical notes and medical publications are often imprecise. Deep phenotyping can be defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The emerging field of precision medicine aims to provide the best available care for each patient based on stratification into disease subclasses with a common biological basis of disease. The comprehensive discovery of such subclasses, as well as the translation of this knowledge into clinical care, will depend critically upon computational resources to capture, store, and exchange phenotypic data, and upon sophisticated algorithms to integrate it with genomic variation, omics profiles, and other clinical information. This special issue of Human Mutation offers a number of articles describing computational solutions for current challenges in deep phenotyping, including semantic and technical standards for phenotype and disease data, digital imaging for facial phenotype analysis, model organism phenotypes, and databases for correlating phenotypes with genomic variation. PMID- 22504887 TI - Molecular markers of adrenocortical tumors. AB - Adrenocortical tumors are common and incidentally discovered in up to 14% of axial imaging studies performed for other indications. Most of these tumors are nonfunctioning but may require removal because of the risk of adrenocortical carcinoma. Unfortunately, most clinical and imaging features are still not accurate enough to allow definitive diagnosis and an increasing number of patients undergo adrenalectomy to exclude a cancer diagnosis. Adrenocortical carcinoma is an aggressive malignancy with no effective therapy for patients with locally advanced and metastatic disease. Studies using new genomic approaches including mRNA, miRNA, methylation, and CGH profiling have identified dysregulated genes and pathways that may have clinical implications in improved molecular diagnosis and prognostication of adrenocortical cancer (ACC). In this review, we highlight recent advances in the molecular diagnosis of adrenocortical tumors. PMID- 22504888 TI - Successful treatment of pigmented dermatofibrosarcoma protuberance on the nasal root with cyberknife radiosurgery. PMID- 22504889 TI - Regulatory role of miR-2909 in cell-mediated immune response. AB - Keeping in view the micromanagement of immune response by micro RNAs, the present study was directed to explore the role of miR-2909 in the differentiation and maturation of T-lymphocytes within the population of normal human peripheral blood mononuclear cells maintained in in vitro culture. The results of such a study revealed that miR-2909 had the inherent capacity to significantly increase Treg (CD4+CD25+Foxp3+) cell population and dominant Th1-type cytokine (especially with decrease in IL-4 level and higher levels of INF-beta and INF-gamma) profile. Based upon these results, we propose that miR-2909 may modulate native immunity in general and help in providing protective immunity against viral infections in particular. PMID- 22504890 TI - A rapidly growing lung mass with air crescent formation. PMID- 22504891 TI - Mesenchymal stem cell therapy in acute lung injury: is it time for a clinical trial? PMID- 22504892 TI - Neuronal responses to an asymmetrical alternating current field can mimic those produced by an imposed direct current field in vitro. AB - The remarkable polarity-dependent growth and anatomical organization of neurons in vitro produced by imposed direct current (DC) voltage gradients (electrical fields; Ef) can be mimicked by another type of electrical cue. This is a properly structured asymmetrical alternating current (AC) electrical field (A-ACEf). Here we provide details on the construction of an AC signal generator in which all components of an AC waveform can be individually controlled. We show that 1) conventional symmetrical AC voltage gradients will not induce growth, guidance, or architectural changes in sympathetic neurons. We also provide the first qualitative and quantitative data showing that an asymmetric AC application can indeed mimic the DC response in chick sympathetic neurons and their growing neurites. This shift in orientation and neuronal anatomy requires dieback of some neurites and the extension of others to produce a preferred orientation perpendicular to the gradient of voltage. Our new results may lead to a noninvasive means to modify nerve growth and organization by magnetic inductive coupling at distance. These data also indicate the possibility of a means to mimic DC-dependent release of drugs or other biologically active molecules from electrically sensitive that can be loaded with these chemical cargos. PMID- 22504893 TI - Parents' preferences for drug treatments in juvenile idiopathic arthritis: a discrete choice experiment. AB - OBJECTIVE: To examine parents' preferences for drug treatments and health outcomes in juvenile idiopathic arthritis (JIA) and identify demographic and health-related factors that significantly impact choice. METHODS: A discrete choice experiment was conducted with 105 parents of children with JIA who were cared for by a rheumatologist at The Hospital for Sick Children in Canada. Attributes evaluated included "drug treatment," "child reported pain from arthritis," "participation in daily activities," "side effects," "days missed from school," and "cost to you." Multinomial logit regression was used to estimate the relative importance of each attribute level and interaction term. RESULTS: Parents made tradeoffs between characteristics of the drug treatments and health outcomes. "Participation in daily activities" was the most important attribute, followed by "child reported pain from arthritis" and "cost to you." Parents of children with longer disease durations had stronger preferences for improved participation in daily activities, whereas parents of older JIA patients had stronger preferences for improved control of pain. CONCLUSION: Parents of children with JIA demonstrated strong preferences for treatments that reduce pain and improve daily functioning regardless of the associated side effects, level of responsibility required for drug administration, and days missed from school. Parents of children with longer disease durations and those who had been prescribed aggressive therapies had a greater preference for treatment effectiveness. These findings support the need for considering parental preferences in decisions regarding the choice of treatment for JIA. PMID- 22504894 TI - Mid-term results after sinutubular junction remodelling with aortic cusp repair. AB - OBJECTIVES: An ascending aortic aneurysm with aortic valve regurgitation (AR) may be treated by sinutubular junction remodelling (STJR) with aortic cusp repair if the root diameter is preserved. We analysed the outcome of STJR with cusp repair. METHODS: Between 1995 and 2010, 1094 patients underwent valve-preserving surgery. Of these, 560 individuals with root replacement, 128 patients with acute aortic dissection and 262 patients with preoperative AR <= II were excluded. The remaining 144 patients (mean age 56.0 +/- 17.0 years, 103 males) underwent STJR +/- cusp repair for ascending aortic aneurysm and AR >= III. In all, sinus dimensions were preserved according to the following criteria: maximum diameter <=42 mm in bicuspid aortic valve (BAV, n = 59) and unicuspid aortic valve (UAV, n = 27), and <=45 mm in tricuspid aortic valves (TAV, n = 58). In BAV, right-left (n = 52) and right-non-coronary (n = 7) cusp fusions were seen. To evaluate the influence of valve morphology, patients were divided into two groups: TAV and non TAV. The patients with non-TAV were younger (P < 0.01) and had less concomitant cardiac surgery (P < 0.01). The mean follow-up was 25.9 +/- 22.0 months. RESULTS: Early mortality was 2.1% (n = 3). The causes of death were cardiac (n = 1), respiratory (n = 1) and mesenteric ischaemia (n = 1). Higher age was the predictor of early mortality by multivariate analysis (P = 0.04, hazard ratio 13.2). Overall 5-year survival was 93.9 +/- 2.9% (TAV, 82.8 +/- 10.2%; non-TAV, 98.5 +/- 1.5%; P = 0.02). Causes of late death were cardiac (n = 1), respiratory (n = 1) and carcinoma (n = 1). Freedom from recurrent AR >= III at 5 years was 80.1 +/- 7.7% (TAV, 97.0 +/- 3.0%; non-TAV, 73.4 +/- 8.7%; P = 0.02). By multivariate analysis, only aortoventricular junction (AVJ) > 28 mm (P < 0.01, hazard ratio 9.7) was a predictor of recurrent AR. Freedom from reoperation at 5 years was 81.9 +/- 7.8% (TAV, 97.0 +/- 3.0%; non-TAV, 76.6 +/- 8.8%; P < 0.05). The causes of reoperation (five re-aortic valve repairs and four valve replacements) were dehiscence of pericardial patch (n = 7) and recurrent cusp prolapse (n = 2). By multivariate analysis, only AVJ > 28 mm was a significant predictor for reoperation (P < 0.01, hazard ratio 11.6). CONCLUSIONS: STJR with cusp repair is a useful technique in patients with an ascending aortic aneurysm and relevant AR. Although the dilated AVJ is a risk of recurrent AR and reoperation, concomitant cusp repair is associated with an acceptable mid-term outcome. PMID- 22504895 TI - The importance of intraoperative fluid balance for the prevention of postoperative acute exacerbation of idiopathic pulmonary fibrosis after pulmonary resection for primary lung cancer. AB - OBJECTIVES: Postoperative acute exacerbation (PAE) of idiopathic pulmonary fibrosis (IPF) is a serious complication that is hard to treat. Therefore, it is important to manage IPF patients in such a way as to avoid PAE. Conversely, the relationship between postoperative acute lung injury and perioperative fluid administration has been reported. Herein, we analyse the perioperative risk factors of PAE of IPF, including fluid management. METHODS: Fifty-two patients diagnosed as having clinical IPF who underwent pulmonary resection (segmentectomy, lobectomy or bilobectomy) for primary lung cancer were analysed retrospectively. Preoperative predictive factors and perioperative management items, especially fluid management, were evaluated. RESULTS: The incidence of PAE of IPF was 13.5% (7 of 52 patients). Six patients (85.7%) died of respiratory failure induced by uncontrollable PAE of IPF. Upon univariate analysis, the amount of the intraoperative fluid infused (ml/kg/h), the intraoperative fluid balance (ml/kg/h) and the preoperative C-reactive protein (CRP) level were found to be significantly higher in IPF patients who developed PAE than in those who did not. A multivariate logistic regression analysis showed that the intraoperative fluid balance and the preoperative CRP were prognostic factors for PAE of IPF [P = 0.026, odds ratio (OR) = 1.312 and P = 0.048, OR = 1.280, respectively]. CONCLUSIONS: To prevent PAE of IPF, intraoperative management that minimizes intravenous fluid administration is essential. Moreover, caution is particularly important in patients with preoperative evidence of inflammation. PMID- 22504896 TI - The effect of morphologic subtype on outcomes following the Sano-Norwood procedure. AB - OBJECTIVES: Controversy exists concerning outcomes of patients with different morphologic subtypes of hypoplastic left heart syndrome undergoing the Norwood procedure, in particular, aortic atresia-mitral stenosis (AA-MS) patients receiving a systemic-pulmonary modified Blalock-Taussig (mBT) shunt. We sought to determine the influence of known risk factors and morphology on early survival in our cohort of Sano-Norwood patients with right ventricle-pulmonary artery (RV-PA) conduits as the source of pulmonary blood flow. METHODS: We studied early survival in patients with Sano-modified Norwood procedures from 2002 to 2010 and included both typical and atypical (including unbalanced atrioventricular canal defect) morphologic variants. We included a comparison group composed of classical Norwood patients with mBT shunts. RESULTS: Of 264 Sano-Norwood patients, 49 had AA-MS and 30 had atypical morphologies. Weight <= 2.5 kg was associated with a poorer 1-year survival (P = 0.0007), though ascending aorta (AscAo) size <2.0 mm was not. We did not observe a difference in 30-day or 1-year Kaplan-Meier (K-M) survival across typical morphologic variants for either a Sano or mBTS group. Atypical variants exhibited a trend towards lower 30-day and 1 year survival in both Sano and mBTS groups though this was not significant. Direct comparison of 30-day K-M survival for Sano versus mBTS in AA-MS patients showed similar outcomes (P = NS). CONCLUSIONS: Use of the RV-PA conduit results in good early survival, even in those with a small AscAo size. Atypical morphologic variants seem to do worse irrespective of the Sano or mBTS group. Further studies will be required to determine conclusively whether the RV-PA shunt confers protective effects in the AA-MS subgroup compared with the mBTS. PMID- 22504897 TI - Haemostatic management in high-risk cardiac surgery: a role of recombinant factor VIIa (NovoSeven RT). PMID- 22504899 TI - Therapeutic apheresis: when things go wrong. AB - Therapeutic apheresis medicine requires in-depth knowledge of physiology, disease mechanisms as well as a thorough understanding of the parameters that can be adjusted in the instrument that are used. We report two cases where critical decision making was crucial during management of patients being treated with therapeutic apheresis. Case 1 involves an adult patient with severe circulating cryoglobulins and Case 2 describes a patient with Waldenstrom's macroglobulinemia and hyperviscosity. Both cases demonstrate the importance of readily available expert supervision of therapeutic apheresis procedures. PMID- 22504900 TI - Synthesis, anti-HIV activity studies, and in silico rationalization of cyclobutane-fused nucleosides. AB - The present work describes some recent approaches to novel 3 oxabicyclo[3.2.0]heptane-type nucleosides structurally similar to the potent anti HIV agent stavudine (d4T). To gain knowledge at the molecular level relevant for further synthetic designs, the lack of activity of these compounds was investigated by computational approaches accounting for three main physiological requirements of anti-HIV nucleosides: their drug-likeness, their activation process, and their subsequent interaction with HIV reverse transcriptase (HIV RT). Our results show that the inclusion of the fused cyclobutane at the 2'- and 3'-positions of the sugar portion provides drug-like compounds. Nonetheless, the presence of this cyclobutane moiety prevents binding orientations consistent with the catalytic activation for at least one of the enzymes known to activate d4T. To the best of our knowledge, this is the first study to explicitly consider the simulation of the entire activation process to rationalize anti-HIV activities. PMID- 22504901 TI - Revisiting concepts of visceral nociception in irritable bowel syndrome. AB - BACKGROUND AND OBJECTIVE: Irritable bowel syndrome (IBS) is a common disorder characterized by abdominal pain related to defecation with a change in bowel habit. Patients with IBS often exhibit increased visceral sensitivity, which can be tested clinically by rectal balloon distension procedures. This paper aims to give an overview of mechanisms involved in visceral hypersensitivity in IBS by reviewing recent literature. DATABASES AND DATA TREATMENT: A literature search in the electronic databases Pubmed and MEDLINE was executed using the search terms 'visceral pain' or 'visceral nociception' or 'visceral hypersensitivity' and 'irritable bowel syndrome.' Both original articles and review articles were considered for data extraction. RESULTS: Recent advances in molecular neurophysiology provide knowledge to better understand the underlying mechanism in pain generation in the human gut, in particular, in IBS patients. Sensitization of peripheral nociceptive afferents, more specifically high threshold afferents, has been proposed as one of the principle mechanism in the development of visceral hypersensitivity. On the other hand, central mechanisms also play an important role. In terms of clinical testing of visceral perception, considerable discrepancies remain, however, across different centres. CONCLUSION: Alterations in the modulatory balance of pro- and antinociceptive central processing of noxious peripheral input may serve as in integrative hypothesis for explaining visceral hypersensitivity in IBS. Nevertheless, it remains troublesome to estimate the contribution of central and peripheral factors in visceral hypersensitivity, posing a challenge in determining effective therapeutic entities. PMID- 22504902 TI - Highly concentrated aqueous dispersions of graphene exfoliated by sodium taurodeoxycholate: dispersion behavior and potential application as a catalyst support for the oxygen-reduction reaction. AB - A high-yielding exfoliation of graphene at high concentrations in aqueous solutions is critical for both fundamental study and future applications. Herein, we demonstrate the formation of stable aqueous dispersions of pristine graphene by using the surfactant sodium taurodeoxycholate under tip sonication at concentrations of up to 7.1 mg mL(-1). TEM showed that about 8% of the graphene flakes consisted of monolayers and 82% of the flakes consisted of less than five layers. The dispersions were stable regardless of freezing (-20 degrees C) or heat treatment (80 degrees C) for 24 h. The concentration could be significantly improved to about 12 mg mL(-1) by vacuum-evaporation of the dispersions at ambient temperature. The as-prepared graphene dispersions were readily cast into conductive films and were also processed to prepare Pt/graphene nanocomposites that were used as highly active electrocatalysts for the oxygen-reduction reaction. PMID- 22504903 TI - Associations between personality changes and nucleus accumbens ablation in opioid addicts. AB - AIM: It has been reported that nucleus accumbens (NAc) lesions can help to prevent relapse in opioid addicts. This article aimed to investigate associations between personality changes and NAc lesions. METHODS: The surgery group consisted of 78 patients who had received bilateral stereotactic lesions of the NAc to treat opioid addiction. Seventy two non-surgery opioid addicts were appropriately paired with the patients of the surgery group as the non-surgery group. All participants were interviewed in person and received urine tests, naloxone provocative tests and hair tests to determine the prevalence of relapse. Eysenck personality questionnaire (EPQ) and the health survey questionnaire (SF-36) were employed to assess personality and functional health, respectively. RESULTS: In the surgery group, 30 participants relapsed, and the non-relapse rate was 61.5% (48/78). Compared with the Chinese normative data, the neuroticism (N) and psychoticism (P) dimensions of the EPQ in the non-surgery group were significantly higher, whereas the lie (L) dimension was significantly lower. There was no significant difference in all dimensions of the EPQ between the surgery group and the Chinese normative data. The N dimension in the relapse group and the L dimension in the surgery group were significantly lower than those of the non-surgery group. The P dimension in the relapse group was significantly higher than that of the non-relapse group. The extraversion (E) dimension was relatively stable between these groups. CONCLUSION: Although the influence of other factors cannot be excluded, it is apparent that surgically induced NAc lesions are associated with lower P and N dimensions for opioid addicts, and a higher P dimension is associated with a tendency to relapse. PMID- 22504904 TI - Celecoxib induces apoptosis and cell-cycle arrest in nasopharyngeal carcinoma cell lines via inhibition of STAT3 phosphorylation. AB - AIM: To investigate the mechanisms underlying the anticancer effect of celecoxib on nasopharyngeal carcinoma (NPC). METHODS: NPC cell lines, HNE1 and CNE1-LMP1, were treated with various concentrations of celecoxib for 48 h. The antiproliferative effect of celecoxib was assessed using MTT assay. Both cell cycle profiles and apoptosis were analyzed using flow cytometry. Western blot was used to measure the levels of signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3(Y705) (pSTAT3(Y705)), COX-2, Survivin, Mcl-1, Bcl-2 and Cyclin D1. RESULTS: Celecoxib (10-75 MUmol/L) inhibited the proliferation of the NPC cell lines in a dose-dependent manner. Celecoxib (25 and 50 MUmol/L) induced apoptosis and cell-cycle arrest at the G(0)/G(1) checkpoint in the NPC cell lines, which was associated with significantly reduced STAT3 phosphorylation. The genes downstream of STAT3 (ie, Survivin, Mcl-1, Bcl-2 and Cyclin D1) were significantly down-regulated after exposure to celecoxib (25 and 50 MUmol/L). CONCLUSION: The anticancer effects of celecoxib on NPC cell lines results from inducing apoptosis and cell cycle arrest, which may be partly mediated through the STAT3 pathway. PMID- 22504906 TI - Exercise intervention may prevent depression. AB - Physical activity is an effective component of depression management. However, the mechanisms by which exercise affects behavioral disorders remain unclear. The present study was conducted to investigate mechanisms by which voluntary exercise ameliorates depression. Plasma cortisol levels and hippocampal monoamine neurotransmitters were measured. Chronic mild stress (CMS) was used to induce depression in a rat model. The rats were allowed to swim for 10 weeks as part of their exercise treatment. Depressive behavior was analyzed using an open-field test and a sucrose consumption test before and after exercise. Serum cortisol levels were measured by radioimmunoassay. The concentrations of monoamine neurotransmitters in the hippocampus were determined using high-performance liquid chromatography with electrochemical detection. The CMS rats showed behavioral improvement after exercise. Compared with the control, serum cortisol levels were significantly increased by CMS. The serotonin, dopamine, and norepinephrine levels in the hippocampi were significantly increased by exercise. These findings indicate that exercise reverses and prevents the decrease in serotonin and noradrenaline, and restores dopamine in the CMS model. PMID- 22504905 TI - Lowering glucose level elevates [Ca2+]i in hypothalamic arcuate nucleus NPY neurons through P/Q-type Ca2+ channel activation and GSK3beta inhibition. AB - AIM: To identify the mechanisms underlying the elevation of intracellular Ca(2+) level ([Ca(2+)](i)) induced by lowering extracellular glucose in rat hypothalamic arcuate nucleus NPY neurons. METHODS: Primary cultures of hypothalamic arcuate nucleus (ARC) neurons were prepared from Sprague-Dawley rats. NPY neurons were identified with immunocytochemical method. [Ca(2+)](i) was measured using fura-2 AM. Ca(2+) current was recorded using whole-cell patch clamp recording. AMPK and GSK3beta levels were measured using Western blot assay. RESULTS: Lowering glucose level in the medium (from 10 to 1 mmol/L) induced a transient elevation of [Ca(2+)](i) in ARC neurons, but not in hippocampal and cortical neurons. The low glucose induced elevation of [Ca(2+)](i) in ARC neurons depended on extracellular Ca(2+), and was blocked by P/Q-type Ca(2+)channel blocker omega-agatoxin TK (100 nmol/L), but not by L-type Ca(2+) channel blocker nifedipine (10 MUmol/L) or N type Ca(2+)channel blocker omega-conotoxin GVIA (300 nmol/L). Lowering glucose level increased the peak amplitude of high voltage-activated Ca(2+) current in ARC neurons. The low-glucose induced elevation of [Ca(2+)](i) in ARC neurons was blocked by the AMPK inhibitor compound C (20 MUmol/L), and enhanced by the GSK3beta inhibitor LiCl (10 mmol/L). Moreover, lowering glucose level induced the phosphorylation of AMPK and GSK3beta, which was inhibited by compound C (20 MUmol/L). CONCLUSION: Lowering glucose level enhances the activity of P/Q type Ca(2+)channels and elevates [Ca(2+)](i) level in hypothalamic arcuate nucleus neurons via inhibition of GSK3beta. PMID- 22504907 TI - The stereocontrolled total synthesis of spirastrellolide A methyl ester. Fragment coupling studies and completion of the synthesis. AB - The spirastrellolides are a novel family of structurally unprecedented marine macrolides which show promising anticancer properties due to their potent inhibition of protein phosphatase 2A. In the preceding paper, a modular strategy for the synthesis of spirastellolide A methyl ester which allowed for the initial stereochemical uncertainties was outlined, together with the synthesis of a series of suitably functionalised fragments. In this paper, the realisation of this synthesis is described. Two alternative coupling strategies were explored for elaborating the C26-C40 DEF bis-spiroacetal fragment: a modified Julia olefination of a C26 aldehyde with a C17-C25 sulfone, and a Suzuki coupling of a C25 trialkylborane with a C17-C24 vinyl iodide, which also required the development of a double hydroboration reaction to install the C23/C24 stereocentres. The latter proved a significantly superior strategy, and was fully optimised to provide a C17 aldehyde which was coupled with a C1-C16 alkyne fragment to afford the C1-C40 carbon framework. The BC spiroacetal was then installed within this advanced intermediate by oxidative cleavage of two PMB ethers with spontaneous spiroacetalisation, which also led to unanticipated deprotection of the C23 TES ether. The ensuing truncated seco-acid was cyclised in high yield to construct the 38-membered macrolactone under Yamaguchi macrolactonisation conditions, suggesting favourable conformational pre organisation. Exhaustive desilylation provided a crystalline macrocyclic pentaol, revealing much about the likely conformation of the macrolactone in solution. Attachment of the remainder of the side chain proved challenging, potentially due to steric hindrance by this macrocycle; an olefin cross-metathesis to install an electrophilic allylic carbonate and subsequent pi-allyl Stille coupling with a C43-C47 stannane achieved this goal. Global deprotection completed the first total synthesis of (+)-spirastrellolide A methyl ester which, following detailed NMR correlation with an authentic sample, validated the full configurational assignment. A series of simplified analogues of spirastrellolide incorporating the C26-C47 region were also prepared by pi-allyl Stille coupling reactions. PMID- 22504908 TI - Preservation of pancreatic islets in cold UW solution before transplantation. AB - Culture of islets prior to transplantation needs to be revisited for maintaining functional islet capacity. This study was conducted to compare cold UW (University of Wisconsin) preservation with conventional culture based on insulin secretory capacity in vitro and in vivo. Islets isolated from Wistar rats were either cultured for 24 h at 37 degrees C in RPMI1640 medium or DMEM containing various concentrations of glucose or preserved for the same period in UW solution or in DMEM solution at 4 degrees C. The islet yield in UW group, but not in other groups, was maintained as comparable with that of fresh islets. Insulin secretory capacity in response to glucose was maintained only in the islets of UW group, but not in other groups. SCID mice given 300 IEQ islets of UW group showed gradual restoration of normoglycemia as found in the mice given freshly isolated islets. Meanwhile, those mice given cultured islets for 24 h at 37 degrees C in RPMI1640 medium showed rapid decrease of blood glucose levels on day 1 followed by relatively elevated levels on day 2, suggesting unstable insulin secretory capacity of islets. Morphological staining with anti-HMGB1 (high mobility group B1) antibody revealed central damage of islets in all culture groups regardless of glucose concentration and in islets of cold DMEM group, whereas those in the UW group were quite intact. These results suggest that cold preservation in UW solution is simple and beneficial in protecting islets morphologically and functionally before transplantation. PMID- 22504909 TI - Lack of "immunological fitness" during fasting in metabolically challenged animals. AB - Subclinical inflammation is frequently associated with obesity. Here, we aim to better define the acute inflammatory response during fasting. To do so, we analyzed representatives of immune-related proteins in circulation and in tissues as potential markers for adipose tissue inflammation and modulation of the immune system. Lipopolysaccharide treatment or high-fat diet led to an increase in circulating serum amyloid (SAA) and alpha1-acid glycoprotein (AGP), whereas adipsin levels were reduced. Mouse models that are protected against diet-induced challenges, such as adiponectin-overexpressing animals or mice treated with PPARgamma agonists, displayed lower SAA levels and higher adip-sin levels. An oral lipid gavage, as well as prolonged fasting, increased circulating SAA concurrent with the elevation of free FA levels. Moreover, prolonged fasting was associated with an increased number of Mac2-positive crown-like structures, an increased capillary permeability, and an increase in several M2-type macrophage markers in adipose tissue. This fasting-induced increase in SAA and M2-type macrophage markers was impaired in metabolically challenged animals. These data suggest that metabolic inflexibility is associated with a lack of "immunological fitness." PMID- 22504910 TI - Testosterone replacement in hypogonadal men alters the HDL proteome but not HDL cholesterol efflux capacity. AB - The effects of androgens on cardiovascular disease (CVD) risk in men remain unclear. To better characterize the relationship between androgens and HDL, we investigated the effects of testosterone replacement on HDL protein composition and serum HDL-mediated cholesterol efflux in hypogonadal men. Twenty-three older hypogonadal men (ages 51-83, baseline testosterone < 280 ng/dl) were administered replacement testosterone therapy (1% transdermal gel) with or without the 5alpha reductase inhibitor dutasteride. At baseline and after three months of treatment, we determined fasting lipid concentrations, HDL protein composition, and the cholesterol efflux capacity of serum HDL. Testosterone replacement did not affect HDL cholesterol (HDL-C) concentrations but conferred significant increases in HDL associated paraoxonase 1 (PON1) and fibrinogen alpha chain (FGA) (P = 0.022 and P = 0.023, respectively) and a decrease in apolipoprotein A-IV (apoA-IV) (P = 0.016). Exogenous testosterone did not affect the cholesterol efflux capacity of serum HDL. No differences were observed between men who received testosterone alone and those who also received dutasteride. Testosterone replacement in older hypogonadal men alters the protein composition of HDL but does not significantly change serum HDL-mediated cholesterol efflux. These effects appear independent of testosterone conversion to dihydrotestosterone. Further research is needed to determine how changes in HDL protein content affect CVD risk in men. PMID- 22504911 TI - Differential signature of fecal microRNAs in patients with pancreatic cancer. AB - The potential value of microRNAs as new biomarkers for pancreatic cancer (PCa) screening was explored in this study. Fecal microRNAs from stool samples obtained from 29 PCa patients, 22 chronic pancreatitis (CP) patients and 13 normal individuals were extracted, and 7 microRNAs (miR-16, miR-21, miR-155, miR-181a, miR-181b, miR-196a and miR-210) were detected. miR-181b and miR-210 discriminated PCa from normal individuals with receiver operating characteristic (ROC) curves and area under curve (AUC-ROC) of 0.745 and 0.772, respectively. There was a significant correlation between miR-196a and the maximum tumor diameter (Spearman r = 0.516, P = 0.041). These findings suggest that fecal microRNAs such as miR 181b and miR-210 may have potential to be used as new biomarkers for PCa screening. PMID- 22504914 TI - H2M: a GP-focused multidisciplinary team for patients living with HIV and hepatitis C. AB - OBJECTIVE: To describe the development and functioning of the HIV and hepatitis C mental health in primary care service (H2M), a multidisciplinary team that works with local general practitioners (GPs) and the St Vincent's Hospital immunology clinic to meet the mental health needs of their patients living with HIV/AIDS and those undergoing interferon-based treatment for hepatitis C. METHOD: The authors describe and review the service, using information from a database of patient characteristics and from a GP satisfaction survey. RESULTS: GP satisfaction with the service was high and participating GPs have increased their knowledge and understanding of their patients' mental health problems. CONCLUSIONS: Over eight years, H2M has become a well utilized and valued specialty team with over 1,200 referrals in that time. Patients with other chronic health conditions, such as diabetes, cardiac and renal disease, could benefit from a similar service model. PMID- 22504913 TI - Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis. AB - Environmental exposures during sensitive windows of development can reprogram normal physiologic responses and alter disease susceptibility later in life in a process known as developmental reprogramming. For example, exposure to the xenoestrogen diethylstilbestrol during reproductive tract development can reprogram estrogen-responsive gene expression in the myometrium, resulting in hyperresponsiveness to hormone in the adult uterus and promotion of hormone dependent uterine leiomyoma. We show here that the environmental estrogens genistein, a soy phytoestrogen, and the plasticizer bisphenol A, differ in their pattern of developmental reprogramming and promotion of tumorigenesis (leiomyomas) in the uterus. Whereas both genistein and bisphenol A induce genomic estrogen receptor (ER) signaling in the developing uterus, only genistein induced phosphoinositide 3-kinase (PI3K)/AKT nongenomic ER signaling to the histone methyltransferase enhancer of zeste homolog 2 (EZH2). As a result, this pregenomic signaling phosphorylates and represses EZH2 and reduces levels of H3K27me3 repressive mark in chromatin. Furthermore, only genistein caused estrogen-responsive genes in the adult myometrium to become hyperresponsive to hormone; estrogen-responsive genes were repressed in bisphenol A-exposed uteri. Importantly, this pattern of EZH2 engagement to decrease versus increase H3K27 methylation correlated with the effect of these xenoestrogens on tumorigenesis. Developmental reprogramming by genistein promoted development of uterine leiomyomas, increasing tumor incidence and multiplicity, whereas bisphenol A did not. These data show that environmental estrogens have distinct nongenomic effects in the developing uterus that determines their ability to engage the epigenetic regulator EZH2, decrease levels of the repressive epigenetic histone H3K27 methyl mark in chromatin during developmental reprogramming, and promote uterine tumorigenesis. PMID- 22504915 TI - New challenges in viral hepatitis. AB - Over the past few decades there has been remarkable progress in viral hepatitis. Beginning with discovery of the viral agents, we now have reliable methods to diagnose and monitor all hepatitis virus infections, as well significant advances in treatment and prevention. Nonetheless, important challenges remain. This supplement to Gut looks forward to the next generation of challenges in the field of viral hepatitis, and this introductory article highlights several key issues. PMID- 22504916 TI - New perspectives in the therapy of chronic hepatitis B. PMID- 22504917 TI - New advances in the molecular biology of hepatitis C virus infection: towards the identification of new treatment targets. AB - Hepatitis C virus (HCV) causes chronic infection in almost 2% of the world's population. If untreated, chronic carriers can develop severe liver disease including fibrosis, cirrhosis and hepatocellular carcinoma. Until recently, hepatitis C was treated with a combination of pegylated interferon and ribavirin, a treatment which was only partially effective and was plagued with side effects. In 2011 two inhibitors of the virally encoded NS3/4 protease have become part of standard therapy, which have improved treatment rates but can exacerbate the problematic side effects. While the addition of these first directly acting antivirals (DAAs) marks a milestone in anti-HCV therapy, new and improved combinations of drugs are desperately needed. New generations of drugs will have to address genetic variability of HCV and issues of viral resistance. Furthermore, combination therapies have to be tailored to effectively cure patient populations that have traditionally been hardest to treat, including patients with cirrhosis, those receiving liver transplants and individuals who are co-infected with HIV or hepatitis B virus. Since the discovery of HCV a plethora of experimental tools have been developed which enabled detailed analysis of various aspects of the viral life cycle and the interaction of HCV with its human host. Such studies have revealed a growing list of targets for therapeutic intervention, some of which will be discussed in this review. PMID- 22504919 TI - HIV and viral hepatitis coinfections: advances and challenges. AB - With a prevalence affecting over 30% of HIV infected patients, coinfection with hepatitis B (HBV) or C (HCV) virus remains one of the most frequent comorbidities in this population, with a significant impact in terms of morbidity and mortality associated with liver disease. Recent findings in the physiopathology of HIV in the liver have confirmed that it may contribute, along with hepatotoxicity of antiretrovirals and the burden of metabolic diseases, to a more rapid progression of liver fibrosis, especially when there is underlying chronic hepatitis coinfection. Both fields of research and clinical appraisal of HBV and HCV coinfection are rapidly evolving and prompt a change in the former paradigms of clinical care and management of chronic hepatic coinfection in the context of HIV. The advent of anti-HCV direct antiviral agents has indeed completely shaken up the treatment guidelines for HCV, and the tricky management of these new agents with antiretrovirals means referring patients to specialised centres. In HBV coinfection, therapeutic options have not changed recently but new challenges have emerged regarding the management of low replicating HBV-DNA in optimally treated patients and long term exposure to antivirals. Finally, the global increase in life expectancy in HIV infected patients has been accompanied in coinfected patients by a higher risk of emergence of end stage liver diseases for which access to orthotopic liver transplantation and innovative procedures such as targeted hepatocellular carcinoma therapies should be facilitated. PMID- 22504918 TI - New direct-acting antiviral agents for the treatment of hepatitis C virus infection and perspectives. AB - Until recently, the standard of care (SOC) for patients with chronic hepatitis C virus (HCV) infection has consisted of a combination of pegylated interferon alpha [corrected] plus ribavirin, administered for 24- to 48-weeks depending on the HCV genotype. The sustained virologic response rate for this SOC has been only about 50% in patients infected with genotype 1 HCV, the most prevalent genotype in Europe and North America. HCV therapy has been revolutionised recently by the approval of two direct-acting antiviral agents (DAA) against the NS3/4A serine protease for use in genotype 1 HCV, the ketoamide inhibitors boceprevir and telaprevir. The novel SOC marks the beginning of an extraordinary new era in HCV therapy. We review this new SOC with an emphasis on practical issues related to protease inhibitors, e.g. prescribing guidelines, futility rules and management of adverse events. We also give a perspective on what to expect in the coming years. Newer DAA with simplified dosing regimens and/or minimal toxicity which, when used in combination, will lead to viral eradication in most if not all CHC patients who undergo treatment. The novel agents in clinical development are paving the way for future interferon-sparing regimens. PMID- 22504920 TI - Management of HBV- and HCV-induced end stage liver disease. AB - Hepatitis B and hepatitis C infections are important causes of end-stage liver disease and primary liver cancer. Successful antiviral treatment prior to the development of cirrhosis will prevent most of the morbidity and mortality associated with those infections. This can be achieved for a high proportion of patients. However, many patients present with end-stage liver disease and ongoing and clinically significant viral replication. Antiviral treatment of HBV can effect recovery of liver function and restores many patients to a state of well compensated cirrhosis. The antiviral treatment of end-stage HCV poses much greater challenges. Interferon remains an essential element of HCV antiviral treatment, but has reduced efficacy and significant toxicity at this stage of cirrhosis. Though yet to be evaluated in the setting of advanced liver disease, the development of direct acting antivirals for HCV offers hope for improved outcomes at this stage of cirrhosis. PMID- 22504921 TI - New insight in the pathobiology of hepatitis B virus infection. AB - Chronic hepatitis B virus (HBV) infection remains a major health burden and the main risk factor for the development of hepatocellular carcinoma worldwide. However, HBV is not directly cytopathic and liver injury appears to be mostly caused by repeated attempts of the host's immune responses to control the infection. Recent studies have shown that the unique replication strategy adopted by HBV enables it to survive within the infected hepatocyte while complex virus host interplays ensure the virus is able to fulfil its replication requirements yet is still able to evade important host antiviral innate immune responses. Clearer understanding of the host and viral mechanisms affecting HBV replication and persistence is necessary to design more effective therapeutic strategies aimed at improving the management of patients with chronic HBV infection to eventually achieve viral eradication. This article focuses on summarising the current knowledge of factors influencing the course of HBV infection, giving emphasis on the use of novel assays and quantitative serological and intrahepatic biomarkers as tools for predicting treatment response and disease progression. PMID- 22504922 TI - The importance of grouping of lymph node stations and rationale of three-field lymphoadenectomy for thoracic esophageal cancer. AB - BACKGROUND AND OBJECTIVES: Although the three-field lymphadenectomy has established as a standard operation for esophageal cancer in Japan, criticism remains due to the lack of randomized controlled trials with a high EBM level. This retrospective study aims to clarify the effectiveness of the three-field lymphadenectomy using the data obtained from 906 consecutive patients with esophageal cancer who underwent R0 esophagectomy with the three-field lymphadenectomy. METHOD: Efficacy Index (EI) was calculated for each lymph node station and grossly cervical, mediastinal, or abdominal dissection field. The values of EI were compared according to main tumor location. RESULTS: Cervical lymph node dissection had high EI in upper and middle thoracic esophageal cancer but it was very small in lower esophageal cancer. Abdominal lymphadenectomy for upper thoracic esophageal cancer had some but limited efficacy only in paracardiac and lesser curvature stations. Cervical lymphadenectomy for lower esophageal cancer showed some but limited efficacy only in cervical paraesophageal stations. CONCLUSION: Our investigation clearly shows the effectiveness and importance of wide range lymph node dissection defined as D3 according to the Japanese N-grouping system for thoracic esophageal cancer. The three-field lymphadenectomy is regarded as a standard procedure for upper and middle thoracic esophageal cancer. PMID- 22504923 TI - Acrosyringeal involvement of palmoplantar lesions of eosinophilic pustular folliculitis. PMID- 22504924 TI - Prevalence and risk factors for intraoperative hypotension during craniotomy for traumatic brain injury. AB - BACKGROUND: Hypotension after traumatic brain injury (TBI) is associated with poor outcomes. However, data on intraoperative hypotension (IH) are scarce and the effect of anesthetic agents on IH is unknown. We examined the prevalence and risk factors for IH, including the effect of anesthetic agents during emergent craniotomy for isolated TBI. METHODS: This is a retrospective cohort study of patients 18 years and above, who underwent emergent craniotomy for TBI at Harborview Medical Center (level 1 trauma center) between October 2007 and January 2010. Demographic, clinical, and radiographic characteristics and hemodynamic and anesthetic data were abstracted from medical and electronic anesthesia records. Hypotension was defined as systolic blood pressure <90 mm Hg. Univariate analyses were performed to compare the clinical characteristics of patients with and without IH, and multiple logistic regression analysis was used to determine independent risk factors for IH. RESULTS: Data abstracted from 113 eligible patients aged 48+/-19 years were analyzed. IH was common (n=73, 65%) but not affected by the choice of anesthetic agent. Independent risk factors for IH were multiple computed tomographic (CT) lesions [adjusted odds ratios (AOR) 19.1; 95% confidence interval (CI), 2.08-175.99; P=0.009], subdural hematoma (AOR 17.9; 95% CI, 2.97-108.10; P=0.002), maximum CT lesion thickness (AOR 1.1; 95% CI, 1.01 1.13; P=0.016), and anesthesia duration (AOR 1.1; 95% CI, 1.01-1.30; P=0.009). CONCLUSIONS: IH was common in adult patients with isolated TBI undergoing emergent craniotomy. The presence of multiple CT lesions, subdural hematoma, maximum thickness of CT lesion, and longer duration of anesthesia increase the risk for IH. PMID- 22504927 TI - Allogeneic stem cell transplantation for elderly patients with myelodysplastic syndrome. AB - Allogeneic hematopoietic stem cell transplantation (SCT) is well accepted as a curative treatment approach for younger patients with myelodysplastic syndrome (MDS) and has become one of the most frequent indications for allogeneic SCT as reported to the Center for International Blood and Marrow Transplant Research. However, MDS patients are usually elderly with a median age of approximately 75 years at diagnosis. Large register studies have confirmed the feasibility of the procedure in elderly MDS patients; and in the register of the European Group for Blood and Marrow Transplantation, one-third of the allogeneic transplant procedures for MDS were performed in 2010 in patients older than 60 years. Despite its curative potential, its role in the treatment of elderly MDS patients is less defined. Because of the inherent complications of the transplantation leading to treatment-related mortality and the risk of relapse, a careful calculation of the benefit for each patient is mandatory, taking into account comorbidities, disease status, donor selection, and effective nontransplant therapies. Prospective multicenter studies are needed to define optimal intensity of the conditioning regimen, timing of transplantation within a treatment algorithm, including drug-based therapies, and posttransplant strategies to reduce the risk of relapse. PMID- 22504926 TI - Control of murine Ly6C(high) monocyte traffic and immunosuppressive activities by atypical chemokine receptor D6. AB - The atypical chemokine receptor D6 is a decoy and scavenger receptor for most inflammatory CC chemokines and prevents the development of exacerbated inflammatory reactions. Here we report that mice lacking D6 expression in the nonhematopoietic compartment have a selective increase in the number of Ly6C(high) monocytes in the circulation and in secondary lymphoid tissues. Under inflammatory conditions, Ly6C(high) monocytes accumulate in increased number in secondary lymphoid organs of D6(-/-) mice in a CCR2-dependent manner. Ly6C(high) monocytes derived from D6(-/-) mice have enhanced immunosuppressive activity, inhibit the development of adaptive immune responses, and partially protect mice from the development of GVHD. Thus, control of CCR2 ligands by D6 regulates the traffic of Ly6C(high) monocytes and controls their immunosuppressive potential. PMID- 22504925 TI - Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. AB - Light-chain (AL) amyloidosis remains incurable despite recent therapeutic advances. Given the activity of the lenalidomide-alkylating agent combination in myeloma, we designed this phase 2 trial of lenalidomide, cyclophosphamide, and dexamethasone in AL amyloidosis. Thirty-five patients, including 24 previously untreated, were enrolled. Nearly one-half of the patients had cardiac stage III disease and 28% had >= 3 organs involved. The overall hematologic response (>= partial response [PR]) rate was 60%, including 40% with very-good partial response or better. Using serum-free light chain for assessing response, 77% of patients had a hematologic response. Organ responses were seen in 29% of patients and were limited to those with a hematologic response. The median hematologic progression-free survival was 28.3 months, and the median overall survival was 37.8 months. Hematologic toxicity was the predominant adverse event, followed by fatigue, edema, and gastrointestinal symptoms. A grade 3 or higher toxicity occurred in 26 patients (74%) including >= grade 3 hematologic toxicity in 16 patients (46%) and >= grade 3 nonhematologic toxicity in 25 patients (71%). Seven patients (20%) died on study, primarily because of advanced disease. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) is an effective combination for treatment of AL amyloidosis and leads to durable hematologic responses as well as organ responses with manageable toxicity. The trial was registered at www.clinicaltrials.gov (NCT00564889). PMID- 22504928 TI - MicroRNA expression in mouse oligodendrocytes and regulation of proteolipid protein gene expression. AB - Overexpression of the major myelin proteolipid protein (PLP) is detrimental to brain development and function and is the most common cause of Pelizaeus Merzbacher disease. microRNA (miRNA), small, noncoding RNAs, have been shown to play critical roles in oligodendrocyte lineage. In this study, we sought to investigate whether miRNAs control PLP abundance. To identify candidate miRNAs involved in this regulation, we have examined differentiation-induced changes in the expression of miRNAs in the oligodendroglial cell line Oli-neu and in enhanced green fluorescent protein positive oligodendrocytes ex vivo. We have identified 145 miRNAs that are expressed in oligodendrocyte cell lineage progression. Dicer1 expression decreases in differentiated oligodendrocytes, and knock down of Dicer1 results in changes in miRNAs similar to those associated with differentiation. To identify miRNAs that control the PLP expression, we have selected miRNAs whose expression is lower in differentiated vs. undifferentiated Oli-neu cells and that have one or more binding site(s) in the PLP 3' untranslated region (3'UTR). The PLP 3'UTR fused to the luciferase gene reduces the activity of the reporter, suggesting that it negatively regulates message stability or translation. Such suppression is relieved by knock down of miR-20a. Overexpression of miR-20a decreases expression of the endogenous PLP in primary oligodendrocytes and of the reporter gene. Deletion or mutation of the putative binding site for miR-20a in the PLP 3'UTR abrogated such effects. Our data indicate that miRNA expression is regulated by Dicer1 levels in differentiated oligodendrocytes and that miR-20a, a component of the cluster that controls oligodendrocyte cell number, regulates PLP gene expression through its 3'UTR. PMID- 22504929 TI - Establishment and characterization of a novel chordoma cell line: CH22. AB - Chordoma is a rare primary malignant bone tumor and there exist only a few established human chordoma cell lines. The scarcity of robust chordoma cell lines has limited the ability to study this tumor. In this report, we describe the establishment of a novel chordoma cell line and characterize its in vitro and in vivo behaviors. The tumor tissue was isolated from a patient with recurrent chordoma of the sacrum. After 6 months in culture, the chordoma cell line, referred here as CH22, was established. Microscopic analysis of two-dimensional culture confirmed that the CH22 cells exhibited a typical vacuolated cytoplasm similar to the well-established chordoma cell line U-CH1. Electron microscopy showed cohesive cells with numerous surface filopodia, pockets of glycogen and aggregates of intermediate tonofilaments in cytoplasm. Three-dimensional culture revealed that the CH22 cells could grow and form clusters by day 8. The MTT assays demonstrated that, compared with sensitive osteosarcoma cell lines, CH22 cells were relatively resistant to conventional chemotherapeutic drugs. Western blotting and immunofluorescence analysis confirmed that the CH22 cells expressed brachyury, vimentin, and cytokeratin. Finally, histological analysis of CH22 xenograft tumor tissues demonstrated the appearance of physaliphorous cells and positive staining of brachyury, cytokeratin, and S100. By CT and MRI, imaging xenografts showed the typical appearances seen in human chordomas. These findings suggest that the established novel human chordoma cell line CH22 and its tumorigenecity in SCID nude mice may serve as an important model for studying chordoma cell biology and the development of new therapeutic modalities. PMID- 22504930 TI - Alveolar concentration and bronchial flux of nitric oxide: two linear modeling methods evaluated in children and adolescents with allergic rhinitis and atopic asthma. AB - OBJECTIVE: Alveolar concentration (C(A)NO) and bronchial flux (J(aw)NO) of nitric oxide (NO) characterize the contributions of peripheral and proximal airways to exhaled NO. Both parameters can be estimated using a two-compartment model if the fraction of NO in orally exhaled air (FE(NO)) is measured at multiple constant expiratory flow rates (V). The aim of this study was to evaluate how departures from linearity influence the estimates of C(A)NO and J(aw)NO obtained with the help of linear regression analysis of the relationships between FE(NO) and 1/V (method P), and between the NO output (V(NO) = FE(NO) * V) and V (method T). Furthermore, differences between patients with atopic asthma (AA) and allergic rhinitis (AR) and between methods P and T were assessed. DESIGN: Measurements of FE(NO) were performed with a chemiluminiscence analyzer at five levels of V ranging from 50 to 250 ml/sec in school children and adolescents with mild to moderate-severe AA treated by inhaled corticosteroids (N = 42) and AR (N = 20). RESULTS: Violation of the linearity condition at V <= 100 ml/sec caused shifts between methods with regard to the partition of exhaled NO into alveolar (C(A)NO: P > T) and bronchial (J(aw)NO: T > P) components. Both methods gave similar results in the linear range of 150-250 ml/sec: The mean ratios P/T and limits of agreement calculated in AA and AR patients were 1.03 (0.49-1.56) and 1.07 (0.55 1.59) for C(A)NO and 1.03 (0.73-1.33) and 0.99 (0.90-1.10) for J(aw)NO, respectively. No significant differences between AA and AR were found in C(A)NO and J(aw)NO calculated in the linear range by the T method {medians (inter quartile ranges): 1.7 ppb (0.9-3.9) vs. 2.3 ppb (0.8-3.7), P = 0.91; 1,800 pl/sec (950-3,560) vs. 1,180 pl/sec (639-1,950), P = 0.061}. However, the flow dependency of the estimates was markedly higher in AA than in AR patients: C(A) NO was decreased 2.8-fold vs. 1.5-fold and J(aw) NO was increased 1.5-fold vs. 1.2-fold in the linear range as compared to the range of 50-250 ml/sec. In both groups, the median standard errors (SE) of the J(aw) NO estimates were similar for the metods P and T and small (<15%) regardless of the range for expiratory flows. The precision of C(A) NO estimates was less in all ranges. For both methods, the SE of the estimates obtained in the range of 150-250 ml/sec exceeded 50% in asthmatics and 30% in AR patients, respectively. The results show that FE(NO) has to be measured at several expiratory flows >=100 ml/sec for the accurate estimation of C(A) NO and J(aw) NO using linear methods P and T in children and adolescents with AA and AR. A stepwise procedure for detecting nonlinearity and evaluating the quality of FE(NO) measurements is suggested. PMID- 22504931 TI - Electrochemistry of nanocrystalline 3C silicon carbide films. AB - Silicon carbide (SiC) films have been used frequently for high-frequency and powder devices but have seldom been applied as the electrode material. In this paper, we have investigated the electrochemical properties of the nanocrystalline 3C-SiC film in detail. A film with grain sizes of 5 to 20 nm shows a surface roughness of about 30 nm. The resistivity of the film is in the range of 3.5-6.2 kOmega cm. In 0.1 M H(2)SO(4) solution, the film has a double-layer capacitance of 30-35 MUF cm(-2) and a potential window of 3.0 V if an absolute current density of 0.1 mA cm(-2) is defined as the threshold. Its electrochemical activity was examined by using redox probes of [Ru(NH(3))(6)](2+/3+) and [Fe(CN)(6)](3-/4-) in aqueous solutions and by using redox probes of quinone and ferrocene in nonaqueous solutions. Diffusion-controlled, quasi-reversible electrode processes were achieved in four cases. The surface chemistry of the nanocrystalline 3C-SiC film was studied by electrochemical grafting with 4 nitrobenzenediazonium salts. The grafting was confirmed by time-of-flight secondary ion mass spectroscopy. All these results confirm that the nanocrystalline 3C-SiC film is promising for use as an electrode material. PMID- 22504932 TI - Impact of cytogenetics risk on outcome after reduced intensity conditioning allo SCT from an HLA-identical sibling for patients with AML in first CR: a report from the acute leukemia working party of EBMT. AB - So far the impact of cytogenetics risk on outcome in the context of reduced intensity conditioning (RIC) allo-SCT has been poorly studied. We have identified 378 AML patients in first CR who underwent RIC allo-SCT from an HLA-matched sibling donor between 2000 and 2007 reported to the European Group for Bone and Marrow Transplantation and for whom detailed cytogenetics data were available (good risk: n=21; intermediate risk: n=304; and poor risk: n=53). With a median follow-up of 24 months (range: 1-93), 2-year non-relapse mortality, relapse rate (RR), leukemia-free survival (LFS) and OS were 14%, 31%, 55% and 61%, respectively. Cytogenetics was significantly associated with RR (good risk: 10%; intermediate risk: 28%; and poor risk: 55% at 2 years, P<0.0001) and LFS (good risk: 64%; intermediate risk: 57%; and poor risk: 38% at 2 years, P=0.003). In a multivariate analysis, RR and LFS were significantly higher and lower, respectively, in the high-risk cytogenetics group (P=0.001, P=0.004) and in patients with a higher WBC at diagnosis (>10 * 10(9)/L) (P<0.001, P=0.004). As documented in the setting of myeloablative allo-SCT, patients with poor cytogenetics had increased RR and decreased LFS after RIC allo-SCT, requiring new prospective strategies to improve results in this subgroup. PMID- 22504934 TI - Dose-escalated radioimmunotherapy as part of reduced intensity conditioning for allogeneic transplantation in patients with advanced high-grade non-Hodgkin lymphoma. AB - A total of 20 patients enrolled in a multicenter phase II dose escalation study of radioimmunotherapy (RIT) using yttrium-90-ibritumomab tiuxetan at two dose levels (22 and 30 MBq/kg) in 10 patients, combined with reduced intensity conditioning (RIC) using fludarabine, melphalan and alemtuzumab followed by allogeneic hematopoietic cell transplantation (HCT) from either matched-related (n=5) or matched-unrelated donors (n=15). Postgrafting immunosuppression with cyclosporine was administered. Diagnoses were diffuse large B-cell lymphoma (n=13), transformed CLL (n=4), blastic mantle cell lymphoma (n=2) and follicular lymphoma grade 3 (n=1). Median age was 51 (range, 29-69) years. All patients were high risk with relapsed/refractory disease or relapse after preceding autologous HCT. Median follow-up of patients alive was 1115 (range, 1006-1252) days. No directly RIT-related toxicities were observed. The cumulative incidence of non relapse mortality was 30%. Incidences of grade II-IV acute and chronic GvHD was 45% and 70%, respectively. Kaplan-Meier estimated 3-year OS and EFS were 20% for both dose levels. In conclusion, dose escalation of RIT and combined use with RIC is feasible with no additional toxicity due to dose escalation. This study is registered on http://clinicaltrials.gov as NCT00302757. PMID- 22504933 TI - Traumeel S in preventing and treating mucositis in young patients undergoing SCT: a report of the Children's Oncology Group. AB - Mucositis can be a serious complication of hematopoietic SCT (HSCT). A previous phase II trial in 32 children undergoing HSCT reported a beneficial effect of the homeopathic remedy Traumeel S. The Children's Oncology Group sought to replicate the results in a multi-institutional trial. The study was an international multi center, double-blind, randomized trial comparing Traumeel with placebo in patients aged 3-25 years undergoing myeloablative HSCT. Traumeel/placebo was started on Day -1 as a five-time daily mouth rinse. Efficacy of the treatment was assessed using the modified Walsh scale for mucositis, scored daily from Day -1 to 20 days after HCST. The main outcome was the sum of Walsh scale scores (area under-the-curve (AUC)) over this period. Other outcomes included narcotic use, days of total parenteral feeding, days of nasogastric feeding and adverse events. In 181 evaluable patients, there was no statistical difference in mucositis (AUC) in the Traumeel group (76.7) compared with placebo (67.3) (P=0.13). There was a trend towards less narcotic usage in the Traumeel patients. No statistically beneficial effect from Traumeel was demonstrated for mucositis. We could not confirm that Traumeel is an effective treatment for mucositis in children undergoing HSCT. PMID- 22504935 TI - A clinician-administered severity rating scale for illness anxiety: development, reliability, and validity of the H-YBOCS-M. AB - BACKGROUND: Clinician-administered measures to assess severity of illness anxiety and response to treatment are few. The authors evaluated a modified version of the hypochondriasis-Y-BOCS (H-YBOCS-M), a 19-item, semistructured, clinician administered instrument designed to rate severity of illness-related thoughts, behaviors, and avoidance. METHODS: The scale was administered to 195 treatment seeking adults with DSM-IV hypochondriasis. Test-retest reliability was assessed in a subsample of 20 patients. Interrater reliability was assessed by 27 interviews independently rated by four raters. Sensitivity to change was evaluated in a subsample of 149 patients. Convergent and discriminant validity was examined by comparing H-YBOCS-M scores to other measures administered. Item clustering was examined with confirmatory and exploratory factor analyses. RESULTS: The H-YBOCS-M demonstrated good internal consistency, interrater and test-retest reliability, and sensitivity to symptom change with treatment. Construct validity was supported by significant higher correlations with scores on other measures of hypochondriasis than with nonhypochondriacal measures. Improvement over time in response to treatment correlated with improvement both on measures of hypochondriasis and on measures of somatization, depression, anxiety, and functional status. Confirmatory factor analysis did not show adequate fit for a three-factor model. Exploratory factor analysis revealed a five-factor solution with the first two factors consistent with the separation of the H-YBOCS-M items into the subscales of illness-related avoidance and compulsions. CONCLUSIONS: H-YBOCS-M appears to be valid, reliable, and appropriate as an outcome measure for treatment studies of illness anxiety. Study results highlight "avoidance" as a key feature of illness anxiety-with potentially important nosologic and treatment implications. PMID- 22504936 TI - Calcium phosphate nanocarriers dual-loaded with bovine serum albumin and ibuprofen: facile synthesis, sequential drug loading and sustained drug release. AB - A simple and green strategy is reported for the preparation, drug loading, and release properties of a drug delivery system consisting of calcium phosphate (CP) nanocarriers dual-loaded with bovine serum albumin (BSA) and hydrophobic drug ibuprofen (IBU). The sequential loading of BSA and IBU in calcium phosphate nanocarriers and in vitro simultaneous release of BSA and IBU are realized and investigated. In this method, BSA, which is used as a model protein drug, is encapsulated in situ in calcium phosphate nanocarriers. Subsequently, the typical hydrophobic drug IBU is loaded in the BSA/CP drug delivery system, forming the IBU/BSA/CP dual drug delivery system. The experiments reveal that the preloaded BSA not only reduces the cytotoxicity of calcium phosphate nanocarriers but also significantly improves the IBU drug loading capacity in calcium phosphate nanocarriers and greatly extends the duration of drug release. Thus, the as prepared IBU/BSA/CP dual drug delivery system is promising for drug delivery applications. PMID- 22504937 TI - Diaminoterephthalate turn-on fluorescence probes for thiols--tagging of recoverin and tracking of its conformational change. AB - Diaminoterephthalates with a maleimide moiety were synthesized and used as fluorescence dyes for sensing thiols. Whereas these "NiWa Blue" dyes showed no emission, the conjugate addition of a thiol to the maleimide group turned on a fluorescence at about 400 nm when irradiating the dye at 338 nm. The neuronal calcium sensor protein recoverin possesses a single cysteine residue at position 39, which reacts with NiWa Blue, and is therefore labeled by a fluorophore with an emission at about 440 nm. In the absence of Ca(2+), irradiation at 280 nm of a tryptophan residue in close proximity to Cys-bound NiWa Blue lead to strong FRET, which was detected by emission of the dye at 440 nm. In the presence of Ca(2+), the protein holds a conformation with distal Trp and Cys residues, thus FRET of irradiated Trp to Cys-bound NiWa Blue was significantly weakened. PMID- 22504938 TI - Evaluation of parotid gland lesions with standard ultrasound, color duplex sonography, sonoelastography, and acoustic radiation force impulse imaging - a pilot study. AB - PURPOSE: To evaluate the impact of standard ultrasound (US), color duplex sonography (CDS), sonoelastography (SE), and acoustic radiation force impulse (ARFI) imaging in the differentiation of parotid gland lesions. MATERIALS AND METHODS: From September 2010 to February 2011, 33 parotid gland lesions of 32 patients were included in this study. Patients underwent high-resolution B-mode US (THI, 9 - 14 MHz), CDS, SE, and ARFI quantification. Then parotidectomy was performed and samples were analyzed by (immuno-) histology. Data was extracted via unpaired t-test and expressed in p-values. RESULTS: There were 12 Wathin's tumors (WT), 11 pleomorphic adenomas (PA), 3 other benign tumors, 3 ductal dilatations, 2 neuroendocrine carcinomas, 1 non-Hodgkin lymphoma, and 1 malignant melanoma metastasis. In B-mode US, acoustic enhancement showed statistical significance between PA and WT (p < 0.005), and CDS determined different vascularization patterns (p < 0.0005). While SE did not visualize any significant difference between PA and WT, ARFI quantification determined different mean values for both entities (p < 0.003). CONCLUSION: B-mode US, CDS, and ARFI quantification distinguish PA from WT. The predictive value of the modern techniques for the differentiation of benign and malignant parotid lesions has to be assessed in a larger series. PMID- 22504939 TI - Gastrointestinal wall thickness measured with transabdominal ultrasonography and its relationship to demographic factors in healthy subjects. AB - PURPOSE: To describe the gastrointestinal (GI) wall thickness and the thickness of individual wall layers in healthy subjects using ultrasound and to determine whether demographic factors, the ultrasound transducer frequency, or a fasting state influences these measurements. MATERIALS AND METHODS: After overnight fasting, the GI wall thickness and wall layers were measured in several regions with transabdominal, high-frequency ultrasound. 122 healthy subjects aged 23 - 79 were included. All measurements were performed with both 8 and 12-MHz transducers except for the rectum measurement (4 MHz). 23 patients were given a 300 Kcal test meal and re-examined after 30 minutes. RESULTS: Wall thickness measurements of the GI tract with transabdominal ultrasonography are dependent on transducer frequency (p < 0.001), weight (p < 0.001) and age (p < 0.018). The thickness of individual wall layers in the ileum and the sigmoid colon was found to be dependent on both age (p = 0.007) and weight (p < 0.001). The mean wall thickness from the jejunum to the sigmoid colon ranged from 0.9 to 1.2 mm with standard deviations (SD) of 0.3 mm or less. The mean (SD) was 2.9 (0.8) mm in the gastric antrum, 1.6 (0.3) mm in the duodenum, and 2.1 (0.5) mm in the rectum. The gastric antrum was thinner and the ileum and sigmoid colon were thicker after the test meal (p < 0.05). CONCLUSION: GI wall thickness depends on weight and age. Provided adequate measurement, an abnormal GI wall should be suspected if the thickness exceeds 2 mm except for in the gastric antrum, duodenum and rectum. Reference values for wall thickness can be used regardless of fasting state or probe frequency except for in the gastric antrum. PMID- 22504940 TI - N-heterocyclic carbene-catalyzed cascade annulation reaction of o vinylarylaldehydes with nitrosoarenes: one-step assembly of functionalized 2,3 benzoxazin-4-ones. AB - The NHC-catalyzed reactions of ortho electron-deficient vinyl substituted arylaldehydes with nitrosoarenes were studied. The reactions produced multifunctional 2,3-benzoxazin-4-ones in good to excellent yields via a cascade aza-benzoin reaction between aldehyde and nitroso groups followed by an intramolecular oxo-Michael addition. The resulting 1-acetate substituted 2,3 benzoxazinones were transformed into a new type of beta-hydroxycarboxylate derivatives or 3-oxo-1-isobenzofuranacetates, respectively, under different reductive conditions. This work not only provides a simple and efficient method for the construction of multifunctional 2,3-benzoxazin-4-ones of potential pharmacological interest, but also expands the application of NHC-catalyzed cascade reactions in the formation of carbon-heteroatom and heteroatom-heteroatom bonds. PMID- 22504941 TI - Mitochondrial genome sequencing of chondrocytes in osteoarthritis by human mitochondria RT2 ProfilerTM PCR array. AB - Mitochondria are not only the main energy generators of the cell, but also mediate several critical biochemical processes such as apoptosis, proliferation and redox homeostasis. As such, mitochondrial dysfunctions can lead to a wide variety of human diseases, including cancer and osteoarthritis (OA). In OA, mitochondrial-associated signaling has been implicated in the molecular events leading to cartilage degradation, including oxidative stress, defective chondrocyte biosynthesis and growth responses, increased cytokine-induced chondrocyte inflammation and matrix catabolism, cartilage matrix calcification and increased chondrocyte apoptosis. Thus, the mitochondrial genome represents an attractive target for molecular therapy and OA research has focused on determining its role in chondrocyte metabolism and subsequent cartilage degradation. In this study, we analyzed the mitochondrial gene expression changes that characterize chondrocytes in OA using the Human Mitochondria RT2 ProfilerTM PCR Array. Twenty-six differentially expressed genes were identified that discriminated chondrocytes in OA from those in normal cartilage, including 17 upregulated and 9 downregulated genes. These genes represent diverse functional categories, including mitochondrial membrane polarization and potential, mitochondrial transport, small molecule transport, targeting proteins to the mitochondria, mitochondrial protein import, outer and inner membrane translocation, mitochondrial fission and fusion, mitochondrial localization and apoptosis. Western blot analysis confirmed that the p53 upregulated modulator of apoptosis (PUMA; encoded by the BB3 gene) was significantly upregulated in OA cartilage. In conclusion, our study generates a differential mitochondrial gene expression profile for chondrocytes in OA and demonstrates that mitochondrial genome dysregulation occurs in cartilage cells during OA. Finally, our results indicate that PUMA may be a new diagnostic and therapeutic target for OA. PMID- 22504942 TI - Retinoids reduce formation of keratin aggregates in heat-stressed immortalized keratinocytes from an epidermolytic ichthyosis patient with a KRT10 mutation*. AB - Epidermolytic ichthyosis (EI) is an autosomal dominant epidermal skin fragility disorder caused by mutations in keratin 1 and 10 (K1 and K10) genes. Mutated keratins form characteristic aggregates in vivo and in vitro. Some patients benefit from retinoid therapy, although the mechanism is not fully understood. Our aim was to demonstrate whether retinoids affect the formation of keratin aggregates in immortalized EI cells in vitro. EI keratinocytes were seeded on cover slips, pre-treated or not with retinoids, heat-stressed, and keratin aggregate formation monitored. K10 aggregates were detected in 5% of cells in the resting state, whereas heat stress increased this proportion to 25%. When cells were pre-incubated with all-trans-retinoic acid (ATRA) or retinoic acid receptor (RAR)-alpha agonists the aggregates decreased in a dose-dependent manner. Furthermore, ATRA decreased the KRT10 transcripts 200-fold as well as diminished the ratio of mutant to wild-type transcripts from 0.41 to 0.35, thus providing a plausible rational for retinoid therapy of EI due to K10 mutations. PMID- 22504943 TI - Primary cardiac lymphoma causing coronary vasospasm. PMID- 22504944 TI - Prediction of left ventricular ejection fraction 6 months after surgical correction of organic mitral regurgitation: the value of exercise echocardiography and deformation imaging. AB - AIMS: Left ventricular (LV) end-systolic diameter and LV ejection fraction (LVEF) are correlated with postoperative LVEF and prognosis in patients with organic mitral regurgitation (MR). However, in some patients, the LVEF does not return to normal 6 months postoperatively, despite normal preoperative diameters. Thus, our study aimed to evaluate whether preoperative LV strain values assessed by echocardiography at rest and during exercise were predictors of postoperative LVEF at 6-month follow-up in patients undergoing surgery for severe organic MR. METHODS AND RESULTS: In total, 88 patients with severe organic MR (mean age 62.6 +/- 1.4 years) were prospectively recruited. All patients underwent an echocardiogram at rest and submaximal exercise (110 +/- 10 bpm) prior to surgery and then at rest 6 months after surgery. Exclusion criteria were significant coronary artery disease, other organic valvular diseases, uncontrolled arrhythmia, and haemodynamic instability. Among the 88 patients, 77 had complete data sets with rest and exercise echocardiograms and underwent isolated mitral valve surgery (repaired, n= 72). Global longitudinal strain (GLS) at rest (R= 0.42, P= 0.011) and during exercise (R= -0.36, P= 0.034) correlated with postoperative LVEF. When normalized for LV end-systolic diameter, GLS during exercise was more closely correlated with postoperative LVEF and was its best predictor based on a multivariate linear regression model. At a cut-off of 5.7%/cm, sensitivity was 0.83, specificity 0.70, negative predictive value 0.64, and positive predictive value 0.86 for predicting a 6-month postoperative LVEF of <50%. CONCLUSION: In patients undergoing surgery for severe organic MR, GLS normalized for LV end-systolic diameter at submaximal exercise may be used as a predictor of postoperative LVEF. PMID- 22504945 TI - A novel mutation in YARS2 causes myopathy with lactic acidosis and sideroblastic anemia. AB - Mutations in the mitochondrial aminoacyl-tRNA synthetases (ARSs) are associated with a strikingly broad range of clinical phenotypes, the molecular basis for which remains obscure. Here, we report a novel missense mutation (c.137G>A, p.Gly46Asp) in the catalytic domain of YARS2, which codes for the mitochondrial tyrosyl-tRNA synthetase, in a subject with myopathy, lactic acidosis, and sideroblastic anemia (MLASA). YARS2 was undetectable by immunoblot analysis in subject myoblasts, resulting in a generalized mitochondrial translation defect. Retroviral expression of a wild-type YARS2 complementary DNA completely rescued the translation defect. We previously demonstrated that the respiratory chain defect in this subject was only present in fully differentiated muscle, and we show here that this likely reflects an increased requirement for YARS2 as muscle cells differentiate. An additional, heterozygous mutation was detected in TRMU/MTU1, a gene encoding the mitochondrial 2-thiouridylase. Although subject myoblasts and myotubes contained half the normal levels of TRMU, thiolation of mitochondrial tRNAs was normal. YARS2 eluted as part of high-molecular-weight complexes of ~250 kDa and 1 MDa by gel filtration. This study confirms mutations in YARS2 as a cause of MLASA and shows that, like some of the cytoplasmic ARSs, mitochondrial ARSs occur in high-molecular-weight complexes. PMID- 22504946 TI - The financial crisis and global health: the International Monetary Fund's (IMF) policy response. AB - In this article, we interrogate the policy response of the International Monetary Fund (IMF) to the global financial crisis, and discuss the likely global health implications, especially in low-income countries. In doing so, we ask if the IMF has meaningfully loosened its fiscal deficit targets in light of the economic challenges posed by the financial crisis and adjusted its macro-economic policy advice to this new reality; or has the rhetoric of counter-cyclical spending failed to translate into additional fiscal space for IMF loan-recipient countries, with negative health consequences? To answer these questions, we assess several post-crisis IMF lending agreements with countries requiring financial assistance, and draw upon recent academic studies and civil society reports examining policy conditionalities still being prescribed by the IMF. We also reference recent studies examining the health impacts of these conditionalities. We demonstrate that while the IMF has been somewhat more flexible in its crisis response than in previous episodes of financial upheaval, there has been no meaningful rethinking in the application of dominant neoliberal macro-economic policies. After showing some flexibility in the initial crisis response, the IMF is pushing for excessive contraction in most low and middle income countries. We conclude that there remains a wide gap between the rhetoric and the reality of the IMF's policy and programming advice, with negative implications for global health. PMID- 22504947 TI - Minimally invasive approaches for gastric cancer-Japanese experiences. AB - Since development of laparoscopy-assisted distal gastrectomy with lymph node dissection in 1991 in Japan, laparoscopic gastrectomy (LAG) is improving and evolving. Recently, advanced LAG techniques including D2 lymph node dissection or anastomosis after total gastrectomy have been developed. Retrospective and prospective multicenter studies have been conducted for early and non-early gastric cancers to establish high-quality evidence. This review summarizes the current trends of minimally invasive approaches for gastric cancer based on current Japanese experiences. PMID- 22504948 TI - A qualitative exploration into young children's perspectives and understandings of emotional difficulties in other children. AB - Research into children's perspectives and understandings of emotional difficulties is limited and methodologically varied. In this paper we explore young children's perspectives and understandings of emotional difficulties in their peers. We conducted five focus groups involving a total of 25 children. The children, aged eight and nine, were presented with vignettes representing peers experiencing emotional difficulties, and invited to discuss their perspectives on possible causes. We also explored their emotional and behavioural reactions to the vignette characters. Using interpretative phenomenological analysis we identified three themes: Searching for an Explanation; Empathy versus Blame; and Consequences and Solutions. The children drew on their own emotional experiences in their sense-making, and the extent to which they held the character responsible for their behaviour was particularly important in influencing their responses towards the characters. PMID- 22504950 TI - Non invasive positive pressure ventilation in infants with respiratory failure. AB - OBJECTIVE: To determine whether non-invasive positive pressure ventilation (NIPPV) delivered via nasal prongs can alleviate the need for tracheal intubation and invasive ventilation in infants admitted to the pediatric intensive care unit (PICU) with impending respiratory failure, and to find predictive factors for success or failure with this mode. DESIGN: A single center retrospective cohort study. SETTING: PICU in a university affiliated hospital. PATIENTS: During the 14 months of the study period we recovered 22 NIPPV episodes in 19 infants (median age 65 days) with impending respiratory failure. The patient's respiratory failure etiologies were bronchiolitis (n = 13), pertussis (n = 3), and other respiratory conditions (n = 6). MEASUREMENTS AND RESULTS: In 64% of the cases, intubation was prevented and the patients were weaned off to spontaneous breathing (Responders group). 36% failed NIPPV and had to be intubated and invasively ventilated (Non-responders group). Apneic episodes were the indication for ventilation in 11 patients (50%) with a 73% success rate in preventing invasive ventilation. Hypoxemic respiratory failure was present in nine patients (41%) and the rate of success was 44%. Two patients with post extubation respiratory distress, improved with NIPPV. Responders and non-responders did not differ with regard to demographics or disease severity prior to initiation of NIPPV. After initiating NIPPV respiratory rate and the need for sedation were lower in the NIPPV responders. CONCLUSIONS: In a set group of patient population such as infants with apnea secondary to bronchiolitis NIPPV may be successful to reduce the need for invasive ventilation. Our study failed to detect any physiological or clinical markers which could distinguish between so called "responders" and "non-responders" before initiating NIPPV. PMID- 22504949 TI - Preclinical analysis of the gamma-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia. AB - T-cell acute lymphoblastic leukemias (T-ALL) and lymphomas are aggressive hematologic cancers frequently associated with activating mutations in NOTCH1. Early studies identified NOTCH1 as an attractive therapeutic target for the treatment of T-ALL through the use of gamma-secretase inhibitors (GSI). Here, we characterized the interaction between PF-03084014, a clinically relevant GSI, and dexamethasone in preclinical models of glucocorticoid-resistant T-ALL. Combination treatment of the GSI PF-03084014 with glucocorticoids induced a synergistic antileukemic effect in human T-ALL cell lines and primary human T-ALL patient samples. Mechanistically PF-03084014 plus glucocorticoid treatment induced increased transcriptional upregulation of the glucocorticoid receptor and glucocorticoid target genes. Treatment with PF-03084014 and glucocorticoids in combination was highly efficacious in vivo, with enhanced reduction of tumor burden in a xenograft model of T-ALL. Finally, glucocorticoid treatment effectively reversed PF-03084014-induced gastrointestinal toxicity via inhibition of goblet cell metaplasia. These results warrant the analysis of PF-03084014 and glucocorticoids in combination for the treatment of glucocorticoid-resistant T ALL. PMID- 22504951 TI - Turning down the heat: the potential role of RIP140 in inflammation. PMID- 22504953 TI - Single line or parallel lines: NK cell differentiation driven by T-bet and Eomes. PMID- 22504952 TI - HIV-1 immunopathogenesis in humanized mouse models. AB - In recent years, the technology of constructing chimeric mice with humanized immune systems has markedly improved. Multiple lineages of human immune cells develop in immunodeficient mice that have been transplanted with human hematopoietic stem cells. More importantly, these mice mount functional humoral and cellular immune responses upon immunization or microbial infection. Human immunodeficiency virus type I (HIV-1) can establish an infection in humanized mice, resulting in CD4(+) T-cell depletion and an accompanying nonspecific immune activation, which mimics the immunopathology in HIV-1-infected human patients. This makes humanized mice an optimal model for studying the mechanisms of HIV-1 immunopathogenesis and for developing novel immune-based therapies. PMID- 22504955 TI - Release of the glucose-regulated protein 94 by baby hamster kidney cells. AB - Glucose-regulated protein 94 (grp94) is a major component of the endoplasmic reticulum (ER) lumen of eukaryotic cells. We showed that grp94 is released from baby hamster kidney (BHK-21) cells into a serum-free medium. The exit of grp94 into the medium was not related to the protein discharge due to cell death and was independent of de novo protein synthesis. The treatment of cells with brefeldin A and monensin, the inhibitors of the classical pathway of protein secretion, did not decrease the extracellular level of grp94, indicating that the discharge of grp94 from cells does not occur through the ER/Golgi-dependent pathway. Exosomes, membrane vesicles secreted by several cell types, were not involved in the release of grp94 from cells. Methyl-beta-cyclodextrin, a substance that disrupts the lipid raft organization, considerably reduced the extracellular level of grp94, indicating that lipid rafts are involved in the liberation of grp94 from BHK-21 cells. The results suggest that BHK-21 cells release grp94 into the serum-free medium via the nonclassical secretory pathway in which lipid rafts play an important role. PMID- 22504956 TI - Covalent attachment of P15 peptide to titanium surfaces enhances cell attachment, spreading, and osteogenic gene expression. AB - P15, a synthetic 15 amino acid peptide, mimics the cell-binding domain within the alpha-1 chain of human collagen is being tested in clinical trials to determine if it enhances bone formation in spinal fusions. We hypothesize that covalent attachment of P15 to titanium implants may also serve to promote osseointegration. To test this hypothesis, we measured osteoblast and mesenchymal cell adhesion, proliferation, and maturation on P15 tethered to a titanium (Ti P15) surface. P15 peptide was covalently bonded to titanium alloy surfaces and incubated with osteoblast like cells. Cell toxicity, adhesion, spreading, and differentiation was then evaluated. Real-time quantitative PCR, Western blot analysis, and fluorescent immunohistochemistry was performed to measure osteoblast gene expression and differentiation. There was no evidence of toxicity. Significant increases in early cell attachment, spreading, and proliferation were observed on the Ti-P15 surface. Increased filapodial attachments, alpha(2) integrin expression, and phosphorylated focal adhesion kinase immunostaining indicated activation of integrin signaling pathways. qRT PCR analysis indicated there was significant increase in osteogenic differentiation markers in cells grown on Ti-P15 compared to control-Ti. Western blotting confirmed these findings. Surface modification of titanium with P15 significantly increased cell attachment, spreading, osteogenic gene expression, and differentiation. Results of this study suggest that Ti-P15 has the potential to safely enhance bone formation and promote osseointegration of titanium implants. PMID- 22504957 TI - Prevention of laboratory animal allergy in the United States: a national survey. AB - OBJECTIVE: Respiratory allergy to laboratory animals is a common and preventable occupational health problem. This study documents current laboratory animal allergy (LAA) prevention programs in the United States. METHODS: An online survey was e-mailed to designated institutional officials at laboratory animal facilities identified by the National Institutes of Health Office of Laboratory Animal Welfare. RESULTS: A total of 198 organizations responded and more than 80% required the use of uniforms and gloves to control exposure. Respirators were required by 25% of organizations. Medical surveillance was mandated by 58% of organizations (70% for organizations with at least 100 employees working with animals). Work restriction practices varied. Only 25% of organizations reported knowing the prevalence (range: 0% to 75%) and 29% reported knowing the incidence of LAA (range: 0% to 18%). CONCLUSIONS: There is broad variation in policy and practice to prevent LAA. An evidence-based consensus would ensure greater protection of workers. PMID- 22504954 TI - Regulation of TH17 cell differentiation by innate immune signals. AB - Upon antigen stimulation, naive T helper cells differentiate into distinct lineages to attain specialized properties and effector functions. T(H)17 cells, a recently identified lineage of CD4(+) effector T cells, play a key role in the immune defense against fungi and extracellular bacteria, but also contribute to the pathogenesis of many autoimmune conditions. The differentiation of T(H)17 cells is orchestrated by an intricate network of signaling pathways and transcriptional regulators in T cells. While the involvement of T cell-intrinsic pathways has been described extensively, we are just beginning to appreciate how T(H)17 cell development is shaped by extrinsic pathways, especially the innate immune signals. Dendritic cells (DCs), the most important cell type to bridge innate and adaptive immunity, drive T(H)17 cell differentiation by providing antigenic, costimulatory and cytokine signals. This is mediated by the recognition of innate and inflammatory signals by DCs via pattern recognition receptors, cytokine receptors and other immunomodulatory receptors that in turn activate the intracellular signaling network. In particular, p38alpha MAP kinase has emerged as a critical pathway to program DC-dependent T(H)17 cell differentiation by integrating multiple instructive signals in DCs. Here, we summarize the current knowledge on the mechanisms by which DC-derived innate immune signals drive T(H)17 cell differentiation. PMID- 22504958 TI - Occupational coccidioidomycosis in California: outbreak investigation, respirator recommendations, and surveillance findings. AB - OBJECTIVE: To describe the investigation of a 2007 occupational coccidioidomycosis outbreak in California, recommend prevention measures, and assess statewide disease burden. METHODS: We evaluated the worksite, observed work practices, interviewed the workers and employer, reviewed medical records, provided prevention recommendations including risk-based respirator selection, and analyzed statewide workers' compensation claims. RESULTS: Ten of 12 workers developed acute pulmonary coccidioidomycosis; none used respiratory protection. We recommended engineering, work practice, and administrative controls, powered air-purifying respirator use, and medical care. Occupational coccidioidomycosis incidence nearly quadrupled in California from 2000 to 2006, with the highest rates in construction and agricultural workers. CONCLUSIONS: Construction workers are at risk for occupational coccidioidomycosis. The high attack rate in this outbreak was due to lack of awareness, rainfall patterns, soil disruption, and failure to use appropriate controls. Multiple risk-based measures are needed to control occupational coccidioidomycosis in endemic areas. PMID- 22504959 TI - Wellness program satisfaction, sustained coaching participation, and achievement of health goals. AB - OBJECTIVE: To examine factors associated with program satisfaction for participants of a comprehensive workplace wellness program. METHODS: Data from satisfaction surveys completed by 17,896 program participants were used to examine the association between demographics, program satisfaction, sustained coaching participation, and odds of meeting health goals. Inferential statistical analysis was used to assess average satisfaction rates, and generalized estimating equations were used to estimate the effect of program satisfaction on sustained coaching participation and odds of meeting health goals while controlling for potential confounds. RESULTS: Statistically significant positive associations were found between participant satisfaction and sustained coaching participation, and factors associated with both were being older, being female, having greater program maturity, having higher incentive amounts, and having participation through telephonic coaching modality. CONCLUSIONS: Wellness program participant satisfaction is positively associated with sustained coaching participation and achievement of health goals. PMID- 22504960 TI - Increase of ryanodine receptors by dopamine D1 receptors is negatively regulated by gamma-aminobutyric acid type B receptors in primary cultures of mouse cerebral cortical neurons. AB - Although upregulation of ryanodine receptor (RyR)-1 and -2 is mediated through the activation of dopamine D1 receptors (D1DRs) in the development of psychostimulant-induced place preference, little is known about how such increased expressions of RyRs are negatively regulated. This study investigated negative regulatory mechanisms of increase of RyR-1 and -2 expression by D1DR stimulation with its full agonist, SKF82958 or A 68930, using cultures of mouse cerebral cortical neurons. Sustained exposure to SKF82958 or A 68930 of the neurons increased RyR-1 and -2 proteins in a dose- and time-dependent-manner. The SKF82958-induced increases of RyR-1 and -2 proteins were significantly suppressed by SCH23390 (a selective D1DR antagonist). In addition, the SKF82958- or A 68930 induced increases of RyR-1 and -2 proteins were completely abolished by baclofen (a selective gamma-aminobutyric acid type B [GABA(B)] receptor agonist), whereas muscimol (an agonist specific to GABA(A) receptors) had no effect. SKF82958 or A 68930 significantly increased intracellular cAMP level, which was completely suppressed by baclofen. Furthermore, sustained exposure to phorbol 12,13 dibutyrate, a protein kinase C activator, did not change the expression of RyR-1 or -2 proteins. Immunohistochemical study showed colocalizaton of immunoreactivities for three types of proteins, D1DRs and GABA(B) receptor R1 and R2 subunits in the same neuronal bodies, suggesting that the neurochemical changes induced by the activation of D1DRs and GABA(B) receptors occur in the same neurons. These results indicate that RyR-1 and -2 expression facilitated by D1DR stimulation are negatively regulated by GABA(B) receptor via suppression of cAMP production. PMID- 22504961 TI - Comparing the American and European diagnostic guidelines for cystic fibrosis: same disease, different language? AB - BACKGROUND: The American and European cystic fibrosis (CF) guidelines recommend different diagnostic criteria. This study assessed diagnostic concordance between these recommendations. METHODS: Subjects with single organ manifestations suggestive of CF (chronic sinopulmonary disease (RESP), chronic/recurrent pancreatitis (PANC) or obstructive azoospermia (AZOOSP)) were prospectively evaluated by sweat test, nasal potential difference and genotyping. Concordance in diagnostic outcomes between the two algorithms was measured using observed agreement and kappa statistics. RESULTS: A total of 208 subjects were evaluated. Observed agreement was 84.8% and level of agreement was excellent (kappa=0.87) between the American and European recommendations. The RESP phenotype was associated with the highest degree of concordance (observed agreement >=90%, kappa=0.92) compared with the PANC (observed agreement 86%, kappa=0.65) and AZOOSP (observed agreement 80%, kappa=0.87) phenotypes. Incorporation of nasal potential difference into the American algorithm failed to improve the overall degree of concordance (good agreement level; kappa=0.75); the level of agreement was unchanged in RESP and PANC subjects, but reduced in AZOOSP subjects (from excellent to good). Extensive genotyping had limited clinical utility in the diagnosis of CF in both algorithms. CONCLUSIONS: Despite inconsistencies between the American and European diagnostic recommendations, concordance in diagnostic outcomes among subjects presenting with single organ manifestations of CF was good to excellent. These diagnostic guidelines provide guidance and promote rigorous evaluation for the diagnosis of CF but neither guideline should be regarded as dogma. PMID- 22504962 TI - Target volume settings for home mechanical ventilation: great progress or just a gadget? PMID- 22504963 TI - Follow-up of the Finnish Asthma Programme 2000-2010: reduction of hospital burden needs risk group rethinking. AB - The Finnish Asthma Programme 1994-2004 focused on early intervention and disease control, thereby resulting in a significant reduction of asthma morbidity. During the follow-up period from 2000 to 2010, the number of hospital days continued to fall by 54%. Patients >=65 years, especially women, accounted for 39% of the hospital days, and they need attention if the hospital burden is to be reduced further. PMID- 22504964 TI - Strong Lewis acids of air-stable metallocene bis(perfluorooctanesulfonate)s as high-efficiency catalysts for carbonyl-group transformation reactions. AB - Strong Lewis acids of air-stable metallocene bis(perfluorooctanesulfonate)s [M(Cp)(2)][OSO(2)C(8)F(17)](2)?nH(2)O?THF (M = Zr (2 a?3 H(2)O?THF), M = Ti (2 b?2 H(2)O?THF)) were synthesized by the reaction of [M(Cp)(2)]Cl(2) (M = Zr (1 a), M = Ti (1 b)) with nBuLi and C(8)F(17)SO(3)H (2 equiv) or with C(8)F(17)SO(3)Ag (2 equiv). The hydrate numbers (n) of these complexes were variable, changing from 0 to 4 depending on conditions. In contrast to well-known metallocene triflates, these complexes suffered no change in open air for a year. thermogravimetry-differential scanning calorimetry (TG-DSC) analysis showed that 2 a and 2 b were thermally stable at 300 and 180 degrees C, respectively. These complexes exhibited unusually high solubility in polar organic solvents. Conductivity measurement showed that the complexes (2 a and 2 b) were ionic dissociation in CH(3)CN solution. X-ray analysis result confirmed 2 a?3 H(2)O?THF was a cationic organometallic Lewis acid. UV/Vis spectra showed a significant red shift due to the strong complex formation between 10-methylacridone and 2 a. Fluorescence spectra showed that the Lewis acidity of 2 a fell between those of Sc(3+) (lambda(em)=474 nm) and Fe(3+) (lambda(em)=478 nm). ESR spectra showed the Lewis acidity of 2 a (0.91 eV) was at the same level as that of Sc(3+) (1.00 eV) and Y(3+) (0.85 eV), while the Lewis acidity of 2 b (1.06 eV) was larger than that of Sc(3+) (1.00 eV) and Y(3+) (0.85 eV). They showed high catalytic ability in carbonyl-compound transformation reactions, such as the Mannich reaction, the Mukaiyama aldol reaction, allylation of aldehydes, the Friedel-Crafts acylation of alkyl aromatic ethers, and cyclotrimerization of ketones. Moreover, the complexes possessed good reusability. On account of their excellent catalytic efficiency, stability, and reusability, the complexes will find broad catalytic applications in organic synthesis. PMID- 22504965 TI - Are they linear, bent, or cyclic? Quantum chemical investigation of the heavier group 14 and group 15 homologues of HCN and HNC. AB - The singlet potential-energy surface (PES) of the system involving the atoms H, X, and E (the (H, X, E) system) in which X=N-Bi and E=C-Pb has been explored at the CCSD(T)/TZVPP and BP86/TZ2P+ levels of theory. The nature of the X-E bonding has been analyzed with charge- and energy-partitioning methods. The calculations show that the linear isomers of the nitrogen systems lin-HEN and lin-HNE are minima on the singlet PES. The carbon compound lin-HCN (HCN=hydrogen cyanide) is 14.9 kcal mol(-1) lower in energy than lin-HNC but the heavier group 14 homologues lin-HEN (E=Si-Pb) are between 64.8 and 71.5 kcal mol(-1) less stable than the lin-HNE isomers. The phosphorous system (H, P, E) exhibits significant differences concerning the geometry and stability of the equilibrium structures compared with the nitrogen system. The linear form lin-HEP of the former system is much more stable than lin-HPE. The molecule lin-HCP is the only minimum on the singlet PES. It is 78.5 kcal mol(-1) lower in energy than lin-HPC, which is a second-order saddle point. The heavier homologues lin-HPE, in which E=Si-Pb, are also second-order saddle points, whereas the bent-HPE structures are the global minima on the PES. They are between 10.3 (E=Si) and 36.5 kcal mol(-1) (E=Pb) lower in energy than lin-HEP. The bent-HPE structures possess rather acute bending angles H-P-E between 60.1 (E=Si) and 79.7 degrees (E=Pb). The energy differences between the heavier group 15 isomers lin-HEX (X=P-Bi) and the bent structures bent-HXE become continuously smaller. The silicon species lin-HSiBi is even 3.1 kcal mol(-1) lower in energy than bent-HBiSi. The bending angle H-X-E becomes more acute when X becomes heavier. The drastic energy differences between the isomers of the system (H, X, E) are explained with three factors that determine the relative stabilities of the energy minima: 1) The different bond strength between the hydrogen bonds H-X and H-E. 2) The electronic excitation energy of the fragment HE from the X (2)Pi ground state to the (4)Sigma(-) excited state, which is required to establish a E=X triple bond in the molecules lin-HEX. 3) The strength of the intrinsic X-E interactions in the molecules. The trends of the geometries and relative energies of the linear, bent, and cyclic isomers are explained with an energy-decomposition analysis that provides deep insight into the nature of the bonding situation. PMID- 22504966 TI - Evaluation of Biocompatibility of Alloplastic Materials: Development of a Tissue Culture In Vitro Test System. AB - Optimized biocompatibility is a major requirement for alloplastic materials currently applied in surgical approaches for hernia, incontinence, and prolapse situations. Tissue ingrowth/adherence and formation of connective tissue seem to have important influence in mesh incorporation at the implant site. In an in vitro approach we randomly investigated 7 different mesh types currently used in surgeries with various indications with regard to their adherence performance. Using a tissue culture approach, meshes were incubated with tissue representative of fibroblasts, muscle cells, and endothelial cells originating from 10 different patients. After 6 weeks, the meshes were assessed microscopically and a ranking of their adherence performance was established. Tissue culture was successful in 100% of the probes. We did not remark on interindividual differences concerning the growth and adherence performance after incubation with the different meshes in the investigated 10 patients. The ranking was consistent in all patients. In this test system, PVDF Dynamesh(r) (FEG Textiltechnik, Aachen, Germany) was the mesh with the best growth-in score. The test system was feasible and reproducible. Pore size seems to be a predictor of adherence performance. The test system may be a helpful tool for further investigations, and the predictive value should be assessed in further in vitro and in vivo experiments. PMID- 22504967 TI - The Tipping Point of Robotic Surgery In Healthcare: From Master-Slave to Flexible Access Bio-Inspired Platforms. AB - Surgical robots were introduced to overcome the technical issues of limited operative dexterity and inadequate visualization in complex body areas. Current surgical robotic systems are based on a master-slave relationship in which the master-surgeon provides operative guidance for the slave-robot to perform operative tasks. Robotic operations are most frequently applied in urology (primarily focusing on prostatectomy) and cardiac surgery. The evolution of surgical robotics has made significant strides in the past decade. There are, however, some limitatio0The future of robotic surgery promises several augmentations to provide improvements in surgical visualization, somatosensory perception, and enhanced robot-surgeon interactions. These can be achieved through advances in robotic research and academic healthcare leadership to develop the next generation of surgical robots such as the novel flexible access bio-inspired (FAB) platforms. The drive to move toward ever less-invasive and safer procedures while maintaining high-quality treatment outcomes has maintained the momentum of progress since the initial birth of minimally invasive surgery, so that robotic surgery can be increasingly applied in a wider range of healthcare settings. PMID- 22504968 TI - Single-Incision Laparoscopic Surgery (SILS) in Reconstructive Urological Cases. AB - Single-incision laparoscopic surgery (SILS) is a recent development in minimally invasive surgery. This is an initial SILS experience in reconstructive urology to prove feasibility and provide a comparison with conventional laparoscopy during perioperative and convalescent periods. A single surgeon performed two complex SILS operations (psoas bladder hitch with Boari flap for high ureteric stricture [SILS-PB] and nephropexy for severe nephroptosis [SILS-Np]). A group of 6 patients with previous experience with conventional laparoscopy by the same surgeon with the same operation complexity was selected for retrospective comparison. SILS was performed through multichannel port (intraumbilical or retroperitoneal). There was no conversion to laparoscopy. Operative time (Or-t) was 365 and 185 minutes for SILS-PB and SILS-Np, respectively. Blood loss was 100 ml for SILS-PB without any intraoperative complications. Baseline demographics, Or-t, blood loss, and hospital stay were comparable to the laparoscopic group. Except for prolonged Or-t, patients undergoing SILS had similar surgical outcomes and comparable convalescent periods. Follow-up was uneventful for both groups. Patients' global satisfaction and willingness to recommend their procedure to others were favorable and equivalent between groups. Thus, SILS-reconstructive operations for high ureteric strictures and severe nephroptosis are feasible. It seems equally as efficacious as conventional laparoscopy maintaining surgical standards without differences in perioperative outcomes and convalescence. PMID- 22504969 TI - Update 2012: Regenerative Medicine in Wounds: Current Use of Growth Factors, Cell Therapy, and Negative Pressure Wound Therapy for Chronic Wounds. AB - While we move toward the brink of being able to regenerate or replace human cells, tissues, or organs to restore or establish normal function, we are not there yet. The techniques that are available and being brought to bear on the field of chronic wounds include: growth factors, gene therapy, stem cell transplantation, tissue engineering, and reprogramming cell and tissue types. We review the biomedical techniques from bench to animal to human application. The clinical approaches from what has been tried in clinical growth factor application to the injection of stem cells or progenitor cells directly into a wound (cell therapy) are also reviewed. In addition, newly opening trials in topical cell therapy, injectable stem cell therapy, and topical autologous growth factor are addressed. Although tissue engineering is a very significant portion of regenerative medicine, it has recently been addressed well by other authors. We focus on why we are spending less time on specific growth factor therapy and more resources on cellular therapy. Finally, we address where negative pressure wound therapy fits into regenerative medicine. PMID- 22504971 TI - Hyperbaric Oxygen Therapy as an Adjunct to Pre-hospital Advanced Trauma Life Support. AB - Most commercial diving operations and naval operations have 24/7, on-site availability of hyperbaric oxygen therapy to perform routine surface decompression or immediate treatment of arterial gas embolism or decompression sickness. Availability and prompt use of hyperbaric oxygen therapy in the field for treatment of divers with dysbaric conditions has demonstrated its efficacy in acute, co-morbid conditions such as acute exsanguination, blast injury, crush injury, and cardiopulmonary arrest affecting those same divers. Hyperbaric oxygen therapy applied in these cases has demonstrated its utility to augment the efficacy of conventional, pre-hospital advanced cardiac life support and advanced trauma life support. Case studies gleaned from actual experience with the diving industry illustrate the use of hyperbaric oxygen therapy in these conditions. The unexpectedly favorable results have been replicated by controlled laboratory animal studies. The deck decompression or saturation multiplace chambers used by offshore diving operations can easily and quickly be converted for use as medical field resuscitative units. Lightweight and mobile hyperbaric chambers can be outfitted for use in ambulances or helicopters to address civilian street injury or military "far-forward" injury. These transport chambers are compact in design to be efficient transport stretchers designed to hold both the patient and the medical support clinician. It is hoped that hyperbaric oxygen therapy will gain an increasing role as an adjunct to pre-hospital advanced cardiac life support and advanced trauma life support resuscitative efforts as a low-cost, high-yield intervention. In this regard HBO as applied to ATLS/ACLS in civilian and military medical systems may be a productive, disruptive new application of technology. PMID- 22504970 TI - Micro-RNAs: New Regulators of Wound Healing. AB - Chronic wounds represent a significant burden to patients, health care professionals, and the health care system. Micro-RNAs (miRNAs) have recently emerged as a novel class of gene expression modulators involved in regulation of multiple biological processes, including development, differentiation, organogenesis, inflammation, cell proliferation, growth control, and apoptosis. Importantly, aberrant expression or activity of miRNAs can lead to a disease state. However, the role of miRNAs in chronic wounds remains to be elucidated. This article reviews available literature on the role of miRNAs in a range of processes important for successful wound healing including epidermal differentiation and proliferation, inflammation and angiogenesis. The potential role of miRNAs in normal wound healing and their contribution to chronic wound pathology has been anticipated. The prospective use of miRNAs as markers for surgical debridement, and as novel diagnostic and therapeutic targets for chronic wounds is also discussed. PMID- 22504972 TI - Laser Science and Limb Salvage. AB - Harnessing light energy in the form of lasers became possible after the discovery of electricity. Scientists found various uses for lasers beginning in the 1960s. Creating large amounts of pulsed UV light with any device, including a laser, remained difficult until excimer lasers were invented in the following decade. The invention of excimer lasers coincided with the advent of balloon angioplasty, leading physicians to speculate about using laser energy to obliterate obstructing arterial lesions. The first report of laser energy to vaporize an atherosclerotic plaque appeared in 1980. The ensuing decades witnessed dramatic refinements of laser fibers, laser energy sources, and catheter delivery systems. The favorable results achieved with excimer laser angioplasty in the early 2000s led to a renewed interest in this technology and to the current widespread use of these devices to treat peripheral as well as coronary artery disease. This paper provides a review of laser energy principles, traces the history of the use of lasers to treat vascular disease, and reviews the current literature pertaining to laser angioplasty and limb salvage. PMID- 22504973 TI - A New Era in Minimally Invasive Liver Resection (MILR) Single-Incision Laparoscopic Liver Resection (SIL-LR): The First Two Cases. AB - Laparoscopy has gained a place in everyday surgical routine as an alternative surgical approach that decreases morbidity and postoperative hospitalization. Single port laparoscopic surgery has been introduced as a further development of laparoscopy. The feasibility and safety of single port laparoscopy is under extensive evaluation in specialized laparoscopic centers. Nevertheless, wide acceptance of the technique requires adequate documentation of the advantages of the approach over conventional laparoscopy and further refinement of surgical instrumentation to overcome intraoperative ergonomic problems. PMID- 22504974 TI - Comparison Among Different Closure Methods of the Appendicular Stump in Laparoscopic Appendectomy. AB - In view of the fact that appendectomy is the most common operation for an acute abdomen, laparoscopic appendectomy has evolved as the most frequently performed procedure. Hospitals, therefore, require at all times the expertise, technique, and staff to ensure a high quality of standard for appendectomies, which not only supports the requirements of the high caseload but also takes into consideration the socio-economical aspects. A critical step is the closure of the appendicular stump. The three most widely employed techniques are an endo-stapler, an endo loop, or a clip. Although the endo-stapler is fairly expensive, it combines closing and transecting the appendix in one step, offers the possibility of a partial caecal resection, and can be used if the appendicular base is inflamed. Endo-loop and clip are equally cost-effective, but the clip appears to be simpler in handling than the endo-loop and, like the stapler, offers closing and cutting the appendix before dissecting the mesoappendix. However, only appendices up to 16 mm in diameter can be clipped, a disadvantage not shared with the loop. PMID- 22504975 TI - An Innovative Technique for Pancreatic Head Resection: The "Uncinate First" Approach. AB - The resection in partial pancreatico-duodenectomy as the standard treatment for malignancies of the pancreatic head is commonly performed starting from the hepatoduodenal ligament after division of the bile duct, stomach, or proximal duodenum and pancreatic body. The "Uncinate First" approach is a technical modification with a retrograde dissection of the pancreatic head as a novel surgical procedure. Caudo-cranial resection of the pancreatic head is characterized by starting with the uncinate process after division and mobilization of the first jejunal loop. Transection of the upper gastrointestinal structures (bile duct, stomach or duodenum and pancreas) is performed at the end of the resection. The retrograde Uncinate First technique offers a comfortable and innovative approach for partial pancreatico-duodenectomy. The superior mesenteric artery as well as the portal and superior mesenteric vein can be very accurately dissected and controlled during the resection phase associated with potentially less blood loss and a more radical resection along the medial margin, which is often the site of R1 resections. Future studies are required to evaluate this procedure regarding operative parameters and postoperative outcome compared with the standard resection. PMID- 22504976 TI - Argon Beam Coagulator in Breast Surgery: Effect on the Incidence of Breast Seroma. AB - Although Argon Beam Coagulators (ABCs) are widely used in urological and gynecological procedures, there have been only two studies published so far on their use and benefits in breast surgery. This study compares the incidence of breast seroma following mastectomy upon the use of ABC versus standard monopolar diathermy. This is a retrospective cohort study, with data collected from January 2006 to August 2008 for all patients who underwent a simple mastectomy and axillary surgery. Outcomes included incidence of seroma, amount of drainage on day of discharge, and timing of seroma formation. Fifty-six patients were studied, with 30 undergoing simple mastectomy using ABC diathermy and 25 using simple diathermy. The incidence of postoperative breast seroma development was 30% (n = 9) in the former group and 36% (n = 9) in the latter. In the ABC group, a high postoperative drainage at discharge was predictive of developing a seroma; this was not observed in the monopolar group. The search for methods to reduce the incidence of seroma in breast surgery is ongoing worldwide. Despite a previous report, this study failed to show any significant difference between ABC and monopolar diathermy in the incidence of breast seroma formation following simple mastectomy and axillary surgery. ABC diathermy is more costly, and its use needs to be carefully considered in an era of a stretched National Health Service financial budget. PMID- 22504977 TI - Enucleation of an Insulinoma of the Pancreas Using Reduced Port Surgery: Report of a Case. AB - Reduced port surgery (RPS) is a new surgical modality producing increased cosmetic benefits over conventional endoscopic surgery. We herein report the first case of insulinoma of the pancreas treated by RPS. RPS enucleation was performed for a 23-year-old Japanese female who was admitted to our hospital with repeated episodes of hypoglycemia attributable to an insulinoma. The preoperative examinations confirmed the diagnosis of a solitary insulinoma of the pancreatic tail. Enucleation of the insulinoma using RPS was performed. A 2.5-cm umbilical incision was made, and three laparoscopic trocars were individually inserted into the abdominal cavity via this incision. Another 3-mm trocar was inserted from the left subcostal region. All procedures that were usually performed in conventional laparoscopic surgery were also performed by RPS: intraoperative ultrasonography, mobilization of the tail of the pancreas, enucleation of the tumor, and suturing of the stump. A mechanical manipulator, the Radius Surgical System (Radius), was used for suturing and ligation. The Radius was sufficient to overcome in-line viewing and hand/instrument collisions, and enabled us to perform precise suturing and ligation. Serial blood sugar, C-peptide immunoreactivity (CPR), and immunoreactive insulin (IRI) measurements revealed that all values were normal after resection. The patient had an uneventful postoperative course. RPS was successfully applied for enucleation of a solitary mass in the tail of the pancreas, and represents an alternative to conventional laparoscopic surgery. This method is technically feasible and results in superior cosmesis. The Radius facilitated advanced laparoscopic surgery and may also have advantages in RPS. PMID- 22504978 TI - Transanal Endoscopic Surgery Using Different Single-Port Devices. AB - Currently, there is a new transanal approach to be used for the excision of selected low-risk rectal cancers and broad-based polyps, the transanal endoscopic surgery using a single-port device. We transferred the single port access surgery (SPA) well-established from laparoscopic surgery as an improvement of the transanal endoscopic microsurgery (TEM). The aim of this article is to give an overview about the technical options and our experiences with different devices. Thirteen patients with selected low-risk rectal cancers or broad-based polyps with dysplasia underwent the SPA modified TEM using the SILS? Port (Covidien Norwalk, CT), the TriPort? (Olympus KeyMed, Southend, UK) or TriPort+? (Olympus KeyMed, Southend, UK), and laparoscopic instruments. The transanal single port procedure was in all cases completely successful without major complications. The transanal placement of SILS? Port (Covidien) and TriPort/TriPort+? (Olympus) was easy to perform; a prior dilatation of the anal sphincter was not necessary. With an excellent view, accurate dissection was possible, all of them are appropriate for transanal single-port device. The postoperative follow-up showed an unremarkable examination. The transanal single port surgery with its benefits is a modified way to replace the TEM procedure. Our first experiences showed comfortable feasibility, less postoperative discomfort, and a reduced risk of damage to the anal sphincter. PMID- 22504979 TI - From Little Acorns, Bariatric Surgery in the United Kingdom, 2011: Personal Journey and Current Status. AB - Bariatric surgery in the United Kingdom dates to the early 1970s, and early pioneers made international contributions. This article gives a personal perspective on historical development from their work through the introduction of laparoscopic and revisional techniques to the present day. Bariatric surgery is becoming recognized in the United Kingdom as a cost-effective force for health improvement, but is hampered by restricted National Health Service prioritization and lack of insurance support. The British Obesity and Metabolic Surgery Society represents an active bariatric clinical community and holds its own scientific meetings. High quality is fostered by a multidisciplinary and team approach in specialized units with adequate volume. Significant advances have been made in professional recognition, science, innovation, guideline development, and health economic validation. Challenges remain in equity of access, service capacity, reimbursement, and clinical quality assurance. The recent establishment of a National Registry will help to overcome these obstacles. PMID- 22504980 TI - Sleeve Gastrectomy: A Procedure in a State of Flux. AB - Originally, sleeve gastrectomy (SG) was part of biliopancreatic diversion (BPD), which is the most effective bariatric procedure for super obese patients. As BPD is a complex procedure with substantial morbidity and mortality, attempts were undertaken to split the procedure into two steps. SG became the first step in a staged BPD procedure assuming that this less-invasive operation would reduce the surgical risk in super obese patients. The second step - the duodenal switch - was thus postponed until after a major weight loss. Several studies have since been published showing data that, besides the successful weight loss, the procedure itself had a positive effect on obesity-associated comorbidities. Sleeve gastrectomy has gained widespread acceptance as a primary and definite bariatric procedure. SG has become an innovative tool in the battle against obesity. Although several variations of SG have been described, standardization is paramount for optimal results. Of particular interest are: the minimally invasive access, the dissection, preservation of the antrum, position of staple line and buttress material, as well as the size of the bougie and the extent of fundal resection. This article describes the different procedural and technical aspects of the operation. In addition, it will line out how we transferred our skills and experience in single incision laparoscopic surgery (SILS) from cholecystectomy and sigmoid resection to sleeve gastrectomy. PMID- 22504981 TI - ULTRAPRO(r) Hernia System: Toward an Ideal Solution? The Bonheiden Experience with a Partially Absorbable and Macroporous Bilayer Device. AB - In 1998, Gilbert introduced the Prolene Hernia System (PHS), a bilayer polypropylene mesh device composed of an onlay patch, a connector, and an underlay patch. The overall concept of its design was to include the best features of all currently available techniques while eliminating their undesirable features. This device is now available in a lightweight version, the Ultrapro(r) Hernia System (UHS; Johnson & Johnson, Somerville, NJ). We present the Bonheiden experience. From 2006 until 2009, we used 890 UHS devices in 712 patients. All patients were requested to join a prospective analysis with follow up at one week and one month. Follow-ups at one and two years were organized using a telephone questionnaire. We were able to monitor 668 UHS implants in 526 patients. Bilateral primary hernias were repaired simultaneously in 142 patients and 6 hernias were a recurrence of a previous nonmesh repair. There were 472 men and 54 women in our cohort, with an average age of 57.5 years and average BMI of 24.79. No recurrences have occurred to date. Superficial wound infection presented in 3 patients. They were treated with antibiotics and no mesh needed to be removed. Seromas are much more common after this bilayer technique and are not considered a true complication. Whereas ecchymosis is very common, large hematomas were seen in 5 patients. One patient presented with a DVT of the iliac vein. She was treated with anticoagulation for three months, stockings, and early mobilization. The Ultrapro Hernia System is a good alternative to other preperitoneal hernia repairs, feasible in a day hospital under locoregional or general anesthesia. It has a very low recurrence rate but carries a more extensive dissection. We think the price paid for this extensive dissection is more than acceptable and is comparable to the Lichtenstein experience. PMID- 22504982 TI - Update on Bioactive Prosthetic Material for the Treatment of Hernias. AB - The use of mesh in the repair of hernias is commonplace. Synthetic mesh, like polypropylene, has been the workhorse for hernia repairs since the 1980s. Surgisis(r) mesh (Cook Surgical, Bloomington, IN), a biologic hernia graft material composed of purified porcine small intestinal submucosa (SIS), was first introduced to the United States in 1998 as an alternative to synthetic mesh materials. This mesh, composed of extracellular matrix collagen, fibronectin and associated glycosaminoglycans and growth factors, has been extensively investigated in animal models and used clinically in many types of surgical procedures. SIS acts as a scaffold for natural growth and strength. We reported our initial results in this publication in July 2006. Since then, there have been many more reports and numerous other bioactive prosthetic materials (BPMs) released. The object of this article is to briefly review some of the current literature on the use of BPM for inguinal hernias, sports hernias, and umbilical hernias. PMID- 22504983 TI - Comparison of Recurrence Rates in Obese and Non-Obese Patients Undergoing Ventral Hernia Repair with Lighter-Weight, Partially Absorbable Mesh. AB - Lighter-weight, large pore meshes with absorbable layers are designed for intra abdominal placement in laparoscopic ventral hernia repair. This retrospective review of 86 patients who underwent ventral hernia repair with PROCEED? Surgical Mesh (Ethicon, Inc., Somerville, NJ) represents an evaluation of a cohort of patients implanted with this mesh. All patients implanted with PROCEED Mesh for ventral hernia repair between October 2006 and December 2007 were contacted and asked to participate in an evaluation of their hernia repair. Patients were evaluated for pain, recurrence of their hernia and other potential complications. Eight patients underwent open repair; all others were performed laparoscopically. One patient continued to have pain at 1 year. Twelve developed seromas early on and 5 required drainage by a single puncture each. None persisted. There were 4 recurrences with none in patients with a Body Mass Index 3 32. One case of abdominal wall cellulitis responded to antibiotics. There were no wound infections, mesh infections, bowel obstructions or enteric fistulas. This study demonstrates the utility of a lighter-weight, large pore, partially absorbable mesh for intraperitoneal use in laparoscopic ventral hernia repair and indicates this mesh is strong enough for use in obese patients. PMID- 22504984 TI - Don't Fear Adhesions: Safe Approaches for Reoperative Minimally Invasive Surgery. AB - Experience in minimally invasive surgery has increased at a rapid pace, and previous abdominal surgery with adhesion formation is no longer considered a contraindication for laparoscopic surgery. Therefore, surgeons across all specialties should be well equipped to approach a reoperative abdomen with minimal complications and satisfactory patient outcomes. Previous abdominal scarring and adhesions present distinct challenges for surgeons performing minimally invasive surgery, and postsurgical adhesions are considered one of the main reasons for conversion from laparoscopy to laparotomy. In this review article, we present the influence of previous abdominal surgeries and pathogenesis of adhesion formation. Methods of laparoscopic entry and technical aspects of adhesiolysis to the ventral abdominal wall, intestinal, and pelvic adhesions are reviewed. Surgeons should have a keen sense of awareness of adhesion-related complications to reduce the morbidity of laparoscopic reoperations. PMID- 22504985 TI - Laparoscopic Management of Ovarian Cysts with Controlled Tissue Sealing - The "Cross Bag" Technique. AB - When ovarian preservation is desired, a minimally invasive laparoscopic surgical procedure using a "cross bag" technique is effective to consistently manage and remove ovarian cysts of concern. In addition to the standard preoperative preparation of patients, a bowel prep is critical, especially if the mass is large or the patient obese. Visualization of all internal structures is achieved using a multi-screen HD system and 5-mm laparoscope. Over 100 cases have been performed using the "cross bag" technique with no spillage of cysts. PMID- 22504986 TI - Sonographically Guided Hysteroscopic Endomyometrial Resection. AB - Hysteroscopic endomyometrial resection (EMR) was first reported by this author in 1994.[1] Several refinements have been made through the years including the addition of sonographic guidance as well as its adaptation into an office-based environment. EMR has many outstanding benefits including its adaptability to a "see-and-treat" procedure appropriate to an office setting. Importantly, EMR has a very high rate of hysterectomy avoidance and provides a complete histologic specimen of the endometrium and superficial myometrium. Finally, EMR is a superior method of managing both resectoscopic and non-resectoscopic endometrial ablation failures. PMID- 22504987 TI - Postoperative Cosmetic Expectations for Patients Considering Labiaplasty Surgery: Our Experience with 550 Patients. AB - Vulvar cosmetic surgery is becoming an increasingly requested and performed surgical procedure in women. Though there are many beliefs as to the desires of the patient's postoperative expectations, scientific research is lacking. The current paper evaluates patients' preoperative perceptions and postoperative expectations of cosmetic vulvar surgery. This is a retrospective analysis of 550 patients who are considering labia minora reduction. Preoperative questionnaires that address patients' preoperative perceptions of their labia as well as their postoperative expectations were reviewed and analyzed. Mean age was 36 (range 12 to 65) and parity 1.52 (range 0 to 8). On examination, 99.5% (547/550) of patients had labia minora protruding beyond the distal edge of the majora. Patients' postoperative desires included: 97.8% preferred the labia minora to be "at" or "below" the level of the labia majora compared with 2.2% preferring it to be "at" or "just above" the labia majora; 96.9% preferred "pink" edges compared with 3.1% desiring "dark" edges. Women presenting for vulvar cosmetic surgery have preoperative perceptions and postoperative expectations that should be considered with regard to surgery. Understanding a patient's postoperative labiaplasty expectations should be considered prior to engaging in surgery. Doing so could possibly alter the surgeon's labiaplasty technique and reduce the need for subsequent revision surgeries. PMID- 22504988 TI - Tissue Removal in Minimally Invasive Surgery (MIS). AB - Removing tissue using minimally invasive surgery (MIS) techniques is a work in progress. A review of existing technologies and techniques is presented along with potential pros and cons of these procedures. Existing data as well as new investigations into prospective avenues in the area of tissue removal at laparoscopy are presented. PMID- 22504989 TI - Alignment in Total Knee Arthroplasty: Where Have We Come From and Where Are We Going? AB - Numerous reports have linked malaligned total knee arthroplasty (TKA) components with increased wear, poor functional outcomes, and possibly early failure due to component loosening. Consequently, proper alignment is critical to a successful outcome. This article will review: the normal mechanical alignment of the knee, classical alignment in TKA, anatomic alignment in TKA, intraoperative reference points for alignment, and the potential for new alignment schema based on the kinematic axes of knee movement. Along with our increased understanding of how the knee functions, modern total knee arthroplasty has evolved to restore a neutral mechanical axis when prostheses are implanted. Although historically the goal has been to aim to be within 3 degrees of this axis, recent reports have challenged the validity of the claim that outliers have an increased risk for revision. In addition, new alignment schemes have been developed based on the kinematic axes, but as yet we await verification of results to determine whether they increase the ability of total knee arthroplasty to provide a better functioning and longer-lasting knee for the patient. PMID- 22504990 TI - Excellent Clinical Outcomes in Total Knee Arthroplasty Performed Without a Tourniquet. AB - Although tourniquet use is the standard protocol for total knee arthroplasties it may lead to postoperative complications including thigh pain, compressive soft tissue problems, and thromboembolic events. The purpose of this study was to explore the perioperative and clinical outcomes of total knee arthroplasty performed without a tourniquet. Thirty consecutive total knee arthroplasties were performed in 30 patients without a tourniquet and compared with 30 procedures (30 matched patients) performed with a tourniquet. Tourniquet patients had statistically lower mean intraoperative blood loss, total blood loss, and change in hematocrit, but these did not have any clinical impact or change the transfusion rate between the groups. At a mean follow-up of 3 years, both groups achieved excellent mean Knee Society scores with similar improvements between groups. There were no complications or radiographic abnormalities in either group. Total knee arthroplasty performed with or without a tourniquet yields similar intraoperative surgical and postoperative clinical outcomes. PMID- 22504991 TI - A Comparison Study of Two Cruciate-Retaining Total Knee Designs: A Preliminary Report. AB - Cruciate-retaining total knee arthroplasties have had high success rates. The purpose of this study was to compare a newer cruciate-retaining design to a previously used implant to determine if there were any changes in clinical or functional outcome. A total of 461 patients (553 knees) were identified who had total knee arthroplasty with this newer design. At latest 2-year follow-up, the mean range of motion was 121 degrees (range 105 to 140 degrees), the mean Knee Society pain score was 91 points (range, 57 to 100 points) and the functional score was 76 points (45 to 100 points). The comparison group of 211 patients (225 knees) had a mean range of motion of 119 degrees at 2 years (range, 90 to 142 degrees) with Knee Society pain and functional scores of 95 and 85 points, respectively (ranges 57 to 100, and 0 to 100, respectively). The use of the newer cruciate-retaining total knee arthroplasty showed comparable results to the previously used design at short-term follow-up. The cruciate-retaining design used in this study had no early failures, though further study is needed to make assessments regarding longer-term functional results and outcomes. PMID- 22504992 TI - Evaluation of Primary Total Knee Arthroplasty Incision Closure with the Use of Continuous Bidirectional Barbed Suture. AB - The purpose of this study is to determine whether operative time for primary total knee arthroplasty can be decreased with the use of a continuous barbed suture. Five hundred patients were retrospectively reviewed and divided into groups based on whether incision closure utilized a continuous barbed suture or an interrupted biodegradable suture. We identified additional variables to determine their relationship to operative time, including body mass index, age, gender, and side of replacement. The results demonstrated a decrease in operative time by an average of 4 minutes (P < .001) with the use of barbed suture, without an associated increase in complications. Statistically significant relationships were found between operative time and variables such as body mass index, age, and gender, but not side of replacement. PMID- 22504993 TI - Surgical Techniques for Staged Revision of the Chronically Infected Total Knee Arthroplasty. AB - Infection after total knee arthroplasty is a rare yet devastating complication requiring multiple hospitalizations, operations, and outpatient visits placing a significant burden on both patient and treating surgeon. Two-stage exchange protocols for the treatment of the chronically infected total knee arthroplasty remain the standard of care in the United States. Thorough debridement, use of antibiotic spacers, treatment with parenteral antibiotics, and delayed reimplantation have resulted in treatment success rates greater than 90%. The use of antibiotic cement spacers has led to increased range of motion, preservation of the joint space, and maintenance of cleaner soft tissue plains making surgery at the time of reimplantation less arduous. This article describes our current surgical technique used for two-stage revision of the chronically infected total knee including: (1) exposure, (2) implant removal and debridement, and (3) construction of both static and mobile antibiotic spacers. PMID- 22504994 TI - Neuromuscular Adaptations in Gluteus Medius Activity Following Resurfacing and Total Hip Arthroplasty. AB - In middle-aged patients, the choice between resurfacing and total hip arthroplasty may be difficult given recent studies showing differences in functional outcomes. Success of clinical outcomes, defined by a greater range of motion and reduced pain following surgery, are dependent on a return in function of incised muscle groups. To identify neuromuscular recovery following hip arthroplasty, hip abductor activity was assessed throughout the first year of recovery. Analysis focused on characterization of the temporal activity of the gluteus medius during activities of daily living. Adaptation in muscle firing and biomechanical outcomes was revealed in both groups, though more pronounced in the THA cohort with increasingly difficult activities. Differences between groups should be considered by clinicians when considering the best treatment options for their patients. PMID- 22504995 TI - Modern Dual Mobility Cups for Total Hip Arthroplasty. AB - Dislocation after total hip arthroplasty remains a primary concern among orthopaedic surgeons. Endeavors to decrease the incidence of dislocation, while maintaining limb function and mobility, have been painstakingly undertaken. Since their advent in the 1970s, dual mobility cups have proven again and again to be effective in reducing dislocation following total hip arthroplasty. The dual mobility cup enables the surgeon to treat patients with an increased risk for dislocation, while maintaining hip stability, favorable wear properties, and an acceptable rate of dislocation. Disadvantages are related to the potential increased wear and surgeon error. With advances in engineering and design, dual mobility cups have proven useful in providing lower dislocation rates for several pathological conditions. As a result, dual mobility cups have moved into the forefront of total hip arthroplasty. PMID- 22504997 TI - Fixation Strategies in Total Hip Arthroplasty. AB - Substantial progress has been achieved in cementless arthroplasty in the recent decades where cementless arthroplasty has evolved from pressfit implantation to porous-coated and later HA-coated implant fixation as its ultimate current state of-the-art incarnation. Key factors for success are adequate primary stability of the device in the bone supported by design and surface structure variables that together with optimal implant biocompatibility result in durable osseo integration of the device. Excellent survival rates past 20 years are documented in both literature and registries with quantitative studies confirming the excellent implant stability and bone quality. Elderly, younger, or medically compromised patients may require specific attention to avoid problems, but in general, every patient can be given the benefit of modern cementless hip arthroplasty. With an optimal consideration for patient-related factors as well as anatomic reconstruction of the arthroplasty, modern cementless arthroplasty provides every patient an outlook on both excellent long-term functionality and survival. PMID- 22504996 TI - The Use of Dual-Mobility Bearings in Difficult Hip Arthroplasty Reconstructive Cases. AB - This report includes a series of eight cases in which a dual-mobility prosthesis was utilized for difficult acetabular reconstructive hip arthroplasty cases. Most of the patients described had multiple reasons for hip instability (including prior multiple surgeries, abductor muscle insufficiency, prior infection). All patients were successfully managed with this device and this report includes a brief description of its use compared with other surgical reconstruction methods for instability. PMID- 22504998 TI - The Use of Modularity in Total Hip Arthroplasty. AB - Modularity is defined as separation of a system into independent parts or modules that can be treated as logical and may be separated and recombined. Historically, the modularity represents the evolution of the concept of "low friction arthroplasty" developed by Sir J. Charnely in 1960. The disadvantage of a one piece stem is the difficulty of restoring the biomechanical feature of the hip. Thus, the natural evolution was the introduction of modularity on both sides, the acetabulum and the femur. Modularity allows the surgeon to accurately match the anatomic characteristics of each patient to obtain improved range of motion, joint stability, abductor strength, and leg length equality. Disadvantages are related to the introduction of different interfaces, which could be sites of wear and corrosion. In accordance with the most recent literature, in primary total hip arthroplasty (THA) the modularity can be reduced to the head and the acetabular component, while a one-piece stem can manage the majority of cases. On the other hand, we believe that during revision surgery, a complete modularity is necessary. PMID- 22504999 TI - A Prospective, Randomized Study of Component Position in Two-Incision MIS Total Hip Arthroplasty: A Preliminary Study. AB - Controversy exists regarding the ability to position the implants reliably in minimally invasive surgery (MIS) total hip arthroplasty (THA). This study compared the ability to accurately position components in the MIS two-incision versus single-incision approaches. Twenty-four patients were randomized to THA through one of three approaches, including the two-incision approach. Component position was measured with computed tomography. The mean deviation from the target acetabular anteversion was 14.8 degrees in the two-incision MIS group versus 6.4 degrees in the other two approaches (p = 0.006). A mean of 9.8 degrees deviation from the target femoral anteversion in the two-incision MIS approach group was observed compared with 5.3 degrees in the single-incision groups (p = 0.05). These results suggest there is a decreased ability to accurately position the components in the two-incision approach. PMID- 22505000 TI - Total Joint Arthroplasty in Patients with Obstructive Sleep Apnea: Strategies for Reduction of Perioperative Complications. AB - Obstructive sleep apnea (OSA) has been associated with increased risk for medical complications following total joint arthroplasty. Our institution employs postoperative precautions for OSA patients in an effort to minimize the impact of postoperative complications in this group. We performed this study to assess the effect of careful monitoring on postoperative complication rates in OSA patients. We identified patients with a clinically suspected or objective diagnosis of OSA who received total joint arthroplasty between January 1998 and January 2008. 1016 cases in 792 OSA patients were matched to 1016 cases in 993 control patients to compare complication rates. There were no differences between OSA and control patients in cardiovascular and respiratory complications following TJA. Patients with OSA experienced increased rates of postoperative acute renal failure when compared with controls (p = 0.02) and experienced mild desaturations (Hb O2 < 92%) (p = 0.002), but not severe desaturations (Hb O2 < 88%) (p = 0.2). We conclude that our postoperative monitoring protocols are successful in reducing postoperative complications most commonly associated with OSA. We were interested to note the increased risk for OSA patients to develop postoperative acute renal failure and believe that future study is warranted to explore the link between OSA and renal failure. PMID- 22505001 TI - Post-traumatic Vertebral Compression Fracture Treated with Minimally Invasive Biologic Vertebral Augmentation for Reconstruction. AB - In the United States, there is a high incidence of motor vehicle and sports injuries among the active population causing symptomatic post-traumatic vertebral compression fracture. At our institution, 28 cases of painful post-traumatic vertebral compression fractures (PPT-VCFs) were successfully treated with percutaneous vertebral augmentation (VA) for stabilization and reconstruction with intravertebral polyethylene mesh sac (OptiMesh(r), Spineology, Inc., Stillwater, MN) and biological morcelized bone graft. The surgical approach provides an efficacious and controlled minimally invasive delivery mechanism to stabilize and reconstruct VCFs, as well as avoiding serious complications from Polymethylmethacrylate (PMMA) of vertebroplasty and kyphoplasty. The construct for biological bone graft/vertebral augmentation is osteoconductive and osteoinductive, and is used to create biologic vertebral stabilization and reconstruction. The adjacent vertebra integrity is protected by the construct with similar elasticity and physical characteristics of the biologic morcelized bone, more matched to that of adjacent bone than PMMA. The surgical techniques are described herein. PMID- 22505002 TI - Percutaneous Posterolateral Transforaminal Endoscopic Discectomy: Clinical Outcome, Complications, and Learning Curve Evaluation. AB - Ongoing technological development combined with better understanding of endoscopic anatomy has made posterolateral endoscopic discectomy an appealing surgical option for the management of herniated lumbar disc. We evaluated clinical outcomes, complication rates, and surgical learning curve with the percutaneous posterolateral transforaminal endoscopic discectomy technique (PPTED). PPTED was performed on 150 patients from 2004 to 2008. And 124 patients were available for follow-up. Data regarding pain, postoperative complications, neurological status, operation time, and subjective patient satisfaction were recorded. A satisfactory clinical outcome as reflected in the VAS (mean 3.6) and ODI improvement (mean 21%) scores was reported; 20.9% of the patients required additional surgery. Learning curve assessment showed a significant difference (p = 0.043) for fewer revision surgeries as surgeons became more experienced. Patients who had endoscopic discectomy as a primary surgery achieved significantly lower VAS (p = 0.04) and ODI improvement (p = 0.004) scores compared with patients having transforaminal endoscopic discectomy as revision surgery. The complication rate was 1.6%, including one case of post-surgery hypoesthesia and one deep wound infection. The percutaneous posterolateral transforaminal endoscopic discectomy technique has a satisfactory clinical outcome with a low complication rate. Results for endoscopic surgery for revision or recurrent disc herniation are comparable to those of open revision surgery; the steep learning curve can be overcome with training and suitable patient selection. PMID- 22505003 TI - Full-endoscopic Operations of the Spine in Disk Herniations and Spinal Stenosis. AB - Degenerative constrictions of the spinal canal with compression of neural elements arise as a result of bony, disk, capsular, or ligament structures. The most frequent causes are disk herniations and spinal stenoses. The lumbar and cervical spine is the most prominent cause. After conservative treatments have been exhausted, surgical intervention may be necessary. Today, microsurgical, microscopically assisted decompression is regarded as the standard procedure for disk herniation and spinal stenosis in the lumbar region, while in the cervical spine microsurgical, microscopically assisted anterior decompression and fusion are standard. Both procedures demonstrate good clinical results but present problems associated with the operation. Decompressions in the area of the spine must be carried out under continuous visualization and must entail the possibility of adequate bone resection. Taking this into account, completely new endoscopes and instrument sets were developed for full-endoscopic operations in tandem with the development of the lateral transforaminal and interlaminar approaches for the lumbar spine and the posterior and contralateral anterior approaches for the cervical spine. The possibilities and results of comparable, established standard procedures were used as a benchmark in the course of clinical validation. The development of surgically created approaches and the new rod lens endoscopes combined with appropriate instrument sets have laid the technical foundations for full-endoscopic operation in the lumbar spine on all primary and recurrent disk herniations inside and outside the spinal canal and on spinal stenoses. This development has also permitted resection of soft disk herniations in the cervical spine. The use of the relevant approaches depends on anatomical and pathological inclusion and exclusion criteria. The clinical results of standard procedures are achieved, which must be regarded as a minimum criterion for the introduction of new technologies. On the basis of EBM criteria, it can be established that using the full-endoscopic techniques developed, adequate decompression is achieved in the defined indications with reduced traumatization, improved visibility conditions, and positive cost benefits. Today, full-endoscopic operations may be regarded as an expansion and alternative within the overall concept of spinal surgery. PMID- 22505004 TI - In-vivo Endoscopic Visualization of Patho-anatomy in Symptomatic Degenerative Conditions of the Lumbar Spine II: Intradiscal, Foraminal, and Central Canal Decompression. AB - The patho-anatomy in an aging spine is partly defined by Rauschning's anatomic cryosections. Theories of pain generation and principles of minimally invasive spine surgery are suggested by close examination of these specimens. If the visualized patho-anatomy can be studied in vivo in a partially sedated patient by spinal probing, spinal pain can be better understood, and rational endoscopic treatment options may then evolve.1 A 1997 IRB-approved study provided evidence that endoscopic transforaminal surgery was feasible for the treatment of a wide spectrum of degenerative conditions in the lumbar spine. The technique incorporated evocative chromo-discography to correlate reproduction of pain with in-vivo probing of patho-anatomy. Laser and radiofrequency ablation augmented mechanical decompression to obtain pain relief.1-3 Endoscopic visualization of patho-anatomy ranging from annular tears to spondylolisthesis and stenosis provided clinical evidence that foraminal decompression, ablation, and irrigation could effectively treat these visualized painful conditions with minimal morbidity. This resulted in a better understanding of the pain generators in the lumbar spine, opening up options for surgical pain management.1-5 The procedure does not burn any bridges for more traditional surgical techniques. The learning curve may be steep for some and long for others, but results are very good, concomitant with each individual surgeon overcoming his personal learning curve. PMID- 22505005 TI - Synthesis of a 3-deoxy-D-manno-octulosonic acid (KDO) building block from D glucose via fermentation. AB - Herein we report the first synthesis of a 3-deoxy-D-manno-octulosonic acid (KDO) building block starting from glucose through pathway engineering of Escherichia coli and subsequent chemical modifications to provide an alternative method to produce KDO, found in plant and bacterial oligosaccharides. PMID- 22505006 TI - Serum protein microarray analysis of patients with preeclampsia. AB - The present study identified novel factors related to preeclampsia. Serum samples were analyzed using a membrane-based human cytokine microarray technology in patients with preeclampsia. Serum was collected from 29 healthy pregnant subjects, 16 gestational hypertensive patients and 31 patients with preeclampsia. The samples for microarray analysis were randomly selected from 8 subjects, 5 patients with preeclampsia and 3 healthy pregnant controls. Serum was analyzed using a custom human cytokine microarray (RayBio(r) Custom Human Cytokine Array) designed to analyze 120 specific cytokines simultaneously. The levels of sTNF-R1, Axl and TIMP-2 were further measured by sandwich enzyme-linked immunosorbent assay (ELISA). In microarray analysis, there were no significant differences in most of the measured parameters among the two study groups, except in serum TNF R1, Axl and TIMP-2 (P = 0.021, P = 0.034 and P = 0.040, respectively). ELISA showed that the serum TNF-R1 levels were significantly higher in preeclampsia patients (288.06 +/- 78.30 pg/ml) compared to patients with gestational hypertension (229.81 +/- 47.65, P=0.005) and healthy pregnant subjects (247.48 +/ 59.00, P = 0.009). Serum Axl levels were markedly higher in patients with preeclampsia (2.28 +/- 0.25 ng/ml) compared to patients with gestational hypertension (2.05 +/- 0.21 ng/ml) and healthy pregnant subjects (2.11 +/- 0.28, P = 0.005). Additionally, preeclamptic patients had higher TIMP-2 levels (3.33 +/ 1.01 ng/ml) as compared to gestational hypertensive patients (3.13 +/- 0.56 ng/ml) and healthy pregnant women (3.00 +/- 0.49 ng/ml), but there was no pronounced difference between the three groups (F = 1.285, P = 0.283 > 0.05). Our results demonstrated that two biological processes related to inflammatory response and endothelium activation are involved in the pathogenesis of preeclampsia. PMID- 22505007 TI - Rhabdoid large cell carcinoma of lung, with illustrative immunohistochemical and molecular findings. AB - Large cell carcinomas with rhabdoid phenotype (LCC-RP) account for <1% of pulmonary large cell carcinomas and are associated with extremely poor prognosis. We report a case of a 64-year-old male patient who presented at an advanced stage with a LCC-RP, arising from a poorly differentiated adenocarcinoma of the lung. Ninety percent of the tumor consisted of large pleomorphic rhabdoid tumor cells that showed eosinophilic cytoplasmic inclusions and the remaining 10% showed evidence of adenomatous differentiation. Rhabdoid areas were immunohistochemically positive for pan-cytokeratin AE1/3, epithelial membrane antigen, vimentin, thyroid transcription factor-1, integrase interactor-1, and negative for desmin. Nuclear positivity was absent for Myo-D1. The parent adenocarcinoma was positive for thyroid transcription factor-1 and cytokeratins 7. Epidermal growth factor receptor mutation analysis revealed the same mutation (p.delL747-T751) in both areas, suggesting that the malignant rhabdoid phenotype represents a dedifferentiation phenomenon of the adenocarcinoma. This is the first reported case of an Exon 19 deletion in epidermal growth factor receptor of the activating type detected in a LCC-RP associated with a poorly differentiated pulmonary adenocarcinoma. PMID- 22505008 TI - Systematic review on hormone receptor testing in breast cancer. AB - Assessment of hormone receptors (estrogen and progesterone) helps to direct therapy for women with breast cancer. Immunohistochemistry is most commonly used to assess hormone receptor status and it is essential that these tests are performed accurately and reliably within and across laboratories. The overall purpose of this guideline is to improve the quality and accuracy of hormone receptor testing and its utility as a prognostic and predictive marker for invasive and in situ breast cancer. Medline, EMBASE, the Cochrane Database of Systematic Reviews, and abstracts from the San Antonio Breast Cancer Symposium were searched. An environmental scan of the internet and of international guideline developers and key organizations was performed. Preanalytic elements such as the collection, fixation, and storage of samples, and analytic elements such as selection of antibodies and scoring methods that seem to offer the best results for immunohistochemical assessment of hormone receptors are presented. Proficiency testing or quality assurance of immunohistochemistry is described. PMID- 22505009 TI - Inhibin-A immunoreactivity in nervous system lesions. AB - To evaluate inhibin-A immunoreactivity and its utility in the differential diagnosis of nervous system neoplasms and non-neoplastic lesions. An immunohistochemical study of 252 central and peripheral nervous system tumors and 40 non-neoplastic lesions was undertaken. Brain lesions included the basic spectrum of astrocytic, oligodendroglial, and ependymal neoplasms, as well as glioneuronal, pineal parenchymal, choroid plexus, and embryonal. Meningeal neoplasms, basic peripheral nerve tumors, and uncommon sellar lesions were also assessed. Non-neoplastic lesions included demyelinating disease, progressive multifocal leukoencephalopathy, organizing infarct, and reactive gliosis. Diffuse cytoplasmic, membranous, and perinuclear cytoplasmic staining patterns were observed. Significant immunoreactivity was noted in glioblastoma (12 of 20), pleomorphic xanthoastrocytoma (6 of 10), ganglioglioma (8 of 10), meningioma (14 of 20), and hemangioblastoma (10 of 10). Peripheral nerve and sellar tumors as well as non-neoplastic lesions were entirely immunonegative. In our study that investigated the inhibin-A immunoreactivity in a broad spectrum of nervous system lesions, inhibin-A positivity was established in various low-grade and high-grade central nervous system tumors. Thus, inhibin-A is not a specific marker of hemangioblastoma and may be of limited utility in the differential diagnosis of astrocytic and meningothelial neoplasms. Its pathophysiologic role in these various tumors remains to be determined. Further evaluation of the possible significance of staining patterns and degrees of reactivity relative to pathobiology and/or prognosis significance is required. PMID- 22505010 TI - Infiltrating CD57+ inflammatory cells in head and neck squamous cell carcinoma: clinicopathological analysis and prognostic significance. AB - This study investigated the immunodetection of CD57+ inflammatory cells in patients with head and neck squamous cell carcinoma (HNSCC) and its association with clinicopathological parameters and overall survival. Data collected from the morphological analysis and immunohistochemical reaction testing of archived HNSCC specimens (n=70) were statistically analyzed by bivariate and multivariate statistical testing at a significance level of P<0.05. The results indicate that CD57+ inflammatory cells predominate within the peritumoral stroma of HNSCC lesions and the existence of two significant relationships: between high CD57+ cell density and the development of a tumor of a large size [odds ratio (OR)=5.610, 95% confidence interval (CI)=1.516-20.763) and between high CD57+ cell density and the development of locoregional metastatic disease (OR=3.401, 95% CI=1.162-9.951). A significant difference in the rate of survival was detected only in HNSCC patients that presented large size tumors (OR=4.747, 95% CI=1.281-17.594). Together, these results suggest that although high CD57+ inflammatory cell density is associated with HNSCC lesions of greater clinical severity, the variable of cell density is not an independent predictor of HNSCC patient survival. Our findings also suggest that the relatively aggressive infiltration of CD57+ inflammatory cells in the peritumoral stroma of head and neck carcinomas may contribute to an ineffective locoregional antitumoral response. PMID- 22505011 TI - Immunohistochemical comparative analysis of cell proliferation and angiogenic index in squamous cell carcinomas of the tongue between young and older patients. AB - Oral squamous cell carcinoma (SCC) is a malignant epithelial tumor that is uncommon in individuals younger than 45 years. This study compared the cell proliferation and angiogenic index in SCCs of the tongue between young and older patients. Forty SCCs of the tongue, 20 diagnosed in young patients (<= 40 y) and 20 diagnosed in older patients (>50 y) were evaluated by immunohistochemistry. Cell proliferation was evaluated using the Ki-67 labeling index (LI). The angiogenic index was determined by microvessel count (MVC) using anti- von Willebrand factor antibody. The mean Ki-67 LI in SCCs of the tongue was 43.8% (range, 26.0% to 72.4%) in young patients and 42.5% (range, 9.0% to 59.4%) in older patients (P=0.968). No significant difference in the Ki-67 LI was observed in relation to clinical stage or histologic grade of malignancy in either group (P>0.05). The mean MVC in SCCs of the tongue was 24.3 (range, 8.6 to 51.6) in young patients and 25.6 (range, 5.4 to 42.4) in older patients (P=0.543). There was no significant difference in MVC in relation to clinical stage or histologic grade of malignancy in either group (P>0.05). In addition, no significant correlation was observed between the Ki-67 LI and the angiogenic index (P>0.05). The results of this study suggest that the more aggressive biological behavior of SCC of the tongue in young patients may not be related to a higher cell proliferation rate or a higher angiogenic index. PMID- 22505012 TI - Stromal matrix metalloproteinase-14 expression correlates with the grade and biological behavior of mammary phyllodes tumors. AB - Phyllodes tumors (PTs) of the breast are rare biphasic tumors with the potential for invasion and metastatic spread. Matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) are involved in several key aspects of tumoral growth, invasion, and metastasis, but little is known of their expression in PTs. The objective of this study was to assess the expression of MMPs and TIMPs in PTs and to determine their association with grade and clinical behavior of PTs. Eighty-two PTs (50 benign, 22 borderline, and 10 malignant) were studied. Automated immunohistochemical staining for MMP-1, -2, -7, -9, -11, -13, and -14 and TIMP-1, -2, and -3 was performed using tissue microarray blocks and the expression of MMPs and TIMPs was assessed in the stromal component. There were no significant differences in the expression of stromal MMPs and TIMPs in the 3 groups of PTs, except for MMP-14. There was a significant increase in stromal MMP-14 expression with increasing PT grade (P<0.01). The stromal MMP-14 expression in the borderline and malignant PTs was higher than that in benign PTs (P<0.05 and P<0.05, respectively). Furthermore, the expression of stromal MMP-14 was associated with a higher rate of recurrence (P<0.05). Our results show for the first time that stromal MMP-14 expression is associated with the grade and clinical behavior of PTs of the breast. PMID- 22505013 TI - Immunohistochemical composition of the human lunotriquetral interosseous ligament. AB - PURPOSE: The human lunotriquetral ligament (LTL) is a functionally important intrinsic hand ligament, which is assumedly subjected to insertion angle changes at the entheses during movement. To clarify whether the current model of the ligament's mechanical environment is reflected in its structural composition, we determined the regional distribution of extracellular matrix-related antigens. METHODS: The extracellular matrix was immunohistochemically investigated in 12 LTLs from both wrists of 6 human donors (Mean age: 60 y). RESULTS: The dorsal, proximal, and volar portions of the ligament immunolabeled for type I, III collagen and versican. Both entheses labeled strongly for type II collagen, aggrecan, and link protein and were distinctly cartilaginous. The ligament midsubstance was positive for collagen II in 30%, for aggrecan in 40%, and for keratocan and lumican in 100% of specimens. In contrast, keratocan and lumican were absent from the fibrocartilaginous entheses and the articular cartilage. Ligament insertion at a carpal bone occurs either directly through fibrocartilage or indirectly through a bilayered configuration of fibrocartilage and hyaline like cartilage. The hyaline-like cartilage is continuous with the neighboring articular cartilage. CONCLUSIONS: The LTL has an extracellular matrix comparable with that of ligaments experiencing a combination of tensile and shear/compressive load at the attachment sites. All regions of the LTL exhibit fibrocartilaginous entheses; purely fibrous attachment sites are rare. The ligament midsubstance shows a more fibrous phenotype than the entheses and expresses keratocan and lumican, which previously have not been recorded in any human hand ligament. PMID- 22505014 TI - Aggressive EBV-associated lymphoproliferative disorder: a prodrome to diffuse large B-cell lymphoma? AB - A 19-year-old male patient presented with intermittent high fever and left cervical lymphadenopathy. The lymph node biopsy findings were interpreted as "Epstein-Barr virus (EBV)-associated lymphoproliferative disorder consistent with infectious mononucleosis." No molecular studies were performed at that time. The patient was followed without treatment. Five months later, the patient again presented with fever, lymphadenopathy, and splenomegaly. The lymph node biopsy showed features of a diffuse large B-cell lymphoma. Molecular studies on this lymph node biopsy showed a clonal EBV population, although polymerase chain reaction studies failed to reveal a clonal B-cell or T-cell population. A concurrent bone marrow biopsy showed features consistent with hemophagocytic syndrome. He had elevated ferritin, soluble interleukin-2 receptors and persistent EBV viremia. The patient responded to Rituxan for a short period with undetectable EBV levels. Subsequent right cervical lymph node, liver, and jejunal biopsies showed involvement by diffuse large B-cell lymphoma and the patient expired soon thereafter. PMID- 22505015 TI - Insecure attachment as a predictor of depressive and anxious symptomology. AB - BACKGROUND: Most studies have shown that insecure attachment and stress are important risk factors in the development of depression and anxiety. However, it is unclear whether distinct patterns of insecure attachment may relate differently to depression and anxiety following stressful events. Thus, the current study examined whether anxious and avoidant attachment, both of which are operationalized as insecure attachment, predict depressive and anxious symptoms following the occurrence of hassles. METHOD: A sample of 662 Chinese university students was recruited from Hunan, China. At the initial assessment, participants completed self-report measures assessing insecure attachment (i.e. anxious and avoidant attachment), hassles, anxious symptoms, and depressive symptoms. Additionally, hassles and symptoms of anxiety and depression were assessed once a month for the subsequent 6 months. RESULTS: The results of hierarchical linear modeling analyses indicated a significant interaction between anxious attachment and hassles in predicting follow-up depressive symptoms. Specifically, participants with high levels of anxious, but not avoidant, attachment reported high levels of depressive symptoms when experiencing high, as opposed to low, levels of hassles. At the same time, while both anxious and avoidant attachment predicted higher levels of anxious symptoms over time, a cross-level, significant interaction did not emerge. CONCLUSIONS: Insecure attachment styles serve as a vulnerability factor in the development of depressive and anxious symptoms in Chinese young adults. Consequently, fostering the development of secure attachment in prevention and intervention programs may, ultimately, prevent the onset and maintenance of depressive and anxious disorders. PMID- 22505016 TI - Differential effects of AKT1(p.E17K) expression on human mammary luminal epithelial and myoepithelial cells. AB - Recently, we identified a somatic mutation in AKT1, which results in a glutamic acid to lysine substitution (p.Glu17Lys or E17K). E17K mutations appear almost exclusively in breast cancers of luminal origin. Cellular models involving cell lines such as human mammary epithelial and MCF10 are model systems that upon transformation lead to rare forms of human breast cancer. Hence, we studied the effects of E17K using a clinically pertinent luminal cell line model while providing evidence to explain why E17K mutations do not occur in the mammary myoepithelium. Thus the purpose of our study was to perform a functional and differential proteomics study to assess the role of AKT1(E17K) in the development of breast cancer. We used a set of genetically matched nontumorigenic and tumorigenic mammary luminal and myoepithelial cells. We demonstrated that in myoepithelial cells, expression of E17K inhibited growth, migration, and protein synthesis compared with wild-type AKT1. In luminal cells, E17K enhanced cell survival and migration, possibly offering a selective advantage in this type of cell. However, antineoplastic effects of E17K in luminal cells, such as inhibition of growth and protein synthesis, may ultimately be associated with favorable prognosis. Our study illustrates the importance of cellular context in determining phenotypic effects of putative oncogenic mutations. PMID- 22505017 TI - Recombinant human albumin supports single cell cloning of CHO cells in chemically defined media. AB - Biologic drugs, such as monoclonal antibodies, are commonly made using mammalian cells in culture. The cell lines used for manufacturing should ideally be clonal, meaning derived from a single cell, which represents a technically challenging process. Fetal bovine serum is often used to support low cell density cultures, however, from a regulatory perspective, it is preferable to avoid animal-derived components to increase process consistency and reduce the risk of contamination from adventitious agents. Chinese hamster ovary (CHO) cells are the most widely used cell line in industry and a large number of serum-free, protein-free, and fully chemically defined growth media are commercially available, although these media alone do not readily support efficient single cell cloning. In this work, we have developed a simple, fully defined, single-cell cloning media, specifically for CHO cells, using commercially available reagents. Our results show that a 1:1 mixture of CD-CHOTM and DMEM/F12 supplemented with 1.5 g/L of recombinant albumin (Albucult(r)) supports single cell cloning. This formulation can support recovery of single cells in 43% of cultures compared to 62% in the presence of serum. PMID- 22505019 TI - Virus capture using anionic polymer-coated magnetic beads (review). AB - The recent incidence of emerging and re-emerging viruses is a serious health concern worldwide. The development of transportation systems, such as air travel, has increased the risk of a global pandemic caused by emerging viruses. Agents causing novel infections are often zoonotic, crossing from the natural host into the human population. Hence, comprehensive surveillance of virus-infected animals as well as humans is required. However, the number of virus particles in clinical and environmental samples is usually very low. Thus, a method to concentrate the virus is sometimes required in order to enable detection. We recently reported that magnetic beads coated with an anionic polymer, poly(methyl vinyl ether maleic anhydride) can be used to facilitate the rapid and sensitive detection of viruses. In this review, we describe recent developments for concentrating viruses using anionic magnetic beads. PMID- 22505018 TI - Multimodal interventional molecular imaging of tumor margins and distant metastases by targeting alphavbeta3 integrin. AB - alpha(v)beta(3) integrin is involved in (tumor-induced) angiogenesis and is a promising candidate for the specific visualization of both primary tumors and of their distant metastases. Combination of radioactive and fluorescent imaging labels in a single multimodal, or rather hybrid, RGD-based imaging agent enables integration of pre-, intra-, and postoperative angiogenesis imaging. A hybrid imaging agent targeting the alpha(v)beta(3) integrin--(111)In-MSAP-RGD (MSAP = multifunctional single-attachment-point reagent), which contains a targeting moiety, a pentetic acid (DTPA) chelate, and a cyanine dye--was evaluated for its potential value in combined lesion detection and interventional molecular imaging in a 4T1 mouse breast cancer model. SPECT/CT and fluorescence imaging were used to visualize the tumor in vivo. Tracer distribution was evaluated ex vivo down to the microscopic level. The properties of (111)In-MSAP-RGD were compared with those of (111)In-DTPA-RGD. Biodistribution studies revealed a prolonged retention and increased tumor accumulation of (111)In-MSAP-RGD relative to (111)In-DTPA RGD. With (111)In-MSAP-RGD, identical features could be visualized preoperatively (SPECT/CT) and intraoperatively (fluorescence imaging). As well as the primary tumor, (111)In-MSAP-RGD also enabled detection and accurate excision of distant metastases in the head and neck region of the mice. Therefore, the hybrid RGD derivative (111)In-MSAP-RGD shows potential in preoperative planning and fluorescence-based surgical intervention. PMID- 22505020 TI - Characteristics of a phage effective for colibacillosis control in poultry. AB - BACKGROUND: Colibacillosis is one of the main causes of economic loss in the poultry industry worldwide. Although antibiotics have been used to control this infection, the emergence of antibiotic-resistant bacteria poses a threat to animal and human health. Phage therapy has been reported as one of the potential alternative methods to control bacterial infections. However, efficient phage therapy is highly dependent on the characteristics of the phage isolated. In the present study the characteristics of a lytic phage, OEC1, which was found to be effective against the causative agent of colibacillosis in chickens in a previous in vivo study, are reported. RESULTS: Examination by transmission electron microscopy revealed that OEC1 is a DNA phage belonging to the Podoviridae family. OEC1 showed an optimum multiplicity of infection of 0.1-1. The latent period of OEC1 was 25 min, with a burst size of 200 particles per infected cell. Under the experimental conditions the maximum adsorption rate for OEC1 was 99.9% within 8 min. OEC1 demonstrated an optimum phage lytic activity at pH 6-9 and 25-41 degrees C. CONCLUSION: These characteristics can serve as a guideline for selection of effective candidates for phage therapy, in this case for collibacillosis control in chickens. PMID- 22505021 TI - Rh-catalyzed [5+1] and [4+1] cycloaddition reactions of 1,4-enyne esters with CO: a shortcut to functionalized resorcinols and cyclopentenones. AB - We have developed novel Rh-catalyzed [n+1]-type cycloadditions of 1,4-enyne esters, which involve an acyloxy migration as a key step. The efficient preparation of functionalized resorcinols, including biaryl derivatives, from readily available 1,4-enyne esters and CO was achieved by Rh-catalyzed [5+1] cycloaddition accompanied by 1,2-acyloxy migration. When enyne esters had an internal alkyne moiety, the reaction proceeded by a [4+1]-type cycloaddition involving 1,3-acyloxy migration, leading to cyclopentenones. PMID- 22505022 TI - DNA hybridization assay at individual, biofunctionalized zinc oxide nanowires. AB - Reliable and efficient identification of DNA is a major goal in on-site diagnostics. One dimensional nanostructures like nanowires (NW) represent potential sensor structures due to their extreme surface-to-bulk ratio, enabling enhanced biomolecule binding which results in optimal signals. While silicon NW are already well studied, NW made from other materials with promising properties like ZnO are not yet established as NW sensor material for bioanalytics. Here we demonstrate the DNA functionalization of ZnO NW even at the single NW level and their successful application in a DNA hybridization assay. PMID- 22505023 TI - The TLR7 7926A>G polymorphism is associated with susceptibility to systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder that predominantly affects women of childbearing age, with a female-to-male ratio of approximately 9:1. Previous findings indicated that male cases of SLE were associated with Klinefelter's syndrome (47, XXY), whereas females with Turner's syndrome (45, X0) did not contract SLE. Additionally, duplicated Toll-like receptor 7 (TLR7) was found to promote lupus-like disease. Consequently, the aim of this study was to evaluate whether the TLR7 gene served as a genetic marker for the development of SLE. A case-control study was performed on one tag single nucleotide polymorphism TLR7 rs1634323 in a population with 507 SLE patients and 513 healthy controls. Genotyping was determined by the TaqMan genotyping assay using the ABI 7300 real-time reverse transcription polymerase chain reaction system. The results showed a significantly elevated risk of SLE with the rs1634323 AG genotype in females (P = 0.040, OR = 1.897, 95% CI 1.031-3.491), whereas a similar association was not replicated in males (P = 0.303, OR = 0.338, 95% CI 0.043-2.656). In a subgroup analysis by clinical manifestation of lupus nephritis, no significant differences were found. These findings indicate that the TLR7 gene rs1634323 polymorphism may contribute to SLE susceptibility in females. PMID- 22505024 TI - Chk1 phosphorylates the tumour suppressor Mig-6, regulating the activation of EGF signalling. AB - The tumour suppressor gene product Mig-6 acts as an inhibitor of epidermal growth factor (EGF) signalling. However, its posttranslational modifications and regulatory mechanisms have not been elucidated. Here, we investigated the phosphorylation of human Mig-6 and found that Chk1 phosphorylated Mig-6 in vivo as well as in vitro. Moreover, EGF stimulation promoted phosphorylation of Mig-6 without DNA damage and the phosphorylation was inhibited by depletion of Chk1. EGF also increased Ser280-phosphorylated Chk1, a cytoplasmic-tethering form, via PI3K pathway. Mass spectrometric analyses suggested that Ser 251 of Mig-6 was a major phosphorylation site by Chk1 in vitro and in vivo. Substitution of Ser 251 to alanine increased inhibitory activity of Mig-6 against EGF receptor (EGFR) activation. Moreover, EGF-dependent activation of EGFR and cell growth were inhibited by Chk1 depletion, and were rescued by co-depletion of Mig-6. Our results suggest that Chk1 phosphorylates Mig-6 on Ser 251, resulting in the inhibition of Mig-6, and that Chk1 acts as a positive regulator of EGF signalling. This is a novel function of Chk1. PMID- 22505025 TI - The mechanism of gamma-Secretase dysfunction in familial Alzheimer disease. AB - The mechanisms by which mutations in the presenilins (PSEN) or the amyloid precursor protein (APP) genes cause familial Alzheimer disease (FAD) are controversial. FAD mutations increase the release of amyloid beta (Abeta)42 relative to Abeta40 by an unknown, possibly gain-of-toxic-function, mechanism. However, many PSEN mutations paradoxically impair gamma-secretase and 'loss-of function' mechanisms have also been postulated. Here, we use kinetic studies to demonstrate that FAD mutations affect Abeta generation via three different mechanisms, resulting in qualitative changes in the Abeta profiles, which are not limited to Abeta42. Loss of E-cleavage function is not generally observed among FAD mutants. On the other hand, gamma-secretase inhibitors used in the clinic appear to block the initial E-cleavage step, but unexpectedly affect more selectively Notch than APP processing, while modulators act as activators of the carboxypeptidase-like (gamma) activity. Overall, we provide a coherent explanation for the effect of different FAD mutations, demonstrating the importance of qualitative rather than quantitative changes in the Abeta products, and suggest fundamental improvements for current drug development efforts. PMID- 22505026 TI - The location of splenic NKT cells favours their rapid activation by blood-borne antigen. AB - Natural killer T (NKT) cells play an important role in mounting protective responses to blood-borne infections. However, though the spleen is the largest blood filter in the body, the distribution and dynamics of NKT cells within this organ are not well characterized. Here we show that the majority of NKT cells patrol around the marginal zone (MZ) and red pulp (RP) of the spleen. In response to lipid antigen, these NKT cells become arrested and rapidly produce cytokines, while the small proportion of NKT cells located in the white pulp (WP) exhibit limited activation. Importantly, disruption of the splenic MZ by chemical or genetic approaches results in a severe reduction in NKT cell activation indicating the need of cooperation between both MZ macrophages and dendritic cells for efficient NKT cell responses. Thus, the location of splenic NKT cells in the MZ and RP facilitates their access to blood-borne antigen and enables the rapid initiation of protective immune responses. PMID- 22505027 TI - The yeast RPL9B gene is regulated by modulation between two modes of transcription termination. AB - RNA Pol II transcription termination can occur by at least two alternative pathways. Cleavage and polyadenylation by the CPF/CF complex precedes mRNA transcription termination, while the Nrd1 complex is involved in transcription termination of non-coding RNAs such as sno/snRNAs or cryptic unstable transcripts. Here we show that transcription of RPL9B, one of the two genes coding for the ribosomal protein Rpl9p, terminates by either of these two pathways. The balance between these two pathways is modulated in response to the RPL9 gene copy number, resulting in the autoregulation of RPL9B gene expression. This autoregulation mechanism requires a conserved potential stem-loop structure very close to the polyadenylation sites. We propose a model in which Rpl9p, when in excess, binds this conserved 3'-UTR structure, negatively interfering with cleavage and polyadenylation to the benefit of the Nrd1-dependent termination pathway, which, being coupled to degradation by the nuclear exosome, results in downregulation of RPL9B gene expression. PMID- 22505028 TI - Shifting a complex debate on gamma-secretase cleavage and Alzheimer's disease. PMID- 22505029 TI - Oligomers of the ATPase EHD2 confine caveolae to the plasma membrane through association with actin. AB - Caveolae are specialized domains present in the plasma membrane (PM) of most mammalian cell types. They function in signalling, membrane regulation, and endocytosis. We found that the Eps-15 homology domain-containing protein 2 (EHD2, an ATPase) associated with the static population of PM caveolae. Recruitment to the PM involved ATP binding, interaction with anionic lipids, and oligomerization into large complexes (60-75S) via interaction of the EH domains with intrinsic NPF/KPF motifs. Hydrolysis of ATP was essential for binding of EHD2 complexes to caveolae. EHD2 was found to undergo dynamic exchange at caveolae, a process that depended on a functional ATPase cycle. Depletion of EHD2 by siRNA or expression of a dominant-negative mutant dramatically increased the fraction of mobile caveolar vesicles coming from the PM. Overexpression of EHD2, in turn, caused confinement of cholera toxin B in caveolae. The confining role of EHD2 relied on its capacity to link caveolae to actin filaments. Thus, EHD2 likely plays a key role in adjusting the balance between PM functions of stationary caveolae and the role of caveolae as vesicular carriers. PMID- 22505030 TI - 40S subunit dissociation and proteasome-dependent RNA degradation in nonfunctional 25S rRNA decay. AB - Eukaryotic cells have quality control systems that eliminate nonfunctional rRNAs with deleterious mutations (nonfunctional rRNA decay, NRD). We have previously reported that 25S NRD requires an E3 ubiquitin ligase complex, which is involved in ribosomal ubiquitination. However, the degradation process of nonfunctional ribosomes has remained unknown. Here, using genetic screening, we identified two ubiquitin-binding complexes, the Cdc48-Npl4-Ufd1 complex (Cdc48 complex) and the proteasome, as the factors involved in 25S NRD. We show that the nonfunctional 60S subunit is dissociated from the 40S subunit in a Cdc48 complex-dependent manner, before it is attacked by the proteasome. When we examined the nonfunctional 60S subunits that accumulated under proteasome-depleted conditions, the majority of mutant 25S rRNAs retained their full length at a single nucleotide resolution. This indicates that the proteasome is an essential factor triggering rRNA degradation. We further showed that ribosomal ubiquitination can be stimulated solely by the suppression of the proteasome, suggesting that ubiquitin-proteasome-dependent RNA degradation occurs in broader situations, including in general rRNA turnover. PMID- 22505033 TI - Expression pattern of ataxia telangiectasia mutated (ATM), p53, Akt, and glycogen synthase kinase-3beta in the striatum of rats treated with 3-nitropropionic acid. AB - 3-Nitropropionic acid (3-NPA) is a mitochondrial toxin used in the laboratory to replicate neurodegenerative conditions that are accompanied by degeneration of the caudate-putamen. 3-NPA induces depletion in ATP production, reactive oxygen species production, and secondary excitotoxicity mediated by activation of N methyl-D-aspartate receptors that culminates in the triggering of cell death mechanisms, including apoptosis. We here examined by immunohistochemical methods whether cellular expression of phospho(Ser1981) -ataxia telangiectasia mutated (ATM), phospho(Ser15) -p53, phospho(Ser473) -Akt, and phospho(Ser9) -glycogen synthase kinase-3beta (GSK3beta), which are key signal molecules that play a critical role in regulating cellular processes related to cell survival and demise, were involved in the striatal neurodegeneration in the brains of rats treated with 3-NPA. Our results indicate that the toxin induced the activation of ATM and p53 only in astrocytes, and a role for these proteins in neuronal degeneration was ruled out. On the other hand, striatal neurons lost the active form of Akt as soon as they began to appear pyknotic, indicating impairment of the PI3K/Akt/GSK3 pathway in their degenerative process. The inactive form of GSK3beta was detected extensively, mainly in the rim of the striatal lesions around degenerating neurons, which could be attributed to a cell death or cell survival response. PMID- 22505032 TI - Genetic inactivation of Cdk7 leads to cell cycle arrest and induces premature aging due to adult stem cell exhaustion. AB - Cyclin-dependent kinase (Cdk)7, the catalytic subunit of the Cdk-activating kinase (CAK) complex has been implicated in the control of cell cycle progression and of RNA polymerase II (RNA pol II)-mediated transcription. Genetic inactivation of the Cdk7 locus revealed that whereas Cdk7 is completely dispensable for global transcription, is essential for the cell cycle via phosphorylation of Cdk1 and Cdk2. In vivo, Cdk7 is also indispensable for cell proliferation except during the initial stages of embryonic development. Interestingly, widespread elimination of Cdk7 in adult tissues with low proliferative indexes had no phenotypic consequences. However, ablation of conditional Cdk7 alleles in tissues with elevated cellular turnover led to the efficient repopulation of these tissues with Cdk7-expressing cells most likely derived from adult stem cells that may have escaped the inactivation of their targeted Cdk7 alleles. This process, a physiological attempt to maintain tissue homeostasis, led to the attrition of adult stem cell pools and to the appearance of age-related phenotypes, including telomere shortening and early death. PMID- 22505031 TI - Large conformational changes in MutS during DNA scanning, mismatch recognition and repair signalling. AB - MutS protein recognizes mispaired bases in DNA and targets them for mismatch repair. Little is known about the transient conformations of MutS as it signals initiation of repair. We have used single-molecule fluorescence resonance energy transfer (FRET) measurements to report the conformational dynamics of MutS during this process. We find that the DNA-binding domains of MutS dynamically interconvert among multiple conformations when the protein is free and while it scans homoduplex DNA. Mismatch recognition restricts MutS conformation to a single state. Steady-state measurements in the presence of nucleotides suggest that both ATP and ADP must be bound to MutS during its conversion to a sliding clamp form that signals repair. The transition from mismatch recognition to the sliding clamp occurs via two sequential conformational changes. These intermediate conformations of the MutS:DNA complex persist for seconds, providing ample opportunity for interaction with downstream proteins required for repair. PMID- 22505034 TI - Differential expression of semaphorin 3A and its receptors during mouse retinal development. AB - Semaphorins not only function in axon guidance during development but also contribute to various other biological processes. We have now examined the expression of semaphorin 3A (Sema3A) and its receptor components neuropilin 1 (Npn1) and plexin A (PlxA) during development of the mouse retina. Immunohistofluorescence analysis revealed that the expression patterns of Sema3A and Npn1 were similar during embryonic and postnatal development. The expression pattern of PlxA was also similar to those of Sema3A and Npn1 during embryonic and early postnatal (before eye opening) developments. However, the pattern of PlxA expression changed markedly after eye opening, with the expression disappearing from the optic nerve and increasing in intensity in the retinal pigment epithelium. Immunoprecipitation analysis showed that Sema3A interacted with PlxA in the retinal pigment epithelial cell line ARPE19 but not in the retinal ganglion cell line RGC5, whereas the opposite pattern of association was apparent for Sema3A and Npn1. Given that atmospheric oxygen is thought to play a role in the differentiation and maintenance of various ocular cell types, our results suggest that Sema3A-PlxA signalling activated by an effect of ambient oxygen on PlxA expression may contribute to differentiation of the retinal pigment epithelium. PMID- 22505035 TI - Are internet service providers responsible for online suicide pacts? PMID- 22505036 TI - Clinical commissioning teams: pathfinders in shaping local health services. PMID- 22505037 TI - 6000 patients are left in limbo as private company fails to record radiograph results. PMID- 22505038 TI - Killing in combat may be independently associated with suicidal ideation. AB - BACKGROUND: The United States military has lost more troops to suicide than to combat for the second year in a row and better understanding combat-related risk factors for suicide is critical. We examined the association of killing and suicide among war veterans after accounting for PTSD, depression, and substance use disorders. METHODS: We utilized a cross-sectional, retrospective, nationally representative sample of Vietnam veterans from the National Vietnam Veterans Readjustment Study (NVVRS). In order to perform a more in depth analysis, we utilized a subsample of these data, the NVVRS Clinical Interview Sample (CIS), which is representative of 1.3 million veterans who were eligible for the clinical interview by virtue of living in proximity to an interview site, located within 28 standard metropolitan regions throughout the United States. RESULTS: Veterans who had higher killing experiences had twice the odds of suicidal ideation, compared to those with lower or no killing experiences (OR = 1.99, 95% CI = 1.07-3.67), even after adjusting for demographic variables, PTSD, depression, substance use disorders, and adjusted combat exposure. PTSD (OR = 3.42, 95% CI = 1.09-10.73), depression (OR = 11.49, 95% CI = 2.12-62.38), and substance use disorders (OR = 3.98, 95% CI = 1.01-15.60) were each associated with higher odds of suicidal ideation. Endorsement of suicide attempts was most strongly associated with PTSD (OR = 5.52, 95% CI = 1.21-25.29). CONCLUSIONS: Killing experiences are not routinely examined when assessing suicide risk. Our findings have important implications for conducting suicide risk assessments in veterans of war. Depression and Anxiety 00:1-6, 2012. (c) 2012 Wiley Periodicals, Inc. PMID- 22505039 TI - Detection of Merkel cell polyomavirus and human papillomaviruses in Merkel cell carcinoma combined with squamous cell carcinoma in immunocompetent European patients. AB - BACKGROUND: About 10% of patients with Merkel cell carcinoma (MCC) suffer from an associated squamous cell carcinoma (SCC). In European patients, Merkel cell polyomavirus (MCPyV) is detectable in 60%-88% of the MCC tumors. In combined lesions, MCPyV was not detectable so far. METHODS: We investigated 2 combined tumors of MCC and SCC for the presence of MCPyV and human papillomavirus (HPV) by polymerase chain reaction and immunohistochemistry. RESULTS: In both lesions, MCPyV DNA was found, and in 1 case, HPV DNA was also detected. This is the first report of a coinfection with HPV and MCPyV in combined MCC-SCC tumors. CONCLUSIONS: The results underline the hypothesis of co-cancerogenesis of 2 oncogenic viruses in nonmelanoma skin cancer. Technical reasons and a low viral copy number of MCPyV hampering immunohistochemical detection may be responsible for the negative results in the literature. PMID- 22505040 TI - Nevus lipomatosus superficialis with dilated hair follicles: an epithelial component in hamartomatous nevoid skin anomalies. PMID- 22505041 TI - Dermatopathology test taking becoming globalized: taking the International Board Certification in Dermatopathology (Diploma in Dermatopathology) (ICDP/UEMS). PMID- 22505043 TI - Infundibular squamous cell carcinoma: a new entity? PMID- 22505044 TI - Staying alive: PI3K pathway promotes primordial follicle activation and survival in response to 3MC-induced ovotoxicity. AB - 3-Methylcholanthrene (3MC) is a potent ovotoxicant capable of causing premature ovarian failure through primordial follicle depletion. Despite 3MCs ovotoxicity having been established for 30 years, relatively little information exists on the mechanisms. In this study, we examined the effects of 3MC exposure on the immature ovarian follicle population. Microarray analysis revealed a complex mechanism of 3MC-induced ovotoxicity involving a number of cellular processes associated with xenobiotic metabolism, ovarian cancer, cell cycle progression, and cell death. 3MC exposure was also found to induce developing follicle atresia and aberrant primordial follicle activation via the stimulation of PI3K/Akt and mammalian target of rapamycin (mTOR) signaling pathways. Inhibition of PI3K/Akt signaling resulted in the severe depletion of the primordial follicle pool, with further analysis identifying increased Akt1-stimulated Bad phosphoinhibition in 3MC-treated primordial follicles. Our results suggest that the primordial follicle pool enters a "prosurvival" state upon 3MC exposure and that its depletion is due to a vicious cycle of primordial follicle activation in an attempt to replace developing follicles undergoing follicular atresia. PMID- 22505045 TI - Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. AB - Assessing the impact of variants of unknown significance (VUS) on splicing is a key issue in molecular diagnosis. This impact can be predicted by in silico tools, but proper evaluation and user guidelines are lacking. To fill this gap, we embarked upon the largest BRCA1 and BRCA2 splice study to date by testing 272 VUSs (327 analyses) within the BRCA splice network of Unicancer. All these VUSs were analyzed by using six tools (splice site prediction by neural network, splice site finder (SSF), MaxEntScan (MES), ESE finder, relative enhancer and silencer classification by unanimous enrichment, and human splicing finder) and the predictions obtained were compared with transcript analysis results. Combining MES and SSF gave 96% sensitivity and 83% specificity for VUSs occurring in the vicinity of consensus splice sites, that is, the surrounding 11 and 14 bases for the 5' and 3' sites, respectively. This study was also an opportunity to define guidelines for transcript analysis along with a tentative classification of splice variants. The guidelines drawn from this large series should be useful for the whole community, particularly in the context of growing sequencing capacities that require robust pipelines for variant interpretation. PMID- 22505046 TI - Modulation of the antioxidant activity of phenols by non-covalent interactions. AB - Non-covalent (H-bonding) interactions, either intramolecular or with the surrounding medium, have a major influence on the activity of natural and synthetic phenolic antioxidants, due to the modulation of their reactivity with radical species, such as peroxyl radicals. Different cases can be distinguished. (i) Intra- or inter-molecular H-bonding involving the reactive -OH moiety will depress the antioxidant activity if the -OH acts as H-bond donor, while the opposite will generally occur if it acts as H-bond acceptor. (ii) Remote intra- and inter-molecular H-bonding, involving a distant -OH group (in polyphenols) or a ring substituent, may increase or decrease the reactivity of an antioxidant toward free radicals, depending on whether the stabilization produced by the H bond increases or decreases along the reaction coordinate, on proceeding from reactants to the transition state. In this Perspective, the role of non-covalent interactions in the complex chemistry of natural polyphenolic antioxidants is discussed with the aid of literature data on simplified model compounds, aiming at the composition of a clear picture that might guide future research. PMID- 22505047 TI - A single nucleotide polymorphism in ycdC alters tRNA synthetase expression and results in hypersecretion in Escherichia coli. AB - The most important approach to the development of platform organisms for recombinant protein production relies on random mutagenesis and phenotypic selection. Complex phenotypes, including those associated with significantly elevated expression and secretion of heterologous proteins, are the result of multiple genomic mutations. Using next generation sequencing, a parent and derivative hypersecreter strain (B41) of Escherichia coli were sequenced with an average coverage of 52.8X and 55X, respectively. A new base-pair calling program, revealed a single nucleotide polymorphism in the B41 genome at position 1,074,787, resulting in translation termination near the N-terminus of a transcriptional regulator protein, RutR, coded by the ycdC gene. We verified the hypersecretion phenotype in a ycdC::Tn5 mutant and observed a 3.4-fold increase in active hemolysin secretion, consistent with the increase observed in B41 strain. mRNA expression profiling showed decreased expression of tRNA-synthetases and some amino acid transporters in the ycdC::Tn5 mutant. This study demonstrates the power of next generation sequencing to characterize mutants leading to successful metabolic engineering strategies for strain improvement. PMID- 22505048 TI - Outer retinal thickness and retinal sensitivity in macula-off rhegmatogenous retinal detachment after successful reattachment. AB - PURPOSE: To determine the relationship between the retinal thickness and sensitivity of the macular region after successful reattachment of an acute macula-off rhegmatogenous retinal detachment (RRD). METHODS: Twenty-three eyes of 23 patients with an acute macula-off RRD were studied (17 men, 6 women). The mean age of the patients was 53.2+/-14.7 years with a range from 20 to 73 years. The interval between the decrease in vision and surgery was <14 days in all cases. At 3 and 6 months after the surgery, the thickness of the inner and outer retina was determined by spectral-domain optical coherence tomography, and the retinal sensitivity was measured by microperimetry with MP-1. The values were compared to those obtained from the unaffected fellow eyes. Changes in the best-corrected visual acuity (BCVA), retinal thickness, and retinal sensitivity at 3 and 6 months from the baseline values were studied. RESULTS: Ten eyes were treated by scleral buckling (SB) and 13 eyes by pars plana vitrectomy (PPV), and the retina was reattached in all eyes. The mean BCVA was significantly improved at 3 and 6 months postoperatively (p<0.001, <0.001). The outer retina of macula was significantly thicker after SB than after PPV (p=0.023 at 3 months; p=0.045 at 6 months). The retinal sensitivity of the central 10 degrees of the retinas after SB was lower than that of eyes after PPV (p=0.029 at 3 months and p=0.008 at 6 months). CONCLUSIONS: The delay in the recovery of outer retinal thickness may be the cause of the lower sensitivity of the macula. PMID- 22505049 TI - 13q deletion syndrome and retinoblastoma in identical dichorionic diamniotic monozygotic twins. AB - PURPOSE: To report the case of identical dichorionic diamniotic female twins with unilateral retinoblastoma in 13q deletion syndrome. METHODS: Clinical and ophthalmoscopic evaluation, combination of multiple ligation-dependent probe amplification, array-comparative genomic hybridization analyses, and magnetic resonance imaging were performed. RESULTS: Peculiar facial features, marked hypotonia, gastroesophageal reflux, interatrial septal defect with left to right shunt and light dilatation of right chambers, 5th finger hypoplasia, 3rd-5th toes clinodactyly, 2nd toe overlapped to 3rd toe, and cutis marmorata were found. Ophthalmoscopic evaluation revealed unilateral retinoblastoma in both girls. Magnetic resonance imaging detected corpus callosum hypoplasia in both twins. A 34.4-Mb deletion involving bands 13q13.2-q21.33 and including the RB1 gene was identified in both twins. The deletion was not present in the DNA of their parents and older brother. CONCLUSIONS: Dysmorphic features in children must be always suspicious of 13q deletion syndrome and a short ophthalmoscopic follow-up is necessary to detect the presence of a retinoblastoma. PMID- 22505050 TI - Do children and adolescents with attention deficit hyperactivity disorder have ocular abnormalities? AB - PURPOSE: To investigate visual function and ocular features in children with attention deficit hyperactivity disorder (ADHD). METHODS: Fifty-one children underwent a detailed ophthalmologic evaluation. Thirty-two were diagnosed with ADHD, and 19 children with attention deficit disorder (ADD). The mean age was 9.9+/-3.1 years. RESULTS: The average best-corrected visual acuity of the better seeing eye was 1 (range 0.9-1.25) and 0.96 (range 0.5-1.25) for the fellow eye. Eighteen percent (10) had amblyopia in one or both eyes (3 had strabismic and 7 had ametropic amblyopia). Heterotropia was found in 5 (10%), and absent stereo acuity was found in 3 (6%). Subnormal convergence amplitude was noted in 2 patients (4%). The mean spherical equivalent (SE) of the eyes in this study was 0.17+/-1.73 (range -5.5 to +7). Twenty-two subjects (43%) had a myopia of -0.50 D or higher. Hyperopia higher than 3.5 D was seen in 10 cases(20%), and astigmatism larger or equal to 1.0 D was observed in 10 patients (20%). With-the-rule a stigmatism was by far most common type in the 29 eyes with an astigmatic refractive error (59%).Significant ametropia was detected in 42 (83%) of the patients. In contrast to other studies, we did not find a higher rate of convergence insufficiency or heterotropia. CONCLUSIONS: Children diagnosed with either ADHD or ADD can present with significant ametropia but infrequent heterotropia. PMID- 22505051 TI - Use of a multicomponent reaction for chemoselective derivatization of multiple classes of metabolites. AB - We demonstrate that the Ugi reaction enables chemoselective derivatization of biological amines, carboxylic acids, aldehydes, or ketones with a chromophore under one set of reaction conditions, even in the presence of water. Derivatization of neurotransmitters, hormones, disease biomarkers and other metabolites bodes well for systems biology and diagnostic medicine. PMID- 22505052 TI - Silencing of c-kit with small interference RNA attenuates inflammation in a murine model of allergic asthma. AB - Asthma is a chronic respiratory disease characterized by the inflammation of the airways due to infiltration and activation of several inflammatory cells that produce cytokines. c-kit, a proto-oncogene that encodes a tyrosine kinase receptor, has been found to be associated with allergic inflammation. The aim of the present study was to assess whether silencing of c-kit with small interference RNA (siRNA) would attenuate inflammation in allergic asthma. A mouse model of ovalbumin (OVA)-induced allergic asthma was treated with systemic administration of anti-c-kit siRNA to inhibit the expression of the c-kit gene. siRNAs were injected through the vena caudalis. We measured inflammatory response in both anti-c-kit siRNA-treated and control mice. Systemic administration of siRNA could effectively inhibit the expression of the c-kit gene and reduce the infiltration of inflammatory cells (eosinophils and lymphocytes) into the lung tissue and bronchoalveolar lavage fluid. In addition, we found that c-kit siRNA can decrease the production of the T-helper type 2 (Th2) cytokines, interleukin 4 (IL-4) and IL-5, but has no influence on IFN-gamma generation. These results show that inhibition of c-kit expression with siRNA can reduce the inflammatory response in allergic asthma. PMID- 22505053 TI - 3 d metal ions in highly unusual eight-coordination: the phosphate-capped dodecapalladate(II) nanocube. AB - Trapped in a noble cube: A novel family of noble metalates has been discovered in which a 3d metal ion M (M = Mn(II), Fe(III), Co(II), Cu(II), Zn(II)) is encapsulated by a 12 palladium-oxo cage {Pd(12)O(32)}, which is capped by eight phosphate groups. Such discrete nanocubes were further investigated by EPR spectroscopy, electrochemistry, and in homogeneous hydrogenation catalysis. PMID- 22505054 TI - Global alteration in gene expression profiles of deciduas from women with idiopathic recurrent pregnancy loss. AB - Recurrent pregnancy loss (RPL) occurs in ~5% of women. However, the etiology is still poorly understood. Defects in decidualization of the endometrium during early pregnancy contribute to several pregnancy complications, such as pre eclampsia and intrauterine growth restriction (IUGR), and are believed to be important in the pathogenesis of idiopathic RPL. We performed microarray analysis to identify gene expression alterations in the deciduas of idiopathic RPL patients. Control patients had one antecedent term delivery, but were undergoing dilation and curettage for current aneuploid miscarriage. Gene expression differences were evaluated using both pathway and gene ontology (GO) analysis. Selected genes were validated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). A total of 155 genes were found to be significantly dysregulated in the deciduas of RPL patients (>2-fold change, P < 0.05), with 22 genes up-regulated and 133 genes down-regulated. GO analysis linked a large percentage of genes to discrete biological functions, including immune response (23%), cell signaling (18%) and cell invasion (17.1%), and pathway analysis revealed consistent changes in both the interleukin 1 (IL-1) and IL-8 pathways. All genes in the IL-8 pathway were up-regulated while genes in the IL-1 pathway were down-regulated. Although both pathways can promote inflammation, IL-1 pathway activity is important for normal implantation. Additionally, genes known to be critical for degradation of the extracellular matrix, including matrix metalloproteinase 26 and serine peptidase inhibitor Kazal-type 1, were also highly up-regulated. In this first microarray approach to decidual gene expression in RPL patients, our data suggest that dysregulation of genes associated with cell invasion and immunity may contribute significantly to idiopathic recurrent miscarriage. PMID- 22505056 TI - A comparison of the acute haemodynamic response to aerobic and resistance exercise in subjects with exercise-induced pulmonary arterial hypertension. AB - BACKGROUND: Exercise-induced pulmonary arterial hypertension (EIPAH) is associated with reduced exercise capacity and abnormal central haemodynamic responses to maximal aerobic exercise. Aerobic and resistance exercise training are commonly employed to treat reduced exercise capacity; however, the haemodynamic response to aerobic and resistance exercise, at training intensities, in subjects with EIPAH is unknown. METHODS: Fourteen subjects (11 with scleroderma, 12 females) with EIPAH underwent cardiopulmonary exercise testing on a cycle ergometer, a one-repetition maximum (1RM) strength test and resistance exercise at 40% and 60% of maximum on a bilateral leg press machine. All tests were performed with a pulmonary artery catheter in situ. Haemodynamic and symptomatic responses to aerobic and resistance exercise, performed at 40% of peak oxygen consumption and 40% of 1RM, and at 60% of peak oxygen consumption and 60% of 1RM, were compared. For maximal exercise, the highest haemodynamic responses recorded during the cycling and 1RM tests were compared. RESULTS: There were no differences in haemodynamic or symptomatic responses between the two modalities of submaximal exercise. At maximal exercise, all haemodynamic and symptomatic responses were lower during resistance compared with aerobic exercise (p < 0.05). CONCLUSIONS: At the intensities studied, lower-limb resistance exercise was well tolerated and was mostly associated with similar or lower haemodynamic responses compared with aerobic exercise, in subjects with EIPAH. PMID- 22505055 TI - Eccentric endurance exercise economically improves metabolic and inflammatory risk factors. AB - INTRODUCTION: Exercise is a cornerstone of cardiovascular prevention. Because many individuals are not willing or not able to perform regular exercise, new methods of exercise (like eccentric exercise) are necessary. Eccentric endurance exercise is supposed to be less strenuous than concentric exercise but its effects on glucose and lipid metabolism in relation to energy expenditure are unclear. METHODS: We randomly allocated 45 healthy sedentary individuals to one of two groups, each hiking upwards or downwards for 2 months, with a crossover for a further 2 months; for the opposite way, a cable car was used. The difference in altitude was 540 metres; the distance was covered between three and five times a week. Energy expenditure was assessed for each hiking period. RESULTS: Both eccentric and concentric endurance exercise improved glucose tolerance vs. baseline (by 4.1%, p = 0.136; 6.2%, p = 0.023, respectively). Of note, adjustment for energy expenditure per exercise unit (127 +/- 22 kcal/unit with eccentric and 442 +/- 78 kcal/unit with concentric exercise) revealed a significantly greater improvement of glucose tolerance per kilocalorie spent by eccentric than by concentric exercise (4-times more economical; 0.1123 mg h/dl/kcal vs. 0.0245 mg h/dl/kcal; p = 0.038). Also the decrease of low-density lipoprotein (LDL) cholesterol per kilocalorie spent was significantly stronger with eccentric exercise (0.0982 mg/dl/kcal vs. 0.0346 mg/dl/kcal, p = 0.014). Serum levels of C-reactive protein and creatine kinase activity were reduced in both groups. CONCLUSION: Eccentric endurance exercise economically improves glucose tolerance and LDL cholesterol. It therefore is a promising new exercise modality for individuals who are not able to participate in more strenuous exercise regimens. PMID- 22505058 TI - Chromatographic separation of clenbuterol by bonded phases bearing nano-baskets of p-tert-calix[4]-1,2-crown-3, -crown-4, -crown-5 and -crown-6. AB - BACKGROUND: Clenbuterol (salbutamol), which increases muscle mass and decreases adipose tissue, is misused as a nutrient-repartitioning agent in livestock. In this paper a new sensitive method for determining clenbuterol in livestock is presented. The novelty of this approach is the separation and determination of salbutamol enantiomers with marked quantitative merits. RESULTS: Four proton di ionisable Nano-baskets, namely 5,11,17,23-tetrakis(1,1-dimethylethyl)-25,26 bis(carboxy-methoxy)calix[4]arene-27,28-crown-3, -crown-4, -crown-5 and -crown-6 in the cone conformation, were synthesised and used to prepare bonded phases for high-performance liquid chromatography separation. The new synthesised bonded phases were characterised and optimised. The bonding interactions of solute/bonded phases were examined and the main interactions are reported. CONCLUSION: The clenbuterol levels in six samples of livestock meat (pork, pork casing, beef, beef casing, mutton and mutton casing) were analysed and the results revealed that for the best bonded phases the limits of detection and quantitation were 0.06 and 0.2 ug mL(-1) respectively. PMID- 22505059 TI - Body mass, phylogeny and diet composition affects kidney morphology in passerine birds. AB - We studied the renal morphology of 16 species of passerines to assess whether the composition of the diet of birds have been paralleled by differences in the characteristics of the kidneys. We determined the number and length of the medullary cones and the percentage of renal medulla in birds with contrasting dietary habits and then correlated these features with the percentage of nitrogen and proportion of invertebrates in the diet. To examine the correlation between kidney and diet variables, we first used standard correlation and least square regression, and correlation and regression on phylogenetically independent data. We found that the mass of the medullary portion of the kidney, and the medullary cone length were negatively correlated with the percentage of invertebrates present in the diet. We hypothesized that the further development of the renal medulla observed in granivorous birds may be correlated with the small amount of water present in the seeds. Our results suggest that the availability of water in different foods is probably one of the main factors that have led to structural and probably functional changes of the kidney in the studied species. PMID- 22505057 TI - Regeneration of silica-supported silicotungstic acid as a catalyst for the dehydration of glycerol. AB - The dehydration reaction of glycerol to acrolein is catalyzed by acid catalysts. These catalysts tend to suffer from the formation of carbonaceous species on their surface (coking), which leads to substantial degradation of their performances (deactivation). To regenerate the as-deactivated catalysts, various techniques have been proposed so far, such as the co-feeding of oxygen, continuous regeneration by using a moving catalytic bed, or alternating between reaction and regeneration. Herein, we study the regeneration of supported heteropolyacid catalysts. We show that the support has a strong impact on the thermal stability of the active phase. In particular, zirconia has been found to stabilize silicotungstic acid, thus enabling the nondestructive regeneration of the catalyst. Furthermore, the addition of steam to the regeneration feed has a positive impact by hindering the degradation reaction by equilibrium displacement. The catalysts are further used in a periodic reaction/regeneration process, whereby the possibility of maintaining long-term catalytic performances is evidenced. PMID- 22505061 TI - Image encryption based on interference that uses fractional Fourier domain asymmetric keys. AB - We propose an image encryption technique based on the interference principle and phase-truncation approach in the fractional Fourier domain. The proposed scheme offers multiple levels of security with asymmetric keys and is free from the silhouette problem. Multiple input images bonded with random phase masks are independently fractional Fourier transformed. Amplitude truncation of obtained spectrum helps generate individual and universal keys while phase truncation generates two phase-only masks analytically. For decryption, these two phase-only masks optically interfere, and this results in the phase-truncated function in the output. After using the correct random phase mask, universal key, individual key, and fractional orders, the original image is retrieved successfully. Computer simulation results with four gray-scale images validate the proposed method. To measure the effectiveness of the proposed method, we calculated the mean square error between the original and the decrypted images. In this scheme, the encryption process and decryption keys formation are complicated and should be realized digitally. For decryption, an optoelectronic scheme has been suggested. PMID- 22505060 TI - Variations in signal intensity with periodical temperature changes in vivo in rat brain: analysis using wide-field optical coherence tomography. AB - In a previous study, we reported measurements of three-dimensional (3D) optical coherence tomography (OCT) images through a thinned skull by reducing temperatures from 28 degrees C to 18 degrees C in vivo in the rat brain to show negative correlation coefficients (CCs) between ratios of signal intensity (RSI) and temperature for applications to monitoring brain viability. In this study, using the same OCT system, we measured 3D OCT images of the rat brain by periodically changing tissue temperatures from 20 degrees C to 32 degrees C in vivo. In the evaluation of CCs among RSI, temperature, and heart rate, the largest number of periods was four, and the longest measurement time was 570 min. Averaged CCs between RSI and temperature, and between RSI and heart rate, were 0.42 to -0.50 and -0.48 to -0.64, respectively. RSI reversibly changed subsequent variations of temperatures and finally increased rapidly just before cardiac arrest. These results indicate that RSI could correspond to decreases in viability because of local ischemia and recovery. PMID- 22505062 TI - Embedded corrugated long-period fiber gratings for sensing applications. AB - We demonstrate a method to make possible the mass production of corrugated long period fiber gratings (C-LPFGs) by utilizing imprint lithography on polycarbonate (PC) substrates. For such C-LPFGs whose working principle is based on photoelastic effect, pretensile tension is required to be applied to inducing periodical refractive index variation. We then present an attempt to use PC as embedding material for providing internal compressive stress for C-LPFGs to have a photoelastic effect. This type of LPFG, termed embedded corrugated long-period fiber gratings (EC-LPFGs), is obtained after reimprinting the C-LPFGs into other PC substrates. Since compressive stress is retained due to the materials of different coefficients of thermal expansion (CTE), unlike C-LPFGs, EC-LPFGs can serve as strain, bending, and temperature sensors without the need of pretensile strain. The two most troublesome problems, the fragility of an etched fiber grating and the requirement of pretensile strain, can be simultaneously alleviated or solved by EC-LPFGs. PMID- 22505063 TI - Passive long-range surface plasmon-polariton devices in Cytop. AB - Passive elements operating with long-range surface plasmon polaritons and constructed as Au stripes embedded in Cytop were investigated theoretically and experimentally at wavelengths near 1310 nm. The elements investigated consist of straight waveguides, S-bends, Y-junctions, couplers, and Mach-Zehnder interferometers. The measured performance of these devices is close to theoretical expectations, although uniformity issues were noted, likely because of fabrication imperfections. Cytop is a low-index polymer suitable for biosensing applications involving aqueous buffers. The elements demonstrated thus could form the basis of integrated biosensing devices operating with long-range surface plasmons. PMID- 22505064 TI - Spectral LADAR: active range-resolved three-dimensional imaging spectroscopy. AB - We present the concept and experimental results for Spectral LADAR, an augmented LADAR imager combining three-dimensional (3D) time-of-flight ranging with active multispectral sensing in the shortwave infrared (1080-1620 nm). The demonstrated technique is based on a nanosecond regime pulsed supercontinuum transmitter and spectrally multiplexed receiver that computes a high-resolution range value for each of 25 spectral bands. A low frame-rate prototype unit is described. Results demonstrating 3D imaging and material type classification of objects, especially those obscured by camouflage, are shown at effective stand-off ranges exceeding 40 m. These capabilities and the highly eye safe wavelengths at which the system operates make it suitable for applications in military imaging and robotic perception. PMID- 22505065 TI - Kernel-based parametric analytical model of source intensity distributions in lithographic tools. AB - This paper proposes a parametric analytical source model for overall representation of the physical distribution property of partially coherent illumination sources in lithographic tools. A set of smooth kernels is adopted to construct the analytical model for the multiple mainstream illumination sources. Corrected parametrical terms are subsequently presented for characterization of different physical distortions of and deviations from actual illumination sources. The corrected parametrical terms can be decomposed into Fourier series, which have special physical meanings of respectively indicating different distortion types, including shift of the center, tilt, and ellipticity, etc. We fully expected that the proposed analytical model will provide both simulation conditions and a theoretical basis for the resolution enhancement technique and related research fields. PMID- 22505066 TI - Si-based tunable flattop photodetector with a stepped Fabry-Perot cavity. AB - This paper presents the design and analysis of a Si-based tunable flattop photodetector realized by the introduction of a stepped Fabry-Perot cavity, which can be thermally tuned via applying tuning power on its tuning electrode. By using a transfer matrix method, the spectral response of the photodetector is simulated in detail, indicating a flattop line shape can be achieved with an optimum step height. A trade-off residing in this device between the free spectrum range and the ease of fabrication of step height is also revealed and analyzed. In the final design of the photodetector, 1 dB linewidth of 0.5 nm, 3 dB linewidth of 0.8 nm, 6 dB linewidth of 1.2 nm, peak quantum efficiency of 40%, tuning efficiency of 91 mW/nm are theoretically obtained. We discuss the epitaxial growth and fabrication of the photodetector in the end, exhibiting the mature technique available for this device. PMID- 22505067 TI - Effect of nanosecond laser pre-irradiation on the femtosecond laser-induced damage of Ta2O5/SiO2 high reflector. AB - The effect of nanosecond laser pre-irradiation on the femtosecond laser-induced damage behaviors of 800 nm 0 degrees AOI Ta(2)O(5)/SiO(2) high reflectors fabricated by e-beam evaporation was explored. Laser pre-irradiation was carried out by Raster-scanning with scanning mode of 1-on-1 and scanning velocities timed such that there was a beam overlap at 70% of the peak fluence, utilizing 5 Hz 1064 nm 12 ns Nd:YAG fundamental lasers. Femtosecond laser damage was investigated by 1 kHz 800 nm 135 fs Ti: sapphire laser system with 1-on-1 mode test. The results indicated that nanosecond laser pre-irradiation did not promote the femtosecond laser-induced damage threshold of reflectors. Instead, the thresholds of all the samples with various fluence steps for pre-irradiation were reduced by about 20%. Furthermore, the damage morphologies were analyzed by optical microscope, SEM and AFM, which displayed deterministic field induced breakdown characteristics. To explain these phenomena, a theoretical model including photoionization, avalanche ionization, and decays of electrons was built to simulate the evolution of electron density in the conduction band. Field ionization mechanism was considered to dominate the femtosecond laser damage process, while the electronic defects induced by nanosecond laser pre-irradiation accelerated the femtosecond laser damage evolution. PMID- 22505068 TI - Quantitative phase and refractive index measurements with point-source digital in line holographic microscopy. AB - Point-source digital in-line holographic microscopy with numerical reconstruction is ideally suited for quantitative phase measurements to determine optical path lengths and to extract changes in refractive index within accuracy close to 0.001 on the submicrometer length scale. This is demonstrated with simulated holograms and with detailed measurements on a number of different micrometer-sized samples such as suspended drops, optical fibers, as well as organisms of biological interest such as E. coli bacteria, HeLa cells, and fibroblast cells. PMID- 22505069 TI - Estimation of measurement uncertainties using virtual fringe projection technique. AB - One of the main tasks of the quality test is the inspection of all relevant geometric parts related to the predefined tolerance range, whereas the uncertainty of measurement has to be less than the tolerance range. The reachable uncertainty of measurement can be determined using method A of the ISO Guide to the Expression of Uncertainty in Measurement (GUM), which is expensive and time consuming and has to be carried out for each individual metrologic case. Furthermore, it is possible to check the suitability of the measurement system for the planned inspection using virtual measurement techniques and therewith to reduce the time and money spent. This means that the uncertainty of measurement is estimated using method B of the GUM. In this paper, a virtual fringe projection system is used for the estimation of the uncertainty of measurement, which is compared with the uncertainty of measurement determined with a real measurement system using method A of the GUM. With the presented method, it is possible to calculate an optimal measurement position within the measurement volume, based on a minimum uncertainty of measurement. Thereby, the influence of the operator related to the uncertainty can be significantly reduced. PMID- 22505070 TI - Angle-resolved reflectance of obliquely aligned silver nanorods. AB - Arrays of silver nanorods (AgNRs) formed by oblique-angle deposition (OAD) are strongly anisotropic, with either metallic or dielectric characteristics depending on the polarization of incident light, and may be used to enhance Raman scattering and surface plasmon polaritons. This work investigates the polarization-dependent reflectance of inclined AgNR arrays at the wavelengths of 635 and 977 nm. The specular reflectance at various incidence angles and the bidirectional reflectance distribution function were measured with a laser scatterometer, while the directional-hemispherical reflectance was measured with an integrating sphere. The AgNR layer is modeled as an effectively homogenous, optically uniaxial material using the effective medium theory to elucidate the dielectric or metallic response for differently polarized incidence. The thin film optics formulation is modified considering optical anisotropy and surface scattering. This study helps gain a better understanding of optical properties of nanostructured materials. PMID- 22505071 TI - Fast response varifocal lenses using KTa(1-x)Nb(x)O3 crystals and a simulation method with electrostrictive calculations. AB - We fabricated cylindrical varifocal lenses with fast responses by using the strong Kerr effect of KTa(1-x)Nb(x)O(3) (KTN) single crystals. We observed focus shifts of up to 87 mm with the assistance of a 250 mm focal length lens, which corresponds to a focus shift from infinity to 720 mm by the KTN lens itself. The response time was as fast as 1 MUs. We also present a simulation method for calculating refractive index distributions in KTN single crystals, which is essential when designing the lens. The method is characterized by the strain contribution, which has not conventionally been typical of electro-optic simulations. We used this method to explain the refractive index modulations that are characteristic of the varifocal lenses. PMID- 22505072 TI - Electrical control of shape of laser beam using axially symmetric liquid crystal cells. AB - This work demonstrates the electrical tuning of laser beam shape using an axially symmetric dye-dope liquid crystal (ASDDLC) device that is fabricated using a photo-alignment method. Various beam shapes can be obtained by linearly polarized Gaussian laser beams through an ASDDLC device under various applied voltages. The far-field intensity patterns generated by laser beams of selected shapes under various applied voltages are simulated, and the results are consistent with experiment. A rotatable petal-shaped beam is obtained by controlling the polarization of the output donut-shaped beam. The tenability of beam shape of light with a wavelength of 1064 nm, which is commonly used in biomedical applications, is also demonstrated. PMID- 22505073 TI - Coherent and incoherent combination of Gaussian beams employing lens array distributed on the spherical chamber. AB - Coherent and incoherent combination of Gaussian beams employing a lens array distributed on the spherical chamber is theoretically analyzed. The output field of each source in the array is coupled through an individual optical system whose local optical axis coincides with the radial direction of the chamber. The resulting intensity profile near the origin is derived. The intensity profile and power in the bucket on the target for rectangular and hexagonal arrangement are numerically calculated. The influences of the center-to-center separation and the ring number of the focusing lens array are given. The synthetic intensity profile of incoherent combination changes little for a lens array scale much smaller than the chamber size. In contrast, the synthetic intensity profile of coherent combination shows an interference pattern with a sharp central peak and sidelobes. PMID- 22505074 TI - Detection of chromium in wastewater from refuse incineration power plant near Poyang Lake by laser induced breakdown spectroscopy. AB - A laser induced breakdown spectroscopy (LIBS) system was developed for determination of toxic metals Cr in wastewater collected from a refuse incineration power plant near Poyang Lake. The plasma was generated by focusing a pulsed Nd:YAG laser at 1064 nm on the surface of liquid. Experimental conditions were optimized for improving the sensitivity and repeatability of the LIBS system through a parametric dependence study in potassium bichromate (K(2)Cr(2)O(7)) aqueous solutions. Calibration curves for Cr I 425.43 and 357.87 nm lines are compared and the limit of detection is found to be 39 and 86 ppm, respectively. This calibration curve of Cr I 425.43 nm has been used for quantification of Cr in wastewater collected from a refuse incineration power plant near Poyang Lake where the concentration of Cr is found to be 97 ppm. The results between LIBS and standard analytical technique such as atomic absorption spectroscopy were compared, and the relative standard deviation was 8.5%. PMID- 22505075 TI - Calibration method for inner product calculation by the volume holographic correlator with randomly interleaved images. AB - A volume holographic correlator is capable of inner product calculations between the input image and multiple stored images in parallel. The inner product that is the center value of the correlation can provide a scalar measure of change between two images. The inner product values are directly acquired by measuring the intensities of the correlation peaks on the CCD. However, the measured intensities are not exactly equal to the theoretical inner product values due to the redundancy correlation. The structure of the correlation peak for randomly interleaved images is analyzed. It can be regarded as two volumes, one pyramid and one prism. The relative inner product value is only determined by the height of the pyramid. The prism, caused by the redundancy correlation, appears as the background noise, which is the main source of the inner product calculation error. A calibration method is proposed to remove the prism from the measured intensity. Based on the geometric structure of the correlation peak, the theoretical expression of the inner product value for the pyramid is derived. A white image is employed as the input image and the measured correlation peak intensity is used to calibrate the inner product value. The calibration method can effectively eliminate the error caused by the redundancy correlation to achieve a high output accuracy of the volume holographic correlator. Experiments are demonstrated for the validity of the method. PMID- 22505076 TI - Measurement of residual stress for ITO/PET substrates by the double beam shadow moire interferometer. AB - This study constructed a measurement system that can quickly and accurately analyze the residual stress of flexible electronics. A double beam shadow moire interferometer was set up to measure and evaluate the residual stress of tin doped indium oxide films on a polyethylene terephthalate substrate. However, this system required only two symmetrical fringes to evaluate the residual stress of transparent conductive oxide films on flexible substrate. Applying the grating translation techniques to the double beam shadow moire interferometer greatly improved the measurement resolution and accuracy, and the relative error was reduced to 1.2%. PMID- 22505077 TI - Evaluation of tracking ability of a phase conjugate mirror using a CCD array and spatial light modulator for optical energy transmission. AB - We investigate the tracking ability of an optical phase conjugator using a commercial CCD array and a projector LCD panel. This system allows one to use two separate laser oscillators for capturing interference patterns and generating phase conjugate light. Since a long coherence length is not required for the latter part, amplification of the phase conjugate light can be easily attained by using a laser oscillator for high-power applications such as machining. The wavelengths of the two laser oscillators can be independently chosen. For our experimental configuration an amplification factor of 7.8*10(4) is theoretically possible. Also, a formula for the maximum tracking range is derived. The proposed system is particularly suitable for power transmission by light. PMID- 22505078 TI - Three-dimensional power splitter based on self-imaging effect in multimode layer by-layer photonic crystal waveguides. AB - The self-imaging effect based on symmetrical interference in multimode layer-by layer photonic crystal waveguides (PhCWs), is numerically studied with finite difference time-domain simulations. With the properties of twofold images, a kind of three-dimensional (3D) PhCW-based power splitters with an ultracompact size using complete photonic bandgaps is proposed, calculated, and analyzed. The presented structure can be extended for the design of M*N power splitters for 3D photonic integrated circuits applications. PMID- 22505079 TI - Light scattering by a multilayered spheroidal particle. AB - The light scattering problem for a confocal multilayered spheroid has been solved by the extended boundary condition method with a corresponding spheroidal basis. The solution preserves the advantages of the approach applied previously to homogeneous and core-mantle spheroids, i.e., the separation of the radiation fields into two parts and a special choice of scalar potentials for each of the parts. The method is known to be useful in a wide range of the particle parameters. It is particularly efficient for strongly prolate and oblate spheroids. Numerical tests are described. Illustrative calculations have shown that the extinction factors converge to average values with a growing number of layers and how the extinction varies with a growth of particle porosity. PMID- 22505080 TI - Generalized data reduction approach for aspheric testing in a non-null interferometer. AB - Data reduction in non-null tests is difficult due to the presence of retrace error. We propose a simple yet effective data reduction approach for aspheric testing in a non-null interferometer. The new approach gives figure error of the aspheric by just subtracting the theoretical wavefront and first-order errors from the real wavefront obtained in the non-null interferometer. Precise prediction of the theoretical wavefront can be achieved by accurate calibration of the partial compensation system. The approach can be considered a generalization of the traditional data processing method in null tests, and errors that may affect its accuracy are discussed. A set of experiments have been carried out to demonstrate its validity and feasibility. PMID- 22505081 TI - Perturbed Talbot patterns for the measurement of low particle concentrations in fluids. AB - Behind periodic amplitude or phase objects, the object transmittance is repeated at the so-called Talbot distances. In these planes perpendicular to the propagation direction, Talbot self-images are formed. In the case of plane wave illumination, the distances between the self-images are equally spaced. A periodic pattern called optical carpet or Talbot carpet is formed along the propagation direction. We show theoretically how the presence of spherical particles (10 to 100 MUm in diameter) behind gratings of 20 and 50 MUm period affects the formation of Talbot carpets and Talbot self-images at 633 nm illumination wavelength. The scattering of the particles is modeled by the Fresnel diffraction of its geometrical shadow. We analytically calculate the interference of the diffraction orders of rectangular and sinusoidal amplitude gratings disturbed by the presence of particles. To verify our model, we present measurements of Talbot carpets perturbed with both opaque disks and transparent spheres, and discuss the effects for various size parameters. We present an approach to simulate the movement of particles within the Talbot pattern in real time. We simulate and measure axial and lateral particle movements within a probe volume and evaluate the effect on the signal formation in a Talbot interferometric setup. We evaluate the best system parameters in terms of grating period and particle-detector-distance for a prospective measuring setup to determine characteristics of flowing suspensions, such as particle volume concentration or particle size distribution. PMID- 22505082 TI - Resonantly pumped 1.645 MUm single longitudinal mode Er:YAG laser with intracavity etalons. AB - We report on a 1.645 MUm single longitudinal mode Er:YAG laser that was resonantly pumped by a 1.532 MUm fiber laser, using intracavity etalons to generate single longitudinal mode operation. We obtained 0.749 W single longitudinal mode output power at 1.645 MUm from an Er:YAG laser with two intracavity etalons. The M2-factors of the Er:YAG laser were 1.041 and 1.068 in the x and y directions, respectively. PMID- 22505083 TI - Three-dimensional Dammann array. AB - We demonstrate a scheme that can produce a three-dimensional (3D) focus spot array in a 3D lattice structure, called a 3D Dammann array, in focal region of an objective. This 3D Dammann array is generated by using two separate micro-optical elements, a Dammann zone plate (DZP) that produces a series of coaxial focus spots and a conventional two-dimensional (2D) Dammann grating (DG). A simple, fast, and clear method is presented to design this binary pure-phase (0,pi) DZP in vectorial Debye theory regime. Based on this kind of DZP, one can always obtain a 3D Dammann array both for low and high numerical aperture (NA) focusing objectives. For experimental demonstration, an arrangement combining a DZP, a 2D DG, and a pair of opposing lenses is proposed to generate a 5*5*5 Dammann array in focal region of an objective with NA=0.127 and another 6*6*7 Dammann array for an objective of NA=0.66. It is shown that this arrangement makes it possible to achieve 3D Dammann arrays with micrometer-sized focus spots and focus spacings of tens of micrometers for various practical applications, such as 3D parallel micro and nanomachining, 3D simultaneous optical manipulation, 3D optical data storage, and multifocal fluorescence microscope, etc. PMID- 22505084 TI - Polarization pattern of vector vortex beams generated by q-plates with different topological charges. AB - We describe the polarization topology of the vector beams emerging from a patterned birefringent liquid crystal plate with a topological charge q at its center (q-plate). The polarization topological structures for different q-plates and different input polarization states have been studied experimentally by measuring the Stokes parameters point-by-point in the beam transverse plane. Furthermore, we used a tuned q=1/2-plate to generate cylindrical vector beams with radial or azimuthal polarizations, with the possibility of switching dynamically between these two cases by simply changing the linear polarization of the input beam. PMID- 22505085 TI - Some current trends of correlation optics metrology of coherence and polarization. AB - New feasibilities for metrology of coherence and polarization of light fields provided by correlation optics approaches are considered. This paper shows these approaches are fruitful in measuring the field parameters that are critical for optical diagnostics using the data on the degree of coherence and the state and the degree of polarization of partially coherent and inhomogeneously polarized fields. PMID- 22505086 TI - Tunable multiwavelength fiber laser based on a double Sagnac HiBi fiber loop. AB - A tunable multiwavelength fiber laser based on double Sagnac loops is proposed and demonstrated. Comb filter characteristics of single and double Sagnac loops are analyzed by Jones matrix. Simulated results show that there are better tunability and controllability with double loops than with a single loop, and this also has been confirmed by experimental results. By adjusting the polarization controller and the length of the polarization maintaining fiber the wavelength range, wavelength spacing, and laser linewidth can be tuned. Experimental results indicate that the linewidth of the multiwavelength fiber laser was 0.0187 nm and the optical sidemode suppression ratio was 50 dB. PMID- 22505087 TI - New scanning technique for the optical vortex microscope. AB - In the optical vortex microscopy the focused Gaussian beam with optical vortex scans a sample. An optical vortex can be introduced into a laser beam with the use of a special optical element--a vortex lens. When moving the vortex lens, the optical vortex changes its position inside the spot formed by a focused laser beam. This effect can be used as a new precise scanning technique. In this paper, we study the optical vortex behavior at the sample plane. We also estimate if the new scanning technique results in observable effects that could be used for a phase object detection. PMID- 22505088 TI - Wavefront sensor based on the Talbot effect with the precorrected holographic grating. AB - A holographic wavefront sensor based on the Talbot effect is proposed. Optical wavefronts are measured by sampling the light amplitude distribution with a two dimensional (2D) precorrected holographic grating. The factors that allow changing an angular measurement range and a spatial resolution of the sensor are discussed. A comparative analysis with the Shack-Hartmann sensor is illustrated with some experimental results. PMID- 22505089 TI - Internal energy flows and instantaneous field of a monochromatic paraxial light beam. AB - It is known that the orbital angular momentum of a paraxial light beam is related to the rotational features of the instantaneous optical-frequency oscillation pattern within the beam cross section [J. Opt. A 11, 094004 (2009)]. Now this conclusion is generalized: any identifiable directed motion of the instantaneous two-dimensional pattern of the field oscillations ("running" behavior of the instant oscillatory pattern) corresponds to the transverse energy flow in the experimentally observable time-averaged field. The transverse orbital flow density can be treated as a natural geometric and kinematic characteristic of this running behavior. PMID- 22505090 TI - Wavelet analysis of Fourier polarized images of the human bile. AB - The model of generalized optical anisotropy of human bile is suggested, and the method of the polarimetric phase Fourier transform of the image of the laser radiation field that is generated by the mechanisms of linear and circular birefringence of polycrystalline networks with a wavelet-diagnosis of cholelithiasis is analytically substantiated. PMID- 22505091 TI - Optical Scully vortex and its spatial evolution. AB - The structure of an optical vortex formed in a partially coherent Laguerre-Gauss laser beam was considered. The main object of study was the recorded vector field of wavefront tilts that consisted of the vortical and potential components. It was found that the vortical motion weakened as the coherence decreased. Main regularities in the behavior of the vortical component can be described by the Scully vortex model of vortical liquid flow. In the spatial evolution, the potential component of tilts may alternate the sign, thus determining the direction of energy flow to the center or to the periphery of the vortex. Energy flow lines in the beam demonstrate the pattern of decay of an optical vortex similar to the pattern of decaying vortical motion in viscous liquid. PMID- 22505092 TI - Modified moment-matching method for estimating pointing parameters in the presence of atmospheric turbulence. AB - An accurate pointing system is required in free-space optical (FSO) communication links. Low energy-transmission efficiency caused by pointing errors would decline the communication system's performance. The statistics of the detected signal or return signal values could be used to estimate the pointing parameters, whereas atmospheric turbulence brings in serious challenges. A modified moment-matching estimation method is presented in this paper. The irradiance fluctuation caused by the atmospheric turbulence is considered, and the probability density function (PDF) in a weak turbulence condition is assumed to be lognormal. This modified approach is evaluated with wave-propagation simulation data and shows significant improvement over the conventional approach. The estimation accuracy and the properties of this new approach are also discussed. Although our method is based on lognormal irradiance PDF under a weak turbulence condition, the irradiance PDF would tend to be lognormal with aperture averaging effect under moderate to strong turbulence, and the ideas can be extended with appropriate PDF models to satisfy different conditions. PMID- 22505093 TI - Investigation of evanescent coupling between tapered fiber and a multimode slab waveguide. AB - A tapered fiber-slab waveguide coupler (TFSC) is proposed in this paper. Both the numerical analysis based on the beam propagation method and experiments are used for investigating the dependencies of TFSC transmission features on their geometric parameters. From the simulations and experimental results, the rules for fabricating a TFSC with low transmission loss and sharp resonant spectra by optimizing the configuration parameters are presented. The conclusions derived from our work may provide helpful references for optimally designing and fabricating TFSC-based devices, such as sensors, wavelength filters, and intensity modulators. PMID- 22505094 TI - Experimental analysis of the Poynting vector characteristics. AB - The possibility of experimental measurement of the Poynting vector characteristics is shown. Under paraxial approximation, these characteristics may be obtained on the basis of local Stokes polarimetry and interferometry of electric field components. The experimental results for elliptically polarized Gaussian beam and heterogeneously polarized elementary fields are presented. PMID- 22505095 TI - Optical vortices in twisted elliptical optical fibers with torsional stress. AB - In the present paper we have derived the analytical expressions for the modes of twisted elliptical fibers with torsional mechanical stress at various relationships of the fiber parameters. It was shown that circularly polarized optical vortices with the topological charges +/-1 can propagate in elliptical fibers as generic modes if ellipticity and the twist-induced circular birefringence suppress the spin-orbit interaction. A comparison of the obtained results with the corresponding results for spun elliptical fibers is made. PMID- 22505096 TI - Optical vortices routing in coupled elliptical spun fibers. AB - We have studied the tunneling of a circularly polarized optical vortex (OV) in parallel strongly spun elliptical fibers. In this case it is possible to route the OV in a pure state from one of the fibers to another. We have determined the power efficiency of this process and have shown that such a directional coupler can serve for inversion of the topological charge of the incoming vortex. PMID- 22505097 TI - Fourier-Stokes polarimetry of laser radiation scattered fields for diagnostics of dystrophic changes of biological tissues histological sections. AB - The optical model of polycrystalline networks of histological sections of rectum wall is suggested. The results of investigating the interrelation between the values of statistical (statistical moments of the 1st-4th order) and correlation (cross correlation coefficients) parameters are presented. Such parameters characterize the coordinate distributions of the fourth parameter of the Stokes vector of Fourier transforms of laser images of myometrium tissues. The diagnostic criteria of myometrium pathologies are determined. PMID- 22505098 TI - Limitations of adaptive control efficiency due to singular points in the wavefront of a laser beam. AB - Optical vortices occur at light propagation in an inhomogeneous medium, disturbing the operation of adaptive optical systems and assuring a priori continuity of the phase fluctuation function. It is clear that the physical process of the light wave propagation has a threshold of complexity relative to the description and measurement of this process, after which the light wave contains points with zero intensity and there is no continuous wavefront. The appearance of zeros indicates the transition of phenomenon in a new condition. The results of numerous studies of phase fluctuations of optical waves in the atmosphere, first of all, provide a basis for estimating the efficiency of operation of adaptive optical systems, second, make it possible to determine the requirements on the wavefront sensors and adaptive mirrors, and, finally, make it possible to determine the structure and properties of phase-conjugated adaptive optical systems. PMID- 22505099 TI - Vectorial pure operatorial Pauli algebraic approach in polarization optics: a theoretical survey and some applications. AB - In the last decade we have elaborated a mathematical tool for the description of the interaction of polarized light with polarization devices, alternative to the standard matrix (Jones and Mueller) formalisms, namely a vectorial pure operatorial Pauli algebraic one. After a brief, coherent survey of this formalism, we present some applicative results obtained in this frame, referring to the gain and the modification of the state of polarization at the interaction of the polarized light with deterministic devices. Due to an adequate parameterization of the problem, specific to this method, symmetric expressions of the gain and of the generalized Malus' law are obtained. On the other hand, the equation of the ellipsoid in which a Poincare sphere of a given degree of polarization is mapped by such a device can be established. PMID- 22505100 TI - Generation and conversion of optical vortices in long-period twisted elliptical fibers. AB - We theoretically demonstrate that long-period twisted elliptical fibers have the ability to change in a certain wavelength range the topological charge of the incoming field by two units. We also show that such fibers can generate charge-2 optical vortices from the incoming Gaussian beams. PMID- 22505101 TI - High-intensive femtosecond singular pulses in Kerr dielectrics. AB - The nonlinear dynamics of a high-power femtosecond singular pulse in Kerr media are analyzed numerically upon optically induced ionization. We examine the plasma inertia impact to stable propagation of optical vortices. Multifoci behavior of vortices in medium are revealed. Next we numerically demonstrate that inertial character of plasma formation provides a quasi-soliton regime of vortex propagation resistant to symmetry-breaking perturbation. PMID- 22505102 TI - Laser-radiation scattering by cement in the process of hydration: simulation of the dynamics and experiment. AB - This paper discusses simulation of speckle-field dynamics during coherent light scattering by a cement surface in the process of hydration. Cement particles are represented by the spheres whose sizes and reflection indices are changing during the hydration process. The study of intensity fluctuations of scattered coherent radiation is a suitable technique for the analysis of both fast and slow processes of mineral binder hydration and formation of polycrystalline structures in the process of hardening. The results of simulation are in good agreement with the experimental data. PMID- 22505103 TI - Spatial-frequency Fourier polarimetry of human blood plasma in the diagnostics of pathological changes. AB - A method of polarization mapping of the optical-anisotropic polycrystalline networks of the blood plasma albumin and globulin proteins with adjusted spatial frequency filtering of the coordinate distributions of the azimuth and ellipticity of the polarization of laser radiation in the Fourier plane is proposed and substantiated. A set of criteria of diagnosing prostate cancer based on the statistical correlation and fractal analysis of the spatial-frequency filtered polarization distributions generated by dendritic networks of albumin and globulin spherulitic networks has been detected and substantiated. PMID- 22505104 TI - Spin-to-orbit conversion at acousto-optic diffraction of light: conservation of optical angular momentum. AB - Acousto-optic diffraction of light in optically active cubic crystals is analyzed from the viewpoint of conservation of optical angular momentum. It is shown that the availability of angular momentum in the diffracted optical beam can be necessarily inferred from the requirements of angular momentum conservation law. As follows from our analysis, a circularly polarized diffracted wave should bear an orbital angular momentum. The efficiency of the spin-to-orbit momentum conversion is governed by the efficiency of acousto-optic diffraction. PMID- 22505105 TI - Engineering of the space-variant linear polarization of vortex-beams in biaxially induced crystals. AB - We considered the propagation of Bessel beams through the biaxially induced birefringent crystal implemented by the mechanical torsion of the uniaxial crystal around its optical axis. Analyzing the solutions to the wave equation in the form of eigenmodes, we found that the system enables us to convert the beams with a uniform distribution of the linear polarization at the beam cross section into radially, azimuthally, and spirally polarized beams. Moreover, we revealed that the above system permits us to convert the beams with the space-variant linear polarization in accordance with the rule -s?s+1, where s is the topological index of the centered polarization singularity. PMID- 22505106 TI - Rotational spin Hall effect in a uniaxial crystal. AB - We have considered the propagation process of the phase-matched array of singular beams through a uniaxial crystal. We have revealed that local beams in the array are rotated when propagating. However the right and left rotations are unequal. There are at least two processes responsible for the array rotation: the interference of local beams and the spatial depolarization. The interference takes place in the vortex birth and annihilation events forming the symmetrical part of the rotation. The depolarization process contributes to the asymmetry of the rotation that is called the rotational spin Hall effect. It can be brought to light due to the difference between the envelopes of the dependences of the angular displacement on the inclination angle of the local beams or the crystal length reaching the value of some angular degree. The direction of the additional array rotation is exclusively defined by the handedness of the circular polarization in the initial beam array. PMID- 22505107 TI - High-power narrow-linewidth quasi-CW diode-pumped TEM00 1064 nm Nd:YAG ring laser. AB - We demonstrated a high average power, narrow-linewidth, quasi-CW diode-pumped Nd:YAG 1064 nm laser with near-diffraction-limited beam quality. A symmetrical three-mirror ring cavity with unidirectional operation elements and an etalon was employed to realize the narrow-linewidth laser output. Two highly efficient laser modules and a 90 degrees quartz rotator for birefringence compensation were used for the high output power. The maximum average output power of 62.5 W with the beam quality factor M(2) of 1.15 was achieved under a pump power of 216 W at a repetition rate of 500 Hz, corresponding to the optical-to-optical conversion efficiency of 28.9%. The linewidth of the laser at the maximum output power was measured to be less than 0.2 GHz. PMID- 22505108 TI - Optical analysis of adsorption sensitivity of titanium, Ti-6Al-4V, and Ti-35Nb 6Ta. AB - Here we report the optical analysis of protein adsorption sensitivity of titanium (Ti), Ti(6)Al(4)V, and Ti(35)Nb(6)Ta. The optical sensor used was a diffractive optical element based sensor, which analyzes magnitude and coherence of probe beam reflected from the measured surfaces. Also, the roughness and other necessary parameters were taken into account on the final verdict. The material Ti(35)Nb(6)Ta showed positive initial reaction to the human plasma fibrinogen, which was the protein used. The Ti(35)Nb(6)Ta was observed to be more active than the grade 2 titanium. PMID- 22505109 TI - Possibilities of using inhomogeneity in light energy distribution for estimating the degree of coherence of superposing waves. AB - The paper presents a new method for determining the degree of coherence of superposing plane linearly polarized waves converging at the angle of 90 degrees . The spatial modulation of polarization, which causes the spatial modulation of the averaged values of the Poynting vector, presets the modulation of the volume energy density. Such an inhomogeneous optical field can affect nano-sized particles randomly caught in this field. The paper shows that the maximum velocity of "trapping" the particles into the regions of maximum averaged values of the Poynting vector determines the degree of coherence of interacting waves. PMID- 22505110 TI - On experimental characterization of polarization fluctuation dynamics in random optical beams. AB - Polarization correlation functions that characterize the rate of change of the instantaneous polarization state of an arbitrary fluctuating electromagnetic beam were recently introduced. In this work, we describe techniques that enable the measurement of these functions leading to the determination of the so-called polarization time of a random field. PMID- 22505111 TI - Reversible holographic recording media based on polymeric composites and their use in energy-saving technologies. AB - The principle of the photothermoplastic method of hologram recording and the general requirements for photothermoplastic holographic recording media based on photoconductive polymer films are considered. The holographic recording media obtained by the authors based on carbazolyl- and ferrocenyl-containing oligomers doped with respective squarillium or merocyanine dyes are discussed. Some examples of practical application of such media in holographic interferometry are demonstrated. PMID- 22505112 TI - Optically induced switching in spin-crossover compounds: microscopic and macroscopic models and their relationship. AB - We present the examination of light induced behavior of spin-crossover compounds. We focus on the switching phenomena between low-spin and high-spin states of the system. The connection between the Ising-like model and the macroscopic evolution equation has been analyzed. By means of numerical simulations, we found the dynamical potential changes, the corresponding light induced hysteresis, and the transient regimes. The statistical properties of the system in contact with a heat bath are shown in a stationary probability distribution. PMID- 22505113 TI - Analysis of the scatter growth in dispersive media with the use of dynamic light scattering. AB - Analysis of the structure functions of intensity fluctuations of scattered laser light was applied to monitor the phase separation in probed disperse media. UV cured mixtures of a liquid crystal and prepolymer were studied during the formation of the structure of dispersive polymer-liquid crystal (DPLC) composites. The experimentally observed features of light beating induced by dynamic light scattering in DPLC systems (the scaling properties of the structure functions, the narrowing of the beating spectrum for certain weight fractions of the liquid-crystalline component) were interpreted in terms of the discrete scattering model using the results of statistical modeling. PMID- 22505114 TI - Topological activity in Bragg elliptical twisted fibers. AB - We have theoretically shown that Bragg twisted elliptical fibers manifest, in certain spectral regions, the property of topological activity--the ability to change in the reflected field the topological charge of incoming optical vortices and fundamental modes by two units. This property could be used for narrowband generation of optical vortices from Gaussian beams and for changing the topological charge of incoming optical vortices. PMID- 22505115 TI - Fourier phasometry of human effusion polycrystalline networks. AB - A model of generalized optical anisotropy of polycrystalline networks of albumin and globulin of the effusion of appendicitis has been suggested. The method of Fourier phasometry of linear and circular birefringence with a spatial-frequency selection of the coordinate distributions for the differentiation of acute and gangrenous conditions have been analytically substantiated. A set of criteria of a polarization-phase differentiation of acute and gangrenous appendicitis states has been detected and substantiated. PMID- 22505116 TI - Digital simulation of two-dimensional random fields with arbitrary power spectra and non-Gaussian probability distribution functions. AB - Methods for simulation of two-dimensional signals with arbitrary power spectral densities and signal amplitude probability density functions are disclosed. The method relies on initially transforming a white noise sample set of random Gaussian distributed numbers into a corresponding set with the desired spectral distribution, after which this colored Gaussian probability distribution is transformed via an inverse transform into the desired probability distribution. In most cases the method provides satisfactory results and can thus be considered an engineering approach. Several illustrative examples with relevance for optics are given. PMID- 22505117 TI - Beam spreading of vortex beams propagating in turbulent atmosphere. AB - We present some results obtained by numerical modeling of the propagation of vortex beams LG(0l) through a randomly inhomogeneous medium. The vortex beams are the lower order Laguerre-Gaussian modes. Such beams, if propagated under conditions of weak turbulence, also experience distortions, like a Gaussian beam. However, the statistically averaged vortex beams (LG(0l)) conserve the central intensity dip with a nonzero intensity on the beam axis. The beam broadening of vortex beams is analyzed. The average vortex beams are found to be broadened less than the Gaussian beam while propagated through a randomly inhomogeneous medium. The higher the topological charge l is, the smaller the beam broadening is. PMID- 22505118 TI - Thermal energy transfer by plasmon-resonant composite nanoparticles at pulse laser irradiation. AB - Heating of composite plasmon-resonant nanoparticles (spherical gold nanoshells) under pulse laser illumination is considered. The numerical solution of the time dependent heat conduction equation accounting for spatial inhomogeneities of absorbed laser radiation is performed. Important features of temperature kinetics and thermal flux inside nanoparticles are analyzed. Possible applications of the observed effects in nanotechnology and medicine are discussed. PMID- 22505119 TI - Ion concentration quantification with the help of single-wavelength dye fluorescence. AB - This paper discusses the task of true physical quantity reconstruction from experimental data on the basis of fluorescence microscopy images when a specific ion indicator is used for an investigation into ion concentration. Brain cell functional activity in the form of calcium oscillation may be processed as quantitation on the basis of measurements of single-wavelength fluorescence intensity using data about dye loading protocol, excitation, and detection conditions without calibration of every experiment. PMID- 22505120 TI - Emerging correlation optics. AB - This feature issue of Applied Optics contains a series of selected papers reflecting the state-of-the-art of correlation optics and showing synergetics between the theoretical background and experimental techniques. PMID- 22505121 TI - Comparison of hepatitis C virus treatment between incarcerated and community patients. AB - The prevalence of chronic hepatitis C virus (HCV) infection among incarcerated individuals in the United States is estimated to be between 12% and 31%. HCV treatment during incarceration is an attractive option because of improved access to health care and directly observed therapy. We compared incarcerated and nonincarcerated HCV-infected patients evaluated for treatment at a single academic center between January 1, 2002 and December 31, 2007. During this period, 521 nonincarcerated and 388 incarcerated patients were evaluated for HCV treatment. Three hundred and nineteen (61.2%) nonincarcerated patients and 234 (60.3%) incarcerated patients underwent treatment with pegylated interferon and ribavirin. Incarcerated patients were more likely to be male, African-American race, and have a history of alcohol or intravenous drug use. Treated incarcerated patients were less likely to have genotype 1 virus and were less likely to have undergone previous treatment. There was a similar prevalence of coinfection with human immunodeficiency virus (HIV) in both groups. A sustained viral response (SVR) was achieved in 97 (42.9%) incarcerated patients, compared to 115 (38.0%) nonincarcerated patients (P = 0.304). Both groups had a similar proportion of patients that completed a full treatment course. Stepwise logistic regression was conducted, and the final model included full treatment course, non-genotype 1 virus, younger age at treatment start, and negative HIV status. Incarceration status was not a significant predictor when added to this model (P = 0.075). CONCLUSION: In a cohort of HCV-infected patients managed in an academic medical center ambulatory clinic, incarcerated patients were as likely to be treated for HCV and as likely to achieve an SVR as nonincarcerated patients. PMID- 22505122 TI - Cryptotanshinone attenuates isoprenaline-induced cardiac fibrosis in mice associated with upregulation and activation of matrix metalloproteinase-2. AB - Cryptotanshinone is an active ingredient of Salvia miltiorrhiza that has been used in traditional Chinese medicine for treating cardiovascular disorders. Thus, we investigated the effects of cryptotanshinone on cardiac fibrosis induced by isoprenaline and examined whether cardiac matrix metalloproteinase (MMP)-2 is involved in this process. Male C57BL/6 mice received a daily injection of 0.9% saline, 3 mg/kg isoprenaline or isoprenaline plus 20 mg/kg cryptotanshinone by gastric gavage for 2 weeks. In this study we demonstrated that cryptotanshinone was able to significantly ameliorate isoprenaline-induced cardiac fibrosis, which was associated with a marked upregulation and activation of MMP-2 in the ventricular myocardium. Additionally, we demonstrated that cryptotanshinone dose dependently upregulated and activated MMP-2 in cultured cardiac fibroblasts. Moreover, incubation with cryptotanshinone also prevented the isoprenaline induced downregulation and inactivation of MMP-2 in cultured cardiac fibroblasts. Taken together, our data suggest that cryptotanshinone is a novel and potent antifibrotic agent. The present findings further our understanding of the role of MMP-2 in cardiac fibrosis and the antifibrotic mechanisms of cryptotanshinone. PMID- 22505123 TI - Concerns about standards of reporting of clinical trials: an RCT comparing the Bobath concept and motor relearning interventions for rehabilitation of stroke patients as an exemplar. PMID- 22505124 TI - Effect of age on anthropometric and physical performance measures in professional baseball players. AB - The purpose of this study was to investigate age-related changes in anthropometric and performance variables in professional baseball players. Baseball players (n = 1,157) from several professional baseball organizations were categorized into 7 cohorts based upon age. All adolescent athletes were categorized as age group 1 (AG1), whereas the next 5 groups (AG2-AG6) consisted of players 20-22, 23-25, 26-28, 29-31, and 31-34 years, respectively. The final group (AG7) comprised athletes >=35 years. All performance assessments were part of the athlete's normal preseason training camp testing routine. Field assessments were used to analyze lower-body power, speed, agility, grip strength, and body composition. The players were heaviest between the ages of 29 and 31 (AG5), and their body mass in that age group was 10.1% (p = 0.004) greater than that of AG1. A 7.0% increase (p = 0.000) in lean body mass occurred between AG1 and AG5. No differences in 10-yd sprint times or agility were seen across any age group or position. A 2.0 seconds (p = 0.001) slower run time for the 300-yd shuttle was seen between AG4 and AG5 for all positions combined. Elevations in grip strength were seen at AG4 compared with AG1 (p = 0.001) and AG2 (p = 0.007) for all positions combined. No other differences were noted. Lower-body power was increased for all positions combined from AG1 to AG3 (p = 0.007). This pattern was similar to that observed in position players, but a 12.4% decrease (p = 0.024) in VJMP was seen between AG7 and AG5 in pitchers. Results of this study indicate that lower-body power is maintained in baseball players until the age of 29-31, whereas speed, agility, and grip strength are maintained in players able to play past the age of 35 years. Age-related differences observed in this study suggest that athletes focus on their strength and conditioning programs to extend the length of their professional careers. PMID- 22505125 TI - Predicting performance and injury resilience from movement quality and fitness scores in a basketball team over 2 years. AB - The purpose of this study was to see if specific tests of fitness and movement quality could predict injury resilience and performance in a team of basketball players over 2 years (2 playing seasons). It was hypothesized that, in a basketball population, movement and fitness scores would predict performance scores and that movement and fitness scores would predict injury resilience. A basketball team from a major American university (N = 14) served as the test population in this longitudinal trial. Variables linked to fitness, movement ability, speed, strength, and agility were measured together with some National Basketball Association (NBA) combine tests. Dependent variables of performance indicators (such as games and minutes played, points scored, assists, rebounds, steal, and blocks) and injury reports were tracked for the subsequent 2 years. Results showed that better performance was linked with having a stiffer torso, more mobile hips, weaker left grip strength, and a longer standing long jump, to name a few. Of the 3 NBA combine tests administered here, only a faster lane agility time had significant links with performance. Some movement qualities and torso endurance were not linked. No patterns with injury emerged. These observations have implications for preseason testing and subsequent training programs in an attempt to reduce future injury and enhance playing performance. PMID- 22505126 TI - Peak vertical jump power estimations in youths and young adults. AB - The purpose of this study was to develop and validate a regression equation to estimate peak power (PP) using a large sample of athletic youths and young adults. Anthropometric and vertical jump ground reaction forces were collected from 460 male volunteers (age: 12-24 years). Of these 460 volunteers, a stratified random sample of 45 subjects representing 3 different age groups (12 15 years [n = 15], 16-18 years [n = 15], and 19-24 years [n = 15]) was selected as a validation sample. Data from the remaining 415 subjects were used to develop a new equation ("Novel") to estimate PP using age, body mass (BM), and vertical jump height (VJH) via backward stepwise regression. Independently, age (r = 0.57), BM (r = 0.83), and VJ (r = 0.65) were significantly (p < 0.05) correlated with PP. However, age did not significantly (p = 0.53) contribute to the final prediction equation (Novel): PP (watts) = 63.6 * VJH (centimeters) + 42.7 * BM (kilograms) - 1,846.5 (r = 0.96; standard error of the estimate = 250.7 W). For each age group, there were no differences between actual PP (overall group mean +/- SD: 3,244 +/- 991 W) and PP estimated using Novel (3,253 +/- 1,037 W). Conversely, other previously published equations produced PP estimates that were significantly different than actual PP. The large sample size used in this study (n = 415) likely explains the greater accuracy of the reported Novel equation compared with previously developed equations (n = 17-161). Although this Novel equation can accurately estimate PP values for a group of subjects, between subject comparisons estimating PP using Novel or any other previously published equations should be interpreted with caution because of large intersubject error (+/- >600 W) associated with predictions. PMID- 22505127 TI - Practical recommendations for coaches and athletes: a meta-analysis of sodium bicarbonate use for athletic performance. AB - Sodium bicarbonate (NaHCO3) is a buffering agent that is suggested to improve performance by promoting the efflux of hydrogen ions from working cells and tissues. Research surrounding its efficacy as an ergogenic aid is conflicting, making it difficult to draw conclusions as to its effectiveness for training and competition. This study performed a meta-analysis of relevant research articles to allow the development of concise practical recommendations for coaches and athletes. The overall effect size for the influence of NaHCO3 on performance was moderate, and was significantly lower for specifically trained as opposed to recreationally trained participants. PMID- 22505128 TI - Strength performance in youth: trainability of adolescents and children in the back and front squats. AB - A basic question for many athletic coaches pertains to the maximum attainable strength level for youth athletes. The aim of this investigation was to establish reference values for the strength performance in the front and back squats in youth athletes. The strength performance in front and back squats of 141 elite youth soccer players was tested by a 1 repetition maximum (1RM) and 1RM related to bodyweight (SREL). The subjects aged between 11 and 19 years and were divided into 2 groups and 4 subgroups (A = younger than 19 years, B = younger than 17 years, C = younger than 15 years, and D = younger than 13 years). For approximately 2 years, one group (control group [CG]) only participated in routine soccer training and the other group (strength training group [STG]) participated in an additional strength training program along with the routine soccer training. Additionally, the strength performance in a 5RM in both squat variants of 105 young elite weightlifters (National Weightlifting Organization Baden Wurttemberg, [BWG]) was examined to show the high level of trainability of children and adolescents and to determine the reference strength values for young athletes. The STG performed in the parallel front squat SREL in the subgroups A 1.7 +/- 0.2, B 1.6 +/- 0.2, C 1.4 +/-0.2 and D 0.9 +/- 0.3. The STG had significantly (p < 0.001) higher strength values in 1RM and SREL than CG. The BWG had higher strength values than STG, but the BWG was not part of the statistical analysis because of the different test protocols (1RM vs. 5RM). Our data show that the SREL in parallel squat for young elite athletes with long-term training experience should be a minimum of 2.0 for 16- to 19-year-olds, 1.5 for 13- to 15 year-olds, and 0.7 for 11- to 12-year-olds. PMID- 22505129 TI - CSCS certification and school enrollment impacts upon high school strength facilities, equipment, and safety. AB - The rapid growth and expanding use of high school strength and conditioning facilities (SCFs) creates a need to research and better understand these vital facilities. This study was designed to examine SCFs at the high school level including facility size, equipment, leadership/staffing, and safety. A 70-item online survey instrument, developed with expert input from certified strength professionals, was used to collect data regarding the SCFs in high schools throughout a midwestern state, and was distributed via email to a total of 390 high school athletic directors. Survey respondents (n = 108) all reported the presence of SCFs with 95.4% indicating a dedicated SCF space. A strong positive correlation (r = 0.610, p <= 0.001) was determined between the variables of SCF size in square feet and school size measured by total enrollment. Analysis of variance and chi2 analyses revealed significant differences in equipment, facility size, and safety factors based on the categorical variables of school size and the presence of certified strength and conditioning specialist (CSCS) leadership. It appears the CSCS's application of their scientific knowledge goes beyond training athletes for the goal of improving athletic performance to actually influence the SCF itself. Athletic administrators at the high school level need to recognize the impact CSCS program leadership can have on the overall quality of the strength and conditioning program and facility. PMID- 22505130 TI - A rationale for assessing the lower-body power profile in team sport athletes. AB - Training at the load that maximizes peak mechanical power (Pmax) is considered superior for the development of power. We aimed to identify the Pmax load ('optimal load') in the jump squat and to quantify small, moderate, large, and very large substantial differences in power output across a spectrum of loads to identify loads that are substantially different to the optimal, and lastly, to investigate the nature of power production (load-force-velocity profiles). Professional Australian Rules Football (ARF; n = 16) and highly trained Rugby Union (RU; n = 20) players (subdivided into stronger [SP] vs. weaker [WP] players) performed jump squats across incremental loads (0-60 kg). Substantial differences in peak power (W.kg(-1)) were quantified as 0.2-2.0 of the log transformed between-athlete SD at each load, backtransformed and expressed as a percent with 90% confidence limits (CL). A 0-kg jump squat maximized peak power (ARF: 57.7 +/- 10.8 W.kg(-1); RU: 61.4 +/- 8.5 W.kg(-1); SP: 64.4 +/- 7.5 W.kg( 1); WP: 54.8 +/- 9.5 W.kg(-1)). The range for small to very large substantial differences in power output was 4.5-55.9% (CL: *//1.36) and 2.8-32.4% (CL: *//1.31) in ARF and RU players, whereas in SP and WP, it was 3.7-43.1% (CL: *//1.32) and 4.3-51.7% (CL: *//1.36). Power declined per 10-kg increment in load, 14.1% (CL: +/-1.6) and 10.5% (CL: +/-1.5) in ARF and RU players and 12.8% (CL: +/ 1.9) and 11.3% (CL: +/-1.7) in SP and WP. The use of a 0-kg load is superior for the development of jump squat maximal power, with moderate to very large declines in power output observed at 10- to 60-kg loads. Yet, performance of heavier load jump squats that are substantially different to the optimal load are important in the development of sport-specific force-velocity qualities and should not be excluded. PMID- 22505131 TI - Effects of a short proprioceptive neuromuscular facilitation stretching bout on quadriceps neuromuscular function, flexibility, and vertical jump performance. AB - The inclusion of relatively long bouts of stretching (repeated static stretches of ~30 seconds) in the warm-up is usually associated with a drop in muscle performance. The purpose of this study was to assess the effect of a novel self administered proprioceptive neuromuscular facilitation (PNF) paradigm with short periods of stretching and contraction on quadriceps neuromuscular function, vertical jump performance, and articular range of motion (ROM). Twelve healthy men (age: 27.7 +/- 7.3 years, height: 178.4 +/- 10.4 cm, weight: 73.8 +/- 16.9 kg) volunteered to participate in a PNF session and a control session separated by 2-7 days. The PNF stretching lasted 2 minutes and consisted of 4 sets of 5 second isometric hamstring contraction immediately followed by 5 seconds of passive static stretch of the quadriceps immediately followed by 5 seconds isometric quadriceps contraction for each leg. For the control session, the participants were asked to walk at a comfortable speed for 2 minutes. Active ROM of knee flexion, vertical jump performance, and quadriceps neuromuscular function were tested before, immediately after, and 15 minutes after the intervention. The PNF stretching procedure did not affect ROM, squat jump, and countermovement jump performances. Accordingly, we did not observe any change in maximal voluntary contraction force, voluntary activation level, M-wave and twitch contractile properties that could be attributed to PNF stretching. The present self administered PNF stretching of the quadriceps with short (5-second) stretches is not recommended before sports where flexibility is mandatory for performance. PMID- 22505132 TI - The workout responses of salivary-free testosterone and cortisol concentrations and their association with the subsequent competition outcomes in professional rugby league. AB - This study assessed the responses of salivary-free testosterone (T) and cortisol (C) concentrations across selected training workouts and their association with the subsequent competition outcomes in professional rugby league. Thirteen rugby league players were assessed for salivary-free T and C concentrations across 5 training workouts performed 3-4 days before a competitive game. The game outcomes included wins and losses and game-ranked performance (1-5) based on the number of points scored, the points differential, and a coach rating. Data were pooled across the winning (n = 3) and losing (n = 2) outcomes. Pooled free T concentrations (absolute and relative changes) were significantly (p < 0.01) elevated across those workouts that preceded winning games, but not the losses, and the relative (percent) T changes were significantly (p < 0.05) higher before winning (30.9%) than before losing (3.4%). Both outcomes were associated with workout decreases in pooled free C concentrations and the relative C changes were not significantly different between wins (-22.9%) and losses (-25.6%). In conclusion, the free T responses to selected training workouts showed some association with subsequent winning (being elevated) and losing (no change) during a limited number of competitive games in professional rugby league. Speculatively, the free T responses to a midweek workout might provide an early sign of team readiness to compete or to recovery state, thereby providing a novel format for implementing training or management strategies to improve the competition outcomes. PMID- 22505133 TI - Differences in climbing-specific strength between boulder and lead rock climbers. AB - The purpose of this study was to compare maximal muscle strength and rapid force capacity of finger flexors between boulder and lead climbers of national international level. Ten boulder (mean +/- SD, age 27 +/- 8 years) and 10 lead climbers (age 27 +/- 6 years) volunteered for the study. Ten nonclimbers (age 25 +/- 4 years) were also tested. Isometric maximal voluntary contraction (MVC) force and rate of force development (RFD) produced in "crimp" and "open-crimp" hand positions were evaluated on an instrumented hold. Climbers were stronger than nonclimbers. More interestingly, MVC force and RFD were significantly greater in boulder compared with lead climbers (p < 0.05), in both crimp and open crimp positions. The RFD was the most discriminatory outcome, as the largest difference between boulder and lead climbers (34-38%) was observed for this variable. The RFD may reflect the specific requirements of bouldering and seems to be more appropriate than pure maximal strength for investigating muscle function in rock climbers. PMID- 22505134 TI - An examination of preactivity and postactivity stretching practices of crosscountry and track and field distance coaches. AB - This study sought to determine the effectiveness of coach certification courses in promoting proper preactivity and postactivity stretching practices in National Collegiate Athletic Association (NCAA) Division I, II, and III crosscountry programs. Distribution of questionnaires to 770 NCAA Division I, Division II, and Division III programs in the U.S.A. resulted in 111 coaches (88 [78.2%] men and 25 [21.8%] women) participating. Chi-square analyses revealed that noncertified coaches reported significantly greater (chi2 = 21.582, p = 0.0174) usage of static stretching alone as their preactivity modality (18.9%, n = 9) vs. their certified counterparts (1.8%, n = 1). In addition, certified coaches reported a higher usage of dynamic flexibility only during the preactivity period (47.4%, n = 27) vs. their noncertified peers (32.4%, n = 16). Coaches were also asked if they allowed for static stretching between interval work and events in track and field, and a significantly higher percentage (chi2 = 11.948, p = 0.0177) of noncertified coaches (45.5%, n = 23) reported allowing the athletes to perform static stretches between intervals at practice than certified peers (37.9%, n = 22). These significant differences help demonstrate that coaching certification courses are an effective tool for communicating current information about stretching practices. However, the results also revealed that there are still many certified coaches who are not implementing best practices in preactivity routines. PMID- 22505135 TI - Quantification of training load and intensity in female collegiate rowers: validation of a daily assessment tool. AB - Session rating of perceived exertion (RPE) has been used to quantify a variety of training activities but has not been tested in rowers, who engage in intermittent patterns of activity. The objective of this study was to evaluate the ability of the subjective session RPE method to quantify on- and off-water rowing training load (TL) compared with a heart rate (HR) summation method. Seven female collegiate rowers (19.7 +/- 0.8 years) were monitored during 2 workout simulations differing in intensity level in the laboratory and several training sessions outside of the laboratory. Training load was calculated using an HR summation method, and RPE was measured after the completion of each simulation or training activity (session RPE). During the workout simulations, despite poor correlation between the HR summation and session RPE methods (r = -0.21, p = 0.52), the session RPE method was significantly correlated with peak WR (r = 0.59, p = 0.05) and posttest blood lactate concentration (r = 0.73, p = 0.007). During training sessions outside of the laboratory, the HR summation (280.7 +/- 108.3) and session RPE (6,432.5 +/- 4,002.0) methods were highly correlated (r = 0.88, p < 0.001). Regression analyses revealed that after controlling for time, training intensity rating was a significant predictor of TL (p < 0.001). We conclude that the session RPE method is a valid metric of TL in female rowers. The method's convenience renders it a feasible option for researchers and coaches to quantify and monitor TL in rowers. PMID- 22505136 TI - A biomechanical comparison of the traditional squat, powerlifting squat, and box squat. AB - The purpose of this study was to compare the biomechanics of the traditional squat with 2 popular exercise variations commonly referred to as the powerlifting squat and box squat. Twelve male powerlifters performed the exercises with 30, 50, and 70% of their measured 1 repetition maximum (1RM), with instruction to lift the loads as fast as possible. Inverse dynamics and spatial tracking of the external resistance were used to quantify biomechanical variables. A range of significant kinematic and kinetic differences (p < 0.05) emerged between the exercises. The traditional squat was performed with a narrow stance, whereas the powerlifting squat and box squat were performed with similar wide stances (48.3 +/- 3.8, 89.6 +/- 4.9, 92.1 +/- 5.1 cm, respectively). During the eccentric phase of the traditional squat, the knee traveled past the toes resulting in anterior displacement of the system center of mass (COM). In contrast, during the powerlifting squat and box squat, a more vertical shin position was maintained, resulting in posterior displacements of the system COM. These differences in linear displacements had a significant effect (p < 0.05) on a number of peak joint moments, with the greatest effects measured at the spine and ankle. For both joints, the largest peak moment was produced during the traditional squat, followed by the powerlifting squat, then box squat. Significant differences (p < 0.05) were also noted at the hip joint where the largest moment in all 3 planes were produced during the powerlifting squat. Coaches and athletes should be aware of the biomechanical differences between the squatting variations and select according to the kinematic and kinetic profile that best match the training goals. PMID- 22505137 TI - Another side of the oxazaphospholidine oxide chiral ortho-directing group. AB - A new ferrocenyl oxazaphospholidine oxide 3 was synthesized together with its P epimer 2 in the reaction of ferrocene lithium with phosphoramidite chloride 1. 3 was successfully derivatized into planar chiral 1,2-ferrocenes, including phosphine ligands, via highly diastereoselective ortho-lithiation and subsequent functionalization; these compounds display opposite planar chirality to those obtained from 2. Some of these 1,2-ferrocenes were further lithiated, allowing for the introduction of a free phosphine group at the oxazaphospholidine ring. The X-ray structures of the compounds 2 and 3 as well as those of the new 1,2 ferrocenes 4 and 7 have been determined. PMID- 22505138 TI - PON-P: integrated predictor for pathogenicity of missense variants. AB - High-throughput sequencing data generation demands the development of methods for interpreting the effects of genomic variants. Numerous computational methods have been developed to assess the impact of variations because experimental methods are unable to cope with both the speed and volume of data generation. To harness the strength of currently available predictors, the Pathogenic-or-Not-Pipeline (PON-P) integrates five predictors to predict the probability that nonsynonymous variations affect protein function and may consequently be disease related. Random forest methodology-based PON-P shows consistently improved performance in cross-validation tests and on independent test sets, providing ternary classification and statistical reliability estimate of results. Applied to missense variants in a melanoma cancer cell line, PON-P predicts variants in 17 genes to affect protein function. Previous studies implicate nine of these genes in the pathogenesis of various forms of cancer. PON-P may thus be used as a first step in screening and prioritizing variants to determine deleterious ones for further experimentation. PMID- 22505139 TI - X-irradiation induces cell death in fetal fibroblasts. AB - The impact of ionizing radiation on developing organisms has been widely studied for risk assessment purposes. Even though efforts have been made to decrease received doses to as low as reasonably achievable, the possibility of accidental exposure has to be considered as well. Mammalian gestation is usually divided into three periods. Radiation exposure during the 'pre-implantation period' may essentially result in embryonic mortality while exposure during the 'organogenesis period' may characteristically lead to malformations. In humans, the 'fetal period' is one of particular sensitivity to radiation induction of mental retardation, especially if the exposure occurs between weeks 8-15 of gestation. It is also admitted that prenatal irradiation may increase the risk of leukemia and childhood cancer, with an equal risk over the whole pregnancy. The aim of this study was to investigate the effects of moderate to high doses of X irradiation on mouse skin fetal fibroblasts, one of the cell types subjected to the highest dose of radiation. Exposure of the cells to X-rays led to a rapid and significant increase in gamma-H2AX foci, indicative of high levels of DNA double strand breaks. High doses (>2 Gy) also led to a pronounced G2-arrest and a decrease in the number of cells in the S phase, which was followed after 24 h by a decrease in cell survival and an increase in the level of apoptosis and necrosis. This study shows that mouse fetal skin fibroblasts are sensitive to high doses of X-irradiation. Furthermore, we report a better repair for higher doses than lower, which seems to indicate that little DNA damage is not necessarily repaired immediately. However, more sensitive approaches are necessary to identify the risk associated with low doses of radiation. PMID- 22505140 TI - A dynamic fed batch strategy for a Pichia pastoris mixed feed system to increase process understanding. AB - Mixed substrate feeding strategies are frequently investigated to enhance the productivity of recombinant Pichia pastoris processes. For this purpose, numerous fed batch experiments or time-consuming continuous cultivations are required to optimize control parameters such as the substrate mixing ratio and the applied methanol concentration. In this study, we decoupled the feeding of methanol and glycerol in a mixed substrate fed batch environment to gain process understanding for a recombinant P. pastoris Muts strain producing the model enzyme horseradish peroxidase. Specific substrate uptake rates (qs) were controlled separately, and a stepwise increased qGly-control scheme was applied to investigate the effect of various substrate fluxes on the culture. The qs-controlled strategy allowed a parallel characterization of the metabolism and the recombinant protein expression in a fed batch environment. A critical-specific glycerol uptake rate was determined, where a decline of the specific productivity occurred, and a time dependent acceleration of protein expression was characterized with the dynamic fed batch approach. Based on the observations on recombinant protein expression, propositions for an optimal feeding design to target maximal productivities were stated. Thus, the dynamic fed batch strategy was found to be a valuable tool for both process understanding and optimization of product formation for P. pastoris in a mixed substrate environment. PMID- 22505141 TI - Intrinsically disordered proteins: from sequence and conformational properties toward drug discovery. AB - Structural disorder of functional proteins under physiological conditions is widespread within eukaryotic proteomes. The lack of stable tertiary and secondary structure offers a variety of functional advantages to intrinsically disordered proteins (IDPs): their malleability of interaction with different partners, specific but low-affinity binding, and their fine modulation by post translational modifications. IDPs are therefore central players in key processes such as cell-cycle control and signal-transduction pathways, and impairment of their function is associated with many disease states such as cancer and neurodegenerative disorders. Fascinating progress in the experimental characterization of IDPs has been made in the last decade, especially in NMR spectroscopy and small-angle X-ray scattering as well as in single-molecule techniques. It has been accompanied by the development of powerful computational tools to translate experimental results in explicit ensemble representations of IDPs. With the aid of bioinformatics tools, these advances have paved the way to targeting IDP interactions in rational drug-discovery projects. PMID- 22505142 TI - Activation of different neural precursor populations in the adult hippocampus: does this lead to new neurons with discrete functions? AB - Resident populations of stem and precursor cells drive the production of new neurons in the adult hippocampus. Recent discoveries have highlighted that a large proportion of these precursor cells are in fact quiescent and can be activated by distinct neuronal activity under both normal physiological and pathological conditions. As growing evidence indicates that newborn neurons play a critical role in cognitive functions such as learning and memory and in mood regulation, it is paramount that we obtain a better understanding of how the reservoirs of stem and precursor cells are maintained and activated. In this review, we critically examine the roles of key molecular mechanisms that have been shown to regulate hippocampal precursor cells, especially their activation. We believe that understanding the mechanistic details of the activity-driven regulation of precursor cells will equip us with the ability to develop tailored strategies to trigger the generation of new neurons, thereby improving the functional outcomes in various neurological and psychiatric conditions. PMID- 22505143 TI - Continuous-flow reactor-based enzymatic synthesis of phosphorylated compounds on a large scale. AB - Acid phosphatase, an enzyme that is able to catalyze the transfer of a phosphate group from cheap pyrophosphate to alcoholic substrates, was covalently immobilized on polymethacrylate beads with an epoxy linker (Immobeads-150 or Sepabeads EC-EP). After immobilization 70% of the activity was retained and the immobilized enzyme was stable for many months. With the immobilized enzyme we were able to produce and prepare D-glucose-6-phosphate, N-acetyl-D-glucosamine-6 phosphate, allyl phosphate, dihydroxyacetone phosphate, glycerol-1-phosphate, and inosine-5'-monophosphate from the corresponding primary alcohol on gram scale using either a fed-batch reactor or a continuous-flow packed-bed reactor. PMID- 22505144 TI - Race- and gender-related variation in natural killer p46 expression associated with differential anti-hepatitis C virus immunity. AB - Major racial and gender differences have been documented in the natural history and treatment responses of chronic hepatitis C virus (HCV) infection; however, distinct mechanisms have remained enigmatic. We hypothesized that racial- and gender-related differences in natural killer (NK) cell populations may explain altered natural history and treatment responses. Our study cohort consisted of 29 African-American (AA; 55% male) and 29 Caucasian-American (CA; 48% male) healthy uninfected control subjects. Multiparameter flow cytometric analysis was used to characterize levels, phenotype with respect to 14 NK receptors, and lymphokine activated killing (LAK) function. Gene expression was assessed by real-time reverse-transcriptase polymerase chain reaction after 6-hour in vitro stimulation with Toll-like receptor (TLR) ligands. The ability to control HCV infection was assessed in the Huh-7.5/JFH-1 coculture system. NK expression of natural cytotoxicity receptor NKp46 was strongly associated with CA race and female gender and correlated positively with LAK activity (P = 0.0054). NKp46(high) NKs were more efficient at controlling HCV than their NKp46(low) counterparts (P < 0.001). Similarly, ligation of NKp46 on isolated NK cells resulted in a significant reduction in the HCV copy number detected in Huh-7.5/JFH-1 coculture (multiplicity of infection: 0.01) at an effector:target ratio of 5:1 (P < 0.005). After TLR stimulation, genes involved in cytotoxicity, but not cytokine genes, were significantly up-regulated in NKp46(high) NKs. Cytokine stimulation (interleukin [IL]-12 and IL-15) demonstrated that NKp46(high) NK cells have significantly higher interferon-gamma production than NKp46(low) cells. TLR stimulation significantly induced degranulation as well as tumor necrosis factor alpha (TNF-alpha)-related apoptosis-inducing ligand, Fas, and TNF-alpha protein expression in NKp46(high) NKs. NKp46 ligand was induced on HCV-infected hepatocytes. CONCLUSIONS: NKp46 expression may contribute to differential HCV responses. NKp46 expression correlates with anti-HCV activity in vitro and thus may prove to be a useful therapeutic target. PMID- 22505145 TI - Ultrastructure and morphology of the cycliophoran female. AB - Knowledge on the morphology of the cycliophoran female has mostly been based on observations of immature females in brood chambers of feeding stages. With the use of light- and transmission electron microscopy, the morphology and ultrastructure of the free and fully mature female of Cycliophora is described now for the first time. The external morphology is characterized by a ciliation consisting of an anteroventral ciliated field, a posterior ciliated tuft, and four sensory structures extending anteriorly from the anteroventral ciliated field. In addition, a small ciliated structure in the midventral region is interpreted as a round-shaped gonopore. Internally, a bilateral cerebral ganglion is situated in the anterior region and a large oocyte is located medially in the body. Several glands are present anteriorly, while posteriorly a pair of glands is associated with the ciliated tuft. Dorsal and ventral longitudinal muscles, as well as, dorsoventral muscles are identified by electron microscopy. Muscle fibers attach to the endocuticle via the epidermis, by means of attachment fibers. An unknown endosymbiont is present throughout the body of the female. We discuss the functional implications of the morphological and ultrastructural aspects of the cycliophoran female. Finally, we compare this life cycle stage with that fromother phyla, suggested as phylogenetically close. PMID- 22505146 TI - Micro-encapsulation of refined olive oil: influence of capsule wall components and the addition of antioxidant additives on the shelf life and chemical alteration. AB - BACKGROUND: Although refined olive oils (ROOs) exhibit lower quality and less stability toward thermal stress than extra-virgin olive oils, these types of oil are gaining importance in the food industry. The inclusion of ROOs in processed food may alter the oxidative stability of the manufactured products, and therefore having technological alternatives to increase oil stability will be an important achievement. For this reason the main goal of this study was to assess the influence of the micro-encapsulation process on the ROO chemical composition and its oxidative stability. Factors such as microcapsule wall constituents and the addition of the antioxidant butyl hydroxytoluene were investigated in order to establish the most appropriate conditions to ensure no alteration of the refined olive oil chemical characteristics. RESULTS: The optimised methodology exhibited high encapsulation yield (>98%), with micro-encapsulation efficiency ranging from 35 to 69% according to the nature of the wall components. The encapsulation process slightly altered the chemical composition of the olive oil and protected the oxidative stability for at least 11 months when protein components were included as wall components. CONCLUSION: It was concluded that the presence of proteins constituents in the microcapsule wall material extended the shelf life of the micro-encapsulated olive oil regardless the use of antioxidant additives. PMID- 22505147 TI - Study on metal-on-metal hip implants was halted a year before UK regulator banned their use. PMID- 22505148 TI - National imperatives could override local priorities of health and wellbeing boards, survey indicates. PMID- 22505149 TI - Multiprofessional interventions to improve patient adherence to cardiovascular medications. AB - BACKGROUND: Poor adherence to medications is a significant health care issue, particularly among cardiovascular patients. A variety of interventions have been tested by researchers in an effort to identify the most effective approach to improving adherence. Interventions delivered by multiple health care professionals (HCPs) may have an impact on improving adherence to medications in patients with chronic conditions, although the evidence to support this is still limited. OBJECTIVE: To investigate the impact of interventions delivered by HCPs within a multiprofessional team to improve patients' adherence to cardiovascular disease medications in community settings. SEARCH STRATEGY: The search strategy involved the use of the following data bases: Google scholar, PubMed, Medline, Cinahl, Embase, IPA, and Cochrane Library, from 1994 to 2010. Search was restricted to articles published in English. SELECTION CRITERIA: Cluster randomized trials, controlled randomized clinical trials, prospective randomized trials, and nonrandomized studies were included. We considered any intervention designed to enhance adherence to medication directed by more than 1 HCP. RESULTS: We included 17 studies testing 3 different types of interventions directed by more than 1 HCP. The HCPs received a variety of training via educational lectures or interactive workshops. Informational, behavioral, and combined interventions were delivered to cardiovascular patients. The majority of studies using only informational interventions or a combination of behavioral and informational interventions showed improvements in clinical outcomes (ie, blood pressure and total cholesterol lowering). However, only 2 studies measured improvements in adherence but the results were not significant. In contrast, all interventions based on the behavior change strategies improved both clinical outcomes and adherence to medication. CONCLUSIONS: Behavioral interventions delivered by a multiprofessional team appear to offer the best opportunity to improve clinical outcomes through improvements in adherence. However, whether interventions delivered by a multiprofessional team are more clinically effective than those delivered by a single HCP remain to be tested. PMID- 22505150 TI - Architecture and pore block of eukaryotic voltage-gated sodium channels in view of NavAb bacterial sodium channel structure. AB - The X-ray structure of the bacterial sodium channel NavAb provides a new template for the study of sodium and calcium channels. Unlike potassium channels, NavAb contains P2 helices in the outer-pore region. Because the sequence similarity between eukaryotic and prokaryotic sodium channels in this region is poor, the structural similarity is unclear. We analyzed it by using experimental data on tetrodotoxin block of sodium channels. Key tetrodotoxin-binding residues are outer carboxylates in repeats I, II, and IV, three positions downstream from the selectivity-filter residues. In a NavAb-based model of Nav1 channels derived from the sequence alignment without insertions/deletions, the outer carboxylates did not face the pore and therefore did not interact with tetrodotoxin. The hypothesis that the evolutionary appearance of Nav1 channels involved point deletions in an ancestral channel between the selectivity filter and the outer carboxylates allowed building of a NavAb-based model with tetrodotoxin-channel contacts similar to those proposed previously. This hypothesis also allowed us to reproduce in Nav1 the folding-stabilizing contacts between long-side chain residues in P1 and P2, which are seen in NavAb. The NavAb-based inner-pore model of Nav1 preserved major features of our previous KcsA-based models, including the access pathway for ligands through the repeat III/IV interface and their interactions with specific residues. Thus, structural properties of eukaryotic voltage-gated sodium channels that are suggested by functional data were reproduced in the NavAb-based models built by using the unaltered template structure but with adjusted sequence alignment. Sequences of eukaryotic calcium channels aligned with NavAb without insertions/deletions, which suggests that NavAb is a promising basis for the modeling of calcium channels. PMID- 22505151 TI - Generation of doubly charged vortex beam by concentrated loading of glass disks along their diameter. AB - We show that a system of glass disks compressed along their diameters enables one to induce a doubly charged vortex beam in the emergent light when the incident light is circularly polarized. Using such a disk system, one can control the efficiency of conversion of the spin angular momentum to the orbital angular momentum by a loading force. The consideration presented here can be extended for the case of crystalline materials with high optical damage thresholds in order to induce high-power vortex beams. PMID- 22505152 TI - Building a 3D scanner system based on monocular vision. AB - This paper proposes a three-dimensional scanner system, which is built by using an ingenious geometric construction method based on monocular vision. The system is simple, low cost, and easy to use, and the measurement results are very precise. To build it, one web camera, one handheld linear laser, and one background calibration board are required. The experimental results show that the system is robust and effective, and the scanning precision can be satisfied for normal users. PMID- 22505153 TI - Transparent superhydrophobic surfaces for applications of controlled reflectance. AB - This work involves a new optical application for transparent superhydrophobic materials, which enables low-energy optical contact between a liquid and solid surface. The new technique described here uses this surface property to control the reflectance of a surface using frustration of total internal reflection. Surface chemistry and appropriate micro-scale and nano-scale geometries are combined to produce interfaces with low adhesion to water and the degree to which incident light is reflected at this interface is controlled by the movement of water, thereby modifying the optical characteristics at the interface. The low adhesion of water to superhydrophobic surfaces is particularly advantageous in imaging applications where power use must be minimized. This paper describes the general approach, as well as a proof-of-principle experiment in which the reflectance was controlled by moving a water drop into and out of contact with a superhydrophobic surface by variation of applied electrostatic pressure. PMID- 22505154 TI - Collimating lens for light-emitting-diode light source based on non-imaging optics. AB - A collimating lens for a light-emitting-diode (LED) light source is an essential device widely used in lighting engineering. Lens surfaces are calculated by geometrical optics and nonimaging optics. This design progress does not rely on any software optimization and any complex iterative process. This method can be used for any type of light source not only Lambertian. The theoretical model is based on point source. But the practical LED source has a certain size. So in the simulation, an LED chip whose size is 1 mm*1 mm is used to verify the feasibility of the model. The mean results show that the lenses have a very compact structure and good collimating performance. Efficiency is defined as the ratio of the flux in the illuminated plane to the flux from LED source without considering the lens material transmission. Just investigating the loss in the designed lens surfaces, the two types of lenses have high efficiencies of more than 90% and 99%, respectively. Most lighting area (possessing 80% flux) radii are no more than 5 m when the illuminated plane is 200 m away from the light source. PMID- 22505155 TI - Relevance of an inverse problem approach to overcome cut-off wavenumbers disparities in infrared stationary Fourier transform spectrometers. AB - One of the major limitations to the use of infrared focal plane arrays (IRFPAs) in stationary Fourier transform spectrometers (FTSs) comes from the spatial inhomogeneities of the pixel responses, where the inhomogeneities of the cut-off wavenumbers of the pixels can prevail. The hypothesis commonly assumed for FTSs that all the pixels are equivalent is thus inaccurate and results in a degradation of the estimated spectrum, even far from the cut-off wavenumbers. However, if the individual spectral responses of the pixels are measured beforehand, this a priori information can be used in the inversion process to produce reliable spectra. Thus, spatial inhomogeneities are not an obstacle for the use of infrared stationary FTS. This result is illustrated in this paper by numerical simulations, based on a realistic description of an IRFPA. PMID- 22505156 TI - Reconstruction of three-dimensional chemiluminescence images with a maximum entropy deconvolution algorithm. AB - Three-dimensional (3D) images of flame emission are reported using a single direction of optical access. A Cassegrain system was designed with narrow depth of field. Images from this system are dominated by emission from the focused object plane with defocused contributions from out-of-plane structures. Translation of one mirror in the system allows for scanning the object plane through the flame. Images were taken at various depths to create a family of images. Reconstruction of the 3D flame structure was accomplished using a maximum entropy algorithm adapted for use with 3D imaging. Spatial resolution in the direction of imaging is examined using laminar flames with variable offset. PMID- 22505157 TI - Nd:Li6Y(BO3)3 crystal waveguide properties at wavelengths of 633 and 1539 nm produced by oxygen or silicon ion implantation. AB - We report on the waveguide formation in the Nd:Li6Y(BO3)3 laser crystal by oxygen or silicon ion implantation, respectively, and how the waveguide structure effectively supports the fundamental mode in the visible and near-infrared telecommunication band. Compared with Si-ion, the waveguide produced by O-ion has a larger effective refractive index of fundamental mode and lower propagation loss, which shows that peak position of implanted ion nuclear energy loss has a significant impact on waveguide features. The investigation of the photoluminescence and Raman spectra demonstrates that the Nd3+ luminescence feature and crystal structure of the waveguide active region do not change significantly and gain good preservation after ion implantation. PMID- 22505158 TI - Palladium bridged gold nanocylinder dimer: plasmonic properties and hydrogen sensitivity. AB - Plasmonic nanodimers facilitate electromagnetic hotspots at their gap junction. By loading these gap junctions with nanomaterials, the plasmonic properties of nanodimer can be varied. In this study, we bridged the gap junction of gold (Au) nanocylinder dimer with palladium (Pd), and numerically evaluated the plasmonic properties of the designed nanostructure. We simulated the far-field extinction spectra of Pd bridged Au nanocylinder dimer, and identified the dipole and quadrupole plasmon modes at 839 and 578 nm, respectively. By varying the geometrical parameters of the Pd bridge, we revealed the ability to tune the dipolar plasmon resonance of the bridged dimer. Further, we exploited the hydrogen sensitivity of Pd bridge to harness the bridged-Au dimer as nanoplasmonic hydrogen sensor. Such nano-optical detection platforms have minimal spatial footprint and can be further harnessed for chip-based plasmonic sensing. PMID- 22505159 TI - Light-emitting-diode-induced fluorescence detection of fluorescent dyes for capillary electrophoresis microchip with cross-polarization method. AB - A cross-polarization scheme is presented to filter out the excitation light from the emission spectrum of fluorescent dyes using green light emitting diodes as a light source and a linear charge coupled device as an intensity detector. The excitation light was linearly polarized and was then used to illuminate the fluorescent dyes in the microchannels of a capillary electrophoresis microchip. The detector was shielded by the second polarizer, oriented perpendicular to the excitation light. The fluorescent signals from Rhodamine B dyes were measured in a dilution series with resulting emission signals and four different concentrations of fluorescent dyes were detected simultaneously with the same excitation source and detector. A limit-of-detection of 1 MUM was demonstrated for Rhodamine B dye under the optimal conditions. PMID- 22505160 TI - Optimal signal processing of nonlinearity in swept-source and spectral-domain optical coherence tomography. AB - We demonstrate the efficiency of the convolution using an optimized Kaiser-Bessel window to resample nonlinear data in wavenumber for Fourier-domain optical coherence tomography (OCT). We extend our previous experimental demonstration that was performed with a specific swept-source nonlinearity. The method is now applied to swept-source OCT data obtained for various simulated swept-source nonlinearities as well as spectral-domain OCT data obtained from both simulations and experiments. Results show that the new optimized method is the most efficient for handling all the different types of nonlinearities in the wavenumber domain that one can encounter in normal practice. The efficiency of the method is evaluated through comparison with common methods using resampling through interpolation prior to performing a fast-Fourier transform and with the accurate but time-consuming discrete Fourier transform for unequally spaced data, which involves Vandermonde matrices. PMID- 22505161 TI - Delay line length selection in generating fast random numbers with a chaotic laser. AB - The chaotic light signals generated by an external cavity semiconductor laser have been experimentally demonstrated to extract fast random numbers. However, the photon round-trip time in the external cavity can cause the occurrence of the periodicity in random sequences. To overcome it, the exclusive-or operation on corresponding random bits in samples of the chaotic signal and its time-delay signal from a chaotic laser is required. In this scheme, the proper selection of delay length is a key issue. By doing a large number of experiments and theoretically analyzing the interplay between the Runs test and the threshold value of the autocorrelation function, we find when the corresponding delay time of autocorrelation trace with the correlation coefficient of less than 0.007 is considered as the delay time between the chaotic signal and its time-delay signal, streams of random numbers can be generated with verified randomness. PMID- 22505162 TI - Simulation research on improved regularized solution of the inverse problem in spectral extinction measurements. AB - We present further results of the simulation research on the constrained regularized least squares (CRLS) solution of the ill-conditioned inverse problem in spectral extinction (turbidimetric) measurements, which we originally presented in this journal [Appl. Opt. 49, 4591 (2010)]. The inverse problem consists of determining the particle size distribution (PSD) function of a particulate system on the basis of a measured extinction coefficient as a function of wavelength. In our previous paper, it was shown that under assumed conditions the problem can be formulated in terms of the discretized Fredholm integral equation of the first kind. The CRLS method incorporates two constraints, which the PSD sought will satisfy: nonnegativity of the PSD values and normalization of the PSD to unity when integrated over the whole range of particle size, into the regularized least squares (RLS) method. This leads to the quadratic programming problem, which is solved by means of the active set algorithm within the research. The simulation research that is the subject of the present paper is a continuation and extension of the research described in our previous paper. In the present research, the performance of the CRLS method variants is compared not only to the corresponding RLS method variants but also to other regularization techniques: the truncated generalized singular value decomposition and the filtered generalized singular value decomposition, as well as nonlinear iterative algorithms: The Twomey algorithm and the Twomey-Markowski algorithm. Moreover, two methods of selecting the optimum value of the regularization parameter are considered: The L-curve method and the generalized cross validation method. The results of our simulation research provide even stronger proof that the CRLS method performs considerably better with reconstruction of PSD than other inversing methods, in terms of better fidelity and smaller uncertainty. PMID- 22505163 TI - External cavity beam combining of 21 semiconductor lasers using SPGD. AB - Active coherent beam combining of laser oscillators is an attractive way to achieve high output power in a diffraction limited beam. Here we describe an active beam combining system used to coherently combine 21 semiconductor laser elements with an 81% beam combining efficiency in an external cavity configuration compared with an upper limit of 90% efficiency in the particular configuration of the experiment. Our beam combining system utilizes a stochastic parallel gradient descent (SPGD) algorithm for active phase control. This work demonstrates that active beam combining is not subject to the scaling limits imposed on passive-phasing systems. PMID- 22505164 TI - Properties of TM resonances on metallic slit gratings. AB - Electromagnetic resonances on metallic slit gratings induced by TM polarized incident light have been investigated and physically interpreted. We have developed an electromagnetic model imposing surface impedance boundary conditions on the metallic grating surface from which we derive simple formulas explaining all physical properties of these resonances. It is demonstrated that Fabry-Perot (or cavity) resonances are generated by the zeroth slit mode yielding extraordinary transmission. For very narrow slits, the resonant H-field is squeezed to the slit walls and causes enhanced power losses. The excitation of surface plasmon polaritons (SPPs), however, is generated by two mode coupling. SPPs are linked to sharp absorption peaks and dips in transmittance. It is shown that these phenomena are primarily caused by the interaction of the electromagnetic fields with the finite conducting slit walls. These findings have been confirmed by measured transmittance data of gold gratings with periods of 0.5 MUm, 1 MUm, and 2 MUm. PMID- 22505165 TI - Computational model for salient object detection with anisotropy. AB - An innovative computational model for salient objects detection is proposed. The model is based on the exploitation of the anisotropy property of images by means of pixelwise directional entropy. The generalized Renyi entropy and the discrete cosine transform (DCT) coefficients are selected for this purpose. An entropy map of an input image can be obtained by calculating the Renyi entropy via local patch-based DCT. Analyzing the statistical property of the power spectrum of the entropy map on log-log scale, we find the power law is also appropriate for entropy maps. Accordingly, a saliency map can be derived from the entropy residual computation. Salient objects are detected using a seeded region growing algorithm. Both qualitative and quantitative experiments are conducted. The corresponding results demonstrate the outstanding performance of the proposed model. PMID- 22505166 TI - Experimental study of an off-axis three mirror anastigmatic system with wavefront coding technology. AB - Wavefront coding (WFC) is a kind of computational imaging technique that controls defocus and defocus related aberrations of optical systems by introducing a specially designed phase distribution to the pupil function. This technology has been applied in many imaging systems to improve performance and/or reduce cost. The application of WFC technology in an off-axis three mirror anastigmatic (TMA) system has been proposed, and the design and optimization of optics, the restoration of degraded images, and the manufacturing of wavefront coded elements have been researched in our previous work. In this paper, we describe the alignment, the imaging experiment, and the image restoration of the off-axis TMA system with WFC technology. The ideal wavefront map is set to be the system error of the interferometer to simplify the assembly, and the coefficients of certain Zernike polynomials are monitored to verify the result in the alignment process. A pinhole of 20 MUm diameter and the third plate of WT1005-62 resolution patterns are selected as the targets in the imaging experiment. The comparison of the tail lengths of point spread functions is represented to show the invariance of the image quality in the extended depth of focus. The structure similarity is applied to estimate the relationship among the captured images with varying defocus. We conclude that the experiment results agree with the earlier theoretical analysis. PMID- 22505167 TI - Method of developing all-optical trinary JK, D-type, and T-type flip-flops using semiconductor optical amplifiers. AB - To meet the demand of very fast and agile optical networks, the optical processors in a network system should have a very fast execution rate, large information handling, and large information storage capacities. Multivalued logic operations and multistate optical flip-flops are the basic building blocks for such fast running optical computing and data processing systems. In the past two decades, many methods of implementing all-optical flip-flops have been proposed. Most of these suffer from speed limitations because of the low switching response of active devices. The frequency encoding technique has been used because of its many advantages. It can preserve its identity throughout data communication irrespective of loss of light energy due to reflection, refraction, attenuation, etc. The action of polarization-rotation-based very fast switching of semiconductor optical amplifiers increases processing speed. At the same time, tristate optical flip-flops increase information handling capacity. PMID- 22505169 TI - Extended viewing angle holographic display system with tilted SLMs in a circular configuration. AB - This paper presents an extended viewing angle holographic display for reconstruction of real world objects in which the capture and display systems are decoupled. This is achieved by employing multiple tilted spatial light modulators (SLMs) arranged in a circular configuration. In order to prove the proper reconstruction and visual perception of holographic images the Wigner distribution function is employed. We describe both the capture system using a single static camera with a rotating object and a holographic display utilizing six tilted SLMs. The experimental results based on the reconstruction of computer generated and real world scenes are presented. The coherent noise removal procedure is described and implemented. The experiments prove the possibility to view images reconstructed in the display binocularly and with good quality. PMID- 22505168 TI - Segment side-pumped Q-switched Nd:YAG laser. AB - In the design of conduction-cooled lasers, a side-pumped configuration is an attempt to solve the space conflict between pump and heat removal. The pump radiation always competes with the heat removal and mechanical support device for the lateral surface of a laser rod. This space conflict can be addressed by a segment side-pumped configuration in which circular laser diode arrays and heat conducting rod holders alternate periodically along the length of the laser rod. This scheme permitted 11 Hz operation of a 190 mJ Q-switched laser at the wavelength of 1064 nm without the use of liquid cooling for both the laser rod and laser diode arrays and the corresponding optical-optical conversion efficiency of 23.1%. Thus, it has great potential to be used in compact and miniature laser systems. PMID- 22505170 TI - Detection of small surface defects of nontransparent scattering materials by using dynamic speckles. AB - We present a novel method for small surface defect detection based on the spatially filtered dynamic speckles. This method possesses high fidelity and versatility. Factors defining resolution of the proposed method is estimated and it is shown that resolution depends solely on the geometrical parameters of the optical system. Experimental results demonstrate feasibility of the proposed method for surface defect detection and are in good agreement with the theoretical estimations. A prototype for online detection of the defects with diameter of 400 um is presented. Ways to improve prototype performance and the method resolution are discussed. PMID- 22505171 TI - Thermal drift compensation method for microbolometer thermal cameras. AB - We propose a new method of compensation for drifts in thermal cameras using a filter in place of a shutter. The latter method requires periodically closing the camera, thus causing the images to appear frozen frequently. Our technique of replacing the shutter with a filter eliminates this frozen image problem. In this paper we discuss the principles of the new method and present the obtained results. PMID- 22505172 TI - Lateral resolution and transfer characteristics of vertical scanning white-light interferometers. AB - White-light interferometers are widely used for high-accuracy topography measurement in industrial and scientific applications. A common way to characterize a white-light interferometer is to assume small surface amplitudes resulting in linear transfer characteristics described by the instrument transfer function (ITF). However, the well-known batwing effect gives rise to systematic errors, causing extra nonlinearity to the ITF. In this paper a model to simulate an interference pattern in the image plane as it is obtained by a vertical scanning white-light interferometer is introduced in order to overcome the limitation of small surface amplitudes. Repeating the simulation procedure for different height positions of the object results in an image stack that can be analyzed by the same algorithms as real measurement data. The simulation results agree with experimental observations: the batwing effect occurs in certain situations and the correct amplitude of a rectangular grating structure can be obtained as long as the structure is optically resolved. Both simulation, as well as experimental results, provide transfer characteristics of broader bandwidth than predicted by theoretical approaches based on linear system behavior. PMID- 22505173 TI - Optical zoom module based on two deformable mirrors for mobile device applications. AB - In recent years, optical zoom functionality in mobile devices has been studied. Traditional zoom systems use motors to change separation of lenses to achieve the zoom function, but these systems result in long total length and high power consumption, which are not suitable for mobile devices. Adopting micromachined polymer deformable mirrors in zoom systems has the potential to reduce thickness and chromatic aberration. In this paper, we propose a 2* continuous optical zoom system with five-megapixel image sensors by using two deformable mirrors. In our design, the thickness of the zoom system is about 11 mm. The effective focal length ranges from 4.7 mm at a field angle of 52 degrees to 9.4 mm. The f-number is 4.4 and 6.4 at the wide-angle and telephoto end, respectively. PMID- 22505174 TI - S-band multiwavelength ring Brillouin/Raman fiber laser with 20 GHz channel spacing. AB - We propose and demonstrate a tunable S-band multiwavelength Brillouin/Raman fiber laser (MBRFL) with a tuning range of between 1490 to 1530 nm. The proposed MBRFL is designed around a 7.7 km long dispersion compensating fiber in a simple ring configuration, acting as a nonlinear medium for the generation of multiple wavelengths from stimulated Brillouin scattering (SBS) and also as a nonlinear gain medium for stimulated Raman scattering (SRS) amplification. A laser source with a maximum power of 12 dBm acts as the Brillouin pump (BP), while two 1420 nm laser diodes with a total power of 26 dBm act as the Raman pumps (RPs). The MBRFL can generate a multiwavelength comb consisting of even and odd Stokes at an average power of -12 dBm and -14 dBm respectively, and by separating the even and odd Stokes outputs, a 20 GHz channel spacing is obtained between two consecutive wavelengths. Due to the four-wave mixing (FWM) effect, anti-Stokes lines are also observed. The multiwavelength comb generated is not dependent on the BP, thus providing high stability and repeatability and making it a highly potential source for many real-world applications. This is the first time, to the knowledge of the authors, that a tunable MBRFL has been developed using SRS to obtain gain in the S-band region. PMID- 22505175 TI - Spectral linewidth narrowing and tunable two-color laser operation of two diode laser arrays. AB - We propose and implement a common external cavity to narrow spectral linewidth of two broad-area laser diode arrays (LDAs) and align their center wavelengths. The locked center wavelength of two LDAs can be tuned in the range of ~10 nm by tuning the tilted angle of the diffraction grating. The output beams of two LDAs are spatially overlapped through the polarization beam splitter of the common external cavity, and the total output power equals the power of two LDAs. The center wavelength of each LDA can be independently tuned by shifting the corresponding fast-axis collimation lens. As a result, the high-power two-color LDA operation is demonstrated with the tunable wavelength difference of up to 2 nm (~1 THz). PMID- 22505176 TI - Master key generation to avoid the use of an external reference wave in an experimental JTC encrypting architecture. AB - In experimental optodigital encrypting architectures, the use of a reference wave is essential. In this contribution, we present an experimental alternative to avoid the reference wave during the encrypting procedure in a joint transform correlator architecture by introducing the concept of a master key. Besides, the master key represents an additional security element for the entire protocol. In our method, the master key is holographically processed and used during the encryption process with the encrypting key. We give the mathematical description for the process in case of a single input object and then we extend it to multiple input objects. We present the experimental demonstration of the proposed method including two examples where this technique is successfully applied for several input objects. PMID- 22505177 TI - Association of ADAMTS12 polymorphisms with rheumatoid arthritis. AB - a disintegrin and metalloproteinase (ADAM) with thrombospondin type 1 motif 12 (ADAMTS12) is a degradative enzyme that interacts with the degradable fragments of cartilage oligomeric matrix protein, which is a prominent non-collagenous matrix component in articular cartilage. ADAMTS12 has been observed in the cartilage, synovial fluid and serum of arthritic patients, and may play an important role in the pathogenesis of arthritis. In the present study, we investigated whether genetic polymorphisms of ADAMTS12 are associated with rheumatoid arthritis (RA). To observe the association between ADAMTS12 and RA, we genotyped three single nucleotide polymorphisms (SNPs) (rs1364044, intron C/T; rs10461703, intron C/T; rs25754, missense Thr1495Ile) of ADAMTS12 using a direct sequencing method in 303 RA patients and 495 control subjects. Multiple logistic regression models were performed to analyze the genetic data. SNPStats and SNPAnalyzer Pro programs were used to estimate the odds ratios, 95% confidence intervals and p-values. Bonferroni's correction (pc) was conducted to obtain a defined result. Of the three SNPs, the genotype frequency of rs10461703 was associated with the development of RA (pc=0.0024 in the co-dominant model; pc=0.0009 in the dominant model; pc=0.0006 in the log-additive model). The allele frequency of rs10461703 also showed a significant difference between RA and controls (pc<0.0001). The C allele frequency of rs10461703 was lower in the RA group (36.6%) compared to the control group (45.7%), whereas the T allele frequency of rs10461703 in the RA group (63.4%) was higher compared to that in the control group (54.3%). The other two SNPs (rs1364044 and rs25754) were not associated with the development of RA. However, we did not find any association between the three tested SNPs and RA patients according to clinical features, including erythrocyte sedimentation rate, C-reactive protein level, rheumatoid factor (+ and -) and bone erosion (+ and -). Our results suggest that ADAMTS12 may be a susceptibility gene for RA development. PMID- 22505178 TI - Building bio-inspired artificial functional nanochannels: from symmetric to asymmetric modification. AB - Over millions of years, complex processes of intelligent control have evolved in nature. Learning from nature is a continuing theme in the development of smart materials and intelligent systems. For example, biological nanochannels, which are typically ion channels, play a very important role in basic biochemical processes in cells. Inspired by ion channels, in which the components are asymmetrically distributed between the membrane surfaces, the generation of biomimetic smart nanochannels is a broad and varied scientific research field. The design and development of new biomimetic channels includes the use of different shapes of channels, different stimuli-responsive molecules, and different symmetric/asymmetric modification methods. In this Minireview, we summarize recent developments in building functional nanochannels by applying various symmetric and asymmetric modifications. PMID- 22505179 TI - Minimum 5-year follow-up after Cormet hip resurfacing. A single surgeon series of 234 hips. AB - The performance of the Cormet hip resurfacing device was evaluated after a minimum of 5 years in 234 hips. The mean age of the patients was 54 years; there were 135 men and 80 women. The primary diagnosis was osteoarthritis in 78% of the patients. Outcome measures were the Harris Hip Score and implant survival. The overall survival rate was 94% with 12 revisions in women and 3 in men. There were 7 femoral and 5 acetabular failures and two revisions for groin pain. Cumulative survival rate in men and women was 98% and 89%, in patients with a femoral component larger than 44 mm and smaller than 44 mm 97% and 89% respectively. Patients with primary osteoarthritis had a 95% cumulative survival rate at 5 years. The risk of failure was 6.4 times higher in women than in men. Our results suggest that hip resurfacing with the Cormet device is an acceptable alternative for active patients with hip arthritis, but patient selection is crucial for good long-term results. PMID- 22505180 TI - Surgical hip dislocation for anatomic reorientation of slipped capital femoral epiphysis: preliminary results. AB - Controversies exist regarding the best treatment for slipped capital femoral epiphysis (SCFE). Subcapital anatomical reorientation of the epiphysis by surgical dislocation and a retinacular soft tissue flap has been described recently as an effective approach. We evaluated the clinical and radiographic efficacy of this technique and compared these to published results. A series of 20 SCFE (18 stable, 2 unstable) treated by subcapital re-orientation through surgical hip dislocation and an extended retinacular soft tissue flap was reviewed retrospectively. Preoperatively and at most recent follow-up, patients were clinically examined with regard to pain and function according to the Harris hip score and to the Western Ontario and McMaster universities (WOMAC) score. Radiological examination included measurement of preoperative and postoperative anteroposterior (AP) and lateral (L) Southwick angles; and at follow-up the alpha angle was measured. The average follow-up time was 24 months. The mean WOMAC score was 2.80 post-operatively. The mean pre-operative slip angle was 40.2 degrees on the AP view and 50.65 degrees on the lateral view. Post-operatively, the mean values were 7,20 degrees on the AP view and 9,45 degrees on the lateral view. The mean post-operative average alpha angle was 43,11 degrees. No cases of avascular necrosis were seen. Our short term clinical and radiographic results are similar to outcomes published in the recent literature. The small number of technical complications appears favourable considering the surgical complexity of the procedure, and our technique offers clear advantages in treating these complex deformities. PMID- 22505181 TI - Mid-term outcome of total hip replacement using the posterior approach for displaced femoral neck fractures. AB - Treatment of displaced femoral neck fractures with total hip replacement (THR) in appropriately selected patients has become more widely accepted. The use of the posterior approach for THR remains controversial due to concerns regarding dislocation, the cause of which is multi-factorial. This study is a single surgeon series of 45 consecutive active, healthy patients (mean age 78 years) with displaced femoral neck fractures treated with THR through a posterior approach. Large diameter heads (32mm in 47%, >=36mm in 48% of patients) and an anatomic posterior soft tissue repair were utilised to minimize the risk of dislocation. Outcomes were reported at a mean of 2 and 6 years. The mortality rate was 13% at 2 years and 40% at 6 years. All revision surgery (4.4%) was performed for dislocations which occurred in 6.7% of patients. Good VAS pain, OHS and SF-12 scores were reported both at 2 and 6 years. Patient satisfaction with the results of surgery was high. PMID- 22505182 TI - Markers of activated inflammatory cells correlate with severity of liver damage in children with nonalcoholic fatty liver disease. AB - Concomitantly to the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in children. NAFLD encompasses a spectrum of histological damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), with possible progression to cirrhosis. There is growing evidence that the immune system plays a pivotal role in the initiation and progression to NASH but the cellular nature of the hepatic inflammation is still unknown. The present study includes 34 children with biopsy-proven NAFLD. Liver damage was evaluated by the NAFLD activity score (NAS), and the inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3 and CD163 which are markers of leukocytes, T cells and activated Kupffer cells/macrophages, respectively. Our results have shown that CD45+ (P<0.0001) and CD163+ (P<0.0001) cells were markedly increased in children with severe histological activity (NAS>=5) compared to children with lower activity (NAS<5), whereas CD3+ cells were significantly lower (P<0.01) in children with severe histological activity. There was a significant association between the numbers of CD45+, CD3+ and CD163+ cells, regarding both the portal tract and liver lobule, and the severity of steatosis, ballooning and fibrosis (P<0.01). These data suggest that the severity and composition of the inflammatory infiltrate correlate with steatosis and the severity of disease in children with NAFLD. Moreover, a decrease in CD3+ cells may be involved in the pathogenesis of liver damage. Future studies should evaluate whether it can predict the progression of liver disease independently of established histological scores. PMID- 22505183 TI - Mannose-specific lectin isolation from Canavalia ensiformis seeds by PHEMA-based cryogel. AB - Mannose-specific lectin Concanavalin A (Con A) was purified from Canavalia ensiformis seeds. For this purpose, mannose attached poly(hydroxyethyl methacrylate) (PHEMA) cryogel was prepared by cryopolymerization. Mannose was used as the affinity ligand and was covalently attached onto the PHEMA cryogel via carbodiimide activation. The PHEMA cryogel containing 23.3 mmol mannose/g polymer were used in the binding studies. Con A binding with the mannose attached PHEMA cryogel from Con A aqueous solution was 5.2 mg/g at pH 7. Maximum binding capacity for Con A from C. ensiformis seed extract was 39 mg/g. Con A was eluted with 0.3 M galactose, and the purity of Con A was determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. It was observed that the mannose attached PHEMA cryogel can be used without significant decrease in Con A binding capacity after six binding-elution cycles. PMID- 22505184 TI - "Frustrated Lewis pair" hydrogenations. AB - This perspective article discusses developments of metal-free hydrogenation catalysts derived from "frustrated Lewis pair" (FLP) systems. The range of catalysts uncovered and the applications to reductions of imines, aziridines, enamines, silyl enol ethers, diimines, metallocene derivatives and nitrogen-based heterocycles are described. In addition, FLP aromatic reduction of aniline derivatives to the cyclohexylamine analogs is discussed. The potential applications of these metal-free reductions are considered. PMID- 22505185 TI - Morphology of the European sea bass (Dicentrarchus labrax) tongue. AB - The European sea bass, a member of the Moronidae family, is a food fish, considered one of the first models for the intensive breeding in salt water. It has nowadays an important and increasing presence in the international fishing markets. Sea basses are carnivorous, feeding on little fishes and invertebrates. Considering the important role of the tongue during the intraoral transport and the swallowing of food, scarce data are present in literature about its morphology. The aim of this study was to analyze the morphology of the tongue by means of scanning electron and light microscopy. Adult sea basses were obtained from the aquarium of the Sicilian Center of Experimental Ichthyiopathology of the University of Messina. The fishes were anaesthetized with MS 222 and the heads were then quickly removed and processed for the paraffin embedding and SEM processing. Three different tongue regions could be distinguished: an apex, a body, and a root. Scanning electron and light microscopy showed the presence of numerous canine-like teeth, surrounded by taste buds and numerous fungiform and conical papillae. The teeth were curved and their tips were posteriorly oriented. The results confirm, in teleosts too, the fundamental role of the tongue in the mechanics of food ingestion. Moreover, the presence of taste buds demonstrates the interaction of food processing and taste. These data could be a potential source to identify new and better methods of nutrition in the breeding of this fish. PMID- 22505186 TI - Analysis of the interface and bond strength of resin-based endodontic cements to root dentin. AB - This study evaluated by scanning electron microscopy the interface between root dentin and resin cements, with or without additional application of a dual-cured one-step self-etching dentin adhesive. In addition, the push-out bond strength of these materials to dentin was evaluated. Root canals of 50 maxillary human canines were subjected to biomechanical preparation and randomly assigned into five groups (n = 10) according to the obturation employed: I. AH Plus/gutta percha; II. Endo-REZ/gutta-percha; III. Epiphany SE/Resilon; IV. Endo-REZ/gutta percha + adhesive; and V. Epiphany SE/Resilon + adhesive. After obturation, two cross sections of 1.0 mm of each third of the root were obtained and analyzed by SEM and push-out. Data were analyzed by Kruskal-Wallis, Two-way ANOVA and Tukey's HSD tests (alpha = 5%). Significant differences occurred between scores for gap parameters and tags; greater tag formation resulted for Epiphany SE (P < 0.05). There were also significant differences between groups for the bond strength. AH Plus (1.24 +/- 0.70) showed higher values (P < 0.05) compared to groups II (0,17 +/- 0.19), III (0.10 +/- 0.06), IV (0.09 +/- 0.08), and V (0.06 +/- 0.03), which were statistically similar (P > 0.05). There was no significant difference between the root thirds (P > 0.05). It was concluded that the use of a self etching adhesive system did not improve the adhesion of resin-based sealers to dentin and that AH Plus showed better bond strength when compared to other cements. PMID- 22505187 TI - Quantitative 3D imaging of yeast by hard X-ray tomography. AB - Full-field hard X-ray tomography could be used to obtain three-dimensional (3D) nanoscale structures of biological samples. The image of the fission yeast, Schizosaccharomyces pombe, was clearly visualized based on Zernike phase contrast imaging technique and heavy metal staining method at a spatial resolution better than 50 nm at the energy of 8 keV. The distributions and shapes of the organelles during the cell cycle were clearly visualized and two types of organelle were distinguished. The results for cells during various phases were compared and the ratios of organelle volume to cell volume can be analyzed quantitatively. It showed that the ratios remained constant between growth and division phase and increased strongly in stationary phase, following the shape and size of two types of organelles changes. Our results demonstrated that hard X-ray microscopy was a complementary method for imaging and revealing structural information for biological samples. PMID- 22505188 TI - Development of a reduction-responsive amino acid that induces peptide bond cleavage in hypoxic cells. AB - Hypoxia-responsive amino acids are indispensable in the preparation of hypoxic tumor-specific peptidyl prodrugs. In this paper, the design and synthesis of a reduction-responsive amino acid that induces peptide bond cleavage after reduction of the nitro group are described. Application to hypoxia-responsive peptide bond cleavage system is also reported. PMID- 22505189 TI - Scaffold-inspired enantioselective synthesis of biologically important spiro[pyrrolidin-3,2'-oxindoles] with structural diversity through catalytic isatin-derived 1,3-dipolar cycloadditions. AB - Catalytic asymmetric construction of the biologically important spiro[pyrrolidin 3,2'-oxindole] scaffold with contiguous quaternary stereogenic centers in excellent stereoselectivities (up to >99:1 d.r., 98% ee) has been established by using an organocatalytic 1,3-dipolar cycloaddition of isatin-based azomethine ylides. This protocol represents the first example of catalytic asymmetric 1,3 dipolar cycloadditions involving azomethine ylides generated in situ from unsymmetrical cyclic ketones. In addition, theoretical calculations were performed on the transition state of the reaction to understand the stereochemistry. Preliminary bioassays with these spiro[pyrrolidin-3,2'-oxindole] revealed that several compounds showed moderate cytotoxicity to SW116 cells. PMID- 22505190 TI - Connexin 36 is expressed in beta and connexins 26 and 32 in acinar cells at the end of the secondary transition of mouse pancreatic development and increase during fetal and perinatal life. AB - To identify when during fetal development connexins (Cxs) 26 (Cx26) 32 (Cx32), and 36 (Cx36) begin to be expressed, as well as to characterize their spatial distribution, real time polymerase chain reaction and immunolabeling studies were performed. Total RNA from mouse pancreases at 13 and 18 days postcoitum (dpc) and 3 days postpartum (dpp) was analyzed. In addition, pancreatic sections of mouse at 13, 14, 15, 16, 18 dpc and 3 dpp and of rat at term were double labeled with either anti-insulin or anti-alpha-amylase and anti-Cx26 or -Cx32 or -Cx36 antibodies and studied with confocal microscopy. From day 13 dpc, Cxs 26, 32, and 36 transcripts were identified and their levels increased with age. At 13-14 dpc, Cxs 26 and 32 were localized in few acinar cells, whereas Cx36 was distributed in small beta cell clumps. From day 14 dpc onwards, the number of labeled cells and relative immunofluorescent reactivity of all three Cxs at junctional membranes of the respective cell types increased. Cxs 26 and 32 colocalized in fetal acinar cells. In rat pancreas at term, a similar connexin distribution was found. Relative Cxs levels evaluated by immunoblotting also increased (two-fold) in pancreas homogenates from day 18 dpc to 3 dpp. The early cell specific, wide distribution, and age dependent expression of Cxs 26, 32, and 36 during fetal pancreas ontogeny suggests their possible involvement in pancreas differentiation and prenatal maturation. PMID- 22505191 TI - Combined therapy of temozolomide and ZD6474 (vandetanib) effectively reduces glioblastoma tumor volume through anti-angiogenic and anti-proliferative mechanisms. AB - Currently, clinically available options for treating glioblastoma (GBM) are quite limited, and there is a clear need to develop novel treatment strategies that can more effectively manage tumors. Here, we present a combination treatment of temozolomide (TMZ), a blood-brain barrier penetrating DNA alkylating agent, and ZD6474 (vandetanib), a VEGFR2 and EGFR dual-targeting anti-angiogenic agent, as a novel treatment strategy for GBM. In a U-87MG orthotopic xenograft model, the combination treatment provided a marked 94% tumor volume reduction. This reduction was greater than that achieved by monotherapy of either agent, and was correlated with a statistically significant reduction in microvessel density (CD31+ cells) and proliferation (PCNA+ cells). These results confirm the necessity to target angiogenesis in addition to utilizing cytotoxic approaches, and provide the rationale for application of TMZ + ZD6474 combination therapy for treating GBM patients in the clinical setting. PMID- 22505192 TI - Development of an on-line molecularly imprinted chemiluminescence sensor for determination of trace olaquindox in chick feeds. AB - BACKGROUND: Olaquindox, as one of the antimicrobial growth accelerants, is usually used in livestock production to improve feed efficiency. Due to health concerns over possible carcinogenic, mutagenic and photoallergenic effects of olaquindox on animals, the development of simple, rapid and sensitive analytical method for determination of olaquindox is crucial and necessary. RESULTS: In this study, a surface molecularly imprinted polymer was prepared by a molecular imprinting technique in combination with a sol-gel process using activated silica gel as a support material. This imprinted material exhibited with good recognition and selective ability, and fast adsorption-desorption dynamics toward olaquindox. Using it as the recognition element, a new on-line molecularly imprinted solid phase extraction coupled with chemiluminescence sensor for the determination of olaquindox was developed. The factors affecting preconcentration of the analytes and sensitivity of the method were all investigated. Under the optimal condition, the linear range of the calibration graph was between 2 * 10( 8) and 1 * 10(-6) g mL(-1) , and the detection limit of this method was 7 * 10( 9) g mL(-1) . The blank chick feed samples spiked with olaquindox at 0.3, 0.9 and 1.5 ug g(-1) levels were extracted and determined by this presented method with recoveries ranging from 87% to 94%. This method was validated by high-performance liquid chromatography and the results correlated well with those obtained by both methods. Moreover, this method was quantitatively analysed with two contaminated chick feed samples. CONCLUSION: This study will provide a sensitive and fast method for the monitoring of olaquindox residues in foods. PMID- 22505193 TI - Muscle fibers in the central nervous system of nemerteans: spatial organization and functional role. AB - The system of muscle fibers associated with the brain and lateral nerve cords is present in all major groups of enoplan nemerteans. Unfortunately, very little is known about the functional role and spatial arrangement of these muscles of the central nervous system. This article examines the architecture of the musculature of the central nervous system in two species of monostiliferous nemerteans (Emplectonema gracile and Tetrastemma cf. candidum) using phalloidin staining and confocal microscopy. The article also briefly discusses the body-wall musculature and the muscles of the cephalic region. In both species, the lateral nerve cords possess two pairs of cardinal muscles that run the length of the nerve cords and pass through the ventral cerebral ganglia. A system of peripheral muscles forms a meshwork around the lateral nerve cords in E. gracile. The actin-rich processes that ramify within the nerve cords in E. gracile (transverse fibers) might represent a separate population of glia-like cells or sarcoplasmic projections of the peripheral muscles of the central nervous system. The lateral nerve cords in T. cf. candidum lack peripheral muscles but have muscles similar in their position and orientation to the transverse fibers. The musculature of the central nervous system is hypothesized to function as a support system for the lateral nerve cords and brain, preventing rupturing and herniation of the nervous tissue during locomotion. The occurrence of muscles of the central nervous system in nemerteans and other groups and their possible relevance in taxonomy are discussed. PMID- 22505195 TI - Cubic molecularly imprinted polymer nanoparticles with a fluorescent core. PMID- 22505196 TI - A comparison of bicarbonate kinetics and acid-base status in high flux hemodialysis and on-line post-dilution hemodiafiltration. AB - OBJECTIVES: To compare bicarbonate kinetics and acid base status in HD and HDF for the same patient; and to investigate the effect of patient physiologic parameters on these kinetics. METHODS: In order to monitor HCO3- kinetics during dialysis, acid-base parameters, pH, blood gases partial pressures, and HCO3- concentrations were recorded during 3 regular dialysis (HD) and 3 on-line post dilution HDF sessions performed on 12 patients, using same dialysis fluid with a 38 mmol/l HCO3- concentration. HCO3- mass transfers through the hemodialyzers membranes and into the patients were continuously calculated during the sessions from HCO3- concentrations, together with HCO3-dialysance. The"apparent" HCO3-gain was calculated by integrating over time the instantaneous mass transfer from dialyzer and re-infusion fluid to the patient. A second method consisted in calculating the patient apparent bicarbonate space (ABS) and HCO3- mass (ABS times plasma concentration) at beginning and end of session. RESULTS: No significant differences were observed between acid base parameters at the end of HD and HDF sessions. In contrast to urea clearances, HCO3- dialysances decayed with time during sessions from 110 to 140 ml/min to about 40 ml/min after one hour. The net HCO3- gain was taken as the difference between final and initial HCO3-masses. This net gain was in average 63% of apparent gain in HD and 74% in HDF. CONCLUSIONS: Uremic acidosis was well corrected without risk of alkalosis. An unexpected result was the continuous decay of bicarbonate dialysance both in HD and HDF during runs. PMID- 22505197 TI - Computational modeling of effects of mechanical shaking on hemodynamics in hollow fibers. AB - INTRODUCTION: Blood-membrane interaction during hemodialysis develops a secondary protein layer on the dialysis membrane surface, resulting in reduction of hemodialyzer performance. Wall shear stress at the surface of the hollow-fiber membrane is one of the determinant factors able to influence dialysis efficiency. Shaking of hemodialyzer during treatment could increase the wall shear stress of the membrane, which could enhance hemodialyzer performance. METHODS: In this study, hemodynamic changes in hollow fibers were analyzed using computational fluid dynamics software for various shaking conditions of hemodialyzer (longitudinal, transverse, rotational motions). RESULTS: Longitudinal motion induced reverse flow, while transverse motion induced symmetric swirling inside the hollow fiber. During rotational motions, nonuniform vortices were developed according to the rotational radius of the hollow fiber. These changes in flow pathlines induced by different shaking profiles increased the relative motion of blood, transmembrane pressure, and wall shear stress on dialysis membrane surfaces. Both longitudinal and transverse shaking profiles showed a linear relationship between shaking velocity (the product of amplitude and frequency) and wall shear stress. CONCLUSION: Performance of hemodialyzer can be enhanced with simple mechanical shaking motions, and optimal shaking profiles for clinical application can be investigated and predicted with the computational fluid dynamics model proposed in this study. PMID- 22505198 TI - Engineering of oriented myocardium on three-dimensional micropatterned collagen chitosan hydrogel. AB - INTRODUCTION: Surface topography and electrical field stimulation are important guidance cues that aid the organization and contractility of cardiomyocytes in vivo. We report here on the use of these biomimetic cues in vitro to engineer an implantable contractile cardiac tissue. METHODS: Photocrosslinkable collagen chitosan hydrogels with microgrooves of 10 um, 20 um and 100 um in width were fabricated using polydimethylsiloxane (PDMS) molds. The hydrogels were seeded with cardiomyocytes, placed into a bioreactor array with the microgrooves aligned with the electrical field lines, and stimulated with biphasic square pulses at 1 Hz and 2.5 V/cm. RESULTS: At Day 6, cardiomyocytes were aligned in the direction of the microgrooves. When cultivated without electrical stimulation, the excitation threshold of engineered cardiac tissues using micropatterned hydrogels was significantly lower than using smooth hydrogels, thus showing the importance of cell alignment to cardiac function. The success rate of achieving beating constructs was higher with the application of electrical stimulation. In addition, formation of dense contractile cardiac organoids was observed in groups with both biomimetic cues. The cultivation of cardiomyocytes on hydrogels with 10 um grooves yielded 100% beating tissues with or without electrical stimulation, thus suggesting a smaller groove width is necessary for cells to communicate and form proper gap junctions. However, electrical field stimulation further increased cell density and enhanced tissue morphology which may be essential for the integration of the tissue construct to the native heart tissue upon implantation. CONCLUSIONS: The biodegradability of the hydrogel substrate allows for the rapid translation of the engineered, oriented cardiac tissue to clinical applications. PMID- 22505194 TI - Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. AB - Previous studies have shown familial aggregation of insulin resistance and nonalcoholic fatty liver disease (NAFLD). Therefore, we aimed to examine whether family history of diabetes mellitus (DM) is associated with nonalcoholic steatohepatitis (NASH) and fibrosis in patients with NAFLD. This was a cross sectional analysis in participants of the NAFLD Database study and PIVENS trial who had available data on family history of DM. One thousand and sixty-nine patients (63% women), with mean age of 49.6 (+/- 11.8) years and body mass index (BMI) of 34.2 (+/- 6.4) kg/m(2) , were included. Thirty percent had DM, and 56% had a family history of DM. Both personal history of DM and family history of DM were significantly associated with NASH, with an odds ratio (OR) of 1.93 (95% confidence interval [CI]: 1.37-2.73; P <0.001) and 1.48 (95% CI: 1.11-1.97; P = 0.01) and any fibrosis with an OR of 3.31 (95% CI: 2.26-4.85; P < 0.001) and 1.66 (95% CI: 1.25-2.20; P < 0.001), respectively. When the models were adjusted for age, sex, BMI, ethnicity, and metabolic traits, the association between diabetes and family history of DM with NASH showed an increased adjusted OR of 1.76 (95% CI: 1.13-2.72; P < 0.001) and 1.34 (95% CI: 0.99-1.81; P = 0.06), respectively, and with any fibrosis with a significant adjusted OR of 2.57 (95% CI: 1.61-4.11; P < 0.0001) and 1.38 (95% CI: 1.02-1.87; P = 0.04), respectively. After excluding patients with personal history of diabetes, family history of DM was significantly associated with the presence of NASH and any fibrosis with an adjusted OR of 1.51 (95% CI: 1.01-2.25; P = 0.04) and 1.49 (95% CI: 1.01-2.20; P = 0.04), respectively. CONCLUSIONS: Diabetes is strongly associated with risk of NASH, fibrosis, and advanced fibrosis. Family history of diabetes, especially among nondiabetics, is associated with NASH and fibrosis in NAFLD. PMID- 22505199 TI - Synchrony relationships between the left ventricle and a left ventricular assist device: an experimental study in pigs. AB - BACKGROUND: Synchronization between the left ventricle and a left ventricular assist device (LVAD) may be important for ventricular unloading and coronary perfusion. We assessed the synchrony between cardiac and LVAD cycles by increasing delays in steps of 100 msec throughout the cycle, under conditions of total and partial left ventricular support. METHODS: We studied 7 healthy minipigs weighing 30-40 kg. A 60-cc Berlin Heart Excor LVAD was implanted and connected to a BCM 1200 console, making it possible to synchronize the LVAD systole and the EKG signal with a prefixed delay. We recorded hemodynamic parameters (including aortic, pulmonary, and left ventricular pressure) and LVAD flow for each delay. RESULTS: Intraventricular pressure during LVAD systole was minimized with delays of around 40-80% of one cycle. In addition, total flow was higher under these conditions. CONCLUSIONS: This study shows that the synchronous mode of LVAD operation is feasible. Moreover, a delay in device contraction until the second half of the cardiac cycle optimizes ventricular unloading and may eventually improve myocardial recovery. PMID- 22505200 TI - Electrophysiological properties and synaptic function of mesenchymal stem cells during neurogenic differentiation - a mini-review. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) have gained considerable interest due to their potential use in cell therapies and tissue engineering. They have been reported to differentiate into various anchorage-dependent cell types, including bone, cartilage, and tendon. Our focus is on the differentiation of MSCs into neuron-like cells through the use of soluble chemical stimuli or specific growth factor supplements. The resulting cells appear to adopt neural phenotypes and express some typical neuronal markers, however, their electrophysiological properties and synaptic function remains unclear. RESULTS: This mini-review illustrates how particular characteristics, electrophysiological properties, and synaptic functions of MSCs change during their neuronal differentiation. In particular we focus on changes in ion currents, ion channels, synaptic communication, and neurotransmitter release. We also highlight conflicting results, caused by inconsistencies in the experimental conditions used and in the methodologies adopted. CONCLUSIONS: We conclude that there is insufficient data and that further, carefully controlled investigations are required in order to ascertain whether MSC-derived neuron-like cells can exhibit the necessary neuronal functions to become clinically relevant for use in neural repairs. PMID- 22505201 TI - In vitro hemodynamic evaluation of ventricular suction conditions of the EVAHEART ventricular assist pump. AB - PURPOSE: Mismatches between pump output and venous return in a continuous-flow ventricular assist device may elicit episodes of ventricular suction. This research describes a series of in vitro experiments to characterize the operating conditions under which the EVAHEART centrifugal blood pump (Sun Medical Technology Research Corp., Nagano, Japan) can be operated with minimal concern regarding left ventricular (LV) suction. METHODS: The pump was interposed into a pneumatically driven pulsatile mock circulatory system (MCS) in the ventricular apex to aorta configuration. Under varying conditions of preload, afterload, and systolic pressure, the speed of the pump was increased step-wise until suction was observed. Identification of suction was based on pump inlet pressure. RESULTS: In the case of reduced LV systolic pressure, reduced preload (=10 mmHg), and afterload (=60 mmHg), suction was observed for speeds=2,200 rpm. However, suction did not occur at any speed (up to a maximum speed of 2,400 rpm) when preload was kept within 10-14 mmHg and afterload=80 mmHg. Although in vitro experiments cannot replace in vivo models, the results indicated that ventricular suction can be avoided if sufficient preload and afterload are maintained. CONCLUSION: Conditions of hypovolemia and/or hypotension may increase the risk of suction at the highest speeds, irrespective of the native ventricular systolic pressure. However, in vitro guidelines are not directly transferrable to the clinical situation; therefore, patient-specific evaluation is recommended, which can be aided by ultrasonography at various points in the course of support. PMID- 22505202 TI - Development of an ultra mini-oxygenator for use in low-volume, buffer-perfused preparations. AB - INTRODUCTION: Small animal models are widely used in basic research. However, experimental systems requiring extracorporeal circuits are frequently confronted with limitations related to equipment size. This is particularly true for oxygenators in systems with limited volumes. Thus we aimed to develop and validate an ultra mini-oxygenator for low-volume, buffer-perfused systems. METHODS: We have manufactured a series of ultra mini-oxygenators with approximately 175 aligned, microporous, polypropylene hollow fibers contained inside a shell, which is sealed at each of the two extremities to isolate perfusate and gas compartments. With this construction, gas passes through hollow fibers, while perfusate circulates around fibers. Performance of ultra mini oxygenators (oxygen partial pressure (PO2), gas and perfusate flow, perfusate pressure and temperature drop) were assessed with modified Krebs-Henseleit buffer in an in vitro perfusion circuit and an ex vivo rat heart preparation. RESULTS: Mean priming volume of ultra mini-oxygenators was 1.2+/-0.5 mL and, on average, 86+/-6% of fibers were open (n=17). In vitro, effective oxygenation (PO2=400-500 mmHg) was achieved for all flow rates up to 50 mL/min and remained stable for at least 2 hours (n=5). Oxygenation was also effective and stable (PO2=456+/-40 mmHg) in the isolated heart preparation for at least 60 minutes ("venous" PO2=151+/-11 mmHg; n=5). CONCLUSIONS: We have established a reproducible procedure for fabrication of ultra mini-oxygenators, which provide reliable and stable oxygenation for at least 60-120 min. These oxygenators are especially attractive for pre-clinical protocols using small, rather than large, animals. PMID- 22505203 TI - Factors influencing the transfer of porcine endogenous retroviruses across the membrane in bioartificial livers. AB - OBJECTIVES: to investigate the factors influencing the transfer of porcine endogenous retroviruses (PERVs) across the membrane in a new bioartificial liver (BAL). METHODS: A new BAL containing 2 circuits was constructed using plasma component separators with membrane pore sizes of 10 nm, 20 nm, 30 nm, and 35 nm, or a plasma filter with a membrane pore size of 500 nm. Cocultured cells of porcine hepatocytes and mesenchymal stem cells or single porcine hepatocytes were incubated in the bioreactors, and the BAL worked for 72 hours, with supernatant samples in internal and external circuits collected every 12 hours. PERV RNA, reverse transcriptase (RT) activity, and in vitro infectivity of the supernatant were detected. RESULTS: With the plasma filters, the results of PERV detection were the same in both circuits. With plasma component separators, PERV RNA was found in the external circuits, but no positive RT activity or HEK293 cell infection was found. The time at which the PERV RNA was first detected varied with the pore size of membrane; the larger the membrane pore size was, the earlier the RNA was detected. The PERV RNA level in the external circuits was reduced significantly compared with that in the internal circuits at any detecting time. CONCLUSIONS: The plasma component separators with membrane pore size =35 nm could significantly reduce the passage of infectious PERVs. And the membrane pore size, the treatment duration, and the viral level in the internal circuit were potential factors influencing the transfer of PERVs across the membrane in a BAL. In addition, a low risk of PERV transmission from porcine hepatocytes to human cells was found. PMID- 22505204 TI - Extracorporeal life support: first year of experience implementing the technique in Slovenia. AB - Extracorporeal life support (ELS) is emerging as a standard treatment option for acute respiratory and/or cardiac failure. In this article we describe our first year of experience with ELS activity in adult medical patients in our center. Veno-venous extracorporeal membrane oxygenation (VV ECMO) support was applied in cases of severe acute respiratory distress syndrome (ARDS) not responsive to conventional treatments. The use of veno-arterial (VA) ECMO support was reserved for cases of cardiac shock refractory to standard treatment and cardiac arrests not responding to conventional resuscitation. A total of 19 patients were treated with ELS during the first year of activity. Eight of these received VV ECMO for ARDS of various etiologies, with a survival rate of 63%. Eleven patients received VA ECMO support due to cardiac failure (2 post-resuscitation). Survival in this group was 45%. We report our results, including complications and organizational issues that we encountered, and describe protocol improvements developed over the short period of time since ELS treatment has been implemented in our center. PMID- 22505205 TI - Development of artificial neural network-based algorithms for the classification of bileaflet mechanical heart valve sounds. AB - OBJECTIVES: As is true for all mechanical prostheses, bileaflet heart valves are prone to thrombus formation; reduced hemodynamic performance and embolic events can occur as a result. Prosthetic valve thrombosis affects the power spectra calculated from the phonocardiographic signals corresponding to prosthetic closing events. Artificial neural network-based classifiers are proposed for automatically and noninvasively assessing valve functionality and detecting thrombotic formations. Further studies will be directed toward an enlarging data set, extending the investigated frequency range, and applying the presented approach to other bileaflet mechanical valves. METHODS: Data were acquired for the normofunctioning St. Jude Regent valve mounted in the aortic position of a Sheffield Pulse Duplicator. Different pulsatile flow conditions were reproduced, changing heart rate and stroke volume. The case of a thrombus completely blocking 1 leaflet was also investigated. Power spectra were calculated from the phonocardiographic signals and used to train artificial neural networks of different topologies; neural networks were then tested with the spectra acquired in vivo from 33 patients, all recipients of the St. Jude Regent valve in the aortic position. RESULTS: The proposed classifier showed 100% correct classification in vitro and 97% when applied to in vivo data: 31 spectra were assigned to the right class, 1 received a false positive classification, and 1 was "not classifiable." CONCLUSION: Early malfunction detection is necessary to prevent thrombotic events in bileaflet mechanical heart valves. Following further clinical validation with an extended patient database, artificial neural network based classifiers could be embedded in a portable device able to detect valvular thrombosis at early stages of formation: this would help clinicians make valvular dysfunction diagnoses before the appearance of critical symptoms. PMID- 22505206 TI - EGCG suppresses prostate cancer cell growth modulating acetylation of androgen receptor by anti-histone acetyltransferase activity. AB - Manipulating acetylation status of key gene targets is likely to be crucial for effective cancer therapy. In this study, we utilized green tea catechins, epicatechin (EC), epigallocatechin (EGC) and epigallocatechin-3-gallate (EGCG) to examine the regulation of androgen receptor acetylation in androgen-dependent prostate cancer cells by histone acetyl-transferase (HAT) activity. EC, EGC and EGCG induced prostate cancer cell death, suppressed agonist-dependent androgen receptor (AR) activation and AR-regulated gene transcription. These results demonstrated a similar tendency to HAT inhibitory activities; EGCG>EGC>EC. The strongest HAT inhibitor among them, EGCG (50 uM), downregulated AR acetylation and finally, AR protein translocation to nucleus from the cytoplasmic compartment was effectively inhibited in the presence of the agonist. These results suggest another mechanism to develop effective therapeutics based on green tea catechins. PMID- 22505207 TI - Effect of low-level laser therapy on intramembranous and endochondral autogenous bone grafts healing. AB - The aim of this study was to evaluate the healing process of intramembranous (IM) and endochondral (EC) bone grafts under low-level laser therapy (LLLT). Male rabbits underwent onlay autogenous bone grafts (1 cm in diameter) retrieved from the calvaria and iliac crest and fixed on parietal bones, divided into four groups: Calvaria (C), Iliac (I), Calvaria + LLLT (C+L), and Iliac + LLLT (I+L). Animals from C+L and I+L Groups had their grafts exposed to LLLT (AlGaAs-808 nm, CW, 30 mW, 0.028 cm2 average laser beam area), 15 s irradiation time (16 J/cm2 per point-total of 64 J/cm2 per session). After 7, 14, 30, and 60 days, grafts were retrieved and resorption pattern analyzed by means of morphometry and TRAP positive osteoclasts detection. Differences in the resorption levels of iliac grafts were observed, presenting 40% in I group against 8% in I+L grafts at the 14th day of evaluation (P < 0.05). After 30 days, resorption was maintained at 41% in I group, whereas I+L presented 15% in the same period (P = 0.0591). No significant differences were noted in the rates of calvaria grafts resorption in all periods. A significant higher number of osteoclasts on the grafts' surface was observed in C+L Group at day 30, in comparison with C group. In I+L Group, prevalence of osteoclasts was marked at day 7 (P < 0.05) in comparison to I Group. In general, it was concluded that biomodulative effects of LLLT did not significantly affect healing and resorption processes of autogenous bone grafts from EC and IM origins. PMID- 22505208 TI - Construction of the biaryl-part of vancomycin aglycon via atropo diastereoselective Suzuki-Miyaura coupling. AB - An atropo-diastereoselective synthesis with dr up to 98/2 towards the biaryl subunit of vancomycin based on the use of enantiopure beta-hydroxysulfoxide derivatives as novel chiral auxiliary is reported. PMID- 22505210 TI - Is molecular diagnostics ready for its cancer close-up?: Genetic information is becoming more useful for managing cancer, but more research is needed. PMID- 22505209 TI - Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells by hepatocyte growth factor signaling in mice. AB - The liver architecture plays an important role in maintaining hemodynamic balance, but the mechanisms that underlie this role are not fully understood. Hepsin, a type II transmembrane serine protease, is predominantly expressed in the liver, but has no known physiological functions. Here, we report that hemodynamic balance in the liver is regulated through hepsin. Deletion of hepsin (hepsin(-/-) ) in mice resulted in enlarged hepatocytes and narrowed liver sinusoids. Using fluorescent microbeads and antihepsin treatment, we demonstrated that metastatic cancer cells preferentially colonized the hepsin(-/-) mouse liver as a result of the retention of tumor cells because of narrower sinusoids. The enlarged hepatocytes expressed increased levels of connexin, which resulted from defective prohepatocyte growth factor (pro-HGF) processing and decreased c-Met phosphorylation in the livers of hepsin(-/-) mice. Treatment of hepsin(-/-) mice with recombinant HGF rescued these phenotypes, and treatment of wild-type mice with an HGF antagonist recapitulated the phenotypes observed in hepsin(-/-) mice. CONCLUSION: Our findings show that the maintenance of hepatic structural homeostasis occurs through HGF/c-Met/connexin signaling by hepsin, and hepsin mediated changes in liver architecture significantly enhance tumor metastasis to the liver. PMID- 22505211 TI - Implementation of FocalPoint GS location-guided imaging system: experience in a clinical setting. AB - BACKGROUND: Recently, the Food and Drug Administration approved the use of the location-guided imaging system FocalPoint GS (FPGS), on SurePath Papanicolaou (Pap) tests for primary screening. The objective of the current study was to evaluate the impact of FPGS on the following: distribution of diagnostic categories; rate of high-risk human papillomavirus (HR-HPV)-positive ASC-US cases; and quality control (QC) data before and after FPGS implementation. METHODS: A search of the laboratory information system was performed to identify all SurePath Pap tests processed in our laboratory for the first 19 months after FPGS implementation. We also retrieved all SurePath specimens from a 16-month period prior to FPGS implementation to serve as the control. During the period from Janaury 2008 to April 2009, the FocalPoint Slide Profiler was used. RESULTS: Implementation of FPGS resulted in a significantly higher percentage of LSIL and ASC-US interpretations, as well as a significant increase in the detection of candidiasis and bacterial vaginosis. The ASC-to-SIL ratio was 1.4 and 1.9 before and after FPGS implementation, respectively. There was a decrease in the HR-HPV positive rate in ASC-US cases, and a decrease in the estimated false-negative fraction after FPGS implementation. CONCLUSIONS: In conclusion, our study seems to demonstrate a favorable performance of FPGS in the routine clinical setting. FPGS may have the potential to be a promising screening tool for gynecologic cytology in a low-risk patient population. PMID- 22505212 TI - Effects of astragaloside IV on eosinophil activation induced by house dust mite allergen. AB - Astragaloside IV (AS-IV) has been noted for its reduction of eosinophilic airway inflammation in a murine model of chronic asthma. To gain a better understanding of the mechanisms involved in this anti-inflammatory phenomenon, the effect of AS IV on human blood eosinophils was studied in vitro. Eosinophils were isolated from the blood of patients with mild atopic asthma, preincubated with AS-IV for 1 h and stimulated in the presence or absence of the house dust mite allergen Dermatophagoides pteronyssinus (Der p) 1 for 4 h. The survival of the eosinophils at 48 h was investigated using trypan blue and the surface expression of CC chemokine receptor 3 (CCR3) and intercellular adhesion molecule-1 (ICAM-1) by the eosinophils was analyzed using flow cytometry. The secretion of cytokines in the supernatants and the chemotaxis of the eosinophils were measured by ELISA and the transwell system, respectively. Der p 1 was found to prolong the survival of the eosinophils. Similarly, the expression of CCR3 and ICAM-1, secretion of interleukin (IL)-1beta, IL-5, tumor necrosis factor (TNF)-alpha and the granulocyte macrophage colony stimulating factor (GM-CSF) and transmigration of the eosinophils were increased in the presence of Der p 1. However, these inductive effects on the eosinophils were significantly inhibited by AS-IV (50 ug/ml). These findings suggest that AS-IV modulates eosinophil activation and trafficking in response to Der p 1 and may therefore be a useful therapeutic option in eosinophilic asthma. PMID- 22505213 TI - Food systems: New-Ruralism versus New-Urbanism. AB - There is a growing debate on whether agricultural land in urban fringes should be maintained or converted to other uses. While 'pro-ruralists' believe agricultural land conversion can threaten food security and cause rural-urban migration, 'pro urbanists' find it a necessary change for transition from a primitive agricultural-based community to an advanced industrial-based society which has the capacity to create mass productions. New-Ruralists follow an agricultural based development approach that promotes small-medium farming and acknowledges rural lifestyle while New-Urbanists give a priority to large industrial-based sectors and encourage urban lifestyle. Given the unlike concerns of different societies, the paper concludes that the approaches might have different priorities in the less developed, developing, and developed world. PMID- 22505215 TI - Unfolding a photoswitchable azo-foldamer reveals a non-covalent reaction mechanism. AB - Simulations on photoswitching of an azobenzene-functionalized helical mPE foldamer reveal several distinct non-covalent reaction channels. It is expected that distinct products can be selectively (de)stabilized by attaching suitable side chains to the backbone. The methodology presented could be applied to study photoinduced manipulation of AB-functionalized proteins. PMID- 22505218 TI - Stimulated release of size-selected cargos in succession from mesoporous silica nanoparticles. PMID- 22505219 TI - Immunohistochemical localization of cathepsin D and a possible role of melanocytes during tail resorption in tadpoles of a tropical toad. AB - Programmed cell death during anuran tail resorption is primarily brought about by apoptosis. Cathepsin D, a lysosomal aspartyl protease, is involved in the death of tail tissues. Thus, anuran tail resorption presents an ideal model to study cathepsin-mediated cell death during vertebrate development. Present study describes the trend of specific activity of cathepsin D in the tail of different developmental stages and immunohistochemical localization of cathepsin D in the tail tissues of the common Asian toad, Duttaphrynus melanostictus. Cathepsin D was involved in programmed cell death in epidermis, muscle, spinal cord, and blood cells in the resorbing tail. Interestingly, it was also involved in the pre resorbing tail before visible tail resorption which indicates initiation of cell death even before actually the tail resorbs. Melanocytes were found to be one of the causative agents in degrading tail tissues and were associated with the degradation of muscle, epidermis and spinal cord of the resorbing tail. PMID- 22505220 TI - Molecular characterization of three major outer membrane proteins, TSA56, TSA47 and TSA22, in Orientia tsutsugamushi. AB - Orientia tsutsugamushi (O. tsutsugamushi), the causative agent of scrub typhus, is an obligate intracellular pathogen. Recent studies have demonstrated the complete genome of O. tsutsugamushi. However, the route and detailed molecular mechanism for O. tsutsugamushi to get accessed into mammalian cells remains unclear. In this study, we demonstrated different adhesive properties of three major outer membrane proteins of O. tsutsugamushi, TSA56, TSA47 and TSA22. TSA56 showed higher antibody responses against patient serum samples compared with those of TSA47 and TSA22. In the adhesion assay, TSA56 exhibited a relative higher adhesion to host cells than TSA47 and TSA22, suggesting that TSA56 is the major outer membrane protein required for O. tsutsugamushi adhesion. Furthermore, the antigen domain (AD) I (residues 19-114) corresponding to the extracellular domain of TSA56 demonstrated a relative high antibody response against the patients' sera than the previously reported ADIII (residues 237-366), which has been suggested to facilitate the invasion of O. tsutsugamushi through interaction with fibronectin. Taken together, our results consistently showed that TSA56 of O. tsutsugamushi is important in the adhesion of Escherichia coli (E. coli) transformants to Vero cells. Moreover, in contrast to known ADIII-fibronectin interactions, TSA56-ADI may also play a role in the adhesion and/or invasion of O. tsutsugamushi to its host cells through unidentified receptors. A further study aimed at delineating the receptor of TSA56-ADI during O. tsutsugamushi infection is warranted. PMID- 22505221 TI - Triazole phosphohistidine analogues compatible with the Fmoc-strategy. AB - Phosphorylation of histidine is essential for bacterial two-component signalling; its importance to modulation of eukaryotic protein function remains undefined. Until recently, no immunochemical probes of this post-translational modification existed, however triazole phosphonate analogues of this modified amino acid have now been applied to the generation of site-specific antibodies. The protecting group strategy used in the original report is incompatible with standard protocols for Fmoc-solid phase peptide synthesis. In this paper, we report the application of P(III) chemistry to generate the complementary dibenzyl and di tert-butyl phosphonate esters. These forms of the triazole analogue are fully compatible with standard Fmoc-SPPS and are therefore ideal for wider application by the chemical and biochemical community. PMID- 22505222 TI - Emotional expressions in voice and music: same code, same effect? AB - Scholars have documented similarities in the way voice and music convey emotions. By using functional magnetic resonance imaging (fMRI) we explored whether these similarities imply overlapping processing substrates. We asked participants to trace changes in either the emotion or pitch of vocalizations and music using a joystick. Compared to music, vocalizations more strongly activated superior and middle temporal cortex, cuneus, and precuneus. However, despite these differences, overlapping rather than differing regions emerged when comparing emotion with pitch tracing for music and vocalizations, respectively. Relative to pitch tracing, emotion tracing activated medial superior frontal and anterior cingulate cortex regardless of stimulus type. Additionally, we observed emotion specific effects in primary and secondary auditory cortex as well as in medial frontal cortex that were comparable for voice and music. Together these results indicate that similar mechanisms support emotional inferences from vocalizations and music and that these mechanisms tap on a general system involved in social cognition. PMID- 22505223 TI - Procyanidins and inflammation: molecular targets and health implications. AB - The inflammatory response has been implicated in the pathogenesis of many chronic diseases. Thus, the modulation of the inflammatory response by the consumption of bioactive food compounds, such as procyanidins, is a powerful tool to promote health. Procyanidin-mediated anti-inflammatory molecular mechanisms include, among others, the modulation of the arachidonic acid pathway, the inhibition of the gene transcription, protein expression and enzymatic activity of eicosanoid generating enzymes, the production and secretion of inflammatory mediators (such as cytokines and nitric oxide), the inhibition of mitogen-activated protein kinase (MAPK) pathway activation, and the modulation of the nuclear factor-kappaB (NF-kappaB) pathway. The NF-kappaB pathway can be regulated by procyanidins at several levels. During early events in NF-kappaB signaling, procyanidins modulate Ikappakappa activity, and the cytoplasmic retention of p65:p50 NF-kappaB by the inhibition of IkappaB phosphorylation and proteasomal degradation, while at late stages, they affect the nuclear translocation of pro/anti-inflammatory NF-kappaB homo/hetero dimers and their subsequent binding to the promoter regions of target genes. To identify and understand the value of procyanidins in the modulation of the inflammatory response, the molecular mechanisms underlying the anti inflammatory activities and prohomeostatic effects of procyanidins need to be investigated further. PMID- 22505224 TI - Investigation on the temperature difference method for producing nanobubbles and their physical properties. AB - In recent years, the possibility of nanobubbles at the solid-liquid interface has drawn wide attention in the scientific community and industry. Thus the search for evidences for the existence of nanobubbles became a scientific hotspot. To produce interfacial nanobubbles, a systematic experiment, called the temperature difference method, is carried out by replacing low temperature water (LTW) with high temperature water (HTW) at the highly-oriented pyrolytic graphite (HOPG) water interface. When LTW (4 degrees C) is mixed with HTW (25-40 degrees C), nanobubbles are observed by atomic force microscopy (AFM), and their size, density and total volume per square micrometer are measured. Furthermore, pancake like gas layers and the coexistence of nanobubbles on top of the pancake layers are also observed. PMID- 22505225 TI - Oncogene-specific formation of chemoresistant murine hepatic cancer stem cells. AB - At least some cancer stem cells (CSCs) display intrinsic drug resistance that may thwart eradication of a malignancy by chemotherapy. We explored the genesis of such resistance by studying mouse models of liver cancer driven by either MYC or the combination of oncogenic forms of activation of v-akt murine thymoma viral oncogene homolog (AKT) and NRAS. A common manifestation of chemoresistance in CSCs is efflux of the DNA-binding dye Hoechst 33342. We found that only the MYC driven tumors contained a subset of cells that efflux Hoechst 33342. This "side population" (SP) was enriched for CSCs when compared to non-SP tumor cells and exhibited markers of hepatic progenitor cells. The SP cells could differentiate into non-SP tumor cells, with coordinate loss of chemoresistance, progenitor markers, and the enrichment for CSCs. In contrast, non-SP cells did not give rise to SP cells. Exclusion of Hoechst 33342 is mediated by ATP binding cassette drug transporter proteins that also contribute to chemoresistance in cancer. We found that the multidrug resistance gene 1 (MDR1) transporter was responsible for the efflux of Hoechst from SP cells in our MYC-driven model. Accordingly, SP cells and their tumor-initiating subset were more resistant than non-SP cells to chemotherapeutics that are effluxed by MDR1. CONCLUSION: The oncogenotype of a tumor can promote a specific mechanism of chemoresistance that can contribute to the survival of hepatic CSCs. Under circumstances that promote differentiation of CSCs into more mature tumor cells, the chemoresistance can be quickly lost. Elucidation of the mechanisms that govern chemoresistance in these mouse models may illuminate the genesis of chemoresistance in human liver cancer. PMID- 22505226 TI - Neck circumference: a useful screening tool of cardiovascular risk in children. AB - OBJECTIVE: Early identification of cardiovascular risk factors consists an essential target for public health. The current study aims to examine the association between neck circumference and several cardiovascular risk factors and to compare it with well-established anthropometric indices. METHODS: Demographic, anthropometric (body weight and height, waist, hip and neck circumference [WC, HC and NC, respectively]), biochemical (total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, triglycerides [TG], fasting plasma glucose and serum insulin), clinical (pubertal stage, systolic and diastolic blood pressure [SBP and DBP, respectively]) and lifestyle (dietary intake, physical activity level) data were collected from 324 children (51.5% boys; 48.5% girls) aged 9-13 in Greece. Body mass index z-score (BMI z-score), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI) and fasting glucose to insulin ratio (FGIR) were calculated. RESULTS: All indices (BMI z-score, NC, WC, HC, WHR and WHtR) were correlated with SBP, HDL and insulin-related indices (insulin, HOMA-IR, QUICKI and FGIR) and all indices except WHR with TG. LDL was correlated with BMI z-score, WC, WHR and WHtR, whereas DBP was correlated with BMI z-score, WC, HC and WHtR. In multivariate analysis, HDL, TG, SBP, insulin, HOMA-IR, QUICKI and FGIR were associated with all anthropometric indices; DBP with WC, HC, NC and WHtR; LDL with BMI z-score, WC, HC and WHtR. CONCLUSIONS: NC is associated with most cardiovascular disease risk factors. These associations are comparable with those observed for BMI z-score, WC, HC, WHR and WHtR. NC could be a simple, alternative screening tool of cardiovascular risk in children. PMID- 22505227 TI - Is it merely a myth that alcoholic beverages such as red wine can be cardioprotective? AB - It has been suggested that although the negative impact of alcohol consumption varies from person to person, on a global level the adverse effect of alcohol on cardiovascular disease outweighs any protective effect by between two- and three fold. This is inaccurate. There is a proven positive relationship between alcohol consumption and cardiovascular disease that is acknowledged by the World Health Organization. For example, moderate alcohol consumption reduces the risk of cardiovascular disease by approximately 25%, such that alcohol consumption per se accounts for -4.7% of the total cardiovascular disease burden in Australia. Correspondingly, cardiovascular disease accounted for 34% of the total number of deaths in Australia in 2008, and 18% of the overall burden of disease in Australia in 2003, with coronary heart disease and stroke contributing over 80% of this burden. Australia is not substantially different from other developed countries having similar demographics to, and the same leading causes of burden as, other high-income developed countries. This article examines the suggestions and evidence surrounding the relationship between light-to-moderate alcohol consumption and benefits to human health. PMID- 22505228 TI - Early development of the postcranial skeleton of the pikeperch Sander lucioperca (Teleostei: Percidae) relating to developmental stages and growth. AB - The early development of the postcranial skeleton (pectoral girdle, pelvic girdle, vertebral column and fins) in pikeperch (Sander lucioperca (L.)) was studied from hatching to days 47 and 43 post fertilization (dpf) at two different rearing temperatures, 15.5 and 18.0 degrees C. Four embryonic and six larval stages were described, ranging from 3.4 +/- 0.3 mm to 21.8 +/- 2.1 mm in total length. The crucial point in larval development is swimbladder inflation, which enables larvae to swim energy efficiently. Until this time point, only the most essential skeletal elements to enable swimming movements have developed. As the larvae become neutrally buoyant, they grow and differentiate postcranial elements rapidly. Concurrently, swimming performance and foraging success seems to improve. A specific size is correlated with a distinct developmental stage defined by a set of traits that includes the skeletal elements. The developmental sequence of skeletal structures is temperature independent, although growth is slower and the individual developmental stages are reached later at 15.5 degrees C than at 18.0 degrees C. PMID- 22505229 TI - Correlation between increased ND2 expression and demethylated displacement loop of mtDNA in colorectal cancer. AB - Change in cellular glucose metabolism is considered to be a biochemical hallmark in cancer cells. The mitochondrion is the key organelle in which glucose metabolism occurs. However, whether DNA methylation at the displacement loop (D loop) region of mitochondrial DNA (mtDNA) has an effect on the expression of the rate-limiting enzyme, and, therefore, on oxidative phosphorylation in colorectal cancer remains to be determined. Quantitative change in ND2 (a subunit of NADH) and the methylation status of the D-loop were observed during the initiation and progression of colorectal cancer. Furthermore, the possible correlations with clinicopathological stage were also investigated. Tumor and corresponding non cancerous tissues were surgically resected from 44 colorectal cancer patients between 2008 and 2009. Cox IV expression was quantified in all of the specimens, and the ND2 expression was calculated. Quantitative changes in ND2 expression exhibited a significant increase. The average relative ratios of ND2 content were 1.67+/-0.44 in the tumor tissues and 0.89+/-0.44 in the corresponding non cancerous tissues (p<0.01). In addition, the D-loop of most corresponding non cancerous tissues was methylated and the percentage was 79.5%, while this percentage was much smaller in the tumor tissues (11.4%). Following correlation with clinicopathological data, changes in the ND2 expression in the colorectal cancer exhibited a significant association with clinicopathological stage. This increase was significant as early as in stage I. Furthermore, the ratios of unmethylated D-loop cases were increased in both tumor and corresponding non cancerous tissues, and the ND2 expression was also increased from stages I to IV. Our results indicate that demethylation of the D-loop plays a key role in regulating ND2 expression during the initiation and/or progression of colorectal cancer. PMID- 22505230 TI - Directing stem cell fate by controlling the affinity and density of ligand receptor interactions at the biomaterials interface. AB - Sticky situation: the differentiation of mesenchymal stem cells can be influenced by the affinity and density of an immobilized ligand for the integrin receptors. Cells adherent to monolayers that present the high-affinity, cyclic-RGD peptide (left) show increased expression of osteogenic markers, while cells on monolayers presenting the lower-affinity, linear-RGD peptide (right) express early markers of myogenesis at a high density and neurogenesis at a low density of the ligand. PMID- 22505231 TI - Antitumor effect of FP3 in combination with cetuximab on patient-derived tumor tissue xenograft models of primary colon carcinoma and related lymphatic and hepatic metastases. AB - FP3 is an engineered protein which contains the extracellular domain 2 of vascular endothelial growth factor (VEGF) receptor 1 (Flt-1) and the extracellular domain 3 and 4 of VEGF receptor 2 (Flk-1, KDR) fused to the Fc portion of human immunoglobulin G1. Previous studies have demonstrated its antiangiogenic effects in vitro and in vivo, and its antitumor activity in vivo. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combined inhibition of VEGF and EGF signaling may act additively or synergistically. In this study, patient-derived tumor tissue (PDTT) xenograft models of primary colon carcinoma and lymphatic and hepatic metastases were established for assessment of the antitumor activity of FP3 in combination with cetuximab. Xenografts were treated with FP3 and cetuximab, alone or in combination. After tumor growth was confirmed, volume and microvessel density in tumors were evaluated. Levels of VEGF, EGFR and PCNA in the tumor were examined by immunohistochemical staining, and levels of related cell signaling pathway proteins were examined by western blotting. FP3 in combination with cetuximab showed significant antitumor activity in three xenograft models (primary colon carcinoma, lymphatic metastasis and hepatic metastasis). The microvessel density in tumor tissues treated with FP3 in combination with cetuximab was lower compared to that of the control. Antitumor activity of FP3 in combination with cetuximab was significantly higher than that of each agent alone in two xenograft models (colon carcinoma lymphatic metastasis and hepatic metastasis). This study indicated that addition of FP3 to cetuximab significantly improved tumor growth inhibition in the PDTT xenograft models of colon carcinoma lymphatic and hepatic metastases. Combination anti-VEGF (FP3) and anti-EGFR (cetuximab) therapies may represent a novel therapeutic strategy for the management of metastatic colon carcinoma. PMID- 22505232 TI - Relationships between progesterone receptor isoforms and the HER/ErbB receptors and ligands network in 299 primary breast cancers. AB - BACKGROUND: The effects of progesterone are mediated by 2 progesterone receptors (PR), PR-A and PR-B. Recently, several lines of evidence have suggested that reduced PR expression may result from hyperactivity in the signaling cascade generated by the HER/ErbB family. The aim of this study was to analyze the relationships between PR isoforms and the network of the HER/ErbB receptors and ligands in breast cancer. PATIENTS AND METHODS: 299 breast cancer samples from patients operated in our institute for locoregional disease between May 1989 and December 1991 were included. The mRNA expression of total PR-A+B isoforms and PR B isoform were quantified by real time quantitative RT-PCR using TaqMan(r) probes. RESULTS: mRNA levels of the PR isoforms positively correlated with protein levels of estradiol receptors (ER) and PR. The PR isoforms mRNA levels were inversely correlated with clinicopathological markers of tumor aggressiveness, such as SBR grading and lymph node involvement. The PR isoforms positively correlated with the mRNA levels of HER/ErbB receptors and ligands associated with a more differentiated phenotype (HER3, HER4, EGF, AREG, NRG3 and NRG4) while they correlated negatively with those associated with aggressiveness (EGFR, TGFa, HB-EGF, EREG, and NRG2). CONCLUSION: Our results demonstrate the existence of strong correlations between mRNA levels of the PR isoforms, protein levels of hormone receptors, HER/ErbB receptors and ligands network, and thus suggest that crosstalks between PR and the HER family are a hallmark of breast cancer growth. PMID- 22505233 TI - Role of monocyte chemoattractant protein-1, tumor necrosis factor-alpha and interleukin-6 in the control of malignant pleural effusion and survival in patients with primary lung adenocarcinoma. AB - This study aimed at assessing the role of monocyte chemoattractant protein-1 (MCP 1), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the control of pleural effusion (PE) and survival in patients with primary lung adenocarcinoma. The concentrations of the 3 cytokines were measured in PE from 79 lung adenocarcinoma patients with malignant pleural effusion (MPE) and 23 patients with tuberculosis. Data were correlated with the efficacy of MPE control and patient survival. The level of MCP-1 in PE was significantly higher in patients with lung adenocarcinoma than those with tuberculosis. By contrast, the levels of TNF-alpha and IL-6 were significantly lower in patients with lung adenocarcinoma than those with tuberculosis. An MCP-1 level greater than 3,187 pg/mL (which was used as a cutoff point) indicated failure to control MPE (odds ratio [OR]=2.82, 95% confidence interval [CI]=1.02-7.82, p=0.04). In multivariate analysis, MCP-1 was confirmed as an independent prognostic factor for progression free survival (hazard ratio [HR]=2.02, 95% CI=1.24-3.30, p=0.01). The level of MCP-1 in PE appears to be a reliable surrogate marker for evaluating the therapeutic efficacy in the control of MPE and predicting survival in lung adenocarcinoma patients with MPE. PMID- 22505234 TI - Nucleophilic addition of enols and enamines to alpha,beta-unsaturated acyl azoliums: mechanistic studies. PMID- 22505235 TI - An unusual case of giant cardiac fibroelastoma mimicking left atrial myxoma in a patient presenting with syncope. AB - Cardiac papillary fibroelastomas are the most common primary valvular tumors. Generally benign, they account only for about 10% of all primary cardiac neoplasms, can occur in normal or diseased hearts, and are associated strongly with open heart surgery and radiotherapy. They are, in most cases, incidental findings, but can be discovered after syncope. We report the case of an elderly female, who was referred for syncope and was found to have a large fibroelastoma at the mitral valve annulus, intermittently obstructing the left ventricular inflow tract, and mimicking the presentation of left atrial myxoma. This case illustrates another potential mechanism of syncope in patients with fibroelastomas. PMID- 22505236 TI - Low sleep and low socioeconomic status predict high body mass index: a 4-year longitudinal study of Australian schoolchildren. AB - OBJECTIVE: The objective of this study was to examine the longitudinal relationships between body mass index (BMI), sleep duration and socioeconomic status (SES) in a 4-year cohort of 939 children aged 7-12 years. METHODS: Children and their mothers completed an annual questionnaire to assess usual weekday sleep and wake times, amount of sleep, physical activity, parental education and school SES. 93% of children were enrolled (939/1010) and retention was 88%, 83% and 81% in consecutive years. Height and weight were measured annually. RESULTS: BMI increased with decreasing amount of sleep and less sleep predicted greater International Obesity Task Force measures of obesity and overweight. In all 4 years, after controlling for baseline BMI, low SES was a significant predictor of high BMI. Children in the upper tertile of sleep in year 1 had a 2.3 kg lower weight gain (standard error [SE]: 0.5) between years 1 and 4 (P < 0.0001) than children in the lower tertile of sleep and a 0.45 kg m(-2) lower increase in BMI (SE: 0.15) (P = 0.004). The difference between children with consistently low and high sleep duration over 4 years was 1 BMI point. Those with the lowest BMI were the children with both high SES and high sleep duration. PA was not associated with BMI. CONCLUSIONS: Both low SES and short sleep duration predict obesity risk in children after controlling for baseline BMI and this trend becomes stronger as children enter adolescence. Obesity prevention should include a sleep promotion component and this may be more beneficial to children of low SES and/or socially disadvantaged backgrounds. PMID- 22505237 TI - Linear and curvilinear correlations of brain gray matter volume and density with age using voxel-based morphometry with the Akaike information criterion in 291 healthy children. AB - We examined linear and curvilinear correlations of gray matter volume and density in cortical and subcortical gray matter with age using magnetic resonance images (MRI) in a large number of healthy children. We applied voxel-based morphometry (VBM) and region-of-interest (ROI) analyses with the Akaike information criterion (AIC), which was used to determine the best-fit model by selecting which predictor terms should be included. We collected data on brain structural MRI in 291 healthy children aged 5-18 years. Structural MRI data were segmented and normalized using a custom template by applying the diffeomorphic anatomical registration using exponentiated lie algebra (DARTEL) procedure. Next, we analyzed the correlations of gray matter volume and density with age in VBM with AIC by estimating linear, quadratic, and cubic polynomial functions. Several regions such as the prefrontal cortex, the precentral gyrus, and cerebellum showed significant linear or curvilinear correlations between gray matter volume and age on an increasing trajectory, and between gray matter density and age on a decreasing trajectory in VBM and ROI analyses with AIC. Because the trajectory of gray matter volume and density with age suggests the progress of brain maturation, our results may contribute to clarifying brain maturation in healthy children from the viewpoint of brain structure. PMID- 22505238 TI - Protein carbonyl, 3beta-, and 17beta-hydroxysteroid dehydrogenases in testes and serum FSH, LH, and testosterone levels in zinc deficient Wistar rats. AB - The present study evaluated protein oxidation, alteration in hydroxysteroid dehydrogenases (3beta- and 17beta HSD) in testes and serum hormonal profiles of dietary zinc deficient Wistar rats. Pre-pubertal rats were divided into three groups: zinc control (ZC), pairfed (PF), and zinc deficient (ZD) and fed 100 ppm (ZC and PF groups) and 1.0 ppm (ZD group) zinc diet for 2- and 4-weeks. The testes from zinc deficient groups exhibited significant increase in total protein (2 weeks) and protein carbonyl (2- and 4-weeks) concentration as well as 3beta- and 17beta-hydroxysteroid dehydrogenase activities (4 weeks), whereas a significant decrease was recorded in total protein (testes 4 weeks; serum 2- and 4-weeks), total zinc (testes and serum 2- and 4-weeks), 3beta- and 17beta hydroxysteroid dehydrogenase activities (testes 2 weeks), and serum hormonal profiles (FSH and testosterone 2- and 4-weeks). However, LH was below the detectable limits. These results reflect that zinc deficiency during pre-pubertal period affected total protein and zinc status, elevates protein oxidation, and causes dysregulation of the hydroxysteroid dehydrogenases. Low level of zinc attenuated the gonadal physiology which indicates that the metabolic regulation of testes is mediated by combined effects of a specific response (caused by decreased zinc concentration) and a nonspecific response (inhibition of gonadotrophin secretion). All these contribute to testicular dysfunction. PMID- 22505239 TI - Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. AB - The interaction between T cell immunoglobulin- and mucin-domain-containing molecule (Tim-3) expressed on T helper 1 (Th1) cells, and its ligand, galectin-9, negatively regulates Th1-mediated immune responses. However, it is poorly understood if and how the Tim-3/galectin-9 signaling pathway is involved in immune escape in patients with hepatocellular carcinoma (HCC). Here we studied the expression, function, and regulation of the Tim-3/galectin-9 pathway in patients with hepatitis B virus (HBV)-associated HCC. We detected different levels of galectin-9 expression on antigen-presenting cell (APC) subsets including Kupffer cells (KCs), myeloid dendritic cells (DCs), and plasmacytoid DCs in HCC. The highest galectin-9 expression was on KCs in HCC islets, not in the adjacent tissues. Furthermore, Tim-3 expression was increased on CD4(+) and CD8(+) T cells in HCC as compared to the adjacent tissues, and Tim-3(+) T cells were replicative senescent and expressed surface and genetic markers for senescence. Interestingly, tumor-infiltrating T-cell-derived interferon (IFN) gamma stimulated the expression of galectin-9 on APCs in the HCC microenvironment. Immunofluorescence staining revealed a colocalization of Tim 3(+) T cells and galectin-9(+) KCs in HCC. Functional studies demonstrated that blockade of the Tim-3/galectin-9 signaling pathway importantly increased the functionality of tumor-infiltrating Tim-3(+) T cells as shown by increased T-cell proliferation and effector cytokine production. Finally, we show that the numbers of Tim-3(+) tumor-infiltrating cells were negatively associated with patient survival. CONCLUSION: Our work demonstrates that the Tim-3/galectin-9 signaling pathway mediates T-cell senescence in HBV-associated HCC. The data suggest that this pathway could be an immunotherapeutic target in patients with HBV-associated HCC. PMID- 22505240 TI - Successful medical treatment of Erysipelothrix rhusiopathiae-induced lumbosacral diskospondylitis in a dog. PMID- 22505241 TI - Effects of pheromones on heart rate in bulls and heifers. PMID- 22505243 TI - Comparison of a digital and an optical analogue hand-held refractometer for the measurement of canine urine specific gravity. AB - Urine specific gravity (USG) is used clinically as a measure of urine concentration, and is routinely assessed by refractometry. A comparison between optical analogue and digital refractometers for evaluation of canine urine has not been reported. The aim of this study was to compare a digital and an optical analogue hand-held refractometer for the measurement of canine USG, and to assess correlation with urine osmolality. Prospective study. Free-catch urine samples were collected from 285 hospitalised adult dogs, and paired USG readings were obtained with a digital and an optical analogue refractometer. In 50 dogs, urine osmolality was also measured using a freezing point depression osmometer. There was a small but statistically significant difference between the two refractometers (P<0.001), with the optical analogue refractometer reading higher than the digital refractometer (mean difference 0.0006, sd 0.0012). Paired refractometer measurements varied by <0.002 in 91.5 per cent of cases. The optical analogue and digital refractometer readings showed excellent correlation with osmolality (r=0.980 and r=0.977, respectively, P<0.001 in both cases). Despite statistical significance, the difference between the two refractometers is unlikely to be clinically significant. Both instruments provide an accurate assessment of USG in dogs. PMID- 22505242 TI - Prevalence, antibiotic resistance and molecular characterisation of Staphylococcus aureus in pigs at agricultural fairs in the USA. AB - Fairs and petting zoos have been associated with outbreaks of zoonotic disease. Previously, the presence of meticillin-resistant Staphylococcus aureus (MRSA) was documented in commercial pigs; therefore, it was hypothesised that antibiotic resistant S aureus may also occur in pigs exhibited at agricultural fairs. To test this hypothesis, 157 pigs were swabbed at two state fairs in 2008 to 2009. Both nares were sampled and cultures were grown in enrichment broth, then plated onto selective MRSA plates and blood plates. S aureus was confirmed using phenotypic and molecular methods, and was analysed using spa typing, gene specific polymerase chain reaction and antibiotic susceptibility testing. The presence of S aureus was confirmed in samples collected from pigs exhibited at USA pig shows. Twenty-five of 157 (15.9 per cent) samples were positive for S aureus. Two isolates (8 per cent) were resistant to meticillin; 23/25 (92 per cent), 14/25 (56 per cent) and 15/25 (60 per cent) were resistant to tetracycline, erythromycin and clindamycin, respectively. spa typing revealed multiple isolates of spa type t034 (9/25, 36 per cent) and t337 (7/25, 28 per cent) and singletons of t002, t209, t526, t1236, t1334, t1683, t3075, t5784 and t5883. These results verify the presence of antibiotic-resistant S aureus in pigs exhibited at USA fairs, suggesting that pigs are a potential reservoir for S aureus within this environment. PMID- 22505244 TI - Visual cleanliness scores of cattle at slaughter and microbial loads on the hides and the carcases. AB - In two abattoirs, visual cleanliness of 100 cattle was assessed before slaughter (on a scale of 1 to 4). From each animal, two sponge swabs (approximately 2000 cm(2) area, each) were taken: (a) from hide, immediately after sticking, and (b) from final carcase, but before chilling. In each swab sample, total viable count (TVC), Enterobacteriaceae count (EC) and the presence of Escherichia coli O157 were determined. The mean TVC/EC status of hides and final carcases differed significantly only between very dirty cattle (category 4) and all other less dirty or clean cattle (categories 1, 2 and 3), but not between the less dirty and clean cattle (between categories 1, 2 and 3). However, no clear relationship between the visual cleanliness of the hide and the occurrence of E coli O157 on hide or dressed carcases was observed. The study indicated the possibility that visual categorisation of cattle into only two main categories - one containing very dirty animals (category 4 in this work, corresponding to categories 4+5 in The UK Food Standards Agency system) and another containing all the other less dirty or clean animals (categories 1+2+3) - could be sufficient in practice. PMID- 22505245 TI - Composition-tunable Pt-Co alloy nanoparticle networks: facile room-temperature synthesis and supportless electrocatalytic applications. AB - Pt-Co alloy nanoparticle networks (NNs) with adjustable composition are synthesized by co-reduction of H(2) PtCl(6) and CoCl(2) with NaBH(4) in an ethylene glycol assisted cetyltrimethylammonium bromide/water/chloroform system at room temperature. Electrochemical measurements indicate that the as-prepared spongelike Pt-Co NNs exhibit composition-dependent electrocatalytic activities and CO tolerance with better durability toward methanol and formic acid oxidation than commercially available Pt/C catalyst. In particular, Pt(3) Co NNs show the highest specific activity, while Pt(2) Co NNs exhibit optimal mass activity among Pt-Co alloy NNs with different composition. These Pt-Co alloy NNs may be promising supportless anode catalysts for the direct methanol and direct formic acid fuel cells. PMID- 22505246 TI - Phosphoinositol 3-kinase, a novel target molecule for the inhibitory effects of juglone on TPA-induced cell transformation. AB - Juglone (5-hydroxy-1,4-naphthalenedione) from black walnut trees induces apoptosis and inhibits proliferation of various malignant cells. Here, we investigated whether juglone affects 12-O-tetradecanoylphorbol-13-acetate (TPA) induced cell transformation through the phosphoinositol 3-kinase (PI3K) pathway. The results showed that TPA- and endothelial growth factor (EGF)-induced anchorage-independent colony formation were suppressed in a dose-dependent manner by treatment of JB6 CI41 mouse skin epidermal cells with juglone (2.5 and 5 uM). We demonstrated that juglone suppressed PI3K activity via direct binding to PI3K by sepharose 4B pull-down assay and western blot analysis. Juglone significantly suppressed TPA-induced protein kinase B (AKT) and c-Jun phosphorylation and c-fos activation, but not mitogen-activated protein-kinase kinase (MEK), extracellular signaling-regulated kinase (ERK) or 90 kDa ribosomal protein S6 kinase (RSK) phosphorylation. Juglone significantly blocked activator protein-1 (AP-1) and cyclooxygenase-2 (COX-2) activation more than the PI3K inhibitors LY294002 and wortmannin. Overall, these results showed the anticancer efficacy of juglone targeting PI3K to prevent TPA-induced tumorigenesis. PMID- 22505247 TI - Application of compressed sensing to multidimensional spectroscopic imaging in human prostate. AB - The application of compressed sensing is demonstrated in a recently implemented four-dimensional echo-planar based J-resolved spectroscopic imaging sequence combining two spatial and two spectral dimensions. The echo-planar readout simultaneously acquires one spectral and one spatial dimension. Therefore, the compressed sensing undersampling is performed along the indirectly acquired spatial and spectral dimensions, and the reconstruction is performed using the split Bregman algorithm, an efficient TV-minimization solver. The four dimensional echo-planar-based J-resolved spectroscopic imaging data acquired in a prostate phantom containing metabolites at physiological concentrations are accurately reconstructed with as little as 20% of the original data. Experimental data acquired in six healthy prostates using the external body matrix "receive" coil on a 3T magnetic resonance imaging scanner are reconstructed with acquisitions using only 25% of the Nyquist-Shannon required amount of data, indicating the potential for a 4-fold acceleration factor in vivo, bringing the required scan time for multidimensional magnetic resonance spectroscopic imaging within clinical feasibility. PMID- 22505249 TI - Is an average of routine postdialysis blood pressure a good indicator of blood pressure control and cardiovascular risk? AB - INTRODUCTION: Hypertension is associated with left ventricular hypertrophy (LVH), a predictor of cardiovascular mortality in haemodialysis (HD) patients. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) blood pressure (BP) targets are pre-HD <140/90 mm Hg, post-HD <130/80 mm Hg. This study aims to assess 3-month mean in-unit BP, pre- and post-HD, for correlations with left ventricular mass index (LVMI), a measure of long-term BP control. METHODS: Of 648 HD patients, including those on HD >6 months, 262 had echocardiograms. Those with significant coronary artery disease, reduced ejection fraction or valvular disease were excluded, as were those without appropriate echocardiogram, leaving 100 patients. Data on BP and confounding factors for LVH were collected covering 3 months prior to echocardiogram. RESULTS: Mean BP pre-HD was 147/77 +/- 19/13 mm Hg, and post-HD, 133/71 +/- 20/11 mm Hg; <50% of patients achieved NKF targets. Mean LVMI was 203.7 +/- 74 g/m(2); 88% of patients had LVH. On univariate analysis, mean pre- and post-HD systolic BP, mean arterial blood pressure (MAP) and post-HD diastolic and pulse pressure correlated with LVMI. On stepwise multiple regression analysis only post-HD MAP correlated with LVMI (p=0.000047, r=0.395). CONCLUSIONS: We conclude that long-term averages of in unit post-HD BP measurements are useful in assessing BP control and cardiovascular risk, especially in the absence of routine ambulatory or home BP monitoring. PMID- 22505250 TI - Acute renal failure in the elderly: epidemiology and clinical features. AB - Structural and functional alterations affecting the aging kidney predispose to an increased risk of acute renal failure (ARF) in the elderly. This is a common problem becoming more relevant because of an increase in life expectancy. The epidemiology of ARF in the elderly is far from being well assessed, because of the lack of uniform definition criteria, variable etiology, coexistence of several comorbidities, and the various clinical settings and geographic areas where the condition is managed, with a higher incidence in developed regions where elderly patients predominate. In 2004, the Acute Dialysis Quality Initiative group proposed the RIFLE criteria for diagnosis and stratification of ARF. More recently, the Acute Kidney Injury Network proposed several refinements to the RIFLE criteria, and the use of the term acute kidney injury (AKI) has been suggested to mean any abrupt reduction in kidney function, while restricting use of the term ARF to severe dysfunction requiring renal replacement treatment. Although in elderly patients the more frequent forms of AKI are functional or obstructive, parenchymal AKI, such as acute tubular necrosis and contrast-induced nephropathy, still frequently occur. Elderly patients with chronic renal disease (CKD) who develop AKI are at high risk for mortality, and are prone to non recovery from AKI and progression to more advanced stages of CKD and even to end stage renal disease. Panels of AKI biomarkers are likely to improve early diagnosis and treatment, thus reducing morbidity and mortality of older patients from this condition in the future. PMID- 22505248 TI - Challenges to enrollment and randomization of the Frequent Hemodialysis Network (FHN) Daily Trial. AB - BACKGROUND: The US National Institutes of Health (NIH) and Centers for Medicare and Medicaid Services (CMS) sponsored a randomized clinical trial comparing six versus three times per week in-center hemodialysis (the Frequent Hemodialysis Network [FHN] Daily Trial), to test the effects of frequent hemodialysis on an array of intermediate outcomes. Herein we report challenges to enrollment and randomization into the trial. METHODS: Screening and enrollment was tracked at all participating dialysis clinics and specific reasons for dropout after baseline assessment were recorded for all enrolled subjects. Reasons for consent refusal were recorded in a subset of (10 out of 65) sites. RESULTS: The trial screened 6276 hemodialysis patients on three times weekly hemodialysis in 65 hemodialysis clinics, 3481 (55%) were considered eligible for enrollment, and 3124 (90%) were approached for consent; 378 (12%) consented and 245 were randomized (65% of those enrolled). Prospective subjects chose not to participate primarily because of the anticipated time required for three extra treatments per week and the difficulties in following the protocol. CONCLUSIONS: Recruitment into the FHN Daily Trial proved challenging but the goal of 250 randomized subjects was almost met. PMID- 22505252 TI - Model building, refinement and validation. PMID- 22505251 TI - Soluble TWEAK level: is it a marker for cardiovascular disease in long-term hemodialysis patients? AB - BACKGROUND: Reduced soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) levels follow declining renal function, are strongly associated with endothelial dysfunction and predict cardiovascular events in nondialyzed chronic kidney disease patients. In contrast, elevated levels of sTWEAK predict poor survival in hemodialysis (HD) patients. Recent evidence suggests a role for sTWEAK in the pathophysiology of vascular calcification. The aim of the study was to investigate plausible links between sTWEAK, atherosclerosis, arterial stiffness and vascular calcification in HD patients. METHODS: Coronary artery calcification score (CACs) determined by multislice computed tomography, arterial stiffness by pulse wave velocity (PWV) and carotid artery intima-media thickness (CA-IMT) by carotid Doppler ultrasonography were assessed in 131 long-term prevalent HD patients. sTWEAK levels were measured by ELISA (Bender MedSystems, Vienna, Austria). RESULTS: Mean serum sTWEAK level was 237.0 +/- 147.5 pg/mL (range 78-937). sTWEAK level was inversely correlated with CA-IMT at a borderline significance (r=-0.168, p=0.05). Neither carotid-radial PWV nor carotid-femoral PWV values correlated with sTWEAK. sTWEAK level was higher in patients with severe vascular calcification (CACs >=400) compared to patients with CACs <400 (264.5 +/- 146.8 pg/mL vs. 205.04 +/- 122.4 pg/mL, p=0.02).The association between sTWEAK and vascular calcification persisted after multivariate adjustment. CONCLUSIONS: There exists a weak inverse correlation between sTWEAK and carotid atherosclerosis and a positive correlation with coronary artery calcification in long-term HD patients. Our data give support for a role for sTWEAK in the pathogenesis of vascular injury in HD patients. PMID- 22505253 TI - Completion of autobuilt protein models using a database of protein fragments. AB - Two developments in the process of automated protein model building in the Buccaneer software are presented. A general-purpose library for protein fragments of arbitrary size is described, with a highly optimized search method allowing the use of a larger database than in previous work. The problem of assembling an autobuilt model into complete chains is discussed. This involves the assembly of disconnected chain fragments into complete molecules and the use of the database of protein fragments in improving the model completeness. Assembly of fragments into molecules is a standard step in existing model-building software, but the methods have not received detailed discussion in the literature. PMID- 22505254 TI - Practical structure solution with ARCIMBOLDO. AB - Since its release in September 2009, the structure-solution program ARCIMBOLDO, based on the combination of locating small model fragments such as polyalanine alpha-helices with density modification with the program SHELXE in a multisolution frame, has evolved to incorporate other sources of stereochemical or experimental information. Fragments that are more sophisticated than the ubiquitous main-chain alpha-helix can be proposed by modelling side chains onto the main chain or extracted from low-homology models, as locally their structure may be similar enough to the unknown one even if the conventional molecular replacement approach has been unsuccessful. In such cases, the program may test a set of alternative models in parallel against a specified figure of merit and proceed with the selected one(s). Experimental information can be incorporated in three ways: searching within ARCIMBOLDO for an anomalous fragment against anomalous differences or MAD data or finding model fragments when an anomalous substructure has been determined with another program such as SHELXD or is subsequently located in the anomalous Fourier map calculated from the partial fragment phases. Both sources of information may be combined in the expansion process. In all these cases the key is to control the workflow to maximize the chances of success whilst avoiding the creation of an intractable number of parallel processes. A GUI has been implemented to aid the setup of suitable strategies within the various typical scenarios. In the present work, the practical application of ARCIMBOLDO within each of these scenarios is described through the distributed test cases. PMID- 22505255 TI - Conventions and workflows for using Situs. AB - Situs is a modular program package for the multi-scale modeling of atomic resolution structures and low-resolution biophysical data from electron microscopy, tomography or small-angle X-ray scattering. This article provides an overview of recent developments in the Situs package, with an emphasis on workflows and conventions that are important for practical applications. The modular design of the programs facilitates scripting in the bash shell that allows specific programs to be combined in creative ways that go beyond the original intent of the developers. Several scripting-enabled functionalities, such as flexible transformations of data type, the use of symmetry constraints or the creation of two-dimensional projection images, are described. The processing of low-resolution biophysical maps in such workflows follows not only first principles but often relies on implicit conventions. Situs conventions related to map formats, resolution, correlation functions and feature detection are reviewed and summarized. The compatibility of the Situs workflow with CCP4 conventions and programs is discussed. PMID- 22505257 TI - Exploiting structure similarity in refinement: automated NCS and target-structure restraints in BUSTER. AB - Maximum-likelihood X-ray macromolecular structure refinement in BUSTER has been extended with restraints facilitating the exploitation of structural similarity. The similarity can be between two or more chains within the structure being refined, thus favouring NCS, or to a distinct 'target' structure that remains fixed during refinement. The local structural similarity restraints (LSSR) approach considers all distances less than 5.5 A between pairs of atoms in the chain to be restrained. For each, the difference from the distance between the corresponding atoms in the related chain is found. LSSR applies a restraint penalty on each difference. A functional form that reaches a plateau for large differences is used to avoid the restraints distorting parts of the structure that are not similar. Because LSSR are local, there is no need to separate out domains. Some restraint pruning is still necessary, but this has been automated. LSSR have been available to academic users of BUSTER since 2009 with the easy-to use -autoncs and -target target.pdb options. The use of LSSR is illustrated in the re-refinement of PDB entries 5rnt, where -target enables the correct ligand binding structure to be found, and 1osg, where -autoncs contributes to the location of an additional copy of the cyclic peptide ligand. PMID- 22505256 TI - Towards automated crystallographic structure refinement with phenix.refine. AB - phenix.refine is a program within the PHENIX package that supports crystallographic structure refinement against experimental data with a wide range of upper resolution limits using a large repertoire of model parameterizations. It has several automation features and is also highly flexible. Several hundred parameters enable extensive customizations for complex use cases. Multiple user defined refinement strategies can be applied to specific parts of the model in a single refinement run. An intuitive graphical user interface is available to guide novice users and to assist advanced users in managing refinement projects. X-ray or neutron diffraction data can be used separately or jointly in refinement. phenix.refine is tightly integrated into the PHENIX suite, where it serves as a critical component in automated model building, final structure refinement, structure validation and deposition to the wwPDB. This paper presents an overview of the major phenix.refine features, with extensive literature references for readers interested in more detailed discussions of the methods. PMID- 22505258 TI - Use of knowledge-based restraints in phenix.refine to improve macromolecular refinement at low resolution. AB - Traditional methods for macromolecular refinement often have limited success at low resolution (3.0-3.5 A or worse), producing models that score poorly on crystallographic and geometric validation criteria. To improve low-resolution refinement, knowledge from macromolecular chemistry and homology was used to add three new coordinate-restraint functions to the refinement program phenix.refine. Firstly, a 'reference-model' method uses an identical or homologous higher resolution model to add restraints on torsion angles to the geometric target function. Secondly, automatic restraints for common secondary-structure elements in proteins and nucleic acids were implemented that can help to preserve the secondary-structure geometry, which is often distorted at low resolution. Lastly, we have implemented Ramachandran-based restraints on the backbone torsion angles. In this method, a phi,psi term is added to the geometric target function to minimize a modified Ramachandran landscape that smoothly combines favorable peaks identified from nonredundant high-quality data with unfavorable peaks calculated using a clash-based pseudo-energy function. All three methods show improved MolProbity validation statistics, typically complemented by a lowered R(free) and a decreased gap between R(work) and R(free). PMID- 22505259 TI - Application of DEN refinement and automated model building to a difficult case of molecular-replacement phasing: the structure of a putative succinyl diaminopimelate desuccinylase from Corynebacterium glutamicum. AB - Phasing by molecular replacement remains difficult for targets that are far from the search model or in situations where the crystal diffracts only weakly or to low resolution. Here, the process of determining and refining the structure of Cgl1109, a putative succinyl-diaminopimelate desuccinylase from Corynebacterium glutamicum, at ~3 A resolution is described using a combination of homology modeling with MODELLER, molecular-replacement phasing with Phaser, deformable elastic network (DEN) refinement and automated model building using AutoBuild in a semi-automated fashion, followed by final refinement cycles with phenix.refine and Coot. This difficult molecular-replacement case illustrates the power of including DEN restraints derived from a starting model to guide the movements of the model during refinement. The resulting improved model phases provide better starting points for automated model building and produce more significant difference peaks in anomalous difference Fourier maps to locate anomalous scatterers than does standard refinement. This example also illustrates a current limitation of automated procedures that require manual adjustment of local sequence misalignments between the homology model and the target sequence. PMID- 22505260 TI - Low-resolution refinement tools in REFMAC5. AB - Two aspects of low-resolution macromolecular crystal structure analysis are considered: (i) the use of reference structures and structural units for provision of structural prior information and (ii) map sharpening in the presence of noise and the effects of Fourier series termination. The generation of interatomic distance restraints by ProSMART and their subsequent application in REFMAC5 is described. It is shown that the use of such external structural information can enhance the reliability of derived atomic models and stabilize refinement. The problem of map sharpening is considered as an inverse deblurring problem and is solved using Tikhonov regularizers. It is demonstrated that this type of map sharpening can automatically produce a map with more structural features whilst maintaining connectivity. Tests show that both of these directions are promising, although more work needs to be performed in order to further exploit structural information and to address the problem of reliable electron-density calculation. PMID- 22505261 TI - Tetartohedral twinning could happen to you too. AB - Tetartohedral crystal twinning is discussed as a particular case of (pseudo)merohedral twinning when the number of twinned domains is four. Tetartohedrally twinned crystals often possess pseudosymmetry, with the rotational part of the pseudosymmetry operators coinciding with the twinning operators. Tetartohedrally twinned structures from the literature are reviewed and the recent structure determination of tetartohedrally twinned triclinic crystals of human complement factor I is discussed. PMID- 22505262 TI - Handling ligands with Coot. AB - Coot is a molecular-graphics application primarily aimed to assist in model building and validation of biological macromolecules. Recently, tools have been added to work with small molecules. The newly incorporated tools for the manipulation and validation of ligands include interaction with PRODRG, subgraph isomorphism-based tools, representation of ligand chemistry, ligand fitting and analysis, and are described here. PMID- 22505263 TI - JLigand: a graphical tool for the CCP4 template-restraint library. AB - Biological macromolecules are polymers and therefore the restraints for macromolecular refinement can be subdivided into two sets: restraints that are applied to atoms that all belong to the same monomer and restraints that are associated with the covalent bonds between monomers. The CCP4 template-restraint library contains three types of data entries defining template restraints: descriptions of monomers and their modifications, both used for intramonomer restraints, and descriptions of links for intermonomer restraints. The library provides generic descriptions of modifications and links for protein, DNA and RNA chains, and for some post-translational modifications including glycosylation. Structure-specific template restraints can be defined in a user's additional restraint library. Here, JLigand, a new CCP4 graphical interface to LibCheck and REFMAC that has been developed to manage the user's library and generate new monomer entries is described, as well as new entries for links and associated modifications. PMID- 22505264 TI - Challenges and surprises that arise with nucleic acids during model building and refinement. AB - The process of building and refining crystal structures of nucleic acids, although similar to that for proteins, has some peculiarities that give rise to both various complications and various benefits. Although conventional isomorphous replacement phasing techniques are typically used to generate an experimental electron-density map for the purposes of determining novel nucleic acid structures, it is also possible to couple the phasing and model-building steps to permit the solution of complex and novel RNA three-dimensional structures without the need for conventional heavy-atom phasing approaches. PMID- 22505265 TI - Use of noncrystallographic symmetry for automated model building at medium to low resolution. AB - A novel method is presented for the automatic detection of noncrystallographic symmetry (NCS) in macromolecular crystal structure determination which does not require the derivation of molecular masks or the segmentation of density. It was found that throughout structure determination the NCS-related parts may be differently pronounced in the electron density. This often results in the modelling of molecular fragments of variable length and accuracy, especially during automated model-building procedures. These fragments were used to identify NCS relations in order to aid automated model building and refinement. In a number of test cases higher completeness and greater accuracy of the obtained structures were achieved, specifically at a crystallographic resolution of 2.3 A or poorer. In the best case, the method allowed the building of up to 15% more residues automatically and a tripling of the average length of the built fragments. PMID- 22505266 TI - Statistical quality indicators for electron-density maps. AB - The commonly used validation metrics for the local agreement of a structure model with the observed electron density, namely the real-space R (RSR) and the real space correlation coefficient (RSCC), are reviewed. It is argued that the primary goal of all validation techniques is to verify the accuracy of the model, since precision is an inherent property of the crystal and the data. It is demonstrated that the principal weakness of both of the above metrics is their inability to distinguish the accuracy of the model from its precision. Furthermore, neither of these metrics in their usual implementation indicate the statistical significance of the result. The statistical properties of electron-density maps are reviewed and an improved alternative likelihood-based metric is suggested. This leads naturally to a chi(2) significance test of the difference density using the real space difference density Z score (RSZD). This is a metric purely of the local model accuracy, as required for effective model validation and structure optimization by practising crystallographers prior to submission of a structure model to the PDB. A new real-space observed density Z score (RSZO) is also proposed; this is a metric purely of the model precision, as a substitute for other precision metrics such as the B factor. PMID- 22505267 TI - To B or not to B: a question of resolution? AB - In choosing and refining any crystallographic structural model, there is tension between the desire to extract the most detailed information possible and the necessity to describe no more than what is justified by the observed data. A more complex model is not necessarily a better model. Thus, it is important to validate the choice of parameters as well as validating their refined values. One recurring task is to choose the best model for describing the displacement of each atom about its mean position. At atomic resolution one has the option of devoting six model parameters (a 'thermal ellipsoid') to describe the displacement of each atom. At medium resolution one typically devotes at most one model parameter per atom to describe the same thing (a 'B factor'). At very low resolution one cannot justify the use of even one parameter per atom. Furthermore, this aspect of the structure may be described better by an explicit model of bulk displacements, the most common of which is the translation/libration/screw (TLS) formalism, rather than by assigning some number of parameters to each atom individually. One can sidestep this choice between atomic displacement parameters and TLS descriptions by including both treatments in the same model, but this is not always statistically justifiable. The choice of which treatment is best for a particular structure refinement at a particular resolution can be guided by general considerations of the ratio of model parameters to the number of observations and by specific statistics such as the Hamilton R-factor ratio test. PMID- 22505268 TI - Implementing an X-ray validation pipeline for the Protein Data Bank. AB - There is an increasing realisation that the quality of the biomacromolecular structures deposited in the Protein Data Bank (PDB) archive needs to be assessed critically using established and powerful validation methods. The Worldwide Protein Data Bank (wwPDB) organization has convened several Validation Task Forces (VTFs) to advise on the methods and standards that should be used to validate all of the entries already in the PDB as well as all structures that will be deposited in the future. The recommendations of the X-ray VTF are currently being implemented in a software pipeline. Here, ongoing work on this pipeline is briefly described as well as ways in which validation-related information could be presented to users of structural data. PMID- 22505269 TI - PDB_REDO: constructive validation, more than just looking for errors. AB - Developments of the PDB_REDO procedure that combine re-refinement and rebuilding within a unique decision-making framework to improve structures in the PDB are presented. PDB_REDO uses a variety of existing and custom-built software modules to choose an optimal refinement protocol (e.g. anisotropic, isotropic or overall B-factor refinement, TLS model) and to optimize the geometry versus data refinement weights. Next, it proceeds to rebuild side chains and peptide planes before a final optimization round. PDB_REDO works fully automatically without the need for intervention by a crystallographic expert. The pipeline was tested on 12 000 PDB entries and the great majority of the test cases improved both in terms of crystallographic criteria such as R(free) and in terms of widely accepted geometric validation criteria. It is concluded that PDB_REDO is useful to update the otherwise 'static' structures in the PDB to modern crystallographic standards. The publically available PDB_REDO database provides better model statistics and contributes to better refinement and validation targets. PMID- 22505270 TI - Early rheumatoid arthritis in Latin America: low socioeconomic status related to high disease activity at baseline. AB - OBJECTIVE: To determine the influence of socioeconomic factors on disease activity in a Latin American (LA) early rheumatoid arthritis (RA) multinational inception cohort at baseline. METHODS: Clinical evaluation, ethnicity, socioeconomic status (SES), 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR), Health Assessment Questionnaire (HAQ) disability index (DI), and erosions were recorded in 1,093 patients with early RA (<1 year from onset). Multivariate analyses evaluated influences of sex, age, marital status, education, medical coverage, SES, and ethnicity on HAQ DI, DAS28-ESR, and presence of erosions. RESULTS: Ethnicities included 43% Mestizo, 31% Caucasian, 19% African LA, 4% Amerindian, and 3% other. Fifty-eight percent were of low/low-middle SES, 42% had <8 years of education, 21% had no medical coverage, median disease duration was 6 months (25th, 75th percentiles 4, 9 months), median HAQ DI score was 1.25 (25th, 75th percentiles 0.63, 2.00), median DAS28-ESR score was 6.2 (25th, 75th percentiles 4.9, 7.2), and 25% had erosions. Women and Mestizos, African LA, and Amerindians had earlier onset than men or Caucasians (P < 0.01). When adjusted by country, the analysis of covariance model showed that low/low-middle SES, female sex, partial coverage, and older age were associated with worse HAQ DI scores; only low/low-middle SES was associated with higher DAS28 scores. Statistically significant differences were found in HAQ DI and DAS28 scores between countries. When excluding country, low/low-middle SES, female sex, and no coverage were associated with worse HAQ DI and DAS28 scores, whereas separated/divorced/widowed status was associated with worse HAQ DI scores and age was associated with worse DAS28 scores. Logistic regression showed that older age, no coverage, and the Amerindian and other ethnic groups were associated with erosions. CONCLUSION: We compared early RA patients from the main LA ethnic groups. Our findings suggest that low/low-middle SES is important in determining disease activity. A more genetic-related background for erosions is possible. PMID- 22505271 TI - Accumulation and distribution characteristics of platinum group elements in roadside dusts in Beijing, China. AB - The concentrations, distribution, and accumulation of platinum group elements (PGEs) were investigated in roadside dusts collected in four different foundational areas in Beijing during February to May 2010. The results showed that PGE levels in all samples were above the average upper crust values, with mean concentrations of 57.5 ng . g(-1) Pd, 28.2 ng . g(-1) Pt, and 9.8 ng . g(-1) Rh, respectively. Palladium concentration has increased rapidly in recent years. The rank of PGE levels in four different functional regions for roadside dusts was: heavy density traffic area > residential area > educational area > tourism area. Palladium, Pt, and Rh concentrations in dusts showed strong positive correlations, indicating a common traffic-related source of these metals. Meanwhile, PGEs in these samples were not correlated with other traffic-related metals except for Cr. The average PGE ratios of road dusts from Beijing were consistent with those in Germany and Western Australia, but lower than those in the United States and Mexico, indicating that various catalyst productions were used in different countries. In addition, grain-size partitioning of PGEs in dusts indicated that concentrations of PGEs differed from one particle size to another. The coarse fraction had higher PGE concentrations than the fine fraction in roadside dusts. These results showed that autocatalyst PGE contamination estimates in the environment would be significantly underestimated if only a fine grain size fraction (<0.063 mm) is analyzed. PMID- 22505272 TI - Alternate layered nanostructures of metal oxides by a click reaction. PMID- 22505273 TI - Transperineal prostate MR elastography: initial in vivo results. AB - This article presents a new approach to magnetic resonance elastography of the prostate using transperineal mechanical excitation. This approach is validated using a prostate elasticity phantom and in vivo studies of healthy volunteers. It is demonstrated that the transperineal approach can generate shear wave amplitudes on the order of 6-30 MUm in the mid-gland region. The driver was implemented using an electromagnetic actuator with a hydraulic transmission system. The magnetic resonance elastography acquisition time has been reduced significantly by using a "second harmonic" approach. Displacement fields are processed using the established three-dimensional local frequency estimation algorithm. The three-dimensional curl-based direct inversion was used to calculate the local wavelength. The traveling wave expansion algorithm was used to reconstruct the wave damping image for one case. Using the proposed method, it was possible to resolve lesions of 0.5 cc in the phantom study. Repeatability experiments were performed and analyzed. The results from this study indicate that transperineal magnetic resonance elastography--without an endorectal coil- is a suitable candidate for a patient study involving multiparametric magnetic resonance imaging of prostate cancer, where magnetic resonance elastography may provide additional information for improved diagnosis and image-based surveillance. PMID- 22505274 TI - In utero treatment of fetal goitrous hypothyroidism in a euthyroid mother: a case report. AB - Fetal goitrous hypothyroidism is a rare condition in euthyroid pregnant women. Complications such as tracheal and esophageal compression with resultant polyhydramnios, as well as the possibility of neurodevelopmental effects of hypothyroidism, have prompted prenatal treatment with intra-amniotic L-thyroxine. We report a case of this condition and its in utero management. PMID- 22505275 TI - Investigation of the effective connectivity of resting state networks in Alzheimer's disease: a functional MRI study combining independent components analysis and multivariate Granger causality analysis. AB - Recent neuroimaging studies have shown that the cognitive and memory decline in patients with Alzheimer's disease (AD) is coupled with abnormal functions of focal brain regions and disrupted functional connectivity between distinct brain regions, as well as losses in small-world attributes. However, the causal interactions among the spatially isolated, but functionally related, resting state networks (RSNs) are still largely unexplored. In this study, we first identified eight RSNs by independent components analysis from resting state functional MRI data of 18 patients with AD and 18 age-matched healthy subjects. We then performed a multivariate Granger causality analysis (mGCA) to evaluate the effective connectivity among the RSNs. We found that patients with AD exhibited decreased causal interactions among the RSNs in both intensity and quantity relative to normal controls. Results from mGCA indicated that the causal interactions involving the default mode network and auditory network were weaker in patients with AD, whereas stronger causal connectivity emerged in relation to the memory network and executive control network. Our findings suggest that the default mode network plays a less important role in patients with AD. Increased causal connectivity of the memory network and self-referential network may elucidate the dysfunctional and compensatory processes in the brain networks of patients with AD. These preliminary findings may provide a new pathway towards the determination of the neurophysiological mechanisms of AD. PMID- 22505277 TI - Bonding of gold with unsaturated species. AB - Interactions of gold(I) catalysts with alkenes and alkynes are analyzed. Neutral chlorido, and cationic phosphine and N-heterocyclic carbene complexes are studied. High-level ab initio calculations are performed to benchmark the accuracy of popular DFT methods. Donation and backdonation contributions in the bond between the gold fragment and the alkene/alkyne substrate are discussed. These contributions depend on the nature of the gold fragment, but also on the substituents on the alkene/alkyne. PMID- 22505276 TI - Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism. AB - Pentoxifylline (PTX) improved the histological features of nonalcoholic steatohepatitis (NASH) in a recent randomized placebo-controlled trial. However, the underlying mechanism responsible for the beneficial effects of PTX in NASH remains unidentified. A key role of lipid oxidation in the pathogenesis and progression of NASH has been established. PTX is known to decrease free-radical mediated oxidative stress and inhibit lipid oxidation. The primary aim of this study was to evaluate the effects of PTX on levels of lipid oxidation products in patients with NASH. Levels of multiple structurally specific oxidized fatty acids including hydroxy-octadecadienoic acids (HODEs), oxo-octadecadienoic acids (oxoODEs), and hydroxy-eicosatetraenoic acids (HETEs) were quantified by mass spectrometry in plasma obtained at baseline and at study completion in patients who completed 1 year of therapy with PTX or placebo in a randomized controlled trial. Therapy with PTX resulted in significant decreases in 9-HODE and 13 oxoODE, oxidized lipid products of linoleic acid (LA) linked to histological severity in nonalcoholic fatty liver disease. Similarly, PTX therapy was associated with significant decreases in 8-HETE, 9-HETE, and 11-HETE compared to placebo. Statistically significant correlations were demonstrated between the decrease in HODEs and oxoODEs and improved histological scores of fibrosis and between the decrease in HETEs and improved lobular inflammation. CONCLUSION: Therapy with PTX compared to placebo was associated with a significant reduction of oxidized fatty acids. This novel evidence supports that the beneficial effects of PTX in patients with NASH are likely partly mediated through decreasing lipid oxidation, largely free-radical-mediated lipid oxidation. Additionally, this is the first report on the link between decreased oxidized lipid products and improved histological disease in the setting of a therapeutic trial in NASH. PMID- 22505278 TI - Risk variant of oligodendrocyte lineage transcription factor 2 is associated with reduced white matter integrity. AB - The oligodendrocyte lineage transcription factor 2 (OLIG2) regulates the genesis of oligodendrocytes, the brain cells responsible for axonal myelination. Although it has been associated with psychiatric and neurological disorders, the impact of this gene on white matter integrity has never been investigated in humans. Using diffusion tensor imaging, we examined the effect of a single nucleotide polymorphism (rs1059004) in OLIG2 previously associated with reduced gene expression, and with psychiatric disorders on fractional anisotropy in 78 healthy subjects. We found that the risk allele (A) was associated with reduced white matter integrity in the corona radiata bilaterally. This is consistent with evidence that it is a schizophrenia susceptibility gene, and suggests that it may confer increased risk through an effect on neuroanatomical connectivity. PMID- 22505279 TI - Cognitive impairment in persons with rheumatoid arthritis. AB - OBJECTIVE: To explore the prevalence and possible predictors of cognitive impairment in persons with rheumatoid arthritis (RA). METHODS: Individuals from a longitudinal cohort study of RA participated in a study visit that included a range of physical, psychosocial, and biologic metrics. Cognitive function was assessed using a battery of 12 standardized neuropsychological measures yielding 16 indices. Subjects were classified as "impaired" if they performed 1 SD below age-based population norms on at least 4 of 16 indices. Logistic regression analyses were conducted to identify which of the following were significant predictors of cognitive impairment: sex, race, income, education, depression, disease duration, disease severity, C-reactive protein (CRP) level, glucocorticoid use, and cardiovascular disease (CVD) risk factors. RESULTS: A total of 115 subjects with a mean +/- SD age of 58.6 +/- 10.8 years were included; 64% were women and 81% were white. The proportion of persons who were classified as cognitively impaired was 31%. Education, income, glucocorticoid use, and CVD risk factors independently predicted cognitive impairment, controlling for sex, race, disease duration, disease severity, CRP level, and depression. Individuals with cognitive impairment were more likely to have low education (odds ratio [OR] 6.18, 95% confidence interval [95% CI] 1.6-23.87), have low income (OR 7.12, 95% CI 1.35-37.51), use oral glucocorticoids (OR 2.92, 95% CI 1.05-8.12), and have increased CVD risk factors (OR 1.61, 95% CI 1.19-2.17 per risk factor). CONCLUSION: The findings of this study suggest that the burden of cognitive impairment in RA is significant, and future studies identifying specific etiologic contributors to cognitive impairment are warranted. PMID- 22505280 TI - The effect of peripherally inserted central catheter (PICC) valve technology on catheter occlusion rates--the 'ELeCTRiC' study. AB - PURPOSE: Peripherally Inserted Central Catheters (PICCs) are increasingly being used to provide short to medium-term central venous access. The current study was designed to test the hypothesis that PICC valve technology does not influence PICC occlusion rates. METHODS: Intensive care unit (ICU) patients who required a PICC were randomized to one of three types of dual lumen PICC (open ended non valved, Groshong valve, PASV valve). PICC occlusions were recorded and managed with a protocol that used urokinase. RESULTS: A total of 102 patients were recruited to the study. The overall risk of occlusion per catheter was 35% (95% CI 26% to 44%). The overall rate of occlusion was 76 occlusions per 1000 catheter days (95% CI 61 to 95). Presence or type of valve did not significantly influence this rate (open-ended non-valved PICC 38% of catheters, 79 occlusions per 1000 catheter days; Groshong 38% of catheters, 60 occlusions per 1000 catheter days; PASV 27% of catheters, 99 occlusions per 1000 catheter days). The dose of urokinase required to treat PICC occlusions did not significantly differ between PICC types. CONCLUSIONS: Valved PICCs do not appear to influence PICC occlusion rates. PMID- 22505282 TI - Double molecular recognition with aminoorganoboron complexes: selective alcoholysis of beta-dicarbonyl derivatives. PMID- 22505281 TI - Relationship between the outcomes of stent placement and the properties of arteriovenous graft outflow vein stenotic lesions. AB - PURPOSE: The mechanisms of venous stenosis in vascular access include vascular constriction and neointimal hyperplasia. One purpose of this study was to examine the properties of stenotic lesions in arteriovenous graft outflow veins and the association with the results of treatment using stent placement. SUBJECTS AND METHODS: The study involved 46 patients who underwent stent placement to treat arteriovenous graft outflow vein stenosis. The properties of stenotic lesions before stent placement were observed by ultrasonography and were classified into three groups: vascular constriction types, neointimal proliferation types, and mixed types. Stent placement was performed when elastic recoil occurred or when restenosis occurred at the same site within three months. The primary patency results for each group were then compared. The primary endpoint included patency of the treatment area. RESULTS: The primary patency rate of the treatment area at 6, 12, 18 and 24 months post-stent placement for the vascular constriction type was 100.0%, 92.3%, 84.6% and 75.2%, respectively. Those rates were 66.7%, 33.3%, 33.3% and 25.0% for the neointimal proliferation type, and 90.5%, 52.4%, 38.1% and 27.2% with the mixed type. The vascular constriction type displayed excellent primary patency rates after stent placement. CONCLUSIONS: It is possible to define the types of stenotic lesions for which stent therapy is effective through morphological diagnosis of those lesions using ultrasound tomography. PMID- 22505283 TI - Structural analysis of a 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase with an N-terminal chorismate mutase-like regulatory domain. AB - 3-Deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAHPS) catalyzes the first step in the biosynthesis of a number of aromatic metabolites. Likely because this reaction is situated at a pivotal biosynthetic gateway, several DAHPS classes distinguished by distinct mechanisms of allosteric regulation have independently evolved. One class of DAHPSs contains a regulatory domain with sequence homology to chorismate mutase-an enzyme further downstream of DAHPS that catalyzes the first committed step in tyrosine/phenylalanine biosynthesis-and is inhibited by chorismate mutase substrate (chorismate) and product (prephenate). Described in this work, structures of the Listeria monocytogenes chorismate/prephenate regulated DAHPS in complex with Mn(2+) and Mn(2+) + phosphoenolpyruvate reveal an unusual quaternary architecture: DAHPS domains assemble as a tetramer, from either side of which chorismate mutase-like (CML) regulatory domains asymmetrically emerge to form a pair of dimers. This domain organization suggests that chorismate/prephenate binding promotes a stable interaction between the discrete regulatory and catalytic domains and supports a mechanism of allosteric inhibition similar to tyrosine/phenylalanine control of a related DAHPS class. We argue that the structural similarity of chorismate mutase enzyme and CML regulatory domain provides a unique opportunity for the design of a multitarget antibacterial. PMID- 22505285 TI - Chemical shift encoded water-fat separation using parallel imaging and compressed sensing. AB - Chemical shift encoded techniques have received considerable attention recently because they can reliably separate water and fat in the presence of off resonance. The insensitivity to off-resonance requires that data be acquired at multiple echo times, which increases the scan time as compared to a single echo acquisition. The increased scan time often requires that a compromise be made between the spatial resolution, the volume coverage, and the tolerance to artifacts from subject motion. This work describes a combined parallel imaging and compressed sensing approach for accelerated water-fat separation. In addition, the use of multiscale cubic B-splines for B(0) field map estimation is introduced. The water and fat images and the B(0) field map are estimated via an alternating minimization. Coil sensitivity information is derived from a calculated k-space convolution kernel and l(1)-regularization is imposed on the coil-combined water and fat image estimates. Uniform water-fat separation is demonstrated from retrospectively undersampled data in the liver, brachial plexus, ankle, and knee as well as from a prospectively undersampled acquisition of the knee at 8.6x acceleration. PMID- 22505284 TI - Extratemporal functional connectivity impairments at rest are related to memory performance in mesial temporal epilepsy. AB - Mesial temporal lobe epilepsy (MTLE) is the most frequent form of focal epilepsy. At rest, there is evidence that brain abnormalities in MTLE are not limited to the epileptogenic region, but extend throughout the whole brain. It is also well established that MTLE patients suffer from episodic memory deficits. Thus, we investigated the relation between the functional connectivity seen at rest in fMRI and episodic memory impairments in MTLE. We focused on resting state BOLD activity and evaluated whether functional connectivity (FC) differences emerge from MTL seeds in left and right MTLE groups, compared with healthy controls. Results revealed significant FC reductions in both patient groups, localized in angular gyri, thalami, posterior cingulum and medial frontal cortex. We found that the FC between the left non-pathologic MTL and the medial frontal cortex was positively correlated with the delayed recall score of a non-verbal memory test in right MTLE patients, suggesting potential adaptive changes to preserve this memory function. In contrast, we observed a negative correlation between a verbal memory test and the FC between the left pathologic MTL and posterior cingulum in left MTLE patients, suggesting potential functional maladaptative changes in the pathologic hemisphere. Overall, the present study provides some indication that left MTLE may be more impairing than right MTLE patients to normative functional connectivity. Our data also indicates that the pattern of extra-temporal FC may vary as a function of episodic memory material and each hemisphere's capacity for cognitive reorganization. PMID- 22505287 TI - Photoinduced electron transfer in a ferrocene-distyryl BODIPY dyad and a ferrocene-distyryl BODIPY-C60 triad. AB - A ferrocene-distyryl BODIPY dyad and a ferrocene-distyryl BODIPY-C(60) triad are synthesized and characterized. Upon photoexcitation at the distyryl BODIPY unit, these arrays undergo photoinduced electron transfer to form the corresponding charge-separated species. Based on their redox potentials, determined by cyclic voltammetry, the direction of the charge separation and the energies of these states are revealed. Femtosecond transient spectroscopic studies reveal that a fast charge separation (k(CS) =1.0*10(10) s(-1)) occurs for both the ferrocene distyryl BODIPY dyad and the ferrocene-distyryl BODIPY-C(60) triad, but that a relatively slow charge recombination is observed only for the triad. The lifetime of the charge-separated state is 500 ps. Charge recombination of the dyad and triad leads to population of the triplet excited sate of ferrocene and the ground state, respectively. PMID- 22505286 TI - Antagonism of sphingosine 1-phosphate receptor 2 causes a selective reduction of portal vein pressure in bile duct-ligated rodents. AB - Sinusoidal vasoconstriction, in which hepatic stellate cells operate as contractile machinery, has been suggested to play a pivotal role in the pathophysiology of portal hypertension. We investigated whether sphingosine 1 phosphate (S1P) stimulates contractility of those cells and enhances portal vein pressure in isolated perfused rat livers with Rho activation by way of S1P receptor 2 (S1P(2) ). Rho and its effector, Rho kinase, reportedly contribute to the pathophysiology of portal hypertension. Thus, a potential effect of S1P(2) antagonism on portal hypertension was examined. Intravenous infusion of the S1P(2) antagonist, JTE-013, at 1 mg/kg body weight reduced portal vein pressure by 24% without affecting mean arterial pressure in cirrhotic rats induced by bile duct ligation at 4 weeks after the operation, whereas the same amount of S1P(2) antagonist did not alter portal vein pressure and mean arterial pressure in control sham-operated rats. Rho kinase activity in the livers was enhanced in bile duct-ligated rats compared to sham-operated rats, and this enhanced Rho kinase activity in bile duct-ligated livers was reduced after infusion of the S1P(2) antagonist. S1P(2) messenger RNA (mRNA) expression, but not S1P(1) or S1P(3) , was increased in bile duct-ligated livers of rats and mice and also in culture-activated rat hepatic stellate cells. S1P(2) expression, determined in S1P 2LacZ/+ mice, was highly increased in hepatic stellate cells of bile duct ligated livers. Furthermore, the increase of Rho kinase activity in bile duct ligated livers was observed as early as 7 days after the operation in wildtype mice, but was less in S1P 2-/- mice. CONCLUSION: S1P may play an important role in the pathophysiology of portal hypertension with Rho kinase activation by way of S1P(2) . The S1P(2) antagonist merits consideration as a novel therapeutic agent for portal hypertension. PMID- 22505288 TI - Exercise training in juvenile dermatomyositis. AB - OBJECTIVE: To investigate the effects of a supervised exercise training program on health parameters, physical capacity, and health-related quality of life in patients with mild and chronic juvenile dermatomyositis (DM). METHODS: This was a prospective longitudinal study following 10 children with mild and chronic juvenile DM (disease duration >1 year). The exercise program consisted of twice-a week aerobic and resistance training. At baseline and after the 12-week intervention, we assessed muscle strength and function, aerobic conditioning, body composition, juvenile DM scores, and health-related quality of life. RESULTS: Child self-report and parent proxy-report Pediatric Quality of Life Inventory scores were improved after the intervention (-40.3%; P = 0.001 and 48.2%; P = 0.049, respectively). Importantly, after exercise, the Disease Activity Score was reduced (-26.9%; P = 0.026) and the Childhood Muscle Assessment Scale was improved (+2.5%; P = 0.009), whereas the Manual Muscle Test presented a trend toward statistical significance (+2.2%; P = 0.081). The peak oxygen consumption and time-to-exhaustion were increased by 13.3% (P = 0.001) and 18.2% (P = 0.003), respectively, whereas resting heart rate was decreased by 14.7% (P = 0.006), indicating important cardiovascular adaptations to the exercise program. Upper and lower extremity muscle strength and muscle function were also significantly improved after the exercise training (P < 0.05). Both the whole-body and the lumbar spine bone mineral apparent density were significantly increased after training (1.44%; P = 0.044 and 2.85%; P = 0.008, respectively). CONCLUSION: We showed for the first time that a 12-week supervised exercise program is safe and can improve muscle strength and function, aerobic conditioning, bone mass, disease activity, and health-related quality of life in patients with active and nonactive mild and chronic juvenile DM with near normal physical function and quality of life. PMID- 22505289 TI - Bats at risk? Bat activity and insecticide residue analysis of food items in an apple orchard. AB - Although bats are reported as being threatened by pesticides, they are currently not considered in European Union pesticide risk assessments. The reason for that contradiction is probably related to the scarcity of information on bat activity in pesticide-treated fields and the pesticide residues on their food items. The authors recorded bat activity and measured pesticide residues on bat-specific food items following applications of two insecticides in an apple orchard. High activity levels of the common pipistrelle bat, a foraging habitat generalist, were detected. Airborne foragers and bats that take part of their food by gleaning arthropods from the vegetation were recorded frequently. The initial value and the decline of pesticide residues were found to depend on the arthropod type, their surface to volume ratio, their mobility, and the mode of action of the applied pesticide. The highest initial residue values were measured on foliage-dwelling arthropods. By following the toxicity-exposure ratio approaches of the current pesticide risk assessment, no acute dietary risk was found for all recorded bat species. However, a potential reproductive risk for bat species that include foliage-dwelling arthropods in their diet was indicated. The results emphasize the importance of adequately evaluating the risks of pesticides to bats, which, compared to other mammals, are potentially more sensitive due to their ecological traits. PMID- 22505290 TI - Practice-related changes in neural activation patterns investigated via wavelet based clustering analysis. AB - OBJECTIVES: To evaluate brain activation using functional magnetic resonance imaging (fMRI) and specifically, activation changes across time associated with practice-related cognitive control during eye movement tasks. EXPERIMENTAL DESIGN: Participants were engaged in antisaccade performance (generating a glance away from a cue) while fMR images were acquired during two separate test sessions: (1) at pre-test before any exposure to the task and (2) at post-test, after 1 week of daily practice on antisaccades, prosaccades (glancing toward a target), or fixation (maintaining gaze on a target). PRINCIPAL OBSERVATIONS: The three practice groups were compared across the two test sessions, and analyses were conducted via the application of a model-free clustering technique based on wavelet analysis. This series of procedures was developed to avoid analysis problems inherent in fMRI data and was composed of several steps: detrending, data aggregation, wavelet transform and thresholding, no trend test, principal component analysis (PCA), and K-means clustering. The main clustering algorithm was built in the wavelet domain to account for temporal correlation. We applied a no trend test based on wavelets to significantly reduce the high dimension of the data. We clustered the thresholded wavelet coefficients of the remaining voxels using PCA K-means clustering. CONCLUSION: Over the series of analyses, we found that the antisaccade practice group was the only group to show decreased activation from pre-test to post-test in saccadic circuitry, particularly evident in supplementary eye field, frontal eye fields, superior parietal lobe, and cuneus. PMID- 22505291 TI - Kinetics of thermally induced heat shock protein 27 and 70 expression by bone marrow-derived mesenchymal stem cells. AB - Although bone marrow-derived mesenchymal stem cells (MSCs) are an attractive cell therapy candidate, their potential is limited by poor survival following transplantation. Over-expression of anti-apoptotic heat shock proteins using viral vectors can improve the survival of these cells under stressful conditions in vitro and in vivo. It is also possible to induce heat shock protein expression in many cell types by simply exposing them to a transient, nonlethal elevation in temperature. The response profile of MSCs to such a thermal stress has not yet been reported. Therefore, this study sought to determine the kinetics of thermally induced heat shock protein expression by MSCs in vitro. To determine if heat shock protein expression was a function of thermal stress exposure time, MSCs were exposed to 42 degrees C for 15, 30, 45, and 60 min and were harvested 24 h later. To establish the time-course of heat shock protein expression, MSCs were heat shocked for 60 min and harvested 2, 24, 48, 72, 96, and 120 h later. The cells were then analyzed for Hsp27 and Hsp70 expression by Western blot. Densitometric analysis revealed that exposure to a thermal stress induced expression of both Hsp27 and Hsp70 and that the level of expression was dependant on stress exposure time. Following 60 min of heat stress, both Hsp27 and Hsp70 accumulated maximal expression after 48 h with both proteins returning to constitutive expression levels by 120 h. This study demonstrates that heat shock protein expression can be induced in MSCs by a simple thermal stress. PMID- 22505293 TI - Should an alternative to the Glasgow Coma Scale be taught to paramedic students? AB - BACKGROUND: The accurate assessment of a patient's conscious state using the Glasgow Coma Scale (GCS) is an important skill for paramedics as it may determine the patient's initial and ongoing management. The objective of this study was to determine if undergraduate paramedic students from a large Australian University were able to accurately interpret a variety of conscious states. METHODS: A prospective double-blinded observational pilot study requiring students to interpret the conscious state of four adult patients using the GCS by viewing a simulation DVD package. RESULTS: There were 137 students who participated in the study, of whom 65% (n=87) were female students. The results demonstrated that undergraduate paramedic students were unable to accurately interpret a number of patient conscious states with only 20% and 37% of students able to accurately identify the GCS of patients 2 (GCS=12) and 3 (GCS=7). The motor component of the GCS appeared to be the component where the least accurate interpretation occurred, with only 47% of students being able to accurately identify the criteria that patient 3 displayed. Participants were however able to accurately interpret the GCS of both patient 1 (GCS=14) (86%) and patient 4 (GCS=15) (92%). CONCLUSION: This pilot study demonstrates that undergraduate paramedic students from an Australian university were unable to accurately interpret a patient's conscious state if their GCS score was <14. These findings have provided academic staff with important information for considering alternative teaching and learning strategies and approaches in conscious state assessment in current paramedic curricula. PMID- 22505292 TI - Hybrid nanomaterials that mimic the food effect: controlling enzymatic digestion for enhanced oral drug absorption. PMID- 22505294 TI - Significant coincidence. PMID- 22505295 TI - Cost and clinical effectiveness of MRI in occult scaphoid fractures: a randomised controlled trial. AB - BACKGROUND: Clinical and radiographic diagnoses of scaphoid fractures are often challenging at the time of injury. Patients are therefore usually reassessed which has cost implications. Various investigations exist but MRI has been suggested as effective in diagnosing these injuries early. AIM: To determine whether early MRI in suspected occult scaphoid fractures is more clinically and cost effective than conventional management with immobilisation and reassessment. METHODS: All patients presenting to the Emergency Department at a district general hospital with a suspected occult scaphoid fracture were randomised into two groups, MRI (early scan of the wrist, discharged if no injury) and control (reassessment in clinic). RESULTS: 84 patients were randomised into MRI (45) and control (39) groups. There were no baseline differences apart from greater dominant hand injuries in the MRI group (62% (26) vs 36% (14), p=0.02). There were three (6.7%) scaphoid fractures in the MRI group and four (10.3%) in the control group (p=0.7). More fractures (15.6% (7) vs 5.1% (2), p=0.9) and other injuries were detected in the MRI group who had fewer mean clinic appointments (1.1 +/- 0.5 vs 2.3 +/- 0.8, p=0.001) and radiographs (1.2 +/- 0.8 vs 1.7 +/- 1.1, p=0.03). Mean management costs were L504.13 (MRI) and L532.87 (control) (p=0.9). The MRI group had better pain and satisfaction scores (not significant) with comparable time off work and sporting activities. CONCLUSION: Early MRI in occult scaphoid fractures is marginally cost saving compared with conventional management and may reduce potentially large societal costs of unnecessary immobilisation. It enables early detection and appropriate treatment of scaphoid and other injuries. PMID- 22505296 TI - Burnout among advanced life support paramedics in Johannesburg, South Africa. AB - OBJECTIVES: To establish the prevalence of burnout among advanced life support (ALS) paramedics in Johannesburg, South Africa and assess the relationship between burnout and a number of demographic characteristics of the sampled ALS paramedics. DESIGN: Cross-sectional internet-based survey. METHOD: Survey invitations were sent via email to 98 registered ALS paramedics in the Johannesburg area. The survey questionnaire was created by combining the Copenhagen Burnout Inventory (CBI) with numerous distractor questions. Burnout was defined as a CBI score >50. Descriptive analysis was performed and results subjected to Chi-square testing in order to establish dependencies between burnout scores and demographic factors. RESULTS: A 46% (n=45) response rate was obtained. Forty responses were eligible for analysis. 30% of these respondents had total burnout according to their CBI score, while 63% exhibited some degree of burnout in one of the CBI subcategories. The results of the subcategory analyses showed that 23% of respondents experienced burnout in the patient care related category, 38% experienced burnout in the work-related category and 53% experienced burnout in the personal burnout category. There were no statistical differences in the burnout scores according to gender (p=0.292), position held (p=0.193), employment sector (p=0.414), years of experience (p=0.228) or qualification (p=0.846). Distractor questions showed that paramedics feel overworked, undervalued, poorly remunerated and unsupported by their superiors. CONCLUSION: This sample of Johannesburg-based paramedics had a greater prevalence of burnout compared with their international counterparts. Further research is needed to identify the true extent of this problem. PMID- 22505297 TI - Are the public ready for organ donation after out of hospital cardiac arrest? AB - OBJECTIVE: To assess Emergency Department (ED) relatives' and patients' opinions on: (1) discussing organ donation (OD) with relatives soon after ED death after cardiac arrest and (2) acceptability of organ preservation procedures both before and after discussion with relatives. METHODS: Questionnaire study; convenience sample. RESULTS: 200 questionnaires were completed. 37.5% of participants were male subjects; mean age was 40.4 (SD 16.9; range 15-85) years. There was no difference in the number willing to discuss OD after brainstem death in intensive care unit compared with circulatory death in the ED (72% vs 72%; p=0.146). The majority were willing to discuss OD soon after ED death after cardiac arrest (106; 54%). 41 (21%) were not willing and 43 (22%) had no strong views (n=198). Organ preservation procedures (groin tube insertion, continuation of mechanical cardiopulmonary resuscitation and continuation of ventilator) were acceptable to between 48% and 57% of respondents if performed before discussion with family increasing to an acceptability of between 64% and 69% after discussion with family. One in four respondents felt these procedures were not acceptable regardless of the timing of discussion with family and some felt these procedures were more acceptable if the patient was a registered organ donor. 122 (61%) patients wished to donate their organs after death but only 59 (30%) were registered donors. CONCLUSIONS: (1) The majority of patients and their relatives are not averse to OD being discussed shortly after ED death. (2) Organ preservation procedures are acceptable to many. Prior discussion and prior organ donor registration may improve acceptability. PMID- 22505298 TI - Total knee dislocation: a falsely reassuring radiograph. PMID- 22505299 TI - Mathematical and drug calculation abilities of paramedic students. AB - AIM: The objective of this study was to determine if undergraduate paramedics could accurately perform common drug calculations and basic mathematical computations normally required in the workplace. METHOD: A descriptive paper based questionnaire collecting demographical data, student attitudes regarding their drug calculation performance, and answers to a series of basic mathematical and drug calculation questions was administered to undergraduate paramedic students. RESULTS: The mean score was 39.5% with only 3.3% of students (n=3) scoring greater than 90%, and 63% (n=58) scoring 50% or less. Conceptual errors made up 48.5%, arithmetical 31.1% and computational 17.4%. CONCLUSION: This study suggests undergraduate paramedics have deficiencies in performing accurate calculations with conceptual errors indicating a fundamental lack of mathematical understanding. PMID- 22505300 TI - Atrial fibrillation with ventricular pre-excitation. PMID- 22505301 TI - Sensitivity and specificity of CT scan and angiogram for ongoing internal bleeding following torso trauma. AB - BACKGROUND: Occult internal bleeding in the trauma patient which remains undiagnosed and unaddressed has the potential to result in morbidity or mortality. Advancements in CT and angiography have played an integral role in the management of this patient population. OBJECTIVE: The purpose of the study was to identify the sensitivity and specificity of CT scan and angiography in detecting ongoing internal bleeding. METHODS: Consecutive patients who sustained torso trauma and subsequently underwent CT scan and angiography were included in this study. Data reviewed included clinical information, CT scan and angiography readings. Extravasations of contrast from CT scan and/or angiogram were considered positive for ongoing internal bleeding. RESULTS: From January 2002 through July 2007, 113 adult trauma patients sustaining torso trauma underwent CT scan of chest or abdomen followed by angiography. Sixty-six patients were negative for extravasation from either of the tests. Twenty-four of 35 patients had both positive CT scans and angiograms. Eleven patients with positive CT scans did not have bleeding on angiogram. Similarly, 12 out of 36 patients with positive angiograms did not show any extravasation of contrast on CT scan. Both modalities had a specificity of 100% based on clinical definition. The sensitivities of CT scan and angiogram were 74.5% and 76.6%, respectively. They were not significantly different (p=0.95). The negative predictive values for CT and angiogram were 84.6% and 85.7%. They were not significantly different (p=0.95) either. When CT scan was used alone, 25.5% of bleeding patients were missed. CONCLUSIONS: The sensitivity of CT scan and angiography at detecting ongoing bleeding was around 75% across the torso injury spectrum. PMID- 22505302 TI - Efficacy of the Disposcope endoscope, a new video laryngoscope, for endotracheal intubation in patients with cervical spine immobilisation by semirigid neck collar: comparison with the Macintosh laryngoscope using a simulation study on a manikin. AB - OBJECTIVE: To evaluate whether endotracheal intubation in patients with cervical spine immobilisation by a semirigid neck collar is easier using the Disposcope endoscope (DE), a new video laryngoscope, than with the Macintosh laryngoscope (ML). METHODS: Sixty-eight medical interns who participated in a training programme for endotracheal intubation using the DE and ML were recruited to the randomised crossover trial 1 week after completing the training programme. In the trial, they used both the DE and the ML to perform intubation on a manikin wearing a semirigid neck collar. The time required to view the vocal cords and to complete intubation, successful endotracheal intubation, modified Cormack-Lehane classification (CL grade) and dental injury were recorded and analysed. RESULTS: The mean (SD) time to view the vocal cords was significantly shorter with the DE than with the ML (10.0 (7.0) vs 20.8 (18.9) s; p<0.0001). There were higher rates of CL grades 1 and 2a (69.1% and 22.1%) using the DE than with the ML (10.3% and 14.7%). All 68 participants had a higher rate of successful endotracheal intubation using the DE than using the ML (68 (100%) vs 47 (69.1%); p<0.0001). It took less time to complete endotracheal intubation with the DE than with the ML (p<0.0001). CONCLUSIONS: In patients with cervical spine immobilisation by a semirigid neck collar, the DE may be a more effective device for endotracheal intubation than the ML. PMID- 22505303 TI - Risk factors for 48-hours mortality after prehospital treatment of opioid overdose. AB - INTRODUCTION: Opioid overdose is commonly treated by prehospital emergency services and the majority of the patients are discharged immediately after treatment and a short observation period. There is a minor risk for rebound opioid toxicity and other life-threatening conditions might occur after such episodes. The authors describe the short-term outcome and identify risk factors for death within 48 h after prehospital treatment of opioid overdose in Copenhagen, the capital of Denmark. METHODS: Data on all cases of opioid overdose treated by the medical emergency care unit between 1994 and 2003 were recorded prospectively. Risk factors for death within 48 h after initial medical emergency care unit contact were analysed in a multivariable logistic regression analysis. RESULTS: The authors recorded 4762 episodes of opioid overdose, covering 1967 unique identified patients. A total of 78 patients (8.4%, 95% CI 7.0 to 10.4) died within 48 h in the period 1999-2003, and 85% (66/78) of these had cardiac arrest and died. The authors found age >50 years and overdose during the weekend significantly associated with 48-h mortality. Gender, former episodes of opioid overdose, time of the day, month or year were not significantly associated with increased mortality. CONCLUSIONS: The author found a 48-hours mortality of 8.4%. Advanced age and opioid overdose in the weekends were significant risk factors. Release on scene after treatment was associated with a very small risk. PMID- 22505304 TI - Improving documentation in prehospital rapid sequence intubation: investigating the use of a dedicated airway registry form. AB - OBJECTIVE: The quality of medical documentation is integral to audit, clinical governance, education, medico-legal aspects and continuity of patient care. This study aims to investigate the introduction of a dedicated 'Airway Registry Form' (ARF) on the quality of documentation in prehospital rapid sequence intubation. METHODS: A retrospective review and comparison of 96 cases predating the introduction of the ARF and 90 cases immediately following its introduction were performed. RESULTS: The introduction of the ARF yielded significant improvement in the recording of selected data points: difficult airway indicators (p<0.0001), Cormack-Lehane grade of laryngoscopy at first attempt (p<0.0001), documentation of confirmation of tracheal intubation with end-tidal carbon dioxide monitoring (p=0.015) and recording of intubator's details (p<0.0001). CONCLUSIONS: This study validates the use of a dedicated ARF for the improvement of documentation and data collection related to prehospital rapid sequence intubation when compared with post-event extraction of data from a generic case-record. PMID- 22505306 TI - Associations between deprivation and rates of childhood overweight and obesity in England, 2007-2010: an ecological study. AB - OBJECTIVES: To investigate the associations between deprivation and rates of childhood overweight and obesity in England, from 2007 to 2010. DESIGN: An ecological study using routine data from the National Child Measurement Programme and Indices of Multiple Deprivation (IMD) 2010 scores. SETTING: Local authority districts in England. PARTICIPANTS: Schoolchildren in Reception year (age 4-5 years) and Year 6 (age 10-11 years) attending non-specialist maintained state schools in England. PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalence of overweight in both Reception and Year 6, prevalence of obesity in both Reception and Year 6 and IMD 2010 scores for each local authority. RESULTS: In 2009-2010, local authority IMD 2010 scores were strongly correlated with obesity rates among schoolchildren in Reception (r=0.625, p<0.001) and Year 6 (r=0.733, p<0.001). There were no statistically significant changes in association between obesity in Reception or Year 6 and IMD from 2007-2008 to 2009-2010. In contrast, the prevalence of overweight was not statistically significantly correlated with local authority IMD scores in Reception (r=0.095, p=0.092) and only weakly correlated in Year 6 (r=0.184, p=0.001). There were no statistically significant changes in association between overweight in Reception or Year 6 and IMD from 2007-2008 to 2009-2010. CONCLUSIONS: Childhood obesity rates in England are strongly associated with deprivation. Given the enormous public health implications of overweight and obesity in the population, these findings suggest that significant effort is required to tackle unhealthy weight in children in all local authorities and that this should be a priority in areas with high levels of deprivation. PMID- 22505305 TI - Selective homonuclear polarization transfer for spectroscopic imaging of GABA at 7T. AB - We develop and implement a selective homonuclear polarization transfer method for the detection of 3.0 ppm C-4 GABA resonance by spectroscopic imaging in the human brain at 7T. This single shot method is demonstrated with simulations and phantoms, which achieves comparable efficiency of detection to that of J difference editing. The macromolecule resonance that commonly co-edits with GABA is suppressed at 7T through use of a narrow band preacquisition suppression pulse. This technique is implemented in humans with an eight channel transceiver array and high degree B(0) shimming to measure supplementary motor area and thalamic GABA in controls (n = 8) and epilepsy patients (n = 8 total). We find that the GABA/N-acetyl aspartate ratio in the thalamus of control volunteers, well controlled and poorly controlled epilepsy patients are 0.053 +/- 0.012 (n = 8), 0.090 +/- 0.012 (n = 2), and 0.038 +/- 0.009 (n = 6), respectively. PMID- 22505307 TI - A quasi-experimental evaluation of an HIV prevention programme by peer education in the Anglican Church of the Western Cape, South Africa. AB - INTRODUCTION: Religion is important in most African communities, but faith-based HIV prevention programmes are infrequent and very rarely evaluated. OBJECTIVE: The aim of this study was to evaluate the effectiveness of a church-based peer education HIV prevention programme that focused on youth. DESIGN: A quasi experimental study design compared non-randomly chosen intervention and control groups. SETTING: This study was conducted in the Cape Town Diocese of the Anglican Church of Southern Africa. PARTICIPANTS: The intervention group of 176 teenagers was selected from youth groups at 14 churches and the control group of 92 from youth groups at 17 churches. Intervention and control churches were chosen to be as similar as possible to decrease confounding. INTERVENTION: The intervention was a 20-session peer education programme (Fikelela: Agents of Change) aimed at changing risky sexual behaviour among youth (aged 12-19 years). Three workshops were also held with parents. PRIMARY AND SECONDARY OUTCOME MEASURES: The main outcome measures were changes in age of sexual debut, secondary abstinence, condom use and numbers of partners. RESULTS: The programme was successful at increasing condom usage (condom use score 3.5 vs 2.1; p=0.02), OR 6.7 (95% CI 1.1 to 40.7), and postponing sexual debut (11.9% vs 21.4%; p=0.04) absolute difference 9.5%. There was no difference in secondary abstinence (14.6% vs 12.5%; p=0.25) or with the number of partners (mean 1.7 vs 1.4; p=0.67) and OR 2.2 (95% CI 0.7 to 7.4). CONCLUSION: An initial exploratory quasi-experimental evaluation of the Agents of Change peer education programme in a church-based context found that the age of sexual debut and condom usage was significantly increased. The study demonstrated the potential of faith-based peer education among youth to make a contribution to HIV prevention in Africa. Further evaluation of the effectiveness of the programme is, however, required before widespread implementation can be recommended. PMID- 22505308 TI - Are neighbourhood food resources distributed inequitably by income and race in the USA? Epidemiological findings across the urban spectrum. AB - OBJECTIVE: Many recent policies focus on socioeconomic inequities in availability of healthy food stores and restaurants. Yet understanding of how socioeconomic inequities vary across neighbourhood racial composition and across the range from rural to urban settings is limited, largely due to lack of large, geographically and socio-demographically diverse study populations. Using a national sample, the authors examined differences in neighbourhood food resource availability according to neighbourhood-level poverty and racial/ethnic population in non urban, low-density urban and high-density urban areas. DESIGN: Cross-sectional data from an observational cohort study representative of the US middle and high school-aged population in 1994 followed into young adulthood. PARTICIPANTS: Using neighbourhood characteristics of participants in the National Longitudinal Study of Adolescent Health (Wave III, 2001-2002; n=13 995 young adults aged 18-28 years representing 7588 US block groups), the authors examined associations between neighbourhood poverty and race/ethnicity with neighbourhood food resource availability in urbanicity-stratified multivariable linear regression. PRIMARY AND SECONDARY OUTCOME MEASURES: Neighbourhood availability of grocery/supermarkets, convenience stores and fast-food restaurants (measured as number of outlets per 100 km roadway). RESULTS: Neighbourhood race and income disparities were most pronounced in low-density urban areas, where high poverty/high-minority areas had lower availability of grocery/supermarkets (beta coefficient (beta)=-1.91, 95% CI -2.73 to -1.09) and convenience stores (beta= 2.38, 95% CI -3.62 to -1.14) and greater availability of fast-food restaurants (beta=4.87, 95% CI 2.26 to 7.48) than low-poverty/low-minority areas. However, in high-density urban areas, high-poverty/low-minority neighbourhoods had comparatively greater availability of grocery/supermarkets (beta=8.05, 95% CI 2.52 to 13.57), convenience stores (beta=2.89, 95% CI 0.64 to 5.14) and fast-food restaurants (beta=4.03, 95% CI 1.97 to 6.09), relative to low-poverty/low minority areas. CONCLUSIONS: In addition to targeting disproportionate fast-food availability in disadvantaged dense urban areas, our findings suggest that policies should also target disparities in grocery/supermarket and fast-food restaurant availability in low-density areas. PMID- 22505309 TI - Structural determinants of food insufficiency, low dietary diversity and BMI: a cross-sectional study of HIV-infected and HIV-negative Rwandan women. AB - OBJECTIVES: In Sub-Saharan Africa, the overlapping epidemics of undernutrition and HIV infection affect over 200 and 23 million people, respectively, and little is known about the combined prevalence and nutritional effects. The authors sought to determine which structural factors are associated with food insufficiency, low dietary diversity and low body mass index (BMI) in HIV negative and HIV-infected Sub-Saharan women. STUDY DESIGN: Cross-sectional analysis of a longitudinal cohort. SETTING: Community-based women's organisations. PARTICIPANTS: 161 HIV-negative and 514 HIV-infected Rwandan women. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes included food insufficiency (reporting 'usually not' or 'never' to 'Do you have enough food?'), low household dietary diversity (Household Dietary Diversity Score <=3) and BMI <18.5 (kg/m(2)). The authors also measured structural and behavioural factors including: income, household size, literacy and alcohol use. RESULTS: Food insufficiency was prevalent (46%) as was low dietary diversity (43%) and low BMI (15%). Food insufficiency and dietary diversity were associated with low income (adjusted odds ratio (aOR)=2.14 (95% CI 1.30 to 3.52) p<0.01), (aOR=6.51 (95% CI 3.66 to 11.57) p<0.001), respectfully and illiteracy (aOR=2.00 (95% CI 1.31 to 3.04) p<0.01), (aOR=2.10 (95% CI 1.37 to 3.23) p<0.001), respectfully and were not associated with HIV infection. Alcohol use was strongly associated with food insufficiency (aOR=3.23 (95% CI 1.99 to 5.24) p<0.001). Low BMI was inversely associated with HIV infection (aOR~0.5) and was not correlated with food insufficiency or dietary diversity. CONCLUSIONS: Rwandan women experienced high rates of food insufficiency and low dietary diversity. Extreme poverty, illiteracy and alcohol use, not HIV infection alone, may contribute to food insufficiency in Rwandan women. Food insufficiency, dietary diversity and low BMI do not correlate with one another; therefore, low BMI may not be an adequate screening tool for food insufficiency. Further studies are needed to understand the health effects of not having enough food, low food diversity and low weight in both HIV-negative and HIV-infected women. PMID- 22505310 TI - A retrospective cohort study assessing patient characteristics and the incidence of cardiovascular disease using linked routine primary and secondary care data. AB - OBJECTIVES: Data linkage combines information from several clinical data sets. The authors examined whether coding inconsistencies for cardiovascular disease between components of linked data sets result in differences in apparent population characteristics. DESIGN: Retrospective cohort study. SETTING: Routine primary care data from 40 Scottish general practitioner (GP) surgeries linked to national hospital records. PARTICIPANTS: 240 846 patients, aged 20 years or older, registered at a GP surgery. OUTCOMES: Cases of myocardial infarction, ischaemic heart disease and stroke (cerebrovascular disease) were identified from GP and hospital records. Patient characteristics and incidence rates were assessed for all three clinical outcomes, based on GP, hospital, paired GP/hospital (similar diagnoses recorded simultaneously in both data sets) or pooled GP/hospital records (diagnosis recorded in either or both data sets). RESULTS: For all three outcomes, the authors found evidence (p<0.05) of different characteristics when using different methods of case identification. Prescribing of cardiovascular medicines for ischaemic heart disease was greatest for cases identified using paired records (p<=0.013). For all conditions, 30-day case fatality rates were higher for cases identified using hospital compared with GP or paired data, most noticeably for myocardial infarction (hospital 20%, GP 4%, p=0.001). Incidence rates were highest using pooled GP/hospital data and lowest using paired data. CONCLUSIONS: Differences exist in patient characteristics and disease incidence for cardiovascular conditions, depending on the data source. This has implications for studies using routine clinical data. PMID- 22505311 TI - Effects of the Great East Japan Earthquake and huge tsunami on glycaemic control and blood pressure in patients with diabetes mellitus. AB - OBJECTIVE: To examine the effects of a huge tsunami resulting from the Great East Japan Earthquake on blood pressure (BP) control and glycaemic control in diabetic patients. DESIGN: A retrospective study. SETTING: Tohoku University, Japan. PARTICIPANTS: 63 patients were visiting Rikuzentakata Hospital for diabetic treatment before the earthquake and returned to the clinic in July after the earthquake, and they were analysed in the present study. The subjects were divided into two groups: those who were hit by the tsunami, the Tsunami (+) group (n=28), and those who were not, the Tsunami (-) group (n=35), and the groups' parameters and their changes were compared. PRIMARY OUTCOME MEASURE: Changes of HbA1c. SECONDARY OUTCOME MEASURES: Changes of BP, body mass index. RESULTS: HbA1c and both BP increased, while the numbers of most drugs taken decreased in both groups. Parameter changes were significantly greater in the Tsunami (+) group. All medical data stored at the hospital was lost in the tsunami. The Tsunami (+) patients also had their own records of treatment washed away, so it was difficult to replicate their pre-earthquake drug prescriptions afterwards. In comparison, the Tsunami (-) patients kept their treatment information, making it possible to resume the treatment they had been receiving before the earthquake. The BP rose only slightly in men, whereas it rose sharply in women, even though they had not been directly affected by the tsunami. BP rose markedly in both genders affected by the tsunami. CONCLUSIONS: All medical information was lost in the tsunami, and glycaemic and BP controls of the tsunami-affected patients worsened more than those of patients who had been affected by the earthquake alone. Women may be more sensitive to changes in the living environment that result from a major earthquake than are men. PMID- 22505312 TI - Unsatisfactory rates vary between cervical cytology samples prepared using ThinPrep and SurePath platforms: a review and meta-analysis. AB - OBJECTIVE: To compare unsatisfactory rates between the two major liquid-based cytology (LBC) platforms, namely ThinPrep (Hologic) and SurePath (Becton Dickinson). DESIGN: The authors performed both a systematic review and a meta analysis. Inclusion criteria were English language, data presented on unsatisfactory rates for either ThinPrep or SurePath, utilising actual patient samples (ie, not laboratory manipulated samples) and no manipulation using acetic acid to increase the satisfactory rate. The authors searched PubMed for articles using the keywords 'SurePath' or 'ThinPrep' and 'unsatisfactory'. References of retrieved studies were searched for additional articles. Key researchers in the field were also contacted. PARTICIPANTS AND INTERVENTIONS: Eligible studies were reviewed for rates of unsatisfactory cervical cytology smears processed on either the ThinPrep or SurePath platforms (compared with a general linear model) or data on unsatisfactory rates for both platforms for the same laboratory and the same patient population (compared with a meta-analysis using a random effects model and pooled RR). PRIMARY OUTCOME MEASURE: Unsatisfactory rate of cervical cytology smears. RESULTS: A total of 1 120 418 cervical cytology smears were reported in 14 different studies using the SurePath platform for an overall unsatisfactory rate (weighted average) of 0.3%. 28 studies reported on 1 148 755 smears prepared using the ThinPrep platform for an overall unsatisfactory rate (weighted average) of 1.3%. The general linear model did not show a difference between LBC platforms when other variables were controlled for; however, the power to detect a difference (0.087) was very low. The meta-analysis performed on four studies where both ThinPrep and SurePath results were reported from the same laboratory showed fewer unsatisfactory tests from the SurePath platform (RR 0.44, 95% CI 0.25 to 0.77, p=0.004). CONCLUSIONS: Multiple factors affect LBC unsatisfactory rates. In a meta-analysis, cervical cytology samples prepared on the SurePath platform show significantly fewer unsatisfactory smears than those prepared on the ThinPrep platform. PMID- 22505314 TI - Self-efficacy and pain catastrophizing in systemic lupus erythematosus: relationship to pain, stiffness, fatigue, and psychological distress. AB - OBJECTIVE: To determine how self-efficacy for pain control and pain catastrophizing, both potentially modifiable pain coping cognitions, are related to pain, stiffness, fatigue, and psychological distress in patients with systemic lupus erythematosus (SLE). METHODS: We conducted a cross-sectional study of patients with SLE who completed measures of pain coping cognitions (i.e., self efficacy for pain control, pain catastrophizing), symptom ratings (i.e., pain, stiffness, fatigue), and psychological distress. RESULTS: Correlational analyses revealed that self-efficacy for pain control and pain catastrophizing were associated with the patients' physical symptom reports and psychological distress. After controlling for age, race, and disease activity, patients with lower levels of self-efficacy for pain control reported much higher levels of pain, stiffness, and fatigue. Patients with higher levels of pain catastrophizing reported much lower positive mood. SLE activity as assessed by the rheumatologist was not associated with physical symptoms, psychological distress, self-efficacy for pain control, or pain catastrophizing. CONCLUSION: These results suggest that pain coping cognitions (i.e., either self-efficacy for pain control or pain catastrophizing) are significantly related to physical symptoms and psychological distress in patients with SLE. This finding is important because the results of studies from other samples of patients with persistent pain conditions have shown that these pain coping variables can be modified using psychological interventions, and that such treatment-related changes in pain cognitions are related to improved patient outcomes. PMID- 22505313 TI - Observational cohort study of the safety of digoxin use in women with heart failure. AB - OBJECTIVES: This study aims to assess whether digoxin has a different effect on mortality risk for women than it does for men in patients with heart failure (HF). DESIGN: This study uses the UK-based The Health Information Network population database in a cohort study of the impact of digoxin exposure on mortality for men and women who carry the diagnosis of HF. Digoxin exposure was assessed based on prescribing data. Multivariable Cox proportional hazards models were used to assess whether there was an interaction between sex and digoxin affecting mortality hazard. SETTING: The setting was primary care outpatient practices. PARTICIPANTS: The study cohort consisted of 17 707 men and 19 227 women with the diagnosis of HF who contributed only time without digoxin exposure and 9487 men and 10 808 women with the diagnosis of HF who contributed time with digoxin exposure. MAIN OUTCOME MEASURES: The main outcome measure was all-cause mortality. RESULTS: The primary outcome of this study was the absence of a large interaction between digoxin use and sex affecting mortality. For men, digoxin use was associated with a HR for mortality of 1.00, while for women, the HR was also 1.00 (p value for interaction 0.65). The results of sensitivity analyses were consistent with those of the primary analysis. CONCLUSION: Observational data do not support the concern that there is a substantial increased risk of mortality due to the use of digoxin in women. This finding is consistent with previous observational studies but discordant with results from a post hoc analysis of a randomised controlled trial of digoxin versus placebo. PMID- 22505315 TI - Does lenticulostriate vasculopathy predipose to ischemic brain infarct? A case report. AB - Lenticulostriate vasculopathy (LSV) is a sonographic finding in infancy with obscure etiology and variable diagnostic and prognostic significance. Ischemic infarct in the territory of the lenticulostriate vessels after mild head trauma is a rare pathology. There are no publications on LSV followed by ischemic infarct. We present the case of an 8-month-old boy who suffered mild head trauma and developed an ischemic brain infarct in the territory of preexisting LSV. It is speculated that LSV might be a predisposing factor for ischemic brain infarct after mild head trauma in infants. PMID- 22505316 TI - Effects of cadmium and arsenic on Pteris vittata under hydroponic conditions. AB - Pteris vittata is known to hyperaccumulate arsenic, and a large number of studies on this fern species can be found in the literature aimed at evaluating its behavior when coexposed to other toxic elements. In the present study, P. vittata was treated with different concentrations of As and/or Cd in a hydroponic system, that is, under complete bioavailability of the elements, with the objective of investigating the effects of these two elements and their interactions. The response of the plant was evaluated by measuring As, Cd, P, and Ca concentrations in different parts of the plant. Moreover, the symptoms of phytotoxicity were assessed in terms of biomass reduction and loss of photosynthetic efficiency related to necrosis of pinnae. The concentrations of As and Cd measured in the fronds and the root system were significantly dependent on the treatment, whereas P and Ca concentrations were not affected. Interaction effects between As and Cd were observed, with maximum toxicity symptoms after treatment with both elements. This could affect the potential use of this fern for phytoremediation. Although As treatment produced a significant effect on leaves (e.g., chlorosis and necrosis), Cd treatment produced a stronger negative impact on plant health, reducing significantly the biomass and photosynthetic efficiency. PMID- 22505317 TI - Subset of Suz12/PRC2 target genes is activated during hepatitis B virus replication and liver carcinogenesis associated with HBV X protein. AB - Chronic hepatitis B virus (HBV) infection is a major risk factor for developing liver cancer, and the HBV X protein (pX) has been implicated as a cofactor in hepatocyte transformation. We have shown that HBV replication as well as in vitro transformation by pX are associated with induction of the mitotic polo-like kinase 1 (Plk1) and down-regulation of the chromatin remodeling components Suz12 and Znf198. Herein, we demonstrate the same inverse relationship between Plk1 and Suz12/Znf198 in liver tumors from X/c-myc bitransgenic mice and woodchuck hepatitis virus (WHV)-infected woodchucks. Employing these animal models and the HBV replicating HepAD38 cells we examined the effect of Suz12/Znf198 down regulation on gene expression. Genes analyzed include hepatic cancer stem cell markers BAMBI, DKK1,2, DLK1, EpCAM, MYC, and proliferation genes CCNA1, CCND2, IGFII, MCM4-6, PLK1, RPA2, and TYMS. Suz12 occupancy at the promoters of BAMBI, CCND2, DKK2, DLK1, EpCAM, and IGFII was demonstrated by chromatin immunoprecipitation in untransformed hepatocytes, but was markedly reduced in pX transformed and Suz12 knockdown cells. Accordingly, we refer to these genes as "Suz12 repressed" genes in untransformed hepatocytes. The Suz12 repressed genes and proliferation genes were induced in HBV-replicating HepAD38 cells and, interestingly, they exhibited distinct expression profiles during hepatocellular carcinoma (HCC) progression in X/c-myc bitransgenics. Specifically, CCND2, EpCAM, and IGFII expression was elevated at the proliferative and preneoplastic stages in X/c-myc bitransgenic livers, whereas BAMBI and PLK1 were overexpressed in hepatic tumors from X/c-myc bitransgenics and WHV-infected woodchucks. Importantly, most of these genes were selectively up-regulated in HBV-induced HCCs. CONCLUSION: The distinct expression profile of the identified Suz12 repressed genes in combination with the proliferation genes hold promise as biomarkers for progression of chronic HBV infection to HCC. PMID- 22505319 TI - In vivo study of the surgical anatomy of the axilla. AB - BACKGROUND: Classical anatomical descriptions fail to describe variants often observed in the axilla as they are based on studies that looked at individual structures in isolation or textbooks of cadaveric dissections. The presence of variant anatomy heightens the risk of iatrogenic injury. The aim of this study was to document the nature and frequency of these anatomical variations based on in vivo peroperative surgical observations. METHODS: Detailed anatomical relationships were documented prospectively during consecutive axillary dissections. Relationships between the thoracodorsal pedicle, course of the lateral thoracic vein, presence of latissimus dorsi muscle slips, variations in axillary and angular vein anatomy, and origins and branching of the intercostobrachial nerve were recorded. RESULTS: Among a total of 73 axillary dissections, 43 (59 per cent) revealed at least one anatomical variant. Most notable variants included aberrant courses of the thoracodorsal nerve in ten patients (14 per cent)--three variants; lateral thoracic vein in 12 patients (16 per cent)--four variants; bifid axillary veins in ten patients (14 per cent); latissimus dorsi muscle slips in four patients (5 per cent); and variants in intercostobrachial nerve origins and branching in 26 patients (36 per cent). The angular vein, a subscapular vein tributary, was found to be a constant axillary structure. CONCLUSION: Variations in axillary anatomical structures are common. Poor understanding of these variants can affect the adequacy of oncological clearance, lead to vascular injury, compromise planned microvascular procedures and result in chronic pain or numbness from nerve injury. Surgeons should be aware of the common anatomical variants to facilitate efficient and safe axillary surgery. PMID- 22505318 TI - Mutagenesis of the bovSERPINA3-3 demonstrates the requirement of aspartate-371 for intermolecular interaction and formation of dimers. AB - The family of serpins is known to fold into a metastable state that is required for the proteinase inhibition mechanism. One of the consequences of this conformational flexibility is the tendency of some mutated serpins to form polymers, which occur through the insertion of the reactive center loop of one serpin molecule into the A-sheet of another. This "A-sheet polymerization" has remained an attractive explanation for the molecular mechanism of serpinopathies. Polymerization of serpins can also take place in vitro under certain conditions (e.g., pH or temperature). Surprisingly, on sodium dodecyl sulfate/polyacrylamide gel electrophoresis, bovSERPINA3-3 extracted from skeletal muscle or expressed in Escherichia coli was mainly observed as a homodimer. Here, in this report, by site-directed mutagenesis of recombinant bovSERPINA3-3, with substitution D371A, we demonstrate the importance of D371 for the intermolecular linkage observed in denaturing and reducing conditions. This residue influences the electrophoretic and conformational properties of bovSERPINA3-3. By structural modeling of mature bovSERPINA3-3, we propose a new "non-A-sheet swap" model of serpin homodimer in which D371 is involved at the molecular interface. PMID- 22505320 TI - Expanding molecular modeling and design tools to non-natural sidechains. AB - Protein-protein interactions encode the wiring diagram of cellular signaling pathways and their deregulations underlie a variety of diseases, such as cancer. Inhibiting protein-protein interactions with peptide derivatives is a promising way to develop new biological and therapeutic tools. Here, we develop a general framework to computationally handle hundreds of non-natural amino acid sidechains and predict the effect of inserting them into peptides or proteins. We first generate all structural files (pdb and mol2), as well as parameters and topologies for standard molecular mechanics software (CHARMM and Gromacs). Accurate predictions of rotamer probabilities are provided using a novel combined knowledge and physics based strategy. Non-natural sidechains are useful to increase peptide ligand binding affinity. Our results obtained on non-natural mutants of a BCL9 peptide targeting beta-catenin show very good correlation between predicted and experimental binding free-energies, indicating that such predictions can be used to design new inhibitors. Data generated in this work, as well as PyMOL and UCSF Chimera plug-ins for user-friendly visualization of non natural sidechains, are all available at http://www.swisssidechain.ch. Our results enable researchers to rapidly and efficiently work with hundreds of non natural sidechains. PMID- 22505321 TI - The 5-HTTLPR polymorphism is associated with altered hemodynamic responses during appetitive conditioning. AB - BACKGROUND: Current models suggest that a variation in the promoter region of the serotonin transporter gene (5-HTTLPR) is associated with altered amygdala reactivity not only towards negative but also towards positive stimuli, which has been neglected in the past. This association may possibly convey an elevated vulnerability for psychopathology like abuse, craving, and relapses. Since appetitive conditioning is a crucial mechanism in the pathogenesis of these psychiatric disorders, the identification of specific factors contributing to interindividual variation is important. METHODS: In the present study (N = 86), an appetitive conditioning paradigm was conducted, in which a neutral stimulus (CS+) was associated with appetitive stimuli, while a second stimulus (CS-) predicted their absence. Subjects were genotyped according to the 5-HTTLPR genotype. RESULTS: As the main result, we report a significant association between the 5-HTTLPR genotype and hemodynamic responses. Individuals with the s allele displayed elevated conditioned bilateral amygdala activity in contrast to l/l-allele carriers. Further, increased hemodynamic responses in s-allele carriers were also found in the extended emotional network including the orbitofrontal cortex, the thalamus, and the ventral striatum. CONCLUSION: The present findings indicate an association of the 5-HTTLPR and altered conditioned responses in appetitive conditioning. Further, the findings contribute to the ongoing debate on 5-HTTLPR dependent hemodynamic response patterns by emphasizing that s-allele carriers are not exclusively biased towards fearful, but also towards positive stimuli. In conclusion, our results imply that s-allele carriers might be better described as hyper-reactive towards salient stimuli, which may convey vulnerability for the development of psychiatric disorders. PMID- 22505323 TI - Catalytic efficiency of a photoenzyme--an adaptation to natural light conditions. PMID- 22505322 TI - Development of consensus treatment plans for juvenile localized scleroderma: a roadmap toward comparative effectiveness studies in juvenile localized scleroderma. AB - OBJECTIVE: Juvenile localized scleroderma (LS) is a chronic inflammatory skin disorder associated with substantial morbidity and disability. Although a wide range of therapeutic strategies has been reported in the literature, a lack of agreement on treatment specifics and accepted methods for clinical assessment has made it difficult to compare approaches and identify optimal therapy. Our objective was to develop standardized treatment plans, clinical assessments, and response criteria for active, moderate to high severity juvenile LS. METHODS: A core group of pediatric rheumatologists, dermatologists, and a lay advisor was engaged by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) to develop standardized treatment plans and assessment parameters for juvenile LS using consensus methods/nominal group techniques. Recommendations were validated in 2 face-to-face conferences with a larger group of practitioners with expertise in juvenile LS and with the full membership of CARRA, which encompasses the majority of pediatric rheumatologists in the US and Canada. RESULTS: Consensus was achieved on standardized treatment plans that reflect the prevailing treatment practices of CARRA members. Standardized clinical assessment methods and provisional treatment response criteria were also developed. Greater than 90% of pediatric rheumatologists responding to a survey (66% of CARRA membership) affirmed the final recommendations and agreed to utilize these consensus plans to treat patients with juvenile LS. CONCLUSION: Using consensus methodology, we have developed standardized treatment plans and assessment methods for juvenile LS. The high level of support among pediatric rheumatologists will support future comparative effectiveness studies and enable the development of evidence-based guidelines for the treatment of juvenile LS. PMID- 22505324 TI - Recognition of sialylated poly-N-acetyllactosamine chains on N- and O-linked glycans by human and avian influenza A virus hemagglutinins. AB - Human influenza viruses are proposed to recognize sialic acids (pink diamonds) on glycans extended with poly-LacNAc chains (LacNAc=(yellow circle+blue square)). N- and O-linked glycans were extended with different poly-LacNAc chains with alpha2 3- and alpha2-6-linked sialic acids recognized by human and avian influenza viruses, respectively. The specificity of recombinant hemagglutinins (receptors in green) was investigated by using glycan microarray technology. PMID- 22505326 TI - Interactions between cigarette smoking and XPC-PAT genetic polymorphism enhance bladder cancer risk. AB - Inherited polymorphisms in the XPC gene that lead to a reduction in DNA repair capacity may increase susceptibility to bladder cancer. We investigated three polymorphisms of the XPC gene (PAT, Ala499Val and Lys939Gln) in 600 subjects with bladder cancer and in 609 healthy controls by a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay in a Chinese Han population. Smoking was associated with a significant increase in the risk for bladder cancer (OR, 2.48; 95% CI, 1.91-3.21). The risk was greater among heavy smokers (OR, 3.09, 95% CI, 2.24-4.25) compared to light smokers (OR, 1.91, 95% CI, 1.37-2.68). In three polymorphisms of XPC, only the XPC-PAT variant genotype exhibited a significantly increased risk for bladder cancer. When the total smoking exposure-gene interaction was examined, the three polymorphisms did not exhibit any significant effect in never smokers but a significant dose-response association in light or heavy smokers. Especially, the bladder cancer risk was significantly elevated among the polymorphisms of XPC-PAT(+/-) (OR, 2.56, 95% CI, 1.56-4.21, p<0.001; OR, 3.41, 95% CI, 2.19-5.29, p<0.001) and XPC-PAT(+/+) (OR, 3. 00, 95% CI, 1.31-6.88, p=0.009; OR, 6. 78, 95% CI, 3.00-15.54, p<0.001) with either light or heavy smoking exposure, respectively. XPC-PAT polymorphisms contribute to the risk for developing bladder cancer and an elevated risk of bladder cancer was significantly associated with the gene-environment (smoking) interaction in a Chinese Han population. PMID- 22505325 TI - A new method for detecting exchanging amide protons using chemical exchange rotation transfer. AB - In this study, we introduce a new method for amide proton transfer imaging based on chemical exchange rotation transfer. It avoids several artifacts that plague conventional chemical exchange saturation transfer approaches by creating label and reference scans based on varying the irradiation pulse rotation angle (pi and 2pi radians) instead of the frequency offset (3.5 and -3.5 ppm). Specifically, conventional analysis is sensitive to confounding contributions from magnetic field (B(0)) inhomogeneities and, more problematically, inherently asymmetric macromolecular resonances. In addition, the lipid resonance at -3.5 ppm complicates the interpretation of the reference scan and decreases the resulting contrast. Finally, partial overlap of the amide signal by nearby amines and hydroxyls obscure the results. By avoiding these issues, our new method is a promising approach for imaging endogenous protein and peptide content and mapping pH. PMID- 22505327 TI - The effect of conjugated spacer on novel carbazole derivatives for dye-sensitized solar cells: density functional theory/time-dependent density functional theory study. AB - The ground-state structure and frontier molecular orbital of D-pi-A organic dyes, CFT1A, CFT2A, and CFT1PA were theoretically investigated using density functional theory (DFT) on B3LYP functional with 6-31G(d,p) basis set. The vertical excitation energies and absorption spectra were obtained using time-dependent DFT (TD-DFT). The adsorptions of these dyes on TiO(2) anatase (101) were carried out by using a 38[TiO(2)] cluster model using Perdew-Burke-Ernzerhof functional with the double numerical basis set with polarization (DNP). The results showed that the introduction of thiophene-thiophene unit (T-T) as conjugated spacer in CFT2A could affect the performance of intramolecular charge transfer significantly due to the inter-ring torsion of T-T being decreased compared with phenylene phenylene (P-P) spacer of CFP2A in the researhcers' previous report. It was also found that increasing the number of pi-conjugated unit gradually enhanced charge separation between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of these dyes, leading to a high-efficiency photocurrent generation. The HOMO-LUMO energy gaps were calculated to be 2.51, 2.37, and 2.50 eV for CFT1A, CFT2A, and CFT1PA respectively. Moreover, the calculated adsorption energies of these dyes on TiO(2) cluster were ~14 kcal/mol, implying that these dyes strongly bind to TiO(2) surface. Furthermore, the electronic HOMO and LUMO shapes of all dye-TiO(2) complexes exhibited injection mechanism of electron via intermolecular charge-transfer transition. PMID- 22505328 TI - Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice. AB - Oxidative stress is a strong contributor to the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen species. In this study, we investigated the effects of hydrogen-rich water and the drug pioglitazone on the progression of NASH in mouse models. A methionine-choline-deficient (MCD) diet mouse model was prepared. Mice were divided into three experimental groups and fed for 8 weeks as follows: (1) MCD diet + control water (CW group); (2) MCD diet + hydrogen-rich water (HW group); and (3) MCD diet mixed with pioglitazone (PGZ group). Plasma alanine aminotransferase levels, hepatic expression of tumor necrosis factor-alpha, interleukin-6, fatty acid synthesis-related genes, oxidative stress biomarker 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis marker terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells in the liver were decreased in the HW and PGZ groups. The HW group showed a smaller decrease in hepatic cholesterol; however, stronger antioxidative effects in serum and lower peroxisome proliferator activated receptor-alpha expression in the liver were seen in comparison with the PGZ group. We then investigated the effects of hydrogen in the prevention of hepatocarcinogenesis in STAM mice, known as the NASH-related hepatocarcinogenesis model. Eight-week-old male STAM mice were divided into three experimental groups as follows: (1) control water (CW-STAM); (2) hydrogen-rich water (HW-STAM); and (3) pioglitazone (PGZ-STAM). After 8 weeks, hepatic tumors were evaluated. The number of tumors was significantly lower in the HW-STAM and PGZ-STAM groups than in the CW-STAM group. The maximum tumor size was smaller in the HW-STAM group than in the other groups. CONCLUSION: Consumption of hydrogen-rich water may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis. PMID- 22505329 TI - Toxic concentrations in fish early life stages peak at a critical moment. AB - During the development of an embryo into a juvenile, the physiology and behavior of a fish change greatly, affecting exposure to and uptake of environmental pollutants. Based on experimental data with sole (Solea solea), an existing bioaccumulation model was adapted and validated to calculate the development of concentrations of persistent organic pollutants in the tissue of developing fish. Simulation revealed that toxic tissue concentrations of pollutants with log octanol-water partition ratio (K(OW)) > 5 peak at the moment when the larvae become free-feeding, when the lipid reserves are depleted. This may explain the delayed effects observed in fish early-life-stage experiments with exposed eggs. In the field, eggs can be exposed through maternal transfer to adult pollutant tissue concentrations, which will increase in the larva to peak tissue concentrations, exceeding those of the adult fish. The results demonstrate the risk of underestimating the effects of lipophilic persistent organic pollutants with log K(OW) > 5 in short-term, early-life-stage fish tests and underscore the importance of maternal transfer as an exposure route in the field situation. PMID- 22505330 TI - Atypical brain activation patterns during a face-to-face joint attention game in adults with autism spectrum disorder. AB - Joint attention behaviors include initiating one's own and responding to another's bid for joint attention to an object, person, or topic. Joint attention abilities in autism are pervasively atypical, correlate with development of language and social abilities, and discriminate children with autism from other developmental disorders. Despite the importance of these behaviors, the neural correlates of joint attention in individuals with autism remain unclear. This paucity of data is likely due to the inherent challenge of acquiring data during a real-time social interaction. We used a novel experimental set-up in which participants engaged with an experimenter in an interactive face-to-face joint attention game during fMRI data acquisition. Both initiating and responding to joint attention behaviors were examined as well as a solo attention (SA) control condition. Participants included adults with autism spectrum disorder (ASD) (n = 13), a mean age- and sex-matched neurotypical group (n = 14), and a separate group of neurotypical adults (n = 22). Significant differences were found between groups within social-cognitive brain regions, including dorsal medial prefrontal cortex (dMPFC) and right posterior superior temporal sulcus (pSTS), during the RJA as compared to SA conditions. Region-of-interest analyses revealed a lack of signal differentiation between joint attention and control conditions within left pSTS and dMPFC in individuals with ASD. Within the pSTS, this lack of differentiation was characterized by reduced activation during joint attention and relative hyper-activation during SA. These findings suggest a possible failure of developmental neural specialization within the STS and dMPFC to joint attention in ASD. PMID- 22505331 TI - Do patients with non-radiographic axial spondylarthritis differ from patients with ankylosing spondylitis? AB - OBJECTIVE: Patients with axial spondylarthritis (SpA) who have structural changes in the sacroiliac joints and/or the spine have been classified as having ankylosing spondylitis (AS), while those without such changes are now classified as having nonradiographic axial SpA (nr-axSpA). The differentiating features are incompletely understood. METHODS: Data from 100 consecutive patients with axial SpA not treated with tumor necrosis factor antagonists were compared clinically and with laboratory parameters, spinal radiographs, and magnetic resonance imaging (MRI) of the spine. Standardized clinical assessment tools were used to assess health status. RESULTS: AS was diagnosed in 56 patients and nr-axSpA in 44 patients. Signs of inflammation were significantly higher in patients with AS than in patients with nr-axSpA, with a median C-reactive protein level of 8.0 versus 3.8 mg/liter, a median Ankylosing Spondylitis Disease Activity Score of 2.2 versus 2.8, respectively, and a median amount of spinal inflammatory lesions on MRI of 2.0 versus 0.0, respectively. Significant differences between these 2 groups were seen in sex (76.8% male AS patients versus 31.8% male nr-axSpA patients). Clinical variables did not differ between patients with AS and nr axSpA (Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Ankylosing Spondylitis Quality of Life questionnaire, Short Form 36 health survey). CONCLUSION: Patients with nr-axSpA were characterized by the low proportion of male patients and the low burden of inflammation compared to patients with AS. While both groups did not differ regarding health status, disease activity, and physical function, they did differ in signs of inflammation; all were higher in patients with AS. Since many patients with nr-axSpA had not developed structural changes after years of symptoms, we propose that those patients should not be regarded as having preradiographic AS but rather as having nr-axSpA. PMID- 22505332 TI - Increased likelihood of long-term gastrostomy tube dependence in head and neck cancer survivors without partners. AB - BACKGROUND: We evaluated factors associated with long-term dependence on percutaneous endoscopic gastrostomy (PEG) tubes. METHODS: One hundred fifty-four patients receiving treatment at the University of Alabama at Birmingham between 2002 and 2004 who underwent PEG tube placement were identified through retrospective review of medical records. Using binary logistic regression, we evaluated the association of various factors on long-term dependence on PEG tubes. RESULTS: A total of 25.3% of survivors remained PEG tube-dependent at 12 months. The odds of long-term PEG tube-dependence were greater for those who did not have partners compared with those who had partners (odds ratio [OR], 3.33; p = .004), for patients who received radiation therapy (OR, 6.21; p = .018), and for those who had a tracheotomy in place for longer than 30 days (OR, 4.328; p = .035). CONCLUSION: Data suggest that interventions targeted at reducing long-term dependence on PEG tubes take into account not only treatment-related factors, but also the important role that social support plays. PMID- 22505333 TI - Elevated T2-values in MRI of stroke patients shortly after symptom onset do not predict irreversible tissue infarction. AB - Distinct from signal alterations in diffusion-weighted images, T(2)-values are also dependent on tissue water content and known to increase with time from symptom onset in acute ischaemic stroke. The purpose of this study was to evaluate whether there is a detectable increase of T(2)-values in different regions in acute ischaemic stroke in the acute and subacute situation and to study the effect of recanalization on the evaluation of T(2)-values in the subacute phase. In addition, we sought to evaluate whether this increase in T(2) values is reversible. For this purpose, 22 patients with acute ischaemic stroke in the territory of the middle cerebral artery underwent magnetic resonance imaging including diffusion-weighted imaging, perfusion-weighted imaging, fluid attenuated inversion recovery to determine final infarct size, time-of-flight angiography (acute and on day 1 or 2) and a triple echo-T(2)-sequence (calculation of T(2) maps) within 6 h after symptom onset. Images were co registered and regions of diffusion restriction and prolonged time-to-peak as well as surviving tissue (surviving tissue = time-to-peak - final infarct size) and lesion growth (lesion growth = final infarct size-diffusion restriction) were defined and superimposed onto the quantitative T(2) map. In addition, patients were dichotomized according to recanalization information. Mean quantitative T(2) values were derived for each patient within each region of interest. Mean T(2) values for patients with recanalization (n = 15) in surviving tissue region of interest were 115.8 +/- 7.2 ms (mean +/- SD) and in the lesion growth region of interest 114.6 +/- 7.0 ms. T(2)-values for patients without recanalization (n = 7) were 117.7 +/- 11.4 ms in surviving tissue region of interest and 117.3 +/- 12.1 ms in lesion growth region of interest. There was no significant difference between T(2)-values measured in lesion growth and surviving tissue region of interest for patients with or without recanalization. Even though it has been shown that T(2)-values increase with time from symptom onset within the infarct core, increased T(2)-values in areas of perfusion impairment do not identify irreversible damaged brain tissue and high T(2)-values are even found in tissue that is not part of the final infarct lesion and can therefore normalize. In conclusion, this study suggests that T(2)-values are not a valid imaging biomarker in acute stroke to predict tissue outcome. PMID- 22505334 TI - Abstracts of the 17th International Symposium on Bioluminescence and Chemiluminescence, May 28th - June 2nd, 2012, Guelph, Ontario, Canada (ISBC 2012). PMID- 22505335 TI - Stereochemical assignments of aldol products of 2-arylimino-3-aryl-thiazolidine-4 ones by 1H NMR. AB - The aldol reactions of 2-arylimino-3-aryl-thiazolidine-4-ones with benzaldehyde carried out at -78 degrees C were found to produce sec-carbinols. Intramolecular hydrogen bonding within the aldol products forming a six-membered ring enabled the assignment of stereochemistries of the major and minor diastereomers via analysis of the syn and anti (3)J(H,H) (1)H NMR coupling constants. PMID- 22505336 TI - Insight into the antiadhesive effect of yeast wall protein 1 of Candida albicans. AB - Ywp1 is a prominent glycosylphosphatidylinositol (GPI)-anchored glycoprotein of the cell wall of Candida albicans; it is present in the yeast form of this opportunistic fungal pathogen but absent from filamentous forms and chlamydospores. Yeast cells that lack Ywp1 are more adhesive and form thicker biofilms, implying an antiadhesive activity for Ywp1, with a possible role in yeast dispersal. The antiadhesive effect of Ywp1 is transplantable from yeast to hyphae, as hyphae that are forced to express YWP1 lose adhesion in an in vitro assay. Deletion of the GPI anchor results in loss of Ywp1 to the surrounding medium and reduction of the antiadhesive effect, implying an importance of time dependent residency in the cell wall. Anchor-negative versions of Ywp1 possessing or lacking a C-terminal green fluorescent protein (GFP) tag were created in C. albicans and harvested from culture supernatants; in addition to serving as quantifiable markers for Ywp1 secretion, they revealed that the cleaved 11-kDa propeptide of Ywp1 remains strongly but noncovalently associated with the Ywp1 core. This association is resistant to highly acidic and basic solutions, 8 M urea, and 1% SDS (below 45 degrees C). Above 50 degrees C, SDS dissociates the isolated complex, but even higher temperatures are required to dissociate the propeptide from native Ywp1 that is anchored in a cell wall. This property has permitted detection, for the first time, of orthologs of Ywp1 in other members of the Candida clade. The cleaved propeptide, which carries the sole N-glycan of Ywp1, must participate in the antiadhesive effect of Ywp1. PMID- 22505338 TI - Macroscopic-scale template synthesis of robust carbonaceous nanofiber hydrogels and aerogels and their applications. PMID- 22505337 TI - Exposure to host ligands correlates with colocalization of Gal/GalNAc lectin subunits in lipid rafts and phosphatidylinositol (4,5)-bisphosphate signaling in Entamoeba histolytica. AB - Entamoeba histolytica is an intestinal parasite that causes dysentery and liver abscess. Parasite cell surface receptors, such as the Gal/GalNAc lectin, facilitate attachment to host cells and extracellular matrix. The Gal/GalNAc lectin binds to galactose or N-acetylgalactosamine residues on host components and is composed of heavy (Hgl), intermediate (Igl), and light (Lgl) subunits. Although Igl is constitutively localized to lipid rafts (cholesterol-rich membrane domains), Hgl and Lgl transiently associate with this compartment in a cholesterol-dependent fashion. In this study, trophozoites were exposed to biologically relevant ligands to determine if ligand binding influences the submembrane distribution of the subunits. Exposure to human red blood cells (hRBCs) or collagen, which are bona fide Gal/GalNAc lectin ligands, was correlated with enrichment of Hgl and Lgl in rafts. This enrichment was abrogated in the presence of galactose, suggesting that direct lectin-ligand interactions are necessary to influence subunit location. Using a cell line that is able to attach to, but not phagocytose, hRBCs, it was shown that physical attachment to ligands was not sufficient to induce the enrichment of lectin subunits in rafts. Additionally, the mutant had lower levels of phosphatidylinositol (4,5) bisphosphate (PIP(2)); PIP(2) loading restored the ability of this mutant to respond to ligands with enrichment of subunits in rafts. Finally, intracellular calcium levels increased upon attachment to collagen; this increase was essential for the enrichment of lectin subunits in rafts. Together, these data provide evidence that ligand-induced enrichment of lectin subunits in rafts may be the first step in a signaling pathway that involves both PIP(2) and calcium signaling. PMID- 22505339 TI - An investigation of the transmission and attenuation of intense pulsed light on samples of human Achilles tendon and surrounding tissue. AB - BACKGROUND: Light therapy is a common mode of treatment for musculoskeletal injuries but the depth of penetration of light radiation is controversial. Evidence exists for the efficacy of intense pulsed light (IPL) treatment for the rejuvenation of skin (superficial tissue) but it is not known if the IPL can penetrate deeper. If the IPL can penetrate to the depth of the Achilles tendon it may provide a potential management options in the treatment of a chronic mid-body Achilles tendinopathy. OBJECTIVES: To examine if any optical radiation produced by an IPL transmits to the depth of the Achilles tendon when applied cutaneously to excised samples of human Achilles tissue. A secondary aim was to establish the relative amount of optical radiation that was attenuated within the tendon. MATERIALS AND METHODS: Three samples of human Achilles tendon and surrounding tissue were harvested following elective lower limb amputation operations. Each sample was irradiated 2-6 cm above the insertion into the calcaneus (area of an Achilles tendinopathy) with IPL (model iPulse; Cyden Ltd, Wales, UK) set at a single pulse of 25 millisecond, wavelength range 530-1,110 nm and fluence of 13 J/cm(2). The transmission of light radiation was evaluated using (a) standard SLR digital camera, (b) spectrometer, and (c) an external energy meter. RESULTS: Light radiation was found to have transmitted through each of the three tissue samples by all three instruments. There were observable differences in the color of light detected for the control photo and the IPL irradiated tissue samples photographs. The percentage of fluence that was detected to have transmitted through the tissue samples by the energy meter was 4-8.1% and wavelengths between 645 and 843 nm were detected to have transmitted through the tissue by the spectrometer. In addition, the percentage of light radiation that attenuated with the tendon was 10.2-17.32%. CONCLUSION: The results of this study provides evidence that IPL penetrates to the depth of the Achilles tendon and attenuates with the tendon. IPL has potential to produce physiological effects in the treatment of patients with a chronic mid-body Achilles tendinopathy. PMID- 22505340 TI - Decoding the representation of numerical values from brain activation patterns. AB - Human neuroimaging studies have increasingly converged on the possibility that the neural representation of specific numbers may be decodable from brain activity, particularly in parietal cortex. Multivariate machine learning techniques have recently demonstrated that the neural representation of individual concrete nouns can be decoded from fMRI patterns, and that some patterns are general over people. Here we use these techniques to investigate whether the neural codes for quantities of objects can be accurately decoded. The pictorial mode (nonsymbolic) depicted a set of objects pictorially (e.g., a picture of three tomatoes), whereas the digit-object mode depicted quantities as combination of a digit (e.g., 3) with a picture of a single object. The study demonstrated that quantities of objects were decodable from neural activation patterns, in parietal regions. These brain activation patterns corresponding to a given quantity were common across objects and across participants in the pictorial mode. Other important findings included better identification of individual numbers in the pictorial mode, partial commonality of neural patterns across the two modes, and hemispheric asymmetry with pictorially-depicted numbers represented bilaterally and numbers in the digit-object mode represented primarily in the left parietal regions. The findings demonstrate the ability to identify individual quantities of objects based on neural patterns, indicating the presence of stable neural representations of numbers. Additionally, they indicate a predominance of neural representation of pictorially depicted numbers over the digit-object mode. PMID- 22505342 TI - Hedgehog/hyaluronic acid interaction network in nonalcoholic fatty liver disease, fibrosis, and hepatocellular carcinoma. PMID- 22505341 TI - Combined analysis of TMPRSS2-ERG and TERT for improved prognosis of biochemical recurrence in prostate cancer. AB - Prostate cancer (PCa) is a heterogeneous disease with diverse clinical outcomes. TMPRSS2-ERG is the most common gene fusion in PCa, whereas activation of telomerase is a common feature of various malignancies. The aim of our study was to explore the combined utility of these and some other biomarkers in predicting biochemical recurrence after radical prostatectomy. Prostate specimens and urine sediments from 179 previously untreated patients with pT2-pT3 stage PCa were analyzed for expression of telomerase (TERT and TR) and the TMPRSS2-ERG fusion gene by means of reverse transcription PCR. Real-time PCR was used for quantification of ERG and SPINK1 expression. In total, 74% (117/158) of the prostate adenocarcinomas were positive for the TMPRSS2-ERG and/or TERT expression. Noninvasively, these transcripts were identified in 31% (19/61) of catheterized urine specimens. Significantly higher expression of ERG was detected in TMPRSS2-ERG-positive tumors (P<0.0001), whereas more intense expression of SPINK1 was characteristic for the TMPRSS2-ERG-negative tumors (P=0.003). TERT positive cases also had elevated levels of ERG (P=0.016), suggesting a possible link between aberrant expression of ERG and reactivation of TERT in prostate tumors. The cases negative for both transcripts, TMPRSS2-ERG and TERT, rarely recurred (P=0.014) and showed significantly longer biochemical recurrence-free period (P=0.022) as compared to the TMPRSS2-ERG and/or TERT-positive cases. The results of our study suggest that combined analysis of TMPRSS2-ERG and TERT expression can be a valuable tool for early prediction of biochemical recurrence of PCa after radical prostatectomy. PMID- 22505344 TI - Effects of a human compact anti-ErbB2 antibody on prostate cancer. AB - Prostate cancer is the most commonly diagnosed malignancy in men in developed countries. ErbB2, a tyrosine kinase receptor overexpressed in many human cancer types, contributes to prostate cancer progression by activating the androgen receptor in a steroid poor environment, thus promoting androgen-independent cell growth. The consequent development of hormone refractory tumors is a major obstacle in prostate cancer therapy. The inhibition of ErbB2 signal transduction pathways by the use of human antibodies could be a valuable alternative strategy for cancer therapy. We performed a comparative analysis in vitro and in vivo of the antitumor effects of three different antibodies targeting different epitopes of ErbB2: Herceptin (trastuzumab), 2C4 (pertuzumab) and Erb-hcAb (human anti ErbB2-compact antibody), a novel fully human compact antibody produced in our laboratory. Herein, we demonstrate that the growth of both androgen-dependent and independent prostate cancer cells was efficiently inhibited by Erb-hcAb. The antitumor effects induced by Erb-hcAb on some cell lines were more potent than those observed for either Herceptin or 2C4. Thus, Erb-hcAb could be a promising candidate in the immunotherapy of prostate cancer for which no obvious treatment has been reported so far. PMID- 22505345 TI - Suppressive subtractive hybridization libraries prepared from the digestive gland of the oyster Crassostrea brasiliana exposed to a diesel fuel water-accommodated fraction. AB - Diesel fuel can cause adverse effects in marine invertebrates by mechanisms that are not clearly understood. The authors used suppressive subtractive hybridization to identify genes up- and downregulated in Crassostrea brasiliana exposed to diesel fuel. Genes putatively involved in protein regulation, innate immune, and stress response, were altered by diesel challenge. Three genes regulated by diesel were validated by quantitative real-time polymerase chain reaction. This study sheds light on transcriptomic responses of oysters to diesel pollution. PMID- 22505343 TI - Nonsteroidal anti-inflammatory drugs and other analgesic use and bladder cancer in northern New England. AB - A few epidemiologic studies have found that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of bladder cancer. However, the effects of specific NSAID use and individual variability in risk have not been well studied. We examined the association between NSAIDs use and bladder cancer risk, and its modification by 39 candidate genes related to NSAID metabolism. A population-based case-control study was conducted in northern New England, enrolling 1,171 newly diagnosed cases and 1,418 controls. Regular use of nonaspirin, nonselective NSAIDs was associated with reduced bladder cancer risk, with a statistically significant inverse trend in risk with duration of use (ORs of 1.0, 0.8, 0.6 and 0.6 for <5, 5-9, 10-19 and 20+ years, respectively; p(trend) = 0.015). This association was driven mainly by ibuprofen; significant inverse trends in risk with increasing duration and dose of ibuprofen were observed (p(trend) = 0.009 and 0.054, respectively). The reduced risk from ibuprofen use was limited to individuals carrying the T allele of a single nucleotide polymorphism (rs4646450) compared to those who did not use ibuprofen and did not carry the T allele in the CYP3A locus, providing new evidence that this association might be modified by polymorphisms in genes that metabolize ibuprofen. Significant positive trends in risk with increasing duration and cumulative dose of selective cyclooxygenase (COX-2) inhibitors were observed. Our results are consistent with those from previous studies linking use of NSAIDs, particularly ibuprofen, with reduced risk. We observed a previously unrecognized risk associated with use of COX-2 inhibitors, which merits further evaluation. PMID- 22505347 TI - Thrombectomy and cavocavostomy for inferior vena cava thrombosis and torsion after piggyback liver transplantation. PMID- 22505346 TI - Body weight changes and corresponding changes in pain and function in persons with symptomatic knee osteoarthritis: a cohort study. AB - OBJECTIVE: To determine if a dose-response relationship exists between percentage changes in body weight in persons with symptomatic knee osteoarthritis (OA) and self-reported pain and function. METHODS: Data from persons in the Osteoarthritis Initiative (OAI) and the Multicenter Osteoarthritis (MOST) study data sets (n = 1,410) with symptomatic function-limiting knee OA were studied. For the OAI, we used baseline and 3-year followup data, while for the MOST study, baseline and 30 month data were used. Key outcome variables were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function and pain change scores. In addition to covariates, the predictor variable of interest was the extent of weight change over the study period divided into 5 categories representing different percentages of body weight change. RESULTS: A significant dose-response relationship (P < 0.003) was found between the extent of percentage change in body weight and the extent of change in WOMAC physical function and WOMAC pain scores. For example, persons who gained >=10% of body weight had WOMAC physical function score changes of -5.4 (95% confidence interval -8.7, -2.00) points, indicating worsening physical function relative to the reference group of persons with weight changes between <5% weight gain and <5% weight reduction. CONCLUSION: Our data suggest a dose-response relationship exists between changes in body weight and corresponding changes in pain and function. The threshold for this response gradient appears to be body weight shifts of >=10%. Weight changes of >=10% have the potential to lead to important changes in pain and function for patient groups as well as individual patients. PMID- 22505348 TI - Rationally designed amide donors for organocatalytic asymmetric Michael reactions. PMID- 22505349 TI - The mechanism behind the novel fibrosis recently described in NASH in HEPATOLOGY 2011 and elsewhere. PMID- 22505350 TI - Associated microsatellite alterations in mitochondrial DNA and in TP53 in thoracic esophageal squamous cell carcinoma. AB - We investigated the microsatellite alterations in mitochondrial DNA (mtDNA) and in TP53 in thoracic esophageal squamous cell carcinomas (TESCC). Using laser microdissection, 66 paired non-cancerous esophageal muscles, non-cancerous esophageal mucosa, cancerous TESCC nests plus 35 metastatic lymph nodes harvested from 66 resected esophagi of TESCC patients were subjected to DNA extraction. D310 and D17S960 were chosen as markers to address microsatellite alterations in mtDNA, including changes in copy number and homoplasmic/heteroplasmic mutations of mtDNA, and in TP53, including loss of heterozygosity (LOH) and microsatellite instability (MI). From non-cancerous esophageal mucosa to cancerous TESCC nests and then metastatic lymph nodes, a trend of homoplasmic D310 mutation (10.6, 25.8, 31.4%; p=0.023), an ever increase of mtDNA copy ratios (0.892, 1.128, 1.183; p=0.018) and an elevated incidence of TP53 LOH (19.7, 34.8, 37.1%; p=0.010) were observed. From T1, T2, T3 to T4 TESCC, the incidence of TP53 LOH (12.5, 16.7, 34.8, 52.2%; p=0.011) was increased, in a stepwise fashion. Furthermore, we observed an association of TP53 LOH with an increased mtDNA copy ratio (p=0.022) and TP53 MI with heteroplasmic D310 mutation (p=0.069) in TESCC. Concurrent and associated microsatellite alterations in mtDNA and in TP53 in TESCC support the cancer clonal expansion theory and imply a possible relationship between the mitochondria and p53 in TESCC. PMID- 22505351 TI - Pregnant women's and their partners' perception of an information model on prenatal screening. AB - OBJECTIVE: Extended verbal information on prenatal screening was given when combined ultrasound and biochemistry screening test was offered at Orebro County Council, Sweden, in 2008. The aim of this study was to describe pregnant women's and her partners' perceptions of this information model. METHOD: The interviews were semi-structured, and altogether, 26 interviews were performed with pregnant women and partners. Qualitative content analysis was used to analyze the data. RESULTS: The result consists of two main categories, 'form and content' and 'managing the information', to describe the couples' perceptions of the information given. Nine categories describe the information model in: voluntariness, a separate visit, a special midwife, the content, missing information, ethical considerations, a visit on equal terms, communication within the couple, communication with other people, and emotional management. CONCLUSION: The information model helps expecting parents to focus on prenatal screening. Only information about prenatal screening and diagnosis was not enough for everybody; some couples want this to be an opportunity to discuss with a professional the pros and cons of prenatal screening as well as ethical considerations. The information visit gives the partner a chance to be involved and an opportunity for the couple to discuss the subject. PMID- 22505352 TI - Clinically significant copy number alterations and complex rearrangements of MYB and NFIB in head and neck adenoid cystic carcinoma. AB - Adenoid cystic carcinoma (ACC) of the head and neck is a malignant tumor with poor long-term prognosis. Besides the recently identified MYB-NFIB fusion oncogene generated by a t(6;9) translocation, little is known about other genetic alterations in ACC. Using high-resolution, array-based comparative genomic hybridization, and massively paired-end sequencing, we explored genomic alterations in 40 frozen ACCs. Eighty-six percent of the tumors expressed MYB NFIB fusion transcripts and 97% overexpressed MYB mRNA, indicating that MYB activation is a hallmark of ACC. Thirty-five recurrent copy number alterations (CNAs) were detected, including losses involving 12q, 6q, 9p, 11q, 14q, 1p, and 5q and gains involving 1q, 9p, and 22q. Grade III tumors had on average a significantly higher number of CNAs/tumor compared to Grade I and II tumors (P = 0.007). Losses of 1p, 6q, and 15q were associated with high-grade tumors, whereas losses of 14q were exclusively seen in Grade I tumors. The t(6;9) rearrangements were associated with a complex pattern of breakpoints, deletions, insertions, inversions, and for 9p also gains. Analyses of fusion-negative ACCs using high resolution arrays and massively paired-end sequencing revealed that MYB may also be deregulated by other mechanisms in addition to gene fusion. Our studies also identified several down-regulated candidate tumor suppressor genes (CTNNBIP1, CASP9, PRDM2, and SFN) in 1p36.33-p35.3 that may be of clinical significance in high-grade tumors. Further, studies of these and other potential target genes may lead to the identification of novel driver genes in ACC. PMID- 22505353 TI - Neural correlates of visual search in patients with hereditary retinal dystrophies. AB - In patients with central visual field scotomata a large part of visual cortex is not adequately stimulated. We investigated evidence for possible upregulation in cortical responses in 22 patients (8 females, 14 males; mean age 41.5 years, range 12-65 years) with central visual field loss due to hereditary retinal dystrophies (Stargardt's disease, other forms of hereditary macular dystrophies and cone-rod dystrophy) and compared their results to those of 22 age-matched controls (11 females, 11 males; mean age, 42.4 years, range, 13-70 years). Using functional magnetic resonance imaging (fMRI) we recorded differences in behavioral and BOLD signal distribution in retinotopic mapping and visual search tasks. Patients with an established preferred retinal locus (PRL) exhibited significantly higher activation in early visual cortex during the visual search task, especially on trials when the target stimuli fell in the vicinity of the PRL. Compared with those with less stable fixation, patients with stable eccentric fixation at the PRL exhibited greater performance levels and more brain activation. PMID- 22505354 TI - Hypoxia and HIF-1 increase S100A8 and S100A9 expression in prostate cancer. AB - S100A8 and S100A9, two heterodimer-forming members of the cytosolic S100 Ca(2+) signaling protein family, are overexpressed in various cancer types, including prostate cancer. They act as proinflammatory danger signals when secreted to the extracellular space and are thought to play an important role during tumorigenesis, affecting inflammatory processes, proliferation, invasion and metastasis of tumor cells. Despite this fact, little is known about tumor environmental factors influencing S100A8/A9 expression. The aim of this study was to test the effect of hypoxia and its master transcriptional regulator hypoxia inducible factor 1 (HIF-1) on S100A8/A9 expression. Hypoxia treatment resulted in induction of S100A8/A9 protein and mRNA expression in prostate epithelial BPH-1 cells, the latter was also confirmed in the prostate cancer cell lines PC-3 and DU-145. Furthermore, overexpression of HIF-1alpha caused increase in S100A8/A9 protein and mRNA expression as well as secretion. Functional hypoxia response elements mediating promoter activation on HIF-1alpha overexpression were identified within the S100A8 and S100A9 promoters using promoter luciferase reporter constructs. Binding of HIF-1alpha to S100A8 and S100A9 promoters was confirmed by chromatin immunoprecipitation. Immunohistochemical analysis of a prostate cancer tissue array showed clear correlation of S100A8 and S100A9 with HIF-1alpha expression. Multivariate proportional hazard analysis revealed association of high S100A9 level with time to prostate cancer recurrence. In conclusion, we identified hypoxia and HIF-1 as novel regulators of S100A8/A9 expression in prostate cancer. S100A9 might be useful as prognostic marker for prostate cancer recurrence after radical prostatectomy. PMID- 22505355 TI - Raman spectroscopic detection of anthrax endospores in powder samples. PMID- 22505357 TI - Cognitive impairment in primary ambulatory health care: pharmacotherapy and the use of potentially inappropriate medicine. AB - OBJECTIVE: Drug intake is associated with a risk of drug-related problems, for example, the intake of potentially inappropriate medication (PIM), especially for cognitively impaired individuals. The proportion of PIM taken by immobile individuals, especially patients with suspicion of dementia in the AGnES studies (German: Arzt-entlastende Gemeinde-nahe E-Health-gestutzte Systemische Intervention), and possible determinants were analyzed. METHODS: In a community based, prospective cohort study in the ambulatory healthcare sector, a sample of 342 patients aged >=65 years were screened for dementia and received a home medication review. The screening for dementia was positive in 111 cases (32.5%). Data assessment included sociodemographic variables and medical diagnoses. The German PRISCUS list was used to detect PIM and drug-condition interactions. RESULTS: Potentially inappropriate medication in dementia was identified in 22 (19.8%) patients with suspicion of dementia. A multivariate binary logistic regression revealed that the number of drugs taken (one to four drugs: OR = 0.059; 95% CI 0.006-0.55, p = 0.0133; Ref.: >9 drugs) and female gender (OR = 10.362; 95% CI: 1.28-83.87) were risk factors for PIM intake in patient with suspicion of dementia. CONCLUSIONS: Inappropriate medication use in a community based sample positively screened for dementia appears to be determined by sex and the number of drugs taken. The intake of fewer than five drugs and receiving support with regard to drug intake protects from the intake of PIM. Patients could benefit from medication management in a collaborative network of healthcare professionals. The implementation of systematic medication review and drug documentation should be extended and standardized in both research studies and routine primary health care. PMID- 22505356 TI - Clostridium difficile infection in hospitalized liver transplant patients: a nationwide analysis. AB - The incidence of Clostridium difficile infection (CDI) is increasing among hospitalized patients. Liver transplantation (LT) patients are at higher risk for acquiring CDI. Small, single-center studies (but no nationwide analyses) have assessed this association. We used the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project (2004-2008) for this retrospective, cross sectional study. Patients with any discharge diagnosis of LT composed the study population, and they were identified with International Classification of Diseases, Ninth Revision, Clinical Modification codes. Those with a discharge diagnosis of CDI were considered cases. Our primary outcomes were the prevalence of CDI and the effects of CDI on inpatient mortality. Our secondary outcomes included the length of stay and hospitalization charges. A regression analysis was used to derive odds ratios (ORs) adjusted for potential confounders. There were 193,174 discharges with a diagnosis of LT from 2004 to 2008. The prevalence of CDI was 2.7% in the LT population and 0.9% in the non-LT population (P < 0.001). Most of the LT patients were 50 to 64 years old. LT patients had higher odds of developing CDI [OR = 2.88, 95% confidence interval (CI) = 2.68-3.10]. Increasing age and increasing comorbidity (including inflammatory bowel disease and nasogastric tube placement) were also independent CDI risk factors. CDI was associated with a higher mortality rate: 5.5% for LT patients with CDI versus 3.2% for LT-only patients (adjusted OR = 1.70, 95% CI = 1.29-2.25). In conclusion, the prevalence of CDI is higher for LT patients versus non-LT patients (2.7% versus 0.9%). CDI is an independent risk factor for mortality in the LT population. PMID- 22505359 TI - Historical overview of prion diseases: a view from afar. AB - The transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of neurodegenerative disorders which include kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker (GSS) syndrome, and fatal familial insomnia in men, natural scrapie in sheep, goats and mufflons, transmissible mink encephalopathy in ranch-reared mink, chronic wasting disease of mule deer and elk, bovine spongiform encephalopathy or "mad cow disease" and its analogues in several exotic species of antelopes and wild felids in zoological gardens, and feline spongiform encephalopathy in domestic cats. This short review summarizes the history of the research to find the nature of the scrapie agent, especially as I have witnessed it unfolding before my eyes. I review the historical background of TSEs starting from the first description of scrapie in 1732. In 1957, the first prion disease in humans, kuru was described and its transmissibility was demonstrated in 1965 by seminal work of Gajdusek, Gibbs and colleagues, followed by transmission of CJD and then, GSS. In 1982, Stanley B. Prusiner formulated "prion hypothesis" which has dominated the field for the last 30 years. This theory had been recently extended to cover other neurodegenerations which are caused by misfolded proteins; these disease are called prionoids. PMID- 22505360 TI - Amyloid and prions: some biochemical investigations of cerebral amyloidosis in mice. AB - Prion-like transmission of protein aggregates or amyloid in several neurodegenerative diseases, such as Parkinson's disease, Huntington's disease and Alzheimer's disease, in addition to the transmissible spongiform encephalopathies (or prion diseases), has been proposed recently. This is a controversial idea and, in this paper, we consider what we mean by a "prion", and by "amyloid", and present some biochemical investigations of cerebral prion amyloidosis in mice. PMID- 22505361 TI - Molecular pathology, classification, and diagnosis of sporadic human prion disease variants. AB - Human prion diseases are a unique group of transmissible neurodegenerative diseases that occur as sporadic, familial or acquired disorders and show a wide range of phenotypic variation. The latter has been attributed to the existence of distinct strains of the agent or prion, and the genetic background of the host, namely the primary sequence of the gene encoding the prion protein, which is the site of mutations and polymorphisms. The characterization of distinct isoforms of the abnormal prion protein in the brain of affected patients, which has been shown to correlate with the disease phenotype, has recently led to the concept of molecular strain typing, in which the different prion protein isoforms or "types", possibly enciphering the strain variability in their conformation, may serve as surrogate markers for individual prion strains. In sporadic Creutzfeldt Jakob disease, the most common human prion disease, there are at least six distinct clinico-pathological disease phenotypes that largely correlate at a molecular level with two prion protein types with distinctive physicochemical properties and the genotype at the methionine/valine polymorphic codon 129 in the prion protein gene. Recent results of transmission studies indicate that five prion strains with distinctive biological properties can be isolated from these six disease variants. It has also been shown that about a third of sporadic cases show a mixed phenotype and the co-occurrence of prion protein types. The origin of prion strains and their co-occurrence as well as the mechanisms underlying the strain-specific neuronal targeting remain largely unexplained and their understanding constitute, together with the development of successful therapies and more sensitive and specific clinical biomarkers, the major challenges that this disease poses for the future. PMID- 22505362 TI - Prion diseases - current theories and potential therapies: a brief review. AB - Prion diseases are a group of infectious diseases that cause lethal neurodegenerative disorders in both humans and animals. Affected patients usually die within one year from the appearance of the first clinical abnormalities. Unfortunately, no viable treatment options are available for prion diseases. The aim of this review is to describe the underlying prion disease pathology and discuss the therapeutic targets that have emerged from this. PMID- 22505363 TI - Variant Creutzfeldt-Jakob disease: an update. AB - Variant Creutzfeldt-Jakob disease (vCJD) is a novel human prion disease caused by the bovine spongiform encephalopathy agent. Most cases have occurred in the UK, with smaller numbers in 11 other countries. All definite vCJD cases have occurred in methionine homozygotes at codon 129 in the prion protein gene. Following oral infection, the vCJD agent appears to replicate in lymphoid tissues during the asymptomatic phase of the incubation period. At present, four probable cases of vCJD infection have been identified following transfusion of red blood cells from asymptomatic donors who subsequently died from vCJD. Recently, one case of likely transmission of vCJD infection by UK Factor VIII concentrates has been reported in an elderly haemophilic patient in the UK. The recent report of a blood test that may be used to detect vCJD has raised the possibility of a new way to identify infected individuals, perhaps even before the onset of clinical symptoms. PMID- 22505364 TI - Non-human primates in prion research. AB - Prion diseases or transmissible spongiform encephalopathies are neurodegenerative disorders affecting a broad range of mammals including humans. Initially thought to be of viral origin, it became apparent that prion diseases are unique transmissible entities where a misfolded, highly stable conformer (PrPSc) of the host encoded prion protein (PrPC) represents an essential component of infectious "prions". Prion diseases are mainly studied in rodents, yet several scientific breakthroughs in prion research can be attributed to prion research in primates. In this review we summarize and discuss how studies in non-human primates have advanced our knowledge on transmissibility, pathophysiology and tissue tropism of prions. We discuss assets of non-human primate and rodent models of prion disease pointing out alternatives to experiments in primates. PMID- 22505365 TI - Association of the PRNP regulatory region polymorphisms with the occurrence of sporadic Creutzfeldt-Jakob disease. AB - The prion protein (PrP) plays a central role in the pathogenesis of Creutzfeldt Jakob disease and other transmissible spongiform encephalopathies (TSEs). Mutations in the coding region of the prion protein (PRNP) gene are linked to inherited forms of TSEs whereas aetiology of sporadic CJD (sCJD) remains obscure. It remains unclear whether the primary DNA sequence at non-coding region of PRNP gene influences development of the sCJD. Several recent reports showed non-coding region polymorphisms associated with sCJD but other could not support those findings. To test the hypothesis that there is a relationship between SNPs polymorphisms of PRNP non-coding regions and susceptibility to sCJD, we compared the primary structure of the regulatory region of the PRNP in 45 Dutch sCJD patients and in 135 healthy controls. We found a significant linkage of +310 C allele (OR 0.27, 95% CI 0.09-0.77; P = 0.009) and +310G/C genotype (OR 0.33, 95% CI 0.11-0.98; P = 0.048) with sCJD. No differences in frequencies of genotypes and allele of -101C/G and +258 G/A polymorphisms were found between sCJD patients and controls. We found two haplotypes protecting from sCJD (C-V in block 1 and G C in block 2) and one susceptible haplotype for sCJD (G-G in block 2). Our findings support the hypothesis that polymorphism in the regulatory region of the PRNP gene may play an important role in the pathogenesis of sCJD. PMID- 22505366 TI - Expression of immunohistochemical markers on microglia in Creutzfeldt-Jakob disease and Alzheimer's disease: morphometric study and review of the literature. AB - INTRODUCTION: Microglia are the resident immune cells of the CNS. They are involved in the pathogenesis of diverse neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, prion diseases as well as multiple sclerosis, amyotrophic lateral sclerosis and AIDS dementia complex. Activated microglia up-regulate many surface receptors such as the major histocompatibility complex (MHC) or complement receptors and secrete a variety of soluble biologically active factors, which are either neurotrophic (e.g. Glia-Derived Neurotrophic Factor [GDNF]) or proinflammatory and neurotoxic (e.g. tumour necrosis factor alpha [TNF-alpha], interleukin 1beta [IL-1beta], nitric oxide [NO], superoxide, eicosanoids, quinolinic acid). AIM: The aim of this work was to assess differences in the expression of microglial markers (ferritin, CD68, and HLA-DR) between AD and Creutzfeldt-Jakob disease (CJD) brains. MATERIAL AND METHODS: Analyses were performed on 65 slices derived from 26 brains [46 CJD (20 brains), 12 AD (4 brains) and 7 controls (2 brains)]. Slices were labelled immunohistochemically using anti-ferritin, anti-HLA-DR and anti-CD68 antibodies. The nonparametric Mann-Whitney U test was used to assess quantitative differences between groups. RESULTS: The expression of microglia markers (HLA-DR and CD68) is more noticeable in CJD than in AD or control brains. There is no difference between AD and controls. The latter statement is only true in the case of using HLA-DR or CD-68 labelling. Furthermore, ferritin is not a recommended marker in this context. CONCLUSIONS: CNS inflammation is more prominent in CJD than in AD or controls. The lack of differences between AD and controls may result from a relatively advanced neurodegeneration in AD brains. In late phases of AD, inflammation is no longer present, in contrast to the early stages of the disease. PMID- 22505367 TI - Prion protein (PrP) deposits in the tectum of experimental Gerstmann-Straussler Scheinker disease following intraocular inoculation. AB - The abnormal misfolded isoform of prion protein (PrPd; "d" for disease) is considered as a surrogate marker for infectivity in the transmissible spongiform encephalopathies (TSEs) or prion diseases, including Creutzfeldt-Jakob disease (CJD). In this experiment, we used intraocular inoculation to study PrPd deposition in the visual system of the brain of mice infected with the Fujisaki (K.Fu) strain of Gerstmann-Straussler-Scheinker (GSS) disease. We report here that PrPd is deposited in the superior colliculus following contralateral intraocular inoculation and thus follows neuronal connections when it spreads into the brain. Until 26 weeks postinoculation, no PrPd-specific immunostaining was observed in the brain. At 27 weeks postinoculation, PrPd targeted to the contralateral superior colliculus as delicate granular synaptic deposits located in the superficial part of this structure. As already reported, a few spongiform vacuoles were visible in the same area by conventional H and E staining. In several other sections, vacuoles were visible but no PrPd staining could be detected. PMID- 22505368 TI - Ultrastructural findings in pigs experimentally infected with bovine spongiform encephalopathy agent. AB - We report here an electron microscopic study of selected nervous system tissues from pigs infected experimentally with the agent of bovine spongiform encephalopathy (BSE). Generally, the ultrastructural neuropathology of BSE affected pig brain resembled that of BSE-affected cattle brain. Spongiform change, in the form of membrane-bound vacuoles separated by septae into secondary chambers, dominated the pathology. Numerous astrocytic processes were visible in close conjunction with elongated microglial cells. Neuronal degeneration presented as either dystrophic neurites or by the formation of autophagic vacuoles. Altered subcellular organelles: mitochondria, electron-dense bodies, autophagic vacuoles, neurofilaments and "branching-cisterns" accumulated in abnormal neurites. Autophagic vacuoles appeared as neuronal cytoplasm of increased electron-density sequestrated by intracytoplasmic membranes. Tubulovesicular structures were numerous, particularly in the cerebellum. Unusual crystalloids were observed in the white matter. In conclusion, experimental BSE in pigs demonstrated ultrastructural pathology in keeping with that observed in other spongiform encephalopathies. PMID- 22505369 TI - Cardiovascular phenotype of nonalcoholic fatty liver disease: hanging the paradigm about the role of distant toxic fat accumulation on vascular disease. PMID- 22505370 TI - Early regeneration of the remnant liver volume after right hepatectomy for living donation: a multiple regression analysis. AB - Early liver regeneration was studied in a series of 70 patients who underwent right hepatectomy for living donation between November 2004 and January 2010. Liver regeneration was evaluated with multidetector computed tomography (MDCT) at a mean of 61.07 days after surgery. Presurgical variables [eg, age, weight, height, body mass index (BMI), liver function tests, creatinine levels, platelet counts, international normalized ratio, and glucose levels] and variables detected with preoperative MDCT imaging [eg, main portal vein diameter, steatosis, original liver volume, and spleen volume (SV)] were investigated as potential predictors of liver regeneration. The future remnant liver volume (FRLV) was preoperatively calculated with a virtual surgical cut. Liver function tests and creatinine levels were recorded on the 30th postoperative day. In addition, the onset of postoperative complications occurring within 90 days of surgery was analyzed, and the complications were codified according to the 5 tiers of the Clavien-Dindo classification. In 26 of the 70 patients (37.14%), 100% or greater hepatic regeneration had occurred at 2 months. There was no association between the clinical outcome and the liver regeneration rate. A stepwise multiple regression analysis showed that a higher BMI (coefficient = 0.035, P < 0.0001) and preoperative parameters such as a smaller FRLV (coefficient = -0.002, P < 0.0001) and a greater SV/FRLV ratio (coefficient = 1.196, P < 0.0001) were predictors of greater liver regeneration. PMID- 22505371 TI - Depressive symptoms among the medically hospitalized older individuals -- a 1 year follow-up study. AB - AIM: The present follow-up study of older medically hospitalized patients from a rural area in Norway assessed the prevalence of depressive symptoms at 1-year follow-up and furthermore explored whether depressive symptoms at follow-up was associated with change in the medical, functional or emotional situation between baseline and follow-up. METHODS: A 1-year follow-up study included 363 (175 men) older medical inpatients with age range 65-98 (mean = 80.2; standard deviation (SD) = 7.5) years. Information was collected at baseline and follow-up using the Hospital Anxiety and Depression scale (HAD), the Mini-Mental State Examination, Lawton and Brody's scales for physical self-maintenance and performance of the instrumental activities of daily living. RESULTS: The prevalence of depressive symptoms, as defined by a score >= 8 at HAD-D, was 10% at baseline and 7% at follow-up. Of those with depressive symptoms at baseline, 78% had experienced remission. The incidence of depressive symptoms at follow-up was 5%. In logistic regression analyses adjusted for age, gender, and depressive symptoms at baseline, becoming or being in need of assistance from nursing or social services (odds ratio (OR) = 8.1, 95% CI: 1.9-34.2 and OR = 4.4, 95% CI: 1.1-17.4, respectively), having a cognitive decline (OR = 1.1, 95% CI: 1.0-1.3), and exhibiting poorer physical self-maintenance (OR = 1.2, 95% CI: 1.0-1.3), becoming vision impaired (OR = 8.3, 95% CI: 2.8-25.0), and with increased anxiety (OR = 1.2, 95% CI: 1.0-1.3) during follow-up was associated with depressive symptoms at follow-up. CONCLUSION: The 1-year follow-up study of older medical inpatients contributes to the research body regarding risk factors of depression in older people. PMID- 22505372 TI - The first experience of eosinophilic esophagitis in Turkish children. AB - BACKGROUND/AIMS: Eosinophilic esophagitis is a rare allergic disease of the esophagus with no published data in Turkish children. METHODS: This is an observational study of children diagnosed as eosinophilic esophagitis in our hospital between February 2009 and January 2011. We retrospectively analyzed the clinical features, allergic work-up, endoscopic and histological findings, and response to treatment. RESULTS: We followed seven patients in this period with a histopathologic diagnosis of eosinophilic esophagitis. The mean age at diagnosis was 5.05+/-2.97 years (range: 1-9 years), and four of them were male. The most frequent symptom was gastroesophageal reflux disease-like symptoms (vomiting, regurgitation, and heartburn) (42.9%). Peripheral eosinophilia and high serum total IgE levels were found in four patients (57.2%). Sensitization to food (71.4%) was more frequent than that of aeroallergens (28.6%). Endoscopic findings suggestive of eosinophilic esophagitis were present in four patients (57.2%). Comorbid allergic disease was present in five patients (71.4%). All patients were treated by elimination diet (85.7%) and/or inhaled corticosteroid treatment (71.4%). The mean follow-up period was 12.4+/-6.1 months (range: 6-24 months). All but one patient showed complete clinical response to their treatment. No significant side effect was observed during the follow-up period. CONCLUSIONS: Eosinophilic esophagitis is a rare gastrointestinal allergic disorder frequently comorbid with other allergic diseases and with different manifestations and response profiles to treatment modalities. PMID- 22505373 TI - Comparison of bismuth-containing quadruple and concomitant therapies as a first line treatment option for Helicobacter pylori. AB - BACKGROUND/AIMS: Helicobacter pylori eradication rates with standard triple regimens are worsening, and alternative treatments are urgently needed in some populations. The present study aimed to compare the efficacy of bismuth-based quadruple and concomitant regimens. METHODS: Consecutive Helicobacter pylori positive patients with non-ulcer dyspepsia were randomized to receive one of two regimens: (i) bismuth subsalicylate 300 mg q.i.d., esomeprazole 40 mg b.i.d., tetracycline 500 mg q.i.d., and amoxicillin 1 g b.i.d. (bismuth group) or (ii) esomeprazole 40 mg b.i.d., tetracycline 500 mg q.i.d., amoxicillin 1 g b.i.d., and metronidazole 500 mg t.i.d. (concomitant group) for 14 days. Gastroscopy and 14C-urea breath test were performed before enrollment, and urea breath test was repeated six weeks after the treatment. RESULTS: A total of 200 patients were randomized, and 180 of them completed the protocols. The intention-to-treat and per-protocol eradication rates were 79% (95% confidence interval 71-87) and 89.7% (95% confidence interval 83-95) in the bismuth group and 74% (95% confidence interval 68-81) and 80.4% (95% confidence interval 72-87) in the concomitant group. The bismuth regimen achieved a slightly better eradication rate compared to the concomitant group in both per-protocol and intention-to-treat analysis, but results were not statistically significant (p>0.05). Ten patients (6 in bismuth, 4 in concomitant groups) dropped out of the study because of side effects. CONCLUSIONS: The quadruple regimens with or without bismuth achieved moderate eradication rates as a first-line eradication option of Helicobacter pylori in our population, in which a bismuth-based regimen seems more appropriate. The compliance and side effects are important issues affecting the success of these regimens. PMID- 22505374 TI - Clinical importance of celiac disease in patients with recurrent aphthous stomatitis. AB - BACKGROUND/AIMS: Recurrent aphthous stomatitis is a common disease of the oral mucosa that is characterized by recurrent, painful ulcers of unknown etiology. The association between celiac disease and recurrent aphthous stomatitis has been evaluated in several studies, but variable results have been reported. The purpose of this study was to determine the prevalence of celiac disease in patients with recurrent aphthous stomatitis. METHODS: The study group consisted of 82 patients, all of whom had a history of recurrent aphthous stomatitis. The control group included 82 patients who did not have aphthous stomatitis. Patients were screened for IgA anti-endomysial antibodies, IgG anti-endomysial antibodies, IgA anti-gliadin antibodies, and IgG anti-gliadin antibodies. Patients with positive serology underwent endoscopic biopsies of the duodenal mucosa. Patients in both groups were also questioned regarding gastrointestinal symptoms. RESULTS: One patient (1.2%) out of 82 in the study group was diagnosed with celiac disease by biopsy. Gastroesophageal reflux disease symptoms, heartburn and regurgitation were determined to be of higher incidence in the study group (p<0.001 and p<0.001, respectively). None of the 82 patients in the control group were diagnosed as having celiac disease. CONCLUSION: It is concluded that there is no apparent etiological link between recurrent aphthous stomatitis and celiac disease and that screening recurrent aphthous stomatitis patients for celiac disease has little clinical value. Additionally, regurgitation of gastric acid to the oral cavity may precipitate the formation of aphthous stomatitis. PMID- 22505375 TI - The effects of provocation by foods with raised IgG antibodies and additives on the course of Crohn's disease: a pilot study. AB - BACKGROUND/AIMS: This study was designed to assess the role of foods with raised IgG antibodies and additives on the symptoms and inflammation of Crohn's disease. METHODS: Eight patients with Crohn's disease in remission were studied. They followed a strict diet during phase I. Then, provocations with two, three-day periods (phases II and III) followed: in phase II, pure forms of foods with high IgG antibodies and in phase III, off-the-shelf forms of those foods were added. Stool samples were collected for fecal calprotectin assay. Blood samples were taken on the 11th and 17th days for highly sensitive C-reactive protein, ferritin, erythrocyte sedimentation rate, white blood cells, and platelets. Patients kept a diet-symptom diary. RESULTS: Increased Crohn's disease activity index scores were found statistically significant (p=0.012) between pre- and during the provocation weeks. There were significant increases according to Harvey-Bradshaw Index when the highest values during the phases I, II (p=0.027) and I, III (p=0.027) were compared. The increases in highly sensitive C-reactive protein (p=0.025) and white blood cells (p= 0.036) were found statistically significant. Fecal calprotectin levels showed day-to-day variability. When compared, the levels of fecal calprotectin increased in all patients on the last day of the restriction (10th day) and the first day of the provocation (11th day) with the exception of one patient. CONCLUSIONS: Foods with raised IgG antibody levels and food additives can provoke the symptoms and may stimulate the inflammation in patients with Crohn's disease. Addition of a proper diet with restriction of those foods may be beneficial in the medical treatment. PMID- 22505376 TI - The efficiency of various doses of topical isosorbide dinitrate in the treatment of chronic anal fissure and the long-term results: a prospective, randomized and controlled clinical trial. AB - BACKGROUND/AIMS: In recent years, numerous studies have reported that the application of topical isosorbide dinitrate can cause fissure recovery with the relaxation of the internal anal sphincter. However, there is no consensus about the dose or duration of the drugs to be applied. In addition, long-term results of the patients with chronic anal fissure treated with nitrate-containing compounds are unknown. In this study, the goal was to investigate the effects of various doses of isosorbide dinitrate on chronic anal fissure and their long-term effects. METHODS: Seventy-five sequential patients with chronic anal fissure were divided into three groups. Only symptomatic treatments were applied to patients in the first group (n=15). The patients in second and third groups (n=30 each) were treated with topical isosorbide dinitrate 5% and 10%, respectively. The patients were examined three times at 20-day intervals. Five years later, 44 patients who were responsive to treatment were contacted by telephone. RESULTS: The rate of full response in the 10% isosorbide dinitrate group was statistically higher than of the 5% isosorbide dinitrate group on the 20th day (53.3% vs. 26.7%, p<0.05). However, the rate of full response did not differ between these groups on the 40th and 60th days (63.3% and 70% vs. 56.7% and 63.3%, p>0.05). Five years later, 52.3% of patients who were responsive to treatment had a symptomatic relapse. CONCLUSIONS: Topical isosorbide dinitrate is a good alternative therapy to protect internal anal sphincter in the treatment of chronic anal fissure. However, the recurrence rates are high in the long-term. PMID- 22505377 TI - Serum complement C4 in chronic hepatitis C: correlation with histopathologic findings and disease activity. AB - BACKGROUND/AIMS: Hepatitis C virus leads to chronic liver disease, cirrhosis and hepatocellular cancer. Viral markers and other laboratory tests used in the diagnosis and follow-up of chronic hepatitis C do not correlate well with disease activity and liver histopathology. Therefore, alternative tests that indicate disease activity and relate with liver biopsy findings are needed. We aimed to investigate the relationship between serum complement levels and biopsy findings in patients with chronic hepatitis C. METHODS: One hundred cases (70 patients, 30 healthy controls) were included in the study. Patients were divided into two groups: chronic hepatitis C patients with high transaminase levels were evaluated as the first group and patients with normal transaminase levels as the second group. Patients with a high transaminase level were biopsied and activity scores were evaluated against complement C3c and C4 levels. In addition, demographic data and laboratory tests were evaluated. Patients with chronic hepatitis C without proteinuria, acute phase response, cirrhosis, or coinfection with another hepatitis virus were included in the prospective study. RESULTS: Serum complement C3c (p<0.01) and C4 (p<0.01) levels were significantly lower in the first group than the second group. Serum complement C3c levels did not correlate with laboratory tests, hepatitis C virus-RNA levels, histological activity index, or fibrosis scores in patients with high transaminase levels, whereas complement C4 levels showed significant correlation with alanine aminotransferase (r: -0.368, p: 0.001) and histological activity index (r: -0.639, p: 0.001). We could not find any relation between serum complement C4 level and fibrosis. CONCLUSIONS: Serum complement C4 levels correlate with the histological activity index of the Knodell scoring system. PMID- 22505378 TI - Effect of beta-glucan in lung damage secondary to experimental obstructive jaundice. AB - BACKGROUND/AIMS: This study aimed at investigating the protective effects of beta glucans on the lungs in obstructive jaundice. METHODS: In total, five groups Sham (1), control (2) and treatment groups (3,4,5)- were established; each comprising randomly selected seven Wistar Albino rats. Beta-glucan was given after choleduct ligation in Group 3 while it was given before and after the choleduct ligation in Group 4. As pre-treatment beta-glucan was given before ligation in Group 5. Beta-glucan was administered in a single dose of 50 mg/kg/day by gavage for a ten-day period. Superoxide dismutase, and myeloperoxidase levels in serum; malondialdehyde, lipid hydroxyperoxidase and glutathione levels in lung tissue; lactate dehydrogenase levels in bronchoalveolar lavage fluid were measured. RESULTS: The blood polymorphonuclear leukocytes level was highest in the control group and lower in the sham and treatment groups. Serum superoxide dismutase and tissue glutathione values were significantly higher in Groups 3 and 4 (p<=0.04) whilst Groups 3 and 4 did not differ from each other. In Groups 3 and 4 malondialdehyde, lipid hydroxyperoxidase, and myeloperoxidase values were significantly lower. However, Groups 3 and 4 did not differ for malondialdehyde or lipid hydroxyperoxidase values. Lactate dehydrogenase level in the bronchoalveolar lavage fluid was significantly lower in all of the treatment groups (Groups 3,4,5) (p<=0.008). When compared to the control group, it was observed that lung damage was much more limited in the treatment groups (p<0.001). CONCLUSION: This study suggests that beta-glucan exhibits protective effect in pulmonary tissue against oxidative damage in obstructive jaundice. PMID- 22505379 TI - Potential proteomic biomarkers in assessing liver fibrosis using SELDI-TOF MS. AB - BACKGROUND/AIMS: The accurate assessment of the severity of liver fibrosis is of paramount importance in determining treatment strategies, response to treatment and prognosis in patients with chronic liver disease. The aim of this study was to investigate potential proteomic biomarkers for assessing stages of hepatic fibrosis. METHODS: Serum samples of 83 patients with chronic liver disease (using METAVIR index, 17 F0, 30 F1, 6 F2, 9 F3, and 21 F4 patients) and 29 healthy controls were analyzed using surface-enhanced laser desorption/ionization time-of flight mass spectrometry on IMAC30 ProteinChip arrays. Discriminatory peaks between groups were identified using Mann-Whitney U non-parametric test. Comparison of mild (F0, F1) and severe fibrosis (F2, F3, F4) was performed using tree classification (cross-validation) with the Biomarker Patterns Software, version 5.0 (Ciphergen Biosystems, US). RESULTS: No statistically significant discriminatory peak was evident between F0, F1 and F2 fibrosis. More than 30 peaks were found to be discriminatory between patients with cirrhosis (F4) and all other stages of liver fibrosis, including F2 and F3. Six surface-enhanced laser desorption/ionization proteomic features were found to be discriminative for mild (F0, F1) vs. advanced (F2, F3, F4) fibrosis (AUROC >=0.8, p<0.05, Mann Whitney test). The decision tree (m/z 4280, 10453 and 6376) yielded a sensitivity of 83.3% (30/36), a specificity of 85.1% (40/47), a positive predictive value of 81.1%, and a negative predictive value of 86.9%, with an AUROC of 0.94. CONCLUSIONS: The results of this study revealed discriminatory peaks between the protein profiles of patients with cirrhosis and other stages of liver fibrosis. Potential proteomic biomarkers can be notably determined for discriminating mild and advanced fibrosis using surface-enhanced laser desorption/ionization time-of- flight mass spectrometry. PMID- 22505380 TI - Imaging and clinical findings of a gossypiboma migrated into the stomach. AB - In the presented case, the radiologic, endoscopic and surgical findings of a gossypiboma that migrated into the stomach are presented. A 63-year-old woman presented with epigastric pain, and her clinical and laboratory findings were compatible with pancreatitis. Upper gastrointestinal endoscopy revealed a foreign body at the greater curvature of the stomach. Computed tomography and magnetic resonance imaging showed a mass consistent with a gossypiboma that had migrated into the stomach transmurally. This is a first case of a gossypiboma diagnosed endoscopically. PMID- 22505381 TI - Extranodal marginal zone B-cell lymphoma of the gastrointestinal tract sparing only the esophagus: a case report. AB - Lymphomas presented in any organ or tissue other than lymph nodes or the spleen are considered primary extranodal non-Hodgkin's lymphomas, and the most common non-Hodgkin's lymphomas are of the gastrointestinal tract. The most common histological subtypes are marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue and diffuse large B-cell lymphoma, and typically only one to two organs are affected. Patients present with a wide variety of vague complaints, making early diagnosis problematic. Herein, we report the case of a 76-year-old male with extranodal marginal zone B-cell lymphoma involving the entire gastrointestinal tract, sparing only the esophagus, who was Helicobacter pylori negative. He underwent six courses of chemotherapy with R-CHOP regimen, and achieved complete remission. PMID- 22505382 TI - A rare combination of intestinal invagination and Meckel's diverticulum in an adult: a case report. AB - Intestinal invagination is a common pathology amongst children, while it is a rare entity in adults. Invagination is responsible for only 1-3% of adult-onset intestinal obstruction. Meckel's diverticulum, on the other hand, is the most common congenital anomaly of the gastrointestinal tract. Most of them are asymptomatic; they are recognized when they complicate, and can present with diverticulitis, gastrointestinal bleeding, intestinal obstruction, perforation, or invagination. A 16-year-old male patient presented to our emergency department with abdominal pain. There was a palpable mass at the right paraumbilical region. Gas-liquid level was seen on the direct abdominal radiography. On the abdominal ultrasonography, it was reported that the mass might be a result of invagination. As the patient had extensive peritonitis findings, with the pre-diagnosis of obstruction as a result of invagination, surgery was decided. During the operation, it was observed that the invaginated ileum loop was too ischemic for reduction; therefore, the invaginated part was resected and ileoileal anastomosis was performed. Examination of the resected segment revealed the Meckel's diverticulum as causing the invagination. In conclusion, with this case, we aimed to present the role of Meckel's diverticulum as an initiating factor of ileoileal invagination, with inversion into the ileum. PMID- 22505383 TI - The use of single port surgery for polyps located in the rectum. AB - Transanal endoscopic microsurgery is a minimally invasive technique for the treatment of rectal lesions which was introduced by Buess. In this report the first clinical experience of transanal endoscopic surgery was performed by a single incision laparoscopic surgical port adapted through the anal canal. In single port surgery, the single incision laparoscopic surgical port has to be stitched around anal orifice. There is no need to use a fixation apparatus. In transanal endoscopic microsurgery procedure, a rigid rectoscope 40 mm in diameter is introduced into the anus by stretching anal sphincter. A single incision laparoscopic surgical port can be disposed through the anal canal where there is no harmful cause because it is made an elastic. The dissection in the transanal endoscopic microsurgery procedure needs specific equipment to improve the surgery; however we could complete the surgical dissection using standard laparoscopic devices with articulated ones. The other factor makes single port surgery easier than transanal endoscopic microsurgery procedure is insufflation. It is easy and controlled way to be insufflated by a particular pump and cheaper than any insufflators. Furthermore, in the operating room, the patient's position on the table was not a limiting factor. As a conclusion, we report that for selected patients, single port surgery can be performed using a single incision laparoscopic surgical port as an adjusted surgical technique. It gives safe and feasible way to remove benign and malign polyps and tumors up to 20 cm in the rectum. PMID- 22505384 TI - Congenital hepatic artery aneurysm: a case report in early infancy. AB - Hepatic artery aneurysm in children is a very unusual pathologic entity. As most patients with this anomaly are asymptomatic, the diagnosis is usually made as an incidental finding on imaging studies performed for other reasons. Here, we report a 35-day-old infant with hepatic artery aneurysm, which was diagnosed accidentally as a liver mass during echocardiography. Considering the age of diagnosis, she most likely had a congenital type of hepatic artery aneurysm. To the best of our knowledge, this is the youngest case to be reported in the literature. PMID- 22505385 TI - A case report: nasobiliary drainage inducing remission in benign recurrent intrahepatic cholestasis. AB - Benign recurrent intrahepatic cholestasis is a rare hereditary disorder characterized by recurrent episodes of cholestasis and pruritus without anatomical obstruction. Generally, medical therapy is not effective in benign recurrent intrahepatic cholestasis. Here, we report the case of a young male patient with benign recurrent intrahepatic cholestasis who presented with cholestatic jaundice and pruritus, refractory to standard therapies. He improved on treatment with temporary endoscopic nasobiliary drainage. We propose that temporary endoscopic nasobiliary drainage should be considered in cholestatic benign recurrent intrahepatic cholestasis patients. A 36-year-old male patient admitted to our outpatient clinic with the complaint of pruritus. His anamnesis revealed that he experienced the same symptoms and signs in 2006. He was hospitalized in a hepatology clinic and was thoroughly examined. Liver biopsy was performed, and he was finally diagnosed as having benign recurrent intrahepatic cholestasis. Medical therapy options all proved to be ineffective and we were able to achieve remission in this patient only with the help of nasobiliary drainage. For this patient, we tried nasobiliary drainage in addition to the standard medical therapies. He improved on nasobiliary drainage. In conclusion, we propose that temporary endoscopic biliary drainage should be considered in cholestatic benign recurrent intrahepatic cholestasis patients. We hope that this case report contributes to the topic, since only a few nasobiliary drainage case experiences have been reported to date. PMID- 22505386 TI - Indirect biliary drainage as an alternative solution for biloma due to complicated biliary drainage. AB - Pancreas cancer has increased morbidity and mortality. It generally result in biliary obstruction which life threatening importance. Main biliary drainage method is endoscopic retrograde cholangiopancreatography. When endoscopic retrograde cholangiopancreatography is not successful, second preferred method is percutaneous biliary drainage. Percutaneous biliary drainage has some complications which is an invasive procedure. A complication of percutaneous biliary drainage due to patient iatrogenity which was not ever reported in the literature biliary drainage according to our literature research. In these circumstances an alternative solution is indirect biliary drainage. PMID- 22505387 TI - A new closure method in NOTES. PMID- 22505388 TI - Gastrointestinal stromal tumor perforation in a case with neurofibromatosis presenting with abdominal pain. PMID- 22505389 TI - Atypical gastrointestinal plasmacytomas presenting with gastrointestinal bleeding in a patient with multiple myeloma. PMID- 22505390 TI - Ileocolic intussusception due to a gastrointestinal stromal tumor. PMID- 22505391 TI - Intramural small bowel hematoma secondary to use of oral anticoagulant therapy. PMID- 22505392 TI - A rare cause of lymphadenopathy near the terminal ileum: immunoproliferative small intestinal disease. PMID- 22505393 TI - Pseudomembranous collagenous colitis. PMID- 22505394 TI - Pancreatic tuberculosis mimicking inoperable pancreatic cancer. PMID- 22505395 TI - Relationship between plasma concentrations of N-terminal pro brain natriuretic peptide and the characteristics and outcome of patients with a clinical diagnosis of diastolic heart failure: a report from the PEP-CHF study. AB - AIM: The aim of this study was to explore the relationships between plasma concentrations of N-terminal pro brain natriuretic peptide (NT-proBNP) and characteristics and prognosis of patients with heart failure and preserved (HFPEF) left ventricular ejection fraction (LVEF). No substantial trial has shown that treatment alters prognosis in patients with HFPEF due, in part, to much lower than anticipated event rates. The lack of a simple, objective test to identify patients with HFPEF at increased risk of cardiovascular events would be valuable. METHODS AND RESULTS: The Perindopril in Elderly People with Chronic Heart Failure Trial (PEP-CHF) was a randomized, controlled trial comparing perindopril and placebo in patients with symptoms and signs of heart failure who had an LVEF >40% and evidence of LV diastolic dysfunction. The primary endpoint was all-cause mortality or heart failure-related hospitalization. NT-proBNP was measured in 375 patients. Quartile thresholds were 176, 409, and 1035 pg/mL. Patients in the highest quartile of NT-proBNP were older, had lower body mass, more often had atrial fibrillation, had greater atrial and ventricular dimensions and a lower LVEF, and were more likely to receive loop diuretic therapy. Compared with the first quartile of NT-proBNP, the hazard ratios for the primary endpoint in the second {1.38 [95% confidence interval (CI) 0.64-2.99]}, third [2.84 (95% CI 1.42-5.72)], and fourth [4.47 (95% CI 2.30-8.72)] quartiles were increased. In a multivariable model, NT-proBNP, but not echocardiographic measures, was associated with outcome. CONCLUSIONS: NT-proBNP is a powerful prognostic marker in patients with HFPEF. PMID- 22505397 TI - Relationship between pump speed and exercise capacity during HeartMate II left ventricular assist device support: influence of residual left ventricular function. AB - AIMS: Patients treated with a Thoratec HeartMate II left ventricular assist device (LVAD) are supported at a fixed pump speed. It is uncertain whether pump speed has a significant effect on exercise capacity. We investigated the relationship between pump speed and exercise capacity and the influence of residual LV function METHODS AND RESULTS: We exercised 30 patients 6 months after HeartMate II implantation at clinical pump speed (typically 9000 r.p.m.) and again at the lowest speed available (6000 r.p.m.). Overall, peak oxygen uptake (pkVO(2)) positively correlated with LV ejection fraction (LVEF) both at the clinical pump speed (r = 0.41, P = 0.03) and after pump speed reduction (r = 0.50, P = 0.01). We divided the patients into two groups; those with higher LVEF (LVEF >=40%) and those with lower LVEF (LVEF <40%) at the time of exercise testing. The response to speed change was different between the two groups. In the higher LVEF group, the impact of LVAD pump speed reduction was minimal (pkVO(2) 21.4 +/- 4.8 mL/kg/min vs. 20.8 +/- 5.5 mL/kg/min, P = 0.38). In the lower LVEF group, the pkVO(2) was lower at both speeds; 17.2 +/- 5.3 and 14.7 +/- 5.9 mL/kg/min, respectively. In the lower LVEF group, the pkVO(2) decreased by 2.5 mL/kg/min (P = 0.02) with speed reduction. CONCLUSIONS: HeartMate II patients with lower residual LV function had a lower pkVO(2) and were more sensitive to pump speed reduction. This suggests that modulation of LVAD speed during exercise could be of benefit to this group of patients. PMID- 22505398 TI - The diabetic patient has a higher benefit from infrapopliteal revascularization than the non-diabetic patient: a 10-year retrospective study. AB - OBJECTIVE: The objective of this article is to evaluate the limb salvage and patency rates after crural arterial revascularization, differences between graft material and co-morbidities. PATIENTS AND METHODS: All patients with crural artery bypasses were analysed retrospectively in a single centre (Department of Vascular Surgery, Thuringen Kliniken Saalfeld, Rudolstadt, Germany) over a 10 year period (1996-2006); 157 patients with 170 consecutive arterial reconstructions could be included. RESULTS: Follow-up time was 55 months (6-119). Median age of the 56 women and the 101 men at the time of operation was 70 years (45.6-93.6). The five-year secondary patency rates were 71.5 +/- 6.22% (vein), 44.3 +/- 10.8% (composite; p = 0.0011), 52.6 +/- 13.4% (prosthetic graft with distal vein cuff/patch; p = 0.00953) and 42 +/- 12% (prosthetic graft without distal vein cuff/patch; p = 0.00443). Limb salvage rates after five years were 79.5 +/- 5.8%, 61.6 +/- 10.3%, 77.9 +/- 11.3% and 70.1 +/- 14.7%, respectively. Cumulative limb salvage rate was significantly higher in diabetic patients (78.9 +/- 4.9%), than in non-diabetic patients (66.6 +/- 6.8); p = 0.023. CONCLUSION: Crural reconstruction is a suitable method for peripheral arterial occlusive disease to prevent amputation, particularly in diabetics. PMID- 22505396 TI - Lack of significant renal tubular injury despite acute kidney injury in acute decompensated heart failure. AB - AIMS: Acute kidney injury (AKI) is a strong predictor of adverse events with an incompletely understood pathophysiology. Neutrophil gelatinase-associated lipocalin (NGAL) is proposed as an early marker of renal tubular injury. Our aim is to determine whether AKI during treatment of acute decompensated heart failure (ADHF) is accompanied by renal tubular injury. METHODS AND RESULTS: Urinary NGAL (uNGAL) and urinary creatinine (uCreat) levels were measured in 141 consecutive patients hospitalized for ADHF and followed for 180 days for death or re hospitalization. AKI was defined as a rise in serum creatinine >=0.3 mg/dl in a 48 h period. Median uNGAL/uCreat levels on Day 1 (baseline) were similar between patients who did and did not develop AKI [22.8 (12.5-106.8) MUg/g vs. 20.6 (12.4 52.0) MUg/g, P = 0.55]. On Day 2 and beyond, the difference between the AKI and no AKI cohorts increased, but was only significant on Day 3 [36.2 (21.7-131.8) MUg/g vs. 29.4 (11.4-54.6) MUg/g, P = 0.02]. The area under the receiver operating characteristic curve for Day 2 uNGAL/uCreat (>= or <32 ug/g) to predict AKI was 0.61. There was no difference in diuretic response between 'uNGAL/uCreat + ' (>= 27 ug/g) and 'uNGAL/uCreat-' (<27 ug/g) patients. However 'uNGAL/uCreat + ' patients had more adverse events after 180 days (66% vs. 52%, P = 0.02). CONCLUSIONS: In patients with ADHF who develop AKI following diuretic therapy, a minor rise in uNGAL precedes AKI. However, the degree of renal tubular insult was much lower than that observed in other forms of AKI. PMID- 22505399 TI - Another case of fraud in structural biology. PMID- 22505401 TI - Response to Detection and analysis of unusual features in the structural model and structure-factor data of a birch pollen allergen. AB - The authors of J. Immunol. 184, 725-735 respond to the article by Rupp (2012), Acta Cryst. F68, 366-376. PMID- 22505400 TI - Detection and analysis of unusual features in the structural model and structure factor data of a birch pollen allergen. AB - Physically improbable features in the model of the birch pollen structure Bet v 1d (PDB entry 3k78) are faithfully reproduced in electron density generated with the deposited structure factors, but these structure factors themselves exhibit properties that are characteristic of data calculated from a simple model and are inconsistent with the data and error model obtained through experimental measurements. The refinement of the 3k78 model against these structure factors leads to an isomorphous structure different from the deposited model with an implausibly small R value (0.019). The abnormal refinement is compared with normal refinement of an isomorphous variant structure of Bet v 1l (PDB entry 1fm4). A variety of analytical tools, including the application of Diederichs plots, Rsigma plots and bulk-solvent analysis are discussed as promising aids in validation. The examination of the Bet v 1d structure also cautions against the practice of indicating poorly defined protein chain residues through zero occupancies. The recommendation to preserve diffraction images is amplified. PMID- 22505402 TI - Structure of the third catalytic domain of the protein disulfide isomerase ERp46. AB - Protein disulfide isomerases are responsible for catalyzing the proper oxidation and isomerization of disulfide bonds of newly synthesized proteins in the endoplasmic reticulum. Here, the crystal structure of the third catalytic domain of protein disulfide isomerase ERp46 (also known as protein disulfide isomerase A5 and TXNDC5) was determined to 2.0 A resolution. The structure shows a typical thioredoxin-like fold, but also identifies regions of high structural variability. In particular, the loop between helix alpha2 and strand beta3 adopts strikingly different conformations among the five chains of the asymmetric unit. Cys381 and Cys388 form a structural disulfide and its absence in one of the molecules leads to dramatic conformational changes. The tryptophan residue Trp349 of this molecule inserts into the cavity formed by helices alpha1 and alpha3 of a neighbouring molecule, potentially mimicking the interactions of ERp46 with misfolded substrates. PMID- 22505403 TI - Structure of MurA (UDP-N-acetylglucosamine enolpyruvyl transferase) from Vibrio fischeri in complex with substrate UDP-N-acetylglucosamine and the drug fosfomycin. AB - The development of new antibiotics is necessitated by the rapid development of resistance to current therapies. UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), which catalyzes the first committed step of bacterial peptidoglycan biosynthesis, is a prime candidate for therapeutic intervention. MurA is the target of the antibiotic fosfomycin, a natural product produced by Streptomyces. Despite possessing a high degree of sequence conservation with MurA enzymes from fosfomycin-susceptible organisms, recent microbiological studies suggest that MurA from Vibrio fischeri (VfiMurA) may confer fosfomycin resistance via a mechanism that is not yet understood. The crystal structure of VfiMurA in a ternary complex with the substrate UDP-N-acetylglucosamine (UNAG) and fosfomycin has been solved to a resolution of 1.93 A. Fosfomycin is known to inhibit MurA by covalently binding to a highly conserved cysteine in the active site of the enzyme. A comparison of the title structure with the structure of fosfomycin susceptible Haemophilus influenzae MurA (PDB entry 2rl2) revealed strikingly similar conformations of the mobile substrate-binding loop and clear electron density for a fosfomycin-cysteine adduct. Based on these results, there are no distinguishing sequence/structural features in VfiMurA that would translate to a diminished sensitivity to fosfomycin. However, VfiMurA is a robust crystallizer and shares high sequence identity with many clinically relevant bacterial pathogens. Thus, it would serve as an ideal system for use in the structure guided optimization of new antibacterial agents. PMID- 22505404 TI - Structures of the pleckstrin homology domain of Saccharomyces cerevisiae Avo1 and its human orthologue Sin1, an essential subunit of TOR complex 2. AB - In eukaryotes, multiprotein complexes termed TOR complex 1 (TORC1) and TOR complex 2 (TORC2) function as major regulators of cell growth, metabolism and ageing. The C-terminal domain of the Saccharomyces cerevisiae TORC2 component Avo1 is required for plasma-membrane localization of TORC2 and is essential for yeast viability. X-ray crystal structures of the C-terminal domain of Avo1 and of its human orthologue Sin1 have been determined. The structures show that the C termini of Avo1 and Sin1 both have the pleckstrin homology (PH) domain fold. Comparison with known PH-domain structures suggests a putative binding site for phosphoinositides. PMID- 22505405 TI - Structure of the tetradecanucleotide d(CCCCGGTACCGGGG)2 as an A-DNA duplex. AB - The crystal structure of the tetradecanucleotide sequence d(CCCCGGTACCGGGG)(2) has been determined at 2.5 A resolution in the tetragonal space group P4(1). This sequence was designed with the expectation of a four-way junction. However, the sequence crystallized as an A-DNA duplex and represents more than one full turn of the A-helix. The crystallographic asymmetric unit consists of one tetradecanucleotide duplex. The structural parameters of the A-type DNA duplex structure and the crystal-packing arrangement are described. One Mn(2+) ion was identified with direct coordination to the N7 position of G(13) and a water molecule at the major-groove side of the C(2).G(13) base pair. PMID- 22505406 TI - Structure of the His269Arg mutant of the rat aldose reductase-like protein AKR1B14 complexed with NADPH. AB - Rat aldose reductase-like protein (AKR1B14) is an orthologue of mouse vas deferens protein (AKR1B7) and plays roles in the detoxification of reactive aldehydes and synthesis of prostaglandin F(2alpha). Here, the 1.87 A resolution crystal structure of the His269Arg mutant of AKR1B14 complexed with NADPH is described and shows that the negatively charged 2'-phosphate group of the coenzyme forms an ionic interaction with the positively charged guanidinium group of Arg269 that is also observed in the human aldose reductase (AKR1B1) structure. Previous experiments on the site-directed mutagenesis of His269 to Arg, Phe and Met revealed fourfold, sevenfold and 127-fold increases in the K(m) for NADPH, respectively, which are in agreement with the present molecular-modelling and X ray crystallographic studies. This is the first tertiary structure of a mutant form of this AKR1B7 orthologue to be reported in order to investigate the structure-function relationship of the nonconserved His269 and its role in coenzyme binding. PMID- 22505407 TI - High-resolution crystal structures of factor XIa coagulation factor in complex with nonbasic high-affinity synthetic inhibitors. AB - Factor XI (FXI) is a key enzyme in the coagulation pathway and an attractive target for the development of anticoagulant drugs. A small number of high resolution crystal structures of FXIa in complex with small synthetic inhibitors have been published to date. All of these ligands have a basic P1 group and bind exclusively in the nonprime side of the active site of FXIa. Here, two structures of FXIa in complex with nonbasic inhibitors that occupy both the prime and nonprime sides of the active site are presented. These new structures could be valuable in the design and optimization of new FXIa synthethic inhibitors. PMID- 22505408 TI - Structure of AKR1C3 with 3-phenoxybenzoic acid bound. AB - Aldo-keto reductase 1C3 (AKR1C3) is a human enzyme that catalyzes the NADPH dependent reduction of steroids and prostaglandins. AKR1C3 overexpression is associated with the proliferation of hormone-dependent cancers, most notably breast and prostate cancers. Nonsteroidal anti-inflammatory drugs (NSAIDs) and their analogues are well characterized inhibitors of AKR1C3. Here, the X-ray crystal structure of 3-phenoxybenzoic acid in complex with AKR1C3 is presented. This structure provides useful information for the future development of new anticancer agents by structure-guided drug design. PMID- 22505409 TI - Structure of Escherichia coli aspartate alpha-decarboxylase Asn72Ala: probing the role of Asn72 in pyruvoyl cofactor formation. AB - The crystal structure of the Asn72Ala site-directed mutant of Escherichia coli aspartate alpha-decarboxylase (ADC) has been determined at 1.7 A resolution. The refined structure is consistent with the presence of a hydrolysis product serine in the active site in place of the pyruvoyl group required for catalysis, which suggests that the role of Asn72 is to protect the ester formed during ADC activation from hydrolysis. In previously determined structures of activated ADC, including the wild type and other site-directed mutants, the C-terminal region of the protein is disordered, but in the Asn72Ala mutant these residues are ordered owing to an interaction with the active site of the neighbouring symmetry-related multimer. PMID- 22505410 TI - Structural analysis of Pneumocystis carinii dihydrofolate reductase complexed with NADPH and 2,4-diamino-6-[2-(5-carboxypent-1-yn-1-yl)-5-methoxybenzyl]-5 methylpyrido[2,3-d]pyrimidine. AB - Structural data are reported for 2,4-diamino-6-[2-(5-carboxypent-1-yn-1-yl)-5 methoxybenzyl]-5-methylpyrido[2,3-d]pyrimidine (PY1014) complexed with Pneumocystis carinii dihydrofolate reductase (pcDHFR) refined to 1.8 A resolution. These data reveal that the carboxylate of the omega-carboxyalkynyl side chain of PY1014, the most pcDHFR-selective analog in this series, forms ionic interactions with the conserved Arg75 in the substrate-binding pocket of pcDHFR. The reversal of the 2',5'-substitution pattern of this analog compared with the highly selective diaminopyrimidine analog PY1011 (i.e. the 5' pentynylcarboxy-5'-methoxy pattern of PY1014 versus the 3',4'-dimethoxy-5' pentynylcarboxy pattern of PY1011) is necessary to achieve optimal interaction with Arg75 as observed in other structures. The larger diaminopyrido[2,3 d]pyrimidine ring of PY1014 places the 5'-methoxy group closer to Leu25 and Ser64 than does the diaminopyrimidine ring of PY1011. The 5'-methoxy O atom forms a hydrogen bond to the amide of Leu25 (O...N, 2.7 A) and the 5'-methoxy methyl group makes a hydrophobic contact of 3.1 A with C(beta) of Ser64. Although the IC(50) values of PY1014 and PY1011 are similar, inhibition data show that the selectivity of PY1011 for pcDHFR is significantly greater. The greater selectivity for pcDHFR compared with mammalian DHFR of these inhibitors is also influenced by the enhanced hydrophobic interactions of the side-chain methylene atoms with Phe69 of pcDHFR compared with Asn64 of mammalian DHFR. PMID- 22505411 TI - Purification, crystallization and preliminary crystallographic studies of a PacL homologue from Listeria monocytogenes. AB - Ca(2+)-ATPases are members of a large family of membrane proteins that maintain the selective movement of cations across biological membranes. A putative Listeria monocytogenes Ca(2+)-ATPase (Lmo0818) was crystallized in an unknown functional state. The crystal belonged to space group P2(1)2(1)2(1) and a complete data set was collected to 3.2 A resolution. The molecular-replacement solution obtained revealed that Lmo0818 is likely to adopt an E2-like state mimicking the phosphorylated intermediate in the functional cycle of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) and a stacked bilayer 'type I' packing in the crystal. PMID- 22505412 TI - Crystallization and crystallographic analysis of the ligand-binding domain of the Pseudomonas putida chemoreceptor McpS in complex with malate and succinate. AB - Methyl-accepting chemotaxis proteins (MCPs) are transmembrane proteins that sense changes in environmental signals, generating a chemotactic response and regulating other cellular processes. MCPs are composed of two main domains: a ligand-binding domain (LBD) and a cytosolic signalling domain (CSD). Here, the crystallization of the LBD of the chemoreceptor McpS (McpS-LBD) is reported. McpS LBD is responsible for sensing most of the TCA-cycle intermediates in the soil bacterium Pseudomonas putida KT2440. McpS-LBD was expressed, purified and crystallized in complex with two of its natural ligands (malate and succinate). Crystals were obtained by both the counter-diffusion and the hanging-drop vapour diffusion techniques after pre-incubation of McpS-LBD with the ligands. The crystals were isomorphous and belonged to space group C2, with two molecules per asymmetric unit. Diffraction data were collected at the ESRF synchrotron X-ray source to resolutions of 1.8 and 1.9 A for the malate and succinate complexes, respectively. PMID- 22505413 TI - Preparation, crystallization and preliminary X-ray diffraction studies of the glycosylated form of human interleukin-23. AB - Interleukin-23 (IL-23), a member of the IL-12 family, is a heterodimeric cytokine composed of p19 and p40 subunits. IL-23 plays crucial roles in the activation, proliferation and survival of IL-17-producing helper T cells which induce various autoimmune diseases. Human p19 and p40 subunits were cloned and coexpressed in N acetylglucosaminyltransferase I-negative 293S cells, which produce high-mannose type glycosylated proteins in order to diminish the heterogeneity of modified N linked glycans. The glycosylated human IL-23 was purified and crystallized by the hanging-drop vapour-diffusion method. X-ray diffraction data were then collected to 2.6 A resolution. The crystal belonged to space group P6(1) or P6(5), with unit-cell parameters a = b = 108.94, c = 83.79 A, gamma = 120 degrees . Assuming that the crystal contains one molecule per asymmetric unit, the calculated Matthews coefficient was 2.69 A(3) Da(-1), with a solvent content of 54.2%. The structure was determined by the molecular-replacement method, with an initial R factor of 52.6%. After subsequent rigid-body and positional refinement, the R(work) and R(free) values decreased to 31.4% and 38.7%, respectively. PMID- 22505414 TI - Crystallization and preliminary crystallographic characterization of the N terminal Kunitz domain of boophilin. AB - Boophilin is a tight-binding thrombin inhibitor composed of two canonical Kunitz type domains in a tandem arrangement. Thrombin-bound boophilin can inhibit a second trypsin-like serine proteinase, most likely through the reactive loop of its N-terminal Kunitz domain. Here, the crystallization and preliminary crystallographic analysis of the isolated N-terminal domain of boophilin is reported. The crystals belonged to the orthorhombic space group P2(1)2(1)2(1) and diffracted to beyond 1.8 A resolution using a sealed-tube home source and to 0.87 A resolution at a synchrotron source. PMID- 22505415 TI - Overexpression, crystallization and preliminary X-ray crystallographic analysis of pyridoxal biosynthesis lyase PdxS from Pyrococcus horikoshii. AB - Pyridoxal biosynthesis lyase (PdxS) is an important player in the biosynthesis of pyridoxal 5'-phosphate (PLP), the biologically active form of vitamin B(6). PLP is an important cofactor involved in the metabolic pathway of amine-containing natural products such as amino acids and amino sugars. PdxS catalyzes the condensation of ribulose 5-phosphate (Ru5P), glyceraldehyde 3-phosphate (G3P) and ammonia, while glutamine amidotransferase (PdxT) catalyzes the production of ammonia from glutamine. PdxS and PdxT form a complex, PLP synthase, and widely exist in eubacteria, archaea, fungi and plants. To facilitate further structural comparisons among PdxS proteins, the structural analysis of PdxS from Pyrococcus horikoshii encoded by the Ph1355 gene was initiated. PdxS from P. horikoshii was overexpressed in Escherichia coli and crystallized at 296 K using 2-methyl-2,4 pentanediol as a precipitant. Crystals of P. horikoshii PdxS diffracted to 2.61 A resolution and belonged to the monoclinic space group P2(1), with unit-cell parameters a = 59.30, b = 178.56, c = 109.23 A, beta = 102.97 degrees . The asymmetric unit contained six monomers, with a corresponding V(M) of 2.54 A(3) Da(-1) and a solvent content of 51.5% by volume. PMID- 22505416 TI - Crystal optimization and preliminary diffraction data analysis of the SCAN domain of Zfp206. AB - Zfp206 (also named Zscan10) is a transcription factor that plays an important role in maintaining the pluripotent state of embryonic stem cells. Zfp206 is a member of the SCAN-domain family of C(2)H(2) zinc-finger transcription factors. The SCAN domain is a highly conserved motif of 84 residues which mediates the self-association of and heterodimerization between SCAN-domain family transcription factors. The SCAN domain may therefore be the key to the selective oligomerization of and may combinatorially enhance the regulatory versatility of C(2)H(2) zinc fingers. This paper describes crystallization attempts with the SCAN domain of Zfp206 (Zfp206SCAN) and optimization strategies to obtain diffraction-quality crystals. The best diffracting crystal was grown in a solution consisting of 0.3 M ammonium sulfate, 0.1 M Tris-HCl pH 8.6, 25% PEG 3350, 0.1 M ethylenediaminetetraacetic acid disodium salt dehydrate (EDTA) using the hanging-drop vapour-diffusion technique. Optimized crystals diffracted to 1.85 A resolution and belonged to space group I422, with unit-cell parameters a = 67.57, c = 87.54 A. A Matthews analysis indicated the presence of one Zfp206SCAN molecule per asymmetric unit. PMID- 22505417 TI - Crystallization and preliminary X-ray diffraction analysis of a novel wild-type blue fluorescent protein from Vibrio vulnificus CKM-1. AB - The use of green fluorescent protein (GFP) for non-invasive in vivo imaging is limited to aerobic systems, as chromophore formation requires oxygen. However, a novel NADPH-dependent blue fluorescent protein from Vibrio vulnificus CKM-1 (BFPvv) that emits blue fluorescence in both aerobic and anaerobic systems has recently been discovered. Wild-type BFPvv was overexpressed in Escherichia coli, purified and crystallized using the sitting-drop vapour-diffusion method. The resulting BFPvv crystals diffracted to a resolution of 1.9 A and belonged to space group P3, with unit-cell parameters a = b = 96.62, c = 214.511 A. Assuming the presence of eight molecules in the unit cell, the solvent content was estimated to be ~56.16%. PMID- 22505418 TI - Crystallization of a novel metal-containing cupin from Acidobacterium sp. and preliminary diffraction data analysis. AB - Recombinant AciX9_0562 from Acidobacterium sp. MP5ACTX9 (UniProt ID E8WYN5) containing sequence motifs characteristic of the RmlC-type cupins superfamily and containing Pfam motif PF07883 has been successfully cloned, expressed and purified. AciX9_0562 crystallized in a number of conditions from the Morpheus protein crystallization screen. The best crystal diffracted to 2.7 A resolution (space group C222(1); unit-cell parameters a = 125.29, b = 254.63, c = 82.99 A). Structure solution was facilitated by the automated molecular-replacement pipeline BALBES. The initial solution was automatically rebuilt using the PHENIX AutoBuild wizard, with final R and R(free) values of 0.23 and 0.26, respectively. The structure is currently undergoing manual refinement. PMID- 22505419 TI - Towards the crystal structure elucidation of eukaryotic UDP-galactopyranose mutase. AB - UDP-galactopyranose mutase (UGM) catalyzes the interconversion of UDP galactopyranose and UDP-galactofuranose. Eukaryotic UGMs from Aspergillus fumigatus and Leishmania major have been purified to homogeneity by means of Ni(2+)-affinity chromatography and crystallized. Eukaryotic UGM structure elucidation was not straightforward owing to high pseudo-symmetry, twinning and very low anomalous signal. Phasing to 2.8 A resolution using SAD was successful for L. major UGM. However, the maps could only be improved by iterative density modification and manual model building. High pseudo-symmetry and twinning prevented correct space-group assignment and the completion of structure refinement. The structure of A. fumigatus UGM to 2.52 A resolution was determined by molecular replacement using the incomplete 2.8 A resolution L. major UGM model. PMID- 22505420 TI - Expression, purification, crystallization and preliminary X-ray diffraction analysis of nurse shark beta2-microglobulin. AB - beta(2)-Microglobulin (beta(2)m) is an essential subunit of the major histocompatibility complex (MHC) class I molecule that helps to stabilize the structure of peptide-MHC I (pMHC I). It is also one of the typical immunoglobulin superfamily (IgSF) molecules in the adaptive immune system (AIS). Sharks belong to the cartilaginous fish, which are the oldest jawed vertebrate ancestors with an AIS to exist in the world. Thus, the study of cartilaginous fish beta(2)m would help in understanding the evolution of IgSF molecules. In order to demonstrate this, beta(2)m from a cartilaginous fish, nurse shark (Ginglymostoma cirratum), was expressed, refolded, purified and crystallized. Diffraction data were collected to a resolution of 2.3 A. The crystal belonged to space group P3(2)21, with unit-cell parameters a = b = 88.230, c = 67.146 A. The crystal structure contained two molecules in the asymmetric unit. The results will provide structural information for study of the evolution of beta(2)m and IgSF in the AIS. PMID- 22505421 TI - Crystallization and preliminary X-ray analysis of stationary phase survival protein E (SurE) from Xylella fastidiosa in two crystal forms. AB - The bacterium Xylella fastidiosa is a phytopathogenic organism that causes citrus variegated chlorosis, a disease which attacks economically important crops, mainly oranges. In this communication, the crystallization and preliminary X-ray crystallographic analysis of XfSurE, a survival protein E from X. fastidiosa, are reported. Data were collected for two crystal forms, I and II, to 1.93 and 2.9 A resolution, respectively. Crystal form I belonged to space group C2, with unit cell parameters a = 172.36, b = 84.18, c = 87.24 A, alpha = gamma = 90, beta = 96.59 degrees , whereas crystal form II belonged to space group C2, with unit cell parameters a = 88.05, b = 81.26, c = 72.84 A, alpha = gamma = 90, beta = 94.76 degrees . PMID- 22505422 TI - Crystallization and preliminary X-ray diffraction analysis of human endoplasmic reticulum aminopeptidase 2. AB - Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a critical enzyme involved in the final processing of MHC class I antigens. Peptide trimming by ERAP2 and the other members of the oxytocinase subfamily is essential to customize longer precursor peptides in order to fit them to the correct length required for presentation on major histocompatibility complex class I molecules. While recent structures of ERAP1 have provided an understanding of the 'molecular-ruler' mechanism of substrate selection, little is known about the complementary activities of its homologue ERAP2 despite their sharing 49% sequence identity. In order to gain insights into the structure-function relationship of the oxytocinase subfamily, and in particular ERAP2, the luminal region of human ERAP2 has been crystallized in the presence of the inhibitor bestatin. The crystals belonged to an orthorhombic space group and diffracted anisotropically to 3.3 A resolution in the best direction on an in-house X-ray source. A molecular replacement solution suggested that the enzyme has adopted the closed state as has been observed in other inhibitor-bound aminopeptidase structures. PMID- 22505423 TI - Purification, crystallization and preliminary X-ray analysis of the aminoglycoside-6'-acetyltransferase AAC(6')-Im. AB - Bacterial resistance to the aminoglycoside antibiotics is primarily the result of enzymatic deactivation of the drugs. The aminoglycoside N-acetyltransferases (AACs) are a large family of bacterial enzymes that are responsible for coenzyme A-facilitated acetylation of aminoglycosides. The gene encoding one of these enzymes, AAC(6')-Im, has been cloned and the protein (comprising 178 amino-acid residues) was expressed in Escherichia coli, purified and crystallized as the kanamycin complex. Synchrotron diffraction data to approximately 2.0 A resolution were collected from a crystal of this complex on beamline BL12-2 at SSRL (Stanford, California, USA). The crystals belonged to the hexagonal space group P6(5), with approximate unit-cell parameters a = 107.75, c = 37.33 A, and contained one molecule in the asymmetric unit. Structure determination is under way using molecular replacement. PMID- 22505424 TI - Crystallization and preliminary crystallographic analysis of the complex between triiodothyronine and the bb' fragment of rat protein disulfide isomerase. AB - Protein disulfide isomerase (PDI) is a multifunctional protein that catalyzes the formation of a disulfide bond in nascent and misfolded proteins and is also known to bind to the thyroid hormone triiodothyronine (T3). When T3 is bound to PDI its catalytic activity is inhibited, but the biological function of this binding is not well understood. In previous studies, it was found that T3 binds to the bb' fragment of PDI. Therefore, to clarify the structure of the complex consisting of PDI bound to T3, a crystallographic analysis of the three-dimensional structure of the T3-rat PDI bb' complex was performed. Native bb' crystals and T3-bb' complex crystals were both obtained using the hanging-drop vapour-diffusion technique with 1.6 M trisodium citrate pH 6.2 as a precipitant. The space group of the native bb' crystals was found to be C222, with unit-cell parameters a = 94.8, b = 114.9, c = 182.9 A, while the space group of the T3-bb' complex crystals was P2(1)2(1)2(1), with unit-cell parameters a = 99.9, b = 184.5, c = 232.2 A. Diffraction data for the native and complex crystals were collected to resolutions of 3.06 and 3.00 A, respectively. PMID- 22505425 TI - Crystallization and preliminary X-ray diffraction studies of the abscisic acid receptor PYL3 and its complex with pyrabactin. AB - Abscisic acid (ABA) modulates many developmental processes and responses to environmental stress. Recently, a family of pyrabactin resistance-like proteins (PYLs) in Arabidopsis thaliana were identified to be abscisic acid receptors. Although the 14 PYLs members share a similar sequence identity, they exhibit different responses toward pyrabactin. Apo-PYL3 is a dimer; however, its oligomeric state changes greatly on the addition of pyrabactin. Moreover, pyrabactin binds dimeric PYL3 in a nonproductive mode which prevents receptor activation and inhibition of PP2Cs. Here, the expression, purification and crystallization of apo-PYL3 and of PYL3 complexed with pyrabactin are reported. Diffraction data were optimized to 2.5 A resolution for apo-PYL3 and to 1.83 A resolution for PYL3-pyrabactin. The crystals of apo-PYL3 and PYL3-pyrabactin belonged to space groups P4(1)2(1)2 and P2(1)2(1)2(1), respectively. PMID- 22505426 TI - Cocrystallization and preliminary crystallographic analysis of an inactive MaoC like hydratase mutant with the substrate crotonyl-CoA. AB - MaoC-like hydratase (MaoC) is a recently identified enzyme involved in the biosynthetic pathway of polyhydroxyalkanoates (PHAs), which are completely biodegradable polymers used to produce green plastics. The inactive mutant D194N MaoC was crystallized in the presence of the substrate crotonyl-CoA. Crystals were grown in a number of conditions, but only those produced using 20%(v/v) ethylene glycol were suitable for structural studies. Data were collected to 2.10 A resolution using X-radiation and the crystal belonged to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 81.40, b = 82.58, c = 123.99 A. PMID- 22505427 TI - In praise of impurity: 30S ribosomal S15 protein-assisted crystallization of turnip yellow mosaic virus proteinase. AB - Turnip yellow mosaic virus is an excellent model for eukaryotic positive-stranded RNA virus replication. Correct processing of the replication polyprotein is dependent on the virally encoded cysteine proteinase (PRO) domain. Crystalline needles obtained from highly pure preparations of the recombinant 17.6 kDa PRO did not diffract. In contrast, small hexagonal prisms that were obtained together with the needles under the same conditions but from a poorly purified preparation diffracted to 2 A resolution and allowed structure determination by MIRAS. It turned out that the hexagonal crystals contained stoichiometric amounts of PRO and Escherichia coli 30S ribosomal S15, a 10.1 kDa protein commonly co-purified by immobilized metal-affinity chromatography. The solvent content is nearly 70%, with S15 bridging parallel infinite helices of PRO across large solvent channels. With hindsight, this spurious interaction not only yielded diffraction-quality crystals but would also have allowed structure determination by molecular replacement using S15 as a search model and subsequent automatic rebuilding of the asymmetric unit. PMID- 22505428 TI - Purification, crystallization and preliminary X-ray analysis of OsAREB8 from rice, a member of the AREB/ABF family of bZIP transcription factors, in complex with its cognate DNA. AB - The AREB/ABF family of bZIP transcription factors play a key role in drought stress response and tolerance during the vegetative stage in plants. To reveal the DNA-recognition mechanism of the AREB/ABF family of proteins, the bZIP domain of OsAREB8, an AREB/ABF-family protein from Oryza sativa, was expressed in Escherichia coli, purified and crystallized with its cognate DNA. Crystals of the OsAREB8-DNA complex were obtained by the sitting-drop vapour-diffusion method at 277 K with a reservoir solution consisting of 50 mM MES pH 6.4, 29% MPD, 2 mM spermidine, 20 mM magnesium acetate and 100 mM sodium chloride. A crystal diffracted X-rays to 3.65 A resolution and belonged to space group C222, with unit-cell parameters a = 155.1, b = 206.7, c = 38.5 A. The crystal contained one OsAREB8-DNA complex in the asymmetric unit. PMID- 22505429 TI - Fast high-pressure freezing of protein crystals in their mother liquor. AB - High-pressure freezing (HPF) is a method which allows sample vitrification without cryoprotectants. In the present work, protein crystals were cooled to cryogenic temperatures at a pressure of 210 MPa. In contrast to other HPF methods published to date in the field of cryocrystallography, this protocol involves rapid sample cooling using a standard HPF device. The fast cooling rates allow HPF of protein crystals directly in their mother liquor without the need for cryoprotectants or external reagents. HPF was first attempted with hen egg-white lysozyme and cubic insulin crystals, yielding good to excellent diffraction quality. Non-cryoprotected crystals of the membrane protein photosystem II have been successfully cryocooled for the first time. This indicates that the presented HPF method is well suited to the vitrification of challenging systems with large unit cells and weak crystal contacts. PMID- 22505430 TI - New Elaphomyces species (Elaphomycetaceae, Eurotiales, Ascomycota) from Guyana. AB - Elaphomyces compleximurus sp. nov. and E. digitatus sp. nov. are described from the Pakaraima Mountains of Guyana. Macromorphological, micromorphological, habitat and DNA sequence data are provided for each new species. This is the first report of Elaphomyces ascomata associated with ectomycorrhizal members of the Fabaceae and also for the genus from the lowland South American tropics. PMID- 22505431 TI - Conlarium duplumascospora gen. et. sp. nov. and Jobellisia guangdongensis sp. nov. from freshwater habitats in China. AB - Conlarium duplumascospora gen. et. sp. nov. and Jobellisia guangdongensis sp. nov. are described and illustrated from submerged wood collected from Guangdong Province, China. Conlarium duplumascospora is characterized by gregarious, coriaceous and beaked ascomata; cylindrical, unitunicate asci with a bipartite apical ring; biseriate, fusiform, hyaline, 0-5-septate ascospores with or without appendages; and anamorph with muriform conidia. Jobellisia guangdongensis is characterized by globose to subglobose, gregarious and papillate ascomata; three layered peridium; cylindrical, unitunicate asci with a refractive apical ring; and one-septate, fusiform, greenish brown ascospores. Sequence analyses of partial nuclear large subunit ribosomal DNA (LSU rDNA) were performed to infer the phylogenetic affinities of these new taxa. A key to species of Jobellisia is provided. PMID- 22505432 TI - Thermophilic fungi in an aridland ecosystem. AB - We report a comprehensive multi-year study of thermophilic fungi at the Sevilleta National Wildlife Refuge in central New Mexico. Recovery of thermophilic fungi from soils showed seasonal fluctuations, with greater abundance correlating with spring and summer precipitation peaks. In addition to grassland soils, we obtained and characterized isolates from grassland and riparian litter, herbivore dung and biological soil crusts. All strains belonged to either the Eurotiales or Sordariales (Chaetomiaceae). No particular substrate or microhabitat associations were detected. Molecular typing of strains revealed substantial phylogenetic diversity, eight ad hoc phylogroups across the two orders were identified and genetic diversity was present within each phylogroup. Growth tests over a range of temperatures showed substantial variation in maximum growth rates among strains and across phylogroups but consistency within phylogroups. Results demonstrated that 45-50 C represents the optimal temperature for growth of most isolates, with a dramatic decline at 60 C. Most strains grew at 60 C, albeit slowly, whereas none grew at 65 C, providing empirical confirmation that 60 C presents an evolutionary threshold for fungal growth. Our results support the hypothesis that fungal thermophily is an adaptation to transient seasonal and diurnal high temperatures, rather than simply an adaptation to specialized high temperature environments. We note that the diversity observed among strains and the frequently confused taxonomy within these groups highlight the need for comprehensive biosystematic revision of thermophilic taxa in both orders. PMID- 22505433 TI - Karyological characterization of meiosis, post-meiotic mitosis and nuclear migration in the ectomycorrhizal fungus Rhizopogon roseolus (= R. rubescens). AB - Karyological characteristics during basidiosporogenesis of Rhizopogon roseolus, a member of the hypogeous Agaricomycetes, were studied by light and transmission electron microscopy. More than 1000 tissue fragments of young basidiomata were stained with HCl-Giemsa and observed by a light microscopy to evaluate nuclear behavior. Basidium morphology in the hymenium was observed by transmission electron microscopy. Meiosis and post-meiotic mitosis took place in the center of the basidium. Sterigmata appeared when the first meiotic division occurred, and the center of the basidium became constricted when the second meiotic division occurred. Asynchronous nuclear migration from the basidium into the basidiospores occurred after post-meiotic mitosis, producing eight uninucleate basidiospores. The nucleus migrated patchily into basidiospores. The pattern of post-meiotic mitosis of R. roseolus, in which post-meiotic mitosis took place in the center of the basidium, is reported for the first time. PMID- 22505434 TI - Allocasuarina tree hosts determine the spatial distribution of hypogeous fungal sporocarps in three tropical Australian sclerophyll forests. AB - Across three tropical Australian sclerophyll forest types, site-specific environmental variables could explain the distribution of both quantity (abundance and biomass) and richness (genus and species) of hypogeous fungi sporocarps. Quantity was significantly higher in the Allocasuarina forest sites that had high soil nitrogen but low phosphorous. Three genera of hypogeous fungi were found exclusively in Allocasuarina forest sites including Gummiglobus, Labyrinthomyces and Octaviania, as were some species of Castoreum, Chondrogaster, Endogone, Hysterangium and Russula. However, the forest types did not all group according to site-scale variables and subsequently the taxonomic assemblages were not significantly different between the three forest types. At site scale, significant negative relationships were found between phosphorous concentration and the quantity of hypogeous fungi sporocarps. Using a multivariate information theoretic approach, there were other more plausible models to explain the patterns of sporocarp richness. Both the mean number of fungal genera and species increased with the number of Allocasuarina stems, at the same time decreasing with the number of Eucalyptus stems. The optimal conditions for promoting hypogeous fungi sporocarp quantity and sporocarp richness appear to be related to the presence and abundance of Allocasuarina (Casuarinaceae) host trees. Allocasuarina tree species may have a higher host receptivity for ectomycorrhizal hypogeous fungi species that provide an important food resource for Australian mycophagous animals. PMID- 22505435 TI - Chaenothecopsis quintralis, a new species of calicioid fungus. AB - Chaenothecopsis quintralis from southwestern Argentina is described and illustrated as a new species in the family Mycocaliciaceae. It has been found in three localities in the Andean Patagonian temperate forests, growing strictly on dung of an endemic marsupial Dromiciops gliroides. The new species is distinguished by the hemispherical, black capitulum of ascoma, the presence of asci with croziers, one-celled brown ascospores, and its fimicolous habitat. Analysis of partial nuclear large subunit rDNA (LSU) sequences showed that this taxon is within Mycocaliciales. PMID- 22505436 TI - Hypocrea britdaniae and H. foliicola: two remarkable new European species. AB - Two new species of Hypocrea are added here to the European funga. Hypocrea britdaniae, a fungus with unknown anamorph and large, conspicuous stromata resembling basidiomata of a corticiaceous fungus, is a sister species to the Longibrachiatum clade, while H. foliicola, a leaf-dwelling species that forms pulvinate stromata, is recognized as an additional member of the pachybasium core group. Hypocrea foliicola sporulates in culture in a reduced verticillium-like manner, while it produces a white, typical pachybasium-like anamorph in nature. Ecologically H. foliicola is remarkable in inhabiting leaves, a substrate rarely recorded for Hypocrea. All relevant morphological teleomorphic and anamorphic traits are given. The phylogenetic placement of the new species within Hypocrea/Trichoderma was determined with combined analyses of rpb2 and tef1 exon sequences. PMID- 22505437 TI - Armillaria altimontana, a new species from the western interior of North America. AB - Armillaria altimontana, previously considered North American biological species (NABS) X, is described as new. To date, it appears that A. altimontana prefers higher-elevation, mesic sites within the dry, conifer forest zone of western interior North America. This species has been found on hardwoods and conifers and is associated most commonly with Abies-dominated forest types in southern British Columbia, Washington, Oregon, Idaho and northern California. Partial elongation factor 1-alpha (tef1) sequences were generated from six isolates of A. altimontana originating from three locations in northern Idaho. Phylogenetic analyses of all 10 North American Armillaria species were carried out with maximum parsimony and maximum likelihood. Results indicate that isolates of A. altimontana formed a monophyletic group and clustered with A. calvescens, A. cepistipes, A. gallica and A. nabsnona, which is in agreement with recent phylogenetic studies of Armillaria. PMID- 22505438 TI - Difference between early clinical features of swine origin A H1N1 influenza confirmed and not confirmed infection in Mexico. AB - INTRODUCTION: The Swine Origin A H1N1 Influenza Virus (SOIV) pandemic emerged in April 2009 affecting people and health-care systems worldwide. This study examined the differences among the early clinical features presented in confirmed SOIV cases, those who tested negative for SOIV infection, fatalities, and hospitalized cases. METHODOLOGY: We reviewed 1,024 initial medical records of patients presenting with acute respiratory symptoms who attended the respiratory emergency room of a general hospital in Mexico and had a confirmatory test for influenza AH1N1 by RT-PCR from April to December 2009. RESULTS: Out of 1,024 cases, 457 (44%) were men with a mean age of 31+/-17 years; however, of these, SOIV confirmed cases were younger (26+/-8, p=0.000). SOIV infection was confirmed in 36% of the patients. Most (%?) cases presented mild infection, 20% of the patients required hospitalization, and 0.09% patients died. Asthma was more frequent in confirmed cases (p=0.028). Presence of COPD, systemic arterial hypertension, and diabetes mellitus was significant in confirmed hospitalized cases. Pulmonary rales, wheezing, and sudden symptom onset were more frequent and statistically significant in confirmed patients. Influenza-like illness was more frequent in confirmed cases (p=0.049). CONCLUSIONS: This study presents one of the largest series of the new SOIV infection confirmed by RT-PCR reported. This infection is frequently mild and affects mainly young adults. Sudden symptoms onset, pulmonary rales, and wheezing are early features of this infection. Asthma, COPD, systemic arterial hypertension, and diabetes mellitus should be identified to identify potentially severe and fatal cases. ILI helps distinguish SOIV infection. PMID- 22505439 TI - OXA-type carbapenemases in Acinetobacter baumannii in South America. AB - Acinetobacter baumannii is an opportunistic pathogen that is frequently involved in outbreaks of infection, occurring mostly in intensive care units. The increasing incidence of carbapenem resistance in A. baumannii worldwide is a concern since it limits drastically the range of therapeutic alternatives. The most important mechanism of carbapenem resistance is the enzymatic hydrolysis mediated by carbapenemases. In A. baumannii these enzymes are usually OXA-type carbapenemases, and belong to class D according to the classification of Ambler. The OXA-type carbapenemases are divided into five subgroups, four of which correspond to acquired carbapenemases, which accounts for the distribution of genes blaOXA in different geographic areas. In this work we review the different types of OXA-type carbapenemases present in A. baumannii, emphasizing the current situation in South America with special mention to the findings in Chile. PMID- 22505440 TI - Susceptibility of community associated methicillin resistant Staphylococcus aureus isolated from faeces to antiseptics. AB - INTRODUCTION: The study aimed to investigate the resistance of methicillin resistant Staphylococcus aureus (MRSA), an indicator used in hospitals but isolated from faecal samples of children in the community, to commonly used antibiotics and antiseptic agents. METHODOLOGY: S. aureus isolates were identified by phenotypic and genotypic techniques such as biochemical tests and polymerase chain reaction. Antibiotic susceptibility was investigated using the disc diffusion technique while the agar dilution method was used to determine the minimum inhibitory concentration (MIC) of antiseptics. RESULTS: MRSA showed considerably higher resistance to other antibiotics than methicillin sensitive Staphylococcus aureus (MSSA). Twelve percent of the MSSA were susceptible to all the antibiotics studied while none of the MRSA had this property. A significant difference in susceptibility between MRSA and MSSA to the three antiseptic agents was observed as 68.8%, 75.0% and 100% of MRSA were less susceptible to benzalkonium chloride, chlorhexidine and cetrimide respectively, while 32.0%, 28.0% and 56.0% of MSSA respectively were less susceptible to these agents compared with S. aureus NCTC 6571. Overall, the MICs for the antiseptics were 2-3 times greater in the MRSA than in the MSSA (p < 0.001). CONCLUSION: Results show that the concentration of antiseptics used in the prevention of the transmission of infectious agents may have to be raised to cope with the possible presence of MRSA in patients coming into hospital. PMID- 22505441 TI - Epidemiological study of shigellosis in an urban area of Argentina. AB - INTRODUCTION: Shigellosis represents one of the main causes of bloody diarrhoea in South America. This study aimed to establish the incidence of shigellosis in an urban zone of Buenos Aires, Argentina, by examining the type of Shigella and living conditions associated with this infection. METHODOLOGY: Between January 2009 and December 2010 we analyzed shigellosis in children admitted to the public health service with bloody diarrhoea from La Plata, the capital of Buenos Aires, Argentina. A total of 372 children under 15 years old with Shigella present in their stool samples were admitted to the study. Variables studied were patient age, type of Shigella, family economic status, and access to sewage services and safe drinking water. RESULTS: Shigella flexneri was found to be present in 66.8% of the cases. Incidence was 187 cases/year/100,000 children under 15 years old. Cases were mainly observed during the summer (38.5%) in the population of under 5 years old (69.1% of all cases). The risk of shigellosis increased 12 times in those children who lacked safe drinking water and this risk increased 1.5 times in the population without sewage services. Fewer cases of shigellosis were noted in downtown areas, while hot spots were identified in the suburbs. Treating one case of shigellosis has a local cost of US $976 while assuring safe drinking water and sewage services for one family costs US $634. CONCLUSION: Incidence of shigellosis in urban areas is associated with quality of water and sewage services. Policies aimed at providing education and improving public utilities networks can help to reduce the incidence of shigellosis. PMID- 22505442 TI - Microbiological and clinical characteristics of diabetic foot infections in northern India. AB - INTRODUCTION: India has the largest diabetic population of 50.8 million that could reach an epidemic proportion by 2030. Diabetic foot infection is one of the dreaded complications of diabetes. Only a few studies that focus on patterns of diabetic foot infection in our region, where diabetic foot care is inadequate, are available. This study evaluated microbial and clinical characteristics of diabetic foot infections that will be helpful in taking appropriate measures for their management. METHODOLOGY: In this prospective study conducted during 2008 2009, sixty-two diabetic foot patients underwent detailed history, clinical examination, and laboratory investigations including parameters of systemic infections. Microbial culture and sensitivity were performed at the time of presentation. RESULTS: Among 62 cases, 43.5% had mono-microbial infection, 35.5% had poly-microbial infections, and 21% had sterile culture. Among 82 bacteria isolated, 68% were Gram negative and 32% were Gram positive. Leukocyte counts were higher (16928+/-9642 versus 14593+/-6687 cells/mm(3)) and haemoglobin (7.9+/ 2.4 versus 9.2+/-2.2 mg/dl) lower in poly-microbial compared to mono-microbial infections. Haemoglobin counts were lower and leukocyte counts higher in Gram negative compared to Gram-positive infections. Patients with sterile cultures also had clinical evidence of persistent infection. Escherichia coli were the most common isolate and piperacillin/tazobactam showed highest sensitivity. CONCLUSIONS: Gram-negative bacteria were most prevalent in diabetic foot infection. It is not uncommon to have culture reports negative despite clinical evidence of infection. This study suggests that piperacillin/tazobactam should be the treatment of choice on an empirical basis prior to a definitive bacteriological study and in cases with negative culture reports. PMID- 22505443 TI - Oral care practice for the ventilated patients in intensive care units: a pilot survey. AB - INTRODUCTION: Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in intensive care units (ICUs). One factor causing VAP is aspiration of oral colonisation, which may result from poor oral care practice. Oral care using tooth brushing can prevent formulation of dental plaque that can be a reservoir for microbes causing VAP. METHODOLOGY: A cross-sectional survey was conducted among 124 nurses, using a self-administered questionnaire, to determine methods used, frequency, and attitude of nurses toward oral care provided to mechanically ventilated patients in Malaysian ICUs. RESULTS: Methods for oral care and their frequency of use varied between nurses even in the same unit. Cotton with forceps was used by 73.4% of the nurses. Some nurses used forceps and gauze (65%) or spatulas and gauze (36%). Toothbrushes were used by 50.8% of the nurses. Nurses in this hospital reported to have positive attitude toward providing oral care. CONCLUSIONS: The survey showed the need to have standardised oral care protocols in ICUs to improve quality of oral care provided to ventilated patients. PMID- 22505444 TI - Occult hepatitis B in Egyptian thalassemic children. AB - INTRODUCTION: Thalassemia is hereditary anemia which requires lifelong transfusion as treatment, and hepatitis viral infection is one of the risks of repeated transfusions. Hepatitis B outbreaks in health-care settings are still a serious public health concern worldwide. Blood samples negative for HBsAg but positive for HBV-DNA, with or without the presence of HBV antibodies, are classified as "occult" HBV infection (OBI). This study investigated the prevalence of occult HBV infection in Egyptian thalassemic children. METHODOLOGY: Eighty patients admitted to the Faculty of Medicine, Cairo University Hospital, were involved in this prospective study. Strict inclusion criteria were set to nullify the effect of confounding variables and further minimize selection bias. The following laboratory investigations were performed: complete blood count (CBC); serum AST and ALT; albumin; bilirubin; HBsAg; HBeAg; HBcAb; HCV-RNA; and HBV-DNA. RESULTS: All our patients had no clinical manifestation suggestive of hepatitis. Molecular biology studies revealed positivity for HCV and HBV at 25% and 32.5% respectively. CONCLUSION: The estimated risk of acquiring hepatitis B and C infection in children receiving multiple blood transfusions is surprisingly high. Moreover, occult hepatitis B infection is a considerably risk. PMID- 22505445 TI - Prevalence of keratinophilic fungi in soils of St. Kitts and Nevis. AB - INTRODUCTION: Information on the prevalence of keratinophilic fungi in West Indies is scanty. Occurrence of keratinophilic fungi in soils of St. Kitts and Nevis has not been investigated previously. METHODOLOGY: The prevalence of keratinophilic fungi was investigated in 108 samples of soils of varying habitats from St. Kitts and 55 such samples from Nevis by hair-baiting technique. Fungal growths appearing on the hair baits after four to eight weeks of incubation at room temperature were microscopically examined and cultured on mycological media. Cultures were identified on the basis of colonial and microscopic features. RESULTS: Forty-nine (45%) of the samples from St. Kitts and 38 (69%) from Nevis were positive for keratinophilic fungi. Microsporum gypseum complex, a well-known geophilic dermatophyte, was the most frequently recovered species being present in 15.7% of soils of St. Kitts and 40% of soils of Nevis. The next commonest species recovered was Chrysosporium indicum, represented by 15 (13.9%) isolates from St. Kitts and seven (12.7%) isolates from Nevis. Other infrequently isolated keratinophilic species included Chrysosporium tropicum, Chrysosporium keratinophilum, and unidentified Chrysosporium species. CONCLUSIONS: This study is the first of its kind in the islands of St. Kitts and Nevis. A high incidence of M. gypseum complex in the soil of these islands is a noteworthy finding of public health significance. PMID- 22505446 TI - Diagnostic potential of nested PCR, galactomannan EIA, and beta-D-glucan for invasive aspergillosis in pediatric patients. AB - INTRODUCTION: Limited specific data and investigations are available for invasive aspergillosis (IA) in pediatric patients. We evaluated the diagnostic potential of three noninvasive tests including the Platelia Aspergillus EIA kit for using galactomannan antigen, (1,3)-beta-D-glucan Detection Reagent Kit, and nested-PCR for Aspergillus DNA in sera. We evaluated the diagnostic potential of three noninvasive tests including EIA for galactomannan antigen (Platelia Aspergillus), nested PCR assay for Aspergillus DNA and test for (1->3)-beta-D glucan (Glucatell assay Kit). METHODOLOGY: All pediatric patients treated at the hematology/oncology unit who were at increased risk of developing invasive aspergillosis were enrolled. Clinical samples were examined for Aspergillus infections by mycological methods. Serial blood samples were collected twice weekly and evaluated by noninvasive tests. RESULTS: We analyzed 230 consecutive blood samples from 62 pediatric patients. The incidence rate of invasive aspergillosis in the patients was found to be 27.4%, and the etiologic agents were Aspergillus flavus, Aspergillus fumigatus, and Aspergillus spp. The sensitivity, specificity, positive and negative predictive values, and likelihood ratios for positive and negative results of galactomannan in patients with proven and probable IA were 90%, 92%, 81.8%, 96%, 11.25, and 0.1; for beta-D-glucan they were 50%, 46%, 26%, 70.6%, 0.9, 0.9; and for nested-PCR they were 80%, 96.2%, 88.9%, 92.6%, 21, and 0.2, respectively. CONCLUSIONS: The conventional methods are not able to detect IA, due to the lack of valid and proper sampling. Galactomannan and nested-PCR tests in serum, with enough accuracy and reliability, can serve as noninvasive methods for the detection of IA in pediatric patients. However, the beta-D-glucan test cannot serve as an efficient diagnostic tool in those with hematologic disorders. PMID- 22505447 TI - First isolation in Argentina of a highly virulent Shiga toxin-producing Escherichia coli O145:NM from a domestic cat. AB - INTRODUCTION: Hemolytic uremic syndrome (HUS) is distributed worldwide. In Argentina, more than 450 cases of HUS, mostly sporadic, are reported annually. The main serotype isolated is O157:H7, and among non-O157 STEC, O145:NM is the most frequent strain. We studied the relationship of companion animals living in contact with a child with sporadic HUS, as carriers of Shiga toxin-producing Escherichia coli (STEC) strains. METHODOLOGY: Duplicate rectal swab samples were taken weekly from the household cat and dog at the home of a patient with HUS. Samples were plated on MacConkey and sorbitol MacConkey-CT agar. Confluent growth from each plate was screened for the presence of stx1, stx2 and rfbO157 gene by PCR assays. Up to 300 individual colonies taken from positive plates at screening were retested by PCR. RESULTS: The strain from the cat belonged to the highly virulent serotype O145:NM. Although this strain differed antigenically from the strain isolated from a child with HUS living in the same house, both carried the stx2, eae and ehxA virulence genes. The strain isolated from the dog belonged to the serotype O178:H19. CONCLUSIONS: An asymptomatic household cat may harbour the high virulent STEC strain, such as O145:NM, the second most frequently STEC serotype associated with HUS in Argentina. Companion animals are probably exposed to the same sources as the humans. More studies are needed to establish dogs and cats as sources of infection in the epidemiological cycle of infections caused by STEC strains, and to develop effective control strategies for this pathogen. PMID- 22505448 TI - Chronic hepatitis B with type I diabetes mellitus and autoimmune thyroiditis development during interferon alpha therapy. AB - Interferon alpha is a molecule frequently used in the treatment of chronic hepatitis B, C, and D, with immunomodulatory and antiviral activity. It is also used in some cancer types. It has been widely claimed that interferon alpha triggers autoimmunity, with its broad adverse effect profile. Here we present the case of a 29-year-old male patient with chronic hepatitis B diagnosis who developed type 1 diabetes mellitus and autoimmune thyroiditis during treatment with interferon alfa-2b. Within four months of initiation of treatment with interferon alfa-2b, the patient presented to our clinic with dry mouth, urinary frequency (8 to 10 times per day), drinking plenty of water, night time urination, and tiredness. He was admitted to the clinic when his fasting blood glucose level was detected to be high. After examinations, the patient was diagnosed with type 1 diabetes and autoimmune thyroiditis and began to receive treatment with insulin and propranolol. Fasting blood glucose levels were controlled and thyroid hormones decreased to normal levels within one month after the treatments began. For patients who will receive treatment with interferon alpha, especially those individuals with chronic hepatitis, pancreatic autoantibodies should be checked and close monitoring should be performed as there may be glucose tolerance impairment in patients with high titers. In addition, follow-up with thyroid function tests should be performed prior to and during the treatment. PMID- 22505449 TI - Spontaneous splenic rupture in dengue fever with non-fatal outcome in an adult. AB - A 26-year-old male presented with fever for five days and abdominal pain for 24 hours. System examination identified a soft abdomen with diffuse tenderness. CT abdomen findings were consistent with splenic rupture with intra and peri-splenic hematoma. Laboratory investigations showed a platelet count of 40,000 per mm(3). In due course he developed hypotension and underwent splenectomy. Non-structural protein 1 (NS1) dengue antigen was positive in the admission sample and IgM dengue antibodies were detected in the follow-up sample. Histopathology of the spleen showed normal architecture with no evidence of hyperplasia, cellular infiltrates or haematological malignancy. Splenic rupture is a rare, but potentially fatal complication of dengue fever and severe dengue which should be suspected when a patient presents with abdominal pain and hypotension. Our case highlights the occurrence of splenic rupture in the viremic phase of dengue illness before the development of IgM antibodies. PMID- 22505450 TI - Class attendance and students' evaluations of teaching: do no-shows bias course ratings and rankings? AB - BACKGROUND: Many university departments use students' evaluations of teaching (SET) to compare and rank courses. However, absenteeism from class is often nonrandom and, therefore, SET for different courses might not be comparable. OBJECTIVE: The present study aims to answer two questions. Are SET positively biased due to absenteeism? Do procedures, which adjust for absenteeism, change course rankings? RESEARCH DESIGN: The author discusses the problem from a missing data perspective and present empirical results from regression models to determine which factors are simultaneously associated with students' class attendance and course ratings. In order to determine the extent of these biases, the author then corrects average ratings for students' absenteeism and inspect changes in course rankings resulting from this adjustment. SUBJECTS: The author analyzes SET data on the individual level. One or more course ratings are available for each student. MEASURES: Individual course ratings and absenteeism served as the key outcomes. RESULTS: Absenteeism decreases with rising teaching quality. Furthermore, both factors are systematically related to student and course attributes. Weighting students' ratings by actual absenteeism leads to mostly small changes in ranks, which follow a power law. Only a few, average courses are disproportionally influenced by the adjustment. Weighting by predicted absenteeism leads to very small changes in ranks. Again, average courses are more strongly affected than courses of very high or low in quality. CONCLUSIONS: No-shows bias course ratings and rankings. SET are more appropriate to identify high- and low-quality courses than to determine the exact ranks of average courses. PMID- 22505451 TI - Postnatal contraceptive choices among women living with HIV: a decade of experience in a community-based integrated sexual health clinic. AB - BACKGROUND: Establishing effective postnatal contraception is essential for HIV seropositive women to avoid the risk of unwanted pregnancy and minimise HIV transmission to HIV-seronegative partners. The authors describe their experience of providing postnatal contraception to HIV-seropositive women who attend a community-based integrated sexual health clinic. METHODS: The authors performed a retrospective case note review of all women who received care for HIV in pregnancy to term at their clinic from September 2000 to October 2010. RESULTS: A total of 107 pregnancies among 95 women were eligible for review. Attendance for contraceptive advice within 4 weeks of delivery occurred in 82/107 (77%) pregnancies. Depo-Provera(r) was prescribed in 21 (21/82, 26%) cases; an intrauterine contraceptive was arranged in 22/82 (27%) cases and sterilisation had occurred as part of a Caesarean delivery in 10/82 (12%) cases. In seven women who discontinued antiretroviral therapy at delivery one subdermal implant was fitted and the combined contraceptive pill was prescribed six times. In 17/82 (21%) cases women opted to use condoms alone. Attendance for postpartum contraceptive advice was missed following 21/107 (20%) pregnancies. CONCLUSIONS: Uptake of a second contraceptive method in addition to condoms is high among women who attend clinic for contraceptive advice in the immediate postnatal period. However, 20% of women did not attend and their contraceptive choices remain unknown. These women are at risk of unwanted pregnancy and transmission of HIV to seronegative partners if appropriate contraceptive methods are not re established postpartum. PMID- 22505452 TI - Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H. AB - Mutations in the E3 ubiquitin ligase tripartite motif-containing 32 (TRIM32) are responsible for the disease limb-girdle muscular dystrophy 2H (LGMD2H). Previously, we generated Trim32 knockout mice (Trim32-/- mice) and showed that they display a myopathic phenotype accompanied by neurogenic features. Here, we used these mice to investigate the muscle-specific defects arising from the absence of TRIM32, which underlie the myopathic phenotype. Using 2 models of induced atrophy, we showed that TRIM32 is dispensable for muscle atrophy. Conversely, TRIM32 was necessary for muscle regrowth after atrophy. Furthermore, TRIM32-deficient primary myoblasts underwent premature senescence and impaired myogenesis due to accumulation of PIAS4, an E3 SUMO ligase and TRIM32 substrate that was previously shown to be associated with senescence. Premature senescence of myoblasts was also observed in vivo in an atrophy/regrowth model. Trim32-/- muscles had substantially fewer activated satellite cells, increased PIAS4 levels, and growth failure compared with wild-type muscles. Moreover, Trim32-/- muscles exhibited features of premature sarcopenia, such as selective type II fast fiber atrophy. These results imply that premature senescence of muscle satellite cells is an underlying pathogenic feature of LGMD2H and reveal what we believe to be a new mechanism of muscular dystrophy associated with reductions in available satellite cells and premature sarcopenia. PMID- 22505453 TI - Akt-mediated phosphorylation of Bmi1 modulates its oncogenic potential, E3 ligase activity, and DNA damage repair activity in mouse prostate cancer. AB - Prostate cancer (PCa) is a major lethal malignancy in men, but the molecular events and their interplay underlying prostate carcinogenesis remain poorly understood. Epigenetic events and the upregulation of polycomb group silencing proteins including Bmi1 have been described to occur during PCa progression. Here, we found that conditional overexpression of Bmi1 in mice induced prostatic intraepithelial neoplasia, and elicited invasive adenocarcinoma when combined with PTEN haploinsufficiency. In addition, Bmi1 and the PI3K/Akt pathway were coactivated in a substantial fraction of human high-grade tumors. We found that Akt mediated Bmi1 phosphorylation, enhancing its oncogenic potential in an Ink4a/Arf-independent manner. This process also modulated the DNA damage response and affected genomic stability. Together, our findings demonstrate the etiological role of Bmi1 in PCa, unravel an oncogenic collaboration between Bmi1 and the PI3K/Akt pathway, and provide mechanistic insights into the modulation of Bmi1 function by phosphorylation during prostate carcinogenesis. PMID- 22505454 TI - ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion. AB - In contrast to the well-studied classic MAPKs, such as ERK1/2, little is known concerning the regulation and substrates of the atypical MAPK ERK3 signaling cascade and its function in cancer progression. Here, we report that ERK3 interacted with and phosphorylated steroid receptor coactivator 3 (SRC-3), an oncogenic protein overexpressed in multiple human cancers at serine 857 (S857). This ERK3-mediated phosphorylation at S857 was essential for interaction of SRC-3 with the ETS transcription factor PEA3, which promotes upregulation of MMP gene expression and proinvasive activity in lung cancer cells. Importantly, knockdown of ERK3 or SRC-3 inhibited the ability of lung cancer cells to invade and form tumors in the lung in a xenograft mouse model. In addition, ERK3 was found to be highly upregulated in human lung carcinomas. Our study identifies a previously unknown role for ERK3 in promoting lung cancer cell invasiveness by phosphorylating SRC-3 and regulating SRC-3 proinvasive activity by site-specific phosphorylation. As such, ERK3 protein kinase may be an attractive target for therapeutic treatment of invasive lung cancer. PMID- 22505455 TI - The DC receptor DNGR-1 mediates cross-priming of CTLs during vaccinia virus infection in mice. AB - In order to prime T cells, DCs integrate signals emanating directly from pathogens and from their noxious action on the host. DNGR-1 (CLEC9A) is a DC restricted receptor that detects dead cells. Therefore, we investigated the possibility that DNGR-1 affects immunity to cytopathic viruses. DNGR-1 was essential for cross-presentation of dying vaccinia virus-infected (VACV-infected) cells to CD8(+) T cells in vitro. Following injection of VACV or VACV-infected cells into mice, DNGR-1 detected the ligand in dying infected cells and mediated cross-priming of anti-VACV CD8(+) T cells. Loss of DNGR-1 impaired the CD8+ cytotoxic response to VACV, especially against those virus strains that are most dependent on cross-presentation. The decrease in total anti-VACV CTL activity was associated with a profound increase in viral load and delayed resolution of the primary lesion. In addition, lack of DNGR-1 markedly diminished protection from infection induced by vaccination with the modified vaccinia Ankara (MVA) strain. DNGR-1 thus contributes to anti-VACV immunity, following both primary infection and vaccination. The non-redundant ability of DNGR-1 to regulate cross presentation of viral antigens suggests that this form of regulation of antiviral immunity could be exploited for vaccination. PMID- 22505456 TI - Efficient SIVcpz replication in human lymphoid tissue requires viral matrix protein adaptation. AB - SIVs infecting wild-living apes in west central Africa have crossed the species barrier to humans on at least four different occasions, one of which spawned the AIDS pandemic. Although the chimpanzee precursor of pandemic HIV-1 strains must have been able to infect humans, the capacity of SIVcpz strains to replicate in human lymphoid tissues (HLTs) is not known. Here, we show that SIVcpz strains from two chimpanzee subspecies are capable of replicating in human tonsillary explant cultures, albeit only at low titers. However, SIVcpz replication in HLT was significantly improved after introduction of a previously identified human specific adaptation at position 30 in the viral Gag matrix protein. An Arg or Lys at this position significantly increased SIVcpz replication in HLT, while the same mutation reduced viral replication in chimpanzee-derived CD4(+) T cells. Thus, naturally occurring SIVcpz strains are capable of infecting HLTs, the major site of HIV-1 replication in vivo. However, efficient replication requires the acquisition of a host-specific adaptation in the viral matrix protein. These results identify Gag matrix as a major determinant of SIVcpz replication fitness in humans and suggest a critical role in the emergence of HIV/AIDS. PMID- 22505457 TI - Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. AB - Autoimmunity is complicated by bone loss. In human rheumatoid arthritis (RA), the most severe inflammatory joint disease, autoantibodies against citrullinated proteins are among the strongest risk factors for bone destruction. We therefore hypothesized that these autoantibodies directly influence bone metabolism. Here, we found a strong and specific association between autoantibodies against citrullinated proteins and serum markers for osteoclast-mediated bone resorption in RA patients. Moreover, human osteoclasts expressed enzymes eliciting protein citrullination, and specific N-terminal citrullination of vimentin was induced during osteoclast differentiation. Affinity-purified human autoantibodies against mutated citrullinated vimentin (MCV) not only bound to osteoclast surfaces, but also led to robust induction of osteoclastogenesis and bone-resorptive activity. Adoptive transfer of purified human MCV autoantibodies into mice induced osteopenia and increased osteoclastogenesis. This effect was based on the inducible release of TNF-alpha from osteoclast precursors and the subsequent increase of osteoclast precursor cell numbers with enhanced expression of activation and growth factor receptors. Our data thus suggest that autoantibody formation in response to citrullinated vimentin directly induces bone loss, providing a link between the adaptive immune system and bone. PMID- 22505460 TI - The RAMIT trial, a pragmatic RCT of cardiac rehabilitation versus usual care: what does it tell us? PMID- 22505458 TI - The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice. AB - DNGR-1 (CLEC9A) is a receptor for necrotic cells required by DCs to cross-prime CTLs against dead cell antigens in mice. It is currently unknown how DNGR-1 couples dead cell recognition to cross-priming. Here we found that DNGR-1 did not mediate DC activation by dead cells but rather diverted necrotic cell cargo into a recycling endosomal compartment, favoring cross-presentation to CD8(+) T cells. DNGR-1 regulated cross-priming in non-infectious settings such as immunization with antigen-bearing dead cells, as well as in highly immunogenic situations such as infection with herpes simplex virus type 1. Together, these results suggest that DNGR-1 is a dedicated receptor for cross-presentation of cell-associated antigens. Our work thus underscores the importance of cross-priming in immunity and indicates that antigenicity and adjuvanticity can be decoded by distinct innate immune receptors. The identification of specialized receptors that regulate antigenicity of virus-infected cells reveals determinants of antiviral immunity that might underlie the human response to infection and vaccination. PMID- 22505461 TI - Is cardiac rehabilitation fit for purpose in the NHS: maybe not. PMID- 22505459 TI - Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. AB - Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial-mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs. PMID- 22505462 TI - The clinical management of relatives of young sudden unexplained death victims; implantable defibrillators are rarely indicated. AB - OBJECTIVE: Following national guidance on management of sudden unexplained death (SUD) in the young, inherited cardiac conditions (ICC) clinics were established to identify and treat relatives thought to be at increased risk. Studies have examined diagnostic yield of these clinics but outcome of clinical management has not been reported. DESIGN: Observational outcome study of consecutively referred relatives of SUD victims. SETTING: Regional ICC clinic. PATIENTS: 193 individuals (108 families) referred to a regional ICC clinic following SUD/aborted cardiac arrest of a young relative (mean follow-up 16.5 months, range 0.1-61). INTERVENTIONS: All individuals underwent assessment by history, examination, ECG and echocardiography. Exercise electrocardiography, ajmaline provocation, further imaging techniques and genetic testing were performed in selected individuals. Implantable cardioverter-defibrillator (ICD) insertion based on national guidelines. MAIN OUTCOME MEASURES AND RESULTS: Forty-five patients (23%) from 38 families (35%) were diagnosed with an inheritable cause of sudden death. Eighteen had potentially prognostically important medication commenced and 4 had an ICD inserted on clinic recommendation (2 hypertrophic cardiomyopathy, 1 dilated cardiomyopathy, 1 arrhythmogenic right ventricular cardiomyopathy). Two other individuals had ICDs removed after negative testing for familial RYR2 mutations. No deaths have occurred during follow-up to date. CONCLUSION: A diagnosis of an inheritable cause of sudden death was obtained in a significant minority of those with a family history of SUD/aborted cardiac arrest. The number of ICDs inserted as a result of specialist assessment was very small (2%). A major function of the clinic is reassurance of the clinically normal and cessation of treatment after exclusion of familial disease by genetic testing. PMID- 22505463 TI - Clinical usefulness of the metabolic syndrome for the risk of coronary heart disease does not exceed the sum of its individual components in older men and women. The Three-City (3C) Study. AB - OBJECTIVES: To investigate the respective associations and clinical usefulness of the metabolic syndrome (MetS) and its individual components to predict the risk of first coronary heart disease (CHD) events in elderly. DESIGN: The Three-City is a French prospective multisite community-based cohort. SETTING: Three large French cities: Bordeaux, Dijon and Montpellier. PARTICIPANTS: 7612 subjects aged 65 and over who were free of CHD at baseline. MAIN OUTCOME MEASURES: The MetS was defined by the 2005 National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS: During a median follow-up of 5.2 years, 275 first CHD events were adjudicated. The MetS was associated with increased risks of total (adjusted HR: 1.78; 95% CI 1.39 to 2.28), fatal (HR: 2.40; 95% CI 1.41 to 4.09) and non-fatal (HR: 1.64; 95% CI 1.24 to 2.17) CHD events. The association with total CHD was significant in women (HR: 2.56; 95% CI 1.75 to 3.75) but not in men (HR: 1.39; 95% CI 0.99 to 1.94; p for interaction=0.012). When in the same multivariable model, hyperglycemia and abdominal adiposity in women, hyperglycemia, lower HDL cholesterol and abdominal adiposity (inverse association) in men were the components significantly associated with CHD. The components of the MetS but not the MetS itself improved risk prediction beyond traditional risk factors (NRI= 9.35%, p<0;001). CONCLUSION: The MetS is a risk marker for CHD in community-dwelling elderly subjects but may not be useful for CHD risk prediction purposes compared to its individual components. PMID- 22505464 TI - Update on mechanical circulatory support in heart failure. PMID- 22505465 TI - RAMIT presents an outdated version of cardiac rehabilitation. PMID- 22505466 TI - The RAMIT trial: its results in the context of 2012 Cochrane review. PMID- 22505468 TI - Cardiac rehabilitation supports a heterogeneous population of patients. PMID- 22505469 TI - Exercise training as an essential component of cardiac rehabilitation. PMID- 22505470 TI - The future of cardiac rehabilitation in the UK. PMID- 22505472 TI - Exosome release of ADAM15 and the functional implications of human macrophage derived ADAM15 exosomes. AB - A disintegrin and metalloproteinase 15 (ADAM15), the only ADAM protein containing an Arg-Gly-Asp (RGD) motif in its disintegrin-like domain, is a widely expressed membrane protein that is involved in tumor progression and suppression. However, the underlying mechanism of ADAM15-mediated tumor suppression is not clearly understood. This study demonstrates that ADAM15 is released as an exosomal component, and ADAM15 exosomes exert tumor suppressive activities. We found that exosomal ADAM15 release is stimulated by phorbol 12-myristate 13-acetate, a typical protein kinase C activator, in various tumor cell types, and this results in a corresponding decrease in plasma membrane-associated ADAM15. Exosomes rich in ADAM15 display enhanced binding affinity for integrin alphavbeta3 in an RGD dependent manner and suppress vitronectin- and fibronectin-induced cell adhesion, growth, and migration, as well as in vivo tumor growth. Exosomal ADAM15 is released from human macrophages, and macrophage-derived ADAM15 exosomes have tumor inhibitory effects. This work suggests a primary role of ADAM15 for exosome mediated tumor suppression, as well as functional significance of exosomal ADAM protein in antitumor immunity. PMID- 22505473 TI - cAMP response element-binding (CREB) recruitment following a specific CpG demethylation leads to the elevated expression of the matrix metalloproteinase 13 in human articular chondrocytes and osteoarthritis. AB - Osteoarthritis is a degenerative joint disease characterized by a progressive and irreversible loss of the articular cartilage, due in main part to the cleavage of type II collagen within the matrix by the enzyme matrix metalloproteinase (MMP)13. Here, we examined the methylation status of MMP13 promoter and report the demethylation of specific CpG dinucleotides within its promoter in osteoarthritic compared to normal cartilage, which correlates with increased MMP13 expression. Of the promoter CpG sites examined, the -104 CpG was consistently demethylated following treatment of human articular chondrocytes with 10 MUM DNA-methyltransferase inhibitor 5-aza-2'-deoxycytidine, again correlating with increased MMP13 expression. Methylation of the -104 CpG site resulted in reduced promoter activity in the chondrosarcoma cell line SW1353 as shown by CpG-free luciferase reporter. Using electrophoretic mobility shift assays, we identified CREB as the regulating factor able to only bind to the MMP13 promoter when the -104 CpG is demethylated, and confirmed this binding by chromatin immunoprecipitation. Finally, we demonstrated that CREB induces MMP13 expression only following treatment of SW1353 with 0.5 MUM Ca(2+) ionophore A23187. In summary, the -104 CpG is demethylated in osteoarthritic cartilage, correlating with the elevated MMP13 expression and cartilage destruction, providing a highly novel link between epigenetic status and arthritic disease. PMID- 22505474 TI - A DNA repair pathway-focused score for prediction of outcomes in ovarian cancer treated with platinum-based chemotherapy. AB - BACKGROUND: New tools are needed to predict outcomes of ovarian cancer patients treated with platinum-based chemotherapy. We hypothesized that a molecular score based on expression of genes that are involved in platinum-induced DNA damage repair could provide such prognostic information. METHODS: Gene expression data was extracted from The Cancer Genome Atlas (TCGA) database for 151 DNA repair genes from tumors of serous ovarian cystadenocarcinoma patients (n = 511). A molecular score was generated based on the expression of 23 genes involved in platinum-induced DNA damage repair pathways. Patients were divided into low (scores 0-10) and high (scores 11-20) score groups, and overall survival (OS) was analyzed by Kaplan-Meier method. Results were validated in two gene expression microarray datasets. Association of the score with OS was compared with known clinical factors (age, stage, grade, and extent of surgical debulking) using univariate and multivariable Cox proportional hazards models. Score performance was evaluated by receiver operating characteristic (ROC) curve analysis. Correlations between the score and likelihood of complete response, recurrence free survival, and progression-free survival were assessed. Statistical tests were two-sided. RESULTS: Improved survival was associated with being in the high scoring group (high vs low scores: 5-year OS, 40% vs 17%, P < .001), and results were reproduced in the validation datasets (P < .05). The score was the only pretreatment factor that showed a statistically significant association with OS (high vs low scores, hazard ratio of death = 0.40, 95% confidence interval = 0.32 to 0.66, P < .001). ROC curves indicated that the score outperformed the known clinical factors (score in a validation dataset vs clinical factors, area under the curve = 0.65 vs 0.52). The score positively correlated with complete response rate, recurrence-free survival, and progression-free survival (Pearson correlation coefficient [r(2)] = 0.60, 0.84, and 0.80, respectively; P < .001 for all). CONCLUSION: The DNA repair pathway-focused score can be used to predict outcomes and response to platinum therapy in ovarian cancer patients. PMID- 22505475 TI - Molecular scores to predict ovarian cancer outcomes: a worthy goal, but not ready for prime time. PMID- 22505476 TI - Understanding charge transfer at PbS-decorated graphene surfaces toward a tunable photosensor. AB - An intrinsic mechanism of photoinduced hole transfer reactions occurring at the grapheme-PbS interface is described with the purpose of building a tunable photosensor with a responsivity of more than 10(3) A W(-1) . It is remarkable that rational utilization of this finding also realizes symmetric, opposing photoswitching effects, which are effectively mirror images, in a single pristine graphene device. These results highlight the vital importance of interface modification as a powerful tool for creating future ultrasensitive optoelectronic devices. PMID- 22505477 TI - RCVS and BSAVA agree position on postgraduate certificates. PMID- 22505478 TI - Review recommends independent food standards agency for Scotland. PMID- 22505479 TI - Time running out for RCVS diplomas. PMID- 22505480 TI - More cases of SBV expected in cattle as reports in sheep start to decline. PMID- 22505483 TI - Technology to the fore in Las Vegas. PMID- 22505484 TI - Getting to grips with gamebirds. PMID- 22505485 TI - Still a risk of mad cows? The need for epidemiological studies. PMID- 22505486 TI - Where do you start in practice? PMID- 22505487 TI - Contagious equine metritis organism confirmed in Gloucestershire. PMID- 22505488 TI - Abundant blood supply and low P-glycoprotein expression on dynamic 99mTc-MIBI imaging predicted better chemotherapy sensitivity for a breast cancer patient: a case report. AB - A patient with a history of breast cancer underwent 3-phase (99m)Tc-methylene diphosphonate (MDP) imaging followed 3 d later by 3-phase (99m)Tc-sestamibi (MIBI) imaging. During the vascular and blood-pool phases, a lymph node over the right clavicle was seen on both the (99m)Tc-MIBI and the (99m)Tc-MDP scans at as early as 30 s and then became hotter. Four months after receiving chemotherapy, the patient achieved a complete response. The lymph node over the right clavicle vanished on ultrasound examination. The similar distribution of the blood-pool phase between the (99m)Tc-MDP and (99m)Tc-MIBI scans indicated that (99m)Tc-MIBI may similarly provide information on vascularization of the lymph node. In addition to indicating vascularization, our (99m)Tc-MIBI protocol may simultaneously provide information on P-glycoprotein expression important for predicting chemotherapy sensitivity. With information on the resistance of a tumor to drugs and the environment in which it dwells, chemotherapy sensitivity might be predicted more precisely. PMID- 22505489 TI - Multiple brain abscesses and facial palsy in a neonate. PMID- 22505490 TI - Comparing measured and simulated wave directions in the left atrium - a workflow for model personalization and validation. AB - Atrial arrhythmias are frequently treated using catheter ablation during electrophysiological (EP) studies. However, success rates are only moderate and could be improved with the help of personalized simulation models of the atria. In this work, we present a workflow to generate and validate personalized EP simulation models based on routine clinical computed tomography (CT) scans and intracardiac electrograms. From four patient data sets, we created anatomical models from angiographic CT data with an automatic segmentation algorithm. From clinical intracardiac catheter recordings, individual conduction velocities were calculated. In these subject-specific EP models, we simulated different pacing maneuvers and measurements with circular mapping catheters that were applied in the respective patients. This way, normal sinus rhythm and pacing from a coronary sinus catheter were simulated. Wave directions and conduction velocities were quantitatively analyzed in both clinical measurements and simulated data and were compared. On average, the overall difference of wave directions was 15 degrees (8%), and the difference of conduction velocities was 16 cm/s (17%). The method is based on routine clinical measurements and is thus easy to integrate into clinical practice. In the long run, such personalized simulations could therefore assist treatment planning and increase success rates for atrial arrhythmias. PMID- 22505491 TI - Computer aided approximation of flow rate through systemic-pulmonary arterial shunts (SPAS). AB - The discrimination of flow rates through bronchial arteries that are affected by pathological SPAS today still happens solely qualitatively. A reproducible quantification of flow rates, however, would enable the comprehension of phenomena like the intensified shunt perfusion seen in cases of chronic inflammations or the characterization of SPAS that may cause cardiovascular problems. A computational program is developed, that allows the modeling of individual bronchial arteries on the basis of the information provided by angiography. Angiographic images are available from the standard clinical assessment of SPAS. The flow through continuous and geometrically measurable vessel segments and SPAS is given by the law of Hagen-Poiseuille. The discharge through healthy branches is calculated by means of allometric scaling laws. The simulation results are verified by flow experiments in artificial vessel networks made of glass and PE tubing. The experimental set-up mimics realistic, pulsating pressure and flow conditions. When applied to the artificial vessel networks, the model described herein provides results for the volumetric flow rate that differ from values measured in laboratory experiments by <6%. The computer model is also applied to real angiographic images. Due to inaccuracies during the deduction of the geometry and due to necessary simplifications of the model, we expect significant deviations between calculated and real flow rates in bronchial systems. Nevertheless, the presented method enables the physician to objectively estimate the order of magnitude of volumetric flow through individual SPAS fairly independently from his experience and without the need of measurements additional to the mandatory angiography. PMID- 22505492 TI - Comparison of flow dynamics of Perimount Magna and Magna Ease aortic valve prostheses. AB - The aim of the present study was to evaluate and compare the in vitro and flow dynamics of the Magna (MB) and the Magna Ease aortic valve bioprosthesis (MEB) within the ascending aorta. A 2D-particle-image-velocimetry (2D-PIV) study was performed to compare the flow dynamics induced by each pericardial Carpentier Edwards Magna and Magna Ease aortic valve prosthesis in the aortic flow field directly behind the valve. Both prostheses (diameter 23 mm) were placed inside an artificial aorta under pulsatile flow conditions (70 Hz and 70 ml stroke volume). The flow field was evaluated according to velocity, shear strength, and vorticity. Both prostheses showed a jet flow type profile with a maximum velocity of 0.97+/-0.09 m/s for MB and 0.83+/-1.8 m/s for MEB. Flow fields of both valves were similar in acceleration, peak flow deceleration and leakage phase. Maximum shear strength was 20,285+/-11,774 l/s2 for MB and 17,006+/-8453 l/s2 for MEB. Vorticity was nearly similar for counterclockwise and clockwise rotation in both prostheses, but slightly higher with MB (251+/-41 l/s and -250+/-39 l/s vs. 225+/ 48 l/s and -232+/-48 l/s). The point-of-interest (POI)-analysis revealed a higher velocity for left-sided aortic wall compared to right-sided at MB (0.12+/-0.09 m/s vs. 0.18+/-0.10 m/s, p<0.001), but was consistent at MEB (0.09+/-0.05 m/s vs. 0.08+/-0.04 m/s, p=0.508), respectively. Velocity, shear strength and vorticity in an in vitro test set-up are lower with MEB compared to MB, thus resulting in improved flow dynamics with a similar flow field, which might have a positive influence on blood rheology and potential valve degeneration. PMID- 22505493 TI - Percutaneous dilational tracheostomy (PDT) and prevention of blood aspiration with superimposed high-frequency jet ventilation (SHFJV) using the tracheotomy endoscope (TED): results of numerical and experimental simulations. AB - We describe an innovative computer-based method for the analysis of gas flow using a modified airway management technique to perform percutaneous dilatational tracheotomy (PDT) with a rigid tracheotomy endoscope (TED). A test lung was connected via an artificial trachea with the tracheotomy endoscope and ventilated using superimposed high-frequency jet ventilation. Red packed cells were instilled during the puncture phase of a simulated percutaneous tracheotomy in a trachea model and migration of the red packed cells during breathing was continuously measured. Simultaneously, the calculation of the gas-flow within the endoscope was numerically simulated. In the experimental study, no backflow of blood occurred during the use of superimposed high-frequency jet ventilation (SHFJV) from the trachea into the endoscope nor did any transportation of blood into the lower respiratory tract occur. In parallel, the numerical simulations of the openings of TED show almost positive volume flows. Under the conditions investigated there is no risk of blood aspiration during PDT using the TED and simultaneous ventilation with SHFJV. In addition, no risk of impairment of endoscopic visibility exists through a backflow of blood into the TED. The method of numerical simulation offers excellent insight into the fluid flow even under highly transient conditions like jet ventilation. PMID- 22505494 TI - Development of a test system to analyze different hip fracture osteosyntheses under simulated walking. AB - The mechanical complications of osteosyntheses after hip fractures are previously investigated by mostly static or dynamic uniaxial loading test systems. However, the physiologic loading of the hip joint during a normal gait is a multiplanar, dynamic movement. Therefore, we constructed a system to test osteosyntheses for hip fractures under physiologic multiplanar loading representative of normal gait. To evaluate the testing system, 12 femora pairs were tested under 25,000 cycles with two standard osteosyntheses (Proximal Femoral Nail Antirotation/Gamma3 Nail). For angular movement, the varus collapse to cut out (?CO) (?CO=4.8 degrees +/-2.1 degrees for blade and ?CO=7.8 degrees +/-3.8 degrees for screw) was the dominant failure mode, and only slight rotational angle shifts (?Rot) (?Rot=1.7 degrees +/-0.4 degrees for blade and ?Rot=2.4 degrees +/-0.3 degrees for screw) of the femoral head around the implant axis were observed. Angular displacements in varus direction and rotation were higher in specimens reinforced with screws. Hence, the cut out model and the migration directions showed a distinction between helical blade and hip screw. However, there were no significant differences between the different implants. The new setup is able to create clinical failures and allows to give evidence about the anchorage stability of different implant types under dynamic gait motion pattern. PMID- 22505495 TI - Influence of cementless hip stems on femoral cortical strain pattern depending on their extent of porous coating. AB - The extent of porous coating of cementless total hip stems is held responsible for radiological periprosthetic changes, the rate of thigh pain, and even its long-term success. However, there is only sparse knowledge on how the biomechanical loading conditions of the femur are influenced by the extent of porous coating in the early phase after implantation of a cementless hip stem. Aiming to evaluate the effect of surface structuring on the strain pattern of the femur, we implanted three anatomic hip stems with different extents of porous coating (full, two-thirds proximal, and penguin type) in second-generation composite femora coated with a photoelastic layer. A cortical strain mapping was conducted before and after insertion of the implants under standardized loading conditions considering relevant muscle forces. The results of the statistical analysis of three different implantation sequences proved that composite femora are suitable for repeated measurements within the applied experimental setup. Cortical strain changes including stress-shielding effects medially (-60%) and laterally (-50%) were validated with a cadaver femur. The extent of porous coating had no significant influence on the surface strain pattern for an immediate postoperative situation. PMID- 22505496 TI - A portable magnetic induction measurement system (PIMS). AB - For contactless monitoring of ventilation and heart activity, magnetic induction measurements are applicable. As the technique is harmless for the human body, it is well suited for long-term monitoring solutions, e.g., bedside monitoring, monitoring of home care patients, and the monitoring of persons in critical occupations. For such settings, a two-channel portable magnetic induction system has been developed, which is small and light enough to be fitted in a chair or bed. Because demodulation, control, and filtering are implemented on a front-end digital signal processor, a PC is not required (except for visualization/data storage during research and development). The system can be connected to a local area network (LAN) or wireless network (WiFi), allowing to connect several devices to a large monitoring system, e.g., for a residential home for the elderly or a hospital with low-risk patients not requiring standard ECG monitoring. To visualize data streams, a Qt-based (Qt-framework by Nokia, Espoo, Finland) monitoring application has been developed, which runs on Netbook computers, laptops, or standard PCs. To induce and measure the magnetic fields, external coils and amplifiers are required. This article describes the system and presents results for monitoring respiration and heart activity in a (divan) bed and for respiration monitoring in a chair. Planar configurations and orthogonal coil setups were examined during the measurement procedures. The measurement data were streamed over a LAN to a monitoring PC running Matlab (The MathWorks Inc, Natick, MA, USA). PMID- 22505497 TI - Differentiation of enamel lesion activity by vertical reflection intensity - a methodical description. AB - This article describes two objective, instrumental approaches for the distinction of enamel lesion activity - the in vitro measurement of surface layer porosity and surface roughness - and on this basis, the in vivo measurement of vertical reflection intensity (VRI). They are based on the subjective visual and tactile criteria of a dull and rough or a shiny and smooth surface, accepted by the known diagnostic systems, Nyvad criteria, International Caries Detection and Assessment System II, and Universal Visual Scoring System. With a scanning white-light interference microscope, the active lesion surface had a high porosity (118 pores) and a high roughness (Ra 190 nm) constituting a field of view of 280*210 MUm. The inactive lesion surface had almost no porosity (one pore) and a more than 10-fold lower roughness (Ra 10 nm) for the same area. These differences result in a different light reflection of the lesion surfaces, which can be measured as VRI with a chromatic confocal sensor with spacer (mean VRI: active lesions, 7%; inactive lesions, 25%; sound enamel, 35%). In addition to monitoring, this sensor allows an in vivo handheld evaluation in a single (visit) examination. PMID- 22505498 TI - Chromosomal mosaicisms in prenatal diagnosis: correlation with first trimester screening and clinical outcome. AB - OBJECTIVE: To investigate the outcome of pregnancy after detection of chromosomal mosaicism and to determine the correlation between human chorionic gonadotropin (free beta-HCG) and pregnancy-associated plasma protein-A (PAPP-A) levels from first-trimester-screening with pregnancy outcome. METHODS: In a single-center, retrospective survey of the results of prenatal diagnostics performed between January 2000 and March 2011, we identified a total of 40 pregnancies with chromosomal mosaicism. Clinical characteristics and results of first-trimester screening, as well as the outcome of these cases, are described. RESULTS: Out of 40 cases, 21 were defined as confined placental mosaicism, 10 classified as true mosaicism and nine were not classifiable cases. Nuchal translucency (NT) was >=2.5 mm in 8/30 cases with respective measurements. PAPP-A levels were <=0.4 MoM in 9/26 cases, with respective measurements, two of them being newborns with growth restriction. Remarkably, in pregnancies of all four children born with severe growth retardation, <3rd percentile PAPP-A levels were below 0.52 MoM. CONCLUSIONS: Our observations show mosaic pregnancy outcomes to be very heterogeneous. Nevertheless, a combination of low PAPP-A and interpretation of chromosomal mosaicism might identify pregnancies at particular risk for fetal growth restriction. PMID- 22505499 TI - Perinatal impact of the use of metformin and glyburide for the treatment of gestational diabetes mellitus. AB - OBJECTIVE: To evaluate the perinatal impact of metformin and glyburide in the treatment of gestational diabetes mellitus (GDM). METHODS: A randomized clinical trial conducted from July 2008 until September 2010 studied 200 pregnant women with GDM who required adjunctive therapy to diet and physical activity. Patients were randomized to use metformin (n=104) or glyburide (n=96). The drugs were replaced by insulin when they reached the maximum dose without glycemic control. Assessed outcomes: weight and neonatal blood glucose. RESULTS: No difference was found (P>0.05) between the groups regarding maternal age, gestational age at inclusion, body mass index, glucose levels in oral glucose tolerance test (OGTT) 75 g and glycemic control. Difference was found in the number of previous pregnancies (2.84 vs. 2.47, P=0.04) and weight gain during pregnancy (7.78 vs. 9.84, P=0.04) in the metformin group and glyburide respectively. The perinatal results showed no difference (P>0.05) in the percentage of cesarean deliveries, gestational age at delivery, number of newborns large for gestational age (LGA), neonatal hypoglycemia, admission to intensive care unit and perinatal death. We found differences in weight (3193 g vs. 3387 g, P=0.01) and ponderal index (2.87 vs. 2.96, P=0.05) of newborns, and in neonatal blood glucose levels at the 1st (59.78 vs. 54.08, P=0.01) and 3rd h (61.53 vs. 55.89, P=0.01) after birth between the metformin and glyburide groups respectively. CONCLUSIONS: Weight and ponderal index were lower in the newborns of the metformin group; glucose levels (1st and 3rd h after birth) were lower in the glyburide group. PMID- 22505500 TI - Incidence and causes of maternal thrombocytopenia in triplet gestation. AB - OBJECTIVE: To determine the incidence, clinical significance and causes of maternal thrombocytopenia in triplet gestations. STUDY DESIGN: The study population consisted of 150 patients with triplet gestation that delivered at our department between 1990 and 2008. Thrombocytopenia was defined as a platelet count <150,000/MUL. Patients were classified on the basis of the lowest recorded platelet count observed during pregnancy. RESULTS: A low platelet count was observed during the triplet gestation in 36 cases (24.0%), and after delivery in another 19 cases (12.7%). Thrombocytopenia was mild, moderate, and severe in 75% (27/36), 16.7% (6/36), and 8.3% (3/36) of the cases, respectively. During pregnancy, thrombocytopenia was associated with pregnancy-induced hypertension in 25.0% (9/36) of patients, while gestational thrombocytopenia was diagnosed in 72.2% of the cases (26/36). The mean platelet count showed a strong negative correlation with gestational age (r=-0.953, P<0.001), and at 36 weeks approached the limit of thrombocytopenia. CONCLUSIONS: Thrombocytopenia occurs more frequently in triplet gestations than in the general pregnant population, and the rate of moderate and severe forms is higher. The distribution of causes is comparable to that of the general pregnant population. The average platelet count in triplet gestations decreases with gestational age. PMID- 22505501 TI - Prospective risk of stillbirth: monochorionic diamniotic twins vs. dichorionic twins. AB - AIMS: To determine reliably the risk of stillbirth among twin pregnancies. METHODS: A data analysis of 3241 and 6581 women with monochorionic diamniotic (MD) and dichorionic (DD) twins, respectively, who gave birth at >=22 weeks of gestation. RESULTS: The prospective risk (per 1000 women) of stillbirth, 25.3 and 11.5 at gestational week 22, decreased to <10.0 at gestational weeks 31 and 28 among the MD and DD twins, respectively. After single intrauterine fetal death, the co-twin died in utero or within 7 days of life more frequently among MD twins than among DD twins [42.7% (35/82) vs. 2.6% (2/76); relative risk, 16.2; 95% confidence interval, 4.0-65.1]. CONCLUSION: Women with MD twins were 2.2-fold more likely to experience stillbirth than women with DD twins. The prospective risks of stillbirth were <1.0% for both groups of women at >=32 weeks of gestation. PMID- 22505502 TI - Association between increased yolk sac diameter and abnormal karyotypes. AB - AIMS: To investigate the association between increased yolk sac diameter and abnormal karyotype. METHODS: Retrospective analysis of 42 patients with no history of diabetes between 6 and 12 weeks of gestation with increased yolk sac diameter measuring >=6 mm was evaluated by transvaginal ultrasound. Sonographic findings were correlated with karyotype. The Fisher's exact test and exact conditional logistic regression analysis were used for statistical analysis. RESULTS: Chromosome abnormalities were found in 76.2% of chorionic villi samples. A statistically significant relationship between karyotype and missed abortion was detected (P=0.001). None of the patients with a yolk size diameter >=8 mm and viable pregnancy had a normal karyotype. Trisomy 15 or 16 was strongly associated with missed abortion (unadjusted odds ratio=14.97, P=0.01). Nine patients with viable pregnancy had a yolk sac >=6 mm (six patients with normal karyotype, one patient with monosomy X, one patient with trisomy 16, and one patient with trisomy 21). CONCLUSION: Our data indicate that enlarged yolk sac may also be visualized in viable pregnancies. Patients with an enlarged yolk sac and normal karyotype require detailed ultrasound evaluation in the second and third trimester. PMID- 22505503 TI - No "masculinization" effect of a male on birth weight of its female co-twin. AB - OBJECTIVE: To test the hypothesis that the presence of a male affects birth weight of its female co-twin. PATIENTS AND METHODS: We evaluated a large population dataset of bichorionic twins after exclusion of potential confounders and after controlling for parity and gestational age. We tested the hypotheses that males (M) are heavier than females (F) irrespective of gender mix, parity and gestational age, and the hypothesis that birth weight of twins might be influenced by the gender of the co-twin. RESULTS: There were 819 MM pairs, 777 FF pairs and 1097 MF sets, for a total of 2735 males and 2651 female twins. Male twins were heavier than female twins, irrespective of parity or gestational age; twins born to multiparas were heavier than twins born to nulliparas, except for very preterm births (<=32 weeks); males from MF pairs were heavier than males from MM pairs, but the mean birth weight of females from MF was not different from that of females from FF sets suggesting no "masculinization" effect of the male on birth weight of its female co-twin, irrespective of parity and gestational age. CONCLUSIONS: After exclusion of potential confounders and controlling for chorionicity, parity, and gestational age, our data do not support the presence of a "masculinization" effect on birth weight. PMID- 22505504 TI - Comparison of risk calculation approaches in a screening programme for Down syndrome. AB - In the Netherlands, both the LifeCycle Elipse (LC) and the Astraia software package are used to calculate the risk of having a child with Down syndrome. Therefore, pregnant women can be presented with dissimilar risks. In this study the conformity between these risks before and after harmonization of the screening program and its influence on the performance indicators of the first trimester screening were evaluated. The agreement between combined risks (based on the biochemical parameters PAPP-A and fbeta-hCG and a nuchal translucency measurement) was expressed as intraclass correlation coefficient (ICC)=0.99. Conformity between combined risks was better after harmonization (Cohen's kappa=0.75) than before harmonization (Cohen's kappa=0.63). For both risk calculation software packages the area under the ROC-curve was 0.84. The database contained 42 Down syndrome cases; based on the odds of being affected given a positive result (OAPR), LC performed slightly better than Astraia before harmonization (17.9 vs. 21.5, respectively). It has been acknowledged that using different software packages could lead to dissimilar risk calculations. In this study the screening performance indicators of two software packages were quite similar. The agreement of the screening performance after harmonization remains to be seen, but is expected to be even higher. PMID- 22505505 TI - Individual decisions in placenta increta and percreta: a case series. AB - OBJECTIVE: Placenta increta or percreta is an uncommon pathology, sometimes associated with high maternal morbidity. Its prevalence increases proportionally to the number of cesarean sections. This study analyzed the changes of our management strategy to devise treatment guidelines for this uncommon disorder. MATERIALS AND METHODOLOGY: Between 2005 and 2011, 10 cases of placenta increta or percreta were managed at our university hospital maternity department. RESULTS: Among the 10 cases, seven were diagnosed prenatally. Two patients were diagnosed early, at 14 and 17 weeks of gestational age, and their pregnancies were terminated. Five had hysterectomies during the intrapartum period, and despite attempted conservative treatment for the two others, hysterectomy proved necessary 2 months postpartum because of intrauterine infections. Seven of the 10 women had hysterectomies. CONCLUSION: Prenatal diagnosis of placenta increta or percreta is essential to plan the delivery in a competent tertiary care center. The decision to perform a cesarean hysterectomy or leave the placenta in situ for spontaneous delivery is based on the extent of infiltration, the patient's hemodynamic status, and her desire to remain fertile. The high-risk of infection and severe hemorrhage must not be overlooked should conservative treatment be chosen. This situation requires prolonged close monitoring. PMID- 22505506 TI - Fetal sex and perinatal outcomes. AB - OBJECTIVE: To evaluate the relationship of fetal sex with obstetric risk factors and perinatal outcomes. MATERIAL AND METHODS: Retrospective study of deliveries during 2003-2009 at a tertiary hospital based on the analysis of obstetric and neonatal risk variables according to neonatal sex. RESULTS: Of the 29,530 deliveries studied, the neonate was a boy in 15,038 (50.92%) and a girl in 14,492 (49.08%). The rates of gestational diabetes, prematurity, true umbilical cord knot and nuchal cord were higher for male newborns, whereas the rate of echographic diagnosis of intrauterine fetal growth retardation was higher for female newborns. Mothers of male fetuses had higher rates of cesarean delivery and instrumental vaginal delivery. The indication for ending labor due to the non reassuring fetal heart rate was also more frequent among male newborns. This group had higher rates of acidemia, although there were no significant differences between sexes in other short-term neonatal outcomes. In all subgroups analyzed here, fetal weight was higher in male newborns. CONCLUSIONS: Male sex is an independent risk factor for unfavorable outcomes of pregnancy and delivery. PMID- 22505507 TI - Fetal magnetocardiography (fMCG): moving forward in the establishment of clinical reference data by advanced biomagnetic instrumentation and analysis. AB - Cardiotocography and echocardiography are currently standard for fetal heart monitoring. However, both do not provide adequate temporal resolution to measure fetal cardiac time intervals and detect arrhythmias, which can occur during normal sinus rhythm. Fetal magnetocardiography (fMCG) is a non-invasive technique measuring magnetic signals generated by fetal heart activity. Most fMCG devices are installed in research institutions limiting the implementation of this method in a clinical setting. Several institutions made a step forward by installing devices, in particular for fetal investigations, in hospital sites to evaluate the clinical benefit. Based on instrumentation differences which can affect signal quality, there is still no established reference database for fetal cardiac time intervals. A new magnetograph dedicated to fetal recordings was implemented with improved patient comfort. The setting was optimized to establish a standard. A total of 103 healthy fetuses starting as early as possible after the first trimester were recorded and fMCG values of cardiac time intervals were compared to former studies. Data allowed high and reliable detection for all fMCG components starting at 17 weeks. The data were comparable to fMCG multicenter studies, fetal electrocardiography and neonatal ECG results and could serve as a database of norm values for further investigation of fetal arrhythmias. PMID- 22505508 TI - Maternal and fetal cord blood lipids in intrauterine growth restriction. AB - AIM: Small for gestational age neonates (SGA) could be subdivided into two groups according to the underlying causes leading to low birth weight. Intrauterine growth restriction (IUGR) is a pathologic condition with diminished growth velocity and fetal compromised well-being, while non-growth restricted SGA neonates are constitutionally (genetically determined) small. Antenatal sonographic measurements are used to differentiate these two subgroups. Maternal metabolic changes contribute to the pathogenesis of IUGR. A disturbed lipid metabolism and cholesterol supply might affect the fetus, with consequences for fetal programming of cardiovascular diseases. We evaluated fetal serum lipids and hypothesized a more atherogenic lipoprotein profile in IUGR fetuses. METHODS: Umbilical cord serum lipids and oxidative modified, low-density lipoprotein (oxLDL) concentrations were measured by colorimetric enzymatic measurements, or by ELISA. Values of IUGR (n=36) and constitutionally small for gestational age neonates (SGA, n=22) were compared with those of healthy, adequate for gestational age, born neonates (CN, n=97). SAS-statistic software was used and two-way ANOVA was adjusted for gestational age at delivery. RESULTS: Fetal high density lipoprotein cholesterol (HDL-C) and total cholesterol (TC) concentrations were found to be lower in the IUGR compared to the CN and SGA groups (HDL-C: P<0.001, TC: P<0.01). Atherogenic indices, including the oxLDL/LDL-C ratio, were increased in the IUGR compared to the CN group (oxLDL/LDL-C ratio: P<0.001). CONCLUSION: Our results support the hypothesis of a disturbed cholesterol supply in IUGR fetuses. Born SGA has been shown to be a risk factor for developing cardiovascular disease later in life. Since HDL-C has anti-inflammatory properties, a reduced HDL-C during fetal development, and an increase in atherogenic indices, might provide a link to this observation in IUGR fetuses. PMID- 22505509 TI - Assessment of long-axis ventricular function in the fetal heart with a tissue tracking algorithm. AB - OBJECTIVE: Tissue-tracking echocardiography (TTE) is a method for quantitative assessment of myocardial contraction and relaxation. The purpose of this study was to assess the feasibility of TTE in fetuses and investigate fetal myocardial properties in normal pregnancies. METHODS: Two hundred thirty pregnant women participated in the study. Fetal four-chamber-view cineloops were saved for off line analysis. Reference values for the global longitudinal peak velocity (V), strain (S), strain rate (SR), and displacement (D) in the fetal heart were established using data from 62 right ventricles (RV) and 68 left ventricles (LV). Furthermore, the change of the motion (V and D) and deformation (S and SR) in the course of the pregnancy was analyzed. Intraobserver variability was assessed in a total of 137 cases. The remaining 93 cases were excluded, as there was no tracking possible. RESULTS: Normal fetuses exhibit a statistically significant increase in all motion parameters in both ventricles with increasing gestational age (GA). In contrast, the deformation parameters with advancing GA decrease. RV has a higher diastolic V and SR than LV. CONCLUSIONS: The increase in motion is attributable to fetal cardiac growth, whereas the decrease in deformation parameters indicates an intrauterine adaptation mechanism. RV appears to have a different relaxation pattern than LV. This study establishes a base for further utilization of TTE in fetal medicine and emphasizes a distinct diastolic difference between RV and LV function. PMID- 22505510 TI - Intermittent flushing improves cannula patency compared to continuous infusion for peripherally inserted venous catheters in newborns: results from a prospective observational study. AB - AIMS: Peripheral cannulas in newborns are commonly used for intravenous treatment. However sustained maintenance of cannula patency is often difficult to achieve in this age group. This study compares the duration for which cannula patency can be maintained in newborns under continuous infusion, or an intermittent flushing regimen, with normal saline. METHODS: A prospective observational study was conducted during a 12-month period. All newborns admitted to the 16-bed intermediate care unit, who required intravenous treatment, received either continuous peripheral infusion with 0.9% saline at an infusion rate of 2 mL/h or an intravenous cannula, which was flushed with 1 mL of 0.9% saline at least once every 24 h. RESULTS: A total of 53 patients with 86 cannulas were included. Twenty-five (47%) patients received 41 continuous infusions. The intermittent flushing group consisted of 28 (53%) patients with 45 cannulas administered. The cannula patency was significantly longer in the intermittent flushing group (mean 62.1 vs. 92.8 h, P=0.01). The patient's underlying disease and the cannula insertion site were not related with the duration of the cannula patency. CONCLUSIONS: Our study shows that intermittent cannula flushing is associated with improved cannula patency for peripherally inserted venous catheters in newborns. PMID- 22505511 TI - Cross-over training in neonatology and obstetrics. AB - Neonatology is a relatively new subspeciality of paediatrics, and before this, newborn babies were often managed by obstetricians. The two fields are closely related in the continuity of care that is being provided, and both specialities involve difficult and critical decisions. From personal experience, training in both specialities, even at a junior level, allows a greater understanding of the complexities surrounding these choices and their implications. As such, I propose a short period of mandatory training in both specialities for anyone considering a career in either. PMID- 22505513 TI - Highlight: the 4th International Symposium on Kallikreins and Kallikrein-related peptidases. PMID- 22505514 TI - Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance. AB - Tissue kallikrein (KLK1) and kallikrein-related peptidases (KLK2-15) comprise a family of 15 highly conserved secreted serine proteases with similar structural characteristics and a wide spectrum of functional properties. Both gene expression and protein activity of KLKs are rigorously controlled at various levels via diverse mechanisms, including extensive steroid hormone regulation, to exert their broad physiological role. Nevertheless, deregulated expression, secretion, and function of KLK family members has been observed in several pathological conditions and, particularly, in endocrine-related human malignancies, including those of the prostate, breast, and ovary. The cancer related abnormal activity of KLKs upon substrates such as growth factors, cell adhesion molecules, cell surface receptors, and extracellular matrix proteins facilitate both tumorigenesis and disease progression to the advanced stages. The well-documented relationship between KLK status and the clinical outcome of cancer patients has led to their identification as promising diagnostic, prognostic, and treatment response monitoring biomarkers for these complex disease entities. The main objective of this review is to summarize the existing knowledge concerning the role of KLKs in prostate, breast, and ovarian cancers and to highlight their continually evolving biomarker capabilities that can provide significant benefits for the management of cancer patients. PMID- 22505515 TI - Epigenetic regulation of kallikrein-related peptidases: there is a whole new world out there. AB - The human kallikreins are a cluster of 15 kallikreins and kallikrein-related peptidases (KLKs). Evidence shows the involvement of KLKs in a wide range of pathophysiological processes, and underscores their potential contribution to cancer, skin and neurodegenerative disorders. The control of KLK expression is not fully elucidated. Understanding the mechanisms controlling KLK expression is an essential step towards exploring the pathogenesis of several diseases and the use of KLKs as disease biomarkers and/or therapeutic targets. Recently, epigenetic changes (including methylation, histone modification and microRNAs [miRNAs]) have drawn attention as a new dimension for controlling KLK expression. Reports showed the effect of methylation on the expression of KLK genes. This was also shown to have potential utility as a prognostic marker in cancer. miRNAs are small RNAs that control the expression of their targets at the post transcriptional level. Target prediction showed that KLKs are potential targets of miRNAs that are dysregulated in tumors, including prostate, kidney and ovarian cancers, with downstream effect on tumor proliferation. Experimental validation remains an essential step to confirm the KLK-miRNA interaction. Epigenetic regulation of KLKs holds promise for an array of therapeutic applications in many diseases including cancer. PMID- 22505516 TI - Non-combinatorial library screening reveals subsite cooperativity and identifies new high-efficiency substrates for kallikrein-related peptidase 14. AB - An array of substrates link the tryptic serine protease, kallikrein-related peptidase 14 (KLK14), to physiological functions including desquamation and activation of signaling molecules associated with inflammation and cancer. Recognition of protease cleavage sequences is driven by complementarity between exposed substrate motifs and the physicochemical signature of an enzyme's active site cleft. However, conventional substrate screening methods have generated conflicting subsite profiles for KLK14. This study utilizes a recently developed screening technique, the sparse matrix library, to identify five novel high efficiency sequences for KLK14. The optimal sequence, YASR, was cleaved with higher efficiency (k(cat)/K(m)=3.81 +/- 0.4 * 10(6) M(-1) s(-1)) than favored substrates from positional scanning and phage display by 2- and 10-fold, respectively. Binding site cooperativity was prominent among preferred sequences, which enabled optimal interaction at all subsites as indicated by predictive modeling of KLK14/substrate complexes. These simulations constitute the first molecular dynamics analysis of KLK14 and offer a structural rationale for the divergent subsite preferences evident between KLK14 and closely related KLKs, KLK4 and KLK5. Collectively, these findings highlight the importance of binding site cooperativity in protease substrate recognition, which has implications for discovery of optimal substrates and engineering highly effective protease inhibitors. PMID- 22505517 TI - One round of SELEX for the generation of DNA aptamers directed against KLK6. AB - Kallikrein-related peptidase 6 (KLK6) is an active serine protease that has been implicated in common pathologies, including neurodegenerative disorders such as Parkinson and Alzheimer disease and certain types of cancer. Antibodies, either polyclonal or monoclonal, that exhibit specificity for distinct members of the extended kallikrein family, including KLK6, were developed. With the exception of KLK3/PSA, the identification and generation of aptamers, as potential new tools with improved characteristics demanded for therapeutic and diagnostic applications, has not been explored for KLKs. Here, we report for the first time the identification of novel DNA aptamers against KLK6 that were isolated using a modified systemic evolution of ligands by exponential enrichment technique. The identified aptamers were characterized using fluorescence spectroscopy, competition ELISA, and quartz crystal microbalance, and two aptamers (008 and 022) were found to exhibit high affinity (K(d) in the low nanomolar range) for KLK6. Aptamers were tested for their ability to bind to serum albumin, to demonstrate their specificity for their target, and the possible involvement of such proteins in the transport of aptamers into the bloodstream. The developed aptamers are expected to assist the development of novel diagnostic, biosensing, and therapeutic strategies. PMID- 22505519 TI - Characterization of SPINK9, a KLK5-specific inhibitor expressed in palmo-plantar epidermis. AB - SPINK9, a Kazal-type serine protease inhibitor, is almost exclusively expressed in the palmo-plantar epidermis. SPINK9 selectively inhibits kallikrein-related peptidase 5 (KLK5), no other target enzyme is known at present. In this study, we defined the reactive loop to residues 48 and 49 of SPINK9 and characterized the inhibition and binding of different SPINK9 variants towards KLK5, KLK7, KLK8 and KLK14. Substitutions of single amino acids in the reactive loop had a large impact on both inhibitory efficiency and specificity. Binding studies showed that it is mainly the dissociation rate that is affected by the amino acid substitutions. The inhibitory effect of wild-type SPINK9 was clearly pH-dependent with an improved effect at a pH similar to that of the outer layers of the skin. Modeling of the enzyme-inhibitor complexes showed that the reactive loop of SPINK9 fits very well into the deep negatively charged binding pocket of KLK5. A decrease in pH protonates His48 of the wild-type protein resulting in a positively charged residue, thereby explaining the observed decreased dissociation rate. Interestingly, substitution with a positively charged amino acid at position 48 resulted in a more efficient inhibitor at higher pH. PMID- 22505518 TI - Kallikrein 6 is a novel molecular trigger of reactive astrogliosis. AB - Kallikrein-related peptidase 6 (KLK6) is a trypsin-like serine protease upregulated at sites of central nervous system (CNS) injury, including de novo expression by reactive astrocytes, yet its physiological actions are largely undefined. Taken with recent evidence that KLK6 activates G-protein-coupled protease-activated receptors (PARs), we hypothesized that injury-induced elevations in KLK6 contribute to the development of astrogliosis and that this occurs in a PAR-dependent fashion. Using primary murine astrocytes and the Neu7 astrocyte cell line, we show that KLK6 causes astrocytes to transform from an epitheliod to a stellate morphology and to secrete interleukin 6 (IL-6). By contrast, KLK6 reduced expression of glial fibrillary acidic protein (GFAP). The stellation-promoting activities of KLK6 were shown to be dependent on activation of the thrombin receptor, PAR1, as a PAR1-specific inhibitor, SCH79797, blocked KLK6-induced morphological changes. The ability of KLK6 to promote astrocyte stellation was also shown to be linked to activation of protein kinase C (PKC). These studies indicate that KLK6 is positioned to serve as a molecular trigger of select physiological processes involved in the development of astrogliosis and that this is likely to occur at least in part by activation of the G-protein coupled receptor, PAR1. PMID- 22505520 TI - The miRNA-kallikrein axis of interaction: a new dimension in the pathogenesis of prostate cancer. AB - Kallikrein-related peptidases (KLKs) are a family of serine proteases that were shown to be useful cancer biomarkers. KLKs have been shown to be dysregulated in prostate cancer (PCa). microRNAs (miRNAs) are short RNA nucleotides that negatively regulate gene expression and have been reportedly dysregulated in PCa. We compiled a comprehensive list of 55 miRNAs that are differentially expressed in PCa from previous microarray analysis and published literature. Target prediction analyses showed that 29 of these miRNAs are predicted to target 10 KLKs. Eight of these miRNAs were predicted to target more than one KLK. Quantitative real-time (qRT)-PCR demonstrated that there was an inverse correlation pattern in the expression (normal vs. cancer) between dysregulated miRNAs and their target KLKs. In addition, we experientially validated the miRNA KLK interaction by transfecting miR-331-3p and miR-143 into a PCa cell line. Decreased expression of targets KLK4 and KLK10, respectively, and decreased cellular growth were observed. In addition to KLKs, dysregulated miRNAs were predicted to target other genes involved in the pathogenesis of PCa. These data show that miRNAs can contribute to KLK regulation in PCa. The miRNA-KLK axis of interaction projects a new element in the pathogenesis of PCa that may have therapeutic implications. PMID- 22505521 TI - Stromal cell-associated expression of kallikrein-related peptidase 6 (KLK6) indicates poor prognosis of ovarian cancer patients. AB - Several members of the human kallikrein-related peptidase family, including KLK6, are up-regulated in ovarian cancer. High KLK6 mRNA or protein expression, measured by quantitative polymerase chain reaction and enzyme-linked immunoassay, respectively, was previously found to be associated with a shortened overall and progression-free survival (OS and PFS, respectively). In the present study, we aimed at analyzing KLK6 protein expression in ovarian cancer tissue by immunohistochemistry. Using a newly developed monospecific polyclonal antibody, KLK6 immunoexpression was initially evaluated in normal tissues. We observed strong staining in the brain and moderate staining in the kidney, liver, and ovary, whereas the pancreas and the skeletal muscle were unreactive, which is in line with previously published results. Next, both tumor cell- and stromal cell associated KLK6 immunoexpression were analyzed in tumor tissue specimens of 118 ovarian cancer patients. In multivariate Cox regression analysis, only stromal cell-associated expression, besides the established clinical parameters FIGO stage and residual tumor mass, was found to be statistically significant for OS and PFS [high vs. low KLK6 expression; hazard ratio (HR), 1.92; p=0.017; HR, 1.80; p=0.042, respectively]. These results indicate that KLK6 expressed by stromal cells may considerably contribute to the aggressiveness of ovarian cancer. PMID- 22505522 TI - The kallikrein 14 gene is down-regulated by androgen receptor signalling and harbours genetic variation that is associated with prostate tumour aggressiveness. AB - Kallikrein 14 (KLK14) has been proposed as a useful prognostic marker in prostate cancer, with expression reported to be associated with tumour characteristics such as higher stage and Gleason score. KLK14 tumour expression has also shown the potential to predict prostate cancer patients at risk of disease recurrence after radical prostatectomy. The KLKs are a remarkably hormone-responsive family of genes, although detailed studies of androgen regulation of KLK14 in prostate cancer have not been undertaken to date. Using in vitro studies, we have demonstrated that unlike many other prostatic KLK genes that are strictly androgen responsive, KLK14 is more broadly expressed and inversely androgen regulated in prostate cancer cells. Given these results and evidence that KLK14 may play a role in prostate cancer prognosis, we also investigated whether common genetic variants in the KLK14 locus are associated with risk and/or aggressiveness of prostate cancer in approximately 1200 prostate cancer cases and 1300 male controls. Of 41 single nucleotide polymorphisms assessed, three were associated with higher Gleason score (>=7): rs17728459 and rs4802765, both located upstream of KLK14, and rs35287116, which encodes a p.Gln33Arg substitution in the KLK14 signal peptide region. Our findings provide further support for KLK14 as a marker of prognosis in prostate cancer. PMID- 22505523 TI - Kallikrein-related peptidase signaling in colon carcinoma cells: targeting proteinase-activated receptors. AB - We hypothesized that kallikrein-related peptidase 14 (KLK14) is produced by colonic tumors and can promote tumorigenesis by activating proteinase-activated receptors (PARs). We found that KLK14 is expressed in human colon adenocarcinoma cells but not in adjacent cancer-free tissue; KLK14 mRNA, present in colon cancer, leads to KLK14 protein expression and secretion; and KLK14 signals viaPAR 2 in HT-29 cells to cause (1) receptor activation/internalization, (2) increases in intracellular calcium, (3) stimulation of ERK1/2/MAP kinase phosphorylation, and (4) cell proliferation. We suggest that KLK14, acting via PAR-2, represents an autocrine/paracrine regulator of colon tumorigenesis. PMID- 22505524 TI - Proteinase-activated receptors (PARs): differential signalling by kallikrein related peptidases KLK8 and KLK14. AB - We compared signalling pathways such as calcium transients, MAPK activation, beta arrestin interactions and receptor internalization triggered by kallikrein related peptidases (KLKs) 8 and 14 in human and rat proteinase-activated receptor (PAR)2-expressing human embryonic kidney (HEK) and Kirsten transformed rat kidney (KNRK) cells. Further, we analysed processing by KLK8 vs. KLK14 of synthetic human and rat PAR2-derived sequences representing the cleavage-activation domain of PAR2. Our data show that like KLK14, KLK8 can unmask a PAR2 receptor activating sequence from a peptide precursor. However, whilst KLK8, like KLK14, can signal in rat-PAR2-expressing KNRK cells, this enzyme cannot signal via human PAR2 in HEK or KNRK cells, but rather, disarms HEK PAR1. Thus, KLK8 and KLK14 can signal differentially via the PARs to affect tissue function. PMID- 22505525 TI - Hereditary breast cancer: beyond BRCA genetic analysis; PALB2 emerges. AB - Abstract Despite the initial enthusiasm following the discovery of the association of BRCA germline mutations with hereditary breast and/or ovarian cancer, in many families affected by the syndrome no pathogenic mutations were detected in the two genes, although exhaustively searched. Many other genes have also been implicated due to their role in the same pathway of DNA repair where the BRCA1/2 genes are involved: homologous recombination (HR). Among them, PALB2 clearly emerges as the third breast cancer susceptibility gene. Its mutations have been detected in most populations investigated so far, albeit rarely: in 1% 4% of families negative for BRCA mutations, with either partial or complete penetrance. In some populations, PALB2 recurrent mutations have been identified and the estimated hazard risks are comparable to those of BRCA mutations. Since new effective targeted therapeutic options are becoming available ("synthetic lethality" with novel PARP inhibitors, etc.) that are applicable to all those patients with a defect in HR pathway, it is imperative to detect all these candidate patients. Data obtained from laboratory tests in the tumor (simple immunohistochemistry, gene expression analysis, etc.) can assist in the recognition of a specific pattern (BRCA1ness, HRless) so that even patients that look "sporadic" could benefit from these targeted therapies. Therefore, a genetic analysis algorithm is proposed, although with the advent of Next Generation Sequencing it is predicted that in the future most germline genetic alterations and also somatic or epigenetic events in the tumor of these genes will be detected. PMID- 22505526 TI - Assay-dependent abnormalities in measurements of prostate-specific antigen in serum: an occasional occurrence, but of clinical significance. PMID- 22505527 TI - The role of red blood cell distribution width in cardiovascular and thrombotic disorders. AB - The red blood cell (RBC) distribution width (RDW) is a measurement of the size variation as well as an index of the heterogeneity of the erythrocytes (i.e., anysocytosis), which is typically used in combination with the mean corpuscular volume to troubleshoot the cause of an underlying anemia. Reliable data emerged from a variety of clinical studies have, however, disclosed a new and unpredictable scenario in the clinical usefulness of this measure, supporting the hypothesis that RDW might be a useful parameter for gathering meaningful clinical information, either diagnostic or prognostic, on a variety of cardiovascular and thrombotic disorders. Highly significant associations have been described between RDW value and all-cause, non-cardiac and cardiac mortality in patients with coronary artery disease, acute and chronic heart failure, peripheral artery disease, stroke, pulmonary embolism and pulmonary arterial hypertension. It is however still unclear whether anysocytosis might be the cause, or a simple epiphenomenon of an underlying disease, such as inflammation, impaired renal function, undernutrition, oxidative damage, or perhaps an element of both. Nevertheless, RDW is an easy, inexpensive, routinely reported test, whose assessment might allow the acquisition of significant diagnostic and prognostic information in patients with cardiovascular and thrombotic disorders. PMID- 22505528 TI - Detection of alpha-globin gene deletion and duplication using quantitative multiplex PCR of short fluorescent fragments. AB - BACKGROUND: The aim of this study was to establish a sensitive method that can detect the presence of not only the common but also the unusual or unknown alpha globin gene deletions for screening of alpha-thalassemia. We used quantitative multiplex PCR of short fluorescent fragments (QMPSF) for the alpha-globin genes (HBA) to screen alpha-thalassemia deletions. METHODS: We set up and validated HBA QMPSF using 50 negative and 100 positive controls of deletional alpha thalassemia. To evaluate its ability to detect the presence of the common and unusual or unknown alpha-globin gene deletions, 579 unrelated samples were simultaneously analyzed using this assay and multiplex Gap polymerase chain reaction (Gap-PCR). The inconsistent results were further confirmed by multiplex ligation-dependent probe amplification (MLPA). RESULTS: HBA-QMPSF was capable of detecting alpha-globin gene deletions with an acceptable variability as shown by mean values (SD) of allele dosage for the heterozygous deleted control obtained from intra- and inter-experimental replicates [0.63 (0.01) and 0.61 (0.03)]. In 572 out of the 579 unrelated subjects, HBA-QMPSF and multiplex Gap-PCR gave consistent results. In seven cases which were finally proved to be composed of one rare deletion--Thai/-alpha3.7, one novel deletion--SEA/-alpha2.8, four alphaalphaalphaanti3.7/alphaalpha and one alphaalphaalphaanti4.2/alphaalpha triplications, HBA-QMPSF showed deletion or duplication in the alpha-globin gene while multiplex Gap-PCR failed to give the correct diagnosis. CONCLUSIONS: HBA QMPSF is able to detect the presence of the common and unusual or unknown alpha thalassemia deletions and duplications. It can be used as an initial screening test for alpha-thalassemia caused by HBA gene copy number alteration. PMID- 22505529 TI - High-throughput detection, genotyping and quantification of the human papillomavirus using real-time PCR. AB - BACKGROUND: The establishment of the causal relationship between high-risk human papillomavirus (HR-HPV) infection and cervical cancer and its precursors has resulted in the development of HPV DNA detection systems. Currently, real-time PCR assays for the detection of HPV, such as the RealTime High Risk (HR) HPV assay (Abbott) and the cobas(r) 4800 HPV Test (Roche Molecular Diagnostics) are commercially available. However, none of them enables the detection and typing of all HR-HPV types in a clinical high-throughput setting. This paper describes the laboratory workflow and the validation of a type-specific real-time quantitative PCR (qPCR) assay for high-throughput HPV detection, genotyping and quantification. This assay is routinely applied in a liquid-based cytology screening setting (700 samples in 24 h) and was used in many epidemiological and clinical studies. METHODS: The TaqMan-based qPCR assay enables the detection of 17 HPV genotypes and beta-globin in seven multiplex reactions. These HPV types include all 12 high-risk types (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59), three probably high-risk types (HPV53, 66 and 68), one low-risk type (HPV6) and one undetermined risk type (HPV67). RESULTS: An analytical sensitivity of <=100 copies was obtained for all the HPV types. The analytical specificity of each primer pair was 100% and an intra- and inter-run variability of <6.4% was observed. CONCLUSIONS: The type-specific real-time PCR approach enables detection of 17 HPV types, identification of the HPV type and determination of the viral load in a single sensitive assay suitable for high-throughput screening. PMID- 22505530 TI - Mid-stream vs. first-voided urine collection by using automated analyzers for particle examination in healthy subjects: an Italian multicenter study. AB - BACKGROUND: In analogy with other areas of laboratory diagnostics, the pre analytical phase is the leading source of variability also in urinalysis. We carried out a multicentric study for comparing results obtained from first-voided and mid-stream urine samples. METHODS: Each of the six hospital-based clinical laboratories participating to this study recruited 50 healthy subjects among laboratory staff and/or their relatives. Two consecutive samples of the first morning micturition were collected by vacuum system, the first from the first void and the second from the mid-stream. Routine urinalysis was performed using dip-stick automated analyzers for chemical examination and automated analyzers for formed particle examination (Sysmex UF-100, Sysmex UF-1000i and Iris iQ-200). RESULTS: Counts of epithelial cells (EC), erythrocytes (ERY) and leukocytes (LEU) but not for cylinders (CAS) were significantly higher in the first-voided samples. A significantly higher count of EC, ERY and LEU was also observed between females and males in first-voided samples, whereas no significant difference could be found in mid-stream samples. Health related analyzer specific upper reference limits (URL) were CAS<=1, EC<=5, ERY<=19, Leu<=13 for UF-100; CAS<=1, EC<=4, ERY<=15, Leu<=11 for UF-1000i; CAS<=1, EC<=4, ERY<=18, Leu<=10 for iQ200. The overall prevalence of subjects with cellular elements count exceeding URL was also higher in first-voided than in mid-stream samples. CONCLUSIONS: Mid stream urine was confirmed as the most appropriate sample, since the presence of contaminating elements, such as bacteria, analytes and formed particles are minimized. PMID- 22505531 TI - Percentage of hypochromic erythrocytes as a potential marker of iron availability. AB - BACKGROUND: The percentage of hypochromic red cells (% Hypo-He) is now available on the Sysmex analyzer XE 5000 (Sysmex Corporation, Kobe, Japan). In this study the reliability of % Hypo-He in the assessment of iron status in the presence of inflammation is investigated. METHODS: Ninety healthy subjects, 91 patients with iron deficiency anemia (IDA) previous to therapy, 65 patients with chronic kidney disease (CKD), 57 patients with anemia of chronic diseases (ACD) and 28 patients with storage iron deficiency (ACD/IDA) receiving therapy were analyzed. Pearson's correlation, Independent samples t-test, receiver operating characteristic (ROC) curve analysis and Cohen's k index were applied. RESULTS: % Hypo-He values inversely correlated with the blood hemoglobin (Hb) (r=-0.78) and Hb content (MHC, r=-0.75). In patients with IDA and ACD/IDA the values obtained for % Hypo He showed no statistical difference (p=0.5037). ROC analysis results for % Hypo He in the detection of iron deficiency defined by a serum transferrin receptor (sTfR) >21 nmol/L. The area under the curve is 0.929; cut-off 3.6%, sensitivity 91.5% and specificity 80.9%. Using the threshold 3.6% the k index obtained in comparison to sTfR was 0.64. CONCLUSIONS: % Hypo-He is a reliable parameter for the detection of iron deficiency in patients with anemia in the presence of inflammation. PMID- 22505532 TI - Laboratory evaluation of a flow cytometric BCR-ABL immunobead assay. AB - BACKGROUND: A new flow cytometric (FC) BCR-ABL immunobead assay has been developed recently. Here we present the laboratory evaluation of the commercially available kit. METHODS: Mononuclear cells were isolated, lysed and processed according to the instructions of the manufacturer. Anti-BCR antibodies adsorbed to capture beads bind the BCR-ABL fusion proteins of the lysed cells, a phycoerythrin (PE)-conjugated anti-ABL antibody is the detector reagent and mean fluorescence intensity (MFI) signals were recorded by flow cytometry. Detection of t(9;22)(q34;q11) translocation was carried out with a quantitative PCR assay. RESULTS: MFI results of 20 normal peripheral blood samples were 88+/-8 (mean+/ SD), CV 9%. K562 cells were used as positive control. Within-batch imprecision was excellent (3.7% in the normal and 10% in the pathological range). Cut-off was chosen at MFI 112, where both sensitivity and specificity were 100%. Altogether 17 chronic myeloid leukemia (CML) and 16 acute leukemia samples were analyzed. All PCR positive samples (n=14) were positive with the FC method and negative results were also concordant (n=15). Frozen cell lysates can be stored up to 4 weeks without significant decrease of MFI signal. CONCLUSIONS: The FC BCR-ABL assay is a fast, reproducible and reliable method that may be incorporated into standard flow cytometric protocols to help clinical decision-making. PMID- 22505533 TI - The performance of high sensitivity troponin for the diagnosis of acute myocardial infarction is underestimated. AB - BACKGROUND: Many papers evaluating high sensitivity troponin assays make the diagnosis of myocardial infarction based on conventional troponin assays in clinical use at the time of recruitment. Such analyses often do not show superiority of high sensitivity assays compared with contemporary assays meeting precision guidelines. METHODS: Three hundred and twenty-two patients presenting to the emergency department between November 2006 and April 2007 for evaluation for acute coronary syndrome had serial (0 h and >6 h) bloods taken to compare troponin assays (Roche hsTnT, Abbott TnI, Roche TnT and Vitros TnI). The diagnosis of myocardial infarction was made using each troponin assay separately with which that same assay was analysed for diagnostic performance. RESULTS: The rate of myocardial infarction would be 38.9% using serial hsTnT, 31.3% using serial Abbott TnI, 27.1% using serial TnT and 26.4% using serial Vitros TnI. The baseline sensitivities (0 h) are 89.9% (85.2-93.3) for hsTnT, 77.9% (71.0-87.5) for Abbott TnI, 73.0% (65.6-78.7) for TnT and 86.8% (74.6-94.4%) for Vitros TnI. The specificities (peak 0 h and >6 h samples) are 93.1% (91.2-93.1) for hsTnT, 88.3% (86.5-88.3) for Abbott TnI, 92.2% (90.5-92.2) for TnT and 90.6% (70.1-90.6) for Vitros TnI. CONCLUSIONS: hsTnT has superior sensitivity for myocardial infarction than even assays at or near guideline precision requirements (Abbott and Vitros TnI). The specificity of hsTnT assay is not as poor as previous analyses suggest. PMID- 22505534 TI - Measurement of high-molecular-weight adiponectin is not useful in assessing coronary stenosis. AB - BACKGROUND: In many studies, high-molecular-weight (HMW) adiponectin has been considered the active form of adiponectin. However, whether HMW adiponectin is a good surrogate marker for coronary artery disease still needs to be elucidated. METHODS: We conducted a hospital-based cross-sectional study to examine the relationship between total, HMW or non-HMW adiponectin concentrations and coronary stenosis in 83 male patients and 138 male controls. RESULTS: Patients with coronary stenosis had significantly lower total adiponectin concentrations compared with controls. Non-HMW adiponectin concentrations in cases were significantly lower than the controls. However, there were no significant differences between cases and controls in HMW adiponectin concentrations. From the receiver operating characteristic (ROC) analysis, the area under the curve (AUC) for total and non-HMW adiponectin was significantly larger than that for HMW adiponectin concentrations. Of the three models, that for non-HMW adiponectin showed the largest AUC (total adiponectin 0.74, HMW adiponectin 0.54, and non-HMW adiponectin 0.79). CONCLUSIONS: Despite associations between total adiponectin levels and coronary stenosis, our data go against any apparent association between HMW adiponectin concentrations and coronary stenosis. PMID- 22505535 TI - Editorial: Targeted therapy for HER-2: personalized medicine for her, too. PMID- 22505536 TI - Circulating levels of HER-2/neu oncoprotein in breast cancer. AB - HER-2/neu, also known as c-erbB-2/neu, is an oncogene located in chromosome 17 which encodes HER-2/neu, a transmembrane protein belonging to the EGFR family. The external domain of this protein is released by the cell and can be studied in serum by immunoassay. HER-2/neu in serum is a specific tumor marker and only slight elevations may be found in the absence of malignancy, mainly in association with liver diseases. Likewise, the highest concentrations of this oncoprotein are found in patients with breast cancer, but lower concentrations may be found in other malignancies, particularly ovarian, prostate and lung cancer (mainly adenocarcinomas). HER-2/neu assay sensitivity in patients with untreated primary loco-regional breast cancer is <10% and seems to be related to overexpression in tissue as well as to the most important prognostic factors: tumor size and nodal involvement. Serial HER-2/neu determinations after surgery seem to be useful in the early diagnosis of recurrence, mainly in patients with HER-2/neu overexpression in tissue, but additional studies are necessary to confirm these results. HER-2/neu sensitivity (proportion of patients with abnormal values) in patients with metastasis is around 40%-45%, with a clear relationship to tissue overexpression and to site (higher in visceral metastases) and number of metastases. The clinical utility of HER-2/neu in patients with advanced disease is mainly for therapeutic monitoring. Likewise, in most of the studies published, a relationship has been found between serum HER-2/neu levels (either pretreatment or at follow-up) with tumor response. PMID- 22505537 TI - Properties and units in the clinical laboratory sciences, Part XXIII. The NPU terminology, principles and implementation -a user's guide (Technical Report 2011) (IFCC-IUPAC). AB - This document describes the application of the syntax, semantic rules and format of the NPU terminology for coded dedicated kinds-of-property in the various subject fields of the clinical laboratory sciences. The document sums up considerations and reasoning by the C-SC-NPU and collects the experience with the system through some 8 years of application in electronic health communication. Access to the NPU terminology in English is currently at www.labterm.dk, via the English download files from the Danish Release Centre under the National Board of Health. Updates to the terminology are usually presented once a month. PMID- 22505538 TI - Diurnal variability of total calcium during normal sleep and after an acute shift of sleep. AB - BACKGROUND: Serum total calcium is becoming a widely used test when screening for hyperparathyroidism (HPT) and other causes of hypercalcemia, even if serum calcium is tightly regulated in the body it is unclear whether the reference values are correct for tests taken at different times of the day or for individuals with altered sleep patterns. Thus, the aim was to investigate how timing of testing and sleep affects serum calcium. METHODS: The diurnal variation of total calcium in serum during night-time and day-time conditions was studied in seven healthy volunteers. Serum samples for calcium measurements were collected every hour (48 samples per individual) to evaluate the effect of sampling times, sleep and food intake on the test results. RESULTS: The median intra-individual coefficients of variations for calcium were 3.3% during night time sleep and 2.8% during day-time sleep conditions. There was a clear diurnal variation in serum calcium, with a trough at 08.00 h in the morning after night time sleep and a difference of approximately 0.07 mmol/L between trough and peak. Calcium was lower around the end of the sleep periods, for both night-time and day-time sleep. Food intake did not affect calcium concentrations. CONCLUSIONS: Evaluation of serum calcium results should take diurnal variation into account and allow slightly higher calcium values in the afternoon in comparison with samples collected in the morning. PMID- 22505539 TI - Extracellular matrix-associated (GAGs, CTGF), angiogenic (VEGF) and inflammatory factors (MCP-1, CD40, IFN-gamma) in type 1 diabetes mellitus nephropathy. AB - BACKGROUND: The aim of the present study was to evaluate the role of extracellular matrix-associated glycosaminoglycans (GAGs), connective tissue growth factor (CTGF), angiogenic vascular endothelial growth factor (VEGF) and inflammatory factors (MCP-1, CD40, IFN-gamma) in the development of diabetic nephropathy in type 1 diabetes (T1DM). METHODS: Plasma and urine samples from 30 T1DM patients and 20 healthy controls were used to measure the levels of CTGF, VEGF, MCP-1, CD40 and IFN-gamma by ELISA. Plasma and urine GAGs were measured using a spectrophotometric method. RESULTS: Plasma levels of GAGs, CD40 and MCP-1 and urine levels of GAGs and CTGF were significantly elevated in normoalbuminuric T1DM patients. A tendency to higher plasma VEGF levels was found in patients compared to controls. The urine/plasma GAGs ratio of T1DM patients was almost similar to that of healthy subjects (HS), whereas the urine/plasma CTGF ratio was about three times greater in diabetic patients compared to HS. CONCLUSIONS: Conclusively, increased GAGs and CTGF excretion are evident in T1DM normoalbuminuric juveniles, possibly reflecting early renal injury signs, before the initiation of albuminuria. PMID- 22505540 TI - Validity of the measurement of capillary cholesterol in the diagnosis of defined hypercholesterolemia. PMID- 22505541 TI - Biological variation and reference change values: an essential piece of the puzzle of laboratory testing. PMID- 22505542 TI - Copeptin for acute coronary syndrome: diamond or decoy? PMID- 22505543 TI - Considerations for early acute myocardial infarction rule-out for emergency department chest pain patients: the case of copeptin. AB - The evaluation of patients admitted at the emergency department (ED) for chest pain is challenging and involves many different clinical specialists including emergency physicians, laboratory professionals and cardiologists. The preferable approach to deal with this issue is to develop joint protocols that will assist the clinical decision-making to quickly and accurately rule-out patients with non life-threatening conditions that can be considered for early and safe discharge or further outpatient follow-up, rule-in patients with acute coronary syndrome and raise the degree of alert of the emergency physicians on non-cardiac life threatening emergencies. The introduction of novel biomarkers alongside the well established troponins might support this process and also provide prognostic information about acute short-term or chronic long-term risk and severity. Among the various biomarkers, copeptin measurement holds appealing perspectives. The utility of combining troponin with copeptin might be cost-effective due to the high negative predictive value of the latter biomarker in the rule-out of an acute coronary syndrome. Moreover, in the presence of a remarkably increased concentration (e.g., more than 10 times the upper limit of the reference range), to reveal the presence of acute life-threatening conditions that may not necessarily be identified with the use of troponin alone. The aim of this article is to review current evidence about the clinical significance of copeptin testing in the ED as well as its appropriate placing within diagnostic protocols. PMID- 22505544 TI - A new dot immunoassay for simultaneous detection of celiac specific antibodies and IgA-deficiency. AB - BACKGROUND: This study investigated whether a dot immunoassay (DIA) can provide simultaneous detection of anti-tissue transglutaminase (tTG), anti-deamidated gliadin (DG) and total IgA antibodies, as required in the work-up of celiac disease (CD) patients. METHODS: Celiac disease patients (n=111) consecutively diagnosed from 2001 to 2011 at the Children's Hospital and Institute of Immunology (Technical University Dresden) were tested for anti-tTG, anti-DG and total IgA by enzyme-linked immunosorbent assay (ELISA) and DIA retrospectively. Blood donors (n=45) and non-CD individuals with low IgA serum levels (n=8) were included as controls. Antibodies to endomysial antigens (EmA) were assessed by indirect immunofluorescence (IIF). RESULTS: Four (3.6%) of 111 CD patients demonstrated an IgA deficiency with total IgA below 50 mg/L by ELISA. Total IgA of the 107 IgA-non-deficient CD patients varied from 70 to 6000 mg/L. All four IgA-deficient CD patients were detected by a reduced reaction control of DIA and demonstrated positive anti-tTG or anti-DG IgG by DIA or ELISA. Detection of anti tTG and anti-DG by DIA and ELISA showed a very good agreement (IgA: kappa=0.972, 0.856, respectively; IgG: 0.921, 0.895, respectively). CONCLUSIONS: Immunodot assay is a reliable and easy-to-use technique for the detection of IgA-deficient CD patients. Simultaneous assessment of anti-tTG and anti-DG IgA antibodies, and IgA deficiency by DIA can improve the efficacy of CD serology. PMID- 22505546 TI - An appeal to medical journal editors: the need for a full description of laboratory methods and specimen handling in clinical study reports. PMID- 22505547 TI - Cancer diagnosis: from dogs to DNA or from DNA to dogs? PMID- 22505548 TI - The never-ending search of an acceptable compromise for pancreatic lipase standardisation. PMID- 22505549 TI - SLCO1B1 gene variability influences lipid-lowering efficacy on simvastatin therapy in Southern Brazilians. AB - BACKGROUND: Variants in uptake and efflux transporters can influence diverse statin pharmacokinetics in different populations. This study aimed to investigate the influence of SLCO1B1 gene polymorphism on simvastatin treatment efficacy in a Brazilian population of European ancestry. METHODS: Two hundred and sixteen hypercholesterolemic patients were treated with 20 mg/day simvastatin for 6 months. Plasma lipid and lipoprotein levels were measured at baseline and after 2 and 6 months of treatment. The single nucleotide polymorphisms (SNPs) c.388A>G, c.463C>A and c.521T>C at SLCO1B1 gene were determined by allelic discrimination with TaqMan 5'-nuclease assays. The 388G allele was observed in 160 patients, the 521 C allele was observed in 64 individuals, whereas 61 subjects were 463 A allele carriers. RESULTS: Carriers of the SLCO1B1 388G allele had a greater reduction of total cholesterol and LDL cholesterol with simvastatin treatment, when compared with 56 388A homozygotes (-28.8% vs. -15.8%, p=0.005 and -39.0% vs. -30.6%, p=0.003; respectively). The c.463C>A and c.521T>C SNPs were not associated with simvastatin treatment. The SLCO1B1 haplotypes showed no statistically significant differences in mean percentage reductions in lipid and lipoprotein levels after simvastatin treatment. CONCLUSIONS: The present study suggests that the SLCO1B1 c.388A>G polymorphism could play a role in the inter individual variation of clinical response to simvastatin in Brazilians. These results add to those that suggest that the effects of SLCO1B1 variants may be statin specific. PMID- 22505550 TI - Serum lactate dehydrogenase levels significantly correlate with radiological extent of disease and spirometric values in patients with silicosis due to denim sandblasting. AB - BACKGROUND: The aim of the present study was to investigate serum lactate dehydrogenase (LD) levels in patients with silicosis due to denim sandblasting (SDDS) and also to investigate possible correlations between serum LD levels and the degree of radiological extent of disease (RED) and pulmonary function tests. METHODS: Forty-four males with SDDS and 32 healthy male subjects were included in the study. Patients and healthy controls were compared for serum LD levels. Correlations between serum LD levels, RED and spirometric values were investigated. RESULTS: Patients with SDDS had significantly higher serum LD levels than healthy controls. Patients with complicated SDDS had significantly higher serum LD levels than patients with simple SDDS. Significant correlations were found between serum LD levels and RED values. Significant correlations were found between serum LD levels and spirometric parameters. CONCLUSIONS: High serum LD levels might be considered as a marker of pulmonary parenchymal involvement in patients with SDDS. This study also suggests that the increase in serum LD levels might be closely related to the degree of pulmonary involvement in SDDS patients. PMID- 22505551 TI - Effects of subcutaneous low molecular weight heparin and intravenous unfractionated heparin on serum S100 concentrations in patients with cerebrovascular diseases. AB - BACKGROUND: S100 plays an important role in diagnosis and prognosis of acute ischemic stroke. The objective was to investigate the effects of clinical heparins administrations on serum S100 concentrations in patients with cerebrovascular diseases. METHODS: Forty cases were enrolled in this study, including 10 patients with percutaneous carotid intervention receiving intravenous unfractionated heparin (UFH) at the beginning of stenting (group A1), 10 patients with carotid angiography receiving UFH-free therapy (group A2), 10 patients with cerebral infarction receiving subcutaneous low molecular weight heparin (LMWH) anticoagulation therapy (group B1) and 10 patients with cerebral infarction receiving LMWH-free therapy (group B2). S100 concentrations were analyzed before and after heparin administrations. RESULTS: A rapid increase of serum S100 (median, 1.74-fold, p<0.05) was observed in group A1 within 15 min of UFH administration. In group B1, S100 significantly increased (median, 1.44-fold, p<0.05) at 3 h after LMWH injection. CONCLUSIONS: Both intravenous UFH and subcutaneous LMWH administration induced increases in serum S100 concentrations. It should be taken into account when using S100 as a biomarker of cerebrovascular diseases. PMID- 22505552 TI - Age- and gender-related alteration in plasma advanced oxidation protein products (AOPP) and glycosaminoglycan (GAG) concentrations in physiological ageing. AB - BACKGROUND: The authors studied the role of increased oxidative stress in the development of oxidative protein damage and extracellular matrix (ECM) components in ageing. The age- and gender-associated disturbances in connective tissue metabolism were evaluated by the plasma chondroitin sulphated glycosaminoglycans (CS-GAG) and non-sulphated GAG-hyaluronan (HA) measurements. Plasma concentration of advanced oxidation protein products (AOPP) was analysed in order to assess oxidative protein damage and evaluate the possible deleterious role of oxidative phenomenon on tissue proteoglycans' metabolism during the physiological ageing process. METHODS: Sulphated and non-sulphated GAGs as well as AOPP were quantified in plasma samples from 177 healthy volunteers. RESULTS: A linear age related decline of plasma CS-GAG level was found in this study (r=-0.46; p<0.05). In contrast, HA concentrations rise gradually with age (r=0.44; p<0.05) in plasma samples. For both ECM components, the observed differences were not gender specific. A strong age-dependent relationship has been shown in regard to AOPP. AOPP levels significantly increased with age (r=0.63; p<0.05), equally strongly in both men (r=0.69; p<0.05) and women (r=0.57; p<0.05) during physiological ageing. A significant correlation was found between the concentrations of AOPP and both CS-GAG (r=-0.31; p<0.05) and HA (r=0.33; p<0.05). CONCLUSIONS: Proceeding with age changes in the ECM are reflected by CS-GAG and HA plasma levels. Strong correlations between AOPP and ECM components indicate that oxidative stress targets protein and non-protein components of the connective tissue matrix during human ageing. PMID- 22505553 TI - Clinical comparison of new monoclonal antibody-based nephelometric assays for free light chain kappa and lambda to polyclonal antibody-based assays and immunofixation electrophoresis. PMID- 22505554 TI - Serum biomarkers for the non-invasive diagnosis of liver fibrosis: the importance of being validated. PMID- 22505555 TI - Primary blood tubes mixing: time for updated recommendations. PMID- 22505556 TI - microRNA and the pathogenesis of ovarian cancer--a new horizon for molecular diagnostics and treatment? AB - Ovarian cancer is the leading cause of death among gynecologic malignancies and despite advances in treatment, more than 50% of all patients will experience recurrence, resulting in worse overall prognosis. Therefore, identification of novel biomarkers for ovarian cancer is of significant interest. microRNA (miRNA) constitute a class of small gene regulatory RNA molecules (18-24 nt) and by sequence complementarity, they negatively regulate messenger RNA (mRNA) translation of target genes. Rising data are available that miRNA are functionally involved in the pathogenesis of ovarian cancer. In this regard, recent advances in profiling studies revealed a variety of miRNA candidates, differently expressed in ovarian carcinomas and in disease-specific conditions like hypoxia or chemo-resistance. This review abstracts recent efforts on establishing miRNA as novel molecular biomarkers for ovarian cancer and depicts the existing preliminary framework for defining peripheral-blood derived miRNA as novel circulating biomarkers. Beside these clinical implications, we highlight the current functional understanding of miRNA alteration and discuss major challenges in miRNA profiling approaches. Finally, we briefly outline methodologies to therapeutically modulate miRNA expression in cancer and try to assess how miRNA can improve our conceptual understanding and the clinical management of ovarian cancer. PMID- 22505557 TI - Quantification of human serum insulin concentrations in clinical pharmacokinetic or bioequivalence studies: what defines the "best method"? AB - BACKGROUND: Historically, quantitative clinical diagnostic assays (QCDAs) have not been accepted for use in pharmacokinetic or bioequivalence studies because they do not fully comply with the US Food and Drug Administration (FDA) Guidance for Industry: Bioanalytical Method Validation (e.g., full calibration curve not generated with each analytical run). Samples from a bioequivalence study were analysed for insulin and C-peptide concentrations with QCDAs and guidance conforming radioimmunoassays (RIAs) and the results compared across and within assays. METHODS: Serum samples (n=1913) from study MKC-TI-142 were analysed first using the Roche E170 electrochemiluminescence immunoassay (ECLIA) for insulin concentration and the Immulite 2000 chemiluminescence immunoassay (CLIA) for C peptide, and then using the corresponding Millipore RIAs. RESULTS: The insulin assays were highly correlated: r2=0.92 excluding samples requiring dilution and R2=0.88 including all samples. There was increasing negative bias of the ECLIA compared with the RIA with increasing insulin, especially with samples that required dilution for the RIA. The ECLIA had significantly fewer below quantifiable-limit samples, a larger dynamic analysis range without dilution, and tighter agreement within incurred sample reanalysis (ISR) as compared with the RIA. The C-peptide assays showed good agreement but the CLIA method produced ISR results that were in closer agreement with the original values. CONCLUSIONS: The science indicates that the QCDAs are appropriate for the quantification of serum insulin (ECLIA) and C-peptide (CLIA) concentrations in human pharmacokinetic and bioequivalence studies even though the calibration curve is not generated in each analytical run. PMID- 22505558 TI - Serum cystatin C is an early biomarker for assessment of renal function in burn patients. AB - BACKGROUND: Early detection of renal dysfunction is important in burn patients. This study evaluated whether serum cystatin C (CysC) is a potentially accurate and sensitive marker for identification of reduced glomerular filtration rate (GFR) and the risk factors of impaired renal function in major burn patients. METHODS: A total of 48 adult patients with major burn injury were enrolled. Renal function was assessed using serum creatinine (sCr), 24-h urinary creatinine clearance (24-hCrCl), sCr-based formulae and CysC-based formulae on the second day and seventh day post-burn. RESULTS: There was a high prevalence (27.1%) of acute impaired renal function in major burn patients in the first week post-burn. CysC-based formulae for estimated GFR (eGFR) are more accurate and sensitive for detection of impaired renal function than sCr-based formulae. Multivariate logistic regression analysis demonstrated that age (OR, 2.08; 95% CI 1.26-4.77) and the percentage of burn area (OR, 3.41; 95% CI 1.64-6.95) were independent risk factors of impaired renal function. CONCLUSIONS: The results of this study suggest that CysC is a more accurate and sensitive marker for identification of acute impaired renal function in major burn patients than sCr. It is important to measure CysC and calculate eGFR to prevent acute renal failure and modify drug doses in burn patients, especially those of older age and with major burn areas. PMID- 22505559 TI - A sensitive quantitative test strip based point-of-care albuminuria screening assay. AB - BACKGROUND: Chronic kidney disease is a major health problem and the global guidelines require screening of albuminuria. Therefore, affordable and sensitive albuminuria screening tests are needed. We explored the potential of urine strips, generally reported in the ordinal scale, measured on an automatic strip reader for reporting quantitative and sensitive albumin results. METHODS: We compared reflectance data of Combur-Test(r) strips obtained from the Cobas U411 reader (Roche) with albuminuria data from a nephelometer BNII (Siemens) and with protein concentrations from the pyrogallol red method (Modular P, Roche) for 389/328 non-pathologic and pathologic urine samples, respectively. RESULTS: Imprecision of the reflectance signal of the Cobas U411 was measured with commercial control material (Bio-Rad). Inter-run coefficients of variations (CVs) for reflectance for levels 1 and 2 were 1.7%/4.9%, respectively, and intra-run CVs were 1.8%/4.2%, respectively. Good agreement was obtained between the albumin concentration of the BNII and the protein strip reflectance data (n=389): Y (10,000/protein reflectance, 1/%)=160+0.132.X (albuminuria BNII, mg/L) 0.0000111.X2 (albuminuria BNII, mg/L); r2=0.921. Lower agreement was found between the protein assay (n=328) and the reflectance (r2=0.831). A calibration curve was made between 11.5 mg/L and 121.5 mg/L. The limit of blank (LOB) was 44.7 mg/L. CONCLUSIONS: The present study demonstrates that reflectance data generated by a test strip reader allows for quantitative analysis of albumin. Although the lower limit of the microalbumin range (30 mg/L) cannot be achieved with the dye-binding method, the results are satisfactory for screening purposes. PMID- 22505561 TI - Demasking of epithelial cell adhesion molecule (EpCAM) on circulating epithelial tumor cells by Tween(r)20 treatment in breast cancer patients. AB - BACKGROUND: The epithelial cell adhesion molecule (EpCAM) embedded in the plasma membrane of circulating epithelial tumor cells (CETC) is used for detection and enrichment of circulating tumor cells in peripheral blood and as a target for anti-epithelial antibodies elicited during immune response in anti-tumor immunization. Although an efficient immune response against EpCAM can be generated, the clinical application of such approaches has not been successful so far and the detection of circulating epithelial cells is highly variable. One reason for these discrepancies may be that not all circulating tumor cells are equally accessible for the specific antibody. A possible reason might be masking of EpCAM by glycoproteins or membrane lipoproteins preventing antibody binding. METHODS: We have tested the application of detergents as demasking agents known to be successful in demasking red blood cell epitopes and determined how and in which way they affect integral membrane proteins and membrane lipids. RESULTS: The results showed that the polysorbate Tween(r)20, a non-ionic detergent like organic solvent is able to demask EpCAM on CETC and makes it better accessible to its specific antibody retaining at the same time full cell viability. CONCLUSIONS: The data presented in this study suggest that EpCAM is present on part of circulating tumor cells in a masked form and that it is possible to demask EpCAM on CETC of breast cancer patients using Tween(r)20 treatment. But further studies are needed to elucidate the mechanism of demasking. PMID- 22505562 TI - Blood presence of circulating oncofetal fibronectin mRNA, by RT-PCR, does not represent a useful specific marker for the management and follow-up of thyroid cancer patients. AB - BACKGROUND: Recent studies strongly suggest the use of oncofetal fibronectin (onfFN) mRNA in diagnostic follow-up and staging due to its very high specificity for thyroid cancers. Since the use of this marker has not been well established yet, particularly in the monitoring of minimal residual disease, we have tried to verify the diagnostic power of onfFN and its usefulness as a prognostic molecular marker. For this reason, we evaluated (by RT-PCR) the presence of onfFN mRNAs, not only in blood samples and thyroid tissues (both normal and neoplastic), but also in different biological fluids (such as K3-EDTA blood samples, saliva and urine) belonging to healthy individuals. METHODS: Molecular investigations, such as RT-PCR protocol, and sequencing of onfFN cDNAs evaluation of the above mentioned samples were performed. RESULTS: The onfFN transcript was largely expressed in all benign and malignant thyroid tissues [differentiated thyroid carcinomas (DTCs)] tested as well as in a large number of biological fluids; in particular, 100% urine samples were positive for onfFN transcript as compared to the thyroglobulin (Tg) mRNA (75%), while saliva was always positive for onfFN and never for Tg. These findings indicate that onfFN cannot be considered a marker specific for thyroid cancer presence. Finally, Tg results were positive in a large part of the samples, but not always in concomitance with onfFN. CONCLUSIONS: We underline how the complexity of onfFN transcripts could affect the RT-PCR procedure. In addition, the presence of onfFN transcripts in several normal and cancer tissues, along with non-thyroid biological fluids or cells, does not allow the use of this marker for cancer monitoring. PMID- 22505560 TI - Independent validation of the Enhanced Liver Fibrosis (ELF) score in the ANRS HC EP 23 Fibrostar cohort of patients with chronic hepatitis C. AB - BACKGROUND: The Enhanced Liver Fibrosis (ELF) score combining serum hyaluronan, N terminal peptide of type III procollagen and tissue inhibitor of metalloproteinase-1, was reported as relevant in predicting liver fibrosis in chronic liver disease and proposed as an alternative to liver biopsy. METHODS: We evaluated the ELF score in a cohort of chronic hepatitis C (CHC) patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar) using commercial reagents, different from those developed by the manufacturer of the Siemens ELFTM test. RESULTS: In 512 CHC, the ELF score, using ROC curves, showed good predictive performances for severe fibrosis [AUROC=0.82; 95% confidence interval (CI) 0.78-0.86]and for cirrhosis (AUROC=0.85; 95% CI 0.81-0.90), but slightly lower for significant fibrosis (AUROC=0.78; 95% CI 0.74-0.82). The Obuchowski measure (0.81) showed that the ELF score globally performed as a marker of liver fibrosis. The ELF score predicted significant fibrosis (cut off=9.0) with a sensitivity of 0.86, a specificity of 0.62, a positive predictive value (PPV) of 0.80 and a negative predictive value (NPV) of 0.70. For extensive fibrosis (cut-off=9.33), sensitivity was 0.90, specificity was 0.63, PPV was 0.73 and NPV was 0.85. For cirrhosis (cut-off=9.35), sensitivity was 0.83, specificity was 0.75, PPV was 0.44 and NPV was 0.95. CONCLUSIONS: This study confirms the ELF score performance as an index to predict liver fibrosis or cirrhosis in CHC. The ELF test, using validated reagents, could be added to the health authorities approved non-invasive tests in assessing fibrosis as surrogate to liver biopsy. PMID- 22505563 TI - Evaluation of the interference by homogentisic acid and other organic acids on the enzymatic and Jaffe method creatinine assay. PMID- 22505564 TI - Falsely decreased ionized calcium results due to analytical interference by teriflunomide, the active metabolite of leflunomide (Arava(r)). PMID- 22505565 TI - Is polyethylene glycol precipitation of hyperprolactinaemic samples required when using the Beckman Coulter DxI-800 prolactin assay? PMID- 22505568 TI - MRI-based attenuation correction for hybrid PET/MRI systems: a 4-class tissue segmentation technique using a combined ultrashort-echo-time/Dixon MRI sequence. AB - Accurate gamma-photon attenuation correction (AC) is essential for quantitative PET/MRI as there is no simple relation between MR image intensity and attenuation coefficients. Attenuation maps (MU-maps) can be derived by segmenting MR images and assigning attenuation coefficients to the compartments. Ultrashort-echo-time (UTE) sequences have been used to separate cortical bone and air, and the Dixon technique has enabled differentiation between soft and adipose tissues. Unfortunately, sequential application of these sequences is time-consuming and complicates image registration. METHODS: A UTE triple-echo (UTILE) MRI sequence is proposed, combining UTE sampling for bone detection and gradient echoes for Dixon water-fat separation in a radial 3-dimensional acquisition (repetition time, 4.1 ms; echo times, 0.09/1.09/2.09 ms; field strength, 3 T). Air masks are derived mainly from the phase information of the first echo; cortical bone is segmented using a dual-echo technique. Soft-tissue and adipose-tissue decomposition is achieved using a 3-point Dixon-like decomposition. Predefined linear attenuation coefficients are assigned to classified voxels to generate MRI based MU-maps. The results of 6 patients are obtained by comparing MU-maps, reciprocal sensitivity maps, reconstructed PET images, and brain region PET activities based on either CT AC, two 3-class MRI AC techniques, or the proposed 4-class UTILE AC. RESULTS: Using the UTILE MRI sequence, an acquisition time of 214 s was achieved for the head-and-neck region with 1.75-mm isotropic resolution, compared with 164 s for a single-echo UTE scan. MRI-based reciprocal sensitivity maps show a high correlation with those derived from CT scans (R(2) = 0.9920). The same is true for PET activities (R(2) = 0.9958). An overall voxel classification accuracy (compared with CT) of 81.1% was reached. Bone segmentation is inaccurate in complex regions such as the paranasal sinuses, but brain region activities in 48 regions across 6 patients show a high correlation after MRI-based and CT-based correction (R(2) = 0.9956), with a regression line slope of 0.960. All overall correlations are higher and brain region PET activities more accurate in terms of mean and maximum deviations for the 4-class technique than for 3-class techniques. CONCLUSION: The UTILE MRI sequence enables the generation of MRI-based 4-class MU-maps without anatomic priors, yielding results more similar to CT-based results than can be obtained with 3-class segmentation only. PMID- 22505569 TI - Worry as a predictor of nutrition behaviors: results from a nationally representative survey. AB - Worry has been shown to predict a variety of health behaviors, such as cancer screening, yet there are few studies linking worry and nutrition. This study used nationally representative data from National Cancer Institute's Food Attitudes and Behavior Survey (n = 3,397) to examine the association between health-related worry and a variety of nutrition behaviors. Greater worry was associated with higher fruit and vegetable consumption (B = 0.19, p < .01), but also more meals eaten when watching television (B = 0.34, p < .01) and fewer with family (B = 0.13, p = .02). Importantly, and counterintuitively, greater worry appeared to reverse the conventional relationship between self-efficacy and dietary restriction; those who were self-efficacious and worried were less likely to restrict unhealthy foods. Similarly, worry attenuated the relationship between perceived benefits and special effort to buy produce. A complex relationship between worry and nutrition emerged, with potentially important clinical implications. PMID- 22505570 TI - Stress management-augmented behavioral weight loss intervention for African American women: a pilot, randomized controlled trial. AB - The relationship between chronic stress and weight management efforts may be a concern for African American (AA) women, who have a high prevalence of obesity, high stress levels, and modest response to obesity treatment. This pilot study randomly assigned 44 overweight/obese AA women with moderate to high stress levels to either a 12-week adaptation of the Diabetes Prevention Program Lifestyle Balance intervention augmented with stress management strategies (Lifestyle + Stress) or Lifestyle Alone. A trend toward greater percentage of baseline weight loss at 3-month data collection was observed in Lifestyle + Stress (-2.7 +/- 3.6%) compared with Lifestyle Alone (-1.4 +/- 2.3%; p = .17) and a greater reduction in salivary cortisol (Lifestyle + Stress: -0.2461 +/- 0.3985 ng/mL; Lifestyle Alone: -0.0002 +/- 0.6275 ng/mL; p = .20). These promising results suggest that augmenting a behavioral weight control intervention with stress management components may be beneficial for overweight/obese AA women with moderate to high stress levels and merit further investigation with an adequately powered trial. PMID- 22505571 TI - Effectiveness of a national media campaign to promote parent-child communication about sex. AB - BACKGROUND: Although there is debate on the effectiveness of youth-focused abstinence education programs, research confirms that parents can influence their children's decisions about sexual behavior. To leverage parent-based approaches to adolescent sexual health, the U.S. Department of Health and Human Services launched the Parents Speak Up National Campaign (PSUNC) to encourage parent-child communication about sex. Previous experimental studies have found the campaign to be efficacious in increasing parent-child communication. But to date, the actual reach of the campaign and its real-world effectiveness in promoting parent-child communication has not been established. The present study addresses this gap. METHOD: The authors surveyed 1,804 parents of 10- to14-year-old children from the nationally representative Knowledge Networks online panel. The survey included questions about parents' awareness of PSUNC ads and parent-child communication behaviors. The authors also analyzed market-level data on campaign gross rating points, a measure of market-level intensity of PSUNC advertising in the United States. Multivariate regressions were used to examine the association between PSUNC exposure and a three-item scale for parent-child communication. RESULTS: Overall, 59.4% of parents in the sample reported awareness of PSUNC. The authors found that higher market-level PSUNC gross rating points were associated with increased parent-child communication. Similar relationships were observed between self-reported awareness of PSUNC and increased frequency of communication and recommendations to wait. These associations were particularly strong among mothers. CONCLUSIONS: This study provides the first field-based data on the real world reach and effectiveness of PSUNC among parents. The data support earlier experimental trials of PSUNC, showing that the campaign is associated with greater parent-child communication, primarily among mothers. Further research may be needed to develop additional messages for fathers. PMID- 22505572 TI - A comparison of maternal outcomes from an alcohol, tobacco, and other drug prevention program for mothers choosing an intervention versus being randomized. AB - Self-determination theory and substantial research findings suggest that more desirable outcomes may occur when participants are able to choose their prevention or treatment interventions, as having a choice may lead to greater motivation and feelings of self-efficacy. The present study examined the influence of having a choice of family-based prevention programs for youth alcohol, tobacco, and other drug use on mothers' communication outcomes. Families (N = 496) were those with an 11- to 12-year-old enrolled in Kaiser Permanente medical centers at one of four locations. Results from multivariate repeated measures analyses supported the importance of having a choice for improved communication outcomes. As compared with families who were randomly assigned to a program, those allowed to choose showed improved tobacco-specific and peer pressure communication, with marginally improved alcohol communication. No differences were found between the groups for general communication. Results suggest that allowing mothers to participate in decisions about health-related interventions for their teens may lead to better outcomes. PMID- 22505573 TI - Health care access and health behaviors among men who have sex with men: the cost of health disparities. AB - Men who have sex with men (MSM) appear to experience barriers to health care compared with general population men. This report examines individual differences in health care access within a diverse sample of urban MSM (N = 871). The authors examined demographic differences in health care access and the relation between access and health-related attitudes, health behaviors, and HIV transmission risk. They operationalized health care access in terms of three indicators: perceived barriers, insurance status, and recent medical visit. Twenty-seven percent (n = 227) of MSM reported zero or one health care access indicator. African American and Latino race/ethnicity, lower income, and HIV-unknown status were associated with limited health care access. Limited health care access was related to health care attitudes (mistrust in the health care system and difficulty disclosing MSM status to providers), general health behaviors (smoking, never being HIV-tested, and drug abuse), and sexual risk-related variables (low self-efficacy for sexual safety, consistent drug use during sex, and HIV transmission risk). Overall, among MSM, less health care access relates to several adverse psychological constructs and health behaviors. Researchers and public health officials should address limited health care access, and its consequences, in this population. PMID- 22505574 TI - Diet and exercise adherence and practices among medically underserved patients with chronic disease: variation across four ethnic groups. AB - Many factors interact to create barriers to dietary and exercise plan adherence among medically underserved patients with chronic disease, but aspects related to culture and ethnicity are underexamined in the literature. Using both qualitative (n = 71) and quantitative (n = 297) data collected in a 4-year, multimethod study among patients with hypertension and/or diabetes, the authors explored differences in self-reported adherence to diet and exercise plans and self reported daily diet and exercise practices across four ethnic groups-Whites, Blacks, Vietnamese, and Latinos-at a primary health care center in Massachusetts. Adherence to diet and exercise plans differed across ethnic groups even after controlling for key sociodemographic variables, with Vietnamese participants reporting the highest adherence. Food and exercise options were shaped by economic constraints as well as ethnic and cultural familiarity with certain foods and types of activity. These findings indicate that health care providers should consider ethnicity and economic status together to increase effectiveness in encouraging diverse populations with chronic disease to make healthy lifestyle changes. PMID- 22505575 TI - Identification and characterization of lineage-specific highly conserved noncoding sequences in Mammalian genomes. AB - Vertebrate genome comparisons revealed that there are highly conserved noncoding sequences (HCNSs) among a wide range of species and many of which contain regulatory elements. However, recently emerged sequences conserved in specific lineages have not been well studied. Toward this end, we identified 8,198 primate and 21,128 specific HCNSs as representative ones among mammals from human marmoset and mouse-rat comparisons, respectively. Derived allele frequency analysis of primate-specific HCNSs showed that these HCNSs were under purifying selection, indicating that they may harbor important functions. We selected the top 1,000 largest HCNSs and compared the lineage-specific HCNS-flanking genes (LHF genes) with ultraconserved element (UCE)-flanking genes. Interestingly, the majority of LHF genes were different from UCE-flanking genes. This lineage specific set of LHF genes was more enriched in protein-binding function. Conversely, the number of LHF genes that were also shared by UCEs was small but significantly larger than random expectation, and many of these genes were involved in anatomical development as transcriptional regulators, suggesting that certain groups of genes preferentially recruit new HCNSs in addition to old HCNSs that are conserved among vertebrates. This group of LHF genes might be involved in the various levels of lineage-specific evolution among vertebrates, mammals, primates, and rodents. If so, the emergence of HCNSs in and around these two groups of LHF genes developed lineage-specific characteristics. Our results provide new insight into lineage-specific evolution through interactions between HCNSs and their LHF genes. PMID- 22505576 TI - Argonaute identity defines the length of mature mammalian microRNAs. AB - MicroRNAs (miRNAs) are 19- to 25-nt-long non-coding RNAs that regulate gene expression by base-pairing with target mRNAs and reducing their stability or translational efficiency. Mammalian miRNAs function in association with four closely related Argonaute proteins, AGO1-4. All four proteins contain the PAZ and the MID domains interacting with the miRNA 3' and 5' termini, respectively, as well as the PIWI domain comprising an mRNA 'slicing' activity in the case of AGO2 but not AGO1, AGO3 and AGO4. However, the slicing mode of the miRNA-programmed AGO2 is rarely realized in vivo and the four Argonautes are thought to play largely overlapping roles in the mammalian miRNA pathway. Here, we show that the average length of many miRNAs is diminished during nervous system development as a result of progressive shortening of the miRNA 3' ends. We link this modification with an increase in the fractional abundance of Ago2 in the adult brain and identify a specific structural motif within the PAZ domain that enables efficient trimming of miRNAs associated with this but not the other three Argonautes. Taken together, our data suggest that mammalian Argonautes may define the length and possibly biological activity of mature mammalian miRNAs in a developmentally controlled manner. PMID- 22505577 TI - A novel source for miR-21 expression through the alternative polyadenylation of VMP1 gene transcripts. AB - miR-21 is the most commonly over-expressed microRNA (miRNA) in cancer and a proven oncogene. Hsa-miR-21 is located on chromosome 17q23.2, immediately downstream of the vacuole membrane protein-1 (VMP1) gene, also known as TMEM49. VMP1 transcripts initiate ~ 130 kb upstream of miR-21, are spliced, and polyadenylated only a few hundred base pairs upstream of the miR-21 hairpin. On the other hand, primary miR-21 transcripts (pri-miR-21) originate within the last introns of VMP1, but bypass VMP1 polyadenylation signals to include the miR-21 hairpin. Here, we report that VMP1 transcripts can also bypass these polyadenylation signals to include miR-21, thus providing a novel and independently regulated source of miR-21, termed VMP1-miR-21. Northern blotting, gene-specific RT-PCR, RNA pull-down and DNA branching assays support that VMP1 miR-21 is expressed at significant levels in a number of cancer cell lines and that it is processed by the Microprocessor complex to produce mature miR-21. VMP1 and pri-miR-21 are induced by common stimuli, such as phorbol-12-myristate-13 acetate (PMA) and androgens, but show differential responses to some stimuli such as epigenetic modifying agents. Collectively, these results indicate that miR-21 is a unique miRNA capable of being regulated by alternative polyadenylation and two independent gene promoters. PMID- 22505578 TI - Epstein-Barr virus protein EB2 stimulates cytoplasmic mRNA accumulation by counteracting the deleterious effects of SRp20 on viral mRNAs. AB - The Epstein-Barr Virus (EBV) protein EB2 (also called Mta, SM and BMLF1), is an essential nuclear protein produced during the replicative cycle of EBV. EB2 is required for the efficient cytoplasmic accumulation of viral mRNAs derived from intronless genes. EB2 is an RNA-binding protein whose expression has been shown to influence RNA stability, splicing, nuclear export and translation. Using a yeast two-hybrid screen, we have identified three SR proteins, SF2/ASF, 9G8 and SRp20, as cellular partners of EB2. Then, by using siRNA to deplete cells of specific SR proteins, we found that SRp20 plays an essential role in the processing of several model mRNAs: the Renilla luciferase reporter mRNA, the human beta-globin cDNA transcript and two EBV late mRNAs. These four mRNAs were previously found to be highly dependent on EB2 for their efficient cytoplasmic accumulation. Here, we show that SRp20 depletion results in an increase in the accumulation of these mRNAs, which correlates with an absence of additive effect of EB2, suggesting that EB2 functions by antagonizing SRp20. Moreover, by using RNA-immunoprecipitation assays we found that EB2 enhances the association of SRp20 with the beta-globin transcript suggesting that EB2 acts by stabilizing SRp20's labile interactions with the RNA. PMID- 22505579 TI - Homologous recombination repairs secondary replication induced DNA double-strand breaks after ionizing radiation. AB - Ionizing radiation (IR) produces direct two-ended DNA double-strand breaks (DSBs) primarily repaired by non-homologous end joining (NHEJ). It is, however, well established that homologous recombination (HR) is induced and required for repair of a subset of DSBs formed following IR. Here, we find that HR induced by IR is drastically reduced when post-DNA damage replication is inhibited in mammalian cells. Both IR-induced RAD51 foci and HR events in the hprt gene are reduced in the presence of replication polymerase inhibitor aphidicolin (APH). Interestingly, we also detect reduced IR-induced toxicity in HR deficient cells when inhibiting post-DNA damage replication. When studying DSB formation following IR exposure, we find that apart from the direct DSBs the treatment also triggers formation of secondary DSBs peaking at 7-9 h after exposure. These secondary DSBs are restricted to newly replicated DNA and abolished by inhibiting post-DNA damage replication. Further, we find that IR-induced RAD51 foci are decreased by APH only in cells replicating at the time of IR exposure, suggesting distinct differences between IR-induced HR in S- and G2-phases of the cell cycle. Altogether, our data indicate that secondary replication-associated DSBs formed following exposure to IR are major substrates for IR-induced HR repair. PMID- 22505580 TI - The transition in spliceosome assembly from complex E to complex A purges surplus U1 snRNPs from alternative splice sites. AB - Spliceosomes are assembled in stages. The first stage forms complex E, which is characterized by the presence of U1 snRNPs base-paired to the 5' splice site, components recognizing the 3' splice site and proteins thought to connect them. The splice sites are held in close proximity and the pre-mRNA is committed to splicing. Despite this, the sites for splicing appear not to be fixed until the next complex (A) forms. We have investigated the reasons why 5' splice sites are not fixed in complex E, using single molecule methods to determine the stoichiometry of U1 snRNPs bound to pre-mRNA with one or two strong 5' splice sites. In complex E most transcripts with two alternative 5' splice sites were bound by two U1 snRNPs. However, the surplus U1 snRNPs were displaced during complex A formation in an ATP-dependent process requiring an intact 3' splice site. This process leaves only one U1 snRNP per complex A, regardless of the number of potential sites. We propose a mechanism for selection of the 5' splice site. Our results show that constitutive splicing components need not be present in a fixed stoichiometry in a splicing complex. PMID- 22505581 TI - Interactions between BRCA2 and RAD51 for promoting homologous recombination in Leishmania infantum. AB - In most organisms, the primary function of homologous recombination (HR) is to allow genome protection by the faithful repair of DNA double-strand breaks. The vital step of HR is the search for sequence homology, mediated by the RAD51 recombinase, which is stimulated further by proteins mediators such as the tumor suppressor BRCA2. The biochemical interplay between RAD51 and BRCA2 is unknown in Leishmania or Trypanosoma. Here we show that the Leishmania infantum BRCA2 protein possesses several critical features important for the regulation of DNA recombination at the genetic and biochemical level. A BRCA2 null mutant, generated by gene disruption, displayed genomic instability and gene-targeting defects. Furthermore, cytological studies show that LiRAD51 can no longer localize to the nucleus in this mutant. The Leishmania RAD51 and BRCA2 interact together and the purified proteins bind single-strand DNA. Remarkably, LiBRCA2 is a recombination mediator that stimulates the invasion of a resected DNA double strand break in an undamaged template by LiRAD51 to form a D-loop structure. Collectively, our data show that LiBRCA2 and LiRAD51 promote HR at the genetic and biochemical level in L. infantum, the causative agent of visceral leishmaniasis. PMID- 22505582 TI - Impaired calcium calmodulin kinase signaling and muscle adaptation response in the absence of calpain 3. AB - Mutations in the non-lysosomal, cysteine protease calpain 3 (CAPN3) result in the disease limb girdle muscular dystrophy type 2A (LGMD2A). CAPN3 is localized to several subcellular compartments, including triads, where it plays a structural, rather than a proteolytic, role. In the absence of CAPN3, several triad components are reduced, including the major Ca(2+) release channel, ryanodine receptor (RyR). Furthermore, Ca(2+) release upon excitation is impaired in the absence of CAPN3. In the present study, we show that Ca-calmodulin protein kinase II (CaMKII) signaling is compromised in CAPN3 knockout (C3KO) mice. The CaMK pathway has been previously implicated in promoting the slow skeletal muscle phenotype. As expected, the decrease in CaMKII signaling that was observed in the absence of CAPN3 is associated with a reduction in the slow versus fast muscle fiber phenotype. We show that muscles of WT mice subjected to exercise training activate the CaMKII signaling pathway and increase expression of the slow form of myosin; however, muscles of C3KO mice do not exhibit these adaptive changes to exercise. These data strongly suggest that skeletal muscle's adaptive response to functional demand is compromised in the absence of CAPN3. In agreement with our mouse studies, RyR levels were also decreased in biopsies from LGMD2A patients. Moreover, we observed a preferential pathological involvement of slow fibers in LGMD2A biopsies. Thus, impaired CaMKII signaling and, as a result, a weakened muscle adaptation response identify a novel mechanism that may underlie LGMD2A and suggest a pharmacological target that should be explored for therapy. PMID- 22505583 TI - Androgen-regulated processing of the oncomir miR-27a, which targets Prohibitin in prostate cancer. AB - MicroRNAs (miRs) play an important role in the development of many complex human diseases and may have tumour suppressor or oncogenic (oncomir) properties. Prostate cancer is initially an androgen-driven disease, and androgen receptor (AR) remains a key driver of growth even in castration-resistant tumours. However, AR-mediated oncomiR pathways remain to be elucidated. We demonstrate that miR-27a is an androgen-regulated oncomir in prostate cancer, acting via targeting the tumour suppressor and AR corepressor, Prohibitin (PHB). Increasing miR-27a expression results in reduced PHB mRNA and protein levels, and increased expression of AR target genes and prostate cancer cell growth. This involves a novel mechanism for androgen-mediated miR regulation, whereby AR induces a transient increase in miR-23a27a24-2 transcription, but more significantly accelerates processing of the primiR-23a27a24-2 cluster. Androgens therefore regulate miR-27a expression both transcriptionally (via AR binding to the cluster promoter) and post-transcriptionally (accelerating primiR processing to the mature form). We further show that a miR-27a anti-sense oligonucleotide, by opposing the effects of mir-27a, has therapeutic potential in prostate cancer. PMID- 22505584 TI - Ryanodine receptor antagonists adapt NPC1 proteostasis to ameliorate lipid storage in Niemann-Pick type C disease fibroblasts. AB - Niemann-Pick type C disease is a lysosomal storage disorder most often caused by loss-of-function mutations in the NPC1 gene. The encoded multipass transmembrane protein is required for cholesterol efflux from late endosomes and lysosomes. Numerous missense mutations in the NPC1 gene cause disease, including the prevalent I1061T mutation that leads to protein misfolding and degradation. Here, we sought to modulate the cellular proteostasis machinery to achieve functional recovery in primary patient fibroblasts. We demonstrate that targeting endoplasmic reticulum (ER) calcium levels using ryanodine receptor (RyR) antagonists increased steady-state levels of the NPC1 I1061T protein. These compounds also promoted trafficking of mutant NPC1 to late endosomes and lysosomes and rescued the aberrant storage of cholesterol and sphingolipids that is characteristic of disease. Similar rescue was obtained using three distinct RyR antagonists in cells with missense alleles, but not with null alleles, or by over-expressing calnexin, a calcium-dependent ER chaperone. Our work highlights the utility of proteostasis regulators to remodel the protein-folding environment in the ER to recover function in the setting of disease-causing missense alleles. PMID- 22505585 TI - The GTPase ARFRP1 controls the lipidation of chylomicrons in the Golgi of the intestinal epithelium. AB - The uptake and processing of dietary lipids by the small intestine is a multistep process that involves several steps including vesicular and protein transport. The GTPase ADP-ribosylation factor-related protein 1 (ARFRP1) controls the ARF like 1 (ARL1)-mediated Golgi recruitment of GRIP domain proteins which in turn bind several Rab-GTPases. Here, we describe the essential role of ARFRP1 and its interaction with Rab2 in the assembly and lipidation of chylomicrons in the intestinal epithelium. Mice lacking Arfrp1 specifically in the intestine (Arfrp1(vil-/-)) exhibit an early post-natal growth retardation with reduced plasma triacylglycerol and free fatty acid concentrations. Arfrp1(vil-/-) enterocytes as well as Arfrp1 mRNA depleted Caco-2 cells absorbed fatty acids normally but secreted chylomicrons with a markedly reduced triacylglycerol content. In addition, the release of apolipoprotein A-I (ApoA-I) was dramatically decreased, and ApoA-I accumulated in the Arfrp1(vil-/-) epithelium, where it predominantly co-localized with Rab2. The release of chylomicrons from Caco-2 was markedly reduced after the suppression of Rab2, ARL1 and Golgin-245. Thus, the GTPase ARFRP1 and its downstream proteins are required for the lipidation of chylo-microns and the assembly of ApoA-I to these particles in the Golgi of intestinal epithelial cells. PMID- 22505586 TI - Preclinical studies of PF-04849285, an interferon-alpha8 fusion protein for the treatment of HCV. AB - BACKGROUND: This study presents preclinical data of a novel interferon (IFN) alpha8 fusion protein, PF-04849285, and compares it with IFN-alpha2 and pegylated IFN-alpha2; the latter being the current standard of care for HCV. METHODS: The antiviral properties were evaluated in vitro using the HCV replication assay (replicon) and the general encephalomyocarditis virus assay. The binding affinity to both IFNR-subunits was assessed using surface plasmon resonance. Ex vivo experiments using cynomolgus monkey and human blood were used for the evaluation of induction of IFN-inducible biomarkers (interferon inducible protein 10 [IP 10], 2'-5'-oligoadenylate synthetase [OAS2] and interleukin-6 [IL-6]). The molecule was tested intravenously and subcutaneously in cynomolgus monkey in a single dose study for two weeks at 0.01, 1, 5 and 20 mg/kg. Each route and dose combination was given to a single male animal, blood samples were collected for evaluation of biomarkers and pharmacokinetics. The compound was also tested in cynomolgus monkey in a multiple dose study for four weeks, with a twice-a-week dosing prior to a three-week wash-out period for toxicokinetics, pharmacokinetics, and biomarker evaluation at 20, 50 or 100 mg/kg subcutaneously and 20 mg/kg intravenously. RESULTS: The molecule is 10* more potent than the pegylated IFN-alpha2a, with potency similar to the unmodified IFN-alpha2a. No unanticipated findings were observed in cynomolgus monkey when dosed up to 20 mg/kg, >10,000-fold margin over the anticipated efficacious human dose. CONCLUSIONS: The biomarker and toxicological findings were consistent with a potent IFN molecule. The potency and pharmacokinetic properties of the molecule are consistent with dosing at least every two weeks with the potential for monthly dosing' and not 'at least twice daily' as presented in the original [corrected]. PMID- 22505587 TI - Vitamin D levels and IL28B polymorphisms are related to rapid virological response to standard of care in genotype 1 chronic hepatitis C. AB - BACKGROUND: Genotype 1 (G1) chronic hepatitis C (CHC) patients achieving a rapid virological response (RVR) on pegylated interferon (PEG-IFN) plus ribavirin have a high chance of sustained virological response (SVR), influenced by IL28B status, viral load, fibrosis and insulin resistance. We assessed whether 25 hydroxyvitamin D (25[OH]D) serum levels are linked to RVR and can be used together with IL28B to construct a pretreatment model to predict RVR. METHODS: A total of 117 consecutive patients with G1 CHC were evaluated by biopsy and anthropometric and metabolic measurements. 25(OH)D serum levels were measured by HPLC. IL28B rs12979860 and rs8099917 polymorphisms were also evaluated. All patients underwent antiviral therapy with PEG-IFN-alpha2a plus ribavirin. HCV RNA was assessed at baseline, week 4, week 12, at the end of therapy and after 6 months of follow-up. RESULTS: Mean +/-SD 25(OH)D serum levels were 26.3 +/-10.6 MUg/l (range 8.0-58.0) and 31 (26.5%) patients had the rs12979860 CC polymorphism. RVR was achieved in 35 (29.9%) patients, and 32 (91.4%) of them had an SVR, compared to 26 of 82 (31.7%) without RVR. The rs12979860 CC polymorphism (OR 4.575, 95% CI 1.761, 11.889; P=0.002) and higher 25(OH)D levels (OR 1.055, 95% CI 1.010, 1.101; P=0.01) were independently associated with the achievement of RVR by multivariate analysis. The likelihood of RVR progressively increased from patients in the worst class (vitamin D<26.8 MUg/l and TT/TC polymorphism; RVR 14.2%), to those with only one positive predictor (RVR 29.7% and 37.5%), and to those in the best class (vitamin D>=26.8 MUg/l and rs12979860 CC polymorphism; RVR 73.3%). CONCLUSIONS: In patients with G1 CHC, 25(OH)D serum levels and IL28B status are independently associated with the likelihood to achieve RVR and SVR. When incorporated into a pretreatment predictive model they can assist in further discriminating patients with a high likelihood of achieving RVR and SVR. PMID- 22505588 TI - Marine snake epibiosis: a review and first report of decapods associated with Pelamis platurus. AB - Under circumstances in which area for settlement is limited, the colonization of living substrata may become a highly valuable strategy for survival of marine invertebrates. This phenomenon, termed epibiosis, results in spatially close associations between two or more living organisms. Pelamis platurus, the yellow bellied sea snake, is the only exclusively pelagic marine snake and its propensity for foraging along ocean slicks facilitates its colonization by pelagic epibionts. Herein, we report epibionts associated with P. platurus inhabiting the waters off the northwestern Pacific coast of Costa Rica. These associations include the first records of decapod epibionts from any marine snake. Decapod epibionts were found on 18.9% of P. platurus, and size of snake (total length) had a significant positive effect on the frequency and intensity of epibiosis. We discuss the spatial and ecological mechanisms that facilitate these interactions, as well as the suite of factors that either promote or deter epibiosis and ultimately dictate the frequency and intensity of these interactions. Finally, we provide a review of marine snake epibiosis. The intention of this review is to (1) provide contemporary researchers with a single, accessible reference to all known reports of epibionts associated with marine snakes and (2) discuss what is currently known with respect to diversity of epibionts from marine snakes. PMID- 22505589 TI - Dispersal in marine organisms without a pelagic larval phase. AB - In contrast to marine organisms whose offspring go through an extended planktonic stage, the young of others develop directly into benthic juveniles or into yolky nonfeeding larvae that spend only a few hours in the plankton before settling. Yet, paradoxically, many such species have geographic distributions that are comparable to those with a pelagic dispersal stage. This article reviews some of the ways in which these organisms can expand their distributions: drifting, rafting, hitchhiking, creeping, and hopping. Drifting applies to species in which larvae may be short-lived, but adults can detach or be detached from their benthic substratum and be passively carried to new areas, floating at the water's surface or below it. Many encrusting species and mobile species can spread by rafting, settling on natural or artificial floating substrata which are propelled by wind and currents to new regions. Hitchhiking applies to those attaching to vessels or being carried in ballast water of ships to a distant region in which their offspring can survive. Other marine species extend their distributions by hopping from one island of hard substratum or favorable sedimentary microhabitat to another, while creeping species extend their distributions along shores or shelves where habitats remain similar for long distances. PMID- 22505590 TI - Spatial and temporal variability in response to hybrid electro-optical stimulation. AB - Hybrid electro-optical neural stimulation is a novel paradigm combining the advantages of optical and electrical stimulation techniques while reducing their respective limitations. However, in order to fulfill its promise, this technique requires reduced variability and improved reproducibility. Here we used a comparative physiological approach to aid the further development of this technique by identifying the spatial and temporal factors characteristic of hybrid stimulation that may contribute to experimental variability and/or a lack of reproducibility. Using transient pulses of infrared light delivered simultaneously with a bipolar electrical stimulus in either the marine mollusk Aplysia californica buccal nerve or the rat sciatic nerve, we determined the existence of a finite region of excitability with size altered by the strength of the optical stimulus and recruitment dictated by the polarity of the electrical stimulus. Hybrid stimulation radiant exposures yielding 50% probability of firing (RE50) were shown to be negatively correlated with the underlying changes in electrical stimulation threshold over time. In Aplysia, but not in the rat sciatic nerve, increasing optical radiant exposures (J cm-2) beyond the RE50 ultimately resulted in inhibition of evoked potentials. Accounting for the sources of variability identified in this study increased the reproducibility of stimulation from 35% to 93% in Aplysia and 23% to 76% in the rat with reduced variability. PMID- 22505592 TI - Small field diode correction factors derived using an air core fibre optic scintillation dosimeter and EBT2 film. AB - There is no commercially available real-time dosimeter that can accurately measure output factors for field sizes down to 4 mm without the use of correction factors. Silicon diode detectors are commonly used but are not dosimetrically water equivalent, resulting in energy dependence and fluence perturbation. In contrast, plastic scintillators are nearly dosimetrically water equivalent. A fibre optic dosimeter (FOD) with a 0.8 mm(3) plastic scintillator coupled to an air core light guide was used to measure the output factors for Novalis/BrainLab stereotactic cones of diameter 4-30 mm and Novalis MLC fields of width 5-100 mm. The FOD data matched the output factors measured by a 0.125 cm(3) Semiflex ion chamber for the MLC fields above 30 mm and those measured with the EBT2 radiochromic film for the cones and MLC fields below 30 mm. Relative detector readings were obtained with four diode types (IBA SFD, EFD, PFD, PTW 60012) for the same fields. Empirical diode correction factors were determined by taking the ratio of FOD output factors to diode relative detector readings. The diodes were found to over-respond by 3%-16% for the smallest field. There was good agreement between different diodes of the same model number. PMID- 22505591 TI - Giant coronary aneurysms exceeding 5 cm in size. AB - Giant coronary artery aneurysms (gCAAs) with a diameter exceeding 5 cm are extremely rare. The pathomechanisms and therapeutical measures in such cases have been controversial topics of discussion. Twenty-seven patients with gCAAs exceeding 5 cm in size described in the literature were evaluated. A case with multiple gCAAs at our department was included in the analysis. Apart from atherosclerosis of all coronary arteries, a large (1.5 2.5 cm) left anterior descending coronary artery aneurysm (CAA) and a gCAA (10.6 9.2 cm) originating from the right coronary artery, the latter causing recurrent myocardial ischaemia with the occlusion of the peripheral right coronary artery and compressing the right cardiac cavities, were the pathological findings in our 43-year old male patient. gCAAs predominantly develop at the proximal right coronary artery. The majority of these aneurysms develop secondary to atherosclerotic lesions in young patients. We performed a successful surgical excision of the right gCAA, tightening of the left anterior descending artery aneurysm and concomitant coronary artery bypass grafting. A pathological examination confirmed advanced atherosclerosis. Microbiological examinations could find no signs of infectious causes. CAAs bear a significant risk of severe complications and have a high risk of mortality. A more aggressive surgical approach should be recommended. PMID- 22505593 TI - Increased mindfulness is related to improved stress and mood following participation in a mindfulness-based stress reduction program in individuals with cancer. AB - BACKGROUND: Mindfulness-based stress reduction (MBSR) has demonstrated efficacy for alleviating cancer-related distress. Although theorized to be the means by which people improve, it is yet to be determined whether outcomes are related to the development or enhancement of mindfulness among participants. This study examined the effect of participation in an MBSR program on levels of mindfulness in a heterogeneous sample of individuals with cancer, and if these changes were related to improvements in stress and mood outcomes. METHODS: In all, 268 individuals with cancer completed self-report assessments of stress and mood disturbances before and after participation in an 8-week MBSR program. Of these, 177 participants completed the Mindful Attention Awareness Scale and 91 participants completed the Five Facet Mindfulness Questionnaire, at both time points. RESULTS: Levels of mindfulness on both measures increased significantly over the course of the program. These were accompanied by significant reductions in mood disturbance (55%) and symptoms of stress (29%). Increases in mindfulness accounted for a significant percentage of the reductions in mood disturbance (21%) and symptoms of stress (14%). Being aware of the present moment and refraining from judging inner experience were the 2 most important mindfulness skills for improvements of psychological functioning among cancer patients. CONCLUSIONS: These results add to a growing literature measuring the impact of mindfulness and its relationship to improved psychological health. Moreover, specific mindfulness skills may be important in supporting these improvements. PMID- 22505594 TI - In vitro anti-angiogenesis effects and active constituents of the saponin fraction from Gleditsia sinensis. AB - BACKGROUND: The anomalous fruits of Gleditsia sinensis Lam. (Leguminosae), a crude drug in China, have long been used in traditional Chinese medicine for the treatment of various diseases. The saponin fraction isolated from the fruits (SFGS) is considered as the active component for the antitumor activity of this crude drug. OBJECTIVES: The present study was performed to investigate the anti angiogenesis activities and active constituents of SFGS. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with SFGS in the presence or absence of basic fibroblast growth factor (bFGF) in vitro. The proliferation, migration, and tube formation were studied by MTT, Transwell, and 2D Matrigel assays, respectively. The cell cycle and apoptosis were analyzed by flow cytometry. Enzyme-linked immunosorbent assay for protein expression of vascular endothelial growth factor (VEGF) and western blot analysis for caspase-3, caspase-8, and caspase-9 as well as Fas were performed. In addition, the effects of 13 saponin compounds isolated from SFGS on the tube formation of HUVECs were screened, and the structure-activity relationships were discussed. RESULTS: SFGS, at concentrations (1, 3, and 10 ug/mL) without significant cytotoxicity on endothelial cells, significantly inhibited the proliferation, migration, and tube formation of HUVECs induced by bFGF (10 ng/mL). It moderately arrested the cell cycle to G1 phase but greatly induced cell apoptosis and increased the expressions of caspases-3, caspase-8, and Fas but not caspase-9 in HUVECs. Moreover, SFGS did not affect the bFGF-induced autosecretion of VEGF from endothelial cells. Among the 13 saponin compounds tested, gleditsiosides B, I, J, O, and Q showed inhibition of the tube formation at a concentration of 3 uM, and only gleditsioside B exerted significant inhibition at 1 uM. CONCLUSION: SFGS is substantially able to prevent angiogenesis by interfering with multiple steps. The findings provide a new explanation for the antitumor effects of G sinensis fruits. Gleditsiosides B, I, J, O, and Q are probably the main active constituents of SFGS. PMID- 22505595 TI - Lactobacillus casei extract induces apoptosis in gastric cancer by inhibiting NF kappaB and mTOR-mediated signaling. AB - Lactobacillus casei extract (LBX) has been reported to prevent gastric cancer, but the underlying mechanism remains unclear. The proliferation and cell death of gastric cancer KATO3 cells were examined after treatment with LBX for various times and at various doses. LBX inhibited the growth of gastric cancer cells and induced apoptosis by inactivating NF-kappaB promoter activity. Apoptosis induced by LBX, however, is not directly associated with the intrinsic mitochondrial pathway. Immunoblot analysis revealed that LBX decreased the expressions of NF kappaB and IkappaB. The reduced NF-kappaB levels led to the decreased phosphorylation of mTOR signaling components, such as PI3K, Akt, and (p70)S6 kinase. These results showed for the first time that LBX induced apoptosis in gastric cancer cells by inhibiting NF-kappaB and mTOR-mediated signaling. PMID- 22505596 TI - Ginkgo May Sensitize Ovarian Cancer Cells to Cisplatin: Antiproliferative and Apoptosis-Inducing Effects of Ginkgolide B on Ovarian Cancer Cells. AB - Ginkgolide B (GB), the primary active component ofGinkgo bilobaextracts, may have antitumor properties. The objective of this study was to determine the effects and possible mechanisms of GB in ovarian cancer cells. In this study, human ovarian cancer cell lines (SKOV3 and CAOV3) were treated with different concentrations of GB alone or in combination with Cis-diaminodichloroplatinum (CDDP). An MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to determine cell viability. The apoptosis rates of cells were measured by flow cytometric analysis. The expression of apoptosis-associated and proliferation-associated proteins was detected by Western blot. The cytotoxicity of GB was analyzed using a lactate dehydrogenase assay. Treatment with 100 uM GB for 3 days significantly inhibited SKOV3 and CAOV3 cell proliferation by 57.3% and 63.1% compared with control cells, respectively, as determined by MTT assay. Similarly, the apoptotic cell population was increased when treated with GB in a dose-dependent manner both in SKOV3 and CAOV3 cells. These effects were characterized by the upregulation of p21, p27, cleaved capase 3, and cleaved caspase-8 and downregulation of cyclin D1. In addition, a combined treatment of low concentrations of GB and CDDP showed an additive effect on the inhibition of SKOV3 cell proliferation. Furthermore, GB had significantly less cytotoxicity than CDDP in normal human ovarian surface epithelial cells. This study suggests that GB can be proposed as an effective antiproliferative and apoptosis-inducing agent with interesting translational application in ovarian cancers, used in addition to conventional chemotherapy. PMID- 22505597 TI - Furano-1,2-Naphthoquinone Inhibits Src and PI3K/Akt Signaling Pathways in Ca9-22 Human Oral Squamous Carcinoma Cells. AB - Furano-1,2-naphthoquinone (FNQ), a biologically active component ofAvicennia marina, has been demonstrated to display anticancer activity. FNQ exerted cytotoxicity with the G2/M cell cycle arrest and apoptosis in Ca9-22 cells. FNQ induced G2/M arrest was correlated with a marked decrease in the expression levels of cyclin A and cyclin B, and their activating partner cyclin-dependent kinases (CDK) 1 and 2 with concomitant induction of p27. FNQ-induced apoptosis was accompanied by Bax and Bad upregulation, and the downregulation of Bcl-2, Bcl XL, Mcl-1, and X-linked inhibitor of apoptosis (XIAP), resulting in cytochrome C release and sequential activation of caspase-9 and caspase-3. Mechanistic studies showed that FNQ suppressed Src phosphorylation, PI3K, and Akt activation in Ca9 22 cells. Moreover, the Src inhibitor PP2 reduced the phosphorylation of Src and activation of PI3K/Akt, which was comparable with FNQ treatment. The combined treatment of FNQ with PP2 enhanced the cell cycle arrest and apoptosis and also led to the downregulation of Bcl-XL, Mcl-1, XIAP, cyclin A, cyclin B, CDK1, and CDK2 and upregulation of p27, Bax, and Bad. These findings suggest that FNQ mediated cytotoxicity of Ca9-22 cells is related with the G2/M cell cycle arrest and apoptosis via inactivation of Src and PI3K/Akt-mediated signaling pathways. PMID- 22505598 TI - Religion, spirituality, and cancer: the question of individual empowerment. AB - It has often been noted that people with a severe illness endeavor to deepen their religious and spiritual practice and knowledge. It is generally accepted that spiritual and religious factors help sick people confront their suffering. The authors conducted a qualitative research on the role of religious and spiritual practices and knowledge among 10 cancer patients in Quebec, Canada. Individual interviews focused on their illness experience confirmed that religion and spirituality can be present and contribute to coping when life is threatened. More precisely, the analyses of the place and use of these resources during the patient's illness showed that these resources contributed to an individual empowerment process that was undertaken in response to a biographic and existential disruption induced by the illness diagnosis. The sick people took advantage of religious and spiritual content in their quest for meaning and a cure, progressing from a stage of despair and powerlessness to a stage of hope, a critical analysis of the disease, and a better management and control of it and its evolution. This article describes how people suffering from cancer use and participate in religious and spiritual content. It demonstrates the contribution of this content to an individual empowerment process. The use of religion and spirituality constitutes a quest for self-mastery, an acquiring of power and control. We understand that religious and spiritual phenomena do not always prevent people from fighting against their suffering, limit their freedom, or systematically reduce people's viewpoints and worldviews. PMID- 22505599 TI - X-ray phase contrast for CO2 microangiography. AB - We demonstrate a laboratory method for imaging small blood vessels using x-ray propagation-based phase-contrast imaging and carbon dioxide (CO(2)) gas as a contrast agent. The limited radiation dose in combination with CO(2) being clinically acceptable makes the method promising for small-diameter vascular visualization. We investigate the possibilities and limitations of the method for small-animal angiography and compare it with conventional absorption-based x-ray angiography. Photon noise in absorption-contrast imaging prevents visualization of blood vessels narrower than 50 um at the highest radiation doses compatible with living animals, whereas our simulations and experiments indicate the possibility of visualizing 20 um vessels at radiation doses as low as 100 mGy. Experimental computed tomography of excised rat kidney shows blood vessels of diameters down to 60 um with improved image quality compared to absorption-based methods. With our present prototype x-ray source, the acquisition time for a tomographic dataset is approximately 1 h, which is long compared to the 1-20 min common for absorption-contrast micro-CT systems. Further development of the liquid-metal-jet microfocus x-ray sources used here and high-resolution x-ray detectors shows promise to reduce exposure times and make this high-resolution method practical for imaging of living animals. PMID- 22505600 TI - Sphingomonas ginsengisoli sp. nov. and Sphingomonas sediminicola sp. nov. AB - Two novel bacteria, designated strains Gsoil 634(T) and Dae 20(T), were isolated in South Korea from soil of a ginseng field and freshwater sediment, respectively and were characterized by a polyphasic approach to clarify their taxonomic positions. Phylogenetic analysis based on 16S rRNA gene sequences indicated that, although they probably represented two distinct species (indicated by a sequence similarity of 96.6 %), both strain Gsoil 634(T) and strain Dae 20(T) belonged to the genus Sphingomonas and were most closely related to 'Sphingomonas humi' PB323 (97.8 % and 96.7 % sequence similarity, respectively), Sphingomonas kaistensis PB56(T) (96.8 % and 96.7 %), Sphingomonas astaxanthinifaciens TDMA-17(T) (96.6 % and 95.4 %) and Sphingomonas jaspsi TDMA-16(T) (95.6 % and 95.8 %). For both novel strains, the major ubiquinone was Q-10, the major polyamine was homospermidine, the major cellular fatty acids included summed feature 7 (C(18 : 1)omega7c, C(18 : 1)omega9t and/or C(18 : 1)omega12t), C(17 : 1)omega6c and C(16 : 0), and the polar lipids included sphingoglycolipid. These chemotaxonomic data supported the affiliation of both strains to the genus Sphingomonas. However, the DNA-DNA relatedness value between strain Gsoil 634(T) and 'Sphingomonas humi' PB323(T) was 31 %. Moreover, the results of physiological and biochemical tests allowed the phenotypic differentiation of strains Gsoil 634(T) and Dae 20(T) from established members of the genus Sphingomonas. Based on these data, the two isolates represent two novel species in the genus Sphingomonas, for which the names Sphingomonas ginsengisoli sp. nov. (type strain Gsoil 634(T) = KCTC 12630(T) = DSM 18094(T) = LMG 23739(T)) and Sphingomonas sediminicola sp. nov. (type strain Dae 20(T) = KCTC 12629(T) = DSM 18106(T) = LMG 23592(T)) are proposed. PMID- 22505601 TI - Flavitalea gansuensis sp. nov., isolated from soil from an arid area, and emended descriptions of the genus Flavitalea and Flavitalea populi. AB - A gram-reaction-negative, rod-shaped, gliding and bright-yellow-pigmented bacterial strain, designated JCN-23(T), was isolated from a soil sample collected from an arid area in Gansu Province in north-west China, and characterized by using a polyphasic taxonomic approach. This isolate grew optimally at 30 degrees C and in the absence of NaCl. The only respiratory quinone was menaquinone-7 and the major cellular fatty acids were iso-C(15 : 0), iso-C(17 : 0) 3-OH, summed feature 9 (iso-C(17 : 1)omega9c and/or C(16 : 0) 10-methyl) and summed feature 3 (C(16 : 1)omega7c and/or C(16 : 1)omega6c). The only polyamine was homospermidine and the major polar lipid was phosphatidylethanolamine. The DNA G+C content was 47.1 mol%. Comparative 16S rRNA gene sequence analysis showed that strain JCN 23(T) was a member of the phylum Bacteroidetes, exhibiting the highest 16S rRNA gene sequence similarity to Flavitalea populi CCTCC AB 208255(T) (97.6 %). No other recognized bacterial species showed more than 93.4 % 16S rRNA gene sequence similarity to the novel isolate. DNA-DNA hybridization experiments showed a low level (26 %) of DNA-DNA relatedness between strain JCN-23(T) and F. populi CCTCC AB 208255(T). On the basis of the phenotypic and genotypic data and phylogenetic inference, strain JCN-23(T) is considered to represent a novel species of the genus Flavitalea, for which the name Flavitalea gansuensis sp. nov. is proposed. The type strain is JCN-23(T) ( = ACCC 05418(T) = KCTC 23071(T)). Emended descriptions of the genus Flavitalea and Flavitalea populi are also proposed. PMID- 22505602 TI - Aspergillus baeticus sp. nov. and Aspergillus thesauricus sp. nov., two species in section Usti from Spanish caves. AB - Two novel species of Aspergillus that are clearly distinct from all known species in section Usti were revealed during a study of microfungal communities in Spanish caves. The novel species identified in this study and additional species of Aspergillus section Usti are associated with places and substrates related to human activities in caves. Novel species are described using data from four loci (ITS, benA, caM and rpb2), morphology and basic chemical and physiological analyses. Members of the species Aspergillus thesauricus sp. nov. were isolated from various substrates, including decaying organic matter, cave air and cave sediment of the Cueva del Tesoro Cave (the Treasure cave); the species is represented by twelve isolates and is most closely related to the recently described Aspergillus germanicus. Members of the species Aspergillus baeticus sp. nov. were isolated from cave sediment in the Gruta de las Maravillas Cave (the Grotto of the Marvels); the species is represented by two isolates. An additional isolate was found in the Cueva del Tesoro Cave and in the Demanovska Peace Cave (Slovakia), suggesting a potentially wide distribution of this micro-organism. The species is related to Aspergillus ustus and Aspergillus pseudoustus. Both species were unable to grow at 37 degrees C, and a weakly positive, light greenish yellow Ehrlich reaction was observed in A. thesauricus. Unique morphological features alone are sufficient to distinguish both species from related taxa. PMID- 22505603 TI - Analgesia after feline ovariohysterectomy under midazolam-medetomidine-ketamine anaesthesia with buprenorphine or butorphanol, and carprofen or meloxicam: a prospective, randomised clinical trial. AB - One hundred female cats undergoing routine ovariohysterectomy under midazolam medetomidine-ketamine anaesthesia were included in a blinded, randomised, prospective clinical study to compare postoperative analgesia produced by four analgesic drug combinations given preoperatively (n = 25 per group). A secondary aim was to assess the effects in kittens and pregnant animals. Buprenorphine 180 ug/m(2) or butorphanol 6 mg/m(2) were given with either carprofen 4 mg/kg (groups BUPC and BUTC, respectively) or meloxicam 0.3 mg/kg (groups BUPM or BUTM, respectively). Medetomidine was not antagonised. A simple, descriptive scale (SDS; 0-4), a dynamic and interactive visual analogue scale (DIVAS; 0-100 mm) and mechanical nociceptive thresholds (MT; 2.5-mm diameter probe) were used to evaluate postoperative pain. All pain scores were low (DIVAS <10 mm, SDS <2 and MT >10 N) and there were no significant differences between the groups. It was concluded that all protocols provided adequate analgesia and when used with midazolam-medetomidine-ketamine are effective for routine feline ovariohysterectomy. PMID- 22505604 TI - GPCR assay automation for leveraging lead optimization. AB - The drug discovery process is dependent on the ability of screening efforts to identify and optimize lead compounds with therapeutic potential. Because G protein-coupled receptors (GPCRs) account for the most "druggable" targets, the development of high-throughput, low-cost, and high-density GPCR assays to accommodate the increasing size of compound collections is significant. In this study, we report the application of an advanced LEADseeker robotic platform equipped with customized IT solutions for rapid data transfer to reduce assay cycles times for support of GPCR panel screening. The advantages of assay throughput, format, automation design, data management flow, and data reproducibility are discussed in terms of gains in productivity for lead optimization. The GPCR robotic platform demonstrates how automation technology can leverage traditional drug discovery processes by providing consistent and reliable data packages to expedite lead optimization efforts. PMID- 22505605 TI - Male versus female lupus: a comparison of ethnicity, clinical features, serology and outcome over a 30 year period. AB - OBJECTIVE: To review the differences between male and female lupus patients with respect to clinical features, serology and outcome over a thirty year period. MATERIAL AND METHODS: An observational study of all SLE patients seen at University College of London Hospital between 1976 and 2005 was performed. Demographic, clinical and serological data and outcome were retrospectively collected from hospital records or questionnaires and reviewed. Comparisons between continuous variables were made using the Kruskal-Wallis test and Student's t-test. Chi-square test or Fisher's exact test were used for categorical variables when it was appropriate. RESULTS: A total of 484 patients (439 females and 45 males) were identified between 1976 and 2005. Their mean age at diagnosis was 29.3 years (SD 12.6) with no significant differences between men and women. There were no significant differences between the number of men and women diagnosed over the different decades or in the mean age at diagnosis. Female gender was significantly associated with the presence of oral ulcers (29.2% vs. 13.3%, p < 0.05) and Ig M ACA (9.9% vs. 0%, p < 0.05). There were no significant differences in the comparison of other variables. With respect to outcome, although renal failure and death were higher in females (6.8% vs. 4.4% and 13.2% vs. 6.6% respectively), no statistically significant differences were found. Cardiovascular disease was the commonest cause of death in men. CONCLUSION: Over this thirty year follow-up period, relatively few differences have emerged comparing the frequencies of clinical and serological features or outcome in male and female lupus patients. PMID- 22505606 TI - ARNT controls the expression of epidermal differentiation genes through HDAC- and EGFR-dependent pathways. AB - Previously we showed that spatial and developmental modulation of ARNT (HIF1beta) expression in mouse epidermis is essential for maintenance of keratinocyte differentiation, proper formation of the barrier and normal desquamation. Here, using lentiviral suppression or induction of ARNT in TERT-immortalized (N-TERT) and HaCaT cells we assessed the nature and mechanisms of ARNT involvement in control of differentiation in human epidermal keratinocytes. ARNT depletion did not affect the levels of basal keratins K5 and K14, but significantly induced expression of several key differentiation markers (an effect abolished by EGF supplementation). Furthermore, ARNT deficiency resulted in the downregulation of amphiregulin (AREG) - the most highly expressed EGFR ligand in human keratinocytes - whereas upregulation of ARNT showed the opposite. In ARNT deficient monolayer cultures and 3D epidermal equivalents, the downregulation of AREG was concurrent with a decline of EGFR and ERK1/2 phosphorylation. TSA, a potent suppressor of HDAC activity, abolished the effects of ARNT deficiency, implying a role for HDACs in ARNT-dependent modulation of the AREG-EGFR pathway and downstream epidermal genes. Total HDAC activity was significantly increased in ARNT-depleted cells and decreased with ARNT overexpression. ARNT-dependent shifts in HDAC activity were specifically attributed to significant changes in the levels of HDAC1, HDAC2 and HDAC3 proteins (but not mRNA) in both monolayer and 3D cultures. Collectively, our results suggest that ARNT controls AREG expression and the downstream EGFR-ERK pathway in keratinocytes, at least in part, by modulating HDAC activity. This novel regulatory pathway targeting advanced stages of epidermal differentiation might have important implications for skin pathology such as psoriasis, atopic dermatitis and cancer. PMID- 22505608 TI - Presynaptic PI3K activity triggers the formation of glutamate receptors at neuromuscular terminals of Drosophila. AB - Synapse transmission depends on the precise structural and functional assembly between pre- and postsynaptic elements. This tightly regulated interaction has been thoroughly characterised in vivo in the Drosophila glutamatergic larval neuromuscular junction (NMJ) synapse, a suitable model to explore synapse formation, dynamics and plasticity. Previous findings have demonstrated that presynaptic upregulation of phosphoinositide 3-kinase (PI3K) increases synapse number, generating new functional contacts and eliciting changes in behaviour. Here, we show that genetically driven overexpression of PI3K in the presynaptic element also leads to a correlated increase in the levels of glutamate receptor (GluRII) subunits and the number of postsynaptic densities (PSDs), without altering GluRII formation and assembly dynamics. In addition to GluRIIs, presynaptic PI3K activity also modifies the expression of the postsynaptic protein Discs large (Dlg). Remarkably, PI3K specifically overexpressed in the final larval stages is sufficient for the formation of NMJ synapses. No differences in the number of synapses and PSDs were detected when PI3K was selectively expressed in the postsynaptic compartment. Taken together, these results demonstrate that PI3K-dependent synaptogenesis plays an instructive role in PSD formation and growth from the presynaptic side. PMID- 22505607 TI - TRC40 can deliver short secretory proteins to the Sec61 translocon. AB - Whilst the co-translational translocation of nascent proteins across the mammalian endoplasmic reticulum (ER) is well defined, the capacity of this organelle for post-translational translocation is poorly delineated. Here we identify two human secretory protein precursors, apelin and statherin, as bona fide substrates for post-translational translocation across the ER membrane. Further studies, in combination with Hyalophora cecropia preprocecropin A (ppcecA), show that all three proteins bind to TRC40 and can utilise this component for their delivery to the ER membrane in a well-established in vitro system. However, ppcecA is not an obligate TRC40 substrate, and it can also be delivered to the ER by an alternative TRC40-independent pathway. Upon arrival at the ER membrane, these short secretory proteins appear to be ubiquitously transported across the ER membrane through the Sec61 translocon, apparently irrespective of their delivery route. We speculate that the post-translational translocation of secretory proteins in higher eukaryotes is more prevalent than previously acknowledged. PMID- 22505609 TI - Conserved motifs in the Msn2-activating domain are important for Msn2-mediated yeast stress response. AB - The Msn2 and Msn4 transcription factors play crucial roles in the yeast general stress response. Previous studies identified several large functional domains of Msn2, mainly through crude truncations. Here, using bioinformatics and experimental approaches to examine Msn2 structure-function relationships, we have identified new functional motifs in the Msn2 transcriptional-activating domain (TAD). Msn2 is predicted to adopt an intrinsically disordered structure with two short structural motifs in its TAD. Mutations in these motifs dramatically decreased Msn2 transcriptional activity, yeast stress survival and Msn2 nuclear localization levels. Using the split-ubiquitin assay, we found that these motifs are important for the interaction of Msn2 with Gal11, a subunit of the mediator complex. Finally, we show that one of these motifs is functionally conserved in several yeast species, highlighting a common mechanism of Msn2 transcriptional activation throughout yeast evolution. PMID- 22505610 TI - Cylindrical cellular geometry ensures fidelity of division site placement in fission yeast. AB - Successful cytokinesis requires proper assembly of the contractile actomyosin ring, its stable positioning on the cell surface and proper constriction. Over the years, many of the key molecular components and regulators of the assembly and positioning of the actomyosin ring have been elucidated. Here we show that cell geometry and mechanics play a crucial role in the stable positioning and uniform constriction of the contractile ring. Contractile rings that assemble in locally spherical regions of cells are unstable and slip towards the poles. By contrast, actomyosin rings that assemble on locally cylindrical portions of the cell under the same conditions do not slip, but uniformly constrict the cell surface. The stability of the rings and the dynamics of ring slippage can be described by a simple mechanical model. Using fluorescence imaging, we verify some of the quantitative predictions of the model. Our study reveals an intimate interplay between geometry and actomyosin dynamics, which are likely to apply in a variety of cellular contexts. PMID- 22505611 TI - Grb2 mediates semaphorin-4D-dependent RhoA inactivation. AB - Signaling through the semaphorin 4D (Sema4D) receptor plexin-B1 is modulated by its interaction with tyrosine kinases ErbB-2 and Met. In cells expressing the plexin-B1-ErbB-2 receptor complex, ligand stimulation results in the activation of small GTPase RhoA and stimulation of cellular migration. By contrast, in cells expressing plexin-B1 and Met, ligand stimulation results in an association with the RhoGTPase-activating protein p190 RhoGAP and subsequent RhoA inactivation--a process that involves the tyrosine phosphorylation of plexin-B1 by Met. Inactivation of RhoA is necessary for Sema4D-mediated inhibition of cellular migration. It is, however, unknown how plexin-B1 phosphorylation regulates RhoGAP interaction and activity. Here we show that the activation of plexin-B1 by Sema4D and its subsequent tyrosine phosphorylation by Met creates a docking site for the SH2 domain of growth factor receptor bound-2 (Grb2). Grb2 is thereby recruited into the plexin-B1 receptor complex and, through its SH3 domain, interacts with p190 RhoGAP and mediates RhoA deactivation. Phosphorylation of plexin-B1 by Met and the recruitment of Grb2 have no effect on the R-RasGAP activity of plexin-B1, but are required for Sema4D-induced, RhoA-dependent antimigratory effects of Sema4D on breast cancer cells. These data show Grb2 as a direct link between plexin and p190-RhoGAP-mediated downstream signaling. PMID- 22505613 TI - Role of triadin in the organization of reticulum membrane at the muscle triad. AB - The terminal cisternae represent one of the functional domains of the skeletal muscle sarcoplasmic reticulum (SR). They are closely apposed to plasma membrane invaginations, the T-tubules, with which they form structures called triads. In triads, the physical interaction between the T-tubule-anchored voltage-sensing channel DHPR and the SR calcium channel RyR1 is essential because it allows the depolarization-induced calcium release that triggers muscle contraction. This interaction between DHPR and RyR1 is based on the peculiar membrane structures of both T-tubules and SR terminal cisternae. However, little is known about the molecular mechanisms governing the formation of SR terminal cisternae. We have previously shown that ablation of triadins, a family of SR transmembrane proteins that interact with RyR1, induced skeletal muscle weakness in knockout mice as well as a modification of the shape of triads. Here we explore the intrinsic molecular properties of the longest triadin isoform Trisk 95. We show that when ectopically expressed, Trisk 95 can modulate reticulum membrane morphology. The membrane deformations induced by Trisk 95 are accompanied by modifications of the microtubule network organization. We show that multimerization of Trisk 95 by disulfide bridges, together with interaction with microtubules, are responsible for the ability of Trisk 95 to structure reticulum membrane. When domains responsible for these molecular properties are deleted, anchoring of Trisk 95 to the triads in muscle cells is strongly decreased, suggesting that oligomers of Trisk 95 and microtubules contribute to the organization of the SR terminal cisternae in a triad. PMID- 22505614 TI - Opposite and redundant roles of the two Drosophila perilipins in lipid mobilization. AB - Lipid droplets are the main lipid storage sites in cells. Lipid droplet homeostasis is regulated by the surface accessibility of lipases. Mammalian adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are two key lipases for basal and stimulated lipolysis, respectively. Perilipins, the best known lipid droplet surface proteins, can either recruit lipases or prevent the access of lipases to lipid droplets. Mammals have five perilipin proteins, which often exhibit redundant functions, precluding the analysis of the exact role of individual perilipins in vivo. Drosophila have only two perilipins, PLIN1/LSD-1 and PLIN2/LSD-2. Previous studies revealed that PLIN2 is important for protecting lipid droplets from lipolysis mediated by Brummer (BMM), the Drosophila homolog of ATGL. In this study, we report the functional analysis of PLIN1 and Drosophila HSL. Loss-of-function and overexpression studies reveal that unlike PLIN2, PLIN1 probably facilitates lipid mobilization. HSL is recruited from the cytosol to the surface of lipid droplets under starved conditions and PLIN1 is necessary for the starved induced lipid droplet localization of HSL. Moreover, phenotypic analysis of plin1;plin2 double mutants revealed that PLIN1 and PLIN2 might have redundant functions in protecting lipid droplets from lipolysis. Therefore, the two Drosophila perilipins have both opposite and redundant roles. Domain swapping and deletion analyses indicate that the C-terminal region of PLIN1 confers functional specificity to PLIN1. Our study highlights the complex roles of Drosophila perilipin proteins and the evolutionarily conserved regulation of HSL translocation by perilipins. PMID- 22505612 TI - Cadherin point mutations alter cell sorting and modulate GTPase signaling. AB - This study investigated the impact of cadherin binding differences on both cell sorting and GTPase activation. The use of N-terminal domain point mutants of Xenopus C-cadherin enabled us to quantify binding differences and determine their effects on cadherin-dependent functions without any potential complications arising as a result of differences in cytodomain interactions. Dynamic cell-cell binding measurements carried out with the micropipette manipulation technique quantified the impact of these mutations on the two-dimensional binding affinities and dissociation rates of cadherins in the native context of the cell membrane. Pairwise binding affinities were compared with in vitro cell-sorting specificity and ligation-dependent GTPase signaling. Two-dimensional affinity differences greater than five-fold correlated with cadherin-dependent in vitro cell segregation, but smaller differences failed to induce cell sorting. Comparison of the binding affinities with GTPase signaling amplitudes further demonstrated that differential binding also proportionally modulates intracellular signaling. These results show that differential cadherin affinities have broader functional consequences than merely controlling cell-cell cohesion. PMID- 22505615 TI - Nuclear p120 catenin unlocks mitotic block of contact-inhibited human corneal endothelial monolayers without disrupting adherent junctions. AB - Contact inhibition ubiquitously exists in non-transformed cells that are in contact with neighboring cells. This phenomenon explains the poor regenerative capacity of in vivo human corneal endothelial cells during aging, injury and surgery. This study demonstrated that the conventional approach of expanding human corneal endothelial cells by disrupting contact inhibition with EDTA followed by bFGF activated canonical Wnt signaling and lost the normal phenotype to endothelial-mesenchymal transition, especially if TGFbeta1 was added. By contrast, siRNA against p120 catenin (CTNND1) also uniquely promoted proliferation of the endothelial cells by activating trafficking of p120 catenin to the nucleus, thus relieving repression by nuclear Kaiso. This nuclear p120 catenin-Kaiso signaling is associated with activation of RhoA-ROCK signaling, destabilization of microtubules and inhibition of Hippo signaling, but not with activation of Wnt-beta-catenin signaling. Consequently, proliferating human corneal endothelial cells maintained a hexagonal shape, with junctional expression of N-cadherin, ZO-1 and Na(+)/K(+)-ATPase. Further expansion of human corneal endothelial monolayers with a normal phenotype and a higher density was possible by prolonging treatment with p120 catenin siRNA followed by its withdrawal. This new strategy of perturbing contact inhibition by selective activation of p120-catenin-Kaiso signaling without disrupting adherent junction could be used to engineer surgical grafts containing normal human corneal endothelial cells to meet a global corneal shortage and for endothelial keratoplasties. PMID- 22505616 TI - SUMOylation of HNF4alpha regulates protein stability and hepatocyte function. AB - The coordination of signalling pathways within the cell is vital for normal human development and post-natal tissue homeostasis. Gene expression and function is therefore tightly controlled at a number of levels. We investigated the role that post-translational modifications play during human hepatocyte differentiation. In particular, we examined the role of the small ubiquitin-like modifier (SUMO) proteins in this process. We used a human embryonic stem cell (hESC)-based model of hepatocyte differentiation to follow changes in protein SUMOylation. Moreover, to confirm the results derived from our cell-based system, we performed in vitro conjugation assays to characterise SUMO modification of a key liver-enriched transcription factor, HNF4alpha. Our analyses indicate that SUMOylation plays an important role during hepatocellular differentiation and this is mediated, in part, through regulation of the stability of HNF4alpha in a ubiquitin-dependent manner. Our study provides a better understanding of SUMOylation during human hepatocyte differentiation and maturation. Moreover, we believe the results will stimulate interest in the differentiation and phenotypic regulation of other somatic cell types. PMID- 22505617 TI - Decision coaching to prepare patients for making health decisions: a systematic review of decision coaching in trials of patient decision AIDS. AB - BACKGROUND: Decision coaching is individualized, nondirective facilitation of patient preparation for shared decision making. PURPOSE: To explore characteristics and effectiveness of decision coaching evaluated within trials of patient decision aids (PtDAs) for health decisions. DATA SOURCES: A subanalysis of trials included in the 2011 Cochrane Review of PtDAs. STUDY SELECTION: Eligible trials allowed the effectiveness of decision coaching to be compared with another intervention and/or usual care. DATA EXTRACTION: Two reviewers independently screened 86 trials, extracted data, and appraised quality. DATA SYNTHESIS: Ten trials were eligible. Decision coaching was provided by genetic counselors, nurses, pharmacists, physicians, psychologists, or health educators. Coaching compared with usual care (n = 1 trial) improved knowledge. Coaching plus PtDA compared with usual care (n = 4) improved knowledge and participation in decision making without reported dissatisfaction. Coaching compared with PtDA alone (n = 4) increased values-choice agreement and improved satisfaction with the decision-making process without any difference in knowledge or participation in decision making. Coaching plus PtDA compared with PtDA alone (n = 4) had no difference in knowledge, values-choice agreement, participation in decision making, or satisfaction with the process. Decision coaching plus PtDA was more cost-effective compared with PtDA alone or usual care (n = 1). LIMITATIONS: Methodological quality, number of trials, and description of decision coaching. CONCLUSIONS: Compared with usual care, decision coaching improved knowledge. However, the improvement in knowledge was similar when coaching was compared with PtDA alone. Outcomes for other comparisons are more variable, some trials showing positive effects and other trials reporting no difference. Given the small number of trials and variability in results, further research is required to determine the effectiveness of decision coaching. PMID- 22505618 TI - Two forms of aftereffects induced by transparent motion reveal multilevel adaptation. AB - Visual adaptation produces remarkable perceptual aftereffects. However, it remains unclear what basic neural mechanisms underlie visual adaptation and how these adaptation-induced neural changes are related to perceptual aftereffects. To address these questions, we examined transparent motion adaptation and traced the effects of adaptation through the motion processing hierarchy. We found that, after adapting to a bidirectional transparent motion display, observers perceived two radically different motion aftereffects (MAEs): segregated and integrated MAEs, depending on testing locations. The segregated MAE yielded an aftereffect opposite to one of the adapting directions in the transparent motion stimulus. Our results revealed that the segregated MAE relies on the integration of local adaptation effects. In contrast, the integrated MAE yielded an aftereffect opposite to the average of the adapting directions. We found that integrated MAE was dominant at non-adapted locations but was reduced when local adaptation effects were weakened. These results suggest that integrated MAE is elicited by a combination of two mechanisms: adaptation-induced changes at a high-level processing stage and integration of local adaptation effects. We conclude that distinct perceptual aftereffects can be observed due to adaptation-induced neural changes at different processing levels, supporting the general hypothesis of multilevel adaptation in the visual hierarchy. PMID- 22505619 TI - Amblyopic deficits in processing structure-from-motion. AB - Amblyopic observers exhibit a range of low- and high-level cortical deficits, and there is strong evidence that the extrastriate cortex is selectively affected for signal/noise tasks but not for simple integration tasks. We tested amblyopic and control observers on a structure-from-motion (SFM) task involving signal integration to gauge whether extrastriate processing is compromised at a level where dorsal and ventral information is combined. SFM tasks require integration of local elements to perceive the global structure using motion-defined depth cues. Observers were monocularly presented with a 2-IFC shape discrimination task and asked to indicate whether two consecutive SFM stimuli represented the same or different depth-defined shapes. Amblyopic observers had higher depth thresholds than control observers, even after controlling for low-level differences in contrast thresholds across eyes and observers. Combined with the presence of the deficit in both the amblyopic and fellow-fixing eyes, this suggests a high-level locus for the SFM deficit. PMID- 22505620 TI - Does visual flicker phase at gamma frequency modulate neural signal propagation and stimulus selection? AB - Oscillatory synchronization of neuronal populations has been proposed to play a role in perceptual integration and attentional processing. However, some conflicting evidence has been found with respect to its causal relevance for sensory processing, particularly when using flickering visual stimuli with the aim of driving oscillations. We tested psychophysically whether the relative phase of gamma frequency flicker (60 Hz) between stimuli modulates well-known facilitatory lateral interactions between collinear Gabor patches (Experiment 1) or crowding of a peripheral target by irrelevant distractors (Experiment 2). Experiment 1 assessed the impact of suprathreshold Gabor flankers on detection of a near-threshold central Gabor target ("Lateral interactions paradigm"). The flanking stimuli could flicker either in phase or in anti-phase with each other. The typical facilitation of target detection was found with collinear flankers, but this was unaffected by flicker phase. Experiment 2 employed a "crowding" paradigm, where orientation discrimination of a peripheral target Gabor patch is disrupted when surrounded by irrelevant distractors. We found the usual crowding effect, which declined with spatial separation, but this was unaffected by relative flicker phase between target and distractors at all separations. These results imply that externally driven manipulations of gamma frequency phase cannot modulate perceptual integration in vision. PMID- 22505621 TI - Cytoplasmic and genomic effects on meiotic pairing in Brassica hybrids and allotetraploids from pair crosses of three cultivated diploids. AB - Interspecific hybridization and allopolyploidization contribute to the origin of many important crops. Synthetic Brassica is a widely used model for the study of genetic recombination and "fixed heterosis" in allopolyploids. To investigate the effects of the cytoplasm and genome combinations on meiotic recombination, we produced digenomic diploid and triploid hybrids and trigenomic triploid hybrids from the reciprocal crosses of three Brassica diploids (B. rapa, AA; B. nigra, BB; B. oleracea, CC). The chromosomes in the resultant hybrids were doubled to obtain three allotetraploids (B. juncea, AA.BB; B. napus, AA.CC; B. carinata, BB.CC). Intra- and intergenomic chromosome pairings in these hybrids were quantified using genomic in situ hybridization and BAC-FISH. The level of intra- and intergenomic pairings varied significantly, depending on the genome combinations and the cytoplasmic background and/or their interaction. The extent of intragenomic pairing was less than that of intergenomic pairing within each genome. The extent of pairing variations within the B genome was less than that within the A and C genomes, each of which had a similar extent of pairing. Synthetic allotetraploids exhibited nondiploidized meiotic behavior, and their chromosomal instabilities were correlated with the relationship of the genomes and cytoplasmic background. Our results highlight the specific roles of the cytoplasm and genome to the chromosomal behaviors of hybrids and allopolyploids. PMID- 22505622 TI - Genetic evidence links the ASTRA protein chaperone component Tti2 to the SAGA transcription factor Tra1. AB - Tra1 is a 3744-residue component of the Saccharomyces cerevisiae SAGA, NuA4, and ASTRA complexes. Tra1 contains essential C-terminal PI3K and FATC domains, but unlike other PIKK (phosphoinositide three-kinase-related kinase) family members, lacks kinase activity. To analyze functions of the FATC domain, we selected for suppressors of tra1-F3744A, an allele that results in slow growth under numerous conditions of stress. Two alleles of TTI2, tti2-F328S and tti2-I336F, acted in a partially dominant fashion to suppress the growth-related phenotypes associated with tra1-F3744A as well as its resulting defects in transcription. tti2-F328S suppressed an additional FATC domain mutation (tra1-L3733A), but not a mutation in the PI3K domain or deletions of SAGA or NuA4 components. We find eGFP-tagged Tti2 distributed throughout the cell. Tti2 is a component of the ASTRA complex, and in mammalian cells associates with molecular chaperones in complex with Tti1 and Tel2. Consistent with this finding, Tra1 levels are reduced in a strain with a temperature-sensitive allele of tel2. Further agreeing with a possible role for Tti2 in the folding or stabilization of Tra1, tra1-F3744A was mislocalized to the cytoplasm, particularly under conditions of stress. Since an intragenic mutation of tra1-R3590I also suppressed F3744A, we propose that Tti2 is required for the folding/stability of the C-terminal FATC and PI3K domains of Tra1 into their functionally active form. PMID- 22505623 TI - Ribosomal DNA organization before and after magnification in Drosophila melanogaster. AB - In all eukaryotes, the ribosomal RNA genes are stably inherited redundant elements. In Drosophila melanogaster, the presence of a Ybb(-) chromosome in males, or the maternal presence of the Ribosomal exchange (Rex) element, induces magnification: a heritable increase of rDNA copy number. To date, several alternative classes of mechanisms have been proposed for magnification: in situ replication or extra-chromosomal replication, either of which might act on short or extended strings of rDNA units, or unequal sister chromatid exchange. To eliminate some of these hypotheses, none of which has been clearly proven, we examined molecular-variant composition and compared genetic maps of the rDNA in the bb(2) mutant and in some magnified bb(+) alleles. The genetic markers used are molecular-length variants of IGS sequences and of R1 and R2 mobile elements present in many 28S sequences. Direct comparison of PCR products does not reveal any particularly intensified electrophoretic bands in magnified alleles compared to the nonmagnified bb(2) allele. Hence, the increase of rDNA copy number is diluted among multiple variants. We can therefore reject mechanisms of magnification based on multiple rounds of replication of short strings. Moreover, we find no changes of marker order when pre- and postmagnification maps are compared. Thus, we can further restrict the possible mechanisms to two: replication in situ of an extended string of rDNA units or unequal exchange between sister chromatids. PMID- 22505624 TI - Chaperoning the chaperone: a role for the co-chaperone Cpr7 in modulating Hsp90 function in Saccharomyces cerevisiae. AB - Heat-shock protein 90 (Hsp90) of Saccharomyces cerevisiae is an abundant essential eukaryotic molecular chaperone involved in the activation and stabilization of client proteins, including several transcription factors and oncogenic kinases. Hsp90 undergoes a complex series of conformational changes and interacts with partner co-chaperones such as Sba1, Cpr6, Cpr7, and Cns1 as it binds and hydrolyzes ATP. In the absence of nucleotide, Hsp90 is dimerized only at the carboxy-terminus. In the presence of ATP, Hsp90 also dimerizes at the amino-terminus, creating a binding site for Sba1. Truncation of a charged linker region of yeast Hsp90 (Hsp82Deltalinker) was known to disrupt the ability of Hsp82 to undergo amino-terminal dimerization and bind Sba1. We found that yeast expressing Hsp82Deltalinker constructs exhibited a specific synthetic lethal phenotype in cells lacking CPR7. The isolated tetratricopeptide repeat domain of Cpr7 was both necessary and sufficient for growth in those strains. Cpr6 and Cpr7 stably bound the carboxy-terminus of wild-type Hsp82 only in the presence of nonhydrolyzable ATP and formed an Hsp82-Cpr6-Cpr7 ternary complex. However, in cells expressing Hsp82Deltalinker or lacking CPR7, Cpr6 was able to bind Hsp82 in the presence or absence of nucleotide. Overexpression of CNS1, but not of other co-chaperones, in cpr7 cells restored nucleotide-dependent Hsp82-Cpr6 interaction. Together, our results suggest that the in vivo functions of Cpr7 include modulating Hsp90 conformational changes, mediating proper signaling of the nucleotide-bound state to the carboxy-terminus of Hsp82, or regulating Hsp82 Cpr6 interaction. PMID- 22505625 TI - Increasing association mapping power and resolution in mouse genetic studies through the use of meta-analysis for structured populations. AB - Genetic studies in mouse models have played an integral role in the discovery of the mechanisms underlying many human diseases. The primary mode of discovery has been the application of linkage analysis to mouse crosses. This approach results in high power to identify regions that affect traits, but in low resolution, making it difficult to identify the precise genomic location harboring the causal variant. Recently, a panel of mice referred to as the hybrid mouse diversity panel (HMDP) has been developed to overcome this problem. However, power in this panel is limited by the availability of inbred strains. Previous studies have suggested combining results across multiple panels as a means to increase power, but the methods employed may not be well suited to structured populations, such as the HMDP. In this article, we introduce a meta-analysis-based method that may be used to combine HMDP studies with F2 cross studies to gain power, while increasing resolution. Due to the drastically different genetic structure of F2s and the HMDP, the best way to combine two studies for a given SNP depends on the strain distribution pattern in each study. We show that combining results, while accounting for these patterns, leads to increased power and resolution. Using our method to map bone mineral density, we find that two previously implicated loci are replicated with increased significance and that the size of the associated is decreased. We also map HDL cholesterol and show a dramatic increase in the significance of a previously identified result. PMID- 22505626 TI - Properties and power of the Drosophila Synthetic Population Resource for the routine dissection of complex traits. AB - The Drosophila Synthetic Population Resource (DSPR) is a newly developed multifounder advanced intercross panel consisting of >1600 recombinant inbred lines (RILs) designed for the genetic dissection of complex traits. Here, we describe the inference of the underlying mosaic founder structure for the full set of RILs from a dense set of semicodominant restriction-site-associated DNA (RAD) markers and use simulations to explore how variation in marker density and sequencing coverage affects inference. For a given sequencing effort, marker density is more important than sequence coverage per marker in terms of the amount of genetic information we can infer. We also assessed the power of the DSPR by assigning genotypes at a hidden QTL to each RIL on the basis of the inferred founder state and simulating phenotypes for different experimental designs, different genetic architectures, different sample sizes, and QTL of varying effect sizes. We found the DSPR has both high power (e.g., 84% power to detect a 5% QTL) and high mapping resolution (e.g., ~1.5 cM for a 5% QTL). PMID- 22505628 TI - Evidence for a natural allelic series at the maize domestication locus teosinte branched1. AB - Despite numerous quantitative trait loci and association mapping studies, our understanding of the extent to which natural allelic series contribute to the variation for complex traits is limited. In this study, we investigate the occurrence of a natural allelic series for complex traits at the teosinte branched1 (tb1) gene in natural populations of teosinte (Zea mays ssp. parviglumis, Z. mays ssp. mexicana, and Z. diploperennis). Previously, tb1 was shown to confer large effects on both plant architecture and ear morphology between domesticated maize and teosinte; however, the effect of tb1 on trait variation in natural populations of teosinte has not been investigated. We compare the effects of nine teosinte alleles of tb1 that were introgressed into an isogenic maize inbred background. Our results provide evidence for a natural allelic series at tb1 for several complex morphological traits. The teosinte introgressions separate into three distinct phenotypic classes, which correspond to the taxonomic origin of the alleles. The effects of the three allelic classes also correspond to known morphological differences between the teosinte taxa. Our results suggest that tb1 contributed to the morphological diversification of teosinte taxa as well as to the domestication of maize. PMID- 22505627 TI - Improved models for transcription factor binding site identification using nonindependent interactions. AB - Identifying transcription factor (TF) binding sites is essential for understanding regulatory networks. The specificity of most TFs is currently modeled using position weight matrices (PWMs) that assume the positions within a binding site contribute independently to binding affinity for any site. Extensive, high-throughput quantitative binding assays let us examine, for the first time, the independence assumption for many TFs. We find that the specificity of most TFs is well fit with the simple PWM model, but in some cases more complex models are required. We introduce a binding energy model (BEM) that can include energy parameters for nonindependent contributions to binding affinity. We show that in most cases where a PWM is not sufficient, a BEM that includes energy parameters for adjacent dinucleotide contributions models the specificity very well. Having more accurate models of specificity greatly improves the interpretation of in vivo TF localization data, such as from chromatin immunoprecipitation followed by sequencing (ChIP-seq) experiments. PMID- 22505629 TI - Unique O-methoxyethyl ribose-DNA chimeric oligonucleotide induces an atypical melanoma differentiation-associated gene 5-dependent induction of type I interferon response. AB - Antisense oligonucleotides (ASO) containing 2'-O-methoxyethyl ribose (2'-MOE) modifications have been shown to possess both excellent pharmacokinetic properties and robust pharmacological activity in several animal models of human disease. 2'-MOE ASOs are generally well tolerated, displaying minimal to mild proinflammatory effect at doses far exceeding therapeutic doses. Although the vast majority of 2'-MOE ASOs are safe and well tolerated, a small subset of ASOs inducing acute inflammation in mice has been identified. The mechanism for these findings is not clear at this point, but the effects are clearly sequence specific. One of those ASOs, ISIS 147420, causes a severe inflammatory response atypical of this class of oligonucleotides characterized by induction in interferon-beta (IFN-beta) at 48 h followed by acute transaminitis and extensive hepatocyte apoptosis and necrosis at 72 h. A large number of interferon stimulated genes were significantly up-regulated in liver as early as 24 h. We speculated that a specific sequence motif might cause ISIS 147420 to be mistaken for viral RNA or DNA, thus triggering an acute innate immune response. ISIS 147420 toxicity was independent of Toll-like receptors, because there was no decrease in IFN-beta in Toll/interleukin-1 receptor-domain-containing adapter inducing IFN-beta or Myd88-deficient mice. The involvement of cytosolic retinoic acid-inducible gene (RIG)-I-like pattern recognition receptors was also investigated. Pretreatment of mice with melanoma differentiation-associated gene 5 (MDA5) and IFN-beta promoter stimulator-1 ASOs, but not RIG-I or laboratory of genetics and physiology 2 (LGP2) ASOs, prevented the increase in IFN-beta and alanine aminotransferase induced by ISIS 147420. These results revealed a novel mechanism of oligonucleotide-mediated toxicity requiring both MDA5 and IPS-1 and resulting in the activation of the innate immune response. PMID- 22505630 TI - Brain. Editorial. PMID- 22505631 TI - Altered brain mechanisms of emotion processing in pre-manifest Huntington's disease. AB - Huntington's disease is an inherited neurodegenerative disease that causes motor, cognitive and psychiatric impairment, including an early decline in ability to recognize emotional states in others. The pathophysiology underlying the earliest manifestations of the disease is not fully understood; the objective of our study was to clarify this. We used functional magnetic resonance imaging to investigate changes in brain mechanisms of emotion recognition in pre-manifest carriers of the abnormal Huntington's disease gene (subjects with pre-manifest Huntington's disease): 16 subjects with pre-manifest Huntington's disease and 14 control subjects underwent 1.5 tesla magnetic resonance scanning while viewing pictures of facial expressions from the Ekman and Friesen series. Disgust, anger and happiness were chosen as emotions of interest. Disgust is the emotion in which recognition deficits have most commonly been detected in Huntington's disease; anger is the emotion in which impaired recognition was detected in the largest behavioural study of emotion recognition in pre-manifest Huntington's disease to date; and happiness is a positive emotion to contrast with disgust and anger. Ekman facial expressions were also used to quantify emotion recognition accuracy outside the scanner and structural magnetic resonance imaging with voxel-based morphometry was used to assess the relationship between emotion recognition accuracy and regional grey matter volume. Emotion processing in pre-manifest Huntington's disease was associated with reduced neural activity for all three emotions in partially separable functional networks. Furthermore, the Huntington's disease-associated modulation of disgust and happiness processing was negatively correlated with genetic markers of pre-manifest disease progression in distributed, largely extrastriatal networks. The modulated disgust network included insulae, cingulate cortices, pre- and postcentral gyri, precunei, cunei, bilateral putamena, right pallidum, right thalamus, cerebellum, middle frontal, middle occipital, right superior and left inferior temporal gyri, and left superior parietal lobule. The modulated happiness network included postcentral gyri, left caudate, right cingulate cortex, right superior and inferior parietal lobules, and right superior frontal, middle temporal, middle occipital and precentral gyri. These effects were not driven merely by striatal dysfunction. We did not find equivalent associations between brain structure and emotion recognition, and the pre-manifest Huntington's disease cohort did not have a behavioural deficit in out-of-scanner emotion recognition relative to controls. In addition, we found increased neural activity in the pre-manifest subjects in response to all three emotions in frontal regions, predominantly in the middle frontal gyri. Overall, these findings suggest that pathophysiological effects of Huntington's disease may precede the development of overt clinical symptoms and detectable cerebral atrophy. PMID- 22505632 TI - Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. AB - Preclinical studies have attributed neuroprotective properties to the antibiotic minocycline. Animal studies and early clinical trials support its use in several neurological diseases. In animal spinal cord injury models, minocycline improved neurological and histological outcomes, reduced neuronal and oligodendroglial apoptosis, decreased microglial activation and reduced inflammation. A single centre, human, double-blind, randomized, placebo-controlled study of minocycline administration after spinal cord injury was undertaken for the purposes of dose optimization, safety assessment and to estimate outcome changes and variance. Neurological, functional, pharmacological and adverse event outcomes were compared between subjects administered 7 days of intravenous minocycline (n = 27) or placebo (n = 25) after acute traumatic spinal cord injury. The secondary outcome used to assess neurological differences between groups that may warrant further investigation was motor recovery over 1 year using the American Spinal Cord Injury Association examination. Recruitment and analyses were stratified by injury severity and injury location a priori given the expected influence of these on the sensitivity of the motor exam. Minocycline administered at higher than previously reported human doses produced steady-state concentrations of 12.7 ug/ml (95% confidence interval 11.6-13.8) in serum and 2.3 ug/ml (95% confidence interval 2.1-2.5) in cerebrospinal fluid, mimicking efficacious serum levels measured in animal studies. Transient elevation of serum liver enzymes in one patient was the only adverse event likely related to the study drug. Overall, patients treated with minocycline experienced six points greater motor recovery than those receiving placebo (95% confidence interval -3 to 14; P = 0.20, n = 44). No difference in recovery was observed for thoracic spinal cord injury (n = 16). A difference of 14 motor points that approached significance was observed in patients with cervical injury (95% confidence interval 0-28; P = 0.05, n = 25). Patients with cervical motor-incomplete injury may have experienced a larger difference (results not statistically significant, n = 9). Functional outcomes exhibited differences that lacked statistical significance but that may be suggestive of improvement in patients receiving the study drug. The minocycline regimen established in this study proved feasible, safe and was associated with a tendency towards improvement across several outcome measures. Although this study does not establish the efficacy of minocycline in spinal cord injury the findings are encouraging and warrant further investigation in a multi-centre phase III trial. ClinicalTrials.gov number NCT00559494. PMID- 22505634 TI - Improving the quality of road injury statistics by using regression models to redistribute ill-defined events. AB - OBJECTIVE: To test the predictive ability of multinomial regression method in obtaining category of death distribution for cases with unknown/ill-defined mortality codes. METHODS: The authors evaluated the performance of the multinomial regression model by fitting the model to trial datasets from 2004 Mexican vital registration data. To predict category of death, the regression method makes use of explanatory variables, such as gender, age, place of crash, place of residence, education and insurance type. The authors compared the results of a full model regression with those of a reduced model that only contained gender and age as explanatory variables. For this comparison, the authors constructed two forms of data: dummy variable adjustment method and case wise deleted method. The comparison was made through estimated area under the curve (AUC) for each outcome variable. RESULTS: The full model significantly outperformed the gender-age (reduced) model using both datasets. In the case-wise deleted method, the AUC was increased from 0.55 to 0.7 for the reduced model and from 0.64 to 0.84 for the full model. Improvement in AUC using the dummy variable adjustment method was less significant. CONCLUSIONS: To predict ill-defined categories of death, adding relevant explanatory variables to gender and age is recommended. Multiple imputations may perform even better than this model especially when significant portion of the data are missing. PMID- 22505633 TI - Biomarkers of increased diffusion anisotropy in semi-acute mild traumatic brain injury: a longitudinal perspective. AB - Mild traumatic brain injury is the most prevalent neurological insult and frequently results in neurobehavioural sequelae. However, little is known about the pathophysiology underlying the injury and how these injuries change as a function of time. Although diffusion tensor imaging holds promise for in vivo characterization of white matter pathology, both the direction and magnitude of anisotropic water diffusion abnormalities in axonal tracts are actively debated. The current study therefore represents both an independent replication effort (n = 28) of our previous findings (n = 22) of increased fractional anisotropy during semi-acute injury, as well as a prospective study (n = 26) on the putative recovery of diffusion abnormalities. Moreover, new analytical strategies were applied to capture spatially heterogeneous white matter injuries, which minimize implicit assumptions of uniform injury across diverse clinical presentations. Results indicate that whereas a general pattern of high anisotropic diffusion/low radial diffusivity was present in various white matter tracts in both the replication and original cohorts, this pattern was only consistently observed in the genu of the corpus callosum across both samples. Evidence for a greater number of localized clusters with increased anisotropic diffusion was identified across both cohorts at trend levels, confirming heterogeneity in white matter injury. Pooled analyses (50 patients; 50 controls) suggested that measures of diffusion within the genu were predictive of patient classification, albeit at very modest levels (71% accuracy). Finally, we observed evidence of recovery in lesion load in returning patients across a 4-month interval, which was correlated with a reduction in self-reported post-concussive symptomatology. In summary, the corpus callosum may serve as a common point of injury in mild traumatic brain injury secondary to anatomical (high frequency of long unmyelinated fibres) and biomechanics factors. A spatially heterogeneous pattern of increased anisotropic diffusion exists in various other white matter tracts, and these white matter anomalies appear to diminish with recovery. This macroscopic pattern of diffusion abnormalities may be associated with cytotoxic oedema following mechanical forces, resulting in changes in ionic homeostasis, and alterations in the ratio of intracellular and extracellular water. Animal models more specific to the types of mild traumatic brain injury typically incurred by humans are needed to confirm the histological correlates of these macroscopic markers of white matter pathology. PMID- 22505635 TI - Fulfilling a promise: the national action plan for child injury prevention. PMID- 22505636 TI - Validity of smoke alarm self-report measures and reasons for over-reporting. AB - OBJECTIVES: Many residential fire deaths occur in homes with no or non functioning smoke alarms (SAs). Self-reported SA coverage is high, but studies have found varying validity for self-report measures. The authors aim to: (1) determine over-reporting of coverage, (2) describe socio-demographic correlates of over-reporting and (3) report reasons for over-reporting. METHODS: The authors surveyed 603 households in a large, urban area about fire safety behaviours and then tested all SAs in the home. 23 participants who over-reported their SA coverage were telephoned and asked about why they had misreported. RESULTS: Full coverage was reported in 70% of households but observed in only 41%, with a low positive predictive value (54.2%) for the self-report measure. Most over reporters assumed alarms were working because they were mounted or did not think a working alarm in a basement or attic was needed to be fully protected. CONCLUSIONS: If alarms cannot be tested, researchers or those counselling residents on fire safety should carefully probe self-reported coverage. Our findings support efforts to equip more homes with hard-wired or 10 year lithium battery alarms to reduce the need for user maintenance. PMID- 22505637 TI - Carbon dioxide rebreathing with the anaesthetic conserving device, AnaConDa(r). AB - BACKGROUND: The anaesthetic conserving device (ACD) AnaConDa((r)) was developed to allow the reduced use of inhaled agents by conserving exhaled agent and allowing rebreathing. Elevated has been observed in patients when using this ACD, despite tidal volume compensation for the larger apparatus dead space. The aim of the present study was to determine whether CO(2), like inhaled anaesthetics, adsorbs to the ACD during expiration and returns to a test lung during the following inspiration. METHODS: The ACD was attached to an experimental test lung. Apparent dead space by the single-breath test for CO(2) and the amount of CO(2) adsorbed to the carbon filter of the ACD was measured with infrared spectrometry. RESULTS: Apparent dead space was 230 ml larger using the ACD compared with a conventional heat and moisture exchanger (internal volumes 100 and 50 ml, respectively). Varying CO(2) flux to the test lung (85-375 ml min(-1)) did not change the measured dead space nor did varying respiratory rate (12-24 bpm). The ACD contained 3.3 times more CO(2) than the predicted amount present in its internal volume of 100 ml. CONCLUSIONS: Our measurements show a CO(2) reservoir effect of 180 ml in excess of the ACD internal volume. This is due to adsorption of CO(2) in the ACD during expiration and return of CO(2) during the following inspiration. PMID- 22505638 TI - PEG-albumin supraplasma expansion is due to increased vessel wall shear stress induced by blood viscosity shear thinning. AB - We studied the extreme hemodilution to a hematocrit of 11% induced by three plasma expanders: polyethylene glycol (PEG)-conjugated albumin (PEG-Alb), 6% 70 kDa dextran, and 6% 500-kDa dextran. The experimental component of our study relied on microelectrodes and cardiac output to measure both the rheological properties of plasma-expander blood mixtures and nitric oxide (NO) bioavailability in vessel walls. The modeling component consisted of an analysis of the distribution of wall shear stress (WSS) in the microvessels. Our experiments demonstrated that plasma expansion with PEG-Alb caused a state of supraperfusion with cardiac output 40% above baseline, significantly increased NO vessel wall bioavailability, and lowered peripheral vascular resistance. We attributed this behavior to the shear thinning nature of blood and PEG-Alb mixtures. To substantiate this hypothesis, we developed a mathematical model of non-Newtonian blood flow in a vessel. Our model used the Quemada rheological constitutive relationship to express blood viscosity in terms of both hematocrit and shear rate. The model revealed that the net effect of the hemodilution induced by relatively low-viscosity shear thinning PEG-Alb plasma expanders is to reduce overall blood viscosity and to increase the WSS, thus intensifying endothelial NO production. These changes act synergistically, significantly increasing cardiac output and perfusion due to lowered overall peripheral vascular resistance. PMID- 22505639 TI - Mast cell deficiency attenuates progression of atherosclerosis and hepatic steatosis in apolipoprotein E-null mice. AB - Mast cells are important cells of the immune system and are recognized as participants in the pathogenesis of atherosclerosis. In this study, we evaluated the role of mast cells on the progression of atherosclerosis and hepatic steatosis using the apolipoprotein E-deficient (ApoE(-/-)) and ApoE(-/-)/mast cell-deficient (Kit(W-sh/W-sh)) mouse models maintained on a high-fat diet. The en face analyses of aortas showed a marked reduction in plaque coverage in ApoE( /-)/Kit(W-sh/W-sh) compared with ApoE(-/-) after a 6-mo regimen with no significant change noted after 3 mo. Quantification of intima/media thickness on hematoxylin and eosin-stained histological cross sections of the aortic arch revealed no significant difference between ApoE(-/-) and ApoE(-/-)/Kit(W-sh/W-sh) mice. The high-fat regimen did not induce atherosclerosis in either Kit(W-sh/W sh) or wild-type mice. Mast cells with indications of degranulation were seen only in the aortic walls and heart of ApoE(-/-) mice. Compared with ApoE(-/-) mice, the serum levels of total cholesterol, low-density lipoprotein and high density lipoprotein were decreased by 50% in ApoE(-/-)/Kit(W-sh/W-sh) mice, whereas no appreciable differences were noted in serum levels of triglycerides or very low density lipoprotein. ApoE(-/-)/Kit(W-sh/W-sh) mice developed significantly less hepatic steatosis than ApoE(-/-) mice after the 3-mo regimen. The analysis of Th1/Th2/Th17 cytokine profile in the sera revealed significant reduction of interleukin (IL)-6 and IL-10 in ApoE(-/-)/Kit(W-sh/W-sh) mice compared with ApoE(-/-) mice. The assessment of systemic generation of thromboxane A(2) (TXA(2)) and prostaglandin I(2) (PGI(2)) revealed significant decrease in the production of PGI(2) in ApoE(-/-)/Kit(W-sh/W-sh) mice with no change in TXA(2). The decrease in PGI(2) production was found to be associated with reduced levels of cyclooxygenase-2 mRNA in the aortic tissues. A significant reduction in T-lymphocytes and macrophages was noted in the atheromas of the ApoE(-/-)/Kit(W-sh/W-sh) mice. These results demonstrate the direct involvement of mast cells in the progression of atherosclerosis and hepatic steatosis. PMID- 22505640 TI - Phospholamban ablation in hearts expressing the high affinity SERCA2b isoform normalizes global Ca2+ homeostasis but not Ca2+-dependent hypertrophic signaling. AB - Cardiomyocytes from failing hearts exhibit reduced levels of the sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA) and/or increased activity of the endogenous SERCA inhibitor phospholamban. The resulting reduction in the Ca(2+) affinity of SERCA impairs SR Ca(2+) cycling in this condition. We have previously investigated the physiological impact of increasing the Ca(2+) affinity of SERCA by substituting SERCA2a with the higher affinity SERCA2b pump. When phospholamban was also ablated, these double knockouts (DKO) exhibited a dramatic reduction in total SERCA levels, severe hypertrophy, and diastolic dysfunction. We presently examined the role of cardiomyocyte Ca(2+) homeostasis in both functional and structural remodeling in these hearts. Despite the low SERCA levels in DKO, we observed near-normal Ca(2+) homeostasis with rapid Ca(2+) reuptake even at high Ca(2+) loads and stimulation frequencies. Well-preserved global Ca(2+) homeostasis in DKO was paradoxically associated with marked activation of the Ca(2+)-dependent nuclear factor of activated T-cell-calcineurin pathway known to trigger hypertrophy. No activation of the MAP kinase signaling pathway was detected. These findings suggest that local changes in Ca(2+) homeostasis may play an important signaling role in DKO, perhaps due to reduced microdomain Ca(2+) buffering by SERCA2b. Furthermore, alterations in global Ca(2+) homeostasis can also not explain impaired in vivo diastolic function in DKO. Taken together, our results suggest that normalizing global cardiomyocyte Ca(2+) homeostasis does not necessarily protect against hypertrophy and heart failure development and that excessively increasing SERCA Ca(2+) affinity may be detrimental. PMID- 22505641 TI - Chronic hypoxia induces right heart failure in caveolin-1-/- mice. AB - Caveolin-1 (Cav-1)-/- mice develop mild pulmonary hypertension as they age. In this study, we sought to determine the effect of chronic hypoxia, an established model of pulmonary hypertension, on young Cav-1-/- mice with no measurable signs of pulmonary hypertension. Exposure of Cav-1-/- mice to chronic hypoxia resulted in an initial rise in right ventricular (RV) systolic pressure (RVSP) similar to wild-type (WT) mice. By three weeks RVSP decreased in the Cav-1-/- mice, whereas it was maintained in WT mice. The drop in RVSP in Cav-1-/- mice was accompanied by decreased cardiac output, increased RV hypertrophy, RV interstitial fibrosis, decreased RV sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a mRNA and decreased RV function compared with WT mice. Importantly, minimal differences were noted in pulmonary vascular remodeling between WT and Cav-1-/- mice, and left ventricular function was normal in hypoxic Cav-1-/- mice. Mechanistically, increased endothelial nitric oxide synthase uncoupling and increased tyrosine nitration of protein kinase G were detected in the RV of Cav-1-/- mice. These hemodynamic, histological, and molecular changes were prevented in Cav-1-/- mice expressing an endothelial-specific Cav-1 transgene or by nitric oxide synthase inhibition. These data suggest that, in Cav-1-/- mice, increased oxidative/nitrosative stress due to endothelial nitric oxide synthase uncoupling modifies the response of the RV to pressure overload, accelerating the deterioration of RV function. PMID- 22505642 TI - Cyclooxygenase inhibition augments central blood pressure and aortic wave reflection in aging humans. AB - The augmentation index and central blood pressure increase with normal aging. Recently, cyclooxygenase (COX) inhibitors, commonly used for the treatment of pain, have been associated with transient increases in the risk of cardiovascular events. We examined the effects of the COX inhibitor indomethacin (Indo) on central arterial hemodynamics and wave reflection characteristics in young and old healthy adults. High-fidelity radial arterial pressure waveforms were measured noninvasively by applanation tonometry before (control) and after Indo treatment in young (25 +/- 5 yr, 7 men and 6 women) and old (64 +/- 6 yr, 5 men and 6 women) subjects. Aortic systolic (control: 115 +/- 3 mmHg vs. Indo: 125 +/- 5 mmHg, P < 0.05) and diastolic (control: 74 +/- 2 mmHg vs. Indo: 79 +/- 3 mmHg, P < 0.05) pressures were elevated after Indo treatment in older subjects, whereas only diastolic pressure was elevated in young subjects (control: 71 +/- 2 mmHg vs. Indo: 76 +/- 1 mmHg, P < 0.05). Mean arterial pressure increased in both young and old adults after Indo treatment (P < 0.05). The aortic augmentation index and augmented pressure were elevated after Indo treatment in older subjects (control: 30 +/- 5% vs. Indo 36 +/- 6% and control 12 +/- 1 mmHg vs. Indo: 18 +/- 2 mmHg, respectively, P < 0.05), whereas pulse pressure amplification decreased (change: 8 +/- 3%, P < 0.05). In addition, older subjects had a 61 +/- 11% increase in wasted left ventricular energy after Indo treatment (P < 0.05). In contrast, young subjects showed no significant changes in any of the variables of interest. Taken together, these results demonstrate that COX inhibition with Indo unfavorably increases central wave reflection and augments aortic pressure in old but not young subjects. Our results suggest that aging individuals have a limited ability to compensate for the acute hemodynamic changes caused by systemic COX inhibition. PMID- 22505643 TI - Sustained therapeutic hypercapnia attenuates pulmonary arterial Rho-kinase activity and ameliorates chronic hypoxic pulmonary hypertension in juvenile rats. AB - Sustained therapeutic hypercapnia prevents pulmonary hypertension in experimental animals, but its rescue effects on established disease have not been studied. Therapies that inhibit Rho-kinase (ROCK) and/or augment nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling can reverse or prevent progression of chronic pulmonary hypertension. Our objective in the present study was to determine whether sustained rescue treatment with inhaled CO(2) (therapeutic hypercapnia) would improve structural and functional changes of chronic hypoxic pulmonary hypertension. Spontaneously breathing pups were exposed to normoxia (21% O(2)) or hypoxia (13% O(2)) from postnatal days 1-21 with or without 7% CO(2) (Pa(CO(2)) elevated by ~25 mmHg) or 10% CO(2) (Pa(CO(2)) elevated by ~40 mmHg) from days 14 to 21. Compared with hypoxia alone, animals exposed to hypoxia and 10% CO(2) had significantly (P < 0.05) decreased pulmonary vascular resistance, right-ventricular systolic pressure, right-ventricular hypertrophy, and medial wall thickness of pulmonary resistance arteries as well as decreased lung phosphodiesterase (PDE) V, RhoA, and ROCK activity. Rescue treatment with 10% CO(2), or treatment with a ROCK inhibitor (15 mg/kg ip Y-27632 twice daily from days 14 to 21), also increased pulmonary arterial endothelial nitric oxide synthase and lung NO content. In contrast, cGMP content and cGMP-dependent protein kinase (PKG) activity were increased by exposure to 10% CO(2), but not by ROCK inhibition with Y-27632. In vitro exposure of pulmonary artery smooth muscle cells to hypercapnia suppressed serum-induced ROCK activity, which was prevented by inhibition of PKG with Rp-8-Br-PET-cGMPS. We conclude that sustained hypercapnia dose-dependently inhibited ROCK activity, augmented NO-cGMP-PKG signaling, and led to partial improvements in the hemodynamic and structural abnormalities of chronic hypoxic PHT in juvenile rats. Increased PKG content and activity appears to play a major upstream role in CO(2)-induced suppression of ROCK activity in pulmonary arterial smooth muscle. PMID- 22505644 TI - Differential impact of short periods of rapid atrial pacing on left and right atrial mechanical function. AB - Current techniques to describe atrial function are limited by their load dependency and hence do not accurately reflect intrinsic mechanical properties. To assess the impact of atrial fibrillation on atrial function, combined pressure volume relationships (PVR) measured by conductance catheters were used to evaluate the right (RA) and left (LA) atrium in 12 isoflurane-anesthetized pigs. Biatrial PVR were recorded over a wide range of volumes during transient caval occlusion at baseline sinus rhythm (SR), after onset of rapid atrial pacing (RAP), after 1 h of RAP, after conversion to SR, and after 1 h of recovery. Cardiac output decreased by 16% (P = 0.008) with onset of RAP. Mean LA and RA pressures increased by 21 and 40% (P < 0.001), respectively, and remained elevated during the entire recovery period. RA reservoir function increased from 51 to 58% and significantly dropped to 43% after resumption of SR (P = 0.017). Immediately after RAP, a right shift of LA end-systolic PVR-intercept for end systolic volume required to generate an atrial end-systolic pressure of 10 mmHg (24.4 +/- 4.9 to 28.1 +/- 5.2 ml, P = 0.005) indicated impaired contractility compared with baseline. Active LA emptying fraction dropped from 17.6 +/- 7.5 to 11.7 +/- 3.7% (P < 0.001), LA stroke volume and DeltaP/Deltat(max)/P declined by 22% (P = 0.038 and 0.026, respectively), while there was only a trend to impaired RA systolic function. Stiffness quantified by the ratio of pressure to volume at end-diastole was increased immediately after RAP only in the RA (P = 0.020), but end-diastolic PVR shifted rightward in both atria (P = 0.011 LA, P = 0.045 RA). These data suggest that even short periods of RAP have a differential impact on RA and LA function, which was sustained for 1 h after conversion to SR. PMID- 22505645 TI - Role of connexin-43 in protective PI3K-Akt-GSK-3beta signaling in cardiomyocytes. AB - Sarcolemmal connexin-43 (Cx43) and mitochondrial Cx43 play distinct roles: formation of gap junctions and production of reactive oxygen species (ROS) for redox signaling. In this study, we examined the hypothesis that Cx43 contributes to activation of a major cytoprotective signal pathway, phosphoinositide 3-kinase (PI3K)-Akt-glycogen synthase kinase-3beta (GSK-3beta) signaling, in cardiomyocytes. A delta-opioid receptor agonist {[d-Ala(2),d-Leu(5)]enkephalin acetate (DADLE)}, endothelin-1 (ET-1), and insulin-like growth factor-1 (IGF-1) induced phosphorylation of Akt and GSK-3beta in H9c2 cardiomyocytes. Reduction of Cx43 protein to 20% of the normal level by Cx43 small interfering RNA abolished phosphorylation of Akt and GSK-3beta induced by DADLE or ET-1 but not that induced by IGF-1. DADLE and IGF-1 protected H9c2 cells from necrosis after treatment with H(2)O(2) or antimycin A. The protection by DADLE or ET-1, but not that by IGF-1, was lost by reduction of Cx43 protein expression. In contrast to Akt and GSK-3beta, PKC-epsilon, ERK and p38 mitogen-activated protein kinase were phosphorylated by ET-1 in Cx43-knocked-down cells. Like diazoxide, an activator of the mitochondrial ATP-sensitive K(+) channel, DADLE and ET-1 induced significant ROS production in mitochondria, although such an effect was not observed for IGF-1. Cx43 knockdown did not attenuate the mitochondrial ROS production by DADLE or ET-1. Cx43 was coimmunoprecipitated with the beta-subunit of G protein (Gbeta), and knockdown of Gbeta mimicked the effect of Cx43 knockdown on ET-1-induced phosphorylation of Akt and GSK-3beta. These results suggest that Cx43 contributes to activation of class I(B) PI3K in PI3K-Akt-GSK 3beta signaling possibly as a cofactor of Gbeta in cardiomyocytes. PMID- 22505646 TI - Prevention of heart failure in mice by an antiviral agent that inhibits type 5 cardiac adenylyl cyclase. AB - Despite numerous discoveries from genetically engineered mice, relatively few have been translated to the bedside, mainly because it is difficult to translate from genes to drugs. This investigation examines an antiviral drug, which also has an action to selectively inhibit type 5 adenylyl cyclase (AC5), a pharmaceutical correlate of the AC5 knockout (KO) model, which exhibits longevity and stress resistance. Our objective was to examine the extent to which pretreatment with this drug, adenine 9-beta-d-arabinofuranoside (Ara-A), favorably ameliorates the development of heart failure (HF). Ara-A exhibited selective inhibition for AC5 compared with the other major cardiac AC isoform, AC6, i.e., it reduced AC activity significantly in AC5 transgenic (Tg) mice, but not in AC5KO mice and had little effect in either wild-type or AC6Tg mice. Permanent coronary artery occlusion for 3 wk in C57Bl/6 mice increased mortality and induced HF in survivors, as reflected by reduced cardiac function, while increasing cardiac fibrosis. The AC5 inhibitor Ara-A significantly improved all of these end points and also ameliorated chronic isoproterenol-induced cardiomyopathy. As with the AC5KO mice, Ara-A increased mitogen/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation. A MEK inhibitor abolished the beneficial effects of the AC5 inhibitor in the HF model, indicating the involvement of the downstream MEK-ERK pathway of AC5. Our data suggest that pharmacological AC5 inhibition may serve as a new therapeutic approach for HF. PMID- 22505647 TI - High expression of IL-13 receptor alpha2 in colorectal cancer is associated with invasion, liver metastasis, and poor prognosis. AB - Autocrine secretion of cytokines by metastatic colorectal cancer cells and their role during invasion and liver homing has been poorly characterized. In this study, we used cytokine arrays to analyze the secretomes of poorly and highly metastatic colorectal cancer cells. Compared with poorly metastatic cancer cells, highly metastatic cells expressed increased levels of the immunosuppressive cytokines interleukin (IL)-4 and IL-13 in addition to increased surface expression of the high affinity IL-13 receptor IL-13Ralpha2, suggesting that IL 13Ralpha2 mediates IL-13 effects in colorectal cancer cells. Silencing of IL 13Ralpha2 in highly metastatic cells led to a decrease in adhesion capacity in vitro and a reduction in liver homing and increased survival in vivo, revealing a role for this receptor in cell adhesion, migration, invasion, and metastatic colonization. In support of this, IL-13 signaling activated the oncogenic signaling molecules phosphoinositide 3-kinase, AKT, and SRC in highly metastatic cells. Clinically, high expression of IL-13Ralpha2 was associated with later stages of disease progression and poor outcome in patients with colorectal cancer. Our findings therefore support a critical role for IL-13Ralpha2 expression in colon cancer invasion and metastasis. PMID- 22505648 TI - Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer. AB - Epigenetic modifications such as histone methylation play an important role in human cancer metastasis. Enhancer of zeste homolog 2 (EZH2), which encodes the histone methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed widely in breast and prostate cancers and epigenetically silences tumor suppressor genes. Expression levels of the novel tumor and metastasis suppressor Raf-1 kinase inhibitor protein (RKIP) have been shown to correlate negatively with those of EZH2 in breast and prostate cell lines as well as in clinical cancer tissues. Here, we show that the RKIP/EZH2 ratio significantly decreases with the severity of disease and is negatively associated with relapse-free survival in breast cancer. Using a combination of loss- and gain-of-function approaches, we found that EZH2 negatively regulated RKIP transcription through repression-associated histone modifications. Direct recruitment of EZH2 and suppressor of zeste 12 (Suz12) to the proximal E-boxes of the RKIP promoter was accompanied by H3-K27-me3 and H3-K9-me3 modifications. The repressing activity of EZH2 on RKIP expression was dependent on histone deacetylase promoter recruitment and was negatively regulated upstream by miR 101. Together, our findings indicate that EZH2 accelerates cancer cell invasion, in part, via RKIP inhibition. These data also implicate EZH2 in the regulation of RKIP transcription, suggesting a potential mechanism by which EZH2 promotes tumor progression and metastasis. PMID- 22505649 TI - ESE3/EHF controls epithelial cell differentiation and its loss leads to prostate tumors with mesenchymal and stem-like features. AB - Cancer stem cells (CSC) play a significant role in tumor progression, disease recurrence, and treatment failure. Here, we show that the endogenously expressed ETS transcription factor ESE3/EHF controls prostate epithelial cell differentiation and stem-like potential. We found that loss of ESE3/EHF induced epithelial-to-mesenchymal transition (EMT), stem-like features, and tumor initiating and metastatic properties in prostate epithelial cells, and reexpression of ESE3/EHF inhibited the stem-like properties and tumorigenic potential of prostate cancer cells. Mechanistically, ESE3/EHF repressed the expression of key EMT and CSC genes, including TWIST1, ZEB2, BMI1, and POU5F1. Analysis of human tissue microarrays showed that reduced ESE3/EHF expression is an early event in tumorigenesis, frequently occurring independently of other ETS gene alterations. Additional analyses linked loss of ESE3/EHF expression to a distinct group of prostate tumors with distinctive molecular and biologic characteristics, including increased expression of EMT and CSC genes. Low ESE3/EHF expression was also associated with increased biochemical recurrence of prostate cancer and reduced overall survival after prostatectomy. Collectively, our findings define a key role for ESE3/EHF in the development of a subset of prostate tumors and highlight the clinical importance of identifying molecularly defined tumor subgroups. PMID- 22505650 TI - Cell-mediated autophagy promotes cancer cell survival. AB - Immune effector cells integrate signals that define the nature and magnitude of the subsequent response. Experimental measures for immune cell-mediated lysis of tumors or virally infected targets rely on average responses of permeability or apoptotic changes within a population of targets. Here, we examined individual target cells following interaction with lymphoid effectors. We found that human peripheral blood lymphocytes not only provide lytic signals but also promote autophagy in the remaining cells. At high effector-to-target ratios, autophagy was induced in several human tumors, as assessed by induction of LC3 puncta and diminished p62. Natural killer cells are a primary mediator of this process. In addition, target cell autophagy was enhanced by provision of interleukin (IL)-2, whereas IL-10 attenuated this effect, and cell-to-cell contact strongly enhanced lymphocyte-mediated autophagy. Although IFN-gamma can induce autophagy in target cells, IFN-alpha acted directly on the targets or in concert with lymphocytes to diminish target autophagy in some cell types. Importantly, cell-mediated autophagy promoted resistance from treatment modalities designed to eradicate tumor cells. Our findings therefore show that the lymphocyte-induced cell mediated autophagy promotes cancer cell survival and may represent an important target for development of novel therapies. PMID- 22505651 TI - In vivo imaging of drug-induced mitochondrial outer membrane permeabilization at single-cell resolution. AB - Observing drug responses in the tumor microenvironment in vivo can be technically challenging. As a result, cellular responses to molecularly targeted cancer drugs are often studied in cell culture, which does not accurately represent the behavior of cancer cells growing in vivo. Using high-resolution microscopy and fluorescently labeled genetic reporters for apoptosis, we developed an approach to visualize drug-induced cell death at single-cell resolution in vivo. Stable expression of the mitochondrial intermembrane protein IMS-RP was established in human breast and pancreatic cancer cells. Image analysis was then used to quantify release of IMS-RP into the cytoplasm upon apoptosis and irreversible mitochondrial permeabilization. Both breast and pancreatic cancer cells showed higher basal apoptotic rates in vivo than in culture. To study drug-induced apoptosis, we exposed tumor cells to navitoclax (ABT-263), an inhibitor of Bcl-2, Bcl-xL, and Bcl-w, both in vitro and in vivo. Although the tumors responded to Bcl-2 inhibition in vivo, inducing apoptosis in around 20% of cancer cells, the observed response was much higher in cell culture. Together, our findings show an imaging technique that can be used to directly visualize cell death within the tumor microenvironment in response to drug treatment. PMID- 22505653 TI - Expression of P2X7 receptor increases in vivo tumor growth. AB - The P2X7 receptor is an ATP-gated ion channel known for its cytotoxic activity. However, recent evidence suggests a role for P2X7 in cell proliferation. Here, we found that P2X7 exhibits significant growth-promoting effects in vivo. Human embryonic kidney cells expressing P2X7 exhibited a more tumorigenic and anaplastic phenotype than control cells in vivo, and the growth rate and size of these tumors were significantly reduced by intratumoral injection of the P2X7 inhibitor-oxidized ATP. The accelerated growth of P2X7-expressing tumors was characterized by increased proliferation, reduced apoptosis, and a high level of activated transcription factor NFATc1. These tumors also showed a more developed vascular network than control tumors and secreted elevated amounts of VEGF. The growth and neoangiogenesis of P2X7-expressing tumors was blocked by intratumoral injection of the VEGF-blocking antibody Avastin (bevacizumab), pharmacologic P2X7 blockade, or P2X7 silencing in vivo. Immunohistochemistry revealed strong P2X7 positivity in several human cancers. Together, our findings provide direct evidence that P2X7 promotes tumor growth in vivo. PMID- 22505652 TI - Gene immunotherapy of chronic lymphocytic leukemia: a phase I study of intranodally injected adenovirus expressing a chimeric CD154 molecule. AB - New therapies for chronic lymphocytic leukemia (CLL) are needed, particularly those that can eradicate residual disease and elicit anti-CLL immune responses. CD40 ligation on CLL cells, which can be achieved using adenovirus encoding chimeric CD154 (Ad-ISF35), enhances their ability to function as antigen presenting cells and increases their sensitivity to clearance by immune-effector mechanisms. In this study, we report the results of a first-in-man phase I trial of intranodal direct injection (IDI) of Ad-ISF35 in patients with CLL to evaluate toxicity, safety, and tolerability. Fifteen patients received a single IDI of 1 * 10(10) to 33 * 10(10) Ad-ISF35 viral particles (vp), with a defined maximum tolerated dose as 1 * 10(11) vp. Although the most common adverse events were transient grade 1 to 2 pain at the injection site and flu-like symptoms following IDI, some patients receiving the highest dose had transient, asymptomatic grade 3 to 4 hypophosphatemia, neutropenia, or transaminitis. Increased expression of death receptor, immune costimulatory molecules, and Ad-ISF35 vector DNA was detected in circulating CLL cells. Notably, we also observed preliminary clinical responses, including reductions in leukemia cell counts, lymphadenopathy, and splenomegaly. Six patients did not require additional therapy for more than 6 months, and three achieved a partial remission. In conclusion, Ad-ISF35 IDI was safely delivered in patients with CLLs and induced systemic biologic and clinical responses. These results provide the rationale for phase II studies in CLLs, lymphomas, and CD40-expressing solid tumors. PMID- 22505654 TI - GWAS-identified colorectal cancer susceptibility loci associated with clinical outcomes. AB - Recent genome-wide association studies (GWAS) have identified several common susceptibility loci associated with the risk of colorectal cancer (CRC). However, whether these loci affect clinical outcomes of CRC is not clear. In this study, we genotyped 26 single nucleotide polymorphisms (SNPs) in 10 GWAS-identified CRC susceptibility regions and evaluated their associations with survival and recurrence in 285 stage II and III patients receiving fluorouracil-based adjuvant chemotherapy. Only one SNP, rs10318 (15q13.3), was significantly associated with recurrence for patients with stage II disease. Three SNPs: rs10749971 (11q23.1), rs961253 (20p12.3) and rs355527 (20p12.3) in two regions were significantly associated with recurrence for patients with stage III disease. Five SNPs: rs961253 (20p12.3), rs355527 (20p12.3), rs4464148 (18q21.1), rs6983267 (8q24.21) and rs10505477 (8q24.21) in three regions were significantly associated with survival for patients with stage III disease. Cumulative effects of multiple unfavorable genotypes were observed for recurrence and survival in patients with stage III CRC. Our results suggest that cancer susceptibility loci may also affect the prognosis of CRC patients receiving fluorouracil-based adjuvant chemotherapy. PMID- 22505656 TI - Contribution of calcium, phosphorus and 25-hydroxyvitamin D to the excessive severity of secondary hyperparathyroidism in African-Americans with CKD. AB - BACKGROUND: Parathyroid hormone (PTH) levels in African-American (AA) chronic kidney disease (CKD) patients exceed those in patients of other races; mechanisms are unknown. METHODS: We performed a cross-sectional analysis of initial laboratory data collected on 2028 CKD patients (505 AA) from US practices using a laboratory CKD service. Serum calcium (Ca), phosphorus (P), 25-hydroxyvitamin D (25-D) and plasma PTH levels were compared between the two groups. RESULTS: Mean PTH for AA exceeded PTH for non-AA in Stages 2-5 (P<0.001, all four stages). 25-D levels were higher for non-AA in Stages 1-3 (P<0.001). Serum Ca and P did not differ between groups at any stage. Full adjustment for these variables using multivariable generalized linear modeling did not remove the effect of AA race: AA PTH values exceeded non-AA values in CKD Stages 2-5 (P<0.02, all four stages). Serum Ca, P and 25-D were all inversely correlated with PTH levels irrespective of race, but all factors combined accounted for ~42% of the variance in PTH. CONCLUSIONS: PTH rises with progressive CKD stage far more in AA than in non-AA patients, and only a moderate component of the rise in PTH is explained by changes in serum Ca, P and 25-D in either group. These findings concur with those from other large CKD cohorts and support the need for further study to determine other factors responsible for this racial difference. PMID- 22505655 TI - p53 N-terminal phosphorylation: a defining layer of complex regulation. AB - The p53 tumor suppressor is a critical component of the cellular response to stress. As it can inhibit cell growth, p53 is mutated or functionally inactivated in most tumors. A multitude of protein-protein interactions with transcriptional cofactors are central to p53-dependent responses. In its activated state, p53 is extensively modified in both the N- and C-terminal regions of the protein. These modifications, especially phosphorylation of serine and threonine residues in the N-terminal transactivation domain, affect p53 stability and activity by modulating the affinity of protein-protein interactions. Here, we review recent findings from in vitro and in vivo studies on the role of p53 N-terminal phosphorylation. These modifications can either positively or negatively affect p53 and add a second layer of complex regulation to the divergent interactions of the p53 transactivation domain. PMID- 22505658 TI - The combined use of surgery and radiotherapy to treat patients with epidural cord compression due to metastatic disease: a cost-utility analysis. AB - Neoplastic metastatic epidural spinal cord compression is a common complication of cancer that causes pain and progressive neurologic impairment. The previous standard treatment for this condition involved corticosteroids and radiotherapy (RT). Direct decompressive surgery with postoperative radiotherapy (S + RT) is now increasingly being chosen by clinicians to significantly improve patients' ability to walk and reduce their need for opioid analgesics and corticosteroids. A cost-utility analysis was conducted to compare S + RT with RT alone based on the landmark randomized clinical trial by Patchell et al. (2005). It was performed from the perspective of the Ontario Ministry of Health and Long-Term Care. Ontario-based costs were adjusted to 2010 US dollars. S + RT is more costly but also more effective than corticosteroids and RT alone, with an incremental cost-effectiveness ratio of US$250 307 per quality-adjusted life year (QALY) gained. First order probabilistic sensitivity analysis revealed that the probability of S + RT being cost-effective is 18.11%. The cost-effectiveness acceptability curve showed that there is a 91.11% probability of S + RT being cost-effective over RT alone at a willingness-to-pay of US$1 683 000 per QALY. In practice, the results of our study indicate that, by adopting the S + RT strategy, there would still be a chance of 18.11% of not paying extra at a willingness-to-pay of US$50 000 per QALY. Those results are sensitive to the costs of hospice palliative care. Our results suggest that adopting a standard S + RT approach for patients with MSCC is likely to increase health care costs but would result in improved outcomes. PMID- 22505659 TI - Angiopoietin-1 mediates inhibition of hypertension-induced release of angiopoietin-2 from endothelial cells. AB - AIMS: Adequate endothelial cell stimulation is a prerequisite for the adaptive remodelling of macro- and microvessels. A pivotal autocrine mechanism following endothelial cell activation is the release of angiopoietin-2 (Ang-2), which subsequently antagonizes the binding of Ang-1 to the Tie-2 receptor, thus sensitizing the endothelial cells to pro-angiogenic and/or pro-inflammatory stimuli. Based on the observation that hypertension in mice reduces the abundance of Ang-2 stored in arterial endothelial cells, this study was aimed at testing the hypothesis that an increase in wall stress (WS) or stretch-a hallmark of hypertension-is sufficient to release Ang-2 from endothelial cells. METHODS AND RESULTS: In fact, stretching of isolated perfused mouse arteries or human cultured endothelial cells rapidly elicited an increased release of Ang-2. In the cultured endothelial cells, this was preceded by a transient rise in intracellular free calcium, abrogated through calcium chelation and accompanied by a decrease in Tie-2 phosphorylation. Interestingly, Ang-1 abolished the stretch-induced release of Ang-2 from both cultured and native endothelial cells through inhibiting the stretch-dependent mobilization of intracellular calcium. CONCLUSION: Collectively, these results indicate that increased WS or stretch facilitates the release of Ang-2 from endothelial cell Weibel-Palade bodies, and that Ang-1 can block this by attenuating the stretch-mediated rise in intracellular calcium. PMID- 22505657 TI - Protein tyrosine phosphatase mu regulates glioblastoma cell growth and survival in vivo. AB - Glioblastoma multiforme (GBM) is the most lethal primary brain tumor. Extensive proliferation and dispersal of GBM tumor cells within the brain limits patient survival to approximately 1 year. Hence, there is a great need for the development of better means to treat GBM. Receptor protein tyrosine phosphatase (PTP)u is proteolytically cleaved in GBM to yield fragments that promote dispersal of GBM cells. While normal brain tissue retains expression of full length PTPu, low-grade human astrocytoma samples have varying amounts of full length PTPu and cleaved PTPu. In the highest-grade astrocytomas (i.e., GBM), PTPu is completely proteolyzed into fragments. We demonstrate that short hairpin RNA mediated knockdown of full-length PTPu and PTPu fragments reduces glioma cell growth and survival in vitro. The reduction in growth and survival following PTPu knockdown is enhanced when cells are grown in the absence of serum, suggesting that PTPu may regulate autocrine signaling. Furthermore, we show for the first time that reduction of PTPu protein expression decreases the growth and survival of glioma cells in vivo using mouse xenograft flank and i.c. tumor models. Inhibitors of PTPu could be used to reduce the growth and survival of GBM cells in the brain, representing a promising therapeutic target for GBM. PMID- 22505660 TI - Pictorial health warnings on cigarette packs in the United States: an experimental evaluation of the proposed FDA warnings. AB - INTRODUCTION: In 2010, the U.S. Food and Drug Administration (FDA) developed 36 proposed health warnings for cigarette packages, from which 9 were subsequently selected for implementation. The current study aimed to evaluate the perceived efficacy of the 36 proposed FDA warnings. METHODS: Web-based surveys were conducted with 783 adult smokers and 510 youth in United States. Participants were randomized to view and rate two sets of 6-7 warnings, each set corresponding to one of nine health effect statements required under the Tobacco Control Act. Warnings included all 36 FDA-proposed warnings and additional warnings for comparison. RESULTS: Youth and adults rated individual warnings similarly; in all cases where differences were found, youth perceived warnings as more effective. Comparisons on specific elements indicated that warnings were perceived as more effective if they were: full color (vs. black and white), featured real people (vs. comic book style), contained graphic images (vs. nongraphic), and included a telephone "quitline" number or personal information. Few sociodemographic differences were observed in overall perceived effectiveness: younger respondents, non-White respondents, and smokers intending to quit rated warnings higher. CONCLUSIONS: Seven of the nine health warnings selected by the FDA for implementation were among the proposed warnings rated as most effective in the current study. However, the warning(s) added for comparison were rated higher than the FDA-selected warning for five of the nine sets, suggesting some warnings could be improved for greater impact. The findings support the inclusion of a telephone "quitline" number and reinforce the importance of depicting "real" people and health effects. PMID- 22505662 TI - Physiology: a networking medical science. PMID- 22505661 TI - The role of left occipitotemporal cortex in reading: reconciling stimulus, task, and lexicality effects. AB - Although the left posterior occipitotemporal sulcus (pOTS) has been called a visual word form area, debate persists over the selectivity of this region for reading relative to general nonorthographic visual object processing. We used high-resolution functional magnetic resonance imaging to study left pOTS responses to combinatorial orthographic and object shape information. Participants performed naming and visual discrimination tasks designed to encourage or suppress phonological encoding. During the naming task, all participants showed subregions within left pOTS that were more sensitive to combinatorial orthographic information than to object information. This difference disappeared, however, when phonological processing demands were removed. Responses were stronger to pseudowords than to words, but this effect also disappeared when phonological processing demands were removed. Subregions within the left pOTS are preferentially activated when visual input must be mapped to a phonological representation (i.e., a name) and particularly when component parts of the visual input must be mapped to corresponding phonological elements (consonant or vowel phonemes). Results indicate a specialized role for subregions within the left pOTS in the isomorphic mapping of familiar combinatorial visual patterns to phonological forms. This process distinguishes reading from picture naming and accounts for a wide range of previously reported stimulus and task effects in left pOTS. PMID- 22505663 TI - Physiological regeneration of skin appendages and implications for regenerative medicine. AB - The concept of regenerative medicine is relatively new, but animals are well known to remake their hair and feathers regularly by normal regenerative physiological processes. Here, we focus on 1) how extrafollicular environments can regulate hair and feather stem cell activities and 2) how different configurations of stem cells can shape organ forms in different body regions to fulfill changing physiological needs. PMID- 22505664 TI - Electrically silent Kv subunits: their molecular and functional characteristics. AB - Electrically silent voltage-gated potassium (KvS) alpha-subunits do not form homotetramers but heterotetramerize with Kv2 subunits, generating functional Kv2/KvS channel complexes in which the KvS subunits modulate the Kv2 current. This poses intriguing questions into the molecular mechanisms by which these KvS subunits cannot form functional homotetramers, why they only interact with Kv2 subunits, and how they modulate the Kv2 current. PMID- 22505666 TI - Neural circuit development in the mammalian cochlea. AB - The organ of Corti, the sensory epithelium of the mammalian auditory system, uses afferent and efferent synapses for encoding auditory signals and top-down modulation of cochlear function. During development, the final precisely ordered sensorineural circuit is established following excessive formation of afferent and efferent synapses and subsequent refinement. Here, we review the development of innervation of the mouse organ of Corti and its regulation. PMID- 22505665 TI - Mechanisms of protein delivery to melanosomes in pigment cells. AB - Vertebrate pigment cells in the eye and skin are useful models for cell types that use specialized endosomal trafficking pathways to partition cargo proteins to unique lysosome-related organelles such as melanosomes. This review describes current models of protein trafficking required for melanosome biogenesis in mammalian melanocytes. PMID- 22505667 TI - Characterization of a novel splice variant of delta ENaC subunit in human lungs. AB - Salt absorption via apical epithelial sodium channels (ENaC) is a critical rate limiting process in maintaining airway and lung lining fluid at the physiological level. delta ENaC (termed delta1 in this article) has been detected in human lung epithelial cells in addition to alpha, beta, and gamma subunits (Ji HL, Su XF, Kedar S, Li J, Barbry P, Smith PR, Matalon S, Benos DJ. J Biol Chem 281: 8233 8241, 2006; Nie HG, Chen L, Han DY, Li J, Song WF, Wei SP, Fang XH, Gu X, Matalon S, Ji HL, J Physiol 587: 2663-2676, 2009) and may contribute to the differences in the biophysical properties of amiloride-inhibitable cation channels in pulmonary epithelial cells. Here we cloned a splicing variant of the delta1 ENaC, namely, delta2 ENaC in human bronchoalveolar epithelial cells (16HBEo). delta2 ENaC possesses 66 extra amino acids attached to the distal amino terminal tail of the delta1 ENaC. delta2 ENaC was expressed in both alveolar type I and II cells of human lungs as revealed by in situ hybridization and real-time RT-PCR. To characterize the biophysical and pharmacological features of the splicing variant, we injected Xenopus oocytes with human ENaC cRNAs and measured whole cell and single channel currents of delta1betagamma, delta2betagamma, and alphabetagamma channels. Oocytes injected with delta2betagamma cRNAs exhibited whole cell currents significantly greater than those expressing delta1betagamma and alphabetagamma channels. Single channel activity, unitary conductance, and open probability of delta2betagamma channels were significantly greater compared with delta1betagamma and alphabetagamma channels. In addition, delta2betagamma and delta1betagamma channels displayed significant differences in apparent Na(+) affinity, dissociation constant for amiloride (K(i)(amil)), the EC(50) for capsazepine activation, and gating kinetics by protons. Channels comprising of this novel splice variant may contribute to the diversities of native epithelial Na(+) channels. PMID- 22505668 TI - Use of reflectance interference contrast microscopy to characterize the endothelial glycocalyx stiffness. AB - Reflectance interference contrast microscopy (RICM) was used to study the mechanics of the endothelial glycocalyx. This technique tracks the vertical position of a glass microsphere probe that applies very light fluctuating loads to the outermost layer of the bovine lung microvascular endothelial cell (BLMVEC) glycocalyx. Fluctuations in probe vertical position are used to estimate the effective stiffness of the underlying layer. Stiffness was measured before and after removal of specific glycocalyx components. The mean stiffness of BLMVEC glycocalyx was found to be ~7.5 kT/nm(2) (or ~31 pN/nm). Enzymatic digestion of the glycocalyx with pronase or hyaluronan with hyaluronidase increased the mean effective stiffness of the glycocalyx; however, the increase of the mean stiffness on digestion of heparan sulfate with heparinase III was not significant. The results imply that hyaluronan chains act as a cushioning layer to distribute applied forces to the glycocalyx structure. Effective stiffness was also measured for the glycocalyx exposed to 0.1%, 1.0%, and 4.0% BSA; glycocalyx compliance increased at two extreme BSA concentrations. The RICM images indicated that glycocalyx thickness increases with BSA concentrations. Results demonstrate that RICM is sensitive to detect the subtle changes of glycocalyx compliance at the fluid-fiber interface. PMID- 22505669 TI - Superiority of PC-SOD to other anti-COPD drugs for elastase-induced emphysema and alteration in lung mechanics and respiratory function in mice. AB - Bronchodilators (such as ipratropium bromide), steroids (such as fluticasone propionate), and newly developed anti-inflammatory drugs (such as roflumilast) are used for patients with chronic obstructive pulmonary disease (COPD). We recently reported that lecithinized superoxide dismutase (PC-SOD) confers a protective effect in mouse models of COPD. We here examined the therapeutic effect of the combined administration of PC-SOD with ipratropium bromide on pulmonary emphysema and compared the effect of PC-SOD to other types of drugs. The severity of emphysema in mice was assessed by various criteria. Lung mechanics (elastance) and respiratory function (ratio of forced expiratory volume in the first 0.05 s to forced vital capacity) were assessed. Administration of PC SOD by inhalation suppressed elastase-induced pulmonary emphysema, alteration of lung mechanics, and respiratory dysfunction. The concomitant intratracheal administration of ipratropium bromide did not alter the ameliorating effects of PC-SOD. Administration of ipratropium bromide, fluticasone propionate, or roflumilast alone did not suppress the elastase-induced increase in the pulmonary level of superoxide anion, pulmonary inflammatory response, pulmonary emphysema, alteration of lung mechanics, or respiratory dysfunction as effectively as did PC SOD. PC-SOD, but not the other drugs, showed a therapeutic effect even when the drug was administered after the development of emphysema. PC-SOD also suppressed the cigarette smoke-induced pulmonary inflammatory response and increase in airway resistance. Based on these results, we consider that the inhalation of PC SOD would be therapeutically beneficial for COPD. PMID- 22505670 TI - beta-Adrenergic agonists differentially regulate highly selective and nonselective epithelial sodium channels to promote alveolar fluid clearance in vivo. AB - beta-Adrenergic receptors (beta-AR) increase epithelial sodium channel (ENaC) activity to promote lung fluid clearance. However, the effect of selective beta AR agonist on highly selective cation (HSC) channels or nonselective cation (NSC) channels in alveolar type 1 (T1) and type 2 (T2) cells is unknown. We hypothesized that stimulation with beta(1)-AR agonist (denopamine) or beta(2)-AR agonist (terbutaline) would increase HSC and/or NSC channel activity in alveolar epithelial cells. We performed single-channel measurements from T1 and T2 cells accessed from rat lung slices. Terbutaline (20 MUM) increased HSC ENaC activity (open probability, NP(o)) in T1 (from 0.96 +/- 0.61 to 1.25 +/- 0.71, n = 5, P <0.05) and T2 cells (from 0.28 +/- 0.14 to 1.0 +/- 0.30, n = 8, P = 0.02). Denopamine (20 MUM) increased NSC NP(o) in T1 cells (from 0.34 +/- 0.09 to 0.63 +/- 0.14, n = 7, P = 0.02) and in T2 cells (from 0.47 +/- 0.09 to 0.68 +/- 0.10, P = 0.004). In vivo X-ray imaging of lung fluid clearance and ICI 118,551 selective inhibition of beta(2)-ARs confirmed patch-clamp findings. cAMP concentrations increased following treatment with denopamine or terbutaline (n = 3, P < 0.002). The effects of systemic (intraperitoneal, IP) and local (intratracheal, IT) modes of delivery on lung fluid clearance were assessed. IT delivery of denopamine promoted alveolar flooding, whereas IP delivery promoted delayed fluid clearance. In summary, beta-AR agonists differentially regulate HSC and NSC in T1 and T2 cells to promote lung fluid clearance in vivo, and the mode of drug delivery is critical for maximizing beta-AR agonist efficacy. PMID- 22505672 TI - Mesenchymal stem cells and the stem cell niche: a new chapter. PMID- 22505671 TI - Platelets induce endothelial tissue factor expression in a mouse model of acid induced lung injury. AB - Although the lung expresses procoagulant proteins under inflammatory conditions, underlying mechanisms remain unclear. Here, we addressed lung endothelial expression of tissue factor (TF), which initiates the coagulation cascade and expression of which signifies development of a procoagulant phenotype in the vasculature. To establish the model of acid-induced acute lung injury (ALI), we intranasally instilled anesthetized mice with saline or acid. Then 2 h later, we isolated pulmonary vascular cells for flow cytometry and confocal microscopy to detect the leukocyte antigen, CD45 and the endothelial markers VE-cadherin and von Willebrand factor (vWf). Acid increased both the number of vWf-expressing cells as well as TF and P-selectin expressions on these cells. All of these effects were markedly inhibited by treating mice with antiplatelet serum, suggesting the involvement of platelets. The increased expressions of TF, vWf, and P-selectin in response to acid also occurred in platelets. Moreover, the effects were replicated in endothelial cells derived from isolated, blood perfused lungs. However, the effect was inhibited completely in lungs perfused with platelet-depleted and, to a lesser extent, with leukocyte-depleted blood. Acid injury increased endothelial expressions of the platelet proteins, CD41 and CD42b, providing evidence that platelet proteins were transferred to the vascular surface. Reactive oxygen species (ROS) were implicated in these responses, in that the endothelial and platelet protein expressions were inhibited. We conclude that acid-induced ALI causes NOX2-mediated ROS generation that activates platelets, which then generate a procoagulant endothelial surface. PMID- 22505673 TI - RAGE signaling by alveolar macrophages influences tobacco smoke-induced inflammation. AB - Receptors for advanced glycation end-products (RAGE) are multiligand cell surface receptors of the immunoglobin family expressed by epithelium and macrophages, and expression increases following exposure to cigarette smoke extract (CSE). The present study sought to characterize the proinflammatory contributions of RAGE expressed by alveolar macrophages (AMs) following CSE exposure. Acute exposure of mice to CSE via nasal instillation revealed diminished bronchoalveolar lavage (BAL) cellularity and fewer AMs in RAGE knockout (KO) mice compared with controls. Primary AMs were obtained from BAL, exposed to CSE in vitro, and analyzed. CSE significantly increased RAGE expression by wild-type AMs. Employing ELISAs, wild-type AMs exposed to CSE had increased levels of active Ras, a small GTPase that perpetuates proinflammatory signaling. Conversely, RAGE KO AMs had less Ras activation compared with wild-type AMs after exposure to CSE. In RAGE KO AMs, assessment of p38 MAPK and NF-kappaB, important intracellular signaling intermediates induced during an inflammatory response, revealed that CSE-induced inflammation may occur in part via RAGE signaling. Lastly, quantitative RT-PCR revealed that the expression of proinflammatory cytokines including TNF-alpha and IL-1beta were detectably decreased in RAGE KO AMs exposed to CSE compared with CSE-exposed wild-type AMs. These results reveal that primary AMs orchestrate CSE induced inflammation, at least in part, via RAGE-mediated mechanisms. PMID- 22505674 TI - Substrate-induced change in the quaternary structure of type 2 isopentenyl diphosphate isomerase from Sulfolobus shibatae. AB - Type 2 isopentenyl diphosphate isomerase catalyzes the interconversion between two active units for isoprenoid biosynthesis, i.e., isopentenyl diphosphate and dimethylallyl diphosphate, in almost all archaea and in some bacteria, including human pathogens. The enzyme is a good target for discovery of antibiotics because it is essential for the organisms that use only the mevalonate pathway to produce the active isoprene units and because humans possess a nonhomologous isozyme, type 1 isopentenyl diphosphate isomerase. However, type 2 enzymes were reportedly inhibited by mechanism-based drugs for the type 1 enzyme due to their surprisingly similar reaction mechanisms. Thus, a different approach is now required to develop new inhibitors specific to the type 2 enzyme. X-ray crystallography and gel filtration chromatography revealed that the enzyme from a thermoacidophilic archaeon, Sulfolobus shibatae, is in the octameric state at a high concentration. Interestingly, a part of the regions that are involved in the substrate binding in the previously reported tetrameric structures is integral to the formation of the tetramer-tetramer interface in the substrate-free octameric structure. Site-directed mutagenesis at such regions resulted in stabilization of the tetramer. Small-angle X-ray scattering, tryptophan fluorescence, and dynamic light scattering analyses showed that substrate binding causes the dissociation of an octamer into tetramers. This property, i.e., incompatibility between octamer formation and substrate binding, might provide clues to develop new specific inhibitors of the archaeal enzyme. PMID- 22505675 TI - The ttpC gene is contained in two of three TonB systems in the human pathogen Vibrio vulnificus, but only one is active in iron transport and virulence. AB - The TonB system of proteins is required for the energy-dependent active transport of iron-bound substrates across the outer membrane of gram-negative bacteria. We have identified three TonB systems within the human pathogen Vibrio vulnificus. The TonB1 system contains the TonB1, ExbD1, and ExbB1 proteins, whereas both the TtpC2-TonB2 and TtpC3-TonB3 systems contain an additional fourth protein, TtpC. Here we report that TtpC3, although highly related to TtpC2, is inactive in iron transport, whereas TtpC2 is essential for the function of the TtpC2-TonB2 system in V. vulnificus. This protein, together with TonB2, is absolutely required for both the uptake of endogenously produced iron-bound siderophores as well as siderophores produced from other organisms. Through complementation we show that V. vulnificus is capable of using different TtpC2 proteins from other Vibrio species to drive the uptake of multiple siderophores. We have also determined that aerobactin, a common bacterial siderophore involved in virulence of enteric bacteria, can only be brought into the cell using the TtpC2-TonB2 system, indicating an important evolutionary adaptation of TtpC2 and TonB2. Furthermore, in the absence of TonB1, TtpC2 is essential for a fully virulent phenotype as demonstrated using 50% lethal dose (LD(50)) experiments in mice. PMID- 22505676 TI - Pangenomic study of Corynebacterium diphtheriae that provides insights into the genomic diversity of pathogenic isolates from cases of classical diphtheria, endocarditis, and pneumonia. AB - Corynebacterium diphtheriae is one of the most prominent human pathogens and the causative agent of the communicable disease diphtheria. The genomes of 12 strains isolated from patients with classical diphtheria, endocarditis, and pneumonia were completely sequenced and annotated. Including the genome of C. diphtheriae NCTC 13129, we herewith present a comprehensive comparative analysis of 13 strains and the first characterization of the pangenome of the species C. diphtheriae. Comparative genomics showed extensive synteny and revealed a core genome consisting of 1,632 conserved genes. The pangenome currently comprises 4,786 protein-coding regions and increases at an average of 65 unique genes per newly sequenced strain. Analysis of prophages carrying the diphtheria toxin gene tox revealed that the toxoid vaccine producer C. diphtheriae Park-Williams no. 8 has been lysogenized by two copies of the omega(tox)(+) phage, whereas C. diphtheriae 31A harbors a hitherto-unknown tox(+) corynephage. DNA binding sites of the tox-controlling regulator DtxR were detected by genome-wide motif searches. Comparative content analysis showed that the DtxR regulons exhibit marked differences due to gene gain, gene loss, partial gene deletion, and DtxR binding site depletion. Most predicted pathogenicity islands of C. diphtheriae revealed characteristics of horizontal gene transfer. The majority of these islands encode subunits of adhesive pili, which can play important roles in adhesion of C. diphtheriae to different host tissues. All sequenced isolates contain at least two pilus gene clusters. It appears that variation in the distributed genome is a common strategy of C. diphtheriae to establish differences in host-pathogen interactions. PMID- 22505677 TI - Osmolality-dependent relocation of penicillin-binding protein PBP2 to the division site in Caulobacter crescentus. AB - The synthesis of the peptidoglycan cell wall is carefully regulated in time and space. In nature, this essential process occurs in cells that live in fluctuating environments. Here we show that the spatial distributions of specific cell wall proteins in Caulobacter crescentus are sensitive to small external osmotic upshifts. The penicillin-binding protein PBP2, which is commonly branded as an essential cell elongation-specific transpeptidase, switches its localization from a dispersed, patchy pattern to an accumulation at the FtsZ ring location in response to osmotic upshifts as low as 40 mosmol/kg. This osmolality-dependent relocation to the division apparatus is initiated within less than a minute, while restoration to the patchy localization pattern is dependent on cell growth and takes 1 to 2 generations. Cell wall morphogenetic protein RodA and penicillin binding protein PBP1a also change their spatial distribution by accumulating at the division site in response to external osmotic upshifts. Consistent with its ecological distribution, C. crescentus displays a narrow range of osmotolerance, with an upper limit of 225 mosmol/kg in minimal medium. Collectively, our findings reveal an unsuspected level of environmental regulation of cell wall protein behavior that is likely linked to an ecological adaptation. PMID- 22505679 TI - Regulation and evolution of malonate and propionate catabolism in proteobacteria. AB - Bacteria catabolize malonate via two pathways, encoded by the mdc and mat genes. In various bacteria, transcription of these genes is controlled by the GntR family transcription factors (TFs) MatR/MdcY and/or the LysR family transcription factor MdcR. Propionate is metabolized via the methylcitrate pathway, comprising enzymes encoded by the prp and acn genes. PrpR, the Fis family sigma 54-dependent transcription factor, is known to be a transcriptional activator of the prp genes. Here, we report a detailed comparative genomic analysis of malonate and propionate metabolism and its regulation in proteobacteria. We characterize genomic loci and gene regulation and identify binding motifs for four new TFs and also new regulon members, in particular, tripartite ATP-independent periplasmic (TRAP) transporters. We describe restructuring of the genomic loci and regulatory interactions during the evolution of proteobacteria. PMID- 22505678 TI - Molecular basis of Yersinia enterocolitica temperature-dependent resistance to antimicrobial peptides. AB - Antimicrobial peptides (APs) belong to the arsenal of weapons of the innate immune system against infections. In the case of gram-negative bacteria, APs interact with the anionic lipid A moiety of the lipopolysaccharide (LPS). In yersiniae most virulence factors are temperature regulated. Studies from our laboratory demonstrated that Yersinia enterocolitica is more susceptible to polymyxin B, a model AP, when grown at 37 degrees C than at 22 degrees C (J. A. Bengoechea, R. Diaz, and I. Moriyon, Infect. Immun. 64:4891-4899, 1996), and here we have extended this observation to other APs, not structurally related to polymyxin B. Mechanistically, we demonstrate that the lipid A modifications with aminoarabinose and palmitate are downregulated at 37 degrees C and that they contribute to AP resistance together with the LPS O-polysaccharide. Bacterial loads of lipid A mutants in Peyer's patches, liver, and spleen of orogastrically infected mice were lower than those of the wild-type strain at 3 and 7 days postinfection. PhoPQ and PmrAB two-component systems govern the expression of the loci required to modify lipid A with aminoarabinose and palmitate, and their expressions are also temperature regulated. Our findings support the notion that the temperature-dependent regulation of loci controlling lipid A modifications could be explained by H-NS-dependent negative regulation alleviated by RovA. In turn, our data also demonstrate that PhoPQ and PmrAB regulate positively the expression of rovA, the effect of PhoPQ being more important. However, rovA expression reached wild-type levels in the phoPQ pmrAB mutant background, hence indicating the existence of an unknown regulatory network controlling rovA expression in this background. PMID- 22505680 TI - HmuP is a coactivator of Irr-dependent expression of heme utilization genes in Bradyrhizobium japonicum. AB - Utilization of heme as an iron source by Bradyrhizobium japonicum involves induction of the outer membrane heme receptor gene hmuR and other genes within the heme utilization locus. Here, we discovered the hmuP gene located upstream of hmuR and transcribed divergently from it along with hmuTUV. hmuP encodes a small protein that accumulated under iron limitation and is transcriptionally controlled by the global iron-responsive regulator Irr, as were all genes within the heme utilization locus. Cross-linking and immunoprecipitation experiments showed that Irr occupies the hmuR-hmuP promoter in vivo. An hmuP mutant did not grow on heme as an iron source, but retained the ability to use ferric chloride. Correspondingly, induction of hmuR mRNA under iron limitation was severely diminished in an hmuP strain, but other genes within the Irr regulon were unaffected. HmuP occupied the hmuR-hmuP promoter, and thus it plays a direct regulatory role in gene expression. HmuP was not required for Irr occupancy, nor was ectopic expression of hmuP from an Irr-independent promoter sufficient to induce the hmuR gene. Thus, both HmuP and Irr occupancy are necessary for hmuR induction. We suggest that HmuP is a coactivator of Irr-dependent expression of hmuR. PMID- 22505681 TI - Genetic analysis of 15 protein folding factors and proteases of the Escherichia coli cell envelope. AB - Each cell hosts thousands of proteins that vary greatly in abundance, structure, and chemical properties. To ensure that all proteins are biologically active and properly localized, efficient quality control systems have evolved. While the structure, function, and regulation of some individual protein folding factors and proteases were resolved up to atomic resolution, others remain poorly characterized. In addition, little is known about which factors are required for viability under specific stress conditions. We therefore determined the physiological implications of 15 factors of the E. coli cell envelope by an integrated genetic approach comprising phenotypic analyses. Our data indicate that surA and tsp null mutations are a lethal combination in rich medium, that surA dsbA and surA dsbC double mutants are temperature sensitive, and that surA ptrA, surA yfgC, dsbA fkpA, degP tsp, degP ppiD, tsp ppiD, and degP dsbA double mutants are temperature sensitive in rich medium containing 0.5 M NaCl, while degP dsbA, degP yfgC, tsp ydgD, and degP tsp double mutants do not grow in the presence of SDS/EDTA. Furthermore, we show that in degP dsbA, degP tsp, and degP yfgC double mutants a subpopulation of LamB exists as unfolded monomers. In addition, dsbA null mutants expressed lower levels of the outer membrane proteins LptD, LamB, FhuA, and OmpW while FhuA levels were reduced in surA single and degP ppiD double mutants. Lower FhuA levels in degP ppiD strains depend on Tsp, since in a tsp degP ppiD triple mutant FhuA levels are restored. PMID- 22505682 TI - Identification of ZapD as a cell division factor that promotes the assembly of FtsZ in Escherichia coli. AB - The tubulin homolog FtsZ forms a polymeric membrane-associated ring structure (Z ring) at midcell that establishes the site of division and provides an essential framework for the localization of a multiprotein molecular machine that promotes division in Escherichia coli. A number of regulatory proteins interact with FtsZ and modulate FtsZ assembly/disassembly processes, ensuring the spatiotemporal integrity of cytokinesis. The Z-associated proteins (ZapA, ZapB, and ZapC) belong to a group of FtsZ-regulatory proteins that exhibit functionally redundant roles in stabilizing FtsZ-ring assembly by binding and bundling polymeric FtsZ at midcell. In this study, we report the identification of ZapD (YacF) as a member of the E. coli midcell division machinery. Genetics and cell biological evidence indicate that ZapD requires FtsZ but not other downstream division proteins for localizing to midcell, where it promotes FtsZ-ring assembly via molecular mechanisms that overlap with ZapA. Biochemical evidence indicates that ZapD directly interacts with FtsZ and promotes bundling of FtsZ protofilaments. Similarly to ZapA, ZapB, and ZapC, ZapD is dispensable for division and therefore belongs to the growing group of FtsZ-associated proteins in E. coli that aid in the overall fitness of the division process. PMID- 22505683 TI - The biofilm-specific antibiotic resistance gene ndvB is important for expression of ethanol oxidation genes in Pseudomonas aeruginosa biofilms. AB - Bacteria growing in biofilms are responsible for a large number of persistent infections and are often more resistant to antibiotics than are free-floating bacteria. In a previous study, we identified a Pseudomonas aeruginosa gene, ndvB, which is important for the formation of periplasmic glucans. We established that these glucans function in biofilm-specific antibiotic resistance by sequestering antibiotic molecules away from their cellular targets. In this study, we investigate another function of ndvB in biofilm-specific antibiotic resistance. DNA microarray analysis identified 24 genes that were responsive to the presence of ndvB. A subset of 20 genes, including 8 ethanol oxidation genes (ercS', erbR, exaA, exaB, eraR, pqqB, pqqC, and pqqE), was highly expressed in wild-type biofilm cells but not in DeltandvB biofilms, while 4 genes displayed the reciprocal expression pattern. Using quantitative real-time PCR, we confirmed the ndvB-dependent expression of the ethanol oxidation genes and additionally demonstrated that these genes were more highly expressed in biofilms than in planktonic cultures. Expression of erbR in DeltandvB biofilms was restored after the treatment of the biofilm with periplasmic extracts derived from wild-type biofilm cells. Inactivation of ethanol oxidation genes increased the sensitivity of biofilms to tobramycin. Together, these results reveal that ndvB affects the expression of multiple genes in biofilms and that ethanol oxidation genes are linked to biofilm-specific antibiotic resistance. PMID- 22505684 TI - Differential effects of DNA supercoiling on Chlamydia early promoters correlate with expression patterns in midcycle. AB - Changes in DNA supercoiling levels during the chlamydial developmental cycle have been proposed as a global mechanism to upregulate midcycle genes, but the effects on early genes are not known. We examined the promoters for 10 Chlamydia trachomatis early genes and found that they could be separated into two subsets based on their responses to DNA supercoiling in vitro. Furthermore, the type of supercoiling response correlated with the in vivo expression pattern for each early gene. One subset of seven early genes had promoters that were transcribed in a supercoiling-insensitive manner over the physiologic range of supercoiling levels that have been measured in Chlamydia. In vivo transcripts for these genes were detected at similar levels during early-stage and midstage times. In contrast, a second subset, represented in our study by three early genes, had supercoiling-dependent promoters that were transcribed at higher levels from more supercoiled templates, which is the response observed for midcycle genes. Genes in this subset were expressed at higher levels at midstage times than at early times in vivo. We propose that this second subset represents a novel class of chlamydial developmental genes with features of both early and midcycle genes. We hypothesize that expression of these supercoiling-dependent early genes is upregulated by increased chlamydial supercoiling levels in midcycle via their supercoiling-responsive promoters in a manner similar to that for midcycle genes. Thus, we propose that DNA supercoiling is utilized in Chlamydia as a general mechanism to regulate genes in the midstage of the developmental cycle and not just midcycle genes. PMID- 22505685 TI - The Bacillus subtilis conjugative transposon ICEBs1 mobilizes plasmids lacking dedicated mobilization functions. AB - Integrative and conjugative elements (ICEs, also known as conjugative transposons) are mobile elements that are found integrated in a host genome and can excise and transfer to recipient cells via conjugation. ICEs and conjugative plasmids are found in many bacteria and are important agents of horizontal gene transfer and microbial evolution. Conjugative elements are capable of self transfer and also capable of mobilizing other DNA elements that are not able to self-transfer. Plasmids that can be mobilized by conjugative elements are generally thought to contain an origin of transfer (oriT), from which mobilization initiates, and to encode a mobilization protein (Mob, a relaxase) that nicks a site in oriT and covalently attaches to the DNA to be transferred. Plasmids that do not have both an oriT and a cognate mob are thought to be nonmobilizable. We found that Bacillus subtilis carrying the integrative and conjugative element ICEBs1 can transfer three different plasmids to recipient bacteria at high frequencies. Strikingly, these plasmids do not have dedicated mobilization-oriT functions. Plasmid mobilization required conjugation proteins of ICEBs1, including the putative coupling protein. In contrast, plasmid mobilization did not require the ICEBs1 conjugative relaxase or cotransfer of ICEBs1, indicating that the putative coupling protein likely interacts with the plasmid replicative relaxase and directly targets the plasmid DNA to the ICEBs1 conjugation apparatus. These results blur the current categorization of mobilizable and nonmobilizable plasmids and indicate that conjugative elements play a role in horizontal gene transfer even more significant than previously recognized. PMID- 22505686 TI - SMU.152 acts as an immunity protein for mutacin IV. AB - Streptococcus mutans, a principal causative agent of dental caries, secretes antimicrobial peptides known as mutacins to suppress the growth of competing species to establish a successful colonization. S. mutans UA159, a sequenced strain, produces at least two major mutacins, mutacins IV and V. Mutacin IV is a two-peptide mutacin encoded by nlmAB genes, which are mapped just upstream of a putative immunity-encoding gene SMU.152. Here we explored the function of SMU.152 as an immunity protein. We observed that overexpression of SMU.152 in two sensitive host strains converted the strains to become immune to mutacin IV. To identify the residues that are important for immunity function, we sequentially deleted residues from the C-terminal region of SMU.152. We observed that deletion of as few as seven amino acids, all of which are highly charged (KRRSKNK), drastically reduced the immunity function of the protein. Furthermore, we identified two other putative immunity proteins, SMU.1909 and SMU.925, which lack the last four charged residues (SKNK) that are present in SMU.152 but contain the KRR residues. Synthetic addition of SKNK residues to either SMU.1909 or SMU.925 to reconstitute the KRRSKNK motif and expressing these constructs in sensitive cells rendered the cells resistant to mutacin IV. We also demonstrated that deletion of Man-PTS system from a sensitive strain made the cells partially resistant to mutacin IV, indicating that the Man-PTS system plays a role in mutacin IV recognition. PMID- 22505687 TI - Roles of Exc protein and DNA homology in the CTnDOT excision reaction. AB - Excision from the chromosome is the first step during the transfer of conjugative transposons (CTns) to a recipient. We previously showed that the excision of CTnDOT is more complex than the excision of lambdoid phages and CTns such as Tn916. The excision in vivo of CTnDOT utilizes four CTnDOT-encoded proteins, IntDOT, Xis2c, Xis2d, and Exc, and a host factor. We previously developed an in vitro excision reaction where the recombination sites attL and attR were located on different plasmids. The reaction was inefficient and did not require Exc, suggesting that the reaction conditions did not mimic in vivo conditions. Here, we report the development of an intramolecular excision reaction where the attL and attR sites are located on the same DNA molecule. We found that Exc stimulates the reaction 3- to 5-fold. The efficiency of the excision reaction was also dependent on the distance between the attL and attR sites and on the sequences of the overlap regions between the sites of the strand exchanges. Substrates with identical overlap sequences recombined more efficiently than ones with heterologous overlap sequences. This was surprising, because the integration reaction is not sensitive to heterology in the overlap regions of the attDOT and attB sites. PMID- 22505688 TI - The Pseudomonas aeruginosa global regulator VqsR directly inhibits QscR to control quorum-sensing and virulence gene expression. AB - The opportunistic pathogen Pseudomonas aeruginosa has at least three quorum sensing (QS) systems, including the acyl-homoserine lactone (acyl-HSL)-mediated las and rhl systems, as well as the 2-alkyl-4(1H)-quinolone (AHQ) signal-based system. A group of key regulators of these QS systems have been identified, such as qteE, vqsM, vqsR, and vfr. However, the underlying regulatory mechanisms of these QS systems are not yet fully understood. Here, using electrophoretic mobility shift assays, we demonstrated that VqsR indirectly regulates acyl-HSL systems but specifically binds to the qscR promoter region, which indicates that VqsR influences QS-controlled pathways through QscR. Through a dye-based DNase I footprint assay, we showed that VqsR interacts with an inverted repeat (IR) motif (TCGCCN(8)GGCGA, where N is any nucleotide) in the promoter region of qscR. A genome-wide search identified 50 other promoter regions carrying the same putative IR motif. The recombinant VqsR protein exists as a homodimer in solution. In addition, using a qscR-lux reporter assay and Northern blot hybridization, we found that the transcription level of qscR increased 4-fold in the vqsR deletion strain compared to the wild-type PAO1 strain, indicating vqsR as a negative regulator of qscR. Taken together, these findings provide new insights into the complex regulation network of QS systems in P. aeruginosa. PMID- 22505689 TI - Cardiac asthma: transforming growth factor-beta from the failing heart leads to squamous metaplasia in human airway cells and in the murine lung. AB - BACKGROUND: Cardiac asthma describes symptoms of airflow obstruction due to heart failure. Chronic heart failure is associated with decreased FEV 1 , and FEV 1 improves after heart transplantation. Fibrotic remodeling of the heart and airways is mediated, in part, through transforming growth factor (TGF)- beta . Blood TGF- b 1 concentration correlates with ventricular remodeling in cardiac disease, and TGF- beta decreases after repair. METHODS: We established a coculture of normal human bronchial epithelial (NHBE) cells differentiated at air liquid interface with submerged basal cardiomyoblasts. Airway cells were immunostained with cytokeratin, actin, and involucrin. TGF- beta synthesis was assayed using enzyme-linked immunosorbent assay. Phosphorylation of Smad in NHBE cells was determined by Western blotting.Mice given doxorubicin developed cardiac failure, and their airways were histologically examined. RESULTS: Coculture induced involucrin-positive squamous metaplasia of NHBE cells, and this was attenuated by TGF- beta antibody. Total TGF- beta 1 was increased in coculture conditioned medium( P < .001). After 14 days of exposure to recombinant TGF- beta 1 , there was squamous transformation of NHBE cells. One week after removing cardiomyoblasts from culture, squamous metaplasia resolved into normal ciliated epithelia. Smad was phosphorylated in NHBE cells with cardiomyoblasts or with recombinant TGF- beta 1 exposure. The airways of mice with heart failure also demonstrated involucrin-positive squamous transformation. CONCLUSIONS: TGF- beta from cardiomyoblasts or from the failing heart can cause airway squamous metaplasia via Smad signaling, and this is blocked by anti-TGF- b antibody and reversed when cardiac cells are removed from culture. This appears to be an important mechanism for airflow obstruction with heart failure, sometimes described as cardiac asthma. PMID- 22505690 TI - Insight into the role of sugars in bud burst under light in the rose. AB - Bud burst is a decisive process in plant architecture that requires light in Rosa sp. This light effect was correlated with stimulation of sugar transport and metabolism in favor of bud outgrowth. We investigated whether sugars could act as signaling entities in the light-mediated regulation of vacuolar invertases and bud burst. Full-length cDNAs encoding two vacuolar invertases (RhVI1 and RhVI2) were isolated from buds. Unlike RhVI2, RhVI1 was preferentially expressed in bursting buds, and was up-regulated in buds of beheaded plants exposed to light. To assess the importance of sugars in this process, the expression of RhVI1 and RhVI2 and the total vacuolar invertase activity were further characterized in buds cultured in vitro on 100 mM sucrose or mannitol under light or in darkness for 48 h. Unlike mannitol, sucrose promoted the stimulatory effect of light on both RhVI1 expression and vacuolar invertase activity. This up-regulation of RhVI1 was rapid (after 6 h incubation) and was induced by as little as 10 mM sucrose or fructose. No effect of glucose was found. Interestingly, both 30 mM palatinose (a non-metabolizable sucrose analog) and 5 mM psicose (a non metabolizable fructose analog) promoted the light-induced expression of RhVI1 and total vacuolar invertase activity. Sucrose, fructose, palatinose and psicose all promoted bursting of in vitro cultured buds under light. These findings indicate that soluble sugars contribute to the light effect on bud burst and vacuolar invertases, and can function as signaling entities. PMID- 22505692 TI - Epigenetic reprogramming in plant reproductive lineages. AB - Monoecious flowering plants produce both microgametophytes (pollen) and megagametophytes (embryo sacs) containing the male and female gametes, respectively, which participate in double fertilization. Much is known about cellular and developmental processes giving rise to these reproductive structures and the formation of gametes. However, little is known about the role played by changes in the epigenome in dynamically shaping these defining events during plant sexual reproduction. This has in part been hampered by the inaccessibility of these structures-especially the female gametes, which are embedded within the female reproductive tissues of the plant sporophyte. However, with the recent development of new cellular isolation technologies that can be coupled to next generation sequencing, a new wave of epigenomic studies indicate that an intricate epigenetic regulation takes place during the formation of male and female reproductive lineages. In this mini review, we assess the fast growing body of evidence for the epigenetic regulation of the developmental fate and function of plant gametes. We describe how small interfereing RNAs and DNA methylation machinery play a part in setting up unique epigenetic landscapes in different gametes, which may be responsible for their different fates and functions during fertilization. Collectively these studies will shed light on the dynamic epigenomic landscape of plant gametes or 'epigametes' and help to answer important unresolved questions on the sexual reproduction of flowering plants, especially those underpinning the formation of two products of fertilization, the embryo and the endosperm. PMID- 22505691 TI - An Arabidopsis FAD pyrophosphohydrolase, AtNUDX23, is involved in flavin homeostasis. AB - Although flavins, riboflavin (RF), FMN and FAD, are essential for primary and secondary metabolism in plants, the metabolic regulation of flavins is still largely unknown. Recently, we found that an Arabidopsis Nudix hydrolase, AtNUDX23, has FAD pyrophosphohydrolase activity and is distributed in plastids. Levels of RF and FAD but not FMN in Arabidopsis leaves significantly increased under continuous light and decreased in the dark. The transcript levels of AtNUDX23 as well as genes involved in flavin metabolism (AtFADS, AtRibF1, AtRibF2, AtFMN/FHy, LS and AtRibA) significantly increased under continuous light. The pyrophosphohydrolase activity toward FAD was enhanced in AtNUDX23 overexpressing (OX-NUDX23) plants and reduced in AtNUDX23-suppressed (KD-nudx23) plants, compared with the control plants. Interestingly intracellular levels of RF, FMN and FAD significantly decreased in not only OX-NUDX23 but also KD-nudx23 plants. The transcript levels of the flavin metabolic genes also decreased in both plants. Similarly, the increase in intracellular levels on treatment with flavins caused a reduction in the transcript levels of genes involved in flavin metabolism. These results suggest that negative feedback regulation of the metabolism of flavins through the hydrolysis of FAD by AtNUDX23 in plastids is involved in flavin homeostasis in plant cells. PMID- 22505693 TI - Transition of chromatin status during the process of recovery from drought stress in Arabidopsis thaliana. AB - Changes in chromatin status are correlated with gene regulation of biological processes such as development and stress responses in plants. In this study, we focused on the transition of chromatin status toward gene repression during the process of recovery from drought stress of drought-inducible genes (RD20, RD29A and AtGOLS2) and a rehydration-inducible gene (ProDH). In response to drought, RNA polymerase II was recruited on the drought-inducible genes and rapidly disappeared after rehydration, although mRNA levels of these genes were maintained to some degree after rehydration, suggesting that the transcriptional activities of these genes were rapidly inactivated by rehydration treatment. Histone H3K9ac was enriched by drought and rapidly removed from these regions by rehydration. In contrast, histone H3K4me3 was gradually decreased by rehydration but was maintained at low levels after rehydration, suggesting that H3K4me3 functions as an epigenetic mark of stress memory. These results show that the transcriptional activity and chromatin status are rapidly changed from an active to inactive mode during the recovery process. Our results demonstrate that histone modifications are correlated with the inactivation of drought-inducible genes during the recovery process by rehydration. PMID- 22505694 TI - Incidence of new-onset and flare of preexisting psoriasis during rituximab therapy for rheumatoid arthritis: data from the French AIR registry. AB - OBJECTIVE: Psoriasis could be a paradoxical reaction to tumor necrosis factor alpha antagonist therapy and it has been reported with rituximab therapy. Our objective was to assess the rates of new-onset and flare of preexisting psoriasis in patients taking rituximab for rheumatoid arthritis (RA). METHODS: The nationwide multicenter prospective AutoImmunity and Rituximab (AIR) registry was set up in 2006 by the French Society for Rheumatology to collect data on patients taking rituximab for joint diseases. We identified patients with RA in the registry who had psoriasis listed as an adverse drug reaction, and we obtained additional information from their physicians if needed. We computed the incidence rates of new-onset and flare of preexisting psoriasis according to the rituximab exposure time. RESULTS: Among the 1927 patients in the registry with RA, 2 had new-onset and 5 had flare of preexisting psoriasis after a median followup of 39.2 weeks. Incidence rates were 1.04/1000 person-years (95% CI 0.13 to 3.8) for new-onset psoriasis and 2.6/1000 person-years (95% CI 0.84 to 6.1) for flare of preexisting psoriasis. Rituximab rechallenge in the 2 new-onset cases and in 2 flare cases was not followed by recurrence or exacerbation of psoriasis. Two of the 5 flare cases developed after discontinuation of methotrexate. CONCLUSION: Despite the small number of cases observed, leading to wide CI, the incidence rates in our study do not support a causative role of rituximab therapy in new onset or flare of preexisting psoriasis in patients with RA. PMID- 22505695 TI - Rheumatic manifestations of autoimmune thyroid disease: the other autoimmune disease. AB - Autoimmune thyroid disease (AITD) is an inflammatory thyroiditis that in some cases is characterized by lymphocytic infiltration of the thyroid gland, also referred to as chronic lymphocytic thyroiditis or Hashimoto thyroiditis. Hashimoto thyroiditis is one of the commonest causes of hypothyroidism. Hypothyroidism has been associated with osteoarthritis (OA) and inflammatory forms of arthritis and with several well defined connective tissue diseases, which in turn can cause arthritis. The presence of arthritis in patients with AITD with normal thyroid function is now being increasingly recognized. There is also considerable evidence to suggest that AITD is highly associated with fibromyalgia syndrome. We review the current literature on the rheumatologic manifestations of AITD and describe the features in its presentation that set it apart from other forms of autoimmune arthritis. PMID- 22505696 TI - Polymorphisms of the genes encoding CD40 and growth differentiation factor 15 and in the 9p21.3 region in patients with rheumatoid arthritis and cardiovascular disease. AB - OBJECTIVE: Genes or gene products associated with coronary artery disease in the general population were analyzed in rheumatoid arthritis (RA) patients with atherothrombotic manifestations (ATM). METHODS: A cross-sectional study of 681 individuals (498 women; 183 men) with RA (American College of Rheumatology criteria), a mean age of 60.6 +/- 13.2 years, and mean disease duration of 15.5 +/- 12.6 years who were consecutively recruited and followed for 6 years. The prevalence of ATM [i.e., myocardial infarction, angina pectoris with intervention, deep vein thrombosis/pulmonary embolism (DVT/PE), and/or stroke/transient ischemic attack (TIA)] was recorded. Polymorphisms were analyzed in the genes coding for growth differentiation factor 15 (GDF15)/monocyte inhibitory cytokine-1 (MIC-1; rs1058587), CD40 (rs1535045 and rs3765459), and the 9p21.3 locus (rs1333049). Controls were randomly selected (n = 687; matched for age and sex). RESULTS: The distribution of genotypes of GDF15/MIC-1 differed significantly between patients with RA and controls (chi-squared = 6.40, 2 df, p = 0.041). ATM were associated with polymorphism of the GDF15/MIC-1 G allele (OR 2.21, 95% CI 1.17-4.18), and with CC genotype of the 9p21.3 locus (rs1333049; OR 1.92, 95% CI 1.15-3.19). Stroke/TIA in women was associated with GDF15/MIC-1 GG genotype (OR 3.75, 95% CI 1.06-13.33), while stroke/TIA in men was associated with CD40 homozygous major alleles (OR 6.48, 95% CI 1.31-32.0 and OR 2.78, 95% CI 0.78-9.91, respectively). DVT/PE was associated with polymorphism in the GDF15/MIC-1 gene (rs1058587) minor allele (OR 3.53, 95% CI 1.30-9.58). CONCLUSION: The gene polymorphisms analyzed were associated with different ATM in RA. The GDF15/MIC-1 gene polymorphism was also associated with RA per se, suggesting a common etiology for RA and ATM. PMID- 22505697 TI - Sex differences in pain scores and localization in inflammatory arthritis: a systematic review and metaanalysis. AB - OBJECTIVE: To systematically identify and examine reports of sex-stratified pain measurements in patients with inflammatory arthritis. METHODS: Data sources included PubMed (1950 to April 2010), Embase (1980 to April 2010), and manual searches of reference lists and conference abstracts. We included cohort studies and randomized trials comparing pain scores, treatment efficacy at reducing pain, or pain localization, between females and males with inflammatory arthritis [rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis, and reactive arthritis]. RESULTS: Twenty-six cohorts and 1 randomized trial reported sex-stratified pain scores, and all but 1 cohort identified worse pain scores at enrollment in females. In a metaanalysis of mean visual analog scale (VAS) scores (0 to 10) in 16 RA cohort studies (reporting on 21,612 females and 6871 males), the standardized mean difference in VAS was 0.21 (95% CI 0.16, 0.26). Treatment with disease-modifying therapy results in improvement in mean scores for both sexes; however, female absolute scores remain higher. In 12 spondyloarthropathy cohorts reporting pain localization, females develop more peripheral arthritis during their disease course (68.9% vs 51.2%) but less inflammatory back pain (50.6% vs 66.4%). CONCLUSION: We identified important sex differences in pain scores in inflammatory arthritis, with higher pain levels in females. In spondyloarthritis, females develop more peripheral arthritis and have less frequent spinal involvement compared to males. These differences may affect a clinician's perception of disease severity and activity, and thus influence management decisions. PMID- 22505698 TI - Indirect treatment comparison of abatacept with methotrexate versus other biologic agents for active rheumatoid arthritis despite methotrexate therapy in the United kingdom. AB - OBJECTIVE: To compare the efficacy of abatacept and alternative biologic disease modifying antirheumatic drugs (DMARD) in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) in the United Kingdom. METHODS: A systematic literature search identified 11 individual studies investigating the efficacy of abatacept, infliximab, adalimumab, etanercept, certolizumab pegol, and golimumab in adult patients with RA that did not respond to MTX. The clinical trials included in this analysis were similar in trial design, baseline patient characteristics, and background therapy (i.e., MTX). The key clinical endpoints of interest were the Health Assessment Questionnaire (HAQ) change from baseline (CFB) and the American College of Rheumatology (ACR) responses at 6 months (24-28 weeks). Results were analyzed using Bayesian network metaanalysis methods, and were expressed as differences in HAQ CFB and ACR20/50/70 relative risks, with 95% credible limits (CrL). RESULTS: Analysis of HAQ CFB at 6 months showed that abatacept is more efficacious than placebo [mean difference in HAQ CFB: -0.30 (95% CrL -0.42; -0.16)] and comparable to all other biologic agents, in patients receiving MTX as background treatment. Abatacept is also expected to result in a higher proportion of ACR responders compared to placebo, with relative risks ranging from 1.90 (95% CrL 1.24; 2.57) for ACR20 to 3.72 (95% CrL 1.50; 10.52) for ACR70, and to result in comparable proportions of ACR responders as other biologic agents, at 6 months. CONCLUSION: Abatacept is expected to result in improvement in functional status comparable to other recommended biologic agents in patients with RA who are unresponsive to MTX in the UK. PMID- 22505699 TI - Interleukin 6 in systemic sclerosis and potential implications for targeted therapy. AB - OBJECTIVE: The purpose of this study was to review the potential importance of interleukin 6 (IL-6) in systemic sclerosis (SSc). METHODS: PubMed and Scopus databases and American College of Rheumatology (from 2009-10) and European League Against Rheumatism abstracts (2009-11) were searched using keywords "scleroderma; SSc; cytokines; interleukins; interleukin 6" and publications were excluded if not pertaining to IL-6 in SSc. Data were extracted from selected articles to construct a cell interaction model of the effects of IL-6 in SSc. RESULTS: A total of 416 reports were found (PubMed, n = 82; Scopus, n = 331; 3 abstracts); 372 were excluded (irrelevant) leaving 41 publications and 3 abstracts (39 from PubMed, 18 from Scopus; but 16 were repeated from PubMed search), where 40 suggested IL-6 was important in SSc and 4 did not. Effects of IL-6 in SSc were summarized schematically. CONCLUSION: Of the 44 publications, 40 suggested that IL-6 may be important in SSc, allowing for a conceptual framework within SSc including effects on macrophages, fibroblasts, plasma cells, monocytes, and extracellular matrix. PMID- 22505700 TI - Effects of double filtration plasmapheresis, leflunomide, and methotrexate on inflammatory changes found through magnetic resonance imaging in early rheumatoid arthritis. AB - OBJECTIVE: To evaluate the effects of double filtration plasmapheresis (DFPP) in combination with leflunomide and methotrexate (MTX) on magnetic resonance imaging (MRI)-detected inflammatory changes (synovitis and bone edema) in patients with early rheumatoid arthritis (RA) with high disease activity. METHODS: Sixty RA patients with highly active disease of 6 months' to 3 years' duration were randomized to receive DFPP in combination with leflunomide and MTX (DFPP group), and leflunomide plus MTX (no-DFPP group). The primary endpoint was the improvement in MRI-detected synovitis from baseline over 6 months. Secondary endpoint variables included DAS28 remission and American College of Rheumatology (ACR) criteria responses for 6 consecutive months. RESULTS: The study achieved significant improvement in synovitis and bone edema, with significantly lower synovitis and bone edema scores in the DFPP group compared with the no-DFPP group (p < 0.001). Synovitis scores in 48.39% of patients (15/31) in the DFPP group were 0 at Month 6. Bone edema scores in 32.26% of patients (10/31) in the DFPP group were 0 at Month 6. We observed significantly greater ACR20, ACR50, ACR70, and ACR90 responses and DAS28 remission rates in the DFPP group than in the no DFPP group (p < 0.001). Sustained DAS28 remission and ACR90 response for at least 6 months were achieved in 100% of patients receiving DFPP therapy. CONCLUSION: The combination of DFPP and disease-modifying antirheumatic drugs (DMARD) was superior to DMARD alone for reducing MRI-detected signs of synovitis and bone edema in patients with early highly active RA. DFPP therapy enabled rapid and more complete suppression of inflammation in patients with highly active RA. Nearly half the patients (48.39%) who had received DFPP therapy achieved both clinical remission and imaging remission, a state characterized as true remission. PMID- 22505701 TI - Building a rheumatology education academy: insights from assessment of needs during a rheumatology division retreat. AB - OBJECTIVE: To implement a rheumatology department education retreat to systematically identify and address the key factors necessary to improve medical education in our division in preparation for developing a rheumatology academy. METHODS: The Hospital for Special Surgery organized a retreat for the Rheumatology Department aimed at (1) providing formal didactics and (2) assessing participants' self-reported skills and interest in education with the goal of directing this information toward formalizing improvement. In a mixed-methods study design, faculty and fellows in the Division of Rheumatology were surveyed online pre- and post-retreat regarding various aspects of the current education program, their teaching abilities, interest and time spent in teaching, divisional resources allocated, and how education is valued. RESULTS: Enthusiasm for teaching was high before and rose further after the retreat. Confidence in abilities was higher than expected before but fell afterward. Many noted that the lack of specific feedback on teaching skills and useful metrics to assess performance prevented the achievement of educational excellence. Most responding felt lack of time, knowledge of how to teach well, and resources prevented them from making greater commitments to educational endeavors and participating fully and effectively in the department's teaching activities. CONCLUSION: While most rheumatology faculty members want to improve as teachers, they know neither where their educational strengths and weaknesses lie nor where or how to begin to change their teaching abilities. The key elements for an academy would thus be an educational environment that elevates the quality of teaching throughout the division and promotes teaching careers and education research, and raises the importance and quality of teaching to equivalence with clinical care and research. PMID- 22505702 TI - Effect of golimumab on patient-reported outcomes in rheumatoid arthritis: results from the GO-FORWARD study. AB - OBJECTIVE: To evaluate the effect of golimumab on physical function, general health, and fatigue in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy. METHODS: In the multicenter, randomized, placebo controlled GO-FORWARD study, 444 adults with active RA despite MTX received subcutaneous placebo + MTX (crossover to golimumab 50 mg at Week 24), golimumab 100 mg + placebo, golimumab 50 mg + MTX, or golimumab 100 mg + MTX every 4 weeks. Physical function and general health were assessed using the Health Assessment Questionnaire-Disability Index (HAQ-DI) and Physical and Mental Component Summary (PCS, MCS) scores of the Medical Outcomes Study Short Form-36 questionnaire (SF 36), respectively, through Week 52. Fatigue was measured through Week 24 using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire. RESULTS: Mean improvements from baseline in HAQ-DI, SF-36 PCS, and FACIT-Fatigue scores (Weeks 14 and 24) were significantly greater for golimumab 50 mg + MTX and 100 mg + MTX versus placebo + MTX. Significantly greater proportions of patients treated with golimumab + MTX achieved clinically meaningful improvements from baseline to Weeks 14 and 24 in HAQ-DI, PCS, and FACIT-Fatigue scores. Mean improvements in SF-36 PCS (Week 14), MCS (Week 24), and FACIT-Fatigue (Weeks 14 and 24) scores were significantly greater for golimumab 100 mg + placebo versus placebo + MTX. Mean improvements from baseline in HAQ-DI, SF-36 PCS, and MCS scores through Week 24 were sustained through Week 52. CONCLUSION: Patients with active RA despite MTX had significant improvement in physical function, general health, and fatigue following golimumab + MTX therapy; improvements in physical function and general health were maintained through Week 52. (Clinical Trials Registration NCT00264550). PMID- 22505703 TI - Correlates of axial gout: a cross-sectional study. AB - OBJECTIVE: A cross-sectional study was undertaken to determine the prevalence of axial gout in patients with established gouty arthritis and to analyze clinical, laboratory, and radiological correlations. METHODS: Forty-eight subjects with a history of gouty arthritis (American College of Rheumatology criteria) for >= 3 years under poor control were included. Subjects underwent history, physical examination, laboratory testing, and imaging studies, including radiographs of the hands and feet and computerized tomography (CT) of the cervical and lumbar spines and sacroiliac joints (SIJ). Patients with characteristic erosions and/or tophi in the spine or SIJ were considered to have axial or spinal gout. RESULTS: Seventeen patients (35%) had CT evidence of spinal erosions and/or tophi, with tophi identified in 7 of the 48 subjects (15%). The spinal location of axial gout was cervical in 7 patients (15%), lumbar in 16 (94%), SIJ in 1 (6%), and more than 1 location in 14 (82%). Duration of gout, presence of back pain, and serum uric acid levels did not correlate with axial gout. Extremity radiographs characteristic of gouty arthropathy found in 21 patients (45%) were strongly correlated with CT evidence of axial gout (p < 0.001). All patients with tophi in the spine had abnormal hand or feet radiographs (p = 0.005). CONCLUSION: Axial gout may be a common feature of chronic gouty arthritis. The lack of correlation with back pain, the infrequent use of CT imaging in patients with back pain, and the lack of recognition of the problem of spinal involvement in gouty arthritis suggest that this diagnosis is often missed. PMID- 22505704 TI - Genetic ancestry, serum interferon-alpha activity, and autoantibodies in systemic lupus erythematosus. AB - OBJECTIVE: To investigate and refine the relationships among systemic lupus erythematosus (SLE) and related autoantibodies, interferon-alpha (IFN-alpha), and various ancestral backgrounds. METHODS: We investigated quantitatively defined genetic ancestry through principal component analysis in place of self-reported ancestry. RESULTS: African ancestry was found to be associated with presence of anti-RNP antibody (p = 0.0026), and anti-RNP was correlated with high levels of IFN-alpha (p = 2.8 * 10(-5)). CONCLUSION: Our data support a model in which African ancestry increases the likelihood of SLE-associated autoantibody formation, which subsequently results in higher levels of serum IFN-alpha. PMID- 22505705 TI - Rituximab therapy leads to reduced imprints of receptor revision in immunoglobulin kappa and lambda light chains. AB - OBJECTIVE: Transient B cell depletion by rituximab (RTX) has become a specific treatment of rheumatoid arthritis (RA). Although phenotypic repopulation kinetics of B cell subsets are well documented, precise molecular analyses of the reconstituting immunoglobulin (Ig) genes encoding the B cell receptor in RA are sparse. METHODS: A total of 708 individual CD19+CD27+ (memory) and CD19+CD27- (naive) B cells from 2 patients with RA were analyzed at baseline and 7 months after RTX at B cell repopulation. Ig light chain variable kappa (Vkappa) and lambda (Vlambda) light chain gene rearrangements were amplified, sequenced, and analyzed with a focus on receptor revision. RESULTS: The naive as well as the memory repertoire repopulated polyclonally with diverse use of variable light chain gene families and minigenes. During the reconstitution phase, B cells used significantly fewer Jkappa distal Vkappa genes (p = 0.0006), with a higher frequency of somatic hypermutation of rearrangements employing Jkappa5 compared to baseline in memory B cells. The use of Vlambda rearrangements in regenerating B cells was also biased toward use of Vlambda genes of the proximal cassette. In general, reemerging CD27+ Ig light chain genes were substantially more highly mutated than before RTX therapy (p < 0.0001, baseline vs during reconstitution). CONCLUSION: Our data indicate that RTX therapy leads to generation of distinct Vkappa/Jkappa and Vlambda/Jlambda gene repertoires consistent with replenishment of antigen-experienced B cells by germinal centers. At baseline, the imprints of receptor revision appeared to be more striking, which indicates that receptor revision is active in patients with RA and can be reduced by RTX. PMID- 22505706 TI - Peptidylarginine deiminase type 4 and methyl-CpG binding domain 4 polymorphisms in Chinese patients with rheumatoid arthritis. AB - OBJECTIVE: Peptidylarginine deiminase type 4 (PADI4) and methyl-CpG binding domain 4 (MBD4) are closely related with rheumatoid arthritis (RA). We hypothesized that PADI4 and MBD4 polymorphisms may contribute to RA susceptibility. METHODS: We studied PADI4 rs2240340 G/A, PADI4 rs874881 C/G, MBD4 rs140693 G/A, and MBD4 rs2005618 T/C gene polymorphisms in 329 patients with RA and 697 controls in a Chinese population. Genotyping was done using matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). RESULTS: When the PADI4 rs2240340 GG homozygote genotype was used as the reference group, the AA genotype was associated with a significantly increased risk of RA. In the recessive model, when PADI4 rs2240340 GG/GA genotypes were used as the reference group, the AA homozygote genotype was associated with a significant increased susceptibility to RA. PADI4 rs874881 C/G was in complete linkage disequilibrium with PADI4 rs2240340 G/A. MBD4 rs140693 G/A and MBD4 rs2005618 T/C polymorphisms were not associated with the risk of RA. In stratification analyses, a significantly increased risk for RA associated with the PADI4 rs2240340 AA genotype was evident among older patients and patients who were anticitrullinated protein antibody (ACPA)-positive compared with the PADI4 rs2240340 GG/GA genotype. CONCLUSION: These findings suggest that the functional single-nucleotide polymorphism PADI4 rs2240340 G/A variant allele is associated with RA development, especially among older patients and ACPA-positive patients. However, our results were obtained from a moderate-sized sample, and therefore this is a preliminary conclusion. Validation by a larger study from a more diverse ethnic population is needed to confirm these findings. PMID- 22505707 TI - Urinary vascular cell adhesion molecule, but not neutrophil gelatinase-associated lipocalin, is associated with lupus nephritis. AB - OBJECTIVE: Vascular cell adhesion molecule-1 (VCAM-1), an adhesion molecule, is involved in the progression of glomerular and tubulointerstitial injury. Neutrophil gelatinase-associated lipocalin (NGAL), a member of the lipocalin superfamily, has been shown to rise in both acute and chronic kidney damage. Both VCAM-1 and NGAL have been found at high levels in the urine of patients with active lupus nephritis. We investigated both as potential biomarkers for lupus nephritis. METHODS: VCAM-1 and NGAL were measured by ELISA during 1 to 8 clinic visits in 107 patients with systemic lupus erythematosus (SLE; 91% women, 51% black, 36% white, 4% Asian, 4% Hispanic, and 5% others) for a total of 190 visits. Patients' mean age was 41 years. We analyzed the relationship between these potential urine biomarkers and the urine protein/creatinine ratio (urine Pr/Cr), the Systemic Lupus International Collaborating Clinics (SLICC) renal activity score, SLE Disease Activity Index renal descriptors, and other clinical variables. RESULTS: VCAM-1 levels were strongly associated with the physician's global estimate of disease activity (p = 0.0002), the renal visual analog scale (p < 0.0001), the urine Pr/Cr (p < 0.0001), and SLICC renal activity score (p < 0.0001). VCAM-1 levels were also associated with a urine Pr/Cr >= 0.5 (p < 0.0001). NGAL was not associated with any measure of disease activity or with lupus serologies. CONCLUSION: Urine VCAM-1 had a strong association with measures of disease activity, including multiple renal activity descriptors. In contrast to previous SLE studies, NGAL failed to show any association with lupus nephritis. PMID- 22505708 TI - Remission in early rheumatoid arthritis -- a comparison of new ACR/EULAR remission criteria to established criteria. AB - OBJECTIVE: To describe the frequency of remission in an early rheumatoid arthritis (ERA) cohort. METHODS: The frequency of remission was evaluated, based on 8 definitions including the Boolean-based American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria. RESULTS: Of 369 patients, remission at 12 months ranged from 18% according to the ACR/EULAR clinical trial criteria to 40% according to the 28-joint Disease Activity Score (DAS28) < 2.6. Higher tender joint count, swollen joint count, and physician global scores were seen for DAS28-based definitions, and patient global assessment (PtGA) scores were almost 5-fold higher for DAS28 remission. CONCLUSION: Remission is achievable in ERA but its frequency differs according to the remission definition applied. Adoption of the new ACR/EULAR definition will limit the number classified as in remission, especially if the PtGA criteria are rated high for reasons other than inflammatory arthritis. PMID- 22505709 TI - p38 mitogen-activated protein kinase and nuclear factor-kappaB facilitate CD40 mediated salivary epithelial cell death. AB - OBJECTIVE: Our previous studies indicated that CD40-mediated Fas-dependent apoptosis is important for the glandular destruction of Sjogren's syndrome (SS), although other immune and nonimmune mechanisms are also involved in exocrine dysfunction. We investigated the roles of p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-kappaB (NF-kappaB) in salivary epithelial cell death in SS. METHODS: Expression of p38, phosphorylated p38 (pp38), and IkappaB-alpha was examined by Western blotting upon CD40 ligation. Activity of NF-kappaB induced by anti-CD40 monoclonal antibody (mAb) was examined by electrophoretic mobility shift assay (EMSA) and Western blotting. Expression of Fas was analyzed by flow cytometry and Western blotting with or without the p38-specific inhibitor SB203580 or the NF-kappaB-specific inhibitor caffeic acid phenethyl ester (CAPE). Induction of apoptosis in salivary epithelial cells was examined by DNA fragmentation and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Expression of phosphorylated p38MAPK and NF-kappaB was measured by immunohistochemistry. RESULTS: pp38MAPK and NF-kappaB p65 were predominantly expressed in the ductal and acinar epithelium adjacent to lymphoid infiltrates of SS salivary gland by immunohistochemistry. CD40 ligation strongly enhanced p38MAPK and NF-kappaB activity by EMSA and Western blotting in cultured salivary epithelial cells. Treatment of cells with anti-CD40 mAb resulted in significantly upregulated Fas expression and induction of Fas-dependent apoptosis. Inhibition of p38MAPK and NF-kappaB activity by SB203580 and/or CAPE reduced Fas expression and apoptosis in salivary epithelial cells, establishing p38MAPK and NF-kappaB as proapoptotic factors in this context. CONCLUSION: CD40 ligation plays an important role in activation of p38MAPK, NF-kappaB, and Fas molecules to initiate proapoptotic signaling. p38MAPK and NF-kappaB collaborate in regulation of proapoptotic signaling in CD40-mediated Fas-dependent apoptosis in salivary epithelial cells. PMID- 22505710 TI - Human heat shock protein 105/110 kDa (Hsp105/110) regulates biogenesis and quality control of misfolded cystic fibrosis transmembrane conductance regulator at multiple levels. AB - Heat shock protein 105/110-kDa (Hsp105/110), a member of the Hsp70 super family of molecular chaperones, serves as a nucleotide exchange factor for Hsc70, independently prevents the aggregation of misfolded proteins, and functionally relates to Hsp90. We investigated the roles of human Hsp105alpha, the constitutively expressed isoform, in the biogenesis and quality control of the cystic fibrosis transmembrane conductance regulator (CFTR). In the endoplasmic reticulum (ER), Hsp105 facilitates CFTR quality control at an early stage in its biosynthesis but promotes CFTR post-translational folding. Deletion of Phe-508 (DeltaF508), the most prevalent mutation causing cystic fibrosis, interferes with de novo folding of CFTR, impairing its export from the ER and accelerating its clearance in the ER and post-Golgi compartments. We show that Hsp105 preferentially associates with and stabilizes DeltaF508 CFTR at both levels. Introduction of the Hsp105 substrate binding domain potently increases the steady state level of DeltaF508 CFTR by reducing its early-stage degradation. This in turn dramatically enhances DeltaF508 CFTR cell surface functional expression in cystic fibrosis airway epithelial cells. Although other Hsc70 nucleotide exchange factors such as HspBP1 and BAG-2 inhibit CFTR post-translational degradation in the ER through cochaperone CHIP, Hsp105 has a primary role promoting CFTR quality control at an earlier stage. The Hsp105-mediated multilevel regulation of DeltaF508 CFTR folding and quality control provides new opportunities to understand how chaperone machinery regulates the homeostasis and functional expression of misfolded proteins in the cell. Future studies in this direction will inform therapeutics development for cystic fibrosis and other protein misfolding diseases. PMID- 22505711 TI - Unexpected link between lipooligosaccharide biosynthesis and surface protein release in Mycobacterium marinum. AB - The mycobacterial cell envelope is characterized by the presence of a highly impermeable second membrane, which is composed of mycolic acids intercalated with different unusual free lipids, such as lipooligosaccharides (LOS). Transport across this cell envelope requires a dedicated secretion system for extracellular proteins, such as PE_PGRS proteins, which are specific mycobacterial proteins with polymorphic GC-rich sequence (PGRS). In this study, we set out to identify novel components involved in the secretion of PE_PGRS proteins by screening Mycobacterium marinum transposon mutants for secretion defects. Interestingly, most mutants were not affected in secretion but in the release of PE_PGRS proteins from the cell surface. These mutants had insertions in a gene cluster associated with LOS biosynthesis. Lipid analysis of these mutants revealed a role at different stages of LOS biosynthesis for 10 novel genes. Furthermore, we show that regulatory protein WhiB4 is involved in LOS biosynthesis. The absence of the most extended LOS molecule, i.e. LOS-IV, and a concomitant accumulation of LOS III was already sufficient to reduce the release of PE_PGRS proteins from the mycobacterial cell surface. A similar effect was observed for major surface protein EspE. These results show that the attachment of surface proteins is strongly influenced by the glycolipid composition of the mycobacterial cell envelope. Finally, we tested the virulence of a LOS-IV-deficient mutant in our zebrafish embryo infection model. This mutant showed a marked increase in virulence as compared with the wild-type strain, suggesting that LOS-IV plays a role in the modulation of mycobacterial virulence. PMID- 22505712 TI - Protein kinase C (PKC)-promoted endocytosis of glutamate transporter GLT-1 requires ubiquitin ligase Nedd4-2-dependent ubiquitination but not phosphorylation. AB - Glutamate transporter-1 (GLT-1) is the main glutamate transporter in the central nervous system, and its concentration severely decreases in neurodegenerative diseases. The number of transporters in the plasma membrane reflects the balance between their insertion and removal, and it has been reported that the regulated endocytosis of GLT-1 depends on its ubiquitination triggered by protein kinase C (PKC) activation. Here, we identified serine 520 of GLT-1 as the primary target for PKC-dependent phosphorylation, although elimination of this serine did not impair either GLT-1 ubiquitination or endocytosis in response to phorbol esters. In fact, we present evidence indicating that the ubiquitin ligase Nedd4-2 mediates the PKC-dependent ubiquitination and down-regulation of GLT-1. Overexpression of Nedd4-2 increased the ubiquitination of the transporter and promoted its degradation. Moreover, phorbol myristate acetate enhanced Nedd4-2 phosphorylation and the formation of GLT-1.Nedd4-2 complexes, whereas siRNA knockdown of Nedd4-2 prevented ubiquitination, endocytosis, and the concomitant decrease in GLT-1 activity triggered by PKC activation. These results indicate that GLT-1 endocytosis is independent of its phosphorylation and that Nedd4-2 mediates PKC-dependent down-regulation of the transporter. PMID- 22505713 TI - Inhibition of choline acetyltransferase as a mechanism for cholinergic dysfunction induced by amyloid-beta peptide oligomers. AB - Dysregulated cholinergic signaling is an early hallmark of Alzheimer disease (AD), usually ascribed to degeneration of cholinergic neurons induced by the amyloid-beta peptide (Abeta). It is now generally accepted that neuronal dysfunction and memory deficits in the early stages of AD are caused by the neuronal impact of soluble Abeta oligomers (AbetaOs). AbetaOs build up in AD brain and specifically attach to excitatory synapses, leading to synapse dysfunction. Here, we have investigated the possibility that AbetaOs could impact cholinergic signaling. The activity of choline acetyltransferase (ChAT, the enzyme that carries out ACh production) was inhibited by ~50% in cultured cholinergic neurons exposed to low nanomolar concentrations of AbetaOs. 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction, lactate dehydrogenase release, and [(3)H]choline uptake assays showed no evidence of neuronal damage or loss of viability that could account for reduced ChAT activity under these conditions. Glutamate receptor antagonists fully blocked ChAT inhibition and oxidative stress induced by AbetaOs. Antioxidant polyunsaturated fatty acids had similar effects, indicating that oxidative damage may be involved in ChAT inhibition. Treatment with insulin, previously shown to down-regulate neuronal AbetaO binding sites, fully prevented AbetaO-induced inhibition of ChAT. Interestingly, we found that AbetaOs selectively bind to ~50% of cultured cholinergic neurons, suggesting that ChAT is fully inhibited in AbetaO-targeted neurons. Reduction in ChAT activity instigated by AbetaOs may thus be a relevant event in early stage AD pathology, preceding the loss of cholinergic neurons commonly observed in AD brains. PMID- 22505714 TI - Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy. AB - Autophagy plays an important role in cellular quality control and is responsible for removing protein aggregates and dysfunctional organelles. Bnip3 is an atypical BH3-only protein that is known to cause mitochondrial dysfunction and cell death. Interestingly, Bnip3 can also protect against cell death by inducing mitochondrial autophagy. The mechanism for this process, however, remains poorly understood. Bnip3 contains a C-terminal transmembrane domain that is essential for homodimerization and proapoptotic function. In this study, we show that homodimerization of Bnip3 is also a requirement for induction of autophagy. Several Bnip3 mutants that do not interfere with its mitochondrial localization but disrupt homodimerization failed to induce autophagy in cells. In addition, we discovered that endogenous Bnip3 is localized to both mitochondria and the endoplasmic reticulum (ER). To investigate the effects of Bnip3 at mitochondria or the ER on autophagy, Bnip3 was targeted specifically to each organelle by substituting the Bnip3 transmembrane domain with that of Acta or cytochrome b(5). We found that Bnip3 enhanced autophagy in cells from both sites. We also discovered that Bnip3 induced removal of both ER (ERphagy) and mitochondria (mitophagy) via autophagy. The clearance of these organelles was mediated in part via binding of Bnip3 to LC3 on the autophagosome. Although ablation of the Bnip3 LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. Our data indicate that Bnip3 regulates the apoptotic balance as an autophagy receptor that induces removal of both mitochondria and ER. PMID- 22505715 TI - Riboswitch (T-box)-mediated control of tRNA-dependent amidation in Clostridium acetobutylicum rationalizes gene and pathway redundancy for asparagine and asparaginyl-trnaasn synthesis. AB - Analysis of the Gram-positive Clostridium acetobutylicum genome reveals an inexplicable level of redundancy for the genes putatively involved in asparagine (Asn) and Asn-tRNA(Asn) synthesis. Besides a duplicated set of gatCAB tRNA dependent amidotransferase genes, there is a triplication of aspartyl-tRNA synthetase genes and a duplication of asparagine synthetase B genes. This genomic landscape leads to the suspicion of the incoherent simultaneous use of the direct and indirect pathways of Asn and Asn-tRNA(Asn) formation. Through a combination of biochemical and genetic approaches, we show that C. acetobutylicum forms Asn and Asn-tRNA(Asn) by tRNA-dependent amidation. We demonstrate that an entire transamidation pathway composed of aspartyl-tRNA synthetase and one set of GatCAB genes is organized as an operon under the control of a tRNA(Asn)-dependent T-box riboswitch. Finally, our results suggest that this exceptional gene redundancy might be interconnected to control tRNA-dependent Asn synthesis, which in turn might be involved in controlling the metabolic switch from acidogenesis to solventogenesis in C. acetobutylicum. PMID- 22505716 TI - Conditional deletion of Notch1 and Notch2 genes in excitatory neurons of postnatal forebrain does not cause neurodegeneration or reduction of Notch mRNAs and proteins. AB - Activation of Notch signaling requires intramembranous cleavage by gamma secretase to release the intracellular domain. We previously demonstrated that presenilin and nicastrin, components of the gamma-secretase complex, are required for neuronal survival in the adult cerebral cortex. Here we investigate whether Notch1 and/or Notch2 are functional targets of presenilin/gamma-secretase in promoting survival of excitatory neurons in the adult cerebral cortex by generating Notch1, Notch2, and Notch1/Notch2 conditional knock-out (cKO) mice. Unexpectedly, we did not detect any neuronal degeneration in the adult cerebral cortex of these Notch cKO mice up to ~2 years of age, whereas conditional inactivation of presenilin or nicastrin using the same alphaCaMKII-Cre transgenic mouse caused progressive, striking neuronal loss beginning at 4 months of age. More surprisingly, we failed to detect any reduction of Notch1 and Notch2 mRNAs and proteins in the cerebral cortex of Notch1 and Notch2 cKO mice, respectively, even though Cre-mediated genomic deletion of the floxed Notch1 and Notch2 exons clearly took place in the cerebral cortex of these cKO mice. Furthermore, introduction of Cre recombinase into primary cortical cultures prepared from postnatal floxed Notch1/Notch2 pups, where Notch1 and Notch2 are highly expressed, completely eliminated their expression, indicating that the floxed Notch1 and Notch2 alleles can be efficiently inactivated in the presence of Cre. Together, these results demonstrate that Notch1 and Notch2 are not involved in the age-related neurodegeneration caused by loss of presenilin or gamma-secretase and suggest that there is no detectable expression of Notch1 and Notch2 in pyramidal neurons of the adult cerebral cortex. PMID- 22505717 TI - Crystal structure of Escherichia coli diaminopropionate ammonia-lyase reveals mechanism of enzyme activation and catalysis. AB - Pyridoxal 5'-phosphate (PLP)-dependent enzymes utilize the unique chemistry of a pyridine ring to carry out diverse reactions involving amino acids. Diaminopropionate (DAP) ammonia-lyase (DAPAL) is a prokaryotic PLP-dependent enzyme that catalyzes the degradation of d- and l-forms of DAP to pyruvate and ammonia. Here, we report the first crystal structure of DAPAL from Escherichia coli (EcDAPAL) in tetragonal and monoclinic forms at 2.0 and 2.2 A resolutions, respectively. Structures of EcDAPAL soaked with substrates were also determined. EcDAPAL has a typical fold type II PLP-dependent enzyme topology consisting of a large and a small domain with the active site at the interface of the two domains. The enzyme is a homodimer with a unique biological interface not observed earlier. Structure of the enzyme in the tetragonal form had PLP bound at the active site, whereas the monoclinic structure was in the apo-form. Analysis of the apo and holo structures revealed that the region around the active site undergoes transition from a disordered to ordered state and assumes a conformation suitable for catalysis only upon PLP binding. A novel disulfide was found to occur near a channel that is likely to regulate entry of ligands to the active site. EcDAPAL soaked with dl-DAP revealed density at the active site appropriate for the reaction intermediate aminoacrylate, which is consistent with the observation that EcDAPAL has low activity under crystallization conditions. Based on the analysis of the structure and results of site-directed mutagenesis, a two-base mechanism of catalysis involving Asp(120) and Lys(77) is suggested. PMID- 22505718 TI - Molecular cloning and characterization of first organic matrix protein from sclerites of red coral, Corallium rubrum. AB - We report here for the first time the isolation and characterization of a protein from the organic matrix (OM) of the sclerites of the alcyonarian, Corallium rubrum. This protein named scleritin is one of the predominant proteins extracted from the EDTA-soluble fraction of the OM. The entire open reading frame (ORF) was obtained by comparing amino acid sequences from de novo mass spectrometry and Edman degradation with an expressed sequence tag library dataset of C. rubrum. Scleritin is a secreted basic phosphorylated protein which exhibits a short amino acid sequence of 135 amino acids and a signal peptide of 20 amino acids. From specific antibodies raised against peptide sequences of scleritin, we obtained immunolabeling of scleroblasts and OM of the sclerites which provides information on the biomineralization pathway in C. rubrum. PMID- 22505719 TI - Distinctive roles for amygdalar CREB in reconsolidation and extinction of fear memory. AB - Cyclic AMP response element binding protein (CREB) plays a critical role in fear memory formation. Here we determined the role of CREB selectively within the amygdala in reconsolidation and extinction of auditory fear. Viral overexpression of the inducible cAMP early repressor (ICER) or the dominant-negative mCREB, specifically within the lateral amygdala disrupted reconsolidation of auditory fear memories. In contrast, manipulations of CREB in the amygdala did not modify extinction of fear. These findings suggest that the role of CREB in modulation of memory after retrieval is dynamic and that CREB activity in the basolateral amygdala is involved in fear memory reconsolidation. PMID- 22505720 TI - Kv4.2 knockout mice have hippocampal-dependent learning and memory deficits. AB - Kv4.2 channels contribute to the transient, outward K(+) current (A-type current) in hippocampal dendrites, and modulation of this current substantially alters dendritic excitability. Using Kv4.2 knockout (KO) mice, we examined the role of Kv4.2 in hippocampal-dependent learning and memory. We found that Kv4.2 KO mice showed a deficit in the learning phase of the Morris water maze (MWM) and significant impairment in the probe trial compared with wild type (WT). Kv4.2 KO mice also demonstrated a specific deficit in contextual learning in the fear conditioning test, without impairment in the conditioned stimulus or new context condition. Kv4.2 KO mice had normal activity, anxiety levels, and prepulse inhibition compared with WT mice. A compensatory increase in tonic inhibition has been previously described in hippocampal slice recordings from Kv4.2 KO mice. In an attempt to decipher whether increased tonic inhibition contributed to the learning and memory deficits in Kv4.2 KO mice, we administered picrotoxin to block GABA(A) receptors (GABA(A)R), and thereby tonic inhibition. This manipulation had no effect on behavior in the WT or KO mice. Furthermore, total protein levels of the alpha5 or delta GABA(A)R subunits, which contribute to tonic inhibition, were unchanged in hippocampus. Overall, our findings add to the growing body of evidence, suggesting an important role for Kv4.2 channels in hippocampal-dependent learning and memory. PMID- 22505721 TI - Serotonin transporter knockout rats show improved strategy set-shifting and reduced latent inhibition. AB - Behavioral flexibility is a cognitive process depending on prefrontal areas allowing adaptive responses to environmental changes. Serotonin transporter knockout (5-HTT(-/-)) rodents show improved reversal learning in addition to orbitofrontal cortex changes. Another form of behavioral flexibility, extradimensional strategy set-shifting (EDSS), heavily depends on the medial prefrontal cortex. This region shows functional changes in 5-HTT(-/-) rodents as well. Here we subjected 5-HTT(-/-) rats and their wild-type counterparts to an EDSS paradigm and a supplementary latent inhibition task. Results indicate that 5 HTT(-/-) rats also show improved EDSS, and indicate that reduced latent inhibition may contribute as an underlying mechanism. PMID- 22505722 TI - Histone H2B ubiquitylation promotes activity of the intact Set1 histone methyltransferase complex in fission yeast. AB - The methylation of histone H3 at lysine 4 (H3K4me) is critical for the formation of transcriptionally active chromatin in eukaryotes. In yeast, Drosophila, and some human cell lines, H3K4me is globally stimulated by the monoubiquitylation of histone H2B (H2Bub1), another histone modification associated with transcription. The mechanism of this "trans-histone" modification pathway remains uncertain, and studies carried out in different experimental systems have suggested that H2Bub1 could either influence the subunit composition of methyltransferase complexes or directly stimulate methyltransferase activity. We have reconstituted this pathway in vitro using the native H3K4-specific methyltransferase complex Set1C purified from the fission yeast Schizosaccharomyces pombe and chromatin substrates that contain semisynthetic H2Bub1. We found that the activity of S. pombe Set1C toward nucleosomal histone H3 is directly enhanced by H2Bub1 in vitro. Importantly, Set1C purified from cells lacking H2Bub1 retained activity on free histone substrates, suggesting that Set1C remains intact in the absence of H2Bub1. Chromatin immunoprecipitation assays revealed a defect in recruitment of intact Set1C to transcribed chromatin in H2Bub1-deficient mutants. Our data argue that trans-histone crosstalk in S. pombe involves direct enhancement of Set1C methyltransferase activity by H2Bub1 and suggest that this represents a conserved aspect of H2Bub1-H3K4me crosstalk in eukaryotes. PMID- 22505723 TI - Urine metabolomics analysis for biomarker discovery and detection of jaundice syndrome in patients with liver disease. AB - Metabolomics is a powerful new technology that allows for the assessment of global metabolic profiles in easily accessible biofluids and biomarker discovery in order to distinguish between diseased and nondiseased status information. Deciphering the molecular networks that distinguish diseases may lead to the identification of critical biomarkers for disease aggressiveness. However, current diagnostic methods cannot predict typical Jaundice syndrome (JS) in patients with liver disease and little is known about the global metabolomic alterations that characterize JS progression. Emerging metabolomics provides a powerful platform for discovering novel biomarkers and biochemical pathways to improve diagnostic, prognostication, and therapy. Therefore, the aim of this study is to find the potential biomarkers from JS disease by using a nontarget metabolomics method, and test their usefulness in human JS diagnosis. Multivariate data analysis methods were utilized to identify the potential biomarkers. Interestingly, 44 marker metabolites contributing to the complete separation of JS from matched healthy controls were identified. Metabolic pathways (Impact-value>=0.10) including alanine, aspartate, and glutamate metabolism and synthesis and degradation of ketone bodies were found to be disturbed in JS patients. This study demonstrates the possibilities of metabolomics as a diagnostic tool in diseases and provides new insight into pathophysiologic mechanisms. PMID- 22505724 TI - Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition. AB - Ubiquitination plays a key role in protein degradation and signal transduction. Ubiquitin is a small protein modifier that is adducted to lysine residues by the combined function of E1, E2, and E3 enzymes and is removed by deubiquitinating enzymes. Characterization of ubiquitination sites is important for understanding the role of this modification in cellular processes and disease. However, until recently, large-scale characterization of endogenous ubiquitination sites has been hampered by the lack of efficient enrichment techniques. The introduction of antibodies that specifically recognize peptides with lysine residues that harbor a di-glycine remnant (K-epsilon-GG) following tryptic digestion has dramatically improved the ability to enrich and identify ubiquitination sites from cellular lysates. We used this enrichment technique to study the effects of proteasome inhibition by MG-132 and deubiquitinase inhibition by PR-619 on ubiquitination sites in human Jurkat cells by quantitative high performance mass spectrometry. Minimal fractionation of digested lysates prior to immunoaffinity enrichment increased the yield of K-epsilon-GG peptides three- to fourfold resulting in detection of up to ~3300 distinct K-GG peptides in SILAC triple encoded experiments starting from 5 mg of protein per label state. In total, we identify 5533 distinct K-epsilon-GG peptides of which 4907 were quantified in this study, demonstrating that the strategy presented is a practical approach to perturbational studies in cell systems. We found that proteasome inhibition by MG 132 and deubiquitinase inhibition by PR-619 induces significant changes to the ubiquitin landscape, but that not all ubiquitination sites regulated by MG-132 and PR-619 are likely substrates for the ubiquitin-proteasome system. Additionally, we find that the proteasome and deubiquitinase inhibitors studied induced only minor changes in protein expression levels regardless of the extent of regulation induced at the ubiquitin site level. We attribute this finding to the low stoichiometry of the majority ubiquitination sites identified in this study. PMID- 22505726 TI - Characterization of the Arabidopsis augmin complex uncovers its critical function in the assembly of the acentrosomal spindle and phragmoplast microtubule arrays. AB - Plant cells assemble the bipolar spindle and phragmoplast microtubule (MT) arrays in the absence of the centrosome structure. Our recent findings in Arabidopsis thaliana indicated that AUGMIN subunit3 (AUG3), a homolog of animal dim gamma tubulin 3, plays a critical role in gamma-tubulin-dependent MT nucleation and amplification during mitosis. Here, we report the isolation of the entire plant augmin complex that contains eight subunits. Among them, AUG1 to AUG6 share low sequence similarity with their animal counterparts, but AUG7 and AUG8 share homology only with proteins of plant origin. Genetic analyses indicate that the AUG1, AUG2, AUG4, and AUG5 genes are essential, as stable mutations in these genes could only be transmitted to heterozygous plants. The sterile aug7-1 homozygous mutant in which AUG7 expression is significantly reduced exhibited pleiotropic phenotypes of seriously retarded vegetative and reproductive growth. The aug7-1 mutation caused delocalization of gamma-tubulin in the mitotic spindle and phragmoplast. Consequently, spindles were abnormally elongated, and their poles failed to converge, as MTs were splayed to discrete positions rendering deformed arrays. In addition, the mutant phragmoplasts often had disorganized MT bundles with uneven edges. We conclude that assembly of MT arrays during plant mitosis depends on the augmin complex, which includes two plant-specific subunits. PMID- 22505727 TI - An inducible RNA interference system in Physcomitrella patens reveals a dominant role of augmin in phragmoplast microtubule generation. AB - Mitosis is a fundamental process of eukaryotic cell proliferation. However, the molecular mechanisms underlying mitosis remain poorly understood in plants partly because of the lack of an appropriate model cell system in which loss-of-function analyses can be easily combined with high-resolution microscopy. Here, we developed an inducible RNA interference (RNAi) system and three-dimensional time lapse confocal microscopy in the moss Physcomitrella patens that allowed in-depth phenotype characterization of the moss genes essential for cell division. We applied this technique to two microtubule regulators, augmin and gamma-tubulin complexes, whose mitotic roles remain obscure in plant cells. Live imaging of caulonemal cells showed that they proceed through mitosis with continual generation and self-organization of acentrosomal microtubules. We demonstrated that augmin plays an important role in gamma-tubulin localization and microtubule generation from prometaphase to cytokinesis. Most evidently, microtubule formation in phragmoplasts was severely compromised after RNAi knockdown of an augmin subunit, leading to incomplete expansion of phragmoplasts and cytokinesis failure. Knockdown of the gamma-tubulin complex affected microtubule formation throughout mitosis. We conclude that postanaphase microtubule generation is predominantly stimulated by the augmin/gamma-tubulin machinery in moss and further propose that this RNAi system serves as a powerful tool to dissect the molecular mechanisms underlying mitosis in land plants. PMID- 22505729 TI - NADPH thioredoxin reductase C is localized in plastids of photosynthetic and nonphotosynthetic tissues and is involved in lateral root formation in Arabidopsis. AB - Plastids are organelles present in photosynthetic and nonphotosynthetic plant tissues. While it is well known that thioredoxin-dependent redox regulation is essential for leaf chloroplast function, little is known of the redox regulation in plastids of nonphotosynthetic tissues, which cannot use light as a direct source of reducing power. Thus, the question remains whether redox regulation operates in nonphotosynthetic plastid function and how it is integrated with chloroplasts for plant growth. Here, we show that NADPH-thioredoxin reductase C (NTRC), previously reported as exclusive to green tissues, is also expressed in nonphotosynthetic tissues of Arabidopsis thaliana, where it is localized to plastids. Moreover, we show that NTRC is involved in maintaining the redox homeostasis of plastids also in nonphotosynthetic organs. To test the relationship between plastids of photosynthetic and nonphotosynthetic tissues, transgenic plants were obtained with redox homeostasis restituted exclusively in leaves or in roots, through the expression of NTRC under the control of organ specific promoters in the ntrc mutant. Our results show that fully functional root amyloplasts are not sufficient for root, or leaf, growth, but fully functional chloroplasts are necessary and sufficient to support wild-type rates of root growth and lateral root formation. PMID- 22505732 TI - Attitude towards plagiarism among Iranian medical students. PMID- 22505730 TI - DNA millichips as a low-cost platform for gene expression analysis. AB - Our goal was to create a DNA chip that is as easy, convenient, and inexpensive as an agarose gel. For a first-generation solution, we describe a low-cost, easy-to use de novo synthesis oligonucleotide microarray technology that draws on the inherent flexibility of the maskless array synthesizer for in situ synthesis of thousands of photolithographically produced oligonucleotides covalently attached to a microscope slide. The method involves physically subdividing the slide into 1 * 1 mm millichips that are hybridized to fluorescent RNA or DNA of biological origin, in a microfuge tube at an ordinary laboratory benchtop, rather than in dedicated hybridization chambers. Fluorescence intensity is then measured with a standard microscope rather than sophisticated DNA chip scanners. For proof of principle, we measured changes in the transcriptome of Arabidopsis (Arabidopsis thaliana) plants induced by growth in the presence of three major environmental abiotic stresses (temperature, light, and water status), in all possible combinations. Validation by comparison with quantitative reverse transcription PCR showed a high correlation coefficient and analysis of variance indicated a high technical reproducibility. These experiments demonstrate that low-cost DNA millichips can be made and reliably used at the benchtop in a normal laboratory setting, without assistance of core facilities containing costly specialized instrumentation. PMID- 22505733 TI - Reply to Marquis: how things stand with the 'future like ours' argument. AB - In an earlier essay in this journal I critiqued Don Marquis's well-known argument against abortion. I distinguished two versions of Marquis's argument, which I refer to as 'the essence argument' and 'the sufficient condition argument'. I presented two counterexamples showing that the essence argument was mistaken, and I argued that the sufficient condition argument should be rejected because Marquis had not adequately responded to an important objection to it. In response to my critique, Marquis put forward in this journal a revised version of his argument. In his modified approach he no longer advocates the essence argument and he offers a new version of the sufficient condition argument. In the current essay, I discuss how Marquis's revised argument deals with my original objections, and I argue that his new sufficient condition argument is unsuccessful. PMID- 22505734 TI - Are momentary measures of positive affect better predictors of mortality than recalled feelings? PMID- 22505735 TI - Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain. AB - This study aims to determine the epigenetic mechanism regulating Kiss1 gene expression in the anteroventral periventricular nucleus (AVPV) to understand the mechanism underlying estrogen-positive feedback action on gonadotropin-releasing hormone/gonadotropin surge. We investigated estrogen regulation of the epigenetic status of the mouse AVPV Kiss1 gene locus in comparison with the arcuate nucleus (ARC), in which Kiss1 expression is down-regulated by estrogen. Histone of AVPV Kiss1 promoter region was highly acetylated, and estrogen receptor alpha was highly recruited at the region by estrogen. In contrast, the histone of ARC Kiss1 promoter region was deacetylated by estrogen. Inhibition of histone deacetylation up-regulated in vitro Kiss1 expression in a hypothalamic non-Kiss1-expressing cell line. Gene conformation analysis indicated that estrogen induced formation of a chromatin loop between Kiss1 promoter and the 3' intergenic region, suggesting that the intergenic region serves to enhance estrogen-dependent Kiss1 expression in the AVPV. This notion was proved, because transgenic reporter mice with a complete Kiss1 locus sequence showed kisspeptin neuron-specific GFP expression in both the AVPV and ARC, but the deletion of the 3' region resulted in greatly reduced GFP expression only in the AVPV. Taken together, these results demonstrate that estrogen induces recruitment of estrogen receptor alpha and histone acetylation in the Kiss1 promoter region of the AVPV and consequently enhances chromatin loop formation of Kiss1 promoter and Kiss1 gene enhancer, resulting in an increase in AVPV-specific Kiss1 gene expression. These results indicate that epigenetic regulation of the Kiss1 gene is involved in estrogen positive feedback to generate the gonadotropin-releasing hormone/gonadotropin surge. PMID- 22505736 TI - Ecological and evolutionary determinants for the adaptive radiation of the Madagascan vangas. AB - Adaptive radiation is the rapid diversification of a single lineage into many species that inhabit a variety of environments or use a variety of resources and differ in traits required to exploit these. Why some lineages undergo adaptive radiation is not well-understood, but filling unoccupied ecological space appears to be a common feature. We construct a complete, dated, species-level phylogeny of the endemic Vangidae of Madagascar. This passerine bird radiation represents a classic, but poorly known, avian adaptive radiation. Our results reveal an initial rapid increase in evolutionary lineages and diversification in morphospace after colonizing Madagascar in the late Oligocene some 25 Mya. A subsequent key innovation involving unique bill morphology was associated with a second increase in diversification rates about 10 Mya. The volume of morphospace occupied by contemporary Madagascan vangas is in many aspects as large (shape variation)--or even larger (size variation)--as that of other better-known avian adaptive radiations, including the much younger Galapagos Darwin's finches and Hawaiian honeycreepers. Morphological space bears a close relationship to diet, substrate use, and foraging movements, and thus our results demonstrate the great extent of the evolutionary diversification of the Madagascan vangas. PMID- 22505737 TI - Reassessment of the 2010-2011 Haiti cholera outbreak and rainfall-driven multiseason projections. AB - Mathematical models can provide key insights into the course of an ongoing epidemic, potentially aiding real-time emergency management in allocating health care resources and by anticipating the impact of alternative interventions. We study the ex post reliability of predictions of the 2010-2011 Haiti cholera outbreak from four independent modeling studies that appeared almost simultaneously during the unfolding epidemic. We consider the impact of different approaches to the modeling of spatial spread of Vibrio cholerae and mechanisms of cholera transmission, accounting for the dynamics of susceptible and infected individuals within different local human communities. To explain resurgences of the epidemic, we go on to include waning immunity and a mechanism explicitly accounting for rainfall as a driver of enhanced disease transmission. The formal comparative analysis is carried out via the Akaike information criterion (AIC) to measure the added information provided by each process modeled, discounting for the added parameters. A generalized model for Haitian epidemic cholera and the related uncertainty is thus proposed and applied to the year-long dataset of reported cases now available. The model allows us to draw predictions on longer term epidemic cholera in Haiti from multiseason Monte Carlo runs, carried out up to January 2014 by using suitable rainfall fields forecasts. Lessons learned and open issues are discussed and placed in perspective. We conclude that, despite differences in methods that can be tested through model-guided field validation, mathematical modeling of large-scale outbreaks emerges as an essential component of future cholera epidemic control. PMID- 22505738 TI - beta-Catenin signaling initiates the activation of astrocytes and its dysregulation contributes to the pathogenesis of astrocytomas. AB - Astrocytes are the most abundant cell of the CNS and demonstrate contact inhibition in which a nonproliferative, nonmotile cellular state is achieved once stable intercellular contacts are formed between mature cells. Cellular injury disrupts these intercellular contacts, causing a loss of contact inhibition and the rapid initiation of healing. Dysregulation of the molecular pathways involved in this process is thought to lead to an aggressive cellular state associated with neoplasia. We investigated whether a comparable correlation exists between the response of astrocytes to injury and the malignant phenotype of astrocytomas. We discovered that the loss of contact inhibition plays a critical role in the initiation and regulation of reactive astrocytes in the healing of wounds. In particular, injury of the astrocytes interrupts and destabilizes the cadherin catenin complexes at the cell membrane leading to nuclear translocation of beta catenin and characteristic changes associated with the activation of astrocytes. Similar signaling pathways are found to be active--but dysregulated--in astrocytomas. Inhibition of beta-catenin signaling diminished both the response of astrocytes to injury and induction of the malignant phenotype of astrocytomas. The findings shed light on a unique mechanism associated with the pathogenesis of astrocytomas and provide a model for the loss of contact inhibition that may broadly apply to understanding the mechanisms of tissue repair and tumorigenesis in the brain. PMID- 22505739 TI - Predator transitory spillover induces trophic cascades in ecological sinks. AB - Understanding the effects of cross-system fluxes is fundamental in ecosystem ecology and biological conservation. Source-sink dynamics and spillover processes may link adjacent ecosystems by movement of organisms across system boundaries. However, effects of temporal variability in these cross-system fluxes on a whole marine ecosystem structure have not yet been presented. Here we show, using 35 y of multitrophic data series from the Baltic Sea, that transitory spillover of the top-predator cod from its main distribution area produces cascading effects in the whole food web of an adjacent and semi-isolated ecosystem. At varying population size, cod expand/contract their distribution range and invade/retreat from the neighboring Gulf of Riga, thereby affecting the local prey population of herring and, indirectly, zooplankton and phytoplankton via top-down control. The Gulf of Riga can be considered for cod a "true sink" habitat, where in the absence of immigration from the source areas of the central Baltic Sea the cod population goes extinct due to the absence of suitable spawning grounds. Our results add a metaecosystem perspective to the ongoing intense scientific debate on the key role of top predators in structuring natural systems. The integration of regional and local processes is central to predict species and ecosystem responses to future climate changes and ongoing anthropogenic disturbances. PMID- 22505740 TI - Biologically relevant mechanism for catalytic superoxide removal by simple manganese compounds. AB - Nonenzymatic manganese was first shown to provide protection against superoxide toxicity in vivo in 1981, but the chemical mechanism responsible for this protection subsequently became controversial due to conflicting reports concerning the ability of Mn to catalyze superoxide disproportionation in vitro. In a recent communication, we reported that low concentrations of a simple Mn phosphate salt under physiologically relevant conditions will indeed catalyze superoxide disproportionation in vitro. We report now that two of the four Mn complexes that are expected to be most abundant in vivo, Mn phosphate and Mn carbonate, can catalyze superoxide disproportionation at physiologically relevant concentrations and pH, whereas Mn pyrophosphate and citrate complexes cannot. Additionally, the chemical mechanisms of these reactions have been studied in detail, and the rates of reactions of the catalytic removal of superoxide by Mn phosphate and carbonate have been modeled. Physiologically relevant concentrations of these compounds were found to be sufficient to mimic an effective concentration of enzymatic superoxide dismutase found in vivo. This mechanism provides a likely explanation as to how Mn combats superoxide stress in cellular systems. PMID- 22505741 TI - Near attack conformers dominate beta-phosphoglucomutase complexes where geometry and charge distribution reflect those of substrate. AB - Experimental observations of fluoromagnesate and fluoroaluminate complexes of beta-phosphoglucomutase (beta-PGM) have demonstrated the importance of charge balance in transition-state stabilization for phosphoryl transfer enzymes. Here, direct observations of ground-state analog complexes of beta-PGM involving trifluoroberyllate establish that when the geometry and charge distribution closely match those of the substrate, the distribution of conformers in solution and in the crystal predominantly places the reacting centers in van der Waals proximity. Importantly, two variants are found, both of which satisfy the criteria for near attack conformers. In one variant, the aspartate general base for the reaction is remote from the nucleophile. The nucleophile remains protonated and forms a nonproductive hydrogen bond to the phosphate surrogate. In the other variant, the general base forms a hydrogen bond to the nucleophile that is now correctly orientated for the chemical transfer step. By contrast, in the absence of substrate, the solvent surrounding the phosphate surrogate is arranged to disfavor nucleophilic attack by water. Taken together, the trifluoroberyllate complexes of beta-PGM provide a picture of how the enzyme is able to organize itself for the chemical step in catalysis through the population of intermediates that respond to increasing proximity of the nucleophile. These experimental observations show how the enzyme is capable of stabilizing the reaction pathway toward the transition state and also of minimizing unproductive catalysis of aspartyl phosphate hydrolysis. PMID- 22505742 TI - Imaging in children presenting with acute neurological deficit: stroke. AB - Neurological deficits in the paediatric age group are much rarer than in adults; however, it is an urgent condition that relies heavily on imaging for a prompt accurate diagnosis. Neurological deficits caused by cerebrovascular diseases are defined as stroke, whereas conditions manifesting with neurological deficits without underlying cerebrovascular diseases are referred to as stroke mimics. To the best of the authors' knowledge, there is a lack of systematic pictorial review that collectively describes the imaging of neurological deficit in children. The purpose of the present series is to discuss the causes and imaging appearance of neurological deficits in childhood, based on the experience of a tertiary paediatric referral centre These are broadly categorised into stroke, infection, inflammation, metabolic disorder, cerebral neoplasms and drug poisoning. Different entities of stroke and their respective imaging findings are discussed. Paediatric stroke can further be divided into arterial ischaemic stroke, sino-venous stroke, haemorrhagic stroke and hypoxic-ischaemic encephalopathy. PMID- 22505743 TI - Suitability of endobronchial ultrasound-guided transbronchial needle aspiration specimens for subtyping and genotyping of non-small cell lung cancer: a multicenter study of 774 patients. AB - RATIONALE: The current management of advanced non-small cell lung cancer (NSCLC) requires differentiation between squamous and nonsquamous subtypes as well as epidermal growth factor receptor (EGFR) mutation status. Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is increasingly used for the diagnosis and staging of lung cancer. However, it is unclear whether cytology specimens obtained with EBUS-TBNA are suitable for the subclassification and genotyping of NSCLC. OBJECTIVES: To determine whether cytology specimens obtained from EBUS-TBNA in routine practice are suitable for phenotyping and genotyping of NSCLC. METHODS: Cytological diagnoses from EBUS-TBNA were recorded from 774 patients with known or suspected lung cancer across five centers in the United Kingdom between 2009 and 2011. MEASUREMENTS AND MAIN RESULTS: The proportion of patients with a final diagnosis by EBUS-TBNA in whom subtype was classified was 77% (95% confidence interval [CI], 73-80). The rate of NSCLC not otherwise specified (NSCLC-NOS) was significantly reduced in patients who underwent immunohistochemistry (adjusted odds ratio, 0.50; 95% CI, 0.28-0.82; P = 0.016). EGFR mutation analysis was possible in 107 (90%) of the 119 patients in whom mutation analysis was requested. The sensitivity, negative predictive value, and diagnostic accuracy of EBUS-TBNA in patients with NSCLC were 88% (95% CI, 86-91), 72% (95% CI, 66-77), and 91% (95% CI, 89-93), respectively. CONCLUSIONS: This large, multicenter, pragmatic study demonstrates that cytology samples obtained from EBUS-TBNA in routine practice are suitable for subtyping of NSCLC and EGFR mutation analysis and that the use of immunohistochemistry reduces the rate of NSCLC-NOS. PMID- 22505744 TI - Bronchoconstriction triggered by breathing hot humid air in patients with asthma: role of cholinergic reflex. AB - RATIONALE: Hyperventilation of hot humid air induces transient bronchoconstriction in patients with asthma; the underlying mechanism is not known. Recent studies showed that an increase in temperature activates vagal bronchopulmonary C-fiber sensory nerves, which upon activation can elicit reflex bronchoconstriction. OBJECTIVES: This study was designed to test the hypothesis that the bronchoconstriction induced by increasing airway temperature in patients with asthma is mediated through cholinergic reflex resulting from activation of these airway sensory nerves. METHODS: Specific airway resistance (SR(aw)) and pulmonary function were measured to determine the airway responses to isocapnic hyperventilation of humidified air at hot (49 degrees C; HA) and room temperature (20-22 degrees C; RA) for 4 minutes in six patients with mild asthma and six healthy subjects. A double-blind design was used to compare the effects between pretreatments with ipratropium bromide and placebo aerosols on the airway responses to HA challenge in these patients. MEASUREMENTS AND MAIN RESULTS: SR(aw) increased by 112% immediately after hyperventilation of HA and by only 38% after RA in patients with asthma. Breathing HA, but not RA, triggered coughs in these patients. In contrast, hyperventilation of HA did not cause cough and increased SR(aw) by only 22% in healthy subjects; there was no difference between their SR(aw) responses to HA and RA challenges. More importantly, pretreatment with ipratropium completely prevented the HA-induced bronchoconstriction in patients with asthma. CONCLUSIONS: Bronchoconstriction induced by increasing airway temperature in patients with asthma is mediated through the cholinergic reflex pathway. The concomitant increase in cough response further indicates an involvement of airway sensory nerves, presumably the thermosensitive C-fiber afferents. PMID- 22505746 TI - Utility of exhaled breath condensates across respiratory diseases. PMID- 22505745 TI - Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. AB - Definitive evidence of clinical efficacy in a Phase 3 trial is best shown by a beneficial impact on a clinically meaningful endpoint-that is, an endpoint that directly measures how a patient feels (symptoms), functions (the ability to perform activities in daily life), or survives. In idiopathic pulmonary fibrosis (IPF), we believe the endpoints that best meet these criteria are all-cause mortality and all-cause nonelective hospitalization. There are no validated measures of symptoms or broader constructs such as health status or functional status in IPF. A surrogate endpoint is defined as an indirect measure that is intended to substitute for a clinically meaningful endpoint. Surrogate endpoints can be appropriate outcome measures if validated. However, validation requires substantial evidence that the effect of an intervention on a clinically meaningful endpoint is reliably predicted by the effect of an intervention on the surrogate endpoint. For patients with IPF, there are currently no validated surrogate endpoints. PMID- 22505747 TI - Free immunoglobulin light chains in chronic obstructive pulmonary disease. PMID- 22505748 TI - Lord of the RING: ubiquitination and directed degradation of skeletal muscle in acute lung injury. PMID- 22505749 TI - Does the hospital make you older faster? PMID- 22505750 TI - Does prolonged red cell storage affect outcomes in the critically ill? PMID- 22505751 TI - Carbon monoxide, a modern "pharmakon" for sepsis. PMID- 22505752 TI - Does breastfeeding impact lung function and asthma risk? PMID- 22505753 TI - Exhaled breath condensates: analyzing the expiratory plume. PMID- 22505754 TI - Achalasia: a diagnosis that's hard to swallow. PMID- 22505755 TI - Inflammation-induced desensitization of beta-receptors in acute lung injury. PMID- 22505756 TI - Has my patient responded? PMID- 22505758 TI - Plastic bronchitis: a complication of myocardial revascularization. PMID- 22505759 TI - Inhaled NO protects cerebral white matter in neonatal rats with combined brain and lung injury. PMID- 22505760 TI - Pulmonary sarcomatoid carcinoma accompanying duodenal involvement. PMID- 22505761 TI - Expiratory resistance increases end-expiratory lung volume during sleep. PMID- 22505762 TI - A classification approach to coreference in discharge summaries: 2011 i2b2 challenge. AB - OBJECTIVE: To create a highly accurate coreference system in discharge summaries for the 2011 i2b2 challenge. The coreference categories include Person, Problem, Treatment, and Test. DESIGN: An integrated coreference resolution system was developed by exploiting Person attributes, contextual semantic clues, and world knowledge. It includes three subsystems: Person coreference system based on three Person attributes, Problem/Treatment/Test system based on numerous contextual semantic extractors and world knowledge, and Pronoun system based on a multi class support vector machine classifier. The three Person attributes are patient, relative and hospital personnel. Contextual semantic extractors include anatomy, position, medication, indicator, temporal, spatial, section, modifier, equipment, operation, and assertion. The world knowledge is extracted from external resources such as Wikipedia. MEASUREMENTS: Micro-averaged precision, recall and F measure in MUC, BCubed and CEAF were used to evaluate results. RESULTS: The system achieved an overall micro-averaged precision, recall and F-measure of 0.906, 0.925, and 0.915, respectively, on test data (from four hospitals) released by the challenge organizers. It achieved a precision, recall and F measure of 0.905, 0.920 and 0.913, respectively, on test data without Pittsburgh data. We ranked the first out of 20 competing teams. Among the four sub-tasks on Person, Problem, Treatment, and Test, the highest F-measure was seen for Person coreference. CONCLUSIONS: This system achieved encouraging results. The Person system can determine whether personal pronouns and proper names are coreferent or not. The Problem/Treatment/Test system benefits from both world knowledge in evaluating the similarity of two mentions and contextual semantic extractors in identifying semantic clues. The Pronoun system can automatically detect whether a Pronoun mention is coreferent to that of the other four types. This study demonstrates that it is feasible to accomplish the coreference task in discharge summaries. PMID- 22505763 TI - Caffeine intake, smoking, and risk of Parkinson disease in men and women. AB - The authors prospectively examined whether caffeine intake was associated with lower risk of Parkinson disease (PD) in both men and women among 304,980 participants in the National Institutes of Health-AARP Diet and Health Study and whether smoking affected this relation. Multivariate odds ratios and 95% confidence intervals were derived from logistic regression models. Higher caffeine intake as assessed in 1995-1996 was monotonically associated with lower PD risk (diagnosed in 2000-2006) in both men and women. After adjustment for age, race, and physical activity, the odds ratio comparing the highest quintile of caffeine intake with the lowest was 0.75 (95% confidence interval: 0.60, 0.94; P(trend) = 0.005) for men and 0.60 (95% confidence interval: 0.39, 0.91; P(trend) = 0.005) for women. Further adjustment for duration of smoking and analyses carried out among never smokers showed similar results. A joint analysis with smoking suggested that smoking and caffeine may act independently in relation to PD risk. Finally, the authors conducted a meta-analysis of prospective studies and confirmed that caffeine intake was inversely associated with PD risk in both men and women. These findings suggest no gender difference in the relation between caffeine and PD. PMID- 22505765 TI - Photo quiz: One or two souvenirs from Africa? Tertian malaria. PMID- 22505764 TI - Association of childhood obesity with maternal exposure to ambient air polycyclic aromatic hydrocarbons during pregnancy. AB - There are concerns that prenatal exposure to endocrine-disrupting chemicals increases children's risk of obesity. African-American and Hispanic children born in the Bronx or Northern Manhattan, New York (1998-2006), whose mothers underwent personal air monitoring for polycyclic aromatic hydrocarbon (PAH) exposure during pregnancy, were followed up to ages 5 (n = 422) and 7 (n = 341) years. At age 5 years, 21% of the children were obese, as were 25% of those followed to age 7 years. After adjustment for child's sex, age at measurement, ethnicity, and birth weight and maternal receipt of public assistance and prepregnancy obesity, higher prenatal PAH exposures were significantly associated with higher childhood body size. In adjusted analyses, compared with children of mothers in the lowest tertile of PAH exposure, children of mothers in the highest exposure tertile had a 0.39-unit higher body mass index z score (95% confidence interval (CI): 0.08, 0.70) and a relative risk of 1.79 (95% CI: 1.09, 2.96) for obesity at age 5 years, and they had a 0.30-unit higher body mass index z score (95% CI: 0.01, 0.59), a 1.93-unit higher percentage of body fat (95% CI: 0.33, 3.54), and a relative risk of 2.26 (95% CI: 1.28, 4.00) for obesity at age 7 years. The data indicate that prenatal exposure to PAHs is associated with obesity in childhood. PMID- 22505766 TI - Evaluation of mycobacterial interspersed repetitive-unit-variable-number tandem repeat genotyping as performed in laboratories in Canada, France, and the United States. PMID- 22505769 TI - ? AB - In cooperatively breeding animals, in which nonbreeding subordinates assist in rearing offspring born to dominants, breeders and helpers may be in conflict over their respective contributions to offspring care and selection may favour breeders that use aggression to elevate the work rates of helpers. We tested the prediction that dominant female meerkats, Suricata suricatta, should increase aggression towards subordinates when the need for help is higher, by playing back recordings of pup begging calls to simulate increased need for help. Second, we tested the prediction that dominants should reduce aggression when subordinates help more, by playing back recordings of feeding calls to simulate elevated pup provisioning rates by subordinates. Neither of the two playback experiments affected rates of aggressive interactions between breeding females and helpers. Instead, breeding females increased their own level of pup provisioning in response to increased pup begging. Hence, our results do not support a role of aggression in regulating helping behaviour in meerkats, but suggest that pup provisioning can be explained by direct and/or indirect benefits derived from helping. As yet, firm evidence that breeders use aggression to promote helping by subordinates in cooperative animal societies remains elusive. PMID- 22505770 TI - ? AB - We study the distribution of triples of codewords of codes and ordered codes. Schrijver [A. Schrijver, New code upper bounds from the Terwilliger algebra and semidefinite programming, IEEE Trans. Inform. Theory 51 (8) (2005) 2859-2866] used the triple distribution of a code to establish a bound on the number of codewords based on semidefinite programming. In the first part of this work, we generalize this approach for ordered codes. In the second part, we consider linear codes and linear ordered codes and present a MacWilliams-type identity for the triple distribution of their dual code. Based on the non-negativity of this linear transform, we establish a linear programming bound and conclude with a table of parameters for which this bound yields better results than the standard linear programming bound. PMID- 22505771 TI - Modelling of maize production in Croatia: present and future climate. AB - Maize is one of the most important agricultural crops in Croatia, and was selected for research of the effect of climate warming on yields. The Decision Support System for the Agrotechnology Transfer model (DSSAT) is one of the most utilized crop-weather models in the world, and was used in this paper for the investigation of maize growth and production in the present and future climate. The impact of present climate on maize yield was studied using DSSAT 4.0 with meteorological data from the Zagreb-Maksimir station covering the period 1949 2004. Pedological, physiological and genetic data from a 1999 field maize experiment at the same location were added. The location is representative of the continental climate in central Croatia. The linear trends of model outputs and the non-parametric Mann-Kendall test indicate that the beginning of silking has advanced significantly by 1.4 days/decade since the mid-1990s, and maturity by 4.5 days/decade. It also shows a decrease in biomass by 122 kg/ha and in maize yield by 216 kg/ha in 10 years.Estimates of the sensitivity of maize growth and yield in future climates were made by changing the initial weather and CO(2) conditions of the DSSAT 4.0 model according to the different climatic scenarios for Croatia at the end of the 21st century. Changed climate suggests increases in global solar radiation, minimal temperature and maximal temperature (*1.07, 2 and 4 degrees C, respectively), but a decrease in the amount of precipitation (*0.92), compared with weather data from the period 1949-2004. The reduction of maize yield was caused by the increase in minimal and maximal temperature and the decrease in precipitation amount, related to the present climate, is 6, 12 and 3%, respectively. A doubling of CO(2) concentration stimulates leaf assimilation, but maize yield is only 1% higher, while global solar radiation growth by 7% increases evapotranspiration by 3%. Simultaneous application of all these climate changes suggested that the maize growth period would shorten by c. 1 month and maize yield would decrease by 9%, with the main reason for maize yield reduction in Croatia being due to extremely warm conditions in the future climate. PMID- 22505772 TI - Effects of high temperature after anthesis on starch granules in grains of wheat (Triticum aestivum L.). AB - The effect of high temperatures (above 25 degrees C) on starch concentration and the morphology of starch granules in the grains of wheat (Triticum aestivum L.) were studied. Wheat plants of cultivars Yangmai 9 (weak-gluten) and Yangmai 12 (medium-gluten) were treated with high temperatures for 3 days at different times after anthesis. The results showed that the starch concentration of grains given a heat-shock treatment above 30 degrees C were lower than those developing at normal temperature in both cultivars. High temperature lowered starch concentration due to the decrease of amylopectin. Under the same temperature, the effect of heat shock from 6 to 8 days after anthesis (DAA) was the greatest, whereas from 36 to 38 DAA the effect was the least. The effects of high temperatures after anthesis on starch-pasting properties were similar to those on starch concentration, especially after 35-40 degrees C treatments. The size, shape and structure of starch granules in wheat grains (determined by electron microscopy) after heat shock were visibly different from the control. When given heat shock during development, the starch granules in mature wheat grains were ellipsoid in shape and bound loosely with a protein sheath in Yangmai 9, while they were damaged and compressed with fissures in Yangmai 12, indicating the differences in resistance to high temperature between cultivars. Ratios of large (type-A) and small (type-B) starch granules significantly decreased under heat shock, which limited the potential sink size for dry matter deposition in the grain. PMID- 22505773 TI - Significance, progress and prospects for research in simplified cultivation technologies for rice in China. AB - Simplified cultivation technologies for rice have become increasingly attractive in recent years in China because of their social, economical and environmental benefits. To date, several simplified cultivation technologies, such as conventional tillage and seedling throwing (CTST), conventional tillage and direct seeding (CTDS), no-tillage and seedling throwing (NTST), no-tillage and direct seeding (NTDS) and no-tillage and transplanting (NTTP), have been developed in China. Most studies have shown that rice grown under each of these simplified cultivation technologies can produce a grain yield equal to or higher than traditional cultivation (conventional tillage and transplanting). Studies that have described the influences of agronomic practices on yield formation of rice under simplified cultivation have demonstrated that optimizing agronomy practices would increase the efficiencies of simplified cultivation systems. Further research is needed to optimize the management strategies for CTST, CTDS and NTST rice which have developed quickly in recent years, to strengthen basic research for those simplified cultivation technologies that are rarely used at present (such as NTTP and NTDS), to select and breed cultivars suitable for simplified cultivation and to compare the practicability and effectiveness of different simplified cultivation technologies in different rice production regions. PMID- 22505774 TI - Decomposing variation in dairy profitability: the impact of output, inputs, prices, labour and management. AB - The UK dairy sector has undergone considerable structural change in recent years, with a decrease in the number of producers accompanied by an increased average herd size and increased concentrate use and milk yields. One of the key drivers to producers remaining in the industry is the profitability of their herds. The current paper adopts a holistic approach to decomposing the variation in dairy profitability through an analysis of net margin data explained by physical input output measures, milk price variation, labour utilization and managerial behaviours and characteristics. Data are drawn from the Farm Business Survey (FBS) for England in 2007/08 for 228 dairy enterprises. Average yields are 7100 litres/cow/yr, from a herd size of 110 cows that use 0.56 forage ha/cow/yr and 43.2 labour h/cow/yr. An average milk price of 22.57 pence per litre (ppl) produced milk output of L1602/cow/yr, which after accounting for calf sales, herd replacements and quota leasing costs, gave an average dairy output of L1516/cow/yr. After total costs of L1464/cow/yr this left an economic return of L52/cow/yr (0.73 ppl) net margin profit. There is wide variation in performance, with the most profitable (as measured by net margin per cow) quartile of producers achieving 2000 litres/cow/yr more than the least profitable quartile, returning a net margin of L335/cow/yr compared to a loss of L361/cow/yr for the least profitable. The most profitable producers operate larger, higher yielding herds and achieve a greater milk price for their output. In addition, a significantly greater number of the most profitable producers undertake financial benchmarking within their businesses and operate specialist dairy farms. When examining the full data set, the most profitable enterprises included significantly greater numbers of organic producers. The most profitable tend to have a greater reliance on independent technical advice, but this finding is not statistically significant. Decomposing the variation in net margin performance between the most and least profitable groups, an approximate ratio of 65:23:12 is observed for higher yields: lower costs: higher milk price. This result indicates that yield differentials are the key performance driver in dairy profitability. Lower costs per cow are dominated by the significantly lower cost of farmer and spouse labour per cow of the most profitable group, flowing directly from the upper quartile expending 37.7 labour h/cow/yr in comparison with 58.8 h/cow/yr for the lower quartile. The upper quartile's greater milk price is argued to be achieved through contract negotiations and higher milk quality, and this accounts for 0.12 of the variation in net margin performance. The average economic return to the sample of dairy enterprises in this survey year was less than L6000/farm/yr. However, the most profitable quartile returned an average economic return of approximately L50 000 per farm/yr. Structural change in the UK dairy sector is likely to continue with the least profitable and typically smaller dairy enterprises being replaced by a smaller number of expanding dairy production units. PMID- 22505775 TI - Effect of household land management on cropland topsoil organic carbon storage at plot scale in a red earth soil area of South China. AB - An inventory of topsoil soil organic carbon (SOC) content in household farms was performed in a village from a red earth region in Jiangxi Province, China in 2003. In this region, the farmland managed by each household is fragmented, consisting of several plots of land that are not necessarily adjacent to each other. A statistical analysis of SOC variation with land use and household management type, and with crop management practices was conducted. Plot size ranged from 0.007 to 0.630 ha with a mean of 0.1 ha, and SOC content ranged from 1.72 to 25.2 g/kg, varying widely with a variety of land management and agricultural practices, arising from individual household behaviours. The mean SOC content in plot size <0.1 ha was 20% lower than in plot size ?0.1 ha. SOC of dry crop plots was 70% lower than that in rice paddies, and SOC of plots contracted from the village was almost double that of plots leased from other householders. Moreover, a 30% increase in SOC was observed with green manure cultivation, and a 55% increase under triple cropping. The difference in SOC levels between the least and most favourable cases of household land management and agricultural practice was up to 150%. The results suggest that policies targeted at crop management alone may not deliver the expected SOC benefits if household land management is also not improved. PMID- 22505776 TI - Soil organic carbon dynamics and crop yield for different crop rotations in a degraded ferruginous tropical soil in a semi-arid region: a simulation approach. AB - In recent years, simulation models have been used as a complementary tool for research and for quantifying soil carbon sequestration under widely varying conditions. This has improved the understanding and prediction of soil organic carbon (SOC) dynamics and crop yield responses to soil and climate conditions and crop management scenarios. The goal of the present study was to estimate the changes in SOC for different cropping systems in West Africa using a simulation model. A crop rotation experiment conducted in Farako-Ba, Burkina Faso was used to evaluate the performance of the cropping system model (CSM) of the Decision Support System for Agrotechnology Transfer (DSSAT) for simulating yield of different crops. Eight crop rotations that included cotton, sorghum, peanut, maize and fallow, and three different management scenarios, one without N (control), one with chemical fertilizer (N) and one with manure applications, were studied. The CSM was able to simulate the yield trends of various crops, with inconsistencies for a few years. The simulated SOC increased slightly across the years for the sorghum-fallow rotation with manure application. However, SOC decreased for all other rotations except for the continuous fallow (native grassland), in which the SOC remained stable. The model simulated SOC for the continuous fallow system with a high degree of accuracy normalized root mean square error (RMSE)=0.001, while for the other crop rotations the simulated SOC values were generally within the standard deviation (s.d.) range of the observed data. The crop rotations that included a supplemental N-fertilizer or manure application showed an increase in the average simulated aboveground biomass for all crops. The incorporation of this biomass into the soil after harvest reduced the loss of SOC. In the present study, the observed SOC data were used for characterization of production systems with different SOC dynamics. Following careful evaluation of the CSM with observed soil organic matter (SOM) data similar to the study presented here, there are many opportunities for the application of the CSM for carbon sequestration and resource management in Sub Saharan Africa. PMID- 22505777 TI - Sensitivity of barley varieties to weather in Finland. AB - Global climate change is predicted to shift seasonal temperature and precipitation patterns. An increasing frequency of extreme weather events such as heat waves and prolonged droughts is predicted, but there are high levels of uncertainty about the nature of local changes. Crop adaptation will be important in reducing potential damage to agriculture. Crop diversity may enhance resilience to climate variability and changes that are difficult to predict. Therefore, there has to be sufficient diversity within the set of available cultivars in response to weather parameters critical for yield formation. To determine the scale of such 'weather response diversity' within barley (Hordeum vulgare L.), an important crop in northern conditions, the yield responses of a wide range of modern and historical varieties were analysed according to a well defined set of critical agro-meteorological variables. The Finnish long-term dataset of MTT Official Variety Trials was used together with historical weather records of the Finnish Meteorological Institute. The foci of the analysis were firstly to describe the general response of barley to different weather conditions and secondly to reveal the diversity among varieties in the sensitivity to each weather variable. It was established that barley yields were frequently reduced by drought or excessive rain early in the season, by high temperatures at around heading, and by accelerated temperature sum accumulation rates during periods 2 weeks before heading and between heading and yellow ripeness. Low temperatures early in the season increased yields, but frost during the first 4 weeks after sowing had no effect. After canopy establishment, higher precipitation on average resulted in higher yields. In a cultivar-specific analysis, it was found that there were differences in responses to all but three of the studied climatic variables: waterlogging and drought early in the season and temperature sum accumulation rate before heading. The results suggest that low temperatures early in the season, delayed sowing, rain 3-7 weeks after sowing, a temperature change 3-4 weeks after sowing, a high temperature sum accumulation rate from heading to yellow ripeness and high temperatures (?25 degrees C) at around heading could mostly be addressed by exploiting the traits found in the range of varieties included in the present study. However, new technology and novel genetic material are needed to enable crops to withstand periods of excessive rain or drought early in the season and to enhance performance under increased temperature sum accumulation rates prior to heading. PMID- 22505779 TI - DO CONSUMER PRICE SUBSIDIES REALLY IMPROVE NUTRITION? AB - Many developing countries use food-price subsidies or controls to improve nutrition. However, subsidizing goods on which households spend a high proportion of their budget can create large wealth effects. Consumers may then substitute towards foods with higher non-nutritional attributes (e.g., taste), but lower nutritional content per unit of currency, weakening or perhaps even reversing the subsidy's intended impact. We analyze data from a randomized program of large price subsidies for poor households in two provinces of China and find no evidence that the subsidies improved nutrition. In fact, it may have had a negative impact for some households. (JEL I38; O12; Q18). PMID- 22505778 TI - Nonlinear dynamic mechanism of vocal tremor from voice analysis and model simulations. AB - Nonlinear dynamic analysis and model simulations are used to study the nonlinear dynamic characteristics of vocal folds with vocal tremor, which can typically be characterized by low frequency modulation and aperiodicity. Tremor voices from patients with disorders such as paresis, Parkinson's disease, hyperfunction, and adductor spasmodic dysphonia show low-dimensional characteristics, differing from random noise. Correlation dimension analysis statistically distinguishes tremor voices from normal voices. Furthermore, a nonlinear tremor model is proposed to study the vibrations of the vocal folds with vocal tremor. Fractal dimensions and positive Lyapunov exponents demonstrate the evidence of chaos in the tremor model, where amplitude and frequency play important roles in governing vocal fold dynamics. Nonlinear dynamic voice analysis and vocal fold modeling may provide a useful set of tools for understanding the dynamic mechanism of vocal tremor in patients with laryngeal diseases. PMID- 22505780 TI - Modular synthesis of diphospholipid oligosaccharide fragments of the bacterial cell wall and their use to study the mechanism of moenomycin and other antibiotics. AB - We present a flexible, modular route to GlcNAc-MurNAc-oligosaccharides that can be readily converted into peptidoglycan (PG) fragments to serve as reagents for the study of bacterial enzymes that are targets for antibiotics. Demonstrating the utility of these synthetic PG substrates, we show that the tetrasaccharide substrate lipid IV (3), but not the disaccharide substrate lipid II (2), significantly increases the concentration of moenomycin A required to inhibit a prototypical PG-glycosyltransferase (PGT). These results imply that lipid IV and moenomycin A bind to the same site on the enzyme. We also show the moenomycin A inhibits the formation of elongated polysaccharide product but does not affect length distribution. We conclude that moenomycin A blocks PG-strand initiation rather than elongation or chain termination. Synthetic access to diphospholipid oligosaccharides will enable further studies of bacterial cell wall synthesis with the long-term goal of identifying novel antibiotics. PMID- 22505782 TI - ? AB - We report the extension of the copper(II) tetrafluoroborate catalysed opening of epoxides with alcohols to include a wider variety of alcohols, a range of solvents and a method to purify the products from the reaction. PMID- 22505781 TI - Pegylated Phthalocyanines: Synthesis and Spectroscopic Properties. AB - The syntheses and spectroscopic properties of a series of pegylated zinc(II) phthalocyanines (Zn-Pcs) containing one, two or eight tri(ethylene glycol) chains are described. The single molecular structure of a phthalonitrile precursor containing one hydroxyl and one PEG group, and its unique intermolecular hydrogen bonding are presented. The pegylated Pcs are highly soluble in polar organic solvents and have fluorescence quantum yields in the range 0.08-0.28. PMID- 22505783 TI - Root-n estimability of some missing data models. AB - It is known that in many missing data models, for example, survival data models, some parameters are root-n estimable while the others are not. When they are, their limiting distributions are often Gaussian and easy to use. When they are not, their limiting distributions, if exists, are often non-Gaussian and difficult to evaluate. Thus it is important to have some preliminary assessments of the root-n estimability in these models. In this article, we study this problem for four missing data models: two-point interval censoring, double censoring, interval truncation, and a case-control genetic association model. For the first three models, we identify some parameters which are not root-n estimable. For some root-n estimable parameters, we derive the corresponding information bounds when they exist. Also, as the Cox regression model is commonly used for such data, we give asymptotic efficient information for these regression parameters. For the case-control genetic association model, we compute the asymptotic efficient information and relative efficiency, in relation to that of the full data, when only the case-control status data are available, as is often the case in practice. PMID- 22505784 TI - Stigma, Culture, and HIV and AIDS in the Western Cape, South Africa: An Application of the PEN-3 Cultural Model for Community-Based Research. AB - HIV- and AIDS-related stigma has been reported to be a major factor contributing to the spread of HIV. In this study, the authors explore the meaning of stigma and its impact on HIV and AIDS in South African families and health care centers. They conducted focus group and key informant interviews among African and Colored populations in Khayelitsha, Gugulethu, and Mitchell's Plain in the Western Cape province. The audio-recorded interviews were transcribed and coded using NVivo. Using the PEN-3 cultural model, the authors analyzed results showing that participants' shared experiences ranged from positive/nonstigmatizing, to existential/unique to the contexts, to negative/stigmatizing. Families and health care centers were found to have both positive nonstigmatizing values and negative stigmatizing characteristics in addressing HIV/AIDS-related stigma. The authors conclude that a culture-centered analysis, relative to identity, is central to understanding the nature and contexts of HIV/AIDS-related stigma in South Africa. PMID- 22505785 TI - "What is this?" Gesture as a potential cue to identify referents in discourse. AB - This study explores whether caregivers follow the discourse-pragmatic principle of information status of referents (given vs. new) in their gestures and how children respond to their caregivers' gestures. Chinese and American caregivers were videotaped while interacting spontaneously with their children. Their speech and gestures were coded for referential expressions. Even though Chinese caregivers gestured more often than American caregivers, we found that both groups produced more gestures when asking their children to identify new referents than when asking their children to identify given referents. In addition, both groups of children were sensitive to the gestures accompanying new referents and using these gestures to identify the referents. Thus, we conclude that gesture serves as a potential cue for both caregivers and children to identify referents according to the discourse-pragmatic principle of information status. PMID- 22505786 TI - Geographic influences on sexual and reproductive health service utilization in rural Mozambique. AB - The HIV/AIDS epidemic remains a major public health issue across the globe, and it is of particular concern in sub-Saharan Africa. Utilization of sexual and reproductive health (SRH) services can significantly impact HIV prevention, transmission, and treatment. SRH service utilization may be determined by individual characteristics, such as education and economic status, but also by the location and accessibility of health care facilities. Using population-based survey data, this study applies exploratory spatial analysis techniques to examine spatial patterns of SRH service utilization among rural married women in southern Mozambique. Clustering among those using services is found as are spatial associations, indicating significant spatial variability in the utilization of health services. The findings provide valuable insights for current and future health care program planning and configuration. PMID- 22505787 TI - Nonparametric Bayes Stochastically Ordered Latent Class Models. AB - Latent class models (LCMs) are used increasingly for addressing a broad variety of problems, including sparse modeling of multivariate and longitudinal data, model-based clustering, and flexible inferences on predictor effects. Typical frequentist LCMs require estimation of a single finite number of classes, which does not increase with the sample size, and have a well-known sensitivity to parametric assumptions on the distributions within a class. Bayesian nonparametric methods have been developed to allow an infinite number of classes in the general population, with the number represented in a sample increasing with sample size. In this article, we propose a new nonparametric Bayes model that allows predictors to flexibly impact the allocation to latent classes, while limiting sensitivity to parametric assumptions by allowing class-specific distributions to be unknown subject to a stochastic ordering constraint. An efficient MCMC algorithm is developed for posterior computation. The methods are validated using simulation studies and applied to the problem of ranking medical procedures in terms of the distribution of patient morbidity. PMID- 22505788 TI - Tweedie's Formula and Selection Bias. AB - We suppose that the statistician observes some large number of estimates z(i), each with its own unobserved expectation parameter MU(i). The largest few of the z(i)'s are likely to substantially overestimate their corresponding MU(i)'s, this being an example of selection bias, or regression to the mean. Tweedie's formula, first reported by Robbins in 1956, offers a simple empirical Bayes approach for correcting selection bias. This paper investigates its merits and limitations. In addition to the methodology, Tweedie's formula raises more general questions concerning empirical Bayes theory, discussed here as "relevance" and "empirical Bayes information." There is a close connection between applications of the formula and James-Stein estimation. PMID- 22505789 TI - Detector Position Estimation for PET Scanners. AB - Physical positioning of scintillation crystal detector blocks in Positron Emission Tomography (PET) scanners is not always exact. We test a proof of concept methodology for the determination of the six degrees of freedom for detector block positioning errors by utilizing a rotating point source over stepped axial intervals. To test our method, we created computer simulations of seven Micro Crystal Element Scanner (MiCES) PET systems with randomized positioning errors. The computer simulations show that our positioning algorithm can estimate the positions of the block detectors to an average of one-seventh of the crystal pitch tangentially, and one-third of the crystal pitch axially. Virtual acquisitions of a point source grid and a distributed phantom show that our algorithm improves both the quantitative and qualitative accuracy of the reconstructed objects. We believe this estimation algorithm is a practical and accurate method for determining the spatial positions of scintillation detector blocks. PMID- 22505790 TI - Parental Compensatory Behaviors and Early Child Health Outcomes in Cebu, Philippines(). AB - A dynamic optimization model of parents choosing investments in their children's health motivates an empirical model of parents' choices of health inputs for their children and the impacts of these decisions on their children's subsequent health. Estimates of the child health input demand functions and the child health production functions from the Cebu Longitudinal Health and Nutrition Survey accord with the prediction that optimizing behavior results in higher levels of aggregate child health. Observable parental behaviors respond to the physical developmental status of their children. These parental responses appear to yield large and statistically significant improvements in children's early physiological outcomes. However, because some health inputs choices are not observable, it is impossible to ascertain whether these measured effects are due solely to variations in the observed input choices. PMID- 22505791 TI - The Intergenerational Effects of Paternal Migration on Schooling and Work: What Can We Learn from Children's Time Allocations? AB - This paper explores the short-run effects of a father's U.S. migration on his children's schooling and work outcomes in Mexico. To get around the endogeneity of paternal migration, I use individual fixed effects and instrumental variables estimation (FEIV) where the instrumental variables are based on U.S. city-level employment statistics in two industries popular with Mexican immigrants. Overall, the estimates suggest that in the short-run, children reduce study hours and increase work hours in response to a father's U.S. migration. Decomposing the sample into sex- and age-specific groups suggests that this is mainly driven by the effects of paternal migration on 12-15 year-old boys. These results are consistent with a story in which the immediate aftermath of a father's migration is one of financial hardship that is borne in part by relatively young children. PMID- 22505792 TI - ? AB - Although nonnegative matrix factorization (NMF) favors a sparse and part-based representation of nonnegative data, there is no guarantee for this behavior. Several authors proposed NMF methods which enforce sparseness by constraining or penalizing the [Formula: see text] of the factor matrices. On the other hand, little work has been done using a more natural sparseness measure, the [Formula: see text]. In this paper, we propose a framework for approximate NMF which constrains the [Formula: see text] of the basis matrix, or the coefficient matrix, respectively. For this purpose, techniques for unconstrained NMF can be easily incorporated, such as multiplicative update rules, or the alternating nonnegative least-squares scheme. In experiments we demonstrate the benefits of our methods, which compare to, or outperform existing approaches. PMID- 22505793 TI - Hepatitis B Virus genotypic differences map structurally close to NRTI resistance hot spots. AB - Despite the availability of a Hepatitis B Virus (HBV) vaccine, there are approximately 350 million people that are chronically infected with this virus that can cause liver cirrhosis and hepatocellular carcinoma. Currently, most approved anti-HBV drugs are nucleoside RT inhibitors (NRTIs) that target the viral enzyme reverse transcriptase (RT or P gene product). They suppress viral replication very efficiently but require long-term therapies, which invariably lead to the development of drug resistant viral strains with drug resistance mutations at the P gene. Because the reading frames of the P and S (surface antigen) genes partially overlap, selection of NRTI-resistance mutations may impart changes on the surface structural landscape of the virus. Conversely, genotypic differences on viral surface residues may also change the amino acid composition of the P gene and in terms affect HBV RT properties such as susceptibility to NRTIs. Interestingly, several studies have shown that patients infected with HBV from various genotypes respond differently to NRTI therapies. Here, we built a three-dimensional homology model of the catalytic core of HBV RT using HIV-1 RT as a template. We then mapped on the molecular model the residues that vary among various HBV genotypes. Surprisingly, the genotypic variability residues are generally in the vicinity of residues that are involved in NRTI resistance. Our results suggest that emergence of NRTI resistance mutations in HBV RT may be constrained by structural interactions with residues that vary among different genotypes. PMID- 22505794 TI - The protective role of religious coping in adolescents' responses to poverty and sexual decision-making in rural Kenya. AB - In this study, we explored how adolescents in rural Kenya apply religious coping in sexual decision-making in the context of high rates of poverty and Human Immunodeficiency Virus (HIV). Semi-structured interviews were conducted with 34 adolescents. One-third (13) reported religious coping related to economic stress, HIV, or sexual decision-making; the majority (29) reported religious coping with these or other stressors. Adolescents reported praying for God to partner with them to engage in positive behaviors, praying for strength to resist unwanted behaviors, and passive strategies characterized by waiting for God to provide resources or protection from HIV. Adolescents in Sub-Saharan Africa may benefit from HIV prevention interventions that integrate and build upon their use of religious coping. PMID- 22505795 TI - Texas Christian University (TCU) Short Forms for Assessing Client Needs and Functioning in Addiction Treatment. AB - The TCU Short Forms contain a revised and expanded set of assessments for planning and managing addiction treatment services. They are formatted as brief (1-page) forms to measure client needs and functioning, including drug use severity and history (TCUDS II), criminal thinking and cognitive orientation (CTSForm), motivation and readiness for treatment (MOTForm), psychological functioning (PSYForm), social relations and functioning (SOCForm), and therapeutic participation and engagement (ENGForm). These instruments facilitate optically-scanned data entry, computerized scoring, and rapid graphical feedback for clinical decisions. The present study (based on 5,022 inmates from eight residential prison treatment programs) examines evidence on scale reliabilities and measurement structures of these tools. Results confirmed their integrity and usefulness as indicators of individual and group-level therapeutic dynamics. PMID- 22505796 TI - Organizational Readiness for Change in Correctional and Community Substance Abuse Programs. AB - Significant needs exist for increased and better substance abuse treatment services in our nation's prisons. The TCU Organizational Readiness for Change (ORC) survey has been widely used in community-based treatment programs and evidence is accumulating for relationships between readiness for change and implementation of new clinical practices. Results of organizational surveys of correctional counselors from 12 programs in two states are compared with samples of community-based counselors. Correctional counselors perceived strong needs for new evidence-based practices but, compared to community counselors, reported fewer resources and less favorable organizational climates. These results have important implications for successfully implementing new practices. PMID- 22505797 TI - Antimicrobials for preterm birth prevention: an overview. AB - OBJECTIVE: Preterm birth (PTB) remains a major cause of neonatal morbidity and mortality. The association between PTB and infection is clear. The purpose of this report is to present a focused review of information on the use of antibiotics to prevent PTB. METHODS: We performed a search of the PubMed database restricted to clinical trials or meta-analyses published in English from 1990 through May 2011 using keywords "antibiotics or antimicrobials" and "preterm." RESULTS: The search yielded 67 abstracts for review. We selected 31 clinical trials (n = 26) or meta-analysis (n = 5) for further full-text review. Discussion of each eligible clinical trial, its specific inclusion criteria, antibiotic regimen used, and study results are presented. Overall, trials evaluating antibiotic treatment to prevent preterm birth have yielded mixed results regarding any benefit. CONCLUSION: Routine antibiotic prophylaxis is not recommended for prevention of preterm birth. PMID- 22505798 TI - Presumed cases of mumps in pregnancy: clinical and infection control implications. AB - Recently, a mumps outbreak in New York and New Jersey was reported by the Centers for Disease Control and Prevention (CDC). Subsequently, the dissemination of the disease was rapid, and, from June 28th 2009 through January 29th 2010, a total of 1,521 cases of mumps were reported in New York and New Jersey. Seven presumed cases occurred in pregnant women cared for at our institution. Mumps diagnosis as per the NYC Department of Health and Mental Hygiene was based on clinical manifestations, particularly parotitis. Prior immunizations with mumps vaccine and negative IgM were not adequate to rule out mumps infections. All of our seven patients had exposure to mumps in either their household or their community, and some of the them had symptoms of mumps. Due to the difficulties in interpreting serologies of these patients, their cases led to a presumed diagnosis of mumps. The diagnosis of mumps lead to the isolation of patients and health care personnel that were in contact with them. In this paper, we detail the presenting findings, diagnostic dilemmas and infection control challenges associated with presumed cases of mumps in pregnancy. PMID- 22505799 TI - Correlates of dual-method contraceptive use: an analysis of the National Survey Of Family Growth (2006-2008). AB - OBJECTIVE: To analyze a nationally representative sample of women for correlates of dual-contraceptive-method use. MATERIALS AND METHODS: We conducted an analysis of the National Survey of Family Growth, 2006-2008, a cross-sectional survey of reproductive-aged women in the United States. RESULTS: Dual method use was reported by 7.3% of the 5,178 women in the sample. Correlates of higher rates of dual-contraceptive-method use included age younger than 36 years and nonmarried marital status. Lower rates of dual method use were observed for women with less than a high-school education and women without consistent health insurance in the past year. Compared to women using oral contraceptives, use of the contraceptive injection or long-acting reversible contraception was associated with lower dual method use. CONCLUSIONS: The overall rate of dual-method use in the USA is low. Future interventions to promote dual method use should target high-risk groups with modifiable risk factors. PMID- 22505801 TI - The prevalence of urogenital infections in pregnant women experiencing preterm and full-term labor. AB - Urogenital infections are extremely prevalent during pregnancy and are an important cause of premature labor. However, the prevalence of urogenital infections during childbirth is not well known. Objective. Identify urogenital infections present at the beginning of labor in both full-term and preterm pregnancies. Study Design. Ninety-four women were admitted to the inpatient maternity clinic of the Federal University of Rio Grande do Norte (UFRN). In total, 49 women in preterm labor and 45 women in full-term labor were included in the study, and samples of urinary, vaginal, and perianal material were collected for microbiological analysis. Results. The prevalences of general infections in the preterm labor group and the full-term labor group were 49.0% and 53.3% (P = 0.8300), respectively. Urogenital infections in the preterm and full-term labor groups included urinary tract infection in 36.7% and 22.2% of women, vaginal candidiasis in 20.4% and 28.9% of women, bacterial vaginosis in 34.7% and 28.9% of women, and group B streptococcus in 6.1% and 15.6% of women, respectively. Conclusions. Urogenital infections were prevalent in women in preterm labor and full-term labor; however, significant differences between the groups were not observed. PMID- 22505800 TI - Effect of HSV-2 suppressive therapy on genital tract HIV-1 RNA shedding among women on HAART: a pilot randomized controlled trial. AB - BACKGROUND: The role of suppressive HSV therapy in women coinfected with HSV-2 and HIV-1 taking highly active antiretroviral therapy (HAART) is unclear. METHODS: 60 women with HIV-1/HSV-2 coinfection on HAART with plasma HIV-1 viral load (PVL) <=75 copies/mL were randomized to receive acyclovir (N = 30) or no acyclovir (N = 30). PVL, genital tract (GT) HIV-1, and GT HSV were measured every 4 weeks for one year. RESULTS: Detection of GT HIV-1 was not significantly different in the two arms (OR 1.23, P = 0.67), although this pilot study was underpowered to detect this difference. When PVL was undetectable, the odds of detecting GT HIV were 0.4 times smaller in the acyclovir arm than in the control arm, though this was not statistically significant (P = 0.07). The odds of detecting GT HSV DNA in women receiving acyclovir were significantly lower than in women in the control group, OR 0.38, P < 0.05. CONCLUSIONS: Chronic suppressive therapy with acyclovir in HIV-1/HSV-2-positive women on HAART significantly reduces asymptomatic GT HSV shedding, though not GT HIV shedding or PVL. PVL was strongly associated with GT HIV shedding, reinforcing the importance of HAART in decreasing HIV sexual transmission. PMID- 22505802 TI - Effects of reactive nitrogen scavengers on NK-cell-mediated killing of K562 cells. AB - This study explored the effects of reactive nitrogen metabolites (RNMS) on natural-killer- (NK-) cell-mediated killing of K562 cells and the influence of RNM scavengers, such as tiopronin (TIP), glutamylcysteinylglycine (GSH), and histamine dihydrochloride (DHT), on reversing the suppressing effect of RNM. We administered exogenous and endogenous RNM in the NK + K562 culture system and then added RNM scavengers. The concentrations of RNM, TNF-beta and IFN-gamma, and NK-cell cytotoxicity (NCC) and the percentage of living NK cells were then examined. We found that both exogenous and endogenous RNM caused the KIR to decrease (P < 0.01); however, RNM scavengers such as TIP and GSH rescued this phenomenon dose dependently. In conclusion, our data suggests that RNM scavengers such as TIP and GSH enhance the antineoplasmic activity of NK cells. PMID- 22505803 TI - Computer-based annotation of putative AraC/XylS-family transcription factors of known structure but unknown function. AB - Currently, about 20 crystal structures per day are released and deposited in the Protein Data Bank. A significant fraction of these structures is produced by research groups associated with the structural genomics consortium. The biological function of many of these proteins is generally unknown or not validated by experiment. Therefore, a growing need for functional prediction of protein structures has emerged. Here we present an integrated bioinformatics method that combines sequence-based relationships and three-dimensional (3D) structural similarity of transcriptional regulators with computer prediction of their cognate DNA binding sequences. We applied this method to the AraC/XylS family of transcription factors, which is a large family of transcriptional regulators found in many bacteria controlling the expression of genes involved in diverse biological functions. Three putative new members of this family with known 3D structure but unknown function were identified for which a probable functional classification is provided. Our bioinformatics analyses suggest that they could be involved in plant cell wall degradation (Lin2118 protein from Listeria innocua, PDB code 3oou), symbiotic nitrogen fixation (protein from Chromobacterium violaceum, PDB code 3oio), and either metabolism of plant-derived biomass or nitrogen fixation (protein from Rhodopseudomonas palustris, PDB code 3mn2). PMID- 22505804 TI - Neuroprotective effect of phosphocreatine on focal cerebral ischemia-reperfusion injury. AB - Phosphocreatine (PCr) is a natural compound, which can donate high-energy phosphate group to ADP to synthesize ATP, even in the absence of oxygen and glucose. At present, it is widely used in cardiac and renal ischemia-reperfusion (IR) disease. In this study, to examine the protective efficacy of PCr against cerebral IR, disodium creatine phosphate was injected intravenously into rats before focal cerebral IR. Intracranial pressure (ICP), neurological score, cerebral infarction volume, and apoptotic neurons were observed. Expression of caspase-3 and aquaporin-4 (AQP4) was analyzed. Compared with IR group, rats pretreated with PCr had better neurologic score, less infarction volume, fewer ultrastructural histopathologic changes, reduced apoptosis, and lower aquaporin-4 level. In conclusion, PCr is neuroprotective after transient focal cerebral IR injury. Such a protection might be associated with apoptosis regulating proteins. PMID- 22505805 TI - Rapamycin conditioning of dendritic cells differentiated from human ES cells promotes a tolerogenic phenotype. AB - While human embryonic stem cells (hESCs) may one day facilitate the treatment of degenerative diseases requiring cell replacement therapy, the success of regenerative medicine is predicated on overcoming the rejection of replacement tissues. Given the role played by dendritic cells (DCs) in the establishment of immunological tolerance, we have proposed that DC, rendered tolerogenic during their differentiation from hESC, might predispose recipients to accept replacement tissues. As a first step towards this goal, we demonstrate that DC differentiated from H1 hESCs (H1-DCs) are particularly responsive to the immunosuppressive agent rapamycin compared to monocyte-derived DC (moDC). While rapamycin had only modest impact on the phenotype and function of moDC, H1-DC failed to upregulate CD40 upon maturation and displayed reduced immunostimulatory capacity. Furthermore, coculture of naive allogeneic T cells with rapamycin treated H1-DC promoted an increased appearance of CD25(hi) Foxp3+ regulatory T cells, compared to moDC. Our findings suggest that conditioning of hESC-derived DC with rapamycin favours a tolerogenic phenotype. PMID- 22505806 TI - Effect of alphaB-crystallin on protein aggregation in Drosophila. AB - Disorganisation and aggregation of proteins containing expanded polyglutamine (polyQ) repeats, or ectopic expression of alpha-synuclein, underlie neurodegenerative diseases including Alzheimer's, Parkinson, Huntington, Creutzfeldt diseases. Small heat-shock proteins, such as alphaB-crystallin, act as chaperones to prevent protein aggregation and play a key role in the prevention of such protein disorganisation diseases. In this study, we have explored the potential for chaperone activity of alphaB-crystallin to suppress the formation of protein aggregates. We tested the ability of alphaB-crystallin to suppress the aggregation of a polyQ protein and alpha-synuclein in Drosophila. We found that alphaB-crystallin suppresses both the compound eye degeneration induced by polyQ and the alpha-synuclein-induced rough eye phenotype. Furthermore, by using histochemical staining we have determined that alphaB crystallin inhibits the aggregation of polyQ in vivo. These data provide a clue for the development of therapeutics for neurodegenerative diseases. PMID- 22505807 TI - All-trans-retinoic acid ameliorated high fat diet-induced atherosclerosis in rabbits by inhibiting platelet activation and inflammation. AB - BACKGROUND: All-trans-retinoic acid (atRA) is effective for many proliferative diseases. We investigated the protective effects of atRA against atherosclerosis. METHODS: Rabbits were randomly allocated to receive basal diet or an HFD for 4 weeks. HFD group then received rosuvastatin (3 mg/day), atRA (5 mg/kg/day), or the same volume of vehicle, respectively, for next 8 weeks. RESULTS: HFD group showed increases in plasma lipids and aortic plaque formation. P-selectin expression and fibrinogen binding on platelets or deposition on the intima of the aorta also increased significantly as did the levels of TNF-alpha, IL-6, and fibrinogen in plasma. After 8 weeks of treatment with atRA, there was a significant decrease in plasma lipids and improvement in aortic lesions. AtRA also inhibited the expression of P-selectin and fibrinogen binding on platelets and deposition on the intima of the aorta. CONCLUSION: AtRA can ameliorate HFD induced AS in rabbits by inhibiting platelet activation and inflammation. PMID- 22505808 TI - Evolution of mosquito-based arbovirus surveillance systems in Australia. AB - Control of arboviral disease is dependent on the sensitive and timely detection of elevated virus activity or the identification of emergent or exotic viruses. The emergence of Japanese encephalitis virus (JEV) in northern Australia revealed numerous problems with performing arbovirus surveillance in remote locations. A sentinel pig programme detected JEV activity, although there were a number of financial, logistical, diagnostic and ethical limitations. A system was developed which detected viral RNA in mosquitoes collected by solar or propane powered CO2 baited traps. However, this method was hampered by trap-component malfunction, microbial contamination and large mosquito numbers which overwhelmed diagnostic capabilities. A novel approach involves allowing mosquitoes within a box trap to probe a sugar-baited nucleic-acid preservation card that is processed for expectorated arboviruses. In a longitudinal field trial, both Ross River and Barmah Forest viruses were detected numerous times from multiple traps over different weeks. Further refinements, including the development of unpowered traps and use of yeast-generated CO2, could enhance the applicability of this system to remote locations. New diagnostic technology, such as next generation sequencing and biosensors, will increase the capacity for recognizing emergent or exotic viruses, while cloud computing platforms will facilitate rapid dissemination of data. PMID- 22505810 TI - Cytokines in systemic lupus erythematosus 2011. PMID- 22505811 TI - Artificial neural network for the prediction of tyrosine-based sorting signal recognition by adaptor complexes. AB - Sorting of transmembrane proteins to various intracellular compartments depends on specific signals present within their cytosolic domains. Among these sorting signals, the tyrosine-based motif (YXXO) is one of the best characterized and is recognized by MU-subunits of the four clathrin-associated adaptor complexes (AP-1 to AP-4). Despite their overlap in specificity, each MU-subunit has a distinct sequence preference dependent on the nature of the X-residues. Moreover, combinations of these residues exert cooperative or inhibitory effects towards interaction with the various APs. This complexity makes it impossible to predict a priori, the specificity of a given tyrosine-signal for a particular MU-subunit. Here, we describe the results obtained with a computational approach based on the Artificial Neural Network (ANN) paradigm that addresses the issue of tyrosine signal specificity, enabling the prediction of YXXO-MU interactions with accuracies over 90%. Therefore, this approach constitutes a powerful tool to help predict mechanisms of intracellular protein sorting. PMID- 22505812 TI - Temporal and quantitative analysis of atherosclerotic lesions in diet-induced hypercholesterolemic rabbits. AB - The diet-induced atherosclerotic rabbit is an ideal model for atherosclerosis study, but temporal changes in atherosclerotic development in hypercholesterolemic rabbits are poorly understood. Japanese white rabbits were fed a high-cholesterol diet to induce sustained hypercholesterolemia, and each group of 10-12 animals was then sacrificed at 6, 12, 16, or 28 weeks. The rabbit aortas were harvested, and the sizes of the gross and intima atherosclerotic lesions were quantified. The cellular component of macrophages (Mphis) and smooth muscle cells (SMCs) in aortic intimal lesions was also quantified by immunohistochemical staining, and the correlation between plasma cholesterol levels and the progress of atherosclerotic lesions was studied. The ultrastructure of the atherosclerotic lesions was observed by transmission electron microscopy (TEM). Widely variable atherosclerotic plaques were found from 6 weeks to 28 weeks, and the lesional progress was closely correlated with cholesterol exposure. Interestingly, a relatively reduced accumulation of Mphi, an increased numbers of SMCs, and a damaged endothelial layer were presented in advanced lesions. Moreover, SMCs were closely correlated with cholesterol exposure and lesional progress for the whole period. Cholesterol exposure directly determines atherosclerotic progress in a rabbit model, and the changes in the cellular component of advanced lesions may affect plaque stability in an atherosclerotic rabbit model. PMID- 22505809 TI - Dendritic cells the tumor microenvironment and the challenges for an effective antitumor vaccination. AB - Many clinical trials have been carried out or are in progress to assess the therapeutic potential of dendritic-cell- (DC-) based vaccines on cancer patients, and recently the first DC-based vaccine for human cancer was approved by the FDA. Herewith, we describe the general characteristics of DCs and different strategies to generate effective antitumor DC vaccines. In recent years, the relevance of the tumor microenvironment in the progression of cancer has been highlighted. It has been shown that the tumor microenvironment is capable of inactivating various components of the immune system responsible for tumor clearance. In particular, the effect of the tumor microenvironment on antigen-presenting cells, such as DCs, does not only render these immune cells unable to induce specific immune responses, but also turns them into promoters of tumor growth. We also describe strategies likely to increase the efficacy of DC vaccines by reprogramming the immunosuppressive nature of the tumor microenvironment. PMID- 22505813 TI - PET/CT imaging in mouse models of myocardial ischemia. AB - Different species have been used to reproduce myocardial infarction models but in the last years mice became the animals of choice for the analysis of several diseases, due to their short life cycle and the possibility of genetic manipulation. Many techniques are currently used for cardiovascular imaging in mice, including X-ray computed tomography (CT), high-resolution ultrasound, magnetic resonance imaging, and nuclear medicine procedures. Cardiac positron emission tomography (PET) allows to examine noninvasively, on a molecular level and with high sensitivity, regional changes in myocardial perfusion, metabolism, apoptosis, inflammation, and gene expression or to measure changes in anatomical and functional parameters in heart diseases. Currently hybrid PET/CT scanners for small laboratory animals are available, where CT adds high-resolution anatomical information. This paper reviews mouse models of myocardial infarction and discusses the applications of dedicated PET/CT systems technology, including animal preparation, anesthesia, radiotracers, and images postprocessing. PMID- 22505814 TI - Physical properties and biocompatibility of a core-sheath structure composite scaffold for bone tissue engineering in vitro. AB - Scaffolds play a critical role in the practical realization of bone tissue engineering. The purpose of this study was to assess whether a core-sheath structure composite scaffold possesses admirable physical properties and biocompatibility in vitro. A novel scaffold composed of poly(lactic-co-glycolic acid)/beta-tricalcium phosphate (PLGA/beta-TCP) skeleton wrapped with Type I collagen via low-temperature deposition manufacturing (LDM) was prepared, and bone mesenchymal stem cells (BMSCs) were used to evaluate cell behavior on the scaffold. PLGA/beta-TCP skeleton was chosen as the control group. Physical properties were evaluated by pority ratio, compressive strength, and Young's modulus. Scanning electron microscope (SEM) was used to study morphology of cells. Hydrophilicity was evaluated by water absorption ratio. Cell proliferation was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay (MTT). Osteogenic differentiation of BMSCs was evaluated by alkaline phosphates activity (ALP). The results indicated that physical properties of the novel scaffold were as good as those of the control group, hydrophilicity was observably better (P < 0.01) than that of control group, and abilities of proliferation and osteogenic differentiation of BMSCs on novel scaffold were significantly greater (P < 0.05) than those of control group, which suggests that the novel scaffold possesses preferable characteristics and have high value in bone tissue engineering. PMID- 22505815 TI - Structural insights into interaction between mammalian methionine sulfoxide reductase B1 and thioredoxin. AB - Maintenance of the cellular redox balance has vital importance for correcting organism functioning. Methionine sulfoxide reductases (Msrs) are among the key members of the cellular antioxidant defence system. To work properly, methionine sulfoxide reductases need to be reduced by their biological partner, thioredoxin (Trx). This process, according to the available kinetic data, represents the slowest step in the Msrs catalytic cycle. In the present paper, we investigated structural aspects of the intermolecular complex formation between mammalian MsrB1 and Trx. NMR spectroscopy and biocomputing were the two mostly used through the research approaches. The formation of NMR detectable MsrB1/Trx complex was monitored and studied in attempt to understand MsrB1 reduction mechanism. Using NMR data, molecular mechanics, protein docking, and molecular dynamics simulations, it was found that intermediate MsrB1/Trx complex is stabilized by interprotein beta-layer. The complex formation accompanied by distortion of disulfide bond within MsrB1 facilitates the reduction of oxidized MsrB1 as it is evidenced by the obtained data. PMID- 22505816 TI - Efficiency of manual scanning in recovering rare cellular events identified by fluorescence in situ hybridization: simulation of the detection of fetal cells in maternal blood. AB - Fluorescence in situ hybridization (FISH) and manual scanning is a widely used strategy for retrieving rare cellular events such as fetal cells in maternal blood. In order to determine the efficiency of these techniques in detection of rare cells, slides of XX cells with predefined numbers (1-10) of XY cells were prepared. Following FISH hybridization, the slides were scanned blindly for the presence of XY cells by different observers. The average detection efficiency was 84% (125/148). Evaluation of probe hybridization in the missed events showed that 9% (2/23) were not hybridized, 17% (4/23) were poorly hybridized, while the hybridization was adequate for the remaining 74% (17/23). In conclusion, manual scanning is a relatively efficient method to recover rare cellular events, but about 16% of the events are missed; therefore, the number of fetal cells per unit volume of maternal blood has probably been underestimated when using manual scanning. PMID- 22505817 TI - Vaxjo: a web-based vaccine adjuvant database and its application for analysis of vaccine adjuvants and their uses in vaccine development. AB - Vaccine adjuvants are compounds that enhance host immune responses to co administered antigens in vaccines. Vaxjo is a web-based central database and analysis system that curates, stores, and analyzes vaccine adjuvants and their usages in vaccine development. Basic information of a vaccine adjuvant stored in Vaxjo includes adjuvant name, components, structure, appearance, storage, preparation, function, safety, and vaccines that use this adjuvant. Reliable references are curated and cited. Bioinformatics scripts are developed and used to link vaccine adjuvants to different adjuvanted vaccines stored in the general VIOLIN vaccine database. Presently, 103 vaccine adjuvants have been curated in Vaxjo. Among these adjuvants, 98 have been used in 384 vaccines stored in VIOLIN against over 81 pathogens, cancers, or allergies. All these vaccine adjuvants are categorized and analyzed based on adjuvant types, pathogens used, and vaccine types. As a use case study of vaccine adjuvants in infectious disease vaccines, the adjuvants used in Brucella vaccines are specifically analyzed. A user friendly web query and visualization interface is developed for interactive vaccine adjuvant search. To support data exchange, the information of vaccine adjuvants is stored in the Vaccine Ontology (VO) in the Web Ontology Language (OWL) format. PMID- 22505818 TI - Reduced striatal dopamine transporters in people with internet addiction disorder. AB - In recent years, internet addiction disorder (IAD) has become more prevalent worldwide and the recognition of its devastating impact on the users and society has rapidly increased. However, the neurobiological mechanism of IAD has not bee fully expressed. The present study was designed to determine if the striatal dopamine transporter (DAT) levels measured by (99m)Tc-TRODAT-1 single photon emission computed tomography (SPECT) brain scans were altered in individuals with IAD. SPECT brain scans were acquired on 5 male IAD subjects and 9 healthy age matched controls. The volume (V) and weight (W) of bilateral corpus striatum as well as the (99m)Tc-TRODAT-1 uptake ratio of corpus striatum/the whole brain (Ra) were calculated using mathematical models. It was displayed that DAT expression level of striatum was significantly decreased and the V, W, and Ra were greatly reduced in the individuals with IAD compared to controls. Taken together, these results suggest that IAD may cause serious damages to the brain and the neuroimaging findings further illustrate IAD is associated with dysfunctions in the dopaminergic brain systems. Our findings also support the claim that IAD may share similar neurobiological abnormalities with other addictive disorders. PMID- 22505819 TI - Effects of ginsenoside Rb1 on skin changes. AB - Ginseng roots (Panax ginseng CA Meyer) have been used traditionally for the treatment, especially prevention, of various diseases in China, Korea, and Japan. Both experimental and clinical studies suggest ginseng roots to have pharmacological effects in patients with life-style-related diseases such as non insulin-dependent diabetic mellitus, atherosclerosis, hyperlipidemia, and hypertension. The topical use of ginseng roots to treat skin complaints including atopic suppurative dermatitis, wounds, and inflammation is also described in ancient Chinese texts; however, there have been relatively few studies in this area. In the present paper, we describe introduce the biological and pharmacological effects of ginsenoside Rb1 isolated from Red ginseng roots on skin damage caused by burn-wounds using male Balb/c mice (in vivo) and by ultraviolet B irradiation using male C57BL/6J and albino hairless (HR-1) mice (in vivo). Furthermore, to clarify the mechanisms behind these pharmacological actions, human primary keratinocytes and the human keratinocyte cell line HaCaT were used in experiments in vitro. PMID- 22505821 TI - Multiple metastasis-like bone lesions in scintigraphic imaging. AB - Multiple benign osteolytic lesions are very hard to differentiate from disseminated bone metastasis. Whole-body bone scintigraphy (WBBS) with technetium 99m methylene diphosphonate (Tc-99m MDP) demonstrates multiple lesions with increased uptake in any bone involved. Even combined with medical history and multiple imaging results, such as MRI and CT, the clinical diagnosis of metastasis lesion remains as a challenge. These clinical characteristics are similar to multiple malignant bone metastases and therefore affect the following treatment procedures. In this paper, we analyzed multiple benign osteolytic lesions, like eosinophilic granuloma (EG), multiple myeloma (MM), disseminated tuberculosis, fibrous dysplasia, or enchondroma, occurring in our daily clinical work and concluded that additional attention should be paid before giving the diagnosis of multiple bone metastases. PMID- 22505820 TI - Xenogenic esophagus scaffolds fixed with several agents: comparative in vivo study of rejection and inflammation. AB - Most infants with long-gap esophageal atresia receive an esophageal replacement with tissue from stomach or colon, because the native esophagus is too short for true primary repair. Tissue-engineered esophageal conducts could present an attractive alternative. In this paper, circular decellularized porcine esophageal scaffold tissues were implanted subcutaneously into Sprague-Dawley rats. Depending on scaffold cross-linking with genipin, glutaraldehyde, and carbodiimide (untreated scaffolds : positive control; bovine pericardium : gold standard), the number of infiltrating fibroblasts, lymphocytes, macrophages, giant cells, and capillaries was determined to quantify the host response after 1, 9, and 30 days. Decellularized esophagus scaffolds were shown to maintain native matrix morphology and extracellular matrix composition. Typical inflammatory reactions were observed in all implants; however, the cellular infiltration was reduced in the genipin group. We conclude that genipin is the most efficient and best tolerated cross-linking agent to attenuate inflammation and to improve the integration of esophageal scaffolds into its surrounding tissue after implantation. PMID- 22505822 TI - Improvement of HbA(1c) and stable weight loss 2 years after an outpatient treatment and teaching program for patients with type 2 diabetes without insulin therapy based on urine glucose self-monitoring. AB - OBJECTIVE: Long-term outcomes after participation in a structured diabetes treatment and teaching program (DTTP) for patients with diabetes without insulin use, primarily based upon postprandial urine glucose self-monitoring (UGSM). METHODS: A total of 126 patients took part in the DTTP in a university outpatient department in 2004-2005. We re-evaluated 119 (94.4%) at baseline and at 6 months, 12 months, and 24 months. Hemoglobin A(1c) (HbA(1c)) was DCCT adjusted. RESULTS: HbA(1c) decreased significantly 6 months after education from 7.33% (+/-1.59%) to 6.89% (+/-0.98%; P = 0.001 versus baseline) and was maintained for up to 12 months (7.02% +/- 1.07%; P = 0.017 versus baseline) as well as up to 24 months (6.96% +/- 1.06%; P = 0.005 versus baseline). Weight decreased from 92.5 kg at baseline to 90.3 kg at 24 months (P = 0.014). A total of 36.5% of patients not on insulin therapy preferred UGSM, whereas 23.5% preferred blood glucose monitoring, at 24 months. Glucose control was similar in both groups at 24 months (HbA(1c) UGSM 7.03 versus blood glucose monitoring 6.97%; P = 0.807). CONCLUSION: Participation in the DTTP resulted in long-term behavior modification. HbA(1c) of patients without insulin met the target 24 months after the DTTP, irrespective of the type of glucose self-monitoring. PMID- 22505823 TI - Practical approach to management of respiratory complications in neurological disorders. AB - Patients with certain neurological diseases are at increased risk of developing chest infections as well as respiratory failure due to muscular weakness. In particular, patients with certain neuromuscular disorders are at higher risk. These conditions are often associated with sleep disordered breathing. It is important to identify patients at risk of respiratory complications early in the course of their disease, although patients with neuromuscular disorders often present in the acute setting with respiratory involvement. This review of the respiratory complications of neurological disorders, with a particular focus on neuromuscular disorders, explores why this happens and looks at how to recognize, investigate, and manage these patients effectively. PMID- 22505824 TI - 38-year-old woman with recurrent abdominal pain, but no fever. AB - A 38-year-old woman presented with 2 days history of left-flank pain. She had similar episodes of abdominal pain as well as chest pain several times, but symptoms disappeared spontaneously. Each time she developed pain, there was no fever. After ruling out common causes of recurrent abdominal pain, familial Mediterranean fever (FMF) was considered as a potential diagnosis. Genetic tests revealed multiple heterozygote mutations, which may be associated with FMF. Patients with Mediterranean fever mutations may present with atypical presentations without fever, like in this case. Astute clinical suspicion is required to make an accurate diagnosis. PMID- 22505825 TI - Quality of informed consent for invasive procedures in central Saudi Arabia. AB - BACKGROUND: Informed consent is considered the most important step in clinical interventions. The aims of this study were (1) to assess the quality of informed consent for invasive procedures with regard to consent process and information given about risks and alternative treatments, and (2) to determine patients' attitude toward informed consent at King Abdulaziz Medical City, Riyadh, Saudi Arabia. METHODS: A cross-sectional study was conducted of 162 adult patients in different wards after undergoing surgery or invasive procedures within 1-2 days of signing the informed consent, using a previously validated interview questionnaire. Data on patients' characteristics, type of invasive procedure, and some informed consent-related issues were collected. Multiple linear regression analysis was used to identify the predictors of the percentage mean score of quality of informed consent, and significance was considered at P <= 0.05. RESULTS: The quality of informed consent was generally poor (% mean score = 50.98 +/- 17.49). About two-thirds of patients were told during the informed consent process that they have to sign merely as routine, 48% thought that if they refused the treatment plan they would lose the interest of the treating physician to help them, 42% thought that by saying no they would lose the good relationship with their physician, and 42.6% were not interested in having a copy of the informed consent document. Significantly higher quality was predicted when the physicians were the ones who explained the informed consent (t = 4.15, P < 0.001) and when informed consent was explained to younger patients (t = 2.754, P = 0.007). The overall attitude of the patients toward the process of informed consent was satisfactory (% mean score = 76.31 +/- 7.63). CONCLUSION: The results suggest either that patients are not aware of their rights or that physician paternalism is practiced in Saudi Arabia. Cultural barriers should not be an argument to diminish the role of informed consent. Further studies should focus on how the value of autonomy can be appreciated in the Saudi culture. PMID- 22505826 TI - Histamine H1 antagonists and clinical characteristics of febrile seizures. AB - BACKGROUND: The purpose of this study was to determine whether seizure susceptibility due to antihistamines is provoked in patients with febrile seizures. METHODS: The current descriptive study was carried out from April 2009 to February 2011 in 250 infants and children who visited the Madinah Maternity and Children's Hospital as a result of febrile convulsions. They were divided into two groups according to administration of antihistamines at the onset of fever. RESULTS: Detailed clinical manifestations were compared between patients with and without administration of antihistamines. The time from fever detection to seizure onset was significantly shorter in the antihistamine group than that in the nonantihistamine group, and the duration of seizures was significantly longer in the antihistamine group than in the nonantihistamine group. No significant difference was found in time from fever detection to seizure onset or seizure duration between patients who received a first-generation antihistamine and those who received a second-generation antihistamine. CONCLUSION: Due to their central nervous system effects, H1 antagonists should not be administered to patients with febrile seizures and epilepsy. Caution should be exercised regarding the use of histamine H1 antagonists in young infants, because these drugs could potentially disturb the anticonvulsive central histaminergic system. PMID- 22505827 TI - Clarithromycin-induced rhabdomyolysis: a case report. AB - Rhabdomyolysis is a clinical and laboratory syndrome that is caused by various etiologies, involving the skeletal muscle. Clarithromycin, like other macrolides, is an inhibitor of CYP450 3A4, the major enzyme responsible for the metabolism of several drugs, in particular some statins. Rhabdomyolysis related to macrolide statin interaction has previously been described. To date, rhabdomyolysis induced by clarithromycin has been described in only one previous report. We describe the case of a 90-year-old Caucasian male, admitted to the University Hospital of Pisa for dyspnea, who developed rhabdomyolysis associated with clarithromycin administration. PMID- 22505828 TI - Demographics and health care seeking behavior of Singaporean women with chronic constipation: implications for therapeutic management. AB - INTRODUCTION: Chronic constipation is significantly more prevalent in women than men in Singapore. We carried out a survey to study patient demographics, symptom prevalence, healthcare-seeking behavior, and patient satisfaction with available treatment options in women with chronic constipation. METHODS: Responses were collected predominantly via a web-based survey from a panel representative of Singapore's women population. Eligibility was established using a nine-question screener. RESULTS: A total of 1006 invited females took part in an online screener survey, of which 911 respondents did not meet the eligibility requirements for the chronic constipation survey. Of the total panelists consenting to participate (via both online and face-to-face interviews), 100 women met eligibility requirements and took the 22-question survey. Eligible respondents were skewed to younger patients but well mixed in terms of marital status. The majority of them were not keen on doing exercise and were working women, especially white collar females. The majority complained of straining and hard stools as the most common constipation symptoms (88% and 80% respectively) and rated constipation symptoms as severe or moderate. On average, respondents experienced constipation symptoms for 6 to 7 months in the last year. In more than two-thirds of respondents, constipation symptoms were frequent (at least 1 in 3 times). Most of the patients had attempted to treat constipation themselves and 80% had tried laxatives before visiting the doctor. Satisfaction with fiber supplements and laxatives was average and many of the users were not satisfied with their effect. Ineffectiveness and prolonged time taken for the treatment to take effect were the most common reasons for dissatisfaction. Nearly all respondents (97%) were interested in considering alternative prescriptive medication that is proven more effective. CONCLUSION: Chronic constipation symptoms in women are often severe and bothersome, and many patients are dissatisfied with available treatment options primarily because of lack of efficacy. PMID- 22505829 TI - Global decline in semen quality: ignoring the developing world introduces selection bias. AB - Multiple studies from around the world have suggested that semen quality is declining globally. However, all studies suffer from variable semen sampling criteria, selection bias with respect to the types of men volunteering to participate, and a bias with respect to a tendency to examine only samples from high-income countries. This heterogeneity in approaches, especially given the undersampling of rural and less affluent men from low-income countries, calls into question researchers' claims of universally declining semen norms. PMID- 22505830 TI - Feasibility of abdominoplasty with Cesarean section. AB - Abdominoplasty is an esthetic surgical procedure that restores abdominal contouring. Repeated pregnancies combined with advancing maternal age usually lead to lower abdominal skin redundancy and excess fat accumulation. Delivery via Cesarean section adds weakness to the lower abdominal wall muscles and yields a lower transverse Cesarean scar. Some patients request whether abdominoplasty can be performed with Cesarean section in the same setting, to avoid a future surgery. This study was designed to evaluate the outcome of combined abdominoplasty with Cesarean section. The study included 50 pregnant women from September 2009 to June 2010 with an average follow-up period of 9 months. Nine patients (18%) developed wound infection; three of them (6%) developed wound dehiscence. Six patients (12%) developed lower abdominal skin necrosis; three of them (6%) were treated conservatively and healed by secondary intention, while surgical debridement and secondary sutures were needed in the other three patients (6%). Residual abdominal skin redundancy in nine patients (18%), outward bulging of the abdomen and lack of waist definition in 16 patients (32%), and outward bulging of the umbilicus in twelve patients (24%) were the reported unesthetic results. The results were compared with results of 80 abdominoplasties in nonpregnant women. PMID- 22505831 TI - Comparing the World Health Organization-versus China-recommended protocol for first-trimester medical abortion: a retrospective analysis. AB - OBJECTIVE: To compare the effectiveness, in terms of complete abortion, of the World Health Organization (WHO)- and the China-recommended protocol for first trimester medical abortion. METHODS: A retrospective analysis of clinical data from women presenting for first trimester medical abortion between January 2009 and August 2010 at reproductive health clinics in Qingdao, Xi'an, Nanjing, Nanning, and Zhengzhou was conducted. One clinic in Qingdao administered the WHO recommended protocol (200 mg mifepristone orally followed by 0.8 mg misoprostol buccally 36-48 hours later). Four clinics in the other locations provided the China-recommended procedure (Day 1: 50 mg of mifepristone in the morning, 25 mg in the afternoon; Day 2: 50 mg of mifepristone in the morning, 25 mg in the afternoon; Day 3: 0.6 mg oral misoprostol). Data on reproductive and demographic characteristics were extracted from clinic records, and complete termination was determined on day 14 (post-mifepristone administration). RESULTS: A total of 337 women underwent early medical abortion (167 WHO- and 170 China-recommended procedures). Complete abortion was significantly higher among women who had the WHO protocol than those who received the China protocol (91.0% vs 77.7%, respectively; P < 0.001). Women using the China-recommended protocol were three times more likely to require an additional dose of misoprostol than women using the WHO protocol (21.8% vs 7.8%, respectively; P < 0.001), and had significantly more bleeding on the day of misoprostol administration (12.5 mL vs 18.5 mL; P < 0.001). CONCLUSION: This clinical audit provides preliminary evidence suggesting the WHO-recommended protocol may be more effective than the China-recommended protocol for early medical abortion. A larger scale study is necessary to compare the methods' effectiveness and acceptability. PMID- 22505832 TI - Incorporating bazedoxifene/conjugated estrogens into the current paradigm of menopausal therapy. AB - Many women experience bothersome vasomotor and vaginal symptoms during the menopausal transition. Decreasing levels of estrogens during menopause are also associated with reduced bone density and an increased risk of osteoporosis. Combined estrogen/progestin therapy (hormone therapy) effectively treats menopausal symptoms and prevents bone loss, but has been associated with some safety and tolerability concerns. A novel menopausal therapy is the tissue selective estrogen complex, which pairs a selective estrogen receptor modulator with one or more estrogens. In preclinical studies, the tissue selective estrogen complex partnering bazedoxifene (BZA) with conjugated estrogens (CE) antagonized stimulation of breast and endometrial tissue, reduced vasomotor instability, and preserved bone mass in rat and mouse models. The specific attributes seen with BZA/CE were different from those observed with other selective estrogen receptor modulator/estrogen pairings. BZA/CE has undergone clinical evaluation in the Phase III Selective estrogens, Menopause, And Response to Therapy (SMART) trials in postmenopausal women with an intact uterus. Of the various doses of BZA/CE evaluated, BZA 20 mg/CE 0.45 mg and 0.625 mg were associated with a low incidence of endometrial hyperplasia (<1%) similar to placebo, and showed significant improvements in hot flushes and vulvar/vaginal symptoms and increases in bone mineral density. BZA 20 mg/CE 0.45 mg and 0.625 mg were associated with a low incidence of breast-related adverse events and demonstrated no difference from placebo in age-related changes in mammographic breast density. Both BZA/ CE doses showed a favorable tolerability profile, with no increases in uterine bleeding or breast tenderness, and had positive effects on metabolic parameters and quality of life. BZA/CE may be a promising alternative to hormone therapy for the treatment of menopausal symptoms and prevention of osteoporosis in nonhysterectomized postmenopausal women. PMID- 22505833 TI - Maternal demand for cesarean section: perception and willingness to request by Nigerian antenatal clients. AB - BACKGROUND: Contrary to the widely reported aversion to cesarean section in the West African subregion, maternal demand for cesarean section (MDCS) seems to be on the increase, and there is little evidence to explain this trend. The purpose of this study was to determine the perception and attitudes of Nigerian antenatal clients towards MDCS, their willingness to request MDCS, and the relationship between willingness to request MDCS and sociodemographic characteristics. METHODS: A cross-sectional survey was undertaken among 843 antenatal clients at Agbongbon/Orayan primary health care centers (PHCs), Adeoyo Maternity Hospital (SHC), and UCH Ibadan (THC), representing the three different levels of health care in Nigeria, ie, primary, secondary, and tertiary. RESULTS: The proportion of women aware of MDCS was 39.6%. Predictors of awareness were education and type of health facility. Women from THC and those with tertiary education and above were more likely to be aware of MDCS than others (P = 0.001). Doctors were major sources of information on MDCS (30.8%) as well as friends (24.3%). Common reasons reported for MDCS were fear of labor pains (68.9%), and fear of poor labor outcome (60.1%), and fear of fecal (20.2%) and urinary incontinence (16.8%). More women from the THC than other facilities believed that requests for MDCS should be granted (P < 0.001). However, willingness to request MDCS was low (6.6%). More than 50% of those willing to request MDCS would likely be criticized, mainly by their husbands. On multiple logistic regression, respondents at the THC were significantly more likely than those at the SHC or the PHCs to request cesarean section and to favor a woman's right of autonomy to choose her mode of delivery. CONCLUSION: The decision for MDCS is a difficult one, because willingness is low and criticism by partners of those who choose MDCS is high. Provision of epidural anesthesia and improved safety of vaginal delivery is recommended. This may prevent Nigerian women from making a difficult choice for MDCS based on fear of pain and poor labor outcome. The role of the male partner should be taken into consideration in order to make sustainable policies or guidelines for MDCS in developing countries. PMID- 22505834 TI - Medical management of recurrent endometrioma with long-term norethindrone acetate. AB - PURPOSE: Evaluate the efficacy of norethindrone acetate in the resolution of symptoms and regression of recurrent endometrioma. PATIENTS AND METHODS: Retrospective chart review at SUNY Downstate Medical Center of patients with a history of surgical excision of endometrioma (with histological confirmation) and recurrent endometrioma (demonstrated by strict sonographic criterion of endometrioma) who were willing to undergo follow-up. Patients were prescribed norethindrone acetate to be taken daily with follow-up sonograms until cysts regressed. Statistical analysis included Student's t-test and a simple linear regression model to assess cyst regression over time during treatment. RESULTS: Degree of pain was significantly lower on treatment when compared to baseline (P < 0.00001). Cyst size was significantly smaller in as little as 3 months (P < 0.0001). Average rate of regression with continuous treatment was 0.025 +/- 0.015 cm/day. Total mean +/- standard deviation regression time is 10.28 +/- 8.25 months. CONCLUSION: Norethindrone acetate was effective in eradicating symptoms and producing complete regression of recurrent endometriomas. It should be considered for patients who are likely to adhere to a prolonged treatment regimen and comply with recommendations for surveillance with serial sonograms. PMID- 22505835 TI - Cumulative Incidence Association Models for Bivariate Competing Risks Data. AB - Association models, like frailty and copula models, are frequently used to analyze clustered survival data and evaluate within-cluster associations. The assumption of noninformative censoring is commonly applied to these models, though it may not be true in many situations. In this paper, we consider bivariate competing risk data and focus on association models specified for the bivariate cumulative incidence function (CIF), a nonparametrically identifiable quantity. Copula models are proposed which relate the bivariate CIF to its corresponding univariate CIFs, similarly to independently right censored data, and accommodate frailty models for the bivariate CIF. Two estimating equations are developed to estimate the association parameter, permitting the univariate CIFs to be estimated either parametrically or nonparametrically. Goodness-of-fit tests are presented for formally evaluating the parametric models. Both estimators perform well with moderate sample sizes in simulation studies. The practical use of the methodology is illustrated in an analysis of dementia associations. PMID- 22505836 TI - In memory of James F. Crow (1916-2012), a life dedicated to population genetics; with an updated list of his publications. PMID- 22505837 TI - Automation of AMOEBA polarizable force field parameterization for small molecules. AB - A protocol to generate parameters for the AMOEBA polarizable force field for small organic molecules has been established, and polarizable atomic typing utility, Poltype, which fully automates this process, has been implemented. For validation, we have compared with quantum mechanical calculations of molecular dipole moments, optimized geometry, electrostatic potential, and conformational energy for a variety of neutral and charged organic molecules, as well as dimer interaction energies of a set of amino acid side chain model compounds. Furthermore, parameters obtained in gas phase are substantiated in liquid-phase simulations. The hydration free energy (HFE) of neutral and charged molecules have been calculated and compared with experimental values. The RMS error for the HFE of neutral molecules is less than 1 kcal/mol. Meanwhile, the relative error in the predicted HFE of salts (cations and anions) is less than 3% with a correlation coefficient of 0.95. Overall, the performance of Poltype is satisfactory and provides a convenient utility for applications such as drug discovery. Further improvement can be achieved by the systematic study of various organic compounds, particularly ionic molecules, and refinement and expansion of the parameter database. PMID- 22505838 TI - Fluorous-Assisted One-Pot Oligosaccharide Synthesis. AB - A new method for oligosaccharide assembly that combines the advantages of one-pot synthesis and fluorous separation is described. After one-pot glycosylations are completed, a fluorous tag is introduced into the reaction mixture to selectively "catch" the desired oligosaccharide, which is rapidly separated from non-fluorous impurities by fluorous solid-phase extraction (F-SPE). Subsequent "release" of the fluo rous tag and F-SPE achieved the purification of the desired oligosaccharide without the use of time- and solvent-consuming silica gel chromatography. Linear and branched oligosaccharides have been synthesized with this approach in just a few hours (for the overall oligosaccharide assembly and purification process). PMID- 22505839 TI - Same-Sex Sexuality and Adolescent Psychological Well-Being: The influence of sexual orientation, early reports of same-sex attraction, and gender. AB - Emerging research has shown that those of sexual-minority (SM) status (i.e., those exhibiting same-sex sexuality) report lower levels of psychological well being. This study aimed to assess whether this relation is largely in place by the onset of adolescence, as it is for other social statuses, or whether it continues to emerge over the adolescent years, a period when SM youth face numerous challenges. Moreover, the moderating influence of sexual orientation (identification), early (versus later) reports of same-sex attractions, and gender were also examined. Using data from Add Health, multiple-group latent growth curve analyses were conducted to examine growth patterns in depressive affect and self-esteem. Results suggested that psychological well-being disparities between SM and non-SM were generally in place by early adolescence. For many, the remainder of adolescence was a recovery period when disparities narrowed over time. Early and stable reporting of same-sex attractions was associated with a greater initial deficit in psychological well-being, especially among males, but it was also associated with more rapid recovery. Independent of the timing and stability of reported same-sex attractions over time, actual sexual orientation largely failed to moderate the relation between SM status and psychological well-being. Importantly, the sizable yet understudied subgroup that identified as heterosexual but reported same-sex attractions appeared to be at substantial risk. PMID- 22505841 TI - Purification of sulphate leach liquor of spent Raneynickel catalyst containing Al and Ni by solvent extraction with organophosphorus-based extractants. AB - Solvent extraction (SX) separation of Al from Ni sulphate leach liquor (LL) of spent Raneynickel catalyst containing 0.12 M Al and 1.448 M Ni using organophosphorus extractants has been investigated. Optimization of process conditions includes aqueous pH, extractant concentration, phase ratio, and stripping. Comparison of Al extraction efficiency with 0.45 M extractant concentration for TOPS 99, PC 88 A, and Cyanex 272 at an equilibrium pH of 2.23 was 81.8%, 98.6%, and 75%, respectively. The corresponding coextraction of Ni was 0.65, 0.6, and 0.9. Among the three extractants screened, PC 88A showed better extraction efficiency for Al at lower pH values than the others. Using 0.45 M PC 88 A, extraction isotherm was obtained at an aqueous-to-organic (A : O) phase ratio of 1 : 1-3 and O : A ratio of 1 : 1-5, which predicted possible separation of Al in 2 stages at A/O ratio of 2. Quantitative stripping was achieved by H(2)SO(4). PMID- 22505840 TI - Cysteine Protease Cathepsins in Atherosclerosis and Abdominal Aortic Aneurysm. AB - Extracellular matrix remodeling is an important mechanism in the initiation and progression of cardiovascular diseases. Cysteine protease cathepsins are among the important proteases that affect major events in the pathogenesis of atherosclerosis and abdominal aortic aneurysm, including smooth muscle cell transmigration through elastic lamina, macrophage foam cell formation, vascular cell and macrophage apoptosis, and plaque rupture. These events have been studied in cathepsin deficiencies and cathepsin inhibitor deficiencies in mice and have provided invaluable insights regarding the roles of cathepsins in cardiovascular diseases. Pharmacological inhibitions for cathepsins are under evaluation for other human diseases and may be used as clinical treatments for cardiovascular diseases in the near future. This article reviews different mechanisms for cathepsins in atherosclerosis and abdominal aortic aneurysm that could be targeted by selective cathepsin inhibitors. PMID- 22505842 TI - Sexual Health Information Networks: What are Urban African American Youth Learning? AB - This qualitative study examined sexual health information networks among urban African American youth living in low-income communities. The authors identified sources, message content, and utility of messages about sex and sexual health in a sample of 15-17-year olds (N = 81). Youth received sexual health information from a variety of sources. Messages from parents and sex education had high utility, whereas messages from the Internet and religion had low utility. Four information network patterns were identified, suggesting considerable variation in how youth are socialized regarding sex. Findings suggest that sexual information networks have the potential to affect sexual health and development. PMID- 22505843 TI - Influences on Sexual Partnering Among African American Adolescents With Concurrent Sexual Relationships. AB - Adolescents often engage in concurrent sexual partnerships as part of a developmental process of gaining experience with sexuality. The authors qualitatively examined patterns of concurrency and variation in normative and motivational influences on this pattern of sexual partnering among African American adolescents (31 males; 20 females), ages 15 to 17 years. Using content analysis, gender and contextual differences in social norms and motivations for concurrency were explored. Findings describe the normative influences on adolescent males and females with regard to sexual concurrency and the transfer of these norms from one generation to the next. PMID- 22505845 TI - Using grizzly bears to assess harvest-ecosystem tradeoffs in salmon fisheries. AB - Implementation of ecosystem-based fisheries management (EBFM) requires a clear conceptual and quantitative framework for assessing how different harvest options can modify benefits to ecosystem and human beneficiaries. We address this social ecological need for Pacific salmon fisheries, which are economically valuable but intercept much of the annual pulse of nutrient subsidies that salmon provide to terrestrial and aquatic food webs. We used grizzly bears, vectors of salmon nutrients and animals with densities strongly coupled to salmon abundance, as surrogates for "salmon ecosystem" function. Combining salmon biomass and stock recruitment data with stable isotope analysis, we assess potential tradeoffs between fishery yields and bear population densities for six sockeye salmon stocks in Bristol Bay, Alaska, and British Columbia (BC), Canada. For the coastal stocks, we find that both bear densities and fishery yields would increase substantially if ecosystem allocations of salmon increase from currently applied lower to upper goals and beyond. This aligning of benefits comes at a potential cost, however, with the possibility of forgoing harvests in low productivity years. In contrast, we detect acute tradeoffs between bear densities and fishery yields in interior stocks within the Fraser River, BC, where biomass from other salmon species is low. There, increasing salmon allocations to ecosystems would benefit threatened bear populations at the cost of reduced long-term yields. To resolve this conflict, we propose an EBFM goal that values fisheries and bears (and by extension, the ecosystem) equally. At such targets, ecosystem benefits are unexpectedly large compared with losses in fishery yields. To explore other management options, we generate tradeoff curves that provide stock-specific accounting of the expected loss to fishers and gain to bears as more salmon escape the fishery. Our approach, modified to suit multiple scenarios, provides a generalizable method to resolve conflicts over shared resources in other systems. PMID- 22505844 TI - A feedback loop between dynamin and actin recruitment during clathrin-mediated endocytosis. AB - Clathrin-mediated endocytosis proceeds by a sequential series of reactions catalyzed by discrete sets of protein machinery. The final reaction in clathrin mediated endocytosis is membrane scission, which is mediated by the large guanosine triophosphate hydrolase (GTPase) dynamin and which may involve the actin-dependent recruitment of N-terminal containing BIN/Amphiphysin/RVS domain containing (N-BAR) proteins. Optical microscopy has revealed a detailed picture of when and where particular protein types are recruited in the ~20-30 s preceding scission. Nevertheless, the regulatory mechanisms and functions that underpin protein recruitment are not well understood. Here we used an optical assay to investigate the coordination and interdependencies between the recruitment of dynamin, the actin cytoskeleton, and N-BAR proteins to individual clathrin-mediated endocytic scission events. These measurements revealed that a feedback loop exists between dynamin and actin at sites of membrane scission. The kinetics of dynamin, actin, and N-BAR protein recruitment were modulated by dynamin GTPase activity. Conversely, acute ablation of actin dynamics using latrunculin-B led to a ~50% decrease in the incidence of scission, an ~50% decrease in the amplitude of dynamin recruitment, and abolished actin and N-BAR recruitment to scission events. Collectively these data suggest that dynamin, actin, and N-BAR proteins work cooperatively to efficiently catalyze membrane scission. Dynamin controls its own recruitment to scission events by modulating the kinetics of actin and N-BAR recruitment to sites of scission. Conversely actin serves as a dynamic scaffold that concentrates dynamin and N-BAR proteins at sites of scission. PMID- 22505846 TI - How much lox is a grizzly bear worth? AB - Using grizzly bears as surrogates for "salmon ecosystem" function, the authors develop a generalizable ecosystem-based management framework that enables decision makers to quantify ecosystem-harvest tradeoffs between wild and human recipients of natural resources like fish. PMID- 22505848 TI - Hormonal signal amplification mediates environmental conditions during development and controls an irreversible commitment to adulthood. AB - Many animals can choose between different developmental fates to maximize fitness. Despite the complexity of environmental cues and life history, different developmental fates are executed in a robust fashion. The nematode Caenorhabditis elegans serves as a powerful model to examine this phenomenon because it can adopt one of two developmental fates (adulthood or diapause) depending on environmental conditions. The steroid hormone dafachronic acid (DA) directs development to adulthood by regulating the transcriptional activity of the nuclear hormone receptor DAF-12. The known role of DA suggests that it may be the molecular mediator of environmental condition effects on the developmental fate decision, although the mechanism is yet unknown. We used a combination of physiological and molecular biology techniques to demonstrate that commitment to reproductive adult development occurs when DA levels, produced in the neuroendocrine XXX cells, exceed a threshold. Furthermore, imaging and cell ablation experiments demonstrate that the XXX cells act as a source of DA, which, upon commitment to adult development, is amplified and propagated in the epidermis in a DAF-12 dependent manner. This positive feedback loop increases DA levels and drives adult programs in the gonad and epidermis, thus conferring the irreversibility of the decision. We show that the positive feedback loop canalizes development by ensuring that sufficient amounts of DA are dispersed throughout the body and serves as a robust fate-locking mechanism to enforce an organism-wide binary decision, despite noisy and complex environmental cues. These mechanisms are not only relevant to C. elegans but may be extended to other hormonal-based decision-making mechanisms in insects and mammals. PMID- 22505847 TI - A novel 3-hydroxysteroid dehydrogenase that regulates reproductive development and longevity. AB - Endogenous small molecule metabolites that regulate animal longevity are emerging as a novel means to influence health and life span. In C. elegans, bile acid-like steroids called the dafachronic acids (DAs) regulate developmental timing and longevity through the conserved nuclear hormone receptor DAF-12, a homolog of mammalian sterol-regulated receptors LXR and FXR. Using metabolic genetics, mass spectrometry, and biochemical approaches, we identify new activities in DA biosynthesis and characterize an evolutionarily conserved short chain dehydrogenase, DHS-16, as a novel 3-hydroxysteroid dehydrogenase. Through regulation of DA production, DHS-16 controls DAF-12 activity governing longevity in response to signals from the gonad. Our elucidation of C. elegans bile acid biosynthetic pathways reveals the possibility of novel ligands as well as striking biochemical conservation to other animals, which could illuminate new targets for manipulating longevity in metazoans. PMID- 22505849 TI - Steroids as central regulators of organismal development and lifespan. AB - Larvae of the nematode Caenorhabditis elegans must choose between reproductive development and dauer diapause. This decision is based on sensing of environmental inputs and dauer pheromone, a small molecule signal that serves to monitor population density. These signals are integrated via conserved neuroendocrine pathways that converge on steroidal ligands of the nuclear receptor DAF-12, a homolog of the mammalian vitamin D receptor and liver X receptor. DAF-12 acts as the main switch between gene expression programs that drive either reproductive development or dauer entry. Extensive studies in the past two decades demonstrated that biosynthesis of two bile acid-like DAF-12 ligands, named dafachronic acids (DA), controls developmental fate. In this issue of PLoS Biology, Wollam et al. showed that a conserved steroid-modifying enzyme, DHS-16, introduces a key feature in the structures of the DAF-12 ligands, closing a major gap in the DA biosynthesis pathway. The emerging picture of DA biosynthesis in C. elegans enables us to address a key question in the field: how are complex environmental signals integrated to enforce binary, organism-wide decisions on developmental fate? Schaedel et al. demonstrated that pheromone and DA serve as competing signals, and that a positive feedback loop based on regulation of DA biosynthesis ensures organism-wide commitment to reproductive development. Considering that many components of DA signaling are highly conserved, ongoing studies in C. elegans may reveal new aspects of bile acid function and lifespan regulation in mammals. PMID- 22505850 TI - The imperative to share clinical study reports: recommendations from the Tamiflu experience. PMID- 22505851 TI - Open clinical trial data for all? A view from regulators. PMID- 22505852 TI - Is food insecurity associated with HIV risk? Cross-sectional evidence from sexually active women in Brazil. AB - BACKGROUND: Understanding how food insecurity among women gives rise to differential patterning in HIV risks is critical for policy and programming in resource-limited settings. This is particularly the case in Brazil, which has undergone successive changes in the gender and socio-geographic composition of its complex epidemic over the past three decades. We used data from a national survey of Brazilian women to estimate the relationship between food insecurity and HIV risk. METHODS AND FINDINGS: We used data on 12,684 sexually active women from a national survey conducted in Brazil in 2006-2007. Self-reported outcomes were (a) consistent condom use, defined as using a condom at each occasion of sexual intercourse in the previous 12 mo; (b) recent condom use, less stringently defined as using a condom with the most recent sexual partner; and (c) itchy vaginal discharge in the previous 30 d, possibly indicating presence of a sexually transmitted infection. The primary explanatory variable of interest was food insecurity, measured using the culturally adapted and validated Escala Brasiliera de Seguranca Alimentar. In multivariable logistic regression models, severe food insecurity with hunger was associated with a reduced odds of consistent condom use in the past 12 mo (adjusted odds ratio [AOR] = 0.67; 95% CI, 0.48-0.92) and condom use at last sexual intercourse (AOR = 0.75; 95% CI, 0.57-0.98). Self-reported itchy vaginal discharge was associated with all categories of food insecurity (with AORs ranging from 1.46 to 1.94). In absolute terms, the effect sizes were large in magnitude across all outcomes. Underweight and/or lack of control in sexual relations did not appear to mediate the observed associations. CONCLUSIONS: Severe food insecurity with hunger was associated with reduced odds of condom use and increased odds of itchy vaginal discharge, which is potentially indicative of sexually transmitted infection, among sexually active women in Brazil. Interventions targeting food insecurity may have beneficial implications for HIV prevention in resource-limited settings. PMID- 22505853 TI - Sleep medicine: the shot heard around the world. PMID- 22505854 TI - Incidence of restless legs syndrome and its correlates. AB - BACKGROUND: Restless legs syndrome (RLS) is a common sensorimotor disorder whose incidence is not known. The aim of the study was to determine the incidence and correlates of RLS in a population-based sample. METHODS: We obtained data from the Tucson Cohort of the Sleep Heart Health Study, a prospective multicenter study. This cohort included 535 participants aged >= 40 years, who answered questions regarding RLS on the 2002 and 2006 sleep surveys. For this study, RLS was defined as the presence of all 4 International RLS Study Group criteria, with symptoms occurring >= 5 days/month and associated with at least moderate distress. RESULTS: Mean age of the predominantly Caucasian (90.8%) participants on the 2002 survey was 59.8 +/- 9.7 years; 52.2% were women. RLS prevalence was 4.1% in 2002 and 7.7% in 2006. The yearly incidence of RLS was 1.7% (6.6% over 4 years). Multivariate analyses demonstrated that estrogen use (OR = 2.5, 95% CI: 1.17-5.10) and self-reported obstructive lung disease (OR = 2.8, 95% CI: 1.37 5.83) were independent risk factors predicting incident RLS. Incident RLS was associated with higher prevalence of insomnia (26.5% vs. 7.6%, p = 0.001), increased sleepiness (38.2% vs. 22%, p = 0.036); and higher sleeping pill use in 2006 (23.5% vs. 9.7%, p = 0.019). CONCLUSION: The incidence of RLS in this population sample was 1.7% per year. Use of estrogen and history of obstructive lung disease were associated with a significantly higher incidence of RLS. RLS, in turn, was associated with insomnia and increased sleepiness. PMID- 22505855 TI - Restless legs syndrome: what have we learned from prevalence studies and how will incidence studies further clinical knowledge? PMID- 22505856 TI - Characteristics of REM sleep behavior disorder in childhood. AB - STUDY OBJECTIVE: To describe our experience regarding the clinical and polysomnographic features of REM sleep behavior disorder (RBD) in childhood. METHODS: This was a retrospective chart review of children and adolescents with RBD and REM sleep without atonia. Demographics, and clinical and polysomnographic information were tabulated. Our findings were compared with those in the existing literature. RESULTS: The 15 subjects identified (13 RBD and 2 having REM sleep without atonia) had a mean age at diagnosis of 9.5 years (range 3-17 years); 11/15 (73%) were male. Nightmares were reported in 13/15 and excessive daytime sleepiness in 6/15. Two children had caused bodily harm to bedmate siblings. Comorbidities, which were multiple in some subjects, included anxiety (8/15), attention deficit disorder (10/15), nonspecific developmental delay (6/15), Smith Magenis syndrome (1/15), pervasive developmental disorder (1/15), narcolepsy (1/15), idiopathic hypersomnia (1/15), and Moebius Syndrome (1/15). Abnormal MRI scans were seen in 5/8 evaluated subjects. Treatments consisted of clonazepam (10/15), melatonin (2/15), and discontinuation of a tricyclic agent (1/15), with a favorable response in 11 of 13. Two of 15 patients with REM sleep without atonia did not require pharmacotherapy. CONCLUSIONS: RBD in children may be associated with neurodevelopmental disabilities, narcolepsy, or medication use. It seems to be modestly responsive to benzodiazepines or melatonin. The etiology is distinct from that of common childhood arousal parasomnias and RBD in adults; congenital and neurodevelopmental disorders, medication effect, and narcolepsy coexisted in some, but none had an extrapyramidal neurodegenerative disorder. PMID- 22505857 TI - Diagnostic delay in REM sleep behavior disorder (RBD). AB - STUDY OBJECTIVES: REM sleep behavior disorder (RBD) is a parasomnia in which normal muscle atonia of REM sleep is lost. The aim of this study was to confirm if diagnostic delay exists in RBD and identify any contributing factors. METHODS: A database was compiled of 49 patients with RBD seen at a tertiary referral center from 2005 to 2011 by retrospective review of referral letters and polysomnographic (PSG) reports. Patients with comorbid narcolepsy were excluded. A questionnaire was sent to investigate diagnostic delay, management, and comorbidities. RESULTS: Mean diagnostic delay was 8.7 +/- 11 (median 4.5, IQR 1.75-11.75) years in 30 questionnaire responders. Common reasons for diagnostic delay included belief that symptoms were not serious enough to consult a doctor (59%), mild or infrequent occurrence of sleep behavior (56%), belief that symptoms may resolve (47%), and lack of knowledge of treatment options (47%). The bed partner was an important influence, with the decision to seek medical attention being made jointly by the patient and partner in 47%. CONCLUSIONS: This study has demonstrated the existence of significant diagnostic delay in RBD, mainly due to lack of understanding of the disorder and its treatment by patients and members of the medical profession. PMID- 22505858 TI - Spanish translation and cross-language validation of a sleep habits questionnaire for use in clinical and research settings. AB - STUDY OBJECTIVES: To translate, back-translate and cross-language validate (English/Spanish) the Sleep Heart Health Study Sleep Habits Questionnaire for use with Spanish-speakers in clinical and research settings. METHODS: Following rigorous translation and back-translation, this cross-sectional cross-language validation study recruited bilingual participants from academic, clinic, and community-based settings (N = 50; 52% women; mean age 38.8 +/- 12 years; 90% of Mexican heritage). Participants completed English and Spanish versions of the Sleep Habits Questionnaire, the Epworth Sleepiness Scale, and the Acculturation Rating Scale for Mexican Americans II one week apart in randomized order. Psychometric properties were assessed, including internal consistency, convergent validity, scale equivalence, language version intercorrelations, and exploratory factor analysis using PASW (Version18) software. Grade level readability of the sleep measure was evaluated. RESULTS: All sleep categories (duration, snoring, apnea, insomnia symptoms, other sleep symptoms, sleep disruptors, restless legs syndrome) showed Cronbach alpha, Spearman-Brown coefficients and intercorrelations >= 0.700, suggesting robust internal consistency, correlation, and agreement between language versions. The Epworth correlated significantly with snoring, apnea, sleep symptoms, restless legs, and sleep disruptors) on both versions, supporting convergent validity. Items loaded on 4 factors accounted for 68% and 67% of the variance on the English and Spanish versions, respectively. CONCLUSIONS: The Spanish-language Sleep Habits Questionnaire demonstrates conceptual and content equivalency. It has appropriate measurement properties and should be useful for assessing sleep health in community-based clinics and intervention studies among Spanish-speaking Mexican Americans. Both language versions showed readability at the fifth grade level. Further testing is needed with larger samples. PMID- 22505859 TI - Spousal involvement in CPAP: does pressure help? AB - STUDY OBJECTIVES: Continuous positive airway pressure (CPAP) improves sleep and quality of life for both patients with obstructive sleep apnea (OSA) and their spouses. However, few studies have investigated spousal involvement in treatment adherence. Aims of this observational study were to assess perceptions of spousal involvement and evaluate associations between involvement and adherence. METHODS: Spousal involvement in CPAP adherence was assessed in 23 married male OSA patients after the first week of treatment. At 3 months, 16 participants completed a second assessment of spousal involvement. Types of involvement assessed included positive (e.g., encouraging), negative (e.g., blaming), collaboration (e.g., working together), and one-sided (e.g., asking). An interpersonal measure of supportive behaviors was also administered at 3 months to evaluate the interpersonal qualities of spousal involvement types. Objective CPAP adherence data were available for 14 participants. RESULTS: Average frequency of spousal involvement ratings were low for each involvement type and only negative spousal involvement frequency decreased at 3 month follow-up (p = 0.003). Perceptions of collaborative spousal involvement were associated with higher CPAP adherence at 3 months (r = 0.75, p = 0.002). Positive, negative and one-sided involvement were not associated with adherence. Collaborative spousal involvement was associated with moderately warm and controlling interpersonal behaviors (affiliation, r = 0.55, p = 0.03, dominance r = 0.47, p = 0.07). CONCLUSIONS: Patients reported low frequency but consistent and diverse perceptions of spousal involvement in CPAP over the first 3 months of treatment. Perceptions of collaborative spousal involvement were the only type associated with adherence and represent moderately warm and controlling interpersonal behavior. Interventions to increase spousal collaboration in CPAP may improve adherence. PMID- 22505860 TI - Sleep apnea is related to the atherogenic phenotype, lipoprotein subclass B. AB - STUDY OBJECTIVES: Sleep apnea has been implicated as an independent risk factor for atherosclerotic coronary artery disease (CAD). An association between the severity of sleep apnea and total cholesterol levels has previously been reported. However, the association with small dense low density lipoprotein (LDL) cholesterol concentration (subclass B), one of the strongest predictors of atherosclerosis, is unknown. We examined the relationship between sleep apnea and LDL subclass B, considering body size. METHODS: This is a cross-sectional observational cohort of participants enrolled in a cardiovascular health study. Sleep apnea was assessed with a validated portable monitor. Lipid panels included total cholesterol, triglycerides, high density lipoprotein cholesterol, LDL cholesterol, and LDL subclasses A, B, and A/B. Sleep apnea was analyzed categorically using the apnea hypopnea index (AHI). RESULTS: A total of 519 participants were evaluated. Mean age was 58.7 +/- 7.4 years; BMI was 29.6 +/- 5.7; 65% were female; 59% were Caucasian, and 37% were African American. Among participants with abnormal waist circumference by ATP III criteria, moderate to severe sleep apnea (AHI >= 25) was not independently associated with LDL subclass B. In contrast, among participants with normal waist circumference, moderate to severe sleep apnea was associated with 4.5-fold odds of having LDL subclass B. CONCLUSIONS: Sleep apnea is independently associated with an atherogenic phenotype (LDL subclass B) in non-obese individuals. The association between sleep apnea and LDL subclass B in those with normal waist circumference may account, in part, for the increased risk of atherosclerosis and subsequent vascular events. PMID- 22505861 TI - Neurophysiological two-channel polysomnographic device in the diagnosis of sleep apnea. AB - STUDY OBJECTIVE: Our objective was to evaluate a portable device (Somte, Compumedics, Australia), which incorporates 2 neurophysiological channels (electroencephalography and electrooculography) with cardiorespiratory monitoring for the diagnosis of obstructive sleep apnea (OSA). METHOD: Full polysomnography (PSG) and Somte recordings were simultaneously performed in 68 patients with suspected OSA. Data were analyzed blindly by 2 scorers. RESULTS: A good agreement between methods in sleep efficiency was observed (68.8% [18.4] with PSG vs 68% [19.1] with Somte [p: n.s.] for scorer 1, and 67.5% [19.1] vs 68.4% [18.5; p: n.s.] for scorer 2). The apnea-hypopnea index (AHI) obtained with Somte was lower than with PSG: 19 (17.8) vs 21.7 (19) (p < 0.001) for scorer 1, and 16.6 (16.7) vs 20 (18.8) (p < 0.001) for scorer 2. The sensitivity of Somte for a PSG-AHI > 5 was 91% for scorer 1 and 90% for scorer 2, while specificity was 77% and 90%, respectively. The areas under the receiver operating curve for different PSG-AHI cutoff points (>= 5, >= 15, and >= 30) were 0.81, 0.90, and 0.86, respectively, for scorer 1, and 0.90, 0.88, and 0.83 for scorer 2. CONCLUSIONS: These data suggest that Somte is an effective device to identify sleep and respiratory variables in patients with suspected OSA. PMID- 22505862 TI - Refill rates of accessories for positive airway pressure therapy as a surrogate measure of long-term adherence. AB - STUDY OBJECTIVES: To identify and validate a surrogate measure of long-term adherence to positive airway pressure (PAP) therapy in patients with obstructive sleep apnea (OSA). DESIGN: Retrospective cohort study. SETTING: Academic center. PARTICIPANTS: 220 consecutive patients with OSA. INTERVENTIONS: N/A. MEASUREMENTS: In patients with OSA who were receiving PAP therapy (for > 1 year), PAP adherence measured by device-download and defined by Medicare criteria was compared to refill rates for mask and other PAP therapy accessories. First, receiver operating characteristic (ROC) curves were constructed to identify a threshold value of refills per year that discriminated best between PAP adherent and non-adherent patients (derivation set; n = 100). Then the predictive accuracy of the threshold value of refills per year was tested in an additional 120 consecutive patients (validation set). RESULTS: From the derivation set, ROC curve with good discriminant characteristics (ROC 0.83; 95% confidence intervals [CI], 0.75, 0.91, p < 0.0001) was used to identify a threshold value of refills (0.7 refills/year) for distinguishing PAP adherent and non-adherent patients. Subsequently, when the threshold was applied to the validation set, the likelihood ratio for a positive test (weighted for prevalence) predicting adherence to PAP therapy was 7.3 (95%CI, 3.8, 14), and likelihood ratio for a negative test was 0.6 (95%CI; 0.4, 0.8). CONCLUSION: Refill rate of PAP accessories exhibited good test characteristics for predicting long-term PAP adherence. Such a surrogate measure based upon insurance claims data can be a powerful epidemiological tool in bioinformatics-aided comparative-effectiveness research and to monitor clinical performance of health systems. PMID- 22505863 TI - Relative prolongation of inspiratory time predicts high versus low resistance categorization of hypopneas. AB - STUDY OBJECTIVES: Sleep disordered breathing events conceptually separate into "obstructive" and "central" events. Esophageal manometry is the definitive but invasive means of classifying hypopneas. The purpose of this project was to identify noninvasive markers for discriminating high vs. low resistance hypopneas. METHODS: Forty subjects with obstructive or central sleep apnea underwent diagnostic polysomnography with nasal cannula airflow and esophageal manometry; 200% resistance relative to reference breaths was used to define "high" resistance. Noninvasive parameters from 292 randomly selected hypopneas in 20 subjects were analyzed and correlated to resistance. The best parameter and cutoff for predicting high relative resistance was determined and tested prospectively in 2 test sets in the 20 remaining subjects. Test Set A: 15 randomly selected hypopneas in each subject; Test Set B: all hypopneas in 7 subjects. RESULTS: In the development set, prolongation of inspiratory time during the 2 smallest breaths of a hypopnea (T(i)) relative to baseline had the best correlation to high relative resistance. In the Test Set A, relative T(i) > 110% classified obstructive events with sensitivity = 72%, specificity = 77%, PPV = 64%, NPV = 83%. Similar numbers were obtained for classification of hypopneas based on presence of flow limitation (FL) alone. When either relative T(i) or presence of FL were used to define high resistance, sensitivity = 84%, specificity = 74%, PPV = 65%, NPV = 89%. Similar results were obtained for Test Set B. CONCLUSIONS: Relative prolongation of T(i) is a good noninvasive predictor of high/low resistance in a dataset with both FL and NFL hypopneas. Combination of FL and relative T(i) improves this classification. The use of T(i) to separate obstructive and central hypopneas needs to be further tested for clinical utility (outcomes and treatment effects). PMID- 22505864 TI - Nighttime awakenings responding to gabapentin therapy in late premenopausal women: a case series. AB - Insomnia related to nighttime awakenings is known to be more prevalent in women than men. Three cases are presented here of late premenopausal women experiencing frequent nighttime awakenings that responded well to bedtime treatment with gabapentin. In one case, what started as isolated nighttime awakenings slowly progressed to awakenings accompanied by typical menopausal night sweats. This led to the theory that the initial isolated nighttime awakenings in this patient may have been secondary to a menopausal etiology related to low serum estradiol levels. In the subsequent 2 cases, early follicular phase serum estradiol was confirmed to be low. It is theorized that isolated nighttime awakenings in some premenopausal women may be caused by low serum estradiol, triggering events physiologically related to menopausal night sweats. Further research is needed to determine if low early follicular phase serum estradiol is associated with nighttime awakenings in premenopausal women not experiencing night sweats. PMID- 22505865 TI - Early sleep psychiatric intervention for acute insomnia: implications from a case of obsessive-compulsive disorder. AB - Insomnia is a common problem among patients with obsessive-compulsive disorder (OCD), and patients suffering from acute insomnia with psychiatric comorbidity are more likely to develop chronic insomnia without appropriate intervention. Here we report a case of obsessive-compulsive disorder with acute insomnia, successfully treated with early sleep psychiatric non-pharmacological intervention. The augmentation of medication runs a risk of exacerbating daytime impairment. Clinicians usually prescribe medication, such as antidepressants and hypnotics without reflections for such complaints. However, the use of these sedative agents is often problematic, especially when patients have kept a good QOL activity in daily life. The rapid recovery from acute insomnia in this case suggests that the appropriate use of actigraphy is a favorable non pharmacological intervention in acute insomnia. PMID- 22505866 TI - Narcolepsy with cataplexy masked by the use of nicotine. AB - This report describes a case of narcolepsy with cataplexy masked by the chronic use of cigarettes and nicotine patches. It has been described that narcoleptic smokers report relief of symptoms by smoking tobacco cigarettes. In addition, a case describing partial treatment of sleepiness using a nicotine patch in an adolescent with narcolepsy was recently reported in this journal. Our case adds to the growing literature that nicotine may be used to manage symptoms associated with narcolepsy. PMID- 22505867 TI - Topiramate-induced somnambulism in a migraineur: a probable idiosyncratic adverse effect. AB - Somnambulism (sleepwalking) is a disorder of arousal that falls under "parasomnia" group and is more common in children. These phenomena occur as primary sleep events or secondary to systemic disease or can be drug induced. Medications that can cause sleepwalking include neuroleptics, hypnotics, lithium, amitriptyline, and beta-blockers. This report presents an unusual adverse effect of topiramate on sleep in a patient with migraine. PMID- 22505868 TI - Obstructive sleep apnea syndrome and perioperative complications: a systematic review of the literature. AB - Obstructive sleep apnea syndrome (OSAS) is a common sleep related breathing disorder. Its prevalence is estimated to be between 2% and 25% in the general population. However, the prevalence of sleep apnea is much higher in patients undergoing elective surgery. Sedation and anesthesia have been shown to increase the upper airway collapsibility and therefore increasing the risk of having postoperative complications in these patients. Furthermore, the majority of patients with sleep apnea are undiagnosed and therefore are at risk during the perioperative period. It is important to identify these patients so that appropriate actions can be taken in a timely fashion. In this review article, we will discuss the epidemiology of sleep apnea in the surgical population. We will also discuss why these patients are at a higher risk of having postoperative complications, with the special emphasis on the role of anesthesia, opioids, sedation, and the phenomenon of REM sleep rebound. We will also review how to identify these patients preoperatively and the steps that can be taken for their perioperative management. PMID- 22505870 TI - Implementing CBTI at the Veterans Health Administration. PMID- 22505869 TI - Dissemination of CBTI to the non-sleep specialist: protocol development and training issues. AB - Strong evidence supports the efficacy of cognitive behavioral therapy for insomnia (CBTI). A significant barrier to wide dissemination of CBTI is the lack of qualified practitioners. We describe challenges and decisions made when developing a CBTI dissemination program in the Veterans Health Administration (VHA). The program targets mental health clinicians from different disciplines (psychiatry, psychology, social work, and nursing) with varying familiarity and experience with general principles of cognitive behavioral therapies (CBT). We explain the scope of training (how much to teach about the science of sleep, comorbid sleep disorders, other medical and mental health comorbidities, and hypnotic-dependent insomnia), discuss adaptation of CBTI to address the unique challenges posed by comorbid insomnia, and describe decisions made about the strategy of training (principles, structure and materials developed/recommended). Among these decisions is the question of how to balance the structure and flexibility of the treatment protocol. We developed a case conceptualization driven approach and provide a general session-by-session outline. Training licensed therapists who already have many professional obligations required that the training be completed in a relatively short time with minimal disruptions to training participants' routine work responsibilities. These "real-life" constraints shaped the development of this competency-based, yet pragmatic training program. We conclude with a description of preliminary lessons learned from the initial wave of training and propose future directions for research and dissemination. PMID- 22505871 TI - Development and growth of a large multispecialty certification examination: sleep medicine certification--results of the first three examinations. AB - This paper summarizes the results of the first three examinations (2007, 2009, and 2011) of the Sleep Medicine Certification Examination, administered by its six sponsoring American Board of Medical Specialty Boards. There were 2,913 candidates who took the 2011 examination through one of three pathways-self attested practice experience, previous certification by the American Board of Sleep Medicine, or formal Sleep Medicine fellowship training. The 2011 exam was the last administration in which candidates who had not previously been admitted could take it without completion of formal Sleep Medicine fellowship training. As expected, the number of candidates admitted to the 2011 examination through the practice experience pathway increased, and the overall scores of these candidates were on average lower than the other candidates. Consequently, the pass rate for all first takers of the 2011 examination (65%) was lower than that observed from the 2009 examination (78%) and the 2007 examination (73%). For each administration, candidates admitted through the fellowship training pathway scored the highest; over 90% of them passed the 2011 and 2009 examinations. PMID- 22505872 TI - A modern artifact in the sleep laboratory. PMID- 22505873 TI - The vicious cycle of leptin-insulin resistance predicts impaired glucose metabolism in obese adults with obstructive sleep apnea. PMID- 22505875 TI - The importance to assess the true "periodicity" of leg movements during sleep in narcolepsy. PMID- 22505878 TI - Synthesis of alpha-Arylphosphonates Using Copper-Catalyzed alpha-Arylation and Deacylative alpha-Arylation of beta-Ketophosphonates. AB - Efficient methods for the direct arylation and deacylative arylation of beta ketophosphonates with iodoarenes in presence of a copper(I) or a copper(II) salt as the catalysts were developed. The corresponding alpha-arylphosphonates were obtained in high yields. A tentative mechanism for the deacylative arylation reaction was proposed on the basis of the experimental data. PMID- 22505879 TI - Metabolite Mapping with Extended Brain Coverage Using a Fast Multisection MRSI Pulse Sequence and a Multichannel Coil. AB - Multisection magnetic resonance spectroscopic imaging is a widely used pulse sequence that has distinct advantages over other spectroscopic imaging sequences, such as dynamic shimming, large region-of-interest coverage within slices, and rapid data acquisition. It has limitations, however, in the number of slices that can be acquired in realistic scan times and information loss from spacing between slices. In this paper, we synergize the multi-section spectroscopic imaging pulse sequence with multichannel coil technology to overcome these limitations. These combined techniques now permit elimination of the gaps between slices and acquisition of a larger number of slices to realize the whole brain metabolite mapping without incurring the penalties of longer repetition times (and therefore longer acquisition times) or lower signal-to-noise ratios. PMID- 22505880 TI - Free radicals and extrinsic skin aging. AB - Human skin is constantly directly exposed to the air, solar radiation, environmental pollutants, or other mechanical and chemical insults, which are capable of inducing the generation of free radicals as well as reactive oxygen species (ROS) of our own metabolism. Extrinsic skin damage develops due to several factors: ionizing radiation, severe physical and psychological stress, alcohol intake, poor nutrition, overeating, environmental pollution, and exposure to UV radiation (UVR). It is estimated that among all these environmental factors, UVR contributes up to 80%. UV-induced generation of ROS in the skin develops oxidative stress, when their formation exceeds the antioxidant defence ability of the target cell. The primary mechanism by which UVR initiates molecular responses in human skin is via photochemical generation of ROS mainly formation of superoxide anion (O(2) (-) (?)), hydrogen peroxide (H(2)O(2)), hydroxyl radical (OH(?)), and singlet oxygen ((1)O(2)). The only protection of our skin is in its endogenous protection (melanin and enzymatic antioxidants) and antioxidants we consume from the food (vitamin A, C, E, etc.). The most important strategy to reduce the risk of sun UVR damage is to avoid the sun exposure and the use of sunscreens. The next step is the use of exogenous antioxidants orally or by topical application and interventions in preventing oxidative stress and in enhanced DNA repair. PMID- 22505881 TI - Drugs and constipation in elderly in nursing homes: what is the relation? AB - Introduction. Constipation is a common adverse drug reaction. Objective. Study associations between drugs and constipation in nursing home residents. Design. Cross-sectional study. Material and Methods. Nursing home residents above 60 years of age were included. Demographics, diet, physical activity, activity of daily living, nutritional status, use of drugs, and diseases were recorded. Constipation was defined as functional constipation or constipation-predominant IBS according to the Rome III criteria and/or regular use of laxatives. Drugs were classified according to the Anatomical-Therapeutic-Chemical Classification System (ATC), and anticholinergic effect was noted. Results. In all, 79 men and 188 women with a mean age of 85.4 (SD 7.1) years were included. The prevalence of constipation was 71.5%. Use of drugs in general, including polypharmacy, was not associated with constipation. Reduced activity of daily living (OR = 0.71, 95% CI : 0.60-0.84, P < 0.001), other antidepressants (N06AX) (OR 3.08, 95% CI : 1.09 8.68, P = 0.03), and benzodiazepine derivatives (N05BA) (OR = 2.80, 95% CI : 1.12 7.04, P = 0.03) were significantly associated with constipation; drugs with markedly anticholinergic effect (OR = 3.7, 95% CI : 0.78-17.53, P = 0.10), natural opium alkaloid (N02AA) (OR = 5.01, 95% CI : 0.95-25.94, P = 0.06), and propionic acid derivatives (M01AE) (OR = 7.00, 95% CI : 0.75-65.08, P = 0.09) showed a trend. Conclusion. In elderly with constipation, focus should be on specific groups of drugs and nonpharmacological factors, not on drugs in general. PMID- 22505882 TI - Irritable bowel syndrome and psychiatric disorders in pakistan: a case control study. AB - Background. The psychiatric disorders like anxiety and depression could have a profound influence on onset, expression, and course of Irritable bowel syndrome (IBS). Aim. To estimate the frequency and strength of association of common mental disorders (CMDs) in patients with IBS and patients with other chronic diseases, that is, migraine and hypertension. Method. This was a case control study. Individuals aged 18-70 years diagnosed as IBS were enrolled as cases. The control groups consisted of patients without IBS but diagnosed to have a chronic disease, that is, migraine or HTN. Self-Reporting Questonnaire-20(SRQ-20) was used as a screening tool for the detection of CMD. Results. 82 patients were enrolled in each group. Mean SRQ score was significantly higher in IBS group than controls (9.9 +/- 4.5 versus 4.9 +/- 3.6, P < 0.001). CMDs were more frequent (67.1% versus 22%) and the odds of CMD were 7.24 times higher among IBS patients than controls (95% CI 3.6-14.5, P < 0.001). No difference was found in frequency of CMDs among various subtypes of IBS. Conclusion. We found that CMDs are more common and strongly associated with IBS as compared to other chronic diseases. Early screening for CMDs might be useful for an effective management of IBS. PMID- 22505883 TI - Allosteric modulation of beta1 integrin function induces lung tissue repair. AB - The cellular cytoskeleton, adhesion receptors, extracellular matrix composition, and their spatial distribution are together fundamental in a cell's balanced mechanical sensing of its environment. We show that, in lung injury, extracellular matrix-integrin interactions are altered and this leads to signalling alteration and mechanical missensing. The missensing, secondary to matrix alteration and cell surface receptor alterations, leads to increased cellular stiffness, injury, and death. We have identified a monoclonal antibody against beta1 integrin which caused matrix remodelling and enhancement of cell survival. The antibody acts as an allosteric dual agonist/antagonist modulator of beta1 integrin. Intriguingly, this antibody reversed both functional and structural tissue injury in an animal model of degenerative disease in lung. PMID- 22505884 TI - Randomised Comparison of the AMBU AuraOnce Laryngeal Mask and the LMA Unique Laryngeal Mask Airway in Spontaneously Breathing Adults. AB - We conducted a randomised single-blind controlled trial comparing the LMA-Unique (LMAU) and the AMBU AuraOnce (AMBU) disposable laryngeal mask in spontaneously breathing adult patients undergoing general anaesthesia. Eighty-two adult patients (ASA status I-IV) were randomly allocated to receive the LMAU or AMBU and were blinded to device selection. Patients received a standardized anesthetic and all airway devices were inserted by trained anaesthetists. Size selection was guided by manufacturer recommendations. All data were collected by a single, unblinded observer. When compared with the LMAU, the AMBU produced significantly higher airway sealing pressures (AMBU 20 +/- 6; LMAU 15 +/- 7 cm H(2)O; P = 0.001). There was no statistical difference between the two devices for overall success rate, insertion time, number of adjustments, laryngeal alignment, blood staining, and sore throat (P >= 0.05). The AMBU AuraOnce disposable laryngeal mask provided a higher oropharyngeal leak pressure compared to the LMA Unique in spontaneously breathing adult patients. PMID- 22505885 TI - Design and implementation of an educational program in advanced airway management for anesthesiology residents. AB - Education and training in advanced airway management as part of an anesthesiology residency program is necessary to help residents attain the status of expert in difficult airway management. The Accreditation Council for Graduate Medical Education (ACGME) emphasizes that residents in anesthesiology must obtain significant experience with a broad spectrum of airway management techniques. However, there is no specific number required as a minimum clinical experience that should be obtained in order to ensure competency. We have developed a curriculum for a new Advanced Airway Techniques rotation. This rotation is supplemented with a hands-on Difficult Airway Workshop. We describe here this comprehensive advanced airway management educational program at our institution. Future studies will focus on determining if education in advanced airway management results in a decrease in airway related morbidity and mortality and overall better patients' outcome during difficult airway management. PMID- 22505886 TI - Electronic and spatial structures of water-soluble dinitrosyl iron complexes with thiol-containing ligands underlying their ability to act as nitric oxide and nitrosonium ion donors. AB - The ability of mononuclear dinitrosyl iron commplexes (M-DNICs) with thiolate ligands to act as NO donors and to trigger S-nitrosation of thiols can be explain only in the paradigm of the model of the [Fe(+)(NO(+))(2)] core ({Fe(NO)(2)}(7) according to the Enemark-Feltham classification). Similarly, the {(RS( ))(2)Fe(+)(NO(+))(2)}(+) structure describing the distribution of unpaired electron density in M-DNIC corresponds to the low-spin (S = 1/2) state with a d(7) electron configuration of the iron atom and predominant localization of the unpaired electron on MO(d(z2)) and the square planar structure of M-DNIC. On the other side, the formation of molecular orbitals of M-DNIC including orbitals of the iron atom, thiolate and nitrosyl ligands results in a transfer of electron density from sulfur atoms to the iron atom and nitrosyl ligands. Under these conditions, the positive charge on the nitrosyl ligands diminishes appreciably, the interaction of the ligands with hydroxyl ions or with thiols slows down and the hydrolysis of nitrosyl ligands and the S-nitrosating effect of the latter are not manifested. Most probably, the S-nitrosating effect of nitrosyl ligands is a result of weak binding of thiolate ligands to the iron atom under conditions favoring destabilization of M-DNIC. PMID- 22505887 TI - Application of Neurochemical Markers for Assessing Health Effects after Developmental Methylmercury and PCB Coexposure. AB - Cholinergic muscarinic receptors (MRs) and monoamine oxidase activity (MAO-B), expressed both in brain and blood cells, were investigated in animals and exposed subjects to assess (i) MeHg (0.5-1 mg/kg/day GD7-PD7) and/or PCB153 (20 mg/kg/day GD10-GD16) effects on cerebellar MAO-B and MRs, and lymphocyte MRs, in dams and offspring 21 days postpartum; (ii) MAO-B in platelets and MRs in lymphocytes of a Faroese 7-year-old children cohort, prenatally exposed to MeHg/PCBs. Animal Data. MAO-B was altered in male cerebellum by MeHg, PCB153, and their combination (35%, 45%, and 25% decrease, resp.). Cerebellar MRs were enhanced by MeHg alone in dams (87%) and male pups (27%). PCB153 alone and in mixture did not modify cerebellar MRs. Similarly to brain, lymphocyte MRs were enhanced in both dams and offspring by MeHg alone. All changes were caused by 1 MeHg mg/kg/day, the lower dose was ineffective. Human Data. Both biomarkers showed homogeneous distributions within the cohort (MRs, range 0.1-36.78 fmol/million cells; MAO-B, 0.95-14.95 nmol/mg protein/h). No correlation was found between the two biomarkers and neurotoxicant concentrations in blood (pre- and postnatally). PMID- 22505888 TI - Role of surrogate markers of atherosclerosis in clinical and subclinical thyroidism. AB - Background. Data on the relationship between homocysteine, plasminogen activator inhibitor 1, hs-CRP, fibrinogen, and carotid intima media thickness (CA-IMT) is plenty but contradicting and the majority of the studies investigated this issue in only specific thyroidism groups. The aim of this paper was to investigate these relations in patients with subclinical and clinical hypo- and hyperthyroidism. Methods. In this cross-sectional study, 16 patients from each thyroidism group and 20 healthy cases were enrolled. Fibrinogen levels and plasminogen activator inhibitor 1 (PAI-1) activity were assessed. CA-IMT was determined by gray-scale high-resolution color Doppler ultrasound. Results. Serum homocysteine levels were higher in hypothyroidic patients compared to the control (P = 0.003). Fibrinogen levels were higher in patients with subclinical hypothyroidism compared to other groups (P < 0.05). There was no difference between groups regarding PAI-1. Whereas total cholesterol, homocysteine, and LDL were correlated with CAIMT, hs-CRP, PAI-1, and fibrinogen were not. In the clinical hypothyroidism group, the correlation of homocysteine with CA-IMT was derived from the correlation between CA-IMT and homocysteine. Conclusions. Homocysteine and fibrinogen levels are higher in patients with clinical and subclinical hypothyroidism, respectively. Homocysteine level is associated with CA-IMTonly in patients with clinical hypothyroidism. PMID- 22505889 TI - Microarchitecture, but not bone mechanical properties, is rescued with growth hormone treatment in a mouse model of growth hormone deficiency. AB - Growth hormone (GH) deficiency is related to an increased fracture risk although it is not clear if this is due to compromised bone quality or a small bone size. We investigated the relationship between bone macrostructure, microarchitecture and mechanical properties in a GH-deficient (GHD) mouse model undergoing GH treatment commencing at an early (prepubertal) or late (postpubertal) time point. Microcomputed tomography images of the femur and L4 vertebra were obtained to quantify macrostructure and vertebral trabecular microarchitecture, and mechanical properties were determined using finite element analyses. In the GHD animals, bone macrostructure was 25 to 43% smaller as compared to the GH sufficient (GHS) controls (P < 0.001). GHD animals had 20% and 19% reductions in bone volume ratio (BV/TV) and trabecular thickness (Tb.Th), respectively. Whole bone mechanical properties of the GHD mice were lower at the femur and vertebra (67% and 45% resp.) than the GHS controls (P < 0.001). Both early and late GH treatment partially recovered the bone macrostructure (15 to 32 % smaller than GHS controls) and the whole bone mechanical properties (24 to 43% larger than GHD animals) although there remained a sustained 27-52% net deficit compared to normal mice (P < 0.05). Importantly, early treatment with GH led to a recovery of BV/TV and Tb.Th with a concomitant improvement of trabecular mechanical properties. Therefore, the results suggest that GH treatment should start early, and that measurements of microarchitecture should be considered in the management of GHD. PMID- 22505890 TI - Synergistic Effect of Hyperglycemia and p27(kip1) Suppression on Adult Mouse Islet Beta Cell Replication. AB - The complementary role of hyperglycemia and p27(kip1) suppression on islet beta cell regeneration was investigated in a syngeneic mouse model. p27(kip1) gene silencing was performed by infecting islets of C57BL/6 with shRNA lentiviral particles. At 54 hours after viral infection, p27(kip1) protein content in cultured targeting islets was 22% of that in freshly isolated islets. Six days after transplantation to diabetic mice, targeting islet graft had considerably more cells with Ki67-staining nuclei than nontargeting islets. The mice in the targeting-islet group had a significantly shorter duration of temporary hyperglycaemia than mice in the non-targeting-islet group. The long-term ex vivo beneficial effect of p27(kip1) silencing on graft function was also indicated by the significantly higher cumulative cure rate for diabetes in mice receiving 200 targeting islets than that in mice receiving 200 non-targeting islets. Our data suggest that hyperglycemia and persistent p27(kip1) suppression have a synergistic effect on islet beta cell replication in adult mice. PMID- 22505892 TI - A pilot study on dietary approaches in multiethnicity: two methods compared. AB - Background. Medical nutritional therapy is the most important method for normalizing glucose levels in pregnancy. In this setting, there is a new problem to consider relating to migrants, their personal food preferences, and ethnic, cultural, and religious aspects of their diet. We compared maternal and fetal outcomes between two multiethnic groups of pregnant women, one adopting a food plan that included dishes typical of the foreign women's original countries (the "ethnic meal plan" group), while the other group adopted a standard meal plan. Findings. To develop the meal plan, each dish chosen by the women was broken down into its principal ingredients. The quantity of each food was given in tablespoons, teaspoons, slices, and cups, and there were photographs of the complete dish. The group treated with the ethnic meal plan achieved a better metabolic control at the end of the pregnancy and a lower weight gain (though the difference was not statistically significant). As for fetal outcome, the group on the ethnic meal plan had babies with a lower birth weight and there were no cases of macrosomia or LGA babies. Conclusions. This preliminary study indicates the positive effect of an ethnic approach to diet on the outcome of pregnancy. PMID- 22505893 TI - Technical considerations in rehabilitation of an edentulous total glossectomy patient. AB - The technician by virtue of his profession plays an important role in fabricating silicone tongue prosthesis for a total glossectomy patient. The technician, with his skills and specialized knowledge in handling material, plays a valuable role as a member of the oncology team. A patient with total glossectomy can be rehabilitated by silicone tongue prosthesis as an aid to improve his speech and swallowing. This paper describes the technical steps involved in fabricating a silicone tongue prosthesis for an edentulous total glossectomy patient. PMID- 22505891 TI - Hypogonadism in the aging male diagnosis, potential benefits, and risks of testosterone replacement therapy. AB - Hypogonadism in older men is a syndrome characterized by low serum testosterone levels and clinical symptoms often seen in hypogonadal men of younger age. These symptoms include decreased libido, erectile dysfunction, decreased vitality, decreased muscle mass, increased adiposity, depressed mood, osteopenia, and osteoporosis. Hypogonadism is a common disorder in aging men with a significant percentage of men over 60 years of age having serum testosterone levels below the lower limits of young male adults. There are a variety of testosterone formulations available for treatment of hypogonadism. Data from many small studies indicate that testosterone therapy offers several potential benefits to older hypogonadal men. A large multicenter NIH supported double blind, placebo controlled study is ongoing, and this study should greatly enhance the information available on efficacy and side effects of treatment. While safety data is available across many age groups, there are still unresolved concerns associated with testosterone therapy. We have reviewed the diagnostic methods as well as benefits and risks of testosterone replacement therapy for hypogonadism in aging men. PMID- 22505894 TI - The current and future therapies of bone regeneration to repair bone defects. AB - Bone defects often result from tumor resection, congenital malformation, trauma, fractures, surgery, or periodontitis in dentistry. Although dental implants serve as an effective treatment to recover mouth function from tooth defects, many patients do not have the adequate bone volume to build an implant. The gold standard for the reconstruction of large bone defects is the use of autogenous bone grafts. While autogenous bone graft is the most effective clinical method, surgical stress to the part of the bone being extracted and the quantity of extractable bone limit this method. Recently mesenchymal stem cell-based therapies have the potential to provide an effective treatment of osseous defects. In this paper, we discuss both the current therapy for bone regeneration and the perspectives in the field of stem cell-based regenerative medicine, addressing the sources of stem cells and growth factors used to induce bone regeneration effectively and reproducibly. PMID- 22505895 TI - A prospective study of early loaded single implant-retained mandibular overdentures: preliminary one-year results. AB - Purpose. To investigate the predictability of simplifying mandibular overdenture treatment using one-stage surgery and early prosthetic loading of a single implant. Materials and Methods. Twenty edentulous patients with problematic existing mandibular dentures were treated. A single implant with a chemically modified surface (SLActive, Straumann AG, Basel, Switzerland) was placed into the mandibular midline. The patients were recalled at 3, 6 and 12 months. Clinical assessments and marginal bone loss using standardized radiographs were recorded. All complications, failures and maintenance were noted. Visual analog-scale questionnaires were used to record patient satisfaction in five categories. ANOVA was used to determine differences between means of marginal bone loss and different categories of patient staisfaction (P = 0.05). Results. The 20 early loaded implants were all surviving at the 12-month recall. All implants showed less than 1 mm of marginal bone loss by the end of the 1-year with a significant increase during the follow-up period. Few prosthetic problems were reported. Patient satisfaction was high with a significant increase in all comfort and functional parameters. Conclusions. These preliminary 1-year results indicate that early loading of a single chemically modified surface implant used to retain a mucosa-borne mandibular overdenture is a safe, reliable, and cost-effective treatment. PMID- 22505897 TI - Postoperative pain after root canal treatment: a prospective cohort study. AB - Aim. To evaluate the incidence and severity of postendodontic treatment pain (PEP) subsequent to root canal treatment (RCT) in vital and necrotic pulps and after retreatment. Methodology. A prospective study. Participants were all patients (n = 274) who underwent RCT in teeth with vital pulp, necrotic pulp, or vital pulp that had been treated for symptomatic irreversible pulpitis or who received root canal retreatment, by one clinician, during an eight-month period. Exclusion criteria were swelling, purulence, and antibiotic use during initial treatment. A structured questionnaire accessed age, gender, tooth location, and pulpal diagnosis. Within 24 h of treatment, patients were asked to grade their pain at 6 and 18 hours posttreatment, using a 1-5 point scale. Results. RCT of teeth with vital pulp induced a significantly higher incidence and severity of PEP (63.8%; 2.46 +/- 1.4, resp.) than RCT of teeth with necrotic pulp (38.5%; 1.78 +/- 1.2, resp.) or of retreated teeth (48.8%; 1.89 +/- 1.1, resp.). No statistical relation was found between type of pain (spontaneous or stimulated) and pulp condition. Conclusion. RCT of teeth with vital pulp induced a significantly higher incidence and intensity of PEP compared to teeth with necrotic pulp or retreated teeth. PMID- 22505896 TI - Possible Involvement of Smad Signaling Pathways in Induction of Odontoblastic Properties in KN-3 Cells by Bone Morphogenetic Protein-2: A Growth Factor to Induce Dentin Regeneration. AB - We examined the effects of bone morphogenetic protein-2 (BMP-2) on growth, differentiation, and intracellular signaling pathways of odontoblast-like cells, KN-3 cells, to clarify molecular mechanisms of odontoblast differentiation during pulp regeneration process. After treatment with BMP-2, the cell morphology, growth, alkaline phosphatase (ALP) activity, and the activation and expression of BMP-induced intracellular signaling molecules, such as Smad1/5/8 and Smad6/7, as well as activities of dentin sialoprotein (DSP) and dentin matrix protein 1 (DMP1), were examined. BMP-2 had no effects on the morphology, growth, or ALP activity of KN-3 cells, whereas it induced the phosphorylation of Smad1/5/8 and expression of Smad6/7. BMP-2 also induced the expressions of DSP and DMP-1. Our results suggest that KN-3 cells may express an odontoblastic phenotype with the addition of BMP-2 through the activation of Smad signaling pathways. PMID- 22505898 TI - Comparative Resistance of AH26 and a New Sealer Prototype to a Bacterial Challenge. AB - Objective. This study compared the leakage resistance of a New Sealer Prototype (NSP) with a traditional sealer (AH 26) in Resilon-filled roots subjected to a bacterial challenge. Study Design. 41 roots were instrumented to ISO size 50 apically. Group 1 (n = 20) contained Resilon and AH 26 sealer and roots in group 2 (n = 21) contained Resilon and NSP. Roots were embedded in a dual-chamber model with the upper chamber containing Streptococcus mutans inoculum. Evidence of bacterial penetration was observed for 1 month. Fisher's Test was used to analyze the data. Results. 8 of 20 roots (40%) in the AH 26 group demonstrated leakage whereas 3 of 21 roots (14%) in the NSP group leaked. The difference in leakage rates was not statistically significant (P = 0.053). Conclusion. The traditional sealer (AH 26) demonstrated increased leakage rates compared to the New Sealer Prototype (NSP), but the difference did not reach statistical significance in this study. PMID- 22505899 TI - Evaluation of osteoconductive and osteogenic potential of a dentin-based bone substitute using a calvarial defect model. AB - The aim of this study was to assess the osteoconductive and osteogenic properties of processed bovine dentin using a robust rabbit calvarial defect model. In total, 16 New Zealand White rabbits were operated to create three circular defects in the calvaria. One defect was left unfilled, one filled with collected autogenous bone, and the third defect was filled with the dentin-based bone substitute. Following surgery and after a healing period of either 1 or 6 weeks, a CT scan was obtained. Following sacrificing, the tissues were processed for histological examination. The CT data showed the density in the area grafted with the dentin-based material was higher than the surrounding bone and the areas grafted with autologous bone after 1 week and 6 weeks of healing. The area left unfilled remained an empty defect after 1 week and 6 weeks. Histological examination of the defects filled with the dentin product after 6 weeks showed soft tissue encapsulation around the dentin particles. It can be concluded that the rabbit calvarial model used in this study is a robust model for the assessment of bone materials. Bovine dentin is a biostable material; however, it may not be suitable for repairing large 4-wall defects. PMID- 22505900 TI - Application of laser-induced bone therapy by carbon dioxide laser irradiation in implant therapy. AB - This study evaluated the application of laser-induced bone therapy (LIBT) to reduce implant healing time in rat tibia. Twenty 10-week-old female Sprague Dawlay rats were used. The rats received laser irradiation (laser group) or sham operation (control group) on either side of the tibia. Five days after invasion, titanium implants were inserted in proximal tibia. Five, 10, and 20 days after implant placement, tibiae were collected. After taking micro-CT and performing a torque test, the tibiae were decalcified and 8-MUm-thick sections were prepared. Specimens were stained with hematoxylin and eosin. Results. Micro-CT images, removal torque values, and histomorphometric analysis data demonstrated a significantly accelerated bone formation in the laser group earlier in the healing process. Conclusion. The use of laser irradiation was effective in promoting bone formation and acquiring osseointegration of titanium implants inserted in rat tibia. LIBT may be suitable for use in implant therapy. PMID- 22505901 TI - Antibacterial properties of dental luting agents: potential to hinder the development of secondary caries. AB - A modified direct contact test was used to evaluate the antibacterial properties of four commercially available dental luting agents (RelyX Unicem, Ketac Cem, Ceramir Crown & Bridge and Harvard Cement) and two reference materials (glass ionomer cement and calcium aluminate cement) compared to a negative-control material (PMMA). Streptococcus mutans bacteria were placed in direct contact with specimens that had been aged for 10 min, 1 day, and 7 days, in order to test the antibacterial properties of the materials. A metabolic assay containing resazurin was used to quantify the amount of viable bacteria remaining after the direct contact tests. The effects of pH and fluoride on bacteria proliferation were also evaluated. Strongest antibacterial properties were found for calcium aluminate cement, followed by Ceramir Crown & Bridge and RelyX Unicem. Ketac Cem, Harvard Cement, and the reference glass-ionomer cement showed bacteria content either higher than or not significantly different from the PMMA control in all instances. pH levels below 6.3 and above 9.0 were found to have negative effects on bacterial proliferation. No correlation between either acidic materials or fluoride release and antibacterial properties could be seen; rather, basic materials showed stronger antibacterial properties. PMID- 22505903 TI - Effects of Chewing Different Flavored Gums on Salivary Flow Rate and pH. AB - Chewing gum increases salivary flow rate (SFR) and pH, but differences in preferences of gum flavor may influence SFR and pH. The aim of this paper was to assess the effect of five different flavors of sucrose-free chewing gum on the salivary flow rate and pH in healthy dental students in Isfahan, Iran. Fifteen (7 men and 8 women) healthy dental student volunteers collected unstimulated saliva and then chewed one of five flavored gums for 6 min. The whole saliva was collected and assessed for 6 consecutive days. After unstimulated saliva was collected, stimulated saliva was collected at interval of 0-1, 1-3, and 3-6 minutes after the start of different flavored chewing gums. The SFR and salivary pH were measured. The SFR increased in all five flavored gums at 1, 3, and 6 minutes after start of chewing gums (P < 0.001). The flow rate of all products reached peak in the 1st minute of stimulation, except spearmint-flavored gums which reached peak in the 6th minute. In the 1st minute, the strawberry-flavored gums showed the highest SFR. During 1-3 minutes, strawberry- and apple-flavored gums showed higher SFR, respectively. Only the spearmint- and cinnamon-flavored gum significantly increased salivary pH. Gum flavored can affect the SFR and pH and special flavors can be advised for different individuals according to their oral conditions. PMID- 22505902 TI - Oral Leukoplakia as It Relates to HPV Infection: A Review. AB - Leukoplakia is the most common potentially malignant lesion of the oral cavity and can be categorised according to its clinical appearance as homogeneous or nonhomogenous. Tobacco and areca nut use, either alone or in combination are the most common risk factors for oral leukoplakia, but some oral leukoplakias are idiopathic. Some leukoplakias arise within fields of precancerized oral epithelium in which the keratinocytes may be at different stages of cytogenetic transformation. Leukoplakias may unpredictably regress, may remain stable, or may progress to carcinoma. There is a greater risk of carcinomatous transformation of idiopathic leukoplakia, of non-homogenous leukoplakia, of leukoplakia affecting the floor of the mouth; the ventrolateral surface of the tongue and the maxillary retromolar and adjoining soft palate (collectively called high-risk sites), of leukoplakia with high-grade epithelial dysplasia, and of leukoplakia in which the keratinocytes carry cytogenetic alterations associated with carcinomatous transformation. Although there appears to be some link between human papillomavirus (HPV) and oral leukoplakia, there is little evidence to support a causal relationship either between HPV infection and oral leukoplakia or between HPV-infected leukoplakic keratinocytes and their carcinomatous transformation. PMID- 22505904 TI - Periodontal status in smokers and nonsmokers: a clinical, microbiological, and histopathological study. AB - A case-control study was done to assess the influence of smoking on clinical, microbiological, and histopathological parameters. Methods. Two hundred dentate male patients (100 smokers and 100 nonsmokers) ranging between 25 and 50 years were enrolled in the study. Periodontal parameters were recorded. Plaque samples were collected for microbial analysis for BANA test. Gingival biopsies were obtained from selected site for assessing histopathological changes. Results. Both groups showed almost similar plaque levels (P=0.258), but smokers had reduced gingival (0.62 +/- 0.31) and bleeding indices (28.53 +/- 17.52) and an increased calculus index (1.62 +/- 0.36). Smokers had an increased probing depth of 4-7 mm (P=0.009) and overall increased CAL. No difference in microbiota was found between the two groups. Histopathologically smokers showed a decreased blood vessel density (8.84 +/- 0.96) and inflammatory cells (52.00 +/- 9.79). Conclusions. It is quite possible that many of the pathogenic mechanisms involved in tissue degradation in periodontitis in smokers could be quite different from those in nonsmokers. PMID- 22505905 TI - Common errors in digital panoramic radiographs of patients with mixed dentition and patients with permanent dentition. AB - Purpose. To compare errors in digital panoramic radiographs of permanent and mixed dentitions. Methods. 143 and 146 digital radiographs of mixed and permanent dentitions were examined. Results. Significantly fewer errors presented in the mixed dentition. Positioning too forward significantly prevalent in the mixed dentition; slumped position and nonpositioning of chin properly were significantly prevailed in the permanent dentition. Blurred or shortened upper incisors were significantly more prevalent in the mixed dentition. Diagnostic ability could be improved by manipulating the brightness or contrast in nearly 45% of all radiographs. In the mixed dentition, tilting the chin down and a slumped position made the lower incisors significantly nondiagnostic. In the permanent dentition, tilting the chin down made the lower incisors to be significantly nondiagnostic. Conclusions. More errors were prevalent in panoramic radiographs of permanent dentitions. Properly positioning the patient is the most important factor in preventing a cascade of errors. PMID- 22505906 TI - Nonnutritive, low caloric substitutes for food sugars: clinical implications for addressing the incidence of dental caries and overweight/obesity. AB - Caries and obesity are two common conditions affecting children in the United States and other developed countries. Caries in the teeth of susceptible children have often been associated with frequent ingestion of fermentable sugars such as sucrose, fructose, glucose, and maltose. Increased calorie intake associated with sugars and carbohydrates, especially when associated with physical inactivity, has been implicated in childhood obesity. Fortunately, nonnutritive artificial alternatives and non-/low-caloric natural sugars have been developed as alternatives to fermentable sugars and have shown promise in partially addressing these health issues. Diet counseling is an important adjunct to oral health instruction. Although there are only five artificial sweeteners that have been approved as food additives by the Food and Drug Administration (FDA), there are additional five non-/low caloric sweeteners that have FDA GRAS (Generally Recognized as Safe) designation. Given the health impact of sugars and other carbohydrates, dental professionals should be aware of the nonnutritive non-/low caloric sweeteners available on the market and both their benefits and potential risks. Dental health professionals should also be proactive in helping identify patients at risk for obesity and provide counseling and referral when appropriate. PMID- 22505908 TI - FE-SEM Evaluation of Dental Specimens Prepared by Different Methods for In Vitro Contamination. AB - Objective. To evaluate through FE-SEM the cleanliness and dentinal alterations promoted by different methods of dental sample preparation. Methods. Twenty-five human single-rooted teeth were used. The teeth were cleaned and autoclaved in wet medium and randomly divided into 5 groups (n = 5), according to the preparation methods employed-control group: no solutions applied; group 1: cement removal and irrigation with 5.25% NaOCl + 17 % EDTA for 4 minutes each; group 2: 17% EDTA + 2.5% NaOCl (4 minutes ultrasonic bath); group 3: cement removal and 17% EDTA + 5.25% NaOCl + phosphate buffer solution + distilled water (10 minutes ultrasonic); group 4: 17% EDTA + 5.25% NaOCl (3 minutes ultrasonic bath). Specimens were analyzed by field emission scanning electron microscope (FE-SEM), at 1500x magnification. Data were submitted to qualitative analysis according to a scoring system and submitted to Kruskal-Wallis test. Results. In ascending order, as to bind parameters, (i) cleanliness: control, group 2, group 3, group 5, and group 4, (ii) dentinal alterations: group 1, group 5, group 2, group 3, and group 4. Conclusion. The proposed protocol was suitable for subsequent microbiological contamination, because it showed less dentinal morphological alterations with increased removal of organic waste. PMID- 22505907 TI - Dental erosion and its growing importance in clinical practice: from past to present. AB - Since the mid-1990s, the focus of studies on tooth wear has steadily shifted from the general condition towards the more specific area of dental erosion; equally, a shift has occurred from studies in adults to those in children and adolescents. During this time, understanding of the condition has increased greatly. This paper attempts to provide a critical overview of the development of this body of knowledge, from earlier perceptions to the present. It is accepted that dental erosion has a multifactorial background, in which individual and lifestyle factors have great significance. Notwithstanding methodological differences across studies, data from many countries confirm that dental erosion is common in children and young people, and that, when present, it progresses rapidly. That the condition, and its ramifications, warrants serious consideration in clinical dentistry, is clear. It is important for the oral healthcare team to be able to recognize its early signs and symptoms and to understand its pathogenesis. Preventive strategies are essential ingredients in the management of patients with dental erosion. When necessary, treatment aimed at correcting or improving its effects might best be of a minimally invasive nature. Still, there remains a need for further research to forge better understanding of the subject. PMID- 22505909 TI - A review of luting agents. AB - Due to the availability of a large number of luting agents (dental cements) proper selection can be a daunting task and is usually based on a practitioner's reliance on experience and preference and less on in depth knowledge of materials that are used for the restoration and luting agent properties. This review aims at presenting an overview of current cements and discusses physical properties, biocompatibility and other properties that make a particular cement the preferred choice depending on the clinical indication. Tables are provided that outline the different properties of the generic classification of cements. It should be noted that no recommendations are made to use a particular commercial cement for a hypothetical clinical situation. The choice is solely the responsibility of the practitioner. The appendix is intended as a guide for the practitioner towards a recommended choice under commonly encountered clinical scenarios. Again, no commercial brands are recommended although the author recognizes that some have better properties than others. Please note that this flowchart strictly presents the author's opinion and is based on research, clinical experience and the literature. PMID- 22505910 TI - A new anatomically based nomenclature for the roots and root canals-part 2: mandibular molars. AB - Several terminologies have been employed in the dental literature to describe the roots and root canal systems of mandibular molars with no consensus being arrived at, thus far. The anatomical relation of roots and their root canals were identified and a naming system was formulated. The proposed nomenclature attempts to make certain essential modifications to the traditional approach to accommodate the naming of various aberrations presented in mandibular molars. A simple, yet extensive nomenclature system has been proposed that appropriately names the internal and external morphology of mandibular molars. PMID- 22505911 TI - Candidates cell sources to regenerate alveolar bone from oral tissue. AB - Most of the cases of dental implant surgery, especially the bone defect extensively, are essential for alveolar ridge augmentation. As known as cell therapy exerts valuable effects on bone regeneration, numerous reports using various cells from body to regenerate bone have been published, including clinical reports. Mesenchymal cells that have osteogenic activity and have potential to be harvested from intra oral site might be a candidate cells to regenerate alveolar bone, even dentists have not been harvested the cells outside of mouth. This paper presents a summary of somatic cells in edentulous tissues which could subserve alveolar bone regeneration. The candidate tissues that might have differentiation potential as mesenchymal cells for bone regeneration are alveolar bone chip, bone marrow from alveolar bone, periosteal tissue, and gingival tissue. Understanding their phenotype consecutively will provide a rational approach for alveolar ridge augmentation. PMID- 22505912 TI - Discrepancies between Abstracts Presented at International Association for Dental Research Annual Sessions from 2004 to 2005 and Full-Text Publication. AB - Purpose. The purpose of this study was to evaluate the discrepancies between abstracts presented at the IADR meeting (2004-2005) and their full-text publication. Material and Methods. Abstracts from the Prosthodontic Section of IADR meeting were obtained. The following information was collected: abstract title, number of authors, study design, statistical analysis, outcome, and funding source. PubMed was used to identify the full-text publication of the abstracts. The discrepancies between the abstract and the full-text publication were examined, categorized as major and minor discrepancies, and quantified. The data were collected and analyzed using descriptive analysis. Frequency and percentage of major and minor discrepancies were calculated. Results. A total of 109 (95.6%) articles showed changes from their abstracts. Seventy-four (65.0%) and 105 (92.0%) publications had at least one major and one minor discrepancies, respectively. Minor discrepancies were more prevalent (92.0%) than major discrepancies (65.0%). The most common minor discrepancy was observed in the title (80.7%), and most common major discrepancies were seen in results (48.2%). Conclusion. Minor discrepancies were more prevalent than major discrepancies. The data presented in this study may be useful to establish a more comprehensive structured abstract requirement for future meetings. PMID- 22505913 TI - Adhesion and cohesion. AB - The phenomena of adhesion and cohesion are reviewed and discussed with particular reference to dentistry. This review considers the forces involved in cohesion and adhesion together with the mechanisms of adhesion and the underlying molecular processes involved in bonding of dissimilar materials. The forces involved in surface tension, surface wetting, chemical adhesion, dispersive adhesion, diffusive adhesion, and mechanical adhesion are reviewed in detail and examples relevant to adhesive dentistry and bonding are given. Substrate surface chemistry and its influence on adhesion, together with the properties of adhesive materials, are evaluated. The underlying mechanisms involved in adhesion failure are covered. The relevance of the adhesion zone and its importance with regard to adhesive dentistry and bonding to enamel and dentin is discussed. PMID- 22505914 TI - Characterisation of flavonoid aglycones by negative ion chip-based nanospray tandem mass spectrometry. AB - Flavonoids are one of the most important classes of natural products having a wide variety of biological activities. There is wide interest in a range of medical and dietary applications, and having a rapid, reliable method for structural elucidation is essential. In this study a range of flavonoid standards are investigated by chip-based negative ion nanospray mass spectrometry. It was found that the different classes of flavonoid studied have a combination of distinct neutral losses from the precursor ion [M-H](-) along with characteristic low-mass ions. By looking only for this distinct pattern of product ions, it is possible to determine the class of flavonoid directly. This methodology is tested here by the analysis of a green tea extract, where the expected flavonoids were readily identified, along with quercetin, which is shown to be present at only about 2% of the most intense ion in the spectrum. PMID- 22505915 TI - Low-Level Detection of Poly(amidoamine) PAMAM Dendrimers Using Immunoimaging Scanning Probe Microscopy. AB - Immunoimaging scanning probe microscopy was utilized for the low-level detection and quantification of biotinylated G4 poly(amidoamine) PAMAM dendrimers. Results were compared to those of high-performance liquid chromatography (HPLC) and found to provide a vastly improved analytical method for the low-level detection of dendrimers, improving the limit of detection by a factor of 1000 (LOD = 2.5 * 10( 13) moles). The biorecognition method is reproducible and shows high specificity and good accuracy. In addition, the capture assay platform shows a promising approach to patterning dendrimers for nanotechnology applications. PMID- 22505916 TI - Chemical Constituents of Essential Oil from Lippia sidoides Cham. (Verbenaceae) Leaves Cultivated in Hidrolandia, Goias, Brazil. AB - Several studies involving the family Verbenaceae, occurring in the Brazilian Cerrado, have emphasized the popular use of many aromatic species. We highlight the use of Lippia sidoides Cham., known as "alecrim pimenta," native to northeastern Brazil and northern Minas Gerais. Leaves of this species were collected in antropized Brazilian Cerrado area, in Hidrolandia, Goias, and their essential oils were extracted by hydrodistillation in a Clevenger-type apparatus and thereafter analyzed GC/MS. Among the compounds identified in this study were the most abundant oxygenated monoterpenes, followed by sesquiterpenes hydrocarbons. The oxygenated monoterpene 1,8-cineole was the major constituent followed by isoborneol and bornyl acetate. The chemical composition of essential oil described in this paper differs from that described in the literature for L. sidoides found in its native environment, where the major constituents are thymol and carvacrol. PMID- 22505917 TI - Concentration of Inorganic Elements Content in Benthic Seaweeds of Fernando de Noronha Archipelago by Synchrotron Radiation Total Reflection X-Ray Fluorescence Analysis (SRTXRF). AB - SRTXRF WAS USED TO DETERMINE AS, BA, BR, CA, CO, CR, CS, CU, DY, FE, K, MN, MO, NI, PB, RB, SR, TI, V, AND ZN IN ELEVEN SEAWEED SPECIES COMMONLY FOUND IN FERNANDO DE NORONHA: Caulerpa verticillata (J. Agardh) (Chlorophyta), Asparagopsis taxiformis (Delile), Dictyurus occidentalis (J. Agardh), Galaxaura rugosa (J. Ellis & Solander) J. V. Lamouroux, G. obtusata (J. Ellis & Solander) J. V. Lamouroux, G. marginata (J. Ellis & Solander) J. V. Lamouroux (Rhodophyta), Dictyota cervicornis (Kutzing), Dictyopteris justii (J. V. Lamouroux), Dictyopteris plagiogramma (Montagne) Vickers, Padina gymnospora (Kutzing) Sonder, and a Sargassum sp. (Phaeophyta). Data obtained were compared to those from the analysis of other parts of the world seaweeds using different analytical techniques and were found to be in general agreement in terms of major and minor elemental components. Results provide baseline information about the absorption and accumulation of these elements by macroalgae in the area. PMID- 22505918 TI - Interaction of avelox with bovine serum albumin and effect of the coexistent drugs on the reaction. AB - The interaction between Avelox and bovine serum albumin (BSA) was investigated at different temperatures by fluorescence spectroscopy. Results showed that Avelox could quench the intrinsic fluorescence of BSA strongly, and the quenching mechanism was a static quenching process with Forester spectroscopy energy transfer. The electrostatic force played an important role on the conjugation reaction between BSA and Avelox. The order of magnitude of binding constants (K(a)) was 10(4), and the number of binding site (n) in the binary system was approximately equal to 1. The binding distance (r) was less than 3 nm and the primary binding site for Avelox was located in subdomain IIA of BSA. Synchronous fluorescence spectra clearly revealed that the microenvironment of amino acid residues and the conformation of BSA were changed during the binding reaction. In addition, the effect of some antibiotics on the binding constant of Avelox with BSA was also studied. PMID- 22505919 TI - Elemental contents in hair of children from two regions in dar es salaam. AB - The work presented in this paper is part of the study which aims at determining the levels of elements in hair of children in Tanzania as a bioindicator of their nutrition and health. In this paper, the levels of trace elements in hair from children living in Dar es Salaam have been analysed. The analysis was carried out by long and short irradiation INAA at the reactor centre of the Institute of Nuclear Physics, Rez Czech Republic. 22 samples were collected from children living at Kiwalani about 12 km from Dar es Salaam city and 16 samples from children living at Mlimani, the main campus of University of Dar es Salaam. A total of 34 elements were found in the hair of the children. There were no big differences between the concentration levels of the essential elements in hair samples collected from the children which might indicate the same food consumption habits. PMID- 22505921 TI - Uptake of Seeds Secondary Metabolites by Virola surinamensis Seedlings. AB - The major secondary metabolites and fatty acids occurring in the seeds of Virola surinamensis were monitored by GC-MS during germination and seedling development. The role as carbon source for seedling development was indicated considering that both classes of compounds were similarly consumed in the seeds and that no selective consumption of compounds could be detected. PMID- 22505920 TI - Sensitive determination of terazosin in pharmaceutical formulations and biological samples by ionic-liquid microextraction prior to spectrofluorimetry. AB - An efficient and environmentally friendly sample preparation method based on the application of hydrophobic 1-Hexylpyridinium hexafluorophosphate [Hpy][PF(6)] ionic liquid (IL) as a microextraction solvent was proposed to preconcentrate terazosin. The performance of the microextraction method was improved by introducing a common ion of pyridinium IL into the sample solution. Due to the presence of the common ion, the solubility of IL significantly decreased. As a result, the phase separation successfully occurred even at high ionic strength, and the volume of the settled IL-phase was not influenced by variations in the ionic strength (up to 30% w/v). After preconcentration step, the enriched phase was introduced to the spectrofluorimeter for the determination of terazosin. The obtained results revealed that this system did not suffer from the limitations of that in conventional ionic-liquid microextraction. Under optimum experimental conditions, the proposed method provided a limit of detection (LOD) of 0.027 MUg L(-1) and a relative standard deviation (R.S.D.) of 2.4%. The present method was successfully applied to terazosin determination in actual pharmaceutical formulations and biological samples. Considering the large variety of ionic liquids, the proposed microextraction method earns many merits, and will present a wide application in the future. PMID- 22505922 TI - Micellar liquid chromatographic determination of carbaryl and 1-naphthol in water, soil, and vegetables. AB - A liquid chromatographic procedure has been developed for the determination of carbaryl, a phenyl-N-methylcarbamate, and its main metabolite 1-naphthol, using a C18 column (250 mm * 4.6 mm) with a micellar mobile phase and fluorescence detection at maximum excitation/emission wavelengths of 225/333 nm, respectively. In the optimization step, surfactants sodium dodecyl sulphate (SDS), Brij-35 and N-cetylpyridinium chloride monohydrate, and organic solvents propanol, butanol, and pentanol were considered. The selected mobile phase was 0.15 M SDS-6% (v/v) pentanol-0.01 M NaH(2)PO(4) buffered at pH 3. Validation studies, according to the ICH Tripartite Guideline, included linearity (r > 0.999), limit of detection (5 and 18 ng mL(-1), for carbaryl and 1-naphthol, resp.), and limit of quantification (15 and 50 ng mL(-1), for carbaryl and 1-naphthol, resp.), with intra- and interday precisions below 1%, and robustness parameters below 3%. The results show that the procedure was adequate for the routine analysis of these two compounds in water, soil, and vegetables samples. PMID- 22505923 TI - Determination of Total Selenium in Infant Formulas: Comparison of the Performance of FIA and MCFA Flow Systems. AB - Two flow methods, based, respectively, on flow-injection analysis (FIA) and on multicommutated flow analysis (MCFA), were compared with regard to their use for the determination of total selenium in infant formulas by hydride-generation atomic absorption spectrometry. The method based on multicommutation provided lower detection and quantification limits (0.08 and 0.27 MUg L(-1) compared to 0.59 and 1.95 MU L(-1), resp.), higher sampling frequency (160 versus. 70 samples per hour), and reduced reagent consumption. Linearity, precision, and accuracy were similar for the two methods compared. It was concluded that, while both methods proved to be appropriate for the purpose, the MCFA-based method exhibited a better performance. PMID- 22505924 TI - Multilayer Films Electrodes Consisted of Cashew Gum and Polyaniline Assembled by the Layer-by-Layer Technique: Electrochemical Characterization and Its Use for Dopamine Determination. AB - We take advantage of polyelectrolyte feature exhibited by natural cashew gum (Anacardium occidentale L.) (CG), found in northeast Brazil, to employ it in the formation of electroactive nanocomposites prepared by layer-by-layer (LbL) technique. We used polyaniline unmodified (PANI) or modified with phosphonic acid (PA), PANI-PA as cationic polyelectrolyte. On the other hand, the CG or polyvinyl sulfonic (PVS) acids were used as anionic polyelectrolytes. The films were prepared with PANI or PANI-PA intercalated with CG or with PVS alternately resulting in four films with different sequences: PANI/CG PANI-PA/CG, PANI/PVS and PANI-PA/PVS, respectively. Analysis by cyclic voltammetry (CV) of the films showed that the presence of gum increases the stability of the films in acidic medium. The performance of the modified electrode of PANI-PA/CG was evaluated in electro analytical determination of dopamine (DA). The tests showed great sensitivity of the film for this analyte that was detected at 10(-5) mol L(-1). PMID- 22505925 TI - Spectrophotometric Determination of Iron(II) and Cobalt(II) by Direct, Derivative, and Simultaneous Methods Using 2-Hydroxy-1-Naphthaldehyde-p Hydroxybenzoichydrazone. AB - Optimized and validated spectrophotometric methods have been proposed for the determination of iron and cobalt individually and simultaneously. 2-hydroxy-1 naphthaldehyde-p-hydroxybenzoichydrazone (HNAHBH) reacts with iron(II) and cobalt(II) to form reddish-brown and yellow-coloured [Fe(II)-HNAHBH] and [Co(II) HNAHBH] complexes, respectively. The maximum absorbance of these complexes was found at 405 nm and 425 nm, respectively. For [Fe(II)-HNAHBH], Beer's law is obeyed over the concentration range of 0.055-1.373 MUg mL(-1) with a detection limit of 0.095 MUg mL(-1) and molar absorptivity E, 5.6 * 10(4) L mol(-1) cm(-1). [Co(II)-HNAHBH] complex obeys Beer's law in 0.118-3.534 MUg mL(-1) range with a detection limit of 0.04 MUg mL(-1) and molar absorptivity, E of 2.3 * 10(4) L mol(-1) cm(-1). Highly sensitive and selective first-, second- and third-order derivative methods are described for the determination of iron and cobalt. A simultaneous second-order derivative spectrophotometric method is proposed for the determination of these metals. All the proposed methods are successfully employed in the analysis of various biological, water, and alloy samples for the determination of iron and cobalt content. PMID- 22505927 TI - Three-Axis Model for Atg Recruitment in Autophagy against Salmonella. AB - Salmonella enterica serovar Typhimurium enter epithelial cells and take up residence there. Within epithelial cells, a portion of the bacteria are surrounded by an autophagosome-like double-membrane structure, and they are still residing within the Salmonella-containing vacuole (SCV). In this paper, we will discuss how the autophagy machinery is recruited in proximity to Salmonella. The formation of this double membrane requires Atg9L1 and FIP200; these proteins are important for autophagy-specific recruitment of the PI3-kinase complex. In the absence of Atg9L1, FIP200, and PI3-kinase activity, LC3 is still recruited to the vicinity of Salmonella. We propose a novel model in which the mechanism of LC3 recruitment is separate from the generation of the isolation membrane. There exist at least three axes in Atg recruitment: ULK1 complex, Atg9L1, and Atg16L complex. PMID- 22505928 TI - Effects of Cisplatin in neuroblastoma rat cells: damage to cellular organelles. AB - Cisplatin (cisPt) is a chemotherapy agent used as a treatment for several types of cancer. The main cytotoxic effect of cisplatin is generally accepted to be DNA damage. Recently, the mechanism by which cisPt generates the cascade of events involved in the apoptotic process has been demonstrated. In particular it has been shown that some organelles are cisPt target and are involved in cell death. This paper aims to describe the morphological and functional changes of the Golgi apparatus and lysosomes during apoptosis induced in neuronal rat cells (B50) by cisplatin. The results obtained show that the cellular organelles are the target of cisPt, so their damage can induce cell death. PMID- 22505926 TI - Anoikis resistance: an essential prerequisite for tumor metastasis. AB - Metastasis is a multistep process including dissociation of cancer cells from primary sites, survival in the vascular system, and proliferation in distant target organs. As a barrier to metastasis, cells normally undergo an apoptotic process known as "anoikis," a form of cell death due to loss of contact with the extracellular matrix or neighboring cells. Cancer cells acquire anoikis resistance to survive after detachment from the primary sites and travel through the circulatory and lymphatic systems to disseminate throughout the body. Because recent technological advances enable us to detect rare circulating tumor cells, which are anoikis resistant, currently, anoikis resistance becomes a hot topic in cancer research. Detailed molecular and functional analyses of anoikis resistant cells may provide insight into the biology of cancer metastasis and identify novel therapeutic targets for prevention of cancer dissemination. This paper comprehensively describes recent investigations of the molecular and cellular mechanisms underlying anoikis and anoikis resistance in relation to intrinsic and extrinsic death signaling, epithelial-mesenchymal transition, growth factor receptors, energy metabolism, reactive oxygen species, membrane microdomains, and lipid rafts. PMID- 22505929 TI - Macrophage Migration and Its Regulation by CSF-1. AB - Macrophages are terminally differentiated cells of the mononuclear phagocytic lineage and develop under the stimulus of their primary growth and differentiation factor, CSF-1. Although they differentiate into heterogeneous populations, depending upon their tissue of residence, motility is an important aspect of their function. To facilitate their migration through tissues, macrophages express a unique range of adhesion and cytoskeletal proteins. Notably, macrophages do not form large, stable adhesions or actin stress fibers but rely on small, short lived point contacts, focal complexes and podosomes for traction. Thus, macrophages are built to respond rapidly to migratory stimuli. As well as triggering growth and differentiation, CSF-1 is also a chemokine that regulates macrophage migration via activation the CSF-1 receptor tyrosine kinase. CSF-1R autophosphorylation of several intracellular tyrosine residues leads to association and activation of many downstream signaling molecules. However, phosphorylation of just one residue, Y721, mediates association of PI3K with the receptor to activate the major motility signaling pathways in macrophages. Dissection of these pathways will identify drug targets for the inhibition of diseases in which macrophages contribute to adverse outcomes. PMID- 22505930 TI - KSHV-Encoded MicroRNAs: Lessons for Viral Cancer Pathogenesis and Emerging Concepts. AB - The human genome contains microRNAs (miRNAs), small noncoding RNAs that orchestrate a number of physiologic processes through regulation of gene expression. Burgeoning evidence suggests that dysregulation of miRNAs may promote disease progression and cancer pathogenesis. Virus-encoded miRNAs, exhibiting unique molecular signatures and functions, have been increasingly recognized as contributors to viral cancer pathogenesis. A large segment of the existing knowledge in this area has been generated through characterization of miRNAs encoded by the human gamma-herpesviruses, including the Kaposi's sarcoma associated herpesvirus (KSHV). Recent studies focusing on KSHV miRNAs have led to a better understanding of viral miRNA expression in human tumors, the identification of novel pathologic check points regulated by viral miRNAs, and new insights for viral miRNA interactions with cellular ("human") miRNAs. Elucidating the functional effects of inhibiting KSHV miRNAs has also provided a foundation for further translational efforts and consideration of clinical applications. This paper summarizes recent literature outlining mechanisms for KSHV miRNA regulation of cellular function and cancer-associated pathogenesis, as well as implications for interactions between KSHV and human miRNAs that may facilitate cancer progression. Finally, insights are offered for the clinical feasibility of targeting miRNAs as a therapeutic approach for viral cancers. PMID- 22505931 TI - PKC-Mediated ZYG1 Phosphorylation Induces Fusion of Myoblasts as well as of Dictyostelium Cells. AB - We have previously demonstrated that a novel protein ZYG1 induces sexual cell fusion (zygote formation) of Dictyostelium cells. In the process of cell fusion, involvements of signal transduction pathways via Ca(2+) and PKC (protein kinase C) have been suggested because zygote formation is greatly enhanced by PKC activators. In fact, there are several deduced sites phosphorylated by PKC in ZYG1 protein. Thereupon, we designed the present work to examine whether or not ZYG1 is actually phosphorylated by PKC and localized at the regions of cell-cell contacts where cell fusion occurs. These were ascertained, suggesting that ZYG1 might be the target protein for PKC. A humanized version of zyg1 cDNA (mzyg1) was introduced into myoblasts to know if ZYG1 is also effective in cell fusion of myoblasts. Quite interestingly, enforced expression of ZYG1 in myoblasts was found to induce markedly their cell fusion, thus strongly suggesting the existence of a common signaling pathway for cell fusion beyond the difference of species. PMID- 22505932 TI - Distinct MicroRNA Subcellular Size and Expression Patterns in Human Cancer Cells. AB - Introduction. Small noncoding RNAs have important regulatory functions in different cell pathways. It is believed that most of them mainly play role in gene post-transcriptional regulation in the cytoplasm. Recent evidence suggests miRNA and siRNA activity in the nucleus. Here, we show distinct genome-wide sub cellular localization distribution profiles of small noncoding RNAs in human breast cancer cells. Methods. We separated breast cancer cell nuclei from cytoplasm, and identified small RNA sequences using a high-throughput sequencing platform. To determine the relationship between miRNA sub-cellular distribution and cancer progression, we used microarray analysis to examine the miRNA expression levels in nucleus and cytoplasm of three human cell lines, one normal breast cell line and two breast cancer cell lines. Logistic regression and SVM were used for further analysis. Results. The sub-cellular distribution of small noncoding RNAs shows that numerous miRNAs and their isoforms (isomiR) not only locate to the cytoplasm but also appeare in the nucleus. Subsequent microarray analyses indicated that the miRNA nuclear-cytoplasmic-ratio is a significant characteristic of different cancer cell lines. Conclusions. Our results indicate that the sub-cellular distribution is important for miRNA function, and that the characterization of the small RNAs sub-cellular localizome may contribute to cancer research and diagnosis. PMID- 22505933 TI - Cancer cell adhesion and metastasis: selectins, integrins, and the inhibitory potential of heparins. AB - Cell adhesion molecules play a significant role in cancer progression and metastasis. Cell-cell interactions of cancer cells with endothelium determine the metastatic spread. In addition, direct tumor cell interactions with platelets, leukocytes, and soluble components significantly contribute to cancer cell adhesion, extravasation, and the establishment of metastatic lesions. Clinical evidence indicates that heparin, commonly used for treatment of thromboembolic events in cancer patients, is beneficial for their survival. Preclinical studies confirm that heparin possesses antimetastatic activities that lead to attenuation of metastasis in various animal models. Heparin contains several biological activities that may affect several steps in metastatic cascade. Here we focus on the role of cellular adhesion receptors in the metastatic cascade and discuss evidence for heparin as an inhibitor of cell adhesion. While P- and L-selectin facilitation of cellular contacts during hematogenous metastasis is being accepted as a potential target of heparin, here we propose that heparin may also interfere with integrin activity and thereby affect cancer progression. This review summarizes recent findings about potential mechanisms of tumor cell interactions in the vasculature and antimetastatic activities of heparin. PMID- 22505935 TI - Annexin A2 at the interface of actin and membrane dynamics: a focus on its roles in endocytosis and cell polarization. AB - Annexins are a family of calcium- and phospholipid-binding proteins found in nearly all eukaryotes. They are structurally highly conserved and have been implicated in a wide range of cellular activities. In this paper, we focus on Annexin A2 (AnxA2). Altered expression of this protein has been identified in a wide variety of cancers, has also been found on the HIV particle, and has been implicated in the maturation of the virus. Recently, it has also been shown to have an important role in the establishment of normal apical polarity in epithelial cells. We synthesize here the known biochemical properties of this protein and the extensive literature concerning its involvement in the endocytic pathway. We stress the importance of AnxA2 as a platform for actin remodeling in the vicinity of dynamic cellular membranes, in the hope that this may shed light on the normal functions of the protein and its contribution to disease. PMID- 22505934 TI - Prostaglandins in cancer cell adhesion, migration, and invasion. AB - Prostaglandins exert a profound influence over the adhesive, migratory, and invasive behavior of cells during the development and progression of cancer. Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E(2) synthase-1 (mPGES-1) are upregulated in inflammation and cancer. This results in the production of prostaglandin E(2) (PGE(2)), which binds to and activates G-protein-coupled prostaglandin E(1-4) receptors (EP(1-4)). Selectively targeting the COX-2/mPGES 1/PGE(2)/EP(1-4) axis of the prostaglandin pathway can reduce the adhesion, migration, invasion, and angiogenesis. Once stimulated by prostaglandins, cadherin adhesive connections between epithelial or endothelial cells are lost. This enables cells to invade through the underlying basement membrane and extracellular matrix (ECM). Interactions with the ECM are mediated by cell surface integrins by "outside-in signaling" through Src and focal adhesion kinase (FAK) and/or "inside-out signaling" through talins and kindlins. Combining the use of COX-2/mPGES-1/PGE(2)/EP(1-4) axis-targeted molecules with those targeting cell surface adhesion receptors or their downstream signaling molecules may enhance cancer therapy. PMID- 22505936 TI - Integrins and their extracellular matrix ligands in lymphangiogenesis and lymph node metastasis. AB - In the 1970s, the late Judah Folkman postulated that tumors grow proportionately to their blood supply and that tumor angiogenesis removed this limitation promoting growth and metastasis. Work over the past 40 years, varying from molecular examination to clinical trials, verified this hypothesis and identified a host of therapeutic targets to limit tumor angiogenesis, including the integrin family of extracellular matrix receptors. However, the propensity for some tumors to spread through lymphatics suggests that lymphangiogenesis plays a similarly important role. Lymphangiogenesis inhibitors reduce lymph node metastasis, the leading indicator of poor prognosis, whereas inducing lymphangiogenesis promotes lymph node metastasis even in cancers not prone to lymphatic dissemination. Recent works highlight a role for integrins in lymphangiogenesis and suggest that integrin inhibitors may serve as therapeutic targets to limit lymphangiogenesis and lymph node metastasis. This review discusses the current literature on integrin-matrix interactions in lymphatic vessel development and lymphangiogenesis and highlights our current knowledge on how specific integrins regulate tumor lymphangiogenesis. PMID- 22505937 TI - IQGAP Family Members in Yeast, Dictyostelium, and Mammalian Cells. AB - IQGAPs are a family of scaffolding proteins with multiple domains, named for the IQ motifs and GTPase activating protein (GAP) related domains. Despite their GAP homology, IQGAP proteins act as effectors for GTP-bound GTPases of the Ras superfamily and do not stimulate GTP hydrolysis. IQGAPs are found in eukaryotic cells from yeast to human, and localize to actin-containing structures such as lamellipodia, membrane ruffles, cell-cell adhesions, phagocytic cups, and the actomyosin ring formed during cytokinesis. Mammalian IQGAPs also act as scaffolds for signaling pathways. IQGAPs perform their myriad functions through association with a large number of proteins including filamentous actin (F-actin), GTPases, calcium-binding proteins, microtubule binding proteins, kinases, and receptors. The focus of this paper is on recent studies describing new binding partners, mechanisms of regulation, and biochemical and physiological functions of IQGAPs in yeast, amoeba, and mammalian cells. PMID- 22505938 TI - Actin dynamics associated with focal adhesions. AB - Cell-matrix adhesion plays a major role during cell migration. Proteins from adhesion structures connect the extracellular matrix to the actin cytoskeleton, allowing the growing actin network to push the plasma membrane and the contractile cables (stress fibers) to pull the cell body. Force transmission to the extracellular matrix depends on several parameters including the regulation of actin dynamics in adhesion structures, the contractility of stress fibers, and the mechanosensitive response of adhesion structures. Here we highlight recent findings on the molecular mechanisms by which actin assembly is regulated in adhesion structures and the molecular basis of the mechanosensitivity of focal adhesions. PMID- 22505939 TI - PI3K/AKT/PTEN Signaling as a Molecular Target in Leukemia Angiogenesis. AB - PI3K/AKT/PTEN pathway is important in the regulation of angiogenesis mediated by vascular endothelial growth factor in many tumors including leukemia. The signaling pathway is activated in leukemia patients as well as leukemia cell lines together with a decrease in the expression of PTEN gene. The mechanism by which the signaling pathway regulates angiogenesis remains to be further elucidated. However, it has become an attractive target for drug therapy against leukemia, because angiogenesis is a key process in malignant cell growth. In this paper, we will focus on the roles and mechanisms of PI3K/AKT/PTEN pathway in regulating angiogenesis. PMID- 22505940 TI - Measuring Thickness of Middle Ear Mucosa Using MRI and CT Imaging versus Histopathology. AB - Objective. Otitis media (OM) is characterized by increased middle ear effusion and inflammation of middle ear tissue. In this study, we compared two radiographic methods of analyzing inflammation by measuring mucosal thickness (MT). Methods. 28 chinchillas were divided into three treatment groups consisting of a vehicle control group and two glucocorticoid groups. 6 underwent treatment by vehicle control, 10 were treated with ciprofloxacin 0.3%/dexamethasone 0.1% (DEX), and 10 received ciprofloxacin 0.2%/hydrocortisone 1% (HC). 96 hrs post-LPS inoculation, chinchillas were euthanized and their temporal bones were removed for analyses. Results. MRI scans (F = 146.0861, P-value <0.0001) and histology (chi(2) = 40.5267, P-value <0.0001) revealed statistically significant differences in MT measurements among treatment groups, whereas CT imaging did not. DEX-treated chinchillas exhibited overall significantly smaller MT values. Conclusion. Imaging MT was effective for determining severity of inflammation due to OM. Previous gold standard methods using histopathology compromise tissue integrity by chemical manipulation and dehydration effects. MRI and CT scanning are viable tools to preserve tissue and examine changes in MT. In this study, MRI provided more information about internal, soft tissue structures. In a clinical setting, MRI could be used for diagnosing and tracking severe or chronic OM. PMID- 22505942 TI - Effectiveness of Space Spraying on the Transmission of Dengue/Dengue Hemorrhagic Fever (DF/DHF) in an Urban Area of Southern Thailand. AB - Timely and extensive space spraying has been widely used to prevent the spread of dengue fever/dengue hemorrhagic fever (DF/DHF). Field evaluations on its effectiveness have been rarely reported. This study aimed to evaluate the timeliness, coverage, and effectiveness of space spraying for DF/DHF control using a geographic information system (GIS). Longitudinal monitoring of DF/DHF cases and spray activities in Songkhla municipality was done between May 2006 and April 2007. After a case was detected, subsequent cases occurring within a 100 meter radius of the index case's house and between 16-35 days of onset were considered as potential secondary cases. During the study period, 140 cases of DF/DHF were detected. Of these, 25 were identified as secondary infections from 20 index cases. Where a secondary infection occurred, the mean attack rate was 2.7 per 1,000 population. Two significant predictors for being a secondary case were both related to the house of the index case, namely, absence of window screens and being constructed with corrugated iron sheets. Our findings suggest that space spraying in the study area was inadequate and often failed to prevent secondary cases of DF/DHF. Control programs should target houses constructed with corrugated iron sheets. PMID- 22505941 TI - TNF-Alpha in the Locomotor System beyond Joints: High Degree of Involvement in Myositis in a Rabbit Model. AB - The importance of TNF-alpha in arthritis is well documented. It may be that TNF alpha is also markedly involved in muscle inflammation (myositis). An animal model where this can be investigated is needed. A newly developed rabbit myositis model involving pronounced muscle overuse and local injections of substances having proinflammatory effects was therefore used in the present study. The aim was to investigate the patterns of TNF-alpha expression in the developing myositis and to evaluate the usefulness of this myositis model for further TNF alpha research. Human rheumatoid arthritis (RA) synovial tissue was examined as a reference. TNF-alpha immunoexpression and TNF-alpha mRNA, visualized via in situ hybridization, were detected in cells in the inflammatory infiltrates of the affected muscle (soleus muscle). Coexistence of TNF-alpha and CD68 immunoreactions was noted, suggesting that the TNF-alpha reactive cells are macrophages. Expression of TNF-alpha mRNA was also noted in muscle fibers and blood vessel walls in areas with inflammation. These findings demonstrate that TNF-alpha is highly involved in the myositis process. The model can be used in further studies evaluating the importance of TNF-alpha in developing myositis. PMID- 22505943 TI - Dynamics of Lymphocyte Populations during Trypanosoma cruzi Infection: From Thymocyte Depletion to Differential Cell Expansion/Contraction in Peripheral Lymphoid Organs. AB - The comprehension of the immune responses in infectious diseases is crucial for developing novel therapeutic strategies. Here, we review current findings on the dynamics of lymphocyte subpopulations following experimental acute infection by Trypanosoma cruzi, the causative agent of Chagas disease. In the thymus, although the negative selection process of the T-cell repertoire remains operational, there is a massive thymocyte depletion and abnormal release of immature CD4(+)CD8(+) cells to peripheral lymphoid organs, where they acquire an activated phenotype similar to activated effector or memory T cells. These cells apparently bypassed the negative selection process, and some of them are potentially autoimmune. In infected animals, an atrophy of mesenteric lymph nodes is also observed, in contrast with the lymphocyte expansion in spleen and subcutaneous lymph nodes, illustrating a complex and organ specific dynamics of lymphocyte subpopulations. Accordingly, T- and B-cell activation is seen in subcutaneous lymph nodes and spleen, but not in mesenteric lymph nodes. Lastly, although the function of peripheral CD4(+)CD8(+) T-cell population remains to be defined in vivo, their presence may contribute to the immunopathological events found in both murine and human Chagas disease. PMID- 22505944 TI - Sex differences in vascular compliance in normal-weight but not obese boys and girls: the effect of body composition. AB - Objectives. To determine the effect of sex and obesity on vascular function in children and explore potential mechanisms that account for differences in vascular function. Methods. Participants were 61 (30 boys) normal-weight (BMI 25 75% ile for age and sex) and 62 (30 boys) obese (BMI >= 95% ile) children of ages 8-18 years. Measurements of large and small artery elastic index (LAEI and SAEI, resp.) and reactive hyperemia index (RHI) were obtained at rest, along with anthropometric and biochemical information. Results. In normal-weight children, LAEI was 16% higher in males than females (P = 0.04) with a similar trend for SAEI (13% higher in males, P = 0.067). In obese children, no sex-related differences in vascular measures were observed. In multivariable models, sex differences in arterial compliance were explained by higher lean mass in normal weight boys. Fat mass predicted LAEI and SAEI in both normal-weight and obese females, but fat mass predicted arterial compliance in boys when fat mass exceeded 24 kg (37% of the sample). Conclusions. Normal-weight males have higher arterial compliance than normal-weight females due to increased lean mass, but sex-related differences were not observed among obese children due to a lack of sex-related differences in lean or fat mass. PMID- 22505945 TI - Chloride Balance in Preterm Infants during the First Week of Life. AB - Objective. To describe the chloride balance in infants born 25-32-week gestation, analyze the association of chloride changes with hydroelectrolytic status and their relationship with perinatal conditions, morbidities, and neurological outcome. Methods. For 7 days after birth, sodium and chloride balance, plasma potassium, phosphate, and total carbon dioxide (tCO(2)) were prospectively determined and strong ion difference (SID) calculated. Three multivariate regression analyses were performed to identify factors associated with high plasma chloride concentration, low SID, and low tCO(2). Results. 107 infants were studied. Plasma chloride concentration was significantly positively associated with plasma sodium concentration. Higher plasma chloride and lower SID were significantly associated with lower plasma tCO(2). Chloride intake was the main independent factor associated with high plasma chloride, low SID, and low plasma tCO(2), with lesser contribution of sodium intake and low gestational age (GA). Also, patent ductus arteriosus and birth weight loss were independent factors affecting plasma chloride and SID. Neither high chloride levels nor low SID were associated to impaired neurological outcome. Conclusions. In preterm infants, chloride balance is influenced by GA and by interrelationship between sodium and chloride intake. High chloride levels are associated with metabolic acidosis but not related to increased risk of impaired neurological outcome. PMID- 22505946 TI - Effect of Rabbit Epididymal Antimicrobial Peptide, REHbbetaP, on LPS-Induced Proinflammatory Cytokine Responses in Human Vaginal Cells In Vitro. AB - Antimicrobial peptides (AMP's) protect epithelial surfaces including epididymis against pathogens and play a key role in orchestrating various defensive responses. Recently, we have identified one such AMP, rabbit epididymal hemoglobin-beta subuit (REHbbetaP) from the epididymal fluid of rabbit, Oryctologus cuniculus. The demonstration of a protective role of REHbbetaP in epididymal epithelial cells (EPEC's) led us to investigate: (1) the identification of LPS interactive domain in REHbbetaP, and (2) whether the REHbbetaP of rabbit origin mediates vaginal cellular immune responses of another species (human). HeLa-S3, human vaginal epithelial cells (hVECs) were exposed to LPS or the LPS-stimulated cells treated with REHbbetaP or neutral peptide, nREHbbetaP. Effect of LPS and cytokines (IL-6 and IL-1alpha) and chemokines (IL 8, MCP-1) levels was determined in the culture supernatants. In response to the LPS, hVECs synthesized these mediators and the levels were significantly higher than controls. This enhancing effect was ameliorated when the LPS-induced hVECs were treated with REHbbetaP. Similar results were obtained on NF-kappaB protein and hBD-1 mRNA expression. Confocal microscopy studies revealed that REHbbetaP attenuated the LPS-induced internalization of E. coli by macrophages. The chemotaxis studies performed using Boyden chamber Transwell assay, which showed elevated migration of U937 cells when the supernatants of LPS-induced hVECs were used, and the effect was inhibited by REHbbetaP. REHbbetaP was found to be localized on the acrosome of rabbit spermatozoa, suggesting its role in sperm protection beside sperm function. In conclusion, REHbbetaP may have the potential to develop as a therapeutic agent for reproductive tract infections (RTI's). PMID- 22505947 TI - Measurement of inhaled corticosteroid adherence in inner-city, minority children with persistent asthma by parental report and integrated dose counter. AB - Parents often overreport adherence to asthma treatment regimens making accurate assessment of medication adherence in clinical practice difficult. This study was conducted to compare two adherence assessment methods clinicians may choose from when assessing patient inhaled corticosteroid (ICS) adherence: parental report and dose counter measurements of metered-dose inhaler (MDI) actuation. Participants included children (N = 50) with persistent asthma and their parents (N = 50). At enrollment, children received a new, marked ICS at the dose prescribed by their physician. Thirty days following enrollment, we measured ICS adherence by parental report and objectively, with a dose counter. Parental report overestimated ICS adherence when compared to dose counter. We found a statistically significant overall difference between parental report and objectively measured adherence. A dose counter that most ICS inhalers are equipped with may be a more reliable alternative measure of ICS adherence in a clinical practice setting. PMID- 22505949 TI - Protecting privacy of shared epidemiologic data without compromising analysis potential. AB - OBJECTIVE: Ensuring privacy of research subjects when epidemiologic data are shared with outside collaborators involves masking (modifying) the data, but overmasking can compromise utility (analysis potential). Methods of statistical disclosure control for protecting privacy may be impractical for individual researchers involved in small-scale collaborations. METHODS: We investigated a simple approach based on measures of disclosure risk and analytical utility that are straightforward for epidemiologic researchers to derive. The method is illustrated using data from the Japanese Atomic-bomb Survivor population. RESULTS: Masking by modest rounding did not adequately enhance security but rounding to remove several digits of relative accuracy effectively reduced the risk of identification without substantially reducing utility. Grouping or adding random noise led to noticeable bias. CONCLUSIONS: When sharing epidemiologic data, it is recommended that masking be performed using rounding. Specific treatment should be determined separately in individual situations after consideration of the disclosure risks and analysis needs. PMID- 22505948 TI - Arsenic, cadmium, lead, and mercury in sweat: a systematic review. AB - Arsenic, cadmium, lead, and mercury exposures are ubiquitous. These toxic elements have no physiological benefits, engendering interest in minimizing body burden. The physiological process of sweating has long been regarded as "cleansing" and of low risk. Reports of toxicant levels in sweat were sought in Medline, Embase, Toxline, Biosis, and AMED as well as reference lists and grey literature, from inception to March 22, 2011. Of 122 records identified, 24 were included in evidence synthesis. Populations, and sweat collection methods and concentrations varied widely. In individuals with higher exposure or body burden, sweat generally exceeded plasma or urine concentrations, and dermal could match or surpass urinary daily excretion. Arsenic dermal excretion was severalfold higher in arsenic-exposed individuals than in unexposed controls. Cadmium was more concentrated in sweat than in blood plasma. Sweat lead was associated with high-molecular-weight molecules, and in an interventional study, levels were higher with endurance compared with intensive exercise. Mercury levels normalized with repeated saunas in a case report. Sweating deserves consideration for toxic element detoxification. Research including appropriately sized trials is needed to establish safe, effective therapeutic protocols. PMID- 22505950 TI - Impact of summer cattle grazing on the Sierra Nevada watershed: aquatic algae and bacteria. AB - INTRODUCTION: We evaluated periphytic algal and microbial communities to assess the influence of human and cattle impact on Sierra water quality. METHODS: 64 sites (lakes and streams from Lake Tahoe to Sequoia National Park, California) were sampled for suspended indicator bacteria and algae following standardized procedures. The potential for nonpoint pollution was divided into three categories: cattle-grazing areas (C), recreation use areas (R), or remote wildlife areas (W). RESULTS: Periphyton was found at 100% of C sites, 89% of R sites, but only 25% of W sites. Eleven species of periphytic algae were identified, including Zygnema, Ulothrix, Chlorella, Spirogyra, mixed Diatoms, and Cladophoria. Mean benthic algae coverage was 66% at C sites compared to 2% at W sites (P < 0.05). The prevalence of E. coli associated with periphyton was 100% at C sites, 25% of R sites, and 0% of W sites. Mean E. coli CFU/gm of algae detected was: C = 173,000, R = 700, W = 0. (P < 0.05). Analysis of neighboring water for E. coli bacteria >100 CFU/100 mL: C = 91%, R = 8%, W = 0 (P < 0.05). CONCLUSION: Higher periphytic algal biomass and uniform presence of periphyton attached E. coli corresponded to watersheds exposed to summer cattle grazing. These differences suggest cattle grazing compromises water quality. PMID- 22505951 TI - Human biological monitoring of diisononyl phthalate and diisodecyl phthalate: a review. AB - High molecular-weight phthalates, such as diisononyl phthalate (DINP), and diisodecyl phthalate (DIDP), are widely used as plasticizers in the manufacturing of polymers and consumer products. Human biological monitoring studies have employed the metabolites of DINP and DIDP as biomarkers to assess human exposure. In this review, we summarize and analyze publicly available scientific data on chemistry, metabolism, and excretion kinetics, of DINP and DIDP, to identify specific and sensitive metabolites. Human biological monitoring data on DINP and DIDP are scrutinised to assess the suitability of these metabolites as biomarkers of exposure. Results from studies carried out in animals and humans indicate that phthalates are metabolised rapidly and do not bioaccmulate. During Phase-I metabolism, ester hydrolysis of DINP and DIDP leads to the formation of hydrolytic monoesters. These primary metabolites undergo further oxidation reactions to produce secondary metabolites. Hence, the levels of secondary metabolites of DINP and DIDP in urine are found to be always higher than the primary metabolites. Results from human biological monitoring studies have shown that the secondary metabolites of DINP and DIDP in urine were detected in almost all tested samples, while the primary metabolites were detected in only about 10% of the samples. This indicates that the secondary metabolites are very sensitive biomarkers of DINP/DIDP exposure while primary metabolites are not. The NHANES data indicate that the median concentrations of MCIOP and MCINP (secondary metabolites of DINP and DIDP, resp.) at a population level are about 5.1 MUg/L and 2.7 MUg/L, respectively. Moreover, the available biological monitoring data suggest that infants/children are exposed to higher levels of phthalates than adults. PMID- 22505952 TI - Oral tolerance induced by transfer of food antigens via breast milk of allergic mothers prevents offspring from developing allergic symptoms in a mouse food allergy model. AB - We examined whether maternal exposure to food antigens during lactation and maternal allergic status would affect the development of food allergy in offspring. OVA-sensitized or OVA-nonsensitized BALB/c female mice were exposed or unexposed to OVA during lactation. After weaning, their offspring were systemically sensitized twice with OVA and repeatedly given OVA by oral intubation. While 97.1% of the mice breastfed by OVA-nonsensitized and OVA unexposed mothers developed allergic diarrhea, 59.7% of the mice breastfed by OVA exposed nonallergic mothers during lactation and 24.6% of the mice breastfed by OVA-exposed allergic mothers during lactation developed food allergy. Furthermore, OVA was detected in breast-milk from OVA-exposed nonallergic mothers during lactation (4.6 +/- 0.5 MUg/mL). In addition, OVA-specific IgG1 titers were markedly increased in breast milk from allergic mothers (OVA-sensitized and OVA unexposed mother: 11.0 +/- 0.5, OVA-sensitized and OVA-exposed mother: 12.3 +/- 0.3). Our results suggest that oral tolerance induced by breast milk-mediated transfer of dietary antigens along with their specific immunoglobulins to offspring leads to antigen-specific protection from food allergy. PMID- 22505954 TI - Semiparametric Transformation Rate Model for Recurrent Event Data. AB - In this article, we propose a class of semiparametric transformation rate models for recurrent event data subject to right-censoring and potentially stopped by a terminating event (e.g., death). These transformation models include both additive rates model and proportional rates model as special cases. Respecting the property that no recurrent events can occur after the terminating event, we model the conditional recurrent event rate given survival. Weighted estimating equations are constructed to estimate the regression coefficients and baseline rate function. In particular, the baseline rate function is approximated by wavelet function. Asymptotic properties of the proposed estimators are derived and a data-dependent criterion is proposed for selecting the most suitable transformation. Simulation studies show that the proposed estimators perform well for practical sample sizes. The proposed methods are used in two real-data examples: a randomized trial of rhDNase and a community trial of Vitamin A. PMID- 22505955 TI - The Neuroprotective Effect of Genetic Mannose-binding Lectin Deficiency is not Sustained in the Sub-acute Phase of Stroke. AB - INTRODUCTION: The complement cascade is a critical mediator of the inflammatory response following cerebral ischemia. Recent work has demonstrated that genetic deficiency of Mannose-binding lectin(MBL) ameliorates reperfusion injury and improves outcome in the acute phase of stroke. The present study sought to further delineate the pathogenic role of MBL in stroke and to examine whether the neuroprotection associated with MBL-deficiency is sustained beyond the acute phase. We hypothesized that genetic MBL deficiency would suppress complement activation and ameliorate reperfusion injury in the acute phase, but that persistent inhibition of complement into the sub-acute phase would serve to abrogate this neuroprotective effect. METHODS: The time-course and localization of post-ischemic cerebral MBL and C3 deposition were characterized using both Western-blot and immunohistochemistry. MBL-a/c null(MBL-KO) mice subjected to transient middle cerebral artery occlusion(MCAO) were then employed to investigate the histologic injury and functional outcome associated with genetic MBL deletion at both 24 hours and 7 days. RESULTS: MBL-a/c rapidly deposit on ischemic endothelium and trigger downstream complement activation in the acute phase. Genetic deficiency of MBL abrogates C3 cleavage as well as the sub-acute accumulation of mononuclear cells in the ischemic region. Although MBL-KO mice demonstrate significantly improved outcome at 24 hours, the neuroprotective effect associated with genetic MBL deletion is not sustained. CONCLUSIONS: Development of a successful anti-complement neuroprotective strategy will require carefully-tailored inhibition coupled with a greater understanding of the functional effects of complement activation during later phases of stroke recovery. PMID- 22505956 TI - The integrated proactive surveillance system for prostate cancer. AB - In this paper, we present the design and implementation of the integrated proactive surveillance system for prostate cancer (PASS-PC). The integrated PASS PC is a multi-institutional web-based system aimed at collecting a variety of data on prostate cancer patients in a standardized and efficient way. The integrated PASS-PC was commissioned by the Prostate Cancer Foundation (PCF) and built through the joint of efforts by a group of experts in medical oncology, genetics, pathology, nutrition, and cancer research informatics. Their main goal is facilitating the efficient and uniform collection of critical demographic, lifestyle, nutritional, dietary and clinical information to be used in developing new strategies in diagnosing, preventing and treating prostate cancer.The integrated PASS-PC is designed based on common industry standards - a three tiered architecture and a Service- Oriented Architecture (SOA). It utilizes open source software and programming languages such as HTML, PHP, CSS, JQuery, Drupal and MySQL. We also use a commercial database management system - Oracle 11g. The integrated PASS-PC project uses a "confederation model" that encourages participation of any interested center, irrespective of its size or location. The integrated PASS-PC utilizes a standardized approach to data collection and reporting, and uses extensive validation procedures to prevent entering erroneous data. The integrated PASS-PC controlled vocabulary is harmonized with the National Cancer Institute (NCI) Thesaurus. Currently, two cancer centers in the USA are participating in the integrated PASS-PC project.THE FINAL SYSTEM HAS THREE MAIN COMPONENTS: 1. National Prostate Surveillance Network (NPSN) website; 2. NPSN myConnect portal; 3. Proactive Surveillance System for Prostate Cancer (PASS-PC). PASS-PC is a cancer Biomedical Informatics Grid (caBIG) compatible product. The integrated PASS-PC provides a foundation for collaborative prostate cancer research. It has been built to meet the short term goal of gathering prostate cancer related data, but also with the prerequisites in place for future evolution into a cancer research informatics platform. In the future this will be vital for successful prostate cancer studies, care and treatment. PMID- 22505953 TI - Gene therapy for dyslipidemia: a review of gene replacement and gene inhibition strategies. AB - Despite numerous technological and pharmacological advances and more detailed knowledge of molecular etiologies, cardiovascular diseases remain the leading cause of morbidity and mortality worldwide claiming over 17 million lives a year. Abnormalities in the synthesis, processing and catabolism of lipoprotein particles can result in severe hypercholesterolemia, hypertriglyceridemia or low HDL-C. Although a plethora of antidyslipidemic pharmacological agents are available, these drugs are relatively ineffective in many patients with Mendelian lipid disorders, indicating the need for new and more effective interventions. In vivo somatic gene therapy is one such intervention. This article summarizes current strategies being pursued for the development of clinical gene therapy for dyslipidemias that cannot effectively be treated with existing drugs. PMID- 22505957 TI - The Risk-based Treatment of Acute Pulmonary Embolism. AB - Risk evaluation and prognostic stratification based upon clinical and radiological findings and new cardiac biomarkers, such as natriuretic peptides (NP) and troponins, represent key points in modern management of acute pulmonary embolism (PE). Literature evidence shows that normotensive PE with right heart dysfunction (RHD), defined as submassive PE, has poorer prognosis when compared to normotensive PE without RHD, defined as non-massive PE; thus whether submassive PE should be managed more aggressively and with closer monitoring represents the crucial question about acute PE treatment. Although the answer is yet unclear, the most recent guidelines address to thrombolysis as treatment choice in selected high risk patients with submassive PE. Guidelines also clarify the indications for unfractioned and low molecular weight heparins and fondaparinux. Therefore, in the present article, the authors focus on modern risk based therapeutic guidelines of acute PE. KEYWORDS: Pulmonary embolism; Treatment; Prognosis; Biomarkers; Chocardiography; Hemodynamic; Guidelines. PMID- 22505958 TI - Chemotherapy induced cardiomyopathy: pathogenesis, monitoring and management. AB - The survival rate of cancer patients has greatly increased over the last 20 years. However, to achieve this result, a considerable price has been paid in terms of the side effects associated with the intensive anticancer treatment. The most common adverse effect is cardiotoxicity which may compromise the clinical effectiveness of chemotherapy, affecting the patient's survival and quality of life independently of the oncological prognosis. There are 2 types of cardiac toxicities, type I which is more serious and result in permanent damage to the myocardium and type II which is usually reversible. Chemotherapies varies in their incidence of inducing cardiomyopathy, and the onset which may occur acutely (during or shortly after treatment), sub-acutely (within days or weeks after completion of chemotherapy) or chronically (weeks to months after drug administration). Cardiac events associated with chemotherapy may consist of mild blood pressure changes, thrombosis, Electrocardiographic (ECG) changes, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, cardiac failure (left ventricular failure), and congestive heart failure (CHF). The risk for such effects depends upon: cumulative dose, rate of drug administration, mediastinal radiation, advanced age, younger age, female gender, pre-existing heart disease and hypertension. Serial measurements of LVEF and fractional shortening are the most common indices monitored to assess left ventricular systolic function and cardiotoxicity. This can be achieved by 2 dimensional, M-mode and color Doppler echocardiographic examination; also Cardiac troponins as a biological marker for myocardial damage can be used for monitoring in patients received anthracyclines. Angiotensin-converting enzyme (ACE) inhibitors (ACEIs) have been shown to slow the progression of left ventricular dysfunction in several different clinical settings, including anthracycline induced cardiomyopathy. Carvedilol and probably with anti-oxidants like Probucol and vitamin E benefits also. KEYWORDS: Anthracyclines; Cardiomyopathy; Chemotherapy. PMID- 22505959 TI - Hepatoblastoma in adult: review of the literature. AB - This study is to review and retrieve data on adult hepatoblastoma (HB) from English literatures in order to gain a better understanding of this disease. We performed Medline, PubMed (from January 1966 to February 2008), and library searches (National Science and Technology Library, Beijing, China, and Wenzhou Medical College Library, from January 1980 to February 2008) using the key words hepatoblastoma in adult, hepatic tumor, hepatoblastoma and adult. Previously reported HB cases were collected and published reviews were also examined. Fifteen cases that met the search criteria were selected. Review of the cases revealed a slight female preponderance. The patients' age ranged from 17 to 82, with median age of 70 for male and 27 for female. The survival time ranged from two weeks to 38 months, and the median survival time was 6 months. In the articles reviewed, HB presented with non-specific initial symptoms, and the diagnosis was not identified until the tumor biopsy after operation or autopsy. Completely surgical resection is still the major treatment for patients with HB and is considered as the only chance of a better prognosis. Due to the rareness of HB in adults, the choice of treatment should be radical resection if possible, and combined with chemotherapy as adopted in children. HB in the adult is extremely rare and the pre-operative diagnosis is often overlooked. The prognosis is so poor that the awareness of the condition in the differential diagnosis in liver tumors could be beneficial. KEY WORDS: Hepatoblastoma; Adult; Diagnosis; Therapy. PMID- 22505960 TI - Self-reported Hypertension on a Caribbean Island. AB - BACKGROUND: Although current guidelines emphasize the importance of hypertension knowledge, little is known about accuracy of this knowledge, factors affecting accuracy and the relationship of self-reported hypertension with cardiovascular disease (CVD). METHODS: One hundred and forty seven subjects were asked to provide self-reported data on hypertension. RESULTS: These were correlated with levels of systolic and diastolic hypertension measures. Demographic characteristics were considered as determinants of awareness and accuracy. Women were more likely than men to be aware of their hypertension levels. However men were more likely to exercise, use salt, smoke and consume alcohol. Women were more likely to be hypertensive, nonsmokers, and moderate drinkers. Higher levels of self-reported hypertension were strongly associated with increased risk of CVD. Women that smoke, have untreated hypertension, or a sedentary lifestyle have a decrease in awareness of their hypertension levels. CONCLUSIONS: Self-reported hypertension underestimates measured values, but is strongly related to CVD. Lack of awareness of elevated hypertension is associated with increased risk of CVD. KEYWORDS: Cardiovascular disease; Hypertension; Risk factors; Self-report; Caribbean. PMID- 22505961 TI - Anti-proliferation Effect of Polypeptide Extracted from Scorpion Venom on Human Prostate Cancer Cells in vitro. AB - BACKGROUND: Prostate cancer is a major cause of cancer-related death in men. Therefore there has been considerable interest to explore neoadjuvant therapy. Polypeptide extracted from scorpion venom (PESV), originally obtained from the East-Asian scorpion Buthus martensi Karsch (BmK), is being studied for both prevention and treatment of various human malignancies including prostate cancer. METHODS: The present study was to investigate the effect of PESV on cell proliferation, cell cycle, and apoptosis in human androgen-independent prostate cancer cells DU-145 in vitro. RESULTS: PESV treatment on these cells resulted in a significantly dose-dependent growth inhibition with a G1 phase arrest at 40MUg/mL after 48h treatment. PESV treatment strongly induced expression of p27 (Kip1), but resulted in a decrease in cyclin E, one of cyclins involved in G1 progression. In other studies, PESV treatment also induced high apoptosis index (AI), confirmed by TdTmediated dUTP-biotin nick-end labeling (TUNEL) assay. Further, the apoptosis induction by PESV (40MUg/mL) in DU145 cells was associated with an increase of pro-apoptotic protein Bax. CONCLUSIONS: These results suggest that PESV modulates the expression of cell cycle-related and apoptosis-related proteins and induces growth inhibition and apoptosis of DU145 cells, providing a strong rationale for future studies to evaluate prevention or/and intervention strategies for PESV in pre-clinical prostate cancer models. KEYWORDS: Prostate cancer, PESV, cell proliferation, cell cycle, apoptosis. PMID- 22505962 TI - The uniqueness and ordinariness of cancer origin and pathogenesis: new epidemiological, clinical and preventive perspectives. AB - BACKGROUND: The article is devoted to a try to reconsider a main paradigm of contemporary oncology, the hypothesis of cancer metastasis. METHODS: The investigation was based on the reassessment of well known data about cancer epidemiology and clinical manifestations from the viewpoint of recent all pathological, immunological, genetic and evolutionary discoveries. RESULTS: The potentially cancerous cell clones settled a human body as a result of crossbreeding between persons with partially different genomes. The clones appeared in the body before postnatal ontogenesis and for many decades exist in it as multiple but smallest stochastically distributed cell populations. But at relevant time of individual life (mainly after 40 years of age), according to own specific programs of the clone ontogenesis, it begin to multiple uncontrolled thus initiating the cancerous growth being unregulated by usual cyto-ecological agents owned by affected body. Its cells come into sight as constitutionally immune to normal regulators of cell reproduction and tissue growth. CONCLUSIONS: The new notion provides a framework for understanding the epidemic nature of cancer and its rising incidence both in the developed world and in developing countries. It forces also to reassess the means and methods of cancer healing. What is more, it accents the possibility of genetic methods for the prevention of epidemic spread of the disease. KEYWORDS: Cancer epidemiology; Cancer pathogenesis; Genetics of cancer origin; Genetic immunity; Molecular physiological regulation. PMID- 22505963 TI - Prevalence of urinary incontinence in female residents of american nursing homes and association with neuropsychiatric disorders. AB - BACKGROUND: Urinary incontinence (UI) is most common in older women. METHODS: We studied the prevalence of UI among female residents of nursing homes and the influence of associated neuropsychiatric problems on the rates of UI using the results of the 2004 National Nursing Home Survey (NNHS). RESULTS: Analysis shows that 37% of female nursing home residents are incontinent, especially those with dementia. Residents with depression or schizophrenia are also more likely to have UI whereas those with anxiety, paranoia, or obsessive-compulsive disorder have less UI rates. There are significant associations with neuropsychiatric disorders except for bipolar disease. CONCLUSIONS: We recommend prioritizing behavioral interventions and environmental manipulations for female residents with dementia, depression, and schizophrenia to increase the cost-effectiveness of UI management programs in nursing homes. KEYWORDS: Urinary incontinence; Female residents; Nursing home; Neurodegenerative; Psychiatric. PMID- 22505964 TI - Carotid atherosclerosis in ischemic cerebrovascular patients. AB - BACKGROUND: Cerebral emboli resulting from atherosclerosis at the carotid bifurcation is a major cause of ischemic stroke. A convenient and prompt evaluation is necessary for secondary prevention and treatment. METHODS: In this study, one hundred and thirty eight patients with cerebral ischemic events were enrolled; 100 patients with nonischemic cerebral diseases were enrolled as controls. Noninvasive ultrasound was used to measure the atherosclerotic plaques and intima-media thickness (IMT) of carotid and femoral artery. RESULTS: Our results showed that patients in study group had higher incidence and severity of carotid and femoral plaques, and higher mean intima-media thickness (IMT) at both the carotid and femoral sites compared with that of controls (p < 0.01). Carotid atherosclerosis were highly prone to have instability plaques in study group(p < 0.001). CONCLUSIONS: This cross-sectional study showed that, the prevalence of carotid atherosclerosis and the unstable plaques were higher in cerebral ischemic patients. KEYWORDS: Carotid artery; Atherosclerosis; Intima-media thickness; Cerebral ischemic stroke. PMID- 22505965 TI - Health status of the clinical dental students in the jordanian universities. AB - BACKGROUND: Dental students are subjected to many stresses that may affect their achievement. The purpose of this study is to assess the mental and physical health of dental students in two Jordanian Universities. METHODS: A total of 265 dental students and 228 non-dental students from two Jordanian Universities participated in the study. They completed the survey questionnaire and their responses were used in calculating the 0-100 scores for the eight health concepts by linear transformations of scores. The ANOVA test was used to determine the significant differences among the student groups, and Tukey test was used for multiple comparisons among groups. All tests were carried out at 95% confidence level. RESULTS: The results indicated that the dental students of the Jordan University of Science and Technology were of better health than their counterparts at the University of Jordan. The health scores attained by the dental students of the two universities were less than those of non-dental students of the same age. CONCLUSIONS: The physical and more significantly the mental health components of dental students should receive more attention, and further work is needed to detect the possible causes and find potent remedies for this problem. KEYWORDS: Health survey; Clinical students; Physical functioning; Mental health; Social functioning. PMID- 22505966 TI - A Case of Acute Aortic Dissection Type B Associated with Cushing's Syndrome. AB - We report a case of a 63-year-old man, with a previous history of hypertension and glucose intolerance associated troncular obesity that was emergently admitted to our Institution for evaluation of a severe, constant posterior chest pain which radiated anteriorly and dyspnoea with a suspected diagnosis of acute aortic dissection. A CT scan of thorax and abdomen demonstrated a dissection starting just below left succlavian artery and extending downward to the left renal artery, involving the celiac tripod and superior mesenteric artery. The dissection was classified as Stanford B, De Bakey III. Moreover, CT scan of abdomen revealed incidentally a left adrenal tumor of 25 mm of diameter. An emergent prosthetic graft was placed just below the origin of the left succlavian artery up-to the diaphragmatic hiatus. Furthermore, a diagnostic evaluation of the mass revealed an increase of cortisol production, and a diagnosis of Cushing's syndrome was done and the patient underwent an adrenalectomy via laparotomic approach. We report an association of acute aortic dissection of acute aortic dissection type B associated to Cushing's syndrome. KEYWORDS: Cushing's syndrome; Adrenocortical adenoma; Aortic dissection type B. PMID- 22505967 TI - Piperacillin/tazobactam Induced Myelosuppression. AB - Neutropenia, secondary to immune destruction or maturation arrest, is the most commonly described adverse haematological effect of beta-lactam antibiotics. We describe a case of reversible pancytopenia, with evidence of hypocellular marrow, after a prolonged course of piperacillin/tazobactam for 26 days. KEYWORDS: Piperacillin; Tazobactam; Myelosuppression; Neutropenia. PMID- 22505968 TI - Chronic non-exertional myalgia and myoadenylate deaminase deficiency: a possible association. AB - Myoadenylate deaminase deficiency is noted in skeletal muscles. It generally presents with exertional myalgias, fatigue and weakness. We present a patient who complained of constant pain unrelated to activity with biopsy finding consistent of myoadenylate deaminase deficiency. KEYWORDS: Myoadenylate deaminase deficiency; Myalgia; Pain. PMID- 22505969 TI - Schatzki's Ring in Angelman Syndrome: A Diagnostic Dilemma in Neurodevelopmentally Disabled Patients. AB - Angelman Syndrome is a neurodevelopmental condition with a characteristic phenotype that includes epilepsy and lack of communication. We describe its first reported association with Schatzki's ring that presented as a life-long history of intermittent retching. Because of associated cognitive dysfunction, careful diagnostic consideration is required to detect this underlying condition. KEYWORDS: Schatzki's ring; Angelman Syndrome; Esophageal "B" ring; Barium esophagogram; Neurodevelopmental delay; Retching. PMID- 22505971 TI - 5-Hydroxytryptamine Receptor Subtypes and their Modulators with Therapeutic Potentials. AB - 5-hydroxytryptamine (5-HT) has become one of the most investigated and complex biogenic amines. The main receptors and their subtypes, e.g., 5-HTI (5-HT1A, 5 HT1B, 5-HTID, 5-HTIE and 5-HT1F), 5-HT2 (5-HT2A, 5-HT2B and 5-HT2C), 5-HT3, 5 HT4, 5-HT5 (5-HT5A, 5-HT5B), 5-HT6 and 5-HT7 have been identified. Specific drugs which are capable of either selectively stimulating or inhibiting these receptor subtypes are being designed. This has generated therapeutic potentials of 5-HT receptor modulators in a variety of disease conditions. Conditions where 5-HT receptor modulators have established their use with distinct efficacy and advantages include migraine, anxiety, psychosis, obesity and cancer therapy induced vomiting by cytotoxic drugs and radiation. Discovery of 5-HT, its biosynthesis, metabolism, physiological role and the potential of 5-HT receptor modulators in various nervous, cardiovascular and gastrointestinal tract disorders, bone growth and micturition have been discussed in this article. KEYWORDS: 5-hydroxytryptamine (5-HT) receptors; Modulators; Biogenic amines. PMID- 22505970 TI - Dental-derived Stem Cells and whole Tooth Regeneration: an Overview. AB - The need for new dental tissue-replacement therapies is evident in recent reports which reveal startling statistics regarding the high incidence of tooth decay and tooth loss. Recent advances in the identification and characterization of dental stem cells, and in dental tissue-engineering strategies, suggest that bioengineering approaches may successfully be used to regenerate dental tissues and whole teeth. Interest in dental tissue-regeneration applications continues to increase as clinically relevant methods for the generation of bioengineered dental tissues, and whole teeth, continue to improve. This paper is concerned about dental-derived stem cells and their characterization. Additionally, since conventional dental treatments partially serve the purpose for replacing missing teeth and always include possible failure rates, the potential of dental-derived stem cells in promoting whole tooth regeneration is also discussed. KEYWORDS: Dental stem cells; Tissue engineering; Tooth regeneration. PMID- 22505972 TI - The effects of disinfectants on dimensional accuracy and surface quality of impression materials and gypsum casts. AB - BACKGROUND: The study aimed to evaluating the effect of disinfecting impression materials on the dimensional accuracy and surface quality of the resulting casts. METHODS: Impressions of a steel die constructed according to ANSI/ADA specification No.18 were made with each of alginate, addition cured silicone, condensation cured silicone and zinc oxide eugenol paste, and disinfected consequently by each of 0.2% chlorhexidine gluconate, 1% sodium hypochlorite, 2% gluteraldehyde for 5 minutes, and 0.5% sodium hypochlorite for 10 minutes. Dimensions of the disinfected impressions and their resultant casts were measured using a computerized digital caliper, and the dimensional changes were calculated. Reproduction of detail and surface quality of the resultant casts were assessed by grading casts surfaces according to a specific scoring system. RESULTS: The 0.5% sodium hypochlorite was found to produce the least dimensional changes in all the impression materials. Corsodyl produced the maximum changes in both alginate and zinc-oxide eugenol while addition-cured silicon was most affected by Gluteraldehyde and condensation-cured silicon was most affected by Hexana. The dimensional changes, however, were minimal and clinically insignificant. Addition-cured silicon showed the best surface quality and dimensional stability followed by condensation-cured silicon. Alginate and zinc oxide eugenol had poorer surface quality and were affected to a higher extent by the disinfection procedures. CONCLUSIONS: The results were comparable with the standard specifications for dimensional stability. Recommendations were made for the use of 10 minutes immersion in 0.5% sodium hypochlorite as the most appropriate disinfection protocol to the investigated impression materials. KEYWORDS: Disinfectants; Gypsum casts; Impressions; Alginate; Addition-cured silicone; Sodium hypochlorite. PMID- 22505973 TI - The pattern of procalcitonin in primary total hip and knee arthroplasty and its implication in periprosthetic infection. AB - BACKGROUND: The serum marker Procalcitonin (PCT) has been shown to be a sensitive indicator of bacterial infection, but very little is known of its behavior in periprosthetic infection. In this study, PCT was compared with standard tests used to aid the diagnosis of infection. As a baseline, its pattern in uncomplicated hip and knee arthroplasty was investigated. METHODS: A prospective study of fifty-nine patients had bloods taken preoperatively, and on days 1, 3, 5, for PCT, C- reactive protein, erythrocyte sedimentation rate and white cell count. RESULTS: Fifty patients (85%) had normal PCT values (< 0.5 ng/ml) and only 5 recorded a value > 1.0ng/ml. On day 5 only 1 patient had a value > 0.5ng/ml. The standard tests all showed sporadic elevations over the 3 days. PCT levels are not significantly elevated by the trauma of this surgery, as they are in other surgical procedures. CONCLUSIONS: PCT may be very useful in patients with suspected periprosthetic infection. KEYWORDS: Infection; Periprosthetic; Procalcitonin; C-reactive protein; Arthroplasty. PMID- 22505975 TI - Determinants of exclusive breastfeeding in South gujarat region of India. AB - OBJECTIVE: To estimate the situation of breastfeeding in Surat among infants and to determine variables associated to major risks for early weaning. DESIGN AND SETTINGS: Mothers coming to the well baby clinic for immunization of infants at Government Medical College and Hospital were interviewed using pretested questionnaire. SUBJECTS: Mothers with their infants who have not completed one year of age. METHODS: In this cross sectional study, 498 mothers were selected for study from May to September, 2008. Survival analysis was the method used to calculate the prevalence and the median duration of breastfeeding. The Chi-square test was performed to compare the proportions; significance level was set at 5%. Odds ratio was used to measure the significance of association, with a 95% confidence interval. Logistic regression analysis was used to identify the risk factors for early weaning. RESULTS: The median length of exclusive breastfeeding was 6 months. Risk factors for early weaning were primiparity (OR = 3.01, 95% CI = 2.01- 4.51), consecutive delivery interval less than 24 months (OR = 1.79, 95% CI = 1.09 - 2.92), maternal age below 20 years (OR = 6.49, 95% CI = 2.69 - 15.61), and paternal occupation as labor (OR = 2.02, 95% CI = 1.36 - 3.00). CONCLUSIONS: Exclusive breastfeeding practices are not in a better situation than at national level. The factors related to early weaning denote a weak breastfeeding support given by maternal and infant health services. KEYWORDS: Exclusive breastfeeding; Weaning; Antenatal care; Postnatal care; Education. PMID- 22505974 TI - Inflammatory markers and intimal media thickness in diabetics with negative myocardial perfusion scan. AB - BACKGROUND: We compared the type and duration of diabetes mellitus (DM), patient demography, high sensitivity C-reactive protein (hsCRP), Homocysteine and other variables with IMT, to determine if these markers were correlated in diabetes (in whom technetium myocardial perfusion scan were negative) and would it be appropriate biomarkers for arthrosclerosis detection in this group of diabetics. METHODS: Forty patients with DM, without CHD history, were screened with stress sintigraphy imaging using 2 days stress/rest Technetium 99 tetrafosmin protocol, employing the standard Bruce protocol. Echocardiography study requested for each patient, two blood samples for hsCRP, were requested for each candidate three weeks apart, Lipid profiles, plasma homocysteine, and hemoglobin A1C were also requested. Finally Intima-media thickness were measured for all patients. RESULTS: There were no relationships between hsCRP level and DM duration or with the type of DM; also there were no relation between DM duration and homocysteine or between DM type and Homocysteine. Intimal media thickness was increased proportionally with the serum level of Homocysteine. CONCLUSIONS: This study did not show any role for the inflammatory markers in predicating the presence of coronary artery disease in participants with DM, without medium size artery disease, which may support that DM is not the only player in initiating atherosclerosis. KEYWORDS: Diabetes mellitus; Inflammatory markers; C-reactive protein; Myocardial ischemia; Homocysteine; Intima-media thickness. PMID- 22505976 TI - Rapid Hemodynamic Deterioration and Death due to Acute Severe Refractory Septic Shock. AB - Despite emergence of early goal directed therapy, septic shock still carries a high mortality. Gram negative septicemia is notorious for rapid deterioration due to endotoxin release. Multi-organ damage due to septic shock carries poor prognosis, and such patients should be managed aggressively with multidisciplinary approach. We present a fatal case of a patient with gram negative septicemia who rapidly deteriorated, and died due to acute refractory severe septic shock. This patient probably developed urosepsis secondary to severe urinary tract infection. He also had infiltrates on chest radiograph. He expired within fifteen hours of presenting to the emergency department. This case emphasizes the importance of early recognition and management of septic shock. Early goal directed therapy has shown to improve mortality. Broad spectrum antibiotics should be started within one hour depending on local immunity of organisms. This case also highlights the fact that despite optimized treatment, this entity has very high mortality rates. KEYWORDS: Hemodynamic deterioration; Refractory septic shock; Gram negative septicemia. PMID- 22505977 TI - Localized malignant myxoid anaplastic mesothelioma of the pericardium. AB - Primary malignant mesothelioma of the pericardium is a rare cardiac neoplasm. Most are diffuse and have poor prognosis with median survival of six months. In the paper, we describe a young male patient having no exposure history of asbestos with localized malignant myxoid mesothelioma of the pericardium. The tumor displayed significant myxoid change in stroma, and anaplastic cytology, including pleomorphy, poor cohesion, prominent nuclei, with high mitoses, which led to difficulty in diagnosis. The tumor showed typical immunohistochemical phenotypes of mesothelioma, positive for WT-1, calretinin and CK5/6. Ki-67 labeling index was about 50% in general and nearly 80% in the most active areas. The patient showed better outcome. The report suggests the diagnosis of myxoid mesothelioma is supposed to rely on clinical data, and immunohistochemistry is assumed to be for differentiation. KEYWORDS: Myxoid mesothelioma; Anaplastic; Diagnosis; Immunohistochemistry; Prognosis. PMID- 22505978 TI - Adult intussusception in hernial sac: a case report. AB - Adult intussusception is rare. The author is reporting a case of adult intussusception in a 60-year-old female inside of incisional hernia sac, acting as a lead point. The presentation was subacute intestinal obstruction. Ultrasonography was useful adjunct in diagnosis. The site for intussusception was jejunum. Intussusception was seen protruding into hernial sac with adhesions of gut to abdominal wall defect. Resection of involved gut was done. KEYWORDS: Intussusception; Hernia sac; Jejunum. PMID- 22505979 TI - An extraosseous plasmacytoma of the nasopharynx. AB - A 75-year-old long-term male smoker and poorly controlled hypertensive presented with a 3-month history of intermittent epistaxis refractory to cauterisation with silver nitrate. Nasopharyngeal examination revealed a mass in the post nasal space. An urgent endoscopic biopsy confirmed an extraosseous plasmacytoma. Post operative radiotherapy was scheduled. No evidence of recurrence of disease following completion of treatment has been detected during clinical surveillance. KEYWORDS: Epistaxis; Nasopharynx; Biopsy; Plasmacytoma; Radiotherapy. PMID- 22505980 TI - Using Clinical Vignettes to Evaluate VTE Protocol Adherence. AB - BACKGROUND: Venous thromboembolism (VTE) prophylaxis is underutilized in hospitalized medical patients. Underutilization might occur as a result of resident practice variation incurred by using a complex risk assessment tool. OBJECTIVE: To examine what impact repetitive exposure to an electronic point based VTE risk assessment tool has on resident inter-rater reliability and protocol adherence. DESIGN: Pre and post intervention cross-sectional cohort study. SETTING: Single academic center. PATIENTS: Convenience samples of Internal Medicine residents. INTERVENTIONS: Residents completed clinical vignettes before and after any exposure to an electronic risk assessment tool and reminder alert. They were asked to make three determinations using a point-based VTE risk assessment tool: risk stratification, identify contraindications, and VTE prevention strategy. MEASUREMENTS: Inter-rater reliability for risk assessment, contraindications, and VTE prophylaxis strategy and protocol adherence. RESULTS: Kappa scores for VTE risk assessment did not change, but improved for VTE plan increasing from 0.28 to 0.37. Protocol adherence improved from 71% in 2008 to 79% (P = 0.06). There was a significant decrease in under-prophylaxis (22% to 6%, P < 0.0001) but a significant increase in over-prophylaxis (7% to 16%, P = 0.001). CONCLUSIONS: Using clinical vignettes, we determined that daily exposure to an electronic risk assessment tool did not improve the inter-rater reliability of a point-based risk assessment tool when used by medical residents. This might be due to inexperienced providers using a complex point-based tool. Overall, adherence improved, and under-prophylaxis decreased, but over-prophylaxis increased. Clinical vignettes are a generalizable method to monitor resident prophylaxis practices and way to identify educational and process improvement opportunities. KEYWORDS: Resident; Inter-rater reliability; Venous thromboembolism; Agreement; Risk assessment score. PMID- 22505981 TI - Nephrotoxin-induced renal cell injury involving biochemical alterations and its prevention with antioxidant. AB - BACKGROUND: Although nephrotoxic agents or nephrotoxins are known to induce acute renal cell injury, their cytotoxic action is not fully elucidated. It is thus crucial to explore such a cytotoxic mechanism and the increasing volume of reports indicated a significant involvement of oxidative stress. To test this possibility, we investigated if a nephrotoxin would exert oxidative stress, leading to renal cell injury accompanied by certain biochemical alterations. We also examined if specific antioxidant might help prevent such oxidative cell injury. These studies may then help establish a prophylactic or preventive modality for renal cell injury induced by nephrotoxins. METHODS: As glycerol has been commonly used for studying acute renal failure in animals, whether it would induce cellular injury was tested in renal proximal tubular OK cells in vitro. Cells were exposed to the varying concentrations of glycerol and cell number/viability was determined in 24 hours. Severity of oxidative stress was assessed by lipid peroxidation assay. Possible effects of glycerol on biochemical parameters were also examined on glyoxalase I activity and heat shock protein 90 using spectrophotometric (enzymatic) assay and Western blot analysis. RESULTS: Glycerol (2.5%) was highly cytotoxic to OK cells, inducing 95% cell death in 24 hours. Lipid peroxidation assay indicated that nearly 3-fold greater oxidative stress was exerted by this glycerol. Concurrently, glyoxalase I activity was drastically lost by 75% and heat shock protein 90 was partially degraded following glycerol exposure. However, N-acetylcysteine, a potent glutathione based antioxidant, was capable of almost completely preventing the glycerol mediated adverse outcomes, such as cell death, glyoxalase I inactivation, and heat shock protein 90 degradation. CONCLUSIONS: Glycerol is cytotoxic, capable of inducing specific biochemical alterations such as inactivation of glyoxalase I and degradation of heat shock protein 90, which may reflect a breakdown of the cellular detoxification and defense systems, leading ultimately to OK cell death. Nevertheless, as N-acetylcysteine can provide full cytoprotection against such glycerol toxicity, it could be considered a prophylactic modality for nephrotoxin induced oxidative renal cell injury and death. KEYWORDS: Glycerol; Glyoxalase I; Heat shock protein; N-acetylcysteine; Renal cell injury. PMID- 22505982 TI - Cardiovascular risk management with liaison critical path in Japan: its effects on implementation of evidence-based prevention in practice. AB - BACKGROUND: Liaison critical paths (LCPs) for coronary artery disease (CAD) were developed to support collaborative care for CAD patients between cardiologists in emergency hospitals and referring physicians through sharing of medical information, including cardioprotective medications and cardiovascular risk factors. However, little is known about the effects of LCPs in practice. METHODS: We conducted an observational study of CAD patients undergoing percutaneous coronary intervention in our hospital between September 2007 and June 2010; these patients were managed with an LCP by referring physicians after discharge. We surveyed implementation of scheduled hospital visits, prescription of cardioprotective medicines, and risk factor measurements 6 and 12 months after discharge. RESULTS: Implementation rate of hospital visits was significantly elevated from 50.7% to 89.3% after establishing LCPs. At the 12-month visit, prescription rates for anti-platelet drugs, statins, beta-blockers, and angiotensin-converting enzyme inhibitors or angiotensin II type I receptor blockers were 99.7%, 95.0%, 77.1%, and 74.3%, respectively. Target achievement rates for low-density lipoprotein cholesterol (LDL-C; < 100 mg/dL) and high density lipoprotein cholesterol (HDL-C; >= 40 mg/dL) significantly increased from 48.6% to 64.5% and 62.0% to 82.7%, respectively, while those for body mass index (BMI; < 25 kg/m(2)), blood pressure (< 130/80 mmHg), triglycerides (< 150 mg/dL), and HbA1c (< 7.0 %) were unchanged. BMI, triglycerides, HDL-C, LDL-C, and HbA1c levels significantly improved in patients who implemented all visits. Moreover, risk factor management did not differ significantly between cardiologists and non cardiologists using LCPs. CONCLUSIONS: LCPs for CAD may facilitate implementation of optimal medical therapy and target achievement of risk factors in practice. KEYWORDS: Liaison critical path; Coronary artery disease; Cardiovascular prevention; Risk factors; Clinical practice. PMID- 22505983 TI - The investigation of serum vaspin level in atherosclerotic coronary artery disease. AB - BACKGROUND: It was speculated that fatty tissue originated adipocytokines may play role in pathogenesis of atherosclerosis. These adipocytokines may alter vascular homeostasis by effecting endothelial cells, arterial smooth muscle cells and macrophages. Vaspin is a newly described member of adipocytokines family. We aimed to investigate whether plasma vaspin level has any predictive value in coronary artery disease (CAD). METHODS: Forty patients who have at least single vessel >= 70 % stenosis demostrated angiographically and 40 subjects with normal coronary anatomy were included to the study. The vaspin levels were measured from serum that is obtained by centrifigation of blood and stored at -20 (o)C by ELISA method. The length, weight and body mass index of patients were measured. Biochemical parameters including total cholesterol, low density lipoprotein, high density lipoprotein, creatinine, sodium, potassium, hemoglobine, uric acid and fasting glucose were also measured. RESULTS: Biochemical markers levels were similar in both groups. Serum vaspin levels were significantly lower in CAD patients than control group (respectively; 256 +/- 219 pg/ml vs. 472 ( 564 pg/ml, P < 0.02). Beside this serum vaspin level was lower in control group with high systolic blood pressure. CONCLUSION: Serum vaspin levels were found significantly lower in patients with CAD than age-matched subjects with normal coronary anatomy. Vaspin may be used as a predictor of CAD. KEYWORDS: Coronary artery disease; Vaspin; Adipokine. PMID- 22505984 TI - The Effect of Motor Learning of Serial Reaction Time Task (SRTT) Through Action Observation on Mu Rhythm and Improvement of Behavior Abilities. AB - BACKGROUND: The aim of this study was investigate whether an action observation would have an effect on the action that requires task understanding in humans. METHODS: Participants who met the criteria for this study (n = 36). To evaluate the performance, reaction time and performance accuracy, the stimulus scheduling software was employed. For the electroencephalogram, the equipment QEEG-8 was used. RESULTS: Concerning the reaction time of the groups of different learning methods a significant difference was found after the learning among the three groups. Regarding the accuracy among the groups of different learning methods, significant difference was found in the action performance accuracy among the three groups. The relative mu power during the SRTT implementation was compared in the CZ, C3 and C4 regions before, during, and after the learning for each group. In the CZ and C4 region, a significant difference was found in the action observation group. In the C3 and C4 region a significant difference was found in the actual practice group. CONCLUSIONS: The result suggests that imitation and learning are involved even in the action that requires task understanding in humans. KEYWORDS: Accuracy; Mirror neuron system; Mu Rhythm; Reaction time; SRTT. PMID- 22505985 TI - Risk factors associated with epidural use. AB - BACKGROUND: Identify variables associated with intrapartum epidural use. METHODS: Odds ratios were calculated to quantify associations between selected variables and epidural use using a population-based case-control study of Washington State birth certificate data from 2009. RESULTS: Non-Whites had 10 - 45% lower odds of epidural use relative to Whites. Foreign-born women had 25 - 45% lower odds of epidural use compared to their US-born counterparts, except for Asians. Women who smoked or induced labor had higher roughly 2-fold higher odds of epidural use compared with non-smokers or women giving birth spontaneously, respectively. Women without a high school diploma or equivalent had lower odds of epidural use relative to those who graduated. Delivering at perinatal units, rural hospitals, or non-profit hospitals had ~50% lower odds of epidural use compared with secondary/teritiary perinatal units, urban hospitals or for-profit hospitals, respectively. CONCLUSION: Several individual and health service-related variables were associated with epidural use. These findings elucidate the clinical relevance of epidural use, and dispariaties in its utilization and in quality of care during delivery. KEYWORDS: Epidural use; Foreign birth; Labor; Racial disparities. PMID- 22505986 TI - Combined Ventricular Assist Device Placement With Adjustable Gastric Band (VAD BAND): A Promising New Technique for Morbidly Obese Patients Awaiting Potential Cardiac Transplantation. AB - BACKGROUND: Morbid obesity remains a potential relative contraindication for cardiac transplantation. Hence, a select population of morbidly obese patients with end-stage heart failure may require a ventricular assist device (VAD) as a bridge to transplantation to afford them time to lose sufficient weight and thus decrease there mortality rate after transplantation. Unfortunately, obtaining suitable weight loss via dietary or exercise regimens is limited by the cardiac limitations of the patients. We report on a new procedure of combining ventricular assist device placement with adjustable gastric band (VAD-BAND) placement to facilitate sufficient weight loss for cardiac transplantation. METHODS: We report on our experience of 2 morbidly obese (BMI 46.6, BMI 43.7) patients with severe non-ischemic cardiomyopathy who underwent a VAD-BAND placement for treatment of morbid obesity and potential future cardiac transplantation. RESULTS: Patient 1 was a 24-year-old male with a body mass index (BMI) of 46.6 admitted in cardiogenic shock with severe non-ischemic cardiomyopathy (New York Functional Class IV, Left Ventricular Ejection Fraction 15.3%) who underwent the VAD-BAND procedure. At 11 months outpatient follow-up the patient had clinically improved with a BMI of 34.2. Patient 2 was a 36-year old male with a body mass index of 43.7 admitted in cardiogenic shock with severe non-ischemic cardiomyopathy (New York Functional Class IV, Left Ventricular Ejection Fraction 17.1%) who underwent placement of a VAD-BAND. At 4 months post operation, the patient was stalwart clinically with a BMI of 34.8. Both patients are now under consideration for cardiac transplantation. CONCLUSION: In conclusion, concurrent placement of a VAD-BAND is a safe and viable option for morbidly obese patients with end-stage heart disease. Further research is needed to define indications and future clinical practice. KEYWORDS: Gastric band; Ventricular assist device; Morbid obesity; Heart failure; Transplantation; Weight loss. PMID- 22505987 TI - Carotid Intima-Media Thickness in Asymptomatic Subjects With Low Lipoprotein(a) Levels. AB - BACKGROUND: Elevated and extreme circulating levels of lipoprotein(a) (Lp(a)) are considered to be an atherosclerotic risk factor, although additional studies on the low levels of Lp(a) are necessary to provide confirmation. The carotid intima media thickness (CIMT) is known as a surrogate index of atherosclerosis. The aim of the present study was to investigate the correlation between the serum Lp(a) and CIMT in asymptomatic subjects with a relatively low Lp(a) level. METHODS: The study included 65 asymptomatic female Japanese subjects (mean age: 60 years) with a serum Lp(a) level < 30 mg/dL. Clinical data including the serum Lp(a) and CIMT were measured, and their correlations were examined. RESULTS: The median Lp(a) level was 18.6 mg/dL and the mean CIMT level was 0.8 mm. There was a significant and inverse correlation between the CIMT and Lp(a) (r = - 0.24, P <= 0.05), in addition to a significant and positive correlation between the CIMT and subject age and systolic blood pressure. A stepwise multiple linear regression analysis identified the Lp(a) to be correlated independently, significantly and inversely with the CIMT. CONCLUSIONS: The Lp(a) levels were inversely correlated with the CIMT in this population, suggesting that subjects with a low Lp(a) level may have a predisposition to carotid atherosclerosis. This finding was preliminary and should be investigated further in larger studies and in additional settings. KEYWORDS: Lp(a); Carotid artery; IMT; Atherosclerosis. PMID- 22505988 TI - Severe scurvy after gastric bypass surgery and a poor postoperative diet. AB - After bariatric gastric bypass surgery patients are at risk of developing micronutrient deficiencies. If gastric bypass surgery is followed by a vitamin deficient diet the patients have a risk of developing vitamin-C deficiency. When spontaneous ecchymosis is observed in the skin, in at-risk patients, scurvy must be considered. When treated with large doses of vitamin-C the symptoms of scurvy rapidly improve even if the patient has developed multiple organ dysfunction syndrome. KEYWORDS: Scurvy; Gastric bypass surgery; Multiorgan dysfunction. PMID- 22505989 TI - Hypertrophic cranial pachymeningitis and skull base osteomyelitis by pseudomonas aeruginosa: case report and review of the literature. AB - Hypertrophic cranial pachymeningitis (HCP) is an uncommon disorder characterized by localized or diffuse thickening of the dura mater, and it usually presents with multiple cranial neurophaties. It has been associated with a variety of inflammatory, infectious, traumatic, toxic and neoplasic diseases, when no specific cause is found the process is called idiopathic. The infectious cases occur in patients under systemic immunosuppression, which have an evident contiguous source or those who have undergone neurosurgical procedures. We describe a case of a 62-year-old immunosuppressed woman with diabetes and rheumatoid arthritis, which had HCP and osteomyelitis of the skull base caused by pseudomonas aeruginosa, presenting with headache and diplopia. We believe this is the second documented case of pachymeningitis secondary to this microorganism. As a multifactorial disease, it is essencial to determine the specific causative agent of HCP before making treatment decisions, and great care is needed with immunocompromised patients. KEYWORDS: Pseudomonas aeruginosa; Hypertrophic pachymeningitis; Ophtalmoplegia, optical neuropathy; Osteomyelitis; Skull base. PMID- 22505990 TI - Metastases from nested variant urothelial carcinoma of the urinary bladder in pancreatic allograft mimicking graft rejection. AB - While not an uncommon tumor, urothelial carcinoma of the urinary bladder is rare in bladders draining pancreatic allografts. A case of urothelial carcinoma directly involving a pancreatic allograft with metastasis that occurred in a 49 year-old pancreas and kidney transplant recipient is described. Her initial clinical presentation and findings of CT scan of the abdomen suggested pancreatitis with features worrisome for rejection. A biopsy of her pancreatic allograft contained poorly differentiated carcinoma and cystoscopic biopsy disclosed an invasive high grade urothelial carcinoma arising in the background of extensive urothelial carcinoma in situ. Exploratory laparotomy revealed that the tumor invaded the right ovary and fallopian tube, cecum, and allograft with extensive retroperitoneal involvement. She underwent en bloc resection of distal ileum and cecum, resection of transplant pancreas, partial cystectomy, ileocolostomy anastomosis, and right salpingo-oophorectomy. Postoperatively, the patient was treated with four cycles of carboplatin and gemcitabine. She ultimately succumbed to her disease approximately 1 year after diagnosis. This case should alert physicians and radiologists to be aware of atypical presentation of urothelial carcinoma in bladder-drained pancreas grafts, the aggressiveness of such lesions, and the need for early biopsy to avoid diagnostic confusion with rejection. KEYWORDS: Bladder cancer; Nested variant of urothelial carcinoma; Pancreas and kidney transplantation. PMID- 22505991 TI - Primary tuberculous abscess of the spleen in an immununocompetent patient diagnosed by biochemical markers and radiologic findings. AB - Tuberculous splenic abscess in an immunocompetent patient is extremely rare. We came across a case of middle aged immunocompetent female who presented with abdominal distension, weight loss, and low grade fever. Abdominopelvic computed tomography showed multiple low density lesions in the spleen with ascites. Interferon-gamma release assay was positive and adenosine deaminase level of ascites was significantly high. No primary focus of infection was detected. The patient was diagnosed as having primary multiple tuberculous splenic abscesses with tuberculous peritonitis causing ascites. Follow up computed tomography, after completion of six month course of anti-tubercular therapy, showed splenic abscess and ascites completely disappeared. KEYWORDS: Spleen; Abscess; Tuberculosis; Immunocompetent; Adenosine deaminase; Interferon-gamma. PMID- 22505992 TI - Microfluidic sorting of microtissues. AB - Increasingly, invitro culture of adherent cell types utilizes three-dimensional (3D) scaffolds or aggregate culture strategies to mimic tissue-like, microenvironmental conditions. In parallel, new flow cytometry-based technologies are emerging to accurately analyze the composition and function of these microtissues (i.e., large particles) in a non-invasive and high-throughput way. Lacking, however, is an accessible platform that can be used to effectively sort or purify large particles based on analysis parameters. Here we describe a microfluidic-based, electromechanical approach to sort large particles. Specifically, sheath-less asymmetric curving channels were employed to separate and hydrodynamically focus particles to be analyzed and subsequently sorted. This design was developed and characterized based on wall shear stress, tortuosity of the flow path, vorticity of the fluid in the channel, sorting efficiency and enrichment ratio. The large particle sorting device was capable of purifying fluorescently labelled embryoid bodies (EBs) from unlabelled EBs with an efficiency of 87.3% +/- 13.5%, and enrichment ratio of 12.2 +/- 8.4 (n = 8), while preserving cell viability, differentiation potential, and long-term function. PMID- 22505993 TI - Foraging fidelity as a recipe for a long life: foraging strategy and longevity in male Southern Elephant Seals. AB - Identifying individual factors affecting life-span has long been of interest for biologists and demographers: how do some individuals manage to dodge the forces of mortality when the vast majority does not? Answering this question is not straightforward, partly because of the arduous task of accurately estimating longevity in wild animals, and of the statistical difficulties in correlating time-varying ecological covariables with a single number (time-to-event). Here we investigated the relationship between foraging strategy and life-span in an elusive and large marine predator: the Southern Elephant Seal (Mirounga leonina). Using teeth recovered from dead males on iles Kerguelen, Southern Ocean, we first aged specimens. Then we used stable isotopic measurements of carbon (delta13C) in dentin to study the effect of foraging location on individual life-span. Using a joint change-point/survival modelling approach which enabled us to describe the ontogenetic trajectory of foraging, we unveiled how a stable foraging strategy developed early in life positively covaried with longevity in male Southern Elephant Seals. Coupled with an appropriate statistical analysis, stable isotopes have the potential to tackle ecological questions of long standing interest but whose answer has been hampered by logistic constraints. PMID- 22505994 TI - Progranulin gene variability and plasma levels in bipolar disorder and schizophrenia. AB - Basing on the assumption that frontotemporal lobar degeneration (FTLD), schizophrenia and bipolar disorder (BPD) might share common aetiological mechanisms, we analyzed genetic variation in the FTLD risk gene progranulin (GRN) in a German population of patients with schizophrenia (n = 271) or BPD (n = 237) as compared with 574 age-, gender- and ethnicity-matched controls. Furthermore, we measured plasma progranulin levels in 26 German BPD patients as well as in 61 Italian BPD patients and 29 matched controls.A significantly decreased allelic frequency of the minor versus the wild-type allele was observed for rs2879096 (23.2 versus 34.2%, P<0.001, OR:0.63, 95%CI:0.49-0.80), rs4792938 (30.7 versus 39.7%, P = 0.005, OR: 0.70, 95%CI: 0.55-0.89) and rs5848 (30.3 versus 36.8, P = 0.007, OR: 0.71, 95%CI: 0.56-0.91). Mean+/-SEM progranulin plasma levels were significantly decreased in BPD patients, either Germans or Italians, as compared with controls (89.69+/-3.97 and 116.14+/-5.80 ng/ml, respectively, versus 180.81+/-18.39 ng/ml P<0.001) and were not correlated with age.In conclusion, GRN variability decreases the risk to develop BPD and schizophrenia, and progranulin plasma levels are significantly lower in BPD patients than in controls. Nevertheless, a larger replication analysis would be needed to confirm these preliminary results. PMID- 22505995 TI - Dissociating object directed and non-object directed action in the human mirror system; implications for theories of motor simulation. AB - Mirror neurons are single cells found in macaque premotor and parietal cortices that are active during action execution and observation. In non-human primates, mirror neurons have only been found in relation to object-directed movements or communicative gestures, as non-object directed actions of the upper limb are not well characterized in non-human primates. Mirror neurons provide important evidence for motor simulation theories of cognition, sometimes referred to as the direct matching hypothesis, which propose that observed actions are mapped onto associated motor schemata in a direct and automatic manner. This study, for the first time, directly compares mirror responses, defined as the overlap between action execution and observation, during object directed and meaningless non object directed actions. We present functional MRI data that demonstrate a clear dissociation between object directed and non-object directed actions within the human mirror system. A premotor and parietal network was preferentially active during object directed actions, whether observed or executed. Moreover, we report spatially correlated activity across multiple voxels for observation and execution of an object directed action. In contrast to predictions made by motor simulation theory, no similar activity was observed for non-object directed actions. These data demonstrate that object directed and meaningless non-object directed actions are subserved by different neuronal networks and that the human mirror response is significantly greater for object directed actions. These data have important implications for understanding the human mirror system and for simulation theories of motor cognition. Subsequent theories of motor simulation must account for these differences, possibly by acknowledging the role of experience in modulating the mirror response. PMID- 22505996 TI - Spherical lactic acid bacteria activate plasmacytoid dendritic cells immunomodulatory function via TLR9-dependent crosstalk with myeloid dendritic cells. AB - Plasmacytoid dendritic cells (pDC) are a specialized sensor of viral and bacterial nucleic acids and a major producer of IFN-alpha that promotes host defense by priming both innate and acquired immune responses. Although synthetic Toll-like receptor (TLR) ligands, pathogenic bacteria and viruses activate pDC, there is limited investigation of non-pathogenic microbiota that are in wide industrial dietary use, such as lactic acid bacteria (LAB). In this study, we screened for LAB strains, which induce pDC activation and IFN-alpha production using murine bone marrow (BM)-derived Flt-3L induced dendritic cell culture. Microbial strains with such activity on pDC were absent in a diversity of bacillary strains, but were observed in certain spherical species (Lactococcus, Leuconostoc, Streptococcus and Pediococcus), which was correlated with their capacity for uptake by pDC. Detailed study of Lactococcus lactis subsp. lactis JCM5805 and JCM20101 revealed that the major type I and type III interferons were induced (IFN-alpha, -beta, and lambda). IFN-alpha induction was TLR9 and MyD88 dependent; a slight impairment was also observed in TLR4(-/-) cells. While these responses occurred with purified pDC, IFN-alpha production was synergistic upon co-culture with myeloid dendritic cells (mDC), an interaction that required direct mDC-pDC contact. L. lactis strains also stimulated expression of immunoregulatory receptors on pDC (ICOS-L and PD-L1), and accordingly augmented pDC induction of CD4(+)CD25(+)FoxP3(+) Treg compared to the Lactobacillus strain. Oral administration of L. lactis JCM5805 induced significant activation of pDC resident in the intestinal draining mesenteric lymph nodes, but not in a remote lymphoid site (spleen). Taken together, certain non-pathogenic spherical LAB in wide dietary use has potent and diverse immunomodulatory effects on pDC potentially relevant to anti-viral immunity and chronic inflammatory disease. PMID- 22505997 TI - Membrane association of the PTEN tumor suppressor: molecular details of the protein-membrane complex from SPR binding studies and neutron reflection. AB - The structure and function of the PTEN phosphatase is investigated by studying its membrane affinity and localization on in-plane fluid, thermally disordered synthetic membrane models. The membrane association of the protein depends strongly on membrane composition, where phosphatidylserine (PS) and phosphatidylinositol diphosphate (PI(4,5)P(2)) act pronouncedly synergistic in pulling the enzyme to the membrane surface. The equilibrium dissociation constants for the binding of wild type (wt) PTEN to PS and PI(4,5)P(2) were determined to be K(d)~12 uM and 0.4 uM, respectively, and K(d)~50 nM if both lipids are present. Membrane affinities depend critically on membrane fluidity, which suggests multiple binding sites on the protein for PI(4,5)P(2). The PTEN mutations C124S and H93R show binding affinities that deviate strongly from those measured for the wt protein. Both mutants bind PS more strongly than wt PTEN. While C124S PTEN has at least the same affinity to PI(4,5)P(2) and an increased apparent affinity to PI(3,4,5)P(3), due to its lack of catalytic activity, H93R PTEN shows a decreased affinity to PI(4,5)P(2) and no synergy in its binding with PS and PI(4,5)P(2). Neutron reflection measurements show that the PTEN phosphatase "scoots" along the membrane surface (penetration <5 A) but binds the membrane tightly with its two major domains, the C2 and phosphatase domains, as suggested by the crystal structure. The regulatory C-terminal tail is most likely displaced from the membrane and organized on the far side of the protein, ~60 A away from the bilayer surface, in a rather compact structure. The combination of binding studies and neutron reflection allows us to distinguish between PTEN mutant proteins and ultimately may identify the structural features required for membrane binding and activation of PTEN. PMID- 22505998 TI - Nitrile hydratase genes are present in multiple eukaryotic supergroups. AB - BACKGROUND: Nitrile hydratases are enzymes involved in the conversion of nitrile containing compounds into ammonia and organic acids. Although they are widespread in prokaryotes, nitrile hydratases have only been reported in two eukaryotes: the choanoflagellate Monosiga brevicollis and the stramenopile Aureococcus anophagefferens. The nitrile hydratase gene in M. brevicollis was believed to have arisen by lateral gene transfer from a prokaryote, and is a fusion of beta and alpha nitrile hydratase subunits. Only the alpha subunit has been reported in A. anophagefferens. METHODOLOGY/PRINCIPAL FINDINGS: Here we report the detection of nitrile hydratase genes in five eukaryotic supergroups: opisthokonts, amoebozoa, archaeplastids, CCTH and SAR. Beta-alpha subunit fusion genes are found in the choanoflagellates, ichthyosporeans, apusozoans, haptophytes, rhizarians and stramenopiles, and potentially also in the amoebozoans. An individual alpha subunit is found in a dinoflagellate and an individual beta subunit is found in a haptophyte. Phylogenetic analyses recover a clade of eukaryotic-type nitrile hydratases in the Opisthokonta, Amoebozoa, SAR and CCTH; this is supported by analyses of introns and gene architecture. Two nitrile hydratase sequences from an animal and a plant resolve in the prokaryotic nitrile hydratase clade. CONCLUSIONS/SIGNIFICANCE: The evidence presented here demonstrates that nitrile hydratase genes are present in multiple eukaryotic supergroups, suggesting that a subunit fusion gene was present in the last common ancestor of all eukaryotes. The absence of nitrile hydratase from several sequenced species indicates that subunits were lost in multiple eukaryotic taxa. The presence of nitrile hydratases in many other eukaryotic groups is unresolved due to insufficient data and taxon sampling. The retention and expression of the gene in distantly related eukaryotic species suggests that it plays an important metabolic role. The novel family of eukaryotic nitrile hydratases presented in this paper represents a promising candidate for research into their molecular biology and possible biotechnological applications. PMID- 22505999 TI - Caveolin-1-enhanced motility and focal adhesion turnover require tyrosine-14 but not accumulation to the rear in metastatic cancer cells. AB - Caveolin-1 is known to promote cell migration, and increased caveolin-1 expression is associated with tumor progression and metastasis. In fibroblasts, caveolin-1 polarization and phosphorylation of tyrosine-14 are essential to promote migration. However, the role of caveolin-1 in migration of metastatic cells remains poorly defined. Here, caveolin-1 participation in metastatic cell migration was evaluated by shRNA targeting of endogenous caveolin-1 in MDA-MB-231 human breast cancer cells and ectopic expression in B16-F10 mouse melanoma cells. Depletion of caveolin-1 in MDA-MB-231 cells reduced, while expression in B16-F10 cells promoted migration, polarization and focal adhesion turnover in a sequence of events that involved phosphorylation of tyrosine-14 and Rac-1 activation. In B16-F10 cells, expression of a non-phosphorylatable tyrosine-14 to phenylalanine mutant failed to recapitulate the effects observed with wild-type caveolin-1. Alternatively, treatment of MDA-MB-231 cells with the Src family kinase inhibitor PP2 reduced caveolin-1 phosphorylation on tyrosine-14 and cell migration. Surprisingly, unlike for fibroblasts, caveolin-1 polarization and re-localization to the trailing edge were not observed in migrating metastatic cells. Thus, expression and phosphorylation, but not polarization of caveolin-1 favor the highly mobile phenotype of metastatic cells. PMID- 22506000 TI - A multi-functional imaging approach to high-content protein interaction screening. AB - Functional imaging can provide a level of quantification that is not possible in what might be termed traditional high-content screening. This is due to the fact that the current state-of-the-art high-content screening systems take the approach of scaling-up single cell assays, and are therefore based on essentially pictorial measures as assay indicators. Such phenotypic analyses have become extremely sophisticated, advancing screening enormously, but this approach can still be somewhat subjective. We describe the development, and validation, of a prototype high-content screening platform that combines steady-state fluorescence anisotropy imaging with fluorescence lifetime imaging (FLIM). This functional approach allows objective, quantitative screening of small molecule libraries in protein-protein interaction assays. We discuss the development of the instrumentation, the process by which information on fluorescence resonance energy transfer (FRET) can be extracted from wide-field, acceptor fluorescence anisotropy imaging and cross-checking of this modality using lifetime imaging by time-correlated single-photon counting. Imaging of cells expressing protein constructs where eGFP and mRFP1 are linked with amino-acid chains of various lengths (7, 19 and 32 amino acids) shows the two methodologies to be highly correlated. We validate our approach using a small-scale inhibitor screen of a Cdc42 FRET biosensor probe expressed in epidermoid cancer cells (A431) in a 96 microwell-plate format. We also show that acceptor fluorescence anisotropy can be used to measure variations in hetero-FRET in protein-protein interactions. We demonstrate this using a screen of inhibitors of internalization of the transmembrane receptor, CXCR4. These assays enable us to demonstrate all the capabilities of the instrument, image processing and analytical techniques that have been developed. Direct correlation between acceptor anisotropy and donor FLIM is observed for FRET assays, providing an opportunity to rapidly screen proteins, interacting on the nano-meter scale, using wide-field imaging. PMID- 22506001 TI - Multi-dimensional, mesoscopic Monte Carlo simulations of inhomogeneous reaction drift-diffusion systems on graphics-processing units. AB - For many biological applications, a macroscopic (deterministic) treatment of reaction-drift-diffusion systems is insufficient. Instead, one has to properly handle the stochastic nature of the problem and generate true sample paths of the underlying probability distribution. Unfortunately, stochastic algorithms are computationally expensive and, in most cases, the large number of participating particles renders the relevant parameter regimes inaccessible. In an attempt to address this problem we present a genuine stochastic, multi-dimensional algorithm that solves the inhomogeneous, non-linear, drift-diffusion problem on a mesoscopic level. Our method improves on existing implementations in being multi dimensional and handling inhomogeneous drift and diffusion. The algorithm is well suited for an implementation on data-parallel hardware architectures such as general-purpose graphics processing units (GPUs). We integrate the method into an operator-splitting approach that decouples chemical reactions from the spatial evolution. We demonstrate the validity and applicability of our algorithm with a comprehensive suite of standard test problems that also serve to quantify the numerical accuracy of the method. We provide a freely available, fully functional GPU implementation. Integration into Inchman, a user-friendly web service, that allows researchers to perform parallel simulations of reaction-drift-diffusion systems on GPU clusters is underway. PMID- 22506002 TI - Traditional taxonomic groupings mask evolutionary history: a molecular phylogeny and new classification of the chromodorid nudibranchs. AB - Chromodorid nudibranchs (16 genera, 300+ species) are beautiful, brightly colored sea slugs found primarily in tropical coral reef habitats and subtropical coastal waters. The chromodorids are the most speciose family of opisthobranchs and one of the most diverse heterobranch clades. Chromodorids have the potential to be a model group with which to study diversification, color pattern evolution, are important source organisms in natural products chemistry and represent a stunning and widely compelling example of marine biodiversity. Here, we present the most complete molecular phylogeny of the chromodorid nudibranchs to date, with a broad sample of 244 specimens (142 new), representing 157 (106 new) chromodorid species, four actinocylcid species and four additional dorid species utilizing two mitochondrial markers (16s and COI). We confirmed the monophyly of the Chromodorididae and its sister group relationship with the Actinocyclidae. We were also able to, for the first time, test generic monophyly by including more than one member of all 14 of the non-monotypic chromodorid genera. Every one of these 14 traditional chromodorid genera are either non-monophyletic, or render another genus paraphyletic. Additionally, both the monotypic genera Verconia and Diversidoris are nested within clades. Based on data shown here, there are three individual species and five clades limited to the eastern Pacific and Atlantic Oceans (or just one of these ocean regions), while the majority of chromodorid clades and species are strictly Indo-Pacific in distribution. We present a new classification of the chromodorid nudibranchs. We use molecular data to untangle evolutionary relationships and retain a historical connection to traditional systematics by using generic names attached to type species as clade names. PMID- 22506003 TI - Blood levels of macrophage migration inhibitory factor after successful resuscitation from cardiac arrest. AB - INTRODUCTION: Ischemia-reperfusion injury following cardiopulmonary resuscitation (CPR) is associated with a systemic inflammatory response, resulting in post resuscitation disease. In the present study we investigated the response of the pleiotropic inflammatory cytokine macrophage migration inhibitory factor (MIF) to CPR in patients admitted to the hospital after out-of-hospital cardiac arrest (OHCA). To describe the magnitude of MIF release, we compared the blood levels from CPR patients with those obtained in healthy volunteers and with an aged- and gender-matched group of patients undergoing cardiac surgery with the use of extracorporeal circulation. METHODS: Blood samples of 17 patients with return of spontaneous circulation (ROSC) after OHCA were obtained upon admission to the intensive care unit, and 6, 12, 24, 72 and 96 h later. Arrest and treatment related data were documented according to the Utstein style. RESULTS: In patients after ROSC, MIF levels at admission (475.2+/-157.8 ng/ml) were significantly higher than in healthy volunteers (12.5+/-16.9 ng/ml, p<0.007) and in patients after cardiac surgery (78.2+/-41.6 ng/ml, p<0.007). Six hours after admission, MIF levels were decreased by more than 50% (150.5+/-127.2 ng/ml, p<0.007), but were not further reduced in the subsequent time course and remained significantly higher than the values observed during the ICU stay of cardiac surgical patients. In this small group of patients, MIF levels could not discriminate between survivors and non-survivors and were not affected by treatment with mild therapeutic hypothermia. CONCLUSION: MIF shows a rapid and pronounced increase following CPR, hence allowing a very early assessment of the inflammatory response. Further studies are warranted in larger patient groups to determine the prognostic significance of MIF. TRIAL REGISTRATION: ClinicalTrials.gov NCT01412619. PMID- 22506004 TI - Optogenetic mimicry of the transient activation of dopamine neurons by natural reward is sufficient for operant reinforcement. AB - Activation of dopamine receptors in forebrain regions, for minutes or longer, is known to be sufficient for positive reinforcement of stimuli and actions. However, the firing rate of dopamine neurons is increased for only about 200 milliseconds following natural reward events that are better than expected, a response which has been described as a "reward prediction error" (RPE). Although RPE drives reinforcement learning (RL) in computational models, it has not been possible to directly test whether the transient dopamine signal actually drives RL. Here we have performed optical stimulation of genetically targeted ventral tegmental area (VTA) dopamine neurons expressing Channelrhodopsin-2 (ChR2) in mice. We mimicked the transient activation of dopamine neurons that occurs in response to natural reward by applying a light pulse of 200 ms in VTA. When a single light pulse followed each self-initiated nose poke, it was sufficient in itself to cause operant reinforcement. Furthermore, when optical stimulation was delivered in separate sessions according to a predetermined pattern, it increased locomotion and contralateral rotations, behaviors that are known to result from activation of dopamine neurons. All three of the optically induced operant and locomotor behaviors were tightly correlated with the number of VTA dopamine neurons that expressed ChR2, providing additional evidence that the behavioral responses were caused by activation of dopamine neurons. These results provide strong evidence that the transient activation of dopamine neurons provides a functional reward signal that drives learning, in support of RL theories of dopamine function. PMID- 22506005 TI - Increase in cerebellar volume in Cavalier King Charles Spaniels with Chiari-like malformation and its role in the development of syringomyelia. AB - Previous research in Cavalier King Charles Spaniels (CKCS) has found that Chiari like malformation and syringomyelia (CM/SM) are associated with a volume mismatch between the caudal cranial fossa (CCF) and the brain parenchyma contained within. The objectives of this study were to i) compare cerebellar volume in CKCS (a "high risk' group which frequently develops CM/SM), small breed dogs (medium risk -occasionally develop CM/SM), and Labradors (low risk--CM/SM not reported); ii) evaluate a possible association between increased cerebellar volume and CM/SM in CKCS; iii) investigate the relationship between increased cerebellar volume and crowding of the cerebellum in the caudal part of the CCF (i.e. the region of the foramen magnum). Volumes of three-dimensional, magnetic resonance imaging derived models of the CCF and cerebellum were obtained from 75 CKCS, 44 small breed dogs, and 31 Labradors. As SM is thought to be a late onset disease process, two subgroups were formed for comparison: 18 CKCS younger than 2 years with SM (CM/SM group) and 13 CKCS older than 5 years without SM (CM group). Relative cerebellar volume was defined as the volume of the cerebellum divided by the total volume of brain parenchyma. Our results show that the CKCS has a relatively larger cerebellum than small breed dogs and Labradors and provide evidence that increased cerebellar volume in CKCS is associated with crowding of cerebellum in the caudal part of the CCF. In CKCS there is an association between increased cerebellar volume and SM. These findings have implications for the understanding of the pathological mechanisms of CM/SM, and support the hypothesis that it is a multifactorial disease process governed by increased cerebellar volume and failure of the CCF to reach a commensurate size. PMID- 22506006 TI - An analysis of 332 fatalities infected with pandemic 2009 influenza A (H1N1) in Argentina. AB - BACKGROUND: The apparent high number of deaths in Argentina during the 2009 pandemic led to concern that the influenza A H1N1pdm disease was different there. We report the characteristics and risk factors for influenza A H1N1pdm fatalities. METHODS: We identified laboratory-confirmed influenza A H1N1pdm fatalities occurring during June-July 2009. Physicians abstracted data on age, sex, time of onset of illness, medical history, clinical presentation at admission, laboratory, treatment, and outcomes using standardize questionnaires. We explored the characteristics of fatalities according to their age and risk group. RESULTS: Of 332 influenza A H1N1pdm fatalities, 226 (68%) were among persons aged <50 years. Acute respiratory failure was the leading cause of death. Of all cases, 249 (75%) had at least one comorbidity as defined by Advisory Committee on Immunization Practices. Obesity was reported in 32% with data and chronic pulmonary disease in 28%. Among the 40 deaths in children aged <5 years, chronic pulmonary disease (42%) and neonatal pathologies (35%) were the most common co-morbidities. Twenty (6%) fatalities were among pregnant or postpartum women of which only 47% had diagnosed co-morbidities. Only 13% of patients received antiviral treatment within 48 hours of symptom onset. None of children aged <5 years or the pregnant women received antivirals within 48 h of symptom onset. As the pandemic progressed, the time from symptom-onset to medical care and to antiviral treatment decreased significantly among case-patients who subsequently died (p<0.001). CONCLUSION: Persons with co-morbidities, pregnant and who received antivirals late were over-represented among influenza A H1N1pdm deaths in Argentina, though timeliness of antiviral treatment improved during the pandemic. PMID- 22506008 TI - Changes in plasma membrane surface potential of PC12 cells as measured by Kelvin probe force microscopy. AB - The plasma membrane of a cell not only works as a physical barrier but also mediates the signal relay between the extracellular milieu and the cell interior. Various stimulants may cause the redistribution of molecules, like lipids, proteins, and polysaccharides, on the plasma membrane and change the surface potential (Phi(s)). In this study, the Phi(s)s of PC12 cell plasma membranes were measured by atomic force microscopy in Kelvin probe mode (KPFM). The skewness values of the Phi(s)s distribution histogram were found to be mostly negative, and the incorporation of negatively charged phosphatidylserine shifted the average skewness values to positive. After being treated with H(2)O(2), dopamine, or Zn(2+), phosphatidylserine was found to be translocated to the membrane outer leaflet and the averaged skewness values were changed to positive values. These results demonstrated that KPFM can be used to monitor cell physiology status in response to various stimulants with high spatial resolution. PMID- 22506007 TI - Global methylation patterns in idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is characterized by profound changes in the lung phenotype including excessive extracellular matrix deposition, myofibroblast foci, alveolar epithelial cell hyperplasia and extensive remodeling. The role of epigenetic changes in determining the lung phenotype in IPF is unknown. In this study we determine whether IPF lungs exhibit an altered global methylation profile. METHODOLOGY/PRINCIPAL FINDINGS: Immunoprecipitated methylated DNA from 12 IPF lungs, 10 lung adenocarcinomas and 10 normal histology lungs was hybridized to Agilent human CpG Islands Microarrays and data analysis was performed using BRB-Array Tools and DAVID Bioinformatics Resources software packages. Array results were validated using the EpiTYPER MassARRAY platform for 3 CpG islands. 625 CpG islands were differentially methylated between IPF and control lungs with an estimated False Discovery Rate less than 5%. The genes associated with the differentially methylated CpG islands are involved in regulation of apoptosis, morphogenesis and cellular biosynthetic processes. The expression of three genes (STK17B, STK3 and HIST1H2AH) with hypomethylated promoters was increased in IPF lungs. Comparison of IPF methylation patterns to lung cancer or control samples, revealed that IPF lungs display an intermediate methylation profile, partly similar to lung cancer and partly similar to control with 402 differentially methylated CpG islands overlapping between IPF and cancer. Despite their similarity to cancer, IPF lungs did not exhibit hypomethylation of long interspersed nuclear element 1 (LINE-1) retrotransposon while lung cancer samples did, suggesting that the global hypomethylation observed in cancer was not typical of IPF. CONCLUSIONS/SIGNIFICANCE: Our results provide evidence that epigenetic changes in IPF are widespread and potentially important. The partial similarity to cancer may signify similar pathogenetic mechanisms while the differences constitute IPF or cancer specific changes. Elucidating the role of these specific changes will potentially allow better understanding of the pathogenesis of IPF. PMID- 22506009 TI - B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease. AB - BACKGROUND: Langerhans cell histiocytosis (LCH) features inflammatory granuloma characterised by the presence of CD1a+ dendritic cells or 'LCH cells'. Badalian Very et al. recently reported the presence of a canonical (V600E)B-RAF mutation in 57% of paraffin-embedded biopsies from LCH granuloma. Here we confirm their findings and report the identification of two novel B-RAF mutations detected in LCH patients. METHODS AND RESULTS: Mutations of B-RAF were observed in granuloma samples from 11 out of 16 patients using 'next generation' pyrosequencing. In 9 cases the mutation identified was (V600E)B-RAF. In 2 cases novel polymorphisms were identified. A somatic (600DLAT)B-RAF insertion mimicked the structural and functional consequences of the (V600E)B-RAF mutant. It destabilized the inactive conformation of the B-RAF kinase and resulted in increased ERK activation in 293 T cells. The (600DLAT)B-RAF and (V600E)B-RAF mutations were found enriched in DNA and mRNA from the CD1a+ fraction of granuloma. They were absent from the blood and monocytes of 58 LCH patients, with a lower threshold of sequencing sensitivity of 1%-2% relative mutation abundance. A novel germ line (T599A)B-RAF mutant allele was detected in one patient, at a relative mutation abundance close to 50% in the LCH granuloma, blood monocytes and lymphocytes. However, (T599A)B RAF did not destabilize the inactive conformation of the B-RAF kinase, and did not induce increased ERK phosphorylation or C-RAF transactivation. CONCLUSIONS: Our data confirmed presence of the (V600E)B-RAF mutation in LCH granuloma of some patients, and identify two novel B-RAF mutations. They indicate that (V600E)B-RAF and (600DLAT)B-RAF mutations are somatic mutants enriched in LCH CD1a(+) cells and absent from the patient blood. Further studies are needed to assess the functional consequences of the germ-line (T599A)B-RAF allele. PMID- 22506010 TI - Genetics of clusterin isoform expression and Alzheimer's disease risk. AB - The minor allele of rs11136000 within CLU is strongly associated with reduced Alzheimer's disease (AD) risk. The mechanism underlying this association is unclear. Here, we report that CLU1 and CLU2 are the two primary CLU isoforms in human brain; CLU1 and CLU2 share exons 2-9 but differ in exon 1 and proximal promoters. The expression of both CLU1 and CLU2 was increased in individuals with significant AD neuropathology. However, only CLU1 was associated with the rs11136000 genotype, with the minor "protective" rs11136000T allele being associated with increased CLU1 expression. Since CLU1 and CLU2 are predicted to encode intracellular and secreted proteins, respectively, we compared their expression; for both CLU1 and CLU2 transfected cells, clusterin is present in the secretory pathway, accumulates in the extracellular media, and is similar in size to clusterin in human brain. Overall, we interpret these results as indicating that the AD-protective minor rs11136000T allele is associated with increased CLU1 expression. Since CLU1 and CLU2 appear to produce similar proteins and are increased in AD, the AD-protection afforded by the rs11136000T allele may reflect increased soluble clusterin throughout life. PMID- 22506011 TI - Determinants of refusal of A/H1N1 pandemic vaccination in a high risk population: a qualitative approach. AB - BACKGROUND: Our study analyses the main determinants of refusal or acceptance of the 2009 A/H1N1 vaccine in patients with cystic fibrosis, a high-risk population for severe flu infection, usually very compliant for seasonal flu vaccine. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a qualitative study based on semi structured interviews in 3 cystic fibrosis referral centres in Paris, France. The study included 42 patients with cystic fibrosis: 24 who refused the vaccine and 18 who were vaccinated. The two groups differed quite substantially in their perceptions of vaccine- and disease-related risks. Those who refused the vaccine were motivated mainly by the fears it aroused and did not explicitly consider the 2009 A/H1N1 flu a potentially severe disease. People who were vaccinated explained their choice, first and foremost, as intended to prevent the flu's potential consequences on respiratory cystic fibrosis disease. Moreover, they considered vaccination to be an indirect collective prevention tool. Patients who refused the vaccine mentioned multiple, contradictory information sources and did not appear to consider the recommendation of their local health care provider as predominant. On the contrary, those who were vaccinated stated that they had based their decision solely on the clear and unequivocal advice of their health care provider. CONCLUSIONS/SIGNIFICANCE: These results of our survey led us to formulate three main recommendations for improving adhesion to new pandemic vaccines. (1) it appears necessary to reinforce patient education about the disease and its specific risks, but also general population information about community immunity. (2) it is essential to disseminate a clear and effective message about the safety of novel vaccines. (3) this message should be conveyed by local health care providers, who should be involved in implementing immunization. PMID- 22506012 TI - Water availability is the main climate driver of neotropical tree growth. AB - * Climate models for the coming century predict rainfall reduction in the Amazonian region, including change in water availability for tropical rainforests. Here, we test the extent to which climate variables related to water regime, temperature and irradiance shape the growth trajectories of neotropical trees. * We developed a diameter growth model explicitly designed to work with asynchronous climate and growth data. Growth trajectories of 205 individual trees from 54 neotropical species censused every 2 months over a 4-year period were used to rank 9 climate variables and find the best predictive model. * About 9% of the individual variation in tree growth was imputable to the seasonal variation of climate. Relative extractable water was the main predictor and alone explained more than 60% of the climate effect on tree growth, i.e. 5.4% of the individual variation in tree growth. Furthermore, the global annual tree growth was more dependent on the diameter increment at the onset of the rain season than on the duration of dry season. * The best predictive model included 3 climate variables: relative extractable water, minimum temperature and irradiance. The root mean squared error of prediction (0.035 mm x d(-1)) was slightly above the mean value of the growth (0.026 mm x d(-1)). * Amongst climate variables, we highlight the predominant role of water availability in determining seasonal variation in tree growth of neotropical forest trees and the need to include these relationships in forest simulators to test, in silico, the impact of different climate scenarios on the future dynamics of the rainforest. PMID- 22506013 TI - Gene regulation of intestinal porcine epithelial cells IPEC-J2 is dependent on the site of deoxynivalenol toxicological action. AB - The intestinal epithelial cell layer represents the border between the luminal and systemic side of the gut. The decision between absorption and exclusion of substances is the quintessential function of the gut and varies along the gut axis. Consequently, potentially toxic substances may reach the basolateral domain of the epithelial cell layer via blood stream. The mycotoxin deoxynivalenol (DON) is a Fusarium derived secondary metabolite known to enter the blood stream and displaying a striking toxicity on the basolateral side of polarised epithelial cell layers in vitro. Here we analysed potential mechanisms of apical and basolateral DON toxicity reflected in the gene expression. We used the jejunum derived, polarised intestinal porcine epithelial cell line IPEC-J2 as an in vitro cell culture model. Luminal and systemic DON challenge of the epithelial cell layer was mimicked by a DON application from the apical or basolateral compartment of membrane inserts for 72 h. We compared the genome-wide gene expression of untreated and DON-treated IPEC-J2 cells with the GeneChip(r) Porcine Genome Array of Affymetrix. Low basolateral DON (200 ng/mL) application triggered 10 times more gene transcripts in comparison to the corresponding apical application (2539 versus 267) despite the intactness of the challenged cell layer as measured by transepithelial electrical resistance. Analysis of the regulated genes by bioinformatic resource DAVID identified several groups of biochemical pathways modulated by concentration and orientation of DON application. Selected genes representing pathways of the cellular metabolism, information processing and structural design were analysed in detail by quantitative PCR. Our findings clearly show that apical and basolateral challenge of epithelial cell layers trigger different gene response profiles paralleled with a higher susceptibility towards basolateral challenge. The evaluation of toxicological potentials of mycotoxins should take this difference in gene regulation dependent on route of application into account. PMID- 22506014 TI - Valproic acid induces hair regeneration in murine model and activates alkaline phosphatase activity in human dermal papilla cells. AB - BACKGROUND: Alopecia is the common hair loss problem that can affect many people. However, current therapies for treatment of alopecia are limited by low efficacy and potentially undesirable side effects. We have identified a new function for valproic acid (VPA), a GSK3beta inhibitor that activates the Wnt/beta-catenin pathway, to promote hair re-growth in vitro and in vivo. METHODOLOGY/ PRINCIPAL FINDINGS: Topical application of VPA to male C3H mice critically stimulated hair re-growth and induced terminally differentiated epidermal markers such as filaggrin and loricrin, and the dermal papilla marker alkaline phosphatase (ALP). VPA induced ALP in human dermal papilla cells by up-regulating the Wnt/beta catenin pathway, whereas minoxidil (MNX), a drug commonly used to treat alopecia, did not significantly affect the Wnt/beta-catenin pathway. VPA analogs and other GSK3beta inhibitors that activate the Wnt/beta-catenin pathway such as 4-phenyl butyric acid, LiCl, and BeCl(2) also exhibited hair growth-promoting activities in vivo. Importantly, VPA, but not MNX, successfully stimulate hair growth in the wounds of C3H mice. CONCLUSIONS/ SIGNIFICANCE: Our findings indicate that small molecules that activate the Wnt/beta-catenin pathway, such as VPA, can potentially be developed as drugs to stimulate hair re-growth. PMID- 22506016 TI - Longer leukocyte telomere length is associated with smaller hippocampal volume among non-demented APOE epsilon3/epsilon3 subjects. AB - Telomere length shortens with cellular division, and leukocyte telomere length is used as a marker for systemic telomere length. The hippocampus hosts adult neurogenesis and is an important structure for episodic memory, and carriers of the apolipoprotein E epsilon4 allele exhibit higher hippocampal atrophy rates and differing telomere dynamics compared with non-carriers. The authors investigated whether leukocyte telomere length was associated with hippocampal volume in 57 cognitively intact subjects (29 epsilon3/epsilon3 carriers; 28 epsilon4 carriers) aged 49-79 yr. Leukocyte telomere length correlated inversely with left (r(s) = 0.465; p = 0.011), right (r(s) = -0.414; p = 0.025), and total hippocampus volume (r(s) = -0.519; p = 0.004) among APOE epsilon3/epsilon3 carriers, but not among epsilon4 carriers. However, the epsilon4 carriers fit with the general correlation pattern exhibited by the epsilon3/epsilon3 carriers, as epsilon4 carriers on average had longer telomeres and smaller hippocampi compared with epsilon3/epsilon3 carriers. The relationship observed can be interpreted as long telomeres representing a history of relatively low cellular proliferation, reflected in smaller hippocampal volumes. The results support the potential of leukocyte telomere length being used as a biomarker for tapping functional and structural processes of the aging brain. PMID- 22506015 TI - Nuclear targeting of IGF-1 receptor in orbital fibroblasts from Graves' disease: apparent role of ADAM17. AB - Insulin-like growth factor-1 receptor (IGF-1R) comprises two subunits, including a ligand binding domain on extra- cellular IGF-1Ralpha and a tyrosine phosphorylation site located on IGF-1Rbeta. IGF-1R is over-expressed by orbital fibroblasts in the autoimmune syndrome, Graves' disease (GD). When activated by IGF-1 or GD-derived IgG (GD-IgG), these fibroblasts produce RANTES and IL-16, while those from healthy donors do not. We now report that IGF-1 and GD-IgG provoke IGF-1R accumulation in the cell nucleus of GD fibroblasts where it co localizes with chromatin. Nuclear IGF-1R is detected with anti-IGF-1Ralpha specific mAb and migrates to approximately 110 kDa, consistent with its identity as an IGF-1R fragment. Nuclear IGF-1R migrating as a 200 kDa protein and consistent with an intact receptor was undetectable when probed with either anti IGF-1Ralpha or anti-IGF-1Rbeta mAbs. Nuclear redistribution of IGF-1R is absent in control orbital fibroblasts. In GD fibroblasts, it can be abolished by an IGF 1R-blocking mAb, 1H7 and by physiological concentrations of glucocorticoids. When cell-surface IGF-1R is cross-linked with (125)I IGF-1, (125)I-IGF-1/IGF-1R complexes accumulate in the nuclei of GD fibroblasts. This requires active ADAM17, a membrane associated metalloproteinase, and the phosphorylation of IGF 1R. In contrast, virally encoded IGF-1Ralpha/GFP fusion protein localizes equivalently in nuclei in both control and GD fibroblasts. This result suggests that generation of IGF-1R fragments may limit the accumulation of nuclear IGF-1R. We thus identify a heretofore-unrecognized behavior of IGF-1R that appears limited to GD-derived fibroblasts. Nuclear IGF-1R may play a role in disease pathogenesis. PMID- 22506017 TI - Searching for cellular partners of hantaviral nonstructural protein NSs: Y2H screening of mouse cDNA library and analysis of cellular interactome. AB - Hantaviruses (Bunyaviridae) are negative-strand RNA viruses with a tripartite genome. The small (S) segment encodes the nucleocapsid protein and, in some hantaviruses, also the nonstructural protein (NSs). The aim of this study was to find potential cellular partners for the hantaviral NSs protein. Toward this aim, yeast two-hybrid (Y2H) screening of mouse cDNA library was performed followed by a search for potential NSs protein counterparts via analyzing a cellular interactome. The resulting interaction network was shown to form logical, clustered structures. Furthermore, several potential binding partners for the NSs protein, for instance ACBD3, were identified and, to prove the principle, interaction between NSs and ACBD3 proteins was demonstrated biochemically. PMID- 22506018 TI - Mycobacterium avium subsp. avium and subsp. hominissuis give different cytokine responses after in vitro stimulation of human blood mononuclear cells. AB - BACKGROUND: Mycobacterium avium is the principal etiologic agent of non tuberculous lymphadenitis in children. It is also a known pathogen for birds and other animals. Genetic typing of M. avium isolates has led to a proposal to expand the set of subspecies to include M. avium subsp. hominissuis. Isolates associated with disease in humans belong to this subspecies. METHODOLOGY/PRINCIPAL FINDINGS: Peripheral blood mononuclear cells from six healthy blood donors were stimulated in vitro with ten isolates of M. avium avium and 11 isolates of M. avium hominissuis followed by multiplex bead array quantification of cytokines in supernatants. M. avium hominissuis isolates induced significantly more IL-10 and significantly less IL-12p70, TNF, IFN-gamma and IL-17 when compared to M. avium avium isolates. All strains induced high levels of IL-17, but had very low levels of IL-12p70. CONCLUSION/SIGNIFICANCE: The strong association between M. avium subsp. hominissuis and disease in humans and the clear differences in the human immune response to M. avium subsp. hominissuis compared to M. avium subsp. avium isolates, as demonstrated in this study, suggest that genetic differences between M. avium isolates play an important role in the pathogenicity in humans. PMID- 22506019 TI - Polygenic sex determination system in zebrafish. AB - BACKGROUND: Despite the popularity of zebrafish as a research model, its sex determination (SD) mechanism is still unknown. Most cytogenetic studies failed to find dimorphic sex chromosomes and no primary sex determining switch has been identified even though the assembly of zebrafish genome sequence is near to completion and a high resolution genetic map is available. Recent publications suggest that environmental factors within the natural range have minimal impact on sex ratios of zebrafish populations. The primary aim of this study is to find out more about how sex is determined in zebrafish. METHODOLOGY/PRINCIPAL FINDINGS: Using classical breeding experiments, we found that sex ratios across families were wide ranging (4.8% to 97.3% males). On the other hand, repeated single pair crossings produced broods of very similar sex ratios, indicating that parental genotypes have a role in the sex ratio of the offspring. Variation among family sex ratios was reduced after selection for breeding pairs with predominantly male or female offspring, another indication that zebrafish sex is regulated genetically. Further examinations by a PCR-based "blind assay" and array comparative genomic hybridization both failed to find universal sex-linked differences between the male and female genomes. Together with the ability to increase the sex bias of lines by selective breeding, these data suggest that zebrafish is unlikely to utilize a chromosomal sex determination (CSD) system. CONCLUSIONS/SIGNIFICANCE: Taken together, our study suggests that zebrafish sex is genetically determined with limited, secondary influences from the environment. As we have not found any sign for CSD in the species, we propose that the zebrafish has a polygenic sex determination system. PMID- 22506020 TI - Versatility of cooperative transcriptional activation: a thermodynamical modeling analysis for greater-than-additive and less-than-additive effects. AB - We derive a statistical model of transcriptional activation using equilibrium thermodynamics of chemical reactions. We examine to what extent this statistical model predicts synergy effects of cooperative activation of gene expression. We determine parameter domains in which greater-than-additive and less-than-additive effects are predicted for cooperative regulation by two activators. We show that the statistical approach can be used to identify different causes of synergistic greater-than-additive effects: nonlinearities of the thermostatistical transcriptional machinery and three-body interactions between RNA polymerase and two activators. In particular, our model-based analysis suggests that at low transcription factor concentrations cooperative activation cannot yield synergistic greater-than-additive effects, i.e., DNA transcription can only exhibit less-than-additive effects. Accordingly, transcriptional activity turns from synergistic greater-than-additive responses at relatively high transcription factor concentrations into less-than-additive responses at relatively low concentrations. In addition, two types of re-entrant phenomena are predicted. First, our analysis predicts that under particular circumstances transcriptional activity will feature a sequence of less-than-additive, greater-than-additive, and eventually less-than-additive effects when for fixed activator concentrations the regulatory impact of activators on the binding of RNA polymerase to the promoter increases from weak, to moderate, to strong. Second, for appropriate promoter conditions when activator concentrations are increased then the aforementioned re-entrant sequence of less-than-additive, greater-than-additive, and less-than-additive effects is predicted as well. Finally, our model-based analysis suggests that even for weak activators that individually induce only negligible increases in promoter activity, promoter activity can exhibit greater than-additive responses when transcription factors and RNA polymerase interact by means of three-body interactions. Overall, we show that versatility of transcriptional activation is brought about by nonlinearities of transcriptional response functions and interactions between transcription factors, RNA polymerase and DNA. PMID- 22506021 TI - Modelling deep water habitats to develop a spatially explicit, fine scale understanding of the distribution of the western rock lobster, Panulirus cygnus. AB - BACKGROUND: The western rock lobster, Panulirus cygnus, is endemic to Western Australia and supports substantial commercial and recreational fisheries. Due to and its wide distribution and the commercial and recreational importance of the species a key component of managing western rock lobster is understanding the ecological processes and interactions that may influence lobster abundance and distribution. Using terrain analyses and distribution models of substrate and benthic biota, we assess the physical drivers that influence the distribution of lobsters at a key fishery site. METHODS AND FINDINGS: Using data collected from hydroacoustic and towed video surveys, 20 variables (including geophysical, substrate and biota variables) were developed to predict the distributions of substrate type (three classes of reef, rhodoliths and sand) and dominant biota (kelp, sessile invertebrates and macroalgae) within a 40 km(2) area about 30 km off the west Australian coast. Lobster presence/absence data were collected within this area using georeferenced pots. These datasets were used to develop a classification tree model for predicting the distribution of the western rock lobster. Interestingly, kelp and reef were not selected as predictors. Instead, the model selected geophysical and geomorphic scalar variables, which emphasise a mix of terrain within limited distances. The model of lobster presence had an adjusted D(2) of 64 and an 80% correct classification. CONCLUSIONS: Species distribution models indicate that juxtaposition in fine scale terrain is most important to the western rock lobster. While key features like kelp and reef may be important to lobster distribution at a broad scale, it is the fine scale features in terrain that are likely to define its ecological niche. Determining the most appropriate landscape configuration and scale will be essential to refining niche habitats and will aid in selecting appropriate sites for protecting critical lobster habitats. PMID- 22506022 TI - Gastrointestinal microbiota do not significantly contribute to T cell activation or GI inflammation in Ndfip1-cKO mice. AB - The bacteria inhabiting the mammalian gastrointestinal (GI) tract play a vital role in normal digestion and immune function. In a healthy host, the immune system is tolerant to gut bacteria and does not mount an effector response to bacteria-derived antigens. Loss of tolerance to intestinal microflora has been associated with inflammatory bowel disease (IBD) in both mice and humans. Mice lacking Ndfip1, an adaptor protein for E3 ubiquitin ligases of the Nedd4-family, in T cells (Ndfip1-cKO) develop a disease resembling IBD. Inflammation in these mice is characterized by increased activation of peripheral T cells, infiltration of eosinophils into the GI tract, and epithelial hypertrophy in the esophagus. We hypothesized that this intestinal inflammation in Ndfip1-cKO mice is caused by a loss of T-cell tolerance to bacterial antigens. Here, we show that treatment of Ndfip1-cKO mice with broad-spectrum antibiotics drastically reduced bacterial load in stool but had little effect on T-cell activation and did not affect eosinophil infiltration into the GI tract or epithelial hypertrophy in the esophagus. Thus, inflammation in Ndfip1-cKO mice is not caused by a loss of tolerance to intestinal microbiota. Rather, T cell activation and eosinophilia may instead be triggered by other environmental antigens. PMID- 22506023 TI - The role of teachers' expectations in the association between children's SES and performance in kindergarten: a moderated mediation analysis. AB - This study examines the role of teachers' expectations in the association between children's socio-economic background and achievement outcomes. Furthermore, the role of children's ethnicity in moderating this mediated relation is investigated. In the present study, 3,948 children from kindergarten are examined. Data are analysed by means of structural equation modeling. First, results show that teachers' expectations mediate the relation between children's SES and their later language and math achievement, after controlling for children's ethnicity, prior achievement and gender. This result indicates that teachers may exacerbate individual differences between children. Second, children's ethnicity moderates the mediation effect of teachers' expectations with respect to math outcomes. The role of teachers' expectations in mediating the relation between SES and math outcomes is stronger for majority children than for minority children. PMID- 22506024 TI - Effect of iron therapy on platelet counts in patients with inflammatory bowel disease-associated anemia. AB - BACKGROUND AND AIMS: Secondary thrombocytosis is a clinical feature of unknown significance. In inflammatory bowel disease (IBD), thrombocytosis is considered a marker of active disease; however, iron deficiency itself may trigger platelet generation. In this study we tested the effect of iron therapy on platelet counts in patients with IBD-associated anemia. METHODS: Platelet counts were analyzed before and after iron therapy from four prospective clinical trials. Further, changes in hemoglobin, transferrin saturation, ferritin, C-reactive protein, and leukocyte counts, before and after iron therapy were compared. In a subgroup the effect of erythropoietin treatment was tested. The results were confirmed in a large independent cohort (FERGIcor). RESULTS: A total of 308 patient records were available for the initial analysis. A dose-depended drop in platelet counts (mean 425 G/L to 320 G/L; p<0.001) was found regardless of the type of iron preparation (iron sulphate, iron sucrose, or ferric carboxymaltose). Concomitant erythropoietin therapy as well as parameters of inflammation (leukocyte counts, C reactive protein) had no effect on the change in platelet counts. This effect of iron therapy on platelets was confirmed in the FERGIcor study cohort (n=448, mean platelet counts before iron therapy: 383 G/L, after: 310 G/L, p<0.001). CONCLUSION: Iron therapy normalizes elevated platelet counts in patients with IBD associated anemia. Thus, iron deficiency is an important pathogenetic mechanism of secondary thrombocytosis in IBD. PMID- 22506025 TI - Channel-forming activities in the glycosomal fraction from the bloodstream form of Trypanosoma brucei. AB - BACKGROUND: Glycosomes are a specialized form of peroxisomes (microbodies) present in unicellular eukaryotes that belong to the Kinetoplastea order, such as Trypanosoma and Leishmania species, parasitic protists causing severe diseases of livestock and humans in subtropical and tropical countries. The organelles harbour most enzymes of the glycolytic pathway that is responsible for substrate level ATP production in the cell. Glycolysis is essential for bloodstream-form Trypanosoma brucei and enzymes comprising this pathway have been validated as drug targets. Glycosomes are surrounded by a single membrane. How glycolytic metabolites are transported across the glycosomal membrane is unclear. METHODS/PRINCIPAL FINDINGS: We hypothesized that glycosomal membrane, similarly to membranes of yeast and mammalian peroxisomes, contains channel-forming proteins involved in the selective transfer of metabolites. To verify this prediction, we isolated a glycosomal fraction from bloodstream-form T. brucei and reconstituted solubilized membrane proteins into planar lipid bilayers. The electrophysiological characteristics of the channels were studied using multiple channel recording and single channel analysis. Three main channel-forming activities were detected with current amplitudes 70-80 pA, 20-25 pA, and 8-11 pA, respectively (holding potential +10 mV and 3.0 M KCl as an electrolyte). All channels were in fully open state in a range of voltages +/-150 mV and showed no sub-conductance transitions. The channel with current amplitude 20-25 pA is anion selective (P(K+)/P(Cl-)~0.31), while the other two types of channels are slightly selective for cations (P(K+)/P(Cl-) ratios ~1.15 and ~1.27 for the high- and low conductance channels, respectively). The anion-selective channel showed an intrinsic current rectification that may suggest a functional asymmetry of the channel's pore. CONCLUSIONS/SIGNIFICANCE: These results indicate that the membrane of glycosomes apparently contains several types of pore-forming channels connecting the glycosomal lumen and the cytosol. PMID- 22506026 TI - Mutual regulation of Bcl-2 proteins independent of the BH3 domain as shown by the BH3-lacking protein Bcl-x(AK). AB - The BH3 domain of Bcl-2 proteins was regarded as indispensable for apoptosis induction and for mutual regulation of family members. We recently described Bcl x(AK), a proapoptotic splice product of the bcl-x gene, which lacks BH3 but encloses BH2, BH4 and a transmembrane domain. It remained however unclear, how Bcl-x(AK) may trigger apoptosis.For efficient overexpression, Bcl-x(AK) was subcloned in an adenoviral vector under Tet-OFF control. The construct resulted in significant apoptosis induction in melanoma and nonmelanoma cell lines with up to 50% apoptotic cells as well as decreased cell proliferation and survival. Disruption of mitochondrial membrane potential, and cytochrome c release clearly indicated activation of the mitochondrial apoptosis pathways. Both Bax and Bak were activated as shown by clustering and conformation analysis. Mitochondrial translocation of Bcl-x(AK) appeared as an essential and initial step. Bcl-x(AK) was critically dependent on either Bax or Bak, and apoptosis was abrogated in Bax/Bak double knockout conditions as well by overexpression of Bcl-2 or Bcl x(L). A direct interaction with Bcl-2, Bax, Bad, Noxa or Puma was however not seen by immunoprecipitation. Thus besides BH3-mediated interactions, there exists an additional way for mutual regulation of Bcl-2 proteins, which is independent of the BH3. This pathway appears to play a supplementary role also for other proapoptotic family members, and its unraveling may help to overcome therapy resistance in cancer. PMID- 22506027 TI - Secular trends in the prevalence of overweight and obesity in Sicilian schoolchildren aged 11-13 years during the last decade. AB - The present study evaluates trends in the prevalence of overweight and obesity in relation to gender and area of residence between two cohorts of students aged 11 13 years in Sicily. The analysis was performed on 1,839 schoolchildren, with 924 and 915 children being studied in 1999-2001 and 2009-2010, respectively. The children who were enrolled during 2009-2010 had significantly higher body mass indexes (BMI), BMI z-scores, and waist circumferences than the children who were studied during 1999-2001 (p<0.0001 for all); these differences was also observed when the cohort was subdivided according to gender or residence area The prevalence of obesity increased significantly from 7.9% in 1999-2001 to 13.7% in 2009-2010 (p<0.0001), whereas thinness decreased significantly from 10.1% to 2.3% (p<0.0001) in the same periods. The increase of trends in the prevalence of obesity was significantly higher in males (9.7% vs. 17.6%, p = 0.0006) than in females (6.3% vs. 9.8%, p = 0.04) and was slightly higher in urban areas (8.8% vs. 14.3%, p = 0.002) than in rural areas (7.8% vs. 13.0%, p = 0.012). The male gender was associated with a higher risk of being overweight or obese (odds ratio: 1.63; 95% confidence intervals: 1.24-2.15; p = 0.0005) in 2009-2010 than in 1999-2001, after adjusting for age and the residence area. In conclusion, this study showed an increasing trend in the prevalence of overweight and obesity in Sicilian schoolchildren during the last decade and that this trend was related to gender, age and the area of residence. More specifically, our data indicated that the prevalence of obesity increased by 5.8%, the prevalence of thinness decreased by 7.8% and the prevalence of normal-weight children did not change over the course of a decade. These results suggest a shift in the body weights of Sicilian children toward the upper percentiles. PMID- 22506028 TI - Haplotype analyses of haemoglobin C and haemoglobin S and the dynamics of the evolutionary response to malaria in Kassena-Nankana District of Ghana. AB - BACKGROUND: Haemoglobin S (HbS) and C (HbC) are variants of the HBB gene which both protect against malaria. It is not clear, however, how these two alleles have evolved in the West African countries where they co-exist at high frequencies. Here we use haplotypic signatures of selection to investigate the evolutionary history of the malaria-protective alleles HbS and HbC in the Kassena Nankana District (KND) of Ghana. METHODOLOGY/PRINCIPAL FINDINGS: The haplotypic structure of HbS and HbC alleles was investigated, by genotyping 56 SNPs around the HBB locus. We found that, in the KND population, both alleles reside on extended haplotypes (approximately 1.5 Mb for HbS and 650 Kb for HbC) that are significantly less diverse than those of the ancestral HbA allele. The extended haplotypes span a recombination hotspot that is known to exist in this region of the genome SIGNIFICANCE: Our findings show strong support for recent positive selection of both the HbS and HbC alleles and provide insights into how these two alleles have both evolved in the population of northern Ghana. PMID- 22506029 TI - Cell-free seminal mRNA and microRNA exist in different forms. AB - BACKGROUND: The great interest in cell-free mRNA, microRNA (miRNA) as molecular biomarkers for clinical applications, and as 'signaling' molecules for intercellular communication highlights the need to reveal their physical nature. Here this issue was explored in human cell-free seminal mRNA (cfs-mRNA) and miRNA (cfs-miRNA). METHODOLOGY/PRINCIPAL FINDINGS: Selected male reproductive organ specific mRNAs, miRNAs, and piRNAs were quantified by quantitative real-time PCR in all experiments. While the stability of cfs-miRNA assessed by time-course analysis (up to 24 h at room temperature) was similar with cfs-mRNA, the reductive changes between cfs-miRNA and cfs-mRNA after filtration and Triton X 100 treatment on seminal plasma were very different, implying their different physical nature. Seminal microvesicles (SMVs) were then recovered and proportions of cfs-mRNA and cfs-miRNA within SMVs were quantified. The amounts of SMVs- sequestered cfs-mRNAs almost were the same as total cfs-mRNA, and were highly variable depending on the different sizes of SMVs. But most of cfs-miRNA was independent of SMVs and existed in the supernatant. The possible form of cfs miRNA in the supernatant was further explored by filtration and protease K digestion. It passed through the 0.10-um pore, but was degraded dramatically after intense protease K digestion. CONCLUSIONS/SIGNIFICANCE: The predominant cfs mRNA is contained in SMVs, while most cfs-miRNA is bound with protein complexes. Our data explained the stability of extracellular RNAs in human semen, and shed light on their origins and potential functions in male reproduction, and strategy of developing them as biomarkers of male reproductive system. PMID- 22506030 TI - Functional characterization of EngA(MS), a P-loop GTPase of Mycobacterium smegmatis. AB - Bacterial P-loop GTPases belong to a family of proteins that selectively hydrolyze a small molecule guanosine tri-phosphate (GTP) to guanosine di phosphate (GDP) and inorganic phosphate, and regulate several essential cellular activities such as cell division, chromosomal segregation and ribosomal assembly. A comparative genome sequence analysis of different mycobacterial species indicates the presence of multiple P-loop GTPases that exhibit highly conserved motifs. However, an exact function of most of these GTPases in mycobacteria remains elusive. In the present study we characterized the function of a P-loop GTPase in mycobacteria by employing an EngA homologue from Mycobacterium smegmatis, encoded by an open reading frame, designated as MSMEG_3738. Amino acid sequence alignment and phylogenetic analysis suggest that MSMEG_3738 (termed as EngA(MS)) is highly conserved in mycobacteria. Homology modeling of EngA(MS) reveals a cloverleaf structure comprising of alpha/beta fold typical to EngA family of GTPases. Recombinant EngA(MS) purified from E. coli exhibits a GTP hydrolysis activity which is inhibited by the presence of GDP. Interestingly, the EngA(MS) protein is co-eluted with 16S and 23S ribosomal RNA during purification and exhibits association with 30S, 50S and 70S ribosomal subunits. Further studies demonstrate that GTP is essential for interaction of EngA(MS) with 50S subunit of ribosome and specifically C-terminal domains of EngA(MS) are required to facilitate this interaction. Moreover, EngA(MS) devoid of N-terminal region interacts well with 50S even in the absence of GTP, indicating a regulatory role of the N-terminal domain in EngA(MS)-50S interaction. PMID- 22506031 TI - Complex control of GABA(A) receptor subunit mRNA expression: variation, covariation, and genetic regulation. AB - GABA type-A receptors are essential for fast inhibitory neurotransmission and are critical in brain function. Surprisingly, expression of receptor subunits is highly variable among individuals, but the cause and impact of this fluctuation remains unknown. We have studied sources of variation for all 19 receptor subunits using massive expression data sets collected across multiple brain regions and platforms in mice and humans. Expression of Gabra1, Gabra2, Gabrb2, Gabrb3, and Gabrg2 is highly variable and heritable among the large cohort of BXD strains derived from crosses of fully sequenced parents--C57BL/6J and DBA/2J. Genetic control of these subunits is complex and highly dependent on tissue and mRNA region. Remarkably, this high variation is generally not linked to phenotypic differences. The single exception is Gabrb3, a locus that is linked to anxiety. We identified upstream genetic loci that influence subunit expression, including three unlinked regions of chromosome 5 that modulate the expression of nine subunits in hippocampus, and that are also associated with multiple phenotypes. Candidate genes within these loci include, Naaa, Nos1, and Zkscan1. We confirmed a high level of coexpression for subunits comprising the major channel--Gabra1, Gabrb2, and Gabrg2--and identified conserved members of this expression network in mice and humans. Gucy1a3, Gucy1b3, and Lis1 are novel and conserved associates of multiple subunits that are involved in inhibitory signaling. Finally, proximal and distal regions of the 3' UTRs of single subunits have remarkably independent expression patterns in both species. However, corresponding regions of different subunits often show congruent genetic control and coexpression (proximal-to-proximal or distal-to-distal), even in the absence of sequence homology. Our findings identify novel sources of variation that modulate subunit expression and highlight the extraordinary capacity of biological networks to buffer 4-100 fold differences in mRNA levels. PMID- 22506033 TI - Oculomotor guidance and capture by irrelevant faces. AB - Even though it is generally agreed that face stimuli constitute a special class of stimuli, which are treated preferentially by our visual system, it remains unclear whether faces can capture attention in a stimulus-driven manner. Moreover, there is a long-standing debate regarding the mechanism underlying the preferential bias of selecting faces. Some claim that faces constitute a set of special low-level features to which our visual system is tuned; others claim that the visual system is capable of extracting the meaning of faces very rapidly, driving attentional selection. Those debates continue because many studies contain methodological peculiarities and manipulations that prevent a definitive conclusion. Here, we present a new visual search task in which observers had to make a saccade to a uniquely colored circle while completely irrelevant objects were also present in the visual field. The results indicate that faces capture and guide the eyes more than other animated objects and that our visual system is not only tuned to the low-level features that make up a face but also to its meaning. PMID- 22506032 TI - MicroRNAs overexpressed in growth-restricted rat skeletal muscles regulate the glucose transport in cell culture targeting central TGF-beta factor SMAD4. AB - The micro-array profiling of micro-RNA has been performed in rat skeletal muscle tissues, isolated from male adult offspring of intrauterine plus postnatal growth restricted model (IPGR). Apparently, the GLUT4 mRNA expression in male sk. muscle was found to be unaltered in contrast to females. The over-expression of miR-29a and miR-23a in the experimental group of SMSP (Starved Mother Starved Pups) have been found to regulate the glucose transport activity with respect to their control counterparts CMCP (Control Mother Control Pups) as confirmed in rat L6 myoblast-myocyte cell culture system. The ex-vivo experimentation demonstrates an aberration in insulin signaling pathway in male sk. muscle that leads to the localization of the membrane-bound Glut4 protein. We have identified through a series of experiments one important protein factor SMAD4, a co-SMAD critical to the TGF-beta signaling pathway. This factor is targeted by miR-29a, as identified in an in vitro reporter-assay system in cell-culture experiment. The other micro RNA, miR-23a, targets SMAD4 indirectly that seems to be critical in regulating insulin-dependent glucose transport activity. MicroRNA mimics, inhibitors and siRNA studies indicate the role of SMAD4 as inhibitory for glucose transport activities in normal physiological condition. The data demonstrate for the first time a critical function of microRNAs in fine-tuning the regulation of glucose transport in skeletal muscle. Chronic starved conditions (IPGR) in sk. muscle up regulates microRNA changing the target protein expression patterns, such as SMAD4, to alter the glucose transport pathways for the survival. The innovative outcome of this paper identifies a critical pathway (TGF-beta) that may act negatively for the mammalian glucose transport machinery. PMID- 22506034 TI - Roles of protein ubiquitination and degradation kinetics in biological oscillations. AB - Protein ubiquitination and degradation play important roles in many biological functions and are associated with many human diseases. It is well known that for biochemical oscillations to occur, proper degradation rates of the participating proteins are needed. In most mathematical models of biochemical reactions, linear degradation kinetics has been used. However, the degradation kinetics in real systems may be nonlinear, and how nonlinear degradation kinetics affects biological oscillations are not well understood. In this study, we first develop a biochemical reaction model of protein ubiquitination and degradation and calculate the degradation rate against the concentration of the free substrate. We show that the protein degradation kinetics mainly follows the Michaelis-Menten formulation with a time delay caused by ubiquitination and deubiquitination. We then study analytically how the Michaelis-Menten degradation kinetics affects the instabilities that lead to oscillations using three generic oscillation models: 1) a positive feedback mediated oscillator; 2) a positive-plus-negative feedback mediated oscillator; and 3) a negative feedback mediated oscillator. In all three cases, nonlinear degradation kinetics promotes oscillations, especially for the negative feedback mediated oscillator, resulting in much larger oscillation amplitudes and slower frequencies than those observed with linear kinetics. However, the time delay due to protein ubiquitination and deubiquitination generally suppresses oscillations, reducing the amplitude and increasing the frequency of the oscillations. These theoretical analyses provide mechanistic insights into the effects of specific proteins in the ubiquitination-proteasome system on biological oscillations. PMID- 22506035 TI - Common genetic denominators for Ca++-based skeleton in Metazoa: role of osteoclast-stimulating factor and of carbonic anhydrase in a calcareous sponge. AB - Calcium-based matrices serve predominantly as inorganic, hard skeletal systems in Metazoa from calcareous sponges [phylum Porifera; class Calcarea] to proto- and deuterostomian multicellular animals. The calcareous sponges form their skeletal elements, the spicules, from amorphous calcium carbonate (ACC). Treatment of spicules from Sycon raphanus with sodium hypochlorite (NaOCl) results in the disintegration of the ACC in those skeletal elements. Until now a distinct protein/enzyme involved in ACC metabolism could not been identified in those animals. We applied the technique of phage display combinatorial libraries to identify oligopeptides that bind to NaOCl-treated spicules: those oligopeptides allowed us to detect proteins that bind to those spicules. Two molecules have been identified, the (putative) enzyme carbonic anhydrase and the (putative) osteoclast-stimulating factor (OSTF), that are involved in the catabolism of ACC. The complete cDNAs were isolated and the recombinant proteins were prepared to raise antibodies. In turn, immunofluorescence staining of tissue slices and qPCR analyses have been performed. The data show that sponges, cultivated under standard condition (10 mM CaCl(2)) show low levels of transcripts/proteins for carbonic anhydrase or OSTF, compared to those animals that had been cultivated under Ca(2+)-depletion condition (1 mM CaCl(2)). Our data identify with the carbonic anhydrase and the OSTF the first two molecules which remain conserved in cells, potentially involved in Ca-based skeletal dissolution, from sponges (sclerocytes) to human (osteoclast). PMID- 22506036 TI - Transcriptional regulation of opaR, qrr2-4 and aphA by the master quorum-sensing regulator OpaR in Vibrio parahaemolyticus. AB - BACKGROUND: Vibrio parahaemolyticus is a leading cause of infectious diarrhea and enterogastritis via the fecal-oral route. V. harveyi is a pathogen of fishes and invertebrates, and has been used as a model for quorum sensing (QS) studies. LuxR is the master QS regulator (MQSR) of V. harveyi, and LuxR-dependent expression of its own gene, qrr2-4 and aphA have been established in V. harveyi. Molecular regulation of target genes by the V. parahaemolyticus MQSR OpaR is still poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: The bioinformatics analysis indicated that V. parahaemolyticus OpaR, V. harveyi LuxR, V. vulnificu SmcR, and V. alginolyticus ValR were extremely conserved, and that these four MQSRs appeared to recognize the same conserved cis-acting signals, which was represented by the consensus constructs manifesting as a position frequency matrix and as a 20 bp box, within their target promoters. The MQSR box-like sequences were found within the upstream DNA regions of opaR, qrr2-4 and aphA in V. parahaemolyticus, and the direct transcriptional regulation of these target genes by OpaR were further confirmed by multiple biochemical experiments including primer extension assay, gel mobility shift assay, and DNase I footprinting analysis. Translation and transcription starts, core promoter elements for sigma factor recognition, Shine Dalgarno sequences for ribosome recognition, and OpaR-binding sites were determined for the five target genes of OpaR, which gave a structural map of the OpaR-dependent promoters. Further computational promoter analysis indicated the above regulatory circuits were shared by several other closely related Vibrios but with slight exceptions. CONCLUSIONS/SIGNIFICANCE: This study gave a comprehensive computational and characterization of the direct transcriptional regulation of five target genes, opaR, qrr2-4 and ahpA, by OpaR in V. parahaemolyticus. These characterized regulatory circuits were conserved in V. harveyi and V. parahaemolyticus. PMID- 22506037 TI - Identification of critical amino acids in an immunodominant IgE epitope of Pen c 13, a major allergen from Penicillium citrinum. AB - BACKGROUND: Pen c 13, identified as a 33-kDa alkaline serine protease, is a major allergen secreted by Penicillium citrinum. Detailed knowledge about the epitopes responsible for IgE binding would help inform the diagnosis/prognosis of fungal allergy and facilitate the rational design of hypoallergenic candidate vaccines. The goal of the present study was to characterize the IgE epitopes of Pen c 13. METHODOLOGY/PRINCIPAL FINDINGS: Serum samples were collected from 10 patients with mold allergy and positive Pen c 13 skin test results. IgE-binding epitopes on rPen c 13 were mapped using an enzymatic digestion and chemical cleavage method, followed by dot-blotting and mass spectrometry. A B-cell epitope predicting server and molecular modeling were used to predict the residues most likely involved in IgE binding. Theoretically predicted IgE-binding regions were further confirmed by site-directed mutagenesis assays. At least twelve different IgE-binding epitopes located throughout Pen c 13 were identified. Of these, peptides S16 (A(148)-E(166)) and S22 (A(243)-K(274)) were recognized by sera from 90% and 100% of the patients tested, and were further confirmed by inhibition assays. Peptide S22 was selected for further analysis of IgE-binding ability. The results of serum screening showed that the majority of IgE-binding ability resided in the C-terminus. One Pen c 13 mutant, G270A (T(261)-K(274)), exhibited clearly enhanced IgE reactivity, whereas another, K274A, exhibited dramatically reduced IgE reactivity. CONCLUSIONS/SIGNIFICANCE: Experimental analyses confirmed in silico-predicted residues involved in an important antigenic region of Pen c 13. The G270A mutant of Pen c 13 has the potential to serve as an additional tool for the diagnosis/prognosis of mold allergy, and the K274A mutant, as a hypoallergenic form of the epitope, may provide a framework for the design and development of a safe and efficient therapeutic strategy for treating human allergic diseases. PMID- 22506039 TI - Evaluation of microbubbles as contrast agents for ultrasonography and magnetic resonance imaging. AB - BACKGROUND: Microbubbles (MBs) can serve as an ultrasound contrast agent, and has the potential for magnetic resonance imaging (MRI). Due to the relatively low effect of MBs on MRI, it is necessary to develop new MBs that are more suitable for MRI. In this study, we evaluate the properties of SonoVue(r) and custom-made Fe(3)O(4)-nanoparticle-embedded microbubbles (Fe(3)O(4)-MBs) in terms of contrast agents for ultrsonography (US) and MRI. METHODOLOGY/PRINCIPAL FINDINGS: A total of 20 HepG2 subcutaneous-tumor-bearing nude mice were randomly assigned to 2 groups (i.e., n = 10 mice each group), one for US test and the other for MRI test. Within each group, two tests were performed for each mouse. The contrast agent for the first test is SonoVue(r), and the second is Fe(3)O(4)-MBs. US was performed using a Technos(MPX) US system (Esaote, Italy) with a contrast-tuned imaging (CnTITM) mode. MRI was performed using a 7.0T Micro-MRI (PharmaScan, Bruker Biospin GmbH, Germany) with an EPI-T(2)* sequence. The data of signal-to noise ratio (SNR) from the region-of-interest of each US and MR image was calculated by ImageJ (National Institute of Health, USA). In group 1, enhancement of SonoVue(r) was significantly higher than Fe(3)O(4)-MBs on US (P<0.001). In group 2, negative enhancement of Fe(3)O(4)-MBs was significantly higher than SonoVue(r) on MRI (P<0.001). The time to peak showed no significant differences between US and MRI, both of which used the same MBs (P>0.05). The SNR analysis of the enhancement process reveals a strong negative correlation in both cases (i.e., SonoVue(r) r = -0.733, Fe(3)O(4)-MBs r = -0.903, with P<0.05). CONCLUSIONS: It might be important to change the Fe(3)O(4)-MBs' shell structure and/or the imagining strategy of US to improve the imaging quality of Fe(3)O(4) MBs on US. As an intriguing prospect that can be detected by US and MRI, MBs are worthy of further study. PMID- 22506038 TI - MiR-133a in human circulating monocytes: a potential biomarker associated with postmenopausal osteoporosis. AB - BACKGROUND: Osteoporosis mainly occurs in postmenopausal women, which is characterized by low bone mineral density (BMD) due to unbalanced bone resorption by osteoclasts and formation by osteoblasts. Circulating monocytes play important roles in osteoclastogenesis by acting as osteoclast precursors and secreting osteoclastogenic factors, such as IL-1, IL-6 and TNF-alpha. MicroRNAs (miRNAs) have been implicated as important biomarkers in various diseases. The present study aimed to find significant miRNA biomarkers in human circulating monocytes underlying postmenopausal osteoporosis. METHODOLOGY/PRINCIPAL FINDINGS: We used ABI TaqMan(r) miRNA array followed by qRT-PCR validation in circulating monocytes to identify miRNA biomarkers in 10 high and 10 low BMD postmenopausal Caucasian women. MiR-133a was upregulated (P=0.007) in the low compared with the high BMD groups in the array analyses, which was also validated by qRT-PCR (P=0.044). We performed bioinformatic target gene analysis and found three potential osteoclast related target genes, CXCL11, CXCR3 and SLC39A1. In addition, we performed Pearson correlation analyses between the expression levels of miR-133a and the three potential target genes in the 20 postmenopausal women. We did find negative correlations between miR-133a and all the three genes though not significant. CONCLUSIONS/SIGNIFICANCE: This is the first in vivo miRNA expression analysis in human circulating monocytes to identify novel miRNA biomarkers underlying postmenopausal osteoporosis. Our results suggest that miR-133a in circulating monocytes is a potential biomarker for postmenopausal osteoporosis. PMID- 22506040 TI - Insulinotropic effect of the non-steroidal compound STX in pancreatic beta-cells. AB - The non-steroidal compound STX modulates the hypothalamic control of core body temperature and energy homeostasis. The aim of this work was to study the potential effects of STX on pancreatic beta-cell function. 1-10 nM STX produced an increase in glucose-induced insulin secretion in isolated islets from male mice, whereas it had no effect in islets from female mice. This insulinotropic effect of STX was abolished by the anti-estrogen ICI 182,780. STX increased intracellular calcium entry in both whole islets and isolated beta-cells, and closed the K(ATP) channel, suggesting a direct effect on beta-cells. When intraperitoneal glucose tolerance test was performed, a single dose of 100 ug/kg body weight STX improved glucose sensitivity in males, yet it had a slight effect on females. In agreement with the effect on isolated islets, 100 ug/kg dose of STX enhanced the plasma insulin increase in response to a glucose load, while it did not in females. Long-term treatment (100 ug/kg, 6 days) of male mice with STX did not alter body weight, fasting glucose, glucose sensitivity or islet insulin content. Ovariectomized females were insensitive to STX (100 ug/kg), after either an acute administration or a 6-day treatment. This long-term treatment was also ineffective in a mouse model of mild diabetes. Therefore, STX appears to have a gender-specific effect on blood glucose homeostasis, which is only manifested after an acute administration. The insulinotropic effect of STX in pancreatic beta-cells is mediated by the closure of the K(ATP) channel and the increase in intracellular calcium concentration. The in vivo improvement in glucose tolerance appears to be mostly due to the enhancement of insulin secretion from beta-cells. PMID- 22506041 TI - Cardiomyocyte microvesicles contain DNA/RNA and convey biological messages to target cells. AB - BACKGROUND: Shedding microvesicles are membrane released vesicles derived directly from the plasma membrane. Exosomes are released membrane vesicles of late endosomal origin that share structural and biochemical characteristics with prostasomes. Microvesicles/exosomes can mediate messages between cells and affect various cell-related processes in their target cells. We describe newly detected microvesicles/exosomes from cardiomyocytes and depict some of their biological functions. METHODOLOGY/PRINCIPAL FINDINGS: Microvesicles/exosomes from media of cultured cardiomyocytes derived from adult mouse heart were isolated by differential centrifugation including preparative ultracentrifugation and identified by transmission electron microscopy and flow cytometry. They were surrounded by a bilayered membrane and flow cytometry revealed presence of both caveolin-3 and flotillin-1 while clathrin and annexin-2 were not detected. Microvesicle/exosome mRNA was identified and out of 1520 detected mRNA, 423 could be directly connected in a biological network. Furthermore, by a specific technique involving TDT polymerase, 343 different chromosomal DNA sequences were identified in the microvesicles/exosomes. Microvesicle/exosomal DNA transfer was possible into target fibroblasts, where exosomes stained for DNA were seen in the fibroblast cytosol and even in the nuclei. The gene expression was affected in fibroblasts transfected by microvesicles/exosomes and among 333 gene expression changes there were 175 upregulations and 158 downregulations compared with controls. CONCLUSIONS/SIGNIFICANCE: Our study suggests that microvesicles/exosomes released from cardiomyocytes, where we propose that exosomes derived from cardiomyocytes could be denoted "cardiosomes", can be involved in a metabolic course of events in target cells by facilitating an array of metabolism-related processes including gene expression changes. PMID- 22506042 TI - Nuclear translocation of beta-catenin during mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotype. AB - Wnt/beta-catenin pathway controls biochemical processes related to cell differentiation. In committed cells the alteration of this pathway has been associated with tumors as hepatocellular carcinoma or hepatoblastoma. The present study evaluated the role of Wnt/beta-catenin activation during human mesenchymal stem cells differentiation into hepatocytes. The differentiation to hepatocytes was achieved by the addition of two different conditioned media. In one of them, beta-catenin nuclear translocation, up-regulation of genes related to the Wnt/beta-catenin pathway, such as Lrp5 and Fzd3, as well as the oncogenes c-myc and p53 were observed. While in the other protocol there was a Wnt/beta-catenin inactivation. Hepatocytes with nuclear translocation of beta-catenin also had abnormal cellular proliferation, and expressed membrane proteins involved in hepatocellular carcinoma, metastatic behavior and cancer stem cells. Further, these cells had also increased auto-renewal capability as shown in spheroids formation assay. Comparison of both differentiation protocols by 2D-DIGE proteomic analysis revealed differential expression of 11 proteins with altered expression in hepatocellular carcinoma. Cathepsin B and D, adenine phosphoribosyltransferase, triosephosphate isomerase, inorganic pyrophosphatase, peptidyl-prolyl cis-trans isomerase A or lactate dehydrogenase beta-chain were up regulated only with the protocol associated with Wnt signaling activation while other proteins involved in tumor suppression, such as transgelin or tropomyosin beta-chain were down-regulated in this protocol. In conclusion, our results suggest that activation of the Wnt/beta-catenin pathway during human mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotype. PMID- 22506043 TI - Increased CD45RA+ FoxP3(low) regulatory T cells with impaired suppressive function in patients with systemic lupus erythematosus. AB - BACKGROUND: The role of naturally occurring regulatory T cells (Treg) in the control of the development of systemic lupus erythematosus (SLE) has not been well defined. Therefore, we dissect the phenotypically heterogeneous CD4(+)FoxP3(+) T cells into subpopulations during the dynamic SLE development. METHODLOGY/PRINCIPAL FINDINGS: To evaluate the proliferative and suppressive capacities of different CD4(+) T cell subgroups between active SLE patients and healthy donors, we employed CD45RA and CD25 as surface markers and carboxyfluorescein diacetatesuccinimidyl ester (CFSE) dilution assay. In addition, multiplex cytokines expression in active SLE patients was assessed using Luminex assay. Here, we showed a significant increase in the frequency of CD45RA(+)FoxP3(low) naive Treg cells (nTreg cells) and CD45RA(-)FoxP3(low) (non Treg) cells in patients with active SLE. In active SLE patients, the increased proportions of CD45RA(+)FoxP3(low) nTreg cells were positively correlated with the disease based on SLE disease activity index (SLEDAI) and the status of serum anti-dsDNA antibodies. We found that the surface marker combination of CD25(+)CD45RA(+) can be used to defined CD45RA(+)FoxP3(low) nTreg cells for functional assays, wherein nTreg cells from active SLE patients demonstrated defective suppression function. A significant correlation was observed between inflammatory cytokines, such as IL-6, IL-12 and TNFalpha, and the frequency of nTreg cells. Furthermore, the CD45RA(+)FoxP3(low) nTreg cell subset increased when cultured with SLE serum compared to healthy donor serum, suggesting that the elevated inflammatory cytokines of SLE serum may promote nTreg cell proliferation/expansion. CONCLUSIONS/SIGNIFICANCE: Our results indicate that impaired numbers of functional CD45RA(+)FoxP3(low) naive Treg cell and CD45RA( )FoxP3(low) non-suppressive T cell subsets in inflammatory conditions may contribute to SLE development. Therefore, analysis of subsets of FoxP3(+) T cells, using a combination of FoxP3, CD25 and CD45RA, rather than whole FoxP3(+) T cells, will help us to better understand the pathogenesis of SLE and may lead to the development of new therapeutic strategies. PMID- 22506044 TI - Heterogeneity in genetic admixture across different regions of Argentina. AB - The population of Argentina is the result of the intermixing between several groups, including Indigenous American, European and African populations. Despite the commonly held idea that the population of Argentina is of mostly European origin, multiple studies have shown that this process of admixture had an impact in the entire Argentine population. In the present study we characterized the distribution of Indigenous American, European and African ancestry among individuals from different regions of Argentina and evaluated the level of discrepancy between self-reported grandparental origin and genetic ancestry estimates. A set of 99 autosomal ancestry informative markers (AIMs) was genotyped in a sample of 441 Argentine individuals to estimate genetic ancestry. We used non-parametric tests to evaluate statistical significance. The average ancestry for the Argentine sample overall was 65% European (95%CI: 63-68%), 31% Indigenous American (28-33%) and 4% African (3-4%). We observed statistically significant differences in European ancestry across Argentine regions [Buenos Aires province (BA) 76%, 95%CI: 73-79%; Northeast (NEA) 54%, 95%CI: 49-58%; Northwest (NWA) 33%, 95%CI: 21-41%; South 54%, 95%CI: 49-59%; p<0.0001] as well as between the capital and immediate suburbs of Buenos Aires city compared to more distant suburbs [80% (95%CI: 75-86%) versus 68% (95%CI: 58-77%), p = 0.01]. European ancestry among individuals that declared all grandparents born in Europe was 91% (95%CI: 88-94%) compared to 54% (95%CI: 51-57%) among those with no European grandparents (p<0.001). Our results demonstrate the range of variation in genetic ancestry among Argentine individuals from different regions in the country, highlighting the importance of taking this variation into account in genetic association and admixture mapping studies in this population. PMID- 22506045 TI - Circulating angiogenic factors in patients with thromboangiitis obliterans. AB - BACKGROUND: Thromboangiitis obliterans (TAO, also known as Buerger's disease) is a non-atherosclerotic inflammatory vascular disease that primarily affects arteries in the extremities of young adult smokers. Since the etiology of TAO is still unknown, therapeutic options are limited. Recent attempts in therapeutic angiogenesis have been promising. Therefore, the aim of our study was to evaluate angiogenic processes and factors including circulating progenitor cells in TAO. METHODOLOGY/PRINCIPAL FINDINGS: TAO patients with critical limb ischemia and age- and gender-matched nonsmokers and smokers without cardiovascular disease (n = 12 in each group) were enrolled in the study. Flow cytometric analysis of peripheral blood showed significantly decreased levels of circulating CD45(dim)CD34(+) progenitor cells in TAO patients and in smokers compared to nonsmokers. In contrast to both control groups, the proportion of CD45(dim)CD34(+) progenitor cells co-expressing VEGF receptor-2 (VEGFR2) was significantly elevated in TAO patients. Enzyme-linked immunosorbent assay (ELISA) of common angiogenic factors (such as VEGF) did not clearly point to pro- or antiangiogenic conditions in serum or plasma of TAO patients. Serum of TAO patients and controls was evaluated in proliferation, migration (scratch assay) and spheroid sprouting assays using human umbilical vein endothelial cells (HUVECs). Serum of TAO patients exhibited a diminished sprouting capacity of HUVECs compared to both control groups. Proliferation and migration of endothelial cells were impaired after treatment with serum of TAO patients. CONCLUSION: Levels of circulating progenitor cells were altered in TAO patients compared to healthy nonsmokers and smokers. Furthermore, serum of TAO patients exhibited an antiangiogenic activity (impaired endothelial cell sprouting, migration and proliferation) on endothelial cells, which may contribute to vascular pathology in this patient population. PMID- 22506046 TI - Prospective study on the association between harm avoidance and postpartum depressive state in a maternal cohort of Japanese women. AB - BACKGROUND: Recent studies have displayed increased interest in examining the relationship between personality traits and the onset, treatment response patterns, and relapse of depression. This study aimed to examine whether or not harm avoidance (HA) was a risk factor for postpartum depression measured by the Edinburgh Postnatal Depression Scale (EPDS) and the state dependency of HA. METHODS: Pregnant women (n=460; mean age 31.9+/-4.2 years) who participated in a prenatal program completed the EPDS as a measure of depressive state and the Temperament and Character Inventory (TCI) as a measure of HA during three periods: early pregnancy (T1), late pregnancy (around 36 weeks), and 1 month postpartum (T2). Changes in EPDS and HA scores from T1 to T2 were compared between the non depressive (ND) group and the postpartum depressive (PD) group. RESULTS: There was no significant difference in the level of HA between the ND and PD groups at T1. In the ND group, EPDS and HA scores did not change significantly from T1 to T2. In the PD group, both scores increased significantly from T1 to T2 (EPDS, p<0.0001; HA, p<0.048). In the ND and PD groups, a significant positive correlation was observed in changes in EPDS and HA scores from T1 to T2 (r=0.31, p=0.002). CONCLUSIONS: These results suggest that HA cannot be considered a risk factor for the development of postpartum depression measured by EPDS. Furthermore, HA may be state dependent. PMID- 22506047 TI - Activation of cell cycle arrest and apoptosis by the proto-oncogene Pim-2. AB - Potent survival effects have been ascribed to the serine/threonine kinase proto oncogene PIM-2. Elevated levels of PIM-2 are associated with various malignancies. In human cells, a single Pim-2 transcript gives rise mainly to two protein isoforms (34, 41 kDa) that share an identical catalytic site but differ at their N-terminus, due to in-frame alternative translation initiation sites. In this study we observed that the 34 kDa PIM-2 isoform has differential nuclear and cytoplasmic forms in all tested cell lines, suggesting a possible role for the balance between these forms for PIM-2's function. To further study the cellular role of the 34 kDa isoform of PIM-2, an N-terminally HA-tagged form of this isoform was transiently expressed in HeLa cells. Surprisingly, this resulted in increased level of G1 arrested cells, as well as of apoptotic cells. These effects could not be obtained by a Flag-tagged form of the 41 kDa isoform. The G1 arrest and apoptotic effects were associated with an increase in T14/Y15 phosphorylation of CDK2 and proteasom-dependent down-regulation of CDC25A, as well as with up-regulation of p57, E2F-1, and p73. No such effects were obtained upon over-expression of a kinase-dead form of the HA-tagged 34 kDa PIM-2. By either using a dominant negative form of p73, or by over-expressing the 34 kDa PIM-2 in p73-silenced cells, we demonstrated that these effects were p73 dependent. These results demonstrate that while PIM-2 can function as a potent survival factor, it can, under certain circumstances, exhibit pro-apoptotic effects as well. PMID- 22506049 TI - A new human NHERF1 mutation decreases renal phosphate transporter NPT2a expression by a PTH-independent mechanism. AB - BACKGROUND: The sodium-hydrogen exchanger regulatory factor 1 (NHERF1) binds to the main renal phosphate transporter NPT2a and to the parathyroid hormone (PTH) receptor. We have recently identified mutations in NHERF1 that decrease renal phosphate reabsorption by increasing PTH-induced cAMP production in the renal proximal tubule. METHODS: We compared relevant parameters of phosphate homeostasis in a patient with a previously undescribed mutation in NHERF1 and in control subjects. We expressed the mutant NHERF1 protein in Xenopus Oocytes and in cultured cells to study its effects on phosphate transport and PTH-induced cAMP production. RESULTS: We identified in a patient with inappropriate renal phosphate reabsorption a previously unidentified mutation (E68A) located in the PDZ1 domain of NHERF1.We report the consequences of this mutation on NHERF1 function. E68A mutation did not modify cAMP production in the patient. PTH induced cAMP synthesis and PKC activity were not altered by E68A mutation in renal cells in culture. In contrast to wild-type NHERF1, expression of the E68A mutant in Xenopus oocytes and in human cells failed to increase phosphate transport. Pull down experiments showed that E68A mutant did not interact with NPT2a, which robustly interacted with wild type NHERF1 and previously identified mutants. Biotinylation studies revealed that E68A mutant was unable to increase cell surface expression of NPT2a. CONCLUSIONS: Our results indicate that the PDZ1 domain is critical for NHERF1-NPT2a interaction in humans and for the control of NPT2a expression at the plasma membrane. Thus we have identified a new mechanism of renal phosphate loss and shown that different mutations in NHERF1 can alter renal phosphate reabsorption via distinct mechanisms. PMID- 22506048 TI - A genome-wide study replicates linkage of 3p22-24 to extreme longevity in humans and identifies possible additional loci. AB - BACKGROUND: Although there is abundant evidence that human longevity is heritable, efforts to map loci responsible for variation in human lifespan have had limited success. METHODOLOGY/PRINCIPAL FINDINGS: We identified individuals from a large multigenerational population database (the Utah Population Database) who exhibited high levels of both familial longevity and individual longevity. This selection identified 325 related "affected individuals", defined as those in the top quartile for both excess longevity (EL = observed lifespan - expected lifespan) and familial excess longevity (FEL = weighted average EL across all relatives). A whole-genome scan for genetic linkage was performed on this sample using a panel of 1100 microsatellite markers. A strongly suggestive peak (Z = 4.2, Monte Carlo-adjusted p-value 0.09) was observed in the vicinity of D3S3547 on chromosome 3p24.1, at a point nearly identical to that reported recently by an independent team of researchers from Harvard Medical School (HMS). Meta-analysis of linkage scores on 3p from the two studies produced a minimum nominal p-value of 1.005*10(-9) at 55 cM. Other potentially noteworthy peaks in our data occur on 18q23-24, 8q23, and 17q21. Meta-analysis results from combined UPDB and HMS data yielded additional support, but not formal replication, for linkage on 8q, 9q, and 17q. CONCLUSIONS/SIGNIFICANCE: Corroboration of the linkage of exceptional longevity to 3p22-24 greatly strengthens the case that genes in this region affect variation in longevity and suggest, therefore, an important role in the regulation of human lifespan. Future efforts should include intensive study of the 3p22-24 region. PMID- 22506050 TI - Fifteen-year population attributable fractions and causal pies of risk factors for newly developed hepatocellular carcinomas in 11,801 men in Taiwan. AB - Development of hepatocellular carcinoma (HCC) is a multi-factorial process. Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are important risk factors of HCC. Host factors, such as alcohol drinking, may also play a role. This study aims to provide a synthesis view on the development of HCC by examining multiple risk factors jointly and collectively. Causal-pie modeling technique was applied to analyze a cohort of 11,801 male residents (followed up for 15 years) in Taiwan, during which a total of 298 incident HCC cases were ascertained. The rate ratios adjusted by age were further modeled by an additive Poisson regression. Population attributable fractions (PAFs) and causal-pie weights (CPWs) were calculated. A PAF indicates the magnitude of case load reduction under a particular intervention scenario, whereas a CPW for a particular class of causal pies represents the proportion of HCC cases attributable to that class. Using PAF we observed a chance to reduce around 60% HCC risk moving from no HBV-related intervention to the total elimination of the virus. An additional ~15% (or ~5%) reduction can be expected, if the HBV-related intervention is coupled with an HCV-related intervention (or an anti-drinking campaign). Eight classes of causal pies were found to be significant, including four dose-response classes of HBV (total CPW=52.7%), one independent-effect class of HCV (CPW=14.4%), one HBV-alcohol interaction class (CPW=4.2%), one HBV-HCV interaction class (CPW=1.7%), and one all-unknown class (CPW=27.0%). Causal-pie modeling for HCC helps clarify the relative importance of each viral and host factor, as well as their interactions. PMID- 22506051 TI - A novel N-terminal domain may dictate the glucose response of Mondo proteins. AB - Glucose is a fundamental energy source for both prokaryotes and eukaryotes. The balance between glucose utilization and storage is integral for proper energy homeostasis, and defects are associated with several diseases, e.g. type II diabetes. In vertebrates, the transcription factor ChREBP is a major component in glucose metabolism, while its ortholog MondoA is involved in glucose uptake. Both MondoA and ChREBP contain five Mondo conserved regions (MCRI-V) that affect their cellular localization and transactivation ability. While phosphorylation has been shown to affect ChREBP function, the mechanisms controlling glucose response of both ChREBP and MondoA remain elusive. By incorporating sequence analysis techniques, structure predictions, and functional annotations, we synthesized data surrounding Mondo family proteins into a cohesive, accurate, and general model involving the MCRs and two additional domains that determine ChREBP and MondoA glucose response. Paramount, we identified a conserved motif within the transactivation region of Mondo family proteins and propose that this motif interacts with the phosphorylated form of glucose. In addition, we discovered a putative nuclear receptor box in non-vertebrate Mondo and vertebrate ChREBP sequences that reveals a potentially novel interaction with nuclear receptors. These interactions are likely involved in altering ChREBP and MondoA conformation to form an active complex and induce transcription of genes involved in glucose metabolism and lipogenesis. PMID- 22506052 TI - Lack of evidence from studies of soluble protein fragments that Knops blood group polymorphisms in complement receptor-type 1 are driven by malaria. AB - Complement receptor-type 1 (CR1, CD35) is the immune-adherence receptor, a complement regulator, and an erythroid receptor for Plasmodium falciparum during merozoite invasion and subsequent rosette formation involving parasitized and non infected erythrocytes. The non-uniform geographical distribution of Knops blood group CR1 alleles Sl1/2 and McC(a/b) may result from selective pressures exerted by differential exposure to infectious hazards. Here, four variant short recombinant versions of CR1 were produced and analyzed, focusing on complement control protein modules (CCPs) 15-25 of its ectodomain. These eleven modules encompass a region (CCPs 15-17) key to rosetting, opsonin recognition and complement regulation, as well as the Knops blood group polymorphisms in CCPs 24 25. All four CR1 15-25 variants were monomeric and had similar axial ratios. Modules 21 and 22, despite their double-length inter-modular linker, did not lie side-by-side so as to stabilize a bent-back architecture that would facilitate cooperation between key functional modules and Knops blood group antigens. Indeed, the four CR1 15-25 variants had virtually indistinguishable affinities for immobilized complement fragments C3b (K(D) = 0.8-1.1 uM) and C4b (K(D) = 5.0 5.3 uM). They were all equally good co-factors for factor I-catalysed cleavage of C3b and C4b, and they bound equally within a narrow affinity range, to immobilized C1q. No differences between the variants were observed in assays for inhibition of erythrocyte invasion by P. falciparum or for rosette disruption. Neither differences in complement-regulatory functionality, nor interactions with P. falciparum proteins tested here, appear to have driven the non-uniform geographic distribution of these alleles. PMID- 22506053 TI - Impact of migration and acculturation on prevalence of type 2 diabetes and related eye complications in Indians living in a newly urbanised society. AB - BACKGROUND: Health of migrants is a major public health challenge faced by governments and policy makers. Asian Indians are among the fastest growing migration groups across Asia and the world, but the impact of migration and acculturation on diabetes and diabetes-related eye complications among Indians living in urban Asia remains unclear. METHODOLOGIES/PRINCIPAL FINDINGS: We evaluated the influence of migration and acculturation (i.e., migration status and length of residence) on the prevalence of type-2 diabetes mellitus (T2DM) and diabetes-related eye complications (diabetic retinopathy (DR) and cataract), among first-generation (defined as participant born in India with both parents born in India, n = 781) and second-generation (participants born in Singapore with both parents born in India, n = 1,112) Indian immigrants from a population based study of Adult Indians in Singapore. Diabetes was defined as HbA1c>=6.5%, use of diabetic medication or a physician diagnosis of diabetes. Retinal and lens photographs were graded for the presence of DR and cataract. Compared to first generation immigrants, second generation immigrants had a higher age- and gender standardized prevalence of T2DM (34.4% versus 29.0%, p<0.001), and, in those with T2DM, higher age- and gender-standardized prevalence of DR (31.7% versus 24.8%, p<0.001), nuclear cataract (13.6% versus 11.6%, p<0.001), and posterior sub capsular cataract (6.4% versus 4.6%, p<0.001). Among first generation migrants, longer length of residence was associated with significantly younger age of diagnosis of diabetes and greater likelihood of having T2DM and diabetes-related eye complications. CONCLUSION: Second generation immigrant Indians and longer length of residence are associated with higher prevalence of diabetes and diabetes-related complications (i.e., DR and cataract) among migrant Indians living in Singapore. These data highlight potential worldwide impacts of migration patterns on the risk and burden of diabetes. PMID- 22506054 TI - Direct ubiquitin independent recognition and degradation of a folded protein by the eukaryotic proteasomes-origin of intrinsic degradation signals. AB - Eukaryotic 26S proteasomes are structurally organized to recognize, unfold and degrade globular proteins. However, all existing model substrates of the 26S proteasome in addition to ubiquitin or adaptor proteins require unstructured regions in the form of fusion tags for efficient degradation. We report for the first time that purified 26S proteasome can directly recognize and degrade apomyoglobin, a globular protein, in the absence of ubiquitin, extrinsic degradation tags or adaptor proteins. Despite a high affinity interaction, absence of a ligand and presence of only helices/loops that follow the degradation signal, apomyoglobin is degraded slowly by the proteasome. A short floppy F-helix exposed upon ligand removal and in conformational equilibrium with a disordered structure is mandatory for recognition and initiation of degradation. Holomyoglobin, in which the helix is buried, is neither recognized nor degraded. Exposure of the floppy F-helix seems to sensitize the proteasome and primes the substrate for degradation. Using peptide panning and competition experiments we speculate that initial encounters through the floppy helix and additional strong interactions with N-terminal helices anchors apomyoglobin to the proteasome. Stabilizing helical structure in the floppy F-helix slows down degradation. Destabilization of adjacent helices accelerates degradation. Unfolding seems to follow the mechanism of helix unraveling rather than global unfolding. Our findings while confirming the requirement for unstructured regions in degradation offers the following new insights: a) origin and identification of an intrinsic degradation signal in the substrate, b) identification of sequences in the native substrate that are likely to be responsible for direct interactions with the proteasome, and c) identification of critical rate limiting steps like exposure of the intrinsic degron and destabilization of an unfolding intermediate that are presumably catalyzed by the ATPases. Apomyoglobin emerges as a new model substrate to further explore the role of ATPases and protein structure in proteasomal degradation. PMID- 22506055 TI - Establishing the breeding provenance of a temperate-wintering North American passerine, the Golden-crowned Sparrow, using light-level geolocation. AB - The migratory biology and connectivity of passerines remains poorly known, even for those that move primarily within the temperate zone. We used light-level geolocators to describe the migratory geography of a North American temperate migrant passerine. From February to March of 2010, we attached geolocator tags to 33 Golden-crowned Sparrows (Zonotrichia atricapilla) wintering on the central coast of California, USA, and recovered four tags the following winter (October to December 2010). We used a bayesian state-space model to estimate the most likely breeding locations. All four birds spent the breeding season on the coast of the Gulf of Alaska. These locations spanned approximately 1200 kilometers, and none of the individuals bred in the same location. Speed of migration was nearly twice as fast during spring than fall. The return rate of birds tagged the previous season (33%) was similar to that of control birds (39%), but comparing return rates was complicated because 7 of 11 returning birds had lost their tags. For birds that we recaptured before spring migration, we found no significant difference in mass change between tagged and control birds. Our results provide insight into the previously-unknown breeding provenance of a wintering population of Golden-crowned Sparrows and provide more evidence of the contributions that light-level geolocation can make to our understanding of the migratory geography of small passerines. PMID- 22506056 TI - Nitroxyl (HNO) stimulates soluble guanylyl cyclase to suppress cardiomyocyte hypertrophy and superoxide generation. AB - BACKGROUND: New therapeutic targets for cardiac hypertrophy, an independent risk factor for heart failure and death, are essential. HNO is a novel redox sibling of NO* attracting considerable attention for the treatment of cardiovascular disorders, eliciting cGMP-dependent vasodilatation yet cGMP-independent positive inotropy. The impact of HNO on cardiac hypertrophy (which is negatively regulated by cGMP) however has not been investigated. METHODS: Neonatal rat cardiomyocytes were incubated with angiotensin II (Ang II) in the presence and absence of the HNO donor Angeli's salt (sodium trioxodinitrate) or B-type natriuretic peptide, BNP (all 1 umol/L). Hypertrophic responses and its triggers, as well as cGMP signaling, were determined. RESULTS: We now demonstrate that Angeli's salt inhibits Ang II-induced hypertrophic responses in cardiomyocytes, including increases in cardiomyocyte size, de novo protein synthesis and beta-myosin heavy chain expression. Angeli's salt also suppresses Ang II induction of key triggers of the cardiomyocyte hypertrophic response, including NADPH oxidase (on both Nox2 expression and superoxide generation), as well as p38 mitogen-activated protein kinase (p38MAPK). The antihypertrophic, superoxide-suppressing and cGMP-elevating effects of Angeli's salt were mimicked by BNP. We also demonstrate that the effects of Angeli's salt are specifically mediated by HNO (with no role for NO* or nitrite), with subsequent activation of cardiomyocyte soluble guanylyl cyclase (sGC) and cGMP signaling (on both cGMP-dependent protein kinase, cGK-I and phosphorylation of vasodilator-stimulated phosphoprotein, VASP). CONCLUSIONS: Our results demonstrate that HNO prevents cardiomyocyte hypertrophy, and that cGMP dependent NADPH oxidase suppression contributes to these antihypertrophic actions. HNO donors may thus represent innovative pharmacotherapy for cardiac hypertrophy. PMID- 22506057 TI - Speech graphs provide a quantitative measure of thought disorder in psychosis. AB - BACKGROUND: Psychosis has various causes, including mania and schizophrenia. Since the differential diagnosis of psychosis is exclusively based on subjective assessments of oral interviews with patients, an objective quantification of the speech disturbances that characterize mania and schizophrenia is in order. In principle, such quantification could be achieved by the analysis of speech graphs. A graph represents a network with nodes connected by edges; in speech graphs, nodes correspond to words and edges correspond to semantic and grammatical relationships. METHODOLOGY/PRINCIPAL FINDINGS: To quantify speech differences related to psychosis, interviews with schizophrenics, manics and normal subjects were recorded and represented as graphs. Manics scored significantly higher than schizophrenics in ten graph measures. Psychopathological symptoms such as logorrhea, poor speech, and flight of thoughts were grasped by the analysis even when verbosity differences were discounted. Binary classifiers based on speech graph measures sorted schizophrenics from manics with up to 93.8% of sensitivity and 93.7% of specificity. In contrast, sorting based on the scores of two standard psychiatric scales (BPRS and PANSS) reached only 62.5% of sensitivity and specificity. CONCLUSIONS/SIGNIFICANCE: The results demonstrate that alterations of the thought process manifested in the speech of psychotic patients can be objectively measured using graph-theoretical tools, developed to capture specific features of the normal and dysfunctional flow of thought, such as divergence and recurrence. The quantitative analysis of speech graphs is not redundant with standard psychometric scales but rather complementary, as it yields a very accurate sorting of schizophrenics and manics. Overall, the results point to automated psychiatric diagnosis based not on what is said, but on how it is said. PMID- 22506058 TI - Daily physical activities and sports in adult survivors of childhood cancer and healthy controls: a population-based questionnaire survey. AB - BACKGROUND: Healthy lifestyle including sufficient physical activity may mitigate or prevent adverse long-term effects of childhood cancer. We described daily physical activities and sports in childhood cancer survivors and controls, and assessed determinants of both activity patterns. METHODOLOGY/PRINCIPAL FINDINGS: The Swiss Childhood Cancer Survivor Study is a questionnaire survey including all children diagnosed with cancer 1976-2003 at age 0-15 years, registered in the Swiss Childhood Cancer Registry, who survived >=5 years and reached adulthood (>=20 years). Controls came from the population-based Swiss Health Survey. We compared the two populations and determined risk factors for both outcomes in separate multivariable logistic regression models. The sample included 1058 survivors and 5593 controls (response rates 78% and 66%). Sufficient daily physical activities were reported by 52% (n = 521) of survivors and 37% (n = 2069) of controls (p<0.001). In contrast, 62% (n = 640) of survivors and 65% (n = 3635) of controls reported engaging in sports (p = 0.067). Risk factors for insufficient daily activities in both populations were: older age (OR for >=35 years: 1.5, 95CI 1.2-2.0), female gender (OR 1.6, 95CI 1.3-1.9), French/Italian Speaking (OR 1.4, 95CI 1.1-1.7), and higher education (OR for university education: 2.0, 95CI 1.5-2.6). Risk factors for no sports were: being a survivor (OR 1.3, 95CI 1.1-1.6), older age (OR for >=35 years: 1.4, 95CI 1.1-1.8), migration background (OR 1.5, 95CI 1.3-1.8), French/Italian speaking (OR 1.4, 95CI 1.2-1.7), lower education (OR for compulsory schooling only: 1.6, 95CI 1.2 2.2), being married (OR 1.7, 95CI 1.5-2.0), having children (OR 1.3, 95CI 1.4 1.9), obesity (OR 2.4, 95CI 1.7-3.3), and smoking (OR 1.7, 95CI 1.5-2.1). Type of diagnosis was only associated with sports. CONCLUSIONS/SIGNIFICANCE: Physical activity levels in survivors were lower than recommended, but comparable to controls and mainly determined by socio-demographic and cultural factors. Strategies to improve physical activity levels could be similar as for the general population. PMID- 22506060 TI - High prevalence and lineage diversity of avian malaria in wild populations of great tits (Parus major) and mosquitoes (Culex pipiens). AB - Avian malaria studies have taken a prominent place in different aspects of evolutionary ecology. Despite a recent interest in the role of vectors within the complex interaction system of the malaria parasite, they have largely been ignored in most epidemiological studies. Epidemiology of the disease is however strongly related to the vector's ecology and behaviour, and there is a need for basic investigations to obtain a better picture of the natural associations between Plasmodium lineages, vector species and bird hosts. The aim of the present study was to identify the mosquito species involved in the transmission of the haemosporidian parasites Plasmodium spp. in two wild populations of breeding great tits (Parus major) in western Switzerland. Additionally, we compared Plasmodium lineages, based on mitochondrial DNA cytochrome b sequences, between the vertebrate and dipteran hosts, and evaluated the prevalence of the parasite in the mosquito populations. Plasmodium spp. were detected in Culex pipiens only, with an overall 6.6% prevalence. Among the six cytochrome b lineages of Plasmodium identified in the mosquitoes, three were also present in great tits. The results provide evidence for the first time that C. pipiens can act as a natural vector of avian malaria in Europe and yield baseline data for future research on the epidemiology of avian malaria in European countries. PMID- 22506059 TI - 3,3'Diindolylmethane suppresses vascular smooth muscle cell phenotypic modulation and inhibits neointima formation after carotid injury. AB - BACKGROUND: 3,3'Diindolylmethane (DIM), a natural phytochemical, has shown inhibitory effects on the growth and migration of a variety of cancer cells; however, whether DIM has similar effects on vascular smooth muscle cells (VSMCs) remains unknown. The purpose of this study was to assess the effects of DIM on the proliferation and migration of cultured VSMCs and neointima formation in a carotid injury model, as well as the related cell signaling mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: DIM dose-dependently inhibited the platelet derived growth factor (PDGF)-BB-induced proliferation of VSMCs without cell cytotoxicity. This inhibition was caused by a G0/G1 phase cell cycle arrest demonstrated by fluorescence-activated cell-sorting analysis. We also showed that DIM-induced growth inhibition was associated with the inhibition of the expression of cyclin D1 and cyclin-dependent kinase (CDK) 4/6 as well as an increase in p27(Kip1) levels in PDGF-stimulated VSMCs. Moreover, DIM was also found to modulate migration of VSMCs and smooth muscle-specific contractile marker expression. Mechanistically, DIM negatively modulated PDGF-BB-induced phosphorylation of PDGF-recptorbeta (PDGF-Rbeta) and the activities of downstream signaling molecules including Akt/glycogen synthase kinase(GSK)3beta, extracellular signal-regulated kinase1/2 (ERK1/2), and signal transducers and activators of transcription 3 (STAT3). Our in vivo studies using a mouse carotid arterial injury model revealed that treatment with 150 mg/kg DIM resulted in significant reduction of the neointima/media ratio and proliferating cell nuclear antigen (PCNA)-positive cells, without affecting apoptosis of vascular cells and reendothelialization. Infiltration of inflammatory cells was also inhibited by DIM administration. CONCLUSION: These results demonstrate that DIM can suppress the phenotypic modulation of VSMCs and neointima hyperplasia after vascular injury. These beneficial effects on VSMCs were at least partly mediated by the inhibition of PDGF-Rbeta and the activities of downstream signaling pathways. The results suggest that DIM has the potential to be a candidate for the prevention of restenosis. PMID- 22506061 TI - The immune response to melanoma is limited by thymic selection of self-antigens. AB - The expression of melanoma-associated antigens (MAA) being limited to normal melanocytes and melanomas, MAAs are ideal targets for immunotherapy and melanoma vaccines. As MAAs are derived from self, immune responses to these may be limited by thymic tolerance. The extent to which self-tolerance prevents efficient immune responses to MAAs remains unknown. The autoimmune regulator (AIRE) controls the expression of tissue-specific self-antigens in thymic epithelial cells (TECs). The level of antigens expressed in the TECs determines the fate of auto-reactive thymocytes. Deficiency in AIRE leads in both humans (APECED patients) and mice to enlarged autoreactive immune repertoires. Here we show increased IgG levels to melanoma cells in APECED patients correlating with autoimmune skin features. Similarly, the enlarged T cell repertoire in AIRE(-/-) mice enables them to mount anti-MAA and anti-melanoma responses as shown by increased anti-melanoma antibodies, and enhanced CD4(+) and MAA-specific CD8(+) T cell responses after melanoma challenge. We show that thymic expression of gp100 is under the control of AIRE, leading to increased gp100-specific CD8(+) T cell frequencies in AIRE(-/ ) mice. TRP-2 (tyrosinase-related protein), on the other hand, is absent from TECs and consequently TRP-2 specific CD8(+) T cells were found in both AIRE(-/-) and AIRE(+/+) mice. This study emphasizes the importance of investigating thymic expression of self-antigens prior to their inclusion in vaccination and immunotherapy strategies. PMID- 22506062 TI - Automated phenotype recognition for zebrafish embryo based in vivo high throughput toxicity screening of engineered nano-materials. AB - A phenotype recognition model was developed for high throughput screening (HTS) of engineered Nano-Materials (eNMs) toxicity using zebrafish embryo developmental response classified, from automatically captured images and without manual manipulation of zebrafish positioning, by three basic phenotypes (i.e., hatched, unhatched, and dead). The recognition model was built with a set of vectorial descriptors providing image color and texture information. The best performing model was attained with three image descriptors (color histogram, representative color, and color layout) identified as most suitable from an initial pool of six descriptors. This model had an average recognition accuracy of 97.40+/-0.95% in a 10-fold cross-validation and 93.75% in a stress test of low quality zebrafish images. The present work has shown that a phenotyping model can be developed with accurate recognition ability suitable for zebrafish-based HTS assays. Although the present methodology was successfully demonstrated for only three basic zebrafish embryonic phenotypes, it can be readily adapted to incorporate more subtle phenotypes. PMID- 22506063 TI - Microtubular stability affects pVHL-mediated regulation of HIF-1alpha via the p38/MAPK pathway in hypoxic cardiomyocytes. AB - BACKGROUND: Our previous research found that structural changes of the microtubule network influence glycolysis in cardiomyocytes by regulating the hypoxia-inducible factor (HIF)-1alpha during the early stages of hypoxia. However, little is known about the underlying regulatory mechanism of the changes of HIF-1alpha caused by microtubule network alternation. The von Hippel-Lindau tumor suppressor protein (pVHL), as a ubiquitin ligase, is best understood as a negative regulator of HIF-1alpha. METHODOLOGY/PRINCIPAL FINDINGS: In primary rat cardiomyocytes and H9c2 cardiac cells, microtubule-stabilization was achieved by pretreating with paclitaxel or transfection of microtubule-associated protein 4 (MAP4) overexpression plasmids and microtubule-depolymerization was achieved by pretreating with colchicine or transfection of MAP4 siRNA before hypoxia treatment. Recombinant adenovirus vectors for overexpressing pVHL or silencing of pVHL expression were constructed and transfected in primary rat cardiomyocytes and H9c2 cells. With different microtubule-stabilizing and -depolymerizing treaments, we demonstrated that the protein levels of HIF-1alpha were down regulated through overexpression of pVHL and were up-regulated through knockdown of pVHL in hypoxic cardiomyocytes. Importantly, microtubular structure breakdown activated p38/MAPK pathway, accompanied with the upregulation of pVHL. In coincidence, we found that SB203580, a p38/MAPK inhibitor decreased pVHL while MKK6 (Glu) overexpression increased pVHL in the microtubule network altered hypoxic cardiomyocytes and H9c2 cells. CONCLUSIONS/SIGNIFICANCE: This study suggests that pVHL plays an important role in the regulation of HIF-1alpha caused by the changes of microtubular structure and the p38/MAPK pathway participates in the process of pVHL change following microtubule network alteration in hypoxic cardiomyocytes. PMID- 22506064 TI - High-level expression of Notch1 increased the risk of metastasis in T1 stage clear cell renal cell carcinoma. AB - BACKGROUND: Although metastasis of clear cell renal cell carcinoma (ccRCC) is basically observed in late stage tumors, T1 stage metastasis of ccRCC can also be found with no definite molecular cause resulting inappropriate selection of surgery method and poor prognosis. Notch signaling is a conserved, widely expressed signal pathway that mediates various cellular processes in normal development and tumorigenesis. This study aims to explore the potential role and mechanism of Notch signaling in the metastasis of T1 stage ccRCC. METHODOLOGY/PRINCIPAL FINDINGS: The expression of Notch1 and Jagged1 were analyzed in tumor tissues and matched normal adjacent tissues obtained from 51 ccRCC patients. Compared to non-tumor tissues, Notch1 and Jagged1 expression was significantly elevated both in mRNA and protein levels in tumors. Tissue samples of localized and metastatic tumors were divided into three groups based on their tumor stages and the relative mRNA expression of Notch1 and Jagged1 were analyzed. Compared to localized tumors, Notch1 expression was significantly elevated in metastatic tumors in T1 stage while Jagged1 expression was not statistically different between localized and metastatic tumors of all stages. The average size of metastatic tumors was significantly larger than localized tumors in T1 stage ccRCC and the elevated expression of Notch1 was significantly positive correlated with the tumor diameter. The functional significance of Notch signaling was studied by transfection of 786-O, Caki-1 and HKC cell lines with full-length expression plasmids of Notch1 and Jagged1. Compared to the corresponding controls, all cell lines demonstrated significant promotion in cell proliferation and migration while cell cycle remained unaffected. CONCLUSIONS/SIGNIFICANCE: High-level expression of Notch signaling increased the risk of metastasis in T1 stage ccRCC by stimulating the proliferation and migration of tumor cells, which may be helpful for the selection of suitable operation method and prognosis of ccRCC. PMID- 22506065 TI - Cultural phylogenetics of the Tupi language family in lowland South America. AB - BACKGROUND: Recent advances in automated assessment of basic vocabulary lists allow the construction of linguistic phylogenies useful for tracing dynamics of human population expansions, reconstructing ancestral cultures, and modeling transition rates of cultural traits over time. METHODS: Here we investigate the Tupi expansion, a widely-dispersed language family in lowland South America, with a distance-based phylogeny based on 40-word vocabulary lists from 48 languages. We coded 11 cultural traits across the diverse Tupi family including traditional warfare patterns, post-marital residence, corporate structure, community size, paternity beliefs, sibling terminology, presence of canoes, tattooing, shamanism, men's houses, and lip plugs. RESULTS/DISCUSSION: The linguistic phylogeny supports a Tupi homeland in west-central Brazil with subsequent major expansions across much of lowland South America. Consistently, ancestral reconstructions of cultural traits over the linguistic phylogeny suggest that social complexity has tended to decline through time, most notably in the independent emergence of several nomadic hunter-gatherer societies. Estimated rates of cultural change across the Tupi expansion are on the order of only a few changes per 10,000 years, in accord with previous cultural phylogenetic results in other language families around the world, and indicate a conservative nature to much of human culture. PMID- 22506066 TI - Genetic variants of IDE-KIF11-HHEX at 10q23.33 associated with type 2 diabetes risk: a fine-mapping study in Chinese population. AB - BACKGROUND: Genome-wide association studies (GWAS) in populations of European ancestry have mapped a type 2 diabetes susceptibility region to chromosome 10q23.33 containing IDE, KIF11 and HHEX genes (IDE-KIF11-HHEX), which has also been replicated in Chinese populations. However, the functional relevance for genetic variants at this locus is still unclear. It is critical to systematically assess the relationship of genetic variants in this region with the risk of type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: A fine-mapping study was conducted by genotyping fourteen tagging single-nucleotide polymorphisms (SNPs) in a 290-kb linkage disequilibrium (LD) region using a two-stage case-control study of type 2 diabetes in a Chinese Han population. Suggestive associations (P<0.05) observed from 1,200 cases and 1,200 controls in the first stage were further replicated in 1,725 cases and 2,081 controls in the second stage. Seven tagging SNPs were consistently associated with type 2 diabetes in both stages (P<0.05), with combined odds ratios (ORs) ranging from 1.14 to 1.33 in the combined analysis. The most significant locus was rs7923837 [OR = 1.33, 95% confidence interval (CI): 1.21-1.47] at the 3'-flanking region of HHEX gene. SNP rs1111875 was found to be another partially independent locus (OR = 1.23, 95% CI: 1.13-1.35) in this region that was associated with type 2 diabetes risk. A cumulative effect of rs7923837 and rs1111875 was observed with individuals carrying 1, 2, and 3 or 4 risk alleles having a 1.27, 1.44, and 1.73-fold increased risk, respectively, for type 2 diabetes (P for trend = 4.1E-10). CONCLUSIONS/SIGNIFICANCE: Our results confirm that genetic variants of the IDE-KIF11-HHEX region at 10q23.33 contribute to type 2 diabetes susceptibility and suggest that rs7923837 may represent the strongest signal related to type 2 diabetes risk in the Chinese Han population. PMID- 22506067 TI - STAT3 regulates monocyte TNF-alpha production in systemic inflammation caused by cardiac surgery with cardiopulmonary bypass. AB - BACKGROUND: Cardiopulmonary bypass (CPB) surgery initiates a controlled systemic inflammatory response characterized by a cytokine storm, monocytosis and transient monocyte activation. However, the responsiveness of monocytes to Toll like receptor (TLR)-mediated activation decreases throughout the postoperative course. The purpose of this study was to identify the major signaling pathway involved in plasma-mediated inhibition of LPS-induced tumor necrosis factor (TNF) alpha production by monocytes. METHODOLOGY/PRINCIPAL FINDINGS: Pediatric patients that underwent CPB-assisted surgical correction of simple congenital heart defects were enrolled (n = 38). Peripheral blood mononuclear cells (PBMC) and plasma samples were isolated at consecutive time points. Patient plasma samples were added back to monocytes obtained pre-operatively for ex vivo LPS stimulations and TNF-alpha and IL-6 production was measured by flow cytometry. LPS-induced p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF) kappaB activation by patient plasma was assessed by Western blotting. A cell permeable peptide inhibitor was used to block STAT3 signaling. We found that plasma samples obtained 4 h after surgery, regardless of pre-operative dexamethasone treatment, potently inhibited LPS-induced TNF-alpha but not IL-6 synthesis by monocytes. This was not associated with attenuation of p38 MAPK activation or IkappaB-alpha degradation. However, abrogation of the IL-10/STAT3 pathway restored LPS-induced TNF-alpha production in the presence of suppressive patient plasma. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that STAT3 signaling plays a crucial role in the downregulation of TNF-alpha synthesis by human monocytes in the course of systemic inflammation in vivo. Thus, STAT3 might be a potential molecular target for pharmacological intervention in clinical syndromes characterized by systemic inflammation. PMID- 22506068 TI - The Chlamydia psittaci genome: a comparative analysis of intracellular pathogens. AB - BACKGROUND: Chlamydiaceae are a family of obligate intracellular pathogens causing a wide range of diseases in animals and humans, and facing unique evolutionary constraints not encountered by free-living prokaryotes. To investigate genomic aspects of infection, virulence and host preference we have sequenced Chlamydia psittaci, the pathogenic agent of ornithosis. RESULTS: A comparison of the genome of the avian Chlamydia psittaci isolate 6BC with the genomes of other chlamydial species, C. trachomatis, C. muridarum, C. pneumoniae, C. abortus, C. felis and C. caviae, revealed a high level of sequence conservation and synteny across taxa, with the major exception of the human pathogen C. trachomatis. Important differences manifest in the polymorphic membrane protein family specific for the Chlamydiae and in the highly variable chlamydial plasticity zone. We identified a number of psittaci-specific polymorphic membrane proteins of the G family that may be related to differences in host-range and/or virulence as compared to closely related Chlamydiaceae. We calculated non-synonymous to synonymous substitution rate ratios for pairs of orthologous genes to identify putative targets of adaptive evolution and predicted type III secreted effector proteins. CONCLUSIONS: This study is the first detailed analysis of the Chlamydia psittaci genome sequence. It provides insights in the genome architecture of C. psittaci and proposes a number of novel candidate genes mostly of yet unknown function that may be important for pathogen host interactions. PMID- 22506069 TI - CCL5 and CCR5 interaction promotes cell motility in human osteosarcoma. AB - BACKGROUND: Osteosarcoma is characterized by a high malignant and metastatic potential. CCL5 (previously called RANTES) was originally recognized as a product of activated T cells, and plays a crucial role in the migration and metastasis of human cancer cells. It has been reported that the effect of CCL5 is mediated via CCR receptors. However, the effect of CCL5 on migration activity and integrin expression in human osteosarcoma cells is mostly unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we found that CCL5 increased the migration and expression of alphavbeta3 integrin in human osteosarcoma cells. Stimulation of cells with CCL5 increased CCR5 but not CCR1 and CCR3 expression. CCR5 mAb, inhibitor, and siRNA reduced the CCL5-enhanced the migration and integrin up-regulation of osteosarcoma cells. Activations of MEK, ERK, and NF-kappaB pathways after CCL5 treatment were demonstrated, and CCL5-induced expression of integrin and migration activity was inhibited by the specific inhibitor and mutant of MEK, ERK, and NF-kappaB cascades. In addition, over-expression of CCL5 shRNA inhibited the migratory ability and integrin expression in osteosarcoma cells. CONCLUSIONS/SIGNIFICANCE: CCL5 and CCR5 interaction acts through MEK, ERK, which in turn activates NF-kappaB, resulting in the activations of alphavbeta3 integrin and contributing the migration of human osteosarcoma cells. PMID- 22506071 TI - Clock gene variation is associated with breeding phenology and maybe under directional selection in the migratory barn swallow. AB - BACKGROUND: In diverse taxa, photoperiodic responses that cause seasonal physiological and behavioural shifts are controlled by genes, including the vertebrate Clock orthologues, that encode for circadian oscillator mechanisms. While the genetic network behind circadian rhythms is well described, relatively few reports exist of the phenological consequences of and selection on Clock genes in the wild. Here, we investigated variation in breeding phenology in relation to Clock genetic diversity in a long-distance migratory bird, the barn swallow (Hirundo rustica). METHODOLOGY/PRINCIPAL FINDINGS: In a sample of 922 adult barn swallows from a single population breeding in Italy we found one very common (Q(7)) and three rare (Q(5), Q(6), Q(8)) length variants of a functionally significant polyglutamine repeat. Rare (2.9%) Q(7)/Q(8) heterozygous females, but not males, bred significantly later than common (91.5%) Q(7)/Q(7) females, consistent with the expectation that 'long' alleles cause late breeding, as observed in a resident population of another bird species. Because breeding date depends on arrival date from migration, present results suggest that the association between breeding date and Clock might be mediated by migration phenology. In addition, fecundity selection appears to be operating against Q(7)/Q(8) because late migrating/breeding swallows have fewer clutches per season, and late breeding has additional negative selection effects via reduced offspring longevity. Genotype frequencies varied marginally non-significantly with age, as Q(7)/Q(8) frequency showed a 4-fold reduction in old individuals. This result suggests negative viability selection against Q(7)/Q(8), possibly mediated by costs of late breeding. CONCLUSIONS/SIGNIFICANCE: This is the first study of migratory birds showing an association between breeding phenology and Clock genotype and suggesting that negative selection occurs on a phenologically deviant genotype. Low polymorphism at Clock may constrain microevolutionary phenological response to changing climate, and may thus contribute to the decline of barn swallow populations. PMID- 22506070 TI - GABA(A) receptors containing the alpha2 subunit are critical for direction selective inhibition in the retina. AB - Far from being a simple sensor, the retina actively participates in processing visual signals. One of the best understood aspects of this processing is the detection of motion direction. Direction-selective (DS) retinal circuits include several subtypes of ganglion cells (GCs) and inhibitory interneurons, such as starburst amacrine cells (SACs). Recent studies demonstrated a surprising complexity in the arrangement of synapses in the DS circuit, i.e. between SACs and DS ganglion cells. Thus, to fully understand retinal DS mechanisms, detailed knowledge of all synaptic elements involved, particularly the nature and localization of neurotransmitter receptors, is needed. Since inhibition from SACs onto DSGCs is crucial for generating retinal direction selectivity, we investigate here the nature of the GABA receptors mediating this interaction. We found that in the inner plexiform layer (IPL) of mouse and rabbit retina, GABA(A) receptor subunit alpha2 (GABA(A)R alpha2) aggregated in synaptic clusters along two bands overlapping the dendritic plexuses of both ON and OFF SACs. On distal dendrites of individually labeled SACs in rabbit, GABA(A)R alpha2 was aligned with the majority of varicosities, the cell's output structures, and found postsynaptically on DSGC dendrites, both in the ON and OFF portion of the IPL. In GABA(A)R alpha2 knock-out (KO) mice, light responses of retinal GCs recorded with two-photon calcium imaging revealed a significant impairment of DS responses compared to their wild-type littermates. We observed a dramatic drop in the proportion of cells exhibiting DS phenotype in both the ON and ON-OFF populations, which strongly supports our anatomical findings that alpha2 containing GABA(A)Rs are critical for mediating retinal DS inhibition. Our study reveals for the first time, to the best of our knowledge, the precise functional localization of a specific receptor subunit in the retinal DS circuit. PMID- 22506072 TI - Simultaneous disruption of mouse ASIC1a, ASIC2 and ASIC3 genes enhances cutaneous mechanosensitivity. AB - Three observations have suggested that acid-sensing ion channels (ASICs) might be mammalian cutaneous mechanoreceptors; they are structurally related to Caenorhabditis elegans mechanoreceptors, they are localized in specialized cutaneous mechanosensory structures, and mechanical displacement generates an ASIC-dependent depolarization in some neurons. However, previous studies of mice bearing a single disrupted ASIC gene showed only subtle or no alterations in cutaneous mechanosensitivity. Because functional redundancy of ASIC subunits might explain limited phenotypic alterations, we hypothesized that disrupting multiple ASIC genes would markedly impair cutaneous mechanosensation. We found the opposite. In behavioral studies, mice with simultaneous disruptions of ASIC1a, -2 and -3 genes (triple-knockouts, TKOs) showed increased paw withdrawal frequencies when mechanically stimulated with von Frey filaments. Moreover, in single-fiber nerve recordings of cutaneous afferents, mechanical stimulation generated enhanced activity in A-mechanonociceptors of ASIC TKOs compared to wild type mice. Responses of all other fiber types did not differ between the two genotypes. These data indicate that ASIC subunits influence cutaneous mechanosensitivity. However, it is unlikely that ASICs directly transduce mechanical stimuli. We speculate that physical and/or functional association of ASICs with other components of the mechanosensory transduction apparatus contributes to normal cutaneous mechanosensation. PMID- 22506073 TI - Gliding motility of Babesia bovis merozoites visualized by time-lapse video microscopy. AB - BACKGROUND: Babesia bovis is an apicomplexan intraerythrocytic protozoan parasite that induces babesiosis in cattle after transmission by ticks. During specific stages of the apicomplexan parasite lifecycle, such as the sporozoites of Plasmodium falciparum and tachyzoites of Toxoplasma gondii, host cells are targeted for invasion using a unique, active process termed "gliding motility". However, it is not thoroughly understood how the merozoites of B. bovis target and invade host red blood cells (RBCs), and gliding motility has so far not been observed in the parasite. METHODOLOGY/PRINCIPAL FINDINGS: Gliding motility of B. bovis merozoites was revealed by time-lapse video microscopy. The recorded images revealed that the process included egress of the merozoites from the infected RBC, gliding motility, and subsequent invasion into new RBCs. The gliding motility of B. bovis merozoites was similar to the helical gliding of Toxoplasma tachyzoites. The trails left by the merozoites were detected by indirect immunofluorescence assay using antiserum against B. bovis merozoite surface antigen 1. Inhibition of gliding motility by actin filament polymerization or depolymerization indicated that the gliding motility was driven by actomyosin dependent process. In addition, we revealed the timing of breakdown of the parasitophorous vacuole. Time-lapse image analysis of membrane-stained bovine RBCs showed formation and breakdown of the parasitophorous vacuole within ten minutes of invasion. CONCLUSIONS/SIGNIFICANCE: This is the first report of the gliding motility of B. bovis. Since merozoites of Plasmodium parasites do not glide on a substrate, the gliding motility of B. bovis merozoites is a notable finding. PMID- 22506074 TI - Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. AB - Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are metabolites formed by gut microbiota from complex dietary carbohydrates. Butyrate and acetate were reported to protect against diet-induced obesity without causing hypophagia, while propionate was shown to reduce food intake. However, the underlying mechanisms for these effects are unclear. It was suggested that SCFAs may regulate gut hormones via their endogenous receptors Free fatty acid receptors 2 (FFAR2) and 3 (FFAR3), but direct evidence is lacking. We examined the effects of SCFA administration in mice, and show that butyrate, propionate, and acetate all protected against diet-induced obesity and insulin resistance. Butyrate and propionate, but not acetate, induce gut hormones and reduce food intake. As FFAR3 is the common receptor activated by butyrate and propionate, we examined these effects in FFAR3-deficient mice. The effects of butyrate and propionate on body weight and food intake are independent of FFAR3. In addition, FFAR3 plays a minor role in butyrate stimulation of Glucagon-like peptide-1, and is not required for butyrate- and propionate-dependent induction of Glucose dependent insulinotropic peptide. Finally, FFAR3-deficient mice show normal body weight and glucose homeostasis. Stimulation of gut hormones and food intake inhibition by butyrate and propionate may represent a novel mechanism by which gut microbiota regulates host metabolism. These effects are largely intact in FFAR3-deficient mice, indicating additional mediators are required for these beneficial effects. PMID- 22506077 TI - Plastidial starch phosphorylase in sweet potato roots is proteolytically modified by protein-protein interaction with the 20S proteasome. AB - Post-translational regulation plays an important role in cellular metabolism. Earlier studies showed that the activity of plastidial starch phosphorylase (Pho1) may be regulated by proteolytic modification. During the purification of Pho1 from sweet potato roots, we observed an unknown high molecular weight complex (HX) showing Pho1 activity. The two-dimensional gel electrophoresis, mass spectrometry, and reverse immunoprecipitation analyses showed that HX is composed of Pho1 and the 20S proteasome. Incubating sweet potato roots at 45 degrees C triggers a stepwise degradation of Pho1; however, the degradation process can be partially inhibited by specific proteasome inhibitor MG132. The proteolytically modified Pho1 displays a lower binding affinity toward glucose 1-phosphate and a reduced starch-synthesizing activity. This study suggests that the 20S proteasome interacts with Pho1 and is involved in the regulation of the catalytic activity of Pho1 in sweet potato roots under heat stress conditions. PMID- 22506076 TI - Type 2 diabetes in Xinjiang Uygur autonomous region, China. AB - BACKGROUND: The aim of this study was to estimate the prevalence and distribution of type 2 diabetes and to determine the status of type 2 diabetes awareness, treatment, and control in Xinjiang, China. Our data came from the Cardiovascular Risk Survey (CRS) study designed to investigate the prevalence and risk factors for cardiovascular diseases in Xinjiang from October 2007 to March 2010. A total of 14 122 persons (5583 Hans, 4620 Uygurs, and 3919 Kazaks) completed the survey and examination. Diabetes was defined by the American Diabetes Association 2009 criteria. METHODOLOGY/PRINCIPAL FINDINGS: Overall, 9.26% of the Han, 6.23% of the Uygur, and 3.65% of the Kazak adults aged >=35 years had diabetes. Among diabetes patients, only 53.0% were aware of their blood glucose level, 26.7% were taking hypoglycemic agents, and 10.4% achieved blood glucose control in Han, 35.8% were aware of their blood glucose level, 7.3% were taking hypoglycemic agents, and 3.13% achieved blood glucose control in Uygur, and 23.8% were aware of their blood glucose level, 6.3% were taking hypoglycemic agents, and 1.4% achieved blood glucose control in Kazak, respectively. CONCLUSIONS/SIGNIFICANCE: Our results indicate that diabetes is highly prevalent in Xinjiang. The percentages of those with diabetes who are aware, treated, and controlled are unacceptably low. These results underscore the urgent need to develop national strategies to improve prevention, detection, and treatment of diabetes in Xinjiang, the west China. PMID- 22506075 TI - Age-related skeletal dynamics and decrease in bone strength in DNA repair deficient male trichothiodystrophy mice. AB - Accumulation of DNA damage caused by oxidative stress is thought to be one of the main contributors of human tissue aging. Trichothiodystrophy (TTD) mice have a mutation in the Ercc2 DNA repair gene, resulting in accumulation of DNA damage and several features of segmental accelerated aging. We used male TTD mice to study the impact of DNA repair on bone metabolism with age. Analysis of bone parameters, measured by micro-computed tomography, displayed an earlier decrease in trabecular and cortical bone as well as a loss of periosteal apposition and a reduction in bone strength in TTD mice with age compared to wild type mice. Ex vivo analysis of bone marrow differentiation potential showed an accelerated reduction in the number of osteogenic and osteoprogenitor cells with unaltered differentiation capacity. Adipocyte differentiation was normal. Early in life, osteoclast number tended to be increased while at 78 weeks it was significantly lower in TTD mice. Our findings reveal the importance of genome stability and proper DNA repair for skeletal homeostasis with age and support the idea that accumulation of damage interferes with normal skeletal maintenance, causing reduction in the number of osteoblast precursors that are required for normal bone remodeling leading to a loss of bone structure and strength. PMID- 22506078 TI - A sensitive membrane-targeted biosensor for monitoring changes in intracellular chloride in neuronal processes. AB - BACKGROUND: Regulation of chloride gradients is a major mechanism by which excitability is regulated in neurons. Disruption of these gradients is implicated in various diseases, including cystic fibrosis, neuropathic pain and epilepsy. Relatively few studies have addressed chloride regulation in neuronal processes because probes capable of detecting changes in small compartments over a physiological range are limited. METHODOLOGY/PRINCIPAL FINDINGS: In this study, a palmitoylation sequence was added to a variant of the yellow fluorescent protein previously described as a sensitive chloride indicator (YFPQS) to target the protein to the plasma membrane (mbYFPQS) of cultured midbrain neurons. The reporter partitions to the cytoplasmic face of the cellular membranes, including the plasma membrane throughout the neurons and fluorescence is stable over 30-40 min of repeated excitation showing less than 10% decrease in mbYFPQS fluorescence compared to baseline. The mbYFPQS has similar chloride sensitivity (k(50) = 41 mM) but has a shifted pKa compared to the unpalmitoylated YFPQS variant (cytYFPQS) that remains in the cytoplasm when expressed in midbrain neurons. Changes in mbYFPQS fluorescence were induced by the GABA(A) agonist muscimol and were similar in the soma and processes of the midbrain neurons. Amphetamine also increased mbYFPQS fluorescence in a subpopulation of cultured midbrain neurons that was reversed by the selective dopamine transporter (DAT) inhibitor, GBR12909, indicating that mbYFPQS is sensitive enough to detect endogenous DAT activity in midbrain dopamine (DA) neurons. CONCLUSIONS/SIGNIFICANCE: The mbYFPQS biosensor is a sensitive tool to study modulation of intracellular chloride levels in neuronal processes and is particularly advantageous for simultaneous whole-cell patch clamp and live-cell imaging experiments. PMID- 22506079 TI - Identification and characterization of a novel diterpene gene cluster in Aspergillus nidulans. AB - Fungal secondary metabolites are a rich source of medically useful compounds due to their pharmaceutical and toxic properties. Sequencing of fungal genomes has revealed numerous secondary metabolite gene clusters, yet products of many of these biosynthetic pathways are unknown since the expression of the clustered genes usually remains silent in normal laboratory conditions. Therefore, to discover new metabolites, it is important to find ways to induce the expression of genes in these otherwise silent biosynthetic clusters. We discovered a novel secondary metabolite in Aspergillus nidulans by predicting a biosynthetic gene cluster with genomic mining. A Zn(II)(2)Cys(6)-type transcription factor, PbcR, was identified, and its role as a pathway-specific activator for the predicted gene cluster was demonstrated. Overexpression of pbcR upregulated the transcription of seven genes in the identified cluster and led to the production of a diterpene compound, which was characterized with GC/MS as ent-pimara 8(14),15-diene. A change in morphology was also observed in the strains overexpressing pbcR. The activation of a cryptic gene cluster by overexpression of its putative Zn(II)(2)Cys(6)-type transcription factor led to discovery of a novel secondary metabolite in Aspergillus nidulans. Quantitative real-time PCR and DNA array analysis allowed us to predict the borders of the biosynthetic gene cluster. Furthermore, we identified a novel fungal pimaradiene cyclase gene as well as genes encoding 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase and a geranylgeranyl pyrophosphate (GGPP) synthase. None of these genes have been previously implicated in the biosynthesis of terpenes in Aspergillus nidulans. These results identify the first Aspergillus nidulans diterpene gene cluster and suggest a biosynthetic pathway for ent-pimara-8(14),15-diene. PMID- 22506080 TI - Higher expression of CCL2, CCL4, CCL5, CCL21, and CXCL8 chemokines in the skin associated with parasite density in canine visceral leishmaniasis. AB - BACKGROUND: The immune response in the skin of dogs infected with Leishmania infantum is poorly understood, and limited studies have described the immunopathological profile with regard to distinct levels of tissue parasitism and the clinical progression of canine visceral leishmaniasis (CVL). METHODOLOGY/PRINCIPAL FINDINGS: A detailed analysis of inflammatory cells (neutrophils, eosinophils, mast cells, lymphocytes, and macrophages) as well as the expression of chemokines (CCL2, CCL4, CCL5, CCL13, CCL17, CCL21, CCL24, and CXCL8) was carried out in dermis skin samples from 35 dogs that were naturally infected with L. infantum. The analysis was based on real-time polymerase chain reaction (PCR) in the context of skin parasitism and the clinical status of CVL. We demonstrated increased inflammatory infiltrate composed mainly of mononuclear cells in the skin of animals with severe forms of CVL and high parasite density. Analysis of the inflammatory cell profile of the skin revealed an increase in the number of macrophages and reductions in lymphocytes, eosinophils, and mast cells that correlated with clinical progression of the disease. Additionally, enhanced parasite density was correlated with an increase in macrophages and decreases in eosinophils and mast cells. The chemokine mRNA expression demonstrated that enhanced parasite density was positively correlated with the expression of CCL2, CCL4, CCL5, CCL21, and CXCL8. In contrast, there was a negative correlation between parasite density and CCL24 expression. CONCLUSIONS/SIGNIFICANCE: These findings represent an advance in the knowledge about skin inflammatory infiltrates in CVL and the systemic consequences. Additionally, the findings may contribute to the design of new and more efficient prophylactic tools and immunological therapies against CVL. PMID- 22506089 TI - Viewing Angle Classification of Cryo-Electron Microscopy Images Using Eigenvectors. AB - The cryo-electron microscopy (cryo-EM) reconstruction problem is to find the three-dimensional structure of a macromolecule given noisy versions of its two dimensional projection images at unknown random directions. We introduce a new algorithm for identifying noisy cryo-EM images of nearby viewing angles. This identification is an important first step in three-dimensional structure determination of macromolecules from cryo-EM, because once identified, these images can be rotationally aligned and averaged to produce "class averages" of better quality. The main advantage of our algorithm is its extreme robustness to noise. The algorithm is also very efficient in terms of running time and memory requirements, because it is based on the computation of the top few eigenvectors of a specially designed sparse Hermitian matrix. These advantages are demonstrated in numerous numerical experiments. PMID- 22506090 TI - Control of Extensively Drug-Resistant Tuberculosis (XDR-TB): A Root Cause Analysis. AB - The threat of global infectious agents has the potential to cripple national and global economies, as the outbreaks of SARS, Avian Flu, H1N1, and XDR-TB have demonstrated. This article offers a Root Cause Analysis (RCA) of one public health case study - the Speaker case of XDR-TB - pinpointing the underlying causal relationships associated with this global health incident and proposing recommendations for preventing its recurrence. An RCA approach identifies corrective actions directed at the root causes of the problem and advances them as necessary to eliminate global contagion with its major international public health risks. To my knowledge, this is the first root cause analysis of a global health problem. The reform this article proposes would be to add a standardized procedure akin to the informed consent process in clinical ethics, but within a shared health governance framework. This approach, addressing infectious agents at their origins or source, is potentially a more effective strategy to reduce uncertainty and avert global health threats. PMID- 22506083 TI - Five-year longitudinal assessment of the downstream impact on schistosomiasis transmission following closure of the Three Gorges Dam. AB - BACKGROUND: Schistosoma japonicum is a major public health concern in the Peoples' Republic of China (PRC), with about 800,000 people infected and another 50 million living in areas at risk of infection. Based on ecological, environmental, population genetic and molecular factors, schistosomiasis transmission in PRC can be categorised into four discrete ecosystems or transmission modes. It is predicted that, long-term, the Three Gorges Dam (TGD) will impact upon the transmission of schistosomiasis in the PRC, with varying degree across the four transmission modes. METHODOLOGY/PRINCIPAL FINDINGS: We undertook longitudinal surveillance from 2002 to 2006 in sentinel villages of the three transmission modes below the TGD across four provinces (Hunan, Jiangxi, Hubei and Anhui) to determine whether there was any immediate impact of the TGD on schistosomiasis transmission. Eight sentinel villages were selected to represent both province and transmission mode. The primary end point measured was human incidence. Here we present the results of this five-year longitudinal cohort study. Results showed that the incidence of human S. japonicum infection declined considerably within individual villages and overall mode over the course of the study. This is also reflected in the yearly odds ratios (adjusted) for infection risk that showed significant (P<0.01) downward trends in all modes over the follow-up period. CONCLUSIONS/SIGNIFICANCE: The decrease in human S. japonicum incidence observed across all transmission modes in this study can probably be attributed to the annual human and bovine PZQ chemotherapy. If an increase in schistosome transmission had occurred as a result of the TGD, it would be of negligible size compared to the treatment induced decline seen here. It appears therefore that there has been virtually no immediate impact of the TGD on schistosomiasis transmission downstream of the dam. PMID- 22506092 TI - Optimizing magnetomotive contrast of SPIO-labeled platelets for thrombosis imaging in optical coherence tomography. AB - Rehydratable, lyophilized platelets loaded with superparamagnetic iron oxides (SPIOs) has the potential to provide magnetomotive imaging contrast to sites of vascular damage, including thrombosis complicating atherosclerosis and hemorrhage. Magnetomotive optical coherence tomography (MMOCT) contrasts SPIO platelets based on their nanoscale, magnetically-induced motion. We report improvements in MMOCT imaging contrast and sensitivity by optimizing the magnetic properties and SPIO loading of the platelets. SPIO-platelets have been shown to specifically adhere to sites of vascular damage in porcine arteries ex vivo. This may lead to new methods for detecting internal bleeding and monitoring the formation of blood clots using infused SPIO-platelets. PMID- 22506084 TI - Canine skin and conjunctival swab samples for the detection and quantification of Leishmania infantum DNA in an endemic urban area in Brazil. AB - BACKGROUND: We evaluated kDNA PCR/hybridization and quantitative real-time PCR (qPCR) targeting the gene of DNA polymerase of Leishmania infantum for CVL diagnosis and assessment of parasite load in clinical samples obtained invasively and non-invasively. METHODOLOGY/PRINCIPAL FINDINGS: Eighty naturally infected dogs from an endemic urban area in Brazil were used. Animals were divided into two groups based on the presence or absence of CVL clinical sings. Skin biopsies, bone marrow, blood and conjunctival swabs samples were collected and submitted to L. infantum DNA detection. In addition, anti-Leishmania antibody titers were measured by Immunofluorescence antibody test. The symptomatic dogs had increased titers compared to asymptomatic dogs (P = 0.025). The frequencies of positive results obtained by kDNA PCR/hybridization for asymptomatic and symptomatic dogs, respectively, were as follows: right conjunctiva, 77.5% and 95.0%; left conjunctiva, 75.0% and 87.5%; skin, 45.0% and 75.0%; bone marrow, 50.0% and 77.5%; and blood, 27.5% and 22.5%. In both groups, the parasite load in the skin samples was the highest (P<0.0001). The parasite loads in the conjunctival swab and bone marrow samples were statistically equivalent within each group. The parasite burden in conjunctival swabs was higher in the dogs with clinical signs than in asymptomatic dogs (P = 0.028). This same relationship was also observed in the bone marrow samples (P = 0.002). No differences in amastigotes load in the skin were detected between the groups. CONCLUSIONS: The conjunctival swab is a suitable clinical sample for qualitative molecular diagnosis of CVL. The highest parasite burdens were detected in skin regardless of the presence of VL associated clinical signs. The qPCR results emphasized the role of dogs, particularly asymptomatic dogs, as reservoirs for CVL because of the high cutaneous parasite loads. These results may help to explain the maintenance of high transmission rates and numbers of CVL cases in endemic urban regions. PMID- 22506082 TI - Prevalence of trachoma in unity state, South Sudan: results from a large-scale population-based survey and potential implications for further surveys. AB - BACKGROUND: Large parts of South Sudan are thought to be trachoma-endemic but baseline data are limited. This study aimed to estimate prevalence for planning trachoma interventions in Unity State, to identify risk factors and to investigate the effect of different sampling approaches on study conclusions. METHODS AND FINDINGS: The survey area was defined as one domain of eight counties in Unity State. Across the area, 40 clusters (villages) were randomly selected proportional to the county population size in a population-based prevalence survey. The simplified grading scheme was used to classify clinical signs of trachoma. The unadjusted prevalence of trachoma inflammation-follicular (TF) in children aged 1-9 years was 70.5% (95% CI: 68.6-72.3). After adjusting for age, sex, county and clustering of cases at household and village level the prevalence was 71.0% (95% CI: 69.9-72.1). The prevalence of trachomatous trichiasis (TT) in adults was 15.1% (95% CI: 13.4-17.0) and 13.5% (95% CI: 12.0-15.1) before and after adjustment, respectively. We estimate that 700,000 people (the entire population of Unity State) require antibiotic treatment and approximately 54,178 people require TT surgery. Risk factor analyses confirmed child-level associations with TF and highlighted that older adults living in poverty are at higher risk of TT. Conditional simulations, testing the alternatives of sampling 20 or 60 villages over the same area, indicated that sampling of only 20 villages would have provided an acceptable level of precision for state-level prevalence estimation to inform intervention decisions in this hyperendemic setting. CONCLUSION: Trachoma poses an enormous burden on the population of Unity State. Comprehensive control is urgently required to avoid preventable blindness and should be initiated across the state now. In other parts of South Sudan suspected to be highly trachoma endemic, counties should be combined into larger survey areas to generate the baseline data required to initiate interventions. PMID- 22506091 TI - Dual-Specificity Phosphatase CDC25A/B Inhibitor Identified from a Focused Library with Nonelectrophilic Core Structure. AB - Focused libraries of enamine derivatives with a nonacidic, nonelectrophilic core structure were screened for inhibitors of dual-specificity protein phosphatases, and an o-hydroxybenzyl derivative RE44 (10d) was identified as a selective inhibitor of CDC25A/B. This inhibitor induced cell-cycle arrest of tsFT210 cells at the G2/M phase and inhibited dephosphorylation of the CDC25B substrate CDK1. Unlike most quinone-based inhibitors, 10d does not generate reactive oxygen species. PMID- 22506088 TI - Particle Filtering with Region-based Matching for Tracking of Partially Occluded and Scaled Targets. AB - Visual tracking of arbitrary targets in clutter is important for a wide range of military and civilian applications. We propose a general framework for the tracking of scaled and partially occluded targets, which do not necessarily have prominent features. The algorithm proposed in the present paper utilizes a modified normalized cross-correlation as the likelihood for a particle filter. The algorithm divides the template, selected by the user in the first video frame, into numerous patches. The matching process of these patches by particle filtering allows one to handle the target's occlusions and scaling. Experimental results with fixed rectangular templates show that the method is reliable for videos with nonstationary, noisy, and cluttered background, and provides accurate trajectories in cases of target translation, scaling, and occlusion. PMID- 22506085 TI - Epidemiology and molecular relationships of Cryptosporidium spp. in people, primates, and livestock from Western Uganda. AB - BACKGROUND: Cryptosporidium is one of the most common parasitic diarrheal agents in the world and is a known zoonosis. We studied Cryptosporidium in people, livestock, and non-human primates in the region of Kibale National Park, Uganda. Land use change near the park has resulted in fragmented forest patches containing small, remnant populations of wild primates that interact intensively with local people and livestock. Our goal was to investigate risk factors for Cryptosporidium infection and to assess cross-species transmission using molecular methods. METHODOLOGY/PRINCIPAL FINDINGS: Diagnostic PCR revealed a prevalence of Cryptosporidium of 32.4% in humans, 11.1% in non-human primates, and 2.2% in livestock. In the case of humans, residence in one particular community was associated with increased risk of infection, as was fetching water from an open water source. Although 48.5% of infected people reported gastrointestinal symptoms, this frequency was not significantly different in people who tested negative (44.7%) for Cryptosporidium, nor was co-infection with Giardia duodenalis associated with increased reporting of gastrointestinal symptoms. Fecal consistency was no different in infected versus uninfected people or animals. DNA sequences of the Cryptosporidium oocyst wall protein gene placed all infections within a well-supported C. parvum/C. hominis clade. However, the only two sequences recovered from primates in the core of the park's protected area fell into a divergent sub-clade and were identical to published sequences from C. parvum, C. hominis, and C. cuniculus, suggesting the possibility of a separate sylvatic transmission cycle. CONCLUSIONS/SIGNIFICANCE: Cryptosporidium may be transmitted frequently among species in western Uganda where people, livestock, and wildlife interact intensively as a result of anthropogenic changes to forests, but the parasite may undergo more host-specific transmission where such interactions do not occur. The parasite does not appear to have strong effects on human or animal health, perhaps because of persistent low-level shedding and immunity. PMID- 22506087 TI - Prevalence, features and risk factors for malaria co-infections amongst visceral leishmaniasis patients from Amudat Hospital, Uganda. AB - BACKGROUND AND METHODOLOGY: Due to geographic overlap of malaria and visceral leishmaniasis (VL), co-infections may exist but have been poorly investigated. To describe prevalence, features and risk factors for VL-malaria co-infections, a case-control analysis was conducted on data collected at Amudat Hospital, Uganda (2000-2006) by Medecins sans Frontieres. Cases were identified as patients with laboratory-confirmed VL and malaria at hospital admission or during hospitalization; controls were VL patients with negative malaria smears. A logistic regression analysis was performed to study the association between patients' characteristics and the occurrence of the co-infection. RESULTS: Of 2414 patients with confirmed VL, 450 (19%) were positively diagnosed with concomitant malaria. Most co-infected patients were males, residing in Kenya (69%). While young age was identified by multivariate analysis as a risk factor for concurrent VL and malaria, particularly the age groups 0-4 (odds ratio (OR): 2.44; 95% confidence interval (CI): 1.52-3.92) and 5-9 years (OR: 2.23, 95% CI: 1.45-3-45), mild (OR: 0.53; 95% CI: 0.32-0.88) and moderate (OR: 0.45; 95% CI: 0.27-0.77) anemia negatively correlated with the co-morbidity. VL patients harboring skin infections were nearly three times less likely to have the co infection (OR: 0.35; 95% CI: 0.17-0.72), as highlighted by the multivariate model. Anorexia was slightly more frequent among co-infected patients (OR: 1.71; 95% CI: 0.96-3.03). The in-hospital case-fatality rate did not significantly differ between cases and controls, being 2.7% and 3.1% respectively (OR: 0.87; 95% CI: 0.46-1.63). CONCLUSIONS: Concurrent malaria represents a common condition among young VL patients living in the Pokot region of Kenya and Uganda. Although these co-morbidities did not result in a poorer prognosis, possibly due to early detection of malaria, a positive trend towards more severe symptoms was identified, indicating that routine screening of VL patients living in malaria endemic-areas and close monitoring of co-infected patients should be implemented. PMID- 22506081 TI - Multiple mitochondrial introgression events and heteroplasmy in trypanosoma cruzi revealed by maxicircle MLST and next generation sequencing. AB - BACKGROUND: Mitochondrial DNA is a valuable taxonomic marker due to its relatively fast rate of evolution. In Trypanosoma cruzi, the causative agent of Chagas disease, the mitochondrial genome has a unique structural organization consisting of 20-50 maxicircles (~20 kb) and thousands of minicircles (0.5-10 kb). T. cruzi is an early diverging protist displaying remarkable genetic heterogeneity and is recognized as a complex of six discrete typing units (DTUs). The majority of infected humans are asymptomatic for life while 30-35% develop potentially fatal cardiac and/or digestive syndromes. However, the relationship between specific clinical outcomes and T. cruzi genotype remains elusive. The availability of whole genome sequences has driven advances in high resolution genotyping techniques and re-invigorated interest in exploring the diversity present within the various DTUs. METHODOLOGY/PRINCIPAL FINDINGS: To describe intra-DTU diversity, we developed a highly resolutive maxicircle multilocus sequence typing (mtMLST) scheme based on ten gene fragments. A panel of 32 TcI isolates was genotyped using the mtMLST scheme, GPI, mini-exon and 25 microsatellite loci. Comparison of nuclear and mitochondrial data revealed clearly incongruent phylogenetic histories among different geographical populations as well as major DTUs. In parallel, we exploited read depth data, generated by Illumina sequencing of the maxicircle genome from the TcI reference strain Sylvio X10/1, to provide the first evidence of mitochondrial heteroplasmy (heterogeneous mitochondrial genomes in an individual cell) in T. cruzi. CONCLUSIONS/SIGNIFICANCE: mtMLST provides a powerful approach to genotyping at the sub-DTU level. This strategy will facilitate attempts to resolve phenotypic variation in T. cruzi and to address epidemiologically important hypotheses in conjunction with intensive spatio-temporal sampling. The observations of both general and specific incidences of nuclear-mitochondrial phylogenetic incongruence indicate that genetic recombination is geographically widespread and continues to influence the natural population structure of TcI, a conclusion which challenges the traditional paradigm of clonality in T. cruzi. PMID- 22506093 TI - Validation study toward measuring the mechanical properties of blood clots using resonant acoustic spectroscopy with optical vibrometry. AB - Clot elastic modulus (CEM) has recently been shown to correlate with various hemostatic and thrombotic disorders and may be an important diagnostic parameter in cardiovascular diseases. Current methods of CEM measurement lack repeatability and require large sample volume. We present a novel method named resonant acoustic spectroscopy with optical vibrometry (RASOV) that has the potential to assess CEM with higher accuracy and speed, and lower sample volume. To validate RASOV, we measured the acoustic spectrum of agarose gel with varied concentrations in open-faced rectangular wells. Results showed a linear relationship between the natural resonant frequency and agarose content within a concentration range of 4 to 12 mg/mL. Furthermore, we observed that the resonant frequencies decrease with increasing transducer mass. As a highly accurate, resonance-based method, RASOV has great potential for biomechanical properties measurement, especially for human blood. PMID- 22506086 TI - In vitro and in vivo efficacy of ether lipid edelfosine against Leishmania spp. and SbV-resistant parasites. AB - BACKGROUND: The leishmaniases are a complex of neglected tropical diseases caused by more than 20 Leishmania parasite species, for which available therapeutic arsenal is scarce and unsatisfactory. Pentavalent antimonials (SbV) are currently the first-line pharmacologic therapy for leishmaniasis worldwide, but resistance to these compounds is increasingly reported. Alkyl-lysophospoholipid analogs (ALPs) constitute a family of compounds with antileishmanial activity, and one of its members, miltefosine, has been approved as the first oral treatment for visceral and cutaneous leishmaniasis. However, its clinical use can be challenged by less impressive efficiency in patients infected with some Leishmania species, including L. braziliensis and L. mexicana, and by proneness to develop drug resistance in vitro. METHODOLOGY/PRINCIPAL FINDINGS: We found that ALPs ranked edelfosine>perifosine>miltefosine>erucylphosphocholine for their antileishmanial activity and capacity to promote apoptosis-like parasitic cell death in promastigote and amastigote forms of distinct Leishmania spp., as assessed by proliferation and flow cytometry assays. Effective antileishmanial ALP concentrations were dependent on both the parasite species and their development stage. Edelfosine accumulated in and killed intracellular Leishmania parasites within macrophages. In vivo antileishmanial activity was demonstrated following oral treatment with edelfosine of mice and hamsters infected with L. major, L. panamensis or L. braziliensis, without any significant side-effect. Edelfosine also killed SbV-resistant Leishmania parasites in in vitro and in vivo assays, and required longer incubation times than miltefosine to generate drug resistance. CONCLUSIONS/SIGNIFICANCE: Our data reveal that edelfosine is the most potent ALP in killing different Leishmania spp., and it is less prone to lead to drug resistance development than miltefosine. Edelfosine is effective in killing Leishmania in culture and within macrophages, as well as in animal models infected with different Leishmania spp. and SbV-resistant parasites. Our results indicate that edelfosine is a promising orally administered antileishmanial drug for clinical evaluation. PMID- 22506097 TI - Spinning Disk Confocal Microscopy of Calcium Signalling in Blood Vessel Walls. AB - Spinning disk confocal laser microscopy systems can be used for observing fast events occurring in a small volume when they include a sensitive electron multiplying CCD camera. Such a confocal system was recently used to capture the first pictures of intracellular calcium signalling within the projections of endothelial cells to the adjacent smooth muscle cells in the blood vessel wall. Detection of these calcium signals required high spatial and temporal resolution. A newly developed calcium ion (Ca(2+)) biosensor was also used. This exclusively expressed in the endothelium and fluoresced when Ca(2+) concentrations increased during signalling. This work gives insights into blood vessel disease because Ca(2+) signalling is critical for blood flow and pressure regulation. PMID- 22506094 TI - Childhood obesity: a global public health crisis. AB - INTRODUCTION: Childhood obesity is a major public health crisis nationally and internationally. The prevalence of childhood obesity has increased over few years. It is caused by imbalance between calorie intake and calories utilized. One or more factors (genetic, behavioral, and environmental) cause obesity in children. Physical, psychological, and social health problems are caused due to childhood obesity. Hence, effective intervention strategies are being used to prevent and control obesity in children. The purpose of this manuscript is to address various factors influencing childhood obesity, a variety of interventions and governmental actions addressing obesity and the challenges ahead for managing this epidemic. METHODS: In order to collect materials for this review a detailed search of CINAHL, MEDLINE, ERIC, Academic Search Premier databases was carried out for the time period 1999-2011. RESULTS: Some of the interventions used were family based, school based, community based, play based, and hospital based. The effective school-based interventions were seen targeting physical activity along with healthy diet education. The major challenges faced by these intervention programs are financial, along with stigmatization of obese children. Governments along with other health care organizations are taking effective actions like policy changing and environmentally safe interventions for children to improve physical activity. CONCLUSIONS: In conclusion, childhood obesity can be tackled at the population level by education, prevention and sustainable interventions related to healthy nutrition practices and physical activity promotion. PMID- 22506101 TI - New enzymes as potential therapeutic targets for trypanosomiases and leishmaniasis. PMID- 22506099 TI - The Modulatory Role of Heme Oxygenase on Subpressor Angiotensin II-Induced Hypertension and Renal Injury. AB - Angiotensin II (AngII) causes hypertension (HTN) and promotes renal injury while simultaneously inducing reno-protective enzymes like heme oxygenase-1 (HO-1). We examined the modulatory role of HO on sub-pressor angiotensin II (SP-AngII) induced renal inflammation and injury. We first tested whether the SP-AngII induced renal dysfunction, inflammation and injury are exacerbated by either preventing (chronic HO-1 inhibition) or reversing (late HO-1 inhibition) SP-AngII induced HO (using tin protoporphyrin; SnPP). We next examined whether additional chronic or late induction of SP-AngII-induced HO (using cobalt protoporphyrin; CoPP), prevents or ameliorates renal damage. We found that neither chronic nor late SnPP altered blood pressure. Chronic SnPP worsened SP-AngII-induced renal dysfunction, inflammation, injury and fibrosis, whereas late SnPP worsened renal dysfunction but not inflammation. Chronic CoPP prevented HTN, renal dysfunction, inflammation and fibrosis, but surprisingly, not the NGAL levels (renal injury marker). Late CoPP did not significantly alter SP-AngII-induced HTN, renal inflammation or injury, but improved renal function. Thus, we conclude (a) endogenous HO may be an essential determining factor in SP-AngII induced renal inflammation, injury and fibrosis, (b) part of HO's renoprotection may be independent of blood pressure changes; and (c) further induction of HO-1 protects against renal injury, suggesting a possible therapeutic target. PMID- 22506096 TI - Development of mesoporous silica nanomaterials as a vehicle for anticancer drug delivery. AB - The development of delivery vehicles that would carry therapeutic agents selectively to cancer cells has become an important focus in biomedical research. Nanoparticles have received much attention because the advances made in this field have resulted in multiple biocompatible materials. In particular, mesoporous silica nanoparticles (MSNs) offer a solid framework with porous structure and high surface area that allows for the attachment of different functional groups. In this article we discuss the different surface modifications made to MSNs that have allowed for the construction of targeted nanoparticles to enhance accumulation and uptake in target sites, the incorporation of nanomachines for controlled cargo release and the combination with superparamagnetic metals for MRI cell labeling. We also discuss biocompatibility, biodistribution and drug-delivery efficacy of MSNs. Finally, we mention the construction of multifunctional nanoparticles that combine all of the previously examined nanoparticle modifications. PMID- 22506095 TI - Nanoparticle-mediated hyperthermia in cancer therapy. AB - A small rise in tumor temperature (hyperthermia) makes cancer cells more susceptible to radiation and chemotherapy. The means of achieving this is not trivial, and traditional methods have certain drawbacks. Loading tumors with systematically asministered energy-transducing nanoparticles can circumvent several of the obstacles to achieve tumor hyperthermia. However, nanoparticles also face unique challenges prior to clinical implementation. This article summarizes the state-of-the-art current technology and discusses the advantages and challenges of the three major nanoparticle formulations in focus: gold nanoshells and nanorods, superparamagnetic iron oxide particles and carbon nanotubes. PMID- 22506102 TI - Four-Year Trends in Cardiometabolic Risk Factors according to Baseline Abdominal Obesity Status in West-African Adults: The Benin Study. AB - The study examined whether abdominal obesity (AO) according to waist circumference was associated with more unfavourable changes in other cardiometabolic risk (CMR) factors in sub-Saharan Africans. The study included 541 randomly selected and apparently healthy subjects (50% women) aged 25-60 years. Complete data at baseline, 24, and 48 months later was available in 366 subjects. AO was associated with higher CMR at baseline and over the follow-up period, except for high blood pressure. A significantly higher incidence of high ratio of total cholesterol : HDL-cholesterol (TC/HDL-C) was associated with AO. Controlling for WC changes, age, baseline diet, and lifestyles, the relative risk (RR) of low HDL-C and high TC/HDL-C was 3.2 (95% CI 1.06-9.61) and 7.4 (95% CI 2.01-25.79), respectively, in AO men; the RR was not significant in women. Over a four-year period, AO therefore appeared associated with an adverse evolution of cholesterolemia in the study population. PMID- 22506098 TI - New Insights on the Inflammatory Role of Lutzomyia longipalpis Saliva in Leishmaniasis. AB - When an haematophagous sand fly vector insect bites a vertebrate host, it introduces its mouthparts into the skin and lacerates blood vessels, forming a hemorrhagic pool which constitutes an intricate environment of cell interactions. In this scenario, the initial performance of host, parasite, and vector "authors" will heavily influence the course of Leishmania infection. Recent advances in vector-parasite-host interaction have elucidated "co-authors" and "new roles" not yet described. We review here the stimulatory role of Lutzomyia longipalpis saliva leading to inflammation and try to connect them in an early context of Leishmania infection. PMID- 22506100 TI - Heme oxygenase-1 induction and organic nitrate therapy: beneficial effects on endothelial dysfunction, nitrate tolerance, and vascular oxidative stress. AB - Organic nitrates are a group of very effective anti-ischemic drugs. They are used for the treatment of patients with stable angina, acute myocardial infarction, and chronic congestive heart failure. A major therapeutic limitation inherent to organic nitrates is the development of tolerance, which occurs during chronic treatment with these agents, and this phenomenon is largely based on induction of oxidative stress with subsequent endothelial dysfunction. We therefore speculated that induction of heme oxygenase-1 (HO-1) could be an efficient strategy to overcome nitrate tolerance and the associated side effects. Indeed, we found that hemin cotreatment prevented the development of nitrate tolerance and vascular oxidative stress in response to chronic nitroglycerin therapy. Vice versa, pentaerithrityl tetranitrate (PETN), a nitrate that was previously reported to be devoid of adverse side effects, displayed tolerance and oxidative stress when the HO-1 pathway was blocked pharmacologically or genetically by using HO-1(+/-) mice. Recently, we identified activation of Nrf2 and HuR as a principle mechanism of HO-1 induction by PETN. With the present paper, we present and discuss our recent and previous findings on the role of HO-1 for the prevention of nitroglycerin-induced nitrate tolerance and for the beneficial effects of PETN therapy. PMID- 22506103 TI - The Relationship between Physical Activity Variety and Objectively Measured Moderate-to-Vigorous Physical Activity Levels in Weight Loss Maintainers and Normal-Weight Individuals. AB - Given the importance of physical activity (PA) for weight control, identifying strategies to achieve higher PA levels is imperative. We hypothesized that performing a greater variety of self-reported moderate-to-vigorous activities (MVPAs) would relate to higher objectively measured MVPA minutes in two groups who were successfully maintaining their body weight: weight loss maintainers (WLM/n = 226) and normal-weight individuals (NW/n = 169). The Paffenbarger Questionnaire and RT3 accelerometer were used to determine variety/number of different MVPAs performed and MVPA minutes, respectively. The variety/number of different activities performed by WLM and NW was similar (1.8 +/- 1.2 versus 1.7 +/- 1.2, P = 0.52). Regression analyses showed that greater variety (P < 0.01) and WLM status (P < 0.05) were each positively related to greater MVPA minutes/day and meeting the >=250 MVPA minutes/week guideline for long-term weight maintenance. The association between greater variety and higher MVPA was similar in NW and WLM. Future studies should test whether variety can facilitate engagement in higher MVPA levels for more effective weight control. PMID- 22506105 TI - Intake of Nutritional Supplements among People Exercising in Gyms in Beirut City. AB - The use of nutritional supplements among exercisers in gyms has been never investigated in the Middle East. The aim of the current study was to assess the prevalence intake of nutritional supplements and the potential influencing factors among people exercising in gyms in Beirut city. In this cross-sectional study, 512 exercisers, aged between 20 and 50 years, were randomly selected from gyms. The intake of nutritional supplements was reported among 36.3% (95% confidence interval 32.2-40.5) of participants, with a weak presence of medical supervision. Patterns of supplement use differed by gender and age. Men and younger exercisers were found to focus on supplements associated with performance enhancement and muscle building, while women and older exercisers were more concerned with health-promoting products such as vitamins, minerals, and herbal supplements. An appropriate dissemination of accurate and scientifically sound information regarding the benefits and side effects of nutritional supplements is highly recommended in the sports environment in Beirut city. PMID- 22506104 TI - Dietary ganglioside reduces proinflammatory signaling in the intestine. AB - Gangliosides are integral to the structure and function of cell membranes. Ganglioside composition of the intestinal brush border and apical surface of the colon influences numerous cell processes including microbial attachment, cell division, differentiation, and signaling. Accelerated catabolism of ganglioside in intestinal disease results in increased proinflammatory signaling. Restoring proper structure and function to the diseased intestine can resolve inflammation, increase resistance to infection, and improve gut integrity to induce remission of conditions like necrotizing enterocolitis (NEC) and Crohn's disease (CD). Maintaining inactive state of disease may be achieved by reducing the rate that gangliosides are degraded or by increasing intake of dietary ganglioside. Collectively, the studies outlined in this paper indicate that the amount of gangliosides GM3 and GD3 in intestinal mucosa is decreased with inflammation, low level of GM3 is associated with higher production of proinflammatory signals, and ganglioside content of intestinal mucosa can be increased by dietary ganglioside. PMID- 22506106 TI - The impact of herbal drug use on adverse drug reaction profiles of patients on antiretroviral therapy in zimbabwe. AB - Background. The main objective was to determine the impact of herbal drug use on adverse drug reactions in patients on antiretroviral therapy (ART). Methodology. Patients receiving first-line ART from the national roll-out program participated in this cross-sectional study. Participants were interviewed and a data collection sheet was used to collect information from the corresponding medical record. Results. The majority (98.2%) of participants were using at least one herbal drug together with ART. The most common herbal remedies used were Allium Sativum (72.7%), Bidens pilosa (66.0%), Eucalyptus globulus (52.3%), Moringa oleifera (44.1%), Lippia javanica (36.3%), and Peltoforum africanum (34.3%). Two indigenous herbs, Musakavakadzi (OR = 0.25; 95% CI 0.076-0.828) and Peltoforum africanum (OR = 0.495; 95% CI 0.292-0.839) reduced the occurrence of adverse drug events. Conclusions. The use of herbal drugs is high in the HIV-infected population and there is need for pharmacovigilance programs to recognize the role they play in altering ADR profiles. PMID- 22506107 TI - Unprotected Sex with Injecting Drug Users among Iranian Female Sex Workers: Unhide HIV Risk Study. AB - Purpose. To assess the prevalence and associated factors of unprotected sex with injecting drug users (IDUs) among a sample of female sex workers (FSWs) in Iran. Methods. This cross-sectional study included 144 FSWs who were interviewed as a part of Unhide HIV Risk Study, a national behavioral survey focusing on various high-risk populations, including IDUs, FSWs, and Men who have Sex with Men (MSMs) in 2009. The survey was conducted in eight provinces in Iran using respondent driven sampling. Participants' sociodemographic status, HIV knowledge, and HIV attitude were analyzed via logistic regression to determine the predictors of unprotected sex with IDU(s) during the past month. Results. Nineteen percent of FSWs reported at least one occasion of unprotected sex with IDU(s) in the month preceding the study. Higher educational level (OR = -0.653, 95%CI = -1.192 to 0.115), perceived HIV risk (OR = -1.047, 95%CI = -2.076 to -0.019), and perceived family intimacy during childhood (OR = -1.104, 95%CI = -1.957 to -0.251) were all independently associated with lower odds of having unprotected sex with IDU(s) in the month preceding the study. Age, marital status, living condition, HIV knowledge, and perceived behavioral control did not affect the odds of FSWs having sex with IDUs. Conclusion. Perceived HIV risk, which is a modifiable factor, seems to be a promising target for harm reduction interventions amongst Iranian female sex workers. Data presented here may aid in reducing or eliminating the role of sex workers as a bridge for HIV transmission from IDUs to the general population in Iran. PMID- 22506108 TI - Eryptotic phenotype in chronic myeloid leukemia: contribution of neutrophilic cathepsin g. AB - In pathological conditions with concurrent neutrophilia, modifications of erythrocyte membrane proteins are reported. In chronic myeloid leukemia (CML), a myeloproliferative disease wherein neutrophilia is accompanied by enhanced erythrophagocytosis, we report for the first time excessive cleavage of erythrocyte band 3. Distinct fragments of band 3 serve as senescent cell antigens leading to erythrophagocytosis. Using immunoproteomics, we report the identification of immunogenic 43 kDa fragment of band 3 in 68% of CML samples compared to their detection in only 38% of healthy individuals. Thus, excessive fragmentation of band 3 in CML, detected in our study, corroborated with the eryptotic phenotype. We demonstrate the role of neutrophilic cathepsin G, detected as an immunogen on erythrocyte membrane, in band 3 cleavage. Cathepsin G from serum adsorbs to the erythrocyte membrane to mediate cleavage of band 3 and therefore contribute to the eryptotic phenotype in CML. PMID- 22506109 TI - Prevalence of anemia and risk of adverse bleeding effect of drugs: implication for therapy. AB - This study aimed to evaluate the progress in reduction of prevalence of anemia in rural Australia. It also investigates the prevalence of hypoviscosity in anaemia with a view to determine the fraction of anaemic patients at risk of drug inducible exacerbation of anemia. Archived clinical pathology data (N = 130, 354) for the period of 1999 to 2008 were utilized. The prevalence of anemia and hypoviscosity was evaluated by working out (i) the number that fell within anemia definition as a percentage of the population and (ii) the number that fell within hypoviscosity definition as a percentage of anemic patients. The prevalence in anemic diabetes and dyslipidaemia was further determined. There was progressive reduction in anemia from 6.1% to 3.2% over the ten years period. Prevalence of anemia is statistically significantly higher in males than in females (P < 0.0001), but protein level is lower in anemic females than in anemic males (P < 0.01). The results further show that up to 75% of anemic patients may benefit from NSAID or salicylates. This paper highlights differences between genders. It suggests more concerted effort in men's health and speculates a new factor to investigate in women's health. PMID- 22506111 TI - Age-related loss of muscle mass and strength. AB - Age-related muscle wasting and increased frailty are major socioeconomic as well as medical problems. In the quest to extend quality of life it is important to increase the strength of elderly people sufficiently so they can carry out everyday tasks and to prevent them falling and breaking bones that are brittle due to osteoporosis. Muscles generate the mechanical strain that contributes to the maintenance of other musculoskeletal tissues, and a vicious circle is established as muscle loss results in bone loss and weakening of tendons. Molecular and proteomic approaches now provide strategies for preventing age related muscle wasting. Here, attention is paid to the role of the GH/IGF-1 axis and the special role of the IGFI-Ec (mechano growth factor/MGF) which is derived from the IGF-I gene by alternative splicing. During aging MGF levels decline but when administered MGF activates the muscle satellite (stem) cells that "kick start" local muscle repair and induces hypertrophy. PMID- 22506110 TI - Role of Uropathogenic Escherichia coli Virulence Factors in Development of Urinary Tract Infection and Kidney Damage. AB - Uropathogenic Escherichia coli (UPEC) is a causative agent in the vast majority of urinary tract infections (UTIs), including cystitis and pyelonephritis, and infectious complications, which may result in acute renal failure in healthy individuals as well as in renal transplant patients. UPEC expresses a multitude of virulence factors to break the inertia of the mucosal barrier. In response to the breach by UPEC into the normally sterile urinary tract, host inflammatory responses are triggered leading to cytokine production, neutrophil influx, and the exfoliation of infected bladder epithelial cells. Several signaling pathways activated during UPEC infection, including the pathways known to activate the innate immune response, interact with calcium-dependent signaling pathways. Some UPEC isolates, however, might possess strategies to delay or suppress the activation of components of the innate host response in the urinary tract. Studies published in the recent past provide new information regarding how virulence factors of uropathogenic E. coli are involved in activation of the innate host response. Despite numerous host defense mechanisms, UPEC can persist within the urinary tract and may serve as a reservoir for recurrent infections and serious complications. Presentation of the molecular details of these events is essential for development of successful strategies for prevention of human UTIs and urological complications associated with UTIs. PMID- 22506113 TI - Aging Phenotypes of Common Marmosets (Callithrix jacchus). AB - Characterizing the phenotypic changes associated with aging in a short-lived primate is necessary in order to develop better translational models for human health, aging, and disease research. A population of conventionally housed marmoset monkeys was assessed to determine if phenotypes of body composition, hematology, and morphometrical measures were associated with age or risk of death. We found that the cause of mortality in older marmosets was more likely to be due to cardiac and chronic kidney disease than in younger marmosets. Older marmosets have decreased fat mass, morphometric measures, and serum albumin. Older marmosets are more likely to show a modified posture while at rest and this modified posture was significantly associated with an increased risk of imminent death. These assessments provide an initial definition of aged health in marmosets and a base for future translational aging research with this species. PMID- 22506112 TI - Nutrition and sarcopenia: a review of the evidence and implications for preventive strategies. AB - Prevention of age-related losses in muscle mass and strength is key to protecting physical capability in older age and enabling independent living. To develop preventive strategies, a better understanding is needed of the lifestyle factors that influence sarcopenia and the mechanisms involved. Existing evidence indicates the potential importance of diets of adequate quality, to ensure sufficient intakes of protein, vitamin D, and antioxidant nutrients. Although much of this evidence is observational, the prevalence of low nutrient intakes and poor status among older adults make this a current concern. However, as muscle mass and strength in later life are a reflection of both the rate of muscle loss and the peak attained in early life, efforts to prevent sarcopenia also need to consider diet across the lifecourse and the potential effectiveness of early interventions. Optimising diet and nutrition throughout life may be key to preventing sarcopenia and promoting physical capability in older age. PMID- 22506114 TI - Endoplasmic Reticulum Stress-Associated Lipid Droplet Formation and Type II Diabetes. AB - Diabetes mellitus (DM), a metabolic disorder characterized by hyperglycemia, is caused by insufficient insulin production due to excessive loss of pancreatic beta cells (type I diabetes) or impaired insulin signaling due to peripheral insulin resistance (type II diabetes). Pancreatic beta cell is the only insulin secreting cell type that has highly developed endoplasmic reticulum (ER) to cope with high demands of insulin synthesis and secretion. Therefore, ER homeostasis is crucial to the proper function of insulin signaling. Accumulating evidence suggests that deleterious ER stress and excessive intracellular lipids in nonadipose tissues, such as myocyte, cardiomyocyte, and hepatocyte, cause pancreatic beta-cell dysfunction and peripheral insulin resistance, leading to type II diabetes. The excessive deposition of lipid droplets (LDs) in specialized cell types, such as adipocytes, hepatocytes, and macrophages, has been found as a hallmark in ER stress-associated metabolic diseases, including obesity, diabetes, fatty liver disease, and atherosclerosis. However, much work remains to be done in understanding the mechanism by which ER stress response regulates LD formation and the pathophysiologic role of ER stress-associated LD in metabolic disease. This paper briefly summarizes the recent advances in ER stress-associated LD formation and its involvement in type II diabetes. PMID- 22506115 TI - Impaired caveolae function and upregulation of alternative endocytic pathways induced by experimental modulation of intersectin-1s expression in mouse lung endothelium. AB - Intersectin-1s (ITSN-1s), a protein containing five SH3 (A-E) domains, regulates via the SH3A the function of dynamin-2 (dyn2) at the endocytic site. ITSN-1s expression was modulated in mouse lung endothelium by liposome delivery of either a plasmid cDNA encoding myc-SH3A or a specific siRNA targeting ITSN-1 gene. The lung vasculature of SH3A-transduced and ITSN-1s- deficient mice was perfused with gold albumin (Au-BSA) to analyze by electron microscopy the morphological intermediates and pathways involved in transendothelial transport or with dinitrophenylated (DNP)-BSA to quantify by ELISA its transport. Acute modulation of ITSN-1s expression decreased the number of caveolae, impaired their transport, and opened the interendothelial junctions, while upregulating compensatory nonconventional endocytic/transcytotic structures. Chronic inhibition of ITSN-1s further increased the occurrence of nonconventional intermediates and partially restored the junctional integrity. These findings indicate that ITSN-1s expression is required for caveolae function and efficient transendothelial transport. Moreover, our results demonstrate that ECs are highly adapted to perform their transport function while maintaining lung homeostasis. PMID- 22506116 TI - Reduced TCA Flux in Diabetic Myotubes: Determined by Single Defects? AB - The diabetic phenotype is complex, requiring elucidation of key initiating defects. Diabetic myotubes express a primary reduced tricarboxylic acid (TCA) cycle flux but at present it is unclear in which part of the TCA cycle the defect is localised. In order to localise the defect we studied ATP production in isolated mitochondria from substrates entering the TCA cycle at various points. ATP production was measured by luminescence with or without concomitant ATP utilisation by hexokinase in mitochondria isolated from myotubes established from eight lean and eight type 2 diabetic subjects. The ATP production of investigated substrate combinations was significantly reduced in mitochondria isolated from type 2 diabetic subjects compared to lean. However, when ATP synthesis rates at different substrate combinations were normalized to the corresponding individual pyruvate-malate rate, there was no significant difference between groups. These results show that the primary reduced TCA cycle flux in diabetic myotubes is not explained by defects in specific part of the TCA cycle but rather results from a general downregulation of the TCA cycle. PMID- 22506117 TI - Urgent Carotid Surgery: Is It Still out of Debate? AB - Patients with symptomatic tight carotid stenosis have an increased short-time risk of stroke and an increased long-term risk of ischaemic vascular events compared with the general population. The aim of this study is to assess the safety, efficacy, and limitations of urgent CEA or CAS, in patients with carotid stenosis greater than 70% and clinically characterized by recurrent TIA or brain damage following a stroke (<2.5 cm). This study involved 28 patients divided into two groups. Group A consisted of sixteen patients who had undergone CEA, and group B consisted of twelve patients who had undergone CAS. Primary endpoints were mortality, neurological morbidity (by NIHSS) and postoperative hemorrhagic cerebral conversion, at 30 days. Ten patients (62.5%) of group A experienced an improvement in their initial neurological deficit while in 4 cases (26%) the deficit remained stable. Two cases of neurologic mortality are presented. At 1 month, 9 patients (75%) of group B experienced an improvement in their initial neurological deficit while 3 patients (25%) had a neurological impairment. Urgent or deferred surgical or endovascular treatment have a satisfactory outcome considering the profile in very high-risk patient population. Otherwise in selected patients CEA seems to be preferred to CAS. PMID- 22506118 TI - Evaluation of serum biomarkers for patients at increased risk of stroke. AB - Early recognition of vulnerable patients is an important issue for stroke prevention. In our study, a multiscore analysis of various biomarkers was performed to evaluate its superiority over the analysis of single factors. Study subjects (n = 110) were divided into four groups: asymptomatic patients with stable (n = 25) and unstable (n = 36) plaques and symptomatic patients with stable (n = 13) and unstable (n = 36) plaques. Serum levels of MMP-1, -2, -3, -7, -8, -9, TIMP-1, -2, TNF-alpha, IL-1b, and IL-6, -8, -10, -12 were measured. Multi score analysis was performed using multiple receiver operating characteristics (ROC) and determination of appropriate cutoff values. Significant differences between the groups were observed for MMP-1, -7, -9 and TIMP-1 in serum of the study subjects (P < 0.05). Multiple biomarker analysis led to a significant increase in the AUC (area under curve). In case of plaque instability, positive predictive value (PPV) for up to 86.4% could be correctly associated with vulnerable plaques. Thus, multiscore analysis might be preferable than the use of single biomarkers. PMID- 22506119 TI - The treatment of breast cancer using liposome technology. AB - Liposome-based chemotherapeutics used in the treatment of breast cancer can in principle enhance the therapeutic index of otherwise unencapsulated anticancer drugs. This is partially attributed to the fact that encapsulation of cytotoxic agents within liposomes allows for increased concentrations of the drug to be delivered to the tumor site. In addition, the presence of the phospholipid bilayer prevents the encapsulated active form of the drug from being broken down in the body prior to reaching tumor tissue and also serves to minimize exposure of the drug to healthy sensitive tissue. While clinically approved liposome-based chemotherapeutics such as Doxil have proven to be quite effective in the treatment of breast cancer, significant challenges remain involving poor drug transfer between the liposome and cancerous cells. In this review, we discuss the recent advancements made in the development of liposome-based chemotherapeutics with respect to improved drug transfer for use in breast cancer therapy. PMID- 22506120 TI - Effects of atelocollagen formulation containing oligonucleotide on endothelial permeability. AB - Atelocollagen is a major animal protein that is used as a highly biocompatible biomaterial. To date, atelocollagen has been used as an effective drug delivery technology to sustain the release of antitumor proteins and to enhance the antitumor activity of oligonucleotides in in vivo models. However, the biological effects of this technology are not fully understood. In the present study, we investigated the effects of atelocollagen on endothelial paracellular barrier function. An atelocollagen formulation containing oligonucleotides specifically increased the permeability of two types of endothelial cells, and the change was dependent on the molecular size, structure of the oligonucleotides used and the concentrations of the oligonucleotide and atelocollagen in the formulation. An immunohistochemical examination revealed that the formulation had effects on the cellular skeleton and intercellular structure although it did not affect the expression of adherens junction or tight junction proteins. These changes were induced through p38 MAP kinase signaling. It is important to elucidate the biological functions of atelocollagen in order to be able to exploit its drug delivery properties. PMID- 22506121 TI - Nanotechnology in medicine: from inception to market domination. AB - Born from the marriage of nanotechnology and medicine, nanomedicine is set to bring advantages in the fight against unmet diseases. The field is recognized as a global challenge, and countless worldwide research and business initiatives are in place to obtain a significant market position. However, nanomedicine belongs to those emerging sectors in which business development methods have not been established yet. Open issues include which type of business model best fits these companies and which strategies would lead them to sustained growth. This paper describes the financial and strategic decisions by nanomedicine start-ups to reach the market successfully, obtain a satisfactory market share, and build and maintain a competitive defendable advantage. Walking nanomedicine-product from the hands of the inventor to those of the doctor, we explored the technological transfer process, which connects laboratories or research institutions to the marketplace. The process involves detailed analysis to evaluate the potentials of end-products, and researches to identify market segment, size, structure, and competitors, to ponder a possible market entry and the market share that managers can realistically achieve at different time horizons. Attracting funds is crucial but challenging. However, investors are starting to visualize the potentials of this field, magnetized by the business of "nano." PMID- 22506122 TI - Design and characterization of a silk-fibroin-based drug delivery platform using naproxen as a model drug. AB - The objective of this proof-of-concept study was to develop a platform for controlled drug delivery based on silk fibroin (SF) and to explore the feasibility of using SF in oral drug delivery. The SF-containing matrixes were prepared via spray-drying and film casting, and the release profile of the model drug naproxen sodium was evaluated. Attenuated total reflectance Fourier transform infrared spectroscopy (FTIR) has been used to observe conformational changes in SF- and drug-containing compositions. SF-based films, spray-dried microparticles, and matrixes loaded with naproxen were prepared. Both FTIR spectra and in vitro dissolution data demonstrated that SF beta-sheet conformation regulates the release profile of naproxen. The controlled release characteristics of the SF-containing compositions were evaluated as a function of SF concentration, temperature, and exposure to dehydrating solvents. The results suggest that SF may be an attractive polymer for use in controlled drug delivery systems. PMID- 22506123 TI - Successfully improving ocular drug delivery using the cationic nanoemulsion, novasorb. AB - Topical ophthalmic delivery of active ingredients can be achieved using cationic nanoemulsions. In the last decade, Novagali Pharma has successfully developed and marketed Novasorb, an advanced pharmaceutical technology for the treatment of ophthalmic diseases. This paper describes the main steps in the development of cationic nanoemulsions from formulation to evaluation in clinical trials. A major challenge of the formulation work was the selection of a cationic agent with an acceptable safety profile that would ensure a sufficient ocular surface retention time. Then, toxicity and pharmacokinetic studies were performed showing that the cationic emulsions were safe and well tolerated. Even in the absence of an active ingredient, cationic emulsions were observed in preclinical studies to have an inherent benefit on the ocular surface. Moreover, clinical trials demonstrated the efficacy and safety of cationic emulsions loaded with cyclosporine A in patients with dry eye disease. Ongoing studies evaluating latanoprost emulsion in patients with ocular surface disease and glaucoma suggest that the beneficial effects on reducing ocular surface damage may also extend to this patient population. The culmination of these efforts has been the marketing of Cationorm, a preservative-free cationic emulsion indicated for the symptomatic treatment of dry eye. PMID- 22506125 TI - Adsorption and desorption of bioactive proteins on hydroxyapatite for protein delivery systems. AB - Hydroxyapatite (HA) is a precursor of bone and has been studied as a biomaterial. We attempted HA to apply to protein delivery systems. In this study, the association and dissociation properties of two types of bioactive proteins, cytochrom c and insulin, to HA were investigated. Cytochrom c was less associated with HA than insulin, which was easily released from it. However, the release of insulin from HA was slow. Insulin was released from HA at pH 7.4 more rapidly than at pH 3. The association and dissociation properties might be influenced by the size, solubility and net charge of protein. HA is a potential protein carrier with controlled release. PMID- 22506124 TI - PLGA Nanoparticles for Ultrasound-Mediated Gene Delivery to Solid Tumors. AB - This paper focuses on novel approaches in the field of nanotechnology-based carriers utilizing ultrasound stimuli as a means to spatially target gene delivery in vivo, using nanoparticles made with either poly(lactic-co-glycolic acid) (PLGA) or other polymers. We specifically discuss the potential for gene delivery by particles that are echogenic (amenable to destruction by ultrasound) composed either of polymers (PLGA, polystyrene) or other contrast agent materials (Optison, SonoVue microbubbles). The use of ultrasound is an efficient tool to further enhance gene delivery by PLGA or other echogenic particles in vivo. Echogenic PLGA nanoparticles are an attractive strategy for ultrasound-mediated gene delivery since this polymer is currently approved by the US Food and Drug Administration for drug delivery and diagnostics in cancer, cardiovascular disease, and also other applications such as vaccines and tissue engineering. This paper will review recent successes and the potential of applying PLGA nanoparticles for gene delivery, which include (a) echogenic PLGA used with ultrasound to enhance local gene delivery in tumors or muscle and (b) PLGA nanoparticles currently under development, which could benefit in the future from ultrasound-enhanced tumor targeted gene delivery. PMID- 22506126 TI - Towards noninvasive detection of oesophageal varices. AB - Current guidelines recommend that all cirrhotic patients should undergo screening endoscopy at diagnosis to identify patients with varices at high risk of bleeding who will benefit from primary prophylaxis. This approach places a heavy burden upon endoscopy units and the repeated testing over time may have a detrimental effect on patient compliance. Noninvasive identification of patients at highest risk for oesophageal varices would limit investigation to those most likely to benefit. Upper GI endoscopy is deemed to be the gold standard against which all other tests are compared, but is not without its limitations. Multiple studies have been performed assessing clinical signs and variables relating to liver function, variables relating to liver fibrosis, and also to portal hypertension and hypersplenism. Whilst some tests are clearly preferable to patients, none appear to be as accurate as upper GI endoscopy in the diagnosis of oesophageal varices. The search for noninvasive tests continues. PMID- 22506127 TI - HIV-Antiretroviral Therapy Induced Liver, Gastrointestinal, and Pancreatic Injury. AB - The present paper describes possible connections between antiretroviral therapies (ARTs) used to treat human immunodeficiency virus (HIV) infection and adverse drug reactions (ADRs) encountered predominantly in the liver, including hypersensitivity syndrome reactions, as well as throughout the gastrointestinal system, including the pancreas. Highly active antiretroviral therapy (HAART) has a positive influence on the quality of life and longevity in HIV patients, substantially reducing morbidity and mortality in this population. However, HAART produces a spectrum of ADRs. Alcohol consumption can interact with HAART as well as other pharmaceutical agents used for the prevention of opportunistic infections such as pneumonia and tuberculosis. Other coinfections that occur in HIV, such as hepatitis viruses B or C, cytomegalovirus, or herpes simplex virus, further complicate the etiology of HAART-induced ADRs. The aspect of liver pathology including liver structure and function has received little attention and deserves further evaluation. The materials used provide a data-supported approach. They are based on systematic review and analysis of recently published world literature (MedLine search) and the experience of the authors in the specified topic. We conclude that therapeutic and drug monitoring of ART, using laboratory identification of phenotypic susceptibilities, drug interactions with other medications, drug interactions with herbal medicines, and alcohol intake might enable a safer use of this medication. PMID- 22506128 TI - Lipid droplet accumulation and impaired fat efflux in polarized hepatic cells: consequences of ethanol metabolism. AB - Steatosis, an early manifestation in alcoholic liver disease, is associated with the accumulation of hepatocellular lipid droplets (LDs). However, the role ethanol metabolism has in LD formation and turnover remains undefined. Here, we assessed LD dynamics following ethanol and oleic acid treatment to ethanol metabolizing WIF-B cells (a hybrid of human fibroblasts (WI 38) and Fao rat hepatoma cells). An OA dose-dependent increase in triglyceride and stained lipids was identified which doubled (P < 0.05) in the presence of ethanol. This effect was blunted with the inclusion of an alcohol metabolism inhibitor. The ethanol/ OA combination also induced adipophilin, LD coat protein involved in the attenuation of lipolysis. Additionally, ethanol treatment resulted in a significant reduction in lipid efflux. These data demonstrate that the metabolism of ethanol in hepatic cells is related to LD accumulation, impaired fat efflux, and enhancements in LD-associated proteins. These alterations in LD dynamics may contribute to ethanol-mediated defects in hepatocellular LD regulation and the formation of steatosis. PMID- 22506129 TI - Simvastatin blocks blood-brain barrier disruptions induced by elevated cholesterol both in vivo and in vitro. AB - Background. Hypercholesterolemia and disruptions of the blood brain barrier (BBB) have been implicated as underlying mechanisms in the pathogenesis of Alzheimer's disease (AD). Simvastatin therapy may be of benefit in treating AD; however, its mechanism has not been yet fully understood. Objective. To explore whether simvastatin could block disruption of BBB induced by cholesterol both in vivo and in vitro. Methods. New Zealand rabbits were fed cholesterol-enriched diet with or without simvastatin. Total cholesterol of serum and brain was measured. BBB dysfunction was evaluated. To further test the results in vivo, rat brain microvascular endothelial cells (RBMECs) were stimulated with cholesterol in the presence/absence of simvastatin in vitro. BBB disruption was evaluated. Results. Simvastatin blocked cholesterol-rich diet induced leakage of Evan's blue dye. Cholesterol content in the serum was affected by simvastatin, but not brain cholesterol. Simvastatin blocked high-cholesterol medium-induced decrease in TEER and increase in transendothelial FITC-labeled BSA Passage in RBMECs. Conclusions. The present study firstly shows that simvastatin improves disturbed BBB function both in vivo and in vitro. Our data provide that simvastatin may be useful for attenuating disturbed BBB mediated by hypercholesterolemia. PMID- 22506130 TI - Specific EEG changes associated with atrophy of hippocampus in subjects with mild cognitive impairment and Alzheimer's disease. AB - We evaluated the association between hippocampal atrophy and increase of the EEG markers alpha3/alpha2 relative power ratio in mild cognitive impairment (MCI) and Alzheimer's disease patients. Seventy-nine subjects with MCI and 11 patients with AD underwent EEG recording and MRI scan. The MCI group was subdivided in three subgroups according to growing hippocampal atrophy. The groups were characterized by alpha3/alpha2 relative power ratio. In AD patients group mapped hippocampal regions were computed and related with alpha3/alpha2 power ratio. Results show that the increase of alpha3/alpha2 power ratio is correlated with atrophy of hippocampus both in MCI and in Alzheimer's disease patients. This finding confirms the possible diagnostic role of EEG markers as diagnostic and prognostic factors in patient with prodromal and declared Alzheimer's disease. PMID- 22506131 TI - The amyloid precursor protein intracellular domain-fe65 multiprotein complexes: a challenge to the amyloid hypothesis for Alzheimer's disease? AB - Since its proposal in 1994, the amyloid cascade hypothesis has prevailed as the mainstream research subject on the molecular mechanisms leading to the Alzheimer's disease (AD). Most of the field had been historically based on the role of the different forms of aggregation of beta-amyloid peptide (Abeta). However, a soluble intracellular fragment termed amyloid precursor protein (APP) intracellular domain (AICD) is produced in conjunction with Abeta fragments. This peptide had been shown to be highly toxic in both culture neurons and transgenic mice models. With the advent of this new toxic fragment, the centerpiece for the ethiology of the disease may be changed. This paper discusses the potential role of multiprotein complexes between the AICD and its adapter protein Fe65 and how this could be a potentially important new agent in the neurodegeneration observed in the AD. PMID- 22506132 TI - Alzheimer's disease and the amyloid cascade hypothesis: a critical review. AB - Since 1992, the amyloid cascade hypothesis has played the prominent role in explaining the etiology and pathogenesis of Alzheimer's disease (AD). It proposes that the deposition of beta-amyloid (Abeta) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs), neuronal cell death, and ultimately dementia. While there is substantial evidence supporting the hypothesis, there are also limitations: (1) SP and NFT may develop independently, and (2) SPs and NFTs may be the products rather than the causes of neurodegeneration in AD. In addition, randomized clinical trials that tested drugs or antibodies targeting components of the amyloid pathway have been inconclusive. This paper provides a critical overview of the evidence for and against the amyloid cascade hypothesis in AD and provides suggestions for future directions. PMID- 22506134 TI - Key Evolutionary Transformations in Homo sapiens. PMID- 22506133 TI - Centella asiatica Extract Improves Behavioral Deficits in a Mouse Model of Alzheimer's Disease: Investigation of a Possible Mechanism of Action. AB - Centella asiatica (CA), commonly named gotu kola, is an Ayurvedic herb used to enhance memory and nerve function. To investigate the potential use of CA in Alzheimer's disease (AD), we examined the effects of a water extract of CA (GKW) in the Tg2576 mouse, a murine model of AD with high beta-amyloid burden. Orally administered GKW attenuated beta-amyloid-associated behavioral abnormalities in these mice. In vitro, GKW protected SH-SY5Y cells and MC65 human neuroblastoma cells from toxicity induced by exogenously added and endogenously generated beta amyloid, respectively. GKW prevented intracellular beta-amyloid aggregate formation in MC65 cells. GKW did not show anticholinesterase activity or protect neurons from oxidative damage and glutamate toxicity, mechanisms of current AD therapies. GKW is rich in phenolic compounds and does not contain asiatic acid, a known CA neuroprotective triterpene. CA thus offers a unique therapeutic mechanism and novel active compounds of potential relevance to the treatment of AD. PMID- 22506135 TI - The Microbiological Context of HIV Resistance: Vaginal Microbiota and Mucosal Inflammation at the Viral Point of Entry. AB - Immune activation is increasingly recognized as a critical element of HIV infection and pathogenesis, causing expansion of virus founder populations at the mucosal port of entry and eventual exhaustion of cellular immune effectors. HIV susceptibility is well known to be influenced by concurrent sexually transmitted infections; however, the role of commensal vaginal microbiota is poorly characterized. Bacterial vaginosis (BV) is a risk factor for HIV acquisition in studies worldwide; however, the etiology of BV remains enigmatic, and the mechanisms by which BV increases HIV susceptibility are not fully defined. A model of how vaginal microbiota influences HIV transmission is considered in the context of a well-established cohort of HIV-exposed seronegative (HESN) commercial sex workers (CSW) in Nairobi, Kenya, many of whom have increased levels of anti-inflammatory factors in vaginal secretions and reduced peripheral immune activation (immune quiescence). Elucidation of the relationship between complex microbial communities and inflammatory mucosal responses underlying HIV infection should be a priority for future prevention-focussed research. PMID- 22506136 TI - Novel Pharmacological Approaches for Inflammatory Bowel Disease: Targeting Key Intracellular Pathways and the IL-23/IL-17 Axis. AB - This review identifies possible pharmacological targets for inflammatory bowel disease (IBD) within the IL-23/IL-17 axis. Specifically, there are several targets within the IL-23/IL-17 pathways for potential pharmacological intervention with antibodies or small molecule inhibitors. These targets include TL1A (tumor necrosis factor-like molecule), DR3 (death receptor 3), IL-23, IL-17 and the receptors for IL-23 and IL-17. As related to IBD, there are also other novel pharmacological targets. These targets include inhibiting specific immunoproteasome subunits, blocking a key enzyme in sphingolipid metabolism (sphingosine kinase), and modulating NF-kappaB/STAT3 interactions. Several good approaches exist for pharmacological inhibition of key components in the IL-23 and IL-17 pathways. These approaches include specific monoclonal antibodies to TL1A, IL-17 receptor, Fc fusion proteins, specific antibodies to IL-17F, and small molecule inhibitors of IL-17 like Vidofludimus. Also, other potential approaches for targeted drug development in IBD include specific chemical inhibitors of SK, specific small molecule inhibitors directed against catalytic subunits of the immunoproteasome, and dual inhibitors of the STAT3 and NF-kappaB signal transduction systems. In the future, well-designed preclinical studies are still needed to determine which of these pharmacological approaches will provide drugs with the best efficacy and safety profiles for entrance into clinical trials. PMID- 22506137 TI - Ovarian Cancer Is an Imported Disease: Fact or Fiction? AB - The cell of origin of ovarian cancer has been long debated. The current paradigm is that epithelial ovarian cancer (EOC) arises from the ovarian surface epithelium (OSE). OSE is composed of flat, nondescript cells more closely resembling the mesothelium lining the peritoneal cavity, with which it is continuous, rather than the various histologic types of ovarian carcinoma (serous, endometrioid, and clear cell carcinoma), which have a Mullerian phenotype. Accordingly, it has been argued that the OSE undergoes a process termed "metaplasia" to account for this profound morphologic transformation. Recent molecular and clinicopathologic studies not only have failed to support this hypothesis but also have provided evidence that EOC stems from Mullerian derived extraovarian cells that involve the ovary secondarily, thereby calling into question the very existence of primary EOC. This new model of ovarian carcinogenesis proposes that fallopian tube epithelium (benign or malignant) implants on the ovary to give rise to both high-grade and low-grade serous carcinomas, and that endometrial tissue implants on the ovary and produces endometriosis, which can undergo malignant transformation into endometrioid and clear cell carcinoma. Thus, ultimately EOC is not ovarian in origin but rather is secondary, and it is logical to conclude that the only true primary ovarian neoplasms are germ cell and gonadal stromal tumors analogous to tumors in the testis. If this new model is confirmed, it has profound implications for the early detection and treatment of "ovarian cancer." PMID- 22506138 TI - The effect of virtual reality training on unilateral spatial neglect in stroke patients. AB - OBJECTIVE: To investigate the effect of virtual reality training on unilateral spatial neglect in stroke patients. METHOD: Twenty-four stroke patients (14 males and 10 females, mean age=64.7) who had unilateral spatial neglect as a result of right hemisphere stroke were recruited. All patients were randomly assigned to either the virtual reality (VR) group (n=12) or the control group (n=12). The VR group received VR training, which stimulated the left side of their bodies. The control group received conventional neglect therapy such as visual scanning training. Both groups received therapy for 30 minutes a day, five days per week for three weeks. Outcome measurements included star cancellation test, line bisection test, Catherine Bergego scale (CBS), and the Korean version of modified Barthel index (K-MBI). These measurements were taken before and after treatment. RESULTS: There were no significant differences in the baseline characteristics and initial values between the two groups. The changes in star cancellation test results and CBS in the VR group were significantly higher than those of the control group after treatment. The changes in line bisection test score and the K MBI in the VR group were not statistically significant. CONCLUSION: This study suggests that virtual reality training may be a beneficial therapeutic technique on unilateral spatial neglect in stroke patients. PMID- 22506139 TI - The synergic effects of mirror therapy and neuromuscular electrical stimulation for hand function in stroke patients. AB - OBJECTIVE: To investigate the synergic effects of mirror therapy and neuromuscular electrical stimulation (NMES) for hand function in stroke patients. METHOD: Sixty patients with hemiparesis after stroke were included (41 males and 19 females, average age 63.3 years). Twenty patients had NMES applied and simultaneously underwent mirror therapy. Twenty patients had NMES applied only, and twenty patients underwent mirror therapy only. Each treatment was done five days per week, 30 minutes per day, for three weeks. NMES was applied on the surface of the extensor digitorum communis and extensor pollicis brevis for open hand motion. Muscle tone, Fugl-Meyer assessment, and power of wrist and hand were evaluated before and after treatment. RESULTS: There were significant improvements in the Fugl-Meyer assessment score in the wrist, hand and coordination, as well as power of wrist and hand in all groups after treatment. The mirror and NMES group showed significant improvements in the Fugl-Meyer scores of hand, wrist, coordination and power of hand extension compared to the other groups. However, the power of hand flexion, wrist flexion, and wrist extension showed no significant differences among the three groups. Muscle tone also showed no significant differences in the three groups. CONCLUSION: Our results showed that there is a synergic effect of mirror therapy and NMES on hand function. Therefore, a hand rehabilitation strategy combined with NMES and mirror therapy may be more helpful for improving hand function in stroke patients than NMES or mirror therapy only. PMID- 22506140 TI - Electrical Stimulation of the Suprahyoid Muscles in Brain-injured Patients with Dysphagia: A Pilot Study. AB - OBJECTIVE: To investigate the therapeutic effects of repetitive electrical stimulation of the suprahyoid muscles in brain-injured patients with dysphagia. METHOD: Twenty-eight brain-injured patients who showed reduced laryngeal elevation and supraglottic penetration or subglottic aspiration during a videofluoroscopic swallowing study (VFSS) were selected. The patients received either conventional dysphagia management (CDM) or CDM with repetitive electrical stimulation of the suprahyoid muscles (ESSM) for 4 weeks. The videofluoroscopic dysphagia scale (VDS) using the VFSS and American Speech-Language-Hearing Association National Outcome Measurement System (ASHA NOMS) swallowing scale (ASHA level) was used to determine swallowing function before and after treatment. RESULTS: VDS scores decreased from 29.8 to 17.9 in the ESSM group, and from 29.2 to 16.6 in the CDM group. However, there was no significant difference between the groups (p=0.796). Six patients (85.7%) in the ESSM group and 14 patients (66.7%) in the CDM group showed improvement according to the ASHA level with no significant difference between the ESSM and CDM groups (p=0.633). CONCLUSION: Although repetitive neuromuscular electrical stimulation of the suprahyoid muscles did not further improve the swallowing function of dysphagia patients with reduced laryngeal elevation, more patients in the ESSM group showed improvement in the ASHA level than those in the CDM group. Further studies with concurrent controls and a larger sample group are required to fully establish the effects of repetitive neuromuscular electrical stimulation of the suprahyoid muscles in dysphagia patients. PMID- 22506142 TI - Bowel function in acute stroke patients. AB - OBJECTIVE: To investigate factors related to bowel function and colon motility in acute stroke patients. METHOD: Fifty-one stroke patients (29 males, mean age 63.4+/-13.6 years, onset 13.4+/-4.8 days) were recruited and divided into two groups: constipation (n=25) and non-constipation (n=26) groups. We evaluated the amount of intake, voiding function, concomitant swallowing problem and colon transit time (CTT) using radio-opaque markers for ascending, descending and rectosigmoid colons. The Adapted Patient Evaluation Conference System (APEC), Korean version of Modified Bathel Index (K-MBI) and Motricity Index (MI) were evaluated. RESULTS: The constipation group showed significantly prolonged CTT of ascending, descending and entire colon (p<0.05) and more severe swallowing problems (p=0.048). The APEC scale (2.65+/-1.44 vs 1.52+/-0.92, p=0.001), K-MBI scores (59.4+/-14.4 vs 28.0+/-24.3, p<0.001) and MI scores (69.1+/-22.3 vs 46.8+/ 25.9, p=0.001) of the constipation group were significantly lower compared to the non-constipation group. CONCLUSION: Our study demonstrated that bowel function in acute stroke patients was associated with functional status and swallowing function, indicating the need for intensive functional training in post-stroke constipation patients. PMID- 22506141 TI - Correlations between Pre-morbid Personality and Depression Scales in Stroke Patients. AB - OBJECTIVE: To investigate the correlation between pre-morbid personality and depression scales in patients with stroke. METHOD: The subjects of this study included 45 patients with stroke and their caregivers. We conducted an interview of patients with Beck Depression Inventory (BDI) and also evaluated general characteristic (age, sex, location of lesion, cause of stroke, duration of illness, educational background, history of medication for depression) and functional level. Caregivers were evaluated with Hamilton Rating Scale for Depression (HRSD) for depressive mood, with NEO-PI (Neuroticism, Extraversion and Openness Personality Inventory) for pre-morbid personality. The results of each questionnaire were analyzed in order to investigate their correlation. The results were statistically analyzed with independent t-test, ANOVA, and Pearson correlation test. RESULTS: The HRSD score of the caregivers had a significant correlation with the BDI score (p=0.001) of the patients. The BDI score correlated with Neuroticism (p=0.021) and the HRSD score also correlated with Neuroticism (p=0.015). There were no statistical correlation of depression with sex, age, case of stroke, location of lesion, duration of illness and functional level. CONCLUSION: Among pre-morbid personalities, neuroticism of NEO-PI is the only factor which is significantly correlated with depression scales in stroke patients. Evaluating pre-morbid personality can be helpful in predicting the depressive mood in stroke patients, so we may have early intervention for it. PMID- 22506143 TI - The effect and complication of botulinum toxin type a injection with serial casting for the treatment of spastic equinus foot. AB - OBJECTIVE: To identify the effect of serial casting combined with Botulinum toxin type A (BTX-A) injection on spastic equinus foot. METHOD: Twenty-nine children with cerebral palsy who had equinus foot were recruited from the outpatient clinic of Rehabilitation Medicine. The children were divided into 2 groups, one of which received serial casting after BTX-A injection, and the other which only received BTX-A injection. Serial casting started 3 weeks after the BTX-A injection, and was changed weekly for 3 times. Spasticity of the ankle joint was evaluated using the modified Ashworth scale (MAS), and the modified Tardieu scale (MTS). Gait pattern was measured using the physician's rating scale (PRS). RESULTS: The degree of ankle dorsiflexion and the MAS improved significantly until 12 weeks following the BTX-A injection in the serial casting group (p<0.001), while the BTX-A injection-only group improved until 6 weeks following injection (p<0.05). The combined group showed a significantly greater increase in the degree of dorsiflexion compared to the BTX-A injection-only group at post injection weeks 6 and 12 (p<0.05). Three children (11.5%) suffered from foot ulcers as a complication caused by the serial casting. CONCLUSION: Our study demonstrated that the effect of BTX-A injection with serial casting was superior and lasted longer than the effect of BTX-A injection only in patients with spastic equinus foot. We therefore recommend BTX-A injection with serial casting for the treatment of equinus foot. However, physicians must also consider the possible complications associated with serial casting. PMID- 22506144 TI - Reliability of visual classification of sagittal gait patterns in patients with bilateral spastic cerebral palsy. AB - OBJECTIVE: To investigate the reliability of inspection-based classification of sagittal gait patterns in children with bilateral spastic cerebral palsy (CP). METHOD: Video clip recordings of gait patterns and sagittal kinematic data obtained by a computerized motion analysis system from 91 patients with bilateral spastic CP were reviewed. The abnormal gait patterns were classified into 4 groups using the method described by Rodda et al. Visual observation-based classification (visual classification) was compared with classification by 3D analysis-based methods (3D classification). The reliabilities of visual classifications made by an experienced physician and a trainee physician were analyzed. RESULTS: The consistency of inspection-based gait classification using kinematic data analysis was demonstrated by an experienced physician (Kappa coefficient (k)=0.67, p<0.001). However, the consistency was low for the trainee physician (k=0.37, p<0.001). Group III (apparent equinus) was commonly confused with group IV (crouch gait) by the trainee physician, resulting in lower agreement for those two evaluation groups than for other patterns. Video observation showed low reliability in comparisons made between the experienced and the trainee physician (k=0.37, p<0.001). CONCLUSION: There was substantial agreement of gait classification between video observation and kinematic data analysis by the experienced physician, but not by the trainee physician. Low reliability was also demonstrated for inspection-based gait classification. PMID- 22506145 TI - The thickness of the sternocleidomastoid muscle as a prognostic factor for congenital muscular torticollis. AB - OBJECTIVE: To examine whether the thickness of the sternocleidomastoid muscle (SCM) could be used as a prognostic factor for congenital muscular torticollis (CMT). METHOD: This was a retrospective study conducted in a pediatric rehabilitation service at a tertiary medical center. Fifty-two children who met the following inclusion criteria were included: 1) children who were 3 month-old or younger, 2) children diagnosed with CMT, 3) passive rotation of the face toward the shoulder of the tilted side <=60 degrees , 4) children who had been managed according to the clinical pathway for CMT, 5) children who had been followed up for 6 months or more after the end of treatment. The duration and total number of stretching exercise sessions were reviewed with reference to the thickness of the SCM. RESULTS: Among the 52 children with CMT, 46 children were successfully managed with only stretching exercise of the SCM for 1-6 weeks (group 1: 88.5%) and 6 children were managed with botulinum toxin A injection, surgical release or both in addition to stretching exercise (group 2: 11.5%). The difference in the SCM thickness between the affected and normal sides was significantly greater in group 2 than that in group 1 (p=0.026). A strong correlation was found between the total duration of stretching exercise and the difference in the SCM thickness in group 1 (Pearson' gamma=0.429; p=0.003). CONCLUSION: Children with a thicker SCM seem to require a longer duration of stretching exercise and other therapeutic interventions in addition to stretching exercise for CMT. Therefore, the thickness of the SCM may be one prognostic factor for CMT treatment. PMID- 22506146 TI - A comparison of the korean-ages and stages questionnaires and denver developmental delay screening test. AB - OBJECTIVE: To evaluate concurrent validity between the Korean-Ages and Stages Questionnaires (K-ASQ) and the Denver Developmental Screening Test II (DDST II), and to evaluate the validity of the K-ASQ as a screening tool for detecting developmental delay of Korean children. METHOD: A retrospective chart review was done to examine concurrent validity of the screening potentials for developmental delay between the K-ASQ and the DDST II (n=226). We examined validity of the K ASQ compared with Capute scale (n=141) and Alberta Infant Motor Scale (AIMS) (n=69) as a gold standard of developmental delay. Correlation analysis was used to determine the strength of the associations between tests. RESULTS: A fair to good strength relationship (k=0.442, p<0.05) was found between the K-ASQ and the DDST II. The test characteristics of the K-ASQ were sensitivity 76.3-90.2%, specificity 62.5-76.5%, positive likelihood ratio (PLR) 2.41-3.40, and negative likelihood ratio (NLR) 0.16-0.32. CONCLUSION: Evidence of concurrent validity of the K-ASQ with DDST II was found. K-ASQ can be used for screening of developmental delay. PMID- 22506147 TI - Prognostic influences of cardiac rehabilitation in korean acute myocardial infarction patients. AB - OBJECTIVE: To observe the prognostic influences of the cardiac rehabilitation (CR) program in Korean acute myocardial infarction (AMI) patients during the first year after an occurrence of the disease. METHOD: A total of 141 AMI patients who underwent percutaneous coronary intervention (PCI) were recruited consecutively for this study and divided into the CR group and the control group. The CR group completed the phase 2 CR program in the hospital for a period of 6-8 weeks and maintained self-exercise in their community by exercise prescription for a year after AMI. We performed a prospective comparison of the patients' demographic data, high sensitive C-reactive protein (hs-CRP) level after the 4 month CR program, and the rate of recurrence (AMI, re-hospitalization, positive coronary angiogram, needed revascularization procedure, or death) between the two groups. RESULTS: Compared to the control group (0.33+/-0.48 mg/dl), the hs-CRP level was lower in the CR group (0.18+/-0.32 mg/dl) after 4 months of exercise. The recurrence rate was lower (10%, 7/69) in the CR group, compared to the control group (24%, 17/72, p<0.05). The number of disease-free days was larger in the CR group (354+/-38.34), compared to the control group (316+/-99.96, p<0.05). In a comparison of statistical methods used for testing the equality of two survivor distributions, the CR group showed a lower recurrence rate than the control group (p<0.05). CONCLUSION: Participation in the CR program designed for AMI patients who underwent PCI-induced normalization of the serum hs-CRP level and lowering of the recurrence rate by 14% during the first year. PMID- 22506148 TI - The effect of a self exercise program in cardiac rehabilitation for patients with coronary artery disease. AB - OBJECTIVE: To investigate the effect of self exercise in cardiac rehabilitation on cardiopulmonary exercise capacity for selected patients with coronary artery disease. METHOD: The subjects of this study were patients who received percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery and who participated in a cardiac rehabilitation program. The supervised exercise group participated in 6-8 weeks of aerobic exercise training with telemetry ECG monitoring in hospital. The self exercise group, whose exercise risk was low, was instructed to participiate in self exercise training in a community exercise environment according to the exercise tolerance test (ETT) using a modified Bruce protocol. Both groups underwent ETTs before and 6 months after initiation of the cardiac rehabilitation program. We compared the supervised group with the self exercise groups on exercise capacity. RESULTS: After 6 months, the supervised exercise group showed significant changes in maximum oxygen consumption, maximal heart rate, resting heart rate, and submaximal rate pressure product. The self exercise group also showed significant improvement of maximum oxygen consumption and submaximal rate pressure product. However, the changing rate of maximum oxygen consumption was significantly higher in the supervised exercise group than the self exercise group. CONCLUSION: Both the supervised and self exercise groups showed similar improvement of cardiopulmonary exercise capacity after 6 months' participation in the cardiac rehabilitation program. However, the changing rate of maximum oxygen consumption, maximal heart rate, and resting heart rate were significantly higher in the supervised exercise group than the self exercise group. PMID- 22506149 TI - Usefulness of ultrasonography to predict response to injection therapy in carpal tunnel syndrome. AB - OBJECTIVE: To verify the feasibility of initial parameters of ultrasonography or electromyography for the prediction of effect after steroid injection therapy in a carpal tunnel syndrome (CTS) patient. METHOD: We recruited individuals with clinical and electrodiagnostic evidence of CTS. Results from the Boston self assessment questionnaire, median motor and sensory nerve conduction studies, and median nerve ultrasonography were evaluated at baseline, 1 month, and 6 months after injection. Evaluation of median nerve ultrasonography parameters included measurements taken at the maximal swelling point (MS), 2 cm proximal from MS (2MS), and 12 cm proximal from MS (12MS), and its ratio (MS/12MS, 2MS/12MS) was calculated. The correlation between improvement of the symptom score after treatment and baseline parameters was estimated. RESULTS: Fourteen individuals (14 women, mean age 53.8 years) with 22 affected wrists were enrolled. After steroid injection therapy, clinical and electromyographic parameters showed significant improvements at 1 month or 6 months after injection, and ultrasonographic parameters showed significant changes in maximal area and area ratio (MS/12MS) of the median nerve. Symptom score improvement showed a positive correlation in the initial 2MS and ratio of 2MS/12MS after 6 months (p<0.05). CONCLUSION: Most of the improvements occurred during the first month after injection and lasted up to 6 months. The initial median nerve swelling and its ratio may be a useful predictor of response after steroid injection. PMID- 22506150 TI - Usefulness of posterolateral transforaminal approach in lumbar radicular pain. AB - OBJECTIVE: To compare the short-term effects and advantages of transforaminal epidural steroid injection (TFESI) performed using the conventional (CL) and posterolateral (PL) approaches. METHOD: Fifty patients with lumbar radicular pain from lumbar spinal stenosis and herniated lumbar disc were enrolled. Subjects were randomly assigned to one of two groups (CL or PL group). All procedures were performed using a C-arm (KMC 950, KOMED, Kwangju, Kyunggi, Korea). We compared the frequency of complications during the procedure and the effects of the pain block between the two groups at 2, 4, and 12 weeks after the procedure. RESULTS: There were no significant differences in the demographic data, initial VNS (Visual numeric scale), or ODI (Oswestry disability index) between the CL group (n=26) and the PL group (n=24). There was no statistically significant difference in the outcome measures (VNS and ODI) between the groups at 2, 4, or 12 weeks. Symptoms of nerve root irritation occurred in 1 case of the CL group and in 7 cases of the PL group (p<0.05). Pricking of spinal nerve during the procedure and transient weakness after the procedure occurred in 6 cases and 3 cases, respectively in the CL group, but did not occur in the PL group. CONCLUSION: Our findings suggest that the posterolateral approach represents an alternative TFESI method in cases with difficult needle tip positioning in the anterior epidural space, and could lower the risk of target nerve root irritation and nerve penetration. PMID- 22506151 TI - The additional effect of hyaluronidase in lumbar interlaminar epidural injection. AB - OBJECTIVE: To evaluate the effect of hyaluronidase in lumbar interlaminar epidural injection (LIEI) for low back pain and sciatica. METHOD: Sixty-one patients suffering from severe low back pain and sciatica were randomly allocated into three groups. Group T (n=18, mean duration of illness: 2.12+/-1.16 months) received lumbar interlaminar epidural injection (LIEI) with 2 ml triamcinolone (40 mg/ml) and 5 ml bupivacaine (0.25%). Group H (n=16, mean duration of illness: 2.05+/-1.12 months) received LIEI with 1,500 IU hyaluronidase and 5 ml bupivacaine (0.25%). Group TH (n=27, mean duration of illness: 2.16+/-1.65 months) received LIEI with 1,500 IU hyaluronidase, 2 ml triamcinolone (40 mg/ml), and 5 ml bupivacaine (0.25%). The effects were evaluated using the Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI) at preinjection and 2 weeks, 4 weeks, and 8 weeks after LIEI. RESULTS: Pain improved in all groups after 2 weeks (p<0.05). After 8 weeks, there was no significant difference in VAS improvement among the 3 groups. However, pain improved in 70.4% of Group TH compared with preinjection, in contrast to 44.4% of Group T and 31.3% of Group H. The ODI improved significantly only in Group TH after 8 weeks (p<0.05). CONCLUSION: LIEI with triamcinolone and hyaluronidase is more effective for reducing pain after 8 weeks than injection with triamcinolone or hyaluronidase alone. PMID- 22506152 TI - Reliability and usefulness of the pressure pain threshold measurement in patients with myofascial pain. AB - OBJECTIVE: To assess the usefulness of a pressure algometer to measure pressure pain threshold (PPT) for diagnosis of myofascial pain syndrome (MPS) in the upper extremity and trunk muscles. METHOD: A group of 221 desk workers complaining of upper body pain participated in this study. Five physiatrists made the diagnosis of MPS using physical examination and PPT measurements. PPT measurements were determined for several muscles in the back and upper extremities. Mean PPT data for gender, side, and dominant hand groups were analyzed. Sensitivity and specificity of Fischer's standard method were evaluated. PPT cut-off values for each muscle group were determined using an ROC curve. RESULTS: Cronbach's alpha for each muscle was very high. The PPT in men was higher than in females, and the PPT in the left side was higher than in the right side for all muscles tested (p<0.05). There was no significant difference in PPT for all muscles between dominant and non-dominant hand groups. Diagnosis of MPS based on Fischer's standard showed relatively high specificity and poor sensitivity. CONCLUSION: The digital pressure algometer showed high reliability. PPT might be a useful parameter for assessing a treatment's effect, but not for use in diagnosis or even as a screening method. PMID- 22506153 TI - Retrodiscal approach of lumbar epidural block. AB - OBJECTIVE: To compare the technical strengths and weaknesses between retrodiscal (RD) and conventional subpedicular (SP) approaches of transforaminal epidural block (TF-EPB). METHOD: Sixty-one patients with L5 radiculopathy who planned to undergo TF-EPB were consecutively enrolled as study subjects. Subjects were randomly assigned to one of two groups. For the RD approach, the positioning of the patient and the C-arm were similar to that for lumbar discography. We compared the pattern of dye spreads, the frequency of complications during the procedures, and the effect of the pain block 2 weeks after the procedure between the two groups. RESULTS: For the RD group (n=24), the contrast dye diffused around the L5 and S1 nerve roots in 16 cases (67%), but it diffused around only the L5 root in 27 cases (73%) in the SP group (n=37) (p<0.05). Two weeks after the procedure, the visual analogue scale (VAS) decreased by the same amount in both groups (RD group: 3.1+/-1.6, SP group: 3.2+/-2.6). Symptoms of nerve root irritation occurred in 1 case of the RD group and in 10 cases of the SD group (p<0.05). CONCLUSION: The RD approach was as efficient as the SP approach for temporary diagnostic relief and offered considerable advantages, such as lower nerve root irritation possible lower risk of vascular injection. Thus, it could be a useful technique when a herniated disc segment is stuck or when the foraminal stenosis is severe. PMID- 22506154 TI - Effect of Dominant Versus Non-dominant Vision in Postural Control. AB - OBJECTIVE: To assess the effect of dominant and non-dominant vision in controlling posture in quiet stance. METHOD: Twenty-five healthy elderly subjects aged over 60 years old and twenty-five young subjects aged under 30 years old were assessed by computerized dynamic posturography. Postural stability was measured in two conditions; dominant eye open and non-dominant eye open. We used the sensory organization test (SOT) for evaluating sensory impairment. A SOT assessed the subject's ability to use and integrate somatosensory input, vision, and vestibular cues effectively to maintain balance. The SOT was conducted 3 times, and the average value of the 3 trials was used for data analysis. Equilibrium scores reflected the subject's anteroposterior sway. The highest possible score was 100, which indicated that the subject did not sway at all, and a score of 0 indicated a fall from the footplate. Determination of ocular dominance was performed by a hole-in-the card test. RESULTS: For the twenty-five young subjects in this study, equilibrium score in two conditions did not differ. However, for elderly subjects over 60 years, the equilibrium score in dominant vision was higher than in nondominant vision (p<0.05). CONCLUSION: In young subjects, there were no significant differences in postural control between dominant vision and non-dominant vision. However, in elderly subjects, postural control in non-dominant vision was significantly impaired. Therefore, the evaluation of a dominant eye should be considered in rehabilitation programs for elderly people. PMID- 22506155 TI - Treatment of transient osteoporosis of the hip with intravenous zoledronate - a case report -. AB - Transient osteoporosis of the hip (TOH) is a rare disorder of unknown etiology that is characterized by acute onset of disabling bone pain. The locally increased bone turnover and low bone mineral density (BMD) associated with this disorder indicate a potential role for an antiresorptive agent such as bisphosphonate as a treatment. A previously healthy 46-year-old man developed the sudden onset of pain in his right buttock and inguinal area, especially during walking and caused him to limp. A thorough medical workup including X-ray, MRI, and bone SPECT revealed transient osteoporosis of the hip, and he was treated with an infusion of zoledronate (5 mg). Two weeks later, he was fully recovered from pain and the gait disturbance. A follow-up MRI of the hip joint taken after 6 months showed complete resolution. The use of intravenous zoledronate provided a successful outcome in the treatment of TOH. The possibility of TOH should be considered in patients complaining of sudden hip pain and a limping gait. MR imaging played an important role for differentiation of TOH from other aggressive conditions with long term sequelae. PMID- 22506156 TI - Acquired Tracheoesophageal Fistula through Esophageal Diverticulum in Patient Who Had a Prolonged Tracheostomy Tube - A Case Report -. AB - Acquired tracheoesophageal fistula through esophageal diverticulum is infrequent. We report tracheoesophageal fistula through esophageal diverticulum in a 55-year old male who had a prolonged tracheostomy tube during 6 months, and a NG tube during 18 months. He suffered from recurrent pneumonia. He complained of a cough associated with eating, and production of sputum mixed with food. To help evaluate the aspiration to the lung and the cause of aspiration, he was tested using gastrointestinal scintigraphy (gastric emptying study), a chest CT scan (pre & post contrast), and esophagoduodenoscopy. The chest CT scan revealed an acquired tracheoesophageal fistula through esophageal diverticulum, and esophagoduodenoscopy revealed a 3 mm sized fistula that was located -33 cm from the upper incisor. We treated the tracheoesophageal fistula by clipping under esophagoduodenoscopy. The symptoms of fever, cough, and aspiration were no long observed after the clipping was completed. PMID- 22506157 TI - Deep vein thrombosis associated with may-thurner syndrome in an amyotrophic lateral sclerosis patient -a case report-. AB - There have been a few reports on deep vein thrombosis (DVT) associated with compression of the left common iliac vein by the right common iliac artery, referred to as May-Thurner syndrome (MTS). However, there have been no reports on DVT associated with MTS in amyotrophic lateral sclerosis (ALS) patients exhibiting similar clinical features to paraplegic spinal cord injury patients. We hereby report a case of DVT associated with MTS in an ALS patient, who was treated successfully. PMID- 22506158 TI - Defining physiatry and future scope of rehabilitation medicine. AB - To identify the 'physiatry' in a single word is difficult. This may be due that physiatry originated from two different fields, physical medicine and rehabilitation and focuses on assisting the general improvement of functional recovery in disabled patients. In addition, physiatry has new markets to develop; health and welfare. Therefore, the identity of physiatry will change depending on how physiatrists act in these fields. We attempt to define the physiatry from several aspects. PMID- 22506159 TI - Effect of virtual reality on cognition in stroke patients. AB - OBJECTIVE: To investigate the effect of virtual reality on the recovery of cognitive impairment in stroke patients. METHOD: Twenty-eight patients (11 males and 17 females, mean age 64.2) with cognitive impairment following stroke were recruited for this study. All patients were randomly assigned to one of two groups, the virtual reality (VR) group (n=15) or the control group (n=13). The VR group received both virtual reality training and computer-based cognitive rehabilitation, whereas the control group received only computer-based cognitive rehabilitation. To measure, activity of daily living cognitive and motor functions, the following assessment tools were used: computerized neuropsychological test and the Tower of London (TOL) test for cognitive function assessment, Korean-Modified Barthel index (K-MBI) for functional status evaluation, and the motricity index (MI) for motor function assessment. All recruited patients underwent these evaluations before rehabilitation and four weeks after rehabilitation. RESULTS: The VR group showed significant improvement in the K-MMSE, visual and auditory continuous performance tests (CPT), forward digit span test (DST), forward and backward visual span tests (VST), visual and verbal learning tests, TOL, K-MBI, and MI scores, while the control group showed significant improvement in the K-MMSE, forward DST, visual and verbal learning tests, trail-making test-type A, TOL, K-MBI, and MI scores after rehabilitation. The changes in the visual CPT and backward VST in the VR group after rehabilitation were significantly higher than those in the control group. CONCLUSION: Our findings suggest that virtual reality training combined with computer-based cognitive rehabilitation may be of additional benefit for treating cognitive impairment in stroke patients. PMID- 22506160 TI - The Factors Associated with Good Responses to Speech Therapy Combined with Transcranial Direct Current Stimulation in Post-stroke Aphasic Patients. AB - OBJECTIVE: To determine factors associated with good responses to speech therapy combined with transcranial direct current stimulation (tDCS) in aphasic patients after stroke. METHOD: The language function was evaluated using Korean version of Western aphasia battery (K-WAB) before and after speech therapy with tDCS in 37 stroke patients. Patients received speech therapy for 30 minutes over 2 to 3 weeks (10 sessions) while the cathodal tDCS was performed to the Brodmann area 45 with 1 mA for 20 minutes. We compared the improvement of aphasia quotient % (AQ%) between two evaluation times according to age, sex, days after onset, stroke type, aphasia type, brain lesion confirmed by magnetic resonance image and initial severity of aphasia. The factors related with good responses were also checked. RESULTS: AQ% improved from pre- to post-therapy (14.94+/-6.73%, p<0.001). AQ% improvement was greater in patients with less severe, fluent type of aphasia who received treatment before 30 days since stroke was developed (p<0.05). The adjusted logistic regression model revealed that patients with hemorrhagic stroke were more likely to achieve good responses (odds ratio=4.897, p<0.05) relative to infarction. Initial severity over 10% in AQ% was also found to be significantly associated with good improvement (odds ratio=8.618, p<0.05). CONCLUSION: Speech therapy with tDCS was established as a treatment tool for aphasic patients after stroke. Lower initial severity was associated with good responses. PMID- 22506161 TI - Inter-rater Agreement for the Clinical Dysphagia Scale. AB - OBJECTIVE: To investigate the inter-rater agreement for the clinical dysphagia scale (CDS). METHOD: Sixty-seven subjects scheduled to participate in a video fluoroscopic swallowing study (VFSS) were pre-examined by two raters independently within a 24-hour interval. Each item and the total score were compared between the raters. In addition, we investigated whether subtraction of items showing low agreement or modification of rating methods could enhance inter rater agreement without significant compromise of validity. RESULTS: Inter-rater agreement was excellent for the total score (intraclass correlation coefficient (ICC): 0.886). Four items (lip sealing, chewing and mastication, laryngeal elevation, and reflex coughing) did not show excellent agreement (ICC: 0.696, 0.377, 0.446, and kappa: 0.723, respectively). However, subtraction of each item either compromised validity, or did not improve agreement. When redefining 'history of aspiration' and 'lesion location' items, the inter-rater agreement (ICC: 0.912, 0.888, respectively) and correlation with new videofluoroscopic dysphagia score (PCC: 0.576, 0.577, respectively) were enhanced. The CDS showed better agreement and validity in stroke patients compared to non-stroke patients (ICC: 0.917 vs 0.835, PCC: 0.663 vs 0.414). CONCLUSION: The clinical dysphagia scale is a reliable bedside swallowing test. We can improve inter-rater agreement and validity by refining the 'history of aspiration' and 'lesion location' item. PMID- 22506162 TI - Clinical Usefulness of Schedule for Oral-Motor Assessment (SOMA) in Children with Dysphagia. AB - OBJECTIVE: To investigate the clinical usefulness of the Schedule for Oral-Motor Assessment (SOMA) in children with dysphagia by comparing findings of SOMA with those of the videofluoroscopic swallowing study (VFSS). METHOD: Both SOMA and VFSS were performed in 33 children with dysphagia (21 boys and 12 girls; mean age 17.3+/-12.1 months) who were referred for oropharyngeal evaluation. Ratings of oral-motor functions indicated by SOMA were based upon the cutting score of each specific texture of food (puree, semi-solids, solids, cracker, liquid-bottle, and liquid-cup). Abnormalities of either the oral phase, or the pharyngeal phase as indicated by VFSS were assessed by a physician and a speech-language pathologist. RESULTS: There was significant consistency between the findings of SOMA and the oral phase evaluation by VFSS (Kappa=0.419, p=0.023). SOMA reached 87.5% sensitivity, 66.6% specificity, and 95.4% positive predictive value when compared with the oral phase of the VFSS. We were able to evaluate oral-motor function by using SOMA in 6 children who were unable to complete the oral phase evaluation by VFSS, due to fear and crying during the study. The findings of SOMA failed to show any consistency with the pharyngeal phase evaluation by VFSS (Kappa=-0.105, p=0.509). CONCLUSION: These results suggest that SOMA is a reliable method for evaluation of oral-motor function in children with dysphagia. In particular, SOMA is recommended for children that were unable to complete the oral phase evaluation by VFSS due to poor cooperation. PMID- 22506163 TI - Screening for the coexistence of congenital muscular torticollis and developmental dysplasia of hip. AB - OBJECTIVE: To investigate the coexistence rate and related factors of developmental dysplasia of the hip (DDH) and congenital muscular torticollis (CMT), and to determine whether ultrasonography (US) gives good value for screening of DDH in CMT. METHOD: We prospectively examined 121 infants (73 males and 48 females) diagnosed with CMT to determine the incidence of DDH by US. We also assessed the relationship between neck US findings and DDH occurrence, and investigated the clinical features of CMT related to DDH. RESULTS: 18 patients (14.9%) were diagnosed as having DDH by US. However, most DDH was subclinical and spontaneously resolved. Only 2 patients (1.7%) needed to be treated with a harness. The positive predictive value of clinical examinations for DDH was 52.6% and patients treated by harness were all clinically positive. DDH was more common in the left side (13 left, 4 right, 1 both), but 6 out of 18 DDH (33.3%) cases presented on the contralateral side of CMT. Sex difference was not observed. Breech presentation and oligohydramnios were not related to DDH occurrence. Neck US findings did not correlate with DDH occurrence. CONCLUSION: The coexistence rate of CMT and DDH was concluded to be 14.9%. If only DDH cases that required treatment were included, the coexistence rate of these two disorders would be lowered to 1.7%. All of these patients showed positive findings in clinical examination. Therefore, hip US should not be recommended routinely for patients with CMT. PMID- 22506164 TI - Relationship between Physical Examinations and Two-Dimensional Computed Tomographic Findings in Children with Intoeing Gait. AB - OBJECTIVE: To evaluate the validity of physical examinations by assessment of correlation between physical examinations and CT measurements in children with intoeing gait and the causes of intoeing gait by age using CT measurements. METHOD: Twenty-six children with intoeing gait participated in this study. The internal and external hip rotation, thigh-foot angle and transmalleolar angle were measured. In addition, femoral anteversion and tibial torsion of the subjects were assessed using a CT scan. The measurements of torsional angles were performed twice by two raters. The correlation coefficients between physical examinations and CT measurements were calculated using Pearson correlation. The data was analyzed statistically using SPSS v12.0. RESULTS: The correlation coefficients between physical examinations and CT measurements were not high. Before 5 years of age, intoeing gait was caused by femoral anteversion in 17.86%, tibial torsion in 32.29% and the combination of causes in 35.71% of cases. After 6 years of age, the contributions changed to 29.17%, 8.33% and 45.83%, respectively. CONCLUSION: Before 5 years of age, the common cause of an intoeing gait was tibial torsion, whereas after 6 years of age it was femoral anteversion. Regardless of age, the most common cause of intoeing gait was a combination of causes. This study shows poor correlation between physical examinations and CT. Therefore, it is limiting to use physical examination only for evaluating the cause of intoeing gait in clinical practice. PMID- 22506165 TI - Foot deformity in charcot marie tooth disease according to disease severity. AB - OBJECTIVE: To investigate the characteristics of foot deformities in patients with Charcot-Marie-Tooth (CMT) disease compared with normal persons according to severity of disease. METHOD: Sixty-two patients with CMT disease were recruited for this study. The normal control group was composed of 28 healthy people without any foot deformity. Patients were classified into a mild group and a moderate group according to the CMT neuropathy score. Ten typical radiological angles representing foot deformities such as pes equinus and pes varus were measured. The CMT group angles were compared with those of the normal control group, and those of the mild group were also compared with those of the moderate group. RESULTS: The lateral (Lat.) talo-first metatarsal angle, anteroposterior talo-first metatarsal angle, Lat. calcaneal-first metatarsal angle, Lat. naviocuboid overlap, Lat. calcaneal pitch, Lat. tibiocalcaneal angle, and Lat. talocalcaneal angle in the CMT group showed a significant difference compared to the normal control group (p<0.05). These findings revealed CMT patients have pes cavus, forefoot adduction, midfoot supination and pes varus deformity. Compared to the mild group, the moderate group significantly showed an increased Lat. calcaneal pitch and decreased Lat. calcaneal-first metatarsal angle, Lat. tibiocalcaneal angle, Lat. talocalcaneal angle, and Lat. talo-first metatarsal angle (p<0.05). These findings revealed that the pes cavus deformity of CMT patients tend to be worse with disease severity. CONCLUSION: The characteristic equinovarus foot deformity patterns in CMT patients were revealed and these deformities tended to be worse with disease severity. Radiographic measures may be useful for the investigation of foot deformities in CMT patients. PMID- 22506166 TI - Clinical characteristics of the causes of plantar heel pain. AB - OBJECTIVE: The objectives of this study were to investigate the causes of plantar heel pain and find differences in the clinical features of plantar fasciitis (PF) and fat pad atrophy (FPA), which are common causes of plantar heel pain, for use in differential diagnosis. METHOD: This retrospective study analyzed the medical records of 250 patients with plantar heel pain at the Foot Clinic of Rehabilitation Medicine at Bundang Jesaeng General Hospital from January to September, 2008. RESULTS: The subjects used in this study were 114 men and 136 women patients with a mean age of 43.8 years and mean heel pain duration of 13.3 months. Causes of plantar heel pain were PF (53.2%), FPA (14.8%), pes cavus (10.4%), PF with FPA (9.2%), pes planus (4.8%), plantar fibromatosis (4.4%), plantar fascia rupture (1.6%), neuropathy (0.8%), and small shoe syndrome (0.8%). PF and FPA were most frequently diagnosed. First-step pain in the morning, and tenderness on medial calcaneal tuberosity correlated with PF. FPA mainly involved bilateral pain, pain at night, and pain that was aggravated by standing. Heel cord tightness was the most common biomechanical abnormality of the foot. Heel spur was frequently seen in X-rays of patients with PF. CONCLUSION: Plantar heel pain can be provoked by PF, FPA, and other causes. Patients with PF or FPA typically show different characteristics in clinical features. Plantar heel pain requires differential diagnosis for appropriate treatment. PMID- 22506168 TI - The test-retest reliability of supraspinatus cross-sectional area measurement by sonography. AB - OBJECTIVE: To evaluate the test-retest reliability of supraspinatus cross sectional area measurement by ultrasonography. METHOD: Both shoulders of 11 normal subjects (22 shoulders in total) were included in this study. The supraspinatus muscle was examined with the arm alongside the body in the coronal oblique and sagittal oblique planes. The occupational ratio of the supraspinatus fossa was measured. To calculate the occupational ratio, the Y view of MRI was reproduced with sonography by locating the suprascapular notch in the coronal oblique plane (in the plane of the scapula) and then rotating the transducer 90 degrees to that plane. The cross-sectional area was measured using the tracing and ellipse tool. The second measurement was performed 7 days after the initial measurement. RESULTS: The Pearson correlation coefficient and intraclass correlation coefficient between the first and the second occupational ratio measurements were 0.43 and 0.44, respectively, for the tracing method, and 0.53 and 0.47, respectively, for the ellipsoidal method. The difference between the first and second occupational ratio measurement was 4.1+/-3.9% (0.1-13.2%) for the tracing method, and 4.5+/-3.4% (0.01-10.5%) for the ellipsoidal method. The maximum difference was 13.2%. The occupational ratio was 86.2+/-5.3% (70.6-95.8%) for the tracing method and 85.0+/-5.2% (69.3-96.1%) for the ellipsoidal method. CONCLUSION: Supraspinatus occupational ratio by sonography is a low to moderately reliable intrarater method. However, the maximum difference was not significant. The main reason for its low to moderate reliability was the narrow value range. Therefore, the study method should be re-evaluated in stroke patients and in patients with rotator cuff disease. Knowledge of the anatomy is a prerequisite to attain intrarater reliability. PMID- 22506167 TI - Effects of transforaminal injection for degenerative lumbar scoliosis combined with spinal stenosis. AB - OBJECTIVE: The objectives of this study were to clarify the short-term effects of transforaminal epidural steroid injection (TFESI) for degenerative lumbar scoliosis combined with spinal stenosis (DLSS), and to extrapolate factors relating to the prognosis of treatment. METHOD: Thirty-six patients with lumbar radicular pain from DLSS were enrolled. Subjects were randomly assigned to one of two groups (steroid or lidocaine group). We compared the effect of pain suppression at 2, 4 and 12 weeks after the procedure between the two groups. Radiographic analysis included measurement of the Cobb's angle, the upper endplate obliquities of L3 and L4, and maximal lateral olisthy between two adjacent lumbar vertebrae. Sagittal plane measurement included lumbar lordosis, and thoracolumbar kyphosis. Statistical analysis of both radiographic and clinical parameters along with treatment outcome was performed to determine any significant correlations between the two. RESULTS: There were no significant differences in the demographic data, initial visual analogue scale (VAS) or Oswestry disability index (ODI) between the steroid group (n=17) and the lidocaine group (n=19). Two, 4, and 12 weeks after injection VAS, ODI showed a significantly greater improvement in the steroid group compared to the lidocaine group (p<0.05). The radiographic and clinical parameters were not significantly correlated with treatment outcome. CONCLUSION: Our findings suggest that fluoroscopic transforaminal epidural steroid injections appear to be an effective non-surgical treatment option for patients with degenerative lumbar scoliosis combined with spinal stenosis (DLSS) and radicular pain. PMID- 22506169 TI - Evaluation of Elbow Stretch Reflex Using a Portable Hand-driven Isokinetic System in Normal Adults. AB - OBJECTIVE: To evaluate normal healthy persons without spasticity to observe normal findings of the elbow stretch reflex using a newly developed, portable, hand-driven spasticity-measuring system. METHOD: Thirty normal persons without any disease involving the central or peripheral nervous system were enrolled in this study. The portable hand-driven isokinetic system is able to measure the joint angle, angular velocity, electromyographic (EMG) signals, and torque during elbow passive extension-flexion. One set of 10 passive elbow extension and flexion movements was performed for data acquisition at each angular velocity, including 60, 90, 120, 150 and 180 degrees per second ( degrees /sec). Electromyographic data were collected from the biceps brachii and the triceps brachii. Torque data were collected from sensors around the wrist. RESULTS: We were able to detect EMG activity and torque in all subjects by using the new portable hand-driven isokinetic system. EMG activity and torque increased with incremental increase of angular velocities. The joint angle of maximal EMG activity according to different angular velocities did not show any significant difference (116 degrees -127 degrees in elbow extension and 37 degrees -66 degrees in elbow flexion). The joint angles of maximal torque according to different angular velocities were not significantly different either. CONCLUSION: Using the portable hand-driven isokinetic system on the elbows of normal subjects, we were able to obtain expected results. By considering our normal findings of the elbow stretch reflex using this system, we propose that the various aspects of spasticity-related data can be measured successfully. PMID- 22506170 TI - The impact of early regular cardiac rehabilitation program on myocardial function after acute myocardial infarction. AB - OBJECTIVE: To determine if an early regular cardiac rehabilitation program would have an adverse effect on myocardial function after acute myocardial infarction (AMI). METHOD: Patients who received percutaneous coronary intervention (PCI) after AMI were divided into the exercise group and control group in accordance with their willingness to participate. Patients in the exercise group (n=18) received ECG monitored exercise for six weeks and were instructed to maintain self exercise in their communities for four months. The control group (n=16) patients were just instructed of risk factor control. All the subjects underwent echocardiography at the time of the AMI as well as six months later. The echocardiography parameters, including the left ventricular ejection fraction (LVEF), stroke volume (SV), left ventricular end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD), were measured. RESULTS: In the exercise group, the LVEF increased to 59.58+/-9.24% and 61.58+/-9.63% after six weeks and six months, respectively (p<0.05), but SV, LVEDD and LVESD did not change (p>0.05). CONCLUSION: Active participation in the cardiac rehabilitation program approximately two weeks after AMI did not have an adverse effect on the size of the left ventricle and myocardial function. PMID- 22506171 TI - Double-peak response in orthodromic sensory nerve conduction of the median nerve. AB - OBJECTIVE: To understand the neural generator of double-peak potentials and the change of latency and amplitude of double peaks with aging. METHOD: In 50 healthy subjects made up of groups of 10 people per decade from the age of 20 to 60, orthodromic sensory nerve conduction studies were performed on the median nerves using submaximal stimulation. Various stimulus durations and interstimulation distances were used to obtain each double peak in the different age groups. The latency and amplitude of the second peak were measured. Statistical analyses included one-way ANOVA and correlation tests. p-values<0.05 were considered significant. RESULTS: When the cathode moved in a proximal direction, the interpeak intervals increased. Second peak amplitudes decreased, and second peak latencies were delayed with aging (p<0.05). In some older people, second peaks were not obtained. CONCLUSION: Our experiments indicate that the double-peak response represented the two stimulation sites under the cathode and anode. The delayed latency and decreased amplitude of the second peak that occurs with aging represented peripheral nerve degeneration in aging, which starts at the distal nerve. PMID- 22506172 TI - Nerve conduction study of the superficial peroneal sensory distal branches in koreans. AB - OBJECTIVE: To perform nerve conduction studies of the four branches of the superficial peroneal nerves to determine normal values and anatomic variations in Koreans. METHOD: Antidromic sensory nerve conduction studies of the four distal branches were performed on 70 healthy subjects (100 feet). We applied electrical stimulation at the midpoint of medial and lateral malleoli for the medial dorsal cutaneous nerve (MDCN), and at the lateral 1/4 point between the medial and lateral malleoli for the 2 branches of the intermediate dorsal cutaneous nerve (IDCN). RESULTS: Reference values (mean+/-SD) of the onset/ peak latency (ms)/ sensory action potential amplitude (uV) for the two branches of the MDCN and for the first branch of the IDCN were 2.2+/-0.3/2.9+/-0.3/9.2+/-3.1, 2.2+/-0.3/2.8+/ 0.3/9.1+/-3.0 and 2.3+/-0.4/2.9+/-0.3/8.5+/-2.8, respectively. For the second IDCN branch, the reference values were 2.3+/-0.4/3.0+/-0.4/7.1+/-2.6 but anomalous sural innervation was also found. Three types of IDCN innervations to the fourth interdigital web space were detected. In type I, the fourth interdigital webspace was innervated solely by the IDCN, whereas in type II, it was innervated by both the IDCN and distal sural nerve. In type III, it was solely innervated by the distal sural nerve. CONCLUSION: The results of this study show the reference values of the distal sensory branches of the superficial peroneal nerve, and provide information on the variant innervations to the fourth interdigital web space. PMID- 22506173 TI - Motor evoked potentials of trunk muscles in traumatic brain injury patients. AB - OBJECTIVE: To evaluate the motor innervation of trunk muscles in traumatic brain injury patients. METHOD: Twenty patients (12 men and 8 women) with traumatic brain injury were enrolled in this study. Their mean age was 41 years. Motor evoked potentials (MEPs) were performed on the motor cortex. Electromyographic activities were recorded from the bilateral rectus abdominis muscles, the external oblique abdominal muscles, and the 4th and 9th thoracic erector spinae muscles. The onset latency and amplitude of contralateral and ipsilateral MEPs were measured. All patients were assessed by the Korean version of the Berg Balance Scale (K-BBS) to investigate the relationship between the frequency of MEPs in trunk muscles and gait ability. RESULTS: The mean frequency of ipsilateral MEPs was 23.8% with more damaged hemisphere stimulation, while the contralateral MEPs showed a mean frequency of 47.5% with more damaged hemisphere stimulation in traumatic brain injury patients. The latencies and amplitudes of MEPs obtained from the more damaged hemisphere were not significantly different from those of the less damaged hemisphere. There was no correlation between the manifestation of MEPs in trunk muscles and gait ability. CONCLUSION: The ipsilateral and contralateral corticospinal pathways to trunk muscles are less likely to be activated in traumatic brain injury patients because of direct injury of the descending corticospinal motor tract or decreased excitability of the corticospinal tract from prefrontal contusion. PMID- 22506174 TI - True Neurogenic Thoracic Outlet Syndrome Following Hyperabduction during Sleep - A Case Report -. AB - True neurogenic thoracic outlet syndrome (TOS) is an uncommon disease and is difficult to diagnose at the early stage and then completely cure. We experienced a case of true neurogenic TOS with typical clinical symptoms and electrophysiologic findings as a result of repetitive habitual sleep posture. A 31-year-old woman who had complained of progressive tingling sensation on the 4th and 5th fingers with shoulder pain was diagnosed of brachial plexopathy at the lower trunk level by electrodiagnostic studies. There was no other cause of brachial plexopathy except her habit of hyperabduction of shoulder during sleep. This case demonstrated that the habitual abnormal posture can be the only major cause of neurogenic TOS. It is of importance to consider TOS with the habitual cause because simple correction of the posture could stabilize or even reverse disease progress. PMID- 22506175 TI - Prolotherapy-induced Cervical Spinal Cord Injury - A Case Report -. AB - A 49-year-old man received prolotherapy in the upper cervical region at a local medical clinic. Immediately after the procedure, he felt a sensation resembling an electric shock in his right upper and lower extremities, and continuously complained of numbness and discomfort in the right hemibody. He visited our clinic a week later. Upon physical examination, there were no significant abnormal findings. The visual analog scale was 60 points. T2-weight magnetic resonance images of the cervical spine showed a 0.7 cm sized bright oval spot on the right side of the spinal cord at the level of C4-C5 disc, suggesting spinal cord injury. There were no definite electrodiagnostic abnormalities. Digital infrared thermal images showed moderately decreased surface temperature on lateral aspect of the right forearm and dorsum of the right hand compared with the other side. Considering that very rare complications like spinal cord injury may develop after prolotherapy, we suggest that special interventions such as prolotherapy be performed by professional experts. PMID- 22506176 TI - A case of central cord syndrome related status epilepticus - a case report -. AB - Central cord syndrome (CCS) is extremely rare as a direct consequence of generalized epileptic seizure. CCS is associated with hyperextension of the spinal cord and has characteristic radiologic findings including posterior ligamentous injury and prevertebral hyperintensity following magnetic resonance imaging (MRI). We experienced the case of a 25-year-old man who suffered CCS after status epilepticus. Cervical spinal MRI revealed high signal intensity at the C1 level but with no signal or structural changes in other sites. After rehabilitation management, the patient significantly improved on the ASIA (American Spinal Injury Association) motor scale and bladder function. We proposed that epilepsy related CCS may be caused by muscle contractions during generalized seizure, which can induce traction injury of the spinal cord or relative narrowing of spinal canal via transient herniated nucleus pulposus or transient subluxation of vertebra. We also suggest CCS without radiologic findings of trauma has good prognosis compared with other CCS. PMID- 22506177 TI - Suppression of seizure by cathodal transcranial direct current stimulation in an epileptic patient - a case report -. AB - Epilepsy is an intractable disease, though many treatment modalities have been developed. Recently, noninvasive transcranial direct current stimulation (tDCS), which can change brain excitability, was introduced and has been applied for therapeutic purposes regarding epilepsy. A suppression of seizures was experienced by cathodal tDCS in a medication refractory pediatric epileptic patient. The patient was an 11-year-old female who had focal cortical dysplasia of the cerebral hemisphere. The patient was treated with antiepileptic drugs but the mean seizure frequency was still eight episodes per month. The tDCS cathode was placed at the midpoint of P4 and T4 in the 10-20 EEG system where the abnormal wave was observed on a sleep EEG. Two mA of tDCS was applied 20 minutes a day, five days a week for two weeks. During a two-month period after treatment termination, only six seizure attacks occurred, and the duration of each seizure episode also decreased. tDCS was applied under the same conditions for another two weeks. For two months after the second treatment session, only one seizure attack occurred, and it showed great improvement compared to the eight seizure attacks per month before the tDCS treatment. The medications were not changed, and there were no notable side effects that were caused by tDCS. PMID- 22506178 TI - Wernicke's Encephalopathy after Sleeve Gastrectomy for Morbid Obesity - A Case Report -. AB - Morbid obesity is a curable systemic disease that can cause several complications, including hypertension, diabetes mellitus, and osteoarthritis. However, it is not easy to control solely by conservative management. Bariatric surgeries, such as sleeve gastrectomy and gastric banding, are recently developed treatments that are applied to patients with morbid obesity in Korea. However, gastric surgery can cause surgical or metabolic complications, such as thiamine deficiency, which can lead to Wernicke's encephalopathy. This metabolic complication presents with typical symptoms of confusion, ophthalmoplegia, nystagmus, and ataxia. In this case report, we present a case of Wernicke's encephalopathy, which developed slowly following sleeve gastrectomy in a patient with morbid obesity. PMID- 22506180 TI - Changes in the muscarinic receptors on the colonic smooth muscles of rats with spinal cord injury. AB - OBJECTIVE: To investigate changes in (1) the colonic response to acetylcholine (Ach), (2) the muscarinic (M) receptors in the colon, and (3) the levels of colonic contraction-related proteins after a spinal cord injury (SCI). METHOD: We divided 16 Sprague-Dawley rats into 2 groups: the control group and the SCI group. A spinal cord transection was performed surgically at the T10 vertebral level. After 1 week, the entire colon was divided into 2 segments, the proximal and distal colon. Each segment was mounted in a longitudinal or circular muscle direction in a 10-ml organ bath. We determined the intergroup differences as percentage changes in contractility after Ach treatment alone, Ach treatment with M2 receptor antagonist (AQ-RA741) pretreatment, and Ach treatment with M3 receptor antagonist (4-DAMP) pretreatment. Western blot analyses were performed to determine the expression level of RhoA, and heat shock protein 27 (HSP27). RESULTS: Compared to the control rats, the SCI rats showed an increased response to Ach along both the directions in the proximal colon (p<0.05). Compared to the control group, in the SCI group, the Ach response was significantly different in the proximal segment under AQ-RA741 pretreatment (p<0.05) and in the distal segment under 4-DAMP pretreatment (p<0.05). Findings of the western blot analyses showed a significant decrease in the level of protein gene product 9.5 in the proximal and distal colon and a significant increase in the level of RhoA and HSP27 in the proximal colon of the SCI rats. CONCLUSION: Our results suggest that changes in colonic contractility after SCI are partly attributable to changes in the M receptor subtypes. PMID- 22506181 TI - Spasticity and electrophysiologic changes after extracorporeal shock wave therapy on gastrocnemius. AB - OBJECTIVE: To evaluate the spasticity and electrophysiologic effects of applying extracorporeal shock wave therapy (ESWT) to the gastrocnemius by studying F wave and H-reflex. METHOD: Ten healthy adults and 10 hemiplegic stroke patients with ankle plantarflexor spasticity received one session of ESWT on the medial head of the gastrocnemius. The modified Ashworth scale (MAS), tibial nerve conduction, F wave, and H-reflex results were measured before and immediately after the treatment. The Visual Analogue Scale (VAS) was used during ESWT to measure the side effects, such as pain. RESULTS: There were no significant effects of ESWT on the conduction velocity, distal latency and amplitude of tibial nerve conduction, minimal latency of tibial nerve F wave, latency, or H-M ratio of H-reflex in either the healthy or stroke group. However, the MAS of plantarflexor was significantly reduced from 2.67+/-1.15 to 1.22+/-1.03 (p<0.05) after applying ESWT in the stroke group. CONCLUSION: After applying ESWT on the gastrocnemius in stroke patients, the spasticity of the ankle plantarflexor was significantly improved, with no changes of F wave or H-reflex parameters. Further studies are needed to evaluate the mechanisms of the antispastic effect of ESWT. PMID- 22506182 TI - Semiconditional electrical stimulation of pudendal nerve afferents stimulation to manage neurogenic detrusor overactivity in patients with spinal cord injury. AB - OBJECTIVE: To evaluate the effect of semiconditional electrical stimulation of the pudendal nerve afferents for the neurogenic detrusor overactivity in patients with spinal cord injury. Forty patients (36 males, 4 males) with spinal cord injury who had urinary incontinence and frequency, as well as felt bladder contraction with bladder filling sense or autonomic dysreflexic symptom participated in this study. METHOD: Patients with neurogenic detrusor overactivity were subdivided into complete injury and incomplete injury groups by ASIA classification and subdivided into tetraplegia and paraplegia groups by neurologic level of injury. Bladder function, such as bladder volumes infused to the bladder until the first occurrence of neurogenic detrusor overactivity (V(ini)) and the last contraction suppressed by electrical stimulation (V(max)) was measured by water cystometry (CMG) and compared with the results of each subgroup. RESULTS: Among the 40 subjects, 35 patients showed neurogenic detrusor overactivity in the CMG study. Among these 35 patients, detrusor overactivity was suppressed effectively by pudendal nerve afferent electrical stimulation in 32 patients. The infusion volume until the occurrence of the first reflex contraction (V(ini)) was 99.4+/-80.3 ml. The volume of saline infused to the bladder until the last contraction suppressed by semiconditional pudendal nerve stimulation (V(max)) was 274.3+/-93.2 ml, which was significantly greater than V(ini). In patients with good response to the pudendal nerve afferent stimulation, the bladder volume significantly increased by stimulation in all the patients. CONCLUSION: In this study, semiconditional electrical stimulation on the dorsal penile afferent nerve could effectively inhibit neurogenic detrusor overactivity and increase bladder volume in patients with spinal cord injury. PMID- 22506184 TI - Unmet healthcare needs in people with disabilities: comparison with the general population in Korea. AB - OBJECTIVE: To determine the degree of disparity in unmet healthcare needs between people with disabilities and the general population in South Korea, and to analyze their perspective reasons. METHOD: Survey results of 9,744 subjects that participated in the 4(th) Korea National Health and Nutrition Examination Survey and 7,000 people that participated in the 2008 Survey of Disabled people were used in this population-based cross-sectional study. Unmet healthcare needs were identified as reporting experience during the last 12 months when there was a need to see a doctor, but were unable to get it. We assessed unmet healthcare needs by demographic variables, social variables and characteristics of disability. Chi-square test and logistic regression were used to determine which variables were related to unmet healthcare needs. RESULTS: A total of 22.1% of people with disabilities and 22.8% of the general population had unmet healthcare needs. However, brain impairment (25.3%) and physical impairment (25.2%) had more unmet healthcare needs than the general population and other disabilities. Unmet healthcare needs of people with disabilities was related to sex, age, self perceived health, marital status, income, occupation and category of disability. Whereas the reasons for unmet healthcare needs in people with disabilities were lack of money (57.3%) and inaccessible transportation (12.8%), those for the general population were no available time (30.2%) and mild symptoms (23.8%). CONCLUSION: Brain and physical impairment cases with limitations to accessible transportation had the higher unmet healthcare needs. In addition, the reasons for people with these disabilities were more environmental than those of the general population. PMID- 22506183 TI - Leisure time physical activity of people with spinal cord injury: mainly with clubs of spinal cord injury patients in busan-kyeongnam, Korea. AB - OBJECTIVE: To estimate hours of leisure time physical activity (LTPA) performed by people with chronic spinal cord injury (SCI) and to identify the demographic and injury-related characteristics associated with LTPA of people with chronic SCI. METHOD: Seventy nine persons with SCI living in Busan and Gyongsangnam-do were recruited. They completed a self-administered questionnaire, which consisted of items about personal characteristics, type of LTPA, hours of LTPA, LTPA intensity, and LTPA satisfaction. RESULTS: Most participants (92.4%) did not work. The respondents reported a daily mean of 3.13 hours (+/-1.47) of LTPA; however, 3.8% reported no LTPA whatsoever. Years post-injury, income sources, and type of medical payment emerged as a predictors of LTPA. Years post-injury were positively correlated with amount of leisure activity. In the case of self income, LTPA was longer than for groups with different income sources (e.g.partner, parents). For patients receiving workers' compensation insurance, LTPA was longer than for patients receiving non-WC insurance. Most LTPA was done at a moderate intensity. The three most frequently reported types of LTPA were wheeling (26%), sports (19%), and stretching exercise (15%). There was overall dissatisfaction with LTPA. CONCLUSION: Daily LTPA hours were longer than previously reported, but wheeling accounted for a large part of the activity. Intensity of activity was generally moderate. The employment rate was very low. Clearly, participating in regular LTPA for health purposes is very important to people with chronic SCI, but it is also important for them to have jobs. PMID- 22506185 TI - Effect of botulinum toxin type a on morphology of salivary glands in patients with cerebral palsy. AB - OBJECTIVE: To investigate the effect of botulinum toxin type A (BTXA) on drooling and the morphologic change of the salivary gland in patients with cerebral palsy. METHOD: Eight cerebral palsy patients suffering from severe drooling participated in this study. BTXA was injected into both submandibular and parotid glands under intravenous sedation and with ultrasound guidance (1 unit/gland/kg: maximum 100 units) in an outpatient or inpatient procedure. The severity of drooling was measured before injection and 3 weeks after injection using the Teacher Drooling Scale, the Drooling Score-severity, frequency and the Visual Analog Scale. To investigate the morphologic change of the salivary glands, the size of salivary glands were measured before injection and 3 weeks after injection using computed tomography of the neck. The measurement values were analyzed by Wilcoxon signed rank test. RESULTS: Statistically significant improvements were shown in all three parameters for assessing the severity of drooling after BTXA injections (p<0.05). Size of the salivary glands were significantly decreased at 3 weeks after BTXA injection (p<0.05). CONCLUSION: Salivary gland injection with BTXA could be a useful treatment method to reduce drooling in patients with cerebral palsy and decreased size of salivary glands may partially explain the mechanism. PMID- 22506186 TI - Comparison of clinical severity of congenital muscular torticollis based on the method of child birth. AB - OBJECTIVE: To compare the clinical severity of congenital muscular torticollis (CMT) based on the method of child birth. METHOD: Children diagnosed with CMT and who were < 6-years-of-age at the time of their first visit at the Center for Torticollis, Ajou Medical Center, were included in this study. The medical records were retrospectively reviewed with reference to the method of child birth and the clinical severity of CMT. The clinical severity of CMT was determined either by whether stretching exercises were needed for the children <6-month-of age or whether surgical release was required for the children >=6-months-of-age at the time of the first visit. RESULTS: One hundred seventy eight subjects with CMT were enrolled. There was no significant difference in the rate of surgical release according to the method of child birth. For 132 patients <6-month-of-age there was also no significant difference in the rate of stretching exercises. CONCLUSION: There was no significant difference in the clinical severity of CMT based on the method of child birth. This finding suggests that prenatal factors alone could be a cause of CMT and that the clinical severity of CMT in children delivered by Cesarean section is not different when compared with the severity of CMT in children born through vaginal delivery. PMID- 22506187 TI - Peroneal neuropathy after tibio-fibular fracture. AB - OBJECTIVE: To investigate the injury mechanism in patients who had peroneal neuropathy after a tibio-fibular fracture and the correlation between tibio fibular fracture location and the severity of the peroneal neuropathy by using electrodiagnosis. METHOD: Thirty-four patients with peroneal neuropathy after a tibio-fibular fracture were recruited for this study. Their medical records, radiologic and electrodiagnostic findings were investigated retrospectively. They were divided into 2 groups according to the existence of a fibular head fracture. The group of patients without the fibular head fracture was further classified according to the criteria of Orthopedic Trauma Association (OTA) classification. The differences between the two groups in the severity of the neuropathy and electrodiagnostic findings were evaluated. RESULTS: Nine cases (26.5%) had tibio fibular fractures with a coexisting fibular-head fracture and 25 cases (73.5%) had tibio-fibular fractures without fractures in the fibular-head area. There was no statistical significance in the correlation between the existence of the fibular head fracture and the severity of the electrodiagnostic findings. Neither was there any statistically significant relationship between the site of the tibio-fibular fracture and the severity of the peroneal neuropathy (p>0.05). CONCLUSION: This study showed there were numerous cases with common peroneal neuropathy after tibiofibular fracture without a coexisting fibular-head fracture, which shows the importance of indirect nerve injury mechanisms as well as that of direct nerve injury as a cause of peroneal neuropathy. In addition, this study showed that there was no statistically significant correlation between the site of tibio-fibular fracture and the severity of peroneal neuropathy. PMID- 22506188 TI - Ulnar nerve conduction study of the first dorsal interosseous muscle in korean subjects. AB - OBJECTIVE: To derive normative values for ulnar nerve conduction study of the active recording electrode on the first dorsal interosseous muscle (FDI) and the reference electrode on the proximal phalanx of the thumb. METHOD: Ulnar nerve motor conduction study with FDI and abductor digiti minimi muscle (ADM) recording was performed in 214 hands of 107 healthy subjects. Ulnar NCS was performed with 2 different recording electrode montages (ADM-base of 5(th) finger; FDI-thumb) and differences in latency and amplitude were compared. Using this technique, the initial positivity of ulnar compound muscle action potential (CMAP) was not observed in any response with FDI recording. RESULTS: The maximal values for distal motor latency to the ADM and FDI muscle were 3.8 ms and 4.4 ms, respectively. The maximal difference of distal motor latency between the bilateral FDI recordings was 0.6 ms. The maximal ipsilateral latency difference between ADM and FDI was 1.4 ms. CONCLUSION: Placement of the reference electrode on the thumb results in a CMAP without an initial positivity and the normative values obtained may be useful in the diagnosis of ulnar neuropathy at the wrist. PMID- 22506189 TI - Subacromial Bursa Injection of Hyaluronate with Steroid in Patients with Peri articular Shoulder Disorders. AB - OBJECTIVE: To investigate the additive effect of sono-guided subacromial bursa injection of hyaluronate with steroid in patients with peri-articular shoulder disorders. METHOD: This prospective randomized controlled trial involved 26 patients who had shoulder pain. Group A, consisting of 13 patients, was treated with a sono-guided subacromial bursa injection containing a mixture of 0.5% lidocaine (5 ml) and triamcinolone 40 mg (1 ml), followed by injection with sodium hyaluronate (2 ml) once a week for 3 weeks. The other 13 patients (Group B) were treated with a sono-guided subacromial bursa injection containing a mixture of 0.5% lidocaine (5 ml) and triamcinolone 40 mg (1 ml) once a week for 3 weeks. The effects were assessed using a visual analogue scale (VAS) of shoulder pain, active range of motion (AROM), shoulder function assessment scale (SFA), shoulder disability questionnaire (SDQ) at study entry and every week from first injection until 4 weeks after the 1(st) injection (= 2 weeks after 3(rd) injection). RESULTS: (1) Demographic features and all parameters measured before injection did not show a significant difference between the 2 groups. (2) Statistically significant improvements were shown in VAS, SFA, SDQ during the 1(st), 2(nd), and 4(th) week after the first injection in both groups (p<0.05). (3) SFA showed significant improvement at 1 week after injection only in group A (p<0.05). (4) AROM of internal rotation showed significant improvement at week 4 after the 1(st) injection only in group A (p<0.05). CONCLUSION: Subacromial bursa injection of hyaluronate with steroid in patients with peri-articular shoulder disorders has additive effects on functional improvement of the affected shoulder, including the AROM of internal rotation. PMID- 22506190 TI - The availability of radiological measurement of tibial torsion: three-dimensional computed tomography reconstruction. AB - OBJECTIVE: To assess the intra-rater and inter-rater reliability for measuring tibial torsion measurements by a radiographic method using three-dimensional computed tomography reconstruction (3D-CT) and to compare the physical measures to those of 3D-CT. METHOD: The study included 33 children who presented with intoeing gait. Tibial torsion was measured by 3D-CT. Distal reference point was the bimalleolar axis. Proximal reference points were the transtibial axis and posterior condylar axis. Physical measurements included thigh-foot angle (TFA) and bimalleolar angle (BMA). 3D-CT measurement and physical measurement were performed twice at both lower extremities by each rater. The intra-rater and inter-rater reliability were calculated by intraclass correlation coefficiency (ICC). The relationship between radiological and physical examination was calculated by Spearman correlation coefficient. RESULTS: The 3D-CT measures for tibial torsion were reliable within individual raters and between different raters. However, physical measures for tibial torsion were reliable within an individual rater but not reliable between raters. The 3D-CT measures by any proximal reference axis were more reliable within a rater and between raters than physical measurements. There was no significant impact introduced by the selection of the proximal reference axis. The correlation coefficiency between 3D CT and physical measurement methods was low. CONCLUSION: Because the 3D-CT measurements for tibial torsion are more reliable than physical measurements, we recommend that accurate diagnosis of internal tibial torsion should be detected by using 3D-CT measurements. Also, considering the disadvantages of radiological measurements, physical measurement may be used for short term follow-up by same raters, as intra-rater reliability is relatively good. PMID- 22506191 TI - Characteristics of computerized neuropsychologic test according to the location of aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: To evaluate characteristics of cognitive impairments according to the location of aneurysmal subarachnoid hemorrhage (SAH) using a computerized neuropsychological test (CNT). METHOD: A total of 211 patients were transferred to our rehabilitation department after becoming neurologically stable following aneurysmal SAH. Twenty four of the 211 patients met the inclusion criteria and participated in a screening test using the mini-mental state examination (MMSE). Twenty patients with a MMSE score <26 were followed prospectively with a CNT and Beck depression inventory (BDI). Eleven patients had anterior communicating artery (ACoA) aneurysms and the other 9 had middle cerebral, internal carotid or posterior communicating artery aneurysms. RESULTS: There were no differences in age, education, Hunt and Hess grade, or Fisher grade between the patients with ACoA aneurysmal SAH compared to patients with other aneurysmal SAH. In patients with ACoA aneurysmal SAH, scores of BDI (p=0.020), verbal learning test were lower than those of other aneurysmal SAH patients. In contrast, patients with non ACoA aneurysmal SAH took significantly more time in auditory (p=0.025) and visual continuous performance tests (p=0.028). The cognitive deficit following aneurysmal SAH could be characterized by its location using CNT. CONCLUSION: Using CNT in aneurysmal SAH patients could be a useful tool for evaluating the characteristics of cognitive impairment and planning rehabilitation programs according to each characteristic. PMID- 22506192 TI - Prediction of treatment outcome with bioimpedance measurements in breast cancer related lymphedema patients. AB - OBJECTIVE: To investigate the usefulness of bioimpedance measurement for predicting the treatment outcome in breast cancer related lymphedema (BCRL) patients. METHOD: Unilateral BCRL patients who received complex decongestive therapy (CDT) for 2 weeks (5 days per week) were enrolled in this study. We measured the ratio of extracellular fluid (ECF) volume by using bioelectrical impedance spectroscopy (BIS), and single frequency bioimpedance analysis (SFBIA) at a 5 kHz frequency before treatment. Arm circumferences were measured at 10 cm above and below the elbow before and after treatment. We also investigated whether there is correlation between ECF ratio and SFBIA ratio with the change of arm circumference after CDT. RESULTS: A total of 73 patients were enrolled in this study. The higher ECF ratio was significantly correlated with higher reduction of arm circumference at both above and below the elbow after treatment, but the higher SFBIA ratio was correlated only with the higher reduction of arm circumference below the elbow. CONCLUSION: These results show that ECF volume measurements and SFBIA before treatment are useful tools for predicting the outcome of patients with lymphedema. We concluded that ECF volume measure can be used as a screening tool for predicting treatment outcome of BCRL patients. PMID- 22506193 TI - Voice onset time variations of korean stop consonants in aphasic speakers. AB - OBJECTIVE: To compare the voice onset time (VOT) differences of Korean stops in the initial and intervocalic positions between the aphasic patients with peculiarities of aspiration and a control group. METHOD: We examined 15 aphasic patients (nine males, six females) who had suffered a stroke (average age 49.7 years) and 15 healthy controls (average age 47.4 years). An aphasia examination was made by an aphasia battery of three standard tests and VOT was analyzed instrumentally. Stop consonants in the initial and intervocalic position were measured to categorize them according to aphasia types, place of articulation, and manner of articulation. RESULTS: VOT of the aphasic patients with peculiarities of aspiration had a greater difference than that of the controls, indicating that the temporal non-coordination between the laryngeal adjustment and oral articulators of aphasic patients happens due to the VOT of stops in the initial and intervocalic positions (p<0.05). CONCLUSION: VOT of stop consonants in the initial position produced by aphasic patients tends to be proportional to their breathing. It can cause glottal width and make aphasic patients' VOT duration longer. Lastly, the method to measure the VOT of aphasic patients is more significant for the types of phonation than for the places of articulation, and makes it possible to induce abnormal VOT. PMID- 22506194 TI - Balance control and knee osteoarthritis severity. AB - OBJECTIVE: To investigate balance control according to the severity of knee osteoarthritis (OA) using clinical tests and Tetra-ataxiometric posturography (Tetrax(r)). METHOD: A total 80 patients with primary knee OA classified according to American College of Rheumatology criteria, and 40 age-matched controls were enrolled in this study. Of those with OA, 39 patients had mild OA (Kellgren-Lawrence [KL] grade 1, 2) and the other 41 had moderate to severe OA (KL grade 3, 4). The postural control capabilities of the subjects were assessed using the timed up and go test (TUG), Berg balance scale (BBS), and Tetrax(r), which utilizes two paired force plates to measure vertical pressure fluctuations over both heels and forefeet. The subjects were checked for their stability index (ST), Fourier index, weight distribution index (WDI), and synchronization index (SI) in eight positions using Tetrax(r). RESULTS: Patients with moderate to severe OA exhibited significantly higher stability indices in all positions than patients with mild OA. The Fourier index was also higher in patients with moderate to severe OA than in patients with mild OA. However, the weight distribution index and synchronization of both heels and forefeet were not significantly different in the three groups. CONCLUSION: These findings suggest that patients with moderate to severe OA have more deficits in balance control than those with mild disease. Therefore, evaluation of balance control and education aimed at preventing falls would be useful to patients with knee OA. PMID- 22506195 TI - Factors associated with depressive symptoms in patients with chronic low back pain. AB - OBJECTIVE: To investigate depressive symptoms and their related factors in patients with chronic low back pain in Korea. METHOD: A cross-sectional study using data from the fourth Korea National Health and Nutrition Examination Survey (KNHANES IV) 2009 was undertaken. The sample consisted of 1,426 participants with chronic low back pain. Multifactorial regression analysis was used to identify the association between depressive symptoms and socioeconomic demographics and other chronic diseases. RESULTS: Among the 371 (26.0%) patients with depression, significant factors associated with depressive symptoms were female gender (odds ratio [OR], 2.691; 95% confidence interval [CI], 1.724-4.199), medical aid beneficiary (OR, 1.371; 95% CI, 1.039-1.810), a dependent group for activities of daily living (OR, 1.570; 95% CI, 1.180-2.087), 'not good' in the perceived health category (OR, 2.309; 95% CI, 1.730-3.081) and in a cancer group (OR, 1.803; 95% CI, 1.051-3.093). CONCLUSION: This study provides the foundation for managing patients with chronic low back pain and depressive symptoms. Clinicians managing chronic low back pain should consider risk factors for depressive symptoms. PMID- 22506197 TI - Pure apraxia of speech - a case report -. AB - Apraxia of speech (AOS) is the impairment of motor programming. However, the exact nature of this deficit remains unclear. In particular, AOS without other speech-language deficit is called pure AOS, but it is very rare. When diagnosing AOS, the characteristic of articulation is considered a crucial criterion, which has been proposed for differentiating AOS from phonological and dysarthric disorders. The present study reports on pure AOS in a 37-year-old right-handed male after a left insular, front, temporal infarction. This report may be useful for further AOS study and diagnosis in the clinical setting. PMID- 22506196 TI - The shoulder gradient in patients with unilateral shoulder impingement syndrome. AB - OBJECTIVE: To investigate the relationship between the shoulder gradient and acromiohumeral interval of both shoulders in patients with unilateral shoulder impingement syndrome. METHOD: Using the angulometer, we measured the shoulder gradient in patients with unilateral shoulder impingement syndrome in a standing position. Using the radiography, we measured the acromiohumeral interval and the angle between a vertical line and a line connecting a superior angle with an inferior angle of the scapula. RESULTS: In patients with unilateral shoulder impingement syndrome, the frequency of shoulder impingement syndrome was 76.2% (16 of 21) on the side of the relatively lower shoulder. The mean acromiohumeral interval on the side of the lower shoulder was 10.03+/-1.28 mm, compared with 10.46+/-1.50 mm for the higher shoulder. The angle between a vertical line and a line connecting a superior angle with an inferior angle of the scapular of the side of the lower shoulder was -0.31+/-3.73 degrees, compared with 3.85+/-4.42 degrees for the higher shoulder. CONCLUSION: The frequency of shoulder impingement syndrome was significantly higher on the side of the relatively lower shoulder, and there is no significant difference in the acromiohumeral interval between the side of the lower shoulder and that of the higher shoulder. In patients with unilateral shoulder impingement syndrome, the scapular on the side of lower shoulder was more rotated downward than on the side of the higher shoulder. PMID- 22506198 TI - Myelopathy caused by spinal dural arterio-venous fistula after first lumbar vertebral body fracture - a case report -. AB - Spinal dural arteriovenous fistula is a rare vascular lesion of the spinal cord associated with progressive myelopathy. Symptoms include progressive gait dysfunction, weakness, sensory loss, and bowel and bladder dysfunction. Because these symptoms overlap with other common causes of myelopathy and the disease is rare, spinal dural arteriovenous fistula is often not suspected and the time to diagnosis is long. We report the case of a 60-year-old woman who presented with progressive lower limb weakness and gait disturbance diagnosed as spinal dural arteriovenous fistula involving a fractured L1 vertebral body. PMID- 22506199 TI - Dural arteriovenous fistula on the brain stem and upper cervical spinal cord - a case report -. AB - A 53-year-old man abruptly developed headache and unconsciousness. Brain computed tomography (CT) and CT angiography showed subarachnoid hemorrhage, intraventricular hemorrhage, and multiple tortuous vascular structures on the brain stem and upper cervical spinal cord. Four-vessel angiography displayed intradural ventral arteriovenous fistula, supplied by the left vertebral and occipital arteries. Drainage was via both sigmoid sinus and cervical venous plexus. He had been treated with transarterial coil embolization of the left vertebral artery. Subsequently, he suffered from left hemiplegia and cognitive problem. Brain magnetic resonance (MR) and MR angiography performed 4 weeks later revealed multiple infarctions on the left cerebellum, left upper cervical spinal cord, and both medial thalamus, as well as occlusion of the left vertebral artery with reduction in varix size. After rehabilitative management, his muscle strength and cognitive function improved. We report a very rare case of dural arteriovenous fistula on the brain stem and upper cervical spinal cord. PMID- 22506200 TI - Dysphagia in Ramsay Hunt's Syndrome - A Case Report -. AB - Ramsay-Hunt syndrome is caused by varicella zoster virus infection in the geniculate ganglion of the facial nerve. It is characterized by facial palsy, otic pain, and herpetic vesicles around the auricle and external auditory canal. Additionally, symptoms may develop related to other cranial nerve involvement, such as dizziness or hearing loss by the vestibulocochlear nerve being invaded. We report a rare case of a Ramsay-Hunt syndrome patient who developed dysphagia due to multiple cranial nerve involvement including the glossopharyngeal nerve and vagus nerve. PMID- 22506201 TI - Combined therapy of orthopedic surgery after deep brain stimulation in cerebral palsy mixed type - a case report -. AB - Dystonia is a symptom defined by involuntary and irregular contractions of the muscles, which cause movement disorders and postural problems. Deep brain stimulation (DBS) in globus pallidus interna (GPi) is a good option for controlling dystonia. DBS has already been shown to have significant effects on primary dystonia as well as Parkinson's disease. Dystonia is very difficult to manage, as seen in cerebral palsy (CP) mixed with spasticity. As CP patients grow, their musculoskeletal problems may require orthopedic surgery. However, the outcome of orthopedic surgery is not usually suitable due to dystonia. Therefore, we attempted to control dystonia through DBS initially and perform orthopedic surgery to correct musculoskeletal deformities after treatment of dystonia. Herein, we report a case that showed remarkable improvement in terms of the dystonia rating scale and gait pattern after combined therapy of DBS and orthopedic surgery. PMID- 22506202 TI - Facilitation of corticospinal excitability according to motor imagery and mirror therapy in healthy subjects and stroke patients. AB - OBJECTIVE: To delineate the changes in corticospinal excitability when individuals are asked to exercise their hand using observation, motor imagery, voluntary exercise, and exercise with a mirror. METHOD: The participants consisted of 30 healthy subjects and 30 stroke patients. In healthy subjects, the amplitudes and latencies of motor evoked potential (MEP) were obtained using seven conditions: (A) rest; (B) imagery; (C) observation and imagery of the hand activity of other individuals; (D) observation and imagery of own ipsilateral hand activity; (E) observation and imagery of the hand activity of another individual with a mirror; (F) observation and imagery of own symmetric ipsilateral hand activity (thumb abduction) with a mirror; and (G) observation and imagery of own asymmetric ipsilateral hand activity (little finger abduction) with a mirror. In stroke patients, MEPs were obtained in the A, C, D, E, F conditions. RESULTS: In both groups, increment of the percentage MEP amplitude (at rest) and latency decrement of MEPs were significantly higher during the observation of the activity of the hand of another individual with a mirror and during symmetric ipsilateral hand activity on their own hand with a mirror than they were without a mirror. In healthy subjects, the increment of percentage MEP amplitude and latency decrement were significantly higher during the observation of the symmetric ipsilateral hand activity with a mirror compared to the observation of the activity of the asymmetric ipsilateral hand with a mirror of their own hand. CONCLUSION: In both groups, corticospinal excitability was facilitated by viewing the mirror image of the activity of the ipsilateral hand. These findings provide neurophysiological evidence supporting the application of various mirror imagery programs during stroke rehabilitation. PMID- 22506203 TI - Motor evoked potentials of the upper extremities in healthy children. AB - OBJECTIVE: To evaluate and compare the organization of descending motor pathways to upper extremity muscles among healthy children. METHOD: The healthy children were 16 males and 7 females aged 1-19 years (average, 9 years), and eight healthy adults were enrolled as the control group. Transcranial magnetic stimulation was applied to bilateral motor cortices, and motor evoked potentials (MEPs) were recorded using surface electrodes from the first dorsal interossei (FDI), the biceps brachii (BIC), and the deltoid (DEL) muscles. The onset latency, central motor conduction time (CMCT), and amplitude were obtained during a relaxed state. RESULTS: MEPs of FDI were obtained from subjects aged 13 months. The frequency of obtaining MEPs in proximal and distal muscles increased with age, although there was a less frequent incidence of obtaining MEPs in the proximal BIC and DEL muscles compared with those in the distal FDI muscle. MEP amplitudes increased with age, whereas latencies were relatively constant. CMCTs showed a similar pattern of maturation, and adult values were obtained by 13-years-of-age. CONCLUSION: These results suggest that the proximal and distal muscles of the upper extremities show different maturation and organization patterns. PMID- 22506204 TI - Effect of repetitive transcranial magnetic stimulation on patients with brain injury and Dysphagia. AB - OBJECTIVE: To investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on recovery of the swallowing function in patients with a brain injury. METHOD: Patients with a brain injury and dysphagia were enrolled. Patients were randomly assigned to sham, and low and high frequency stimulation groups. We performed rTMS at 100% of motor evoked potential (MEP) threshold and a 5 Hz frequency for 10 seconds and then repeated this every minute in the high frequency group. In the low frequency group, magnetic stimulation was conducted at 100% of MEP threshold and a 1 Hz frequency. The sham group was treated using the same parameters as the high frequency group, but the coil was rotated 90 degrees to create a stimulus noise. The treatment period was 2 weeks (5 days per week, 20 minutes per session). We evaluated the Functional Dysphagia Scale (FDS) and the Penetration Aspiration Scale (PAS) with a videofluoroscopic swallowing study before and after rTMS. RESULTS: Thirty patients were enrolled, and mean patient age was 68.2 years. FDS and PAS scores improved significantly in the low frequency group after rTMS, and American Speech-Language Hearing Association National Outcomes Measurements System Swallowing Scale scores improved in the sham and low frequency groups. FDS and PAS scores improved significantly in the low frequency group compared to those in the other groups. CONCLUSION: We demonstrated that low frequency rTMS facilitated the recovery of swallowing function in patients with a brain injury, suggesting that rTMS is a useful modality to recover swallowing function. PMID- 22506205 TI - Usefulness of the Scale for the Assessment and Rating of Ataxia (SARA) in Ataxic Stroke Patients. AB - OBJECTIVE: To examine the usefulness of the Scale for the Assessment and Rating of Ataxia (SARA) in ataxic stroke patients. METHOD: This was a retrospective study of 54 patients following their first ataxic stroke. The data used in the analysis comprised ambulation status on admission and scores on the SARA, the Korean version of the Modified Barthel Index (K-MBI) and the Berg Balance Scale (BBS). The subjects were divided into four groups by gait status and into five groups by level of dependency in activities of daily living (ADLs) based on their K-MBI scores. Data were subjected to a ROC curve analysis to obtain cutoff values on the SARA for individual gait status and levels of activity dependency. The correlations between the SARA, K-MBI and BBS scores were also computed. RESULTS: There was significant correlation between the SARA and the K-MBI scores (p<0.001), and this correlation (r=-0.792) was higher than that found between the BBS and the K-MBI scores (r=0.710). The SARA scores of upper extremity ataxia categories were significantly related to the K-MBI scores of upper extremity related function (p<0.001). The SARA scores were also significantly correlated negatively with ambulation status (p<0.001) and positively with ADL dependency (p<0.001). In the ROC analysis, patients with less than 5.5 points on the SARA had minimal dependency in ADL, while those with more than 23 points showed total dependency. CONCLUSION: SARA corresponds well with gait status and ADL dependency in ataxic stroke patients and is considered to be a useful functional measure in that patient group. PMID- 22506207 TI - Improvement of quiet standing balance in patients with wallenberg syndrome after rehabilitation. AB - OBJECTIVE: To evaluate quiet standing balance of patients with Wallenberg syndrome before and after rehabilitation. METHOD: Six patients with Wallenberg syndrome were enrolled within one month after being affected by an infarct of the lateral medulla. Quiet standing balance was assessed using posturography with eyes open and closed. The assessment was repeated after the patients had undergone rehabilitation treatment for three to nine months, and the results of the two assessments were compared. RESULTS: The quiet standing balance evaluation was performed by measurement of center of pressure (CoP) movement. In the initial test, the mean scores of mediolateral and anteroposterior speed, velocity movement, mediolateral and anteroposterior extent of CoP were all high, indicating impairments of quiet standing balance in the patients. After rehabilitation treatment, the anteroposterior speed and extent, the mediolateral speed and extent, and velocity moment of CoP showed statistically significant reductions in the eyes open condition (p<0.05), and the anteroposterior speed and extent and velocity moment of CoP had decreased in the eyes closed condition (p<0.05). Mediolateral speed and extent of CoP in the eyes closed condition had also decreased, but the reduction was not statistically significant. CONCLUSION: This study demonstrated improvements of quiet standing balance, especially anteroposterior balance, in patients with Wallenberg syndrome following rehabilitation. We suggest that balance training is important in the rehabilitation of Wallenberg syndrome and that, as an objective measure of balance status, posturography is useful in the assessment of quiet standing balance. PMID- 22506206 TI - Rick factors associated with aspiration in patients with head and neck cancer. AB - OBJECTIVE: To determine the major risk factors and abnormal videofluoroscopic swallowing study (VFSS) findings associated with aspiration in patients with head and neck cancer (HNC). METHOD: Risk factors associated with aspiration were investigated retrospectively in 241 patients with HNC using medical records and pre-recorded VFSS. Age, gender, lesion location and stage, treatment factors, and swallowing stage abnormalities were included. RESULTS: Aspiration occurred in 50.2% of patients. A univariate analysis revealed that advanced age, increased duration from disease onset to VFSS, higher tumor stage, increased lymph node stage, increased American Joint Committee on Cancer (AJCC) stage, operation history, chemotherapy history, and radiotherapy history were significantly associated with aspiration (p<0.05). Among them, advanced age, increase AJCC stage, operation history, and chemotherapy history were significantly associated with aspiration in the multivariate analysis (p<0.05). Delayed swallowing reflex and reduced elevation of the larynx were significantly associated with aspiration in the multivariate analysis (p<0.05). CONCLUSION: The major risk factors associated with aspiration in patients with HNC were advanced age, higher AJCC stage, operation history, and chemotherapy history. A VFSS to evaluate aspiration is needed in patients with NHC who have these risk factors. Delayed swallowing reflex and reduced elevation of the larynx were major abnormal findings associated with aspiration. Dysphagia rehabilitation should focus on these results. PMID- 22506208 TI - Length of hospital stay in patients with spinal cord injury. AB - OBJECTIVE: To provide the latest statistics about the length of hospital stay (LOS) and the number of hospitals where the patient was admitted (NHA) for patients with spinal cord injury (SCI) and to investigate the correlated demographic characteristics. METHOD: In total, 277 patients with SCI who were members of the Korea Spinal Cord Injury Association were included in the analysis. The survey was conducted by self-completed questionnaires to collect data on LOS, NHA, and demographic variables. RESULTS: Mean LOS was 13.5+/-9.7 months and the mean NHA was 2.7+/-1.4. Patients who suffered from SCI by traffic accidents showed a longer LOS and larger NHA than those with other causes. The mean LOS for patients with traumatic SCI was longer than that whose cause of injury was disease. Patients discharged in the 2000s had a longer LOS and a larger NHA than those discharged earlier. Other factors such as gender, age at the time of injury, neurological category, and ambulation capability did not result in a significant difference in either LOS or NHA. CONCLUSION: The mean LOS of domestic patients with SCI was longer than the values reported in foreign studies. Interestingly, neither neurological category nor functional status were related to LOS. These findings suggest that other factors such as socio psychological factors, other than the medical state of the patient, have an effect on the LOS of patients with SCI in Korea. PMID- 22506209 TI - Clinical, Electrophysiological Findings in Adult Patients with Non-traumatic Plexopathies. AB - OBJECTIVE: To ascertain the etiology of non-traumatic plexopathy and clarify the clinical, electrophysiological characteristics according to its etiology. METHOD: We performed a retrospective analysis of 63 non-traumatic plexopathy patients that had been diagnosed by nerve conduction studies (NCS) and needle electromyography (EMG). Clinical, electrophysiological, imaging findings were obtained from medical records. RESULTS: We identified 36 cases with brachial plexopathy (BP) and 27 cases with lumbosacral plexopathy (LSP). The causes of plexopathy were neoplastic (36.1%), thoracic outlet syndrome (TOS) (25.0%), radiation induced (16.7%), neuralgic amyotrophy (8.3%), perioperative (5.6%), unknown (8.3%) in BP, while neoplastic (59.3%), radiation induced (22.2%), neuralgic amyotrophy (7.4%), psoas muscle abscess (3.7%), and unknown (7.4%) in LSP. In neoplastic plexopathy, pain presented as the first symptom in most patients (82.8%), with the lower trunk of the brachial plexus predominantly involved. In radiation induced plexopathy (RIP), pain was a common initial symptom, but the proportion was smaller (50%), and predominant involvements of bilateral lumbosacral plexus and whole trunk of brachial or lumbosacral plexus were characteristic. Myokymic discharges were noted in 41.7% patients with RIP. Abnormal NCS finding in the medial antebrachial cutaneous nerve was the most sensitive to diagnose TOS. Neuralgic amyotrophy of the brachial plexus showed upper trunk involvement in all cases. CONCLUSION: By integrating anatomic, pathophysiologic knowledge with detailed clinical assessment and the results of ancillary studies, physicians can make an accurate diagnosis and prognosis. PMID- 22506210 TI - Motor unit number estimation and motor unit action potential analysis in carpal tunnel syndrome. AB - OBJECTIVE: To evaluate the clinical significance of motor unit number estimation (MUNE) and quantitative analysis of motor unit action potential (MUAP) in carpal tunnel syndrome (CTS) according to electrophysiologic severity, ultrasonographic measurement and clinical symptoms. METHOD: We evaluated 78 wrists of 45 patients, who had been diagnosed with CTS and 42 wrists of 21 healthy controls. Median nerve conduction studies, amplitude and duration of MUAP, and the MUNE of the abductor pollicis brevis were measured. The cross sectional area (CSA) of the median nerve at the pisiform and distal radioulnar joint level was determined by high resolution ultrasonography. Clinical symptom of CTS was assessed using the Boston Carpal Tunnel Questionnaire (BCTQ). RESULTS: The MUNE, the amplitude and the duration of MUAP of the CTS group were significantly different from those found in the control group. The area under the ROC curve was 0.944 for MUNE, 0.923 for MUAP amplitude and 0.953 for MUAP duration. MUNE had a negative correlation with electrophysiologic stage of CTS, amplitude and duration of MUAP, CSA at pisiform level, and the score of BCTQ. The amplitude and duration of MUAP had a positive correlation with the score of BCTQ. The electrophysiologic stage was correlated with amplitude but not with the duration of MUAP. CONCLUSION: MUNE, amplitude and duration of MUAP are useful tests for diagnosis of CTS. In addition, the MUNE serves as a good indicator of CTS severity. PMID- 22506211 TI - Short-term effects of pulsed radiofrequency on chronic refractory cervical radicular pain. AB - OBJECTIVE: To evaluate the short-term effectiveness of pulsed radiofrequency on the dorsal root ganglion (DRG) in patients with chronic refractory cervical radicular pain. METHOD: Fifteen patients (13 males, 2 females; mean age, 55.9 years) with chronic radicular pain due to cervical disc herniation or foraminal stenosis refractory to active rehabilitative management, including transforaminal cervical epidural steroid injection and exercise, were selected. All patients received pulsed radiofrequency on the symptomatic cervical dorsal root ganglion and were carefully evaluated for neurologic deficits and side effects. The clinical outcomes were measured using a visual analogue scale (VAS) and a neck disability index (NDI) before treatment, one and three months after treatment. Successful pain relief was defined as a 50% or greater reduction in the VAS score as compared with the pre-treatment score. After three months, we categorized the patients' satisfaction. RESULTS: The average VAS for radicular pain was reduced significantly from 5.3 at pretreatment to 2.5 at 3 months post-treatment (p<0.05). Eleven of 15 patients (77.3%) after cervical pulsed RF stimulation reported pain relief of 50% or more at the 3 month follow-up. The average NDI was significantly reduced from 44.0% at pretreatment to 35.8% 3 months post-treatment (p<0.05). At 3 months post-treatment, eleven of fifteen patients (73.3%) were satisfied with their status. No adverse effects were observed. CONCLUSION: The results demonstrate that the application of pulsed radiofrequency on DRG might be an effective short-term intervention for chronic refractory cervical radicular pain. Further studies, including a randomized controlled trial with long-term follow-up, are now needed. PMID- 22506212 TI - Kambin's Triangle Approach of Lumbar Transforaminal Epidural Injection with Spinal Stenosis. AB - OBJECTIVE: To compare the short-term effect and advantage of transforaminal epidural steroid injection (TFESI) performed using the Kambin's triangle and subpedicular approaches. METHOD: Forty-two patients with radicular pain from lumbar spinal stenosis were enrolled. Subjects were randomly assigned to one of two groups. All procedures were performed using C-arm KMC 950. The frequency of complications during the procedure and the effect of TFESI at 2 and 4 weeks after the procedure between the two groups were compared. Short-term outcomes were measured using a visual numeric scale (VNS) and a five-grade scale. Multiple logistic regression analyses were performed to evaluate the relationship between possible outcome predictors (Kambin's triangle or subpedicular approach, age, duration of symptoms and sex) and the therapeutic effect. RESULTS: VNS was improved 2 weeks after the injection and continued to improve until 4 weeks in both groups. There were no statistical differences in changes of VNS, effectiveness and contrast spread pattern between these two groups. No correlation was found between the other variables tested and therapeutic effect. Spinal nerve pricking occurred in five cases of the subpedicular and in none of the cases of the Kambin's triangle approach (p<0.05). CONCLUSION: The Kambin's triangle approach is as efficacious as the subpedicular approach for short-term effect and offers considerable advantages (i.e., less spinal nerve pricking during procedure). The Kambin's triangle approach maybe an alternative method for transforaminal epidural steroid injection in cases where needle tip positioning in the anterior epidural space is difficult. PMID- 22506213 TI - Predictive risk factors for refracture after percutaneous vertebroplasty. AB - OBJECTIVE: To identify risk factors for developing a vertebral refracture after percutaneous vertebroplasty. METHOD: A retrospective analysis of 60 patients who had undergone percutaneous vertebroplasty between January 2008 and April 2010 was conducted. All patients were observed for a 1 year follow-up period, and fracture was defined when it was both clinically reported and radiographically confirmed. Twenty-seven patients with a refractured vertebra and 33 patients without a refracture were included. Of the 60 patients, 20 presented with a refracture from a cemented vertebra, whereas the remaining 40 patients did not. Clinical, imaging and procedure-related factors for each group were analyzed by the Fisher's exact, chi-square, and the Mann-Whitney U-tests. RESULTS: Local kyphotic angle and sagittal index were significant as a result of researching various risk factors related to vertebral refracture (p<0.001, p<0.001, respectively) and refracture from a cemented vertebra itself (p=0.004, p<0.001, respectively). Other factors were not significant. CONCLUSION: Patients who had a high preoperative local kyphotic angle and a high sagittal index required a close follow-up and attention. PMID- 22506215 TI - Predictive Value of Test of Infant Motor Performance for Infants based on Correlation between TIMP and Bayley Scales of Infant Development. AB - OBJECTIVE: To assess the relationship of scores on the test of infant motor performance (TIMP), with those on the Bayley scales of infant development (BSID), and to investigate the sensitivity and specificity of TIMP and the optimal cut off value of TIMP scores using ROC analysis. METHOD: Seventy-six preterm and term infants were recruited from neonatal intensive care units. Subjects were tested with the TIMP at their initial visit and after 6 months, they were tested by using BSID. RESULTS: In the reliability study, TIMP scores showed highly significant correlation with the Bayley physical developmental index (BPDI) (p=0.001) and Bayley mental developmental index (BMDI) (p=0.017). Receiver operator characteristics (ROC) curve analysis was performed to evaluate the TIMP test for screening infant motor development. ROC analysis showed an area under the curve (AUC) of 0.825 (p=0.005) in BPDI and 0.992 (p=0.014) in BMDI, indicating an excellent classification performance of the model. The optimal cut off value where a sensitivity of 86%, and specificity of 68% were achieved with the TIMP was 1.50 (between average and below average) in BPDI and where a sensitivity of 100%, and specificity of 66% were achieved with the TIMP was 1.50 in BMDI. CONCLUSION: Our results indicate that the TIMP provides a reliable and valid measurement that can be used for the evaluation of motor function in preterm and term infants. TIMP was highly sensitive and specific with the follow up examination of BSID. Therefore it can be used as a reliable screening tool for neonates and infants aged <4 months. PMID- 22506214 TI - Association between Cross-sectional Areas of Lumbar Muscles on Magnetic Resonance Imaging and Chronicity of Low Back Pain. AB - OBJECTIVE: To investigate the prognostic value of cross-sectional areas (CSA) of paraspinal (multifidus and erector spinae) and psoas muscles on magnetic resonance imaging (MRI) in chronicity of low back pain. METHOD: Thirty-eight subjects who visited our hospital for acute low back pain were enrolled. Review of their medical records and telephone interviews were done. Subjects were divided into two groups; chronic back pain group (CBP) and a group showing improvement within 6 months after onset of pain (IBP). The CSA of paraspinal and psoas muscles were obtained at the level of the lower margin of L3 and L5 vertebrae using MRI. RESULTS: CSA of erector spinae muscle and the proportion of the area to lumbar muscles (paraspinal and psoas muscles) at L5 level in the CBP group were significantly smaller than that of the IBP group (p<0.05). The mean value of CSA of multifidus muscle at L5 level in the CBP group was smaller than that of the IBP group, but was not statistically significant (p>0.05). CSA of psoas muscle at L5 level and all values measured at L3 level were not significantly different between the groups (p>0.05). CONCLUSION: CSA of erector spinae muscle at the lower lumbar level and the proportion of the area to the lumbar muscles at the L5 level can be considered to be prognostic factors of chronicity of low back pain. PMID- 22506216 TI - Neurodevelopmental disorders of children screened by the infantile health promotion system. AB - OBJECTIVE: To perform an in depth evaluation of children, and thus provide a systematic method of managing children, who after infantile health screening, were categorized as suspected developmental delay. METHOD: 78 children referred to the Developmental Delay Clinic of Ilsan Hospital after suspected development delay on infantile health examinations were enrolled. A team comprised of a physiatrist, pediatrician and pediatric psychiatrist examined the patients. Neurological examination, speech and cognitive evaluation were done. Hearing tests and chromosome studies were performed when needed clinically. All referred children completed K-ASQ questionnaires. Final diagnoses were categorized into specific language impairment (SLI), global developmental delay (GDD), intellectual disability (ID), cerebral palsy (CP), motor developmental delay (MD) or autism spectrum disorder (ASD). RESULTS: 72 of the 78 patients were abnormal in the final diagnosis, with a positive predictive value of 92.3%. Thirty (38.4%) of the 78 subjects were diagnosed as GDD, 28 (35.8%) as SLI, 5 (6.4%) as ASD, 9 (12.5%) as MD, and 6 (7.6%) as normal. Forty five of the 78 patients had risk factors related to development, and 18 had a positive family history for developmental delay and/or autistic disorders. The mean number of abnormal domains on the K-ASQ questionnaires were 3.6 for ASD, 2.7 for GDD, 1.8 for SLI and 0.6 for MD. Differences between these numbers were statistically significant (p<0.05). CONCLUSION: Because of the high predictive value of the K-ASQ, a detailed evaluation is necessary for children suspected of developmental delay in an infantile health promotion system. PMID- 22506218 TI - Effects of modified dynamic metacarpophalangeal joint flexion orthoses after hand burn. AB - OBJECTIVE: To assess the effectiveness of modified dynamic metacarpophalangeal joint flexion orthoses for treatment of post-burn hand contractures. METHOD: We enrolled 42 hand burn patients with limited range of motion at the metacarpophalangeal joints in this study. The patients were randomly assigned into either a control or an orthotic group. Both groups received the standard rehabilitation therapy focused on hand therapy; 21 subjects in the orthotic group wore a splint for 3 hours per day for 8 weeks. Hand function was measured by active range of motion, grip strength and other assessment tools. All parameters were estimated using the Mann-Whitney U test at the beginning and the end of the treatment after 8 weeks. RESULTS: The 21 subjects that had an orthotic intervention showed significant improvement in the range of motion at 2nd, 3rd, 4th and 5th metacarpophalangeal joints (p<0.05). However, the grip strength was not significantly increased after the 8 weeks of treatment compared to control group (p>0.05). There was a significant difference in the hand function scales between the 2 groups (p<0.05). CONCLUSION: The modified dynamic metacarpophalangeal joint flexion orthoses provide continuous flexion to metacarpophalangeal joint that is needed for the restoration of range of motion in post-burn hand contractures. For the clinical application of hand orthoses in patients with hand disorders, additional research into its affects are required. PMID- 22506217 TI - Comparison of manual balance and balance board tests in healthy adults. AB - OBJECTIVE: To investigate the correlations of scores on the Timed Up and Go (TUG) test and the Single Leg Stance (SLS) test with stability scores on the Biodex Balance System (BBS) in healthy adults. METHOD: The postural balance of 73 participants was measured on the TUG and SLS tests and with the Overall Stability Index (OSI) on the BBS. The participants were divided into groups by age and by times on the TUG and SLS. The correlations between TUG or SLS and OSI scores were analyzed by groups. RESULTS: TUG scores were significantly correlated with OSI scores in age under 65 years, TUG over 10 seconds and SLS over 30 seconds groups (level 12). TUG scores were also correlated with OSI in total (level 10) and TUG under 10 seconds groups (level 2). However, there were no significant relationships between SLS and OSI scores. CONCLUSION: OSI scores on the BBS are significantly correlated with TUG scores, especially at the easy levels. According to the findings of present study, relatively easy BBS levels are considered to assess the postural balance in healthy adults. PMID- 22506219 TI - Effects of the off-loading brace on the activation of femoral muscles -a preliminary study-. AB - OBJECTIVE: To provide the off-loading knee brace was designed relief for the pain associated with osteoarthritis by reduce loads on the degenerative compartment of the knee. This study examined the effects of the off-loading knee brace on activation of femoral muscles during squatting, slow and fast walking exercise in healthy young individuals. METHOD: Ten healthy male subjects without a history of knee pain were recruited. Each subject was asked to do squatting, slow and fast walking exercises with a brace secured to the dominant leg. The same exercises were repeated without the brace. Surface electromyographic (sEMG) data was collected from the vastus medialis oblique (VMO), vastus lateralis (VL) and biceps femoris (BF) muscles from the dominant side of the leg. All dynamic root mean squre (RMS) values of sEMG were standardized to static RMS values of the maximal isometric contraction and expressed as a percentage of maximal activity. RESULTS: We found that VMO activity was significantly decreased with application of the off-loading knee brace during squatting and fast walking exercise. However there were no significant differences in VMO activity with application of the off loading knee brace during slow walking exercise. CONCLUSION: These results suggest that the external moment of the brace which effectively stabilized the patella in the movement in which the knee joints become relatively unstable. The brace could be useful in the short term, but for long-term use, weakening of the VMO is predicted. Therefore the program of selective muscular strength strengthening for the VMO should be emphasized. PMID- 22506220 TI - The influence of backrest inclination on buttock pressure. AB - OBJECTIVE: To assess the effects of backrest inclination of a wheelchair on buttock pressures in spinal cord injured (SCI) patients and normal subjects. METHOD: The participants were 22 healthy subjects and 22 SCI patients. Buttock pressures of the participants were measured by a Tekscan(r) pressure sensing mat and software while they were sitting in a reclining wheelchair. Buttock pressures were recorded for 90 degrees , 100 degrees , 110 degrees , 120 degrees and 130 degrees seat-to-back angles at the ischial tuberosity (IT) and sacrococcygeal (SC) areas. Recordings were made at each angle over four seconds at a sampling rate of 10 Hz. RESULTS: The side-to-side buttock pressure differences in the IT area for the SCI patients was significantly greater than for the normal subjects. There was no significant difference between the SCI patients and the normal subjects in the buttock pressure change pattern of the IT area. Significant increases in pressure on the SC area were found as backrest inclination angle was changed to 90 degrees , 100 degrees and 110 degrees in the normal subjects, but no significant differences were found in the SCI patients. CONCLUSION: Most of the SCI patients have freeform posture in wheelchairs, and this leads to an uneven distribution of buttock pressure. In the SCI patients, the peak pressure in the IT area reduced as the backrest angle was increased, but peak pressure at the SC area remained relatively unchanged. To reduce buttock pressure and prevent pressure ulcers and enhance ulcer healing, it can be helpful for tetraplegic patients, to have wheelchair seat-to-back angles above 120 degrees . PMID- 22506221 TI - A survey on activities of daily living and occupations of upper extremity amputees. AB - OBJECTIVE: To assess prosthetic use by upper extremity amputees, and their difficulties with prostheses in activities of daily living and occupations. METHOD: This study is based on a survey of 307 subjects, who were using prostheses manufactured in the Center of Prosthetics and Orthotics. The survey questionnaire included items about general demographic characteristics, side and level of amputation, type of prosthesis and its use, and difficulties in the activities of daily living, employment and driving. RESULTS: The most common type of prosthesis was the cosmetic hand type (80.2%). There were no statistically significant correlations between satisfaction with prosthesis and the amputation level or type of prosthesis. The most common difficulties in daily living activities experienced by amputees were lacing shoes, removing bottle-tops with a bottle opener, and using scissors. Only 7.3% of amputees received rehabilitation services. Less than half of the amputees (44.7%) used their prostheses for eight or more hours a day, and 76.9% used their prostheses for regular or irregular cosmetic purposes. After amputation, most of the respondents (69.0%) became unemployed or changed workplaces. CONCLUSION: In our study, respondents preferred cosmetic usage to functional usage. Only 30.0% of respondents reported satisfaction with their prostheses. Many of the amputees had difficulties in complex tasks and either changed jobs or became unemployed. Clerical workers were the occupation group, which was most likely to return to work. The development of a more functional prosthetic hand and additional rehabilitation services are required. PMID- 22506222 TI - Lipedema, a rare disease. AB - Lipedema is a chronic disease of lipid metabolism that results in the symmetrical impairment of fatty tissue distribution and storage combined with the hyperplasia of individual fat cells. Lipedema occurs almost exclusively in women and is usually associated with a family history and characteristic features. It can be diagnosed based on clinical history and physical examination. Lipedema is usually symmetrical, but spares the feet, is often painful to palpation, and is negative for Stemmer's sign. Additionally, lipedema patients can present with microangiopathies and lipomas. The well-known therapies for lipedema include complex decongestive therapy, pneumatic compression, and diet modifications. However, whether these treatments help reduce swelling is debatable. We encountered a case of lipedema that was initially misdiagnosed as lymphedema. The patient's clinical features and history were different from those typical of lymphedema, prompting a diagnosis of lipedema and she was treated with a complex decongestive therapy program. PMID- 22506223 TI - Cauda equina syndrome caused by spinal dural arteriovenous fistula. AB - Spinal dural arteriovenous fistula (SDAVF) is rare but still the most commonly encountered vascular malformation of the spinal cord. A 31-year-old male developed gait disturbance due to weakness of his lower extremities, voiding difficulty and sexual dysfunction with a progressive course since 3 months. He showed areflexia in both knees and ankles. Electromyographic findings were suggestive of multiple root lesions involving bilateral L2 to S4 roots of moderate degree. Magnetic resonance images showed high signal intensity with an ill-defined margin in T2-weighted images and intensely enhanced by a contrast agent through the lumbosacral spinal cord. Selective spinal angiography confirmed a dural arteriovenous fistula with a nidus at the L2 vertebral level. After selective endovascular embolization, his symptoms drastically improved except sexual dysfunction. We report a rare case of cauda equina syndrome due to spinal arteriovenous fistula with drastic improvement after endovascular embolization. PMID- 22506224 TI - Collet-sicard syndrome in a patient with jefferson fracture. AB - Collet-Sicard syndrome is a rare condition characterized by the unilateral paralysis of the 9th through 12th cranial nerves. We describe a case of a 46-year old man who presented with dysphagia after a falling down injury. Computed tomography demonstrated burst fracture of the atlas. Physical examination revealed decreased gag reflex on the left side, decreased laryngeal elevation, tongue deviation to the left side, and atrophy of the left trapezius muscle. Videofluoroscopic swallowing study (VFSS) revealed frequent aspirations of a massive amount of thick liquid and incomplete opening of the upper esophageal sphincter during the pharyngeal phase. We report a rare case of Collet-Sicard syndrome caused by Jefferson fracture. PMID- 22506225 TI - Lance-adams syndrome. AB - Lance-Adams syndrome (LAS) is a rare complication of successful cardiopulmonary resuscitation and is often accompanied by action myoclonus. LAS is seen in patients who have undergone a cardiorespiratory arrest, later regained consciousness, and then developed myoclonus days or weeks after the event. Less than 150 cases of LAS have been reported in the worldwide medical literature. Here, we present a 32-year-old man who suffered from myoclonus after hypoxic brain damage due to hanging himself. This case was diagnosed as Lance-Adams syndrome according to a history of hypoxic brain damage, the clinical features, and the neuroimages such as brain SPECT. Making an early diagnosis and properly managing LAS is positively related to improving the patient's functional outcome. If patients have posthypoxic myoclonus after successful cardiopulmonary resuscitation, we should consider the diagnosis of LAS and initiate a proper rehabilitation program. PMID- 22506226 TI - Focal myositis of unilateral leg. AB - Focal myositis is a rare, benign inflammatory pseudotumor of the skeletal muscle of unknown etiology. In Korea, there is no case report of focal myositis, which is not combined with connective tissue disease. We present an unusual case of focal myositis with ankle contracture, involving more than two muscles. A 26-year old man visited our clinic complaining of right ankle contracture and leg muscle pain. Physical examination revealed no muscle weakness or any other neurological abnormality. T2-weighted magnetic resonance imaging of the right leg demonstrated diffuse high signal intensity of the right gastrocnemius, flexor digitorum longus, and tibialis anterior muscles. Needle electromyography showed profuse denervation potentials with motor unit action potentials of short duration and small amplitude from the involved muscles. All these findings suggested a diagnosis of focal inflammatory myositis and the patient was put under oral prednisolone and physical therapy. PMID- 22506227 TI - Crossed transcortical motor aphasia, left spatial neglect, and limb and magnetic apraxia due to right anterior cerebral artery infarction. AB - Crossed aphasia refers to language disturbance due to right-hemisphere lesions in right-handed individuals, while magnetic apraxia is described as 'forced grasping and groping' caused by lesions in the contralateral frontal lobe. This is a case report of a 70-year-old right handed woman who suffered from crossed transcortical motor aphasia and left hand magnetic apraxia due to right anterior cerebral artery infarction. The definite mechanism of this disorder is not yet understood, but neurophysiological observations suggest that affected supplementary motor areas may be responsible for this phenomenon. PMID- 22506228 TI - A nasogastric tube inserted into the gastrocutaneous fistula. AB - We reported a case in which a nasogastric tube was inserted into the gastrocutaneous fistula, diagnosed by abdominal computed tomography. A 78-year old man with a history of recurrent cerebral hemorrhage had a percutaneous endoscopic gastrostomy tube due to dysphagia for 2 years. However, soft tissue infection at the gastrostomy site caused the removal of the tube. Immediately, antibiotic agents were infused. For appropriate hydration and medication, a nasogastric tube was inserted. However, there was no significant improvement of the soft tissue infection. Moreover, the amount of bloody exudate increased. Abdominal computed tomography revealed the nasogastric tube placed under the patient's skin via gastrocutaneous fistula. The nasogastric tube was removed, and an antibiotic agents were maintained. After 3 weeks, the signs of infection fully improved, and percutaneous endoscopic gastrostomy was performed again. This case shows necessities of an appropriate interval between removal of the gastrostomy tube and insertion of a nasogastric tube, and suspicion of existence of gastrocutaneous fistula. PMID- 22506229 TI - Effect of Stimulation Polarity of Transcranial Direct Current Stimulation on Non dominant Hand Function. AB - OBJECTIVE: To evaluate motor excitability and hand function on the non-dominant side according to the polarity of transcranial direct current stimulation (tDCS) on the motor cortex in a healthy person. METHOD: tDCS was applied to the hand motor cortex for 15 minutes at an intensity of 1 mA in 28 healthy right-handed adults. Subjects were divided randomly into four groups: an anodal tDCS of the non-dominant hemisphere group, a cathodal tDCS of the non-dominant hemisphere group, an anodal tDCS of the dominant hemisphere group, and a sham group. We measured the motor evoked potential (MEP) in the abductor pollicis brevis and Jabsen-Taylor hand function test (JTT) in the non-dominant hand prior to and following tDCS. All study procedures were done under double-blind design. RESULTS: There was a significant increase in the MEP amplitude and a significant improvement in the JTT in the non-dominant hand following anodal tDCS of the non dominant hemisphere (p<0.05). But there was no change in JTT and a significant decrease in the MEP amplitude in the non-dominant hand following cathodal tDCS on the non-dominant hemisphere and anodal tDCS of the dominant hemisphere. CONCLUSION: Non-dominant hand function is improved by increased excitability of the motor cortex. Although motor cortex excitability is decreased in a healthy person, non-dominant hand function is maintained. A homeostatic mechanism in the brain might therefore be involved in preserving this function. Further studies are warranted to examine brain functions to clarify this mechanism. PMID- 22506230 TI - An Objective Assessment Scale for "Come-to-Sit" Using a Specifically Designed Jacket in Stroke Patients. AB - OBJECTIVE: To compare an objective assessment scale for "come-to-sit" in stroke patients with the previously established subjective assessment scales of "performance-based assessment" and the "ability for basic movement scale". METHOD: A specifically designed jacket was used to determine the objective degree of assistance needed for patients to perform the task. While patients were sitting up, the investigator evaluated the amount of assistance needed in a fully dependent state (A) and with maximal effort (B). Using this measure, we obtained an objective scale, {(A-B)/A} *100. In addition, patients were tested in two starting positions: hemiplegic-side lying and sound-side lying. We then compared the objective scale with subjective scales and other parameters related to functional outcomes. RESULTS: For both starting positions, the objective assessment scale showed high correlation with the previously established subjective scales (p<0.01). Only the hemiplegic-side lying-to-sit objective scale showed a significant correlation with the parameters used to assess functional outcomes (p<0.05). In terms of Brunnstrom stages, only the leg stage showed a significant correlation with the objective "come-to-sit" scale (p<0.01). CONCLUSION: The objective scale was comparable to established subjective assessment scales when used by an expert. The hemiplegic-side lying-to-sit maneuver had a high correlation with patient's functional recovery. Specifically, balance and lower extremity function appear to be important factors in the "come to-sit" activity. PMID- 22506231 TI - The effect of prolonged inpatient rehabilitation therapy in subacute stroke patients. AB - OBJECTIVE: To evaluate the effect of prolonged inpatient rehabilitation therapy in subacute stroke patients. METHOD: We enrolled 52 subacute stroke patients who had received 3 months of inpatient rehabilitation therapy. Thirty stroke patients received additional inpatient rehabilitation therapy for 3 months and 22 control patients received only home-based care. The evaluation was measured at 3 and at 6 months after stroke occurrence. Functional improvement was measured using the modified motor assessment scale (MMAS), the timed up and go test (TUG), the 10 meter walking time (10 mWT), the Berg balance scale (BBS) and the Korean-modified Barthel index (K-MBI). The health-related quality of life was evaluated using the medical outcome study, 36-item short form survey (SF-36). RESULTS: In the experimental group, significant improvements were observed for all parameters at 6 months (p<0.05). However, significant improvements were observed only in MMAS, BBS, and K-MBI at 6 months in the Control group (p<0.05). In comparing the 2 groups, significant difference were observed in all parameters (p<0.05) except 10 meter walking time (p=0.73). The improvement in SF-36 was meaningfully higher in experimental group compared to control group. CONCLUSION: This study demonstrates that subacute stroke patients can achieve functional improvements and an enhanced quality of life through prolonged inpatient rehabilitation therapy. PMID- 22506232 TI - The correlation analysis of functional factors and age with duchenne muscular dystrophy. AB - OBJECTIVE: To correlate existing evaluation tools with clinical information on Duchenne muscular dystrophy (DMD) patients following age and to investigate genetic mutation and its relationship with clinical function. METHOD: The medical records of 121 children with DMD who had visited the pediatric rehabilitation clinic from 2006 to 2009 were reviewed. The mean patient age was 9.9+/-3.4 years and all subjects were male. Collected data included Brooke scale, Vignos scale, bilateral shoulder abductor and knee extensor muscles power, passive range of motion (PROM) of ankle dorsi-flexion, angle of scoliosis, peak cough flow (PCF), fractional shortening (FS), genetic abnormalities, and use of steroid. RESULTS: The Brooke and Vignos scales were linearly increased with age (Brooke (y(1)), Vignos (y(2)), age (x), y(1)=0.345x-1.221, R(Brooke) (2)=0.435, y(2)=0.813x 3.079, R(Vignos) (2)=0.558, p<0.001). In relation to the PROM of ankle dorsi flexion, there was a linear decrease in both ankles (right and left R(2)=0.364, 0.372, p<0.001). Muscle power, Cobb angle, PCF, and FS showed diversity in their degrees, irrespective of age. The genetic test for dystrophin identified exon deletions in 58.0% (69/119), duplications in 9.2% (11/119), and no deletions or duplications in 32.8% (39/119). Statistically, the genetic abnormalities and use of steroid were not definitely associated with functional scale. CONCLUSION: The Brooke scale, Vignos scale and PROM of ankle dorsi-flexion were partially available to assess DMD patients. However, this study demonstrates the limitations of preexisting scales and clinical parameters incomprehensively reflecting functional changes of DMD patients. PMID- 22506233 TI - Reliability of hip migration index in children with cerebral palsy: the classic and modified methods. AB - OBJECTIVE: To determine reliability and clinical use of two methods of migration index (MI) in CP patients with or without hip dysplasia. METHOD: The materials included radiographs of 200 hips of children with cerebral palsy. Conventional anteroposterior radiographs of the pelvis were taken with the child in the supine position with standardized methods. Two rehabilitation doctors measured the migration index using two methods. In the classic method, the lateral margin of the acetabular roof was used as a landmark and in the modified method the lateral margin of the sourcil was used as a landmark. Each rater measured the migration index at three separate times with a time interval of at least one week. Intraclass correlation (ICC) was used to test the inter- and intra-rater reliability. RESULTS: MI shows excellent intra-rater reliability in both the classic and modified methods, but the inter-rater reliability was higher in the classic method than in the modified method. When categorized according to the sourcil classification, inter-rater reliability was higher in the normal sourcil type and lower in the dysplastic sourcil types. CONCLUSION: Generally, the classic method showed higher reliability than the modified method, even though the reliability of the MI measurement was relatively high with both methods. PMID- 22506234 TI - The Effect of Comprehensive Hand Repetitive Intensive Strength Training (CHRIST) Using Motion Analysis in Children with Cerebral Palsy. AB - OBJECTIVE: To investigate the effect of Comprehensive Hand Repetitive Intensive Strength Training (CHRIST) on upper limb function in children with cerebral palsy using motion analysis. METHOD: The subjects in this study included 19 children (10 males, 9 females, mean age=8.8 years) with cerebral palsy. The experimental group (n=10) received CHRIST and general rehabilitation therapy. The control group (n=9) received a home program as well as general rehabilitation therapy. Both groups received 30 sessions of CHRIST or home program training for 60 minutes per session 3 times a week during the 10-week period. The reaching movements were captured by a motion analysis system. Kinematic variables including movement time (MT), mean velocity (MV), normalized jerk score (NJS), mean angular velocity (MAV) and normalized jerk score of the shoulder, elbow and wrist joint with comfortable and fast speed were analyzed between groups and the pre-post training group. RESULTS: After pre- and post-training experimental group, MT, MV, NJS, MAV of shoulder, elbow, wrist and NJS of elbow and wrist improved significantlyin reaching movement of both comfortable and fast speed (p<0.05). However, After pre- and post-training control group, MV improved significantlyin reaching movement of only comfortable speed (p<0.05). Between two groups, MT and MAV of the elbow at comfortable speed and NJS of the elbow at fast speed were statisticallysignificant (p<0.05). CONCLUSION: CHRIST proved to be an effective intervention for improving upper limb extremity function of reaching movement in children with cerebral palsy. PMID- 22506235 TI - Magnetic resonance findings of acute severe lower back pain. AB - OBJECTIVE: To determine abnormal MRI findings in adults hospitalized with acute severe axial LBP. METHOD: Sixty patients with back pain were divided into 3 groups consisting of 1) 23 adults with acute axial severe LBP who could not sit up or stand up for several days, but had not experienced previous back-related diseases or trauma (group A), 2) 19 adults who had been involved in a minor traffic accident, and had mild symptoms but not limited mobility (group B), and 3) 18 adults with LBP with radicular pain (group C)., Various MRI findings were assessed among the above 3 groups and compared as follows: disc herniation (protrusion, extrusion), lumbar disc degeneration (LDD), annular tear, high intensity zone (HIZ), and endplate changes. RESULTS: THE MRI FINDINGS OF A GROUP WERE AS FOLLOWS: disc herniation (87%), LDD (100%), annular tear (100%), HIZ (61%), and end plate changes (4.4%). The findings of disc herniation, annular tear, HIZ, and LDD were more prevalent in A group than in B group (p<0.01). HIZ findings were more prevalent in A group than in group B or group C (p<0.05). CONCLUSION: Patients with acute severe axial LBP were more likely to have disc herniation, LDD, annular tear, HIZ. Among LBP groups, there was a significant association of HIZ on MRI with acute severe axial LBP. PMID- 22506236 TI - Development and application of a newly designed massage instrument for deep cross friction massage in chronic non-specific low back pain. AB - OBJECTIVE: To introduce a newly designed massage instrument, the Hand Grip T-bar (HT-bar) and use it to relieve chronic non-specific low back pain (nLBP) through deep cross-friction massage (roptrotherapy). METHOD: 22 subjects (9 males and 13 females, aged 51.6+/-6.7) with chronic nLBP were allocated randomly to a Roptrotherapy group (n=12) and a Transcutaneous Electrical Nerve Stimulation (TENS) group (n=10). The Roptrotherapy group received deep cross-friction massage with the HT-bar, which was made of metal and had a cylinder for increasing weight and grooves for an easy grip. It was applied across the middle and lower back for 20 minutes a day, 3 days a week for 2 weeks. The TENS group received TENS for 20 minutes a day, 5 days a week for 2 weeks. The outcome was measured on the pain numeric rating scale (PNRS), by the Oswestry disability index (ODI), and by the Roland & Morris Disability Questionnaire (RMDQ) at pre-treatment, at immediate post-treatment and 2 weeks later. The application of the HT-bar was assessed by a questionnaire to 19 therapists. RESULTS: At post-treatment, immediately and 2 weeks later, both groups showed significant improvement in PNRS, ODI and RMDQ. During the two weeks after post-treatment, however, the Roptrotherapy group improved in PNRS, ODI and RMDQ, but the TENS group did not. Over 80% of the therapists responded that the HT-bar was useful and comfortable. CONCLUSION: This study suggests that deep cross-friction massage can be a beneficial therapeutic technique and that the HT-bar can be a useful instrument in deep cross-friction massage for chronic nLBP patients. PMID- 22506237 TI - Efficacy of ultrasonography-guided injections in patients with facet syndrome of the low lumbar spine. AB - OBJECTIVE: To investigate the efficacy of ultrasonography (US)-guided injections in patients with low lumbar facet syndrome, compared with that in patients who received fluoroscopy (FS)-guided injections. METHOD: Fifty-seven subjects with facet syndrome of the lumbar spine of the L4-5 and L5-S1 levels were randomly divided into two groups to receive intraarticular injections into the facet joint. One group received FS-guided facet joint injections and the other group received US-guided facet joint injections. Treatment effectiveness was assessed using a visual analogue scale (VAS), physician's and patient's global assessment (PhyGA, PaGA), and the modified Oswestry Disability Index (MODI). All parameters were evaluated four times: before injections, and at a week, a month, and three months after injections. We also measured, in both groups, how long it took to complete the whole procedure. RESULTS: Each group showed significant improvement from the facet joint injections on the VAS, PhyGA, PaGA, and MODI (p<0.05). However at a week, a month, and three months after injections, no significant differences were observed between the groups with regard to VAS, PhyGA, PaGA, and MODI (p>0.05). Statistically significant differences in procedure time were observed between groups (FS: 248.7+/-6.5 sec; US: 263.4+/-5.9 sec; p=0.023). CONCLUSION: US-guided injections in patients with lumbar facet syndrome are as effective as FS-guided injections for pain relief and improving activities of daily living. PMID- 22506238 TI - Ultrasonography of median nerve and electrophysiologic severity in carpal tunnel syndrome. AB - OBJECTIVE: To investigate the correlation of the ultrasonographic wrist-to forearm median nerve area ratio (WFR) and cross sectional area of median nerve at the wrist (CSA-W) to the electrophysiologic severity in patients with carpal tunnel syndrome (CTS). METHOD: One hundred and ten wrists electrophysiologically graded as mild, moderate, and severe CTS and 38 healthy controls underwent ultrasonography of median nerve at the distal wrist crease and mid-forearm. WFR and CSA-W were analyzed according to the severity of CTS. RESULTS: WFR was 1.12+/ 0.14, 1.91+/-0.33, 2.27+/-0.47 and 3.02+/-0.97 and the CSAs-W was 7.23+/-1.67 mm(2), 13.51+/-3.72 mm(2), 14.67+/-2.93 mm(2), and 18.74+/-6.01 mm(2) in controls, mild (n=28), moderate (n=46), and severe (n=36) CTS, respectively. CSA W displayed significant differences between the control and the mild CTS, moderate CTS and severe CTS groups. However, there was no significant difference between mild CTS and moderate CTS groups. WFR revealed significant difference between all groups. The sensitivity and specificity of the WFR in grading the severity of CTS were higher than those of the CSA-W. CONCLUSION: Ultrasonography is a useful complementary tool for the evaluation of CTS. Both WFR and CSA-W are highly correlated with severity grade of CTS. However, WFR is superior to CSA-W for diagnosis and grading of the severity of CTS. PMID- 22506239 TI - Effect of Ultra-marathon (308 km) Race on Bone Metabolism and Cartilage Damage Biomarkers. AB - OBJECTIVE: To evaluate the potential effects of a 308-km ultra-marathon on bone and cartilage biomarkers. METHOD: Venous blood samples were collected at pre race, 100 km, 200 km, and 308 km checkpoints. The following markers of cartilage damage and bone metabolism were studied: osteocalcin (OC), osteoprotegerin (OPG), and calcium, phosphorous, and cartilage oligomeric matrix protein (COMP). RESULTS: Blood samples were taken from 20 male runners at four different checkpoints. Serum COMP was increased by 194.1% (130.7% at 100 km and 160.4% at 200 km). Serum OPG was significantly increased by 158.57% at 100 km and 114.1% at 200 km compared to the pre-race measures. OC was transiently suppressed at 200 km. Serum calcium and phosphorous concentrations decreased compared to the pre race measures. CONCLUSION: This study showed that the 308-km ultra-marathon induced several changes, including transient uncoupling of bone metabolism, increased bone resorption, suppressed bone formation, and bone turnover and had a major impact on cartilage structure. PMID- 22506240 TI - Comparison of Sono-guided Capsular Distension with Fluoroscopically Capsular Distension in Adhesive Capsulitis of Shoulder. AB - OBJECTIVE: To investigate the short-term effects and advantages of sono-guided capsular distension, compared with fluoroscopically guided capsular distension in adhesive capsulitis of shoulder. METHOD: In this prospective, randomized, and controlled trial, 23 patients (group A) were given an intra-articular injection of a mixture of 0.5% lidocaine (9 ml), contrast dye (10 ml), and triamcinolone (20 mg); they received the injection once every 2 weeks, for a total of 6 weeks, under sono-guidance. Twenty-five patients (group B) were treated similarly, under fluoroscopic guidance. Instructions for the self-exercise program were given to all subjects, without physiotherapy and medication. Effects were then assessed using a visual numeric scale (VNS), and the shoulder pain and disability index (SPADI), as well as a range of shoulder motion examinations which took place at the beginning of the study and 2 and 6 weeks after the last injection. Incremental cost-effective ratio (ICER), effectiveness, preference, and procedure duration were evaluated 6 weeks post-injection. RESULTS: The VNS, SPADI, and shoulder motion range improved 2 weeks after the last injection and continued to improve until 6 weeks, in both groups. However, no statistical differences in changes of VNS, SPADI, ROM, and effectiveness were found between these groups. Patients preferred sono-guided capsular distension to fluoroscopically guided capsular distension due to differences in radiation hazards and positional convenience. Procedure time was shorter for sono-guided capsular distension than for fluoroscopically guided capsular distension. CONCLUSION: Sono-guided capsular distension has comparable effects with fluoroscopically guided capsular distension for treatment of adhesive capsulitis of the shoulder. Sono-guided capsular distension can be substituted for fluoroscopic capsular distension and can be advantageous from the viewpoint of radiation hazard mitigation, time, cost effectiveness and convenience. PMID- 22506241 TI - The effect of the forward head posture on postural balance in long time computer based worker. AB - OBJECTIVE: To estimate the effects of a relatively protruded head and neck posture on postural balance, in computer based worker. METHOD: Thirty participants, who work with computers for over 6 hrs per day (Group I), and thirty participants, who rarely work with computers (Group II), were enrolled. The head and neck posture was measured by estimating angles A and B. A being the angle between the tragus of the ear, the lateral canthus of the eye, and horizontal line and B the angle between the C7 spinous process, the tragus of the ear, and the horizontal line. The severity of head protrusion with neck extension was assessed by the subtraction of angle A from angle B. We also measured the center of gravity (COG) and postural balance by using computerized dynamic posturography to determine the effect of computer-based work on postural balance. RESULTS: Results indicated that group I had a relatively more protruded head with extensive neck posture (angle B-A of group I and group II, 28.2+/-8.3, 32.9+/ 6.0; p<.05). The COG of group I tended more toward the anterior than that of group II. Postural imbalance and impaired ability to regulate movement in forward and backward direction were also found. CONCLUSION: The results of this study suggest that forward head postures during computer-based work may contribute to some disturbance in the balance of healthy adults. These results could be applied to education programs regarding correct postures when working at a computer for extended periods of time. PMID- 22506242 TI - The additive effects of hyaluronidase in subacromial bursa injections administered to patients with peri-articular shoulder disorder. AB - OBJECTIVE: To evaluate the additive effects of hyaluronidase combined with steroids in patients with peri-articular shoulder disorder. METHOD: Thirty patients with peri-articular shoulder disorder were given subacromial bursa injections once a week for three consecutive weeks. Fifteen patients (Group A) underwent subacromial bursa injections with hyaluronidase 1,500 IU, triamcinolone 40 mg and 0.5% lidocaine (total 6 ml). Another fifteen patients (Group B) underwent the same injections with triamcinolone 40 mg and 0.5% lidocaine (total 6 ml). We examined the active range of motion (AROM) in the shoulder, used a visual analogue scale (VAS) for measurement, and administered a shoulder disability questionnaire (SDQ) at the commencement of the study and then every week until one week after the third injection. RESULTS: There were no significant difference between group A and B before the injections took place (p>0.05). Statistically significant improvement was seen in the VAS, SDQ, and AROM of flexion, abduction, internal rotation at one week after the first and second injections compared with the parameters measured at previous visits in both groups (p<0.05), except the SDQ between one week after the first and second injections in group B (p>0.05). Improvement in all parameters measured at one week after the third injection compared with the measurement values at one week after the second injection were not statistically significant in both groups (p>0.05). However, group A (the hyaluronidase group) showed significantly greater improvements than group B in terms of their SDQ and AROM of internal rotation scores one week after the three injections had taken place (p<0.05). CONCLUSION: Peri-articular shoulder disorder patients who underwent subacromial bursa injections using hyaluronidase and steroids showed greater functional improvements than those who were given only steroid injections. PMID- 22506243 TI - Factors affecting test results and standardized method in quiet standing balance evaluation. AB - OBJECTIVE: To identify factors affecting test results of the quiet standing balance evaluation conducted by posturography and to investigate the standardized method by comparing results according to feet width. METHOD: The study cohort consisted of 100 healthy individuals. We assessed the quiet standing balance of subjects by using 3 different methods: standing on a force plate with feet width the same as shoulder width (test 1); with feet width the same as half the shoulder width (test 2); with feet width determined by the subject's comfort (test 3). Subjects underwent each test with their eyes open and closed for 30 seconds each time. Parameters for measuring standing balance included the mean mediolateral and anteroposterior extent, speed, and the velocity moment of center of pressure (COP) movement. RESULTS: All parameters showed better results when the subject's eyes were open rather than closed, and the mean AP extent and speed increased as the age of the subjects increased (p<0.01). However, there was no significant correlation between height and the study parameters, and no differences between men and women. Mean mediolateral extent and speed were significantly longer and faster in test 1 compared with tests 2 and 3 (p<0.01). The results of test 2 were better than the results of test 3, but the difference was not statistically significant. CONCLUSION: COP movements increased with age and when subjects closed their eyes in an evaluation of quiet standing balance conducted by posturography. Gender and height did not affect results of the test. We suggest that an appropriate method for conducting posturography is to have the subject stand on a force plate with their feet width the same as half the shoulder width, because this posture provided relatively accurate balance capacity. PMID- 22506244 TI - Depression and Quality of Life in Patients within the First 6 Months after the Spinal Cord Injury. AB - OBJECTIVE: To evaluate the severity of depression, degree of life satisfaction, level of stress, and resilience among patients in the first 6 months after a spinal cord injury (SCI). METHOD: 36 patients with SCI were asked to fill out questionnaires concerning Beck Depression Inventory (BDI), World Health Organization Quality of Life Questionnaire-BREF, Stress Response Inventory, and Connor-Davidson resilience scale. All patients had experienced an SCI within the last 6 months before the commencement of this study. RESULTS: In our study, the patients who experienced the SCI within the last six months had a higher rate of depression (63.9%) and a higher overall level of depression (13.8 points). The unmarried group had a significantly higher quality of life (QOL; p<0.05) when compared with the married group. In the motor complete group, severity of depression and level of stress were higher, whereas QOL was lower than the motor incomplete group (p<0.05). The mean American Spinal Injury Association (ASIA) Motor Score (AMS) was much higher in the non-depressive group (p<0.05) when compared with the depressive group. CONCLUSION: We found the patients within six months after SCI injury had higher rate of depression and higher overall level of depression. Also, patients with motor complete injury had affected significantly on depression, QOL and stress. We found the married patients had poorer QOL and depressive group had lower AMS score of lower extremity. Therefore, there should be emphasis of psychological care who have motor complete injury and are married during the early stage. PMID- 22506245 TI - The Significance of Transcutaneous Continuous Overnight CO(2) Monitoring in Determining Initial Mechanical Ventilator Application for Patients with Neuromuscular Disease. AB - OBJECTIVE: To reveal the significance of continuous transcutaneous carbon dioxide (CO(2)) level monitoring through reviewing cases which showed a discrepancy in CO(2) levels between arterial blood gas analysis (ABGA) and continuous transcutaneous blood gas monitoring. METHOD: Medical record review was conducted retrospectively of patients with neuromuscular diseases who had started home mechanical ventilation between June 2008 and May 2010. The 89 patients underwent ABGA at the 1st hospital day, and changes to their CO(2) level were continuously monitored overnight with a transcutaneous blood gas analysis device. The number of patients who initially appeared to show normal PaCO(2) through ABGA, yet displayed hypercapnea through overnight continuous monitoring, was counted. RESULTS: 36 patients (40.45%) presented inconsistent CO(2) level results between ABGA and continuous overnight monitoring. The mean CO(2) level of the 36 patients using ABGA was 37.23+/-5.11 mmHg. However, the maximum and mean CO(2) levels from the continuous monitoring device were 52.25+/-6.87 mmHg and 46.16+/-6.08 mmHg, respectively. From the total monitoring period (357.28+/-150.12 minutes), CO(2) retention over 45 mmHg was detected in 198.97 minutes (55.69%). CONCLUSION: Although ABGA only reflects ventilatory status at the puncturing moment, ABGA results are commonly used to monitor ventilatory status in most clinical settings. In order to decide the starting point of home mechanical ventilation in neuromuscular patients, continuous overnight monitoring should be considered to assess latent CO(2) retention. PMID- 22506246 TI - The Effect of Power-walking in Phase 2 Cardiac Rehabilitation Program. AB - OBJECTIVE: To evaluate the effects of power walking (PW) training on a treadmill in patients with coronary heart disease (CHD) and to compare the cardiovascular effects of PW with usual walking (UW). METHOD: Patients were recruited as participants in phase 2 cardiac rehabilitation program after receiving percutaneous coronary intervention (PCI) due to acute coronary syndrome from our hospital. The participants were divided into the PW group (n=16) and UW group (n=18). All participants received graded exercise test (GXT) and significant difference in maximal oxygen consumption (VO(2Max)) was not observed between the groups. Aerobic exercise training on treadmill was given for 50 minutes per session, three times a week, for six weeks. Physiological and hematological parameters were tested before and 6 weeks after the cardiac rehabilitation program. Exercise duration, VO(2Max), heart rate, blood pressure, and rate pressure product were evaluated through graded exercise test. Hematological measurements included serum lipid profile, and high-sensitivity C reactive protein (hs-CRP). RESULTS: There were no significant differences in resting heart rate, maximal heart rate, resting systolic and diastolic blood pressures, lipid profile, hs-CRP, VO(2Max), and RPP between the PW group and UW group. However, after 6 weeks of the intervention, VO(2Max) in the PW group (36.03+/-5.69 ml/kg/min) was significantly higher than that in the UW group (29.73+/-5.63 ml/kg/min) (p<0.05). CONCLUSION: After six weeks of phase 2 cardiac rehabilitation program, the PW group showed significant improvement in VO(2Max) than the UW group. Thus, it will beneficial to recommend power walking in cardiac rehabilitation program. PMID- 22506247 TI - Cyclic vomiting syndrome developed after stroke. AB - Cyclic vomiting syndrome is characterized by recurrent episodes of stereotyped vomiting separated by regular symptom-free periods. We describe a case of cyclic vomiting syndrome developed after stroke, which has not been reported to date. A 69-year-old woman experienced recurrent vomiting following left cerebral infarct. The patient's vomiting pattern was consistent with cyclic vomiting syndrome, and the diagnosis of cyclic vomiting syndrome was established by exclusion of other known disorders which could have resulted in vomiting. She was treated with imipramine hydrochloride and her symptom was well controlled. PMID- 22506248 TI - A case of rheumatoid arthritis with unilateral knee synovial hypertrophy in hemiplegia. AB - A 64-year-old woman suffering right hemiplegia came in with pain and swelling on her left knee, general weakness and poor oral intake for 2 months. On physical examination we were able to palpate a mass with irregular margin around the left suprapatellar area. From the results of the magnetic resonance imaging (MRI), synovial proliferative disease, infectious arthritis, or gouty arthritis was suspected. We performed a blood laboratory test to detect rheumatologic diseases, knee joint aspiration, and bone scan for differential diagnosis, and were able to diagnose rheumatoid arthritis (RA) from the results of blood laboratory, physical examination, and bone scan. Consequently, we started medications for controlling RA. Herein, we report a case of rheumatoid arthritis with unilateral knee synovial hypertrophy in hemiplegia. If a right hemiplegic patient has recurrent pain on the left knee and synovial hypertrophy, and fails to respond to treatment for osteoarthritis, early detection by evaluation for rheumatic disease is crucial to prevent severe sequelae influencing rehabilitation of hemiplegia. PMID- 22506249 TI - Treatment of Dysphagia with pyridostigmine bromide in a patient with the pharyngeal-cervical-brachial variant of guillain-barre syndrome. AB - A 24-year-old male developed bulbar palsy, ophthalmoplegia, ptosis, and shoulder weakness bilaterally 2 weeks after he had experienced an upper respiratory infection. The electrodiagnostic study demonstrated axonal polyradiculoneuropathy. The repetitive nerve stimulation study (RNS) showed no significant decrement of the compound muscle action potentials (CMAPs). The videofluoroscopic swallowing study (VFSS) showed severe impairment of the pharyngeal phase of swallowing. He was diagnosed as having the pharyngeal cervical-brachial variant of Guillain-Barre syndrome. The patient's dysphagia was not improved for 3 months. A follow up RNS showed a significant decrement of the CMAPs. Pyridostigmine bromide was tried to improve the dysphagia. The patient showed immediate improvement of his dysphagia on the VFSS after the trial with pyridostigmine bromide. Pyridostigmine bromide was given before each meal for 8 days and he showed continuous improvement of his dysphagia. The follow up VFSS after 3 months showed complete recovery of dysphagia. PMID- 22506250 TI - Severe Spastic Trismus without Generalized Spasticity after Unilateral Brain Stem Stroke. AB - A 62-year-old female patient diagnosed with left brain stem stroke 2 months ago was admitted to our clinic for rehabilitation. She had no generalized spasticity on both extremities, but could open her mouth only approximately 2 mm between her upper and lower teeth due to severe trismus. On needle electromyography, the left masseter muscle showed paradoxically increased muscle activity during mouth opening. We injected 50 units of type A botulinum toxin (Botox(r)) into the left masseter muscle, and 20 units into the left temporalis muscle with guidance of ultrasonography. The interincisal distance increased to 8 mm on the 3(rd) day after injection, and 9 mm on the 4(th) day. One month later, the interincisal distance increased to 14 mm. The increased interincisal distance was maintained for 13 months after injection, and the quality of hygienic care and compliance of oral stimulation therapy also improved. PMID- 22506251 TI - Cefepime neurotoxicity in patients with renal insufficiency. AB - Cefepime is a fourth-generation cephalosporin that is active against both gram positive and gram-negative organisms. It is administered parenterally for the treatment of severe infections. Approximately 85% of the drug is excreted unchanged by the kidneys. Neurotoxicity in patients with renal failure who are treated with cefepime has been reported sporadically. We report on two senile patients with renal impairment who developed neurotoxicity including lethal outcome after treatment with cefepime. PMID- 22506252 TI - Painful os peroneum syndrome presenting as lateral plantar foot pain. AB - Lateral plantar foot pain can be caused by various entities, and the painful os peroneum syndrome should be considered in the differential diagnosis. Recent developments in musculoskeletal ultrasonography are very useful for initial diagnosis. We discuss a 69-year-old female who experienced lateral plantar foot pain for over one month. Through physical examination, radiography, ultrasound and magnetic resonance imaging, she was diagnosed with the painful os peroneum syndrome with a chronic fatigue fracture of multipartite os peroneum and peroneus longus tenosynovitis, for which she underwent surgery. We herein report this rare condition and reviewed the relevant literature. PMID- 22506253 TI - A case of cephalic tetanus with unilateral ptosis and facial palsy. AB - Cephalic tetanus is defined as a combination of trismus and paralysis of one or more cranial nerves. Cranial nerves III, IV, VI, VII, and XII may be affected, but the facial nerve is most frequently implicated. A 64-year-old female visited hospital for left ptosis followed by facial palsy after a left forehead abrasion in a car accident. At nine days post injury, left ptosis developed, left facial palsy developed twelve days post injury, and at fifteen days post injury, trismus and dysphagia developed. The following day, there was progression of symptoms to generalized tetanus, such as dyspnea and generalized rigidity. Videofluoroscopic swallow study showed penetration and aspiration. We report a case of cephalic tetanus with ptosis, facial palsy, and dysphagia, which progressed to generalized tetanus. PMID- 22506254 TI - Boosting Protein Threading Accuracy. AB - Protein threading is one of the most successful protein structure prediction methods. Most protein threading methods use a scoring function linearly combining sequence and structure features to measure the quality of a sequence-template alignment so that a dynamic programming algorithm can be used to optimize the scoring function. However, a linear scoring function cannot fully exploit interdependency among features and thus, limits alignment accuracy.This paper presents a nonlinear scoring function for protein threading, which not only can model interactions among different protein features, but also can be efficiently optimized using a dynamic programming algorithm. We achieve this by modeling the threading problem using a probabilistic graphical model Conditional Random Fields (CRF) and training the model using the gradient tree boosting algorithm. The resultant model is a nonlinear scoring function consisting of a collection of regression trees. Each regression tree models a type of nonlinear relationship among sequence and structure features. Experimental results indicate that this new threading model can effectively leverage weak biological signals and improve both alignment accuracy and fold recognition rate greatly. PMID- 22506255 TI - The SATELLITE Sexual Violence Assessment and Care Guide for Perinatal Patients. AB - Sexual violence (SV) is a prevalent public health problem affecting millions of women across the lifespan. Poor pregnancy outcomes have been shown to be related to SV experiences; therefore, the perinatal period is an important time for healthcare practitioners (HCPs) to intervene. Various healthcare organizations suggest or even mandate screening for SV. Although SV screening tools are available, many practitioners do not routinely screen their patients. Barriers to screening include lack of comfort with or knowledge about how to screen and intervene, and reluctance on the part of the patient to disclose information. The SATELLITE Sexual Violence Assessment and Care Guide for Patients in the Perinatal Period was designed to overcome these barriers. The guide leads practitioners through the process of setting the context for screening, the screening itself, and the interventions after a positive screen finding, including specific questions to be asked and statements to be made by the practitioner in providing care for an SV survivor. By using this guide, nurse practitioners can increase their feelings of comfort and confidence as they assess and care for SV survivors during the perinatal period. PMID- 22506256 TI - Prediction of bleeding etiology: the clinician is vindicated! PMID- 22506257 TI - Predictors of a variceal source among patients presenting with upper gastrointestinal bleeding. AB - BACKGROUND: Patients with upper gastrointestinal bleeding (UGIB) require an early, tailored approach best guided by knowledge of the bleeding lesion, especially a variceal versus a nonvariceal source. OBJECTIVE: To identify, by investigating a large national registry, variables that would be predictive of a variceal origin of UGIB using clinical parameters before endoscopic evaluation. METHODS: A retrospective study was conducted in 21 Canadian hospitals during the period from January 2004 until the end of May 2005. Consecutive charts for hospitalized patients with a primary or secondary discharge diagnosis of UGIB were reviewed. Data regarding demographics, including historical, physical examination, initial laboratory investigations, endoscopic and pharmacological therapies administered, as well as clinical outcomes, were collected. Multivariable logistic regression modelling was performed to identify clinical predictors of a variceal source of bleeding. RESULTS: The patient population included 2020 patients (mean [+/- SD] age 66.3+/-16.4 years; 38.4% female). Overall, 215 (10.6%) were found to be bleeding from upper gastrointestinal varices. Among 26 patient characteristics, variables predicting a variceal source of bleeding included history of liver disease (OR 6.36 [95% CI 3.59 to 11.3]), excessive alcohol use (OR 2.28 [95% CI 1.37 to 3.77]), hematemesis (OR 2.65 [95% CI 1.61 to 4.36]), hematochezia (OR 3.02 [95% CI 1.46 to 6.22]) and stigmata of chronic liver disease (OR 2.49 [95% CI 1.46 to 4.25]). Patients treated with antithrombotic therapy were more likely to experience other causes of hemorrhage (OR 0.44 [95% CI 0.35 to 0.78]). CONCLUSION: Presenting historical and physical examination data, and initial laboratory tests carry significant predictive ability in discriminating variceal versus nonvariceal sources of bleeding. PMID- 22506258 TI - The over-the-scope clip system--a novel technique for gastrocutaneous fistula closure: the first North American experience. AB - BACKGROUND: The mainstay of therapy for gastrocutaneous (GC) fistulas has been surgical intervention. However, endoclips are currently used for management of perforations and fistulas but are limited by their ability to entrap and hold the tissue. OBJECTIVE: To report the first North American experience with a commercially available over-the-scope clip (OTSC) device, a novel and new tool for the endoscopic entrapment of tissue for the closure of fistula and perforations. METHODS: The present single-centre study was conducted at a tertiary referral academic gastroenterology unit and centre for advanced therapeutic endoscopy and involved patients referred for endoscopic treatment for the closure of a GC fistula. The OTSC device was mounted on the tip of the endoscope and passed into the stomach to the level of the fistula. The targeted site of the fistula was grasped with the tissue anchoring tripod and pulled into the cap with concomitant scope channel suction. Once the tissue was trapped in the cap, a 'bear claw' clip was deployed. RESULTS: The patients recovered with fistula closure. No complication or recurrence was noted. Fistula sizes >1 cm, however, were difficult to close with the OTSC system. The length of stay of the bear claw clip at the fistula site is unpredictable, which may lead to incomplete closure of the fistula. CONCLUSION: Closure of a GC fistula using a novel 'bear claw' clip system is feasible and safe. PMID- 22506261 TI - The Bockus International Society of Gastroenterology: historical review. AB - The Bockus International Society of Gastroenterology was founded in 1958 in honour of Dr Henry L Bockus (1894-1982) by his former students, residents and fellows at the Graduate School of Medicine of the University of Pennsylvania, Philadelphia, USA. It was a celebrated tribute to Dr Bockus' outstanding leadership in the development and teaching of clinical gastroenterology as a subspecialty, which was in its infancy in the post-World War II era. He established the first formal training course in clinical gastroenterology in America. His department of gastroenterology became the leading graduate school of clinical gastroenterology in the world, training many clinical gastroenterologists in America and from many regions around the world. For many years, Dr Bockus was the most prominent American in world gastroenterology. The Bockus Society holds biennial scientific congresses in different continents, thus continuing to foster Dr Bockus' lifelong interest and vision to promote international medical friendship, and excellence in education and research collaboration. PMID- 22506262 TI - Re: Tuitt D, Knight F, Lipman. A bibliometric analysis of digestive health research in Canada. Can J. Gastroenterol 2011; 11:609-614. PMID- 22506259 TI - Patient satisfaction with medication for gastroesophageal reflux disease: a systematic review. AB - BACKGROUND: Patient satisfaction is increasingly regarded as an important aspect of measuring treatment success in individuals with gastroesophageal reflux disease (GERD). OBJECTIVE: To review how satisfied patients with GERD are with their medication, and to analyze the usefulness of patient satisfaction as a clinical end point by comparing it with symptom improvement. METHODS: Systematic searches of the PubMed and EMBASE databases identified clinical trials and patient surveys published between 1966 and 2009. RESULTS: Twelve trials reported that 56% to 100% of patients were 'satisfied' or 'very satisfied' with proton pump inhibitor (PPI) treatment for GERD. Patient satisfaction levels were higher for PPIs than other GERD medications in two trials. The sample-size-weighted average proportion of patients 'satisfied' with their PPI after four weeks of treatment in trials was 93% (95% CI 87% to 99%), with 73% (95% CI 62% to 83%) being 'very satisfied'. In four surveys, the average proportion of patients 'satisfied' with their PPI treatment was 82% (95% CI 73% to 90%) and 62% (95% CI 48% to 75%) were 'very satisfied'. Seven trials found a positive association between patient satisfaction and symptom improvement, and two surveys between satisfaction and improved health-related quality of life. Three trials found that continuous treatment yielded higher rates of satisfaction than on-demand therapy. CONCLUSIONS: More than one-half of patients were satisfied with their PPI medication in trials, and more patients were satisfied with PPIs than other medication types. An association between patient satisfaction and symptom resolution was found, suggesting that patient satisfaction is a useful end point for evaluating GERD treatment success. PMID- 22506260 TI - Review of boceprevir and telaprevir for the treatment of chronic hepatitis C. AB - OBJECTIVE: To summarize and evaluate the published literature pertaining to boceprevir and telaprevir, and to provide clinicians with suggestions for use in patients with chronic hepatitis C infection. METHODS: A standardized search strategy was performed using the MEDLINE, EMBASE, Google Scholar and International Pharmaceuticals Abstracts databases using the search terms "boceprevir", "telaprevir", "boceprevir and hepatitis C", and "telaprevir and hepatitis C". A manual search of references was performed to identify articles missed by the electronic search. Studies were included in the review if they assessed either boceprevir or telaprevir in comparison with standard of care in chronic hepatitis C patients. RESULTS: The studies identified assessed boceprevir and telaprevir in genotype-1 hepatitis C patients. In both treatment-naive and treatment-experienced patients, sustained virological response rates were achieved more often with boceprevir or telaprevir in combination with pegylated interferon and ribavirin compared with pegylated interferon and ribavirin alone. Both medications were well tolerated, with anemia presenting as the most treatment-limiting adverse effect. CONCLUSIONS: Boceprevir and telaprevir will revolutionize the management of hepatitis C genotype 1 patients and will most likely decrease the burden of end-stage disease worldwide. However, current clinical limitations include establishing appropriate and cost-effective treatment durations, and use in special populations such as transplant patients and patients coinfected with HIV. Future research will need to clarify these clinical obstacles to clearly define the role of these agents in hepatitis C management. PMID- 22506263 TI - Re: Vanner S. "fair is foul, and foul is fair". Can J. Gastroenterol 2011; 11:601 2. PMID- 22506264 TI - New poly(ionic liquid)-grafted silica multi-mode stationary phase for anion exchange/reversed-phase/hydrophilic interaction liquid chromatography. AB - A new poly(ionic liquid)-grafted silica stationary phase was prepared and characterized. It was then applied for multi-mode chromatographies, including ion exchange, reversed-phase, and hydrophilic interaction liquid chromatographies for the effective separation of anions, hydrophobic compounds, and small polar molecules, respectively. PMID- 22506265 TI - A TEMPO-conjugated fluorescent probe for monitoring mitochondrial redox reactions. AB - We report a mitochondrial targeted redox probe (MitoRP) that comprises a nitroxide radical (TEMPO) moiety and coumarin 343. Using isolated mitochondria in the presence/absence of substrates and inhibitors of oxidative phosphorylation, we demonstrated that MitoRP is a useful probe to monitor the electron flow associated with complex I. PMID- 22506266 TI - Interior aliphatic C-H bond activation on iron(II) N-confused porphyrin through synergistic nitric oxide binding and iron oxidation. AB - Iron oxidation, in conjunction with NO coordination, achieved a C-H bond activation to convert [Fe(II)(HCTPPCH(3))Br] into [Fe(HCTPPCH(2))(NO)](BF(4)) at ambient temperature. The structural data and theoretical calculations confirmed the role of nitric oxide behaving as a pi-accepting ligand to assist the C-H bond activation. PMID- 22506267 TI - Open diamondoid amino-functionalized MOFs for CO2 capture. AB - Solvent-induced chiral single-crystal to achiral single-crystal structural transformation is presented by two isomeric amino-functionalized metal-organic frameworks with 2-fold interpenetrating diamond topology, and the achiral form has high CO(2) uptake capacity. PMID- 22506268 TI - Monomeric Sn(II) and Ge(II) hydrides supported by a tridentate pincer-based ligand. AB - Herein we report the syntheses of terminal Sn(II) (3) and Ge(II) (4) hydrides from the corresponding chloride precursors [{2,6 iPr(2)C(6)H(3)NCMe}(2)C(6)H(3)MCl] (M = Sn (1), Ge (2)) using [K{B(sec-Bu)(3)}H] as a hydrogenating agent. Combination of steric shielding and intramolecular N -> M interactions resulted in the protection of M(II)-H bonds. PMID- 22506269 TI - A long-lived photo-induced metastable state of linkage isomerization accompanied with a spin transition. AB - In addition to the generally observed LIESST phenomenon, polymorph D of trans [Fe(II)(abpt)(2)(NCS)(2)] exhibits a long-lived photo-induced metastable state through linkage isomerization accompanied with a spin crossover transition, which is stable up to 108 K. PMID- 22506270 TI - Cations-modified cluster model for density-functional theory simulation of potential dependent Raman scattering from surface complex/electrode systems. AB - Aiming to solve the problem of simulation of the potential dependent surface Raman spectra of anion containing surface complexes on electrodes, we developed a new simulation model by adding different cations (Li(+), Na(+), K(+), Rb(+) or Cs(+)) attached to the bottom layer of a large metallic cluster while the surface complex sits on the top layer. PMID- 22506271 TI - Enantioselective direct aminalization with primary carboxamides catalyzed by chiral ammonium 1,1'-binaphthyl-2,2'-disulfonates. AB - A highly effective catalytic enantioselective direct aminal synthesis was developed. Chiral ammonium 1,1'-binaphthyl-2,2'-disulfonates, which were prepared in situ from (R)-BINSA and achiral amines, promoted the enantioselective addition of primary amides to aromatic aldimines. PMID- 22506272 TI - Polynuclear complexes of main group and transition metals with polyaminopolycarboxylate and polyoxometalate. AB - Six supramolecular compounds constructed by main group and transition metals, polyoxotungstates (SiW(12)O(40)(4-)) and trans-N,N,N',N'-1,2 cyclohexanediaminotetraacetic acid (H(4)CyDTA), (NH(4))(3)[Ni(4)Na(H(2)O)(10)(CyDTA)(2)][SiW(12)O(40)].10H(2)O (1) (NH(4))(2)[Cu(3)Na(2)(HCyDTA)(2)(H(2)O)(13)][SiW(12)O(40)].5H(2)O (2), (NH(4))(2)[Zn(5)(CyDTA)(2)(H(2)O)(16)][SiW(12)O(40)].8H(2)O (3), (NH(4))(4)[Cd(4)(CyDTA)(2)(H(2)O)(8)][SiW(12)O(40)].6H(2)O (4), (NH(4))(4)[Sr(3)(HCyDTA)(2)(H(2)O)(14)][SiW(12)O(40)].2H(2)O (5) and [Ca(4)(H(2)CyDTA)(2)(H(2)O)(22)][SiW(12)O(40)].8H(2)O (6), were synthesized in aqueous solution and characterized by IR spectroscopy, thermogravimetric analysis and single-crystal X-ray diffraction techniques. Single-crystal structure analyses indicate they are constructed by the complexes with different nuclearity and polyoxometalates. In the sequence of Ni, Cu, Zn the nuclearity of the homometallic complex units increases from 2 to 5. Cadmium ions gives a tetranuclear complex with a compact structure. In 5 and 6 the main group metal ions and CyDTA form polymeric chains. CyDTA exhibits rather different coordination patterns to main group metal ions and transition metal ions due to their ionic radii and electronic configuration. The complex units and polyoxometalates arrange in different patterns due to the different shapes of the complex units. The compounds exhibit different thermal decomposition processes and the formation of compounds 3 and 4 quenches ligand-centered emissions and gives a ligand-to-metal emission. The study on various temperature susceptibilities of 1 and 2 shows that there is an antiferromagnetic coupling in the two compounds but coupling patterns are different. PMID- 22506273 TI - Variation in the biomolecular interactions of nickel(II) hydrazone complexes upon tuning the hydrazide fragment. AB - Three new bivalent nickel hydrazone complexes have been synthesised from the reactions of [NiCl(2)(PPh(3))(2)] with H(2)L {L = dianion of the hydrazones derived from the condensation of o-hydroxynaphthaldehyde with furoic acid hydrazide (H(2)L(1)) (1)/thiophene-2-acid hydrazide (H(2)L(2)) (2)/isonicotinic acid hydrazide (H(2)L(3)) (3)} and formulated as [Ni(L(1))(PPh(3))] (4), [Ni(L(2))(PPh(3))] (5) and [Ni(L(3))(PPh(3))] (6). Structural characterization of these compounds 4-6 were accomplished by using various physico-chemical techniques. Single crystal X-ray diffraction data of complexes 4 and 5 proved their distorted square planar geometry. In order to ascertain the potential of the above synthesised compounds towards biomolecular interactions, additional experiments involving interaction with calf thymus DNA (CT DNA) and bovine serum albumin (BSA) were carried out. All the ligands and corresponding nickel(ii) chelates have been screened for their scavenging effect towards O(2)(-), OH and NO radicals. The efficiency of complexes 4-6 to arrest the growth of HeLa, HepG-2 and A431 tumour cell lines has been studied along with the cell viability test against the non-cancerous NIH 3T3 cells under in vitro conditions. PMID- 22506274 TI - In situ ligand and complex transformation of an iron(III) Schiff base complex: structural evidence and theoretical calculations. AB - A C-C coupling reaction has been achieved at room temperature by in situ ligand transformation. The iron(III) complexes before and after the in situ transformation, [FeNaL(1)(2)(H(2)O)(4)](2).2H(2)O (1) (H(2)L(1) = (Z)-2-(2 hydroxyl)benzylideneamino) and [FeL(2)](2).7.5H(2)O (2) (H(3)L(2) = (E)-2-(2 hydroxyl-benzylideneamino)-3-hydroxyl-3-(2-hydroxyphenyl), have been studied by elemental analyses, FT-IR, UV-vis, TGA and X-ray single crystal diffraction analysis. The proposed mechanism of this in situ transformation has been determined based on structural evidence and theoretical calculations using the density functional theory (DFT) M06 method. PMID- 22506275 TI - Reactions and structural characterization of gold(III) complexes with amino acids, peptides and proteins. AB - The present review article highlights recent findings in the field of gold(III) complexes with amino acids, peptides and proteins. The first section of this article provides an overview of the gold(III) reactions with amino acids, such as glycine, alanine, histidine, cysteine and methionine. The second part of the review is mainly focused on the results achieved in the mechanistic studies of the reactions between gold(III) and different peptides and structural characterization of gold(III)-peptide complexes as the final products in these reactions. The last section of this article deals with the reactions of gold(III) complexes with proteins as primary targets for cytotoxic gold compounds. Systematic summaries of these results contribute to the future development of gold(III) complexes as potential antitumor agents and also have importance in relation to the severe toxicity of gold-based drugs. PMID- 22506276 TI - Cellular delivery of pyrenyl-arene ruthenium complexes by a water-soluble arene ruthenium metalla-cage. AB - Three pyrenyl-arene ruthenium complexes (M(1)-M(3)) of the general formula [Ru(eta(6)-arene-pyrenyl)Cl(2)(pta)] (pta = 1,3,5-triaza-7-phosphaadamantane) have been synthesised and characterised. Prior to the coordination to ruthenium, pyrene was connected to the arene ligand via an alkane chain containing different functional groups: ester (L(1)), ether (L(2)) and amide (L(3)), respectively. Furthermore, the pyrenyl moieties of the M(n) complexes were encapsulated within the hydrophobic cavity of the water soluble metalla-cage, [Ru(6)(eta(6)-p cymene)(6)(tpt)(2)(donq)(3)](6+) (tpt = 2,4,6-tri-(pyridin-4-yl)-1,3,5-triazine; donq = 5,8-dioxydo-1,4-naphthoquinonato), while the arene ruthenium end was pointing out of the cage, thus giving rise to the corresponding host-guest systems [M(n)?Ru(6)(eta(6)-p-cymene)(6)(tpt)(2)(donq)(3)](6+) ([M(n)?cage](6+)). The antitumor activity of the pyrenyl-arene ruthenium complexes (M(n)) and the corresponding host-guest systems [M(n)?cage][CF(3)SO(3)](6) were evaluated in vitro in different types of human cancer cell lines (A549, A2780, A2780cisR, Me300 and HeLa). Complex M(2), which contains an ether group within the alkane chain, demonstrated at least a 10 times higher cytotoxicity than the reference compound [Ru(eta(6)-p-cymene)Cl(2)(pta)] (RAPTA-C). All host-guest systems [M(n)?cage](6+) showed good anticancer activity with IC(50) values ranging from 2 to 8 MUM after 72 h exposure. The fluorescence of the pyrenyl moiety allowed the monitoring of the cellular uptake and revealed an increase of uptake by a factor two of the M(2) complex when encapsulated in the metalla-cage [Ru(6)(eta(6)-p cymene)(6)(tpt)(2)(donq)(3)](6+). PMID- 22506277 TI - Backbone conformational preferences of an intrinsically disordered protein in solution. AB - We have performed a 4-MUs molecular dynamics simulation to investigate the native conformational preferences of the intrinsically disordered kinase-inducible domain (KID) of the transcription factor CREB in solution. There is solid experimental evidence showing that KID does not possess a bound-like structure in solution; however, it has been proposed that coil-to-helix transitions upon binding to its binding partner (CBP) are template-driven. While these studies indicate that IDPs possess a bias towards the bound structure, they do not provide direct evidence on the time-dependent conformational preferences of IDPs in atomic detail. Our simulation captured intrinsic conformational characteristics of KID that are in good agreement with experimental data such as a very small percentage of helical structure in its segment alpha(B) and structural disorder in solution. We used dihedral principal component analysis dPCA to map the conformations of KID in the microsecond timescale. By using principal components as reaction coordinates, we further constructed dPCA-based free energy landscapes of KID. Analysis of the free energy landscapes showed that KID is best characterized as a conformational ensemble of rapidly interconverting conformations. Interestingly, we found that despite the conformational heterogeneity of the backbone and the absence of substantial secondary structure, KID does not randomly sample the conformational space in solution: analysis of the (Phi, Psi) dihedral angles showed that several individual residues of KID possess a strong bias toward the helical region of the Ramachandran plot. We suggest that the intrinsic conformational preferences of KID provide a bias toward the folded state without having to populate bound-like conformations before binding. Furthermore, we argue that these conformational preferences do not represent actual structural constraints which drive binding through a single pathway, which allows for specific interactions with multiple binding partners. Based on this evidence, we propose that the backbone conformational preferences of KID provide a thermodynamic advantage for folding and binding without negatively affecting the kinetics of binding. We further discuss the relation of our results to previous studies to rationalize the functional implications of the conformational preferences of IDPs, such as the optimization of structural disorder in protein-protein interactions. This study illustrates the importance in obtaining atomistic information of intrinsically disordered proteins in real time to reveal functional features arising from their complex conformational space. PMID- 22506278 TI - Integrated investigation of lipidome and related signaling pathways uncovers molecular mechanisms of tetramethylpyrazine and butylidenephthalide protecting endothelial cells under oxidative stress. AB - Tetramethylpyrazine (TMP) and butylidenephthalide (BP) are two bioactive components isolated from Ligusticum chuanxiong Hort and Angelica sinensis, respectively. These two traditional Chinese medicines have been widely used in clinical treatments for vascular disease. The mechanism by which TMP and BP protect endothelial cells (ECs) against oxidative stress remains unknown, as does their effects on the steady state of the lipidome of ECs. Here, we demonstrate that both compounds protect EA.hy926 cells against H(2)O(2) induced injury in a dose-dependent manner. We then apply an integrated analysis of the lipidome and signal transduction pathways to explore the underlying mechanism of their protective effects. We found that TMP elevates the content of several phosphatidylcholine (PC) species, reduces the release of arachidonic acid (AA) and inhibits the phosphorylation of cytosolic phospholipase A(2) (cPLA(2)). Compared to eicosatetraynoic acid (ETYA), a cPLA(2) inhibitor, TMP preferentially increases the content of arachidonoyl PCs. We also show that BP mainly elevates the pool of phosphatidylinositol (PI) species and inhibits the phosphorylation of both phospholipase C(gamma) (PLC(gamma)) and extracellular signal-regulated kinase 1/2 (ERK1/2). In contrast, specific inhibition of ERK1/2 by PD98059 decreases the cell viability and increases pool of phosphatidylserine (PS). Taken together, these results demonstrate that TMP protects oxidatively stressed ECs through inhibition of cPLA(2) and preferential increase of arachidonoyl PC levels. Conversely, the effects of BP are tied to inhibition of PLC(gamma) and an increase in PI levels. The current work suggests that the interaction of the lipidome and phospholipases can serve as a promising therapeutic target in oxidatively stressed ECs. PMID- 22506279 TI - Philippe G. Schyns. PMID- 22506281 TI - Innovation: The big idea of technology transfer. PMID- 22506280 TI - Prediction of whole-body and segmental body composition by bioelectrical impedance in morbidly obese subjects. AB - BACKGROUND: Validated equations for body composition analysis using bioelectrical impedance (BIA) in morbidly obese (MO) subjects are scarce. Thus, our aim was todevelop new equations from physical and BIA parameters to estimate whole-body and segmental body composition inMO subjects, with dual-energy X-ray absorptiometry(DXA) as the reference method. METHODS: A cross-sectional study on 159 Caucasian MO subjects (female 78%, age 43.5 +/- 11.8 years, BMI 45.6 +/- 4.9 kg/m2) divided in two groups was conducted: model building cohort (n = 110) and model validation cohort (n 0 49). Stepwise regression analysis was used to develop specific fat free mass (FFM) and fat mass (FM) equations. RESULTS: Gender, body weight, and height2/impedance accounted, respectively, for 89.4% (p < 0.001) and 89.3% (p < 0.001) of the variability of DXA-total FFM in the two cohorts. Using the new equation, the mean difference between the DXA-FFM and BIA FFM estimates was +0.180 kg (95% CI: -0.34 to +0.7 kg, p 0 NS), and the resulting limits of agreement were +6.76 and -6.40 kg. Similarly, good estimates of DXA truncal-, android-, and gynoid-FM from anthropometric and BIA parameters could be obtained from weight, height2/impedance, and waist and hip circumferences (respectively, R2 adjusted: 0.657, 0.776, and 0.770; p < 0.001). CONCLUSIONS: The new equations derived from physical and BIA parameters provide accurate estimates of body composition in MO subjects. PMID- 22506282 TI - A mental health review board in action. PMID- 22506283 TI - DSM-IV versus DSM-5: implementation of proposed DSM-5 criteria in a large naturalistic database. AB - OBJECTIVE: Problems with the current DSM-IV eating disorder (ED) section have resulted in proposed changes toward the upcoming DSM-5 (http://www.dsm5.org/ProposedRevisions/Pages/EatingDisorders.aspx). We investigated consequences of these by implementing the proposal in a large naturalistic database. METHOD: Patients were 2,584 children/adolescents and adults enrolled at specialized ED clinics in Sweden. DSM-IV diagnoses anorexia nervosa, bulimia nervosa, and "not otherwise specified" examples were compared with DSM-5 anorexia, bulimia, and binge ED, as well as atypical anorexia, subthreshold bulimia, and binge eating, purging disorder, and the residual unspecified category. Assessment methods included a semistructured diagnostic interview and self-ratings of ED and psychiatric symptoms. RESULTS: We studied age-separated diagnostic distributions and explained variance in clinical variables associated with the two systems. Results showed some improvement of diagnostic specification as well as a slight increase in explained variance. DISCUSSION: Remaining problems with the proposed changes were also highlighted, and possible further refinement is discussed. PMID- 22506284 TI - Advanced reproductive age and fertility: no. 269, November 2011. AB - OBJECTIVE: To improve awareness of the natural age-related decline in female and male fertility with respect to natural fertility and assisted reproductive technologies (ART) and provide recommendations for their management,and to review investigations in the assessment of ovarian aging. OPTIONS: This guideline reviews options for the assessment of ovarian reserve and fertility treatments using ART with women of advanced reproductive age presenting with infertility. OUTCOMES: The outcomes measured are the predictive value of ovarian reserve testing and pregnancy rates with natural and assisted fertility. EVIDENCE: Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in June 2010, using appropriate key words (ovarian aging, ovarian reserve, advanced maternal age, advanced paternal age, ART). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated into the guideline to December 2010. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table). BENEFITS, HARMS, AND COSTS: Primary and specialist health care providers and women will be better informed about ovarian aging and the age-related decline in natural fertility and about options for assisted reproductive technology. PMID- 22506285 TI - Re: Effects of mandibular incisor intrusion obtained using a conventional utility arch vs bone anchorage. Angle Orthod. 2011;81:767-775, by Esen Aydogdu and Omur Polat Ozsoy. PMID- 22506286 TI - Organization and expression of the Australian sheep blowfly (Lucilia cuprina) hsp23, hsp24, hsp70 and hsp83 genes. AB - In this study we report the isolation and characterization of a heat shock protein 70 (hsp70) gene, the hsp83 gene and two genes that encode small Hsps (Lchsp23 and Lchsp24) from the Australian sheep blowfly, Lucilia cuprina, a major agricultural pest. Phylogenetic analyses indicate that the LcHsp23 protein is the orthologue of Drosophila melanogaster Hsp23 and LcHsp24 is the orthologue of Sarcophaga crassipalpis Hsp23. Quantitative reverse-transcriptase PCR analysis showed that the basal level of Lchsp83 RNA is relatively high at all developmental stages and only moderately induced by heat shock. In contrast, Lchsp70 transcripts are present at low levels and strongly induced by heat shock at all stages. The basal levels of expression and degrees of heat induction of the Lchsp23 and Lchsp24 transcripts were more variable across the different developmental stages. Putative heat shock factor binding sites were identified in the Lchsp24, Lchsp70 and Lchsp83 gene promoters. The isolation of these hsp gene promoters will facilitate constitutive or conditional expression of a gene of interest in transgenic Lucilia. PMID- 22506287 TI - Variable waveforms in downbeat nystagmus imply short-term gain changes. AB - A patient with downbeat nystagmus subsequent to ankylosing spondylitis was studied. His nystagmus was found to exhibit both increasing- and decreasing velocity exponential slow phases as well as the linear form more often reported. Alternation between waveforms sometimes occurred on a beat-to-beat or even intrabeat basis. Possible explanations for all three waveforms are presented in terms of short-term gain changes in cerebellar compensation for leaky brainstem neural integrators. A computer model was developed and its results are discussed. PMID- 22506288 TI - Proceedings of the First International Symposium on A Molecular View of Steroid Biosynthesis and Metabolism, October 14-17, 1991, Jerusalem, Israel. PMID- 22506289 TI - Proceedings of the 1st International Symposium on Fermented Meats, April 13-16, 2011, Freising, Germany. PMID- 22506290 TI - Atypical multiple lipomatosis as sole manifestation of a mitochondrial disorder. PMID- 22506291 TI - Paraneoplastic anti-HU syndrome associated with uterine tumor. PMID- 22506292 TI - Spontaneous occlusion of the temporal AVM associated with tinnitus. PMID- 22506294 TI - Validation of maternal and neonatal tetanus elimination in Ghana, 2011. PMID- 22506296 TI - [On neurology viewed by an authority on electrophysiology: an interview of Dr. Jun Kimura by Dr. Imaharu Nakano]. PMID- 22506295 TI - Successful liver transplantation for a child with life-threatening recurrent bleeding episodes due to congenital factor X deficiency: a case report. AB - Factor X (FX) deficiency is a rare, autosomal-recessive coagulation disorder. Diagnosis can be confirmed by a factor X assay. Although fresh frozen plasma and prothrombin complex concentrates have been used as a temporary treatment of bleeding symptoms and preparation for surgery, frequent transfusion has its risk and prothrombin complex is not available in Korea. We report the first pediatric case of successful liver transplantation for the correction of a severe congenital FX deficiency in a child with recurrent life-threatening hemorrhagic episodes. PMID- 22506297 TI - [Neurological CPC. A 16-year-old woman with an onset of acute psychiatric symptoms followed by recurrent status epilepticus]. PMID- 22506298 TI - From the ideal to the real world: a phenomenological inquiry into student sojourners' reentry adaptation. AB - This phenomenological study examines the thematic structure of reentry transition for international music therapy graduates who have returned home after studying in the United States. Emphasis is placed upon career development. Standardized open-ended interviews were used to obtain rich and in-depth descriptions of the participants' experiences. Ten music therapists from six countries participated in the study. The themes that emerged from the data include moving from the ideal to the real world, shifting from the role of student to professional, confronting reality and working through challenges, and achieving personal growth and self transformation. The dynamics of cross-cultural comparison, confronting the home culture, and redefining music therapy and professional identities within the local cultural context are illustrated via quotations from the participants. Implications and recommendations for music therapy education and career preparation for international graduates are discussed. PMID- 22506299 TI - The effect of a music therapy social skills training program on improving social competence in children and adolescents with social skills deficits. AB - Three separate studies were conducted in school, residential and after-school care settings to test the effectiveness of a music therapy-based social skills intervention program on improving social competence in children and adolescents. A total of 45 children (n = 12; n = 13; n = 20) aged 6-17 years with social skills deficits participated in a group-based five session intervention program. The same curriculum, adapted to be age appropriate, was used at all 3 sites. Specific deficits within the social skills areas of peer relations and self management skills were targeted. Active interventions like music performance, movement to music and improvisation were used. Cognitive-behavioral techniques like modeling, feedback, transfer training and problem solving were also incorporated. Data on social functioning were collected before, during, and after the music therapy intervention from participants, appropriate adult personnel and via behavioral observations. Results indicated that significant improvements in social functioning were found in (a) school participant pre and post self ratings, (b) researcher pre and post ratings of school participants, (c) case manager's pre and post treatment ratings for the residential participants, (d) after-school care participants' pre and post self-ratings, and (e) behavioral observations at all three settings. Additional changes, although not significant, were noted in teacher ratings, residential participant self- and peer ratings, and after-school case manager ratings. Results from these studies suggest that the music therapy intervention was effective in improving social competence in children and adolescents with social deficits. More research is warranted to provide additional guidance about the use of music therapy interventions to improve social functioning. PMID- 22506300 TI - Active music engagement with emotional-approach coping to improve well-being in liver and kidney transplant recipients. AB - Liver and kidney transplant recipients report elevated psychological distress following transplant in comparison to other types of organ transplant recipients. Negative affective states can lead to immune dysregulation and adverse health behaviors, and therefore may contribute to disease. In contrast, positive affective states can broaden individuals' thoughts and actions to promote the accumulation of coping resources. Coping strategies have traditionally been conceived of as being either problem-focused or emotion-focused in nature, while contemporary theory and research supports a different division: approach-oriented strategies versus avoidance-oriented strategies. Emotional expression and processing may function as an approach-oriented coping strategy. Emotional approach coping relates to the use of emotional expression, awareness and understanding to facilitate coping with significant life stressors. The current study evaluated the impact of music therapy with and without a specific emphasis on emotional-approach coping. This randomized, controlled trial aimed to use Active Music Engagement with Emotional-Approach Coping to improve well-being in post-operative liver and kidney transplant recipients (N = 29). Results indicated that music therapy using Emotional-Approach Coping led to significant increases in positive affect, music therapy using Active Music Engagement led to significant decreases in pain, and both conditions led to significant decreases in negative affect, an indicator of perceived stress/anxiety. PMID- 22506301 TI - The effect of a music therapy intergenerational program on children and older adults' intergenerational interactions, cross-age attitudes, and older adults' psychosocial well-being. AB - The purpose of this study was to examine the effect of participation in a music based intergenerational music program on cross-age interactions and cross-age attitudes of elementary-age children and older adults, and older adults' psychosocial well-being. Twenty-one children in the 4th grade volunteered to participate in the experimental (n = 12) or control (n = 9) group. Twenty-six older adults from a retirement living facility also volunteered to participate in the experimental (n = 14) or control (n = 12) group. Ten 30-min music sessions occurred in which participants engaged in singing, structured conversation, moving to music, and instrument playing interventions. Data analysis of cross-age interactions revealed that the interventions "structured conversation" and "moving to music" were more effective in eliciting interaction behaviors than the interventions "singing" and "instrument playing." Standardized measures revealed that children's attitudes towards older adults improved, though not significantly so, after participation in the intergenerational program. Results of biweekly post-session questionnaires revealed a decrease in negative descriptions of older adults and an increase in positive descriptions of older adults--suggesting a more positive view towards aging. Results revealed that older adults' attitudes towards children improved significantly after their participation in the intergenerational program. While standardized measures revealed that older adults did not perceive a significant improvement in their psychosocial well-being, their bi-weekly post-session questionnaires showed they perceived increased feelings of usefulness and other personal benefits from the intergenerational interactions. Suggestions for future research, the utility of varied measurement instruments, and implications for practice are discussed. PMID- 22506302 TI - Effects of music therapy on change readiness and craving in patients on a detoxification unit. AB - The purpose of this study was to determine the effect of a "rockumentary" music therapy intervention on readiness to change and craving in patients on a detoxification unit utilizing psychometric instruments in a randomized three group design. Participants (N = 141) were randomized by group to a rockumentary music therapy intervention, verbal therapy, or recreational music therapy condition. All interventions were scripted and manualized in a posttest only design. Concerning readiness to change, results indicated there were significant between-group differences in Contemplation and Action subscales, with participants in the rockumentary and recreational music therapy conditions having higher means than participants in the verbal therapy condition. There were no differences between the two music therapy conditions concerning readiness to change variables. Although not significant, participants in both music therapy conditions tended to have lower mean craving scores than participants in the verbal therapy condition. Concerning Likert-type ratings of motivation to change, perception of helpfulness, and perception of enjoyment, participants in both music therapy conditions tended to have slightly higher mean scores than participants in the verbal therapy conditions. Participants' posttest written comments were positive, regardless of condition. Limitations of the study, suggestions for the future inquiry, and implications for clinical practice are provided. PMID- 22506303 TI - The effects of music therapy incorporated with applied behavior analysis verbal behavior approach for children with autism spectrum disorders. AB - This study compared a common form of Applied Behavior Analysis Verbal Behavior (ABA VB) approach and music incorporated with ABA VB method as part of developmental speech-language training in the speech production of children with Autism Spectrum Disorders (ASD). This study explored how the perception of musical patterns incorporated in ABA VB operants impacted the production of speech in children with ASD. Participants were 22 children with ASD, age range 3 to 5 years, who were verbal or pre verbal with presence of immediate echolalia. They were randomly assigned a set of target words for each of the 3 training conditions: (a) music incorporated ABA VB, (b) speech (ABA VB) and (c) no training. Results showed both music and speech trainings were effective for production of the four ABA verbal operants; however, the difference between music and speech training was not statistically different. Results also indicated that music incorporated ABA VB training was most effective in echoic production, and speech training was most effective in tact production. Music can be incorporated into the ABA VB training method, and musical stimuli can be used as successfully as ABA VB speech training to enhance the functional verbal production in children with ASD. PMID- 22506304 TI - Development and preliminary evaluation of a music-based attention assessment for patients with traumatic brain injury. AB - Impairments in attention are commonly seen in individuals with traumatic brain injury (TBI). While visual attention assessment measurements have been rigorously developed and frequently used in cognitive neurorehabilitation, there is a paucity of auditory attention assessment measurements for patients with TBI. The purpose of this study was to field test a researcher-developed Music-based Attention Assessment (MAA), a melodic contour identification test designed to assess three different types of attention (i.e., sustained attention, selective attention, and divided attention), for patients with TBI. Additionally, this study aimed to evaluate the readability and comprehensibility of the test items and to examine the preliminary psychometric properties of the scale and test items. Fifteen patients diagnosed with TBI completed 3 different series of tasks in which they were required to identify melodic contours. The resulting data showed that (a) test items in each of the 3 subtests were found to have an easy to moderate level of item difficulty and an acceptable to high level of item discrimination, and (b) the musical characteristics (i.e., contour, congruence, and pitch interference) were found to be associated with the level of item difficulty, and (c) the internal consistency of the MAA as computed by Cronbach's alpha was .95. Subsequent studies using a larger sample of typical participants, along with individuals with TBI, are needed to confirm construct validity and internal consistency of the MAA. In addition, the authors recommend examination of criterion validity of the MAA as correlated with current neuropsychological attention assessment measurements. PMID- 22506305 TI - The Child and Adolescent Twin Study in Sweden (CATSS). AB - The Child and Adolescent Twin Study in Sweden (CATSS) is an ongoing longitudinal twin study targeting all twins born in Sweden since July 1, 1992. Since 2004, parents of twins are interviewed regarding the children's somatic and mental health and social environment in connection with their 9th or 12th birthdays (CATSS-9/12). By January 2010, 8,610 parental interviews concerning 17,220 twins had been completed, with an overall response rate of 80%. At age 15 (CATSS-15) and 18 (CATSS-18), twins and parents complete questionnaires that, in addition to assessments of somatic and mental health, include measures of personality development and psychosocial adaptation. Twin pairs in CATSS-9/12 with one or both twins screening positive for autism spectrum disorders, attention deficit/hyperactivity disorder, tic disorders, developmental coordination disorder, learning disorders, oppositional defiant disorder, conduct disorder, obsessive-compulsive disorder, and/or eating problems have been followed with in depth questionnaires on family, social environment and personality, and subsequently by clinical assessments at age 15 together with randomly selected population controls, including 195 clinically assessed twin pairs from the first 2 year cohorts (CATSS-15/DOGSS). This article describes the cohorts and study groups, data collection, and measures used. Prevalences, distributions, heritability estimates, ages at onset, and sex differences of mental health problems in the CATSS-9/12, that were analyzed and found to be overall comparable to those of other clinical and epidemiological studies. The CATSS study has the potential of answering important questions on the etiology of childhood mental health problems and their role in the development of later adjustment problems. PMID- 22506306 TI - Returns to education: what do twin studies control? AB - The current article examines the assumptions of the MZ co-twin control method that has been applied in attempts to gain more accurate estimates of the returns to education by naturally 'controlling' for individual differences on which MZ twins are matched. The current study examined 1738 MZ and 926 DZ twins from Minnesota, including 133 pairs of MZ and 101 pairs of DZ twins discordant for university attendance. They were assessed prospectively on personality, intelligence, GPA, and academic motivation; a subset also has reported income at age 29. MZ twins discordant for university attendance differed significantly and prospectively on verbal IQ, personality traits, and GPA. While MZ co-twin control studies can provide more accurate estimates of the returns to education than analyses of single individuals, these studies do not entirely obviate the need to control for differences between university students and non-students that predate university attendance and might account for income differentials and even non monetary outcomes. PMID- 22506307 TI - The relationship between the genetic and environmental influences on common externalizing psychopathology and mental wellbeing. AB - To determine the relationship between the genetic and environmental risk factors for externalizing psychopathology and mental wellbeing, we examined detailed measures of emotional, social and psychological wellbeing, and a history of alcohol-related problems and smoking behavior in the last year in 1,386 individual twins from same-sex pairs from the MIDUS national US sample assessed in 1995. Cholesky decomposition analyses were performed withthe Mx program. The best fit model contained one highly heritable common externalizing psychopathology factor for both substance use/abuse measures, and one strongly heritable common factor for the three wellbeing measures. Genetic and environmental risk factors for externalizing psychopathology were both negatively associated with levels of mental wellbeing and accounted for, respectively, 7% and 21% of its genetic and environmental influences. Adding internalizing psychopathology assessed in the last year to the model, genetic risk factors unique for externalizing psychopathology were now positively related to levels of mental wellbeing, although accounting for only 5% of the genetic variance. Environmental risk factors unique to externalizing psychopathology continued to be negatively associated with mental wellbeing, accounting for 26% of the environmental variance. When both internalizing psychopathology and externalizing psychopathology are associated with mental wellbeing, the strongest risk factors for low mental wellbeing are genetic factors that impact on both internalizing psychopathology and externalizing psychopathology, and environmental factors unique to externalizing psychopathology. In this model, genetic risk factors for externalizing psychopathology predict, albeit weakly, higher levels of mental wellbeing. PMID- 22506308 TI - Differential age and sex effects in the assessment of major depression: a population-based twin item analysis of the DSM criteria. AB - A twin item factor analytic model was developed to test for the presence of noninvariant age, sex, and age by sex interaction effects on the individual DSM III-R criteria for major depression (MD). Based on 1-year reports, six of the nine MD criteria and duration requirement were found to have covariate factor loading and/or threshold effects that significantly deviated from their corresponding factor level expectations. A significant age effect was found for the binary duration variable factor loading. The 'loss of interest', 'weight problems' and 'psychomotor problems' criteria all displayed forms of threshold only effects. 'Depressed mood', 'fatigue', and 'feeling worthless' had more complex patterns that included both factor loading and threshold effects. A significant factor age by sex interaction effect indicating an increasing female mean difference with age was found to be largely associated with the presence of differential threshold covariate effects. Disagreement between estimated factor scores and DSM-derived affected vs. unaffected classification was approximately 1.3%. Status on the duration requirement was found to be the one feature common to all discrepancies. The MD criteria set provided maximum information for calibrating MD factor scores in the scale region where discrepancies occurred. The dimensional modeling results are discussed in the broader context of epidemiological research and clinical assessment of major depression. PMID- 22506309 TI - A behavioral-genetic study of alexithymia and its relationships with trait emotional intelligence. AB - The present study is the first to examine relationships between alexithymia and trait emotional intelligence (trait El or trait emotional self-efficacy) at the phenotypic, genetic, and environmental levels. The study was also conducted to resolve inconsistencies in previous twin studies that have provided estimates of the extent to which genetic and environmental factors contribute to individual differences in alexithymia. Participants were 216 monozygotic and 45 dizygotic same-sex twin pairs who completed the Toronto Alexithymia Scale-20. In a pilot study, a sub-sample of 118 MZ and 27 DZ pairs also completed the Trait Emotional Intelligence Questionnaire. Results demonstrated that a combination of genetic and non-shared environmental influences contribute to individual differences in alexithymia. As expected, alexithymia and trait El were negatively correlated at the phenotypic level. Bivariate behavioral genetic analyses showed that that all but one of these correlations was primarily attributable to correlated genetic factors and secondarily to correlated non-shared environmental factors. PMID- 22506311 TI - Heritability of cortisol regulation in children. AB - BACKGROUND: The normal development of cortisol regulation during childhood is thought to be influenced by a complex interplay between environmental and genetic factors. METHOD: The aim of this study was to estimate genetic and environmental influences on basal cortisol levels in a sample of 151 twin pairs aged 9-16 years. Salivary cortisol was collected on two consecutive days when the children attended school--immediately after awakening, 30 min post-awakening and at bedtime. RESULTS: Heritability was highest (60%) for cortisol levels about 30 min after awakening. For samples taken immediately at awakening heritability was less pronounced (28%) and in the evening low (8%). CONCLUSION: The limited genetic influence on evening levels, moderate on cortisol at awakening and high on awakening response, might imply two genetic regulation patterns, one specifically for awakening response and one for the circadian rhythm proper. These findings could explain divergent results in previous studies and highlight the importance of taking the circadian rhythm into account in studies of cortisol levels in children. PMID- 22506310 TI - Shorter adult stature increases the impact of risk factors for cognitive impairment: a comparison of two Nordic twin cohorts. AB - We analyzed the association between mean height and old age cognition in two Nordic twin cohorts with different childhood living conditions. The cognitive performance of 4720 twin individuals from Denmark (mean age 81.6 years, SD = 4.59) and Finland (mean age 74.4 years, SD = 5.26) was measured using validated cognitive screens. Taller height was associated with better cognitive performance in Finland (beta-estimates 0.18 SD/10cm, p value < .001, for men and 0.13 SD, p = .008, for women), but this association was not significant in Denmark (beta estimates 0.0093 SD, p value = .16, for men and 0.0075 SD, p value = .016, for women) when adjusted for age and education/social class. Among Finnish participants higher variability of cognitive performance within shorter height quintiles was observed. Analysis using gene-environment interaction models showed that environmental factors exerted a greater impact on cognitive performance in shorter participants, whereas in taller participants' it was explained mainly by genetic factors. Our results suggest that shorter participants with childhood adversity are more vulnerable to environmental risk factors for cognitive impairment. PMID- 22506312 TI - Investigation of two Wnt signalling pathway single nucleotide polymorphisms in a breast cancer-affected Australian population. AB - In the mammary gland, Wnt signals are strongly implicated in initial development of the mammary rudiments and in the ductal branching and alveolar morphogenesis that occurs during pregnancy. Previously, we identified two Wnt signaling pathway implicated genes, PPP3CA and MARK4, as having a role in more aggressive and potentially metastatic breast tumors. In this study, we examined two SNPs within PPP3CA and MARK4 in an Australian case-control study population for a potential role in human breast cancers. 182 cases and 180 controls were successfully genotyped for the PPP3CA SNP (rs2850328) and 182 cases and 177 controls were successfully genotyped for the MARK4 SNP (rs2395) using High Resolution Melt (HRM) analysis. Genotypes of randomly selected samples for both SNPs were validated by dye terminator sequencing. Chi-square tests were performed to determine any significant differences in the genotype and allele frequencies between the cases and controls. Chi-square analysis showed no statistically significant difference (p > .05) for genotype frequencies between cases and controls for rs2850328 (chi2 = 1.2, p = .5476) or rs2395 (chi2 = .3, p = .8608). Similarly, no statistical difference was observed for allele frequencies for rs2850328 (chi2 = .68, p = .4108) or rs2395 (chi2 = .02, p = .893). Even though an association of the polymorphisms rs2850328 and rs2395 and breast cancer was not detected in our case-control study population, other variants within the PPP3CA and MARK4 genes may still be associated with breast cancer, as both genes are implicated with processes involved in the disease as well as their mutual partaking in the Wnt signaling pathway. PMID- 22506313 TI - Environmental and genetic contributions to indicators of oral malodor in twins. AB - This study aimed to: (1) determine concordance rates of self-reported and subjectively determined indicators of oral malodor in twins; (2) determine the relative contributions of genetic and environmental factors to levels of volatile sulfur compounds (VSCs) in intraoral and exhaled breath. Fifty-one twin pairs participated in the study. Measurements of VSCs were obtained by a halimeter. The presence of tongue coatings was determined and twins filled out a 32-item questionnaire on oral malodor indicators independently of one another. Estimates of heritability (h2) for halimeter measurements were computed by SOLAR. The concordance rates for the presence of tongue coating among identical and fraternal twins were 67% and 11%, respectively. In the 10 most informative items, 70% exhibited higher concordance rates for identical than for fraternal twins. Of particular interest were the differences in concordance rates for dry mouth, sinus infection and unusual sweating. The h2 for intraoral breath was 0.28 +/- 0.17 (NS), whereas the h2 for exhaled breath was 0.50 +/- 0.20 (p = .0207). The concordance rates of tongue coatings and malodor indicators were higher in identical twins than in fraternal twins. Intraoral breath VSC values were primarily attributable to environmental factors, whereas exhaled breath VSC values were partially explained by genetic factors. PMID- 22506314 TI - Twin-to-twin delivery time: neonatal outcome of the second twin. AB - OBJECTIVE: To examine the effect of twin-to-twin delivery time (TTDT) on neonatal outcome. METHODS: We evaluated twin deliveries >34 weeks of gestation. Twin pregnancies with both twins delivered by cesarean section and pregnancies with antenatal complications were excluded. We analyzed TTDT and neonatal outcomes of the second twin (umbilical arterial pH value (pH(art)), Apgar scores at 1, 5 and 10 minutes, need for intensive care). The study population was divided into two homogenous groups based on the mode of delivery: (A) vertex presentation and vaginal delivery of both twins, (B) vertex presentation and vaginal or vaginal operative delivery of twin I, breech or transverse presentation and vaginal breech delivery or cesarean section (CS) of twin II. RESULTS: A total of 207 twin pairs were included in our study. In Group A (n = 151) there were no significant correlations between TTDT and pH(art) or Apgar scores at 1,5 and 10 minutes of twin II (p = .156; 0.861; 0.151 and 0.384, respectively). In Group B (n = 56), the mean pH(art) of twin II was inversely correlated to TTDT, but not significantly (p = .417). TTDT was inversely related to 1-min and 5-min Apgar scores, but not significantly (p = .330; p = .138, respectively). The 10-min Apgar score showed no correlation with TTDT (p = .638). CONCLUSION: Increasing TTDT was not associated with adverse fetal outcome. Expectant management of the second twin appears possible and elapsed time alone does not appear to be an indication for intervention. PMID- 22506315 TI - Variable outcome in quintuplets pregnancy based on obstetric care. AB - The incidence of multiple pregnancies has increased dramatically over the last few years in developed countries, largely attributed to delayed childbearing and the increasing use of assisted reproduction technologies and ovulation inducing hormones. Relatively few countries have population-based statistics covering birth statistics. Of those that do, the numbers of quintuplet pregnancies rose sharply in the nineties while, at the same time, their delivery rates decreased greatly because of the use of fetal reduction. Fetal reduction is not possible or legal in some countries, Poland being one of them, and therefore obstetricians are faced with the challenges of quintuplet deliveries. Conservative treatment and management is difficult, and outcomes often vary greatly. Despite this, expert care provided at tertiary care centers can positively influence outcomes. The objective of this article is to present different care options and their consequences in two illustrative cases, as well as to establish a set of obstetric care and management goals that would allow prolongation of the gestation time. Quintuplet pregnancy is rare but poses relevant clinical problems to both the obstetrician and the neonatologist. It should be managed with close cooperation between all concerned. Due to the extreme and invariable risk of premature delivery associated with quintuplet pregnancies, we recommend early diagnosis, adequate prenatal care at one tertiary medical center, routine hospitalization and bed rest, repeated ante partum ultrasound surveillance with tests of fetal well-being, tocolytic therapy at first signs of the risk of premature labor, and specialized neonatology care after delivery. PMID- 22506316 TI - Pregnancy outcome of monochorionic twins: does amnionicity matter? AB - OBJECTIVE: To compare the fetal loss rate of monochorionic (MC) twin pregnancies according to their amnionicity. METHODS: A retrospective review of all MC pregnancy outcomes in a tertiary centre. Pregnancy outcomes were compared for monochorionic monoamniotic (MCMA) versus monochorionic diamniotic (MCDA) pregnancies. RESULTS: 29 MCMA and 117 MCDA twin pregnancies were identified. The overall fetal loss rate was significantly higher in MCMA (23/52, 44.2%) compared to MCDA pregnancies (28/233, 12%, Chi squared = 30.03, p < .001). Kaplan-Meier analysis showed that fetal survival rate in MCDA twins were significantly higher than in MCMA twins (Log-rank Chi-squared = 27.9, p < .0005). Early pregnancy ultrasound identified the causes for these fetal losses in some MCMA twins. After exclusion of identifiable causes, the difference in fetal survival was not significant in the two groups (Log-rank chi-squared = 0.373, p = .54). CONCLUSION: The loss rate for MCMA twins is high and occurs mainly due to discordant congenital abnormality, conjoint twins or twin reversed arterial perfusion (TRAP) sequence. Although the fetal loss rate in MCDA is lower than in MCMA pregnancies, the majority of fetal loss in MCDA pregnancies cannot be predicted at the first scan at presentation. The data of this study questions the widespread policy of a difference in the scheduling of elective delivery for MCMA and MCDA twins. PMID- 22506317 TI - The value of twin studies: a response to Slate Magazine. PMID- 22506319 TI - [HELLP syndrome--severe complication during pregnancy]. AB - HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) is a severe microcirculatory disturbance during pregnancy, associated with pre-eclampsia, but it may occur also without it. In HELLP maternal morbidity and mortality have increased. Typical complications include coagulation disorder, acute respiratory failure, acute renal failure, infections, central nervous system symptoms, hepatic failure and bleeding, and premature ablation of the placenta. The only effective means to treat the syndrome during pregnancy is termination of pregnancy. PMID- 22506318 TI - Estimation of the contribution of assisted and non-assisted reproductive technology fertility treatments to multiple births during the past 30 years in Japan: 1979-2008. AB - The effect of assisted reproductive technology (ART) and non-ART ovulation stimulation fertility treatment on the number and rate of multiple live births from 1979-2008 in Japan was estimated using two independent data sources, ART statistics and vital statistics. Japanese ART statistics presented by the Japan Society of Obstetrics and Gynecology between 1989 and 2008 were gathered and reanalyzed. The number and rates of ART between 1984 and 1988 were interpolated using an approximation formula, using the values from 1983, when the first ART baby was born in Japan, and the 1989-1992 values. The number of ART multiples between 1979-1982 was set as equal to zero. The minimum (or maximum) number of non-ART iatrogenic multiple births was estimated by subtracting the maximum (or minimum) ART multiples from the total iatrogenic multiples, which was estimated by vital statistics assuming that spontaneous multiple-birth rates according to maternal age class would be constant. There was an overall increase in the non ART multiple births during the 30-year period, whereas ART multiples tended to increase from 1983 to 2005, and then rapidly decreased thereafter. The number or percentage of ART multiples was almost consistently lower than that of non-ART multiples. The percentage of non-ART multiples (33%) among the total multiples was estimated to be about three times more than the ART multiples (11-12%) in 2008. Given the medical and social impact of multiple births, it is imperative to construct a hospital-based monitoring system for fertility treatments, specially non-ART fertility treatments and multiple births. PMID- 22506320 TI - [Current therapy of chronic myeloid leukemia]. AB - Chronic myeloid leukemia (CML) originates from a hematopoietic stem cell carrying the Philadelphia (Ph) chromosome and oncogenic BCR-ABL1 fusion gene. The first tyrosine-kinase inhibitor (TKI) imatinib was introduced to clinical practice 10 years ago, and it radically improved the outcome of CML patients. The rare patients that are imatinib resistant or intolerant can be treated with second generation TKIs such as dasatinib or nilotinib. As second generation TKIs appear to be more effective than imatinib and well tolerated, they may become standard first-line treatment for CML. The major future aim in CML is curative drug therapy. PMID- 22506321 TI - [Osler's disease or hereditary hemorrhagic telangiectasia]. AB - According to current knowledge, Osler's disease may be caused by gene defects of several distinct genes, causing vascular fragility and lack of contractility. The most typical symptoms are recurrent spontaneous nose bleedings. Other target organs of the disease include skin, lungs, intestinal tract, brain and liver, but symptoms in these organs are less common. The diagnosis is based on clinical findings, family history and can, if necessary, be confirmed by a gene test. Osler's disease is treated symptomatically. There is no curative treatment. PMID- 22506322 TI - [When external otitis does not heal]. AB - An illness initially started as external otitis in a healthy and physically fit middle-aged person turned out to be a difficult-to-manage Langerhans cell histiocytosis. The disease occurs mostly in children, and international clinical guidelines have accordingly been devised mainly for juvenile patients. Treatment of adult patients is thus essentially empirical. The disease may affect several organs, as in our case report, in which the disease after progression to a multisystemic disease led to secondary leukemia and death of the patient. PMID- 22506323 TI - [Update on current care guidelines: urinary incontinence (female)]. AB - Female urinary incontinence (UI) is divided into stress (SUI), urgency (UUI), mixed (MUI) and overflow incontinence (chronic retention). Advanced age, obesity and pregnancy are the most important risk factors. Standardised questionnaires are used in diagnosis. The pad test, cough stress test and bladder diary are objective tools. A gynaecological examination includes pelvic floor muscle palpation and residual urine measurement. Urodynamics, cystoscopy and ultrasonography are complementary tools. Guided pelvic floor-muscle training is the first-line therapy. UUI can be treated with anticholinergic medicines. If conservative treatments are ineffective, SUI and MUI can be treated surgically with mid-urethral slings (TVT TOT and TVT-0). PMID- 22506324 TI - [Depression as a systemic disease]. AB - Depression has traditionally been considered as a mental illness, because basic biological methods previously failed to reveal any associated somatic changes. New more sensitive methods have, however, revealed many kinds of biological changes associated with depression. Scientific research has shown that the categorical division into mind and body is not justified. Instead, depression can be considered a systemic illness due to the manifold associated biological changes predisposing to somatic diseases and worsening their prognosis. PMID- 22506325 TI - [Liaison psychiatry--bridge between specialized fields]. AB - Mental symptoms and illnesses are common in community health center and general hospital patients. Collaboration between psychiatric team and those responsible for somatic care is beneficial to the patient. Practical forms of collaboration include for instance consultation and group practice with the psychiatrist and the somatic physician. Timely consultations with a clearcut and comprehensive recommendations concerning the follow-up and medications are essential. Support for the personnel of the somatic ward by the psychiatric team should also be provided. PMID- 22506327 TI - [Delirium]. AB - The pathophysiology of delirium is poorly known and scientific evidence of effective forms of treatment is scarce. Detection of triggering factors and their appropriate treatment still constitute the cornerstone of the treatment. If drug therapy is required, an antipsychotic drug is the first-line treatment. Only in the case of the delirium tremens syndrome benzodiazepine is chosen as the first line treatment. The use of restraint systems should be avoided. The delirium experience is often gravely traumatizing for the patient, and the psychological aftercare of delirium must therefore not be ignored. PMID- 22506326 TI - [Assessment and treatment of conversion disorder: the most fascinating borderline of psychiatry and neurology]. AB - Conversion disorder or functional neurological disorder is a neurological symptom complex originating from psychological factors, which manifests in voluntary motor and sensory functions or as unexplained epilepsy-like seizures. Until the 1980's the disorder was called hysterical neurosis. Later on, various general terms, such as unexplained somatic symptoms, pseudoneurological, somatoformic, psychogenic, or psychosomatic symptoms, have been applied. The latest phrase, functional neurological symptoms, emphasizes the change in the functioning of the nervous system rather than in its structure. PMID- 22506328 TI - [Somatic involuntary hospitalization]. AB - In a situation where the patient's own wish concerning her/his somatic treatment cannot be reliably assessed, the attending physician is obliged to treat the patient in the best possible way. Such situations include for instance unconsciousness, confusion and also severe mental disorders, such as psychoses. If the decision making capacity of the patient is lowered and immediate threat to somatic health is present, treatment decisions are made by the physician responsible for somatic care. The patient may be under somatic treatment also during involuntary psychiatric care. PMID- 22506329 TI - From "old boys" to "all girls": changing PA demographics. PMID- 22506330 TI - DVT prophylaxis with aspirin in orthopedic surgery patients. PMID- 22506331 TI - A widespread rash that interfered with sleep. PMID- 22506332 TI - A day in the life. PMID- 22506333 TI - Tuberculosis screening: prevention in the patient with immunosuppression. PMID- 22506334 TI - The pathophysiology, diagnosis, and management of proteinuria. PMID- 22506336 TI - Localized, dull abdominal pain in an otherwise asymptomatic woman. PMID- 22506335 TI - Vomiting and periumbilical pain from an unexpected source of infection. PMID- 22506337 TI - Dysfunctional uterine bleeding from the primary care perspective. PMID- 22506338 TI - Updated guidelines for the diagnosis of Alzheimer disease: a clinical review. PMID- 22506339 TI - Generations of certified physician assistants. AB - Attitudes, expectations, and behaviors vary across generational cohorts, which have implications for the physician-PA team. Among physician assistants, generational differences are further amplified by a dramatic shift in gender ratios, which have grown increasingly pronounced with each new generation. PMID- 22506340 TI - The certified physician assistant iin the United States: a 2011 snapshot. AB - This analysis characterizes the most up-to-date demographic data and practice profile for certified physician assistants (PAs) in the United States. PMID- 22506341 TI - Should PAs assess and address the impact of implicit bias on patient care? PMID- 22506342 TI - Gradual onset of left-sided temporal headache and ptosis. PMID- 22506343 TI - Looking through a glass darkly, then seeing face to face. PMID- 22506344 TI - Case of the month. Marjolin ulcer. PMID- 22506345 TI - [Structural basis for the inhibitory function of the parietal cortex efferent systems]. AB - Relative quantitative distribution of all the associative and descending efferent fibers and the ultrastructural organization of the terminals of the parietal cortex areas 5 and 7 in the caudate (NC) and red nucleus (NR) in the cat were analyzed after a local, pointed destruction of the cortex of these areas. The maximal numbers of the associative fibers were found to project to the fundus areas of the motor cortex and to the area of Clare-Bishop; moderate projections were detected to the areas 31, 19 and single degenerating fibers were registered in the areas 1,2, 3a, 3b, 30, and 23. The descending efferents were maximally projecting to NC, NR, reticular nuclei of the thalamus, midbrain, and pons, in all of which, according to the immunocytochemical studies, GABA-ergic terminals are prevalent. On the basis on the electron microscopical studies, it was suggested that the influence of the parietal cortex is mediated by the axo-spinal synapses of the medium shortaxonal spiny cells of the dorsolateral part of NC caput and by the axo-dendritic synapses of Golgi II cells of the parvocellular part of NR. On the basis of the maximal involvement of the fundus areas of the motor cortex, as well as of the inhibitory subcortical (NC) and stem nuclei (NR, reticular nuclei of the thalamus, midbrain, and nuclei pontis), it is suggested that these structures serve as the morphological substrates for the realization of the inhibitory, integrative function of the parietal cortex. PMID- 22506346 TI - [Gender-related peculiarities of cytoarchitecture of speech-motor fields 44 and 45]. AB - Cytoarchitecture of brain speech-motor fields 44 and 45 was studied in 5 adult men and 5 women. The width of the cortex and its layers, the profile field area of layer III and V neurons, the numerical density of layer III neurons in area 45, and the numerical density of satellite gliocytes and neurons surrounded by them, were measured in 20 microm thick total frontal sections, stained with cresyl violet. Both in men and women, the tendency for the left hemisphere dominance was detected for the values of the number of the cytoarchitectural indices, including the width of the associative layer III, the value of the profile field area of the neurons of this layer, the increased frequency of large and super large neurons. Interhemispheric differences of these indices were more expressed in men as compared to women. Several signs of sexual dimorphism were found between men and women. The most significant of these were the increase of neuronal numerical density and of the density of satellite gliocytes and neurons surrounded by them, found in women. PMID- 22506347 TI - [Development of primary visual cortex connections with the motion processing center: the role of visual environment]. AB - Development of axonal connections between cat primary visual area 17 and visual motion processing center was studied to investigate cortico-cortical connection plasticity in ontogenesis as affected by an experimental modification of visual environment (flickering light stimulation). By using a retrograde axonal labeling by horseradish peroxidase, a distribution of initial neurons in area 17 that send afferent projections to PMLS (posterior medial part of lateral suprasylvian sulcus) was analyzed. Sixteen 5-week-old and 12-14-week-old kittens, than were reared in normal visual environment or were subjected to a flickering light of 15 Hz frequency, were examined. It was shown that session stimulation by flickering light led to an impairment of normal development of regular organization of the connections between these visual areas including the decrease of labeled surface area and labeled initial neuron density in area 17. The data obtained elucidate the structural bases of cortical mechanisms that underlie motion processing disturbances in kittens stimulated by a flickering light. PMID- 22506348 TI - [Structural organization of superficial glial limiting membrane and layer I astrocytes in rat brain cortex]. AB - A study of structural and functional organization of the boundaries separating CNS compartments is a fundamental task of neurobiology. Taking into account the contradictory data on the structure of superficial layers of mammalian neocortex, it is pertinent to study structural and cytochemical organization of astrocytes- the main components of the brain barrier system in animals that are often used for experimental modeling of brain diseases and injuries. The aim of the present work was to study the structural organization of layer I astrocytes of rat neocortex. Astrocytes were demonstrated immunocytochemically using anti-GFAP, anti-vimentin and anti-nestin antibodies using light and confocal laser microscopy. The results of the study demonstrated that the superficial glial limiting membrane had significant structural differences in different cortical regions. Astrocytes in layer I of rat neocortex were different from typical protoplasmic astrocytes, common to gray matter The regional peculiar features of superficial glial limiting membrane organization that were found in this study, are probably determined by the differences in functional characteristics of CSF encephalic barrier in the specific regions of the brain. PMID- 22506349 TI - [Posttraumatic changes of rat spinal cord after transplantation of human umbilical cord blood mononuclear cells transfected with VEGF and FGF2 genes]. AB - Using the model of the rat spinal cord dosed contusion injury at T8 level, cross sectional area of the pathological cavities was measured and the number of myelinated nerve fibers was calculated in the outer zones of white matter after immediate single injection in the damaged area of human umbilical cord blood mononuclear cells (UCB-MC) transfected with plasmid with vegf and fgf2 genes. UCB MC transfected with pEGFP-N2 plasmid with egfp gene of enhanced green fluorescent protein were injected into the rats of control group under similar conditions. By Day 30 after the injection of UCB-MC transfected with vegf and fgf2 genes, total cross-sectional area of the cavities in outer zones of white matter at a distance of 3 mm caudally from the epicenter of the injury was reduced more than twice as compared with that found in control group. Number of myelinated nerve fibers in the same zones of white matter at the same distance from the epicentre in rostral and caudal directions, was increased by 20% on the average as compared with control, and at a distance of 5 mm in rostral direction--by 40 to 70%. Thus, the delivery to the injury region of the therapeutic genes vegf and fgf2 reduced cavitation, restrained the processes of secondary degeneration and supported the number of myelinated fibers in the injured spinal cord. PMID- 22506350 TI - [Structural changes of eye chorioretinal complex after total cerebral ischemia and their correction]. AB - Structural changes of eye chorioretinal complex were investigated in 40 adult male outbred albino rats after total transient cerebral ischemia using electron microscopy and morphometric analysis. Furthermore, the influence of a new sterically hindered phenolic antioxidant dibornol on these processes was estimated. Our studies demonstrated that total transient cerebral ischemia in rats resulted in the capillary thrombosis of the choriocapillary lamina of the uvea, structural disturbances of the blood-retinal barrier, degeneration of the retinal neurons and radial glia. Course administration of dibornol was shown to improve the microcirculation and to protect the retinal neuronal structures, pigment epithelium, and radial glia. PMID- 22506351 TI - [Morphological basis of ocular desympathetization as a new method for experimental cataract modeling]. AB - The aim of this study was to obtain the morphological basis for ocular desympathetization as a method for cataract modeling in vivo. The study was conducted on 20 outbred rabbits, in which the bilateral removal of superior cervical ganglia of sympathetic trunk resulted in the change of tone of the sympathetic division of the nervous system. 5-7 months after this operation, biomicroscopy of the anterior portion of both eyes was performed that has demonstrated in 16 out of 20 rabbits the initial manifestations of lenticular opacity. 12-14 months after the operation, their area was significantly increased, and the formation of wedge-shaped opacity with its basis facing the lens periphery, was documented. This was associated with the dissociation of lens fibers, as well as the extracellular liquid accumulation. Histological and phenotypic changes of the lens were similar to those in age-related cortical cataract, detected in man. In both age-related cataract, and that one received by a proposed modeling method, the immunopositive reaction was found demonstrating neuron-specific enolase, vimentin and S-100 protein in lenticular cortex. The proposed method of cataract modeling in vivo may be used for the study of cataract pathogenesis and for the development of measures of its prophylaxis and therapy. PMID- 22506353 TI - [Stress-induced experimental myocardial changes]. AB - Morphological changes in myocardium resulting from experimental stress loads were investigated. Experiment model: group 1 - unloaded swimming (30 rats), group 2 - loaded swimming (30 rats), group 3 - control animals (30 rats - no swimming, maintenance in vivarium). The experimental groups were further divided into 4 subgroups: 1A (adapted animals, n=20), 1NA (unadapted animals, n=10), 2A (adapted animals, n=13), 2NA (unadapted animals, n=17). Histological study of myocardium in subgroups 2A, 1NA and 2NA demonstrated dystrophic changes that were either moderate (subgroups 2A and 1NA) or expressed (subgroup 2NA). Foci of interstitial edema and perivascular hemorrhages were detected. In subgroups 1NA and 2NA, cardiomyocyte cross striation disappeared, cell cytoplasm became vacuolated, foci of cardiomyocyte destruction and necrosis were present. The degree of myocardial changes was found to depend upon stress intensity and individual tolerance of rats. Computer morphometry was unable to detect any significant differences in the thickness of cardiomyocyte fibers between the subgroups. PMID- 22506352 TI - [Innervation of cardiac muscle tissue in rat pulmonary veins]. AB - The pulmonary vein (PV) of 16 adult male Wistar rat was studied using synaptophysin immunohistochemistry and staining with toluidine blue and hematoxylin. Its intrapulmonary trunk wall was found to have a unique structure. The middle tunic contained cross-striated muscle tissue that was identical to the cardiac muscle tissue in posterior wall of the myocardial atrium. The thickness of the muscular tunic increased with the increase of vein diameter. The thickest layer of cardiac muscle fibers was located in the orifice of the main trunk, and the thinnest - in the lateral veins (50-100 microm in diameter), carrying the arterial blood from the respiratory portion of pulmonary lobe. Along their whole length, cardiac muscle fibers are densely innervated. Efferent synaptophysin positive endings of the terminal plexus were found to be tightly associated with cardiac muscle fibers, capillaries of the media in the area of PV orifice and vasa vasorum of the adventitia. PMID- 22506354 TI - [Morphology and cytochemistry of abnormal cytoplasmic granules in blood leukocytes in sapphire minks (cytological and cytochemical study)]. AB - Detailed morphological and cytochemical investigation of blood leukocytes was performed in minks of three genotypes: dark-brown minks (n=10), which had the color resembling that of the wild type, mutant silver-blue (p/p) minks (n=10), and sapphire minks (a/a p/p) (n=10). The sapphire minks were demonstrate to have a hereditary defect of leukocyte granules containing peroxidase, nonspecific esterases and non-enzymatic cationic protein. These granules have abnormally large size, the neutrophil cytoplasm contains one to several abnormal granules, they are numerous in eosinophil and basophil cytoplasm and rare in lymphocytes and monocytes. Morphological and cytochemical features indicate the similarity of hereditary leukocytes pathology of sapphire mink with that one found in human Chediak-Higashi syndrome. PMID- 22506355 TI - [Comparative characteristic of morphometric parameters of germinal centers in the aggregated lymphoid nodules of the small intestine and mesenteric lymph nodes following acute emotional stress]. AB - Under physiological conditions, the germinal center (GC) area of aggregated lymphoid nodules of the small intestine in adult male Wistar rats was greater than that of the similar structures in the mesenteric lymph nodes. Moreover, these differences were more pronounced in a group of stress-resistant rats as compared to stress-prone animals. The exposure to acute emotional stress (immobilization in plexiglas boxes for 1 hour with the irritation of the back area with the electric current) reduced GC size. Restoration of the morphometric parameters studied in the group of stress-resistant rats was completed at an earlier date (by Day 3 after exposure to stress), while in susceptible animals it took place by Day 7. By Day 14 after an acute emotional stress, GC size in a group of stress-resistant rats were similar to those in control group, while in susceptible animals they were lower than the baseline values, indicating that the depletion of the functional capacities of lymphoid tissue in this group of animals. PMID- 22506356 TI - [Morphological bases of dopamine effect on HEP-2 tumor cells viability]. AB - The purpose of the present investigation was to study the morpho-functional organization of a classical object of cytological research - cultured HEp-2 tumor cells, using dopamine as a penetrating agent, inducing the polymerization of cytosolic actin. It was demonstrated that dopamine introduced into the incubation medium reduced viability and caused morphological disturbances of cultured HEp-2 cells; these effects were proportional to dopamine concentrations (1.0 x 10(-4) M to 1.0 x 10(-3) M) and exposure duration (2 to 3 days). These cells, according to ultrastructural data, underwent fusion and lysis because of the appearance of actin filaments network in the loci of globular actin prevalence in control cells. Dopamine receptors had no effect on cytotoxic effect of dopamine. This was indicated by fluorescent microscopical evidence of dopamine penetration into experimental cells in the presence of haloperidol, as well as destruction of HEp 2 cells under the action of pyrimidinethione, similar to dopamine by characteristics, but lacking its own receptors. It is suggested that cytoplasmic target for dopamine is globular actin and that induced polymerization of this cytoskeletal protein caused injury to tumour cells. PMID- 22506357 TI - [Cellular composition of the lamina propria mucous membrane in different segments of ureter in the newborns and children of first years of life]. AB - Cellular composition of the lymphoid tissue in the superior and inferior segments of ureteral mucous membrane was studied using quantitative method in newborns, infants and children of the first years of life on autopsy material (n=12). It was found that during the first years of life lymphoid tissue was poorly developed in the lamina propria of the ureteral mucous membrane and it was represented by diffuse lymphoid tissue. Processes of lymphocytopoiesis were not expressed, while high degree of cell destruction was observed that was increased with age. The content of plasma cells was increased by the early period of infancy, indicating the activation of local humoral immunity. Regional peculiarities included higher content of plasma cells, granulocytes and lower concentration of destroyed cells in the superior ureteral segment as compared with the inferior one. These peculiarities were preserved during all childhood ages. PMID- 22506358 TI - [Regeneration of the damaged mandibular bone in rat after the injection of autologous mesenchymal stem cells of bone marrow origin adsorbed on the fibrin clot]. AB - The processes of the repair of the damaged mandibular bone in rats were studied using light microscopy and x-ray densitometry at various time intervals after the local injection of the platelet-rich fibrin clot (PRFC), autologous mesenchymal (stromal) stem cells of bone marrow origin (AMSCBMO) or AMSCBMO, adsorbed on PRFC, into the damaged site. The best results were obtained after the application of PRFC with AMSCBMO. One week after the operation, the mandibular bone defect was largely filled with the newly formed bone tissue. It seems most probable that in this case the effects of fibrin and stem cells on the damaged bone were summarized or even amplified. Bone formation in these cases appeared to begin in the center, but not at the edges, of the defect. AMSCBMO were distributed over the whole volume of PRFC, filling all the defect more or less uniformly. As a result, maximally fast and successful restoration of bone tissue was reached in the area of the defect. PMID- 22506360 TI - [Fundamental research and practical orientation of teaching histology of human locomotor system]. PMID- 22506359 TI - [Rat brain cells containing ezrin (cytovillin)]. AB - Ezrin (cytovillin or p81 protein) is an actin-binding protein, a member of ERM (ezrin, radixin and moesin) family, which species contribute to stabilization of the plasma membrane-formed structures. The aim of the present study was to demonstrate the ezrin-containing cells in the rat brain and to describe their topography and morphological features. The most pronounced immunohistochemical reaction to ezrin was found in the epithelium of the choroid plexus, cells of the subcommissural organ and ventricular ependyma. Moreover, ezrin staining was also detected in the unidentifiable cells in the subventricular zone, rostral migration pathway and astrocytes in various brain areas. Preferential ezrin localization in the brain cells contributing to formation of barrier structures suggests its involvement in transport processes in the CNS. PMID- 22506361 TI - [Years, events, people... (To the 75th anniversary of the Department of Human Anatomy of Tver' State Medical Academy)]. PMID- 22506362 TI - [The practice of nursing is to be the bearer of humanity]. PMID- 22506363 TI - [The fight against tuberculosis is a global priority]. PMID- 22506364 TI - [Psychoactive substance in the workplace]. PMID- 22506365 TI - [Alcohol, an addiction like any other]. AB - The current treatment available to people in difficulty with regard to their consumption of alcohol is not merely limited to forced abstinence. It benefits from the advances made in addictology and research into treatment based on the concept of controlled consumption. In the framework of a therapeutic alliance, multidisciplinary teams offer medication-based treatments and individualised and diversified psycho-social treatment. PMID- 22506366 TI - [Four strategies of addition treatment]. AB - The vocation of the addiction treatment, research and teaching centre at Paul Brousse hospital in Paris, is to offer therapeutic care in addictology. In this framework and within the four care structures, the nurse maintains the therapeutic link to support patients at every stage of the treatment. PMID- 22506367 TI - [Nursing support in post-treatment care]. AB - People undergoing post-treatment care are looking to reinforce the abstinence which they have put in place during the physical withdrawal carried out in hospital. They are received in a follow-up care and rehabilitation centre (CSSR) specialised in addictology in Brest by a multi-disciplinary team for a period of three months, which can be extended depending on the progress of each patient. The nurse's role in the post-treatment period focuses on support. PMID- 22506368 TI - [Modifying the relationship with psychoactive substances]. AB - In addictology, caregivers use various psychological help and support relationship techniques to help patients become aware of a misuse of alcohol and to encourage a change in behaviour. Motivational interviewing is part of the process. It seeks to develop the therapeutic alliance and to make the patients players in their own care project. PMID- 22506369 TI - [Abstainer relations, players in caregiving]. AB - Teetotaler associations play an important role in supporting people with alcoholism. Abstaining completely from all alcoholic consumption is the shared objective around which the members come together. A nurse from the psychiatric sector gives an account of his encounter with this universe where a great sense of humanity prevails. PMID- 22506370 TI - [Research is for the benefit of professionals and patients]. PMID- 22506371 TI - [Cultivating the ability of patient autonomy]. AB - Confronted with a patient still able to express desires but not always able to act on them, caregivers are faced with certain questions: Should they decide for the patient and force him or her to act, as far as is possible? Should they take into account how the patient was in the past, or detach themselves from the patient's past preferences? Some answers and developments arising from a practical case. PMID- 22506372 TI - [The pulse, an essential measurement]. AB - As has been known for a long time, the measurement of the pulse enables the patient's haemodynamic state to be assessed. Pulse, rate, rhythm and amplitude are indicators that enable monitoring of health status in different situations. Therefore, the nurse, in her daily practice, can and must use this measurement in preference to that provided by devices whose relevance is limited. PMID- 22506373 TI - [A nurse in an emergency department in French Guiana]. AB - Invited by a member of her family living abroad, Charline Routier, a recently qualified nurse, worked for three months in French Guiana. Working with the teams of Cayenne hospital, she discovered pathologies and treatments which were different from those seen during her initial training. Testimony. PMID- 22506374 TI - [Impact of the nurse consultation on the diagnosis of cancer]. AB - An emblematic measure of the first Cancer Plan (2003-2007), the diagnosis announcement procedure is used in health care institutes. The nurse support which it involves favours the emergence of new skills. At Saint-Louis hospital in Paris, patients were questioned about its impact, the way it complements their treatment pathway and its capacity to provide pertinent answers to their questions. The results are highly encouraging. PMID- 22506376 TI - [The nurse and urodynamic testing in the framework of cooperation between professionals]. AB - Two expert nurses can now carry out urodynamic testing in accordance with a protocol of cooperation between health professionals signed last November. The urology department of Rouen University Hospital is thereby validating two years of work and is fully in line with the framework of the hospital, patients, health and territories law. An account of a process which serves as a model. PMID- 22506375 TI - [The practical placement at the heart of training]. AB - A senior health manager and a nurse have established, as part of the new nursing training reference framework, a closer partnership between the gynaecology and obstetrics unit of Tenon hospital in Paris and the nursing training institute. They have also drawn up a personalised induction programme for students doing their practical placement and a method for the transfer of knowledge and practices based on a tutor and a placement supervisor. Team work for the benefit of future professionals. PMID- 22506377 TI - Coping with psychotic disorders. AB - Pierre is on the night shift at the Accident & Emergency Department. He likes working there because the patients and the tasks are very varied. He finds much to learn about diseases, techniques of caring and human relationships. Tonight, he will discover what mental illness can be about. PMID- 22506378 TI - [Nursing care of hypothermia]. PMID- 22506379 TI - [Obsessive compulsive disorders]. PMID- 22506380 TI - [Non-verbal communication in an emergency situation abroad]. PMID- 22506381 TI - [Tracheotomy]. PMID- 22506382 TI - [Study on tissue culture and plant regeneration of the stem-tips and buds of Periploca forrestii]. AB - OBJECTIVE: To establish the rapid propagation systems of the stem-tips and buds of Periploca forrestii. METHODS: Inserted the stem-tips and buds of Periploca forrestii into MS medium with different concentrations of 6-BA, NAA and 2.4-D and induced them growing into complete plants. RESULTS AND CONCLUSION: The optimal culture medium for bud induction is MS + 6-BA 1.0 mg/L + NAA 0.3 mg/L and the bud induction rate can reach 86.29%. The optimal culture medium for stem-tips induction is MS +6-BA 2.0 mg/L + NAA 0.5 mg/L and the bud induction rate can reach 86.29%. The optimal culture medium for bud multiplication is MS + 6-BA 2.0 mg/L + NAA 0.1 mg/L and the multiplication coefficient can reach 2.10. The best rooting medium is 1/2 MS + IBA 0.5 mg/L and the rooting rate is 53.33%. PMID- 22506383 TI - [Study on tissue culture and rapid propagation of Oxytropis myriophylla]. AB - OBJECTIVE: To study the plant tissue culture and rapid proagation of O. myriophylla. METHODS: The adventitious buds which were from the seedlings germinated from the seeds on the initial medium were taken as explants. These explants were cultured on MS culture media by adding different portions of hormones at various conditions. RESULTS: The proper initial medium for the adventitious buds was MS +6-BA 0.5 mg/L + NAA 0.2 mg/L,and the best medium for rooting was 1/2MS + NAA 0.1 mg/L. CONCLUSION: Tissue culture of O. myriophylla could make its propagation rapidly. PMID- 22506384 TI - [Study on the physiological and biochemical characteristics of different types of leaves of Aquilaria sinensis]. AB - OBJECTIVE: To study the physiological and biochemical characteristics of different types of leaves of Aquilaria sinensis. METHODS: Six types of leaves' physiological and biochemical indexes were studied and analysed, these indicators included: malondialdehyde (MDA), soluble sugar content, soluble protein content, peroxidase activity (POD), catalase activity (CAT) and superoxide dismutase activity (SOD). RESULTS: POD, CAT, SOD had no significant difference; POD, CAT, and SOD had a coordinating role on cleaning-up oxidation products MDA; The soluble protein contents of different types of leaves was negative corelatad with the centent of MDA; The contents of soluble sugar among them were signifiant different. CONCLUSION: Growth activity sequence of different types of Aquilaria sinensis is as follows: lobular type > large-leaved type, transitional leaf type > elliptical leaf type. PMID- 22506385 TI - [Study on quality control methods for different varieties of Meconopsis of Gansu]. AB - OBJECTIVE: To establish the quantitative determination method and TLC identification of Meconopsis and study the Vis-UV spectrum character for fast identification. METHODS: Meconopsis were identified by TLC, and the content of quercetin was determined by HPLC. RESULTS: The acid hydrolyze condition was HCl 80% MeOH(8:25) 90 degrees C calefaction by water for 1.5 hour. The condition of HPLC: Hypersil-Keystone-C18 (250 mm x 4.6 mm, 5 microm) column, MeOH-Water (50: 50) as mobile phase, detection wavelength at 360nm, flow rate at 1.0 mL/min, column temperature at 35 degrees C, quercetin showed a good linear relationship at a range of 0.01 - 0.12 microg, r =0.9997. The average recovery was 98.83%, and RSD was 1.69% (n = 9). The contents of quercetin in Meconopsis integrifolia and Meconopsis quintuplinervia of Gansu were 0.1135 mg/g and 0.0842 mg/g respectively. CONCLUSION: The method is simple, accurate and specific. It can be used for the quality control and fast identification of Meconopsis. PMID- 22506386 TI - [Factors influence volatile oil content in Ocimun basilicum introduced from Xinjiang province to south-east China]. AB - OBJECTIVE: To obtain the information on ecological adaptation of Ocimun basilicum introduced from Xinjiang to Hangzhou and study the effect of different harvesting times, drying methods, and different organs of Ocimun basilicum on Volatile oil content METHODS: Extraction was undertaken according to The Pharmacopoeia of China, 2010 edition. RESULTS: Sun-drying was the most efficient way to obtain Volatile oil compared with other methods. The largest biomass was harvested at 3rd, September. Furthermore, Volatile oil was found to accumulate mostly in the flowers and little in the stems. CONCLUSION: Ocimun basilicum can readily inhabit in Hangzhou and its economic value can be significant improved by growing two seasons per year. Only harvest leaves and flowers can significantly reduce the cost for transport and also increase oil extract rate of Volatile oil. PMID- 22506387 TI - [The study of removing salt in salt Aconiti Lateralis Radix Praeparata]. AB - OBJECTIVE: To study the method and technique to remove the salt of salt Aconiti Lateralis Radix Praeparata. METHODS: Took the Aconiti Lateralis Radix Praeparata alkaloids, polysaccharides and the content of removing salt as the indexes, and then compared with the original process. RESULTS: There was no obvious difference between these two way on the content of the Aconiti Lateralis Radix Praeparata alkaloids and polysaccharides,and the time of removing salt has reduced from 7 days (168 h) to 1.5 h. CONCLUSION: The new way reduces the time to remove salt obviously, and saves water; The research fills in the gaps of removing the salt of salt Aconiti Lateralis Radix Praeparata and provides thought and method for processing technology of Aconiti Lateralis Radix Praeparata PMID- 22506388 TI - [Comparative identification research on different extracts of Dai Medicine "Pokou" and its processed product by FTIR]. AB - OBJECTIVE: To study identification methods of different extracts of Dai Medicine "Pokou" (the rhizome of Homalomena gigantea Engl. ) and its processed product made by immersing it in water, and provide reference for identification of the drug in further researches and applications. METHODS: FTIR technique was used for identifying the features of different extracted parts of this crude drug and its processed product. RESULTS: Compared with the crude drug, the petroleum ether extracted parts of processed product turned out to have no obvious distinction in the FTIR. There was a large difference in the ethyl acetate-extracted parts, and the n-butanol-extracted parts also had certain discrepancy. A preliminary analysis was made on the chemical fundamentals which caused the changes in the FTIR before and after the drug's processing. CONCLUSION: The results provide an infrared spectral identification method for the drug and its applications. PMID- 22506389 TI - [HPLC fingerprint analysis of acetoacetate extraction of Polygonum orientale]. AB - OBJECTIVE: To establish the HPLC fingerprint analysis method for the quality control of acetoacetate extraction of Polygonum orientale. METHODS: Agilent C18 (4.6 mm x 250 mm, 5 microm); DAD detector; Mobile phase: methyl alcohol-water gradient elution at a flow rate of 1.0 mL/min, and at a column temperature of 30 degrees C. RESULTS: 26 peaks were selected as the common fingerprint peaks. The relative standard deviations for relative retention values were less than 3% in the precision and repeated test. CONCLUSION: The repetition, stability and precision of the method is good and it can be used to control the quality of Polygonum orientale. PMID- 22506390 TI - [Pharmacognostic identification of Ferula syreitschikowii]. AB - OBJECTIVE: To identify Ferula syreitschikowii by identification of pharmacognosy and provide the scientific evidence for its identification and application. METHODS: The crude drug identification, morphological, UV spectrum identifications, microscopic identification and thin layer chromatography (TLC) were adopted. RESULTS: There were specialization in morphology, microscopic characteristic, UV spectrum identifications and thin layer chromatography (TLC). CONCLUSION: These characteristics can be used for scientific basis for gruffs identification of crude drug and providing reference information for further development. PMID- 22506391 TI - [Microscopic identification and UV-Vis spectrum identification on Sapium sebiferum]. AB - OBJECTIVE: To study the microscopic and UV-Vis spectrum characteristic of Sapium sebiferum. METHODS: The microscopic identification and UV-Vis spectrum identification were adopted. RESULTS: There were cluster crystals in cortical cells of roots and stems and parenchyma cells of the leaves. A few stone cells were found in cortex of the stem. The vascular bundles arranged in the form of a circle in the main vein of the leaves. It could be observed that many crystals and crystal fibers in the powder. Six kinds of solvent of crude drug had absorption peaks between 200 - 800 nm. CONCLUSION: These results can provide the scientific evidence for the establishment of standard for quality control and further study. PMID- 22506392 TI - [Study on chemical constituents of the Ixeris chinensis]. AB - OBJECTIVE: To study the chemical constituents of the Ixeris chinensis . METHODS: The constituents were isolated by silica gel column chromatography, HPLC and recrystallization and their structures were elucidated on the basis of spectral analysis. RESULTS: Fifteen compounds were isolated and identified as Methyl-4 hydroxyphenylacetate (1), Daucosterol (2), Sitosterol (3), Luteolin-7-O-beta-D glucoside (4), 15-hydroxy-2-oxoguaia-1 (10), 3,11 (13)-triene-12,6-lactone (5), Chinensiolide B (6), Chinensiolide E (7), Ixerochinoside (8), Chinensiolide C (9), 10alpha-hydroxy-guaia-4(15)-ene-12,6-lactone (10), 10alpha-hydroxy-guaia-4 (15), 11 (13)-diene-12,6-lactone-3beta-O-beta-D-(6'-p-hydroxyphenylacetyl) glucopyranoside (11), Epiloliolide (12), Apigenin-O-beta-D-glucopyranoside (13), Luteolin (14), Lutein (15). CONCLUSION: Compounds 1,10,11,12 and 15 are isolated from this plant for the first time. PMID- 22506393 TI - [Study on the chemical constituents from the aerial parts of Medicago sativa and their hypolipidemic activity]. AB - OBJECTIVE: To research the chemical constituents from the aerial parts of Medicago sativa. METHODS: Various column chromatographies were emoployed to isolate and purify the constituents. Their structures were elucidated by spectral analysis (IR, UV, MS, 1H-NMR, 13C-NMR) and chemical evidence. RESULTS: Two constituents were obtained and identified as soysaponin I (I), azukisaponin V (II). CONCLUSION: These two compounds are isolated from the arial parts of Mesicago sativa for the first time. Moreover,the compounds are found to have hypolipidemic activity. PMID- 22506394 TI - [Analyze on the component of rosmarinic acid in Prunella vulgaris and its effect on alpha-glycosidase activity]. AB - OBJECTIVE: To analyze rosmarinic acid in Prunella vulgaris and its effect on the activity of alpha-glycosidase. METHODS: Qualitative and quantitative analyses of Rosmarinic acid in Prunella vulgaris were carried out by HPLC. The activity of different micro reaction systems like alpha-amylase, alpha-glucosidase and alpha maltase, which were added to Rosmarinic acid and Acarbose, was determined by Bernfeld, pNPG and GOD. RESULTS: The contents of Rosmarinic acid in the aqueous extract and its dry powder, and extractum of Prunella vulgaris were 0.1494, 0.1657 and 0.2739 mg/g respectively, equal to crude drug. The Rosmarinic acid inhibited alpha-glycosidase, and its inhibition from alpha-maltase in small intestine was noncompetitive. CONCLUSION: The aqueous extract of Prunella vulgaris and its extractum's inhibition from alpha-glycosidase is related to Rosmarinic acid. PMID- 22506395 TI - [Chemical constituents of flavonoids from flowers of Koelreuteria paniculata]. AB - OBJECTIVE: To study the chemical constituents from flowers of Koelreuteria paniculata. METHODS: Column chromatography and spectral analysis were used to isolate and identify the constituents. RESULTS: The EtOAc fraction from flowers of Koelreuteria paniculata was separated and purified. Nine compounds were obtained and identified as:sitosterol glucoside (I), gallic acid (II), kaempferol (III), luteolin (IV), kaempferol-3-O-(6"-acetyl)-beta-D-glucopyranoside (V), hyperoside-2"-O-acetyl (VI), hyperoside-2"-O-galloyl (VII), hyperoside (VIII), kaempferol-3-O-D-glucopyranoside (IX). CONCLUSION: Nine compounds are isolated for the first time from flowers of Koelreuteria paniculata. Compounds IV, V, VI and IX are isolated from this genus for the first time. PMID- 22506396 TI - [Study on chemical constituents of Peganum multisectum]. AB - OBJECTIVE: To study the chemical consituents of Peganum multisectum. METHODS: The compounds were isolated by chromatographic methods and their structures were elucidated by physicochemical properties and spectral analysis. RESULTS: Six alkaloids were isolated and identifiedas deoxyvasicinone (1), l-vasicinone (2), harmine (3), vasicine (4), evodiamin (5), and fagomine (6). CONCLUSION: Compounds 5 and 6 are isolated from this genus for the first time. PMID- 22506397 TI - [Analyze on volatile compounds of Antrodia camphorata using HS-SPME-GC-MS]. AB - OBJECTIVE: To analyze the volatile compounds of Antrodia camphorata in solid state and submerged cultures. METHODS: A headspace solid-phase microextraction (HS-SPME) coupled with gas chromatography-mass spectrometry(GC-MS) were used to evaluate the profile of the volatile compounds. RESULTS: 49 volatile compounds were identified in A. camphorata mycelia in submerged culture, while 43 volatile compounds were identified in mycelia in solid-state culture. 1-octen-3-ol, 3 octanone, 1-octen-3-ylacetate, acetic acid octyl ester and ethanol were the main volatile compounds in A. camphorata mycelia in submerged culture, while 1-octen-3 ol, 3-octanone, 3-methyl-butyraldenhyde, gamma-podecalactone and methyl 2-furozte were the most potent key volatile compounds in mycelia in solid-state culture. CONCLUSION: The volatile compounds in the mycelia of A. camphorata in solid-state and submerged cultures are similar but their relative contents are different. PMID- 22506398 TI - [Analyze on chemical compositions of Dalbergia odorifera essential oils extracted by CO2-supercritical-fluid-extraction and steam distillation extraction]. AB - OBJECTIVE: To analyze the chemical compositions of Dalbergia odorifera essential oils extacted by CO2-supercritical-fluid-extraction (SFE-CO2) and steam distillation extraction (SD). METHODS: The essential oils of Dalbergia odorifera were extracted by steam distillation extraction and SFE-CO2. The chemical components were separated and analyzed by gas chromatography-mass spectrometry. RESULTS: 12 compounds were identified in SFE sample. The major components from essential oils were 2-propenoic acid-3(4-methoxyphenyl)-ethyl ester (14.53%), nerolidol (14.95%), ageratochromene (1.33%). 9 compounds were identified in SD sample. The major components from essential oils were nerolidol (26.61%), cedrol (1.65%). CONCLUSION: The SFE method is better than the SD method in reliability stability and reproducibility, and suitable for essential oils extraction of Dalbergia odorifera. PMID- 22506399 TI - [Study on the chemical constituents of vinegar Schisandra chinensis]. AB - OBJECTIVE: To study the chemical constituents of vinegar Schisandra chinensis. METHODS: Column chromatography was used in the isolation procedure. The structures of isolated compounds were elucidated by spectral data. RESULTS: Five compounds were isolated and their structures were identified as kadsuranin (I), beta-sitosterol (II), schizandrin (III), 5,5'-[oxybis (methylene)] bis-2 furancarboxaldehyde (IV) and (NH)-form-2-Hydroxyquinoline4-carboxylic acid (V). CONCLUSION: Compound 5 is isolated from this genus for the first time. PMID- 22506400 TI - [A new natural polyphenol BJA32531 inhibited the proliferation and regulated miRNA expression in human HepG2 hepatocarcinoma cells]. AB - OBJECTIVE: To study the effect of 1,2,6-Tri-O-galloyl-beta-D-glucopyranose (BJA32531) on the miRNA expression during BJA32531-induced cytotoxicity in human HepG2 hepatocarcinoma cells. METHODS: Cell proliferation was assessed using a colorimetric assay (cell counting kit-8). Apoptosis was assessed by annexin V and propidium iodide staining. The miRNA expression profile of the cancer cells was analyzed by a miRNA array and quantitative real-time PCR. RESULTS: BJA32531 inhibited the cell proliferation and increased apoptosis in HepG2 cancer cells. Cellular exposure to BJA32531 influenced the miRNA expression pattern in the cells, including 19 upregulated and 85 down-regulated miRNAs in the cells. The up regulations of let-7a and miR-10b as well as the down-regulations of miR-132 and miR-125b were verified to be consistent with the the results of the miRNA array. CONCLUSION: Our study suggests that the mechanisms by which BJA32531 exerted the antiproliferative effects on HepG2 cancer cells may be related to its regulation of miRNA. PMID- 22506401 TI - [Effects of CVB-D on hemodynamic in anaesthetized dogs in vivo]. AB - OBJECTIVE: To investigate hemodynamic in anaesthetized dogs after the intravenous injection of cyclovirobuxine D (CVB-D). METHODS: The hemodynamic of anaesthetized dogs were observed after intravenous injection of CVB-D at doses of 0.1, 0.2, 0.4 mg/kg. RESULTS: CVB-D of 0.2 and 0.4 mg/kg could decrease HR, TPVR and increase CBF. In addition, CVB-D of 0.4 mg/kg could increase SAP and SV. Yet MAP and CO of dogs showed no remarkable changes with the treatment of CVB-D. CONCLUSION: CVB-D has effect of improving cardiac function, which may be the mechanism of anti myocardial ischemia effect of CVB-D. PMID- 22506402 TI - [The inhibitory effect of luteolin on inflammation in LPS-induced microglia]. AB - OBJECTIVE: To study the inhibitory effect of Luteolin on LPS-induced BV-2 cell. METHODS: BV-2 cells were treated with LPS (0.1 microg/mL) for inflammation model; MTT assay was used to detect the viability of BV-2 cells; Nitric oxide (NO) was detected by the method of nitric acid reductase assay; Induce type II nitric oxide synthase (iNOS) enzyme activity was determined by type of nitric oxide synthase assay;TLR4 protein expression was examined by the Western Blot analysis. RESULTS: Luteolin significantly decreased the NO production and TLR4 protein expression as well as iNOS activity in LPS-activated microglial cell. CONCLUSION: LPS induced activation of microglia lead to inflammatory response and its mechanism may be related to inhibiting TLR4 signaling pathway. PMID- 22506403 TI - [Neuroprotective effect of ferulic acid in vitro]. AB - OBJECTIVE: To investigate the neuroprotective effect of ferulic acid on PC12 cells injuries. METHODS: With three models of PC12 cells injured by hypoxia, excitatory amino acids (EAA) and radical, the effect of ferulic acid on injured PC12 cells was observed by MTT assay. RESULTS: Compared with three models, ferulic acid (1-100 micromol/L) could promote cell viability notably (P<0.05 or P<0.01). CONCLUSION: Ferulic acid has notable protective effect on PC12 cells injured by hypoxia, EAA and radical. PMID- 22506405 TI - [Optimization of the ultrasound assisted extraction of saikosaponins from Bupleurum falcatum using response surface methodology]. AB - OBJECTIVE: To investigate the optimization of extraction conditions of saikosaponins a, c and d from Bupleurum falcatum. METHODS: Experimental factors and levels were firstly selected by one-factor test. According to the central composite experimental design principle, the response surface methodology with 3 factors and 3 levels was adopted. Used HPLC to determine the contents of saikosaponins a, c and d. Used column symmetry C18 (150 mm x 4.6 mm, 5 microm); Mobile phase was acetonitrile-water gradient elution, flow rate was 1.0 mL/min, the detection wavelength was 200 nm, detecting temperature was 25 degrees C. RESULTS: The optimum conditions of aikosaponins extraction were as follows:extraction time was 93 min, power was 150 W, solvent to solid ratio was 60. The predicted total saikosaponin extraction yield was 13.66 mg/g,while the actual extraction yield was 13.64 mg/g, with relative error of 0.15%. CONCLUSION: The optimum extraction process is reasonable, reliable and high yield of extracting effective content. PMID- 22506404 TI - [Effect of 5-hydroxymethyl furfural on BCL-2 and NF-kappaB gene expression of apoptotic rat hippocampal neurons injured by H2O2]. AB - OBJECTIVE: To investigate the effect of 5-hydroxymethyl furfural (5-HMF) on apoptosis and BCL-2, NF-kappaB gene expression of rat hippocampal neurons injured by hydroperoxide (H2O2). METHODS: Hippocampal neurons of newly born rat were cultured in vivo and injured by H2O2. Effect of different concentration of 5-HMF on cell viability was measured by MTT. Flow cytometer (FCM) was used to measure the apoptosis of rat hippocampal neurons pre-cultured with different concentration of 5-HMF,Western blotting was used to measure the expression of BCL 2 and NF-kappaB gene. RESULTS: It revealed that the high and medium dosage of 5 HMF could increase the activity of rat hippocampal. The high, medium and low dosage of 5-HMF also increased the expression of BCL-2 gene and decreased the expression of NF-kappaB gene. CONCLUSION: 5-HMF could restrain the apoptosis of cultured hippocampal neurons injured by H2O2. The mechanism may be related to increasing in BCL-2 level and decreasing in NF-kappaB level. PMID- 22506406 TI - [Extraction technology of diester-type alkaloids from Radix Aconiti lateralis]. AB - OBJECTIVE: To determine the suitable extraction technology of diester-type alkaloids, such as mesaconitine, aconitine and hypaconitine from the roots of Aconitum carmichaeli (Radix Aconiti lateralis). METHODS: The contents of mesaconitine, aconitine and hypaconitine were determined by HPLC. Single-factor experiment was used to study the extraction factors. RESULTS: The suitable extraction technology for diester-type alkaloids was as follows: coarse sizings of Radix Aconiti lateralis was extracted by 10 times ethanol for 3 times (each time for 1 day) at 15 degrees C. The total yield of diester-type alkaloids was 0.57%, including 0.16% aconitine, 0.032% mesaconitine and 0.38% hypaconitine, and the purity was 18.81%. CONCLUSION: The extraction technology is efficient, harmfulless, economical, convenient and can be used for industrial production. PMID- 22506408 TI - [Progress in expression and molecular modification of microbial transglutaminase]. AB - Microbial transglutaminase, which could catalyze the cross-linking of many proteins or non-protein materials, has been widely used in food, pharmaceutical and textile industry. To enhance the yield of the enzyme and establish corresponding platform for molecular modification, the researchers of Japanese Ajinomoto began to construct the recombinant strain producing transglutaminase in the 1990s. So far, the enzyme has been successfully expressed in different expression systems. Some of the recombinant strains are more productive than wild strains. Recently, progress has been made in the molecular modification of microbial transglutaminase, and the activity, thermo-stability and specificity of the enzyme are improved. This review briefly summarized and analyzed the strategies involved in these studies, and noted its trends. PMID- 22506407 TI - [Preparation of curcumin solid dispersion and inclusion complex]. AB - OBJECTIVE: To prepare the curcumin solid dispersion and the curcumin inclusion complex, evaluate its stability and the transdermal properties. METHODS: The samples were prepared with hydrophilic, or water-soluble polymers, by solvent and solvent-melting methods. The optical microscope and the melting point were used to identify the state of the drug existence in it, and UV-Vis spectrophotometer was used to determine the solubility and content of different samples. They were placed under conditions of light, phosphate buffers with different pH values and different metal ions to determine their stability. The lipid/aqueous partition coefficients and the permeation of samples were measured. RESULTS: The content and solubility of curcumin in the solid dispersion prepared with PVP k-30 as the carrier were larger than those of other solid dispersions, with 81.26% and 337.59 microg/mL, respectively. The oil-water distribution coefficient was 26.04, indicating good penetration properties. CONCLUSION: The solubilty and stability of curcumin can be improved to various degrees. The solubility and oil-water partition coefficient of the curcumin solid dispersion prepared by povidone k-30 as a carrier is the largest. PMID- 22506409 TI - [Progress in the sequence and structure properties, thermostability mechanism and molecular modification of xylose isomerase: a review]. AB - With the development of low-carbon economy and renewable resource, fermentation of the pentose sugar xylose to produce ethanol becomes a very hot topic. The recombinant Saccharomyces cerevisiae can be constructed by expressing heterologous xylose isomerase (XI). Because Thermus thermophilus XI (TthXI) does not need cofactor, it has been developed for establishing the utilization pathway of xylose in S. cerevisiae. In this article, we reviewed the progress on xylose isomerase. We first introduced the primary properties, sequence and structure characters of xylose isomerase, and discussed its thermostability. The molecular modification of xylose isomerase, including of substrate specificity and thermostability were discussed in detail. Meanwhile, combined with our own research, we also discussed how to improve the xylose isomerase activity at room temperature. Finally, we suggested perspectives of xylose isomerase. PMID- 22506410 TI - [Functions of plant phosphoenolpyruvate carboxylase and its applications for genetic engineering]. AB - Phosphoenolpyruvate carboxylase (PEPC, EC 4.1.1.31) is an important ubiquitous cytosol enzyme that fixes HCO3 together with phosphoenolpyruvate (PEP) and yields oxaloacetate that can be converted to intermediates of the citric acid cycle. In plant cells, PEPC participates in CO2 assimilation and other important metabolic pathways, and it has broad functions in different plant tissues. PEPC is also involved in the regulation of storage product synthesis and metabolism in seeds, such as affecting the metabolic fluxes from sugars/starch towards the synthesis of fatty acids or amino acids and proteins. In this review, we introduced the progress in classification, structure and regulation of PEPC in plant tissues. We discussed the potential applications of plant PEPCs in genetic engineering. The researches in functions and regulation mechanism of plant PEPCs will provide beneficial approaches to applications of plant PEPCs in high-yield crops breeding, energy crop and microbe genetic engineering. PMID- 22506411 TI - [Isolation, identification and bioactivity characterization of goose avian beta defensin 3]. AB - The objective of the study was to clone avian beta-defensin (AvBD) 3 gene from goose tissues, express the recombinant AvBD3 protein in Escherichia coli, and determine its antimicrobial activity. The mRNA of goose AvBD3 was cloned from spleen and bursa of Fabricius of the gooses by RT-PCR. The sequence analysis showed that the genefragment of AvBD3 contained 182 bp, and encoded 60 amino acids. Homology analysis showed that goose AvBD3 shared the highest percentage of amino acid homology (100%) with chicken AvBD3. The cDNA of goose AvBD3 was sub cloned into BamH I and Sal I sites of pGEX-6p-1 vector to construct recombinant plasmid pGEX-goose AvBD3. The recombinant plasmid was transformed into E. coli BL21 and the bacteria was induced with IPTG It was demonstrated by SDS-PAGE that a 31 kDa protein which was equal to goose AvBD3 protein in molecular weight was highly expressed. The purified recombinant goose AvBD3 exhibited extensive antimicrobial activity against twelve bacteria strains, including Gram-positive and Gram-negative investigated. At high salt ions conditions, antimicrobial activity of recombinant goose AvBD3 protein against both Staphylococcus aureus and Pasteurella multocida decreased significantly. In addition, hemolysis activity of the recombinant protein was extremely low, and the recombinant protein remained antimicrobial activity under different pH values. PMID- 22506412 TI - [Expression and characterization of the dermonecrotic toxin gene of Bordetella bronchiseptica]. AB - Dermonecrotic toxin (DNT) is identified as one of the most important virulence factor of Bordetella bronchiseptica. The complete coding sequence (4 356 bp) of the dnt gene was cloned into the prokaryotic expression vector pET-28a, and expressed in the Eschierichia coli BL21 (DE3) under IPTG (Isopropyl-beta-D thiogalactopyranoside) induction. The recombinant His6-DNT protein showed immunological reactivity in the Western-blot analysis. The recombinant protein was purified from crude lysates of BL21 harboring pET-DNT with the purity of 93.2%. His6-DNT showed the dermonecrotic effects in the infant mouse assay. However, rabbit anti-serum against recombinant DNT protein could neutralize the dermonecrotic effects of native DNT to the infant mice in vivo. These findings suggest that the recombinant DNT protein retained the characteristics and immunogenicity of native DNT. Furthermore, this approach could be used to induce active immunity and serum immunoglobulin for production of a passive therapeutic reagent. In this study, we have shown that the recombinant His6-DNT protein retained the characteristics of native DNT of B. bronchiseptica, which built a good foundation for the further research on the structure and function of DNT. PMID- 22506413 TI - [Effect of the glycine-rich region deleted PPV VP2 to the VLPs]. AB - The N-terminal of porcine parvovirus (PPV) viral protein 2 (VP2) links a glycine rich domain which is a cleavage site of PPV VP3.In order to confirm that the glycine-rich domain was essential for the self-assembling of virus-like particles (VLPs).The VP2 gene with glycine-rich domain deleted and the complete VP2 gene were inserted to eukaryotic expression vector pCI-neo and were named pCI-AVP2 and pCI-VP2. Then, pCI-delta VP2, pCI-VP2 and pCI-neo were transferred into Vero Cells by liposome and the VLPs was detected by SDS-PAGE, Western blotting, indirect immunofluorescence and immunoelectron microscopy. Furthermore, 56 female Kunming mice were divided into 5 groups and injected intramuscularly with pCI delta VP2, pCI-VP2 and pCI-neo as DNA vaccine, PPV inactivated vaccine and normal saline separately. The peripheral blood of the mice was collected to analyze the subgroups of the peripheral blood mononuclear cell by flow cytometry, to detect the antibody and lymphocyte proliferation by indirect-ELISA and MTT assay separately. The results show that the VLPs were observed both in the pCI-delta VP2 and pCI-VP2 transferred Vero Cells. The two VLPs could agglutinate guinea pig erythrocytes. The results also show that both the pCI-delta VP2 and pCI-VP2 vaccine induced special cellular and humoral immunity effectively. Those results revealed that the glycine-rich domain is not essential for the VPL's self assembling. This study provides a new theoretical evidence for the relationship between the gene structure and protein function of VP2. PMID- 22506414 TI - [Production of 2, 3-butanediol and succinic acid by Salinivibrio YS]. AB - The production of 2, 3-butanediol and succinic acid by a moderate halophile under anaerobic condition was investigated. This halophile, termed Salinivibrio YS, was isolated from the solid samples collected from Aydingkol Lake. Based on the single factor experiment, the parameters and their values for the production were obtained. Then, the optimum values of these parameters by the orthogonal experiments were obtained: temperature, 33 degrees C; initial pH of fermentation, 8.0; the pH during fermentation, 7.0; the concentration of acetic acid was 3 g/L and NaC1 was 10 g/L. Finally, a 3-L fermentation based on these conditions was carried out. After 108 h of fermentation under anaerobic condition, 35.05 g/L of 2, 3-butanediol and 22.46 g/L of succinic acid were obtained. About 50% of total glucose conversion was achieved. The study on 2, 3-butanediol and succinic acid by a halophile under anaerobic condition will expand the applications of halophiles and open a new area of production of 2, 3-butanediol and succinic acid. PMID- 22506415 TI - [Enzymes related with NAD synthesis promote conversion of 1,4-butanediol to 4 hydroxybutyrate]. AB - Besides medical application, 4-hydroxybutyrate (4-HB) is a precursor of P3HB4HB, a bioplastic showing excellent physical properties and degradability. Escherichia coli S17-1 (pZL-dhaT-aldD) can transform 1, 4-butanediol (1,4-BD) into 4HB with participation of cofactor NAD. To enhance productivity, nicotinic acid phosphoribosyltransferase (PncB) and nicotinamide adenine dinucleotide synthetase (NadE) were overexpressed to increase intracellular nicotinamide adenine dinucleotide concentration and promote reaction process. The shake flask fermentation result showed that the conversion rate increased by 13.03% with help of PncB-NadE, leading to 4.87 g/L 4HB from 10 g/L 1,4-BD, and productivity was increased by 40.91% to 1.86 g/g. These results demonstrated that expression of PncB and NadE is beneficial for conversion of 1,4-BD to 4HB. PMID- 22506416 TI - [Expression of Vitreoscilla hemoglobin improves recombinant lipase production in Pichia pastoris]. AB - Yarrowia lipolytica lipase Lip2 (YlLip2) is an important industrial enzyme with many potential applications. To alleviate the dissolved oxygen (DO) limitation and improve YlLip2 production during high-cell density fermentation, the YlLip2 gene lip2 and Vitreoscilla hemoglobin (VHb) gene vgb were co-expressed in Pichiapastoris under the control of AOX1 and PsADH2 promoter, respectively. The PsADH2 promoter from Pichia stipitis could be activated under oxygen limitation. The SDS-PAGE and CO-difference spectrum analysis indicated that VHb and YlLip2 had successfully co-expressed in recombinant strains. Compared with the control cells (VHb-, GS115/9Klip2), the expression levels of YlLip2 in VHb-expressing cells (VHb+, GS115/9Klip2-pZPVT) under oxygen limitation were improved 25% in shake-flask culture and 83% in a 10 L fermentor. Moreover, the VHb+ cells displayed higher biomass than VHb- cells at lower DO levels in a 10 L fermentor. In this study, we also achieved a VHb-expressing clone harboring multicopy lip2 gene (GS115/9Klip2-pZPVTlip2 49#), which showed the maximum lipolytic activity of 33 900 U/mL in a 10 L fermentor under lower DO conditions. Therefore, it can be seen that expression of VHb with PsADH2 promoter in P. pastoris combined with increasing copies of lip2 gene is an effective strategy to improve YlLip2 production. PMID- 22506417 TI - [Effect of mufti-gene knockout of L-tryptophan transport system on L-tryptophan production in Escherichia coli]. AB - In Escherichia coli, uptake of L-tryptophan is done by three distinct permeases, encoded by mtr, tnaB, and aroP. Based on the mtr single-gene knockout, we constructed the mtr.tnaB and mtr.aroP double-gene knockout mutants and the mtr.tnaB.aroP triple-gene knockout mutant. The fermentation results showed that the mtr.tnaB and mtr.aroP knockout mutants produced 1.38 g/L and 1.27 g/L L tryptophan, respectively, which was 17% and 9% higher than that of the mtr knockout mutant. However, the mtr.tnaB.aroP knockout mutant was significantly affected on cell growth and only produced 0.63 g/L L-tryptophan. During the fed batch fermentation in a 3-L fermentor, the mtr.tnaB knockout mutant produced 12.2 g/L L-tryptophan, which was 27% higher than that of the mtr knockout mutant. This study demonstrates the effect of multi-gene knockouts of L-tryptophan transport system of Escherichia coli on the biosynthesis of L-tryptophan. PMID- 22506418 TI - [Medium optimization for mycelia production of Antrodia camphorata based on artificial neural network-genetic algorithm]. AB - To illustrate the complex fermentation process of submerged culture of Antrodia camphorata ATCC 200183, we observed the morphology change of this filamentous fungus. Then we used two optimization models namely response surface methodology (RSM) and artificial neural network (ANN) to model the fermentation process of Antrodia camphorata. By genetic algorithm (GA), we optimized the inoculum size and medium components for Antrodia camphorata production. The results show that fitness and prediction accuracy of ANN model was higher when compared to those of RSM model. Using GA, we optimized the input space of ANN model, and obtained maximum biomass of 6.2 g/L at the GA-optimized concentrations of spore (1.76x 10(5) /mL) and medium components (glucose, 29.1 g/L; peptone, 9.3 g/L; and soybean flour, 2.8 g/L). The biomass obtained using the ANN-GA designed medium was (6.1+/-0.2) g/L which was in good agreement with the predicted value. The same optimization process may be used to improve the production of mycelia and bioactive metabolites from potent medicinal fungi by changing the fermentation parameters. PMID- 22506419 TI - Codon optimization, expression and enzymatic comparison of Rhizopus oryzae lipases pro-ROL and m-ROL in Pichia pastoris. AB - Rhizopus oryzae lipase (ROL) is not only a biocatalyst used in a broad range of biotechnological fields, but also a model to investigate the function of intramolecular chaperone in the post-translational processing of lipase. In this study, we cloned and expressed the mature lipase gene (m-ROL) containing the pre sequence (pro-ROL) of R. oryzae HU3005 in Pichia pastoris GS115 and characterized their enzymatic activities. m-ROL exhibited higher hydrolysis activity towards middle-chain substrates (C10 and C12) at pH 9.0, whereas pro-ROL preferred short chain substrates (C4) and displayed maximal activity at pH 8.0. Moreover, pro-ROL possessed better thermal stability than m-ROL. This enzymatic discrepancy between m-ROL and p-ROL may be due to the pre-sequence that affects the folding and conformation of the mature lipase domain. To improve the expression level of m ROL in P. pastoris, overlap extension PCR was conducted to substitute eight less frequently used codons of m-ROL with frequently used codons. After methanol induced expression for 72 h, the activity and protein content of the codon optimized m-ROL reached 132.7 U/mL and 50.4 mg/L, while the activity of the parental m-ROL and pro-ROL are 28.7 U/mL and 14.4 mg/L, 29.6 U/mL and 14.1 mg/L, respectively. PMID- 22506420 TI - [Influence of methanol concentration on purification recovery of consensus interferon-a produced by Pichia pastoris]. AB - We observed the influence of methanol concentration on purification recovery of recombinant human consensus interferon-a (cIFN) produced by Pichia pastoris. Fermentations controlled at 0.75% (W/V) methanol showed a 24% increase in clFN expression compared to using 0.25% methanol. However, the purification recovery rate of cIFN at 0.25% methanol was 3.75-fold higher than that at 0.75% methanol. To seek the reason, we analyzed the stability of clFN by SDS-PAGE and Native-PAGE as well as Western blotting. The electrophoresis results revealed that cIFN formed a lot of aggregates in media when the induction was controlled at 0.75% methanol, and two different aggregate forms were found: disulfide bond covalent aggregates and non-covalent aggregates. However, these aggregates almost disappeared when the methanol concentration was controlled at 0.25%, at the same time, cIFN bioactivity of supernatant increased almost 4.48-fold. Finally, 0.73g monomer cIFN was obtained after purification from 1 liter supernatant at 0.25% methanol induction, showed a 2.84-fold increase compare to the induction at 0.75% methanol. PMID- 22506421 TI - [Improvement of catalytic capability of Paecilomyces thermophila J18 thermostable beta-1,3-1,4-glucanase under acidic condition by directed evolution]. AB - Directed evolution was used to improve the performance of beta-1,3-1,4-glucanase (designated as PtLicl6A) from Paecilomyces thermophila J18 under acidic condition. A mutant library was constructed by error-prone PCR and DNA shuffling, and positive clones were screened by Congo red staining. More than 1 500 mutants were selected. One mutant (PtLic16AM1) exhibited an optimal activity at pH 5.5, while the optimal pH of the wild-type enzyme was 7.0. The mutant PtLic16AM1 kept the high specific activity and thermotolerence of the wild-type enzyme. Sequence analysis revealed that the mutant enzyme has four sense substitutions which caused four amino acid substitutions - namely T58S, Y110N, G195E and D221G.. Homology modeling showed that among the four amino acid substitutions, Y110N was near the active site of the enzyme, while the other three was distant. T58S and G195E may play key roles in the change of optimal pH. This study provided a new perspective of obtaining applicable 3-1,3-1,4-glucanase for industrial use. PMID- 22506422 TI - [Investigation of dependability of laryngopharyngeal reflux and disorders of phonation]. AB - OBJECTIVE: To investigate the voice features of laryngopharyngeal reflux (LPR), and analyze the effects of LPR to the life qualities of patients. To analyze the dependability between objective and subjective ways. METHOD: One hundred and ninety-six of the patients who were suspected of LPR were received the surveys of general state, electronic nasopharyngolaryngoscope, evaluation of the reflux symptom index (RSI) and the reflux finding score (RFS). One hundred of patients whose RSI>13, RFS>7 were diagnosed as LPR and were received evaluation of voice handicap index (VHI), analysis of vocal acoustics and examination of glottogram. RESULT: The funda mental frequency included male and female depressed,the perturbation of fundamental frequency, the perturbation of amplitude and normalization noise energy increased. Differences were statistically significant (P<0.01) compa ring with the normal control. The contiguity rate depressed, maximum phonation time shorten, the differences in which were statistically significant (P<0.01) comparing with the normal control. In the evaluation of VHI, the score of physiology was the highest, the function was second and the emotion was the lowest. The RSI and VHI had correlations (P<0.05), while RFS, RSI and VHI had not (P>0.05). Physiology, function and emotion had correlations in LPR. CONCLUSION: From the analysis of vocal acoustics and examination of glottogram,we knew that vocal function was effected because the vocal cord was injured by LPR. The fundamental frequency depressed and the vibrations of vocal cords were not instability, glottis wasn't closed up well and contact time was depressed. Patients who had the reflux symptoms uncertainty had the reflux findings. PMID- 22506423 TI - [Expression of TGM3 protein and its significance in laryngeal carcinoma]. AB - OBJECTIVE: To investigate the expression of TGM3 in laryngeal carcinoma and analyze the relation of TGM3 and clinical factors. METHOD: We measured the expression of TGM3 protein in 50 laryngeal carcinoma fresh samples and 50 para carcinoma tissues (to cutting margin > 0.5 cm) by Flow Cytometry (Epics-XL II), 20 normal laryngeal mucosa samples were also studied as controls. RESULT: 1) The quantitative and qualitative expression of TGM3 protein in laryngeal carcinoma tissues is obviously lower than those in para-carcinoma and normal laryngeal mucosa tissues respectively (P<0.05). There is no significant expression difference between the para-carcinoma and normal laryngeal mucosa tissues. 2) In laryngeal carcinoma, the expression of TGM3 protein isn't significantly related to patients' clinical classification, tumor size, patients' age and gender but related to lymphaden metastasis. differentiation and clinical stage. CONCLUSION: The low expression of TGM3 may contribute to the carcinogenesis and development of laryngeal carcinoma. It is an important index of judging differentiation, infiltration, metastasis and staging of laryngeal carcinoma by measure the expression of TGM3 protein. PMID- 22506424 TI - [The effects of the plastic operation on upper respiratory tract at one-stage for patients with OSAHS through the assessment of 3-D reconstruction of CT images]. AB - OBJECTIVE: The method of three-dimensional reconstruction of CT images is adopted to evaluate the effects of the plastic operation on upper respiratory tract at one-stage (stage one) for patients with multi-level obstructive sleep apnea hypopnea syndrome. METHOD: Polysomnography is used to diagnose patients with OSAHS. The obstruction parts of patients with OSAHS are determined by CT and endoscopy examinations in the upper air way. To reconstruct the tri-dimensional cavity of upper respiratory tract from data, the CT examinations on the sinuses and nasopharynx are rescanned to obtain the CT data after surgery. The changed situations before and after surgery are compared, and the narrow parts of the upper respiratory tract can be identified and measured intuitively. RESULT: Symptoms and PSG test results show that the effects of the surgical results are very good. and the cross sections of upper respiratory tract narrow parts were enlarged by more than 100%. Hydromechanical evidence approved the same results. CONCLUSION: Calculating the increment of the cross sections of the upper respiratory tract through tri-dimensional reconstruction can not only find the preoperative stenosis, but also assess the surgical effects objectively. Since the body of endoscope has a certain volume, surface anesthesia is needed to enter the nasal cavity and nasopharyngeal which will impact the objectivity of the assessment of the upper respiratory tract stenosis. PMID- 22506425 TI - [Aggressive fibromatosis of the head and neck (A report of two cases and literature review)]. AB - OBJECTIVE: To evaluate the clinic manifestation, pathologic behavior, therapy and prognosis of rare aggressive fibromatosis in the head and neck. METHOD: Two cases of aggressive fibromatosis were analyzed and relevant literatures were reviewed. RESULT: Aggressive fibromatosis was characterized as infiltrative, locally aggressive and tended to recur after surgical resection. Pathology showed fibroblastic monoclonal proliferation. Fibromatosis was composed of well differentiated fibroblasts and myofibroblasts, lacking cytological features of malignancy and scanty or absent mitotic activity. Complete surgical excision of aggressive fibromatosis was considered to be the only effective method of cure by most authorities. Chemotherapy and radiotherapy can be used together with surgery in recurrence or unsatisfactory surgical margin. In our study, one patient recurred after the first operation, and after another operation, the patient did not recur after 6 months follow up, and the other one did not recur after 6 months follow up. CONCLUSION: The diagnosis of aggressive fibromatosis depended on pathological examination. Radical removal was an important way to reduce recurrence rate. Radiation therapy and chemotherapy can be used as adjuvant therapy in patients with recurrent or unresectable or inoperable disease. PMID- 22506426 TI - [A meta-analysis for the effectiveness external radiation vs transoral laser surgery for treatment of early glottic carcinoma]. AB - OBJECTIVE: To investigate the effectiveness external radiation (XRT) vs transoral laser surgery (TOL) for treatment of early glottic carcinoma. METHOD: Medline (1990-2010), Embase (1990-2010), Cochrane Library, CBM (1990-2010), CNKI (1994 2010), Wanfang Database were searched for published case-control studies investigating the effectiveness external radiation vs transoral laser surgery for treatment of early glottic carcinoma. The odds ratio was calculated. Meta analyses were performed by RevMan5. 0. 2 Software. RESULT: In the complications of this study, there was significant heterogeneity in the literatures, so Meta analysis was given up. In the recurrence and 5-years locoregional control, XRT group was no significant difference with TOL group by eliminating the heterogeneity or using the subgroup analysis, but the results till showed there was less recurrence and more locoregional control in TOL group than those in XRT group. In death of disease, overall survival and laryngeal preservation, the differences were statistically significant. CONCLUSIONS: TOL could be complete in the clinic and the cost was much more cheaper than XRT. So TOL could be used as the first choice for the treatment of early glottic carcinoma versus XRT. But for larger tumors, involving the anterior commissure, there was no clear conclusion. Based on literatures, traditional surgery was the proposed choice. We recognize that the datas included in our study are retrospective studies, for a more scientific conclusion, we need more RCTs. PMID- 22506427 TI - [Coblation-assisting uvulopalatopharyngoplasty combining coblation-channeling of the tongue for patients with severe OSAHS]. AB - OBJECTIVE: To investigate the therapeutic efficacy of coblation-assisting uvulopalatopharyngoplasty (CAUPPP) combining with coblation-channeling of the tongue (CCT) for patients with severe obstructive sleep apnea-hypopnea syndrome (OSAHS). METHOD: A retrospective analysis was made on patients with severe OSAHS treated by CAUPPP combining with CCT. The adult with severe OSAHS were involved in the study and the apnea-hypopnea index (AHI) were beyond 40/h and lowest arterial oxygen saturation (LSaO2) were under or equal to 80%. Surgical approach: The UPPP was performed to decrease the size of soft palate with coblation and coblation-channeling in the soft palate and decrease the size of tongue by CCT. All patients were followed up for 6 to 12 months and underwent polysomnography (PSG). RESULT: Subjective symptoms of patients improved more significantly than that of preoperation. The function of soft palate is normal without significant nasopharyngeal regurgitation. Compared with the preoperative data, AHI values were significantly decreased (P<0.01) and the lowest oxygen saturations increased significantly (P<0.01) and the effective rate was 91.7%. CONCLUSION: There are usually multiple obstruction levels in patients with severe OSAHS and the traditional surgical treatment is not ideal. This study demonstrated that with the assistance of coblation, combining CAUPPP with CCT for patients with severe OSAHS is an effective surgical method. It has less blood loss, minimally invasive, retained the normal function of the soft palate, etc., should be widely applied. PMID- 22506428 TI - [The significance of anastomosing the recurrent laryngeal nerve in the thyroidectomy]. AB - OBJECTIVE: To study the significance of exposure of the recurrent laryngeal nerve (RLN ) in thyroid gland surgery. METHOD: Three hundred and thirty-two thyroidectomy cases were studied from January 2008 to June 2011. All patients had general anesthesia, and RLN were exposed during operation. One hundred and thirty one cases were operated with total lobectomies, 138 cases with subtotal thyroidectomy, 51 cases with total lobectomies and contralateral subtotal thyroidectomy, 12 cases with total thyroidectomy. RESULT: Five hundred and thirty three RLNs were exposed, 4 cases came with hoarseness postoperatively, All cases recovered within 3 months. CONCLUSION: Exposure the recurrent laryngeal nerve in the thyroidectomy was available and could protect RLN. PMID- 22506429 TI - [Nasal-cardiac reflex initiated by nasal packing (three cases report and literature review)]. AB - OBJECTIVE: To sum up the diagnosis and treatment experience of the nasal-cardiac reflex initiated by postoperative nasal packing. METHOD: The clinical data of 3 cases with nasal-cardiac reflex initiated by postoperative nasal packing were analyzed retrospectively. RESULT: In the period of postoperative nasal packing, 3 patients had abruptly drops in heart rate and blood pressure associated with symptoms of autonomic dysfunction such as flustered, chest tightness, tachypnea, body sweating et al. There are no positive signs of pathological significance in the cardiovascular and respiratory system. The reflex had spontaneously to be offset with oxygen, comfort touch therapy, pull out the stuffing, no other special treatment for all cases. CONCLUSION: The key of the diagnosis for nasal cardiac reflex is a drop in mean arterial blood pressure (MABP) and the heart rate (HR) more than 20% above the baseline values. The cause of nasal-cardiac reflex initiated by postoperative nasal packing is long-term mechanical pressure on the nasal mucosa and mental factors. Comfort touch therapy and pull out the nasal packing material is effective method to terminate the reflex and the prognosis is good. Correct understanding of the characteristics of the reflex and preventing the occurrence of its adverse consequences have important clinical significance. PMID- 22506430 TI - [Expression of EGFR about different region tissues and its relationship with histological differentiation in laryngeal carcinoma]. AB - OBJECTIVE: To detect the expression of EGFR in different region of laryngeal tissue, and use quantitive analysis to discuss the relation between expression of EGFR and histological differentiation. METHOD: Collected 36 cases of laryngeal tissue example, which be divided in to three groups based on pathobiology. Using Western Blot to detect the EGFR expression in cancer tissue, para cancer tissue and normal tissue, and combined imaging analytical technique to analyse the relation between expression of EGFR and histological differentiation. RESULT: In same region of cancer tissue the expression of EGFR is different along with different tissue differentiation (P<0.05), but in normal tissue this different is not existing (P>0.05). In same tissue differentiation the expression of EGFR is different in cancer tissue, para cancer tissue and normal tissue (P<0.05). CONCLUSION: EGFR highly express in laryngeal cancer tissue, and relate with the tissue differentiation of laryngeal cancer. EGFR is an important indicator to study the emerging and progression of laryngeal cancer. PMID- 22506431 TI - [The rule of lymphatic formation in rabbit VX2 supraglottic carcinoma model with lymph node metastasis]. AB - OBJECTIVE: Establishment of transplanted model of VX2 supraglottic carcinoma in rabbits and investigation the rule of lymphatic vessels formation. METHOD: After establishment of VX2 tumor-bearing rabbits, the carcinoma tissues were transplanted into the operculum laryngis submucosa in sixty New-Zealand white rabbits to establish transplanted tumor model. Vascular endothelial growth factor 3 (VEGFR-3) label staining was performed to observe lymphatic vessels. Number density, volume density of lymphatics periphery region of carcinoma, normal region and centre region were measured using computer image analysis system. RESULT: There was no lymphatic vessels in carcinomatous centre region,but the lymphatic vessels number density, volume density in periphery region was much more than normal region. Their cavities were dilated. The discrepancy had statistical significance (P<0.01). CONCLUSION: The rule of lymphatic formation in rabbit VX2 supraglottic carcinoma model mimesis rule of lymphatic formation anthropo- supraglottic carcinoma. Lymphatic multiplication and dilation at periphery region of carcinoma is associated with lymph node metastasis. Evaluation of it at periphery region of carcinoma may be useful in predicting lymph node metastasis in patients with supraglottic carcinoma. This conclusion provides theoretical basis for utility of the anti-tumor medicines which inhibit lymphatic formation in animal model. PMID- 22506432 TI - Healing options during the plague: survivor stories from a fourteenth-century canonization inquest. AB - Witness testimonies in the 1363 canonization inquest for Countess Delphine de Puimchel help us explore differing reactions to the first two waves of plague in 1348 and 1361, the diverse social and healing networks available to the sick, and the importance of affect in the healing process. Every witness in the inquest had lived through both the 1348 and 1361 epidemics. Their testimonies show that sufferers actively sought out healing even when they feared that none existed, healing practitioners continued to care for the sick through both waves of epidemic, and emotion played an important role in sufferers' healing. Their language allows us to look at the interaction between miracle and medicine, the interaction of healing practitioners, and the expectations of sufferers during severe epidemics in the later Middle Ages. PMID- 22506433 TI - "A variety of tastes": the Lancet in the early-nineteenth-century periodical press. AB - This article examines the opening years of Thomas Wakley's 1823 journal the Lancet, which rose to dominate the precarious early-nineteenth-century medical publishing market. The author argues that Wakley was an editor acutely aware of his journal's relationship to a wider nonmedical press and that this awareness may have even contributed to the Lancet's early success. In addition to, and often contiguous with, the journal's strongly worded critique and detailed medical content, Wakley sought to attract readers by importing entertaining formal components from lay periodicals. PMID- 22506434 TI - Beasts, murrains, and the British Raj: reassessing colonial medicine in India from the veterinary perspective, 1860-1900. AB - Assessments of colonial medicine in India have, until now, focused almost exclusively on questions related to human health. This article shifts attention to the subject of animal health and reexamines existing hypotheses about colonial medicine in India from this new perspective. It looks at the linkages between veterinary medicine and the military and fiscal policies of the colonial state, arguing that animal health in the larger colony remained neglected throughout the late nineteenth century as a result of these policies. In arguing this, the essay examines several areas related to veterinary medicine in India, including bacteriology, veterinary training, horse breeding, and disease control. PMID- 22506435 TI - Debating a duty to treat: AIDS and the professional ethics of American medicine. AB - A heated ethical and professional debate occurred in the United States in the late 1980s over whether doctors had an ethical obligation to treat people with AIDS. Sparked by public refusals to treat by physicians, the debate was linked to changes in the epidemic and general tensions about the character of the profession. Despite widespread public consensus on the existence of a duty, the outcome of the debate was limited. Physicians' obligations for HIV/AIDS were defined by law; no general and durable obligation in the face of epidemics was secured. The professional system proved weak in the face of potential crisis. PMID- 22506436 TI - Zonisamide for bipolar disorder, mania or mixed states: a randomized, double blind, placebo-controlled adjunctive trial. AB - OBJECTIVE: This is the first multicenter, double blind, randomized, placebo controlled trial to evaluate the safety and efficacy of adjunctive zonisamide for the treatment of bipolar mania or mixed state. EXPERIMENTAL DESIGN: One hundred four patients with Bipolar Disorder, Type I, II or NOS, in a manic, hypomanic or mixed state of illness were randomized to either adjunctive zonisamide or placebo. The study consisted of three phases: a 7 to 30 day screening and stabilization phase, 6 weeks of blinded treatment and a 1 to 3 week discontinuation phase. The primary outcome variable for manic and hypomanic patients was the Young Mania Rating Scale (YMRS) both the YMRS and Montgomery Asberg Depression Rating Scale (MADRS) served as primary outcome variables for patients in mixed states. Secondary outcome measures included the Clinical Global Impression for Bipolar Disorder (CGI-BP), the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and an a priori analysis of response and remission. Metabolic parameters including weight, waist-hip ratio, body mass index, fasting glucose, cholesterol and triglyceride levels were also analyzed. Side effects were measured using the SAFTEE. PRINCIPAL OBSERVATIONS: There were no statistically significant differences for any of the primary or secondary outcome measures between zonisamide and placebo-treated patients. CONCLUSIONS: In contrast to previous studies that suggested efficacy of adjunctive zonisamide in bipolar mania or mixed state, these results were not confirmed in this double blind controlled study. PMID- 22506437 TI - Which rating scales are regarded as 'the standard' in clinical trials for schizophrenia? A critical review. AB - BACKGROUND: This paper reviewed which rating scales past studies adopted as an outcome measure in clinical trials for schizophrenia, for which a consensus has been lacking. METHODS: A PubMed search was conducted using keywords 'outcome', 'rating scales' and 'schizophrenia'. Studies published in 1999, 2004 and 2009 were examined to globally see if a trend has changed over the last decade. RESULTS: One-hundred fifty articles were inspected. As for psychopathology, the positive and negative syndrome scale (PANSS) has been by far the most frequently utilized scale (46%, 79%, and 78% in the respective years), followed by the brief psychiatric rating scale. Affective/anxiety symptoms have been only rarely recorded Extrapyramidal symptoms have been assessed mostly with the Simpson Angus scale (SAS), more frequently in combination with the abnormal involuntary movement scale (AIMS) and Barnes akathisia scale (BARS) recently. Non-motor adverse effects have been typically reported without a usage of formal rating scales. Depending on the interest of investigation, other critical domains of the illness including functioning, cognition and subjective perspectives have been sporadically reported through the rating scales. The assessment scales were similarly utilized across the years, except for a numerical rise in scale utilization to rate the latter three domains in 2009. CONCLUSIONS: The PANSS and set of AIMS, BARS and SAS, which are expected to take about 60 minutes to complete, are frequently utilized and may be regarded as a 'standard' in clinical trials for schizophrenia. Clinical implication of the findings and practical challenges with the existing scales are discussed. PMID- 22506439 TI - Test of treatment in psychiatric practice. AB - Due to lack of laboratorial investigations in psychiatric practice, tests of treatment are often used to aid diagnosis. This article provides examples of test of treatment in psychiatric practice and outlines their limitations. PMID- 22506440 TI - Suicidal obsessions as dose dependent side-effect of clozapine. AB - OBJECTIVE: Although numerous reports suggest that different atypical antipsychotics can exacerbate or induce (de novo) obsessive-compulsive symptoms, there is no report of the development of ego-dystonic, suicidal obsessions during treatment with these medications. Here, the authors report the first case of clozapine-induced suicidal obsessions. METHOD: The authors report a case of a patient diagnosed with bipolar disorder and who developed suicidal obsessions in the weeks after the dose of clozapine was increased from 150 mg/day to 300 mg/day. RESULTS: Symptoms quickly resolved after the treatment with clozapine was changed to the treatment with quetiapine and sodium valproate. Suicidal obsessions decreased promptly, within a few days, and disappeared completely when the dose of clozapine was 100 mg/day, quetiapine 600 mg/day, and sodium valproate 900 mg/day, 16 days after the initiation of changes in the medications. CONCLUSION: The case report emphasizes the crucial need of differentiation between genuine suicidal desires and ego-dystonic suicidal obsessions. The authors suggest that in similar cases a change in antipsychotic medications to those with stronger antidopaminergic properties and lower 5HT2 receptor affinity should be considered, but also assume that the use of sodium valproate in treatment of obsessive-compulsive symptoms deserves further study. PMID- 22506441 TI - Euprolactinemic gynecomastia and galactorrhea with risperidone-fluvoxamine combination. AB - Risperidone is associated with hyperprolactinemia and its consequent symptoms such as gynecomastia, galactorrhea and sexual dysfunction in adults, and less so in adolescents. Rarely, serotonin reuptake inhibitors are also associated with such adverse effects. We report a case of gynecomastia and galactorrhea in an adolescent male while on a combination of risperidone and fluvoxamine, although the serum prolactin was within normal range. PMID- 22506442 TI - [Sexuality as a concept and sexuality as an impulse]. PMID- 22506443 TI - [Dental care and sexuality]. AB - It must be stressed that a comprehensive evaluation of the general health condition is a pre-requisite in any screening process of a specific sexual activity. In the same way, the oral health examination should include the soft tissues such as the tongue and the lips, and the oral breath as well as the teeth to stress their possible implication in disorders of any kind. A special attention is given to the connexion between a good sexual life and a good aspect of all the dentition. The main purpose is to presume the importance particularly of smile, kisses and a good breath in the sexual life of a couple. PMID- 22506444 TI - [Oxytocin: the hormone of love, trust and social bond. Clinical use in autism and social phobia]. AB - Oxytocin, an octapeptide synthesized in the hypothalamus, stimulates milk election and uterine contractions. In the brain this hormone acts as a neuropeptide. It could inhibit through the GABAergic system the activity of limbic amygdala, which is involved in the response to fear. Oxytocin could also induce the protective behaviour of the mother towards its offspring through the dopaminergic system. In mankind, oxytocin plays a role in trust, empathy, generosity, stress and sexuality. Clinical studies are testing potential benefits of oxytocin administration in autism, depression and social phobia. Results are still preliminary. PMID- 22506445 TI - [Sexuality and heart disease]. AB - Sexual activity represents a light physical effort in most subjects with or without heart disease. In a small number of patients with heart disease sexual activity may trigger cardiac symptoms and even induce serious cardiac problems, such as myocardial infarction or sudden cardiac death due to malignant ventricular arrhythmias. However, the global risk remains very low. Thus, it is important to stratify patients with heart disease into risk groups which may help to counsel them to resume sexual activity, to identify those patients at higher risk for cardiac events and to treat those with sexual dysfunction, particularly when using 5-phosphodiesterase inhibitors for erectile dysfunction. PMID- 22506438 TI - Factors associated with response to clozapine in schizophrenia: a review. AB - BACKGROUND: Clozapine has been serving as the gold standard medication for patients with treatment-resistant schizophrenia who failed to respond to other antipsychotics. However, factors affecting response to this medication have not been comprehensively reviewed recently. METHODS: In order to find factors associated with response to clozapine in schizophrenia, a literature search was conducted using PubMed through January 2011 with keywords of clozapine, response, and schizophrenia. Cross-referencing of relevant articles was also performed. Factors were arbitrarily classified into the following: demographic/clinical, oral dosage/pharmacokinetic, biochemical, (electro)physiological, genetic, imaging, and combinations. RESULTS: A synthesis from 280 articles indicated that demographic and clinical variables such as high baseline symptoms and low premorbid functioning have not been particularly useful in predicting response to clozapine. Pharmacokinetic evidence points to a threshold clozapine level of 350 ng/ml but in a context of significant inter- as well as intra-individual variability. Pharmacokinetic perspectives appear to have more implication in special situations including poor response, suspected toxicity and nonadherence. A number of laboratory-based studies have reported on many potential candidates for response prediction to clozapine, however, reproducibility, specificity, robustness of the findings, as well as clinical feasibility and cost effectiveness all pose a significant practical challenge, in relation with the fact that pathophysiological bases of treatment resistance in schizophrenia largely remain to be elucidated. CONCLUSIONS: No unequivocal factors to clozapine response were found despite a relatively rich body of the literature, which calls for more works on this important topic. Clozapine level of 350 ng/ml appears to be useful in case of nonresponse. PMID- 22506446 TI - [Sexuality and subjective experience]. AB - Sexual satisfaction could depend at first on the bodily self-perception of everyman. Moreover, this person needs to be capable of integrating pleasure, which is fleeting, without neglecting the quality of the relationship with the partner. PMID- 22506447 TI - [The evolution of psychiatric troubles in patients suffering from primary hypogonadism treated by a testicular transplant]. AB - Observation of a group of 60 patients affected by a primary hypogonadism and followed before and after a testicular transplant. They were separated into three sub-groups and the final evaluation was established according to the differences of each sub-group. PMID- 22506448 TI - [Atypical anorexia nervosa in male patients who also have endocrinological disturbances and dysmorphomania]. AB - A systematic study of 37 male patients, between 18 and 35, suffering from anorexia nervosa, but also affected by endocrinological problems. However, from a psychiatric point of view they disclosed symptoms dysmorphophobia. PMID- 22506449 TI - [Nutritional deficiency after gastric bypass surgery: a review of the literature and guidelines for follow-up]. AB - Roux-en-Y gastric bypass (RYGB) is the most frequently performed bariatric surgical procedure in Switzerland. The incidence of postoperative nutritional deficiencies is high. Therefore, guidelines have been established for patient follow-up and prophylactic treatment of such complications. This article makes use of a case report and a review of the literature to emphasize the importance of such measures. PMID- 22506450 TI - [Viktor von Weizsacker and national socialism]. PMID- 22506451 TI - [Moderate alcohol drinking is a risk factor for breast cancer]. PMID- 22506452 TI - [Autism: who has a say in treatment?]. PMID- 22506453 TI - [Before sitting down to eat, should we ask how is the animal killed?]. PMID- 22506454 TI - [Campaign against co-sleeping]. PMID- 22506455 TI - [The smoker is a squirrel in a cage (2)]. PMID- 22506456 TI - [Abortion, women, solidarity]. PMID- 22506457 TI - [Clinical significance of thoracic pedicle classification by inner cortical width of pedicles on CT images in posterior vertebral column resection for treatment of rigid and severe spinal deformities]. AB - OBJECTIVE: To investigate the clinical significances of the thoracic pedicle classification determined by inner cortical width of pedicle in posterior vertebral column resection (PVCR) with free hand technique for the treatment of rigid and severe spinal deformities. METHODS: Between October 2004 and July 2010, 56 patients with rigid and severe spinal deformities underwent PVCR. A total of 1098 screws were inserted into thoracic pedicles at T(2-12). The inner cortical width of the thoracic pedicle was measured and divided into 4 groups: group 1 (0 1.0 mm), group 2 (1.1-2.0 mm), group 3 (2.1-3.0 mm), and group 4 (> 3.1 mm). The success rate of screw-insertion into the thoracic pedicles was analyzed statistically. A new 3 groups was divided according to the statistical results and the success rate of screw-insertion into the thoracic pedicles was analyzed statistically again. And statistical analysis was performed between different types of thoracic pedicles classification for pedicle morphological method by Lenke. RESULTS: There were significant differences in the success rate of screw insertion between the other groups (P < 0.008) except between group 3 and group 4 (chi2 = 2.540, P = 0.111). The success rates of screw-insertion were 35.05% in group 1, 65.34% in group 2, and 88.32% in group 3, showing significant differences among 3 groups (P < 0.017). According to Lenke classification, the success rates of screw-insertion were 82.31% in type A, 83.40% in type B, 80.00% in type C, and 30.28% in type D, showing no significant differences (P > 0.008) among types A, B, and C except between type D and other 3 types (P < 0.008). In the present study, regarding the distribution of different types of thoracic pedicles, types I, II a, and II b thoracic pedicles accounted for 17.67%, 16.03%, and 66.30% of the total thoracic pedicles, respectively. The type I, II a, and II b thoracic pedicles at the concave side accounted for 24.59%, 21.13%, and 54.28%, and at the convex side accounted for 10.75%, 10.93%, and 78.32%, respectively. CONCLUSION: A quantification classification standard of thoracic pedicles is presented according to the inner cortical width of the pedicle on CT imaging: type I thoracic pedicle, an absent channel with an inner cortical width of 0-1.0 mm; type II thoracic pedicle, a channel, including type IIa thoracic pedicle with an inner cortical width of 1.1-2.0 mm, and type IIb thoracic pedicle with an inner cortical width more than 2.1 mm. The thoracic pedicle classification method has high prediction accuracy of screw-insertion when PVCR is performed. PMID- 22506458 TI - [Management of rigid post-traumatic thoracolumbar kyphosis by simultaneous posterior-anterior circumferential releasing and correction with preserved posterior vertebral wall]. AB - OBJECTIVE: To evaluate the surgical management of rigid post-traumatic thoracolumbar kyphosis (RPTK) by simultaneous posterior-anterior circumferential releasing, correction and anterior corpectomy with preserved posterior vertebral wall. METHODS: Twenty patients with RPTK were treated between October 2004 and October 2010 by posterior releasing, anterior subtotal corpectomy with preserved posterior vertebral wall, correction, strut graft, and short segmental fixation. There were 14 males and 6 females with an average age of 43.2 years (range, 23-63 years). The time between injury and operation was 4 months to 23 years (mean, 1.4 years). The affected locations were T11 in 1 case, T12 in 8 cases, L1 in 10 cases, and L2 in 1 case. The Cobb angle and the intervertebral height of the fractured vertebra body were measured before and after operations. The degrees of low back pain were assessed by Japanese Orthopaedic Association (JOA) scores. RESULTS: No incision infection, nerve injury, or cerebral spinal fluid leakage occurred. Seventeen patients were followed up 1-5 years with an average of 2.8 years. The JOA score at last follow-up (26.2 +/- 3.9) was significantly improved when compared with the pre-operative score (14.0 +/- 5.7) (t = 4.536, P = 0.001). One patient had aggravation of kyphosis at 3 months postoperatively, who was in stabilized condition after prolonging immobilized time. The Cobb angle was corrected from (43.2 +/- 11.5) degrees preoperatively to (9.8 +/- 5.7) degrees at last follow-up, showing significant difference (P < 0.01). There was significant difference in the intervertebral height of the fractured vertebra body between preoperation and last follow-up (P < 0.05). The intervertebral height of fractured vertebra was restored to 87.0% +/- 11.2% of adjacent disc height. CONCLUSION: Posterior-anterior circumferential releasing and anterior corpectomy with preserved posterior vertebral wall can achieve satisfactory clinical results, not only in pain relieving, kyphosis correction, vertebral height restoration, and spinal stability restoration, but also in the risk reduce of bleeding and spinal cord disturbance. PMID- 22506459 TI - [Clinical evaluation of one-stage radical debridement combined with posterior pedicle internal fixation for brucellar spondylitis of the thoracic and lumbar vertebrae]. AB - OBJECTIVE: To discuss the surgical treatment method and effectiveness of brucellar spondylitis. METHODS: Between January 2002 and October 2010, 78 patients underwent one-stage radical debridement and posterior pedicle internal fixation, who were definitely diagnosed as having brucellar spondylitis of the thoracic and lumbar vertebrae. There were 42 males and 36 females, aged 24 to 65 years (mean, 45 years). The disease duration was 8-29 months (mean, 12 months). Two vertebrae were involved in 70 cases and three vertebrae were involved in 8 cases. All of the cases complicated by nerve function damage in different extent before operation. The patients were followed up regularly after operation. The pain score (visual analogue score, VAS), nerve function Frankel classification, effectiveness evaluation, and the blind test evaluation of X-ray and MRI were performed. RESULTS: All 78 cases were followed up 12 to 30 months (mean, 26 months). No sinus tract and recurrence occurred. The VAS scores were significantly improved at 1 month (2.4 +/- 0.3), 3 months (1.0 +/- 0.2), 6 months (0.5 +/- 0.4), and 12 months (0) when compared with preoperative score (9.2 +/- 0.6) (P < 0.05). The nerve function Frankel classification after operation was significantly improved when compared with preoperative one (P < 0.05); the patients in grade C and grade D had the most obvious improvement. The effectiveness evaluation indicated no aggravated cases. As time went on, the improved and unchanged patients were cured gradually and the improvement rate and the curative rate were 100% and 91.03%, respectively at 12 months after operation. The imaging scores were significantly improved at 1 month (4.11 +/- 0.09), 3 months (4.68 +/- 0.04), 6 months (4.92 +/- 0.08), and 12 months (5) when compared with the preoperative score (0.17 +/- 0.03) (P < 0.05). CONCLUSION: One stage radical debridement combined with posterior pedicle internal fixation is an ideal therapeutic method for brucellar spondylitis of the thoracic and lumbar vertebrae, which has obvious superiority in pain relief, the spine stability, the nerve function recovery, and early rehabilitation. PMID- 22506460 TI - [Surgical treatment of discogenic low back pain by minimally invasive transforaminal lumbar interbody fusion combined with unilateral pedicle screw fixation]. AB - OBJECTIVE: To investigate the effectiveness of surgical treatment for discogenic low back pain (DLBP) by minimally invasive transforaminal lumbar interbody fusion (TLIF) combined with unilateral pedicle screw fixation (UPSF). METHODS: Between March 2006 and July 2009, 57 patients with single-level DLBP were treated by minimally invasive TLIF combined with UPSF, including 27 males and 30 females with an average age of 45.6 years (range, 38-61 years) and a disease duration of 3.8 years (range, 9 months to 11 years). The involved segments included L2, 3 in 2 cases, L3, 4 in 5 cases, L4, 5 in 29 cases, and L5, S1 in 21 cases. The operative time, incision length, intraoperative blood loss, postoperative drainage volume, hospitalization times, fusion rate, and complications were observed. The effectiveness were evaluated through Oswestry disability index (ODI) and visual analogue score (VAS), and the operative outcomes were compared in different groups classified according to various pressures of the contrast medium and sensitivities to disc block after inducing consistent pain. RESULTS: The operation time, incision length, blood loss, postoperative drainage volume, and hospitalization times were (84.6 +/- 37.4) minutes, (3.4 +/- 0.6) cm, (132.5 +/- 23.2) mL, (58.7 +/- 21.4) mL, and (6.5 +/- 0.8) days, respectively. All patients were followed up 2 years and 2 months to 5 years and 4 months (mean, 3.2 years). At last follow-up, ODI and VAS scores were significantly improved when compared with preoperative scores (P < 0.05). The effectiveness according to ODI were excellent in 27 cases, good in 22 cases, fair in 6 cases, and poor in 2 cases, with an excellent and good rate of 86.0%. All patients acquired strong interbody fusion. At last follow-up according to ODI and VAS scores, better results were found in patients of low-pressure sensitive group and high-sensitive disc block group (P < 0.05). CONCLUSION: Minimally invasive TLIF combined with UPSF is reliable for DLBP with minimal surgical trauma, less paravertebral tissue injury, and fewer complications, but the indications for operation must be strictly followed. Patients being sensitive to low-pressure or high-sensitive to disc block can achieve better surgical results. PMID- 22506461 TI - [Early effectiveness of discover cervical artificial disc replacement in treatment of cervical spondylosis]. AB - OBJECTIVE: To investigate the early effectiveness of the Discover cervical artificial disc replacement in treating cervical spondylosis. METHODS: Qualified for the selective standard, 24 patients with cervical spondylosis were treated between March 2010 and March 2011. Of 24 patients, 13 patients underwent anterior cervical decompression and fusion (ACDF) (ACDF group, between March 2010 and September 2010) and 11 patients underwent Discover cervical artificial disc replacement (CADR group, between September 2010 and March 2011). There was no significant difference in gender, age, disease duration, lesions typing, and affected segments between 2 groups (P > 0.05). The operative time, blood loss, and complications were recorded. Japanese Orthopaedic Association (JOA) scores, Neck Disability Index (NDI) scores, and Odom's scores were used to evaluate the postoperative effectiveness. In CADR group, the cervical range of motion (ROM) in all directions, and prosthesis eccentricity were measured before and after operation. RESULTS: Symptoms disappeared and no complication occurred after operation in the patients of 2 groups. The patients were followed up 12 to 18 months (mean, 15.3 months) in ACDF group and 6 to 12 months (mean, 9.6 months) in CADR group. The NDI scores in CADR group were significantly higher than those in ACDF group at 1, 3, and 6 months (P < 0.05), but no significant difference was observed in JOA score improvement rate between 2 groups (P > 0.05). According to Odom's score at last follow-up, the results were excellent in 6 cases, good in 4 cases, and fair in 3 cases with an excellent and good rate of 76.92% in ACDF group, and were excellent in 9 cases, good in 1 case, and poor in 1 case with an excellent and good rate of 90.91% in CADR group, showing no significant difference (chi2 = 3.000, P = 0.223). The patients in CADR group had significant limit of cervical joint ROM in flexion and extension and right bending at 1 month (P < 0.05), but cervical joint ROM restored after 3 months. The ROMs of left bending at 3 months and 6 months were bigger than preoperative value (P < 0.05). Meanwhile, ROM in left bending were bigger than that in right bending in replaced segment and upper segment (P < 0.05), and the ROM difference between left bending and right bending in upper segment was 2 times higher than that in the replaced segment; a marked linear correlation (P < 0.05) existed between the ROM difference and prosthesis eccentricity, and prosthesis bias had bigger ROM in lateral bending. CONCLUSION: Discover cervical artificial disc replacement for treatment of cervical spondylosis can provide a good effectiveness and cervical postoperative movement function. As a new prosthesis, it has some merits such as simple operative steps and less complications. PMID- 22506462 TI - [Research progress of complications of expansive laminoplasty]. AB - OBJECTIVE: To review the progress in the research of complications after expansive laminoplasty such as axial symptom, kyphotic deformity, and segmental motor paralysis. METHODS: Recent articles about complications after expansive laminoplasty were reviewed, and comprehensive analysis was done. RESULTS: The pathogenesis of axial symptom, kyphotic deformity, and segmental motor paralysis has not yet fully been understood, but has brought new finding, such as the importance of the spinous process-ligament-muscle complex, C5 palsy theory, and the involvement of the spinal cord mechanism. CONCLUSION: The pathogenesis of axial symptom, kyphotic deformity, and segmental motor paralysis should be further investigated to prevent and treat the complications. PMID- 22506464 TI - [Effectiveness of multiple joint arthroplasty in treating lower limb joint disease]. AB - OBJECTIVE: To explore the effectiveness of multiple joint arthroplasty in treating lower limb joint disease. METHODS: Between January 2000 and December 2007, 5 patients with lower limb joint disease (three or more joints were involved) were treated with total hip and knee arthroplasty. There were 3 males and 2 females, aged from 27 to 59 years (mean, 41.8 years). Two patients had ankylosing spondylitis and 3 had rheumatoid arthritis, whose hip and knee joints were involved. Four patients lost the ability of walking preoperatively, 1 patient could only walk with crutch. The Harris score was 24 +/- 24 and the Hospital for Special Surgery (HSS) score was 28 +/- 15. All patients underwent multiple joint arthroplasty simultaneously (2 cases) or multiple-stage (3 cases). RESULTS: Wounds healed by first intention in all patients. In 1 patient who had dislocation of the hip after operation, manipulative reduction and immobilization with skin traction were given for 3 weeks, and no dislocation occurred; in 2 patients who had early sign of anemia, blood transfusion was given. All patients were followed up 46-140 months with an average of 75 months. The patients could walk normally, and had no difficulty in upstairs and downstairs. The stability of the hip and knee was good, and no joint infection or loosening occurred. The Harris score was 88 +/- 6 at last follow-up, showing significant difference when compared with the preoperative score (t = 8.16, P = 0.00); the HSS score was 86 +/- 6, showing significant difference when compared with the preoperative score (t = 13.96, P = 0.00). CONCLUSION: Multiple joint arthroplasty is an effective treatment method in patients with lower limb joint disease, which can significantly improve life quality of patients. PMID- 22506463 TI - [A method to avoid lengthening lower limbs after total hip arthroplasty in patients with congenital short femoral neck]. AB - OBJECTIVE: To investigate the method to avoid lengthening lower limbs after total hip arthroplasty in patients with congenital short femoral neck. METHODS: The clinical data were analyzed retrospectively from 38 patients undergoing unilateral total hip arthroplasty between April 2005 and December 2010. There were 26 males and 12 females, aged 45-78 years (mean, 62.3 years). Among these cases, there were 11 cases of avascular necrosis of the femoral head, 17 cases of hip osteoarthritis, and 10 cases of femoral neck fracture. Before operation, 29 cases had leg length discrepancy; and the shortened length of the legs was 10-24 mm with an average of 14.5 mm by clinical measurement, and was 11-25 mm with an average of 14.7 mm by X-ray film measurement. The Harris score before operation was 44.0 +/- 3.6. RESULTS: At 1 day after operation, 3 cases had legs lengthening by clinical and X-ray film measurement; limb length difference less than 10 mm was regarded as equal limb length in the other 35 patients (92.1%). All incisions healed by first intention, and no complication of infection or lower limb deep venous thrombosis occurred. In 3 patients who had legs lengthening, 1 patient had abnormal gait and slight limping after increasing heel pad because the lower limb was lengthened by 16 mm, and 2 patients had slight limping. The other patients could walk normally and achieved pain relief of hip. Thirty-six patients were followed up 12-68 months (mean, 43.8 months). The Harris score was 86.7 +/- 2.3 after 6 months, showing significant difference (t = 3.260, P = 0.031) when compared with that before operation. The X-ray films showed no prosthetic loosening or subsidence. CONCLUSION: For patients with congenital short femoral neck during total hip arthroplasty, the surgeons should pay attention to osteotomy plane determination, limb length measurement, and use of the prosthesis with collar to avoid the lengthening lower limbs. PMID- 22506465 TI - [Correlation analysis between residual displacement and hip function after reconstruction of acetabular fractures]. AB - OBJECTIVE: To investigate the relationships between residual displacement of weight-bearing and non weight-bearing zones (gap displacement and step displacement) and hip function by analyzing the CT images after reconstruction of acetabular fractures. METHODS: The CT measures and clinical outcome were retrospectively analyzed from 48 patients with displaced acetabular fracture between June 2004 and June 2009. All patients were treated by open reduction and internal fixation, and were followed up 24 to 72 months (mean, 36 months); all fractures healed after operation. The residual displacement involved the weight bearing zone in 30 cases (weight-bearing group), and involved the non weight bearing zone in 18 cases (non weight-bearing group). The clinical outcomes were evaluated by Merle d'Aubigne-Postel criteria, and the reduction of articular surface by CT images, including the maximums of two indexes (gap displacement and step displacement). All the data were analyzed in accordance with the Spearman rank correlation coefficient analysis. RESULTS: There was strong negative correlation between the hip function and the residual displacement values in weight-bearing group (r(s) = -0.722, P = 0.001). But there was no correlation between the hip function and the residual displacement values in non weight bearing group (r(s) = 0.481, P = 0.059). The results of clinical follow-up were similar to the correlation analysis results. In weight-bearing group, the hip function had strong negative correlation with step displacement (r(s) = 0.825, P = 0.002), but it had no correlation with gap displacement (r(s) = 0.577, P = 0.134). CONCLUSION: In patients with acetabular fracture, the hip function has correlation not only with the extent of the residual displacement but also with the location of the residual displacement, so the residual displacement of weight bearing zone is a key factor to affect the hip function. In patients with residual displacement in weight-bearing zone, the bigger the step displacement is, the worse the hip function is. PMID- 22506466 TI - [Diagnostic significance of "bay sign" of medial meniscus under arthroscope in medial collateral ligament rupture of knee]. AB - OBJECTIVE: When knee medial collateral ligament (MCL) rupture, the upper surface of medial meniscus is exposed totally, like the gulf panoramic, which is called "panoramic views of the bay sign" or the "bay sign". To investigate the reliability and significance of the "bay sign" in diagnosis of knee MCL rupture under arthroscope. METHODS: Between March 2007 and March 2011, 127 patients with knees injuries were divided into the observation group (n = 59) and control group (n = 68) based on the MRI results. In the observation group, 59 patients had MCL rupture by MRI, including 12 cases of MCL injury alone, 16 cases of MCL injury with lateral meniscus torn, 27 cases of MCL injury with anterior cruciate ligament (ACL) injury, 3 cases of MCL injury with ACL and posterior cruciate ligament (PCL) injury, and 1 case of MCL injury with patellar dislocation; there were 38 males and 21 females with an average age of 23.2 years (range, 16-39 years). In the control group, 68 patients had no MCL rupture by MRI, including 38 cases of ACL injury, 4 cases of ACL and PCL injury, and 26 cases of ACL and lateral meniscus injury; there were 45 males and 23 females with an average age of 31.8 years (range, 25-49 years). The "bay sign" was observed under arthroscope in 2 groups before and after operation. RESULTS: The positive "bay sign" was seen under arthroscope in the patients of the observation group before MCL repair; the "bay sign" disappeared after repair. No "bay sign" was seen in patients of the control group before and after ACL reconstruction. CONCLUSION: The "bay sign" is a reliable diagnostic evidence of MCL injury. It can be used as a basis to judge the success of MCL reconstruction during operation. PMID- 22506467 TI - [Correlation analysis between recurrent anterior shoulder dislocation and secondary intra-articular injuries]. AB - OBJECTIVE: To explore the effect of recurrent anterior shoulder dislocation on the secondary intra-articular injuries through analyzing the correlation between the number of dislocation, disease duration, and the secondary intraarticular injuries. METHODS: The clinical data were analyzed retrospectively from 59 patients with recurrent anterior shoulder dislocation who underwent arthroscopic Bankart reconstruction using suture anchor between January 2005 and June 2009. There were 48 males and 11 females, and the average age was 27.6 years (range, 15 42 years). The causes of first dislocation included contact sports (21 cases), non-contact sports (13 cases), daily activities (11 cases), and trauma (14 cases). The average number of preoperative dislocations was 10.6 times (range, 3 32 times). The time between first dislocation and surgery was 11 months to 12 years (median, 5.9 years). The results of apprehension test and relocation test were positive in all patients. The University of California Los Angeles (UCLA) score was 22.3 +/- 2.4, and Constant-Murley score was 73.1 +/- 5.8 preoperatively. According to the arthroscopic findings, the effect of recurrent anterior shoulder dislocation on the secondary intra-articular injuries was analyzed. RESULTS: All incisions healed by first intention, and no early complication occurred. All 59 patients were followed up 37.3 months on average (range, 16-58 months). At last follow-up, UCLA score was 34.6 +/- 1.7 and Constant-Murley score was 86.7 +/- 6.1, showing significant differences when compared with preoperative scores (P < 0.05). The number of preoperative dislocations was positively correlated with the severity of secondary articular cartilage injury (r(s) = 0.345, P = 0.007) and the severity of Hill-Sachs injury (r(s) = 0.708, P = 0.000). The time between first dislocation and surgery had a positive correlation with the severity of secondary articular cartilage injury (r(s) = 0.498, P = 0.000), but it had no correlation with the severity of Hill Sachs injury (r(s) = 0.021, P = 0.874). CONCLUSION: For patients with recurrent anterior shoulder dislocation, early Bankart reconstruction is benefit to functional recovery of shoulder and can avoid or delay the occurrence or development of secondary intra-articular injuries. PMID- 22506468 TI - [Effectiveness of pedicled sternocleidomastoid muscle flap in repairing defect after parotidectomy]. AB - OBJECTIVE: To investigate the effectiveness of pedicled sternocleidomastoid muscle flap in repairing defect after parotidectomy by comparing with direct suture. METHODS: The clinical data were retrospectively analyzed, which were from 73 patients with parotid tumor undergoing parotidectomy between January 2002 and April 2010. After parotidectomy, defects were repaired with pedicled sternocleidomastoid muscle flap in 38 cases (flap group) and with direct suture in 35 cases (control group). There was no significant difference in gender, age, disease duration, tumor location and size between 2 groups (P > 0.05). Meanwhile the complications, such as local intercession deformity, Frey's syndrome and parotid gland fistula were observed. RESULTS: In flap group, the flaps were all alive and incisions healed by first intention; in control group, all incisions healed by first intention. All patients were followed up 6-98 months and no tumor recurred. There was significant difference in local intercession deformity between 2 groups (chi2 = 53.202, P = 0.000). The parotid gland fistula was found in 1 case (2.6%) of the flap group and in 8 cases (22.8%) of the control group, Frey's syndrome was found 1 case (2.6%) of the flap group and in 20 cases (57.1%) of the control group, showing significant differences between 2 groups (P < 0.05). CONCLUSION: The use of pedicled sternocleidomastoid muscle flap for defect repair after parotidectomy can avoid the complications of local intercession deformity, Frey's syndrome, and parotid gland fistula. PMID- 22506469 TI - [Reverse anterolateral thigh flap for repair of wound defects with exposed tibia]. AB - OBJECTIVE: To investigate the method and effectiveness of reverse anterolateral thigh flap and muscle flap for repair of wound defects with exposed tibia in the proximal-middle leg. METHODS: Between October 2005 and April 2010, 16 patients with wound defects with exposed tibia in the proximal-middle leg were treated with reverse anterolateral thigh flap and muscle flap. There were 10 males and 6 females, aged from 16 to 52 years. Injury was caused by traffic accident in 11 cases and by crushing in 5 cases. The disease duration of 1-6 hours (mean, 3 hours) in 10 patients and 6-14 days (mean, 10 days) in 6 patients, who underwent tibial fracture plate fixation in other hospitals. The size of wound ranged from 13 cm x 7 cm to 20 cm x 13 cm. The size of the flap ranged from 16 cm x 10 cm to 23 cm x 15 cm. The donor sites were covered with splite thickness skin grafts. RESULTS: Infection occurred in 2 flaps at 5-7 days and was cured after 1 week of dressing change; the other flaps survived and the wounds healed by first intention. The incisions healed well and the skin grafts survived at the donor sites. All cases were followed up 10-23 months (mean, 18 months). The appearance of the flap was slightly overstaffed, but the color and texture were satisfactory. All fractures healed at 8-10 months after operation. CONCLUSION: It is effective to repair wound defects with exposed tibia in the proximal-middle leg with reverse anterolateral thigh flap and muscle flap. PMID- 22506470 TI - [Clinical application of modified upper gluteal rhomboid fasciocutaneous flap in repairing sacrococcygeal pressure sores]. AB - OBJECTIVE: To investigate the method and effectiveness of repairing sacrococcygeal pressure sores with modified upper gluteal rhomboid fasciocutaneous flap. METHODS: Between January 2004 and March 2011, 43 patients with sacrococcygeal pressure sores were treated. There were 25 males and 18 females with an average age of 63 years (range, 38-95 years). The disease duration was 3 months to 2 years and 6 months (mean, 8.5 months). The size of pressure sores ranged from 6 cm x 5 cm to 18 cm x 13 cm. According to the extent and lesion degree of pressure scores, 23 pressure sores were rated as degree III and 20 pressure sores as degree IV. The modified upper gluteal rhomboid flap was designed, one-side upper gluteal fasciocutaneous flaps were transplanted to repair sacrococcygeal pressure sores in 19 cases and two-side flaps in 24 cases. The size of one side flap ranged from 6.5 cm x 4.5 cm to 18.0 cm x 11.5 cm. RESULTS: Fluid under flap occurred in 1 case and edge necrosis of the flaps in 3 cases at 7 days after operation, which were cured after drainage and dressing change; the other flaps survived, and incisions healed by first intention. All patients were followed up 6 months to 3 years with an average of 11 months. Two patients relapsed at 5 months and 8 months, respectively; the other patients had no recurrence. The color of the flaps was normal, and the appearance and elasticity of the flaps were good. CONCLUSION: The modified upper gluteal rhomboid fasciocutaneous flap has the advantages of simple design and operation, less injury, and reliable effect in repairing sacrococcygeal pressure sores. PMID- 22506471 TI - [Effects of Angelica dahurica extracts on biological characteristics of human keratinocytes]. AB - OBJECTIVE: To observe the effects of Angelica dahurica extracts on the biological characteristics of human keratinocytes (KC) in vitro and to explore the possible mechanism in promoting wound healing. METHODS: HaCaT cells of passage 5 from KC were used during the experiment. Different concentrations (5 x 10(-2), 5 x 10( 3), 5 x 10(-4), and 5 x 10(-5) g/L) of Angelica dahurica extracts, which was obtained by 95% ethanol from Angelica dahurica raw material, were prepared by DMEM containing 0.25% fetal bovine serum (FBS). After the extracts at different concentrations were respectively used for KC culture for 5 days, the cell proliferation activities were detected by MTT, and DMEM containing 0.25% FBS served as the negative control. According to the cell proliferation activity, the optimal concentration was determined. KC was further treated with Angelica dahurica extracts of the optimal concentration (experimental group) or with DMEM containing 0.25% FBS (control group) for 48 hours. The cell cycle was tested by flow cytometry. Cyclin D1 and Caspase-3 mRNA levels were also detected by real time fluorescent quantitative PCR technique. RESULTS: Angelica dahurica extracts at concentrations of 5 x 10(-4), 5 x 10(-3), and 5 x 10(-2) g/L could significantly enhance KC proliferation, showing significant differences in absorbance (A) values compared with that of control group (P < 0.05) with an optimal concentration of 5 x 10(-3) g/L. At this concentration, an increased percentage of S and G2/M phase cells and a decreased percentage of G0/G1 phase cells were detected, showing significant differences when compared with control group (P < 0.05). Real-time fluorescent quantitative PCR revealed that the cyclin D1 and Caspase-3 mRNA levels of experimental group was significantly down regulated, showing significant differences when compared with control group (P < 0.05). CONCLUSION: Angelica dahurica extracts can promote the proliferation of KC, accelerate the cell cycle of KC by down-regulating mRNA expressions of cyclin D1, and inhibit apoptosis by down-regulating mRNA expressions of Caspase-3. These effects might enhance the process of wound healing by expediting the process of epithelization. PMID- 22506472 TI - [Effect of early dermatoplastic repair on testicular Survivin protein expression in juvenile pigs with entire third degree burn wound of scrotum]. AB - OBJECTIVE: To explore the effect of early scrotal dermatoplasty on spermatogenic functional rehabilitation of testis in juvenile pigs with third degree burn wound of the scrotum. METHODS: Thirty healthy male Guizhou miniature pigs (weighing 10 15 kg, 2-month-old) were divided into 3 groups: control group (group A, n = 10), natural healing group (group B, n = 10), and dermatoplasty group (group C, n = 10). In group A, the pig was not given any treatment; after third degree burn model of the scrotum was prepared, wounds were not treated in group B and the burn skin was excised and whole hypogastric pachydermia was used for dermatoplasty in group C. At 3 months and 1 year after model preparation, bilateral testis were collected from 5 pigs, respectively. HE staining was performed to observe the effects of different repair method on the morphology of spermatogenic cells and immunohistochemical staining was used to detect Survivin protein expression. RESULTS: All pigs survived to the end of the experiment and the wound healed successfully. Histological observation showed that spermatogenic cells had normal shape at all stages and mature sperms were seen in lumens in group A; the thickness of seminiferous epithelium was thinner, having one layer or two layers of spermatogenic cells in group B; the spermatogenic cells in group C were slightly more than that in group B with some spermatids; and in groups B and C, the spermatogenic cells at 1 year were more than that at 3 months. Immunohistochemistry staining showed that the Survivin protein expression in groups B and C was less than in group A, and group B was less than group C, showing significant differences at 3 months and 1 year (P < 0.05), but no significant difference between 3 months and 1 year in the same group (P > 0.05). CONCLUSION: Dermatoplasty has inhibitory effect on spermatogenic functional rehabilitation of testis. Dermatoplasty can decrease spermatogenic cells and reduce Survivin protein expression, but some spermatids still survive in seminiferous tubule. PMID- 22506473 TI - [Transforming growth factor beta1/Smad3 signal transduction pathway and post traumatic scar formation]. AB - OBJECTIVE: To summarize the recent progress in related research on transforming growth factor beta1 (TGF-beta1)/Smad3 signal transduction pathway and post traumatic scar formation. METHODS: Recent related literature at home and abroad on TGF-beta1/Smad3 signal transduction pathway and post-traumatic scar formation was reviewed and summarized. RESULTS: TGF-beta1 is an important influence factor of fibrotic diseases, and it plays biological effects by TGF-beta1/ Smad3 signal transduction pathway. The pathway is regulated by many factors and has crosstalk with other signal pathways at cellular and molecular levels. The pathway is involved in the early post-traumatic inflammatory response, wound healing, and late pathological scar formation. Intervening the transduction pathway at the molecular level can influence the process of fibrosis and extracellular matrix deposition. CONCLUSION: TGF-beta1/Smad3 signal transduction pathway is an important way to affect post-traumatic scar formation and extracellular matrix deposition. The further study on the pathway will provide a theoretical basis for promotion of wound healing, as well as prevention and treatment of pathological scar formation. PMID- 22506474 TI - [Influencing factor analysis of no-reflow phenomenon after reperfusion in patients with chronic limb ischemia associated with acute thrombosis]. AB - OBJECTIVE: To analyze the influencing factors of no-reflow phenomenon after reperfusion in patients with chronic limb ischemia associated with acute thrombosis. METHODS: Between January 2009 and December 2010, 59 patients (67 limbs) with chronic limb ischemia associated with acute thrombosis were treated. According to whether the no-reflow phenomenon occurred or not, the patients were divided into no-reflow group (19 patients, 21 limbs) and reflow group (40 patients, 46 limbs). Logistic regression was used to analyze the roles of ischemia time, ischemia extent, smoking, hypertension, cardiovascular and cerebrovascular disease, diabetes, surgical procedure, platelet count, fibrinogen (FBG), prostaglandin 12 (PGI2), and thromboxane A2 (TXA2) on no-reflow phenomenon after reperfusion. RESULTS: The results of the logistic regression analysis indicated that ischemia time (OR =7.196; 95%CI: 1.679-27.960), ischemia extent (OR = 5.116; 95% CI: 1.399-109.338), smoking (OR = 6.893; 95% CI: 3.704-2 291.003), diabetes (OR = 3.864; 95% CI: 1.009-421.702), PGI2 (OR = 7.985; 95% CI: 1.001-1.043), and TXA2 (OR = 7.643; 95% CI: 1.011-1.065) were the high risk factors of no-reflow phenomenon. The levels of TXA2 and FBG in no-reflow group were significantly increased and the level of PGI2 was decreased, showing significant differences when compared with the reflow group (P < 0.05). However, no significant difference was found in the platelet count between 2 groups (P > 0.05). CONCLUSION: Ischemia extent and ischemia time are the main influencing factors of no-reflow phenomenon after reperfusion in patients with chronic limb ischemia associated with acute thrombosis, and the patients combined with smoking or diabetes are high risk population of the no-reflow phenomenon. Postoperative patients with no-reflow phenomenon are at a hypercoagulable state in vivo, in which prostacyclin plays an important role. PMID- 22506475 TI - [Functional reconstruction of trapezius muscle through transpositional anastomosis of C4 anterior trunk and accessory nerve]. AB - OBJECTIVE: To investigate the feasibility of transpositional anastomosis of C4 anterior trunk and accessory nerve for functional reconstruction of the trapezius muscle so as to provide theoretical basis of repairing accessory nerve defects. METHODS: Thirty-six adult male Sprague-Dawley rats (weighing 200-250 g) were randomly divided into the experimental group (n = 18) and control group (n = 18). The transpositional anastomosis of C4 anterior trunk and accessory nerve was performed in the left sides of experimental group; the accessory nerve was transected in the left sides of control group; and the right sides of both groups were not treated as within-subject controls. The electrophysiological and histological changes of the trapezius muscle were measured. The values of the latencies and amplitudes of compound muscle action potential (CMAP) were recorded in the experimental group at 1, 2, and 3 months; the latency delaying rate, amplitude recovery rate, and restoration rate of muscular tension were calculated. The counts of myelinated nerve fibers from distal to the anastomotic site were analyzed. The transverse area of the trapezius muscle was also measured and analyzed in 2 groups. Meanwhile, the muscles and nerves were harvested for transmission electron microscope observation in the experimental group at 1 and 3 months. RESULTS: As time passed by, the experimental group showed increased amplitudes of CMAP, shortened latencies of CMAP, and improved muscular tension. At 3 months, the amplitude recovery rates were 63.61% +/- 9.29% in upper trapezius muscle and 73.13% +/- 11.85% in lower trapezius muscle; the latency delaying rates were 130.45% +/- 37.27% and 112.62% +/- 19.57%, respectively; and the restoration rate of muscular tension were 77.27% +/- 13.64% and 82.47% +/- 22.94%, respectively. The passing rate of myelinated nerve fibers was 82.55% +/- 5.00%. With the recovery of innervation, the transverse area of the trapezius muscle increased, showing significant differences between experimental group and control group at different time points (P < 0.05). The transmission electron microscope showed that the myotome arranged in disorder at 1 month and tended to order at 3 months. CONCLUSION: Transpositional anastomosis of C4 anterior trunk and the accessory nerve can effectively reconstruct the function of the trapezius muscle of rats. PMID- 22506476 TI - [Promoting effect of massage on quadriceps femoris repair of rabbit in vivo]. AB - OBJECTIVE: To investigate the effect of massage on quadriceps femoris repair and the expressions of Desmin and alpha-Actin in rabbits so as to explore the possible molecular mechanisms of massage in repair of muscle injury. METHODS: Twenty-seven New Zealand white rabbits, weighing (2.0 +/- 0.5) kg, were randomly divided into 3 groups: groups A (n = 3), B (n = 12), and C (n = 12). In group A, the rabbits were not treated as controls; in groups B and C, the rabbit models of quadriceps femoris injury were prepared by self-made beater. In group B, no massage therapy was given as nature recovery controls; in group C, RT-N2 intelligent massage device was used for massage therapy at 8 days after injury, at 3 000-3 100 r/min for 15 minutes, every day for 7 days or for 14 days. The quadriceps femoris specimens were taken from 6 rabbits of groups B and C at 14 days and 21 days, respectively. HE staining was employed to detect the histomorphological change. Immunohistochemistry staining and Western blot were used to detect Desmin and alpha-Actin expressions. The massage therapy effect was evaluated by the histomorphological change and Desmin and alpha-Actin expressions. RESULTS: All rabbits survived to the end of experiment in groups B and C. No histological change was found with regular order of muscle fibers and no connective tissue in group A; obvious tissue necrosis was seen with broken muscular fibers, muscle atrophy, and irregular order in group B; and in group C, the skeletal muscle morphology and muscle atrophy were obviously improved with regenerated muscle fibers when compared with group B. Immunohistochemistry staining showed that the Desmin and alpha-Actin expressions obviously reduced in groups B and C, which were significantly weaker than that in group A (P < 0.05); the Desmin and alpha-Actin expressions were significantly stronger in group C than in group B (P < 0.05), and at 21 days than at 14 days in group C (P < 0.05). Western blot results showed that the Desmin and alpha-Actin expressions were significantly higher in group A than in groups B and C (P < 0.05), and the expressions were lowest at 14 days in group B. CONCLUSION: The histomorphology and cytoskeletal structure can be significantly improved after massage, which may help to repair muscle injury by up-regulation of Desmin and alpha-Actin expressions. PMID- 22506477 TI - [Effects of exogenous prostaglandin E2 on collagen content of Achilles tendon of rabbits in vivo]. AB - OBJECTIVE: Prostaglandin E2 (PGE2) production increases in human tendon fibroblasts after the tendon injuries and repetitive mechanical loading in vitro. To analyze the relations between PGE2 and tendinopathy by observing the changes of collagen content and proportion after the Achilles tendon of rabbits is repeatedly exposed to PGE2. METHODS: Twenty-four Japanese rabbits (aged 3-4 months, weighing 2.0-2.5 kg, and male or female) were equally randomized into 2 groups according to injection dose of PGE2: low dose group (50 ng) and high dose group (500 ng). Corresponding PGE2 (0.2 mL) was injected into the middle segment of the Achilles tendon of hindlimb, the same dose saline into the same site of the other side as controls once a week for 4 weeks or 8 weeks. The Achilles tendons were harvested at 4 and 8 weeks after injection. HE staining was used to observe the cell structure and matrix, and picric acid-sirius red staining to observe the distribution and types of collagen fibers, and transmission electron microscopy was used to measure the density of the unit area and diameter of collagen fibers. RESULTS: HE staining showed that collagen structural damage was observed in low dose and high dose groups. Picric acid-sirius red staining showed that the content of type I collagen significantly decreased while the content of type III collagen significantly increased in experimental side of 2 groups at 4 and 8 weeks after injection when compared with control sides (P < 0.05). The content of type I collagen was significantly lower and the content of type III collagen and ratio of type III to type I were significantly higher in high dose group than in low dose group (P < 0.05). Transmission electron microscopy showed that the collagen fibers density of unit area was significantly lower and the diameter was significantly smaller in high dose and low dose groups than in the controls (P < 0.05), and in high dose group than in low dose group (P < 0.05). CONCLUSION: Repeat exposure of the Achilles tendon of rabbit to PGE2 can cause the decrease of type I collagen, the increase of type III collagen, the reverse ratio of type I to type III, reduced unit density of collagen fibers, and thinner collagen fibers diameter, which is related with tendinopathy. PMID- 22506478 TI - [In vivo study on tissue engineered skeletal muscle with hypoglossal nerve implantation]. AB - OBJECTIVE: To construct tissue engineered skeletal muscle in vivo using glial cell derived neurotrophic factor (GDNF) genetically modified myoblast (Mb) on acellular collagen sponge with hypoglossal nerve implantation, and to observe whether structural or functional connection could be established between engineered tissue and motor nerve or not. METHODS: Mbs were isolated from 7 male Lewis rats at age of 2 days, cultured and genetically modified by recombinant adenovirus carrying GDNF cDNA (Mb(GDNF)). Calf skin-derived acellular collagen sponge was used as scaffold; cell adhesion was detected by scanning electron microscope after 24 hours. Hypoglossal nerve was implanted into Mb-scaffold complex (Mb group, n = 27) or Mb(GDNF)-scaffold complex (Mb(GDNF) group, n = 27) in 54 female Lewis rats at age of 8 weeks. HE staining was performed at 1, 6, and 12 weeks postoperatively, and immunohistochemistry staining and fluorescence in situ hybridization were used. RESULTS: Mb(GDNF) could highly expressed GDNF gene. Mb and Mb(GDNF) could adhere to the scaffold and grew well. HE staining showed tight junctions between implant and peripheral tissue with new muscle fiber and no distinguished line at 12 weeks in 2 groups. Immunohistochemistry staining showed that positive cells of myogenin and slow skeletal myosin were detected, as well as positive cells of acetylcholine receptor alpha1 at 1, 6, and 12 weeks. The positive cells of Y chromosome decreased with time. At 1, 6, and 12 weeks, the positive neurons were 261.0 +/- 6.6, 227.3 +/- 8.5, and 173.3 +/- 9.1, respectively in Mb(GDNF) group, and were 234.7 +/- 5.5, 196.0 +/- 13.5, and 166.7 +/- 11.7, respectively in Mb group; significant differences were found between 2 groups at 1 and 6 weeks (P < 0.05), no significant difference at 12 weeks (P > 0.05). CONCLUSION: Connection can be established between engineered tissue and implanted hypoglossal nerve. Recombinant GDNF produced by Mb(GDNF) might play a critical role in protecting central motor neurons from apoptosis by means of retrograde transportation. PMID- 22506479 TI - [Acute hemolytic anemia after liver transplantation in one case]. AB - OBJECTIVE: To report 1 case of acute hemolytic anemia after liver transplantation because of ABO compatibility and therapeutic experience. METHODS: The patient with liver cancer underwent orthotopic piggyback liver transplantation on September 2010 after radiofrequency ablation of the tumors. The donor and recipient ABO blood types were type O and type A, separately. Acute hemolytic anemia occurred at 10 days after transplantation and hemoglobin decreased to 56 g/L. The bone marrow showed active hyperplasia; and myeloid : erythroid was 0.52 : 1. The immunosuppressants were used and type O washed red blood cells were transfused immediately. RESULTS: The general condition of the patient was improved; hemoglobin increased gradually and returned to 111 g/L at 34 days after liver transplantation. At 12 months of follow-up, hemoglobin was within normal range. CONCLUSION: Using graft blood type washed red blood cells transfusion and immunosuppressants could be an effective therapeutic procedure in the patient with ABO compatibility graft when acute hemolytic anemia occurs. PMID- 22506480 TI - [Basic and clinical research progress of lateral column lengthening]. AB - OBJECTIVE: To review the basic and clinical research progress of lateral column lengthening (LCL). METHODS: The recent literature concerning LCL at home and abroad was extensively reviewed, and the research and development were summarized. RESULTS: LCL is one of the important surgical procedures for flatfoot deformity, and it has two procedures. There are some disputes in surgical selection of the Evans osteotomy and calcaneocuboid distraction arthrodesis for the treatment of flatfoot deformity. CONCLUSION: Lateral column lengthening has been used more widely in clinical practice, but biomechanical and the long-term follow-up are needed. PMID- 22506482 TI - The BASES Expert Statement on exercise and cancer survivorship. AB - This statement provides a concise overview of the evidence on the benefits of staying active after a cancer diagnosis and the current guidelines for exercise prescription with this population. PMID- 22506481 TI - A novel alpha-conotoxin MII-sensitive nicotinic acetylcholine receptor modulates [(3) H]-GABA release in the superficial layers of the mouse superior colliculus. AB - Mouse superficial superior colliculus (SuSC) contains dense GABAergic innervation and diverse nicotinic acetylcholine receptor subtypes. Pharmacological and genetic approaches were used to investigate the subunit compositions of nicotinic acetylcholine receptors (nAChR) expressed on mouse SuSC GABAergic terminals. [(125) I]-Epibatidine competition-binding studies revealed that the alpha3beta2* and alpha6beta2* nicotinic subtype-selective peptide alpha-conotoxin MII-blocked binding to 40 +/- 5% of SuSC nAChRs. Acetylcholine-evoked [(3) H]-GABA release from SuSC crude synaptosomal preparations is calcium dependent, blocked by the voltage-sensitive calcium channel blocker, cadmium, and the nAChR antagonist mecamylamine, but is unaffected by muscarinic, glutamatergic, P2X and 5-HT3 receptor antagonists. Approximately 50% of nAChR-mediated SuSC [(3) H]-GABA release is inhibited by alpha-conotoxin MII. However, the highly alpha6beta2* subtype-selective alpha-conotoxin PIA did not affect [(3) H]-GABA release. Nicotinic subunit-null mutant mouse experiments revealed that ACh-stimulated SuSC [(3) H]-GABA release is entirely beta2 subunit-dependent. alpha4 subunit deletion decreased total function by >90%, and eliminated alpha-conotoxin MII-resistant release. ACh-stimulated SuSC [(3) H]-GABA release was unaffected by beta3, alpha5 or alpha6 nicotinic subunit deletions. Together, these data suggest that a significant proportion of mouse SuSC nicotinic agonist-evoked GABA-release is mediated by a novel, alpha-conotoxin MII-sensitive alpha3alpha4beta2 nAChR. The remaining alpha-conotoxin MII-resistant, nAChR agonist-evoked SuSC GABA release appears to be mediated via alpha4beta2* subtype nAChRs. PMID- 22506483 TI - Mental workload during brain-computer interface training. AB - It is not well understood how people perceive the difficulty of performing brain computer interface (BCI) tasks, which specific aspects of mental workload contribute the most, and whether there is a difference in perceived workload between participants who are able-bodied and disabled. This study evaluated mental workload using the NASA Task Load Index (TLX), a multi-dimensional rating procedure with six subscales: Mental Demands, Physical Demands, Temporal Demands, Performance, Effort, and Frustration. Able-bodied and motor disabled participants completed the survey after performing EEG-based BCI Fitts' law target acquisition and phrase spelling tasks. The NASA-TLX scores were similar for able-bodied and disabled participants. For example, overall workload scores (range 0-100) for 1D horizontal tasks were 48.5 (SD = 17.7) and 46.6 (SD 10.3), respectively. The TLX can be used to inform the design of BCIs that will have greater usability by evaluating subjective workload between BCI tasks, participant groups, and control modalities. PRACTITIONER SUMMARY: Mental workload of brain-computer interfaces (BCI) can be evaluated with the NASA Task Load Index (TLX). The TLX is an effective tool for comparing subjective workload between BCI tasks, participant groups (able-bodied and disabled), and control modalities. The data can inform the design of BCIs that will have greater usability. PMID- 22506484 TI - Structural modifications that alter the P-glycoprotein efflux properties of compounds. PMID- 22506485 TI - Uveitis and common variable immunodeficiency: data from the DEF-I study and literature review. AB - PURPOSE: To examine the relation between uveitis and common variable immunodeficiency (CVID). METHODS: Retrospective analysis of patients included in the French DEFI cohort of adults with CVID and of patients identified by reviewing the literature. RESULTS: Four patients were identified in the DEFI study (frequency of uveitis: 1.6%). The course of uveitis was not changed in the patients who started intravenous immunoglobulins replacement therapy after CVID diagnosis. Ten cases of CVID-associated uveitis were listed in the literature. Overall, among the 14 patients, uveitis was always chronic, usually bilateral (n = 11) and granulomatous (n = 9). Seven patients presented with a "sarcoid-likea syndrome. Nine patients had granulomatous uveitis suggestive of ocular sarcoidosis. Five patients were treated with local corticosteroids, and 9 required systemic treatment (corticosteroids alone n = 5 and/or immunosuppressive agents n = 4). CONCLUSIONS: CVID can be associated with uveitis. Since uveitis can reveal the immunodeficiency, CVID diagnosis should be considered at the time of uveitis diagnosis. PMID- 22506486 TI - Instantaneous and quantitative functionalization of gold nanoparticles with thiolated DNA using a pH-assisted and surfactant-free route. AB - The attachment of thiolated DNA to gold nanoparticles (AuNPs) has enabled many landmark works in nanobiotechnology. This conjugate chemistry is typically performed using a salt-aging protocol where, in the presence of an excess amount of DNA, NaCl is gradually added to increase DNA loading over 1-2 days. To functionalize large AuNPs, surfactants need to be used, which may generate difficulties for downstream biological applications. We report herein a novel method using a pH 3.0 citrate buffer to complete the attachment process in a few minutes. More importantly, it allows for quantitative DNA adsorption, eliminating the need to quantify the number of adsorbed DNA and allowing the adsorption of multiple DNAs with different sequences at predetermined ratios. The method has been tested for various DNAs over a wide range of AuNP sizes. Our work suggests a synergistic effect between pH and salt in DNA attachment and reveals the fundamental kinetics of AuNP aggregation versus DNA adsorption, providing a novel means to modulate the interactions between DNA and AuNPs. PMID- 22506487 TI - Direct evidence from electron paramagnetic resonance for additional configurations in uncommon paddlewheel Re2(7+) units surrounded by an unsymmetrical bicyclic guanidinate. AB - Three rare compounds have been synthesized and structurally characterized; these species have paddlewheel structures and Re(2)(7+) cores surrounded by four bicyclic guanidinates and two axial ligands along the Re-Re axis. Each possesses a formal bond order of 3.5 and a sigma(2)pi(4)delta(1) electronic configuration that entails the presence of one unpaired electron for each compound. The guanidinate ligands characterized by having CH(2) entities and a central C(N)(3) unit that joins two cyclic units--one having two fused 6-membered rings (hpp) and the other having a 5- and a 6-membered ring fused together (tbn)--allowed the isolation of [Re(2)(tbn)(4)Cl(2)]PF(6), 1, [Re(2)(tbn)(4)Cl(2)]Cl, 2, and [Re(2)(hpp)(4)(O(3)SCF(3))(2)](O(3)SCF(3)), 3. Because of the larger bite angle of the tbn relative to the hpp ligand, the Re-Re bond distances in 1 and 2 (2.2691(14) and 2.2589(14) A, respectively) are much longer than that in 3 (2.1804(8) A). Importantly, electron paramagnetic resonance (EPR) studies at both X-band (~9.4 GHz) and W-band (112 GHz) in the solid and in frozen solution show unusually low g-values (~1.75) and the absence of zero-field splitting, providing direct evidence for the presence of one metal-based unpaired electron for both 1 and 3. These spectroscopic data suggest that the unsymmetrical 5-/6-membered ligand leads to the formation of isomers, as shown by significantly broader EPR signals for 1 than for 3, even though both compounds possess what appears to be similar ideal crystallographic axial symmetry on the X-ray time scale. PMID- 22506489 TI - Nano structures of group 13-15 mixed heptamer clusters: a computational study. AB - The structural and thermodynamic characteristics of lowest-energy structures of group 13-15 mixed heptamers in two distinct series [(HM)(k)(HM')(l)(NH)(7)] (M, M' = B, Al, Ga and k + l = 7) and [(HGa)(7)(YH)(m)(Y'H)(n)] (Y,Y' = N, P, As and m + n = 7) have been systematically investigated using the density functional approach. Our main goal is to get knowledge of the preferential bonding patterns of the first three rows of group 13-15 elements for the construction of mixed heptameric clusters. Structural parameters, thermodynamic properties of oligomerization reaction, band gaps, and dipole moments of the 18 lowest-energy structures of the studied heptamers in each series are compared to their corresponding binary parents, that is, [(HM)(7)(NH)(7)] and [(HGa)(7)(YH)(7)]. The stability of different isomer structures is discussed to reveal the competitiveness of group 13 and 15 bonding. Mixed heptamers are predicted to be thermodynamically more stable compared to a mixture of monomers. However, the favorability for the generation of mixed heptamers strongly depends on the nature of inserted metal and nonmetal pairs of group 13-15. Moreover, it is found that among all studied heptamers the smaller band gaps correspond to arsenic containing species which are close to the semiconducting regime, around 4.62-4.98 eV. PMID- 22506488 TI - Cytogenetic analysis of 5572 patients referred for suspected chromosomal abnormalities in Morocco. AB - OBJECTIVES: The aim of this study was (1) to identify the profile of patients being referred for cytogenetic analysis in Morocco, (2) to determine the prevalence and type of chromosomal abnormalities in the different groups, (3) to compare the results with those of similar studies done in other countries. MATERIAL AND METHODS: 5572 patients ranging from newborns to 50 years of age were referred to the department of medical genetics, of the Moroccan National Institute of Health between 1993 and 2010, with a variety of clinical disorders such as mental retardation; multiple congenital malformations; clinical features of Down syndrome, Turner's syndrome, and Klinefelter syndrome; ambiguous sex; sterility; amenorrhea; recurrent miscarriage; and chromosome breakage syndromes. RESULTS: Of the 5572 cases studied, 4068 (73%) had a normal karyotype and 1504 (27%) had chromosomal abnormalities. Various types of chromosomal anomalies were found. The most common autosomal abnormalities were Down syndrome (1095 cases) and Turner's syndrome (122 cases) in abnormalities of sex chromosomes. CONCLUSION: This study compares the results of cytogenetic analysis of chromosomal abnormalities in the Moroccan population with other countries and research centers. This comparison will help Moroccan clinicians to determine the priority for requesting a cytogenetic analysis in individual cases. PMID- 22506490 TI - Antipsychotic polypharmacy: never say never, but never say always. PMID- 22506492 TI - Perceived chewing ability and need for long-term care in the elderly: a 5-year follow-up study. AB - Increasing need for long-term care in older adults is expected with the ageing of Japan's population. The aim of the present study was to show the relationship between perceived chewing ability and long-term care needs for over 5 years in elderly persons. The chewing ability of 812 elderly persons living independently was evaluated at baseline using self-assessed masticatory ability, and it was classified into one of three categories: ability to chew all foods (good masticatory ability), ability to chew only slightly hard food (fair masticatory ability), and ability to only chew soft or pureed food (poor masticatory ability). Participants' care needs were then followed through Japan's long-term care insurance system for over 5 years. The log-rank test and Cox proportional hazard model were used to examine statistical differences in the frequency of care-needs certification between participants with good and fair or poor masticatory ability. Among participants aged 65-79 years, the frequency of care needs certification was significantly higher in those with fair or poor masticatory ability than in those with good masticatory ability, and the relative hazard ratio was significantly higher in those with fair or poor masticatory ability than in those with good masticatory ability, after adjusting for age, gender, current employment status, educational background, social interaction, chronic medical conditions and dentition status. These relationships were not found among those aged 80-93 years. Impairment in perceived chewing ability may be associated with higher incidence of certification in Japan's long-term care insurance system among elderly persons aged 65-79. PMID- 22506493 TI - Assessing compressibility and compactibility of powder formulations with Near Infrared Spectroscopy. AB - CONTEXT: The compressibility and compatibility of a powder formulation is usually determined by compaction and following destructive tensile strength and relative density measurement of the final compact. OBJECTIVE: In this study, a non destructive method with Near-Infrared Spectroscopy (NIRS) was designed and evaluated for the measurement of powder compressibility and compactibility. MATERIALS AND METHODS: 12 different formulations with a wide range of difference in properties were investigated by compaction and analysis of the resulting tablets. Two similar tablet batches were produced with every formulation. Relative density and tensile strength were measured with the traditional, destructive method on one tablet batch while a newly developed non-destructive chemometric NIRS method was applied for the second batch. The outcomes of the two approaches were compared to validate the developed method. All data sets were applied to three established mathematical equations to calculate equation factors, which are claimed to represent the formulation compressibility and compactibility. The study focus was set on the equation factor value comparison between the traditional and the newly designed method. RESULTS & DISCUSSION: The results showed a high similarity between the outcomes of the two methods. An essential difference was noticed for the outcomes of the equation factors after application to the Leuenberger equation. CONCLUSION: The approach with the NIRS is suggested as a promising tool for a reliable inline quality monitoring in the tablet manufacturing process. PMID- 22506494 TI - Selection of hereditary transthyretin amyloid patients for liver transplantation: the Swedish experience. AB - Liver transplantation (LTx) is currently an accepted treatment for hereditary transthyretin amyloidosis (h-ATTR). However, to optimize the outcome, careful selection of patients is required, since increased mortality compared with that found for nontransplanted historical controls are observed for several groups of h-ATTR patients. We have noted that malnourished patients and patients with a late onset of the disease especially in combination with findings of cardiomyopathy are at risk for an increased mortality and morbidity. Recently detection of different types of amyloid fibrils that appears to be related to the phenotype of the patient may facilitate patient selection for LTx. PMID- 22506495 TI - Modified Shapiro reactions with bismesitylmagnesium as an efficient base reagent. AB - Bismesitylmagnesium has been shown to successfully mediate the Shapiro reaction. A range of tosylhydrazones has been subjected to the developed system, which furnishes exceptionally high incorporation of the introduced electrophiles and good yields of the functionalized styrenes. At conveniently accessible temperatures and with a comparably small excess of base reagent, this protocol offers an efficient alternative to the lithium-mediated process. Importantly, 1.05 equiv of Weinreb amides are sufficient to obtain aryl enones in good yields. PMID- 22506496 TI - Experimental and theoretical studies on the binding of epigallocatechin gallate to purified porcine gastric mucin. AB - Binding of epigallocatechin gallate (EGCG) to highly purified short side-chain porcine gastric mucin similar to human MUC6 type has been studied by ultraviolet visible absorption spectroscopy (UV-vis), ultrafiltration isothermal titration microcalorimetry (ITC) and transmission electron microscopy (TEM). The thermodynamic equilibrium of EGCG binding to mucin has been quantitatively determined using ultrafiltration and high-performance liquid chromatography (HPLC)-UV/vis. The relationship suggests multilayer binding rather than simple Langmuir monolayer binding of EGCG. By combining the ultrafiltration and ITC data, the thermodynamic parameters of EGCG binding to mucin have been obtained. The binding constant for the first layer is about an order of magnitude higher than that of the consecutive multilayers. Negative entropy indicates multilayer of EGCG formed. Hydrogen bonding may be responsible for the multilayer formation. Increasing temperature resulted in a decrease in the binding affinity, further suggesting that hydrogen bonds dominated the interaction energy. A TEM micrograph of the EGCG-mucin complex revealed a monodispersion of blobs similar to pure mucin solution but with relatively bigger size (about twice). It is proposed that the EGCG-mucin binding process occurs by single and/or cluster of EGCG molecules driven to the surface of the two hydrophobic globules of mucin by hydrophobic interaction followed by hydrogen bond interaction between EGCG and mucin. Further adsorption of EGCG molecules onto bound EGCG molecules to form multilayers can also occur. This fits well with the observations that EGCG-mucin interaction followed a multilayer adsorption isotherm, the energy released is dominated by hydrogen bonds, and no large aggregates were formed. PMID- 22506497 TI - Sequential effects in facial expression categorization. AB - Facial expressions are highly dynamic signals that are rarely categorized as static, isolated displays. However, the role of sequential context in facial expression categorization is poorly understood. This study examines the fine temporal structure of expression-based categorization on a trial-to-trial basis as participants categorized a sequence of facial expressions. The results showed that the local sequential context provided by preceding facial expressions could bias the categorical judgments of current facial expressions. Two types of categorization biases were found: (a) Assimilation effects-current expressions were categorized as close to the category of the preceding expressions, and (b) contrast effects-current expressions were categorized as away from the category of the preceding expressions. The effects of such categorization biases were modulated by the relative distance between the preceding and current expressions, as well as by the different experimental contexts, possibly including the factors of face identity and the range effect. Thus, the present study suggests that facial expression categorization is not a static process. Rather, the temporal relation between the preceding and current expressions could inform categorization, revealing a more dynamic and adaptive aspect of facial expression processing. PMID- 22506498 TI - Meditation and the startle response: a case study. AB - The effects of two kinds of meditation (open presence and focused) on the facial and physiological aspects of the defensive response to an aversive startle stimulus were studied in a Buddhist monk with approximately 40 years of meditation experience. The participant was exposed to a 115-db, 100-ms acoustic startle stimulus under the 2 meditation conditions, a distraction condition (to control for cognitive and attentional load) and an unanticipated condition (startle presented without warning or instruction). A completely counterbalanced 24-trial, single-subject design was used, with each condition repeated 6 times. Most aspects of the participant's responses in the unanticipated condition did not differ from those of a comparison group of 12 age-matched male controls. Both kinds of meditation produced physiological and facial responses to the startle that were smaller than in the distraction condition. Within meditation conditions, open presence meditation produced smaller physiological and facial responses than focused meditation. These results from a single highly expert meditator indicate that these 2 kinds of meditation can differentially alter the magnitude of a primitive defensive response. PMID- 22506499 TI - What emotion does the "facial expression of disgust" express? AB - The emotion attributed to the prototypical "facial expression of disgust" (a nose scrunch) depended on what facial expressions preceded it. In two studies, the majority of 120 children (5-14 years) and 135 adults (16-58 years) judged the nose scrunch as expressing disgust when the preceding set included an anger scowl, but as angry when the anger scowl was omitted. An even greater proportion of observers judged the nose scrunch as angry when the preceding set also included a facial expression of someone about to be sick. The emotion attributed to the nose scrunch therefore varies with experimental context. PMID- 22506500 TI - Cross-cultural generality and specificity in self-regulation: avoidance personal goals and multiple aspects of well-being in the United States and Japan. AB - The authors examined avoidance personal goals as concurrent (Study 1) and longitudinal (Study 2) predictors of multiple aspects of well-being in the United States and Japan. In both studies, participants adopted more avoidance personal goals in Japan relative to the United States. Both studies also demonstrated that avoidance personal goals were significant negative predictors of the most relevant aspects of well-being in each culture. Specifically, avoidance personal goals were negative predictors of intrapersonal and eudaimonic well-being in the United States and were negative predictors of interpersonal and eudaimonic well being in Japan. The findings clarify and extend puzzling findings from prior empirical work in this area, and raise provocative possibilities about the nature of avoidance goal pursuit. PMID- 22506501 TI - Out of sight but not out of mind: unseen affective faces influence evaluations and social impressions. AB - Using Continuous Flash Suppression (CFS), we demonstrated in four experiments that affective information extracted from unseen faces influences both affective and personality judgments of neutral faces. In four experiments, participants judged neutral faces as more pleasant or unpleasant (Studies 1 and 2) or as more or less trustworthy, likable, and attractive (Study 3) or as more or less competent or interpersonally warm (Study 4) when paired with unseen smiling or scowling faces compared to when paired with unseen neutral faces. These findings suggest that affective influences are a normal part of everyday experience and provide evidence for the affective foundations consciousness. Affective misattribution arises even when affective changes occur after a neutral stimulus is presented, demonstrating that these affective influences cannot be explained as a simple semantic priming effect. These findings have implications for understanding the constructive nature of experience, as well as the role of affect in social impressions. PMID- 22506502 TI - Isolation and characterization of wide host range lytic bacteriophage AP22 infecting Acinetobacter baumannii. AB - Acinetobacter baumannii plays a significant role in infecting patients admitted to hospitals. Many A. baumannii infections, including ventilation-associated pneumonia, wound, and bloodstream infections, are common for intensive care and burn units. The ability of the microorganism to acquire resistance to many antibiotics, disinfectants, and dehydration assures its long-term survival in hospital settings. The application of bacteriophages is a potential tool to control A. baumannii infections. Bacteriophage AP22 lytic for A. baumannii was isolated from clinical materials and classified as a member of the Myoviridae family. The phage had an icosahedral head of 64 nm in diameter and a contractile tail of 85-90 nm in length. According to restriction analysis, AP22 had 46-kb double-stranded DNA genome. The phage AP22 exhibited rapid adsorption (> 99% adsorbed in 5 min), a large burst size (240 PFU per cell), and stability to the wide range of pH. The bacteriophage was shown to specifically infect and lyse 68% (89 of 130) genotype-varying multidrug-resistant clinical A. baumannii strains by forming clear zones. Thus, it could be used as a candidate for making up phage cocktails to control A. baumannii-associated nosocomial infections. PMID- 22506503 TI - Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B. AB - BACKGROUND: Adefovir and tenofovir are nucleotide analogues used as long-term therapy of chronic hepatitis B. Side effects are few, but prolonged and high-dose therapy has been associated with proximal renal tubular dysfunction (RTD). AIM: To assess the incidence of RTD during long-term nucleotide therapy of chronic hepatitis B. METHODS: A total of 51 patients being treated at the Clinical Center, National Institutes of Health were studied. Diagnosis of RTD required de novo appearance of at least three of five features: hypophosphataemia, hypouricaemia, serum creatinine elevation, proteinuria or glucosuria. RESULTS: Among 51 patients treated for 1-10 (mean 7.4) years with adefovir (n = 42), tenofovir (n = 4) or adefovir followed by tenofovir (n = 5), 7 (14%) developed RTD. Time to onset ranged from 22 to 94 (mean 49) months with an estimated 10 year cumulative rate of 15%. All seven had low urinary percent maximal tubular reabsorption of phosphate (<82%). Patients with RTD were older (58 vs. 44 years; P = 0.01) and had lower baseline glomerular filtration rates (82 vs. 97 cc/min; P = 0.08) compared to those without; but did not differ in other features. Six patients with RTD were switched to entecavir, all subsequently had improvements in serum phosphate (2.0-3.0 mg/dL), creatinine (1.6-1.1 mg/dL), uric acid (2.7 3.8 mg/dL) and proteinuria. CONCLUSIONS: Renal tubular dysfunction develops in 15% of patients treated with adefovir or tenofovir for 2-9 years and is partially reversible with change to other antivirals. Monitoring for serum phosphate, creatinine and urinalysis is prudent during long-term adefovir and tenofovir therapy. PMID- 22506504 TI - Using the UKROC dataset to make the case for resources to improve cost-efficiency in neurological rehabilitation. AB - PURPOSE: A key challenge for providers and commissioners of rehabilitation services is to find optimal balance between service costs and outcomes. This article presents a "real-life" application of the UK Rehabilitation Outcomes Collaborative (UKROC) dataset. We undertook a comparative cohort analysis of case episode data (n = 173) from two specialist neurological rehabilitation units (A and B), to compare the cost-efficiency of two service models. KEY MESSAGES: (i) Demographics, casemix and levels of functional dependency on admission and discharge were broadly similar for the two units. (ii) The mean length of stay for Unit A was 1.5 times longer than Unit B, which had 85% higher levels of therapy staffing in relation to occupied bed days so despite higher bed-day costs, Unit B was 20% more cost-efficient overall, for similar gain. (iii) Following analysis, engagement with service commissioners led to successful negotiation of a business plan for service reconfiguration with increased staffing levels for Unit A and further development of local community rehabilitation services. CONCLUSION: (i) Lower front-end service costs do not always signify optimal cost-efficiency. (ii) Analysis of routinely collected clinical data can be used to engage commissioners and to make the case for resources to maximise efficiency and improve patient care. PMID- 22506505 TI - Combinatorics of the breakage-fusion-bridge mechanism. AB - The breakage-fusion-bridge (BFB) mechanism was proposed over seven decades ago and is a source of genomic variability and gene amplification in cancer. Here we formally model and analyze the BFB mechanism, to our knowledge the first time this has been undertaken. We show that BFB can be modeled as successive inverted prefix duplications of a string. Using this model, we show that BFB can achieve a surprisingly broad range of amplification patterns. We find that a sequence of BFB operations can be found that nearly fits most patterns of copy number increases along a chromosome. We conclude that this limits the usefulness of methods like array CGH for detecting BFB. PMID- 22506506 TI - Rapid transformation from spherical nanoparticles, nanorods, cubes, or bipyramids to triangular prisms of silver with PVP, citrate, and H2O2. AB - Rapid sphere-to-prism (STP) transformation of silver was studied in aqueous AgNO(3)/NaBH(4)/polyvinylpyrrolidone (PVP)/trisodium citrate (Na(3)CA)/H(2)O(2) solutions by monitoring time-dependent surface plasmon resonance (SPR) bands in the UV-vis region, by examining transmission electron microscopic (TEM) images, and by analyzing emitted gases during fast reaction. Roles of PVP, Na(3)CA, and H(2)O(2) were studied without addition of a reagent, with different timing of each reagent's addition, and with addition of H(2)O(2) to mixtures of spheres and prisms. Results show that prisms can be prepared without addition of PVP, although it is useful to synthesize smaller monodispersed prisms. A new important role of citrate found in this study, besides a known role as a protecting agent of {111} facets of plates, is an assistive agent for shape-selective oxidative etching of Ag nanoparticles by H(2)O(2). The covering of Ag nanoparticles with carboxylate groups is necessary to initiate rapid STP transformation by premixing citrate before H(2)O(2) addition. Based on our data, rapid prism formation starts from the consumption of spherical Ag particles because of shape-selective oxidative etching by H(2)O(2). Oxidative etching of spherical particles by H(2)O(2) is faster than that of prisms. Therefore, spherical particles are selectively etched and dissolved, leaving only seeds of prisms to grow into triangular prisms. When pentagonal Ag nanorods and a mixture of cubes and bipyramids were used as sources of prisms, rod-to-prism (RTP), cube-to-prism (CTP), and bipyramid-to-prism (BTP) transformations were observed in Ag nanocrystals/NaBH(4)/PVP/Na(3)CA/H(2)O(2) solutions. Shape-selective oxidative etching of rods was confirmed using flag-type Ag nanostructures consisting of a triangular plate and a side rod. These data provide useful information for the size-controlled synthesis of triangular Ag prisms, from various Ag nanostructures and using a chemical reduction method, having surface plasmon resonance (SPR) bands at a desired wavelength. PMID- 22506508 TI - Acute coenurosis of dairy sheep from 11 flocks in Greece. AB - CASE HISTORY: A syndrome of acute neurological dysfunction with increased mortality was observed in lambs of 10 dairy sheep flocks and adult animals in one flock in Central and Northern Greece. Each farmer completed a questionnaire regarding the management and feeding of their flocks. In seven of the 11 flocks the affected animals were grazing pasture, while in the remaining four flocks (5, 8, 9, 10) the animals were fed alfalfa hay (Medicago sativa) and concentrates indoors. A follow-up study of the affected flocks was conducted during the next 12 months. CLINICAL FINDINGS: Of 42 sheep with acute coenurosis that were examined, the most prominent neurological abnormalities were ataxia, depression, blindness, scoliosis, coma and dysmetria. Except for the four sheep that were comatose, all other animals had normal body temperatures and their appetites remained normal or were slightly decreased. Haematological findings of 15 examined sheep were within normal limits. The affected sheep were subject to euthanasia. A histopathological examination was performed in 13 cases. Faecal samples from dogs associated with these flocks were negative for taeniid infections. During the following 12 months cases of chronic coenurosis in these flocks were observed. PATHOLOGICAL FINDINGS: In the 42 animals that were necropsied, the main gross findings were cystic formations between 0.5-1 cm in diameter with translucent walls that were seen lying free on the leptomeninges or partly penetrating the brain tissue, sterile microabscecess and brain necrosis. Histopathological evaluation of tissue sections of 13 brains showed multifocal purulent or pyogranulomatous meningoencephalitis, accompanied by eosinophilic infiltrations. No bacteria were isolated following bacterial culture of brain tissue Parasitological examination of the cysts from five cases revealed whitish specks on the transparent cyst wall and germination membrane representing the scolices. DIAGNOSIS: Acute coenurosis was diagnosed in all cases studied. CLINICAL RELEVANCE: Acute coenurosis can be one of the causes of acute encephalopathy mainly in lambs, but also in adult sheep. This condition is incurable, but can be controlled by changing the feeding regime. Cases of chronic coenurosis may be seen a few months later in the same flock. PMID- 22506509 TI - Anything goes: discontinuation of hormone therapy. PMID- 22506510 TI - Evaluation and outcome of antenatal hydronephrosis: a prospective study. AB - Antenatal hydronephrosis (AHN), defined as dilatation of renal pelvis and/or calyces, is the most frequently detected antenatal abnormality. However, postnatal management of AHN is controversial. The purpose of this study was to describe the clinical outcomes of infants with AHN and to contribute to the definition of the postnatal evaluation of these patients. One hundred and thirty six infants with AHN were prospectively followed up to 18 months. Patients were divided into two groups according to the degree of sonographic hydronephrosis (HN) on days 5-7: group I (n = 87, 64%) included patients who had grades 1 and 2 (64%) and group II (n = 49, 36%) included patients who had grade 3 and above HN. The grade of HN was found to be correlated with the increased risk of urologic pathologies. Frequency of vesicoureteral reflux was found to be significantly lower in patients with mild HN (6%) as compared to patients with severe AHN (29%) (p = 0.005). In addition, the risk of urinary tract infection increases with increasing grades of HN (10% vs. 29%, p = 0.006). The frequency of spontaneous resolution in patients with mild AHN (64%) was also significantly higher than in patients with severe HN (29%) (p < 0.001). The degree of AHN can be used for making decision about further diagnostic imaging and treatment. Our results strongly suggest that low-grade HN is a relatively self-limited condition and needs minimal investigation. In contrast, the outcome of more severe degrees of AHN needs clarification. PMID- 22506507 TI - RAGE: a new frontier in chronic airways disease. AB - Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand-RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions. PMID- 22506511 TI - Cord blood intestinal fatty acid-binding protein (I-FABP) in full-term intrauterine growth restricted pregnancies. AB - OBJECTIVE: To prospectively investigate cord blood concentrations of intestinal fatty acid-binding protein-[I-FABP, a useful marker in the early detection of necrotizing enterocolitis-(NEC)] in full-term intrauterine-growth-restricted (IUGR, associated with NEC, regardless of gestational age) and appropriate-for gestational-age-(AGA) pregnancies. We also aimed to determine cord blood I-FABP concentrations in IUGR cases with abnormal versus normal antenatal Doppler results and investigate a possible association with feeding intolerance or NEC. METHODS: I-FABP concentrations were determined by ELISA in 154 mixed arteriovenous cord blood samples from IUGR (n = 50) and AGA (n = 104) singleton full-term infants. RESULTS: Cord blood I-FABP concentrations did not differ between IUGR and AGA groups, as well as between IUGR infants with normal versus abnormal(however, lacking absent/ reversed end-diastolic umbilical artery flow) antenatal Doppler results. No infant presented with feeding intolerance or NEC. Customized centiles were lower in IUGR infants with abnormal versus normal antenatal Doppler results (p < 0.001). CONCLUSIONS: Full-term IUGR infants present with normal cord blood I-FABP concentrations and do not seem to be at higher risk for developing feeding intolerance or NEC, including those with compromised fetal perfusion. PMID- 22506512 TI - Long-term skeletal stability after maxillary advancement with distraction osteogenesis in cleft lip and palate patients. AB - OBJECTIVE: To systematically review the long-term skeletal stability after maxillary advancement with distraction osteogenesis (DO) in cleft lip and palate (CLP) patients. MATERIALS AND METHODS: Electronic databases, grey literature, and reference list searches were conducted. The inclusion criteria were stability of maxillary advancement with distraction osteogenesis assessed at the posttreatment follow-up >= 1 year in CLP patients. Full articles were retrieved from abstracts or titles that appear to meet the inclusion criteria or lacked sufficient detail for immediate exclusion. Once full articles were collected, they were again reviewed considering more detailed inclusion criteria for a final selection decision. A methodologic quality assessment tool was utilized. RESULTS: Thirty abstracts/titles met the initial search criteria, and 13 articles were finally selected. Overall, methodologic quality scores were high in only one randomized clinical trial. After maxillary advancement with DO in CLP patients, the long term horizontal relapse in A-point was less than 15% in eight studies and between 20% and 25% in four studies. The study that was judged as a high-quality study reported 8.2% horizontal relapse in A-point. The relapse rate was higher in DO with external distracter device than DO with internal distracter device. CONCLUSIONS: Current evidence suggests maxillary advancement with DO has good stability in CLP patients with moderate and severe maxillary hypoplasia. PMID- 22506513 TI - Comparison of the effects of surface treatments on roughness of two ceramic systems. AB - OBJECTIVE: The aim of this study was to evaluate the effects of different surface treatments on the surface roughness of lithium disilicate-based core (IPS Empress 2, shade 210, Ivoclar Vivadent, Schaan, Liechtenstein) and feldspathic ceramics (Vita VM9, VITA Zahnfabrik H. Rauter GmbH & Co. KG, Bad Sackingen, Germany). BACKGROUND DATA: Er:YAG laser irradiation is expected to be an alternative surface treatment, thus enhances surface roughness of procelains and produces morphological changes. METHODS: Fifty lithium disilicate-based core ceramic discs and 50 feldspathic ceramic discs were prepared (diameter, 10 mm; thickness, 1 mm) according to the manufacturers' instructions. All-ceramic discs were polished to standardize, and surface roughness of the discs was evaluated before treatment and serving as controls. Both of two ceramic groups were divided into five groups (n=10), and the following treatments were applied: (1) sandblasting with aluminum oxide (Al(2)O(3); Group SB); (2) Al(2)O(3)+Er:YAG laser (Group SB-L); (3) Er:YAG laser irradiation (distance, 1 mm; 500 mJ; 20 Hz; 10W; manually, contact handpiece [R 14]) (Group L); (4) 5% hydrofluoric acid etching (Group HF); and (5) Er:YAG laser +5% hydrofluoric acid (Group HF-L). Surface roughness was evaluated by profilometry, and specimens were then examined with atomic force microscopy. RESULTS: Data were analyzed by Wilcoxon signed rank, Mann-Whitney U, and Kruskal Wallis tests (alpha=0.05). The Wilcoxon signed rank test results indicated that surface roughness after sandblasting was significantly different from the surface roughness after laser irradiation and acid etching (p<0.001). Mann-Whitney U and Kruskal-Wallis test results indicated that groups SB and SB-L had significantly higher mean roughness values (p<0.05) than those in the other groups. CONCLUSIONS: Groups SB and SB-L had rougher surfaces than the groups subjected to the other surface treatment methods. There was no significant difference in surface roughness between the HF acid etching, Er:YAG laser irradiation, and HF and Er:YAG (p<0 .05). PMID- 22506514 TI - Measuring CREB activation using bioluminescent probes that detect KID-KIX interaction in living cells. AB - The cyclic adenosine monophosphate response element-binding protein (CREB) is a transcription factor that contributes to memory formation. The transcriptional activity of CREB is induced by its phosphorylation at Ser-133 and subsequent interaction with the CREB-binding protein (CBP)/p300. We designed and optimized firefly split luciferase probe proteins that detect the interaction of the kinase inducible domain (KID) of CREB and the KIX domain of CBP/p300. The increase in the light intensity of the probe proteins results from the phosphorylation of the responsible serine corresponding to Ser-133 of CREB. Because these proteins have a high signal-to-noise ratio and are nontoxic, it has become possible for the first time to carry out long-term measurement of KID-KIX interaction in living cells. Furthermore, we examined the usefulness of the probe proteins for future high-throughput cell-based drug screening and found several herbal extracts that activated CREB. PMID- 22506515 TI - Systematic review: acute liver failure - one disease, more than 40 definitions. AB - BACKGROUND: Acute liver failure (ALF) is a clinical syndrome with very high mortality estimates ranging between 60% and 80%. AIM: To investigate the explicitness and extent of variability in the used ALF definitions in the ALF prognostic literature. METHODS: All studies that pertain to the prognosis of patients with ALF were electronically searched in MEDLINE (1950-2012) and EMBASE (1950-2012). Identified titles and abstracts were independently screened by three reviewers to determine eligibility for additional review. We included English articles that reported original data from clinical trials or observational studies on ALF patients. RESULTS: A total of 103 studies were included. Of these studies 87 used 41 different ALF definitions and the remaining 16 studies did not report any explicit ALF definition. Four components underlying ALF definitions accounted for the differences: presence and/or grading of hepatic encephalopathy (HE); the interval between onset of disease and occurrence of HE; presence of coagulopathy and pre-existing liver disease. CONCLUSIONS: The diversity in acute liver failure definitions hinders comparability and quantitative analysis among studies. There is room for improvement in the reporting of acute liver failure definitions in prognostic studies. The result of this review may be useful as a starting point to create a uniform acute liver failure definition. PMID- 22506516 TI - Discovery of novel allosteric mitogen-activated protein kinase kinase (MEK) 1,2 inhibitors possessing bidentate Ser212 interactions. AB - Using structure-based design, two novel series of highly potent biaryl amine mitogen-activated protein kinase kinase (MEK) inhibitors have been discovered. These series contain an H-bond acceptor, in a shifted position compared with previously disclosed compounds, and an adjacent H-bond donor, resulting in a bidentate interaction with the Ser212 residue of MEK1. The most potent compound identified, 1 (G-894), is orally active in in vivo pharmacodynamic and tumor xenograft models. PMID- 22506517 TI - Developmental relationships as the active ingredient: a unifying working hypothesis of "what works" across intervention settings. AB - Developmental relationships are characterized by reciprocal human interactions that embody an enduring emotional attachment, progressively more complex patterns of joint activity, and a balance of power that gradually shifts from the developed person in favor of the developing person. The working hypothesis of this article is that developmental relationships constitute the active ingredient of effective interventions serving at-risk children and youth across settings. In the absence of developmental relationships, other intervention elements yield diminished or minimal returns. Scaled-up programs and policies serving children and youth often fall short of their potential impact when their designs or implementation drift toward manipulating other "inactive" ingredients (e.g., incentive, accountability, curricula) instead of directly promoting developmental relationships. Using empirical studies as case examples, this study demonstrates that the presence or absence of developmental relationships distinguishes effective and ineffective interventions for diverse populations across developmental settings. The conclusion is that developmental relationships are the foundational metric with which to judge the quality and forecast the impact of interventions for at-risk children and youth. It is both critical and possible to give foremost considerations to whether program, practice, and policy decisions promote or hinder developmental relationships among those who are served and those who serve. PMID- 22506518 TI - Coming full circle: a social context for Henry Kempe's work. PMID- 22506519 TI - Can policy reduce the collateral damage caused by the criminal justice system? Strengthening social capital in families and communities. PMID- 22506520 TI - Cuban public health: living the Marxist dream. PMID- 22506521 TI - Understanding interpersonal trauma in children: why we need a developmentally appropriate trauma diagnosis. AB - Childhood exposure to victimization is prevalent and has been shown to contribute to significant immediate and long-term psychological distress and functional impairment. Children exposed to interpersonal victimization often meet criteria for psychiatric disorders other than posttraumatic stress disorder (PTSD). Therefore, this article summarizes research that suggests directions for broadening current diagnostic conceptualizations for victimized children, focusing on findings regarding victimization, the prevalence of a variety of psychiatric symptoms related to affect and behavior dysregulation, disturbances of consciousness and cognition, alterations in attribution and schema, and interpersonal impairment. A wide range of symptoms is common in victimized children. As a result, in the current psychiatric nosology, multiple comorbid diagnoses are necessary-but not necessarily accurate-to describe many victimized children, potentially leading to both undertreatment and overtreatment. Related findings regarding biological correlates of childhood victimization and the treatment outcome literature are also reviewed. Recommendations for future research aimed at enhancing diagnosis and treatment of victimized children are provided. PMID- 22506522 TI - The relationship between loss of parents in the holocaust, intrusive memories, and distress among child survivors. AB - The prevalence of intrusive memories of the Holocaust and their relationship to distress was examined among 272 child survivors in Israel. Using attachment theory as a conceptual framework, the authors also examined the effects of type of experience and loss of parents in the Holocaust, psychological resources, other life events, and sociodemographic characteristics on distress and symptomatic behavior. Eighty five percent of the participants reported suffering from intrusive memories. Structural equation modeling showed that survivors who lost one or both parents in the Holocaust suffered more distress because of more intrusive memories. These findings suggest that intrusive memories may be part of unfinished mourning processes related to the loss of parents in the Holocaust. PMID- 22506523 TI - Family context, victimization, and child trauma symptoms: variations in safe, stable, and nurturing relationships during early and middle childhood. AB - Based on a nationally representative sample of 2,017 children age 2-9 years, this study examines variations in "safe, stable, and nurturing" relationships (SSNRs), including several forms of family perpetrated victimization, and documents associations between these factors and child trauma symptoms. Findings show that many children were exposed to multiple forms of victimization within the family (such as physical or sexual abuse, emotional maltreatment, child neglect, sibling victimization, and witnessing family violence), as evidenced by substantial intercorrelations among the different forms of victimization. Moreover, victimization exposure was significantly associated with several indices of parental dysfunction, family adversity, residential instability, and problematic parenting practices. Of all SSNR variables considered, emotional abuse and inconsistent or hostile parenting emerged as having the most powerful independent effects on child trauma symptoms. Also, findings supported a cumulative risk model, whereby trauma symptom levels increased with each additional SSNR risk factor to which children were exposed. Implications for research and practice are discussed. PMID- 22506524 TI - Confronting destruction: social context and life story in the diaries of two adolescents in eastern European ghettos during the shoah. AB - Life-writing, such as in diaries and memoirs, offers a means for managing misfortune and fosters an enhanced sense of self-coherence. The devastation that accompanied the effort by the Third Reich to destroy Europe's Jewish citizens challenged resilience, sense of personal agency, and the capacity to deal with personal loss and the destruction of community. The capacity for writing a coherent life story first emerges during adolescence. Reporting on the diaries of two adolescents living in Eastern European ghettos, this study considers the coping techniques that these adolescent diarists used even as they confronted their own demise. At the same time, the differing social contexts of the Lodz and Vilna ghettos posed somewhat different challenges to the resilience of these diarists. This study considers both life-writing and coping in the context both of adolescent psychological development and social context using Lazarus' portrayal of problem-focused and emotion-focused coping as conditions became ever more dire in each ghetto. PMID- 22506525 TI - Sensation seeking, coping with stress, and readiness to engage in therapy: does ego development influence the psychosocial functioning of substance-abusing mothers? AB - Ego development, the capacity to derive coherent, nuanced meaning from one's life experiences, often has significant impact on psychosocial adjustment during adulthood. Research with nonclinical populations has indicated links between higher ego development and healthy emotional coping and interpersonal relationships. Emerging research with substance-abusing mothers suggests that higher levels of ego development are associated with improved parenting but also with increased rates of psychopathology. Less is known about how ego development is related to other psychosocial factors important for substance-abusing mothers' functioning and capacity to parent, including the proclivity to engage in risky behaviors, adaptive coping behaviors, and readiness to engage in psychotherapy. The present study examines these links. Participants included 182 methadonemaintained women who expressed interest in a randomized clinical trial testing the efficacy of a relational parenting intervention for substance-abusing mothers (Luthar, Suchman, & Altomare, 2007). Data were analyzed using a series of MANCOVAs and ANCOVAs controlling for maternal IQ and depression. Mothers with higher levels of ego development reported more adaptive coping techniques and greater readiness to engage in psychotherapy but also reported a heightened desire for strong sensations. Findings are discussed in light of mothers' psychological processes and parenting capacities. The significance of findings for developing parenting interventions for substance-abusing mothers is also discussed. PMID- 22506526 TI - Time bound: the timescape of secondary trauma of the surviving teachers of the Wenchuan Earthquake. AB - This article introduces a timescape perspective to enrich our understanding of postdisaster secondary trauma and social capital. Drawing upon a 2-year ethnographic study in 2008-2010 of a high school most devastated by the Wenchuan Earthquake in Sichuan, China, this article discusses how the national future oriented timescape of recovery produced the secondary trauma among the surviving teachers. In particular, this article elucidates the pervasiveness of the industrial linear and mechanical calendar and clock time in the state and societal response. This article proposes that human connectedness-the key component of social capital crucial to the restoration of self and community efficacy in postdisaster recovery-requires a temporal frame that allows multiple levels and rhythms of grieving and reconnecting with existing social relations. This article also highlights the critical role of teachers in the collective healing of students and the community efficacy of the school. PMID- 22506527 TI - Potentially traumatic events at different points in the life span and mental health: findings from SHARE-Israel. AB - This study addressed the association between adversity cumulated at different points in the life span and present mental health. Data of 1,130 participants aged 50+ were drawn from the Israeli component of the Survey of Health, Ageing and Retirement in Europe (SHARE). Measures included an inventory of potentially traumatic events, mental distress (depressive symptoms), and well-being (quality of life, life satisfaction). Adversity reported to have occurred early in life was positively related to mental health (i.e., to lower distress and higher well being), whereas adversity reported to occur in late life was negatively related (i.e., to higher distress and lower well-being). Additional analyses showed that the positive association between early-life adversity and mental health was mainly restricted to adversity in which the primary harm was to another person (other-oriented adversity). In contrast, the negative association between late life adversity and mental health was mainly restricted to adversity in which the primary harm was to the self (self-oriented adversity). This study suggests that the differential association between cumulative adversity and mental health is best captured when accounting for both time of occurrence and adversity type. PMID- 22506528 TI - An interaction between perceived stress and 5HTTLPR genotype in the prediction of stable depressive symptomatology. AB - A significant amount of research has examined the interaction between a functional polymorphism in the serotonin transporter gene (5HTTLPR) and stressful life events in the prediction of depression and depressive symptomatology. The results of these studies have produced conflicting evidence, with some studies substantiating a significant interaction and others failing to detect a significant interaction. The purpose of the current study was to add to this line of research by testing for an interaction between 5HTTLPR and perceived stress in the prediction of stable depressive symptomatology. Analysis of data from the National Longitudinal Study of Adolescent Health (Add Health) indicates that the association between perceived stress and depression is moderated by 5HTTLPR genotype for females, but not for males. Specifically, females who were homozygous for the short allele were significantly more likely to report symptoms of depression in the face of perceived stress when compared to females who were homozygous or heterozygous for the long allele. PMID- 22506529 TI - Can positive thinking help? Positive automatic thoughts as moderators of the stress-meaning relationship. AB - The purpose of this study was to test whether positive automatic cognitions moderated the relationship between event stressfulness and meaning in life. Measures of these constructs were administered to 232 students and community dwelling adults. Supporting hypotheses and the literature, positive automatic cognitions moderated the relationship between event stressfulness and meaning in life. For persons with high levels of positive thinking, greater event stressfulness was associated with higher meaning in life. For persons with low levels of positive thinking, greater event stressfulness was associated with lower meaning in life. These results were obtained when controlling for positive affect, as well as the positive affect * event stressfulness interaction. The positive cognitions * event stressfulness interaction accounted for 2.9% of variance, and the overall model accounted for 47% of the variance in meaning in life. PMID- 22506530 TI - A brief self-help toolkit intervention for gambling problems: a randomized multisite trial. AB - Two studies conducted in Massachusetts and Nevada evaluated the efficacy of a self-help toolkit for problem gambling. Individuals concerned about gambling related problems, in response to public notices and newspaper advertisements, volunteered for a randomized trial of the self-help toolkit, Your First Step to Change: Gambling. Participants were randomly assigned to 1 of 3 conditions: (a) a printed toolkit, (b) the toolkit and a brief guide to the toolkit's content, or (c) assignment to a wait-list condition. Participants, 145 in Massachusetts and 170 in Nevada, reported their gambling behavior, beliefs and attitudes about chance, and recent and planned help seeking at baseline, 88% at 1 month later, and 79% at 3 months later. Findings for the complete and intent-to-treat analyses at both sites indicated that participants significantly improved. At the end of the study period, significantly more toolkit recipients than control group participants reported recently abstaining from gambling. Minimally invasive, self directed resources like this self-help toolkit can assist remediating gambling related problems among gamblers who do not engage in formal treatment. PMID- 22506531 TI - Three-dimensional reduced-symmetry of colloidal plasmonic nanoparticles. AB - Owing to their novel optical properties, three-dimensional plasmonic nanostructures with reduced symmetry such as a nanocrescent and a nanocup have attracted considerable current interest in biophotonic imaging and sensing. However, their practical applications have been still limited since the colloidal synthesis of such structures that allows, in principle, for in vivo application and large-scale production has not been explored yet. To date, these structures have been fabricated only on two-dimensional substrates using micro/nanofabrication techniques. Here we demonstrate an innovative way of breaking symmetry of colloidal plasmonic nanoparticles. Our strategy exploits the direct overgrowth of Au on a hybrid colloidal dimer consisting of Au and polystyrene (PS) nanoparticles without the self-nucleation of Au in an aqueous solution. Upon the overgrowth reaction, the steric crowding of PS leads to morphological evolution of the Au part in the dimer ranging from half-shell, nanocrescent to nanoshell associated with the appearance of the second plasmon absorption band in near IR. Surface-enhanced Raman scattering signal is obtained directly from the symmetry-broken nanoparticles solution as an example showing the viability of the present approach. We believe our concept represents an important step toward a wide range of biophotonic applications for optical nanoplasmonics such as targeting, sensing/imaging, gene delivery, and optical gene regulations. PMID- 22506532 TI - Both alpha1- and beta1-adrenoceptors in the bed nucleus of the stria terminalis are involved in the expression of conditioned contextual fear. AB - BACKGROUND AND PURPOSE: The bed nucleus of the stria terminalis (BNST) is a limbic structure that is involved in the expression of conditioned contextual fear. Among the numerous neural inputs to the BNST, noradrenergic synaptic terminals are prominent and some evidence suggests an activation of this noradrenergic neurotransmission in the BNST during aversive situations. Here, we have investigated the involvement of the BNST noradrenergic system in the modulation of behavioural and autonomic responses induced by conditioned contextual fear in rats. EXPERIMENTAL APPROACH: Male Wistar rats with cannulae bilaterally implanted into the BNST were submitted to a 10 min conditioning session (6 footshocks, 1.5 ma/ 3 s). Twenty-four hours later freezing and autonomic responses (mean arterial pressure, heart rate and cutaneous temperature) to the conditioning box were measured for 10 min. The adrenoceptor antagonists were administered 10 min before the re-exposure to the aversive context. KEY RESULTS: L-propranolol, a non-selective beta-adrenoceptor antagonist, and phentolamine, a non-selective alpha-adrenoceptor antagonist, reduced both freezing and autonomic responses induced by aversive context. Similar results were observed with CGP20712, a selective beta(1) -adrenoceptor antagonist, and WB4101, a selective alpha(1) -antagonist, but not with ICI118,551, a selective beta(2) -adrenoceptor antagonist or RX821002, a selective alpha(2) -antagonist. CONCLUSIONS AND IMPLICATIONS: These findings support the idea that noradrenergic neurotransmission in the BNST via alpha(1) - and beta(1) adrenoceptors is involved in the expression of conditioned contextual fear. PMID- 22506533 TI - Socioeconomic status and self-reported oral health in Iranian adolescents: the role of selected oral health behaviors and psychological factors. AB - OBJECTIVES: This study investigated health inequality for self-reported oral health outcomes among adolescents. The role of oral health behaviors and psychological factors in explaining oral health inequality was investigated using the hypothesis of mediation. METHODS: This was a cross-sectional study that used self-completed questionnaires. This study sampled 639 (315 male and 324 female) 15- to 17-year-old adolescents (second and third grade high school students) of both sexes in the city of Sanandaj in the province of Kurdistan, western Iran. Socioeconomic indicators of the study were subjective socioeconomic status, wealth index, and parental education. Oral health behaviors were measured as toothbrushing frequency, dental flossing frequency, and dental visits. Psychological factors were self-esteem, anxiety, and depression. Self-reported oral health outcomes were single item self-rated oral health and the experience of dental pain. Regression analysis was used to test four conditions for the hypothesis of mediation. RESULTS: The results showed that the inequality is present in oral health for some pairs of relationships between socioeconomic status and oral health outcomes. Adjustment for oral health behaviors and psychological factors, individually and simultaneously, led to loss of statistical significance for some pairs of the relationships. However, adjustment for oral health behaviors and psychological factors led to only small changes in the associations between socioeconomic status and self-reported oral health outcomes. CONCLUSIONS: This study found a graded oral health inequality, but no strong evidence to support the hypothesis that oral health behaviors and psychological factors mediate oral health inequality for self-reported oral health outcomes. PMID- 22506534 TI - Reversible interconversion of a divalent vanadium bronze between delta and beta quasi-1D structures. AB - Charge fluctuations along the quasi-1D frameworks of M(x)V(2)O(5) bronzes have evinced much recent interest owing to the manifestation of colossal metal insulator transitions and superconductivity. Depending upon the nature of the intercalating cation (M), distinctive geometries of the V(2)O(5) framework are accessible. Herein, we demonstrate an unprecedented reversible transformation between double-layered (delta) and tunnel (beta) quasi-1D geometries for nanowires of a divalent vanadium bronze, Ca(x)V(2)O(5) (x ~ 0.23), upon annealing induced dehydration and hydrothermally induced hydration. Such a facile hydration/dehydration-induced interconversion between two prominent quasi-1D structures (accompanied by a change in charge-ordering motifs) has not been observed in the bulk and is posited to result from the ease of propagation of crystallographic slip processes across the confined nanowire widths for the delta -> beta conversion and the facile diffusion of water molecules within the tunnel geometries for the beta -> delta reversion. PMID- 22506535 TI - Nitric oxide synthase 3 (NOS3) 4b/a, T-786C and G894T polymorphisms in association with diabetic retinopathy susceptibility: a meta-analysis. AB - AIMS: To assess the association between the NOS3 4b/a, T-786C and G894T polymorphisms and diabetic retinopathy (DR) susceptibility. MATERIALS AND METHODS: Twenty-one studies covering 8,111 subjects were included. The fixed or random effect model used was based on heterogeneity. RESULTS: A significant association of the intron 4a allele in the NOS3 4b/a polymorphism with reduced risk of DR was found in dominant (OR 0.778, 95% CI 0.654-0.926) and additive (OR 0.809, 95% CI 0.698-0.937) models. Subgroup analysis revealed that the intron 4a allele additive model (OR 0.807, 95% CI 0.697-0.935) was associated with DR risk in type 2 diabetic patients. We also found a marginally significant association of the C allele in the T-786C polymorphism with reduced risk of proliferative DR. In contrast, no statistically significant association was observed between the G894T polymorphism and DR risk, either in the overall or subgroup analyses. CONCLUSIONS: The intron 4a allele of the 4b/a polymorphism in the eNOS gene has protective effects against DR, especially in type 2 diabetic patients. The C allele of the T-786C polymorphism may be a protective factor for proliferative DR. However, the G894T polymorphism does not appear to influence the development of DR. This conclusion warrants confirmation by further studies. PMID- 22506536 TI - Mapping reads on a genomic sequence: an algorithmic overview and a practical comparative analysis. AB - Mapping short reads against a reference genome is classically the first step of many next-generation sequencing data analyses, and it should be as accurate as possible. Because of the large number of reads to handle, numerous sophisticated algorithms have been developped in the last 3 years to tackle this problem. In this article, we first review the underlying algorithms used in most of the existing mapping tools, and then we compare the performance of nine of these tools on a well controled benchmark built for this purpose. We built a set of reads that exist in single or multiple copies in a reference genome and for which there is no mismatch, and a set of reads with three mismatches. We considered as reference genome both the human genome and a concatenation of all complete bacterial genomes. On each dataset, we quantified the capacity of the different tools to retrieve all the occurrences of the reads in the reference genome. Special attention was paid to reads uniquely reported and to reads with multiple hits. PMID- 22506537 TI - Comparison of the therapeutic efficacy of a fixed low-dose combination of cinnarizine and dimenhydrinate with betahistine in vestibular neuritis: a randomized, double-blind, non-inferiority study. AB - BACKGROUND: Vestibular neuritis (VN) is a strongly disabling disease of the peripheral vestibular system. Rapid and effective relief of symptoms is important to allow patients to promptly return to normal physical activity. OBJECTIVE: The aim of this prospective, randomized, double-blind study was to evaluate the efficacy of a fixed low-dose combination of cinnarizine and dimenhydrinate in unilateral VN in comparison with betahistine in terms of improvement of vertigo and concomitant symptoms, and performance in neurotological testing. METHODS: Sixty-two patients were randomized to receive either cinnarizine 20 mg/dimenhydrinate 40 mg as a fixed combination or betahistine 12 mg, each three times daily for 4 weeks. Vertigo and concomitant symptoms, activities of daily living (ADL), posturography and a battery of vestibulo-ocular tests, registered by electronystagmography including spontaneous nystagmus, bithermal caloric and rotatory test, among others, were assessed at baseline (t(0)), after 1 week (t(1w)) and after 4 weeks (t(4w)). The primary endpoint was the Mean Vertigo Score (MVS) at t(1w), a composite of 12 individual scores for unprovoked and provoked vertigo, each assessed using a 10 cm visual analogue scale (VAS). Non inferiority of the fixed combination versus betahistine would be assumed if the two-sided 95% confidence intervals (CIs) for between-group differences in MVS lay entirely below the non-inferiority margin of 1.25 (12.5% of VAS range). RESULTS: The fixed combination led to significantly greater improvements in MVS than betahistine both at t(1w) (primary endpoint) and at t(4w) (95% CI for the difference in baseline-adjusted means -0.95, -0.64 at t(1w), -0.77, -0.44 at t(4w); p < 0.001). Vegetative symptoms and ADL also improved significantly more under the fixed combination than under betahistine at t(1w) (p < 0.001, each parameter) and t(4w) (p < 0.001 and p < 0.01, respectively), both showing a nearly complete remission at t(4w). In the two groups, pathological posturography and electronystagmography parameters normalized during the 4-week treatment. The fixed combination group showed an earlier recovery of spontaneous nystagmus than the betahistine group (t(1w), p < 0.001) and slightly higher improvements in asymmetry of rotation-induced nystagmus at t(1w) and t(4w) (p = 0.041, each time point). No significant differences were found between the treatments in abatement of spontaneous nystagmus at t(4w) and decrease of caloric lateralization or improvement of equilibrium (sensory organization test [SOT], conditions 5/6) at t(1w) and t(4w). No patient reported any adverse event. CONCLUSION: The results showed that the fixed low-dose combination of cinnarizine and dimenhydrinate is an effective and well tolerated option for symptomatic treatment in unilateral VN. The fixed combination led to significant improvements in vertigo and ADL within the first week, and to a nearly complete recovery after 4 weeks. Neurotological testing revealed no signs of a possible detrimental influence of the 4-week treatment with the fixed combination compared with betahistine in terms of recovery of caloric responsiveness and abatement of rotation-induced nystagmus. PMID- 22506538 TI - Acute cold exposure and cognitive function: evidence for sustained impairment. AB - Several industries experience periods of cold exposure and rewarming throughout the workday but mental performance under these conditions is unknown. A better understanding of cognition during the rewarming phase after cold exposure may help reduce accidents and improve performance. Ten young men (wearing ~0.1 clo) underwent three consecutive mornings trials where they were exposed to cold air (10 degrees C) and then subsequently rewarmed (25 degrees C air). A computerised test battery was administered during each stage of the protocol to determine working memory, choice reaction time, executive function and maze navigation. Rectal and skin temperature, oxygen consumption and thermal sensation were also measured throughout and showed a typical response. Relative to baseline performance, working memory, choice reaction time and executive function declined during exposure to 10 degrees C, and these impairments persisted 60 min into the recovery period (i.e. once physiological parameters had returned to baseline). Further work is needed to develop countermeasures to this predicament. PRACTITIONER SUMMARY: This study showed that working memory, choice reaction time and executive function declined during exposure to 10 degrees C air, and these impairments persisted 60 min into the rewarming period (i.e. once measurable physiological parameters had returned to normal). Individuals may be at risk for injury after removal from a cold environment. PMID- 22506539 TI - Survival of Phytophthora alni, Phytophthora kernoviae, and Phytophthora ramorum in a simulated aquatic environment at different levels of pH. AB - Phytophthora ramorum, Phytophthora alni, and Phytophthora kernoviae present significant threats to biosecurity. As zoosporic oomycetes, these plant pathogens may spread through natural waterways and irrigation systems. However, survival of these pathogens in aquatic systems in response to water quality is not well understood. In this study, we investigated their zoospore survival at pH 3-11 in a 10% Hoagland's solution over a 14-day period. The results showed that all three pathogens were most stable at pH 7, although the populations declined overnight irrespective of pH. Extended survival of these species depended on the tolerance of pH of their germinants. Germinants of P. alni ssp. alni and P. ramorum were more basic tolerant (pH 5-11), while those of P. kernoviae were more acidic tolerant (pH 3-9). These tolerant germinants formed compact hyphae or secondary sporangia to allow longer survival of these pathogens. Long-term survival at a broad pH range suggests that these pathogens, especially P. ramorum, are adapted to an aquatic environment and pose a threat to new production areas through water dispersal. PMID- 22506540 TI - Reactivity of hydrated monovalent first row transition metal ions M(+)(H2O)n, M = V, Cr, Mn, Fe, Co, Ni, Cu, Zn, toward molecular oxygen, nitrous oxide, and carbon dioxide. AB - The reactions of hydrated monovalent transition metal ions M(+)(H(2)O)(n), M = V, Cr, Mn, Fe, Co, Ni, Cu, Zn, toward molecular oxygen, nitrous oxide, and carbon dioxide were studied by Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry. Clusters containing monovalent chromium, cobalt, nickel, or zinc were reactive toward O(2), while only hydrated cobalt was reactive toward N(2)O. A strongly size dependent reactivity was observed. Chromium and cobalt react very slowly with carbon dioxide. Nanocalorimetric analysis, (18)O(2) exchange, and collision induced dissociation (CID) experiments were done to learn more about the structure of the O(2) products. The thermochemistry for cobalt, nickel, and zinc is comparable to the formation of O(2)(-) from hydrated electrons. These results suggest that cobalt, nickel, and zinc are forming M(2+)/O(2)(-) ion pairs in the cluster, while chromium rather forms a covalently bound dioxygen complex in large clusters, followed by an exothermic dioxide formation in clusters with n <= 5. The results show that hydrated singly charged transition metal ions exhibit highly specific reactivities toward O(2), N(2)O, and CO(2). PMID- 22506541 TI - Occlusion on implants - is there a problem? AB - Oral rehabilitation restores form and function and impacts on general health. Teeth provide a discriminating sense of touch and directional specificity for occlusal perception, management of food with mastication and swallowing, and awareness of its texture and hardness. Peripheral feedback for control of jaw muscles includes the enamel-dentine-pulp complex and mechanoreceptors in the periodontal tissues. The implications of feedback from periodontal and other intra-oral mechanoreceptors as well as changes in central representation are significant for function and adaptation to oral rehabilitation. With implants, in the absence of the periodontium and periodontal mechanoreceptor feedback, fine motor control of mastication is reduced, but patients are still able to function adequately. Further, there is no significant difference in function with full arch fixed prostheses on teeth in comparison with implants. Predictable implant outcomes depend on bone support. Optimum restoration design appears to be significant for bone remodelling and bone strains around implants with occlusal loading. Finite element analysis data confirmed load concentrations at the coronal bone around the upper section of the implant where bone loss is commonly observed clinically. Load concentration increased with steeper cusp inclination and broader occlusal table and decreased with central fossa loading and narrower occlusal table size. It is recommended that occlusal design should follow a narrow occlusal table, with central fossa loading in intercuspal contact and low cusp inclination to minimise lateral loading in function and parafunction. Acknowledging these features should address potential problems associated with the occlusion in implant therapy. PMID- 22506543 TI - Lanthanide-doped Na(x)ScF(3+x) nanocrystals: crystal structure evolution and multicolor tuning. AB - Rare-earth-based nanomaterials have recently drawn considerable attention because of their unique energy upconversion (UC) capabilities. However, studies of Sc(3+) based nanomaterials are still absent. Herein we report the synthesis and fine control of Na(x)ScF(3+x) nanocrystals by tuning of the ratio of oleic acid (OA, polar surfactant) to 1-octadecene (OD, nonpolar solvent). When the OA:OD ratio was increased from low (3:17) to high (3:7), the nanocrystals changed from pure monoclinic phase (Na(3)ScF(6)) to pure hexagonal phase (NaScF(4)) via a transition stage at an intermediate OA:OD ratio (3:9) where a mixture of nanocrystals in monoclinic and hexagonal phases was obtained and the coexistence of the two phases inside individual nanocrystals was also observed. More significantly, because of the small radius of Sc(3+), Na(x)ScF(3+x):Yb/Er nanocrystals show different UC emission from that of NaYF(4):Yb/Er nanocrystals, which broadens the applications of rare-earth-based nanomaterials ranging from optical communications to disease diagnosis. PMID- 22506542 TI - Antibacterial polyelectrolyte micelles for coating stainless steel. AB - In this study, we report on the original synthesis and characterization of novel antimicrobial coatings for stainless steel by alternating the deposition of aqueous solutions of positively charged polyelectrolyte micelles doped with silver-based nanoparticles with a polyanion. The micelles are formed by electrostatic interaction between two oppositely charged polymers: a polycation bearing 3,4-dihydroxyphenylalanine units (DOPA, a major component of natural adhesives) and a polyanion (poly(styrene sulfonate), PSS) without using any block copolymer. DOPA units are exploited for their well-known ability to anchor to stainless steel and to form and stabilize biocidal silver nanoparticles (Ag(0)). The chlorine counteranion of the polycation forms and stabilizes biocidal silver chloride nanoparticles (AgCl). We demonstrate that two layers of micelles (alternated by PSS) doped with silver particles are enough to impart to the surface strong antibacterial activity against gram-negative E. coli. Moreover, micelles that are reservoirs of biocidal Ag(+) can be easily reactivated after depletion. This novel water-based approach is convenient, simple, and attractive for industrial applications. PMID- 22506544 TI - The effects of religious socialization and religious identity on psychosocial functioning in Korean American adolescents from immigrant families. AB - This study examined religious identity as a mediator and moderator between religious socialization by parents, peers, and religious mentors and psychosocial functioning (i.e., social competence, internalizing and externalizing behavior problems) among 155 Korean American adolescents. Religious socialization by parents and peers were positively associated with adolescents' religious identity and social competence. Religious identity fully mediated the relationship between religious socialization by parents and social competence, and partially mediated the relationship between religious socialization by peers and social competence. A competing model with religious identity as a moderator found adolescents with low religious identity showed significantly more externalizing behavior problems when they received more religious socialization from parents. PMID- 22506545 TI - Determinants of atrazine contamination in the homes of commercial pesticide applicators across time. AB - Twenty-nine commercial pesticide applicator households in eastern Iowa were enrolled to investigate in-home contamination of atrazine, the most commonly used corn herbicide in the Unites States. From each home, four vacuum dust samples were collected during atrazine application season (Visit 1) and again 6 months later during winter months (Visit 2). Samples were taken from the following locations: primary entryway for pesticide applicator, living room, master bedroom, and kitchen. The applicator completed an atrazine handling log and household questionnaire with spouse. Of the 230 dust samples, only 2 were below the level of detection, 2 ng of atrazine per gram (ng/g) of fine dust (dust particle size 5-150 MUm). Dust levels were standardized to chemical loading. During application season the entryway (2.68 ng/cm(2)) and kitchen (0.47 ng/cm(2)) had the highest geometric mean atrazine chemical loading. The entryway chemical loading during Visit 2 was the second highest aggregate (0.55 ng/cm(2)). Aggregate concentrations were significantly higher at Visit 1 compared with Visit 2 when paired by location (p<=0.02). Analysis showed that job (application, mixing/loading, or both) was not associated with in-home atrazine contamination. Linear regression showed a strong positive association between atrazine handling (number of acres applied with atrazine, number of days atrazine handled, and pounds of atrazine handled) and aggregate dust chemical loading from both visits (p = 0.06, 0.03, and 0.10, respectively). Frequency of vacuuming was inversely associated with Visit 2 concentrations (p = 0.10) and showed a weaker association with Visit 1 (p = 0.30). Removing shoes outside the home was associated with lower atrazine chemical loading (p = 0.03), and applicators changing work clothes in the master bedroom had significantly increased atrazine chemical loading in master bedrooms (p = 0.01). Changes in hygiene practices for commercial pesticide applicators could significantly reduce atrazine and, likely, other pesticide contaminations in the home. PMID- 22506546 TI - Therapy for older patients with acute myeloblastic leukemia: a problem in search of a solution. PMID- 22506547 TI - Hypothermia for neonatal hypoxic-ischemic encephalopathy: may an early amplitude integrated EEG improve the selection of candidates for cooling? AB - OBJECTIVE: To report our experience in the selection of newborns candidate to therapeutic hypothermia. METHODS: Retrospective study involving 47 newborns suffering from perinatal asphyxia from January 2008 to September 2011. RESULTS: Thirty-five of 47 newborns admitted to our hospital fulfilled metabolic and neurological criteria for recruitment and were cooled. aEEG was carried out in 26 of them and resulted always abnormal. In three of the 12 newborns with only metabolic criteria, aEEG was moderately abnormal. They were cooled and their outcome (evaluated by General Movements and Griffiths Mental Development Scales for children aged 0-2 years) is good. Three additional newborns who only met the metabolic criterion reached our hospital after the therapeutic window for hypothermia and exhibited seizures; their outcome is poor. CONCLUSIONS: In our experience, the inclusion of aEEG in the entry criteria would not have precluded newborns with neurological criteria from cooling. On the contrary, without an early aEEG, we would have excluded from hypothermia infants with moderate hypoxic ischemic encephalopathy without precocious neurological signs who exhibited only the metabolic criterion, but with abnormal aEEG. If further studies will confirm that early aEEG might identify newborns suitable for cooling even in the absence of clinical signs, a revision of the entry criteria should be considered. PMID- 22506549 TI - Modification of a styryl dye binding mode with calf thymus DNA in vesicular medium: from minor groove to intercalative. AB - This paper reports an interesting transformation of binding mode of 2-(4 (dimethylamino)styryl)-1-methylpyridinium iodide (DASPMI) with calf thymus DNA from minor groove binding in buffer solution to intercalative binding when the dye is encapsulated inside a vesicle formed by the interaction of 1,8 naphthalimide (a charge transfer dye) with the supramolecular association of sodium dodecyl sulfate and block-copolymer polyethylene-b-polyethylene glycol. The pre-encapsulated dye in the vesicular interior binds intercalatively to ct DNA, as evinced by the high value of equilibrium binding constant of DASPMI-DNA complex, changes in CD-spectra of DNA and isosbestic point, along with downshift and hypochromicity of absorption band. Increase in anisotropy decay by 1.5 times with a single component strongly confirms restricted motion of the probe inside ct-DNA confirming intercalative binding. The compaction of ct-DNA caused by the interaction of the vesicle allows DASPMI to bind ct-DNA in the intercalative mode. However, the groove binding mode in ct-DNA-DASPMI remains unaffected by the retro-addition of the vesicles to the already bound dye to ct-DNA. PMID- 22506548 TI - Ascites complicating unilateral nephrectomy and peritoneal dialysis catheter implantation in a patient with massive polycystic kidney and liver disease. AB - Peritoneal dialysis (PD) is a well-established therapeutic option for patients with polycystic kidney disease. However, in patients with massive polycystic kidney and liver disease, subclinical hepatic venous outflow obstruction may elicit the appearance of ascites after implantation of a peritoneal catheter. The case of a patient who developed ascites after implantation of a PD catheter and further lowering of abdominal pressure after unilateral nephrectomy is discussed. PMID- 22506551 TI - Caregiver acceptability and preferences for preventive dental treatments for young African-American children. AB - Our prior research focused on parental treatment acceptability (TA) and treatment preferences (TPs) for preventive dental treatments for young Hispanic children. We adapted the interview for administration to parents of young African-American children. OBJECTIVE: In a sample of African-American parents, determine parental TA and TP for five dental treatments to prevent early childhood caries. METHODS: Interviewed 48 parents/caregivers of African-American children attending Head Start, assessing TA and TP for three treatments for children: toothbrushing (TB) with fluoride toothpaste, fluoride varnish (FV), and xylitol in food (XF); and two treatments for mothers: xylitol gum (XG) and chlorhexidine (CHX) rinse. The interview included verbal information, illustrated treatment cards, photos/video clips, and samples. Parents provided TA of each treatment (one to five scale), TP between each of 10 pairs of the five treatments, and open-ended reasons for their preferences. TPs were summed (zero to four) to create overall preference. RESULTS: All treatments were acceptable (means 4.4-4.9). TB was more acceptable than FV and XF (P < 0.05). Summed TP revealed a strong preference for TB (mean 3.1) above other treatments (all P < 0.01). Primary reasons for preferring TB were the following: promotes healthy habits; child focused; and effectiveness. CONCLUSIONS: All treatments were acceptable, however, parents/guardians strongly preferred TB. Parents' emphasis on healthy habits and child-focused treatment supports efforts for oral health education programs in early childhood settings. Some parents expressed concerns about FV, XF, and CHX. Results may be useful in planning prevention programs for young children in African-American communities. PMID- 22506550 TI - In vitro guidance of dental pulp cells by Nd:YAG laser-irradiated endothelial cells. AB - OBJECTIVE: After endothelial cells were ablated by neodymium:yttrium-aluminum garnet (Nd:YAG) laser irradiation, we investigated the response of pulp cells by examining the expression of transforming growth factor beta-1 (TGF-beta1). BACKGROUND DATA: The reaction of stimulated blood vessels is related to the initiation of dentinogenesis. After artificial injury of endothelial cells, pulp cells migrate to the site of the injured endothelial cells. MATERIALS AND METHODS: Rat aortic endothelial cells were cultured in the lower compartment of the experimental assembly, and a pulsed Nd:YAG laser was used to ablate these cells. Pulp cells were fluorescence labeled and cultured in the upper compartment. After 7-14 days of laser irradiation, total RNA was extracted from the cells in the lower chamber, and RT-PCR was performed to examine the expression of TGF-beta1 and osteocalcin mRNA. TGF-beta1 was also examined with immunohistochemistry. RESULTS: Seven days after laser irradiation, migrating pulp cells that expressed TGF-beta1 were observed in the lower compartment, and the expression of TGF-beta1 mRNA and osteocalcin mRNA was altered. Without laser irradiation, few migrating pulp cells were observed, and the expression of TGF beta1 mRNA and osteocalcin mRNA was weak. These results suggested that TGF-beta1 mRNA expression is detected earlier in pulp cells rather than in endothelial cells following injury to endothelial cells. CONCLUSIONS: Using the Nd:YAG laser as an ablative stimulant, this study model was useful for investigating pulp endothelial cell interactions in reparative dentinogenesis. PMID- 22506552 TI - Undetectable HBV DNA at month 12 of entecavir treatment predicts maintained viral suppression and HBeAg-seroconversion in chronic hepatitis B patients at 3 years. AB - BACKGROUND: On-treatment monitoring of serum hepatitis B virus (HBV) DNA to guide treatment strategy for patients on entecavir has received little attention. AIM: To investigate the predictive value of on-treatment HBV DNA levels for responses to entecavir. METHODS: This was a retrospective cohort study among nucleos(t)ide analogue-naive HBV-infected patients on entecavir with a minimum follow-up of 2 years. Maintained virological suppression was defined as undetectable HBV DNA (<20 IU/mL) until the last visit. Genotypic drug resistance was screened by using the INNO-LiPA DR assay. RESULTS: A total of 440 chronic hepatitis B patients (160 HBeAg-positive) followed for 34 +/- 9 months were included. The cumulative probability of maintained virological suppression at year 1, 2 and 3 were 76.5%, 83.0% and 88.3% respectively. On multivariate analysis, lower baseline HBV DNA, undetectable HBV DNA at month 12 and negative HBeAg were the independent predictors of maintained virological suppression. M12 responders (who had undetectable HBV DNA at month 12) had higher probability of maintained virological suppression at 3 years (99.1%) as compared to non responders (57.5%; P < 0.001). The cumulative probability of HBeAg-seroconversion at year 1, 2 and 3 were 19.0%, 27.2% and 33.5% respectively. M12 responders had higher probability of HBeAg-seroconversion at 3 years (43.2%) than the non responders (19.0%; P = 0.003). M12 responders had lower probability of drug resistance at 3 years (0%) than the non responders (2.6%; P = 0.004). CONCLUSION: Month 12 HBV DNA responses could predict the probability of maintained virological suppression, HBeAg seroconversion and risk of drug resistance among patients on entecavir treatment at 3 years. PMID- 22506554 TI - Self-assembled GaN nanowires on diamond. AB - We demonstrate the nucleation of self-assembled, epitaxial GaN nanowires (NWs) on (111) single-crystalline diamond without using a catalyst or buffer layer. The NWs show an excellent crystalline quality of the wurtzite crystal structure with m-plane faceting, a low defect density, and axial growth along the c-axis with N face polarity, as shown by aberration corrected annular bright-field scanning transmission electron microscopy. X-ray diffraction confirms single domain growth with an in-plane epitaxial relationship of (10 10)(GaN) [parallel] (01 1)(Diamond) as well as some biaxial tensile strain induced by thermal expansion mismatch. In photoluminescence, a strong and sharp excitonic emission reveals excellent optical properties superior to state-of-the-art GaN NWs on silicon substrates. In combination with the high-quality diamond/NW interface, confirmed by high-resolution transmission electron microscopy measurements, these results underline the potential of p-type diamond/n-type nitride heterojunctions for efficient UV optoelectronic devices. PMID- 22506555 TI - Physiological and cognitive responses when riding an electrically assisted bicycle versus a classical bicycle. AB - The present study compared the physiological responses and the subsequent cognitive performance when riding an electrically assisted (EB) versus a classical (CB) bicycle. Oxygen uptake, heart rate and leg extensor muscles electromyographic (EMG) activity were recorded in 10 subjects during a 30-min intermittent cycling exercise performed with EB versus CB. Cognitive performance was evaluated by a mail sorting test, performed at rest and after each cycling session. Averaged oxygen uptake and heat rate were significantly (P < 0.05) lower during EB cycling than during CB cycling. The EMG activities of the vastus lateralis, rectus femoris and gastrocnemius medialis muscles were significantly (P < 0.001) greater during CB cycling than during EB cycling. The time to complete the mail sorting test was significantly (P < 0.05) shorter after EB cycling than after CB cycling. Because EB cycling reduced muscle strains and physiological stress, it might offer benefits for those using bicycles in their work, such as postal workers and police officers. STATEMENT OF RELEVANCE: This study compared physiological and cognitive responses when riding an electrically assisted versus a classical bicycle. The results showed that the electrically assisted bicycle led to reduced muscle strains and physiological stress and, therefore, might offer benefits for those using bicycles in their work, such as postal workers and police officers. PMID- 22506553 TI - Translation of sonoelastography from Thiel cadaver to patients for peripheral nerve blocks. AB - Ultrasound guidance is now common in regional anaesthesia practice, but remains limited by poor visibility of the needle tip and poor quantification of local anaesthetic spread. Sonoelastography based on tissue compression is a technique depicting tissue strain. Hitherto used largely for tumour diagnosis, we used it in both Thiel embalmed cadavers and two patients receiving interscalene and femoral blocks to observe changes in tissue strain during local anaesthetic injection. The primary aim of our study was to measure the area under the curve (weighted for time) of the strain pattern in Thiel perineural tissue when using a range of volumes of embalming fluid (0.25, 0.5, 1, 2.5, 5 and 7.5 ml) for interscalene and femoral blocks using sonoelastography. Our secondary aims were to evaluate static images of anatomy and videos of needle insertion and perineural injection using combined B-Mode ultrasound and sonoelastography. Independent raters assessed the anatomy and spread using a 7-point Likert scale, ranked from extremely poor to extremely good. We performed 83 blocks in cadavers. Concordance between both raters was good, with weighted Kappa (95% CI) 0.66 (0.61 0.71). The characteristics of spread were similar with both interscalene and femoral block; spread increased with injectate volume up to 1 ml. Analysis of variance showed differences in spread between injection volumes (p = 0.009), but not between regional blocks (p = 0.05). Post-hoc analysis showed greater spread with 1 and 2.5 ml volumes compared with 0.25 ml. In patients, visibility of strain during injection was better with sonoelastography than with B-Mode ultrasound and showed a dose response from 1 to 5 ml volumes of local anaesthetic. Colour strain recognition using sonoelastography offers the ability to differentiate between nerve and surrounding tissue during local anaesthetic injection by improving visibility of spread (p = 0.04). PMID- 22506556 TI - In vitro selective depletion of CD4(+)CD25(+) regulatory T-cells from PBMC using anti-tac-SAP. AB - It has been shown that naturally occurring regulatory T-cells (CD4(+)CD25(+) Foxp3(+) T-cells) have critical roles in tumor invasion and down-regulation of immune response against established tumors. High expression of CD25 (IL-2Ralpha) by regulatory T (T(reg)) cells may cause an inefficient response when using IL-2 based cancer vaccines. It seems that selective elimination of T(reg) cells before treatment of tumor-bearing T-cells can strongly increase the efficacy of a vaccine. The aim of this study was to set up an efficient cost-effective protocol to eliminate CD4(+)CD25(+) T-cells-using the immunotoxin anti-tac-SAP. Peripheral blood mononuclear cells (PBMC) taken from colon cancer patients were treated with different concentrations (i.e., 0-100 ug/dl) of the immunotoxin. Flow cytometric analyses were then preformed to analyze expression of CD4, CD25, CD3, CD8, and CD45 surface markers; semi-quantitative fluorescent-PCR was used for the detection of Foxp3 expression before and after anti-tac-SAP treatment. The results indicated that anti-tac-SAP effectively eliminated CD4(+)CD25(+) T(reg) cells and that 25 ug/dl was the optimal concentration of anti-tac-SAP for selective depletion of these cells. These outcomes were verified by analyses of Foxp3 expression. The results also indicated that this immunotoxin had no non specific effects on other T-cells, including CD4(+)CD25(-) and CD8(+)CD45(+) T cells. Building on the work here, ongoing/future studies with the anti-tac-SAP will focus on functional assessments of the remaining (i.e., non-eliminated) T cells (i.e., CD8, CD4; using proliferation and peptide sensitization assays) to ascertain if the immunotoxin inadvertently alters the functions of these cells-an untoward outcome. PMID- 22506558 TI - A polyoxometalate-cyanometalate multilayered coordination network. AB - The reaction of the epsilon-Keggin polyoxometalate (POM) [PMo(12)O(36)(OH)(4){La(H(2)O)(4)}(4)](5+) with Fe(II)(CN)(6)(4-) under typical bench conditions at room temperature and ambient pressure has afforded the novel [epsilon-PMo(12)O(37)(OH)(3){La(H(2)O)(5)(Fe(CN)(6))(0.25)}(4)] network, which exhibits a three-dimensional multilayered structure. The compound has been fully characterized by synchrotron-radiation X-ray crystallography, IR spectroscopy, elemental analysis, and thermogravimetric analysis. This coordination network constitutes the first example of a cyanometalate bonded to a POM unit. PMID- 22506557 TI - Activation of endothelial and epithelial K(Ca) 2.3 calcium-activated potassium channels by NS309 relaxes human small pulmonary arteries and bronchioles. AB - BACKGROUND AND PURPOSE: Small (K(Ca) 2) and intermediate (K(Ca) 3.1) conductance calcium-activated potassium channels (K(Ca) ) may contribute to both epithelium- and endothelium-dependent relaxations, but this has not been established in human pulmonary arteries and bronchioles. Therefore, we investigated the expression of K(Ca) 2.3 and K(Ca) 3.1 channels, and hypothesized that activation of these channels would produce relaxation of human bronchioles and pulmonary arteries. EXPERIMENTAL APPROACH: Channel expression and functional studies were conducted in human isolated small pulmonary arteries and bronchioles. K(Ca) 2 and K(Ca) 3.1 currents were examined in human small airways epithelial (HSAEpi) cells by whole cell patch clamp techniques. RESULTS: While K(Ca) 2.3 expression was similar, K(Ca) 3.1 protein was more highly expressed in pulmonary arteries than bronchioles. Immunoreactive K(Ca) 2.3 and K(Ca) 3.1 proteins were found in both endothelium and epithelium. K(Ca) currents were present in HSAEpi cells and sensitive to the K(Ca) 2.3 blocker UCL1684 and the K(Ca) 3.1 blocker TRAM-34. In pulmonary arteries contracted by U46619 and in bronchioles contracted by histamine, the K(Ca) 2.3/ K(Ca) 3.1 activator, NS309, induced concentration dependent relaxations. NS309 was equally potent in relaxing pulmonary arteries, but less potent in bronchioles, than salbutamol. NS309 relaxations were blocked by the K(Ca) 2 channel blocker apamin, while the K(Ca) 3.1 channel blocker, charybdotoxin failed to reduce relaxation to NS309 (0.01-1 uM). CONCLUSIONS AND IMPLICATIONS: K(Ca) 2.3 and K(Ca) 3.1 channels are expressed in the endothelium of human pulmonary arteries and epithelium of bronchioles. K(Ca) 2.3 channels contributed to endo- and epithelium-dependent relaxations suggesting that these channels are potential targets for treatment of pulmonary hypertension and chronic obstructive pulmonary disease. PMID- 22506559 TI - Assessment of the Correlation between Insertion Torque and Resonance Frequency Analysis of Implants placed in Bone Tissue of Different Densities. AB - Abstract The primary stability of a dental implant is fundamental for the osseointegration. Therefore, the aim of this study was to assess the correlation between insertion torque (IT) and resonance frequency analysis (RFA) of implants placed in the mandible and maxilla of different bone densities. Eighty dental implants were placed in the maxilla and mandible and IT and the implant stability quotient (ISQ) were measured at the time of implant insertion. Bone density was assessed subjectively by the Lekholm and Zarb index (1985). The Type I and II densities were grouped together (Group A) and Type III and IV densities in another group (Group B). The IT in Group A was higher (student-t Test, p=0.0013) than IT in Group B (46.27 + 18.51 N/cm, 33.62 + 14.74 N/cm, respectively). The implants placed in Group A showed higher ISQ (student-t Test, p=0.0004) than those placed in Group B (70.09 + 7.50, 63.66 + 8.00, respectively). A significant correlation between IT and the ISQ value was observed for Group A (Pearson correlation test; r= 0.35; p= 0.0213) and for Group B (r= 0.37; p= 0.0224). Within the limitations of this study, it was possible to conclude that there is a correlation between IT and RFA of implants placed in the mandible and maxilla of different bone densities. PMID- 22506560 TI - Ab initio chemical kinetics for the hydrolysis of N2O4 isomers in the gas phase. AB - The mechanism and kinetics for the gas-phase hydrolysis of N(2)O(4) isomers have been investigated at the CCSD(T)/6-311++G(3df,2p)//B3LYP/6-311++G(3df,2p) level of theory in conjunction with statistical rate constant calculations. Calculated results show that the contribution from the commonly assumed redox reaction of sym-N(2)O(4) to the homogeneous gas-phase hydrolysis of NO(2) can be unequivocally ruled out due to the high barrier (37.6 kcal/mol) involved; instead, t-ONONO(2) directly formed by the association of 2NO(2), was found to play the key role in the hydrolysis process. The kinetics for the hydrolysis reaction, 2NO(2) + H(2)O <-> HONO + HNO(3) (A) can be quatitatively interpreted by the two step mechanism: 2NO(2) -> t-ONONO(2), t-ONONO(2) + H(2)O -> HONO + HNO(3). The predicted total forward and reverse rate constants for reaction (A), k(tf) = 5.36 * 10(-50)T(3.95) exp(1825/T) cm(6) molecule(-2) s(-1) and k(tr) = 3.31 * 10(-19)T(2.478) exp(-3199/T) cm(3) molecule(-1) s(-1), respectively, in the temperature range 200-2500 K, are in good agreement with the available experimental data. PMID- 22506561 TI - Novel steroid inhibitors of glucose 6-phosphate dehydrogenase. AB - Novel derivatives of the steroid DHEA 1, a known uncompetitive inhibitor of G6PD, were designed, synthesized, and tested for their ability to inhibit this dehydrogenase enzyme. Several compounds with approximately 10-fold improved potency in an enzyme assay were identified, and this improved activity translated to efficacy in a cellular assay. The SAR for steroid inhibition of G6PD has been substantially developed; the 3beta-alcohol can be replaced with 3beta-H-bond donors such as sulfamide, sulfonamide, urea, and carbamate. Improved potency was achieved by replacing the androstane nucleus with a pregnane nucleus, provided a ketone at C-20 is present. For pregnan-20-ones incorporation of a 21-hydroxyl group is often beneficial. The novel compounds generally have good physicochemical properties and satisfactory in vitro DMPK parameters. These derivatives may be useful for examining the role of G6PD inhibition in cells and will assist the future design of more potent steroid inhibitors with potential therapeutic utility. PMID- 22506562 TI - Sleep bruxism increases the risk for painful temporomandibular disorder, depression and non-specific physical symptoms. AB - To explore the relationship between sleep bruxism (SB), painful temporomandibular disorders (TMD) and psychologic status in a cross-sectional study. The sample consisted of 272 individuals. The Research Diagnostic Criteria for TMD (RDC/TMD) was used to diagnose TMD; SB was diagnosed by clinical criteria proposed by The American Academy of Sleep Medicine. The sample was divided into four groups: (1) patients without painful TMD and without SB, (2) patients without painful TMD and with SB, (3) patients with painful TMD and without SB and (4) patients with painful TMD and with SB. Data were analysed by Odds Ratio test with a 95% confidence interval. Patients with SB had an increased risk for the occurrence of myofascial pain (OR = 5.93, 95% CI: 3.19-11.02) and arthralgia (2.34, 1.58-3.46). Group 3 had an increased risk for moderate/severe depression and non-specific physical symptoms (10.1, 3.67-27.79; 14.7, 5.39-39.92, respectively), and this risk increased in the presence of SB (25.0, 9.65-64.77; 35.8, 13.94-91.90, respectively). SB seems to be a risk factor for painful TMD, and this in turn is a risk factor for the occurrence of higher depression and non-specific physical symptoms levels, but a cause-effect relationship could not be established. PMID- 22506563 TI - Epstein-Barr virus-associated B-cell lymphoma of the spleen resembling infectious mononucleosis morphologically. PMID- 22506564 TI - Case of rice allergy induced by epicutaneous sensitization to rice bran due to handling rice bran pickles. PMID- 22506565 TI - A pharmacoepidemiological network model for drug safety surveillance: statins and rhabdomyolysis. AB - BACKGROUND: Recent withdrawals of major drugs have highlighted the critical importance of drug safety surveillance in the postmarketing phase. Limitations of spontaneous report data have led drug safety professionals to pursue alternative postmarketing surveillance approaches based on healthcare administrative claims data. These data are typically analysed by comparing the adverse event rates associated with a drug of interest to those of a single comparable reference drug. OBJECTIVE: The aim of this study was to determine whether adverse event detection can be improved by incorporating information from multiple reference drugs. We developed a pharmacological network model that implemented this approach and evaluated its performance. METHODS: We studied whether adverse event detection can be improved by incorporating information from multiple reference drugs, and describe two approaches for doing so. The first, reported previously, combines a set of related drugs into a single reference cohort. The second is a novel pharmacoepidemiological network model, which integrates multiple pair-wise comparisons across an entire set of related drugs into a unified consensus safety score for each drug. We also implemented a single reference drug approach for comparison with both multi-drug approaches. All approaches were applied within a sequential analysis framework, incorporating new information as it became available and addressing the issue of multiple testing over time. We evaluated all these approaches using statin (HMG-CoA reductase inhibitors) safety data from a large healthcare insurer in the US covering April 2000 through March 2005. RESULTS: We found that both multiple reference drug approaches offer earlier detection (6-13 months) than the single reference drug approach, without triggering additional false positives. CONCLUSIONS: Such combined approaches have the potential to be used with existing healthcare databases to improve the surveillance of therapeutics in the postmarketing phase over single-comparator methods. The proposed network approach also provides an integrated visualization framework enabling decision makers to understand the key high-level safety relationships amongst a group of related drugs. PMID- 22506567 TI - Partnership with industry: Olympus' view on CROES projects. PMID- 22506566 TI - A cohort study exploring determinants of safety-related regulatory actions for biopharmaceuticals. AB - BACKGROUND: The characteristics of biopharmaceuticals may require a tailored approach to their safety management. However, information on what tools and methods are employed to assess the safety of biopharmaceuticals post authorization is lacking. OBJECTIVE: This study investigates determinants that contribute to the post-authorization management of biopharmaceuticals. METHODS: A cohort study was performed including all centrally approved biopharmaceuticals for which a Direct Healthcare Professional Communication (DHPC) was issued during 1997-2009. Safety-related regulatory actions were defined as updates of the summary of product characteristics through type II variations. Determinants of these actions were identified based on publicly available data. Urgent variations, defined as variations accompanied by a DHPC, were compared with other, 'non-urgent', safety-related variations. RESULTS: We identified 133 variations relating to 15 products, 24 urgent and 109 other variations. For 55% of urgent variations, spontaneous reports were the sole source of regulatory action, post-approval studies accounted for 33%, and 12% were based on other sources or combinations of sources. For the non-urgent variations, spontaneous reports were the sole source for 36%, post-approval studies for 28%, and 36% were based on other sources or combinations. Overall, most variations included safety issues categorized as 'infections and infestations' (33.1%), 'general disorders and administration site conditions' (25.6%), and 'neoplasms' (14.3%). CONCLUSION: Determinants of urgent and non-urgent safety-related regulatory actions of biopharmaceuticals are largely similar. Spontaneous reports are an important pillar for both urgent and non-urgent actions and remain an important tool in the post-authorization safety management of biopharmaceuticals. PMID- 22506568 TI - Statistical significance of optical map alignments. AB - The Optical Mapping System constructs ordered restriction maps spanning entire genomes through the assembly and analysis of large datasets comprising individually analyzed genomic DNA molecules. Such restriction maps uniquely reveal mammalian genome structure and variation, but also raise computational and statistical questions beyond those that have been solved in the analysis of smaller, microbial genomes. We address the problem of how to filter maps that align poorly to a reference genome. We obtain map-specific thresholds that control errors and improve iterative assembly. We also show how an optimal self alignment score provides an accurate approximation to the probability of alignment, which is useful in applications seeking to identify structural genomic abnormalities. PMID- 22506569 TI - Oral health in pregnancy: educational needs of dental professionals and office staff. AB - OBJECTIVE: Dental care during pregnancy is important for pregnant women and their children. Comprehensive guidelines for the provision of dental services for pregnant patients were published in 2006, but there is relatively little information about their use in actual practice. The aim of this study was to examine differences in knowledge and attitudes regarding dental care in pregnancy among dentists, dental hygienists, dental assistants, and nonclinical office staff. A secondary aim was to identify sources of influence on attitudes and knowledge regarding the guidelines. METHODS: A survey was used to collect information from 766 employees of a Dental Care Organization based in Oregon; responses from 546 were included in the analyses reported here. RESULTS: Statistically significant differences in knowledge were found among the professional-role groups. Dentists and hygienists consistently answered more items correctly than did other respondents. Within all professional-role groups, knowledge gaps existed and were most pronounced regarding provision of routine and emergency services. Positive perceptions of providing dental care during pregnancy were associated with higher knowledge scores (z = 4.16, P < 0.001). CONCLUSIONS: Updated dental education and continuing education for all dental office personnel are needed to promote the diffusion of current evidence-based guidelines for dental care during pregnancy. PMID- 22506570 TI - The role of antenatal factors on tibial speed of sound values in newborn infants. AB - OBJECTIVE: To evaluate the role of some antenatal factors on bone status of newborn infants. METHODS: Tibial bone speed of sound (SOS) value was measured by quantitative ultrasound within 5 days after birth in 205 neonates whose gestational ages ranged between 31 and 40 weeks. The cohort was divided into two groups according to intrauterine growth curves, as small- (SGA) and appropriate for-gestational age (AGA). All cases were also been evaluated by antenatal ultrasonography for oligohydroamniosis. RESULTS: The mean SOS value was found significantly higher in SGA (n = 43) than AGA infants (n = 162) (p < 0.001). The mean tibial SOS value of infants with a history of oligohydroamniosis (n = 28) was also higher than those without oligohydroamniosis (n = 177) (p < 0.001). But, in SGA infants with a history of oligohydroamniosis (n = 17), the mean tibial SOS value was similar to those SGA infants without oligohydroamniosis (n = 26) (p > 0.05). Infants whose mothers had smoked during pregnancy (n = 18) had significantly higher tibial SOS values compared to those of whose mothers had not (n = 187) (p = 0.006). In addition, mean tibial SOS values were determined higher in male infants (n = 116) compared to female infants (n = 89) (p = 0.036). There was a significant correlation between tibial SOS values and gestational age (r = 0.178, p = 0.011). CONCLUSIONS: While creating reference curves of SOS values at birth, smallness for gestational age, maternal smoking and gender as well as gestational age should be taken into account. PMID- 22506571 TI - Clinical predictors of apnoea-hypopnoea during propofol sedation in patients undergoing spinal anaesthesia. AB - This study assessed the relationship between the occurrence of apnoea-hypopnoea during propofol sedation for spinal anaesthesia and two different predictive tests of sleep apnoea: the STOP-Bang score (snoring while sleeping, daytime tiredness, observed breathing stoppages, high blood pressure-body mass index, age, neck circumference, gender); and the obstructive sleep apnoea (OSA) score. Thirty-four middle-aged men not diagnosed with obstructive sleep apnoea received propofol infusions adjusted to produce a bispectral index of 70-75. ApnoeaLink(TM) was used to estimate the incidence of apnoea-hypopnoea. The median (IQR [range]) apnoea-hypopnoea index was 17 (8-24 [0-70]) events.h(-1) and correlated weakly with the STOP-Bang score (p = 0.022, r = 0.423) and moderately with the OSA score (p < 0.001, r = 0.693). Severe apnoea-hypopnoea developed more frequently in patients with a higher OSA score (34.5% vs 0%) or higher STOP-Bang score (27.6% vs 6.9%). Both assessment tools have some predictive value for the occurrence of apnoea-hypopnoea during propofol sedation in patients undergoing spinal anaesthesia. PMID- 22506572 TI - Rothia dentocariosa repeat and relapsing peritoneal dialysis-related peritonitis: a case report and literature review. AB - Peritonitis is well recognized as the Achilles tendon of peritoneal dialysis (PD). Reoccurrence of peritonitis due to the same organism, defined as either repeat or relapsing peritonitis under the 2005 guidelines by the International Society for Peritoneal Dialysis, often results in PD technique failure. Rothia dentocariosa, a low-virulent human oropharynx commensal, is a rarely reported pathogen in human infection, particularly infective endocarditis. R. dentocariosa PD-related peritonitis is exceedingly uncommon yet potentially results in repeat or relapsing peritonitis which requires catheter removal. We report a case of R. dentocariosa repeat and relapsing peritonitis in a PD patient who was treated successfully with antimicrobial therapy. PMID- 22506573 TI - The role of culinary-medicinal mushrooms on human welfare with a pyramid model for human health. AB - Mushrooms are part of fungal biota characterized by wonder. They rise up from lignocellulosic wastes: yet they become so bountiful and nourishing. Mushrooms are environmentally friendly. They biosynthesize their own food from agricultural crop residues, which would otherwise cause health hazards. The extant records show the continued use of some mushrooms, e.g., Lentinus edodes, Ganoderma lucidum, and Cordyceps sinensis are now centuries old. This review presents a pyramid model for mushroom uses (industries), as food, dietary supplements (tonic), and medicine. A regular intake of mushrooms can make us healthier, fitter, and happier, and help us live longer. The sense of purpose and vision for the mushroom industries is also briefly discussed. A variety of mushrooms have been used traditionally in many different cultures for the maintenance of health and in the prevention and treatment of various diseases. A total of 126 medicinal functions are thought to be produced by medicinal mushrooms (MM) and fungi, including antitumor, immunomodulating, antioxidant, radical scavenging, cardiovascular, anti-hypercholesterolemia, antiviral, antibacterial, anti parasitic, antifungal, detoxification, hepatoprotective, and anti-diabetic effects. Special attention is paid to mushroom polysaccharides. Many, if not all, higher Basidiomycetes mushrooms contain biologically active polysaccharides in fruit bodies, cultured mycelium, and cultured broth. The data on mushroom polysaccharides are summarized for approximately 700 species of higher Hetero- and Homobasidiomycetes. In particular, the most important for modern medicine are polysaccharides with antitumor and immunostimulating properties. Several of the mushroom polysaccharide compounds have proceeded through phase I, II, and III clinical trials and are used extensively and successfully as drugs in Asia to treat various cancers and other diseases. Mushrooms are superior sources of different types of dietary supplements (DSs) (tonics). The advantages of using mushroom-based DSs as a matter of safety (as opposed to herbal preparations) are: (1) The overwhelming majority of mushrooms used for production of DSs are cultivated commercially (and not gathered in the wild). (2) Mushrooms are easily propagated vegetatively and thus keep to one clone. The mycelium can be stored for a long time, and the genetic and biochemical consistency can be checked after a considerable time. (3) The main advantage, in our opinion, is that many mushrooms are capable of growing in the form of mycelial biomass in submerged cultures. In this review, we discuss legal and regulatory issues introducing and controlling DSs from MMs in different countries, including the United States, the European Community, Australia, New Zealand, Japan, and P.R. China, and guidelines of the World Health Organization. One of the targets of the present review is also to draw attention to many critically important unsolved problems in the future development of medicinal mushroom science in the 21st century. PMID- 22506574 TI - Safety study of culinary-medicinal Royal Sun Agaricus, Agaricus brasiliensis S. Wasser et al. KA21 (higher Basidiomycetes) assessed by prokaryotic as well as eukaryotic systems. AB - As part of the safety evaluation of culinary-medicinal Royal Sun Agaricus, Agaricus brasiliensis KA21, for human consumption, we performed the bacterial reverse mutation test, the mouse micronucleus test, and mouse lymphoma test using A. brasiliensis KA21 as the test substance. The reverse mutation test utilized five bacterial strains, including Salmonella typhimurium TA100, TA1535, TA98, and TA1537, and Escherichia coli WP2 uvrAO. For the micronucleus test we used mice. For the mouse lymphoma test, we used one of the most commonly used mammalian cell mutagenesis systems; the L5178YTK +/- mouse lymphoma-TK assay detects the mutations at the thymidine kinase locus caused by base-pair changes, frameshift, and small deletions. All the tests were conducted according to the guidelines for genotoxicity testing of drugs by the Ministry of Health, Labor, and Welfare, Japan. In the bacterial reverse mutation test, no toxicity was observed up to a dose of 5,000 MUg/plate. In the mouse micronucleus test, no toxicity was noted up to a dose of 1 g/kg body weight. In the mouse lymphoma test, frequency of the mutation was equal both in the presence or absence of KA21. Supporting the long history of human consumption of A. brasiliensis, the data shown in this study strongly indicate the safety of this mushroom. PMID- 22506575 TI - Screening of medicinal higher Basidiomycetes mushrooms from Turkey for lovastatin production. AB - As a first attempt, a study was carried out to test for lovastatin production ability in local higher Basidiomycetes mushroom isolates from Turkey. An extended screening was performed for lovastatin production in yeast lactose agar medium, among a total of 136 macrofungi isolates from the Basidiomycetes Culture Collection of Eskisehir Osmangazi University. Lovastatin production was evaluated by disc diffusion method and was also confirmed by TLC and HPLC. Only six isolates were found to be lovastatin producers. The highest production of lovastatin was obtained from the extracts from Omphalotus olearius OBCC 2002 and Pleurotus ostreatus OBCC 1031. The lovastatin amount produced by commercial strains, Aspergillus terreus NRRL 255 (7.0 mg/L) and Penicillium citrinum NRRL 1841 (7.0 mg/L), was nearly comparable to the amount produced by Pleurotus ostreatus OBCC 1031 (5.8 mg/L) and Omphalotus olearius OBCC 2002 (4 mg/L). PMID- 22506576 TI - Antrodia albida (Fr.) Donk (higher Basidiomycetes) as a source of metabolites of biotechnological interest. AB - The basidiomycete Antrodia albida was grown in different culture media to study the production of biomass and its active substances. A progressive increase in fungal biomass throughout the 30-day incubation period was observed. The extracts showed discrete antibacterial activity, and the chemical analysis by gas chromatography coupled with mass spectrometry revealed a total of 17 substances in the fungal extracts, including sugars and furanones. PMID- 22506577 TI - The effect of culture liquid ethyl acetate mycelium extracts of medicinal mushrooms on the viability of human pancreatic cancer cells. AB - Pancreatic cancer, one of the deadliest of all solid malignancies, is one of the leading causes of cancer death worldwide, with 232,000 new cases and 213,000 deaths reported each year. These unfortunate statistics reflect the advanced stage at which most patients with pancreatic cancer are diagnosed and the paucity of effective chemotherapeutic regimens. Fungal metabolites have been gaining scientific interest because of their medicinal properties. In the present study, 31 different mushroom extracts of 12 medicinal mushroom species were screened for their effect on the viability of human pancreatic adenocarcinoma cells. Extraction procedures were executed with organic solvents--ethanol (EAL), ethyl acetate (EAC), and chloroform (CHL). In some cases, culture liquid (CL) extraction was also performed. All extracts were diluted to a concentration of 50 mg/mL dimethyl sulfoxide. Extract effects on cell viability were examined in human pancreatic adenocarcinoma cells HPAF-II (well differentiated) and PL5 (porrly differentiated), using XTT assay and crystal violet assay (CV). Furthermore, extract effects on LDH leakage were also studied in order to exclude necrotic damage of the extract. The screening phase revealed that among the total 31 extracts examined with various treatment doses (50-500 MUg/mL) administered for 72 h, the CL extract of the mushroom Cyathus striatus exhibited the most prominent decrease in cell viability. Moreover, exposure of cells to lower concentrations then the above (1, 2.5, 5, 7.5, 10, 15, 20, and 50 MUg/mL) for 24, 48, and 72 h showed a significant decrease in cell viability. Crystal violet results support these findings, and LDH levels measured suggest the lack of a necrotic effect of the extract. Our results indicate that C. striatus CL extract inhibits the viability of human pancreatic adenocarcinoma cells; HPAF-II and PL45. Growth inhibition can be achieved in low concentrations of the extract and a short exposure period. This effect can be mediated through apoptosis induction and/or cell cycle arrest; therefore, additional experiments are needed in order to elucidate the extract mechanism of action. These findings may lead to the development of new therapeutic strategies for the treatment of pancreatic cancer. PMID- 22506578 TI - Optimization of solid state culture conditions for the production of adenosine, cordycepin, and D-mannitol in fruiting bodies of medicinal caterpillar fungus Cordyceps militaris (L.:Fr.) Link (Ascomycetes). AB - In general, Cordyceps sinensis is much more popular than C. militaris, though both species contain quite similar bioactive ingredients and exhibit medicinal activities. Many bioactive ingredients have been isolated from C. militaris, such as adenosine, cordycepin, D-mannitol, and exopolysaccharides. C. militaris is claimed to have extensive pharmacological properties, such as: anti-inflammatory; anti-fatigue; anti-bacterial; anti-diabetic; improve lung, liver, and kidney functions; to be beneficial for treating cancer as well as male and female sexual dysfunctions. C. militaris is fast gaining momentum for its so-called health benefits, and it is often used as a substitute for C. sinensis. In view of the growing popularity of C. militaris, nowadays C. militaris cultivation for stroma is also done. There is a great diversity of compounds from different strains of Cordyceps and different artificially cultivated products. This study is to determine the optimum culture parameters integrated with substrate of choice to bring the indoor-cultivated C. militaris to a higher and more consistent level of quality. To achieve the above objective, the resultant products after growth were analyzed for adenosine, cordycepin, and D-mannitol using the high-performance liquid chromatography method. The optimum culture condition to produce a high level of adenosine is by using millet as solid substrate. It must be cultivated in the dark for the first 7 days and harvested on day 40. The optimum culture condition to produce a high level of cordycepin is by using soybean as solid substrate. It must be cultivated in the dark for the first 14 days and harvested on day 50. While a high level of D-mannitol is achieved with millet as the solid substrate. It must be kept in the dark for the first 7 days and harvested on day 50. The adenosine level decreased and cordycepin increased from day 40 of culture to day 50 generally. PMID- 22506579 TI - Optimization of cultivation conditions of fermented shaggy ink cap culinary medicinal mushroom, Coprinus comatus (O.Mull.:Fr.) Pers. (higher Basidiomycetes) rich in Vanadium. AB - The present paper is mainly aimed at optimization of cultivation conditions of fermented mushrooms of Coprinus comatus rich in vanadium (CCRV). Initial screening of effects of carbon source, temperature, pH, and inoculum size were done by using a one-factor-at-a-time method. The results obtained in that study showed that the optimal medium composition was 30 g glucose/Lin YEPG medium, initial pH 6.0, inoculum volume 10%, and incubation time 120 h. Then the medium was subjected to screening of the most significant parameters using the L9 orthogonal array to solve multivariable equations simultaneously. The results obtained in this study showed that the optimal medium composition was 0.4% V and 30 g glucose/Lin YEPG medium, initial pH 5.0, inoculum volume 15%, and incubation time 120 h. At this medium composition, the mycelial biomass and V content were 7.18 +/- 0.24 g/L and 3786.0 +/- 17 MUg/g, respectively. The anti-diabetic potential of CCRV produced with the optimal level was tested in alloxan-induced diabetes. After the mice were administered (i.g.) with CCRV, the level of blood sugar in the CCRV group was very close to that of the control group. These findings suggested that CCRV produced with the optimal level is useful in the control of diabetes mellitus. PMID- 22506580 TI - Production of biomass, polysaccharides, and ganoderic acid using non-conventional carbon sources under submerged culture of the Lingzhi or Reishi medicinal mushroom, Ganoderma lucidum (W.Curt.:Fr.)P. Karst. (higher Basidiomycetes). AB - The effect of different non-conventional carbon sources was studied in the submerged culture of Lingzhi or Reishi medicinal mushroom, Ganoderma lucidum, for simultaneous production of mycelial biomass, bioactive ganoderic acid, and polysaccharides, in less time, using non-conventional carbon sources to minimize the high costs of current culture media. The optimal medium composition was defined as (g/L): 50 of barley flour, 0.2 of KH2PO4, 0.1 of MgSO4i7H2O, and 1 NH4Cl. Cultivated under this complex culture medium, the mycelial biomass production was 23.49 +/- 0.37 g/L; the extracellular polysaccharides production was 2.72 +/- 0.11 g/L; the intracellular polysaccharides production was 2.22 +/- 0.06 g/L; the ganoderic acids production was 299.67 +/- 11.63 mg/L. One liter of culture medium developed in this project was priced at USD $ 0.11 if barley flour is used as carbon source or $ 0.13 with oat flour in order to get a good amount of products of interest. PMID- 22506581 TI - Groups 5 and 6 terminal hydrazido(2-) complexes: N(beta) substituent effects on ligand-to-metal charge-transfer energies and oxidation states. AB - Brightly colored terminal hydrazido(2-) (dme)MCl(3)(NNR(2)) (dme = 1,2 dimethoxyethane; M = Nb, Ta; R = alkyl, aryl) or (MeCN)WCl(4)(NNR(2)) complexes have been synthesized and characterized. Perturbing the electronic environment of the beta (NR(2)) nitrogen affects the energy of the lowest-energy charge-transfer (CT) transition in these complexes. For group 5 complexes, increasing the energy of the N(beta) lone pair decreases the ligand-to-metal CT (LMCT) energy, except for electron-rich niobium dialkylhydrazides, which pyramidalize N(beta) in order to reduce the overlap between the Nb?N(alpha) pi bond and the N(beta) lone pair. For W complexes, increasing the energy of N(beta) eventually leads to reduction from formally [W(VI)=N-NR(2)] with a hydrazido(2-) ligand to [W(IV)?N?NR(2)] with a neutral 1,1-diazene ligand. The photophysical properties of these complexes highlight the potential redox noninnocence of hydrazido ligands, which could lead to ligand- and/or metal-based redox chemistry in early transition metal derivatives. PMID- 22506582 TI - Pre-operative use of anti-TNF-alpha agents and the risk of post-operative complications in patients with ulcerative colitis - a nationwide cohort study. AB - BACKGROUND: It is still controversial whether pre-operative anti-tumour necrosis factor-alpha (anti-TNF-alpha) agents increase post-operative complications in patients with ulcerative colitis (UC). AIM: In a nationwide Danish cohort of patients with UC, we aimed to examine the impact of pre-operative use of anti-TNF alpha agents on post-operative adverse outcomes after colectomy for UC. Outcomes (within 30 and 60 days after surgery) were reoperation, anastomosis leakage, intra-abdominal abscess, bacteremia and death. METHODS: Based on the Danish National Patient Registry we identified all UC patients, aged >=15 years, having their first surgery for UC in the period of 1 January 2003-31 December 2010 (n = 1226). Patients were classified according to use of anti-TNF-alpha agents within 12 weeks before surgery or not. Outcome data were obtained from Danish registries. Logistic regression analyses were used to estimate adjusted risks [with 95% confidence intervals (CI)] of post-operative outcomes among patients treated with anti-TNF-alpha agents, relative to those not treated. RESULTS: A total of 199 UC patients were exposed to anti-TNF-alpha agents within 12 weeks before colectomy, and 1027 were not. Among exposed, the adjusted odds ratio of reoperation and anastomosis leakage within 30 days after colectomy was 1.07 (95% CI: 0.71-1.59) and 0.52 (95% CI: 0.06-4.11) respectively. No deaths, cases of abscess drainage or bacteremia occurred among exposed within 30 days. Furthermore, no increased relative risks were found within 60 days after colectomy. CONCLUSIONS: Based on nationwide data on UC patients having colectomies, pre-operative use of anti-TNF-alpha agents did not increase the risk of post-operative complications. PMID- 22506584 TI - Identifying careless responses in survey data. AB - When data are collected via anonymous Internet surveys, particularly under conditions of obligatory participation (such as with student samples), data quality can be a concern. However, little guidance exists in the published literature regarding techniques for detecting careless responses. Previously several potential approaches have been suggested for identifying careless respondents via indices computed from the data, yet almost no prior work has examined the relationships among these indicators or the types of data patterns identified by each. In 2 studies, we examined several methods for identifying careless responses, including (a) special items designed to detect careless response, (b) response consistency indices formed from responses to typical survey items, (c) multivariate outlier analysis, (d) response time, and (e) self reported diligence. Results indicated that there are two distinct patterns of careless response (random and nonrandom) and that different indices are needed to identify these different response patterns. We also found that approximately 10% 12% of undergraduates completing a lengthy survey for course credit were identified as careless responders. In Study 2, we simulated data with known random response patterns to determine the efficacy of several indicators of careless response. We found that the nature of the data strongly influenced the efficacy of the indices to identify careless responses. Recommendations include using identified rather than anonymous responses, incorporating instructed response items before data collection, as well as computing consistency indices and multivariate outlier analysis to ensure high-quality data. PMID- 22506583 TI - An FT-IR study on packing defects in mixed beta-aggregates of poly(L-glutamic acid) and poly(D-glutamic acid): a high-pressure rescue from a kinetic trap. AB - Under favorable conditions of pH and temperature, poly(L-glutamic acid) (PLGA) adopts different types of secondary and quaternary structures, which include spiral assemblies of amyloid-like fibrils. Heating of acidified solutions of PLGA (or PDGA) triggers formation of beta(2)-type aggregates with morphological and tinctorial properties typical for amyloid fibrils. In contrast to regular antiparallel beta-sheet (beta(1)), the amide I' vibrational band of beta(2) fibrils is unusually red-shifted below 1600 cm(-1), which has been attributed to bifurcated hydrogen bonds coupling C?O and N-D groups of the main chains to glutamic acid side chains. However, unlike for pure PLGA, the amide I' band of aggregates precipitating from racemic mixtures of PLGA and PDGA (beta(1)) is dominated by components at 1613 and 1685 cm(-1)-typically associated with intermolecular antiparallel beta-sheets. The coaggregation of PLGA and PDGA chains is slower and biphasic and leads to less-structured assemblies of fibrils, which is reflected in scanning electron microscopy images, sedimentation properties, and fluorescence intensity after staining with thioflavin T. The beta(1)-type aggregates are metastable, and they slowly convert to fibrils with the infrared characteristics of beta(2)-type fibrils. The process is dramatically accelerated under high pressure. This implies the presence of void volumes within structural defects in racemic aggregates, preventing the precise alignment of main and side chains necessary to zip up ladders of bifurcated hydrogen bonds. As thermodynamic costs associated with maintaining void volumes within the racemic aggregate increase under high pressure, a hyperbaric treatment of misaligned chains leads to rectifying the packing defects and formation of the more compact form of fibrils. PMID- 22506586 TI - Spatial frequencies in aesthetic website evaluations--explaining how ultra-rapid evaluations are formed. AB - This study investigates how aesthetic website evaluations, especially those formed after very brief presentations, depend on visual information that is encoded in low- or high-spatial frequencies. A total of 92 participants took part in the experiment. The study used a 3 * 3 mixed design in which presentation time (50, 500 and 10000 ms) and spatial filtering (low-pass filtered, high-pass filtered and unfiltered stimuli) were manipulated. First, we replicate prior results from online studies of high- and low-spatial frequencies. Second, we confirm a prediction from neurocognitive models that only low-spatial frequencies are relevant to aesthetic judgements in ultra-rapid presentation modes. Third, we demonstrate that stimulus repetitions lead to an overestimation of the importance of ultra-rapid stimulus presentations. Taken together, our results highlight the utility of neurocognitive models of visual processing to explain the rapid aesthetic evaluation of websites. PRACTITIONER SUMMARY: Using neurocognitive models we present an approach to explain how aesthetic impressions are formed. We show that ultra-rapid judgements are connected with low- but not with high spatial frequencies, which are neurologically processed in different visual pathways. Furthermore we identify possible methodological problems in previous studies of ultra-rapid website perception. PMID- 22506587 TI - Synthesis, characterization, and 3D-FDTD simulation of Ag@SiO2 nanoparticles for shell-isolated nanoparticle-enhanced Raman spectroscopy. AB - Au-seed Ag-growth nanoparticles of controllable diameter (50-100 nm), and having an ultrathin SiO(2) shell of controllable thickness (2-3 nm), were prepared for shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS). Their morphological, optical, and material properties were characterized; and their potential for use as a versatile Raman signal amplifier was investigated experimentally using pyridine as a probe molecule and theoretically by the three dimensional finite-difference time-domain (3D-FDTD) method. We show that a SiO(2) shell as thin as 2 nm can be synthesized pinhole-free on the Ag surface of a nanoparticle, which then becomes the core. The dielectric SiO(2) shell serves to isolate the Raman-signal enhancing core and prevent it from interfering with the system under study. The SiO(2) shell also hinders oxidation of the Ag surface and nanoparticle aggregation. It significantly improves the stability and reproducibility of surface-enhanced Raman scattering (SERS) signal intensity, which is essential for SERS applications. Our 3D-FDTD simulations show that Ag core SHINERS nanoparticles yield at least 2 orders of magnitude greater enhancement than Au-core ones when excited with green light on a smooth Ag surface, and thus add to the versatility of our SHINERS method. PMID- 22506588 TI - Dialectical thinking and health behaviors: the effects of theory of planned behavior. AB - The primary purpose of this study was to investigate whether the theory of planned behavior (TPB) mediated the relationship between dialectical thinking and health behaviors. A sample of 285 undergraduates was tested with a dialectical thinking styles scale, health promoting lifestyle profiles, and TPB questionnaires. Structural equation modeling was used for data analysis. Results indicated that all the three dimensions of thinking styles (belief in the connection, acceptance of change, and acceptance of contradiction) exerted significant effects on TPB constructs. Specifically, the connection and the change dimensions had positive effects on health behaviors mediated by TPB, whereas the contradiction dimension had a negative effect. Model 2 showed a satisfactory fit, demonstrating the influential pathways between dialectical thinking and health behaviors. Implications in issues of health promotion and future research are discussed. PMID- 22506589 TI - Selective gas sensing with a single pristine graphene transistor. AB - We show that vapors of different chemicals produce distinguishably different effects on the low-frequency noise spectra of graphene. It was found in a systematic study that some gases change the electrical resistance of graphene devices without changing their low-frequency noise spectra while other gases modify the noise spectra by inducing Lorentzian components with distinctive features. The characteristic frequency f(c) of the Lorentzian noise bulges in graphene devices is different for different chemicals and varies from f(c) = 10 20 Hz to f(c) = 1300-1600 Hz for tetrahydrofuran and chloroform vapors, respectively. The obtained results indicate that the low-frequency noise in combination with other sensing parameters can allow one to achieve the selective gas sensing with a single pristine graphene transistor. Our method of gas sensing with graphene does not require graphene surface functionalization or fabrication of an array of the devices with each tuned to a certain chemical. PMID- 22506591 TI - Active implant peri-apical lesion: a case report treated via guided bone regeneration with a 5-year clinical and radiographic follow-up. AB - Abstract Implant peri-apical lesion (IPL) is a periapical lesion, usually asyntomatic, in which the coronal portion of the implant achieves a normal bone to implant interface. A case of IPL following immediate implant placement and treated with GBR principles is described. Five year clinical and radiographic follow-up with cone-beam assessment showed complete healing of the bone. GBR principles applied to IPL could completely solve the lesion. PMID- 22506590 TI - Positive allosteric modulation by ivermectin of human but not murine P2X7 receptors. AB - BACKGROUND AND PURPOSE: In mammalian cells, the anti-parasitic drug ivermectin is known as a positive allosteric modulator of the ATP-activated ion channel P2X4 and is used to discriminate between P2X4- and P2X7-mediated cellular responses. In this paper we provide evidence that the reported isoform selectivity of ivermectin is a species-specific phenomenon. EXPERIMENTAL APPROACH: Complementary electrophysiological and fluorometric methods were applied to evaluate the effect of ivermectin on recombinantly expressed and on native P2X7 receptors. A biophysical characterization of ionic currents and of the pore dilation properties is provided. KEY RESULTS: Unexpectedly, ivermectin potentiated currents in human monocyte-derived macrophages that endogenously express hP2X7 receptors. Likewise, currents and [Ca(2+) ](i) influx through recombinant human (hP2X7) receptors were potently enhanced by ivermectin at submaximal or saturating ATP concentrations. Since intracellular ivermectin did not mimic or prevent its activity when applied to the bath solution, the binding site of ivermectin on hP2X7 receptors appears to be accessible from the extracellular side. In contrast to currents through P2X4 receptors, ivermectin did not cause a delay in hP2X7 current decay upon ATP removal. Interestingly, NMDG(+) permeability and Yo-Pro-1 uptake were not affected by ivermectin. On rat or mouse P2X7 receptors, ivermectin was only poorly effective, suggesting a species specific mode of action. CONCLUSIONS AND IMPLICATIONS: The data indicate a previously unrecognized species-specific modulation of human P2X7 receptors by ivermectin that should be considered when using this cell-biological tool in human cells and tissues. PMID- 22506592 TI - NAT2 and CYP2E1 polymorphisms associated with antituberculosis drug-induced hepatotoxicity in Chinese patients. AB - 1. The present study investigated the relationship between antituberculosis (anti TB) drug-induced hepatotoxicity and genetic polymorphisms of two important drug metabolizing enzymes involved in the metabolism of isoniazid, namely N acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1). 2. A polymerase chain reaction direct sequencing approach was used to detect genetic polymorphisms of the NAT2 and CYP2E1 genes in tuberculosis (TB) patients with (n = 101) or without (n = 107) anti-TB drug-induced hepatotoxicity. Associations between various genetic polymorphisms and anti-TB drug-induced hepatotoxicity were then determined. 3. Patients with NAT2 (282TT , 590AA and 857GA) alleles had an increased susceptibility to anti-TB drug-induced hepatotoxicity. The slow acetylator NAT2 genotypes (especially NAT2*6A/7B and NAT2*6A/6A) were risk factors for hepatotoxicity (odds ratio (OR) 9.57 (P < 0.001) for NAT2*6A/7B; OR 5.24 (P = 0.02) for NAT2*6A/6A). 4. The CYP2E1 genotype per se was not significantly associated with the development of anti-TB drug-induced hepatotoxicity. However, the combination of the CYP2E1 C1/C1 genotype with a slow acetylator NAT2 genotype increased the risk of anti-TB drug-induced hepatotoxicity (OR 5.33; P = 0.003) compared with the combination of a rapid acetylator NAT2 genotype with either a C1/C2 or C2/C2 genotype. 5. Thus, slow acetylators with the NAT2*6A/7B and NAT2*6A/6A genotypes combined with the C1/C1 CYP2E1 genotype may be involved in the pathogenesis of anti-TB drug-induced hepatotoxicity. 6. The present findings may be explained, in part, by changes in the metabolism of the anti-TB drug isoniazid induced via NAT2 and CYP2E1, a metabolic process known to produce hepatotoxic intermediates. PMID- 22506593 TI - Size selectivity in field-flow fractionation: lift mode of retention with near wall lift force. AB - A simple theoretical model for the size selectivity, S(d), in the lift mode of retention in field-flow fractionation (FFF) is developed on the basis of the near wall lift force expression. S(d) is made up of two contributions: the flow contribution, S(d,f), arising from the variation of the flow velocity at center of particle due to a change in particle position with particle size, and a slip contribution, S(d,s), arising from the concomitant change in the extent of retardation due to the presence of a nearby channel wall. The slip contribution is minor, but not negligible, and amounts to 10-20% of the overall size selectivity. It contributes to reduce S(d) in sedimentation FFF but to enhance it in flow FFF. S(d) would steadily increase with particle size if the flow profile was linear (Couette flow). Because of the curvature of the flow profile encountered in the classical Poiseuille flow, S(d) exhibits a maximum at some specific particle size. The model predicts a significant difference in S(d) between sedimentation FFF and flow FFF, arising from the different functional dependences of the field force with particle size between these two methods. The predictions are in good agreement with the various S(d) values reported in the literature in both sedimentation and flow FFF. On the basis of the model, guidelines are given for adjusting the operating parameters (carrier flow rate and field strength) to optimize the size selectivity. Finally, it is found that S(d) generally decreases with decreasing channel thickness. PMID- 22506594 TI - Selective inhibition of human type-5 17beta-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis. AB - The human aldo-keto reductase (AKR) 1C3, also known as type-5 17beta hydroxysteroid dehydrogenase and prostaglandin F synthase, has been suggested as a therapeutic target in the treatment of prostate and breast cancers. In this study, AKR1C3 inhibition was examined by Brazilian propolis-derived cinnamic acid derivatives that show potential antitumor activity, and it was found that baccharin (1) is a potent competitive inhibitor (K(i) 56 nM) with high selectivity, showing no significant inhibition toward other AKR1C isoforms (AKR1C1, AKR1C2, and AKR1C4). Molecular docking and site-directed mutagenesis studies suggested that the nonconserved residues Ser118, Met120, and Phe311 in AKR1C3 are important for determining the inhibitory potency and selectivity of 1. The AKR1C3-mediated metabolism of 17-ketosteroid and farnesal in cancer cells was inhibited by 1, which was effective from 0.2 MUM with an IC(50) value of about 30 MUM. Additionally, 1 suppressed the proliferation of PC3 prostatic cancer cells stimulated by AKR1C3 overexpression. This study is the first demonstration that 1 is a highly selective inhibitor of AKR1C3. PMID- 22506595 TI - Impact of inherited thrombophilias on first and second trimester maternal serum markers for aneuploidy. AB - OBJECTIVE: To evaluate first and second-trimester maternal serum markers in pregnancies complicated with inherited thrombophilias. METHODS: A case-control study was conducted in 50 pregnancies complicated with hereditary thrombophilia and 100 control pregnancies. RESULTS: Each woman with inherited thrombophilia received low molecular weight heparin (LMWH) throughout her pregnancy. Gravidity, parity, number of first-trimester and second-trimester abortions, and rate of adverse pregnancy outcomes (APO) were significantly higher in the thrombophilia group compared to the control group (P < 0.001 for all). Among the thrombophilia group median values of pregnancy associated placental protein-A (PAPP-A) (0.6 vs. 0.9; P < 0.001) and free beta-human chorionic gonadotropin (beta-hCG) (0.9 vs. 1.1; P = 0.001) in the first trimester; median values of alpha-fetoprotein (AFP) (0.7 vs. 1.1; P = 0.027), unconjugated estriol 3 (uE3) (0.9 vs. 1.1; P < 0.001), and hCG (0.7 vs. 1.2; P < 0.001) in the second trimester were significantly lower with respect to control pregnancies. Multivariate analysis revealed that low uE3 and hCG levels were independently associated with APO. CONCLUSION: Pregnant women with hereditary thrombophilias, all of whom were treated with LMWH, had decreased levels of all first and second trimester serum markers. In addition, levels of hCG and uE3 in the second trimester could independently predict placenta-related disorders and adverse outcomes in these patients. PMID- 22506596 TI - Phase I and pharmacokinetic study of the oral histone deacetylase inhibitor vorinostat in Japanese patients with relapsed or refractory cutaneous T-cell lymphoma. AB - A phase I study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of the oral histone deacetylase (HDAC) inhibitor vorinostat in Japanese patients with relapsed or refractory cutaneous T cell lymphoma (CTCL). Six patients received vorinostat (400 mg p.o., once daily). Dose-limiting toxicities (DLT) were evaluated in all six patients during the 28 days of the first cycle. One of the six patients who received vorinostat developed a DLT (grade 4 thrombocytopenia). The most common drug-related adverse events included nausea (4/6, 67%), thrombocytopenia (4/6, 67%), hyperbilirubinemia (3/6, 50%) and vomiting (3/6, 50%). Most of these events were reversible and were resolved by supportive care and/or the interruption of vorinostat treatment. The safety and PK profiles of vorinostat in Japanese patients with CTCL did not appear to differ from those previously observed in non Japanese and Japanese patients with advanced solid tumors. None of the patients achieved an objective response in this study. However, one unconfirmed partial response and two cases of sustained stable disease for 12 weeks or longer were observed among the six patients in the study. One of the three evaluable patients experienced pruritus relief. Vorinostat was well tolerated at a dose of 400 mg p.o. once daily and showed potential efficacy in Japanese patients with CTCL, warranting further investigation. PMID- 22506597 TI - Factors associated with mutans streptococci among young WIC-enrolled children. AB - OBJECTIVES: The objective of this study is to assess relationships between the presence or absence of mutans streptococci (MS) and other covariates in children aged 12-49 months. METHODS: Data were analyzed using baseline information from 411 children enrolled in the Special Supplemental Food Program for Women, Infants and Children (WIC) who participated in a psychoeducational study in Iowa. Children were assessed for MS using a semiquantitative method (RODAC plates). Dental examinations using d(1) d(2) .(3) criteria and presence of visible plaque on incisors and molars were completed. Mothers completed a series of detailed questionnaires regarding their child's oral health, their socioeconomic status, their child's dietary/oral hygiene habits, and beverage consumption, among other behaviors. Bivariate relationships with the presence of MS were assessed and followed by multivariable modeling using logistic regression (alpha = 0.05). RESULTS: MS was present in 144 children (35 percent). Bivariate relationships with MS presence were identified for multiple covariates that included demographic characteristics, type of beverage consumption, dental caries, and plaque measures. Multivariate logistic regression modeling suggested that MS presence in children was positively associated with nonwhite race of the child, number of teeth present, presence of cavitated lesions, proportion of teeth with plaque, and lower levels of maternal education. CONCLUSIONS: The presence of MS was associated with greater caries and plaque scores and with low maternal education and nonwhite racial background. PMID- 22506598 TI - Detection of anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer and related issues in ALK inhibitor therapy: a literature review. AB - Anaplastic lymphoma kinase (ALK) encodes a receptor tyrosine kinase, and ALK gene rearrangement (ALK+) is implicated in the oncogenesis of non-small cell lung carcinomas (NSCLCs), especially adenocarcinomas. The ALK inhibitor crizotinib was approved in August 2011 by the US Food and Drug Administration (FDA) for treating late-stage NSCLCs that are ALK+, with a companion fluorescent in situ hybridization (FISH) test using the Vysis ALK Break Apart FISH Probe Kit. This review covers pertinent issues in ALK testing, including approaches to select target patients for the test, pros and cons of different detection methods, and mechanisms as well as monitoring of acquired crizotinib resistance in ALK+ NSCLCs. PMID- 22506600 TI - NME1 and NME2 as markers for myeloid leukemias. PMID- 22506599 TI - SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing. AB - The lion's share of bacteria in various environments cannot be cloned in the laboratory and thus cannot be sequenced using existing technologies. A major goal of single-cell genomics is to complement gene-centric metagenomic data with whole genome assemblies of uncultivated organisms. Assembly of single-cell data is challenging because of highly non-uniform read coverage as well as elevated levels of sequencing errors and chimeric reads. We describe SPAdes, a new assembler for both single-cell and standard (multicell) assembly, and demonstrate that it improves on the recently released E+V-SC assembler (specialized for single-cell data) and on popular assemblers Velvet and SoapDeNovo (for multicell data). SPAdes generates single-cell assemblies, providing information about genomes of uncultivatable bacteria that vastly exceeds what may be obtained via traditional metagenomics studies. SPAdes is available online ( http://bioinf.spbau.ru/spades ). It is distributed as open source software. PMID- 22506601 TI - Effect of low birth weight on impaired renal development and function and hypertension in rat model. AB - BACKGROUND/AIM: Epidemiological studies have shown that low birth weight (LBW) is associated with a higher incidence of hypertension in adulthood. LBW may affect the kidney development, which in turn leads to impaired renal function and hypertension. METHODS: Sprague-Dawley rats were fed isocaloric diets containing either 21% (w/w) (control group) or 10% (w/w) (LBW group) protein throughout pregnancy and chow during lactation. Renal function and structure of the offspring were measured from birth to 3 months. RESULTS: At 3 weeks and 2 months, there was no difference in the volume of 24 h urine protein between the two groups. However, the volume was higher (117.17 +/- 10.40 vs. 79.28 +/- 14.26, p < 0.01) in LBW group at 3 months. Maternal protein intake did not alter serum creatinine in this study, but urine creatinine was lower in LBW group at 2 and 3 months. The creatinine clearance rate (Ccr) was significantly lower in LBW group than in control group at all time points. Glomerular number was reduced significantly in LBW group (22,720 +/- 639 vs. 28,520 +/- 526, p < 0.01) at 2 months, which was accompanied by an increase in blood pressure. There was a statistically significant negative correlation between the blood pressure and the glomerular number at 2 months (r = -0.919, p = 0.008). CONCLUSIONS: These data showed that abnormal kidney development and renal dysfunction occurred in LBW rats due to a maternal low-protein diet. Possessing a decreased glomerular number might be a risk factor for hypertension in LBW rats. PMID- 22506603 TI - Age, gender, and arousal in recognition of negative and neutral pictures 1 year later. AB - Compared with nonarousing stimuli, arousing stimuli enhance memory performance. The most robust effects have been reported for negative stimuli, "the negativity effect," although a number of mediating factors prevent definitive conclusions, for example, age, gender, memory task, retention period, and alternative arousal measures. To clarify whether the negativity effect is robust across age, gender, and time, we studied incidental recognition of neutral and negative pictures from the International Affective Picture System (Lang, Bradley, & Cuthbert, 1999) in healthy younger and older adults--women and men--after a 1-year retention interval. Memory performance was related to 2 arousal measures at encoding, skin conductance response (SCR), and intensity rating of unpleasantness. The results showed weaker overall memory performance for older adults compared with younger adults. The negativity effect on accuracy (d') was gender dependent and age independent. In contrast, the negativity effect on response bias (c) interacted with age, but not gender, being weaker for older adults. Despite significant differences in arousal (SCR and arousal rating) between negative and neutral pictures, the correlations between arousal measures and memory performance were weak. Controlling for age and gender, a small negative partial correlation was found between arousal ratings and accuracy. The results extend previous studies by relating long-term recognition to both age and gender as well as to arousal at encoding. PMID- 22506604 TI - Alteration of nC60 in the presence of environmentally relevant carboxylates. AB - C(60) forms colloidally stable nanoscale particles (nC(60)) when mixed with water for extended periods. Past studies have shown that macromolecules such as natural organic matter (NOM) and proteins accelerate nC(60) formation and stabilize the resulting nanoparticles. To better elucidate the mechanisms underlying this behavior, nC(60) was produced via extended mixing in the presence of sodium citrate and other carboxylates. Carboxyl groups are a predominant functional group in many environmentally relevant macromolecules, thus studies examining carboxyl-C(60) interactions are merited. nC(60) produced in the presence of citrate (cit/nC(60)) and other carboxylates differs from nC(60) produced in water alone (aq/nC(60)), exhibiting enhanced negative surface charge, smaller particle size, and different spectroscopic characteristics. Importantly, the simultaneous detection of irregular nC(60) nanoparticles and small, regularly shaped nC(60) suggests that mixing-mediated "top-down" and carboxyl group-mediated "bottom-up" processes occur concurrently when nC(60) is produced in the presence of carboxylates and, by extension, in the presence of carboxylate-containing macromolecules. The "bottom-up" process is expected to involve molecular C(60) or small clusters of C(60) molecules as an important intermediate. PMID- 22506605 TI - On the plausibility of homeopathic 'similitude'. AB - The homeopathic principle of similitude is not based on the principle of vaccination but on the more general principle of inversion of effects, a widespread medical phenomenon. Based on the systemic networks which play an important role in response to stress, this principle concerns the reorganization of regulation systems, through a coherent response to the medicine. This model is backed by a large number of published studies from our laboratory and others, by toxicological evidence such as the emerging fields of 'hormesis', of neuropharmacology, and of systems biology. The immune system is just one example of the possible application of this law of similitude, which constitutes the true 'heart' of the homeopathic idea, and again ethically justifies the attempt to apply it to experimental pharmacology. PMID- 22506606 TI - Dye molecular structure device open-circuit voltage correlation in Ru(II) sensitizers with heteroleptic tridentate chelates for dye-sensitized solar cells. AB - Dicarboxyterpyridine chelates with pi-conjugated pendant groups attached at the 5 or 6-position of the terminal pyridyl unit were synthesized. Together with 2,6 bis(5-pyrazolyl)pyridine, these were used successfully to prepare a series of novel heteroleptic, bis-tridentate Ru(II) sensitizers, denoted as TF-11-14. These dyes show excellent performance in dye-sensitized solar cells (DSCs) under AM1.5G simulated sunlight at a light intensity of 100 mW cm(-2) in comparison with a reference device containing [Ru(Htctpy)(NCS)(3)][TBA](3) (N749), where H(3)tctpy and TBA are 4,4',4"-tricarboxy-2,2':6',2"-terpyridine and tetra-n-butylammonium cation, respectively. In particular, the sensitizer TF-12 gave a short-circuit photocurrent of 19.0 mA cm(-2), an open-circuit voltage (V(OC)) of 0.71 V, and a fill factor of 0.68, affording an overall conversion efficiency of 9.21%. The increased conjugation conferred to the TF dyes by the addition of the pi conjugated pendant groups increases both their light-harvesting and photovoltaic energy conversion capability in comparison with N749. Detailed recombination processes in these devices were probed by various spectroscopic and dynamics measurements, and a clear correlation between the device V(OC) and the cell electron lifetime was established. In agreement with several other recent studies, the results demonstrate that high efficiencies can also be achieved with Ru(II) sensitizers that do not contain thiocyanate ancillaries. This bis tridentate, dual-carboxy anchor configuration thus serves as a prototype for future omnibearing design of highly efficient Ru(II) sensitizers suited for use in DSCs. PMID- 22506607 TI - Novice performance of ultrasound-guided needle advancement: standard 38-mm transducer vs 25-mm hockey stick transducer. AB - The optimal method to develop expertise in ultrasound-guided regional anaesthesia is unknown. Studies of laryngoscopic expertise in novices demonstrate that the choice of laryngoscope affects performance. In this study, we aimed to compare the effect of two different linear array transducers (38-mm standard vs 25-mm hockey stick) on novice performance of ultrasound-guided needle advancement. Following randomisation, participants watched a video model of expert performance of ultrasound-guided needle advancement. Recruits performed the modelled task on a turkey breast model. The median (IQR [range]) composite error score was statistically significantly larger for participants in the hockey stick transducer group compared with the standard transducer group; 10.0 (7.3-14.3 [2.5 29.0]) vs 7.5 (4.5-10.0 [2.0-28.0]) respectively, (p = 0.01). This study has demonstrated that performance of ultrasound-guided needle advancement by novice operators after simple video instruction is better (as assessed using a composite error score) with a standard 38-mm transducer than with a 25-mm hockey stick transducer. PMID- 22506608 TI - Taxonomy of the extrasolar planet. AB - When a star is described as a spectral class G2V, we know that the star is similar to our Sun. We know its approximate mass, temperature, age, and size. When working with an extrasolar planet database, it is very useful to have a taxonomy scale (classification) such as, for example, the Harvard classification for stars. The taxonomy has to be easily interpreted and present the most relevant information about extrasolar planets. I propose an extrasolar planet taxonomy scale with four parameters. The first parameter concerns the mass of an extrasolar planet in the form of units of the mass of other known planets, where M represents the mass of Mercury, E that of Earth, N Neptune, and J Jupiter. The second parameter is the planet's distance from its parent star (semimajor axis) described in a logarithm with base 10. The third parameter is the mean Dyson temperature of the extrasolar planet, for which I established four main temperature classes: F represents the Freezing class, W the Water class, G the Gaseous class, and R the Roasters class. I devised one additional class, however: P, the Pulsar class, which concerns extrasolar planets orbiting pulsar stars. The fourth parameter is eccentricity. If the attributes of the surface of the extrasolar planet are known, we are able to establish this additional parameter where t represents a terrestrial planet, g a gaseous planet, and i an ice planet. According to this taxonomy scale, for example, Earth is 1E0W0t, Neptune is 1N1.5F0i, and extrasolar planet 55 Cnc e is 9E-1.8R1. PMID- 22506609 TI - A cognitive perspective on mindfulness. AB - Mindfulness, the core teaching of the Buddhist tradition, has been receiving serious attention from the West in recent decades as evidence of the efficacy of mindfulness-based interventions for emotional distress have become available. Although traditional Buddhist texts have described the mechanisms of mindfulness and the way to cultivate it in great detail, much is still not known from the perspective of Western science. In particular, there is no general agreement on the conceptualization and operationalization of mindfulness. Several conceptual models of mindfulness (referred to as "state" or "trait") have been put forward to elucidate different aspects of this phenomenon, but none has gained sufficient empirical validation. This article proposes a new cognitive model of mindfulness. It has been our goal to describe and interrelate a relatively comprehensive group of determinants of a state of mindfulness, the consequences of its regular practicing, the mechanisms responsible for its beneficial effects, and the feedback mechanisms operating between the various constituents of the model. Within this model, the primary emphasis has been placed on understanding the cognitive processes shaping a state of mindfulness (i.e., the links between consciousness, meta-awareness and the unconscious), and on their determinants (i.e., the executive functions of attention and the components of working memory). A metacognitive system promoting mindfulness, as well as the general capability of the central executive system, is suggested as a factor explaining individual differences in mindfulness, whereas decentering, self-compassion, and reduction of self-focused attention are proposed as mechanisms mediating beneficial changes. We hope that the model presented will encourage further discussion and orient future studies in the area of mindfulness. PMID- 22506610 TI - Engineering the hypersonic phononic band gap of hybrid Bragg stacks. AB - We report on the full control of phononic band diagrams for periodic stacks of alternating layers of poly(methyl methacrylate) and porous silica combining Brillouin light scattering spectroscopy and theoretical calculations. These structures exhibit large and robust on-axis band gaps determined by the longitudinal sound velocities, densities, and spacing ratio. A facile tuning of the gap width is realized at oblique incidence utilizing the vector nature of the elastic wave propagation. Off-axis propagation involves sagittal waves in the individual layers, allowing access to shear moduli at nanoscale. The full theoretical description discerns the most important features of the hypersonic one-dimensional crystals forward to a detailed understanding, a precondition to engineer dispersion relations in such structures. PMID- 22506611 TI - Eight-year Follow-up of a Fixed-Detachable Maxillary Prosthesis Utilizing an Attachment System: Clinical protocol for individuals with skeletal Class III malocclusions. AB - Abstract Objective: The aim of this article is to describe a successful clinical protocol for prosthodontic rehabilitation of a patient with a skeletal Class III malocclusion using a fixed-detachable maxillary prosthesis supported by six implants and the MK1 attachment system. The patient was followed up for eight years. Clinical report: A 46 year-old edentulous woman with a skeletal Class III malocclusion expressed dissatisfaction with her old existing maxillary denture from an aesthetic point of view, and frustration regarding its function. A fixed detachable maxillary prosthesis using the MK1 attachment system was made. The patient was followed up clinically and radiographically for eight years. No bone loss, fracture of prosthetic components, or fracture of the prosthesis was detected in that period. Conclusion: A fixed detachable maxillary prosthesis utilizing the MK1 attachment system is a treatment option for patients with class III malocclusions who opt not to undergo orthognathic surgery. PMID- 22506612 TI - Androgens and doping tests: genetic variation and pit-falls. AB - The large variation in disposition known for most drugs is also true for anabolic androgenic steroids. Genetic factors are probably the single most important cause of this variation. Further, there are reasons to believe that there is a corresponding variation in efficacy of doping agents. Doped individuals employ a large variety of doping strategies in respect of choice of substance, dose, dose interval, duration of treatment and use of other drugs for enforcement of effects or correction of side effects. Metabolic steps up-stream and down-stream of testosterone are genetically variable and contribute substantially to the variation in disposition of testosterone, the most common doping agent in sports and in society. Large inter- and intra-ethnic variation in testosterone glucuronidation and excretion is described as well as the pit-falls in evaluation of testosterone doping test results. The hydrolysis and bioactivation of testosterone enanthate is also genetically variable yielding a 2-3 fold variation in excretion rate and serum concentration, thereby implicating a substantial variation in 'efficacy' of testosterone. Given this situation it is logical to adopt the new findings in the doping control programme. The population based cut off level for the testosterone : epitestosterone ratio should be replaced by a Bayesian interpretation of consecutive tests in the same individual. When combined with the above genetic information the sensitivity of the test is considerably improved. The combination of the three approaches should reduce the rate of falsely negative or positive results and the number of expensive follow up tests, stipulated by the World Anti-Doping Agency. PMID- 22506613 TI - Force, frequency and gripping alter upper extremity muscle activity during a cyclic push task. AB - Factors, such as high repetition, high force and gripping play a role in the development of upper extremity work-related musculoskeletal disorders. The purpose of this study was to systematically examine the effects of push load and frequency on muscle activity with and without concurrent gripping. A total of 10 men and 10 women performed a cyclic bimanual pushing task. All combinations of three push loads (1 kg, 2 kg, 4 kg), three frequencies (4/min, 8/min, 16/min) and two grip conditions (no required grip and 30% of maximum grip force) were performed in randomised order. The muscle activity of the upper arm and shoulder complex reflected both frequency and load, often with significant interactions, thus may be better described by workload, the product of force and frequency. In the forearm, muscle activities were generally low but adding a submaximal grip superseded the effects of push load, with the activity reflecting frequency and grip. PRACTITIONER SUMMARY: Force and frequency are important risk factors for upper extremity disorders. We found that upper extremity muscle activity responds to workload (force * frequency) in a complex way which may be superseded if a grip is present. This electromyographic study provides physiological insights to muscular loading as basis for a variety of workplace disorders. PMID- 22506614 TI - Pigmentation above the constitutive level: an indicator of excimer laser radiation-induced erythema in Koreans. AB - Ultraviolet (UV) irradiation induces skin erythema, but it is not clear which factors have the greatest effects on UV sensitivity. Six healthy Korean adult men were enrolled and their melanin index (MI) and increment of erythema index (DeltaEI) were measured. In each individual, 12 different sites were selected and 36 spots were irradiated with a single shot of monochromatic excimer laser with a dose of 350 mJ/cm(2) . The sites were categorized into three groups based on the cumulative sun exposure: UZ, unexposed zones; FEZ, frequently exposed zones; and IEZ, intermittently exposed zones. The sun exposure indexes (SEI) were also calculated based on previously described methods. DeltaEI, MI and SEI were measured and calculated. The DeltaEI of UZ was significantly higher than that of FEZ, but lower than that of IEZ. In general, there was a significant relationship between DeltaEI and MI (R(2) = 0.135). However, IEZ did not show significant results. In contrast, there was a stronger relationship between DeltaEI and SEI (R(2) = 0.344). Overall, the values were significantly higher for the SEI (0.541 [UZ], 0.281 [IEZ] and 0.228 [FEZ]) than for MI (0.311 [UZ], 0.011 [IEZ] and 0.073 [FEZ]). There were significant site variations in UV sensitivity along with skin pigmentation. In addition, significant differences were observed according to the exposure frequency. The SEI was found to be strongly correlated with UV sensitivity. These results suggest that the induced level of pigmentation above the constitutive level will be a better indicator for UV sensitivity than baseline MI. PMID- 22506616 TI - Is homeopathy really 'morally and ethically unacceptable'? A critique of pure scientism. AB - In this short response we show that Kevin Smith's moral and ethical rejections of homeopathy(1) are fallacious and rest on questionable epistemology. Further, we suggest Smith's presumption of a utilitarian stance is an example of scientism encroaching into medicine. PMID- 22506615 TI - Caries prevalence, severity, and 3-year increment, and their impact upon New Zealand adolescents' oral-health-related quality of life. AB - OBJECTIVE: To examine dental caries experience among New Zealand adolescents and determine the nature of caries-associated differences in oral-health-related quality of life (OHRQoL) among adolescents. METHOD: Follow-up was conducted of a random sample of 430 children first examined in 2003 at age 13, when they completed the Child Perceptions Questionnaire (CPQ(11-14) ). At age 16, 255 (59.3% of the baseline sample) were re-examined and again completed the CPQ(11 14) . RESULTS: Caries prevalence (1 + DMFS) rose from 68% to 79.2%; mean DMFS rose from 2.9 (SD 4.7) to 3.6 (SD 4.8), and the prevalence of high caries experience (5 + DMFS) rose from 20.0% to 40.8%. The 3-year mean net caries increment of 0.5 surfaces (SD 2.6) was dominated by occlusal surfaces. At both ages, overall CPQ(11-14 ) scores, as well as emotional well-being subscale scores, were significantly higher for those with DMFS values of 5 or more. CONCLUSION: Caries experience increased over the three years; this age group is caries-active. Dental caries affects adolescents' OHRQoL, although not as strongly as maybe expected. PMID- 22506617 TI - WT1 mutations and single nucleotide polymorphism rs16754 analysis of patients with pediatric acute myeloid leukemia in a Chinese population. AB - Acute myeloid leukemia (AML) is relatively rare in children. Somatic mutations including the single nucleotide polymorphism (SNP) rs16754 in Wilms tumor 1 gene (WT1) and their prognostic relevance in pediatric AML have not been studied in Chinese populations. We analyzed WT1 mutations and rs16754 genotypes in a cohort of 86 patients with de novo pediatric AML in a Chinese population. We detected WT1 mutations in approximately 20% of the patients. Most of the mutations identified were deletions and insertions clustered in exons 7 and 9. No differences were observed with respect to overall survival and relapse-free survival between patients with and without WT1 mutations. The analysis of rs16754 in WT1 exon 7 revealed G as the major allele. Patients with the rs16754(GG) genotype had improved overall survival (p =0.020) and relapse-free survival (p =0.025) compared with those with either rs16754(GA) or rs16754(AA). Moreover, better overall survival (p =0.044) and relapse-free survival (p =0.068) were observed among patients with wild-type CEBPA with rs16754(GG) compared with those carrying rs16754(GA/AA). PMID- 22506618 TI - Intravitreal bevacizumab for retinopathy of prematurity as first line or rescue therapy with focal laser treatment. A case series. AB - OBJECTIVES: Laser therapy is effective in the treatment of severe forms of retinopathy of prematurity (ROP), and aggressive posterior ROP (APROP), but always damages the retina. We report our preliminary findings in seven premature infants with complicated ROP or APROP who were treated with intravitreal bevacizumab (IVB) as first line monotherapy or rescue therapy combined with laser treatment. METHODS: We studied retrospectively seven preterm infants, who were affected by APROP (n = 4) or pre-threshold ROP (n = 3). Infants were treated with IVB (0.625 mg; Avastin(r), Roche, Basel, Switzerland) monotherapy (n = 2) when they were too sick to undergo lengthy laser treatment. RESULTS: Monotherapy IVB (n = 3 eyes) and IVB combined with laser therapy (n = 3 eyes) of APROP cases were followed by regression of the ROP and complete peripheral vascularization. The combined therapy with IVB and laser therapy of pre-threshold ROP (5 eyes) produced a regression of neovascularization and good retinal anatomical outcome. CONCLUSIONS: In our series, IVB was successful in treating ROP in a small cohort of extremely preterm infants with APROP or pre-threshold ROP, both as monotherapy or rescue treatment after laser therapy, without the development of ocular and systemic short- and long-term adverse effects. PMID- 22506619 TI - Contractile, but not endothelial, dysfunction in early inflammatory arthritis: a possible role for matrix metalloproteinase-9. AB - BACKGROUND AND PURPOSE: Excess morbidity/mortality in rheumatoid arthritis (RA) is associated with increased incidence of cardiovascular disease. In this 'proof of-concept' study, vascular function was characterized in the murine collagen induced arthritis (mCIA) model, the benchmark choice for evaluation of the pathological processes and assessment of new therapies. EXPERIMENTAL APPROACH: Mice in the very early stages of arthritis development [and appropriate naive (non-immunized) age-matched controls] were used in the study. Blood pressure was measured using tail cuff plethysmography. Vascular function in rings of isolated aorta was studied with isometric tension myography. Levels of NO metabolites (NO(x)), MMP-9 protein and IL-1beta in plasma and MMP-9 protein in aortic homogenates were quantified. KEY RESULTS: Impaired vascular contractile responses in arthritis were unaffected by ex vivo inhibition of NOS (endothelial/neuronal and inducible) or COX activities. Endothelium-dependent and -independent relaxation, plasma NO(x) and blood pressure were unaffected by arthritis. Plasma and aortic homogenate MMP-9 protein levels were increased significantly in arthritis. Incubation of aortic tissues from naive control animals with exogenous MMP-9 impaired subsequent contractile responses, mirroring that observed in arthritis. A role for IL-1beta in perpetuating contractile dysfunction and increasing aortic MMP-9 was excluded. CONCLUSIONS AND IMPLICATIONS: These data identify for the first time a relationship between early arthritis and contractile dysfunction and a possible role for MMP-9 therein, in the absence of overt endothelial dysfunction or increased NO production. As such, MMP-9 may constitute a significant target for early intervention in RA patients with a view to decreasing risk of cardiovascular disease. PMID- 22506620 TI - Bioactive quassinoids from the seeds of Brucea javanica. AB - Six new quassinoids (1-6) and eight known compounds of this type (7-14) were isolated from the seeds of Brucea javanica. Their structures were elucidated by analysis of their spectroscopic data and from chemical evidence. Compounds 1-5 were found to be unusual quassinoids with a 2,3-seco A ring. The configurations at C-4 in 4 and 5 were determined by a difference circular dichroism method. In in vitro bioassays, 8 and 10 showed inhibitory activities for nitric oxide production in LPS-activated macrophages, with IC(50) values of 1.9 and 5.0 MUM, respectively, while compounds 6, 8-11, 13, and 14 exhibited cytotoxicity against five human tumor cell lines (HCT-8, HepG2, BGC-823, A549, and SKVO3), having IC(50) values in the range 0.12-9.3 MUM. PMID- 22506621 TI - CO2 reduction at low overpotential on Cu electrodes resulting from the reduction of thick Cu2O films. AB - Modified Cu electrodes were prepared by annealing Cu foil in air and electrochemically reducing the resulting Cu(2)O layers. The CO(2) reduction activities of these electrodes exhibited a strong dependence on the initial thickness of the Cu(2)O layer. Thin Cu(2)O layers formed by annealing at 130 degrees C resulted in electrodes whose activities were indistinguishable from those of polycrystalline Cu. In contrast, Cu(2)O layers formed at 500 degrees C that were >=~3 MUm thick resulted in electrodes that exhibited large roughness factors and required 0.5 V less overpotential than polycrystalline Cu to reduce CO(2) at a higher rate than H(2)O. The combination of these features resulted in CO(2) reduction geometric current densities >1 mA/cm(2) at overpotentials <0.4 V, a higher level of activity than all previously reported metal electrodes evaluated under comparable conditions. Moreover, the activity of the modified electrodes was stable over the course of several hours, whereas a polycrystalline Cu electrode exhibited deactivation within 1 h under identical conditions. The electrodes described here may be particularly useful for elucidating the structural properties of Cu that determine the distribution between CO(2) and H(2)O reduction and provide a promising lead for the development of practical catalysts for electrolytic fuel synthesis. PMID- 22506622 TI - Involvement of lymphocyte infiltration in the progression of mouse peritoneal fibrosis model. AB - Peritoneal fibrosis is a serious complication in patients with severe chronic kidney disease who are undergoing peritoneal dialysis (PD). One of the pathological characteristics of peritoneal fibrosis is the infiltration of macrophages in the thickened submesothelial compact zone. In addition, infiltration of lymphocytes, including T and B lymphocytes, is observed in the fibrotic peritoneum. However, the relationship between lymphocyte infiltration and progression of peritoneal fibrosis remains unclear. In this study, we investigated the role of lymphocytes in the development of peritoneal fibrosis induced by chlorhexidine gluconate (CG) by comparing the histological changes observed in severe combined immunodeficient (SCID) mice (largely lacking functional T and B lymphocytes) with those observed in wild-type (WT) mice. As expected, CG-injected WT mice showed a thickening of the submesothelial compact zone together with massive collagen deposition accompanied by increased numbers of infiltrating macrophages and T and B lymphocytes. In the peritoneum of SCID mice, the submesothelial compact zone was thicker and the number of macrophages and B lymphocytes was significantly higher than that observed in control immunodeficient and WT mice. In contrast, the number of T lymphocytes in the peritoneum of SCID mice was significantly lower than that in the peritoneum of WT mice. These results suggest that T and B lymphocytes modulate the process of peritoneal fibrosis via macrophage infiltration. PMID- 22506623 TI - Long-term safety and efficacy of ambrisentan in Japanese adults with pulmonary arterial hypertension. AB - OBJECTIVE: To investigate the safety and efficacy of long-term administration of ambrisentan in Japanese adults with pulmonary arterial hypertension (PAH). RESEARCH DESIGN AND METHODS: In this open-label extension of a preceding multicenter dose-escalation study, 21 Japanese patients with PAH received treatment with 5 or 10 mg of ambrisentan once daily and were comprehensively evaluated every 12 weeks. The primary endpoint was the safety of long-term ambrisentan administration, as defined by the incidence and severity of adverse events. The secondary (efficacy) endpoints were change in exercise capacity (as indicated by 6-minute walk distance), World Health Organization functional class, Borg dyspnea index, plasma brain natriuretic peptide level, cardiopulmonary hemodynamics, and time to clinical worsening of PAH. CLINICAL TRIAL REGISTRATION: NCT00554619. RESULTS: The mean total duration of treatment (i.e., including the preceding dose-escalation study) was approximately 139 weeks. There were fewer adverse events related to ambrisentan in this study than in the preceding study, and we identified no new safety signals that might preclude the long-term use of ambrisentan among Japanese adults with PAH. Improvements observed in efficacy endpoints in the preceding study were maintained in the present study. LIMITATIONS: This study did not include a control group and lacked the statistical power to reach definite conclusions regarding the efficacy of ambrisentan. CONCLUSION: Our results suggest that long-term administration of ambrisentan is well tolerated and efficacious for Japanese adults with PAH. PMID- 22506624 TI - Patient perceptions associated with the 5% lidocaine medicated plaster in daily practice. AB - OBJECTIVE: To evaluate patients' perceptions of 5% lidocaine medicated plaster for treatment of chronic neuropathic pain in daily clinical practice. RESEARCH DESIGN AND METHODS: In a prospective, multicentre, non-interventional observation, patient-reported outcome data were collected in clinical practices in Germany using the German Pain Questionnaire for pre-treatment documentation and the German Pain Diary for documentation of weekly treatment-associated changes. Questionnaires were completed by the patients without input from their physicians. MAIN OUTCOME MEASURES: Mean changes over the 12-week treatment period in pain intensity, in impairments of daily activities (modified pain disability index, mPDI) and of quality of life (quality of life impairment by pain inventory, QLIP), in Hospital Anxiety and Depression Scale scores (HADS-A and HADS-D), and in overall burden of pain. RESULTS: Data of 922 patients were evaluated. Mean average pain intensity over 24 h improved by 5.1 points (74%) from 6.9 +/- 1.6 points at baseline. A 30% reduction in overall pain intensity was already observed within the first 2-3 weeks with continuous further reductions until end of observation. Marked improvements in anxiety and depression scores (40% and 52%, respectively), and in pain-related restrictions in daily life activities (66%) and quality of life (157%) were also noted. Burden of pain was reduced by 56.2 points (73%) from 77.5 points at baseline. Stratification by diagnosis showed a treatment effect of lidocaine plaster for all underlying conditions with highest treatment effects for diabetic polyneuropathy and postherpetic neuralgia. CONCLUSIONS: In a patient population where 46% of individuals already suffered from chronic to markedly chronic pain, patients perceive the 5% lidocaine medicated plaster as an efficacious topical treatment of chronic neuropathic pain in daily clinical practice. Strongest pain relief as well as associated improvements in pain-related restrictions were observed within the first five treatment weeks; however, beneficial effects continued until end of observation. PMID- 22506625 TI - Effectiveness of adjuvant imatinib in patients with gastrointestinal stromal tumor: results of a population-based, matched-cohort study. AB - OBJECTIVE: Data are limited on the use of adjuvant imatinib in patients with gastrointestinal stromal tumor (GIST) outside of clinical trials. This retrospective, population-based, matched-cohort study evaluated adjuvant imatinib treatment patterns, assessed impact on clinical outcomes, and estimated effectiveness based on number needed to treat (NNT). RESEARCH DESIGN AND METHODS: GIST-related claims from the PharMetrics claims database were included (2000 2010). A stepwise identification algorithm identified appropriate patients based on GIST-related ICD-9-CM codes, who were classified as 'imatinib (IM) patients' receiving imatinib within 84 days post-surgery and 'non-imatinib (non-IM) patients' undergoing surgery but not receiving imatinib during the study period. The primary composite outcome was based on incidence of a second GIST-related surgery and long-term follow-up in the matched cohorts. IM patients were matched with up to eight non-IM patients on age, gender, ICD-9-CM code, and first surgery date. RESULTS: A total of 118 IM and 4088 non-IM patients with possible GIST ICD 9s and surgery were included. The median duration between first and second surgeries was significantly longer in IM than non-IM patients (488 vs. 290 days; p = 0.0005). IM patients also had longer median follow-up from initial surgery to composite outcome (433 vs. 320 days; p = 0.002). Adherence to IM, measured by medication possession ratio, was 0.83 and 0.73 during the first and second years of treatment, respectively. IM patients were less likely to have the composite outcome compared with non-IM patients (hazard ratio = 0.501; p = 0.0005). The NNT to prevent one outcome was 4. CONCLUSIONS: Patients receiving adjuvant imatinib treatment were less likely to have second surgery or be lost to follow-up, and had a longer interval to second surgery. Although treatment with adjuvant imatinib in patients with primary GIST is effective, adherence to imatinib and treatment duration are less than recommended by current treatment guidelines. PMID- 22506626 TI - The structure of Diagnostic and Statistical Manual of Mental Disorders (4th edition, text revision) personality disorder symptoms in a large national sample. AB - We examined the latent structure underlying the criteria for DSM-IV-TR (American Psychiatric Association, 2000, Diagnostic and statistical manual of mental disorders (4th ed., text revision). Washington, DC: Author.) personality disorders in a large nationally representative sample of U.S. adults. Personality disorder symptom data were collected using a structured diagnostic interview from approximately 35,000 adults assessed over two waves of data collection in the National Epidemiologic Survey on Alcohol and Related Conditions. Our analyses suggested that a seven-factor solution provided the best fit for the data, and these factors were marked primarily by one or at most two personality disorder criteria sets. A series of regression analyses that used external validators tapping Axis I psychopathology, treatment for mental health problems, functioning scores, interpersonal conflict, and suicidal ideation and behavior provided support for the seven-factor solution. We discuss these findings in the context of previous studies that have examined the structure underlying the personality disorder criteria as well as the current proposals for DSM-5 personality disorders. PMID- 22506627 TI - A parallel process growth model of avoidant personality disorder symptoms and personality traits. AB - Avoidant personality disorder (AVPD), like other personality disorders, has historically been construed as a highly stable disorder. However, results from a number of longitudinal studies have found that the symptoms of AVPD demonstrate marked change over time. Little is known about which other psychological systems are related to this change. Although cross-sectional research suggests a strong relationship between AVPD and personality traits, no work has examined the relationship of their change trajectories. The current study sought to establish the longitudinal relationship between AVPD and basic personality traits using parallel process growth curve modeling. Parallel process growth curve modeling was applied to the trajectories of AVPD and basic personality traits from the Longitudinal Study of Personality Disorders (Lenzenweger, M. F., 2006, The longitudinal study of personality disorders: History, design considerations, and initial findings. Journal of Personality Disorders, 20, 645-670. doi:10.1521/pedi.2006.20.6.645), a naturalistic, prospective, multiwave, longitudinal study of personality disorder, temperament, and normal personality. The focus of these analyses is on the relationship between the rates of change in both AVPD symptoms and basic personality traits. AVPD symptom trajectories demonstrated significant negative relationships with the trajectories of interpersonal dominance and affiliation, and a significant positive relationship to rates of change in neuroticism. These results provide some of the first compelling evidence that trajectories of change in PD symptoms and personality traits are linked. These results have important implications for the ways in which temporal stability is conceptualized in AVPD specifically, and PD in general. PMID- 22506628 TI - Comparison of expected outcomes between patients and neurologists using Kano's methodology in symptomatic migraine treatment. AB - OBJECTIVES: Our objective was to evaluate the potential usefulness of the Kano conceptual model to assess expectations of patients and neurologists in Spain regarding symptomatic migraine treatment. METHODS: We performed a multicenter, cross-sectional study in adult migraine patients with at least 1 year of disease evolution and at least one prescription of anti-migraine drugs within the last year. Data collection was performed using questionnaires that included sociodemographic and treatment expectations. Using Kano's methodology, treatment attributes were classified as the following: Must-be; One-dimensional; Attractive; Indifferent; Reverse; or Questionable. RESULTS: A total of 204 migraine patients (mean age 39.2 years [SD 11.9]; 84.6% women) and 68 neurologists (mean age 44 years [SD 8.8]; 63.2% men) were surveyed. None of the treatment attributes evaluated by the patients showed a dominant Must-be feature. Among patients and neurologists, the attributes that led to a greater dissatisfaction when absent and that were ranked as the three most important attributes were those related to treatment safety (absence of long-term adverse effects), efficacy (pain relief achievement), and quality of life (possibility of resuming occupational or academic activities). Differences in attributes' classification were noted among patients and neurologists. The attribute that was considered most important by the patients was achievement of total disappearance of pain, whereas for neurologists the most important attribute was absence of long-term adverse effects. CONCLUSIONS: Kano's methodology is a useful tool to analyze differences in migraine treatment expectations among patients and neurologists. The main difference between patients and neurologists related to basic priorities. Therefore, when selecting treatment for migraine, physicians should invite the patient to participate in the decision making of which treatment is more appropriate. PMID- 22506630 TI - Nucleophilic addition of beta-amino carbanions to arynes: one-pot synthesis of 4 aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines. AB - A novel approach for the direct C-4 arylation of N-methyl-1,2,3,4 tetrahydroisoquinolines by nucleophilic addition of beta-aminocarbanions to benzynes is described which provides a one-pot procedure for synthesis of the title compounds. PMID- 22506629 TI - Risk and resilience: the moderating role of social coping for maternal mental health in a setting of political conflict. AB - Violence can threaten individual wellbeing and tear at the social fabric of communities. At the same time, suffering can mobilize social coping and mutual support. Thus, the backdrop of political violence increases risk factors and stimulates resilience. The current study examined the moderating role of social coping as reflective of risk and resiliency in Northern Ireland, a setting of protracted conflict. Specifically, structural equation modeling was used to investigate whether social coping protects from or exacerbates the negative impact of sectarian crime and nonsectarian crime on maternal mental health (N = 631). Nonsectarian crime predicted greater psychological distress for mothers in Belfast. Mixed support was found for the buffering and depletion moderation hypotheses; social coping functioned differently for nonsectarian crime and sectarian crime. Greater social coping buffered mothers' psychological distress from the negative effects of nonsectarian crime, but exacerbated maternal mental health problems when facing sectarian crime. Results suggest that social coping is a complex phenomenon, particularly in settings of protracted political violence. Implications for interventions aimed at alleviating psychological distress by enhancing mothers' social coping in contexts of intergroup conflict are discussed. PMID- 22506632 TI - Conventional vs. implant retained overlay dentures: a clinical trial of masseter and anterior temporalis electromyography. AB - Abstract Background: Implant supported overlay dentures (ISODs) have been widely accepted among patients using conventional removable complete dentures (CRCDs). The present study aimed to comparatively study conventional and ISODs in terms of function and coordination of masticatory muscles using electromyograms.Materials and methods: Included were 10 patients with ISODs (each with 2 implants in the intercanine area). The mean wave range (MWR) and frequency (MWF) of masseter and temporalis were recorded with (ISOD) and without (CRCD) ball attachments while maximum clenching on cotton rolls (cotton roll clenching), maximum intercuspal clenching (clenching), and unilateral gum chewing (chewing) using electromyography. Data were analyzed in SPAW using t-paired for matched groups and independent sample t-tests for unmatched ones. Results: MWF differences were not statistically significant with or without attachments (p > 0.05). Without attachments in place, MWF of both masseter and temporalis muscles significantly decreased when patients clenched on cotton rolls (p = 0.01 and 0.02, respectively) and when chewing unilaterally (p = 0.01 both). With attachments present, the right and left temporalis muscles did not show identical mean wave ranges while chewing (p = 0.01). Without attachments, this disharmony was seen in the left and right masseter muscles (p = 0.03). MWR of masseter was higher in men while chewing with attachments (p = 0.02). Without attachments, MWR of temporalis was higher in women while cotton roll clenching (p = 0.03) and chewing (p = 0.02). Conclusion: These findings are seemingly in favor of improved masticatory function and coordination in edentulous patients with the application of ISODs. PMID- 22506631 TI - Room-temperature synthesis of self-assembled Sb2S3 films and nanorings via a two phase approach. AB - The freestanding Sb(2)S(3) films were easily synthesized at the interface of water and toluene at room temperature, where Na(2)S and (C(2)H(5)OCS(2))(3)Sb (xanthate, O-ethyldithiocarbonate) acted as sulfur and antimony source, respectively. After 3 h of aging, the Sb(2)S(3) films with a flat surface toward organic side and rough surface toward aqueous side were assembled by sheaflike Sb(2)S(3) nanowires. The Sb(2)S(3) nanorings formed by end-to-end connection of the bundled nanowires appeared in the water layer when the reaction time reached 24 h. The Sb(2)S(3) nanorings showed higher photocatalytic activity for methyl orange degradation under visible light than the Sb(2)S(3) films owing to broader spectrum response and better aqueous dispersion. PMID- 22506633 TI - Metabotropic glutamate receptor 4 (mGlu4)-positive allosteric modulators for the treatment of Parkinson's disease: historical perspective and review of the patent literature. AB - INTRODUCTION: Metabotropic glutamate receptor 4 (mGlu(4)) is a group III GPCR and has been demonstrated to play a major role in a number of therapeutic areas within the CNS. As the orthosteric site of all glutamate receptors is highly conserved, modulating mGlu(4) via allosteric modulation has emerged as a very attractive mode-of-action and has been validated preclinically in a number of animal models for Parkinson's disease, anxiety, pain, and neuroinflammation. AREAS COVERED: In this review, the patent literature for mGlu(4)-positive allosteric modulators over the past 4 years will be provided. Patents from all companies are discussed and an overview of the chemical matter and relevant biological properties will be given. EXPERT OPINION: Although there has yet to be an mGlu(4)-positive allosteric modulator progressed into clinical trials, there is a wealth of preclinical data from the primary literature that shows the promise of this emerging target. A number of academic and industry laboratories have recently published exciting patent data covering a multitude of chemical matter. Positive allosteric modulation of mGlu(4) remains one of the more attractive non-dopaminergic therapies for Parkinson's disease, as well as emerging data for other indications such as pain, neuroinflammation, schizophrenia and diabetes, which could potentially make mGlu(4) a significant therapeutic target going forward. PMID- 22506634 TI - Treatment of hepatitis C virus infection in adults and children: updated Swedish consensus recommendations. AB - Swedish recommendations for the treatment of hepatitis C virus (HCV) infection were updated at a recent expert meeting. Therapy for acute HCV infection should be initiated if spontaneous resolution does not occur within 12 weeks. The recommended standard-of-care therapy for chronic HCV genotype 1 infection is an HCV protease inhibitor in combination with peginterferon (peg-IFN) and ribavirin. Treatment is strongly recommended in patients with bridging fibrosis and cirrhosis, whereas in patients with less advanced fibrosis, deferring therapy may be preferential in light of likely therapeutic improvements in the near future. Patients with chronic genotype 2/3 infection should generally be treated with peg IFN and ribavirin for 24 weeks. In patients with a very rapid viral response (i.e. HCV RNA below 1000 IU/ml on day 7), or favourable baseline characteristics and undetectable HCV RNA week 4, treatment can be shortened to 12-16 weeks, provided that no dose reductions are needed. PMID- 22506635 TI - Novel neuronal and endocrine autoantibody targets in Autoimmune Polyendocrine Syndrome type 1. AB - CONTEXT: Although pituitary autoantibodies have frequently been reported in Autoimmune Polyendocrine Syndrome type 1 (APS1), the autoimmune involvement of the hypothalamic-pituitary axis remains to be elucidated. OBJECTIVE: Our aim was to identify in APS1 patients novel autoantibodies, especially against hypothalamic-pituitary targets, and to correlate their presence with clinical features. PATIENTS: We analyzed 14 APS1 patients from Sardinia, compared to other diseases and healthy donors. MEASURE(S): We used immunohistochemistry, on tissues substrates from various neuroendocrine organs, to detect autoantibody targets. Immunoenzymatic assays, as well as absorption with specific antigens were used to reveal autoantibodies against growth hormone (GH), luteinizing hormone (LH) and somatocrinin (GHRH). Clinical evaluations included GH secretory and cardiovascular autonomic neuropathy tests. RESULTS: Sera from 12/14 APS1 patients revealed autoantibodies reacting with the hypothalamic-pituitary axis, cerebellum, substantia nigra, and/or adrenal medulla, as well as with GH, LH and/or GHRH. Of APS1 patients, 5 showed GH deficiency, in association (4/5 cases) with autoantibodies to hypothalamic and/or pituitary targets. Hypogonadotrophic hypogonadism was revealed in one APS1 patient, together with autoantibodies against gonadotropes. Autonomic neuropathy was detected in 5 of 10 patients, associated with autoantibodies to adrenal medulla in 2 cases. Of 5 patients with autoantibodies to cerebellar neurons, 2 reported emotional or memory alterations. CONCLUSIONS: The majority of Sardinian APS1 patients developed autoantibodies to an assortment of neuroendocrine cells. Novel targets of clinical relevance may include pituitary hormones, uncharacterized pituitary targets, and adrenal medullary cells. An high prevalence of GH deficiency, and possibly of autonomic neuropathy, were also revealed. PMID- 22506636 TI - Primary signet-ring cell/histiocytoid carcinoma of the axilla expressing human epidermal growth factor receptor 2. PMID- 22506637 TI - Review of patient safety incidents reported from critical care units in North West England in 2009 and 2010. AB - We categorised and established the rates of patient safety incidents reported during 2009 and 2010 from critical care units in 12 hospital trusts in North-West England. We identified a total of 4219 incidents reported during 127, 467 calendar days of critical care with a median (IQR [range]) of 31 (26-45 [20-57]) incidents per 1000 days per trust. A median (IQR [range]) of 10 (7-13 [3.5-27]) incidents per 1000 days were associated with harm. Pressure sores were the most common cause of harm, with a median (IQR [range]) of 3.9 (1.0-6.6 [0-20.4]) incidents per 1000 days. Only 89 (2.1%) incidents described more than temporary harm, of which 12 were airway related incidents. Five incidents described the use of inappropriate arterial flush solutions. It is possible to compare rates of incident reporting in different trusts over time to determine if different methods of care are associated with different reporting rates. The wide range of reported pressure sore rates suggests that their incidence could be reduced. PMID- 22506639 TI - Isotope effects and heavy-atom tunneling in the Roush allylboration of aldehydes. AB - Intermolecular (13)C kinetic isotope effects (KIEs) for the Roush allylboration of p-anisaldehyde were determined using a novel approach. The experimental (13)C KIEs fit qualitatively with the expected rate-limiting cyclic transition state, but they are far higher than theoretical predictions based on conventional transition state theory. This discrepancy is attributed to a substantial contribution of heavy-atom tunneling to the reaction, and this is supported by multidimensional tunneling calculations that reproduce the observed KIEs. PMID- 22506638 TI - HPLC-ESIMS(n) profiling, isolation, structural elucidation, and evaluation of the antioxidant potential of phenolics from Paepalanthus geniculatus. AB - The methanol extract of the flowers of Paepalanthus geniculatus Kunth. showed radical-scavenging activity in the TEAC assay. An analytical approach based on HPLC-ESIMS(n) was applied to obtain the metabolite profile of this extract and led to the rapid identification of 19 polyphenolic compounds comprising flavonoids and naphthopyranones. The new naphthopyranone (10, 16), quercetagetin (1, 5, 7, 13), and galetine derivatives (9, 11, 17, 19), and a flavonol glucoside cyclodimer in the truxillate form (12), were identified. Compounds 2, 6, and 7 showed the highest antioxidant capacity and ability to affect the levels of intracellular ROS in human prostate cancer cells (PC3). PMID- 22506640 TI - Reliance on prey-derived nitrogen by the carnivorous plant Drosera rotundifolia decreases with increasing nitrogen deposition. AB - * Carnivory in plants is presumed to be an adaptation to a low-nutrient environment. Nitrogen (N) from carnivory is expected to become a less important component of the N budget as root N availability increases. * Here, we investigated the uptake of N via roots versus prey of the carnivorous plant Drosera rotundifolia growing in ombrotrophic bogs along a latitudinal N deposition gradient through Sweden, using a natural abundance stable isotope mass balance technique. * Drosera rotundifolia plants receiving the lowest level of N deposition obtained a greater proportion of N from prey (57%) than did plants on bogs with higher N deposition (22% at intermediate and 33% at the highest deposition). When adjusted for differences in plant mass, this pattern was also present when considering total prey N uptake (66, 26 and 26 MUg prey N per plant at the low, intermediate and high N deposition sites, respectively). The pattern of mass-adjusted root N uptake was opposite to this (47, 75 and 86 MUg N per plant). * Drosera rotundifolia plants in this study switched from reliance on prey N to reliance on root-derived N as a result of increasing N availability from atmospheric N deposition. PMID- 22506641 TI - Preterm preeclampsia: 32 to 37 weeks gestation. AB - OBJECTIVE: To evaluate neonatal outcomes in late preterm infants delivered due to preeclampsia. METHODS: A retrospective cohort of 3580 infants delivered at 32 0/7 to 36 6/7 weeks gestation was examined. Neonatal outcomes of infants delivered due to preeclampsia were compared with outcomes of infants delivered prematurely due to other etiologies. Multivariate logistic regression was used to analyze the association between preeclampsia and the neonatal outcomes. RESULTS: Infants of women with preeclampsia were more likely to be SGA (26.8% vs. 8.4%). They were also more likely to be admitted to the ICN (54.3% versus 39.0%); however, they were less likely to suffer a neonatal death (2.2% vs. 3.4%). Infants born to women with preeclampsia had similar rates of RDS (19.8% vs. 14.2%). DISCUSSION: Neonatal outcomes in late preterm infants born to preeclamptic mothers are significantly different from outcomes in late preterm neonates delivered due to other indications. PMID- 22506642 TI - A mass spectrometric approach for characterization of amyloid-beta aggregates and identification of their post-translational modifications. AB - Endogenous amyloid-beta (Abeta) oligomeric aggregates have been proposed as toxic agents in Alzheimer's disease (AD). Knowledge of their structures not only may provide insight into the basis of their neurotoxicities but also may reveal new targets for therapeutic drugs and diagnostic tools. However, the low levels of these Abeta oligomers have impeded structural characterization. Evidence suggests that the endogenous oligomers are covalently modified in vivo. In this report, we demonstrate an established mass spectrometry (MS) methodology called precursor ion mapping (PIM) that potentially may be applied to endogenous oligomer characterization. First, we illustrate the use of this PIM technique with a synthetic Abeta(1-40) monomer sample that had been cross-linked with transglutaminase (TGase) and digested with pepsin. From PIM analysis of an Abeta(4-13) MS/MS fragment, precursor ions were identified that corresponded to peptic fragments of three TGase cross-linked species: Abeta(4-19)--(4-19), Abeta(4-19)--(20-34), and Abeta(1-19)--(20-34). Next, we demonstrate the applicability of the PIM technique to an endogenous Abeta sample that had been purified and concentrated by immunoaffinity chromatography. Without pepsin digestion, we successfully identified the full length and C-terminally truncated monomeric Abeta species 1-35 to 1-42, along with select methionine-oxidized counterparts. Because PIM focuses only on a subpopulation of ions, namely the related precursor ions, the resulting spectra are of increased specificity and sensitivity. Therefore, this methodology shows great promise for structural analysis and identification of post-translational modification(s) in endogenous Abeta oligomers. PMID- 22506643 TI - Myeloid sarcoma of the heart. PMID- 22506644 TI - How biologics targeting the IL-1 system are being considered for the treatment of type 2 diabetes. AB - Metabolic diseases are associated with activation of the innate immune system in various tissues and characterized by elevated inflammatory factors and the presence of immune cells. Type 2 diabetes develops when islet beta cells are deficient in producing sufficient insulin to overcome peripheral insulin resistance. Intra-islet IL-1beta activity diminishes beta cell function and survival and governs islet inflammation. Targeting the IL-1 system with the IL-1 receptor antagonist IL1Ra improved insulin secretion, glycaemia and reduced systemic inflammation in a proof of concept study with patients with type 2 diabetes. Currently, long lasting and specific IL-1beta blocking antibodies are being evaluated in clinical trials and this may lead to a novel cytokine-based treatment for type 2 diabetes. PMID- 22506645 TI - Work domain analysis for enhancing collaborations: a study of the management of microsystems design. AB - Collaboration is an important process that enables organisations to achieve goals or solve problems and, in design processes, is an important factor for accomplishing interdisciplinary and multidisciplinary tasks. An understanding of the functional configuration of organisations could therefore offer a useful insight into collaborations of designers. This study makes use of work domain analysis (WDA) to analyse the management of design by organisations within the microsystems technology (MST) domain. The WDA considers the functional configuration of MST companies in terms of management constraints and boundaries. This study also makes use of the WDA to suggest ways of establishing collaborative design and enhancing collaboration between organisations. Practitioner Summary: The results of this methodical analysis offer useful insights for managing design functions. This study also presents recommendations for enhancing collaboration in organisations. The ability to manage and collaborate in design functions is valuable for improving the productivity, cost effectiveness and time-to-market systems. PMID- 22506646 TI - Psychological needs, purpose in life, and problem video game playing among Chinese young adults. AB - The negative impacts of excessive and problematic video game playing on both children and adults are attracting increasing concern. Based on self determination theory (SDT; Ryan & Deci, 2000), this study hypothesized that the three basic psychological needs of autonomy, competence, and relatedness are positively associated with purpose in life, which in turn acts as a protective factor against problem video game playing among Chinese young adult players. Through a questionnaire survey with a sample of 165 Chinese adults aged between 18 and 30 years (mean age = 22.7 years), we found that perceived autonomy, competence, relatedness, and purpose in life were all negatively correlated with problem game playing. The demographic and psychological factors explained 38% of the variances of problem game playing. Specifically, gender, perceived relatedness, and purpose in life emerged as the three most salient predictors of problem game playing among the Chinese young adults. The mediating role of purpose in life was evidenced and it was found that purpose in life mediated the influences of the psychological needs proposed by SDT on problem game playing. Moreover, young men were significantly more susceptible to problem game playing than their female counterparts. To conclude, psychological needs and purpose in life influenced Chinese young adults' vulnerability to problem game playing directly or indirectly. Intervention programs that encourage social involvement and voluntary work, as well as counseling service that helps clients to search for life purpose, are suggested for intervening in problem game playing among Chinese young adults. PMID- 22506647 TI - Why and when peer prediction is superior to self-prediction: the weight given to future aspiration versus past achievement. AB - Peer predictions of future behavior and achievement are often more accurate than those furnished by the self. Although both self- and peer predictions correlate equally with future outcomes, peers tend to avoid the degree of overoptimism so often seen in self-predictions. In 3 studies, the authors tested whether this differential accuracy arises because people give more weight to past behavior when predicting others, but emphasize agentic information, in particular data about their aspiration level, when predicting the self. Studies 1 and 3 showed that the exact same participants rated past behavior more diagnostic of future performance when predicting another person but viewed aspiration-level data as more valuable when someone else was trying to predict them. In Studies 2 and 3 (predicting an upcoming exam score and performance in a lab task, respectively), participants gave greater weight in self-predictions to aspiration-level data than did a yoked peer, who instead gave greater weight to evidence of past achievement. This differential weighting explained why peer predictions tended to be less optimistic and, thus, more accurate. Discussion centers on strategies for predicting future behavior and why people may remain ignorant of their own incompetence despite feedback. PMID- 22506648 TI - Does symptom type moderate the relationship between insight and outcome in cognitive behavioral therapy for psychosis? A preliminary investigation. AB - Insight has emerged as a potential predictor variable in cognitive behavioral therapy for psychosis (CBTp). However, previous research has produced mixed results. The present study aimed to clarify whether symptom type is a moderating variable. A group of psychotic patients (n = 44) were assessed through pre- and post-treatment in a CBTp specialty track in a partial hospital-based program in the USA. The Insight Scale was used to measure insight, and psychotic symptomatology was assessed using the Mini-International Neuropsychiatric Interview and the Behavior and Symptom Identification Scale. Patients showed a significant decrease in psychotic symptom scores over the course of treatment [t(43) = 3.59, p < .001, Cohen's d = .64]. Furthermore, illness awareness was specifically associated with a decrease in psychotic symptoms for patients who endorsed visual hallucinations (r = - .68, p < .01), auditory hallucinations (r = - .49, p = .01), and/or ideas of reference (r = - .66, p < .01). Insight did not confer additional benefit for patients with paranoid delusions, mind reading, or thought insertion symptoms. These results are discussed in relation to treatment implications within the current US health care delivery system. PMID- 22506649 TI - Cellular membrane phospholipids act as a depository for quaternary amine containing drugs thus competing with the acetylcholine/nicotinic receptor. AB - We previously demonstrated that ammonium- or guanidinium-phosphate interactions are key to forming noncovalent complexes (NCXs) through salt bridge formation with G-protein coupled receptors (GPCR), which are immersed in the cell membrane's lipids. The present work highlights MALDI ion mobility coupled to orthogonal time-of-flight mass spectrometry (MALDI IM oTOF MS) as a method to determine qualitative and relative quantitative affinity of drugs to form NCXs with targeted GPCRs' epitopes in a model system using, bis-quaternary amine based drugs, alpha- and beta- subunit epitopes of the nicotinic acetylcholine receptor' (nAChR) and phospholipids. Bis-quaternary amines proved to have a strong affinity for all nAChR epitopes and negatively charged phospholipids, even in the presence of the physiological neurotransmitter acetylcholine. Ion mobility baseline separated isobaric phosphatidyl ethanolamine and a matrix cluster, providing an accurate estimate for phospholipid counts. Overall this technique is a powerful method for screening drugs' interactions with targeted lipids and protein respectively containing quaternary amines and guanidinium moieties. PMID- 22506651 TI - Universal surface-initiated polymerization of antifouling zwitterionic brushes using a mussel-mimetic peptide initiator. AB - We report a universal method for the surface-initated polymerization (SIP) of an antifouling polymer brush on various classes of surfaces, including noble metals, metal oxides, and inert polymers. Inspired by the versatility of mussel adhesive proteins, we synthesized a novel bifunctional tripeptide bromide (BrYKY) that combines atom-transfer radical polymerization (ATRP) initiating alkyl bromide with l-3,4-dihydroxyphenylalanine (DOPA) and lysine. The simple dip-coating of substrates with variable wetting properties and compositions, including Teflon, in a BrYKY solution at pH 8.5 led to the formation of a thin film of cross-linked BrYKY. Subsequently, we showed that the BrYKY layer initiated the ATRP of a zwitterionic monomer, sulfobetaine methacrylate (SBMA), on all substrates, resulting in high-density antifouling pSBMA brushes. Both BrYKY deposition and pSBMA grafting were unambiguously confirmed by ellipsometry, X-ray photoelectron spectroscopy, and goniometry. All substrates that were coated with BrYKY/pSBMA dramatically reduced bacterial adhesion for 24 h and also resisted mammalian cell adhesion for at least 4 months, demonstrating the long-term stability of the BrYKY anchoring and antifouling properties of pSBMA. The use of BrYKY as a primer and polymerization initiator has the potential to be widely employed in surface grafted polymer brush modifications for biomedical and other applications. PMID- 22506652 TI - Validation of a method for simultaneous isolation of Shiga toxin-producing Escherichia coli O26, O103, O111, and O145 from minced beef by an international ring-trial. AB - An isolation method described by Posse et al. (FEMS Microbiol Lett 2008;282:124 131) was satisfactorily validated in an international ring-trial using artificially contaminated minced beef samples. Until now, no validated method existed for the simultaneous isolation of Shiga toxin-producing Escherichia coli serogroups O26, O103, O111, and O145 in food. Twelve laboratories from five European countries participated and received 16 inoculated beef samples contaminated with cold-stressed cells of the four serogroups O26, O103, O111, and O145 in two levels (approximately 30 and 300 CFU 25 g-1) in duplicate. In addition, they received four non-inoculated samples. The isolation protocol comprised a selective enrichment step, a selective isolation step on a non-O157 agar plate differentiating the serogroups by color, followed by confirmation by plating on confirmation agar media and agglutination. All laboratories were able to isolate the inoculated serogroups from the samples, both for the high and the low inoculation level. Results did not differ whether in-house-prepared or ready to-use non-O157 agar plates were used, demonstrating that by following the instructions laboratories managed to perform the complete protocol with success. PMID- 22506653 TI - Evaluation of current molecular approaches for genotyping of Campylobacter jejuni strains. AB - Campylobacter jejuni has been recognized as the most common bacterial cause of gastroenteritis worldwide, in both developed and developing countries, since the late 1970s. A number of genotyping schemes have been developed to identify the sources and route of transmission of these foodborne pathogens so that proper control measures can be developed. In this review, we provide current genotypic schemes developed for Campylobacter spp. (particularly C. jejuni) over the last decades, along with an evaluation of the strength and weakness of these techniques and their applications. PMID- 22506654 TI - Hydrogen bonding in 1-butyl- and 1-ethyl-3-methylimidazolium chloride ionic liquids. AB - A detailed investigation of hydrogen bonding in the pure ionic liquids [C4C1im]Cl and [C2C1im]Cl has been carried out using primarily molecular dynamics techniques. Analyses of the individual atom-atom pair radial distribution functions, and in particular those for C...Cl(-), have revealed that hydrogen bonding to the first methylene or methyl units of the substituent groups is important. Multiple geometric criteria for defining a hydrogen bond have been applied, and in particular the choice of the cutoff angle has been carefully examined. The interpretation of hydrogen bonding within these ionic liquids is highly angle dependent, and justification is provided for why it may be appropriate to employ a wider angle criteria than the 30 degrees used for water or alcohol systems. The different types of hydrogen bond formed are characterized, and "top" conformations where the Cl anion resides above (or below) the imidazolium ring are investigated. The number of hydrogen bonds undertaken by each hydrogen atom (and the chloride anion) is quantified, and the propensity to form zero, one, or two hydrogen bonds is established. The effects of an increase in temperature on the static hydrogen bonding are also briefly examined. PMID- 22506656 TI - Letter: "Prognostic value of initial tumor parameters after metastatic relapse: do not miss the tumoral stroma". PMID- 22506655 TI - Unilateral bullous pemphigoid without erythema and eosinophil infiltration in a hemiplegic patient. AB - In this report, we describe an 88-year-old male stroke patient with unilateral bullous pemphigoid limited to the hemiplegic side. Physical examinations revealed multiple tense bullae with clear and/or bloody contents without apparent erythema on the right thigh and lower leg, accompanied by erosions on the right chest. Histopathologically, no eosinophils were infiltrated into and around the subepidermal bullae. Immunofluorescence revealed deposited and circulating immunoglobulin (Ig)G anti-basement membrane zone antibodies. Immunoblot assays using various antigen sources and enzyme-linked immunosorbent assay revealed that IgG antibodies in this case reacted with unique epitopes between NC16a and C terminal domains on the 120-kDa LAD-1, the extracellular truncated form of BP180. Three observations were unique in our case. First, the distribution of bullae in our patient was limited to the hemiplegic side. Second, there was no apparent erythema clinically and no eosinophilic infiltration histopathologically. Third, the patient achieved remission without the use of oral corticosteroids. The unusual epitopes in this case may contribute to these phenomena. PMID- 22506657 TI - Clinical outcomes of patients with nonseminomatous germ cell tumours and negative postchemotherapy positron emission tomography. AB - Univariate and multivariate analyses were carried out to identify factors associated with the failure of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) to correctly predict relapse-free survival in patients with nonseminomatous germ cell tumours. Ninety-three patients with negative postchemotherapy FDG-PET scan were analyzed in the retrospective study. The FDG PET result was validated by long-term follow-up and, in some patients, by resection of the residual tumour mass. The negative predictive value of FDG-PET was 81.7%. Higher tumour marker levels and nodal stage at diagnosis, presence of residual mass, and teratoma or teratocarcinoma in the primary histology were associated with FDG-PET failure. PMID- 22506658 TI - For homeopathy: a practising physician's perspective. AB - This article is a rebuttal to Kevin Smith's 'Against Homeopathy,' which was posted on 14 February 2011.(1) It contends that his argument rests entirely on the assumption that homeopathic remedies are nothing but placebos. His argumentation is good, but his assumption is false. Evidence is presented to show that the Law of Similars is plausible and that ultradilute remedies do indeed have biological activity. PMID- 22506659 TI - Enhanced mass transport of electroactive species to annular nanoband electrodes embedded in nanocapillary array membranes. AB - Electroosmotic flow (EOF) is used to enhance the delivery of Fe(CN)(6)(4 )/Fe(CN)(6)(3-) to an annular nanoband electrode embedded in a nanocapillary array membrane, as a route to high efficiency electrochemical conversions. Multilayer Au/polymer/Au/polymer membranes are perforated with 10(2)-10(3) cylindrical nanochannels by focused ion beam (FIB) milling and subsequently sandwiched between two axially separated microchannels, producing a structure in which transport and electron transfer reactions are tightly coupled. The middle Au layer, which contacts the fluid only at the center of each nanochannel, serves as a working electrode to form an array of embedded annular nanoband electrodes (EANEs), at which sufficient overpotential drives highly efficient electrochemical processes. Simultaneously, the electric field established between the EANE and the QRE (>10(3) V cm(-1)) drives electro-osmotic flow (EOF) in the nanochannels, improving reagent delivery rate. EOF is found to enhance the steady state current by >10* over a comparable structure without convective transport. Similarly, the conversion efficiency is improved by approximately 10-fold compared to a comparable microfluidic structure. Experimental data agree with finite element simulations, further illustrating the unique electrochemical and transport behavior of these nanoscale embedded electrode arrays. Optimizing the present structure may be useful for combinatorial processing of on-chip sample delivery with electrochemical conversion; a proof of concept experiment, involving the generation of dissolved hydrogen in situ via electrolysis, is described. PMID- 22506663 TI - Dengue fever-like illnesses: how different are they from each other? AB - In tropical countries and possibly elsewhere, dengue fever can be confused with other common tropical infections like enteric fever, leptospirosis, typhus fever, malaria, etc. Many of these illnesses can present in significant numbers after rains, and because of similar early presentations, can cause confusion in decision-making. With global warming, these diseases can assume significant proportions even in non-endemic areas. Identifying these illnesses in a non immune returning traveller is equally challenging. Recognition of these diseases is important to diagnose them and treat them early, in order to avoid potentially fatal complications. This review is an attempt to highlight important clinical and laboratory differences among dengue fever-like illnesses. PMID- 22506660 TI - Augmentation of cognitive function by NS9283, a stoichiometry-dependent positive allosteric modulator of alpha2- and alpha4-containing nicotinic acetylcholine receptors. AB - BACKGROUND AND PURPOSE: Positive allosteric modulation of alpha4beta2 nicotinic acetylcholine (nACh) receptors could add a new dimension to the pharmacology and therapeutic approach to these receptors. The novel modulator NS9283 was therefore tested extensively. EXPERIMENTAL APPROACH: Effects of NS9283 were evaluated in vitro using fluorescence-based Ca(2+) imaging and electrophysiological voltage clamp experiments in Xenopus oocytes, mammalian cells and thalamocortical neurons. In vivo the compound was tested in models covering a range of cognitive domains in mice and rats. KEY RESULTS: NS9283 was shown to increase agonist evoked response amplitude of (alpha4)(3) (beta2)(2) nACh receptors in electrophysiology paradigms. (alpha2)(3) (beta2)(2) , (alpha2)(3) (beta4)(2) and (alpha4)(3) (beta4)(2) were modulated to comparable extents, but no effects were detected at alpha3-containing or any 2alpha : 3beta stoichiometry nACh receptors. Native nACh receptors in thalamocortical neurons similarly displayed DHbetaE sensitive currents that were receptive to modulation. NS9283 had favourable effects on sensory information processing, as shown by reversal of PCP-disrupted pre-pulse inhibition. NS9283 further improved performance in a rat model of episodic memory (social recognition), a rat model of sustained attention (five choice serial reaction time task) and a rat model of reference memory (Morris water maze). Importantly, the effects in the Morris water maze could be fully reversed with mecamylamine, a blocker of nACh receptors. CONCLUSIONS AND IMPLICATIONS: These results provide compelling evidence that positive allosteric modulators acting at the (alpha4)(3) (beta2)(2) nACh receptors can augment activity across a broad range of cognitive domains, and that alpha4beta2 nACh receptor allosteric modulation therefore constitutes a promising therapeutic approach to symptomatic treatment of cognitive impairment. PMID- 22506664 TI - Short photoirradiation induces flavonoid synthesis and increases its production in postharvest vegetables. AB - It is desirable to increase the flavonoid contents of postharvest vegetables since flavonoids play a beneficial role in human health promotion. In the present study, we show that postharvest vegetables increasingly produced flavonoids when irradiated with light near the absorption wavelength of flavonoids in the plant. Three-day exposure to UV-B for 5 min, 98 MUmol m-2 s-1 per day, increased the contents of jaceidin in spinach, kaempherol glycoside in radish sprout, apigenin glycosides in parsley, and isovitexin in Indian spinach after 6 days of storage in a refrigerator, compared to the contents in plants without irradiation. Six days of storage of unripe green strawberry under green light for 5 min, 98 MUmol m-2 s-1 per day, enabled them to mature and turn red, accompanied by 3.5-fold increased contents of pelargonidin. Elucidation of the mechanism in parsley found the stimulating expression of the flavonoid synthesis gene, PAL, C4H, 4CL, CHS, and FNS, 6 h after exposure to single irradiation with UV-B for 5 min, and the higher expression was maintained for 24 h. After 3 days irradiation during 6 days of storage, parsley did not show adverse changes in the contents of ascorbic acid, beta-carotene, chlorophyll, and moisture. PMID- 22506665 TI - Evaluation of a new analyser for rapid measurement of blood propofol concentration during cardiac surgery. AB - We report laboratory and clinical evaluations of a blood propofol concentration analyser. Laboratory experiments used volunteer blood spiked with known propofol concentrations over the clinically relevant concentrations from 0.5 to 16 MUg.ml( 1) to assess linearity and the influence of haematocrit and concurrent drug administration. Analyser concentrations demonstrated excellent linearity (R(2) = 0.999). Blood spiked with commonly used drugs showed no significant variation compared to unspiked controls. Propofol measurements were largely independent of haemoglobin concentration. A 6% decay in propofol concentration was observed at the highest prepared concentration. Clinical performance of the analyser was assessed using 80 arterial blood samples from 72 patients receiving propofol infusions during cardiac surgery. Samples were processed using the propofol analyser, and high performance liquid chromatography (HPLC) used as a gold standard comparator. These data demonstrated excellent agreement between the propofol analyser and HPLC with a bias of 0.13 MUg.ml(-1) and precision of -0.16 to 0.42 MUg.ml(-1). PMID- 22506666 TI - Combination of phosphatidylinositol 3-kinases pathway inhibitor and photodynamic therapy in endothelial and tumor cells. AB - Tumor recurrence due to incomplete eradication of tumor cells is a major problem facing current cancer therapies. To overcome this problem, it is necessary to enhance cell killing and/or prevent cell regrowth after treatment. Because phosphatidylinositol 3-kinases (PI3K) pathway plays an important role in stimulating cell survival and growth, we studied the feasibility of using a PI3K pathway inhibitor NVP-BEZ235 (BEZ235) to enhance the effectiveness of vascular targeted photodynamic therapy (vPDT) with verteporfin. We found that BEZ235 or PDT alone significantly inhibited cell growth in both SVEC endothelial and PC-3 prostate cancer cells, although SVEC cells appeared to be more responsive than PC 3 cells. Autophagy was detected after both BEZ235 and verteporfin-PDT in both cell lines. Autophagy appeared to protect cells from PDT-induced cell death because inhibition of autophagy increased cell death. Autophagic flux assay revealed that PDT actually decreased autophagic flux especially at a high dose of verteporfin. Combination of BEZ235 and PDT caused greater inhibition of PI3K signaling pathway, leading to enhanced cell growth inhibition in both cell lines. SVEC cells exhibited a higher sensitivity towards such a combination than PC-3 cells. Our data indicated that BEZ235 in combination with PDT provides a promising approach of enhancing therapeutic response. PMID- 22506667 TI - Influence of sensory loss on the perception of verticality in stroke patients. AB - PURPOSE: The aim of this study was to investigate the relationship between somatosensory loss and perception of verticality in stroke patients suffering single-hemisphere lesions. METHOD: Somatosensory loss was measured using the Rivermead Assessment for Somatosensory Performance (RASP). Perception of verticality was assessed with the Subjective Visual Vertical (SVV) and the Subjective Postural Vertical (SPV) tests. Absolute Values of SVV and SPV were used to analyze the amount of deviation in relation to somatosensory loss. RESULTS: Thirty-two patients were included in the study (mean age = 45.91 SD = 31.88 years). Analysis showed that somatosensory loss was related to results of the SVV (r = -0.552, p = 0.001, Pearson Rank) and the SPV (r = -0.661, p < 0.001, Spearman I). Furthermore, results showed that both joint-related (SVV: r = 0.411, p = 0.019, Pearson Rank; SPV: r = -0.597, p = 0.001, Spearman I) and skin related (SVV: r = -0.595, p < 0.001, Pearson Rank; SPV: r = -0.663, p < 0.001, Spearman I) somatosensory information is related to verticality perception. CONCLUSIONS: This study provides evidence that perception of verticality is related to somatosensory loss, which means that somatosensory loss will lead to a larger amount of deviation of SVV and SPV in relation to the gravitational vector. Furthermore, it is interesting to note that both SVV and SPV are influenced by somatosensory loss. IMPLICATIONS FOR REHABILITATION: * Somatosensory information is related to both visual and postural aspects of verticality perception. * Both joint- and cutaneous-related modalities of sensory information are related to perception of verticality. * Sensory training could be important in the recovery of verticality perception. PMID- 22506668 TI - Fetal hyperechogenic bowel may indicate congenital cytomegalovirus disease responsive to immunoglobulin therapy. AB - OBJECTIVE: To determine whether fetal hyperechogenic bowel is associated with a poor outcome with or without immunoglobulin therapy. METHODS: Sixteen pregnant women whose 17 fetuses had hyperechogenic bowel were followed by a protocol of offering additional serologic testing, amniocentesis, hyperimmunoglobulin (HIG), serial ultrasounds, and evaluation of their children. RESULTS: Of 17 fetuses with hyperechogenic bowel, 13 showed hyperechogenic bowel as a single or first ultrasound sign compared to four who showed it concomitantly or after other ultrasound abnormalities appeared (P = 0.02). Of the 17 fetuses with hyperechogenic bowel, nine were treated with HIG. Eight of the nine were normal at birth and during a follow-up of 3-8 years. One treated fetus is deaf at 4 years of age. A significantly different result (P < 0.0004) occurred among seven untreated fetuses who were each severely affected at 2-7 years of age, and the remaining one died soon after preterm birth. Among seven of nine fetuses (77.8%) of treated mothers the fetal hyperechogenic bowel resolved after HIG administration. There were no significant differences between treated and untreated fetuses for gestational age at maternal infection, gestational age at birth, and birth weight. CONCLUSION: Hyperechogenic bowel may be a marker of congenital cytomegalovirus (CMV) disease, which may be prevented by HIG. PMID- 22506669 TI - Immunohistological diagnosis of plasma cell myeloma based on cytoplasmic kappa/lambda ratio of CD138-positive plasma cells. AB - For differentiating reactive plasmacytosis from clonal plasma cell neoplasms such as plasma cell myeloma (PCM), it is important to determine the expression of the cytoplasmic light chain accurately. Through retrospective analysis, we studied the cytoplasmic kappa/lambda ratio of CD138-positive plasma cells in bone marrow from 50 patients with PCM and 50 controls by immunohistological analysis. The percentage of cytoplasmic light chain immunoreactive cells out of the total plasma cell population was shown by a novel quantitative image analysis approach using an Aperio ScanScope CS and the Membrane v9 algorithm. PCM cells were distinguished from normal plasma cells by cut-off levels between 0.35 and 5.5, a sensitivity of 100% and a specificity of 98.0%. Detection of the cytoplasmic kappa/lambda ratio of CD138-positive plasma cells could be a useful tool for simple, efficient and accurate diagnosis of PCM. PMID- 22506670 TI - MicroRNA profiling in pediatric acute lymphoblastic leukemia: novel prognostic tools. PMID- 22506671 TI - Palladium-catalyzed asymmetric allylic alkylation of electron-deficient pyrroles with meso electrophiles. AB - Pyrroles can serve as competent nucleophiles with meso electrophiles in the Pd catalyzed asymmetric allylic alkylation. The products from this transformation were obtained as a single regio- and diastereomer in high yield and enantiopurity. A nitropyrrole-containing nucleoside analogue was synthesized in seven steps to demonstrate the synthetic utility of this transformation. PMID- 22506672 TI - Cannabidiol as potential anticancer drug. AB - Over the past years, several lines of evidence support an antitumourigenic effect of cannabinoids including Delta(9)-tetrahydrocannabinol (Delta(9)-THC), synthetic agonists, endocannabinoids and endocannabinoid transport or degradation inhibitors. Indeed, cannabinoids possess anti-proliferative and pro-apoptotic effects and they are known to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization. However, the clinical use of Delta(9)-THC and additional cannabinoid agonists is often limited by their unwanted psychoactive side effects, and for this reason interest in non psychoactive cannabinoid compounds with structural affinity for Delta(9)-THC, such as cannabidiol (CBD), has substantially increased in recent years. The present review will focus on the efficacy of CBD in the modulation of different steps of tumourigenesis in several types of cancer and highlights the importance of exploring CBD/CBD analogues as alternative therapeutic agents. PMID- 22506673 TI - Probing the caveolin-1 P132L mutant: critical insights into its oligomeric behavior and structure. AB - Caveolin-1 is the most important protein found in caveolae, which are cell surface invaginations of the plasma membrane that act as signaling platforms. A single point mutation in the transmembrane domain of caveolin-1 (proline 132 to leucine) has deleterious effects on caveolae formation in vivo and has been implicated in various disease states, particularly aggressive breast cancers. Using a combination of gel filtration chromatography and analytical ultracentrifugation, we found that a fully functional construct of caveolin-1 (Cav1(62-178)) was a monomer in dodecylphosphocholine micelles. In contrast, the P132L mutant of Cav1(62-178) was dimeric. To explore the dimerization of the P132L mutant further, various truncated constructs (Cav1(82-178), Cav1(96-178), Cav1(62-136), Cav1(82-136), Cav1(96-136)) were prepared which revealed that oligomerization occurs in the transmembrane domain (residues 96-136) of caveolin 1. To characterize the mutant structurally, solution-state NMR experiments in lyso-myristoylphosphatidylglycerol were undertaken of the Cav1(96-136) P132L mutant. Chemical shift analysis revealed that, compared to the wild-type, helix 2 in the transmembrane domain was lengthened by four residues (wild-type, residues 111-129; mutant, residues 111-133), which corresponds to an extra turn in helix 2 of the mutant. Lastly, point mutations at position 132 of Cav1(62-178) (P132A, P132I, P132V, P132G, P132W, P132F) revealed that no other hydrophobic amino acid can preserve the monomeric state of Cav1(62-178), which indicates that proline 132 is critical in supporting proper caveolin-1 behavior. PMID- 22506674 TI - Implementation of physical coordination training and cognitive behavioural training interventions at cleaning workplaces--secondary analyses of a randomised controlled trial. AB - This study evaluates the implementation of physical coordination training (PCT) and cognitive behavioural training (CBTr) interventions in a randomised controlled trial at nine cleaners' workplaces. Female cleaners (n = 294) were randomised into a PCT, a CBTr or a reference (REF) group. Both 12-week interventions were performed in groups guided by an instructor. Records were kept on intervention dose (adherence) unanticipated events at the work place (context) and quality of intervention delivery (fidelity). Participant adherence was 37% in the PCT and 49% in the CBTr interventions. Optimal implementation was reached by only 6% in PCT and 42% in the CBTr. Analysis of the barriers to successful implementation indicated that the intervention process is sensitive to unanticipated events. In order to succeed in improving the health of high-risk populations such as cleaners and to correctly interpret intervention effects, more research on implementation is needed. TRIAL REGISTRATION: ISRCTN96241850. PRACTITIONER SUMMARY: Both physical coordination training and cognitive behavioural training are potential effective workplace interventions among low educated job groups with high physical work demands. However, thorough consideration should be given to feasibility in the design of interventions. The optimal intervention should be tailored to closely match the implementation context and be robust and flexible to minimise susceptibility to changes in work organisation. PMID- 22506675 TI - Deformation of confined poly(ethylene oxide) in multilayer films. AB - The effect of confinement on the deformation behavior of poly(ethylene oxide) (PEO) was studied using melt processed coextruded poly(ethylene-co-acrylic acid) (EAA) and PEO multilayer films with varying PEO layer thicknesses from 3600 to 25 nm. The deformation mechanism was found to shift as layer thickness was decreased between 510 and 125 nm, from typical axial alignment of the crystalline fraction, as seen in bulk materials, to nonuniform micronecking mechanisms found in solution-grown single crystals. This change was evaluated via tensile testing, wide-angle X-ray diffraction (WAXD), atomic force microscopy (AFM), and differential scanning calorimetry (DSC). With the commercially relevant method of melt coextrusion, we were able to overcome the limitations to the testing of solution-grown single crystals, and the artifacts that occur from their handling, and bridged the gap in knowledge between thick bulk materials and thin single crystals. PMID- 22506676 TI - Enhanced water photolysis with Pt metal nanoparticles on single crystal TiO2 surfaces. AB - Two novel deposition methods were used to synthesize Pt-TiO(2) composite photoelectrodes: a tilt-target room temperature sputtering method and aerosol chemical vapor deposition (ACVD). Pt nanoparticles (NPs) were sequentially deposited by the tilt-target room temperature sputtering method onto the as synthesized nanostructured columnar TiO(2) films by ACVD. By varying the sputtering time of Pt deposition, the size of deposited Pt NPs on the TiO(2) film could be precisely controlled. The as-synthesized composite photoelectrodes with different sizes of Pt NPs were characterized by various methods, such as SEM, EDS, TEM, XRD, and UV-vis. The photocurrent measurements revealed that the modification of the TiO(2) surface with Pt NPs improved the photoelectrochemical properties of electrodes. Performance of the Pt-TiO(2) composite photoelectrodes with sparsely deposited 1.15 nm Pt NPs was compared to the pristine TiO(2) photoelectrode with higher saturated photocurrents (7.92 mA/cm(2) to 9.49 mA/cm(2)), enhanced photoconversion efficiency (16.2% to 21.2%), and increased fill factor (0.66 to 0.70). For larger size Pt NPs of 3.45 nm, the composite photoelectrode produced a lower photocurrent and reduced conversion efficiency compared to the pristine TiO(2) electrode. However, the surface modification by Pt NPs helped the composite electrode maintain higher fill factor values. PMID- 22506677 TI - Successful treatment with adalimumab in a patient with psoriatic arthritis and generalized pustular psoriasis. PMID- 22506678 TI - Temporal clustering and sequencing in short-term memory and episodic memory. AB - A model of short-term memory and episodic memory is presented, with the core assumptions that (a) people parse their continuous experience into episodic clusters and (b) items are clustered together in memory as episodes by binding information within an episode to a common temporal context. Along with the additional assumption that information within a cluster is serially ordered, the model accounts for a number of phenomena from short-term memory (with a focus on serial recall) and episodic memory (with a focus on free recall). The model also accounts for the effects of aging on serial and free recall, apparent temporal isolation effects in short- and long-term memory, and the relation between individual differences in working memory and episodic memory performance. PMID- 22506679 TI - Behavioral variability of choices versus structural inconsistency of preferences. AB - Theories of rational choice often make the structural consistency assumption that every decision maker's binary strict preference among choice alternatives forms a strict weak order. Likewise, the very concept of a utility function over lotteries in normative, prescriptive, and descriptive theory is mathematically equivalent to strict weak order preferences over those lotteries, while intransitive heuristic models violate such weak orders. Using new quantitative interdisciplinary methodologies, we dissociate the variability of choices from the structural inconsistency of preferences. We show that laboratory choice behavior among stimuli of a classical "intransitivity" paradigm is, in fact, consistent with variable strict weak order preferences. We find that decision makers act in accordance with a restrictive mathematical model that, for the behavioral sciences, is extraordinarily parsimonious. Our findings suggest that the best place to invest future behavioral decision research is not in the development of new intransitive decision models but rather in the specification of parsimonious models consistent with strict weak order(s), as well as heuristics and other process models that explain why preferences appear to be weakly ordered. PMID- 22506680 TI - Speed of emotional information processing and emotional intelligence. AB - The present study aimed to investigate the relationship between the speed of emotional information processing and emotional intelligence (EI). To evaluate individual differences in the speed of emotional information processing, a recognition memory task consisted of two subtests similar in design but differing in the emotionality of the stimuli. The first subtest required judgment about whether an emotional facial expression in the test face was identical to one of the four emotional expressions of the same individual previously presented. The second subtest required deciding whether the test face with a neutral emotional expression was identical to one of the four neutral faces of different individuals previously presented. Mean response latencies were calculated for "Yes" and "No" responses. All latencies were correlated with other measures of processing speed such as discrimination time and time of figure recognition. However, the emotional expression recognition subtest was hypothesized to require the processing of emotional information in addition to that of facial identity. Latencies in this subtest were longer than those in the face recognition subtest. To obtain a measure of the additional processing that was called for by the emotionality of the stimuli, a subtraction method and regression analysis were employed. In both cases, measures calculated for "No" responses were related to ability EI, as assessed via a self-report questionnaire. According to structural equation modeling, there was a moderately negative association between latent EI and the latency of "No" responses in the subtest with emotional stimuli. These relationships were not observed for "Yes" responses in the same subtest or for responses in the subtest with neutral face stimuli. Although the differences between "Yes" and "No" responses in their associations with EI require further investigation, the results suggest that, in general, individuals with higher EI are also more efficient in the processing of emotional information. PMID- 22506681 TI - Palladium-catalyzed asymmetric synthesis of silicon-stereogenic dibenzosiloles via enantioselective C-H bond functionalization. AB - A Pd-catalyzed asymmetric synthesis of Si-stereogenic dibenzosiloles is developed through enantioselective C-H bond functionalization of prochiral 2 (arylsilyl)aryl triflates. High chemo- and enantioselectivities are achieved by employing a Josiphos-type ligand under mild conditions. PMID- 22506682 TI - The prevalence of alpha-1 antitrypsin deficiency among patients found to have airflow obstruction. AB - INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a genetic disease that may be manifested by chronic obstructive pulmonary disease. Despite professional society guidelines that recommend broad testing of at-risk individuals, fewer than 10% of affected individuals have been identified. The goals of this study were to estimate the frequency of abnormal AAT genotypes among patients found to have fixed airflow obstruction and to assess the feasibility of having Pulmonary Function Laboratory personnel administer the study. METHODS: Nineteen medical centers in the United States participated in the study. Eligible patients (> GOLD II, FEV(1)/FVC ratio < 0.7, with post-bronchodilator FEV(1)<80% predicted) were offered testing for AATD by the Pulmonary Function Laboratory personnel at the time of pulmonary function testing. RESULTS: A total of 3,457 patients were tested, of whom 3152 were eligible. Deficient patients (ZZ, SZ) constituted 0.63% of subjects, while 10.88% were carriers (MS, MZ). Neither demographic (except African-American race) nor post-bronchodilator pulmonary function variables (FEV(1), FVC, FEV(1)/FVC ratio, TLC, and FEV(1)/FVC) allowed us to predict AAT heterozygote or deficiency status. CONCLUSIONS: The prevalence of AATD among patients undergoing pulmonary function tests with fixed airflow obstruction was 0.63%. Pulmonary Function Laboratory personnel effectively conducted the study. PMID- 22506683 TI - Identification of EFEMP2 as a serum biomarker for the early detection of colorectal cancer with lectin affinity capture assisted secretome analysis of cultured fresh tissues. AB - Early diagnosis plays a decisive role in the outcome of colorectal cancer (CRC) therapy. The ex vivo culture of fresh CRC tissues and paired normal colorectal tissues provides a feasible way to explore potential serum biomarkers for CRC early detection under near-physiological conditions. In the present work, we applied a lectin affinity based approach to enrich and increase the detection number of secreted proteins in the conditioned media of cultured tissues. The captured proteins were then analyzed by the proteomic strategy of one-dimensional gel electrophoresis coupled to liquid chromatography-tandem mass spectrometry. By quantification with label-free spectral counting, we found 123 differentially expressed secreted proteins (DESPs) with 68 DESPs up-regulated in CRC tissues. EFEMP2, one of the top 10 up-regulated DESPs, was further validated by immunohistochemistry at tissue level and enzyme-linked immunosorbent assay at serum level. We found the expression level of EFEMP2 was dramatically increased in CRC patients, even at the early stage. Moreover, the diagnostic accuracy of EFEMP2 was superior to the established CRC biomarker carcinoembryonic antigen evidenced by the area under the receiver operating characteristic curve for the two biomarkers were 0.923 and 0.728, respectively. These results indicated EFEMP2 is a promising serum biomarker for CRC early detection. PMID- 22506684 TI - Osseointegration of dental implants and osteonecrosis of the jaw in patients treated with bisphosphonate therapy: A systematic review. AB - Abstract Bisphosphonate (BP) drugs are a commonly prescribed group of medications used in the treatment of metabolic and oncologic bone pathoses. The aim of this study was to conduct a systematic review in order to evaluate whether patients on BP therapy are appropriate candidates for dental implants as compared to patients not taking BP with respect to successful implant osseointegration and the risk of developing bisphosphonate-related osteonecrosis of the jaw (BRONJ). Based on the current literature, a history of oral or intravenous BP use is not an absolute contraindication for dental implant placement, and dental implants can osseointegrate successfully in this patient population. Importantly, the studies currently available on this topic are of moderate to weak strength of evidence with inherent bias and limitations and hence results must be interpreted in this context. Well-controlled studies with higher strength of evidence and larger population sizes are required to more accurately address this topic in the future. PMID- 22506685 TI - Homeopathy and extraordinary claims--a response to Smith's utilitarian argument. AB - Kevin Smith's utilitarian argument against homeopathy(1) is flawed because he did not review and refute the relevant basic science literature on ultra-high dilutions. He also failed to appreciate that allopathic medicine is based on a deductive-nomothetic method and that homeopathic medicine is based on an inductive-idiographic method, and thus that the implications for clinical research are very different. His misunderstanding of provings and of the holism of homeopathic medicine also demonstrated his failure to understand the history, philosophy and method of homeopathy. Finally, I questioned the value of introducing ethical judgment into an ongoing scientific debate. PMID- 22506686 TI - Selective block of K(ATP) channels: why the anti-diabetic sulphonylureas and rosiglitazone have more in common than we thought. AB - Rosiglitazone, the thiazolidinedione class anti-diabetic withdrawn from Europe in 2010 amid reports of adverse cardiovascular effects, is revealed by Yu et al. in this issue of the British Journal of Pharmacology to be a selective blocker of ATP-sensitive potassium (K(ATP) ) channels. This seems little cause for excitement given that the closure of pancreatic K(ATP) channels is integral to insulin secretion; and sulphonylureas, which inhibit K(ATP) channels, are widely used to treat type II diabetes. However, rosiglitazone, whose primary targets are nuclear transcription factors that regulate genes involved in lipid metabolism, blocks K(ATP) channels by a novel mechanism different to that of the sulphonylureas and has a worrying preference for blood flow-regulating vascular K(ATP) channels. Identification of a new molecule that modulates K(ATP) channel gating will not only tell us more about how these complex metabolic sensors work but also raises questions as to whether rosiglitazone suppresses the cardiovascular system's ability to cope with metabolic stress - a claim that has dogged the sulphonylureas for many years. PMID- 22506687 TI - Ab initio study of the emissive charge-transfer states of solvated chromophore functionalized silsesquioxanes. AB - Recent experimental advances in the ability to tune the optical properties of silsesquioxanes by functionalizing them with photoactive ligands have made these compounds attractive candidates for building blocks of photovoltaic materials. We employ state-of-the-art ab initio methodologies to determine the nature of the excited charge-transfer (CT) states that give rise to a large red-shift between absorption and emission in these molecules, in comparison to the corresponding red-shift in the individual ligand. The calculations are based on time-dependent density functional theory and employ the recently developed Baer-Neuhauser Livshits range-separated hybrid (RSH) functional. Solvent effects are accounted for via a combination of charge-constrained density functional theory and the polarizable continuum model. We find that the experimentally observed red-shift is consistent with identifying the emissive state as a ligand-to-ligand, rather than a ligand-to-silsesquioxane, CT state. We also find that the enhanced red shift cannot be explained without accounting for solvation effects, and we demonstrate the importance of using a RSH functional to obtain reliable predictions regarding the emissive state. PMID- 22506688 TI - A resource perspective on the work-home interface: the work-home resources model. AB - The objective of this article is to provide a theoretical framework explaining positive and negative work-home processes integrally. Using insights from conservation of resources theory, we explain how personal resources (e.g., time, energy, and mood) link demanding and resourceful aspects of one domain to outcomes in the other domain. The resulting work-home resources (W-HR) model describes work-home conflict as a process whereby demands in one domain deplete personal resources and impede accomplishments in the other domain. Enrichment is described as a process of resource accumulation: Work and home resources increase personal resources. Those personal resources, in turn, can be utilized to improve home and work outcomes. Moreover, our resource approach to the work-home interface allows us to address two other issues that have thus far lacked a solid theoretical foundation. The W-HR model also explains how conditional factors such as personality and culture may influence the occurrence of work-home conflict and enrichment. Furthermore, the model allows us to examine how work-home conflict and enrichment develop over time. Finally, the model provides useful insights for other psychology subdisciplines, such as gender studies and developmental psychology. PMID- 22506689 TI - The attitude of 'low risk' pregnant women in Japan toward midwife-led care during pregnancy and labor. PMID- 22506690 TI - Primers and probes development for specific PCR detection of genetically modified common bean (Phaseolus vulgaris) Embrapa 5.1. AB - The genetically modified common bean Embrapa 5.1, developed by Brazilian Agricultural Research Corporation (Embrapa), is the first commercial GM plant produced in Latin America. It presents high resistance to the Bean golden mosaic virus. In this work, primers and probes targeting a taxon-specific reference DNA sequence for the common bean (Phaseolus vulgaris L.) and a construct-specific DNA sequence of Embrapa 5.1 GM common bean were successfully developed. The primers and probes showed high specificity for the target detection. Both methods showed suitable efficiency and performance to be used as an endogenous target for detection of common bean DNA and for construct-specific detection of GM common bean Embrapa 5.1, respectively. Both real-time PCR assays proved to be valuable for future assessment of interlaboratory studies. PMID- 22506691 TI - The role of positive affect on social participation following stroke. AB - PURPOSE: To examine the association between positive affect and social participation in adults with first-time stroke after in-patient medical rehabilitation. METHODS: A prospective cohort design using information from the Stroke Recovery in Underserved Populations database (SRUP) for the years 2005 2006. Data were collected at discharge from in-patient medical rehabilitation and 3 months post-discharge. Participants were aged 50 and older with first-time stroke (n = 605) and admitted to 1 of 11 in-patient medical rehabilitation facilities across the United States. Primary measures included a positive affect scale and a home and community social participation instrument. RESULTS: The mean age was 71.6 years, 50.3% were women, and 56.5% were married. Results of cumulative logit models showed each 1 point increase in positive affect was significantly associated with a 17% odds of higher social participation (OR: 1.17, 95% CI 1.10, 1.25), after adjusting for demographics, clinical characteristics, and negative affect. CONCLUSIONS: High positive affect at discharge from in-patient medical rehabilitation was associated with higher levels of social participation 3 months post-discharge. The significant association between higher positive affect and higher levels of social participation adds to accumulating evidence linking positive affect with beneficial physical and psychological outcomes after an acute event such as stroke. PMID- 22506692 TI - Topical 5% tranexamic acid for the treatment of melasma in Asians: a double-blind randomized controlled clinical trial. AB - BACKGROUND: Topical tranexamic acid has been claimed to lighten melasma without serious adverse effects. However, controlled studies assessing the efficacy and safety of topical tranexamic acid (TA) for the treatment of melasma is limited. OBJECTIVE: To assess in a double blind, randomized, prospective study, the efficacy of topical 5% tranexamic acid versus vehicle for treatment of melasma. METHODS: Twenty-three women with bilateral epidermal melasma enrolled in a split face trial lasting 12 weeks. Patients blindly applied topical 5% tranexamic acid and its vehicle, to the designated sides of the face twice daily in addition to the assigned sunscreen each morning. Pigmentation and erythema were measured objectively using a mexameter and Melasma Area and Severity Index (MASI), in addition to physician and patient global assessments. RESULTS: Twenty-one patients completed the study. Eighteen out of twenty-three patients (78.2%) showed decrease in the melanin index on either or both sides of the face by the end of 12 weeks compared to baseline. The MASI scores were also significantly reduced on both tested sides. However, lightening of pigmentation induced by TA gel was neither superior nor different (p > 0.05) compared to its vehicle although erythema was significant on the TA-applied site (p < 0.05). CONCLUSIONS: Although lightening of pigmentation was obtained, the results were not significant between the two regimens. However, topical TA produced erythema. PMID- 22506693 TI - Cellulose nanocrystal/silver nanoparticle composites as bifunctional nanofillers within waterborne polyurethane. AB - Developing bionanocomposites from renewable biomass is a viable supplement for materials produced from mineral and fossil fuel resources. In this study, nanocomposites composed of carboxylated cellulose nanocrystals (CCNs) and silver nanoparticles (AgNPs) were prepared and used as bifunctional nanofillers to improve the mechanical and antimicrobial properties of waterborne polyurethane (WPU). Morphology, structure and performance of the CCNs/AgNPs nanocomposites and WPU-based films were investigated. WPU-based composite films were homogeneous and reinforced. The WPU/CCNs/AgNPs composite showed excellent antimicrobial properties in killing both Gram-negative E. coli and Gram-positive S. aureus. The CCNs/AgNPs nanocomposites could be applied as bifunctional nanofillers within WPU. PMID- 22506694 TI - The effect of dynamic sitting on the prevention and management of low back pain and low back discomfort: a systematic review. AB - Dynamic sitting has been proposed to reduce low back pain (LBP) and/or low back discomfort (LBD) while sitting. This is supported by studies suggesting that subjects with LBP assume more static, sustained postures while sitting. This systematic review investigated the effect of dynamic sitting on LBP among subjects with LBP and the development of LBD among pain-free subjects. Electronic databases were searched by two independent assessors. All prospective studies which compared the effect of a dynamic sitting condition on LBP or LBD to another sitting condition were eligible, with no minimum follow-up period applied. The quality of the included studies was assessed using the PEDro scale. Seven high quality studies were eligible, including five crossover studies and two randomised controlled trials. The results suggest there is currently no evidence to support the use of dynamic sitting as a stand-alone approach in the management of LBP. PRACTITIONER SUMMARY: This systematic review investigated the effect of dynamic sitting on LBP or LBD. Seven high-quality studies met the inclusion and exclusion criteria. Overall, the evidence suggests that dynamic sitting approaches are not effective as a stand-alone management approach for LBP. PMID- 22506695 TI - Cyclocondensation of amino-propargyl silanes. AB - Amino-propargyl silanes condense with carbonyl compounds to form imines and subsequently cyclize to form allenylidene tetrahydroquinolines. The cyclocondensations are catalyzed by a variety of Bronsted acids, among which phosphoric acids provide the highest yields. Subsequent intramolecular and intermolecular additions to the allene moiety provide complex polycyclic amines. PMID- 22506697 TI - A solitary erythematous nodule in a 62-year-old man. PMID- 22506696 TI - Inactivation kinetics of spores of Bacillus cereus strains treated by a peracetic acid-based disinfectant at different concentrations and temperatures. AB - The purpose of this study was to assess the effect of a commercial peracetic acid based disinfectant against spores of Bacillus cereus, to identify the most influential factor for the final number of microorganisms after different disinfection procedures, and to evaluate the nature of the inactivation kinetics. The spores of four different strains of B. cereus (DSM 318, 4312, 4313, and 4384) were treated with five different disinfectant concentrations (0.25%, 0.5%, 1.0%, 1.5%, and 2.0% [w/v]) at three different temperatures (10 degrees C, 15 degrees C, and 20 degrees C) with or without protein load. A higher temperature and PES 15/23 concentration resulted in a higher inactivation. Inactivation of B. cereus strain 4312 was around 2 log10 cycles at 10 degrees C and around 7 log10 at 20 degrees C (conc=1% [w/v] PAA; t=60 min; without protein). The protein load at higher concentrations did not significantly reduce the efficacy of the disinfectant (p>0.05). This article indicates the applicability of the Weibull model to fit the B. cereus disinfectant survival curves. A Monte Carlo simulation was used to carry out a sensitivity analysis, which revealed the most influential factors affecting the final number of microorganisms after the disinfection process. PMID- 22506698 TI - A comparison of the Pentax Airway ScopeTM with the AirtraqTM in an infant manikin. AB - We compared the Pentax Airway Scope(TM) with the Airtraq(TM) optical laryngoscope in an infant manikin. Twenty-three anaesthetists randomly performed tracheal intubation: at rest, (a) with the Airway Scope and (b) with the Airtraq; and during chest compressions, (c) with the Airway Scope and (d) with the Airtraq. The success rate, modified Cormack and Lehane classification for glottic view, time taken to view the glottis, and time to place the tracheal tube were recorded. There was no difference in intubation success rate or quality of glottic view between the two devices. The median (IQR [range]) time taken to obtain a view of the glottis was 4.5 (3.7-6.4 [1.8-14.0]) s using the Airway Scope compared with 7.1 (5.5-9.6 [3.3-12.0]) s using the Airtraq (p = 0.001), and to successful placement of the tracheal tube was 8.3 (6.8-9.4 [3.7-20.7]) s using the Airway Scope compared with 11.2 (10.4-13.8 [4.9-23.7]) s using the Airtraq (p = 0.001). During chest compressions, the median (IQR [range]) time taken to view the glottis was 5.1 (4.0-7.2 [2.0-12.4]) s using the Airway Scope compared with 7.5 (5.0-13.2 [4.2-26.4]) s using the Airtraq (p = 0.006), and to successful placement of the tracheal tube was 9.5 (6.6-13.7 [4.5-16.2]) s using the Airway Scope compared with 11.7 (9.1-18.1 [6.2-37.4]) s using the Airtraq (p = 0.022). We conclude that both devices provided good quality views of the glottis and successful tracheal intubation in an infant manikin both at rest and during external chest compressions. Use of the Airway Scope resulted in a shorter time to view the glottis and perform successful tracheal intubation compared with the Airtraq. PMID- 22506699 TI - Synergistic effect of the combination of immobilized TiO2, UVA and ozone on the decomposition of dichloroacetic acid. AB - The performance of a heterogeneous photocatalytic ozonation system (TiO(2)/UVA/O(3)) was evaluated on the degradation and mineralization of dichloroacetic acid as a contaminant in aqueous solutions by means of a planar reactor. The commercial product "Pilkington ActiveTM glass" was used as the immobilized TiO(2) photocatalyst and it was irradiated by near UV light in this study. The synergistic interaction between ozone and the photoactivated TiO(2) surface was discussed and highlighted. Furthermore, the influences of initial concentration and temperature on the degradation rate of dichloroacetic acid and the ozone consumption level during the oxidation process were investigated. The concentrations of dichloroacetic acid and chloride anions produced during degradation were measured using ion chromatography. The mineralization of dichloroacetic acid was evaluated by Total Organic Carbon (TOC) measurements. The degradation of dichloroacetic acid by photocatalytic ozonation showed good agreement with the kinetics of first-order reactions with respect to dichloroacetic acid. PMID- 22506700 TI - Anaerobic toxicity assay of plasticisers. AB - Plasticisers are commonly found in landfill leachate and accumulate in the environment. Some of them are known as disruptive endocrine compound. This manuscript assessed the toxicity of three common plasticisers, including Bis(2 Ethylhexyl)phthalate (DEHP), o-hydroxybiphenyl (HBP) and 2,6-di-tert-butyl-4 (dimethylaminomethyl) phenol (MAMP) on the methanogens during the anaerobic process. It was found that DEHP and MAMP did not impede methanogenesis up to 200 mg/L, but no additional methane could be obtained from their degradation. In contrast, HBP severely inhibited methanogens at 200 mg/L, but after acclimatisation it could be metabolised resulting in a 25% increase in methane production compared to the control. PMID- 22506701 TI - Photo-Fenton degradation of non-ionic surfactant and its mixture with cationic or anionic surfactant. AB - The oxidative degradation of non-ionic surfactants by the photo-Fenton process has been examined. The photo-Fenton degradation kinetics of mixtures of non-ionic surfactant and other type surfactants has been also investigated since mixtures of non-ionic and ionic surfactants are commonly used to utilize their synergistic effects in many practices. Effects of operating parameters such as dosages of Fenton reagents (iron and hydrogen peroxide) and UV light intensity on the degradation of commercial non-ionic surfactant Sannonic SS-90 (polyoxyethylene alkyl ether) were studied. Although the dosages of the Fenton reagents increased the degradation rate up to the optimum dosages, further addition of the reagents could not enhance the degradation rate. Excess dosages of Fe and H(2)O(2) caused excess OH radicals which could be a scavenger of OH radicals and as a result could not enhance the degradation of the surfactant. The increase in UV light intensity resulting in the faster photo-Fenton process or the enhancement of OH radical formation rate led to the increase in degradation rate of non-ionic surfactant. Although the existence of the anionic surfactant (sodium dodecylbenzene sulphonate) would inhibit the degradation of the non-ionic surfactant due to the formation of complex with Fe ion, the existence of cationic surfactant (dodecyltrimethyl ammonium chloride) affected insignificantly the photo-Fenton degradation process of the non-ionic surfactant. PMID- 22506702 TI - Chemical evolution and vegetation response in an altered wetland ecosystem, Hula Valley, Israel (1988-2004). AB - The Hula Nature Reserve (HNR) (0.3 km(2)) in northern Israel is a semiarid wetland ecosystem within the greater Hula Valley. In the 1950s, approximately 60 km(2) of wetlands were drained and converted to farmland. The HNR was established during this time to preserve some of the native flora and fauna. Agricultural runoff and a reflooding of the area with peat water in 1999 resulted in high sulfate (SO(4) (2-)) concentrations of 66.67 +/- 4.00 mg/L. We identified the existence of SO(4) (2-), nitrate (NO(3) (-)), and ammonium (NH(4) (+)) nutrient gradients as well as related mechanisms affecting the growth and dieback of Cyperus papyrus. The observed changes in the C. papyrus populations were caused primarily by fluctuations in SO(4) (2-). After two key events that affected levels of SO(4) (2-) in the HNR, C. papyrus coverage was altered by more than 80%. PMID- 22506703 TI - An analysis of the link between strokes and soils in the South Carolina coastal plains. AB - The Stroke Belt is a geographical region of the Southeastern United States where resident individuals suffer a disproportionately higher rate of strokes than the rest of the population. While the "buckle" of this Stroke Belt coincides with the Southeastern Coastal Plain region of North and South Carolina and Georgia, there is a paucity of information pinpointing specific causes for this phenomenon. A number of studies posit that an exposure event-potentially microbial in nature early in life, could be a risk factor. The most likely vector for such an exposure event would be the soils of the Southeastern Coastal Plain region. These soils may have chemical and physical properties which are conducive to the growth and survival of microorganisms which may predispose individuals to stroke. To this aim, we correlated SC stroke mortality data to soil characteristics found in the NRCS SSURGO database. In statewide comparisons, depth to water table (50 to 100 cm, R = 0.62) and soil drainage class (poorly drained, R = 0.59; well drained, R = -0.54) both showed statistically significant relationships with stroke rate. In a 20 county comparison, depth to water table, drainage class, hydric rating (hydric soils, R = 0.56), and pH (very strongly acid, R = 0.66) all showed statistically significant relationships with stroke rate. These data should help direct future research and epidemiology efforts to pinpoint the exact exposure events which predispose individuals to an increased stroke rate. PMID- 22506704 TI - Evaluating the dispersion of toxic odour emissions from complex sources. AB - This article describes an original approach for evaluating exposure to toxic odour emissions, based on methods commonly used for assessing the impact of odour, adopted in this specific case to examine the non-carcinogenic health effects of odours in the city of Terni, Italy. First the hazardous volatile organic compounds emitted from the main odour sources were identified and quantified by chemical analysis. The Hazard Index (HI) was used to assess the toxicity associated with the emissions. The HI is the sum of the concentrations of the hazardous compounds weighted with their Reference Concentration (RfC). A RfC is the estimated continuous inhalation concentration at which people are unlikely to risk any deleterious effects during their lifetime. Atmospheric dispersion modelling was based on the Toxicity Emission Rate (TER) which, like the Odour Emission Rate (OER) conventionally used to quantify odour emissions, relates the HI with the air flow of an emission source; it is as a simple but effective method for the general characterization of toxic odour emissions in complex scenarios. The results indicated that citizens' exposure to the non carcinogenic toxic compounds involved in odour emissions was below the level expected to have adverse effects on human health. Classical risk assessment techniques should now be employed to define the pollutants and their effects better and to validate this approach. PMID- 22506705 TI - An air dispersion model for the city of Toronto, Ontario, Canada. AB - Air quality is a major concern for the public; therefore, the reliability of accurate models in predicting the air quality is of a major interest. In this study, a Gaussian air dispersion model, known as the Air dispersion model for Road Sources in Urban areaS (ARSUS), was developed to predict the ground level concentrations for a contaminant of interest. It was demonstrated that this model could be used successfully in place of or in conjunction with ambient air monitoring stations in determining the local Air Quality Index (AQI). The ARSUS model was validated against the US EPA ISC3 model before it was used to conduct two studies in this investigation. These two studies simulated weekday morning rush-hour tailpipe emissions of CO and predicted ground level concentrations. The first study used the ARSUS model to predict ground level concentrations of CO from the tailpipe emissions for roads and highways located in the vicinity of the Toronto West ambient air monitoring station. The second study involved an expansion of the domain to predict ground level concentrations of CO from tailpipe emissions from highways in the City of Toronto, Ontario, Canada. The predicted concentrations were then compared to the data collected from the Toronto West ambient air monitoring station. The results of the ARSUS model indicated that the air quality in the immediate vicinity of roads or highways is highly impacted by the tailpipe emissions. Higher concentrations were observed for the areas adjacent to the road and highway sources. The tailpipe emissions of CO from highways had a higher contribution to the local air quality. The predicted ground level concentrations from the ARSUS model under-predicted when compared to the observed data from the monitoring station; however, despite this, the predictive model is viable. PMID- 22506706 TI - Application of aqueous saponin on the remediation of polycyclic aromatic hydrocarbons-contaminated soil. AB - The aim of this research was to evaluate the feasibility of aqueous saponin for the removal and biodegradation of polycyclic aromatic hydrocarbons (PAHs) from contaminated soil. Dissolution test confirmed the ability of saponin to increase the apparent solubility of the tested 3-5 rings PAH above the critical micelle concentration (approximately 1000 mg/L). Microbial test with pure culture of Sphingomonas sp. showed that saponin significantly enhanced the degradation of pyrene. For example, the percent degradation was 2.1 times higher in the presence of 2500 mg/L saponin than that of control without saponin after 60 hours incubation at around 10(8) CFU/mL initial cell loading. These results suggest that the binding of pyrene with saponin does not pose a serious constraint to bacterial uptake. Contrary to pyrene, saponin was chemically stable against the PAHs degrader. It is also not toxic to the cell at least up to 2500 mg/L. Finally, using a spiked soil sample, extraction tests with 10,000 mg/L of saponin showed that around 52.7% and 0.3% of pyrene was removed from low and high organic spiked soils, respectively. The results from this study indicate that aqueous saponin is appropriate as a washing agent as well as biodegradation enhancer for the detoxification of PAHs-contaminated low organic carbon soil. PMID- 22506707 TI - Removal of antimonate ions from an aqueous solution by anion exchange with magnesium-aluminum layered double hydroxide and the formation of a brandholzite like structure. AB - A magnesium-aluminum layered double hydroxide intercalated with NO(3)(-) (NO(3)*Mg-Al LDH) removed Sb(V) in solution. The antimony (Sb) removal increased with time and with an increasing molar ratio of Al/Sb, i.e., the quantity of NO(3)*Mg-Al LDH. The removal of Sb(V) in solution by NO(3)*Mg-Al LDH was not due to the reaction of Sb(V) with dissolved Mg(2+) but was rather caused by anion exchange between Sb(V), i.e., Sb(OH)(6)(-), in an aqueous solution and NO(3)(-) in the interlayer of the Mg-Al LDH. The intercalation of Sb(OH)(6)(-) in the interlayer of Mg-Al LDH is thought to result in the formation of a brandholzite like structure. Some Sb(OH)(6) (-) was likely adsorbed on the surface of the NO(3)*Mg-Al LDH. The efficiency of the Sb removal decreased in the following order, irrespective of the reaction time: NO(3)*Mg-Al LDH ~ Cl*Mg-Al LDH > SO(4)*Mg-Al LDH > CO(3)*Mg-Al LDH. The removal of Sb by SO(4)*Mg-Al LDH and Cl*Mg Al LDH was also caused by anion exchange between Sb(V), i.e., Sb(OH)(6) (-), in an aqueous solution and SO(4)(2-) and Cl(-) in the interlayer of Mg-Al LDH, which formed a brandholzite-like structure due to the intercalation of Sb(OH)(6)(-) into the interlayer. In the case of SO(4)*Mg-Al LDH, hydrogen bonds between the Mg-Al LDH-positive host layer and Sb(OH)(6)(-) were probably stronger than the electrostatic force of attraction between the Mg-Al LDH-positive host layer and SO(4)(2-). The results suggested that Cl*Mg-Al LDH was as effective as NO(3)*Mg Al LDH for the treatment of Sb(V) in aqueous solutions. PMID- 22506709 TI - Biosecurity aspects and pathogen inactivation in acidified high risk animal by products. AB - The aim of the study was to investigate the effects of formic acid addition to ground high risk animal by-products (ABP 1) in terms of stabilization and pathogen inactivation and to evaluate the biosecurity risk connected with the ABP 1 based combustion fuel Biomal. Laboratory studies were performed on the persistence of Salmonella Typhimurium, Bacillus cereus spores, porcine herpes virus, avian influenza virus, bovine viral diarrhea virus, equine rhinitis A virus and porcine parvovirus in Biomal at different storage times. It was shown that Salmonella and enveloped viruses were inactivated within 1 day (24 h). Bacillus cereus spores were not reduced during 147 days and the non-enveloped virus porcine parvovirus was still detected after 168 days of storage. The conclusion that can be drawn from the study is that transmission of some highly contagious diseases such as foot-and-mouth-disease, swine vesicular disease and egg drop syndrome, caused by non-enveloped viruses, may follow accidental leakages of Biomal. In addition, there is a risk of transmission of the diseases anthrax and black leg, caused by sporulating bacteria. PMID- 22506708 TI - Major factors affecting in situ biodegradation rates of jet-fuel during large scale biosparging project in sedimentary bedrock. AB - Biodegradation of petroleum hydrocarbons (TPH), mainly jet fuel, had taken place at the former Soviet Army air base in the Czech Republic. The remediation of large-scale petroleum contamination of soil and groundwater has provided valuable information about biosparging efficiency in the sandstone sedimentary bedrock. In 1997 petroleum contamination was found to be present in soil and groundwater across an area of 28 hectares, divided for the clean-up purpose into smaller clean-up fields (several hectares). The total estimated quantity of TPH released to the environment was about 7,000 metric tons. Biosparging was applied as an innovative clean-up technology at the site and was operated over a 10-year period (1997-2008). Importance of a variety of factors that affect bacterial activity in unsaturated and saturated zones was widely studied on the site and influence of natural and technological factors on clean-up efficiency in heavily contaminates areas of clean-up fields (initial contaminant mass 111-452 metric ton/ha) was evaluated. Long-term monitoring of the groundwater temperature has shown seasonal rises and falls of temperature which have caused a fluctuation in biodegradation activity during clean-up. By contrast, an overall rise of average groundwater temperature was observed in the clean-up fields, most probably as a result of the biological activity during the clean-up process. The significant rise of biodegradation rates, observed after air sparging intensification, and strong linear correlation between the air injection rates and biodegradation activities have shown that the air injection rate is the principal factor in biodegradation efficiency in heavily contaminated areas. It has a far more important role for achieving a biodegradation activity than the contamination content which appeared to have had only a slight effect after the removal of about 75% of initial contamination. PMID- 22506710 TI - Conversion of agricultural residues into activated carbons for water purification: Application to arsenate removal. AB - The conversion of two agricultural wastes, sugar beet pulp and peanut hulls, into sustainable activated carbons is presented and their potential application for the treatment of arsenate solution is investigated. A direct and physical activation is selected as well as a simple chemical treatment of the adsorbents. The material properties, such as BET surface areas, porous volumes, elemental analysis, ash contents and pH(PZC), of these alternative carbonaceous porous materials are determined and compared with a commercial granular activated carbon. An adsorption study based on experimental kinetic and equilibrium data is conducted in a batch reactor and completed by the use of different models (intraparticle diffusion, pseudo-second-order, Langmuir and Freundlich) and by isotherms carried out in natural waters. It is thus demonstrated that sugar beet pulp and peanut hulls are good precursors to obtain activated carbons for arsenate removal. PMID- 22506711 TI - A combined CaO/electrochemical treatment of the acid mine drainage from the "Robule" Lake. AB - The purpose of this work was development and application of the purification system suitable for the treatment of the acid mine drainage (AMD) accumulated in the "Robule" Lake, which represents the part of the Bor copper mining and smelting complex, Serbia. The study was undertaken in order to minimize adverse effect on the environment caused by the discharge of untreated AMD, which was characterized with low pH value (2.63) and high concentration of heavy metals (up to 610 mg/L) and sulfates (up to 12,000 mg/L). The treatment of the effluent included pretreatment/pH adjustment with CaO followed by electrocoagulation using iron and aluminum electrode sets. Following the final treatment, the decrease in the concentration of heavy metals ranged from 40 up to 61000 times depending on the metal and its initial concentration. The parameters, color and turbidity were removed completely in the pretreatment step, while the removal efficiencies for other considered parameters were as follows: EC = 55.48%, SO(4) (2-) = 70.83%, Hg = 98.36%, Pb = 97.50%, V = 98.43%, Cr = 99.86%, Mn = 97.96%, Fe = 100.00%, Co = 99.96%, Ni = 99.78%, Cu = 99.99% and Zn = 99.94%. Because the concentrations of heavy metals in the electrochemically treated AMD (ranging from 0.001 to 0.336 mg/L) are very low, the negative impact of this effluent on the aquatic life and humans is not expected. The sludge generated during the treatment of AMD is suitable for reuse for at least two purposes (pretreatment of AMD and covering of the flotation waste heap). From the presented results, it could be concluded that electrochemical treatment is a suitable approach for the treatment of AMD. PMID- 22506712 TI - BiOCl-assisted photodegradation of Rhodamine B under white light and monochromatic green pulsed laser irradiation. AB - BiOCl-assisted photodegradation of Rhodamine B (Rh. B) molecules was investigated by using white light and green pulsed laser as sources of irradiation in the visible region for the first time. The dependences of removal efficiencies on catalyst dosage, incident pulsed laser energy were investigated and discussed. The dissolved oxygen was found to play an important role during the photochemical reaction. In addition the lowest unoccupied molecular orbital (LUMO) and highest occupied molecular orbital (HOMO) levels of Rh. B molecular were calculated using a Gaussian 03 program. These calculations were valuable to identify the possible photo-catalytic excitation process involved in degradation of Rh.B. PMID- 22506714 TI - Pinch and ligation method: a new non-surgical approach to viral warts. PMID- 22506715 TI - Attachment and exploration in adulthood: the mediating effect of social support. AB - Research examining the relationship between adult attachment styles and exploratory behavior has shown that anxious and avoidant attachment styles are negatively related to exploration. However, little research has been conducted on the mediation process between adult attachment styles and exploration. Given that perceived social support has been shown to be the basis for secure attachment and may be related to exploration behavior, the current study examines whether perceived social support mediates the relationship between adult attachment and exploration. University students in Taiwan (N = 168) completed questionnaires that assessed attachment styles; perceived social support from their father, mother, and best friend; and their intellectual, social, and environmental exploration. Our results revealed that perceived social support mediates the relationship between avoidant attachment and exploration behavior. PMID- 22506716 TI - Ipilimumab (MDX-010) in the treatment of non-small cell lung cancer. AB - INTRODUCTION: Non-small cell lung cancer (NSCLC) is one of the main causes of cancer-related deaths worldwide. Although new therapies have become available, innovative treatments are still needed for advanced disease. Ipilimumab , a monoclonal antibody targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), enhances the immune response against the tumor mass and has been proven effective against malignant melanoma. AREAS COVERED: The authors explored the role of ipilimumab in NSCLC using a literature review. The clinical trials involving ipilimumab for lung cancer have shown progression-free survival (PFS) benefits. The use of ipilimumab is related to unusual adverse events resulting from increased or excessive immune activity. Because ipilimumab shows unique response patterns, more suitable criteria known as immune-related response criteria (ir-RC), different from RECIST and WHO criteria, are required. EXPERT OPINION: Although NSCLC is not known as an immunogenic-mediated malignancy, in the past few years, the authors have observed an increasing interest in the development of therapies able to modulate the immune response including vaccines and non-specific immunoregulatory drugs (such as ipilimumab). Ipilimumab may become a new, powerful strategy for the management of NSCLC patients. Further investigation is needed to confirm the optimal treatment schedule and determine the potential predictors of response to the CTLA-4 blockade. PMID- 22506713 TI - Organization of the ENaC-regulatory machinery. AB - The control of fluid and electrolyte homeostasis in vertebrates requires the integration of a diverse set of signaling inputs, which control epithelial Na(+) transport, the principal ionic component of extracellular fluid. The key site of regulation is a segment of the kidney tubules, frequently termed the aldosterone sensitive distal nephron, wherein the epithelial Na(+) channel (or ENaC) mediates apical ion entry. Na(+) transport in this segment is strongly regulated by the salt-retaining hormone, aldosterone, which acts through the mineralocorticoid receptor (MR) to influence the expression of a selected set of target genes, most notably the serine-threonine kinase SGK1, which phosphorylates and inhibits the E3 ubiquitin ligase Nedd4-2. It has long been known that ENaC activity is tightly regulated in vertebrate epithelia. Recent evidence suggests that SGK1 and Nedd4 2, along with other ENaC-regulatory proteins, physically associate with each other and with ENaC in a multi-protein complex. The various components of the complex are regulated by diverse signaling networks, including steroid receptor-, PI3-kinase-, mTOR-, and Raf-MEK-ERK-dependent pathways. In this review, we focus on the organization of the targets of these pathways by multi-domain scaffold proteins and lipid platforms into a unified complex, thereby providing a molecular basis for signal integration in the control of ENaC. PMID- 22506718 TI - Centrifugal force induces human ligamentum flavum fibroblasts inflammation through activation of JNK and p38 pathways. AB - Inflammation has been proposed to be an important causative factor in ligamentum flavum hypertrophy. However, the mechanisms of mechanical load on inflammation of ligamentum flavum remain unclear. In this study, we used an in vitro model of human ligamentum flavum fibroblasts subjected to centrifugal force to elucidate the effects of mechanical load on cultured human ligamentum flavum fibroblasts; we further studied its molecular and biochemical mechanisms. Human ligamentum flavum fibroblasts were obtained from six patients undergoing lumbar spine surgery. Monolayer cultures of human ligamentum flavum fibroblasts were subjected to different magnitudes of centrifugal forces. Cell viability, cell death, biochemical response, and molecular response to centrifugal forces were analyzed. It was found that centrifugal stress significantly suppressed cell viability without inducing cell death. Centrifugal force at 67.1 g/cm(2) for 60 min significantly increases the production of prostaglandin E2 and nitric oxide as well as gene expression of proinflammatory cytokines, including interleukin (IL) 1alpha, IL-1beta and IL-6, showed that centrifugal force-dependent induction of cyclooxygense-2 and inducible NO synthase required JNK and p38 mitogen-activated protein kinase, but not ERK 1/2 activities. This study suggested that centrifugal force does induce inflammatory responses in human ligamentum flavum fibroblasts. The activation of both JNK and p38 mitogen-activated protein kinase mechanotransduction cascades is a crucial intracellular mechanism that mediates cyclooxygense-2/prostaglandin E2 and inducible NO synthase/nitric oxide production. PMID- 22506717 TI - Platelets increase survival of adenocarcinoma cells challenged with anticancer drugs: mechanisms and implications for chemoresistance. AB - BACKGROUND AND PURPOSE: Cancer cells grow without the restraints of feedback control mechanisms, leading to increased cancer cell survival. The treatment of cancer is often complicated by the lack of response to chemotherapy leading to chemoresistance and persistent survival of tumour cells. In this work we studied the role of platelets in chemotherapy-induced cancer cell death and survival. EXPERIMENTAL APPROACH: Human adenocarcinoma cells, colonic (Caco-2) and ovarian (59 M) cells, were incubated with 5-fluorouracil (1-300 ug.mL(-1) ) or paclitaxel (1-200 ug.mL(-1) ) in the presence or absence of platelets (1.5 * 10(8) mL(-1) ) for 1, 24 or 72 h. Following incubation, cancer cells were harvested and cell survival/death was assayed using flow cytometry, Western blotting, real-time PCR, TaqMan(r) Gene Expression Assays and proteomics. KEY RESULTS: Human platelets increased the survival of colonic and ovarian adenocarcinoma cells treated with two standard anticancer drugs, 5-fluorouracil and paclitaxel. In the presence of platelets, cancer cells up-regulated anti-apoptotic and down-regulated pro apoptotic genes, increased the number of cells in the synthesis of DNA and decreased the number in the quiescent phase, increased expression of cyclins, DNA repair proteins and MAPKs. The analysis of platelet-Caco-2 secretome demonstrated the release of the chemokine RANTES, thrombospondin-1, TGF-beta and clusterin. Finally, human recombinant RANTES and thrombospondin-1 improved survival of Caco 2 cells challenged with paclitaxel. CONCLUSIONS AND IMPLICATIONS: These data demonstrate that platelets increase adenocarcinoma cells survival, proliferation and chemoresistance to standard anticancer drugs. Modulating cancer cell-platelet interactions may offer a new strategy to improve the efficacy of chemotherapy. PMID- 22506720 TI - Simple and efficient solid-phase preparation of azido-peptides. AB - A shelf-stable and easily prepared diazotransfer reagent, imidazole-1-sulfonyl azide hydrochloride, was used to transform the N-terminus of a model peptide on solid phase into an azide moiety. It is demonstrated that this conversion was accomplished within 30 min with high efficiency under aqueous conditions on a NovaPEG resin or in DMF on polystyrene beads. PMID- 22506721 TI - A quasi-experimental study of after-event reviews and leadership development. AB - We examine how structured reflection through after-event reviews (AERs) promotes experience-based leadership development and how people's prior experiences and personality attributes influence the impact of AERs on leadership development. We test our hypotheses in a time-lagged, quasi-experimental study that followed 173 research participants for 9 months and across 4 distinct developmental experiences. Findings indicate that AERs have a positive effect on leadership development, and this effect is accentuated when people are conscientious, open to experience, and emotionally stable and have a rich base of prior developmental experiences. PMID- 22506722 TI - A convergent and stereocontrolled cycloaddition strategy toward eudesmane sesquiterpenoid: total synthesis of (+/-)-6beta,14-epoxyeudesm-4(15)-en-1beta-ol. AB - We present in this report the development of a convergent and highly stereocontrolled cycloaddition strategy toward the synthesis of C-1, C-6, and C 14 tris-oxygenated eudesmane sesquiterpenoids. This approach was demonstrated in the first total synthesis of (+/-)-6beta,14-epoxyeudesm-4(15)-en-1beta-ol (1), a structurally unique ethereal eudesmane sesquiterpenoid, via an effective Diels Alder construction of a compact functionalized tricycle intermediate from readily available N-benzylfurfurylamine (2) and homoprenyl maleic anhydride (3) as the C(5) and C(10) building blocks, respectively. PMID- 22506723 TI - Structural determinants of protein kinase CK2 regulation by autoinhibitory polymerization. AB - CK2 is a Ser/Thr protein kinase essential for cell viability whose activity is anomalously high in several cancers. CK2 is a validated target for cancer therapy with one small molecule inhibitor in phase I clinical trials. This enzyme is not regulated by mechanisms common to other protein kinases, and how its activity is controlled is still unclear. We present a new crystal structure of the CK2 holoenzyme that supports an autoinhibitory mechanism of regulation whereby the beta-subunit plays an essential role in the formation of inactive polymeric assemblies. The derived structural model of (down)regulation by aggregation contributes to the interpretation of biochemical and functional data and paves the way for new strategies in the modulation of CK2 activity and for the design of non-ATP-competitive inhibitors targeting the interaction between the alpha catalytic and the beta regulatory subunits. PMID- 22506724 TI - Dual role of cyclooxygenase-2 during tissue repair induced by low level laser therapy: an intriguing issue. AB - Tissue repair is an excellent example of pathophysiological model for studying the role of cyclooxygenase-2 (COX-2) on eukaryotic cells. It has been established that two COX isoforms are expressed in human tissues: constitutive or induced. COX-1 activity is constitutive, present in nearly all cell types at a constant level; COX-2 activity is normally absent from cells, and when induced, the protein levels increase and decrease in a matter of hours after a single stimulus. Thus, the purpose of this review was to describe the role of COX-2 during tissue repair induced by low level laser therapy (LLLT) in humans and experimental models. COX-2 expression has been implicated in the onset or the exacerbation of inflammation during tissue repair induced by LLLT in a number of studies, Many studies are conducted to investigate the role of COX-2 during tissue repair induced by LLLT using different experimental protocols and dosages. Therefore, this is an area that warrants investigation, since the estimation of COX-2 expression from using such important techniques in therapeutics with respect to tissue repair will be added to those already established in the literature as a way to improve health status and prevention of side effects. PMID- 22506725 TI - Effects of firefighters' self-contained breathing apparatus' weight and its harness design on the physiological and subjective responses. AB - To examine the effects of firefighters' self-contained breathing apparatus' (SCBA) weight and its harness design on the physiological and subjective responses, eight male students performed treadmill exercise under four conditions: the 8 kg firefighter protective clothing (PC) (Control), the PC + an 11 kg SCBA with an old harness (Test A), the PC + a 6.4 kg SCBA with an old harness (Test B) and the PC + a 6.4 kg SCBA with a new harness (Test C), at ambient temperatures (T(a)) of 22 degrees C and 32 degrees C. Besides highlighting the fact that a heavy SCBA had a significant effect on the oxygen consumption and metabolic rate, this experiment also found that in a T(a) of 32 degrees C, in particular, the combined effect of 4.7 kg lighter SCBA and new harness design could reduce metabolic rate and improved subjective muscle fatigue and thermal discomfort. PRACTITIONER SUMMARY: An effort to alleviate the physiological and subjective burden of firefighters by reducing the weight of SCBA and by using the new harness design has provided satisfactory results in reduced oxygen consumption and in improved subjective responses in a hot air environment. PMID- 22506727 TI - Iodine(III)-mediated intermolecular allylic amination under metal-free conditions. AB - A new approach to direct intermolecular allylic amination has been developed using metal-free conditions at room temperature. The reaction employs a hypervalent iodine(III) reagent as an oxidant and bistosylimide as a nitrogen source. A series of different allylic aminations are presented with up to a 99% yield. Mechanistic studies including isotope labeling and Hammett correlation suggest that depending on the substrate structure two different mechanisms can be operating. PMID- 22506726 TI - Association of resistin with metabolic syndrome in Indian subjects. AB - BACKGROUND: The role of resistin in insulin sensitivity and metabolic syndrome has been controversial until now. Increased plasma/serum resistin levels are associated with metabolic syndrome and insulin resistance. The aim of this study was to investigate the relationship between serum resistin levels with markers of metabolic syndrome in males. METHODS: A total of 386 male volunteers were enrolled in a case-control study. All of the enrolled volunteers were analyzed to confirm metabolic syndrome following the guidelines of National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) of 2001. Of the 386 volunteers, 192 were categorized as cases of metabolic syndrome, whereas 194 were registered as controls without metabolic syndrome. Volunteers enrolled in the study were analyzed for anthropometrical parameters, lipid profile status, insulin, insulin resistance, and resistin. RESULTS: Higher levels of resistin were observed in cases when compared to controls (12.49 +/- 4.73 ng/mL vs. 6.99 +/- 1.98 ng/mL). Resistin was positively and significantly associated with serum triglyceride, cholesterol, and very-low-density lipoprotein, whereas it was negatively and significantly associated with serum high-density lipoprotein (HDL) levels. Multiple regression analysis of the data observed indicated that the triglyceride level was the major determinant for the development of metabolic syndrome in male samples. CONCLUSION: This study demonstrates a positive correlation between resistin and factors of metabolic syndrome, except for HDL cholesterol (HDL-C), which was found to be negatively correlated in Indian male subjects. The study also found resistin to be a suitable peripheral blood marker. PMID- 22506728 TI - Improving the oral bioavailability of curcumin using novel organogel-based nanoemulsions. AB - Curcumin is a natural bioactive compound with many health-promoting benefits. Its low oral bioavailability limits its application in functional foods. In the present study, novel organogel-based nanoemulsions have been developed for oral delivery of curcumin and improvement of its bioavailability. Recently developed curcumin organogel was used as the oil phase in the curcumin nanoemulsion formulation. Tween 20 was selected as the emulsifier on the basis of maximum in vitro bioaccessibility of curcumin in the nanoemulsion. In vitro lipolysis profile revealed that the digestion of nanoemulsion was significantly faster and more complete than the organogel. Permeation experiments on Caco-2 cell monolayers suggested that digestion-diffusion was the major absorption mechanism for curcumin in the nanoemulsion. Furthermore, in vivo pharmacokinetics analysis on mice confirmed that the oral bioavailability of curcumin in the nanoemulsion was increased by 9-fold compared with unformulated curcumin. This novel formulation approach may also be used for oral delivery of other poorly soluble nutraceuticals with high loading capacity, which has significant impact in functional foods, dietary supplements and pharmaceutical industries. PMID- 22506729 TI - Male gender promotes an increased inflammatory response to lipopolysaccharide in umbilical vein blood. AB - OBJECTIVES: To establish gender-specific differences in maternal and fetal immune response in healthy human fetuses at term. METHODS: Forty-five women with elective caesarean sections for uncomplicated singleton pregnancies were recruited for two studies. Using a multiplex biomarker immunoassay system, unstimulated maternal and fetal plasma concentrations of interleukin (IL)-1beta, IL-1ra, IL-6, IL-8, macrophage inflammatory protein (MIP)-1alpha, and tumor necrosis factor (TNF)-alpha were measured from one study population. Lipopolysaccharide (LPS)-stimulated cytokine response was measured in a second study. RESULTS: There were no significant gender differences in either maternal or fetal unstimulated plasma cytokine concentrations, but concentrations of the proinflammatory cytokines IL-1beta and IL-6 were significantly greater in male fetal LPS-stimulated samples than in female fetal samples. CONCLUSIONS: Blood of male fetuses mounts a larger pro-inflammatory response to lipopolysaccharide (LPS). This heightened response could be a critical pathway in promoting premature rupture of membranes (PPROM) and may be associated with life long differential gender response to infection. PMID- 22506730 TI - Reticular groove of the domestic ruminants: histochemical and immunocytochemical study. AB - The reticular groove mucosa of adult cattle, buffalo and sheep was investigated by histochemical and immunocytochemical techniques. Intense NADPH-d staining was observed in the folds of the epithelium mucosa and at the bottom of the reticular groove in all domestic ruminants studied. The NADPH-d staining showed that the innervations of the tunica muscularis of the reticular groove lip were composed of nerve corpuscles, nerve fibres and nerve cells of the mucosa epithelium. SEM analysis showed an intense nitric oxide synthase (NOS) I immunoreactivity in deep and medium cellular layers. It is interesting to note that the same morphologies were observed in samples of the mucosa epithelium, and of the tunica muscularis processed by NADPH-d and in those processed by immunogold techniques. This study has demonstrated that nitric oxide (NO) is involved in the rumination activity and that it plays a double role in this activity in the reticular groove of all domestic ruminants studied: (1) NO plays a role similar to the one it has in the mucosa epithelium of all the other compartments of the ruminant forestomach, (2) The lip sections of the reticular groove has shown abundant innervations that may indirectly coordinate and control the forestomach motility through the direct activation of the nitrergic (nitroxidergic) nerve cells and nerve fibres. PMID- 22506731 TI - Standardization and international multicenter validation of a PulseNet pulsed field gel electrophoresis protocol for subtyping Shigella flexneri isolates. AB - Shigella flexneri is one of the agents most frequently linked to diarrheal illness in developing countries and often causes outbreaks in settings with poor hygiene or sanitary conditions. Travel is one of the means by which S. flexneri can be imported into developed countries, where this pathogen is not commonly seen. A robust and discriminatory subtyping method is needed for the surveillance of S. flexneri locally and regionally, and to aid in the detection and investigation of outbreaks. The PulseNet International network utilizes standardized pulsed-field gel electrophoresis (PFGE) protocols to carry out laboratory-based surveillance of foodborne pathogens in combination with epidemiologic data. A multicenter validation was carried out in nine PulseNet laboratories located in North and South America, Europe, and Asia, and it demonstrated that a new protocol is highly robust and reproducible for subtyping of S. flexneri. This protocol, already approved for PulseNet laboratories, applies NotI and XbaI as primary and secondary restriction enzymes, respectively, under electrophoresis conditions of initial switch time of 5 s to final switch time of 35 s, at 6 volts/cm. PMID- 22506732 TI - Effect of potential therapeutic agents in reducing oxidative stress in pulmonary tissues of recurrent airway obstruction-affected and clinically healthy horses. AB - REASONS FOR PERFORMING STUDY: To determine and compare the reactive oxygen and nitrogen species (ROS and RNS) in pulmonary tissues of horses affected with recurrent airway obstruction (RAO) and clinically healthy horses, and to evaluate the effectiveness of potential therapeutic agents in reducing ROS and RNS in the tissues of these horses. OBJECTIVES: We hypothesised that RAO-affected horses would have high levels of reactive species and that the test agents would reduce them. The objectives were as follows: 1) to determine the level of ROS and RNS in pulmonary tissues (bronchial and arterial rings) of RAO-affected and clinically healthy horses; and 2) to determine the ability of pentoxifylline, pyrrolidine dithiocarbamate and a combined use of endothelin A and B receptor antagonists (BQ123 and BQ788, respectively) in reducing reactive species. METHODS: Arterial and bronchial rings were collected from the diaphragmatic lung lobe of each horse immediately after euthanasia. The levels of ROS and RNS were measured in control tissues and those incubated with test agents, using an electron paramagnetic resonance instrument. RESULTS: The levels of ROS and RNS were significantly greater in arterial and bronchial tissues of RAO-affected than of clinically healthy horses. Pentoxifylline and endothelin antagonists reduced both ROS and RNS in tissues from RAO-affected horses. Basal levels of reactive species in clinically healthy horses were not affected by these agents. No difference in the level of reactive species was observed between arterial and bronchial tissues. CONCLUSIONS: Horses affected by RAO had higher ROS and RNS than clinically healthy horses. Pentoxifylline and endothelin antagonists effectively reduced ROS and RNS in pulmonary tissues of RAO-affected horses. POTENTIAL RELEVANCE: The study suggested a potential use for pentoxifylline and endothelin antagonists in treating RAO-affected horses. As endothelin is involved in physiological functions, therapeutic use of its antagonists is cautioned. PMID- 22506734 TI - Differences in body mass index z-scores and weight status in a Dutch pediatric psychiatric population with and without use of second-generation antipsychotics. AB - OBJECTIVE: Weight gain and metabolic adverse effects of second-generation antipsychotics (SGAs) have become a major concern, particularly in youth. However, the specific contribution of SGAs versus other medications or the underlying illness is unclear. METHODS: In a chart review study of psychiatric outpatients aged <= 18 years treated with SGAs and psychiatric controls without lifetime SGA, use body mass index (BMI) z-scores between patients and controls were compared in the entire sample, patients without co-medications, diagnostic subgroups, and age subgroups. In patients with follow-up data, weight z-score change was calculated. RESULTS: Altogether, 592 Caucasian patients aged 4-18 (mean: 10.0) years with a psychiatric diagnosis were included. BMI z-scores in 96 youth treated with SGAs for 9.0 +/- 6.1 months were significantly higher than in 496 patients without lifetime SGA use (0.81 +/- 1.1 vs. 0.05 +/- 1.2; p<0.0001). BMI z-score differences remained significant in all age groups <16 years old. In sub-analyses, results remained the same after eliminating patients on any co medication (0.82 +/- 1.2 vs. 0.23 +/- 1.2; p<0.0001) and in patients with (0.75 +/- 1.2 vs. 0.17 +/- 1.1, p<0.0001) or without autism spectrum disorders (1.1 +/- 1.0 vs. -0.02 +/- 1.2, p<0.0001). Significantly more SGA-treated youth were obese (27.1% vs. 9.5%, odds ratio [OR]: 3.55, 95% confidence interval [CI]:2.07-6.08) or overweight (21.9% vs. 8.3%, OR: 3.11, 95%CI: 1.75-5.52). In 24 patients (92.3% antipsychotic-naive) with 6.6 months follow-up, weight z-score increased significantly from -0.17 +/- 1.5 to 0.25 +/- 1.4 (p<0.0001) with 12.5% transitioning to overweight or obese status. CONCLUSION: These data show robust and significant differences in sex- and age-adjusted body weight and weight status in young pediatric Caucasian samples with and without use of SGAs independent of Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision (DSM-IV-TR) (American Psychiatric Association 2000 ) diagnosis and nonantipsychotic medications. Weight status and metabolic effects of SGAs require careful attention, especially in youth. PMID- 22506736 TI - Identifying the nature of impairment in planning ability with normal aging. AB - Planning ability, a subset of executive functioning, has been shown to decline with normal aging. However, the exact nature of this decline has yet to be adequately examined. In this study, 50 younger adults and 50 older adults completed a map task designed to tease apart the formulation and execution stages of planning. Participants were tasked with reading a map layout of a university apartment and planning an efficient route to complete several tasks. There were two conditions, aid and no-aid. During the formulation stage, participants wrote out their plan for later task completion. In the execution stage, half of the participants were instructed to utilize their written aid during task completion while the other half completed tasks without the use of their aid. Older adults performed more poorly than younger adults during both the formulation and execution stages on measures of accuracy and efficiency. There was no effect of using the aid during execution. Thus, using an open-ended planning task involving real-world stimuli, we found age-related deficits in planning ability associated with both the formulation and execution components, and not exclusively with formulation. We also found that both groups successfully updated and adjusted their formulated plans during execution. PMID- 22506737 TI - Ethicovigilance in clinical trials. AB - This article provides an ethical critique of the Good Clinical Practice (GCP) and Declaration of Helsinki (DoH) documents. While the previous criticisms of GCP are entirely correct, there is much more wrong with the document than has previously been acknowledged, including a circular definition and an astonishing vagueness about ethical principles. In addition to its failure to provide adequate ethical protection of participants, the procedurally dense nature of GCP lends itself to a box-ticking culture where important ethical issues are overlooked because they are not 'mentioned on the form'. In contrast, the DoH is a much more effective ethical document, but actually goes too far in one respect. It transpires that the best ethical guidelines for clinical research would be neither over prescriptive in regard to particular ethical issues (as the DoH is) nor neglectful of them (as GCP is); correctly framed ethical principles will provide sufficient protection to participants while also ensuring a culture of ethicovigilance in clinical trials. PMID- 22506738 TI - Is 'starting on time' useful (or useless) as a surrogate measure for 'surgical theatre efficiency'? AB - We analysed more than 7000 theatre lists from two similar UK hospitals, to assess whether start times and finish times were correlated. We also analysed gap times (the time between patients when no anaesthesia or surgery occurs), to see whether these affected theatre efficiency. Operating list start and finish times were poorly correlated at both hospitals (r(2) = 0.077 and 0.043), and cancellation rates did not increase with late starts (remaining within 2% and 10% respectively at the two hospitals). Start time did not predict finish time (receiver operating curve areas 0.517 and 0.558, respectively), and did not influence theatre efficiency (~80-84% at either hospital). Median gap times constituted just 7% of scheduled list time and did not influence theatre efficiency below cumulative gap times of less than 15% scheduled list time. Lists with no gaps still exhibited extremely variable finish times and efficiency. We conclude that resources expended in trying to achieve prompt start times in isolation, or in reducing gap times to under ~15% of scheduled list time, will not improve theatre productivity. Instead, the primary focus should be towards quantitative improvements in list scheduling. PMID- 22506739 TI - Sensitive assay for mycoplasma detection in mammalian cell culture. AB - Mycoplasma contamination in mammalian cell cultures is often overlooked yet is a serious issue which can induce a myriad of cellular changes leading to false interpretation of experimental results. Here, we present a simple and sensitive assay to monitor mycoplasma contamination (mycosensor) based on degradation of the Gaussia luciferase reporter in the conditioned medium of cells. This assay proved to be more sensitive as compared to a commercially available bioluminescent assay in detecting mycoplasma contamination in seven different cell lines. The Gaussia luciferase mycosensor assay provides an easy tool to monitor mammalian cell contaminants in a high-throughput fashion. PMID- 22506740 TI - A comparative study of cell-free apoptotic and genomic DNA using FISH and massive parallel sequencing. AB - OBJECTIVE: Study of circulating DNA (cirDNA) generation mechanisms with respect to their influence on the content of cirDNA is very important since it could indicate the best molecular targets for diagnostic applications. Since apoptosis was shown to be one of the main sources of cirDNA, we performed in vitro comparative study of cell-free apoptotic and genomic DNA (gDNA). METHODS: DNA isolated from culture medium of apoptotic human umbilical vein endothelial cells (cm-apoDNA) and the gDNA from the same living cells was analyzed using FISH and sequenced on SOLiD 3 platform. RESULTS/CONCLUSIONS: FISH demonstrates overrepresentation of C-positive chromosome regions in cm-apoDNA. SOLiD 3 data show enrichment of cm-apoDNA for Alu repeats: the content of AluJ, AluS and AluY repeats was, respectively, 2.47-fold (standard deviation (SD) 3.6%), 2.45-fold (SD 5.5%) and 2.79-fold (SD 6.1%) higher in cm-apoDNA. By contrast, some of L1 elements were underrepresented in cm-apoDNA: the content of L1MA and L1ME was, respectively, 1.4-fold (SD 22%) and 1.45-fold (SD 9%) lower in cm-apoDNA. In contrast to FISH, these data and the predominant location of Alu repeats in euchromatic regions evidence the non-uniform gDNA degradation during apoptosis leading to the enrichment of cm-apoDNA with coding sequences. PMID- 22506741 TI - Relationships and the social brain: integrating psychological and evolutionary perspectives. AB - Psychological studies of relationships tend to focus on specific types of close personal relationships (romantic, parent-offspring, friendship) and examine characteristics of both the individuals and the dyad. This paper looks more broadly at the wider range of relationships that constitute an individual's personal social world. Recent work on the composition of personal social networks suggests that they consist of a series of layers that differ in the quality and quantity of relationships involved. Each layer increases relationship numbers by an approximate multiple of 3 (5-15-50-150) but decreasing levels of intimacy (strong, medium, and weak ties) and frequency of interaction. To account for these regularities, we draw on both social and evolutionary psychology to argue that relationships at different layers serve different functions and have different cost-benefit profiles. At each layer, the benefits are asymptotic but the costs of maintaining a relationship at that level (most obviously, the time that has to be invested in servicing it) are roughly linear with the number of relationships. The trade-off between costs and benefits at a given level, and across the different types of demands and resources typical of different levels, gives rise to a distribution of social effort that generates and maintains a hierarchy of layered sets of relationships within social networks. We suggest that, psychologically, these trade-offs are related to the level of trust in a relationship, and that this is itself a function of the time invested in the relationship. PMID- 22506742 TI - Comment on Relationships and the social brain: integrating psychological and evolutionary perspectives. PMID- 22506743 TI - Is Dunbar's number up? PMID- 22506744 TI - The missing link: leadership, identity, and the social brain. AB - How the cohesion of a social network is being maintained in spite of having different layers of social interaction is an important question. I argue that the evolution of both (political) hierarchy and social identity play a crucial role in scaling up and bonding social networks. Together they are missing links in the social brain hypothesis, and further research is needed to understand the functions of leadership and social identity. PMID- 22506746 TI - Body image, shape, and volumetric assessments using 3D whole body laser scanning and 2D digital photography in females with a diagnosed eating disorder: preliminary novel findings. AB - We piloted three-dimensional (3D) body scanning in eating disorder (ED) patients. Assessments of 22 ED patients (including nine anorexia nervosa (AN) patients, 12 bulimia nervosa (BN) patients, and one patient with eating disorder not otherwise specified) and 22 matched controls are presented. Volunteers underwent visual screening, two-dimensional (2D) digital photography to assess perception and dissatisfaction (via computerized image distortion), and adjunctive 3D full-body scanning. Patients and controls perceived themselves as bigger than their true shape (except in the chest region for controls and anorexia patients). All participants wished to be smaller across all body regions. Patients had poorer veridical perception and greater dissatisfaction than controls. Perception was generally poorer and dissatisfaction greater in bulimia compared with anorexia patients. 3D-volume:2D-area relationships showed that anorexia cases had least tissue on the torso and most on the arms and legs relative to frontal area. The engagement of patients with the scanning process suggests a validation study is viable. This would enable mental constructs of body image to be aligned with segmental volume of body areas, overcoming limitations, and errors associated with 2D instruments restricted to frontal (coronal) shapes. These novel data could inform the design of clinical trials in adjunctive treatments for eating disorders. PMID- 22506747 TI - Subjective judgements of synergistic risks: a cognitive reasoning perspective. AB - Mounting evidence that certain hazard combinations present synergistic risks for adverse outcomes, including violent crime, cancer, and species extinction, highlights the importance of understanding the risk attributable to combined hazards. However, previous studies indicate that individuals often misjudge synergistic risks as additive or sub-additive risks, and there is little research that explores the cognitive reasoning that may lead individuals to make such judgements. This study aims to fill this gap. Participants were asked to review several scenarios that described the risk magnitude presented by a combined hazard. They were required to judge whether each scenario was possible and to explain the reasoning that led to their judgement. The results show that many participants demonstrated an awareness of synergistic risk and that their reasoning was typically characterized by rudimentary knowledge of an underlying causal mechanism for the increased risk (e.g., a chemical reaction between drugs). Conversely, several participants adopted a line of reasoning that precluded the concept of synergistic risk. Many of these participants appeared to employ an additive model of risk, corresponding to the notion of 'adding' one hazard to another. Contrary to much previous research, we found little evidence to indicate that people tend to employ a sub-additive model of risk for combined hazards. Implications for future research and the improvement of risk communications concerning synergistic risks are discussed. PMID- 22506748 TI - Re-imagining motor imagery: building bridges between cognitive neuroscience and sport psychology. AB - One of the most remarkable capacities of the mind is its ability to simulate sensations, actions, and other types of experience. A mental simulation process that has attracted recent attention from cognitive neuroscientists and sport psychologists is motor imagery or the mental rehearsal of actions without engaging in the actual physical movements involved. Research on motor imagery is important in psychology because it provides an empirical window on consciousness and movement planning, rectifies a relative neglect of non-visual types of mental imagery, and has practical implications for skill learning and skilled performance in special populations (e.g., athletes, surgeons). Unfortunately, contemporary research on motor imagery is hampered by a variety of semantic, conceptual, and methodological issues that prevent cross-fertilization of ideas between cognitive neuroscience and sport psychology. In this paper, we review these issues, suggest how they can be resolved, and sketch some potentially fruitful new directions for inter-disciplinary research in motor imagery. PMID- 22506749 TI - The influence of sensitivity to reward and punishment, propensity for sensation seeking, depression, and anxiety on the risky behaviour of novice drivers: a path model. AB - Young novice drivers are significantly more likely to be killed or injured in car crashes than older, experienced drivers. Graduated driver licensing (GDL), which allows the novice to gain driving experience under less-risky circumstances, has resulted in reduced crash incidence; however, the driver's psychological traits are ignored. This paper explores the relationships between gender, age, anxiety, depression, sensitivity to reward and punishment, sensation-seeking propensity, and risky driving. Participants were 761 young drivers aged 17-24 (M=19.00, SD=1.56) with a Provisional (intermediate) driver's licence who completed an online survey comprising socio-demographic questions, the Impulsive Sensation Seeking Scale, Kessler's Psychological Distress Scale, the Sensitivity to Punishment and Sensitivity to Reward Questionnaire, and the Behaviour of Young Novice Drivers Scale. Path analysis revealed depression, reward sensitivity, and sensation-seeking propensity predicted the self-reported risky behaviour of the young novice drivers. Gender was a moderator; and the anxiety level of female drivers also influenced their risky driving. Interventions do not directly consider the role of rewards and sensation seeking, or the young person's mental health. An approach that does take these variables into account may contribute to improved road safety outcomes for both young and older road users. PMID- 22506750 TI - Team history and choking under pressure in major soccer penalty shootouts. AB - This study examined the links between historical team results and individual players' subsequent performances in a high-pressure real-world sport situation. Videos were obtained from all soccer penalty shootouts held in two major international tournaments (World Cup and European Championships) between 1976 and 2006 (n=260 players/309 kicks), and we controlled for team ability and country. The results showed that players on teams with preceding losses performed worse and generally took their shots more quickly than players on teams with preceding wins. These differences were also found with players who took no personal part in the preceding games. In conclusion, the results support the existence of historical dependency effects for performance on important and dramatic high pressure tasks and they are in part consistent with a view of choking under pressure as a function of threatened egotism and self-regulation failure. PMID- 22506752 TI - The heart's content: the association between positive psychological well-being and cardiovascular health. AB - This review investigates the association between positive psychological well being (PPWB) and cardiovascular disease (CVD). We also consider the mechanisms by which PPWB may be linked with CVD, focusing on the health behaviors (e.g., smoking, alcohol consumption, physical activity, sleep quality and quantity, and food consumption) and biological functions (e.g., cardiovascular, inflammatory, and metabolic processes) that are most relevant for cardiovascular health. Because PPWB is a broad concept, not all aspects of PPWB may be associated with cardiovascular health. Thus, we distinguish between eudaimonic well-being, hedonic well-being, optimism, and other measures of well-being when reviewing the literature. Findings suggest that PPWB protects consistently against CVD, independently of traditional risk factors and ill-being. Specifically, optimism is most robustly associated with a reduced risk of cardiovascular events. In general, PPWB is also positively associated with restorative health behaviors and biological function and inversely associated with deteriorative health behaviors and biological function. Cardiovascular health is more consistently associated with optimism and hedonic well-being than with eudaimonic well-being, although this could be due in part to more limited evidence being available concerning eudaimonic well-being. Some similarities were also evident across different measures of PPWB, which is likely due to measurement overlap. A theoretical context for this research is provided, and suggestions for future research are given, including the need for additional prospective investigations and research that includes multiple constructs of psychological well-being and ill-being. PMID- 22506753 TI - Anchoring and adjustment during social inferences. AB - Simulation theories of social cognition suggest that people use their own mental states to understand those of others-particularly similar others. However, perceivers cannot rely solely on self-knowledge to understand another person; they must also correct for differences between the self and others. Here we investigated serial adjustment as a mechanism for correction from self-knowledge anchors during social inferences. In 3 studies, participants judged the attitudes of a similar or dissimilar person and reported their own attitudes. For each item, we calculated the discrepancy between responses for the self and other. The adjustment process unfolds serially, so to the extent that individuals indeed anchor on self-knowledge and then adjust away, trials with a large amount of self other discrepancy should be associated with longer response times, whereas small self-other discrepancy should correspond to shorter response times. Analyses consistently revealed this positive linear relationship between reaction time and self-other discrepancy, evidence of anchoring-and-adjustment, but only during judgments of similar targets. These results suggest that perceivers mentalize about similar others using the cognitive process of anchoring-and-adjustment. PMID- 22506754 TI - Fixation-dependent memory for natural scenes: an experimental test of scanpath theory. AB - Many modern theories propose that perceptual information is represented by the sensorimotor activity elicited by the original stimulus. Scanpath theory (Noton & Stark, 1971) predicts that reinstating a sequence of eye fixations will help an observer recognize a previously seen image. However, the only studies to investigate this are correlational ones based on calculating scanpath similarity. We therefore describe a series of 5 experiments that constrain the fixations during encoding or recognition of images in order to manipulate scanpath similarity. Participants encoded a set of images and later had to recognize those that they had seen. They spontaneously selected regions that they had fixated during encoding (Experiment 1), and this was a predictor of recognition accuracy. Yoking the parts of the image available at recognition to the encoded scanpath led to better memory performance than randomly selected image regions (Experiment 2), and this could not be explained by the spatial distribution of locations (Experiment 3). However, there was no recognition advantage for re-viewing one's own fixations versus someone else's (Experiment 4) or for retaining their serial order (Experiment 5). Therefore, although it is beneficial to look at encoded regions, there is no evidence that scanpaths are stored or that scanpath recapitulation is functional in scene memory. This paradigm provides a controlled way of studying the integration of scene content, spatial structure, and oculomotor signals, with consequences for the perception, representation, and retrieval of visual information. PMID- 22506755 TI - Reading impairments in schizophrenia relate to individual differences in phonological processing and oculomotor control: evidence from a gaze-contingent moving window paradigm. AB - Language and oculomotor disturbances are 2 of the best replicated findings in schizophrenia. However, few studies have examined skilled reading in schizophrenia (e.g., Arnott, Sali, Copland, 2011; Hayes & O'Grady, 2003; Revheim et al., 2006; E. O. Roberts et al., 2012), and none have examined the contribution of cognitive and motor processes that underlie reading performance. Thus, to evaluate the relationship of linguistic processes and oculomotor control to skilled reading in schizophrenia, 20 individuals with schizophrenia and 16 demographically matched controls were tested using a moving window paradigm (McConkie & Rayner, 1975). Linguistic skills supporting reading (phonological awareness) were assessed with the Comprehensive Test of Phonological Processing (R. K. Wagner, Torgesen, & Rashotte, 1999). Eye movements were assessed during reading tasks and during nonlinguistic tasks tapping basic oculomotor control (prosaccades, smooth pursuit) and executive functions (predictive saccades, antisaccades). Compared with controls, schizophrenia patients exhibited robust oculomotor markers of reading difficulty (e.g., reduced forward saccade amplitude) and were less affected by reductions in window size, indicative of reduced perceptual span. Reduced perceptual span in schizophrenia was associated with deficits in phonological processing and reduced saccade amplitudes. Executive functioning (antisaccade errors) was not related to perceptual span but was related to reading comprehension. These findings suggest that deficits in language, oculomotor control, and cognitive control contribute to skilled reading deficits in schizophrenia. Given that both language and oculomotor dysfunction precede illness onset, reading may provide a sensitive window onto cognitive dysfunction in schizophrenia vulnerability and be an important target for cognitive remediation. PMID- 22506756 TI - Lost thoughts: implicit semantic interference impairs reflective access to currently active information. AB - Why do we lose, or have trouble accessing, an idea that was in the focus of attention only a moment ago, especially in the absence of any apparent distraction? We tested the hypothesis that accessing a single item that is already active is affected by implicit interference (interference of which we have little or no awareness). We presented masked words that were semantically related or unrelated to a single visible target word that participants were cued to think of (refresh) a half second after its offset. Masked related but not unrelated words increased time to refresh the target but did not influence time required to read a target that was physically present. These findings provide novel evidence that an item in the focus of attention is subject to semantic interference. We suggest that such implicit semantic interference may contribute to the common "lost thought" experience and to cognitive deficits in populations in which refreshing is impaired. PMID- 22506757 TI - An expeditious total synthesis of both diastereoisomeric lipid dihydroxytetrahydrofurans from Notheia anomala. AB - Short, high yielding syntheses of both diastereomers of the naturally occurring oxylipids 1 and 2 using a combination of organocatalytic hydroxylation of an aldehyde, alkene cross metathesis, and palladium(0) catalyzed cyclization chemistry (six-step process) are reported. Furthermore, the influence of the catalyst on the cross metathesis reaction of the homoallylic 1,2-diol has been studied in detail. PMID- 22506751 TI - The dominance behavioral system and psychopathology: evidence from self-report, observational, and biological studies. AB - The dominance behavioral system (DBS) can be conceptualized as a biologically based system that guides dominance motivation, dominant and subordinate behavior, and responsivity to perceptions of power and subordination. A growing body of research suggests that problems with the DBS are evident across a broad range of psychopathologies. We begin by describing psychological, social, and biological correlates of the DBS. Extensive research suggests that externalizing disorders, mania proneness, and narcissistic traits are related to heightened dominance motivation and behaviors. Mania and narcissistic traits also appear related to inflated self-perceptions of power. Anxiety and depression are related to subordination and submissiveness, as well as a desire to avoid subordination. Models of the DBS have received support from research with humans and animals; from self-report, observational, and biological methods; and use of naturalistic and experimental paradigms. Limitations of available research include the relative lack of longitudinal studies using multiple measures of the DBS and the absence of relevant studies using diagnosed samples to study narcissistic personality disorder and bipolar disorder. We provide suggestions for future research on the DBS and psychopathology, including investigations of the potential usefulness of DBS in differentiating specific disorder outcomes, the need for more sophisticated biological research, and the value of longitudinal dynamical research. Implications of using the DBS as a tool in clinical assessment and treatment are discussed. PMID- 22506758 TI - Morphopathological features of a severe ulcerative disease outbreak associated with Tenacibaculum maritimum in cultivated sole, Solea senegalensis (L.). AB - This study describes morphopathologic changes in naturally infected farmed Senegalese sole affected by tenacibaculosis caused by Tenacibaculum maritimum. Macroscopic observation, in addition to light microscopy and scanning electron microscopy, was used to study the lesions. Main lesions were characterized by complete loss of epidermis and dermis, as well as extensive necrosis of muscle layers. Mild-to-moderate inflammatory response with the presence of macrophages was noted around hyaline degenerated muscle cells. Gram-negative filamentous bacteria could be detected only at the dermis. Under scanning electron microscopy, filamentous bacteria located over the scales without epithelium could be observed. These findings together with the isolation and PCR detection of the bacteria in kidney and skin tissues suggest that once the bacteria reach the dermis, probably through eroded epidermis, they are able to proliferate and produce enzymes that are responsible for the damage in the underlying tissues. PMID- 22506759 TI - Young people's topography of musical functions: personal, social and cultural experiences with music across genders and six societies. AB - How can we understand the uses of music in daily life? Music is a universal phenomenon but with significant interindividual and cultural variability. Listeners' gender and cultural background may influence how and why music is used in daily life. This paper reports the first investigation of a holistic framework and a new measure of music functions (RESPECT-music) across genders and six diverse cultural samples (students from Germany, Kenya, Mexico, New Zealand, Philippines, and Turkey). Two dimensions underlie the mental representation of music functions. First, music can be used for contemplation or affective functions. Second, music can serve intrapersonal, social, and sociocultural functions. Results reveal that gender differences occur for affective functions, indicating that female listeners use music more for affective functions, i.e., emotional expression, dancing, and cultural identity. Country differences are moderate for social functions (values, social bonding, dancing) and strongest for sociocultural function (cultural identity, family bonding, political attitudes). Cultural values, such as individualism-collectivism and secularism traditionalism, can help explain cross-cultural differences in the uses of music. Listeners from more collectivistic cultures use music more frequently for expressing values and cultural identity. Listeners from more secular and individualistic cultures like to dance more. Listeners from more traditional cultures use music more for expressing values and cultural identity, and they bond more frequently with their families over music. The two dimensions of musical functions seem systematically underpinned by listeners' gender and cultural background. We discuss the uses of music as behavioral expressions of affective and contemplative as well as personal, social, and sociocultural aspects in terms of affect proneness and cultural values. PMID- 22506761 TI - Cellular responses to metal ions released from implants. AB - Abstract AbstractIn the process of calcified tissue formation cells secrete a protein rich matrix into which they add a metal ion that nucleates in the presence of phosphorus to form an inorganic salt, usually calcium hydroxyapatite. Cellular/ tissue responses to metal ions, released from implants for example, can therefore be considered from the perspective of how cells handle calcium ions. A critical factor in determining cellular toxicity will be free ion concentrations and the competitive interactions that occur in a physicochemical manner. Three of the parameters used to assess the biocompatibility of implant materials are: the ability to influence mitotic activity, intercellular adhesion and promotion of cell death. A spectrum of responses, to free intracellular calcium ions, can be identified ranging from presence of the ion being essential for cell division through to an excess of the free ion that results in cell death (apoptosis). In between these extremes cells may become post-mitotic and express phenotypic variations as they adapt to their environment and establish an equilibrium to maintain intracellular calcium homeostasis. The response of cells to implants can be linked to ions released and interactions between these and other ions, and/or molecules, present in the tissues, similar to the manner in which cells handle calcium ions. PMID- 22506760 TI - Evaluation of a long pulsed 1064-nm Nd:YAG laser for improvement in appearance of cellulite. AB - BACKGROUND: Cellulite is a common, unwanted condition, which is challenging to treat. OBJECTIVES: The objective of this investigation was to evaluate safety and effectiveness of a long-pulsed 1064 Nd:YAG laser as a method for improvement in cellulite appearance and to evaluate parameter selection. MATERIALS AND METHODS: Twenty-two female subjects with posterior leg cellulite were randomly assigned to treatment of left or right thigh with higher energy treatment with cryogen spray cooling (CSC) (10-mm spot size; 50 J/cm(2); 50-ms pulse duration and CSC settings of 30-ms duration with a 20-ms delay) or lower energy treatment with no CSC (10 mm; 20 J/cm(2); 50 ms). Subjects received three treatments at 4 weeks intervals. Digital photographs and circumference measurements were taken pre-treatment and up to 6 months post-treatment. RESULTS: Nineteen subjects completed three treatments and 16 subjects completed 6-month follow-up. Circumference measurements pre- and post-treatment were not significantly different. Blinded evaluators noted mild improvement in three of seven subjects in high energy group and moderate improvement in two of nine subjects in low energy group. CONCLUSION: Multiple passes with a long-pulsed 1064 Nd:YAG achieved mild or moderate improvement in some subjects as rated by blinded evaluators. PMID- 22506762 TI - A method to cleave target molecules in a neocartilage. AB - The mechanical function of many matrix molecules is unknown. A common method to determine whether a molecule is a load-carrying structural molecule is to measure the mechanical properties of a tissue, digest the tissue with an enzyme specific for cleaving that molecule, and then remeasure the mechanical properties. A limitation of this technique is that there are no specific lytic enzymes for most molecules of interest. This article introduces a method that may allow evaluation of a large number of candidate structural molecules. A translated thrombin proteolytic recognition and cleavage site is inserted in the cDNA of a target molecule, and the target molecule then expressed in a cell that produces a tissue. After growing the tissue with cells expressing the engineered target molecule, the traditional procedure of mechanical testing, digesting, and retesting is performed. This method was demonstrated using decorin and its dermatan sulfate (DS) glycosaminoglycan chain in a neocartilage. A tissue was generated with cells expressing a genetically engineered decorin with a thrombin cleavage site. The tissue was then tested in tension and compression, digested with thrombin, and mechanically retested. The decorin protein was found in the tissue, the DS glycosaminoglycan chain was removed with thrombin digestion, and there was no change in the mechanical properties of the tissue due to the thrombin digestion relative to controls. These findings were in agreement with previously reported tests on decorin, collectively supporting the proposed method. All methods involving animals were reviewed and approved by our Institutional Review Board. PMID- 22506763 TI - Novel inhibitors for PRMT1 discovered by high-throughput screening using activity based fluorescence polarization. AB - Protein arginine methyltransferases (PRMTs) catalyze the posttranslational methylation of arginine using S-adenosylmethionine (SAM) as a methyl-donor. The PRMT family is widely expressed and has been implicated in biological functions such as RNA splicing, transcriptional control, signal transduction, and DNA repair. Therefore, specific inhibitors of individual PRMTs have potentially significant research and therapeutic value. In particular, PRMT1 is responsible for >85% of arginine methyltransferase activity, but currently available inhibitors of PRMT1 lack specificity, efficacy, and bioavailability. To address this limitation, we developed a high-throughput screening assay for PRMT1 that utilizes a hyper-reactive cysteine within the active site, which is lacking in almost all other PRMTs. This assay, which monitors the kinetics of the fluorescence polarization signal increase upon PRMT1 labeling by a rhodamine containing cysteine-reactive probe, successfully identified two novel inhibitors selective for PRMT1 over other SAM-dependent methyltransferases. PMID- 22506764 TI - The substrate-bound crystal structure of a Baeyer-Villiger monooxygenase exhibits a Criegee-like conformation. AB - The Baeyer-Villiger monooxygenases (BVMOs) are a family of bacterial flavoproteins that catalyze the synthetically useful Baeyer-Villiger oxidation reaction. This involves the conversion of ketones into esters or cyclic ketones into lactones by introducing an oxygen atom adjacent to the carbonyl group. The BVMOs offer exquisite regio- and enantiospecificity while acting on a wide range of substrates. They use only NADPH and oxygen as cosubstrates, and produce only NADP(+) and water as byproducts, making them environmentally attractive for industrial purposes. Here, we report the first crystal structure of a BVMO, cyclohexanone monooxygenase (CHMO) from Rhodococcus sp. HI-31 in complex with its substrate, cyclohexanone, as well as NADP(+) and FAD, to 2.4 A resolution. This structure shows a drastic rotation of the NADP(+) cofactor in comparison to previously reported NADP(+)-bound structures, as the nicotinamide moiety is no longer positioned above the flavin ring. Instead, the substrate, cyclohexanone, is found at this location, in an appropriate position for the formation of the Criegee intermediate. The rotation of NADP(+) permits the substrate to gain access to the reactive flavin peroxyanion intermediate while preventing it from diffusing out of the active site. The structure thus reveals the conformation of the enzyme during the key catalytic step. CHMO is proposed to undergo a series of conformational changes to gradually move the substrate from the solvent, via binding in a solvent excluded pocket that dictates the enzyme's chemospecificity, to a location above the flavin-peroxide adduct where catalysis occurs. PMID- 22506765 TI - Alginate-PEG sponge architecture and role in the design of insulin release dressings. AB - Wound healing is a natural process involving several signaling molecules and cell types over a significant period of time. Although current dressings help to protect the wound from debris or infection, they do little in accelerating the healing process. Insulin has been shown to stimulate the healing of damaged skin. We have developed an alginate sponge dressing (ASD) that forms a hydrogel capable of providing a moist and protective healing environment. By incorporating insulin loaded poly(d,l-lactide-co-glycolide) (PLGA) microparticles into ASD, we successfully stabilized and released insulin for up to 21 days. Insulin release and water absorption and transfer through the ASD were influenced by altering the levels of poly(ethylene glycol) (PEG) in the dressing matrix. Bioactivity of released insulin can be maintained for at least 10 days, demonstrated using a human keratinocyte migration assay. Results showed that insulin-loaded PLGA microparticles, embedded within PEG-ASD, functioned as an effective long-term delivery platform for bioactive insulin. PMID- 22506766 TI - Phosphine-free palladium-catalyzed direct arylation of imidazo[1,2-a]pyridines with aryl bromides at low catalyst loading. AB - Ligand-free Pd(OAc)(2) was found to catalyze very efficiently the direct arylation of imidazo[1,2-a]pyridines at C3 under very low catalyst concentration. The reaction can be performed employing as little as 0.1-0.01 mol % catalyst with electron-deficient and some electron-excessive aryl bromides. PMID- 22506768 TI - Pitfalls in lung cancer molecular pathology: how to limit them in routine practice? AB - New treatment options in advanced non-small cell lung carcinoma (NSCLC) targeting activating epidermal growth factor receptor (EGFR) gene mutations and other genetic alterations demonstrated the clinical significance of the molecular features of specific subsets of tumors. Therefore, the development of personalized medicine has stimulated the routine integration into pathology departments of somatic mutation testing. However, clinical mutation testing must be optimized and standardized with regard to histological profile, type of samples, pre-analytical steps, methodology and result reporting. Routine molecular testing in NSCLC is currently moving beyond EGFR mutational analysis. Recent progress of targeted therapies will require molecular testing for a wide panel of mutations for a personalized molecular diagnosis. As a consequence, efficient testing of multiple molecular abnormalities is an urgent requirement in thoracic oncology. Moreover, increasingly limited tumor sample becomes a major challenge for molecular pathology. Continuous efforts should be made for safe, effective and specific molecular analyses. This must be based on close collaboration between the departments involved in the management of lung cancer. In this review we explored the practical issues and pitfalls surrounding the routine implementation of molecular testing in NSCLC in a pathology laboratory. PMID- 22506767 TI - A comparison of adaptive and adaptable automation under different levels of environmental stress. AB - The effectiveness of different forms of adaptive and adaptable automation was examined under low- and high-stress conditions, in the form of different levels of noise. Thirty-six participants were assigned to one of the three types of variable automation (adaptive event-based, adaptive performance-based and adaptable serving as a control condition). Participants received 3 h of training on a simulation of a highly automated process control task and were subsequently tested during a 4-h session under noise exposure and quiet conditions. The results for performance suggested no clear benefits of one automation control mode over the other two. However, it emerged that participants under adaptable automation adopted a more active system management strategy and reported higher levels of self-confidence than in the two adaptive control modes. Furthermore, the results showed higher levels of perceived workload, fatigue and anxiety for performance-based adaptive automation control than the other two modes. PRACTITIONER SUMMARY: This study compared two forms of adaptive automation (where the automated system flexibly allocates tasks between human and machine) with adaptable automation (where the human allocates the tasks). The adaptable mode showed marginal advantages. This is of relevance, given that this automation mode may also be easier to design. PMID- 22506769 TI - The progress of selective fluorescent chemosensors by boronic acid. AB - As a cutting-edge scientific research field, the detection of biological active substance is very important for the prevention, diagnosis and treatment of diseases. Boronic acid interacts with cis-1,2-or 1,3-diol to form five- or six membered ring which could be used as the reporter of fluorescent sensors to probe carbohydrates and bioactive substance. This review summarizes the recent progress of boronic acid sensors for carbohydrates, L-dopamine, fluoride, copper ion, mercury ion and hydrogen peroxide. In this article, we will briefly introduce the chemistry of boronic acid, and then give a description of the fluorescence properties of each boronic acid sensor, such as fluorescence intensity change, excitation and emission wavelengths, quantum yields and water solubility. In addition, we summarize the mechanisms of fluorescent signal output for some representative sensors and discuss the strategies for developing new fluorescent probes. PMID- 22506770 TI - The chemistry and biology of the bryostatins: potential PKC inhibitors in clinical development. AB - The bryostatins, powerful protein kinase C (PKC) agonists, are a family of complex macrolactone natural products. They are originally isolated from the marine bryozoan Bugula neritina. So far tweenty bryostatins have been obtained naturally and exhibit a remarkable range of biological activities, including antineoplastic activity, synergistic chemotheoreputic activity, cognition and memory enhancement, etc. Of the 20 known members, the most extensively studied is bryostatin 1. The effects of bryostatin 1 are mainly linked to its ability of selectively modulating the function of various individual protein kinase C (PKC) isozymes. Moreover, bryostatin 1, or in combination with other agents, has been proposed for phase I and phase II clinical trials. The bryostatins have excellent biological properties, but are scarce in nature. Therefore, it has attracted considerable interests in structural modification over the past two decades. In this review, we will attempt to summarize the main developments that have occurred in the structure-activity relationship and biology of bryostatins over the period 1982-2011. PMID- 22506771 TI - Differential effects of flavonoids on barrier integrity in human intestinal Caco 2 cells. AB - Flavonoids, present in fruits, vegetables, and teas, provide beneficial effects for our health. We investigated the effect of a number of flavonoids on tight junction (TJ) barrier integrity in human intestinal Caco-2 cells. Transepithelial electrical resistance (TER; a TJ integrity marker) across cell monolayers was measured in cells incubated with flavonoids for 24 h. Chrysin decreased the TER, indicating a decrease in TJ integrity. Daidzein, hesperetin, naringenin, and morin increased the TER, indicating increased TJ integrity. Luteolin and genistein increased or normalized the TER after a transient decrease. Immunoblot analysis revealed that these changes in TER were caused by modification of the cytoskeletal association and expression of TJ proteins, zonula occludens (ZO)-1, ZO-2, occludin, junctional adhesion molecule-1, and/or claudins. Our results suggest that various flavonoids participate in the regulation of intestinal TJ barrier integrity and that this regulation may partially contribute to the flavonoid-mediated biological effects on our health. PMID- 22506772 TI - Purine biosynthesis mutants (purA and purB) of serotype 4b Listeria monocytogenes are severely attenuated for systemic infection in intragastrically inoculated A/J Mice. AB - In this study, we demonstrate that purA and purB transposon mutants of serotype 4b Listeria monocytogenes were severely impaired in their ability to colonize the gastrointestinal tract and cause systemic infection of the spleen, liver, and gallbladder following intragastric inoculation of A/J mice. The mutant strains were also impaired in their ability to multiply within Caco-2 human intestinal epithelial cells. Neither mutant was affected in resistance to synthetic gastric fluid (pH 4.5). These findings indicate that purine biosynthesis is critical for gastrointestinal virulence of L. monocytogenes serotype 4b in mice. PMID- 22506773 TI - The use of equipment and training practices and the prevalence of owner-reported ridden behaviour problems in UK leisure horses. AB - REASONS FOR PERFORMING STUDY: UK leisure horses are owned primarily for riding. Ridden behaviour problems may compromise the use of the horse in this role and lead to harsh redress or relinquishment of the horse. Despite the consequences of these problems little is known about their prevalence or the working lives of UK leisure horses. OBJECTIVES: To generate data on the work undertaken by leisure horses, the equipment and training practices used with them and prevalence of ridden behaviour problems. METHODS: An internet survey was used to generate horse level data from a convenience sample of leisure horse carers. Respondents were asked to report on their practices in the week prior to the survey's completion to minimise recall bias. The survey was online for one year to allow for seasonal variation in practices. Data were collected on the tack and equipment used on the horse, the regularity that professional services (e.g. farriers) were used, type of training employed and frequency the owner reported that horse displayed 15 ridden behaviour problems. RESULTS: The survey generated data on 1326 individual horses. Data describing practices relating to the horse's working life are presented. Ridden behaviour problems were reported in 91% of horses in the week preceding data collection. CONCLUSIONS AND POTENTIAL RELEVANCE: Descriptive data on the working lives of UK leisure horses provides valuable baseline statistics for this largest section of the UK horse population. High prevalence of owner reported ridden behaviour problems represents a concern in such leisure horses and may indicate significant rider safety and horse welfare concerns. PMID- 22506774 TI - Bariatric surgery for morbid obesity in craniopharyngioma. AB - OBJECTIVE: To retrospectively analyse the effectiveness of bariatric surgery for hypothalamic obesity in patients with craniopharyngioma (CP). PATIENTS: Patients who developed morbid obesity after surgery for CP and who underwent laparoscopic gastric banding (LAGB), laparoscopic sleeve gastrectomy or gastric bypass were included (n = 9). Patients with common obesity who underwent bariatric surgery served as controls (LAGB n = 40, sleeve gastrectomy n = 49 and gastric bypass n = 54). RESULTS: CP was diagnosed during childhood or adolescence [median (range) 10 (1-21) years] and age at bariatric surgery was 17 [12-30] years. Six patients underwent gastric banding [median follow-up 5.5 years (range 1-9)], 4 had a sleeve gastrectomy [median follow-up 2 (0.4-4) years] and two patients had gastric bypass surgery (median follow-up 3 years). Three patients had more than one type of bariatric surgery. Different from controls, no weight loss was observed after LAGB or sleeve gastrectomy. The two patients who had gastric bypass surgery lost body weight comparable with controls. CONCLUSION: With LAGB and sleeve gastrectomy, no significant loss of body weight was achieved in young adult patients with craniopharyngioma-associated morbid obesity. PMID- 22506775 TI - Does coronary artery bypass surgery improve survival? AB - OBJECTIVES: According to guide-lines, coronary bypass surgery improves survival in high risk patients. The evidence for this is more than 20 years old and may be questioned. Long waiting lists for coronary bypass surgery are detrimental but offer the possibility to compare the risk of death before and after surgery. We hypothesized that the risk of death is lower after bypass surgery than before the operation in high risk patients in a more recent cohort. DESIGN AND RESULTS: Death hazard functions were calculated by the use of Poisson regression scheduled for bypass surgery between 1 Jan 1995 and 31 July 2005. The analyses were performed in two states: 1) in the period after triage until admission for surgery during which optimal medication was intended and 2) after surgery and up to 11 years (corresponding to 57,548 patient years). The probability of death was calculated by entering individual risk profile data into the two multivariable functions. There were several significant differences between the hazard functions in the two states. All variables reflecting angiographic severity of coronary lesions indicated lower risk of death after bypass surgery. The risk associated with left ventricular impairment was lower after surgery (beta coefficients - 0.0546 vs. - 0.0234, p <0.001). Only one variable, age, indicated higher risk after surgery (which is also seen in a general population over time). The reduction of risk was dependent on preoperative risk with a large reduction when preoperative risk was high and vice versa. When preoperative risk was low, however, the risk increased due to surgical mortality. CONCLUSIONS: The risk of death is lower after bypass surgery than before the operation in high risk patients. This is most likely explained by a prognostic gain from bypass surgery. The gain is largest in high-risk patients but small or absent in low risk patients. PMID- 22506776 TI - High throughput investigative Dermatology in 2012 and beyond: A new era beckons. AB - High throughput molecular biology began around the mid-1990s with the introduction of microarrays - a technology that enabled investigators to quantify the cellular expression levels of tens of thousands of mRNA transcripts simultaneously. To date, a large number of microarray experiments have been performed in the investigation of RNA expression signatures in normal and pathological tissues. This review focuses on a next generation tool in high throughput investigation: RNA sequencing or RNA-Seq, highlighting its advantages over traditional microarray investigation and discussing its utility in investigative dermatology. In contrast with the results obtained from microarray experiments, RNA-Seq generates mRNA abundance counts, can identify novel transcripts and splice variants, and provides sequence resolution at the level of single base-pairs. Implementing RNA-Seq in the investigation of skin disease will yield novel insights into the pathogenesis of disease, will facilitate the discovery of new diseases and new mechanisms of disease, and will allow researchers to probe genetic disease in high resolution and with unprecedented efficiency. PMID- 22506777 TI - Alkylated dihydroxybenzoic acid as a MALDI matrix additive for hydrophobic peptide analysis. AB - Hydrophobic peptides are generally difficult to detect using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) because the majority of MALDI matrixes are hydrophilic and therefore have a low affinity for hydrophobic peptides. Here, we report on a novel matrix additive, o-alkylated dihydroxybenzoic acid (ADHB), which is a 2,5-dihydroxybenzoic acid (DHB) derivative incorporating a hydrophobic alkyl chain on a hydroxyl group to improve its affinity for hydrophobic peptides, thereby improving MALDI-MS sensitivity. The addition of ADHB to the conventional matrix alpha-cyano-4-hydroxycinnamic acid (CHCA) improved the sensitivity of hydrophobic peptides 10- to 100-fold. The sequence coverage of phosphorylase b digest was increased using ADHB. MS imaging indicated that hydrophobic peptides were enriched in the rim of a matrix/analyte dried spot when ADHB was used. In conclusion, the addition of ADHB to the standard matrix led to improved sensitivity of hydrophobic peptides by MALDI-MS. PMID- 22506778 TI - Top-down control of attention: it's gradual, practice-dependent, and hierarchically organized. AB - When searching for a "pop-out" target, interference from a salient but irrelevant distractor can be reduced or even prevented under certain circumstances. Here, five experiments were conducted to further our understanding of three different aspects of top-down interference reduction: first, whether or not qualitatively different search modes can account for different reduction patterns; second, whether distractor practice plays a causal role in reduction; and third, how specific reduction is, that is, whether interference by intradimensional distractors can be reduced as effectively as interference by cross-dimensional distractors. The results provide evidence that interference reduction does not critically depend on the implementation of a feature search mode, but rather on practice with the distractor, that is, the acquisition of an effective suppression strategy. In addition, they suggest that interference reduction is based on hierarchically organized feature weighting ("dimension weighting"), rather than on completely independent feature weighting. PMID- 22506779 TI - The perception of prototypical motion: synchronization is enhanced with quantitatively morphed gestures of musical conductors. AB - Aesthetic theories have long suggested perceptual advantages for prototypical exemplars of a given class of objects or events. Empirical evidence confirmed that morphed (quantitatively averaged) human faces, musical interpretations, and human voices are preferred over most individual ones. In this study, biological human motion was morphed and tested for prototype effects in task-specific actions, perceptual judgments, and kinematic characteristics. A motion capture system recorded the movements of six novice and six expert orchestral conductors while they performed typical beat patterns in time with a metronome. Point-light representations of individual conductors and morphs of experts, novices, and a grand average morph were generated. In a repeated-measures sensorimotor synchronization paradigm, participants tapped a finger in time with the conducting and provided evaluations of the gestures' characteristics. Quantitatively averaged conducting motion resulted in reduced jerk (i.e., smoother motion) as well as higher synchronization accuracy and tapping consistency. Perceived beat clarity and quality of the gestures correlated with the timing of vertical acceleration in the conductors' movements. While gestures of individual conductors were perceived to be more expressive, morphs appeared more conventional. Thus, due to smoother spatiotemporal profiles of morphs, perception and action advantages were observed for prototypes that are presumably based both on motor resonance mechanisms and cognitive representations. PMID- 22506780 TI - Perceived causalities of physical events are influenced by social cues. AB - In simple mechanical events, we can directly perceive causal interactions of the physical objects. Physical cues (especially spatiotemporal features of the display) are found to associate with causal perception. Here, we demonstrate that cues of a completely different domain--social cues--also impact the causal perception of physical events: The causally ambiguous events are more likely to be perceived as causal if the faces superimposed on the objects change from neutral to fearful. This effect has the following major properties: (a) The effect is caused by social information because it disappears when the faces are inverted or when the expression changes are unreasonable; (b) the social cues are integrated in a temporal window different from physical cues; and (c) the social cues impact the perception process rather than the decision process as the impact also appears in the causality-induced illusion. These findings suggest that the visual system relies on social information to infer the causal structure of the physical world. PMID- 22506781 TI - Action alters object identification: wielding a gun increases the bias to see guns. AB - Stereotypes, expectations, and emotions influence an observer's ability to detect and categorize objects as guns. In light of recent work in action-perception interactions, however, there is another unexplored factor that may be critical: The action choices available to the perceiver. In five experiments, participants determined whether another person was holding a gun or a neutral object. Critically, the participant did this while holding and responding with either a gun or a neutral object. Responding with a gun biased observers to report "gun present" more than did responding with a ball. Thus, by virtue of affording a perceiver the opportunity to use a gun, he or she was more likely to classify objects in a scene as a gun and, as a result, to engage in threat-induced behavior (raising a firearm to shoot). In addition to theoretical implications for event perception and object identification, these findings have practical implications for law enforcement and public safety. PMID- 22506782 TI - Temporal constraints of the word blindness posthypnotic suggestion on Stroop task performance. AB - The present work investigated possible temporal constraints on the posthypnotic word blindness suggestion effect. In a completely within-subjects and counterbalanced design 19 highly suggestible individuals performed the Stroop task both with and without a posthypnotic suggestion that they would be unable to read the word dimension of the Stroop stimulus, both when response-stimulus interval (RSI) was short (500 ms) or equivalent to previous studies (3500 ms). The suggestion reduced Stroop interference in the short RSI condition (54 vs. 6 ms) but not in the long RSI condition (52 vs. 56 ms), and did not affect Stroop facilitation. Our results suggest that response to the suggestion involves reactive top-down control processes that persist only if levels of activation can be maintained. (PsycINFO Database Record (c) 2012 APA, all rights reserved). PMID- 22506783 TI - Distractor inhibition: principles of operation during selective attention. AB - Research suggests that although target amplification acts as the main determinant of the efficacy of selective attention, distractor inhibition contributes under some circumstances. Here we aimed to gain insight into the operating principles that regulate the use of distractor inhibition during selective attention. The results suggest that, in contrast to target amplification, distractor inhibition does not onset earlier or strengthen in response to advance location information. Instead, when the location of the impending distractor was predictable, evidence of inhibitory processing weakened. Furthermore, the results suggest that distractor inhibition does not operate as a compensatory mechanism for target amplification, as evidenced by the lack of an increase in inhibitory effects when reliance on target amplification was disrupted. Unexpected emergence of inhibitory effects for improbable targets provided evidence that distractor inhibition was at work even when no inhibitory effects manifested. Overall, the pattern of inhibitory effects is interpreted as indicating that, although distractor inhibition mounts primarily reactively rather than preemptively, advance information can help prevent overreaction to the distractor. Of course, less overreaction reduces the chances of behavioral inhibitory effects manifesting even when distractor inhibition has contributed to selective attention; thus, interpreting an absence of inhibitory effects should be done cautiously. PMID- 22506784 TI - Guidance of spatial attention by incidental learning and endogenous cuing. AB - Our visual system is highly sensitive to regularities in the environment. Locations that were important in one's previous experience are often prioritized during search, even though observers may not be aware of the learning. In this study we characterized the guidance of spatial attention by incidental learning of a target's spatial probability, and examined the interaction between endogenous cuing and probability cuing. Participants searched for a target (T) among distractors (Ls). The target was more often located in one region of the screen than in others. We found that search reaction time (RT) was faster when the target appeared in the high-frequency region rather than the low-frequency regions. This difference increased when there were more items on the display, suggesting that probability cuing guides spatial attention. Additional data indicated that on their own, probability cuing and endogenous cuing (e.g., a central arrow that predicted a target's location) were similarly effective at guiding attention. However, when both cues were presented at once, probability cuing was largely eliminated. Thus, although both incidental learning and endogenous cuing can effectively guide attention, endogenous cuing takes precedence over incidental learning. PMID- 22506785 TI - Face inversion disproportionately disrupts sensitivity to vertical over horizontal changes in eye position. AB - Presenting a face inverted (upside down) disrupts perceptual sensitivity to the spacing between the features. Recently, it has been shown that this disruption is greater for vertical than horizontal changes in eye position. One explanation for this effect proposed that inversion disrupts the processing of long-range (e.g., eye-to-mouth distance) more than local (e.g., interocular distance) spatial relations. Here we investigated the spacing inversion effect for horizontal and vertical changes that could involve long- and short-range spatial relations. Our results replicated the finding of larger inversion effects for vertical than for horizontal changes, and found it was observed regardless of the spatial distance. These results argue against a long-range versus short-range spatial relations explanation of the horizontal versus vertical difference in the size of the spacing inversion effect for eye position. We support the view that inversion effects are relatively small when spacing changes occur within the eye region, but are larger when they occur outside of this region in the absence of focal attention. PMID- 22506786 TI - Human odometry verifies the symmetry perspective on bipedal gaits. AB - Bipedal gaits have been classified on the basis of the group symmetry of the minimal network of identical differential equations (alias cells) required to model them. Primary gaits are characterized by dihedral symmetry, whereas secondary gaits are characterized by a lower, cyclic symmetry. This fact was used in a test of human odometry. Results suggest that when distance is measured and reported by gaits from the same symmetry class, primary and secondary gaits are comparable. Switching symmetry classes at report compresses (primary to secondary) or inflates (secondary to primary) measured distance, with the compression and inflation equal in magnitude. Lessons are drawn from modeling the dynamics of behaviors executed in parallel (e.g., interlimb coordination) to model the dynamics of human odometry, in which the behaviors are executed sequentially. The major observations are characterized in terms of a dynamics of sequentially coupled measure and report phases, with relative velocity as an order parameter, or equilibrium state, and difference in symmetry class as an imperfection parameter, or detuning, of that dynamic. PMID- 22506787 TI - Contextual distinctiveness produces long-lasting priming of pop-out. AB - Maljkovic and Nakayama have demonstrated memory influences in singleton search from one trial to the next, an effect they termed priming of pop-out (PoP). This effect was described as resulting from the persistence of an implicit memory trace, the influence of which could be observed for around 5-8 subsequent trials. Thomson and Milliken (2012) recently reported that PoP effects can survive a lag of up to 16 trials for "rare" trials that were composed of distinct target and distracter colors relative to intervening "common" trials. The present experiments tested the idea that long-term PoP effects can depend on the retrieval of distinct contextual cues. Across the experiments reported here, rare trials differed from common trials in spatial location (Experiments 1A and 2A), stimulus configuration (Experiments 1B and 2B), target and distracter colors (Experiments 2A and 2B), or response-selection task (Experiment 3). PoP effects that survived 15 intervening trials were observed with rare search stimuli that were composed of distinct target and distracter colors or required a distinct selection task. Distinct stimulus location and distinct stimulus configuration failed to produce a measurable effect on PoP for rare trials, either on their own or in conjunction with other distinct features. These results are interpreted as evidence that episodic memory retrieval processes can produce relatively long term PoP effects. PMID- 22506788 TI - Orienting attention to sound object representations attenuates change deafness. AB - According to the object-based account of attention, multiple objects coexist in short-term memory (STM), and we can selectively attend to a particular object of interest. Although there is evidence that attention can be directed to visual object representations, the assumption that attention can be oriented to sound object representations has yet to be validated. Here, we used a delayed match-to sample task to examine whether orienting attention to sound object representations influences change detection within auditory scenes consisting of 3 concurrent sounds, each occurring at a different location. On some trials, the 2 scenes were identical; in the remaining trials, the locations of 2 sounds were switched. In a control experiment, we first identified auditory scenes, in which the 3 sounds were unambiguously segregated, for the subsequent experiments. In 2 experiments, we showed that orienting attention to a sound object representation during memory retention (via a retro-cue) enhanced performance relative to uncued trials, up to 4 s of memory retention. Our study shows that complex auditory scenes composed of cooccurring sound sources are quickly parsed into sound object representations--which are then available for top-down selective attention. Here, we demonstrate that attention can be guided toward 1 of those representations, thereby attenuating change deafness. Furthermore, the effects of retro-cues in audition extend analogous findings in the visual domain, thereby suggesting that orienting attention to an object within visual or auditory STM may follow similar processing principles. PMID- 22506789 TI - Individual differences in preferences for matched-ethnic mentors among high achieving ethnically diverse adolescents in STEM. AB - This short-term longitudinal study examined (a) adolescents' contact with mentors who share their background in relation to the importance they place on having such mentors, and (b) the associations of these perceptions with self-efficacy, identity, and commitment to a science career. Participants were 265 ethnically diverse adolescents (M age = 15.82) attending a 4-week science education program. Cluster analyses indicated that at Time 1, underrepresented ethnic minorities were more often in the cluster defined by feelings of importance of having a matched-background mentor but not having much contact. Perceptions of contact increased over time for these students and were associated with increased feelings of identity as a science student. The results suggest the need for attending to individual differences in students' preferences for matched background mentors. PMID- 22506790 TI - Circulating nucleic acids and protease activities in blood of tumor patients. AB - INTRODUCTION: Carcinogenesis is accompanied by deregulated tumor cell death and changes in proliferative processes. Apoptotic cells release different components, such as nucleosomes and caspases, into the blood circulation that can be detected by minimally invasive assays. Caspases belong to a large family of proteases, which are frequently overexpressed in various cancer entities and involved in metastases. One critical event of tumor invasion that signals the initiation of the metastatic cascade is the degradation of basement membrane components by protease supporting invasive cell migration and the dissemination of tumor cells. AREAS COVERED: In consideration of PubMed publications, the current review article specifically focuses on the clinical utility of circulating nucleosomes along with protease and caspase activities and discusses the quantification of these parameters as potential, minimally invasive assay. EXPERT OPINION: The quantification of these circulating cell death products is a promising marker for the pathogenesis of malignant diseases and monitoring of anticancer therapies. The measurement of circulating protease activities and tumor cells in the blood may provide additional information on tumor progression and metastases. PMID- 22506791 TI - A preliminary trial of a prototype Internet dissonance-based eating disorder prevention program for young women with body image concerns. AB - OBJECTIVE: A group dissonance-based eating disorder prevention program, in which young women critique the thin ideal, reduces eating disorder risk factors and symptoms, but it can be difficult to identify school clinicians with the time and expertise to deliver the intervention. Thus, we developed a prototype Internet version of this program and evaluated it in a preliminary trial. METHOD: Female college students with body dissatisfaction (N = 107; M age = 21.6 years, SD = 6.6) were randomized to the Internet intervention, group intervention, educational video condition, or educational brochure condition. RESULTS: Internet and group participants showed greater pre-post reductions in eating disorder risk factors and symptoms than video controls (M ds = 0.47 and 0.54, respectively) and brochure controls (M ds = 0.75 and 0.72, respectively), with many effects reaching significance. Effects did not differ significantly for Internet versus group participants (M ds = -0.13) or for video versus brochure controls (M d = 0.25). Effect sizes for the Internet intervention were similar to those previously observed for group versions of this intervention. CONCLUSIONS: Results suggest that this prototype Internet intervention is as efficacious as the group intervention, implying that there would be merit in completing this intervention and evaluating it in a fully powered trial. PMID- 22506792 TI - Premature discontinuation in adult psychotherapy: a meta-analysis. AB - OBJECTIVE: Premature discontinuation from therapy is a widespread problem that impedes the delivery of otherwise effective psychological interventions. The most recent comprehensive review found an average dropout rate of 47% across 125 studies (Wierzbicki & Pekarik, 1993); however, given a number of changes in the field over the past 2 decades, an updated meta-analysis is needed to examine the current phenomenon of therapy dropout. METHOD: A series of meta-analyses and meta regressions were conducted in order to identify the rate at which treatment dropout occurs and predictors of its occurrence. This review included 669 studies representing 83,834 clients. RESULTS: Averaging across studies using a random effects model, the weighted dropout rate was 19.7%, 95% CI [18.7%, 20.7%]. Further analyses, also using random effects models, indicated that the overall dropout rate was moderated by client diagnosis and age, provider experience level, setting for the intervention, definition of dropout, type of study (efficacy vs. effectiveness), and other design variables. Dropout was not moderated by orientation of therapy, whether treatment was provided in an individual or group format, and a number of client demographic variables. CONCLUSIONS: Although premature discontinuation is occurring at a lower rate than what was estimated 20 years ago (Wierzbicki & Pekarik, 1993), it is still a significant problem, with about 1 in every 5 clients dropping out of therapy. Special efforts should be made to decrease premature discontinuation, particularly with clients who are younger, have a personality or eating disorder diagnosis, and are seen by trainee clinicians. PMID- 22506794 TI - Generalized anxiety disorder: a comparison of symptom change in adults receiving cognitive-behavioral therapy or applied relaxation. AB - OBJECTIVE: Generalized anxiety disorder (GAD) is characterized by excessive worry and somatic symptoms of anxiety (e.g., restlessness, muscle tension). Several psychological treatments lead to significant reductions in GAD symptoms by posttreatment. However, little is known about how GAD symptoms change over time. Our main goal was to examine how GAD symptoms changed in relation to one another during 2 distinct but efficacious psychological treatments: cognitive-behavioral therapy (CBT) and applied relaxation (AR). Specifically, we asked whether change in worry accounted for change over time in somatic anxiety (or the reverse) to the same degree in CBT and AR. METHOD: We examined data from 57 individuals with GAD enrolled in a randomized controlled trial. Self-report measures of worry and somatic anxiety were obtained daily during treatment. RESULTS: Although the direction of influence between changes in worry and somatic anxiety was bidirectional to some extent in both treatments, a significant difference was also observed: Change in worry accounted for subsequent change in somatic anxiety to a greater extent in CBT than in AR. CONCLUSIONS: These findings allowed us to identify differences in a mechanism of change in GAD symptoms during 2 treatments and to provide some support for the idea that similarly efficacious treatments may produce symptom change via different mechanisms in a manner that is consistent with the theoretical rationales on which the treatments are based. PMID- 22506793 TI - A family-school intervention for children with ADHD: results of a randomized clinical trial. AB - OBJECTIVE: Accumulating evidence highlights the importance of using psychosocial approaches to intervention for children with attention-deficit/hyperactivity disorder (ADHD) that target the family and school, as well as the intersection of family and school. This study evaluated the effectiveness of a family-school intervention, Family-School Success (FSS), designed to improve the family and educational functioning of students in Grades 2-6 who meet criteria for ADHD combined and inattentive types. Key components of FSS were conjoint behavioral consultation, daily report cards, and behavioral homework interventions. METHOD: FSS was provided over 12 weekly sessions, which included 6 group sessions, 4 individualized family sessions, and 2 school-based consultations. Participating families were given the choice of placing their children on medication; 43% of children were on medication at the time of random assignment. Children (n = 199) were randomly assigned to FSS or a comparison group controlling for non-specific treatment effects (Coping With ADHD Through Relationships and Education [CARE]). Outcomes were assessed at post-intervention and 3-month follow-up. The analyses controlled for child medication status. RESULTS: FSS had a significant effect on the quality of the family-school relationship, homework performance, and parenting behavior. CONCLUSIONS: The superiority of FSS was demonstrated even though about 40% of the participants in FSS and CARE were on an optimal dose of medication and there were significant time effects on each measure. This relatively brief intervention produced effect sizes comparable to those of the more intensive Multimodal Treatment Study of Children With ADHD (MTA) behavioral intervention. PMID- 22506795 TI - Training substance abuse clinicians in motivational interviewing using live supervision via teleconferencing. AB - OBJECTIVE: Training through traditional workshops is relatively ineffective for changing counseling practices. Teleconferencing supervision (TCS) was developed to provide remote, live supervision for training motivational interviewing (MI). METHOD: Ninety-seven drug treatment counselors completed a 2-day MI workshop and were randomized to live supervision via teleconferencing (TCS; n = 32), standard tape-based supervision (tape; n = 32), or workshop alone (workshop; n = 33). Supervision conditions received 5 weekly supervision sessions at their sites using actors as standard patients. Sessions with clients were rated for MI skill with the Motivational Interviewing Treatment Integrity (MITI) Coding System pre workshop and 1, 8, and 20 weeks post-workshop. Mixed-effects linear models were used to test training condition on MI skill at 8 and 20 weeks. RESULTS: TCS scored better than workshop on the MITI for spirit (mean difference = 0.76; p < .0001; d = 1.01) and empathy (mean difference = 0.68; p < .001; d = 0.74). TCS was superior to workshop in reducing MI non-adherence and was superior to workshop and tape in increasing reflection to question ratio. Tape was superior to TCS in increasing complex reflections. Percentage of counselors meeting proficiency differed significantly between training conditions for the most stringent threshold (spirit and empathy scores >= 6). CONCLUSIONS: TCS shows promise for promoting new counseling behaviors following participation in workshop training. However, further work is needed to improve supervision methods to bring more clinicians to high levels of proficiency and facilitate dissemination of evidence-based practices. PMID- 22506798 TI - A non-photochemical approach to the bicyclo[3.2.0]heptane core of bielschowskysin. AB - An asymmetric synthesis of the tricyclic core (-)-1 of the marine diterpene bielschowskysin is described. In particular, a methodology was developed to introduce the crucial quaternary center at C-12. PMID- 22506796 TI - Patterns of developmental trajectories in toddlers with autism spectrum disorder. AB - OBJECTIVE: Our objective was to follow toddlers referred for risk of autism, using standardized observational measures administered frequently from age 18 months to age 36 months. METHOD: Sixty-five children who were consecutive referrals and 13 children from other research projects were seen approximately every 2 months, from age 18 months to age 36 months, for standardized assessments and clinical judgments by the same examiner and every 6 months by an examiner blind to previous scores. RESULTS: Thirty children never received an autism spectrum disorder (ASD) diagnosis; 48 children (all referrals) received at least 1 diagnosis of ASD. The best trajectory typology, using Autism Diagnostic Observation Schedule (ADOS) scores, revealed 4 trajectory classes with high probabilities for fit to the most likely class: severe persistent (21%), worsening (21%), improving (19%), and nonspectrum (40%). Classes differed by trajectories in verbal and nonverbal mental ages; never-ever ASD groups differed on Autism Diagnostic Interview-Revised (ADI-R) domain scores and clinician judgments, but improving-worsening trajectory groups did not. CONCLUSIONS: The results replicated the findings from studies of infants whose siblings have autism and infants whose siblings do not have autism, suggesting variability in early trajectories and supporting the need for early identification, regular monitoring, and standardized assessments of young children suspected of having ASD. PMID- 22506800 TI - Repair of a multiple implant-supported fixed superstructure with a metal-ceramic resin-bonded fixed partial denture: A clinical report. AB - Abstract Even in the case of implant loss, re-placement of the implant and re fabrication of the superstructure are often sufficient, as long as the bone and soft tissue are in good condition. However, if implant loss accompanied by serious bone resorption occurs with a fixed implant superstructure supported by multiple implants, it is very difficult to treat. This clinical report is to describe the process by which a multiple implant-supported fixed metal ceramic restorations were repaired with a metal ceramic resin bonded FPD (MC RBFPD) without complete re-fabrication following removal of one of the implants due to severe bone resorption. The 3-year follow-up indicated excellent serviceability and a well-satisfied patient. PMID- 22506799 TI - Combined transcriptomic and physiological approaches reveal strong differences between short- and long-term response of rice (Oryza sativa) to iron toxicity. AB - Ferrous iron toxicity is a mineral disorder frequently occurring under waterlogged soils where rice is cultivated. To decipher the main metabolic pathways involved in rice response to iron excess, seedlings have been exposed to 125 mg L(-1) FeSO(4) for 3 weeks. A combined transcriptomic, biochemical and physiological study has been performed after short-term (3 d) or long-term (3 weeks) exposure to iron in order to elucidate the strategy of stress adaptation with time. Our results showed that short- and long-term exposure involved a very different response in gene expression regarding both the number and function. A larger number of genes were up- or down-regulated after 3 d than after 3 weeks of iron treatment; these changes also occurred in shoot even though no significant difference in iron concentration was recorded. Those modifications in gene expression after 3 d affected not only genes involved in hormonal signalling but also genes involved in C-compound and carbohydrate metabolism, oxygen and electron transfer, oxidative stress, and iron homeostasis and transport. Modification in some gene expression can be followed by modification in corresponding metabolic products and physiological properties, or differed in time for some others, underlying the importance of an integrated study. PMID- 22506801 TI - The influence of the sleeping on the formation of facial wrinkles. AB - OBJECTIVE: The study addressed the influence of sleep as an important but overlooked contributory factor to the formation and progression of facial wrinkles and an alternative pillow was designed to reduce them. MATERIALS AND METHODS: Fifteen healthy young participants of both sexes (aged 26-42 years) volunteered for this study. We used a transparent PVC pillow filled with air to demonstrate mechanical forces and deformations of the face as a consequence of sleeping on a pillow. We used a Podometer (PDMTR) (integrated fluorescent luminaire lamp) as a diagnostic device to visualize and to document the imprint of facial deformities on a glass, as seen during sleeping. RESULTS: We observed various facial deformities and wrinkles during sleep ('crow's feet' fine lines, lines around the mouth, flattening of the forehead, blunting of the nasofrontal angle, melolabial and nasolabial folds) and design an alternative pillow to reduce them by redistributing the pressure from the wrinkling parts of the face. PMID- 22506802 TI - A pragmatic approach for employers to improve measurement in workforce health and productivity. PMID- 22506804 TI - Care Continuum Alliance carries 2011 advocacy momentum into 2012. PMID- 22506803 TI - Alliance for a Healthy Border: factors related to weight reduction and glycemic success. AB - We examined the factors related to success in achieving weight reduction and glycemic control in Alliance for a Healthy Border (AHB), a chronic disease prevention program implemented from 2006 to 2009 through 12 federally qualified community health centers serving primarily Hispanics in communities located along the US-Mexico border region. We analyzed data from Phase I of AHB using logistic regression to examine the determinants of success in achieving weight reduction and glycemic control among the participants in AHB programs. Factors affecting weight reduction success were sex, age, employment status, income, insurance, diabetes, baseline body mass index (BMI), smoking status, family history of diabetes, session type, program duration, and physical activity changes. Factors affecting achievement of glycemic success included sex, age, employment status, diabetes, baseline BMI, family history of diabetes, program duration, and physical activity changes. We found that the AHB interventions were more successful in reducing participants' HbA1c level than BMI. In addition to sociodemographic factors, participants with better baseline health conditions (ie, participants without diabetes or family history of diabetes, normal BMI, former smokers) were more likely to achieve success after the interventions. Of the 4 key features defining each of the 12 interventions, session type and program duration were associated with success. Within a relatively short time period, physical activity improvements had a stronger effect on weight reduction and glycemic success than improvements in dietary habits. The effectiveness of diabetes and cardiovascular disease prevention programs can be improved substantially by considering these factors during program design and structure. PMID- 22506805 TI - Comparison of citalopram and other selective serotonin reuptake inhibitor ingestions in children. AB - CONTEXT: In adults, citalopram is more likely to cause seizures and ECG changes than other selective serotonin reuptake inhibitors (SSRIs). Data in children are lacking, yet the 2007 American Association of Poison Control Centers out-of hospital citalopram consensus guideline mirrors the guideline for other SSRIs. OBJECTIVE: To compare the clinical effects and hazard index of citalopram with other SSRIs in pediatric ingestions. METHODS: An 11-year retrospective analysis of national poison center data was conducted. Acute, known-type SSRI ingestions in children younger than 6 years with known outcome were included. Clinical effects and hazard index (number of major or fatal outcomes/1000 SSRI ingestions) were compared. Citalopram dose-response was evaluated. RESULTS: The 35 296 included cases by SSRI type were citalopram (3747), escitalopram (4815), fluoxetine (5946), fluvoxamine (273), paroxetine (7157), and sertraline (13 358). The overall hazard index was 0.340. The hazard index for citalopram (0.801) was 2.8-fold higher than for non-citalopram SSRIs (0.285). Comparing seizures (single or multiple discrete) and cardiac effects (conduction disturbances, other ECG changes or other dysrhythmia) of citalopram with the other SSRIs, pediatric citalopram ingestions were more likely to develop seizures (5 of 3747 [0.13%] vs. 10 of 31 549 [0.03%], OR = 4.2; 1.4-12.3) and cardiac toxicity (9 of 3747 [0.24%] vs. 25 of 31 549 [0.08%], OR = 3.0; 1.4-6.5). Clinical effects occurring more frequently with other SSRIs included tachycardia (p = 0.0236), oral irritation (p = 0.0412), vomiting (p = 0.0036), agitation/irritability (p = 0.0104), and hyperthermia (p = 0.0314). There was a dose response only for single or multiple discrete seizures, mydriasis and clinically significant responses (a predetermined subset of CNS and cardiopulmonary clinical effects). Meaningful triage thresholds for citalopram could not be determined due to the low frequency of significant clinical effects. CONCLUSION: Children develop minimal toxicity with SSRI ingestions. Seizures and ECG changes, while uncommon, occur more frequently with citalopram. Doses associated with significant outcomes suggest that the triage guideline for citalopram does not need to be modified. PMID- 22506806 TI - Overview of the stability of alpha-chymotrypsin in different solvent media. PMID- 22506807 TI - Sequential enzymatic epoxidation involved in polyether lasalocid biosynthesis. AB - Enantioselective epoxidation followed by regioselective epoxide opening reaction are the key processes in construction of the polyether skeleton. Recent genetic analysis of ionophore polyether biosynthetic gene clusters suggested that flavin containing monooxygenases (FMOs) could be involved in the oxidation steps. In vivo and in vitro analyses of Lsd18, an FMO involved in the biosynthesis of polyether lasalocid, using simple olefin or truncated diene of a putative substrate as substrate mimics demonstrated that enantioselective epoxidation affords natural type mono- or bis-epoxide in a stepwise manner. These findings allow us to figure out enzymatic polyether construction in lasalocid biosynthesis. PMID- 22506808 TI - SAR distribution in a bio-medium in close proximity with dual segment cylindrical dielectric resonator antenna. AB - This paper reports simulation and experimental studies of input characteristics of a dual segment cylindrical dielectric resonator antenna (DSCDRA) in free space and in the presence of a bio-medium (synthetic muscle) along with specific absorption rate (SAR) distribution in the synthetic muscle medium due to the antenna at microwave frequencies. The simulation study has been carried out using CST Microwave Studio software. The experimental SAR distribution has been obtained using two 50 Omega L-shaped and straight coaxial probes and Agilent 3 Hz 50 GHz spectrum analyser. The experimental results for variation in return loss versus frequency for the DSCDRA and SAR distribution in synthetic muscle medium due to the antenna are compared with simulated results. PMID- 22506809 TI - Attentional effects on gaze preference for salient loci in traffic scenes. AB - Alerting drivers for self-regulation of attention might decrease crash risks attributable to absent-minded driving. However, no reliable method exists for monitoring driver attention. Therefore, we examined attentional effects on gaze preference for salient loci (GPS) in traffic scenes. In an active viewing (AV) condition requiring endogenous attention for traffic scene comprehension, participants identified appropriate speeds for driving in presented traffic scene images. In a passive viewing (PV) condition requiring no endogenous attention, participants passively viewed traffic scene images. GPS was quantified by the mean saliency value averaged across fixation locations. Results show that GPS was less during AV than during PV. Additionally, gaze dwell time on signboards was shorter for AV than for PV. These results suggest that, in the absence of endogenous attention for traffic scene comprehension, gaze tends to concentrate on irrelevant salient loci in a traffic environment. Therefore, increased GPS can indicate absent-minded driving. PRACTITIONER SUMMARY: The present study demonstrated that, without endogenous attention for traffic scene comprehension, gaze tends to concentrate on irrelevant salient loci in a traffic environment. This result suggests that increased gaze preference for salient loci indicates absent-minded driving, which is otherwise difficult to detect. PMID- 22506810 TI - Arabidopsis ENDO2: its catalytic role and requirement of N-glycosylation for function. AB - The Arabidopsis thaliana At1g68290 gene encoding an endonuclease was isolated and designated ENDO2, which was cloned into a binary vector to overexpress ENDO2 with a C-terminal 6 * His-tag in A. thaliana. Our Arabidopsis transgenic lines harboring 35SP::ENDO2 produced stable active enzyme with high yield. The protein was affinity purified from transgenic plants, and its identity was confirmed by liquid chromatography-mass spectrometry and automatic Edman degradation. ENDO2 enzyme digests RNA, ssDNA, and dsDNA, with a substrate preference for ssDNA and RNA. The activity toward ssDNA (361.7 U/mg) is greater than its dsDNase activity (14.1 U/mg) at neutral pH. ENDO2 effectively cleaves mismatch regions in heteroduplex DNA containing single base pair mismatches or insertion/deletion bases and can be applied to high-throughput detection of single base mutation. Our data also validated that the removal of sugar groups from ENDO2 strongly affects its enzymatic stability and activity. PMID- 22506811 TI - Short- and long-term results following standing fracture repair in 34 horses. AB - REASONS FOR PERFORMING STUDY: Standing fracture repair in the horse is a recently described surgical procedure and currently there are few follow-up data. This case series contains 2 novel aspects in the standing horse: repair of incomplete sagittal fractures of the proximal phalanx and medial condylar repair from a lateral aspect. OBJECTIVES: To describe outcome in a case series of horses that had lower limb fractures repaired under standing sedation at Rossdales Equine Hospital. METHOD: Case records for all horses that had a fracture surgically repaired, by one surgeon at Rossdales Equine Hospital, under standing sedation and local anaesthesia up until June 2011, were retrieved. Hospital records, owner/trainer telephone questionnaire and the Racing Post website were used to evaluate follow-up. RESULTS: Thirty-four horses satisfied the inclusion criteria. Fracture sites included the proximal phalanx (incomplete sagittal fracture, n = 14); the third metacarpal bone (lateral condyle, n = 12, and medial condyle, n = 7); and the third metatarsal bone (lateral condyle, n = 1). One horse required euthanasia due to caecal rupture 10 days post operatively. Twenty horses (66.7% of those with available follow-up) have returned to racing. Where available, mean time from operation to return to racing was 226 days (range 143-433 days). CONCLUSIONS: Standing fracture repair produced similar results to fracture repair under general anaesthesia in terms of both the number of horses that returned to racing and the time between surgery and race. POTENTIAL RELEVANCE: Repair of lower limb fracture in the horse under standing sedation is a procedure that has the potential for tangible benefits, including avoidance of the inherent risks of general anaesthesia. The preliminary findings in this series of horses are encouraging and informative when discussing options available prior to fracture repair. PMID- 22506812 TI - Developing dietetic positions in rural areas: what are the key lessons? AB - INTRODUCTION: Rural and remote communities in Australia are typically underserviced by dietitians. The recruitment of dietitians to rural areas has improved in recent years; however, retention remains an issue. Key factors that lead to an increase in funding and the development of more dietetic positions in rural areas are unknown. The purpose of this study was to describe dietetic services in rural areas and to determine the drivers for and barriers to the development of dietetic positions in rural areas. METHODS: A sequential explanatory mixed methods approach was used to examine six case study sites of dietetic service delivery in rural northern New South Wales (NSW) Australia between 1991 and 2006. The six sites represented different models of dietetic service delivery from the study area. Data sources included workforce documents and in-depth individual interviews on position development with 40 key informants, including past and present dietitians, dietetic managers and health service managers. Interview data were thematically analysed with the aid of NVivo7 (www.qsrinternational.com). Themes were coded into common categories, using a constant comparison inductive approach. RESULTS: Forty key informants agreed to participate in the in-depth, semi-structured interview. Participants included 28 dietitians (past and present), three dietetics managers and nine managers. The majority of participants were female (87.5%). Document analysis showed that the dietetic workforce had a 5.6-fold increase across the six sites over the 15 years. Themes that emerged from the interviews indicated that new positions were established through ad hoc and opportunistic funding, a gradual increase in funding or due to concerted efforts by champions advocating for increased funding. CONCLUSION: The findings from this study have important implications for the development of dietetic staffing in rural areas. There is an inconsistent approach to the development of dietetic positions in rural areas of Australia. Factors that inhibited the development of positions included a general lack of funds and competing priorities. A systematic, planned approach to the development of dietetic positions is needed in rural Australia. Champions for the development of positions were effective in increasing positions, particularly when they have management support. PMID- 22506813 TI - Effects of bovine sperm cryopreservation using different freezing techniques and cryoprotective agents on plasma, acrosomal and mitochondrial membranes. AB - The success of semen cryopreservation is influenced by several factors, such as freezing curves and cryoprotectants. These two factors are of special interest once they may lead to many important physical-chemical changes resulting in different degrees of damage in spermatozoa structure. This experiment was designed to compare the effect of bull semen cryopreservation using two freezing techniques: conventional (CT--cooling rate of -0.55 degrees C min(-1) and freezing rate of -19.1 degrees C min(-1) and automated (AT--cooling rate of 0.23 degrees C min(-1) and freezing rate of -15 degrees C min(-1)), performed with different curves, and with three cryoprotectants (glycerol, ethylene glycol and dimethyl formamide) on bovine sperm motility and integrity of plasma, acrosomal and mitochondrial membranes. These variables were simultaneously evaluated using the fluorescence probes propidium iodide, fluorescein-conjugated Pisum sativum agglutinin and MitoTracker Green FM. The effects of freezing techniques, as well as of different cryoprotectants were analysed by the analysis of variance. The means were compared by Fisher's test. There were no significant differences between freezing techniques (P > 0.05). Glycerol showed higher percentages of motility, vigour and integrity of plasma, acrosomal and mitochondrial membranes than other two cryoprotectants (P < 0.05). Ethylene glycol preserved higher motility and integrity of plasma and mitochondrial membranes than dimethyl formamide (P < 0.05). Sperm motility with glycerol was 30.67 +/- 1.41% and 30.50 +/- 1.06%, with ethylene glycol was 21.17 +/- 1.66% and 21.67 +/- 1.13% and with dimethyl formamide was 8.33 +/- 0.65% and 9.17 +/- 0.72% to CT and AT curves, respectively. The percentage of spermatozoa with simultaneously intact plasma membrane, intact acrosome and mitochondrial function (IPIAH) was 14.82 +/- 1.49% (CT) and 15.83 +/- 1.26% (AT) to glycerol, 9.20 +/- 1.31% (CT) and 9.92 +/- 1.29% (AT) to ethylene glycol 4.65 +/- 0.93% (CT) and 5.17 +/- 0.87% (AT) to dimethyl formamide. Glycerol provided the best results, although nearly 85% of spermatozoa showed some degree of injury in their membranes, suggesting that further studies are required to improve the results of cryopreservation of bovine semen. PMID- 22506814 TI - Meaning making in middle childhood: an exploration of the meaning of ethnic identity. AB - Social identity, including identification with one's ethnic group, is an important aspect of social development. However, little is known about the subjective meaning associated with social group memberships, particularly during middle childhood. Using second- and fourth-graders responses to an open-ended question, we explored the meaning of ethnic identity with a sample of Chinese, Dominican, Russian, White, and Black American children. Analyses revealed that middle childhood is an active period for meaning making as children described the ethnic identity to include ideas such as language, physical appearance, pride, relative social position, and culture. While there were few differences in the ethnic identity meaning responses of second- and fourth-grade children, the meaning of ethnic identity varied considerably across the ethnic groups underscoring how the unique features and experiences of different ethnic groups shapes the subjective meaning of ethnic identity. These findings align with prior research on the meaning of ethnic identity among adults and adolescents and offer insight for future research regarding the conceptualization and measurement of the meaning of social group membership. PMID- 22506815 TI - Neighborhood context and adjustment in African American youths from single mother homes: the intervening role of hopelessness. AB - African American youths from single mother homes are more likely to live in neighborhoods characterized by greater risk and fewer resources than youth from two parent homes or European American youths; in turn, such adverse conditions are associated with increased adjustment problems. Despite this well-established vulnerability, relatively little is known about variables linking neighborhood context to youth adjustment. With the aim of identifying a potential youth focused intervening variable amenable to intervention, this study examined the intervening role of hopelessness in the association between neighborhood context and adjustment problems in a sample of 171 African American youths (11-16 year olds) from single mother homes. Findings revealed direct associations between neighborhood context and youth adjustment, as well as indirect associations through youth hopelessness, although findings varied by the marker of neighborhood context (sense of community or perceived crime) and adjustment (internalizing or externalizing problems). Building on prior work noting that hopelessness is amenable to psychosocial intervention, the present findings suggest that hopelessness may afford a valuable target for prevention and intervention programming among African American youths from single mother homes in the context of adverse neighborhood conditions. PMID- 22506816 TI - The relationship between racial identity status attitudes, racism-related coping, and mental health among Black Americans. AB - To date, few studies have examined how different strategies for coping with racism affect the mental health of Black Americans, and none have explored how racial identity status attitudes and racism-related coping affect mental health. This study sought to examine the relationship between racial identity status attitudes, the specific strategies used by Black Americans to cope with racism, and mental health outcomes. Participants were 233 Black adults, and cluster analysis identified four cluster groups that differed significantly with respect to the patterns of racial identity attitudes and racism-related coping strategies employed. Although the groups did not differ significantly in well-being, the group with predominantly high Internalization status attitudes and that used primarily Empowered Resistance racism-related coping strategies had the least psychological symptoms. Implications for mental health and research are discussed. PMID- 22506817 TI - Prescriptive stereotypes and workplace consequences for East Asians in North America. AB - We pursue the idea that racial stereotypes are not only descriptive, reflecting beliefs about how racial groups actually differ, but are prescriptive as well, reflecting beliefs about how racial groups should differ. Drawing on an analysis of the historic and current status of East Asians in North America, we study descriptive and prescriptive stereotypes of East Asians along the dimensions of competence, warmth, and dominance and examine workplace consequences of violating these stereotypes. Study 1 shows that East Asians are descriptively stereotyped as more competent, less warm, and less dominant than Whites. Study 2 shows that only the descriptive stereotype of East Asians as less dominant than Whites is also a prescriptive stereotype. Study 3 reveals that people dislike a dominant East Asian coworker compared to a nondominant East Asian or a dominant or a nondominant White coworker. Study 4 shows that East Asians who are dominant or warm are racially harassed at work more than nondominant East Asians and than dominant and nondominant employees of other racial identities. Implications for research and theory are discussed. PMID- 22506818 TI - The Racial Microaggressions Scale (RMAS): a new scale to measure experiences of racial microaggressions in people of color. AB - Racial microaggressions refer to the racial indignities, slights, mistreatment, or offenses that people of color may face on a recurrent or consistent basis. Racial microaggressions may represent a significant source of stress endured by people of color. The purpose of this study was to develop a scale to measure racial microaggressions. Exploratory factor analyses and confirmatory factor analyses were used to assess the dimensionality of the scale. The internal reliability, convergent validity, and concurrent validity of the scale were also explored. Results indicated that the Racial Microaggression Scale is a multidimensional tool to assess perceptions of racial microaggressions by people of color. PMID- 22506819 TI - Bringing social identity to work: the influence of manifestation and suppression on perceived discrimination, job satisfaction, and turnover intentions. AB - In the current article, we explored whether manifesting or suppressing an identity (race/ethnicity, gender, age, religion, sexual orientation, or disability) at work is related to perceived discrimination, job satisfaction, and turnover intentions. Participants included 211 working adults who completed an online survey. The results showed that efforts to suppress a group identity were positively (and behavioral manifestations of group identity negatively) related to perceived discrimination, which predicted job satisfaction and turnover intentions. These results suggest that diverse employees actively manage their nonwork identities while at work and that these identity management strategies have important consequences. PMID- 22506820 TI - Born in the USA: how immigrant generation shapes meritocracy and its relation to ethnic identity and collective action. AB - Endorsing meritocracy can make low-status group members more accepting of inequality. This study examined whether rejecting meritocracy is related to increased ethnic identification among Latino immigrants, and whether identity in turn is related to increased support for collective action. We hypothesize that these relationships depend upon immigrant generation. A survey was conducted with 184 first- and second-generation Latino immigrants in New York City. Second generation Latinos endorsed meritocracy less than those in the first generation, at least in part because they perceived that other Americans viewed their group in a less positive light (i.e., lower public regard). Further, meritocracy was negatively linked to ethnic identity and, through it, support for collective action among the second generation. Among the first generation, meritocracy was not related to ethnic identity and was positively related to support for collective action. We discuss the implications of growing up near the bottom of the U.S. social hierarchy for ethnic identity and collective action. PMID- 22506821 TI - Social anxiety among East Asians in North America: East Asian socialization or the challenge of acculturation? AB - North American research has consistently reported higher social anxiety among people of Asian heritage compared to people of Western heritage. The present study used a cross-national sample of 692 university students to explore explanatory hypotheses using planned contrasts of group differences in social anxiety and related variables. The East Asian socialization hypothesis proposed social anxiety would show a linear relation corresponding to the degree of exposure to East Asian cultural norms. This hypothesis was not supported. The cultural discrepancy hypothesis examined whether bicultural East Asian participants (residing in Canada) would endorse higher social anxiety in comparison to unicultural participants (Western-heritage Canadians and native Koreans and Chinese). Compared to unicultural participants, bicultural East Asian participants reported higher social anxiety and depression, a relation that was partially mediated by bicultural participants' reports of lower self-efficacy about initiating social relationships and lower perceived social status. Overall, the results suggest higher reports of social anxiety among bicultural East Asians may be conceptualized within the context of cultural discrepancy with the mainstream culture. PMID- 22506823 TI - An examination of racial bias in the Beck Depression Inventory-II. AB - Historically, many psychological measures were developed and standardized based on a primarily Caucasian population. These tests are subsequently applied to minorities and may be inappropriate and possibly even pathologizing. The widely used Beck Depression Inventory-II (BDI-II) was initially standardized on a sample of Caucasian university students and its use with minorities has only recently been investigated. This study examined the possibility of racial bias in the BDI II by comparing Caucasian and African American Midwestern university students. A hierarchical multiple regression compared the scores of the BDI-II with a similar measure of depression that is standardized for use with African Americans. There was no evidence of racial bias discovered in the BDI-II in this sample. Implications and future directions of research are discussed. PMID- 22506822 TI - Multicultural web-based motivational interviewing for clients with a first-time DUI offense. AB - Culturally and linguistically appropriate interventions are needed to reduce the risk of driving under the influence (DUI) recidivism among diverse populations. Using core elements of Motivational Interviewing, we developed a culturally relevant web-MI intervention (web-MI) in English and Spanish to serve as a standalone or adjunctive program in DUI educational settings and evaluated its feasibility and acceptability among clients with first-time DUI offenses. We conducted an iterative formative assessment using focus groups with staff (n = 8) and clients (n = 27), and usability interviews with clients (n = 21). Adapting MI for the web was widely accepted by staff and clients. Clients stated the web-MI was engaging, interactive and personal, and felt more comfortable than past classes and programs. Spanish-speaking clients felt less shame, embarrassment, and discomfort with the web-MI compared to other in-person groups. Results support the viability of web-MI for DUI clients at risk for recidivism and highlight the importance of adapting the intervention for diverse populations. Key decisions used to develop the web-MI are discussed. PMID- 22506825 TI - Model selection for Cox models with time-varying coefficients. AB - Summary Cox models with time-varying coefficients offer great flexibility in capturing the temporal dynamics of covariate effects on right-censored failure times. Because not all covariate coefficients are time varying, model selection for such models presents an additional challenge, which is to distinguish covariates with time-varying coefficient from those with time-independent coefficient. We propose an adaptive group lasso method that not only selects important variables but also selects between time-independent and time-varying specifications of their presence in the model. Each covariate effect is partitioned into a time-independent part and a time-varying part, the latter of which is characterized by a group of coefficients of basis splines without intercept. Model selection and estimation are carried out through a fast, iterative group shooting algorithm. Our approach is shown to have good properties in a simulation study that mimics realistic situations with up to 20 variables. A real example illustrates the utility of the method. PMID- 22506826 TI - Alterations in methylation status of immune response genes promoters in cell-free DNA during a hemodialysis procedure. AB - OBJECTIVE: Elevations of cell-free DNA (cfDNA) concentrations during hemodialysis (HD) sessions were reported in numerous studies regardless of an applied therapeutic protocol. It is generally thought that the elevated concentrations represent the consequence of apoptosis on the dialysis membranes. No data concerning the qualitative characteristics of cfDNAs in HD patients have been published till today; therefore, we focus on the promoter methylation status of genes involved in immune response. RESEARCH DESIGN AND METHODS: We isolated cfDNA from randomly selected patients before and after a HD session and from healthy subjects examined two times per day with 4 h interval. The extent of promoter methylation of 24 genes involved in immune response was examined using the 'EpiTect Methyl qPCR Array Inflammatory Response and Autoimmunity'. RESULTS: In our pilot study, we discovered significant changes in methylation patterns of genes IL-7, IL-13, IL-17C and TYK2 between HD patients and healthy subjects. CONCLUSION: Methylation of immune response genes promoters may be detected using EpiTect Methyl qPCR Array Inflammatory Response and Autoimmunity at the level of cfDNA to provide the information about the actual state of immune response in HD patients. PMID- 22506827 TI - Osteoprotegerin as a marker of atherosclerosis: a systematic update. AB - OBJECTIVE: Osteoprotegerin (OPG) may be involved in development of atherosclerosis. To evaluate plasma concentrations of OPG in individuals with stable coronary artery disease (CAD), acute coronary syndrome (ACS), peripheral artery disease (PAD), and cerebrovascular disease (CBVD) a systematic literature review was performed. DESIGN AND METHODS: Studies investigating OPG concentrations in stable CAD, ACS, PAD, and CBVD were extracted from PubMed and the Cochrane Library, retrieving 280 articles. Nonrelevant articles were excluded and after thorough evaluation, and only 14 studies with clearly defined cohorts qualified for this review. RESULTS: In 11 studies, OPG concentrations were elevated. Severity of atherosclerosis was significantly associated with higher OPG concentrations compared to healthy controls. No association between PAD and OPG concentrations was observed. CONCLUSION: OPG concentrations are associated with the presence and severity of stable CAD, ACS, and CBVD. Larger studies are needed to reach conclusions concerning OPG concentrations in PAD. Studies addressing a putative role for OPG in suspected CAD and CBVD are warranted. PMID- 22506828 TI - Gastric ventilation: a new approach to metal phosphide fumigant ingestion. AB - INTRODUCTION: Phosphine is absorbed rapidly across mucous membranes causing systemic poisoning including functional cellular hypoxia. Following ingestion of metal phosphides, continuous absorption of phosphine could contribute to the intractable systemic manifestations. CASE REPORT: A 16-year-old male was admitted to hospital 1-hour post-ingestion of two fresh 3 g tablets of aluminum phosphide 56%. He complained of abdominal discomfort and burning pain, thirst, nausea, and foul-odor vomitus. The silver nitrate test was positive by exhaled breath and gastric content, confirming exposure to phosphine. Initial therapy included intravenous fluids and gastric lavage with sodium bicarbonate and potassium permanganate. Hypotension, severe agitation and tachypnea prompted endotracheal intubation and treatment with gastric ventilation. This procedure involves insertion of a nasogastric tube to insufflate air into the distal part of the stomach. An orogastric tube is inserted near the gastro-esophageal junction as an inflow air tract. Ventilation was provided by blowing fresh air using an air-pump into the naso-gastric tube and phosphine contaminated air escaped via the wide bore orogastric tube; the treatment continued for several hours. Although there was some evidence of progression of poisoning, including metabolic acidosis, arterial fibrillation, and mild gastrointestinal bleeding, the patient subsequently recovered and was discharged 6 days later with no persisting complications. This case report discusses probable benefit, availability, and simplicity of this treatment. We suggest that further clinical trials are required to confirm that this treatment improves outcomes in this highly toxic poisoning. PMID- 22506829 TI - Intralesional injections of alefacept may predict systemic response to intramuscular alefacept: results from a pilot study. AB - BACKGROUND: Alefacept (Amevive(r)) was the first biologic agent to be approved by the FDA for use in moderate to severe chronic plaque psoriasis and remains one of the safest systemic agents. However, alefacept is the least utilized of all the biologic agents due to the finding that it is only effective in a small proportion of patients and its maximal efficacy is not seen until approximately 6 weeks after treatment completion. OBJECTIVE: To determine whether intralesional injections with a biologic agent can predict who will be a responder or a non responder to the medication. METHODS: This was a single-center 22-week study consisting of three phases: i) intralesional injection to a target plaque, ii) intramuscular alefacept injections for 12 weeks (standard dose) and iii) post treatment follow-up. RESULTS: There appears to be a perfect correlation between patients who show a response to an intralesional injection of alefacept to a small, target plaque and those who eventually respond to a full 12-week systemic course of the medication (achieve at least 70% improvement in their PASI scores from baseline) (p = 0.0003). LIMITATIONS: This study had a small sample size and was limited by the fact that it was open-label without a control arm. CONCLUSION: The results from this pilot study demonstrated that alefacept appears to work intralesionally and this may be usable to predict systemic response. More importantly, these results strongly suggest that a biologic agent can work locally - a novel concept that contradicts the common notion that biologic agents must work "systemically". PMID- 22506830 TI - Monitoring molecular mass transfer in cation-free nanoporous host crystals of type AlPO-LTA. AB - Micro-imaging is employed to monitor the evolution of intra-crystalline guest profiles during molecular adsorption and desorption in cation-free zeolites AlPO LTA. The measurements are shown to provide direct evidence on the rate of intra crystalline diffusion and surface permeation and their inter-relation. Complemented by PFG NMR and integral IR measurements, a comprehensive overview of the diffusivities of light hydrocarbons in this important type of host materials is provided. PMID- 22506831 TI - Evaluating the ergonomics of BCI devices for research and experimentation. AB - The use of brain computer interface (BCI) devices in research and applications has exploded in recent years. Applications such as lie detectors that use functional magnetic resonance imaging (fMRI) to video games controlled using electroencephalography (EEG) are currently in use. These developments, coupled with the emergence of inexpensive commercial BCI headsets, such as the Emotiv EPOC ( http://emotiv.com/index.php ) and the Neurosky MindWave, have also highlighted the need of performing basic ergonomics research since such devices have usability issues, such as comfort during prolonged use, and reduced performance for individuals with common physical attributes, such as long or coarse hair. This paper examines the feasibility of using consumer BCIs in scientific research. In particular, we compare user comfort, experiment preparation time, signal reliability and ease of use in light of individual differences among subjects for two commercially available hardware devices, the Emotiv EPOC and the Neurosky MindWave. Based on these results, we suggest some basic considerations for selecting a commercial BCI for research and experimentation. STATEMENT OF RELEVANCE: Despite increased usage, few studies have examined the usability of commercial BCI hardware. This study assesses usability and experimentation factors of two commercial BCI models, for the purpose of creating basic guidelines for increased usability. Finding that more sensors can be less comfortable and accurate than devices with fewer sensors. PMID- 22506832 TI - Could the Fountain of Youth Be All in Your Bones? AB - Abstract Melatonin, a molecule released from the pineal gland in response to darkness, has long been known to keep one's sleep-wake cycles entrained to the light-dark cycle; however, there has been a surge in publications showing that melatonin has protective effects on bone. Disruption of nocturnal melatonin levels by light exposure at night, and through the natural aging process, produces adverse effects on bone. Use of melatonin to prevent bone loss or enhance bone formation has great clinical utility, including preventing maxillofacial bone loss and/or enhancing bone regeneration in maxillofacial bone reconstructive surgeries. This brief editorial comment sheds some "light" into a novel use for melatonin in preventing facial bone loss. PMID- 22506833 TI - Comparison of the anaesthetic efficacy of and heart rate changes after periodontal ligament or intraosseous X-Tip injection in mandibular molars: a randomized controlled clinical trial. AB - AIM: To compare the efficacy of supplemental anaesthesia using periodontal ligament injections (PDL) and intraosseous injections with the X-Tip system in terms of the measured heart rate and patient reported pain level. METHODOLOGY: In this single-blind randomized clinical trial, 40 patients (22 women, 18 men) with irreversible pulpitis who had experienced unsuccessful pain management by inferior alveolar nerve block with 2% lidocaine and 1 : 100 000 epinephrine were selected. Patients were divided equally and randomly into two groups. Supplementary anaesthesia was provided through intraosseous injection with the X Tip system (X-Tip group) or by PDL injection (PDL group). After each step of injection, pain severity was assessed using a visual analogue scale. Patient heart rate was recorded with a pulse oximeter. Data were coded and analysed using Mann-Whitney U-test with SPSS (version 16) software. RESULTS: Anaesthetic success was obtained in 100% of X-Tip and 70% of PDL group patients after the first supplemental injection. Compared with the first PDL injection, the first intraosseous injection resulted in a significant increase in heart rate (P = 0.001); however, this increase was short-lived (mean increase: 9-10 beats per min). No significant difference in heart rate or anaesthesia success was observed between men and women. CONCLUSION: Intraosseous injection using the X-Tip system was more effective than PDL injection as a supplementary anaesthetic for pulpectomy in mandibular molars or second premolars. However, the former resulted in a transient increase in heart rate. PMID- 22506834 TI - A wireless power transmission system for an active capsule endoscope for colon inspection. AB - Multipurpose active capsule endoscopes (ACE) have drawn considerable attention in recent years, but these devices continue to suffer from energy limitations. In order to deliver stable and sufficient energy safely, a wireless power transmission system based on inductive coupling is presented. The system consists of a double-layer solenoid pair primary coil outside and a multiple secondary coils inside the body. At least 500 mW usable power can be transmitted under the worst geometrical conditions and the safety restraints in a volume of Phi13 * 13 mm. The wireless power transmission system is integrated to an ACE and applied in animal experiments. The designed wireless power transmission is proved to be feasible and potentially safe in a future application. PMID- 22506835 TI - Switch: a planning tool for power systems with large shares of intermittent renewable energy. AB - Wind and solar power are highly variable, so it is it unclear how large a role they can play in future power systems. This work introduces a new open-source electricity planning model--Switch--that identifies the least-cost strategy for using renewable and conventional generators and transmission in a large power system over a multidecade period. Switch includes an unprecedented amount of spatial and temporal detail, making it possible to address a new type of question about the optimal design and operation of power systems with large amounts of renewable power. A case study of California for 2012-2027 finds that there is no maximum possible penetration of wind and solar power--these resources could potentially be used to reduce emissions 90% or more below 1990 levels without reducing reliability or severely raising the cost of electricity. This work also finds that policies that encourage customers to shift electricity demand to times when renewable power is most abundant (e.g., well-timed charging of electric vehicles) could make it possible to achieve radical emission reductions at moderate costs. PMID- 22506836 TI - Social support matters: longitudinal effects of social support on three dimensions of school engagement from middle to high school. AB - This study examined the relative influence of adolescents' supportive relationships with teachers, peers, and parents on trajectories of different dimensions of school engagement from middle to high school and how these associations differed by gender and race or ethnicity. The sample consisted of 1,479 students (52% females, 56% African American). The average growth trajectories of school compliance, participation in extracurricular activities, school identification, and subjective valuing of learning decreased from 7th to 11th grades (mean ages = 12.9 years to 17.2 years). Different sources of social support were not equally important in their impact on school engagement, and the effect of these sources differed by the aspect of engagement studied. For instance, peer social support predicted adolescents' school compliance more strongly and school identification less strongly than teacher social support. PMID- 22506838 TI - Prevalence of gingival overgrowth among elderly patients under amlodipine therapy at a large Indian teaching hospital. AB - OBJECTIVES: To determine the prevalence of amlodipine-induced gingival overgrowth (GO) among elderly subjects attending an Indian teaching hospital and find any association with demographic factors, drug variables, oral hygiene status and gingival inflammation. METHODS: A cross-sectional pilot study included 157 dentate patients aged 60 years or more, taking Amlodipine for at least 3 months. Data were collected from past medical records and oral examination. Clinical assessment of GO was correlated with patient's age, gender, drug dosage (2.5, 5 or 10 mg/day), duration of drug therapy (3-4, 4-6, 6-12, 12-24 and >24 months) and also with subjects' plaque index and gingival index scores. RESULTS: Eight patients (5.09%) had GO. No statistically significant relation was observed between age (p = 0.79), gender (p = 0.56), drug dosage (p = 0.25) and duration of drug intake (p = 0.62) and prevalence of GO. GO prevalence related highly significantly (p < 0.001) with plaque and gingival index scores. CONCLUSIONS: Prevalence of amlodipine-associated GO in the sample of elderly Indian patients was noted higher than that previously reported. Plaque and gingival inflammation were highly correlated with this condition, while demographic characteristics and drug dosage did not relate significantly. PMID- 22506837 TI - Chronic exposure to stress hormones promotes transformation and tumorigenicity of 3T3 mouse fibroblasts. AB - Epinephrine and norepinephrine are produced during psychological stress and can directly bind to cells to induce DNA damage. These effects may have more long lasting consequences such as DNA mutations resulting in an increased potential for cellular transformation and/or tumor progression. This study examined the molecular effects of a chronic (24 h) in vitro exposure to these stress hormones on murine 3T3 cells. Long exposures (24 h) in dose-response experiments with norepinephrine or epinephrine induced significant increases in DNA damage in treated cells compared to that of untreated controls as measured by the alkaline comet assay. Pre-treatment with a blocking agent (the beta-adrenergic receptor antagonist propranolol) eliminated this increase in damage. In addition, both norepinephrine and epinephrine increased cellular transformation, as assessed by growth in soft agar, and 3T3 cells pre-treated with either norepinephrine or epinephrine induced a more rapid onset of tumors and more aggressive tumor growth in nude mice. In summary, incubation of 3T3 cells with catecholamines results in long-term DNA damage as measured by increased transformed phenotypes and tumor progression, indicating that they are important mediators of stress effects on genomic instability and vulnerability to tumor formation. PMID- 22506840 TI - Regeneration of pancreatic beta-cell mass for the treatment of diabetes. AB - INTRODUCTION: The study of the endocrine compartment of the pancreas (the islets of Langerhans) is of great translational interest, as strategies aimed at restoring its mass could become therapies for glycemic dysregulation in type 1 and 2 diabetes mellitus, drug-related diabetes following diabetogenic therapies or hyperglycemic disturbances following the treatment of cancer and nesidioblastosis. Such strategies generally fall under one of the 'three Rs,' namely, replacement (islet transplantation and stem cell differentiation), reprogramming (chiefly from the exocrine compartment of the pancreas) and regeneration (replication and induction of endogenous stem cells). AREAS COVERED: This expert opinion focuses on the latter, as islets are known to regenerate under specific circumstances of physiological (e.g., pregnancy), pathological (e.g., obesity, hyperglycemia, mutations in the glucose-sensing pathway) or experimental (e.g., partial pancreatectomy, cellophane wrapping, partial duct ligation) nature. This review presents the different models of pancreatic regeneration, which encompass the replication of existing beta-cells, reversible epithelial-to-mesenchymal transition and the reactivation of resident stem cells. EXPERT OPINION: Rather than a set mechanism, the pancreas appears to possess a wide range of facultative regeneration pathways. These are discussed in the context of the development of potential strategies aimed at restoring beta-cell function in insulin-dependent diabetes. PMID- 22506839 TI - Computerized assessment facilitates disclosure of sensitive HIV risk behaviors among African Americans entering substance abuse treatment. AB - BACKGROUND: Individuals entering substance abuse treatment are at elevated risk for HIV infection, and clinicians must generally rely on patient self-report to gauge their involvement in risk behaviors. Strategies to improve accurate reporting of personally sensitive or stigmatizing risk behaviors are needed. OBJECTIVE: This study compared computerized and face-to-face interview methods in eliciting self-disclosure of HIV risk behaviors among a high-risk sample of urban African Americans entering substance abuse treatment (N = 146). METHODS: Participants completed a standardized HIV risk behavior screening as a face-to face interview. Several days later, the same participants completed a computerized self-interview with the same measure, covering the same time frame. RESULTS: Disclosure rates for many sensitive risk behaviors were considerably higher on the computerized interview. Participants had significantly higher odds of disclosure on the computerized interview compared to the face-to-face interview on 2 of 6 drug risk behaviors examined (ORs between 2.75 and 3.15) and 9 of 13 sex risk behaviors examined (ORs between 1.60 and 6.45). The advantage of the computerized interview was most evident for highly stigmatized behaviors, such as unprotected sex with someone other than a spouse or main partner (OR = 3.93; p < .001), unprotected sex during a commercial sex transaction (OR = 5.63; p < .001), unprotected anal sex (OR = 6.45; p < .001), and using unsterilized syringes (OR = 3.15; p < .05). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Findings support the utility of computerized risk behavior assessment with African Americans entering substance abuse treatment. Computerized assessment of HIV risk behaviors may be clinically useful in substance abuse treatment and other healthcare venues serving high-risk populations. PMID- 22506841 TI - Scandium(III)-catalyzed enantioselective allylation of isatins using allylsilanes. AB - The scandium(III)-catalyzed enantioselective Hosomi-Sakurai allylation of isatins with various substituted allylic silanes is described. A catalyst loading as low as 0.05 mol % is utilized at room temperature to afford the 3-allyl-3-hydroxy-2 oxindoles in excellent yields and enantioselectivity up to 99% ee, including a demonstration of a gram-scale reaction. The effects of additives and varying silyl groups were explored to demonstrate the scope and application. PMID- 22506842 TI - Fatty acid profile of pig meat after probiotic administration. AB - The aim of this work was to study the fatty acid profile of pig meat after probiotic administration. Thirty postweaned pigs (25 day old) were distributed into 2 groups: control (n = 15) and probiotic (n = 15). Each experimental group was fed ad libitum on a commercial diet for 35 days. Lactobacillus amylovorus and Enterococcus faecium mixed culture (10(8) CFU/ml)was daily orally delivered to the probiotic group. At the end of the assay, six pigs randomly selected from each group were slaughtered and muscle samples (Longissimus dorsi) were taken for fatty acid analysis. Tissues from the probiotic group animals exhibited an increase in monounsaturated and polyunsaturated fatty acids; furthermore, linoleic acid (C18:2), linolenic acid (18:3), and cis-9,trans-11 conjugated linoleic acid (CLA) concentrations were significantly higher (p < 0.05) compared to the control group. These results suggest probiotic administration could be useful to modify and improve the fatty acid profile of pig meat. PMID- 22506843 TI - Cell processing for haplo-identical hematopoietic stem cell transplantation: automated washing and immunomagnetic-positive selection. AB - BACKGROUND AIMS: Immunomagnetic cell selection (ICS) of CD34(+) cells is being used increasingly in allogeneic transplantation in order to reduce T-cell quantity. The aim of this study was to evaluate an automated washing protocol before immunomagnetic selection. METHODS: The automated method was compared with a conventional washing procedure. In the study group the cell processing using the automated procedure, both before and after antibody incubation, was performed with a Sepax S-100 device. The efficacy of the automated procedure was compared with the control group, where washing were performed using a standard method. RESULTS: The results obtained after pre-incubation washing performed using the automated system showed a total nucleated cell (NC) and CD34(+) cell recovery of 84.87% (71.80-105, SD 8.62; range, standard deviation) and 83.45% (47-109, SD 16.12), respectively. The NC and CD34(+) cell recovery after the pre-incubation washing cycle was performed using the standard method was 75.54% (38.36-97.76, SD 22.5) and 61.51% (30.87-81.79, SD 19.3), respectively. The CD34(+) cell recovery after ICS was 51.27% (13.77-98.82, SD 24.97) and 48.89% (15.57-88.24, SD 25.91) for group 1 and group 2, respectively. The average purity in group 1 was 86.46% (67.4-96.10, SD 13.07) and in group 2 84.97% (58.1-97.8, SD 15.58). CONCLUSIONS: The efficacy of the ICS led to an optimal purity without affecting cell recovery, which was higher in group 1. Overall, our data suggest that the automated method is suitable for washing hematopoietic progenitor cell apheresis (HPC-A) concentrates before immunomagnetic cell selection in daily clinical routines. PMID- 22506844 TI - Crystallization and interconversions of vapor-sensitive, luminescent polymorphs of [(C6H11NC)2Au(I)](AsF6) and [(C6H11NC)2Au(I)](PF6). AB - The remarkable, vapor-induced transformation of the yellow polymorphs of [(C(6)H(11)NC)(2)Au(I)](AsF(6)) and [(C(6)H(11)NC)(2)Au(I)](PF(6)) into the colorless forms are reported along with related studies of the crystallization of these polymorphs. Although the interconversion of these polymorphs is produced by vapor exposure, molecules of the vapor are not incorporated into the crystals. Thus, our observations may have broad implications regarding the formation and persistence of other crystal polymorphs where issues of stability and reproducibility of formation exist. Crystallographic studies show that the colorless polymorphs, which display blue luminescence, are isostructural and consist of linear chains of gold(I) cations that self-associate through aurophilic interactions. Significantly, the yellow polymorph of [(C(6)H(11)NC)(2)Au(I)](AsF(6)) is not isostructural with the yellow polymorph of [(C(6)H(11)NC)(2)Au(I)](PF(6)). Both yellow polymorphs exhibit green emission and have the gold cations arranged into somewhat bent chains with significantly closer Au...Au separations than are seen in the colorless counterparts. Luminescence differences in these polymorphs clearly enhance the ability to detect and monitor their phase stability. PMID- 22506845 TI - Acetaminophen injection: a review of clinical information including forms not available in the United States. AB - Acetaminophen injection is an antipyretic and analgesic agent recently marketed in the United States as Ofirmev. A recent review published in the Journal of Pain & Palliative Care Pharmacotherapy focused on the labeled uses of acetaminophen injection in the United States. A variety of studies were excluded that may be of interest to clinicians. This addendum provides these citations and further insight into the strategy used to develop the review. Acetaminophen injection represents another agent for multimodal pain management. PMID- 22506846 TI - Interprofessional clinical training for undergraduate students in an emergency department setting. AB - Interprofessional education (IPE) for teams of undergraduate students has since 1999 been carried out at the orthopedic emergency department at the Karolinska University Hospital. During a 2-week period, teams of medical, nursing and physiotherapy students practice together. With the aim of training professional and collaboration skills, the teams take care of patients with varying acute complaints, under the guidance of supervisors from each profession. This study describes the educational model and compares the attitudes of the different student categories participating in this unique IPE model. All students who participated in this experience during the period 2008-2010 were asked to fill in a questionnaire on completion of their training period. Results showed that all three categories, with no significant difference, highly appreciated the setting and the team training. Results also showed that the training significantly increased the students' knowledge of their own professional role as well as their knowledge of the other professions. We conclude that training at an emergency department can provide excellent opportunities for interprofessional team training for undergraduate students. The teamwork enhances the students' understanding of the professional roles and can contribute to a more holistic approach to patient care. PMID- 22506847 TI - Trust in technology-mediated collaborative health encounters: constructing trust in passive user interactions with technologies. AB - The present study investigated factors that explain patient trust in health technology and the relationship between patient trust in technology and trust in their care provider. Sociotechnical systems theory states that changes in one part of the system are likely related to other parts of the system. Therefore, attitudes about technologies, like trust, are likely related to other aspects of the system. Contributing to appropriate trust at the technological, interpersonal, and system levels can potentially lead to positive health outcomes. The study described in this manuscript used data collected from 101 patients with a Trust in Medical Technology instrument. The instrument measured patients' trust in (1) their providers, (2) the technology, and (3) how their providers used the technology. Measure 3 was positively associated with measures 1 and 2, while measures 1 and 2 were not positively or negatively associated with one another. These results may indicate that patient assessments of the trustworthiness of care providers and technologies are based on their observations of how providers use technologies. PRACTITIONER SUMMARY: Though patients are not active users of technologies in health care, the results of this study show that their perceptions of how providers use technology are related to their trust in both technology and the care provider. Study findings have implications for how trust is conceptualised and measured in interpersonal relationships and in technologies. PMID- 22506849 TI - Tooth discoloration induced by endodontic materials: a laboratory study. AB - AIM: To investigate the discoloration potential of endodontic materials using a bovine tooth model. METHODOLOGY: Two hundred and 10 dentine-enamel cuboid blocks (10 * 10 * 3.5 mm) were prepared out of the middle thirds of bovine tooth crowns. Standardized cavities were prepared in the walls of the pulp chamber leaving 2 mm of enamel and dentine on the labial wall of the crown. The specimens were randomly assigned to 14 groups (n = 15). Endodontic materials were placed into the cavities as follows: group A: empty, group B: blood, group C: calcium hydroxide, group D: ApexCal, group E: Ultracal XS, group F: Ledermix, group G: triple antibiotic paste (3Mix), group H: grey MTA(GMTA), group I: GMTA + blood, group J: white MTA (WMTA), group K: WMTA + blood, group L: Portland cement (PC), group M: PC + blood and group N: AH Plus. The cavities were sealed with composite and stored in water. Standardized colour measurement (VITA Easyshade compact) was performed at the following intervals: prior to (T0) and after placement of the filling (T1), 1 week (T2), 1 month (T3), 3 months (T4), 6 months (T5) and after 1 year (T6). Colour change (DeltaE) values were calculated. A two-way analysis of variance was used to assess significant differences between the endodontic materials. The mean values of all groups were compared using the Tukey multiple comparison test (alpha = 0.05). RESULTS: Significant differences were detected amongst the experimental groups after 12 months (P < 0.0001). The lowest colour change values were observed in the groups N (AH Plus, 3.2 +/- 1.5), A (empty, 3.8 +/- 1.4), L (PC, 4.1 +/- 1.7), C (calcium hydroxide, 4.7 +/- 1.5), E (Ultracal XS, 5.1 +/- 1.9) and J (WMTA, 7.9 +/- 6.7). The most discoloration was measured in groups G (3Mix, 66.2 +/- 9.9) and F (Ledermix, 46.2 +/- 11.6). PC showed the best colour stability amongst the Portland cement-based materials; however, when contaminated with blood (group M), a significantly higher DeltaE value (13.6 +/- 4.2) was detected (P = 0.032). CONCLUSION: Materials used in endodontics may stain teeth. Therefore, the choice of material should not rely solely on biological and functional criteria, but also take aesthetic considerations into account. PMID- 22506850 TI - Chromosomal bacterial type II toxin-antitoxin systems. AB - Most prokaryotic chromosomes contain a number of toxin-antitoxin (TA) modules consisting of a pair of genes that encode 2 components, a stable toxin and its cognate labile antitoxin. TA systems are also known as addiction modules, since the cells become "addicted" to the short-lived antitoxin product (the unstable antitoxin is degraded faster than the more stable toxin) because its de novo synthesis is essential for their survival. While toxins are always proteins, antitoxins are either RNAs (type I, type III) or proteins (type II). Type II TA systems are widely distributed throughout the chromosomes of almost all free living bacteria and archaea. The vast majority of type II toxins are mRNA specific endonucleases arresting cell growth through the mechanism of RNA cleavage, thus preventing the translation process. The physiological role of chromosomal type II TA systems still remains the subject of debate. This review describes the currently known type II toxins and their characteristics. The different hypotheses that have been proposed to explain their role in bacterial physiology are also discussed. PMID- 22506851 TI - Potential role of a quetiapine metabolite in quetiapine-induced neutropenia and agranulocytosis. AB - Clozapine was the first of the atypical antipsychotics to be developed, but its use has been restricted because of toxicity issues, particularly the risk of potentially life-threatening drug-induced neutropenia and agranulocytosis, which occurs in about 1% of patients. Bioactivation of clozapine by peroxidases forms a reactive nitrenium ion, which covalently adducts to protein and leads to neutrophil toxicity. The current generation of clozapine-inspired atypical antipsychotics has reduced toxicity through improved potency/decreased dose or through structural modification to prevent peroxidase-catalyzed nitrenium ion formation. Through the substitution of sulfur for the bridging nitrogen found in clozapine, quetiapine does not directly form a nitrenium ion when incubated with myeloperoxidase/H(2)O(2). We present evidence that cytochrome P450 2D6 catalyzes the formation of 7-hydroxyquetiapine, which can be oxidized by human myeloperoxidase to form a reactive quinone-imine and a reactive radical, which may account for the continued, although reduced, neutrophil toxicity. In the presence of myeloperoxidase/H(2)O(2) and glutathione, covalent 7 hydroxyquetiapine-glutathione adducts were formed. Bioactivation of quetiapine was verified in vivo in rat where three 7-hydroxyquetiapine-mercaptate adducts and a 7-hydroxyquetiapine-glutathione adduct were detected from bile after oral dosing. The decreased incidence of agranulocytosis with quetiapine over clozapine is postulated to be due to the lower exposure of the toxic precursor, 7 hydroxyquetiapine versus clozapine, respectively. PMID- 22506852 TI - Diastereoselective imine-bond formation through complementary double-helix formation. AB - Optically active amidine dimer strands having a variety of chiral and achiral linkers with different stereostructures are synthesized and used as templates for diastereoselective imine-bond formations between two achiral carboxylic acid monomers bearing a terminal aldehyde group and racemic 1,2-cyclohexanediamine, resulting in a preferred-handed double helix stabilized by complementary salt bridges. The diastereoselectivity of the racemic amine is significantly affected by the chirality of the amidine residues along with the rigidity and/or chirality of the linkers in the templates. NMR and kinetic studies reveal that the present imine-bond formation involves a two-step reversible reaction. The second step involves formation of a preferred-handed complementary double helix assisted by the chiral amidine templates and determines the overall reaction rate and diastereoselectivity of the amine. PMID- 22506853 TI - Oil release from Macondo well MC252 following the Deepwater Horizon accident. AB - Oil flow rates and cumulative discharge from the BP Macondo Prospect well in the Gulf of Mexico are calculated using a physically based model along with wellhead pressures measured at the blowout preventer (BOP) over the 86-day period following the Deepwater Horizon accident. Parameters appearing in the model are determined empirically from pressures measured during well shut-in and from pressures and flow rates measured the preceding day. This methodology rigorously accounts for ill-characterized evolution of the marine riser, installation and removal of collection caps, and any erosion at the wellhead. The calculated initial flow rate is 67,100 stock-tank barrels per day (stbd), which decays to 54,400 stbd just prior to installation of the capping stack and subsequent shut in. The calculated cumulative discharge is 5.4 million stock-tank barrels, of which 4.6 million barrels entered the Gulf. Quantifiable uncertainties in these values are -9.3% and +7.5%, yielding a likely total discharge in the range from 4.9 to 5.8 million barrels. Minimum and maximum credible values of this discharge are 4.6 and 6.2 million barrels. Alternative calculations using the reservoir and sea-floor pressures indicate that any erosion within the BOP had little affect on cumulative discharge. PMID- 22506854 TI - Treatment protocol for denture stomatitis, prior to anatomical molding. AB - BACKGROUND: Microorganisms of the genus Candida have been recovered from complete dentures made of acrylic resin, with high numbers of colony forming units and species diversity, which can act as infectious agents causing chronic atrophic candidiasis (denture stomatitis). OBJECTIVE: The objective of this paper is present a treatment protocol for chronic atrophic candidiasis (denture stomatitis). MATERIALS AND METHODS: The work describes three cases of totally edentulous patients presenting palate stomatitis who were submitted for treatment associating denture rebasing with chemically-activated acrylic resin, night immersion in 2.5% sodium hypochlorite and use of topical antifungals for two weeks. RESULTS: In all cases, remission of the inflammatory process occurred. CONCLUSION: The proposed treatment protocol proved to be to be effective. PMID- 22506855 TI - Neuropsychological evaluation in an adolescent with cerebellar hypoplasia diagnosed with Asperger's Syndrome. AB - There is a growing body of literature describing cases of cognitive impairment associated with both acquired and developmental damage to the cerebellum. The current case study describes such a case involving a 17-year-old male with cerebellar hypoplasia, having incomplete formation of the vermis and atrophy of the interior cerebellar hemispheres. He had previously been diagnosed as having Asperger's Syndrome. A full neuropsychological evaluation was performed, including effort testing. This is followed by a comparison of the current results to previously reported cases, with a discussion of the heterogeneity of deficits associated with developmental cerebellum malformation. PMID- 22506856 TI - Microbial spectrum and resistance patterns in endophthalmitis: a 21-year (1988 2008) review in northeast United States. AB - PURPOSE: To study the microbial spectrum and antibacterial susceptibility of vitreous cultures in a tertiary referral center in Northeast United States. METHODS: All vitreous samples sent to the microbiology laboratory at a tertiary referral center from January 1988 to December 2008 were included in the study. The distribution and antibiotic susceptibility of all isolates from culture positive samples were compared across 3 equal time periods 1988-1994, 1995-2001, and 2002-2008. RESULTS: One hundred forty-three positive cultures, where 11.9% (n=17) were polymicrobial, yielded a total of 160 isolates that consisted of 80.6% (n=129) gram-positive isolates, 12.5% (n=20) gram-negative isolates, and 6.9% (n=11) fungal isolates. The most prevalent organisms were coagulase-negative Staphylococcus (CoNS) (37.5%, n=60), Viridans Streptococcus (11.3%, n=18), and Streptococcus pneumoniae (6.9%, n=11). Other common gram-positive isolates include Propionibacterium acnes (5.6%, n=9), other Streptococcus species (4.4%, n=7), Staphylococcus aureus (4.4%, n=7), and Enterococcus faecalis (3.8%, n=6). The most common gram-negative isolates were Klebsiella species (3.1%, n=5), Moraxella species (3.1%, n=5), and Haemophilus species (2.5%, n=4). Vancomycin was effective against all CoNS, Sta. aureus, Viridans Streptococcus, and E. faecalis tested, and all Sta. aureus isolates were oxacillin sensitive. Of all CoNS isolates, 83.3% during 1988-1994, 73.1% during 1995-2001, and 100% during 2002-2008 were resistant to at least 1 of the antibiotics tested in the study with the last time period showing an increase in resistance (P=0.021, adjusted standard residual=2.0). CoNS showed a decreasing resistance over time to chloramphenicol and gentamicin (P=0.010, P=0.007, respectively) and an increase in resistance to penicillin and tetracycline during 2002-2008 (P=0.003, P=0.040, respectively). Susceptibility to other antibiotics did not show significant dependence on time. CONCLUSION: Bacteria causing endophthalmitis showed variable resistance to antibiotics over time. The importance of adequately treating endophthalmitis in the setting of these resistance pattern changes stresses the importance of periodic evaluation of causative organisms to ensure appropriate empiric treatment. PMID- 22506857 TI - Is something better than nothing? An evaluation of early childhood programs in Cambodia. AB - This study evaluated the relative effectiveness of home-based, community-based, and state-run early childhood programs across Cambodia. A total of 880 five-year olds (55% girls) from 6 rural provinces in Cambodia attending State Preschools, Community Preschools, Home-Based Programs, or no programs were assessed twice using the Cambodian Developmental Assessment Test. Controlling for baseline differences, children who participated in any early childhood programs performed significantly better in posttest than those of children who did not participate in any programs. Children in State Preschools scored significantly higher than those in either Community Preschools or Home-Based Programs; scores did not differ as a function of attending Community Preschools or Home-Based Programs. The results indicate that some preschool experience is better than none at all. PMID- 22506858 TI - Oral health care and smoking cessation practices of interprofessional home care providers for their patients with HIV. AB - The need for oral health services among patients with HIV, especially those in advanced stages of disease and those who smoke, has been well documented. Patients receiving HIV-related home care services provide an opportunity for assessment of oral health and smoking cessation needs; however, the majority of home care providers lack formal training to provide these services, thus interprofessional collaborations may be of value. This study assessed the oral health and smoking cessation practices of a random sample of 81 HIV home care providers. Results showed very favorable attitudes toward providing these services with some differences across disciplines. More than 70% of nurses would like to receive additional training in comprehensive oral health assessment by dental professionals. The study provides evidence for the potential of expanding these services for patients with HIV through interprofessional collaboration, in particular with nurses and dentists. PMID- 22506859 TI - Compounding risk for hypoglycemia: type 1 diabetes and Addison's disease. PMID- 22506860 TI - Effect of harvesting system and fruit cold storage on virgin olive oil chemical composition and quality of superintensive cultivated 'Arbequina' olives. AB - Storage at 3 and 18 degrees C of 'Arbequina' olives (Olea europaea L.) cultivated in hedgerows and harvested manually or mechanically (wine grape harvester) was tested. Fruit characteristics and oil quality were monitored. Mechanical harvesting caused internal fruit damage that induced its rapid softening and decay, but also facilitated obtaining higher amounts of oil, which suffered a rapid deterioration during fruit storage. This oil presented lower tocopherol and phenol contents and lower oxidative stability than the oil extracted from manually harvested olives, but showed similar fatty acid composition. Cold storage (3 degrees C) delayed all of these deterioration processes. It allowed maintaining the best commercial level of quality ("extra") in the oil from mechanically harvested olives for 10 days. This cold storage could be considered as an alternative to the increase in machinery for processing the growing olive production, due to both hedgerow cultivation and mechanized harvesting. PMID- 22506861 TI - Unsupervised category learning with integral-dimension stimuli. AB - Despite the recent surge in research on unsupervised category learning, the majority of studies have focused on unconstrained tasks in which no instructions are provided about the underlying category structure. Relatively little research has focused on constrained tasks in which the goal is to learn predefined stimulus clusters in the absence of feedback. The few studies that have addressed this issue have focused almost exclusively on stimuli for which it is relatively easy to attend selectively to the component dimensions (i.e., separable dimensions). In the present study, we investigated the ability of participants to learn categories constructed from stimuli for which it is difficult, if not impossible, to attend selectively to the component dimensions (i.e., integral dimensions). The experiments demonstrate that individuals are capable of learning categories constructed from the integral dimensions of brightness and saturation, but this ability is generally limited to category structures requiring selective attention to brightness. As might be expected with integral dimensions, participants were often able to integrate brightness and saturation information in the absence of feedback--an ability not observed in previous studies with separable dimensions. Even so, there was a bias to weight brightness more heavily than saturation in the categorization process, suggesting a weak form of selective attention to brightness. These data present an important challenge for the development of models of unsupervised category learning. PMID- 22506862 TI - Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae: a review of epidemiological and clinical aspects. AB - INTRODUCTION: The indiscriminate use of antibiotics associated with other situations has revealed a considerable increase in outbreaks caused by microorganisms resistant to antimicrobial drugs. Among these is the Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae. AREAS COVERED: This review provides an overview of the KPC-producing K. pneumoniae with emphasis on the epidemiological and clinical aspects. EXPERT OPINION: The KPC-producing K. pneumoniae was first described in the US. Most cases were reported between 2007 and 2009. It is widespread in almost all continents. The presence of severe comorbidities, previous use of fluoroquinolones and broad-spectrum cephalosporin are independent factors for this type of infection. Besides the increasing number of resistant strains that greatly complicates the therapeutic management of patients, the clinical characteristics of infection make the diagnosis difficult, resulting in high morbidity and mortality rates. The spread of KPC-producing K. pneumoniae shows how we are prone to pandemics. Transport systems, the exchange of healthcare professionals, the transfer of patients between hospitals and, mainly, the lack of preventive measures such as hand washing are related to the spread of KPC-producing Klebsiella pneumoniae in virtually all continents. PMID- 22506863 TI - (Ultra)fast catalyst-free macromolecular conjugation in aqueous environment at ambient temperature. AB - Tailor-made water-soluble macromolecules, including a glycopolymer, obtained by living/controlled RAFT-mediated polymerization are demonstrated to react in water with diene-functionalized poly(ethylene glycol)s without pre- or post functionalization steps or the need for a catalyst at ambient temperature. As previously observed in organic solvents, hetero-Diels-Alder (HDA) conjugations reached quantitative conversion within minutes when cyclopentadienyl moieties were involved. However, while catalysts and elevated temperatures were previously necessary for open-chain diene conjugation, additive-free HDA cycloadditions occur in water within a few hours at ambient temperature. Experimental evidence for efficient conjugations is provided via unambiguous ESI-MS, UV/vis, NMR, and SEC data. PMID- 22506864 TI - Repair technique for fractured implant-supported metal-ceramic restorations. A clinical report. AB - Abstract The fracture of porcelain structures have been related in either natural dentition or implant-supported restorations. Techniques using a composite resin or indirect methods can be used. This article presents a porcelain fracture on implant-supported metal-ceramic restoration. IPS Empress e.max laminate veneer restoration was used to repair the fracture. With this technique, it was possible to restore aesthetics and function, combined with low cost and patient satisfaction. PMID- 22506865 TI - Denaturing gradient gel electrophoresis for nonlethal detection of Aeromonas salmonicida in salmonid mucus and its potential for other bacterial fish pathogens. AB - Denaturing gradient gel electrophoresis (DGGE) of 16S rDNA was used to nonlethally detect Aeromonas salmonicida and other bacteria in salmonid skin mucus. Mucus samples from wild spawning coho salmon (Oncorhynchus kisutch) with endemic A. salmonicida and from cultured lake trout (Salvelinus namaycush) were tested by PCR-DGGE and were compared with mucus culture on Coomassie brilliant blue agar and internal organ culture. PCR-DGGE gave a highly reproducible 4-band pattern for 9 strains of typical A. salmonicida, which was different from other Aeromonas spp. Aeromonas salmonicida presence in mucus was evident as a band that comigrated with the bottom band of the A. salmonicida 4-band pattern and was verified by sequencing. PCR-DGGE found 36 of 52 coho salmon positive for A. salmonicida, compared with 31 positive by mucus culture and 16 by organ culture. Numerous other bacteria were detected in salmonid mucus, including Pseudomonas spp., Shewanella putrefaciens, Aeromonas hydrophila and other aeromonads. However, Yersinia ruckeri was not detected in mucus from 27 lake trout, but 1 fish had a sorbitol-positive Y. ruckeri isolated from organ culture. Yersinia ruckeri seeded into a mucus sample suggested that PCR-DGGE detection of this bacterium from mucus was possible. PCR-DGGE allows nonlethal detection of A. salmonicida in mucus and differentiation of some Aeromonas spp. and has the potential to allow simultaneous detection of other pathogens present in fish mucus. PMID- 22506866 TI - The influence of product aesthetics and usability over the course of time: a longitudinal field experiment. AB - A longitudinal field experiment was carried out over a period of 2 weeks to examine the influence of product aesthetics and inherent product usability. A 2 * 2 * 3 mixed design was used in the study, with product aesthetics (high/low) and usability (high/low) being manipulated as between-subjects variables and exposure time as a repeated-measures variable (three levels). A sample of 60 mobile phone users was tested during a multiple-session usability test. A range of outcome variables was measured, including performance, perceived usability, perceived aesthetics and emotion. A major finding was that the positive effect of an aesthetically appealing product on perceived usability, reported in many previous studies, began to wane with increasing exposure time. The data provided similar evidence for emotion, which also showed changes as a function of exposure time. The study has methodological implications for the future design of usability tests, notably suggesting the need for longitudinal approaches in usability research. PRACTITIONER SUMMARY: This study indicates that product aesthetics influences perceived usability considerably in one-off usability tests but this influence wanes over time. When completing a usability test it is therefore advisable to adopt a longitudinal multiple-session approach to reduce the possibly undesirable influence of aesthetics on usability ratings. PMID- 22506867 TI - Racial differences in co-occurring substance use and serious psychological distress: the roles of marriage and religiosity. AB - The study examined how marriage and religiosity can protect members of certain racial/ethnic groups against co-occurring substance use and serious psychological distress. Using the national dataset 2007 National Survey on Drug Use and Health, we analyzed data via multinomial logistic regression, observing several important results. Our findings generally support the deprivation-compensation thesis, in that religiosity elevates the mental health of racial/ethnic minority individuals more than that of Whites. We also found, however, that race/ethnicity moderates effects of education and poverty on the co-occurring behaviors, with Whites' mental health benefiting more from wealth and education than Blacks' or Hispanics' mental health did. PMID- 22506868 TI - An omnibus consistent adaptive percentile modified Wilcoxon rank sum test with applications in gene expression studies. AB - We present an adaptive percentile modified Wilcoxon rank sum test for the two sample problem. The test is basically a Wilcoxon rank sum test applied on a fraction of the sample observations, and the fraction is adaptively determined by the sample observations. Most of the theory is developed under a location-shift model, but we demonstrate that the test is also meaningful for testing against more general alternatives. The test may be particularly useful for the analysis of massive datasets in which quasi-automatic hypothesis testing is required. We investigate the power characteristics of the new test in a simulation study, and we apply the test to a microarray experiment on colorectal cancer. These empirical studies demonstrate that the new test has good overall power and that it succeeds better in finding differentially expressed genes as compared to other popular tests. We conclude that the new nonparametric test is widely applicable and that its power is comparable to the power of the Baumgartner-Weibeta Schindler test. PMID- 22506869 TI - Two-directional desymmetrization by double 1,4-addition of silicon and boron nucleophiles. AB - The two-directional desymmetrization of prochiral precursors with alpha,beta unsaturated branches by catalyst-controlled 1,4-addition of silicon and likewise boron nucleophiles allows for a general enantioselective access to syn,anti triols with 1,n + 1,2n + 1 (n = 2 and 3) substitution patterns. The utility is demonstrated in the synthesis of the C17-C25 fragment of dermostatin A. PMID- 22506872 TI - Claiming and displaying national identity: Irish travellers' and students' strategic use of 'banal' and 'hot' national identity in talk. AB - Two complementary explanations have been offered by social psychologists to account for the universal hold of national identity, first that national identity is ideologically assumed, as it forms the 'banal' background of everyday life, and second that national identity is 'hotly' constructed and contested in political and everyday settings to great effect. However, 'banal' and 'hot' aspects of national identity have been found to be distributed unevenly across national and subnational groups and banality itself can be strategically used to distinguish between different groups. The present paper develops these ideas by examining possible reasons for these different modes and strategies of identity expression. Drawing upon intergroup theories of minority and majority relations, we examine how a group who see themselves unequivocally as a minority, Irish Travellers, talk about their national identity in comparison to an age and gender matched sample of Irish students. We find that Travellers proactively display and claim 'hot' national identity in order to establish their Irishness. Irish students 'do banality', police the boundaries and reputation of Irishness, and actively reject and disparage proactive displays of Irishness. The implications for discursive understandings of identity, the study of intra-national group relations and policies of minority inclusion are discussed. PMID- 22506873 TI - Quantum dots confined in an organic drop as luminescent probes for detection of selenium by microfluorospectrometry after hydridation: study of the quenching mechanism and analytical performance. AB - Following a preliminary work (Costas-Mora, I.; Romero, V.; Pena-Pereira, F.; Lavilla, I.; Bendicho, C. Anal. Chem.2011, 83, 2388-2393), a quenching mechanism has been established for the selective detection of Se (as selenium hydride) by microfluorospectrometry using CdSe quantum dots (QDs) as luminescent probes stabilized with hexadecylamine and confined in an organic droplet. For this purpose, luminescence, luminescence lifetime, UV-vis absorption, total reflection X-ray fluorescence, transmission electron microscopy, and atomic force microscopy measurements were performed. The presence of stabilizing agents of QDs in the droplet was found to cause a critical effect on both extraction efficiency of selenium hydride in the drop and luminescence quenching. A self-quenching mechanism due to the aggregation of QDs is suggested. Aggregation is thought to occur as a result of the binding between selenide trapped into the organic drop as selenium hydride and Cd(2+) present in the surface of QDs, which in turn, may cause the loss of stabilizing hexadecylamine groups. After full optimization of main variables influencing the luminescent response, the analytical performance was established. A detection limit as low as 0.08 MUg L(-1) Se(IV) and a repeatability expressed as relative standard deviation of 4.6% were obtained. The method was validated against CRM NWTM-27.2 lake water, and a recovery study was performed with synthetic seawater. The use of CdSe as luminescent probes in an organic drop may constitute an extremely selective, sensitive, and miniaturized assay for in situ detection of Se(IV) in water. PMID- 22506874 TI - Multiple topologies from glycopolypeptide-dendron conjugate self-assembly: nanorods, micelles, and organogels. AB - Glycopolypeptides (GPs) were synthesized by ring-opening polymerization of glycosylated N-carboxyanhydride monomer and attached to hydrophobic dendrons at one chain end by "click" reaction to obtain amphiphilic anisotropic macromolecules. We show that by varying polypeptide chain length and dendron generation, an organogel was obtained in dimethylsulfoxide, while nanorods and micellar aggregates were observed in aqueous solutions. Assemblies in water were characterized by electron microscopy and dye encapsulation. Secondary structure of the GP chain was shown to affect the morphology, whereas the chain length of the poly(ethylene glycol) linker between the GP and dendron did not alter rod like assemblies. Bioactive surface chemistry of these assemblies displaying carbohydrate groups was demonstrated by interaction of mannose-functionalized nanorods with ConA. PMID- 22506875 TI - Fuel miles and the blend wall: costs and emissions from ethanol distribution in the United States. AB - From 1991 to 2009, U.S. production of ethanol increased 10-fold, largely due to government programs motivated by climate change, energy security, and economic development goals. As low-level ethanol-gasoline blends have not consistently outperformed ethanol-free gasoline in vehicle performance or tailpipe emissions, national-level economic and environmental goals could be accomplished more efficiently by concentrating consumption of gasoline containing 10% ethanol (i.e., E10) near producers to minimize freight activity. As the domestic transportation of ethanol increased 10-fold in metric ton-kilometers (t-km) from 2000 to 2009, the portion of t-km potentially justified by the E10 blend wall increased from less than 40% to 80%. However, we estimate 10 billion t-km took place annually from 2004 to 2009 for reasons other than the blend wall. This "unnecessary" transportation resulted in more than $240 million in freight costs, 90 million L of diesel consumption, 300,000 metric tons of CO(2)-e emissions, and 440 g of human intake of PM(2.5). By 2009, the marginal savings from enabling Iowa to surpass E10 would have exceeded 2.5 g CO(2)-e/MJ and $0.12/gallon of ethanol, as the next-closest customer was 1600 km away. The use of a national network model enables estimation of marginal transportation impacts from subnational policies, and benefits from policies encouraging concentrated consumption of renewable fuels. PMID- 22506876 TI - Retrieval-induced forgetting: testing the competition assumption of inhibition theory. AB - Practicing the retrieval of some information can lead to poorer retrieval of other related information, a phenomenon called retrieval-induced forgetting (RIF). This pattern has been explained as the result of inhibition of the related information during practice (Anderson, 2003). A core assumption of this inhibition account is that, to be suppressed, the related information must compete with the target information at the time of retrieval practice. Three experiments are reported that test this competition assumption. One experiment showed that RIF did not occur without specific retrieval practice of the target items when semantic generation of subordinates was performed. However, in 2 further experiments, RIF did occur when the semantic generation task was paired with category retrieval. Although there was no need for competition between target information and related information in these experiments, RIF was observed. These experiments undermine the competition assumption and hence the inhibition account. PMID- 22506877 TI - [When generative and preventive mechanisms meet with compatible and incompatible information in casual reasoning probability]. AB - Several recent models of probabilistic causal reasoning in adults propose the existence of multiple interactions between ascending and descending factors. The aim of the present study is to evaluate the potential interactions between knowledge about generative and preventive mechanisms, the delta p of the data, and the relative importance given to the type of data provided. Two experiments involving 54 participants each are conducted, in which participants are invited to quantify the nature of a potential link (causal or associative) between adding a chemical substance to the asphalt of the roads and the formation of a slippery road in the winter, after being given information suggestive of (1) a generative mechanism, (2) a preventive mechanism, or (3) nothing special. Results show an influence of the suggested mechanisms on the reading of data that were provided, especially those with a delta p that is compatible with the a priori mechanism. These results are interpreted and discussed in line with the importance of considering multiple factors in probabilistic causal reasoning. (PsycINFO Database Record (c) 2012 APA, all rights reserved). PMID- 22506878 TI - Dissociations among judgments do not reflect cognitive priority: an associative explanation of memory for frequency information in contingency learning. AB - Previous research on causal learning has usually made strong claims about the relative complexity and temporal priority of some processes over others based on evidence about dissociations between several types of judgments. In particular, it has been argued that the dissociation between causal judgments and trial-type frequency information is incompatible with the general cognitive architecture proposed by associative models. In contrast with this view, we conduct an associative analysis of this process showing that this need not be the case. We conclude that any attempt to gain a better insight on the cognitive architecture involved in contingency learning cannot rely solely on data about these dissociations. PMID- 22506879 TI - Inactivation of ice nucleating activity of silver iodide by antifreeze proteins and synthetic polymers. AB - Antifreeze proteins (AFPs) and poly(vinyl alcohol) (PVA) are known as anti-ice nucleating agents (anti-INAs), which inhibit ice nucleation initiated by ice nucleating agents (INAs). Although the effectiveness of anti-INAs depends on the type of INA, most previous studies on anti-INAs used only a few types of biological INAs as targets to inactivate. In this study, the effects of fish AFPs (AFP I and AFP III) and PVA on the ice nucleating activity of silver iodide (AgI) were measured by using emulsified solutions. Results showed that AgI was inactivated not only by AFPs and PVA but also by two other polymers previously not considered as anti-INAs, namely, poly(vinylpyrrolidone) and poly(ethylene glycol). Even in the presence of AgI, a non-negligible fraction, typically more than 10%, of emulsified droplets of these anti-INA solutions at 1.0 mg mL(-1) was supercooled to about -37 degrees C, which corresponds to ice nucleation temperature measured in the absence of AgI. PMID- 22506880 TI - Effects of sublingual immunotherapy on allergic inflammation: an update. AB - The most common allergic diseases, and especially the respiratory disorders such as rhinitis and asthma, are closely related to the allergic inflammation elicited by the causative allergen. This makes inflammation the main target of anti allergic therapies. Among the available treatments, allergen specific immunotherapy (AIT) has a patent effect on allergic inflammation, which persists also after its discontinuation, and is the only therapy able to modify the natural history of allergy. The traditional, subcutaneous route of administration was demonstrated to modify the allergen presentation by dendritic cells (DCs) that in turn correct the phenotype of allergen-specific T cells, switching from the Th2-type response, typical of allergic inflammation and characterized by the production of IL-4, IL-5, IL-13, IL-17, and IL-32 cytokines to a Th1-type response. This immune deviation is related to an increased IFN-gamma and IL-2 production as well as to the anergy of Th2 or to tolerance, the latter being related to the generation of allergen-specific T regulatory (Treg) cells, which produce cytokines such as IL-10 and TGF-beta. Anti-inflammatory mechanisms observed during sublingual AIT with high allergen doses proved to be similar to subcutaneous immunotherapy. Data obtained from biopsies clearly indicate that the pathophysiology of the oral mucosa, with particular importance for mucosal DCs, plays a crucial role in inducing tolerance to the administered allergen. PMID- 22506881 TI - Interstitial lung disease in systemic sclerosis: pathophysiology, current and new advances in therapy. AB - Systemic sclerosis is an autoimmune connective tissue disorder characterized by fibrosis of the skin and visceral organs. Interstitial lung disease (ILD) is a major complication of this disease and along with pulmonary arterial hypertension is the leading cause of mortality in scleroderma patients. The pathogenesis of pulmonary fibrosis is characterized by epithelial cell injury, activation of the coagulation pathway and inflammation, which create a profibrogenic environment in the lung in the setting of autoimmunity. The current standard of treatment for ILD in systemic sclerosis is cyclophosphamide. In view of the modest benefits in pulmonary function seen with cyclophosphamide in two recent trials and its significant toxicity, the search for alternative treatments is ongoing. With the advances in our understanding of the pathogenic mechanisms of pulmonary fibrosis, many promising therapeutic agents have come into view, but their efficacy needs to be evaluated before they can be recommended clinically. This review discusses the pathogenesis of pulmonary fibrosis with a focus on the potential target pathways, the current treatment options and recent advances in the treatment of ILD in systemic sclerosis. PMID- 22506882 TI - A case of tinea versicolor of the eyelids. AB - Tinea versicolor is a commonly encountered superficial fungal infection often presenting on the chest and back with hyperpigmented or hypopigmented scaly macules and patches. We report an unusual and rare presentation of tinea versicolor affecting only the eyelids. PMID- 22506883 TI - The Mandarin Chinese shortened version of Oral Health Impact Profile for partially edentate patients with implant-supported prostheses. AB - This study was to validate a mandarin Chinese version of Oral Health Impact Profile (OHIP-49) in China and to develop a shortened version of OHIP appropriate for use in partially dentate patients with implant-supported prostheses. The original 49 items of OHIP were translated into mandarin Chinese using a forward backward method and administered to 580 subjects selected by stratified random sampling. Self-perceived oral health status and treatment need were also collected. Reliability and validity of the Chinese version of OHIP (OHIP-C49) were validated. A shortened version (OHIP-I) was derived from the OHIP-C49 by exploratory factor analysis (EFA) as well as expert-based approach in partially dentate patients (n=102) with implant-supported prostheses. For validation of the new modified shortened version, another independent sample of 97 partially dentate patients completed OHIP-I and their self-perceived oral health status at baseline and at least 3 months after dental implant rehabilitation. Five hundred and thirty-seven effectual questionnaires were reclaimed from the 580 subjects interviewed. Cronbach's alpha ranged from 0.78 to 0.96 and test-retest correlation coefficients ranged from 0.84 to 0.97 for subscale and summary scores. Construct validity was demonstrated by priori hypothesised associations between the OHIP-C49 scores and self-perceived oral health (P<0.001). The reliability and validity of OHIP-I were similar to which of the OHIP-C49, and the responsiveness appeared able to measure the effect of dental implant therapy effectively. The mandarin version of OHIP-49 showed sufficient psychometric properties for Chinese. The modified shortened version (OHIP-I) may be appropriate for the evaluation of implant therapy outcomes in partially dentate Chinese patients. PMID- 22506884 TI - Effects of music therapy on intravitreal injections: a randomized clinical trial. AB - PURPOSE: To investigate the effects of music therapy on anxiety, perceived pain, and satisfaction in patients undergoing intravitreal injections in the outpatient setting. METHODS: This is a randomized clinical trial. Seventy-three patients were recruited from the retina clinic at 1 institution and randomized into a music therapy (n=37) or control (n=36) group. Prior to injection, patients completed the state portion of the Spielberger State Trait Anxiety Inventory (STAI-S). The music therapy group listened to classical music through computer speakers while waiting for and during the injection. The control group underwent the injection in the same setting without music. Afterward, all patients completed another STAI-S and a satisfaction and pain questionnaire. The main outcome measures were objective anxiety derived from STAI-S scores and subjective pain and anxiety from the post procedure questionnaire. RESULTS: The music therapy group had a greater decrease in anxiety than the control group (P=0.0480). Overall, 73% of all patients requested music for future injections (P=0.0001). The music therapy group (84%) requested music in future injections more frequently than the control group (61%) (P=0.0377). Both groups reported similar levels of pain (P=0.5879). CONCLUSIONS: Classical music before and during intravitreal injections decreases anxiety in patients without decreasing pain. Most patients desire to have music during future injections. Music therapy is a low-cost, easy, safe intervention that reduces anxiety during intravitreal injections in the outpatient setting. PMID- 22506885 TI - The excitability of dorsal horn neurons is affected by cerebrospinal fluid from humans with osteoarthritis. AB - Changes in central neural processing are thought to contribute to the development of chronic osteoarthritis pain. This may be reflected as the presence of inflammatory mediators in the cerebral spinal fluid (CSF). We therefore exposed organotypically cultured slices of rat spinal cord to CSF from human subjects with osteoarthritis (OACSF) at a ratio of 1 part CSF in 9 parts culture medium for 5-6 days, and measured changes in neuronal electrophysiological properties by means of whole-cell recording. Although OACSF had no effect on the membrane properties and excitability of neurons in the substantia gelatinosa, synaptic transmission was clearly altered. The frequency of spontaneous excitatory postsynaptic currents (sEPSC) in delay-firing putative excitatory neurons was increased, as was sEPSC amplitude and frequency in tonic-firing inhibitory neurons. These changes could affect sensory processing in the dorsal horn, and may affect the transfer of nociceptive information. Although OACSF also affected inhibitory synaptic transmission (frequency of spontaneous inhibitory synaptic currents; sIPSC), this may have little bearing on sensory processing by substantia gelatinosa neurons, as sEPSC frequency is >3* greater than sIPSC frequency in this predominantly excitatory network. These results support the clinical notion that changes in nociceptive processing at the spinal level contribute to the generation of chronic osteoarthritis pain. PMID- 22506886 TI - Understanding interprofessional relationships by the use of contact theory. AB - The importance and necessity of interprofessional collaboration (IPC) present challenges for educators as they determine how best to achieve IPC through interprofessional education (IPE). Simulation-based teaching has been shown to enhance students' understanding of professional roles and promote positive attitudes toward team members; yet, empirical evidence providing direction on the conditions necessary to promote these positive outcomes is lacking. This study used a quasi-experimental design with a pre-/post-test to examine changes in undergraduate healthcare students' perceptions and attitudes toward IPC following their participation in an interprofessional simulation program. Allport's (1954) intergroup contact theory was used to help understand the nature of this IPE workshop and its reported outcomes. Participants included students in the final year of their respective programs (n = 84) such as pharmacy technician, paramedic, nursing and occupational therapy assistant/physical therapy assistant programs. These students were engaged in simulation exercises with interactive contact opportunities. Using the interdisciplinary education perceptions scale, statistically significant increases in positive attitudes in three of four sub scales were found. An analysis of the structure and format of the workshop suggests that this IPE initiative fulfilled the key conditions suggested by intergroup contact theory. Attention to the key conditions provided by Allport's theory in the context of successful intergroup relationships may help provide direction for educators interested in planning IPE initiatives with student groups enrolled in various health programs. PMID- 22506887 TI - Multi-drug-resistant Enterococcus spp. as a cause of non-responsive septic synovitis in three horses. AB - CASE HISTORY: Three Thoroughbred horses, a 6-week-old filly (Case 1), a 15-year old broodmare (Case 2) and a yearling filly (Case 3), sustained synovial sepsis secondary to trauma. CLINICAL FINDINGS: Case 1 presented with a heel bulb laceration communicating with the distal interphalangeal joint. Arthroscopic lavage was performed and treatment commenced using systemic and local broad spectrum antimicrobial drugs. A pure growth of multi-drug-resistant (MDR) Enterococcus gallinarum was cultured from samples of synovium and joint fluid. Antimicrobial treatment was changed according to the susceptibility results. Response to treatment was poor and despite repeat arthroscopic lavage and intra osseous regional perfusion of antimicrobials the filly was subject to euthanasia 24 days after the initial injury. Post-mortem examination confirmed septic synovitis, cartilage degeneration and osteomyelitis. Case 2 sustained a full thickness wound to the carpus which was sharply debrided and closed. The wound dehisced with effusion within the tendon sheath. Drainage was established and treatment included systemic broad spectrum antimicrobials, topical lavage with povodine-iodine and manuka honey infusion. A mixed infection including MDR Enterococcus faecalis was cultured from the synovial fluid. Antebrachiocarpal joint effusion developed 21 days after initial injury and joint sepsis was confirmed. Arthroscopic lavage and tendon sheath debridement were performed, followed by treatment with systemic and local antimicrobials. The mare improved and was discharged. Three months later lameness recurred and corticosteroids were administered intra-articularly. The mare became non-weight bearing lame and was subject to euthanasia. Post-mortem examination confirmed joint sepsis of the antebrachiocarpal and intercarpal joint. Case 3 presented with a complete articular open fracture of the tibial crest. Under general anaesthesia the fracture was stabilised and the wounds debrided and closed. Systemic broad spectrum antimicrobials were administered. Six days later the wound dehisced and a bone fragment was removed. Three weeks post-surgery the wound deteriorated with a purulent discharge. Culture of the discharge revealed a mixed bacterial infection, including a MDR Enterococcus faecalis. Femoropatellar joint involvement was confirmed, and treatment included joint lavage, local and systemic antibiosis, and manuka honey instilled into the wound. The filly initially improved, and then deteriorated such that euthanasia was performed. DIAGNOSIS: All three cases had synovial sepsis with MDR Enterococcus spp. CLINICAL RELEVANCE: Increased awareness of MDR pathogens in equine wound infections is essential. Prompt diagnostic testing, appropriate therapy, infection control strategies and on-going monitoring and management are vital to limit the clinical impact of these organisms. PMID- 22506888 TI - Exosomal RNA as biomarkers and the therapeutic potential of exosome vectors. AB - INTRODUCTION: Exosomes are nano-sized (40 - 100 nm), extracellular vesicles, of endosomal origin. They are released by cells and found in many body fluids, including plasma. Exosomes contain proteins, microRNAs (miRNAs), and messenger RNAs (mRNAs) that can be transferred between cells. The discovery that exosomes contain RNA, and that this encapsulated RNA could potentially be transferred over distances in vivo, reinforced the importance of exosomes in cell-to-cell communication. AREAS COVERED: The existence of exosomes, as a naturally occurring delivery system of RNA, enables their use as both biomarkers and vectors in gene therapy. This review provides an overview of studies reporting that exosomal miRNA and mRNA in plasma can serve as a diagnostic marker in various types of cancers. In addition, the recent finding that exosomes can be used as vectors for delivery of small interfering RNA (siRNA) in mice, with therapeutic effects, is also reviewed. EXPERT OPINION: The data reviewed here suggest that exosomal RNA has the potential to play an important role in the diagnosis, prognosis, and treatment of diseases in the future. PMID- 22506889 TI - Increasing young children's contact with print during shared reading: longitudinal effects on literacy achievement. AB - Longitudinal results for a randomized-controlled trial (RCT) assessing the impact of increasing preschoolers' attention to print during reading are reported. Four year-old children (N = 550) in 85 classrooms experienced a 30-week shared reading program implemented by their teachers. Children in experimental classrooms experienced shared-book readings 2 or 4 times per week during which their teachers verbally and nonverbally referenced print. Children in comparison classrooms experienced their teachers' typical book reading style. Longitudinal results (n = 356, 366) showed that use of print references had significant impacts on children's early literacy skills (reading, spelling, comprehension) for 2 years following the RCT's conclusion. Results indicate a causal relation between early print knowledge and later literacy skills and have important implications concerning the primary prevention of reading difficulties. PMID- 22506891 TI - Postoperative perforation of the Schneiderian membrane in maxillary sinus augmentation: a case report. AB - Abstract Perforation of the Schneiderian membrane constitutes a major intraoperative complication of maxillary sinus floor elevation with graft materials, but postoperative perforation of the sinus membrane is very rare. This case report demonstrates that conservative treatment involving drainage and the administration of systemic antibiotics can be used to successfully treat postoperative sinus membrane perforation with infection of the graft material. PMID- 22506890 TI - Coexisting adult polyglucosan body disease with frontotemporal lobar degeneration with transactivation response DNA-binding protein-43 (TDP-43)-positive neuronal inclusions. AB - Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) is one of the most common pathological findings associated with the clinical FTLD syndromes. However, molecular characterization with genetic sequencing and protein expression techniques are recognizing many new subtypes for FTLDs. FTLDs are diverse and new nomenclature schemes have been proposed based on the molecular defects that are being discovered ( Mackenzie et al., 2010 , Acta Neuropathologica, 119, 1). Adult polyglucosan body disease (APBD) is a very rare disorder associated with systemic neurological signs and symptoms including progressive dementia with executive dysfunction and motor neuron disease. We report the clinical course of an individual with a clinical FTLD and the as yet unreported findings of coexistent APBD with FTLD-U and transactivation response DNA-binding protein-43 (TDP-43)-positive inclusions at autopsy (or more accurately, FTLD-TDP). It is unclear if these distinct findings are coincidental in this individual, or if pathogenic pathways may intersect to promote these coexisting pathologies. PMID- 22506892 TI - Genetic variants in the microRNA machinery gene GEMIN4 are associated with risk of prostate cancer: a case-control study of the Chinese Han population. AB - Single-nucleotide polymorphisms located in the microRNA biogenesis pathway could alter the risk for developing prostate cancer. The present study was intended to identify common genetic variants responsible for prostate cancer susceptibility in the GEMIN4 gene. The high-resolution melting method was used to genotype seven polymorphisms (rs7813, rs4968104, rs3744741, rs2740348, rs1062923, rs910925, and rs910924) in the GEMIN4 gene in 300 prostate cancer patients and 244 matched controls. The encouraging discovery in this study was in the rs2740348. Patients carrying the variant heterozygote GC genotype in the rs2740348 were at a 36% decreased risk of prostate cancer (odds ratio [OR] = 0.64; 95% confidence interval [CI] = 0.42, 0.99). Similarly, this variant allele carrier showed significant risk for prostate cancer (OR = 0.64). In addition, subjects carrying the homozygote TT genotype in the rs7813 had a significantly increased risk of prostate cancer (OR = 2.53, 95% CI = 1.07, 6.28). Two common haplotypes were found to be associated with decreased risk of prostate cancer. In the subgroup analysis, higher risk of more severity of prostate cancer (clinical stage III and IV) was observed in individuals with the rs7813 TT genotype (OR = 2.64, 95% CI = 1.02, 7.64), while lower risk of more severity of prostate cancer was observed in individuals with the rs3744741 T allele (OR = 0.69, 95% CI = 0.50, 0.96). Overall, our study provides substantial support for the association between the GEMIN4 gene and the risk of prostate cancer. PMID- 22506893 TI - A hybrid EM and Monte Carlo EM algorithm and its application to analysis of transmission of infectious diseases. AB - In epidemics of infectious diseases such as influenza, an individual may have one of four possible final states: prior immune, escaped from infection, infected with symptoms, and infected asymptomatically. The exact state is often not observed. In addition, the unobserved transmission times of asymptomatic infections further complicate analysis. Under the assumption of missing at random, data-augmentation techniques can be used to integrate out such uncertainties. We adapt an importance-sampling-based Monte Carlo Expectation Maximization (MCEM) algorithm to the setting of an infectious disease transmitted in close contact groups. Assuming the independence between close contact groups, we propose a hybrid EM-MCEM algorithm that applies the MCEM or the traditional EM algorithms to each close contact group depending on the dimension of missing data in that group, and discuss the variance estimation for this practice. In addition, we propose a bootstrap approach to assess the total Monte Carlo error and factor that error into the variance estimation. The proposed methods are evaluated using simulation studies. We use the hybrid EM-MCEM algorithm to analyze two influenza epidemics in the late 1970s to assess the effects of age and preseason antibody levels on the transmissibility and pathogenicity of the viruses. PMID- 22506894 TI - Differential effects of articulatory suppression on cue-switch and task-switch trials in random task cueing with 2:1 mapping. AB - Recent studies have revealed that verbal representations play an important role in various task-switching situations. This study examined whether verbal representations contribute to the actual switching process using random task cueing with two cues per task. This procedure allowed us to produce a trial in which the cue switched, but the task repeated, thereby separating the cue switching process from the actual task-switching process. Participants performed colour or shape judgements that were initiated by an arbitrary symbol cue (Experiments 1 and 2) or a kanji cue (Experiment 3) under control, articulatory suppression, and foot-tapping conditions. In Experiments 1 and 2 with the arbitrary cues, articulatory suppression impaired performance in only the cue switch condition. In Experiment 3, in which a kanji cue indicated the upcoming task name, articulatory suppression did not have any effects. These results suggest that the involvement of verbal representations in random task cueing is based on the cue-switching process rather than on the task-switching process. PMID- 22506895 TI - Experimental detection of achiral and chiral naturally abundant 13C-2H isotopomers by 2D-NMR in liquids and chiral oriented solvents. AB - The recent technological and methodological developments in NMR spectroscopy have dramatically decreased its detection limit, hence expanding its application areas. Herein, we report the first experimental detection of (2)H-(13)C isotopomeric isomers (isotopomers) in natural abundance (1.7 * 10(-4)%) both in liquids and oriented systems by combining cryoprobe, high magnetic field, and carefully chosen 2D heteronuclear correlation techniques. These experimental results require the detection of one molecule among 600,000 and demonstrate the sensivity and the selectivity of the employed NMR techniques. Besides, we show that (2)H-(13)C enantio-isotopomers can be distinguished using 2D NMR in chiral polypeptide alignment media, thus providing a new tool for the chiral analysis. This method opens fruitful propects in various analytical fields such as molecular source authentication, metabolism studies, or the fight against counterfeiting. PMID- 22506896 TI - Competition and interplay between sigma-hole and pi-hole interactions: a computational study of 1:1 and 1:2 complexes of nitryl halides (O2NX) with ammonia. AB - Quantum calculations at the MP2/cc-pVTZ, MP2/aug-cc-pVTZ, and CCSD(T)/cc-pVTZ levels have been used to examine 1:1 and 1:2 complexes between O(2)NX (X = Cl, Br, and I) with NH(3). The interaction of the lone pair of the ammonia with the sigma-hole and pi-hole of O(2)NX molecules have been considered. The 1:1 complexes can easily be differentiated using the stretching frequency of the N-X bond. Thus, those complexes with sigma-hole interaction show a blue shift of the N-X bond stretching whereas a red shift is observed in the complexes along the pi hole. The SAPT-DFT methodology has been used to gain insight on the source of the interaction energy. In the 1:2 complexes, the cooperative and diminutive energetic effects have been analyzed using the many-body interaction energies. The nature of the interactions has been characterized with the atoms in molecules (AIM) and natural bond orbital (NBO) methodologies. Stabilization energies of 1:1 and 1:2 complexes including the variation of the zero point vibrational energy (DeltaZPVE) are in the ranges 7-26 and 14-46 kJ mol(-1), respectively. PMID- 22506897 TI - Discursive and scientific psychology. AB - I begin with the origins of Loughborough University's Discourse and Rhetoric Group (DARG), and in particular discursive psychology (DP). Rather than attempting to summarize DP, versions of which are plentiful, the article attempts to clarify various relationships and tensions between DP and other kinds of social psychology, particularly experimental. Common sense psychology is defined as DP's topic rather than rival; the aim is to study how people deploy everyday psychological notions and manage psychological business within talk and text, and what they accomplish by such deployments, rather than trying, as experimental psychology is often characterized as doing, to replace it all with something purportedly better. Claims for DP being particularly interpretative rather than scientific are rejected, by appeal to an 'interpretative gap' between phenomena, data, analysis, and conclusions that all research must manage, that gap being often much larger in quantitative and experimental work. The importance of pursuing causal explanations of psychological phenomena is questioned, and the importance asserted, of discovering, through rigorous empirical and conceptual analysis, the normative bases of human conduct and accountability. PMID- 22506898 TI - Selective etching induces selective growth and controlled formation of various platinum nanostructures by modifying seed surface free energy. AB - We present a strategy to achieve heterogeneous seeded growth on nanoparticle (NP) surfaces and construct various Pt nanostructures (cage- and ring-like) by using selective etching as surface-free-energy-distribution modifier. Preprepared Au polyhedron NPs (octahedron, decahedron, nanorod, and nanoplate) are mixed with KI, H(2)PtCl(6), and surfactant. Under heating, KI is first oxidized to I(2), which then selectively etches the edges of Au polyhedrons. Consequently, the partial removal of surface Au atoms creates highly active sites (exposed high index facets, atom steps, and kinks) on the etched edges. Then the reduced Pt(0) atoms deposit on the etched edges preferentially and grow further, generating bimetallic nanostructures, Au octahedrons, or decahedrons with edges coated by Pt. The Pt layer protects the Au on the etched edges against further etching, changing the etching route and causing the Au on {111} facets without a Pt layer to be etched. After the Au is removed completely from the bimetallic nanostructures, ring-like, frame-like, and octahedral cage-like Pt nanostructures form. The evolution from Au polyhedrons to Pt ring or octahedron cage is investigated systematically by high-resolution transmission electron microscopy, transmission electron microscopy, scanning electron microscopy, energy-dispersive X-ray, scanning transmission electron microscopy, and high-angle annular dark field. PMID- 22506899 TI - Dodecagonal quasicrystalline morphology in a poly(styrene-b-isoprene-b-styrene-b ethylene oxide) tetrablock terpolymer. AB - A dodecagonal quasicrystalline (QC) morphology is identified in a poly(styrene-b isoprene-b-styrene-b-ethylene oxide) (SISO) tetrablock terpolymer based on evidence provided by transmission electron microscopy (TEM), small-angle X-ray scattering, and dynamic mechanical spectroscopy measurements. The QC state occurs at temperatures between those associated with simple hexagonal order (HEX) and the sigma-phase (P4(2)/mnm), T(HEX) < T(QC) < T(sigma) < T(ODT), where T(ODT) is the order-disorder transition temperature. All three morphologies are formed from spherical domains containing an O core surrounded by a shell of S that screens unfavorable segment-segment interactions with an I-rich matrix. TEM analysis reveals a QC morphology with 12-fold rotational symmetry but devoid of long-range translational order, along with locally coordinated structures consistent with dodecagonal quasicrystalline approximants. The SISO molecular architecture decouples control over the domain shape and interdomain interactions, leading to a multiplicity of packing symmetries. PMID- 22506900 TI - Toward understanding of toxic side effects of a polyene antibiotic amphotericin B: fluorescence spectroscopy reveals widespread formation of the specific supramolecular structures of the drug. AB - Amphotericin B (AmB) is a lifesaving polyene antibiotic used widely to treat deep seated mycoses. Both the pharmaceutical effectiveness as well as toxic side effects depend on molecular organization of the drug. In the present study, we analyzed steady-state fluorescence, fluorescence anisotropy spectra, fluorescence lifetimes, and fluorescence anisotropy decays of AmB in the systems believed to ensure monomeric organization of the drug and in model lipid membranes. The results of the analyses show that in all of the systems studied, the drug appears in, at least, two spectral forms, interpreted as monomeric and aggregated. Spectroscopic and fluorescence lifetime characteristics of both forms are provided. Interpretation of the fluorescence anisotropy spectra of AmB incorporated into liposomes formed with dipalmitoylphosphatidylcholine let us conclude that monomers of the drug are more tightly bound to the lipid membranes as compared to the aggregates and that AmB aggregates destabilize the membrane structure. Structural model analysis, compared to the analysis of spectral shifts, leads to the conclusion that basic constituents of AmB aggregated structure is a tetramer composed of two hydrogen-bond-stabilized dimers, each dimer formed by molecules twisted by ca. 170 degrees . The tetramer itself can span lipid bilayers and can act as a transmembrane ion channel. Specific aggregate formation of AmB has been concluded as a universal and ubiquitous form of molecular organization of the drug. This process is discussed in terms of toxic side effects of AmB. PMID- 22506901 TI - Quantifying the impacts of stratification and nutrient loading on hypoxia in the northern Gulf of Mexico. AB - Stratification and nutrient loading are two primary factors leading to hypoxia in coastal systems. However, where these factors are temporally correlated, it can be difficult to isolate and quantify their individual impacts. This study provides a novel solution to this problem by determining the effect of stratification based on its spatial relationship with bottom-water dissolved oxygen (BWDO) concentration using a geostatistical regression. Ten years (1998 2007) of midsummer Gulf of Mexico BWDO measurements are modeled using stratification metrics along with trends based on spatial coordinates and bathymetry, which together explain 27-61% of the spatial variability in BWDO for individual years. Because stratification effects explain only a portion of the year-to-year variability in mean BWDO; the remaining variability is explained by other factors, with May nitrate plus nitrite river concentration the most important. Overall, 82% of the year-to-year variability in mean BWDO is explained. The results suggest that while both stratification and nutrients play important roles in determining the annual extent of midsummer hypoxia, reducing nutrient inputs alone will substantially reduce the average extent. PMID- 22506902 TI - Iron-promoted tandem reaction of anilines with styrene oxides via C-C cleavage for the synthesis of quinolines. AB - A novel iron-promoted tandem reaction of anilines with styrene oxides via C-C cleavage and C-H activation has been developed. The reaction utilizes an inexpensive FeCl(3) as promoter and is suitable for forming a variety of 3 arylquinolines from the simple and readily available starting materials. PMID- 22506903 TI - Metabolic and genetic factors modulating subject specific LDL-C responses to plant sterol therapy. AB - Reducing intestinal cholesterol absorption with plant sterol consumption is a well-characterized strategy to lower LDL-C and potentially reduce cardiovascular disease risk. However, over 50 years of clinical research demonstrate that there is significant heterogeneity in the individual LDL-C lowering response to plant sterol therapy. A clear understanding of why plant sterols work effectively in some individuals but not in others will ensure optimal integration of plant sterols in future personalized nutritional lipid-lowering strategies. This review will examine the current knowledge base surrounding the metabolic and genetic determinants of LDL-C lowering in response to plant sterol consumption. PMID- 22506904 TI - Determining the direction of tooth grinding: an in vitro study. AB - The analysis of microwear patterns, including scratch types and widths, has enabled reconstruction of the dietary habits and lifestyles of prehistoric and modern humans. The aim of this in vitro study was to determine whether an assessment of microwear features of experimental scratches placed on enamel, perpendicularly to the direction of grinding, could predict the grinding direction. Experimental scratches were placed using a scalpel blade on standardised wear facets that had been prepared by wearing opposing enamel surfaces in an electromechanical tooth wear machine. These control 'baseline' facets (with unworn experimental scratches) were subjected to 50 wear cycles, so that differential microwear could be observed on the leading and trailing edges of the 'final' facets. In Group 1 (n=28), the 'footprint' microwear patterns corresponding to the known grinding direction of specimens in the tooth wear machine were identified. Then, they were used to predict the direction of tooth grinding blindly in the same sample after a 2-week intermission period. To avoid overfitting the predictive model, its sensitivity was also cross-validated in a new sample (Group 2, n=14). A crescent-shaped characteristic observed in most experimental scratches matched the grinding direction on all occasions. The best predictor of the direction of grinding was a combined assessment of the leading edge microwear pattern and the crescent characteristic (82.1% in Group 1 and 92.9% in Group 2). In conclusion, a simple scratch test can determine the direction of tooth grinding with high reliability, although further improvement in sensitivity is desirable. PMID- 22506906 TI - Examining patients' and other group members' agreement about their alliance to the group as a whole and changes in patient symptoms using response surface analysis. AB - There is a lack of research examining patients' and other group members' agreement about their therapeutic alliance. In the present study, the person group (P-G) fit model was adopted to predict that the group member symptom reduction will be greater when the group member's and the other group members' perceptions of their alliance to the group-as-a-whole fit and are high. In addition, the effect of disagreement between the group member and the other group members in their perceptions of the group alliance on the individual's outcome was investigated by using response surface analysis. Thirty-two patients from 5 long-term (> 1 year) psychodynamic group treatments were studied. Participants filled out the California Psychotherapy Alliance Scale-Group (CALPAS-G; Gaston & Marmar, 1993) and the Outcome Questionnaire-45 (OQ-45; Lambert et al., 1996) monthly over the course of group treatment until termination. As hypothesized, patient's symptom reduction was greater when there was agreement between the group member and the other group members that their alliance to the group as a whole was strong. Contrary to the authors' hypothesis, a lack agreement on alliance to the group as a whole between the patient and the other group members was not related to less symptom reduction, as lack of fit increased, symptom reduction decreased. Also contrary to the authors' hypothesis, when other group members saw their alliance to the group as a whole as stronger than did the patient, there was increased symptom reduction. The findings suggest that the P-G fit model may be a useful strategy to examine group process variables in the psychotherapy context. PMID- 22506907 TI - Recognizing social class in the psychotherapy relationship: a grounded theory exploration of low-income clients. AB - The process of psychotherapy among 16 low-income clients was explored using grounded theory (Charmaz, 2006; Glaser & Strauss, 1967) in order to understand and identify their unique experiences and needs. Semistructured interviews were conducted with 12 women and 4 men who had attended at least 6 sessions of psychotherapy within 6 months of the interview. Our grounded theory that evolved depicted a tapestry of the dynamic process by which low-income clients experience social class within psychotherapy. Specific therapist behaviors that contribute to more and less positive experiences emerged from the data and pointed to the importance of acknowledging social class within the therapy room. The significance of therapists enhancing the 50-min hour via advocacy and meaningful moments within and outside of the therapy room was highlighted among all participants. Implications for practice with low-income clients and directions for future research are provided. PMID- 22506908 TI - Role of identity integration on the relationship between perceived racial discrimination and psychological adjustment of multiracial people. AB - This study examined relations between perceived racial discrimination, multiracial identity integration (i.e., racial distance and racial conflict), and psychological adjustment (i.e., distress symptoms, positive affect, and negative affect) of 263 multiracial adults, using an online cross-sectional survey design. As hypothesized, higher levels of perceived racial discrimination was related to lower levels of psychological adjustment (i.e., higher distress symptoms and negative affect). Also, higher levels of multiracial identity integration with low racial conflict was related to higher levels of psychological adjustment (i.e., lower distress symptoms and negative affect), whereas higher levels of multiracial identity integration with low racial distance was related to higher levels of psychological adjustment (i.e., lower negative affect). Finally, multiracial identity integration (i.e., lower racial conflict) moderated the relationship between perceived racial discrimination and psychological adjustment (i.e., negative affect) with results suggesting multiracial identity integration related to low racial conflict buffers the negative effects of perceived racial discrimination on psychological adjustment. Findings from this study are discussed in terms of future research on the psychological well-being of multiracial individuals and implications for clinical practice with multiracial adults. PMID- 22506909 TI - Development of the Coping Flexibility Scale: evidence for the coping flexibility hypothesis. AB - Coping flexibility was defined as the ability to discontinue an ineffective coping strategy (i.e., evaluation coping) and produce and implement an alternative coping strategy (i.e., adaptive coping). The Coping Flexibility Scale (CFS) was developed on the basis of this definition. Five studies involving approximately 4,400 Japanese college students and employees were conducted to test the hypothesis that flexible coping produces more adaptive outcomes. Studies 1, 2, and 3 provided evidence of the reliability of the CFS scores as well as of its convergent and discriminant validity for Japanese samples. Study 4 further demonstrated that flexible coping was positively associated with improved psychological health, including reduced depression, anxiety, and distress. In Study 5, coping flexibility as measured by the CFS was associated with reduced future depression, even after controlling for the effects of other coping flexibility measures and popular coping strategies. Overall, these results suggest that a valid approach for assessing coping flexibility has been developed and that flexible coping can contribute to psychological health. The implications of these findings for clinical practice are discussed. PMID- 22506910 TI - Predictors of satisfaction in geographically close and long-distance relationships. AB - In this study, the authors examined geographically close (GCRs) and long-distance (LDRs) romantic relationship satisfaction as explained by insecure attachment, self-disclosure, gossip, and idealization. After college student participants (N = 536) completed a Web survey, structural equation modeling (SEM) multigroup analysis revealed that the GCR and LDR models were nonequivalent, as expected. Self-disclosure mediated the insecure attachment-idealization path differently in GCRs and in LDRs. Self-disclosure was positively associated with idealization in GCRs and negatively associated with idealization in LDRs, with the insecure attachment-idealization and the insecure attachment-satisfaction paths negative for both GCRs and LDRs. Furthermore, the insecure attachment-idealization path was stronger than the mediated path, especially for LDRs; the insecure attachment satisfaction path was stronger than the mediation model for GCRs and LDRs. In other words, the GCR and LDR models differed despite some similarities. For both, with higher insecure (i.e., anxious and avoidant) attachment, the person discloses less to the partner, idealizes the partner less, and is less satisfied with the relationship. Also, people who idealize are more satisfied. In contrast, in LDRs only, with higher insecure attachment, the people tend to gossip more. With higher insecure attachment and with higher self-disclosure, people idealize more in GCRs but idealize less in LDRs. Overall, attachment insecurity explained more idealization and satisfaction in LDRs than in GCRs. Implications are discussed. PMID- 22506911 TI - Advancing career counseling and employment support for survivors: an intervention evaluation. AB - The purpose of this research was to conduct a replication-based and extension study examining the effectiveness of a 5-week career group counseling intervention, Advancing Career Counseling and Employment Support for Survivors (ACCESS; Chronister, 2008). The present study was conducted in a markedly different geographic region within a larger community as compared with the original investigation conducted by Chronister and McWhirter (2006). Women survivors of intimate partner violence (N = 73) participated in ACCESS, with career-search self-efficacy, perceived career barriers, perceived career supports, anxiety, and depression assessed at preintervention, postintervention, and 8-week follow-up. Women survivors demonstrated significant improvements in career-search self-efficacy and perceived career barriers at postintervention. Moreover, these same improvements were maintained at the 8-week follow-up assessment with the addition of significant improvements in perceived future financial supports, anxiety, and depression compared with preintervention scores. This work replicates the initial findings regarding the effectiveness of ACCESS with respect to career-search self-efficacy (Chronister & McWhirter, 2006) as well as extends the initial research to include improvements in perceived career barriers and perceived career supports. Moreover, the present study extends the work to include the mental health outcomes of anxiety and depression; results demonstrated improvements in these areas at 8-week follow-up. This investigation begins to fill a critical need for evaluated career-focused interventions for the underserved population of women survivors of intimate partner violence. PMID- 22506912 TI - Intraobserver reliability of two-dimensional ultrasound derived strain imaging in the assessment of the left ventricle, right ventricle, and left atrium of healthy human hearts. AB - AIMS: To determine the intraobserver reproducibility of peak and temporal values for myocardial strain (E) and strain rate (SR) using a speckle tracking technique in the left ventricle (LV), right ventricle (RV), and left atrium (LA). METHODS AND RESULTS: Myocardial speckle tracking echocardiograms of the LV, RV, and LA were obtained on 20 healthy adults to provide indices of longitudinal, radial, circumferential E, and SR as well as LV rotation and twist. Each participant had two separate acquisitions approximately 30 minutes apart. No systematic bias was present in E data. LV E across all planes provided "good" to "very good" intraclass correlation coefficient (ICC) values (0.714-0.807), however radial E was inferior in terms of coefficients of variation (CoV) (19%). SR data were more variable than E with LV radial SR performing least favorably. RV and LA E demonstrated excellent reproducibility (ICCs of 0.834, 0.959, and CoVs of 7% and 6%, respectively). RV and LA SR were again more variable but generally acceptable ICC > 0.6 and CoV < 15%. Peak basal and apical rotation demonstrated quite high variability while derived torsion had low variability and excellent agreement (ICC = 0.940, CoV = 10%). Time-to-peak values demonstrated acceptable agreement with the exception of systolic SR from all chambers. CONCLUSION: Good reproducibility was obtained for peak E indices although radial E performs less favorably. Intraobserver variation of peak E appears superior to values obtained for peak SR. Time-to-peak values demonstrate very good intraobserver reproducibility across all planes of contraction with exception of (time-to-peak) systolic strain rate (SRS). PMID- 22506913 TI - Self-assembled calixarene derivative as a supramolecular polymer. AB - A light scattering study shows that the HCl-promoted self-assembly of an amino calix[5]arene monomer precursor UC5-NH(2), bearing an ancillary ureido binding site, efficiently yields supramolecular polymers with a concentration-independent average mass. These polymers adopt a random-coil conformation and interact among themselves via the adhesive hard sphere pair potential. The findings also indicate the formation of polymer clusters, coexisting in low concentration with the polymers and resulting from the adhesive interpolymer interactions. Unlike polymers, the size of these clusters depends on the monomer concentration. PMID- 22506914 TI - The linear transformation model with frailties for the analysis of item response times. AB - The item response times (RTs) collected from computerized testing represent an underutilized source of information about items and examinees. In addition to knowing the examinees' responses to each item, we can investigate the amount of time examinees spend on each item. In this paper, we propose a semi-parametric model for RTs, the linear transformation model with a latent speed covariate, which combines the flexibility of non-parametric modelling and the brevity as well as interpretability of parametric modelling. In this new model, the RTs, after some non-parametric monotone transformation, become a linear model with latent speed as covariate plus an error term. The distribution of the error term implicitly defines the relationship between the RT and examinees' latent speeds; whereas the non-parametric transformation is able to describe various shapes of RT distributions. The linear transformation model represents a rich family of models that includes the Cox proportional hazards model, the Box-Cox normal model, and many other models as special cases. This new model is embedded in a hierarchical framework so that both RTs and responses are modelled simultaneously. A two-stage estimation method is proposed. In the first stage, the Markov chain Monte Carlo method is employed to estimate the parametric part of the model. In the second stage, an estimating equation method with a recursive algorithm is adopted to estimate the non-parametric transformation. Applicability of the new model is demonstrated with a simulation study and a real data application. Finally, methods to evaluate the model fit are suggested. PMID- 22506915 TI - Antibody therapy for familial amyloidotic polyneuropathy. AB - Although it is believed that altered conformations exposing cryptic regions are intermediary and critical steps in the mechanism of transthyretin (TTR) amyloid formation, no effective therapy targeting this step is available. In this study, to establish the antibody therapy for familial amyloidotic polyneuropathy (FAP), we generated a monoclonal anti-TTR antibody, which specifically reacts with surface epitopes of TTR (MAb ATTR) and evaluated its binding affinity and specificity for TTR amyloid fibrils. MAb ATTR showed specific binding affinity for TTR amyloid fibrils, but not for native form of TTR. Moreover, MAb ATTR indeed showed the high consistency with Congo red positive areas in tissue specimens from FAP ATTR V30M patients, indicating that MAb ATTR showed binding affinity and specificity for TTR amyloid fibrils in vitro and in vivo. MAb ATTR may have a potential to suppress TTR amyloid deposition and become a candidate for the antibody therapy for FAP. PMID- 22506916 TI - In silico mutagenesis and docking study of Ralstonia solanacearum RSL lectin: performance of docking software to predict saccharide binding. AB - In this study, in silico mutagenesis and docking in Ralstonia solanacearum lectin (RSL) were carried out, and the ability of several docking software programs to calculate binding affinity was evaluated. In silico mutation of six amino acid residues (Agr17, Glu28, Gly39, Ala40, Trp76, and Trp81) was done, and a total of 114 in silico mutants of RSL were docked with Me-alpha-L-fucoside. Our results show that polar residues Arg17 and Glu28, as well as nonpolar amino acids Trp76 and Trp81, are crucial for binding. Gly39 may also influence ligand binding because any mutations at this position lead to a change in the binding pocket shape. The Ala40 residue was found to be the most interesting residue for mutagenesis and can affect the selectivity and/or affinity. In general, the docking software used performs better for high affinity binders and fails to place the binding affinities in the correct order. PMID- 22506917 TI - Maternal depressive symptoms, dysfunctional cognitions, and infant night waking: the role of maternal nighttime behavior. AB - Mechanisms were examined to clarify relations between maternal depressive symptoms, dysfunctional cognitions, and infant night waking among 45 infants (1 24 months) and their mothers. A mother-driven mediational model was tested in which maternal depressive symptoms and dysfunctional cognitions about infant sleep predicted infant night waking via their impact on mothers' bedtime and nighttime behavior with infants (from video). Two infant-driven mediational models were also examined, in which infant night waking predicted maternal depressive symptoms, or dysfunctional cognitions, via their impact on nighttime maternal behavior. Stronger support for the mother-driven model was obtained, which was further supported by qualitative observations from video-recordings. This study provides important insights about maternal depression's effects on nighttime parenting, and how such parenting affects infant sleep. PMID- 22506918 TI - Longitudinal serological survey and herd-level risk factors for Leptospira spp. serovars Hardjo-bovis and Pomona on deer farms with sheep and/or beef cattle. AB - AIM: To investigate the seroprevalence of Leptospira spp. serovars Hardjo-bovis and Pomona on deer and mixed deer, sheep and/or beef cattle farms in the lower North Island of New Zealand and to examine associations between putative risk factors for seropositive deer herds. METHODS: Serological screening was conducted on 19 commercial deer farms, 16 with sheep and/or beef cattle, between August and October each year between 2006 and 2008. No leptospiral vaccination had been conducted on the farms. On each farm every year, serum samples were collected from a random sample of 20 or more rising 2-year-old replacement animals from each species. The microscopic agglutination test (MAT) was used to detect leptospiral antibodies against Leptospira borgpetersenii serovar Hardjo-bovis and Leptospira interrogans serovar Pomona. For both serovars, a titre of >=1:48 was considered positive and a herd was considered seropositive if >3 of 20 serum samples were positive. Information on potential herd-level risk factors for deer herds being seropositive was obtained from a questionnaire completed by the farm owner or manager. RESULTS: The mean percentage of deer, cattle and sheep herds seropositive for Hardjo-bovis alone over 3 years was 42%, 53% and 54%, respectively, and for serovar Pomona was 7%, 5% and 0%, respectively. Antibodies to both serovars were found in 23%, 16% and 10% of deer, cattle and sheep herds, respectively. At the individual animal level, 228/1,107 (21%) deer, 308/767 (40%) cattle and 369/1,244 (30%) sheep were seropositive for Hardjo-bovis, 102 (9%) deer, 51 (7%) cattle and 23 (2%) sheep were seropositive for Pomona, and 49 (4%) deer, 28 (4%) cattle and 18 (1%) sheep were seropositive for both serovars. Deer herds were more likely to be seropositive for Hardjo-bovis in 2006 than 2008 (p=0.008), when seropositive in the preceding year (p=0.016) and on hilly compared with flat topography (p<0.001). Deer herds were more likely to be seropositive for Pomona when seropositive in the preceding year (p=0.016), when co-grazing with sheep flocks that were seropositive for Pomona (p<0.001), and when herds had a closed- compared with open-herd replacement policy (p<0.001). CONCLUSIONS: Exposure to Leptospira spp. was widely distributed in deer, sheep and beef cattle in the lower North Island of New Zealand. Co-grazing of deer with sheep that were seropositive was a potential risk factor for deer herds to be seropositive. PMID- 22506919 TI - What factors influence obstetrician-gynecologists to follow recommended HIV screening and testing guidelines? AB - BACKGROUND: The purpose of this study was to determine what factors may influence obstetrician-gynecologists' HIV testing practices and to learn more about obstetrician-gynecologists' current HIV screening and testing practices. METHODS: Survey questionnaires were sent to 1200 American College of Obstetricians and Gynecologists (the College) Fellows and Junior Fellows in practice between October 2009 and January 2010. Four hundred of the recipients were members of the Collaborative Ambulatory Research Network (CARN), and 800 recipients were randomly selected from the ACOG Fellows and Junior Fellows in practice. RESULTS: The survey response rate was 62.0% (248 of 400) for CARN and 31.1% (249 of 800) for non-CARN. Nearly 100% (99.7%) of the study sample report recommending HIV testing to all pregnant women at least once during each pregnancy, while reported rates for repeat testing in the third trimester remain low (20.1% for all patients and 42.6% for high-risk patients). Two thirds (66.0%) of respondents recommend labor and delivery testing to women with unknown or undocumented HIV status. Fewer than 22.0% of respondents report routinely recommending HIV screening to all non-pregnant women, citing a low-risk population as the most common reason. State laws and regulations have only moderate influence on obstetrician-gynecologists' HIV testing practice, as do practice type, location, and setting. CONCLUSIONS: The results of this study suggest that the provider's perception about the patients' risk for being infected as well as practice type and location are important factors influencing an obstetrician-gynecologist's decision to screen a nonpregnant woman for HIV. PMID- 22506921 TI - Detecting population structure and recent demographic history in endangered livestock breeds: the case of the Italian autochthonous donkeys. AB - Since its domestication, about 5000 years ago, the donkey (Equus asinus) has been extensively used as a work or draft animal in agricultural activities and for the transportation of people and goods. In the last century, technology improvement and growing mechanization strongly affected agriculture and the management and use of this livestock species in the industrialized countries. Nowadays, the use of donkeys for work or transport has almost disappeared, together with the need for mules or hinny breeding. During the last five decades, Italian autochthonous donkey populations suffered from a severe reduction in population size, which led to the extinction of several breeds. At present, eight breeds remain, all classified by FAO as critically endangered or endangered: Asinara, Pantesco, Grigio Siciliano, Romagnolo, Amiatino, Sardo Grigio, Martina Franca, and Ragusano. To evaluate the extant genetic variability of Italian donkeys, we typed 16 microsatellite loci in 258 individuals from these breeds. The results highlighted moderate levels of inbreeding ( F (IS) = 0.127) and a significant partition of genetic variation into breeds, as suggested by fixation index ( F (ST) = 0.109) and analysis of molecular variance (10.86% of total variation assigned to the between-breeds level) analyses. This was confirmed by a Bayesian clustering procedure that also highlighted a further partitioning at lower hierarchical levels corresponding to the farms of origin. This evidence suggests that an effective management strategy for Italian donkey populations should focus on breeds as conservation units. However, this requires a synergic management strategy at the farm level to maintain diversity and avoid inbreeding. PMID- 22506922 TI - PEG-PE-based micelles co-loaded with paclitaxel and cyclosporine A or loaded with paclitaxel and targeted by anticancer antibody overcome drug resistance in cancer cells. AB - The over-expression of the P-glycoprotein (P-gp) in cancer cells is one of the main reasons of the acquired Multidrug Resistance (MDR). Combined treatment of MDR cancer cells with P-gp inhibitors and chemotherapeutic agents could result in reversal of resistance in P-gp-expressing cells. In this study, paclitaxel (PTX) was co-encapsulated in actively targeted (anticancer mAb 2C5-modified) polymeric lipid-core PEG-PE-based micelles with Cyclosporine A (CycA), which is one of the most effective first generation P-gp inhibitors. Cell culture studies performed using MDCKII (parental and MDR1) cell lines to investigate the potential MDR reversal effect of the formulations. The average size of both empty and loaded PEG2000-PE/Vitamin E mixed micelles was found between 10 and 25 nm. Zeta potentials of the formulations were found between -7 and -35 mV. The percentage of PTX in the micelles was found higher than 3% for both formulations and cumulative PTX release of about 70% was demonstrated. P-gp inhibition with CycA caused an increase in the cytotoxicity of PTX. Dual-loaded micelles demonstrated significantly higher cytotoxicity in the resistant MDCKII-MDR1 cells than micelles loaded with PTX alone. Micelle modification with mAb 2C5 results in the highest cytotoxicity against resistant cells, with or without P-gp modulator, probably because of better internalization bypassing the P-gp mechanism. Our results suggest that micelles delivering a combination of P-gp modulator and anticancer drug or micelles loaded with only PTX, but targeted with mAb 2C5 represent a promising approach to overcome drug resistance in cancer cells. PMID- 22506920 TI - Timeliness of cervical cancer diagnosis and initiation of treatment in the National Breast and Cervical Cancer Early Detection Program. AB - OBJECTIVES: To examine time intervals from cervical cancer screening to diagnosis and treatment initiation among low-income and uninsured women in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) during two consecutive time periods. METHODS: We analyzed NBCCEDP data for women with abnormal Pap tests (n=100,167), from which 1,417 invasive cervical cancers were diagnosed. We examined two time intervals for this study: diagnostic interval (time from abnormal Pap test to the date of definitive diagnosis) and treatment initiation interval (time from definitive diagnosis to treatment initiation) for two time periods: 1996-2002 and 2003-2009. We compared median time intervals for diagnostic and treatment initiation using the Kruskal-Wallis test. Adjusted proportions (predicted marginals) were calculated using logistic regression to examine diagnosis and treatment within program benchmarks (<=60 days). RESULTS: Median diagnostic intervals decreased overall by 6 days (54 vs. 48 days, p<0.001). This decrease in the median diagnostic interval was noted for all variables examined. The median treatment initiation intervals remained stable over the two time periods. CONCLUSIONS: Women screened by the NBCCEDP receive diagnostic follow-up and initiate treatment within preestablished program guidelines. PMID- 22506923 TI - Fetal DNA in maternal plasma: a noninvasive tool for prenatal diagnosis of beta thalassemia. AB - INTRODUCTION: In pregnancy, the discovery of fetal DNA in maternal blood outlined new scenarios for noninvasive prenatal diagnosis of numerous fetal pathological conditions based on a new source of fetal genetic material. Tests on fetal DNA circulating in maternal plasma are expected to replace or reduce invasive procedures, such as chorionic villi sampling and amniocentesis, that are typically carried out late in pregnancy and pose a risk of miscarriage. AREAS COVERED: Nevertheless, at present, no accurate and simple methods for noninvasive prenatal diagnosis of genetic diseases are available, thus preventing a widespread clinical application. EXPERT OPINION: Two highly different sensitive methodologies are reported both allowing the identification of fetal paternally inherited mutations in maternal plasma DNA during the first trimester of pregnancy in a clinically relevant genetic disease. The first one includes mutant enrichment amplification protocols either based on the use of PNA (peptide nucleic acids) or on CO-amplification at Lower Denaturation temperature-PCR (COLD PCR). In the second approach, an extremely sensitive microarray substrates are exploited which allows the detection of fetal mutated alleles even without the need of any enrichment strategy. Beta-thalassemia has been chosen as a model of clinically relevant genetic disease. PMID- 22506924 TI - Experimental and computational thermochemical study of 2-thiobarbituric acid: structure-energy relationship. AB - This paper reports an experimental and computational thermochemical study on 2 thiobarbituric acid (2-thioxodihydropyrimidine-4,6(1H,5H)-dione), [CAS 504-17-6]. The value of the standard (p(0) = 0.1 MPa) molar enthalpy of formation in the gas phase at T = 298.15 K has been determined. The energy of combustion was measured by bomb combustion calorimetry, using a rotatory bomb, and from the result obtained, the standard molar enthalpy of formation in the crystalline state at T = 298.15 K was calculated as -(396.8 +/- 0.9) kJ.mol(-1). The enthalpy of sublimation was determined using a transference (transpiration) method in a saturated N(2) stream and a value of the enthalpy of sublimation at T = 298.15 K was derived as (118.3 +/- 2.2) kJ.mol(-1). From these results a value of -(278.5 +/- 2.4) kJ.mol(-1) for the gas-phase enthalpy of formation at T = 298.15 K was determined. Theoretical calculations at the G3 and G4 levels were performed, and a study of the molecular and electronic structure of the compound has been carried out. Calculated enthalpies of formation are in very good agreement with the experimental value. PMID- 22506925 TI - Understanding the metal-directed growth of single-crystal M-TCNQF4 organic nanowires with time-resolved, in situ X-ray diffraction and first-principles theoretical studies. AB - The deterministic growth of oriented crystalline organic nanowires (CONs) from the vapor-solid chemical reaction (VSCR) between small-molecule reactants and metal nanoparticles has been demonstrated in several studies to date; however, the growth mechanism has not yet been conclusively understood. Here, the VSCR growth of M-TCNQF(4) (where M is Cu- or Ag-) nanowires is investigated both experimentally and theoretically with time-resolved, in situ X-ray diffraction (XRD) and first-principles atomistic calculations, respectively, to understand how metals (M) direct the assembly of small molecules into CONs, and what determines the selectivity of a metal for an organic vapor reactant in the growth process. Analysis of the real-time growth kinetics data using a modified Avrami model indicates that the formation of CONs from VSCR follows a one-dimensional ion diffusion-controlled tip growth mechanism wherein metal ions diffuse from a metal film through the nanowire to its tip where they react with small molecules to continue growth. The experimental data and theoretical calculations indicate that the selectivity of different metals to induce nanowire growth depends strongly upon effective charge transfer between the organic molecules and the metal. Specifically, the experimental finding that Cu ions can exchange and replace Ag ions in Ag-TCNQF(4) to form Cu-TCNQF(4) nanowires is explained by the significantly stronger chemical bond between Cu and TCNQF(4) molecules than for Ag, due to the strong electronic contribution of Cu d-orbitals near the Fermi level. Understanding how to control the VSCR growth process may enable the synthesis of novel organic nanowires with axial or coaxial p/n junctions for organic nanoelectronics and solar energy harvesting. PMID- 22506926 TI - From highly monodisperse indium and indium tin colloidal nanocrystals to self assembled indium tin oxide nanoelectrodes. AB - Indium tin oxide (ITO) nanopatterned electrodes are prepared from colloidal solutions as a material saving alternative to the industrial vapor phase deposition and top down processing. For that purpose highly monodisperse In(1 x)Sn(x) (x < 0.1) colloidal nanocrystals (NCs) are synthesized with accurate size and composition control. The outstanding monodispersity of the NCs is evidenced by their self-assembly properties into highly ordered superlattices. Deposition on structured substrates and subsequent treatment in oxygen plasma converts the NC assemblies into transparent electrode patterns with feature sizes down to the diameter of single NCs. The conductivity in these ITO electrodes competes with the best values reported for electrodes from ITO nanoparticle inks. PMID- 22506927 TI - Ectopic adrenocortical tissue: an incidental finding during inguinal surgery in children. AB - Adrenal rests are usually unrecognized during operation, and the incidence of ectopic adrenal cortical tissue in pediatric patients during inguinal surgery procedures is unknown. We performed 3028 groin surgical explorations in 2680 patients aged 1 month to 17 years. Ectopic adrenal tissue was found in 69 inguinal operations (2.2%): 37 during 1.524 orchiopexy (2.4%), 23 during 1.115 herniectomy (2.0%), and 9 during 389 hydrocoela operation (2.3%). Statistically there were no significant differences among those three groups. No adrenal rests were detected in females. Although a few reported cases with hormonal activity of ectopic adrenocortical tissue (EACT), the recommendation is to remove them if found. PMID- 22506928 TI - Usefulness of OCT4/3 immunostain in pediatric malignant germ cell tumors. AB - Octamer4/3 is a POU transcription factor that regulates pluripotentiality in embryonic stem and germ cells and primordial germ cells. When expressed in post embryonic life, Octamer4/3 may lead to malignant germ cell tumors (GCT). Thirty samples were selected for this study (26 GCT samples and 4 cryptorchid testes samples) and 16 non-GCT were used as controls. Samples were stained with an anti Octamer4/3 antibody. All cases of GCT were positive for Octamer4/3, and the non GCT were negative. This article focuses on pediatric populations where we found that Octamer4/3 immunostaining is a useful diagnostic tool in undifferentiated pediatric tumors. PMID- 22506929 TI - Bilateral mesenchymal hamartoma of the chest wall in an infant boy. AB - Mesenchymal chest wall hamartoma is an extremely rare tumor striking neonates and infants. Histologically, the tumor is composed of islands of hyaline cartilage intermixed with mesenchymal-like stroma and hemorrhagic cysts. We present a case of a congenital bilateral mesenchymal chest wall hamartoma (MCWH) in an infant boy. This extremely rare benign entity may be misdiagnosed as malignant tumor and shares features with another tumor of childhood-fibrocartilagenous mesenchymoma of bone. PMID- 22506930 TI - An Arthrobacter spp. bacteremia leading to fetal death and maternal disseminated intravascular coagulation. AB - A 34-year-old parous woman developed high fever and threatened preterm labor after a 1-day trip, for which she was receiving prenatal care at a hospital. Three days after onset, at 24 4/7 weeks of gestation, she was transferred to our hospital in an emergency. Soon after the woman's arrival at our hospital, the infant was spontaneously stillborn via a transvaginal delivery. Laboratory tests revealed severe maternal disseminated intravascular coagulation with renal and liver insufficiency. Histopathologic examination of the placenta revealed vast fibrin deposition and remarkable neutrophilic infiltration in the intervillous space, suggesting a rare bacterial infection caused by Arthrobacter spp. The bacteria were predominantly detected in the placenta and maternal blood serum by common bacterial 16S rRNA sequencing after polymerase chain reaction amplification. We report the first case, to our knowledge, of bacteremia with Arthrobacter spp., which may lead to maternal disseminated intravascular coagulation and intrauterine fetal death. PMID- 22506931 TI - Twin pregnancies with single fetal death: analysis of 38 cases. AB - The objective of this study is to evaluate fetal and maternal outcomes of twin pregnancies with intrauterine single fetal death. In 13 cases, intrauterine death of one fetus was found during the first trimester; in 25 cases, it was found after the first trimester. Obstetric complications and fibrinogen levels were compared. There were no significant differences in the number of preterm delivery, preeclampsia, and intrauterine growth restriction and there were significant differences in gestational age at delivery and birth weight between groups. Coagulation disorders did not occur. The risk for adverse pregnancy outcomes with a single fetal death during and after the first trimester is similar. PMID- 22506932 TI - Exercise-training reduced blood pressure and improve placental vascularization in pregnant spontaneously hypertensive rats--pilot study. AB - Assess the effects of exercise-training on resting arterial pressure and heart rate, placental fetuses morphologic alterations in pregnant spontaneously hypertensive rats (SHRs).Twenty SHRs and their respective control normotensive rats (WKY) were submitted or not to a swimming protocol during 9 weeks, resulting in four pregnant experimental groups: sedentary hypertensive (PSH), trained hypertensive (PTH), sedentary normotensive (PSN), and trained normotensive (PTN). Exercise-training by swimming attenuates arterial pressure in pregnant SHRs, and can contribute to an increase in the length of fetuses and the percentage of the vessels in the placenta. PMID- 22506933 TI - Prune-belly syndrome: case series and review of the literature regarding early prenatal diagnosis, epidemiology, genetic factors, treatment, and prognosis. AB - Prune-belly syndrome (PBS) is a rare congenital syndrome characterized by deficient abdominal muscles, urinary tract malformation, and in males, cryptorchidism and has an estimated incidence of 1 in 35,000 to 1 in 50,000 live births. The syndrome might be due to severe bladder outlet obstruction or to abdominal muscle deficiency secondary to a migrational defect of the lateral mesoblast between weeks 6 and 7 of pregnancy. The current review of the medical record reports a special focus on epidemiology, genetic factors, early prenatal diagnosis clusters, treatment, and prognosis of PBS. PMID- 22506934 TI - Occlusal dysesthesia: a qualitative systematic review of the epidemiology, aetiology and management. AB - Occlusal dysesthesia refers to a persistent complaint of uncomfortable bite sensation with no obvious occlusal discrepancy. This systematic review aimed to draw a picture of such patients, to present an agreement of previously reported diagnostic criteria and to analyse the evidence level of the recommended management approaches. An electronic search for all relevant reports on occlusal dysesthesia was thoroughly performed based on previous nomenclatures (e.g. phantom bite, occlusal hyperawareness) in PubMed and The Cochrane Library in July, 2011. A total of 84 reports were matched, among which only 11 studies were included after a two-step (abstract and detailed full-text revision) screening process. Additionally, a thorough manual review of reference lists of the included reports enabled the inclusion of two additional studies. Data analysis revealed that 37 occlusal dysesthesia patients presented a mean age of 51.7 +/- 10.6 years and were predominantly women (male/female: 1/5.1) with symptom duration of more than 6 years (average: 6.3 +/- 7.5 years) and with concomitant psychological disturbances (e.g. mood disorders, somatoform disorders, personality disorders). Only four authors presented diagnostic criteria for occlusal dysesthesia, which served as the basis for an agreement in the diagnostic criteria. Treatment approaches included psychotherapy, cognitive/behaviour therapy, splint therapy and prescription of anti-depressants or anti-anxiety drugs. Classification of evidence level of management approaches, however, revealed that most of them were expert opinions with single- or multiple case report(s). Future studies are necessary for a deeper understanding of the mechanisms behind the occlusal dysesthesia symptoms, and consequently, for improvements in evidence-based management approaches. PMID- 22506935 TI - Production of gas phase NO2 and halogens from the photochemical oxidation of aqueous mixtures of sea salt and nitrate ions at room temperature. AB - Nitrate and halide ions coexist in a number of environmental systems, including sea salt particles, the Arctic snowpack, and alkaline dry lakes. However, little is known about potential synergisms between halide and nitrate ions. The effect of sea salt on NO(3)(-) photochemistry at 311 nm was investigated at 298 K using thin films of deliquesced NaNO(3)-synthetic sea salt mixtures. Gas phase NO(2), NO, and halogen products were measured as a function of photolysis time using NO(y) chemiluminescence and atmospheric pressure ionization mass spectrometry (API-MS). The production of NO(2) increases with the halide-to-nitrate ratio, and is similar to that for mixtures of NaCl with NaNO(3). Gas phase halogen production also increased with the halide-to-nitrate ratio, consistent with NO(3)(-) photolysis yielding OH which oxidizes halide ions in the film. Yields of gas phase halogens and NO were strongly dependent on the acidity of the solution, while that of NO(2) was not. An additional halogen formation mechanism in the dark involving molecular HNO(3) is proposed that may be important in other systems such as reactions on surfaces. These studies show that the yield of Br(2) relative to NO(2) during photolysis of halide-nitrate mixtures could be as high as 35% under some atmospheric conditions. PMID- 22506936 TI - Statins and glycaemic control--a cause for concern? PMID- 22506937 TI - siRNA-mediated knock-down of COX-2 in melanocytes suppresses melanogenesis. AB - Cyclooxygenase-2 (COX-2) is an enzyme induced in response to multiple mitogenic and inflammatory stimuli, including UV light. UV-induced COX-2 expression induces production of prostaglandin E2 (PGE2) in keratinocytes, which mediates inflammation and cell proliferation. Until recently, studies regarding COX-2 and PGE2 in the skin have focused on keratinocytes and skin cancer and the effect of PGs produced by keratinocytes on melanocytes. However, the effects of COX-2 itself or COX-2 inhibitors on melanogenesis are not well known. Therefore, to establish the role of COX-2 in melanogenesis, we investigated the effects of knock-down of COX-2 in melanocytes on melanin production and the expression of melanogenic molecules through silencing of COX-2 expression with COX-2 short interfering RNA (siRNA). COX-2 knock-down in melanocytes decreased the expressions of tyrosinase, TRP-1, TRP-2, gp100 and MITF and also reduced tyrosinase enzyme activity. Furthermore, COX-2 siRNA-transfected melanocytes showed markedly reduced alpha-melanocyte stimulating hormone (alpha-MSH)-induced melanin production. In addition, alpha-MSH-induced COX-2 expression in both scrambled siRNA-transfected and COX-2 siRNA-transfected melanocytes was greater than alpha-MSH-untreated cells. Our results suggest that COX-2 might be a candidate target for the development of anti-melanogenic agents and alpha-MSH induced pigmentation could be closely associated with COX-2 expression. COX-2 inhibitors might therefore be of particular use in whitening cosmetics for hyperpigmentation disorders such as melasma, postinflammatory hyperpigmentation and solar lentigo. PMID- 22506939 TI - Late-onset familial amyloid polyneuropathy in Japan. AB - Transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) is the most common form of FAP. We compared the clinicopathological features and natural history of late-onset FAP ATTR Val30Met cases from non endemic areas of Japan with early-onset cases from endemic foci. The characteristics of early-onset cases from endemic foci of Japan included the presence of sensory dissociation and marked autonomic dysfunction associated with a predominant loss of small-diameter myelinated and unmyelinated nerve fibers. These characteristics were not common in the late-onset cases from non-endemic areas. The distribution and characteristics of amyloid deposits in late-onset cases were similar to those of senile systemic amyloidosis with wild-type TTR deposition. The causal mechanism of differences between the early- and late-onset forms of FAP with the same mutation in the TTR gene has not yet been determined. PMID- 22506938 TI - Oral salmon calcitonin attenuates hyperglycaemia and preserves pancreatic beta cell area and function in Zucker diabetic fatty rats. AB - BACKGROUND AND PURPOSE: Oral salmon calcitonin (sCT), a dual-action amylin and calcitonin receptor agonist, improved glucose homeostasis in diet-induced obese rats. Here, we have evaluated the anti-diabetic efficacy of oral sCT using parameters of glycaemic control and beta-cell morphology in male Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. EXPERIMENTAL APPROACH: Male ZDF rats were treated with oral sCT (0.5, 1.0 or 2 mg.kg(-1) ) or oral vehicle twice daily from age 8 to 18 weeks. Zucker lean rats served as control group. Fasting and non-fasted blood glucose, glycosylated haemoglobin (HbA1c) and levels of pancreas and incretin hormones were determined. Oral glucose tolerance test and i.p. glucose tolerance test were compared, and beta-cell area and function were evaluated. KEY RESULTS: Oral sCT treatment dose-dependently attenuated fasting and non-fasted hyperglycaemia during the intervention period. At the end of the study period, oral sCT treatment by dose decreased diabetic hyperglycaemia by ~9 mM and reduced HbA1c levels by 1.7%. Furthermore, a pronounced reduction in glucose excursions was dose-dependently observed for oral sCT treatment during oral glucose tolerance test. In addition, oral sCT treatment sustained hyperinsulinaemia and attenuated hyperglucagonaemia and hypersecretion of total glucagon-like peptide-1 predominantly in the basal state. Lastly, oral sCT treatment dose-dependently improved pancreatic beta-cell function and beta-cell area at study end. CONCLUSIONS AND IMPLICATIONS: Oral sCT attenuated diabetic hyperglycaemia in male ZDF rats by improving postprandial glycaemic control, exerting an insulinotropic and glucagonostatic action in the basal state and by preserving pancreatic beta-cell function and beta-cell area. PMID- 22506940 TI - Efficacy of patient-controlled analgesia for patients with acute abdominal pain in the emergency department: a randomized trial. AB - OBJECTIVES: The objective was to assess the efficacy of patient-controlled analgesia (PCA) in the emergency department (ED) and to compare two PCA dosing regimens. METHODS: A randomized controlled trial with three treatment arms was performed in an urban ED. A convenience sample of ED patients ages 18 to 65 years with abdominal pain of 7 days or less duration requiring intravenous (IV) opioid analgesia was enrolled between April 2009 and June 2010. All patients received an initial dose of 0.1 mg/kg IV morphine followed by physician-managed analgesia as needed. Patients in the PCA arms also received IV morphine with on-demand doses of 1 or 1.5 mg, with a 6-minute lockout between doses. Pain intensity was rated by patients on an 11-point numeric rating scale (NRS). Satisfaction with pain treatment, desire for the same treatment in the future, and need for additional analgesia were assessed at study end. Adverse events (O(2) sat < 92%, respiratory rate [RR] < 10/min, systolic blood pressure [sBP] < 90 mm Hg, and naloxone use) were counted. One-way analysis of variance was used to test the difference among groups in short-term pain relief, as assessed by mean change in NRS pain intensity from baseline to 30 minutes and pain over the entire 2-hour study period measured by area under the curve (AUC) of NRS pain ratings. A post hoc hierarchical linear model was used to test the observed difference in NRS between the groups between 30 and 120 minutes. RESULTS: A total of 211 patients were enrolled. A sharp, nearly identical decline in mean NRS scores occurred from baseline to 30 minutes in the three groups (p = 0.82). Between 30 and 120 minutes, there was little further decline in the non-PCA NRS scores, while both PCA groups continued to decline (p = 0.004). The net treatment effect over the entire 2 hours was smallest in the non-PCA group and largest in the group receiving 1.5 mg of morphine (p = 0.06). The mean decline in pain from baseline to 120 minutes postbaseline in both PCA groups was 1.4 NRS units (95% confidence interval [CI] = 0.3 to 2.4) greater than the decline in patients treated without PCA. More patients in the PCA arms reported satisfaction, wanting the same pain management in the future, and not wanting further analgesics at 120 minutes than patients who did not receive PCA. There were no clinically or statistically significant differences in any outcomes between the two PCA groups. One PCA patient had a transient oxygen saturation of 88% after the initial bolus only, and one non-PCA patient had a brief drop in sBP to 87 mm Hg. CONCLUSIONS: This study provides support for efficacy of PCA when applied to the ED setting. Future studies designed to assess implementation of this modality in the context of conditions of actual ED staffing and competing patient demands are warranted. PMID- 22506941 TI - Epidemiology of 6.6 million knee injuries presenting to United States emergency departments from 1999 through 2008. AB - BACKGROUND: While knee injuries are treated by a wide range of clinicians, patients with knee injuries frequently present to emergency departments (EDs). The knee is the most commonly injured joint by adolescent athletes with an estimated 2.5 million sports-related injuries presenting to EDs annually. OBJECTIVES: The objective was to examine the epidemiology of knee injuries presenting to EDs in the United States from 1999 through 2008. METHODS: The Consumer Product Safety Commission National Electronic Injury Surveillance System database (NEISS) was used to examine causes of knee injuries treated in U.S. EDs from 1999 through 2008. RESULTS: An estimated 6,664,324 knee injuries presented to U.S. EDs from 1999 through 2008, for a rate of 2.29 knee injuries per 1,000 population. Those 15 to 24 years of age had the highest injury rate (3.83), while children younger than 5 years had the lowest rate (0.55). The most common diagnoses were strains and sprains (42.1%), contusions and abrasions (27.1%), and lacerations and punctures (10.5%). The most common general product categories causing injury were sports and recreation (49.3%), home structures (30.2%), and home furnishings (13.6%). Several sex and age group differences were identified. For example, males sustained a higher proportion of basketball-related injuries (11.1%) than females (3.6%; injury proportion ratio [IPR] = 3.11, 95% confidence interval [CI] = 2.79 to 3.46, p < 0.001). Additionally, individuals 65 years and older sustained a higher proportion of injury due to stairs, ramps, landings, and floors (42.0%), compared to all other ages (20.1%; IPR = 2.09, 95% CI = 1.95 to 2.23, p < 0.001). CONCLUSIONS: Rates and patterns of knee injuries vary by sex and age. Although knee injuries will likely continue to occur most frequently among youth and young adult athletes, anticipating and responding to trends such as an increase in the incidence of knee injuries among adult and senior patients will enable clinicians to better anticipate caseloads, allocate resources, and determine best practices for diagnosis and treatment of knee injuries in different age groups. PMID- 22506942 TI - Long-term follow-up after voluntary human immunodeficiency virus/sexually transmitted infection counseling, point-of-service testing, and referral to substance abuse treatment from the emergency department. AB - OBJECTIVES: Public health initiatives have lowered human immunodeficiency virus (HIV) transmission risk associated with injection drug use in the United States, making sexual risk behaviors a greater source of transmission. Strategies are therefore needed to reduce these risk behaviors among all emergency department (ED) patients who use drugs, regardless of route of administration. Although recent articles have focused on the opportunity for early HIV detection and treatment through an array of ED screening and testing strategies, the effect of voluntary HIV testing and brief counseling (VT/C) on the sexual behaviors of out of-treatment drug users over time has not yet been reported. METHODS: From November 2004 to May 2008, the study screened 46,208 urban ED patients aged 18 to 54 years; 2,148 (4.6%) reported cocaine or heroin use within 30 days, 1,538 met eligibility criteria (Drug Abuse Severity Test [DAST] scores >=3 and were either English- or Spanish-speaking), and 1,030 were enrolled. These data were obtained in the course of a randomized, controlled trial (Project SAFE) of a brief motivational intervention focused on reducing risky sexual behaviors. Although the intervention itself did not demonstrate any differential effect on the number or percentage of unprotected sexual acts, both control and intervention group participants received baseline VT/C and referral for drug treatment as part of the study protocol. This study is a report of a secondary analysis of cohort data to describe changes in sexual behaviors over time among drug users after the VT/C and referral. RESULTS: The mean (+/-SD) age of enrollees was 35.8 (+/-8.4) years; 67% were male, 39% were non-Hispanic black or African American, 41% were white non-Hispanic, and 19% were Hispanic. Half injected drugs, and 53% met criteria for posttraumatic stress disorder (PTSD). At baseline testing, 8.8% were HIV positive on enzyme-linked immunosorbent assay. Follow-ups were conducted at 6 and 12 months, with an attrition rate of 22%. Known HIV-positive patients accounted for 84 of 1,030 cases (8.1%), and 13 new cases were discovered: 7 of 946 at were discovered at the baseline contact (0.74%), 2 of 655 were discovered at 6 months (0.3%), and 4 of 706 (0.57%) were discovered at the 12-month contact. Twelve of the 13 returned for confirmatory testing and were actively enrolled in our infectious disease clinic. For all partners, there was a reduction in the percentage of unprotected sex acts over time (p < 0.0001), with decreases at 6 months versus baseline (odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.60 to 0.83), sustained at 12 months versus baseline (OR = 0.69, 95% CI = 0.58 to 0.82). For the outcome of percentage of sex acts while high, there was also a significant reduction over time (p < 0.0001), with a drop-off at 6 months versus baseline (OR = 0.31, 95% CI = 0.25 to 0.37) that was sustained at 12 months (OR vs. baseline 0.25, 95% CI = 0.20 to 0.30). In an adjusted model, male sex, older age, and HIV positivity predicted significant declines over time in the likelihood of unprotected sexual acts. Older age and higher baseline drug severity predicted significant decreases over time in the likelihood of sex acts while high. CONCLUSIONS: Voluntary testing and counseling for HIV or sexually transmitted infections, accompanied by referral to drug treatment, for this population of ED cocaine and heroin users was associated with reduction in unprotected sex acts and fewer sex acts while high. PMID- 22506943 TI - Are patients with longer emergency department wait times less likely to consent to research? AB - OBJECTIVES: There are unique challenges to enrolling patients in emergency department (ED) clinical research studies, including the time-sensitive nature of emergency conditions, the acute care environment, and the lack of an established relationship with patients. Prolonged ED wait times have been associated with a variety of adverse effects on patient care. The objective of this study was to assess the effect of ED wait times on patient participation in ED clinical research. The hypothesis was that increased ED wait times would be associated with reduced ED clinical research consent rates. METHODS: This was a retrospective cohort study of all patients eligible for two diagnostic clinical research studies from January 1, 2008, through December 31, 2008, in an urban academic ED. Sex, age, race, study eligibility, and research consent decisions were recorded by trained study personnel. The wait times to registration and to be seen by a physician were obtained from administrative databases and compared between consenters and nonconsenters. An analysis of association between patient wait times for the outcome of consent to participate was performed using a multivariate logistic regression model. RESULTS: A total of 903 patients were eligible for enrollment and were asked for consent. Overall, 589 eligible patients (65%) gave consent to research participation. The consent rates did not change when patients were stratified by the highest and lowest quartile wait times for both time from arrival to registration (68% vs. 65%, p = 0.35) and time to be seen by a physician (65% vs. 66%, p = 0.58). After adjusting for patient demographics (age, race, and sex) and study, there was still no relationship between wait times and consent (p > 0.4 for both wait times). Furthermore, median time from arrival to registration did not differ between those who consented to participate (15 minutes; interquartile range [IQR] = 9 to 36 minutes) versus those who did not (15.5 minutes; IQR = 10 to 39 minutes; p = 0.80; odds ratio [OR] = 1.00, 95% confidence interval [CI] = 0.99 to 1.01). Similarly, there was no difference in the median time to be seen by a physician between those who consented (25 minutes; IQR = 15 to 55 minutes) versus those who did not (25 minutes; IQR = 15 to 56 minutes; p = 0.70; OR = 1.00, 95% CI = 0.99 to 1.01). CONCLUSIONS: Regardless of wait times, nearly two-thirds of eligible patients were willing to consent to diagnostic research studies in the ED. These findings suggest that effective enrollment in clinical research is possible in the ED, despite challenges with prolonged wait times. PMID- 22506944 TI - The "Refrige-a-RAT-or": an accurate, inexpensive, and clinically relevant small animal model of therapeutic hypothermia. AB - BACKGROUND: Physical and molecular mechanisms for the neuroprotective effect of therapeutic hypothermia are not completely understood, and new therapeutic applications incorporating hypothermia remain to be developed and tested. Clinically relevant animal models of therapeutic hypothermia are not well established or consistent. OBJECTIVES: The objective was to develop and test an inexpensive small animal therapeutic hypothermia system that models those in widespread clinical use and verify that such a system confers neuroprotection in a rat model of global brain ischemia. METHODS: A water-cooled extracorporeal system and attendant anesthesia/sedation protocol were developed and tested. In Stage 1, animals were instrumented for brain, temporalis, and rectal temperature monitoring, and the system was tested for its effect on temperature and hemodynamics. In Stage 2, animals were instrumented for rectal temperature only, subjected to global brain ischemia by two-vessel occlusion and hypotension for 8 minutes, and given either sham therapy (37 degrees C) or hypothermia (32 degrees C) for 4 hours. Viable CA1 neurons were counted at 7 days. RESULTS: The system was well tolerated, provided exquisite control of animal core and brain temperatures, and conferred robust neuroprotection at 7 days. The median and interquartile ranges (IQRs) of viable neurons per 300-MUm field were 130 (IQR = 128 to 135) for sham control, 19 (IQR = 15 to 30) for untreated ischemic animals, and 101 (IQR = 94 to 113) for ischemic animals treated with hypothermia (p < 0.05 for comparison between all groups). CONCLUSIONS: Like human protocols, this model incorporates sedation and analgesia, results in robust neuroprotection, is well tolerated, and offers exquisite temperature control. The system is noninvasive and inexpensive and offers a model that is similar to methods used in clinical practice. This system will be of interest to investigators using small animal models to examine neuroprotective mechanisms of hypothermia and translational strategies that combine hypothermia with targeted pharmacotherapy. PMID- 22506946 TI - Feasibility of percutaneous vagus nerve stimulation for the treatment of acute asthma exacerbations. AB - OBJECTIVES: This study assessed the feasibility of an investigational vagus nerve stimulation (VNS) device for treating acute asthma exacerbations in patients not responding to at least 1 hour of initial standard care therapy. METHODS: This was a prospective, nonrandomized study of patients treated in the ED for moderate to severe acute asthma (forced expiratory volume in 1 second [FEV(1)] 25% to 70% of predicted). Treatment entailed percutaneous placement of an electrode near the right carotid sheath and 60 minutes of VNS and continued standard care. VNS voltage was adjusted to perceived improvement, muscle twitching, or adverse events (AEs). All AEs, vital signs, FEV(1), perceived work of breathing (WOB), and final disposition were recorded. RESULTS: Twenty-five subjects were enrolled. There were no serious AEs and no significant changes in vital signs. No subject required terminating VNS. One patient had minor bleeding from the procedure, and one had a hematoma and withdrew prior to VNS. AEs related to VNS were temporary and included cough (1 of 24), swallowing difficulty (2 of 24), voice change (2 of 24), and muscle twitching (14 of 24). These resolved when VNS ended. The FEV(1) improved at 15 minutes (median = 15.8%, 95% confidence interval [CI] = 9.3% to 22.4%), 30 minutes (median = 21.3%, 95% CI = 8.1% to 36.5%), and 60 minutes (median = 27.5%, 95% CI = 11.3% to 43.5%). WOB improved at 15 minutes (median = 53.9%, 95% CI = 33.7% to 73.9%), 30 minutes (median = 69.1%, 95% CI = 56.4% to 81.8%), and 60 minutes (median = 81.0%, 95% CI = 68.5% to 93.5%). CONCLUSIONS: Percutaneous VNS did not result in serious AEs and was associated with improvements in FEV(1) and perceived dyspnea. Percutaneous VNS appears to be feasible for use in the treatment of moderate to severe acute asthma in patients unresponsive to initial standard care treatment. PMID- 22506945 TI - The Emergency Department Action in Smoking Cessation (EDASC) trial: impact on delivery of smoking cessation counseling. AB - OBJECTIVES: The focus on acute care, time pressure, and lack of resources hamper the delivery of smoking cessation interventions in the emergency department (ED). The aim of this study was to 1) determine the effect of an emergency nurse initiated intervention on delivery of smoking cessation counseling based on the 5As framework (ask-advise-assess-assist-arrange) and 2) assess ED nurses' and physicians' perceptions of smoking cessation counseling. METHODS: The authors conducted a pre-post trial in 789 adult smokers (five or more cigarettes/day) who presented to two EDs. The intervention focused on improving delivery of the 5As by ED nurses and physicians and included face-to-face training and an online tutorial, use of a charting/reminder tool, fax referral of motivated smokers to the state tobacco quitline for proactive telephone counseling, and group feedback to ED staff. To assess ED performance of cessation counseling, a telephone interview of subjects was conducted shortly after the ED visit. Nurses' and physicians' self-efficacy, role satisfaction, and attitudes toward smoking cessation counseling were assessed by survey. Multivariable logistic regression was used to assess the effect of the intervention on performance of the 5As, while adjusting for key covariates. RESULTS: Of 650 smokers who completed the post-ED interview, a greater proportion had been asked about smoking by an ED nurse (68% vs. 53%, adjusted odds ratio [OR] = 2.0, 95% confidence interval [CI] = 1.3 to 2.9), assessed for willingness to quit (31% vs. 9%, adjusted OR= 4.9, 95% CI = 2.9 to 7.9), and assisted in quitting (23% vs. 6%, adjusted OR = 5.1, 95% CI = 2.7 to 9.5) and had arrangements for follow-up cessation counseling (7% vs. 1%, adjusted OR = 7.1, 95% CI = 2.3 to 21) during the intervention compared to the baseline period. A similar increase was observed for emergency physicians (EPs). ED nurses' self-efficacy and role satisfaction in cessation counseling significantly improved following the intervention; however, there was no change in "pros" and "cons" attitudes toward smoking cessation in either ED nurses or physicians. CONCLUSIONS: Emergency department nurses and physicians can effectively deliver smoking cessation counseling to smokers in a time-efficient manner. This trial also provides empirical support for expert recommendations that call for nursing staff to play a larger role in delivering public health interventions in the ED. PMID- 22506947 TI - Adult emergency department patients with sickle cell pain crisis: results from a quality improvement learning collaborative model to improve analgesic management. AB - OBJECTIVES: The aims of this study were to 1) estimate differences in pain management process and patient-reported outcomes, pre- and postimplementation of analgesic protocols for adults with sickle cell disease (SCD), and 2) examine the effects of site and visit frequency on changes in pain scores and time to analgesic. METHODS: A multicenter, prospective, longitudinal study enrolled patients from three academic medical centers between October 2007 and September 2009. All ED patients 18 years or older with a chief complaint of a sickle cell pain episode were enrolled. Sites formed a SCD quality improvement (QI) team and implemented standard nurse-initiated emergency department (ED) analgesic protocols; outcomes were compared between study periods defined as pre- and postimplementation of protocols. Medical record review was conducted to measure time to administration of initial analgesic, opioids used, route of opioid administration, the change in pain scores from arrival to discharge (negative numbers reflect a decrease in pain scores), and the number of ED visits per individual patient during the study period at each site. On day 7 after the ED visit, a follow-up phone interview was conducted. Patients were queried about their ED pain management using a scale from 1 to 10 (1 = outstanding, 10 = worst). Descriptive statistics are used to report the results. Ordinary least squares regression models were constructed to measure the effect of time period, site, and number of visits per patient on change in pain score. RESULTS: During the study period, 342 unique patients (57% female, mean +/- SD age = 32 +/- 11 years) were enrolled and had a total of 2,934 visits. There was no difference in time to administration of the initial analgesic between study periods. Overall, there was a significant decrease in pain scores from arrival to discharge between the pre- and postintervention study periods: the average difference in arrival to discharge pain scores (cm) was greater during the postimplementation period than during the preintervention period (-4.1 vs. -3.6, t = 2.6, p < 0.01). Site 1 had significant improvement between study periods (mean difference = -0.87, t = 2.63, p < 0.01; F = 14.3, p < 0.01). Patients with few ED visits (one to six annual visits, mean difference = -1.55, t = 2.1, p = 0.04) and those with frequent ED visits (7 to 19 annual visits, mean difference = -1.65, t = 3.52, p < 0.01) had a significant decrease in pain scores compared to patients with very frequent ED visits (>19 visits). There was an overall decrease in the use of morphine sulfate (MS) and increase in the use of hydromorphone (chi(2) = 105.67, p < 0.001) between study periods and a significant increase in the use of oral (PO) and subcutaneous (SC) routes, with a corresponding decrease in the intravenous (IV) route (chi(2) = 13.67, p < 0.001). There were no statistically significant differences in patient-reported satisfaction with the attempt to manage pain in the ED between study periods (p = 0.54). CONCLUSIONS: While the use of a learning collaborative and implementation of nurse-initiated analgesic protocols was not associated with improvement in time to administration of the initial analgesic, improvements in the decrease in the arrival to discharge pain score and increased use of hydromorphone and the SC route were noted in adults with SCD in the ED. PMID- 22506948 TI - Patients who leave without being seen in emergency departments: an analysis of predictive factors and outcomes. AB - OBJECTIVES: The objective was to identify predictive factors and outcomes associated with patients who leave emergency departments (EDs) without being seen in Victoria, Australia. METHODS: This was a retrospective observational study of Victorian ED patient visits between July 1, 2000, and June 30, 2005, using linked hospital, ED, and death registration data. Index ED visits were identified for patients who left without being seen (LWBS) and for those who completed ED treatment and were discharged home. Statistical analyses included a general description and univariate analysis of patient, ED visit, temporal, and hospital level factors. Logistic regression models were developed to assess risk factors associated with LWBS status compared to patients who completed treatment, to assess 48 hour re-presentations to ED; 48-hour hospital admissions; and 2-,7-, and 30-day mortality among those who LWBS compared to those who completed treatment. Adjusted odds ratios (ORs) and 99% confidence intervals (CIs) are presented. RESULTS: There were 239,305 LWBS episodes, for 205,500 patients over the 5-year period. Independent factors associated with LWBS patients in comparison to those who completed treatment include patients who are younger (15 to 24 years, OR = 2.46, 99% CI = 2.37 to 2.56), male (OR = 1.07, 99% CI = 1.05 to 1.08), of Australian indigenous background (OR = 1.63, 99% CI = 1.53 to 1.73), of non-English-speaking background (OR = 1.08, 99% CI = 1.06 to 1.10), noncompensable status (OR = 1.73, 99% CI = 1.68 to 1.79), self-referring (OR = 1.46, 99% CI = 1.43 to 1.49), nonassisted arrival mode (OR = 1.35, 99% CI = 1.30 to 1.40), and those with a hospital admission in the 12 months before the ED presentation (OR = 1.53, 99% CI = 1.51 to 1.55). Patients who LWBS had triage categories of lower urgency (nonurgent, OR = 8.21, 99% CI = 8.00 to 8.43), attended during the evening (OR = 1.10, 99% CI = 1.08 to 1.12), on either Sunday (OR = 1.20, 99% CI = 1.18 to 1.23) or Monday (OR = 1.20, 99% CI = 1.17 to 1.23), in winter (OR = 1.14, 99% CI = 1.12 to 1.16), with higher rates occurring in higher volume EDs (OR = 2.20, 99% CI = 2.15 to 2.26). There was no greater risk of mortality for LWBS patients compared to patients who completed treatment. The risk of hospital admission within 48 hours of discharge was lower for LWBS patients (OR = 0.60, 99% CI = 0.58 to 0.62); however, ED re-presentation risk was higher (OR = 1.63, 99% CI = 1.60 to 1.67). CONCLUSIONS: Patients who leave EDs in Victoria, Australia, without being seen are at lower risk of hospital admission and at no greater risk of mortality, but are at higher risk of re-presenting to an ED compared to patients who complete treatment and are discharged home. PMID- 22506950 TI - Factors that influence medical student selection of an emergency medicine residency program: implications for training programs. AB - OBJECTIVES: An understanding of student decision-making when selecting an emergency medicine (EM) training program is essential for program directors as they enter interview season. To build upon preexisting knowledge, a survey was created to identify and prioritize the factors influencing candidate decision making of U.S. medical graduates. METHODS: This was a cross-sectional, multi institutional study that anonymously surveyed U.S. allopathic applicants to EM training programs. It took place in the 3-week period between the 2011 National Residency Matching Program (NRMP) rank list submission deadline and the announcement of match results. RESULTS: Of 1,525 invitations to participate, 870 candidates (57%) completed the survey. Overall, 96% of respondents stated that both geographic location and individual program characteristics were important to decision-making, with approximately equal numbers favoring location when compared to those who favored program characteristics. The most important factors in this regard were preference for a particular geographic location (74.9%, 95% confidence interval [CI] = 72% to 78%) and to be close to spouse, significant other, or family (59.7%, 95% CI = 56% to 63%). Factors pertaining to geographic location tend to be out of the control of the program leadership. The most important program factors include the interview experience (48.9%, 95% CI = 46% to 52%), personal experience with the residents (48.5%, 95% CI = 45% to 52%), and academic reputation (44.9%, 95% CI = 42% to 48%). Unlike location, individual program factors are often either directly or somewhat under the control of the program leadership. Several other factors were ranked as the most important factor a disproportionate number of times, including a rotation in that emergency department (ED), orientation (academic vs. community), and duration of training (3-year vs. 4-year programs). For a subset of applicants, these factors had particular importance in overall decision-making. CONCLUSIONS: The vast majority of applicants to EM residency programs employed a balance of geographic location factors with individual program factors in selecting a residency program. Specific program characteristics represent the greatest opportunity to maximize the success of the immediate interview experience/season, while others provide potential for strategic planning over time. A working knowledge of these results empowers program directors to make informed decisions while providing an appreciation for the limitations in attracting applicants. PMID- 22506951 TI - The ethics of health care reform: impact on emergency medicine. AB - The recent enactment of the Patient Protection and Affordable Care Act (ACA) of 2010, and the ongoing debate over reform of the U.S. health care system, raise numerous important ethical issues. This article reviews basic provisions of the ACA; examines underlying moral and policy issues in the U.S. health care reform debate; and addresses health care reform's likely effects on access to care, emergency department (ED) crowding, and end-of-life care. The article concludes with several suggested actions that emergency physicians (EPs) should take to contribute to the success of health care reform in America. PMID- 22506949 TI - Implementation of the exception from informed consent regulations in a large multicenter emergency clinical trials network: the RAMPART experience. AB - Clinical trials investigating therapies for acutely and critically ill and injured patients in the earliest phases of treatment often can only be performed under regulations allowing for exception from informed consent (EFIC) for emergency research. Implementation of these regulations in multicenter clinical trials involves special challenges and opportunities. The Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART), the first EFIC trial conducted by the Neurological Emergencies Treatment Trials (NETT) network, combined centralized resources and coordination with retention of local control and flexibility to facilitate compliance with the EFIC regulations. Specific methods used by the NETT included common tools for community consultation and public disclosure, sharing of experiences and knowledge, and reporting of aggregate results. Tracking of community consultation and public disclosure activities and feedback facilitates empirical research on EFIC methods in the network and supports quality improvements for future NETT trials. The NETT model used in RAMPART demonstrates how EFIC may be effectively performed in established clinical trial networks. PMID- 22506953 TI - Controlled trials of transport modality in trauma are feasible. PMID- 22506952 TI - Evaluating the use of existing data sources, probabilistic linkage, and multiple imputation to build population-based injury databases across phases of trauma care. AB - OBJECTIVES: The objective was to evaluate the process of using existing data sources, probabilistic linkage, and multiple imputation to create large population-based injury databases matched to outcomes. METHODS: This was a retrospective cohort study of injured children and adults transported by 94 emergency medical systems (EMS) agencies to 122 hospitals in seven regions of the western United States over a 36-month period (2006 to 2008). All injured patients evaluated by EMS personnel within specific geographic catchment areas were included, regardless of field disposition or outcome. The authors performed probabilistic linkage of EMS records to four hospital and postdischarge data sources (emergency department [ED] data, patient discharge data, trauma registries, and vital statistics files) and then handled missing values using multiple imputation. The authors compare and evaluate matched records, match rates (proportion of matches among eligible patients), and injury outcomes within and across sites. RESULTS: There were 381,719 injured patients evaluated by EMS personnel in the seven regions. Among transported patients, match rates ranged from 14.9% to 87.5% and were directly affected by the availability of hospital data sources and proportion of missing values for key linkage variables. For vital statistics records (1-year mortality), estimated match rates ranged from 88.0% to 98.7%. Use of multiple imputation (compared to complete case analysis) reduced bias for injury outcomes, although sample size, percentage missing, type of variable, and combined-site versus single-site imputation models all affected the resulting estimates and variance. CONCLUSIONS: This project demonstrates the feasibility and describes the process of constructing population-based injury databases across multiple phases of care using existing data sources and commonly available analytic methods. Attention to key linkage variables and decisions for handling missing values can be used to increase match rates between data sources, minimize bias, and preserve sampling design. PMID- 22506960 TI - Robust adaptation and homeostasis by autocatalysis. AB - Robust homeostatic mechanisms are essential for the protection and adaptation of organisms in a changing and challenging environment. Integral feedback is a control-engineering concept that leads to robust, i.e., perturbation-independent, adaptation and homeostatic behavior in the controlled variable. Addressing two component negative feedback loops of a controlled variable A and a controller molecule E, we have shown that integral control is closely related to the presence of zero-order fluxes in the removal of the manipulated variable E. Here we show that autocatalysis is an alternative mechanism to obtain integral control. Although the conservative and marginal stability of the Lotka-Volterra oscillator (LVO) with autocatalysis in both A and E is often considered as a major inadequacy, homeostasis in the average concentrations of both A and E ( and ) is observed. Thus, autocatalysis does not only represent a mere driving force, but may also have regulatory roles. PMID- 22506959 TI - Engaging the hearts and minds of clinicians in outcome measurement - the UK Rehabilitation Outcomes Collaborative approach. AB - PURPOSE: This article explores the rationale for choosing the instruments included within the UK Rehabilitation Outcomes Collaborative (UKROC) data set. Using one specialist neuro-rehabilitation unit as an exemplar service, it describes an approach to engaging the hearts and minds of clinicians in recording the data. KEY MESSAGES AND IMPLICATIONS: Measures included within a national data set for rehabilitation should be psychometrically robust and feasible to use in routine clinical practice; they should also support clinical decision-making so that clinicians actually want to use them. Learning from other international casemix models and benchmarking data sets, the UKROC team has developed a cluster of measures to inform the development of effective and cost-efficient rehabilitation services. These include measures of (1) "needs" for rehabilitation (complexity), (2) inputs provided to meet those needs (nursing and therapy intervention), and (3) outcome, including the attainment of personal goals as well as gains in functional independence. CONCLUSIONS: By integrating the use of the data set measures in everyday clinical practice, we have achieved a very high rate of compliance with data collection. However, staff training and ongoing commitment from senior staff and managers are critical to the maintenance of effort required to provide assurance of data quality in the longer term. PMID- 22506961 TI - Subtyping of Escherichia coli O157:H7 strains isolated from human infections and healthy cattle in Argentina. AB - Shiga toxin-producing Escherichia coli (STEC) cause nonbloody (NBD) and bloody diarrhea (BD), and hemolytic uremic syndrome (HUS). Cattle have been described as their main reservoir. STEC O157:H7 is recognized as the predominant serotype in clinical infections, but much less is known about the dominant subtypes in humans and animals or their genetic relatedness. The aims of this study were to compare the STEC O157 subtypes found in sporadic human infections with those in the bovine reservoir using stx-genotyping, phage typing, and XbaI-pulsed-field gel electrophoresis (PFGE), and correlate the subtypes with the severity of clinical manifestations. The 280 STEC O157:H7 strains collected included in this study were isolated from HUS (n=122), BD (n=69), and NBD (n=30) cases, and healthy carriers (n=5), and from bovines (n=54) in the abattoirs. The stx-genotyping showed that stx2/stx(2c(vh-a)) was predominant in human (76.1%) and in bovine strains (55.5%), whereas the second more important genotype was stx2 (20.8%) in human and stx(2c(vh-a)) (16.7%) in cattle strains. In human strains, PT4 (37.6%), PT49 (24.3%), and PT2 (18.6%) were the most frequent PTs (80.5%). In bovine isolates, PT2 (26%), PT39 (16.7%), and PT4 and PT49 (11.1% each) were predominant. By XbaI-PFGE, all 280 strains yielded 148 patterns with 75% similarity, and 169 strains were grouped in 37 clusters. Identical PT-PFGE-stx profile combinations were detected in strains of both origins: PT4-AREXH01.0011 stx2/stx(2c(vh-a)) (12 humans and one bovine), PT4-AREXH01.0543-stx2/stx(2c(vh a)) (one human and four bovines), PT2-AREXH01.0076-stx2/stx(2c(vh-a)) (one human and four bovines), PT49-AREXH01.0175-stx2/stx(2c(vh-a)) (seven humans and one bovine), and PT49-AREXH01.0022-stx2/stx(2c(vh-a)) (seven humans and one bovine). No correlation was found among the stx-genotypes, the phage type, and the clinical symptoms. PMID- 22506962 TI - Analysis of Campylobacter jejuni whole-genome DNA microarrays: significance of prophage and hypervariable regions for discriminating isolates. AB - Campylobacter is a leading cause of foodborne illness in humans, and improving our understanding of the epidemiology of this organism is essential. The objective of this study was to identify the genes that discriminate isolates of C. jejuni by analysis with whole-genome DNA microarrays. Statistical analyses of whole-genome data from 95 geographically diverse cattle, chicken, and human C. jejuni isolates identified 142 most significant variable genes. Of this total, 125 (88%) belonged to genomic prophage and hypervariable regions. The significance of genomic prophage and hypervariable regions in determining C. jejuni isolate genomic diversity is emphasized by these results. These genes will be useful as biomarkers and components of genotyping systems for C. jejuni to improve our understanding of the epidemiology and population genetics of this major foodborne pathogen. PMID- 22506963 TI - Granule matrix property and rapid "kiss-and-run" exocytosis contribute to the different kinetics of catecholamine release from carotid glomus and adrenal chromaffin cells at matched quantal size. AB - Catecholamine-containing small dense core granules (SDCGs, vesicular diameter of ~100 nm) are prominent in carotid glomus (chemosensory) cells and some neurons, but the release kinetics from individual SDCGs has not been studied in detail. In this study, we compared the amperometric signals from glomus cells with those from adrenal chromaffin cells, which also secrete catecholamine but via large dense core granules (LDCGs, vesicular diameter of ~200-250 nm). When exocytosis was triggered by whole-cell dialysis (which raised the concentration of intracellular Ca(2+) ([Ca(2+)](i)) to ~0.5 umol/L), the proportion of the type of signal that represents a flickering fusion pore was 9-fold higher for glomus cells. Yet, at the same range of quantal size (Q, the total amount of catecholamine that can be released from a granule), the kinetics of every phase of the amperometric spike signals from glomus cells was faster. Our data indicate that the last phenomenon involved at least 2 mechanisms: (i) the granule matrix of glomus cells can supply a higher concentration of free catecholamine during exocytosis; (ii) a modest elevation of [Ca(2+)](i) triggers a form of rapid "kiss and-run" exocytosis, which is very prevalent among glomus SDCGs and leads to incomplete release of their catecholamine content (and underestimation of their Q value). PMID- 22506964 TI - Melatonin affects the temporal pattern of vocal signatures in birds. AB - In humans and other animals, melatonin is involved in the control of circadian biological rhythms. Here, we show that melatonin affects the temporal pattern of behavioral sequences in a noncircadian manner. The zebra finch (Taeniopygia guttata) song and the crow of the Japanese quail (Coturnix japonica) are courtship vocalizations composed of a stereotyped sequence of syllables. The zebra finch song is learned from conspecifics during infancy, whereas the Japanese quail crow develops normally without auditory input. We recorded and analyzed the complete vocal activity of adult birds of both species kept in social isolation for several weeks. In both species, we observed a shortening of signal duration following the transfer from a light-dark (LD) cycle to constant light (LL), a condition known to abolish melatonin production and to disrupt circadian rhythmicity. This effect was reversible because signal duration increased when the photoperiod was returned to the previous LD schedule. We then tested whether this effect was directly related to melatonin by removal of the pineal gland, which is the main production site of circulating melatonin. A shortening of the song duration was observed following pinealectomy in LD. Likewise, melatonin treatment induced changes in the temporal structure of the song. In a song learning experiment, young pinealectomized finches and young finches raised in LL failed to copy the temporal pattern of their tutor's song. Taken together, these results suggest that melatonin is involved in the control of motor timing of noncircadian behavioral sequences through an evolutionary conserved neuroendocrine pathway. PMID- 22506965 TI - A conserved cysteine residue is involved in disulfide bond formation between plant plasma membrane aquaporin monomers. AB - AQPs (aquaporins) are conserved in all kingdoms of life and facilitate the rapid diffusion of water and/or other small solutes across cell membranes. Among the different plant AQPs, PIPs (plasma membrane intrinsic proteins), which fall into two phylogenetic groups, PIP1 and PIP2, play key roles in plant water transport processes. PIPs form tetramers in which each monomer acts as a functional channel. The intermolecular interactions that stabilize PIP oligomer complexes and are responsible for the resistance of PIP dimers to denaturating conditions are not well characterized. In the present study, we identified a highly conserved cysteine residue in loop A of PIP1 and PIP2 proteins and demonstrated by mutagenesis that it is involved in the formation of a disulfide bond between two monomers. Although this cysteine seems not to be involved in regulation of trafficking to the plasma membrane, activity, substrate selectivity or oxidative gating of ZmPIP1s (Zm is Zea mays), ZmPIP2s and hetero-oligomers, it increases oligomer stability under denaturating conditions. In addition, when PIP1 and PIP2 are co-expressed, the loop A cysteine of ZmPIP1;2, but not that of ZmPIP2;5, is involved in the mercury sensitivity of the channels. PMID- 22506966 TI - Inhibition of placenta growth factor with TB-403: a novel antiangiogenic cancer therapy. AB - INTRODUCTION: There is clinical evidence that therapies targeting the vascular endothelial growth factor pathway are effective in delaying cancer progression. However, tumors may be either intrinsically resistant or evolve resistance to such therapies. Hence, there is a need for new therapies targeting angiogenesis. AREAS COVERED: The data are obtained by searching in the PubMed database. The search terms used included antiangiogenic therapy, TB-403 (RO5323441), placenta growth factor (PlGF) and VEGFR-1 (Flt-1). We review preclinical data concerning the function and inhibition of PlGF and summarize data on expression of PlGF in cancer patients. Data from early-phase clinical trials of TB-403 (RO5323441), a monoclonal antibody inhibiting PlGF, are discussed. Future development strategies, therapeutic potentials and limitations of TB-403 are further evaluated. EXPERT OPINION: There are some conflicting data on the function of PlGF and the importance of its role in primary tumor growth. Data from some preclinical models of PlGF inhibition and early-phase clinical trials with TB-403 are, however, promising, although the true potential of the drug is yet to be determined. Further clinical development should be preceded by molecular studies in the context of well-designed preclinical models and/or small translational studies. Future challenges involve identifying predictive biomarkers. PMID- 22506967 TI - Computerized detection and segmentation of mitochondria on electron microscope images. AB - Mitochondrial function plays an important role in the regulation of cellular life and death, including disease states. Disturbance in mitochondrial function and distribution can be accompanied by significant morphological alterations. Electron microscopy tomography (EMT) is a powerful technique to study the 3D structure of mitochondria, but the automatic detection and segmentation of mitochondria in EMT volumes has been challenging due to the presence of subcellular structures and imaging artifacts. Therefore, the interpretation, measurement and analysis of mitochondrial distribution and features have been time consuming, and development of specialized software tools is very important for high-throughput analyses needed to expedite the myriad studies on cellular events. Typically, mitochondrial EMT volumes are segmented manually using special software tools. Automatic contour extraction on large images with multiple mitochondria and many other subcellular structures is still an unaddressed problem. The purpose of this work is to develop computer algorithms to detect and segment both fully and partially seen mitochondria on electron microscopy images. The detection method relies on mitochondria's approximately elliptical shape and double membrane boundary. Initial detection results are first refined using active contours. Then, our seed point selection method automatically selects reliable seed points along the contour, and segmentation is finalized by automatically incorporating a live-wire graph search algorithm between these seed points. In our evaluations on four images containing multiple mitochondria, 52 ellipses are detected among which 42 are true and 10 are false detections. After false ellipses are eliminated manually, 14 out of 15 fully seen mitochondria and 4 out of 7 partially seen mitochondria are successfully detected. When compared with the segmentation of a trained reader, 91% Dice similarity coefficient was achieved with an average 4.9 nm boundary error. PMID- 22506968 TI - Neurological variant of Lemierre's Syndrome with purulent meningitis: a case report and literature review. AB - We report an unusual variant of Lemierre's Syndrome (LS) in a 10-year-old-girl admitted to the intensive care unit for septic shock with meningitis. The primary infection was otitis media. A gram negative bacillus was identified in the direct exam of the purulent ear discharge and the cerebrospinal fluid but cultures were negative. Computerized tomography of the neck revealed a thrombus in the internal jugular vein. Septic shock improved rapidly under supportive treatment. The patient recovered without sequellae after a prolonged duration of parenteral antibiotherapy and hospital stay. Neurologic variants of LS with meningitis, previously reported in the literature, are reviewed. PMID- 22506969 TI - Obstacle avoidance locomotor tasks: adaptation, memory and skill transfer. AB - The aim of this study was to explore the neural basis of adaptation, memory and skill transfer during human stepping over obstacles. Whilst walking on a treadmill, subjects had to perform uni- and bilateral obstacle steps. Acoustic feedback information about foot clearance was provided. Non-noxious electrical stimuli were applied to the right tibial nerve during the mid-stance phase of the right leg, i.e. 'prior' to the right or 'during' the left leg swing over the obstacle. The electromyogram (EMG) responses evoked by these stimuli in arm and leg muscles are known to reflect the neural coordination during normal and obstacle steps. The leading and trailing legs rapidly adapted foot clearance during obstacle steps with small further changes when the same obstacle condition was repeated. This adaptation was associated with a corresponding decrease in arm and leg muscle reflex EMG responses. Arm (but not leg) muscle EMG responses were greater when the stimulus was applied 'during' obstacle crossing by the left leg leading compared with stimulation 'prior' to right leg swing over the obstacle. A corresponding difference existed in arm muscle background EMG. The results indicate that, firstly, the somatosensory information gained by the performance and adaptation of uni- and bilateral obstacle stepping becomes transferred to the trailing leg in a context-specific manner. Secondly, EMG activity in arm and leg muscles parallels biomechanical adaptation of foot clearance. Thirdly, a consistently high EMG activity in the arm muscles during swing over the obstacle is required for equilibrium control. Thus, such a precision locomotor task is achieved by a context-specific, coordinated activation of arm and leg muscles for performance and equilibrium control that includes adaptation, memory and skill transfer. PMID- 22506970 TI - Solution behavior of normal and reverse triblock copolymers (pluronic L44 and 10R5) individually and in binary mixture. AB - Solution properties of pluronics L44 or L [(PEO)(10)(PPO)(23)(PEO)(10)] and 10R5 or R [(PPO)(8)(PEO)(22)(PPO)(8)] were studied individually as well in their binary mixtures in aqueous medium. The critical micelle concentration (CMC), critical micelle temperature, and cloud point (CP) were determined. Ideal and nonideal behaviors of their mixtures in the formation of CMC and CP were observed; the energetics of the studied processes were determined. Spectrophotometry, isothermal titration calorimetry and dynamic light scattering (DLS) methods were used for evaluations. Morphologies of the dispersed L, R, and their mixtures along with their polydispersities were determined from DLS measurements. Atomic force microscopy was also employed. The interfacial properties of L and R were investigated forming Langmuir monolayers in a surface balance. The surface pressures (pi) generated by the compounds were moderate, the area per molecule was higher for R than L. R has shown antibacterial activity against both gram positive and gram negative bacteria whereas L was inactive in this respect. PMID- 22506971 TI - Epigenetic alteration of the dopamine transporter gene in alcohol-dependent patients is associated with age. AB - Chronic alcohol abuse and dependence are associated with dysfunctional dopaminergic neurotransmission in mesocorticolimbic circuits. Genetic and environmental factors have been shown to modulate susceptibility to alcohol dependence, and both may act through epigenetic mechanisms that can modulate gene expression, e.g. DNA methylation at CpG sites. Recent studies have suggested that DNA methylation patterns may change over time. However, few data are available concerning the rate of these changes in specific genes. A recent study found that hypermethylation of the promoter of the dopamine transporter (DAT) gene was positively correlated with alcohol dependence and negatively correlated with alcohol craving. The aim of the present study was to replicate these findings in a larger sample of alcohol-dependent patients and population-based controls matched for age and sex. No difference in methylation level was observed between patients and controls, and no difference in methylation level was observed before and after alcohol withdrawal in patients. However, patients with more severe craving showed a trend towards lower DAT methylation levels (P = 0.07), which is consistent with previous findings. Furthermore, in our overall sample, DAT methylation levels increased with age. Interestingly, a separate analysis of patients suggested that this finding was mainly driven by the patient group. Although the present data do not clarify whether chronic alcohol abuse is responsible for this phenomenon or merely enhances an ageing-specific process, our findings suggest that hypermethylation in alcohol-dependent patients is a consequence, rather than a cause, of the disorder. PMID- 22506972 TI - Transpalatal approach with pedicled palatal osteo-muco-periosteal flap. AB - BACKGROUND: In the conventional technique of transpalatal approach, the palatal mucoperiosteum is incised and widely elevated and hard palate bone is removed in piece meal and discarded. These technique lead to complications, namely, temporary or permanent palatal fistula, palatal scarring leading to palatal disfiguration and velopharyngeal incompetence. In this article we describe a new technique of doing palatotomy to avoid these complications. METHODS: A retrospective review of post-operative complications of 20 patients that underwent transpalatal approach by the conventional technique was performed. To avoid the complications encountered in these cases, a new approach was designed when the palatal mucoperiosteum on the pathological side was elevated partially, greater palatine artery was coagulated and palatal osteotomy was performed from the oral side. On the non-pathological side, hard palate was sectioned from the nasal side, thus preserving the ipsilateral palatal mucoperiosteum. The entire mucoperiosteum with attached hard palate was reflected orally as a single block which was pedicled on the greater palatine artery and palatal mucoperiosteum of the non-pathological side, thereby creating palatal osteo-mucoperiosteal flap. The flap was placed back at the end of the procedure. Eight patients were operated by this new technique. RESULTS: All 20 patients operated by the conventional transpalatal approach developed post-operative complications. In the eight patients operated by the new technique, no post-operative complications were encountered after 2 years' follow-up. CONCLUSIONS: We found palatal osteo mucoperiosteal flap an easy and safe way of preserving the hard palate mucoperiosteum and bone with its vasculature resulting in quicker healing and minimal functional impairment. PMID- 22506973 TI - Improvement of ligninolytic properties in the hyper lignin-degrading fungus Phanerochaete sordida YK-624 using a novel gene promoter. AB - We identified a highly expressed protein (BUNA2) by two-dimensional gel electrophoresis from the hyper lignin-degrading fungus Phanerochaete sordida YK 624 under wood-rotting conditions. Partial amino acid sequences of BUNA2 were determined by LC-MS/MS analysis, and BUNA2 gene (bee2) and promoter region were PCR-cloned and sequenced. The bee2 promoter was used to drive the expression of the manganese peroxidase gene (mnp4) in P. sordida YK-624. Eighteen mnp4 expressing clones were obtained, with most showing higher ligninolytic activity and selectivity than wild-type YK-624. Examination of the ligninolytic properties of the most effective lignin-degrading transformant, BM-65, cultured on wood meal revealed that this strain exhibited higher lignin degradation and MnP activities than those of wild type. Transcriptional analysis confirmed the increased expression of recombinant mnp4 in the transformant. These results indicate that use of the bee2 promoter to drive the expression of ligninolytic enzymes may be an effective approach for improving the lignin-degrading properties of white-rot fungi. PMID- 22506974 TI - Increased risk of severe acute pancreatitis in patients with diabetes. AB - AIMS: We prospectively assessed the age- and sex-specific incidence rates and relative risks of overall and severe acute pancreatitis in Taiwanese with diabetes. METHODS: The study cohort included age- and-sex-matched groups of patients with (n = 547,554) and without (n = 584,373) diabetes. Incidence rate was estimated under Poisson assumption and relative risks of acute pancreatitis and severe acute pancreatitis, based on modified Atlanta criteria, were indicated by hazard ratios estimated from Cox proportional hazard regression models. RESULTS: Over an 8-year follow-up period, the incidence of acute pancreatitis was 2.98 and 1.68 per 1000 person-years for patients with and without diabetes, respectively, representing a covariate adjusted hazard ratio of 1.53 (95% confidence interval 1.49-1.58). Diabetes was associated with a significantly elevated risk of acute pancreatitis in all sex and age stratifications, with the highest hazard ratio noted for study subjects aged < 45 years (men 2.37; women 2.95). Diabetes was also significantly associated with an increased hazard ratio of severe acute pancreatitis [1.46 (1.36-1.57)], and especially of acute pancreatitis with local complications [1.65 (1.14-2.39)]. CONCLUSIONS: Diabetes is associated with an increased risk of overall and severe acute pancreatitis, and the relation is stronger in women and young patients. PMID- 22506976 TI - A longitudinal analysis of estimation, counting skills, and mathematical ability across the first school year. AB - In response to claims that the quality (and in particular linearity) of children's mental representation of number acts as a constraint on number development, we carried out a longitudinal assessment of the relationships between number line estimation, counting, and mathematical abilities. Ninety-nine 5-year-olds were tested on 4 occasions at 3 monthly intervals. Correlations between the 3 types of ability were evident, but while the quality of children's estimations changed over time and performance on the mathematical tasks improved over the same period, changes in one were not associated with changes in the other. In contrast to the earlier claims that the linearity of number representation is potentially a unique contributor to children's mathematical development, the data suggest that this variable is not significantly privileged in its impact over and above simple procedural number skills. We propose that both early arithmetic success and estimating skill are bound closely to developments in counting ability. PMID- 22506975 TI - The link between harsh home environments and negative academic trajectories is exacerbated by victimization in the elementary school peer group. AB - This article presents a prospective investigation focusing on the moderating role of peer victimization on associations between harsh home environments in the preschool years and academic trajectories during elementary school. The participants were 388 children (198 boys, 190 girls) who we recruited as part of an ongoing multisite longitudinal investigation. Preschool home environment was assessed with structured interviews and questionnaires completed by parents. Peer victimization was assessed with a peer nomination inventory that was administered when the average age of the participants was approximately 8.5 years. Grade point averages (GPAs) were obtained from reviews of school records, conducted for 7 consecutive years. Indicators of restrictive punitive discipline and exposure to violence were associated with within-subject declines in academic functioning over 7 years. However, these effects were exacerbated for those children who had also experienced victimization in the peer group during the intervening years. PMID- 22506977 TI - Control-display mapping in brain-computer interfaces. AB - Event-related potential (ERP) based brain-computer interfaces (BCIs) employ differences in brain responses to attended and ignored stimuli. When using a tactile ERP-BCI for navigation, mapping is required between navigation directions on a visual display and unambiguously corresponding tactile stimuli (tactors) from a tactile control device: control-display mapping (CDM). We investigated the effect of congruent (both display and control horizontal or both vertical) and incongruent (vertical display, horizontal control) CDMs on task performance, the ERP and potential BCI performance. Ten participants attended to a target (determined via CDM), in a stream of sequentially vibrating tactors. We show that congruent CDM yields best task performance, enhanced the P300 and results in increased estimated BCI performance. This suggests a reduced availability of attentional resources when operating an ERP-BCI with incongruent CDM. Additionally, we found an enhanced N2 for incongruent CDM, which indicates a conflict between visual display and tactile control orientations. PRACTITIONER SUMMARY: Incongruency in control-display mapping reduces task performance. In this study, brain responses, task and system performance are related to (in)congruent mapping of command options and the corresponding stimuli in a brain computer interface (BCI). Directional congruency reduces task errors, increases available attentional resources, improves BCI performance and thus facilitates human-computer interaction. PMID- 22506978 TI - Temporal and histological evaluation of melatonin patterns in a 'basal' metazoan. AB - While recent advances suggest functional pleiotropy of melatonin in higher organisms, an understanding of the biological significance of this ancient molecule in early evolutionary groups is lacking. Here, endogenous melatonin production was identified for the first time in the sea anemone Actinia equina, a nonsymbiotic hexacorallian cnidarian. Day/night activity profiles of melatonin in this anemone indicated that melatonin levels oscillate with significant nocturnal peaks. However, dynamic changes in melatonin concentration did not persist under constant dark conditions and therefore were not circadian in nature. Thus, the oscillating pattern of melatonin in A. equina is presumed to be the result of alternative, simpler melatonin control mechanism that likely involves direct regulation by the daily photocycle. As nocturnal melatonin signals still potentially provide 'time-of-day' information and can illustrate the seasonally changing length of the biological night, we hypothesize that melatonin may be relevant to temporal coordination of timed processes also in anthozoans. Spatial patterns of melatonin distribution found in this study indicate abundant melatonin distribution in the endodermal filaments wrapped around gametes. This finding supports the possibility that one of the melatonin-responsive processes in this basal metazoan species may involve reproductive functions. PMID- 22506979 TI - Ancient microbial activity recorded in fracture fillings from granitic rocks (Aspo Hard Rock Laboratory, Sweden). AB - Fracture minerals within the 1.8-Ga-old Aspo Diorite (Sweden) were investigated for fossil traces of subterranean microbial activity. To track the potential organic and inorganic biosignatures, an approach combining complementary analytical techniques of high lateral resolution was applied to drill core material obtained at -450 m depth in the Aspo Hard Rock Laboratory. This approach included polarization microscopy, time-of-flight secondary ion mass spectrometry (ToF-SIMS), confocal Raman microscopy, electron microprobe (EMP) and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The fracture mineral succession, consisting of fluorite and low-temperature calcite, showed a thin (20-100 MUm), dark amorphous layer lining the boundary between the two phases. Microscopic investigations of the amorphous layer revealed corrosion marks and, in places, branched tubular structures within the fluorite. Geochemical analysis showed significant accumulations of Si, Al, Mg, Fe and the light rare earth elements (REE) in the amorphous layer. In the same area, ToF SIMS imaging revealed abundant, partly functionalized organic moieties, for example, C(x)H(y)+, C(x)H(y)N+, C(x)H(y)O+. The presence of such functionalized organic compounds was corroborated by Raman imaging showing bands characteristic of C-C, C-N and C-O bonds. According to its organic nature and the abundance of relatively unstable N- and O- heterocompounds, the organic-rich amorphous layer is interpreted to represent the remains of a microbial biofilm that established much later than the initial cooling of the Precambrian host rock. Indeed, delta13C, delta18O and 87Sr/86Sr isotope data of the fracture minerals and the host rock point to an association with a fracture reactivation event in the most recent geological past. PMID- 22506980 TI - Estimation of blood flow rates in large microvascular networks. AB - OBJECTIVE: Recent methods for imaging microvascular structures provide geometrical data on networks containing thousands of segments. Prediction of functional properties, such as solute transport, requires information on blood flow rates also, but experimental measurement of many individual flows is difficult. Here, a method is presented for estimating flow rates in a microvascular network based on incomplete information on the flows in the boundary segments that feed and drain the network. METHODS: With incomplete boundary data, the equations governing blood flow form an underdetermined linear system. An algorithm was developed that uses independent information about the distribution of wall shear stresses and pressures in microvessels to resolve this indeterminacy, by minimizing the deviation of pressures and wall shear stresses from target values. RESULTS: The algorithm was tested using previously obtained experimental flow data from four microvascular networks in the rat mesentery. With two or three prescribed boundary conditions, predicted flows showed relatively small errors in most segments and fewer than 10% incorrect flow directions on average. CONCLUSIONS: The proposed method can be used to estimate flow rates in microvascular networks, based on incomplete boundary data, and provides a basis for deducing functional properties of microvessel networks. PMID- 22506981 TI - Association of symptoms of colon cancer patients with tumor location and TNM tumor stage. AB - OBJECTIVE: Colon cancer is the second most common cause of cancer death in Iceland and accounts for 8% of malignancies. We related information on symptoms of colon cancer patients with information on tumor location and pTNM-stage. MATERIAL AND METHODS: The study is retrospective and population-based. Information on all patients diagnosed with colon cancer in Iceland in 1995-2004 was obtained. Information on symptoms of patients and blood hemoglobin was collected from patients' files. The pathological parameters were derived from a previously performed study. RESULTS: A total of 768 patients (422 males, 346 females) participated in this study. Median age was 73 years. Nearly 60% had anemia at the time of diagnosis, 53% had visible blood in stools, and 65% had changes in bowel habits. Around 84% had visible blood in stools and/or anemia. Of those with right-sided tumors, 75% had anemia and were more likely to be diagnosed incidentally (40%) than those with left-sided tumors (20%). Left-sided tumors were associated with blood in stools (68% compared to 41%, p < 0.05) and changes in bowel habits (74% compared to 57%, p < 0.05). Multivariate analysis indicated that blood in stools was strongly associated with a lower TNM-stage (OR = 0.75, p < 0.05). Anemia was strongly associated with a higher TNM-stage (OR = 1.84, p < 0.05). CONCLUSION: Right-sided tumors were associated with anemia and incidental diagnosis; left-sided tumors were associated with visible blood in stools and changes in bowel habits. Visible blood in stools was significantly associated with lower TNM-stage, whereas abdominal pain, general and acute symptoms were associated with higher TNM-stage. PMID- 22506982 TI - The barriers and facilitators to routine outcome measurement by allied health professionals in practice: a systematic review. AB - BACKGROUND: Allied Health Professionals today are required, more than ever before, to demonstrate their impact. However, despite at least 20 years of expectation, many services fail to deliver routine outcome measurement in practice. This systematic review investigates what helps and hinders routine outcome measurement of allied health professionals practice. METHODS: A systematic review protocol was developed comprising: a defined search strategy for PsycINFO, MEDLINE and CINHAL databases and inclusion criteria and systematic procedures for data extraction and quality appraisal. Studies were included if they were published in English and investigated facilitators and/or barriers to routine outcome measurement by allied health professionals. No restrictions were placed on publication type, design, country, or year of publication. Reference lists of included publications were searched to identify additional papers. Descriptive methods were used to synthesise the findings. RESULTS: 960 papers were retrieved; 15 met the inclusion criteria. Professional groups represented were Physiotherapy, Occupational Therapy, and Speech and Language Therapy. The included literature varied in quality and design. Facilitators and barriers to routine outcome measurement exist at individual, managerial and organisational levels. Key factors affecting professionals' use of routine outcome measurement include: professionals' level of knowledge and confidence about using outcome measures, and the degree of organisational and peer-support professionals received with a view to promoting their work in practice. CONCLUSIONS: Whilst the importance of routinely measuring outcomes within the allied health professions is well recognised, it has largely failed to be delivered in practice. Factors that influence clinicians' ability and desire to undertake routine outcome measurement are bi-directional: they can act as either facilitators or barriers. Routine outcome measurement may only be deliverable if appropriate action is taken at individual therapist, team, and organisational levels of an organisation. PMID- 22506983 TI - The use of sinecatechins (polyphenon E) ointment for treatment of external genital warts. AB - INTRODUCTION: Sinecatechins is a standardized extract of green tea leaves, containing a mixture of catechin compounds. The 15% ointment has been approved for the topical treatment of condylomata acuminata (CA), caused by particular human papillomaviruses (HPV), mainly HPV types 6 and 11. OBJECTIVE: To update the use of sinecatechins for treatment of CA and to describe possible mechanisms involved in the mode of action. AREAS COVERED: The clearance rate of wart lesions after treatment with sinecatechins is similar to other topically applied drugs, like imiquimod and podophyllotoxin, but recurrences are seen less frequently after treatment with sinecatechins. The molecular mode of action underlying the clinical efficacy has yet not been characterized, but the following properties are likely to be involved in the regression of genital warts: activation of cellular immune reactions, induction of cell cycle arrest and apoptosis, inhibition of HPV gene expression. EXPERT OPINION: Sinecatechins is a safe and effective treatment option for CA. Due to the variety of molecular activities of catechins the product has great potential for application to other viral and tumor lesions in the future. PMID- 22506984 TI - No evidence of horizontal infection in horses kept in close contact with dogs experimentally infected with canine influenza A virus (H3N8). AB - BACKGROUND: Since equine influenza A virus (H3N8) was transmitted to dogs in the United States in 2004, the causative virus, which is called canine influenza A virus (CIV), has become widespread in dogs. To date, it has remained unclear whether or not CIV-infected dogs could transmit CIV to horses. To address this, we tested whether or not close contact between horses and dogs experimentally infected with CIV would result in its interspecies transmission. METHODS: Three pairs of animals consisting of a dog inoculated with CIV (10(8.3) egg infectious dose 50/dog) and a healthy horse were kept together in individual stalls for 15 consecutive days. During the study, all the dogs and horses were clinically observed. Virus titres in nasal swab extracts and serological responses were also evaluated. In addition, all the animals were subjected to a gross pathological examination after euthanasia. RESULTS: All three dogs inoculated with CIV exhibited clinical signs including, pyrexia, cough, nasal discharge, virus shedding and seroconversion. Gross pathology revealed lung consolidations in all the dogs, and Streptococcus equi subsp. zooepidemicus was isolated from the lesions. Meanwhile, none of the paired horses showed any clinical signs, virus shedding or seroconversion. Moreover, gross pathology revealed no lesions in the respiratory tracts including the lungs of the horses. CONCLUSIONS: These findings may indicate that a single dog infected with CIV is not sufficient to constitute a source of CIV infection in horses. PMID- 22506985 TI - Ampakine CX546 increases proliferation and neuronal differentiation in subventricular zone stem/progenitor cell cultures. AB - Ampakines are chemical compounds known to modulate the properties of ionotropic alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-subtype glutamate receptors. The functional effects attributed to ampakines involve plasticity and the increase in synaptic efficiency of neuronal circuits, a process that may be intimately associated with differentiation of newborn neurons. The subventricular zone (SVZ) is the main neurogenic niche of the brain, containing neural stem cells with brain repair potential. Accordingly, the identification of new pharmaceutical compounds with neurogenesis-enhancing properties is important as a tool to promote neuronal replacement based on the use of SVZ cells. The purpose of the present paper is to examine the possible proneurogenic effects of ampakine CX546 in cell cultures derived from the SVZ of early postnatal mice. We observed that CX546 (50 MUm) treatment triggered an increase in proliferation, evaluated by BrdU incorporation assay, in the neuroblast lineage. Moreover, by using a cell viability assay (TUNEL) we found that, in contrast to AMPA, CX546 did not cause cell death. Also, both AMPA and CX546 stimulated neuronal differentiation as evaluated morphologically through neuronal nuclear protein (NeuN) immunocytochemistry and functionally by single-cell calcium imaging. Accordingly, short exposure to CX546 increased axonogenesis, as determined by the number and length of tau-positive axons co-labelled for the phosphorylated form of SAPK/JNK (P-JNK), and dendritogenesis (MAP2-positive neurites). Altogether, this study shows that ampakine CX546 promotes neurogenesis in SVZ cell cultures and thereby may have potential for future stem cell-based therapies. PMID- 22506986 TI - A tan in a test tube - in vitro models for investigating ultraviolet radiation induced damage in skin. AB - Presently, global rates of skin cancers induced by ultraviolet radiation (UVR) exposure are on the rise. In view of this, current knowledge gaps in the biology of photocarcinogenesis and skin cancer progression urgently need to be addressed. One factor that has limited skin cancer research has been the need for a reproducible and physiologically-relevant model able to represent the complexity of human skin. This review outlines the main currently-used in vitro models of UVR-induced skin damage. This includes the use of conventional two-dimensional cell culture techniques and the major animal models that have been employed in photobiology and photocarcinogenesis research. Additionally, the progression towards the use of cultured skin explants and tissue-engineered skin constructs, and their utility as models of native skin's responses to UVR are described. The inherent advantages and disadvantages of these in vitro systems are also discussed. PMID- 22506987 TI - Melatonin attenuates inflammation and promotes regeneration in rabbits with fulminant hepatitis of viral origin. AB - The objective of the present study was to investigate the effect of melatonin on the liver inflammatory and regenerative response in an animal model of fulminant hepatic failure (FHF) of viral origin. Rabbits were experimentally infected with 2*10(4) hemagglutination units of a rabbit hemorrhagic disease virus (RHDV) isolate and received melatonin at two concentrations of 10 or 20mg/kg at 0, 12 and 24hr postinfection. RHDV infection induced an inflammatory response, with increased expression of toll-like receptor 4, high-mobility group box (HMGB)1, interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, and C-reactive protein, and decreased expression of decay accelerating factor (DAF/CD55). These effects were significantly reduced by melatonin. Matrix metalloproteinase-9 expression was also lowered in melatonin-treated rabbits. RHDV infection inhibited the hepatic regenerative/proliferative response, with a reduced expression of hepatocyte growth factor (HGF), epidermal growth factor, platelet derived growth factor (PDGF)-B and vascular endothelial growth factor and their receptors; these responses were prevented by melatonin administration. Melatonin treatment also resulted in reduced expression of phosphorylated Janus kinase and enhanced expression of extracellular mitogen-activated protein kinase (ERK) and signal transducer and activator of transcription (STAT) 3. Our findings show that anti-inflammatory effects and stimulation of regenerative mechanisms contribute to the beneficial effects of melatonin in rabbits with experimental infection by RHDV and support a potential hepatoprotective role of melatonin in FHF. PMID- 22506988 TI - Mesenchymal stem cells overexpressing hepatocyte growth factor (HGF) inhibit collagen deposit and improve bladder function in rat model of bladder outlet obstruction. AB - Bladder outlet obstruction (BOO) caused by collagen deposit is one of the most common problems in elderly male. This study was performed to examine the capability of human mesenchymal stem cells (MSCs) overexpressing hepatocyte growth factor (HGF) to inhibit collagen deposition in rat model of bladder outlet obstruction (BOO). HGF is known for its antifibrotic effect and the most promising agent for treating bladder fibrosis. BM3.B10 stable immortalized human MSC line (B10) was transduced to encode human HGF with a retroviral vector was prepared (B10.HGF). Two weeks after the onset of BOO, B10, and B10.HGF cells were injected into the rat's bladder wall. After 4 weeks, bladder tissues were harvested and Masson's trichrome staining was performed. Transgene expression in HGF-expressing B10 cells was demonstrated by reverse transcriptase polymerase chain reaction and immunohistochemical staining, and the high levels of HGF secreted by B10.HGF cells was confirmed by ELISA. The mean bladder weight in BOO rats was 5.8 times of the normal controls, while in animals grafted with B10.HGF cells, the weight was down to four times of the control [90.2 +/- 1.6 (control), 89.9 +/- 2.8 (sham), 527.9 +/- 150.9 (BOO), 447.7 +/- 41.0 (BOO + B10), and 362.7 +/- 113.2 (BOO + B10.HGF)]. The mean percentage of collagen area increased in BOO rats, while in the animals transplanted with B10.HGF cells, the collagen area decreased to the normal control level [12.2 +/- 1.3, (control), 12.8 +/- 1.1 (sham), 26.6 +/- 2.7 (BOO), 19.9 +/- 6.0 (BOO + B10), and 13.3 +/- 2.1 (BOO + B10.HGF)]. The expression of collagen and TGF-b protein increased after BOO, while the expression of HGF and c-met protein increased in the group with B10.HGF transplantation after BOO. Intercontraction interval decreased after BOO, but it recovered after B10.HGF transplantation. Maximal voiding pressure (MVP) increased after BOO, and it recovered to levels of the normal control after transplantation of B10.HGF cells. Residual urine volume (RU) increased after BOO, but the RU increase was not reversed by transplantation of B10.HGF cells. Human MSCs overexpressing HGF inhibited collagen deposition and improved cystometric parameters in bladder outlet obstruction of rats. The present study indicates that transplantation of MSCs modified to overexpress HGF could serve as a novel therapeutic strategy against bladder fibrosis in patients with bladder outlet obstruction. PMID- 22506989 TI - Multiple complications and frequent severe hypoglycaemia in 'elderly' and 'old' patients with Type 1 diabetes. AB - AIM: Elderly and old patients with Type 1 diabetes represent a growing population that requires thorough diabetes care. The increasing relevance of this subgroup, however, plays only a minor role in the literature. Here, we describe elderly patients with Type 1 diabetes on the basis of a large multi-centre database in order to point out special features of this population. METHOD: Data of 64609 patients with Type 1 diabetes treated by 350 qualified diabetes treatment centres were assessed and analysed by age group. RESULTS: Compared with the age group <= 60 years, patients aged >60 years (n=3610 61-80 years and n=377 >80 years old) were characterized by a longer diabetes duration (27.7 vs. 7.7 years), an almost double risk for severe hypoglycaemia (40.1 vs. 24.3/100 patient-years), a lower level of HbA(1c) [60 vs. 67 mmol/mol (7.6 vs. 8.3%)] and higher percentages of microalbuminuria (34.5 vs. 15.6%), diabetic retinopathy (45.2 vs. 8.3%), myocardial infarction (9.0 vs. 0.4%) or stroke (6.8 vs. 0.3%). Elderly patients used insulin pumps less frequently (12.2 vs. 23.8%), but more often used conventional premixed insulin treatment (10.8 vs. 3.8%). Differences between elderly and younger patient groups were significant, respectively. CONCLUSION: Diabetes care of elderly patients with Type 1 diabetes involves individualized treatment concepts. Increased hypoglycaemia risk and functional impairment attributable to diabetes-associated and/or age-related disorders must be taken into account. PMID- 22506990 TI - Homers regulate calcium entry and aggregation in human platelets: a role for Homers in the association between STIM1 and Orai1. AB - Homer is a family of cytoplasmic adaptor proteins that play different roles in cell function, including the regulation of G-protein-coupled receptors. These proteins contain an Ena (Enabled)/VASP (vasodilator-stimulated phosphoprotein) homology 1 domain that binds to the PPXXF sequence motif, which is present in different Ca2+-handling proteins such as IP3 (inositol 1,4,5-trisphosphate) receptors and TRPC (transient receptor potential canonical) channels. In the present study we show evidence for a role of Homer proteins in the STIM1 (stromal interaction molecule 1)-Orai1 association, as well as in the TRPC1-IP3RII (type II IP3 receptor) interaction, which might be of relevance in platelet function. Treatment of human platelets with thapsigargin or thrombin results in a Ca2+ independent association of Homer1 with TRPC1 and IP3RII. In addition, thapsigargin and thrombin enhanced the association of Homer1 with STIM1 and Orai1 in a Ca2+-dependent manner. Interference with Homer function by introduction of the synthetic PPKKFR peptide into cells, which emulates the proline-rich sequences of the PPXXF motif, reduced STIM1-Orai1 and TRPC1- IP3RII associations, as compared with the introduction of the inactive PPKKRR peptide. The PPKKFR peptide attenuates thrombin-evoked Ca2+ entry and the maintenance of thapsigargin induced store-operated Ca2+ entry. Finally, the PPKKFR peptide attenuated thrombin-induced platelet aggregation. The findings of the present study support an important role for Homer proteins in thrombin-stimulated platelet function, which is likely to be mediated by the support of agonist-induced Ca2+ entry. PMID- 22506991 TI - Zebrafish Parla- and Parlb-deficiency affects dopaminergic neuron patterning and embryonic survival. AB - Many genes associated with familial Parkinson's disease contribute to mitochondrial morphology and function. Some of these genes, for example, Pink1 and Parkin, are part of a common pathway. The presenilin-associated rhomboid-like (PARL) gene was recently linked to familial Parkinson's disease. The PARL gene product is found in the inner mitochondrial membrane and cleaves the optic atrophy 1 protein, involved in mitochondrial morphology and apoptosis. In Drosophila, the PARL-related rhomboid-7 gene acts upstream of pink1 and parkin. However, such a genetic relationship is still unknown in vertebrates. Here, we show that the zebrafish genome comprises two parl paralogs: parla and parlb. Morpholino-mediated loss of parla and/or parlb function resulted in mild neurodegeneration, as evidenced by a lower density of dopaminergic neurons. Patterning of dopaminergic neurons was also perturbed in the ventral diencephalon. Morphants exhibited extensive cell death throughout the entire body as well as increased larval mortality. The morphant phenotype could be rescued by injection of human PARL mRNA, but not catalytically inactive PARL, suggesting functional conservation between the human and zebrafish proteins. More importantly, the zebrafish pink1 mRNA as well as the human PINK1 mRNA, but not kinase-dead nor Parkinson's disease-linked mutant PINK1 mRNA, also rescued the morphant phenotype, providing evidence that Parl genes may function upstream of Pink1, as part of a conserved pathway in vertebrates. PMID- 22506992 TI - Substrate properties of stable fly (Diptera: Muscidae) developmental sites associated with round bale hay feeding sites in eastern Nebraska. AB - Residues at sites where stationary feeders were used to provide hay as supplemental forage for cattle during the winter are developmental substrates for immature stable flies, Stomoxys calcitrans (L.), in the central United States. Spatial patterns in physical (substrate depth, temperature, water content), chemical (pH, electrical conductivity [EC(lab)], total nitrogen [N] and carbon [C], ammoniacal nitrogen [NH(4)-N], extractable phosphorus [P]), and biological (microbial respiration rate) substrate properties for two feeding sites were estimated and the correlations between these properties and adult emergence were characterized. Hay feeding sites had a circular footprint with residues extending ~7 m from the feeder. With the exception of extractable P and total N, all substrate properties exhibited spatial patterns centered on the feeder location. Adult stable fly emergence densities were significantly correlated with substrate microbial respiration rate, NH(4)-N concentration, EC(lab), total C concentration, pH, and moisture content. Logistic regression indicated that EC best predicted the probability of stable flies emerging from a substrate and that the other properties did not provide additional information. A better understanding of the physical, chemical, and biological conditions needed for stable fly larval development may help in identifying previously unrecognized developmental habitats and management of this pest. Targeted implementation of management practices such as sanitation and chemical treatments can be applied to smaller areas reducing labor and improving cost effectiveness. PMID- 22506993 TI - Ant diversity and distribution (Hymenoptera: Formicidae) throughout Maine lowbush blueberry fields in Hancock and Washington Counties. AB - A 6-yr survey (2003-2008) identifying the ant fauna present in Maine lowbush blueberry fields was conducted in Washington and Hancock Counties. Pitfall trapping, leaf litter, and hand collections, as well as protein and sugar baits were used to characterize the resident ant community in this habitat. Estimates of faunal richness as impacted by the blueberry crop stage (pruned or fruit bearing), methods of pest management (grower standard, reduced-risk, or organic), and location within fields (middle, edge, or forested perimeters) were determined. In total, 42 species were collected from blueberry fields, comprising five subfamilies and 15 genera. Myrmica sculptilis Francoeur, Myrmica americana Weber, and Formica exsectoides Forel were the three most abundant species. Formica ulkei Emery, Myrmecina americana Emery, and Leptothorax canadensis Provancher represent new species records for Maine. Ants were most diverse in organic fields, and along the edge and within the wooded areas surrounding fields. Results suggest insecticide application reduces ant diversity. PMID- 22506994 TI - Hymenopteran parasitoids associated with frugivorous larvae in a Brazilian caatinga-cerrado ecotone. AB - The purpose of this study was to investigate native species of parasitoids of frugivorous larvae and their associations with host plants in commercial guava orchards and in typical native dry forests of a caatinga-cerrado ecotone in the State of Minas Gerais, Brazil. Nine species of parasitoids were associated with larvae of Anastrepha (Tephritidae) and Neosilba (Lonchaeidae) in fruit of Psidium guajava L. (Myrtaceae), Ziziphus joazeiro Mart. (Rhamnaceae), Spondias tuberosa Arruda (Anacardiaceae), Spondias dulcis Forst. (Anacardiaceae), Syzygium cumini (L.) Skeels (Myrtaceae), and Randia armata (Sw.) DC. (Rubiaceae). Doryctobracon areolatus was the most abundant species, obtained from puparia of Anastrepha zenildae, An. sororcula, An. fraterculus, An. obliqua, and An. turpiniae. This is the first report of Asobara obliqua in Brazil and of As. anastrephae and Tropideucoila weldi in dry forests of Minas Gerais State. The number of species of parasitoids was higher in areas with greater diversity of cultivated species and lower pesticide use. The forest fragments adjacent to the orchards served as shelter for parasitoids of frugivorous larvae. PMID- 22506995 TI - A comparison of dung beetle (Coleoptera: Scarabaeidae) attraction to native and exotic mammal dung. AB - Although the preference of dung beetles (Coleoptera: Scarabaeidae) for specific types and conditions of dung has been given substantial attention, little has been done to investigate the potential effects of exotic mammal introduction for game farms or rewilding projects. We used pitfall traps baited with various native and exotic herbivore, carnivore, and omnivore dung to evaluate dung beetle preference in the Great Plains of North America. Additionally, we analyzed of the nutrient quality of each dung type. In total, 9,089 dung beetles from 15 species were captured in 2 yr of sampling. We found significant differences (P < 0.05) in mean dung beetle capture among omnivore, herbivore, and carnivore dung, as well as differences in individual species preference for dung type. Omnivore dung was the most attractive with chimpanzee and human dung having the highest mean capture (291.1 +/- 27.6 and 287.5 +/- 28.5 respectively). Carrion also was highly attractive with a mean of 231.9 +/- 20.6 beetles per trap (N = 8). Our results suggest definitive local preference of carrion in Phanaeus vindex Macleay and Onthophagus hecate (Panzer), while the congener, O. pennsylvanicus (Harold), was rarely captured in carrion and highly preferred omnivore dung. Preference for a specific bait type does not appear to be correlated with dung quality, mammalian diet, or origin of mammal. Results suggest niche segregation by dung type among dung beetle species. PMID- 22506996 TI - Occurrence of emerald ash borer (Coleoptera: Buprestidae) and biotic factors affecting its immature stages in the Russian Far East. AB - Field surveys were conducted from 2008 to 2011 in the Khabarovsk and Vladivostok regions of Russia to investigate the occurrence of emerald ash borer, Agrilus planipennis Fairmaire, and mortality factors affecting its immature stages. We found emerald ash borer infesting both introduced North American green ash (Fraxinus pennsylvanica Marshall) and native oriental ashes (F. mandshurica Rupr. and F. rhynchophylla Hance) in both regions. Emerald ash borer densities (larvae/m(2) of phloem area) were markedly higher on green ash (11.3-76.7 in the Khabarovsk area and 77-245 in the Vladivostok area) than on artificially stressed Manchurian ash (2.2) or Oriental ash (10-59). Mortality of emerald ash borer larvae caused by different biotic factors (woodpecker predation, host plant resistance and/or undetermined diseases, and parasitism) varied with date, site, and ash species. In general, predation of emerald ash borer larvae by woodpeckers was low. While low rates (3-27%) of emerald ash borer larval mortality were caused by undetermined biotic factors on green ash between 2009 and 2011, higher rates (26-95%) of emerald ash borer larval mortality were caused by putative plant resistance in Oriental ash species in both regions. Little (<1%) parasitism of emerald ash borer larvae was observed in Khabarovsk; however, three hymenopteran parasitoids (Spathius sp., Atanycolus nigriventris Vojnovskaja Krieger, and Tetrastichus planipennisi Yang) were observed attacking third - fourth instars of emerald ash borer in the Vladivostok area, parasitizing 0-8.3% of emerald ash borer larvae infesting Oriental ash trees and 7.3-62.7% of those on green ash trees (primarily by Spathius sp.) in two of the three study sites. Relevance of these findings to the classical biological control of emerald ash borer in newly invaded regions is discussed. PMID- 22506997 TI - Fungi associated with Scolytogenes birosimensis (Coleoptera: Curculionidae) infesting Pittosporum tobira. AB - The bark beetle Scolytogenes birosimensis Niijima is suspected to be involved in the decline of Pittosporum tobira (Thunb. ex Murray) Aiton in the coastal areas of Japan. We isolated fungi from adult S. birosimensis in nine different localities in Japan to assess their potential association and predict their contribution to the success of the beetle. Results from morphological identification of associated fungi showed that the beetle was associated with Fusarium solani and Candida spp. Furthermore, molecular analysis showed that F. solani was most closely related to the plant pathogenic fungus F. solani f. sp. mori. Fungal isolation from surface-sterilized, dissected beetles and scanning electron miscroscope (SEM) observation of the body surface suggested that the associated fungi were carried in the pits on the beetles' elytra. These findings contribute to the understanding of the relationships between S. birosimensis and its associated fungi. PMID- 22506998 TI - Prevalence of Candidatus Erwinia dacicola in wild and laboratory olive fruit fly populations and across developmental stages. AB - The microbiome of the olive fruit fly, Bactrocera oleae (Gmelin), a worldwide pest of olives (Olea europaea L.), has been examined for >100 yr as part of efforts to identify bacteria that are plant pathogens vectored by the fly or are beneficial endosymbionts essential for the fly's survival and thus targets for possible biological control. Because tephritid fruit flies feed on free-living bacteria in their environment, distinguishing between the transient, acquired bacteria of their diet and persistent, resident bacteria that are vertically transmitted endosymbionts is difficult. Several culture-dependent and independent studies have identified a diversity of species in the olive fruit fly microbiome, but they have not distinguished the roles of the microbes. Candidatus Erwinia dacicola, has been proposed to be a coevolved endosymbiont of the olive fruit fly; however, this was based on limited samples from two Italian populations. Our study shows that C. Erwinia dacicola was present in all New and Old World populations and in the majority of individuals of all life stages sampled in 2 yr. Olive fruit flies reared on olives in the laboratory had frequencies of C. Erwinia dacicola similar to that of wild populations; however, flies reared on artificial diets containing antibiotics in the laboratory rarely had the endosymbiont. The relative abundance of C. Erwinia dacicola varied across development stages, being most abundant in ovipositing females and larvae. This uniform presence of C. Erwini dacicola suggests that it is a persistent, resident endosymbiont of the olive fruit fly. PMID- 22506999 TI - Feasibility of using an alternative larval host and host plants to establish Cotesia flavipes (Hymenoptera: Braconidae) in the temperate Louisiana sugarcane ecosystem. AB - Attempts to establish Cotesia flavipes Cameron (Hymenoptera: Braconidae) in Louisiana sugarcane fields to control the sugarcane borer, Diatraea saccharalis (F.) (Lepidoptera: Crambidae) have been unsuccessful. Experiments were conducted to investigate the feasibility of using an alternative larval host and host plants to overcome barriers preventing establishment. In addition, we evaluated C. flavipes' ability to search for D. saccharalis in sugarcane without above ground internodes. Diatraea evanescens Dyar (Lepidoptera: Crambidae) was investigated as an alternative host for C. flavipes. Cotesia flavipes was reared for five generations on D. evanescens without any indication of diminishing fitness as measured by days to parasite pupation and average cocoon mass weight. However, there was a significant reduction in percent parasitism, cocoon mass weight, and percent emergence when C. flavipes parasitized D. evanescens as compared with D. saccharalis, resulting in a 75% reduction in the gross reproductive rate (R(0)). Greenhouse studies indicated little difference in parasitism of D. saccharalis on the weed hosts johnsongrass, Sorghum halepense (L.), and vaseygrass, Paspalum urvillei Steud. However, when planted as refuge plots, we found it difficult to establish infestations of D. saccharalis in either of these hosts, or in two energy sugarcanes. After 3 yr of infesting host plants and releasing parasitoids only one parasitized D. saccharalis larvae was recovered within the johnsongrass refuge. Diatraea evanescens readily established in vaseygrass; however, these larvae appear inaccessible to C. flavipes. In contrast, parasitism of D. saccharalis by C. flavipes infesting young sugarcane was 30%. PMID- 22507000 TI - Impact of Rag1 aphid resistant soybeans on Binodoxys communis (Hymenoptera: Braconidae), a parasitoid of soybean aphid (Hemiptera: Aphididae). AB - Multiple strategies are being developed for pest management of the soybean aphid, Aphis glycines Matsumura; however, there has been little published research thus far to determine how such strategies may influence each other, thereby complicating their potential effectiveness. A susceptible soybean (Glycine max L.) variety without the Rag1 gene and a near isogenic resistant soybean variety with the Rag1 gene were evaluated in the laboratory for their effects on the fitness of the soybean aphid parasitoid, Binodoxys communis (Gahan). The presence or absence of the Rag1 gene was verified by quantifying soybean aphid growth. To test for fitness effects, parasitoids were allowed to attack soybean aphids on either a susceptible or resistant plant for 24 h and then aphids were kept on the same plant throughout parasitoid development. Parasitoid fitness was measured by mummy and adult parasitoid production, adult parasitoid emergence, development time, and adult size. Parasitoids that attacked soybean aphids on susceptible plants produced more mummies, more adult parasitoids, and had a higher emergence rate compared with those on resistant plants. Adult parasitoids that emerged from resistant plants took 1 d longer and were smaller compared with those from susceptible plants. This study suggests that biological control by B. communis may be compromised when host plant resistance is widely used for pest management of soybean aphids. PMID- 22507001 TI - Natural enemies associated with Sirex noctilio (Hymenoptera: Siricidae) and S. nigricornis in Ontario, Canada. AB - Sirex noctilio F. is an exotic woodwasp now found in eastern North America where it shares natural enemies with native woodwasps of Pinus spp. To study the extent to which native hymenopteran parasitoids and parasitic nematodes could affect woodwasp populations, 60 Pinus trees with symptoms of S. noctilio attack were felled in 2007 and 2008 in Ontario, Canada. Each tree bole was cut into 1-m sections that were placed in individual rearing tubes; emergence was monitored from May to November of the year of felling. Female S. noctilio were dissected to assess parasitism by the nematode Deladenus siricidicola Bedding. Two species of Siricidae emerged from these trees; S. noctilio, which accounted for most of the specimens collected, and S. nigricornis F. Of the three species of parasitoid that emerged, Ibalia leucospoides (Hochenwarth) was the most abundant, accounting for an overall hypothetical Siricidae parasitism rate of almost 20%. This parasitoid emerged over a similar time period as S. noctilio-between early July and early September. Except in trees >15 m in height, parasitism by I. leucospoides generally appeared uniform throughout the bole. Parasitism rates did not vary between the 2 yr, but did between sites in 1 yr. Parasitic nematodes were found in the haemocoel of about one third of S. noctilio females dissected but were never found sterilizing the eggs; none were found in S. noctilio emerging from P. resinosa. These findings suggest that I. leucospoides is currently the primary invertebrate natural enemy of S. noctilio in Ontario. PMID- 22507002 TI - Cumulative impact of a clover cover crop on the persistence and efficacy of Beauveria bassiana in suppressing the pecan weevil (Coleoptera: Curculionidae). AB - The pecan weevil, Curculio caryae (Horn), is a key pest of pecan. Endemic levels of the entomopathogenic fungus Beauveria bassiana (Balsamo) Vuillemin can occur in pecan orchards and contribute to natural control of C. caryae. Commercial formulations of the fungus can also be applied for suppression of C. caryae. We hypothesized that a clover cover crop enhances B. bassiana efficacy and persistence (e.g., by protecting the fungus against abiotic environmental stresses). The hypothesis was tested by conducting field trials in a pecan orchard in Byron, GA, in 2009 and 2010. The study included four treatments arranged in a factorial with two levels of fungus (endemic fungus only, and application of a commercial B. bassiana product), and two levels of clover (white clover, Trifolium repens L., and no clover). Fungal persistence was measured by determining the number of CFUs per gram of soil over time (during 42 d postapplication of B. bassiana in 2009 and 29 d in 2010). Efficacy was measured by capturing naturally emerging C. caryae and subsequently determining mortality and mycosis (over 24 d in 2009 and 17 d in 2010). In 2009, greater prevalence of B. bassiana conidia was detected in plots receiving fungal applications compared with no fungus applications, and no clear effect of clover was observed in plots receiving B. bassiana applications in either year. In 2010, B. bassiana prevalence in the endemic fungus plus clover treatment was higher than fungus without clover, and was similar to plots receiving additional B. bassiana applications. Given that we observed enhanced persistence of endemic B. bassiana in 2010 but not 2009, the impact of clover appears to be a cumulative effect. Mortality of C. caryae (averaged over the sampling periods) ranged between 68 74% in plots receiving B. bassiana applications and 51-56% in plots with endemic fungus only. C. caryae mortality and mycosis data also provided evidence that endemic B. bassiana efficacy was enhanced by clover relative to plots without clover (with no clear clover effect on plots receiving fungus applications). Thus, we conclude that natural control of C. caryae can increase when clover is grown in pecan orchards with endemic populations of B. bassiana. PMID- 22507003 TI - Biology and reproductive parameters of the brown lygodium moth, Neomusotima conspurcatalis--a new biological control agent of Old World climbing fern in Florida. AB - Neomusotima conspurcatalis Warren was first released in Florida as a weed biological control agent against Old World climbing fern in 2008, and readily established large field populations. A related biocontrol agent, Austromusotima camptozonale, had previously failed to establish despite several years of releases. Life history studies were conducted to determine whether aspects of the reproductive biology of N. conspurcatalis might account for these different outcomes. At 26.5 degrees C, development from egg to adult averaged 22.2 +/- 0.1 d, with 75% of larvae emerging as adults. The sex ratio averaged 1:0.8 (?:?), with both sexes emerging at the same time. Female moths typically mated once, on the first night after emergence, and began oviposition the next night. Females laid half their eggs on the first night and lived an average of 10.7 +/- 0.8 d. Individual females maintained in cages with a male-biased sex ratio (3?:1?) produced significantly more larvae over their lifetime (140 +/- 6.6 larvae) than individual females maintained at a ratio of 1?:1? (111 +/- 9.1 larvae). Sexual selection, either through 'male-male competition' or 'female choice' was likely responsible for this result, because there were no significant differences in mating frequency, duration of ovipositional period or female longevity to otherwise explain the difference. Two-fold greater lifetime reproductive output (average 127 +/- 6.3 larvae) and deposition of half this output on the first night of oviposition, likely contributed to rapid field establishment of N. conspurcatalis compared with A. camptozonale. PMID- 22507004 TI - Introduction, establishment, and potential geographic range of Carmenta sp. nr ithacae (Lepidoptera: Sesiidae), a biological control agent for Parthenium hysterophorus (Asteraceae) in Australia. AB - Parthenium (Parthenium hysterophorus L.), a major weed causing economic, environmental, and human and animal health problems in Australia and several countries in Asia, Africa, and the Pacific, has been a target for biological control in Australia since the mid-1970s. Nine species of insects and two rust fungi have been introduced as biological control agents into Australia. These include Carmenta sp. nr ithacae, a root feeding agent from Mexico. The larvae of C. sp. nr ithacae bore through the stem-base into the root where they feed on the cortical tissue of the taproot. During 1998-2002, 2,816 larval-infested plants and 387 adults were released at 31 sites across Queensland, Australia. Evidence of field establishment was first observed in two of the release sites in central Queensland in 2004. Annual surveys at these sites and nonrelease sites during 2006-2011 showed wide variations in the incidence and abundance of C. sp. nr ithacae between years and sites. Surveys at three of the nine release sites in northern Queensland and 16 of the 22 release sites in central Queensland confirmed the field establishment of C. sp. nr ithacae in four release sites and four nonrelease sites, all in central Queensland. No field establishment was evident in the inland region or in northern Queensland. A CLIMEX model based on the native range distribution of C. sp. nr ithacae predicts that areas east of the dividing range along the coast are more suitable for field establishment than inland areas. Future efforts to redistribute this agent should be restricted to areas identified as climatically favorable by the CLIMEX model. PMID- 22507005 TI - Demographic parameters of Spodoptera exigua (Lepidoptera: Noctuidae) on different soybean cultivars. AB - Life table, reproduction, and population growth parameters of the beet armyworm, Spodoptera exigua (Hubner) (Lepidoptera: Noctuidae), were determined on nine soybean (Glycine max L.) cultivars ('032', '033', 'Hill', 'M4', 'M7', 'M9', 'M11', 'TMS', and 'Zane') at 25 degrees C. The age-specific survival rate of eggs and immature stages was higher on 033 in comparison with other cultivars. The gross fecundity rate ranged from 911 on M9 to 1,296 on Zane, but the differences were not statistically significant. The net fecundity rate was significantly higher on 033 (1,082 eggs per female) than on other cultivars. The gross fertility rate significantly differed on tested cultivars, and was the highest on Zane (1,257 eggs per female) and lowest on Hill (813 eggs per female). The net fertility rate varied from 532 on M11 to 1,082 eggs per female on 033. Both daily number of eggs and daily number of fertile eggs laid per female varied significantly among the different cultivars, and were the highest on TMS (90 for both parameter) and lowest on M7 (47 and 43), respectively. The values of net reproductive rate, intrinsic rate of increase, and finite rate of increase were significantly higher on 033. The shortest generation time (23 d), shortest doubling time (1.66 d), and highest percentage of female offspring (56%) also were obtained on 033. According to population growth parameters, 033 and Hill partially were susceptible and resistant, respectively, to S. exigua. The results of this study provide direction to design a more comprehensive integrated pest management program for this pest. PMID- 22507006 TI - The effects of nutrients and secondary compounds of Coffea arabica on the behavior and development of Coccus viridis. AB - Phytochemicals may modify the food quality, reduce a plant's palatability to insects, or defend against pests. This work aimed to study 1) relationships between the nitrogen and potassium levels given to plants in nutritive solutions and the foliar phytochemical concentrations, 2) the effect of nutrients and secondary compounds of Coffea arabica on the behavior of Coccus viridis, and 3) tolerance of C. arabica to losses. Deficient, normal, and excessive nitrogen and potassium fertilization treatments were used. Each treatment had two plants (one infested and one noninfested plant). The contents of phytochemicals in the infested plants' leaves and their dry matter of roots, stems, and leaves as well as the total contents in noninfested plants, were determined. The adults and nymphs of C. viridis were counted for 60 d in all treatments. It was verified that elevated nitrogen and potassium levels in the nutritional solutions led to increased of nymphs and adults of C. viridis to the coffee plants over time. Potassium and nitrogen had both direct and indirect effects on C. viridis. The direct effect was because of the increase of the nitrogen content in the leaves. The indirect effect instead was because of reductions in the caffeine and chlorogenic acid contents in the leaves. This is the first study to show relationship nutrient levels of coffee phytochemicals in response to herbivory by scale insects. Caffeine and chlorogenic acid applied on coffee leaves stimulated the locomotory activity of the green scale, thus reducing their feeding compared with untreated leaves. The elevation of caffeine and chlorogenic acid levels in coffee leaves affect this generalist insect by stimulating the locomotion of crawlers. PMID- 22507007 TI - Injury to cotton by adult Lygus hesperus (Hemiptera: Miridae) of different gender and reproductive states. AB - Lygus hesperus Knight (Hemiptera: Miridae) is a key pest of cotton (Gossypium spp.) in the western United States that injures floral buds (squares) and developing fruit (bolls). However, no clear relationship between Lygus population level and plant injury has been established. Age-dependent feeding activity by L. hesperus is a possible source of variation that has not been examined for its influence in studies of the impact of Lygus on cotton. Recent video-based laboratory studies indicated that feeding behaviors and trivial movement varied among L. hesperus adults of different gender and reproductive states (prereproductive; reproductive and unmated; and reproductive and mated). We compared within-plant distributions and accumulations of feeding injury to intact cotton plants corresponding to adult L. hesperus of different gender and reproductive states. Adult females, regardless of reproductive state, were observed on squares and axillary buds more often than were males. Additionally, prereproductive adults were observed on squares and axillary buds more often than were mated or unmated reproductive adults, regardless of gender. Plants that were exposed to prereproductive adults exhibited more abscised squares and more squares with injured anthers compared with plants exposed to reproductive adults. However, feeding injury did not differ by insect mating status or gender. These results are consistent with results of our previous video-based assays, and indicate adult reproductive state represents a source of variation that should be controlled in studies to evaluate Lygus-induced injury to cotton and other crop plants. PMID- 22507009 TI - The statistical analysis of insect phenology. AB - We introduce two simple methods for the statistical comparison of the temporal pattern of life-cycle events between two populations. The methods are based on a translation of stage-frequency data into individual 'times in stage'. For example, if the stage-k individuals in a set of samples consist of three individuals counted at time t(1) and two counted at time t(2), the observed times in stage k would be (t(1), t(1), t(1), t(2), t(2)). Times in stage then can be compared between two populations by performing stage-specific t-tests or by testing for equality of regression lines of time versus stage between the two populations. Simulations show that our methods perform at close to the nominal level, have good power against a range of alternatives, and have much better operating characteristics than a widely-used phenology model from the literature. PMID- 22507008 TI - Effect of host plants on developmental time and life table parameters of Carposina sasakii (Lepidoptera: Carposinidae) under laboratory conditions. AB - Studies were designed to examine the effects of host plants (apricot, Prunus armeniaca L.; plum, Prunus salicina L.; peach, Prunus persica L.; jujube, Zizyphus jujuba Will.; apple, Malus domestica Mill.; and pear, Pyrus sorotina Will) on the development and life table parameters of the peach fruit moth, Carposina sasakii Matsumura (Lepidoptera: Carposinidae) under laboratory conditions. Peach fruit moth developed faster (12.48 d) and had the highest preimaginal survival rate (50.54%) on plum compared with the other host plants. Adult longevity was significantly longer on jujube for both female and male moths. Adult females from larvae reared on jujube and peach laid significantly greater numbers of eggs (214.50 and 197.94 eggs per female, respectively) compared with those reared on the other four host plants. Life-table parameters were calculated for each host plant and compared by jackknife procedures. The intrinsic rate of natural increase (r(m)) was significantly greatest on plum (0.1294 eggs per female per d), followed by jujube and apricot (0.1201 and 0.1128 eggs per female per d), respectively. Implications of the various measures of population performance are discussed. PMID- 22507010 TI - Management of winter weeds affects Frankliniella fusca (Thysanoptera: Thripidae) dispersal. AB - Frankliniella fusca (Hinds) naturally disperses from winter weeds to crops in spring, causing direct and indirect damage. Field preparation before planting includes use of herbicides or cultivation to kill unwanted vegetation, which adversely affects F. fusca host plants and potentially influences F. fusca dispersal. Common chickweed, Stellaria media (L.), infested with F. fusca, was used as a model to study effects of timing and type of vegetation management on adult dispersal. Infested weeds were caged and F. fusca weekly dispersal was monitored using sticky traps. Weed management treatments performed at an early (14 April-11 May) or late (2 wk after early treatment) date consisted of glyphosate, paraquat, disking, hoeing, or untreated control. Late glyphosate and hoeing treatments resulted in cumulative dispersal statistically similar to or greater than from control plots. Compared with the control, significantly more F. fusca dispersed from the glyphosate and hoeing plots during the 3 wk after treatment. More thrips dispersed from the late paraquat treatment 1 wk post application than from the control. Dispersal from the disked treatment and early paraquat treatment was similar to that of the control 1- to 3-wk post-treatment. Early treatments resulted in significantly smaller cumulative dispersal than the control in all but one instance. Late disking and paraquat treatments resulted in cumulative F. fusca captures that were statistically similar or less than that in the control. Winter weed management type and timing affect F. fusca dispersal magnitude and duration. PMID- 22507011 TI - Emergence of blueberry maggot flies (Diptera: tephritidae) from mulches and soil at various depths. AB - Control of blueberry maggot, Rhagoletis mendax Curran, typically is achieved with insecticides targeting adult flies before females oviposit in ripening fruit. Management strategies targeting other life stages have received less attention. We tested effects of compost or pine needle mulches on emergence of blueberry maggot flies under laboratory and field conditions. Few flies emerged from pupae that were buried under 20 cm of pine needles in all experiments, but burial in 20 cm of compost did not always result in low fly emergence. Burial of pupae in 5 cm of compost or pine needles did not reduce fly emergence compared with 1 cm in soil. Low emergence with increased mulch depth appeared to be primarily because of failure of flies to ascend to the surface after they exited puparia. Low emergence also was associated with high moisture levels causing rotten, discolored pupae, particularly in the laboratory in compost. No flies emerged from pupae buried in 1 cm of pine needles in the field. In this case no flies exited puparia, likely because high temperatures (>30 degrees C) at the surface killed pupae. Thus, mulch application under highbush blueberries (Vaccinium corymbosum L.) after maggots drop from berries can reduce emergence success of flies from buried pupae, but the level of control will depend on mulch depth and may vary with rainfall and temperature. PMID- 22507012 TI - Reduced risk insecticides to control scale insects and protect natural enemies in the production and maintenance of urban landscape plants. AB - Armored scale insects are among the most difficult to manage and economically important arthropod pests in the production and maintenance of urban landscape plants. This is because of morphological traits that protect them from contact insecticides. I compared initial and season-long control of euonymus scale, Unaspis euonymi Comstock (Hemiptera: Diaspidae), by reduced-risk insecticides (insect growth regulators [IGRs], neonicotinoids, spirotetramat) to determine if they controlled scale as well as more toxic insecticides such as the organophosphate, acephate, and pyrethroid, bifenthrin. I also evaluated how these insecticides affected natural enemy abundance on experimental plants and survival when exposed to insecticide residue. All insecticides tested reduced first generation euonymus scale abundance. In 2009, reinfestation by second generation euonymus scale was highest on plants treated with acetamiprid and granular dinotefuran. In 2010, systemic neonicotinoids and spirotetramat prevented cottony cushion scale infestation 133 d after treatment whereas scale readily infested plants treated with bifenthrin and horticultural oil. Encarsia spp. and Cybocephalus spp. abundance was related to scale abundance. These natural enemies were generally less abundant than predicted by scale abundance on granular dinotefuran treated plants and more abundant on granular thiamethoxam treated plants. Bifenthrin residue killed 90-100% of O. insidiosus and E. citrina within 24 h. My results indicate that reduced risk insecticides can provide season-long scale control with less impact on natural enemies than conventional insecticides. This could have economic and environmental benefits by reducing the number of applications necessary to protect nursery and landscape plants from scale. PMID- 22507013 TI - Influence of host fruit and conspecifics on the release of the sex pheromone By Toxotrypana curvicauda males (Diptera: Tephritidae). AB - The release of tephritid sex pheromones depends significantly on the age of the male, the social context (presence of conspecifics) and chemical context (host volatiles). In this study, the influence of host fruit and conspecific (males and females) on the emission of the pheromonal compound 2-methyl-6-vinylpyrazine (2,6 mvp) by Toxotrypana curvicauda (Gerstaecker) males was investigated under laboratory conditions. Males were divided into one control group (nonexposed to treatment) and five experimental groups were placed 1 hr before volatile collection with: 1) host fruit (unripe papaya), 2) two females, 3) two males, 4) host fruit plus two females, and 5) host fruit plus two males. The volatiles were sampled by means of solid phase microextraction and analyzed with gas chromatography-mass spectrometry, with a focus on 2,6 mvp. Males emitted volatiles from the first day after adult emergence. The maximum peak and the temporal pattern of 2,6 mvp release were modified by the presence of host fruit and conspecific males or females. On day 5, males in the presence of fruit maintained a constant release of 2,6 mvp while the presence of conspecific caused a decrease of pheromone release. The release of 2,6 mvp was increased significantly in males exposed to both types of stimuli simultaneously. The stimuli (fruit and conspecifics) modified the release of 2,6 mvp, however the effect depended on male age. PMID- 22507014 TI - The legacy of attack: implications of high phloem resin monoterpene levels in lodgepole pines following mass attack by mountain pine beetle, Dendroctonus ponderosae Hopkins. AB - The mountain pine beetle (Dendroctonus ponderosae Hopkins) is the most serious pest of pines (Pinus) in western North America. Host pines protect themselves from attack by producing a complex mixture of terpenes in their resin. We sampled lodgepole pine (Pinus contorta variety latifolia) phloem resin at four widely separated locations in the interior of British Columbia, Canada, both just before (beginning of July) and substantially after (end of August) the mountain pine beetle dispersal period. The sampled trees then were observed the next spring for evidence of survival, and the levels of seven resin monoterpenes were compared between July and August samples. Trees that did not survive consistently had significantly higher phloem resin monoterpene levels at the end of August compared with levels in July. Trees that did survive mainly did not exhibit a significant difference between the two sample dates. The accumulation of copious defense-related secondary metabolites in the resin of mountain pine beetle-killed lodgepole pine has important implications for describing the environmental niche that the beetle offspring survive in as well as that of parasitoids, predators, and other associates. PMID- 22507015 TI - Evaluating dispensers loaded with codlemone and pear ester for disruption of codling moth (Lepidoptera: Tortricidae). AB - Polyvinyl chloride polymer (PVC) dispensers loaded with ethyl (E,Z)-2,4 decadienoate (pear ester) plus the sex pheromone, (E,E)-8,10-dodecadien-1-ol (codlemone) of codling moth, Cydia pomonella (L.), were compared with PVC dispensers and a commercial dispenser (Isomate-C Plus) loaded with codlemone. Evaluations were conducted in replicated plots (0.1-0.2 ha) in apple, Malus domestica (Borkhausen) during both generations of codling moth from 2007 to 2009. Dispensers were applied at 1,000 ha(-1). Male captures in traps baited with virgin female moths and codlemone lures were recorded. Residual analysis of field-aged dispensers over both moth generations was conducted. Dispensers exhibited linear declines in release rates of both attractants, and pear ester was released at a significantly higher rate than codlemone during both time periods. The proportion of virgin female-baited traps catching males was significantly lower with combo dispenser TRE24 (45/110, mg codlemone/mg pear ester) during the second generation in 2007 and the combo dispensers TRE144 (45/75) and TRE145 (75/45) during the first generation in 2008 compared with Isomate-C Plus. Similarly, male catches in female-baited traps in plots treated with the combo dispensers TRE144 during the first generation in 2008 and TRE23 (75/110) during the second generation, in 2007 were significantly lower than in plots treated with Isomate-C Plus. No significant differences were found for male catches in codlemone-baited traps in plots treated with Isomate-C Plus and any of the combo dispensers. However, male catches were significantly lower in plots treated with Cidetrak CM (codlemone-only dispenser) than the combo TRE144 dispenser during both generations in 2009. PMID- 22507016 TI - Monitoring codling moth (Lepidoptera: Tortricidae) in sex pheromone-treated orchards with (E)-4,8-dimethyl-1,3,7-nonatriene or pear ester in combination with codlemone and acetic acid. AB - Traps baited with ethyl (E,Z)-2,4-decadienoate (pear ester) or (E)-4,8-dimethyl 1,3,7-nonatriene (DMNT) in two- or three-way combinations with the sex pheromone (E,E)-8,10-dodecadien-1-ol (codlemone) and acetic acid (AA) were evaluated for codling moth, Cydia pomonella (L.). All studies were conducted in apple orchards, Malus domestica Borkhausen, treated with sex pheromone dispensers during 2010. Septa were loaded with codlemone, DMNT, and pear ester individually or codlemone with either DMNT or pear ester together (combo lures). Polyethylene vials loaded with AA were added as a co-lure. Residual analyses of field-aged combo lures and weight loss of the AA co-lure were conducted. AA vials lost 50 150 mg wk(-1). Weekly weight loss was not affected by field aging, but was closely correlated with the daily mean temperature. Pear ester was released from septa at a slightly higher but nonsignificant rate than codlemone. DMNT was released at a significantly higher rate than codlemone, and lures were effective for 4 wk. The addition of codlemone to traps baited with either host plant volatile plus AA had either no effect or significantly increased total moth catches. The addition of AA significantly increased the catch of female moths with either combo lure. Total moth catches in traps baited with pear ester or DMNT combo lures and AA did not differ and were either significantly higher or similar to the pear ester combo lure. These data suggest that codling moth may be more effectively monitored in sex pheromone-treated orchards with multi component lures, including codlemone, AA, and host plant volatiles. PMID- 22507017 TI - Physiological consequences of laboratory rearing of Lygus hesperus (Hemiptera: Miridae). AB - Several aspects of the basic biology of the western tarnished plant bug, Lygus hesperus Knight, are poorly known despite the economic importance of this species. Among these are the factors regulating the adult diapause. Reports of recent studies questioned the validity of earlier reports of diapause in L. hesperus, in part because of the demonstrated loss of diapause response in insects obtained from long-standing laboratory colonies. However, use of laboratory reared insects would facilitate additional diapause research, so long as those insects exhibit a diapause response similar to that of the field population. L. hesperus, originating as eggs from field-collected insects, were reared in the laboratory for four generations to examine corresponding changes in selected biological characteristics. Over the course of the four generations, incidence of diapause in both L. hesperus genders decreased whereas the frequency of oviposition by virgin females increased. Measurable changes were not observed in frequency of occurrence of a specific fat body type (glass bead fat) or nymphal development time. These results suggest L. hesperus used in diapause research should be as close to the field population as possible, but no further removed than three generations. Results further demonstrate variability among different biological characteristics in their responses to selection from laboratory rearing. Collectively, these findings demonstrate the importance of understanding the influences of rearing on specific biological characteristics under study, and the need to verify the similarity of laboratory-reared insects to their native counterparts in studies used to draw inferences regarding the field population. PMID- 22507018 TI - Spatial and temporal genetic variation in Tunisian field populations of Macrosiphum euphorbiae (Thomas). AB - The potato aphid Macrosiphum euphorbiae (Thomas) is a major pest of several economic crops in Tunisia. Using 10 microsatellites, we analyzed five populations of M. euphorbiae sampled during the 2004-2005 solanaceous and cucurbit season (April through September) from five geographic origins. From 235 aphids, 61 different multilocus genotypes were identified of which three genotypes MLG1, MLG2, and MLG42 were predominant on all host plants and regions. MLG1 and MLG2 genotypes were detected in 2004 and did not reappear in spring 2005, while the genotype MLG42 was detected only in 2005. All populations showed significant deviation from Hardy-Weinberg equilibrium even in data sets including one individual per genotype. chi(2) independence tests and analysis of molecular variance showed no significant differentiation among populations collected on different host plant and from different geographic origin, but differences between populations from two successive years were significant. Factorial component analysis corroborates these results. The probable causes of this seasonal variation were discussed. PMID- 22507019 TI - Polymorphic microsatellite loci from an indigenous Asian fungus-growing termite, Macrotermes gilvus (Blattodea: Termitidae) and cross amplification in related taxa. AB - The fungus-growing termite, Macrotermes gilvus (Hagen), an indigenous species from Southeast Asia distributed from Myanmar to Indonesia and the Philippines, offers great potential as an ecological model system to elucidate the effects of geography on gene flow within this region. We used next generation sequencing (Roche 454 pyrosequencing) to identify microsatellite markers from the genomic DNA of M. gilvus. A modest sequencing volume generated 34,122 reads, with 1,212 (3.6%) reads contains microsatellites with di-, tri-, tetra-, penta-, and hexa nucleotide repeat motifs. Thirty-seven loci were selected for primer development and tested for polymorphism across 22 colonies of M. gilvus. Eleven loci were found to be polymorphic with 2-4 alleles per locus. Observed and expected heterozygosities ranged between 0.091-0.727 and 0.090-0.540, respectively. Cross taxa amplification was successful across a panel of four related termite species and four multiplex groups were designed for future population genetic studies. These markers will open new avenues for the study of phylogeography and population genetics of this fungus-growing termite. This study also has effectively demonstrated the use of 454 pyrosequencing for the rapid development of informative microsatellite markers from a termite genome. PMID- 22507020 TI - Honoring excellence. PMID- 22507021 TI - Tempering technology with care. PMID- 22507022 TI - Lessons for spinal cord injury rehabilitation taken from adult developmental psychology: 2011 Essie Morgan Lecture. AB - BACKGROUND/OBJECTIVE: Developmental phases affect how individuals cope with and challenge threats to self-concept, health and functioning. Understanding prominent models of adult psychological development can help spinal cord injury/disease (SCI/D) rehabilitation professionals facilitate positive change and growth. DESIGN: Author's theoretical model informed by literature review and personal experience. SETTING: Veterans administration (VA) medical center interdisciplinary outpatient clinic providing primary and specialty care to veterans with spinal cord injuries and disorders. CONCLUSION: Threats to life expectations, health, well-being, identity, and other aspects of self create crises that can result in psychopathology or psychological growth. SCI/D can present multiple threats across the lifespan. For example, self-image, ability to perform various activities, ability to feel attractive, and even life itself may be challenged by SCI/D or its complications. Threats may be perceived at the time of injury or onset of symptoms. Also, as the injured body declines further over time, complications can cause significant temporary or permanent functional decline. Individuals interpret each of these threats in the context of current developmental needs. How people cope is influenced by developmental factors and personality traits. An integrated model of adult psychological development based on the works of Erikson, Gutmann, and Baltes is related to the literature on coping with SCI/D. This model provides insights that interdisciplinary rehabilitation teams may use to facilitate personal growth, optimal functioning, and physical health as adults with SCI negotiate normal developmental challenges throughout their lifetimes. PMID- 22507024 TI - Effect of choice of recovery patterns on handrim kinetics in manual wheelchair users with paraplegia and tetraplegia. AB - BACKGROUND: Impact forces experienced by the upper limb at the beginning of each wheelchair propulsion (WCP) cycle are among the highest forces experienced by wheelchair users. OBJECTIVE: To determine whether the magnitude of hand/forearm velocity prior to impact and effectiveness of rim impact force are dependent on the type of hand trajectory pattern chosen by the user during WCP. Avoiding patterns that inherently cause higher impact force and have lower effectiveness can be another step towards preserving upper limb function in wheelchair users. METHODS: Kinematic (50 Hz) and kinetic (2500 Hz) data were collected on 34 wheelchair users (16 with paraplegia and 18 with tetraplegia); all participants had motor complete spinal cord injuries ASIA A or B. The four-hand trajectory patterns were analyzed based on velocity prior to contact, peak impact force and the effectiveness of force at impact. RESULTS: A high correlation was found between the impact force and the relative velocity of the hand with respect to the wheel (P<0.05). The wheelchair users with paraplegia were found to have higher effectiveness of force at impact as compared to the users with tetraplegia (P<0.05). No significant differences in the impact force magnitudes were found between the four observed hand trajectory patterns. CONCLUSION: The overall force effectiveness tended to be associated with the injury level of the user and was found to be independent of the hand trajectory patterns. PMID- 22507023 TI - A biomechanical analysis of exercise in standing, supine, and seated positions: Implications for individuals with spinal cord injury. AB - CONTEXT/OBJECTIVE: The distal femur is the primary fracture site in patients with osteoporosis after spinal cord injury (SCI). OBJECTIVE: To mathematically compare the compression and shear forces at the distal femur during quadriceps stimulation in the standing, supine, and seated positions. A force analysis across these positions may be a consideration for people with SCI during neuromuscular electrical stimulation of the quadriceps. DESIGN: A biomechanical model. SETTING: Research laboratory. OUTCOME MEASURES: Compression and shear forces from the standing, supine, and seated biomechanical models at the distal femur during constant loads generated by the quadriceps muscles. RESULTS: The standing model estimated the highest compressive force at 240% body weight and the lowest shear force of 24% body weight at the distal femur compared with the supine and seated models. The supine model yielded a compressive force of 191% body weight with a shear force of 62% body weight at the distal femur. The seated model yielded the lowest compressive force of 139% body weight and the highest shear force of 215% body weight. CONCLUSIONS: When inducing a range of forces in the quadriceps muscles, the seated position yields the highest shear forces and lowest compressive forces when compared with the supine and standing positions. Standing with isometric contractions generates the highest compressive loads and lowest shear forces. Early active resistive standing may provide the most effective means to prevent bone loss after SCI. PMID- 22507025 TI - Association between reliance on devices and people for walking and ability to walk community distances among persons with spinal cord injury. AB - OBJECTIVE: To identify and describe the frequency of reliance on assistive devices and/or people for ambulating distances and stair climbing. DESIGN: Survey. SETTING: A total of 429 adults with traumatic spinal cord injury who were able to walk at least 10 m were identified through inpatient and outpatient hospital databases at a specialty hospital in the southeast United States. OUTCOME MEASURE: Data were collected using a self-report questionnaire including items related to distances walked and devices used for ambulation. RESULTS: Participants best able to ambulate community distances were those who were independent with ambulation and those who used one cane or crutch. Reliance on people or use of a walker was associated with walking shorter distances. Regression analysis indicated reliance on devices or people for walking predicted variation in ability to ambulate community distances after controlling for demographic and injury characteristics. CONCLUSION: This study suggests that reliance on devices or a person for assistance is important to consider when assessing potential for achieving functional community ambulation. PMID- 22507027 TI - Post-laminectomy rotokyphoscoliosis causing paraplegia in long term: case report. AB - CONTEXT: Childhood laminectomy can lead to spinal deformity. This is a report of a case of paraplegia caused by rotokyphoscoliosis, a late complication of laminectomy. FINDINGS: A 55-year-old woman developed paraplegia due to post laminectomy kyphoscoliosis. She had surgery for a spinal tumor at age 13 years. She developed kyphosis 2 years after the laminectomy, which has been gradually progressing over the years. She experienced weakness of lower limbs that progressed to paraplegia. There was no evidence for tumor recurrence. To our knowledge, this is the first reported case of post-laminectomy kyphoscoliosis causing late-onset paraplegia. CONCLUSIONS/CLINICAL RELEVANCE: This case highlights a possible long-term complication of laminectomy without stabilization or untreated kyphoscoliosis. Children should be followed closely after laminectomy because development of spinal deformity is very common. Without intervention, the kyphosis might progress and in the long term, serious neurological complications may result, including paraplegia. PMID- 22507028 TI - Simultaneously diagnosed pulmonary thromboembolism and hemopericardium in a man with thoracic spinal cord injury. AB - BACKGROUND: Simultaneous pulmonary thromboembolism (PTE) and hemopericardium is a rare but life-threatening condition. As hemopericardium is a contraindication to anticoagulation treatment, it is challenging to handle both conditions together. OBJECTIVE: The objective of the study was to report a rare case of a man with thoracic spinal cord injury presenting with simultaneous PTE and hemopericardium. DESIGN: Case report. SUBJECT: A 43-year-old man with incomplete T9 paraplegia (American Spinal Injury Association Impairment Scale D) complained of fever one and a half months after spinal cord injury sustained in a fall. FINDINGS: During evaluation of fever origin, chest computed tomography and transthoracic echocardiogram revealed simultaneous PTE and hemopericardium. After serial echocardiograms over 2 days demonstrated stability, intravenous heparin, and oral warfarin were administered and his medical status was observed closely. Ultimately, both conditions improved without significant complications. CONCLUSION: We report successful treatment of man with acute spinal cord injury who presented with simultaneously diagnosed PTE and hemopericardium, a rare complication involving two distinct and opposing pathological mechanisms and conflicting treatments. PMID- 22507029 TI - Report of practicability of a 6-month home-based functional electrical stimulation cycling program in an individual with tetraplegia. AB - BACKGROUND: Sedentarism is common among people with spinal cord injury (SCI). However, new technologies such as functional electrical stimulation cycles with internet connectivity may provide incentive by removing some of the limitations and external barriers. OBJECTIVE: To determine the effectiveness of a long-term home-based functional electrical stimulation lower extremities cycling (FES-LEC) program on exercise adherence, body composition, energy expenditure, and quality of life (QOL) in an adult with chronic tetraplegia. PARTICIPANT: A 53-year-old man, 33 years post-motor complete C4 SCI participated in FES-LEC in his home, three sessions per week for 24 weeks. METHODS: Exercise adherence was calculated as the percentage of performed cycling sessions relative to the recommended number of cycling sessions. Body composition was measured by dual-energy X-ray absorptiometry. Energy expenditure was measured using a COSMED K4b2 and QOL via the World Health Organization Quality of Life (WHO-QOL) Brief Questionnaire. Testing was performed before and after the 24-week exercise program. RESULTS: The participant cycled 59 out of a recommended 72 sessions which is an exercise adherence rate of 82%. Body composition displayed increases in total body lean mass (LM) with an increase of 3.3% and an increase in leg LM of 7.1%. Energy expenditure increased by 1.26 kcal/minute or greater than 200%. The physical and psychological domain scores of QOL increased by 25 and 4.5%, respectively. CONCLUSION: This case study provides encouragement concerning the practicality of a home-based FES-LEC program for those with SCI. PMID- 22507026 TI - Development of less invasive neuromuscular electrical stimulation model for motor therapy in rodents. AB - BACKGROUND: Combination therapy is essential for functional repairs of the spinal cord. Rehabilitative therapy can be considered as the key for reorganizing the nervous system after spinal cord regeneration therapy. Functional electrical stimulation has been used as a neuroprosthesis in quadriplegia and can be used for providing rehabilitative therapy to tap the capability for central nervous system reorganization after spinal cord regeneration therapy. OBJECTIVE: To develop a less invasive muscular electrical stimulation model capable of being combined with spinal cord regeneration therapy especially for motor therapy in the acute stage after spinal cord injury. METHODS: The tibialis anterior and gastrocnemius motor points were identified in intact anesthetized adult female Fischer rats, and stimulation needle electrodes were percutaneously inserted into these points. Threshold currents for visual twitches were obtained upon stimulation using pulses of 75 or 8 kHz for 200 ms. Biphasic pulse widths of 20, 40, 80, 100, 300, and 500 us per phase were used to determine strength-duration curves. Using these parameters and previously obtained locomotor electromyogram data, stimulations were performed on bilateral joint muscle pairs to produce reciprocal flexion/extension movements of the ankle for 15 minutes while three dimensional joint kinematics were assessed. RESULTS: Rhythmic muscular electrical stimulation with needle electrodes was successfully done, but decreased range of motion (ROM) over time. High-frequency and high-amplitude stimulation was also shown to be effective in alleviating decreases in ROM due to muscle fatigue. CONCLUSIONS: This model will be useful for investigating the ability of rhythmic muscular electrical stimulation therapy to promote motor recovery, in addition to the efficacy of combining treatments with spinal cord regeneration therapy after spinal cord injuries. PMID- 22507030 TI - Distribution and survival of Vibrio vulnificus genotypes in postharvest Gulf Coast (USA) oysters under refrigeration. AB - AIMS: The effect of refrigeration on the seafood-borne pathogen Vibrio vulnificus was investigated in terms of genotype selection and persistence in refrigerated oysters. METHODS AND RESULTS: Naturally occurring numbers of V. vulnificus in oysters from two different locations were compared during a 2-week period under refrigeration conditions. At different time points, V. vulnificus isolates were recovered from oysters and ascribed to 16S rRNA gene type A, B or AB using restriction fragment length polymorphism. Initial V. vulnificus numbers were higher than 10(4) most probable number (MPN) g(-1) and remained unchanged throughout the duration of the study. 16S rRNA gene type B isolates accounted for 53% of the isolates recovered. Amplified fragment length polymorphism analysis confirmed the high genetic variability previously observed within this species but revealed the presence of two main genetic groups within the species that matched 16S rRNA gene ascription. CONCLUSIONS: Vibrio vulnificus numbers in oysters did not significantly declined over the shelf life of the product and refrigeration did not select for specific V. vulnificus types. SIGNIFICANCE AND IMPACT OF THE STUDY: The prevalence of V. vulnificus 16S rRNA gene type B in oysters was higher than previously reported from the same geographic area and was not significantly reduced during the storage period. Vibrio vulnificus is divided into two clear genotypes, regardless of the genetic marker used. PMID- 22507032 TI - Combined single-level subtotal corpectomy and decompression for cervical spondylotic myelopathy treatment. AB - BACKGROUND: The purpose of this study was to summarize outcomes of patients with refractory multisegmental cervical spondylotic myelopathy (CSM) who were treated by combined single-level subtotal corpectomy and decompression of the intervertebral space using the anterior approach. METHODS: Forty-five consecutive patients with multisegmental CSM were included; their ages ranged from 37 to 72 years. Seventeen (37.8%) patients had noncontiguous or 'jumping' multisegmental CSM and 28 (62.2%) had contiguous multisegmental CSM. The mean preoperative Japanese Orthopedic Association (JOA) score was 8.1 points. All patients underwent combined single-level decompression of the involved intervertebral space and subtotal corpectomy together with subsequent fusion and internal fixation. An anterior approach was used for all patients. A cage filled with bone graft was inserted and internal fixation was performed after single-level intervertebral space decompression. Mesh filled with bone graft was inserted and plate internal fixation was performed after subtotal corpectomy. RESULTS: Follow up data (average follow-up, 14 months) were available for all 45 patients; the mean postoperative JOA score was 13.2 points, which was significantly different from the preoperative JOA score. Bony fusion was achieved in all patients based on postoperative radiography, and no pseudoarthrosis was observed during follow up. CONCLUSIONS: An excellent outcome can be achieved with the combination of single-level subtotal corpectomy and decompression of the intervertebral space using the anterior approach to treat multisegmental CSM. PMID- 22507031 TI - Implementing a public-private mix model for tuberculosis treatment in urban Pakistan: lessons and experiences. AB - SETTING: Six towns of Karachi, Pakistan. OBJECTIVES: 1) To strengthen the capacity of general practitioners (GPs) in providing tuberculosis (TB) treatment through DOTS; and 2) to enhance collaboration between the public and private sectors in TB management and case reporting. DESIGN: A quasi-experimental study design was adopted to ensure enrolment of TB patients through trained GPs with the support of laboratory networks and to improve the case detection rate. RESULTS: The following challenges were faced during implementation of the model in urban settings: no systematic list of GPs was available; the majority of the GPs were untrained health practitioners working in squatter settlements, where formally trained GPs are most needed; the motivation of GPs with high patient loads is very low; and access to a laboratory is difficult. Of 35 patients enrolled in the first quarter (third quarter 2009), 87% completed their treatment successfully. CONCLUSION: Public-private mix (PPM) DOTS is feasible in the cities of Pakistan. However, the cost, time and effort required to establish the programme is higher than in many other developing countries. PMID- 22507033 TI - Glucocorticoids in pediatric inflammatory bowel disease. AB - Children with moderate to severe inflammatory bowel disease (IBD) are treated with systemic glucocorticoids (GCs). The majority of the patients respond to the given treatment; however, steroid resistance and dependency are significant clinical problems. Also therapy-related side effects limit the use of GCs in the control of active inflammation. This review summarizes recent knowledge of GC treatment in pediatric patients with IBD. PMID- 22507034 TI - Contribution of serine racemase/d-serine pathway to neuronal apoptosis. AB - Recent data indicate that age-related N-methyl-d-aspartate receptor (NMDAR) transmission impairment is correlated with the reduction in serine racemase (SR) expression and d-serine content. As apoptosis is associated with several diseases and conditions that generally occur with age, we investigated the modulation of SR/d-serine pathway during neuronal apoptosis and its impact on survival. We found that in cerebellar granule neurons (CGNs), undergoing apoptosis SR/d-serine pathway is crucially regulated. In the early phase of apoptosis, the expression of SR is reduced, both at the protein and RNA level through pathways, upstream of caspase activation, involving ubiquitin proteasome system (UPS) and c-Jun N terminal kinases (JNKs). Forced expression of SR, together with treatment with NMDA and d-serine, blocks neuronal death, whereas pharmacological inhibition and Sh-RNA-mediated suppression of endogenous SR exacerbate neuronal death. In the late phase of apoptosis, the increased expression of SR contribute to the last, NMDAR-mediated, wave of cell death. These findings are relevant to our understanding of neuronal apoptosis and NMDAR activity regulation, raising further questions as to the role of SR/d-serine in those neuro-pathophysiological processes, such as aging and neurodegenerative diseases characterized by a convergence of apoptotic mechanisms and NMDAR dysfunction. PMID- 22507035 TI - Liver X receptor agonist alleviated high glucose-induced endothelial progenitor cell dysfunction via inhibition of reactive oxygen species and activation of AMP activated protein kinase. AB - OBJECTIVE: Liver X receptors (LXRs) are key regulators of cholesterol homeostasis. Synthetic LXR agonists are anti-atherogenic and anti-inflammatory. However, the effect of LXR agonists on endothelial progenitor cell (EPC) function is largely unknown. Here, we explored the effect of the LXR agonist TO901317 (TO) on EPC biology and the underlying mechanisms. METHODS: Endothelial progenitor cells were cultured in mannitol or 30 mm glucose (high glucose) for 24 hours. For TO treatments, cells were pretreated with TO (10 MUm) for 12 hours, then mannitol or high glucose was added for an additional 24 hours. EPCs function, reactive oxygen species (ROS) release, and phosphorylation of adenosine monophosphate activated protein kinase (AMPK) were analyzed. RESULTS: TO could restore the high glucose-impaired adhesion and migration capacity of EPCs. High glucose impaired EPC-mediated angiogenesis, and TO reversed the impairment. TO also alleviated ROS release induced by high glucose. Western blot analysis revealed that high glucose downregulated the phosphorylation of AMPK and endothelial nitric oxide synthase, which could be reversed with TO treatment. Furthermore, inhibiting AMPK activation by compound C could abolish the protective effects of TO on EPCs. CONCLUSIONS: TO had a protective effect on EPCs under high glucose by inhibiting ROS release and activating AMPK. PMID- 22507036 TI - Commentary: Epidermal barrier function: clinical implications and therapeutic relevance. PMID- 22507037 TI - Structure and function of the epidermis related to barrier properties. AB - The most important function of the skin is the formation of a barrier between the "inside" and the "outside" of the organism, which prevents invasion of pathogens and fends off chemical assaults as well as the unregulated loss of water and solutes. The physical barrier is mainly localized in the stratum corneum, which consists of protein-enriched cells and lipid-enriched intercellular domains. Any modifications in epidermal differentiation and lipid composition results in altered barrier function, a central event in various skin alterations and diseases. This contribution presents a brief description of the structure of the skin, paying attention to the most important components responsible for skin barrier function. PMID- 22507038 TI - Regulation of permeability barrier homeostasis. AB - A major function of the skin is to provide a barrier to the movement of water and electrolytes, which is required for life in a terrestrial environment. This permeability barrier is localized to the stratum corneum and is mediated by extracellular lipid-enriched lamellar membranes, which are delivered to the extracellular spaces by the secretion of lamellar bodies by stratum granulosum cells. A large number of factors have been shown to regulate the formation of this permeability barrier. Specifically, lamellar body secretion and permeability barrier formation are accelerated by decreases in the calcium content in the stratum granulosum layer of the epidermis. In addition, increased expression of cytokines and growth factors and the activation of nuclear hormone receptors (peroxisome proliferator-activated receptors, liver X receptors, vitamin D receptor) accelerate permeability barrier formation. In contrast, nitric oxide, protease-activated receptor 2 activation, glucocorticoids, and testosterone inhibit permeability barrier formation. The ability of a variety of factors to regulate permeability barrier formation allows for a more precise and nuanced regulation. PMID- 22507039 TI - Influence of skin type, race, sex, and anatomic location on epidermal barrier function. AB - The intact skin represents a barrier to the uncontrolled loss of water, proteins, and plasma components from the organism. Owing to its complex structure, the epidermal barrier with its major layer, the stratum corneum, is the rate-limiting unit for the penetration of exogenous substances through the skin. The epidermal barrier is not a static structure. The status of different functions of the epidermis can be monitored by assessing specific biophysical parameters such as transepidermal water loss, stratum corneum hydration, and skin surface pH. Variables originating from the individual as well as exogenous factors have an important influence on the epidermal barrier parameters. PMID- 22507040 TI - Effects of age (neonates and elderly) on skin barrier function. AB - Skin, together with its appendages, forms an organ with several defensive roles; among them it acts as a barrier, which is one of its very important protective functions. There has been increased interest in studying the effects of age on these functions. There are different intensities and timing involved in this process and also differences between men and women, all relating to skin structure. We review the current knowledge of the skin as a barrier in neonates and in the elderly in an attempt to explain the changes that occur with aging. PMID- 22507041 TI - Epidermal barrier function and systemic diseases. AB - The skin is a vital organ for life and, among its many functions, the role as a protective barrier is one of the most important. It is the main boundary between the body and the external environment. As defensive barrier, the epidermis protects internal organs from physical and chemical trauma, microorganism invasion, and ultraviolet radiation. It also acts in the regulation of transepidermal movement of water and electrolytes, and in preventing dehydration, all of which are essential for sustaining life. The main role is allotted to the stratum corneum and to the lipid matrix located in the intercellular space. The occurrence of dysfunction in the epidermal barrier is an important factor in the physiopathogenesis of skin diseases, particularly atopic dermatitis and psoriasis. There are few, but important, systemic changes that influence or are influenced by dysfunctions in the epidermal barrier. We review the effects of some systemic diseases on the maintenance of the skin's homeostasis. PMID- 22507042 TI - Psychological stress and epidermal barrier function. AB - The skin is the organ that acts as a barrier between the outer and inner environments of the body. It is thus exposed not only to a wide variety of physical, chemical, and thermal insults from the outside world but also to inner endogenous stimuli. Stress, once an abstract psychologic phenomenon, has taken research's center stage in recent years. The "mind-body connection" is now less of an obscure New Age term and more of an elaborate physiologic pathway by which bilateral communication occurs between body and brain. Dermatologists and dermatologic patients have long acknowledged the effect of stress on the skin and its capability to initiate, maintain, or exacerbate several skin diseases. Because disruption of epidermal barrier integrity may be important in the development of some common skin diseases, it is crucial to understand its vulnerability to psychologic stress. PMID- 22507043 TI - Effect of moisturizers on epidermal barrier function. AB - A daily moisturizing routine is a vital part of the management of patients with atopic dermatitis and other dry skin conditions. The composition of the moisturizer determines whether the treatment strengthens or deteriorates the skin barrier function, which may have consequences for the outcome of the dermatitis. One might expect that a patient's impaired skin barrier function should improve in association with a reduction in the clinical signs of dryness. Despite visible relief of the dryness symptoms, however, the abnormal transepidermal water loss has been reported to remain high, or even to increase under certain regimens, whereas other moisturizers improve skin barrier function. Differing outcomes have also been reported in healthy skin: some moisturizers produce deterioration in skin barrier function and others improve the skin. Possible targets for barrier influencing moisturizing creams include the intercellular lipid bilayers, where the fraction of lipids forming a fluid phase might be changed due to compositional or organizational changes. Other targets are the projected size of the corneocytes or the thickness of the stratum corneum. Moisturizers with barrier-improving properties may delay relapse of dermatitis in patients with atopic dermatitis. In a worst-case scenario, treatment with moisturizing creams could increase the risks of dermatitis and asthma. PMID- 22507044 TI - Effect of soaps and detergents on epidermal barrier function. AB - The past decade has witnessed an explosion of new impartial information about the complex interaction of the skin with topically applied substances, including soaps and detergents. Despite of all these new data, our knowledge on the exact pathomechanism and molecular events leading to detergent-induced barrier dysfunction remains incomplete and the answers continue to elude us. The longtime prevailing opinion which contends that the damaging effect of soaps and detergents is related to their property to extract and remove useful intercellular lipids has mostly been abandoned. Although this effect might be involved in the damaging effect, it is definitely not the sole mechanism, nor, indeed, is it even the main one. Skin proteins damage, the interaction with keratins and their denaturation, swelling of cell membranes and collagen fibers, cytotoxicity expressed with cellular lysis are other important mechanisms. One proposed mechanism is that an initial stratum corneum hyper-hydration results from a continuous disruption of the secondary and tertiary structures of keratin protein by surfactants, exposing new water-binding sites, thereby increasing the hydration of the membrane. Following evaporation of excess water, the denatured keratin possesses a decreased water-binding capacity and decreased ability to function as a barrier. Recent studies have also emphasized the effects of detergents on lipid synthesis, on lipid-metabolizing enzymes and on keratinocyte differentiation. PMID- 22507045 TI - Noninvasive test methods for epidermal barrier function. AB - New bioengineering techniques provide noninvasive opportunities to evaluate clinically the application of various products on the skin. The skin barrier function and its integrity can be studied by transepidermal water loss, stratum corneum water content, transcutaneous flux of carbon dioxide and oxygen, and transepidermal movement of ions, particularly chloride, potassium, and hydrogen ions. The benefits of noninvasive techniques are due not only to their lack of skin barrier destruction but also to their potential for early detection of any subclinical effects not detected by the naked eyes. PMID- 22507047 TI - Abnormal epidermal barrier in the pathogenesis of psoriasis. AB - Almost 2 decades ago, Williams and Elias suggested a unifying concept for the pathogenesis of disorders of cornification, according to which the integrity of the epidermal barrier and its effective function is an important factor in the regulation of epidermal DNA synthesis. Interference with the barrier integrity or function will result in epidermal hyperplasia and may be the primary event leading to hyperproliferative skin diseases, such as psoriasis. We have analyzed alterations to several structures of the epidermal barrier that might be responsible for barrier dysfunction and thus lead to hyperproliferation of the epidermis in an attempt to repair the barrier and, as a result, might be inducers of psoriasis. There are several convincing reports indicating that inhibiting of epidermal transglutaminase may lead to epidermal hyperproliferation and that this stimulus might trigger psoriasis among genetically predisposed patients. Disturbance of epidermal barrier function caused by derangement of lipid or cholesterol or ceramide synthesis leads to increased DNA synthesis and epidermal hyperplasia and as a result might be an inducer of psoriasis. We could find little evidence to show that defective defense of the epidermis or an abnormal response of it to bacteria plays a role in the pathogenesis of psoriasis. Accumulating data indicate that there is an association of psoriasis and mutations of genes within the epidermal differentiation complex, which are crucial for the development, maturation, cornification, cross-linking, and terminal differentiation of the epidermis, called psoriasis susceptibility locus 4. PMID- 22507046 TI - Abnormal barrier function in the pathogenesis of ichthyosis: therapeutic implications for lipid metabolic disorders. AB - Ichthyoses, including inherited disorders of lipid metabolism, display a permeability barrier abnormality in which the severity of the clinical phenotype parallels the prominence of the barrier defect. The pathogenesis of the cutaneous phenotype represents the consequences of the mutation for epidermal function, coupled with a "best attempt" by affected epidermis to generate a competent barrier in a terrestrial environment. A compromised barrier in normal epidermis triggers a vigorous set of metabolic responses that rapidly normalizes function, but ichthyotic epidermis, which is inherently compromised, only partially succeeds in this effort. Unraveling mechanisms that account for barrier dysfunction in the ichthyoses has identified multiple, subcellular, and biochemical processes that contribute to the clinical phenotype. Current treatment of the ichthyoses remains largely symptomatic: directed toward reducing scale or corrective gene therapy. Reducing scale is often minimally effective. Gene therapy is impeded by multiple pitfalls, including difficulties in transcutaneous drug delivery, high costs, and discomfort of injections. We have begun to use information about disease pathogenesis to identify novel, pathogenesis-based therapeutic strategies for the ichthyoses. The clinical phenotype often reflects not only a deficiency of pathway end product due to reduced-function mutations in key synthetic enzymes but often also accumulation of proximal, potentially toxic metabolites. As a result, depending upon the identified pathomechanism(s) for each disorder, the accompanying ichthyosis can be treated by topical provision of pathway product (eg, cholesterol), with or without a proximal enzyme inhibitor (eg, simvastatin), to block metabolite production. Among the disorders of distal cholesterol metabolism, the cutaneous phenotype in Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD syndrome) and X-linked ichthyosis reflect metabolite accumulation and deficiency of pathway product (ie, cholesterol). We validated this therapeutic approach in two CHILD syndrome patients who failed to improve with topical cholesterol alone, but cleared with dual treatment with cholesterol plus lovastatin. In theory, the ichthyoses in other inherited lipid metabolic disorders could be treated analogously. This pathogenesis (pathway)-driven approach possesses several inherent advantages: (1) it is mechanism-specific for each disorder; (2) it is inherently safe, because natural lipids and/or approved drugs often are utilized; and (3) it should be inexpensive, and therefore it could be used widely in the developing world. PMID- 22507048 TI - Abnormal epidermal barrier in the pathogenesis of atopic dermatitis. AB - Despite the acknowledged contributions of a defective epidermal permeability barrier, dryness of the skin, and the propensity to develop secondary infections to the etiology and pathophysiology of atopic dermatitis (AD), these epidermal changes have, until recently, been assumed to reflect downstream consequences that are secondary phenomena of the primary immunologic abnormality--the historical "inside-outside" view that AD is basically an intrinsic inflammatory disease. In this review, we focused on the role of the epidermal barrier function in the pathophysiology of AD. Specifically, we presented data in support of a barrier-initiated pathogenesis of AD, ie, the "outside-inside" concept. First, we reviewed the evidence on the existence of inherited barrier abnormalities in AD. Reported studies on the possible association of mutations in the filaggrin gene (FLG) and data on human tissue kallikreins (KLKs) and AD have been addressed. We then dealt with the question of the causal link between impaired epidermal barrier and inflammation. Finally, the association between innate immune defense system and the increased avidity of Staphylococcus aureus for atopic skin was examined. Despite very convincing evidence to support the barrier-initiated pathogenesis of AD, the view that AD reflects the downstream consequences of a primary immunologic abnormality cannot be dismissed out of hand. Almost every line of evidence in support of the role of the epidermal barrier as the "driver" of the disease activity can be challenged and at least partially contradicted by opposing evidence. Until more data are available and until all the dust settles around this issue, we should take advantage of what we already know and use our knowledge for practical purposes. Deployment of specific strategies to restore the barrier function in AD means the use of moisturizers as first-line therapy. PMID- 22507049 TI - Abnormal epidermal barrier in the pathogenesis of contact dermatitis. AB - A crucial role of the epidermal permeability barrier is obvious in contact dermatitis. An intact skin barrier prevents the penetration of harmful substances into the skin. Irritants and allergens that stay on the skin surface and come into contact with the stratum corneum only do not harm the skin. After disruption of the skin barrier, however, irritants may penetrate into the living epidermal layers, injure the keratinocyte membrane, and release cytokines, which leads to inflammation and to irritant contact dermatitis. The skin barrier is often disrupted by chronic exposure to water plus detergents, solvents, or other irritants. A disrupted barrier in irritant contact dermatitis also allows for the penetration of allergens. Allergens may come into contact with Langerhans and T cells, induce immunological reactions, and cause inflammation, which results in allergic contact dermatitis. Treatments in contact dermatitis should restore the skin barrier to prevent relapse of the disease. Topical corticosteroids, most often used in treating contact dermatitis, reduce immunological reactions and inflammation but do not lead to a complete barrier repair. Skin barrier repair is more complete after treatment with calcineurin inhibitors and bland lipid-based emollient; therefore, these preparations should be preferred for long-term treatment of contact dermatitis. PMID- 22507050 TI - New treatments for restoring impaired epidermal barrier permeability: skin barrier repair creams. AB - Skin health depends on an intact barrier composed of protein-rich corneocytes surrounded by the lamellar intercellular lipids. This barrier provides waterproof protection for the body, preventing infection, regulating electrolyte balance, maintaining body temperature, and providing a mechanism for sensation. Damage to the skin barrier results in skin disease that can be treated by a variety of externally applied substances, such as ceramides, hyaluronic acid, licorice extracts, dimethicone, petrolatum, and paraffin wax. These substances are found in moisturizers that are sold as cosmetics and in prescriptions as 510(k) devices. This contribution examines the formulation and effect of skin barrier creams. PMID- 22507051 TI - Chronic idiopathic urticaria and post-traumatic stress disorder (PTSD): an under recognized comorbidity. AB - A large body of literature supports the role of psychologic stress in urticaria; however, the comorbidity between chronic idiopathic urticaria (CIU) and post traumatic stress disorder (PTSD), a classic stress-mediated syndrome, has received little attention. The underlying etiology of urticaria is not identifiable in about 70% of patients, possibly because of difficulties with identification of a direct cause-and-effect relationship between a potential causative factor and the onset of urticaria. The core features of PTSD (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision [DSMIV-TR]) that are important in urticaria include (1) autonomic nervous system reactivity and state of sympathetic hyperarousal that can manifest as CIU, and (2) the persistent re-experiencing of the traumatic events in PTSD, which can manifest as urticaria or angioedema, or both, affecting a previously traumatized body region (eg, urticarial wheals affecting the body region where the patient had been stabbed years earlier). The following features of PTSD make it difficult to use the cause-and-effect model for the determination of causation: (1) PTSD may first emerge years after the initial trauma and is classified as PTSD with Delayed Onset (DSMIV-TR); and (2) the traumatic triggers that precipitate the PTSD symptoms may be unique and idiosyncratic to the patient and not even qualify as stressful or traumatic by standard criteria (eg, precipitating events for the PTSD may include smell of a certain cologne that was used by the perpetrator or witnessing a scene in a movie that was reminiscent of the location where the abuse occurred). Finally, in PTSD with Delayed Onset, patients may not make a conscious association between their recurrent urticaria and their earlier traumas because they can develop classically conditioned associations between stimuli that are reminiscent of the original abuse situation and their somatic reactions such as urticaria. The clinician needs to be aware of these factors, because satisfactory resolution of the CIU may not occur without treatment of the PTSD. If the clinician suspects underlying PTSD, it is best to refer the patient to a qualified mental health professional, because detailed history taking about traumatic experiences alone can have an acute destabilizing effect and heighten PTSD symptoms in some patients. PMID- 22507052 TI - Forensic art and crime solving: a potential role for dermatologists. AB - This article suggests ways dermatologists can help solve crimes by sharing knowledge with detectives about abnormalities observed in forensic sketches of suspects. PMID- 22507053 TI - Noninvasive prenatal diagnosis of monogenic disorders. AB - INTRODUCTION: Since the presence of circulating cell-free fetal DNA (ccffDNA) in maternal peripheral blood was demonstrated in 1997, great efforts have been done in order to use this source of fetal material for noninvasive prenatal diagnosis. The advantage that it represents is avoiding the obstetric invasive procedures required for conventional prenatal diagnosis. AREAS COVERED: Efforts are mainly focused on finding the most accurate way to diagnose the most common fetal aneuploidies, paying special attention to trisomy 21. Recent advances in technology offer new diagnostic tools with high degrees of sensitivity thus generating great expectations for this type of diagnosis. However, there are other reasons why pregnant women undergo conventional prenatal diagnosis. Being at risk of transmitting a monogenic disorder is one of them. And although the percentage of those pregnancies may represent a small percentage of the diagnosis performed in the first trimester, these numbers should not be underestimated. EXPERT OPINION: Management of pregnancies at risk of an X-linked Mendelian disorder has changed thanks to the noninvasive fetal sex assessment. As for other Mendelian disorders, until recently, their study was limited to those cases paternally inherited. Nevertheless, the new emerging technologies are also opening the scope to maternally inherited disorders. PMID- 22507054 TI - Structural basis for bifunctional zinc(II) macrocyclic complex recognition of thymine bulges in DNA. AB - The zinc(II) complex of 1-(4-quinoylyl)methyl-1,4,7,10-tetraazacyclododecane (cy4q) binds selectively to thymine bulges in DNA and to a uracil bulge in RNA. Binding constants are in the low-micromolar range for thymine bulges in the stems of hairpins, for a thymine bulge in a DNA duplex, and for a uracil bulge in an RNA hairpin. Binding studies of Zn(cy4q) to a series of hairpins containing thymine bulges with different flanking bases showed that the complex had a moderate selectivity for thymine bulges with neighboring purines. The dissociation constants of the most strongly bound Zn(cy4q)-DNA thymine bulge adducts were 100-fold tighter than similar sequences with fully complementary stems or than bulges containing cytosine, guanine, or adenine. In order to probe the role of the pendent group, three additional zinc(II) complexes containing 1,4,7,10-tetraazacyclododecane (cyclen) with aromatic pendent groups were studied for binding to DNA including 1-(2-quinolyl)methyl-1,4,7,10-tetraazacyclododecane (cy2q), 1-(4-biphenyl)methyl-1,4,7,10-tetraazacyclododecane (cybp), and 5 (1,4,7,10-tetraazacyclododecan-1-ylsulfonyl)-N,N-dimethylnaphthalen-1-amine (dsc). The Zn(cybp) complex binds with moderate affinity but little selectivity to DNA hairpins with thymine bulges and to DNA lacking bulges. Similarly, Zn(dsc) binds weakly both to thymine bulges and hairpins with fully complementary stems. The zinc(II) complex of cy2q has the 2-quinolyl moiety bound to the Zn(II) center, as shown by (1)H NMR spectroscopy and pH-potentiometric titrations. As a consequence, only weak (500 MUM) binding is observed to DNA with no appreciable selectivity. An NMR structure of a thymine-bulge-containing hairpin shows that the thymine is extrahelical but rotated toward the major groove. NMR data for Zn(cy4q) bound to DNA containing a thymine bulge is consistent with binding of the zinc(II) complex to the thymine N3(-) and stacking of the quinoline on top of the thymine. The thymine-bulge bound zinc(II) complex is pointed into the major groove, and there are interactions with the guanine positioned 5' to the thymine bulge. PMID- 22507055 TI - Enhancement of neural representation capacity by modular architecture in networks of cortical neurons. AB - Biological networks are ubiquitously modular, a feature that is believed to be essential for the enhancement of their functional capacities. Here, we have used a simple modular in vitro design to examine the possibility that modularity enhances network functionality in the context of input representation. We cultured networks of cortical neurons obtained from newborn rats in vitro on substrate-integrated multi-electrode arrays, forcing the network to develop two well-defined modules of neural populations that are coupled by a narrow canal. We measured the neural activity, and examined the capacity of each module to individually classify (i.e. represent) spatially distinct electrical stimuli and propagate input-specific activity features to their downstream coupled counterpart. We show that, although each of the coupled modules maintains its autonomous functionality, a significant enhancement of representational capacity is achieved when the system is observed as a whole. We interpret our results in terms of a relative decorrelation effect imposed by weak coupling between modules. PMID- 22507056 TI - Critical issues in clinical periodontal research. AB - As periodontal researchers and clinicians, we are challenged every day to make decisions relating to the clinical management of our patients and about how best to conduct clinical periodontal research. This volume of Periodontology 2000 addresses some of the critical issues in contemporary clinical periodontics and periodontal research that are of direct relevance to clinicians, researchers, teachers and students. The 11 review articles in this volume of Periodontology 2000 focus on aspects of periodontal research methodology and clinical periodontology. In terms of research methodology, the articles aim to inform the reader on topics relating to randomized controlled trials in periodontal research, evidence-based dentistry, calibration of clinical examiners and statistics relevant to periodontal research. The clinical periodontology articles address issues relating to decisions on retaining periodontally compromised teeth or replacing them with implants, periodontal management in the patient with osteoporosis, surgical approaches for root coverage and the emerging science of advanced regenerative technologies, including the use of stem cells, for periodontal regeneration. It is hoped that these critical reviews will address many of the dilemmas that confront us on a regular basis and provide practical guidance to those engaged in both clinical periodontology and clinical periodontal research. PMID- 22507057 TI - Randomized controlled trials: what are they and who needs them? AB - Dentistry is rapidly entering a new era of evidence-based practice, and society is demanding prevention and treatment that has been proven to be effective in terms of meaningful health outcomes. Practitioners, individual patients and the public need randomized controlled trials because they provide the highest level of scientific evidence to change clinical practice and inform public health policy. Well-designed randomized controlled trials are conceptually simple but deceptively complex to design, implement and translate into clinical practice. Randomized controlled trials are fundamentally different from observational clinical research because they randomly assign volunteers to receive test or control interventions, they are prospective and the success of the test intervention is based on a meaningful clinical outcome that is specified before the trial begins. To be successful, randomized controlled trials must be carefully designed and powered to answer a specific question that will be generalizable to the population under study. Randomized controlled trials can be designed to evaluate efficacy, effectiveness, superiority, equivalence or noninferiority. Prominent issues and challenges in designing and conducting randomized controlled trials include carefully defining enrollment criteria, establishing an organizational infrastructure, use of a data-coordinating center, developing a manual of procedures, obtaining informed consent, recruiting and ensuring the safety of volunteer subjects, ensuring data quality, analysis and publication of trial outcomes, and translating results into clinical practice. PMID- 22507058 TI - Randomized clinical trials: is periodontal research good for patients? AB - Randomized controlled trials, in which randomization is used to allocate patients to a treatment arm, are a relatively new concept. Randomized controlled trials are increasingly high-stakes endeavors requiring a high level of planning and considerable financial support. Randomized controlled trials are the gold standard by which effectiveness of various treatments or interventions are determined. However, the methods involved in randomized controlled trials raise the question: is clinical research good for the participants? This paper discusses patient-centered issues relating to randomized controlled trials, for example, whether the informed-consent process results in subjects who are knowledgeable and informed about their participation, which, in turn, involves patient autonomy, health literacy and treatment preferences. Other issues discussed are those of statistical vs. clinical significance, professional ethics and ethical justification for randomized controlled trials, and differences in perceptions between patients and clinicians regarding the level of care being provided by the randomized controlled trials. Because our goal, as clinicians, is to provide treatment that improves the quality of life for the patient, it would seem logical that randomized controlled trials should include variables rated as important by patients as valid outcome measures. As clinicians and researchers, we can no longer afford to view randomized controlled trials from an ivory tower. Research participants, although autonomous agents, are inherently different from the patient seeking clinical care. Researchers have an ethical responsibility to consider the informed consent process as it relates to the subject's health literacy and potential for therapeutic and procedural misperceptions. PMID- 22507059 TI - Examiner alignment and assessment in clinical periodontal research. AB - Periodontal research typically relies on clinical examiners to assess variables such as gingival inflammation, plaque scores or probing depths as a means of determining treatment outcomes or for performing group comparisons. The quality of the gathered information is dependent, to a large extent, on the skills of the examiner(s) and on the validity of the assessment methods that are used. Attempts have been made to increase the objectivity of periodontal assessments, for example by introducing scoring systems for gingival inflammation, but within these systems there is often considerable scope for variation when interpreting the scoring criteria, leading to subjectivity when assigning scores to individual periodontal sites. This has led to an awareness of the importance of examiner alignment and assessment to improve the data quality by standardizing techniques and improving examiner reliability. Examiner alignment and assessment is used in preference to the term 'examiner calibration' because calibration implies comparison with an accurate or 'gold' standard, which is not available in periodontal research. In this review, we consider the historical perspective that led to the development of clinical scoring systems for periodontal research using gingival inflammation as an example. A clinical protocol for undertaking examiner alignment and assessment is presented, and we review the common sources of error and bias that can lead to difficulties in aligning examiners, and consider how they can be eliminated. It is particularly important that subjects who are recruited to the examiner alignment and assessment study present with a comparable level of disease to the subjects who will ultimately be recruited to the planned clinical trial. Another challenge in examiner alignment and assessment is applying appropriate statistical tests to assess the outcome of the alignment exercise. In the periodontal literature, the statistic kappa is frequently used to confirm an adequate degree of examiner agreement, but kappa is bound to significant restrictions when applied for this purpose. Through the use of case studies, we present different approaches to data analysis from calibration studies, focusing on continuous variables (such as probing depths and attachment levels) or ordinal data (such as gingival or plaque indices), to enable a correct, although frequently conservative, interpretation of data generated during examiner alignment and assessment studies. PMID- 22507060 TI - Application of evidence-based dentistry: from research to clinical periodontal practice. AB - Dentists need to make daily decisions regarding patient care, and these decisions should essentially be scientifically sound. Evidence-based dentistry is meant to empower clinicians to provide the most contemporary treatment. The benefits of applying the evidence-based method in clinical practice include application of the most updated treatment and stronger reasoning to justify the treatment. A vast amount of information is readily accessible with today's digital technology, and a standardized search protocol can be developed to ensure that a literature search is valid, specific and repeatable. It involves developing a preset question (population, intervention, comparison and outcome; PICO) and search protocol. It is usually used academically to perform commissioned reviews, but it can also be applied to answer simple clinical queries. The scientific evidence thus obtained can then be considered along with patient preferences and values, clinical patient circumstances and the practitioner's experience and judgment in order to make the treatment decision. This paper describes how clinicians can incorporate evidence-based methods into patient care and presents a clinical example to illustrate the process. PMID- 22507061 TI - Key statistical and analytical issues for evaluating treatment effects in periodontal research. AB - Statistics is an indispensible tool for evaluating treatment effects in clinical research. Due to the complexities of periodontal disease progression and data collection, statistical analyses for periodontal research have been a great challenge for both clinicians and statisticians. The aim of this article is to provide an overview of several basic, but important, statistical issues related to the evaluation of treatment effects and to clarify some common statistical misconceptions. Some of these issues are general, concerning many disciplines, and some are unique to periodontal research. We first discuss several statistical concepts that have sometimes been overlooked or misunderstood by periodontal researchers. For instance, decisions about whether to use the t-test or analysis of covariance, or whether to use parametric tests such as the t-test or its non parametric counterpart, the Mann-Whitney U-test, have perplexed many periodontal researchers. We also describe more advanced methodological issues that have sometimes been overlooked by researchers. For instance, the phenomenon of regression to the mean is a fundamental issue to be considered when evaluating treatment effects, and collinearity amongst covariates is a conundrum that must be resolved when explaining and predicting treatment effects. Quick and easy solutions to these methodological and analytical issues are not always available in the literature, and careful statistical thinking is paramount when conducting useful and meaningful research. PMID- 22507062 TI - Hierarchical decisions on teeth vs. implants in the periodontitis-susceptible patient: the modern dilemma. AB - It is estimated that advanced periodontitis typically affects about 10% of most adult populations studied. These individuals can be considered highly susceptible to periodontitis and often present difficulties for clinicians in therapeutic decision making, especially when dental implants are involved. Poor plaque control and smoking are well established risk factors for periodontitis, as well as for peri-implant disease. Long-term follow-up studies have clearly demonstrated that treatment of periodontal disease, even if advanced, can be successful in arresting disease progression and preventing (or at least significantly delaying) tooth loss. With the increasing development of implant dentistry, traditional well documented and evidence-based therapies to treat periodontal diseases may sometimes not be used to their full potential. Instead, there appears to be an increasing tendency to extract periodontally compromised teeth and replace them with implants, as if implants can solve the problem. However, peri-implant diseases are prevalent, affecting between 28% and 56% of people with implants, and (at the implant level) 12-43% of implants. A history of periodontal disease, smoking and poor oral hygiene are all risk factors for developing peri-implantitis. Unlike periodontitis, there are currently no predictable means for treating peri-implantitis, although resective surgery seems to be the most effective technique. Consequently, if implant treatment is considered in patients who are susceptible to periodontitis, it should be preceded by appropriate and adequate periodontal treatment or re-treatment to control the condition, and should be followed by a stringent supportive maintenance program to prevent the development of peri-implant disease. The decision whether implant treatment should be performed should be based on an assessment of the patient's risk profile at the subject level, as well as at the site level. PMID- 22507063 TI - Osteoporosis and osteopenia: implications for periodontal and implant therapy. AB - How does low bone mineral density alter treatment decisions? Osteoporosis and osteopenia are major health care issues that may impact on periodontal and implant therapy. Because of the prevalence of osteoporosis, understanding its etiology and the current treatment regimens for patients with low bone mineral density is essential for dental professionals. Millions of patients are now taking medications for the treatment of osteoporosis, and periodontists should be aware of the many medication options that are prescribed. The most frequently prescribed drugs are the bisphosphonates. It is important to be aware that bisphosphonates are not all the same, and patient responses to treatment may vary depending on which bisphosphonates they are taking. Due to recent concerns about bisphosphonate-induced osteonecrosis of the jaw, this paper provides guidance to help the clinician regarding decision-making about preventive and interventional dental treatment when their patient has been prescribed a bisphosphonate. An understanding of current bisphosphonates, their uses, their structural differences and their intended actions helps to improve clinical decision-making. Current knowledge regarding the effects of osteoporosis/osteopenia on periodontal diseases and alveolar bone loss is inconclusive. It is certainly clear that bisphosphonates are not indicated as an adjunctive treatment as part of periodontal therapy because of the risk of osteonecrosis. Regarding implant placement, there are no convincing data that dental implant placement is contraindicated in the osteoporotic patient. However, patients should understand the small risk of compromised bone healing following implant placement if the patient has been taking bisphosphonates. Due to the risks of osteonecrosis, dental clinicians should work closely with their medical colleagues prior to the physician prescribing oral bisphosphonates. Ideally, optimal periodontal and dental health should be established before the patient commences bisphosphonate therapy. PMID- 22507064 TI - Utilizing collagen membranes for guided tissue regeneration-based root coverage. AB - Gingival recession is a common clinical problem that can result in hypersensitivity, pain, root caries and esthetic concerns. Conventional soft tissue procedures for root coverage require an additional surgical site, thereby causing additional trauma and donor site morbidity. In addition, the grafted tissues heal by repair, with formation of long junctional epithelium with some connective tissue attachment. Guided tissue regeneration-based root coverage was thus developed in an attempt to overcome these limitations while providing comparable clinical results. This paper addresses the biologic foundation of guided tissue regeneration-based root coverage, and describes the indications and contraindications for this technique, as well as the factors that influence outcomes. The step-by-step clinical techniques utilizing collagen membranes are also described. In comparison with conventional soft tissue procedures, the benefits of guided tissue regeneration-based root coverage procedures include new attachment formation, elimination of donor site morbidity, less chair-time, and unlimited availability and uniform thickness of the product. Collagen membranes, in particular, benefit from product biocompatibility with the host, while promoting chemotaxis, hemostasis, and exchange of gas and nutrients. Such characteristics lead to better wound healing by promoting primary wound coverage, angiogenesis, space creation and maintenance, and clot stability. In conclusion, collagen membranes are a reliable alternative for use in root coverage procedures. PMID- 22507065 TI - Coronally advanced flap and combination therapy for root coverage. Clinical strategies based on scientific evidence and clinical experience. AB - During the past three decades, several surgical techniques have been proposed to treat single and multiple gingival recessions. Evidence indicates that coronally advanced flap-based approaches result in the best clinical results. Among all the different techniques, the use of a graft under a coronally advanced flap results in the best short- and long-term outcomes in terms of root coverage and gain in keratinized tissue. The use of a coronally advanced flap + connective tissue graft would appear to be the best choice for root coverage. However, harvesting a graft from the palate adds morbidity, surgical chair-time and requires increased surgical skills. A potential alternative could be the use of enamel matrix derivatives under a coronally advanced flap, and this achieves similar clinical outcomes and is less invasive, but adds economic costs to the treatment. Evidence shows that a coronally advanced flap alone in many instances results in complete root coverage and is stable over time. A coronally advanced flap is less invasive for the patient, requires less chair-time and probably less surgical skill. It would therefore be desirable to use a coronally advanced flap approach when indicated. It has been hypothesized that a coronally advanced flap approach alone could be successfully applied when the residual gingiva is thick and wide, although existing evidence does not support this hypothesis in full. Accordingly, the adjunctive use of a graft or enamel matrix derivatives could be restricted to sites at which there is thin and narrow residual gingiva. PMID- 22507067 TI - Clinical utility of stem cells for periodontal regeneration. AB - The aim of this review is to discuss the clinical utility of stem cells in periodontal regeneration by reviewing relevant literature that assesses the periodontal-regenerative potential of stem cells. We considered and described the main stem cell populations that have been utilized with regard to periodontal regeneration, including bone marrow-derived mesenchymal stem cells and the main dental-derived mesenchymal stem cell populations: periodontal ligament stem cells, dental pulp stem cells, stem cells from human exfoliated deciduous teeth, stem cells from apical papilla and dental follicle precursor cells. Research into the use of stem cells for tissue regeneration has the potential to significantly influence periodontal treatment strategies in the future. PMID- 22507068 TI - The latest breakthroughs on more fundamental concepts of microbial communities and on their applications in environmental technologies and nutritional/biomedical sciences. PMID- 22507066 TI - Advanced reconstructive technologies for periodontal tissue repair. AB - Reconstructive therapies to promote the regeneration of lost periodontal support have been investigated through both preclinical and clinical studies. Advanced regenerative technologies using new barrier-membrane techniques, cell-growth stimulating proteins or gene-delivery applications have entered the clinical arena. Wound-healing approaches using growth factors to target the restoration of tooth-supporting bone, periodontal ligament and cementum are shown to significantly advance the field of periodontal-regenerative medicine. Topical delivery of growth factors, such as platelet-derived growth factor, fibroblast growth factor or bone morphogenetic proteins, to periodontal wounds has demonstrated promising results. Future directions in the delivery of growth factors or other signaling models involve the development of innovative scaffolding matrices, cell therapy and gene transfer, and these issues are discussed in this paper. PMID- 22507071 TI - Melatonin regulates Arabidopsis root system architecture likely acting independently of auxin signaling. AB - Melatonin (N-acetyl-5-methoxytryptamine) is a tryptophan-derived signal with important physiological roles in mammals. Although the presence of melatonin in plants may be universal, its endogenous function in plant tissues is unknown. On the basis of its structural similarity to indole-3-acetic acid, recent studies mainly focusing on root growth in several plant species have suggested a potential auxin-like activity of melatonin. However, direct evidence about the mechanisms of action of this regulator is lacking. In this work, we used Arabidopsis thaliana seedlings as a model system to evaluate the effects of melatonin on plant growth and development. Melatonin modulated root system architecture by stimulating lateral and adventitious root formation but minimally affected primary root growth or root hair development. The auxin activity of melatonin in roots was investigated using the auxin-responsive marker constructs DR5:uidA, BA3:uidA, and HS::AXR3NT-GUS. Our results show that melatonin neither activates auxin-inducible gene expression nor induces the degradation of HS::AXR3NT-GUS, indicating that root developmental changes elicited by melatonin were independent of auxin signaling. Taken together, our results suggest that melatonin is beneficial to plants by increasing root branching and that root development processes elicited by this novel plant signal are likely independent of auxin responses. PMID- 22507070 TI - Type 1 diabetes in pre-school children--long-term metabolic control, associated autoimmunity and complications. AB - AIMS: To identify clinical characteristics and co-morbidity rates of children diagnosed with Type 1 diabetes mellitus at younger than 6 years of age. METHODS: Data were obtained from a retrospective chart review of 103 patients diagnosed with Type 1 diabetes at younger than 6 years (study group) and 220 patients at older than 6 years (comparison group). Measures of glycaemic control and occurrence of co-morbidities (coeliac disease, autoimmune thyroid disease, hypertension, nephropathy and retinopathy) were compared. RESULTS: The mean follow-up period was more than 8 years. For the study group, mean HbA(1c) levels ranged from 64 mmol/mol to 66 mmol/mol (8.0-8.2%) until age 10 years, and then rose to 73 mmol/mol (8.8%). The HbA(1c) levels were higher in the study than in the comparison group for comparable ages (P = 0.003). After adjustment for duration of diabetes this difference was not significant. The overall rate of severe hypoglycaemic events was greater in the study group than in the comparison group (P = 0.03). Kaplan-Meier diagnosis rates of celiac disease, 10 years after Type 1 diabetes diagnosis, were 14.4% and 4.2% in the study and comparison groups, respectively (P log-rank = 0.03). There were no differences in rates of autoimmune thyroid disease, hypertension, nephropathy or retinopathy. CONCLUSIONS: Children diagnosed with Type 1 diabetes before the age of 6 years were in greater risk of developing celiac disease, compared with children diagnosed after the age of 6 years. For children diagnosed with Type 1 diabetes aged under 6 years, good metabolic control was achievable until age 10 years, after which it deteriorated. Higher HbA(1c) levels observed in children diagnosed before the age of 6 years were associated with longer duration of disease. PMID- 22507072 TI - Cardiac sympathetic hyperinnervation in deoxycorticosterone acetate-salt hypertensive rats. AB - Sympathetic activities are elevated in the central SNSs (sympathetic nervous systems) of hypertensive animals, but it is not known whether sympathetic innervation is also elevated in the heart. Sympathetic hyper-responsiveness in hypertension may result from oxidative stress. The aim of the present study was to investigate sympathetic hyperinnervation in DOCA (deoxycorticosterone acetate) salt hypertensive rats with established hypertension. At 4 weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were randomized into three groups for 8 weeks: vehicle, NAC (N-acetylcysteine) and triple therapy (hydralazine, hydrochlorothiazide and reserpine). DOCA-salt was associated with increased oxidant release. DOCA-salt produced concentric left ventricular hypertrophy and cardiomyocyte hypertrophy. Sympathetic hyperinnervation was observed in DOCA-salt rats, as assessed by myocardial noradrenaline levels, immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and Western blotting and real-time quantitative RT-PCR (reverse transcription-PCR) of NGF (nerve growth factor). Arrhythmic scores during programmed stimulation in DOCA-salt rats were significantly higher than those in the control rats. Triple therapy, despite being effective on BP (blood pressure), offered neither attenuated cardiomyocyte hypertrophy nor anti-arrhythmia. The effects of DOCA-salt treatment on NGF expression, sympathetic hyperinnervation and arrhythmias were attenuated by NAC. Furthermore, the effects of NAC on NGF were abolished by administering BSO (L-buthionine sulfoximine), an inhibitor of glutamate-cysteine ligase. In conclusion, DOCA-salt treatment contributes to up regulation of NGF proteins probably through a free radical-dependent pathway in a BP-independent manner. DOCA-salt rats treated with NAC attenuate sympathetic hyperinnervation and thus show a beneficial effect on arrhythmogenic response to programmed electrical stimulation. PMID- 22507073 TI - Estimation of frontal alignment error of the extramedullary tibial guide on the bi-malleolar technique: a simulation study with magnetic resonance imaging. AB - PURPOSE: The bi-malleolar technique for the extramedullary tibial guide is a representative method for determining the ankle center in total knee arthroplasty (TKA). The purpose of this study is to estimate three-dimensionally the lateral errors (difference between the real ankle center and the bi-malleolar center) and the varus angular errors of this technique under the condition that the malleolar prominences were correctly identified. METHODS: Magnetic resonance images of 51 lower limbs from 51 healthy volunteers were analyzed. The lateral errors were measured, including or excluding the subcutaneous thickness, along the line perpendicular to the transmalleolar axis (TMA) or along the tibial anteroposterior (AP) axis. Furthermore, we evaluated the effects of the tibial torsion and the difference between the subcutaneous thicknesses on the malleoli on the lateral error. RESULTS: When including the skin, the mean lateral errors of the ankle center observed along the line perpendicular to the TMA and along the tibial AP axis were 3.7 +/- 1.4mm and 1.2 +/- 1.5mm, respectively. The mean angular errors were 0.6 +/- 0.2 degrees and 0.2 +/- 0.3 degrees , respectively. A significant correlation between the tibial torsion and the lateral error was noted when observed along the tibial AP axis. The difference between the subcutaneous thicknesses on the malleoli affected the lateral error. CONCLUSION: The errors were small enough to determine the mechanical axis of the tibia if the tibial guide could catch the bi-malleolar prominences of the ankle accurately and align along the tibial AP axis. PMID- 22507074 TI - Branch thoracic stent graft repair for arch aneurysm. AB - Aortic arch aneurysms involving the major vessels of the neck pose great challenges in their repair. Open repair of these aneurysms are associated with a significant morbidity and mortality. The major challenge for endovascular repair of these complex aneurysms is the maintenance of cerebral perfusion during stent implantation and long-term durability. This paper discusses preoperative planning and technical aspects to successful endovascular repair of a large aortic arch aneurysm involving the distal take-off of the left subclavian artery. PMID- 22507075 TI - Effects of aging and reproduction on protein quality control in soma and gametes of Drosophila melanogaster. AB - In organisms with a soma-germ demarcation, the germline must be 'preserved' such that harmful damage is not transmitted to the offspring. Keeping the progeny free of damage may be achieved by gametes enjoying elevated, and/or more functional, homeostatic maintenance systems. This possibility was approached here by testing whether the soma and maturating oocytes (eggs) dissected from female Drosophila melanogaster in reproductive ages display differential capacities for protein quality control and whether these capacities change during aging and mating. Eggs exhibited a high capacity to prevent protein aggregation, strong capacity for 26S proteasome-dependent degradation and reduced levels of oxidatively damaged (carbonylated) proteins compared to the soma. The capacity to prevent protein aggregation was not affected in either soma or eggs by age and/or mating, while the 26S proteasome capacity declined in the soma but was maintained in the eggs of aged females. However, the levels of carbonylated proteins increased with age in both soma and eggs, and this increase was more pronounced in females allowed to mate continuously. Furthermore, the levels of carbonylated proteins in the eggs of mated flies correlated negatively with the propensity of the eggs to develop into an adult fly. In young flies, mating caused a decrease in 26S proteasome capacity and an increase in protein carbonylation in the soma, but not in the eggs. These results are in line with trade-off theories of aging where aging is considered a consequence of investment in reproduction over somatic maintenance. PMID- 22507076 TI - Bacteribilia with resistant microorganisms after preoperative biliary drainage- the influence of bacteria on postoperative outcome. AB - BACKGROUND: In pancreatic surgery, preoperative biliary drainage (PBD) leads to bacteribilia. Whether positive bile duct cultures are associated with a higher postoperative morbidity might be related to the resistance of the species isolated from bile. STUDY: Intraoperative bile duct cultures were collected from all patients who underwent pancreatic surgery. Postoperative morbidity was analyzed according to the species and the resistance found on bile duct cultures. RESULTS: Fifty-five percent (166/301) of patients had PBD, while 45% (135/301) underwent primary operation. PBD was associated with a positive bile duct culture in 87% (144/166) versus 21% (28/135) in patients without PBD (p = 0.001) and polymicrobial infections in 53% (88/166) versus 6% (8/135) (p = 0.001). Postoperative morbidity was 40% (121/301); mortality was 3% (9/301). PBD was not associated with morbidity and mortality, but resistant species on bile duct cultures lead to significantly more postoperative complications, 54% (25/46) versus 38% (96/255) (p = 0.033), with significantly more antibiotic therapies. CONCLUSION: PBD is associated with polymicrobial infections with resistant microorganisms, resulting in more postoperative complications. Since PBD cannot always be avoided, surgeons and gastroenterologists must be aware of their institutional surveillance data to identify patients at risk for postoperative complications. PMID- 22507077 TI - HTS techniques for patch clamp-based ion channel screening - advances and economy. AB - INTRODUCTION: Ten years ago, the first publication appeared showing patch clamp recordings performed on a planar glass chip instead of using a conventional patch clamp pipette. "Going planar" proved to revolutionize ion channel drug screening as we know it, by allowing high quality measurements of ion channels and their effectors at a higher throughput and at the same time de-skilling the highly laborious technique. Over the years, platforms evolved in response to user requirements regarding experimental features, data handling plus storage, and suitable target diversity. AREAS COVERED: This article gives a snapshot image of patch clamp-based ion channel screening with focus on platforms developed to meet requirements of high-throughput screening environments. The commercially available platforms are described, along with their benefits and drawbacks in ion channel drug screening. EXPERT OPINION: Automated patch clamp (APC) platforms allow faster investigation of a larger number of ion channel active compounds or cell clones than previously possible. Since patch clamp is the only method allowing direct, real-time measurements of ion channel activity, APC holds the promise of picking up high quality leads, where they otherwise would have been overseen using indirect methods. In addition, drug candidate safety profiling can be performed earlier in the drug discovery process, avoiding late-phase compound withdrawal due to safety liability issues, which is highly costly and inefficient. PMID- 22507078 TI - Characterization, GFP gene Nucleofection, and allotransplantation in injured tendons of ovine amniotic fluid-derived stem cells. AB - Amniotic fluid has drawn increasing attention in the recent past as a cost effective and accessible source of fetal stem cells. Amniotic fluid-derived mesenchymal stem cells (AFMSCs) that display high proliferation rate, large spectrum of differentiation potential, and immunosuppressive features are considered optimal candidates for allogeneic repair of mesenchymal damaged tissues. In this study, ovine AFMSCs (oAFMSCs) isolated from 3-month-old sheep fetuses were characterized for their proliferation rate, specific surface antigen and pluripotency marker expression, genomic stability, and mesenchymal lineage differentiation during their in vitro expansion (12 passages) and after nucleofection. The high proliferation rate of oAFMSCs gradually decreased during the first six subculture passages while the expression of surface molecules (CD29, CD58, CD166) and of pluripotency-associated markers (OCT4, TERT, NANOG, SOX2), the in vitro osteogenic differentiation potential, and a normal karyotype were maintained. Afterwards, oAFMSCs were nucleofected with a selectable plasmid coding for green fluorescent protein (GFP) using two different programs, U23 and C17, previously optimized for human mesenchymal stem cells. Transfection efficiencies were ~63% and ~37%, while cell recoveries were ~10% and ~22%, respectively. Nucleofected oAFMSCs expressing the GFP transgene conserved their pluripotency marker profile and retained a normal karyotype and the osteogenic differentiation ability. Seven single clones with a GFP expression ranging from 80% to 97% were then isolated and expanded over 1 month, thus providing stably transfected cells with long-term therapeutic potential. The in vivo behavior of GFP-labeled oAFMSCs was tested on a previously validated preclinical model of experimentally induced Achille's tendon defect. The allotransplanted oAFMSCs were able to survive within the host tissue for 1 month enhancing the early phase of tendon healing as indicated by morphological and biomechanical results. Altogether these data suggest that genetically modified oAFMSCs might represent a valuable tool for in vivo preclinical studies in a highly valid translational model. PMID- 22507081 TI - Bactericidal activity and oral pathogen inactivation by electromagnetic wave irradiation. AB - AIMS: The aim of this work was to clarify the effects of electromagnetic wave irradiation (EMWI) on oral bacterial pathogens. METHODS AND RESULTS: A Gram negative (Porphyromonas gingivalis) or Gram-positive (Streptococcus mutans, S. intermedius, Enterococcus faecalis) bacterial suspension was irradiated by EMW apparatus (500-1000 kHz, 5-15 times, 1 s time(-1) ). Quantification of survival bacteria by CFU counting revealed that EMWI exhibited marked bactericidal activity against all tested bacteria and bactericidal activity at 500 kHz increased in an irradiation number-dependent manner. After EMWI at 500 kHz, scanning electron microscopic observations showed that the chain of S. mutans cells was shortened after 5 irradiations and the outlines of bacterial cells (S. mutans and P. gingivalis) were unclear after 5-10 irradiations. EMWI inhibited the inductive effect of S. mutans on pro-inflammatory cytokine production in human monocytes and this inhibitory effect was comparable with that of heat killed bacteria. Furthermore, using an enzyme activity assay, EMWI partially inactivated the activities of gingipains from P. gingivalis. CONCLUSIONS: These findings demonstrated that EMWI has inactivation and bactericidal activities against single microbial species among four kinds of oral pathogens. SIGNIFICANCE AND IMPACT OF THE STUDY: Electromagnetic wave irradiation may be applicable for medical disinfection and sterilization, such as refractory periapical periodontitis. PMID- 22507080 TI - Randomized trial of a diabetes self-management education and family teamwork intervention in adolescents with Type 1 diabetes. AB - AIMS: To evaluate the effectiveness of a family-centred group education programme, in adolescents with Type 1 diabetes. METHODS: Three hundred and five adolescents with Type 1 diabetes; age 13.1 +/- 1.9 years, diabetes duration 5.6 +/- 3.3 years, BMI 20.9 +/- 3.7 kg/m(2) , HbA(1c) 78 +/- 6 mmol/mol (9.3 +/- 1.9%) were randomly allocated to the Families and Adolescents Communication and Teamwork Study (FACTS) diabetes education programme; (six 90-min monthly sessions attended by parents and adolescents incorporating skills training and family teamwork) or conventional clinical care. Primary outcome was HbA(1c) at 18 months (12 months post-intervention). Secondary outcomes were HbA(1c) at 9 months, psychosocial outcomes, adolescent quality of life, well-being, family responsibility and insulin dose adjustment behaviours at 12 months (6 months post intervention) and episodes of severe hypoglycaemia and diabetic ketoacidois during the 12 months post-intervention. All analyses are intention to treat. RESULTS: Session attendance was poor with 48/158 families (30.4%) not attending any sessions and only 75/158 (47.5%) families attending >= 4 group education sessions. All biomedical and psychosocial outcomes were comparable between groups. At 18 months there was no significant difference in HbA(1c) in either group and no between-group differences over time: intervention group 75 mmol/mol (9.0%) to 78 mmol/mol (9.3%), control group 77 mmol/mol (9.2%) to 80 mmol/mol (9.5%). Adolescents perceived no changes in parental input at 12 months. CONCLUSION: Poor attendance of group education sessions delivered in routine clinics was a major challenge. More personalized educational approaches may be required to support and motivate families who are struggling to integrate the demands of intensive insulin regimens into their daily lives. PMID- 22507082 TI - Development of a novel immunoassay for the measurement of type II collagen neoepitope generated by collagenase cleavage. AB - BACKGROUND: To evaluate cartilage degeneration in arthritis, we developed a novel enzyme-linked immunosorbent assay (ELISA) with the capacity to determine urinary concentrations of type II collagen neoepitope (CIINE) generated by collagenase cleavage. METHODS: Two monoclonal antibodies, 20A10 and 6G4, were generated. Of these antibodies, 20A10 recognized CIINE regardless of hydroxylation of Pro771, and 6G4 recognized the type II collagen-specific region adjacent to the neoepitope. A sandwich ELISA was constructed using these antibodies. RESULTS: The ELISA positively determined CIINE concentrations from human and dog urine samples, and from tissue culture supernatant of rat and bovine cartilage. Validation with human urine samples revealed that the ELISA had a detection limit of 100 pmol/l, with intra- and inter-assay coefficients of less than 15%. Recovery of extraneously added CIINE peptide to human urine samples was 83.1 104%. Measurement with the ELISA demonstrated that urine samples from OA patients contained CIINE at significantly higher concentrations compared with those from healthy controls (P<0.01). CONCLUSIONS: The ELISA can determine the CIINE concentration in human urine sensitively and accurately. This assay may also be useful to determine the concentration of CIINE of various animal samples. PMID- 22507083 TI - Analysis of laboratory sample rejections in the pre-analytical stage at an oncology center. AB - BACKGROUND: Effective patient management depends on the accuracy of laboratory results. Sample collection errors constitute an important reason for repeat collections. This study was conducted at the laboratory diagnostic services of a tertiary care oncology center with a hematopoietic stem cell transplant unit to determine the common causes of sample rejections and see the effects of corrective action. METHODS: A retrospective, intervention and prospective analysis of the samples rejected from the total samples received in our laboratories, during a nine month period from January to September 2011 was undertaken. Causes of sample rejections were determined and intervention in the form of training relevant staff was instituted. RESULTS: Out of 32,548 samples received during Jan-Sep 2011, 177 samples (0.54%) were rejected. The most common reasons for rejection in hematology and biochemistry areas were clotted blood specimen (51.2%), improperly labeled specimen containers (14.46%) and hemolyzed blood samples (11.45%). For microbiology these included labeling errors, collection of specimen in wrong containers and specimen collection date and time not being entered, unacceptable specimen source and delayed transit time (18.2% each). CONCLUSIONS: Directed interventions may help reduce the incidence of sample rejections. PMID- 22507084 TI - Validation and comparison of tumor-associated trypsin inhibitor (TATI) immunoassays. AB - BACKGROUND: Tumor-associated trypsin inhibitor (TATI) is mainly proposed as a tumor marker for ovarian cancer. However, recent discoveries of TATI in cancer and inflammatory diseases show that assay of TATI in biological samples is of increasing interest. METHODS: We validated a previously described TR-IFMA and a newly developed dual-monoclonal sandwich ELISA for TATI. These methods were compared with a commercial radioimmunoassay (RIA). We studied preanalytical factors affecting serum TATI concentrations and established age- and gender specific reference intervals using serum samples from 195 healthy volunteers. RESULTS: The assay range and precision were 0.8-45 MUg/L and <9.1% for the ELISA, and 0.13 MUg/L-150 MUg/L and <12.5% for the TR-IFMA, respectively. Both assays correlated well with a RIA. Type of blood sample and nutritional status were not critical and TATI was stable in serum samples when stored at +4 degrees C and -20 degrees C for 4 weeks and at -80 degrees C for 8 weeks. The 95% reference limits for serum TATI in adults were 5.2-15.3 MUg/L in the age group 18-70 years and 7.5 21.3 MUg/L in the age group >70 years. CONCLUSIONS: Significantly higher concentrations of serum TATI were observed in elderly women and in men. Both ELISA and TR-IFMA technologies can be employed to develop sensitive and robust immunoassays for TATI using monoclonal antibodies. PMID- 22507086 TI - Endoscopic ablation therapy for gastrointestinal superficial neoplasia. AB - AIM: In Japan, endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have been widely accepted and standardized for the treatment of gastrointestinal superficial neoplasia. METHODS: In contrast, mucosal ablation techniques are more common in Western countries and a variety of endoscopic ablation modalities, including argon plasma coagulation (APC), photodynamic therapy (PDT) and lasers, are used. RESULTS: Recently developed modalities such as radiofrequency ablation (RFA) and cryotherapy are also available for the treatment of superficial lesions such as dysplasia of Barrett's esophagus. CONCLUSION: Although we should understand that the completeness of destruction of neoplastic tissue can only be judged at follow up, endoscopic ablation is a viable alternative to endoscopic resection for dysplasia and early-stage malignancies, especially for poor candidates of surgery or endoscopic resection. PMID- 22507085 TI - New vaccines for the prevention of tuberculosis in human immunodeficiency virus infection. AB - The prevention of human immunodeficiency virus (HIV) associated tuberculosis (TB) remains challenging. Several vaccines against TB have advanced to clinical trials in patients with HIV infection. The DarDar Trial, a large, randomized, placebo controlled efficacy trial conducted in Tanzania, has demonstrated that a multiple dose series of an inactivated whole cell mycobacterial vaccine is safe in HIV and can prevent HIV-associated TB in patients with childhood bacille Calmette-Guerin vaccination and CD4 counts of >=200 cells/mm(3). These developments offer promise that in the not too distant future immunization with an effective vaccine against TB can be added to other strategies for the prevention of HIV-associated TB. This expanded approach is referred to as the Five 'I's': intensified case finding, infection control, isoniazid preventive therapy (IPT), initiation of antiretroviral therapy (ART), and immunization against TB. We encourage additional studies of new TB vaccines in HIV, and propose a strategy to reduce the risk of TB by integrating IPT, ART and immunization into routine HIV care. At the time of HIV diagnosis, patients with CD4 counts of >=200 cells/mm(3) could receive immunization, IPT and, as appropriate, ART. In patients presenting with lower CD4 counts or already on ART, immunization could be initiated at CD4 counts of >=200 cells/mm(3) to add to the protection afforded by IPT and ART. PMID- 22507087 TI - Ultrathin endoscopy for gastrointestinal strictures. AB - BACKGROUND AND AIM: The assessment and treatment of advanced gastrointestinal (GI) strictures, which are defined as the inability to pass through the strictured segment with standard endoscopes, might require radiological work-up, repeated endoscopies and surgery. The aim of the present study was to assess the role of ultrathin endoscopy (UTE) for the evaluation and treatment of advanced GI strictures. METHODS: Patients in whom an initial diagnostic upper or lower endoscopy attempt was incomplete because of a tight stricture underwent a second procedure with a UTE (5.9 mm diameter) in the same session. An interventional endoscopic therapy was also carried out according to the etiology and nature of the stricture using the same UTE. Diagnostic and therapeutic outcomes were recorded and followed up prospectively. The study was conducted in a tertiary endoscopy center. RESULTS: During a one and half year study period, 62 patients (51 at upper and 11 at lower endoscopy) were detected with advanced GI stricture among 8456 diagnostic upper and 3815 lower endoscopy patients. A complete endoscopic examination was successful with UTE in 40 (78%) patients with upper and in nine patients (82%) with lower GI strictures. An interventional procedure was also carried out in 16 patients with the assistance of UTE. CONCLUSION: UTE is a useful tool for the evaluation of patients with advanced GI strictures. It provides a complete diagnostic endoscopy in most patients and gives an opportunity for therapeutic endoscopic procedures. PMID- 22507088 TI - Capsule endoscopy findings in patients with occult or overt bleeding older than 80 years. AB - BACKGROUND: Overt and occult bleeding are the main indications for a wireless capsule endoscopy (WCE) study of the small bowel. Most published studies omit patients aged over 80. AIM: To determine whether WCE is feasible in patients with overt or occult bleeding over age 80 and to define the spectrum of small bowel pathologies in this age group. PATIENTS AND METHODS: In a retrospective non-randomized tertiary care study, 60 patients at least 80 years or older (aged group) and 120 matched patients aged <80 years (younger group) with overt or occult bleeding (including iron deficiency anaemia) and no significant gastroscopic or colonoscopic findings underwent WCE. RESULTS: Of the 180 patients, 46 (77%) patients in the aged group and 97 (81%) in the younger group successfully completed small bowel study (P = 0.51). There was no difference in gastric transit time and small bowel passing time between the two groups. More patients in the aged group (48 cases, 80%) than the younger group (56 cases, 47%) presented with small bowel angiodysplasias (P < 0.0001). Nevertheless, there was no difference between the two groups concerning ulcerative and neoplastic lesions. No patient presented with capsule impaction, but more patients in the aged group (35 cases, 58%) than in the younger group (10 cases, 8%) found the study difficult and tiresome (P < 0.001). Preparation validation was poor in 34% of small bowel lumen in the aged group and 19% in the younger group (P = 0.03). CONCLUSION: WCE is feasible, although rather tiresome, in patients over the age of 80. Though the vast majority of patients older than 80 presented with angiodysplasias, there were no differences between the aged and younger groups in the presence of ulcerative lesions and polyps or tumors. PMID- 22507089 TI - Efficacy of endoscopic submucosal resection with a ligation device for removing small rectal carcinoid tumor compared with endoscopic mucosal resection: analysis of 100 cases. AB - AIM: Conventional endoscopic mucosal resection (EMR) of carcinoid tumors is often associated with involvement of the resection margin, which necessitates further intervention. Endoscopic submucosal resection with a ligation device (ESMR-L) is a novel technique for the removal of carcinoid tumors. The aim of the present study was to compare the clinical usefulness of endoscopic submucosal resection with a ligation device with that of EMR for the complete resection of rectal carcinoid tumors. METHODS: Between January 2001 and October 2010, a total of 100 patients with 100 rectal carcinoid tumors that were estimated to be 10 mm or less in diameter and that were resected either using ESMR-L or EMR were recruited for this study. The complete resection rate and complications associated with these two procedures were analyzed. RESULTS: Forty-five out of 100 lesions were resected using ESMR-L, and 55 lesions were resected using EMR. Histopathologically, all tumors were free from lymphovascular and perineural invasion. The overall ESMR-L complete resection rate was higher than that of EMR (93.3% vs 65.5%, respectively, P = 0.001). Furthermore, the location of the tumors had no influence on the complete resection rate when ESMR-L was carried out, in contrast to the results of EMR. The procedure-related variables of procedure time and complication rate were not significantly different between the two groups. CONCLUSION: ESMR-L is a significantly superior modality to EMR for the complete removal of small rectal carcinoid tumors that are 10 mm or less in diameter. PMID- 22507090 TI - Does a fitted abdominal corset makes colonoscopy more tolerable? AB - BACKGROUND AND AIM: The present study evaluated the usefulness of a fitted abdominal corset for colonoscopy, enabling proper compression of the abdomen during the entire examination. METHODS: Patients undergoing colonoscopy were subjected to either traditional methods or to using a fitted abdominal corset. Two hundred and sixteen patients were divided into two groups: group 1 (conventional colonoscopy) and group 2 (colonoscopy with abdominal corset). Cecal intubation rate and time need for manual compression and change of position were recorded. At the end of each colonoscopic examination, the patient evaluated pain by an 11-point visual analog scale from 0 to 10 (0: no pain, 10: worst pain). RESULTS: Cecal intubation time was shorter, the need for extra manual compression and change of position decreased and patients felt less pain during the procedure as denoted by lower visual analog scale scores in the group using a fitted abdominal corset, when compared to the group without a corset, in a statistically proven manner. CONCLUSION: Our data confirm the usefulness of the abdominal corset in decreasing the degree of patient pain and it makes colonoscopy easier and quicker with less manipulation, so we propose using a fitted abdominal corset during routine colonoscopic procedures. PMID- 22507092 TI - Head-to-head comparison of practice with endoscopic retrograde cholangiopancreatography computer and mechanical simulators by experienced endoscopists and trainees. AB - BACKGROUND AND AIM: The endoscopic retrograde cholangiopancreatography (ERCP) mechanical simulator (EMS) and computer simulator (ECS) are described herein. No direct hands-on comparison has been reported to reflect the perception of trainers and trainees regarding the efficacy of each model for trainee ERCP education. We compared the trainers' and trainees' assessments of the EMS and ECS for trainee education. METHODS: Eighteen gastrointestinal trainees and 16 trainers with varying ERCP experience completed a questionnaire survey before and after practice with each simulator at hands-on ERCP practice workshops. They carried out scope insertion, selective bile duct cannulation, guidewire negotiation of a bile duct stricture, biliary papillotomy and insertion of a single biliary stent using both simulators. Main outcome measurement was respondents' assessments of comparative efficacy of EMS and ECS practice for trainee education. RESULTS: Compared to pre-practice evaluation, both EMS and ECS received higher scores after hands-on practice. Both trainers and trainees showed significantly greater increases in scores for EMS when compared with ECS in facilitating understanding of ERCP procedure, enhancing confidence in carrying out ERCP and the simulator as a credible option for supplementing clinical ERCP training (P < 0.05). Participants also scored EMS significantly higher in realism and usefulness as an instructional tool. CONCLUSIONS: Both computer and mechanical simulators are accepted modalities for ERCP training. The current data (based on a head-to-head comparison of hands-on practice experience) indicate EMS practice is rated higher than ECS practice in supplementing clinical ERCP training. EMS offers the additional advantage of coordinated practice with real equipment and accessories. PMID- 22507091 TI - Prospective randomized controlled study comparing cell block method and conventional smear method for pancreatic juice cytology. AB - AIM: To elucidate the diagnostic efficacy of the cell block (CB) method by comparing it with that of conventional smear cytology for pancreatic juice obtained by endoscopic retrograde cholangiopancreatography (ERCP) in a randomized controlled trial fashion. METHODS: A total of 170 patients with pancreatic lesions suspicious of being malignant who underwent pancreatic juice collection without giving secretin under ERCP were enrolled in this study. After sampling, the pancreatic juice was randomized to the CB method (n = 85) or to smear cytology (n = 85). CB sections were subjected to hematoxylin-eosin, periodic acid Schiff-Alcian blue, and immunohistochemical stains. Both Papanicolaou stain and Giemsa stain were used for smear cytology. RESULTS: The final diagnosis was malignancy in 54 patients: pancreatic cancer, 45; intraductal papillary-mucinous carcinoma, six; and endocrine tumor, three. The number of patients with a cytological borderline malignancy in the CB group (3.5%) was significantly smaller than that in the smear group (27.1%) (P < 0.001). The diagnostic accuracy of the CB method and that of smear cytology were 76.5% (65/85) and 74.1% (63/85), respectively (P = 0.72), and their respective sensitivities were 50% (14/28) and 38.5% (10/26) (P = 0.39). The sensitivity of the CB method (88.9%) was better than that of smear cytology (42.9%) for invasive ductal carcinoma in the pancreas head (P = 0.048). CONCLUSIONS: The CB method using immunostaining for pancreatic juice cytology showed a much lower rate of equivocal borderline malignancy and a tendency for a higher diagnostic yield compared with smear cytology. Its diagnostic sensitivity, however, was not satisfactory except for pancreatic-head cancer. PMID- 22507093 TI - Endoscopic removal of a spontaneously fractured biliary uncovered self-expandable metal stent. AB - Self-expandable metal stents (SEMS) are widely used for the palliative treatment of unresectable malignant biliary obstruction. However, the long-term durability of SEMSs in biliary strictures is not clear. We describe a case of endoscopic removal of spontaneously fractured uncovered biliary SEMS. A 59-year-old woman presented to our institution with a 1-year history of recurrent cholangitis. Her medical history included a proctectomy for rectal cancer and right hemihepatectomy for liver metastasis 10 years earlier. Five years after these operations, she developed a benign hilar stricture and had an uncovered SEMS placed in another hospital. Endoscopic retrograde cholangiopancreatography demonstrated that the SEMS was torn in half and the distal part of the stent was floating in the dilated common bile duct. The papillary orifice was dilated by endoscopic papillary large balloon dilation (EPLBD) using a 15-mm wire-guided balloon catheter. Subsequently, we inserted biopsy forceps into the bile duct and grasped the distal end of the broken SEMS under fluoroscopy. We successfully removed the fragment of the SEMS from the bile duct, along with the endoscope. The patient was discharged without complications. Placement of an uncovered biliary SEMS is not the preferred treatment for benign biliary strictures. Spontaneous fracture of an uncovered biliary SEMS is an extremely rare complication. We should be aware that stent fracture can occur when placing uncovered biliary SEMSs in patients with a long life expectancy. EPLBD is very useful for retrieving the fractured fragment of SEMS. PMID- 22507094 TI - Unique usage of a partially covered metal stent for drainage of a pancreatic pseudocyst via endosonography-guided transcystgastrostomy. AB - Pancreatic pseudocysts are frequent complications of pancreatitis episodes. The current therapeutic modalities for drainage of pancreatic pseudocysts include surgical, percutaneous, and endoscopic drainage modalities. Endosonography assisted endoscopic drainage of these pseudocysts with the placement of multiple plastic or fully covered self-expanding biliary metal stents is becoming more commonly carried out. The present case report discusses the unique and successful drainage of a pancreatic pseudocyst with the placement of a partially covered self-expanding metal stent. PMID- 22507095 TI - Endoscopy and hemoglobinopathies. PMID- 22507096 TI - Percutaneous transhepatic cholangioscopy using a flexible digital ureteroscope through a 10-fr vascular sheath: a novel method to evaluate bile duct injury in patients with Roux-en-Y gastric bypass surgery. PMID- 22507097 TI - Endoscopic mucosal resection using a cap-fitted panendoscope as a diagnostic procedure in a case of scirrhous gastric carcinoma. PMID- 22507098 TI - Temporary endosonography-guided biliary drainage for transesophageal placement of a metal stent in recurrent cholangiocarcinoma. PMID- 22507099 TI - N-butyl-2-cyanoacrylate (histoacryl) glue in the right atrium after endoscopic injection for a ruptured duodenal varix: complication of histoacryl injection. PMID- 22507100 TI - Pseudo-diverticular formation due to a cytomegalovirus infection in the colorectum. PMID- 22507102 TI - Successful lithotripsy under fluoroscopy without cholangiography and confirmation: absence of remnant stones using gadolinium chelate combined with intraductal ultrasound in a patient anaphylactic to iodine-based contrast agent. PMID- 22507101 TI - Giant gastric polyp resection using two poly loops and endoscopic submucosal dissection technique. PMID- 22507104 TI - H. pylori: should we still be looking for it? What should we be doing about it? A case-based approach. PMID- 22507105 TI - The influence of neighbourhood disadvantage on smoking cessation and its contribution to inequalities in smoking status. AB - INTRODUCTION AND AIMS: Individual smokers from disadvantaged backgrounds are less likely to quit, which contributes to widening inequalities in smoking. Residents of disadvantaged neighbourhoods are more likely to smoke, and neighbourhood inequalities in smoking may also be widening because of neighbourhood differences in rates of cessation. This study examined the association between neighbourhood disadvantage and smoking cessation and its relationship with neighbourhood inequalities in smoking. DESIGN AND METHODS: A multilevel longitudinal study of mid-aged (40-67 years) residents (n = 6915) of Brisbane, Australia, who lived in the same neighbourhoods (n = 200) in 2007 and 2009. Neighbourhood inequalities in cessation and smoking were analysed using multilevel logistic regression and Markov chain Monte Carlo simulation. RESULTS: After adjustment for individual level socioeconomic factors, the probability of quitting smoking between 2007 and 2009 was lower for residents of disadvantaged neighbourhoods (9.0-12.8%) than their counterparts in more advantaged neighbourhoods (20.7-22.5%). These inequalities in cessation manifested in widening inequalities in smoking: in 2007 the between-neighbourhood variance in rates of smoking was 0.242 (P <= 0.001) and in 2009 it was 0.260 (P <= 0.001). In 2007, residents of the most disadvantaged neighbourhoods were 88% (OR 1.88, 95% credible intervals (CrI) 1.41-2.49) more likely to smoke than residents in the least disadvantaged neighbourhoods: the corresponding difference in 2009 was 98% (OR 1.98, 95% CrI 1.48-2.66). CONCLUSION: Fundamentally, social and economic inequalities at the neighbourhood and individual levels cause smoking and cessation inequalities. Reducing these inequalities will require comprehensive, well-funded and targeted tobacco control efforts and equity-based policies that address the social and economic determinants of smoking. PMID- 22507106 TI - The mitigation effects of exogenous melatonin on salinity-induced stress in Malus hupehensis. AB - As an indoleamine molecule, melatonin mediates many physiological processes in plants. We investigated its role in regulating growth, ion homeostasis, and the response to oxidative stress in Malus hupehensis Rehd. under high-salinity conditions. Stressed plants had reduced growth and a marked decline in their net photosynthetic rates and chlorophyll contents. However, pretreatment with 0.1MUm melatonin significantly alleviated this growth inhibition and enabled plants to maintain an improved photosynthetic capacity. The addition of melatonin also lessened the amount of oxidative damage brought on by salinity, perhaps by directly scavenging H(2) O(2) or enhancing the activities of antioxidative enzymes such as ascorbate peroxidase, catalase, and peroxidase. We also investigated whether melatonin might control the expression of ion-channel genes under salinity. Here, MdNHX1 and MdAKT1 were greatly up-regulated in the leaves, which possibly contributed to the maintenance of ion homeostasis and, thus, improved salinity resistance in plants exposed to exogenous melatonin. PMID- 22507107 TI - Neurosurgery in the age of Cushing: the achievement of Leonard Lindon. AB - Leonard Lindon was the first neurosurgeon on the staff of the Royal Adelaide Hospital, and headed this hospital's neurosurgical service from 1931 to 1951, with an interruption from war service. Like other early neurosurgeons, Lindon began as a general surgeon. In 1929, when he was well established in his surgical practice, he took unpaid leave from his hospital duties to undertake a study tour of neurosurgical centres in Europe and North America. Lindon visited the London Hospital, where Hugh Cairns, like him, an Adelaide medical graduate and veteran of Gallipoli, was establishing a modern neurosurgical service. Lindon also visited Harvey Cushing in Boston, USA. Cushing was then at the zenith of his reputation as the master of a safe neurosurgical operative technique; he was also famous for his contributions in the neurosciences. Lindon was deeply impressed by Cushing's philosophy and his operative methods. When Lindon returned to Adelaide in 1930, he prepared a plan for a neurosurgical unit in Adelaide, and over the next 20 years, he achieved some of his aims. In this plan, Lindon gave priority to the management of head injuries as a role for neurosurgeons. PMID- 22507108 TI - Carbapenemase-producing Enterobacteriaceae: a call for action! PMID- 22507109 TI - Rapid evolution and spread of carbapenemases among Enterobacteriaceae in Europe. AB - Plasmid-acquired carbapenemases in Enterobacteriaceae, which were first discovered in Europe in the 1990s, are now increasingly being identified at an alarming rate. Although their hydrolysis spectrum may vary, they hydrolyse most beta-lactams, including carbapenems. They are mostly of the KPC, VIM, NDM and OXA 48 types. Their prevalence in Europe as reported in 2011 varies significantly from high (Greece and Italy) to low (Nordic countries). The types of carbapenemase vary among countries, partially depending on the cultural/population exchange relationship between the European countries and the possible reservoirs of each carbapenemase. Carbapenemase producers are mainly identified among Klebsiella pneumoniae and Escherichia coli, and still mostly in hospital settings and rarely in the community. Although important nosocomial outbreaks with carbapenemase-producing Enterobacteriaceae have been extensively reported, many new cases are still related to importation from a foreign country. Rapid identification of colonized or infected patients and screening of carriers is possible, and will probably be effective for prevention of a scenario of endemicity, as now reported for extended-spectrum beta-lactamase (mainly CTX-M) producers in all European countries. PMID- 22507110 TI - Identification and screening of carbapenemase-producing Enterobacteriaceae. AB - Carbapenem-hydrolysing beta-lactamases are the most powerful beta-lactamases, being able to hydrolyse almost all beta-lactams. They are mostly of the KPC, VIM, IMP, NDM and OXA-48 types. Their current extensive spread worldwide in Enterobacteriaceae is an important source of concern, as these carbapenemase producers are multidrug-resistant. Detection of infected patients and of carriers are the two main approaches for prevention of their spread. Phenotypic and molecular-based techniques are able to identify these carbapenemase producers, although with variable efficiencies. The detection of carriers still relies mostly on the use of screening culture media. PMID- 22507113 TI - Mortgaging the future of medical research. PMID- 22507111 TI - Interventional strategies and current clinical experience with carbapenemase producing Gram-negative bacteria. AB - The wide dissemination of carbapenemase-producing Gram-negatives (CPGNs), including enterobacterial species and non-fermenters, has caused a public health crisis of global dimensions. These organisms cause serious infections in hospitalized patients, and are associated with increased mortality. Cross transmission is common, and outbreaks may occur in healthcare facilities where the infection control practices are inadequate. CPGNs exhibit extensive drug resistant phenotypes, complicate therapy, and limit treatment options. Systematic data on therapy are limited. However, regimens combining two or more active agents seem to be more efficacious than monotherapy in carbapenemase-producing Klebsiella pneumoniae infections. Strict infection control measures, including active surveillance for timely detection of colonized patients, separation of carriers from non-carriers, and contact precautions, are of utmost importance, and may be the only effective way of preventing the introduction and transmission of these bacteria in healthcare settings. PMID- 22507114 TI - Forging the Association for Clinical and Translational Science (ACTS). PMID- 22507115 TI - Patient-oriented research in the era of personalized medicine. PMID- 22507117 TI - Invited response to: Preparedness of the CTSA's structural and scientific assets to support the mission of the National Center for Advancing Translational Sciences (NCATS). PMID- 22507118 TI - Strengthening the career development of clinical translational scientist trainees: a consensus statement of the Clinical Translational Science Award (CTSA) Research Education and Career Development Committees. AB - The challenges for scholars committed to successful careers in clinical and translational science are increasingly well recognized. The Education and Career Development (EdCD) of the national Clinical and Translational Science Award consortium gathered thought leaders to propose sustainable solutions and an agenda for future studies that would strengthen the infrastructure across the spectrum of pre- and postdoctoral, MD and PhD, scholars. Six consensus statements were prepared that include: (1) the requirement for career development of a qualitatively different investigator; (2) the implications of interdisciplinary science for career advancement including institutional promotion and tenure actions that were developed for discipline-specific accomplishments; (3) the need for long-term commitment of institutions to scholars; (4) discipline-specific curricula are still required but curricula designed to promote team work and interdisciplinary training will promote innovation; (5) PhD trainees have many pathways to career satisfaction and success; and (6) a centralized infrastructure to enhance and reward mentoring is required. Several themes cut across all of the recommendations including team science, innovation, and sustained institutional commitment. Implied themes include an effective and diverse job force and the requirement for a well-crafted public policy that supports continued investments in science education. PMID- 22507119 TI - Strategies for a National Evaluation of the Clinical and Translational Science Awards. PMID- 22507116 TI - Preparedness of the CTSA's structural and scientific assets to support the mission of the National Center for Advancing Translational Sciences (NCATS). AB - The formation of the National Center for Advancing Translational Sciences (NCATS) brings new promise for moving basic science discoveries to clinical practice, ultimately improving the health of the nation. The Clinical and Translational Science Award (CTSA) sites, now housed with NCATS, are organized and prepared to support in this endeavor. The CTSAs provide a foundation for capitalizing on such promise through provision of a disease-agnostic infrastructure devoted to clinical and translational (C&T) science, maintenance of training programs designed for C&T investigators of the future, by incentivizing institutional reorganization and by cultivating institutional support. PMID- 22507123 TI - Factual Errors about ClinicalTrials.gov and other federal mandates in special report by Shuster. PMID- 22507125 TI - Independent effects of adding weight and inertia on balance during quiet standing. AB - BACKGROUND: Human balance during quiet standing is influenced by adding mass to the body with a backpack, with symmetrically-applied loads to the trunk, or with obesity. Adding mass to the body increases both the weight and inertia of the body, which theoretically could provide counteracting effects on body dynamics and balance. Understanding the independent effects of adding weight and inertia on balance may provide additional insight into human balance that could lead to novel advancements in balance training and rehabilitation. Therefore, the purpose of this study was to investigate the independent effects of adding weight and inertia on balance during quiet standing. METHODS: Sixteen normal-weight young adult participants stood as still as possible on a custom-built backboard apparatus under four experimental conditions: baseline, added inertia only, added weight only, and added inertia and weight. RESULTS: Adding inertia by itself had no measurable effect on center of pressure movement or backboard movement. Adding weight by itself increased center of pressure movement (indicated greater effort by the postural control system to stand as still as possible) and backboard movement (indicating a poorer ability of the body to stand as still as possible). Adding inertia and weight at the same time increased center of pressure movement but did not increase backboard movement compared to the baseline condition. CONCLUSIONS: Adding inertia and adding weight had different effects on balance. Adding inertia by itself had no effect on balance. Adding weight by itself had a negative effect on balance. When adding inertia and weight at the same time, the added inertia appeared to lessen (but did not eliminate) the negative effect of adding weight on balance. These results improve our fundamental understanding of how added mass influences human balance. PMID- 22507126 TI - Phospholipase A and glycerophosphodiesterase activities in the cell membrane of Mycoplasma hyorhinis. AB - Mycoplasma hyorhinis, the major contaminant of tissue cultures, has been implicated in a variety of diseases in swine. Most human and animal mycoplasmas remain attached to the surface of epithelial cells. Nonetheless, we have recently shown that M. hyorhinis is able to invade and survive within nonphagocytic melanoma cells. The invasion process may require the damaging of the host cell membrane by either chemical, physical or enzymatic means. In this study, we show that M. hyorhinis membranes possess a nonspecific phospholipase A (PLA) activity capable of hydrolyzing both position 1 and position 2 of 1-acyl-2-(12-[N-(7 nitrobenz-2-oxa-1,3-diazol-4-yl)] aminododecanoyl) phosphatidylcholine. In silico analysis of the M. hyorhinis genome shows that the PLA of M. hyorhinis shares no homology to described phospholipases. The PLA activity of M. hyorhinis was neither stimulated by Ca (2+) nor inhibited by EGTA and had a broad pH spectrum. Mycoplasma hyorhinis also possess a potent glycerophosphodiesterase (GPD), which apparently cleaves the glycerophosphodiester formed by PLA to yield glycerol-3 phosphate. Possible roles of PLA and GPD in invading host eukaryotic cells and in forming mediators upon the interaction of M. hyorhinis with eukaryotic cells are suggested. PMID- 22507127 TI - Regulation and cellular functions of class II phosphoinositide 3-kinases. AB - Class II isoforms of PI3K (phosphoinositide 3-kinase) are still the least investigated and characterized of all PI3Ks. In the last few years, an increased interest in these enzymes has improved our understanding of their cellular functions. However, several questions still remain unanswered on their mechanisms of activation, their specific downstream effectors and their contribution to physiological processes and pathological conditions. Emerging evidence suggests that distinct PI3Ks activate different signalling pathways, indicating that their functional roles are probably not redundant. In the present review, we discuss the recent advances in our understanding of mammalian class II PI3Ks and the evidence suggesting their involvement in human diseases. PMID- 22507128 TI - Lentiviral vectors: basic to translational. AB - More than two decades have passed since genetically modified HIV was used for gene delivery. Through continuous improvements these early marker gene-carrying HIVs have evolved into safer and more effective lentiviral vectors. Lentiviral vectors offer several attractive properties as gene-delivery vehicles, including: (i) sustained gene delivery through stable vector integration into host genome; (ii) the capability of infecting both dividing and non-dividing cells; (iii) broad tissue tropisms, including important gene- and cell-therapy-target cell types; (iv) no expression of viral proteins after vector transduction; (v) the ability to deliver complex genetic elements, such as polycistronic or intron containing sequences; (vi) potentially safer integration site profile; and (vii) a relatively easy system for vector manipulation and production. Accordingly, lentivector technologies now have widespread use in basic biology and translational studies for stable transgene overexpression, persistent gene silencing, immunization, in vivo imaging, generating transgenic animals, induction of pluripotent cells, stem cell modification and lineage tracking, or site-directed gene editing. Moreover, in the present high-throughput '-omics' era, the commercial availability of premade lentiviral vectors, which are engineered to express or silence genome-wide genes, accelerates the rapid expansion of this vector technology. In the present review, we assess the advances in lentiviral vector technology, including basic lentivirology, vector designs for improved efficiency and biosafety, protocols for vector production and infection, targeted gene delivery, advanced lentiviral applications and issues associated with the vector system. PMID- 22507130 TI - Pref-1 preferentially inhibits heat production in brown adipose tissue. AB - In mammals there are two types of adipocytes with opposing functions. Brown adipocytes are characterized by a high number of mitochondria and are specialized for heat production (thermogenesis), expressing thermogenic genes such as UCP1 (uncoupling protein 1). White adipocytes, on the other hand, store energy. Although many key regulators in the differentiation of white adipocytes have been established, our current knowledge on the same proteins in brown adipogenesis is lagging behind. One example is Pref-1 (pre-adipocyte factor-1), which maintains white pre-adipocytes in an undifferentiated state, but is only poorly characterized in the brown pre-adipocyte lineage. In this issue of the Biochemical Journal, Armengol et al. now shed new light on the role and regulation of Pref-1 in brown pre-adipocytes. First, Pref-1 specifically inhibits the thermogenic gene programme in brown pre-adipocytes. Secondly, they identified the transcription factor C/EBPdelta (CCAAT/enhancer-binding protein delta) as a direct positive regulator of Pref-1 expression, whereas this protein does not fulfil this role in white adipogenesis. Taken together, these findings indicate that specific manipulation of brown adipocyte differentiation and/or function without interfering with their white adipocyte counterparts may be possible, which may open up new therapeutic ways to combat obesity-associated health problems. PMID- 22507129 TI - Indian Hedgehog signalling triggers Nkx3.2 protein degradation during chondrocyte maturation. AB - The Ihh (Indian Hedgehog) pathway plays an essential role in facilitating chondrocyte hypertrophy and bone formation during skeletal development. Nkx3.2 (NK3 homeobox 2) is initially induced in chondrocyte precursor cells, maintained in early-stage chondrocytes and down-regulated in terminal-stage chondrocytes. Consistent with these expression patterns, Nkx3.2 has been shown to enhance chondrocyte differentiation and cell survival, while inhibiting chondrocyte hypertrophy and apoptosis. Thus, in the present study, we investigated whether Nkx3.2, an early-stage chondrogenic factor, can be regulated by Ihh, a key regulator for chondrocyte hypertrophy. We show that Ihh signalling can induce proteasomal degradation of Nkx3.2. In addition, we found that Ihh can suppress levels of Lrp (low-density-lipoprotein-receptor-related protein) (Wnt co receptor) and Sfrp (secreted frizzled-related protein) (Wnt antagonist) expression, which, in turn, may selectively enhance Lrp-independent non-canonical Wnt pathways in chondrocytes. In agreement with these findings, Ihh-induced Nkx3.2 degradation requires Wnt5a, which is capable of triggering Nkx3.2 degradation. Finally, we found that Nkx3.2 protein levels in chondrocytes are remarkably elevated in mice defective in Ihh signalling by deletion of either Ihh or smoothened. Thus these results suggest that Ihh/Wnt5a signalling may play a role in negative regulation of Nkx3.2 for appropriate progression of chondrocyte hypertrophy during chondrogenesis. PMID- 22507131 TI - Novel quantitative perfusion analysis with contrast-enhanced harmonic EUS for differentiation of autoimmune pancreatitis from pancreatic carcinoma. AB - OBJECTIVE: Autoimmune pancreatitis (AIP) is often misdiagnosed as pancreatic carcinoma (PC) despite recent advances in imaging tests. The aim of the study was to evaluate whether the quantitative perfusion analysis using software "Time intensity curve" with contrast-enhanced harmonic EUS (CH-EUS) facilitate the differentiation of AIP from PC. METHODS: Consecutive patients with focal AIP and pancreatic carcinoma who underwent CH-EUS from January 2009 to September 2010 were analyzed. CH-EUS was performed with intravenous administration of an ultrasonographic contrast (Sonazoid) and electronic radial echoendoscope. The graph of time intensity curve (TIC) for pancreatic mass was generated to depict the changes in signal intensity over time within the region of interest (ROI). ROI was placed to cover an area with a pancreatic mass lesion. Based on the analysis of TIC, base intensity before injection (BI), peak intensity (PI), time to peak, and maximum intensity gain (MIG: PI-BI) were calculated. RESULTS: Eight patients with focal AIP and twenty-two patients with PC were evaluated by TIC. PI and MIG of mass lesion of AIP were significantly higher than that of PC (21.4 dB vs. 9.6 dB, 17.5 vs. 6.6). Receiver operating characteristics analysis yielded an optimal MIG cutoff value of 12.5 with high sensitivity and specificity. CONCLUSION: Pancreatic mass lesions of AIP and PC exhibited markedly different patterns with the TIC. This novel diagnostic modality using TIC generated by CH EUS might offer an opportunity to improve accuracy in the differential diagnosis between pancreatic mass lesion of AIP and PC. PMID- 22507132 TI - Successful toric intraocular lens implantation in a patient with induced cataract and astigmatism after posterior chamber toric phakic intraocular lens implantation: a case report. AB - INTRODUCTION: We report the case of a patient in whom simultaneous toric phakic intraocular lens removal and phacoemulsification with toric intraocular lens implantation were beneficial for reducing pre-existing astigmatism and acquiring good visual outcomes in eyes with implantable collamer lens-induced cataract and astigmatism. CASE PRESENTATION: A 53-year-old woman had undergone toric implantable collamer lens implantation three years earlier. After informed consent was obtained, we performed simultaneous toric implantable collamer lens removal and phacoemulsification with toric intraocular lens implantation. Preoperatively, the manifest refraction was 0, -0.5 * 15, with an uncorrected visual acuity of 0.7 and a best spectacle-corrected visual acuity of 0.8. Postoperatively, the manifest refraction was improved to 0, -0.5 * 180, with an uncorrected visual acuity of 1.2 and a best spectacle-corrected visual acuity of 1.5. No vision-threatening complications were observed. CONCLUSION: Toric intraocular lens implantation may be a good surgical option for the correction of spherical and cylindrical errors in eyes with implantable collamer lens-induced cataract and astigmatism. PMID- 22507134 TI - Nanoparticles as delivery carriers for anticancer prodrugs. AB - INTRODUCTION: Prodrugs are inactive compounds which are metabolized in the body to produce parent active agents. It has been shown that prodrugs hold some advantages over conventional drugs, such as increased solubility, improved permeability and bioavailability, reduced adverse effects and prolonged half lives. Optimization of the vehicles used is very important in order to employ the advantages of prodrugs. Nanocarriers are currently being widely used as prodrug vehicles because of their ability to enhance storage stability, modulate prodrug release and tumor-targeted delivery and protect against enzymatic attack. This combined approach of prodrugs and nanoparticles has a particular attraction for developing anticancer therapies. AREAS COVERED: This paper discusses liposomes, polymeric nanoparticles and lipid nanoparticles, which are all carriers commonly used for prodrug encapsulation. Macromolecular prodrugs can spontaneously form self-assembled nanoparticles with no intervention of other additives. This review also describes recent developments in prodrug delivery using nanoparticulate strategies. Pharmacokinetic, pharmacodynamic and cytotoxicity evaluations of anticancer prodrugs are systematically elucidated in this review. EXPERT OPINION: More profiles involved in animal and clinical studies will encourage the future applicability of prodrug nanocarrier therapy. The possible toxicity associated with nanoparticles is a concern for development of prodrug delivery. PMID- 22507135 TI - Fine structure in cellulose microfibrils: NMR evidence from onion and quince. AB - It has been controversial for many years whether in the cellulose of higher plants, the microfibrils are aggregates of 'elementary fibrils', which have been suggested to be about 3.5 nm in diameter. Solid-state NMR spectroscopy was used to examine two celluloses whose fibril diameters had been established by electron microscopy: onion (8-10 nm, but containing 40% of xyloglucan as well as cellulose) and quince (2 nm cellulose core). Both of these forms of cellulose contained crystalline units of similar size, as estimated from the ratio of surface to interior chains, and the time required for proton magnetisation to diffuse from the surface to the interior. It is suggested that the onion microfibrils must therefore be constructed from a number of cellulose subunits 2 nm in diameter, smaller than the 'elementary fibrils' envisaged previously. The size of these subunits would permit a hexagonal arrangement resembling the cellulose synthase complex. PMID- 22507133 TI - Anti-fibrotic activity and enhanced interleukin-6 production by hepatic stellate cells in response to imatinib mesylate. AB - OBJECTIVE: To examine imatinib mesylate's effects on stellate cell responses in vivo and in vitro. The hepatic stellate cell (HSC) is a key target of anti fibrotic therapies. Imatinib mesylate is a small molecule receptor tyrosine kinase inhibitor indicated for treatment of chronic myelogenous leukaemia and GI stromal tumours. DESIGN: Because imatinib inhibits beta-PDGFR signalling, which stimulates HSC proliferation, we assessed its activity in culture and in vivo, and examined downstream targets in a human stellate cell line (LX-2) using cDNA microarray. METHODS AND RESULTS: Imatinib inhibited proliferation of LX-2 cells (0.5-10 mM) but not primary human stellate cells, with no effect on viability, associated with attenuated beta-PDGFR phosphorylation. Mitochondrial activity and superoxide anion production were decreased in response to imatinib. cDNA microarray uncovered up-regulation of 29 genes in response to imatinib, including interleukin-6 (IL-6) mRNA, which was correlated with progressive IL-6 secretion. Imatinib also decreased gene expression of collagen alpha(1) (I), alpha smooth muscle actin, beta-PDGFR, transforming growth factor beta receptor type 1, matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2. In vivo, imatinib administered to rats beginning 4 weeks after starting thioacetamide (TAA) led to reduced collagen content, with significant reductions in portal pressure and down-regulation of fibrogenic genes in whole liver. Importantly, hepatic IL-6 mRNA levels were significantly increased in TAA-treated animals receiving imatinib. CONCLUSIONS: These findings reinforce the anti-fibrotic activity of imatinib and uncover an unexpected link between inhibition of HSC activation by imatinib and enhanced secretion of IL-6, a regenerative cytokine. PMID- 22507136 TI - Changes in the cytoskeleton accompanying infection-induced nuclear movements and the hypersensitive response in plant cells invaded by rust fungi. AB - During the infection of cowpea (Vigna unguiculata) by the cowpea rust fungus (Uromyces vignae, race 1 ) the plant nucleus moves towards and away from the invading hypha and eventually moves close to the fungus in the susceptible cultivar while it remains away in two cultivars which subsequently respond by resistance gene-dependent plant cell death (the hypersensitive response, HR). The role of plant cytoskeleton in these responses was investigated by fluorescent microscopy and treatments with anticytoskeletal drugs. Observations of microtubule organization prior to cell death revealed that the sequence of events leading to protoplast collapse differed between the two resistant cultivars, suggesting a possibility of multiple pathways for cellular degradation during the HR. Different fixations produced two different microfilament patterns: a filament network and cables. Microfilament network remained visible even at later stages of cell death. Oryzalin and taxol reduced the incidence of autofluorescence that develops late in the death process, indicating a role of microtubules in the deposition of phenolics by adjacent living cells. Cell death and nuclear movements were not affected by oryzalin and taxol but were inhibited by cytochalasin E, suggesting that the microfilaments are required for the HR. PMID- 22507137 TI - Early post-embryonic root formation is specifically affected in the maize mutant lrt1. AB - The isolation and detailed characterisation of the maize mutant lrt1 , which is completely deficient in the initiation of lateral roots at the primary and seminal lateral roots and of the crown roots at the coleoptilar node is described. The monogenic and recessive mutant was isolated from a segregating EMS mutagenised population, maps to the short arm of chromosome 2, and acts independently of the nodal root deficient rtcs locus. Histological analysis revealed that the mutation acts at a very early stage of root initiation, as indicated by the absence of primordia formation in the affected roots. At later stages of plant development lateral and crown root initiations recover leading to fertile plants. If grown in the dark, the mutant does not form an elongated mesocotyl, although the photomorphogenic response appears to be normal in the mutant. Furthermore, the wild-type cannot be rescued from mutants by the application of auxin to germinating kernels. The gene impaired in lrt1 seems to be of great importance for the general mechanism of early post-embryonic root initiation, both from root and nodal tissues, since lateral and crown root initiation are both affected to the same extent and in the same transient time pattern. PMID- 22507138 TI - Ozone-induced oxidative burst in the ozone biomonitor plant, tobacco Bel W3. AB - Localized cell death is a common feature of ozone phytotoxicity and is generally thought to be initiated by the strong oxidant ozone itself as well as by ozone derived reactive oxygen intermediates (ROIs). Here we report that ozone (150 nl l(-1), 5 h) elicits cellular ROI production in the ozone-sensitive tobacco cv. Bel W3, but not in the tolerant cv. Bel B. Both cultivars exhibited a transient first maximum of apoplastic ROI accumulation followed by a comparable induction of glutathione peroxidase transcript levels. During postcultivation in pollutant free air, a second and sustained peak of apoplastic ROI accumulation was detected only in cv. Bel W3. Histochemical staining revealed a spot-like accumulation of H(2)O(2) and, to a lesser extent, of superoxide anion radicals in this cultivar. The H(2)O(2) spots ('burst initiation sites') occurred mainly in the vicinity of leaf veins and correlated in number and distribution with discrete sites of local cell death and with visible symptoms that evolved between 15 and 72 h. The results indicate that ozone effects are amplified in the sensitive tobacco cv. Bel W3 by an oxidative burst which participates in the generation of hypersensitive cell death-like lesions. PMID- 22507140 TI - Worldwide variability in deceased organ donation registries. AB - The variability in deceased organ donation registries worldwide has received little attention. We considered all operating registries, where individual wishes about organ donation were recorded in a computerized database. We included registries which recorded an individual's decision to be a donor (donor registry), and registries which only recorded an individual's objection (non donor registry). We collected information on 15 characteristics including history, design, use and number of registrants for 27 registries (68%). Most registries are nationally operated and government-owned. Registrations in five nations expire and require renewal. Some registries provide the option to make specific organ selections in the donation decision. Just over half of donor registries provide legally binding authorization to donation. In all national donor registries, except one, the proportion of adults (15+) registered is modest (<40%). These proportions can be even lower when only affirmative decisions are considered. One nation provides priority status on the transplant waiting list as an incentive to affirmative registration, while another nation makes registering a donation decision mandatory to obtain a driver's license. Registered objections in non-donor registries are rare (<0.5%). The variation in organ donor registries worldwide necessitates public discourse and quality improvement initiatives, to identify and support leading practices in registry use. PMID- 22507139 TI - Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on progression of diabetic neuropathy and other microvascular complications: multivariate epidemiological analysis based on patient background factors and severity of diabetic neuropathy. AB - AIMS: The goal of the study was to evaluate the efficacy of epalrestat, an aldose reductase inhibitor, on diabetic retinopathy and diabetic nephropathy, based on analysis of the results of the Aldose Reductase Inhibitor-Diabetes Complications Trial, a 3-year multicentre comparative clinical trial of conventional therapy (control group) and epalrestat therapy (epalrestat group) in Japanese patients with mild diabetic neuropathy. METHODS: The subjects of the study were patients enrolled in the Aldose Reductase Inhibitor-Diabetes Complications Trial for whom data for major patient characteristics, severity of diabetic neuropathy at the end of the study and time-courses of diabetic retinopathy and diabetic nephropathy were available (57 and 52 patients from the control and epalrestat groups, respectively). Progression of diabetic retinopathy/nephropathy (a primary endpoint) in relation to major patient characteristics, severity of diabetic neuropathy at the end of the study (assessed from the mean of z-scores in four neurological function tests) and epalrestat treatment were analysed using univariate analysis and multiple logistic regression analysis. RESULTS: Progression of diabetic retinopathy/nephropathy was significantly inhibited in the epalrestat group compared with the control group (odds ratio = 0.323, P = 0.014) and was dependent on the severity of diabetic neuropathy at the end of the study (odds ratio = 2.131, P = 0.025). CONCLUSIONS: Epalrestat prevented progression of diabetic neuropathy and retinopathy/nephropathy. The effect on diabetic retinopathy/nephropathy may have occurred indirectly because of the prevention of progression of diabetic neuropathy, in addition to the inhibitory action of epalrestat on aldose reductase. PMID- 22507141 TI - Early ileostomy closure: is there a downside? AB - BACKGROUND: A loop ileostomy is a common adjunct to formation of a low colorectal anastomosis. However, it is not without significant physical and psychological morbidity, and financial cost. Feasibility of early closure during the index admission has previously been reported. This pilot study examines the safety of early closure compared with traditional timing. METHODS: A retrospective audit of consecutive ileostomy closures performed in a tertiary colorectal unit from January 2008 to January 2010. Demographic data, treatment data and complications were collected by a single investigator from a prospective clinical audit database and hospital records. Patients undergoing early closure (within 10 days of the index operation) were compared with the traditional timing group. RESULTS: A total of 93 patients underwent closure of loop ileostomy during the study period (44 female; 49 male). Median patient age was 61 years. Nineteen patients (20%) underwent early closure. There were six wound infections in the early closure group (32%), and five in the traditional timing group (7%) (P = 0.01). There was no significant difference in other complications between the two groups. There was a significantly shorter overall hospital stay in the early closure group with a median stay of 14 days (range 10-26), and in the traditional timing group a median stay of 17 days (range 7-80) (P = 0.05). Seven patients (9%) in the traditional timing group had ileostomy-related complications. CONCLUSION: Early ileostomy closure appears to be associated with an increased wound infection rate but otherwise appears to be a safe alternative to traditional closure in selected patients and may reduce overall hospital stay. PMID- 22507142 TI - Functional analysis to identify genes in wine yeast adaptation to low-temperature fermentation. AB - AIMS: To identify genes and proteins involved in adaptation to low-temperature fermentations in a commercial wine yeast. METHODS AND RESULTS: Nine proteins were identified as representing the most significant changes in proteomic maps during the first 24 h of fermentation at low (13 degrees C) and standard temperature (25 degrees C). These proteins were mainly involved in stress response and in glucose and nitrogen metabolism. Transcription analysis of the genes encoding most of these proteins within the same time frame of wine fermentation presented a good correlation with proteomic data. Knockout and overexpressing strains of some of these genes were constructed and tested to evaluate their ability to start the fermentation process. The strain overexpressing ILV5 improved its fermentation activity in the first hours of fermentation. This strain showed a quicker process of mitochondrial degeneration, an altered intracellular amino acid profile and laxer nitrogen catabolite repression regulation. CONCLUSIONS: The proteomic and transcriptomic analysis is useful to detect key molecular adaptation mechanisms of biotechnological interest for industrial processes. ILV5 gene seems to be important in wine yeast adaptation to low-temperature fermentation. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides information that might help improve the future performance of wine yeast, either by genetic modification or by adaptation during industrial production. PMID- 22507143 TI - Differentiation of chromaffin progenitor cells to dopaminergic neurons. AB - The differentiation of dopamine-producing neurons from chromaffin progenitors might represent a new valuable source for replacement therapies in Parkinson's disease. However, characterization of their differentiation potential is an important prerequisite for efficient engraftment. Based on our previous studies on isolation and characterization of chromaffin progenitors from adult adrenals, this study investigates their potential to produce dopaminergic neurons and means to enhance their dopaminergic differentiation. Chromaffin progenitors grown in sphere culture showed an increased expression of nestin and Mash1, indicating an increase of the progenitor subset. Proneurogenic culture conditions induced the differentiation into neurons positive for neural markers beta-III-tubulin, MAP2, and TH accompanied by a decrease of Mash1 and nestin. Furthermore, Notch2 expression decreased concomitantly with a downregulation of downstream effectors Hes1 and Hes5 responsible for self-renewal and proliferation maintenance of progenitor cells. Chromaffin progenitor-derived neurons secreted dopamine upon stimulation by potassium. Strikingly, treatment of differentiating cells with retinoic and ascorbic acid resulted in a twofold increase of dopamine secretion while norepinephrine and epinephrine were decreased. Initiation of dopamine synthesis and neural maturation is controlled by Pitx3 and Nurr1. Both Pitx3 and Nurr1 were identified in differentiating chromaffin progenitors. Along with the gained dopaminergic function, electrophysiology revealed features of mature neurons, such as sodium channels and the capability to fire multiple action potentials. In summary, this study elucidates the capacity of chromaffin progenitor cells to generate functional dopaminergic neurons, indicating their potential use in cell replacement therapies. PMID- 22507144 TI - How effective is continuing professional development? PMID- 22507145 TI - Barriers encountered using skill-mix to deliver caries prevention in dental practices. AB - This opinion paper provides an analysis of the barriers and successes experienced when developing and implementing a pilot scheme to deliver caries prevention using skill-mix in the National Health Service (NHS) General Dental Services. A training programme was initiated to develop the skills of extended duties dental nurses to deliver fluoride varnish to patients in selected dental practices in Croydon, London, UK. In the light of the evaluation of this programme, a recommendation is made that similar preventive schemes should be delivered in the future within the NHS dental contract. PMID- 22507146 TI - Positioning, identity and professionalism: a searching question for dental faculties. AB - As the new Joint Dental Council appointed by the two Dental Faculties of The Royal College of Surgeons of England begins its work to improve inter-faculty collaboration, this paper suggests some of the issues that will need to be addressed. Drawing on the concepts of 'positioning', 'identity' and 'professionalism', the question is raised as to how the Faculties may seek to engage more meaningfully with dental professionals at large. The need for all Dental Faculties in the British Isles to learn to work together is emphasised. Attention is drawn to the importance, in the rapidly evolving social context in which dental professionals work, of reflecting deeply on the nature of professionalism in contemporary society, and the moral and humanitarian issues that need to be addressed if dentists are to continue to be deemed worthy of the status 'profession'. PMID- 22507147 TI - Two audits of the diagnosis of oral cancer and the two-week rule following referrals from primary care practitioners in Newcastle. AB - AIM: The aim of the two audits was to evaluate the success of the two-week rule in the oral and maxillofacial surgery (OMFS) department at the Newcastle General Hospital (NGH) and then subsequently in the oral surgery and oral medicine departments at Newcastle Dental Hospital (NDH). METHODS: All two-week referrals seen at the NGH over a one-year period were examined retrospectively. An identical subsequent audit was carried out at the NDH over a second one-year period, also retrospectively. RESULTS: In the initial audit at the NGH, a total of 63 two-week referrals were received during the one-year period analysed. Of these, 57 (90%) were seen within the appropriate time period, and 60 (95%) conformed to the Department of Health guidelines. Seven (11%) of the 63 referred patients were diagnosed with head and neck cancer, indicating a positive oncology detection rate of 11%.In the later audit at the NDH, 49 urgent referrals were assessed. Forty-three of the 49 referrals (88%) were seen within the appropriate time period and thirty-nine (80%) were compliant with the referring guidelines. Forty-five patients attended for assessment and the resultant positive oncology detection rate for these patients was 7%. In both audits, the patients diagnosed as having positive oncology results all had referrals that were compliant with the Department of Health guidelines. CONCLUSIONS: Both of these audits indicated that the national guide- lines for two-week referrals were usually appropriately followed in the two departments that were audited. However, in the future, further education of referring practitioners should ensure that these guidelines are followed better, making the service provided more efficient for all concerned. PMID- 22507148 TI - Mentoring and dental foundation training. AB - This paper is based on an assignment written as part of the work required for the Faculty of General Dental Practice (UK)'s Certificate in Mentoring in Dentistry. Its author is currently a trainer for the first year of foundation training in a general dental practice in Kent. The paper commences by defining mentoring. It explores the relationship between postgraduate trainers and trainees and goes on to explain how it is the trainer's role to help trainees to use their strengths to overcome weaknesses. It details the person-centred approach, mentoring theories, helping models, the application of Kolb's learning cycle, the Inner Game theory, and the GROW model. It explores the role of foundation dental trainers as mentors to aid their trainee's ability to use reflective learning, and goes on to consider the implications of the changes that may result in the relationship between trainers and trainees as a consequence of the introduction of national recruitment. Finally, the author reflects on his experiences as a foundation dental trainer. PMID- 22507149 TI - An introduction to research for primary dental care clinicians part 8: stage 9. Analysing the data. AB - INTRODUCTION: This paper, the eighth in the series, will address the ninth stage of a research project suggested in the first paper. The ten suggested stages are: 1. The initial idea (asking a research question). 2. Searching the literature. 3. Refining the research question. 4. Planning the study. 5. Writing a protocol. 6. Obtaining ethics approval and funding. 7. Piloting the project and project management. 8. Collecting data. 9. Analysing the data. 10. Writing up and disseminating the results. The previous paper outlined how to collect data during a research project. The next stage is to analyse the data that have been collected. This paper briefly introduces readers to data analysis and basic statistics. It updates the Faculty of General Dental Practice (UK) research advice sheets: Introduction to Statistics, Statistics for Research, Testing for Statistical Significance. PMID- 22507150 TI - An introduction to research for primary dental care clinicians part 9: stage 10. Writing up and disseminating the results. AB - INTRODUCTION: This paper, the ninth and final one in the series, will address the tenth and final stage of a research project suggested in the first paper. The ten suggested stages are: 1. The initial idea (asking a research question). 2. Searching the literature. 3. Refining the research question. 4. Planning the study. 5. Writing a protocol. 6. Obtaining ethical approval and funding. 7. Piloting the methodology and project management. 8. Collecting data. 9. Analysing the data. 10. Writing up and disseminating the results. The paper outlines the steps that authors should take when seeking to publish the results of research in peer-reviewed journals and how to disseminate results through presentations at scientific conferences. These steps represent the final stage in the research process. PMID- 22507151 TI - Parental employment, income, education and allergic disorders in children: a prebirth cohort study in Japan. AB - SETTING: Epidemiological evidence on the relationship between socio-economic status and allergic disorders has been inconsistent. OBJECTIVES: We examined the associations between maternal employment, maternal job type, household income, and paternal and maternal educational levels and the risk of allergic disorders in Japanese children aged 4.5 years. DESIGN: Subjects were 480 mother-child pairs. Definitions of wheeze and eczema symptoms were based on criteria of the International Study of Asthma and Allergies in Childhood. Data on self-reported doctor-diagnosed asthma and atopic eczema were available. RESULTS: Compared with children whose mothers had received less than 13 years of education, those with mothers with >=15 years of education had a significantly increased risk of wheeze and doctor-diagnosed asthma: the adjusted ORs were respectively 2.41 (95%CI 1.18 5.17) and 2.70 (95%CI 1.03-8.08). Fifteen years or more of paternal education was independently associated with an increased risk of eczema, but not of doctor diagnosed atopic eczema (adjusted OR 1.89, 95%CI 1.07-3.42). Mother's employment, mother's job type and household income were not related to any of the outcomes. CONCLUSIONS: Higher maternal educational level may increase the risk of wheeze and asthma, while higher paternal educational level may increase the risk of eczema. PMID- 22507152 TI - Diabetes caused by Kir6.2 mutation: successful treatment with oral glibenclamide switched from continuous subcutaneous insulin infusion in the early phase of the disease. PMID- 22507153 TI - Life-threatening acute renal failure due to imperforate hymen in an infant. PMID- 22507154 TI - Congenital brain tumor: fetal case of congenital germ cell intracranial tumor. PMID- 22507155 TI - Vincristine, actinomycin D, cyclophosphamide chemotherapy resolves Kasabach Merritt syndrome resistant to conventional therapies. PMID- 22507157 TI - Slowly progressive sleep apnea in late-onset central hypoventilation syndrome. PMID- 22507156 TI - Retinitis from cytomegalovirus during maintenance treatment for acute lymphoblastic leukemia. PMID- 22507158 TI - Mycoplasma pneumoniae-associated necrotizing pneumonitis in children. PMID- 22507159 TI - Rapid development of severe respiratory distress due to a vallecular cyst in a 3 day-old infant. PMID- 22507160 TI - Prenatal diagnosis of coronary artery fistula: a case report and review of literature. PMID- 22507161 TI - Mild case of D-bifunctional protein deficiency associated with novel gene mutations. PMID- 22507162 TI - Fatal varicella with multi-organ failure associated with low-dose adrenocorticotropic hormone therapy. PMID- 22507163 TI - Unusual presentation of acute rheumatic fever: complete atrioventricular block. PMID- 22507164 TI - Hypochloremic metabolic alkalosis in a child with Henoch-Schonlein purpura. PMID- 22507165 TI - Fever and ascites underlying abdominal aspergillosis in a 3-year-old boy. PMID- 22507166 TI - Abdominal pain in Henoch-Schonlein purpura and its association with superior mesenteric artery syndrome. PMID- 22507167 TI - Advanced paternal age and impaired childhood cognitive development. PMID- 22507168 TI - Pneumonia during the first 2 years of life and asthma in preschool-age children. PMID- 22507169 TI - Reduced frequency of apnea and bradycardia episodes caused by exposure to biological maternal sounds. PMID- 22507170 TI - Validity of the Diabetic Neuropathy Score and Diabetic Neuropathy Examination score as screening tools for the detection of distal symmetrical diabetic neuropathy. PMID- 22507171 TI - Feasibility study of secure closure of gastric fundus perforation using over-the scope clips in a dog model. AB - BACKGROUND AND AIM: Gastric fundus perforation is a serious complication of endoscopic mucosal resection and endoscopic submucosal dissection performed for the removal of early gastric cancers or subepithelial tumors. The novel over-the scope clip (OTSC) has recently been found to be effective for closing gastrointestinal-tract perforations and accesses for natural orifice transluminal endoscopic surgery. However, feasibility studies of OTSCs in gastric fundus perforation are still lacking. The aim of this study was therefore to demonstrate the feasibility of endoscopic closure of gastric fundus perforation using the OTSC system in a dog model. METHODS: Gastric fundus perforations were created by needle-knife electrocautery in seven dogs. The perforations were then closed using the OTSC clipping system. Stomach distension was maintained by maximum insufflation with air and methylene blue solution (500 mL) was instilled to submerge the closed perforation. Leaks were detected laparoscopically. RESULTS: Perforations were closed in all seven cases with a mean time of 18.5 +/- 6.4 min (11-28 min). Twin Grasper assistance failed to release the OTSCs in two of the seven cases (2/7, 28.6%) because of difficulties associated with the J-maneuver (retroflexion of endoscope) required for the gastric fundus procedure, and OTCS were forced into place by suction. Minor leakage was observed in one case (1/7, 14.3%). No damages related to the clip system were found during postmortem examinations. CONCLUSIONS: Despite difficulties associated with the J-maneuver of the endoscope, this small series demonstrated that sufficient closure of gastric fundus perforation could be achieved using the OTSC system. PMID- 22507173 TI - The galU gene expression in Streptococcus pneumoniae. AB - The polysaccharide capsule of Streptococcus pneumoniae is the main virulence factor making the bacterium resistant to phagocytosis. The galU gene of S. pneumoniae encodes a UDP-glucose pyrophosphorylase absolutely required for capsule biosynthesis. In silico analyses indicated that the galU gene is co transcribed with the gpdA gene, and four putative promoter regions located upstream of gpdA were predicted. One of them behaved as a functional promoter in a promoter reporter system. It is conceivable that the sequence responsible for initiating transcription of gpdA-galU operon is an extended -10 site TATGATA(T/G)AAT. Semi-quantitative real-time reverse transcription PCR experiments indicated that galU was expressed mainly in the exponential phase of growth. PMID- 22507174 TI - Possible effects of changes in the meteorological state over semi-arid areas on the general well-being of weather-sensitive patients. AB - BACKGROUND: The influence of the changes in atmospheric states, typical for areas close to big deserts, on general well-being of hypertensive persons was analyzed. METHODS: Under test was the group of 20 hypertensive weather-sensitive patients; their blood pressure, pulse rate and appearance of 4 symptoms of discomfort sensations: arthritic pain, unjustified anxiety, severe headache and inexplicable tiredness- were registered. Symptoms are classified in ICD-9 code (780-790) and scored on a 4-point scale. Results were defined as positive (no departure from the range of normal values) or problematic; the daily number of the latter results was collected under the name "pathological reactions" NPR if at least two of these 7 checked symptoms (of one patient) were outside the normal range. Comparison of the current weather conditions with their means, questioning of patients and repeated examinations are used to gain information. The data was analyzed employing the SAS statistical software. Pearson and Spearman correlations were used, applied on the best and worst days, when a minimum and a maximum of pathological changes NPR in the patients' well-being were observed. The statistical significance was p < 0.05 in all cases. RESULTS: ~1500 medical observations and verbal statements were registered in the Primary Care Clinic (Be'er-Sheva, Israel) during 2001-2002. No meaning correlation was found between NPR and absolute values of temperature, humidity and atmospheric pressure. Variations in wind speed WS and direction were expressed in blood pressure changes and in exacerbation of discomfort of various degrees. Unfavorable conditions correspond to days with dominant desert air streams and to high WS, when NPR reaches 85.7%; during the days with prevalent sea breeze NPR was <=22.9%. The role of wind direction in NPR occurrence is prevalent when WS > 4 m.s-1. The Spearman test gives higher correlation than Pearson test (rho ~ 0.14, p < 0.03 against rho ~ 0.1, p < 0.04). CONCLUSIONS: NPR is more affected by the air streams than by absolute values of meteorological parameters. The method of this study might give to family doctors some additional tools to predict deterioration in general feelings of chronic patients and could be related to other health problems influenced by the meteorological environment. PMID- 22507177 TI - I see people: The presence of human faces impacts the processing of complex emotional stimuli. AB - Both emotional images and human faces are particularly salient compared to other categories of visual stimuli. The late positive potential (LPP) is larger for emotional than neutral images, and some evidence suggests that the LPP is further enhanced for images containing people. Studies of emotion frequently compare pleasant and unpleasant IAPS pictures to neutral, without an explicit understanding of how the presence of faces in these images may affect attentional allocation and psychophysiological response. The present experiment examined the effect of faces on the LPP elicited by neutral and threatening IAPS images. The LPP was enhanced by faces in neutral images, but no difference was observed between threatening images with and without faces. These results demonstrate that the inclusion of faces in IAPS images significantly impacts the LPP; however, this effect is unique to neutral images. PMID- 22507176 TI - Familial glucocorticoid deficiency presenting with generalized hyperpigmentation in an Egyptian child: a case report. AB - INTRODUCTION: Familial glucocorticoid deficiency, or hereditary unresponsiveness to adrenocorticotropic hormone, is a rare autosomal recessive disease characterized by glucocorticoid deficiency in the absence of mineralocorticoid deficiency. It may present in infancy or early childhood with hyperpigmentation, failure to thrive, recurrent infections, hypoglycemic attacks and convulsions that may result in coma or death. Here, we report the case of an 18-month-old Egyptian boy with familial glucocorticoid deficiency. CASE PRESENTATION: An 18 month-old Egyptian boy was referred to our institution for evaluation of generalized hyperpigmentation of the body associated with recurrent convulsions; one of his siblings, who had died at the age of nine months, also had generalized hyperpigmentation of the body. The initial clinical examination revealed generalized symmetrical deep hyperpigmentation of the body as well as hypotonia, normal blood pressure and normal male genitalia. He had low blood glucose and cortisol levels, normal aldosterone and high adrenocorticotropic hormone levels. Based on the above mentioned data, a provisional diagnosis of familial glucocorticoid deficiency was made, which was confirmed by a molecular genetics study. Oral hydrocortisone treatment at a dose of 10 mg/m2/day was started. The child was followed up after two months of treatment; the hyperpigmentation has lessened in comparison with his initial presentation and his blood sugar and cortisol levels were normalized. CONCLUSION: Familial glucocorticoid deficiency is a rare, treatable disease that can be easily missed due to nonspecific presentations. The consequences of delayed diagnosis and treatment are associated with high rates of morbidity and mortality. PMID- 22507175 TI - Carbonic anhydrase III regulates peroxisome proliferator-activated receptor gamma2. AB - Carbonic anhydrase III (CAIII) is an isoenzyme of the CA family. Because of its low specific anhydrase activity, physiological functions in addition to hydrating CO(2) have been proposed. CAIII expression is highly induced in adipogenesis and CAIII is the most abundant protein in adipose tissues. The function of CAIII in both preadipocytes and adipocytes is however unknown. In the present study we demonstrate that adipogenesis is greatly increased in mouse embryonic fibroblasts (MEFs) from CAIII knockout (KO) mice, as demonstrated by a greater than 10-fold increase in the induction of fatty acid-binding protein-4 (FABP4) and increased triglyceride formation in CAIII(-/-) MEFs compared with CAIII(+/+) cells. To address the underlying mechanism, we investigated the expression of the two adipogenic key regulators, peroxisome proliferator-activated receptor-gamma2 (PPARgamma2) and CCAAT/enhancer binding protein-alpha. We found a considerable (approximately 1000-fold) increase in the PPARgamma2 expression in the CAIII(-/-) MEFs. Furthermore, RNAi-mediated knockdown of endogenous CAIII in NIH 3T3-L1 preadipocytes resulted in a significant increase in the induction of PPARgamma2 and FABP4. When both CAIII and PPARgamma2 were knocked down, FABP4 was not induced. We conclude that down-regulation of CAIII in preadipocytes enhances adipogenesis and that CAIII is a regulator of adipogenic differentiation which acts at the level of PPARgamma2 gene expression. PMID- 22507178 TI - The recurrent Guillain-Barre syndrome: a long-term population-based study. AB - OBJECTIVES: To describe a population-based material of patients with recurrent Guillain-Barre syndrome (RGBS), examine the long time course, and search for factors predisposing to recurrence. MATERIALS AND METHODS: We performed a follow up study of the neurology and neurophysiology and a systematic study of the acute microbial serology of patients with RGBS. These parameters were compared with the results of a previous study of monophasic GBS. RESULTS: The patients with RGBS (n = 15) were retrieved from admissions of 229 patients with GBS during a 17-year period. They had 2-7 (median 3) episodes occurring at irregular intervals over decades. Of the 11 patients who accepted a follow-up examination, six were in full remission, and five had moderate sequelae. Nine had a demyelinating subtype, one had an axonal motor variant, and one patient with incomplete Miller Fisher syndrome had associated arachnoiditis. Two patients showed ultimate transition to a course similar to chronic inflammatory demyelinating polyneuropathy. Episodes were generally shorter in RGBS than in GBS, and an initial episode duration <45 days was predictive of recurrence and related to a younger onset age (univariate P = 0.005-0.009). Triggering infections occurred in all patients, in 32 of 41 episodes (78%) with few examples of etiological promiscuity. Serological findings did not differ from those in GBS. CONCLUSIONS: Episodes in RGBS were shorter than in monophasic GBS. We were unable to identify further immunological predisposing factors for recurrence beyond the previously demonstrated relationship to a weaker respiratory burst. We observed no obvious tendency for the recurrence frequency to wane. PMID- 22507179 TI - Application of time-of-flight-secondary ion mass spectrometry for the detection of enzyme activity on solid wood substrates. AB - Time-of-flight-secondary ion mass spectrometry (TOF-SIMS) is a surface analysis technique that is herein demonstrated to be a viable tool for the detection of enzyme activity on solid substrates. Proof-of-principle experiments are presented that utilize commercial cellulase and laccase enzymes, which are known to modify major polymeric components of wood (i.e., cellulose and lignin, respectively). Enzyme activity is assessed through principle component analysis (PCA) as well as through peak ratios intended to measure selective enzymatic wood degradation. Spectral reproducibility of the complex wood substrates is found to be within 5% relative standard deviation (RSD), allowing for relative quantification of changes in wood composition. Procedures are also presented to identify and avoid the influence of mass interferences from protein adsorption by the enzyme solutions. The activity of a cellulase cocktail is clearly evident through the TOF-SIMS spectra and is supported by high-pressure liquid chromatography (HPLC) measurements of sugar release and by complementary X-ray photoelectron spectroscopy (XPS) measurements of the wood surfaces. Laccase activity, which is mediated through small organic molecules, can be detected in the TOF-SIMS spectra through a decrease in G and S lignin peaks. This work has positive implications for the development of qualitative, high-throughput screening assays for enzyme activity on industrially relevant, lignocellulosic substrates. PMID- 22507180 TI - Assessing toxicological data quality: basic principles, existing schemes and current limitations. AB - Existing toxicological data may be used for a variety of purposes such as hazard and risk assessment or toxicity prediction. The potential use of such data is, in part, dependent upon their quality. Consideration of data quality is of key importance with respect to the application of chemicals legislation such as REACH. Whether data are being used to make regulatory decisions or build computational models, the quality of the output is reflected by the quality of the data employed. Therefore, the need to assess data quality is an important requirement for making a decision or prediction with an appropriate level of confidence. This study considers the biological and chemical factors that may impact upon toxicological data quality and discusses the assessment of data quality. Four general quality criteria are introduced and existing data quality assessment schemes are discussed. Two case study datasets of skin sensitization data are assessed for quality providing a comparison of existing assessment methods. This study also discusses the limitations and difficulties encountered during quality assessment, including the use of differing quality schemes and the global versus chemical-specific assessments of quality. Finally, a number of recommendations are made to aid future data quality assessments. PMID- 22507181 TI - Current limits and future challenges in the management of renal dysfunction in patients with cirrhosis: report from the International Club of Ascites. AB - Advanced cirrhosis is often complicated by a multi organ failure syndrome which involves many different organs besides the liver. The high morbidity and mortality secondary to this clinical setting is often related to renal dysfunction, either alone or, more frequently, in combination with other organ dysfunction. A clear definition of renal dysfunction, an accurate differential diagnostic process of its different phenotypes as well as of full understanding of its pathophysiological mechanisms are crucial to the development of strategies for the management of this complication. This article is based either on the more recent knowledge on renal dysfunction in advanced cirrhosis or current opinions among the members of the International Club of Ascites (ICA) on the management of this complication, obtained through a survey and discussed during the EASL-ICA Joint Meeting in Berlin in March 2011. It reviews critically our current knowledge and it outlines future perspectives, on the management of renal dysfunction in patients with cirrhosis. PMID- 22507182 TI - Examining the orthopaedic examiners: reliability of the Part 2 Orthopaedic Clinical Fellowship Examination in Australia. AB - BACKGROUND: The Final Examination for Orthopaedic Surgeons in Australia comprises seven components of which two are written responses and five are oral examinations involving separate pairs of examiners. METHODS: The reliability of the examination process and close marking system was assessed by using a standardized DVD of a sham examination. Fifteen current examiners viewed the DVD and scored the viewed examination independently. RESULTS: The results demonstrated consistency in scoring and reliability. This validation is likely to be further increased by the current system of the pairing of examiners. Additionally, the patient-based examination segments were found to be as reliably scored as the criterion-referenced computer-based examination stations. CONCLUSIONS: Candidates for the Fellowship Examination should be reassured that this study has shown that the examination process has inter-examiner reliability and consistency. PMID- 22507183 TI - Recurrence from primary and secondary glomerulopathy after renal transplant. AB - Glomerulonephritis is the primary cause of end-stage renal failure in 30-50% of kidney transplant recipients and recurrence of the initial disease is an important determinant of long-term graft outcome after transplantation. Although renal transplantation remains the best treatment option for patients with end stage renal diseases in most cases, diagnosis and management of recurrences of glomerulopathies are critical for the optimization and improvement of long-term kidney transplant graft survival and provide a unique opportunity to explore the pathogenesis of native kidney disease. This review aims to update knowledge for a large panel of recurrent primary and secondary glomerulonephritis after kidney transplantation, excluding diabetic nephropathy including primary focal and segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, membranoproliferative glomerulonephritis, lupus, vasculitis but also less usual secondary nephropathy related to sarcoidosis, AA and AL amyloidosis, monoclonal immunoglobulin deposition disease, and fibrillary glomerulonephritis. PMID- 22507184 TI - Childhood diabetic neuropathy: functional impairment and non-invasive screening assessment. AB - AIM: Sensory diabetic neuropathy, determined by nerve conduction studies, is common in children with Type 1 diabetes. Diabetic neuropathy diagnoses are rarely made in paediatric daily care because they are asymptomatic, vibration detection is mostly normal and nerve-conduction testing is impractical. The present study aims to: (1) describe somatosensory dysfunction in children with diabetes, (2) test whether diabetes duration and HbA(1c) are related to somatosensory dysfunction and (3) identify the best screening test for large-fibre dysfunction, as indicated by nerve conduction studies. METHODS: Forty-five children (age 13.2 +/- 2.5 years) with Type 1 diabetes for 6.7 +/- 2.5 years and matched control subjects were assessed by neurological examinations, nerve conduction tests and quantitative sensory testing on the feet using the protocol of the German Research Network on Neuropathic Pain. Abnormal nerve conduction was used as gold standard to define neuropathies. RESULTS: We found a high prevalence of mechanical (38%) and thermal (24%) hypoesthesia often associated with hyperalgesia (47%). Tactile hypoesthesia (33%) was more frequent than pallhypaesthesia (11%). Only cold detection and mechanical pain thresholds were related to HbA(1c). Tactile hypoesthesia had the highest sensitivity (75%), specificity (89%) and positive (75%) and negative (89%) predictive values for neuropathies defined by nerve conduction tests (31% abnormal). CONCLUSIONS: Almost half of the children with diabetes have subclinical large- and small-fibre neuropathies. Tactile detection was better than vibration for neuropathy assessment. Quantitative sensory testing is a valuable tool for assessment of neuropathy as well as a target of interventional studies in children with diabetes. PMID- 22507185 TI - Pediatric hospitalizations with influenza A infection during the 2009-2010 pandemic in five hospitals in Japan. AB - BACKGROUND: The aim of this study was to identify the clinical characteristics of hospitalized children with the 2009 pandemic influenza virus infection in Japan. METHODS: We retrospectively reviewed cases of hospitalized children younger than 16 years with laboratory-confirmed influenza A virus infection during the 2009 2010 pandemic season in five hospitals in Japan. RESULTS: A total of 515 cases were included in the analysis. The median age was 6.3 years (range 0-15), and 216 subjects (41.9%) had one or more underlying medical conditions. There were no fatalities, but 16 patients (3.1%) required intensive care. More than 93% of the subjects received neuraminidase inhibitors, and more than 87% received these medications within 48 h of the onset of symptoms. Approximately 80% of all subjects were admitted to hospital within 48 h of the onset of symptoms. CONCLUSIONS: There were no fatalities, and the proportion of patients with serious illness was substantially lower than previously reported from other countries. Good access to medical services and proactive treatment may have contributed to the lower disease burden of the 2009 influenza pandemic on Japanese children. PMID- 22507186 TI - Microbial production of volatile sulphur compounds in the large intestine of pigs fed two different diets. AB - AIMS: To investigate the production of volatile sulphur compounds (VSC) in the segments of the large intestine of pigs and to assess the impact of diet on this production. METHODS AND RESULTS: Pigs were fed two diets based on either wheat and barley (STD) or wheat and dried distillers grains with solubles (DDGS). Net production of VSC and potential sulphate reduction rate (SRR) (sulphate saturated) along the large intestine were determined by means of in vitro incubations. The net production rate of hydrogen sulphide and potential SRR increased from caecum towards distal colon and were significantly higher in the STD group. Conversely, the net methanethiol production rate was significantly higher in the DDGS group, while no difference was observed for dimethyl sulphide. The number of sulphate-reducing bacteria and total bacteria were determined by quantitative PCR and showed a significant increase along the large intestine, whereas no diet-related differences were observed. CONCLUSION: VSC net production varies widely throughout the large intestine of pigs and the microbial processes involved in this production can be affected by diet. SIGNIFICANCE AND IMPACT OF THE STUDY: This first report on intestinal production of all VSC shows both spatial and dietary effects, which are relevant to both bowel disease- and odour mitigation research. PMID- 22507187 TI - Estimating the effect of SNP genotype on quantitative traits from pooled DNA samples. AB - BACKGROUND: Studies to detect associations between DNA markers and traits of interest in humans and livestock benefit from increasing the number of individuals genotyped. Performing association studies on pooled DNA samples can provide greater power for a given cost. For quantitative traits, the effect of an SNP is measured in the units of the trait and here we propose and demonstrate a method to estimate SNP effects on quantitative traits from pooled DNA data. METHODS: To obtain estimates of SNP effects from pooled DNA samples, we used logistic regression of estimated allele frequencies in pools on phenotype. The method was tested on a simulated dataset, and a beef cattle dataset using a model that included principal components from a genomic correlation matrix derived from the allele frequencies estimated from the pooled samples. The performance of the obtained estimates was evaluated by comparison with estimates obtained using regression of phenotype on genotype from individual samples of DNA. RESULTS: For the simulated data, the estimates of SNP effects from pooled DNA are similar but asymptotically different to those from individual DNA data. Error in estimating allele frequencies had a large effect on the accuracy of estimated SNP effects. For the beef cattle dataset, the principal components of the genomic correlation matrix from pooled DNA were consistent with known breed groups, and could be used to account for population stratification. Correctly modeling the contemporary group structure was essential to achieve estimates similar to those from individual DNA data, and pooling DNA from individuals within groups was superior to pooling DNA across groups. For a fixed number of assays, pooled DNA samples produced results that were more correlated with results from individual genotyping data than were results from one random individual assayed from each pool. CONCLUSIONS: Use of logistic regression of allele frequency on phenotype makes it possible to estimate SNP effects on quantitative traits from pooled DNA samples. With pooled DNA samples, genotyping costs are reduced, and in cases where trait records are abundant this approach is promising to obtain SNP associations for marker-assisted selection. PMID- 22507188 TI - Protective effects of cathelicidin-encoding Lactococcus lactis in murine ulcerative colitis. AB - BACKGROUND AND AIM: Intrarectal administration of mouse cathelin-related antimicrobial peptide (mCRAMP) reduced intestinal inflammation in mice. In the current study, we examined whether mCRAMP-transformed Lactococcus lactis given orally attained similar protective effects. METHOD: mCRAMP was produced and secreted from the transformed L. lactis. Murine colitis was induced by ingestion of 3% dextran sulfate sodium (DSS) for 7 days. Eight or 10 log colony forming unit (cfu) L. lactis or the transformed strains with or without nisin induction were given orally as a parallel treatment with DSS. The body weight, fecal microbiota populations, clinical symptoms and histological examinations of colonic tissues were determined. Myeloperoxidase (MPO) activity and malondialdehyde (MDA) level were also evaluated to reflect the degree of inflammation. A prototype anti-inflammatory drug sulfasalazine was used as a reference drug to compare the efficacy and mechanisms of action for ulcerative colitis (UC). RESULT: Compared with the control group with colitis, cathelicidin transformed L. lactis could improve the clinical symptoms, maintain crypt integrity and preserve mucus content (P < 0.01). The number of apoptotic cells, MPO activity and MDA level were also significantly reduced (P < 0.05). The increases of fecal microbiota in colitis animals were markedly prevented (P < 0.001). Unlike mCRAMP-encoding L. lactis, effective doses of sulfasalazine only alleviated the clinical symptoms (P < 0.01) but not the mucosal damage in the colon. CONCLUSION: mCRAMP-transformed L. lactis has been shown to produce mCRAMP, effectively preventing murine UC. Oral administration of this biological preparation is better than sulfasalazine for the treatment of UC. PMID- 22507189 TI - Decrease of global methylation improves significantly hepatic differentiation of Ad-MSCs: possible future application for urea detoxification. AB - Hepatocyte transplantation is considered to be an alternative to orthotopic liver transplantation. Cells can be used to bridge patients waiting for a donor organ, decrease mortality in acute liver failure, and support metabolic liver diseases. The limited availability of primary human hepatocytes for such applications has led to the generation of alternative hepatocyte-like cells from various adult stem or precursor cells. The aim of this study was to generate hepatocyte-like cells from adipose-derived mesenchymal stem cells (Ad-MSCs) for clinical applications, which are available "off the shelf." Epigenetic changes in hepatocyte-like cells were induced by 5-azacytidine, which, in combination with other supplements, leads to significantly improved metabolic and enzymatic activities compared to nontreated cells. Cells with sufficient hepatic features were generated with a four-step protocol: 5-azacytidine (step 1); epidermal growth factor (step 2); fibroblast growth factor-4, dexamethasone, insulin transferrin-sodium-selenite, and nicotinamide (step 3); and hepatocyte growth factor, dexamethasone, insulin-transferrin-sodium-selenite, and nicotinamide (step 4). Generated differentiated cells had higher phase I (CYP1A1/2, CYP2E1, CYP2B6, CYP3A4) and phase II activities compared to the undifferentiated cells. A strong expression of CYP3A7 and a weak expression of 3A4, as well as the important detoxification markers alpha-fetoprotein and albumin, could also be detected at the mRNA level. Importantly, urea metabolism (basal, NH4-stimulated, NH4- and ornithine-stimulated) was comparable to freshly isolated human hepatocytes, and unlike cryopreserved human hepatocytes, this activity was maintained after 6 months of cryopreservation. These findings suggest that these cells may be suitable for clinical application, especially for treatment of urea cycle disorders. PMID- 22507190 TI - IRF5 promotes the proliferation of human thyroid cancer cells. AB - BACKGROUND: Interferon Regulatory Factor 5 is a transcription factor that regulates the expression of genes involved in the response to viral infection and in the stimulation of the immune system. Moreover, multiple studies have demonstrated that it negatively regulates cell growth and oncogenesis, favoring cell differentiation and apoptosis.Thyroid carcinoma represents 98% of all thyroid malignancies and has shown a steady increase in incidence in both the USA and western European countries. FINDINGS: We investigated the expression, localization and function of IRF5 in thyroid cancer cells and found that it is highly expressed in both primary and immortalized thyroid carcinomas but not in normal thyrocytes. IRF5 levels were variably modulated by Interferon alpha but IRF5 only localized in the cytoplasmic compartment, thus failing to induce p21 expression as previously reported in different cell models. Furthermore, ectopic IRF5 increased both the proliferation rate and the clonogenic potential of malignant thyroid cells, protecting them from the cytotoxic effects of DNA damaging agents. These results were directly attributable to IRF5, as demonstrated by the reduction in colony-forming ability of thyroid cancer cells after IRF5 silencing. An IRF5-dependent induction of endogenous B-Raf observed in all thyroid cancer cells might contribute to these unexpected effects. CONCLUSIONS: These findings suggest that, in thyroid malignancies, IRF5 displays tumor-promoting rather than tumor-suppressor activities. PMID- 22507191 TI - A perturbation in glutathione biosynthesis disrupts endoplasmic reticulum morphology and secretory membrane traffic in Arabidopsis thaliana. AB - To identify potentially novel and essential components of plant membrane trafficking mechanisms we performed a GFP-based forward genetic screen for seedling-lethal biosynthetic membrane trafficking mutants in Arabidopsis thaliana. Amongst these mutants, four recessive alleles of GSH2, which encodes glutathione synthase (GSH2), were recovered. Each allele was characterized by loss of the typical polygonal endoplasmic reticulum (ER) network and the accumulation of swollen ER-derived bodies which accumulated a soluble secretory marker. Since GSH2 is responsible for converting gamma-glutamylcysteine (gamma EC) to glutathione (GSH) in the glutathione biosynthesis pathway, gsh2 mutants exhibited gamma-EC hyperaccumulation and GSH deficiency. Redox-sensitive GFP revealed that gsh2 seedlings maintained redox poise in the cytoplasm but were more sensitive to oxidative challenge. Genetic and pharmacological evidence indicated that gamma-EC accumulation rather than GSH deficiency was responsible for the perturbation of ER morphology. Use of soluble and membrane-bound ER markers suggested that the swollen ER bodies were derived from ER fusiform bodies. Despite the gross perturbation of ER morphology, gsh2 seedlings did not suffer from constitutive oxidative ER stress or lack of an unfolded protein response, and homozygotes for the weakest allele could be propagated. The link between glutathione biosynthesis and ER morphology and function is discussed. PMID- 22507192 TI - Molecular analysis of isoniazid-resistant Mycobacterium tuberculosis isolates in Uruguay. AB - The incidence of tuberculosis (TB) is increasing in high-risk populations in Uruguay, possibly owing to emerging resistance. Mycobacterial interspersed repetitive units (MIRU) genotyping and katG sequence analysis of isoniazid (INH) resistance-associated mutations were performed in 45 INH-resistant Mycobacterium tuberculosis isolates in Uruguayan patients. The genotype distribution among INH resistant isolates shares features of that of neighbouring countries, with a predominance of Latin American and Mediterranean, T and Haarlem genotypes, although the S genotype was particularly frequent among our isolates. Forty-four per cent of INH-resistant strains harboured the S315T mutation in katG; we found novel katG mutations (W321X, G269T, P232R and G221Wfs1) that could explain INH resistance. PMID- 22507193 TI - Increased beta-cell replication and beta-cell mass regeneration in syngeneically transplanted rat islets overexpressing insulin-like growth factor II. AB - Insulin-like growth factor II (IGF2) is a growth-promoting peptide that increases beta-cell proliferation and survival. The aim of the study was to determine the effect of IGF2 overexpression on beta-cell mass in transplanted islets. Islets infected with adenovirus encoding for IGF2 (Ad-IGF2 group), for luciferase (Ad Luc control group), or with uninfected islets (control group) were syngeneically transplanted to streptozotocin-diabetic Lewis rats. Eight hundred islets, a minimal mass model to restore normoglycemia, or 500 islets, a clearly insufficient mass, were transplanted. Rats transplanted with 800 Ad-IGF2 islets showed a better metabolic evolution than control groups. As expected, rats transplanted with 500 Ad-IGF2 or control islets maintained similar hyperglycemia throughout the study, ensuring comparable metabolic conditions among both groups. beta-Cell replication was higher in Ad-IGF2 group than in control group on days 3 [1.45% (IQR: 0.26) vs. 0.58% (IQR: 0.18), p = 0.006], 10 [1.58% (IQR: 1.40) vs. 0.90% (IQR: 0.61), p = 0.035], and 28 [1.35% (IQR: 0.35) vs. 0.64% (IQR: 0.28), p = 0.004] after transplantation. beta-Cell mass was similarly reduced on day 3 after transplantation in Ad-IGF2 and control group [0.36 mg (IQR: 0.26) vs. 0.38 mg (IQR: 0.19)], it increased on day 10, and on day 28 it was higher in Ad-IGF2 than in control group [0.63 mg (IQR: 0.38) vs. 0.42 mg (IQR: 0.31), p = 0.008]. Apoptosis was similarly increased in Ad-IGF2 and control islets after transplantation. No differences in insulin secretion were found between Ad-IGF2 and uninfected control islets. In summary, IGF2 overexpression in transplanted islets increased beta-cell replication, induced the regeneration of the transplanted beta-cell mass, and had a beneficial effect on the metabolic outcome reducing the beta-cell mass needed to achieve normoglycemia. PMID- 22507194 TI - Stent implantation for a totally occluded right coronary artery in a six-year-old boy after Kawasaki disease: a case report. AB - INTRODUCTION: Coronary stenting has previously been considered to be less feasible in children under 12 years old due to the limitation of vascular access. We report the case of a six-year-old boy who successfully underwent stent implantation for his totally occluded right coronary artery. CASE PRESENTATION: A Taiwanese boy aged six years and nine months old was found to have giant aneurysms after an acute episode of Kawasaki disease. An angiography revealed that his middle right coronary artery was totally occluded. A 0.014-inch guidewire was advanced to cross the totally occluded site. After pre-dilating the middle portion of his right coronary artery with a 1.5 mm balloon, stenting of his right coronary artery was accomplished using a 2.5 * 28 mm and a 2.5 * 18 mm bare metal stent. A final angiography demonstrated no residual stenosis or dissection. CONCLUSION: Coronary stenting could be a therapeutic option for children as young as six years old. Close follow-up is mandatory because the long term outcome is still unclear, especially in a small child. PMID- 22507195 TI - Critical approaches in physical therapy research: investigating the symbolic value of walking. AB - Research using a critical social science perspective is uncommon in physiotherapy (PT) despite its potential advantages for investigating questions other approaches cannot address. Critical approaches can be used to expose ideas and concepts that are dominant, given, or taken-for-granted in practice in order to reflect on how "things could be otherwise." The purpose of this paper is to use an example of research examining the symbolic value of walking to outline the key features of critical research and its application to PT. The study drew from Pierre Bourdieu's sociology of practice to illuminate how socially ingrained notions of normality and disability are reflected in rehabilitation practices and affect parents and children with cerebral palsy. Dominant social assumptions about the value of walking are shown to shape individual choices and contribute to parental feelings of angst and doubt, and negative self-identities for children. The example reveals how critical approaches to research can be used to reveal the socio-political dimension of rehabilitation practice and address important research questions that have been largely neglected. PMID- 22507196 TI - The effect of adjuvant and microbial challenge on the expression of antimicrobial polypeptides in channel catfish (Ictalurus punctatus). AB - While antimicrobial polypeptides (AMPPs) are increasingly recognized as one of the most important components of innate immunity, there is very little information in vertebrates that documents their upregulation to levels that are microbicidal in vivo. Here we demonstrate that intraperitoneal injection of either Freund's complete adjuvant (FCA) or live Tetrahymena pyriformis (a parasitic ciliate) upregulated AMPP expression in channel catfish skin. FCA induced significant upregulation of total antibacterial activity, anti Edwardsiella ictaluri activity (the fraction of antibacterial activity active against E. ictaluri), and HLP-1 (the major AMPP in channel catfish skin). Tetrahymena induced a similar upregulation, except that HLP-1 was not significantly induced and the response appeared to be more transient than FCA immunostimulation. AMPP levels were increased up to five-fold higher than resting levels and levels expressed were well within concentrations known to be inhibitory to many important pathogens in vitro. These results provide encouragement that AMPP upregulation may be a promising tool in aquaculture for enhancing the resistance of fish to disease. PMID- 22507197 TI - Immune responses of zebrafish (Danio rerio) induced by bath-vaccination with a live attenuated Vibrio anguillarum vaccine candidate. AB - A fish vaccine candidate, live attenuated Vibrio anguillarum, which can protect fish from vibriosis, was established in our laboratory. In this study, the protective immunological mechanism of live attenuated V. anguillarum was investigated in zebrafish as a model animal. After bath-vaccinated with the live attenuated strain, zebrafish were challenged with wild pathogenic strain to test the immunoprotection of the live attenuated strain. As the results, specific antibody response of fish against V. anguillarum was found to gradually increase during 28 days post-vaccination, and remarkable protection was showed with a high relative protection survival (RPS) of about 90%. Moreover, the vaccination changed the expressions of several immune-related genes in the spleens and livers of zebrafish. Among them, the expressions of pro-inflammatory factors such as IL 1 and IL-8 were tenderly up-regulated with about 3-4 fold in 1-7 days post vaccination, while MHC II rose to a peak level of 4-fold in 7th day post vaccination. These results gave some important messages about the mechanism of specific protection induced by live attenuated V. anguillarum and showed the availability of zebrafish model in the evaluation of the vaccine candidate. PMID- 22507198 TI - A two-dimensional screen for AMPK substrates identifies tumor suppressor fumarate hydratase as a preferential AMPKalpha2 substrate. AB - AMP-activated protein kinase (AMPK) is emerging as a central cellular signaling hub involved in energy homeostasis and proliferation. The kinase is considered as a suitable target for pharmacological intervention in several energy-related pathologies like diabetes type II and cancer, although its signaling network is still incompletely understood. Here we apply an original two-dimensional in vitro screening approach for AMPK substrates that combines biophysical interaction based on surface plasmon resonance with in vitro phosphorylation. By enriching for proteins that interact with a specific AMPK isoform, we aimed to identify substrates that are also preferentially phosphorylated by this specific AMPK isoform. Application of this screen to full-length AMPK alpha2beta2gamma1 and soluble rat liver proteins identified the tumor suppressor fumarate hydratase (FH). FH was confirmed to interact with and to be preferentially phosphorylated by the AMPKalpha2 isoform by using yeast-two-hybrid and in vitro phosphorylation assays. AMPK-mediated phosphorylation of FH significantly increased enzyme activity in vitro and in vivo, suggesting that it is a bona fide AMPK substrate. In vivo, AMPKalpha2 is supposed to target the cytosolic/nuclear pools of FH, whose tumor suppressor function relies on DNA damage repair and inhibition of HIF 1alpha-signaling. PMID- 22507199 TI - Effects of chronic tramadol exposure on the zebrafish brain: a proteomic study. AB - Tramadol hydrochloride (TH), has become the most prescribed opioid worldwide. However, its neurotoxicity and abuse potential are not well documented. In the present study, TH administration induced abnormal behavior and body and brain mean weight loss. Two principal metabolites O- and N-desmethyltramadol were detected in the brain tissue, and N-desmethyltramadol was the main metabolite produced. A total of 30 differential protein spots were identified using semi quantitative 2D-PAGE and proteomic analyses, and classified into 13 categories, in which subtypes of 14-3-3 proteins, creatine kinase, ATP synthase beta chain, and tubulin were identified at the separated location on the gels 3, 3, 4, and 11 times respectively. Many TH responsive proteins have functions related to oxidative stress, including 14-3-3 proteins, creatine kinase BB, ubiquitin carboxy-terminal hydrolase L-1, ATP synthase, synaptosome-associated protein, tubulin and actin. Irrespective of oxidative damage, other pathways affected include apoptosis, energy metabolism, signal disorders, and cytoskeletal structure. Ultrastructural observation of mitochondria showed a series of morphological changes in the case of TH exposure. PMID- 22507200 TI - Alpha-Dystrobrevin and its associated proteins in human promyelocytic leukemia cells induced to apoptosis. AB - Dystrobrevin is a dystrophin-related component of the dystrophin-associated protein complex (DAPC). Using alpha-dystrobrevin as indicator, we aimed to elucidate the interaction network of the DAPC with other proteins during apoptosis of promyelocytic HL-60 cells. The precise role(s) of DBs are not known, but we and others have shown that they play a role in intracellular signal transduction and cellular organization. Apoptosis was induced with etoposide in the absence or presence of Z-VAD to block caspase activity, and we then followed the cellular distribution of alpha-DB and its association with other proteins, using confocal imaging and cell fractions analyses after immune-precipitation with anti-alpha-DB and mass spectrometry. Confocal imaging revealed distinct spatial relocalizations of alpha-DB between the cell membrane, cytosol and nucleus after induction of apoptosis. The expression levels of the identified proteins were evaluated with computer-assisted image analysis of the gels. We thus identified associations with structural and transport proteins (tropomyosin, myosin), membrane (ADAM21, syntrophin), ER-Golgi (TGN51, eIF38) and nuclear (Lamins, ribonucleoprotein C1/C2) proteins. These results suggest that apoptosis induction in HL-60 cells involves not only classical markers of apoptosis but also a network alpha-DB-associated proteins at the cell membrane, the cytoplasm and nucleus, affecting key cellular transport processes and cellular structure. PMID- 22507201 TI - Proteomic analysis of porcine mesenteric lymph-nodes after Salmonella typhimurium infection. AB - In this study we employed for the first time an in vivo approach coupled to DIGE based proteomics to explore the response of porcine mesenteric lymph nodes (MLN) to Salmonella typhimurium infection. MLN samples were collected from four control and twelve infected pigs (at 1, 2 and 6 days post infection) for histological analysis, protein and RNA purification. Afterwards, expressed proteins were screened by differential in gel analysis and data were analyzed by bioinformatic tools to generate interaction networks, and identify enriched signaling pathways and biological annotations. S. typhimurium labeling in tissue and phagocyte infiltration were analyzed by immunohistochemistry and RNA was employed to determine the relative expression of immune-related genes by quantitative RNA analysis. The proteome response of porcine MLN to infection was associated to the induction of processes such as phagocyte infiltration, cytoskeleton remodeling and pyroptosis. Moreover, our results suggest that S. typhimurium antigens are cross-presented via MHC-I in a proteasome-dependent manner in porcine MLN. Since pathogen burden in tissue was noticeably reduced at the end of the time course, we infer that host innate and adaptive immunity act in association in MLN to control S. typhimurium dissemination in swine infections. PMID- 22507202 TI - Identifying differentiation stage of individual primary hematopoietic cells from mouse bone marrow by multivariate analysis of TOF-secondary ion mass spectrometry data. AB - The ability to self-renew and differentiate into multiple types of blood and immune cells renders hematopoietic stem and progenitor cells (HSPCs) valuable for clinical treatment of hematopoietic pathologies and as models of stem cell differentiation for tissue engineering applications. To study directed hematopoietic stem cell (HSC) differentiation and identify the conditions that recreate the native bone marrow environment, combinatorial biomaterials that exhibit lateral variations in chemical and mechanical properties are employed. New experimental approaches are needed to facilitate correlating cell differentiation stage with location in the culture system. We demonstrate that multivariate analysis of time-of-flight secondary ion mass spectrometry (TOF SIMS) data can be used to identify the differentiation state of individual hematopoietic cells (HCs) isolated from mouse bone marrow. Here, we identify primary HCs from three distinct stages of B cell lymphopoiesis at the single cell level: HSPCs, common lymphoid progenitors, and mature B cells. The differentiation state of individual HCs in a test set could be identified with a partial least-squares discriminant analysis (PLS-DA) model that was constructed with calibration spectra from HCs of known differentiation status. The lowest error of identification was obtained when the intrapopulation spectral variation between the cells in the calibration and test sets was minimized. This approach complements the traditional methods that are used to identify HC differentiation stage. Further, the ability to gather mass spectrometry data from single HSCs cultured on graded biomaterial substrates may provide significant new insight into how HSPCs respond to extrinsic cues as well as the molecular changes that occur during cell differentiation. PMID- 22507204 TI - Three phases of the Pacific Islands Project (1995-2010). AB - The Pacific Islands Project (PIP), funded by AusAid and managed by the Royal Australasian College of Surgeons (RACS), has progressed through three phases from 1995 to 2010. During this time, it has sent over 520 teams to 11 Pacific Island Countries, providing over 60,000 consultations and some 16,000 procedures. In addition to this delivery of specialist medical and surgical services that were not previously available in-country, the project has contributed as a partner in capacity building with the Fiji School of Medicine and Ministries of Health of the individual nations. By 2011, Fiji School of Medicine, which began postgraduate specialist training in 1998, had awarded 51 doctors a diploma in surgery (1 year), 20 of whom had completed their Masters in Medicine (4 years). PIP was independently evaluated on completion of every phase, including the bridging Phase III (2006-2010). The project delivered on its design, to deliver services, and also helped build capacity. The relationship established with the RACS throughout the project allowed Pacific Island graduates to access the Rowan Nicks scholarship, and the majority of MMed graduates received International Travel Grants to attend the Annual Scientific Meeting. PIP has been a highly successful partnership in delivering and building specialist medical services. Although AusAid contributed some $20 million over 16 years, the value added from pro bono contributions by Specialist Teams, Specialty Coordinators and the Project Directors amounted to an equivalent amount. With the emergence of Pacific Island-trained specialists, PIP is ready to move into a new phase where the agendas are set, monitored and managed within the Pacific, and RACS fulfils the role of a service provider. A critical mass of Pacific Island surgeons has been trained, so that sub-specialization will be an option for the general surgeons of the larger island nations. PMID- 22507203 TI - Regulation of proline metabolism in mycobacteria and its role in carbon metabolism under hypoxia. AB - Genes with a role in proline metabolism are strongly expressed when mycobacterial cells are exposed to nutrient starvation and hypoxia. Here we show that proline metabolism in mycobacteria is mediated by the monofunctional enzymes Delta(1) pyrroline-5-carboxylate dehydrogenase (PruA) and proline dehydrogenase (PruB). Proline metabolism was controlled by a unique membrane-associated DNA-binding protein PruC. Under hypoxia, addition of proline led to higher biomass production than in the absence of proline despite excess carbon and nitrogen. To identify the mechanism responsible for this enhanced growth, microarray analysis of wild type Mycobacterium smegmatis versus pruC mutant was performed. Expression of the DNA repair machinery and glyoxalases was increased in the pruC mutant. Glyoxalases are proposed to degrade methylglyoxal, a toxic metabolite produced by various bacteria due to an imbalance in intermediary metabolism, suggesting the pruC mutant was under methylglyoxal stress. Consistent with this notion, pruB and pruC mutants were hypersensitive to methylglyoxal. Delta(1) -pyrroline-5 carboxylate is reported to react with methylglyoxal to form non-toxic 2-acetyl-1 pyrroline, thus providing a link between proline metabolism and methylglyoxal detoxification. In support of this mechanism, we show that proline metabolism protects mycobacterial cells from methylglyoxal toxicity and that functional proline dehydrogenase, but not Delta(1) -pyrroline-5-carboxylate dehydrogenase, is essential for this protective effect. PMID- 22507205 TI - A comparative study of backbone versus side chain peptide cyclization: application for HIV-1 integrase inhibitors. AB - Peptide cyclization is an important tool for overcoming the limitations of linear peptides as drugs. Backbone cyclization (BC) has advantages over side chain (SC) cyclization because it combines N-alkylation for extra peptide stability. However, the appropriate building blocks for BC are not yet commercially available. This problem can be overcome by preparing SC cyclic peptide analogs of the most active BC peptide using commercially available building blocks. We have recently developed BC peptides that inhibit the HIV-1 integrase enzyme (IN) activity and HIV-1 replication in infected cells. Here we used this system as a model for systematically comparing the BC and SC cyclization modes using biophysical, biochemical and structural methods. The most potent SC cyclic peptide was active almost as the BC peptide and inhibited IN activity in vitro and blocked IN activity in cells even after 6 days. We conclude that both cyclization types have their respective advantages: The BC peptide is more active and stable, probably due to the N-alkylation, while SC cyclic peptides are easier to synthesize. Due to the high costs and efforts involved in preparing BC peptides, SC may be a more approachable method in many cases. We suggest that both methods are interchangeable. PMID- 22507207 TI - Evaluation of a synthetic C34 trimer of HIV-1 gp41 as AIDS vaccines. AB - An artificial antigen forming the C34 trimeric structure targeting membrane fusion mechanism of HIV-1 has been evaluated as an HIV vaccine. The C34 trimeric molecule was previously designed and synthesized using a novel template with C3 symmetric linkers by us. The antiserum produced by immunization of the C34 trimeric form antigen showed 23-fold higher binding affinity for the C34 trimer than for the C34 monomer and showed significant neutralizing activity. The present results suggest effective strategies of the design of HIV vaccines and anti-HIV agents based on the native structure mimic of proteins targeting dynamic supramolecular mechanisms in HIV fusion. PMID- 22507206 TI - Discovery of Ipragliflozin (ASP1941): a novel C-glucoside with benzothiophene structure as a potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus. AB - A series of C-glucosides with various heteroaromatics has been synthesized and its inhibitory activity toward SGLTs was evaluated. Upon screening several compounds, the benzothiophene derivative (14a) was found to have potent inhibitory activity against SGLT2 and good selectivity versus SGLT1. Through further optimization of 14a, a novel benzothiophene derivative (14h; ipragliflozin, ASP1941) was discovered as a highly potent and selective SGLT2 inhibitor that reduced blood glucose levels in a dose-dependent manner in diabetic models KK-A(y) mice and STZ rats. PMID- 22507208 TI - Paviosides A-H, eight new oleane type saponins from Aesculus pavia with cytotoxic activity. AB - A phytochemical analysis of Aesculus pavia has led to the isolation of eight novel triterpenoid saponins, based on oleane type skeleton and named paviosides A H (1a, 1b-4a, 4b). On the basis of chemical, and 2D NMR and mass spectrometry data, the structures of the new compounds were elucidated as 3-O-[beta-D xylopyranosyl (1 -> 2)] [-beta-d-glucopyranosyl (1 -> 4)]-beta-D glucopyranosiduronic acid 21-tigloyl-22-acetyl barringtogenol C (1a), 3-O-[beta-D xylopyranosyl (1 -> 2)] [-beta-D-glucopyranosyl (1 -> 4)]-beta-D glucopyranosiduronic acid 21-angeloyl-22-acetyl barringtogenol C (1b), 3-O-[beta D-xylopyranosyl (1 -> 2)] [-beta-D-galactopyranosyl (1 -> 4)]-beta-D glucopyranosiduronic acid 21-tigloyl-22-acetyl barringtogenol C (2a), 3-O-[beta-D xylopyranosyl (1 -> 2)] [-beta-D-galactopyranosyl (1 -> 4)]-beta-D glucopyranosiduronic acid 21-angeloyl-22-acetyl barringtogenol C (2b), 3-O-[beta D-xylopyranosyl (1 -> 2)] [-beta-D-xylopyranosyl (1 -> 4)]-beta-D glucopyranosiduronic acid 21-tigloyl-22-acetyl barringtogenol C (3a), 3-O-[beta-D xylopyranosyl (1 -> 2)] [-beta-D-xylopyranosyl (1 -> 4)]-beta-d glucopyranosiduronic acid 21-angeloyl-22-acetyl barringtogenol C (3b), 3-O-[beta D-xylopyranosyl (1 -> 2)] [-beta-D-xylopyranosyl (1 -> 4)]-beta-D glucopyranosiduronic acid 21-tigloyl-22-acetyl protoaescigenin (4a), and 3-O [beta-D-xylopyranosyl (1 -> 2)] [-beta-D-xylopyranosyl (1 -> 4)]-beta-D glucopyranosiduronic acid 21-angeloyl-22-acetyl protoaescigenin (4b). The compounds showed cytotoxic activity on J-774, murine monocyte/macrophage, and WEHI-164, murine fibrosarcoma, cell lines. Among them, paviosides E-H (3a, 3b and 4a, 4b) showed higher activity with values ranging from 2.1 to 3.6 MUg/mL. Structure-activity relationship studies indicated the positive effect on the activity of xylose unit in the place of glucose, while a little detrimental effect is observed when glucose is substituted by galactose. The aglycone structure and the presence of a tigloyl or an angeloyl group at C-21 do not affect significantly the inhibitory activity on both tested cell lines. PMID- 22507210 TI - Isolated penile lymphedema in an adolescent male: a case of metastatic Crohn's disease. AB - OBJECTIVE: Metastatic Crohn's disease is a rare and complex inflammatory condition distinguished by cutaneous granulomatous lesions outside the gastrointestinal tract. Genital involvement is rare; with less than 10 cases reported involving isolated penile lymphedema. Here, we present a case of isolated lymphedema of the penis as a consequence of extra-intestinal Crohn's disease. CASE REPORT: The patient is an 18-year-old African American male with a complex history of inflammatory bowel disease, who initially presented with a chief complaint of 6 weeks of swelling of his penis at age 13. A modified circumcision and lymphangectomy of the penis were performed; histopatholgy demonstrated a granulomatous infiltrate and interstitial edema of the distal penis. CONCLUSION: Surgical intervention is an applicable therapeutic alternative and last-line therapy for treatment of isolated penile lymphedema in select patients with appropriate pathology, and can be a suitable adjunct to medical management in these cases. PMID- 22507209 TI - Cardiogenic shock as the initial presentation of systemic lupus erythematosus: a case report and review of the literature. PMID- 22507211 TI - The science behind the art of hand therapy. PMID- 22507212 TI - Understanding the biomechanical nature of musculoskeletal tissue. AB - This article provides a general overview of the biomechanical principles associated with hand therapy. Specifically, it reviews the basic topics of material properties (including both theoretical principles and practical concepts), static analysis (including forces, moments, muscle forces, and Newton's laws), and ends with a clinical example involving analysis of the risk of damage to the A3 pulley. PMID- 22507213 TI - Tendinopathies of the elbow, wrist, and hand: histopathology and clinical considerations. AB - This article reviews the current opinion of the histopathological findings of common elbow, wrist, and hand tendinopathies. Implications for client management including examination, diagnosis, prognosis, intervention, and outcomes are addressed. Concepts for further research regarding common therapeutic interventions are discussed. PMID- 22507214 TI - Interventions in the disturbances in the motor and sensory environment. AB - Treatment of peripheral nervous system (PNS) pathology presents intervention challenges to every therapist. Many of the current and future interventions will be directed at restoring the normal anatomy, function, and biomechanical properties of the PNS, restoring normal neural physiology and ultimately patient function and quality of life. Present interventions use mechanical (movement) or electrical procedures to affect various properties of the peripheral nerve. The purpose of this article was to apply basic science to clinical practice. The pathology and accompanying structural and biomechanical changes in the PNS will be presented in three specific areas commonly encountered in the clinic: nerve injury and laceration; compression neuropathies; and neuropathic pain and neural tension dysfunction. The intent is to address possible interventions exploring the clinical reasoning process that combines basic science and evidence-based best practice. The current lack of literature to support any one intervention requires a strong foundation and understanding of the PNSs' structure and function to refine current and develop new intervention strategies. Current evidence will be presented and linked with future considerations for intervention and research. During this interlude of development and refinement, best practice will rely on sound clinical reasoning skills that incorporate basic science to achieve a successful outcome when treating these challenging patients. PMID- 22507215 TI - Orthotic considerations for dense connective tissue and articular cartilage--the need for optimal movement and stress. AB - Orthotic intervention is an essential component of hand rehabilitation, addressing biological factors that affect activity and participation. Functional, pain-free joint mobility requires skeletal stability, healthy articular cartilage, and appropriate extensibility of periarticular dense connective tissues (DCTs). This article addresses basic science underlying clinical reasoning when considering orthoses to maintain or restore structural integrity, mobility and function of DCT structures, and articular cartilage. However, these tissues often have different and sometimes conflicting requirements for the maintenance and restoration of integrity and health. The duration of immobilization, especially at end range, should be carefully considered, as it impairs nutrition of tissues and adversely compresses articular cartilage, causing injury that may not be reversible. Immobilization also reduces extensibility of DCT. Thus, an intermittent orthotic wearing schedule is suggested, allowing movement wherever possible to promote tissue health. To optimize benefits and minimize harmful effects of orthotic intervention, further research on physiological responses of human tissues to immobilization and tension is needed. PMID- 22507217 TI - Humanized mice: current states and perspectives. AB - The development of chimeric mice bearing the components of a human immune system to serve as animal models for "human" diseases has been the goal of many years of research. In this review we will discuss the latest advances in this field, their remaining shortcomings and challenges to the generation of new models of mouse/human chimeras. PMID- 22507216 TI - Novel evidence of the involvement of calreticulin in major psychiatric disorders. AB - Calreticulin (CALR) is a multi-functional protein that is strictly conserved across species. Two mRNA transcripts have been recognized for the CALR gene in humans, which use a common promoter sequence. We have recently reported mutations in the CALR promoter that co-occur with psychosis. One of those mutations at 220A increases gene expression in human BE(2)-C and HEK-293 cell lines. This mutation is the first instance of a functional cognition-deficit mutation reversing a human gene promoter to the primitive type. In the current study, we analyzed the effect of the most widely-used mood-stabilizing drug, valproic acid (VPA), on nucleotide -220 in two neuronal cell lines, LAN-5 and N2A. Remarkably, VPA increased gene expression in the cells with the wild-type -220C construct, whereas a dramatic decrease in gene expression was observed in the cell lines with the mutant construct (p<0.000004 and p<0.016, respectively). We also sequenced the 600-bp CALR promoter, and the highly conserved intron 1 sequence in an independent sample of patients afflicted with major psychiatric disorders and controls. A new case of major depressive disorder with psychotic features with the -220A mutation was identified. A novel 1-bp insertion was also detected in intron 1 at IVSI-310, in a case of amphetamine-induced psychosis. As for the psychosis-linked CALR promoter mutations identified to-date, the IVSI mutation was not detected in the control pool. This mutation creates a RREB-1 transcription factor binding site within the first intron. Our present findings identify the site of action of VPA in the CALR promoter, and introduce a novel mutation in a case of substance-induced psychosis in the first intron of CALR. PMID- 22507218 TI - Characterisation of simian immunodeficiency virus-infected cells in pigtail macaques. AB - Defining which cells become infected with simian immunodeficiency virus (SIV) in vivo should assist in unravelling the pathogenesis of human immunodeficiency virus (HIV)/SIV infection. HIV/SIV infection of CD4(+) T cells resulted in down regulation of CD3 and CD4 surface molecules in vitro, however this phenomenon is poorly characterised in vivo. Intracellular SIV p27 was studied by flow cytometry in serial blood samples and lymph node samples during acute infection of 17 SIVmac-infected pigtail macaques. Two weeks after infection, a mean of 56+/-6.8% the p27(+) cells were lymphocytes negative for surface CD4 and CD3, and indeed the highest proportion of SIV infected cells were found in the small subset of CD3(Lo)CD4(-)CD8(-) lymphocytes, indicating that infection has lead to down regulation of these markers in vivo. Furthermore, the relative amount of SIV p27 within lymphocytes (based of mean fluorescence intensity) was higher in CD3(Lo)CD4(-) and CD3(-) infected cells than in CD3(+) or CD4(+) p27(+) populations, consistent with greater viral production in CD4(+) T cells down regulating CD3 and CD4 molecules. The CD3(-)CD4(-) infected cells expressed T cell markers CD2 and CD5 and were negative for monocyte, NK and B cell markers. The majority of infected cells were CD28(+)CD95(+) central memory T cells. Surprisingly, p27(+) blood lymphocytes were mostly negative for activation markers CD25 and CD69, but most of the infected lymph nodes cells were activated. Our results characterise productively-infected macaque lymphocytes in vivo. The high proportion of SIV-infected lymphocytes that are CD3(-)CD4(-) has important implications for the in vivo study of pathogenesis of SIV/HIV infections. PMID- 22507219 TI - A new prospect in cancer therapy: targeting cancer stem cells to eradicate cancer. AB - According to the cancer stem cell theory, cancers can be initiated by cancer stem cells. This makes cancer stem cells prime targets for therapeutic intervention. Eradicating cancer stem cells by efficient targeting agents may have the potential to cure cancer. In this review, we summarize recent breakthroughs that have improved our understanding of cancer stem cells, and we discuss the therapeutic strategy of targeting cancer stem cells, a promising future direction for cancer stem cell research. PMID- 22507220 TI - Epidemiologic differences in esophageal cancer between Asian and Western populations. AB - Esophageal cancer is a common cancer worldwide and has a poor prognosis. The incidence of esophageal squamous cell cancer has been decreasing, whereas the incidence of esophageal adenocarcinoma has been increasing rapidly, particularly in Western men. Squamous cell cancer continues to be the major type of esophageal cancer in Asia, and the main risk factors include tobacco smoking, alcohol consumption, hot beverage drinking, and poor nutrition. In contrast, esophageal adenocarcinoma predominately affects the whites, and the risk factors include smoking, obesity, and gastroesophageal reflux disease. In addition, Asians and Caucasians may have different susceptibilities to esophageal cancer due to different heritage backgrounds. However, comparison studies between these two populations are limited and need to be addressed in the near future. Ethnic differences should be taken into account in preventive and clinical practices. PMID- 22507221 TI - YC-1 exerts inhibitory effects on MDA-MB-468 breast cancer cells by targeting EGFR in vitro and in vivo under normoxic condition. AB - 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), the hypoxia-inducible factor-1 alpha (HIF-1alpha) inhibitor, suppresses tumor proliferation and metastasis by down-regulating HIF-1alpha expression under hypoxic conditions. Our previous studies demonstrated that YC-1 inhibited breast cancer cell proliferation under normoxic conditions. In the current study, we investigated the targets of YC-1 and mechanism of its action in MDA-MB-468 breast cancer cells. In the in vitro experiments, we found that YC-1 significantly inhibited MDA-MB-468 cell proliferation in normoxia and hypoxia. Under normoxic conditions, YC-1 induced apoptosis of MDA-MB-468 cells and blocked cell cycle in the G1 phase, and these effects were possibly related to caspase 8, p21, and p27 expression. RT-PCR and Western blotting results showed that YC-1 primarily inhibited HIF-1alpha at the mRNA and protein levels under hypoxic conditions, but suppressed the expression of epidermal growth factor receptor(EGFR) at the mRNA and protein levels under normoxic conditions. In vivo, YC-1 prolonged survival, increased survival rate, decreased tumor size and metastasis rate, and inhibited tissue EGFR and HIF-1alpha expression. However, YC-1 exerted no obvious effect on body weight. These results indicate that YC-1 inhibits the proliferation of MDA MB-468 cells by acting on multiple targets with minimal side effects. Thus, YC-1 is a promising target drug for breast cancer. PMID- 22507222 TI - Screening for novel lead compounds increasing insulin expression in medullary thymic epithelial cells. AB - Insulin expression in the thymus has been implicated in regulating the negative selection of autoreactive T cells and in mediating the central immune tolerance to pancreatic beta-cells. Thymic insulin expression modulation might be an important drug target for preventing type 1 diabetes. We performed a high throughput screening to identify compounds with such activity. A reporter plasmid was constructed with the human insulin promoter sequence including a short allele of the upstream variable number tandem repeat (VNTR) sequence (32 repeats), subcloned into the pGL4.17 vector. The plasmid was stably transfected into an insulin-transcribing medullary thymic epithelial cell (mTEC) line. Primary high throughput screening assays were carried out by stimulating with candidate compounds for 24h, and the activity of luciferase was measured. Positive compounds were further validated by real-time PCR. Of 19,707 compounds, we identified one compound that could enhance mTEC insulin expression, as confirmed by real-time PCR. We also observed that transfection with the autoimmune regulator (AIRE) increased endogenous AIRE expression in mTECs. Our insulin-VNTRI promoter reporter system is consistent with the insulin expression regulation in mTECs, and one compound that was identified could increase insulin expression in mTECs. A positive feedback effect of AIRE in mTECS was observed. Whether these efforts in murine thymus cells apply to humans remains to be determined. PMID- 22507223 TI - An analysis of the relative risk for hypothyroidism in patients with Type 2 diabetes. AB - AIMS: We aimed to assess the relative risk for hypothyroidism in patients with Type 2 diabetes. METHODS: In this study, 1112 patients with Type 2 diabetes (58% women, mean age 66.7 years, median duration of diabetes 10 years, 179 with previous history of thyroid disease) and 911 subjects without diabetes were evaluated. RESULTS: The gender-, age- and weight-adjusted relative risk (odds ratio) of newly identified hypothyroidism in patients with Type 2 diabetes in comparison with control subjects was 2.81 (1.77-4.48). This odds ratio was significant in patients over 65 years [4.02 (1.95-8.31)], as well as in both men [4.84 (1.58-14.80)] and women [2.60 (1.54-4.38)], in obese patients [2.56 (1.36 4.82)] and non-obese patients [3.11 (1.56-6.20)] and in individuals with [4.26 (1.73-10.46)] and without [2.93 (1.50-5.75)] thyroid autoantibodies. Logistic regression analysis showed that newly diagnosed hypothyroidism was significantly and directly related not only with thyroid autoimmunity [19.15 (8.73-42.01)], but also with the presence of macroangiopathy [2.85 (1.51-5.35)] and metformin treatment [2.51 (1.28-4.92)]. CONCLUSIONS: Our results favour screening for hypothyroidism in patients with Type 2 diabetes older than 65 years, especially in the presence of diabetic macroangiopathy or treatment with metformin. PMID- 22507224 TI - Review of preschool vision screening referrals in South Auckland, New Zealand. AB - BACKGROUND: Limited data are available on the causes of visual impairment in preschool children in New Zealand. We aimed to review demographic and visual parameters in children referred to the Ophthalmology Department, Manukau Super Clinic from vision screening programs in South Auckland. METHODS: Retrospective medical record review of 131 children, aged three to five years, referred from community-based vision screening programs to the Ophthalmology Department for further assessment. Medical records were reviewed to determine: the reason for referral; findings from ophthalmic assessments; treatment received; and visual acuity at the final visit. The main outcome measures were the cause of visual impairment in children referred from preschool vision screening and the visual acuity at the final follow-up visit. RESULTS: Thirty-eight (29.0 per cent) children were discharged after their initial assessment as false positive referrals. Almost half (45.5 per cent) of the children were prescribed glasses for the correction of refractive error, amblyopia or strabismus. Twenty-nine (22.1 per cent) children were diagnosed with amblyopia with an average follow-up period of 17.5 +/- 2.7 months. In general, compliance with therapy for amblyopia was poor with 48.3 per cent non-compliant with their prescribed treatment regimen. Despite this, visual outcomes were good with an average final visual acuity in the amblyopic eye of 0.294 +/- 0.231 logMAR (Snellen 6/12). CONCLUSIONS: The 'positive predictive value' for the Counties-Manukau preschool vision screening program was 47.4 per cent, suggesting that the visual acuity measurements alone produce a significant number of false positive results. In children diagnosed with amblyopia, early detection and intervention showed significant improvement in vision in the amblyopic eye, with many children also showing improved binocular function. PMID- 22507226 TI - Murine gammaherpesvirus-68 expands, but does not activate, CD11b+ gr-1+ splenocytes in vivo. AB - BACKGROUND: Murine gammaherpesvirus 68 (HV-68) is an efficient pathogen, capable of infecting and establishing lifelong latency in rodents. While many studies have demonstrated the ability of this viral infection to modulate immune responses, a unifying mechanism for HV-68-induced subversion of a protective host response remains elusive. We questioned whether infection with HV-68 could expand a population of myeloid derived suppressor cells (MDSC) as one mechanism for altering protective immunity. METHODS: Mice were infected with HV-68, with viral latency being established in these animals. At varying times post-infection, cells were isolated for detection of viral genomes, phenotyping of myeloid cell populations, and ex vivo analysis of suppressor activity of myeloid cells. RESULTS: CD11b + Gr-1+ myeloid cells accumulated in the spleens, but not the bone marrow, of HV-68 infected mice. These cells were predominantly Gr-1+ Ly-6 G+, and could be found to contain viral genomes. Increased levels of serum S100A8/A9 produced during viral infection were consistent with the expansion of these CD11b + Gr-1+ myeloid cells. Despite their expansion, these cells exhibited no increased arginase 1 or iNOS activity, and did not have the ability to suppress anti-CD3 antibody activated T lymphocyte responses. CONCLUSIONS: We concluded that HV-68 infection was capable of expanding a population of myeloid cells which were phenotypically similar to MDSC. However these cells were not sufficiently activated during the establishment of viral latency to actively suppress T cell responses. PMID- 22507225 TI - The effect of dietary zinc--and polyphenols intake on DMBA-induced mammary tumorigenesis in rats. AB - BACKGROUND: The aim of the study was to investigate the effect of dietary supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein, on the effectiveness of chemically induced mammary cancer and the changes in the content of selected elements (Zn, Cu, Mg, Fe, Ca) in tumors as compared with normal tissue of the mammary gland. METHODS: Female Sprague-Dawley rats were divided into study groups which, apart from the standard diet and DMBA (7,12-dimethyl-1,2- benz[a]anthracene), were treated with zinc ions (Zn) or zinc ions + resveratrol (Zn + resveratrol) or zinc ions + genistein (Zn + genistein) via gavage for a period from 40 days until 20 weeks of age. The ICP-OES (inductively coupled plasma optical emission spectrometry) technique was used to analyze the following elements: magnesium, iron, zinc and calcium. Copper content in samples was estimated in an atomic absorption spectrophotometer. RESULTS: Regardless of the diet (standard; Zn; Zn + resveratrol; Zn + genistein), DMBA induced breast carcinogenesis was not inhibited. On the contrary, in the Zn + resveratrol supplemented group, tumorigenesis developed at a considerably faster rate. On the basis of quantitative analysis of selected elements we found- irrespectively of the diet applied--great accumulation of copper and iron, which are strongly prooxidative, with a simultaneous considerable decrease of the magnesium content in DMBA-induced mammary tumors. The combination of zinc supplementation with resveratrol resulted in particularly large differences in the amount of the investigated elements in tumors as compared with their content in normal tissue. CONCLUSIONS: Diet supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein had no effect on the decreased copper level in tumor tissue and inhibited mammary carcinogenesis in the rat. Irrespectively of the applied diet, the development of the neoplastic process in rats resulted in changes of the iron and magnesium content in the cancerous tissue in comparison with the healthy mammary tissue. The application of combined diet supplementation with zinc ions and resveratrol considerably promoted the rate of carcinogenesis and increased the number of DMBA-induced mammary tumors. PMID- 22507227 TI - Classification of schizophrenia patients and healthy controls from structural MRI scans in two large independent samples. AB - The purpose of this study is to create a model that can classify schizophrenia patients and healthy controls based on whole brain gray matter densities (voxel based morphometry, VBM) from structural magnetic resonance imaging (MRI) scans. In addition, we investigated the stability of the accuracy of the models, when built with different sample sizes. Using a support vector machine, we built a model from 239 subjects (128 patients and 111 healthy controls) and classified 71.4% correct (leave-one-out). We replicated and validated this result by testing the unaltered model on a completely independent sample of 277 subjects (155 patients and 122 healthy controls), scanned with a different scanner. The classification rate of the validation sample was 70.4%. The model's discriminative pattern showed, amongst other differences, gray matter density decreases in frontal and superior temporal lobes and hippocampus in schizophrenia patients with respect to healthy controls and increases in gray matter density in basal ganglia and left occipital lobe and. Larger training samples gave more reliable models: Models based on sample sizes smaller than N=130 should be considered unstable and can even score below chance. PMID- 22507228 TI - The neural mechanisms by which testosterone acts on interpersonal trust. AB - Recently, we demonstrated that the steroid-hormone testosterone reduces interpersonal trust in humans. The neural mechanism which underlies this effect is however unknown. It has been proposed that testosterone increases social vigilance via neuropeptide systems in the amygdala, augmenting communication between the amygdala and the brain stem. However, testosterone also affects connectivity between the orbitofrontal cortex (OFC) and the amygdala, which could subsequently lead to increased vigilance by reduced top-down control over the amygdala. Here, in a placebo-controlled testosterone administration study with 16 young women, we use functional magnetic resonance imaging to get more insights into neural mechanisms whereby testosterone acts on trust. Several cortical systems, among others the OFC, are involved in the evaluation of facial trustworthiness. Testosterone administration decreased functional connectivity between amygdala and the OFC during judgments of unfamiliar faces, and also increased amygdala responses specifically to the faces that were rated as untrustworthy. Finally, connectivity between the amygdala and the brain stem was not affected by testosterone administration. Although speculative, a neurobiological explanation for these findings is that in uncertain social situations, testosterone induces sustained decoupling between OFC and amygdala by a prefrontal-dopaminergic mechanism, subsequently resulting in more vigilant responses of the amygdala to signals of untrustworthiness. PMID- 22507229 TI - Does parametric fMRI analysis with SPM yield valid results? An empirical study of 1484 rest datasets. AB - The validity of parametric functional magnetic resonance imaging (fMRI) analysis has only been reported for simulated data. Recent advances in computer science and data sharing make it possible to analyze large amounts of real fMRI data. In this study, 1484 rest datasets have been analyzed in SPM8, to estimate true familywise error rates. For a familywise significance threshold of 5%, significant activity was found in 1%-70% of the 1484 rest datasets, depending on repetition time, paradigm and parameter settings. This means that parametric significance thresholds in SPM both can be conservative or very liberal. The main reason for the high familywise error rates seems to be that the global AR(1) auto correlation correction in SPM fails to model the spectra of the residuals, especially for short repetition times. The findings that are reported in this study cannot be generalized to parametric fMRI analysis in general, other software packages may give different results. By using the computational power of the graphics processing unit (GPU), the 1484 rest datasets were also analyzed with a random permutation test. Significant activity was then found in 1%-19% of the datasets. These findings speak to the need for a better model of temporal correlations in fMRI timeseries. PMID- 22507230 TI - Disentangling the brain networks supporting affective speech comprehension. AB - Areas involved in social cognition, such as the medial prefrontal cortex (mPFC) and the left temporo-parietal junction (TPJ) appear to be active during the classification of sentences according to emotional criteria (happy, angry or sad, [Beaucousin et al., 2007]). These two regions are frequently co-activated in studies about theory of mind (ToM). To confirm that these regions constitute a coherent network during affective speech comprehension, new event-related functional magnetic resonance imaging data were acquired, using the emotional and grammatical-person sentence classification tasks on a larger sample of 51 participants. The comparison of the emotional and grammatical tasks confirmed the previous findings. Functional connectivity analyses established a clear demarcation between a "Medial" network, including the mPFC and TPJ regions, and a bilateral "Language" network, which gathered inferior frontal and temporal areas. These findings suggest that emotional speech comprehension results from interactions between language, ToM and emotion processing networks. The language network, active during both tasks, would be involved in the extraction of lexical and prosodic emotional cues, while the medial network, active only during the emotional task, would drive the making of inferences about the sentences' emotional content, based on their meanings. The left and right amygdalae displayed a stronger response during the emotional condition, but were seldom correlated with the other regions, and thus formed a third entity. Finally, distinct regions belonging to the Language and Medial networks were found in the left angular gyrus, where these two systems could interface. PMID- 22507231 TI - Impaired hemodynamic response in the ischemic brain assessed with BOLD fMRI. AB - The study aims to investigate the effect of cerebral ischemia or hypoperfusion in the evaluation of neural activity with blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI), and to examine whether the severity of the compromised hemodynamic status in patients with major cerebral artery diseases could, conversely, be assessed with the use of neural activity as endogenous vasodilator. 28 neurological impairment-free patients with anterior circulation-territory ischemia performed a bimanual hand-grasping task. Magnitude and temporal shift of evoked BOLD response, baseline cerebral blood flow (CBF) and its increment, and the severity of hemodynamic impairment stratified by blood flow pattern were evaluated. For fMRI data, both conventional analysis with a canonical HRF and an HRF-model-free analysis were performed. The severity of hemodynamic impairment was significantly correlated (p<0.0001) with baseline CBF, CBF increment, and magnitude and delay of BOLD response. BOLD response delay was also significantly correlated (p<0.0001) with baseline CBF, CBF increment, and response magnitude. In 10 out of 45 ischemic motor cortices, conventional analysis completely failed to detect areas of activation that were demonstrated by HRF-model-free analysis. These data suggest that delay and reduced magnitude of BOLD response can be an indicator of the severity of compromised hemodynamic status, and that reduced regional baseline CBF and its increment underlie impaired BOLD response, which necessitates an alternative approach to conventional analysis with any single HRF. PMID- 22507232 TI - Achilles tendon regeneration can be improved by amniotic epithelial cell allotransplantation. AB - Amniotic epithelial cells (AECs) are ideal seed cells for tissue regeneration, but no research has yet been reported on their tendon regeneration potential. This study investigated the efficiency of AEC allotransplantation for tendon healing, as well as the mechanism involved. To this aim ovine AECs, characterized by specific surface and stemness markers (CD14(-), CD31(-), CD45(-), CD49f, CD29, CD166, OCT4, SOX2, NANOG, TERT), were allotransplanted into experimentally induced tissue defects in sheep Achilles tendon. In situ tissue repair revealed that AEC-treated tendons had much better structural and mechanical recoveries than control ones during the early phase of healing. Immunohistochemical and biochemical analyses indicated that extracellular matrix remodeling was more rapid and that immature collagen fibers were completely replaced by mature ones in 28 days. Moreover, spatial-temporal analysis of cellularity, proliferation index, vascular area, and leukocyte infiltration revealed that AECs induced a specific centripetal healing process that first started in the tissue closer to the healthy portion of the tendons, where AECs rapidly migrated to then progress through the core of the lesion. This peculiar healing evolution could have been induced by the growth factor stimulatory influence (TGF-beta1 and VEGF) and/or by the host progenitor cells recruitment, but also as the consequence of a direct tenogenic AEC differentiation resulting in the regeneration of new tendon matrix. These findings demonstrate that AECs can support tendon regeneration, and their effects may be used to develop future strategies to treat tendon disease characterized by a poor clinical outcome in veterinary medicine. PMID- 22507233 TI - PETAL LOSS is a boundary gene that inhibits growth between developing sepals in Arabidopsis thaliana. AB - Flower primordia are partitioned by boundaries during their early development. Such boundaries occur between whorls of organs, and also between organs within whorls. PETAL LOSS (PTL) is a trihelix transcription factor gene that is expressed in boundaries between sepal primordia in the outer whorl. Over expression of PTL results in growth suppression suggesting that PTL normally inhibits growth between newly arising sepals. We have tested this by examining the consequences of loss of PTL function using confocal imaging. The size of the inter-sepal zone in stage 4 buds expands radially by 35-40% in ptl-1 mutants as a consequence of additional cell proliferation. There is no change in the size of PTL-expressing cells. PTL expression does not overlap with the sites of petal initiation identified using the DR5 auxin response reporter. The latter are closer to the centre of the flower. Thus the consequence of loss of PTL function on petal initiation is indirect, perhaps through interference with a mobile petal initiation signal or movement of the PTL protein. CUP-SHAPED COTYLEDON (CUC) genes are also involved in defining inter-sepal boundaries. However, genetic studies combining ptl with loss of cuc1 function, and gain of CUC function in extra early petals-1 (miR164c) mutants, have revealed that CUC and PTL act differently. CUC suppresses growth of sepal tissues from the boundary region whereas PTL acts to keep the size of the boundary in check. PMID- 22507234 TI - A dual-centre, cohort comparison of open, laparoscopic and robotic-assisted radical cystectomy. AB - INTRODUCTION: The role of minimally invasive radical cystectomy as opposed to open surgery for bladder cancer is not yet established. We present comparative outcomes of open, laparoscopic and robotic-assisted radical cystectomy MATERIAL AND METHODS: Prospective cohort comparison of 158 patients from 2003-2008 undergoing open radical cystectomy (ORC) (n = 52), laparoscopic radical cystectomy (LRC) (n =58) or robotic-assisted radical cystectomy (RARC) (n = 48) performed by a team of three surgeons at two hospitals. Peri-operative data, complication rates, length of hospital stay, oncological outcome (including lymph node status) and survival were recorded. Statistical analyses were adjusted to account for potential confounding factors such as ASA grade, gender, age, diversion type and final histology. RESULTS: RARC took longer than LRC and ORC. Patients were about 30 times more likely to have a transfusion if they had ORC than if they had RARC (p < 0.0001) and about eight times more likely to have a transfusion if they had LRC compared with RARC (p < 0.006). Patients were four times more likely to have a transfusion if they had ORC as compared with LRC (p < 0.007). Patients were four times more likely to have complications if they had ORC than RARC (p = 0.006) and about three times more likely to have complications with LRC than with RARC (p = 0.02). Hospital stay was mean 19 days after ORC, 16 days after LRC and 10 days after RARC. CONCLUSIONS: Despite study limitations, RARC had the lowest transfusion and complication rates and the shortest length of stay, although taking the longest to perform. PMID- 22507235 TI - Breath analysis as a potential diagnostic tool for tuberculosis. AB - SETTING: Cape Town, South Africa. OBJECTIVES: We investigated the potential of breath analysis by gas chromatography-mass spectrometry (GC-MS) to discriminate between samples collected prospectively from patients with suspected tuberculosis (TB). DESIGN: Samples were obtained in a TB-endemic setting in South Africa, where 28% of culture-proven TB patients had Ziehl-Neelsen (ZN) negative sputum smear. A training set of breath samples from 50 sputum culture-proven TB patients and 50 culture-negative non-TB patients was analysed using GC-MS. We used support vector machine analysis for classification of the patient samples into TB and non-TB. RESULTS: A classification model with seven compounds had a sensitivity of 72%, a specificity of 86% and an accuracy of 79% compared with culture. The classification model was validated with breath samples from a different set of 21 TB and 50 non-TB patients from the same area, giving a sensitivity of 62%, a specificity of 84% and an accuracy of 77%. CONCLUSION: This study shows that GC MS breath analysis is able to differentiate between TB and non-TB breath samples even among patients with a negative ZN sputum smear but a positive culture for Mycobacterium tuberculosis. We conclude that breath analysis by GC-MS merits further research. PMID- 22507236 TI - Impaired anticipatory control of grasp during obstacle crossing in Parkinson's disease. AB - During self-paced walking, people with Parkinson's disease maintain anticipatory control during object grasping. However, common functional tasks often include carrying an object while changing step patterns mid-path and maneuvering over obstacles, increasing task complexity and attentional demands. Thus, the present study investigated the effect of Parkinson's disease on the modulation of grasping force changes as a function of gait-related inertial forces. Subjects with Parkinson's disease maintained the ability to scale and to couple over time their grip and inertial forces while walking at irregular step lengths, but were unable to maintain the temporal coupling of grasping forces compared to controls during obstacle crossing. We suggest that this deterioration in anticipatory control is associated with the increased demands of task complexity and attention during obstacle crossing. PMID- 22507237 TI - Modulation of amplitude sensitivity by bilateral collicular interaction among different frequency laminae. AB - In the ascending auditory pathway, the commissure of the inferior colliculus (IC) interconnects the two ICs and may therefore mediate bilateral collicular interaction during sound processing. In this study, we show that electrically stimulates one IC produces facilitation or suppression of acoustically evoked response of neurons in the other IC. The facilitated IC neurons (14%) are located in bilateral corresponding frequency laminae while the suppressed IC neurons (86%) are widespreadly located in bilateral different frequency laminae. Whereas induced facilitation increases the dynamic range but decreases the slope of the rate-amplitude function of modulated IC neurons, induced suppression produces the opposite effect. As a result, bilateral collicular facilitation increases the sensitivity of modulated IC neurons to a wider range of sound amplitude while bilateral collicular suppression improves the sensitivity of modulated IC neurons to minor change in sound amplitude over a narrower range of sound amplitude. The degree of suppression is significantly greater for suppressed IC neurons located in bilateral corresponding frequency laminae than in non-corresponding frequency laminae. We suggest that bilateral collicular interaction through the commissure of the IC may play a role in modulation of amplitude sensitivity and in shaping the binaural property of IC neurons. PMID- 22507238 TI - FTY720, sphingosine 1-phosphate receptor modulator, selectively radioprotects hippocampal neural stem cells. AB - Cranial irradiation is an effective treatment modality for both primary and metastatic brain tumors, yet it induces cognitive decline in a substantial number of patients. At present, there are no established methods for neuroprotection. Recent investigations have revealed a link between radiation-induced cognitive dysfunction and the loss of neural precursor cells in the hippocampus. Hence, identifying pharmacological agents, capable of protecting this cell population, is of interest. FTY720 (fingolimod), an FDA-approved oral drug for the treatment of multiple sclerosis, has been shown to promote the survival and differentiation of neural progenitors, as well as remyelination and repair after brain injury. In this study, we show that FTY720, used at nanomolar concentrations, is capable of increasing the viability and neurogenicity of irradiated neural stem cells from the hippocampus. In contrast, it does not provide radioprotection in a human breast cancer cell line and two glioma cell lines. These results suggest a potential therapeutic role for FTY720 as a neuroprotector during cranial irradiation. Further preclinical studies are warranted to evaluate this possibility. PMID- 22507239 TI - DL-3-n-Butylphthalide protects rat bone marrow stem cells against hydrogen peroxide-induced cell death through antioxidation and activation of PI3K-Akt pathway. AB - Bone marrow stem cells (BMSCs) have been one of the most important cell sources for cell replacement therapy (CRT) in cerebral infarction. However, long-lasting oxidative stress during stroke, which plays an important role in neuron damage, deteriorates the microenvironment for cell survival, differentiation and removal. Thus the outcome of CRT in ischemic diseases was poor. DL-3-n-Butylphthalide (NBP) has protective effects on ischemic brain tissue through multiple mechanisms and has been used for stroke treatment in China for several years. In this study, hydrogen peroxide (H(2)O(2)) was used to induce oxidative stress injury to rat bone marrow stem cells (rBMSCs), imitating the microenvironment surrounding transplanted cells in the ischemic brain in vitro. The protective effects of NBP on rBMSCs against apoptosis induced by oxidative stress were investigated. Our results indicated that NBP could protect rBMSCs against apoptosis due to antioxidative properties and modulation of PI3K/Akt pathway. NBP could be used in combination with BMSCs for the treatment of cerebral infarction by improving the oxidative stress microenvironments and cell survival, however, further studies remain warranted. PMID- 22507240 TI - Analysis of the MRPL3, DNAJC13 and OFCC1 variants in Chinese Han patients with TS CTD. AB - Tourette syndrome/chronic tic phenotype (TS-CTD) is a neurological disorder manifested particularly by motor and vocal tics and associated with a variety of behavioral abnormalities. Recently, the mitochondrial ribosomal protein L3 gene (MRPL3) S75N, the DnaJ (Hsp40) homolog subfamily C member 13 gene (DNAJC13) A2057S, the orofacial cleft 1 candidate 1 gene (OFCC1) R129G and c.-5A>G variants are reported to be associated with Tourette syndrome/chronic tic phenotype (TS CTD) in patients of European ancestry. To evaluate whether these variants are associated with TS-CTD in Chinese Han patients, we screened 132 Chinese Han patients from Mainland China. None of the 132 samples from patients with TS-CTD showed the MRPL3 S75N, DNAJC13 A2057S, OFCC1 R129G and c.-5A>G variants, and these variants probably are a rare cause of TS-CTD in a Chinese Han ethnic group. Genetic heterogeneity of TS should be considered and tests designed to detect these variants in Chinese Han ethnic group probably will not have a diagnostic utility in clinical practice. PMID- 22507241 TI - Granulocyte colony-stimulating factor and interleukin-1beta are important cytokines in repair of the cirrhotic liver after bone marrow cell infusion: comparison of humans and model mice. AB - We previously described the effectiveness of autologous bone marrow cell infusion (ABMi) therapy for patients with liver cirrhosis (LC). We analyzed chronological changes in 19 serum cytokines as well as levels of specific cytokines in patients after ABMi therapy and in a mouse model of cirrhosis generated using green fluorescent protein (GFP)/carbon tetrachloride (CCl4). We measured expression profiles of cytokines in serum samples collected from 13 patients before and at 1 day and 1 week after ABMi. Child-Pugh scores significantly improved in all of these patients. To analyze the meaning of early cytokine change, we infused GFP positive bone marrow cells (BMCs) into mice with CCl4-induced LC and obtained serum and tissue samples at 1 day and as well as at 1, 2, 3, and 4 weeks later. We compared chronological changes in serum cytokine expression in humans and in the model mice at 1 day and 1 week after BMC infusion. Among 19 cytokine, both granulocyte colony-stimulating factor (G-CSF) and interleukin-1beta(IL-1beta) in serum was found to show the same chronological change pattern between human and mice model. Next, we examined changes in cytokine expression in cirrhosis liver before and at 1, 2, 3, and 4 weeks after BMC infusion. Both G-CSF and IL-1beta were undetectable in the liver tissues before and at 1 week after BMC infusion but increased at 2 weeks and continued until 4 weeks after infusion. The infused BMCs induced an early decrease of both G-CSF and IL-1beta in serum and an increase in the model mice with LC. These dynamic cytokine changes might be important to repair liver cirrhosis after BMC infusion. PMID- 22507242 TI - Targeting epigenetic mediators of gene expression in thoracic malignancies. AB - Lung and esophageal cancers and malignant pleural mesotheliomas are highly lethal neoplasms that are leading causes of cancer-related deaths worldwide. Presently, limited information is available pertaining to epigenetic mechanisms mediating initiation and progression of these neoplasms. The following presentation will focus on the potential clinical relevance of epigenomic alterations in thoracic malignancies mediated by DNA methylation, perturbations in the histone code, and polycomb group proteins, as well as ongoing translational efforts to target epigenetic regulators of gene expression for treatment of these neoplasms. This article is part of a Special Issue entitled: Chromatin in time and space. PMID- 22507243 TI - Paramyotonia congenita: from clinical diagnosis to in silico protein modeling analysis. AB - BACKGROUND: Paramyotonia congenita (PMC) is an autosomal dominant disorder characterized by cold- or exercise-induced myotonia. PMC is caused by a mutation in SCN4A which encodes the alpha-subunit of the skeletal muscle sodium channel. METHODS: The patient was an 11-year-old Japanese girl who was diagnosed as having PMC. To confirm the diagnosis, an orbital ice-pack test and blinking tests were performed. Next, to identify the mutation, genetic analysis of SCN4A was performed. Finally, to evaluate the mutation effect on the protein structure, in silico protein modeling analysis was performed. RESULTS: Cold- and exercise induced myotonia was reproduced in the patient with non-invasive bedside tests: ice-pack and blinking tests. In the genetic analysis, a missense mutation, c.4343G>A in SCN4A, was identified, which may result in an arginine to histidine substitution at 1448 in the protein sequence (p.Arg1448His). According to the protein modeling analysis, the mutation neutralized the positive electrostatic charge at 1448 in the DIV/S4 segment and disrupted the beginning of the helical structure in the DIV/S3-S4 linker of the SCN4A protein. CONCLUSIONS: Diagnostic physical interventions in the patient confirmed the phenotype presentation consistent with PMC, and the in silico protein modeling analysis of p.Arg1448His predicted structural changes which can affect function of the protein. All the data confirmed the diagnosis of PMC in the patient and added to existing literature emphasizing the important role of arginine residue at 1448. PMID- 22507244 TI - Fabry disease presenting with sudden hearing loss and otosclerosis: a case report. AB - INTRODUCTION: Fabry disease is an X-linked lysosomal storage disorder resulting in a multiple-system disorder with a wide spectrum of physical signs and symptoms, predominantly affecting the central and peripheral nervous systems, skin, heart, kidneys, and eyes. CASE PRESENTATION: We describe the case of a 26 year-old European Caucasian man who had Fabry disease and who presented with episodic sudden unilateral hearing loss and was treated with glucocorticoids, pentoxifylline, hyperbaric oxygen, and fluoride because of concomitant audiometric evidence of otosclerosis. This case demonstrates the partial and transient beneficial effect of standard treatment for sudden hearing loss not related to Fabry disease and analyzes the possible connection between typical Fabry disease inner-ear lesions and otosclerosis. Whereas hearing loss has been described in connection with Fabry disease, otosclerosis-associated hearing loss in Fabry disease has not yet been described. CONCLUSIONS: Although progressive hearing loss in patients with Fabry disease seems to be influenced by replacement therapy, few data concerning treatment of sudden hearing loss are available. The lack of literature concerning the pathogenesis of the otological involvement in Fabry disease makes it impossible to identify a connection between the latter and otosclerosis. Therefore, this report may help to reinforce the importance of a thorough evaluation of hearing in patients with Fabry disease and may be of help with therapeutic decision-making. PMID- 22507245 TI - Photoselective vaporization of the prostate using the 180W lithium triborate laser. AB - INTRODUCTION: Photoselective vaporization of the prostate (PVP) is widely used to treat benign prostatic obstruction (BPO), but there is little experience reported on the new more powerful 180W lithium triborate (LBO) laser. This study evaluates the safety and efficacy of using the 180W LBO laser to treat BPO by examining a multicentre Australian experience. METHODS: Retrospective review of prospectively collected data on all men treated by 180W LBO laser PVP by eight urologists across six Australian hospitals, from July 2011 to August 2011, was performed. Perioperative and functional outcomes were examined at baseline and 3 months. RESULTS: Of the 85 men (median age 70 years, prostate volume 51 cm(3)) identified, 27% (23/85) were in urinary retention and 44% (37/85) were taking antiplatelet/anticoagulant medication. Median operating time was 46 min, laser time 27 min, energy use 211 kJ, post-operative duration of catheterization 15 h and hospitalization 22 h. Functional outcomes from baseline to 3 months, respectively, were for IPSS 25-7; QoL 5-2; Qmax 7.7-18.4; and PVR 147-38. All improvements were statistically significant (P < 0.01). Thirty-eight percent (32/85) of patients experienced at least one adverse event. Most adverse events were low Clavien-Dindo grade I-II. There were five grade III, two grade IV and no grade V adverse events. Sixty per cent (51/85) of men were able to be discharged home voiding successfully without a catheter within 24-h post-PVP. CONCLUSIONS: Our early multicentre Australian experience indicates the 180W LBO laser PVP is an efficacious and safe treatment for BPO. PMID- 22507246 TI - Controlled-pH tissue cleanup protocol for signal enhancement of small molecule drugs analyzed by MALDI-MS imaging. AB - The limit of detection of low-molecular weight compounds in tissue sections, analyzed by matrix assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), was significantly improved by employing sample washing using a pH controlled buffer solution. The pH of the washing solutions were set at values whereby the target analytes would have low solubility. Washing the tissue sections in the buffered solution resulted in removal of endogenous soluble ionization-suppressing compounds and salts, while the target compound remained in situ with minor or no delocalization during the buffered washing procedure. Two pharmaceutical compounds (cimetidine and imipramine) and one new protease inhibitor compound were successfully used to evaluate the feasibility of the pH controlled tissue washing protocol for MALDI-MSI. Enhancement in signal-to-noise ratio was achieved by a factor of up to 10. PMID- 22507247 TI - Design of modified U1i molecules against HIV-1 RNA. AB - Several gene therapeutic approaches have been proposed to add to current antiretroviral therapy against HIV-1. U1 interference (U1i) is a promising new gene therapy tool that targets mRNAs with modified U1 snRNAs. For efficient inhibition, the 3'-terminal exon of pre-mRNAs must be recognized by the modified U1 snRNA. Subsequent interaction between the U1-associated 70K protein and poly(A) polymerase leads to inhibition of polyadenylation and consequently degradation of the pre-mRNA. We designed 14 new U1i inhibitors against HIV-1 mRNA regions that are 100% complementary to at least 70% of HIV-1 sequences listed in the HIV database. All U1i inhibitors were tested transiently in HIV-1 production assays as well as luciferase reporter experiments and three candidates were examined further in stably lentivirus-transduced T cell lines. We identified U1i J that targets the region encoding the NF-kappaB binding sites as the most effective inhibitor that substantially reduced viral protein expression. The potency of J is determined in part by the presence of a duplicated target within the HIV-1 mRNA. The stably transduced SupT1 T cells were challenged with HIV-1 but no antiviral effect was detected. U1i inhibitors can be potent suppressors of HIV-1 production in transient assays but further optimization of this antiviral approach is needed. PMID- 22507248 TI - Multiresistant Enterobacteriaceae with class 1 and class 2 integrons in a municipal wastewater treatment plant. AB - In this study, 1832 strains of the family Enterobacteriaceae were isolated from different stages of a municipal wastewater treatment plant, of which 221 (12.1%) were intI-positive. Among them 61.5% originated from raw sewage, 12.7% from aeration tank and 25.8% from the final effluent. All of the intI-positive strains were multiresistant, i.e. resistant to at least three unrelated antimicrobials. Although there were no significant differences in resistance range, defined as the number of antimicrobial classes to which an isolate was resistant, between strains isolated from different stages of wastewater treatment, for five beta lactams the percentage of resistant isolates was the highest in final effluent, which may reflect a selective pressure the bacteria are exposed to, and the possible route of dissemination of beta-lactam resistant strains to the corresponding river. The sizes of the variable part of integrons ranged from 0.18 to 3.0 kbp and contained up to four incorporated gene cassettes. Sequence analysis identified over 30 different gene cassettes, including 24 conferring resistance to antibiotics. The highest number of different gene cassettes was found in bacteria isolated from the final effluent. The gene cassettes were arranged in 26 different resistance cassette arrays; the most often were dfrA1 aadA1, aadA1, dfrA17-aadA5 and dfrA12-orfF-aadA2. Regarding the diversity of resistance genes and the number of multiresistant bacteria in the final effluent, we concluded that municipal sewage may serve as a reservoir of integron-embedded antibiotic resistance genes. PMID- 22507249 TI - Phosphorus addition reverses the positive effect of zebra mussels (Dreissena polymorpha) on the toxic cyanobacterium, Microcystis aeruginosa. AB - We tested the hypothesis that zebra mussels (Dreissena polymorpha) have positive effects on the toxin-producing cyanobacterium, Microcystis aeruginosa, at low phosphorus (P) concentrations, but negative effects on M. aeruginosa at high P, with a large-scale enclosure experiment in an oligotrophic lake. After three weeks, mussels had a significantly positive effect on M. aeruginosa at ambient P (total phosphorus, TP ~10 MUg L-1), and a significantly negative effect at high P (simulating a TP of ~40 MUg L-1 in lakes). Positive and negative effects were strong and very similar in magnitude. Thus, we were able to ameliorate a negative effect of Dreissena invasion on water quality (i.e., promotion of Microcystis) by adding P to water from an oligotrophic lake. Our results are congruent with many field observations of Microcystis response to Dreissena invasion across ecosystems of varying P availability. PMID- 22507250 TI - Impact of water boundary layer diffusion on the nitrification rate of submerged biofilter elements from a recirculating aquaculture system. AB - Total ammonia nitrogen (TAN) removal by microbial nitrification is an essential process in recirculating aquaculture systems (RAS). In order to protect the aquatic environment and fish health, it is important to be able to predict the nitrification rates in RAS's. The aim of this study was to determine the impact of hydraulic film diffusion on the nitrification rate in a submerged biofilter. Using an experimental batch reactor setup with recirculation, active nitrifying biofilter units from a RAS were exposed to a range of hydraulic flow velocities. Corresponding nitrification rates were measured following ammonium chloride, NH4Cl, spikes and the impact of hydraulic film diffusion was quantified. The nitrification performance of the tested biofilter could be significantly increased by increasing the hydraulic flow velocity in the filter. Area based first order nitrification rate constants ranged from 0.065 m d-1 to 0.192 m d-1 for flow velocities between 2.5 m h-1 and 40 m h-1 (18 degrees C). This study documents that hydraulic film diffusion may have a significant impact on the nitrification rate in fixed film biofilters with geometry and hydraulic flows corresponding to our experimental RAS biofilters. The results may thus have practical implications in relation to the design, operational strategy of RAS biofilters and how to optimize TAN removal in fixed film biofilter systems. PMID- 22507251 TI - Size distribution and settling velocities of suspended particles in a tidal embayment. AB - Field studies were carried out to investigate seasonal and bay-wide variations in the particle size distributions (PSDs) and settling velocities of suspended particles in Newport Bay, the second largest tidal embayment in southern California. Maximum Entropy Classification (MEC) of the data identified three PSD groups: (1) suspended particles with a single mode around 10-20 MUm (Group 1), (2) suspended particles with a single mode similar to Group 1, but shifted to smaller particle sizes (Group 2), and (3) suspended particles with a coarse mode at around 100 MUm (Group 3). The three PSD groups have distinct seasonal and spatial patterns, and different size-settling velocity relationships, consistent with the hypothesis that Newport Bay longitudinally fractionates allochthonous particles from its tributaries by both size and settling velocity, and generates large and fast settling autochthonous particles, probably in the form of biological debris. Particle concentrations in Groups 1 and 2 are significantly correlated with fecal indicator bacteria, suggesting possible linkages between fecal pollution and particle transfer in this tidal embayment. PMID- 22507252 TI - Spatial configuration of extracellular polymeric substances of Bacillus megaterium TF10 in aqueous solution. AB - Configuration of extracellular polymeric substances (EPS) excreted by microorganisms is related greatly to the inherent properties of EPS, and has a significant effect on the physicochemical characteristics of microbial aggregates, such as activated sludge for wastewater treatment, as well as their interaction with other substances in aqueous systems. In this work, the spatial configuration of microbial EPS is characterized using laser light scattering (LLS) technique, with EPS extracted from Bacillus megaterium TF10 as an example. The combined utilization of static light scanning (SLS) and dynamic light scanning (DLS) offers an effective avenue to explore the EPS configuration in aqueous solution, thus enables a better understanding about the physicochemical properties of EPS. The results show that EPS exist in the form of colloids in neutral aqueous solution (pH 7.0) and that their shape is random coil with incompletely extending chains. The attraction interaction between EPS colloids is related with the high flocculability of B. megaterium TF10. The cryo-electron microscopy image further confirms the spherical shape of EPS colloids. The LLS approach offers a powerful and convenient tool for characterizing microbial EPS configuration and understanding their behaviors in biological wastewater treatment systems. PMID- 22507253 TI - Effect of cyclic aeration on fouling in submerged membrane bioreactor for wastewater treatment. AB - Due to the inefficiency of aeration measures in preventing fouling by soluble and colloidal particles. The effect of alternating high/low cyclic aeration mode on the membrane fouling in the submerged membrane bioreactor was studied by comparing to fouling in a constant aeration mode. Results indicated a higher overall fouling rate in the cyclic aeration mode than in the constant aeration. However, a higher percentage of reversible fouling was observed for the cyclic aeration mode. The membrane permeability can be more easily recovered from physical cleaning such as backwashing in the cyclic aeration mode. The activated sludge floc size distribution analysis revealed a floc destruction and re flocculation processes caused by the alternating high/low aeration. The short high aeration period could prevent the destruction of strong strength bonds within activated sludge flocs. Therefore, less soluble and colloidal material was observed in the supernatant due to the preservation of the strong strength bonds. The weak strength bonds damaged in the high aeration period could be recovered in the re-flocculation process in the low aeration period. The floc destruction and re-flocculation processes were suggested to be the main reason for the low irreversible fouling in the cyclic aeration mode. PMID- 22507254 TI - Construction of the descriptive system for the Assessment of Quality of Life AQoL 6D utility instrument. AB - BACKGROUND: Multi attribute utility (MAU) instruments are used to include the health related quality of life (HRQoL) in economic evaluations of health programs. Comparative studies suggest different MAU instruments measure related but different constructs. The objective of this paper is to describe the methods employed to achieve content validity in the descriptive system of the Assessment of Quality of Life (AQoL)-6D, MAU instrument. METHODS: The AQoL program introduced the use of psychometric methods in the construction of health related MAU instruments. To develop the AQoL-6D we selected 112 items from previous research, focus groups and expert judgment and administered them to 316 members of the public and 302 hospital patients. The search for content validity across a broad spectrum of health states required both formative and reflective modelling. We employed Exploratory Factor Analysis and Structural Equation Modelling (SEM) to meet these dual requirements. RESULTS AND DISCUSSION: The resulting instrument employs 20 items in a multi-tier descriptive system. Latent dimension variables achieve sensitive descriptions of 6 dimensions which, in turn, combine to form a single latent QoL variable. Diagnostic statistics from the SEM analysis are exceptionally good and confirm the hypothesised structure of the model. CONCLUSIONS: The AQoL-6D descriptive system has good psychometric properties. They imply that the instrument has achieved construct validity and provides a sensitive description of HRQoL. This means that it may be used with confidence for measuring health related quality of life and that it is a suitable basis for modelling utilities for inclusion in the economic evaluation of health programs. PMID- 22507255 TI - Exogenous glutathione is essential in the testing of antioxidant capacity using radical-induced haemolysis. AB - INTRODUCTION: Radical-induced haemolysis has been employed by many investigators to determine the antioxidant capacity of novel compounds. However the free radical generator 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) results in the complete depletion of intracellular reduced glutathione (GSH) in cells that can no longer synthesise macromolecules. As GSH is essential in recycling certain antioxidants back to their active form, the current study examined the effects of exogenous GSH on the antioxidant capacity of quercetin, phenol, ebselen and nitroxide detected using AAPH-induced haemolysis. Here we report a modification that increases the likelihood of detecting antioxidant activity in a radical-induced haemolysis assay. METHODS: C57Bl/6 mouse erythrocyte suspensions were pre-incubated with 1, 3 or 10 MUM of phenol, ebselen, nitroxide or 10, 20 or 30 MUM of quercetin for 30 min in the presence or absence of 1mM of glutathione. AAPH (150 mM) was added to each well to induce haemolysis. Absorbance of erythrocytes was measured spectrophotometrically at 690 nm over 5h. Haemolysis in the presence of different pre-treatments was quantified by calculating the time to 50% lysis. RESULTS: AAPH in the presence and absence of GSH resulted in a decrease in absorbance over time as cells lysed. Pre-incubating cells with ebselen or phenol (10 MUM) delayed AAPH-induced haemolysis by 37 and 74 min only in the presence of exogenous GSH. Nitroxide accelerated radical-induced haemolysis by 40 min in the absence of exogenous GSH, however delayed haemolysis by 38 min in the presence of exogenous GSH. The antioxidant actions of quercetin were unaffected by the presence of exogenous GSH. DISCUSSION: The results demonstrate that exogenous GSH is required to detect the antioxidant capacity of certain antioxidant moieties using the radical-induced haemolysis assay. This is particularly important as numerous groups use this technique as a high throughput screening assay of antioxidant activity. PMID- 22507256 TI - Breast tissue contrast-simulating materials using energy-dispersive X-ray diffraction. AB - Breast lesions and normal tissues have different molecular arrangements that affect their diffraction patterns. Different mouldable and non-mouldable materials were analysed using an energy dispersive X-ray diffraction system based on a conventional X-ray source (operated at 70 kVp) and a CdTe detector (Amptek XT-100), including a conventional spectroscopic chain. Combinations of materials were identified to have a contrast comparable to that achieved in diffraction imaging for different breast tissues at the momentum transfer values carrying the greatest amount of information (1.1 nm(-1) and 1.6 nm(-1)). PMID- 22507257 TI - Exploring parent perceptions of the food environment in youth sport. AB - OBJECTIVE: To examine parent perceptions of the food environment in youth sport. METHODS: Eight focus group discussions were held with parents (n = 60) of youth aged 6-13 years participating in basketball programs in Minnesota. Key themes and concepts were identified via transcript-based analysis. RESULTS: Parents reported that youth commonly consume unhealthful food and beverages during sports. According to parents, few healthful food and beverage options are available in sport settings, whereas unhealthful options are widely available. Parents were generally dissatisfied with food available in youth sport settings and wanted sport-specific nutrition knowledge. Time constraints and low availability of nutritious food at sport venues were barriers to healthful eating. CONCLUSIONS AND IMPLICATIONS: Youth sport is a promising setting for promoting nutrition. Potential interventions may include advice about healthful eating to overcome the challenges associated with youth sport and policy changes that promote greater availability of healthful food at concessions stands. PMID- 22507258 TI - Evaluation of supplemental nutrition assistance program education: application of behavioral theory and survey validation. AB - OBJECTIVE: Application of the Transtheoretical Model (TTM) to Supplemental Nutrition Assistance Program Education (SNAP-Ed) evaluation and development and validation of an evaluation tool used to measure TTM constructs is described. METHODS: Surveys were collected from parents of children receiving food at Summer Food Service Program sites prior to SNAP-Ed participation. RESULTS: Item analysis of survey data (n = 149) suggests the survey is valid and reliable. Structural Equation Modeling confirmed the use of the TTM constructs in predicting SNAP-Ed participants' fruit and vegetable consumption. Perceived barriers (P = .04) and self-efficacy (P = .006) were associated with fruit and vegetable consumption, whereas perceived benefits were not. CONCLUSIONS AND IMPLICATIONS: Application of theory and survey validation can enhance SNAP-Ed evaluation. PMID- 22507259 TI - Inflow graft interruption as a simple method for left ventricular assist device removal after successful bridge to recovery. AB - In this report we provide another method of ventricular assist device separation by simply transecting the inflow graft of a Heart Mate II LVAD without the need of dissecting the left ventricular apex for cases of myocardial recovery. PMID- 22507260 TI - Seasonality and monthly dynamics of marine myovirus communities. AB - Marine myoviruses (i.e. bacteriophages with a contractile tail sheath) are numerically abundant and genetically diverse. We developed a terminal restriction fragment length polymorphism assay (TRFLP) for g23, the conserved gene encoding the major capsid protein, to investigate T4-like myovirus communities at USC's Microbial Observatory at the San Pedro Ocean Time-series (SPOT), where we previously reported bacterial seasonality. Between 71 and 154 operational taxonomic units (OTUs) were observed monthly over 3 years. Roughly 25% of OTUs were detected in 31 or more months. T4-like myoviral community structure varied seasonally with some OTUs peaking repeatedly in spring-summer and others in fall winter, while moderately abundant OTUs persisted year-round. Recurring community structure was demonstrated using discriminant function analysis (DFA, selecting taxa that best predict months) and average Bray-Curtis similarity. DFA showed communities from adjacent months or 12 months apart were positively auto correlated, while communities 3-7 months apart were negatively auto-correlated. Bray-Curtis similarity was highest between adjacent months - with a local maximum at 12-month and local minima at 6- and 18- to 20-month lags. The T4-like virus community at SPOT exhibited seasonality, yet the somewhat unexpected persistence of moderately abundant OTUs and predictability of the community add new twists to existing conceptual models of marine viruses. PMID- 22507261 TI - Diagram to map the locations of endometriosis. AB - OBJECTIVE: To develop and test a visual map that corresponds practically and objectively to the anatomical areas affected by endometriosis. METHOD: The study comprised 150 questionnaires concerning 10 clinical cases of endometriosis presented as a visual diagram that were distributed at 3 different scientific events, among 3 groups of 50 gynecologists. Data were analyzed to evaluate the diagram's ability to graphically represent the endometriosis sites. RESULTS: After presentation at the first event, the rate of correct answers on the site of endometriosis was 84.7%; at the second event, after modifications implemented after feedback from the first event, the rate of correct answers was 97.4%; and at the third event, when all suggestions and modifications had been made, the rate was 99.7%. CONCLUSION: The diagram proposed to map the location of endometriosis lesions appears to be an adequate and effective instrument to represent the site of the disease, with correlation at almost 100%. PMID- 22507262 TI - The effect of bladder fullness on evaluation of pelvic organ prolapse. AB - OBJECTIVE: To investigate the effect of bladder fullness on pelvic organ prolapse (POP) staging via the Pelvic Organ Prolapse Quantification System (POP-Q). METHODS: Sixty women with advanced POP underwent pelvic examination with maximal Valsalva straining via POP-Q with an empty bladder and after transcatheter bladder filling to maximum cystometric capacity, with simultaneous intra abdominal and intravesical pressure recordings. Main outcome measures included POP-Q values and staging with full versus empty bladder. RESULTS: An empty bladder was associated with a significantly higher POP-Q staging (median, 3 vs 2; P<0.0001); and a lower location of points Ba (4.51 vs 1.37; P<0.0001), Aa (2.58 vs 0.62; P<0.0001), Bp (-0.68 vs -1.10; P=0.01), Ap (0.83 vs -1.27; P=0.002), C (1.57 vs -1.07; P<0.0001), and D (0.14 vs -2.77; P<0.0001) compared with a full bladder. However, genital hiatus, perineal body, and total vaginal length values were not significantly affected by bladder fullness. No differences in intra abdominal or detrusor pressures were noted between empty and full bladder states. CONCLUSION: POP-Q assessment with a full bladder is associated with underestimation of POP severity. Therefore, bladder emptying should be a standard requirement for POP-Q staging and reporting. PMID- 22507263 TI - Factors associated with disclosure of HIV serostatus to sexual partners of patients receiving HIV care in Kabale, Uganda. AB - OBJECTIVE: To evaluate factors independently associated with disclosure of HIV serostatus in the era of widespread access to antiretroviral agents (ARVs) among individuals receiving HIV care in Uganda. METHODS: Between January 1 and August 31, 2009, 403 HIV-positive individuals attending Kabale Hospital in southwestern Uganda were interviewed about their sociodemographic characteristics; sexuality; contraceptive use and sexual behavior; and disclosure of HIV serostatus to sexual partners. Data regarding disclosure versus nondisclosure were analyzed to identify factors independently associated with disclosure of serostatus. RESULTS: The study participants were predominantly female (74.0%). In all, 82.5% of the patients were receiving ARVs. Disclosure of HIV serostatus to regular sexual partners was reported by 50.9% of the participants, while 49.1% had chosen not to disclose their serostatus. Factors independently associated with nondisclosure were marital status; current use of ARVs; having children who had died (from any cause); being sexually active in the previous 6 months; and the number of sexual partners during the previous 6 months (P<0.05 for all associations). Fear of stigma was the main reason for nondisclosure of HIV serostatus. CONCLUSION: Despite receiving treatment with ARVs, many of the study participants neither disclosed their own HIV serostatus nor knew the HIV serostatus of their sexual partners. PMID- 22507264 TI - Effect of a yoga program on glucose metabolism and blood lipid levels in adolescent girls with polycystic ovary syndrome. AB - OBJECTIVE: To assess the efficacy of yoga therapy on glucose metabolism and blood lipid values in adolescent girls with polycystic ovary syndrome (PCOS). METHODS: A prospective, randomized, interventional controlled trial recruited 90 adolescents aged between 15 and 18 years who met the Rotterdam criteria for PCOS. A yoga group practiced suryanamaskara, asanas, pranayama, and meditation 1 hour per day each day for 12 weeks while another group practiced conventional physical exercises. The Mann-Whitney U test was used to compare score changes between the 2 groups. RESULTS: The changes in fasting insulin, fasting blood glucose, and homeostasis model assessment of insulin resistance were significantly different in the 2 groups (P<0.05). Except for high-density lipoprotein cholesterol, the changes in blood lipid values were also significantly different (P<0.05). The changes in body mass index, waist circumference, hip circumference, and waist-to hip ratio, however, were not significantly different (P>0.05). CONCLUSION: Yoga was found to be more effective than conventional physical exercises in improving glucose, lipid, and insulin values, including insulin resistance values, in adolescent girls with PCOS independent of anthropometric changes. Central Trial Registry of India No.: REFCTRI-2008 000291. PMID- 22507265 TI - An interactive 1-h educational programme for junior doctors, increases their confidence and improves inpatient diabetes care. AB - AIM: To evaluated whether a 1 hour, interactive, case-based programme could improve the quality of care and juniors' confidence. METHODS: We designed an educational programme using a patient's journey from admission to discharge in order to teach avoidance of common errors, while enhancing familiarity with local charts and protocols. The intervention was delivered in four hospitals, to doctors within 4 years of training following graduation. Feedback was received. The quality of care provided and the confidence of juniors' in its provision was evaluated before and after the intervention. RESULTS: Of the 242 trainees taught, 205 (85%) provided feedback. The programme was rated 'very' or 'extremely' easy to understand by 94.1%. The format was thought to improve attention and participation, 'quite a lot' or 'extremely' by 94.1% and was 'highly' or 'extremely highly' recommended for other areas of teaching by 93.1%. The mean confidence score increased from 17.6 (SD 4) to 24.9 (SD 2.7) (P < 0.001), with Cronbach alpha coefficients of 0.81 and 0.86 for the questionnaires before and after the programme. Insulin prescription errors were reduced by 49% (15.4% before and 7.8% after, P < 0.05). CONCLUSION: The inpatient diabetes education programme, which is deliverable within 1 h, was liked by juniors, increased their confidence and improved the quality of inpatient diabetes care. PMID- 22507266 TI - 'maskBAD'--a package to detect and remove Affymetrix probes with binding affinity differences. AB - BACKGROUND: Hybridization differences caused by target sequence differences can be a confounding factor in analyzing gene expression on microarrays, lead to false positives and reduce power to detect real expression differences. We prepared an R Bioconductor compatible package to detect, characterize and remove such probes in Affymetrix 3'IVT and exon-based arrays on the basis of correlation of signal intensities from probes within probe sets. RESULTS: Using completely mouse genomes we determined type 1 (false negatives) and type 2 (false positives) errors with high accuracy and we show that our method routinely outperforms previous methods. When detecting 76.2% of known SNP/indels in mouse expression data, we obtain at most 5.5% false positives. At the same level of false positives, best previous method detected 72.6%. We also show that probes with differing binding affinity both hinder differential expression detection and introduce artifacts in cancer-healthy tissue comparison. CONCLUSIONS: Detection and removal of such probes should be a routine step in Affymetrix data preprocessing. We prepared a user friendly R package, compatible with Bioconductor, that allows the filtering and improving of data from Affymetrix microarrays experiments. PMID- 22507267 TI - Effect of age on outcome on patients hospitalized with heart failure: from a 20 year registry in a middle-eastern country (1991-2010). AB - The association between age, risk factors, and outcome of non-Caucasian patients hospitalized with heart failure (HF) is not clear. A total of 7066 consecutive patients hospitalized with HF at Hamad General Hospital, Doha, Qatar, from 1991 through 2010 were studied. Patients were divided into 3 groups according to age: group 1, 50 years and younger; group 2, older than 50 and up to 70 years; and group 3, older than 70 years. The prevalence of hypertension, chronic renal impairment, and atrial fibrillation increased with increased age. On admission, the older the age of the HF patient, the less likely they were to receive beta blockers and vasodilators. In-hospital mortality rate was higher in older patients when compared with the younger groups (10.6% group 3 vs 7% group 1 and 7.2% group 2; P=.001). During the study period, the relative reduction in mortality rates was higher in the younger when compared with the older patients (55%, 49%, and 41%, respectively). The clinical characteristics of Middle-Eastern HF patients vary considerably according to age. Over time, an overall marked improvement in hospital survival for HF was observed, which was associated with progressively increased treatment with evidence-based therapies. This survival improvement over time appears to be less pronounced in the elderly. PMID- 22507268 TI - CD36 promotes adipocyte differentiation and adipogenesis. AB - BACKGROUND: CD36 is a membrane glycoprotein, contributing to the pathogenesis of metabolic disorders, like obesity, which has become a major health concern worldwide. METHODS: A potential functional role of the scavenger receptor CD36 was investigated in in vitro adipocyte differentiation and in vivo adipogenesis. RESULTS: During differentiation of 3T3-F442A preadipocytes into mature adipocytes, expression of CD36 was upregulated and CD36 gene silencing resulted in impaired differentiation, as monitored by Oil Red O staining and expression of adipogenic markers. De novo fat pad formation in NUDE mice following injection of preadipocytes was significantly reduced upon CD36 gene silencing as compared to control. This was associated with marked adipocyte hypotrophy and reduced adipose tissue adipocyte content. Macrophage infiltration in de novo fat tissues derived from preadipocytes with CD36 gene silencing was not significantly different from controls. Collagen content was significantly higher in de novo fat with CD36 gene silencing. In a nutritionally induced obesity model, total body weight as well as subcutaneous and gonadal adipose tissue mass were significantly lower in CD36 deficient mice as compared to wild-type littermates. GENERAL SIGNIFICANCE: Thus, our data support a functional role of CD36 in promoting adipogenesis in vitro as well as in vivo. PMID- 22507270 TI - Blebbistatin, a myosin inhibitor, is phototoxic to human cancer cells under exposure to blue light. AB - BACKGROUND: Blebbistatin is a new inhibitor of cell motility. It is used to study dynamics of cytokinesis machinery in cells. However, the potential of this inhibitor as an anticancer agent has not been studied so far. METHODS: Cytotoxicity of blebbistatin was evaluated in five human cell lines, FEMX-I melanoma, U87 glioma, androgen independent Du145 and androgen sensitive LNCaP prostate adenocarcinoma, and F11-hTERT immortalized fibroblasts. Phototoxicity of blebbistatin was assessed in these cell lines after their exposure to a blue light (390-470 nm). Photostability of blebbistatin and its reactive oxygen species (ROS) generating properties were measured during irradiation with the blue light. RESULTS: Blebbistatin at a concentration range of 10-200 MUmol/L was toxic to all studied cells. Toxic concentrations (TC) were about 10-25 MUmol/L corresponding to TC10, 50-100 MUmol/L to TC50 and 140-190 MUmol/L to TC90. Only for the U87 glioma cells TC90 could not be measured as the highest studied concentration of 200 MUmol/L gave around 70% toxicity. However, after exposure to the blue light blebbistatin exhibited phototoxicity on the cells, with a cytotoxicity enhancement ratio that was greatest for the FEMX-I cells (about 9) followed by LNCaP (5), Du145 (3), U87 (2) and F11-hTERT (1.7) cells. CONCLUSIONS: Blebbistatin inhibits cell motility and viability. Under exposure to the blue light blebbistatin exhibits photodynamic action on human cancer cells. During the irradiation blebbistatin oxidizes dihydrorhodamine 123 but not Singlet Oxygen Sensor Green. GENERAL SIGNIFICANCE: Our findings offer new possibilities for blebbistatin as a potential anticancer and photodynamic agent. PMID- 22507269 TI - Thyroid hormone receptors and cancer. AB - BACKGROUND: Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that mediate the actions of the thyroid hormone (T3) in development, growth, and differentiation. The THRA and THRB genes encode several TR isoforms that express in a tissue- and development-dependent manner. In the past decades, a significant advance has been made in the understanding of TR actions in maintaining normal cellular functions. However, the roles of TRs in human cancer are less well understood. The reduced expression of TRs because of hypermethylation, or deletion of TR genes found in human cancers suggests that TRs could function as tumor suppressors. A close association of somatic mutations of TRs with human cancers further supports the notion that the loss of normal functions of TR could lead to uncontrolled growth and loss of cell differentiation. SCOPE OF REVIEW: In line with the findings from association studies in human cancers, mice deficient in total functional TRs (Thra1(-/-)Thrb( /-) mice) or with a targeted homozygous mutation of the Thrb gene (denoted PV; Thrb(PV/PV) mice) spontaneously develop metastatic thyroid carcinoma. This review will examine the evidence learned from these genetically engineered mice that provided strong evidence to support the critical role of TRs in human cancer. MAJOR CONCLUSIONS: Loss of normal functions of TR by deletion or by mutations could contribute to cancer development, progression and metastasis. GENERAL SIGNIFICANCE: Novel mechanistic insights are revealed in how aberrant TR activities lead to carcinogenesis. Mouse models of thyroid cancer provide opportunities to identify molecular targets as potential treatment modalities. This article is part of a Special Issue entitled Thyroid hormone signalling. PMID- 22507271 TI - Mitotic chromosome structure. AB - Mounting evidence is compiling linking the physical organizational structure of chromosomes and the nuclear structure to biological function. At the base of the physical organizational structure of both is the concept of loop formation. This implies that physical proximity within chromosomes is provided for otherwise distal genomic regions and thus hierarchically organizing the chromosomes. Together with entropy many experimental observations can be explained with these two concepts. Among the observations that can be explained are the measured physical extent of the chromosomes, their shape, mechanical behavior, the segregation into territories (chromosomal and territories within chromosomes), the results from chromosome conformation capture experiments, as well as linking gene expression to structural organization. PMID- 22507273 TI - Controlling systems of nucleic acid sensing-TLRs restrict homeostatic inflammation. AB - Nucleic acid sensing-TLRs recognize pathogen-derived nucleic acids (NAs) and induce anti-microbial immune responses. NA-sensing TLRs are reported to have a risk of mistakenly responding to self-derived NAs and causing a variety of autoimmune diseases. To warrant innate immune responses without detrimental inflammation, NA-sensing TLRs need to be tightly controlled in multiple aspects including expression and downstream signaling pathways. Along this line, TLR7 vs 9 balance has emerged as a new mechanism that controls activation of RNA-sensor TLR7. In this review, we discuss mechanisms controlling NA-sensing TLRs and autoimmune diseases as consequences of the dysregulated control mechanisms. PMID- 22507272 TI - Survivin knockdown increased anti-cancer effects of (-)-epigallocatechin-3 gallate in human malignant neuroblastoma SK-N-BE2 and SH-SY5Y cells. AB - Neuroblastoma is a solid tumor that mostly occurs in children. Malignant neuroblastomas have poor prognosis because conventional chemotherapeutic agents are hardly effective. Survivin, which is highly expressed in some malignant neuroblastomas, plays a significant role in inhibiting differentiation and apoptosis and promoting cell proliferation, invasion, and angiogenesis. We examined consequences of survivin knockdown by survivin short hairpin RNA (shRNA) plasmid and then treatment with (-)-epigallocatechin-3-gallate (EGCG), a green tea flavonoid, in malignant neuroblastoma cells. Our Western blotting and laser scanning confocal immunofluorescence microscopy showed that survivin was highly expressed in malignant neuroblastoma SK-N-BE2 and SH-SY5Y cell lines and slightly in SK-N-DZ cell line. Expression of survivin was very faint in malignant neuroblastoma IMR32 cell line. We transfected SK-N-BE2 and SH-SY-5Y cells with survivin shRNA, treated with EGCG, and confirmed knockdown of survivin at mRNA and protein levels. Survivin knockdown induced morphological features of neuronal differentiation, as we observed following in situ methylene blue staining. Combination of survivin shRNA and EGCG promoted neuronal differentiation biochemically by increases in the expression of NFP, NSE, and e-cadherin and also decreases in the expression of Notch-1, ID2, hTERT, and PCNA. Our in situ Wright staining and Annexin V-FITC/PI staining showed that combination therapy was highly effective in inducing, respectively, morphological and biochemical features of apoptosis. Apoptosis occurred with activation of caspase-8 and cleavage of Bid to tBid, increase in Bax:Bcl-2 ratio, mitochondrial release of cytochrome c, and increases in the expression and activity of calpain and caspase 3. Combination therapy decreased migration of cells through matrigel and inhibited proliferative (p-Akt and NF-kappaB), invasive (MMP-2 and MMP-9), and angiogenic (VEGF and b-FGF) factors. Also, in vitro network formation ability of cells was significantly inhibited by survivin silencing and completely by combination of survivin silencing and EGCG treatment. Collectively, survivin silencing potentiated anti-cancer effects of EGCG in human malignant neuroblastoma cells having survivin overexpression. PMID- 22507274 TI - Arabidopsis SMALL AUXIN UP RNA63 promotes hypocotyl and stamen filament elongation. AB - Auxin regulates plant growth and development in part by activating gene expression. Arabidopsis thaliana SMALL AUXIN UP RNAs (SAURs) are a family of early auxin-responsive genes with unknown functionality. Here, we show that transgenic plant lines expressing artificial microRNA constructs (aMIR-SAUR-A or B) that target a SAUR subfamily (SAUR61-SAUR68 and SAUR75) had slightly reduced hypocotyl and stamen filament elongation. In contrast, transgenic plants expressing SAUR63:GFP or SAUR63:GUS fusions had long hypocotyls, petals and stamen filaments, suggesting that these protein fusions caused a gain of function. SAUR63:GFP and SAUR63:GUS seedlings also accumulated a higher level of basipetally transported auxin in the hypocotyl than did wild-type seedlings, and had wavy hypocotyls and twisted inflorescence stems. Mutations in auxin efflux carriers could partially suppress some SAUR63:GUS phenotypes. In contrast, SAUR63:HA plants had wild-type elongation and auxin transport. SAUR63:GFP protein had a longer half-life than SAUR63:HA. Fluorescence imaging and microsomal fractionation studies revealed that SAUR63:GFP was localized mainly in the plasma membrane, whereas SAUR63:HA was present in both soluble and membrane fractions. Low light conditions increased SAUR63:HA protein turnover rate. These results indicate that membrane-associated Arabidopsis SAUR63 promotes auxin-stimulated organ elongation. PMID- 22507275 TI - Laparoendoscopic single-site cholecystectomy versus conventional laparoscopic cholecystectomy: a systematic review of randomized controlled trials. AB - BACKGROUND: Laparoendoscopic single-site surgery is a revolution in minimally invasive surgery in recent years, and cholecystectomy is the most common intervention. However, laparoendoscopic single-site cholecystectomy (LESSC) is a controversial procedure. Its safety, cosmetic results, complications, post operative pain and post-operative stay are not confirmed by multi-centre randomized controlled studies. OBJECTIVES: This review examined the impact of LESSC versus conventional laparoscopic cholecystectomy (CLC). The primary outcomes were conversional rate and intraoperative and post-operative complications, and other outcomes were cosmetic results, operative time, post operative pain and post-operative stay. DATA SOURCES: Pubmed, EMbase, Web of Science, Ovid, clinical trials of the US National Institutes of Health and Cochrane Database of Systematic Reviews and Controlled Trials Register were searched to identify all possible randomized controlled trials (RCTs). METHODS: Two reviewers completed article search, and eligible data were entered into a computerized spreadsheet for analysis. RESULTS: Nine studies were obtained using the search strategy. Patients accepting LESSC had a higher conversion rate than those having CLC (7.17 (3.00, 17.11) (P < 0.01)). There was no significant difference for total complications between the two groups (1.17 (0.76, 1.80) (P = 0.46)), but incidence of incisional hernia and haemorrhage (seroma) in the LESSC group was obviously higher than that in the CLC group. Operative time was much longer in the LESSC group (mean difference: 10.69 (3.14, 18.24) (P = 0.006)). Cosmetic results favoured LESSC; however, post-operative abdominal pain and post operative stay were not significantly different between the two groups in most of the nine studies. CONCLUSIONS: LESSC can be safely performed with better cosmetic results; however, it carries a higher conversion rate and a longer operative time, and offers no benefit in terms of post-operative abdominal pain and post operative stay. Further RCTs, according to the CONSORT statement, are advocated to validate its objective benefits. PMID- 22507276 TI - Randomized controlled trial of probiotics to reduce common cold in schoolchildren. AB - BACKGROUND: The common cold is responsible for the largest proportion of school and work absenteeism and causes a huge economic burden. None of the current interventions is greatly effective for prevention. Our aim was to assess the efficacy of a two-strain combination probiotic for prevention of common cold symptoms in healthy schoolchildren. METHODS: A double-blind randomized controlled trial was performed during the winter season in a public school of central Thailand. Children, aged 8-13 years, were randomized to receive either a two strain combination probiotic (Lactobacillus acidophilus and Bifidobacterium bifidum) or placebo given twice a day for 3 months. The primary outcome was any symptom of cold during the 3-month study period while vomiting, diarrhea, use of antibiotics, school absence due to any cause, school absence due to cold and duration of all symptoms were secondary outcomes. RESULTS: Of the 40 children in each group, 31 (77%) in the probiotic group, compared to 38 (95%) in the placebo group (P= 0.048), developed at least one symptom of cold. Children in the probiotics group had significantly lower risk of fever, cough, rhinorrhea, school absence and school absence related to common cold compared to children in the placebo group. There was no impact on diarrhea and vomiting. CONCLUSION: A two strain probiotic combination given twice a day for 3 months was able to reduce the symptoms of the common cold and school absenteeism in schoolchildren. PMID- 22507277 TI - Metastatic carcinoma presenting as neuralgia involving the trigeminal nerve. AB - Breast carcinoma is the leading cause of cancer death in women. Metastatic tumours of the oral cavity arising from breast cancer (and other forms of cancer) may be similar to hyperplastic or reactive lesions. They are uncommon and typically appear when various organs have already been affected by the neoplasia. A 53-Year-old woman presented with "discomfort" in her left mandible, specifically, swelling of recent onset accompanied by progressive loss of sensation. The mandibular swelling had been preceded by neuralgia involving the trigeminal nerve. Biopsy and histologic examination of the intrabony mass revealed ductal adenocarcinoma with infiltration of bone and stromal tissues. The lesion was determined to be metastatic from previously undiagnosed breast cancer. The neuralgia was also related to a metastatic lesion. PMID- 22507278 TI - The feminization of dentistry: implications for the profession. AB - Over the last 40 years, the proportion of women in dentistry has been rising steadily, raising questions about the effects of this feminization on the profession. A review of the literature, although limited, highlights potentially important areas related to gender, including impact on work hours, practice models, professional incomes, the dentist-patient relationship, clinical philosophies, specialty practice, academia and leadership. Although cohorts of predominantly female dentists are only beginning to enter the workforce and, thus, it is difficult to predict the long-term effects, some trends are evident: women are less likely than men to own their practice; women may work 4-6 fewer hours a week and see fewer patients; there is a pay differential; female general practitioners and specialists appear more likely to work in urban centres; and women are less prominent in the specialties, academia and leadership roles. Thus, the profession may shift toward less entrepreneurship, more urbanization and, possibly, fewer clinical hours available to the population as a result of feminization. With the ultimate goal of excellence in patient care, this may entail increases in student enrolment, formal incentives for practice relocation to rural communities, more business education and policies to modify advanced education and training for women with children. This knowledge, although still not robust, is relevant for policy, educational institutions and professional governing bodies. PMID- 22507279 TI - Periodontitis: a syndromic condition. PMID- 22507280 TI - Listening to each other in Australia and beyond. PMID- 22507283 TI - Professionalism: we can all do our part. PMID- 22507284 TI - Hemolytic anemia following intravenous immunoglobulin therapy in patients treated for Kawasaki disease: a report of 4 cases. AB - BACKGROUND: Hemolytic anemia is a rare but reported side effect of intravenous immunoglobulin (IVIG) therapy. The risk of significant hemolysis appears greater in those patients who receive high dose IVIG. The etiology is multifactorial but may relate to the quantity of blood group antibodies administered via the IVIG product. FINDINGS: We describe 4 patients with significant hemolytic anemia following treatment with IVIG for Kawasaki disease (KD). Direct antibody mediated attack as one of the mechanisms for hemolysis, in this population, is supported by the demonstration of specific blood group antibodies in addition to a positive direct antiglobulin test in our patients. CONCLUSIONS: Clinicians should be aware of this complication and hemoglobin should be closely monitored following high dose IVIG therapy. PMID- 22507285 TI - Quantifying ligand binding to large protein complexes using electrospray ionization mass spectrometry. AB - An electrospray ionization mass spectrometry (ESI-MS) method for quantifying protein-ligand complexes that cannot be directly detected by ESI-MS is described. The proxy protein ESI-MS method combines direct ESI-MS binding measurements with competitive protein-ligand binding. To implement the method, a proxy protein (P(proxy)), which interacts specifically with the ligand of interest with known affinity and can be detected directly by ESI-MS, is used to quantitatively monitor the extent of ligand binding to the protein of interest. A mathematical framework for establishing the association constant (K(a)) for protein-ligand binding by the proxy protein ESI-MS method, implemented with a P(proxy) containing a single ligand binding site, is given. A modified form of the proxy protein ESI-MS method, which accounts for real-time changes in ligand concentration, is also described. The reliability of these methods is demonstrated for the interactions between the 180 kDa wildtype homotrimeric tailspike protein of the bacteriophage P22 and its endorhamnosidase point mutant (D392N) with its ligands comprising two and three O-antigen repeats from Salmonella enterica serovar Typhimurium: octasaccharide ([alpha-Gal-(1->2)-[alpha Abe-(1->3)]-alpha-Man-(1->4)-alpha-Rha](2)) and dodecasaccharide ([alpha-Gal-(1 >2)-[alpha-Abe-(1->3)]-alpha-Man-(1->4)-alpha-Rha](3)). A 27 kDa single chain antibody, which binds to both ligands, served as P(proxy). The results of binding measurements performed at 10 and 25 degrees C are in excellent agreement with K(a) values measured previously using a fluorescence quenching assay. PMID- 22507286 TI - Low pore connectivity in natural rock. AB - As repositories for CO(2) and radioactive waste, as oil and gas reservoirs, and as contaminated sites needing remediation, rock formations play a central role in energy and environmental management. The connectivity of the rock's porespace strongly affects fluid flow and solute transport. This work examines pore connectivity and its implications for fluid flow and chemical transport. Three experimental approaches (imbibition, tracer concentration profiles, and imaging) were used in combination with network modeling. In the imbibition results, three types of imbibition slope [log (cumulative imbibition) vs. log (imbibition time)] were found: the classical 0.5, plus 0.26, and 0.26 transitioning to 0.5. The imbibition slope of 0.26 seen in Indiana sandstone, metagraywacke, and Barnett shale indicates low pore connectivity, in contrast to the slope of 0.5 seen in the well-connected Berea sandstone. In the tracer profile work, rocks exhibited different distances to the plateau porosity, consistent with the pore connectivity from the imbibition tests. Injection of a molten metal into connected pore spaces, followed by 2-D imaging of the solidified alloy in polished thin sections, allowed direct assessment of pore structure and lateral connection in the rock samples. Pore-scale network modeling gave results consistent with measurements, confirming pore connectivity as the underlying cause of both anomalous behaviors: imbibition slope not having the classical value of 0.5, and accessible porosity being a function of distance from the edge. A poorly connected porespace will exhibit anomalous behavior in fluid flow and chemical transport, such as a lower imbibition slope (in air-water system) and diffusion rate than expected from classical behavior. PMID- 22507287 TI - Yield of interview screening and chest X-ray abnormalities in a tuberculosis prevalence survey. AB - BACKGROUND: Tuberculosis (TB) prevalence surveys generally rely on a combination of screening methods to identify suspects eligible for sputum culture. OBJECTIVE: To assess the yield of screening methods applied in a recent prevalence survey in Viet Nam and estimate the proportion of TB cases missed due to incomplete participation. METHODS: TB suspects were identified based on self-reported TB history or productive cough by interview and chest X-ray (CXR). We calculated the case yield of these two screening methods by dividing the number of cases detected per method by the total number of cases detected. As not all participants underwent the full screening procedure, we recalculated the maximum yield of the screening methods using multiple imputation methods. RESULTS: The yield from screening by interview and CXR were respectively 38% and 91%. Adjusting for missing data by multiple imputation, we estimated that we missed 9.9% (95%CI 6.8-14.2) of expected TB cases. CONCLUSION: In prevalence surveys, screening by pre-structured interview is insufficient, and should be supplemented with CXR to achieve sufficient identification of TB cases. The effect of incomplete participation in the full screening procedure may be substantial and should be adjusted for in the analysis. PMID- 22507288 TI - Incidence, risk factors and clinical features of venous thromboembolism in newly diagnosed lymphoma patients: results from a prospective cohort study with Asian population. AB - INTRODUCTION: Venous thromboembolism (VTE) may be associated with treatment failure rate and quality of life deterioration in lymphoma patients. However, the majority of data regarding VTE has come from retrospective studies done in Western countries. MATERIALS AND METHODS: We analyzed VTE, including pulmonary embolism and deep vein thrombosis, from Asian patients enrolled a prospective cohort study. All patients were newly diagnosed Hodgkin's lymphoma (HL) and non Hodgkin's lymphoma (NHL). RESULTS: A total of 686 patients were analyzed, and the median follow-up duration was 21.8 months. There were 54 cases of VTE including deep vein thrombosis alone (33/54, 61.1%) and pulmonary embolism (21/54, 38.9%). The median time to VTE was 1.97 months, and the one-year actuarial incidence was 7.9%. The global incidence of VTE was higher in patients with NHL (51/641, 8.0%) than HL (3/45, 6.7%). All cases of VTE occurred in patients receiving chemotherapy whereas no VTE in patients without chemotherapy. VTE was also independently associated with age older than 60 years and primary central nervous system (CNS) lymphoma. No VTE-related deaths were reported among all cases of VTE. Thus, overall survival was not different between patients with and without VTE. The subgroup analysis of patients with diffuse large B-cell lymphoma showed 8.9% of one-year actuarial incidence, but the occurrence of VTE did not influence its overall survival, either. CONCLUSIONS: The incidence of VTE in our study population was comparable to that of Western countries, and VTE was associated with chemotherapy, brain involvement and old age. PMID- 22507290 TI - In situ survey of life cycle phases of the coccolithophore Emiliania huxleyi (Haptophyta). AB - The cosmopolitan coccolithophore Emiliania huxleyi is characterized by a strongly differentiated haplodiplontic life cycle consisting of a diploid phase, generally bearing coccoliths (calcified) but that can be also non-calcified, and a non calcified biflagellated haploid phase. Given most studies have focused on the bloom-producing calcified phase, there is little-to-no information about non calcified cells in nature. Using field mesocoms as experimental platforms, we quantitatively surveyed calcified and non-calcified cells using the combined calcareous detection fluorescent in situ hybridization (COD-FISH) method and qualitatively screened for haploid specific transcripts using reverse transcription-PCR during E. huxleyi bloom successions. Diploid, calcified cells formed dense blooms that were followed by the massive proliferation of E. huxleyi viruses (EhVs), which caused bloom demise. Non-calcified cells were also detected throughout the experiment, accounting for a minor fraction of the population but becoming progressively more abundant during mid-late bloom periods concomitant with EhV burst. Non-calcified cell growth also paralleled a distinct window of haploid-specific transcripts and the appearance of autotrophic flagellates morphologically similar to haploid cells, both of which are suggestive of meiosis and sexual life cycling during natural blooms of this prominent marine phytoplankton species. PMID- 22507289 TI - Ecological partitioning and diversity in tropical planktonic foraminifera. AB - BACKGROUND: Ecological processes are increasingly being viewed as an important mode of diversification in the marine environment, where the high dispersal potential of pelagic organisms, and a lack of absolute barriers to gene flow may limit the occurrence of allopatric speciation through vicariance. Here we focus on the potential role of ecological partitioning in the diversification of a widely distributed group of marine protists, the planktonic foraminifera. Sampling was conducted in the tropical Arabian Sea, during the southwest (summer) monsoon, when pronounced environmental conditions result in a strong disparity in temperature, salinity and productivity between distinct northern and southern water masses. RESULTS: We uncovered extensive genetic diversity within the Arabian Sea planktonic foraminifera, identifying 13 morphospecies, represented by 20 distinct SSU rRNA genetic types. Several morphospecies/genetic types displayed non-random biogeographical distributions, partitioning between the northern and southern water masses, giving a strong indication of independent ecological adaptations. CONCLUSIONS: We propose sea-surface primary productivity as the main factor driving the geographical segregation of Arabian Sea planktonic foraminifera, during the SW monsoon, with variations in symbiotic associations possibly playing a role in the specific ecological adaptations observed. Our findings suggest that ecological partitioning could be contributing to the high levels of 'cryptic' genetic diversity observed within the planktonic foraminifera, and support the view that ecological processes may play a key role in the diversification of marine pelagic organisms. PMID- 22507291 TI - Health-related quality of life and glycaemic control in patients with Type 2 diabetes mellitus in Singapore. AB - AIMS: To investigate the health-related quality of life of patients with diabetes mellitus in Singapore and its associations with diabetes-related characteristics and glycaemic control. METHODS: An interviewer-administered, cross-sectional survey was conducted in a sample of 301 adult diabetes patients under primary care. The survey questionnaire included both a generic health-related quality of life measure, the Euroqol 5-D and a diabetes-specific instrument, the Audit of Diabetes-dependent Quality of Life. Patients' most recent HbA(1c) values were extracted from their medical records. RESULTS: After excluding patients who lacked the 90-day HbA(1c) test result, the final number of responses analysed was 282. Pain/discomfort was the most common complaint among the five Euroqol 5-D domains (by 28.0% of the respondents). Lack of freedom to eat was the Audit of Diabetes-dependent Quality of Life domain with the greatest negative average weighted impact (= -3.8, on a scale of -9 to 3). A significant association was observed between Audit of Diabetes-dependent Quality of Life average weighted impact and both duration of diabetes and use of insulin. A negative correlation was found between health-related quality of life and HbA(1c) values in both health-related quality of life measures (both r=-0.2, P=0.001). CONCLUSIONS: Patients with diabetes in primary-care settings frequently reported problems with pain/discomfort and restrictions in diet. Poorer health-related quality of life was found to be associated with higher HbA(1c) values. The chronicity of diabetes and insulin therapy may have a negative impact on patients' diabetes-related health-related quality of life. This study indicates the importance of achieving better disease management to improve the health-related quality of life of patients with diabetes. PMID- 22507292 TI - Changes in temporomandibular joint and ramus after sagittal split ramus osteotomy in mandibular prognathism patients with and without asymmetry. AB - The purpose of this study was to examine the changes in the temporomandibular joint (TMJ) and ramus after sagittal split ramus osteotomy (SSRO) with and without Le Fort I osteotomy. The subjects consisted of 87 Japanese patients diagnosed with mandibular prognathism with and without asymmetry. They were divided into 2 groups (42 symmetric patients and 45 asymmetric patients). The TMJ disc tissue was assessed by magnetic resonance imaging (MRI) and the TMJ space, condylar and ramus angle were assessed by computed tomography (CT) preoperatively and postoperatively. Medial joint space on the deviation side in the asymmetry group was significantly larger than that in the symmetry group (P = 0.0043), and coronal ramus angle on the non-deviation side in the asymmetry group was significantly larger than that in the symmetry group preoperatively (P = 0.0240). The horizontal condylar angle on the deviation side in the asymmetry group was significantly larger than that in the symmetry group (P = 0.0302), posterior joint space on the non-deviation side in the symmetry group was significantly larger than that in the asymmetry group postoperatively (P = 0.00391). The postoperative anterior joint space was significantly larger than the preoperative value on both sides in both groups (the deviation side in the symmetry group: P = 0.0016, the non-deviation side in the symmetry group: P < 0.0001, the deviation side in the asymmetry group: P = 0.0040, the non-deviation side in the asymmetry group: P = 0.0024). The preoperative disc position could was not changed in either group. These results suggest that significant expansion of anterior joint space could occur on the deviation side and non-deviation side in the asymmetry group as well as on both sides in the symmetry group, although disc position did not change in either group. PMID- 22507293 TI - Pulmonary metastases from an Ameloblastoma: case report and review of the literature. AB - Ameloblastomas have a high recurrence rate, and because of their biological tendency towards local invasion are considered borderline tumours. Despite this, reports of metastasis of these tumours are rare. This report presents a patient with mandibular ameloblastoma that recurred 29 years after surgery and metastasized to both lungs. Because of the large range of the area of metastasis, complete surgical resection of the tumours was impossible. After confirming the diagnosis by biopsy of the pulmonary lesions the pulmonary metastases were not treated actively. Observation over 4 years showed no obvious change in the lung metastasis. Recent cases are summarized and analyzed in this paper, with respect to its occurrence, pathological types, methods of treatment and other related aspects. PMID- 22507294 TI - Innovation in anterior mandibular alveolar distraction osteogenesis: introduction of a new bone-borne distraction device and first clinical results. AB - Segmental distraction osteogenesis of the anterior mandibular alveolar process (frontblock) is a sufficient method to avoid extractions in patients with dental crowding and to decompensate retroalveolism. Up to now dental-borne devices were used, but limitate the indications for front-block distraction. A new bone-borne distraction device for mandibular alveolar front-block movement is introduced in this study. The distractor allows sufficient segmental transport without loading on the teeth. Clinical evaluations of 7 patients have been performed including the feasibility and predictability of the distraction, postoperative pain and patients' discomfort. The results indicate that this technique is a promising strategy in the correction of dental crowding, correcting the curve of Spee and to decompensate mandibular retroalveolism even in patients with impaired periodontal health and a thin mandibular symphysis. PMID- 22507295 TI - Mandibular reconstruction in the rabbit using beta-tricalcium phosphate (beta TCP) scaffolding and recombinant bone morphogenetic protein 7 (rhBMP-7) - histological, radiographic and mechanical evaluations. AB - This investigation assesses the histological, radiographic and mechanical properties of regenerated bone in a unilateral critical-size osteoperiosteal mandibular continuity defect in the rabbit model, following the application of beta-tricalcium phosphate (beta-TCP) scaffolding and recombinant human bone morphogenetic protein 7 (rhBMP-7). The study was carried out on nine cases; in six cases the critical-size defect was filled with rhBMP-7 in the beta-TCP scaffolding, and in three cases the beta-TCP was used alone. The cases were sacrificed 3 months post-operatively. Histologically the overall mean of the percentage of regenerated bone volume in the cases that received rhBMP-7 was 29.41% +/- 6.25%, which was considerably greater than the 6.35% +/- 3.08% in the cases treated with beta-TCP alone. Mechanical testing of the cases treated with rhBMP-7 gave failure moments (55 mNm-2.040 Nm) that were consistently greater than those treated with beta-TCP alone (0 mNm-48 mNm). In some cases the mechanical properties of the regenerated bone were comparable to those of untreated bone. RhBMP-7 in prefabricated beta-TCP scaffolding appeared, radiographically and histologically, to be an effective method for bone regeneration in mandibular critical-size defects in the rabbit model. This points towards possible future clinical applications. PMID- 22507296 TI - Surgical induction of TMJ bony ankylosis in growing sheep and the role of injury severity of the glenoid fossa on the development of bony ankylosis. AB - OBJECTIVE: The purpose of this paper is to summarize our experiences in creating an animal model of TMJ bony ankylosis based on 2 sequential experiments. METHODS: Two sequential experiments were performed with the aim of creating a model of TMJ bony ankylosis. Seven growing sheep were used in the first experiment, in which 1 was served as a control animal. Condylar fracture with disc preservation was performed on the control side. On the contralateral side, condylar fracture, excision of the lateral 2/3 disc and injury to the glenoid fossa were performed to induce bony ankylosis. Three animals were sacrificed respectively at 3 and 6 months after surgery. In the second experiment, 7 growing sheep were used. The only difference of modeling between the 2 experiments was that more serious injury to the glenoid fossa was made in the ankylosis-induced side in experiment 2. Three, 2, and 2 animals were sacrificed respectively at 1, 3, and 6 months postoperatively. The TMJ complexes were examined by computed tomography (CT) and histological evaluation. RESULTS: In experiment 1, only fibrous ankylosis was observed in the ankylosis-induced side both at 3 and 6 months postoperatively. In experiment 2, CT and histological evaluation showed that the outcomes of the ankylosis-induced side were fibrous-bony ankylosis, fibrous-bony ankylosis, and bony ankylosis respectively at 1, 3, and 6 months after surgery. CONCLUSION: Through summarizing the differences of the modeling and the different outcomes in the 2 experiments, we concluded that severe damage to the glenoid fossa played an important role in the development of TMJ bony ankylosis. PMID- 22507297 TI - Three dimensional comparative measurement of polyurethane milled skull models based on CT and MRI data sets. AB - OBJECTIVE: Due to the increase in the number and complexity of surgical procedures, available to craniomaxillofacial surgeons, allied to the rapid progress of technological developments, the use and production of 3D models has become important, especially for planning complex cases. The radiation exposure of additional CT based examinations is always subject to debate, so the feasibility of producing 3D models for surgical planning based on MRI imaging has been raised. MATERIAL AND METHODS: 12 male and 3 female patients (n=15) between 47 and 84 years of age (mean age=65) were selected in a prospective study. Both magnetic resonance and computed tomography data sets of the facial bones were collected. Two milled models per patient were prepared: one based on the MRI scan and one based on the CT scan. The milled models were compared in a coordinative surveying procedure within 7 representative distances using a tentative measurement method. RESULTS: Difference values between CT and MRI based models ranged from 0.1mm to 5.9 mm. On average MRI based models were smaller by 0.381 mm (SD 1.176 mm) than those on CT based. The accuracy of models based on MRI data was similar to those based on CT data. MRI based three dimensional milled models provide precise structure accuracy. PMID- 22507298 TI - Phosphodiesterase inhibitors, congestive heart failure, and sudden death: time for re-evaluation. AB - A 42-year-old diabetic man was admitted with systolic heart failure and pulmonary hypertension being treated with sildenafil for the previous year. With an increase in creatinine, he experienced 3 episodes of ventricular tachycardia and ventricular fibrillation. Withdrawal of the phosphodiesterase (PDE) inhibitor resulted in no further episodes of dysrhythmias. The basic pharmacology of PDE inhibitors is presented and the use of PDE-3 inhibitors for the treatment of heart failure causing an increase in sudden death is also reviewed. There have been several cases of sudden death associated with sildenafil use and with its increasing use in patients with severe pulmonary hypertension and decompensated heart failure. The authors also reviewed the electrophysiologic effects of PDE-5 inhibitors associated with their use. The crossover between PDE-3 and PDE-5 inhibitors is also discussed and caution is urged when contemplating the use of PDE-5 inhibitors in patients with systolic heart failure and pulmonary hypertension. PMID- 22507299 TI - Three-dimensional characterization of resorption cavity size and location in human vertebral trabecular bone. AB - The number and size of resorption cavities in cancellous bone are believed to influence rates of bone loss, local tissue stress and strain and potentially whole bone strength. Traditional two-dimensional approaches to measuring resorption cavities in cancellous bone report the percent of the bone surface covered by cavities or osteoclasts, but cannot measure cavity number or size. Here we use three-dimensional imaging (voxel size 0.7*0.7*5.0 MUm) to characterize resorption cavity location, number and size in human vertebral cancellous bone from nine elderly donors (7 male, 2 female, ages 47-80 years). Cavities were 30.10 +/- 8.56 MUm in maximum depth, 80.60 +/- 22.23*10(3) MUm(2) in surface area and 614.16 +/- 311.93*10(3) MUm(3) in volume (mean +/- SD). The average number of cavities per unit tissue volume (N.Cv/TV) was 1.25 +/- 0.77 mm( 3). The ratio of maximum cavity depth to local trabecular thickness was 30.46 +/- 7.03% and maximum cavity depth was greater on thicker trabeculae (p<0.05, r(2)=0.14). Half of the resorption cavities were located entirely on nodes (the intersection of two or more trabeculae) within the trabecular structure. Cavities that were not entirely on nodes were predominately on plate-like trabeculae oriented in the cranial-caudal (longitudinal) direction. Cavities on plate-like trabeculae were larger in maximum cavity depth, cavity surface area and cavity volume than cavities on rod-like trabeculae (p<0.05). We conclude from these findings that cavity size and location are related to local trabecular microarchitecture. PMID- 22507300 TI - Porous scaffolds support extrahepatic human islet transplantation, engraftment, and function in mice. AB - Islet transplantation as a therapy or cure for type 1 diabetes has significant promise but has been limited by islet mass requirements and long-term graft failure. The intrahepatic and intravascular site may be responsible for significant loss of transplanted islets. Nonencapsulating biomaterial scaffolds provide a strategy for architecturally defining and modulating extrahepatic sites beyond the endogenous milieu to enhance islet survival and function. We utilized scaffolds to transplant human islets into the intraperitoneal fat of immunodeficient mice. A smaller human islet mass than previously reported reversed murine diabetes and restored glycemic control at human blood glucose levels. Graft function was highly dependent on the islet number transplanted and directly correlated to islet viability, as determined by the ATP-to-DNA ratio. Islets engrafted and revascularized in host tissue, and glucose tolerance testing indicated performance equivalent to healthy mice. Addition of extracellular matrix, specifically collagen IV, to scaffold surfaces improved graft function compared to serum-supplemented media. Porous scaffolds can facilitate efficient human islet transplantation and provide a platform for modulating the islet microenvironment, in ways not possible with current clinical strategies, to enhance islet engraftment and function. PMID- 22507301 TI - Thiamine deficiency degrades the link between spatial behavior and hippocampal synapsin I and phosphorylated synapsin I protein levels. AB - The links between spatial behavior and hippocampal levels of synapsin I and phosphosynapsin I were assessed in normal rats and in the pyrithiamine-induced thiamine deficiency (PTD) rat model of Wernicke-Korsakoff's syndrome. Synapsin I tethers small synaptic vesicles to the actin cytoskeleton in a phosphorylation dependent manner, is involved in neurotransmitter release and has been implicated in hippocampal-dependent learning. Positive correlations between spontaneous alternation behavior and hippocampal levels of both synapsin I and phosphorylated synapsin I were found in control rats. However, spontaneous alternation performance was impaired in PTD rats and was accompanied by a significant reduction (30%) in phosphorylated synapsin I. Furthermore, no correlations were observed between either form of synapsin I and behavior in PTD rats. These data suggest that successful spontaneous alternation performance is related to high levels of hippocampal synapsin I and phosphorylated synapsin I. These results not only support the previous findings that implicate impaired hippocampal neurotransmission in the spatial learning and memory deficits associated with thiamine deficiency, but also suggest a presynaptic mechanism. PMID- 22507302 TI - Concentration and chain length of polyethylene glycol in islet isolation solution: evaluation in a pancreatic islet transplantation model. AB - To improve graft preservation and consequently reduce conservation injuries, the composition of preservation solution is of outmost importance. It was demonstrated that the colloid polyethylene glycol (PEG), used in SCOT solution, has protective effects on cell membranes and immunocamouflage properties. The aim of this study was to optimize the concentration and chain length of PEG to improve pancreatic islet preservation and outcome. In a model of murine islet allotransplantation, islets were isolated with SCOT containing various concentrations of PEG 20 kDa or 35 kDa. Better islet yield (IEQ) was obtained with SCO +PEG at 15-30 g/L versus other PEG concentrations and control CMRL-1066 + 1% BSA solution (p < 0.05). Allograft survival was better prolonged (up to 20 days) in the groups SCOT + PEG 20 kDa 10-30 g/L compared to PEG 35 kDa (less than 17.8 days) and to control solutions (less than 17.5 days). In terms of graft function recovery, the use of PEG 20 kDa 15-30 g/L induced no primary nonfunction and delayed graft function contrary to CMRL-1066 and other PEG solutions. The use of the extracellular-type solution SCOT containing PEG 20 kDa 15 g/L as colloid could be a new way to optimize graft integrity preservation and allograft outcome. PMID- 22507303 TI - Examining the interrelationships between social anxiety, smoking to cope, and cigarette craving. AB - Smokers with symptoms of social anxiety often report smoking as a way to cope with negative affect. These individuals have lower success rates when attempting cessation compared with the general population. However, there is a paucity of research examining the role of social anxiety in nicotine dependence. The present study explored the relationships between symptoms of social anxiety, smoking to cope with these symptoms during social situations (STC), and cigarette craving. Thirty-eight participants completed measures of social anxiety and STC at baseline. Cigarette craving was subsequently assessed pre and post exposure to smoking-related images during periods of nicotine satiation and deprivation. Regression analyses revealed that greater symptoms of social anxiety predicted the frequency of STC behaviors and the number of cigarettes participants thought they would need in order to feel more comfortable in social situations. Symptoms of social anxiety and several behaviors associated with STC (e.g., avoiding social situations in which smoking is not permitted) predicted increases in craving during nicotine deprivation, but not satiation. These findings suggest that symptoms of social anxiety and STC behaviors may play a role in the maintenance of smoking behaviors. Further, targeting symptoms of social anxiety within the context of smoking cessation treatment may be particularly helpful and may improve the rates of smoking cessation among individuals with symptoms of social anxiety. PMID- 22507304 TI - From Animal House to Old School: a multiple mediation analysis of the association between college drinking movie exposure and freshman drinking and its consequences. AB - Does exposure to college drinking movies impact upon subsequent college student drinking? If so, what mechanisms mediate such an effect? In the first study to address these questions, we assessed college drinking movie exposure in a sample of 479 college freshmen early in their first semester and examined its relation to subsequent drinking and drinking consequences one month later. Hypothesized mediators of this effect included college alcohol beliefs (beliefs that drinking is central to college life), positive and negative alcohol expectancies, and descriptive and injunctive norms. Using bootstrapping procedures, results indicated that movie exposure exerted direct effects on both drinking and drinking consequences. Movie exposure also had significant indirect effects on drinking through all of the hypothesized mediators, with the exception of negative alcohol expectancies. All mediated movie exposure's effects on drinking consequences, with the exception of injunctive norms. Contrast analyses revealed that college alcohol beliefs had the strongest mediational effects in the relationship between movie exposure and both drinking and consequences. The implications of these findings for precollege alcohol education programs are discussed. PMID- 22507305 TI - Breast cancer presenting within or adjacent to the breast implant capsule: a case series and clinical recommendations. PMID- 22507306 TI - Hemoglobin status associated with performance IQ but not verbal IQ in Chinese preschool children. AB - BACKGROUND: Despite the body of literature that links anemia with poorer cognition in children and the evidence that the severity of the effects of anemia on children's cognition vary in different populations, few studies have investigated the effects of anemia on the cognitive development of Chinese children. METHODS: This longitudinal cohort included 171 children from a developing region of China. Hemoglobin (Hb) and iron levels were taken when the children were 4 years old. At age 6, the children's cognition was tested with the Chinese Wechsler Preschool and Primary Scale of Intelligence. Psychosocial information was also used in analyses. RESULTS: Results showed that the children who had low Hb levels had significantly lower scores in performance IQ (PIQ), but not verbal IQ. Although blood Fe levels were not shown to moderate the link between Hb levels and IQ, we found children who performed the best on IQ tests exhibited low iron levels concurrent with high Hb levels, whereas the group who performed the worst exhibited high iron but low Hb levels. We also found that psychosocial adversity did not differ significantly between children who had normal or low Hb levels, although the effect of Hb on PIQ became only suggestive after controlling for psychosocial adversity, therefore the correlation is not causal but only a suggestive association. CONCLUSION: Our findings are in agreement with literature on the negative effects of anemia on children's cognition and point to the possibility that the portions of the brain associated with PIQ components are particularly affected by low Hb during crucial periods of development. PMID- 22507307 TI - Asynchronous magnetic bead rotation microviscometer for rapid, sensitive, and label-free studies of bacterial growth and drug sensitivity. AB - The long turnaround time in antimicrobial susceptibility testing (AST) endangers patients and encourages the administration of wide spectrum antibiotics, thus resulting in alarming increases of multidrug resistant pathogens. A method for faster detection of bacterial proliferation presents one avenue toward addressing this global concern. We report on a label-free asynchronous magnetic bead rotation (AMBR) based viscometry method that rapidly detects bacterial growth and determines drug sensitivity by measuring changes in the suspension's viscosity. With this platform, we observed the growth of a uropathogenic Escherichia coli isolate, with an initial concentration of 50 cells per drop, within 20 min; in addition, we determined the gentamicin minimum inhibitory concentration (MIC) of the E. coli isolate within 100 min. We thus demonstrated a label-free, microviscometer platform that can measure bacterial growth and drug susceptibility more rapidly, with lower initial bacterial counts than existing commercial systems, and potentially with any microbial strains. PMID- 22507308 TI - A common mechanism and a new categorization for anti-ganglioside antibody mediated neuropathies. AB - Serum antibodies to different gangliosides have been identified in some Guillain Barre (GBS) subtypes and variants. In the January issue of Experimental Neurology Susuki and colleagues (2012) showed that in experimental neuropathies associated with antibodies to GM1, GD1a and GD1b the common mechanism is a complement mediated dysfunction and disruption of the nodes of Ranvier which causes a pathophysiological continuum from early reversible conduction failure to axonal degeneration. These observations, correlated and integrated with electrophysiological and pathological findings in humans indicate that the GBS subtypes acute motor conduction block neuropathy, acute motor axonal neuropathy, acute motor and sensory neuropathy and acute sensory neuropathy and possibly also a chronic disorder as multifocal motor neuropathy represent a spectrum of the same immunopathologic process. Being the nodal axolemma and the paranode the focus of the nerve injury, these immune mediated neuropathies could be more properly classified as nodo-paranodopathies. PMID- 22507309 TI - The role of OsCOM1 in homologous chromosome synapsis and recombination in rice meiosis. AB - COM1/SAE2 is a highly conserved gene from yeast to higher eukaryotes. Its orthologs, known to cooperate with the MRX complex (Mre11/Rad50/Xrs2), are required for meiotic DNA double-strand break (DSB) ends resection and specific mitotic DSB repair events. Here, the rice (Oryza sativa, 2n = 2x = 24) COM1/SAE2 homolog was identified through positional cloning, termed OsCOM1. Four independent mutants of OsCOM1 were isolated and characterized. In Oscom1 mutants, synaptonemal complex (SC) formation, homologous pairing and recombination were severely inhibited, whereas aberrant non-homologous chromosome entanglements occurred constantly. Several key meiotic proteins, including ZEP1 and OsMER3, were not loaded normally onto chromosomes in Oscom1 mutants, whereas the localization of OsREC8, PAIR2 and PAIR3 seemed to be normal. Moreover, OsCOM1 was loaded normally onto meiotic chromosomes in Osrec8, zep1 and Osmer3 mutants, but could not be properly loaded in Osam1, pair2 and OsSPO11-1(RNAi) plants. These results provide direct evidence for the functions of OsCOM1 in promoting homologous synapsis and recombination in rice meiosis. PMID- 22507310 TI - Influence of the distensibility of large arteries on the longitudinal impedance: application for the development of non-invasive techniques to the diagnosis of arterial diseases. AB - BACKGROUND: This study shows that the arterial longitudinal impedance constitutes a hemodynamic parameter of interest for performance characterization of large arteries in normal condition as well as in pathological situations. For this purpose, we solved the Navier-Stokes equations for an incompressible flow using the finite element analysis method and the Arbitrary Lagrangian Eulerian (ALE) formulation. The mathematical model assumes a two-dimensional flow and takes into account the nonlinear terms in the equations of fluid motion that express the convective acceleration, as well as the nonlinear deformation of the arterial wall. Several numerical simulations of the blood flow in large vessels have been performed to study the propagation along an arterial vessel of a pressure gradient pulse and a rate flow pulse. These simulations include various deformations of the wall artery leading to parietal displacements ranging from 0 (rigid wall) to 15% (very elastic wall) in order to consider physiological and pathological cases. RESULTS: The results show significant changes of the rate flow and the pressure gradient wave as a function of aosc, the relative variation in the radius of the artery over a cardiac cycle. These changes are notable beyond a critical value of aosc equal to 0.05. This critical value is also found in the evolution of the longitudinal impedance. So, above a variation of radius of 5%, the convective acceleration, created by the fluid-wall interactions, have an influence on the flow detectable on the longitudinal impedance. CONCLUSIONS: The interpretation of the evolution of the longitudinal impedance shows that it could be a mean to test the performance of large arteries and can contribute to the diagnosis of parietal lesions of large arteries. For a blood vessel with a wall displacement higher than 5% similar to those of large arteries like the aorta, the longitudinal impedance is substantially greater than that obtained in the absence of wall displacement. This study also explains the effects of convective acceleration, on the shape of the decline of the pressure gradient wave and shows that they should not be neglected when the variation in radius is greater than 5%. PMID- 22507311 TI - Neuro-immuno-endocrine processes in vitiligo pathogenesis. AB - Vitiligo is a cutaneous disorder of depigmentation, clinically characterized by well-demarcated, white macules of varying size and distribution. It can affect up to 2 percent of the population, especially younger ages. In spite of recent findings implicating genetic, immune and oxidative stress factors, the exact pathogenesis of vitiligo remains obscure. Here, we briefly discuss the prevailing theories, and offer new suggestions that could explain in part the damage of melanocyte in the vitiliginous lesions. Our emerging hypothesis is that neuropeptides released from peripheral nerve endings could synergize with new cytokines to adversely affect melanocyte function and viability. These may include corticotropin- releasing hormone (CRH) and neurotensin (NT), as well as interleukin 33 (IL-33) and thymic stromal lymphopoietin (TSLP). Such interactions could serve the basis for further research, possibly leading to new treatments. PMID- 22507312 TI - Advanced glycation end products: possible link between metabolic syndrome and periodontal diseases. AB - On a planetary scale, Metabolic Syndrome (MetS)is the third cause of inability after malnutrition and nicotinism, even higher than water shortage and sedentariness. In the USA, the prevalence is estimated at over 25 percent of the population; in Italy, it involves approximately 25 percent of men and even 27 percent of women. These are very high figures, corresponding to approximately 14 million affected individuals. The prevalence is alarming and must not be underestimated, particularly in the dental field, where more than one patient out of four sitting in a dentist chair is affected. The etiology of periodontal disease has not yet been clarified, and recently the idea to consider it as a multifactor pathology has been developed. Cofactors such as the formation of free radicals of oxygen (ROS), oxidative stress, lipid peroxidation, and formation of glycation end-products (AGEs) probably play an important role in the onset of periodontal disease. The AGEs are compounds physiologically produced by the cells. However, they accumulate and cause pro-inflammatory conditions, when the cellular clearance fails, or in hyperglycemic and oxidative states. All these conditions can be clinically summarized as Metabolic Syndrome. The purpose of this literature review is to establish a relationship between two pathologies with very high prevalence: Metabolic Syndrome and Periodontal Disorder. The literature seems to have clarified that MetS involves a pro-oxidation status, which induces AGE formation. AGEs play a very important role in the course and severity of periodontal diseases. PMID- 22507313 TI - Why glucocorticosteroids should remain in the list of prohibited substances: a sports medicine viewpoint. AB - In addition to their therapeutic applications, glucocorticosteroids have been widely used and abused in the belief that these substances may enhance athletic performance. Analysis of athlete urine samples by antidoping laboratories around the world support this conclusion. It is commonly accepted in medical practice to use local glucocorticosteroid injections in the treatment of non-infectious local musculotendinous inflammatory conditions conveying symptom relief and often a speedier return to sporting activity. This practice is not to be considered illicit, but sports physicians must accept that such an intervention is not in itself an immediate cure and that an athlete will still require a period of recuperation before continuing sporting activity. How long such a period of recuperation should last is a matter of conjecture and there is little concrete data to support what is, or what is not, an acceptable period of inactivity. In the interest of athlete safety, we would propose to maintain systemic glucocorticosteroids on the World Anti-Doping Agency's (WADA) list of prohibited substances, both in and out-of-competition as well as a mandatory period of 48 hours of rest from play after receiving a local glucocorticosteroid injection. PMID- 22507314 TI - Statins and cardiovascular risk in rheumatic diseases. AB - Chronic inflammatory rheumatic diseases are associated with an increased risk of cardiovascular (CV) atherosclerotic events. The inflammatory state, which is the hallmark of chronic rheumatic diseases, is the important driving force for accelerated atherogenesis. Since the control of traditional risk factors alone is insufficient in reducing the risk, much attention has been directed towards the potential use of statins. Statins, a family of drugs that suppress cholesterol biosynthesis by inhibiting the hydroxymethyl glutaryl coenzyme A reductase, have been shown to significantly reduce CV-related morbidity and mortality. In addition to lower lipid levels, several non-lipid lowering pleiotropic effects, including anti-inflammatory and immunomodulatory activities, make statins potential therapeutic agents in chronic rheumatic diseases. However, lipid metabolism in chronic rheumatic diseases is complex, since inflammatory states can induce alterations in lipid levels and function, so that cholesterol target levels from general guidelines may not be adequate in chronic inflammatory rheumatic diseases. Larger trials are needed to refine the precise benefits and health-utility associated with this therapy. PMID- 22507315 TI - IL-37 (IL-1F7) the newest anti-inflammatory cytokine which suppresses immune responses and inflammation. AB - Cytokines such as interleukins, chemokines and interferons are immunomodulating and inflammatory agents, characterized by considerable redundancy, in that many cytokines appear to share similar functions. Virtually all nucleated cells, but especially epithelial cells and macrophages, are potent producers of cytokines. The objective of this study is to review the detailed mechanism of action and the biological profiles of IL-37, the newest anti-inflammatory cytokine. This review focuses on IL-37, a key cytokine in regulating inflammatory responses, mainly by inhibiting the expression, production and function of proinflammatory cytokines: IL-1 family pro-inflammatory effects are markedly suppressed by IL-37. PMID- 22507316 TI - In vitro and in vivo therapeutics of beta-thujaplicin on LPS-induced inflammation in macrophages and septic shock in mice. AB - beta-thujaplicin, an active constituent from Chamaecyparis obtusa, has been shown to have acaricidal and antimicrobial effects. Very few studies have focused on the potential of the anti-inflammatory effect of beta-thujaplicin. Moreover, its capability of inhibiting inflammatory mediators e.g. TNF-a gene transcription, nitric oxide (NO) and prostaglandin E2, remains unknown. Besides those molecular mechanisms behind the anti-inflammatory effect of beta-thujaplicin, solid proof of its effectiveness in vivo has not yet been studied. In our study, in vitro effects of beta thujaplicin were verified on RAW 264.7 macrophages which were stimulated by LPS. Indomethacin was used as a positive control. The inducible NO production after stimulation was measured by Griess reagent. PGE2, IL-6 and TNF alpha were measured by ELISA methods. Protein expressions of iNOS, COX2, and NF kappaB were evaluated by Western blotting. Septic ICR mice were administered 20 mg/kg of LPS and then the mortality rate was monitored. Within the concentration range which was devoid of cytotoxicty, beta-thujaplicin exhibited a clear dose dependent inhibition on LPS-induced NO production. Furthermore, beta-thujaplicin inhibited LPS-induced PGE2, IL-6, and TNF-alpha production as well as iNOS, COX2, and NF- kappaB protein expression more substantially potent than indomethacin. In agreement with the in vitro study, beta-thujaplicin was shown to be effective in vivo for inhibiting LPS-induced NO and TNF-alpha production and a significant decrease in mortality rate of mice suffering from septic shock was observed. This study demonstrates the potential of beta-thujaplicin in treatment of inflammation and sepsis. These effects occur through an efficient blockage of TNF-alpha and iNOS production. beta-thujaplicin efficacy is comparable to that of indomethacin thus it can be a substitution but bear less depletion of PGE2, making this compound very promising in clinical applications. beta-thujaplicin, an active constituent from Chamaecyparis obtusa, has been shown to have acaricidal and antimicrobial effects. Very few studies have focused on the potential of the anti inflammatory effect of beta-thujaplicin. Moreover, its capability of inhibiting inflammatory mediators e.g. TNF-alpha gene transcription, nitric oxide (NO) and prostaglandin E2, remains unknown. Besides those molecular mechanisms behind the anti-inflammatory effect of beta-thujaplicin, solid proof of its effectiveness in vivo has not yet been studied. In our study, in vitro effects of beta-thujaplicin were verified on RAW 264.7 macrophages which were stimulated by LPS. Indomethacin was used as a positive control. The inducible NO production after stimulation was measured by Griess reagent. PGE2, IL-6 and TNF-alpha were measured by ELISA methods. Protein expressions of iNOS, COX2, and NF-kB were evaluated by Western blotting. Septic ICR mice were administered 20 mg/kg of LPS and then the mortality rate was monitored. Within the concentration range which was devoid of cytotoxicty, beta-thujaplicin exhibited a clear dose-dependent inhibition on LPS induced NO production. Furthermore, beta-thujaplicin inhibited LPS-induced PGE2, IL-6, and TNF-alpha production as well as iNOS, COX2, and NF-kB protein expression more substantially potent than indomethacin. In agreement with the in vitro study, beta-thujaplicin was shown to be effective in vivo for inhibiting LPS-induced NO and TNF-alpha production and a significant decrease in mortality rate of mice suffering from septic shock was observed. This study demonstrates the potential of beta-thujaplicin in treatment of inflammation and sepsis. These effects occur through an efficient blockage of TNF-alpha and iNOS production. beta-thujaplicin efficacy is comparable to that of indomethacin thus it can be a substitution but bear less depletion of PGE2, making this compound very promising in clinical applications. PMID- 22507317 TI - APP/PS1 transgenic mice treated with aluminum: an update of Alzheimer's disease model. AB - There is still no animal model available that can mimic all the cognitive, behavioral, biochemical, and histopathological abnormalities observed in patients with Alzheimer's disease (AD). We undertook to consider the interaction between genetic factors, including amyloid precursor protein (APP) and presenilin-1 (PS1), and environmental factors, such as Aluminum (Al) in determining susceptibility outcomes when studying the pathogenesis of AD. In this article, we provide an AD model in APP/PS1 transgenic mice triggered by Al. The animal model was established via intracerebral ventricular microinjection of aluminum chloride once a day for 5 days in APP/PS1 transgenic mice. Twenty wild type (WT) mice and 20 APP/PS1 transgenic (TG) mice were separately divided into 2 groups (control and Al group), and a stainless steel injector with stopper was used for microinjection into the left-lateral cerebral ventricle of each mouse. The Morris water maze task was used to evaluate behavioral function of learning and memory ability on the 20th day after the last injection. This AD model's brain was analyzed by: (1) amyloid beta immunohistochemical staining; (2) Tunnel staining; (3) apoptotic rates; (4) caspase-3 gene expression. Here, decrease of cognitive ability and neural cells loss were shown in APP/PS1 transgenic mice exposed to Al, which were more extensive than those in APP/PS1 TG alone and WT mice exposed to Al alone. These findings indicate that there is a close relationship between over-expression of APP and PS1 genes and Al overload. It is also suggested that APP/PS1 TG mice exposed to Al have potential value for improving AD models. PMID- 22507318 TI - GITR-expressing regulatory T-cell subsets are increased in tumor-positive lymph nodes from advanced breast cancer patients as compared to tumor-negative lymph nodes. AB - Lymph node (LN) infiltration by neoplastic process involves important changes in lymph node immune microenvironment. In particular, regulatory T cells (Treg) seem to have a key role in altering the immunoediting function of the immune system which leads to the elusion of the tumor from immune surveillance. In this study, we evaluated the expression of T-cell markers in CD4+ and CD8+ subsets from tumor positive and tumor-negative lymph nodes from the same, advanced stage breast cancer patient. The study was carried out on 3 patients and similar results were obtained. Flow cytometric analysis of CD8+ cells demonstrated a significant difference in the expression of CD25, CD45RA, CD45RO, and GITRL (Glucocorticoid Induced TNF receptor-Related ligand). Flowcytometric analysis of CD4+ cells demonstrated a significant difference in the expression of GITR (Glucocorticoid Induced TNF receptor-Related), CD25, FoxP3 (Forkhead box P3), CD28, and CD45RA. Multiple staining allowed the identification of two Treg subpopulations, CD4+ CD25 highGITR+ CD127-/low and CD4+ CD25 low GITR+ CD127+ cells, proving that both are increased in the positive nodes in comparison with the negative nodes from the same patient. We identified for the first time the CD4+ CD25 low GITR+ CD127+ Treg subpopulation in cancer, and the 2.6 fold increase in positive LN suggests that this Treg subpopulation could be a key player in metastasis. We also found GITRL expression in the CD8 lymphocytes, which may also contribute to the changes of metastatic lymph node microenvironment. These findings make both GITR and GITRL good possible co-candidates for future therapeutical intervention against metastasis and perhaps also as disease evolution biomarkers. PMID- 22507319 TI - Is there a role for prostate tumour overexpressed-1 in the diagnosis of HGPIN and of prostatic adenocarcinoma? A comparison with alpha-methylacyl CoA racemase. AB - Prostate Tumour Overexpressed-1 (PTOV1) was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer (PCa). Alpha-Methyl-CoA racemase (AMACR) mRNA was identified as being overexpressed in PCa. PTOV1 and racemase were immunohistochemically evaluated in PCa, high-grade prostatic intraepithelial neoplasia (HGPIN), atrophy and normal-looking epithelium (NEp) in 20 radical prostatectomies (RPs) with pT2a Gleason score 6 prostate cancer with the aim of analyzing the differences in marker expression between PTOV1 and AMACR. The level of expression of PTOV1 and AMACR increased from NEp and atrophy through HGPIN, away from and adjacent to prostate cancer, to PCa. With the ROC curve analysis the overall accuracy in distinguishing PCa vs HGPIN away from and adjacent to cancer was higher for AMACR than for PTOV1. In conclusion, AMACR can be considered a more accurate marker than PTOV1 in the identification of HGPIN and of PCa. However, PTOV1 may aid in the diagnosis of PCa, at least to supplement AMACR as another positive marker of carcinoma and to potentially increase diagnostic accuracy. PMID- 22507320 TI - Endothelial progenitor cell-derived microvesicles improve neovascularization in a murine model of hindlimb ischemia. AB - Paracrine mediators released from endothelial progenitor cells (EPCs) have been implicated in neoangiogenesis following ischemia. Recently, we demonstrated that microvesicles (MVs) derived from EPCs are able to activate an angiogenic program in quiescent endothelial cells by a horizontal transfer of RNA. In this study we aim to investigate whether EPC-derived MVs are able to induce neoangiogenesis and to enhance recovery in a murine model of hindlimb ischemia. Hindlimb ischemia was induced in severe combined immunodeficient (SCID) mice by ligation and resection of the left femoral artery and mice were treated with EPC-derived MVs (MVs), RNase-inactivated MVs (RnaseMVs), fibroblast-derived MVs or vehicle alone as control (CTL). Since MVs contained the angiogenic miR-126 and miR-296, we evaluated whether microRNAs may account for the angiogenic activities by treating mice with MVs obtained from DICER-knock-down EPC (DICER-MVs). The limb perfusion evaluated by laserdoppler analysis demonstrated that MVs significantly enhanced perfusion in respect to CTL (0.50+/-0.08 vs 0.39+/-0.03, p<0.05). After 7 days, immunohistochemical analyses on the gastrocnemius muscle of the ischemic hindlimb showed that MVs but not fibroblast-MVs significantly increased the capillary density in respect to CTL (MVs vs CTL: 24.7+/-10.3 vs 13.5+/-6, p<0.0001) and (fibroblast-MVs vs CTL: 10.2+/-3.4 vs 13.5+/-6, ns); RNaseMVs and DICER-MVs significantly reduced the effect of MVs (RNaseMVs vs CTL: 15.7+/-4.1 vs 13.5+/-6, ns) (MVs vs DICER-MVs 24.7+/-10.3 vs 18.1+/-5.8, p <0.05), suggesting a role of RNAs shuttled by MVs. Morphometric analysis confirmed that MVs enhanced limb perfusion and reduced injury. The results of the present study indicate that treatment with EPC-derived MVs improves neovascularization and favors regeneration in severe hindlimb ischemia induced in SCID mice. This suggests a possible use of EPCs-derived MVs for treatment of peripheral arterial disease. PMID- 22507321 TI - Impact of different concentrations of human recombinant growth hormone on T lymphocytes. AB - The aim of the present study is to evaluate the effects induced by increasing concentrations of human recombinant growth hormone on T lymphocytes. Ten healthy volunteers and twelve subjects with symptomatic allergies were enrolled in the study. Peripheral blood mononuclear cells and purified T lymphocytes were cultured in the presence of graded concentrations of growth hormone. Following appropriate in vitro stimulations, the proportion of apoptotic T cells, the percentage of activated T lymphocyte subpopulations, the phytohemagglutinin responsiveness and the Th2 response were assessed by flow cytometry analysis. Moreover, in order to evaluate the phosphoinositol-3-kinase signaling pathway involvement, cells were also analyzed after treatment with LY294002. The treatment with different concentrations of growth hormone did not influence the activation pattern of un-stimulated T lymphocytes. On the contrary, growth hormone was able to modify the CD38/HLA-DR co-expression of T cells activated with phytohemoagglutinin. A different response was observed when samples obtained from healthy donors and from subjects with symptomatic allergies were analysed. Moreover, growth hormone treatment was able to increase the Th2 response in the samples obtained from healthy donors only. The results of the present study strongly support the hypothesis that growth hormone administration may play an important role in conditions of impaired/activated immune systems. The observation that growth hormone administration at high doses may reverse its effects and that it may promote a Th2-oriented response have significant clinical implications when considering the use of this hormone for artificially enhancing the physical performances of healthy athletes. PMID- 22507322 TI - Increased percentages of tumor necrosis factor-alpha+/interferon-gamma+ T [corrected] lymphocytes and calprotectin+/tumor necrosis factor-alpha+ monocytes in patients with acute Kawasaki disease. AB - In vivo exposure to microorganisms resident in the oral cavity is considered as a possible cause of Kawasaki disease (KD), and some epitopes derived from streptococci display homology with Factor H of Complement. Additionally, calprotectin, a major calcium binding protein released by neutrophils and activated monocytes, could be directly involved in endothelial damage occurring in KD. The aim of our study is to evaluate the percentages of IFN-gamma+ and/or TNF-alpha+ lymphocytes and double positive calprotectin/TNF-alpha monocytes (CD14+) after in vitro stimulation with streptococcal- and/or Factor H-derived peptides, in patients with acute KD. Peripheral Blood Mononuclear Cells (PBMCs) obtained from KD patients and febrile controls were stimulated in vitro with peptides. After culture, cells were collected, stained with fluorochrome-labelled monoclonal antibodies against CD3, CD14, calprotectin, IFN-gamma and TNF-alpha, and cytofluorimetric analyses were performed. Our results showed increased percentages of TNF-alpha+/IFN-gamma+ lymphocytes in KD patients in respect to controls when PBMCs were stimulated with streptococcal or Factor H derived epitopes. In addition, also calprotectin+/TNF-alpha+ monocytes from KD patients were activated after PBMC in vitro stimulation. These findings lead us to speculate that some peptides, derived from oral streptococci and cross reactive with the human Factor H of Complement, could induce lymphocyte and monocyte activation potentially involved in the pathogenesis of KD. Our results should be confirmed by further studies enrolling more patients and controls than those analyzed in our study. PMID- 22507323 TI - Expression of gelatinases (MMP-2, MMP-9) and cyclooxygenases (COX-1, COX-2) in some benign salivary gland tumors. AB - Salivary gland tumors, most of which are rare benign tumors, represent a histologically heterogenous group with the greatest diversity of morphological and cellular features. The aim of this study is to analyse the expression and possible interactions between gelatinases (MMP-2, MMP-9) and cyclooxygenases (COX 1, COX-2) in some benign salivary gland tumors. We investigated the expression of gelatinases and cyclooxigenases in control salivary gland, Pleomorphic adenoma and Warthin's tumor through immunohistochemistry and Reverse Transcription - Polymerase Chain Reaction (PCR). We identified the expression of both classes of enzyme in normal samples and in the two types of pathological samples without any quantitative differences. From the present data no significant differences emerge in the expression of these enzymes among the different pathologies examined. Nevertheless, due to the small number of samples included in this study, general statements regarding correlation between the degree of severity of the tumoral pathology and the quantitative expression of these potential tumoral markers can not be made. PMID- 22507324 TI - Neurotrophins, their receptors and KI-67 in human GH-secreting pituitary adenomas: an immunohistochemical analysis. AB - Pituitary adenomas are a diverse group of tumors arising from the pituitary gland. Typically, they are small, slow-growing, hormonally inactive lesions that come to light as incidental findings on radiologic or postmortem examinations, although some small, slow-growing lesions with excessive hormonal activity may manifest with a clinical syndrome. The family of neurotrophins plays a key role in the development and maintenance of the pituitary endocrine cell function and in the regulation of hypothalamo-pituitary-adrenocortical axis activity. The objective of our experimental study is to investigate the localization of the neurotrophins, their relative receptors and to detect the expression level of Ki 67 to determine whether all these factors participate in the transformation and development of human pituitary adenomas. A very strong expression of Neurotrophin 3 (NT-3) and its receptor TrKC was observed in the extracellular matrix (ECM) and vessel endothelium, together with a clear/marked presence of Brain-derived neurotrophic factor (BDNF), and its receptor TrKB, thus confirming their direct involvement in the progression of pituitary adenomas. On the contrary, NGF (Nerve growth factor) and its receptor TrKA and p75NTR were weakly expressed in the epithelial gland cells and the ECM. PMID- 22507325 TI - Comparison of immuno-phenotypes of stem cells from human dental pulp and periodontal ligament. AB - It has been established that human dental pulp and periodontal ligament contain a population of mesenchymal stem cells (MSCs). However, the phenotypic analysis in terms of putative stem cell markers expressed by these stem cell populations is incomplete. It is relevant to understand whether stem cells derived from closely related tissues are programmed differently. The aim of the present study is to analyze whether these stem cells depict distinct characteristics by gaining insight into differences in their immunophenotype. Dental pulp and periodontal ligament tissue samples were obtained from extracted impacted wisdom teeth. Cell cultures were analyzed for surface and intracellular markers by indirect immunoflourescence. Detailed immunophenotype analysis was carried out by flow cytometry using relevant markers. The present study data shows dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) expressed embryonic stem (ES) cell markers Oct-4, Nanog and mesodermal marker Vimentin by indirect immunoflourescence. PDLSCs, however, had a weak expression of Nanog. Immunophenotyping revealed strong expression of MSC markers (CD73, CD90) in DPSCs and PDLSCs. Differences were observed in expression of stemness-related markers. DPSCs displayed increased percentages of SSEA4, CD13 and CD166 and decreased CD9 expression compared to PDLSCs. Both stem cells express common MSC markers, different levels of expression suggests there might be more than one stem cell population existing within these tissues which differ in their embryonic status, and DPSCs are a more primitive stem cell population in comparison to PDLSCs. PMID- 22507326 TI - Aberrant beta-catenin and LEF1 expression may predict the clinical outcome for patients with oropharyngeal cancer. AB - Beta-catenin, normally expressed on the epithelial cell surface, plays a crucial role in cadherin-mediated cell adhesion. Recent evidence suggests that beta-catenin is also involved in other functions such as intracellular signaling via the Wnt pathway by creating a nuclear complex with members of the Lymphoid Enhancer-Factor/T-Cell-Factor (LEF/TCF) family of transcription factors, and gene regulation that it is implicated in the development of several tumors. Little information is available on beta-catenin expression and its main partner in the Wnt signaling pathway, LEF1, in oropharyngeal squamous cell carcinomas (OP-SCCs). The aim of this study is to investigate the expression of beta catenin and LEF1 expression in human primary OP-SCCs and to evaluate their clinical and prognostic significance. OP-SCCs and normal peritumoral areas were analyzed by immunohistochemistry, Western-blot and RT-PCR. Beta-catenin was overexpressed in tumors in comparison to normal peritumoral areas and displayed predominantly intracellular (cytosolic/nuclear) localization in 62% of the tumors. Immunoreactivity was correlated with clinicopathological parameters and long-term follow-up, and a significant association was found between protein expression and development of local recurrences (P =0.03). The OP-SCCs with poor clinical outcome, which displayed intracellular beta-catenin expression, were also strongly positive for LEF1, with their co-expression statistically significant (P = 0.040). All (100%) advanced (stages 3+4) SCCs, 66.7% of the SCCs with positive lymph nodes and 80% of the SSCs that developed local recurrences were LEF1 positive. Cox regression analysis confirmed a poorer overall survival in cases with high expression of beta-catenin and LEF1. Our results suggest that assessing intracellular beta-catenin and LEF1 expression might help in patient risk stratification and outcome prediction, and serve as novel therapeutic targets in advanced OP-SCC. PMID- 22507327 TI - Altered immune responses during septicaemia in patients suffering from haematological malignancies. AB - Septicaemia is a frequent complication in patients with haematological malignancies. In this study we analysed markers of inflammation/immune activation (C- reactive protein, interleukin-6, neopterin), tryptophan metabolites and mannose binding lectin (MBL) levels consecutively in 36 septic patients with haematological malignancies (HM) and non-haematological diseases [intensive care unit (ICU) patients]. During septicaemia different chronological sequences for inflammation markers CRP, IL-6 and neopterin were seen in HM and ICU patients. Septic ICU-patients presented with significantly increased tryptophan degradation and higher neopterin and CRP levels at baseline, while MBL levels were lower in this group compared to subjects with HM. Concentrations of inflammation markers were linked to each other and associated with enhanced tryptophan degradation. Patients who died during follow-up of 28 days tended to have lower baseline MBL concentrations than survivors. Septic patients with HM showed an impaired pro-inflammatory immune response compared to patients with non-haematological diseases. PMID- 22507328 TI - Prostaglandin E2 to diagnose between reversible and irreversible pulpitis. AB - The aim of this work is to verify a correlation between the grade of inflammation and the concentration of PGE2 in human dental pulp. A total of 25 human dental pulps were examined by histological analysis and radioimmunologic dosage of PGE2. The pulps used in this experiment were from healthy and symptomatic teeth; the first ones were collected from teeth destined to be extracted for orthodontic reasons. An increase was observed of PGE2 in reversible pulpitis compared with healthy pulps and with the irreversible pulpitis and the clear decrease of these when NSAIDs are taken. This study demonstrates that PGE2 level is correlated to histological analysis thus allowing to distinguish symptomatic teeth in reversible and irreversible pulpitis. PMID- 22507329 TI - Electromagnetic stimulation to optimize the bone regeneration capacity of gelatin based cryogels. AB - One of the key challenges in reconstructive bone surgery is to provide living constructs that possess the ability to integrate in the surrounding host tissue. Bone graft substitutes and biomaterials have already been widely used to heal critical-size bone defects due to trauma, tumor resection and tissue degeneration. In the present study, gelatin-based cryogels have been seeded with human SAOS-2 osteoblasts followed by the in vitro culture of the cells. In order to overcome the drawbacks associated with static culture systems, including limited diffusion and in homogeneous cell-matrix distribution, the present work describes the application of a bioreactor to physically enhance the cell culture in vitro using an electromagnetic stimulus. The results indicate that the physical stimulation of cell-seeded gelatin-based cryogels upregulates the bone matrix production. We anticipate that the scaffolds developed consisting of human bone proteins and cells could be applied for clinical purposes related to bone repair. PMID- 22507330 TI - Exhaled nitric oxide is related to bronchial eosinophilia and airway hyperresponsiveness to bradykinin in allergen-induced asthma exacerbation. AB - Exhaled nitric oxide (FeNO) has been associated with bronchial eosinophilia and with airway hyperresponsiveness (AHR) in mild stable asthma. We previously demonstrated in a large project that allergen exposure is able to raise FeNO and to worsen AHR to bradykinin. We postulated that allergen-induced increase in FeNO could be related to heightened mucosal eosinophils and AHR to bradykinin in atopic asthma. We performed a new immunohistochemical analysis on bronchial biopsy specimens, previously obtained from the same large project, in order to assess the number of mucosal eosinophils (EG-2+ cell) and other inflammatory cells at 48 hours after diluent and allergen exposures. Inflammatory cell counts were related to FeNO and AHR to BK (expressed as logPD20 bradykinin). In 10 atopic mild asthmatics, we found that the numbers of EG-2+ and CD4+ cells in bronchial submucosa were significantly increased after allergen compared to the respective counts after diluent (p < 0.01). EG-2+ cells in the bronchial submucosa were negatively correlated with logPD20 bradykinin only after allergen challenge (rho = -0.709, p = 0.027). We also found a positive strong correlation between EG-2+ cells and FeNO values in atopic asthmatics at 48 hours after both diluent (rho = 0.746, p = 0.017) and allergen (rho = 0.644, p = 0.049) challenge. FeNO values negatively correlated with responsiveness to bradykinin only after allergen challenge (rho = -0.675, p = 0.039). This study indicates that after allergen exposure heightened level of exhaled NO may reflect augmented airway eosinophilic inflammation and airway responsiveness to bradykinin indicating loss of asthma control. PMID- 22507331 TI - Immunohistochemical profile of neurotrophins and MIB-1 in jugulotympanic paragangliomas: prognostic value and review of the literature. AB - Jugulo-tympanic paragangliomas are the most common primary neoplasm of the middle ear, but little is still known about the histological features differentiating the benign and malignant forms. We investigated, with an immunohistochemical procedure, the expression of neurotrophins with their receptors, in fifteen samples of paragangliomas, and MIB-1 in order to consider them as prognostic factors of malignancy. We observed a general positivity for NGF - TrKA - NT4 - TrKC in the cytoplasm, and a strong expression for BDNF in the extracellular space. MIB-1 was moderate in the nucleus of neoplastic cells, weak in the cytoplasm and totally absent in the extracellular space. The comparison between the clinical recurrences and the rate of cytoplasmatic neurotrophins showed strong immunoreactivity in recurrent patients. It should be emphasized that 2 of the 3 recurrences had a wider distribution of the neutrophins, leading to hypothesize the involvement of these substances in the cell proliferation of glomus tumors. Malignant forms of these rare glomus tumors cannot be clearly identified using MIB-1 as a prognostic marker, although we can affirm that neurotrophins and their receptors can be considered as a panel of potential diagnostic markers to monitor the development of such malignancies. Although the small number of patients does not allow definitive conclusions to be made, our findings showed a possible trend towards significance which requires a more powerful study to evaluate this further. PMID- 22507332 TI - Medical management and sublingual immunotherapy practices in patients with house dust mite-induced respiratory allergy: a retrospective, observational study. AB - The primary objective of this study is to retrospectively describe the treatment regimens (initiation, maintenance, dosage and duration) in sublingual immunotherapy (SLIT) with house dust mite (HDM) extracts in routine practice in France. The secondary objectives include a description of the respiratory allergies that led to treatment and an evaluation of the treatment's efficacy and safety, patient satisfaction and compliance (as assessed by the physician) and patient management practices. Randomly-selected allergy specialists each included ten patients over the age of five with a respiratory allergy and proven sensitization to HDM (positive skin test and/or specific IgE >0.7 kUI) and in whom SLIT had been initiated in 2002 or 2005. The participants were monitored for at least two years. A total of 139 physicians participated in the study and contributed data from 1,289 patients (57% of whom were under the age of 18). More than 70% of the patients suffered from moderate-to-severe allergic rhinitis and 50% also suffered from asthma. More than 60% of the patients were polysensitized. A shift to shorter SLIT protocols was observed over time. Longer protocols tended to be used in children. Compliance was deemed good or very good in 84% of the patients. Treatment was deemed effective or very effective in 82% of the patients. Symptoms of rhinitis and/or asthma improved in 66% and 63% of the patients respectively, with a concomitant reduction in symptomatic medication intake. The majority of the patients were satisfied with their treatment, which was well tolerated. The results of this large, retrospective, observational study confirm the efficacy and tolerability of HDM SLIT in routine French practice in a real-world setting. PMID- 22507333 TI - Recurrent acute rhinosinusitis: a single blind clinical study of N-acetylcysteine vs ambroxol associated to corticosteroid therapy. AB - The aim of rhinosinusitis treatment is to restore sinusal eutrophism and to normalize ventilation and mucociliary transport. Frequently the improvement of sinusal physiological conditions is associated with a reduction of infections and pulmonary symptoms. The treatment of these diseases often requires the combination of medical and surgical strategies. In particular, the aim of the medical therapy is multiple: to treat the infection (with antibiotics), to reduce the mucosal swelling (with corticosteroids) and to improve mucus drainage (with mucolytics or muco-regulators). The use of atomized nasal douche, as a washing of the nasal fossas, is chosen because of its local action minimizing systemic adverse effects. The surgical treatment is secondary to medical failure, and it is focused on clearing the sinusal ostia in the sphenoethmoidal recess and the osteomeatal complex. In case of recurrent sinonasal diseases the importance of the surgical operation is represented by the fact that the medical treatment better reaches the target in the sinusal space. This study is focused on the primary medical treatment of acute recurrent rhinosinusitis. The patients who immediately needed surgical treatment were excluded from the study (because of the presence of an anatomical obstruction of the osteomeatal complex and/or the sphenoethmoidal recess, hence non-susceptible to improvement by medical therapy alone), and these patients were immediately addressed to undergo a CT scan examination in order to be involved in a future surgical programme. The medical treatment for those forms which do not require antibiotics (i.e. when infections are not involved), is based on the use of topical corticosteroids. While there are controversies on the real efficacy of adding mucolytic agents to the steroids, they are commonly prescribed in clinical practice, with the rationale of reducing viscosity and improving clearance of mucus in order to help the restoration of the physiological sinus conditions. The primary aim of the medical treatment is to reduce the number of acute episodes and thus to increase the time between the exacerbations, allowing a good quality of life without necessitating surgical procedure. PMID- 22507334 TI - Neuroprotective and anti-inflammatory activities of atorvastatin in a rat chronic constriction injury model. AB - Atorvastatin is an HMG-CoA reductase inhibitor used to treat hypercholesterolemic conditions associated with hypertension. This study aims to investigate the anti-inflammatory and neuroprotective effects of atorvastatin on peripheral neuropathic pain. Peripheral neuropathic pain was induced by chronic constriction injury (CCI) in Sprague-Dawley rats. Rats were divided into 3 groups including sham-operated, CCI, and atorvastatin-treated. Atorvastatin (10 mg/kg) or phosphate-buffered saline was orally administered for 2 weeks. All animals were assessed by neurobehavioral tests before surgery and at days 3, 7, 14 after surgery. Inflammatory and neuroprotective factors were evaluated by Western blot analysis. eNOS, COX2 and iNOS in the sciatic nerve were also studied using immunohistochemistry. Atorvastatin attenuated CCI-induced nociceptive sensitization and thermal hyperalgesia in a time-dependent manner. Atorvastatin improved CCI-induced neurobehavioral/inflammatory activity by inhibition of TGF beta, pIkB/IkB, NFkB, COX2, iNOS, EP1 and EP4 in the sciatic nerve. Atorvastatin was also found to increase neuroprotection factors pAkt/Akt, eNOS and VEGF. Taken together, these data indicate that atorvastatin could protect the sciatic nerve against CCI-induced neuroinflammation and nociception. PMID- 22507335 TI - A comparative study of loratadine syrup and cyproheptadine HCL solution for treating perennial allergic rhinitis in Taiwanese children aged 2-12 years. AB - We assessed the efficacy of loratadine syrup compared with cyproheptadine HCl solution for treating children aged from 2 to 12 years with perennial allergic rhinitis (PAR) in Taiwan. Sixty children with mite-induced PAR were enrolled and randomly placed into two treatment groups: loratadine syrup or cyproheptadine HCl solution. Treatment efficacy and symptom changes from baseline to post-treatment were evaluated by total symptom scores and visual analogue scales (VAS) during a 2-week period. There were no differences in age, gender, height, or weight between the two groups. After 2 weeks of treatment, there was a significantly greater reduction in symptom scores in the loratadine group than in the cyproheptadine group (p<0.001). Clinical and subjective VAS showed significant differences in percentage changes from baseline between the loratadine and cyproheptadine groups at all time points (all p<0.001, in favor of loratadine). Clinical VAS change at week 1: 95.1 vs 11.3; subjective VAS change at week 1: 88.6 vs 13.6; clinical VAS change at week 2: 125.5 vs 18.3; subjective VAS change at week 2: 101.4 vs 7.1. Thus, loratadine was superior to cyproheptadine for alleviating both nasal and non-nasal symptoms of perennial allergic rhinitis in Taiwanese children aged 2-12 years. PMID- 22507336 TI - AvidinOX™ for tissue targeted delivery of biotinylated cells. AB - AvidinOXTM, a product containing aldehyde groups, generated by ligand-assisted sugar oxidation of avidin by sodium periodate, maintains the capacity to bind biotin with very high affinity and exhibits the property to chemically link cellular and tissue proteins through Schiff's base formation thus residing in tissues for weeks. In recent studies, we have shown that AvidinOX exhibits much higher persistency in the skeletal muscle than native avidin. The aim of the present study is to evaluate whether AvidinOX-biotin interaction might be exploited to target biotinylated cells to an AvidinOX pre-treated muscle. To accomplish this we performed the following experiments: 1) The proliferation and differentiation properties of biotinylated C2C12 myoblasts were tested in vitro upon linkage to AvidinOX; 2) Bone marrow-derived cells (BMDC) were isolated from GFP positive transgenic mice [strain C57 BL/6-tg (UBC-GFP)] and after biotinylation (bBMDC) were intravenously administered to naive and MAVA+ (Mouse anti Avidin Antibody) C57/B6 mice previously injected with AvidinOX in a tibial muscle (TM). Localization efficiency of GFP+ bBMDC was evaluated on serial sections of the AvidinOX- and vehicle-treated (contra lateral limb) TM, 5 days after transplantation. Results show that biotinylated C2C12 cells, once linked to AvidinOX, maintain their proliferation and differentiation capacity, in vitro. Intravenous injection of biotinylated GFP+ bone marrow-derived cells leads to their specific and efficient localization in the AvidinOX-pre-treated, but not contra lateral muscle of both naive and MAVA+ mice. The present data suggest a potential use of AvidinOX to improve tissue targeted delivery of biotinylated cells. PMID- 22507337 TI - Effects of highly active antiretroviral therapy on platelet activating factor metabolism in naive HIV-infected patients: ii) study of the abacavir/lamivudine/efavirenz HAART regimen. AB - Human Immunodeficiency Virus (HIV)-infected patients are at increased risk for cardiovascular diseases partly due to chronic inflammation. Some antiretroviral drugs and Highly Active Anti-Retroviral Therapy (HAART) regimens seem to be related and amplify this increased risk, especially the ones containing abacavir. Platelet-Activating-Factor (PAF) is a potent inflammatory mediator that is implicated in both cardiovascular diseases and HIV-related manifestations. Our objective is to study the in vivo effect of the abacavir/lamivudine/efavirenz first-line HAART regimen on PAF metabolism in HIV-infected patients. The specific activities of PAF basic biosynthetic enzymes in leukocytes and platelets, PAF cholinephosphotransferase (PAF-CPT) and lyso-PAF-acetyltransferase (Lyso-PAF AT), but also those of PAF-basic catabolic enzymes, PAF acetylhydrolase (PAF-AH) in leukocytes and platelets and Lipoprotein-associated-Phospholipase-A2 (LpPLA2) in plasma, were measured in blood samples of 10 asymptomatic naive male HIV infected patients just before and after 1, 3 and 6 months of treatment. CD4 cell counts, viral load and several biochemical markers were also measured in the same blood samples of these patients. The repeated ANOVA measures and the Pearson r criterion were used for studying statistical differences and correlations - partial correlations respectively. Even though viral load was decreased and CD4 cell counts were beneficially increased after treatment with the abacavir/lamivudine/efavirenz regimen, the main enzyme of the remodelling PAF synthesis that is implicated in pro-atherogenic inflammatory procedures, Lyso-PAF AT activity, was increased at 3 months of treatment in both leukocytes and platelets, while the main enzyme of PAF-degradation, PAF-AH, was increased as a response only in leukocytes at the 3rd month. Although the abacavir/lamivudine/efavirenz HAART regimen exhibits very efficient antiretroviral activities, on the other hand it induces an in vivo transient increase in the inflammation-related remodeling PAF-biosynthetic pathway. This finding supports the hypothesis of inflammation-mediated increased cardiovascular risk in HIV-infected patients during the first months of abacavir-containing HAART. PMID- 22507338 TI - Protective activity of the ethanol extract of Cynanchum paniculatum (BUNGE) Kitagawa on treating herpes simplex encephalitis. AB - To date there has been no valid treatment for herpes simplex encephalitis (HSV). This study explores the protective activity of ethanol extract of Cynanchum paniculatum (bunge) kitagawa for treatment of HSV. Cell models and animal models were established and divided into 4 groups: normal group, virus group, cynanchum paniculatum group and Dexamethasone group. Flow cytometry was employed to detect apoptosis of cell model and TUNEL assay was chosen to detect apoptosis of animal tissues. The survival time of the animal models was observed. ELISA was used to measure TNF-alpha expression and the Greiss method to measure Nitric Oxide (NO) expression in the mouse brain. As a result, it was found that extract of Cynanchum paniculatum can improve the survival rate of HSV-infected mice. The extract could prevent apoptosis in the neuron cell model and reduce apoptosis rate in brain tissue after HSV infection. With the extract intervention, TNF alpha and NO levels in brain tissue were significantly decreased in the animal model. In conclusion, the extract of Cynanchum paniculatum can prevent HSV inducing impairment in the cell and animal model of HSE. PMID- 22507339 TI - An IgE immediate reaction to thiocolchicoside. AB - Hypersensitivity reactions due to muscle relaxant drugs may be related either to a nonspecific release of allergic mediators or to allergic reactions induced by the molecules themselves. Rare cases of hypersensitivity reactions have been associated to thiocolchicoside, and no case of IgE-mediated immediate reaction has actually been reported to date. We report the first documented case of immediate anaphylaxis to thiocolchicoside. PMID- 22507341 TI - Transient global amnesia as the first symptom of primary antiphospholipid syndrome: a case report. AB - We describe the case of a 45-year-old woman who had drawn our attention for some recent episodes of transient global amnesia that, upon further examination, resulted from ischemic events caused by multiple arterial thrombosis (bilateral internal carotid occlusion, significant stenosis of the right external carotid, mild stenosis of the right vertebral artery, right anterior cerebral artery occlusion and severe stenosis of the anterior descending coronary artery) due to primary antiphospholipid syndrome. Revascularisation of either carotid was not attempted. A percutaneous intervention in the anterior descending coronary artery stenosis was performed successfully. Due to severe arterial thrombosis, the patient was discharged with only duplex antiplatelet treatment and subcutaneous anticoagulant therapy, since immunotherapy is not indicated in primary APS. The occurrence of transient global amnesia should raise the suspicion of APS. PMID- 22507340 TI - Switch to icatibant in a patient affected by hereditary angioedema with high disease activity: a case report. AB - Icatibant, an antagonist of the bradykinin B2 receptor, was approved for the treatment of acute attacks of hereditary angioedema in the EU in 2008. This paper presents the case of a 65-year-old woman affected by frequent acute attacks of hereditary angioedema who benefitted from a change of therapy to icatibant, following years of treatment with C1-inhibitor. PMID- 22507342 TI - Similar serum levels of IL-6 and its soluble receptors in patients with HCV related arthritis and rheumatoid arthritis: a pilot study. AB - The high serum levels of Interleukin-6 (IL-6) and its soluble receptors (sIL-6r and sgp130), described in the course of Rheumatoid Arthritis (RA), have been linked to the enhanced activity of this cytokine in this disorder. In this study, the serum concentrations of IL-6 and its soluble receptors were determined in a group of patients with HCV-related arthritis (HCVrA), a condition resembling RA in several aspects, and then compared to those found in a sample of subjects affected by RA. Twenty-one patients with HCVrA, 24 patients with RA and 20 healthy subjects (control group) were examined. Different ELISA methods were used for determination of serum concentrations of IL-6, sIL-6r and sgp130. Increased IL-6 serum levels were found in 15 (71 %) of the patients with HCVrA and in 16 (62 %) of those with RA. Eight (38 %) of the patients with HCVrA and 11 (46%) of those with RA denoted high levels of sIL-6r, while sgp130 levels were elevated in 21 (76%) of the patients with HCVrA and in 16 (69%) of those with RA. A significant difference between the median values of sIL-6r and sgp130 levels in the two groups of patients versus controls was found. A mild correlation of these parameters with RF levels was detected in the RA group. Furthermore, in HCVrA patients the serum levels of IL-6, sIL-6r and sgp130 appeared unrelated to HCV viraemia and to levels of transaminases. The enhanced serum levels of IL-6 in HCVra patients indicate an increased synthesis and hyperactivity of this cytokine in HCVrA, and the substantial similarity of the behaviour of IL-6 and its serum receptors in the two groups of patients suggests common mechanisms with RA, in which the function of I L-6 is central. PMID- 22507343 TI - Clinical and histological outcome predictors in renal limited pauci-immune crescentic glomerulonephritis: a single centre experience. AB - Renal-limited vasculitis is a pauci-immune crescentic glomerulonephritis with no signs of systemic involvement, representing one of the most common causes of rapidly progressive glomerulonephritis. The study aims to examine clinical and histological features in twenty-four patients with RLV diagnosed by the Nephrology Department of Sapienza University of Rome, Italy, evaluating the role of these parameters in predicting renal survival. Patients details, clinical and histological features and outcomes were recorded at the time of renal biopsy and over a mean follow-up period of 36+/-6 months. In our study, serum creatinine at presentation was significantly higher in patients who had a poor outcome than in those who survived with independent renal function (6.3+/-2.47 mg/dl vs 2.84+/ 2.01 mg/dl, P= 0.002). The presence of C3c was found in the area of glomerular fibrinoid necrosis and in small arteries and arterioles with fibrinoid necrosis in 17 patients (P= 0.018). In conclusion, serum creatinine at presentation and focal C3c depositions in areas of glomerular and arteriolar fibrinoid necrosis were the best determinants of poor renal outcome, maybe underlining the pathogenic role of alternative pathway activation of complement system but also demonstrating the focal distribution of necrotizing lesions. PMID- 22507344 TI - Hepatitis C virus-related arthritis and rheumatoid arthritis: could they be different aspects of the same disease? AB - The role played by HCV in the genesis of many autoimmune disorders has been reported in several studies. In particular, the onset of arthritis has been described in about 2-3 percent of HCV infection cases. At present, this HCV related arthritis is classified as a reactive arthritis, but a real distinction of this form from classical rheumatoid arthritis is often difficult. In this presentation, the Authors distinguish two arthritic forms observed in HCV-related arthritis patients: one, characterized by asymmetrical oligoarticular involvement, and another, with poly-articular symmetrical involvement. The Authors suggest that the latter can be considered as a form of rheumatoid arthritis, because of the similarity of the main clinical aspects and laboratory findings (rheumatoid factor, anti-cyclic citrullinated peptide antibodies) to those of classical rheumatoid arthritis, which make the two forms indistinguishable. Therefore, HCV could be considered the etiologic agent of a limited number of cases of rheumatoid arthritis. PMID- 22507345 TI - Occurrence of salivary gland tumours in two patients treated with biological agents. AB - We report two cases of salivary gland tumors arising in two psoriatic patients treated with an anti- TNF-alpha agent. A clear causal relationship could not be established, but the exceptional onset of a bilateral Warthin's tumor in one of these patients should be emphasized. PMID- 22507346 TI - Can the association of Ciclosporine A and Methotrexate maintain remission/low disease activity induced by etanercept in early Rheumatoid Arthritis patients? Evaluation by Magnetic Resonance Imaging. AB - The opportunity to induce remission/low disease activity in Rheumatoid Arthritis (RA) patients has been achieved in recent years by the adoption of more sensitive diagnostic methods [Magnetic Resonance Imaging (MRI), ultrasonography] and early aggressive treatments (combination of biologics and synthetic DMARDs). On the other hand, data are still scarce and contrasting about the management of long-term remission. The aim of this preliminary study is to evaluate whether the association of Methotrexate + Ciclosporine A (MTX + CSA) therapy in early RA (eRA) patients is able to maintain remission/low disease activity and avoid structural progression, evaluated by MRI. Etanercept was suspended in patients who reached remission/low disease activity and CSA+MTX therapy was introduced (T0), all patients continued to receive MTX; at this time MRI showed mild/moderate synovitis and erosions in all the patients; 1-year after (T1), a slight reduction in mean synovitis, bone edema and total score was observed, whereas the erosion score was unchanged. The mean DAS44 remained stable from T0 to T1 and 6/7 patients maintained a low disease activity score. No side effects were reported. These results confirm the good clinical efficacy and safety of the combination therapy CSA+MTX in eRA patients and demonstrate a parallel arrest of structural damage evaluated by MRI 1-year after etanercept suspension. PMID- 22507347 TI - Satisfaction with allergy treatments depends on symptom severity but not on allergen specificity in patients with allergic rhinitis. AB - Allergic rhinitis is characterized by troublesome symptoms that may be particularly severe. Most of rhinitics are dissatisfied with drug treatments. The dissatisfaction level depends on symptoms severity, but not on the type of causal allergen. PMID- 22507348 TI - Possible role of oral ibandronate administration in Osteonecrosis of the Jaw: a case report. AB - We describe a case of Osteonecrosis of the Jaw (ONJ) that developed in a 65-year old Caucasian woman with osteopenia and other risk factors who was receiving low doses of oral bisphosphonate therapy (ibandronate, 150 mg monthly). Computed tomography (CT), panoramic radiographs (OPT), 99mTc-Sn-MDP scintigraphy, and magnetic resonance imaging (MRI) were performed to study the diseased area; cytological examination also revealed the presence of suppurative material around the area of exposed bone. A diagnosis of bisphosphonate-related osteonecrosis of the jaw complicated by osteomyelitis was made. The patient was prescribed a drug protocol consisting of metronidazole 250 mg 2 times daily, chlorhexidine mouthwashes 3 times daily and chewing exercises for two months. Ibandronate was stopped and replaced with strontium ranelate. The symptoms improved and the patient is still under close follow-up. Assessment of the benefits versus risks is particularly necessary in patients with several risk factors to ascertain their eligibility for treatment with antiresorptive drugs and when this is not possible to choose alternative medications. PMID- 22507349 TI - Biomechanical evaluation of the relationship between postural control and body mass index. AB - Postural stability is crucial in maintaining body balance during quiet standing, locomotion, and any activities that require a high degree of balance performance, such as participating in sports and dancing. Research has shown that there is a relationship between stability and body mass. The aims of this study were to examine the impact that two variables had on static postural control: body mass index (BMI) and gender. Eighty healthy young adults (age=21.7+/-1.8 yr; height=1.65+/-0.09 m; mass=67.5+/-19.0 kg) participated in the study and the static postural control was assessed using the Biodex Balance System, with a 20 Hz sampling rate in the bipedic stance (BLS) and unipedic stance (ULS) for 30s. Five test evaluations were performed for each balance test. Postural control was found to be negatively correlated with increased adiposity, as the obese BMI group performed significantly poorer than the underweight, normal weight and overweight groups during BLS and ULS tests. The underweight, normal weight and overweight groups exhibited greater anterior-posterior stability in postural control during quiet stance. In addition, female displayed a trend of having a greater postural sway than male young adults, although it was evidenced in only some BMI groups. This study revealed that BMI do have an impact on postural control during both BLS and ULS. As such, BMI and gender-specific effects should be taken into consideration when selecting individuals for different types of sporting activities, especially those that require quiet standing. PMID- 22507350 TI - Shoe midsole hardness, sex and age effects on lower extremity kinematics during running. AB - Previous studies investigating the effects of shoe midsole hardness on running kinematics have often used male subjects from within a narrow age range. It is unknown whether shoe midsole hardness has the same kinematic effect on male and female runners as well as runners from different age categories. As sex and age have an effect on running kinematics, it is important to understand if shoe midsole hardness affects the kinematics of these groups in a similar fashion. However, current literature on the effects of sex and age on running kinematics are also limited to a narrow age range distribution in their study population. Therefore, this study tested the influence of three different midsole hardness conditions, sex and age on the lower extremity kinematics during heel-toe running. A comprehensive analysis approach was used to analyze the lower extremity kinematic gait variables for 93 runners (male and female) aged 16-75 years. Participants ran at 3.33+/-0.15 m/s on a 30 m-long runway with soft, medium and hard midsoles. A principal component analysis combined with a support vector machine showed that running kinematics based on shoe midsole hardness, sex, and age were separable and classifiable. Shoe midsole hardness demonstrated a subject-independent effect on the kinematics of running. Additionally, it was found that age differences affected the more dominant movement components of running compared to differences due to the sex of a runner. PMID- 22507351 TI - Sensitivity of model predictions of muscle function to changes in moment arms and muscle-tendon properties: a Monte-Carlo analysis. AB - Hill-type muscle models are commonly used in musculoskeletal models to estimate muscle forces during human movement. However, the sensitivity of model predictions of muscle function to changes in muscle moment arms and muscle-tendon properties is not well understood. In the present study, a three-dimensional muscle-actuated model of the body was used to evaluate the sensitivity of the function of the major lower limb muscles in accelerating the whole-body center of mass during gait. Monte-Carlo analyses were used to quantify the effects of entire distributions of perturbations in the moment arms and architectural properties of muscles. In most cases, varying the moment arm and architectural properties of a muscle affected the torque generated by that muscle about the joint(s) it spanned as well as the torques generated by adjacent muscles. Muscle function was most sensitive to changes in tendon slack length and least sensitive to changes in muscle moment arm. However, the sensitivity of muscle function to changes in moment arms and architectural properties was highly muscle-specific; muscle function was most sensitive in the cases of gastrocnemius and rectus femoris and insensitive in the cases of hamstrings and the medial sub-region of gluteus maximus. The sensitivity of a muscle's function was influenced by the magnitude of the muscle's force as well as the operating region of the muscle on its force-length curve. These findings have implications for the development of subject-specific models of the human musculoskeletal system. PMID- 22507352 TI - Low local recurrence rates in young Asian patients with phyllodes tumours: less is more. AB - BACKGROUND: Phyllodes tumours are increasingly being discovered incidentally in young patients after excision of a seemingly innocuous breast lump. The clinical course of this group of patients has not been well-described, especially in the Asian population. METHODS: A retrospective review of 44 consecutive patients below 25 years of age undergoing surgery for phyllodes tumours at our institution from 1992 to 2010 was conducted. Clinico-pathological data, local recurrence rates and margin involvement were recorded. RESULTS: The majority of the patients had benign lesions treated with simple enucleation, and there were no local recurrences documented after a mean and median length of follow-up of 47.6 and 29.5 months, respectively. CONCLUSION: We conclude that in young Asian patients who present with benign phyllodes tumours, simple excision, followed by close follow-up is sufficient, regardless of surgical margin status. PMID- 22507353 TI - Elevated CO2 increases Cs uptake and alters microbial communities and biomass in the rhizosphere of Phytolacca americana Linn (pokeweed) and Amaranthus cruentus L. (purple amaranth) grown on soils spiked with various levels of Cs. AB - General concern about increasing global atmospheric CO(2) levels owing to the ongoing fossil fuel combustion and elevated levels of radionuclides in the environment, has led to growing interest in the responses of plants to interactive effects of elevated CO(2) and radionuclides in terms of phytoremediation and food safety. To assess the combined effects of elevated CO(2) and cesium contamination on plant biomass, microbial activities in the rhizosphere soil and Cs uptake, Phytolacca americana Linn (pokeweed, C3 specie) and Amaranthus cruentus L. (purple amaranth, C4 specie) were grown in pots of soils containing five levels of cesium (0, 100, 300, 500 and 1000 mg Cs kg(-1)) under two levels of CO(2) (360 and 860 MUL L(-1), respectively). Shoot and root biomass of P. americana and Amaranthus crentus was generally higher under elevated CO(2) than under ambient CO(2) for all treatments. Both plant species exhibited higher Cs concentration in the shoots and roots under elevated CO(2) than ambient CO(2). For P. americana grown at 0, 100, 300, 500 and 1000 mg Cs kg( 1), the increase magnitude of Cs concentration due to elevated CO(2) was 140, 18, 11, 34 and 15% in the shoots, and 150, 20, 14, 15 and 19% in the roots, respectively. For A. cruentus, the corresponding value was 118, 28, 21, 14 and 17% in the shoots, and 126, 6, 11, 17 and 22% in the roots, respectively. Higher bioaccumulation factors were noted for both species grown under elevated CO(2) than ambient CO(2). The populations of bacteria, actinomycetes and fungi, and the microbial C and N in the rhizosphere soils of both species were higher at elevated CO(2) than at ambient CO(2) with the same concentration of Cs. The results suggested that elevated CO(2) significantly affected plant biomass, Cs uptake, soil C and N concentrations, and community composition of soil microbes associated with P. americana and A. cruentus roots. The knowledge gained from this investigation constitutes an important advancement in promoting utilization of CO(2) fertilization for improvement of phytoextraction of soils contaminated with radionuclides. PMID- 22507354 TI - Radium isotopes in the Polish Outer Carpathian mineral waters of various chemical composition. AB - The paper presents the activity concentrations of radium isotopes ((226)Ra, (228)Ra) and chemical compositions of above 70 mineral water samples collected from several dozens of springs and boreholes localized in the Polish Outer Carpathians. The activity concentrations of both radium isotopes clearly increase with the increase of water TDS, but decrease when the SO(4)(2-) content increases. These concentrations vary in the broad interval from a few to near 1000 mBq/L. The coefficient of the linear correlation between concentrations of these isotopes amounts to 0.85, and the activity ratio (226)Ra/(228)Ra is >1 for chloride-sodium waters, being ~1 for hydrogen-carbonate and <1 for the sulfate ones. PMID- 22507355 TI - Pilot study of a pharmaceutical care intervention in an outpatient lung transplant clinic. AB - BACKGROUND: Lung transplant recipients have complex drug regimens. Study objectives were to assess drug therapy problems (DTPs), pharmacist recommendations, and patient satisfaction with pharmacist services. METHODS: Using a pharmaceutical care assessment process, pharmacists identified DTPs and made therapeutic recommendations. Number of DTPs identified per pharmacist visit was calculated and compared to standard care visits through retrospective chart review. Potential clinical impact of recommendations was evaluated by blinded clinicians. Patient satisfaction was assessed via survey. RESULTS: Fifty-five DTPs were identified in 43 patients over 50 pharmacist visits (1.05 +/- 1.34 DTPs per visit). In these same patients, rate of DTP identification was 0.51 +/- 0.64 DTPs per standard visit in the preceding two-wk period (p = 0.018 vs. pharmacist visit). The most common DTPs identified by the pharmacist were adverse drug effect (27%) and untreated indication (25%). Overall, 62% of pharmacist recommendations were rated very significant or significant. Survey return rate was 58% and satisfaction scores ranged from 3 to 5 out of 5. Review of medications and teaching regarding the use of medications received the most "very satisfied" and "highly important" scores. CONCLUSIONS: Pharmacists can make valuable contributions in a lung transplant clinic setting by identifying DTPs and making recommendations with a positive impact on patient outcomes and satisfaction. PMID- 22507356 TI - High frequency of CD4+ CD25- CD69+ T cells is correlated with a low risk of acute graft-versus-host disease in allotransplants. AB - Regulatory T cells (Tregs) maintain transplantation tolerance and suppress graft versus-host disease (GvHD) in humans. We monitored 17 subjects with acute GvHD to determine whether Treg frequency correlates with acute GvHD. We found the percent of CD4(+) CD25(-) CD69(+) Tregs decreases when acute GvHD develops and increases after acute GvHD is controlled. We next sequentially studied 50 subjects receiving conventional allotransplants. We show a high frequency and increased numbers of CD4(+) CD25(-) CD69(+) Tregs are associated with a reduced risk of acute GvHD. We also show that CD4(+) CD25(-) CD69(+) Treg numbers increase substantially early after allografts and that a low percent of CD4(+) CD25(-) CD69(+) Tregs is associated with an increased risk of acute GvHD. Reconstitution of Tregs early post-transplant is associated with less acute GvHD. These data imply that CD4(+) CD25(-) CD69(+) Tregs are a novel subset of regulatory T cells that may protect against acute GvHD after allotransplants. PMID- 22507357 TI - Hyperlipidemia after allogeneic stem cell transplantation: prevalence, risk factors, and impact on prognosis. AB - Hyperlipidemia is one of the late complications after allogeneic stem cell transplantation (SCT). Although intrahepatic cholestasis caused by chronic graft versus-host disease (GVHD) or calcineurin inhibitors has been considered as possible etiologies, its prevalence, risk factors, and impact on prognosis have not been investigated well. We performed a retrospective analysis of 194 patients who underwent allogeneic SCT between 1995 and 2008 in our institute and survived more than 100 d after SCT. Overall, 83 (42.8%) and 99 (50.8%) patients developed hypercholesterolemia (>=240 mg/dL) and hypertriglyceridemia (>=200 mg/dL), respectively. In multivariate analysis, the development of chronic GVHD (hazard ratio [HR] 2.04, p < 0.05) and steroid use (HR 2.24, p < 0.01) were independently associated with hypercholesterolemia, while administration of calcineurin inhibitors was not. As for the prognostic impact, multivariate analysis showed that the patients with hypercholesterolemia had a tendency of lower rate of relapse (HR: 0.44, p = 0.07). There was no difference in non-relapse mortality or overall survival between the groups. In conclusion, the development of hypercholesterolemia is regarded as one of the symptoms accompanied with chronic GVHD and might indicate a better control of the primary disease. PMID- 22507358 TI - Best tests/clinical findings for screening and diagnosis of patellofemoral pain syndrome: a systematic review. AB - BACKGROUND: Diagnosis of patellofemoral pain syndrome (PFPS) is commonly performed using a myriad of clinical and imaging-based criteria. OBJECTIVES: The objective of this systematic literature review was to summarize the research on accuracy of individual clinical tests/findings for PFPS. DATA SOURCES: MEDLINE, ProQuest Nursing and Allied Health, Cochrane Trials, PEDro, and CINAHL. STUDY SELECTION OR ELIGIBILITY CRITERIA: PRISMA guidelines were followed for this review. To be considered for review, the study required: (1) a description of a clinical test or tests used for diagnosing PFPS (including a test that was combined with another finding such as patient history), (2) a report of the diagnostic accuracy of the measures (e.g., sensitivity and specificity), and (3) an acceptable reference standard for comparison. STUDY APPRAISAL OR SYNTHESIS METHODS: Quality Assessment of Studies of Diagnostic Accuracy (QUADAS) scores were completed on each selected article. Sensitivity, specificity, and negative and positive likelihood ratios (LR-/LR+) were calculated for each diagnostic test described. RESULTS: The systematic search strategy and hand search revealed 704 potential articles, 9 of which met the criteria for this review; analysing a total of 22 PFPS clinical tests. After assessment using the QUADAS score, 1 of the 9 articles was of high quality. The tests with the highest reported diagnostic value were also associated with studies that had the lowest QUADAS values. CONCLUSION: A majority of the studies that have investigated diagnostic accuracy of clinical tests for PFPS demonstrate notable design or reporting biases, and at this stage, determining the best tests for diagnosis of PFPS is still difficult. PMID- 22507359 TI - Exercise for rotator cuff tendinopathy: a systematic review. AB - BACKGROUND: Shoulder pain due to rotator cuff tendinopathy is a common problem. Exercise is one intervention used to address this problem but conclusions from previous reviews have been mixed. OBJECTIVE: To systematically review the effectiveness of exercise, incorporating loaded exercise (against gravity or resistance), for rotator cuff tendinopathy. DATA SOURCES: An electronic search of AMED, CiNAHL, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PEDro and SPORTDiscus was undertaken from their inception to November 2010 and supplemented by hand searching related articles and contact with topic experts. STUDY ELIGIBILITY CRITERIA: Randomised controlled trials evaluating the effectiveness of exercise, incorporating loaded exercise, in participants with rotator cuff tendinopathy. STUDY APPRAISAL AND SYNTHESIS METHODS: Included studies were appraised for risk of bias using the tool developed by the Cochrane Back review Group. Due to heterogeneity of studies, a narrative synthesis was undertaken based upon levels of evidence. RESULTS: Five articles detailing four studies were included, all of which were regarded as presenting a low risk of bias. Overall, the literature was supportive of the use of exercise in terms of pain and functional disability. LIMITATIONS: The results should be regarded with some degree of caution due to limitations associated with the studies including lack of blinding, no intervention control groups and limitations of the outcome measures used. CONCLUSION AND IMPLICATIONS OF KEY FINDINGS: The available literature is supportive of the use of exercise but due to the paucity of research and associated limitations further study is indicated. PMID- 22507360 TI - Integrating physical and psychological approaches to treatment in low back pain: the development and content of the STarT Back trial's 'high-risk' intervention (StarT Back; ISRCTN 37113406). AB - A new randomised controlled trial of intervention in low back pain has been described recently. In this trial, a screening and targeted approach was found to be more effective and cost-effective than current best practice. Nested within the intervention arm were three different interventions targeting patients identified as 'low', 'medium' or 'high' risk dependent on the presence of (mainly) psychosocial risk factors. In this paper, the development and content of the STarT Back trial's 'high-risk' intervention is described. It offers a systematic approach, termed 'psychologically informed practice', to the integration of physical and psychological approaches to treatment for the management of people with low back pain by physiotherapists. The term 'disability' is used to refer to self-reported pain-associated functional limitations, and 'psychological' is used to refer to the beliefs/expectations, emotional responses and behavioural responses associated with low back pain. PMID- 22507361 TI - Evidence-based clinical guidelines for the diagnosis, assessment and physiotherapy management of contracted (frozen) shoulder: quick reference summary. PMID- 22507362 TI - Development and delivery of an exercise intervention for rheumatoid arthritis: strengthening and stretching for rheumatoid arthritis of the hand (SARAH) trial. AB - This paper describes the development and implementation of a hand exercise intervention for rheumatoid arthritis (RA) as part of a large multi-centred randomised controlled trial in a U.K. National Health Service (NHS) setting. Participants are eligible if diagnosed with RA according to American College of Rheumatology criteria, have a history of disease activity, functional deficit or impairment in the hand and/or wrist, and have been on a stable medication regime for at least 3 months. The intervention development was informed by the current evidence base, published guidelines, clinician and expert opinion, and a pilot study. The exercise programme targets known, potentially modifiable physical impairments of the hand with 5 exercise sessions and a home exercise component over a 12 week period. The intervention will be provided to 240 participants along with usual care. A further 240 will receive usual care only as part of the control arm. Specific details of the treatments delivered are described. [ISRCTN no: 89936343]. PMID- 22507363 TI - Evaluation of physiotherapists as primary assessors of patients with musculoskeletal disorders seeking primary health care. AB - OBJECTIVES: To evaluate primary physiotherapist assessment and management of patients with musculoskeletal disorders in primary care, and to compare patient satisfaction with primary assessment by a physiotherapist or a general practitioner (GP). DESIGN: An observational, retrospective cohort study reviewing medical records, and a separate consecutive non-randomised study of patient satisfaction. SETTING: Primary healthcare centre. PARTICIPANTS: Four hundred and thirty-two patients with musculoskeletal disorders, primarily assessed by a physiotherapist. Fifty-one of these patients primarily assessed by a physiotherapist and 42 patients assessed by a GP answered a patient satisfaction questionnaire. INTERVENTIONS: Primary assessment and management of patients with musculoskeletal disorders. MAIN OUTCOME MEASURES: Data from medical records within 3-month after the visit, and patient satisfaction questionnaire. RESULTS: Eighty-five percent (367/432) of patients did not need to see a GP. Serious pathologies were found among the 6% (26/432) of patients who were referred to a GP by a physiotherapist, but no serious pathologies were found among the 9% (39/432) of patients who subsequently returned for a GP appointment for the same disorder. Patients assessed by a physiotherapist were more satisfied with the information received about their disorder and self-care than patients assessed by a GP. Patients also had higher confidence in the ability of physiotherapists to assess their disorder (P<0.002). CONCLUSION: Physiotherapists can be considered primary assessors of patients with musculoskeletal disorders in primary care as few patients needed additional assessment by a GP, patients with confirmed serious pathologies were identified by the physiotherapists, and patients were satisfied with assessment by a physiotherapist. PMID- 22507364 TI - Assessment of the presence/absence of the palmaris longus muscle in different sports, and elite and non-elite sport populations. AB - OBJECTIVES: To investigate whether higher presence of the palmaris longus muscle is associated with sports that require hand grip. DESIGN: Cross-sectional study. PARTICIPANTS: Six hundred and forty-two medical students, members of sports clubs and national athletes. METHODS: Participants were invited to complete a questionnaire that assessed their main sport, elite or non-elite level of participation, and level of activity. The presence of the palmaris longus was assessed visually using a standardised test. MAIN OUTCOME MEASURES: Presence of the palmaris longus, type of hand grip required for the sport and the level of participation. RESULTS: The presence of the palmaris longus was higher in elite athletes (21/22, 96%) than non-elite athletes (66/84, 79%; P=0.066) for sports that require a dominant-handed or two-handed cylindrical grip (18/22, 82% and 19/35, 54%, respectively; P=0.034). For both elite and non-elite athletes, the presence of the palmaris longus was higher in those participating in sustained grip sports (325/387, 84%) compared with sports that do not require a sustained grip (150/197, 76%; P=0.012). CONCLUSIONS: The palmaris longus may provide an advantage in certain types of sport that require hand grip, and for elite athletes participating in sports that require a dominant-handed or two-handed cylindrical hand grip. Orthopaedic specialists considering the use of the palmaris longus for a grafting procedure on an athlete should consider the level of participation and the type of hand grip required in the athlete's sport. PMID- 22507365 TI - Interferential laser therapy in the treatment of shoulder pain and disability from musculoskeletal pathologies: a randomised comparative study. AB - BACKGROUND: Interference is an important feature of the waves. When two or more in phase light waves meet, a new and reinforced wave is generated. Shoulder pain is a common clinical problem and laser is one of the treatments frequently used to relieve it. OBJECTIVE: To test the safety of interferential laser therapy generated by two independent low level lasers and compare its effectiveness with conventional single laser therapy in the reduction of shoulder musculoskeletal pain and associated disability. DESIGN: Randomised and single-blind controlled clinical trial. SETTING: Physiotherapy Unit and Rehabilitation Department of Ramon y Cajal University Hospital (Madrid). PARTICIPANTS: 200 patients with shoulder musculoskeletal pain were randomly assigned in two groups, 100 people each. INTERVENTIONS: Group I, experimental (n=100) received interferential laser, placing two probes opposite each other over the shoulder joint. Group II, control (n=100) received conventional laser therapy, using a single probe along with a second inactive dummy probe. Lasers used were GaAlAs diode (810 nm, 100 mW), in continuous emission. Laser was applied in contact mode through ten sessions, on 5 shoulder points (7 Joules/point) per session. MAIN OUTCOME MEASURES: visual analogue scale (VAS) score and shoulder pain disability index (SPADI), recorded before and after laser treatment. RESULTS: There were no differences between both groups in the reduction of pain, either assessed by VAS scale (median difference=0, 95% CI of the difference = -.6 to .5, p = 0.81) or SPADI index (median difference = .4, 95% CI of the difference = -2.9 to 3.8, p = 0.80), using the Mann-Whitney U-test. Comparison between the scores recorded before and after the treatment, within each group, showed significant differences for VAS during movement (median difference=3, 95% CI of the difference = 2.07 to 4, p < 0.001) and SPADI index (median difference=3.5, 95% CI of the difference = 2.67 to 3.85, Wilcoxon test, p < 0.001), for both groups. CONCLUSIONS: In this study, the application of two low level lasers in order to generate interference inside the irradiated tissue showed to be a safe therapy. Both interferential and conventional laser therapy reduced shoulder pain and disability. Nevertheless, differences between them were not detected. Future research in this field could include applying this technique with other laser parameters or application forms. PMID- 22507366 TI - Does the application of an algorithm for non-invasive ventilation in chronic obstructive pulmonary disease improve the initiation process and patient outcomes? AB - OBJECTIVES: Non-invasive ventilation (NIV) for acute hypercapnic respiratory failure in chronic obstructive pulmonary disease (COPD) has been shown to decrease endotracheal intubation and mortality; however, little guidance exists on NIV initiation. This study aimed to explore patient outcomes and the process of NIV initiation following the introduction of an algorithm. DESIGN: Prospective, modified time-series study. Baseline measures were performed during the control period and repeated in the algorithm phase. SETTING: Acute secondary care teaching hospital, wherever NIV was commenced (accident and emergency, medical assessment unit, thoracic medicine unit). PARTICIPANTS: Thirty-four patients with COPD and acute hypercapnic respiratory failure. INTERVENTIONS: An algorithm was devised for use when initiating NIV, highlighting four aspects of care from the evidence base: synchronisation, tidal volume, oxygenation and comfort. MAIN OUTCOME MEASURES: Arterial pH value, Borg scale rating of breathlessness, and a staff questionnaire on the process of NIV initiation. RESULTS: No significant difference was found in changes in pH or Borg score. However, three of the four aspects of care promoted by the algorithm were reported more frequently in the intervention phase. Increased assessment of tidal volume (5/17 cases in control phase, 95% confidence interval 0.05 to 0.54; 12/17 cases in algorithm phase, 95% confidence interval 0.46 to 0.95) reached statistical significance (P=0.038, Fisher's exact test). CONCLUSIONS: This study presents an algorithm to assist the application of NIV, and has demonstrated changes in practice following its introduction. It is proposed that the algorithm is considered for use within services that initiate NIV. Further work is required to explore the effects of staff education and the promotion of ownership. PMID- 22507367 TI - Three-dimensional kinematic analysis of pelvic and lower extremity differences during trunk rotation in subjects with and without chronic low back pain. AB - OBJECTIVE: To investigate three-dimensional angular changes of the pelvis and lower extremities during trunk axial rotation in subjects with and without chronic low back pain (LBP). DESIGN: Repeated-measures design. PARTICIPANTS: Thirty volunteers participated in the study (15 with LBP, 15 without LBP). The mean age of the subjects was 44 (standard deviation 15.8) years (range 27 to 63 years). MAIN OUTCOME MEASURES: All participants were asked to perform five sets of axial trunk rotation activities with a bar in a standing position. The outcome measures included three-dimensional rotational angles of the pelvis and lower extremities (foot, calf and thigh). RESULTS: The angular change of the pelvis in the sagittal plane differed between subjects with and without LBP (P=0.03). There were no significant differences in angular changes of the lower extremities in the frontal and transverse planes between groups. CONCLUSIONS: The angular change of the pelvis in the sagittal plane differed significantly between groups. Further research is needed to investigate the three-dimensional characteristics of biomechanical and neuromuscular aspects in subjects with LBP. PMID- 22507368 TI - Contemporary undergraduate physiotherapy education in terms of physical activity and exercise prescription: practice tutors' knowledge, attitudes and beliefs. AB - OBJECTIVES: Practice tutors' evaluation to (i) establish current physical activity and exercise promotion and prescription curriculum content and (ii) their knowledge, attitudes and beliefs concerning physical activity and exercise prescription in clinical education, in terms of contemporary and emerging health trends and priorities. DESIGN: A cross sectional survey employing a questionnaire and focus groups. PARTICIPANTS: All practice tutors delivering physiotherapy undergraduate education in four physiotherapy schools in Ireland (n=38) were invited to participate. Thirty participated giving a response rate of 79%. METHODS: Two methods of data collection were employed. Clinical content questionnaires were administered, the results of which informed follow-up focus groups. Focus group transcriptions were analysed using the 'Framework Analysis' method. RESULTS: 66% of practice tutors were unhappy with their own knowledge and felt they required further training in the following areas: strategies for changing physical activity behaviour; exercise promotion and prescription for public health; exercise prescription for lifestyle related disease. Main themes emerging from the focus groups were (i) perceptions of the physiotherapist's role, (ii) perceptions of the practice tutor's role and (iii) facilitators and barriers to change. CONCLUSION: In terms of physical activity and exercise prescription education, practice tutors identified a need for further education to improve their knowledge base. However, their attitudes and beliefs relating to physiotherapists' and educators' role in terms of teaching contemporary and emerging health trends and priorities were mixed. Results of this study provide useful data to inform future physiotherapy curricula development in terms of physical activity and exercise content. PMID- 22507369 TI - Measurement properties of a hand-held inclinometer during straight leg raise neurodynamic testing. AB - OBJECTIVES: The most common lower quarter neurodynamic test is the straight leg raise (SLR) test. Quantification of limb motion during SLR testing should utilize reliable and valid measurement tools that are highly sensitive to change. The purpose of this study was to determine the psychometric properties of a hand-held inclinometer commonly utilized during SLR testing. DESIGN: Cross-sectional measurement, intra-rater reliability and validity study. SETTING: Research laboratory. PARTICIPANTS: Twenty individuals without pain in their low back or extremities and no history of nerve injury participated in the study. MAIN OUTCOME MEASURES: Two repetitions of the SLR were performed in each limb in two ankle positions (plantar flexion and dorsiflexion). A digital inclinometer and digital goniometer were utilized as the comparisons for range of motion measurements. RESULTS: Intra-rater reliability for the hand-held inclinometer during SLR testing was excellent (ICCs, 0.95 to 0.98). The standard error of measurement was between 0.54 degrees and 1.22 degrees and the minimal detectable change was between 1.50 degrees and 3.41 degrees . Construct validity revealed hand-held inclinometer measurements were highly correlated with both the digital inclinometer and digital goniometer measures. The mean difference scores between hand-held inclinometer and digital inclinometer (~1.5 degrees ) and digital goniometer (~10 degrees ) suggest that the hand-held inclinometer better matches the construct measured by the digital inclinometer (limb elevation angle) compared to the digital goniometer (hip flexion angle). CONCLUSIONS: The hand held inclinometer is a valid method for measuring limb elevation angle during the SLR neurodynamic test in a research setting. The hand-held inclinometer has high reliability and low minimal detectable change when used in healthy individuals. PMID- 22507370 TI - Patient-centered research. PMID- 22507371 TI - Two-layer synchronized ternary quantum-dot cellular automata wire crossings. AB - : Quantum-dot cellular automata are an interesting nanoscale computing paradigm. The introduction of the ternary quantum-dot cell enabled ternary computing, and with the recent development of a ternary functionally complete set of elementary logic primitives and the ternary memorizing cell design of complex processing structures is becoming feasible. The specific nature of the ternary quantum-dot cell makes wire crossings one of the most problematic areas of ternary quantum-dot cellular automata circuit design. We hereby present a two layer wire crossing that uses a specific clocking scheme, which ensures the crossed wires have the same effective delay. PMID- 22507372 TI - Outcomes among tuberculosis patients with isoniazid resistance in Georgia, 2007 2009. AB - BACKGROUND: The optimal management strategy for patients with isoniazid (INH) monoresistant forms of tuberculosis (TB) has been widely debated. The current daily 9-month regimen of rifampin, pyrazinamide and ethambutol was established based largely on trials in settings with low TB rates and low rates of drug resistance. OBJECTIVE: To explore the outcomes of patients with INH-monoresistant TB in the country of Georgia, a setting with both high TB rates and drug resistant forms of the disease. METHODS: Retrospective record review of all patients diagnosed with smear-positive pulmonary TB resistant to either INH or INH+SM (streptomycin) in Georgia between 2007 and 2009. RESULTS: Of 8752 patients with pulmonary TB registered in Georgia, 909 were found to have INH or INH+SM resistance. Treatment outcomes were relatively poor in this group, with only 71% treatment success. Outcomes were significantly worse among patients with older age and a history of previous treatment. CONCLUSIONS: INH or INH+SM resistance in pulmonary TB patients in Georgia is common. The low rates of treatment success suggest the need for an improved treatment regimen for patients with resistance to these first-line drugs; this need is particularly pronounced among the subset of patients with a history of previous treatment. PMID- 22507373 TI - Glucocorticoid receptor gene polymorphisms are associated with reduced first phase glucose-stimulated insulin secretion and disposition index in women, but not in men. AB - AIM: Glucocorticoids are efficacious anti-inflammatory agents, but, in susceptible individuals, these drugs may induce glucose intolerance and diabetes by affecting beta-cell function and insulin sensitivity. We assessed whether polymorphisms in the glucocorticoid receptor gene NR3C1 associate with measures of beta-cell function and insulin sensitivity derived from hyperglycaemic clamps in subjects with normal or impaired glucose tolerance. METHODS: A cross-sectional cohort study was conducted in four academic medical centres in the Netherlands and Germany. Four hundred and forty-nine volunteers (188 men; 261 women) were recruited with normal glucose tolerance (n=261) and impaired glucose tolerance (n=188). From 2-h hyperglycaemic clamps, first- and second-phase glucose stimulated insulin secretion, as well as insulin sensitivity index and disposition index, were calculated. All participants were genotyped for the functional NR3C1 polymorphisms N363S (rs6195), BclI (rs41423247), ER22/23EK (rs6189/6190), 9beta A/G (rs6198) and ThtIIII (rs10052957). Associations between these polymorphisms and beta-cell function parameters were assessed. RESULTS: In women, but not in men, the N363S polymorphism was associated with reduced disposition index (P=1.06 10(-4) ). Also only in women, the ER22/23EK polymorphism was associated with reduced first-phase glucose-stimulated insulin secretion (P=0.011) and disposition index (P=0.003). The other single-nucleotide polymorphisms were not associated with beta-cell function. Finally, none of the polymorphisms was related to insulin sensitivity. CONCLUSION: The N363S and ER22/23EK polymorphisms of the NR3C1 gene are negatively associated with parameters of beta-cell function in women, but not in men. PMID- 22507375 TI - Development of a target component extraction method from GC-MS data with an in house program for metabolite profiling. AB - After gas chromatography-mass spectrometry (GC-MS) analysis, data processing, including retention time correction, spectral deconvolution, peak alignment, and normalization prior to statistical analysis, is an important step in metabolomics. Several commercial or free software packages have been introduced for data processing, but most of them are vendor dependent. To design a simple method for Agilent GC/MS data processing, we developed an in-house program, "CompExtractor", using Microsoft Visual Basic. We tailored the macro modules of an Agilent Chemstation and implanted them in the program. To verify the performance of CompExtractor processing, 30 samples from the three species of the genus Papaver were analyzed with Agilent 5973 MSD GC-MS. The results of CompExtractor processing were compared with those of AMDIS-SpectConnect processing by hierarchical cluster analysis (HCA) and principal component analysis (PCA). The two methods showed good classification according to their species in HCA. The PC1+PC2 scores were 54.32-63.62% for AMDIS-SpectConnect and 56.65-85.92% for CompExtractor in PCA. Although the CompExtractor processing method is an Agilent GC-MS-specific application and the target compounds must be selected first, it can extract the target compounds more precisely in the raw data file with batch mode and simultaneously assemble the matrix text file. PMID- 22507376 TI - A high-affinity anti-salbutamol monoclonal antibody: key to a robust lateral-flow immunochromatographic assay. AB - Among the components that make up a lateral-flow immunochromatographic assay (ICA), antibody is the key. In this paper, salbutamol (SAL) as a model analyte was meticulously designed to prepare immunogen and coating antigen in distinctly different ways. Four hybridoma cell lines were prepared and identified. Among them, C9 had highest affinity, best dose-response behavior, lowest limit of detection, and highest specificity and was chosen to be labeled with colloidal gold as the detector reagent and applied on the conjugate pad. Goat anti-mouse antibody and SAL-BSA conjugate were sprayed on a nitrocellulose membrane as test line and control line, respectively. Under the optimized conditions, the ICA strip was constructed based on a binding inhibition format. Color intensity on the test line was visually distinguishable from that of the negative sample within 5 min, with the visual detection limit of 1 ngml(-1) in phosphate-buffered saline. Cross-reactions with other beta-agonists were not found (<1%). The results from ICA were in a good agreement with those obtained by enzyme-linked immunosorbent assay. The developed ICA has potential as a useful on-site screening tool for SAL in swine urine. PMID- 22507374 TI - A second generation framework for the analysis of microsatellites in expressed sequence tags and the development of EST-SSR markers for a conifer, Cryptomeria japonica. AB - BACKGROUND: Microsatellites or simple sequence repeats (SSRs) in expressed sequence tags (ESTs) are useful resources for genome analysis because of their abundance, functionality and polymorphism. The advent of commercial second generation sequencing machines has lead to new strategies for developing EST-SSR markers, necessitating the development of bioinformatic framework that can keep pace with the increasing quality and quantity of sequence data produced. We describe an open scheme for analyzing ESTs and developing EST-SSR markers from reads collected by Sanger sequencing and pyrosequencing of sugi (Cryptomeria japonica). RESULTS: We collected 141,097 sequence reads by Sanger sequencing and 1,333,444 by pyrosequencing. After trimming contaminant and low quality sequences, 118,319 Sanger and 1,201,150 pyrosequencing reads were passed to the MIRA assembler, generating 81,284 contigs that were analysed for SSRs. 4,059 SSRs were found in 3,694 (4.54%) contigs, giving an SSR frequency lower than that in seven other plant species with gene indices (5.4-21.9%). The average GC content of the SSR-containing contigs was 41.55%, compared to 40.23% for all contigs. Tri SSRs were the most common SSRs; the most common motif was AT, which was found in 655 (46.3%) di-SSRs, followed by the AAG motif, found in 342 (25.9%) tri-SSRs. Most (72.8%) tri-SSRs were in coding regions, but 55.6% of the di-SSRs were in non-coding regions; the AT motif was most abundant in 3' untranslated regions. Gene ontology (GO) annotations showed that six GO terms were significantly overrepresented within SSR-containing contigs. Forty-four EST-SSR markers were developed from 192 primer pairs using two pipelines: read2Marker and the newly developed CMiB, which combines several open tools. Markers resulting from both pipelines showed no differences in PCR success rate and polymorphisms, but PCR success and polymorphism were significantly affected by the expected PCR product size and number of SSR repeats, respectively. EST-SSR markers exhibited less polymorphism than genomic SSRs. CONCLUSIONS: We have created a new open pipeline for developing EST-SSR markers and applied it in a comprehensive analysis of EST SSRs and EST-SSR markers in C. japonica. The results will be useful in genomic analyses of conifers and other non-model species. PMID- 22507377 TI - Optimization of a malachite green assay for detection of ATP hydrolysis by solubilized membrane proteins. AB - We studied the activity of the fluorescently labeled membrane transporter MalGFK(2), which transports maltose at the expense of ATP hydrolysis. We used a commercially available malachite green assay (SensoLyte MG phosphate assay kit; Anaspec) to quantify the liberated phosphate upon ATP hydrolysis. However, strong variations in phosphate concentration were measured when using the supplier's handling protocol. We optimized the protocol, taking into account the effects mediated by glycerol, SDS, and fluorescent label on the sample. As a result we obtained highly reproducible phosphate concentration values under conditions optimal for solubilized membrane proteins. PMID- 22507378 TI - Increasing productivity, reducing cost and improving quality in elective surgery in New Zealand: the Waitemata District Health Board joint arthroplasty pilot. AB - BACKGROUND: In 2010, Waitemata District Health Board piloted a new model of care for total hip and knee arthroplasties. The pilot was incentive based and clinically led. The participating surgeons and anaesthetists were responsible for increasing surgical throughput. The pilot aimed to increase productivity, reduce cost and increase quality for patients. AIM: To compare costs and outcomes for elective hip and knee arthroplasties carried out at the pilot site (Waitakere Hospital) compared with the main District Health Board hospital site (North Shore Hospital (NSH)). METHODS: A retrospective matched cohort study of hip and knee replacements discharged between 1 July 2010 and 31 March 2011, comparing costs and outcomes at the pilot site compared with the NSH site. Only non-complex procedures were included, and routinely collected data were used. RESULTS: One hundred and seventy-seven hip replacements (77 NSH, 100 pilot) and 158 knee replacements (88 NSH, 70 pilot) were analysed. Total inpatient event costs were 12% and 17% lower for hip and knee replacements, respectively, at the pilot site compared with NSH. Significant reduction in operation length (39% hip, 36% knee) and length of stay (38% hip, 39% knee) were found in the pilot groups compared with NSH. CONCLUSION: Implementation of an innovative new model in a public hospital setting has produced significant increases in productivity and reduced overall costs. This model could potentially be used in other public healthcare settings for non-complex elective surgery. PMID- 22507379 TI - Ciliate and bacterial communities associated with White Syndrome and Brown Band Disease in reef-building corals. AB - White Syndrome (WS) and Brown Band Disease (BrB) are important causes of reef coral mortality for which causal agents have not been definitively identified. Here we use culture-independent molecular techniques (DGGE and clone libraries) to characterize ciliate and bacterial communities in these diseases. Bacterial (16S rRNA gene) and ciliate (18S rRNA gene) communities were highly similar between the two diseases. Four bacterial and nine ciliate ribotypes were observed in both diseases, but absent in non-diseased specimens. Only one of the bacteria, Arcobacter sp. (JF831360) increased substantially in relative 16S rRNA gene abundance and was consistently represented in all diseased samples. Four of the eleven ciliate morphotypes detected contained coral algal symbionts, indicative of the ingestion of coral tissues. In both WS and BrB, there were two ciliate morphotypes consistently represented in all disease lesion samples. Morph1 (JN626268) was observed to burrow into and underneath the coral tissues at the lesion boundary. Morph2 (JN626269), previously identified in BrB, appears to play a secondary, less invasive role in pathogenesis, but has a higher population density in BrB, giving rise to the visible brown band. The strong similarity in bacterial and ciliate community composition of these diseases suggests that they are actually the same syndrome. PMID- 22507382 TI - Uncertainty in techno-economic estimates of cellulosic ethanol production due to experimental measurement uncertainty. AB - BACKGROUND: Cost-effective production of lignocellulosic biofuels remains a major financial and technical challenge at the industrial scale. A critical tool in biofuels process development is the techno-economic (TE) model, which calculates biofuel production costs using a process model and an economic model. The process model solves mass and energy balances for each unit, and the economic model estimates capital and operating costs from the process model based on economic assumptions. The process model inputs include experimental data on the feedstock composition and intermediate product yields for each unit. These experimental yield data are calculated from primary measurements. Uncertainty in these primary measurements is propagated to the calculated yields, to the process model, and ultimately to the economic model. Thus, outputs of the TE model have a minimum uncertainty associated with the uncertainty in the primary measurements. RESULTS: We calculate the uncertainty in the Minimum Ethanol Selling Price (MESP) estimate for lignocellulosic ethanol production via a biochemical conversion process: dilute sulfuric acid pretreatment of corn stover followed by enzymatic hydrolysis and co-fermentation of the resulting sugars to ethanol. We perform a sensitivity analysis on the TE model and identify the feedstock composition and conversion yields from three unit operations (xylose from pretreatment, glucose from enzymatic hydrolysis, and ethanol from fermentation) as the most important variables. The uncertainty in the pretreatment xylose yield arises from multiple measurements, whereas the glucose and ethanol yields from enzymatic hydrolysis and fermentation, respectively, are dominated by a single measurement: the fraction of insoluble solids (fIS) in the biomass slurries. CONCLUSIONS: We calculate a $0.15/gal uncertainty in MESP from the TE model due to uncertainties in primary measurements. This result sets a lower bound on the error bars of the TE model predictions. This analysis highlights the primary measurements that merit further development to reduce the uncertainty associated with their use in TE models. While we develop and apply this mathematical framework to a specific biorefinery scenario here, this analysis can be readily adapted to other types of biorefining processes and provides a general framework for propagating uncertainty due to analytical measurements through a TE model. PMID- 22507381 TI - Paracrine cytokine interaction between UVB-exposed epidermal keratinocytes and dermal fibroblasts in stimulating expression of skin fibroblast-derived elastase. AB - BACKGROUND: We recently reported that over-expression of skin fibroblast-derived elastase (SFE) plays a pivotal role in the mechanism of UVB-induced skin wrinkling. Since UVB penetrates only modestly to the dermis, we hypothesized that factors secreted by UVB-exposed keratinocytes in the epidermis trigger fibroblasts in the dermis to increase their expression of SFE which then degrades the elastic fibers. OBJECTIVE: In this study, we characterized the paracrine interaction between human keratinocytes (HK) and human fibroblasts (HF) which leads to increased expression of SFE. METHODS AND RESULTS: Medium conditioned by UVB-exposed HK contained increased levels of IL-1alpha, GM-CSF, IL-6, TNFalpha and IL-8. While HF cultured with those conditioned medium slightly down-regulated the gene expression of collagen and elastin, they significantly increased their expression of SFE at the transcriptional, translational and enzymatic levels. Neutralizing antibodies to IL-1alpha or GM-CSF significantly abolished the increased expression of SFE at the translational and/or enzymatic levels in HF cultured with those conditioned medium, while neutralizing antibodies to IL-6, IL 8 or TNFalpha had no such effect. The addition of IL-1alpha or GM-CSF, but not TNFalpha, IL-6 or IL-8, at concentrations ranging from 1 to 10nm, significantly stimulated the enzymatic levels of SFE in HF. CONCLUSIONS: The sum of these findings suggests that IL-1alpha and GM-CSF are intrinsic cytokines secreted by UVB-exposed HK that stimulate expression of SFE by HF, leading to UVB-induced wrinkle formation. PMID- 22507380 TI - D-dopachrome tautomerase (D-DT or MIF-2): doubling the MIF cytokine family. AB - D-dopachrome tautomerase (D-DT) is a newly described cytokine and a member of the macrophage migration inhibitory factor (MIF) protein superfamily. MIF is a broadly expressed pro-inflammatory cytokine that regulates both the innate and the adaptive immune response. MIF activates the MAP kinase cascade, modulates cell migration, and counter-acts the immunosuppressive effects of glucocorticoids. For many cell types, MIF also acts as an important survival or anti-apoptotic factor. Circulating MIF levels are elevated in the serum in different infectious and autoimmune diseases, and neutralization of the MIF protein via antibodies or small molecule antagonists improves the outcome in numerous animal models of human disease. Recently, a detailed investigation of the biological role of the closely homologous protein D-DT, which is encoded by a gene adjacent to MIF, revealed an overlapping functional spectrum with MIF. The D DT protein also is present in most tissues and circulates in serum at similar concentrations as MIF. D-DT binds the MIF cell surface receptor complex, CD74/CD44, with high affinity and induces similar cell signaling and effector functions. Furthermore, an analysis of the signaling properties of the two proteins showed that they work cooperatively, and that neutralization of D-DT in vivo significantly decreases inflammation. In this review, we highlight the similarities and differences between MIF and D-DT, which we propose to designate "MIF-2", and discuss the implication of D-DT/MIF-2 expression for MIF-based therapies. PMID- 22507383 TI - Parents and adolescents growing up in the digital age: latent growth curve analysis of proactive media monitoring. AB - The current study examined how parents' use of restrictive and active monitoring and deference changed over three years, and examined both adolescent and parent characteristics as predictors of initial levels of media monitoring, as well as change in media monitoring. Participants included 276 mother-child dyads (M age of child = 12.08, SD = .63, 50% female) taken from Time 2 of the Flourishing Families Project, 96% of whom had complete data for Time 4 (N = 266). Active monitoring was the most common approach at the first and second time points, while active monitoring and deference were equally common by the final time point. Latent growth curve analysis revealed that restrictive and active monitoring decreased over time, while deference increased. In addition, both adolescent and parent characteristics were predictive of initial levels of all three types of monitoring, and of change in restrictive monitoring. Discussion focuses on developmental implications of these findings. PMID- 22507384 TI - Cap binding-independent recruitment of eIF4E to cytoplasmic foci. AB - Eukaryotic translation initiation factor 4E (eIF4E) is required for cap-dependent initiation. In addition, eIF4E occurs in cytoplasmic foci such as processing bodies (PB) and stress granules (SG). We examined the role of key functional amino acid residues of eIF4E in the recruitment of this protein to cytoplasmic foci. We demonstrate that tryptophan residues required for mRNA cap recognition are not required for the recruitment of eIF4E to SG or PB. We show that a tryptophan residue required for protein-protein interactions is essential for the accumulation of eIF4E in granules. Moreover, we show, by the analysis of two Drosophila eIF4E isoforms, that the tryptophan residue is the common feature for eIF4E for the transfer of active mRNA from polysomes to other ribonucleoprotein particles in the cytoplasm. This residue resides in a putative interaction domain different than the eIF4E-BP domain. We conclude that protein-protein interactions rather than interactions with the mRNA are essential for the recruitment of eIF4E and for a putative nucleation function. PMID- 22507385 TI - The etiology-filling pattern-pulmonary artery pressure score: a simple tool for risk stratification of patients with systolic heart failure. AB - Heart failure (HF) is a leading cause of morbidity and mortality. The detection of patients at high risk for death is a major challenge in HF management. The authors compared the prognostic value of 23 clinical Doppler echocardiography and cardiopulmonary exercise indexes in a stable, moderately symptomatic, systolic HF outpatient population receiving optimal medical therapy. The end point was the incidence of overall mortality. Between January 2002 and December 2008, a total of 146 patients with left ventricular (LV) ejection fraction 0.31+/-0.8 and New York Heart Association functional class II or III were enrolled. The prognostic power of single variables was assessed using chi-square test for categoric variables and t test for continuous variables. Variables associated with the prespecified end point were included as predictors in a binary logistic regression multivariate model. At multivariate analysis, "restrictive" LV filling pattern (P=.004), ischemic etiology (P=.022), pulmonary artery systolic pressure (PASP) >=50 mm Hg (P=.027), and peak oxygen uptake (VO(2) ) <15.9 mL/kg/min (P=.046) resulted independent predictors of the outcome. A simple risk score was then obtained using these significant independent variables, excluding peak VO(2) because of only borderline significance. Patients with ischemic etiology, restrictive LV filling pattern, and PASP >=50 mm Hg have a very high risk of death (odds ratio, 33.77; 95% confidence interval, 5.74-198.8; P<.001, compared with patients with no risk factors). In this high-risk group, evaluation of peak VO(2) could be superfluous. A very simple clinical echocardiographic model based on etiology-LV filling and pulmonary pressure is a powerful tool for risk stratification of systolic HF in ambulatory patients. PMID- 22507386 TI - Effect of Bifidobacterium administration on very-low-birthweight infants. AB - BACKGROUND: The aim of this study was to evaluate the efficacy and safety of early administration of Bifidobacterium bifidum OLB6378 (B. bifidum) on accelerating enteral feeding and bacterial colonization in very-low-birthweight (VLBW) infants. METHODS: We conducted a single-center prospective pilot study. Thirty-six VLBW infants were randomly divided into two groups: group E, wherein B. bifidum was supplemented within 48 h of birth, and group L, wherein it was supplemented more than 48 h after birth. RESULTS: Group E and group L reached a total feeding volume of 100 mL/(kg/day) after 10 [7-13] days and 11 [10-15] days, respectively (median [quartile]). The daily bodyweight gain in group E was significantly higher (21.4 +/- 3.2 g/day vs 18.3 +/- 4.0 g/day, P < 0.02; 11.1 +/ 1.5 g/kg/day vs 10.4 +/- 1.2 g/kg/day, P < 0.04). No significant differences were found in the fecal Bifidobacterium level between the groups quantitated with a real-time polymerase chain reaction assay at 1 and 4 weeks of age. However, the highest colonization rate of Bifidobacterium was observed when the supplementation started between 24 and 48 h after birth. The incidence of morbidities between the groups was similar. CONCLUSION: The early administration of B. bifidum to VLBW infants seems effective in promoting growth during the stay in the neonatal intensive care unit without increasing the incidence of morbidity. Furthermore, the preferable timing of starting the probiotic supplementation for VLBW infants is at latest less than 48 h after birth. PMID- 22507387 TI - Kujigamberol, a new dinorlabdane diterpenoid isolated from 85million years old Kuji amber using a biotechnological assay. AB - A new compound, 15,20-dinor-5,7,9-labdatriene-18-ol (1), named kujigamberol, was isolated from amber, fossilized tree resin from the Kuji area in Japan, has been dated as being 85 million years old (late Cretaceous). Kujigamberol was identified using the hypersensitive mutant yeast (zds1? erg3? pdr1? pdr3?) with respect to Ca(2+)-signal transduction. The structure was elucidated on the basis of spectroscopic analysis including 1D NMR, 2D NMR and HR-EI-MS. It was different from known diterpenoids with a similar activity isolated from Baltic amber (agathic acid 15-monomethyl ester (2), dehydroabietic acid (3) and pimaric acid (4)). Kujigamberol showed glycogen synthase kinase-3beta (GSK-3beta) inhibition activity involving the growth restored activity against the mutant yeast and was cytotoxic to HL60 cells (IC(50)=19.6 MUM). PMID- 22507388 TI - Field assessment of a snap bean ozone bioindicator system under elevated ozone and carbon dioxide in a free air system. AB - Ozone-sensitive (S156) and -tolerant (R123 and R331) genotypes of snap bean (Phaseolus vulgaris L.) were tested as a plant bioindicator system for detecting O(3) effects at current and projected future levels of tropospheric O(3) and atmospheric CO(2) under field conditions. Plants were treated with ambient air, 1.4* ambient O(3) and 550 ppm CO(2) separately and in combination using Free Air Concentration Enrichment technology. Under ambient O(3) concentrations pod yields were not significantly different among genotypes. Elevated O(3) reduced pod yield for S156 (63%) but did not significantly affect yields for R123 and R331. Elevated CO(2) at 550 ppm alone did not have a significant impact on yield for any genotype. Amelioration of the O(3) effect occurred in the O(3) + CO(2) treatment. Ratios of sensitive to tolerant genotype pod yields were identified as a useful measurement for assessing O(3) impacts with potential applications in diverse settings including agricultural fields. PMID- 22507390 TI - Mobile software applications for hand surgeons. PMID- 22507391 TI - Electrothermal collagen shrinkage. PMID- 22507392 TI - Glomus tumor of digital nerve: case report. AB - Glomus tumors consist of modified perivascular, smooth muscle involved in thermoregulatory activity of digital blood flow. Digits, especially in the subungual region, are often affected. These tumors only rarely arise in peripheral nerves; digital nerve involvement is exceptional. We describe a glomus tumor occurring in the digital nerve at the level of the distal phalanx. PMID- 22507393 TI - Venous thromboembolism and cancer. AB - BACKGROUND: Venous thromboembolism (VTE) remains one of the most important causes of mortality and morbidity in the hospitalized patient. This is particularly evident in patients with cancer who are exposed to a four- to sixfold increased risk of VTE compared with those patients without cancer. METHODS: A review of the current literature was undertaken on prophylaxis and management of VTE in patients with cancer. RESULTS: Primary VTE prophylaxis is recognized to be the single most effective strategy that improves patient safety. Many clinical trials have demonstrated the benefit of primary prophylaxis for patients with cancer and evidence-based, best practice guidelines for specific subgroups of patients with cancer are well accepted by most clinicians. Despite this, many patients at high risk for VTE either receive no VTE prophylaxis or are exposed to VTE complications due to sub-optimal prophylaxis. Implementation of best practice guidelines still falls far short of clinical acceptable levels for VTE prophylaxis and management. CONCLUSION: VTE prevention in patients with cancer results in reduced morbidity and mortality, outcomes that are unquestionably attainable. This review of the current evidence supporting VTE prophylaxis in patients with cancer will hopefully act as a stimulus to provide patients with cancer access to the best, evidence-based, thromboprophylactic management available. PMID- 22507394 TI - Increased rates of adverse outcomes for gestational diabetes and pre-pregnancy diabetes in on-reserve First Nations Women in Ontario, Canada. AB - AIMS: To compare the prevalence of diabetes in pregnancy, pregnancy care and adverse pregnancy outcomes in on-reserve First Nations women vs. non-First Nations women in Ontario, Canada. METHODS: A retrospective population-based cohort study was performed. All 487368 live singleton hospital deliveries between 1 April 2002 and 31 March 2010 were identified. Outcomes were defined by linking mothers and infants to provincial healthcare administrative databases. RESULTS: Diabetes in pregnancy was more prevalent in First Nations women (10.3 vs. 6.0%). They received less pregnancy care and had higher rates of adverse outcomes than non-First Nations women with diabetes. CONCLUSIONS: First Nations women are at a higher risk of diabetes in pregnancy and adverse outcomes. This highlights the need for increased care for pregnant First Nations women. PMID- 22507396 TI - Ten-yr renal allograft survival of patients with antiphospholipid antibody syndrome. AB - BACKGROUND: Long-term allograft survival of antiphospholipid antibody syndrome (APAS) patients as well as patients who have antiphospholipid antibodies but no thrombotic complications remains largely unknown. This study evaluates long-term allograft survival of APA as well as patients with APAS. METHODS: During the study period from January 1, 1992 through May 31, 2009, 1625 patients with ESRD awaiting renal transplants were screened for APAS. Ninety-four (5.8%) of these patients had circulating levels of anticardiolipin antibodies (ACA) and 39 of these patients had documented evidence of clotting disorders and were diagnosed with APAS. Twenty-one patients with APAS received transplants on either low molecular weight (LMW) heparin or Coumadin as anticoagulation therapy. Of 94 patients with only ACA, 46 received renal transplants. Of the remaining 1492 patients, 1285 patients with no evidence of either ACA or APAS received renal transplants. RESULTS: Ten-yr allograft survival of patients with APAS treated with Coumadin was similar to those treated with LMW heparin (18% vs. 20%, NS). However, those allograft survivals were significantly lower than those patients positive for ACA (28%) alone (ACA vs. LMW heparin or Coumadin p=0.0001). CONCLUSION: Despite anticoagulation therapies, patients with APAS have lower long term graft survival than those patients who have circulating ACA but no APAS. PMID- 22507395 TI - Detailed analysis of Helicobacter pylori Fur-regulated promoters reveals a Fur box core sequence and novel Fur-regulated genes. AB - In Helicobacter pylori, iron balance is controlled by the Ferric uptake regulator (Fur), an iron-sensing repressor protein that typically regulates expression of genes implicated in iron transport and storage. Herein, we carried out extensive analysis of Fur-regulated promoters and identified a 7-1-7 motif with dyad symmetry (5'-TAATAATnATTATTA-3'), which functions as the Fur box core sequence of H. pylori. Addition of this sequence to the promoter region of a typically non Fur regulated gene was sufficient to impose Fur-dependent regulation in vivo. Moreover, mutation of this sequence within Fur-controlled promoters negated regulation. Analysis of the H. pylori chromosome for the occurrence of the Fur box established the existence of well-conserved Fur boxes in the promoters of numerous known Fur-regulated genes, and revealed novel putative Fur targets. Transcriptional analysis of the new candidate genes demonstrated Fur-dependent repression of HPG27_51, HPG27_52, HPG27_199, HPG27_445, HPG27_825 and HPG27_1063, as well as Fur-mediated activation of the cytotoxin associated gene A, cagA (HPG27_507). Furthermore, electrophoretic mobility shift assays confirmed specific binding of Fur to the promoters of each of these genes. Future experiments will determine whether loss of Fur regulation of any of these particular genes contributes to the defects in colonization exhibited by the H. pylori fur mutant. PMID- 22507398 TI - Carbon nanotube counter electrode for high-efficient fibrous dye-sensitized solar cells. AB - High-efficient fibrous dye-sensitized solar cell with carbon nanotube (CNT) thin films as counter electrodes has been reported. The CNT films were fabricated by coating CNT paste or spraying CNT suspension solution on Ti wires. A fluorine tin oxide-coated CNT underlayer was used to improve the adherence of the CNT layer on Ti substrate for sprayed samples. The charge transfer catalytic behavior of fibrous CNT/Ti counter electrodes to the iodide/triiodide redox pair was carefully studied by electrochemical impedance and current-voltage measurement. The catalytic activity can be enhanced by increasing the amount of CNT loading on substrate. Both the efficiencies of fibrous dye-sensitized solar cells using paste coated and sprayed CNT films as counter electrodes are comparative to that using Pt wires, indicating the feasibility of CNT/Ti wires as fibrous counter electrode for superseding Pt wires. PMID- 22507397 TI - Low temperature condition prevents hypoxia-induced islet cell damage and HMGB1 release in a mouse model. AB - One of the major issues in clinical islet transplantation is the poor efficacy of islet isolation. During pancreas preservation and islet isolation, islets suffer from hypoxia as islets are highly sensitive to hypoxic conditions.Cold preservation has been applied to minimize hypoxia-induced cell damage during organ preservation.However, the studies related to hypoxia-induced islet cell damage during islet isolation are limited. Recently,we demonstrated that mouse islets contain high levels of high-mobility group box 1 protein (HMGB1), and during proinflammatory cytokine-induced damage, islets release HMGB1 outside the cell. The released HMGB1 is involved in the initial events of early islet loss. In the present study, we hypothesize that low temperature conditions could prevent both hypoxia induced islet cell damage and HMGB1 release from islets in a mouse model. Isolated mouse islets underwent normoxic condition (95% air and 5% CO(2)) at 37 degrees C or hypoxic conditions (1% O(2), 5% CO(2), and 94% N(2)) at 37 degrees C (hypoxia-37 degrees C islets), 22 degrees C (hypoxia-22 degrees C islets), or 4 degrees C (hypoxia-4 degrees C islets) for 12 h. In vitro and in vivo viability and functionality tests were performed. HMGB1, IL-6, G-CSF, KC, RANTES, MCP-1, and MIP-1alpha levels in the medium were measured. Low temperature conditions substantially reduced hypoxia-induced necrosis (p < 0.05) and apoptosis (p < 0.05). In addition, low temperature islet culture significantly increased the insulin secretion from islets by high glucose stimulation (p < 0.05). All of the recipient mice reversed diabetes after receiving the hypoxia-4 degrees C islets but not after receipt of hypoxia-37 degrees C or 22 degrees C islets. The amounts of released HMGB1, IL-6, G-CSF, KC, RANTES, MCP-1, and MIP 1alpha were significantly reduced in the hypoxia-4 degrees C islets compared to those of the hypoxia-37 degrees C islets (p < 0.05). In conclusion, low temperature conditions could prevent hypoxia-induced islet cell damage, inflammatory reactions in islets, and HMGB1 release and expression. Low temperature conditions should improve the efficacy of isolated islets. PMID- 22507399 TI - A conserved domain in the N-terminus is important for LEAFY dimerization and function in Arabidopsis thaliana. AB - The floral meristem identity gene LEAFY (LFY) of Arabidopsis thaliana is essential for the formation of fertile flowers and has roles in the control of several aspects of floral development, which include phyllotaxy and organ number and identity. This gene encodes a land plant-specific transcription factor and regulates expression of a number of genes that include other floral meristem identity genes and floral homeotic genes. Although the LFY DNA-binding domain has a structure that resembles that of helix-turn-helix proteins, LFY and its orthologs represent a novel family of transcription factors that are characterized by a conserved N-terminus domain of unknown function and a C terminus DNA-binding domain. Many transcription factors act as dimers. These dimers are essential for the biological activity of the proteins. We demonstrate that LFY forms homodimers or oligomers in solution. This association is mediated through the N-terminus conserved region of the LFY protein. Although mutant LFY proteins that cannot dimerize in solution can bind DNA, the binding is weaker than that of wild type LFY protein. LFY-LFY interactions mediated by the N terminus domain are essential for the biological activity of this protein, as mutations that abolish the ability to self-associate cannot complement an lfy null allele. Our data indicate: (i) that LFY, and probably its orthologs in other plants, must act in complexes that contain at least two LFY molecules; and (ii) that the N-terminus is essential for stabilization of LFY complexes. This situation is integral to the ability of LFY to regulate gene expression. PMID- 22507400 TI - Analysis of plant LTR-retrotransposons at the fine-scale family level reveals individual molecular patterns. AB - BACKGROUND: Sugarcane is an important crop worldwide for sugar production and increasingly, as a renewable energy source. Modern cultivars have polyploid, large complex genomes, with highly unequal contributions from ancestral genomes. Long Terminal Repeat retrotransposons (LTR-RTs) are the single largest components of most plant genomes and can substantially impact the genome in many ways. It is therefore crucial to understand their contribution to the genome and transcriptome, however a detailed study of LTR-RTs in sugarcane has not been previously carried out. RESULTS: Sixty complete LTR-RT elements were classified into 35 families within four Copia and three Gypsy lineages. Structurally, within lineages elements were similar, between lineages there were large size differences. FISH analysis resulted in the expected pattern of Gypsy/heterochromatin, Copia/euchromatin, but in two lineages there was localized clustering on some chromosomes. Analysis of related ESTs and RT-PCR showed transcriptional variation between tissues and families. Four distinct patterns were observed in sRNA mapping, the most unusual of which was that of Ale1, with very large numbers of 24nt sRNAs in the coding region. The results presented support the conclusion that distinct small RNA-regulated pathways in sugarcane target the lineages of LTR-RT elements. CONCLUSIONS: Individual LTR-RT sugarcane families have distinct structures, and transcriptional and regulatory signatures. Our results indicate that in sugarcane individual LTR-RT families have distinct behaviors and can potentially impact the genome in diverse ways. For instance, these transposable elements may affect nearby genes by generating a diverse set of small RNA's that trigger gene silencing mechanisms. There is also some evidence that ancestral genomes contribute significantly different element numbers from particular LTR-RT lineages to the modern sugarcane cultivar genome. PMID- 22507401 TI - Promoting immobilization and catalytic activity of horseradish peroxidase on mesoporous silica through template micelles. AB - New concept on the promotion of immobilization and catalytic activity of enzyme on mesoporous silica through template micelles is proposed and realized in this paper. Proper P123 templates are controllable retained in the as-synthesized SBA 15, not only to anchor the horseradish peroxidase (HRP) guest, but also to establish the crowding-like microenvironment around the enzyme. The influence of retaining templates on the pore structure of SBA-15, immobilization, and catalytic activity of HRP is studied, and the possible process of template removal is proposed. Ethanol refluxing of 6 h is conformable to prepare the optimal mesoporous support characterized with the retained templates of about 8%. With the assistance of retained templates in SBA-15, up to 49 mg g(-1) of HRP can be immobilized, 100% more than that on calcined SBA-15. Furthermore, the thermal stability, the resistance of pH variation and denaturing agent urea, and the recycle usage of HRP immobilized are obviously elevated, paving a novel and low cost route to develop enzyme catalysts. PMID- 22507403 TI - Monash medical student's foray into surgical research. PMID- 22507404 TI - How can we improve research opportunities for Australian junior doctors? PMID- 22507405 TI - Adolescent bariatric surgery: ANZ guidance and recommendations. PMID- 22507406 TI - Surgical ethics, law and mandatory reporting. PMID- 22507409 TI - Pro patria et spes gentis: military medicine, paediatric surgery and those who care for children. AB - Children and military medicine have many links. On humanitarian and disaster deployments, the surgery of war has increasingly seen children as the focus of clinical salvage. When Romans spoke of children, they used the phrase 'spes gentis'-'the hope of the race'. In modern times, there developed a synergy, in the context of defensive war, that its prosecution depended not only on the defence of territory but also on its hopes for continuation of people and culture, into the future. In the 19th century, in Australia, several regiments had the motto 'Pro Aris et Focis'-'For the Defence of Hearth and Home'. Hearth implies the family and that implies children. From the point of view of an attending military clinician, the centrum of all medical care is the patient himself, and that centrality is reflected equally in the helplessness of a bomb blast or gunshot victim as it is in the vulnerability of a sick or injured infant or child. The life and service of Major General Rupert Downes (1885-1945), whom the Downes Memorial Lecture commemorates, reflected this nexus. His career was that of a national leader in military medicine and that of paediatric surgery. The 2011 Rupert Downes Lecture explores and documents the extraordinary corpus of service of Australian paediatric surgeons and their contributions to military medicine from the 19th to the 21st centuries. PMID- 22507410 TI - Laparoscopic cholecystectomy: Australian beginnings. AB - Chance meetings in the USA and in France lead to the realization of the potential for cholecystectomy to be performed laparoscopically. Outlined are the steps taken to learn the technique and perform the first such operation in Australia (with unusual circumstances), immediately followed by the introduction of audit and training courses. Historical narrative. PMID- 22507411 TI - Cardiac surgery in the Pacific Islands. AB - BACKGROUND: Rheumatic heart disease constitutes a significant disease burden in under-resourced communities. Recognition of the devastating impact of rheumatic heart disease has resulted in volunteer cardiac teams from Australasia providing surgical services to regions of need. The primary objective of this study was to compare New Zealand hospitals' volunteer cardiac surgical operative results in Samoa and Fiji with the accepted surgical mortality and morbidity rates for Australasia. METHODS: A retrospective review from seven volunteer cardiac surgical trips to Samoa and Fiji from 2003 to 2009 was conducted. Patient data were retrospectively and prospectively collected. Preoperative morbidity and mortality risk were calculated using the European System for Cardiac Operative Risk Evaluation (euroSCORE). Audit data were collated in line with the Australasian Society of Cardiac and Thoracic Surgeons guidelines. RESULTS: One hundred and three operations were performed over 6 years. EuroSCORE predicted an operative mortality of 3.32%. In-hospital mortality was 0.97% and post-discharge mortality was 2.91%, resulting in a 30-day mortality of 3.88%. CONCLUSION: This study demonstrated that performing cardiac surgery in Fiji and Samoa is viable and safe. However, the mortality was slightly higher than predicted by euroSCORE. Difficulties exist in predicting mortality rates in patients with rheumatic heart disease from Pacific Island nations as known risk scoring models fail to be disease, ethnically or culturally inclusive. Audit processes and risk model development and assessment are an essential part of this complex surgical charity work and will result in improved patient selection and outcomes. PMID- 22507412 TI - Incidence of osteoradionecrosis of the temporal bone. AB - BACKGROUND: Osteoradionecrosis of the temporal bone is a serious, late complication of radiotherapy to the temporal bone region. The aim of this study was to determine the incidence, risk and protective factors relating to the development of osteoradionecrosis of the temporal bone. METHODS: This is a retrospective review of prospectively collected data. A single surgeon collated a database over a 10-year period regarding patients undergoing surgery and subsequent radiotherapy for head and neck malignancies. This was reviewed, and information pertaining to demographics, nature of disease, radiation treatment regime and complications including osteoradionecrosis was extracted. Statistical analysis was then completed independently. RESULTS: A total of seven patients from the cohort of 82 developed osteoradionecrosis of the temporal bone within the period of the data collection. This represents an incidence of 8.5% (95% confidence interval = 3.6-13.4%). All who developed osteoradionecrosis had a metastatic parotid squamous cell carcinoma treated operatively with subsequent radiotherapy. There were no statistically significant risks or prognostic factors identified. Mean duration of follow-up was 32 months. CONCLUSION: The incidence of osteoradionecrosis of the temporal bone was 8.5% (95% confidence interval = 3.6-13.4%). Osteoradionecrosis of the temporal bone can present in excess of 10 years after treatment completion. This result may actually under -represent the true incidence of the complication. It has significant morbidity associated with its development and, occasionally, mortality. Those people undergoing radiotherapy to the parotid region may be at higher risk of osteoradionecrosis. A new classification system for osteoradionecrosis of the temporal bone has been proposed. PMID- 22507413 TI - Fresh frozen cadavers in surgical teaching: a gelatine arterial infusion technique. AB - BACKGROUND: Fresh frozen human cadavers have been used at the Clinical Training and Evaluation Centre, The University of Western Australia, Perth, WA for years and are an excellent model for surgical dissection thanks to their representative tissue quality. Differentiation between artery and vein can be difficult as both collapse post mortem. A historical technique was therefore refined to increase arterial rigidity using gelatine prior to freezing. METHODS: Two fresh human cadavers were selected after ethical approval. Gelatine was infused into the carotid artery in one, and into the common femoral artery in the second at a more dilute concentration. In both cases, infusion continued until the rate slowed spontaneously indicating filling prior to setting. The cadavers were frozen according to our standard policy and thawed for a teaching course. RESULTS: These were observational. Examination by palpation and dissection after freezing and subsequent thawing revealed arterial turgor to have developed at the popliteal and brachial levels in the first cadaver, and to the distal vessels in the second. Arterial/venous discrimination was therefore enhanced and confirmed by participant feedback on subsequent courses. CONCLUSION: The fresh frozen cadaver is already a superior model for teaching thanks to its near life-like representation of tissue quality and handling. A successful technique for infusion of gelatine into the arterial tree of fresh human cadavers prior to freezing has been refined resulting in enhancement of arterial/venous discrimination during anatomical, interventional and surgical teaching, further optimizing its use in teaching and this now our standard means of preparation. PMID- 22507414 TI - Quantitative lymph node evaluation as an independent marker of long-term prognosis in stage III rectal cancer. AB - BACKGROUND: The prognostic significance of lymph node evaluation is not well described for rectal cancer due to a lack of reproducibility in nodal counts and variable use of adjuvant and neoadjuvant therapy. The aim of this study was to examine the role of quantitative lymph node evaluation as an independent marker of prognosis in stage III rectal cancer. METHODS: New Zealand Cancer Registry data were retrieved for consecutive patients with rectal cancer from January 1995 to July 2003. Cases with node-negative tumours, distant metastases, death within 30 days of surgery and incomplete data fields were excluded. Three nodal stratification systems were investigated - Total Number of Nodes examined (TNN), Absolute number of Positive Nodes (APN) and Lymph Node Ratio (LNR). Univariate and Cox regression analyses were performed with 5-year all-cause mortality as the primary end point. RESULTS: The study identified 895 stage III rectal cancer cases. The mean APN and LNR were significantly higher in patients who died within 5 years. An increasing APN or LNR was associated with a significant increase in 5 year mortality. The APN and LNR were also powerful predictors of 5-year mortality after correcting for other factors using Cox regression. The TNN was of no prognostic significance. CONCLUSIONS: Both the APN and LNR are highly effective at independently predicting and stratifying 5-year mortality in stage III rectal cancer. The significant predictive value of the LNR is likely to be a reflection of the APN rather than one functioning in autonomy, given that the TNN was of no prognostic significance. PMID- 22507415 TI - Challenges in non-muscle invasive bladder cancer: lessons from a regional review. AB - BACKGROUND: Surveillance programmes for bladder cancer are invasive and expensive. Existing guidelines are complex, and the capacity to implement these is untested. The present study examined treatment consistency, and ease of guideline implementation, for patients undergoing surveillance of non-muscle invasive bladder cancer. METHOD: Eligible cancers treated between 1 January 2005 and 30 June 2009 were identified from a prospective database in a regional South Australian Urology service. Each was analysed with respect to the timing of cystoscopic surveillance and the use of intraoperative chemotherapy. For high risk patients, the use of urine cytology, upper tract imaging, adjuvant therapy and re-resection of T1 cancers was reviewed. RESULTS: Eight hundred and nineteen cystoscopies were performed in the surveillance of 313 cancers in 193 patients. Within each risk category, the pattern of cystoscopic surveillance varied widely. In high-risk patients, the use of cytology, upper tract imaging, adjuvant therapy and re-resection was infrequent (3-56%). An attempt was made to standardize management through the implementation of guidelines. No overall practice improvement was observed after 18 months. Difficulty incorporating new algorithms into practice and ensuring a consistent longitudinal focus in care were felt contributory. Of 78 low-risk cancer patients, 55% underwent more cystoscopies than would have been expected. In 235 cancer patients at high or intermediate risk, 43% received less follow-up than would have been recommended. CONCLUSION: Surveillance patterns were inconsistent across all risk categories. The development of consensus recommendations did not significantly alter clinical practice. Implementation of clinical guidelines for this important disease represents a significant challenge in acute hospital settings. PMID- 22507416 TI - Safety and efficacy of trisectionectomy for hepatocellular carcinoma. AB - BACKGROUND: Right or left trisectionectomy represents the most extensive and difficult type of hepatic resection, and carries an unfavourably high morbidity and mortality. This retrospective study aimed to evaluate the safety and efficacy of trisectionectomy for hepatocellular carcinoma (HCC). METHODS: From January 2000 to December 2008, 35 patients with HCC were treated with trisectionectomy. The treatment outcomes of these patients were retrospectively analysed. RESULTS: Twenty-three right and 12 left trisectionectomies were performed. The overall operative morbidity and mortality were 42.8% (n= 15) and 2.8% (n= 1), respectively. The 1-, 3-, and 5-year overall survival rates were 82.9%, 51.4% and 23.8%, while the 1-, 3- and 5-year disease-free survival rates were 71.4%, 42.9% and 12.9%, respectively. CONCLUSIONS: With careful patient selection and meticulous surgical technique, trisectionectomy can be performed safely and is associated with long-term survival in a subset of patients with HCC. PMID- 22507417 TI - Vital endowments: Sir Charles Bell and the history of some congenital abnormalities of the upper limb. AB - Born in Edinburgh in 1774 Sir Charles Bell, as a young man, studied anatomy and surgery in his hometown. There followed a distinguished career that culminated in his becoming the first professor of Anatomy and Surgery at the College of Surgeons in London. Renowned as a brilliant neuroanatomist he was invited, on the advice of His Grace the Archbishop of Canterbury and the Bishop of London, to contribute one of eight volumes of a work on the Power Wisdom and Goodness of God as manifested in the Creation - known as the Bridgewater Treatises. 'The Hand its Mechanism and Vital Endowments as Evincing Design' was published in 1833 and it is an account of his considering the hand as a machine that has been engineered to exacting standards to interact with the environment in which we live. In it he expressed a deep understanding of the similarity of the structure of the upper limbs of the higher orders of animals. The similarity of the paddle of a turtle and a human hand with acrosymbrachydactyly is unmistakable. This congenital abnormality, given the eponymous title of Apert's syndrome, is one of a number of congenital abnormalities that have parallels in the animal kingdom. Others who have had similar syndromes named after them include Poland, Marfan, Streeter and a number of others. The life and times of these men and their contributions to medicine will be presented in this paper. PMID- 22507418 TI - The papal anatomist: Eustachius in renaissance Rome. AB - Bartholomeo Eustachi, usually latinized as Eustachius, was an important anatomist in the 16th century, arguably second only to his contemporary and rival Andreas Vesalius. He was the first to identify several important anatomical structures, including the suprarenal glands, though he was probably not the first to describe the Eustachian tube. However, it has been hard to evaluate his achievements, because during his lifetime he published only some short monographs, and his career as a teacher in Rome is not well documented. He and his assistant P.M. Pini were the first to use copper plate engravings to illustrate human and animal anatomy, but most of their engravings were not published in their time, and the original plates were lost for some 140 years after the death of Eustachius. Early in the 18th century, these plates were rediscovered by the anatomist and papal physician G.M. Lancisi; he published the engravings in a book which aroused much interest and many reprintings. In 1744, Bernhard Siegfried Albinus of Leiden University published a version of these engravings, with commentaries by himself. The engraved illustrations prepared by Eustachius and Pini are clear and largely accurate. They idealize the findings of actual dissections, and have a diagrammatic quality that facilitates understanding and memory. They are the ancestors of later anatomical atlases, which have helped generations of surgeons in teaching and in planning operations. PMID- 22507419 TI - Sir Kenelm Digby (1603-1665): diplomat, entrepreneur, privateer, duellist, scientist and philosopher. AB - Kenelm Digby was a man with widely differing interests. He studied at Oxford but left without a degree. At the age of 20, he was involved in a dramatic street brawl in Madrid; the following year saw him as a successful privateer in the Mediterranean and adjacent Atlantic waters, and he was then appointed a naval administrator with lucrative trade monopolies. He practised medicine without formal qualifications and gained notoriety by promoting the use of 'sympathetic' powder for healing wounds. Befriended by King James I and his son who succeeded him, he became chancellor to Queen Henrietta and was knighted by King James I on 21 October 1623 and appointed to the Privy Council. At one time, he even spent a brief time in prison, but he later became a founding member of the Royal Society and published two major philosophical treatises as well as a popular cookbook. He designed and manufactured wine bottles with tapered necks for simpler pouring and square sides for easy stacking. He dabbled in mathematics and corresponded with Fermat of 'Last Theorem' fame. In 1641, he challenged a French nobleman who publicly cast a slur on the British King to a 'digladiation' (a sword duel) and quickly dispatched him. He was a friend and admirer of Sir Thomas Browne whose 'Religio Medici' he helped to publish. The Cowlishaw Library holds a 1659 5th edition copy of this remarkable book, with Digby's name on the spine. Truly, Digby must qualify as a Renaissance man. PMID- 22507424 TI - A rare case of sinonasal ameloblastoma presenting with complete nasal obstruction. PMID- 22507420 TI - Weasels, keys and Thersites. AB - It was the achievement of Andreas Vesalius (1514-1564) to redefine the understanding of human anatomy; and that of Homer was to write the first historical novel. This paper offers a link between the works of these two venturers, by way of an examination of the clinical anatomy of the clavicle. PMID- 22507425 TI - Iron bezoar. PMID- 22507426 TI - Carotid body tumour. PMID- 22507427 TI - Dangerous fishing. PMID- 22507428 TI - Maintaining adequate surgical training in a time of doctor shortages and working time restriction (Re: ANZ J. Surg. 2011; 81: 495-6). PMID- 22507429 TI - Inguinal hernia resulting from bull horn injury. PMID- 22507430 TI - Penile fracture: well heard; rarely seen. PMID- 22507431 TI - An unusual case of caecal volvulus. PMID- 22507432 TI - Urinary catheter bulb mimicking obstructed femoral hernia. PMID- 22507433 TI - Acute thrombosis of abdominal aortic aneurysm presenting with lower limb ischaemia. PMID- 22507434 TI - Preputial cyst in an adult causing difficulty in coitus. PMID- 22507435 TI - A facial dismasking approach for resection of an infratemporal fossa sclerosing epithelioid fibrosarcoma. PMID- 22507436 TI - Pneumatosis cystoides intestinalis. PMID- 22507437 TI - Local recurrence of an oral squamous cell carcinoma confined to a free flap. PMID- 22507438 TI - Forgotten presentation of extraperitoneal bladder rupture. PMID- 22507439 TI - Should there be a national core curriculum for anatomy? (Re: ANZ J. Surg. 2010; 80: 475-7). PMID- 22507441 TI - Paradoxical response in HIV-negative patients with pleural tuberculosis: a retrospective multicentre study. AB - OBJECTIVE: To evaluate the incidence, clinical characteristics and predicting factors for the development of paradoxical response in human immunodeficiency virus negative patients with isolated pleural tuberculosis (TB). DESIGN: A multicentre, retrospective cohort study including 458 patients who were diagnosed and treated with isolated pleural TB between March 2005 and February 2010. RESULTS: Paradoxical response developed in 72 patients (16%) with isolated pleural TB. The mean time to development of paradoxical response was 8.8 +/- 6.4 weeks after initiation of anti-tuberculosis treatment. The main presentation of paradoxical response was aggravation of pre-existing pleural effusion in 58 patients (81%). However, the majority of the patients who developed paradoxical response had no associated symptoms (n = 49, 68%). In multiple logistic regression analysis, development of paradoxical response was independently associated with the proportion of eosinophils (adjusted OR 1.293, 95%CI 1.077 1.553) and protein concentrations (adjusted OR 0.590, 95%CI 0.397-0.878) in the pleural fluid at the time of diagnosis. CONCLUSION: Paradoxical response developed in 16% of the patients approximately 2 months after initiation of anti tuberculosis treatment, presenting with aggravation of pre-existing pleural effusion. Development of paradoxical response was associated with the proportion of eosinophils and protein concentrations in the pleural fluid at the time of diagnosis. PMID- 22507442 TI - Resistant ticks inhibit Metarhizium infection prior to haemocoel invasion by reducing fungal viability on the cuticle surface. AB - We studied disease progression of, and host responses to, four species in the Metarhizium anisopliae complex expressing green fluorescent protein (GFP). We compared development and determined their relative levels of virulence against two susceptible arthropods, the cattle tick Rhipicephalus annulatus and the lepidopteran Galleria mellonella, and two resistant ticks, Hyalomma excavatum and Rhipicephalus sanguineus. Metarhizium brunneum Ma7 caused the greatest mortality of R. annulatus, Metarhizium robertsii ARSEF 2575 and Metarhizium pingshaense PPRC51 exhibited intermediate levels of virulence, and Metarhizium majus PPRC27 caused low mortality of cattle ticks. Conidia of all four species germinated on all hosts examined, but on resistant hosts, sustained hyphal growth was inhibited and GFP emission steadily and significantly decreased over time, suggesting a loss of fungal viability. Cuticle penetration was observed only for the three most virulent species infecting susceptible hosts. Cuticles of resistant and susceptible engorged female ticks showed significant increases in red autofluorescence at sites immediately under fungal hyphae. This is the first report (i) of tick mortality occurring after cuticle penetration but prior to haemocoel colonization and (ii) that resistant ticks do not support development of Metarhizium germlings on the outer surface of the cuticle. Whether reduced Metarhizium viability on resistant tick cuticles is due to antibiosis or limited nutrient availability is unknown. PMID- 22507443 TI - Losartan improves adipose tissue-derived stem cell niche by inhibiting transforming growth factor-beta and fibrosis in skeletal muscle injury. AB - Recently, adipose tissue-derived stem cells (ASCs) were emerged as an alternative, abundant, and easily accessible source of stem cell therapy. Previous studies revealed losartan (an angiotensin II type I receptor blocker) treatment promoted the healing of skeletal muscle by attenuation of the TGF-beta signaling pathway, which inhibits muscle differentiation. Therefore, we hypothesized that a combined therapy using ASCs and losartan might dramatically improve the muscle remodeling after muscle injury. To determine the combined effect of losartan with ASC transplantation, we created a muscle laceration mouse model. EGFP-labeled ASCs were locally transplanted to the injured gastrocnemius muscle after muscle laceration. The dramatic muscle regeneration and the remarkably inhibited muscular fibrosis were observed by combined treatment. Transplanted ASCs fused with the injured or differentiating myofibers. Myotube formation was also enhanced by ASC(+) satellite coculture and losartan treatment. Thus, the present study indicated that ASC transplantation effect for skeletal muscle injury can be dramatically improved by losartan treatment inducing better niche. PMID- 22507444 TI - Focal muscle vibration in the treatment of upper limb spasticity: a pilot randomized controlled trial in patients with chronic stroke. AB - OBJECTIVE: To examine the clinical effect of repetitive focal muscle vibration (rMV) on the motor function of the upper extremity 1 month after treatment in patients with chronic stroke. DESIGN: We performed a pilot randomized controlled trial using a double-blind, parallel-group study design. SETTING: Medical center. PARTICIPANTS: Patients with chronic stroke (N=49). INTERVENTIONS: Patients randomly assigned to the study group (SG) received rMV, while patients in the control group (CG) received a placebo vibratory treatment. The patients and the clinical examiner were blind to the intervention. MAIN OUTCOME MEASURES: The primary endpoint was an improvement of more than .37 points on the Functional Ability Scale of the Wolf Motor Function Test (WMFT FAS). The Modified Ashworth Scale and the visual analog scale were the secondary outcome measures. All measures were administered before the treatment (t0) and 1 week (t1) and 1 month (t2) after the treatment. RESULTS: Twenty-eight patients were allocated to the SG and 21 to the CG. The analysis of variance for repeated measurements revealed a significant difference in the expression of the WMFT FAS score over time only in the SG (P=.006). The treatment was successful for 7 (33%) of 21 patients recruited in the SG and for 2 (13%) of 15 patients recruited in the CG. The relative risk was 2.5 (95% confidence interval, .60-10.39), and the number needed to treat was 5. The Wilcoxon test showed a statistically significant difference between t0 and t2 in the SG (P=.02). No adverse event was observed in the 2 groups. CONCLUSIONS: Our results suggest that rMV treatment of the upper limb may improve the functional ability of chronic stroke patients, but a larger, multicenter, randomized controlled study is needed. PMID- 22507445 TI - The Xenopus oocyte: a model for studying the metabolic regulation of cancer cell death. AB - Abnormal metabolism and the evasion of apoptosis are both considered hallmarks of cancer. A remarkable biochemical model system, the Xenopus laevis oocyte, exhibits altered metabolism coupled to its apoptotic machinery in a similar fashion to cancer cells. This review considers the theory that these two hallmarks of cancer are coupled in tumor cells and provides strong proof that the Xenopus laevis oocyte system is an appropriate model in which to dissect the biochemical events underlying the connection between the two hallmarks. By further elucidating the mechanisms through which metabolism suppresses apoptotic machinery, we may gain a better understanding about how normal cells transform into cancer cells. PMID- 22507446 TI - Comparison of shoe-length fit between people with and without diabetic peripheral neuropathy: a case-control study. AB - BACKGROUND: Amongst the many identified mechanisms leading to diabetic foot ulceration, ill-fitting footwear is one. There is anecdotal evidence that people with diabetic peripheral neuropathy wear shoes that are too small in order to increase the sensation of fit. The aim of this study was to determine whether people with diabetic sensory neuropathy wear appropriate length footwear. METHODS: A case-control design was used to compare internal shoe length and foot length differences between a group of people with diabetes and peripheral sensory neuropathy and a group of people without diabetes and no peripheral sensory neuropathy. Shoe and foot length measurements were taken using a calibrated Internal Shoe Size Gauge(r) and a Brannock Device(r), respectively. RESULTS: Data was collected from 85 participants with diabetes and 118 participants without diabetes. The mean difference between shoe and foot length was not significantly different between the two groups. However, a significant number of participants within both groups had a shoe to foot length difference that lay outside a previously suggested 10 to 15 mm range. From the diabetic and non-diabetic groups 82% (70/85) and 66% (78/118), respectively had a foot to shoe length difference outside this same range. CONCLUSIONS: This study shows that although there is no significant difference in shoe-length fit between participants with and without neuropathy, a significant proportion of these populations wear shoes that are either too long or too short for their foot length according to the 10 to 15 mm value used for comparison. The study has highlighted the need for standardised approaches when considering the allowance required between foot and internal shoe length and for the measurement and comparison of foot and shoe dimensions. PMID- 22507447 TI - Methodologies for screening of bacteria-carbohydrate interactions: anti-adhesive milk oligosaccharides as a case study. AB - Many studies have demonstrated the capacity of glycan-based compounds to disrupt microbial binding to mucosal epithelia. Therefore, oligosaccharides have potential application in the prevention of certain bacterial diseases. However, current screening methods for the identification of anti-adhesive oligosaccharides have limitations: they are time-consuming and require large amounts of oligosaccharides. There is a need to develop analytical techniques which can quickly screen for, and structurally define, anti-adhesive oligosaccharides prior to using human cell line models of infection. Considering this, we have developed a rapid method for screening complex oligosaccharide mixtures for potential anti-adhesive activity against bacteria. Our approach involves the use of whole bacterial cells to "deplete" free oligosaccharides from solution. As a case study, the free oligosaccharides from the colostrum of Holstein Friesian cows were screened for interactions with whole Escherichia coli cells. Reductions in oligosaccharide concentrations were determined by High pH Anion Exchange Chromatography and Hydrophilic Interaction Liquid Chromatography (HILIC-HPLC). Oligosaccharide structures were confirmed by a combination of HILIC HPLC, exoglycosidase digestion and off-line negative ion mode MS/MS. The depletion assay confirmed selective bacterial interaction with certain bovine oligosaccharides which in previous studies, by other methodologies, had been shown to interact with E. coli. In particular, the bacterial cells depleted the following oligosaccharides in a population dependent manner: 3'-sialyllactose, disialyllactose, and 6'-sialyllactosamine. The assay methodology was further validated by studies in which we demonstrated the inhibitory activity of 3' sialyllactose, and a mixture of bovine colostrum oligosaccharides, on E. coli adhesion to differentiated HT-29 cells. PMID- 22507449 TI - Molecular characterisation and regulation of a Nicotiana tabacum S-domain receptor-like kinase gene induced during an early rapid response to lipopolysaccharides. AB - The isolation, characterization and regulation of the first lipopolysaccharide (LPS)-responsive S-domain receptor-like kinase (RLK) in Nicotiana tabacum are reported. The gene, corresponding to a differentially expressed LPS-responsive EST, was fully characterised to investigate its involvement in LPS-induced responses. The full genomic sequence, designated Nt-Sd-RLK, encodes for a S domain RLK protein containing conserved modules (B-lectin-, S- and PAN-domains) reported to function in mediating protein-protein and protein-carbohydrate interactions in its extracellular domain, as well as the molecular architecture to transduce signals intracellularly through a Ser/Thr kinase domain. Phylogenetic analysis clustered Nt-Sd-RLK with S-domain RLKs induced by bacteria, wounding and salicylic acid. Perception of LPS induced a rapid, bi-phasic response in Nt-Sd-RLK expression with a 17-fold up-regulation at 3 and 9h. A defence-related W-box cis element was found in the promoter region of Nt-Sd-RLK and the transient induction of Nt-Sd-RLK in cultured cells by LPS exhibited a pattern typical of early response defence genes. Nt-Sd-RLK was also responsive to salicylic acid induction and was expressed in differentiated leaf tissue, where LPS elicited local as well as systemic up-regulation. The results contribute new knowledge about the potential role that S-domain RLKs may play within interactive signal transduction pathways associated with immunity and defence. PMID- 22507448 TI - Hormones in the city: endocrine ecology of urban birds. AB - Urbanization dramatically changes the landscape, presenting organisms with novel challenges and often leading to reduced species diversity. Urban ecologists have documented numerous biotic and abiotic consequences of urbanization, such as altered climate, species interactions, and community composition, but we lack an understanding of the mechanisms underlying organisms' responses to urbanization. Here, I review findings from the nascent field of study of the endocrine ecology of urban birds. Thus far, no clear or consistent patterns have been revealed, but we do have evidence that urban habitat can shape endocrine traits, and that those traits might contribute to adaptation to the urban environment. I suggest strong approaches for future work addressing exciting questions about the role of endocrine traits in mediating responses to urbanization within species across the globe. PMID- 22507451 TI - 7th International Association of Biological Standardization (IABS) Symposium on Advances in Transfusion Safety. PMID- 22507450 TI - Bioinformatics evidence for the transfer of mycosporine-like amino acid core (4 deoxygadusol) synthesizing gene from cyanobacteria to dinoflagellates and an attempt to mutate the same gene (YP_324358) in Anabaena variabilis PCC 7937. AB - We have identified a homologue of 4-deoxygadusol (core of mycosporine-like amino acids) synthesizing gene (ZP_05036788) from Synechococcus sp. PCC 7335 that was found to have additional functionally unknown N-terminal domain similar to homologues from dinoflagellates based on the ClustalW analysis. Phylogenetic analysis revealed that Synechococcus sp. (ZP_05036788) makes a clade together with dinoflagellates and was closest to the Oxyrrhis marina. This study shows for the first time that N-terminal additional sequences that possess upstream plastid targeting sequence in Heterocapsa triquetra and Karlodinium micrum were already evolved in cyanobacteria, and plastid targeting sequence were evolved later in dinoflagellates after divergence from chloroplast lacking Oxyrrhis marina. Thus, MAAs synthesizing genes were transferred from cyanobacteria to dinoflagellates and possibly Synechococcus sp. PCC 7335 acted as a donor during lateral gene transfer event. In addition, we also tried to mutate 4-deoxygadusol synthesizing gene (YP_324358) of Anabaena variabilis PCC 7937 by homologous recombination, however, all approaches to get complete segregation of the mutants from the wild type were unsuccessful, showing the essentiality of YP_324358 for A. variabilis PCC 7937. PMID- 22507452 TI - Outcomes of patients with appendicitis who present to an outer metropolitan hospital. AB - BACKGROUND: The present study investigates patients with acute appendicitis who presented to a hospital with no acute surgical service (group A) and compares the outcomes of these patients with those that presented to a tertiary centre with an acute surgical service within the same health network (group B). All group A patients were transferred to the group B hospital for appendicectomy. METHODS: During a 10-month period, 257 patients (80 in group A, 177 in group B) with acute appendicitis were analysed retrospectively. Demographics, emergency department parameters, time to waiting bay, time to surgery, operative time, complications, length of stay and the stage of appendicitis were all noted for each group. A comparison of each of these parameters was made between the two groups of patients. RESULTS: There were 80 patients in group A and 177 patients in group B. There was a significant difference between the two groups in the fields of length of stay in the emergency department (P = 0.003), bed availability (P = 0.038), time to waiting bay (P = 0.006) and time to surgery (P = 0.006). There was no significant difference in the total length of stay and complication rates between the two groups (P = 0.58 and 0.78, respectively). CONCLUSION: This study concludes that patients with acute appendicitis presenting to a hospital with no acute surgical services had a greater waiting period prior to surgery. However, this did not translate into greater complication rates or length of stay for these patients. We propose a prospective study to further analyse the outcomes in such patients. PMID- 22507453 TI - Biofabrication of stratified biofilm mimics for observation and control of bacterial signaling. AB - Signaling between cells guides biological phenotype. Communications between individual cells, clusters of cells and populations exist in complex networks that, in sum, guide behavior. There are few experimental approaches that enable high content interrogation of individual and multicellular behaviors at length and time scales commensurate with the signal molecules and cells themselves. Here we present "biofabrication" in microfluidics as one approach that enables in-situ organization of living cells in microenvironments with spatiotemporal control and programmability. We construct bacterial biofilm mimics that offer detailed understanding and subsequent control of population-based quorum sensing (QS) behaviors in a manner decoupled from cell number. Our approach reveals signaling patterns among bacterial cells within a single biofilm as well as behaviors that are coordinated between two communicating biofilms. We envision versatile use of this biofabrication strategy for cell-cell interaction studies and small molecule drug discovery. PMID- 22507454 TI - Risk factors for cardiovascular disease and type 2 diabetes retained from childhood to adulthood predict adult outcomes: the Princeton LRC Follow-up Study. AB - BACKGROUND: Pediatric risk factors predict adult cardiovascular disease (CVD) and type 2 diabetes (T2DM), but whether they predict events independently of adult risk factors is not fully known. OBJECTIVE: Assess whether risk factors for CVD and T2DM retained from childhood to adulthood predict CVD and T2DM in young adulthood. STUDY DESIGN: 770 schoolchildren, ages 5-20 (mean age 12), 26-yr prospective follow-up. We categorized childhood and adult risk factors and 26 year changes (triglycerides [TG], LDL cholesterol, BMI, blood pressure [BP] and glucose >=, and HDL cholesterol < pediatric and young adult cutoffs). These risk factors and race, cigarette smoking, and family history of CVD and T2DM were assessed as predictors of CVD and T2DM at mean age 38. RESULTS: Children who had high TG and retained high TG as adults had increased CVD events as adults (p = .0005). Children who had normal BMI and retained normal BMI as adults had reduced CVD events as adults (p = .02). Children who had high BP or high TG and retained these as adults had increased T2DM as adults (p = .0006, p = .003). CONCLUSIONS: Risk factors for CVD and T2DM retained from childhood to adulthood predict CVD and T2DM in young adulthood and support universal childhood screening. PMID- 22507455 TI - Strategic selection of an optimal sorbent mixture for in-situ remediation of heavy metal contaminated sediments: framework and case study. AB - Aquatic sediments contaminated with heavy metals originating from mining and metallurgical activities pose significant risk to the environment and human health. These sediments not only act as a sink for heavy metals, but can also constitute a secondary source of heavy metal contamination. A variety of sorbent materials has demonstrated the potential to immobilize heavy metals. However, the complexity of multi-element contamination makes choosing the appropriate sorbent mixture and application dosage highly challenging. In this paper, a strategic framework is designed to systematically address the development of an in-situ sediment remediation solution through Assessment, Feasibility and Performance studies. The decision making tools and the experimental procedures needed to identify optimum sorbent mixtures are detailed. Particular emphasis is given to the utilization and combination of commercially available and waste-derived sorbents to enhance the sustainability of the solution. A specific case study for a contaminated sediment site in Northern Belgium with high levels of As, Cd, Pb and Zn originating from historical non-ferrous smelting is presented. The proposed framework is utilized to achieve the required remediation targets and to meet the imposed regulations on material application in natural environments. PMID- 22507457 TI - Pre-culturing human adipose tissue mesenchymal stem cells under hypoxia increases their adipogenic and osteogenic differentiation potentials. AB - OBJECTIVES: Hypoxia is an important factor in many aspects of stem-cell biology including their viability, proliferation, differentiation and migration. We evaluated whether low oxygen level (2%) affected human adipose tissue mesenchymal stem-cell (hAT-MSC) phenotype, population growth, viability, apoptosis, necrosis and their adipogenic and osteogenic differentiation potential. MATERIALS AND METHODS: hAT-MSCs from four human donors were cultured in growth medium under either normoxic or hypoxic conditions for 7 days and were then transferred to normoxic conditions to study their differentiation potential. RESULTS: Hypoxia enhanced hAT-MSC expansion and viability, whereas expression of mesenchymal markers such as CD90, CD73 and endothelial progenitor cell marker CD34, remained unchanged. We also found that pre-culturing hAT-MSCs under hypoxia resulted in their enhanced ability to differentiate into adipocytes and osteocytes. CONCLUSIONS: This protocol could be useful for maximizing hAT-MSC potential to differentiate in vitro into the adipogenic and osteogenic lineages, for use in plastic and reconstructive surgery, and in tissue engineering strategies. PMID- 22507456 TI - Transcriptomic and proteomic analyses of Desulfovibrio vulgaris biofilms: carbon and energy flow contribute to the distinct biofilm growth state. AB - BACKGROUND: Desulfovibrio vulgaris Hildenborough is a sulfate-reducing bacterium (SRB) that is intensively studied in the context of metal corrosion and heavy metal bioremediation, and SRB populations are commonly observed in pipe and subsurface environments as surface-associated populations. In order to elucidate physiological changes associated with biofilm growth at both the transcript and protein level, transcriptomic and proteomic analyses were done on mature biofilm cells and compared to both batch and reactor planktonic populations. The biofilms were cultivated with lactate and sulfate in a continuously fed biofilm reactor, and compared to both batch and reactor planktonic populations. RESULTS: The functional genomic analysis demonstrated that biofilm cells were different compared to planktonic cells, and the majority of altered abundances for genes and proteins were annotated as hypothetical (unknown function), energy conservation, amino acid metabolism, and signal transduction. Genes and proteins that showed similar trends in detected levels were particularly involved in energy conservation such as increases in an annotated ech hydrogenase, formate dehydrogenase, pyruvate:ferredoxin oxidoreductase, and rnf oxidoreductase, and the biofilm cells had elevated formate dehydrogenase activity. Several other hydrogenases and formate dehydrogenases also showed an increased protein level, while decreased transcript and protein levels were observed for putative coo hydrogenase as well as a lactate permease and hyp hydrogenases for biofilm cells. Genes annotated for amino acid synthesis and nitrogen utilization were also predominant changers within the biofilm state. Ribosomal transcripts and proteins were notably decreased within the biofilm cells compared to exponential-phase cells but were not as low as levels observed in planktonic, stationary-phase cells. Several putative, extracellular proteins (DVU1012, 1545) were also detected in the extracellular fraction from biofilm cells. CONCLUSIONS: Even though both the planktonic and biofilm cells were oxidizing lactate and reducing sulfate, the biofilm cells were physiologically distinct compared to planktonic growth states due to altered abundances of genes/proteins involved in carbon/energy flow and extracellular structures. In addition, average expression values for multiple rRNA transcripts and respiratory activity measurements indicated that biofilm cells were metabolically more similar to exponential-phase cells although biofilm cells are structured differently. The characterization of physiological advantages and constraints of the biofilm growth state for sulfate reducing bacteria will provide insight into bioremediation applications as well as microbially-induced metal corrosion. PMID- 22507459 TI - Measurement of anti-ADAMTS13 neutralizing autoantibodies: a comparison between CBA and FRET assays. PMID- 22507458 TI - Auditory perception and syntactic cognition: brain activity-based decoding within and across subjects. AB - The present magnetoencephalography study investigated whether the brain states of early syntactic and auditory-perceptual processes can be decoded from single trial recordings with a multivariate pattern classification approach. In particular, it was investigated whether the early neural activation patterns in response to rule violations in basic auditory perception and in high cognitive processes (syntax) reflect a functional organization that largely generalizes across individuals or is subject-specific. On this account, subjects were auditorily presented with correct sentences, syntactically incorrect sentences, correct sentences including an interaural time difference change, and sentences containing both violations. For the analysis, brain state decoding was carried out within and across subjects with three pairwise classifications. Neural patterns elicited by each of the violation sentences were separately classified with the patterns elicited by the correct sentences. The results revealed the highest decoding accuracies over temporal cortex areas for all three classification types. Importantly, both the magnitude and the spatial distribution of decoding accuracies for the early neural patterns were very similar for within-subject and across-subject decoding. At the same time, across subject decoding suggested a hemispheric bias, with the most consistent patterns in the left hemisphere. Thus, the present data show that not only auditory perceptual processing brain states but also cognitive brain states of syntactic rule processing can be decoded from single-trial brain activations. Moreover, the findings indicate that the neural patterns in response to syntactic cognition and auditory perception reflect a functional organization that is highly consistent across individuals. PMID- 22507461 TI - Life-threatening sinking skin flap syndrome due to CSF leak after lumbar puncture - treated with epidural blood patch. PMID- 22507460 TI - Cortical and leptomeningeal involvement in three cases of neuromyelitis optica. PMID- 22507462 TI - Amiodarone-associated neuromyopathy: a report of four cases. PMID- 22507464 TI - Marked vitamin D deficiency in patients with diabetes in the UK: ethnic and seasonal differences and an association with dyslipidaemia. PMID- 22507465 TI - Steroid-free living donor liver transplantation for HCV--a multicenter prospective cohort study in Japan. AB - This prospective, non-randomized, multicenter cohort study analyzed the safety and efficacy of a steroid-free immunosuppressive (IS) protocol for hepatitis C virus (HCV)-positive living donor liver transplant (LDLT) recipients in Japan. Of 68 patients enrolled from 13 transplant centers, 56 fulfilled the inclusion/exclusion criteria; 27 were assigned the steroid-free IS protocol (Fr group) and 29 the traditional steroid-containing IS protocol (St group). Serum HCV RNA levels increased over time and were higher in the St group until postoperative day 90 (POD 14, p=0.013). Preemptive anti-HCV therapy was started in a higher percentage of recipients (59.3%) in the Fr group than in the St group (31.0%, p=0.031), mainly due to early HCV recurrence. The incidence of HCV recurrence at one yr was lower in the Fr group (22.2%) than in the St group (41.4%; p=0.066). The incidence of acute cellular rejection was similar between groups. New onset diabetes after transplant, cytomegalovirus infection, and renal dysfunction were significantly less frequent in the Fr group than in the St group (p=0.022, p<0.0001, p=0.012, respectively). The steroid-free IS protocol safely reduced postoperative morbidity and effectively suppressed both the HCV viral load in the early post-transplant period and HCV recurrence in HCV-positive LDLT recipients. PMID- 22507466 TI - Pan-European societies cohesion. PMID- 22507467 TI - Forty years on - the ever changing pattern and progress of venereology. PMID- 22507468 TI - Assessment of the efficacy of topical anesthetics using the tactile spatial resolution method. AB - The aim of this study was to compare the purported advantages of 4% tetracaine gel (Ametop gel) and 4% liposomal lidocaine gel (LMX4 gel) with EMLA cream (eutectic mixture of 2.5% lidocaine and 2.5% prilocaine) using an objective and repeatable method. Ametop gel and LMX4 gel were administered under occlusion for 30 min and compared to EMLA cream applied for 30 and 60 min on the intact upper lip skin of 15 volunteers each. The efficacy of the anesthetics was assessed by the spatial resolution method. Measurements were conducted just after removal of the products from the skin, then 20, 40 and 60 min later. Each of the formulations, except for EMLA cream applied for 30 min, decreased tactile spatial discrimination thresholds significantly just after removal from the skin when compared to the output levels (p<0.05). Ametop gel kept significantly good skin anesthesia also 20, 40 and 60 min later (p<0.05). The efficacy of LMX4 gel and EMLA(60) cream decreased to the initial levels after 40-min application. Ametop gel anesthetized the skin in a highly homogeneous manner providing similar effect in most subjects, which was not the case in the EMLA and LMX4 groups. In conclusion, LMX4 gel and Ametop gel appeared to be faster acting than EMLA cream. Our results showed the 30-min application of LMX4 and Ametop gel under occlusion to be equivalent to 60-min administration of EMLA cream. Ametop gel, in contrast to the rest, provides very good anesthesia for up to 60 min. The application of EMLA cream under occlusion over only 30 min cannot guarantee appropriate effects. PMID- 22507469 TI - Detection of plasma and urinary monoamines and their metabolites in nonsegmental vitiligo. AB - Vitiligo is one of the most troubling diseases to both patient and physician. Monoamines are chemical compounds derived from the hydroxyderivative of amino acids. They have been implicated in many dermatoses, but their role in the etiopathogenesis of vitiligo remains obscure. The aim of the study was to evaluate the role of the neural factor in the pathogenesis of nonsegmental vitiligo (NSV) by measuring catecholamines and their metabolites in plasma and urine of patients suffering from NSV, and to correlate these factors with the onset and activity of the disease. The study included 20 patients with NSV and 20 healthy individuals. All subjects were subjected to plasma and urine detection of catecholamines and 5-hydroxyindoleacetic acid (5-HIAA) using high-performance liquid chromatography and electrochemical detection. Comparison of plasma and urinary catecholamines and 5-HIAA between the patient and control groups revealed a statistically significant increase in the group of NSV patients (P<0.05). There was no statistically significant difference (P>0.05) between the patients with recent and old onset of NSV. In conclusion, the increase in the level of monoamines may be the initiating event in the pathogenesis of NSV. PMID- 22507470 TI - Systemic lupus erythematosus progressing to non-Hodgkin's lymphoma complicated by fatal hemophagocytic syndrome: case report. AB - Hemophagocytic syndrome (HPS) may be provoked by infections, malignancies and autoimmune diseases. We report on a 56-year-old woman with long-lasting systemic lupus erythematosus (SLE) who presented with malar rash, inflammatory livedo reticularis, fever, weight loss, pancytopenia and mild splenomegaly with cervical lymphadenopathy. She had criteria for SLE flare-up (malar rash, high antinuclear antibody titer, complement consumption, pathological urinary sediment, and retinal vasculitis). Despite high-dose glucocorticoid therapy, pancytopenia and fever worsened. Important elevations of triglycerides and ferritin were also found. Bone marrow aspirate demonstrated hemophagocytosis, which confirmed the coexistence of HPS and SLE. The treatment with glucocorticoids, immunoglobulins, cyclophosphamide, filgrastim and antimicrobial therapy was unsuccessful. After one month, the patient developed Pneumocystis jirovecii pneumonia with fatal outcome. Bone marrow biopsy, taken 5 days before death, showed high grade diffuse large B-cell (CD20+, Ki-67+) non-Hodgkin's lymphoma (DLBCL). We are the first to report the association of both SLE and non-Hodgkin's lymphoma complicated by HPS. We showed that, based on clinical and laboratory data, it was difficult to distinguish the early phase of HPS from SLE flare-up and new-onset DLBCL. Therapy of such a complex case of HPS has not been standardized, and opportunistic infections remain a difficult issue. PMID- 22507471 TI - HMB-45 negative clear cell perivascular epithelioid cell tumor of the skin. AB - The first case of cutaneous clear cell perivascular epithelioid cell tumor (PEComa) with negative HMB-45 marker is presented. The tumor was a nodule 3x2 cm in size, located on the right foot in a 60-year-old man. The lesion consisted of large irregularly shaped cells with clear cytoplasm, negative for S-100 protein, HMB-45, Melan-A, pancytokeratin, epithelial membrane antigen and CAM5.2. Multifocal positivity for desmin, microphthalmia transcription factor and tyrosinase was found. The diagnosis of cutaneous PEComa of clear cell type was made. Clear cell change is a very unusual finding in PEComa and may pose problems in diagnostic differentiation from other clear cell cutaneous lesions that may be excluded with immunohistochemistry. In our case, the HMB-45 negativity may be explained by extensive clear cell change. Additional studies are necessary to accept the clear cell cutaneous HMB-45 negative PEComa as a new variant of perivascular epithelioid cell tumor. PMID- 22507473 TI - Multiple nodular cutaneous metastases as the first clinical sign of signet ring cell gastric carcinoma: case report. AB - Cutaneous metastases from signet ring cell gastric carcinoma are uncommon. A 35 year-old male presented with a three-month history of multiple asymptomatic, indurated, pinky colored nodules of 2.5 to 4 cm in diameter, without any local and general symptoms. Nodule biopsy revealed an infiltrating signet ring cell carcinoma. Gastroscopy and biopsy confirmed the diagnosis of gastric carcinoma with signet ring cells. The present report describes an unusual clinical case of a young patient diagnosed with cutaneous metastasis before detection of his gastric carcinoma. PMID- 22507472 TI - Penile cutaneous horn ten years after treatment of verrucous squamous cell carcinoma on penile glans: case report. AB - Penile cutaneous horn is a clinical term that describes protruding hyperkeratosis, usually conical in shape, located on penile glans. Penile localization of this lesion, predominantly located on sun-exposed areas, is very rare. The association with malignancy on the penis makes proper identification of these lesions essential. We present a 45-year-old man with a cutaneous horn, 25 mm in size, located on the basis of penile glans. The patient had a history of phimosis, pseudoepitheliomatous balanoposthitis, surgical excision of penile verrucous squamous cell carcinoma (SCC) and postoperative radiotherapy of carcinoma in situ on the same localization, ten years before. Complete surgical removal of the horn with separate excision of the margins and base was done. Pathologic examination revealed squamous hyperplasia with suspicion of carcinoma in situ. Additional negative p16(INK4a) immunohistochemical analysis confirmed benign proliferative lesion. DNA polymerase chain reaction for human papilloma virus infection was negative. These findings suggested sparing surgical procedure in our patient, without indication for partial penile amputation, but with mandatory follow-up. Our case confirmed the association of pseudoepitheliomatous balanoposthitis with verrucous SCC, as well as the possible influence of radiotherapy on the development of penile cutaneous horn. Additionally, we showed the important role p16(INK4a) immunohistochemical analysis in the differential diagnosis of alterations adjacent to invasive SCC of the penis. PMID- 22507474 TI - Severe skin necrosis in adult: an unusual complication of fulminant meningococcal sepsis. AB - We report on a 20-year-old female high-school student with fulminant meningococcal sepsis presenting as severe skin necrosis in lower extremities. The wound surface affected 2% of her total body surface area and was covered with black eschar. The adipose tissue beneath the eschar was degenerated and turned to necrosis as to deep fascia and periosteum of lower tibia. Excision of necrotic eschar, then covered with flaps on both legs resulted in a successful outcome. PMID- 22507475 TI - Lichen sclerosus in the oral mucosa: a rare form of presentation. AB - Lichen sclerosus is a chronic inflammatory disease of unknown origin, which affects mostly women in the fifth and sixth decades of life, but can also occur in men and children. The involvement of the oral mucosa alone or together with other forms of presentation is extremely rare, requiring a differential diagnosis with other diseases of the oral cavity, particularly lichen planus. There are less than 30 cases of lichen sclerosus in the oral mucosa described in the literature and there are no reports on malignant transformation so far. We describe a patient with skin, oral and genital lesions of lichen sclerosus. PMID- 22507476 TI - Unusual presentation of dermatofibrosarcoma protuberans in deep skin over the breast - imaging findings. PMID- 22507477 TI - Syphilitic alopecia in HIV infected homosexual men: case reports. PMID- 22507478 TI - Cardiac arrhythmia as a side effect of ketanserin therapy in a patient with systemic scleroderma. PMID- 22507479 TI - Five years of sucsessful prevention of malignant epidermal tumors: data from the Referral Center of Dermatologic Oncology, Ministry of Health and Social Welfare, Croatia. PMID- 22507480 TI - Euromelanoma 2012 Campaign. PMID- 22507484 TI - Teleconference fracture clinics: a trial for rural hospitals. PMID- 22507482 TI - Genipin-cross-linked microencapsulated human adipose stem cells augment transplant retention resulting in attenuation of chronically infarcted rat heart fibrosis and cardiac dysfunction. AB - Stem cell transplantation has been widely acknowledged for their immense potential in regenerative medicine. In these procedures, the implanted cells need to maintain both their viability and functional properties for effective therapeutic outcomes. This has long been a subject of major concern and intensive studies. Microencapsulation of stem cells within polymeric microcapsules can be an efficient approach to achieve this goal, particularly for heart diseases. This study reports the use of biocompatible, fluorogenic genipin cross-linked alginate chitosan (GCAC) microcapsules in delivery of human adipose stem cells (hASCs) with an aim to increase the implant retention in the infarcted myocardium for maximum clinical benefits. In vitro results show, under hypoxic conditions, the microencapsulated cells overexpressed significantly higher amount of biologically active vascular endothelial growth factor (VEGF). We investigated on the in vivo potential using immunocompetent female rats after induction of myocardial infarction. For this, animal groups (n = 8) received empty control microcapsules, 1.5 * 10(6) free male hASCs, or 1.5 * 10(6) microencapsulated male hASCs. Results show significant retention (3.5 times higher) of microencapsulated hASCs compared to free hASCs after 10 weeks of transplantation. Microencapsulated hASCs showed significantly attenuated infarct size compared to free hASCs and empty microcapsule group (21.6% +/- 1.1% vs. 27.2% +/- 3.1% vs. 33.3% +/- 3.2%; p < 0.05), enhanced vasculogenesis, and improved cardiac function (fractional shortening: 24.2% +/- 2.1% vs. 19.1% +/- 0.5% vs. 12.0% +/- 4.0%; p < 0.05). These data suggest that microencapsulated hASCs can contribute significantly to the improvement in cardiac functions. Their greater retentions exhibit reduced fibrosis and cardiac dysfunction in experimental animals. However, further research is needed to fully comprehend the underlying biological and immunological effects of microencapsulated hASCs, which jointly play important roles in cardiac repair. PMID- 22507485 TI - Improving care for patients with melanoma. PMID- 22507486 TI - History of surgical oncology in Australasia. PMID- 22507487 TI - Medicine in small doses. PMID- 22507489 TI - Current medical students' understanding of Surgical Education and Training. AB - BACKGROUND: The current Surgical Education and Training (SET) programme in Australia and New Zealand has been implemented to streamline surgical training. As applications to the SET programme can occur as early as the 2nd post-graduate year, early preparation is vital to ensure a successful outcome in gaining a SET position. We wish to demonstrate to what degree medical students are aware of the SET structure and application requirements to determine if further assistance to future SET candidates is required. METHODS: A standardized questionnaire was delivered to students of an Australian Medical School via an online medium. Ethics approval was granted, and all surveys were completed anonymously and voluntarily. One hundred eighty-two completed surveys were received. RESULTS: Eighteen percent of surveyed participants felt they had a good understanding of the SET programme, with 82% stating they had minimal or no understanding of the programme. Fourteen percent felt they had the information needed to pursue a career in surgery. Fifty-three percent were unaware that the College outlined areas of core competencies required in their training, with 75% unable to name any core competencies. CONCLUSION: There are a large proportion of medical students potentially considering a career in surgery. However, only a small number feel that they have been adequately equipped throughout their medical course to understand the steps needed to build a strong application for SET. PMID- 22507490 TI - A meta-analysis comparing laparoscopic partial versus Nissen fundoplication. AB - BACKGROUND: For proven gastro-oesophageal reflux disease, partial fundoplication is considered as effective as Nissen, but with fewer side effects. The aim of this meta-analysis was to compare the effect of laparoscopic partial fundoplication (LPF) with laparoscopic Nissen fundoplication (LNF). METHODS: Extensive medical literature searches of the PubMed, Medline and Embase databases were performed up to April 2010 for all randomized clinical trials that compared LPF versus LNF. The effect variables analysed were the incidence of post operative dysphagia, heartburn, inability to belch, outcome or satisfaction and Visick score. Meta-analyses were carried out using odds ratios (ORs) with 95% confidence interval. RESULTS: Thirteen randomized trials were considered suitable for the meta-analysis. A total of 1374 patients underwent LPF or LNF. There was a significant reduction of the incidence of post-operative dysphagia (OR = 0.44, P < 0.0001) and inability to belch (OR = 0.41, P < 0.005) for the LPF compared to that of the LNF group. Compared with LPF, LNF resulted in a significant reduction of the incidence of post-operative heartburn (OR = 1.94, P < 0.01). The outcome or satisfaction of patients and Visick I and II scores were comparable between the two groups. CONCLUSION: Both LPF and LNF are effective for the treatment of proven gastro-oesophageal reflux disease. LPF enables a decreased post-operative dysphagia and gas-related side effects, while LNF is more successful in controlling reflux symptoms, particularly heartburn, than LPF. A balance should be found between anti-reflux and side effects. PMID- 22507492 TI - Impact of 18F-FDG-PET in decision making for liver metastectomy of colorectal cancer. AB - BACKGROUND: The ability of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) to impact on management of patients with recurrent colorectal cancer is high. However, direct impact of FDG-PET on surgical management of patients with potentially resectable hepatic metastases is limited. METHODS: FDG-PET scans of patients with colorectal cancer at Austin Hospital in a 2-year period were retrospectively evaluated. Data were collected on patient demographics, scan indication and sites of disease pre- and post-PET. Results of standard imaging tests and FDG-PET scans were analysed. The potential impact of FDG-PET on proposed surgical management plans was assessed by an experienced surgeon. RESULTS: There were 585 FDG-PET scans performed on 470 patients (309M : 161F, mean age 61.9 years) with colorectal cancer. Hepatic metastases were identified on standard imaging in 232 (39.7%) patients, and FDG-PET confirmed hepatic metastasis in 203 cases, including 22 cases with new lesions, and clarified presence of disease in 34/37 (92%) cases with equivocal standard imaging. In 54 patients, FDG-PET was performed for disease assessment before hepatic resection. FDG-PET had substantial management plan impact in 36/54 (66.7%) patients. CONCLUSIONS: FDG-PET can profoundly impact on the management plan of patients with colorectal cancer who may be suitable for hepatic metastectomy. PMID- 22507491 TI - The developing clinical problem of chemotherapy-induced hepatic injury. AB - Chemotherapy is being administered to an increasing number of patients with colorectal liver metastases (CRLM), whether they have resectable disease or not. Although this may be appropriate to downstage patients with unresectable disease, and offers theoretical advantages to those who have resectable disease, there is a price to be paid in the development of chemotherapy-induced hepatic injuries (CIHI). These include chemotherapy-associated fatty liver diseases and sinusoidal injuries. The main chemotherapeutic agents currently used in the adjuvant setting for colorectal carcinoma, and the neoadjuvant treatment of CRLM include 5 flurouracil, oxaliplatin and irinotecan, and while there are non-specific and overlapping injury profiles, oxaliplatin does appear to be primarily associated with sinusoidal injury and irinotecan with steatohepatitis. In this review, the rationale for administering chemotherapy to patients with CRLM is presented, and the problems this brings are outlined. The specific injury patterns will be detailed, as well as the data correlating specific chemotherapy regimens to these injury patterns. Finally, the clinical outcomes of patients with CRLM who undergo neoadjuvant chemotherapy followed by hepatic resection will be considered. The need for methods to identify patients at risk of CIHI and to recognize established CIHI prior to surgery will be emphasized. PMID- 22507493 TI - Low-dose computed tomography versus plain abdominal radiography in the investigation of an acute abdomen. AB - BACKGROUND: To compare low-dose abdominal computed tomography (LDCT) with plain abdominal radiography (AR) in the primary investigation of acute abdominal pain to determine if there is a difference in diagnostic yield, the number of additional investigations required and hospital length of stay (LOS). METHODS: This randomized controlled trial was approved by the institutional review board, and informed consent was obtained. Patients presenting to the emergency department with an acute abdomen and who would normally be investigated with AR were randomized to either AR or LDCT. The estimated radiation dose of the LDCT protocol was 2-3 mSv compared to 1.1 mSv for AR. Pearson's chi-square and the independent samples t-test were used for the statistical analysis. RESULTS: A total of 142 patients were eligible, and after exclusions and omitting those with incomplete data, 55 patients remained for analysis in the AR arm and 53 in the LDCT arm. A diagnosis could be obtained in 12 (21.8%) patients investigated with AR compared to 34 (64.2%) for LDCT (P < 0.001). Twenty-eight (50.9%) patients in the AR group required further imaging during their admission compared to 14 (26.4%) in the LDCT group (P= 0.009). There was no difference in the median hospital LOS (3.84 days for AR versus 4.24 days for LDCT, P= 0.83). CONCLUSION: LDCT demonstrates a superior diagnostic yield over AR and reduces the number of subsequent imaging tests for a minimal cost in radiation exposure. However, there is no difference in the overall hospital LOS between the two imaging strategies. PMID- 22507494 TI - Role of fine needle aspiration cytology in the preoperative investigation of branchial cysts. AB - BACKGROUND: Successful preoperative diagnosis of a branchial cyst requires a systematic approach. The aim of this study was to evaluate methods of investigation of a lateral neck swelling suspicious for a branchial cyst, and to highlight cases where a less benign cause for the swelling should be suspected and therefore management altered appropriately. METHODS: A retrospective case study of 24 patients with presumed branchial cysts managed operatively was undertaken. Demographic, clinical, imaging, cytology and histopathological data were analysed to formulate an approach to the work-up of a lateral neck swelling suspected to be a branchial cyst. RESULTS: All 24 patients presented with a lateral neck mass thought to be a branchial cyst preoperatively underwent preoperative fine-needle aspiration cytology. The overall accuracy of cytology in predicting a benign branchial cyst histopathologically was 83.3% (20 out of 24). CONCLUSION: Successful preoperative diagnosis of a branchial cyst requires a combination of imaging and cytology. If there is concern that a lateral neck swelling is not a branchial cyst on clinical, imaging or cytological features, then a full preoperative work-up, including computed tomography scan of the neck and upper aero-digestive tract endoscopy should be performed, prior to an excisional biopsy. PMID- 22507495 TI - Master John of Arderne (1307-1380): a founder of modern surgery. AB - BACKGROUND: John of Arderne (1307-1380) was one founder of surgery as the profession is known today. He was the first English surgeon of whom biographic details survive. Born on the Arderne Estates at Newark, England, he served as a military surgeon in France in campaigns where gunpowder was used in combat for the first time. His best-known work, the Practica (De Arte Phisicali et de Cirurgia), formed the basis of practical surgical teaching in the medical schools of medieval Europe. METHOD: Biographic research of primary and secondary archives and documents. RESULTS: John of Arderne's surgical practice was undertaken against a background of turbulent political, military and medical events. He survived the Black Death (1347) and its cyclical recurrences. He lived through the turbulent reigns of Edward II and Edward III and practised in London in the decades preceding the simmering unrest which preceded the Peasant's Revolt of 1381. Surgical and medical practice in the late Middle Ages was enmeshed in astrological beliefs. It was greatly influenced by church doctrine of disease causation. CONCLUSION: In this paper, the known details of John of Arderne's life are placed in the perspective of these societal and professional influences. He is one of several pre-Renaissance European doctors who were the first to challenge the received medical lore of Galen and later Arabic surgeons. Writing when he was 70 years of age, John of Arderne was the first to advocate that surgeons should trust their own clinical experience 'Wele ymagynyng subtile things' rather than following the directions of others, even including those advocated by himself. PMID- 22507496 TI - Diagnostic value of an initial C-reactive protein level in acute surgical patients. AB - BACKGROUND: In surgical patients, C-reactive protein (CRP) levels are often measured as a marker of inflammation and infection. However, the diagnostic and prognostic value of a single initial CRP measurement in the acute presentation has not been well established. This study was performed to investigate the usefulness of measuring CRP in such a setting. METHODS: CRP levels were measured retrospectively in 473 surgical patients who presented to the Royal Adelaide Hospital emergency department. This was correlated with patient outcomes, defined by the need for imaging tests and/or surgical interventions, the length of hospital stay and 30-day mortality. Spearman's rank correlation and one-way analysis of variance were used for statistical analysis. RESULTS: Of 473 patients, 42% had a CRP test in the emergency department within 24 h of admission. Approximately 80% of patients required imaging for diagnosis and 40% required surgery, regardless of the initial CRP level. No correlation was evident between initial CRP level and length of hospital stay (r= 0.06). One-way analysis of variance revealed no variation in levels between patients who required imaging or had surgery compared to those who did not, with P-values of 0.76 and 0.85, respectively. Two patients died within 30 days of presentation. CONCLUSIONS: CRP has poor diagnostic and prognostic capabilities as a single initial measurement in acute surgical patients. The statistical analyses imply that CRP levels are unable to accurately predict outcomes of such patients. Therefore, we suggest that CRP should not be used as a routine screening tool. PMID- 22507497 TI - Dynamic hip screws versus proximal femoral nails for intertrochanteric fractures. AB - BACKGROUND: It is essential to determine the optimal treatment of intertrochanteric fractures due to their high incidence and related public health burden. Debate remains as to whether dynamic hip screws (DHS) or proximal femoral nails (PFNs) are best practice, and this pilot study seeks to collect information relevant to this query. METHODS: We undertook a retrospective audit of 144 patients who received a dynamic hip screw or a proximal femoral nail in order to compare age, sex, duration of surgery, duration of hospitalization, time of first mobilization, and rate anaemia, sepsis, avascular necrosis, prosthesis failure, revision, deep vein thrombosis, pulmonary embolus, non-ST elevation myocardial infarction, common peroneal nerve palsy and death between implantation of a DHS and a PFN. RESULTS: No differences were found between groups in age, duration of surgery, duration of hospitalization, time of first mobilization and rate of complications. Statistically significant differences were found in sex distributions, operation time and length of stay. However, analysis of median operation time and length of stay when adjusted for sex revealed no significant differences. CONCLUSION: This study demonstrated no statistically significant differences in peri- and post-operative measures between patients undergoing intertrochanteric fracture fixation via PFN or DHS. This is the only data from Australian hospitals, and further national research is needed. PMID- 22507498 TI - Perianal abscess in children: aiming for optimal management. AB - BACKGROUND: Perianal abscess is common in infants and children, yet the optimal surgical management is argued: incision and drainage alone is a simple procedure but is associated with a much higher recurrence rate than incision and drainage with simultaneous laying open of the associated fistula. This retrospective review established the institutional recurrence rate and its close association with how the fistula was managed at the initial operation. METHODS: A retrospective review of all children requiring an operation for a perianal abscess over a 13-year period from 1996 to 2009 was performed. Data were compared with published series. RESULTS: A fistula was sought in 89 of 91 (98%) patients, and identified in 66 (73%). Recurrence occurred in 5/66 (8%) in whom a fistula was identified at the initial operation, compared with 6/25 (24%) (P = 0.06) in whom a fistula was not identified. CONCLUSION: Recurrence of perianal infection is influenced by whether a fistula was identified and laid open at the initial operation. The recurrence rate is higher when the abscess is treated with incision and drainage alone. Given the ease with which most fistulae may be identified, and laid open without morbidity, optimal treatment involves drainage of the abscess and laying open of the fistulous tract. PMID- 22507499 TI - Re-resection for metachronous primary hepatocellular carcinoma: is it justified? AB - BACKGROUND: In management of intrahepatic recurrence of hepatocellular carcinoma (HCC), controversy exists over the efficacy of re-resection for patients with preserved liver function. This study aimed to determine the long-term outcomes of re-resection in these patients. METHODS: Prospectively collected data of 47 patients having re-resection (Group R) with curative intent for metachronous primary HCC between December 1989 and December 2007 were compared with those of 863 patients having primary resection (Group P) in the same period. There was no overlap of patient. All patients had gross tumour-free resection margin. RESULTS: The two groups had comparable demographics. Group R had a median age of 58 years (range, 48-67 years), and had almost all patients belonging to Child-Pugh class A (46/47). Median blood loss was 0.66 L (range, 0.3-1.28 L) for Group P and 0.37 L (range, 0.13-0.92 L) for Group R. Both groups had median blood transfusion rate at 0. Median operative time was 365 min (range, 240-490 min) for Group P and 270 min (range, 193-360 min) for Group R. Group R had significantly fewer tumour nodules and the only one operative death. Median follow-up was 41 months for Group P and 37 months for Group R (P= 0.133). The two groups displayed no significant differences in disease-free survival and overall survival. Univariate analysis showed that re-resection was not a significant risk factor in overall survival. CONCLUSION: Re-resection for metachronous primary HCC for patients with preserved liver function can achieve favourable survival outcome. PMID- 22507500 TI - Surgical services: shaping future directions. AB - BACKGROUND: Advances in surgical techniques and anaesthetic practise have facilitated a significant change in the way surgery is currently delivered. In particular, short stay surgery including ambulatory surgery has become the norm for the majority of surgical conditions. However, the planning of surgical services has not always kept pace with nor capitalised on these clinical advances. Like many major urban centres in Australia, the Greater Sydney region is changing, in terms of population growth and configuration of clinical and operational networks. In conjunction with NSW Department of Health, the ministerially appointed Surgical Services Taskforce was tasked with determining the shape and direction of surgery in Greater Sydney over the next 5 to 10 years. METHODS: Over 400 clinicians either attended hospitals forums or were contacted by the Surgery Futures project team. RESULTS: From the consultations, three models of service delivery were strongly advocated. These were the development of high volume short stay surgery centres, the establishment of specialty centres and the expansion of the streaming of planned and emergency surgery. CONCLUSION: These three major recommendations will require a significant reorganisation of surgical services in NSW. However, they are also relevant to surgical services planning elsewhere in Australia. It is imperative that these recommendations are incorporated into long term surgical planning in order to improve the efficiency and sustainability of surgical service delivery. PMID- 22507501 TI - Diagnostic lobectomy is not routinely required to exclude malignancy in thyroid nodules greater than four centimetres. AB - BACKGROUND: Surgical excision has been recommended as a diagnostic test for thyroid nodules >= 4 cm, due to the supposedly higher rate of cancer in larger nodules and the higher reported false-negative rates of fine-needle aspiration cytology (FNAC) testing (>10%). The aims of this study are to determine the prevalence of thyroid cancer in nodules >= 4 cm, to examine if a relationship between increasing nodule size and malignancy rate was present and to study the accuracy of preoperative FNAC diagnosis. METHODS: Retrospective analysis of data from patients with thyroid nodules >= 4 cm undergoing surgical resection between 1994 and 2008. Malignancy rates, cytology results and indications for surgery were analysed. RESULTS: A total of 223 patients with thyroid nodules >= 4 cm underwent thyroid resection between 1994 and 2008. The overall prevalence of thyroid cancer was 7.2% (95% confidence interval (CI): 4.2-11.4%). The malignancy rate did not vary significantly with increasing nodule size. The sensitivity of FNAC was 93.8% (95% CI: 69.8-99.8%), while the specificity of FNAC was 62.2% (95% CI: 54.9-69.2%). The most common indicator for surgery was compression symptoms. A positive FNAC test was the most significant indicator of underlying malignancy, with a likelihood ratio of 2.5 (95% CI: 2.0-3.1). CONCLUSIONS: Many patients with large thyroid nodules undergo thyroidectomy for symptom relief alone, regardless of their FNAC results. In such patients where other clinical indicators for thyroidectomy are not present, a benign FNAC result can reassure both patient and surgeon that mandatory surgical excision is not needed to exclude malignancy. PMID- 22507502 TI - Migrating orthopaedic pin. PMID- 22507503 TI - Endoscopic resection of neonatal nasopharyngeal teratoma. PMID- 22507504 TI - Surgical management of a tumour involving both peri-mandibular spaces and skull base. PMID- 22507506 TI - Pigmented liver cell adenoma: rare but benign. PMID- 22507505 TI - Obturator externus muscle abscess: an unusual complication post-optical urethrotomy. PMID- 22507507 TI - Painful true aneurysm in a brachio-basilic arterio-venous fistula. PMID- 22507508 TI - Contemporary teaching of anatomy in Australian medical schools: are we doing enough? (Re: ANZ J. Surg. 2011; 81: 662-3). PMID- 22507509 TI - Peripheral nerve sheath tumour mimicking thrombophlebitis. PMID- 22507510 TI - Stone or stricture: does the calibre of intrahepatic bile ducts predict the diagnosis? PMID- 22507511 TI - De Garengeot hernia. PMID- 22507512 TI - Importance of core biopsy in the diagnosis of thyroid lymphoma. PMID- 22507513 TI - Two cases of non-melanocytic skin cancer confused as trauma. PMID- 22507514 TI - Squamous cell carcinoma associated with large bladder calculus. PMID- 22507515 TI - Late complication of prostatic radiotherapy. PMID- 22507516 TI - Post-operative partial hypoparathyroidism: an under-recognized disorder (Re: ANZ J. Surg. 2011; 81: 524-7). PMID- 22507517 TI - Endoscopic ultrasound-guided fine needle aspiration as a diagnostic tool for gastric glomus tumours. PMID- 22507518 TI - Laparoscopic double cholecystectomy. PMID- 22507519 TI - Vascular closure device: a simple solution for inadvertent arterial catheterization. PMID- 22507520 TI - Delayed splenectomy following colonoscopy-associated splenic injury. PMID- 22507521 TI - Alternative sputum preparation to improve polymerase chain reaction assay for Mycobacterium tuberculosis detection. AB - BACKGROUND: Tuberculosis (TB), one of the major airborne infectious bacterial diseases, remains an important health problem worldwide. It is estimated that there are 1700 new cases per year in Santa Catarina State, Brazil. OBJECTIVE: To improve polymerase chain reaction (PCR) sensitivity in detecting Mycobacterium tuberculosis in sputum samples. METHODS: This study proposed the use of glass beads as a modification of the routine protocol for sputum preparation used in the Laboratory of Molecular Biology and Mycobacteria at the Federal University of Santa Catarina, Florianopolis, Brazil. The study comprised 120 sputum samples, 60 of which were treated with the routine protocol, while 60 were treated with the modified protocol using glass beads. RESULTS: Samples treated with the routine protocol had a sensitivity of 56.7% (95%CI 44.1-69.2) in 16S rRNA PCR and 81.7% (95%CI 71.9-91.5) in insertion sequence (IS) 6110 PCR, compared with culture. Samples treated with the modified protocol had a sensitivity of 73.3% (95%CI 62.1-84.5) in 16S rRNA PCR and 100% in IS6110 PCR. CONCLUSION: The modified protocol using glass beads greatly improved mycobacterial detection in sputum samples compared with the routine protocol. PMID- 22507522 TI - Differential changes of fat-soluble vitamins and pollutants during lactation in northern elephant seal mother-pup pairs. AB - We investigated the changes of vitamins A and E as well as PCBs and DDTs during lactation in northern elephant seal (Mirounga angustirostris) mother-pup pairs. On average, milk vitamin A concentrations were 6 times higher during late lactation than during early lactation, a pattern that differs dramatically from terrestrial mammals. Vitamin A concentrations also significantly increased in the inner blubber throughout lactation, whereas they remained constant in the outer blubber. Similar dynamics were observed for PCBs and DDTs in maternal blubber and milk. Blubber appears to be an important storage site for vitamin A and organochlorines in seals and a direct transfer of those molecules to the mammary gland may occur. The dynamics of vitamin A, PCBs and DDTs differed from those of vitamin E. There was a significant drop in milk vitamin E concentrations between early and late lactation, which is the usual pattern observed in terrestrial mammals. The dynamics of vitamin E in the blubber layers also differed from those of vitamin A, suggesting different mechanisms of mobilization and transfer into the milk. PMID- 22507523 TI - Low O2 avoidance is associated with physiological perturbation but not exhaustion in the snapper (Pagrus auratus: Sparidae). AB - It is already known that the New Zealand snapper (Pagrus auratus, Sparidae) does not avoid hypoxia until reaching an oxygen partial pressure (PO(2)) of 3.1+/-1.2 kPa at 18 degrees C. Avoidance at this level of PO(2) and temperature is below the critical oxygen partial pressure of the species (P(crit)=5.8+/-0.6 kPa, 43.5+/-4.5 mmHg) and is therefore expected to result in major physiological stress. Results from the current study showed that avoidance was associated with numerous physiological perturbations, including a significant endocrine response, haematological changes, osmoregulatory disturbance and metabolic adjustments in the heart, liver and muscle. Snapper clearly experienced physiological stress at the point of avoidance but they were not however in a state of physiological exhaustion since some fuel reserves were still available. In addition to avoidance, snapper also showed a subtle reduction in swimming speed - this energy saving response may have helped snapper minimise the physiological challenge of low O(2) residence. It is therefore concluded that snapper can reside in water below their P(crit) threshold for brief periods of time and, without any evidence of physiological exhaustion at the point of avoidance, fish should recover quickly once normoxia is selected. Lastly, with signs of anaerobic metabolism in cardiac tissue at the point of avoidance, we tentatively suggest that snapper may leave hypoxia to protect heart function. PMID- 22507524 TI - Haemophilia prophylaxis: how can we justify the costs? AB - Severe haemophilia results in increased mortality and poorer quality of life. Factor prophylaxis leads to a more normal life, but is very costly; most of the cost is due to the high cost of replacement factor. Despite its high cost, factor prophylaxis has been adopted throughout the developed world--even in different health care systems. We argue that there are at least five possible reasons why societies may value factor prophylaxis despite its cost: (i) it is directed towards an inherited disease, (ii) the treatment is largely directed towards children, (iii) the disease is rare and the overall cost to society is small, (iv) the treatment is preventative, and v) the high cost is largely the result of providing safe products. In an era of rising health care costs, there is a strong research agenda to establish the factors that determine the value of expensive therapies for rare diseases like haemophilia. PMID- 22507525 TI - A role for dorsal and ventral hippocampus in response learning. AB - The hippocampus and the striatum have been traditionally considered as part of different and independent memory systems despite growing evidence supporting that both brain regions may even compete for behavioral control in particular learning tasks. In this regard, it has been reported that the hippocampus could be necessary for the use of idiothetic cues in several types of spatial learning tasks. Accordingly, the ventral striatum receives strong anatomical projections from the hippocampus, suggesting a participation of both regions in goal-directed behavior. Our work examined the role of the dorsal and ventral hippocampus on a response learning task. Cytochrome c oxidase (C.O.) quantitative histochemistry was used as an index of brain oxidative metabolism. In addition, determination of C.O. subunit I levels in the hippocampus by western blot analysis was performed to assess the contribution of this subunit to overall C.O. activity. Increased brain oxidative metabolism was found in most of the studied hippocampal subregions when experimental group was compared with a swim control group. However, no differences were found in the amount of C.O. subunit I expressed in the hippocampus by western blot analysis. Our results support that both the dorsal and ventral hippocampus are associated with the use of response strategies during response learning. PMID- 22507526 TI - Convergent inputs from electrically and topographically distinct orexin cells to locus coeruleus and ventral tegmental area. AB - Orexin/hypocretin (orx/hcrt) neurons are thought to ensure that reward-seeking is accompanied by alertness, but the underlying circuit organization is unclear. Reports of differential regulation of lateral versus medial orx/hcrt cells produced a hypothesis of 'efferent dichotomy', in which lateral orx/hcrt cells innervate the ventral tegmental area (VTA) and control reward, while medial orx/hcrt cells innervate locus coeruleus (LC) and control arousal. Two distinct types of orx/hcrt cells also emerged from analysis of intrinsic and input-driven single-cell electrical activity. To examine the projections of these emerging orx/hcrt subtypes to LC and VTA, we injected retrograde tracer into these regions in the mouse brain in vivo, and then examined the properties of tracer-containing orx/hcrt cells in hypothalamic slices. VTA- and LC-projecting orx/hcrt cells were found across the entire orx/hcrt field, including the zona incerta, perifornical area, dorsomedial/anterior and lateral hypothalamus. Within these areas, orx/hcrt cells had similar probabilities of projecting to VTA or LC. Examination of lateral versus medial sections revealed that VTA and LC received inputs from both lateral and medial orx/hcrt cells, but, unexpectedly, lateral orx/hcrt cells were more likely to project to LC than medial orx/hcrt cells. Finally, patch-clamp recordings revealed that VTA and LC received projections from both electrical classes of orx/hcrt cells, which had similar likelihoods of projecting to VTA or LC. Contrary to previous predictions, our data suggest that medial and lateral orx/hcrt cells, and the different electrical and morphological subclasses of orx/hcrt cells identified to date, send projections to both LC and VTA. PMID- 22507527 TI - The effect of early onset common mental disorders on educational attainment in Australia. AB - Early onset mental disorders may lead to the early termination of education and thereby have long term adverse social and economic consequences on outcomes such as employment and financial security. This issue is important to address as governments seek to develop new ways to minimise the impacts of mental health problems and maximise workforce participation. The current investigation examines the impact of early onset affective, anxiety and substance use disorders on the early termination of secondary school education in Australia. The analyses used data from those aged between 20 and 34 in the 2007 Australian National Survey of Mental Health and Wellbeing (NSMHWB) (n=2055). The NSMHWB is a population based survey administered by the Australian Bureau of Statics and included a WMH-CIDI 3.0 assessment to determine whether respondents met diagnostic criteria for any lifetime affective, anxiety, and/or substance use disorder as well as age of onset information. The results show that early onset mental disorders are significantly associated with the termination of secondary education in Australia, particularly early onset substance use disorders such as alcohol, cannabis and stimulant use. These disorders were most likely to disrupt completion in the middle years of high school (year 10 completion), in comparison to the final year 12 milestone. Policies and interventions promoting prevention and early intervention and offering educational support for young people with psychiatric illness and substance use problems, should intervene prior to the middle years of high school to help prevent adverse social and economic consequences. PMID- 22507530 TI - Chondrogenesis of adipose stem cells in a porous polymer scaffold: influence of the pore size. AB - This study examined how the difference in pore size of porous scaffolds affected the in vitro chondrogenic differentiation of seeded adipose stem cells (ASCs) and the in vivo cartilage repair of ASC/scaffold construct. ASCs were isolated from 18 rabbits and seeded in a porous poly (epsilon-caprolactone) (PCL) scaffold with different pore sizes (100, 200, 400 MUm). The ASCs underwent in vitro chondrogenic induction under TGF-beta2 and BMP-7 for 21 days before analysis. The ASC/scaffold construct was also implanted on the osteochondral defect created on the distal femur of the same rabbits, and the quality of cartilage regeneration was analyzed after 8 weeks. At day 21, the ASCs proliferated and spread on the surface of the scaffolds with a pore size 100 and 200 MUm, whereas there were many lumps of conglomerated ASCs on those with a pore size of 400 MUm. The DNA content was significantly lower in the scaffold with a pore size of 400 MUm than in that with a pore size of 100 or 200 MUm. Proteoglycan production was significantly greater in the scaffold with a pore size of 400 and 200 MUm than in that with a pore size of 100 MUm. The chondrogenic marker gene expression including SOX9 and COL2A1 was greatest in the scaffold with a pore size of 400 MUm followed by 200 MUm. Immunofluorescent imaging showed that, while SOX9 was localized to nucleus, type II collagen was observed on the cytoplasm and secreted matrix around the cells most abundantly in the scaffold with a pore size of 400 MUm followed by 200 MUm. The gross and histological findings from the osteochondral defects showed that the cartilage repair was better in the scaffold with a pore size of 400 and 200 MUm than in that with a pore size of 100 MUm. PMID- 22507528 TI - Neuronal RING finger protein 11 (RNF11) regulates canonical NF-kappaB signaling. AB - BACKGROUND: The RING domain-containing protein RING finger protein 11 (RNF11) is a member of the A20 ubiquitin-editing protein complex and modulates peripheral NF kappaB signaling. RNF11 is robustly expressed in neurons and colocalizes with a population of alpha-synuclein-positive Lewy bodies and neurites in Parkinson disease patients. The NF-kappaB pathway has an important role in the vertebrate nervous system, where the absence of NF-kappaB activity during development can result in learning and memory deficits, whereas chronic NF-kappaB activation is associated with persistent neuroinflammation. We examined the functional role of RNF11 with respect to canonical NF-kappaB signaling in neurons to gain understanding of the tight association of inflammatory pathways, including NF kappaB, with the pathogenesis of neurodegenerative diseases. METHODS AND RESULTS: Luciferase assays were employed to assess NF-kappaB activity under targeted short hairpin RNA (shRNA) knockdown of RNF11 in human neuroblastoma cells and murine primary neurons, which suggested that RNF11 acts as a negative regulator of canonical neuronal NF-kappaB signaling. These results were further supported by analyses of p65 translocation to the nucleus following depletion of RNF11. Coimmunoprecipitation experiments indicated that RNF11 associates with members of the A20 ubiquitin-editing protein complex in neurons. Site-directed mutagenesis of the myristoylation domain, which is necessary for endosomal targeting of RNF11, altered the impact of RNF11 on NF-kappaB signaling and abrogated RNF11's association with the A20 ubiquitin-editing protein complex. A partial effect on canonical NF-kappaB signaling and an association with the A20 ubiquitin-editing protein complex was observed with mutagenesis of the PPxY motif, a proline-rich region involved in Nedd4-like protein interactions. Last, shRNA-mediated reduction of RNF11 in neurons and neuronal cell lines elevated levels of monocyte chemoattractant protein 1 and TNF-alpha mRNA and proteins, suggesting that NF kappaB signaling and associated inflammatory responses are aberrantly regulated in the absence of RNF11. CONCLUSIONS: Our findings support the hypothesis that, in the nervous system, RNF11 negatively regulates canonical NF-kappaB signaling. Reduced or functionally compromised RNF11 could influence NF-kappaB-associated neuronal functions, including exaggerated inflammatory responses that may have implications for neurodegenerative disease pathogenesis and progression. PMID- 22507529 TI - Knockdown of aberrantly expressed nuclear localized decorin attenuates tumour angiogenesis related mediators in oral cancer progression model in vitro. AB - BACKGROUND: Oral cancer accounts for roughly 3% of cancer cases in the world with about 350,000 newly reported cases annually and a 5-year survival rate of only 50%. Majority of oral cancers are squamous cell carcinomas that originate in the oral mucosal epithelial linings. We have previously shown that in human malignant squamous cells carcinoma (SCC-25) as well as in dysplastic oral keratinocytes (DOK), a small leucine-rich multifunctional proteoglycan decorin is aberrantly expressed and localized in the nucleus where it interacts with nuclear epidermal growth factor receptor (EGFR). Post-transcriptional silencing of nuclear decorin significantly reduced IL-8 and IL8-dependent migration and invasion in these dysplastic and malignant oral epithelia. The objective of this study was to further examine the effects of nuclear decorin silencing on angiogenesis and angiogenesis related mediators in this oral cancer progression cell line model. METHODS: We have used multiplex PCR, western blotting, and in vitro endothelial tube formation assay to study angiogenesis and related pathways in nuclear decorin silenced (stable knockdown) DOK and SCC-25 cells. RESULTS: Nuclear decorin knockdown resulted in significant down regulation of IL-8 expression, however IL-10, and TGF-beta expression was not affected in either DOK or SCC25 cells as measured by multiplex RT PCR. IL-8 receptor CXCR 1 and 2 expression was slightly lower in nuclear decorin silenced cells indicating a contributing mechanism in previously shown reduced IL-8 mediated migration and invasion phenotype in these cells. IL-8 is known to induce Matrix metalloproteinase 9 (MMP9) which not only plays a role in tumour migration and invasion but also induces angiogenic switch. We found MMP9 to be significantly reduced in nuclear decorin silenced dysplastic and malignant oral epithelia. Other potent angiogenic mediators, VEGF189 and ANG-1 were either significantly reduced or completely abrogated in these cells. Angiogenesis as measured by endothelial tube-like formations of HUVEC cells was reduced by almost 50 percent when HUVECs were incubated in the presence of conditioned medium form nuclear decorin silenced dysplastic and malignant cell lines as compared to respective controls. CONCLUSIONS: Together these results indicate that aberrantly expressed nuclear localized decorin strongly influences angiogenic potential of dysplastic and malignant oral epithelial cells. PMID- 22507531 TI - Detection of sentinel lymph nodes in patients with endometrial cancer undergoing robotic-assisted staging: a comparison of colorimetric and fluorescence imaging. AB - OBJECTIVE: To retrospectively compare results from lymphatic mapping of pelvic sentinel lymph nodes (SLN) using fluorescence near-infrared (NIR) imaging of indocyanine green (ICG) and colorimetric imaging of isosulfan blue (ISB) dyes in women with endometrial cancer (EC) undergoing robotic-assisted lymphadenectomy (RAL). A secondary aim was to investigate the ability of SLN biopsies to increase the detection of metastatic disease. METHODS: Thirty-five patients underwent RAL with hysterectomy. One mL ISB was injected submucosally in four quadrants of the cervix, followed by 0.5 mL ICG [1.25mg/mL] immediately prior to placement of a uterine manipulator. Retroperitoneal spaces were dissected for colorimetric detection of lymphatic pathways. The da Vinci((r)) camera was switched to fluorescence imaging and results recorded. SLN were removed for permanent analysis with ultra-sectioning, H&E, and IHC staining. Hysterectomy with RAL was completed. RESULTS: Twenty-seven (77%) and 34 (97%) of patients had bilateral pelvic or aortic SLN detected by colorimetric and fluorescence, respectively (p=0.03). Considering each hemi-pelvis separately, 15/70 (21.4%) had "weak" uptake of ISB in SLN confirmed positive with fluorescence imaging. Using both methods, bilateral detection was 100%. Ten (28.6%) patients had lymph node (LN) metastasis, and 9 of these had SLN metastasis (90% sensitivity, one false negative SLN biopsy). Seven of nine (78%) SLN metastases were ISB positive and 100% were ICG positive. Twenty-five had normal LN, all with negative SLN biopsies (100% specificity). Four (40%) with LN metastasis were detected only by IHC and ultra-sectioning of SLN. CONCLUSIONS: Fluorescence imaging with ICG detected bilateral SLN and SLN metastasis more often than ISB, and the combination resulted in 100% bilateral detection of SLN. Ultra-sectioning/IHC of SLN increased the detection of lymph node metastasis. PMID- 22507532 TI - Cardiovascular disease is the leading cause of death among endometrial cancer patients. AB - OBJECTIVE: To evaluate the causes of death among women with endometrial cancer. METHODS: SEER registries from 1973-1988 were queried to perform a retrospective cohort study of women with invasive epithelial endometrial cancer. Causes of death were compared according to grade and stage. RESULTS: 33,232 women with incident cases of endometrial cancer had died at the time of last follow up. Overall, women were most likely to die from cardiovascular disease (35.9%, 95% CI 35.3-36.3%), followed by other causes, other malignancies, and endometrial cancer. Women with low grade localized cancer were most likely to die of cardiovascular disease, while women with high grade advanced cancer were least likely to die of cardiovascular disease and most likely to die of endometrial cancer. For the entire population, risk of death from cardiovascular causes surpasses the risk of death from endometrial cancer 5 years after diagnosis. CONCLUSIONS: Higher risk of cardiac death among endometrial cancer patients likely reflects the high probability of curative cancer treatment and the prevalence of cardiac disease and risk factors. As the probability of dying of endometrial cancer decreases with time, the probability of dying of cardiovascular disease increases. Interventions and investigations aimed at addressing risk factors for cardiovascular disease may have the greatest potential to improve survival for women diagnosed with endometrial cancer and should feature prominently in treatment and survivorship plans. PMID- 22507533 TI - Impact of operative start time on surgical outcomes in patients undergoing primary cytoreduction for advanced ovarian cancer. AB - OBJECTIVES: To evaluate the impact of operative start time (OST) on surgical outcomes in patients with advanced ovarian cancer. METHODS: All stage IIIB-IV serous ovarian cancer patients who underwent primary surgery at our institution from 1/01 to 1/10 were identified. Fourteen factors were evaluated for an association with surgical outcomes including OST and OR tumor index (1 point each for carcinomatosis and/or bulky [>= 1 cm] upper abdominal disease). Univariate logistic regression considering within-surgeon clustering was performed for cytoreduction to <= 1 cm versus >1cm residual disease. In patients with <= 1 cm residual disease, univariate logistic regression considering within-surgeon clustering was performed for 1-10mm residual disease versus complete gross resection (CGR, 0mm residual). A multivariate logistic model was developed based on univariate analysis results in the <= 1 cm residual disease cohort. RESULTS: Of 422 patients, residual disease was: 0mm, 144 (34.1%); 1-10mm, 175 (41.5%); >10mm, 103 (23.3%). OST was not associated with cytoreduction to <= 1 cm residual disease on univariate analysis. In the <= 1 cm residual disease cohort, albumin, CA-125, ascites, ASA score, stage, OR tumor index, and OST were associated with CGR on univariate analysis. Earlier OSTs were associated with increased rates of CGR. On multivariate analysis, CA-125 was independently associated with CGR. OST was associated with CGR in patients with an OR tumor index of 2 but not an OR tumor index<2. CONCLUSIONS: OST was not associated with cytoreduction to <= 1 cm residual disease in patients with advanced serous ovarian cancer. In the cohort of patients with <= 1 cm residual disease, later OSTs were associated with reduced rates of CGR in patients with greater tumor burden. PMID- 22507534 TI - Centralisation of services for gynaecological cancers - a Cochrane systematic review. AB - OBJECTIVE: Gynaecological cancers are the second most common cancers among women. It has been suggested that centralised care improves outcomes but consensus is lacking. This systematic review assesses the effectiveness of centralisation of care for patients with gynaecological cancer, in particular, survival advantage. METHODS: A comprehensive search of the Cochrane Gynaecological Cancer Group Trials Register, CENTRAL (The Cochrane Library, Issue 4, 2010), MEDLINE, and EMBASE up to November 2010 was conducted. Registers of clinical trials, abstracts of scientific meetings, and reference lists of included studies were also searched. Randomised controlled trials (RCTs), quasi-RCTs, controlled before-and after studies, interrupted time series studies, and observational studies were included and multivariable analysis to adjust for baseline case mix were used. RESULTS: Five retrospective observational studies met the inclusion criteria. Meta-analysis of three studies assessing over 9000 women suggested that institutions with gynaecologic oncologists on site may prolong survival in women with ovarian cancer, compared to community or general hospitals: hazard ratio (HR) of death was 0.90 (95% confidence interval (CI) 0.82 to 0.99). Similarly, another meta-analysis of three studies assessing over 50,000 women, found that teaching centres or regional cancer centres may prolong survival in women with any gynaecological cancer compared to community or general hospitals (HR 0.91; 95% CI 0.84 to 0.99). The largest of these studies included all gynaecological malignancies and assessed 48,981 women, so the findings extend beyond ovarian cancer. One study compared community hospitals with semi-specialised gynaecologists versus general hospitals and reported non-significantly better disease-specific survival in women with ovarian cancer (HR 0.89; 95% CI 0.78 to 1.01). The findings of included studies were highly consistent. CONCLUSIONS: The meta-analysis provides evidence to suggest that women with gynaecological cancer who received treatment in specialised centres had longer survival than those managed elsewhere. PMID- 22507535 TI - The prognostic significance of age in surgically staged patients with Type II endometrial carcinoma. AB - OBJECTIVE: Many studies have examined the impact of older age on tumor recurrence and survival after hysterectomy for patients with endometrioid carcinoma. However, there is paucity of data examining the prognostic significance of age in patients with Type II endometrial carcinoma. The study was conducted to determine the prognostic impact of age in this patient population. MATERIALS AND METHODS: In this Institutional Review Board (IRB)-approved study, our prospectively maintained database of 1305 patients with endometrial cancer was reviewed. Seventy-two consecutive patients with serous and clear carcinoma 2009 FIGO stages I-II were identified with at least one year follow-up after surgical staging. Patients with mixed histology and those who received preoperative therapy were excluded. All the patients underwent surgical staging from 1989 to 2009. Their medical records were reviewed. The study cohort was divided into two groups based on their age at hysterectomy (<= 65 vs. >65). Patient's demographics, pathologic features and treatment-related factors were compared. The impact of age on recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) were calculated. Following univariate analysis, multivariate modeling was done using step-wise Cox proportional hazards analysis to assess the impact of age on clinical outcomes after adjusting for various clinical variables. RESULTS: Median follow-up for the study cohort was 45 months (range 13 246). Fifty percent of patients received adjuvant platinum-based chemotherapy and/or adjuvant radiation treatment (RT). Thirty-five patients were older than 65 years (49%) and 37 were <= 65 (51%). There were no significant differences between the two groups in regard to race (African American vs Caucasian), FIGO stage, number of lymph nodes dissected, lymphovascular space involvement (LVSI), or adjuvant therapy received. There were more clear cell histology in the younger age group (p=0.035). Patients >65 years old developed more recurrences with a 5 year RFS of 59% compared to 84% for younger patients (p=0.036). The five-year DSS was not statistically different between the two groups (68% vs. 79%, respectively with p=0.313). 5-year OS was significantly shorter in the elderly patients (58% vs. 78% with p=0.014). On multivariate analysis, the presence of LVSI, not receiving RT and age >65 were independent predictors of worse RFS (p=<0.001, 0.005, and 0.040 respectively). CONCLUSION: In this study for surgically staged FIGO I-II patients with Type II endometrial carcinoma, age more than 65 years is a significant adverse prognostic factor for tumor recurrence. PMID- 22507537 TI - A retrospective database study of insulin initiation in patients with Type 2 diabetes in UK primary care. AB - AIMS: This study characterized UK primary care patients with Type 2 diabetes who initiated insulin treatment, and described the initial insulin regimens used, overall metabolic changes and health-care resource usage. METHODS: A retrospective cohort study was performed using quality-checked patient data from The Health Improvement Network database. Eligible patients who initiated insulin for the first time between 2004 and 2006 were grouped into four cohorts according to the type of insulin regimen initiated. Data on patient characteristics, metabolic and clinical outcomes and health-care resource use were collected at baseline and during 6 months of follow-up. RESULTS: In total, 4045 eligible adults [2269 male, 1776 female; mean age 62.6 +/- 13.3 years; mean baseline HbA(1c) 82 +/- 22 mmol/mol (9.6% +/- 2.0%)] initiated insulin. Approximately half (52.4%) initiated insulin as basal insulin only, 41.6% as premixed only, 4.0% as basal-bolus and 2.1% as prandial insulin only. Among patients with >= 180 days follow-up (n=3815), the initial insulin regimen was not changed during follow-up in 75.1% of patients, while 13.7% discontinued, 7.0% switched and 4.7% intensified insulin therapy. The mean change in HbA(1c) was -14 mmol/mol (-1.3%, n=2881), with 17.3% of patients achieving an HbA(1c) of <53 mmol/mol (7%, n=3024). The mean weight change was +0.9 kg (n=2345). CONCLUSIONS: Basal and premixed insulin were the most common types of insulin initiated and in most patients no changes were made to the initial regimen over 6 months. However, few patients achieved glycemic control targets. PMID- 22507536 TI - A comparative study of nemertean complete mitochondrial genomes, including two new ones for Nectonemertes cf. mirabilis and Zygeupolia rubens, may elucidate the fundamental pattern for the phylum Nemertea. AB - BACKGROUND: The mitochondrial genome is important for studying genome evolution as well as reconstructing the phylogeny of organisms. Complete mitochondrial genome sequences have been reported for more than 2200 metazoans, mainly vertebrates and arthropods. To date, from a total of about 1275 described nemertean species, only three complete and two partial mitochondrial DNA sequences from nemerteans have been published. Here, we report the entire mitochondrial genomes for two more nemertean species: Nectonemertes cf. mirabilis and Zygeupolia rubens. RESULTS: The sizes of the entire mitochondrial genomes are 15365 bp for N. cf. mirabilis and 15513 bp for Z. rubens. Each circular genome contains 37 genes and an AT-rich non-coding region, and overall nucleotide composition is AT-rich. In both species, there is significant strand asymmetry in the distribution of nucleotides, with the coding strand being richer in T than A and in G than C. The AT-rich non-coding regions of the two genomes have some repeat sequences and stem-loop structures, both of which may be associated with the initiation of replication or transcription. The 22 tRNAs show variable substitution patterns in nemerteans, with higher sequence conservation in genes located on the H strand. Gene arrangement of N. cf. mirabilis is identical to that of Paranemertes cf. peregrina, both of which are Hoplonemertea, while that of Z. rubens is the same as in Lineus viridis, both of which are Heteronemertea. Comparison of the gene arrangements and phylogenomic analysis based on concatenated nucleotide sequences of the 12 mitochondrial protein-coding genes revealed that species with closer relationships share more identical gene blocks. CONCLUSION: The two new mitochondrial genomes share many features, including gene contents, with other known nemertean mitochondrial genomes. The tRNA families display a composite substitution pathway. Gene order comparison to the proposed ground pattern of Bilateria and some lophotrochozoans suggests that the nemertean ancestral mitochondrial gene order most closely resembles the heteronemertean type. Phylogenetic analysis proposes a sister-group relationship between Hetero- and Hoplonemertea, which supports one of two recent alternative hypotheses of nemertean phylogeny. PMID- 22507538 TI - The human epidermal differentiation complex: cornified envelope precursors, S100 proteins and the 'fused genes' family. AB - The skin is essential for survival and protects our body against biological attacks, physical stress, chemical injury, water loss, ultraviolet radiation and immunological impairment. The epidermal barrier constitutes the primordial frontline of this defense established during terminal differentiation. During this complex process proliferating basal keratinocytes become suprabasally mitotically inactive and move through four epidermal layers (basal, spinous, granular and layer, stratum corneum) constantly adapting to the needs of the respective cell layer. As a result, squamous keratinocytes contain polymerized keratin intermediate filament bundles and a water-retaining matrix surrounded by the cross-linked cornified cell envelope (CE) with ceramide lipids attached on the outer surface. These cells are concomitantly insulated by intercellular lipid lamellae and hold together by corneodesmosmes. Many proteins essential for epidermal differentiation are encoded by genes clustered on chromosomal human region 1q21. These genes constitute the 'epidermal differentiation complex' (EDC), which is divided on the basis of common gene and protein structures, in three gene families: (i) CE precursors, (ii) S100A and (iii) S100 fused genes. EDC protein expression is regulated in a gene and tissue-specific manner by a pool of transcription factors. Among them, Klf4, Grhl3 and Arnt are essential, and their deletion in mice is lethal. The importance of the EDC is further reflected by human diseases: FLG mutations are the strongest risk factor for atopic dermatitis (AD) and for AD-associated asthma, and faulty CE formation caused by TG1 deficiency causes life-threatening lamellar ichthyosis. Here, we review the EDC genes and the progress in this field. PMID- 22507539 TI - Climate-driven diversity dynamics in plants and plant-feeding insects. AB - The origin of species-rich insect-plant food webs has traditionally been explained by diversifying antagonistic coevolution between plant defences and herbivore counter-defences. However, recent studies combining paleoclimatic reconstructions with time-calibrated phylogenies suggest that variation in global climate determines the distribution, abundance and diversity of plant clades and, hence, indirectly influences the balance between speciation and extinction in associated herbivore groups. Extant insect communities tend to be richest on common plant species that have many close relatives. This could be explained either by climate-driven diffuse cospeciation between plants and insects, or by elevated speciation and reduced extinction in herbivore lineages associated with expanding host taxa (resources). Progress in paleovegetation reconstructions in combination with the rapidly increasing availability of fossil-calibrated phylogenies provide means to discern between these alternative hypotheses. In particular, the 'Diffuse cospeciation' scenario predicts closely matching main diversification periods in plants and in the insects that feed upon them, while the 'Resource abundance-dependent diversification' hypothesis predicts that both positive and negative responses of insect diversity are lagged in relation to host-plant availability. The dramatic Cenozoic changes in global climate provide multiple possibilities for studying the mechanisms by which climatic shifts may drive diversity dynamics in plants and insect herbivores. PMID- 22507540 TI - DNA from soil mirrors plant taxonomic and growth form diversity. AB - Ecosystems across the globe are threatened by climate change and human activities. New rapid survey approaches for monitoring biodiversity would greatly advance assessment and understanding of these threats. Taking advantage of next generation DNA sequencing, we tested an approach we call metabarcoding: high throughput and simultaneous taxa identification based on a very short (usually <100 base pairs) but informative DNA fragment. Short DNA fragments allow the use of degraded DNA from environmental samples. All analyses included amplification using plant-specific versatile primers, sequencing and estimation of taxonomic diversity. We tested in three steps whether degraded DNA from dead material in soil has the potential of efficiently assessing biodiversity in different biomes. First, soil DNA from eight boreal plant communities located in two different vegetation types (meadow and heath) was amplified. Plant diversity detected from boreal soil was highly consistent with plant taxonomic and growth form diversity estimated from conventional above-ground surveys. Second, we assessed DNA persistence using samples from formerly cultivated soils in temperate environments. We found that the number of crop DNA sequences retrieved strongly varied with years since last cultivation, and crop sequences were absent from nearby, uncultivated plots. Third, we assessed the universal applicability of DNA metabarcoding using soil samples from tropical environments: a large proportion of species and families from the study site were efficiently recovered. The results open unprecedented opportunities for large-scale DNA-based biodiversity studies across a range of taxonomic groups using standardized metabarcoding approaches. PMID- 22507541 TI - Mitochondrial aldehyde dehydrogenase 2 activation and cardioprotection. AB - Cardiac ischemia and reperfusion promote oxidative stress, leading to the accumulation of reactive aldehydes that cause cardiac damage. Mitochondrial aldehyde dehydrogenase 2 is emerging as a key cardioprotective enzyme for its central role in the detoxification of reactive aldehydes. Mitochondrial aldehyde dehydrogenase 2 activity strongly correlates to a better cardioprotective effect, and mitochondrial aldehyde dehydrogenase 2 can be activated by several pathways. After phosphorylation, the active mitochondrial aldehyde dehydrogenase 2 can reduce the build-up of aldehydes, inhibit autophagy, inhibit opening of the mitochondrial permeability transition pore, and prevent reperfusion arrhythmias. Therefore, mitochondrial aldehyde dehydrogenase 2 activation by small molecule activators suggests a promising new direction in cardiovascular research and the development of novel cardioprotective strategies. This review will discuss the cardioprotective effects of mitochondrial aldehyde dehydrogenase 2 activation in detail. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism". PMID- 22507542 TI - Restoration of glucose metabolism in leptin-resistant mouse hearts after acute myocardial infarction through the activation of survival kinase pathways. AB - In the normal heart, leptin modulates cardiac metabolism. It is unknown, however, what effect leptin has on cardiac metabolism and outcomes in acute myocardial infarction (MI). This study was performed to test the hypothesis that leptin signaling increases glucose metabolism and attenuates injury in the acutely infarcted heart. Mice with (ObR(+/+)) and without (ObR(-/-)) cardiomyocyte specific expression of leptin receptor (ObR) were randomly assigned to experimental MI or sham procedure, and studied 3 days later. ObR(+/+) and ObR(-/ ) sham mice were not significantly different in any measured outcome. However, after MI, ObR(-/-) mice had greater cardiac dysfunction, left ventricular dilation, and levels of oxidative stress. These worse indices of cardiac injury in ObR(-/-) mice were associated with attenuated signal transducer and activator of transcription (STAT) 3, phosphatidylinositol-3-kinase (PI3K), and Akt signaling, decreased malonyl CoA content, and reduced mitochondrial pyruvate dehydrogenase and electron transport Complex I, II and IV activities. Furthermore, ObR(-/-) mice maintained high rates of cardiac fatty acid oxidation after MI, whereas ObR(+/+) mice demonstrated a switch away from fatty acid oxidation to glucose metabolism. Restoration of cardiac STAT3, PI3K and Akt activity and mitochondrial function in ObR(-/-) mice post-MI was accomplished by ciliary neurotrophic factor (CNTF), an established STAT3 activator, administered immediately after MI. Moreover, CNTF therapy resulted in mitigation of cardiac structural and functional injury, attenuated levels of oxidative stress, and rescued glucose metabolism in the infarcted ObR(-/-) heart. These data demonstrate that impaired cardiac leptin signaling results in metabolic inflexibility for glucose utilization in the face of cardiac stress, and greater morbidity after MI. Further, these studies show that cardiac glucose metabolism can be restored in leptin-resistant hearts by CNTF-mediated activation of survival kinases, resulting in multiple improved structural and functional outcomes post-MI. PMID- 22507543 TI - Genotoxicity of styrene-7,8-oxide and styrene in Fisher 344 rats: a 4-week inhalation study. AB - The cytogenetic alterations in leukocytes and the increased risk for leukemia, lymphoma, or all lymphohematopoietic cancer observed in workers occupationally exposed to styrene have been associated with its hepatic metabolisation into styrene-7,8-oxide, an epoxide which can induce DNA damages. However, it has been observed that styrene-7,8-oxide was also found in the atmosphere of reinforced plastic industries where large amounts of styrene are used. Since the main route of exposure to these compounds is inhalation, in order to gain new insights regarding their systemic genotoxicity, Fisher 344 male rats were exposed in full body inhalation chambers, 6 h/day, 5 days/week for 4 weeks to styrene-7,8-oxide (25, 50, and 75 ppm) or styrene (75, 300, and 1000 ppm). Then, the induction of micronuclei in circulating reticulocytes and DNA strand breaks in leukocytes using the comet assay was studied at the end of the 3rd and 20th days of exposure. Our results showed that neither styrene nor styrene-7,8-oxide induced a significant increase of the micronucleus frequency in reticulocytes or DNA strand breaks in white blood cells. However, in the presence of the formamidopyridine DNA glycosylase, an enzyme able to recognize and excise DNA at the level of some oxidized DNA bases, a significant increase of DNA damages was observed at the end of the 3rd day of treatment in leukocytes from rats exposed to styrene but not to styrene-7,8-oxide. This experimental design helped to gather new information regarding the systemic genotoxicity of these two chemicals and may be valuable for the risk assessment associated with an occupational exposure to these molecules. PMID- 22507544 TI - Fibrinogen counteracts the antiadhesive effect of fibrin-bound plasminogen by preventing its activation by adherent U937 monocytic cells. AB - BACKGROUND: Fibrinogen and plasminogen strongly reduce adhesion of leukocytes and platelets to fibrin clots, highlighting a possible role for these plasma proteins in surface-mediated control of thrombus growth and stability. In particular, adsorption of fibrinogen on fibrin clots renders their surfaces non-adhesive, while the conversion of surface-bound plasminogen to plasmin by transiently adherent blood cells results in degradation of a superficial fibrin layer, leading to cell detachment. Although the mechanisms whereby these proteins exert their antiadhesive effects are different, the outcome is the same: the formation of a mechanically unstable surface that does not allow firm cell attachment. OBJECTIVES: Since fibrin clots in circulation are exposed to both fibrinogen and plasminogen, their combined effect on adhesion of monocytic cells was examined. METHODS: Fibrin gels were coated with plasminogen and its activation by adherent U937 monocytic cells in the presence of increasing concentrations of fibrinogen was examined by either measuring (125) I-labeled fibrin degradation products or plasmin amidolytic activity. RESULTS: Unexpectedly, the antiadhesive effects of two fibrin binding proteins were not additive; in fact, in the presence of fibrinogen, the effect of plasminogen was strongly reduced. An investigation of the underlying mechanism revealed that fibrinogen prevented activation of fibrin bound plasminogen by cells. Confocal microscopy showed that fibrinogen accumulates in a thin superficial layer of a clot, where it exerts its blocking effect on activation of plasminogen. CONCLUSION: The results point to a complex interplay between the fibrinogen- and plasminogen-dependent antiadhesive systems, which may contribute to the mechanisms that control the adhesiveness of a fibrin shell on the surface of hemostatic thrombi. PMID- 22507545 TI - Endothelial progenitor cells are suppressed in anemic patients with acute coronary syndrome. AB - OBJECTIVE: Anemia is an independent predictor of poor prognosis in acute coronary syndrome. Endothelial progenitor cells are bone marrow-derived cells that are mobilized into the circulation in response to ischemia. The number of circulating endothelial progenitor cells increases within days of acute coronary syndrome. There is no confirmation regarding the correlation between the occurrence of anemia and the deficiency in endothelial progenitor cells in patients with acute coronary syndrome. The correlation between chronic anemia and endothelial progenitor cells in patients with acute coronary syndrome was investigated. METHODS: Endothelial progenitor cells were examined in 26 patients with acute coronary syndrome. Fifteen patients had chronic nonprogressive anemia, and 11 patients had a normal blood count. Blood samples were drawn on the first day of admission and 4 to 7 days later. Mononuclear cells were separated and cultured on fibronectin-coated plates with EndoCult medium (StemCell Technologies, Vancouver, BC, Canada) for 5 days. Colony forming unit count and a migration assay were performed at each time point. RESULTS: Baseline colony forming unit in the non anemic group was higher than in the anemic group (P<.0001). There was a highly significant correlation between admission hemoglobin and colony forming unit count (R=0.83, P<.0001). Colony forming units increased in both groups on the second measurement but to a lower extent in the anemic group (P = .0004). The migration assay in the non-anemic group was higher than in the anemic group at baseline (P = .017) and 4 to 7 days later (P = .0054). CONCLUSION: Patients with acute coronary syndrome with anemia demonstrate a reduced number of peripheral endothelial progenitor cells with impaired function, possibly representing a lower capacity for vascular healing. These phenomena may partly explain the poor prognosis observed in patients with acute coronary syndrome and anemia. PMID- 22507546 TI - Quality of life in haemophilia A: Hemophilia Utilization Group Study Va (HUGS Va). AB - This study describes health-related quality of life (HRQoL) of persons with haemophilia A in the United States (US) and determines associations between self reported joint pain, motion limitation and clinically evaluated joint range of motion (ROM), and between HRQoL and ROM. As part of a 2-year cohort study, we collected baseline HRQoL using the SF-12 (adults) and PedsQL (children), along with self-ratings of joint pain and motion limitation, in persons with factor VIII deficiency recruited from six Haemophilia Treatment Centres (HTCs) in geographically diverse regions of the US. Clinically measured joint ROM measurements were collected from medical charts of a subset of participants. Adults (N = 156, mean age: 33.5 +/- 12.6 years) had mean physical and mental component scores of 43.4 +/- 10.7 and 50.9 +/- 10.1, respectively. Children (N = 164, mean age: 9.7 +/- 4.5 years) had mean total PedsQL, physical functioning, and psychosocial health scores of 85.9 +/- 13.8, 89.5 +/- 15.2, and 84.1 +/- 15.3, respectively. Persons with more severe haemophilia and higher self-reported joint pain and motion limitation had poorer scores, particularly in the physical aspects of HRQoL. In adults, significant correlations (P < 0.01) were found between ROM measures and both self-reported measures. Except among those with severe disease, children and adults with haemophilia have HRQoL scores comparable with those of the healthy US population. The physical aspects of HRQoL in both adults and children with haemophilia A in the US decrease with increasing severity of illness. However, scores for mental aspects of HRQoL do not differ between severity groups. These findings are comparable with those from studies in European and Canadian haemophilia populations. PMID- 22507547 TI - Categorical representation of objects in the central nucleus of the monkey amygdala. AB - The primate amygdala consists of several subnuclei. Neurons in this brain area have been known to respond to stimuli belonging to specific categories of objects, such as faces, animals, and artifacts. However, little is known about the functional differences among the nuclei of the primate amygdala. To clarify functional differences among these subnuclei in object categorization, we compared the responsiveness of neuronal populations among the lateral, basal and central nuclei of the monkey amygdala. The activity of 203 neurons was recorded while video clips of 13 stimuli belonging to three categories (monkey, human, and artifact) were presented. Of these neurons, 37, 39 and 37 neurons in the lateral, basal and central nuclei, respectively, responded to at least one of the stimuli. We applied a cluster analysis to the neuronal population responses from these nuclei, and also calculated information about the three categories and monkey identity from each neuronal population. We found that the three categories and monkey identity could be more properly classified by neuronal responsiveness in the central nucleus, which is an output gate of the amygdala, than by that in the lateral and basal nuclei. These results suggest that the information about objects suitable for the generation of appropriate emotional response is built up within the primate amygdala via an intra-amygdala network from the lateral nucleus to the central nucleus. PMID- 22507548 TI - The function of mitochondrial F(O)F(1) ATP-synthase from the whiteleg shrimp Litopenaeus vannamei muscle during hypoxia. AB - The effect of hypoxia and re-oxygenation on the mitochondrial complex F(O)F(1) ATP synthase was investigated in the whiteleg shrimp Litopenaeus vannamei. A 660 kDa protein complex isolated from mitochondria of the shrimp muscle was identified as the ATP synthase complex. After 10h at hypoxia (1.5-2.0 mg oxygen/L), the concentration of L-lactate in plasma increased significantly, but the ATP amount and the concentration of ATPbeta protein remained unaffected. Nevertheless, an increase of 70% in the ATPase activity was detected, suggesting that the enzyme may be regulated at a post-translational level. Thus, during hypoxia shrimp are able to maintain ATP amounts probably by using some other energy sources as phosphoarginine when an acute lack of energy occurs. During re oxygenation, the ATPase activity decreased significantly and the ATP production continued via the electron transport chain and oxidative phosphorylation. The results obtained showed that shrimp faces hypoxia partially by hydrolyzing the ATP through the reaction catalyzed by the mitochondrial ATPase which increases its activity. PMID- 22507549 TI - Characterization and expression of calmodulin gene during larval settlement and metamorphosis of the polychaete Hydroides elegans. AB - The polychaete Hydroides elegans (Serpulidae, Lophotrochozoa) is a problematic marine fouling organism in most tropical and subtropical coastal environment. Competent larvae of H. elegans undergo the transition from the swimming larval stage to the sessile juvenile stage with substantial morphological, physiological, and behavior changes. This transition is often referred to as larval settlement and metamorphosis. In this study, we examined the possible involvement of calmodulin (CaM) - a multifunctional calcium metabolism regulator, in the larval settlement and metamorphosis of H. elegans. A full-length CaM cDNA was successfully cloned from H. elegans (He-CaM) and it contained an open reading frame of 450 bp, encoding 149 amino acid residues. It was highly expressed in 12h post-metamorphic juveniles, and remained high in adults. In situ hybridization conducted in competent larvae and juveniles revealed that He-CaM gene was continuously expressed in the putative growth zones, branchial rudiments, and collar region, suggesting that He-CaM might be involved in tissue differentiation and development. Our subsequent bioassay revealed that the CaM inhibitor W7 could effectively inhibit larval settlement and metamorphosis, and cause some morphological defects of unsettled larvae. In conclusion, our results revealed that CaM has important functions in the larval settlement and metamorphosis of H. elegans. PMID- 22507550 TI - A lipid-and-polymer-based novel local drug delivery system--BonyPidTM: from physicochemical aspects to therapy of bacterially infected bones. AB - Bacterial infection of bone may result in bone destruction and is difficult to cure due to poor accessibility to bone of systemically-administrated antibiotic and poor performance of currently available local antibacterial treatments. We developed a novel local drug delivery system based on self-assembly of specific familiar lipids and polymers that encapsulate the desired drug (exemplified by doxycycline). The entrapped doxycycline present in the anhydrous environment of the formulation is fully protected from long-term water-exposure-related degradation. The fine coating of the tricalcium phosphate bone filler by this doxycycline-containing formulation (BonyPidTM) is capable of releasing intact and active drug at a steady, zero-order rate for a predetermined period of up to 30 days and in amount sufficient to achieve therapy potentially capable of eliminating the contaminating bacteria. Therefore a clinical evaluation is proposed for testing the efficacy and toxicity of BonyPid for therapy of bacterial bone infections. PMID- 22507551 TI - Utility of 14 novel biomarkers in patients with acute chest pain and undetectable levels of conventional cardiac troponin. AB - BACKGROUND: Patients with acute chest pain having serial undetectable cardiac troponin (cTn) levels, as measured with conventional assays, are considered at very low risk. The aim of this multicenter study was to determine the accuracy of multiple biomarkers in these patients. METHODS: We enrolled 1247 consecutive patients with suspected AMI. Of these, 325 had undetectable levels of cTnT (Roche, 4th generation assay) at presentation and at 6h. Fourteen novel markers quantifying cardiomyocyte damage, inflammation and/or plaque rupture, and neurohormonal activation were measured at presentation. The occurrence of death or acute myocardial infarction (AMI) (primary end point) and unplanned coronary revascularization (secondary endpoint) were recorded during long-term follow-up. RESULTS: During a mean follow-up of 668 +/- 241 days, death/AMI occurred in 23 patients (7%), unplanned revascularization in 46 (14%). Among all biomarkers, high-sensitive cTnT (hs-cTnT), Midregional pro-adrenomedullin (MR-proADM) and growth differentiation factor-15 (GDF-15) were independently associated with future death/AMI; hs-cTnT was 0.013 (0.008-0.017) MUg/l versus 0.006 (0.003 0.010) MUg/l, MR-proADM was 0.78 (0.66-1.09) nmol/l versus 0.60 (0.18-0.80) nmol/l and GDF-15 was 1800 (1600-2200) ng/l versus 1100 (800-1700) ng/l in patients with versus without death/AMI during follow-up (p<0.001 each). The area under the receiver-operating characteristics curve to predict death/AMI was 0.73 (95%CI 0.63-0.83) for hs-cTnT, 0.71 (95% CI 0.62-0.81) for MR-proADM and 0.78 (95%CI 0.71-0.86) for GDF-15. CONCLUSION: Patients with serial undetectable levels of cTnT using the contemporary 4th generation assay are at low but not negligible risk of future cardiac events. Hs-cTnT, MR-proADM and/or GDF-15 might help to further improve risk-stratification in this group. PMID- 22507552 TI - Depression, antidepressants, and long-term mortality in heart failure. AB - BACKGROUND: This study was designed to assess whether depression and the use of antidepressants were related to long-term mortality in heart failure. METHODS: Heart failure outpatients (n=1017) from a specialized tertiary unit in Spain were prospectively studied for a median follow-up of 5.4 years (IQR 3.1-8.1). Depressive symptoms were assessed using an abbreviated version of the geriatric depression scale. Survival rates during the study period (August 2001 until December 2010) and hazard ratios (HR) for mortality were adjusted by several demographic and clinical variables. RESULTS: Depressive symptoms were detected in 302 patients (29.7%) at baseline and 222 (21.8%) de novo during follow-up; 304 patients (29.9%) received at least one prescription of antidepressants, mainly selective serotonin reuptake inhibitors (92.8%); 441 patients (43.4%) died. In a multivariate Cox proportional hazard model, depression was associated with an increased all-cause (HR, 1.39; 95% CI, 1.15-1.68), but not cardiovascular, mortality risk after adjustment for several demographic and clinical confounders. The use of any antidepressant was not independently associated with mortality (HR, 0.89; 95% CI, 0.71-1.13), but benzodiazepines showed a protective role (HR, 0.70; 95% CI, 0.57-0.87). On the contrary, fluoxetine prescriptions, but not duration of fluoxetine treatment, were associated with increased mortality (HR, 1.66; 95% CI, 1.13-2.44). CONCLUSIONS: Depressive symptoms are associated with long-term mortality, but the use of antidepressants and benzodiazepines is safe regarding survival in HF patients, although further research is needed considering individual antidepressants separately. PMID- 22507554 TI - Human amnion epithelial cells do not abrogate pulmonary fibrosis in mice with impaired macrophage function. AB - Since current treatments for both acute and chronic lung diseases are less than ideal, there has been recent interest in the use of cell-based therapies for inflammatory lung disease. Specifically, human amnion epithelial cells (hAECs) have been shown to reduce bleomycin-induced lung injury and prevent subsequent loss of respiratory function, primarily through modulation of the host immune response. The precise mechanisms of this effect remain unclear. We aimed to investigate the potential of hAECs to mitigate bleomycin-induced lung injury in surfactant protein C deficient (Sftpc(-/-)) mice, which are highly susceptible to pulmonary injury as a result of impairment of macrophage function. Primary hAECs were administered to wild-type (Sftpc(+/+)) and Sftpc(-/-) mice 24 h after exposure to bleomycin. Compared to Sftpc(+/+) mice receiving bleomycin alone, Sftpc(+/+) mice administered hAECs 24 h after bleomycin exposure had decreased expression of proinflammatory genes, decreased macrophage and neutrophil infiltration, fibrosis, collagen content, and alpha-smooth muscle actin as well as a significant improvement in lung function. Compared to Sftpc(-/-) mice given bleomycin alone, Sftpc(-/-) mice administered hAECs 24 h after bleomycin did not have a decrease in inflammatory gene expression or a reduction in macrophage pulmonary infiltration. Subsequently, Sftpc(-/-) mice did not show any decrease in pulmonary fibrosis or improvement of lung function after hAEC administration. The ability of hAECs to mitigate bleomycin-induced lung injury is abolished in Sftpc(-/-) mice, suggesting that hAECs require normal host macrophage function to exert their reparative effects. PMID- 22507553 TI - Albumin induces upregulation of matrix metalloproteinase-9 in astrocytes via MAPK and reactive oxygen species-dependent pathways. AB - BACKGROUND: Astrocytes are an integral component of the blood-brain barrier (BBB) which may be compromised by ischemic or traumatic brain injury. In response to trauma, astrocytes increase expression of the endopeptidase matrix metalloproteinase (MMP)-9. Compromise of the BBB leads to the infiltration of fluid and blood-derived proteins including albumin into the brain parenchyma. Albumin has been previously shown to activate astrocytes and induce the production of inflammatory mediators. The effect of albumin on MMP-9 activation in astrocytes is not known. We investigated the molecular mechanisms underlying the production of MMP-9 by albumin in astrocytes. METHODS: Primary enriched astrocyte cultures were used to investigate the effects of exposure to albumin on the release of MMP-9. MMP-9 expression was analyzed by zymography. The involvement of mitogen-activated protein kinase (MAPK), reactive oxygen species (ROS) and the TGF-beta receptor-dependent pathways were investigated using pharmacological inhibitors. The production of ROS was observed by dichlorodihydrofluorescein diacetate fluorescence. The level of the MMP-9 inhibitor tissue inhibitor of metalloproteinase (TIMP)-1 produced by astrocytes was measured by ELISA. RESULTS: We found that albumin induces a time-dependent release of MMP-9 via the activation of p38 MAPK and extracellular signal regulated kinase, but not Jun kinase. Albumin-induced MMP-9 production also involves ROS production upstream of the MAPK pathways. However, albumin-induced increase in MMP-9 is independent of the TGF-beta receptor, previously described as a receptor for albumin. Albumin also induces an increase in TIMP-1 via an undetermined mechanism. CONCLUSIONS: These results link albumin (acting through ROS and the p38 MAPK) to the activation of MMP-9 in astrocytes. Numerous studies identify a role for MMP-9 in the mechanisms of compromise of the BBB, epileptogenesis, or synaptic remodeling after ischemia or traumatic brain injury. The increase in MMP-9 produced by albumin further implicates both astrocytes and albumin in the acute and long-term complications of acute CNS insults, including cerebral edema and epilepsy. PMID- 22507555 TI - Cytoprotective and anti-inflammatory effects of melatonin in hydrogen peroxide stimulated CHON-001 human chondrocyte cell line and rabbit model of osteoarthritis via the SIRT1 pathway. AB - Melatonin has potent antioxidant, analgesic, and antinociceptive properties. However, the effects of melatonin against oxidative stress-induced cytotoxicity and inflammatory mediators in human chondrocytes remain poorly understood. This study examined the effects and underlying mechanism of melatonin in hydrogen peroxide (H(2) O(2) )-stimulated human chondrocytes and rabbit osteoarthritis (OA) model. Melatonin markedly inhibited hydrogen peroxide (H(2) O(2) ) stimulated cytotoxicity, iNOS, and COX-2 protein and mRNA expression, as well as the downstream products, NO and PGE(2) . Incubation of cells with melatonin decreased H(2) O(2) -induced Sirtuin 1 (SIRT1) mRNA and protein expression. SIRT1 inhibition by sirtinol or Sirt1 siRNA reversed the effects of melatonin on H(2) O(2) -mediated induction of pro-inflammatory cytokines (NO, PGE(2) , TNF-alpha, IL-1beta, and IL-8) and the expression of iNOS, COX-2, and cartilage destruction molecules. Melatonin blocked H(2) O(2) -induced phosphorylation of PI3K/Akt, p38, ERK, JNK, and MAPK, as well as activation of NF-kappaB, which was reversed by sirtinol and SIRT1 siRNA. In rabbit with OA, intra-articular injection of melatonin significantly reduced cartilage degradation, which was reversed by sirtinol. Taken together, this study shows that melatonin exerts cytoprotective and anti-inflammatory effects in an oxidative stress-stimulated chondrocyte model and rabbit OA model, and that the SIRT1 pathway is strongly involved in this effect. PMID- 22507556 TI - Study of CCN3 (NOV) and DDR1 in normal melanocytes and vitiligo skin. AB - We have hypothesised that melanocytes disappear in vitiligo because they are weakly attached to the epidermal basal membrane (melanocytorrhagy). In the epidermis, attachment of melanocytes to collagen IV is mediated through DDR1, which is under the control of CCN3. DDR1 genetic variants have been associated with vitiligo in patients of different ethnic origin. In vitro studies have shown that inhibition of CCN3 induces the detachment of melanocytes. We have studied in parallel the expression of CCN3 and DDR1 in lesional and perilesional skin of patients with vitiligo and the impact of the silencing of CCN3 and DDR1 in normal human melanocytes on their behaviour in epidermal reconstructs. Our in vivo study provides evidence of a dysregulation of the DDR1-CCN3 interaction in vitiligo skin as melanocytes remaining in perilesional skin did not express CCN3. Expression of DDR1 was decreased in lesional versus perilesional vitiligo skin in the majority of patients, and the expression of collagen IV was found decreased in all patients. Silencing of CCN3 in melanocytes induced a significant inhibition of cell adhesion to collagen IV whereas melanocytes transduced with shDDR1 still adhered well on collagen IV and did not increase melanocyte loss in epidermal reconstructs as compared with normal melanocytes. Melanocyte detachment was observed but not in all reconstructs using CCN3 silenced melanocytes. Overall, our study confirms that a downregulation of CCN3 is implicated in melanocyte adhesion in part through DDR1. In vitiligo skin, the interaction of CCN3 with other molecules, such as TGFbeta and CCN2, needs to be addressed. PMID- 22507557 TI - Caution when D-ealing with vitamin D-based multidimensional nomogram: the parathyroid hormone D-ilemma. PMID- 22507559 TI - American Association of Clinical Endocrinologists' Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis: executive summary. PMID- 22507560 TI - Patterns of facial hair growth in hirsute women. PMID- 22507561 TI - Top-down determinants of niche structure and adaptation among African Acacias. AB - The role of top-down factors like herbivory and fire in structuring species' niches, even in disturbance-dependent biomes like savanna, remains poorly understood. Interactions between herbivory and fire may set up a potential tradeoff axis, along which unique adaptations contribute to structuring communities and determining species distributions. We examine the role of herbivory and fire in structuring distributions of Acacia saplings in Hluhluwe iMfolozi Park in South Africa, and the relationship of species' niche structure to traits that help them survive herbivory or fire. Results suggest that (1) fire and herbivory form a single trade-off axis, (2) Acacia sapling distributions are constrained by fire and herbivory, and (3) Acacia saplings have adaptations that are structured by the tradeoff axis. Herbivory-adapted species tend to have 'cage'-like architecture, thicker bark, and less starch storage, while fire adapted species tend to have 'pole'-like architecture, relatively thinner bark, and more starch storage. PMID- 22507562 TI - The iceman cometh. PMID- 22507563 TI - Longer delay in accessing treatment among current smokers with new sputum smear positive tuberculosis in Nepal. AB - SETTING: Kathmandu, Nepal, which has 7% of the national population and 18% of the tuberculosis (TB) burden. OBJECTIVES: To determine the association of smoking with total delay among new sputum smear-positive TB patients. METHODS: Direct interviews were conducted among 605 TB patients registered in 37 randomly selected clinics within 30 days of initiating anti-tuberculosis treatment using a semi-structured questionnaire. Total delay was calculated from the date of the first reported symptom to the commencement of treatment. Logistic regression analyses were performed to determine the factors associated with total delay. RESULTS: Of the 605 TB patients interviewed, 271 (44.8%) were current smokers, 33 (5.5%) were ex-smokers and 301 (49.8%) were never smokers. The median total delay was 103 days (current smokers 133 days, ex-smoker 103 days and never smokers 80 days). Longer delay was more common among current smokers (aOR 2.03, 95%CI 1.24 3.31). Covariates with significantly more delay were female sex, lower levels of education and higher degrees of sputum smear positivity. CONCLUSION: Total delay was unacceptably longer in current smokers. Anti-smoking interventions are needed as an integral part of the TB programme to address this problem. PMID- 22507564 TI - Tissue transglutaminase treatment leads to concentration-dependent changes in dendritic cell phenotype--implications for the role of transglutaminase in coeliac disease. AB - Dendritic cells (DCs) are part of the innate immune system with a key role in initiating and modulating T cell mediated immune responses. Coeliac disease is caused by inappropriate activation of such a response leading to small intestinal inflammation when gluten is ingested. Tissue transglutaminase, an extracellular matrix (ECM) protein, has an established role in coeliac disease; however, little work to date has examined its impact on DCs. The aim of this study was to investigate the effect of small intestinal ECM proteins, fibronectin (FN) and tissue transglutaminase 2 (TG-2), on human DCs by including these proteins in DC cultures.The study used flow cytometry and scanning electron microscopy to determine the effect of FN and TG-2 on phenotype, endocytic ability and and morphology of DCs. Furthermore, DCs treated with FN and TG-2 were cultured with T cells and subsequent T cell proliferation and cytokine profile was determined.The data indicate that transglutaminase affected DCs in a concentration-dependent manner. High concentrations were associated with a more mature phenotype and increased ability to stimulate T cells, while lower concentrations led to maintenance of an immature phenotype.These data provide support for an additional role for transglutaminase in coeliac disease and demonstrate the potential of in vitro modelling of coeliac disease pathogenesis. PMID- 22507565 TI - Influence of environmental factors on meal intake in overweight and normal-weight male adolescents. A laboratory study. AB - OBJECTIVE: To investigate the influence of environmental conditions on energy intake at lunch time in normal-weight versus overweight male adolescents. DESIGN: Healthy 15-17 year-old adolescents (19 normal-weight, 19 overweight) participated in lunch tests under laboratory settings. Four conditions were compared: eating in groups, eating alone, eating alone while viewing television, eating alone while listening to music. The same menus (two solid foods, three drinks) were offered ad libitum. RESULTS: Significant group differences between meal conditions were observed for energy intake from solid foods, but not from drinks: normal-weight participants ate more solids while listening to music (5731+/-426 kJ) than when eating alone (5012+/-364 kJ, P=0.026) or in groups (4974+/-272 kJ, P=0.049), whereas overweight participants ate more solid foods while viewing television (5806+/-330 kJ) than when eating in groups (5208+/-201 kJ, P=0.014) or while listening to music (5288+/-255 kJ, P=0.035). On average, total energy intake at lunch (solids plus liquids) was found to be increased only in the overweight when viewing television (8527+/-535 kJ) compared to eating in group (7348+/-445 kJ, P=0.037) or while listening to music (7532+/-435 kJ, P=0.049). CONCLUSION: Environmental conditions modulate total energy intake at lunch in adolescents and susceptibility to external factors can be affected by weight status. Whether such effects can in turn affect energy balance and weight status remains to be investigated. PMID- 22507566 TI - Unhealthy diet and ultrafine carbon black particles induce senescence and disease associated phenotypic changes. AB - Diet and pollution are environmental factors known to compromise "healthy aging" of the cardiovascular and respiratory systems. The molecular consequences of this permanent burden in these cells are still unknown. Therefore, this study investigates the impact of unhealthy diet on aging-related signaling pathways of human, primary cardiovascular cells and of airborne particles on lung epithelial and human endothelial cells. Nutrition health reports have shown that the diet in industrialized countries contains more than 100mg/dl low density lipoprotein (LDL) and a high fraction of added sugars, especially fructose. Several studies demonstrated that ultrafine particles can enter the circulation and thus may interact with endothelial cells directly. Both, dietary compounds and pollution derived particles, have been shown to increase the risk for cardiovascular diseases. To simulate an unhealthy diet, we supplemented cell culture media of human primary endothelial cells, smooth muscle cells and cardiomyocytes with LDL and replaced 1/3 of glucose with fructose. We observed hypertrophy in cardiomyocytes, enhanced proliferation in smooth muscle cells and increased senescence, loss of endothelial nitric oxide synthase and increased nuclear FoxO3A in endothelial cells. With respect to pollution we have used ultrafine carbon black particles (ufCB), one of the major constituents of industrial and exhaust emissions, in concentrations our lungs and vessels are constantly exposed to. These concentrations of ufCB increased reactive oxygen species in lung epithelial and vascular endothelial cells and reduced the S-NO content, a marker for NO-bioavailability, in endothelial cells. NO increases activation of Telomerase Reverse Transcriptase (TERT), an enzyme essential for telomere maintenance. TERT is required for proper endothelial cell function and is inactivated by Src kinase under conditions of oxidative stress. ufCB significantly increased Src kinase activation and reduced Telomerase activity in endothelial and lung epithelial cells. As a consequence, ufCB increased senescence of endothelial cells. To investigate whether ufCB show also effects in vivo, we instilled ufCB in concentrations not inducing inflammation into mice. Indeed, eNOS expression was reduced in the abdominal aorta of animals treated with ufCB. Thus, a combination of fructose and LDL in the diet and ufCB, as a major constituent of air pollution, seem to accelerate respiratory and cardiovascular cellular changes, which may compromise "healthy aging" and can lead to cardiovascular and pulmonary diseases. PMID- 22507567 TI - Effects of 900 MHz radiofrequency on corticosterone, emotional memory and neuroinflammation in middle-aged rats. AB - The widespread use of mobile phones raises the question of the effects of electromagnetic fields (EMF, 900 MHz) on the brain. Previous studies reported increased levels of the glial fibrillary acidic protein (GFAP) in the rat's brain after a single exposure to 900 MHz global system for mobile (GSM) signal, suggesting a potential inflammatory process. While this result was obtained in adult rats, no data is currently available in older animals. Since the transition from middle-age to senescence is highly dependent on environment and lifestyle, we studied the reactivity of middle-aged brains to EMF exposure. We assessed the effects of a single 15 min GSM exposure (900 MHz; specific absorption rate (SAR)=6 W/kg) on GFAP expression in young adults (6 week-old) and middle-aged rats (12 month-old). Brain interleukin (IL)-1beta and IL-6, plasmatic levels of corticosterone (CORT), and emotional memory were also assessed. Our data indicated that, in contrast to previously published work, acute GSM exposure did not induce astrocyte activation. Our results showed an IL-1beta increase in the olfactory bulb and enhanced contextual emotional memory in GSM-exposed middle aged rats, and increased plasmatic levels of CORT in GSM-exposed young adults. Altogether, our data showed an age dependency of reactivity to GSM exposure in neuro-immunity, stress and behavioral parameters. Reproducing these effects and studying their mechanisms may allow a better understanding of mobile phone EMF effects on neurobiological parameters. PMID- 22507568 TI - Endothelial progenitor cells improve directly and indirectly early vascularization of mesenchymal stem cell-driven bone regeneration in a critical bone defect in rats. AB - Early vascularization of a composite in a critical bone defect is a prerequisite for ingrowth of osteogenic reparative cells to regenerate bone, since lack of vessels does not ensure a sufficient nutritional support of the bone graft. The innovation of this study was to investigate the direct and indirect effects of endothelial progenitor cells (EPCs) and cotransplanted mesenchymal stem cells (MSCs) on the in vivo neovascularization activity in a critical size defect at the early phase of endochondral ossification. Cultivated human EPCs and MSCs were loaded onto beta-TCP in vitro. A critical-sized bone defect (5 mm) was created surgically in the femoral diaphysis of adult athymic rat and stabilized with an external fixateur. The bone defects were filled with beta-TCP, MSCs seeded on beta-TCP, EPCs seeded on beta-TCP, and coculture of MSCs and EPCs seeded on beta TCP or autologous bone of rat. After 1 week, the rats were sacrificed. Using quantitative CD34 immunohistochemistry as well as qualitative analysis of vascularization (staining of MHC and VEGF) in decalcified serial sections were performed by means of an image analysis system. Fluorescence microscopy analyzed the direct effects and indirect effects of human implanted EPCs for vessel formation at bone regeneration site. Formation of a primitive vascular plexus was also detectable in the beta-TCP, MSC, or autologous bone group, but on a significantly higher level if EPCs alone or combined with MSCs were transplanted. Moreover, highest amount of vascularization were detected when EPCs and MSCs together were implanted. Early vascularization is improved by transplanted EPCs, which formed new vessels directly. Indeed the indirect effect of EPCs to vascularization is much higher. Transplanted EPC release chemotactic factors (VEGF) to recruit EPCs of the host and stimulate vascularization in the bone defect. Transplantation of human EPCs displays a promising approach to improve early vascularization of a scaffold in a critical bone defect. Moreover, coculture of EPCs and MSCs demonstrate also a synergistic effect on new vessel formation and seems to be a potential osteogenic construct for in vivo application. PMID- 22507570 TI - Use of nicotine replacement therapy for smoking reduction and temporary abstinence: an update of beard et al. (2011). PMID- 22507571 TI - Fifty years of surgery for single ventricle: now what? PMID- 22507569 TI - Critical von Willebrand factor A1 domain residues influence type VI collagen binding. AB - BACKGROUND: von Willebrand factor (VWF) binds to subendothelial collagen at sites of vascular injury. Laboratory testing for von Willebrand disease (VWD), however, does not always include collagen binding assays (VWF:CB) and standard VWF:CB assays use type I and/or type III collagen rather than type VI collagen. OBJECTIVES: We report here on several mutations that exclusively alter binding to type VI collagen. PATIENTS/METHODS: Healthy controls and index cases from the Zimmerman Program for the Molecular and Clinical Biology of VWD were analyzed for VWF antigen (VWF:Ag), VWF ristocetin cofactor activity and VWF:CB with types I, III and VI collagen. VWF gene sequencing was performed for all subjects. RESULTS: Two healthy controls and one type 1 VWD subject were heterozygous for an A1 domain sequence variation, R1399H, and displayed a selective decreased binding to type VI collagen but not types I and III. Expression of recombinant 1399H VWF resulted in absent binding to type VI collagen. Two other VWF A1 domain mutations, S1387I and Q1402P, displayed diminished binding to type VI collagen. An 11 amino acid deletion in the A1 domain also abrogated binding to type VI collagen. CONCLUSIONS: VWF:CB may be useful in diagnosis of VWD, as a decreased VWF:CB/VWF:Ag ratio may reflect specific loss of collagen binding ability. Mutations that exclusively affect type VI collagen binding may be associated with bleeding, yet missed by current VWF testing. PMID- 22507572 TI - The curbside consultation: legal, moral, and ethical considerations. PMID- 22507573 TI - Superimposed segmental vitiligo should not be categorized as "type 2 mosaicism". PMID- 22507574 TI - Clarification on dermatoscopy versus Tzanck smear test: a comparison of the value of two tests in the diagnosis of pigmented skin lesions. PMID- 22507578 TI - Squamous cell carcinoma and junctional epidermolysis bullosa. PMID- 22507576 TI - How "unsafe" is propranolol when used in the treatment of infantile hemangioma? PMID- 22507580 TI - Testicular choriocarcinoma resembling a lipoma. PMID- 22507581 TI - Diffuse hair loss in Addison disease: a reason for X-linked adrenoleukodystrophy screening. PMID- 22507583 TI - JAAD grand rounds. A young woman with papules on the neck and axillae. PMID- 22507582 TI - JAAD grand rounds. Erythematous macules and crusted erosions in sun-exposed areas. PMID- 22507584 TI - JAAD grand rounds. Increased fragility and bulla formation on the dorsal surface of the hand. PMID- 22507586 TI - Sarcoidosis: a comprehensive review and update for the dermatologist: part II. Extracutaneous disease. AB - Sarcoidosis is a multisystemic, granulomatous disease with protean manifestations and variable prognosis. Because the skin can be the only organ in which the disease is recognized, dermatologists may be responsible for the care of sarcoidosis patients. Therefore, dermatologists should be cognizant of the disease's extracutaneous manifestations to assure appropriate evaluation and treatment. Part II of this review describes the diagnostic approach and management of the extracutaneous manifestations of sarcoidosis. PMID- 22507585 TI - Sarcoidosis: a comprehensive review and update for the dermatologist: part I. Cutaneous disease. AB - Sarcoidosis is a common systemic, noncaseating granulomatous disease of unknown etiology. The development of sarcoidosis has been associated with a number of environmental factors and genes. Cutaneous sarcoidosis, the "great imitator," can baffle clinicians because of its diverse manifestations and its ability to resemble both common and rare cutaneous diseases. Depending on the type, location, and distribution of the lesions, treatment can prevent functional impairment, symptomatic distress, scarring, and disfigurement. Numerous therapeutic options are available for the treatment of cutaneous sarcoidosis, but there are few well designed trials to guide practitioners on evidence-based, best practice management. In part I, we review the current knowledge and advances in the epidemiology, etiology, pathogenesis, and genetics of sarcoidosis, discuss the heterogeneous manifestations of cutaneous sarcoidosis, and provide a guide for treatment of cutaneous sarcoidosis. PMID- 22507589 TI - Effects of contiguous scars in dermatoscopic evaluation of clinically atypical melanocytic nevi. PMID- 22507590 TI - The role of antinuclear autoantibodies in patients with psoriasis treated with anti-tumor necrosis factor-alpha agents: a retrospective long-term study. PMID- 22507591 TI - A high serum concentration of chemerin in pustular dermatitis paradoxically induced by etanercept. PMID- 22507592 TI - Treatment of psoriasis with rituximab. PMID- 22507593 TI - Can we vaccinate against depression? AB - Major depression is common in the context of autoimmune and inflammatory diseases and is frequently associated with persistently raised levels of proinflammatory cytokines and other markers of inflammation, even in the absence of another diagnosable immune pathology to account for these findings. Therefore immunoregulation-inducing vaccines or manipulations of the gut microbiota might prevent or treat depression. These strategies are already undergoing clinical trials for chronic inflammatory disorders, such as allergies, autoimmunity and inflammatory bowel disease. In this article, we summarize data suggesting that this approach might be effective in depression and encourage the initiation of clinical vaccination trials in this disorder. PMID- 22507594 TI - Evidence-based approach to assess passive diffusion and carrier-mediated drug transport. AB - Evidence supporting the action of passive diffusion and carrier-mediated (CM) transport in drug bioavailability and disposition is discussed to refute the recently proposed theory that drug transport is CM-only and that new transporters will be discovered that possess transport characteristics ascribed to passive diffusion. Misconceptions and faulty speculations are addressed to provide reliable guidance on choosing appropriate tools for drug design and optimization. PMID- 22507595 TI - Spinal lordosis optimizes the requirements for a stable erect posture. AB - BACKGROUND: Lordosis is the bending of the lumbar spine that gives the vertebral column of humans its characteristic ventrally convex curvature. Infants develop lordosis around the time when they acquire bipedal locomotion. Even macaques develop a lordosis when they are trained to walk bipedally. The aim of this study was to investigate why humans and some animals develop a lumbar lordosis while learning to walk bipedally. RESULTS: We developed a musculoskeletal model of the lumbar spine, that includes an asymmetric, dorsally shifted location of the spinal column in the body, realistic moment arms, and physiological cross sectional areas (PCSA) of the muscles as well as realistic force-length and force velocity relationships. The model was used to analyze the stability of an upright body posture. According to our results, lordosis reduces the local joint torques necessary for an equilibrium of the vertebral column during an erect posture. At the same time lordosis increases the demands on the global muscles to provide stability. CONCLUSIONS: We conclude that the development of a spinal lordosis is a compromise between the stability requirements of an erect posture and the necessity of torque equilibria at each spinal segment. PMID- 22507597 TI - Imbalanced suppression of excitatory and inhibitory synaptic transmission onto mouse striatal projection neurons during induction of anesthesia with sevoflurane in vitro. AB - Suppression of movement during induction of anesthesia is mediated through subcortical structures. We studied the effects of a brief, 5-min application of a clinically relevant concentration of sevoflurane (two minimum alveolar concentration) on the electrophysiological activities of the medium spiny neurons (MSNs) of the striatum in brain slice preparations, using a whole-cell patch clamp technique. We found that sevoflurane slightly depolarized principal neurons in the cortex and the striatum without a significant alteration in spike threshold. Furthermore, it depressed the peak, as well as the net, charge transfer of intrastriatally evoked inhibitory postsynaptic currents (eIPSCs) much more strongly than those of excitatory postsynaptic currents (EPSCs), and this inhibition was accompanied by an elevated paired-pulse ratio. The strong suppression of eIPSCs paralleled a significant suppression of the frequency, but not the amplitude, of miniature IPSCs (mIPSCs), and was associated with a transient increase in the frequency of spontaneous EPSCs. Treatment with the Ca(2+) channel blocker Cd(2+) restored the frequency of mIPSCs to the control level, indicating sevoflurane's strong presynaptic suppression of gamma aminobutyric acid release in the striatum. In contrast, in hippocampal CA1 pyramidal neurons sevoflurane produced an enhancement of the net charge transfer of IPSCs, while it suppressed EPSCs to an equivalent degree to that in striatal MSNs. These results suggest that, in contrast to its effects on other brain structures, sevoflurane shifts the balance between synaptic excitation and inhibition in the direction of excitation in the striatum, thereby causing involuntary movements during induction of anesthesia by sevoflurane. PMID- 22507598 TI - Type 1 IFN-induced protein MxA and plasmacytoid dendritic cells in lesions of morphea. AB - Morphea is an autoimmune sclerotic skin disease of unknown pathogenesis. As type 1 interferons (IFN) have been implicated in the pathogenesis of systemic sclerosis, we proposed that type 1 IFN promote localized inflammation and fibrosis in morphea. To investigate the expression of the type 1 IFN-inducible protein myxovirus A (MxA) and the presence of plasmacytoid dendritic cells (pDC) in lesions of morphea, lesional skin of 10 patients with morphea was examined by immunohistochemistry for the presence of the type 1 IFN-inducible protein, myxovirus A (MxA), and the pDC markers, CD123 and BDCA-2, and was compared with lesional skin of cutaneous lupus erythematosus, lichen planus and keloid. Lesional and non-lesional morphea skin was compared. MxA was expressed in the epidermis as well as the reticular dermis and subcutis in morphea. pDCs were abundant around vessels and between fibrous bundles. Non-lesional biopsies demonstrated little or no expression of MxA and pDC markers. Keloid showed minimal expression of MxA and pDC markers. We demonstrate the expression of type 1 IFN-related protein MxA and plasmacytoid DCs in lesional but not in non lesional biopsies of morphea. These findings suggest a potential role for type 1 interferons in the pathogenesis of morphea. PMID- 22507596 TI - Radiofrequency ablation: effect of tumor- and organ-specific pharmacologic modulation of arterial and portal venous blood flow on coagulation diameter in an N1-S1 tumor model. AB - PURPOSE: To investigate inherent differences in vasculature of tumors versus normal parenchyma and efficacy of radiofrequency (RF) ablation with glucagon, adenosine, and a combination of the two compared with normal saline solution (NS) controls in an N1-S1 tumor model implanted in Sprague-Dawley rat livers. MATERIALS AND METHODS: A total of 17 tumors were established in the left lobes of rats. Tumor perfusion relative to surrounding liver parenchyma was evaluated with contrast-enhanced ultrasound with intermittent-bolus technique before and after administration of glucagon, adenosine, a combination of the two, or NS. Tumors were ablated with a 22-gauge RF probe with 1 cm of exposed tip at 80 degrees C for 2 min. Tumor size, zone of necrosis, and viable tumor were measured in tumors after 2,3,5-triphenyltetrazolium chloride staining. Results were compared with degree of tumor perfusion. RESULTS: The normalized tumor perfusion ratio did not significantly change with administration of NS (1.38% +/- 3.93). Vasomodulation resulted in significant decreases in normalized tumor perfusion ratio: 66.22% +/- 24.57 (P < .01) with glucagon, 71.45% +/- 22.72 (P < .01) with adenosine, and 74.98% +/- 16.58 (P < .01) with glucagon plus adenosine. After tumor ablation, there was an increase in size of the ablated area by 100%-165% in the three treatment groups compared with NS controls. Differences among treatment groups were not statistically significant. CONCLUSIONS: Tumor blood flow may be significantly altered by using systemic injection of appropriate medications. This tumor- and organ-specific approach to tumor vasomodulation may be used to enhance current therapeutic options. PMID- 22507599 TI - Acoustic evaluation and adjustment of an open-plan office through architectural design and noise control. AB - Arranging office space into a single open room offers advantages in terms of easy exchange of information and interaction among coworkers, but reduces privacy and acoustic comfort. Thus, the purpose of this work was to evaluate the acoustic quality of a real open-plan office and to propose changes in the room to improve the acoustic conditioning of this office. The computational model of the office under study was calibrated based on RT and STI measurements. Predictions were made of the RT and STI, which generated the radius of distraction r(D), and the rate of spatial decay of sound pressure levels per distance doubling DL(2) in the real conditions of the office and after modifications of the room. The insertion of dividers between work stations and an increase in the ceiling's sound absorption improved the acoustic conditions in the office under study. PMID- 22507601 TI - The development of a global program for the elimination of brain damage due to iodine deficiency. AB - Iodine deficiency is the most common preventable cause of brain damage with more than 2 billion people from 130 countries at risk. The global problem of iodine deficiency has been redefined by a readily transmitted population concept, with an easy acronym - the concept of the iodine deficiency disorders (IDD) - referring to all the effects of iodine deficiency in a population, that can be totally prevented by correction of iodine deficiency with special emphasis on brain damage and not just to goitre and cretinism (1983). This was followed by the creation of the International Council for Control of Iodine Deficiency Disorders (ICCIDD) supported by WHO and UNICEF with 700 multidisciplinary professionals from more than 100 countries, committed to providing technical assistance to national programs for the elimination of IDD (1986). The WHO policy of Universal Salt Iodization (USI) has been widely adopted which requires iodization of all food for human and animal consumption by the use of iodized salt (25-40 mg I/kilo). Simple practical methods for monitoring - by the measurement of salt iodine and urine iodine were developed and promoted on a large scale with the technical assistance of the ICCIDD. PMID- 22507600 TI - Genetic deletion of dectin-1 does not affect the course of murine experimental colitis. AB - BACKGROUND: It is believed that inflammatory bowel diseases (IBD) result from an imbalance in the intestinal immune response towards the luminal microbiome. Dectin-1 is a widely expressed pattern recognition receptor that recognizes fungi and upon recognition it mediates cytokine responses and skewing of the adaptive immune system. Hence, dectin-1 may be involved in the pathogenesis of IBD. METHODS: We assessed the responses of dectin-1 deficient macrophages to the intestinal microbiota and determined the course of acute DSS and chronic Helicobacter hepaticus induced colitis in dectin-1 deficient mice. RESULTS: We show that the mouse intestinal microbiota contains fungi and the cytokine responses towards this microbiota were significantly reduced in dectin-1 deficient macrophages. However, in two different colitis models no significant differences in the course of inflammation were found in dectin-1 deficient mice compared to wild type mice. CONCLUSIONS: Together our data suggest that, although at the immune cell level there is a difference in response towards the intestinal flora in dectin-1 deficient macrophages, during intestinal inflammation this response seems to be redundant since dectin-1 deficiency in mice does not affect intestinal inflammation in experimental colitis. PMID- 22507602 TI - Anemia in Cambodia: prevalence, etiology and research needs. AB - Anemia is a severe global public health problem with serious consequences for both the human and socio-economic health. This paper presents a situation analysis of the burden of anemia in Cambodia, including a discussion of the country-specific etiologies and future research needs. All available literature on the prevalence and etiology of anemia in Cambodia was collected using standard search protocols. Prevalence data was readily identified for pre-school aged children and women of reproductive age, but there is a dearth of information for school-aged children, men and the elderly. Despite progress in nation-wide programming over the past decade, anemia remains a significant public health problem in Cambodia, especially for women and children. Anemia is a multifaceted disease and both nutritional and non-nutritional etiologies were identified, with iron deficiency accounting for the majority of the burden of disease. The current study highlights the need for a national nutrition survey, including collection of data on the iron status and prevalence of anemia in all population groups. It is impossible to develop effective intervention programs without a clear picture of the burden and cause of disease in the country. PMID- 22507603 TI - A digital calliper for training and study purposes. AB - A quick and valid method for evaluating percentage body fat is based on the use of skinfold callipers. However, limitations associated to their use and characteristics led the authors to improve a traditional calliper (Harpenden) and to integrate it with a software application. Such a measuring system, LipoTool, is meant to have better accuracy and reliability, including data processing and digital recording at a very low cost. At first, a sample of 49 older adults was used to evaluate the performance of LipoTool by comparing its results to those obtained with the traditional Harpenden calliper. A strong positive association in %BF was achieved. This digital sensing system was later improved by incorporating wireless communication between the calliper and the software application, adding other functionalities. The software application works in any computer and is flexible to incorporate new coming models, linear regressions or new algorithms. This new system was validated against the standard Dual-Energy X Ray Absorptiometry system, using a sample of 40 adults with positive results. This solution is a valid and reliable alternative to traditional reference callipers, simplifying the percentage of body fat evaluation and providing a more effective use in daily practice with less expenditure of time and resources. Its implemented guided procedure turns it into a precious training tool based on a non-invasive, portable device, and not requiring special individual preparation. Ongoing activities are focused on the design of a new mechanical structure, with novel functionalities and for exploring other studies. PMID- 22507604 TI - Validity and correspondence of non-invasively determined hemoglobin concentrations by two trans-cutaneous digital measuring devices. AB - Hemoglobin (Hb) concentration is the central diagnostic indicator for anemia, including nutritional anemia. The objective of this study was to compare the Hb values determined by two portable, non-invasive devices across a wide Hb spectrum against formal laboratory measurements, and with each other. Eighty Guatemalan adults (40 highland men, 40 lowland pregnant women) provided venous blood for formal Hb colorimetric determination. Hb was also registered sequentially on the Rad-87TM pulse CO-Oximeter with Rainbow Set technology (Masimo) and Haemospect(r) (MBR Optical Systems) by non-invasive skin-probe contact procedures as per manufacturers' instructions. Whole blood Hb concentrations ranged from 7.8 to 18.5 g/dL (mean, 12.9+/-2.3 g/dL and median, 13.3 g/dL). Corresponding descriptive statistics were: range, 9.6 to 16.2 g/dL; mean, 12.1+/-1.5 g/dL; and median, 11.9 g/L, respectively, with the Rad-87TM (nail bed). They were: range, 8.7 to 15.8 g/dL; mean, 12.7+/-1.8 g/dL; and median13.0 g/dL for the Hemospect(r) for forearm contact. They were: range, 9.1 to 17.5 g/dL; mean, 13.2+/-2.1 g/dL; and median, 13.4 g/dL for palm contact. The Pearson correlation coefficient of venous blood Hb with the former device's Hb values was r=0.59 (p<0.001), and r=0.94 (p<0.001) and r=0.90 (p<0.001) with those of the latter device at the palm and forearm, respectively. The inter-site Lin coefficient was r=0.84. Sensitivity and specificity were variable across devices, depending on Hb cut-off and measurement procedures. With Hb cut-off values of <12.0 g/dL for adult (non pregnant women and <13.0 g/dL for adult men), the Haemospect device's performance here would provide adequate potential for screening purposes. PMID- 22507605 TI - Adding glycaemic index and glycaemic load functionality to DietPLUS, a Malaysian food composition database and diet intake calculator. AB - This paper outlines the methodology to add glycaemic index (GI) and glycaemic load (GL) functionality to food DietPLUS, a Microsoft Excel-based Malaysian food composition database and diet intake calculator. Locally determined GI values and published international GI databases were used as the source of GI values. Previously published methodology for GI value assignment was modified to add GI and GL calculators to the database. Two popular local low GI foods were added to the DietPLUS database, bringing up the total number of foods in the database to 838 foods. Overall, in relation to the 539 major carbohydrate foods in the Malaysian Food Composition Database, 243 (45%) food items had local Malaysian values or were directly matched to International GI database and another 180 (33%) of the foods were linked to closely-related foods in the GI databases used. The mean +/- SD dietary GI and GL of the dietary intake of 63 women with previous gestational diabetes mellitus, calculated using DietPLUS version3 were, 62 +/- 6 and 142 +/- 45, respectively. These values were comparable to those reported from other local studies. DietPLUS version3, a simple Microsoft Excel-based programme aids calculation of diet GI and GL for Malaysian diets based on food records. PMID- 22507607 TI - Weight-related behaviors among non-overweight adolescents: results from the Korean national survey from 2005 to 2007. AB - This study aimed to assess the prevalence of overweight misperception, unhealthy diet practices, and factors associated with these weight-related behaviors among Korean adolescents. The subjects were a nationally representative sample of non overweight students (52,515 in 2005, 64,084 in 2006, and 67,113 in 2007) in middle and high schools who completed the Korea Youth Risk Behavior Web-Based Survey. The prevalence of weight-related behaviors and factors associated with these behaviors were assessed using a complex sampling design. Of non-overweight students, 14.9% of boys and 22.2% of girls reported their weight as overweight/obese. Dieting within the last year was reported by 19.8% of boys and 41.8% of girls. Of those who attempted dieting, 17.1% of boys and 24.6% of girls indicated practicing at least one unhealthy diet behavior within the last month. Overweight misperceptions were independently associated with diet attempts and unhealthy diets after adjustment for weight status, and demographic, social, and psychological factors. Additionally, these weight-related behaviors were also associated with psychosocial factors such as low school achievement, sadness, suicidal ideation, increased stress perception, and cigarette or alcohol use. In conclusion, the high prevalence of inappropriate weight-related behaviors suggests a need for comprehensive approaches to improve weight-related behaviors in non-overweight Korean adolescents. PMID- 22507606 TI - Chicken-based formula is better tolerated than extensively hydrolyzed casein formula for the management of cow milk protein allergy in infants. AB - The effective treatment of cow milk allergy in infants consists of elimination of cow milk protein and the introduction of formulas based on an extensively hydrolyzed protein formula or an amino acid-based formula. However, about 10% of these infants are still allergic to an extensively hydrolyzed protein formula and an amino acid-based formula is very expensive. We conducted a study to verify whether the new chicken-based formula will be better tolerated than an extensively hydrolyzed protein formula for the treatment of cow milk allergy in infants. One hundred infants, diagnosed with cow milk allergy by double-blind, placebo-controlled food challenge tests, were enrolled in a double-blind, randomized, cross-over study to compare a response to an extensively hydrolyzed protein formula and the chicken-based formula. Subjects were randomly given one of the two formulas for 2 weeks. There was a 2-week washout period of taking an amino acid-based formula before being switched to the other formula for another 2 weeks. If the subjects showed allergic symptoms during the 2 weeks of test formula, they would be announced as intolerance or allergic to that formula. Sixty seven of 80 confirmed subjects agreed to enroll their infants. Fifty-eight subjects completed the study. Twenty and 33 infants were tolerant whereas and 38 and 25 infants were intolerant to an extensively hydrolyzed protein formula and the chicken-based formula, respectively. The chicken-based formula showed significantly better tolerance than an extensively hydrolyzed protein formula in the management of cow milk allergy in infants. PMID- 22507608 TI - Diagnostic value of anthropometric indices for initial stage of atherosclerosis in adult women. AB - Excess body weight is a cardiovascular risk factor. The relationship between anthropometric indices and cardiovascular health is not completely understood. Carotid Intima-Media Thickness (CIMT) is a subclinical marker of atherosclerosis. This study aimed to investigate the best anthropometric obesity indicator for diagnosis of initial stage of atherosclerosis by CIMT. This cross-sectional study included 100 adult women, aged 18-50 years. Anthropometric indices were measured with standard protocol and CIMT was measured by non-invasive ultrasound. Receiver Operating Characteristics (ROC) curve analysis was carried out to determine the optimal cut-off values of anthropometric indices, and the best indices for atherosclerosis diagnosis. On ROC curve analysis the suggested appropriate cut offs of waist circumference (WC), waist to hip ratio (WHR), waist to height ratio (WHtR), body mass index (BMI) and percentage body fat (%BF) were 96 cm, 0.86, 0.64, 31.29 kg/m2 and 30.42%, respectively. The area under the ROC curve of BMI (AUC=0.74, 95%CI=0.62-0.86) and WHtR (AUC=0.74, 95%CI=0.63-0.85) were greater than other anthropometric indices. The AUC for WHR was the lowest among the studied obesity indices AUC=0.68 (95% CI=0.54-0.81). In our study, WHtR and BMI were the best diagnostic parameters of initial stage of atherosclerosis while WHR was the worst based on AUC. PMID- 22507609 TI - Prevalence of metabolically healthy obesity and its impacts on incidences of hypertension, diabetes and the metabolic syndrome in Taiwan. AB - Obesity is an epidemic health problem related to morbidity and mortality of metabolic and cardiovascular diseases. However, little is known regarding the development of cardiometabolic diseases in an obese subgroup with a healthy metabolic risk profile. This study examined the prevalence of baseline metabolically healthy obese subjects and its impacts on the incidences of cardiometabolic diseases using a nation-wide population cohort. Metabolically healthy obese were prevalent in 8.2% of the baseline population and 28.5% of the obese subjects. Subjects included were 1,547 men and women (age range, 18-59 years), who were free of components of the metabolic syndrome except waist criteria. During an average 5.4-year follow-up, the cumulative incidences of hypertension, type 2 diabetes and the metabolic syndrome were 7.8%, 1.2% and 5.6%, respectively. The hazard ratios (95% CIs) for the metabolic syndrome incidence were significantly higher at BMI levels of >=23.0 kg/m2 [4.68 (2.22 9.86)] for BMI of 23-24.9 kg/m2; 8.82 (4.01-19.4) for BMI of 25-26.9 kg/m2; and 24.43 (12.33-48.41) for BMI of >=27 kg/m2). The hazard ratios for diabetes or hypertension incidence were significantly higher at BMI levels of >=25.0 kg/m2. Each kg/m2 of BMI gained was associated with an 18% increase in the risk of developing hypertension and a 26% increase in risk for the metabolic syndrome. We conclude that metabolically healthy obese individuals are at higher risk to develop hypertension, type 2 diabetes and the metabolic syndrome than their non obese counterparts. Our data provide further evidence that opposes the notion of metabolically healthy obese as harmless conditions. PMID- 22507610 TI - Relationship between child feeding practices and malnutrition in 7 remote and poor counties, P R China. AB - The World Health Organization reported that inappropriate feeding in children is responsible for one-third of the cases of malnutrition. This cross-sectional study aimed to determine the prevalence of malnutrition and identify the relationship between feeding practices and malnutrition in children below 5 years, in 7 remote and poor counties of China. A sample of 2201 children and 1978 caregivers were obtained with multistage cluster random sampling. A survey about feeding practices among the caregivers was implemented using a structured questionnaire, and the health status of children was evaluated using anthropometric measurements. We found 5 problems: first, high prevalence of stunting, underweight and wasting in children below 5 years old (19.3%, 13.1% and 5.5%); second, short duration of breastfeeding for children below 36 months; third, low prevalence of exclusive breastfeeding among children below 6 months of age and continued breastfeeding to 1 year (17.5% and 32.2%). Fourth, although most of the infants (81.1%) between 6 and 8 months of age were given complementary foods, some of the 6- to 8-month-old infants did not receive any complementary foods. Last, a higher prevalence of stunting among Chinese children who had never been breastfed, who had been breastfed for less than 1 year, or had been fed with semi-solid foods of poor quality. Therefore, we suggest that more programs to increase caregivers' feeding knowledge and practices be conducted, to improve the health of children in remote and poor areas in China. PMID- 22507611 TI - Greater length-for-age increases the odds of attaining motor milestones in Vietnamese children aged 5-18 months. AB - Early childhood malnutrition has been associated with delayed development. Limited data exist however about the timing of developmental delay early in life. We assessed motor milestone (MM) achievement using the World Health Organization's windows of achievement for gross motor milestones. We performed secondary analysis of baseline data of 158 Vietnamese children aged 5-18 months from a randomized community intervention trial. Median age of motor milestone achievement was compared to WHO reported medians. Multivariate logistic regression was used to identify socioeconomic, anthropometric and dietary factors associated with motor milestone achievement during the windows of achievement. Thirty four per cent of the children were stunted. Median age of MM achievement of Vietnamese children lagged by 2.4-3.7 months, compared to the WHO median for all MMs. Greater length-for-age increased the odds for walking with assistance, standing alone and walking alone by more than 3 times. Greater weight-for-age increased the odds by 3.6 for hand-and-knees crawling. Likewise, frequency of daily complementary feeding raised the odds by 3.6 for standing with assistance. In this first application of WHO windows of achievement in Viet Nam, pre schoolers achieved motor milestones later than WHO reported median age. High prevalence of stunting and association of length-for-age with motor milestone achievement underscore the importance of addressing chronic malnutrition to optimize children's growth and development. PMID- 22507612 TI - Intrauterine nutrition and carotid intimal media thickness in young Thai adults. AB - Several studies show that intrauterine nutrition restriction is associated with vascular disease. Animal studies have shown that atherosclerosis can be affected by a constrained intrauterine diet, but this relationship in humans is controversial. The purpose of this study was to investigate the relationship between maternal intake during pregnancy and carotid intimal media thickness (CIMT). We measured CIMT in 565 twenty year old young adults whose mothers, while pregnant, participated in a nutritional study during 1989-1990 at two hospitals in Chiang Mai, Thailand. Maternal diet during pregnancy was assessed by two methods in each trimester, namely, the 24 hours food recall method and the food frequency method. Carotid intimal media thickness was greater in males and participants who showed higher blood glucose, higher body mass index and higher systolic blood pressure. Maternal protein intake during the first trimester was negative correlated with thickness of CIMT (p=0.02). The mean CIMT of participants whose mothers were in the lowest quarter of the distribution of protein intake in the first trimester was 0.45 mm (95% confidence interval (CI): 0.44-0.46) more than that of those whose mothers were in the highest quarter of the distribution (0.43 mm 95% CI: 0.42-0.44). In conclusion, lower maternal protein intake during early pregnancy may increase CIMT in adolescents. PMID- 22507613 TI - Trends in Chinese snacking behaviors and patterns and the social-demographic role between 1991 and 2009. AB - This study investigates the dynamic shifts in snacking behaviors and patterns in China. Using four waves (1991, 2004, 2006, and 2009) from the China Health and Nutrition Survey (CHNS), with full socioeconomic and demographic data and 3-day, 24-hour dietary recall data, 45,402 individuals age two and older were studied. Multiple logistic regressions were performed to examine the association of social demographic factors on snacking behaviors. Results show that snacking prevalence, frequency of daily snacking occasions, and percentage of total daily energy intake (EI) from snacks increased significantly across all ages between 1991 and 2009, with a dramatic increase after 2004. Snacking was much more prevalent among children and higher-income, urban, and educated populations over time. Evening was the preferred snacking occasion, and the proportion of total daily EI from snacks varied between 4.1% and 12.3% for all snackers. Fruits, grains, and beverages were the most popular snacks and the highest contributors to snacking EI over all age groups. A marked transition from a tradition of two or three meals per day toward meals combined with snacks is underway. Further research is needed to develop a better understanding of the nutritional implications of Chinese snacking behaviors. PMID- 22507614 TI - Relationship between dietary patterns and serum uric acid concentrations among ethnic Chinese adults in Taiwan. AB - The evidence for a relationship between dietary patterns and uric acid concentrations is scanty. Here, we used a validated food frequency questionnaire for an ethnic Chinese population in Taiwan to investigate the relationship between dietary patterns and uric acid concentrations. A cross-sectional study on 266 adults, who were interviewed with a 38-item food frequency questionnaire, was conducted and serum uric acid levels were measured. Three dietary patterns were derived from the questionnaire by exploratory factor analysis. Participants in the higher vegetable and fruit pattern quartiles were more likely to have a lower uric acid concentration (6.5 for the first, 5.7 for the second, 6.0 for the third, and 6.0 mg/dL for the fourth quartile, p = 0.030). For uric acid-prone patterns, as the quartiles increased, the adjusted mean uric acid concentrations increased significantly (5.88, 5.93, 5.99 and 6.38 mg/dL for each quartile, respectively, p = 0.04). However, the significance level was attenuated after adjusting for additional confounding factors. In conclusion, three dietary patterns were identified for ethnic Chinese in Taiwan, and the relationship between these dietary patterns and uric acid was not significant after adjustment. PMID- 22507615 TI - Cluster analysis reveals important determinants of cardiometabolic risk patterns in Filipino women. AB - With modernization, the Philippines has experienced increasing rates of obesity and related cardiometabolic diseases. Studying how risk factors cluster in individuals may offer insight into cardiometabolic disease etiology. We used cluster analysis to group women who share the following cardiometabolic biomarkers: fasting triglycerides, HDL-C and LDL-C, C-reactive protein, systolic and diastolic blood pressure, homeostasis model assessment of insulin resistance, and fasting glucose. Participants included 1,768 women (36-69 years) in the Cebu Longitudinal Health and Nutrition Survey. We identified five distinct clusters characterized by: 1) low levels of all risk factors (except HDL-C and LDL-C) or "healthy"; 2) low HDL-C in the absence of other risk factors; 3) elevated blood pressure; 4) insulin resistance; and 5) high C-reactive protein. We identified predictors of cluster membership using multinomial logistic regression. Clusters differed by age, menopausal status, socioeconomic status, saturated fat intake, and combinations of overweight (BMI >23) and high waist circumference (>80 cm). In comparison to the healthy cluster, overweight women without high waist circumference were more likely to be in the high CRP cluster (OR=2.26, 95% CI=1.24-4.11), while women with high waist circumference and not overweight were more likely to be in the elevated blood pressure (OR=2.56, 95% CI=1.20-5.46) or insulin resistant clusters (OR=4.05, 95% CI=1.39-11.8). In addition, a diet lower in saturated fat uniquely increased the likelihood of membership to the low HDL-C cluster. Cluster analysis identified biologically meaningful groups, predicted by modifiable risk factors; this may have implications for the prevention of cardiometabolic diseases. PMID- 22507616 TI - Pacific parents' rationale for purchased school lunches and implications for obesity prevention. AB - Pacific children and adolescents are burdened with higher prevalences of obesity compared to other groups in New Zealand. Previous research shows Pacific young people purchase their lunch food items significantly more than other groups. The aim of this study is to describe school lunch food consumption patterns and the influences on these among low-income Pacific adolescents and their parents. Using mixed-methodology design; a self-completion questionnaire was administered to 4216 students who participated in the New Zealand arm of the Obesity Prevention In Communities (OPIC) project. Thirty Pacific households (33 adolescents and 35 parents) were interviewed in the qualitative phase of the study. Results found a greater proportion of Pacific students purchased school food items compared to other ethnic groups. Purchasing school food was related to having higher amounts of daily food money (>=NZD 6-15) and this was associated with increased quantities of soft drink consumption and after-school food purchasing of high fat, high-sugar snack foods. There were no differences in school food purchasing behaviour by Pacific weight status (n=2485), with both Healthy weight (67.6%) and Obese students (66.9%) sourcing lunch from school canteens or shops outside of school rather than from home. Time-constrained parents confirmed convenience, poverty compensation and valuing students' independence as three reasons for choosing to make money available for students to purchase lunch food items. The social effects of poverty affect the health-promoting behaviours of Pacific communities in New Zealand. Social policies that decrease social inequities should be the intervention priority. PMID- 22507617 TI - Serum folate, total homocysteine levels and methylenetetrahydrofolate reductase 677C>T polymorphism in young healthy female Japanese. AB - Environmental and genetic factors influence serum total homocysteine (tHcy), a risk factor for vascular diseases. The gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) is reported to be a genetic factor for influencing tHcy. However, it is not clear whether MTHFR polymorphism influences tHcy in the younger generation. To investigate the influence of MTHFR polymorphism on vascular disease risks in young Japanese females, we determined dietary intakes, serum folate and tHcy, and examined the influence of MTHFR 677C>T polymorphism in healthy junior and high school students (n=192, 12-18y). The relationships between MTHFR polymorphism and folate intake, serum folate or tHcy were investigated by dividing participants into CC, CT and TT types. Among individuals with the TT genotype, folate and tHcy levels were significantly lower (p<0.05) or higher (p<0.0001), respectively, than in those with the other genotypes; although there were no significant differences in the intake of folate among genotypes. In addition, a significant inverse correlation between folate and tHcy (p<0.05) was noted in all genotypes, even in young females, so far not examined in Asian populations. Therefore, MTHFR genotypes were proven to be a significant determinant for folate and tHcy concentrations. However, the association of increased folate intake with lower tHcy concentration, even in cases of the mutation TT type, indicates the importance of folate intake in young Japanese females for early detection of risk, as well as the prevention of vascular diseases. PMID- 22507618 TI - Association of the adiponectin gene (ADIPOQ) +45 T > G polymorphism with the metabolic syndrome among Han Chinese in Sichuan province of China. AB - The metabolic syndrome is a cluster of abnormalities characterized by obesity, impaired glucose metabolism, hypertension or elevated blood pressure, and dyslipidemia. The aim of this study was to investigate the association of the adiponectin gene (ADIPOQ) +45 T > G polymorphism with the metabolic syndrome among Han Chinese in Sichuan province of China. A case-control design was used including 116 patients with the metabolic syndrome and 108 unrelated controls, matched on age and gender. The ADIPOQ +45G allele (TG+GG) had a significant association with risk of the metabolic syndrome (odds ratio=1.88, 95% confidence interval: 1.03-3.44, p=0.039) adjusted for education, physical activity, family history of related diseases, smoking and drinking, compared with subjects with TT genotype. The association between the ADIPOQ +45 T>G polymorphism and the metabolic syndrome was independent of multiple confounders. PMID- 22507619 TI - Association and interaction between dietary pattern and VEGF receptor-2 (VEGFR2) gene polymorphisms on blood lipids in Chinese Malaysian and Japanese adults. AB - BACKGROUND/AIMS: Dietary pattern and genetic predisposition of each population have different impacts on lifestyle-related chronic diseases. This study was conducted to evaluate the association and interaction between dietary patterns and VEGFR2 or KDR gene polymorphisms on physical and biochemical risk factors of cardiovascular disease in two Asian populations (179 Chinese Malaysian and 136 Japanese adults). METHODS: Dietary patterns were constructed from food frequency questionnaire using factor analysis. Genotyping of rs1870377 and rs2071559 was performed by real-time PCR using TaqMan probes. Physical measurements: body mass index, systolic and diastolic blood pressures and biochemical parameters: glycated hemoglobin A1c and blood lipids (total cholesterol, triglycerides, LDL cholesterol, HDL-cholesterol and total cholesterol/HDL-C ratio) were measured. RESULTS: Two dietary patterns were extracted for: Japanese ('Japanese diet' and 'Western diet') and Chinese Malaysians ('Balanced diet'; and 'Meat, rice and noodles diet'). In Japanese, 'Western Diet' and rs2071559 were associated with LDL-C and HDL-C, respectively. In Chinese Malaysians, 'Meat, rice and noodles diet' was asso-ciated with triglycerides, HDL-C and total cholesterol/HDL ratio while rs1870377 and rs2071559 were associated with total cholesterol and/or LDL C. The interaction between 'Western Diet' and rs2071559 in Japanese and 'Meat, rice and noodles diet' and rs1870377 in Malaysians had significant effects on blood lipids after adjusting for confounders. CONCLUSIONS: The association and interaction of dietary patterns and VEGFR2 gene polymorphisms on blood lipids differ between Chinese Malaysian and Japanese subjects by either decreasing or increasing the risk of cardiovascular disease. PMID- 22507620 TI - Association between the Xba I polymorphism of APOB gene and plasma lipid level in Mexican patients with coronary artery disease. AB - Some studies, that consider polymorphisms of the apolipoprotein B (APOB) gene as risk factors for coronary artery disease (CAD), have reported discordant results. The aim of the present study was to search for associations between plasma lipid profiles with the DNA Xba I polymorphism of the APOB gene in CAD patients diagnosed by angiography (CAD+). In the present study we compared 114 Mexican patients (80 men and 34 women) with CAD+ and 132 control patients (59 men and 73 women) without evidence of ischemia or arterial damage (CAD-). The frequency of X+/X+ genotype of Xba I polymorphism, in CAD+ group, was 23% (26/114) compared with 8% (11/132) in the CAD- (OR 3.25, p = 0.002). The patients with X+/X+ for the Xba I genotype APOB gene had higher concentration of triglycerides (TG) and VLDL in plasma than CAD- (p< 0.05). The genotype X+/X+ in the CAD had an effect increasing the TG and VLDL plasma levels when compared with individuals with X-/X and X-/X+ genotypes. The present study indicated that the X+X+ genotype of Xba I polymorphism is associated with CAD+ patients and high plasma levels of TG and VLDL, in the Mexican population. PMID- 22507621 TI - IL-10 high producing genotype predisposes HIV infected individuals to TB infection. AB - Interleukin (IL-10), an anti-inflammatory cytokine, is known to have dual effect on the host immune system. One of these roles is that it provides an effective autoregulatory mechanism which protects the host from excessive inflammation and tissue damage which is in part initiated by the Th1 driven pro-inflammatory immune responses during infections (such as TB, HIV and malaria). However, though beneficial, this autoregulatory mechanism is at times exploited by pathogens which evade elimination by Th1 driven immune response leading to chronic infections. The main aim of this study therefore was to study the influence of IL 10 polymorphism in relation to its levels with respect to HIV-TB co-infection. A total of 452 participants were categorized into HIV (121), active tuberculosis (TB) (118), HIV-TB (HT) (106) groups and healthy control group (107). Polymorphism for IL-10 gene (positions -1082, -819, -592) was studied using ARMS PCR, RFLP. IL-10 and IFN-gamma levels in antigen stimulated cultures were measured using ELISA. Statistical analysis was performed using Chi-Square (chi(2)) test, One-way ANOVA and t-tests. IL-10 (-1082) GG genotype was positively associated with HIV-TB, whereas AG with HIV and AA with TB. The cohort with GG genotype also had significantly high stimulated levels of IL-10 compared to AG and AA. AC genotype was significantly frequent in HIV-TB group at IL-10 ( 592) position when compared with controls. HIV positive individuals with GG genotype at IL-10 (-1082) position and high IL-10 levels may have a high risk of developing TB co-infection. PMID- 22507622 TI - Effects of NKG2D haplotypes on the cell-surface expression of NKG2D protein on natural killer and CD8 T cells of peripheral blood among atomic-bomb survivors. AB - NKG2D is a primary activating receptor that triggers cell-mediated cytotoxicity in NK cells against tumor and virus-infected cells. We previously identified the NKG2D haplotypes in the natural killer gene complex region on chromosome 12p. Two major haplotype alleles, LNK1 and HNK1, were closely related to low and high natural cytotoxic activity phenotypes, respectively. Furthermore, the haplotype of HNK1/HNK1 has revealed a decreased risk of cancer compared with LNK1/LNK1. In the present study, using flow cytometry, we evaluated the functional effects of NKG2D haplotypes and five htSNPs in terms of the cell-surface expression of NKG2D protein on NK and CD8 T cells of peripheral blood among 732 atomic-bomb survivors. NKG2D expression on NK cells showed significant increases, in the order of LNK1/LNK1, LNK1/HNK1 and HNK1/HNK1 haplotypes (p for trend=0.003), or with major homozygous, heterozygous, and minor homozygous genotypes for individual htSNPs (p for trend=0.02-0.003). The same trend was observed for NKG2D expression on CD8 T cells. Our findings indicate that the NKG2D haplotypes are associated with the expression levels of NKG2D protein on NK and CD8 T cells, resulting in inter-individual variations in human cytotoxic response. PMID- 22507623 TI - Genetic susceptibility to Kawasaki disease: analysis of pattern recognition receptor genes. AB - Kawasaki disease (KD) is a systemic vasculitis of unknown etiology occurring in infants and children. Several lines of evidence suggested the importance of genetic factors and infectious triggers for the pathogenesis of KD. We have reported that oral administration of a pure NOD1 ligand induces coronary arteritis in mice without fail. Since NOD1 is one of the pattern recognition receptors (PRRs) which play important roles in the innate immunity for the detection of microbial substances and induce inflammatory responses, we have investigated the association of PRR genes with the development of KD. Forty-six tagging-SNPs in 19 PRR genes were genotyped in Japanese KD patients (n=356, consisting of two groups) and controls (n=215). The genotypes and allele frequencies of each SNP or haplotype were compared between KD patients and controls. As a result, we did not find any genes with strongly contributed to the development of KD. A haplotype, G-T-C-C, in the NOD1 gene, was associated with lower risk for KD development (KD 1st group versus controls: 23.2% versus 35.3%, Pc=0.0385). The second-round case-control study in KD group 2 demonstrated that a haplotype, T-T-C-G-A-C, in the NLRP1 gene was associated with a higher risk for KD development (4.9% versus 1.2%, Pc=0.035). From the association analysis of SNPs and haplotypes of 19 PRR genes, NOD1 and NLRP1 seemed to partly contribute to the development of KD. Further analysis with larger samples of another independent set would be needed to find confirmative results. PMID- 22507624 TI - Tumor necrosis factor (TNF) and lymphotoxin-alpha (LTA) single nucleotide polymorphisms: importance in ARDS in septic pediatric critically ill patients. AB - Accumulating evidence indicates that genetic background influences the outcome of sepsis, which despite medical advances continues to be a major cause of morbidity and mortality. This study aimed to evaluate the influence of SNPs LTA +252A>G, TNF-863C>A and TNF-308G>A on susceptibility to sepsis, acute respiratory distress syndrome (ARDS), septic shock and sepsis mortality. A prospective case-control study was carried out in a Brazilian pediatric intensive care unit and included 490 septic pediatric patients submitted to mechanical ventilation and 610 healthy children. No SNP association was found with respect to sepsis susceptibility. Nevertheless, a haplotype was identified that was protective against sepsis (+252A/-863A/-308G; OR=0.65; p=0.03). We further observed protection against ARDS in TNF-308 GA genotype carriers (OR=0.29; p=0.0006) and -308A allele carriers (OR=0.40; p=0.003). In addition, increased risk for ARDS was detectable with the TNF-863 CA genotype (OR=1.83; p=0.01) and the -863A carrier status (OR=1.82; p=0.01). After stratification according to age, this outcome remained significantly associated with the -308GA genotype in infants. Finally, protection against sepsis-associated mortality was found for the TNF-308 GA genotype (OR=0.22; p=0.04). Overall, our findings document a protective effect of the TNF 308 GA genotype for the ARDS and sepsis mortality outcomes, further providing evidence for an increased risk of ARDS associated with the TNF-863 CA genotype. Trial registration (www.clinicaltrials.gov): NCT00792883. PMID- 22507625 TI - Association between polymorphisms in cytokine genes IL-17A and IL-17F and development of allergic rhinitis and comorbid asthma in Chinese subjects. AB - BACKGROUND: Th17 cell lineage, a distinct pro-inflammatory lineage characterized by preferential synthesis of cytokines IL-17A and IL-17F, is thought to play an important role in the pathogenesis of allergic rhinitis (AR). OBJECTIVES: Our aim was to investigate whether polymorphisms in and around IL-17A and IL-17F genes are associated with AR and comorbid asthma. METHODS: A case-control comparison was performed in a cohort of 279 AR patients, 197 allergic rhinitis with asthma (AR-A) patients and 281 control Chinese subjects, to investigate associations between 19 tagging single-nucleotide polymorphisms (SNPs) in IL-17A and IL-17F gene regions and manifestation of AR or AR-A. Genotyping was performed using the Sequenom MassARRAY platform. RESULTS: SNP rs3819024 in IL-17A gene, intergenic SNPs rs1892280 and rs10807439 were specifically associated with AR protective or risk effects, while rs3819024 in IL-17A gene, intergenic SNP rs13192563 in IL-17F gene were associated with AR-A protective or risk effects. Haplotype analysis showed significant AR risk in haplotype AA (rs1892280G-rs13192563A) and AR protective effect in haplotype GT (rs7758579A-rs11966760T); the haplotype AT(rs7758579-rs11966760) were considered AR-A risk. CONCLUSIONS: Our findings preliminarily indicate IL17A and IL17F SNPs, and some intergenic variants have the potential association with AR and comorbid asthma in Chinese population. PMID- 22507626 TI - An eUtils toolset and its use for creating a pipeline to link genomics and proteomics analyses to domain-specific biomedical literature. AB - BACKGROUND: Numerous biomedical software applications access databases maintained by the US National Center for Biotechnology Information (NCBI). To ease software automation, NCBI provides a powerful but complex Web-service-based programming interface, eUtils. This paper describes a toolset that simplifies eUtils use through a graphical front-end that can be used by non-programmers to construct data-extraction pipelines. The front-end relies on a code library that provides high-level wrappers around eUtils functions, and which is distributed as open source, allowing customization and enhancement by individuals with programming skills. METHODS: We initially created an application that queried eUtils to retrieve nephrology-specific biomedical literature citations for a user-definable set of genes. We later augmented the application code to create a general-purpose library that accesses eUtils capability as individual functions that could be combined into user-defined pipelines. RESULTS: The toolset's use is illustrated with an application that serves as a front-end to the library and can be used by non-programmers to construct user-defined pipelines. The operation of the library is illustrated for the literature-surveillance application, which serves as a case-study. An overview of the library is also provided. CONCLUSIONS: The library simplifies use of the eUtils service by operating at a higher level, and also transparently addresses robustness issues that would need to be individually implemented otherwise, such as error recovery and prevention of overloading of the eUtils service. PMID- 22507627 TI - Predicting plant responses to mycorrhizae: integrating evolutionary history and plant traits. AB - We assessed whether (1) arbuscular mycorrhizal colonization of roots (RC) and/or plant responses to arbuscular mycorrhizae (MR) vary with plant phylogeny and (2) MR and RC can be more accurately predicted with a phylogenetic predictor relative to a null model and models with plant trait and taxonomic predictors. In a previous study, MR and RC of 95 grassland species were measured. We constructed a phylogeny for these species and found it explained variation in MR and RC. Next, we used multiple regressions to identify the models that most accurately predicted plant MR. Models including either phylogenetic or phenotypic and taxonomic information similarly improved our ability to predict MR relative to a null model. Our study illustrates the complex evolutionary associations among species and constraints of using phylogenetic information, relative to plant traits, to predict how a plant species will interact with AMF. PMID- 22507628 TI - Presence of faecal coliforms, Escherichia coli and diarrheagenic E. coli pathotypes in ready-to-eat salads, from an area where crops are irrigated with untreated sewage water. AB - Consumption of ready-to-eat (RTE) salads has increased worldwide. Consequently, the number of outbreaks caused by food-borne pathogens, including diarrheagenic E. coli pathotypes (DEPs), associated with the consumption of RTE-salads has increased. DEPs include enterotoxigenic (ETEC), typical and atypical enteropathogenic (tEPEC, aEPEC), enteroinvasive (EIEC), enteroaggregative (EAEC), diffuse adherent (DAEC) and Shiga toxin-producing (STEC) E. coli. In less developed areas of the world, fresh crops continue to be irrigated with untreated sewage water. The aims of this study were to evaluate the microbiological quality and prevalence of DEPs in RTE-salads of raw vegetables, purchased from restaurants at Pachuca-City, Hidalgo, Mexico, where most locally consumed vegetables are irrigated with untreated sewage water. A total of 130 salads were purchased from restaurants of three categories: A) national chain restaurants and B) local restaurants, both with the H distinctive (a recognition that the Secretary of Tourism grants to restaurants that manage supplies with high levels of hygiene); and C) local small inexpensive restaurants without H distinctive. A total of 6 restaurants were included, 2 per category (A(1-2), B(1-2), C(1-2)). Each sample was tested for the presence of faecal coliforms (FC) and E. coli by standard procedures. E. coli strains were further characterized for the presence of DEPs loci by two multiplex polymerase chain reactions. Among the 130 salad samples 99% (129) were contaminated with FC; 85% (110/129) harboured E. coli and 7% (8/110) DEPs. The amount of positive salad samples for FC and E. coli was similar between restaurants and categories. The FC mean (571 FC/g) of all samples was significantly higher (p<0.001) than the E. coli mean (63 E. coli/g). A weak correlation of 7.7% (r(2)=0.077, p=0.003) between median FC and E. coli MPN (most probable number) per sample was found. Of the 8 salad samples contaminated with DEPs, 2 were spinach salads from restaurant A(2) and 3 were (Mixed salad) samples from each C restaurant. Three samples harboured non-O157 STEC strains, 2 EIEC, 1 ETEC and 2 samples had non-O157 STEC and EIEC strains, simultaneously. A significant difference (p=0.008) between the prevalence of E. coli vs. DEPs was observed. Independently of the restaurants' overall hygienic status, most RTE salads had a poor microbiological quality and some harboured DEPs that have been associated with illness in Mexico. Health authorities should focus on implementing DEPs screening in raw vegetables and enforcing the legislation that forbids irrigation with untreated sewage water of both root and leafy vegetables. PMID- 22507629 TI - Estimating the diagnostic accuracy of three culture-dependent methods for the Listeria monocytogenes detection from a Bayesian perspective. AB - The objective of this study was to estimate the test accuracy measures (classification probabilities [CPs], predictive values [PVs], likelihood ratios [LRs] and area under receiving operating characteristic curve [AUC]) of three different culture-dependent methods, commonly used during routine analysis for the detection of the foodborne pathogen Listeria monocytogenes, from a Bayesian perspective. Data from a previous study by Andritsos et al. (2010) were used to define measures of accuracy for the diagnostic tests. Samples of minced pork meat obtained from local markets were tested for L. monocytogenes presence by parallel testing using selective media (PALCAM, ALOA and RAPID'L.mono). Dirichlet distribution, which is the multivariate expression of a Beta distribution, was used to analyze the data. Bayesian analysis determines characteristics of the posterior distribution from available prior information. Results showed that all methods were best at ruling in L. monocytogenes presence than ruling it out. PALCAM seemed to have better performance based on positive PV, positive LR and AUC, but it was not so sensitive as RAPID'L.mono was. Results also showed that none of the media were perfect in detecting L. monocytogenes, i.e. sensitivity and specificity equal to one. Besides, the problem of observing zero counts may be overcome by applying Bayesian analysis, making the determination of a test performance feasible. PMID- 22507631 TI - Melatonin reduces lung oxidative stress in patients with chronic obstructive pulmonary disease: a randomized, double-blind, placebo-controlled study. AB - Chronic obstructive pulmonary disease (COPD), a major cause of death and disability, is attributed to an abnormal inflammatory response by the lungs to noxious substances, primarily from cigarette smoke. Although oxidative stress is regarded as central to the pathogenesis of COPD, very few studies have examined the effects of antioxidants in this condition. This was a randomized, double blind, placebo-controlled study on the effects of melatonin in COPD. Thirty-six consecutive patients with clinically stable moderate to very severe COPD (30 men; mean+/-S.D.=66.6+/-7.8yr) were randomized to receive 3mg melatonin (N=18) or placebo for 3 months. Oxidative stress was evaluated by 8-isoprostane levels in exhaled breath condensate at baseline (T0) and after one (T1), two (T2), and three months (T3) of treatment. Additionally, exhaled breath condensate levels of IL-8, dyspnea severity (Medical Research Council scale), lung function (spirometry), and functional exercise capacity (six min walk test) were compared at baseline and after treatment. Patients receiving melatonin showed a decrease in 8-isoprostane (T0: mean+/-S.E.M.=20.41+/-2.92pg/mL; T1: 18.56+/-2.68pg/mL; T2: 12.68+/-2.04pg/mL; T3: 12.70+/-2.18pg/mL; P=0.04; repeated measures ANOVA) with significant differences from baseline after 2 (P=0.03) and 3months (P=0.01). Dyspnea was improved by melatonin (P=0.01), despite no significant changes in lung function or exercise capacity. Placebo-treated patients, but not those who were given melatonin, showed an increase in IL-8 (P=0.03). In summary, melatonin administration reduced oxidative stress and improved dyspnea in COPD. Further studies are necessary to determine the potential role for melatonin in the long term management of these patients. PMID- 22507630 TI - Mild cerebellar neurodegeneration of aged heterozygous PCD mice increases cell fusion of Purkinje and bone marrow-derived cells. AB - Bone marrow-derived cells have different plastic properties, especially regarding cell fusion, which increases with time and is prompted by tissue injury. Several recessive mutations, including Purkinje Cell Degeneration, affect the number of Purkinje cells in homozygosis; heterozygous young animals have an apparently normal phenotype but they undergo Purkinje cell loss as they age. Our findings demonstrate that heterozygous pcd mice undergo Purkinje cell loss at postnatal day 300, this slow but steadily progressing cell death starting sooner than has been reported previously and without massive reactive gliosis or inflammation. Here, transplantation of bone marrow stem cells was performed to assess the arrival of bone marrow-derived cells in the cerebellum in these heterozygous mice. Our results reveal that a higher number of cell fusion events occurs in heterozygous animals than in the controls, on days 150 and 300 postnatally. In sum, this study indicates that mild cell death promotes the fusion of bone marrow derived cells with surviving Purkinje neurons. This phenomenon suggests new therapies for long-lasting neurodegenerative disorders. PMID- 22507632 TI - Quadriceps keystone island flap for radical inguinal lymphadenectomy: a reliable locoregional island flap for large groin defects. AB - BACKGROUND: Radical inguinal lymphadenectomy (RIL) for bulky metastatic melanoma and non-melanoma skin cancers of the inguinal region, while shown to improve morbidity and survival oncologically, can result in substantial morbidity from wound complications. Skin defects cannot be closed primarily and the substantial dead space predisposes to seroma, wound dehiscence and infection. Despite the clear need for reconstructive options, extended series describing reconstruction of large inguinal defects in this setting have not been reported. METHODS: A prospectively entered, retrospectively reviewed study of 20 consecutive patients undergoing quadriceps keystone island flaps (QKIF) for the closure of complicated inguinal defects is described. RESULTS: There was 100% flap survival, with no partial or complete flap losses. A reduction in wound breakdown/dehiscence from reported rates was seen, with four patients (20%) having wound breakdown, compared to double that rate in reported series. Other wound complications comprised six patients (30%) with mild wound infections, seven patients (35%) with seromas and two patients (10%) with haematomas. CONCLUSION: The QKIF is an effective means of reconstructing inguinal defects after RIL, particularly in high-risk patients, and is technically simpler than other reconstructive techniques advocated for this purpose. Furthermore, the QKIF offers patients with advanced disease (where management is primarily palliative) a potentially improved quality of life with reduced operative morbidity. PMID- 22507633 TI - Personalized cancer medicine - a strategy to counteract an increasing cancer challenge. PMID- 22507634 TI - Curcumin inhibits tumor proliferation induced by neutrophil elastase through the upregulation of alpha1-antitrypsin in lung cancer. AB - Lung carcinogenesis is a complex process in an unregulated inflammatory environment. Curcumin has been extensively investigated as a multi-target anti tumor and anti-inflammation compound. In this paper, we demonstrate a novel inflammation-related mechanism for curcumin-induced inhibition of lung tumor growth. We found that neutrophil elastase, an important regulator of inflammatory processes, directly triggered tumor cell proliferation in human lung adenocarcinoma A549 cells, and curcumin could completely suppress the excess tumor proliferation induced by neutrophil elastase. alpha1-antitrypsin is synthesized by tumor cells and is the natural inhibitor of neutrophil elastase. We found that curcumin counteracted the decrease of alpha1-antitrypsin induced by neutrophil elastase by inducing the promoter activity of alpha1-antitrypsin and promoting its expression in A549 cells. The inhibition of neutrophil elastase induced proliferation by curcumin was dependent on the PI3K/Akt pathway. Knockdown of alpha1-antitrypsin by siRNA further enhanced the tumor cell proliferation induced by neutrophil elastase and significantly blocked the anti proliferation effect of curcumin against neutrophil elastase. Curcumin remarkably inhibited the primary tumor growth of Lewis lung carcinoma (LLC) in C57BL/6 mice. We further showed that curcumin upregulated the level of alpha1-antitrypsin in primary tumor tissue by promoting its local expression, and the protein level of neutrophil elastase in tumor tissue was obviously decreased in mice treated with curcumin. Overall, our results suggest that neutrophil elastase and alpha1 antitrypsin play important roles in modulating lung tumor proliferation in inflammatory microenvironment and curcumin inhibits neutrophil elastase-induced tumor proliferation via upregulating alpha1-antitrypsin expression in vitro and in vivo. PMID- 22507636 TI - Is there an affective working memory deficit in patients with chronic schizophrenia? AB - Research interest in affective working memory has rapidly grown in the last decade. In this study we investigated working memory functions for affective and neutral words in a group of 22 patients with chronic schizophrenia and 22 healthy controls. In particular, participants were administered the operation working memory span task in which affective and neutral words had to be remembered. Results showed that patients made significantly more intrusion errors, recalling off-goal information, and showed poorer long-term memory performance than controls. In addition, affective trials showed the largest number of intrusion errors. These results suggest that a general attentional control deficit, especially over affective information, may underly failures to remember in chronic schizophrenia patients. PMID- 22507635 TI - Resveratrol downregulates acute pulmonary thromboembolism-induced pulmonary artery hypertension via p38 mitogen-activated protein kinase and monocyte chemoattractant protein-1 signaling in rats. AB - AIMS: In the present study, we explored the hypothesis that initiation of PH involves the upregulation of monocyte chemoattractant protein-1 (MCP-1) in acute PTE. We evaluated the effects of resveratrol and the role of p38 mitogen activated protein kinase (MAPK) in this process. MAIN METHODS: A rat model of acute PTE was established by infusion of an autologous blood clot into the pulmonary artery through a polyethylene catheter. Rats were randomly divided into 1, 4, and 8 hour time groups. Resveratrol, C1142 (a rodent chimeric mAb that neutralizes rat MCP-1) or SB203580 (a p38MAPK specific inhibitor) was administered to the animals beginning 1 h prior to the start of the acute PTE protocol. At each time point, the mean pulmonary artery pressure (mPAP), mRNA and protein expressions of MCP-1 were measured. The phosphorylation of p38 MAPK (p pMAPK) was also detected. KEY FINDINGS: Acute PTE elicited significant increases in mean pulmonary artery pressure (mPAP), and up-regulated the expression of monocyte chemoattractant protein-1 (MCP-1) and phosphorylation of p38 mitogen activated protein kinase (p-p38 MAPK). Administration of C1142 markedly reduced mPAP. Furthermore, pre-treatment of rats with resveratrol significantly reduced mPAP and down-regulated the expression of MCP-1, which was associated with robustly suppressed acute PTE-induced p-p38MAPK expression. SIGNIFICANCE: These findings suggested that MCP-1 was involved in the formation of acute PTE-induced PH, and resveratrol down-regulated the expression of MCP-1 by inhibiting acute PTE-induced p-p38MAPK activation, which contributed to the decrease in PH. PMID- 22507637 TI - Neuropsychological functioning and social anhedonia: three-year follow-up data from a longitudinal community high risk study. AB - Social anhedonia is a promising vulnerability marker for schizophrenia-spectrum pathology. Prior research has demonstrated that individuals with psychometrically defined social anhedonia show a range of "schizophrenia-like" neurocognitive abnormalities. However, this research is limited in that it is based largely on the study of college students. The present article reports findings from a longitudinal study of social anhedonia recruited from a community sample. As part of this study, a neurocognitive battery was administered at baseline and at three year follow-up sessions to participants with (n = 78) versus without (n = 77) social anhedonia. Additional measures of global functioning and schizotypal, schizoid and paranoid schizophrenia-spectrum symptoms were also administered. Across groups, subjects showed significant improvement in neurocognitive functioning over time. Compared to controls, at follow-up, individuals with social anhedonia showed significantly poorer attentional vigilance and simple processing speed, but failed to evidence impairments in immediate or delayed verbal memory, immediate or delayed visual memory, visual or verbal working memory, olfaction or executive abilities. At follow-up, within the social anhedonia group, schizoid (and to a lesser extent, schizotypal) symptom severity was associated with a range of neurocognitive impairments. Neurocognitive impairments were generally not associated with paranoid symptoms or global functioning. Baseline neurocognitive performance was not significantly predictive of follow-up symptom severity or functioning. Collectively, these findings suggest that neurocognitive dysfunctions only characterize a subset of individuals with social anhedonia. PMID- 22507638 TI - A direct method to determine the strength of the dermal-epidermal junction in a mouse model for epidermolysis bullosa. AB - Epidermolysis bullosa (EB) describes a spectrum of rare, incurable, inherited mechanobullous disorders unified by the fact that they are caused by structural defects in the basement membrane zone which disrupt adhesion between the epidermis and dermis. Mouse models provide valuable tools to define the molecular basis of these diseases and to test novel therapeutic approaches. There is need for rapid, quantitative tests that measure the integrity of dermal-epidermal adhesions in such models. To address this need, we describe a novel quantitative method to determine the mechanical strength of the adhesion between tail skin epidermis and dermis. We show that this test reliably measures the force required to cause dermal-epidermal separation in tails of mice that are genetically predisposed to a form of non-Herlitz Junctional EB which develops as the result of a hypomorphic mutation in the laminin gamma 2 gene (Lamc2(jeb) ). This simple, quantitative method of directly measuring the tensile strength of dermal epidermal adhesion provides a novel dimension to the pathophysiological screening, evaluation, and therapeutic treatment of mice that may develop progressive forms of EB and potentially other disorders that compromise cutaneous integrity. PMID- 22507639 TI - Intrafamilial transmission of hepatitis C virus in patients with severe haemophilia A. AB - The history behind the production of clotting factor concentrates produced differences in the prevalence of Hepatitis C Virus (HCV) and other blood-borne infections in haemophilic patients. Prevalence rates of HCV infection up to 100% were reported in patients treated with concentrates before 1985. Conversely, nowadays, viral inactivation and recombinant technologies have effectively prevented transfusion-transmitted viral pathogens. Recently, new HCV infections in three young brothers were observed. In the absence of any other risk of transmission, their HIV/HCV coinfected uncle, who was living in the same house, was subject to study. Plasma samples of the four relatives were investigated in order to test whether the infections have a common source. A phylogenetic approach using the most variable (E2) viral sequences was carried out using samples from the four family members. The HCV sequences from the study resulted highly related, being those obtained from the uncle the most ancestral ones. Because of the chronological order in which the infections occurred and the relatedness of the sequences, an infection from the uncle to his nephews is the most likely explanation. Special cares must be applied in the case of household contact among members of a family with inherited bleeding disorders. PMID- 22507640 TI - Alcohol's involvement in recurrent child abuse and neglect cases. AB - AIMS: This paper examined whether or not: (a) care-giver 'alcohol abuse' is associated with recurrent child maltreatment; (b) other 'risk factors' affect this relationship; and (c) which of alcohol abuse or other drug abuse plays a stronger role. It also examined (d) how children and families where alcohol related child abuse was identified were managed by child protection services (CPS) in Victoria, Australia. DESIGN, SETTING AND PARTICIPANTS: Using anonymized data from Victorian CPS, repeat cases were examined involving 29 455 children identified between 2001 and 2005. MEASUREMENTS: Carer alcohol abuse, other drug abuse, mental ill-health, carer experience of abuse as a child, child age and gender, family type, socio-economic variables and level of child protection service intervention as recorded in the CPS electronic database were examined as risk factors for recurrence, using bivariate and multivariate techniques. FINDINGS: Almost one-quarter of children in CPS experienced a recurrent incident of child maltreatment in a 5-year period. Where carer alcohol abuse was identified children were significantly more likely to experience multiple incidents compared with children where this was not identified (P < 0.001), as were children where other family risk factors (including markers of socio economic disadvantage) were identified. The majority of children whose carers were identified with alcohol abuse experienced either repeat incidents or interventions (84%), although almost three-quarters of these children were managed without resort to the most serious outcome, involving court orders. CONCLUSIONS: Alcohol and drug abuse in carers are important risk-factors for recurrent child maltreatment after accounting for other known risk factors; the increased risk appears to be similar between alcohol and drug abuse. PMID- 22507642 TI - Re: "Ex vivo fucosylation improves human cord blood engraftment in NOD-SCID IL 2Rgamma(null) mice". PMID- 22507643 TI - Comparison of type I, type III and type VI collagen binding assays in diagnosis of von Willebrand disease. AB - BACKGROUND: von Willebrand factor (VWF) plays a key role in coagulation by tethering platelets to injured subendothelium through binding sites for collagen and platelet GPIb. Collagen binding assays (VWF:CB), however, are not part of the routine work-up for von Willebrand disease (VWD). OBJECTIVES: This study presents data on collagen binding for healthy controls and VWD subjects to compare three different collagens. PATIENTS/METHODS: VWF antigen (VWF:Ag), VWF ristocetin cofactor activity and VWF:CB with types I, III and VI collagen were examined for samples obtained from the Zimmerman Program. RESULTS: Mean VWF:CB in healthy controls was similar and highly correlated for types I, III and VI collagen. The mean VWF:CB/VWF:Ag ratios for types I, III and VI collagen were 1.31, 1.19 and 1.21, respectively. In type 1 VWD subjects, VWF:CB was similar to VWF:Ag with mean VWF:CB/VWF:Ag ratios for types I, III and VI collagen of 1.32, 1.08 and 1.1, respectively. For type 2A and 2B subjects, VWF:CB was uniformly low, with mean ratios of 0.62 and 0.7 for type I collagen, 0.38 and 0.4 for type III collagen, and 0.5 and 0.47 for type VI collagen. CONCLUSIONS: Normal ranges for type I, III and VI collagen are correlated, but higher values were obtained with type I collagen as compared with types III and VI. The low VWF:CB in type 2A and 2B subjects suggests that VWF:CB may also supplement analysis of multimer distribution. However, these results reflect only one set of assay conditions per collagen type and therefore may not be generalizable to all collagen assays. PMID- 22507644 TI - Human papillomavirus and gene mutations in head and neck squamous carcinomas. AB - BACKGROUND: Human papillomavirus (HPV) infection is implicated as an aetiological factor in head and neck squamous carcinomas (HNSCC), especially in the tonsils of the oropharyngeal region. This study investigates the frequency of HPV infection, p16 and p53 tumour profile and mutations in epidermal growth factor receptor (EGFR), Kirsten RNA Associated Rat Sarcoma 2 Virus (KRAS) and B-Raf proto oncogene serine/threonine protein kinase (BRAF) genes in tonsillar and non tonsillar HNSCCs and correlates with clinical outcome and histopathological parameters in previously unstudied cohort of patients. METHODS: A retrospective clinical study was performed utilising the demographic data and pathological specimens from 60 out of 726 head and neck cancer patients. Smoking and alcohol history, tumour staging, treatment and outcomes were recorded. Histopathology and immunochemistry for p16 and p53 was performed and HPV DNA was detected with polymerase chain reaction. Genomic DNA from all cancers were analysed for somatic mutations of EGFR, BRAF and KRAS genes. RESULTS: 20 (33%) of 60 cases were tonsillar squamous carcinomas and 38 (66%) were non-tonsillar. 19 (95%) of the 20 tonsillar cancers and three (8%) of 38 non-tonsillar patients were patients who were HPV 16-positive. Nine (47%) of the 19 HPV 16-positive tonsillar cases were p16 positive. Gene mutations were rare. There was a statistically significant (P < 0.05) improved survival of patients with HPV positive tonsillar tumours, younger age and non-smokers. CONCLUSION: Although limited in numbers, this study reinforces the role of HPV infection in HNSCC and its association with a more favourable clinical course in younger non-smokers worldwide. Gene mutation frequencies were low in all cancers tested and routine testing not recommended. PMID- 22507645 TI - Clinical prediction rule for differentiating tuberculous from viral meningitis. AB - SETTING: The Professor Dr Matei Bals National Institute of Infectious Diseases, Bucharest, Romania. OBJECTIVE: To create a prediction rule to enable clinicians to differentiate patients with tuberculous meningitis (TBM) from those with viral meningitis. DESIGN: We retrospectively analysed patients admitted to a tertiary care facility between 2001 and 2011 with viral meningitis and TBM. Patients were defined as having TBM according to a recently published consensus definition, and as viral meningitis if a viral aetiology was confirmed, or after ruling out bacterial, fungal and non-infectious causes of meningitis. RESULTS: We identified 433 patients with viral meningitis and 101 TBM patients and compared their clinical and laboratory features. Multivariable analysis showed a statistically significant association between TBM and the following variables: duration of symptoms before admission of >=5 days, presence of neurological impairment (altered consciousness, seizures, mild focal signs, multiple cranial nerve palsies, dense hemiplegia or paraparesis), cerebrospinal fluid/blood glucose ratio < 0.5 and cerebrospinal fluid protein level > 100 mg/dl. We propose a diagnostic score based on the coefficients derived from the logistic regression model with a sensitivity and specificity for TBM of respectively 92% and 94%. CONCLUSIONS: Our study suggests that easily available clinical and laboratory data are very useful for differentiating TBM from other causes of meningitis. PMID- 22507646 TI - Solitary renal cysts: worth a second look? PMID- 22507647 TI - Condition-specific disease treatment in dialysis patients: utilization, costs, and guideline and policy imperatives. PMID- 22507648 TI - Dialysis and kidney transplantation: why have our rehabilitation hopes not been achieved fully? PMID- 22507649 TI - Delivering accountable care to patients with complicated chronic illness: how does it fit into care models and do nephrologists have a role? PMID- 22507651 TI - Oral vitamin D effects on PTH levels. PMID- 22507652 TI - A large dialysis provider committed to home modalities. PMID- 22507654 TI - Quiz page May 2012: Severe hypocalcemia in a hemodialysis patient. PMID- 22507655 TI - Alum-adjuvanted H5N1 whole virion inactivated vaccine (WIV) enhanced inflammatory cytokine productions. AB - Alum-adjuvanted H5 whole virion inactivated vaccine (WIV) was licensed for adults in Japan but induced marked febrile reactions with significantly stronger antibody responses in children. In this study, the mechanisms behind the different responses were investigated. Lymphocytes were obtained from 25 healthy subjects who were not immunized with H5 vaccine, to examine the innate immune impact of the various vaccine formulations, analyzing the cytokine production profile stimulated with alum adjuvant alone, alum-adjuvanted H5 WIIV, plain H5 WIV, and H5 split vaccine. Alum adjuvant did not induce cytokine production, but H5 split induced IFN-gamma and TNF-alpha. H5 WIV induced IL-6, IL-17, TNF-alpha, MCP-1, IFN-gamma, and IFN-alpha. An extremely low level of IL-1beta was produced in response to H5 WIV, and alum-adjuvanted H5 WIV enhanced IL-1beta production, with similar levels of other cytokines stimulated with H5 WIV. Enhanced production of cytokines induced by alum-adjuvanted H5 WIV may be related to the higher incidence of febrile reactions with stronger immune responses in children but it should be further investigated why efficient immune responses with febrile illness were observed only in young children. PMID- 22507656 TI - Algorithm to assess causality after individual adverse events following immunizations. AB - Assessing individual reports of adverse events following immunizations (AEFI) can be challenging. Most published reviews are based on expert opinions, but the methods and logic used to arrive at these opinions are neither well described nor understood by many health care providers and scientists. We developed a standardized algorithm to assist in collecting and interpreting data, and to help assess causality after individual AEFI. Key questions that should be asked during the assessment of AEFI include: Is the diagnosis of the AEFI correct? Does clinical or laboratory evidence exist that supports possible causes for the AEFI other than the vaccine in the affected individual? Is there a known causal association between the AEFI and the vaccine? Is there strong evidence against a causal association? Is there a specific laboratory test implicating the vaccine in the pathogenesis? An algorithm can assist with addressing these questions in a standardized, transparent manner which can be tracked and reassessed if additional information becomes available. Examples in this document illustrate the process of using the algorithm to determine causality. As new epidemiologic and clinical data become available, the algorithm and guidelines will need to be modified. Feedback from users of the algorithm will be invaluable in this process. We hope that this algorithm approach can assist with educational efforts to improve the collection of key information on AEFI and provide a platform for teaching about causality assessment. PMID- 22507657 TI - Pneumococcal vaccination may induce anti-oxidized low-density lipoprotein antibodies that have potentially protective effects against cardiovascular disease. AB - Many animal and human studies have found an inverse association between anti oxidized low-density lipoprotein (oxLDL) antibodies (anti-oxLDL) and atherosclerotic burden. Furthermore, anti-oxLDL antibodies have been shown to cause regression of atherosclerotic plaque in mice. Animal studies indicate that the 23-valent pneumococcal vaccine may induce the production of these potentially protective anti-oxLDL antibodies, and human epidemiological studies support their potentially beneficial effect in reducing cardiovascular events. Here we describe the association between self-reported pneumococcal vaccination, vaccination verified by linkage to health records, and anti-pneumococcal antibody titers, and anti-ox-LDL titers in a group of 116 older people. We found a bimodal distribution of anti-oxLDL antibodies, and a significant association between pneumococcal IgG and anti-oxLDL antibody titers that remained after multivariate adjustment for potential confounders (p=0.04). There was no significant association between self-reported vaccination or vaccination verified by health record linkage and ox-LDL titers, which may be due to reporting error or variability in response to the vaccine. These results support a mechanistic link between pneumococcal vaccination and a potential protective effect on cardiovascular disease, and indicate that self-reported or verified vaccine status may not be sufficient to detect this association. PMID- 22507658 TI - Comparative evaluation of a vaccine candidate expressing enterotoxigenic Escherichia coli (ETEC) adhesins for colibacillosis with a commercial vaccine using a pig model. AB - In this study, a comparative evaluation of a novel live vaccine candidate expressing enterotoxigenic Escherichia coli (ETEC) fimbriae and a commercial ETEC vaccine was carried out in suckling to weaned piglets. The E. coli K88ab, K88ac, K99, FasA and F41 fimbrial genes were individually inserted into an expression/secretion plasmid, pBP244. These plasmids were subsequently transfected into attenuated Salmonella, which were used as the vaccine candidate. Eighteen pregnant sows and 107 of their piglets were used in this comparative study. All the vaccinated groups of sows and piglets exhibited significantly increased antibody levels relative to specific antigens when compared with those in the unimmunized control. The experimental piglets with the vaccine candidate did not experience diarrhea following challenge with the virulent ETEC strains. However, diarrhea was observed in 36.8% of the piglets in the group immunized with the commercial vaccine and in 50% of the control group after challenge with the ETEC strains. These findings indicate that immunization of sows with the candidate vaccine can effectively protect their young pigs against colibacillosis. PMID- 22507659 TI - Simple model systems: a challenge for Alzheimer's disease. AB - The success of biomedical researches has led to improvement in human health and increased life expectancy. An unexpected consequence has been an increase of age related diseases and, in particular, neurodegenerative diseases. These disorders are generally late onset and exhibit complex pathologies including memory loss, cognitive defects, movement disorders and death. Here, it is described as the use of simple animal models such as worms, fishes, flies, Ascidians and sea urchins, have facilitated the understanding of several biochemical mechanisms underlying Alzheimer's disease (AD), one of the most diffuse neurodegenerative pathologies. The discovery of specific genes and proteins associated with AD, and the development of new technologies for the production of transgenic animals, has helped researchers to overcome the lack of natural models. Moreover, simple model systems of AD have been utilized to obtain key information for evaluating potential therapeutic interventions and for testing efficacy of putative neuroprotective compounds. PMID- 22507660 TI - Incentive payments are not related to expected health gain in the pay for performance scheme for UK primary care: cross-sectional analysis. AB - BACKGROUND: The General Medical Services primary care contract for the United Kingdom financially rewards performance in 19 clinical areas, through the Quality and Outcomes Framework. Little is known about how best to determine the size of financial incentives in pay for performance schemes. Our aim was to test the hypothesis that performance indicators with larger population health benefits receive larger financial incentives. METHODS: We performed cross sectional analyses to quantify associations between the size of financial incentives and expected health gain in the 2004 and 2006 versions of the Quality and Outcomes Framework. We used non-parametric two-sided Spearman rank correlation tests. Health gain was measured in expected lives saved in one year and in quality adjusted life years. For each quality indicator in an average sized general practice we tested for associations first, between the marginal increase in payment and the health gain resulting from a one percent point improvement in performance and second, between total payment and the health gain at the performance threshold for maximum payment. RESULTS: Evidence for lives saved or quality adjusted life years gained was found for 28 indicators accounting for 41% of the total incentive payments. No statistically significant associations were found between the expected health gain and incentive gained from a marginal 1% increase in performance in either the 2004 or 2006 version of the Quality and Outcomes Framework. In addition no associations were found between the size of financial payment for achievement of an indicator and the expected health gain at the performance threshold for maximum payment measured in lives saved or quality adjusted life years. CONCLUSIONS: In this subgroup of indicators the financial incentives were not aligned to maximise health gain. This disconnection between incentive and expected health gain risks supporting clinical activities that are only marginally effective, at the expense of more effective activities receiving lower incentives. When designing pay for performance programmes decisions about the size of the financial incentive attached to an indicator should be informed by information on the health gain to be expected from that indicator. PMID- 22507661 TI - The vascular endothelial growth factor (VEGF)-E encoded by orf virus regulates keratinocyte proliferation and migration and promotes epidermal regeneration. AB - Vascular endothelial growth factor (VEGF)-A, a key regulator of cutaneous blood vessel formation, appears to have an additional role during wound healing, enhancing re-epithelialization. Orf virus, a zoonotic parapoxvirus, induces proliferative skin lesions that initiate in wounds and are characterized by extensive blood vessel formation, epidermal hyperplasia and rete ridge formation. The vascular changes beneath the lesion are largely due to viral-expressed VEGF E. This study investigated using mouse skin models whether VEGF-E can induce epidermal changes such as that seen in the viral lesion. Injection of VEGF-E into normal skin increased the number of endothelial cells and blood vessels within the dermis and increased epidermal thickening and keratinocyte number. Injection of VEGF-E into wounded skin, which more closely mimics orf virus lesions, increased neo-epidermal thickness and area, promoted rete ridge formation, and enhanced wound re-epithelialization. Quantitative RT-PCR analysis showed that VEGF-E did not induce expression of epidermal-specific growth factors within the wound, but did increase matrix metalloproteinase (MMP)-2 and MMP-9 expression. In cell-based assays, VEGF-E induced keratinocyte migration and proliferation, responses that were inhibited by a neutralizing antibody against VEGF receptor (VEGFR)-2. These findings demonstrate that VEGF-E, both directly and indirectly, regulates keratinocyte function, thereby promoting epidermal regeneration. PMID- 22507662 TI - Tracking differential incorporation of dissolved organic carbon types among diverse lineages of Sargasso Sea bacterioplankton. AB - Bacterioplankton are the primary trophic conduit for dissolved organic carbon (DOC) and linking community structure with DOC utilization is central to understanding global carbon cycling. We coupled stable isotope probing (SIP) with 16S rRNA pyrosequencing in dark seawater culture experiments on euphotic and mesopelagic communities from the Sargasso Sea. Parallel cultures were amended with equimolar quantities of four DO(13) C substrates to simultaneously evaluate community utilization and population-specific incorporation. Of the substrates tested - two cyanobacterial products (exudates or lysates from a culture of Synechococcus) and two defined monosaccharides (glucose or gluconic acid) - the cyanobacterial exudates were incorporated by the greatest diversity of oligotrophic bacterioplankton populations in surface waters, including taxa from > 10 major subclades within the Flavobacteria, Actinobacteria, Verrucomicrobia and Proteobacteria (including SAR11). In contrast, the monosaccharide glucose was not incorporated by any taxa belonging to extant oligotrophic oceanic clades. Conversely, proteobacterial copiotrophs, which were rare in the ambient water (< 0.1% of sequences), grew rapidly on all DOC amendments at both depths, but with different substrate preferences among lineages. We present a new analytical framework for using SIP to detect DOC incorporation across diverse oligotrophic bacterioplankton and discuss implications for the ecology of bacterial-DOC interactions among populations of diverging trophic strategies. PMID- 22507663 TI - Synaesthetic perception of colour and visual space in a blind subject: an fMRI case study. AB - In spatial sequence synaesthesia (SSS) ordinal stimuli are perceived as arranged in peripersonal space. Using fMRI, we examined the neural bases of SSS and colour synaesthesia for spoken words in a late-blind synaesthete, JF. He reported days of the week and months of the year as both coloured and spatially ordered in peripersonal space; parts of the days and festivities of the year were spatially ordered but uncoloured. Words that denote time-units and triggered no concurrents were used in a control condition. Both conditions inducing SSS activated the occipito-parietal, infero-frontal and insular cortex. The colour area hOC4v was engaged when the synaesthetic experience included colour. These results confirm the continued recruitment of visual colour cortex in this late-blind synaesthetes. Synaesthesia also involved activation in inferior frontal cortex, which may be related to spatial memory and detection, and in the insula, which might contribute to audiovisual integration related to the processing of inducers and concurrents. PMID- 22507664 TI - Promethazine inhibits NMDA-induced currents - new pharmacological aspects of an old drug. AB - BACKGROUND AND PURPOSE: The phenothiazine derivative promethazine was first introduced into clinical practice as an antiallergic drug owing to its H1 receptor antagonizing properties. Nowadays, promethazine is primarily used as a sedative and/or as an antiemetic. The spectrum of clinically relevant effects is mediated by different molecular targets. Since glutamate is the predominant excitatory transmitter in the vertebrate brain and involved in alertness control, pain processing, and neurotoxicity we tested the hypothesis that promethazine interacts with excitatory ionotropic glutamate receptors. EXPERIMENTAL APPROACH: Electrophysiological experiments were performed by means of the patch-clamp technique at glutamate receptors heterologously expressed in human TsA cells. KEY RESULTS: Promethazine selectively inhibited NMDA receptors whereas AMPA- and kainate receptors were hardly affected. Inhibition of NMDA-induced membrane currents occurred in a reversible manner with a half-maximal effect at around 20 MUM promethazine. The inhibition occurred in a non-competitive manner as it did neither vary with the glutamate nor the glycine concentration. Analysis of the underlying mechanism revealed only a weak dependency on receptor usage, pH value (pH 6.8-7.8), and membrane potential (zdelta = 0.44 +/- 0.04 according to the Woodhull-model). In line with the latter finding, promethazine did not interact with the Mg(2+) binding site. However, the displacement of promethazine by 9 aminoacridine indicates that promethazine may interact with the channel pore more externally in relation to the Mg(2+) binding site. CONCLUSION AND IMPLICATIONS: Promethazine inhibits NMDA-mediated membrane currents in a reversible and concentration-dependent manner. The results presented here provide evidence that the NMDA receptor antagonism may contribute to clinically relevant effects of promethazine like sedation, analgesia or neuroprotection. PMID- 22507665 TI - Lithium: a switch from LTD- to LTP-like plasticity in human cortex. AB - Lithium, a simple cation, is the mainstay treatment of bipolar disorder. Deficient synaptic plasticity is considered one important mechanism of this disease. Lithium inhibits glycogen synthase kinase-3beta (GSK-3beta), which is involved in the regulation of synaptic plasticity. In animal preparations, inhibition of GSK-3beta by lithium up-regulated long-term potentiation (LTP) of excitatory synapses but down-regulated long-term depression (LTD). The effects of lithium on plasticity in the human brain are unexplored. We tested the effects of a single oral dose of 900 mg of lithium on LTP-/LTD-like plasticity in human motor cortex induced by established paired associative transcranial magnetic stimulation (PAS(LTP), PAS(LTD)) protocols. We studied 10 healthy adults in a placebo-controlled double-blind randomized crossover design. PAS-induced plasticity was indexed by change in motor evoked potential amplitude recorded in a hand muscle. In the placebo session, subjects were stratified, according to the known variability of the PAS(LTP) response, into PAS(LTP) 'LTP responders' and PAS(LTP) 'LTD responders' (n = 5 each). Lithium did not affect the PAS(LTP) induced LTP-like plasticity in the 'LTP responders', but switched the PAS(LTP) induced LTD-like plasticity in the 'LTD responders' to LTP-like plasticity. In contrast, lithium had no effect on the PAS(LTD)-induced LTD-like plasticity in the 'LTD responders'. We provide first-time evidence that lithium significantly modulates brain stimulation induced plasticity in human cortex. The switch from LTD- to LTP-like plasticity is best explained by the inhibitory action of lithium on GSK-3beta. This conclusion is necessarily circumstantial because GSK-3beta activity was not directly measured. We discuss that other important plasticity related modes actions of lithium cannot explain our findings. PMID- 22507666 TI - mGlu5R promotes glutamate AMPA receptor phosphorylation via activation of PKA/DARPP-32 signaling in striatopallidal medium spiny neurons. AB - Group I metabotropic glutamate receptors (mGluRs), which comprise mGlu1Rs and mGlu5Rs, are enriched in striatal medium spiny neurons (MSNs), where they modulate glutamatergic transmission. Here, we have examined the effect of group I mGluRs on the regulation of the state of phosphorylation of the GluA1 subunit of the AMPA glutamate receptor. We found that incubation of mouse striatal slices with the group I mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) promotes GluA1 phosphorylation at the cAMP-dependent protein kinase (PKA) site, Ser845. This effect is prevented by 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), a selective mGlu5R antagonist. The increase in GluA1 phosphorylation produced by DHPG is also prevented by blockade of adenosine A2A receptors (A2ARs), which are known to promote cAMP signaling specifically in striatopallidal MSNs, as well as by enzymatic degradation of endogenous adenosine, achieved with adenosine deaminase. The ability of DHPG to increase PKA dependent phosphorylation of GluA1 depends on concomitant activation of the dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32). Thus, inactivation of the PKA phosphorylation site of DARPP-32 abolishes the effect of DHPG. Moreover, cell-specific knock out of DARPP-32 in striatopallidal, but not in striatonigral, MSNs prevents the increase in Ser845 phosphorylation induced by DHPG. These results indicate that activation of mGlu5Rs promotes PKA/DARPP-32 dependent phosphorylation of downstream target proteins in striatopallidal MSNs and that this effect is exerted via potentiation of tonic A2AR transmission. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID- 22507667 TI - Factors influencing the assimilation of arsenic in a deposit-feeding polychaete. AB - We investigated mechanisms leading to the assimilation of particle-bound arsenic (As) ingested by the deposit-feeding polychaete Alitta succinea using a radiotracer approach. The release of As from different particle types into extracted gut fluid or bovine serum albumin (BSA), a gut fluid mimic, was measured. In addition, gut fluid proteins were analyzed by separating proteins via 2D gel electrophoresis, and protein peptide sequences were determined by mass spectrometry. Major ions in the gut fluid were measured by ion chromatography and metals by mass spectrometry. Percentages of particulate As release were related to As assimilation efficiencies (AEs) in polychaetes feeding on different particle types. AEs of As were highest from radiolabeled pure diatoms (72%) and radiolabeled diatoms added to sediment (51%), lower from radiolabeled sediment (10%), and lowest from a radiolabeled iron oxide mineral, goethite (2%). It appears that As release from particles is a necessary but not sufficient requirement of As assimilation. For example, 15% of As was released from goethite into the gut fluid but only 2% was assimilated by A. succinea. Our results suggest that the likelihood of As assimilation is higher when it is bound to an organic compound of nutritional value in the ingested particles. PMID- 22507668 TI - Molecular cloning and characterization of estrogen receptor gene in the scallop Chlamys farreri: expression profiles in response to endocrine disrupting chemicals. AB - In order to gain insights into the mechanism of sex steroid signaling in molluscs, the full-length cDNA of estrogen receptor (ER) was isolated and characterized from Chlamys farreri for the first time. The positions of cysteine residues and other residues around them that constitute the two zinc finger motifs and the P-box are conserved. Phylogenetic analysis revealed that the CfER is an ortholog of the other mollusk ERs. Tissue distribution analysis of the CfER mRNA revealed that the expression of ER mRNA was observed in various tissues, and highest in the gonad of males and females. C. farreri were exposed for 10 days to endocrine disrupting chemicals including Benzo(a)pyrene (B(a)p) and polybrominated diphenyl ethers (BDE-47). B(a)p exposure at 0.4 and 2 MUg/L caused significant increase in mRNA expression of ER and VTG, but B(a)p at 10 MUg/L down regulated CfER and VTG mRNA expression compared to control. Varying increase of ER and VTG mRNA transcripts was resulted in by BDE-47 at 0.1, 1 and 10 MUg/L. These results elucidate potential roles of CfER induced by xenobiotics in C. farreri and can be helpful for investigating the mechanism of sex steroid signaling in bivalve mollusks. PMID- 22507669 TI - Basal cell carcinoma characteristics as predictors of depth of invasion. AB - BACKGROUND: Pretreatment risk stratification of basal cell carcinoma (BCC) is largely based on histologic subtype reported from biopsy specimens. OBJECTIVE: We sought to determine the degree of concordance between characteristics identified on biopsy specimen and excision and to determine if histologic characteristics other than subtype correlated with depth of invasion. METHODS: Histologic specimens of 100 BCC biopsy specimens and corresponding excisions were reviewed. Anatomic site, histologic subtype, maximum depth of extension, contour of the lobules at the leading edge, elastosis characteristics, presence of necrosis, calcification, and ulceration were recorded. Concordance between biopsy specimens and their excisions with relation to depth of tumor lobules was analyzed. RESULTS: The concordance between the subtype of biopsy specimen and excision was 62%. Micronodular tumors had the greatest mean depth, followed by infiltrative, nodular, and superficial subtypes. Subtype reported from biopsy specimen (P = .0002) and excision (P < .0001) correlated to depth and was superior to age, contours of excision specimens, the presence of necrosis, and the extent of excisional solar elastosis. Gender, anatomic site, contours of biopsy specimens, elastosis color, elastosis type, the presence of ulceration, and calcification did not correlate with depth. LIMITATIONS: Selection bias is present as only standard excisions were included; BCCs treated by other methods were not examined. CONCLUSIONS: BCC subtype identified on biopsy specimen may not correlate with subtype identified on excision. Morphologic subtype has the highest correlation with depth and reporting should reflect the highest risk growth pattern if a biopsy specimen contains more than one pattern. Consideration should be given to reporting necrosis and degree of solar elastosis. PMID- 22507671 TI - Challenges in obtaining aesthetic breast ideals: reply to 'Concepts in aesthetic breast dimensions - analysis of the ideal breast'. PMID- 22507670 TI - miR-146a, an IL-1beta responsive miRNA, induces vascular endothelial growth factor and chondrocyte apoptosis by targeting Smad4. AB - INTRODUCTION: miR-146a is one of the first identified miRNAs expressed differentially in osteoarthritis (OA) cartilage. However, the role it plays in OA pathogenesis is not clear. The aim of this study is to identify a molecular target of miR-146a, thereby elucidating its function in chondrocytes during OA pathogenesis. METHODS: Primary chondrocytes from Sprague-Dawley rats were treated with IL-1beta before the expression levels of miR-146a, Smad4 and vascular endothelial growth factor (VEGF) were quantified by real-time PCR and/or western blotting. The effect of miR-146a on cellular response to transforming growth factor (TGF)-beta1 was quantified by a luciferase reporter harboring TGF-beta1 responsive elements and by extracellular signal-regulated kinase assay. The effect of miR-146a on apoptosis was quantified by the TUNEL assay. OA pathogenesis was surgically induced with joint instability in rats, evaluated by histopathological analysis with safranin O staining, and the expression levels of miR-146a, Smad4, and VEGF were quantified using real-time PCR and/or immunohistochemistry. RESULTS: IL-1beta treatment of chondrocytes increased the expression levels of miR-146a and VEGF and decreased the levels of Smad4 in a time-dependent manner. miR-146a upregulated VEGF expression and downregulated Smad4 expression in chondrocytes, while a miR-146a inhibitor acted in a converse manner. Smad4, a common mediator of the TGF-beta pathway, is identified as a direct target of miR-146a by harboring a miR-146a binding sequence in the 3'-UTR region of its mRNA. Mutation of the binding sequence significantly relieved the inhibition of the Smad4 reporter activity by miR-146a. Furthermore, miR-146a upregulation of VEGF is mediated by Smad4. Expression of miR-146a led to a reduction of cellular responsiveness to TGF-beta and an increase of apoptosis rate in chondrocytes. In vivo, cartilage from surgically induced OA rats displayed higher levels of miR-146a and VEGF compared with the sham group. In contrast, Smad4 expression level was lower in the OA group than the sham group. CONCLUSION: IL-1beta responsive miR-146a is overexpressed in an experimentally induced OA model, accompanied by upregulation of VEGF and downregulation of Smad4 in vivo. miR-146a may contribute to OA pathogenesis by increasing VEGF levels and by impairing the TGF-beta signaling pathway through targeted inhibition of Smad4 in cartilage. PMID- 22507672 TI - Perforator anatomy of the ulnar forearm fasciocutaneous flap. AB - The ulnar forearm fasciocutaneous flap (UFFF) is a favourable alternative to the radial forearm flap when thin and pliable tissue is required. The precise anatomy of the cutaneous perforators of UFFF has not been previously reported. The position of cutaneous perforators>0.5 mm was recorded while raising 52 consecutive free UFFFs in 51 patients at our Centre. Three (6%) UFFFs in two patients demonstrated direct cutaneous supply through a superficial ulnar artery, a known anatomic variance. There was no cutaneous perforator>0.5 mm in one flap. Among the remaining 48 dissections, an average of 3 (range, 1-6) cutaneous perforators were identified. Ninety-four percent of these forearms demonstrated at least one perforator>0.5 mm within 3 cm, and all had at least one perforator within 6 cm of the midpoint of the forearm. Proximal perforators were more likely to be musculo-cutaneous through the edge of flexor carpi ulnaris or flexor digitorum superficialis, while mid- to distal perforators were septo-cutaneous. UFFF skin paddle designed to overlie an area within 3 cm of the midpoint between the medial epicondyle and the pisiform is most likely to include at least one cutaneous perforator from the ulnar artery, without a need for intra-operative skin island adjustment. This novel anatomic finding and other practical generalisations are discussed to facilitate successful elevation of UFFF. PMID- 22507673 TI - Feasibility of intracoronary GLP-1 eluting CellBeadTM infusion in acute myocardial infarction. AB - Cell therapy is a field of growing interest in the prevention of post acute myocardial infarction (AMI) heart failure. Stem cell retention upon local delivery to the heart, however, is still unsatisfactory. CellBeads were recently developed as a potential solution to this problem. CellBeads are 170-MUm alginate microspheres that contain mesenchymal stem cells (MSCs) genetically modified to express glucagon-like peptide-1 (GLP-1) supplementary to inherent paracrine factors. GLP-1 is an incretin hormone that has both antiapoptotic and cardioprotective effects. Transplanting CellBeads in the post-AMI heart might induce cardiomyocyte salvage and ultimately abrogate adverse cardiac remodeling. We aimed to investigate the feasibility of intracoronary infusion of CellBeads in a large animal model of AMI. Four pigs were used in a pilot study to assess the maximal safe dose of CellBeads. In the remaining 21 animals, an AMI was induced by balloon occlusion of the left circumflex coronary artery for 90 min. During reperfusion, 60,000 CellBeads (n = 11), control beads (n = 4), or lactated Ringers' (n = 6) were infused. Animals were sacrificed after 2 or 7 days, and the hearts were excised for histological analyses. Intracoronary infusion did not permanently affect coronary flow in any of the groups. Histological analysis revealed CellBeads containing viable MSCs up to 7 days. Viability and activity of the MSCs was confirmed by qPCR analysis that showed expression of recombinant GLP 1 and human genes after 2 and 7 days. CellBeads reduced inflammatory infiltration by 29% (p = 0.001). In addition, they decreased the extent of apoptosis by 25% (p = 0.001) after 2 days. We show that intracoronary infusion of 5 million encapsulated MSCs is safe and feasible. Also, several parameters indicate that the cells have paracrine effects, suggesting a potential therapeutic benefit of this new approach. PMID- 22507674 TI - Favor, not fear, the clinical advancement of neurorestoratology: a brief introduction to the IANR supplement issue. PMID- 22507675 TI - Clinical achievements, obstacles, falsehoods, and future directions of cell-based neurorestoratology. AB - Neurorestoratology is a newborn and emerging distinct discipline in the neuroscience family. Its establishment will definitely speed up the advance of this promising frontier realm. A worldwide association for Neurorestoratology and several official journals covering this discipline have recently been set up. Clinical practice has demonstrated that the sequelae of damages and diseases of the CNS can be functionally restored to some degree. Obstacles that hinder the promising methods of Neurorestoratology to be translated from the bench to the bedside include political, governmental, religious, ethical, economic, and scientific factors or in most instances they work in combination. Falsehoods against the recognition of neurorestoratology include: 1) no therapeutic method is currently available that suggests that it is possible to repair, even partially, neurological functions; 2) according to the media, a cure will be very soon found for patients with severe spinal cord injury, brain trauma, and progressively deteriorated CNS degenerative diseases; 3) randomizing double blind control designed studies are the only gold standard for clinical study; self comparison designed studies should be ignored and neglected. Future directions for neurorestoratology include the comparison and integration of current and upcoming available neurorestoration methods to look for the optimization regimes, and edit and publish clinical neurorestoratology treatment guidelines. PMID- 22507676 TI - Intra-arterial infusion of autologous bone marrow mononuclear cells in patients with moderate to severe middle cerebral artery acute ischemic stroke. AB - Transplantation of autologous bone marrow mononuclear cells (BMMCs) has been proven safe in animal and human studies. However, there are very few studies in stroke patients. In this study, intra-arterial autologous BMMCs were infused in patients with moderate to severe acute middle cerebral artery infarcts. The subjects of this study included 20 patients with early or late spontaneous recanalization but with persistent deficits, in whom treatment could be initiated between 3 and 7 days after stroke onset. Mononuclear cells were isolated from bone marrow aspirates and infused at the proximal middle cerebral artery of the affected hemisphere. Safety analysis (primary endpoint) during the 6-month follow up assessed death, any serious clinical events, neurological worsening with >= 4 point increase in National Institutes of Health Stroke Scale (NIHSS) scores, seizures, epileptogenic activity on electroencephalogram, and neuroimaging complications including new ischemic, hemorrhagic, or neoplastic lesions. Satisfactory clinical improvement (secondary endpoint) at 90 days was defined according to the pretreatment NIHSS scores as follows: modified Rankin Scale score of 0 in patients with NIHSS <8, modified Rankin Scale scores of 0-1 in patients with NIHSS 8-14, or modified Rankin Scale scores 0-2 in patients with NIHSS >14. Good clinical outcome was defined as mRS <=2 at 90 days. Serial clinical, laboratory, electroencephalogram, and imaging evaluations showed no procedure-related adverse events. Satisfactory clinical improvement occurred in 6/20 (30%) patients at 90 days. Eight patients (40%) showed a good clinical outcome. Infusion of intra-arterial autologous BMMCs appears to be safe in patients with moderate to severe acute middle cerebral artery strokes. No cases of intrahospital mortality were seen in this pilot trial. Larger prospective randomized trials are warranted to assess the efficacy of this treatment approach. PMID- 22507677 TI - Long-term outcome of olfactory ensheathing cell therapy for patients with complete chronic spinal cord injury. AB - The neurorestorative effect of the parenchymal transplantation of olfactory ensheathing cells (OECs) for cord trauma remains clinically controversial. The aim of this article is to study the long-term result of OECs for patients with complete chronic spinal cord injury (SCI). One hundred and eight patients suffered from complete chronic SCI were followed up successfully within the period of 3.47 +/- 1.12 years after OEC therapy. They were divided into two groups based on the quality and quantity of their rehabilitative training: group A (n = 79) in sufficient rehabilitation (or active movement-target enhancement neurorehabilitation therapy, AMTENT) and group B (n = 29) in insufficient rehabilitation. All patients were assessed by using the American Spinal Injury Association (ASIA) standard and the International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS). Thirty-one patients were evaluated by the tests of magnetic resonance imaging (MRI), electromyography (EMG), and paravertebral sensory evoked potential (PVSEP). We found the following. 1) According to ASIA and IANR-SCIFRS assessment for all 108 patients, averaged motor scores increased from 37.79 +/- 18.45 to 41.25 +/- 18.18 (p < 0.01), light touch scores from 50.32 +/- 24.71 to 55.90 +/- 24.46 (p < 0.01), pin prick scores from 50.53 +/- 24.92 to 54.53 +/- 24.62 (p < 0.01); IANR-SCIFRS scores increased from 19.32 +/- 9.98 to 23.12 +/- 10.30 (p < 0.01). 2) The score changes in terms of motor, light touch, pin prick, and IANR SCIFRS in group A were remarkably different (all p < 0.01). The score changes in group B were remarkably different in terms of motor (p < 0.05) and IANR-SCIFRS (p < 0.01), but not light touch or pin prick (p > 0.05). 3) Comparing group A with group B, the increased scores in terms of motor, light touch, and pin prick were remarkably different (all p < 0.01), but not IANR-SCIFRS (p > 0.05). 4) Fourteen of 108 patients (12.96%) became ASIA B from ASIA A; 18 of 108 (16.67%) became ASIA C from ASIA A. Nine of them (8.33%) improved their walk ability or made them rewalk by using a walker with or without assistance; 12 of 84 men (14.29%) improved their sex function. 5) MRI examinations were taken for 31 patients; there were no neoplasm, bleeding, swelling, cysts, neural tissue destruction or infection (abscess) or any other pathological changes in or around OEC transplant sites. 6) EMG examinations were done on 31 patients; 29 showed improvement and the remaining 2 had no change. PVSEP tests were performed in 31 patients; 28 showed improvements and the remaining 3 had no change. 7) No deterioration or complications were observed in our patients within the follow-up period. Our data suggest OEC therapy is safe and can improve neurological functions for patients with complete chronic SCI and ameliorate their quality of life; the AMTENT most likely plays a critical role in enhancing functional recovery after cell-based neurorestorotherapy. PMID- 22507678 TI - Clinical observation of fetal olfactory ensheathing glia transplantation (OEGT) in patients with complete chronic spinal cord injury. AB - This study was designed to observe the functional changes after fetal olfactory ensheathing glia transplantation (OEGT) into the spinal cord of patients with chronic spinal cord injury (SCI). Patients whose recovery had plateaued for longer than 6 months were enrolled. Six thoracic patients were tested for safety and five cervical patients for efficacy. OEGT was performed according to the method developed by Huang. Average follow-up was 14 months (range 1.0-1.5 years). Sensation improved moderately (light touch 14.2, pin prick 13.6); as did spasticity (1-2 modified Ashworth scale down). Locomotion recovery was minimal (1.6). Useful reticular formation functions were observed, but due to a lack of appropriate outcome measure, they were not recorded and reported. PMID- 22507679 TI - Transplantation of autologous activated Schwann cells in the treatment of spinal cord injury: six cases, more than five years of follow-up. AB - Schwann cells (SCs) are the main glial cells of the peripheral nervous system, which can promote neural regeneration. Grafting of autologous SCs is one of the well-established and commonly performed procedures for peripheral nerve repair. With the aim to improve the clinical condition of patients with spinal cord injury (SCI), a program of grafting autologous activated Schwann cells (AASCs), as well as a series of appropriate neurorehabilitation programs, was employed to achieve the best therapeutic effects. We selected six patients who had a history of SCI before transplantation. At first, AASCs were obtained by prior ligation of sural nerve and subsequently isolated, cultured, and purified in vitro. Then the patients accepted an operation of laminectomy and cell transplantation, and no severe adverse event was observed in any of these patients. Motor and sensitive improvements were evaluated by means of American Spinal Injury Association (ASIA) grading and Functional Independence Measure (FIM); bladder and urethral function were determined by clinical and urodynamic examination; somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) were used to further confirm the functional recovery following transplantation. The patients were followed up for more than 5 years. All of the patients showed some signs of improvement in autonomic, motor, and sensory function. So we concluded that AASC transplantation might be feasible, safe, and effective to promote neurorestoration of SCI patients. PMID- 22507680 TI - Effects of hematopoietic autologous stem cell transplantation to the chronically injured human spinal cord evaluated by motor and somatosensory evoked potentials methods. AB - International standards for stem cell treatment of neurological disorders have not yet been established. In particular, specific quantitative methods have not yet been adopted to assess the effectiveness of stem cell treatment. The aim of this study is to evaluate the functional changes detectable by conventional neurophysiologic methods in an injured spinal cord during stem cell therapy. Twenty adult patients with chronic spinal cord injury at C4-C8 level were examined by somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) methods, the first time prior to the treatment and then regularly during its course (1-4 years). The treatment consisted of repeated intrathecal transplantations of autologous hematopoietic stem cells. After at least 1 year of treatment, four effects were detected: 1) restoration of the initially absent short-latency SEP (three patients); 2. N20P23 interpeak amplitude increase in SEP elicited by median nerve stimulation (four patients); 3) P38 latency reduction in SEP elicited by tibial nerve stimulation (two patients); 4) appearance of MEP (three patients). The nonidentical effects of stem cell transplantation in different patients presumably reflect the variety of the regeneration processes in different pathways of the spinal cord, depending on the extent and nature of lesion of the spinal cord pathways in different patients. The local effects of stem cell treatment at the cervical level were evaluated by median SEP and wrist muscle MEP demonstrate the ability of stem cells to spread within the spinal cord at least from lumbar to the cervical level, home there, and participate in the neurorestoration processes. PMID- 22507681 TI - Feasibility, safety, and preliminary proof of principles of autologous neural stem cell treatment combined with T-cell vaccination for ALS patients. AB - Uncontrolled activation of the innate immune system promotes the deterioration of neurons in different neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). T-cell vaccination (TCV) was developed by Irun Cohen and coworkers at the Weizmann Institute of Science (Israel) during the late 1970s and has been demonstrated to be an effective treatment for human autoimmune diseases and a regulator of macrophage activation in animal models. We treated seven ALS patients with this cell therapy and were able to slow or stop disease progression in the affected individuals. The median survival, which is 3.5 years, was extended to 6 years. They were also treated with autologous adult neural stem cells associated with effector T cells. The observed neurologic improvements after treatment lasted for at least 1 year. Clinical recovery in the treated ALS patients was confirmed by an independent, skilled neurologist using the ALS Functional Rating Scale-Revised (ALSFRS-R). TCV in conjunction with an autologous neural stem cell treatment might be a feasible, minimally invasive, safe, and effective approach to obtain enduring therapeutic effects in ALS patients. PMID- 22507682 TI - Olfactory ensheathing cell neurorestorotherapy for amyotrophic lateral sclerosis patients: benefits from multiple transplantations. AB - Our previous series of studies have proven that olfactory ensheathing cell (OEC) transplantation appears to be able to slow the rate of clinical progression after OEC transplantation in the first 4 months and cell intracranial (key points for neural network restoration, KPNNR) and/or intraspinal (impaired segments) implants provide benefit for patients (including both the bulbar onset and limb onset subtypes) with amyotrophic lateral sclerosis (ALS). Here we report the results of cell therapy in patients with ALS on the basis of long-term observation following multiple transplants. From March of 2003 to January of 2010, 507 ALS patients received our cellular treatment. Among them, 42 patients underwent further OEC therapy by the route of KPNNR for two or more times (two times in 35 patients, three times in 5 patients, four times in 1 patient, and five times in 1 patient). The time intervals are 13.1 (6-60) months between the first therapy and the second one, 15.2 (8-24) months between the second therapy and the third one, 16 (6-26) months between the third therapy and the fourth one, and 9 months between the fourth therapy and the fifth time. All of the patients exhibited partial neurological functional recovery after each cell-based administration. Firstly, the scores of the ALS Functional Rating Scale (ALS-FRS) and ALS Norris Scale increased by 2.6 + 2.4 (0-8) and 4.9 + 5.2 (0-20) after the first treatment, 1.1 + 1.3 (0-5) and 2.3 + 2.9 (0-13) after the second treatment, 1.1 + 1.5 (0-4), and 3.4 + 6.9 (0-19) after the third treatment, 0.0 + 0.0 (0-0), and 2.5 + 3.5 (0-5) after the fourth treatment, and 1 point after the fifth cellular therapy, which were evaluated by independent neurologists. Secondly, the majority of patients have achieved improvement in electromyogram (EMG) assessments after the first, second, third, and fourth cell transplantation. After the first treatment, among the 42 patients, 36 (85.7%) patients' EMG test results improved, the remaining 6 (14.3%) patients' EMG results showed no remarkable change. After the second treatment, of the 42 patients, 30 (71.4%) patients' EMG results improved, 11 (26.2%) patients showed no remarkable change, and 1 (2.4%) patient became worse. After the third treatment, out of the 7 patients, 4 (57.1%) patients improved, while the remaining 3 (42.9%) patients showed no change. Thirdly, the patients have partially recovered their breathing ability as demonstrated by pulmonary functional tests. After the first treatment, 20 (47.6%) patients' pulmonary function ameliorated. After the second treatment, 18 (42.9%) patients' pulmonary function improved. After the third treatment, 2 (28.6%) patients recovered some pulmonary function. After the fourth and fifth treatment, patients' pulmonary function did not reveal significant change. The results show that multiple doses of cellular therapy definitely serve as a positive role in the treatment of ALS. This repeated and periodic cell-based therapy is strongly recommended for the patients, for better controlling this progressive deterioration disorder. PMID- 22507683 TI - Administration of autologous bone marrow-derived mononuclear cells in children with incurable neurological disorders and injury is safe and improves their quality of life. AB - Neurological disorders such as muscular dystrophy, cerebral palsy, and injury to the brain and spine currently have no known definitive treatments or cures. A study was carried out on 71 children suffering from such incurable neurological disorders and injury. They were intrathecally and intramuscularly administered autologous bone marrow-derived mononuclear cells. Assessment after transplantation showed neurological improvements in muscle power and a shift on assessment scales such as FIM and Brooke and Vignos scale. Further, imaging and electrophysiological studies also showed significant changes in selective cases. On an average follow-up of 15 +/- 1 months, overall 97% muscular dystrophy cases showed subjective and functional improvement, with 2 of them also showing changes on MRI and 3 on EMG. One hundred percent of the spinal cord injury cases showed improvement with respect to muscle strength, urine control, spasticity, etc. Eighty-five percent of cases of cerebral palsy cases showed improvements, out of which 75% reported improvement in muscle tone and 50% in speech among other symptoms. Eighty-eight percent of cases of other incurable neurological disorders such as autism, Retts Syndrome, giant axonal neuropathy, etc., also showed improvement. No significant adverse events were noted. The results show that this treatment is safe, efficacious, and also improves the quality of life of children with incurable neurological disorders and injury. PMID- 22507684 TI - Effects of neural progenitor cell transplantation in children with severe cerebral palsy. AB - Cerebral palsy (CP) is a chronic nervous system disease that severely damages the physical and developmental health of children. Traditional treatment brings about only improvement of mild to moderate CP, but severe CP still lacks effective interventions. To explore safety and efficacy of using neural progenitor cells (NPCs) to treat CP in children, we performed NPC transplantation in 45 patients with severe CP by injecting NPCs derived from aborted fetal tissue into the lateral ventricle. Gross motor function measures (GMFM), the Peabody Developmental Motor Scale-Fine Motor (PDMS-FM) test, and a unified survey questionnaire designed specifically for children with CP were used to evaluate neurological function of the patients. Motor development was significantly accelerated within the first month after cell transplantation, but the rate of improvement gradually slowed to preoperative levels. However, after 1 year, the developmental level in each functional sphere (gross motor, fine motor, and cognition) of the treatment group was significantly higher compared to the control group. No delayed complications of this therapy were noted. These results suggest that NPC transplantation is a safe and effective therapeutic method for treating children with severe CP. PMID- 22507686 TI - Delayed- and early-onset hypotheses of antipsychotic drug action in the negative symptoms of schizophrenia. AB - The competing hypotheses that the action onset to antipsychotic medication assumes a course of early- or a delayed-response have been tested in positive and not negative symptoms in schizophrenia. The current study aims to test the early- and delayed-onset hypotheses with regard to negative symptoms. Data were re analyzed from three clinical trials that compared placebo or amisulpride for up to 60 day. Participants had predominantly negative symptoms of schizophrenia (n=487). Response was examined with the incremental percentage Scale for the Assessment of Negative Symptoms (SANS) reduction over time. Response to the treatment, visit and treatment-visit interaction was assessed with mixed modeling. Effect size differences on response between the amisulpride and placebo groups were reported at each visit. Across trials, mixed modeling showed that the incremental SANS reductions by the treatment-visit interaction that tests the action-onset hypothesis were not statistically significantly different across periods. The effect size differences of medication less placebo in the incremental percent SANS reduction showed non-significant differences based on overlapping confidence intervals with a moderate improvement at 8-14 day (ES=.33; 95% CI: -.07,.31), the least improvement at 28-30 day (ES=.12; 95% CI: -.07,.31), and a moderate improvement at 42-60 day to (ES=.39, 95%, CI: .19,.60). Generally, early- and delayed-response differences to antipsychotic were limited. PMID- 22507687 TI - Reduced plasma levels of asymmetric di-methylarginine (ADMA) in patients with alcohol dependence normalize during withdrawal. AB - Asymmetric di-methylarginine, an endogenous inhibitor of nitric oxide synthase, is increasingly recognized as vascular risk factor. Elevated ADMA levels have been described not only in 'typical' vascular diseases like congestive heart failure, artherosclerosis and diabetes but also for major depression and Alzheimer's disease. As homocysteine increases ADMA levels and elevated homocysteine serum levels are present in patients with alcohol dependence, the aim of the present study was to examine plasma ADMA levels in patients with alcohol dependence during withdrawal. ADMA and homocysteine levels were measured in the plasma from 42 patients drawn at baseline, on day 1, day 3 and day 7-10 of inpatient detoxification treatment. Measurements were compared against 32 healthy controls. We found significantly lower levels of ADMA in patients at baseline and on day 1 and 3, while no differences were present at the end of treatment. Plasma ADMA levels significantly increased during withdrawal. We found no association between homocysteine and ADMA levels. Our finding of reduced ADMA levels in actively drinking alcohol dependent patients is in apparent contrast to other findings regarding cardiovascular risk factors in alcoholism. However an influence of alcohol on arginine metabolism may help explain the so called 'French paradox'. PMID- 22507688 TI - Protective effects of pioglitazone on renal ischemia-reperfusion injury in mice. AB - BACKGROUND: Renal ischemia-reperfusion injury (IRI) is a complex pathophysiologic process involving cell apoptosis and oxidant damages that leads to acute renal failure in both native kidneys and renal allografts. Pioglitazone is a novel class of oral antidiabetic agents currently used to treat type 2 diabetes mellitus. Pioglitazone exerts protective effects on acute myocardial ischemia and acute cerebral ischemia. The aim of this study was to investigate the possible beneficial effects of pioglitazone on renal IRI in mice. METHODS: IRI was induced by bilateral renal ischemia for 45 min followed by reperfusion. Fifty-five healthy male Balb/c mice were randomly assigned to one of the following groups: PBS + IRI, pioglitazone + IRI, PBS + sham IRI, pioglitazone + sham IRI. Kidney function tests, histopathologic examination, renal cell Bcl-2, and Bax expression were determined 24 h after reperfusion. Animals' survival was examined 7 days after operation. RESULTS: Animals pretreated with pioglitazone had lower plasma levels of blood urea nitrogen and creatinine caused by IRI, lower histopathologic scores, and improved survival rates following IRI. Renal cell apoptosis induced by IRI was abrogated in kidneys of mice pretreated by pioglitazone, with an increase in Bcl-2 expression and a decrease in Bax expression. Furthermore, pioglitazone pretreatment protected against lethal renal IRI. CONCLUSIONS: Peroxisome proliferator-activated receptor activation by pioglitazone exerts protective effects on renal IRI in mice by abrogating renal cell apoptosis. Thus, pioglitazone could be a novel therapeutic tool in renal IRI. PMID- 22507689 TI - Factors associated with imaging modality choice in children with appendicitis. AB - BACKGROUND: The aim of this study was to evaluate a cohort of children undergoing imaging prior to appendectomy in order to identify factors that were associated with undergoing computed tomography (CT) alone as compared to ultrasound (US) alone or US and CT. MATERIALS AND METHODS: The Kids' Inpatient Database was queried for children 1-18 y of age with imaging reported. Logistic regression models identified factors associated with CT-alone imaging modality. RESULTS: There were 6519 patients (69.5%) who underwent CT alone, 2076 (22.1%) who underwent US alone, and 782 (8.4%) who underwent US and CT. The negative appendectomy rates were higher for US alone (6.5%) and US and CT (6.6%) compared to the CT alone group (3.6%, P < 0.001). The perforated appendicitis rates were highest for the US and CT group (36.3%) compared to the CT alone group (31.8%) and the US alone group (29.8%, P = 0.004). Older patients were more likely to undergo CT alone compared to younger patients (odds ratio [OR] 1.44, 95% confidence interval [CI] 1.26-1.64). Girls were less likely to undergo CT alone compared to boys (OR 0.51, 95% CI 0.46-0.56). Hospital factors associated with lower CT-alone imaging included children's centers (OR 0.46, 95% CI 0.41-0.52), teaching hospitals (OR 0.53, 95% CI 0.48-0.60), and urban location (OR 0.40, 95% CI 0.32-0.49). CONCLUSIONS: Though patient factors such as age and sex influence imaging use, children's centers are associated with lower CT-alone imaging compared to non-children's centers. As focus increases on limiting CT use in children, opportunities for improvement based on hospital factors exist. PMID- 22507690 TI - Effects of parental radiation exposure on developmental instability in grasshoppers. AB - Mutagenic and epigenetic effects of environmental stressors and their transgenerational consequences are of interest to evolutionary biologists because they can amplify natural genetic variation. We studied the effect of parental exposure to radioactive contamination on offspring development in lesser marsh grasshopper Chorthippus albomarginatus. We used a geometric morphometric approach to measure fluctuating asymmetry (FA), wing shape and wing size. We measured time to sexual maturity to check whether parental exposure to radiation influenced offspring developmental trajectory and tested effects of radiation on hatching success and parental fecundity. Wings were larger in early maturing individuals born to parents from high radiation sites compared to early maturing individuals from low radiation sites. As time to sexual maturity increased, wing size decreased but more sharply in individuals from high radiation sites. Radiation exposure did not significantly affect FA or shape in wings nor did it significantly affect hatching success and fecundity. Overall, parental radiation exposure can adversely affect offspring development and fitness depending on developmental trajectories although the cause of this effect remains unclear. We suggest more direct measures of fitness and the inclusion of replication in future studies to help further our understanding of the relationship between developmental instability, fitness and environmental stress. PMID- 22507691 TI - Octopamine, unlike other trace amines, inhibits responses of astroglia-enriched cultures to lipopolysaccharide via a beta-adrenoreceptor-mediated mechanism. AB - Trace amines (TAs), i.e. beta-phenylethylamine, tyramine and octopamine, are generally regarded as sympathomimetic compounds with structural and functional analogy with catecholamines. Previous reports have shown particularly high levels of circulating TAs in migraine and cluster headache patients. However, no clues are yet available as to the pathophysiological significance of these alterations. The effect of different TAs on the release of nitric oxide was investigated in rat astroglial cells stimulated with lipopolysaccharide (LPS). Octopamine substantially inhibited the release of NO evoked by LPS. Tyramine and beta-PEA were ineffective. The inhibitory effect of octopamine was fully reverted by two selective antagonists of beta-adrenergic receptors, while alpha-adrenergic blockade was ineffective. These data, consistent with a role of octopamine as a modulator of NO release, uncover an interaction between octopamine and beta adrenergic receptors in astroglial cells. These results may have an impact in understanding the mechanisms underlying migraine pathophysiology. PMID- 22507693 TI - Torsion of intraperitoneal kidney transplant. AB - BACKGROUND: Torsion of kidney transplant refers to rotation of the kidney transplant graft around its vascular pedicle resulting in vascular compromise and infarction. It is a rare complication of kidney transplantation associated with a high rate of graft loss. Clinical presentation and diagnostic imaging modalities are non-specific, and surgical exploration is therefore often delayed. METHODS: We present a case report and review of the literature. Studies were identified by searching Medline and Embase from January 1954 to December 2010. Data was extracted regarding the clinical presentation, investigation, findings on surgical exploration, and treatment outcomes of patients with torsion of kidney transplant. RESULTS: Eight manuscripts with 16 cases of kidney torsion were found. Presenting symptoms were decreased renal function (13 cases), abdominal pain (10 cases), oliguria/anuria (9 cases), nausea and vomiting (4 cases), fever (3 cases), diarrhoea (3 cases), weight gain (2 cases), oedema (3 cases), fatigue (1 case) and impalpable graft (1 case). Investigations were Doppler sonography (11 cases), grey-scale sonography (7 cases), nuclear scintigraphy (5 cases), computed tomography scan (4 cases), and magnetic resonance imaging/magnetic resonance angiography (1 case). Of the 16 published cases of torsion, seven (44%) grafts were detorted and salvaged, three (19%) grafts were detorted but subsequently lost and six (38%) patients underwent immediate nephrectomy. CONCLUSIONS: A prompt consideration of the diagnosis of torsion of kidney transplant is required to prevent delay in surgical intervention. We recommend urgent Doppler ultrasound be used as first-line investigation, followed by prompt surgical exploration. We recommend the use of prophylactic nephropexy to prevent torsion. PMID- 22507692 TI - Oxytocin regulates changes of extracellular glutamate and GABA levels induced by methamphetamine in the mouse brain. AB - Oxytocin (OT), a neurohypophyseal neuropeptide, affects adaptive processes of the central nervous system. In the present study, we investigated the effects of OT on extracellular levels of glutamate (Glu) and gamma-aminobutyric acid (GABA) induced by methamphetamine (MAP) in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DHC) of freely moving mice, using in vivo microdialysis coupled to high-performance liquid chromatography and fluorescence detection. The results showed that OT had no effect on basal Glu levels, but attenuated MAP induced Glu increase in the mPFC and decrease in the DHC. OT increased the basal levels of extracellular GABA in mPFC and DHC of mice, and inhibited the MAP induced GABA decrease in DHC. Western blot results indicated that OT significantly inhibited the increased glutamatergic receptor (NR1 subunit) levels in the PFC after acute MAP administration, whereas OT further enhanced the elevated levels of glutamatergic transporter (GLT1) induced by MAP in the hippocampus of mice. Atosiban, a selective inhibitor of OT receptor, antagonized the effects of OT. The results provided the first neurochemical evidence that OT, which exerted its action via its receptor, decreased Glu release induced by MAP, and attenuated the changes in glutamatergic neurotransmission partially via regulation of NR1 and GLT1 expression. OT-induced extracellular GABA increase also suggests that OT acts potentially as an inhibitory neuromodulator in mPFC and DHC of mice. PMID- 22507694 TI - Is telemonitoring an option against shortage of physicians in rural regions? Attitude towards telemedical devices in the North Rhine-Westphalian health survey, Germany. AB - BACKGROUND: General practitioners (GP) in rural areas of Germany are struggling to find successors for their private practices. Telemonitoring at home offers an option to support remaining GPs and specialists in ambulatory care. METHODS: We assessed the knowledge and attitude towards telemedicine in the population of North Rhine-Westphalia (NRW), Germany, in a population-based telephone survey. RESULTS: Out of 2,006 participants, 734 (36.6%) reported an awareness of telemedical devices. Only 37 participants (1.8%) have experience in using them. The majority of participants were in favour of using them in case of illness (72.2%). However, this approval declined with age. These findings were similar in rural and urban areas. Participants who were in favour of telemedicine (n = 1,480) strongly agreed that they would have to see their doctor less often, and that the doctor would recognize earlier relevant changes in their vital status. Participants who disliked to be monitored by telemedical devices preferred to receive immediate feedback from their physician. Especially, the elderly fear the loss of personal contact with their physician. They need the direct patient physician communication. CONCLUSIONS: The fear of being left alone with the technique needs to be compensated for today's elderly patients to enhance acceptance of home telemonitoring as support for remaining doctors either in the rural areas or cities. PMID- 22507695 TI - Drug, patient, and physician characteristics associated with off-label prescribing in primary care. AB - BACKGROUND: Off-label prescribing may lead to adverse drug events. Little is known about its prevalence and determinants resulting from challenges in documenting treatment indication. METHODS: We used the Medical Office of the XXI Century electronic health record network in Quebec, Canada, where documentation of treatment indication is mandatory. One hundred thirteen primary care physicians wrote 253 347 electronic prescriptions for 50 823 patients from January 2005 through December 2009. Each drug indication was classified as on label or off-label according to the Health Canada drug database. We identified off-label uses lacking strong scientific evidence. Alternating logistic regression was used to estimate the association between off-label use and drug, patient, and physician characteristics. RESULTS: The prevalence of off-label use was 11.0%; of the off-label prescriptions, 79.0% lacked strong scientific evidence. Off-label use was highest for central nervous system drugs (26.3%), including anticonvulsants (66.6%), antipsychotics (43.8%), and antidepressants (33.4%). Drugs with 3 or 4 approved indications were associated with less off label use compared with drugs with 1 or 2 approved indications (6.7% vs 15.7%; adjusted odds ratio [AOR], 0.44; 95% CI, 0.41-0.48). Drugs approved after 1995 were prescribed off-label less often than were drugs approved before 1981 (8.0% vs 17.0%; AOR, 0.46; 95% CI, 0.42-0.50). Patients with a Charlson Comorbidity Index of 1 or higher had lower off-label use than did patients with an index of 0 (9.6% vs 11.7%; AOR, 0.94; 95% CI, 0.91-0.97). Physicians with evidence-based orientation were less likely to prescribe off-label (AOR, 0.93; 95% CI, 0.88 0.99), a 7% reduction per 5 points in the evidence section of the Evidence Practicality-Conformity Scale. CONCLUSIONS: Off-label prescribing is common and varies by drug, patient, and physician characteristics. Electronic prescribing should document treatment indication to monitor off-label use. PMID- 22507697 TI - What does off-label prescribing really mean? PMID- 22507696 TI - A randomized controlled trial of telemonitoring in older adults with multiple health issues to prevent hospitalizations and emergency department visits. AB - BACKGROUND: Efficiently caring for frail older adults will become an increasingly important part of health care reform;telemonitoring within homes may be an answer to improve outcomes. This study sought to assess differences in hospitalizations and emergency department (ED) visits among older adults using telemonitoring vs usual care. METHODS: A randomized controlled trial was performed among adults older than 60 years at high risk for rehospitalization. Participants were randomized to telemonitoring (with daily input) or to patient-driven usual care. Telemonitoring was accomplished by daily biometrics,symptom reporting, and videoconference. The primary outcome was a composite end point of hospitalizations and ED visits in the 12 months following enrollment. Secondary end points included hospitalizations,ED visits, and total hospital days. Intent to-treat analysis was performed. RESULTS: Two hundred five participants were enrolled,with a mean age of 80.3 years. The primary outcome of hospitalizations and ED visits did not differ between the telemonitoring group (63.7%) and the usual care group(57.3%) (P=.35). No differences were observed in secondary end points, including hospitalizations, ED visits,and total hospital days. No significant group differences in hospitalizations and ED visits were found between the pre-enrollment period vs the post-enrollment period. Mortality was higher in the telemonitoring group (14.7%)than in the usual care group (3.9%) (P=.008). CONCLUSIONS: Among older patients, telemonitoring did not result in fewer hospitalizations or ED visits. Secondary outcomes demonstrated no significant differences between the telemonitoring group and the usual care group.The cause of greater mortality in the telemonitoring group is unknown. PMID- 22507698 TI - Another sobering result for home telehealth-and where we might go next. PMID- 22507699 TI - Imaging models of valuation during social interaction in humans. AB - The role of dopamine neurons in value-guided behavior has been described in computationally explicit terms. These developments have motivated new model-based probes of reward processing in healthy humans, and in recent years these same models have also been used to design and understand neural responses during simple social exchange. These latter applications have opened up the possibility of identifying new endophenotypes characteristic of biological substrates underlying psychiatric disease. In this report, we review model-based approaches to functional magnetic resonance imaging in healthy individuals and the application of these paradigms to psychiatric disorders. We show early results from the application of model-based human interaction at three disparate levels: 1) interaction with a single human, 2) interaction within small groups, and 3) interaction with signals generated by large groups. In each case, we show how reward-prediction circuitry is engaged by abstract elements of each paradigm with blood oxygen level-dependent imaging as a read-out; and, in the last case (i.e., signals generated by large groups) we report on direct electrochemical dopamine measurements during decision making in humans. Lastly, we discuss how computational approaches can be used to objectively assess and quantify elements of complex and hidden social decision-making processes. PMID- 22507700 TI - Non-hospital DOT and early diagnosis of tuberculosis reduce costs while achieving treatment success. AB - OBJECTIVE: 1) To evaluate the tuberculosis (TB) related financial burden of patients and health care providers over the course of diagnosis and treatment by choice of directly observed treatment (DOT); and 2) to examine treatment outcomes for different DOT programmes in Cambodia. SETTING AND DESIGN: Subjects were patients diagnosed with smear-positive pulmonary TB between July 2008 and January 2009 at 17 health facilities providing multiple DOT programmes. Treatment outcomes for the different DOT programmes as well as direct and indirect household costs and medical delivery costs for the treatment and care of 277 patients were examined. RESULTS: Per patient costs of anti-tuberculosis treatment for patients with non-multidrug-resistant TB who did not have human immunodeficiency virus co-infection ranged from a high of US$1900 for in-patient DOT to a low of $395 for DOT provided at home. All costs among patients treated with hospital DOT were consistently higher than for those treated with non hospital DOT. The percentage of treatment success was not significantly different between hospital and non-hospital DOT programmes (all >89%). CONCLUSION: Non hospital DOT programmes ease the financial burden on both patients and health care providers, while resulting in treatment success rates similar to those of hospital DOT. PMID- 22507704 TI - Peritoneal mesothelioma masquerading as an inguinal hernia. AB - We report a case of an 80-year-old man who presented with a right inguinal hernia that appeared incarcerated. On exploration a sausage shaped mass was found in the sac, which was debulked and histologically shown to be a well differentiated malignant peritoneal mesothelioma. Rare tumours may present as inguinal hernias and palliative debulking may be effective when they present in inguinal hernia sacs. PMID- 22507702 TI - Deletion of PLCB1 gene in schizophrenia-affected patients. AB - A prevalence of 1% in the general population and approximately 50% concordance rate in monozygotic twins was reported for schizophrenia, suggesting that genetic predisposition affecting neurodevelopmental processes might combine with environmental risk factors. A multitude of pathways seems to be involved in the aetiology and/or pathogenesis of schizophrenia, including dopaminergic, serotoninergic, muscarinic and glutamatergic signalling. The phosphoinositide signal transduction system and related phosphoinositide-specific phospholipase C (PI-PLC) enzymes seem to represent a point of convergence in these networking pathways during the development of selected brain regions. The existence of a susceptibility locus on the short arm of chromosome 20 moved us to analyse PLCB1, the gene codifying for PI-PLC beta1 enzyme, which maps on 20p12. By using interphase fluorescent in situ hybridization methodology, we found deletions of PLCB1 in orbito-frontal cortex samples of schizophrenia-affected patients. PMID- 22507705 TI - Management of jejunal pouch dysfunction following total gastrectomy and Roux-en-Y reconstruction for gastric cancer: a case report. AB - INTRODUCTION: Total gastrectomy with oesophagojejunal pouch anastomosis and Roux en-Y reconstruction is a well recognised procedure for patients undergoing curative resections for gastric malignancy. The formation of a jejunal pouch is thought by some to create a reservoir that, when compared with straight oesophagojejunal anastomosis, reduces the incidence of post-operative dumping. CASE HISTORY: A patient presented two years after a total gastrectomy with oesophagojejunal pouch anastomosis and Roux-en-Y reconstruction for a T3N2M0 adenocarcinoma of the stomach, with postprandial vomiting and dysphagia resulting in massive weight loss and malnutrition. Recurrent cancer and stricturing was ruled out by gastroscopy and computed tomography, and distal obstruction was ruled out by an oral contrast study. The diagnosis of a functional jejunal pouch disorder was made by exclusion. Balloon dilatation of the pouch and the oesophagojejunal anastomosis found little symptomatic improvement. The patient's deteriorating nutritional status prompted us to urgently perform revisional surgery. A re-laparotomy and pouch-jejunal bypass procedure was performed. Post operatively, the patient made a full symptomatic recovery and began gaining weight. CONCLUSIONS: A pouch-enteric bypass is a suitable treatment option for patients with functional jejunal pouch dysmotility following a total gastrectomy and jejunal pouch formation in the absence of distal obstruction and recurrent disease. PMID- 22507706 TI - Emergency presentation of retrograde intussusception as a late complication of gastric bypass. AB - Retrograde intussusception is a rare complication of a Roux-en-Y gastric bypass. With the rising number of gastric bypass operations being performed in the UK, the incidence of retrograde intussusception is likely to increase. We report the first case in the UK and highlight its insidious presentation and the importance of considering intussusception in any patient with a history of a Roux-en-Y gastric bypass. PMID- 22507701 TI - Origin and evolution of spliceosomal introns. AB - Evolution of exon-intron structure of eukaryotic genes has been a matter of long standing, intensive debate. The introns-early concept, later rebranded 'introns first' held that protein-coding genes were interrupted by numerous introns even at the earliest stages of life's evolution and that introns played a major role in the origin of proteins by facilitating recombination of sequences coding for small protein/peptide modules. The introns-late concept held that introns emerged only in eukaryotes and new introns have been accumulating continuously throughout eukaryotic evolution. Analysis of orthologous genes from completely sequenced eukaryotic genomes revealed numerous shared intron positions in orthologous genes from animals and plants and even between animals, plants and protists, suggesting that many ancestral introns have persisted since the last eukaryotic common ancestor (LECA). Reconstructions of intron gain and loss using the growing collection of genomes of diverse eukaryotes and increasingly advanced probabilistic models convincingly show that the LECA and the ancestors of each eukaryotic supergroup had intron-rich genes, with intron densities comparable to those in the most intron-rich modern genomes such as those of vertebrates. The subsequent evolution in most lineages of eukaryotes involved primarily loss of introns, with only a few episodes of substantial intron gain that might have accompanied major evolutionary innovations such as the origin of metazoa. The original invasion of self-splicing Group II introns, presumably originating from the mitochondrial endosymbiont, into the genome of the emerging eukaryote might have been a key factor of eukaryogenesis that in particular triggered the origin of endomembranes and the nucleus. Conversely, splicing errors gave rise to alternative splicing, a major contribution to the biological complexity of multicellular eukaryotes. There is no indication that any prokaryote has ever possessed a spliceosome or introns in protein-coding genes, other than relatively rare mobile self-splicing introns. Thus, the introns-first scenario is not supported by any evidence but exon-intron structure of protein-coding genes appears to have evolved concomitantly with the eukaryotic cell, and introns were a major factor of evolution throughout the history of eukaryotes. PMID- 22507707 TI - Bladder injuries in emergency/expedited laparoscopic surgery in the absence of previous surgery: a case series. AB - INTRODUCTION: The use of laparoscopy as a diagnostic and therapeutic tool is being used increasingly in the emergency setting with many of these procedures being performed by trainees. While the incidence of iatrogenic injuries is reported to be low, we present six emergency or expedited cases in which the bladder was perforated by the suprapubic trocar. CASES: Three cases were related to the management of appendicitis, two to negative diagnostic laparoscopies for lower abdominal pain and one to an ectopic pregnancy. Management of the bladder injuries varied from a urinary catheter alone to laparotomy with debridement of the abdominal wall due to sepsis and later reconstruction. Four of the six cases were performed by registrars. CONCLUSIONS: Although the incidence of bladder injury is low, its importance is highlighted by the large number of laparoscopies being performed. In addition to catheterisation of the patient, care must be taken with the insertion of low suprapubic ports and consideration should be made regarding alternative sites. Adequate laparoscopic supervision and training in port site planning is required for surgical trainees. PMID- 22507708 TI - Bilateral pisotriquetral loose bodies. AB - Case reports detailing diagnosis and effective treatment of pisotriquetral loose bodies are scarce. This article describes an even rarer case of bilateral pisotriquetral joint loose bodies, explores the relative diagnostic roles of magnetic resonance imaging versus computed tomography, and outlines effective strategies used for the management of this condition drawn from the literature and our own experience. PMID- 22507709 TI - Pilocytic astrocytoma mimicking craniopharyngioma: a case series. AB - Although they are one of the most common brain tumours in childhood, pilocytic astrocytomas are rare in adulthood. We report a series of three pilocytic astrocytomas presenting as an intra/suprasellar mass in the fourth to sixth decades of life. All three radiologically mimicked the appearance of a craniopharyngioma, thus representing a potential radiological and diagnostic pitfall. In this series all three patients underwent successful operative management and have remained well throughout follow-up. The majority of information concerning pilocytic astrocytomas is derived from paediatric populations and so only limited and often conflicting data exist for pilocytic astrocytomas developing in adulthood. Decisions regarding treatment of pilocytic astrocytomas in adults must be made on a multidisciplinary, case-by-case basis. PMID- 22507710 TI - Arthroscopic excision of heterotopic calcification in a chronic rectus femoris origin injury: a case report. AB - Rectus femoris origin injuries in adult athletes are uncommon. In the acute phase, conservative treatment seems to have a favourable outcome, with surgical repair reserved for unsuccessful cases only. However, a group of patients may develop chronic pain and disability after recovery from the acute phase due to heterotopic calcification occurring at the site of injury. Open and arthroscopic excision of such calcifications has been described in the literature although arthroscopic excision of large calcified lesions in the rectus femoris has not been reported previously. A relevant case is presented and discussed. PMID- 22507711 TI - Acute neck pain referred to the surgeon: Lemierre's syndrome as a differential diagnosis. AB - Lemierre's syndrome is usually reported in the young and in fit individuals. We report a case of an 81-year-old woman who presented with thrombophlebitis of the internal jugular vein with a pulmonary embolism. PMID- 22507712 TI - Acute popliteal pseudoaneurysm rupture secondary to distal femoral osteochondroma in a patient with hereditary multiple exostoses. AB - A 21-year-old man with known hereditary multiple exostoses presented with a 24 hour history of atraumatic bruising and swelling of the posterior thigh. A leaking popliteal pseudoaneurysm was diagnosed on ultrasonography and an emergency saphenous vein bypass graft procedure performed. The patient required a post-operative blood transfusion but otherwise made a full recovery. Vascular complications from osteochondromas are rare and include vessel displacement, stenosis, occlusion, arteriovenous fistulas and pseudoaneurysm formation. Pseudoaneurysms usually present as an enlarging mass behind the knee. Acute rupture of an occult popliteal pseudoaneurysm caused by a distal femoral exostosis has not been reported previously. PMID- 22507713 TI - Retraction of Manikantan K, Dwivedi RC, Sayed SI, Pathak KA, Kazi R. Current concepts of surveillance and its significance in head and neck cancer. PMID- 22507714 TI - Peri-operative antithrombotic therapy: bridging the gap. PMID- 22507715 TI - Retrievable inferior vena cava filter use in major trauma. AB - Venous thromboembolism (VTE) remains a devastating complication among trauma patients. However, conventional VTE prophylaxis is often contraindicated in major trauma patients due to concurrent injuries. This article discusses the use of retrievable inferior vena cava filters as a method for VTE prophylaxis in major trauma patients. PMID- 22507717 TI - Factors predicting significant pathology on ultrasonography in women presenting with non-specific lower abdominal pain. AB - INTRODUCTION: Ultrasonography is used frequently to exclude significant pathology in young women presenting with non-specific lower abdominal pain (NSLAP). This study examined parameters that predicted the likelihood of significant findings on ultrasonography. These results could be used to select patients for priority imaging or identify those who could be managed with no ultrasonography. METHODS: A total of 65 women with NSLAP were identified from 283 admissions. Group 1 (n=42) consisted of patients with normal imaging. Group 2 (n=23) included patients with 'positive' scans requiring treatment. White cell count (WCC), C reactive protein (CRP) levels, platelet count, age, duration of pain and length of stay in hospital were compared between the groups. RESULTS: The median WCC and CRP were greater in Group 2 than in Group 1: 15 x 10(9)/l and 123 mg/l versus 11 x 10(9)/l and 72 mg/l respectively (p=0.01 and p=0.05). CRP was a weak predictor of positive pathology on ultrasonography (area under curve [AUC]=0.66, p=0.027) and WCC was a strong predictor of abnormal pathology on ultrasonography (AUC=0.7, p=0.005). A WCC of >12.8 x 10(9)/l was 65% sensitive and 71% specific in predicting subsequent pathology on ultrasonography. The median wait for ultrasonography was 24 hours (range: 1-96 hours). CONCLUSIONS: This study failed to define any criteria that could select patients not requiring ultrasonography. Since ultrasonography is a relatively cheap and safe investigation, its continued use to screen women with NSLAP is justified. WCC should be used to prioritise imaging. PMID- 22507716 TI - What is the role of minimally invasive surgery in a fast track hip and knee replacement pathway? AB - INTRODUCTION: Minimally invasive hip and knee replacement surgery (MIS) continues to receive coverage in both the popular press and scientific literature. The cited benefits include a smaller scar, less soft tissue trauma, faster recovery, reduced hospital stay, decreased blood loss and reduced post-operative pain. These outcomes are highly desirable and consistent with the aims of fast track hip and knee pathways. This paper evaluates the literature and discusses whether performing MIS over conventional surgical techniques offers advantages in a fast track hip and knee pathway. METHODS: An English language literature search was performed using the MEDLINE and PubMed databases. Case series, randomised controlled trials and systematic reviews were included in the review. RESULTS: The reported improvements in recovery brought about by MIS must be considered multifactorial. In combination with improved clinical pathways, MIS can be associated with quicker recovery and shorter length of hospital stay. CONCLUSIONS: There is insufficient evidence to indicate that surgical technique alone makes a significant difference to recovery or reduces soft tissue trauma. No consensus on whether to use MIS techniques in fast track hip and knee replacement pathways can therefore be drawn. This is especially important given that the complication rates of MIS in the low to medium volume surgeon appear unacceptably high compared with standard approaches. It is also too early to assess the long-term effects of MIS on implant survival. PMID- 22507718 TI - Gallbladder selection for histopathological analysis based on a simple method: a prospective comparative study. AB - INTRODUCTION: After a cholecystectomy, the current and traditional practice is to send each resected gallbladder to the pathologist for analysis. Some reports have suggested the possibility of selecting only those gallbladders that need to be analysed. The purpose of this study was to show a simple method for selecting which gallbladders should be sent to the pathologist. METHODS: A prospective comparative study was carried out. Two 'tests' were performed in 150 patients to detect or rule out gallbladder cancer. The first test included the patient's variables and a macroscopic gallbladder analysis performed by the surgeon (MGAS). The second test was the analysis performed by the pathologist. The results were compared. RESULTS: Of the 150 patients, 132 were women and 18 men; 130 were under 60 years old. One patient had inflammatory bowel disease, seven had changes on ultrasonography and in four cases intra-operative disturbances were observed. During the MGAS, disturbances were found in 30 patients. Eighty one cases (54%) had at least one or more risk factors for gallbladder cancer. PMID- 22507719 TI - The impact of routine histopathological examination on cholecystectomy specimens from an Asian demographic. AB - INTRODUCTION: Most gallbladder carcinoma cases are suspected pre-operatively or intra-operatively. In Malaysia histopathological examination of cholecystectomy specimens has become routine practice. The aim of this study was to assess the impact of routine histological examinations on cholecystectomy specimens from an Asian demographic, which may differ from a Caucasian demographic. METHODS: A retrospective study was performed of all histopathology reports for cholecystectomies (laparoscopic and open) undertaken over a period of 12 years (1997-2008) in a single teaching hospital. RESULTS: A total of 1,375 gallbladder specimens were sent for histopathological analysis, with 7 (0.5%) being reported as malignant while only three (0.2%) were found to contain primary gallbladder carcinoma. Other premalignant findings included two specimens with dysplastic changes of the mucosa and one tubulovillous adenoma with a dysplastic epithelium. From the ten malignant and premalignant specimens, seven were diagnosed pre operatively, two were suspected intra-operatively and one was diagnosed with dysplastic changes on the histopathology report post-operatively. CONCLUSIONS: This study supports earlier research carried out in the UK and the demographic difference does not affect the impact of the histology examination on cholecystectomy specimens in diagnosing this disease. A selective policy is recommended in Malaysia. PMID- 22507720 TI - Nicorandil associated anal ulcers: an estimate of incidence. AB - INTRODUCTION: Nicorandil is a commonly prescribed antianginal medication that has been found to be associated with painful anal ulceration. The incidence of this complication is unknown. We have used the best data available to us to make an estimate of this figure in a health district with a remarkably stable population of approximately 200,000 people. METHODS: using an electronic search of all letters generated from colorectal and gastroenterology clinics as well as endoscopy reports from January 2004 to November 2010, patients with anal ulceration who were taking nicorandil were identified. Other causes of ulceration were excluded by biopsy in the majority of cases. The central hospital and community pharmacy database was interrogated to estimate the number of patients who were prescribed nicorandil over a six-year period (2004-2010). RESULTS: A total of 30 patients (24 men, 6 women) with a median age of 79.5 years were identified who fulfilled the criteria of: taking nicorandil; having no other identified cause for anal ulceration; and achieving eventual healing after withdrawal of nicorandil. In the six-year period an estimated mean of 1,379 patients were prescribed nicorandil each year. The mean annual incidence of anal ulcers among nicorandil users is therefore calculated to be in the region of 0.37%. CONCLUSIONS: Anal ulceration appears to occur in approximately four in every thousand patients prescribed nicorandil each year. Prescribing physicians should explain the risk of this unpleasant complication to their patients. PMID- 22507721 TI - Current practice in abdominoperineal resection: an email survey of the membership of the Association of Coloproctology. AB - INTRODUCTION: This study aimed to gain insight into current preferences for type of surgical approach and patient positioning in abdominoperineal excision of the rectum (APER), to identify whether these factors affect self-reported oncological outcomes and complication rates, and to assess the opinions of members of the Association of Coloproctology of Great Britain and Ireland (ACPGBI) with regards to the benefit of a national training programme for APER surgery. METHODS: Members of the ACPGBI were surveyed using a questionnaire designed to examine surgeon/departmental demographics, type of APER practised, audit of results and complications, opinions regarding extralevator APER (ELAPER) and opinions regarding the potential benefit of a national training programme. RESULTS: According to the survey, 62% of surgeons perform perineal dissection in the supine position and 57% perform a standard APER technique. Surgeons who only practise colorectal surgery (p=0.002) and surgeons performing prone dissection (p<0.0001) are more likely to perform ELAPER. Three-quarters (76%) audit their results for perineal wound complication rates. Over 80% audit their oncological outcomes. The vast majority (94.6%) of those who perform ELAPER believe there is a benefit to this method while 59.6% of those who do not perform ELAPER still believe there is a benefit to ELAPER. Only 50% feel that there should be a national training programme. CONCLUSIONS: There is a distinct discordance with regards to the APER technique. Among UK colorectal surgeons, although a significant proportion favours ELAPER, there remains a larger proportion still performing standard APER techniques. PMID- 22507722 TI - Complications and reintervention following elective open abdominal aortic aneurysm repair: a 10-year retrospective analysis. AB - INTRODUCTION: Recent data have shown higher rates of graft related complication or reintervention in patients undergoing endovascular aneurysm repair compared with open aneurysm surgery (OAS). However, there are fewer data available regarding procedure related reinterventions following OAS. The aim of this study was to investigate the incidence of procedure related complications and reintervention following elective open abdominal aortic aneurysm repair. METHODS: This was a retrospective analysis of prospectively collected data from the dedicated Portsmouth POSSUM database. Data from 361 patients (median age: 72 years, 91.4% male) who underwent elective OAS between 1993 and 2004 were analysed. The incidences of early and late complications and subsequent reintervention were investigated. RESULTS: The median follow-up duration was 10 years 4 months (range: 5 years - 16 years 4 months). There were 52 reinterventions in the follow-up period. Of these, 34.6% were for incisional hernias or small bowel obstruction with the majority of the remaining laparotomies performed for bleeding or distal ischaemic complications. Almost two thirds (63.5%) of reinterventions occurred in the first 30 days. There were 30 emergency readmissions to the acute surgical wards that did not require reintervention. CONCLUSIONS: OAS carries a significant reintervention rate. In this study, 54% of reinterventions were directly related to laparotomy. PMID- 22507723 TI - Investigation prior to thyroglossal duct cyst excision. AB - INTRODUCTION: Investigation of the anterior midline neck lump has been debated over the years with little agreement on best practice. Thyroglossal duct cysts (TDCs) are the most common aetiology. A TDC may contain ectopic thyroid tissue, which may affect the decision to excise. METHODS: A computerised survey was sent to a representative sample of UK-based ENT surgeons to determine current practice in investigation of presumed TDCs and the incidence of ectopic thyroid tissue. RESULTS: Overall, 95% of those surveyed use ultrasonography, with 32% also arranging thyroid function tests. Fifteen per cent had encountered absent normal thyroid tissue in the presence of a midline neck swelling. In 64% of cases this represented the only functioning thyroid tissue. Thyroid function tests were normal in all but two cases. CONCLUSIONS: The results show a significant change in practice over the last decade. All surgeons would arrange some form of investigation of a presumed TDC, with the vast majority using ultrasonography. Radioisotope scanning should only be used if the ultrasonography or thyroid function tests are abnormal. The incidence of ectopic thyroid tissue in this survey was higher than previously calculated, with a 0.17% prevalence of midline neck lumps representing the only functioning thyroid tissue. PMID- 22507724 TI - Evaluation of disinfection of flexible nasendoscopes using Tristel wipes: a prospective single blind study. AB - INTRODUCTION: The otorhinolaryngology department at Northwick Park Hospital uses the Tristel wipes system for cleaning nasendoscopes in the outpatient clinics. This system uses chlorine dioxide as its only disinfectant. The manufacturer claims the system provides safe sterilisation of nasendoscopes. However, there appear to be no reports in the literature to date that evaluate the efficacy of this system in a clinical setting. The aim of this study was to evaluate the 'in use' efficacy of Tristel wipes in decontaminating nasendoscopes and to identify any significant contamination between cleaning and usage. METHODS: A total of 31 cleaning episodes were performed. Each cleaning episode included two swabs after cleaning the scopes, one from the tip and the other from the handle. Another two swabs from the same areas were also taken before application to the patient. The microbiology unit evaluated all swabs for bacterial, fungal and mycobacterial growth. RESULTS: Overall, 123 swabs from 31 cleaning episodes were tested. None of the swabs taken from the tips (n=31) or handles (n=31) after cleaning with Tristel wipes developed any organism growth. Furthermore, none of the swabs taken from the tip of the scopes before using on patients (n=31) developed any growth. Of the 31 swabs taken from the handle before use, 3 developed significant staphylococcal growth. CONCLUSIONS: In our study, the 'in use' efficacy of Tristel wipes in cleaning the scopes of bacteria, fungi and mycobacteria was 100%. Attention to hand hygiene and the use of gloves should be considered when handling the cleaned scopes to minimise the risk of contamination between cleaning and application to patients. PMID- 22507725 TI - Total elbow replacement with the Coonrad-Morrey prosthesis: our medium to long term results. AB - INTRODUCTION: Semiconstrained total elbow replacement is now a well recognised and reliable surgical option for advanced elbow disease, mainly rheumatoid arthritis. METHODS: We report a retrospective analysis of 31 primary total elbow replacements in 28 patients with a mean follow-up duration of 55 months. The mean age of the patients was 65 years. The indications included 27 cases of rheumatoid arthritis, 3 fractures and 1 case of osteoarthritis. Twenty-one elbows in nineteen patients were assessed using the Mayo elbow performance score (MEPS) in a special follow-up clinic. In the other nine patients (ten elbows), the assessment was carried out with case notes and x-rays. RESULTS: The mean pre operative MEPS in the 21 elbows recalled was 40. This improved to 89 post operatively (range: 55-100). Sixteen of the twenty-one elbows were considered excellent, two good, two fair and one poor. The range of movement was recorded in eight of the other ten elbows and the mean was 98 degrees . At the last follow up visit, x-rays were normal in 23 elbows although the ulnar component was loose in 3, the humeral component loose in 2. There were also two cases of non-union of the medial epicondyle and one patient had mild heterotopic ossification. Complications included one infection, which needed irrigation and debridement with a satisfactory final result, and two cases of ulnar nerve palsy/neurapraxia. Two elbows were considered failures due to severe pain caused by prosthetic loosening. These were referred for revision surgery. CONCLUSIONS: Excellent pain relief and good function can be achieved in the medium and long term with the Coonrad-Morrey-semiconstrained total elbow replacement prosthesis in patients with severe destructive elbow arthropathy. PMID- 22507727 TI - Is there a need for early post-operative x-rays in primary total knee replacements? Experience of a centre in the UK. AB - INTRODUCTION: Early post-operative x-rays are often taken in total knee replacements (TKRs). Patient mobilisation may be delayed until these x-rays are obtained and this may prolong discharge. The aim of this study was to assess the value of such early x-rays and whether they influenced the early post-operative management of these patients. METHODS: A total of 624 consecutive TKRs performed at the Blackpool Victoria Hospital over a 34-month period were evaluated. Plain anteroposterior and lateral x-rays were examined. RESULTS: Two patients were found to have significant abnormalities: an undisplaced periprosthetic tibial fracture and a partial inferior pole patellar avulsion. Neither of these required further treatment or influenced mobility. No other complications were noted that changed routine post-operative management. CONCLUSIONS: These results question the need for immediate x-rays in primary TKRs. PMID- 22507726 TI - Total hip replacement for the treatment of acute femoral neck fractures: results from the National Joint Registry of England and Wales at 3-5 years after surgery. AB - INTRODUCTION: This paper describes, for the first time, the outcomes of patients undergoing total hip replacement for acute fractured neck of femur (#NOF) as recorded by the National Joint Registry of England and Wales (NJR). METHODS: In the NJR we identified 1,302 of 157,232 Hospital Episode Statistics linked patients who had been recorded as having a total hip replacement for acute #NOF between April 2003 and November 2008. RESULTS: The revision rate at five years for fully uncemented components was 4.1% (95% confidence interval [CI]: 2.2 7.3%), for hybrid it was 2.2% (95% CI: 0.9%-5.3%) and for fully cemented components 0.9% (95% CI: 0.4-2.0%). Five-year revision rates were increased for those whose operations were performed via a posterior versus a lateral approach. The Kaplan-Meier estimate of 30-day mortality was 1.4% (95% CI: 1.0-2.4%), which is over double the 30-day mortality rate for total hip replacement identified by the Office for National Statistics. The mean length of stay was also increased for those undergoing total hip replacements for #NOF compared with non-emergency indications. CONCLUSIONS: Our data suggest that total hip replacements for acute #NOF give comparable results with total hip replacements for other indications. PMID- 22507728 TI - The appropriateness of blood transfusion following primary total hip replacement. AB - INTRODUCTION: A significant proportion of all red cell transfusions are given to patients undergoing elective orthopaedic surgery. Concern over transfusion safety and cost, coupled with evidence showing that restrictive transfusion policies benefit patients, prompted us to audit our blood prescribing practice at Gloucestershire Hospitals NHS Foundation Trust in order to assess the appropriateness of every transfusion episode following elective primary total hip replacement. METHODS: All patients undergoing a primary total hip replacement in our department over a six-month period were included in the study. Data were collected retrospectively using case note examination and transfusion service data. Standards were dictated by the British Orthopaedic Association guidelines on blood conservation in elective orthopaedic surgery. RESULTS: Twenty-seven per cent of patients (39/143) were transfused. Forty-six per cent of these (18/39) were transfused inappropriately and twenty-three per cent (9/39) appropriately. Thirteen per cent (5/39) had a valid indication for transfusion but were over transfused and in eighteen per cent (7/39) the quality of documentation did not allow an assessment to be made. Fifty-two per cent of patients who had surgical drains (29/56) were transfused. Reaudit following staff education and amendments to the local transfusion policy did not demonstrate a reduction in transfusion rates. CONCLUSIONS: This audit showed that significant potential exists for reducing transfusion rates based on optimising prescribing practice alone. It also demonstrated that changing local practice based on audit data can be challenging. PMID- 22507729 TI - The development of a supraregional network for the management of penile cancer. AB - INTRODUCTION: Although its incidence is increasing, penile cancer remains a rare disease in the UK. In view of this low volume, the National Institute for Clinical Excellence recommended that treatment is centralised in a limited number of centres arranged as supraregional networks. The aim of this centralisation is to allow the best standardised treatment for the primary tumours and nodal disease, thereby avoiding under or overtreatment. In this paper we review the formation and functioning of our network in the East Midlands. METHODS: Data were collected up to August 2010 from our prospective penile network database since its inception in 2005. These data were analysed to see our workload, patterns of referral and surgeries performed over this time period. RESULTS: The structure and function of the East Midlands network are described. There has been an increase in the number of cases discussed since its formation. There has also been a trend towards more conservative surgery, both of the primary tumour and of nodal management. Between September 2009 and August 2010, 16 glansectomies were performed versus 5 total and 9 partial penectomies. The same period saw 18 dynamic sentinel lymph node biopsies against 7 bilateral and 3 unilateral superficial groin dissections. There was a very high patient satisfaction rate, with patients feeling they had good support and information. CONCLUSIONS: On reviewing the literature it can be clearly seen that supraregional networks have led to a decrease in overtreatment and better recognition of the need to manage lymph node status optimally. Our network has demonstrated the trend toward conservative surgery and sentinel node biopsy. The formation of supraregional networks with a multidisciplinary approach will facilitate high volume centres that will offer optimal surgical therapy and also allow recruitment into studies and new chemotherapeutic regimens. It will also allow better data collection to aid clinical studies that hopefully will also demonstrate better outcomes. PMID- 22507730 TI - Laparoscopically assisted insertion of feeding jejunostomy. PMID- 22507731 TI - Pink tape for suturing practice. PMID- 22507732 TI - Modified dissection scissors with a functional ligation aid. PMID- 22507733 TI - A simple technique to make identification of the rectum easier when performing a posterior sagittal anorectoplasty. PMID- 22507734 TI - Achieving abdominal closure following emergency laparotomy in patients with connective tissue disorders. PMID- 22507735 TI - Repair of giant abdominal incisional hernia: our technique. PMID- 22507736 TI - Economical negative pressure wound therapy. PMID- 22507737 TI - Comment on: Peritonsillar abscess after tonsillectomy. PMID- 22507738 TI - Ankle arthroscopy in children. PMID- 22507740 TI - Guidelines and pharmacopoeial standards for pharmaceutical impurities: overview and critical assessment. AB - ICH/regional guidances and agency scrutiny provide the regulatory framework for safety assessment and control of impurities in small-molecule drug substances and drug products. We provide a critical assessment of the principal impurity guidances and, in particular, focus on deficiencies in the derivation of the threshold of toxicological concern (TTC) as applied to genotoxic impurities and the many toxicological anomalies generated by following the current guidelines on impurities. In terms of pharmacopoeial standards, we aim to highlight the fact that strictly controlling numerous impurities, especially those that are minor structural variants of the active substance, is likely to produce minimal improvements in drug safety. It is believed that, wherever possible, there is a need to simplify and rebalance the current impurity paradigm, moving away from standards derived largely from batch analytical data towards structure-based qualification thresholds and risk assessments using readily available safety data. Such changes should also lead to a minimization of in vivo testing for toxicological qualification purposes. Recent improvements in analytical techniques and performance have enabled the detection of ever smaller amounts of impurities with increased confidence. The temptation to translate this information directly to the regulatory sphere without any kind of safety evaluation should be resisted. PMID- 22507741 TI - Estradiol ameliorates arthritis and protects against systemic bone loss in Staphylococcus aureus infection in mice. AB - INTRODUCTION: Staphylococcus aureus is a common cause of bacterial arthritis, which is associated with progressive bone loss in affected joints. We recently showed that S. aureus infection also induces a significant systemic bone loss in mice. This study was performed to assess the effect of estradiol treatment on the clinical course and outcome of S. aureus arthritis and on infection-induced bone loss in experimental S. aureus infection. METHODS: Mice were ovariectomized, treated with estradiol or placebo, and S. aureus infection was established by intravenous inoculation of bacteria. RESULTS: Estradiol treatment was found to decrease significantly the frequency and clinical severity of S. aureus arthritis, a finding that was accompanied with significantly higher serum levels of interleukin-10 in estradiol-treated mice. Estradiol was also highly protective against S. aureus-induced systemic trabecular, and cortical bone loss. Lack of endogenous estrogens and S. aureus infection had additive effects on trabecular bone loss. The S. aureus-infected, ovariectomized mice lost as much as 76% of their trabecular bone mass. CONCLUSIONS: Treatment with estradiol ameliorates S. aureus arthritis and is protective against infection-induced systemic bone loss in experimental S. aureus infection. PMID- 22507742 TI - Cohort Profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort. AB - Summary The Avon Longitudinal Study of Children and Parents (ALSPAC) was established to understand how genetic and environmental characteristics influence health and development in parents and children. All pregnant women resident in a defined area in the South West of England, with an expected date of delivery between 1st April 1991 and 31st December 1992, were eligible and 13761 women (contributing 13867 pregnancies) were recruited. These women have been followed over the last 19-22 years and have completed up to 20 questionnaires, have had detailed data abstracted from their medical records and have information on any cancer diagnoses and deaths through record linkage. A follow-up assessment was completed 17-18 years postnatal at which anthropometry, blood pressure, fat, lean and bone mass and carotid intima media thickness were assessed, and a fasting blood sample taken. The second follow-up clinic, which additionally measures cognitive function, physical capability, physical activity (with accelerometer) and wrist bone architecture, is underway and two further assessments with similar measurements will take place over the next 5 years. There is a detailed biobank that includes DNA, with genome-wide data available on >10000, stored serum and plasma taken repeatedly since pregnancy and other samples; a wide range of data on completed biospecimen assays are available. Details of how to access these data are provided in this cohort profile. PMID- 22507743 TI - Cohort Profile: the 'children of the 90s'--the index offspring of the Avon Longitudinal Study of Parents and Children. AB - The Avon Longitudinal Study of Parents and Children (ALSPAC) is a transgenerational prospective observational study investigating influences on health and development across the life course. It considers multiple genetic, epigenetic, biological, psychological, social and other environmental exposures in relation to a similarly diverse range of health, social and developmental outcomes. Recruitment sought to enroll pregnant women in the Bristol area of the UK during 1990-92; this was extended to include additional children eligible using the original enrollment definition up to the age of 18 years. The children from 14541 pregnancies were recruited in 1990-92, increasing to 15247 pregnancies by the age of 18 years. This cohort profile describes the index children of these pregnancies. Follow-up includes 59 questionnaires (4 weeks-18 years of age) and 9 clinical assessment visits (7-17 years of age). The resource comprises a wide range of phenotypic and environmental measures in addition to biological samples, genetic (DNA on 11343 children, genome-wide data on 8365 children, complete genome sequencing on 2000 children) and epigenetic (methylation sampling on 1000 children) information and linkage to health and administrative records. Data access is described in this article and is currently set up as a supported access resource. To date, over 700 peer-reviewed articles have been published using ALSPAC data. PMID- 22507744 TI - Plasmodium falciparum centromeres display a unique epigenetic makeup and cluster prior to and during schizogony. AB - Centromeres are essential for the faithful transmission of chromosomes to the next generation, therefore being essential in all eukaryotic organisms. The centromeres of Plasmodium falciparum, the causative agent of the most severe form of malaria, have been broadly mapped on most chromosomes, but their epigenetic composition remained undefined. Here, we reveal that the centromeric histone variant PfCENH3 occupies a 4-4.5 kb region on each P. falciparum chromosome, which is devoid of pericentric heterochromatin but harbours another histone variant, PfH2A.Z. These CENH3 covered regions pinpoint the exact position of the centromere on all chromosomes and revealed that all centromeric regions have similar size and sequence composition. Immunofluorescence assay of PfCENH3 strongly suggests that P. falciparum centromeres cluster to a single nuclear location prior to and during mitosis and cytokinesis but dissociate soon after invasion. In summary, we reveal a dynamic association of Plasmodium centromeres, which bear a unique epigenetic signature and conform to a strict structure. These findings suggest that DNA-associated and epigenetic elements play an important role in centromere establishment in this important human pathogen. PMID- 22507745 TI - Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients. AB - INTRODUCTION: Germline TP53 mutations cause an increased risk to early-onset breast cancer in Li-Fraumeni syndrome (LFS) families and the majority of carriers identified through breast cancer cohorts have LFS or Li-Fraumeni-like (LFL) features. However, in Asia and in many low resource settings, it is challenging to obtain accurate family history and we, therefore, sought to determine whether the presence of early-onset breast cancer is an appropriate selection criteria for germline TP53 testing. METHODS: A total of 100 patients with early-onset breast cancer (<= 35 years) treated at University Malaya Medical Centre between 2003 and 2009, were analyzed for germline mutations in BRCA1, BRCA2 and TP53 by full DNA sequencing. Of the mutations identified, we examined their likely pathogenicity on the basis of prevalence in a case-control cohort, co-segregation analyses and loss of heterozygosity (LOH) in tumor tissues. RESULTS: We identified 11 BRCA1 (11%) and 6 BRCA2 (6%) germline carriers among early-onset breast cancer patients. Of the 83 BRCA-negative patients, we identified four exonic variants and three intronic variants in TP53. Of these, two exonic variants are clinically relevant (E346X and p. G334_R335dup6) and two novel missense mutations (A138V and E285K) are likely to be clinically relevant, on the basis of co-segregation and loss of heterozygosity (LOH). Notably, E285K was found in two unrelated individuals and haplotype analyses suggest a founder effect. Two of the three intronic variants are likely benign based on their prevalence in a control population. Clinically relevant TP53 germline mutations were identified in three of the four patients (75%) with a family history of at least two LFS-linked cancers (breast, bone or soft tissue sarcoma, brain tumors or adrenocortical cancer); 1 of the 17 patients (6%) with a family history of breast cancer only, and 1 of the 62 patients (< 2%) with no family history of breast or LFS-linked cancers. CONCLUSIONS: Our study reports germline BRCA1, BRCA2 and TP53 mutations are found in early-onset breast cancer patients at 11%, 6% and 5% respectively, suggesting that TP53 mutation screening should be considered for these patients. However, we find that even in low resource Asian settings where family history is poorly reported, germline TP53 mutations are found predominantly among breast cancer patients with a family history of LFS linked cancers. PMID- 22507746 TI - Weak estrogenic transcriptional activities of Bisphenol A and Bisphenol S. AB - In 2011, the European Commission has restricted the use of Bisphenol A in plastic infant feeding bottles. In a response to this restriction, Bisphenol S is now often used as a component of plastic substitutes for the production of babybottles. One of the major concerns leading to the restriction of Bisphenol A was its weak estrogenic activity. By using two highly standardised transactivation assays, we could demonstrate that the estrogenic activity of Bisphenol A and Bisphenol S is of a comparable potency. Furthermore, some insights about the structure-activity relationships of these two chemicals and their metabolites could be gained from in silico predictions of their relative estrogen receptor-binding affinities and their liver phase-I biotransformation. PMID- 22507747 TI - Precise mapping of the somatotopic hand area using neuromagnetic steady-state responses. AB - The body surface is represented in somatotopically organized maps in the primary somatosensory cortex. Estimating the size of the hand area with neuromagnetic source analysis has been used as a metric for monitoring neuroplastic changes related to training, learning, and brain injury. Commonly, results were significant as group statistics only because source localization accuracy was limited by factors such as residual noise and head motion. In this study we aimed to develop a robust method for obtaining the somatotopic map of the hand area in individuals using the bootstrap framework. Furthermore, a comprehensive analysis of the different factors affecting the accuracy of the obtained maps was provided. We applied vibrotactile touch stimuli to the tip of the index finger or the ring finger of the right hand and recorded the 22-Hz steady-state response using MEG. Single equivalent dipole sources were localized in contralateral left somatosensory cortex. Bootstrap resampling revealed the confidence intervals for the source coordinates using a single block of 5 min MEG recording. Residual noise in the averaged evoked response predominantly affected source localization, and the related confidence interval was reciprocally related to the signal-to noise ratio. Apparently, head movements within a block of MEG recording contributed less to the variability of source localization in cooperative volunteers. The results of the current study indicate that significant separations of index finger and ring finger representations along the somatotopic map can be revealed in an individual using bootstrap framework. PMID- 22507748 TI - Antenatal iron supplements consumed daily produce oxidative stress in contrast to weekly supplementation in Mexican non-anemic women. AB - Universal prenatal daily supplementation with iron (60-120mg iron) plus folic acid (0.4mg), as recommended by INACG/WHO/UNICEF, prevents anemia where iron deficiency is prevalent but may be excessive for non-anemic women. Weekly supplementation with 120mg iron plus various amounts of folic acid similarly prevents significant anemia. OBJECTIVE: Determine, in non-anemic pregnant women, if oxidative stress is produced by recommended daily or weekly supplementation schemes. PROCEDURE: 100 non-anemic pregnant women, 30% iron-deficient at week 20, were randomly supplemented daily followed by weekly, each for 8 weeks, or in reversed order. RESULTS: With daily supplementation thio-barbituric-acid-reacting substances (TBARS) increased significantly and high serum ferritin, iron, and excessively elevated hemoglobin occurred near term. During weekly supplementation significant anemia and high iron parameters were prevented, and elevated TBARS declined. CONCLUSION: In non-anemic pregnant women both schemes prevented significant anemia. Oxidative stress occurred only during daily supplementation periods. Weekly supplementation appears safer. PMID- 22507750 TI - Heterozygous UDP-GlcNAc 2-epimerase and N-acetylmannosamine kinase domain mutations in the GNE gene result in a less severe GNE myopathy phenotype compared to homozygous N-acetylmannosamine kinase domain mutations. AB - BACKGROUND: Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE) myopathy, also called distal myopathy with rimmed vacuoles (DMRV) or hereditary inclusion body myopathy (HIBM), is a rare, progressive autosomal recessive disorder caused by mutations in the GNE gene. Here, we examined the relationship between genotype and clinical phenotype in participants with GNE myopathy. METHODS: Participants with GNE myopathy were asked to complete a questionnaire regarding medical history and current symptoms. RESULTS: A total of 71 participants with genetically confirmed GNE myopathy (27 males and 44 females; mean age, 43.1+/-13.0 (mean+/-SD) years) completed the questionnaire. Initial symptoms (e.g., foot drop and lower limb weakness) appeared at a mean age of 24.8+/-8.3 years. Among the 71 participants, 11 (15.5%) had the ability to walk, with a median time to loss of ambulation of 17.0+/-2.1 years after disease onset. Participants with a homozygous mutation (p.V572L) in the N-acetylmannosamine kinase domain (KD/KD participants) had an earlier disease onset compared to compound heterozygous participants with mutations in the uridine diphosphate-N acetylglucosamine (UDP-GlcNAc) 2-epimerase and N-acetylmannosamine kinase domains (ED/KD participants; 26.3+/-7.3 vs. 21.2+/-11.1 years, respectively). KD/KD participants were more frequently non-ambulatory compared to ED/KD participants at the time of survey (80% vs. 50%). Data were verified using medical records available from 17 outpatient participants. CONCLUSIONS: Homozygous KD/KD participants exhibited a more severe phenotype compared to heterozygous ED/KD participants. PMID- 22507752 TI - Modulation of nitric oxide synthase by arginase and methylated arginines during the acute phase of experimental multiple sclerosis. AB - We explore the nitric oxide synthase modulation by methylated arginines, asymmetric (ADMA) and symmetric (SDMA) dimethyl-l-arginine and arginase, in early phase of experimental autoimmune encephalomyelitis (EAE), the most frequently used animal model for studying the multiple sclerosis (MS), during the treatment with selective inducibile nitric oxide synthase inhibitor - aminoguanidine (AG) and oxidative scavenger N-acetyl-l-cysteine (NAC), compared to the clinical signs, continual to our previous research. The given results showed that the arginase activity was significantly increased in EAE rats compared to the healthy and AG treated EAE animals (p<0.05), and it was significantly decreased compared to the NAC treated EAE animals (p<0.05) in examined tissues. The ADMA and SDMA levels were significantly decreased in EAE untreated animals compared to the AG and NAC treated EAE animals (p<0.05). As we have reported in our previous papers, nitric oxide (NO) production, was significantly increased in examined tissues of EAE rats compared to the control group (p<0.05). In AG and NAC treated EAE group NO production was decreased in all tissues compared to untreated EAE animals (p<0.05). Also, the AG and NAC treatment of EAE rats during the development of the disease, significantly decreased the clinical score of EAE treated animals compared to EAE group. Arginase and methylated arginine derivatives, involving also NO, appear to be essential modulators of the inflammatory response in acute phase of MS. The continued research of these findings may provide a new area in the treatment of multiple sclerosis acute phase. PMID- 22507751 TI - Increasing age at disability milestones among MS patients in the MSBase Registry. AB - OBJECTIVE: To analyze time-trends in age at disability milestones among MS patients who were enrolled into the MSBase International Registry during 1996 2010 period. METHODS: We used linear regression to describe the relationship between mean age at major EDSS benchmarks and calendar time. We then assessed time-trend in age at initial EDSS rating with a three level linear growth model specifying that patients were nested within each of 20 participating countries. The model estimated the average of time-trends in mean age at initial clinical assessment within each country while controlling for patients' EDSS and sex in each country. Analyses were repeated in subsamples of patients diagnosed according to Poser or McDonald criteria. RESULTS: The MSBase Registry contained data on 11,108 MS patients enrolled between 1996 and 2010 who fulfilled our inclusion criteria. During the 1996-2010 period, enrollment age for patients with EDSS 4/4.5 increased by 7.9 years, from 43 to 51 years (p<0.001), and for EDSS 6/6.5 - by 4.9 years, from 48 to 53 year (p<0.001). These trends were consistent across 20 investigator countries and were observed in Poser-diagnosed as well as McDonald-diagnosed patient subsets. CONCLUSIONS: The more recent MSBase enrollees in each of the mild-to-moderate disability strata were significantly older than earlier enrollees. Possible explanations for this phenomenon are discussed. PMID- 22507753 TI - Preserved autonomic function in patients with POEMS syndrome. AB - AIM: We systematically performed autonomic testing on patients with polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome (POEMS) to determine whether autonomic function is preserved in such patients. METHODS: We studied 17 POEMS patients, 17 diabetic neuropathy (DN) patients and 17 age-matched normal subjects. Blood pressure responses to the head-up tilt test and heart rate variability were used to evaluate cardiovascular autonomic function. Sweat responses and cutaneous vasoconstriction to several stimuli were recorded via the finger tips to estimate cutaneous sympathetic function. In addition, motor nerve conduction studies were performed. RESULTS: Although the results of the autonomic testing were normal in POEMS patients, motor disability was severe, and motor nerve conduction studies provided evidence of extensive axonal loss. The DN patients showed significantly impaired autonomic responses despite mild motor dysfunction. CONCLUSIONS: Autonomic function was normal in POEMS patients, indicating the preservation of autonomic fibers and selective involvement of large fibers. PMID- 22507754 TI - No evidence for the 'expensive-tissue hypothesis' from an intraspecific study in a highly variable species. AB - The 'expensive-tissue hypothesis' states that investment in one metabolically costly tissue necessitates decreased investment in other tissues and has been one of the keystone concepts used in studying the evolution of metabolically expensive tissues. The trade-offs expected under this hypothesis have been investigated in comparative studies in a number of clades, yet support for the hypothesis is mixed. Nevertheless, the expensive-tissue hypothesis has been used to explain everything from the evolution of the human brain to patterns of reproductive investment in bats. The ambiguous support for the hypothesis may be due to interspecific differences in selection, which could lead to spurious results both positive and negative. To control for this, we conduct a study of trade-offs within a single species, Thalassoma bifasciatum, a coral reef fish that exhibits more intraspecific variation in a single tissue (testes) than is seen across many of the clades previously analysed in studies of tissue investment. This constitutes a robust test of the constraints posited under the expensive-tissue hypothesis that is not affected by many of the factors that may confound interspecific studies. However, we find no evidence of trade-offs between investment in testes and investment in liver or brain, which are typically considered to be metabolically expensive. Our results demonstrate that the frequent rejection of the expensive-tissue hypothesis may not be an artefact of interspecific differences in selection and suggests that organisms may be capable of compensating for substantial changes in tissue investment without sacrificing mass in other expensive tissues. PMID- 22507755 TI - A unique 3D endoanal ultrasound feature of perianal Crohn's fistula: the 'Crohn ultrasound fistula sign'. AB - AIM: Using a high-resolution 3D endoanal ultrasound, we have observed that some perianal fistulas show a hypoechogenic fistula tract surrounded by a well-defined hyperechogenic area with a thin hypoechogenic edge in patients with Crohn's disease ['Crohn's Ultrasound Fistula Sign' (CUFS)], unlike conventional fistula tracks. The study aimed to determine the prevalence of CUFS in a consecutive series of patients with anal fistula. METHOD: Of 157 patients (median age 45, range 14-86 years, 100 males) with perianal fistula were examined with 3D endoanal ultrasound. All 3D volumes were stored and analysed retrospectively by two independent observers blinded to the clinical information of the patients. RESULTS: There were 29 patients with Crohn's disease of whom 20 (69%) showed CUFS. CUFS was absent in 125 (98%) of 128 patients without Crohn's disease. The positive and negative predictive value of CUFS for Crohn's disease was 87% and 93%, respectively. The kappa value of the two independent observers was 0.77, indicating a substantial interobserver agreement. CONCLUSION: This study provides a new 3D endoanal ultrasound criterion, CUFS, of perianal fistula in patients with Crohn's disease. The sign can be used to discriminate a Crohn's from other types of fistula, which may be useful in the management of patients with anal fistula. PMID- 22507756 TI - Principal component analysis of dynamic fluorescence tomography in measurement space. AB - Challenges remain in resolving metabolic processes of drugs within small animals using a fluorescence tomographic image. In our previous work, using principal component analysis (PCA), we detected functional structures with different kinetic behaviors, where PCA was applied in fluorescence tomographic sequence (i.e. in the image space). As a result, all measurement data had to be reconstructed before performing PCA, which imposed a large computational burden. In this paper, we propose a new approach and apply PCA directly to fluorescence projection sequence (i.e. in the measurement space). Utilizing the compression property of PCA, it is possible to resolve regions with different kinetics by reconstructing only a few principal components. Hence, the computational cost can be significantly reduced. To evaluate the performance of the new method, numerical simulation and a phantom experiment are performed on a hybrid fluorescence and x-ray computed tomography imaging system. The results demonstrate that the proposed method greatly reduces the computational time compared with the previous method, while keeping a similar resolving capability. PMID- 22507757 TI - Magnetic resonance and computed tomography imaging of a carotid body tumor in a dog. AB - A 5-year-old castrated male Labrador Retriever was presented to a referring veterinarian for a swelling in the neck region. Based on the results of histopathology, a carotid body tumor, was diagnosed. The dog was referred to a medical imaging unit for further staging and follow up. This report describes the magnetic resonance (MR) and computed tomographic (CT) appearance of a carotid body tumor. PMID- 22507758 TI - The extent to which school district competitive food and beverage policies align with the 2010 Dietary Guidelines for Americans: implications for federal regulations. AB - The Healthy, Hunger-Free Kids Act of 2010 authorized the Secretary of the US Department of Agriculture to establish science-based nutrition standards for competitive foods and beverages sold in school that are, at a minimum, aligned with the 2010 Dietary Guidelines for Americans (DGA), while still providing districts with discretion in regulating the competitive food and beverage environment. The objective of this study was to examine the extent to which district competitive food and beverage policies had specific and required limits aligned with 2010 DGA recommendations, and to inform US Department of Agriculture efforts as they develop competitive food and beverage standards. Competitive food and beverage policies were compiled for the 2009-2010 school year from a nationally representative sample of 622 districts. Each policy was double-coded for compliance with selected 2010 DGA recommendations (ie, restrictions on sugars, fats, trans fats, and sodium in foods and restrictions on regular soda, other sugar-sweetened beverages, and fat content of milk). Descriptive statistics were computed, clustered to account for the sample design, and weighted to account for districts nationwide. District nutrition policies were strongest for elementary schools. Nationwide, <5% of districts met or exceeded all of the previously mentioned nutrient requirements examined. Fat and sugar content of foods and soda availability were more commonly addressed. Areas that require attention include stronger nutrition standards at the secondary level, limits on trans fats, sodium, sugar-sweetened beverages other than soda, and fat content of milk, and greater availability of produce and whole grains at all sale locations. PMID- 22507759 TI - Vaccination of mice with recombinant bacille Calmette-Guerin harboring Rv1357c protects similarly to native BCG. AB - Despite the availability of a Mycobacterium bovis bacille Calmette Guerin (BCG) vaccine, tuberculosis (TB) remains a global public health problem. In this study, we introduced the c-di-GMP phosphodiesterase gene Rv1357c, implicated in regulating mycobacterial replication within macrophages, into BCG Pasteur, and tested the resulting strain for its capacity to serve as a vaccine against TB in a murine model. Modified BCG was more phagocytosed than its parental strain, but halted bacterial replication, and protected against M. tuberculosis challenge similarly to unmodified BCG. PMID- 22507760 TI - Amygdala and hippocampal volume reductions as candidate endophenotypes for borderline personality disorder: a meta-analysis of magnetic resonance imaging studies. AB - Borderline personality disorder (BPD) is a genetically influenced psychiatric illness with disruptions in neural systems supporting cognition and emotion regulation. Volumetric decreases of the hippocampus and amygdala may characterize BPD and serve as putative endophenotypes for the illness. The purpose of the present study was to evaluate whether the magnitude of these volume reductions and their associations with state-of-illness factors and psychiatric disorders which often co-occur with BPD warrant their consideration as potential endophenotypes. Volumetric magnetic resonance imaging results from 11 studies comprising 205 BPD patients and 222 healthy controls were quantitatively synthesized using meta-analytic techniques. Patients showed an average 11% and 13% decrease in the size of the hippocampus and amygdala, respectively. These volumetric differences were not attenuated in patients being treated with psychotropic medications. Comorbid depression, post-traumatic stress disorder, and substance use disorders were unrelated to volumetric decreases in either structure. These findings suggest modest volume reductions of the amygdala and hippocampus bilaterally in BPD which cannot be attributed to illness state or comorbid psychopathology. Decreased volumes of these key limbic structures may hold promise as candidate endophenotypes for BPD. PMID- 22507761 TI - Hippocampal neurometabolite changes in depression treatment: a (1)H magnetic resonance spectroscopy study. AB - Previous studies using magnetic resonance spectroscopy have related abnormalities in hippocampal metabolism to depression. Current evidence is consistent with the conclusion that the hippocampal formation plays an important role in the presentation of depressive symptoms. Eighteen adult patients with major depressive disorder, aged 20 to 60 years, underwent magnetic resonance spectroscopy of the hippocampus during a period of depressive symptomatology and after 7-11 weeks of antidepressant medication with at least 50% reduction in the Montgomery-Asberg Depression Rating Scale ()MADRS score. During therapy, we found a significantly decreased Lac/Cr ratio in the left hippocampus. The Ins/Cr ratio showed a significant negative correlation with the severity of depression as assessed by the MADRS at baseline. Moreover, we found a negative association of NAA/Cho with age and a positive association of Cho/Cr with age, both on the left and right sides at baseline. In light of our findings and previous studies results we hypothesize that mitochondrial dysfunction leading to predominantly anaerobic glycolysis in connection with the intracellular signaling pathways disturbances and decreased astrocytic function/number might subsequently lead to decreased brain neuroplasticity in depression. These mechanisms could be positively influenced by antidepressant treatment with selective serotonin or norepineprine reuptake inhibitors, with potential effects on untimely neuronal aging in depression. PMID- 22507762 TI - Psychotropic drug effects on gene transcriptomics relevant to Parkinson's disease. AB - OBJECTIVES: Psychotropic drugs are widely prescribed in Parkinson's disease (PD) without regard to their pathobiological effects, and these drugs affect the transcription of a large number of genes. Effects of these drugs on PD risk gene transcription were therefore surveyed. METHODS: Results summarize a comprehensive survey of psychotropic effects on messenger ribonucleic acid (mRNA) expression evident in published data for 70 genes linked to PD risk. RESULTS: Psychotropic drugs can meaningfully affect PD risk gene mRNA transcription, including antipsychotics (upregulate dopamine receptors D2 and D3 (DRD2, DRD3); downregulate low-density lipoprotein receptor-related protein 8 (LRP8), ubiquitin carboxyl-terminal esterase L1 (UCHL1, also known as PARK5)), haloperidol (upregulates DRD3, parkin (PRKN, also known as PARK2), DRD2; downregulates brain derived neurotrophic factor (BDNF)), risperidone (upregulates monoamine oxidase B (MAOB), DRD2), olanzapine (upregulates transmembrane protein 163 (TMEM163), BDNF, glutathione S-transferase mu 1 (GSTM1), MAOB, DRD2, solute carrier organic anion transporter family, member 3A1 (SLCO3A1)), aripiprazole (upregulates DRD2), quetiapine, paliperidone, lurasidone, carbamazepine, and many antidepressants (upregulate BDNF), lithium and bupropion (downregulate BDNF), amitriptyline (upregulates DRD3, DRD2), imipramine (upregulates BDNF, DRD3, DRD2), desipramine (upregulates BDNF, DRD3), and fluoxetine (upregulates acid beta-glucosidase (GBA), coiled-coil domain containing 62 (CCDC62), BDNF, DRD3, UCHL1, unc-13 homolog B (UNC13B), and perhaps huntingtin interacting protein 1 related (HIP1R); downregulates microtubule-associated protein tau (MAPT), methylcrotonoyl-coenzyme A carboxylase I (MCCC1), GSTM1, 28kDa calbindin 1 (CALB1)). Fluoxetine effects on BDNF and UCHL1 in GEO Profiles were statistically robust. CONCLUSIONS: This report provides an initial summary and framework to understand the potential impact of psychotropic drugs on PD-relevant genes. Antipsychotics and serotoninergic antidepressants may potentially attenuate PD risk, and lithium and bupropion may augment risk, through MAPT, GBA, CCDC62, HIP1R, BDNF, and DRD2 transcription, with MAPT, GBA, and CCDC62 being strongly associated with PD risk in recent meta-analyses. Limitations of these findings and a research agenda to better relate them to the nigrostriatum and PD are discussed. PMID- 22507763 TI - Complexity and schizophrenia. AB - Complexity estimators have been broadly utilized in schizophrenia investigation. Early studies reported increased complexity in schizophrenia patients, associated with a higher variability or "irregularity" of their brain signals. However, further investigations showed reduced complexities, thus introducing a clear divergence. Nowadays, both increased and reduced complexity values are reported. The explanation of such divergence is a critical issue to understand the role of complexity measures in schizophrenia research. Considering previous arguments a complementary hypothesis is advanced: if the increased irregularity of schizophrenia patients' neurophysiological activity is assumed, a "natural" tendency to increased complexity in EEG and MEG scans should be expected, probably reflecting an abnormal neuronal firing pattern in some critical regions such as the frontal lobes. This "natural" tendency to increased complexity might be modulated by the interaction of three main factors: medication effects, symptomatology, and age effects. Therefore, young, medication-naive, and highly symptomatic (positive symptoms) patients are expected to exhibit increased complexities. More importantly, the investigation of these interacting factors by means of complexity estimators might help to elucidate some of the neuropathological processes involved in schizophrenia. PMID- 22507764 TI - Adipose tissue-derived mesenchymal cells support skin reepithelialization through secretion of KGF-1 and PDGF-BB: comparison with dermal fibroblasts. AB - Epidermal organization and homeostasis are regulated by mesenchymal influences through paracrine actions. Until today, dermal fibroblasts (DFs) are used in the "dermal" layer to support keratinocyte growth in vitro in dermal and skin substitutes. In the present work, we used human adipose tissue-derived mesenchymal cells (ADMCs) as a support of keratinocyte growth in vitro (in monolayer culture and in 3D skin cell culture models) and in vivo (mouse wound healing models) and compared our findings with those obtained using dermal fibroblasts. ADMCs induce reepithelialization during wound healing more efficiently than DFs, by enhancing keratinocyte proliferation through cell cycle progression, and migration. This effect is mediated (at least partially) by a paracrine action of KGF-1 and PDGF-BB, which are more prominently expressed in ADMCs than in DFs. Furthermore, replacement of DFs by ADMCs in the dermal compartment of organotypic skin cultures leads to an artificial epidermis resembling to that of normal skin, concerning the general histology, although with a higher expression of cytokeratins 5 and 19. In Rag1 knockout mice, ADMCs induced a more rapid reepithelialization and a more effective wound healing, compared to dermal fibroblasts. In conclusion, we provide evidence that ADMCs can serve as supportive cells for primary keratinocyte cultures. In addition, because of their abundance and the great cell yield achieved during ADMC isolation, they represent an interesting cell source, with potential aspects for clinical use. PMID- 22507765 TI - Hematology. Editorial. PMID- 22507766 TI - Multiple myeloma: treatment evolution. AB - Melphalan-prednisone (MP) was introduced for the treatment of MM in late 1960s. In the subsequent 30 years, the treatment improvements remained stagnant, since more complex chemotherapy combinations, such as vincristine, doxorubicin, and dexamethasone (VAD), or with the addition of BCNU (VBAD) or melphalan and cyclophosphamide (VCMP), only led to small increases in the overall response rate but without differences in survival, as assessed in a large meta-analysis that included over 6000 patients. The next step forward was the use of high-dose melphalan followed by stem cell support (autologous stem cell transplant - ASCT) for young myeloma patients, which resulted in a significant improvement in disease free survival and overall survival. However, for elderly patients MP remained as the standard of care. From year 2000, a revolution in the treatment armamentarium of MM has emerged with the availability of new agents with singular mechanism of action such as thalidomide and lenalidomide (Revlimid(r)), both immunomodulatory drugs and the proteasome inhibitor bortezomib (Velcade(r)). PMID- 22507767 TI - Planetary change and biochemical adaptation: molecular evolution of corrinoid and heme biosyntheses. AB - This review examines the evidence suggesting that the anaerobic biosynthesis of cobalamin (vitamin B12) evolved during early stages of cell evolution and was quickly recruited in the pathway leading to deoxyribonucleotides, the building blocks of DNA genomes. Biochemical evolution preceding the synthesis of the heme group and related molecules is discussed within the framework of geological evolution in which the appearance and accumulation of an oxygen-rich atmosphere stands as one of the major events in the evolution of the planet and the biosphere. PMID- 22507768 TI - Treatment of acquired aplastic anemia in children. AB - Aplastic anemia (AA) is an uncommon but serious disorder characterized by pancytopenia resulting from non-function of the bone marrow. The incidence of AA is approximately 3 fold more common in East Asia than in Europe and United States where yearly incidence rates are approximately two patients per one million. PMID- 22507769 TI - Allogeneic transplantation for aplastic anemia. AB - OBJECTIVE: To discuss the role of allogeneic transplantation for the treatment of severe aplastic anemia. METHODS: Published reports for treatment of severe aplastic anemia were searched with Medline. Search terms included severe aplastic anemia, HLA-matched sibling, unrelated donor, hematopoietic stem cell transplantation. RESULTS: Survival after HLA-matched sibling donor transplantation is approximately 80% in patients aged less than 20 years. Survival rates are lower in older patients ranging from 50-70%. The risks of transplant-related morbidity and mortality increase with age and explain the observed lower survival rates in older patients. Unrelated donor transplantation is reserved for patients who lack a matched related donor and have failed at least one course of immunosuppressive therapy. Survival after unrelated donor transplantation has also improved in recent years and largely attributed to the selection of donors who are fully HLA-matched to the patient. The risks of transplant-related complications are higher than after HLA-matched sibling transplantation. Graft-versus-host disease (GVHD) is higher; GVHD can lead to significant morbidity and mortality. Other frequent complications include graft failure and pulmonary complications. The use of peripheral blood progenitor cells has also contributed to higher GVHD risks and consequently excess deaths. DISCUSSION: The results of allogeneic transplantation, from related and unrelated donors have improved substantially in the last decade. Early referral for transplantation, selection of HLA-matched donors and improved supportive care has contributed to the success of this treatment. The choice of graft used for transplantation is important regardless of donor type; bone marrow is the preferred graft. PMID- 22507770 TI - Bone marrow failure and the new telomere diseases: practice and research. AB - The telomeropathies are a newly described group of human diseases based on the genetics and molecular biology of the telomeres, the ends of chromosomes. Telomeres are repeated hexanucleotides and their associated proteins; the protect chromosomes from recognition as damaged DNA, and their inevitable gradual loss with DNA replication is harmless as they are noncoding. However, when telomeres become critically short in a cell, senescence, apoptosis, or, rarely malignant transformation results. In individuals with mutations in genes involved in telomere repair, especially the enzymatic telomerase complex, telomere attrition is accelerated. Severe deficiencies result in dyskeratosis congenita, a congenital aplastic anemia with associated mucocutaneous abnormalities. Mutations in TERT, the catalytic component, and TERC, the RNA template, can behave as risk factors for the development of bone marrow failure, pulmonary fibrosis, and hepatic cirrhosis. Both penetrance and organ specificity are variable and not well understood. Chromosome instability is a result of critical shortening of telomeres and cancer. For example, short telomeres are the major prognostic risk factor for clonal evolution to myelodysplasia and acute leukemia. Practically, hematologists need to recognize the multisystem presentation of telomere disease, implications for outcomes, and options for therapy. PMID- 22507771 TI - Rituximab in the treatment of TTP. AB - Thrombotic thrombocytopenic purpura (TTP) is an acute life threatening disorder, for which mortality remains relatively unchanged since the introduction of plasma therapy. Improved understanding of the pathophysiology has identified that the majority of cases result from antibodies directed against ADAMTS 13, which is required to cleave von Willebrand Factor. The use of monoclonal anti-CD 20 therapy removes IgG antibodies, resulting in increased ADAMTS 13 activity, improved time to remission and prevention of recurrent relapses. While further follow-up is required, the side effect profile of anti-CD 20 therapy appears improved compared to conventional immunosuppressive treatments. The use of ADAMTS 13 activity for monitoring can identify patients at risk of a TTP relapse and preemptive therapy with an anti-CD 20 can be considered. PMID- 22507772 TI - Monoclonal antibodies in the treatment of immune thrombocytopenic purpura (ITP). AB - Immune thrombocytopenic purpura is characterized by antibody-mediated destruction of platelets and suboptimal platelet production. Initially the treatment of ITP includes corticosteroids, IgG-anti-D, and intravenous immunoglobulins. Splenectomy and monoclonal antibodies are usually considered for refractory and chronic ITP patients. There are new data suggesting that early administration of rituximab is important, and this antibody has been used as first-line therapy in adults. In this concise review the role of rituximab and other monoclonal antibodies is analyzed. These agents have the capability of sparing splenectomy and possibly curing the disease in some patients. PMID- 22507773 TI - Thalassemia. AB - Thalassemia is the most common form of inherited anemia worldwide. The World Health Organization reports suggest that about 60,000 infants are born with a major thalassemia every year. Although individuals originating from the tropical belt are most at risk, it is a growing global health problem due to extensive population migrations. Despite important advances on curative approaches such as stem cell transplantation and promising results of gene therapy, blood transfusions and iron chelation still remain as cornerstones of disease management. The purpose of this article is to focus on mainly the clinical aspects and management of beta-thalassemia major. PMID- 22507774 TI - Adult T-cell leukemia-lymphoma. AB - Adult T-cell leukemia-lymphoma (ATL) was first described in 1977 as a distinct clinico-pathological entity with a suspected viral etiology. Subsequently, a novel RNA retrovirus, human T-cell leukemia/lymphotropic virus type 1 (HTLV-1) was isolated from a cell line established from the leukemic cells of an ATL patient, and the finding of a clear association with ATL led to its inclusion among human carcinogenic pathogens. The three major routes of HTLV-1 transmission are mother-to-child infections via breast milk, sexual intercourse, and blood transfusions. HTLV-1 infection early in life, presumably from breast feeding, is crucial in the development of ATL. The diversity in clinical features and prognosis of patients with this disease has led to its subtype-classification into four categories, acute, lymphoma, chronic, and smoldering types defined by organ involvement, and LDH and calcium values. In cases of acute, lymphoma, or unfavorable chronic subtypes (aggressive ATL), intensive chemotherapy such as VCAP-AMP-VECP is usually recommended. In cases of favorable chronic or smoldering ATL (indolent ATL), watchful waiting until disease progression has been recommended although the long term prognosis was inferior to those of, for instance, chronic lymphoid leukemia. Retrospective analysis suggested that the combination of interferon alpha and zidovudine was apparently promising for the treatment of ATL, especially for types with leukemic manifestation. Allogeneic hematopoietic stem cell transplantation is also promising for the treatment of aggressive ATL possibly reflecting graft vs. ATL effect. Several new agent-trials for ATL are ongoing and in preparation, including a defucosylated humanized anti CC chemokine receptor 4 monoclonal antibody. Two steps should be considered for the prevention of HTLV-1-associated ATL. The first is the prevention of HTLV-1 infections and the second is the prevention of ATL among HTLV-1 carriers. So far, no agent has been found to be effective for the latter. Further investigation on the pathogenesis of ATL is crucial for the prevention and treatment of this refractory leukemia-lymphoma. PMID- 22507776 TI - Molecular genetics of acute myeloid leukemia: clinical implications and opportunities for integrating genomics into clinical practice. AB - Advances in sequencing technologies have led to the discovery of a series of mutations in a sizeable proportion of patients with acute myeloid leukemia (AML) over the last 10 years. Clinical correlative studies are now beginning to decipher the clinical importance, prevalence and potential prognostic significance of these mutations in AML but few studies have assessed the clinical implications of these mutations in a comprehensive fashion. Nonetheless, mutations in DNMT3A, TET2, and ASXL1 are emerging as important adverse prognosticators in subsets of patients with AML independent of FLT3 mutations whereas mutations in IDH2 at residue 140 are potential predictors of improved outcome in AML. Further improvements in cost, throughput, and clinical validation of second-generation sequencing technologies may allow for clinical implementation of comprehensive genetic profiling in the clinical care of AML patients. PMID- 22507775 TI - The impact of medical education and networking on the outcome of leukemia treatment in developing countries. The experience of International Consortium on Acute Promyelocytic Leukemia (IC-APL). AB - OBJECTIVES: Several clinical trials conducted in Europe and US reported favorable outcomes of patients with APL treated with the combination of all trans retinoic acid (ATRA) and anthracyclines. Nevertheless, the results observed in developing countries with the same regimen was poorer, mainly due to high early mortality mainly due bleeding. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) is an initiative of the International Members Committee of the ASH and the project aims to reduce this gap through the establishment of international network, which was launched in Brazil, Mexico and Uruguay. METHODS: The IC-APL treatment protocol is similar to the PETHEMA 2005, but changing idarubicin to daunorubicin. All patients with a suspected diagnosis of APL were immediately started on ATRA, while bone marrow samples were shipped to a national central lab where genetic verification of the diagnosis was performed. The immunofluorescence using an anti-PML antibody allowed a rapid confirmation of the diagnosis and, the importance of supportive measures was reinforced. RESULTS: The interim analysis of 97 patients enrolled in the IC-APL protocol showed that complete remission (CR) rate was 83% and the 2-year overall survival and disease free survival were 80% and 90%, respectively. Of note, the early mortality rate was reduced to 7.5%. DISCUSSION: The results of IC-APL demonstrate the impact of educational programs and networking on the improvement of the leukemia treatment outcome in developing countries. PMID- 22507777 TI - Novel therapeutic strategies for AML in 2012. AB - During the last four decades, much progress has been made in understanding the molecular pathogenesis of acute myeloid leukemia and in identifying prognostic factors predictive of outcome. However, progress in therapy has been much slower. Since the initial description of the combination of an anthracycline and cytarabine for induction, few major advances have changed the standard of care. Furthermore, these few advances apply to younger patients and those with inherently more favorable disease biology. Intensification of post-remission cytarabine improves the cure rate of patients in first complete remission (CR). Daunorubicin dose intensification improves outcome in younger patients. Finally, allogeneic hematopoietic cell transplantation is an effective strategy for many patients in first CR. The discovery of drugs with novel mechanisms of action which are directly at specific molecular targets is among the most exciting areas of research and holds great promise for the development of effective treatment. PMID- 22507778 TI - Acute leukemia in adults: novel allogeneic transplant strategies. AB - Acute myeloid leukemia (AML) is the most common indication for hematopoietic cell transplantation (HCT). Significant improvements in histocompatibility testing have resulted in identifying better alternative donors to provide grafts; coupled with expanding use of reduced-intensity conditioning (RIC) regimens, patient outcomes have improved. Most AML patients in complete remission now can undergo allogeneic HCT procedures with an anticipated result that approaches that obtained with sibling donors and myeloablative conditioning (MAC). Treatment related mortality (TRM), relapse, GVHD and, for umbilical cord blood (UCB) grafts, slow engraftment/engraftment failures, however, continue to plague HCT. Newer strategies include the use of double unit UCB HCT and ex vivo expansion of UCB units using: multipotent mesenchymal stromal cells (MSCs); polyamine copper chelator tetraethylenepentamine (TEPA); and Notch ligand. Haploidentical bone marrow and blood HCT are increasing in numbers given the improved outcome with post-HCT cyclophosphamide therapy. Novel chemotherapeutic preparative regimens incorporating agents such as clofarabine and treosulfan, and novel radiation preparative regimens utilizing selective radiation approaches (helical tomotherapy) and targeted myeloablative radioimmunotherapy appear to enhance the anti-AML effect. Immunological approaches with chimeric antigen receptor redirected T lymphocytes have been added to the armamentarium. Other novel maneuvers include more sophisticated T-cell depletion of the donor graft and post transplant immunotherapy with regulatory T cell (Treg) therapy and MSCs for GVHD prevention. These and other strategies are improving the outlook of AML HCT recipients. PMID- 22507779 TI - Monoclonal antibodies in adult acute lymphoblastic leukemia. AB - Monoclonal antibodies targeting surface markers in acute lymphocytic leukemia (CD19, CD20 and CD22) are showing promising results and are reviewed. PMID- 22507780 TI - Breakthroughs in myeloproliferative neoplasms. AB - The discovery of the JAK2V617F mutation ushered the field of Philadelphia negative myeloproliferative neoplasms (MPNs) into the era of targeted therapy. Currently, there are several JAK2 inhibitors in clinical trials for patients with MPNs, particularly for patients with myelofibrosis (MF). These drugs act by blocking the proliferation of neoplastic cells by disrupting the JAK2-STAT signaling and by abrogating inflammatory cytokine signaling which is dependent on JAK kinases. Therapy with JAK2 inhibitors can improve splenomegaly and debilitating constitutional symptoms in great majority of MF patients, improving greatly their quality of life. Long-term follow-up will reveal whether these drugs can also prolong survival by better controlling signs and symptoms of the MF. There are other compounds in clinical trials for MPNs, including the new immunomodulatory drug pomalidomide, and inhibitor of mammalian target of Rapamycin everolimus. In this article, we briefly review the latest therapeutic advances in the field of Philadelphia-negative MPNs. PMID- 22507781 TI - Molecular targeted therapy in acute myeloid leukemia. AB - The treatment of acute myeloid leukemia has not changed significantly over the last 40 years. Recent progress in understanding the biology of this disease and identification of driver mutations has ushered in a new era of molecular therapeutics. Although a number of molecular markers and pathways have been identified and may serve as potential therapeutic targets, the best studied amongst these include FMS like tyrosine kinase 3 (FLT3), RAS/RAF/MEK/ERK and Janus kinase (JAK-2). In this review we discuss the molecular biology of AML, with a special focus on the above mentioned pathways. We discuss novel molecular targeted therapies that are in preclinical and clinical development. These include AC-220, sorafenib and midostaurin in FLT3 mutated patients; GSK1120212 and MSC1936369B in RAS mutated patients; and INCB018424 in JAK2 mutated patients. Identification of such molecular mutations and appropriate use of targeted therapies, either alone or in combinations, may eventually revolutionize the treatment of AML. PMID- 22507782 TI - Minimal disease detection of B-cell lymphoproliferative disorders by flow cytometry: multidimensional cluster analysis. AB - Flow cytometric analysis of cell suspensions involves the sequential 'registration' of intrinsic and extrinsic parameters of thousands of cells in list mode files. Thus, it is almost irresistible to describe phenomena in numerical terms or by 'ratios' that have the appearance of 'accuracy' due to the presence of numbers obtained from thousands of cells. The concepts involved in the detection and characterization of B cell lymphoproliferative processes are revisited in this paper by identifying parameters that, when analyzed appropriately, are both necessary and sufficient. The neoplastic process (cluster) can be visualized easily because the parameters that distinguish it form a cluster in multidimensional space that is unique and distinguishable from neighboring clusters that are not of diagnostic interest but serve to provide a background. For B cell neoplasia it is operationally necessary to identify the multidimensional space occupied by a cluster whose kappa:lambda ratio is 100:0 or 0:100. Thus, the concept of kappa:lambda ratio is without meaning and would not detect B cell neoplasia in an unacceptably high number of cases. PMID- 22507783 TI - Molecular biology strategies to detect residual disease. AB - The prognostic significance of minimal residual disease (MRD) has been demonstrated for a variety of hematologic malignancies. PCR based assays are among the most important methods for identifying MRD. They are aimed at detecting genetic abnormalities of residual leukemic cells with high specificity and sensitivity and represent an important diagnostic tool to assess the quality of therapeutic response, for clinical risk assessment, and for clinical management. In the present review technical aspects of different MRD detection methods are discussed which depend on the available targets regularly present in the respective leukemia type and subtype. As such fusion transcripts, gene mutations, and clonal rearrangements of antigen-receptor genes may be available for detection. Emphasis is given on discussing benefits and limitations of MRD detection and quantification in CML, AML and ALL. PMID- 22507784 TI - Donor cell leukemia. AB - Minimal residual disease refers to the tumour cells that are still present in a given patient after completion of a therapeutic scheme. The demonstration and quantification of residual neoplastic cells has a crucial impact in clinical decision making, for it might prompt continuation of treatment, while the absence of such cells might serve as evidence to withdraw therapy. Therefore, both sensitivity and specificity of the methods used to unravel residual neoplastic cells must be highly reliable and robust. Flow cytometry has been widely used for this purpose, and its clinical performance depends mainly on the criteria of interpretation, rather than in the technique by itself; molecular biology techniques have proved to be highly sensitive and specific but unfortunately they cannot be used in all patients or in all types of leukemia. Finally, the development of donor cell leukemia in transplanted patients, might mimic residual disease and add more confusion to an already controversial issue. These topics are discussed in this paper. PMID- 22507785 TI - CML treatment in Asia-Pacific region. AB - CML in Asia seems to affect the younger age group and more patients are in the high and intermediate Sokal risk group. Cytogenetic study and molecular testing are done mostly at diagnosis, but monitoring the response is limited due to the cost and accessibility. The treatment of chronic phase CML has changed dramatically within the last decade and imatinib has become the standard treatment for CP, CML. Since the cost of imatinib is quite high, most Asian patients cannot afford it. Patients in several countries get imatinib through Glivec International Patient Assistant Program. Patients who are intolerant or resistant to imatinib usually get the second generation tyrosine kinase inhibitors (TKIs), either nilotinib or dasatinib. The National Health Insurance covers all or most of the cost of imatinib in South Korea, Hong Kong and Taiwan. Both nilotinib and dasatinib are partially or fully covered by national insurance in Australia, Japan, Singapore and Taiwan as the second-line therapy. TKIs treatment remains out of reach for many Asian CML patients, especially those in the rural areas and those who are not eligible for patient access programs or covered by the national insurance. The cytogenetic response to imatinib in Asian CML patients varies considerably, from as low as 24% to as high as 96%. The Asia CML Study Alliance was briefly presented. PMID- 22507786 TI - Chronic myeloid leukaemia in South Africa. AB - Despite the challenges of a resource-limited environment, the outcome of chronic myeloid leukaemia (CML) patients in South Africa is similar to that in developed countries, thanks to access to tyrosine kinase inhibitors through patient assistance programmes and clinical trials. A number of challenges are faced in terms of reimbursement of drugs, simultaneous co-infection with human immunodeficiency virus, access to allogeneic stem cell transplantation and, until recently, a lack of local recommendations appropriate for our setting. It is hoped that the newly published recommendations for the management of CML in South Africa will close many of the gaps in knowledge and practice and thus translate into better patient outcomes. Epidemiological data are limited and there is a need for more collaborative studies locally to elucidate issues such as incidence, prevalence and response to treatment. The challenges experienced in the management of CML and other cancers in the developing world are often economical and political in nature and require a comprehensive approach by clinicians, pathologists, health economists, medical insurers and policy makers if we are to find sustainable solutions. PMID- 22507787 TI - Hematopoietic cell transplantation for chronic myeloid leukemia in developing countries: perspectives from Latin America in the post-tyrosine kinase inhibitor era. AB - Tyrosine kinase inhibitors (TKIs) are currently the first line treatment for chronic myelogenous leukemia (CML) in countries with high and intermediate-high gross national income. Hematopoietic cell transplantation (HCT) in these countries is considered salvage therapy for eligible patients who failed TKI or progress to advanced disease stages. In Latin America, treatment for CML also changed with availability of TKI in the region. However, many challenges remain, as the cost of this class of medication and recommended monitoring is high. CML treatment practices in Latin America demonstrate that the majority of patients are treated with TKI at some point after diagnosis, most commonly imatinib mesylate, but still TKI can only be used after interferon failure in some countries. Other treatment practices are different from established international guidelines, outlying the importance of continuing medical education. Allogeneic HCT is a treatment option for CML in this region and could be considered a cost effective approach in a small subset of young patients with available donors, as the overall cost of long-term non-transplant treatment may surpass the cost of transplantation. However, there are many challenges with HCT in Latin America such as access to experienced transplant centers, donor availability, and cost of essential drugs used after transplant, which further impacts expansion of this treatment approach in patients in need. In conclusion, Latin American patients with CML have access to state of the art CML treatment. Yet, drug costs have a tremendous impact on developing health systems. Optimization of CML treatment in the region with appropriate monitoring, recognizing patients who would be transplant candidates, and expanding access to transplantation for eligible patients may curtail these costs and further improve patient care. PMID- 22507788 TI - Viral lymphomas: can antivirals be used to treat cancer? AB - Current knowledge suggests that EBV, KSHV and HTLV-1 contribute to lymphomagenesis by subverting the host-cell molecular signaling machinery to deregulate cell growth and survival. Some signaling pathways that are affected by these viruses are well characterized, such as the NF-kB pathway, which is activated by these three viruses to promote cellular survival by inhibiting apoptosis, thereby playing a critical role in tumorigenesis. Other pathways, such as MTOR and JAK-STAT are also likely involved in viral lymphomagenesis. This provides the opportunity to inhibit these cellular pathways using drugs developed for the treatment of other malignancies. However, since these compounds target cellular proteins, they always have the potential for toxicity. In the context of viral malignancies, we have the unique opportunity of targeting viral proteins, and developing completely specific therapies. Here we will examine the question of whether the pathobiology of EBV, KSHV and HTLV-1 will allow the use of such an approach. PMID- 22507789 TI - Lymphomas and leukemias due to infectious organisms. AB - World-wide, approximately 25% of all human malignancies are caused by infectious organisms, including approximately 10% of cancers occurring in resource rich areas of the world. While some of these disorders are more likely to be seen in patients with underlying immunodeficiency, this is not a requisite for development of malignancy, and most patients, in fact, are not immune-suppressed at the time of diagnosis. In considering hematologic malignancies, several organisms have been implicated in disease etiology. These organisms include Human Herpesvirus 8 (HHV8/KSHV), which is linked to primary effusion lymphoma and to multicentric Castleman s disease, as well as to development of Kaposi's sarcoma; Epstein Barr Virus (EBV) which has been associated with Burkitt lymphoma and nasal T cell lymphoma, among others; Human T lymphotrophic virus type I (HTLV 1), which is associated with Adult T cell leukemia/lymphoma (ATLL); Hepatitis C virus, associated with splenic marginal and other lymphomas; and Helicobacter pylori, associated with gastric MALT lymphoma. The presentation will focus on the latter three disorders, describing pathogenesis of disease, clinical manifestations and therapeutic options. PMID- 22507790 TI - Metronomic therapy for refractory/relapsed lymphoma: the PEP-C low-dose oral combination chemotherapy regimen. AB - BACKGROUND: Metronomic therapy is the application of continuous, low dose chemotherapy. The doses of chemotherapy are usually not sufficient to destroy neoplastic cells, but impact the milieu, particularly angiogenesis. OBJECTIVE: To determine if the oral PEP-C regimen, consisting of prednisone 20 mgm, etoposide 50 mgm, procarbazine 50 mgm, and cyclophosphamide 50 mgm given in either a daily, alternate day, or fractionated basis, is effective in a variety of lymphomas. METHODS: One hundred twenty two patients were studied although the majority had low grade or mantle cell lymphoma. All had received at least two or more prior therapies. RESULTS: Overall, 75% achieved an objective response (OR) with 38% complete responses (CRs) or CRs unconfirmed, and 37% partial responses. ORs were achieved in mantle cell (85%), follicular (88%), marginal zone (71%), and small lymphocytic (67%) lymphomas. Chemosensitive disease was more responsive. Toxicity was minimal. CONCLUSION: The PEP-C regimen is an easily administered highly effective treatment for heavily pretreated mantle cell and low grade lymphomas. PMID- 22507791 TI - New developments in the management of diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma is the most common adult non-Hodgkin lymphoma and is potentially curable. Immunochemotherapy, R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone) is the standard of care. This regimen has been incorporated in other approaches and reevaluated in different trials in different age groups. The duration of cycle therapy has varied from 14 to 21 days. In addition, R-ACVBP has been evaluated in randomized trials. Autologous stem cell transplantation (ASCT) has been evaluated in randomized clinical trials. Ongoing studies are evaluating new regimens such as EPOCH-R and novel maintenance therapy approaches in the upfront management of DLBCL. In the relapse and refractory setting, autologous stem cell transplantation remains the standard of care with treatment with R-ICE or R-DHAP followed by different conditioning regimens prior to ASCT. The outcomes of patients who relapse following ASCT are improving with the treatment of new agents targeting different pathways such as lenalidomide. New monoclonal antibodies are under evaluation. The Bruton s tyrosine kinase inhibitor is in early stages of development. Targeted therapy has changed the natural history of diffuse large B-cell lymphoma. Past microarray and new DLBCL hypersequencing data are revealing new pathways and targets to further explore therapeutically. This review will describe the contribution of immunochemotherapy and other interventions in diffuse large B-cell lymphoma evaluating past clinical trials, review early clinical trial observations, and discuss current future directions. PMID- 22507792 TI - New developments in the field of diffuse large cell lymphoma. AB - This update will focus on new developments which can impact the understanding and management of patients with DLCL. The latter disorder is mostly derived from B lymphocytes which can be further subdivided into those that originate from the germinal center versus those that arise from non-germinal center areas in the lymph node. The differences between these two types will be discussed. The management of several new entities that relate to DLCL such as 'double hit lymphoma' and so called borderline entities will also be featured. New entities such as breast implant associated anaplastic large cell lymphoma will be described. PMID- 22507793 TI - Frontline treatment of multiple myeloma. AB - The treatment of myeloma has been revolutionized by the availability of new drugs. Combination therapy followed by stem cell transplant holds the promise of ultimately curing a fraction of patients. Objective responses are the norm for induction therapy and up to 50% of patients achieve a complete remission. Ongoing clinical trials continue to address the role of long term maintenance therapy. Understanding the proper management of these agents is paramount to providing patients disease control and yet minimizing side effects from treatment. PMID- 22507794 TI - Novel therapeutics in multiple myeloma. AB - Most myeloma patients still experience recurrent relapse and eventually become resistant and/or intolerant of effective agents such as corticosteroids, alkylating agents, immune modulators (lenalidomide and thalidomide) or proteasome inhibitors such as bortezomib. Once this happens average survivals are less than one year. Progress has been made for such patients, however, with the demonstration of clinical benefit of novel proteasome inhibitors (carfilzomib) and immune modulators (pomalidomide). Pomalidomide when used with dexamethasone has activity in 30-60% of patients depending on disease stage. Carfilzomib is an irreversible proteasome inhibitor with favorable toxicity profile (minimal neuropathy) and response rates of 17-54% depending on the disease stage treated. Novel targets are also being explored. Histone deacetylase inhibitors such as vorinostat and panobinostat are in phase II testing although results from a randomized trial combining vorinostat with bortezomib were disappointing. Other small molecules or monoclonal antibodies with novel targets such as kinase inhibitors(AKT, CDK5) and cell surface receptors (e.g. elotuzumab) are undergoing active investigation. PMID- 22507795 TI - Myeloma: diagnosis complications and supportive care. AB - A key approach to current treatment is the rapid reduction of the myeloma clone to minimal disease levels. This approach has significantly improved outcomes but it remains critical to manage the side effects of the disease and of treatment emergent side effects. While these supportive care options are directed towards improving patient quality of life, they also have significant effect against the disease and can improve survival. PMID- 22507796 TI - Waldenstrom macroglobulinemia. AB - Waldenstrom macroglobulinemia is a lymphoplasmacytic lymphoma. A serum monoclonal IgM protein is required to establish this diagnosis. The clinical features patients develop include normochromic normocytic anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy and signs of hyperviscosity. The International Staging System for Waldenstrom macroglobulinemia divides patients prognostically based on age, hemoglobin, platelet count, IgM level, and beta2 microglobulin. Some patients with Waldenstrom macroglobulinemia have a smoldering form and can be observed without intervention. Active agents in the treatment of Waldenstrom macroglobulinemia include rituximab, chlorambucil, cyclophosphamide, fludarabine, bortezomib, lenalidomide, bendamustine, everolimus, and alemtuzumab. The current preferred Mayo Clinic non-study treatment is rituximab, cyclophosphamide, and dexamethasone. The median survival associated with this disease is now over 10 years. PMID- 22507797 TI - Stem cell transplantation for multiple myeloma: current and future status. AB - High-dose melphalan with autologous stem cell support has been an integral part of myeloma therapy for more than 25 years either as salvage therapy or as consolidation of an initial remission. Although multiple phase III trials have demonstrated that this therapy results in higher response rates and longer remission duration than conventional chemotherapy the use of thalidomide, lenalidomide and bortezomib as induction therapy have limited the clinical relevance of these trials. In this manuscript, we will summarize the results of ongoing and recently published clinical trials and describe how they have impacted current transplant recommendations, and their relevance to the treatment of myeloma patients in developing countries. PMID- 22507799 TI - Targeted therapy of multiple myeloma. AB - The diagnosis of multiple myeloma requires the presence of monoclonal bone marrow plasma cells, a monoclonal (M) protein in serum and/or urine and evidence of end organ damage from the plasma cell proliferative disorder. Initial therapy for transplant-eligible patients includes thalidomide, bortezomib or lenalidomide, all with dexamethasone. Stem cells for a possible autologous stem cell transplant (ASCT) should be collected if the patient is considered eligible for an ASCT. Initial therapy for patients ineligible for an autologous stem cell transplant includes melphalan and prednisone as well as thalidomide, bortezomib or lenalidomide. More than 100 agents are in phase I, II or III clinical trials. The most promising are carfilzomib and pomalidomide. PMID- 22507798 TI - Novel therapies in monoclonal gammopathies. AB - Multiple myeloma (MM) is a plasma cell malignancy with an incidence of approximately 20 000 cases per year. Over the past decade, the advent of novel therapies has resulted in a positive shift in survival for patients with advanced MM. Over the last decade progress has been made in the understanding of the mechanisms involved in myeloma cell proliferation, trafficking and survival. Through this understanding, molecular therapeutic targets have been identified and treatment programs which incorporate these concepts are beginning to appear. The current review does not intend to be a comprehensive compendium of available treatments rather to highlight the most exciting avenues of research in myeloma therapeutics. Novel immunomodulating drugs, proteasome inhibitors and monoclonal antibodies will be highlighted. PMID- 22507800 TI - JAK2 inhibitors and their impact in myeloproliferative neoplasms. AB - The BCR-ABL-negative myeloproliferative neoplasms (MPNs) include essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Historically, complex biochemical alterations defining these heterogeneously distinct malignancies have remained elusive and constrained available therapy options. The discovery of Janus kinase (JAK) mutations collectively present in BCR-ABL negative MPNs has led to a resurgence of medical interest in JAK-STAT targeted treatment modalities, as well as provided a unique platform for inhibiting symptom-directing proinflammatory cytokines. INCB018424, CYT387, SB1518, and TG101348 are among the most propitious JAK2 inhibitors under investigation, providing substantial improvement in constitutional symptoms, transfusion dependent cytopenias, and reduction in spleen size. Despite their attributes, evidence of complete or partial remission has yet to be observed with therapy. Many uncertainties surrounding the full clinical potential of JAK2 inhibitors persist. Treatment guidelines addressing optimal stages for drug implementation, ideal dosing parameters and criteria for medication continuation/withdrawal may effectively resolve these ongoing concerns and provide advancements in the morbidity and mortality of these multifaceted disease processes. PMID- 22507801 TI - Improving treatment for patients with chronic lymphocytic leukemia. AB - The last two decades have been time of tremendous progress in treatment for patients with chronic lymphocytic lymphoma (CLL). Chemoimmunotherapy (CIT) combining anti-CD20 monoclonal antibodies with purine nucleoside analogs has been a substantial advance for patients with CLL and results in increased response rates, progression-free survival, and overall survival. Despite these improved outcomes, only ~ 45% of patients achieve a complete remission with CIT and nearly all patients eventually relapse and their remains a need to improve efficacy. Although new combinations of traditional agents may lead to incremental progress, more substantive improvements are likely to result through therapeutic targeting of novel pathways critical to CLL B-cell survival including targeting: (1) leukemia cell apoptotic resistance; (2) survival signals mediated through the B cell receptor; and (3) nurturing interactions with the microenvironment. In this mini-review, we summarize Mayo Clinic's recent efforts to improve CIT for patients with CLL. PMID- 22507802 TI - Targeted therapy of acute myeloid leukemia in 2012: towards individualized therapy. AB - Advances in molecular diagnostics in acute myeloid leukemia (AML) have translated into significant advances in our understanding of disease prognosis and biology, and the identification of new targets for therapy. The best described of these are mutations in Fms-like tyrosine kinase 3, nucleophosmin 1, and CCAAT enhancer binding protein-alpha in those with cytogenetically AML, which allow more accurate risk stratification and help better 'target' patients who may benefit from allogeneic transplantation (specifically those with activating FLT3 mutation). Among the new targets identified for clinical trials are FLT3 mutation (a target for tyrosine kinase inhibitors), CD33 expression (a target of monoclonal antibodies and immunotoxins), aberrant methylation (target of hypomethylating agents), and overexpression of the chemokine receptor CXCR4 (a target for inhibition by small molecule or monoclonal antibody). We are advancing towards an era of personalized medicine in AML, and can now better identify specific patients who may benefit from specific therapies with less toxicity. PMID- 22507803 TI - Comprehensive care in hemophilia. AB - Hemophilia is a chronic and inherited X-linked bleeding disorder that requires life-long medical care. Hemophilia treatment is costly and complex partly because of the cost of the factor concentrates used in replacement therapy. However, the management of hemophilia is not based solely on achieving access to better treatment with safe factor concentrates; it also includes accurately diagnosing the disorder and providing specialized comprehensive care by a multidisciplinary team of specialists trained in hemophilia management. Comprehensive care for the person with hemophilia is defined as the continuous supervision of all medical and psychological aspects affecting the patient and his family and it demands the establishment of specialized centers, called Hemophilia Treatment Centers. The services that should be offered by a comprehensive hemophilia healthcare center are diverse and the multidisciplinary team should be coordinated preferably by a hematologist with the participation of other health professionals. It has been demonstrated that the benefits of establishing hemophilia centers are observed even in developing countries and that changes can be achieved when resources are re-organized, especially when education and training are provided at all levels. To reach these objectives, it is essential to have the participation of the patient and family members, and to strive to obtain the financial and legislative support from the State or Government in order to achieve a national comprehensive care program contemplating all the aspects needed for improving the quality of life for the community of patients with hemophilia and other bleeding disorders. PMID- 22507805 TI - Ensuring maximum outcomes and benefits in comprehensive care for bleeding disorders through surveillance and data collection. AB - OBJECTIVES: In order to maximize the impact and outcome of comprehensive care, it is important to track the identification of people with bleeding disorders and to evaluate their health outcomes over a long-term period. METHODS: Establishment of a comprehensive care program for the care of patients with bleeding disorders is an essential feature of national health systems desiring to achieve the best health outcomes for their patients. Implementation of a surveillance system in conjunction with a comprehensive care program allows assessments to be made on data, with regards to optimizing resources and outcomes for the patients. RESULTS: This data provides governments with answers about the bleeding disorders population, and indicates what the trends are, what the best practices are and what interventions may be required. DISCUSSION: The challenges of answering government and payer demands for evidence-based medicine and cost justification for the introduction and enhancement of treatment and care are ever-present and growing. To sustain and continue the expansion of access to care globally it is critical to build the body of outcome data for individual patients, within HTCs, nationally, regionally and globally. Doing so will not only improve clinical practices and support the allocation of scare resources, but most importantly, the well-being of patients will improve as well. PMID- 22507804 TI - Public health surveillance and data collection: general principles and impact on hemophilia care. AB - Public health surveillance is the ongoing collection, analysis, and dissemination of health related data to provide information that can be used to monitor and improve the health of populations. Such surveillance systems can be established in many settings to study a variety of populations and conditions. The most effective systems are designed around specific, well-defined objectives, collect data in a standardized fashion, analyze the data frequently, and disseminate the results to those who need to know the information. Surveillance has been used to determine the occurrence rates of hemophilia and to characterize the population affected by this rare but potentially serious congenital disorder. Data from surveillance systems have been used to identify risk factors for complications that, once identified, have been modified through public health interventions. The effectiveness of these interventions can be assessed by continued surveillance, thereby assuring improvement in care of people affected by hemophilia around the world. PMID- 22507806 TI - Von Willebrand factor (VWF) as a risk factor for bleeding and thrombosis. AB - The von Willebrand factor (VWF) is analysed as a bleeding and thrombotic risk marker. When the VWF level is increased, it predicts a thrombotic phenotype and when VWF level is low in plasma, the phenotype varies to bleeding disorder. But it is quite challenging to define when the level is low, normal or high taking into account that these values are capricious and overlap. This matter should be solved by extensive epidemiologic studies. VWD is a hereditary disorder with several described mutations. VWF is a major acute-phase reactant, besides the physiological conditions such as blood group and pregnancy that affect plasmatic VWF levels. Subjects with O blood group have 25% less VWF than those of non O blood groups, and the latter show higher thrombus burden. VWF would be sensitive though not specific diagnostic marker of myocardial infarction. For the assessment of bleeding severity there are special surveys, scores and pictorial charts. The identification of VWF as a thrombotic risk marker has not been clearly established yet, but it has been involved in stroke and coronary disease. We only have the specific replacement therapy for the bleeding phenotype and we can speculate that enoxaparin and PEG-hirudin are able to blunt the VWF rise in patients with unstable angina pectoris and it is associated with a more favourable clinical outcome. Only two questions remain: does VWF as a bleeding risk marker have the same value as a thrombotic risk marker? Will successful treatments like those achieved for bleeding be also possible in the future for thrombosis? PMID- 22507807 TI - Bleeding in the antiphospholipid syndrome. AB - Antiphospholipid syndrome (APS) is an autoimmune disease characterized clinically by the occurrence of venous or arterial thrombosis, and/or pregnancy morbidity. The detection of persistently elevated levels of antiphospholipid antibodies (aPL) is a requisite laboratory feature for the diagnosis of APS. The positivity for at least one aPL test: lupus anticoagulant and/or IgG/IgM anticardiolipin and/ or IgG/IgM anti-beta2 glycoprotein I antibodies must be detected. Sometimes aPL coagulopathy may start with a hemorrhagic syndrome when a severe thrombocytopenia, or an acquired thrombocytopathy, or an acquired factor VIII inhibitor, or an acquired prothrombin deficiency is present. aPL-associated thrombocytopenia is usually moderate without clinical manifestations. Except in the occasional situations in which thrombocytopenia is associated with thrombotic microangiopathy, such as catastrophic APS, bleeding is uncommon in APS patients. When platelet counts are less than 30 * 109/L and there are symptoms of bleeding, the treatments used are the same for idiopathic thrombocytopenic purpura. In rare occasions a hemorrhagic diathesis due to the occurrence of non-neutralizing anti prothrombin antibodies causing severe hypoprothrombinemia (HPT) can be observed. Levels of prothrombin in plasma are less than 10-20% in cases with HPT-related bleeding requiring transfusion and/or corticosteroid treatment. The APS mainly causes thrombosis, and pregnancy losses. However, other clinical manifestations are also associated with the presence of persistent autoimmune aPL. Bleeding is uncommon but can be the first clinical manifestation in patients having severe thrombocytopenia or prothrombin deficiency. PMID- 22507808 TI - Thrombosis in rare bleeding disorders. AB - Inherited deficiencies of blood coagulation factors are usually associated with lifelong bleeding tendency. In addition to Haemophilias A and B and von Willebrand disease, congenital deficiencies of such factors as fibrinogen, prothrombin (FII)), FV, FVII, FX, FXI, FXIII, and combined deficiencies occur and can lead to a diversity of clinical conditions. Paradoxically, for some of these disorders associated with significant bleeding tendency there are reports of thrombotic events, both arterial and venous. Thrombosis in hemophilia patients has a multifactorial pathogenesis and the main conditions associated with this complication are the use of long-term central venous catheters, intensive replacement therapy usually in the setting of surgical procedures, the use of bypassing agents or the coexistence of acquired or inherited prothrombotic risk factors. Regarding other rare bleeding disorders, thrombotic phenomena has been described particularly in patients with afibrinogenemia, FXI and FVII deficiency and the events can occur even in young patients, in the presence of concomitant risk factors or spontaneously. Replacement therapy must be individualized and should take into account past history of haemostatic challenges, family history of bleeding and thrombosis, just like the level of factor. For mild deficiencies when patients are asymptomatic the use of antithrombotic prophylaxis must be considered with or without concomitant use of replacement therapy. In patients with history of thrombosis it may be helpful to perform a thrombophilia screening to exclude coexisting prothrombotic defects and for all patients it is recommended to control known cardiovascular disease risk factors. PMID- 22507809 TI - Thrombosis in stem cell transplantation. AB - Hemostatic changes and thrombotic events are frequent in patients undergoing stem cell transplantation. Arterial and venous thromboses are major causes of morbidity and mortality. Thrombotic complications can be classified into four groups including: catheter-related thrombosis, venous thromboembolic (VTE) events, sinusoidal obstructive syndrome (SOS)/veno-occlusive disease, and transplant-associated thrombotic microangiopathy (TAM). The incidence of catheter related thrombosis is 8-20% in patients undergoing autologous hematopoietic stem cell transplantation (HSCT), and the incidence is low in syngeneic and allogeneic transplant patients. Venous duplex Doppler ultrasound, venogram, and computed tomography scan are required to visualize the venous thrombus. The treatment should be aimed at the prevention of pulmonary embolism, the avoidance of thrombus extension, and the preservation of catheter patency. Patients undergoing HSCT may have risk factors for VTE including underlying malignancy, traumatic brain injury, prolonged hospitalization, administration of conditioning regimens, and central venous catheters. Important risk factors are presence of history of VTE and graft-versus-host disease. One-year incidence of symptomatic VTE is 3.7%. SOS, also known as veno-occlusive disease, is a serious liver disease, seen in approximately 50-60% of HSCT patients. The mortality rate from the severe form of SOS is 84.3% and majority of the patients have multi-organ failure. The frequency is quite low after autologous transplantation. Risk factors for SOS include pre existing hepatic damage, previous high-dose chemotherapy and abdominal irradiation, female gender and donor-recipient human leukocyte antigen disparity. Cyclophosphamide and busulphan are the most common agents with the highest incidence and fatal SOS. Histopathologic features of SOS include dilatation of sinusoids, necrosis of perivenular hepatocytes, and obstruction of small intrahepatic central venules by microthrombi and fibrin deposition. Signs of SOS usually occur within first 30 days after HSCT including hyperbilirubinemia, hepatomegaly, ascites, and weight gain. Symptoms of liver failure, including encephalopathy, coagulopathy, and renal failure will appear in severe form. A hepatic venous pressure gradient above 10 mmHg is highly specific for SOS. Early use of defibrotide has been shown to be effective in the treatment of high-risk SOS. TAM is a distinct, infrequent, and significant life-threatening complication of HSCT. TAM is seen in the range of 0.5-76% and was reported to be 10-25% in patients undergoing allogeneic HSCT with a mortality rate around 50%. It can also be seen after autologous HSCT and mainly affects the glomerular capillaries. There has been no standard therapy for TAM. Few case series reported good response to rituximab and high-dose corticosteroids were used with limited success. Trials with complement inhibitors such as eculizumab are currently underway. PMID- 22507810 TI - Inherited thrombophilic conditions. AB - Since 1965, when antithrombin deficiency was identified as the first congenital defect of hemostasis able to increase the risk of thrombosis, we have assisted in a substantial evolution of thrombophilia. From the original monogenic view, it has been demonstrated that thrombosis is a polygenic and complex disorder that involves potentially hundreds of polymorphisms and rare mutations, as well as multiple acquired and triggering factors. From the enthusiasm of searching prothrombotic polymorphisms that might contribute to the risk of each individual to have a thrombotic episode, to the frustration of considering that thrombophilic tests might have no clinical relevance. Also the methods used in thrombophilic analysis have significantly changed from original simple analysis to recent and complex technological approaches. It is time to analyze carefully, without any pressure, the real state of the art and to moderate the conclusions, separating clinical use and research of inherited thrombophilic conditions. PMID- 22507811 TI - Thrombopoietin: too much or too little. AB - The basis of treatment for immune thrombocytopenia (ITP) has conventionally relied on non-specific immune suppression designed to reduce platelet destruction. As a consequence, at least half of the morbidity and mortality in the condition is related to infection secondary to treatment and alternate treatments are desirable. It has been shown that ITP is not purely due platelet destruction and in a significant proportion platelet production is suboptimal. Further interest developed with the discovery that the recombinant thrombopoietins (TPOs) could enhance platelet production in a variety of thrombocytopenic states. With the development of the second generation of TPOs that had no sequence homology to endogenous TPO, studies confirmed clinical effect. Two agents, romiplostim and eltrombopag, are now licensed and their place in the treatment is being evaluated. Platelet responses are seen in a much greater percentage than in other second-line studies, and these are maintained while the drugs continue to be administered. Both are well tolerated with no significant adverse effects over placebo and have an effect both pre- and post splenectomy. An interesting initial observation has been that the platelet response is associated with an improved quality of life in many patients when compared with conventional management. Clinical trials are also being conducted in patients with thrombocytopenia relating to liver disease, HCV infection, myelodysplasia, and post-chemotherapy. PMID- 22507812 TI - Thrombosis and acute leukemia. AB - Thrombosis is a common complication in patients with acute leukemia. While the presence of central venous lines, concomitant steroids, the use of Escherichia coli asparaginase and hereditary thrombophilic abnormalities are known risk factors for thrombosis in children, information on the pathogenesis, risk factors, and clinical outcome of thrombosis in adult patients with acute lymphoid leukemia (ALL) or acute myeloid leukemia (AML) is still scarce. Expert consensus and guidelines regarding leukemia-specific risk factors, thrombosis prevention, and treatment strategies, as well as optimal type of central venous catheter in acute leukemia patients are required. It is likely that each subtype of acute leukemia represents a different setting for the development of thrombosis and the risk of bleeding. This is perhaps due to a combination of different disease specific pathogenic mechanisms of thrombosis, including the type of chemotherapy protocol chosen, the underlying patients health, associated risk factors, as well as the biology of the disease itself. The risk of thrombosis may also vary according to ethnicity and prevalence of hereditary risk factors for thrombosis; thus, it is advisable for Latin American, Asian, and African countries to report on their specific patient population. PMID- 22507813 TI - Thrombosis in myeloproliferative and myelodysplastic syndromes. AB - Myeloproliferative neoplasms (MPNs) and myelodisplastic syndromes (MDs) are clonal disorders caused by mutations of myeloid stem cells. Among MPNs, polycythemia vera and essential thrombocythemia are relatively benign disorders in which arterial and venous thromboses represent the main cause of morbidity and mortality. The natural history of MDs is often complicated by both thromboses and haemorrhages, mainly due to platelet quantitative and quantitative anomalies, as well as to treatment complications. In this short review, we focus the attention on the main aspects of thrombophilia in both disorders. PMID- 22507815 TI - In vitro biology of human hematopoietic stem and progenitor cells. AB - Hematopoietic stem and progenitor cells from human umbilical cord blood have been the focus of both basic and clinical research during the last 20 years. It has been clearly demonstrated that such sells possess higher proliferation and expansion potentials, as compared to their adult counterparts, and their capacity to reconstitute the hematopoietic system of mammals has also been shown. Different In vitro systems have been used to characterize the biology of these hematopoietic cells and some culture methods are being currently used to expand the numbers of such cells for clinical purposes. PMID- 22507814 TI - Thrombosis in multiple myeloma (MM). AB - Thrombosis is a frequent feature in individuals with myeloma, particularly those treated with oral immunomodulatory drugs (IMID) such as thalidomide or lenalidomide concomitantly with anthracyclines or dexamethasone. Up to a third of these individuals may develop venous thrombosis if not given the benefit of prophylaxis. Interestingly, in contrast to individuals with solid tumors in whom thrombosis is a marker of poor prognosis, thrombosis does not impact overall survival in patients with myeloma. This finding suggests that the mechanisms of thrombosis in hematological neoplasms may differ from solid epithelial tumors and that thrombosis in the former may be driven by therapy and not by a procoagulant phenotype of the neoplastic plasma cells. This may also explain why thrombosis in the context of IMID-based therapy may be prevented by the use of prophylactic aspirin. In this text, we review the pathogenesis of thrombosis in myeloma, its relation to different chemotherapeutic regimens and the use of thrombo-prophylaxis. PMID- 22507816 TI - Cord blood banking: current status. AB - OBJECTIVES: Cord blood is increasingly used as a hematopoietic progenitor cell source for bone marrow transplantation. METHODS: Development of cord blood banks for altruistic use was essential to open the possibility of opting for cord blood therapy for patients lacking a conventional donor. RESULTS: Cord blood has major advantages as a resource for donor provision. First, it universalizes the access to the therapy since it allows transplantation of partially matched HLA grafts, benefiting ethnicities less represented in the adult volunteer list. Second, it is an off-the-shelf, ready-to-use source that avoids donor risk and attrition. Third, potentially it has better long term sustainability if a defined optimal size of the inventory is achieved; currently, more than 80% of patients, regardless ethnicity, can find a reliable cord blood donor with the current worldwide inventory. CONCLUSION: In order that this approach may definitely solve the problem of an equitable access to the therapy, two aspects need to be improved: the quality of CB inventories (driven by a higher stringency of regulatory requirements), and clinical outcomes, particularly understanding the appropriate donor selection and focusing research on accelerating the speed of engraftment and immune reconstitution. PMID- 22507817 TI - Hematopoietic cell transplantation in Latin America. AB - The first bone marrow transplantation in Latin America was performed more than 30 years ago and since then several countries have started transplant programs. The Center for International Blood and Marrow Transplant Research captured information on 13,473 transplants performed in Latin America from 1981 to 2009. The current report summarizes this activity. Argentina, Mexico, and Brazil have the largest activity in the region. Despite increase in the annual number of transplants, the activity is limited to sibling donor and autologous transplants. Indications are similar to other regions with a proportionally higher number of pediatric transplants for treatment of non-malignant diseases. Unrelated donor transplant activity is also increasing through collaborations with international donor registries and the development of the first national donor registry in Brazil. Umbilical cord transplants were also reported in Latin American centers, mainly in Brazil and most commonly used for treatment of children with malignant diseases. In conclusion, hematopoietic cell transplantation is routinely performed in several centers in Latin America. However, the activity is low compared to the population in need. Challenges with costs of transplantation, donor availability, number of centers of excellence, and trained personnel need to be addressed for further development of this field in the region. Additionally, more integration between countries and transplant centers is an important next step and can assist in improving awareness for the field and maximizing the transplant activity in Latin America. PMID- 22507818 TI - Hematopoietic stem cell transplantation in Europe. Differences between Eastern and Western countries. AB - Hemopoietic stem cell transplantation (HSCT) is increasingly used worldwide. The geographical distribution of this procedure is not homogenous within a particular continent. We have previously reviewed these differences in the use of bone marrow transplant in Europe, and in two reports we emphasized the economical reasons explaining these differences. The increasing demand for this high cost procedure represents a challenge for health care institutions. While patients need an optimal therapy, public health is confronted with limited resources. Information on changes in HSCT technology and on factors associated with its utilization might be of help. Insights into mechanisms of HSCT use are essential for rational decision making. PMID- 22507819 TI - A Mexican way to cope with stem cell grafting. AB - The widespread practice of stem cell grafting faces several problems in the world, derived mainly from the high costs of the procedure when conducted using traditional methods. In order to cope with this problem, we have implemented in Mexico procedures to make stem cell grafting, both autologous and allogeneic, more affordable to patients living in our country and in other developing countries. The simplification of these procedures which have been done in our country are described; they have resulted in and increased number of patients both autografted and allografted in Mexico. In the case of autografts, the changes have relied on the use of non-frozen autologous peripheral blood stem cells and short conditioning schedules delivered as outpatients, whereas in the case of allografts, changes have relied mainly in conducting the allografts fully on an outpatient basis and employing reduced-intensity conditioning preparative schedules. PMID- 22507820 TI - Economic evaluation of hematopoietic stem cell transplantation. AB - Hematopoietic stem cell transplantation is a highly expensive clinical intervention with considerable therapeutic benefit but serious adverse effects on health status in some circumstances. Consequently, it is an important target for economic evaluation in which the monetary costs and clinical consequences of optional treatment strategies are compared. The need for such formal assessment is further demanded by the expanded use of hematopoietic stem cell transplantation globally, including its utilization in developing countries. With respect to costs, those incurred by patients and families are often substantial, while those incurred by hospitals may be inadequately reimbursed. Determination of consequences should not be limited to measurements of clinical effectiveness but rather include adjustments for quality of life. Rigorous economic evaluation can provide hard evidence in deliberations of value for money, especially in the context of limited resources for health care. PMID- 22507821 TI - The plurality of payers' perspectives on hematopoietic stem cell transplantation. AB - This review focuses on the economic considerations of pediatric hematopoietic stem cell transplantation from the perspective of the myriad stakeholders: patients and their families; institutions providing care; and employers/payers who are covering its costs. The article is organized by phase of transplant and by component of cost. In addition to referenced peer-reviewed literature, preliminary empirical data are also included with which to understand the cost implications. Areas of future research are identified. PMID- 22507822 TI - The cost of hematopoietic stem cell transplantation in the real world. AB - In Brazil, the majority of the population does not have private health insurance and the government provides universal health care. Our 'Unique Healthcare System' pays for 95% of the 1500 hematopoietic stem cell transplants (HSCT) performed in the country every year. Hospitals are reimbursed a flat rate, ranging from US$ 13,000 for autologous to US$ 40,500 for unrelated donor transplants, excluding expenses with donor search and acquisition of the graft. The actual cost of the procedure is not captured routinely. Because unrelated donor recipients may have many clinical complications, most HSCT centers offer few or no beds to perform such transplants. The Pediatric Oncology Institute - GRAACC - is a non-profit organization that provides comprehensive care at no cost to the families, including unrelated donor HSCT. We are evaluating retrospectively the unrelated donor transplant costs to have data to present to the health authorities, looking for an appropriate funding formula for HSCT. PMID- 22507823 TI - Enoxaparin sodium prevents intestinal microcirculatory dysfunction in endotoxemic rats. AB - INTRODUCTION: During severe sepsis or septic shock, activation of the inflammatory and coagulatory systems can result in microcirculatory dysfunction as well as microvascular thrombosis, culminating in multiple organ dysfunction and death. Enoxaparin can inhibit factor Xa and attenuate endothelial damage. The primary purpose of this study was to investigate the effect of enoxaparin on intestinal microcirculation in endotoxemic rats. METHODS: Thirty male Wistar rats were divided into the following three groups: sham operated (OP); lipopolysaccharide (LPS); and LPS + Enoxaparin group. The rats received a midline laparotomy to exteriorize a segment of terminal ileum for microcirculation examination by full-field laser perfusion imager and sidestream dark field video microscope on mucosa, muscle, and Peyer's patch. In the LPS and LPS + Enoxaparin groups, 15 mg/kg LPS was administered intravenously to induce endotoxemia, and 400 IU/kg enoxaparin sodium was also administered in the LPS + Enoxaparin group. RESULTS: At 240 minutes, the mean arterial pressure was higher in the LPS + Enoxaparin group than in the LPS group (93 +/- 9 versus 64 +/- 16 mm Hg, P < 0.001). Microcirculatory blood flow intensity was higher in the LPS + Enoxaparin group than in the LPS group as follows: mucosa (1085 +/- 215 versus 617 +/- 214 perfusion unit [PU], P < 0.001); muscle (760 +/- 202 versus 416 +/- 223 PU, P = 0.001); and Peyer's patch (1,116 +/- 245 versus 570 +/- 280 PU, P < 0.001). Enoxaparin inhibited LPS-induced reduction in perfused small vessel density and increase in heterogeneity of microcirculation. CONCLUSIONS: Enoxaparin can prevent intestinal microcirculatory dysfunction in endotoxemic rats by preventing microvascular thrombosis formation and maintaining normal mean arterial pressure. PMID- 22507825 TI - Tissue microenvironments define and get reinforced by macrophage phenotypes in homeostasis or during inflammation, repair and fibrosis. AB - Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and an-tiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more anti inflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. PMID- 22507824 TI - Meditation, mindfulness and executive control: the importance of emotional acceptance and brain-based performance monitoring. AB - Previous studies have documented the positive effects of mindfulness meditation on executive control. What has been lacking, however, is an understanding of the mechanism underlying this effect. Some theorists have described mindfulness as embodying two facets-present moment awareness and emotional acceptance. Here, we examine how the effect of meditation practice on executive control manifests in the brain, suggesting that emotional acceptance and performance monitoring play important roles. We investigated the effect of meditation practice on executive control and measured the neural correlates of performance monitoring, specifically, the error-related negativity (ERN), a neurophysiological response that occurs within 100 ms of error commission. Meditators and controls completed a Stroop task, during which we recorded ERN amplitudes with electroencephalography. Meditators showed greater executive control (i.e. fewer errors), a higher ERN and more emotional acceptance than controls. Finally, mediation pathway models further revealed that meditation practice relates to greater executive control and that this effect can be accounted for by heightened emotional acceptance, and to a lesser extent, increased brain-based performance monitoring. PMID- 22507826 TI - The relationship between tumour site, clinicopathological characteristics and cancer-specific survival in patients undergoing surgery for colorectal cancer. AB - AIM: It is recognised that colorectal cancer may arise from different genomic instability pathways. There is evidence to suggest that colon and rectal cancers exhibit different clinicopathological features. We examined the relationship between tumour site, clinicopathological characteristics and cancer-specific survival in patients undergoing potentially curative resection for colorectal cancer. METHOD: Four hundred and eleven patients who underwent surgery. Clinicopathological data including components of the Peterson index, Klintrup scores, haemoglobin and the modified Glasgow Prognostic Score (mGPS) were studied. RESULTS: There were 134 (33%) right sided, 125 (30%) left sided and 152 (37%) rectal tumours. Emergency presentation (P < 0.001), anaemia (P < 0.001), higher mGPS (P < 0.001), advanced T stage (P < 0.001), poor differentiation (P < 0.001) and older age (P < 0.05) were more commonly observed in right sided cancer. The mean follow-up was 94 months (minimum 36 months) and 114 patients died of cancer. There was no difference between tumour site and survival (P = 0.427). On multivariate analysis older age (P = 0.015), lymph node ratio (P < 0.001), mGPS (P = 0.028), Peterson Index (P < 0.001) and Klintrup score (P = 0.008) were independently related to cancer-specific survival. Klintrup score was only associated with poor cancer-specific survival in rectal cancer (P = 0.009). CONCLUSION: The study suggests that colorectal cancer is a group of heterogeneous tumours with different clinicopathological features. Despite this, there was no difference between tumour site and survival. The prognostic role of clinicopathological factors in tumours arising from different genomic instability pathways requires further study. PMID- 22507827 TI - CGG-repeat expansion in FMR1 is not associated with amyotrophic lateral sclerosis. AB - Recently, repeat expansions in several genes have been shown to cause or be associated with amyotrophic lateral sclerosis (ALS). It has been demonstrated that an intronic hexanucleotide repeat expansion in C9ORF72 is a major cause of both familial (approximately 40%) and sporadic (approximately 5%) ALS, as well as frontotemporal dementia (FTD). In addition, a CAG-repeat expansion in exon 1 of ATXN2, otherwise known to cause spinocerebellar ataxia type 2, has been identified as a major risk factor for sporadic ALS. Intermediate repeat expansions in the fragile X mental retardation 1 (FMR1) gene (55-200 repeats) are known to cause fragile X-associated premature ovarian insufficiency [(FX)POI; female carriers] or fragile X-associated tremor/ataxia syndrome (FXTAS; male carriers) by CGG-mediated RNA toxicity. The present investigation involves screening FMR1 repeat length in 742 sporadic ALS patients and 792 matched controls. Our conclusion is that FMR1 repeat expansions are not associated with ALS. PMID- 22507828 TI - Finding the optimal statistical model to describe target motion during radiotherapy delivery--a Bayesian approach. AB - Early approaches to characterizing errors in target displacement during a fractionated course of radiotherapy assumed that the underlying fraction-to fraction variability in target displacement, known as the 'treatment error' or 'random error', could be regarded as constant across patients. More recent approaches have modelled target displacement allowing for differences in random error between patients. However, until recently it has not been feasible to compare the goodness of fit of alternate models of random error rigorously. This is because the large volumes of real patient data necessary to distinguish between alternative models have only very recently become available. This work uses real-world displacement data collected from 365 patients undergoing radical radiotherapy for prostate cancer to compare five candidate models for target displacement. The simplest model assumes constant random errors across patients, while other models allow for random errors that vary according to one of several candidate distributions. Bayesian statistics and Markov Chain Monte Carlo simulation of the model parameters are used to compare model goodness of fit. We conclude that modelling the random error as inverse gamma distributed provides a clearly superior fit over all alternatives considered. This finding can facilitate more accurate margin recipes and correction strategies. PMID- 22507829 TI - C-Terminal acidic domain of ubiquitin-conjugating enzymes: a multi-functional conserved intrinsically disordered domain in family 3 of E2 enzymes. AB - E2 ubiquitin-conjugating enzymes are key elements of the ubiquitin (Ub) pathway, since they influence processivity and topology of the Ub chain assembly and, as a consequence, the fate of the target substrates. E2s are multi-domain proteins, with accessory N-terminal or C-terminal domains that can contribute to the specificity for the cognate Ub-like molecules, or even the E3. In this context, the thorough structural characterization of E2 accessory domains is mandatory, in particular when they are associated to specific functions. We here provide, by computational and comparative studies, the first evidence of an acidic domain (AD) conserved in the E2 sub-family 3R. It is an intrinsically disordered domain, in which elements for Ub or E3 recognition are maintained. This conserved acidic domain (AD) shows propensity for alpha-helix structures (185-192 and 204-218) in the proximity of the sites for interaction with the Ub or the cognate E3. Moreover, our results also suggest that AD can explore conformations with tertiary contacts mainly driven by aromatic and hydrophobic interactions, in absence of its interaction partners. The globular states are likely to be regulated by multiple phosphorylation events, which can trigger conformational changes toward more extended conformations, as judged by MD simulations of the phospho-variants. The extended conformations, in turn, promote the accessibility of the interaction sites for Ub and the E3. We also trace a parallel between this new and natively unfolded structural motif for Ub-recognition and the natively folded ubiquitin associated domain (UBA) typical of family 1 of E2 enzymes, which includes Ubc1. In fact, according to our calculations, Ubc1 maps at the interface between the space of the natively unfolded and folded proteins, as well as it shares common features with the acidic domain of family 3 members. PMID- 22507830 TI - Biologically controlled mineralization in the hypercalcified sponge Petrobiona massiliana (Calcarea, Calcaronea). AB - Hypercalcified sponges, endowed with a calcium carbonate basal skeleton in addition to their spicules, form one of the most basal metazoan group engaged in extensive biomineralization. The Mediterranean species Petrobiona massiliana was used to investigate biological controls exerted on the biomineralization of its basal skeleton. Scanning and transmission electron microscopy (SEM, TEM) confirmed that basopinacocytes form a discontinuous layer of flattened cells covering the skeleton and display ultrastructural features attesting intense secretory activity. The production of a highly structured fibrillar organic matrix framework by basopinacocytes toward the growing skeleton was highlighted both by potassium pyroantimonate and ruthenium red protocols, the latter further suggesting the presence of sulfated glycosaminoglycans in the matrix. Furthermore organic material incorporated into the basal skeleton was shown by SEM and TEM at different structural levels while its response to alcian blue and acridine orange staining might suggest a similar acidic and sulfated chemical composition in light microscopy. Potassium pyroantimonate revealed in TEM and energy electron loss spectroscopy (EELS) analysis, heavy linear precipitates 100-300 nm wide containing Ca(2+) and Mg(2+) ions, either along the basal cell membrane of basopinacocytes located toward the decalcified basal skeleton or around decalcified spicules in the mesohyl. Based on the results of the previous mineralogical characterization and the present work, an hypothetical model of biomineralization is proposed for P. massiliana: basopinacocytes would produce an extracellular organic framework that might guide the assemblage of submicronic amorphous Ca- and Mg-bearing grains into higher structural units. PMID- 22507831 TI - Toll-like receptors (TLR2 and TLR4) recognize polysaccharides of Pseudallescheria boydii cell wall. AB - Pseudallescheria boydii is an opportunistic fungus widespread in the environment, and has recently emerged as an agent of localized as well as disseminated infections in both immunocompromised and immunocompetent hosts. The host response to fungi is in part dependent on the activation of evolutionary conserved receptors including Toll-like receptors and phagocytic receptors. This review will discuss the isolation and structural characterization of alpha-glucans and rhamnomannans from P. boydii cell wall and their roles in the induction of innate immune response. PMID- 22507832 TI - Structure revision of hupehensis saponin F and G and characterization of new trace triterpenoid saponins from Anemone hupehensis by tandem electrospray ionization mass spectrometry. AB - Electrospray ionization ion-trap tandem mass spectrometry (ESI-MS(n)) was first employed for reinvestigating the structures of hupehensis saponin F and G previously isolated from Anemone hupehensis in our lab. Hupehensis saponin G was determined to contain one more trisaccharide unit (Rha-(1->4)-Glc-(1->6)-Glc-), not a glucose residue, than saponin F based on their molecular weights deduced from their [M+Na](+) ions in ESI-MS spectra. The (2,4)A(4alpha)-ion at m/z 551.3 formed by retro-Diels-Alder (RDA) rearrangement in positive mode illustrated that the C-28 sugar chains of the two saponins were composed of trisaccharide repeating moieties with (1->4) linkages rather than (1->3) linkages. The interpretation of 2D-NMR spectra of the two compounds also confirmed the results obtained by ESI-MS(n). Moreover, from the water soluble part of A. hupehensis, two novel triterpene saponins were tentatively characterized to contain 4 and 5 (1->4)-linked above trisaccharide repeating moieties at C-28 position according to their ESI-MS(n) behaviors, respectively. PMID- 22507833 TI - Positive correlation between erythrocyte levels of n-3 polyunsaturated fatty acids and bone mass in postmenopausal Korean women with osteoporosis. AB - BACKGROUND: Osteoporosis, a major health problem among postmenopausal women, is influenced by dietary factors. The purpose of the present study was to evaluate the hypothesis that erythrocyte levels of n-3 polyunsaturated fatty acid (PUFA) and the dietary intake of fish are associated with risk of osteoporosis and correlate with bone mass in postmenopausal Korean women with the disease. METHODS: Fifty cases and 100 controls were recruited. Osteoporosis was defined according to the International Society for Clinical Densitometry guideline as a score lower than -2.5 SD below the T-score for lumbar vertebrae L1-L4, femoral neck or femoral total. RESULTS: The T-score of the femoral neck was positively correlated with erythrocyte levels of n-3 PUFA, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and the intake of fish, and was negatively correlated with the ratio of n-6/n-3 PUFA after adjusting for age, years after menopause and height. In addition, the risk of osteoporosis was positively associated with erythrocyte levels of saturated fatty acids but negatively associated with EPA + DHA. CONCLUSIONS: Erythrocyte levels of n-3 PUFA and the intake of fish were positively correlated with bone mass. In particular, erythrocyte levels of EPA + DHA reduced the risk of osteoporosis in postmenopausal Korean women. PMID- 22507834 TI - Whole abdominal radiation using helical tomotherapy-based intensity-modulated radiotherapy: a potential for consolidation therapy in adequately treated locally advanced epithelial ovarian cancers. PMID- 22507835 TI - Fibrin(ogen)-independent role of plasminogen activators in acetaminophen-induced liver injury. AB - Hepatic fibrin(ogen) has been noted to occur after acetaminophen (APAP)-induced liver injury in mice. Deficiency in plasminogen activator inhibitor-1 (PAI-1), an endogenous inhibitor of fibrinolysis, increases APAP-induced liver injury in mice. However, the roles of fibrinogen and fibrinolysis in APAP-induced liver injury are not known. We tested the hypothesis that hepatic fibrin(ogen) deposition reduces severity of APAP-induced liver injury. APAP-induced (300 mg/kg) liver injury in mice was accompanied by thrombin generation, consumption of plasma fibrinogen, and deposition of hepatic fibrin. Neither fibrinogen depletion with ancrod nor complete fibrinogen deficiency [via knockout of the fibrinogen alpha chain gene (Fbg(-/-))] affected APAP-induced liver injury. PAI-1 deficiency (PAI-1(-/-)) increased APAP-induced liver injury and hepatic fibrin deposition 6 hours after APAP administration, which was followed by marked hemorrhage at 24 hours. As in PAI-1(-/-) mice, administration of recombinant tissue plasminogen activator (tenecteplase, 5 mg/kg) worsened APAP-induced liver injury and hemorrhage in wild-type mice. In contrast, APAP-induced liver injury was reduced in both plasminogen-deficient mice and in wild-type mice treated with tranexamic acid, an inhibitor of plasminogen activation. Activation of matrix metalloproteinase 9 (MMP-9) paralleled injury, but MMP-9 deficiency did not affect APAP-induced liver injury. The results indicate that fibrin(ogen) does not contribute to development of APAP-induced liver injury and suggest rather that plasminogen activation contributes to APAP-induced liver injury. PMID- 22507836 TI - c-mip down-regulates NF-kappaB activity and promotes apoptosis in podocytes. AB - The mechanisms of podocyte disorders in cases of idiopathic nephrotic syndrome (INS) are complex and remain incompletely elucidated. The abnormal regulation of NF-kappaB may play a key role in the pathophysiology of these podocyte diseases, but at present, NF-kappaB has not been thoroughly investigated. In this study, we report that induction of c-mip in podocytes of patients with INS is associated with a down-regulation of RelA, a potent antiapoptotic factor that belongs to the NF-kappaB family. Overexpression of c-mip in differentiated podocytes promotes apoptosis by inducing caspase-3 activity and up-regulating the proapoptotic protein Bax, whereas the overall levels of the antiapoptotic protein Bcl-2 was concomitantly decreased. The associated overexpression of RelA prevented the proapoptotic effects of c-mip. In addition, the targeted induction of c-mip in podocytes in vivo inhibited the expression of the RelA protein and increased the Bax/Bcl-2 ratio. The expression of both c-mip and active caspase-3 increased in focal and segmental glomerulosclerosis biopsies, and both proteins displayed a close spatial relationship. These results suggest that alterations in NF-kappaB activity might result from the up-regulation of c-mip and are likely to contribute to podocyte disorders in cases of INS. PMID- 22507837 TI - Generation of kidney from pluripotent stem cells via blastocyst complementation. AB - Because a shortage of donor organs has been a major obstacle to the expansion of organ transplantation programs, the generation of transplantable organs is among the ultimate goals of regenerative medicine. However, the complex cellular interactions among and within tissues that are required for organogenesis are difficult to recapitulate in vitro. As an alternative, we used blastocyst complementation to generate pluripotent stem cell (PSC)-derived donor organs in vivo. We hypothesized that if we injected PSCs into blastocysts obtained from mutant mice in which the development of a certain organ was precluded by genetic manipulation, thereby leaving a niche for organ development, the PSC-derived cells would developmentally compensate for the defect and form the missing organ. In our previous work, we showed proof-of-principle findings of pancreas generation by injection of PSCs into pancreas-deficient Pdx1(-/-) mouse blastocysts. In this study, we have extended this technique to kidney generation using Sall1(-/-) mouse blastocysts. As a result, the defective cells were totally replaced, and the kidneys were entirely formed by the injected mouse PSC-derived cells, except for structures not under the influence of Sall1 expression (ie, collecting ducts and microvasculature). These findings indicate that blastocyst complementation can be extended to generate PSC-derived kidneys. This system may therefore provide novel insights into renal organogenesis. PMID- 22507838 TI - Blocking CCR7 at the ocular surface impairs the pathogenic contribution of dendritic cells in allergic conjunctivitis. AB - CCR7 plays a key role in mobilizing tissue dendritic cells (DCs) to the lymphoid compartment for consequent elicitation of adaptive immunity. Interfering with CCR7 function therapeutically would therefore be anticipated to inhibit the progression of atopic conditions, for example, allergic conjunctivitis (AC). However, the CCR7-CCL19/CCL21 system in the ocular surface is poorly understood as is the precise role of DCs in AC immunopathogenesis. T cells from ovalbumin (OVA)-primed mice were adoptively transferred into wild-type (WT) hosts. Exogenous WT (eGFP(+)) versus CCR7(-/-) DCs were engrafted subconjunctivally (SCJ), and hosts were challenged with OVA (Texas-Red+) eye drops. AC immunopathogenesis was evaluated via clinical examinations, infiltration of mast cells and eosinophils, Th2 reactivity, and serum IgE levels. AC was also assessed in actively immunized mice challenged with OVA eye drops containing 1% anti-CCR7 antibody or isotype control. In eye-draining lymph nodes (LNs), OVA(+) SCJ engrafted WT DCs conferred upregulated CCR7 and caused augmentation of clinical signs. This result was corroborated by increased conjunctival infiltration, Th2 cytokines in LNs, and serum OVA-specific IgE. Strikingly, this was completely reversed with SCJ engrafted CCR7(-/-) DCs in all parameters tested. Furthermore, topical antibody blockade of CCR7 in actively immunized mice significantly inhibited AC. Ocular surface DCs via CCR7 expression contribute to the immunopathogenesis of AC, thereby allowing significant inhibition of this experimental condition via topical CCR7 antibody blockade. PMID- 22507839 TI - Platelet-derived growth factor-BB mediates cell migration through induction of activating transcription factor 4 and tenascin-C. AB - The acute response to vascular cell injury, which underpins vasculo-occlusive pathologies such as atherogenesis and restenosis after percutaneous coronary intervention, involves a complex series of molecular events that alter patterns of gene expression and favor a synthetic phenotype. One transcription factor that has been implicated in this process is the evolutionarily conserved mammalian stress response pathway regulator activating transcription factor 4 (ATF-4). Here, we show for the first time that both mRNA and protein levels of ATF-4 are induced in smooth muscle cells (SMCs) by the potent migratory factor PDGF-BB through PDGFR-beta. PDGF-BB also stimulates the expression of tenascin-C (TN-C), an extracellular matrix glycoprotein that regulates the activity of focal adhesion complexes, facilitating the SMC migration that underlies negative vascular remodeling in response to injury. Overexpression of ATF-4 increased transcript levels of the four TN-C isoforms in rat vascular SMCs, and ATF-4 knockdown inhibited PDGF-BB-inducible TN-C expression in vitro and injury inducible TN-C protein expression in the balloon-injured rat artery wall. Furthermore, we show that ATF-4 is required for PDGF-BB-inducible SMC migration in response to injury. PDGF-BB-induced migration was also compromised in ATF-4 null mEFs, and this effect was rescued by the addition of TN-C. Our findings thus demonstrate the role of ATF-4 in both injury- and PDGF-BB-inducible TN-C expression and cell migration. PMID- 22507840 TI - Comparative analysis on the effect of Lycopersicon esculentum (tomato) in reducing cadmium, mercury and lead accumulation in liver. AB - SCOPE: L. esculentum (tomato) contain compounds with anti-oxidant and anti inflammatory properties, able to synthesize metal chelating proteins. We examined the ability of fruit extract to protect against mercury (Hg), lead (Pb) and cadmium (Cd) accumulation in the liver. METHODS AND RESULTS: Rats were fed on tomato mixed with rat chow (10% w/w), while Hg (10 ppm), Cd (200 ppm) and Pb (100 ppm) was given in drinking water. Tomato was administered together with the metals (group 2), a week after exposure (group 3) or a week before metal exposure (group 4) for a period of six weeks. The metal accumulations in the liver were determined using AAS. There was a significant (P<0.05) increase in protection by tomato to Cd and Hg accumulation but not to Pb (P<0.05) in weeks 2 and 4 for groups 2 and 3. The protective ability was significantly (P<0.05) increased for Pb in group 4, but was less comparable to Cd and Hg. CONCLUSION: Tomato reduces uptake while enhancing the elimination of these metals in a time dependent manner. The highest hepatoprotective effect was to Cd followed by Hg and least to Pb. Its administration is beneficial in reducing heavy metal accumulation in the liver. PMID- 22507841 TI - Nadir hematocrit during cardiopulmonary bypass: end-organ dysfunction and mortality. AB - OBJECTIVE: To discover the effects of the lowest hematocrit during cardiopulmonary bypass on end-organ function and mortality in patients who did not receive red blood cell transfusion and to identify predictors of nadir hematocrit. METHODS: From November 1, 2004, to October 1, 2009, 7957 patients underwent cardiac surgery supported by cardiopulmonary bypass and were not transfused. The relationship between nadir hematocrit and morbidity, markers of end-organ function, and survival was studied using generalized propensity score analysis. Factors associated with nadir hematocrit were identified by linear regression. RESULTS: Median nadir hematocrit was 30% (25th to 75th percentile, 27%-33%). Lower nadir hematocrit was associated with higher maximum intraoperative lactic acid (intrasubject correlation, -0.44). After risk adjustment, nadir hematocrit was associated with worse renal function (lower estimated glomerular filtration rate; P = .012), more myocardial injury (higher troponin level; P = .004), longer postoperative ventilator support (P < .001), longer hospital stay (P < .001), and higher mortality (P = .042). Female gender, older age, lower body mass index, higher New York Heart Association class, and combined valve procedure and coronary artery bypass were associated with lower nadir hematocrit; however, the strongest correlate was preoperative hematocrit (correlation coefficient, 0.74). CONCLUSIONS: Although red blood cell transfusion has associated morbidity risk, there must be a tradeoff between adverse effects of low hematocrit during cardiac surgery and those of transfusion. The strong association of nadir hematocrit with preoperative hematocrit suggests the need for investigation and optimization before elective cardiac surgery. PMID- 22507842 TI - Thoracic stent graft sizing for frozen elephant trunk repair in acute type A dissection. AB - OBJECTIVE: Although stenting of the descending aorta simultaneously with proximal aortic repair has become an accepted part of the therapy for acute type A dissection, no general recommendations have been accepted regarding the choice of diameter and length of the stent grafts. The present study explored the safety and effectiveness of sizing the stent graft of the hybrid prosthesis in relation to the total aortic diameter and extending the landing zone to the level of the T10-T12 vertebrae. METHODS: The frozen elephant trunk procedure was performed on 32 patients with acute type A aortic dissection. The stent graft size was chosen according to the total aortic diameter measured on contrast-enhanced computed tomography scans. The stent graft was inserted with the distal landing zone at the level of vertebrae T10-T12. All patients underwent computed tomography or magnetic resonance angiography before discharge; 8 patients underwent subsequent endovascular stent extension. RESULTS: The 30-day survival was 100%, with 3.1% (1/32) overall mortality at 17 +/- 4 months (range, 1-33) of follow-up. The postoperative complications included pneumonia in 5, pulmonary embolism in 3, sepsis in 1, and permanent recurrent laryngeal nerve damage in 1 patient. No ischemic brain or spinal cord injury occurred. During follow-up, no endoleaks or false lumen patency developed. CONCLUSIONS: Sizing the stent graft of the hybrid prosthesis according to the total aortic diameter and choosing a distal landing zone between vertebrae T10 and T12 is safe, with low midterm mortality and morbidity. It allows an extensive repair of the dissected aorta with early definite occlusion of the false lumen and prepares for potential endovascular extension of the graft. PMID- 22507843 TI - Gaming in risk-adjusted mortality rates: effect of misclassification of risk factors in the benchmarking of cardiac surgery risk-adjusted mortality rates. AB - OBJECTIVE: Upcoding or undercoding of risk factors could affect the benchmarking of risk-adjusted mortality rates. The aim was to investigate the effect of misclassification of risk factors on the benchmarking of mortality rates after cardiac surgery. METHODS: A prospective cohort was used comprising all adult cardiac surgery patients in all 16 cardiothoracic centers in The Netherlands from January 1, 2007, to December 31, 2009. A random effects model, including the logistic European system for cardiac operative risk evaluation (EuroSCORE) was used to benchmark the in-hospital mortality rates. We simulated upcoding and undercoding of 5 selected variables in the patients from 1 center. These patients were selected randomly (nondifferential misclassification) or by the EuroSCORE (differential misclassification). RESULTS: In the random patients, substantial misclassification was required to affect benchmarking: a 1.8-fold increase in prevalence of the 4 risk factors changed an underperforming center into an average performing one. Upcoding of 1 variable required even more. When patients with the greatest EuroSCORE were upcoded (ie, differential misclassification), a 1.1-fold increase was sufficient: moderate left ventricular function from 14.2% to 15.7%, poor left ventricular function from 8.4% to 9.3%, recent myocardial infarction from 7.9% to 8.6%, and extracardiac arteriopathy from 9.0% to 9.8%. CONCLUSIONS: Benchmarking using risk-adjusted mortality rates can be manipulated by misclassification of the EuroSCORE risk factors. Misclassification of random patients or of single variables will have little effect. However, limited upcoding of multiple risk factors in high-risk patients can greatly influence benchmarking. To minimize "gaming," the prevalence of all risk factors should be carefully monitored. PMID- 22507844 TI - Transcatheter aortic valve implantation combined with conventional heart surgery: hybrid approach for complex cardiac pathologic features. PMID- 22507845 TI - Quality of life 4 years after complex heart surgery in infancy. AB - OBJECTIVE: To determine the health-related quality of life at 4 years of age in children who had undergone cardiac surgery for congenital heart disease in early infancy. METHODS: A prospective cohort study of infants undergoing cardiac surgery at 6 weeks of age or younger from July 2000 to June 2005 at the Stollery Children's Hospital. The quality of life was assessed using the Pediatric Quality of Life Inventory, version 4.0, generic core scales, and compared with normative values for the same age. The association between the perioperative variables and health-related quality of life was explored. RESULTS: A total of 242 infants underwent complex heart surgery during the study period. Of the 166 eligible survivors, 130 were included. No significant differences were present between the children with single ventricle versus biventricular repairs, except for lower physical health summary scores in the single ventricle patients (P = .007). Compared with the normative data, the children with biventricular repair had lower total Pediatric Quality of Life Inventory, version 4.0, scores (P = .001) and psychosocial health summary scores (P < .001). The children with single ventricle repair also had lower physical health summary scores (P = .003). Older age at surgery and markers of postoperative low cardiac output syndrome were associated with worse health-related quality of life, and greater socioeconomic status was associated with better quality of life. CONCLUSIONS: At 4 years of age, health-related quality of life was significantly lower in children who had undergone surgery for congenital heart disease in early infancy. An association was found between age at surgery and postoperative low cardiac output and socioeconomic status and quality of life. PMID- 22507846 TI - Computed tomography lymphography by transbronchial injection of iopamidol to identify sentinel nodes in preoperative patients with non-small cell lung cancer: a pilot study. AB - OBJECTIVE: The objective of the present study was to assess the safety and feasibility of computed tomography lymphography by transbronchial injection of a water-soluble extracellular computed tomography contrast agent. METHODS: From April 2010 to May 2011, patients with clinical stage I non-small cell lung cancer who were candidates for lobectomy were enrolled in the present study. An ultrathin bronchoscope was inserted to the target bronchus under the guidance of virtual bronchoscopic navigation images. Computed tomography images of the chest were obtained 0.5 and 5 minutes after 2 or 3 mL of iopamidol was injected through a microcatheter. Sentinel nodes were identified when the maximum computed tomography attenuation value of the lymph nodes on the postcontrast computed tomography images increased by 30 Hounsfield units or more compared with the precontrast images. Patients underwent lobectomy with standard lymph node dissection. RESULTS: The ultrathin bronchoscope could access the targeted bronchus, and iopamidol was delivered into the peritumoral area in all 13 patients without any complications. Sentinel nodes were identified in 12 (92.3%) of the 13 patients. The average number of sentinel nodes was 1.5 (range, 1-2). Pathologic examination revealed metastatic lymph nodes in 2 patients. Metastatic nodes were included with the sentinel nodes. CONCLUSIONS: Computed tomography lymphography by transbronchial injection of iopamidol was a safe and feasible method to identify the sentinel nodes in patients with clinical stage I non-small cell lung cancer. PMID- 22507848 TI - Mandating health care by creeps and jerks. PMID- 22507847 TI - Assessing adherence-based quality measures in epilepsy. AB - OBJECTIVE: To examine the relationship of three alternative measures of adherence with seven negative outcomes associated with epilepsy for development of a quality measure in epilepsy. DESIGN: Retrospective cohort analysis. SETTING: PharMetrics national claims database. PARTICIPANTS: Patients in the PharMetrics database for the years 2004-08 taking antiepileptic drugs. INTERVENTION: None. MAIN OUTCOME MEASURES: For each definition of adherence, the odds ratios (ORs) comparing non-adherent with adherent groups were assessed for consistency and direction for the number of hospital admissions, emergency room (ER) visits, head injuries including traumatic brain injuries, falls, motor vehicle accidents (MVAs), fractures and a 'seizure' outcome defined as hospital admissions or ER visits with a primary diagnosis of epilepsy or convulsions. RESULTS: The inclusion criteria were met by 31 635 individuals. In the multivariate analysis, the adherent group had lower odds of hospital admissions with ORs for the eight specifications ranging from 0.729 to 0.872 and ER visits where ORs for the eight specifications ranged from 0.750 to 0.893. The eight ORs for head injuries ranged from 0.647 to 0.888. For fractures, the ORs ranged from 0.407 to 0.841. Our proxy for seizure was inconsistently associated with adherence status. CONCLUSIONS: All the adherence measures defined non-adherent groups that were associated with negative outcomes in epilepsy. PMID- 22507849 TI - An adverse event screening tool based on routinely collected hospital-acquired diagnoses. AB - OBJECTIVE: The aim was to develop an electronic adverse event (AE) screening tool applicable to acute care hospital episodes for patients admitted with chronic heart failure (CHF) and pneumonia. DESIGN: Consensus building using a modified Delphi method and descriptive analysis of hospital discharge data. PARTICIPANTS: Consultant physicians in general medicine (n = 38). INTERVENTION: In-hospital acquired (C-prefix) diagnoses associated with CHF and pneumonia admissions to 230 hospitals in Victoria, Australia, were extracted from the Victorian Admitted Episodes Data Set between July 2004 and June 2007. A 9-point rating scale was used to prioritize diagnoses acquired during hospitalization (routinely coded as a 'C-prefix' diagnosis to distinguish from diagnoses present on admission) for inclusion within an AE screening tool. Diagnoses rated a group median score between 7 and 9 by the physician panel were included. MAIN OUTCOME MEASURES: Selection of C-prefix diagnoses with a group median rating of 7-9 in a screening tool, and the level of physician agreement, as assessed using the Interpercentile Range Adjusted for Symmetry. RESULTS: Of 697 initial C-prefix diagnoses, there were high levels of agreement to include 113 (16.2%) in the AE screening tool. Using these selected diagnoses, a potential AE was flagged in 14% of all admissions for the two index conditions. Intra-rater reliability for each clinician ranged from kappa 0.482 to 1.0. CONCLUSIONS: A high level of physician agreement was obtained in selecting in-hospital diagnoses for inclusion in an AE screening tool based on routinely collected data. These results support further tool validation. PMID- 22507851 TI - Rapid on-site detection of Acidovorax citrulli by cross-priming amplification. AB - Cross-priming amplification (CPA) for Acidovorax citrulli detection was evaluated in this study. The sensitivity of CPA assay for pure bacterial culture was 3.7 * 10(3) CFU/ml. Bacteria on naturally infected watermelon seeds were detected using CPA assay, suggesting this method is suitable for A. citrulli on-site detection from watermelon seeds. PMID- 22507850 TI - Timing and risk factors associated with relapse among smokers attempting to quit in Malaysia. AB - BACKGROUND: Many smokers attempt to quit smoking, but very few succeed. OBJECTIVE: To identify the timing and risk factors involved in smoking relapse. METHODS: We conducted a prospective cohort study among staff in two public universities in Malaysia. Behavioural therapy with free nicotine replacement therapy was given as treatment. Participants were followed up for 6 months. Relapse was defined as returning to smoking after having quit for at least 24 h. RESULTS: Of 185 smokers who volunteered to participate, 120 achieved at least 24 h abstinence, and 80% of these relapsed within 2 months. Compared to participants who attended a single smoking cessation session, participants who attended three sessions had a lower likelihood of relapse within 6 months of quitting. In contrast, smokers with a much longer exposure to cigarette smoking in the workplace (>3 h per week) had a greater chance of relapse compared to those with no exposure. CONCLUSIONS: Frequent attendance at clinic sessions and less exposure to other people smoking in the workplace can potentially reduce the likelihood of relapse among smokers who have recently quit. PMID- 22507852 TI - Coat color DNA testing in dogs: theory meets practice. AB - DNA tests to detect particular dog coat color alleles are in use in several DNA diagnostic laboratories. The original two genes studied were MC1R and TYRP1 and therefore these tests have been used most widely, and for the longest period of time. The original research was conducted to determine the mutation associated with a particular phenotype in one to a few dog breeds, and was subsequently expanded to include more dog breeds. The application of this testing now includes an even wider range of dog breeds, some of which would not have been expected to have some of the alleles detected. This retrospective study demonstrates that a DNA test may be designed for a particular application, but is used by clients for additional applications that were not originally anticipated. A robust protocol with DNA obtained by cheek brushes and interchanges among dog owners via the internet, have likely lead to this expanded use by clients. PMID- 22507854 TI - Antibody targeting of cell-bound MUC1 SEA domain kills tumor cells. AB - The cell-surface glycoprotein MUC1 is a particularly appealing target for antibody targeting, being selectively overexpressed in many types of cancers and a high proportion of cancer stem-like cells. However the occurrence of MUC1 cleavage, which leads to the release of the extracellular alpha subunit into the circulation where it can sequester many anti-MUC1 antibodies, renders the target problematic to some degree. To address this issue, we generated a set of unique MUC1 monoclonal antibodies that target a region termed the SEA domain that remains tethered to the cell surface after MUC1 cleavage. In breast cancer cell populations, these antibodies bound the cancer cells with high picomolar affinity. Starting with a partially humanized antibody, DMB5F3, we created a recombinant chimeric antibody that bound a panel of MUC1+ cancer cells with higher affinities relative to cetuximab (anti-EGFR1) or tratuzumab (anti-erbB2) control antibodies. DMB5F3 internalization from the cell surface occurred in an efficient temperature-dependent manner. Linkage to toxin rendered these DMB5F3 antibodies to be cytotoxic against MUC1+ cancer cells at low picomolar concentrations. Our findings show that high-affinity antibodies to cell-bound MUC1 SEA domain exert specific cytotoxicity against cancer cells, and they point to the SEA domain as a potential immunogen to generate MUC1 vaccines. PMID- 22507853 TI - Identification of an epigenetic profile classifier that is associated with survival in head and neck cancer. AB - Panels of prognostic biomarkers selected using candidate approaches often do not validate in independent populations, so additional strategies are needed to identify reliable classifiers. In this study, we used an array-based approach to measure DNA methylation and applied a novel method for grouping CpG dinucleotides according to well-characterized genomic sequence features. A hypermethylation profile among 13 CpG loci, characterized by polycomb group target genes, mammalian interspersed repeats, and transcription factor-binding sites (PcG/MIR/TFBS), was associated with reduced survival (HR, 3.98; P = 0.001) in patients with head and neck squamous cell carcinoma. This association was driven by CpGs associated with the TAP1 and ALDH3A1 genes, findings that were validated in an independent patient group (HR, 2.86; P = 0.04). Together, the data not only elucidate new potential targets for therapeutic intervention in head and neck cancer but also may aid in the identification of poor prognosis patients who may require more aggressive treatment regimens. PMID- 22507855 TI - Induced pluripotent stem cells without c-Myc attenuate acute kidney injury via downregulating the signaling of oxidative stress and inflammation in ischemia reperfusion rats. AB - Induced pluripotent stem (iPS) cells have potential for multilineage differentiation and provide a resource for stem cell-based treatment. However, the therapeutic effect of iPS cells on acute kidney injury (AKI) remains uncertain. Given that the oncogene c-Myc may contribute to tumorigenesis by causing genomic instability, herein we evaluated the therapeutic effect of iPS cells without exogenously introduced c-Myc on ischemia-reperfusion (I/R)-induced AKI. As compared with phosphate-buffered saline (PBS)-treated group, administration of iPS cells via intrarenal arterial route into kidneys improved the renal function and attenuated tubular injury score at 48 h after ischemia particularly at the dose of 5 * 10(5) iPS cells. However, a larger number of iPS cells (5 * 10(7) per rat) diminished the therapeutic effects for AKI and profoundly reduced renal perfusion detected by laser Doppler imaging in the reperfusion phase. In addition, the green fluorescence protein-positive iPS cells mobilized to the peritubular area at 48 h following ischemia, accompanied by a significant reduction in infiltration of macrophages and apoptosis of tubular cells, and a remarkable enhancement in endogenous tubular cell proliferation. Importantly, transplantation of iPS cells reduced the expression of oxidative substances, proinflammatory cytokines, and apoptotic factors in I/R kidney tissues and eventually improved survival in rats of ischemic AKI. Six months after transplantation in I/R rats, engrafted iPS cells did not result in tumor formation in kidney and other organs. In summary, considering the antioxidant, anti-inflammatory, and antiapoptotic properties of iPS cells without c-Myc, transplantation of such cells may be a treatment option for ischemic AKI. PMID- 22507856 TI - Donating umbilical cord blood to a public bank or storing it in a private bank: knowledge and preference of blood donors and of pregnant women. AB - BACKGROUND: Umbilical cord blood (UCB) is a source of stem cells for allogeneic haematopoietic transplantation in paediatric and adult patients with haematological malignancies and other indications. Voluntary donation is the basis for the success of unrelated UCB transplantation programmes. In the last few years a growing number of private banks offer their services to expectant parents, to store UCB for future use. The debate concerning UCB donation and private preservation has been ongoing for several years. The aims of this single centre study were to explore knowledge about UCB stem cells and attitudes towards voluntary UCB donation or private UCB preservation among both blood donors and pregnant women. MATERIALS AND METHODS: This study was conducted at the "Sapienza" University of Rome. Two types of anonymous questionnaires were prepared: one type was administered to 1,000 blood donors while the other type was distributed to 300 pregnant women. RESULTS: Most blood donors as well as the majority of pregnant women had some general knowledge about UCB (89% and 93%, respectively) and were aware of the possibility of donating it (82% and 95%). However, the level of knowledge regarding current therapeutic use resulted generally low, only 91 (10%) among informed blood donors and 69 (31%) among informed pregnant women gave a correct answer. The survey revealed a preference for voluntary donation both among blood donors (76%) and among pregnant woman (55%). Indeed, a minority of blood donors (6.5%) and of pregnant women (9%) would opt to store UCB for private use. DISCUSSION: The study raises the following considerations: (i) the large support for UCB donation expressed by blood donors and by pregnant women suggests that UCB preservation does not represent an obstacle to the expansion of UCB donation and to development of unrelated transplantation programmes; (ii) information about UCB donation and preservation should be carefully given by professionals and institutions. PMID- 22507857 TI - Incidental finding of monoclonal gammopathy in blood donors: a follow-up study. AB - BACKGROUND: The incidental finding of monoclonal immunoglobulin in the sera of healthy blood donors is a relatively frequent event and in such cases the subjects are commonly deferred permanently from donating blood. However, no follow-up studies of these cases have been published so far. MATERIALS AND METHODS: Since 2000, all regular blood donors at Trieste Blood Bank have undergone annual screening by serum protein electrophoresis. Cases presenting with monoclonal gammopathy between January 2000 and December 2008 were registered and follow-up was performed until December 2010. RESULTS: Out of 8,197 regular blood donors, monoclonal gammopathy was detected in 104 subjects (1.3%). The median age at detection was 53 years, the median monoclonal protein concentration was 0.2 g/dL and the cumulative follow-up of these cases amounted to 763 person/years. In two cases asymptomatic multiple myeloma was diagnosed within 6 months of detection of the gammopathy and in 14 cases, the monoclonal gammopathy was transient. The remaining 88 cases were classified as having monoclonal gammopathy of undetermined significance (MGUS). Out of these, two events related to monoclonal gammopathy were observed during the follow up: one lymphoma and one light chain deposition nephropathy. DISCUSSION: According to current prognostic staging systems, the majority of blood donors with monoclonal gammopathy were classified as having low-risk MGUS and had a very low incidence of lymphoproliferative diseases. Permanent deferral of blood donors with stable MGUS causes about a 1% loss of potential blood donations and it represents a "precautionary measure" that needs to be substantiated and validated. PMID- 22507858 TI - Thawed solvent/detergent-treated plasma: too precious to be wasted after 6 hours? AB - BACKGROUND: Coagulopathy associated with trauma and bleeding requires early administration of haemostatic agents. Solvent/detergent-treated plasma (S/D plasma) requires thawing and its availability for clinical use is, therefore, delayed. The long-term stability of clotting factors in thawed S/D-plasma has not been thoroughly investigated. The purpose of this study was to evaluate stability of clotting factors and inhibitors in thawed S/D-plasma stored at 4 degrees C for 6 days. MATERIALS AND METHODS: Clotting factor levels and bacterial contamination were investigated using 20 units of S/D-plasma. Fibrinogen, factor (F) II, FV, FVII, FVIII, FIX, FX, FXI, FXII, FXIII, antithrombin, von Willebrand antigen (VWF-Ag), plasmin inhibitor, protein C and free protein S were analysed over time. RESULTS: After 6 days of storage the results were as follows: fibrinogen 270 mg/dL (-10 mg/dL, p=0.0204), FII 75% (-5%, p<0.0001), FV 88% ( 14%, p<0.0001), FVII 81% (-24%, p<0.0001), FVIII 70% (-16%, p<0.0001), FIX 96% ( 8, p<0.0001), FX 92% (-1%, p<0.0001), FXI 119% (-4%, p=0.3666), FXII 94% (-2%, p=0.3602), FXIII 89% (-1%, p 0.0019), free protein S 76% (-4%, p<0.0001), protein C 96% (+1%, p=0.0371), antithrombin 92% (-3%, p<0.0001), plasmin inhibitor 29% ( 4%, p<0.0299), VWF-Ag 137% (+2%, p=0.2205). FVII and FVIII showed a critical drop of more than 20% or approached the lower quality assurance threshold after storage for more than 24 hours. No S/D-plasma showed bacterial contamination. CONCLUSION: All clotting factors in thawed S/D plasma remained stable for up to 24 hours when stored at 4 degrees C. Storage of thawed S/D plasma may improve the availability of this product in emergency situations. PMID- 22507859 TI - Acute hepatitis B virus (HBV) infection in a repeat blood donor during anti-HBV vaccination. PMID- 22507861 TI - Infectious transfusion risks: myth or reality? PMID- 22507860 TI - Temporal sequence of major biochemical events during blood bank storage of packed red blood cells. AB - BACKGROUND: We used sensitive spectroscopic techniques to measure changes in Band 3 oligomeric state during storage of packed red blood cells (RBC); these changes were compared to metabolic changes, RBC morphology, cholesterol and membrane protein loss, phospholipid reorganisation of the RBC membrane, and peroxidation of membrane lipid. The aim of the study was to temporally sequence major biochemical events occurring during cold storage, in order to determine which changes may underlie the structural defects in stored RBC. MATERIALS AND METHODS: Fifteen RBC units were collected from normal volunteers and stored under standard blood bank conditions; both metabolic changes and lipid parameters were measured by multiple novel assays including a new mass spectrometric measurement of isoprostane (lipid peroxidation) and flow cytometric assessment of CD47 expression. Band 3 oligomeric state was assessed by time-resolved phosphorescence anisotropy, and RBC morphology by microscopy of glutaraldehyde-fixed RBC. RESULTS: Extracellular pH decreased and extracellular potassium increased rapidly during cold storage. Band 3 on the RBC membrane aggregated into large oligomers early in the storage period and coincident with changes in RBC morphology. Membrane lipid changes, including loss of unesterified cholesterol, lipid peroxidation and expression of CD47, also changed early during the storage period. In contrast loss of acetylcholinesterase activity and haemolysis of RBC occurred late during storage. DISCUSSION: Our results demonstrate that changes in the macromolecular organisation of membrane proteins on the RBC occur early in storage and suggest that lipid peroxidation and/or oxidative damage to the membrane are responsible for irreversible morphological changes and loss of function during red cell storage. PMID- 22507862 TI - Ethical issues and concerns about the use of biosimilar granulocyte colony stimulating factors for the mobilisation of stem cells in normal donors. PMID- 22507863 TI - Long time survival of Bartonella bacilliformis in blood stored at 4 degrees C. A risk for blood transfusions. PMID- 22507864 TI - Platelet function analyser (PFA)-100 closure time in the evaluation of non steroidal anti-inflammatory drug-induced platelet dysfunction in children with bleeding symptoms. PMID- 22507865 TI - Management of complaints in blood establishments: thirteen years of experience at the Croatian Institute of Transfusion Medicine. AB - BACKGROUND: The aim of the study is to present the results and experience in the management of complaints in a transfusion service in order to draw attention to the importance of this segment of quality management and to stimulate publication of other studies on the topic. MATERIALS AND METHODS: This study is based on data from the Croatian Institute of Transfusion Medicine obtained by analysis of complaints recorded during a 13-year period (1998-2010). The distribution of the types and frequencies of complaints is presented, along with the level of their justifiability and criticality. The dynamics of the complaints is analysed overall and within particular categories. In addition, corrective actions and other factors that may have influenced the trends observed are discussed. RESULTS: During the study period, 817 complaints were received, most of which (40.9%) referred to the positive direct antiglobulin test in red cell concentrates, followed by blood product issuing and distribution (12.9%) and blood product quality (9.4%). Of the 817 complaints, 177 (21.7%) were assessed as serious and 645 (78.9%) as justified based on the testing performed. CONCLUSION: Data collected by systematic recording and analysis of complaints provide a basis for problem identification, implementation of corrective and preventive actions, and improvement of product and service quality, and, thereby, customer satisfaction. PMID- 22507866 TI - In vivo genotoxicity of furan in F344 rats at cancer bioassay doses. AB - Furan, a potent rodent liver carcinogen, is found in many cooked food items and thus represents a human cancer risk. Mechanisms for furan carcinogenicity were investigated in male F344 rats using the in vivo Comet and micronucleus assays, combined with analysis of histopathological and gene expression changes. In addition, formamidopyrimidine DNA glycosylase (Fpg) and endonuclease III (EndoIII)-sensitive DNA damage was monitored as a measure of oxidative DNA damage. Rats were treated by gavage on four consecutive days with 2, 4, and 8mg/kg bw furan, doses that were tumorigenic in 2-year cancer bioassays, and with two higher doses, 12 and 16mg/kg. Rats were killed 3h after the last dose, a time established as producing maximum levels of DNA damage in livers of furan-treated rats. Liver Comet assays indicated that both DNA strand breaks and oxidized purines and pyrimidines increased in a near-linear dose-responsive fashion, with statistically significant increases detected at cancer bioassay doses. No DNA damage was detected in bone marrow, a non-target tissue for cancer, and peripheral blood micronucleus assays were negative. Histopathological evaluation of liver from furan-exposed animals produced evidence of inflammation, single cell necrosis, apoptosis, and cell proliferation. In addition, genes related to apoptosis, cell-cycle checkpoints, and DNA-repair were expressed at a slightly lower level in the furan-treated livers. Although a mixed mode of action involving direct DNA binding cannot be ruled out, the data suggest that furan induces cancer in rat livers mainly through a secondary genotoxic mechanism involving oxidative stress, accompanied by inflammation, cell proliferation, and toxicity. PMID- 22507867 TI - The use of ex vivo human skin tissue for genotoxicity testing. AB - As a result of the chemical legislation concerning the registration, evaluation, authorization and restriction of chemicals (REACH), and the Seventh Amendment to the Cosmetics Directive, which prohibits animal testing in Europe for cosmetics, alternative methods for safety evaluation of chemicals are urgently needed. Current in vitro genotoxicity assays are not sufficiently predictive for the in vivo situation, resulting in an unacceptably high number of misleading positives. For many chemicals and ingredients of personal care products the skin is the first site of contact, but there are no in vitro genotoxicity assays available in the skin for additional evaluation of positive or equivocal responses observed in regulatory in vitro genotoxicity assays. In the present study ex vivo human skin tissue obtained from surgery was used for genotoxicity evaluation of chemicals by using the comet assay. Fresh ex vivo human skin tissue was cultured in an air liquid interface and topically exposed to 20 chemicals, including true positive, misleading positive and true negative genotoxins. Based on the results obtained in the present study, the sensitivity, specificity and accuracy of the ex vivo skin comet assay to predict in vivo genotoxicity were 89%, 90% and 89%, respectively. Donor and experimental variability were mainly reflected in the magnitude of the response and not the difference between the presence and absence of a genotoxic response. The present study indicates that human skin obtained from surgery is a promising and robust model for safety evaluation of chemicals that are in direct contact with the skin. PMID- 22507868 TI - An update on the use of C-reactive protein in early-onset neonatal sepsis: current insights and new tasks. AB - C-reactive protein (CRP) is one of the most studied and most used laboratory tests for neonatal sepsis. As part of the acute-phase reaction to infection, it plays a central role in the humoral response to bacterial invasion. The delayed synthesis during the inflammatory response accounts for its low sensitivity during the early phases of the disease. Diagnostic accuracy clearly improves by the performance of serial determinations and by the combination with earlier markers such as interleukins or procalcitonin. CRP is as well particularly useful for monitoring the response to treatment and guiding antibiotic therapy, though nothing replaces the clinical impression and the gold standard (i.e. culture results). In spite of the large amount of research done on CRP in neonates, some topics are still not fully understood, such as the influence of noninfectious factors on CRP levels in healthy as well as in symptomatic neonates and the role of gestational age and birthweight on CRP kinetics. In this review, we aim to give an update on the current evidence on the use of CRP in neonates. PMID- 22507869 TI - Familial occurrence of cervical artery dissection--coincidence or sign of familial predisposition? AB - BACKGROUNDAND PURPOSE: The etiology of spontaneous cervical artery dissection (CeAD) is poorly understood in most patients. Mild cervical trauma preceding the dissection event is a common finding, but many CeAD occur spontaneously. It is likely that genetic factors may increase the risk for CeAD. However, familial cases are excedingly rare. Familial clustering of CeAD may be accidental or associated with genetic or environmental risk factors shared between affected relatives. In this explorative study, we aim to show that specific risk factors for familial CeAD exist. METHODS: Age of onset, sex, affected artery and number of recurrent CeAD were documented for familial patients and compared with published findings from patients with sporadic CeAD. Concordance of age, sex and dissected artery within the families was analyzed by correlation analysis and by analysis of variance or Kruskal-Wallis testing. RESULTS: The study sample consisted of 9 new patients with a family history of CeAD enrolled in the Neurology Department of the University of Heidelberg or referred to Heidelberg from other centers. The study sample also included published findings from another 23 patients, in total 32 patients. The mean age of the patients with familial CeAD at their first dissections was 38.4 +/- 13.3 years. Twenty (62.5%) patients were female and 12 patients (37.5%) suffered multiple dissections. Four patients (12.5%) presented with recurrent dissections after >1 year. Patients with a familial history of CeAD were younger (p = 0.023) and presented more often with multiple dissections (p = 0.024) and recurrent dissections (p = 0.018). Age at the first event (correlation analysis p = 0.026; analysis of variance p = 0.029) and site of the dissection (correlation analysis p = 0.032; Kruskal-Wallis test p = 0.018) differed between the families, and there was no concordance of gender of affected family members (correlation analysis p = 0.500; Kruskal-Wallis test p = 0.211). CONCLUSIONS: The high prevalence of multiple dissection events and of long-term (>1 year) recurrent dissections in patients with a familial history of CeAD indicates that a specific predisposition for familial CeAD exists. Since age of onset and affected vessel differ between families, the risk profile for familial CeAD is heterogeneous. A large-scale (whole exome) sequencing analysis of 14 patients from 7 of the analyzed families is currently being performed in order to identify causative genetic variants. PMID- 22507870 TI - Trends in the epidemiology of childhood tuberculosis in Greece. AB - SETTING: A hospital referral center for childhood tuberculosis (TB). OBJECTIVE: To evaluate the epidemiological and clinical features of childhood TB in the Greater Athens area in the last decade. DESIGN: We retrospectively reviewed the medical records of patients aged <14 years treated for active TB between January 2000 and December 2009 at our pediatric TB clinic and compared the results with the patient turnover during the previous decade (1990-1999). Data concerning demographic and clinical characteristics were analyzed. RESULTS: A total of 321 children (median age 5.57 years, 157 males) with active TB were identified. About one third originated from areas where TB was previously recognized to be highly endemic. Twenty-three children (7%) had extra-pulmonary TB, and 61% of them originated from TB-endemic areas. Bacteriological confirmation was obtained in 40% of patients from whom specimens were obtained: 1 of 26 (3.8%) strains was multidrug-resistant. Most cases with drug-resistant Mycobacterium tuberculosis were noted among immigrant children. The average annual TB incidence was estimated at 5.37 per 100 000 for children aged <14 years in the Greater Athens area. Time trend analysis for the 20-year period revealed a significant reduction in the total number of TB cases (P = 0.002) and in TB among children from low incidence countries (P < 0.0001). CONCLUSIONS: In our settings, active TB is decreasing among children of Greek origin; disease epidemiology and drug resistance is influenced by the increasing influx of immigrants from areas where the disease is highly prevalent. PMID- 22507871 TI - Small molecule inhibitors of the Pyk2 and FAK kinases modulate chemoattractant induced migration, adhesion and Akt activation in follicular and marginal zone B cells. AB - B-lymphocytes produce protective antibodies but also contribute to autoimmunity. In particular, marginal zone (MZ) B cells recognize both microbial components and self-antigens. B cell trafficking is critical for B cell activation and is controlled by chemoattactants such as CXCL13 and sphingosine 1-phosphate (S1P). The related tyrosine kinases focal adhesion kinase (FAK) and proline-rich tyrosine kinase (Pyk2) regulate cell migration and adhesion but their roles in B cells are not fully understood. Using a novel Pyk2-selective inhibitor described herein (PF-719), as well as a FAK-selective inhibitor, we show that both Pyk2 and FAK are important for CXCL13- and S1P-induced migration of B-2 cells and MZ B cells. In contrast, LFA-1-mediated adhesion required only Pyk2 whereas activation of the Akt pro-survival kinase required FAK but not Pyk2. Thus Pyk2 and FAK mediate critical processes in B cells and these inhibitors can be used to further elucidate their functions in B cells. PMID- 22507873 TI - Is there any clinically relevant cannabinoid-induced analgesia? PMID- 22507874 TI - Single-fraction simulation of relative cell survival in response to uniform versus hypoxia-targeted dose escalation. AB - The purpose of this study was to investigate the increase in cell kill that can be achieved by tumor irradiation with heterogeneous dose distributions targeting hypoxic regions that can be visualized with non-invasive imaging. Starting with a heterogeneous distribution of microvessels, a microscopic two-dimensional model of tumor oxygenation was developed using planar simulation of oxygen diffusion. Non-invasive imaging of hypoxia was simulated taking partial volume effect into account. A dose-modulation scheme was implemented with the goal of delivering higher doses to the hypoxic pixels, as seen in simulated hypoxia images. To determine the relative cell kill in response to hypoxia-targeting irradiation, tumor cell survival fractions were compared to those resulting from treatments delivering the same average dose to the lesion in a spatially uniform fashion. It was shown that hypoxia-targeting dose modulation may be better suited for tumors with low alpha/beta, low hypoxic fraction and spatially aggregated hypoxic features. Most importantly, it was determined that at low fraction doses there is no cell kill increase from targeting hypoxic regions alone versus escalating the total tumor dose. However, for higher doses per fraction (>=8 Gy/fraction), the effectiveness of hypoxia-targeting irradiation increases, resulting in the tumoricidal effect of up to 30% higher than that of uniform tumor irradiation delivering the same average tumor dose. PMID- 22507872 TI - Mycobacterium tuberculosis ManLAM inhibits T-cell-receptor signaling by interference with ZAP-70, Lck and LAT phosphorylation. AB - Immune evasion is required for Mycobacterium tuberculosis to survive in the face of robust CD4(+) T cell responses. We have shown previously that M. tuberculosis cell wall glycolipids, including mannose capped lipoarabinomannan (ManLAM), directly inhibit polyclonal murine CD4(+) T cell activation by blocking ZAP-70 phosphorylation. We extended these studies to antigen-specific murine CD4(+) T cells and primary human T cells and found that ManLAM inhibited them as well. Lck and LAT phosphorylation also were inhibited by ManLAM without affecting their localization to lipid rafts. Inhibition of proximal TCR signaling was temperature sensitive, suggesting that ManLAM insertion into T cell membranes was required. Thus, M. tuberculosis ManLAM inhibits antigen-specific CD4(+) T cell activation by interfering with very early events in TCR signaling through ManLAM's insertion in T cell membranes. PMID- 22507875 TI - Delayed and unsuccessful endoscopic retrograde cholangiopancreatography are associated with worse outcomes in patients with acute cholangitis. AB - BACKGROUND & AIMS: Acute ascending cholangitis usually is treated with antibiotics, and biliary drainage is treated by endoscopic retrograde cholangiopancreatography (ERCP). We investigated the effects of the timing of ERCP on outcomes of patients with acute cholangitis factors that predict prolonged hospital stays, increased costs of hospitalization, and composite clinical outcomes (death, persistent organ failure, and admission to the intensive care unit). METHODS: We performed a retrospective analysis of data from 90 patients (mean age, 60 y; 48% female) admitted to Johns Hopkins Hospital from January 1994 to June 2010 who were diagnosed with acute cholangitis and underwent ERCP. A delayed ERCP was defined as one performed more than 72 hours after admission. Electronic and paper medical records were reviewed, and relevant data were abstracted. RESULTS: ERCP was performed successfully in 92% of the patients, at a mean time period of 38 hours after admission (14% of ERCPs were delayed). Factors that were associated independently with prolonged length of hospital stay (top 10%) included unsuccessful ERCP (odds ratio [OR], 52.5; P = .002) and delayed ERCP (OR, 19.8; P = .008). Factors associated with increased hospitalization cost (top 10%) included unsuccessful ERCP (OR, 33.8; P = .004) and delayed ERCP (OR, 11.3; P = .03). Factors associated with composite clinical outcome included age (OR, 1.1; P = .01), total level of bilirubin (OR, 1.36; P = .002), and delayed ERCP (OR, 7.8; P = .04). CONCLUSIONS: Delayed and failed ERCP are associated with prolonged hospital stays and increased costs of hospitalization. Delayed ERCP is associated with composite clinical outcome (death, persistent organ failure, and/or intensive care unit stay). Older age and higher levels of bilirubin also are associated with patients' composite end point. PMID- 22507876 TI - Similar risk of renal events among patients treated with tenofovir or entecavir for chronic hepatitis B. AB - BACKGROUND & AIMS: Tenofovir is a nucleotide reverse-transcriptase inhibitor approved for treatment of human immunodeficiency virus infection, as well as chronic hepatitis B (CHB). We evaluated nephrotoxicity among patients with CHB treated with tenofovir. METHODS: We performed a community-based, retrospective cohort study of 80 patients with CHB who received tenofovir, alone or in a combination regimen; they were matched for age and sex with 80 CHB patients who received only entecavir. Incidences of serum creatinine (SCr) increase >=0.2 mg/dL and new SCr levels of 1.5, 2.0, or 2.5 mg/dL were assessed. Patients with an estimated glomerular filtration rate (eGFR) <60 mL/min, calculated using the Modification of Diet in Renal Disease or Cockcroft-Gault formula, or who had >=20% decrease in eGFR were also recorded. RESULTS: More patients given entecavir had increases in SCr >=2.5 mg/dL (1 vs 6; P = .053), whereas more patients given tenofovir had a new Cockcroft-Gault eGFR of <60 mL/min (15 vs 6; P = .022) and at least 1 dose adjustment (13 vs 4; P = .021). By multivariate analysis, the only significant factors associated with an increase in SCr were a history of organ transplantation (adjusted odds ratio, 6.740; 95% confidence interval, 1.799 28.250; P = .005) and pre-existing renal insufficiency (adjusted odds ratio, 10.960; 95% confidence interval, 2.419-48.850; P = .002). No factors, including therapy assignment, were associated with a new eGFR <60 mL/min. CONCLUSIONS: Markers of renal function indicated that patients who received tenofovir were no more likely to have changes in renal function than patients treated with entecavir. History of transplant and pre-existing renal insufficiency were the only factors independently associated with increases in SCr. PMID- 22507877 TI - Colonic angiosarcoma: a rare cause of bleeding. PMID- 22507878 TI - Management of high-grade dysplasia and intramucosal adenocarcinoma in Barrett's esophagus. PMID- 22507879 TI - Waiving cost sharing for screening colonoscopy; free, but not clear. PMID- 22507880 TI - The structure of the von Willebrand factor is not altered in patients with colorectal carcinoma. AB - AIM: Elevated levels of von Willebrand factor (VWF) are often observed in many diseases including colorectal cancer, but this finding is not definite. The aim of our study was to examine the change in VWF multimer distribution in patients with colorectal cancer. METHOD: We randomly selected nine patients from each of the four Union for International Cancer Control (UICC) stages of colon cancer. VWF antigen (VWF:Ag), VWF-cleaving protease ADAMTS-13 level and factor VIII activity (FVIII:C) were determined. The multimer distribution of VWF was visualized using electrophoretic multimer analysis. RESULTS: The VWF multimer structure was normal with no difference between the four UICC stages. There was no significant increase in VWF:Ag and FVIII:C levels in the more advanced UICC stages. There was no significant difference in the ADAMTS-13 level according to the UICC stage. CONCLUSION: There was no change in the VWF multimer distribution to indicate acquired von Willebrand disease. PMID- 22507881 TI - DEP induction of ROS in capillary-like endothelial tubes leads to VEGF-A expression. AB - Inhalation of diesel exhaust particles (DEPs) is associated with pulmonary and cardiovascular disease. One contributor to pathogenesis is inhaled particles reaching and injuring the lung capillary endothelial cells, and possibly gaining access to the blood stream. Using in vitro capillary tubes as a simplified vascular model system for this process, it was previously shown that DEPs induce the redistribution of vascular endothelial cell-cadherin (VE-Cad) away from the plasma membrane to intracellular locations. This allowed DEPs into the cell cytoplasm and tube lumen, suggesting the tubes may have become permeable (Chao et al., 2011). Here some of the mechanisms responsible for endothelial tube changes after DEP exposure were examined. The results demonstrate that endothelial tube cells mounted an oxidative stress response to DEP exposure. Hydrogen peroxide and oxidized proteins were detected after 24h of exposure to DEPs. Particles induced relocalization of Nrf2 from the cytoplasm to the nucleus, upregulating the expression of the enzyme heme oxygenase-1 (HO-1). Surprisingly, vascular endothelial cell growth factor-A (VEGF-A), initially termed "vascular permeability factor" (VPF), was found to be up-regulated in response to the HO-1 expression induced by DEPs. Similar to DEPs, applied VEGF-A induced relocalization of VE-Cadherin from the cell membrane surface to an intracellular location, and relocalization of VE-cadherin was associated with permeability. These data suggest that the DEPs may induce or contribute to the permeability of capillary-like endothelial tube cells via induction of HO-1 and VEGF-A. PMID- 22507883 TI - Allergen and ozone exacerbate serotonin-induced increases in airway smooth muscle contraction in a model of childhood asthma. AB - BACKGROUND: Serotonin (5-HT) modulates cholinergic neurotransmission and exacerbates airway smooth muscle (ASM) contraction in normal animal and nonasthmatic human tissue. Exposure to house dust mite allergen (HDMA) and ozone (O(3)) leads to airway hyperreactivity and 5-HT-positive cells in the airway epithelium of infant rhesus monkeys. Research shows that concomitant exposure in allergic animals has an additive effect on airway hyperreactivity. OBJECTIVES: In this study, the hypothesis is that the exposure of allergic infant rhesus monkeys to HDMA, O(3) and in combination, acting through 5-HT receptors, enhances 5-HT modulation of postganglionic cholinergic ASM contraction. METHODS: Twenty-four HDMA-sensitized infant monkeys were split into 4 groups at the age of 1 month, and were exposed to filtered air (FA), HDMA, O(3) or in combination (HDMA+O(3)). At the age of 6 months, airway rings were harvested and postganglionic, and parasympathetic-mediated ASM contraction was evaluated using electrical-field stimulation (EFS). RESULTS: 5-HT exacerbated the EFS response within all exposure groups, but had no effect in the FA group. 5-HT(2), 5-HT(3) and 5-HT(4) receptor agonists exacerbated the response. 5-HT concentration-response curves performed after incubation with specific receptor antagonists confirmed the involvement of 5-HT(2), 5-HT(3) and 5-HT(4) receptors. Conversely, a 5-HT(1) receptor agonist attenuated the tension across all groups during EFS, and in ASM contracted via exogenous acetylcholine. CONCLUSIONS: HDMA, O(3) and HDMA+O(3) exposure in a model of childhood allergic asthma enhances 5-HT exacerbation of EFS-induced ASM contraction through 5-HT(2), 5-HT(3) and 5-HT(4) receptors. A nonneurogenic inhibitory pathway exists, unaffected by exposure, mediated by 5-HT(1) receptors located on ASM. PMID- 22507882 TI - Novel 2-amino-isoflavones exhibit aryl hydrocarbon receptor agonist or antagonist activity in a species/cell-specific context. AB - The aryl hydrocarbon receptor (AhR) mediates the induction of a variety of xenobiotic metabolism genes. Activation of the AhR occurs through binding to a group of structurally diverse compounds, most notably dioxins, which are exogenous ligands. Isoflavones are part of a family which include some well characterised endogenous AhR ligands. This paper analysed a novel family of these compounds, based on the structure of 2-amino-isoflavone. Initially two luciferase based cell models, mouse H1L6.1c2 and human HG2L6.1c3, were used to identify whether the compounds had AhR agonistic and/or antagonistic properties. This analysis showed that some of the compounds were weak agonists in mouse and antagonists in human. Further analysis of two of the compounds, Chr-13 and Chr 19, was conducted using quantitative real-time PCR in rat H4IIE and human MCF-7 cells. The results indicated that Chr-13 was an agonist in rat but an antagonist in human cells. Chr-19 was shown to be an agonist in rat but more interestingly, a partial agonist in human. Luciferase induction results not only revealed that subtle differences in the structure of the compound could produce species specific differences in response but also dictated the ability of the compound to be an AhR agonist or antagonist. Substituted 2-amino-isoflavones represent a novel group of AhR ligands that must differentially interact with the AhR ligand binding domain to produce their species-specific agonist or antagonist activity and future ligand binding analysis and docking studies with these compounds may provide insights into the differential mechanisms of action of structurally similar compounds. PMID- 22507884 TI - Treatment of gamma-aminobutyric acid B receptor-antibody autoimmune encephalitis with oral corticosteroids. AB - BACKGROUND: Autoimmune encephalitis is increasingly identified as a cause of nonviral, idiopathic encephalitis. Present treatment algorithms recommend costly immune-modulating treatments and do not identify a role for oral corticosteroids. OBJECTIVE: To present a patient with gamma-aminobutyric acid(B) receptor-antibody encephalitis before and after treatment with oral corticosteroids. DESIGN: Case report. SETTING: The inpatient course as well as outpatient follow-up is discussed. PATIENT: A 43-year-old man with initial presentation of seizures and altered mental status. INTERVENTION: Our patient was treated with an extended course of oral corticosteroids as an outpatient. RESULTS: After treatment with oral corticosteroids, our patient had steady clinical improvement, achieved seizure freedom, and experienced improved mental status to within normal limits. CONCLUSIONS: This case supports the use of low-cost oral corticosteroids in treating patients with gamma-aminobutyric acid(B) receptor-antibody encephalitis. PMID- 22507885 TI - Anti-glutamic acid decarboxylase limbic encephalitis without epilepsy evolving into dementia with cerebellar ataxia. AB - OBJECTIVES: To expand the spectrum of the clinical presentation of anti-glutamic acid decarboxylase antibodies-related limbic encephalitis and to improve the recognition of this entity. DESIGN: Case study. SETTING: University hospital. PATIENT: An 11-year-old-girl with progressive mood and behavioral disorder, speech impairment, and short-term memory impairment who manifested cerebellar ataxia with nystagmus during the disease course. INTERVENTIONS: Blood and cerebrospinal fluid analysis including autoantibodies, electroencephalography, brain and spinal magnetic resonance imaging, and cognitive and neuropsychological assessment were performed. High-dose methylprednisolone sodium succinate pulses, cycles of intravenous immunoglobulins, mycophenolate mofetil, and rituximab as well as antipsychotics and benzodiazepine were administered. RESULTS: Diagnosis of anti-glutamic acid decarboxylase antibodies-related limbic encephalitis was made. The clinical features during the first months of disease included only mood, behavioral, and memory impairment. After 5 months, despite immunotherapies, cerebellar ataxia with nystagmus appeared with brain magnetic resonance imaging evidence of cerebral atrophy. No clinical or infraclinical seizures were recorded during follow-up. CONCLUSIONS: Anti-glutamic acid decarboxylase antibodies related limbic encephalitis can present with only behavioral or neuropsychological symptoms without any epileptic disorder. Moreover, cerebellar ataxia related to anti-glutamic acid decarboxylase antibodies can be observed in patients with limbic encephalitis during the disease course. PMID- 22507886 TI - omega-3 fatty acid treatment in multiple sclerosis (OFAMS Study): a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: To investigate whether omega-3 fatty acids reduce magnetic resonance imaging (MRI) and clinical disease activity in patients with multiple sclerosis, both as monotherapy and in combination with interferon beta-1a treatment. DESIGN: Multicenter, randomized, double-blind, placebo-controlled clinical trial conducted from 2004 to 2008. SETTING: Thirteen public neurology departments in Norway. PARTICIPANTS: Patients aged 18 to 55 years with active relapsing remitting multiple sclerosis, with a disability score equivalent to 5.0 or less on the Kurtzke Expanded Disability Status Scale. Ninety-two patients were randomized to omega-3 fatty acids (n = 46) or placebo capsules (n = 46). INTERVENTIONS: Administration of 1350 mg of eicosapentaenoic acid and 850 mg of docosahexaenoic acid daily or placebo. After 6 months, all patients in addition received subcutaneously 44 MUg of interferon beta-1a 3 times per week for another 18 months. MAIN OUTCOME MEASURE: The primary outcome measure was MRI disease activity as measured by the number of new T1-weighted gadolinium-enhancing lesions during the first 6 months. Secondary outcome measures included MRI disease activity after 9 months and 24 months, relapse rate, disability progression, fatigue, quality of life, and safety. RESULTS: The cumulative number of gadolinium-enhancing MRI lesions during the first 6 months were similar in the omega-3 fatty acids and placebo groups (median difference, 1; 95% CI, 0 to 3; P = .09). No difference in relapse rate was detected after 6 (median difference, 0; 95% CI, 0 to 0; P = .54) or 24 (median difference, 0; 95% CI, 0 to 0; P = .72) months. The proportion of patients without disability progression was 70% in both groups (P > .99). No differences were detected in fatigue or quality-of-life scores, and no safety concerns appeared. Serum analyses of fatty acids showed an increase in omega-3 fatty acids (mean difference, 7.60; 95% CI, 5.57 to 7.91; P < .001) in the patients treated with omega-3 fatty acids compared with the placebo group. CONCLUSION: No beneficial effects on disease activity were detected from omega-3 fatty acids when compared with placebo as monotherapy or in combination with interferon beta-1a. Magnetic resonance imaging disease activity was reduced as expected by interferon beta-1a. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00360906. PMID- 22507887 TI - The diagnostic pitfall of infratentorial subdural empyema. PMID- 22507889 TI - Re: A double-blind randomized controlled clinical trial to assess the effect of Doppler optimized intraoperative fluid management on outcome following radical cystectomy: P. Pillai, I. McEleavy, M. Gaughan, C. Snowden, I. Nesbitt, G. Durkan, M. Johnson, J. Cosgrove and A. Thorpe J Urol 2011; 186: 2201-2206. PMID- 22507888 TI - Effects of age and sex on aquaporin-4 autoimmunity. AB - OBJECTIVE: To determine the sex and age distribution of aquaporin-4 (AQP4) autoimmunity using data derived from clinical service laboratory testing of 56,464 patient samples. DESIGN: Observational analysis. SETTING: Mayo Clinic Neuroimmunology Laboratory. PATIENTS: Between October 1, 2005, and January 4, 2011, 56,464 patients were tested for AQP4-IgG; 2960 (5.2%) patients were seropositive. MAIN OUTCOME MEASURE: Seropositivity for AQP4-IgG. RESULTS: Patients seropositive for AQP4-IgG were older than seronegative patients (mean [SD] age, 46 [16] vs 42 [15] years, respectively; P < .001). More females than males were tested (37,662 vs 16,810, respectively; P < .001). Among 2743 seropositive patients, 146 (5.3%) were pediatric (aged <=18 years) and 333 (12.1%) were elderly (aged >=65 years). The sex distribution of seropositive patients was 2465 females and 306 males (absolute female:male ratio, 8.1:1; P < .001). After adjusting for the number of females tested, an excess of females persisted (adjusted female:male ratio, 3.6:1). Female predominance for AQP4-IgG was more striking in adults (absolute female:male ratio, 8.4:1; adjusted female:male ratio, 3.5:1) than in pediatric patients (absolute female:male ratio, 4.3:1; adjusted female:male ratio, 2.9:1) (P < .001). Elderly women were more likely to be seropositive than individuals in other age categories (13.1% vs 6.0%, respectively; P < .001). The proportion of AQP4-IgG-seropositive individuals (detection rate), defined by decade of age, increased exponentially in women after age 50 years. CONCLUSIONS: Seropositivity for AQP4-IgG occurs predominantly in females, particularly in individuals older than 18 years. Among seropositive patients, 1 in 6 is in the extremes of age. The detection rate of AQP4-IgG increased in women after age 50 years. PMID- 22507891 TI - Role of two clusters of male alcoholics in treatment retention. AB - AIMS: This study aimed to classify alcohol-dependent outpatients on the basis of clinical factors and to verify if the resulting types show different treatment retention. METHODS: The sample comprised 332 alcoholics that were enrolled in three different pharmacological trials carried out at Sao Paulo University, Brazil. Based on four clinical factors - problem drinking onset age, familial alcoholism, alcohol dependence severity, and depression - K-means cluster analysis was performed by using the average silhouette width to determine the number of clusters. A direct logistic regression was performed to analyze the influence of clusters, medication groups, and Alcoholics Anonymous (AA) attendance in treatment retention. RESULTS: Two clusters were delineated. The cluster characterized by earlier onset age, more familial alcoholism, higher alcoholism severity, and less depression symptoms showed a higher chance of discontinuing the treatment, independently of medications used and AA attendance. Participation in AA was significantly related to treatment retention. DISCUSSION: Health services should broaden the scope of services offered to meet heterogeneous needs of clients, and identify treatment practices and therapists which improve retention. Information about patients' characteristics linked to dropout should be used to make treatment programs more responsive and attractive, combining pharmacological agents with more intensive and diversified psychosocial interventions. PMID- 22507892 TI - What is the clinical benefit of preoperative chemoradiotherapy with 5FU/leucovorin for T3-4 rectal cancer in a pooled analysis of EORTC 22921 and FFCD 9203 trials: surrogacy in question? AB - BACKGROUND: Two phase III trials of neoadjuvant treatment in T3-4 rectal cancer established that adding chemotherapy (CRT) to radiotherapy (RT) improves pathological complete response (pCR) and local control (LC). We combined trials to assess the clinical benefit of CRT on overall (OS) and progression free survival (PFS) and to explore the surrogacy of pCR and LC. PATIENTS AND METHODS: Individual patient data from European Organisation for Research and Treatment of Cancer (EORTC) 22921 (1011 patients) and FFCD 9203 (756 patients) were pooled. Meta-analysis methodology was used to compare neoadjuvant CRT to RT for OS, PFS LC and distant progression (DP). Weighted linear regression was used to estimate trial-level association (surrogacy R(2)) between treatment effects on candidate surrogate (pCR, LC, DP) and OS. RESULTS: The median follow-up was 5.6 years. Compared to RT (881 pts), CRT (886 pts) did not prolong OS, DP or PFS. The 5-y OS rate was 66.3% with CRT versus 65.9% in RT (hazard ratios (HR) = 1.04 {0.88 1.21}). CRT significantly improved LC (HR = 0.54, 95%confidence interval (CI): 0.41-0.72). PFS was validated as surrogate for OS with R(2) = 0.88. Neoadjuvant treatment effects on LC (R(2) = 0.17) or DP (R(2) = 0.31) did not predict effects on OS. CONCLUSION: Preoperative CRT does not prolong OS or PFS. pCR or LC do not qualify as surrogate for PFS or OS while PFS is surrogate. Phase III trials should use OS or PFS as primary endpoint. PMID- 22507894 TI - Galangin induces autophagy through upregulation of p53 in HepG2 cells. AB - AIM: To investigate the mechanism by which galangin, a polyphenolic compound derived from medicinal herbs,induces autophagy of HepG2 cells. METHODS: The MTT[3 (4,5-dimethyl-thiazol-2-yl)2,5-diphenyl-tetrazolium bromide]assay was used to measure cell viability. Apoptosis was evaluated by TUNEL assay with flow cytometry, and PARP cleavage was detected by Western blotting. Autophagy was measured by fluorescence microscopy and transmission electron microscopy. Protein expressions were detected by Western blotting. Pifithrin- was used for pretreatment and siRNA was used to knock down p53 expression to explore the pathway mediated by galangin in HepG2 cells. Furthermore, Hep3B cells were used to express the exogenous wild-type p53. RESULTS: Galangin treatment inhibited cell proliferation and induced autophagy (130 MU mol/l) and apoptosis (370 MU mol/l). In particular, galangin treatment in HepG2 cells caused (1) an accumulation of autophagosomes, (2) elevated levels of microtubule-associated protein light chain 3, and (3) an increased percentage of cells with vacuoles. p53 expression was also increased. The galangin-induced autophagy was attenuated by the inhibition of p53 in HepG2 cells, and overexpression of p53 in Hep3B cells restored the galangin-induced higher percentage of cells with vacuoles to normal level. CONCLUSION: Our results indicate that galangin not only induced apoptosis but also prompted cell autophagy indifferent concentrations. Galangin mediates autophagy through a p53-dependent pathway in HepG2 cells. Our findings may help in the discovery of a chemotherapeutic drug with the novel pattern of inhibiting cell proliferation for the treatment of hepatocellular carcinoma cells. PMID- 22507893 TI - Synthesis and antitumor evaluation of novel benzo[d]pyrrolo[2,1-b]thiazole derivatives. AB - A series of novel 2,3-bis(hydroxymethyl)benzo[d]pyrrolo[2,1-b]thiazoles and their bis(alkylcarbamate) derivatives were synthesized starting from benzothiazole via reaction with dimethyl acetylenedicarboxylate (DMAD)/tetra-fluoro boric acid, catalytic hydrogenation, and alkylcarbamoylation. The anti-proliferative activity of these agents against human leukemia and various solid tumor cell growth in vitro was studied. The structure-activity relationship studies revealed that the bis(alkylcarbamates) derivatives are generally more cytotoxic than the corresponding bis(hydroxymethyl) congeners in inhibiting human lymphoblastic leukemia CCRF-CEM and various human solid tumor cell growth in culture. These agents have no cross-resistance to taxol or vinblastine. Studies on the therapeutic effect against human breast carcinoma MX-1 xenograft showed that complete tumor remission (CR) were achieved by treating with C1-4'-F- or C1-4'-Cl Ph-bis(i-propylcarbamates) derivatives (19b and 19c, respectively) and more than 99% tumor suppression by the corresponding bis(ethylcarbamates) 18b and 18c at the maximal tolerated dose. Alkaline agarose gel shifting assay revealed that the newly synthesized compounds are able to induce DNA interstrand cross-linking. The present studies generated a series of new potent DNA interstrand cross-linking agents, which have potential for further antitumor drug development. PMID- 22507895 TI - Alcohol use and the management of multidrug-resistant tuberculosis in Tomsk, Russian Federation. AB - SETTING: Alcohol use increases the risk of multidrug-resistant tuberculosis (MDR TB) and poses challenges for successful MDR-TB treatment, including the potential for additional adverse events. AIM: To investigate the association between alcohol consumption during MDR-TB treatment and adverse events and treatment outcomes in a cohort of patients in Tomsk, Russia. DESIGN: From 2000 to 2004, retrospective data were collected on 407 MDR-TB patients in Tomsk. Factors associated with treatment outcomes were assessed using logistic regression. RESULTS: Of the 407 patients, 253 (62.2%) consumed alcohol during treatment ('drinkers'), and 367 (90.2%) had at least one documented adverse advent. No significant differences were noted in frequency of adverse events in drinkers vs. non-drinkers. Drinkers had less favourable treatment outcomes (OR 0.28, 95%CI 0.18-0.45). Among drinkers, favourable treatment outcome was associated with adherence to at least 80% of prescribed doses (OR 2.89, 95%CI 1.30-6.43) and the occurrence of an adverse event requiring treatment interruption (OR 2.49, 95%CI 1.11-5.59). CONCLUSIONS: Alcohol use did not appear to increase the risk of adverse events during MDR-TB treatment; however, alcohol consumption was associated with poor outcome. Our findings suggest that individuals who drink alcohol should receive aggressive attention to optimise treatment adherence and manage adverse events. PMID- 22507897 TI - Virion-mediated transfer of SV40 epigenetic information. AB - In eukaryotes, epigenetic information can be encoded in parental cells through modification of histones and subsequently passed on to daughter cells in a process known as transgenerational epigenetic regulation. Simian Virus 40 (SV40) is a well-characterized virus whose small circular DNA genome is organized into chromatin and, as a consequence, undergoes many of the same biological processes observed in cellular chromatin. In order to determine whether SV40 is capable of transgenerational epigenetic regulation, we have analyzed SV40 chromatin from minichromosomes and virions for the presence of modified histones using various ChIP techniques and correlated these modifications with specific biological effects on the SV40 life cycle. Our results demonstrate that, like its cellular counterpart, SV40 chromatin is capable of passing biologically relevant transgenerational epigenetic information between infections. PMID- 22507896 TI - DMSO is a strong inducer of DNA hydroxymethylation in pre-osteoblastic MC3T3-E1 cells. AB - Artificial induction of active DNA demethylation appears to be a possible and useful strategy in molecular biology research and therapy development. Dimethyl sulfoxide (DMSO) was shown to cause phenotypic changes in embryonic stem cells altering the genome-wide DNA methylation profiles. Here we report that DMSO increases global and gene-specific DNA hydroxymethylation levels in pre osteoblastic MC3T3-E1 cells. After 1 day, DMSO increased the expression of genes involved in DNA hydroxymethylation (TET) and nucleotide excision repair (GADD45) and decreased the expression of genes related to DNA methylation (Dnmt1, Dnmt3b, Hells). Already 12 hours after seeding, before first replication, DMSO increased the expression of the pro-apoptotic gene Fas and of the early osteoblastic factor Dlx5, which proved to be Tet1 dependent. At this time an increase of 5-methyl cytosine hydroxylation (5-hmC) with a concomitant loss of methyl-cytosines on Fas and Dlx5 promoters as well as an increase in global 5-hmC and loss in global DNA methylation was observed. Time course-staining of nuclei suggested euchromatic localization of DMSO induced 5-hmC. As consequence of induced Fas expression, caspase 3/7 and 8 activities were increased indicating apoptosis. After 5 days, the effect of DMSO on promoter- and global methylation as well as on gene expression of Fas and Dlx5 and on caspases activities was reduced or reversed indicating down-regulation of apoptosis. At this time, up regulation of genes important for matrix synthesis suggests that DMSO via hydroxymethylation of the Fas promoter initially stimulates apoptosis in a subpopulation of the heterogeneous MC3T3-E1 cell line, leaving a cell population of extra-cellular matrix producing osteoblasts. PMID- 22507898 TI - Standardization and quality controls for the methylated DNA immunoprecipitation technique. AB - MeDIP (Methylated DNA Immunoprecipitation) is a relatively recent technique aimed to enrich the methylated fraction of DNA with an antibody directed against 5 methyl-cytosine. MeDIP processed samples are suitable for investigation of the methylation status of specific genomic loci and for performing genome-wide screening when hybridized to DNA methylation microarrays or analyzed by deep sequencing. Here, we describe a standardization protocol and quality controls to assess the specificity, reproducibility and efficiency of the MeDIP procedure. These may have utility when comparing results between samples and experiments within laboratories and between laboratories. PMID- 22507899 TI - Conversion of cytochrome c into a peroxidase: inhibitory mechanisms and implication for neurodegenerative diseases. AB - A further function of cytochrome c (cyt c), beyond respiration, is realized outside mitochondria in the apoptotic program. In the early events of apoptosis, the interaction of cyt c with a mitochondrion-specific phospholipid, cardiolipin (CL), brings about a conformational transition of the protein and acquirement of peroxidase activity. The hallmark of cyt c with peroxidase activity is its partial unfolding accompanied by loosening of the Fe sixth axial bond and an enhanced access of the heme catalytic site to small molecules like H2O2. To investigate the peroxidase activity of non-native cyt c, different forms of the protein were analyzed with the aim to correlate their structural features with the acquired enzymatic activity and apoptogenic properties (wt cyt c/CL complex and two single cyt c variants, H26Y and Y67H, free and bound to CL). The results suggest that cyt c may respond to different environments by changing its fold thus favouring the exertion of different biological functions in different pathophysiological cell conditions. Transitions among different conformations are regulated by endogenous molecules such as ATP and may be affected by synthetic molecules such as minocycline, thus suggesting a mechanism explaining its use as therapeutic agent impacting on disease-associated oxidative and apoptotic mechanisms. PMID- 22507900 TI - Discrimination of three basic female voice types in female singing students by voice range profile-derived parameters. AB - AIMS: To assess whether individual parameters or combinations of voice range profile parameters (also called 'features') are able to yield a clear cluster separation with which three basic female voice categories can be discriminated and can provide a basis for settling the issue of voice classification. METHODS: The voice range profiles of 206 female conservatory singing students were recorded, parameterized into more compact descriptions ('features'), and subjected to a cluster analysis. RESULTS: The three-cluster case provided the most consistent solution across all feature combinations. The feature that led to the best cluster separation was the ratio of the perimeter length of the chest voice part of the voice range profile versus the total perimeter length. CONCLUSIONS: Based on a statistical analysis of voice range profile parameters, the ratio of the perimeter length of the chest voice versus the total perimeter length was shown to yield a clear separation into three basic female voice types, which in turn may give us a basis for settling the issue of voice classification. PMID- 22507901 TI - Hepatic arterial embolization versus chemoembolization in the treatment of liver metastases from well-differentiated midgut endocrine tumors: a prospective randomized study. AB - BACKGROUND: Liver surgery is the best treatment for endocrine liver metastases, but it is often impossible due to diffuse disease. Systemic chemotherapy is poorly effective. Hepatic arterial embolization (HAE) and chemoembolization (HACE) have shown efficacy but have never been compared. PATIENTS AND METHODS: Patients with progressive unresectable liver metastases from midgut endocrine tumors were randomly assigned to receive HAE or HACE (two procedures at 3-month interval). The primary end point was the 2-year progression-free survival (PFS) rate. Secondary end points were response rates, overall survival, and safety. RESULTS: Twelve patients were assigned to receive HACE and 14 to receive HAE. The patient characteristics were well matched across the treatment arms. The 2-year PFS rates were 38 and 44% in the HACE and HAE arms, respectively (p = 0.90). Age, gender, previous resection of the primary tumor or liver metastases, extent of liver involvement, and concomitant treatment with somatostatin analogues were not associated with changes in PFS, whereas elevated baseline urinary 5-HIAA and serum chromogranin A levels were associated with shorter PFS. The 2-year overall survival rates were 80 and 100% in the HACE and HAE arms, respectively (p = 0.16). The disease control rate on CT scan was 95%. Grade 3 toxicity occurred in 19% of patients, with no treatment-related deaths and no differences in the treatment arms. CONCLUSION: HACE and HAE are safe and permit tumor control in 95% of patients with progressive liver metastases from midgut endocrine tumors. The 2 year PFS was not higher among patients receiving HACE, not favoring the hypothesis of an additive efficacy of arterial chemotherapy or embolization alone. PMID- 22507902 TI - Biodegradation and detoxification of bisphenol A with one newly-isolated strain Bacillus sp. GZB: kinetics, mechanism and estrogenic transition. AB - A facultative anaerobic bacterial strain, Bacillus sp. GZB, was isolated and identified to effectively degrade bisphenol A (BPA) under anaerobic and aerobic conditions. Under anaerobic condition, Fe(3+) can be used as an electron acceptor for Bacillus sp. GZB, while 5 mg L(-1) BPA can be fully removed and 51% was mineralized under optimal aerobic conditions. Additionally, seven metabolites were identified by GC-MS, four of which were doubly confirmed by authentic standards (two synthesized) and three of four initial degradation intermediates were also quantified during BPA aerobic degradation. The evolution of 1-(4 hydroxyphenyl)ethanone showed a similar tendency with estrogenic activity changing during BPA biodegradation course, indicating its potential estrogenicity. The estrogenicity temporary increase first and decline ultimately during BPA degradation revealing the GZB can effectively detoxify BPA as well as its estrogenic intermediates. This was the first study to report a facultative anaerobic strain can degrade BPA with or without of oxygen. PMID- 22507903 TI - Enhancement of hydrogen production during waste activated sludge anaerobic fermentation by carbohydrate substrate addition and pH control. AB - The effects of carbohydrate/protein ratio (CH/Pr) and pH on hydrogen production from waste activated sludge (WAS) were investigated. Firstly, the optimal pH value for hydrogen production was influenced by the CH/Pr ratio, which was pH 10, 9, 8, 8, 8 and 6 at the CH/Pr ratio (COD based) of 0.2 (sole sludge), 1, 2.4, 3.8, 5 and 6.6, respectively. The maximal hydrogen production (100.6 mL/g-COD) was achieved at CH/Pr of 5 and pH 8, which was due to the synergistic effect of carbohydrate addition on hydrogen production, the enhancement of sludge protein degradation and protease and amylase activities, and the suitable fermentation pathway for hydrogen production. As hydrogen consumption was observed at pH 8, in order to further increase hydrogen production a two-step pH control strategy (pH 8+pH 10) was developed and the hydrogen production was further improved by 17.6%. PMID- 22507904 TI - Effects of extraction methods on the composition and molar mass distributions of exopolymeric substances of the bacterium Sinorhizobium meliloti. AB - The influence of the extraction methods on the composition, size diversity, molar mass and size distributions of exopolymeric substances (EPS) from the bacterium Sinorhizobium meliloti wild type (WT) and by the exoY strain deficient in exopolysaccharide production was investigated. EPS obtained by centrifugation, EDTA and formaldehyde/NaOH were compared. It was found that the extraction method influenced TOC, TN and total protein content in EPS from both strains. However, no difference between EDTA and formaldehyde/NaOH methods was observed for the exopolysaccharide components. Similar functional groups and fluorescence pattern were found in the EPS obtained by different methods; however their relative abundance was method dependent. The extraction method also affected the molar mass and size distribution, HP SEC diversity among different treatment and bacterial strains. PMID- 22507905 TI - Production of aromatic hydrocarbons through catalytic pyrolysis of gamma valerolactone from biomass. AB - In the present study, gamma-valerolactone (GVL) is firstly reported to be converted into aromatic hydrocarbons through catalytic pyrolysis. The catalysts and reaction conditions are both critical in maximizing the hydrocarbon selectivity. Four zeolites, i.e. MCM-41, beta-zeolite, ZSM-5 and HZSM-5 were tested in this work, among which HZSM-5 (Si/Al=25) was found to be the most effective catalyst in both reactivity and selectivity. Under the reaction temperature of 500 degrees C, the highest carbon yield of 56.71% of aromatics was achieved from GVL with HZSM-5 (Si/Al=25) as catalyst. Moreover, the HZSM-5 catalyst was recycled for five times without significant decrease in product selectivity. PMID- 22507906 TI - Biotrickling filtration of complex pharmaceutical VOC emissions along with chloroform. AB - Biodegradation of chloroform along with a mixture of VOCs (methanol, ethanol, acetone and toluene) commonly found in pharmaceutical emissions using a biotrickling filter (BTF) was evaluated. The performance of the BTF was evaluated for both steady and transient conditions, for different inlet loading rates (ILR), empty bed residence time (EBRT) and inlet chloroform concentrations. Among the VOCs studied before chloroform feeding, toluene removal was the least, under all the operating conditions. Complete removal of all pollutants was achieved up to a chloroform loading rate of 14.22 g/m(3)/h. Increase in loading rate of chloroform adversely affected the removal efficiency of toluene and declined the overall performance of BTF. The results suggest that biodegradation of VOCs is influenced by the inlet loading rate and complexity of pollutants in the inlet air stream. Results from studies on shock loading and starvation indicated that the system was highly resilient to transient operating conditions. PMID- 22507907 TI - High ligation of the fistula track by lateral approach: a modified sphincter saving technique for advanced anal fistulas. AB - AIM: Ligation of the intersphincteric fistula track is a novel surgical procedure with the advantage of avoiding anal incontinence. We conducted a preliminary investigation of a modified technique for complicated trans-sphincteric anal fistula by high ligation of the track using a lateral approach. METHOD: From June 2010 to May 2011, 10 patients received high ligation of the fistula track using a lateral approach. Patients selected for the procedure had a mature trans sphincteric type of anal fistula that involved a significant amount of the external sphincter. Patients with early fistulous abscess or with a history of previous anal surgery were excluded. The surgical technique involved making an incision from the external opening and extending this towards the direction of the internal opening, dissection of the fistula from the underlying soft tissue, high ligation above the internal sphincter and removal of the distal part of the fistula track for pathological examination. RESULTS: Of the 10 patients, eight were men and the mean +/- SD age was 40.5 +/- 7.23 years. The median (range) duration of follow-up was 7 (6-10) months. In all patients, the wound was completely healed by the sixth postoperative week. Two cases of recurrence were noted later and were successfully managed by traditional fistulotomy. CONCLUSION: High-ligation surgery of the fistula track for trans-sphincteric anal fistula, aimed at total anal sphincter preservation, has shown encouraging early results. Long-term follow-up and randomized controlled trials are necessary. PMID- 22507908 TI - Analysis of the expression of microtubule plus-end tracking proteins (+TIPs) during Xenopus laevis embryogenesis. AB - Microtubules are a component of the cytoskeleton and are important for maintaining cell structure and providing platforms for intracellular transport in diverse cellular processes. Microtubule plus-end tracking proteins (+TIPs), a structurally and functionally diverse group of proteins, are specifically accumulated in the microtubule plus end and regulate dynamic microtubule behavior. We characterized the +TIPs, Clip1, p150(glued), Clasp1, Lis1 and Stim1, in Xenopus laevis and report their expression patterns during embryogenesis in this paper. All the five +TIP genes are maternally expressed and have similar expression patterns during Xenopus embryo development. The expression of +TIPs is localized in the animal hemisphere and ectoderm region at early stages of embryonic development. As development progresses to later stages, the ectodermal expression of +TIPs persists in head and neural tube structures. Clasp1, p150(glued) and Lis1 in particular are specifically expressed in the cranial nerves. Importantly, +TIPs are also expressed in the involuting mesoderm during gastrulation. This is the first study of developmental expression patterns of +TIPs, and our analysis provides insight that could serve as the basis for future research of microtubules in vertebrate development, cell movements during gastrulation and neurogenesis. PMID- 22507909 TI - Ex vivo alloanergization with belatacept: a strategy to selectively modulate alloresponses after transplantation. AB - Ex vivo alloanergization of human immune cells, via allostimulation in the presence of costimulatory blockade with either a combination of anti-B7.1 and anti-B7.2 antibodies or first-generation cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4-Ig), induces alloantigen-specific hyporesponsiveness and expands alloantigen-specific regulatory T cells (Treg). We have successfully used this approach in the clinical setting of haploidentical hematopoietic stem cell transplantation. Recently, the in vivo use of a new second-generation CTLA4-Ig, belatacept, has shown promise in controlling alloresponses after transplantation of both human kidneys and islet cells. We therefore compared the efficiency of first- and second-generation CTLA4-Ig in alloanergizing human peripheral blood mononuclear cells (PBMCs) and investigated whether ex vivo alloanergization with belatacept could be used to engineer an alloantigen-specific immunoregulatory population of autologous cells suitable for administration to recipients of cellular or solid organ transplant recipients. Alloanergization of HLA-mismatched human PBMCs with belatacept resulted in a greater reduction in subsequent alloresponses than alloanergization with first generation CTLA4-Ig. Moreover, subsequent ex vivo re-exposure of alloanergized cells to alloantigen in the absence of belatacept resulted in a significant expansion of Tregs with enhanced alloantigen-specific suppressive function. Alloanergized PBMCs retained functional Epstein-Barr virus (EBV)-specific T-cell responses, and expanded Tregs did not suppress EBV-specific proliferation of autologous cells. These results suggest that ex vivo alloanergization with belatacept provides a platform to engineer populations of recipient Treg with specificity for donor alloantigens but without nonspecific suppressive capacity. The potential advantages of such cells for solid organ transplantation include (1) reduction of the need for nonspecific immunosuppression, (2) retention of pathogen-specific immunity, and (3) control of graft rejection, if used as an intervention. PMID- 22507910 TI - Diagnostic value of an interleukin-6 bedside test in term and preterm neonates at the time of clinical suspicion of early- and late-onset bacterial infection. AB - BACKGROUND: For quick detection or exclusion of neonatal early-onset bacterial infection (EOBI) or late-onset bacterial infection (LOBI), interleukin (IL)-6 is used. Its clinical use is sometimes limited due to prolonged recall times. Therefore, an IL-6 bedside test was established. OBJECTIVE: To compare the diagnostic value of plasma IL-6 and an IL-6 bedside test at the time of clinical suspicion in the course of EOBI and LOBI. METHODS: Eighteen term (mean gestational age 40.2 weeks, SD 1.3) and 88 preterm (mean gestational age 30.1 weeks, SD 4.2) neonates with clinical and serological signs of bacterial infection were analysed. Eight had an EOBI, and 24 had a LOBI, of whom 13 were blood culture positive. Twelve term and 62 preterm neonates with risk factors but without proven EOBI/LOBI served as a non-infected group. RESULTS: At the time of clinical suspicion, the sensitivity of the IL-6 bedside test in comparison to plasma IL-6 was 69 versus 75% (p = 0.7744, McNemar's test), and specificity was 77 versus 81% (p = 0.6476, McNemar's test; cutoff level 50 ng/l). For LOBI, both the sensitivity (75%) and specificity (82%) of the bedside test exceeded values calculated for EOBI (sensitivity 50%, specificity 75%). CONCLUSION: No significant difference between the bedside and established plasma IL-6 test was detected for LOBI. For detection of EOBI, the bedside test was not sensitive enough. Larger studies are needed to verify our findings before IL-6 bedside tests can be recommended routinely. PMID- 22507911 TI - Exposure to potentially toxic hydrocarbons and halocarbons released from the dialyzer and tubing set during hemodialysis. AB - BACKGROUND: Although much is known about the effect of chronic kidney failure and dialysis on the composition of solutes in plasma, little is known about their impact on the composition of gaseous compounds in exhaled breath. This study was designed to explore the effect of uremia and the hemodialysis (HD) procedure on the composition of exhaled breath. Breath samples were collected from 10 dialysis patients immediately before, during, and after a dialysis session. To determine the potential introduction of gaseous compounds from dialysis components, gasses emitted from dialyzers, tubing set, dialysate, and water supplies were collected. STUDY DESIGN: Prospective cohort study. PARTICIPANTS: 10 HD patients and 10 age matched healthy individuals. PREDICTOR: Predictors include the dialyzers, tubing set, dialysate, and water supplies before, during, and after dialysis. OUTCOMES: Changes in the composition of exhaled breath. MEASUREMENTS: A 5-column/detector gas chromatography system was used to measure hydrocarbon, halocarbon, oxygenate, and alkyl nitrate compounds. RESULTS: Concentrations of 14 hydrocarbons and halocarbons in patients' breath rapidly increased after the onset of the HD treatment. All 14 compounds and 5 others not found in patients' breath were emitted from the dialyzers and tubing sets. Contrary to earlier reports, exhaled breath ethane concentrations in our dialysis patients were virtually unchanged during the HD treatment. LIMITATIONS: Single-center study with a small sample size may limit the generalizability of the findings. CONCLUSIONS: The study documented the release of several potentially toxic hydrocarbons and halocarbons to patients from the dialyzer and tubing sets during the HD procedure. Because long-term exposure to these compounds may contribute to the morbidity and mortality in dialysis population, this issue should be considered in the manufacturing of the new generation of dialyzers and dialysis tubing sets. PMID- 22507912 TI - The antinociceptive activity of harmicine on chemical-induced neurogenic and inflammatory pain models in mice. AB - Harmicine is a beta-carboline alkaloid isolated and identified as a major active compound present in many plant species and marine invertebrates. This alkaloid exhibits a wide spectrum of pharmacological activities, including antispasmodic, antipyretic, and anticancer properties. This report described the antinociceptive properties of harmicine by means of chemical experimental models in order to evaluate the use for pain relief. The results demonstrating the potential analgesic properties of harmicine administered intraperitoneally were shown with the writhing test, reducing writhes around 60% (1 mg/kg), and in the formalin test, where harmicine was more effective toward neurogenic (reducing reaction time around 60%, 1 mg/kg) than inflammatory (68% reduction, 10 mg/kg) pain responses. Furthermore, these effects may operate via vanilloid receptors as revealed by the capsaicin test (41% reduction, with 3 mg/kg), as well as via peripheral glutamate receptors as shown by the glutamate test (50% reduction, with 1 mg/kg). Moreover, the opioid antagonist naloxone hydrochloride did not interfere in the antinociceptive properties of harmicine in the writhing test, revealing that this effect may not have a relationship with the opioid systems. Concluding, this report highlights harmicine as a new candidate to be used as analgesic in the future. Therefore, further studies are being undertaken in order to understand the exact mechanisms involved with the antinociceptive properties of harmicine. PMID- 22507913 TI - High novelty-seeking predicts greater sensitivity to the conditioned rewarding effects of cocaine. AB - Novelty-seeking in rodents, defined as enhanced specific exploration of novel situations, is considered to predict the response of animals to drugs of abuse and, thus, identify "drug-vulnerable" individuals. The main objective of this work was to determine the capacity of two animal models-the novel object recognition task and the novel environment test-for evaluating to what extent novelty-seeking can predict greater sensitivity to the rewarding properties of cocaine in young adult (PND 56) and adolescent (PND 35) OF1 mice of both sexes. Conditioned place preference, a useful tool for evaluating the sensitivity of individuals to the incentive properties of addictive drugs, was induced with a sub-threshold dose of cocaine (1 mg/kg, i.p.). Three factors that predispose individuals to addiction were considered: age, sex and novelty-seeking trait. CPP was detected only in the young adults that spent most time exploring the novel environment (High Novel Environment Seekers, High-Environment-NS). The novel environment test seemed to be more effective than the novel object recognition task in identifying young adults vulnerable to drugs; specifically, it revealed a distinction between High- and Low-Environment-NS mice that predicted greater sensitivity to the rewarding properties of cocaine among young adults but not among adolescents. Although our results reveal a higher novelty preference among young adult females than among their male counterparts in the two NS tests, both sexes showed similar susceptibility to the rewarding effects of a sub-threshold dose of cocaine in the CPP. These findings suggest that screening can identify humans at-risk of becoming drug users, and may contribute to the development of prevention strategies based on specific vulnerabilities. PMID- 22507914 TI - Experimental hypertension induced vascular dementia: pharmacological, biochemical and behavioral recuperation by angiotensin receptor blocker and acetylcholinesterase inhibitor. AB - Involvement of vascular pathology has been suggested in hypertension as well as vascular dementia (VaD), which also have a very high degree of co-occurrence in ageing population. We have recently reported that experimental diabetes as well as hyperhomocystenemia induces VaD. In the present research work, for the first time we are reporting the genesis of VaD by deoxycorticosterone acetate (DOCA) salt induced experimental hypertension. Furthermore, we have also investigated the beneficial effect of telmisartan, an angiotensin II type 1 receptor blocker (ARB) and donepezil, an acetylcholinesterase inhibitor (AChEI), on DOCA-salt hypertension induced VaD in rats. DOCA-salt hypertensive rats performed poorly on Morris water maze, reflecting impairment in their learning and memory. Furthermore, DOCA-salt treatment has shown a significant impairment of vascular endothelial function (DOCA attenuated acetylcholine induced endothelium dependent relaxation), with a significant reduction in serum nitrite/nitrate levels, along with increased aortic, serum and brain oxidative stress levels (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and brain acetylcholinesterase activity. Treatments of telmisartan as well as donepezil significantly attenuated DOCA-salt hypertension induced learning and memory deficits, endothelial dysfunction, and changes in various biochemical parameters. It may be concluded that DOCA-salt hypertension induces VaD in rats. ARBs and AChEIs may be considered as potential pharmacological agents for the management of hypertension induced VaD. PMID- 22507916 TI - Are higher cited papers accepted faster for publication? PMID- 22507915 TI - Low oral doses of bisphenol A increase volume of the sexually dimorphic nucleus of the preoptic area in male, but not female, rats at postnatal day 21. AB - Perinatal treatment with relatively high doses of bisphenol A (BPA) appears to have little effect on volume of the rodent sexually dimorphic nucleus of the preoptic area (SDN-POA). However, doses more relevant to human exposures have not been examined. Here, effects of pre- and post-natal treatment with low BPA doses on SDN-POA volume of postnatal day (PND) 21 Sprague-Dawley rats were evaluated. Pregnant rats were orally gavaged with vehicle, 2.5 or 25.0 MUg/kg BPA, or 5.0 or 10.0 MUg/kg ethinyl estradiol (EE2) on gestational days 6-21. Beginning on the day after birth, offspring were orally treated with the same dose their dam had received. On PND 21, offspring (n=10-15/sex/group; 1/sex/litter) were perfused and volume evaluation was conducted blind to treatment. SDN-POA outline was delineated using calbindin D28K immunoreactivity. Pairwise comparisons of the significant treatment by sex interaction indicated that neither BPA dose affected female volume. However, females treated with 5.0 or 10.0 MUg/kg EE2 exhibited volumes that were larger than same-sex controls, respectively (p<0.001). Males treated with either BPA dose or 10.0 MUg/kg/day EE2 had larger volumes than same sex controls (p<0.006). These data indicate that BPA can have sex-specific effects on SDN-POA volume and that these effects manifest as larger volumes in males. Sensitivity of the methodology as well as the treatment paradigm was confirmed by the expected EE2-induced increase in female volume. These treatment effects might lead to organizational changes within sexually dimorphic neuroendocrine pathways which, if persistent, could theoretically alter adult reproductive physiology and socio-sexual behavior in rats. PMID- 22507917 TI - Enhancement of the antitumor effect on combination therapy of an anticancer drug and its antibody against carcinoembryonic antigen. AB - BACKGROUND: Carcinoembryonic antigen (CEA) is frequently overexpressed in various types of human cancers and is associated with cell adhesion. There are three possible mechanisms of cancer therapy that employ anti-CEA antibody (Ab): Ab dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) or the prevention of CEA interaction with the extracellular matrix and/or intercellular adhesion molecules resulting in anoikis. In this study, the effect of C2-74, a human anti-CEA monoclonal Ab was evaluated. METHODS: ADCC, CDC and anoikis assays in combination with C2-74 and an anticancer drug (5-fluorouracil or cisplatin) were investigated using tumor cell lines (MKN-45, MKN-74 and KATO III). In the anoikis assay, other human anti-CEA Abs and mouse anti-CEA-related cell adhesion molecule 6 Abs were also investigated using HLC-1 cells. RESULTS: Additive cytotoxicity was observed when the anticancer drug and C2-74 on tumor cells were combined in the CDC assays, whereas in the anoikis assay, no such additive effect was observed. Anti-CEA-related cell adhesion molecule 6 Abs, but not anti-CEA Abs, accelerated anoikis in HLC-1 cells. CONCLUSION: A mechanism for the additive antitumor effect when an anticancer drug and C2-74 are combined is indicated mainly by CDC activity but is irrelevant to anoikis in tumor cells. PMID- 22507918 TI - A brain aggregate model gives new insights into the pathobiology and treatment of prion diseases. AB - Brain aggregates (BrnAggs) derived from fetal mouse brains contain mature neurons and glial cells. We determined that BrnAggs are consistently infected with Rocky Mountain Laboratory scrapie strain prions and produce increasing levels of the pathogenic form of the prion protein (PrP). Their abundant dendrites undergo degeneration shortly after prion infection. Treatment of prion-infected BrnAggs with drugs, such as a gamma-secretase inhibitors and quinacrine (Qa), which stop PrP formation and dendritic degeneration, mirrors the results from rodent studies. Because PrP is trafficked into lysosomes by endocytosis and autophagosomes by phagocytosis in neurons of prion strain-infected BrnAggs, we studied the effects of drugs that modulate subcellular trafficking. Rapamycin (Rap), which activates autophagy, markedly increased light-chain 3-II (LC3-II) positive autophagosomes and cathepsin D-positive lysosomes in BrnAggs but could not eliminate the intracellular PrP within them. Adding Qa to Rap markedly reduced the number of LC3-II-positive autolysosomes. Rap + Qa created a competition between Rap increasing and Qa decreasing LC3-II. Rapamycin + Qa decreased total PrP by 56% compared with that of Qa alone, which reduced PrP by 37% relative to Rap alone. We conclude that the decrease was dominated by the ability of Qa to decrease the formation of PrP. Therefore, BrnAggs provide an efficient in vitro tool for screening drug therapies and studying the complex biology of prions. PMID- 22507921 TI - Adaptive external gating based on the updating method of internal/external correlation and gating window before each beam delivery. AB - The purpose of this study is to evaluate the performance of an adaptive gating method, which is designed to accommodate the beam-to-beam and day-to-day variation of the internal/external correlation, as well as the real tumor position during respiratory-gated fractionated radiotherapy. We define a two-step procedure: (1) before each treatment, target positions are detected and synchronized with an external surrogate for establishing the internal/external correlation model and determining the position of the gating window, and then (2) during the delivery of the treatment beam, the gating is triggered by an external signal based on the updated internal/external correlation and window position. This correlation is described by a linear-quadratic model including a time shift between the internal and external signals. To simulate the proposed method, data of tumor motion in the superior-inferior direction synchronized with an external surrogate during hypo-fractionated radiotherapy from five lung patients are analyzed retrospectively. Duty cycle (DC), target coverage (TC) and the average distance (AD) between the internal target position and the edge of the gating window for all false positives are calculated as evaluative criteria. Under a 5 mm gating window, the average TC is 88.9%, with a DC around 45% and a mean AD of 0.7 mm. A daily update is also simulated for comparison, and it is found that beam-to-beam updating is superior. In conclusion, the combined updating of internal/external correlation and the gating window for each beam can improve the accuracy and reliability of respiratory-gated radiotherapy. PMID- 22507920 TI - Botulinum toxin for vaginismus treatment. AB - BACKGROUND/AIMS: Vaginismus is characterized by recurrent or persistent involuntary contraction of the perineal muscles surrounding the outer third of the vagina when penile, finger, tampon, or speculum penetration is attempted. Recent results have suggested the use of botulinum toxin for the treatment of vaginismus. Here, we assessed previously published data to evaluate the therapeutic effectiveness of botulinum toxin for vaginismus. METHODS: We have carried out a systematic review followed by a meta-analysis. RESULTS: Our results indicate that botulinum toxin is an effective therapeutic option for patients with vaginismus (pooled odds ratio of 8.723 with 95% confidence interval limits of 1.942 and 39.162, p = 0.005). This may hold particularly true in treatment refractory patients because most of the studies included in this meta-analysis have enrolled these subjects in their primary analysis. CONCLUSION: Botulinum toxin appears to bea reasonable intervention for vaginismus. However, this conclusion should be read carefully because of the deficiency of placebo controlled randomized clinical trials and the quality issues presented in the existing ones. PMID- 22507922 TI - Delayed carotid surgery: what are the causes in the north west of England? AB - INTRODUCTION: Carotid endarterectomy (CEA) should be performed within two weeks of symptoms for patients with carotid stenosis >50%. Whether these standards are being achieved and causes of delay between symptoms and CEA were investigated. DESIGN: An analysis of prospectively collected multi-centre data. MATERIALS: Consecutive data for patients undergoing CEA between January-2006 and September 2010 were collected. Asymptomatic patients and those with no details on the timing of cerebral symptoms were excluded. METHODS: 'Delay' from symptom to CEA was defined as more than two weeks and 'prolonged-delay' more than eight weeks. Univariable and multivariable analyses were used to identify factors associated with these delays. RESULTS: Of 2147 patients with symptoms of cerebral ischaemia, 1522(70.9%) experienced 'delay' and 920(42.9%) experienced 'prolonged delay'. Patients with ischaemic heart disease were more likely to experience 'delay' (OR = 1.56; 95% CI 1.11-2.19, p = 0.011), whereas patients with stroke (OR = 0.77; 95%CI 0.63-0.94, p = 0.011) and those treated at hospitals with a stroke prevention clinic (OR = 0.57; 95%CI 0.46-0.71, p < 0.001) were less likely to experience 'delay'. Patients treated after the publication of National Institute for Health and Clinical Excellence (NICE) guidelines were less likely to experience 'prolonged delay' (OR = 0.77; 95%CI 0.65-0.91, p = 0.003) but not 'delay'. CONCLUSION: Few patients achieved CEA within two weeks of symptoms. Introducing stroke-prevention clinics with one-stop carotid imaging appears important. PMID- 22507923 TI - Asymptomatic carotid artery stenosis: identification of subgroups with different underlying plaque characteristics. AB - OBJECTIVES: Optimal surgical treatment of patients with asymptomatic carotid artery stenosis (ACAS) remains a matter of debate. Established definitions of ACAS include: (1) patients who never suffered from ipsilateral cerebrovascular events (group 1) or (2) patients who suffered from ipsilateral cerebrovascular events more than 6 months prior to revascularisation (group 2). Cerebrovascular symptoms are closely related to underlying carotid plaque composition and therefore we investigated potential plaque differences between these definition based subgroups. DESIGN: Cross-sectional analysis of a longitudinal prospective biobank study. MATERIAL AND METHODS: Carotid atherosclerotic plaques from 264 asymptomatic patients were harvested during endarterectomy, and subjected to histopathological examination. Patients were divided into two groups: group 1: truly asymptomatic (n = 182), and group 2: patients with ipsilateral events more than 6 months before carotid endarterectomy (CEA) (n = 82). RESULTS: Patients in group 1 had relatively more stable plaque characteristics as compared with patients in group 2, with a higher median plaque smooth muscle cell content (2.1 (0.0-18.7) vs. 1.6 (0.0-14.4); P = 0.036), a higher proportion of heavily calcified plaques (67.7% (123/182) vs. 48.8% (40/82); P = 0.005) and less frequently intraplaque haemorrhages (11.5% (21/182) vs. 30.5% (25/82); P = 0.001). CONCLUSION: Different plaque characteristics within subgroups of ACAS patients can be identified based on reported past ipsilateral events, which might result in adjusted future treatment strategies. PMID- 22507924 TI - Diagnostic laparoscopy for early detection of acute mesenteric ischaemia in patients with aortic dissection. AB - INTRODUCTION: Recognition of acute mesenteric ischaemia (AMesI) in patients with aortic dissection (AoD) may be a challenge and exploratory laparotomy is often performed. METHODS: We retrospectively analysed our experience with the use of diagnostic laparoscopy (DL) for the early detection of AMesI in patients with AoD, either undergoing medical treatment or after open/endovascular interventions. RESULTS: Between 2004 and 2011, 202 consecutive AoDs were treated in our centre (71 acute type A AoD; 131 acute and chronic type B AoD). Among the 17 (8.4%) patients in which AMesI was suspected, nine (52.9%) were selected for DL. Three DLs were performed during medical treatment of patients with acute type B AoD, six after treatment of AoD (both surgical and endovascular). Three second look DLs were also performed. Eight DLs were negative, three showed AMesI and the patients underwent successful emergent revascularisation. One DL was not conclusive and laparotomy was required. Among the eight patients not submitted to DL, one case of bowel infarction was recorded. CONCLUSIONS: In our series DL was feasible and safe. The low invasiveness and repeatability were the main advantages. Although additional experience is mandatory, DL seems a promising technique for the detection of AMesI in patients with AoD. PMID- 22507925 TI - Comparative stability of sodium tetradecyl sulphate (STD) and polidocanol foam: impact on vein damage in an in-vitro model. AB - OBJECTIVES: To compare the half-life of STD and polidocanol air-based foams and the damage they inflict upon human great saphenous vein in an in-vitro model. METHODS: The time for the volume of 3% STD and polidocanol foams to reduce by 10% (T(90)) and 50% (T(50)) was recorded in an incubator at 37 degrees C. Segments of proximal GSV harvested during varicose vein surgery were filled with foam for 5 or 15 min. Histological analysis determined percentage endothelial cell loss and depth of media injury. RESULTS: Median (+/-IQR) T(90) and T(50) for polidocanol were 123.3 s (111.7-165.6) and 266.3 s (245.6-383.1) versus 102.03 s (91.1-112) and 213.13 s (201-231.6) for STD (T(90)p = 0.008, T(50)p = 0.004). Median endothelial loss with polidocanol was; 63.5% (62.2-82.8) and 85.9% (83.8 92.5) versus 86.3% (84.8-93.7) and 97.64% (97.3-97.8) for STD after 5 and 15 min (p = 0.076 and p = 0.009). The median depth and % media thickness injured were 0 MUm (0-0 MUm) and 0% for both assessments with polidocanol versus 37.4 MUm (35.3 45.8 and 43.4 MUm (42.1-46.7) and 3.5% (3.1-3.6) and 5.3% (3.7-6.0) after 5 and 15 min for STD (p < 0.01 for all comparisons). CONCLUSION: Although polidocanol foam shows greater stability than STD foam perhaps remaining in the vein for longer, endothelial cell loss and damage to the media were significantly greater with STD. PMID- 22507926 TI - Commentary on 'Delayed carotid surgery: what are the causes in the north west of England?'. PMID- 22507928 TI - How can this be? Preventing death in patients with HIV-associated tuberculosis. PMID- 22507929 TI - Treatment of MDR-TB: is hepatotoxicity a problem? PMID- 22507930 TI - Are national asthma programmes needed in resource-limited settings? PMID- 22507927 TI - Antiviral agents and HIV prevention: controversies, conflicts, and consensus. AB - Antiviral agents can be used to prevent HIV transmission before exposure as preexposure prophylaxis (PrEP), after exposure as postexposure prophylaxis, and as treatment of infected people for secondary prevention. Considerable research has shed new light on antiviral agents for PrEP and for prevention of secondary HIV transmission. While promising results have emerged from several PrEP trials, the challenges of poor adherence among HIV-negative clients and possible increase in sexual risk behaviors remain a concern. In addition, a broader pipeline of antiviral agents for PrEP that focuses on genital tract pharmacology and safety and resistance issues must be developed. Antiretroviral drugs have also been used to prevent HIV transmission from HIV-infected patients to their HIV-discordant sexual partners. The HIV Prevention Trials Network 052 trial demonstrated nearly complete prevention of HIV transmission by early treatment of infection, but the generalizability of the results to other risk groups - including intravenous drug users and MSM - has not been determined. Most importantly, the best strategy for use of antiretroviral agents to reduce the spread of HIV at either the individual level or the population level has not been developed, and remains the ultimate goal of this area of investigation. PMID- 22507931 TI - Global guidelines for treatment of tuberculosis among persons living with HIV: unresolved issues. AB - The Revised National Tuberculosis Control Programme (RNTCP) in India uses a fully intermittent thrice-weekly rifampicin-containing regimen for all tuberculosis (TB) patients, including those who are human immunodeficiency virus (HIV) infected, whereas the World Health Organization (WHO) recommends daily anti tuberculosis treatment at least during the intensive phase. The WHO recommendation was based on the results of a meta-analysis demonstrating increased risk of recurrence and failure among HIV-infected TB patients receiving intermittent TB treatment compared to a daily regimen. Review of the primary evidence indicates limited, low-quality information on intermittency, mostly from observational studies in the pre-antiretroviral treatment (ART) era. Molecular epidemiology in India indicates that most of the recurrences and many of the failures result from exogenous re-infection, suggesting poor infection control and high transmission rather than poor regimen efficacy. Subsequently published studies have shown acceptable treatment outcomes among HIV-infected TB patients receiving intermittent anti-tuberculosis regimens with concomitant ART. Treatment outcomes among HIV-infected TB patients treated under programmatic conditions show low failure rates but high case fatality; death has been associated with lack of ART. The highest priority is therefore to reduce mortality by linking all HIV-infected TB patients to ART. While urgently seeking to reduce death rates among HIV-infected TB patients, given the poor evidence for change and operational advantages of an intermittent regimen, the RNTCP intends to collect the necessary evidence to inform national policy decisions through randomised clinical trials. PMID- 22507932 TI - FEV3, FEV6 and their derivatives for detecting airflow obstruction in adult Chinese. AB - BACKGROUND: Forced expiratory volume in 3 seconds (FEV(3)) and 6 seconds (FEV(6)) could complement FEV(1) and forced vital capacity (FVC) for detecting airflow obstruction. OBJECTIVE: To compare FEV(1)/ FEV(6) and FEV(3)/FVC with FEV(1)/FVC in the detection of airflow obstruction. METHOD: Previous lung function data were re-analysed to establish reference values for FEV(3) and FEV(6). Data from a separate cohort of male smokers were used as test set. FEV(1), FEV(3), FEV(6), FVC, FEV(1)/FVC, FEV(1)/ FEV(6) and FEV(3)/FVC were regressed against age, standing height, weight and body mass index, and the mean and 95% confidence intervals for the lower limit of normal (LLN) values for these parameters were determined. RESULTS: The percentage of smokers with airflow obstruction in the test population using FEV(1)/FVC < LLN was 15.0%, while using FEV(1)/ FEV(6) < LLN and FEV(3)/FVC < LLN they were respectively 18.5% and 18.1%. Using FEV(1)/FVC < LLN as reference, the sensitivity and specificity of FEV(1)/ FEV(6) < LLN in identifying airflow obstruction were 82.3% and 92.8%, while those for FEV(3)/FVC < LLN were 78.5% and 92.6%; the positive and negative predictive values were 67% and 96.7% for FEV(1)/ FEV(6) < LLN and 65.3% and 96% for FEV(3)/FVC < LLN. CONCLUSION: FEV(3)/FVC < LLN and FEV(1)/ FEV(6) < LLN are comparable to FEV(1)/FVC < LLN for detecting airflow obstruction. FEV(3)/FVC < LLN could be useful in screening for airflow obstruction, while FEV(1)/ FEV(6) < LLN is useful in detecting airflow limitation in the elderly or in subjects with severe airflow obstruction. PMID- 22507934 TI - Location of Xpert(r) MTB/RIF in centralised laboratories in South Africa undermines potential impact. PMID- 22507936 TI - Should Xpert(r) MTB/RIF be rolled out in low-income countries? PMID- 22507938 TI - Global laboratory initiative tool for a stepwise process towards tuberculosis laboratory accreditation. PMID- 22507933 TI - The challenges of replicating the methodology between Phases I and III of the ISAAC programme. AB - BACKGROUND: The International Study of Asthma and Allergies in Childhood (ISAAC) used standardised methods to examine symptom prevalence of asthma, rhinitis and eczema in adolescents and children between Phases I and III. Centres followed essential rules to ensure comparability of methodology, examined by a centralised data centre. METHODS: Centre reports (CRs) were compared for both phases and age groups. Methodological differences were categorised under major deviations (centres excluded), minor deviations (deviations identified in published tables) and very minor deviations (deviations not identified). RESULTS: There were 112 CRs for adolescents and 70 for children. Six centres for adolescents and four for children had major deviations and were excluded. Minor deviations (35 for adolescents and 20 for children) were identified in the publications. Very minor deviations (92 for adolescents and 51 for children) were not identified. The odds ratios for having any differences in methodology between phases with a change in Principal Investigator were 0.80 (95%CI 0.36 1.81) for adolescents and 0.91 (95%CI 0.32-2.62) for children. CONCLUSION: The majority of the centres replicated the ISAAC methodology to a high standard. Careful documentation of methodology using standardised tools with careful checks allows the full potential of studies such as ISAAC to be realised. PMID- 22507939 TI - Line probe and automated real-time PCR TB assays warrant adherence to strict quality assurance measures. PMID- 22507940 TI - Scientific and patient care evidence to change susceptibility breakpoints for first-line anti-tuberculosis drugs. PMID- 22507941 TI - TB screening in an HIV clinic: how interferon-gamma assays improve screening compliance. PMID- 22507942 TI - A presentation of Poncet's disease identified following immunosuppressive steroid therapy. PMID- 22507943 TI - Almost universal coverage: HIV testing among TB patients in a rural public programme. PMID- 22507944 TI - Geographic variability in COPD prevalence. PMID- 22507946 TI - Biological water oxidation: lessons from nature. AB - Hydrogen production by water splitting may be an appealing solution for future energy needs. To evolve hydrogen efficiently in a sustainable manner, it is necessary first to synthesize what we may call a 'super catalyst' for water oxidation, which is the more challenging half reaction of water splitting. An efficient system for water oxidation exists in the water oxidizing complex in cyanobacteria, algae and plants; further, recently published data on the Manganese-calcium cluster have provided details on the mechanism and structure of the water oxidizing complex. Here, we have briefly reviewed the characteristics of the natural system from the standpoint of what we could learn from it to produce an efficient artificial system. In short, to design an efficient water oxidizing complex for artificial photosynthesis, we must learn and use wisely the knowledge about water oxidation and the water oxidizing complex in the natural system. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial. PMID- 22507947 TI - Auditory-perceptual voice characteristics in pre-operative patients undergoing thyroid or parathyroid surgery. AB - OBJECTIVES: To systematically evaluate auditory perceptual voice characteristics in people with thyroid disease prior to undergoing thyroid surgery. PATIENTS AND METHODS: This study examined the auditory perceptual voice characteristics of 96 individuals with thyroid disease. Participants were categorised by type of thyroid disease (i.e. multinodular goitre, thyroid cancer, thyroid nodule, toxicity or parathyroidism) and by status of compression (i.e. compression versus no compression). Auditory perceptual voice ratings were made on samples of connected speech by using the Perceptual Voice Profile. RESULTS: A high prevalence of participants had deviant auditory perceptual voice features; however, the majority of these abnormalities were slight to mild in severity and only 8% of participants had a clinically significant auditory perceptual abnormality. There was no significant difference in features between diagnostic categories, and only high pitch was rated as more significantly deviant in patients without compression versus those with compression. CONCLUSIONS: This study supports the need for auditory-perceptual ratings to be included as part of pre-operative multidimensional assessment of voice in patients with thyroid disease. PMID- 22507948 TI - Outcomes of HIV-infected patients treated for recurrent tuberculosis with the standard retreatment regimen. AB - SETTING: The Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (the GHESKIO AIDS and TB Center) in Port-au-Prince, Haiti. OBJECTIVE: To measure the effectiveness of the standard TB retreatment regimen (2HRZES/1HRZE/5HRE) in human immunodeficiency virus (HIV) infected adults. DESIGN: Cohort study. RESULTS: Of 1318 HIV-infected patients with access to antiretroviral therapy following World Health Organization guidelines, 56 were diagnosed with recurrent pulmonary TB and retreated with the standard retreatment regimen: 10 patients (18%) died during retreatment, 3 (5%) defaulted, and 2 (4%) failed treatment. Forty-one patients (73%) achieved retreatment 'success' (cure, treatment completed). Of these, 8 (20%) died during follow-up, 5 (12%) were lost, and 5 (12%) had a second recurrence of TB. Only 26 (46%) of the 56 patients remained alive, in care, and TB-free after a median of 36 months of follow-up. CONCLUSION: HIV-infected patients treated for recurrent TB with the standard retreatment regimen have high mortality and poor long-term outcomes. PMID- 22507949 TI - A brief history of INA and ICOH SCNP: International Neurotoxicology Association and International Congress on Occupational Health Scientific Committee on Neurotoxicology and Psychophysiology. AB - Two international scientific societies dedicated to research in neurotoxicology and neurobehavioral toxicology are the International Neurotoxicology Association (INA) and the International Congress on Occupational Health International Scientific Committee on Neurotoxicology and Psychophysiology (ICOH SCNP). From June 5-10, 2011 these two societies held a joint conference in Xi'an China entitled the Xi'an International Neurotoxicology Conference, Neurotoxicity and Neurodegeneration: Local Effect and Global Impact. At the conference two featured talks presented a brief history of the two societies. This article is a synthesis and expansion of those two presentations. The history of INA and ICOH SCNP is described in relation to the antecedent events leading to the formation of the two societies, their parallel developments, the nature of the societies and their scientific conferences, and a brief description of some of their accomplishments. Together, the historical development of these two societies is an important component of the development of the scientific discipline of neurotoxicology. PMID- 22507950 TI - Neuroinflammation: a need to understand microglia as resident cells of the developing brain. AB - Neuroinflammation and microglia as the resident immune cells of the brain has garnered a significant amount of interest with regards to brain injury and neurotoxicology. Much of this interest and research has been focused on responses in the adult brain with little attention paid to the role of these cells during development. The available data suggests that one must view microglia and their processes during development somewhat differently. In addition, modification to microglia during development may lay a framework for subtle to significant changes in the susceptibility of the mature brain to secondary insults. A number of these point are now being raised for consideration. PMID- 22507951 TI - A perverse 'net' effect? Health insurance and ex-ante moral hazard in Ghana. AB - Incentive problems in insurance markets are well-established in economic theory. One of these incentive problems is related to reduced prevention efforts following insurance coverage (ex-ante moral hazard). This prediction is yet to be tested empirically with regard to health insurance, as the health domain is often considered relatively immune to perverse incentives, despite its validation in other insurance markets that entail adverse shocks. This paper tests for the presence of ex-ante moral hazard with reference to malaria prevention in Ghana. We investigate whether enrollment in the country's National Health Insurance Scheme (NHIS) negatively affects ownership and use of insecticide-treated bed nets (ITNs). We use a panel of 400 households in the Brong Ahafo region for this purpose and employ a propensity-adjusted household fixed effects model. Our results suggest that ex-ante moral hazard is present, especially when the level of effort and cost required for prevention is high. Implications of perverse incentive effects for the NHIS are briefly outlined. PMID- 22507952 TI - Governing the moral economy: animal engineering, ethics and the liberal government of science. AB - The preferred Western model for science governance has come to involve attending to the perspectives of the public. In practice, however, this model has been criticised for failing to promote democracy along participatory lines. We argue that contemporary approaches to science policy making demonstrate less the failure of democracy and more the success of liberal modes of government in adapting to meet new governance challenges. Using a case study of recent UK policy debates on scientific work mixing human and animal biological material, we show first how a 'moral economy' is brought into being as a regulatory domain and second how this domain is governed to align cultural with scientific values. We suggest that it is through these practices that the state assures its aspirations for enhancing individual and collective prosperity through technological advance are met. PMID- 22507953 TI - Can we rely on PET in the follow-up of advanced seminoma patients? AB - The management of residuals after completion of chemotherapy in advanced seminoma is controversial. It has been proposed that fluorodeoxyglucose-positron emission tomography (FDG-PET) can be used as a follow-up. In this study we investigated FDG-PET as a follow-up tool in advanced seminoma patients treated previously with chemotherapy or radiotherapy. Thirty-seven patients assigned to an advanced seminoma group based on CT and/or FDG-PET/CT and then treated with chemotherapy were included in the study. All these patients underwent FDG-PET/CT examination as a part of the follow-up scheme. Patients underwent retroperitoneal lymph node dissection (RPLND), radiotherapy, or were followed clinically by CT and/or PET/CT every 6 months. In 8 cases FDG-PET was positive: 5 of them underwent RPLND and 3 radiotherapy. Two patients with negative FDG-PET but positive CT also underwent RPLND. The remaining patients with negative FDG-PET results were followed up. FDG PET/CT was false positive in one case >3 cm and one <3 cm, in 6 cases >3 cm it was true negative. While FDG-PET can find a viable tumor, there also is an important question of false positive results. It was clinically proven that a negative FDG-PET was correlated with stable disease, but we were unable to examine specimens in these cases. PMID- 22507954 TI - RNA-Seq analysis of frontal cortex and cerebellum from 5XFAD mice at early stage of disease pathology. AB - The pathogenesis of Alzheimer's disease (AD), especially the early events of AD pathology, remains unknown because of the complexity of AD and limitation of analysis methods. Transcriptome analysis has provided comprehensive insights to investigate the complex cellular activity in brain, but the transcriptome profiles from AD patients with microarray have generated discordant results. Here, for the first time, we performed transcriptome analysis of frontal cortex and cerebellum in 7-week-old 5XFAD transgenic mice (before extracellular amyloid plaque deposits) using high-throughput RNA-Seq analysis. Specific functional annotations were identified with differentially expressed genes (DEGs) of frontal cortex (a typically vulnerable region of AD pathology) and cerebellum (a typically non-vulnerable region of AD pathology). Cardiovascular disease-related genes were significantly found in down-regulated DEGs of frontal cortex, and mitochondrial dysfunction-related genes were evident in down-regulated DEGs of cerebellum. Additionally, we found RNA variants at the nucleotide level in transgenic mice compared with non-transgenic mice. Our results indicate that both frontal cortex and cerebellum in 5XFAD transgenic mice show specific pathological processes in the early pathophysiology of AD. PMID- 22507957 TI - The biological effects of subacute inhalation of diesel exhaust following addition of cerium oxide nanoparticles in atherosclerosis-prone mice. AB - BACKGROUND: Cerium oxide (CeO(2)) nanoparticles improve the burning efficiency of fuel, however, little is known about health impacts of altered emissions from the vehicles. METHODS: Atherosclerosis-prone apolipoprotein E knockout (ApoE(-/-)) mice were exposed by inhalation to diluted exhaust (1.7 mg/m(3), 20, 60 or 180 min, 5 day/week, for 4 weeks), from an engine using standard diesel fuel (DE) or the same diesel fuel containing 9 ppm cerium oxide nanoparticles (DCeE). Changes in hematological indices, clinical chemistry, atherosclerotic burden, tissue levels of inflammatory cytokines and pathology of the major organs were assessed. RESULTS: Addition of CeO(2) to fuel resulted in a reduction of the number (30%) and surface area (10%) of the particles in the exhaust, whereas the gaseous co pollutants were increased (6-8%). There was, however, a trend towards an increased size and complexity of the atherosclerotic plaques following DE exposure, which was not evident in the DCeE group. There were no clear signs of altered hematological or pathological changes induced by either treatment. However, levels of proinflammatory cytokines were modulated in a brain region and liver following DCeE exposure. CONCLUSIONS: These results imply that addition of CeO(2) nanoparticles to fuel decreases the number of particles in exhaust and may reduce atherosclerotic burden associated with exposure to standard diesel fuel. From the extensive assessment of biological parameters performed, the only concerning effect of cerium addition was a slightly raised level of cytokines in a region of the central nervous system. Overall, the use of cerium as a fuel additive may be a potentially useful way to limit the health effects of vehicle exhaust. However, further testing is required to ensure that such an approach is not associated with a chronic inflammatory response which may eventually cause long-term health effects. PMID- 22507958 TI - Allium ursinum L.: bioassay-guided isolation and identification of a galactolipid and a phytosterol exerting antiaggregatory effects. AB - AIMS: We wanted to investigate the possible antithrom botic effects and elucidate the chemical identity of the active principles involved in inhibitory effects against adenosine diphosphate(ADP)-induced aggregation of human platelets by wild garlic, Allium ursinum L. METHODS: For this purpose, a bioassay-guided isolation procedure was used followed by spectrometric identification of pure active compounds. For the bioassay, blood was taken from healthy human volunteers and platelet-rich plasma was prepared for turbidimetric platelet aggregation tests. Platelet-rich plasma, stimulated with 20 MU mol/l of ADP, was treated with extracts of different polarities, fractions and isolated single compounds from A. ursinum. The extracts were investigated by thin-layer chromatography(TLC), HPLC, mass spectroscopy, electrospray ionization mass spectrometry (ESI-MS) and 1/2 dimensional (1)H/(13) C-nuclear magnetic resonance (NMR) spectroscopic techniques. RESULTS: Fresh A. ursinum leaves were extracted with ethanol, which was the potent form that effectively inhibited ADP-induced aggregation of human platelets. Thisethanolic extract was subjected to liquid-liquid partition. Whilst the aqueous phase, containing the moiety of cysteine sulphoxide and thiosulphinate derivatives, showed only weak activity on platelet aggregation, the ethyl-acetate and particularly the chloroform partitions showed the high estaggregation-inhibiting potency. Thus, in our bioassay, the effects of alliins/allicins could be neglected. The chloroform phase, possessing the strongest activity, was separated into 28 fractions by gradient-elution open column chromatography on silica gel. The most active fractions 11-17 were separated again, yielding 10 subfractions. This afforded 1,2-di-O-alpha linolenoyl-3-O-beta-D-galactopyranosyl-sn-glycerol and beta-sitosterol-3-O-beta-D glucopyranoside, the structures of which were determined by ESI-MS and 1/2 dimensional (1)H/(13) CNMR spectroscopic techniques. Furthermore, the minute amounts of volatile oil of A. ursinum leaves obtained by steam distillation according to Ph. Eur. could be evaluated asa third aggregation-inhibiting principle. CONCLUSION: In our study, for the first time, 2 active, non-sulphur containing constituents of wild garlic, namely a galactolipid and a phytosterol,could be identified exhibiting inhibitory action on ADP-induced aggregation in human blood platelets. As a major constituent, the galactolipid, 1,2-di-O-alpha-linolenoyl-3-O-beta-D-galactopyranosyl-sn-glycerol, not yet found in Allium sp., appears as a new, highly useful marker substance for A. ursinum drugs, or their pharmaceutical or food preparations,as shown by our orientating TLC analyses. PMID- 22507959 TI - Influence of maternal factors on health outcomes in gastroschisis: a Canadian population-based study. AB - BACKGROUND: Gastroschisis is increasing in incidence worldwide. There is a need for a disease-specific, population-based approach to determining factors linked with gastroschisis and its outcome. OBJECTIVES: To examine racial, socioeconomic, health and geographic predictors of gastroschisis and its outcome in Canada. METHODS: 535 cases of gastroschisis from the Canadian Pediatric Surgery Network national database were included from May 2005 to May 2010. Baseline characteristics of mothers were compared with those reported by Statistics Canada. Factors associated with adverse neonatal outcomes were examined using regression analyses. RESULTS: Mothers of infants with gastroschisis are young, often from small communities. Smoking (37%) and illicit drug use are common in this population. Single mothers receive less perinatal care (OR 0.06; 95% CI 0.02 0.28). Geographically isolated mothers are more likely to undergo caesarian section (OR 3.84; 95% CI 1.26-11.74). Cocaine use predicts a lower odds of delivering at a planned center (OR 0.25; 95% CI 0.08-0.79), and is also associated with an increased likelihood of intestinal injury at birth (OR 6.26; 95% CI 1.52-25.72). Infants of mothers from isolated communities will spend a mean of 31.9 days longer in hospital. Aboriginal status is not independently predictive of perinatal or neonatal outcome. CONCLUSION: Gastroschisis in Canada occurs frequently in young mothers, aboriginals and smokers. Features associated with worse outcomes include single parent status, cocaine use and maternal hometown geographic isolation. PMID- 22507960 TI - Synthesis and acrosin inhibitory activity of methyl 5-substituted-1H benzo[d]imidazol-2-yl carbamate derivatives. AB - A series of novel methyl 5-substituted 1H-benzo[d]imidazol-2-ylcarbamates were designed, synthesized, and their acrosin inhibitory activities evaluated in vitro. The results of acrosin inhibitory activity showed that all title compounds were more potent than the control TLCK. Compound 4w displayed the most potent acrosin inhibitory activity among all the compounds, with an IC(50) of 6.3*10( 5)M. The studies provide a new structural class for the development of novel acrosin inhibitory agents. PMID- 22507961 TI - Synthesis and biological evaluation of new potent and selective HCV NS5A inhibitors. AB - NS5A inhibitors are a new class of direct-acting antiviral agents which display very potent anti-HCV activity in vitro and in humans. Rationally designed modifications to the central biphenyl linkage of a known NS5A series led to selection of several compounds that were synthesized and evaluated in a HCV genotype 1b replicon. The straight triphenyl linked compound 11a showed similar anti-HCV activity to the clinical compound BMS-790052 and a superior cytotoxicity profile in three different cell lines, with an EC(50) value of 26 pM and a therapeutic index of over four million in an HCV replicon assay. This triphenyl analog warrants further preclinical evaluation as an anti-HCV agent. PMID- 22507962 TI - The central valine concept provides an entry in a new class of non peptide inhibitors of the p53-MDM2 interaction. AB - Disrupting the interaction between the p53 tumor suppressor and its regulator MDM2 is a promising therapeutic strategy in anticancer drug research. In our search for non peptide inhibitors of this protein-protein interaction, we have devised a ligand design concept exploiting the central position of Val 93 in the p53 binding pocket of MDM2. The design of molecules based on this concept has allowed us to rapidly identify compounds having a 3-imidazolyl indole core structure as the first representatives of a new class of potent inhibitors of the p53-MDM2 interaction. PMID- 22507963 TI - Continued optimization of the MLPCN probe ML071 into highly potent agonists of the hM1 muscarinic acetylcholine receptor. AB - This Letter describes the continued optimization of the MLPCN probe molecule ML071. After introducing numerous cyclic constraints and novel substitutions throughout the parent structure, we produced a number of more highly potent agonists of the M(1) mACh receptor. While many novel agonists demonstrated a promising ability to increase soluble APPalpha release, further characterization indicated they may be functioning as bitopic agonists. These results and the implications of a bitopic mode of action are presented. PMID- 22507965 TI - Incidence of pediatric acute mastoiditis: 1997-2006. AB - OBJECTIVES: To evaluate the incidence of acute mastoiditis in children in the United States over the years 1997 through 2006 and to explore possible explanations for the conflicting conclusions of recent studies of this topic. DESIGN: Comparison of periodic incidence over a decade. SETTING: Academic and community, general, and pediatric specialty hospitals in the United States. PATIENTS: Children younger than 18 years in the United States treated and discharged with a diagnosis of acute mastoiditis during the years 1997 through 2006. MAIN OUTCOME MEASURES: To compare true incidence of acute mastoiditis in the pediatric population of the United States, data from Healthcare Costs and Utilization Project-Kids' Inpatient Database (HCUP-KID) was examined for nationally weighted estimates of hospital discharges, demographics (age and sex), hospital characteristics, and insurance characteristics. RESULTS: No significant change was found in the incidence of acute mastoiditis over the study period (from 1.88 to 1.62 per 100,000 person-years) (regression coefficient -0.024 [95% CI, -0.110 to 0.024]) (P = .37). Children admitted with acute mastoiditis had an increased odds of presenting to a teaching hospital (odds ratio [OR], 1.38 [95% CI, 1.31-1.45]) (P < .001), a children's hospital (OR, 1.08 [95% CI, 1.03-1.14]) (P = .001), and to a metropolitan location (OR, 1.10 [95% CI, 1.02-1.18]) (P = .016) over calendar time. CONCLUSIONS: The incidence of acute mastoiditis in the United States is not increasing. The changes in hospital factors identified over the course of this study may explain the perception of increased incidence identified in studies that have not used population-level data. PMID- 22507964 TI - Crystal structures of AKR1C3 containing an N-(aryl)amino-benzoate inhibitor and a bifunctional AKR1C3 inhibitor and androgen receptor antagonist. Therapeutic leads for castrate resistant prostate cancer. AB - Castrate resistant prostate cancer (CRPC) is associated with increased androgen receptor (AR) signaling often brought about by elevated intratumoral androgen biosynthesis and AR amplification. Inhibition of androgen biosynthesis and/or AR antagonism should be efficacious in the treatment of CRPC. AKR1C3 catalyzes the formation of potent AR ligands from inactive precursors and is one of the most upregulated genes in CRPC. AKR1C3 inhibitors should not inhibit the related isoforms, AKR1C1 and AKR1C2 that are involved in 5alpha-dihydrotestosterone inactivation in the prostate. We have previously developed a series of flufenamic acid analogs as potent and selective AKR1C3 inhibitors [Adeniji, A. O. et al., J. Med. Chem.2012, 55, 2311]. Here we report the X-ray crystal structure of one lead compound 3-((4-(trifluoromethyl)phenyl) amino)benzoic acid (1) in complex with AKR1C3. Compound 1 adopts a similar binding orientation as flufenamic acid, however, its phenylamino ring projects deeper into a subpocket and confers selectivity over the other AKR1C isoforms. We exploited the observation that some flufenamic acid analogs also act as AR antagonists and synthesized a second generation inhibitor, 3-((4-nitronaphthalen-1-yl)amino)benzoic acid (2). Compound 2 retained nanomolar potency and selective inhibition of AKR1C3 but also acted as an AR antagonist. It inhibited 5alpha-dihydrotestosterone stimulated AR reporter gene activity with an IC(50)=4.7 MUM and produced a concentration dependent reduction in androgen receptor levels in prostate cancer cells. The in vitro and cell-based effects of compound 2 make it a promising lead for development of dual acting agent for CRPC. To illuminate the structural basis of AKR1C3 inhibition, we also report the crystal structure of the AKR1C3.NADP(+).2 complex, which shows that compound 2 forms a unique double-decker structure with AKR1C3. PMID- 22507966 TI - Radiotherapy in parotid acinic cell carcinoma: does it have an impact on survival? AB - OBJECTIVE: Acinic (or acinar) cell carcinoma (ACC) represents approximately 10% of salivary gland malignant tumors and most commonly occurs in the parotid gland. It carries a propensity for locoregional and distant metastasis. Although it is selectively used as an adjuvant in this tumor, radiotherapy (RT) has not been sufficiently examined in large population studies for survival impact. DESIGN: Retrospective database review. SETTING: Tertiary care center. PATIENTS: A total of 1241 cases of parotid ACC in the Surveillance, Epidemiology, and End Results (SEER) Program database from 1988 to 2007 were identified and analyzed. INTERVENTIONS: Comparison groups were surgery and surgery plus RT. Kaplan-Meier survival curves were generated for oncologic stage and histologic grade. MAIN OUTCOME MEASURES: Overall survival. RESULTS: A total of 969 patients had sufficient staging data for inclusion. When comparing surgery with surgery with adjuvant RT, there was no statistical difference in overall survival when stratifying for stage I (P = .57), stage II (P = .37), stage III (P = .25), and stage IV (P = .24) tumors. Similarly, adjuvant RT did not demonstrate a survival advantage when stratified by histologic grade of tumor. The highest-grade and highest-stage tumors were fewer in number, however. CONCLUSIONS: To our knowledge, this study represents the largest cohort of patients treated for ACC of the parotid. Adjuvant RT does not seem to provide a significant survival advantage for early-stage or lower-grade parotid ACC. Radiotherapy for highest stage and highest-grade tumors requires further study. PMID- 22507967 TI - Overcoming unresponsiveness in experimental autoimmune encephalomyelitis (EAE) resistant mouse strains by adoptive transfer and antigenic challenge. AB - Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the central nervous system (CNS) and has been used as an animal model for study of the human demyelinating disease, multiple sclerosis (MS). EAE is characterized by pathologic infiltration of mononuclear cells into the CNS and by clinical manifestation of paralytic disease. Similar to MS, EAE is also under genetic control in that certain mouse strains are susceptible to disease induction while others are resistant. Typically, C57BL/6 (H-2(b)) mice immunized with myelin basic protein (MBP) fail to develop paralytic signs. This unresponsiveness is certainly not due to defects in antigen processing or antigen presentation of MBP, as an experimental protocol described here had been used to induce severe EAE in C57BL/6 mice as well as other reputed resistant mouse strains. In addition, encephalitogenic T cell clones from C57BL/6 and Balb/c mice reactive to MBP had been successfully isolated and propagated. The experimental protocol involves using a cellular adoptive transfer system in which MBP-primed (200 MUg/mouse) C57BL/6 donor lymph node cells are isolated and cultured for five days with the antigen to expand the pool of MBP-specific T cells. At the end of the culture period, 50 million viable cells are transferred into naive syngeneic recipients through the tail vein. Recipient mice so treated normally do not develop EAE, thus reaffirming their resistant status, and they can remain normal indefinitely. Ten days post cell transfer, recipient mice are challenged with complete Freund adjuvant (CFA)-emulsified MBP in four sites in the flanks. Severe EAE starts to develop in these mice ten to fourteen days after challenge. Results showed that the induction of disease was antigenic specific as challenge with irrelevant antigens did not induce clinical signs of disease. Significantly, a titration of the antigen dose used to challenge the recipient mice showed that it could be as low as 5 MUg/mouse. In addition, a kinetic study of the timing of antigenic challenge showed that challenge to induce disease was effective as early as 5 days post antigenic challenge and as long as over 445 days post antigenic challenge. These data strongly point toward the involvement of a "long-lived" T cell population in maintaining unresponsiveness. The involvement of regulatory T cells (Tregs) in this system is not defined. PMID- 22507968 TI - Novel thermal-sensitive hydrogel enhances both humoral and cell-mediated immune responses by intranasal vaccine delivery. AB - A novel thermal sensitive hydrogel was formulated with N-[(2-hydroxy-3 trimethylammonium) propyl] chitosan chloride (HTCC) and alpha, beta glycerophosphate (alpha, beta-GP). A serial of hydrogels containing different amount of GP and HTCC with diverse quarternize degree (QD, 41%, 59%, 79.5%, and 99%) were prepared and characterized by rheological method. The hydrogel was subsequently evaluated for intranasal vaccine delivery with adenovirus based Zaire Ebola virus glycoprotein antigen (Ad-GPZ). Results showed that moderate quarternized HTCC (60% and 79.5%) hydrogel/antigen formulations induced highest IgG, IgG1, and IgG2a antibody titers in serum, as well as mucosal IgA responses in lung wash, which may attributed to the prolonged antigen residence time due to the thermal-sensitivity of this hydrogel. Furthermore, CD8(+) splenocytes for IFN gamma positive cell assay and the release profile of Th1/Th2 type cytokines (IFN gamma, IL-2, IL-10, and IL-4) showed that hydrogel/Ad-GPZ generated an overwhelmingly enhanced Th1 biased cellular immune response. In addition, this hydrogel displayed low toxicity to nasal tissue and epithelial cells even by frequently intranasal dosing of hydrogel. All these results strongly supported this hydrogel as a safe and effective delivery system for nasal immunization. PMID- 22507969 TI - Unchanged antibiotic susceptibility in Escherichia coli and Pseudomonas aeruginosa after long-term in vitro exposure to antineoplastic drugs. AB - BACKGROUND: Certain antineoplastic drugs inhibit bacterial growth. Whether these drugs also cause genetic changes in bacteria that lead to increased antibiotic resistance is not yet documented. Given the massive and repeated antibiotic treatment most cancer patients undergo, this question is important. We have examined the possible effects of in vitro long-term antineoplastic exposure on antibiotic resistance. METHODS: Using the disc diffusion method, two bacterial strains (Escherichia coli, ATCC 25922, and Pseudomonas aeruginosa, ATCC 27583) were exposed to methotrexate, fluorouracil, vincristine, doxorubicin and cytarabine during 50 overnight cycles. The bacterial strains were susceptibility tested to several antibiotics before and after repeated exposure to antineoplastics. RESULTS: No changes in antibiotic susceptibility were seen in the two bacterial strains after long-term exposure to any of the antineoplastic drugs tested. CONCLUSION: Long-term in vitro antineoplastic exposure did not change the antibiotic susceptibility in the E. coli or P. aeruginosa strains. PMID- 22507970 TI - Coronary artery disease: Risk models for revascularization--the search continues. PMID- 22507971 TI - An unusual cause of systolic murmur. PMID- 22507972 TI - Endothelial-dependent vasomotion in a coronary segment treated by ABSORB everolimus-eluting bioresorbable vascular scaffold system is related to plaque composition at the time of bioresorption of the polymer: indirect finding of vascular reparative therapy? AB - AIMS: To analyse the vasoreactivity of a coronary segment, previously scaffolded by the ABSORB bioresorbable vascular scaffold (BVS) device, in relationship to its intravascular ultrasound-virtual histology (IVUS-VH) composition and reduction in greyscale echogenicity of the struts. Coronary segments, transiently scaffolded by a polymeric device, may in the long-term recover a normal vasomotor tone. Recovery of a normal endothelial-dependent vasomotion may be enabled by scaffold bioresorption, composition of the underlying tissue, or a combination of both mechanisms. METHODS AND RESULTS: All patients from the ABSORB Cohort A and B trials, who underwent a vasomotion test and IVUS-VH investigation at 12 and 24 months, were included. Acetylcholine (Ach) and nitroglycerin were used to test either the endothelial-dependent or -independent vasomotion of the treated segment. Changes in polymeric strut echogenicity-a surrogate for bioresorption IVUS-VH composition of the tissue underneath the scaffold and their relationship with the pharmacologically induced vasomotion were all evaluated. Overall, 26 patients underwent the vasomotion test (18 at 12 and 8 at 24 months). Vasodilatory response to Ach was quantitatively associated with larger reductions over time in polymeric strut echogenicity (y= -0.159x- 6.85; r= -0.781, P< 0.001). Scaffolded segments with vasoconstriction to Ach had larger vessel areas (14.37 +/- 2.50 vs. 11.85 +/- 2.54 mm(2), P= 0.030), larger plaque burden (57.31 +/- 5.96 vs. 49.09 +/- 9.10%, P= 0.018), and larger necrotic core (NC) areas [1.39 (+1.14, +1.74) vs. 0.78 mm(2) (+0.20, +0.98), P= 0.006] compared with those with vasodilation. CONCLUSION: Vasodilatory response to Ach, in coronary segments scaffolded by the ABSORB BVS device, is associated with a reduction in echogenicity of the scaffold over time, and a low amount of NC. In particular, the latter finding resembles the behaviour of a native coronary artery not caged by an intracoronary device. PMID- 22507973 TI - Effect of mitochondrial aldehyde dehydrogenase-2 genotype on cardioprotection in patients with congenital heart disease. AB - AIMS: About 40% of East Asians carry an aldehyde dehydrogenase-2*2 (ALDH2*2) allele, and the influence of the ALDH2*2 allele on human cardioprotection has not been studied. This study was designed to evaluate the effect of ALDH2*2 allele on cardioprotection of patients with congenital heart diseases after open-heart surgery. METHODS AND RESULTS: The right atrial appendage was harvested before performing cardiopulmonary bypass in cyanotic and acyanotic congenital heart disease groups (n = 20 per group). Tissues were assayed to determine the impact of cyanosis on metabolic remodelling. A prospective cohort of Tetralogy of Fallot (TOF) patients (n = 118) was recruited to investigate the influence of the ALDH2*2 allele on cardioprotection after surgical repair. Myocardium samples were dissected after cardioplegia. ALDH2 activity, oxidative stress and glutathione (GSH) levels, and activating transcription factor-4 (ATF4) were analysed. After genotyping and grouping, all of the experimental and clinical results were compared between ALDH2*2 carriers and non-carriers. Cyanosis inhibited ALDH2 activity and led to aldehyde accumulation in ALDH2*2 carriers. This accumulation in turn increased expression of ATF4 and resulted in larger myocardium GSH pools. The differences in ALDH2 activity and GSH level between carriers and non-carriers disappeared during cardioplegic arrest, and more aldehydes accumulated in the non carriers. Consequently, ALDH2*2 carriers showed lower postoperative troponin I, inotrope score, and shorter postoperative length of ICU and hospital stay. CONCLUSIONS: ALDH2*2 carriers with cyanotic congenital heart disease were associated with an induced metabolic remodelling phenotype and a compensatory myocardium GSH pool. When ALDH2 activity was impaired during open-heart surgery, this larger GSH pool could lead to unexpectedly better cardioprotection. This may aid in the prediction of cardioprotection outcomes and identification of individualized cardioprotective strategies. PMID- 22507974 TI - Non-invasive anatomic and functional imaging of vascular inflammation and unstable plaque. AB - Over the last several decades, basic cardiovascular research has significantly enhanced our understanding of pathobiological processes leading to formation, progression, and complications of atherosclerotic plaques. By harnessing these advances in cardiovascular biology, imaging has advanced beyond its traditional anatomical domains to a tool that permits probing of particular molecular structures to image cellular behaviour and metabolic pathways involved in atherosclerosis. From the nascent atherosclerotic plaque to the death of inflammatory cells, several potential molecular and micro-anatomical targets for imaging with particular selective imaging probes and with a variety of imaging modalities have emerged from preclinical and animal investigations. Yet, substantive barriers stand between experimental use and wide clinical application of these novel imaging strategies. Each of the imaging modalities described herein faces hurdles-for example, sensitivity, resolution, radiation exposure, reproducibility, availability, standardization, or costs. This review summarizes the published literature reporting on functional imaging of vascular inflammation in atherosclerotic plaques emphasizing those techniques that have the greatest and/or most immediate potential for broad application in clinical practice. The prospective evaluation of these techniques and standardization of protocols by multinational networks could serve to determine their added value in clinical practice and guide their development and deployment. PMID- 22507975 TI - The multidimensional role of calcium in atrial fibrillation pathophysiology: mechanistic insights and therapeutic opportunities. AB - Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and its prevalence is increasing with the ageing of the population. Presently available treatment options are far from optimal and new insights into underlying mechanisms are needed to improve therapy. A variety of recent lines of research are converging to reveal important and relatively underappreciated multidimensional roles of cellular Ca(2+) content, distribution, and handling in AF pathophysiology. The objective of the present paper is to review the participation of changes in cell Ca(2+) and related processes in the mechanisms that lead to AF initiation and maintenance, and to consider the relevance of new knowledge in this area to therapeutic innovation. We first review the involvement of Ca(2+)-related functions in the principal arrhythmia mechanisms underlying AF: focal ectopic activity due to afterdepolarizations and re-entrant mechanisms. The detailed molecular pathophysiology of focal ectopic and re-entrant activity is then discussed in relationship to the participation of cell Ca(2+) changes and related Ca(2+)-handling and Ca(2+)-sensitive signalling systems. We then go on to consider the participation of Ca(2+)-related functions in electrical and structural remodelling processes leading to the AF substrate. Finally, we consider the implications for development of new arrhythmia management approaches and future research and development. PMID- 22507976 TI - Reconstitution of aged bone marrow with young cells repopulates cardiac-resident bone marrow-derived progenitor cells and prevents cardiac dysfunction after a myocardial infarction. AB - AIMS: The study was designed to evaluate the mechanisms of cardiac regeneration after injury and to determine how to restore that capacity in aged individuals. The adult heart retains a small population of nascent cells that have myeloid, mesenchymal, and mesodermal capabilities, which play an essential role in the recovery of ventricular function after injury. In aged individuals, these cells are diminished and dysfunctional. We evaluated the derivation of some of these cardiac progenitors and a method to restore their number and function. METHODS AND RESULTS: We first demonstrated that aged mice have fewer progenitors in both the bone marrow (BM) and the myocardium, which correlated with the extent of cardiac dysfunction after injury. Bone marrow chimerism established in aged mice with young BM donors restored both myocardial progenitors and cardiac function, but neither was restored with aged BM donors. Cardiac micro-chimerism in aged mice was established with young BM cells, which restored cardiac function after injury, even with old peripheral BM cells. The young cardiac-resident BM-derived progenitor cells in the aged myocardium persisted for at least a year, and after myocardial infarction they actively proliferated and enhanced cardiac repair through paracrine mechanisms. CONCLUSION: Bone marrow reconstitution with young BM cells in aged recipients restored progenitors in both the BM and, most importantly, the myocardium. The number and function of cardiac-resident BM derived progenitor cells in the aged myocardium prior to injury was the major determinant for successful recovery of cardiac function. The aged heart was rejuvenated with young BM cells. PMID- 22507977 TI - Discriminating clinical features of heart failure with preserved vs. reduced ejection fraction in the community. AB - AIMS: Heart failure (HF) is a major public health burden worldwide. Of patients presenting with HF, 30-55% have a preserved ejection fraction (HFPEF) rather than a reduced ejection fraction (HFREF). Our objective was to examine discriminating clinical features in new-onset HFPEF vs. HFREF. METHODS AND RESULTS: Of 712 participants in the Framingham Heart Study (FHS) hospitalized for new-onset HF between 1981 and 2008 (median age 81 years, 53% female), 46% had HFPEF (EF >45%) and 54% had HFREF (EF <=45%). In multivariable logistic regression, coronary heart disease (CHD), higher heart rate, higher potassium, left bundle branch block, and ischaemic electrocardiographic changes increased the odds of HFREF; female sex and atrial fibrillation increased the odds of HFPEF. In aggregate, these clinical features predicted HF subtype with good discrimination (c statistic 0.78). Predictors were examined in the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) study. Of 4436 HF patients (median age 75 years, 47% female), 32% had HFPEF and 68% had HFREF. Distinguishing clinical features were consistent between FHS and EFFECT, with comparable discrimination in EFFECT (c statistic 0.75). In exploratory analyses examining the traits of the intermediate EF group (EF 35-55%), CHD predisposed to a decrease in EF, whereas other clinical traits showed an overlapping spectrum between HFPEF and HFREF. CONCLUSION: Multiple clinical characteristics at the time of initial HF presentation differed in participants with HFPEF vs. HFREF. While CHD was clearly associated with a lower EF, overlapping characteristics were observed in the middle of the left ventricular EF range spectrum. PMID- 22507978 TI - Accelerated platelet inhibition by switching from atorvastatin to a non-CYP3A4 metabolized statin in patients with high platelet reactivity (ACCEL-STATIN) study. AB - AIMS: CYP3A4-metabolized statins can influence the pharmacodynamic effect of clopidogrel. We sought to assess the impact of switching to a non-CYP3A4 metabolized statin on platelet function among patients receiving clopidogrel and atorvastatin with high on-treatment platelet reactivity (HPR). METHODS AND RESULTS: Percutaneous coronary intervention (PCI)-treated patients (n= 50) with HPR [20 MUM adenosine diphosphate (ADP)-induced maximal platelet aggregation (MPA) >50%] were enrolled during chronic administration of atorvastatin (10 mg/day) and clopidogrel (75 mg/day) (>=6 months). They were randomly assigned to a 15-day therapy with either rosuvastatin 10 mg/day (n= 25) or pravastatin 20 mg/day (n= 25). Platelet function was assessed before and after switching by conventional aggregometry and the VerifyNow P2Y12 assay. Genotyping was performed for CYP2C19*2/*3, CYP3A5*3, and ABCB1 C3435T alleles. The primary endpoint was the absolute change in 20 MUM ADP-induced MPA. After switching, MPAs after stimuli with 20 and 5 MUM ADP were decreased by 6.6% (95% confidence interval: 3.2-10.1%; P < 0.001), and 6.3% (95% confidence interval: 2.5-10.2%; P = 0.002), respectively. Fifty-two P2Y12 reaction units fell (95% confidence interval: 35 70; P < 0.001) and the prevalence of HPR decreased (24%; P < 0.001). Pharmacodynamic effects were similar after rosuvastatin and pravastatin therapy. In addition to smoking status, the combination of calcium channel blocker usage and ABCB1 C3435T genotype significantly affected the change of 20 MUM ADP-induced MPA. CONCLUSIONS: Among PCI-treated patients with HPR during co-administration of clopidogrel and atorvastatin, switching to a non-CYP3A4-metabolized statin can significantly decrease platelet reactivity and the prevalence of HPR. This switching effect appears similar irrespective of the type of non-CYP3A4 metabolized statin. PMID- 22507979 TI - Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. AB - AIMS: A randomized, double-blind, placebo-controlled study was conducted to investigate the safety and efficacy of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, in patients who are statin intolerant and at high risk for cardiovascular disease (CVD). METHODS AND RESULTS: Thirty-three subjects, not receiving statin therapy because of statin intolerance, received a weekly subcutaneous dose of 200 mg mipomersen or placebo (2:1 randomization) for 26 weeks. The primary endpoint was per cent change in LDL cholesterol (LDL-c) from the baseline to Week 28. The other efficacy endpoints were per cent change in apoB and lipoprotein a [Lp(a)]. Safety was determined using the incidence of treatment-emergent adverse events (AEs) and clinical laboratory evaluations. After 26 weeks of mipomersen administration, LDL-c was reduced by 47 +/- 18% (P < 0.001 vs. placebo). apoB and Lp(a) were also significantly reduced by 46 and 27%, respectively (P < 0.001 vs. placebo). Four mipomersen (19%) and two placebo subjects (17%) discontinued dosing prematurely due to AEs. Persistent liver transaminase increases >= 3* the upper limit of normal were observed in seven (33%) subjects assigned to mipomersen. In selected subjects, liver fat content was assessed, during and after treatment, using magnetic resonance spectroscopy. Liver fat content in these patients ranged from 0.8 to 47.3%. Liver needle biopsy was performed in two of these subjects, confirming hepatic steatosis with minimal inflammation or fibrosis. CONCLUSION: The present data suggest that mipomersen is a potential therapeutic option in statin-intolerant patients at high risk for CVD. The long-term follow-up of liver safety is required. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00707746. PMID- 22507980 TI - A new approach to managing the 'statin-intolerant' patient? PMID- 22507981 TI - The human sympathetic nervous system: its relevance in hypertension and heart failure. AB - Evidence assembled in this review indicates that sympathetic nervous system dysfunction is crucial in the development of heart failure and essential hypertension. This takes the form of persistent and adverse activation of sympathetic outflows to the heart and kidneys in both conditions. An important goal for clinical scientists is translation of the knowledge of pathophysiology, such as this, into better treatment for patients. The achievement of this 'mechanisms to management' transition is at different stages of development with regard to the two disorders. Clinical translation is mature in cardiac failure, knowledge of cardiac neural pathophysiology having led to the introduction of beta-adrenergic blockers, an effective therapy. With essential hypertension perhaps we are on the cusp of effective translation, with recent successful testing of selective catheter-based renal sympathetic nerve ablation in patients with resistant hypertension, an intervention firmly based on the demonstration of activation of the renal sympathetic outflow. Additional evidence in this regard is provided by the results of pilot studies exploring the possibility to reduce blood pressure in resistant hypertensives through electrical stimulation of the area of carotid baroreceptors. Despite the general importance of the sympathetic nervous system in blood pressure regulation, and the specific demonstration that the blood pressure elevation in essential hypertension is commonly initiated and sustained by sympathetic nervous activation, drugs antagonizing this system are currently underutilized in the care of patients with hypertension. Use of beta adrenergic blocking drugs is waning, given the propensity of this drug class to have adverse metabolic effects, including predisposition to diabetes development. The blood pressure lowering achieved with carotid baroreceptor stimulation and with the renal denervation device affirms the importance of the sympathetic nervous system in hypertension pathogenesis, and perhaps suggests a wider role for anti-adrenergic antihypertensives, such as the imidazoline drug class (moxonidine, rilmenidine) which act within the CNS to inhibit central sympathetic outflow, although the lack of large-scale outcome trials with this drug class remains a very material deficiency. PMID- 22507982 TI - Increasing ceramides sensitizes genistein-induced melanoma cell apoptosis and growth inhibition. AB - The aim of the current study is to investigate the effect of ceramides on genistein-induced anti-melanoma effects in vitro. We found that exogenously added cell-permeable short-chain ceramides (C6) dramatically enhanced genistein-induced growth inhibition and apoptosis in cultured melanoma cells. Genistein treatment only induced a moderate intracellular ceramides accumulation in B16 melanoma cells. Two different agents including 1-phenyl-2-decanoylamino-3-morpholino-1 propanol (PDMP), a ceramide glucosylation inhibitor, and the sphingosine kinase-1 (SphK1) inhibitor II (SKI-II), a sphingosine (ceramides precursor) phosphorylation inhibitor, both facilitated genistein-induced ceramides accumulation and melanoma cell apoptosis. Co-administration of ceramide (C6) and genistein induced a significant Akt inhibition and c-jun-NH(2)-kinase (JNK) activation, caspase-3 cleavage and cytochrome c release. Caspase-3 inhibitor z DVED-fmk, JNK inhibitor SP 600125, or to restore Akt activation by introducing a constitutively active form of Akt (CA-Akt) diminished ceramide (C6) and genistein co-administration-induced in vitro anti-melanoma effect. Our study suggests that increasing cellular level of ceramides may sensitize genistein-induced anti melanoma effects. PMID- 22507983 TI - Inhibition of cell proliferation and migration by oxidative stress from ascorbate driven juglone redox cycling in human bladder-derived T24 cells. AB - The effects of juglone on T24 cells were assessed in the presence and absence of ascorbate. The EC(50) value for juglone at 24 h decreased from 28.5 MUM to 6.3 MUM in the presence of ascorbate. In juglone-treated cells, ascorbate increased ROS formation (4-fold) and depleted GSH (65%). N-acetylcysteine or catalase restricted the juglone/ascorbate-mediated effects, highlighting the role of oxidative stress in juglone cytotoxicity. Juglone alone or associated with ascorbate did not cause caspase-3 activation or PARP cleavage, suggesting necrosis-like cell death. DNA damage and the mild ER stress caused by juglone were both enhanced by ascorbate. In cells treated with juglone (1-5 MUM), a concentration-dependent decrease in cell proliferation was observed. Ascorbate did not impair cell proliferation but its association with juglone led to a clonogenic death state. The motility of ascorbate-treated cells was not affected. Juglone slightly restricted motility, but cells lost their ability to migrate most noticeably when treated with juglone plus ascorbate. We postulate that juglone kills cells by a necrosis-like mechanism inhibiting cell proliferation and the motility of T24 cells. These effects are enhanced in the presence of ascorbate. PMID- 22507984 TI - GRK5 deficiency decreases diet-induced obesity and adipogenesis. AB - Identification of the protein factors that regulate the adipogenesis and lipid metabolism of adipose tissue is critical for the understanding of the physiology and pathology of obesity and energy homeostasis. In this study, we found that G protein coupled receptor (GPCR) kinase 5 (GRK5) was expressed at a relatively high level in the white adipose tissue. When fed on a high-fat diet, GRK5(-/-) mice gained significantly less weight and had decreased WAT mass than their wild type littermates, which could not be attributed to alterations in food consumption or energy expenditure. However, GRK5(-/-) mice showed a 30-70% decreased expression of lipid metabolism and adipogenic genes in WAT. Moreover, GRK5(-/-) embryonic fibroblasts and preadipocytes exhibited 40-70% decreased expression of adipogenic genes and impaired adipocyte differentiation when induced in vitro. Taken together, these results suggest that GRK5 is an important regulator of adipogenesis and is crucial for the development of diet-induced obesity. PMID- 22507985 TI - Protective effect of Bacillus anthracis surface protein EA1 against anthrax in mice. AB - Bacillus anthracis spores germinate to vegetative forms in host cells, and produced fatal toxins. A toxin-targeting prophylaxis blocks the effect of toxin, but may allow to grow vegetative cells which create subsequent toxemia. In this study, we examined protective effect of extractable antigen 1 (EA1), a major S layer component of B. anthracis, against anthrax. Mice were intranasally immunized with recombinant EA1, followed by a lethal challenge of B. anthracis spores. Mucosal immunization with EA1 resulted in a significant level of anti-EA1 antibodies in feces, saliva and serum. It also delayed the onset of anthrax and remarkably decreased the mortality rate. In addition, the combination of EA1 and protective antigen (PA) protected all immunized mice from a lethal challenge with B. anthracis spores. The numbers of bacteria in tissues of EA1-immunized mice were significantly decreased compared to those in the control and PA alone immunized mice. Immunity to EA1 might contribute to protection at the early phase of infection, i.e., before massive multiplication and toxin production by vegetative cells. These results suggest that EA1 is a novel candidate for anthrax vaccine and provides a more effective protection when used in combination with PA. PMID- 22507986 TI - Acetylation and glycation of fibrinogen in vitro occur at specific lysine residues in a concentration dependent manner: a mass spectrometric and isotope labeling study. AB - Aspirin may exert part of its antithrombotic effects through platelet-independent mechanisms. Diabetes is a condition in which the beneficial effects of aspirin are less prominent or absent - a phenomenon called "aspirin resistance". We investigated whether acetylation and glycation occur at specific sites in fibrinogen and if competition between glucose and aspirin in binding to fibrinogen occurs. Our hypothesis was that such competition might be one explanation to "aspirin resistance" in diabetes. After incubation of fibrinogen in vitro with aspirin (0.8 mM, 24 h) or glucose (100 mM, 5-10 days), we found 12 modified sites with mass spectrometric techniques. Acetylations in the alpha chain: alphaK191, alphaK208, alphaK224, alphaK429, alphaK457, alphaK539, alphaK562, in the beta-chain: betaK233, and in the gamma-chain: gammaK170 and gammaK273. Glycations were found at betaK133 and gammaK75, alternatively gammaK85. Notably, the lysine 539 is a site involved in FXIII-mediated cross linking of fibrin. With isotope labeling in vitro, using [(14)C-acetyl]salicylic acid and [(14)C]glucose, a labeling of 0.013-0.084 and 0.12-0.5 mol of acetylated and glycated adduct/mol fibrinogen, respectively, was found for clinically (12.9 100 MUM aspirin) and physiologically (2-8 mM glucose) relevant plasma concentrations. No competition between acetylation and glycation could be demonstrated. Thus, fibrinogen is acetylated at several lysine residues, some of which are involved in the cross-linking of fibrinogen. This may mechanistically explain why aspirin facilitates fibrin degradation. We find no support for the idea that glycation of fibrin(ogen) interferes with acetylation of fibrinogen. PMID- 22507988 TI - [Economic crisis and health of the population]. PMID- 22507987 TI - The relaxant effect of ginseng saponin on the bladder and prostatic urethra: an in vitro and in vivo study. AB - AIM: To assess the effects of ginseng saponin on relaxation of the bladder and prostatic urethra and to determine its mechanism of action. MATERIALS AND METHODS: For the in vitro study, prostatic urethra muscle strips were harvested from 18 male New Zealand rabbits. The strips were mounted in organ baths and connected to force displacement transducers. After stabilization, maximal tissue contractions were obtained by the application of phenylepinephrine to the urethra strips, and a dose-response curve for ginseng saponin was constructed (10(-6)-10( 2)M). After pretreatment of urethra strips with N-nitro-L-arginine methyl ester (L-NAME), another dose-response curve for ginseng saponin was constructed. For the in vivo study, we used adult male Sprague-Dawley rats divided into three groups [control, partial bladder outlet obstruction (PBOO) and saponin-fed groups], and we monitored the vesical pressure (P(ves)) and urethral perfusion pressure (UPP). RESULTS: The ginseng saponin induced a significant dose-dependent relaxant effect on the prostatic urethra strips. A significant relaxant effect of ginseng saponin was observed from 10(-3)M, and ginseng saponin significantly relaxed urethra strips by 50.2 +/- 20.26% at 10(-2)M. The relaxant effect was partially inhibited with L-NAME pretreatment. In the in vivo study, the change in UPP between baseline and relaxation was significantly higher in the saponin group than in the control or PBOO group (p < 0.001). The saponin group showed a significantly lower baseline P(ves) than the PBOO group. CONCLUSIONS: We observed a significant relaxation effect of ginseng saponin on the bladder and prostatic urethra in both in vitro and in vivo studies. The mechanism by which ginseng saponin induces relaxation appears to involve the nitric oxide/nitric oxide synthase pathway. PMID- 22507989 TI - [Unhealthy food choices of adolescent schoolchildren in the Campania region (Italy)]. AB - A questionnaire study to evaluate the eating habits of a sample of adolescents was conducted in 2009-2010 in Campania (Italy). The study involved 1,066 secondary school students aged 15 to 16 years. Fifty-two percent of participants were male and 96% lived in an urban area. Questionnaires were self-administered and anonymous. Results show an association between the consumption of different types of alcoholic beverages. Adolescents who drink carbonated beverages as a mid morning snack tend to do the same during the mid-afternoon snack. Moreover, drinking carbonated beverages during morning and afternoon snacks was associated with the use of vending machines. Twenty-nine percent of participating students reported eating red meat more than four times per week. PMID- 22507990 TI - [A computerized system for the management of letters of authorization for access to sensitive data in a research and teaching hospital]. AB - This paper describes the experience of a hospital which has introduced a system of computerized management of letters of authorization for healthcare workers to access sensitive health data, through the use of open source software. A new corporate intranet portal was created with access given only to the privacy contacts of each operational unit of the hospital. Once the privacy contact has entered the relevant user authorization, these must be approved first by the Directors of the respective operational units and finally by the privacy officer. The introduction of this system has allowed a systematic approach to the management of authorization for access to health data by hospital staff, regular updating and monitoring of the authorization and the start of a process of digitalization of documents. PMID- 22507991 TI - [Prevalence of infections in nursing homes in the Vercelli area (Piemonte, Italy)]. AB - The frequency of infections in nursing homes is similar to that found in acute care hospitals: infectious complications are reported in 5-10% of hospitalized patients and 5-16% of nursing home residents. In Italy, the prevalence of infections in nursing homes ranges from 2.7% to 32.7%.The main objective of this study was to estimate the prevalence of acquired infections in nursing homes located in the territory of the Vercelli (VC) local health unit in northern Italy. We also aimed to assess which were the most frequently prescribed antibiotics among the nursing home guests, the reasons for antibiotics prescriptions, whether their use is supported by appropriate microbiological tests, the most common types of microorganisms isolated and the prevalence of antimicrobial resistance. METHODS: the survey was conducted from 1 July to 31 August 2010 in 14 publicly-funded nursing homes in the VC local health unit. Data for each nursing home were collected in a single day. A modified version of the "Healthcare-Associated Infections in European Long-Term care Facilities" questionnaire was used. Only subjects living in the nursing homes for more than 24 hours, who had signs or symptoms of infection or who were being treated with an antibiotic and who gave informed consent, were included in the study. Multiple linear regression models were used to assess the effects of independent variables on the risk of infection. RESULTS: the study population consisted of 450 subjects, 46% of whom aged over 85 years, 24% male and 88% living in a nursing home since more than one year. The overall prevalence of infection on the day of the study was 25.5%. Acquired infections were more prevalent among bedridden and wheelchair-bound guests, those who had undergone invasive procedures and those affected by decubitus ulcers. Thirty-two percent of subjects were using antibiotics. Fluoroquinolones were the most frequently used antibiotics and the most frequent reason for antibiotic use was respiratory tract infection followed by urinary tract infection. In 21% of cases no indication for antibiotic use was identified. 12.5% of E coli strains isolated by urine culture were resistant as were 100% of Klebsiella pneumoniae. CONCLUSIONS: the data highlight a high prevalence of infections in nursing homes in Vercelli as well as worryingly elevated frequencies of antibiotic prescriptions and resistance. PMID- 22507992 TI - Bacterial colonization patterns of periodontal pockets in different ages. AB - The aim of this study was to investigate subgingival bacterial composition of untreated Italian subjects with aggressive and chronic periodontitis. The total bacterial load, pathogenic bacteria belonging to "red" and "orange" complexes and Aggregatibacter actinomycetemcomitans were determined by Real-Time PCR in 1216 patients. Data were analysed by looking for relationships between bacteriological parameters, age and periodontal probing depth. The obtained results showed a significant higher number of red complex bacteria in older rather than in younger patients. The total number of bacteria and the presence of A. actinomycetemcomitans did not clearly associate with an age group. PMID- 22507993 TI - [Risk communication during health crises: results of a cross-sectional study to evaluate the effectiveness of adopted corporate communication strategies during the H1N1 influenza pandemic in Italy and on the training needs of health professionals]. AB - The objectives of this study were to evaluate the effectiveness of corporate communication activities carried out during the A(H1N1) pandemic influenza in Italy and to identify educational needs of health professionals with regards to crisis communication. The study compared two samples representing respectively the general population and health professionals, living in different regions of northern, central and southern Italy. A self-administered questionnaire was used, with questions on knowledge about preventive measures during a pandemic and on satisfaction with the adopted communication campaigns. Study results highlight that both samples had very little knowledge of appropriate preventive behaviors to be adopted during a pandemic. The sample of health professionals received a greater amount of information about the pandemic with respect to the general population and showed a strong interest toward the problem of receiving adequate training in risk communication. The degree of knowledge about preventive measures is directly proportional to the existence of institutional communication activities and to having consulted a health professional. PMID- 22507994 TI - [EpiInfo as a research and teaching tool in epidemiology and statistics: strengths and weaknesses]. AB - EpiInfo is a free software developed in 1988 by the Centers for Disease Control and Prevention (CDC) in Atlanta to facilitate field epidemiological investigations and statistical analysis. The aim of this study was to assess whether the software represents, in the Italian biomedical field, an effective analytical research tool and a practical and simple epidemiology and biostatistics teaching tool. A questionnaire consisting of 20 multiple-choice and open questions was administered to 300 healthcare workers, including doctors, biologists, nurses, medical students and interns, at the end of a CME course in epidemiology and biostatistics. Sixty-four percent of participants were aged between 26 and 45 years, 52% were women and 73% were unmarried. Results show that women are more likely to utilize EpiInfo in their research activities with respect to men (p = 0.023), as are individuals aged 26-45 years with respect to the older and younger age groups (p = 0.023) and unmarried participants with respect to those married (p = 0.010). Thirty-one percent of respondents consider EpiInfo to be more than adequate for analysis of their research data and 52% consider it to be sufficiently so. The inclusion of an EpiInfo course in statistics and epidemiology modules facilitates the understanding of theoretical concepts and allows researchers to more easily perform some of the clinical/epidemiological research activities. PMID- 22507995 TI - [Neisseria meningitidis: new vaccines and preventive strategies]. AB - Invasive disease caused by Neisseria meningitidis raise concern in the population and Public Health Authority is called to propose and test strategies for optimizing resources available for its prevention. Polysaccharide vaccines started the approach to immune prophylaxis, the introduction of conjugate vaccines brought to major advances for the prevention of this disease and the future availability of a vaccine against serogroup B will provide an additional tool to protect the population. PMID- 22507996 TI - [Indoor air quality in school buildings: risk for respiratory and allergic diseases. Current situation in Italy and preventive strategies. Introduction]. PMID- 22507997 TI - [Indoor air quality (IAQ) in school buildings. The institutional frame of reference]. PMID- 22507998 TI - [Structural and environmental hygiene of buildings for pre-school and mandatory education, in Italy]. PMID- 22507999 TI - [Analysis of epidemiologic evidence on risk factors for respiratory and allergic diseases in school buildings]. PMID- 22508000 TI - [Structural and environmental hygiene of buildings for pre-school and mandatory education, in Italy]. PMID- 22508001 TI - [Indoor air quality (IAQ) in school buildings: initiatives in Europe]. PMID- 22508002 TI - [Round table: the Italian experience. The SEARCH project (School Environment and Respiratory Health of Children)]. PMID- 22508003 TI - [Indoor allergens in public and private places]. PMID- 22508004 TI - [Assessment and prevention of risk factors for indoor air quality in school buildings]. PMID- 22508005 TI - [Residential indoor air quality: significant parameters in light of the new trends]. PMID- 22508006 TI - [Round table: the Italian experience with indoor air quality]. PMID- 22508007 TI - Sunitinib causes dose-dependent negative functional effects on myocardium and cardiomyocytes. AB - OBJECTIVES: To examine the acute effects of sunitinib on inotropic function, intracellular Ca(2+) transients, myofilament Ca(2+) sensitivity and generation of reactive oxygen species (ROS) in human multicellular myocardium and isolated mouse cardiomyocytes. To search for microRNAs as suitable biomarkers for indicating toxic cardiac effects. PATIENTS AND METHODS: After exposure to sunitinib (0.1-10 ug/mL) developed force, diastolic tension and kinetic variables were assessed in isolated human myocardium. Changes in myocyte sarcomere length, whole-cell calcium transients, myofilament force-Ca(2+) relationship, and ROS generation were examined in isolated ventricular mouse cardiomyocytes. Microarray and realtime-PCR were used to screen for differentially expressed microRNAs in cultured cardiomyocytes that were exposed for 24 h to sunitinib. RESULTS: We found that higher concentrations of sunitinib (1 and 10 ug/mL) decreased developed force at 30 minutes 76.9 + 2.8 and 54.5 + 6.3%, compared to 96.1 + 2.6% in controls (P < 0.01). Sunitinib exposure significantly decreased sarcomere shortening and Ca2+ transients. Myofilament Ca(2+) sensitivity was not altered, while ROS levels were significantly increased after exposure to the drug. MicroRNA expression patterns were not altered by sunitinib. CONCLUSIONS: Sunitinib elicits a dose-dependent negative inotropic effect in myocardium, accompanied by a decline in intracellular Ca(2+) and increased ROS generation. In clinical practice, these cardiotoxic effects should be considered in cases where cardiac concentrations of sunitinib could be increased. PMID- 22508008 TI - Platinum catalyzed 7-endo cyclization of internal alkynyl amides and its application to synthesis of the caprazamycin core. AB - The scope and limitations of the platinum catalyzed 7-endo cyclization of internal alkynyl amides were investigated. Substitution of the alkyne with an aryl group gave better results, presumably because it stabilized the transition state. Applying the reaction to a secondary amide, the caprazamycin core was successfully synthesized from commercially available material in eight steps. PMID- 22508009 TI - Flavour chemistry of methylglyoxal and glyoxal. AB - Methylglyoxal (MGO) and glyoxal (GO), known as reactive carbonyl species, can be generated endogenously and exogenously (human body and food system). They are attracting increased attention because of their relationship with diabetes and flavour generation. In this review, their characteristics relating to flavour chemistry are discussed. MGO and GO can be detected in food systems by GC and HPLC after derivatization. MGO and GO formed in the Maillard reaction play important roles as precursors of aroma and colour compounds, especially in Strecker degradation, a major flavour generation reaction. When combined with amino acids they undergo Schiff base formation, decarboxylation and alpha aminoketone condensation leading to heterocyclic aroma compounds such as pyrazines, pyrroles and pyridines. They attack amine groups in amino acids, peptides and proteins to form advanced glycation end products (AGEs) and cause carbonyl stress followed by oxidative stress and tissue damage. Therefore, many studies about scavengers of MGO and GO are seen. The influence of these scavengers on flavour generation is also discussed. PMID- 22508011 TI - Reducing drug related mortality in Europe - a seemingly intractable public health issue. AB - Drawing on an analysis of data from over 30 cohort studies, it can be estimated that between 10.000 and 20.000 opioid users die each year in Europe. Typically, annual mortality rates are between 10-20/1000, representing an excess mortality 10 to 20 times greater than expected. Most deaths occur among males in their mid thirties. Four broad categories of cause of death can be identified: overdoses, diseases, suicide and trauma. While the long term trend in HIV related mortality among drug users is downwards, other causes of mortality have shown little sign of decreasing in recent years. Of particular concern are overdoses which account for 6300 to 8400 deaths reported annually. The fact that deaths have not decreased is surprising given the scaling up of treatment and other services. Opioid substitution treatment in particular is known to be protective and the numbers of those in substitution treatment in Europe has increased dramatically. A number of interrelated factors may help explain this intractable problem. These include: the possibility of an aging cohort becoming more vulnerable; the use of alcohol and other drugs; high levels of ill-health, risk behaviour, and co morbidity; and social exclusion and marginalisation. Reducing overall morbidity among heroin users remains a key issue for Europe's public health services. More efforts are required to better understand and target both the direct and indirect factors associated with mortality among problem drugs users, if this major health cost associated with drug consumption is to be reduced. PMID- 22508010 TI - MPV17 mutation causes neuropathy and leukoencephalopathy with multiple mtDNA deletions in muscle. AB - Disorders of mitochondrial DNA (mtDNA) maintenance are clinically and genetically heterogeneous, embracing recessive mtDNA depletion syndromes affecting children and adult-onset multiple mtDNA deletion disorders. Here we show that mutation of MPV17 - a gene implicated in severe, infantile hepatocerebral mtDNA depletion disorders characterised by a loss of mtDNA copies - can also cause clonally expanded mtDNA deletion and focal cytochrome c oxidase (COX) deficiency in skeletal muscle associated with an adult presentation of neuropathy and leukoencephalopathy. The mpv17 protein is therefore intimately involved in both the mtDNA replication and repair processes and associated with both quantitative and qualitative mtDNA abnormalities. PMID- 22508012 TI - [Eating Disorders and drug use in adolescents]. AB - The aim of the study was to show whether there was a connection between drug use and Eating Disorders, as well as to identify the type of drugs most widely used and to ascertain whether they are used to suppress appetite. An "ad hoc" scale was developed using the items of the Eating Disorder Diagnostic Scale, whose aim is to detect cases at risk of certain types of eating disorder, and items for assessing drug use. This scale was applied to samples of teenagers (n=446) aged 13-18 from various secondary schools in the Valencia Region (Comunidad Valenciana) in Spain. An association was found between teenagers that use drugs, and particularly between the variable "use of some kind of drug as an appetite suppressant", and being at risk of having an eating disorder. Tobacco was the drug most commonly used (accounting for 66% of those within the risk threshold of the Eating Disorder Diagnostic Scale). We conclude that those teenagers from the sample who fall within any of the risk thresholds consume more drugs than those who do not fall within the risk threshold of the Eating Disorder Diagnostic Scale. Stimulant-type drugs are those most widely used by these teenagers with the aim of suppressing appetite. PMID- 22508013 TI - [Functional and dysfunctional impulsivity in young binge drinkers]. AB - The pattern of binge drinking (BD), found especially among young people, has become an important social and health problem. However, its prevalence has not been carefully studied until recently, together with its consequences in the mid and long run and the possible risk factors. The aim of this work is to study, for the first time, the possible differences in the dimensions of functional and dysfunctional impulsivity in Dickman's model among university students with BD and non-consumers of alcohol or control group. 80 subjects (40 men) with a pattern of BD and 80 controls (40 men) participated in the study, aged 18 to 25 (21,38 +/- 1,91). They all completed Dickman's Impulsivity Inventory (DII, 1990). Several variables known to affect the results, such as circadian typology, were controlled for. The scores on dysfunctional impulsivity were higher in the BD group compared to the controls, while no differences were found according to functional impulsivity. Men showed a higher degree of impulsivity than women, both functional and dysfunctional, although in dysfunctional impulsivity this is significant only in the BD group. The DII has proven sensitive to detecting BD, and thus it could become an assessment tool to take into account in preventive or treatment approaches in the future. PMID- 22508014 TI - Alcohol consumption and ischemic heart disease mortality in Russia. AB - It has been repeatedly emphasized that alcohol provides the most plausible explanation for both the high rate of cardiovascular mortality rate and its dramatic fluctuations in Russia over recent decades, while other traditional risk factors identified in epidemiological studies have little predictive value. The aim of this study was to examine the relation between alcohol consumption and ischemic heart disease (IHD) mortality rates in Russia. A ge-standardized sex specific male and female IHD mortality data for the period 1980-2005 and data on overall alcohol consumption were analyzed by means of ARIMA time series analysis. The results of the analysis showed that alcohol consumption was significantly associated with both male and female IHD mortality rates: a 1-liter increase in overall alcohol consumption would result in a 3.9% increase in the male IHD mortality rate and a 2.7% increase in the female IHD mortality rate. As a conclusion, the results of this study provide indirect support for the hypothesis that the drastic fluctuations in IHD mortality in Russia over recent decades are related to alcohol, as indicated by the close temporal association between number of deaths from IHD and overall alcohol consumption per capita. PMID- 22508015 TI - [Drug abuse in adolescent offenders: analysis of the psychosocial variables involved]. AB - Research shows that drugs and delinquency are frequently linked, the abuse of various types of substance being a widespread practice among young offenders. At the same time, some psychosocial characteristics are associated with both drug abuse and criminal/antisocial behavior. To help us explore the relationship between young offenders' drug abuse and certain psychosocial variables, we examined closed judicial files on young offenders from the Juvenile Justice Service in Jaen (Spain) corresponding to the period 2001 to 2010. From the contents of these judicial files we analyzed demographic variables such as gender and age, as well as psychosocial variables such as drug abuse, peer group, violent behavior, self-control, tolerance to frustration and attributional style. The results show that most of the young offenders use some type of drug, as well as revealing differential patterns of use according to gender. Also observed is a link between drug abuse and deviant peer group, violent behavior and the above mentioned psychological variables. Finally, we found some differences in these psychological variables depending on the type of drug used. PMID- 22508016 TI - [Spanish adaptation and validation of The Adolescent-Cannabis Problems Questionnaire (CPQ-A)]. AB - Cannabis is a widely used substance among adolescents and young adults, but demand for help and treatment from this age group continues to be low. It is therefore essential to develop instruments especially designed for the early detection of problems associated with cannabis use in this population. The purpose of this work is to adapt and validate the CPQ-A (Adolescent Cannabis Problems Questionnaire) for its use as a screening instrument in Spanish population. The sample was made up of 144 young people (71.5% male) aged 16 to 20 (M = 17.12; SD = 1.17) who had used cannabis in the last month and were on some kind of study or training course at various educational institutions in Asturias (a region in northern Spain). Factor analysis of the CPQ-A in this sample provides evidence of a unidimensional structure, with a Cronbach's Alpha of 0.86 for the questionnaire. The evidence also shows that the instrument's convergent validity is good. The CPQ-A score permits discrimination between moderate and excessive cannabis users over the last month, is positively related to score on the CAST (Cannabis Abuse Screening Test), and presents adequate sensitivity and specificity for identifying cases of cannabis abuse and dependence according to the DSM IV-TR criteria. It is also sensitive to young people's degree of concern about cannabis use and the psychopathological effects associated with it. In accordance with the results obtained, the CPQ-A can be considered a useful screening tool for young cannabis users with problems. PMID- 22508017 TI - [Neuropsychological characterization of functional and dysfunctional impulsivity in drug addicts: clinical implications]. AB - Impulsivity is a stable correlate throughout the course of drug addiction. However, it has always been studied as a negative condition, linked to psychopathology. Dickman (1990) proposed two subdimensions of impulsivity, dysfunctional (DI) and functional (FI). He defines the latter as the tendency for rapid, goal-oriented decision-making characterized by well calculated risks. Only a few studies have attempted to differentiate between these two subdimensions using classical neuropsychological tests. Fifty two drug addicts in treatment were tested using Dickman's Impulsivity Inventory and a battery of classical neuropsychological tests. FI shows moderate to high correlations with many classical neuropsychological test scores in relation to enhanced executive functioning, whereas DI reveals surprisingly weak and scarce correlations with indicators of impaired executive functioning. DI appears to be a trait related to some difficulties in classical neuropsychological tests, while FI emerges as a consistent and much stronger predictor of higher attention capacity, lower distractibility, better precision, fewer errors, and better maintenance of goal oriented strategies. Thus, functional impulsivity is related to positive conditions and more efficient cognitive functioning. Implications for the treatment of drug addictions are suggested. PMID- 22508018 TI - [Emotional responsiveness of substance abusers under outpatient treatment]. AB - The emotions predispose to action providing information from both internal and external environment. There is evidence indicating that the emotional response in drugdependent patients is different from that of the not consuming population. The present work analyzed the emotions of drugdependent under ambulatory treatment (N=57), following the Lang's theory of emotion, considering the dimensions of valence, arousal and dominance or control, across the International Affective Picture System (IAPS), individually applied. The results were contrasted with a control group of not consuming persons (N=44) of similar age, since this variable concerns emotional experience. The influence of sex was also analyzed, considering the possible differences between men and women in emotional experience. The results can be summarized in the following points: (1) There were significant differences between substance abusers and not consumers in the dimension of valence, valuing the consumers the emotional stimuli of the most extreme form (the agreeable ones as better, and the disagreeable ones as worse); (2) there were no differences between both groups in the arousal and dominance dimensions; and (3) women reported more arousal before aversive images, and less before the sexual ones, than males, independently of they were or not substance abusers. Finally, it is suggested the need to deep into the analysis of sex differences and into the images selected, as well as into the usefulness of the emotion centred therapies for the treatment of drugdependency. PMID- 22508019 TI - [Methadone substitution treatment for heroin addiction: a program assessment in Colombia]. AB - Assessment of a methadone substitution and maintenance treatment program in Colombia using the OTI (Opiate Treatment Index) instrument. Descriptive study with a 50-patient sample attended in the period 2007- 2008 for their heroin addiction. The OTI instrument was implemented to assess drug use, HIV risk-taking behavior, social functioning, criminality, health status and psychological functioning. Men accounted for 74% of the sample, women for 26%. Mean age was 22, with 64% in the 20-24 age group. Mean reported age at onset of heroin use was 18, with a range of 13-28. In 38% of the sample (19 patients) comorbidity with other mental disorders was found, 47% of these being personality disorders. Median reported current methadone dose was 40 mg/day, with a range of 15-80 mg/day. According to the OTI subscales, HIV risk-taking behavior was low-moderate, while social functioning, criminality and health status were low-risk. In the case of psychological adjustment, a low-moderate risk score was obtained for the 0-12 month treatment group, and a moderate risk score for the 12-24 and >= 24 month groups. Starting age for heroin use in this population is early . In general, the risk assessed in the OTI areas is low, possibly due to problematic heroin use being in its early stages in Colombia, but comorbidity with personality disorders is high. PMID- 22508020 TI - Energetics of paraplegic cycling: adaptations to 12 months of high volume training. AB - PURPOSE: The efficiency of functional electrical-stimulation (FES) cycling in spinal cord injured and anaesthetised able-bodied cyclists has been found to be about one third of that reported during volitional cycling. The stimulation paradigm itself appears to be the main source of this inefficiency. It is unknown whether a period of high-volume training can induce adaptations that may influence the metabolic and electrical cost of FES cycling. METHOD: 11 individuals with paraplegia completed a 12-month, home-based, progressive FES cycle training programme (up to 5 * 60 min per wk). Stimulation cost, oxygen cost, efficiency and markers of anaerobic metabolism were determined before and after 6 and 12 months of training, during constant work-rate tests. RESULTS: Oxygen cost and efficiency did not significantly change after training. Total stimulation cost and blood lactate values reduced overall, while respiratory exchange ratios remained relatively high. CONCLUSIONS: The high metabolic cost of FES cycling is a result of non-physiological recruitment of predominantly fast muscle fibres. The electrical cost of cycling reduced by 37%, probably due to motor unit hypertrophy, and lactate oxidation capacity improved. PMID- 22508022 TI - The effect of the Nintendo Wii Fit and exercise in improving balance and quality of life in community dwelling elders. AB - INTRODUCTION: This study compared the effect of Nintendo Wii Fit to the Matter of Balance program, a valid and reliable program, on improving balance, and well being to decrease the risk of falls. METHODS: Residents of an independent living senior housing facility were recruited and thirty-two residents ages 63 to 90 participated. Participants were separated into three groups: (1) Wii Fit group (n=11) completed balance games on the Wii Fit in individual sessions twice a week and supplemental home exercises; (2) Matter of Balance Group (n=11) completed exercises from the Matter of Balance Program in a group setting twice a week; (3) Control group (n=10) received no intervention. Intervention lasted three weeks. RESULTS/FINDINGS: One-way ANOVA's were completed. Scores from the assessments were not statistically significant at post-test Berg Balance Scale (p=0.837); Tinetti Gait and Balance Assessment (p=0.913); SF-36 (p=0.256). Results from a self-report demonstrated that Wii Fit is an enjoyable form of exercise for an elderly population. CONCLUSION: Although, the interventions failed to significantly increase balance, with an increase in intervention duration of Wii Fit or Matter of Balance balance may be improved. Although results were not significant this study adds to the growing body of evidence regarding the use of Wii Fit as a rehabilitation tool. PMID- 22508021 TI - Clinical and radiological results after implantation of the femoral neck preserving Delfi M hip prosthesis: a case series. AB - Various types of bone preserving total hip prostheses with a proximal force transmission concept have been developed for younger adults, one of these being the implant "Delfi M(r)", produced by ESKA until 2009. Since the demand could not meet the expectations, the production was stopped due to economic reasons so that only 31 implants of this type were sold and even less actually implanted. This study followed up 15 Delfi M(r) prostheses in 12 patients for 3.1 years and represents the only existing valid data about this implant.Demographical, preoperative and postoperative data including clinical scores (HOOS and mHHS) were collected retrospectively. Postoperative X-rays were analyzed by an independent radiologist. One implant had to be exchanged due to an infection and another one due to excessive implant migration. The mHHS and the HOOS scores showed a significant improvement after surgery. In the radiological analysis, there were no signs of radiolucent lines or osteolyses.This trial demonstrates good clinical and radiological midterm results for the Delfi M prosthesis. Limitations of this study are a small sample size and a follow-up time of 3 years at only one timepoint. PMID- 22508023 TI - Assessment of the malnutrition related information on the internet. AB - BACKGROUND: Technological development has made the health information easily accessible to the general community through the internet. The number of health information seekers is increasing gradually and there is sufficient evidence indicating its usefulness in informed decision making. The objective of the study is to evaluate the quality of malnutrition related information on the internet by using different search engines. METHODS: The three search engines: Google, MSN/Bing, and Yahoo were used to search malnutrition related information. The general assessment tool and content assessment tool were adopted to evaluate the quality of the included websites from different groups such as .org, .com, .gov, and others. The analysis was performed by using SPSS 17.0. RESULTS: Of all 29 sites, the .gov group showed the highest score for general assessment (mean=317; SD=14.68) and content assessment (mean=51.5; SD=18.26). The .org group got the lowest scores for both the tools. Reliability was 57% among rater1 and rater2 for the general assessment tool while it was 51% between rater2 and rater3 for content assessment. CONCLUSION: The study produced a quality assessment of websites containing malnutrition information. Sites provided more information on etiology, clinical information, and available treatment option for malnutrition. Assessment tools that were used in the study were good, extensive in assessing both surface and content quality. PMID- 22508024 TI - Preliminary clinical report of flexible videoarthroscopy in diagnostic knee and hip arthroscopy. AB - INTRODUCTION: Compared to rigid arthroscopic optics, a flexible camera system offers theoretically significant advantages: It has the potential to adapt to the naturally curved surface of joints, to move within the joint without stress to the cartilage or capsule and thereby to reduce the number of portals needed. Former studies evaluated flexible fiberoptic systems which were insufficient regarding image resolution. This is the first report on a new flexible videoendoscope with the so called "chip-on-the-tip" technology used in human joints. METHODS: With a plasma sterilized 3.9 diameter flexible video endoscopy system (Visera ENF V, OLYMPUS) commonly used in diagnostic rhino-laryngoscopy, we performed preliminary testing in cadaveric knee joints. After successful feasibility testing we utilized the tool in two qualitative diagnostic knee and five hip arthroscopies in combination with conventional rigid 30 degrees and 70 degrees arthroscopes (STORZ). RESULTS: Qualitative evaluation showed superior visualisation of the posterior aspects of the knee joint as insertion of the posterior medial and lateral meniscal horn, tibial insertion of the posterior cruciate ligament and the posterolateral capsulo-ligamentous corner with acceptable image resolution and clarity compared to the rigid arthroscope. In the hip, it was possible to pass around the femoral neck, avoiding additional portals. There seemed to be virtually no risk for cartilage damage at all. Difficulties of the system were scope handling, navigation and orientation within the joint as well as potential damage to the tool itself. CONCLUSION: This is to our knowledge the first report on flexible videoarthroscopy. Some of the expectations were met, such as to reach virtually every corner the joint with minimal risk for the cartilage or other joint structures and with acceptable image quality. However, there are many significant disadvantages which question the routine use of such a videoendoscopic system with its present technical features. PMID- 22508025 TI - Tensegrity finite element models of mechanical tests of individual cells. AB - A three-dimensional finite element model of a vascular smooth muscle cell is based on models published recently; it comprehends elements representing cell membrane, cytoplasm and nucleus, and a complex tensegrity structure representing the cytoskeleton. In contrast to previous models of eucaryotic cells, this tensegrity structure consists of several parts. Its external and internal parts number 30 struts, 60 cables each, and their nodes are interconnected by 30 radial members; these parts represent cortical, nuclear and deep cytoskeletons, respectively. This arrangement enables us to simulate load transmission from the extracellular space to the nucleus or centrosome via membrane receptors (focal adhesions); the ability of the model was tested by simulation of some mechanical tests with isolated vascular smooth muscle cells. Although material properties of components defined on the basis of the mechanical tests are ambiguous, modelling of different types of tests has shown the ability of the model to simulate substantial global features of cell behaviour, e.g. "action at a distance effect" or the global load-deformation response of the cell under various types of loading. Based on computational simulations, the authors offer a hypothesis explaining the scatter of experimental results of indentation tests. PMID- 22508026 TI - Effects of enterally administered surfactant in a rat model of necrotizing enterocolitis. AB - BACKGROUND: Despite technical and scientific improvements in neonatal medicine, there is still no efficient treatment for or prevention of neonatal necrotizing enterocolitis (NEC). OBJECTIVE: The aim of this study was to determine the protective effect of surfactant on intestinal cells in hypoxia-induced experimental NEC in rats. METHODS: The study was performed on Sprague Dawley rat pups divided into three groups. Group 1 served as nonhypoxic controls (n = 15). Group 2 rats (untreated; n = 15) were subjected to hypoxia and reoxygenation (H/O). Group 3 rats (surfactant treated; n = 15) were treated with surfactant (Curosurf; 400 mg/kg enterally) for 5 days and then subjected to H/O. All animals were killed on day 5, and histological and biochemical examinations were performed on intestinal samples. RESULTS: There were no histopathological changes in the control group. The histological findings in untreated rats were similar to those seen in neonatal NEC, with destruction of villi and crypts and extension to the muscularis layer. The mean histological grade of group 1 was 0.2 (range 0-1), and in group 2, it was 2.1 (range 1-3). There was no statistical difference between the histological grades of groups 2 and 3 (p > 0.05). However, there was a difference between the groups that did and did not receive surfactant with regard to superoxide dismutase (SOD), glutathione peroxidase (GSH) and malondialdehyde (MDA). CONCLUSION: Although surfactant did not have a protective effect on histological changes in hypoxic neonatal rat intestine, it improves biochemical markers such as SOD and GSH and reduces MDA levels. PMID- 22508027 TI - Multiple phenotypes in Huntington disease mouse neural stem cells. AB - Neural stem (NS) cells are a limitless resource, and thus superior to primary neurons for drug discovery provided they exhibit appropriate disease phenotypes. Here we established NS cells for cellular studies of Huntington's disease (HD). HD is a heritable neurodegenerative disease caused by a mutation resulting in an increased number of glutamines (Q) within a polyglutamine tract in Huntingtin (Htt). NS cells were isolated from embryonic wild-type (Htt(7Q/7Q)) and "knock in" HD (Htt(140Q/140Q)) mice expressing full-length endogenous normal or mutant Htt. NS cells were also developed from mouse embryonic stem cells that were devoid of Htt (Htt(-/-)), or knock-in cells containing human exon1 with an N terminal FLAG epitope tag and with 7Q or 140Q inserted into one of the mouse alleles (Htt(F7Q/7Q) and Htt(F140Q/7Q)). Compared to Htt(7Q/7Q) NS cells, HD Htt(140Q/140Q) NS cells showed significantly reduced levels of cholesterol, increased levels of reactive oxygen species (ROS), and impaired motility. The heterozygous Htt(F140Q/7Q) NS cells had increased ROS and decreased motility compared to Htt(F7Q/7Q). These phenotypes of HD NS cells replicate those seen in HD patients or in primary cell or in vivo models of HD. Huntingtin "knock-out" NS cells (Htt(-/-)) also had impaired motility, but in contrast to HD cells had increased cholesterol. In addition, Htt(140Q/140Q) NS cells had higher phospho AKT/AKT ratios than Htt(7Q/7Q) NS cells in resting conditions and after BDNF stimulation, suggesting mutant htt affects AKT dependent growth factor signaling. Upon differentiation, the Htt(7Q/7Q) and Htt(140Q/140Q) generated numerous Beta(III)-Tubulin- and GABA-positive neurons; however, after 15 days the cellular architecture of the differentiated Htt(140Q/140Q) cultures changed compared to Htt(7Q/7Q) cultures and included a marked increase of GFAP-positive cells. Our findings suggest that NS cells expressing endogenous mutant Htt will be useful for study of mechanisms of HD and drug discovery. PMID- 22508029 TI - Diagnosis: Dying from a cancer diagnosis. PMID- 22508028 TI - Patient-derived tumour xenografts as models for oncology drug development. AB - Progress in oncology drug development has been hampered by a lack of preclinical models that reliably predict clinical activity of novel compounds in cancer patients. In an effort to address these shortcomings, there has been a recent increase in the use of patient-derived tumour xenografts (PDTX) engrafted into immune-compromised rodents such as athymic nude or NOD/SCID mice for preclinical modelling. Numerous tumour-specific PDTX models have been established and, importantly, they are biologically stable when passaged in mice in terms of global gene-expression patterns, mutational status, metastatic potential, drug responsiveness and tumour architecture. These characteristics might provide significant improvements over standard cell-line xenograft models. This Review will discuss specific PDTX disease examples illustrating an overview of the opportunities and limitations of these models in cancer drug development, and describe concepts regarding predictive biomarker development and future applications. PMID- 22508031 TI - Targeted therapies: Glioma--it's all in the site occupancy. PMID- 22508035 TI - Double osteotomy of the pelvis for treatment of an anterior hip subluxation in a 9-year-old child with cerebral palsy: a variation of the Salter osteotomy. AB - Treatment with an unconventional double osteotomy of the pelvis in a 9-year-old girl with recurrent anterior hip subluxation after hip reconstruction in cerebral palsy is presented. Classical Pemberton or Salter osteotomy is effective for superolateral acetabular dysplasia, but corrections in the anterior or posterior direction are limited. In this case, double osteotomy of the pubic and iliac bone allowed better coverage in the anterior part of the acetabulum. The bone provided sufficient elasticity to achieve the desired correction without an ischial cut, therefore providing more stability of the pelvis. PMID- 22508036 TI - Recent secular trends in pubertal timing: implications for evaluation and diagnosis of precocious puberty. AB - The decline in age at puberty in the general population has been paralleled by an increase in the number of girls referred for evaluation of precocious puberty (PP). In 1999, The Lawson Wilkins Pediatric Endocrine Society recommended a lowering of the age limit for evaluation of PP in girls. However, the limited evidence on which these recommendations were based led many experts to question these new suggestions. The emergence of new European pubertal timing data evaluated by robust clinical as well as biochemical markers has broadened our insight on how to interpret the recent pubertal changes. The recent pubertal trends have resulted in a concomitant lowering of the lower limit of normality of the pubertal onset. However, evidence suggests that age at the gonadotropin and sex steroid surges have not changed. Thus, it looks as if an increasing proportion of contemporary early pubertal girls may experience isolated gonadotropin-independent thelarche rather than central PP, which may not be discernible on pubertal examination alone. Thus, the population-based limits of normality should not be directly translated into revision of age limits for evaluation of PP due to the risk of misdiagnosing rapid progressive PP as well as intracranial and other underlying pathology. PMID- 22508037 TI - Odorant-induced responses recorded from olfactory receptor neurons using the suction pipette technique. AB - Animals sample the odorous environment around them through the chemosensory systems located in the nasal cavity. Chemosensory signals affect complex behaviors such as food choice, predator, conspecific and mate recognition and other socially relevant cues. Olfactory receptor neurons (ORNs) are located in the dorsal part of the nasal cavity embedded in the olfactory epithelium. These bipolar neurons send an axon to the olfactory bulb (see Fig. 1, Reisert & Zhao, originally published in the Journal of General Physiology) and extend a single dendrite to the epithelial border from where cilia radiate into the mucus that covers the olfactory epithelium. The cilia contain the signal transduction machinery that ultimately leads to excitatory current influx through the ciliary transduction channels, a cyclic nucleotide-gated (CNG) channel and a Ca(2+) activated Cl(-) channel (Fig. 1). The ensuing depolarization triggers action potential generation at the cell body. In this video we describe the use of the "suction pipette technique" to record odorant-induced responses from ORNs. This method was originally developed to record from rod photoreceptors and a variant of this method can be found at jove.com modified to record from mouse cone photoreceptors. The suction pipette technique was later adapted to also record from ORNs. Briefly, following dissociation of the olfactory epithelium and cell isolation, the entire cell body of an ORN is sucked into the tip of a recording pipette. The dendrite and the cilia remain exposed to the bath solution and thus accessible to solution changes to enable e.g. odorant or pharmacological blocker application. In this configuration, no access to the intracellular environment is gained (no whole-cell voltage clamp) and the intracellular voltage remains free to vary. This allows the simultaneous recording of the slow receptor current that originates at the cilia and fast action potentials fired by the cell body. The difference in kinetics between these two signals allows them to be separated using different filter settings. This technique can be used on any wild type or knockout mouse or to record selectively from ORNs that also express GFP to label specific subsets of ORNs, e.g. expressing a given odorant receptor or ion channel. PMID- 22508038 TI - Use of endotracheal tube electrodes in treating glossopharyngeal neuralgia: technical note. AB - BACKGROUND/AIMS: This paper describes the use of endotracheal tube surface electrodes to help delineate the sensory and motor vagal rootlets which may be sacrificed during the surgical treatment of glossopharyngeal neuralgia. METHODS: Three patients with glossopharyngeal neuralgia were studied. All patients had their procedure under general anesthesia and a nerve integrity monitor electromyography endotracheal tube (Medtronic Xomed, Jacksonville, Fla., USA) was inserted under direct vision by the anesthesiologist. A bipolar stimulating electrode identified which, if any, of the upper rootlets of the vagus nerve caused a motor contraction near the vocal cords (i.e. motor branch) and which did not cause contractions (i.e. sensory branch). Sectioning of the glossopharyngeal and any purely sensory rootlets of the vagus nerve was subsequently performed. RESULTS: All patients had immediate and long-lasting relief of their glossopharyngeal neuralgia. In all 3 patients, use of the bipolar stimulating electrode on the lower vagal rootlets induced a recordable muscle action potential in the region of the vocal cords with low current (<0.2 mA). There were no complications consequent to placement of the nerve integrity monitor endotracheal tube. CONCLUSION: Due to the ease of use and reduced trauma, compared to needle electrodes, we would advocate endotracheal tube surface electrode monitoring in all patients undergoing surgical treatment of their glossopharyngeal neuralgia or any intracranial procedure where the integrity of the vagal nerve is in jeopardy. PMID- 22508039 TI - The proton-activated G protein coupled receptor OGR1 acutely regulates the activity of epithelial proton transport proteins. AB - The Ovarian cancer G protein-coupled Receptor 1 (OGR1; GPR68) is proton-sensitive in the pH range of 6.8 - 7.8. However, its physiological function is not defined to date. OGR1 signals via inositol trisphosphate and intracellular calcium, albeit downstream events are unclear. To elucidate OGR1 function further, we transfected HEK293 cells with active OGR1 receptor or a mutant lacking 5 histidine residues (H5Phe-OGR1). An acute switch of extracellular pH from 8 to 7.1 (10 nmol/l vs 90 nmol/l protons) stimulated NHE and H(+)-ATPase activity in OGR1-transfected cells, but not in H5Phe-OGR1-transfected cells. ZnCl(2) and CuCl(2) that both inhibit OGR1 reduced the stimulatory effect. The activity was blocked by chelerythrine, whereas the ERK1/2 inhibitor PD 098059 had no inhibitory effect. OGR1 activation increased intracellular calcium in transfected HEK293 cells. We next isolated proximal tubules from kidneys of wild-type and OGR1-deficient mice and measured the effect of extracellular pH on NHE activity in vitro. Deletion of OGR1 affected the pH-dependent proton extrusion, however, in the opposite direction as expected from cell culture experiments. Upregulated expression of the pH-sensitive kinase Pyk2 in OGR1 KO mouse proximal tubule cells may compensate for the loss of OGR1. Thus, we present the first evidence that OGR1 modulates the activity of two major plasma membrane proton transport systems. OGR1 may be involved in the regulation of plasma membrane transport proteins and intra- and/or extracellular pH. PMID- 22508040 TI - Glucose transport by acinar cells in rat parotid glands. AB - BACKGROUND/AIMS: Salivary glucose is often considered as being from glandular origin. Little information is available, however, on the possible role of glucose transporters in the secretion of the hexose by salivary glands. The major aim of the present study was to investigate the expression and localization of several distinct glucose transporters in acinar cells of rat parotid glands. METHODS: Quantitative real-time PCR analysis, immunohistochemistry and western blotting techniques were used to assess the presence of SGLT1, GLUT1, GLUT2 and GLUT4 in acinar cells of rat parotid glands. RESULTS: Quantitative real-time PCR documented the expression of SGLT1 and GLUT1 in parotid tissues, with a much lower level of GLUT4 mRNA and no expression of GLUT2 mRNA. Western blot analysis revealed the presence of SGLT1, GLUT1 and GLUT4 proteins, but not GLUT2 proteins in the parotid extract. Immunohistochemistry confirmed these findings. SGLT1 was specifically located at the baso-lateral membrane, co-localizing with Na(+)/K(+) ATPase. GLUT1 was found both at the baso-lateral and apical level. GLUT4 appeared to be also located at the baso-lateral level. However, too little GLUT4 was present to allow co-localization labeling. CONCLUSION: Based on these findings, a model is proposed for the transport of glucose into the acinar cells and thereafter into the acinar lumen. PMID- 22508041 TI - MiR-155 negatively regulates c-Jun expression at the post-transcriptional level in human dermal fibroblasts in vitro: implications in UVA irradiation-induced photoaging. AB - OBJECTIVE: C-Jun plays a critical role in ultraviolet A (UVA) irradiation-induced photoaging. The exact mechanisms by which UVA irradiation up-regulates c-Jun expression in human dermal fibroblasts (HDFs) are still not completely understood. We undertook this study to investigate whether microRNA-155 (miR-155) directly regulates the expression of c-Jun in HDFs in vitro. METHODS: Expression of c-Jun mRNA and protein and miR-155 in UVA-irradiated HDFs were detected using quantitative real-time RT-PCR and Western blotting. Luciferase reporter assays were performed to examine whether a miR-155 binding site in the 3'-untranslated region (3'-UTR) of the c-Jun gene is responsible for miR-155-mediated c-Jun regulation in HEK293A cells, and expression of c-Jun mRNA and protein in UVA non exposed and exposed HDFs trasfected with a miR-155 mimic or a miR-155 inhibitor was detected by quantitative real-time RT-PCR and Western blotting. RESULTS: Expression of miR-155 was markedly reduced and that of c-Jun mRNA and protein was significantly up-regulated in UVA-irradiated HDFs. Luciferase reporter assays indicated that c-Jun is a direct target of miR-155 in HEK293A cells. In both UVA non-exposed and exposed HDFs, miR-155 mimic decreased c-Jun protein levels, while miR-155 inhibitor increased c-Jun protein levels, but both had no effect on c-Jun mRNA expression, which suggest that miR-155-induced c-Jun inhibition occurs at the post-transcriptional level. CONCLUSIONS: Our results demonstrate that miR-155 directly controls c-Jun expression in HDFs at the post-transcriptional level and might function as a protective miRNA in HDFs. PMID- 22508042 TI - EMT phenotype is induced by increased Src kinase activity via Src-mediated caspase-8 phosphorylation. AB - Caspase-8 governs multiple cell responses to the microenvironmental cues. However, its integration of "death-life" signalings remains elusive. In our study, the role of caspase-8-Src is well-established as a promoter for migration or metastasis in Casp8(+)Src(+) A549/H226 cells in vivo and in vitro. In particular for nude mice models, mice implanted with Casp8(+)Src(+) A459/H226 cells remarkably increased spontaneous tumor metastatic burden with a significant survival disadvantage. Additionally, we detect that Src-mediated caspase-8 phosphorylation stimulates Src phosphorylation at Tyr-416 via the linkage of Src SH2 domain with phosph-Tyr-380 site of caspase-8. In turn, activated Src can efficiently induce epithelial-mesenchymal transition (EMT) phenotypic features to promote tumor cells metastasis. Surprisingly, RXDLL motif deletion in the DEDa of caspase-8 attenuates tumor cell migration or metastasis via impairing the recruitment of caspase-8 into the cellular periphery where activated Src is subject to caspase-8 phosphorylation. Together, a simple model is that the peripherization of caspase-8 is well-poised to facilitate Src-mediated caspase-8 phosphrylation at Tyr-380, then binding of phospho-Tyr380 of caspase-8 to Src SH2 domain may maintain Src in an active conformation to induce EMT phenotype, a key step toward cancer metastasis. PMID- 22508043 TI - Trolox enhances curcumin's cytotoxicity through induction of oxidative stress. AB - Curcumin, a natural polyphenol in the spice turmeric, has been found to exhibit anticancer activity. Although curcumin is generally considered an antioxidant, it is also able to elicit apoptosis through the generation of ROS, thereby functioning as a pro-oxidant in cancer cells. The present study investigated the effects of antioxidant pretreatment on curcumin-induced cytotoxicity in the human cancer cell lines A2780, MCF-7, and MDA-MB-231. Cytotoxicity was enhanced by trolox, vitamin C or vitamin E; trolox, a water soluble vitamin E derivative, was the most potent. The combination of curcumin (10 MUM) and trolox (10-50 MUM) induced apoptosis of cancer cells as evidenced by PARP cleavage and caspase-3 activation. Furthermore, expression of the pro-apoptotic protein Bad was up regulated and expression of the anti-apoptotic proteins Bcl-2 and Bcl-xl was down regulated in cells that had been treated with trolox plus curcumin. ROS generation was detected in curcumin-treated cells and was significantly enhanced when cells were treated with trolox plus curcumin. Exogenous catalase or SOD1 did not alter cytotoxicity, while over-expression of either catalase or SOD1 did, pointing to the importance of intracellular hydrogen peroxide generation in cell killing. In conclusion, we demonstrated for the first time that antioxidants such as trolox can potentiate cancer cell killing by curcumin, a finding which may help in the development of novel drug combination therapies. PMID- 22508044 TI - RNA interference of PARG could inhibit the metastatic potency of colon carcinoma cells via PI3-kinase/Akt pathway. AB - AIMS: To investigate the role and mechanism of PARG inhibition of metastatic behavior in colonic carcinoma cells. METHODS: We examined the effects of PARG protein knockdown by RNA interference on invasion, migration and matrix adhesion of colon carcinoma cell lines in vitro and using a murine in vivo model of liver metastasis. Metastasis related genes were detected using mRNA and protein levels. Moreover, LY294002, an Akt phosphorylation inhibitor, was used to determine whether the suppression of metastatic behavior of colon carcinoma cells was mediated by Akt phosphorylation that was confirmed by EMSA. Pyrrolidine dithiocarbamate (PDTC) was used as a selective NFkappa-B inhibitor to clarify the relationship between PARG, PARP and NF-kappaB. RESULTS: PARG protein was undetectable following specific shRNA transfection; mRNA and protein levels of PARP were significantly decreased. PARG-shRNA cells showed high levels of phosphorylated Akt with decreased expression of NF-kappaB (both total & nuclear), MMP2 and MMP9. However, no additional changes were noted following inhibition of PI3K/Akt pathway by LY294002 in the PARG-shRNA cells; these cells displayed reduced number of liver metastases when characterized in the murine in vivo model. CONCLUSION: PARG knockdown, concomitant with inhibition of PARP, suppressed the metastatic potency of colon carcinoma cells by activation of PI3K/Akt signaling pathway. PMID- 22508045 TI - Influence of dichloroacetate (DCA) on lactate production and oxygen consumption in neuroblastoma cells: is DCA a suitable drug for neuroblastoma therapy? AB - Many cancer cells metabolize glucose preferentially via pyruvate to lactate instead to CO(2) and H(2)O (oxidative phosphorylation) even in the presence of oxygen (Warburg effect). Dichloroacetate (DCA) is a drug which is able to shift pyruvate metabolism from lactate to acetyl-CoA (tricarboxylic acid cycle) by indirect activation of pyruvate dehydrogenase (PDH). This can subsequently lead to an increased flow of oxygen in the respiratory chain, associated with enhanced generation of reactive oxygen species (ROS) which may cause apoptosis. In order to investigate if DCA may be suitable for neuroblastoma therapy, it was investigated on three human neuroblastoma cell lines whether DCA can reduce lactate production and enhance oxygen consumption. The data show, that DCA (in the low millimolar range) is able to reduce lactate production, but there was only a slight shift to increased oxygen consumption and almost no effect on cell vitality, proliferation and apoptosis of the three cell lines investigated. Therefore, DCA at low millimolar concentrations seems to be only of minor efficacy for neuroblastoma treatment. PMID- 22508046 TI - MiR-206 regulates neural cells proliferation and apoptosis via Otx2. AB - MiR-206 was involved in a series of cellular activities, such as the growth and development of skeletal muscle and the tumorigenesis. MiR-206 was characterized previously as a differentially expressed gene in sodium arsenite (SA)-induced neural tube defects (NTDs) in chick embryos via miRNA microarray analysis. However, the role of miR-206 in the pathological process of nerve cells remained elusive. In this study we found differential expression of miR-206 in SA-treated chick embryos by Northern blot analysis. Ectopic expression of miR-206 inhibited cell proliferation, and promoted cell apoptosis in U343 and SK-N-SH cell by using MTT, Edu Apollo assay and Flow cytometry analysis. Further investigation revealed that miR-206 can interact with 3'-untranslated region (UTR) of Otx2. MiR-206 mimics down-regulated the endogeneous Otx2 expression, whereas the miR-206 inhibitor obviously up-regulated the expression of Otx2. These findings indicate that overexpression of miR-206 promotes cell apoptosis and low expression of miR 206 inhibits cell apoptosis. Otx2 may play an important role in the process of miR-206-mediated cell apoptosis. PMID- 22508047 TI - CB1 cannabinoid receptor activation rescues amyloid beta-induced alterations in behaviour and intrinsic electrophysiological properties of rat hippocampal CA1 pyramidal neurones. AB - BACKGROUND: Amyloid beta (Abeta) is believed to be responsible for the synaptic failure that occurs in Alzheimer's disease (AD), but there is little known about the functional impact of Abeta on intrinsic neuronal properties. Here, the cellular effect of Abeta-induced neurotoxicity on the electrophysiological properties of CA1 pyramidal neurons and the mechanism(s) of neuroprotection by CB1 cannabinoid receptor activation was explored. METHODS: A combination of behavioural, molecular and electrophysiological approaches was used. RESULTS: Bilateral injections of the Abeta peptide fragment (1-42) into the prefrontal cortex caused a significant impairment in the retention and recall capability in the passive avoidance tasks and significantly increased the level of active caspase-3 in the hippocampus. Whole-cell patch clamp recordings revealed a significant reduction in the intrinsic action potential (AP) frequency and an increase in the discharge irregularity in the absence of synaptic inputs in Abeta treated group. Abeta treatment induced also significant changes in both the spontaneous and evoked neuronal responses. However, co-treatment with ACEA, a CB1 receptor agonist, preserved almost the normal intrinsic electrophysiological properties of pyramidal cells. CONCLUSIONS: In vivo Abeta treatment altered significantly the intrinsic electrophysiological properties of CA1 pyramidal neurons and the activation of CB1 cannabinoid receptors exerted a strong neuroprotective action against Abeta toxicity. PMID- 22508048 TI - Lycorine, a candidate for the control of period length in mammalian cells. AB - Plants of the Amaryllidaceae family have been used as therapeutic agents against CNS related maladies such as Alzheimer's disease. The known primary alkaloid constituents have significant biological activity. We identified the Lycoris alkaloids lycorine and lycoricidinol from Amaryllidaceae using a real-time reporter gene assay system based on NIH3T3 cells. These alkaloids have a wide spectrum of pharmacological actions and dose-dependently lengthen the circadian period. When cells that had been incubated with lycorine or lycoricidinol were washed and then incubated without these alkaloids, period length reverted to that of control cells, suggesting that elongation of the circadian period induced by lycorine and lycoricidinol is reversible. Although one of its major activities is the inhibition of protein synthesis, lycorine induced dose-dependent period elongation regardless of the presence of cycloheximide and moreover, cycloheximide, itself did not affect period length, suggesting that lycorine dose dependently extends the circadian period by a mechanism other than translational inhibition. Real-time RT-PCR showed that lycorine enhanced RORalpha and Bmal1 transcription, and exogenous expression and knockdown of Bmal1 also caused long and short periods, respectively, thus confirming the phenotype indicated by lycorine. These data indicate that lycorine and lycoricidinol modulate Bmal1 transcription and the circadian period, and also suggest that Lycoris alkaloids are novel contributors to the control of period length in mammalian cells. PMID- 22508049 TI - S100B serves as a Ca(2+) sensor for ROS-GC1 guanylate cyclase in cones but not in rods of the murine retina. AB - Rod outer segment membrane guanylate cyclase (ROS-GC1) is a bimodal Ca(2+) signal transduction switch. Lowering [Ca(2+)](i) from 200 to 20 nM progressively turns it "ON" as does raising [Ca(2+)](i) from 500 to 5000 nM. The mode operating at lower [Ca(2+)](i) plays a vital role in phototransduction in both rods and cones. The physiological function of the mode operating at elevated [Ca(2+)](i) is not known. Through comprehensive studies on mice involving gene deletions, biochemistry, immunohistochemistry, electroretinograms and single cell recordings, the present study demonstrates that the Ca(2+)-sensor S100B coexists with and is physiologically linked to ROS-GC1 in cones but not in rods. It up regulates ROS-GC1 activity with a K(1/2) for Ca(2+) greater than 500 nM and modulates the transmission of neural signals to cone ON-bipolar cells. Furthermore, a possibility is raised that under pathological conditions where [Ca(2+)](i) levels rise to and perhaps even enter the micromolar range, the S100B signaling switch will be turned "ON" causing an explosive production of CNG channel opening and further rise in [Ca(2+)](i) in cone outer segments. The findings define a new cone-specific Ca(2+)-dependent feature of photoreceptors and expand our understanding of the operational principles of phototransduction machinery. PMID- 22508051 TI - Renin-angiotensin-aldosterone system gene polymorphisms and coronary artery disease: detection of gene-gene and gene-environment interactions. AB - OBJECTIVE: The objective of this study was to explore the association between coronary artery disease and genetic polymorphisms of the renin-angiotensin aldosterone system (RAAS) pathway. In addition, we examined the interactions between demographic and lifestyle risk factors (environmental factors including age, sex, smoking status, alcohol intake) and RAAS polymorphisms on disease risk. METHODS: A total of 1089 subjects who underwent coronary angiography were enrolled in this study. Eight RAAS polymorphisms were genotyped in this population: the G2350A (rs4343) polymorphism in exon 17 of the angiotensin converting enzyme (ACE) gene, 1166A->C (rs5186) and 573C/T (rs5182) in the angiotensin II type 1 receptor (AGTR1) gene, the -344C->T transversion (rs1799998) in the aldosterone synthase (CYP11B2) gene, and the G-217A (rs5049), G-6A (rs5051), M235T (rs699; T4072C), and T174M (rs4762; C3889T) polymorphisms in the angiotensinogen (AGT) gene. Subjects with coronary heart disease were defined as those with at least 50% stenosis in at least one major coronary artery, and, the severity of coronary atherosclerosis was defined by the Gensini scoring system. RESULTS: Compared to the subjects with AA genotype, the subjects with AG + GG genotype of rs1799998 had significant lower gensini score (p=0.029). After adjusting for age, gender, cigarette smoking, and alcohol intake status, the AG genotype (OR 0.717 95%CI 0.541-0.950, p=0.021) and the AG + GG genotype (OR 0.730 95%CI 0.559-0.954, p=0.021) distributions of rs1799998 were significantly different between the cases and controls compare to the AA genotype. Subjects with three at-risk loci had increased risk of coronary artery disease compared to subjects carrying 0 or 1 risk-associated polymorphism (OR [95% CI]:1.579 [1.077 2.316], p=0. 019), and the significance of the association was not reduced after adjusting for age, sex, cigarette smoking, or alcohol intake (adjusted OR [95% CI]: 1.673 [1.116-2.507], p=0.013). The results of multifactor-dimensionality reduction analysis revealed an interaction effect of CYP11B2 -344C->T, age, and smoking status on the risk of coronary heart disease (training OR [95% CI]: 3.7685 [2.8463-4.9895], p<0.0001; testing OR [95% CI]: 2.7583 [1.2038-6.3203], p=0.015). CONCLUSIONS: Subjects who carried the G allele of the rs1799998 polymorphism significantly associated with coronary heart disease and severity of coronary atherosclerosis estimated by the Gensini score in the whole population of the study. And, multiple RAAS gene polymorphisms are associated with coronary artery disease. The interaction of the CYP11B2 -344C->T polymorphism (rs1799998), age, and smoking status is also associated with enhanced risk of coronary artery disease. PMID- 22508050 TI - Comparative effects of liensinine and neferine on the human ether-a-go-go-related gene potassium channel and pharmacological activity analysis. AB - Liensinine and neferine, a kind of isoquinoline alkaloid, can antagonize the ventricular arrhythmias. The human ether-a-go-go-related gene (hERG) is involved in repolarization of cardiac action potential. We investigated the effects of liensinine and neferine on the biophysical properties of hERG channel and the underlying structure-activity relationships. The effects of liensinine and neferine were examined on the hERG channels in the stable transfected HEK293 cells using a whole-cell patch clamp technique, western blot analysis and immunofluorescence experiment. The pharmacokinetics and tissue distribution determination of liensinine and neferine in rats were determined by a validated RP-HPLC method. Liensinine and neferine induced decrease of current amplitude in dose-dependent. Liensinine reduced hERG tail current from 70.3+/-6.3 pA/pF in control group to 56.7+/-2.8 pA/pF in the 1 MUM group, 53.0+/-2.3 pA/pF (3 MUM) and 17.8+/-0.7 pA/pF (30 MUM); the corresponding current densities of neferine treated cells were 41.9+/-3.1 pA/pF, 32.3+/-3.1 pA/pF and 16.2+/-0.6 pA/pF, respectively. Neferine had binding affinity for the open and inactivated state of hERG channel, liensinine only bound to the open state. The inhibitory effects of liensinine and neferine on hERG current were attenuated in the F656V or Y652A mutant channels. Neferine distributed more quickly than liensinine in rats, which was found to be in higher concentration than liensinine. Both liensinine and neferine had no effect on the generation and expression of hERG channels. In conclusion, neferine is a more potent blocker of hERG channels than liensinine at low concentration (<10 MUM), which may be due to higher hydrophobic nature of neferine compared with liensinine. Neferine may be safety even for long-term treatment as an antiarrhythmic drug. PMID- 22508052 TI - Downregulation of quinone reductase 2 attenuates vascular smooth muscle cells proliferation and neointimal formation in balloon injured rat carotid artery. AB - BACKGROUND/AIMS: Quinone reductase 2 (NQO2) is a flavoprotein that catalyzes the metabolic reduction of quinines, but its biological mechanism in vascular smooth muscle cells (VSMCs) is unclear. The aim of this study was to evaluate the role of NQO2 on VSMCs proliferation and the neointimal formation in balloon injured rat carotid artery. METHODS: Left common carotid arteries from Sprague-Dawley rats were injured by a balloon catheter, and the injured arteries were incubated with 50 MUL solution of NQO2-siRNA-GFP lentiviral vectors, NC-siRNA-GFP lentiviral vectors or PBS for 1 h. The rats were euthanized for morphometric and immunohistochemical analysis, real-time PCR and western blot analysis at 2 weeks after balloon injury and gene transfer. The cultured rat VSMCs transduced with NQO2-siRNA-GFP or NC-siRNA-GFP lentiviral vectors were used for cell proliferation assay, real-time PCR and western blot analysis. In order to detect the vascular or intracellular ROS level, the lentiviral vectors without GFP were used to transfect the injured common carotid arteries and the cultured rat VSMCs. RESULTS: Lentiviral vectors bearing NQO2 siRNA could reduce NQO2 protein level and suppress NQO2 mRNA expression in balloon injured artery walls and cultured rat VSMCs. Downregulation of NQO2 significantly suppressed VSMCs proliferation and intimal formation. NQO2 siRNA treatment could reduce vascular or intracellular ROS level and decrease the phosphorylation of the ERK1/2 in balloon injured artery walls and cultured rat VSMCs. CONCLUSION: Our study suggests that downregulation of NQO2 significantly suppresses VSMCs proliferation and progression of neointimal formation after vascular injury. PMID- 22508054 TI - Carbon monoxide protects against ischemia-reperfusion injury in vitro via antioxidant properties. AB - Carbon monoxide (CO) is believed to mediate many of the cytoprotective effects attributed to the activation of heme oxygenase (HO-1), the enzyme responsible for CO production. Recently, the study of CO-releasing molecules (CO-RMs) has provided a new approach for the delivery of CO. In the present study, we examined whether the cardioprotective properties of CO-RM2 in isolated rat hearts subjected to an ischemia-reperfusion (I/R) sequence were associated with the presence of CO. In addition, the antioxidant properties of CO-RM2 were evaluated. In hearts pretreated with CO-RM2, the improvement in contractile function at the end of the reperfusion period after 20 min of global total ischemia was significantly greater than in controls. These beneficial effects were accompanied by a reduction in 1) LDH activity release 2) infarct size 3) ventricular superoxide production. The improvement in myocardial function and the reduction in oxidative stress were not observed when hearts were pretreated with inactivated CO-RM2 (iCO-RM2). Additionally, CO-RM2, but not iCO-RM2, was found to exert antioxidant properties. These results suggest that the production of CO is a necessary factor in the cardioprotective and antioxidant actions of CO releasing compound. These results may open up new ground for a novel class of cardioprotective compounds. PMID- 22508053 TI - Neuropeptide Y reverses chronic stress-induced baroreflex hypersensitivity in rats. AB - Chronic stress, as a risk factor for cardiovascular diseases, has been reported to result in elevated plasma neuropeptide Y (NPY) and be highly associated with abnormal cardiac autonomic function. This study aimed to explore the effect of NPY on the chronic stress-induced abnormal baroreceptor reflex sensitivity (BRS). Seven types of recognized stressors were used to develop chronic stress rat model. Subcutaneously implanting ALZET mini-osmotic pumps containing NPY were used to evaluate the action of NPY on the stressed male rats. We found that chronic stress showed no influence on baseline systolic blood pressure (SBP) and heart rate (HR), whereas NPY (85 MUg for 30 days) could elevate baseline SBP and induce bradycardia in rats intervened by various stimuli. NPY pretreatment could preserve chronic stress-induced decreases in left ventricular systolic pressure (LVSP) and the maximum rate of change in left ventricular pressure in the isovolumic contraction period (+dp/dt(max)) but has shown no effect on left ventricular end diastolic pressure (LVEDP) and the maximum rate of change in left ventricular pressure in the isovolumic relaxation period (-dp/dt(max)). Notably, chronic stress led to baroreflex oversensitivity indicated by the elevated ratio of Deltaheart rate (HR)/ Deltamean arterial blood pressure (MABP) in rats followed by vasoconstrictor (phenylephrine, PE) or vasodilator (sodium nitroprusside, SNP) administration, which was almost completely reversed by NPY pretreatment. The expressions of substance P (SP) and gamma aminobutyric acid A receptor (GABA(A)R) in nucleus tractus solitarius were increased in chronic stress rats, which were counteracted by NPY pretreatment. We conclude that chronic stress-induced baroreflex hypersensitivity could be blocked by NPY pretreatment. Furthermore, the altered expressions of neurotransmitters and receptors in the brainstem might contribute to this process. PMID- 22508055 TI - Effects of nicotine on PTHrP and PTHrP receptor expression in rat coronary endothelial cells. AB - AIMS: The study was aimed to investigate whether nicotine affects endothelial expression of PTHrP and PTHrP receptor, a peptide system involved in endothelial protection against apoptosis. METHODS: Isolated and cultured rat coronary endothelial cells were used. Immunoblot techniques were used to study activation of mitogen-activated protein (MAP) kinases and to quantify PTHrP and PTHrP receptor expression. Real-time RT-PCR was used to quantify PTHrP, PTHrP-receptor, bcl-2, and bax mRNA expression. The rate of apoptosis was determined by HOE33258 staining and confirmed by quantification of the bcl-2-to-bax ratio. In vitro data were compared to hearts from rats exposed to cigarette smoking. RESULTS: Nicotine induced PTHrP protein expression at nanomolar levels and small increases of PTHrP release (~8%). Antagonists directed against the alpha7 subunit of cholinergic receptors, the most prominent isoform, attenuated nicotine-dependent increases of PTHrP expression. This effect of nicotine was p38 MAPK dependent. Nicotine at micromolar concentrations reduced PTHrP receptor expression. In vitro and in vivo we found a correlation between PTHrP receptor expression and bcl-2 expression. CONCLUSION: Nicotine induces PTHrP expression in endothelial cells but excessive concentrations of nicotine reduce PTHrP receptor expression thereby attenuating any protective effects of PTHrP against apoptosis. PMID- 22508056 TI - mTOR-dependent modulation of gastric nesfatin-1/NUCB2. AB - BACKGROUND: Nesfatin-1, an 82 amino acid peptide derived from the prohormone nucleobindin-2 (NUCB2), is a novel satiety hormone acting through a leptin independent mechanism in the hypothalamus. The mechanisms by which production of nesfatin-1/NUCB2 is regulated remain unknown. METHODS: Nesfatin-1/NUCB2 mRNA and immunoreactivity were examined in gastric tissue and Min-6 cells by RT-PCR and immunofluorescent staining or Western blotting. RESULTS: Nesfatin-1/NUCB2 is co localized with pS6K1, the downstream target of mammalian target of rapamycin (mTOR), in gastric X/A like cells. A parallel relationship between gastric mTOR signaling and nesfatin-1/NUCB2 was observed during changes in energy status. Both mTOR activity and gastric nesfatin-1/NUCB2 were down-regulated by fasting, and returned to basal levels with re-feeding. In high fat diet induced obese mice, gastric mTOR signaling and nesfatin-1/NUCB2 were increased. Inhibition of the gastric mTOR signaling by rapamycin attenuated the expression of gastric nesfatin 1/NUCB2 mRNA and protein in both lean and obese mice. Attenuation of mTOR activity by rapamycin or over-expression of TSC1 or TSC2 reduced the expression of nesfatin-1/NUCB2 in Min-6 cells, suggesting a direct effect of mTOR signaling. CONCLUSION: Gastric mTOR is a gastric energy sensor whose activity is linked to the regulation of gastric nesfatin-1/NUCB2. PMID- 22508058 TI - Procaterol-stimulated increases in ciliary bend amplitude and ciliary beat frequency in mouse bronchioles. AB - The beating cilia play a key role in lung mucociliary transport. The ciliary beating frequency (CBF) and ciliary bend amplitude (CBA) of isolated mouse bronchiolar ciliary cells were measured using a light microscope equipped with a high-speed camera (500 Hz). Procaterol (abeta(2)-agonist) increased CBA and CBF in a dose dependent manner via cAMP. The time course of CBA increase is distinct from that of CBF increase: procaterol at 10 nM first increased CBA and then CBF. Moreover, 10 pM procaterol increased CBA, not CBF, whereas 10 nM procaterol increased both CBA and CBF. Concentration-response studies of procaterol demonstrated that the CBA curve was shifted to a lower concentration than the CBF curve, which suggests that CBA regulation is different from CBF regulation. Measurements of microbead movements on the bronchiole of lung slices revealed that 10 pM procaterol increased the rate of ciliary transport by 37% and 10 nM procaterol increased it by 70%. In conclusion, we have shown that increased CBA is of particular importance for increasing the bronchiolar ciliary transport rate, although CBF also plays a role in increasing it. PMID- 22508057 TI - Involvement of Na(+)-leak channel in substance P-induced depolarization of pacemaking activity in interstitial cells of Cajal. AB - Interstitial cells of Cajal (ICCs) are the pacemaking cells in the gastrointestinal muscles that generate the rhythmic oscillations in membrane potential known as slow waves. ICCs also mediate or transduce inputs from the enteric nervous system. Substance P (SubP) is a member of the family of mammalian tachykinin peptides that are predominantly released by enteric neurons. This study assessed the relationship of Na(+)-leak channel (NALCN) in the SubP-induced depolarization in pacemaking activity in the gastrointestinal tract. The patch clamp technique for whole-cell recording was used in cultured cluster and single ICCs. Electrophysiological and pharmacological properties of SubP in ICC pacemaking activity were similar to those of NALCN. Reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemistry all showed abundant and localized expression of NALCN messenger RNA and protein in mouse small intestine. NALCN is involved in the SubP-induced depolarization of intestinal pacemaking activity. The protein is a potential target for pharmacological treatment of motor disorders of the gut. PMID- 22508059 TI - Modulation of lung allergic response by renal ischemia and reperfusion injury. AB - The Th1/Th2 balance represents an important factor in the pathogenesis of renal ischemia-reperfusion injury (IRI). In addition, IRI causes a systemic inflammation that can affect other tissues, such as the lungs. To investigate the ability of renal IRI to modulate pulmonary function in a specific model of allergic inflammation, C57Bl/6 mice were immunized with ovalbumin/albumen on days 0 and 7 and challenged with an ovalbumin (OA) aerosol on days 14 and 21. After 24 h of the second antigen challenge, the animals were subjected to 45 minutes of ischemia. After 24 h of reperfusion, the bronchoalveolar lavage (BAL) fluid, blood and lung tissue were collected for analysis. Serum creatinine levels increased in both allergic and non-immunized animals subjected to IRI. However, BAL analysis showed a reduction in the total cells (46%) and neutrophils (58%) compared with control allergic animals not submitted to IRI. In addition, OA challenge induced the phosphorylation of ERK and Akt and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lung homogenates. After renal IRI, the phosphorylation of ERK and expression of COX-2 and iNOS were markedly reduced; however, there was no difference in the phosphorylation of Akt between sham and ischemic OA-challenged animals. Mucus production was also reduced in allergic mice after renal IRI. IL-4, IL-5 and IL 13 were markedly down-regulated in immunized/challenged mice subjected to IRI. These results suggest that renal IRI can modulate lung allergic inflammation, probably by altering the Th1/Th2 balance and, at least in part, by changing cellular signal transduction factors. PMID- 22508060 TI - Effect of azathioprine on Na(+)/H(+) exchanger activity in dendritic cells. AB - Azathioprine is a powerful immunosuppressive drug, which is partially effective by interfering with the maturation and function of dendritic cells (DCs), antigen presenting cells linking innate and adaptive immunity. DCs are stimulated by bacterial lipopolysaccharides (LPS), which trigger the formation of reactive oxygen species (ROS), paralleled by activation of the Na(+)/H(+) exchanger. The carrier is involved in the regulation of cytosolic pH, cell volume and migration. The present study explored whether azathioprine influences Na(+)/H(+) exchanger activity in DCs. DCs were isolated from murine bone marrow, cytosolic pH (pH(i)) was estimated utilizing 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF-AM) fluorescence, Na(+)/H(+) exchanger activity from the Na(+)-dependent realkalinization following an ammonium pulse, cell volume from forward scatter in FACS analysis, ROS production from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, TNFalpha release utilizing ELISA, and migration utilizing transwell migration assays. Exposure of DCs to lipopolysaccharide (LPS, 1 MUg/ml) led to a transient increase of Na(+)/H(+) exchanger activity, an effect paralleled by ROS formation, increased cell volume, TNFalpha production and stimulated migration. Azathioprine (10 MUM) did not significantly alter the Na(+)/H(+) exchanger activity, cell volume and ROS formation prior to LPS exposure but significantly blunted the LPS-induced stimulation of Na(+)/H(+) exchanger activity, ROS formation, cell swelling, TNFalpha production and cell migration. In conclusion, azathioprine interferes with the activation of dendritic cell Na(+)/H(+) exchanger by bacterial lipopolysaccharides, an effect likely participating in the anti-inflammatory action of the drug. PMID- 22508061 TI - Rapamycin sensitive ROS formation and Na(+)/H(+) exchanger activity in dendritic cells. AB - Rapamycin, a widely used immunosuppressive drug, has been shown to interfere with the function of dendritic cells (DCs), antigen-presenting cells contributing to the initiation of primary immune responses and the establishment of immunological memory. DC function is governed by the Na(+)/H(+) exchanger (NHE), which is activated by bacterial lipopolysaccharides (LPS) and is required for LPS-induced cell swelling, reactive oxygen species (ROS) production and TNF-alpha release. The present study explored, whether rapamycin influences NHE activity and/or ROS formation in DCs. Mouse DCs were treated with LPS in the absence and presence of rapamycin (100 nM). ROS production was determined from 2',7' dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, cytosolic pH (pH(i)) from 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) fluorescence, NHE activity from the Na(+)-dependent realkalinization following an ammonium pulse, cell volume from forward scatter in FACS analysis, and TNF-alpha production utilizing ELISA. In the absence of LPS, rapamycin did not significantly modify cytosolic pH, NHE activity or cell volume but significantly decreased ROS formation. LPS stimulated NHE activity, enhanced forward scatter, increased ROS formation, and triggered TNF-alpha release, effects all blunted in the presence of rapamycin. NADPH oxidase inhibitor Vas-2870 (10 MUM) mimicked the effect of rapamycin on LPS induced stimulation of NHE activity and TNF-alpha release. The effect of rapamycin on TNF-alpha release was also mimicked by the antioxidant ROS scavenger Tempol (30 MUM) and partially reversed by additional application of tert-butylhydroperoxide (10 MUM). In conclusion, in DCs rapamycin disrupts LPS induced ROS formation with subsequent inhibition of NHE activity, cell swelling and TNF-alpha release. PMID- 22508062 TI - IL-6 production stimulated by CD14(+) monocytes-paracrined IL-1beta does not contribute to the immunosuppressive activity of human umbilical cord mesenchymal stem cells. AB - BACKGROUND/AIMS: Human umbilical cord mesenchymal stem cells (hUC-MSCs) possess immunosuppressive activities but the mechanisms of such activities are not fully understood. Here, we investigated the role of IL-6, one of the characteristic factors of MSCs, in the immunoregulating effect of hUC-MSCs on CD4(+) T lymphocytes. METHODS: The condition media from human peripheral blood mononuclear cells (hPBMCs) or CD14+/- cell were tested if stimulating IL-6 production by hUC MSCs. The related signaling pathway of IL-6, and the immunosuppressive activity of IL-6 on CD4(+) T lymphocytes were studied. RESULT: IL-6 production was dramatically increased by hUC-MSCs when co-culturing with resting or activated hPBMCs. CD14(+) monocytes-paracrined IL-1beta promoted the secretion of IL-6 by hUC-MSCs via JNK and NF-kappaB signaling pathway. Blocking of PGE2 synthesis did not affect the secretion of IL-6, anti-IL-6 antibody was not able to reverse hUC MSCs-mediated inhibition on CD4(+) T lymphocytes. IL-6 did not mediate the suppressive activity of IL-1beta-hUC-MSCs- PGE2 on CD4(+) T cell. CONCLUSION: CD14(+) monocytes-paracrined IL-1beta promotes IL-6 secretion by hUC-MSCs through activating JNK and NF-kappaB signaling pathway. However, increased IL-6 production does not contribute to immunosuppressive activity of IL-1beta-hUC-MSCs PGE2 on CD4(+) T cells. PMID- 22508063 TI - Cockroach allergen Per a 7 down-regulates expression of Toll-like receptor 9 and IL-12 release from P815 cells through PI3K and MAPK signaling pathways. AB - BACKGROUND: As a major source of indoor allergens, cockroach causes perennial rhinitis and asthma. Recently, cockroach feces were reported to contain TLR2 agonist, which could directly activate neutrophils to release cytokines. CpG oligodeoxynucleotide (ODN), a Toll-like receptor (TLR)9 activator was also found to induce proinflammatory cytokine release from mast cells. However, influence of specific cockroach allergen on Th1 cytokine release and expression of TLR9 in mast cells remains uninvestigated. METHODS: To investigate effects of Per a 7 on TLR expression and cytokine release from mast cells and their cell signaling mechanisms, P815 cells were challenged by recombinant Per a 7 (rPer a 7), and expression of TLR9 mRNA and protein was assessed mainly by real time PCR and flow cytometry analysis. Detection of phosphorylation of cell signaling components was performed with Western blotting technique. RESULTS: The results showed that rPer a 7 induced up to 72 and 46% down-regulation of expression of TLR9 mRNA and protein, respectively following 16 h incubation period. It induced also approximately 41.1% reduction of IL-12 release. When PD98059, U0126 and LY294002 were pre-incubated with the cells for 30 min they diminished rPer a 7 induced reduction of TLR9 expression and IL-12 release, indicating these events are via activation of ERK and PI3K/Akt signaling pathways. CONCLUSION: Reduction of IL-12 production and expression of TLR9 in P815 mastocytoma cells by Per a 7 suggests that this major cockroach allergen might contribute to the development of cockroach allergy. PMID- 22508064 TI - Supplementation with undenatured whey protein during diabetes mellitus improves the healing and closure of diabetic wounds through the rescue of functional long lived wound macrophages. AB - Long and persistent uncontrolled diabetes tends to degenerate the immune system and increase the incidence of infections in diabetic patients. A serious complication of diabetes is impaired healing, which diminishes physical activity and, in some cases, leads to chronic wounds and limb amputation. Whey proteins (WPs) enhance immunity during early development and have a protective role in some immune disorders. The effect of camel WPs on wound healing in a streptozotocin-induced type 1 diabetic mice model was investigated. Sixty male mice were equally distributed into 3 experimental groups: group 1, non-diabetic control mice; group 2, diabetic mice; and group 3, diabetic mice that were orally supplemented with undenatured WP (100 mg/kg body weight/day for 1 month through oral gavage). We observed that the diabetic mice exhibited delayed wound closure characterized by a significant reduction in collagen deposition, prolonged elevation in inflammatory cytokines, aberrant activation of STAT3 and reduction in the activation of Akt and NF-kappaB when compared with the control mice. Moreover, in the diabetic mice, the wound-resident macrophages were dysfunctional and demonstrated increased apoptosis, a significant reduction in their phagocytotic ability, aberrant activation of STAT3 and a marked reduction in the activation of Akt. Interestingly, the supplementation of diabetic mice with WP significantly enhanced the collagen deposition, limited the inflammatory stimuli, restored the activation of STAT3, Akt and NF-kappaB and greatly improved the closure of diabetic wounds compared with the control mice. Most important, the supplementation of diabetic mice with WP rescued functional, long-lived wound resident macrophages. Our data reveal the benefits of WP supplementation in improving the healing and closure of diabetic wounds. PMID- 22508065 TI - Ganoderma lucidum polysaccharide accelerates refractory wound healing by inhibition of mitochondrial oxidative stress in type 1 diabetes. AB - BACKGROUND/AIMS: Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens. The present study was designed to determine the protective effect of Ganoderma lucidum polysaccharide (Gl-PS) on diabetic wound healing and investigate underlying mechanisms. METHODS: Streptozotocin (STZ)-induced type 1 diabetic mice with full-thickness excisional wounds were intragastrically administered with 10, 50 or 250 mg/kg/day of Gl-PS. RESULTS: Gl-PS dose-dependently rescued the delay of wound closure in diabetic mice. 50 and 250 mg/kg/day of Gl-PS treatment significantly increased the mean perfusion rate around the wound in diabetic mice. Diabetic conditions markly increased mitochondrial superoxide anion (O(2).( )) production, nitrotyrosine formation, and inducible nitric oxide synthase (iNOS) activity in wound tissues, which were normalized with Gl-PS treatment. In diabetic wound tissues, the protein level of manganese superoxide dismutase (MnSOD) was unchanged whereas MnSOD activity was inhibited and its nitration was potentiated; Gl-PS administration suppressed MnSOD nitration and increased MnSOD and glutathione peroxidase (GPx) activities. Moreover, Gl-PS attenuated the redox enzyme p66Shc expression and phosphorylation dose-dependently in diabetic mice skin. CONCLUSION: Gl-PS rescued the delayed wound healing and improved wound angiogenesis in STZ-induced type 1 diabetic mice, at least in part, by suppression of cutaneous MnSOD nitration, p66Shc and mitochondrial oxidative stress. PMID- 22508066 TI - Tunicamycin inhibits diabetes. AB - BACKGROUND: Autoimmune diseases are characterized by a breakdown of immunologic tolerance, and this breakdown can lead to life-threatening or lifelong disorders. Moreover; drugs that are used to treat these diseases are few in number and are associated with many serious adverse effects. METHODS: We used the rat insulin promoter-glycoprotein mouse model to analyze the role of tunicamycin in the process of autoimmune diabetes; the P14 mouse model to analyze the effect of tunicamycin on CD8(+) T cells; chop knockout mice to analyze the role of tunicamycin on an endoplasmic reticulum stress model; and fluorescence-activated cell sorting, quantitative real-time polymerase chain reaction, and histologic methods. RESULTS: We found that a single dose of tunicamycin reduced the activation and pancreatic infiltration of CD8(+) T cells. This activity delayed the incidence of virus-induced diabetes and improved survival rates. CONCLUSION: Tunicamycin may offer therapeutic opportunities for T cell-mediated autoimmune diseases such as diabetes. PMID- 22508067 TI - Sparse principal component analysis for identifying ancestry-informative markers in genome-wide association studies. AB - Genome-wide association studies (GWAS) routinely apply principal component analysis (PCA) to infer population structure within a sample to correct for confounding due to ancestry. GWAS implementation of PCA uses tens of thousands of single-nucleotide polymorphisms (SNPs) to infer structure, despite the fact that only a small fraction of such SNPs provides useful information on ancestry. The identification of this reduced set of ancestry-informative markers (AIMs) from a GWAS has practical value; for example, researchers can genotype the AIM set to correct for potential confounding due to ancestry in follow-up studies that utilize custom SNP or sequencing technology. We propose a novel technique to identify AIMs from genome-wide SNP data using sparse PCA. The procedure uses penalized regression methods to identify those SNPs in a genome-wide panel that significantly contribute to the principal components while encouraging SNPs that provide negligible loadings to vanish from the analysis. We found that sparse PCA leads to negligible loss of ancestry information compared to traditional PCA analysis of genome-wide SNP data. We further demonstrate the value of sparse PCA for AIM selection using real data from the International HapMap Project and a genomewide study of inflammatory bowel disease. We have implemented our approach in open-source R software for public use. PMID- 22508068 TI - From furuncle to axillary web syndrome: shedding light on histopathology and pathogenesis. AB - Axillary web syndrome (AWS) is defined as a cord-like structure extending from the axilla to the medial arm following axillary surgery in women with breast cancer. There is only limited literature on the pathogenesis of this syndrome and the etiology of the cord. A 57-year-old man presented with a band-like skin depression and tightness over the medial aspect of his arm extending from the axilla to the antecubital fossa following development of a furuncle in the ipsilateral axilla. Histopathologic examination of the 'band' revealed fibroblastic proliferation surrounding the lymphatic vessel which was identified by presence of an obvious valve as well as positive staining for D2-40, a specific marker for lymphatic endothelium. This is the first report of AWS following axillary furunculosis. This case adds to the limited data on the histopathology of AWS, further confirming the etiology of the 'cord' to be of lymphatic origin. PMID- 22508069 TI - Early intervention in bipolar disorder: the Jano program at Hospital Universitario Marques de Valdecilla. AB - In order to improve relapse and recurrence prevention in bipolar disorder, the purposes of this paper are: (i) to summarize the evidence published on treatments for this disorder, particularly on psychological interventions in its early phases; (ii) to provide a description of the Jano Intervention and Research Program on the Early Phases of Bipolar Disorder, which is being developed at Valdecilla Hospital (Santander, Spain). Firstly, we review the data from randomized controlled trials and systematic reviews regarding four psychotherapies proven to be effective in the treatment of bipolar disorder: psychoeducation, cognitive-behavioral therapy, family therapy and interpersonal and social rhythm therapy. Secondly, we display a systematic review on the effectiveness of psychological therapies during the early stage of bipolar disorder. Out of 456 studies, all were excluded due to not meeting the inclusion criteria. Finally, we outline the Jano Program, which provides psychiatric management, psychoeducation, psychotherapy and family therapy for patients in the early stage of bipolar disorder. Several standardized clinical, social and neuropsychological tests are administered to the patients at the beginning of the program, and also at 2, 4, 6 and 8 weeks, 3 and 6 months, 1, 2, 3 and 5 years later. CONCLUSIONS: It's necessary to enlarge the sample and finish our data collection in order to determine the effectiveness and efficiency of this kind of program, and specially of its psychological components. Early intervention for bipolar disorder may need to be adapted in some way from usual treatments to better reach our goals. PMID- 22508070 TI - Borderline Personality Disorder (BPD) diagnosis with the self-report Personality Diagnostic Questionnaire-4+(PDQ-4+): confirmation of the 3-factor structure. AB - INTRODUCTION: The clinical heterogeneity and elevated comorbidity of Borderline Personality Disorder (BPD) have suggested the possible existence of several factors or subtypes of this construct. Studies published to date mainly show that this diagnosis could be represented either as a 1-dimensional model or 3-factor model. However, most of the studies have analyzed the factorial structure of the BPD DSM-IV criteria only using semi-structured interviews. This study has aimed to analyze the factorial structure of BPD DSM-IV criteria used in the self-report PDQ-4+. METHOD: A total of 159 psychiatric outpatients with suspicion of BPD diagnosis were evaluated. Confirmatory Factor Analyses (CFA) was performed for BPD criteria in PDQ-4+ and two previously defined structures were examined and compared: a 1-dimensional model and a 3-factor model. RESULTS: Both models showed good fit indexes. However, the results of the CFA showed better goodness of fit indexes (chi(2)/gl; CFI; RMSEA; TLI; AIC and GFI) for the 3-factor model. CONCLUSIONS: BPD is a construct that can be used to describe three factors of criteria that represent different features of this disorder. The three factors, which could be called Disturbed Relatedness, Affective Instability and Behavioral Dyscontrol, can also be explained by the combination of different diagnostic criteria. The existence of these factors could indicate the presence of different subgroups of BPD patients with different clinical patterns. PMID- 22508071 TI - Treatment adherence to treatment in substance users referred from Psychiatric Emergency service to outpatient treatment. AB - OBJECTIVES: The main objective was to evaluate the treatment adherence of patients attended at the Psychiatric Emergency Room and referred to an Outpatient Drug Clinic. Our aim was to describe the degree of adherence and the factors related to it. METHODS: A naturalistic study was conducted through examination of the clinical records of the patients attended in the Psychiatric Emergency Room of our hospital during one year (n=5052). Inclusion criteria consisted of substance dependence meeting DSM-IV criteria, belonging to our district, referral when discharged to an Outpatient Drug Clinic, and absence of previous treatment for Drug Addiction follow-ups (n=72). We evaluated further to the center link, adherence to the deviceduring the next year. RESULTS: 33.4% of the patients referred to an Outpatient Drug Clinic didn't request for a visit. From those who requested a first appointment, 20.83% didn't attend. From those who attended the first appointment, 47.37% abandoned treatment in the first 12 months. No differences between substance of use or time of the year of referral were observed. DISCUSSION: Independently to the accessibility to the Outpatient Clinic, difficulties in the adherence to drug addiction treatment exist. Inicial adherence to drug addiction treatment is medium. Patient's attendance to the clinics are important due to it's relation with retention doubling. Efforts should be made to improve the compliance with pharmacologic and nonpharmacologic treatment. PMID- 22508072 TI - The genetics of depression: what information can new methodologic approaches provide? AB - Major depressive disorder is a genetically complex disease involving several minor, or susceptibility, genes whose expression may be modulated by many environmental factors. From the classical early linkage studies to the complete genome-wide association (GWA) study methodologies, it is evident that it is difficult to understand the genetic bases of this mental disorder. Many studies have identified one or more gene regions whose variability confers a small risk for developing depressive disorder, explaining a small percentage of the total genetic component of disease with low predictive value. Although the results to date are inconclusive, new approaches based on gene-environment interactions and biological pathway analysis (based on GWA studies) open new and promising perspectives in the investigation of the genetic and biological basis of major depression. PMID- 22508073 TI - Psychosocial interventions in bipolar disorder: a review. AB - INTRODUCTION: Multiple psychosocial interventions for bipolar disorder have been proposed in recent years. Therefore, we consider that a critical review of empirically validated models would be useful. METHODS: A review of the literature was conducted in Medline/PubMed for articles published during 2000-2010 that respond to the combination of "bipolar disorder" with the following key words: "psychosocial intervention", "psychoeducational intervention" and "psychotherapy". RESULTS: Cognitive-behavioral, psychoeducational, systematic care models, interpersonal and family therapy interventions were found to be empirically validated. All of them reported significant improvements in therapeutic adherence and in the patients' functionality. CONCLUSIONS: Although there are currently several validated psychosocial interventions for treating bipolar disorder, their efficacy needs to be specified in relation to more precise variables such as clinical type, comorbid disorders, stages or duration of the disease. Taking into account these clinical features would enable a proper selection of the most adequate intervention according to the patient's specific characteristics. PMID- 22508074 TI - Differential diagnosis by EEG of dissociative status versus nonconvulsive status epilepticus. AB - INTRODUCTION: Nonconvulsive status epilepticus (NCSE) has different clinical presentations, from minimal confusion to bizarre behavioral manifestations, psychosis or coma. As a result, patients can sometimes be misdiagnosed and labeled as psychiatric cases. CLINICAL CASE: The patient was alert and disoriented in time, with disconnection episodes, generalized slowness, slow mental response, faltering language and slow answers. A differential diagnosis between dissociative status and NCSE was proposed. The physical and neurological examinations were normal. The cranial CT scan findings were normal. Only the EEG provided the definitive diagnostic data, consisting of generalized spike and wave discharges of 2-3 Hz against a desynchronized background. CONCLUSIONS: Diagnosis of NCSE requires the availability of an EEG. Often patients are on the border between medical conditions and mental disorders. Observation of the disease evolution and an open-minded attitude of physicians are necessary for the correct diagnosis and treatment. PMID- 22508075 TI - Rhabdomyolysis secondary to quetiapine. AB - Quetiapine is one of the drugs used most in current Psychiatry due to its therapeutic efficiency and clinical safety. We report the case of a 26-year-old male patient with severe mental retardation due to Y-chromosome partial deletion who initiated treatment with quetiapine for the control of his aggressiveness, and who developed severe rhabdomyolysis two weeks later. In spite of the confirmed clinical safety of quetiapine, doctors must monitor the appearance of rare but serious adverse effects as that presented in this clinical case. PMID- 22508076 TI - Epileptic status as a complication of electroconvulsive therapy: a case report. AB - INTRODUCTION: Electroconvulsive therapy (ECT) is a safe and effective treatment for multiple indications in psychiatric disorders. However, rare complications, such as cardiovascular compromise, post-stroke agitation and epileptic status, can occur. CASE REPORT: The case of an 83-year old female who had clinical symptoms consistent with psychotic depression, intense anguish, pronounced psychomotor retardation and who refused intake with secondary dehydration is presented. Treatment was started with ECT with great improvement of the symptoms, but in the third session of ECT, with the same intensity as the previous ones, electrical epileptic status with no clinical manifestations appeared. It lasted approximately 700 seconds. ECT was suspended and the patient was monitored electroencephalographically. Recovery since then has been progressive but much slower. CONCLUSION: It is essential to recognize and treat prolonged seizures during ECT to prevent progression to epileptic status. We recommend conducting a retrospective study aimed at identifying risk factors for the occurrence of nonconvulsive status epilepticus in potential patients and to protocolize preventive measures in order to avoid this complication. PMID- 22508077 TI - Prodromal obsessive-compulsive symptoms in a case of schizophrenia. PMID- 22508078 TI - Retraction. "Schizophrenia treatment. Critical review on the drugs and mechanisms of action of antipsychotics". PMID- 22508079 TI - Cartilage-specific beta-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development. AB - The WNT/beta-catenin signaling pathway is a critical regulator of chondrocyte and osteoblast differentiation during multiple phases of cartilage and bone development. Although the importance of beta-catenin signaling during the process of endochondral bone development has been previously appreciated using a variety of genetic models that manipulate beta-catenin in skeletal progenitors and osteoblasts, genetic evidence demonstrating a specific role for beta-catenin in committed growth-plate chondrocytes has been less robust. To identify the specific role of cartilage-derived beta-catenin in regulating cartilage and bone development, we studied chondrocyte-specific gain- and loss-of-function genetic mouse models using the tamoxifen-inducible Col2Cre(ERT2) transgene in combination with beta-catenin(fx(exon3)/wt) or beta-catenin(fx/fx) floxed alleles, respectively. From these genetic models and biochemical data, three significant and novel findings were uncovered. First, cartilage-specific beta-catenin signaling promotes chondrocyte maturation, possibly involving a bone morphogenic protein 2 (BMP2)-mediated mechanism. Second, cartilage-specific beta-catenin facilitates primary and secondary ossification center formation via the induction of chondrocyte hypertrophy, possibly through enhanced matrix metalloproteinase (MMP) expression at sites of cartilage degradation, and potentially by enhancing Indian hedgehog (IHH) signaling activity to recruit vascular tissues. Finally, cartilage-specific beta-catenin signaling promotes perichondrial bone formation possibly via a mechanism in which BMP2 and IHH paracrine signals synergize to accelerate perichondrial osteoblastic differentiation. The work presented here supports the concept that the cartilage-derived beta-catenin signal is a central mediator for major events during endochondral bone formation, including chondrocyte maturation, primary and secondary ossification center development, vascularization, and perichondrial bone formation. PMID- 22508080 TI - An evaluation of the role and treatment of elevated male hormones in autism spectrum disorders. AB - Autism, Asperger's syndrome (AS), and pervasive developmental disorder - not otherwise specified (PDD-NOS) compose the overall diagnostic category of autism spectrum disorder (ASD). Subjects diagnosed with an ASD have a male:female ratio of 4:1, and among subjects diagnosed with AS the male:female ratio is as high as 9:1. The purpose of this study was to examine evidence of the association between hyperandrogenism and autistic traits (ATs) among subjects diagnosed with an ASD, and to evaluate the effectiveness of anti-androgen therapy as a means to help treat ATs in subjects diagnosed with an ASD. Evidence of hyperandrogenism in subjects diagnosed with an ASD is supported by multiple studies in the areas of psychological framework, brain pathology, tissue culture, and pre- and postnatal androgen levels. Data from subjects diagnosed with other conditions associated with elevated androgens reveals many of these individuals have ATs. Finally, in a placebo-controlled trial of testosterone administration to neurotypical subjects, testosterone was found to increase ATs. In addition, a controlled trial of human transsexuals revealed a significant increase in ATs in female-to-male transsexuals and a decrease in ATs in male-to-female transsexuals. Data from multiple animals and human clinical trials suggest that antiandrogen medications have the ability to significantly reduce ATs in patients diagnosed with an ASD. In light of the robust association between hyperandrogenism and ASD, it is recommended subjects diagnosed with an ASD should undergo routine screening for elevated androgens, and appropriate treatment should be initiated for those with elevated androgens. PMID- 22508081 TI - Cloning and functional analysis of P2X1b, a new variant in rat optic nerve that regulates the P2X1 receptor in a use-dependent manner. AB - P2X receptors are trimeric, ATP-gated cation channels. In mammals seven P2X subtypes have been reported (P2X1-P2X7), as well as several variants generated by alternative splicing. Variants confer to the homomeric or heteromeric channels distinct functional and/or pharmacological properties. Molecular biology, biochemical, and functional analysis by electrophysiological methods were used to identify and study a new variant of the P2X1 receptor named P2X1b. This new variant, identified in rat optic nerve, was also expressed in other tissues. P2X1b receptors lack amino acids 182 to 208 of native P2X1, a region that includes residues that are highly conserved among distinct P2X receptors. When expressed in Xenopus oocytes, P2X1b was not functional as a homomer; however, when co-expressed with P2X1, it downregulated the electrical response generated by ATP compared with that of oocytes expressing P2X1 alone, and it seemed to form heteromeric channels with a modestly enhanced ATP potency. A decrease in responses to ATP in oocytes co-expressing different ratios of P2X1b to P2X1 was completely eliminated by overnight pretreatment with apyrase. Thus, it is suggested that P2X1b regulates, through a use-dependent mechanism, the availability, in the plasma membrane, of receptor channels that can be operated by ATP. PMID- 22508082 TI - Correlation of nitric oxide levels in the cerebellum and spinal cord of experimental autoimmune encephalomyelitis rats with clinical symptoms. AB - Experimental autoimmune encephalomyelitis (EAE) is a well-established cell mediated autoimmune inflammatory disease of the CNS, which has been used as a model of the human demyelinating disease. EAE is characterized by infiltration of the CNS by lymphocytes and mononuclear cells, microglial and astrocytic hypertrophy, and demyelination which cumulatively contribute to clinical expression of the disease. EAE was induced in female Sprague-Dawley rats, 3 months old (300 g +/- 20 g), by immunization with myelin basic protein (MBP) in combination with Complete Freund's adjuvant (CFA). The animals were divided into 7 groups: control, EAE, CFA, EAE + aminoguanidine (AG), AG, EAE + N-acetyl-L cysteine (NAC) and NAC. The animals were sacrificed 15 days after EAE induction, and the level of nitric oxide (NO(.)) production was determined by measuring nitrite and nitrate concentrations in 10% homogenate of cerebellum and spinal cord. Obtained results showed that the level of NO(.) was significantly increased in all examined tissues of the EAE rats compared to the control and CFA groups. Also, AG and NAC treatment decreased the level of NO(.) in all tissues compared to the EAE group. The level of NO(.) is increased significantly in the spinal cord compared to the cerebellum. The clinical course of the EAE was significantly decreased in the EAE groups treated with AG and NAC during the development of the disease compared to EAE group and its correlates with the NO(.) level in cerebellum and spinal cord. The findings of our work suggest that NO(.) and its derivatives play an important role in multiple sclerosis (MS). It may be the best target for new therapies in human demyelinating disease and recommend the new therapeutic approaches based on a decreased level of NO(.) during the course of MS. PMID- 22508083 TI - Long-lasting stress, quantitative changes in nitric oxide concentration and functional state of brain mitochondria. AB - We have studied biochemical changes occurring in brain cell mitochondria of white rats on the background of stress induced by 30-day isolation and disruption of circadian rhythms. It was ascertained that due to long-lasting stress, there occurs activation of oxidative processes in mitochondria as well as inhibition of anti-oxidant system activity, causing development of energy deficiency in brain cells. The above-mentioned biochemical processes become the reason for activation and opening of the mitochondrial permeability transition pore (MPTP), which, in its turn, signals the start of neuroapoptosis and various neurodegenerative processes. PMID- 22508084 TI - Neural generators of the auditory evoked potential components P3a and P3b. AB - The aim of the present study was to define the scalp topography of the two subcomponents of the P3 component of the auditory evoked potential elicited in a three-stimulus oddball paradigm and to identify their cortical generators using the standardized low resolution electromagnetic tomography (sLORETA). Subjects were presented with a random sequence of auditory stimuli and instructed to respond to an infrequently occurring target stimulus inserted into a sequence of frequent standard and rare non-target stimuli. Results show that the magnitude of the frontal P3a is determined by the relative physical difference among stimuli, as it was larger for the stimulus more deviant from the standard. Major neural generators of the P3a were localized within frontal cortex and anterior cingulate gyrus. In contrast to this, the P3b, showing maximal amplitude at parietal locations, was larger for stimuli demanding a response than for the rare non target. Major sources of the P3b included the superior parietal lobule and the posterior part of the cingulate gyrus. Our findings are in line with the hypothesis that P3a is related to alerting activity during the initial allocation of attention, while P3b is related to activation of a posterior network when the neuronal model of perceived stimulation is compared with the attentional trace. PMID- 22508085 TI - Psychomotor and rewarding properties of the neurosteroids dehydroepiandrosterone sulphate and androsterone: effects on monoamine and steroid metabolism. AB - The neurosteroids, dehydroepiandrosterone sulfate (DHEAS) and androsterone, are implicated in drug addictions. We examined their influence on locomotor activity and reward in male Wistar rats, and on steroid and monoamine metabolism in the hippocampus and striatum. In the open field test, DHEAS injections (10, 40, 80 mg/kg, i.p.) 30 min prior the test had no significant effect on ambulation, but androsterone (10 mg/kg) increased general locomotion and at doses 1-10 mg/kg, increased central field activity, suggestive of an anxiolytic action. In the conditioned place preference test, both steroids had a biphasic effect: DHEAS was rewarding at doses of 10 and 40 mg/kg, but not at 80 mg/kg, while androsterone was rewarding at doses of 1 and 10 mg/kg, but aversive at 40 mg/kg. Monoamine and steroid concentrations were analyzed in homogenates from the hippocampus and striatum of DHEAS and androsterone injected rats. DHEAS reduced the hippocampal dopamine level, increased striatal homovanilic acid (HVA) and decreased the striatal serotonin concentrations. Androsterone did not affect dopamine levels or turnover, but increased noradrenaline concentration and serotonin turnover in the hippocampus. DHEAS administration augmented concentrations of DHEA, pregnenolone, androstendiol and androstentriol in both brain structures, while androsterone injections increased brain levels of androsterone, epiandrosterone, 5alpha dihydrotestosterone, and androstandiol. Present data document that although psychobehavioral and neurochemical effects of DHEAS and androsterone differ in several aspects; both neurosteroids have rewarding properties at certain dose ranges, suggesting their likely involvement in addictions, which entail different mechanisms. PMID- 22508087 TI - Determinants of filled/empty optical illusion: differential effects of patterning. AB - A subdivided path in the visual field appears longer than an empty path of the same length. This effect may be attributed to the division of the path into multiple segments, or to an influence of the visual elements used to mark the subdivision, and thus filling-up the estimated space. To address this question, we used two series of stimuli, in which the spatial distribution of the filling optical mater, or the form of the dividers, was varied while the relative coverage of the filled space was kept constant. We found significant dependence of the effect magnitude on a number of filling elements as well as on their form. These results indicate that the illusory space expansion is not merely an effect of 'filling-up' the space, but it also depends on the filling pattern. Consequences of these findings for the theory of the Oppel-Kundt phenomenon are briefly discussed. PMID- 22508086 TI - Assessing changes in pial artery resistance and subarachnoid space width using a non-invasive method in healthy humans during the handgrip test. AB - The aim of this study was to assess the influence of the handgrip test (HGT) on: (1) pial artery pulsation (cc-TQ), (2) subarachnoid space (SAS) width (sas-TQ) and (3) the relationship between peripheral blood pressure (BP), heart rate (HR), cerebral blood flow velocity (CBFV), resistive index (RI), cc-TQ and sas-TQ. The study was performed on 29 healthy volunteers (11 men and 18 women) with a mean age of 29.3 +/- SE 4.0. HGT was performed in the sitting position at 30% of maximal voluntary contraction. cc-TQ and sas-TQ were registered using near infrared transillumination/backscattering sounding (NIR-T/BSS); BP and heart rate (HR) were measured using a Finapres monitor. CBFV and RI were recorded using a transcranial Doppler. A significant reduction in cc-TQ (-34.3%, P<0.0001) and sas TQ (-12.9%, P<0.001) were observed, while mean arterial pressure and HR increased (+34.8%, P<0.0001 and +7.9%, P<0.0001, respectively). There was no significant change in CBFV (+1.0 percent) while RI increased (+12.0 percent, P<0.05). Correlation and regression analysis did not reveal any interdependencies between the investigated variables. HGT evoked a significant increase in pial artery resistance, with a simultaneous decrease in the width of the SAS. A decrease in pial artery compliance should be seen as protective mechanism against acute BP elevation, most likely mediated by sympathetic activation. NIR-T/BSS recordings allowed for non-invasive assessments of changes in pial artery compliance, and were consistent with data from the literature and physiological knowledge. PMID- 22508088 TI - Expression of BMP-2 and BMP-4 proteins by type-1 and type-2 astrocytes induced from neural stem cells under different differentiation conditions. AB - Bone morphogenetic proteins (BMPs), a subgroup of the TGF-beta superfamily, play critical roles in neural progenitor cell fate determination. Neural stem cells (NSCs) are multipotent progenitor cells that can differentiate into neurons, oligodendrocytes and astrocytes under certain conditions. In our recent report, using an antibody that can recognize both BMP-2 and BMP-4 (BMP-2/4), we showed that BMP-2/4 is only expressed in astrocytes differentiated from NSCs in a medium containing 1% fetal bovine serum (FBS). In this in vitro model, the astrocytic differentiation of NSCs was mainly toward type-2. When NSCs were cultured in a medium containing 10% FBS, most of the cells differentiated into type-1 astrocytes. However, little information is available for BMP-2 and BMP-4 expression in type-1 and type-2 astrocytes induced from NSCs under these different culture conditions. In this study, using two antibodies specific for BMP-2 and BMP-4, respectively, we discriminated the presence of BMP-2 and BMP-4 in NSCs and their derivatives under 1% and 10% FBS culture conditions by RT-PCR, western blot and immunofluorescence staining. We found that BMP-2 and BMP-4 are highly expressed in both type-1 and type-2 astrocytes, and no detectable expression in NSCs, neurons and oligodendrocytes. This suggests that the astrocytes might be one source of BMPs during the differentiation of NSCs. However, in our model, we cannot exclude the possibility that microglia or endothelial cells could also be a source of BMPs. PMID- 22508089 TI - P50 potential-associated gamma band activity: modulation by distraction. AB - We aimed to evaluate the effect of changing attentional demands towards stimulation in healthy subjects on P50 potential-related high-frequency beta and gamma oscillatory responses, P50 and N100 peak amplitudes and their gating measures. There are no data showing effect of attention on P50 potential-related beta and gamma oscillatory responses and previous results of attention effects on P50 and N100 amplitudes and gating measures are inconclusive. Nevertheless the variation in the level of attention may be a source of variance in the recordings as well as it may provide additional information about the pathology under study. Nine healthy volunteers participated in the study. A standard paired stimuli auditory P50 potential paradigm was applied. Four stimulation conditions were selected: focused attention (stimuli pair counting), unfocused attention (sitting with open eyes), easy distraction (reading a magazine article), and difficult distraction (searching for Landolt rings with appropriate gap orientation). Time frequency responses to both S1 and S2 were evaluated in slow beta (13-16 Hz, 45 175 ms window); fast beta (20-30 Hz, 45-105 ms window) and gamma (32-46 Hz, 45-65 ms window) ranges. P50 and N100 peak amplitudes in response to both S1 and S2 and their ratio were evaluated. The phase-locked P50 potential-associated gamma activity was attenuated during distraction tasks as compared to focused attention and an unfocused attention condition. The amplitudes and gating measures of P50 and N100 waves and beta activity were not sensitive to the competing distraction task performance. The use of a distraction task is not favorable when phase locked gamma range activity is a key interest in auditory potential studies. PMID- 22508090 TI - "Quality matters". PMID- 22508092 TI - Expert opinion: MDCT aortic root measurements for transcatheter aortic valve implantation. PMID- 22508094 TI - Wholemount immunohistochemistry for revealing complex brain topography. AB - The repeated and well-understood cellular architecture of the cerebellum make it an ideal model system for exploring brain topography. Underlying its relatively uniform cytoarchitecture is a complex array of parasagittal domains of gene and protein expression. The molecular compartmentalization of the cerebellum is mirrored by the anatomical and functional organization of afferent fibers. To fully appreciate the complexity of cerebellar organization we previously refined a wholemount staining approach for high throughput analysis of patterning defects in the mouse cerebellum. This protocol describes in detail the reagents, tools, and practical steps that are useful to successfully reveal protein expression patterns in the adult mouse cerebellum by using wholemount immunostaining. The steps highlighted here demonstrate the utility of this method using the expression of zebrinII/aldolaseC as an example of how the fine topography of the brain can be revealed in its native three-dimensional conformation. Also described are adaptations to the protocol that allow for the visualization of protein expression in afferent projections and large cerebella for comparative studies of molecular topography. To illustrate these applications, data from afferent staining of the rat cerebellum are included. PMID- 22508095 TI - Autoimmunity: Pinpointing progression to T1DM in children at genetic risk. PMID- 22508096 TI - Thyroid function: Lithium improves Graves therapy. PMID- 22508097 TI - Noninvasive monitoring of immunosuppressive drug efficacy to prevent rejection of intracerebral glial precursor allografts. AB - The development of cell-based therapies opens up new avenues for treating a myriad of diseases of the central nervous system (CNS). While significant effort is being directed toward development of patient-specific, autologous transplantable cells, at present, the majority of cell transplantation studies performed clinically utilize allografts. In this context, the issue of graft rejection and immunoprotection is of key importance. In this study, we transplanted mouse glial-restricted progenitors into immunodeficient, immunocompetent, and immunosuppressed mice and monitored their survival noninvasively using bioluminescence imaging (BLI). With the use of serial BLI, we evaluated both the prevalence and dynamics of cell rejection. We demonstrate that allografts in immunocompetent mice were rejected at a rate of 69.2% (n = 13) indicating that graft tolerance is possible even without immunosuppression. Immunosuppression using a combination of rapamycin and FK506 or cyclosporin failed to fully protect the grafts. FK506 and rapamycin treatment resulted in a slight improvement of immunoprotection (22.2% rejected, n = 9) compared to cyclosporin A (55.6% rejected, n = 9); however, the difference was not significant. Notably, immunohistochemistry revealed leukocytes infiltrating the graft area in both rejecting and nonrejecting immunocompetent animals, but not in immunodeficient animals. The induction of an inflammatory process, even in surviving allografts, has implications for their long-term survival and functionality. PMID- 22508098 TI - Biology and microscopy: the friendship strengthens.... PMID- 22508100 TI - The potential of 3D-FISH and super-resolution structured illumination microscopy for studies of 3D nuclear architecture: 3D structured illumination microscopy of defined chromosomal structures visualized by 3D (immuno)-FISH opens new perspectives for studies of nuclear architecture. AB - Three-dimensional structured illumination microscopy (3D-SIM) has opened up new possibilities to study nuclear architecture at the ultrastructural level down to the ~100 nm range. We present first results and assess the potential using 3D-SIM in combination with 3D fluorescence in situ hybridization (3D-FISH) for the topographical analysis of defined nuclear targets. Our study also deals with the concern that artifacts produced by FISH may counteract the gain in resolution. We address the topography of DAPI-stained DNA in nuclei before and after 3D-FISH, nuclear pores and the lamina, chromosome territories, chromatin domains, and individual gene loci. We also look at the replication patterns of chromocenters and the topographical relationship of Xist-RNA within the inactive X-territory. These examples demonstrate that an appropriately adapted 3D-FISH/3D-SIM approach preserves key characteristics of the nuclear ultrastructure and that the gain in information obtained by 3D-SIM yields new insights into the functional nuclear organization. PMID- 22508105 TI - Self-pressurized rapid freezing (SPRF) as a simple fixation method for cryo electron microscopy of vitreous sections. AB - Cryo-electron microscopy of vitreous sections (CEMOVIS) is currently considered the method of choice to explore cellular ultrastructure at high resolution as close as possible to their native state. Here, we apply a novel, easy-to-use and low-cost freeze fixation method for CEMOVIS, avoiding the use of high-pressure freezing apparatus. Cells are placed in capillary metal tubes, which are tightly closed and plunged directly into liquid ethane cooled by liquid nitrogen. In some parts of the tube, crystalline ice is formed, building up pressure sufficient for the liquid-glass transition of the remaining specimen. We verified the presence of vitreous ice in these preparations using CEMOVIS and electron diffraction. Furthermore, different tube materials being less poisonous than copper were established to minimize physiological alterations of the specimen. Bacteria, yeast and mammalian cells were tested for molecular resolution. The quality of results is equivalent to samples prepared by conventional high pressure freezing apparatus, thus establishing this novel method as fast, easy-to-use and low-cost freeze fixation alternative for cryo-EM. PMID- 22508104 TI - Structure and size determination of bacteriophage P2 and P4 procapsids: function of size responsiveness mutations. AB - Bacteriophage P4 is dependent on structural proteins supplied by a helper phage, P2, to assemble infectious virions. Bacteriophage P2 normally forms an icosahedral capsid with T=7 symmetry from the gpN capsid protein, the gpO scaffolding protein and the gpQ portal protein. In the presence of P4, however, the same structural proteins are assembled into a smaller capsid with T=4 symmetry. This size determination is effected by the P4-encoded protein Sid, which forms an external scaffold around the small P4 procapsids. Size responsiveness (sir) mutants in gpN fail to assemble small capsids even in the presence of Sid. We have produced large and small procapsids by co-expression of gpN with gpO and Sid, respectively, and applied cryo-electron microscopy and three-dimensional reconstruction methods to visualize these procapsids. gpN has an HK97-like fold and interacts with Sid in an exposed loop where the sir mutations are clustered. The T=7 lattice of P2 has dextro handedness, unlike the laevo lattices of other phages with this fold observed so far. PMID- 22508106 TI - Is lung surfactant ready 'to protect and to serve' in necrotizing enterocolitis? Commentary on F.E. Canpolat et al.: Effects of enterally administered surfactant in a rat model of necrotizing enterocolitis (Neonatology 2012;102:53-58). PMID- 22508107 TI - Etiologies and clinical presentation of gigantism in Algeria. AB - BACKGROUND/AIMS: True gigantism is an exceptional and fascinating pediatric disease. Our aim in this study was to describe the different etiologies of a large group of children with gigantism and the natural history of their growth. METHODS: In this multicenter study, we considered as giant children, adolescents and adults whose heights were >=3 SD compared to their target stature or to our population average lengths. Isolated hypogonadism and Klinefelter syndrome were excluded from this series. All underwent clinical exam, and hormonal and neurological investigations. RESULTS: From 1980 to 2010, we observed 30 giants: 26 males (86.6%) and 4 females (mean age 19.8 +/- 11 years). Among the 13 patients (40.3%) who consulted before the age of 16 years, 9 had acromegaly and 6 had mental retardation and body malformations. Based on growth hormone (GH) secretion evaluation, 2 groups were observed: pituitary gigantism (n = 16): GH = 150 +/- 252 ng/ml (n <= 5), and other causes with normal GH (0.7 +/- 0.6 ng/ml): 6 Sotos syndrome and 8 idiopathic cases. Only the first group had neurological, ophthalmological, metabolic and cardiovascular complications and received treatment. The result was not optimal as GH normalization was not observed. Reduction of tumor size and decreased GH plasma values were not observed. CONCLUSION: Gigantism predominates in males. The main cause is GH excess. The diagnosis was very late except for cerebral gigantism. Complications were observed in pituitary gigantism only. PMID- 22508108 TI - Out of fuzzy chemistry: from prebiotic chemistry to metabolic networks. AB - The origin of life on Earth was a chemical affair. So how did primitive biochemical systems originate from geochemical and cosmochemical processes on the young planet? Contemporary research into the origins of life subscribes to the Darwinian principle of material causes operating in an evolutionary context, as advocated by A. I. Oparin and J. B. S. Haldane in the 1920s. In its simplest form (e.g., a bacterial cell) extant biological complexity relies on the functional integration of metabolic networks and replicative genomes inside a lipid boundary. Different research programmes have explored the prebiotic plausibility of each of these autocatalytic subsystems and combinations thereof: self maintained networks of small molecules, template chemistry, and self-reproductive vesicles. This tutorial review focuses on the debates surrounding the origin of metabolism and offers a brief overview of current studies on the evolution of metabolic networks. I suggest that a leitmotif in the origin and evolution of metabolism is the role played by catalysers' substrate ambiguity and multifunctionality. PMID- 22508109 TI - Diagnostic sensitivity of culture and drug resistance patterns in Korean patients with intestinal tuberculosis. AB - SETTING: It is challenging to differentiate between intestinal tuberculosis (ITB) and Crohn's disease in areas where TB is still prevalent. The use of diagnostic tools and verifying the drug resistance patterns of ITB can be helpful for its correct diagnosis. OBJECTIVE: To determine the diagnostic sensitivity of a culture assay using colonoscopic biopsy specimens and the drug resistance patterns of Mycobacterium tuberculosis isolated from ITB. DESIGN: Data from 400 patients diagnosed with ITB were retrospectively analysed. RESULTS: Of the 400 patients, 170 (42.5%) were males; the median age at diagnosis was 40 years. The sensitivity of culture was 44.1% (145/329). Resistance to at least one anti tuberculosis drug was identified in 13 (17.6%) and multidrug-resistant TB (MDR TB) was diagnosed in two (2.7%) of the 74 patients for whom drug susceptibility testing was performed. Including M. tuberculosis isolated from respiratory specimens, the proportion of MDR-TB was 4.4% (5/113); previous anti-tuberculosis treatment was an independent risk factor for MDR-TB (26.7% vs. 1.0%, P < 0.01). CONCLUSION: Culture of colonoscopic biopsy specimens shows substantial diagnostic sensitivity; the frequency of MDR-TB is higher in previously treated cases than in new cases. PMID- 22508110 TI - Mutagenicity and DNA adduct formation by aristolochic acid in the spleen of Big Blue(r) rats. AB - Aristolochic acid (AA) is a potent human nephrotoxin and carcinogen. We previously reported that AA treatment resulted in DNA damage and mutation in the kidney and liver of rats. In this study, we have determined the DNA adducts and mutations induced by AA in rat spleen. Big Blue(r) transgenic rats were gavaged with 0, 0.1, 1.0, and 10.0 mg AA/kg body weight five-times/week for 3 months. Three DNA adducts, [7-(deoxyadenosin-N(6)-yl)-aristolactam I, 7-(deoxyadenosin N(6)-yl)-aristolactam II and 7-(deoxyguanosin-N(2)-yl)-aristolactam I], were identified by (32)P-postlabeling. Over the dose range studied, there were strong linear dose-responses for AA-DNA adduct formation in the treated rat spleens, ranging from 4.6 to 217.6 adducts/10(8) nucleotides. Spleen cII mutant frequencies also increased in a dose-dependent manner, ranging from 32.7 to 286.2 * 10(-6) in the treated animals. Mutants isolated from the different treatment groups were sequenced; analysis of the resulting spectra indicated that there was a significant difference between the pattern of mutation in the 10 mg/kg AA treated and the vehicle control rats. A:T -> T:A transversion was the major type of mutation in AA-treated rats, whereas G:C -> A:T transition was the main type of mutation in the vehicle controls. These results indicate that AA is genotoxic in the spleen of rats exposed under conditions that result in DNA adduct formation and mutation induction in kidney and liver. PMID- 22508111 TI - Transapical transcatheter aortic valve implantation using the JenaValveTM system: acute and 30-day results of the multicentre CE-mark study. AB - OBJECTIVES: Transcatheter aortic valve implantation (TAVI) has shown promising results in patients with severe aortic stenosis (AS) at high risk for conventional heart surgery. The safety and efficacy of transapical aortic valve implantation using the JenaValveTM, a second-generation TAVI device, were evaluated. The system consists of a tested porcine root valve mounted on a nitinol stent with feeler-guided positioning and clip fixation on the diseased leaflets. METHODS: This multicentre, prospective, single-arm study, conducted at seven German sites, enrolled 73 patients (mean age 83.1 +/- 3.9), European System for Cardiac Operative Risk Evaluation (EuroSCORE) (28.4 +/- 6.5%) of whom 67 patients underwent elective TAVI. Three sizes were used for annular diameters up to 23 mm (n = 21), 25 mm (n = 31) and 27 mm (n = 15). Clinical and echocardiographic evaluations were performed at baseline, post-procedure, discharge and 30 days, and also at 3, 6 and 12 months. The primary endpoint was all-cause mortality at 30 days. Secondary endpoints were procedural success, major adverse cardiac and cerebrovascular events and echocardiographic performance. RESULTS: TAVI with the JenaValveTM device was successful in 60 patients (procedural success rate 89.6%). The overall mortality at 30 days was 7.6%. Conversion to surgery was necessary in four patients (6%), two patients underwent valve-in-valve implantations (3%), one patient was withdrawn per protocol after conversion to TAVI using a balloon-expandable valve (1.5%) since the patient did not receive the study device. Perioperative stroke occurred in two cases (3%). Pacemaker implantation for new onset conduction disorders was necessary in six patients (9.1%). No ostial coronary obstructions were seen. Post procedure TAVI resulted in favourable reduction of mean transvalvular gradients (40.6 +/- 15.9 vs. 10.0 +/- 7.2 mmHg, P < 0.0001) and increase in valve opening area (0.7 +/- 0.2 vs. 1.7 +/- 0.6 cm2, P < 0.0001). The majority of successfully treated patients revealed no or minimal paravalvular aortic regurgitation (86.4%); none of the patients had severe post-procedural regurgitation (>2+). CONCLUSIONS: Transapical JenaValveTM implantation was safe and effective in the treatment of severe AS in elderly patients at high risk for surgery. Active clip fixation on the native leaflets and anatomically correct feeler-guided positioning led to good functionality and prevented ostial coronary impairment. Implantation without the need for rapid pacing prevented haemodynamic compromise during valve implantation. PMID- 22508112 TI - Gamma knife radiosurgery in the treatment of tumor-related facial pain. AB - BACKGROUND: Intracranial neoplasms can cause pain similar to trigeminal neuralgia. Literature regarding radiosurgery for this is limited. We present a retrospective review of patients with tumor-related facial pain from benign lesions treated with gamma knife radiosurgery (GKRS) at Wake Forest University. OBJECTIVES: The primary objectives were to determine long-term pain relief and predictive factors for pain alleviation. METHODS: We reviewed 515 patients treated with GKRS for benign meningioma, vestibular schwannoma or trigeminal schwannoma between August 1999 and August 2010. Twenty-one eligible patients had tumor-related facial pain prior to GKRS. The median marginal tumor dose was 12 Gy. Long-term pain relief data were obtained by chart review and telephone interview. RESULTS: The median follow-up for symptom evaluation was 3.8 years. Seventeen of 21 patients (81%) experienced a Barrow Neurological Institute (BNI) score of I-III at 6 months following GKRS. Kaplan-Meier estimates of freedom from BNI IV-V relapse were 66% at 1 year and 53% at 2 years. No pain relapses occurred after 2 years. CONCLUSION: GKRS of benign lesions is a noninvasive option for patients with tumor-related facial pain. Pain relief is modest, with the majority of pain relapses occurring within 2 years and approximately one half of patients maintaining relief beyond 2 years. PMID- 22508113 TI - Evaluation of the adsorption capacity of alkali-treated waste materials for the adsorption of sulphamethoxazole. AB - The present work is to develop potential adsorbents from waste material and employ them for the removal of a hazardous antibacterial, sulphamethoxazole, from the wastewater by the Adsorption technique. The Adsorption technique was used to impound the dangerous antibiotics from wastewater using Deoiled Soya (DOS), an agricultural waste, and Water Hyacinth (WH), a prolific colonizer. The adsorption capacity of these adsorbents was further enhanced by treating them with sodium hydroxide solution and it was seen that the adsorption capacity increases by 10 to 25%. Hence a comparative account of the adsorption studies of all the four adsorbents, i.e. DOS, Alkali-treated DOS, WH and Alkali-treated Water Hyacinth has been discussed in this paper. Different isotherms like Freundlich, Langmuir and Dubinin-Radushkevich were also deduced from the adsorption data. Isotherm studies were in turn used in estimating the thermodynamic parameters. DOS showed sorption capacity of 0.0007 mol g(-1) while Alkali-treated Deoiled Soya exhibited 0.0011 mol g(-1) of sorption capacity, which reveals that the adsorption is higher in case of alkali-treated adsorbent. The mean sorption energy (E) was obtained between 9 and 12 kJ mol, which shows that the reaction proceeds by ion exchange reaction. Kinetic study reveals that the reaction follows pseudo-second order rate equation. Moreover, mass transfer studies performed for the ongoing processes show that the mass transfer coefficient obtained for alkali-treated moieties was higher than the parent moieties. The breakthrough curves plotted from the column studies show percentage saturation of 90-98%. About 87-97% of sulphamethoxazole was recovered from column by desorption. PMID- 22508114 TI - Use of submerged anaerobic membrane bioreactor (SAMBR) containing powdered activated carbon (PAC) for the treatment of textile effluents. AB - This work investigated the use of submerged anaerobic membrane bioreactors (SAMBRs) in the presence and absence of powdered activated carbon (PAC) for the treatment of genuine textile wastewater. The reactors were operated at 35 degrees C with an HRT of 24 h and the textile effluent was diluted (1:10) with nutrient solution containing yeast extract as the source of the redox mediation riboflavin. The results showed that although both SAMBRs exhibited an excellent performance, the presence of PAC inside SAMBR-1 enhanced reactor stability and removal efficiency of chemical oxygen demand (COD), volatile fatty acids (VFA), turbidity and color. The median removal efficiencies of COD and color in SAMBR-1 were, 90 and 94% respectively; whereas for SAMBR-2 (without PAC) these values were 79 and 86%, In addition, the median values of turbidity and VFA were 8 NTU and 8 mg/L for SAMBR-1 and 14 NTU and 26 mg/L for SAMBR-2, indicating that the presence of PAC inside SAMBR-1 led to the production of an anaerobic effluent of high quality regarding such parameters. PMID- 22508115 TI - Photocatalytic oxidation of humic acid and its effect on haloacetic acid formation potential: a fluorescence spectrometry study. AB - By fluorescence spectrometry method, molecular conformation changes of humic acid (HA) during the photocatalytic oxidation process were studied. Haloacetic acids formation potential (HAAFP) changes during the oxidation process were also measured. The results indicated that aromatic rings of HA decreased and conjugated double bonds were destroyed at the beginning of the process. Meanwhile, organic matter with large molecular weight decomposed into intermediates with smaller molecular weight, such as tryptophan and tyrosine. HA can be degraded almost completely, but not be mineralized thoroughly. Structures of the intermediates were changing during the oxidation process. Molecular structure transformation of HA led to the fluctuation tendency of the HAAFP changes during the photocatalytic oxidation process. HAAFP increased to 1.22 times that in raw water after 30 min of ultraviolet (UV) radiation, and decreased to 0.66 times that in raw water after 60 min of photocatalytic oxidation. PMID- 22508116 TI - Application of cuprous oxide synthesized from copper-containing waste liquid to treat aqueous reactive dye. AB - Cuprous oxide that was prepared from Cu-containing waste liquid from a printed circuit board manufacturer was used to carry out Fenton-like and photo-Fenton like oxidation reactions to decolorize a reactive dye (RB19). A microwave hydrothermal method was applied in the synthesis. The highest recovery rate of Cu from wastewater was 87% and was obtained when the synthesis was performed at a power of 200 W for 15 min. An RB19 decolorization efficiency of 99.9% was achieved when the Fenton-like reaction was conducted with 50 mmol/L H(2)O(2) and 0.9 g/L of Cu(2)O. The decolorization of RB19 was more effective when the system was irradiated with visible light than with UV light. Under irradiation, the decolorization rate was the highest when the decolorization was performed in the RB19 solution that contained 50 mmol/L H(2)O(2) and 0.9 g/L CuO(2) in the Fenton like and the 365 nm-irradiated photo-Fenton-like reactions. In the case of irradiation under 410 nm visible light, the system was operated with lower H(2)O(2) (30 mmol/L) and Cu(2)O (0.5 g/L) to achieve a decolorization rate higher than 365 nm-irradiated photo-Fenton-like reactions. PMID- 22508117 TI - HBMO algorithm for calibrating water distribution network of Langarud city. AB - In this paper a new meta-heuristic approach based on the nature of honey bees mating has been used for the calibration of a real city in the north of Iran named Langarud. This city has a population of nearly 68,000 people and about 43,000 water consumers. Langarud's area is about 900 km(2). The method was used to determine the Hazen-Williams roughness factor of the main pipes of the town and a correction factor for the nodal demands in the main nodes of the network. PMID- 22508118 TI - Heavy metal adsorption changes of EAF steel slag after phosphorus adsorption. AB - A kind of electric arc furnace (EAF) steel slag was phosphated, and its isothermal and dynamic adsorptions of copper, cadmium, and lead ions were measured to determine if heavy metal adsorption changes after phosphorus adsorption. The surface area increased greatly after the slag was phosphated. Isothermal adsorption experiments showed that the theoretical Q(max) of the EAF steel slag on Cu(2+), Cd(2+), and Pb(2+) improved 59, 50, and 89% respectively after it was phosphated. Dynamic adsorption results showed that the greatest adsorption capacities of unit volume of Cu(2+), Cd(2+), and Pb(2+) were 2.2, 1.8, and 1.8 times that of the column packed with original EAF steel slag when the column was packed with phosphate EAF steel slag at the same heavy metal ion concentration. The breakthrough time, the exhaustion time and elution efficiency of the column also increased when the column was packed with phosphated EAF steel slag compared with that packed with original EAF steel slag. Phosphorus adsorption could further improve the heavy metal ion adsorption of the EAF steel slag. PMID- 22508119 TI - An evaluation of waste gypsum-based precipitated calcium carbonate for acid mine drainage neutralization. AB - Precipitated CaCO(3) compounds recovered from pulped waste gypsum using some carbonate and hydroxide-based reagents were evaluated for their utilization in acid mine drainage (AMD) neutralization. The neutralization potentials, acid neutralization capacities and compositions of the CaCO(3) compounds were determined and compared with some commercial CaCO(3). It was observed that CaCO(3) recovered from waste gypsum using Na(2)CO(3) significantly neutralized AMD compared with commercial CaCO(3) and that recovered using both (NH(4))(2)CO(3) or NH(4)OH-CO(2) reagents. Moreover, a higher acid neutralization capacity of 1,370 kg H(2)SO(4)/t was determined for CaCO(3) recovered from waste gypsum using Na(2)CO(3) compared with an average of 721 and 1,081 kg H(2)SO(4)/t for ammonium-based CaCO(3) and commercial CaCO(3) respectively. The inorganic carbon content for the CaCO(3) recovered using Na(2)CO(3) and ammonium-based reagents of 49 and 34% respectively confirmed their observed neutralization potentials and acid neutralization capacities, while energy dispersive X-ray fluorescence suggested absence of major oxide impurities, with the exception of residual SO(4)(2-) and Na(2)O which still requires further reduction in the respective compounds. PMID- 22508120 TI - Distillery wastes as external carbon sources for denitrification in municipal wastewater treatment plants. AB - In this study, by-products from alcohol production were examined in terms of their potential application as external carbon sources for enhancing denitrification in biological nutrient removal systems. Three types of batch tests were used to compare the effects of the distillery by-products, such as fusel oil, syrup and reject water, on the non-acclimated activated sludge. Much higher nitrate utilization rates (NURs) were observed for the latter two carbon sources. In the conventional NUR measurements (one-phase experiments), the observed NURs with syrup and reject water were 3.2-3.3 g N/(kg VSS h) compared with 1.0 g N/(kg VSS h) obtained for fusel oils from two different distilleries. When the carbon sources were added at the beginning of the anoxic phase preceded by an anaerobic phase (two-phase experiments), the NURs were 4.2 g N/(kg VSS h) (syrup and reject water) and 2.4-2.7 g N/(kg VSS h) (fusel oils). The heterotrophic yield coefficient, determined based on the conventional OUR measurements, varied in a relatively narrow range (0.72-0.79 g COD/g COD) for all the examined carbon sources. Due to advantageous composition (much higher COD concentrations and COD/N ratios), fusel is a preferred carbon source for practical handling in full-scale wastewater treatment plants. PMID- 22508121 TI - Removal of alkylphenols and polybromodiphenylethers by a biofiltration treatment plant during dry and wet-weather periods. AB - This paper investigates the occurrence of alkylphenols (APs) and polybromodiphenylethers (PBDEs) in raw wastewater during dry and wet-weather periods, and their removal by physico-chemical lamellar settling and biofiltration techniques. Due to in-sewer deposit erosion and, to a lesser extent, to external inputs, raw effluents exhibit from 1.5 to 5 times higher AP and PBDE concentrations during wet periods compared with dry ones. The lamellar settler obtains high removal of APs and PBDEs under both dry and wet-weather flows (>53% for Sigma(6)AP and >89% for Sigma(4)PBDE), confirming the insensitivity of this technique to varying influent conditions. Indeed, despite the higher pollutant concentrations observed in raw effluents under wet-weather flows, adjusting the addition of coagulant-flocculent allows for efficient removal. By combining physical and biological processes, the biofiltration unit treats nutrient pollution, as well as Sigma(6)AP and Sigma(4)PBDE contamination (58 +/- 5% and 75 +/- 6% respectively). Although the operating conditions of the biofiltration unit are modified during wet periods, the performance in nutrient pollution, APs and light PBDE congeners remains high. Nevertheless, lower efficiency has been noted in nitrogen pollution, i.e. no denitrification occurs, and BDE-209 (not removed during wet-weather periods). In conclusion, this study demonstrates that the combination of both techniques treats AP and PBDE pollution efficiently during dry periods, but that they are also suitable for stormwater treatment. PMID- 22508122 TI - Integrated coagulation-trickling filter-ultrafiltration processes for domestic wastewater treatment and reclamation. AB - More and more research effort has been put into the development of affordable and high-efficiency wastewater reclamation technology for small communities. In this study, an integrated chemically enhanced primary treatment (CEPT), trickling filter (TF) and ultrafiltration (UF) process was developed with success. Coagulant produced from fly ash was used to enhance primary treatment, while trickling filter packed with coal cinder through four-layer structure without aeration was employed for further removal of COD and ammonium-nitrogen from the CEPT effluent. 95 and 88% removal of COD and ammonium were achieved, while total phosphorus (TP) and suspended solid (SS) were found to be removed completely at a coagulant dosage of 2.5 mL/L in the CEPT-TF-UF system. The product water can meet the standard of Reuse of Recycling Water for Urban Water Quality Standard for Urban Miscellaneous Water Consumption (GB/T 18920-2002, China). PMID- 22508123 TI - GRACE, GLDAS and measured groundwater data products show water storage loss in Western Jilin, China. AB - Water storage depletion is a worsening hydrological problem that limits agricultural production in especially arid/semi-arid regions across the globe. Quantifying water storage dynamics is critical for developing water resources management strategies that are sustainable and protective of the environment. This study uses GRACE (Gravity Recovery and Climate Experiment), GLDAS (Global Land Data Assimilation System) and measured groundwater data products to quantify water storage in Western Jilin (a proxy for semi-arid wetland ecosystems) for the period from January 2002 to December 2009. Uncertainty/bias analysis shows that the data products have an average error <10% (p < 0.05). Comparisons of the storage variables show favorable agreements at various temporal cycles, with R(2) = 0.92 and RMSE = 7.43 mm at the average seasonal cycle. There is a narrowing soil moisture storage change, a widening groundwater storage loss, and an overall storage depletion of 0.85 mm/month in the region. There is possible soil-pore collapse, and land subsidence due to storage depletion in the study area. Invariably, storage depletion in this semi-arid region could have negative implications for agriculture, valuable/fragile wetland ecosystems and people's livelihoods. For sustainable restoration and preservation of wetland ecosystems in the region, it is critical to develop water resources management strategies that limit groundwater extraction rate to that of recharge rate. PMID- 22508124 TI - Estimation and modeling of direct rapid sand filtration for total fecal coliform removal from secondary clarifier effluents. AB - The filtration of fecal coliform from a secondary clarifier effluent was investigated using direct rapid sand filters as tertiary wastewater treatment on a pilot scale. The effect of the flocculation dose, flow loading rate, and grain size on fecal coliform removal was determined. Direct rapid sand filters can remove 0.6-1.5 log-units of fecal coliform, depending on the loading rate and grain size distribution. Meanwhile, the flocculation dose has little effect on coliform removal, and increasing the loading rate and/or grain size decreases the bacteria removal efficiency. A model was then developed for the removal process. Bacteria elimination and inactivation both in the water phase and the sand bed can be described by first-order kinetics. Removal was successfully simulated at different loading rates and grain size distributions and compared with the data obtained using pilot-scale filters. PMID- 22508125 TI - Net environmental benefit: introducing a new LCA approach on wastewater treatment systems. AB - Life cycle assessment (LCA) allows evaluating the potential environmental impacts of a product or a service in relation to its function and over its life cycle. In past LCAs applied to wastewater treatment plants (WWTPs), the system function definition has received little attention despite its great importance. This has led to some limitations in LCA results interpretation. A new methodology to perform LCA on WWTPs is proposed to avoid those limitations. It is based on net environmental benefit (NEB) evaluation and requires assessing the potential impact of releasing wastewater without and with treatment besides assessing the impact of the WWTP's life cycle. The NEB allows showing the environmental trade offs between avoided impact due to wastewater treatment and induced impact by the WWTP's life cycle. NEB is compared with a standard LCA through the case study of a small municipal WWTP consisting of facultative aerated lagoons. The NEB and standard LCA show similar results for impact categories solely related to the WWTP's life cycle but differ in categories where wastewater treatment environmental benefit is accounted for as NEB considers influent wastewater quality whereas standard LCA does not. PMID- 22508126 TI - Adsorptive performance of penta-bismuth hepta-oxide nitrate, Bi5O7NO3, for removal of methyl orange dye. AB - The adsorption of methyl orange dye from aqueous solution onto penta-bismuth hepta-oxide nitrate, Bi(5)O(7)NO(3), synthesized by precipitation method, was studied in a batch adsorption system. The effects of operation parameters such as adsorbent dose, initial dye concentration, pH and temperature were investigated. The adsorption equilibrium and mechanism of adsorption was evaluated by Langmuir and Freundlich isotherm and different kinetic models, respectively. The results indicate that adsorption is highly dependent on all operation parameters. At optimum conditions, the adsorption capacity was found to be 18.9 mg/g. The adsorption data fits well with the Langmuir isotherm model indicating monolayer coverage of adsorbate molecules on the surface of Bi(5)O(7)NO(3). The kinetic studies show that the adsorption process is a second-order kinetic reaction. Although intra-particle diffusion limits the rate of adsorption, the multi linearity plot of intra-particle model shows the importance of both film and intra-particle diffusion as the rate-limiting steps of the dye removal. Thermodynamic parameters show that the adsorption process is endothermic, spontaneous and favourable at high temperature. PMID- 22508127 TI - Local head loss monitoring using acoustic instrumentation in partially full sewer pipes. AB - After an increase in capital investment in UK sewers to reduce hydraulic capacity problems, the proportion of sewer flooding incidents now linked to blockages has increased. It is clear that if sewer operators are to continue to reduce flooding incidents, then better blockage management is now required. Sewer blockage formation is poorly understood; blockages are intermittent and occur in a number of circumstances. This paper reports on the development of low-cost acoustic instrumentation that can identify the location of a pipe blockage and then estimate the local head loss as a result of the presence of a blockage. A set of experiments were carried out in two full-scale laboratory pipes. The pipes' condition was altered by inserting blockages of different sizes. Acoustic data were recorded and presented in terms of the acoustic energy reflected from the partially blocked pipe. The results of this study show that the total reflected acoustic energy correlates with the measured head loss. A new empirical relation between the reflected acoustic energy and head loss due to a blockage is derived. This knowledge can then be used to estimate the reduction in flow capacity resulting from a blockage based on a single remote measurement. PMID- 22508128 TI - MBR technology: a promising approach for the (pre-)treatment of hospital wastewater. AB - Membrane bioreactor (MBR) technology is a very reliable and extensively tested solution for biological wastewater treatment. Nowadays, separate treatment of highly polluted wastewater streams especially from hospitals and other health care facilities is currently under investigation worldwide. In this context, the MBR technology will play a decisive role because an effluent widely cleaned up from solids and nutrients is absolutely mandatory for a subsequent further elimination of organic trace pollutants. Taking hospital wastewater as an example, the aim of this study was to investigate to what extent MBR technology is an adequate 'pre-treatment' solution for further elimination of trace pollutants. Therefore, we investigated - within a 2-year period - the performance of a full-scale hospital wastewater treatment plant (WWTP) equipped with a MBR by referring to conventional chemical and microbiological standard parameters. Furthermore, we measured the energy consumption and tested different operating conditions. According to our findings the MBR treatment of the hospital wastewater was highly efficient in terms of the removal of solids and nutrients. Finally, we did not observe any major adverse effects on the operation and performance of the MBR system which potentially could derive from the composition of the hospital wastewater. In total, the present study proved that MBR technology is a very efficient and reliable treatment approach for the treatment of highly polluted wastewater from hospitals and can be recommended as a suitable pre-treatment solution for further trace pollutant removal. PMID- 22508129 TI - Bulking control by low-dose ozonation of returned activated sludge in a full scale wastewater treatment plant. AB - Sludge bulking is still a problem in the operation of state-of-the-art wastewater treatment plants (WWTPs). The ozonation of returned activated sludge (RAS) is an innovative option as a non-specific measure for the control of filament growth. The applicability of sludge ozonation for bulking control of a large wastewater treatment plant was investigated. At a full-scale WWTP one lane was equipped with a sludge ozonation plant for RAS. The implemented sludge ozonation of RAS was tested against the two identical references lanes of the same WWTP. The positive effect on settleability could be clearly proven. Low-dose sludge ozonation could be a technical alternative in comparison with the established chemical measures for bulking control. PMID- 22508130 TI - Lipid peroxidation in the freshwater shrimp Caridina nilotica as a biomarker of Roundup((r)) herbicide pollution of freshwater systems in South Africa. AB - Glyphosate-based herbicides used to control weeds and invading alien plant species in South Africa ultimately end up in freshwater ecosystems, but no South African environmental water quality guideline exists to regulate these bio-active chemicals. Ecotoxicological tests to assess the possibility of using lipid peroxidation (LPx) in Caridina nilotica as a potential biomarker of Roundup((r)), a glyphosate-based herbicide, pollution were conducted. In two separate tests, 40 days post hatch shrimps were exposed to different concentrations of 4.3, 6.7, 10.5, 16.4, 25.6 and 40.0 mg/L in a 96 h acute toxicity test; and 2.2, 2.8, 3.4, 4.3 and 5.4 mg/L in a 21 d chronic toxicity test, using static-non renewal and static-renewal methods, respectively. Shrimp whole body LPx was estimated by thiobarbituric acid reactive species (TBARS) assay, performed by a malondialdehyde (MDA) reaction with 2-thiobarbituric acid (TBA) measured spectrophotometrically. Final MDA concentrations were expressed as nmol MDA produced/mg protein. Results showed that LPx was significantly lower in control animals than in animals exposed to different Roundup((r)) concentrations, (p < 0.05). The present work provides an ecotoxicological basis for the possible use of LPx in Caridina nilotica as a biomarker for monitoring Roundup((r)) pollution in freshwater ecosystems. PMID- 22508131 TI - Decision support system to divide a large network into suitable District Metered Areas. AB - This paper presents a new approach to divide large Water Distribution Networks (WDN) into suitable District Metered Areas (DMAs). It uses a hydraulic simulator and two operational models to identify the optimal number of DMAs, their entry points and boundary valves, and the network reinforcement/replacement needs throughout the project plan. The first model divides the WDN into suitable DMAs based on graph theory concepts and some user-defined criteria. The second model uses a simulated annealing algorithm to identify the optimal number and location of entry points and boundary valves, and the pipes reinforcement/replacement, necessary to meet the velocity and pressure requirements. The objective function is the difference between the economic benefits in terms of water loss reduction (arising from the average pressure reduction) and the cost of implementing the DMAs. To illustrate the proposed methodology, the results from a hypothetical case study are presented and discussed. PMID- 22508132 TI - Conditions and technologies of biological wastewater treatment in Hungary. AB - A survey has been carried out involving 55 Hungarian wastewater treatment plants in order to evaluate the wastewater quality, the applied technologies and the resultant problems. Characteristically the treatment temperature is very wide ranging from less than 10 degrees C to higher than 26 degrees C. Influent quality proved to be very variable regarding both the organic matter (typical COD concentration range 600-1,200 mg l(-1)) and the nitrogen content (typical NH(4)-N concentration range 40-80 mg l(-1)). As a consequence, significant differences have been found in the carbon availability for denitrification from site to site. Forty two percent of the influents proved to lack an appropriate carbon source. As a consequence of carbon deficiency as well as technologies designed and/or operated with non-efficient denitrification, rising sludge in the secondary clarifiers typically occurs especially in summer. In case studies, application of intermittent aeration, low DO reactors, biofilters and anammox processes have been evaluated, as different biological nitrogen removal technologies. With low carbon source availability, favoring denitrification over enhanced biological phosphorus removal has led to an improved nitrogen removal. PMID- 22508133 TI - SBR treatment of olive mill wastewaters: dilution or pre-treatment? AB - The olive-oil extraction industry is an economically important activity for many countries of the Mediterranean Sea area, with Spain, Greece and Italy being the major producers. This activity, however, may represent a serious environmental problem due to the discharge of highly polluted effluents, usually referred to as 'olive mill wastewaters' (OMWs). They are characterized by high values of chemical oxygen demand (COD) (80-300 g/L), lipids, total polyphenols (TPP), tannins and other substances difficult to degrade. An adequate treatment before discharging is therefore required to reduce the pollutant load. The aim of the present paper was to evaluate performances of a biological process in a sequencing batch reactor (SBR) fed with pre-treated OMWs. Pre-treatment consisted of a combined acid cracking (AC) and granular activated carbon (GAC) adsorption process. The efficiency of the system was compared with that of an identical SBR fed with the raw wastewater only diluted. Combined AC and GAC adsorption was chosen to be used prior to the following biological process due to its capability of providing high removal efficiencies of COD and TPP and also appreciable improvement of biodegradability. Comparing results obtained with different influents showed that best performances of the SBR were obtained by feeding it with raw diluted OMWs (dOMWs) and at the lowest dilution ratio (1:25): in this case, the removal efficiencies were 90 and 76%, as average, for COD and TPP, respectively. Feeding the SBR with either the pre-treated or the raw dOMWs at 1:50 gave very similar values of COD reduction (74%); however, an improvement of the TPP removal was observed in the former case. PMID- 22508134 TI - Microbiological risks of recycling urban stormwater via aquifers. AB - With the release of the Australian Guidelines for Water Recycling: Managed Aquifer Recharge (MAR), aquifers are now being included as a treatment barrier when assessing risk of recycled water systems. A MAR research site recharging urban stormwater in a confined aquifer was used in conjunction with a Quantitative Microbial Risk Assessment to assess the microbial pathogen risk in the recovered water for different end uses. The assessment involved undertaking a detailed assessment of the treatment steps and exposure controls, including the aquifer, to achieve the microbial health-based targets. PMID- 22508135 TI - Behavior of solid carbon sources for biological denitrification in groundwater remediation. AB - The present study was conducted to compare the behavior of wheat straw, sawdust and biodegradable plastic (BP) as potential carbon sources for denitrification in groundwater remediation. The results showed that a greater amount of nitrogen compounds were released from wheat straw and sawdust than from BP in leaching experiments. In batch experiments, BP showed higher nitrate removal efficiency and longer service life than wheat straw and sawdust, which illustrated that BP is the most appropriate carbon source for stimulation of denitrification activity. In column experiments, BP was able to support complete denitrification at influent nitrate concentrations of 50, 60, 70, 80, and 90 mg NO(3)(-)-N/L, showing corresponding denitrification rates of 0.12, 0.14, 0.17, 0.19, and 0.22 mg NO(3)(-)-N.L(-1).d(-1).g(-1), respectively. These findings indicate that BP is applicable for use as a carbon source for nitrate-polluted groundwater remediation. PMID- 22508136 TI - Municipal wastewater treatment by biofiltration: comparisons of various treatment layouts. Part 1: assessment of carbon and nitrogen removal. AB - One of the largest wastewater treatment plants in the Paris conurbation (240,000 m(3)/d) has been studied over several years in order to provide technical and economical information about biological treatment by biofiltration. Biofiltration systems are processes in which carbon and nitrogen pollution of wastewater are treated by ascendant flow through immersed fixed cultures. This paper, focused on technical information, aims: (1) to compare performances of the three biological treatment layouts currently used in biofiltration systems: upstream denitrification (UD), downstream denitrification (DD) and combined upstream downstream denitrification (U-DD) layouts; and (2) to describe in detail each treatment step. Our study has shown that more than 90% of the carbon and ammoniacal pollution is removed during biological treatment, whatever the layout used. Nitrate, produced during nitrification, is then reduced to atmospheric nitrogen. This reduction is more extensive when the denitrification stage occurs downstream from the treatment (DD layout with methanol addition), whereas it is only partial when it is inserted upstream from the treatment (UD layout - use of endogenous carbonaceous substrate). So, the UD layout leads to a nitrate concentration that exceeds the regulatory threshold in the effluent, and the treatment must be supplemented with a post-denitrification step (U-DD layout). Our work has also shown that the optimal ammonium-loading rate is about 1.1-1.2 kg N-NH(4)(+) per m(3) media (polystyrene) and day. For denitrification, the optimal nitrate-loading rate is about 2.5 kg N per m(3) media (expanded clay) and day in the case of DD with methanol, and is about 0.25 kg N-NO(3)(-) per m(3) media and day in the case of UD with exogenous carbonaceous substrate. PMID- 22508137 TI - Municipal wastewater treatment by biofiltration: comparisons of various treatment layouts. Part 2: assessment of the operating costs in optimal conditions. AB - This work aims to compare the operation costs (energy, reagents, waste management) for the three layouts usually used in wastewater treatment plants incorporating biofilters, using technical and economical data acquired during 10 years of operation of a Parisian plant (Seine Centre, 240,000 m(3) d(-1) -800,000 equivalent inhabitants). The final objective is to establish general economical data and tendencies that can be translated from our study to any biofiltration plant. Our results evidenced the savings achieved through the treatment process combining upstream and downstream denitrification. To use this layout reduced the operating costs by some 10% as compared with conventional processing only comprising downstream denitrification. Operating costs were respectively estimated at 37 and 34 ?/1,000 m(3) for downstream denitrification and combining upstream and downstream denitrification layouts. PMID- 22508138 TI - Spectral-domain optical coherence tomography in uveitic macular edema: morphological features and prognostic factors. AB - AIM: To assess the morphological characteristics of uveitic macular edema studied with Spectralis optical coherence tomography (OCT) and to investigate the correlation between the tomographic features and visual acuity. METHODS: 71 eyes of 55 patients underwent examination with Spectralis OCT (Heidelberg Engineering, Germany). Data was correlated with logMAR best-corrected visual acuity (BCVA). RESULTS: Two morphological patterns were observed: cystoid macular edema (CME) in 69% and diffuse macular edema in 31% of eyes. BCVA was 0.2 in CME, 0.1 in diffuse edema (p = 0.008). Foveal thickness was 413.4 +/- 212 um in CME, 311.27 +/- 53 um in diffuse edema (p = 0.03). BVCA was 0.3 in eyes with serous retinal detachment (SRD), 0.2 in eyes without SRD (p = 0.02). BCVA was 0.4 in eyes with inner segment/outer segment (IS/OS) disruption, 0.1 in eyes with integrity of the IS/OS junction (p = 0.01). CONCLUSIONS: BCVA is negatively correlated with cystoid pattern, foveal thickening and SRD. Disruption of the IS/OS junction is associated with poor vision in uveitic macular edema. PMID- 22508139 TI - Renal health and the environment: heavy metal nephrotoxicity. AB - We currently recognise that environmental toxins such as cadmium, lead, and arsenic play a significant role in the development of chronic renal failure. Epidemiological studies have shown a strong association between exposure to these metals and the presence of chronic kidney injury. The physiopathological mechanisms behind metal-induced kidney injury are complex, and some aspects of their metabolism and damage mechanisms remain unknown. This review aims to analyse the physiopathological mechanisms of kidney injury due to cadmium, lead and arsenic. PMID- 22508140 TI - Elderly patients with chronic kidney disease: outcomes after 5 years of follow up. AB - INTRODUCTION: In recent years, chronic kidney disease (CKD) has come to be considered an epidemic problem, and there is considerable interest in early diagnosis in order to slow its progression to end-stage renal disease (ESRD) and prepare patients for dialysis and transplantation programmes. Many elderly patients are labelled as having CKD based solely on having a glomerular filtration rate (GFR) of <60 ml/min. OBJECTIVE: Monitor renal function (RF) and outcomes associated with CKD (morbidity, mortality and progress to ESRD) in an elderly cohort. PATIENTS AND METHOD: A total of 80 clinically stable patients, with a median age of 83 years (range 69-97; 69% female, 35% diabetic, 83% hypertensive) were recruited at random in our Geriatric Medicine and Nephrology Departments between January and April 2006, and monitored for 5 years. During the recruitment stage we established two groups based on baseline serum creatinine (SCr) concentration: Group 1, 38 patients with SCr <1.1mg/dl (range 0.7-1.1) and Group 2, 42 patients with SCr >1.1mg/dl (range 1.2-3). We determined baseline blood levels of creatinine and urea, calculated eGFR using an abbreviated Modification of Diet in Renal Disease (MDRD) formula, and repeated these measurements after 5 years. We recorded baseline comorbidity according to the Charlson comorbidity index (CCI); hospital admissions; new cardiovascular events; treatments; progression to ESRD requiring dialysis; and mortality. RESULTS: In the 39 patients surviving after 5 years there were no significant differences between Groups 1 and 2 in total number of hospital admissions, episodes of heart failure and new ischaemic heart disease. Overall, the most commonly used drugs were diuretics (76.9%), while beta-blockers were used the least (10.3%). There were 41 deaths (51.3%): of these patients, 15 died due to overall decline, 8 due to infections, 4 due to stroke, 4 due to neoplasia, 3 due to cardiovascular problems, 2 due to complications from fractures and 5 due to unknown causes. Mortality was higher in Group 2 (66.7% vs 34.2%, P=.004) and patient age was also higher in that group (84.73 +/- 5.69 vs 80.12 +/- 6.5, P=.001). No significant differences in mortality were attributable to sex, diabetes, hypertension or CCI. Only 2 patients in Group 2 progressed to ESRD, they received conservative treatment due to comorbidity (no patients in the study have started dialysis). The evolution of RF (baseline/5 years) in all patients surviving at 5 years was as follows: SCr (mg/dl): 1.15 +/- 0.41/1.21 +/- 0.49 (not significant [NS]), urea (mg/dl) 52.21 +/- 13.0/61.21 +/- 27.0 (P=.047), MDRD (ml/min/1.73m2) 57.47 +/- 15/54.86 +/- 17 (NS). There were no differences in progression between the 2 groups. In the logistic regression analysis for overall mortality (independent variables: age, sex, CCI, cardiovascular history, SCr and group), only age (relative risk [RR]: 1.12; 1.03-1.23, P=.009) and group (RR: 3.06; 1.10-8.40, P=.031) were independently associated with mortality. CONCLUSION: Screening for CKD using GFR only may lack clinical relevance in this population since RF slowly deteriorates in elderly patients without proteinuria. Mortality due to all causes was higher in elderly patients with a poorer baseline RF, and mortality rates were higher than rates of CKD progression to ESRD. PMID- 22508141 TI - Use of sirolimus in patients with primary steroid-resistant nephrotic syndrome. AB - Persistent nephrotic syndrome that does not respond to treatment may cause progression to kidney failure. We designed a therapeutic protocol with sirolimus for this group of patients. We conducted a prospective, interventional, time series, cohort study lasting 20 months. Thirteen patients were enrolled, with a mean age of 10 years (range: 8-18 years old) with steroid-resistant primary nephrotic syndrome and a histological diagnosis of focal and segmental glomerulosclerosis. We administered sirolimus 3.6mg/m2/day. The duration of this regimen was 12 months in responsive patients. The protocol's efficacy was assessed according to reduction of proteinuria (3 response levels: total, partial, or no response). Severity of histological renal damage and mean time from clinical diagnosis to protocol initiation were also assessed. Nine of 13 patients responded to the treatment with sirolimus, and mean progression time and the severity of histological renal damage influenced response to therapy. We believe that sirolimus is a valid treatment option in patients with steroid resistant nephrotic syndrome, even though this regimen probably requires an earlier treatment. PMID- 22508142 TI - Is there impact of mortality prior hemodialysis therapy in peritoneal dialysis patients? AB - AIM: The aim of this study is to investigate the mortality and the factors which may affect it in patients who were transferred to peritoneal dialysis (PD) from hemodialysis (HD), compared to patients assigned to PD as first-line therapy. MATERIAL AND METHODS: A total of 322 patients treated with PD between 2001 and 2010 were evaluated retrospectively. Twenty three patients were excluded and the data of remaining 299 patients (167F, mean follow up time 38.5+/-26.8 months, mean age 44.7+/-15.9 years) were evaluated. Patients were separated into two groups according to their HD history. Group 1 and group 2 consisted of patients with (n=48) and without (n=251) a history of prior HD, respectively. Socio demographic characteristics such as who helped administer the PD and the preference of patients (compulsory vs their preference) were obtained from the patient records. The clinical data obtained during the last clinical evaluation before the initiation of PD (blood pressure, daily urine volumes, daily ultrafiltration amounts and laboratory parameters) were recorded. Additional systemic diseases and information about the etiologies of the end stage renal disease (ESRD) of all patients were recorded. Frequencies of the infectious complications were recorded. Patient and technique survival were investigated and compared between groups. RESULTS: In group 1, the patients were older and had less urine amounts (p=0.028 and 0.041 respectively). Thirty five patients (70%) and 25 patients (9.3%) have been transferred to PD due to vascular problems in group 1 and 2, respectively (p<0.001). In group 1, 37 (74%) patients were carrying out PD treatment by themselves, compared to 222 (88.4%) patients in group 2 (p=0.016). Incidences of peritonitis and catheter exit site/tunnel infection attacks were found 24.9+/-26.8 and 27.2+/-26.5 patient-months in group 1, and 27.4+/-22.4 and 33.4+/-24.5 patient-months in group 2, respectively (p=0.50 and 0.12). In group 1, twenty three patients have death and 2 patients have discontinued the treatment due to transplantation. In group 2, 174 patients have discontinued the treatment (55 patients have died, 80 patients have been switched to hemodialysis and 39 patients have received renal transplantation). There were significant differences between groups according to the last condition (p<0.001). Mean patient survival were found 22.9+/-4.2 and 55.5+/-2.8 patient months in group 1 and group 2, respectively. The patient survival rates by Kaplan Meier analysis were 50%, 40.9%, 27.3% and 9.1% at 1, 2, 3, and 4 years in group 1 and 90.9%, 81.6%, 73.9%, 64.9% and 53.1% at 1, 2, 3, 4 and 5 years in group 2, respectively. The mortality rate is higher in patients who have undergone HD before PD compared without HD history (log rank:<0.001). In the Cox proportional hazards model analysis, preference of PD (RR: 7.72, p<0.001), presence of diabetes (RR: 2.26, p=0.01), pretreatment serum albumin level (RR: 0.37, p<0.001) and catheter exit size infection attacks (RR:0.34, p=0.01) were identified as predictors of mortality. CONCLUSION: Our data show that mortality in patients transferred to PD from HD was higher than in patients undergoing PD as first-line therapy. Compulsory choice such as vascular access problems and social factors were the most important causes of increasing mortality in patients transferred to PD from HD. PMID- 22508143 TI - Peripheral arterial disease and kidney failure: a frequent association. AB - OBJECTIVES: To determine the prevalence of kidney failure in people older than 49 years old with peripheral arterial disease and to analyse its relationship with risk factors and cardiovascular disease. MATERIAL AND METHOD: Prospective epidemiological study 3 years in duration with selection by simple random sampling in the general population aged over 49 years. Data on demographic, clinical, prevalence of risk factors and cardiovascular disease were registered. We defined peripheral arterial disease (PAD) by ankle-brachial index (ABI) <=0.9 and chronic kidney disease (CKD) according to estimated glomerular filtration rates by the MDRD <60 ml/min/1.73m2. Baseline data are presented. RESULTS: 511 people were included. The mean age was 66.6 (9.7) years (SD), 37% were men. The prevalence of PAD was 12.4% (N=63) of the sample, average age 72.6 years, 46% men. The presence of CKD stages 3-5 was 39.7%. Patients with PAD and CKD compared with those with normal renal function were older (75.6 vs. 70.6, p=0.08), predominantly women (64% vs 47.4%, p=ns), and showed higher values for systolic and diastolic blood pressure (159.2 vs 146.1, p=ns and 85.7 vs 80.3 mmHg, p=0.09), CRP (1.23 vs 0.38 mg/dl, p=0.05) and albumin creatinine ratio (90.2 vs 26.4 mg/g, p=ns). In this group, the prevalence of cardiovascular risk factors and associated cardiovascular disease, were significantly higher without reaching statistical significance. CONCLUSIONS: Kidney failure is present in 39.7% of patients with PAD and it defines a subgroup of patients with high cardiovascular risk. PMID- 22508144 TI - Optimising expanded donor organs through dual kidney transplantation: a case control study. AB - INTRODUCTION: In order to take full advantage of ECD kidneys, which may not provide sufficient renal mass if used individually, it has been suggested that such organs be used in dual or bilateral kidney transplantation (DTx). PATIENTS AND METHOD: We analysed the experience in a single hospital between May 2007 and March 2011 in a case-control study. Criteria for determining whether to perform single or dual Tx were defined in a protocol in which the biopsy score was important, but not the only factor. Donor's age, medical history, kidney size and creatinine clearance were also considered. During this time period, 80 kidneys from donors over age 65 were transplanted. Single transplants (STx) accounted for 40 of the organs, and another 40 were used in DTx. RESULTS: Mean donor age for STx was 68.7 +/- 3.0 years; for DTx, it was 74.2 +/- 4.3 years (P<.001), with more female donors for DTx (75%) than for STx (40%) (P<.001). There were no differences between groups with regard to glomerular filtration rate or proteinuria. Kidneys assigned to DTx received higher biopsy scores than those assigned to STx (2.95 +/- 1.01 vs 1.8 +/- 1.04; P<.001). DTx recipients were older than STx recipients. There were no differences between the groups regarding cold ischaemia time, delayed graft function, haemorrhagic complications or re surgeries. However, DTx recipients achieved better creatinine clearance at 1, 3, 6 and 12 months, although the difference was only statistically significant at 6 months (53.4 +/- 19.5ml/min vs 44.5 +/- 15.6ml/min; P<.05). Renal artery thrombosis appeared in 2 STx patients and in both kidneys of 1 DTx patient. Another 2 patients in the DTx group each lost 1 kidney due to thrombosis and ureteral necrosis respectively, but were able to remain dialysis-free. Graft survival at 3 years was 90% for both groups. During the study period 3 patients died (2 in the STx group and 1 in the DTx group). CONCLUSIONS: Our preliminary experience indicates that DTx provides good results in terms of survival and renal function data, despite surgery being more complicated and the organs having characteristics that probably make them unsuitable for STx. The decision to perform DTx makes using ECD kidneys easier, and it should be based on a combination of pre-transplant histological criteria and the donor's clinical characteristics. PMID- 22508145 TI - Pregnancy in women on chronic dialysis: a review. AB - The frequency of pregnancy in women on dialysis is extremely low, but the percentage of successful pregnancies in this context has increased over the years, with some studies placing the survival rate above 70%. These pregnancies are not exempt from both maternal and foetal complications, and so their management requires the joint efforts of nephrologists, gynaecologists, nurses, and nutritionists. Currently, we have been unable to establish consistent systematic treatment from both nephrological and gynaecological specialists in these patients. The main changes that need to be made are: increased time on dialysis, maintaining low levels of pre-dialysis urea, avoiding: maternal hypertension and hypotension, anaemia, urinary tract infections, and fluctuations in electrolytes. Adequate foetal monitoring is also necessary. PMID- 22508146 TI - Single-step direct cholangioscopy by freehand intubation using standard endoscopes for diagnosis and therapy of biliary diseases. AB - OBJECTIVES: Commercially available 10F cholangioscope systems have limitations in examination of the biliary tree. Further, they are not readily available in all endoscopy units. Direct cholangioscopy (DC) using slim and ultraslim gastroscopes have been utilized to detect and treat bile duct (BD) diseases. It often requires initial duodenoscope introduction, followed by over-the-wire exchange to a gastroscope for BD intubation. We report a novel single-step DC technique using forward-viewing endoscopes without requiring tandem-scope exchange. METHODS: In patients with native papilla, a "J" maneuver, accomplished by retroflexing the endoscope in the second portion of the duodenum and withdrawing the retroflexed scope into the BD, was used to achieve free intubation. A variety of readily available standard endoscopes were used. For biliary-enteric anastomoses, balloon dilation, if necessary followed by enteroscope advancement, was utilized for BD visualization. RESULTS: A total of 18 patients underwent 22 DC procedures (8 male, 10 female, mean age 69 years). Direct intubation was successful in all procedures. Indications included BD stone (n=10), BD stricture or tumor (n=8). A native papilla was present in 13 patients and biliary-enteric anastomoses in 5; 8 patients had altered gastrointestinal anatomy. Sphincterotomy was required in 12/13 native papilla patients to facilitate DC. Free intubation of the BD was accomplished in 19 of 22 exams, and 3 facilitated by guidewire (over-the-wire in 2 and alongside a guidewire in 1). Overtube-assisted enteroscopy was used to reach the BD in four patients. The findings were stones (n=6), strictures or tumors (n=7), abnormal mucosa (n=5), a dilated duct confirming stone clearance without stricture (n=3), and retained stent (n=1). Interventions were biopsy (n=8), stone extraction (n=5), electrohydraulic lithotripsy (n=3), chromoendoscopy (n=2), narrow-band imaging (n=2), through the scope stricture dilation (n=2), and argon-plasma coagulation of biliary tumor (n=1). Complications were cholangitis managed with intavenous antibiotics (n=1). CONCLUSIONS: Single-step DC can be achieved without using tandem-scope exchange, and may be clinically useful for diagnostic and therapeutic purposes in managing select biliary tract diseases. PMID- 22508147 TI - Chronic gastrointestinal consequences of acute infectious diarrhea: evolving concepts in epidemiology and pathogenesis. AB - Acute infectious diarrhea is a frequent occurrence both in the developing world, where it results in considerable mortality, and in developed countries, where it accounts for a significant number of health visits, hospitalizations, and medical and non-medical losses. Recent evidence in basic, clinical, and epidemiological science domains has emerged that suggest that the burden caused by these infections is not limited to the acute illness, but may result in triggering or contributing to the pathogenesis of a number of chronic health problems. This review considers the breadth of this information for the purpose of consolidating what is currently known, identifying gaps in knowledge, and describing future directions and policy implications related to the chronic consequences of acute infectious diarrhea. A unifying hypothesis of this review is that infections may trigger a number of long-lasting changes in gut physiology and immunity that can increase the risk to a variety of chronic gastrointestinal diseases, particularly in genetically susceptible individuals. PMID- 22508148 TI - Esomeprazole alone compared with esomeprazole plus aspirin for the treatment of aspirin-related peptic ulcers. AB - BACKGROUND: Aspirin-related peptic ulcers are a common disorder. However, whether or not aspirin should be continued during treatment for aspirin-related ulcers remains unclear. AIMS: To compare esomeprazole alone with esomeprazole plus aspirin in the treatment of aspirin-related peptic ulcers and to investigate the independent factors associated with the failure of ulcer healing. METHODS: From January 2008 to July 2011, patients with aspirin-related peptic ulcers were randomized to receive esomeprazole (40 mg per day) alone or esomeprazole (40 mg per day) plus aspirin (100 mg per day) for 8 weeks. The subjects with Helicobacter pylori infection were treated with standard triple therapy. Follow up endoscopy was carried out at the end of the 8th week. The primary end point was the healing of peptic ulcers. RESULTS: In all, 178 patients (89 receiving esomeprazole alone and 89 receiving esomeprazole plus aspirin) were enrolled and underwent follow-up endoscopy. The healing rate of ulcers by modified intention to-treat analysis was 82.5% (95% confidence interval (CI), 74.2-90.8%) among patients treated with esomeprazole alone and 81.5% (95% CI, 73.0-90.0%) among patients treated with esomeprazole plus aspirin (difference, 1.0%; 95% CI, -11.2 to 12.6%). The per-protocol analysis yielded similar results (healing rate: 83.1% vs. 83.8%, respectively; difference, 0.7%; 95% CI, -11.2 to 12.6%). Multivariate analysis disclosed that use of steroids during treatment (odds ratio: 5.6; 95% CI, 1.1-27.7%) was the only independent factor associated with the failure of ulcer healing. CONCLUSIONS: The observed ulcer healing rates were comparable in the esomeprazole and esomeprazole-plus-aspirin groups, but the wide CIs do not rule out clinically meaningful differences of more than 10%. PMID- 22508149 TI - Does celiac disease occur in Afro-derived Brazilian populations? AB - BACKGROUND: Celiac disease is an autoimmune disorder that occurs in genetically susceptible individuals in whom the ingestion of dietary gluten induces intestinal mucosa inflammation. Previous studies suggest that celiac disease may either be very rare or underdiagnosed in African and/or African-derived population. AIM: Determine the prevalence of celiac disease in Sub-Saharan African-derived Brazilian communities using serological screening. SUBJECTS AND METHODS: Inhabitants from 10 African-derived communities from Northeastern of Brazil were screened for celiac disease. All sera were tested for endomysial class IgA antibody using indirect immunofluorescence. RESULTS: No positive test for IgA-endomysial was observed in the 860 individuals tested. CONCLUSION: Our data suggests a low prevalence of celiac disease in African-derived Brazilian populations. PMID- 22508150 TI - Non-invasive cardiac output monitoring in neonates using bioreactance: a comparison with echocardiography. AB - OBJECTIVES: Non-invasive cardiac output monitoring is a potentially useful clinical tool in the neonatal setting. Our aim was to evaluate a new method of non-invasive continuous cardiac output (CO) measurement (NICOMTM) based on the principle of bioreactance in neonates. METHODS: In this prospective observational study, 10 neonates underwent 97 paired NICOM and echocardiography (echo) assessments of left ventricular output (LVO). For each neonate, NICOM measurements of left ventricular stroke volume (SV) and LVO over a 2- to 4-hour period were correlated with blinded, simultaneous, discrete echo measurements of SV and LVO. The precision and accuracy of the NICOM monitor relative to echo during periods of steady state were assessed. RESULTS: The infants' median birth weight was 2.72 kg (IQR 1.56-3.23 kg, range 1.44-4.00) and their median gestation was 37 weeks (IQR 31-40 weeks, range 31-41). Median NICOM SV and LVO readings were consistently lower than echo (2.6 ml [IQR 1.4-3.2, range 0.6-5.3] vs. 3.5 ml [IQR 2.1-4.4, range 1.1-6.8], and 400 ml/min [IQR 233-476] vs. 559 ml/min [IQR 386-652], p < 0.001). The NICOM LVO readings were lower than the echo readings by a mean of 153 +/- 56 ml/kg. NICOM consistently under-read LVO by 31 +/- 8%, and this systematic difference was constant across the range of LVOs obtained. There was a strong correlation between NICOM and echo measurements of LVO (r = 0.95, p < 0.001). CONCLUSION: Non-invasive cardiac output monitoring is feasible in neonates. Further validation studies in neonatal animal experimental models and human neonates need to be conducted before routine clinical use. PMID- 22508151 TI - Optimization of growth hormone dosing in children born small for gestational age: an open-label, randomized study of children during the fourth year of therapy. AB - BACKGROUND: Optimal dosage for growth hormone (GH) therapy in short, prepubertal children born small for gestational age (SGA) is controversial. METHODS: SGA OPTIMIS (NCT00249821) is a multicenter, open-label, parallel-group, pilot study of short children born SGA who had received recombinant human GH (r-hGH) (57 MUg/kg/day) for 3 years. Children were randomized 1:1 to receive either 57 or 35 MUg/kg/day r-hGH during year 4. The primary endpoint was height gain during year 4. RESULTS: 22 children were randomized (57 MUg/kg/day, n = 10; 35 MUg/kg/day, n = 12) and 21 completed the fourth year of therapy; 22 were included in efficacy analyses. During year 4, mean [standard deviation (SD)] height velocity was 6.4 (1.4) and 4.4 (1.2) cm/year (p = 0.001) and height velocity SD score (SDS) was 0.3 (0.3) and -0.1 (0.2) (p = 0.002) in the 57 and 35 MUg/kg/day groups, respectively. The 57 MUg/kg/day group continued with catch-up growth, had a significantly higher mean weight gain (p = 0.015) and significantly higher insulin-like growth factor-I levels at 12 months (p = 0.038). Five treatment emergent adverse events were reported; none was serious or caused study withdrawal. CONCLUSIONS: Children who continued receiving 57 MUg/kg/day r-hGH in year 4 had significantly greater height gain than those receiving 35 MUg/kg/day r hGH. PMID- 22508152 TI - Confused HCl: hydrogen chloride or hydrochloric acid? PMID- 22508153 TI - Young men with cancer: a literature review. AB - BACKGROUND: The impacts of cancer on young men are reportedly different from the experiences of others. These impacts may adversely affect the health and the healthcare of young men. OBJECTIVE: The purpose of this article was to conduct a literature review to examine what is known about the experiences of young men with cancer. METHODS: A systematic strategy was used to locate original research that included 4 electronic databases using the search terms men, young men, male, father, parents, and cancer experience. RESULTS: Sixteen studies met the inclusion criteria. Twelve studies used qualitative methodology, and 4 studies used a quantitative method; no mixed-method studies were found. Of the studies reviewed, 6 focused on the experiences of men but not young men aged 20 to 44 years exclusively, 10 studies had male and female respondents. Analysis revealed 5 themes: (1) manhood in question, (2) the good father or not, (3) family and that special bond, (4) silencing cancer talk, and (5) living with uncertainty. CONCLUSIONS: Young men are building resources while creating family bonds, and they identify themselves through their work. Young men with cancer have needs specific to their gender and cohort. IMPLICATIONS FOR PRACTICE: Methodological and conceptual recommendations are presented. This includes conducting research focusing on this cohort and using a life-course perspective. Understanding the overall experience of this cohort will enable the development of clinical interventions for young men with cancer. Supportive care in a nonthreatening environment is needed to help young men cope with the problems described. PMID- 22508154 TI - New [(D-terpyridine)-Ru-(D or A-terpyridine)][4-EtPhCO2]2 complexes (D = electron donor group; A = electron acceptor group) as active second-order non linear optical chromophores. AB - The dipolar and octupolar contributions of the second order nonlinear optical properties of [(4'-(C(6)H(4)-p-D)-2,2':6',2''-terpyridine)-Ru-(4'-(C(6)H(4)-p-A) 2,2':6',2''-terpyridine)]Y(2) heteroleptic complexes (D and A are donor and acceptor groups, respectively), and related free terpyridines and homoleptic complexes, have been obtained by means of a comprehensive combination of Electric Field Induced Second Harmonic generation, Third Harmonic Generation, and Harmonic Light Scattering measurements. These results evidence how a metal can act as a bridge between two pi-delocalized terpyridine moieties bearing a D and an A group, respectively, leading to a large quadratic hyperpolarizability hugely dominated by the octupolar contribution. PMID- 22508155 TI - Presence or absence of cardiac disease in Duchenne muscular dystrophy. PMID- 22508158 TI - Acute and chronic pouchitis--pathogenesis, diagnosis and treatment. AB - Restorative proctocolectomy with ileal pouch-anal anastomosis has become the procedure of choice for the majority of patients with ulcerative colitis who require surgical treatment. Pouchitis, the most common long-term complication of the procedure, involves a spectrum of disease processes with heterogeneous risk factors, clinical features, disease courses and prognoses. In addition, clinical symptoms of pouchitis are not specific and often overlap with those of other inflammatory and functional pouch disorders, such as Crohn's disease of the pouch and irritable pouch syndrome. Pouchoscopy and biopsy, along with laboratory and radiographic evaluations, are often required for accurate diagnosis in patients with symptoms indicative of pouchitis. Dysbiosis has been implicated as a triggering factor for pouchitis, and concurrent infection with pathogens, such as Clostridium difficile, might contribute to disease relapse and exacerbation. Antibiotic therapy is the main treatment modality. However, the management of antibiotic-dependent and antibiotic-refractory pouchitis remains challenging. Secondary causes of pouchitis, such as ischaemia, NSAID use, the presence of concurrent primary sclerosing cholangitis and other systemic immune-mediated disorders, should be evaluated and properly managed. PMID- 22508162 TI - Transplantation: Sharing of donated livers is not equal. PMID- 22508163 TI - Imaging: Differentiation of colorectal lesions. PMID- 22508159 TI - MicroRNAs in pancreatic cancer metabolism. AB - Advances in understanding the biology of tumour progression and metastasis have clearly highlighted the importance of aberrant tumour metabolism, which supports not only the energy requirements but also the enormous biosynthetic needs of tumour cells. Such metabolic alterations modulate glucose, amino acid and fatty acid-dependent metabolite biosynthesis and energy production. Although much progress has been made in understanding the somatic mutations and expression genomics behind these alterations, the regulation of these processes by microRNAs (miRNAs) is only just beginning to be appreciated. This Review focuses on the miRNAs that are potential regulators of the expression of genes whose protein products either directly regulate metabolic machinery or serve as master regulators, indirectly modulating the expression of metabolic enzymes. We focus particularly on miRNAs in pancreatic cancer. PMID- 22508161 TI - Virus-drug interactions--molecular insight into immunosuppression and HCV. AB - Liver transplantation is an effective treatment for end-stage liver disease that is attributable to chronic HCV infection. However, long-term outcomes are compromised by universal virological recurrence in the graft. Reinfection that occurs after transplantation has increased resistance to current interferon-based antiviral therapy and often leads to accelerated development of cirrhosis. Important risk factors for severe HCV recurrence are linked to immunosuppression. Owing to the lack of good randomized, controlled trials, the optimal choice of immunosuppressants is still debated. By contrast, much progress has been made in the understanding of HCV biology and the antiviral action of interferons. These new insights have greatly expanded our knowledge of the molecular interplay between HCV and immunosuppressive drugs. In this article, we explore the effect of different immunosuppressants on the complex cellular events involved in HCV infection and interferon signalling. Potential implications for clinical practice and future drug development are discussed. PMID- 22508165 TI - Conduit diameter and wall remodeling in elite athletes and spinal cord injury. AB - PURPOSE: This study aimed to investigate localized and systemic effects of chronic exercise and inactivity on conduit artery remodeling in humans. METHODS: We recruited elite athletes engaged in predominantly lower limb (LL runners/cyclists, n = 10) or upper limb (UL canoe paddlers, n = 12) exercise and matched able-bodied, recreationally active, controls (C, n = 16). We also studied wheelchair controls (spinal cord injury, n = 9) and athletes (spinal cord injury, n = 1; spina bifida, n = 4). Carotid, brachial, and superficial femoral (SF) artery diameter and wall thickness were assessed using high-resolution ultrasound. RESULTS: Brachial diameters were significantly larger in UL and wheelchair users (athletes and controls) compared with C (both P < 0.05). SF artery diameter in wheelchair controls was significantly smaller compared with the other groups, with LL athletes having significantly greater lumen diameter than controls (both P < 0.05). In all arteries, a lower wall thickness was found in able-bodied athletes compared with C, including wheelchair athletes compared with wheelchair controls (P < 0.001). In the SF artery, wall-to-lumen-ratio was significantly lower in able-bodied athletes and higher in wheelchair controls compared with able-bodied controls (P < 0.001). In the brachial and carotid arteries, able-bodied and wheelchair athletes demonstrated lower wall-to-lumen ratio than less active wheelchair controls and able-bodied controls (P < 0.001). CONCLUSIONS: These findings suggest that remodeling of the arterial wall occurs systemically in response to exercise training and is unrelated to exercise type in humans. Conversely, localized effects are evident with respect to the effect of exercise on arterial diameter. These findings have implications for our understanding of the effects of exercise on arterial structure and function in humans. PMID- 22508168 TI - Two-year course of subfoveal pigment epithelial detachment in eyes with age related macular degeneration and visual acuity better than 20/40. AB - PURPOSE: To investigate the course of subfoveal pigment epithelial detachments (PEDs) in eyes with age-related macular degeneration (AMD) and best-corrected visual acuity (BCVA) >=20/40. METHODS: Thirty-seven eyes of 35 patients with a subfoveal PED were divided into an avascular PED group (n = 11), a vascularized PED group due to polypoidal choroidal vasculopathy (PCV, n = 14) and an occult choroidal neovascularization (CNV) group (n = 12). Intravitreal bevacizumab or ranibizumab was given as needed. The BCVA, central foveal thickness, PED thickness, and lesion size were measured at baseline and at 2 years after the initial examination. RESULTS: The BCVA did not change significantly in the avascular group, decreased from 0.06 +/- 0.11 to 0.23 +/- 0.15 logMAR units in the PCV group and from 0.12 +/- 0.12 to 0.71 +/- 0.70 logMAR units in the CNV group. At 2 years, the central foveal and PED thicknesses were not significantly different among the 3 groups, and the lesion was significantly larger in the PCV and CNV groups than in the avascular group. CONCLUSIONS: The vascularized PED cases had a poorer visual outcome than avascular PEDs with anti-VEGF drugs at the 2-year follow-up. PMID- 22508169 TI - Is isoniazid for 6 months more cost-effective than isoniazid for 9 months? AB - SETTING: The optimal treatment for latent tuberculosis infection consists of isoniazid (H, INH) for 9-12 months. Although INH for 6 months (6H) is more cost effective than the 12-month regimen, the cost-effectiveness of the 6H regimen and that of INH for 9 months (9H) have not been compared. OBJECTIVE: To compare the cost-effectiveness of treatment with 6H and 9H. METHODS: Cost-effectiveness was evaluated using the ratio of the cost of preventing one tuberculosis case using 6H vs. 9H. The cost was estimated as the product of the number of patients to be treated to prevent one case using 6H or 9H * the cost of 6H or 9H. RESULTS: A total of 1039 patients were studied. The number of patients that needed to be treated to prevent one case was 33 (95%CI 21-83) using 6H and 26 (95%CI 18-50) using 9H. The cost of 6H and 9H was respectively ?444.34 and ?578.26, and the cost ratio of preventing one case with 6H/9H was 0.98 (95%CI 0.6-1.5). CONCLUSIONS: The cost-effectiveness of treatment with 6H and 9H is similar. PMID- 22508170 TI - Bilateral cingulotomy and anterior capsulotomy applied to patients with aggressiveness. AB - OBJECTIVE: To perform a preliminary study on the effects and safety of bilateral cingulotomy and anterior capsulotomy in patients with aggressive behavior. PATIENTS AND METHODS: Twenty-three psychiatric patients showing aggressive behavior refractory to conventional treatment were initially evaluated. The subjects were clinically selected using the Overt Aggression Scale (OAS) and the Global Assessment of Functioning Scale (GAF). Each case was carefully reviewed by the Ethics Committee of Mexico's General Hospital. Once selection criteria were met, stereotactic lesions were made using radiofrequency on the anterior limb of the internal capsule and supragenual cingulum. Statistical differences were evaluated with a Wilcoxon test at 6 months and at 4 years. RESULTS: Ten patients underwent surgery. Their OAS and GAF scores decreased after the procedure at the 6-month (p < 0.05) and at the 4-year (p = 0.068) follow-up. Four patients showed mild and transitory postsurgical complications (hyperphagia and somnolence). CONCLUSIONS: Bilateral anterior capsulotomy in combination with cingulotomy may reduce aggressive behavior and improve clinical evaluations. Very strict clinical and ethical evaluations were applied prior to considering patients for this treatment. PMID- 22508174 TI - Pharmacokinetic equivalence of Taxotere and SID530, a novel docetaxel formulation containing hydroxypropyl-beta-cyclodextrin in monkeys. AB - SID530 is a new parenteral formulation of docetaxel containing hydroxypropyl-beta cyclodextrin (HP-beta-CD). In this study, a comparative pharmacokinetic study of 2 docetaxel parenteral solutions, SID530 and Taxotere, was carried out. In a crossover experimental design, 6 male cynomolgus monkeys received each formulation by intravenous infusion of a single dose. The concentration of docetaxel in whole blood and plasma was determined using liquid chromatography tandem mass spectrometry (LC-MS/MS). The 2 formulations showed similar pharmacokinetic parameters in both whole blood and plasma, and displayed comparable values for maximum serum concentration (Cmax), time to peak concentration (Tmax), and area under the concentration-time curve (AUC). The 90% confidence intervals for the ratios of Cmax and AUC values for SID530 to Taxotere were within the acceptable range of 0.80-1.20 in both plasma and whole blood. These findings indicate that SID530 and Taxotere are comparable in terms of their distribution in the blood and their plasma profile; consequently, these drugs are bioequivalent in the monkey. PMID- 22508175 TI - Intersex effect of lamotrigine on the pharmacokinetic parameters of CDRI-97/78, a novel trioxane antimalarial compound, in rats. AB - Reports regarding drug toxicity and adverse events resulting from coadministration of multiple drugs are increasing at an alarming rate. CDRI-97/78 is an 1,2,4-trioxane antimalarial agent under development which gets metabolized to the in vivo active metabolite 97/63. In order to assess its drug interaction potential, CDRI-97/78 was administered alone and in combination with lamotrigine to male and female rats via the oral route. Quantification of the active metabolite 97/63 in rat plasma was achieved with an LC-MS/MS assay. After oral administration of 97/78, the Tmax and Cmax values of 97/63 in male rats were 1.75+/-0.77 h and 862+/-306 ng/mL while female rats showed values for Cmax of 622.75+/-95.09 ng/mL and for Tmax of 7.5+/-0.5 h. Coadministration of 97/78 and lamotrigine resulted in decreased Tmax and Cmax values in both male and female rats (Tmax and Cmax of 0.77+/-0.16 h and 58.58+/-6.43 ng/mL in male rats; 1.13+/ 0.22 h and 62.95+/-12.00 ng/mL in female rats, respectively). A statistically significant difference (P<0.05) was observed for the pharmacokinetic parameters of 97/63 after oral administration of 97/78 alone and upon its coadministration with lamotrigine except for the Cmax and Tmax values in male and for the T1/2 value in female rats. Statistically, no significant difference for the pharmacokinetic parameters of 97/63 between male and female rats after oral administration of 97/78 alone or in combination with lamotrigine was determined except for Tmax. The study indicates that coadministration of 97/78, an antimalarial agent, and the antiepileptic lamotrigine may require dose adjustments. Additional clinical drug interaction trials may be required to confirm these findings. PMID- 22508176 TI - Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. AB - Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disorder, is caused by mutations in PKD1 or PKD2. The molecular diagnosis of ADPKD is complicated by extensive allelic heterogeneity and particularly by the presence of six highly homologous sequences of PKD1 exons 1-33. Here, we screened PKD1 and PKD2 for both conventional mutations and gross genomic rearrangements in up to 700 unrelated ADPKD patients--the largest patient cohort to date--by means of direct sequencing, followed by quantitative fluorescent multiplex polymerase chain reaction or array-comparative genomic hybridization. This resulted in the identification of the largest number of new pathogenic mutations (n = 351) in a single publication, expanded the spectrum of known ADPKD pathogenic mutations by 41.8% for PKD1 and by 23.8% for PKD2, and provided new insights into several issues, such as the population-dependent distribution of recurrent mutations compared with founder mutations and the relative paucity of pathogenic missense mutations in the PKD2 gene. Our study, together with others, highlights the importance of developing novel approaches for both mutation detection and functional validation of nondefinite pathogenic mutations to increase the diagnostic value of molecular testing for ADPKD. PMID- 22508177 TI - Absence of clinically relevant growth acceleration in untreated children with non classical congenital adrenal hyperplasia. AB - BACKGROUND/AIMS: In classical congenital adrenal hyperplasia (CAH), elevation of adrenal androgens leads to accelerated growth and bone maturation with compromised adult height. In untreated children with non-classical CAH (NC-CAH), in which adrenal androgens are generally only slightly increased, growth velocity may not be significantly elevated. METHODS: Twenty-four patients were included and divided into a symptomatic and an asymptomatic group. Height was expressed as height standard deviation scores (HSDS) and corrected for target height (HSDS THSDS). Bone maturation was expressed as bone age acceleration (BA(c) = bone age calendar age). Linear mixed models with random factor patient were used for the analysis of growth and bone age. RESULTS: In symptomatic patients (n = 17), HSDS THSDS only slightly increased by 0.06 SDS per year (95% CI 0.02-0.10). Mean BA(c) was 2.21 years (SDS 0.66, p < 0.0001). In asymptomatic patients (n = 7), no significant growth acceleration or BA(c) was found. CONCLUSIONS: In untreated NC CAH children, growth acceleration is small and generally not visible on their growth charts. BA(c) is more pronounced. Therefore, the absence of an increase in growth velocity does not exclude the diagnosis of NC-CAH. When considering this diagnosis, bone age acceleration should also be taken into account. PMID- 22508178 TI - Energetics of thermoregulation by an industrious endotherm. AB - OBJECTIVES: Thermoregulation by modern industrial humans is unique among endothermic animals, in that it is largely accomplished by controlling the temperature of our external environment. The objective of this study was to view the relationship between thermoregulatory energy use and environmental temperature in modern humans from the perspective of comparative physiology. METHODS: Monthly residential energy use estimates from the US Energy Information Administration were divided by the annual number of American households from the US Census Bureau, giving average monthly energy consumption per American household for the years 2006 through 2010. Monthly energy consumption was then plotted against average monthly temperature across the United States from the National Climatic Data Center. RESULTS: The resulting graph bore a striking resemblance to a classic Scholander-Irving curve, exhibiting clear upper (22 degrees C) and lower (15 degrees C) critical temperatures, and an increase in energy use as temperatures extend above (90 W degrees C(-1) increase) or below (244 W degrees C(-1) decrease) those critical temperatures. Allometric equations from comparative physiology indicate that the energetic costs of our current thermoregulatory habits are ~30 to 50 times those predicted for an endotherm of our size. CONCLUSIONS: Modern humans have redefined what it means to be a homeothermic endotherm, using large quantities of extrametabolic energy to regulate the temperature of our surroundings. Despite this sophistication, the signal of our individual physiology is readily discernible in national data on energy consumption. PMID- 22508180 TI - The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. AB - Despite improvements in outcomes of renal transplantation, kidney allograft loss remains substantial, and is associated with increased morbidity, mortality and costs. Identifying the pathologic pathways responsible for allograft loss, and the attendant development of therapeutic interventions, will be one of the guiding future objectives of transplant medicine. One of the most important advances of the past decade has been the demonstration of the destructive power of anti-HLA alloantibodies and their association with antibody-mediated rejection (ABMR). Compelling evidence exists to show that donor-specific anti-HLA antibodies (DSAs) are largely responsible for the chronic deterioration of allografts, a condition previously attributed to calcineurin inhibitor toxicity and chronic allograft nephropathy. The emergence of sensitive techniques to detect DSAs, together with advances in the assessment of graft pathology, have expanded the spectrum of what constitutes ABMR. Today, subtler forms of rejection -such as indolent ABMR, C4d-negative ABMR, and transplant arteriopathy--are seen in which DSAs exert a marked pathological effect. In addition, arteriosclerosis, previously thought to be a bystander lesion related to the vicissitudes of aging, is accelerated in ABMR. Advances in our understanding of the pathological significance of DSAs and ABMR show their primacy in the mediation of chronic allograft destruction. Therapies aimed at B cells, plasma cells and antibodies will be important therapeutic options to improve the length and quality of kidney allograft survival. PMID- 22508186 TI - Effects of Aspergillus spp. exogenous fibrolytic enzymes on in vitro fermentation of tropical forages. AB - BACKGROUND: Cellulose and hemicellulose are quantitatively the most important structural carbohydrates present in ruminant diets. Rumen micro-organisms produce enzymes that catalyse their hydrolysis, but the complex network formed by structural carbohydrates and lignin reduces their digestibility and restricts efficient utilisation of feeds by ruminants. This study aimed to produce two enzymatic extracts, apply them in ruminant diets to determine the best levels for ruminal digestibility and evaluate their effects on in vitro digestibility. RESULTS: In experiment 1 a two-stage in vitro technique was used to examine the effects of different enzymatic levels of Aspergillus japonicus and Aspergillus terricola on tropical forages. Enzyme addition had minor effects on corn silage at the highest enzymatic level. In experiment 2 an in vitro gas production (GP) technique was applied to determine apparent in vitro organic matter digestibility and metabolisable energy. The addition of enzymes in GP showed interesting results. Good data were obtained using sugar cane and Tifton-85 hay supplemented with extracts of A. japonicus and A. terricola respectively. CONCLUSION: Overall, the study suggests that addition of crude extracts containing exogenous fibrolytic enzymes to ruminant diets enhances the effective utilisation of ruminant feedstuffs such as forages. PMID- 22508185 TI - Marrow fat and preadipocyte factor-1 levels decrease with recovery in women with anorexia nervosa. AB - Women with anorexia nervosa (AN) have elevated marrow fat mass despite low visceral and subcutaneous fat depots, which is inversely associated with bone mineral density (BMD). Whether marrow fat mass remains persistently elevated or decreases with recovery from AN is currently unknown. In this study, we investigated changes in marrow fat in women who have recovered from AN (AN-R). We also studied the relationship between preadipocyte factor (Pref)-1-a member of the EGF-like family of proteins and regulator of adipocyte and osteoblast differentiation-and fat depots and BMD in AN-R compared with women with AN and healthy controls (HC). We studied 29 women: 14 with active or recovered AN (30.7 + 2.2 years [mean +/- SEM]) and 15 normal-weight controls (27.8 +/- 1.2 years). We measured marrow adipose tissue (MAT) of the L4 vertebra and femur by (1) H magnetic resonance spectroscopy; BMD of the spine, hip, and total body by DXA; and serum Pref-1 and leptin levels. We found that MAT of the L4 vertebra was significantly lower in AN-R compared with AN (p = 0.03) and was comparable to levels in HC. Pref-1 levels were also significantly lower in AN-R compared with AN (p = 0.02) and comparable to levels in healthy controls. Although Pref-1 was positively associated with MAT of the L4 vertebra in AN (R = 0.94; p = 0.002), we found that it was inversely associated with MAT of the L4 vertebra in HC (R = 0.71; p = 0.004). Therefore, we have shown that MAT and Pref-1 levels decrease with recovery from AN. Our data suggest that Pref-1 may have differential effects in states of nutritional deprivation compared with nutritional sufficiency. PMID- 22508187 TI - On optimal gene-based analysis of genome scans. AB - Univariate analysis of markers has modest power when there are multiple causal variants within a gene. Under this scenario, combining the effects of all variants from a gene in a gene-wide statistic is thought to increase power. However, it is not really clear (1) what is the performance of most commonly used gene-wide methods for whole genome scans and (2) how scalable these methods are for more computationally intensive analyses, e.g. analysis of genome-wide sequence data. We attempt to answer these questions by using realistic simulations to assess the performance of a range of gene-based methods: (1) commonly used, e.g. VEGAS and GATES; (2) less commonly used, e.g. Simes, adaptive sum (aSUM), and kernel methods; and (3) a combination of univariate and multivariate tests we proposed for the analysis of markers in linkage disequilibrium. Simes is the fastest method and has good power for single causal variant models. aSUM method has good power for multiple causal variant models, especially at lower gene lengths. Our proposed statistic yields good power for all causal models. Given the extreme data volumes coming from sequencing studies, we recommend a two step analysis of genome scans. The initial step uses the very fast Simes procedure to flag possibly interesting genes. The second step refines interesting signals by using more computationally intensive methods, e.g. (1) aSUM for shorter and (2) VEGAS for larger gene lengths. Alternatively, genome scans can be analyzed using only our proposed method while sacrificing only a modest amount of power. PMID- 22508181 TI - Management of polyomavirus-associated nephropathy in renal transplant recipients. AB - Polyomavirus-associated nephropathy (PVAN) remains an important infectious complication after renal transplantation, affecting 1-10% of recipients and causing graft loss in approximately 50% of cases. With the lack of effective antiviral therapy, intensive monitoring for BK virus (BKV) using nucleic acid testing or urine cytology--in combination with a reduction of immunosuppressive therapy--is advocated to detect and prevent BKV reactivation and PVAN, respectively. In this Review, new insights into BKV biology and the development of PVAN are discussed. Clinical diagnostic approaches for the detection, surveillance and therapeutic monitoring of BKV are described. In addition, various strategies for reduction of immunosuppressive therapy are reviewed and an evaluation provided of the mechanisms of action and clinical effects of currently used adjuvant medication such as cidofovir, leflunomide, intravenous immunoglobulins and fluoroquinolone antibiotics. Finally, novel compounds and their in vitro actions against BKV are discussed together with future prospects for specific antiviral drug development. PMID- 22508188 TI - Selectively deposited noble metal nanoparticles on Fe3O4/graphene composites: stable, recyclable, and magnetically separable catalysts. AB - A simple, efficient, and general approach was developed to selectively deposit noble metal (Pt, Pd, or PtPd) nanoparticles 3-5 nm in size on magnetite/graphene composites. The biomolecule L-lysine with two kinds of functional groups (NH(2) and COOH) played the key role of connecter between noble metals and Fe(3)O(4)/graphene composites. These composites were characterized by TEM, XRD, energy-dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy. The results indicated that the noble metals are mostly dispersed on the magnetite surfaces of the composites. The as-obtained composites are ideal recyclable catalysts for liquid-phase reactions owing to their stability and efficient magnetic separation. Among these catalysts, the PtPd-based composites exhibited the highest activity and resistance to poisoning during the catalytic reduction of 4-nitrophenol to 4-aminophenol by NaBH(4). Such hybrid catalysts obtained by this simple, efficient method are expected to find use in industrial applications, where separation and recycling are critically required to reduce cost and waste production. PMID- 22508189 TI - Development of nanoaptamers using a mesoporous silica model labeled with (99m)tc for cancer targeting. AB - The use of mesoporous silica in targeted cancer therapy is increasing daily. The combination of a rigid model of nanoparticles like mesoporous silica and biological compounds with an affinity for oncological diseases is the most promising drug-targeting system nowadays. In this study, we used the mesoporous silica SBA-15 combined with aptamer (functionalized for tumor with MUC1). The results obtained were of interest and showed the formation of the silica mesoporous structure. The impregnation methodology of mesoporous silica with the aptamer was also confirmed. Cytotoxicity results demonstrated that the particle associated with the aptamer has no cytotoxicity. We conclude that although further studies are required, the mesoporous silica nanoparticle model loaded with aptamer is very functional and can be used for other applications, especially in nuclear medicine. PMID- 22508190 TI - Effect of soft tissue thickness over the posterior border of the vertebral body and disc space on cage placement during posterior lumbar interbody fusion: a cadaveric study. AB - In the present study, we investigated whether there is a difference between visual depth (VD) and radiological image depth (RD) of cages (i.e., structural interbody support devices) placed in disc spaces during posterior lumbar interbody fusion and whether soft tissues covering the posterior border of the vertebral body and associated disc space are the cause of any observed differences. Using digital calipers, cages were inserted at a depth of 5 mm from the soft tissues covering the posterior border of the vertebral body and disc space under direct vision; this depth was defined as VD. After insertion, RD was measured in triplicate. The reliability of RD measurements was evaluated using an intraclass coefficient test. To identify the cause of differences between VD and RD, the thicknesses of soft tissues were measured microscopically. A total of 40 lumbar intervertebral disc spaces with cages were evaluated. The mean RD of cages was 3.12 mm, while the mean difference between the VD and RD of cages (DVRD) was 1.91 mm. On histological examination, the mean thickness of the soft tissue was 2.02 mm. Comparative analysis between histological values and DVRD showed no statistical difference (P = 1.14, 1.55, 0.06). There was a significant difference between VD and RD during cage placement, and soft tissue structure appeared to be responsible for the DVRD of inserted cages. Therefore, cages should be inserted deeper to account for differences between visual and radiological image depths. PMID- 22508191 TI - Superior (de)hydrogenation properties of Mg-Ti-Pd trilayer films at room temperature. AB - In this paper, a series of Mg-Ti-Pd trilayer films with various thicknesses of the Ti interlayer were prepared by magnetron sputtering. The trilayer films could be reversibly (de)hydrogenated at room temperature. The relationship between structure and properties of Mg-Ti-Pd trilayer films was comprehensively investigated. Our studies showed that the hydrogen storage properties of Mg-Pd films were significantly improved with the addition of a Ti interlayer. The optimal hydrogenation properties were obtained when the Ti interlayer was 1 nm. The superior hydrogenation properties achieved by introduction of the Ti interlayer could be attributed to several aspects: prevention of Mg-Pd alloying; catalytic dissociation of H(2) molecules and provision of heterogeneous nucleation sites. These results were elucidative for the development of high performance intermetallic hydrogen storage materials and thin film based functional devices. PMID- 22508192 TI - Food allergy guidelines and assessing allergic reaction risks: a regulatory perspective. AB - PURPOSE OF REVIEW: To review information in food allergy guidelines and the literature on assessing and understanding food allergic reaction risks. RECENT FINDINGS: Current food allergy guidelines have focused on tools for better diagnosis of food allergy and treatment of reactions. These guidelines have not addressed the growing body of literature on risk assessment and diagnostic tools being used to assess dose-response relationships in relation to food-allergen exposures. The literature includes substantial data from food-allergen challenges performed in sensitive individuals, and probabilistic modeling of these data may help to elucidate the relationship between allergen dose exposures, including thresholds, and reaction risk in allergic individuals. Understanding this relationship has potential to improve the health-related quality of life of allergic consumers. SUMMARY: Recent findings in the literature have highlighted improved diagnostic tools and other information that can be used to assess risks for allergic reaction to low-dose allergen exposures (thresholds) and reaction severity in food allergic consumers. Recommendations to better define and stratify allergic reaction risks for consumers could be adopted into guidelines for the diagnosis and clinical management of food allergy. PMID- 22508193 TI - Extensively heated milk and egg as oral immunotherapy. AB - PURPOSE OF REVIEW: The introduction of extensively heated milk and egg protein into the diet has been explored in recent years. RECENT FINDINGS: Studies have suggested that a large subset of children who react to unheated milk or egg can tolerate extensively heated forms of these foods. Immunologic changes induced by a diet containing baked milk and egg are similar to changes that have been observed during oral immunotherapy trials. The baked milk and egg diet appears to accelerate the development of regular milk and egg tolerance when compared with strict avoidance. SUMMARY: An oral challenge to extensively heated milk and egg into milk and egg allergic children's diets should be considered when appropriate. Oral food challenges are the most reliable means of establishing a diagnosis and should be undertaken under physician supervision. PMID- 22508194 TI - Speech prosthesis aspiration. PMID- 22508195 TI - Why do people volunteer for community first responder groups? AB - BACKGROUND: There is a growing number of community first responder (CFR) groups in the UK who provide emergency care in their local communities. OBJECTIVE: To understand why people volunteer for, and continue to be active in CFR groups. DESIGN: Qualitative study, using focus groups of CFRs. Five focus groups were conducted, with a total of 35 participants. RESULTS: Ideas of altruism and a sense of community were found to be important to volunteers, though motives were complex and individual. Many volunteers had some sort of prior experience relevant to the CFR role, either as health professionals or first-aiders. CONCLUSION: Though volunteers' motives had some commonalities with the limited literature, there were issues that were unique to the CFR context. The flexibility and autonomy of CFR volunteering was particularly attractive to volunteers. It remains to be seen how sustainable the CFR model is. PMID- 22508196 TI - Capability of identifying red nuclei in different pulse sequences of regular 1.5 tesla magnetic resonance images. AB - OBJECTIVE: To investigate the optimal pulse sequences of commonly used 1.5-tesla MRI for identifying the red nucleus (RN) to aid targeting of the subthalamic nucleus (STN). METHODS: Forty-six healthy adults were enrolled for this prospective study. All subjects underwent MR studies of 5 sequences: diffusion weighted imaging (DWI), T(1)-weighted fluid-attenuated inversion recovery (T1IR), fast spin echo T(2)-weighted imaging (FSE-T2WI), T(2)-weighted fluid-attenuated inversion recovery (T2FLAIR) and T(2)*-weighted gradient-echo (T2*-GRE) sequences. The clearness of the RN contour was analyzed. RESULTS: Overall, the RN was identified in 98% subjects without gender and age differences. The RN was demarcated on a 5-mm slice relatively better in T2FLAIR (93.5%), followed by FSE T2WI (78.3%), T2*-GRE (65.2%) and DWI (43.5%) sequences, but was completely invisible on the T1IR image. Generally, the signal intensity in all MR sequences decreased mildly on 2-mm slices with a similar identifying power. The detecting power on 5-mm slices was in favor of T2FLAIR with 94% sensitivity, 10% specificity, and 1.89 odds ratio compared to FSE-T2WI. In addition, the scanning time of T2FLAIR was longer in comparison to the FSE-T2WI study. CONCLUSION: T2FLAIR is an alternative to FSE-T2WI that can readily demarcate the RN to help target the STN. PMID- 22508198 TI - Alternative procedure to allow continuation of dapsone therapy despite serious adverse reaction in a case of dapsone-sensitive erythema elevatum diutinum. AB - Dapsone has potent anti-inflammatory effects and remains an effective therapy in a variety of skin disorders: cutaneous vasculitis, neutrophilic dermatoses and blistering disorders. However it may cause a severe idiosyncratic reaction compatible with drug-induced DRESS (drug reaction with eosinophilia and systemic symptoms) leading to the discontinuation of the treatment despite its effectiveness. We report a 68-year-old woman who was successfully treated with dapsone for erythema elevatum diutinum. However she developed a hypersensitivity syndrome compatible with DRESS with fever, skin rash and acute hepatitis confirmed in vitro by the presence of circulating dapsone- specific T cells. Dapsone therapy was suspended, leading to a relapse of erythema elevatum diutinum. While alternative therapies were totally ineffective in our patient to improve her skin condition, we proposed a tolerance induction protocol to dapsone with excellent results. PMID- 22508199 TI - Journey forward. PMID- 22508197 TI - Molecular strain typing of Mycobacterium tuberculosis complex in Bamako, Mali. AB - OBJECTIVE: To identify strains of Mycobacterium tuberculosis complex (MTC) circulating in Bamako and to examine the relationship between the strains and their drug susceptibility profiles. METHODS: Between 2006 and 2010, we conducted a cross-sectional study using spoligotyping to identify strains of MTC recovered from 126 tuberculosis (TB) patients under treatment in Bamako, Mali. RESULT: Three members of the MTC were isolated: M. tuberculosis (71.4%), M. africanum (27.8%) and M. bovis (0.8%). Of these, three strains were found to be the most prevalent: M. tuberculosis T1 (MTB T1; 38.9%), M. africanum F2 (MAF2; 26.2%) and M. tuberculosis Latin American and Mediterranean 10 (MTB LAM 10; 10.3%). MAF2 and MTB LAM 10 strains have a lower risk of multidrug resistance (MDR) than MTB T1 (respectively OR 0.1, 95%CI 0.03-0.4 and OR 0.1, 95%CI 0.01-0.8). Age >= 32 years (OR 1.4, 95%CI 0.4-3.9), negative human immunodeficiency virus status (OR 0.4, 95%CI 0.1-2.5) and male sex (OR 4, 95%CI 0.9-16.5) were not associated with MDR. The prevalence of MDR among treatment and retreatment failure patients was respectively 25% and 81.8% compared to new patients (2.9%). CONCLUSION: This study indicates a low level of primary drug resistance in Bamako, affirms the importance of using correct drug regimens, and suggests that the MTB T1 strain may be associated with the development of resistance. PMID- 22508200 TI - A randomized prospective analysis of alteration of hemostatic function in patients receiving tranexamic acid and hydroxyethyl starch (130/0.4) undergoing off pump coronary artery bypass surgery. AB - Postoperative hemorrhagic complications is still one of the major problems in cardiac surgeries. It may be caused by surgical issues, coagulopathy caused by the side effects of the intravenous fluids administered to produce plasma volume expansion such as hydroxyl ethyl starch (HES). In order to thwart this hemorrhagic issue, few agents are available. Fibrinolytic inhibitors like tranexamic acid (TA) may be effective modes to promote blood conservation; but the possible complications of thrombosis of coronary artery graft, precludes their generous use in coronary artery bypass graft surgery. The issue is a balance between agents that promote coagulation and those which oppose it. Therefore, in this study we have assessed the effects of concomitant use of HES and TA. Thromboelastogram (TEG) was used to assess the effect of the combination of HES and TA. With ethical committee approval and patient's consent, 100 consecutive patients were recruited for the study. Surgical and anesthetic techniques were standardized. Patients fulfilling our inclusion criteria were randomly allocated into 4 groups of 25 each. The patients in group A received 20 ml/kg of HES (130/0.4), 10 mg/kg of T.A over 30 minutes followed by infusion of 1 mg/kg/hr over the next 12 hrs. The patients in group B received Ringer's lactate + TA at same dose. The patients in the Group C received 20 ml/kg of HES. Group D patients received RL. Fluid therapy was goal directed. Total blood loss was assessed. Reaction time (r), alpha angle, maximum amplitude (MA) values of TEG were assessed at baseline, 12, 36 hrs. The possible perioperative myocardial infraction (MI) was assessed by electrocardiogram (ECG) and troponin T values at the baseline, postoperative day 1. Duration on ventilator, length of stay (LOS) in the intensive care unit (ICU) were also assessed. The demographical profile was similar among the groups. Use of HES increased blood loss significantly (P < 0.05). Concomitant use of TA reduced blood loss when used along with HES. r value was prolonged at 12 hours in all the groups and alpha angle was reduced at 12 hours in all the groups, where as MA value was reduced at 12 th hour in the HES group compared to the baseline and increased in TA + HES group. These findings were statistically significant. No significant change in Troponin T values/ECG, duration of ventilation and LOS ICU was observed. No adverse events was noticed in any of the four groups. HES (130/0.4) used at a dose of 20 ml/kg seems to produce coagulopathy causing increased blood loss perioperatively. Hemodilution produced by fluid therapy seems to produce Coagulopathy as observed by TEG parameters. Concomitant use of TA with HES appears to reverse these changes without causing any adverse effects in patients undergoing OPCAB surgery. PMID- 22508201 TI - Pre-operative Tei Index does not predict left ventricular function immediately after mitral valve repair. AB - Echocardiographic assessment of systolic left ventricular (LV) function in patients with severe mitral regurgitation (MR) undergoing mitral valve (MV) repair can be challenging because the measurement of ejection fraction (EF) or fractional area change (FAC) in pathological states is of questionable value. The aim of our study was to evaluate the usefulness of the pre-operative Tei Index in predicting left ventricular EF or FAC immediately after MV repair. One hundred and thirty patients undergoing MV repair with sinus rhythm pre- and post operatively were enrolled in this prospective study. Twenty-six patients were excluded due to absence of sinus rhythm post-operatively. Standard transesophageal examination (IE 33, Philips, Netherlands) was performed before and after cardiopulmonary bypass according to the guidelines of the ASE/SCA. FAC was determined in the transgastric midpapillary short-axis view. LV EF was measured in the midesophageal four- and two-chamber view. For calculation of the Tei Index, the deep transgastric and the midesophageal four-chamber view were used. Statistical analysis was performed with SPSS 17.0. values are expressed as mean with standard deviation. LV FAC and EF decreased significantly after MV repair (FAC: 56+/-12% vs. 50+/-14%, P<0.001; EF: 58+/-11 vs. 50+/-12Epsilon P<0.001). The Tei Index decreased from 0.66+/-0.23 before MV repair to 0.41+/ 0.19 afterwards (P<0.001). No relationship between pre-operative Tei Index and post-operative FAC or post-operative EF were found (FAC: r=-0.061, P=0.554; EF: r=-0.29, P=0.771). CONCLUSION: Pre-operative Tei Index is not a good predictor for post-operative FAC and EF in patients undergoing MV repair. PMID- 22508202 TI - Occluding the pulmonary artery to improve detection of patent foramen ovale during ventricular assist device placement. AB - Unrecognized patent foramen ovale (PFO) in patients after left ventricular assist device (VAD) placement could cause significant hypoxemia and paradoxical embolism. We aim to improve the techniques for PFO detection in this patient population before left ventricular device initiation. We evaluated the effects of main pulmonary artery occlusion on patients' hemodynamic and detection of PFO by transesophageal echocardiography (TEE). We compared between the standard and pulmonary artery occlusion technique. Sixty-two patients with ASA physical status class IV were studied. They presented with end-stage heart failure for left VAD placement. All patients received both Valsava maneuver and occlusion of their pulmonary arteries to assess their influence on detection of PFO. Occlusion of the main pulmonary artery consistently increased right atrial to left atrial pressure gradient. The PFO detection rate using TEE was significantly improved from 0% to 10% by this maneuver compared with the Valsava maneuver. Occlusion of the main pulmonary artery is a simple and effective method to improve PFO detection by TEE before left VAD initiation. PMID- 22508203 TI - Intrathecal morphine is superior to intravenous PCA in patients undergoing minimally invasive cardiac surgery. AB - Aim of our study was to evaluate the beneficial effect of low dose intrathecal morphine on postoperative analgesia, over the use of intravenous patient controlled anesthesia (PCA), in patients undergoing fast track anesthesia during minimally invasive cardiac surgical procedures. A randomized controlled trial was undertaken after approval from local ethical committee. Written informed consent was obtained from 61 patients receiving mitral or tricuspid or both surgical valve repair in minimal invasive technique. Patients were assigned randomly to 2 groups. Group 1 received general anesthesia and intravenous patient controlled analgesia (PCA) pump with Piritramide (GA group). Group 2 received a single shot of intrathecal morphine (1.5 MUg/kg body weight) prior to the administration of general anesthesia (ITM group). Site of puncture was confined to lumbar (L1-2 or L2-3) intrathecal space. The amount of intravenous piritramide used in post anesthesia care unit (PACU) and the first postoperative day was defined as primary end point. Secondary end points included: time for tracheal extubation, pain and sedation scores in PACU upto third postoperative day. For statistical analysis Mann-Whitney-U Test and Fishers exact test (SPSS) were used. We found that the demand for intravenous opioids in PACU was significantly reduced in ITM group (P <0.001). Pain scores were significantly decreased in ITM group until second postoperative day (P <0.01). There was no time delay for tracheal extubation in ITM group, and sedation scores did not differ in either group. We conclude that low dose single shot intrathecal morphine provides adequate postoperative analgesia, reduces the intravenous opioid consumption during the early postoperative period and does not defer early extubation. PMID- 22508204 TI - Infusion of low-dose vasopressin improves left ventricular function during separation from cardiopulmonary bypass: a double-blind randomized study. AB - We aimed to investigate whether low-dose vasopressin administered to patients undergoing coronary artery bypass grafting (CABG) surgery with preexisting mild to moderate systolic dysfunction can produce sustained improvement in cardiac function. This double-blind randomized study was conducted in a hospital where a single anesthetic and surgical team performed elective CABG. Twenty patients aged 32-61 years who underwent elective CABG between January 2007 and December 2007 were enrolled in this study. The patients randomly received either vasopressin 0.03 IU/min (Group A) or normal saline (Group B) in equal volume for 60 min after cardiopulmonary bypass (CPB). The cardiac output, cardiac index, stroke volume index, fractional area of contraction and systemic vascular resistance index were significantly higher in Group A than in Group B. Adrenaline (mean dose: 0.06 MUg/kg x min-1) was required in seven patients from Group B but in none of the Group A patients on initial separation from CPB (P< 0.05). Of the 10 patients in Group B, five required phenylepherine to maintain the mean arterial pressure (MAP) >65 mmHg, whereas none of the Group A patients required phenylephrine for MAP regulation (P< 0.05). We conclude that Infusion of low-dose vasopressin for patients with mild to moderate left ventricular systolic dysfunction during separation from CPB is beneficial for the postoperative hemodynamic profile, reduces the catecholamine doses required and improves left ventricular systolic function. PMID- 22508205 TI - Anesthetic implications of total anomalous systemic venous connection to left atrium with left isomerism. AB - Total anomalous systemic venous connection (TASVC) to the left atrium (LA) is a rare congenital anomaly. An 11-year-old girl presented with complaints of palpitations and cyanosis. TASVC with left isomerism and noncompaction of LV was diagnosed after contrast echocardiogram and computed tomography angiogram. The knowledge of anatomy and pathophysiology is essential for the successful management of these cases. Anesthetic concerns in this case were polycythemia, paradoxical embolism and rhythm abnormalities. The patient was successfully operated by rerouting the systemic venous connection to the right atrium. PMID- 22508206 TI - Dilated ascending aorta is associated with the difficulty in correct placement of pulmonary artery catheter. AB - The present case report highlights that a tense mega-sized aortic root and ascending aorta can mechanically resist the passage of fully inflated (1.5 ml air) balloon to wedge-trace position in the pulmonary artery. Any attempt to push the catheter rather predisposed its recoiling and rebutting into the right ventricle and the cardiac arrhythmia. Inflating continuous cardiac output catheter balloon with lesser volume of air (1 ml) is suggested to overcome this problem. PMID- 22508207 TI - Iatrogenic hemorrhage from left umbilical vein after cardiac surgery: an unusual complication. AB - Postoperative bleeding is a concern for all patients undergoing heart surgery, which could be due to surgical causes or coagulation disorder. The patients at risk for coagulopathy include those patients with complex or prolonged procedures, those exposed to preoperative anticoagulants and, to a lesser extent, patients with a preoperatively elevated prothrombin time and activated clotting time. However, intraabdominal bleeding after cardiac surgery is rare (0.3-2%). As the mortality rate of patients exposed to these complications is high (11-59%), timely recognition and prompt management is vital for patient's safety and for avoidance of postoperative complications. Here, we present a case of free intraabdominal hemorrhage as sequelae of pacing wire insertion in open heart surgery and its successful management. PMID- 22508208 TI - Transesophageal echocardiography: instrumentation and system controls. AB - Transesophageal echocardiography (TEE) is a semi-invasive, monitoring and diagnostic tool, which is used in the perioperative management of cardiac surgical and hemodynamically unstable patients. The low degree of invasiveness and the capacity to visualize and assimilate dynamic information that can change the course of the patient management is an important advantage of TEE. Although TEE is reliable, comprehensive, credible, and cost-effective, it must be performed by a trained echocardiographer who understands the indications and the potential complications of the procedure, and has the ability to achieve proper acquisition and interpretation of the echocardiographic data. Adequate knowledge of the physics of ultrasound and the TEE machine controls is imperative to optimize image quality, reduce artifacts, and prevent misinterpretation of diagnosis. Two-dimensional (2D) and Motion (M) mode imaging are used for obtaining anatomical information, while Doppler and Color Flow imaging are used for information on blood flow. 3D technology enables us to view the cardiac structures from different perspectives. Despite the recent advances of 3D TEE, a sharp, optimized 2D image is pivotal for the reconstruction. This article describes the relevant underlying physical principles of ultrasound and focuses on a systematic approach to instrumentation and use of controls in the practical use of transesophageal echocardiography. PMID- 22508209 TI - Trans-esophageal echocardiography: an indispensible guide for transcatheter device closure of ruptured sinus of Valsalva aneurysm. PMID- 22508210 TI - Cardiac computed tomography as a diagnostic tool for coronary artery aneurysm following percutaneous coronary intervention. PMID- 22508211 TI - Anomalous ridge on the left atrial side of the atrial septum. PMID- 22508212 TI - Disappearing ring in chest cavity. PMID- 22508213 TI - Thoracic epidural anesthesia in elderly patients undergoing cardiac surgery for mitral regurgitation feasibility study. PMID- 22508214 TI - Inadvertent placement of left central venous catheter into left internal thoracic vein: a case report. PMID- 22508215 TI - Sinus venosus atrial septal defect in a patient with Pentalogy of Fallot. PMID- 22508216 TI - Hitting back HIT. PMID- 22508217 TI - Perioperative management of pulmonary atresia with intact ventricular septum in a 5-year old. PMID- 22508218 TI - Tracheal injury causing massive air leak during mitral valve replacement surgery. PMID- 22508219 TI - Inflow occlusion on beating heart: how long and how? PMID- 22508220 TI - Identification of ages and determination of paeoniflorin in roots of Paeonia lactiflora Pall. From four producing areas based on growth rings. AB - Growth rings were used to determine the root age of medicinal Paeonia lactiflora from four producing areas, and their corresponding paeoniflorin content were measured based on the identification of ages. Different P. lactiflora root samples of different ages were collected from the four major growing areas in China: Bozhou, Anhui Province; Pan'an, Zhejiang Province; Zhongjiang, Sichuan Province; and Heze, Shandong Province. The relationship between the number of growth rings and age was analyzed using hand sections and paraffin sections. The paeoniflorin content in the roots of different P. lactiflora cultivars from different growing areas was measured using high-performance liquid chromatography (HPLC). The growth rings in the P. lactiflora roots were consistent with the age of the plant from Heze, Zhongjiang, Pan'an, whereas that for the P. lactiflora from Bozhou was one less than the age of the plant. The HPLC results show that the paeoniflorin content was highest in P. lactiflora 'Baihuachuanshaoyao,' followed by 'Baihuahangshaoyao,' 'Honghuachuanshaoyao,' and 'Honghuahangshaoyao,' 'Bozhoushaoyao' had the lowest levels of paeoniflorin. With increasing age, the paeoniflorin in the roots of the different P.lactiflora cultivars slowly declined or remained the same. In summary, the age of the roots of P. lactiflora from different growing areas can be determined using growth rings. The paeoniflorin content in the roots of P. lactiflora is correlated with cultivar and it was slowly declined with increasing age. PMID- 22508221 TI - Stereoselective total synthesis of the acetylenic carotenoids alloxanthin and triophaxanthin. AB - Stereoselective total synthesis of the C(40)-diacetylenic carotenoid alloxanthin (1) and the C(31)-acetylenic apocarotenoid triophaxanthin (2) was accomplished by Wittig condensation of C(10)-dialdehyde 20 or C(16)-keto aldehyde 19, respectively, with C(15)-acetylenic tri-n-butylphosphonium salt 12. PMID- 22508222 TI - DIVERGENOME: a bioinformatics platform to assist population genetics and genetic epidemiology studies. AB - Large-scale genomics initiatives such as the HapMap project and the 1000-genomes rely on powerful bioinformatics support to assist data production and analysis. Contrastingly, few bioinformatics platforms oriented to smaller research groups exist to store, handle, share, and integrate data from different sources, as well as to assist these scientists to perform their analyses efficiently. We developed such a bioinformatics platform, DIVERGENOME, to assist population genetics and genetic epidemiology studies performed by small- to medium-sized research groups. The platform is composed of two integrated components, a relational database (DIVERGENOMEdb), and a set of tools to convert data formats as required by popular software in population genetics and genetic epidemiology (DIVERGENOMEtools). In DIVERGENOMEdb, information on genotypes, polymorphism, laboratory protocols, individuals, populations, and phenotypes is organized in projects. These can be queried according to permissions. Here, we validated DIVERGENOME through a use case regarding the analysis of SLC2A4 genetic diversity in human populations. DIVERGENOME, with its intuitive Web interface and automatic data loading capability, facilitates its use by individuals without bioinformatics background, allowing complex queries to be easily interrogated and straightforward data format conversions (not available in similar platforms). DIVERGENOME is open source, freely available, and can be accessed online (pggenetica.icb.ufmg.br/divergenome) or hosted locally. PMID- 22508226 TI - Epilepsy: MRI follow-up in paediatric convulsive status epilepticus. PMID- 22508227 TI - Stroke: Haemorrhage risk after thrombolysis--the SEDAN score. PMID- 22508229 TI - Parkinson disease: Interactive WalkMate system improves gait and stability in patients with Parkinson disease. PMID- 22508230 TI - Neurodegenerative disease: Modelling connectivity networks of the brain--can neurodegeneration and dementia progression be predicted? PMID- 22508232 TI - Epilepsy: Bidirectional link between epilepsy and psychiatric disorders. PMID- 22508234 TI - Neurodevelopmental disorders: Immature functional networks in Tourette syndrome. PMID- 22508235 TI - Neuro-oncology: Imaging measurements can predict outcome for glioma after radiotherapy. PMID- 22508236 TI - Pains in Parkinson disease--many syndromes under one umbrella. AB - Pain is a nonmotor symptom that substantially affects the quality of life of at least one-third of patients with Parkinson disease (PD). Interestingly, patients with PD frequently report different types of pain, and a successful approach to distinguish between these pains is required so that effective treatment strategies can be established. Differences between these pains are attributable to varying peripheral pain mechanisms, the role of motor symptoms in causing or amplifying pain, and the role of PD pathophysiology in pain processing. In this Review, we propose a four-tier taxonomy to improve classification of pain in PD. This taxonomy assigns nociceptive, neuropathic and miscellaneous pains to distinct categories, as well as further characterization into subcategories. Currently, treatment of pain in PD is based on empirical data only, owing to a lack of controlled studies. The facultative symptom of 'dopaminergically maintained pain' refers to pain that benefits from antiparkinson medication. Here, we also present additional pharmacological and nonpharmacological treatment approaches, which can be targeted to a specific pain following classification using our taxonomy. PMID- 22508240 TI - Leptin and adiponectin: distribution and associations with cardiovascular risk factors in men and women of the general population. AB - OBJECTIVE: In view of the increasing prevalence of obesity worldwide, understanding the role of the recently discovered adipokines leptin and adiponectin is of high clinical relevance. The aim of the present study was to assess the association between levels of leptin and adiponectin with age, known cardiovascular risk factors and to establish whether there are differences between men and women of the general population. METHODS: A total of 98 men and 107 women of the general population, aged between 20 and 74 years, underwent a medical examination at a clinical research center and fasting morning blood samples were also taken. RESULTS: Leptin (mean 7.5 MUg l(-1) in men and 16.0 MUg l(-1) in women) and adiponectin (mean 7.3 mg l(-1) in men and 11.9 mg l(-1) in women) levels were higher in women than men (Ps < 0.001). Both leptin and adiponectin levels increased with advancing age in both men and women (Ps < 0.05). Leptin was highly associated with factors for metabolic syndrome in men while in women, leptin was highly associated with inflammatory factors. Adiponectin was associated with blood lipids in both men and women, and glucose homeostasis more in women than in men. CONCLUSIONS: Leptin and adiponectin levels were ~2 times and 1.5 times higher in women than in men, respectively. In addition, although leptin and adiponectin were associated to CVD risk factors in both men and women, we observed differences in specific CVD risk factor groups between men and women. These differences may be due to different regulatory mechanisms and effects of these adipokines in men and women. PMID- 22508239 TI - Changes in bone biomarker concentrations and musculoskeletal symptoms among breast cancer patients initiating aromatase inhibitor therapy and women without a history of cancer. AB - The objectives of this study were to examine: (1) changes in bone formation (osteocalcin) and bone resorption (cross-linked N-telopeptides of bone type I collagen [NTXs]) markers, as well as calcium, phosphorus, and intact parathyroid hormone, over the first 6 months of aromatase inhibitor (AI) therapy among a cohort of breast cancer patients compared with a group of unexposed women without a history of cancer; and (2) whether bone marker changes were associated with musculoskeletal pain. Eligible breast cancer patients (n = 49) and postmenopausal women without a history of cancer (n = 117) were recruited and followed for 6 months. At baseline, 3 months, and 6 months, a questionnaire was administered to assess pain and medication use, and a blood sample was drawn. Results showed that, among the breast cancer patients, calcium concentrations decreased significantly (-7.8% change; p = 0.013) and concentrations of NTXs increased significantly from baseline to 6 months (9.6% change; p = 0.012). Changes were not observed for women in the comparison group. Statistically significant differences in percent change between the breast cancer patients and the women in the comparison group were observed for calcium at 6 months (-7.8% versus 0.0%; p = 0.025), phosphorus at 6 months (-5.1% versus 16.7%; p = 0.003), NTXs at 6 months (9.6% versus -0.7%; p = 0.017), and osteocalcin at 6 months (11.5% versus 3.6%; p = 0.016). No statistically significant associations were observed between bone turnover marker changes and musculoskeletal pain among the breast cancer patients, although baseline NTXs were higher among women with onset or increase in pain compared with those reporting no pain (p = 0.08). Findings from this study suggest that AIs cause changes in bone turnover during the first 6 months of treatment; however, these changes are not associated with musculoskeletal pain. Breast cancer patients initiating AI therapy should be assessed and monitored for fracture risk using known clinical risk factors, including bone density, and managed appropriately. PMID- 22508241 TI - First-line bevacizumab-containing therapy for triple-negative breast cancer: analysis of 585 patients treated in the ATHENA study. AB - BACKGROUND: The prognosis for patients with triple-negative breast cancer (TNBC) is poor and treatment options are limited. Bevacizumab improves the efficacy of standard first-line therapy in locally recurrent/metastatic breast cancer (LR/mBC). The benefit of bevacizumab seen in patients with TNBC appears similar to that observed in the overall population. We conducted an exploratory analysis of patients with TNBC treated in the single-arm routine oncology practice ATHENA study. METHODS: Patients with previously untreated LR/mBC received standard first line chemotherapy combined with bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks, until progression, unacceptable toxicity, or patient/physician decision). RESULTS: Of 2,264 patients treated in ATHENA, 585 (26%) had TNBC. Most patients received single-agent taxane with bevacizumab. In the TNBC subgroup, the overall response rate was 49%, including complete responses in 10%; only 16% had primary resistant disease. Median time to progression was 7.2 months (95% CI 6.6 7.8) and median overall survival was 18.3 months (95% CI 16.4-19.7). The 1-year overall survival rate was 60%. The safety profile in TNBC was consistent with results in the overall population. CONCLUSION: This exploratory subgroup analysis suggests that first-line chemotherapy in combination with bevacizumab is an active regimen in patients with metastatic TNBC. PMID- 22508244 TI - Controlled orientation in a bio-inspired assembly of Ag/AgCl/ZnO nanostructures enables enhancement in visible-light-induced photocatalytic performance. AB - In a bio-inspired approach, polyamine-mediated mineralization of ZnO was explored to develop an environmentally benign methodology for synthesizing Ag/AgCl/ZnO nanostructures. The assembling properties displayed by the polyamines to create composite structures was utilized to have the nanocomponents effectively interact with each other in a way that is desirable for the application envisaged. The polyamines, which act as a mineralizing agent for ZnO nanoparticles, also facilitate the formation of Ag/AgCl within ZnO under ambient conditions. Thus synthesized Ag/AgCl/ZnO nanostructures represent a multi-heterojunction system in which the nanocomponents lead in a synergistic way to enhancement in the photocatalytic activity under visible-light irradiation. PMID- 22508245 TI - Electrophilic attack on trinuclear titanium imido-nitrido systems. AB - Alkylation of [{Ti(eta(5)-C(5)Me(5))(MU-NH)}(3)(MU(3)-N)] with MeOTf occurs at the imido ligands to produce the methylamido derivative [Ti(3)(eta(5) C(5)Me(5))(3)(MU(3)-N)(MU-NH)(2)(MU-NHMe)(OTf)] which readily rearranges to form the methylimido complex [Ti(3)(eta(5)-C(5)Me(5))(3)(MU(3)-N)(MU-NH)(MU-NH(2))(MU NMe)(OTf)]. PMID- 22508243 TI - Synergistic interaction of dietary cholesterol and dietary fat in inducing experimental steatohepatitis. AB - The majority of patients with nonalcoholic fatty liver disease (NAFLD) have "simple steatosis," which is defined by hepatic steatosis in the absence of substantial inflammation or fibrosis and is considered to be benign. However, 10% 30% of patients with NAFLD progress to fibrosing nonalcoholic steatohepatitis (NASH), which is characterized by varying degrees of hepatic inflammation and fibrosis, in addition to hepatic steatosis, and can lead to cirrhosis. The cause(s) of progression to fibrosing steatohepatitis are unclear. We aimed to test the relative contributions of dietary fat and dietary cholesterol and their interaction on the development of NASH. We assigned C57BL/6J mice to four diets for 30 weeks: control (4% fat and 0% cholesterol); high cholesterol (HC; 4% fat and 1% cholesterol); high fat (HF; 15% fat and 0% cholesterol); and high fat, high cholesterol (HFHC; 15% fat and 1% cholesterol). The HF and HC diets led to increased hepatic fat deposition with little inflammation and no fibrosis (i.e., simple hepatic steatosis). However, the HFHC diet led to significantly more profound hepatic steatosis, substantial inflammation, and perisinusoidal fibrosis (i.e., steatohepatitis), associated with adipose tissue inflammation and a reduction in plasma adiponectin levels. In addition, the HFHC diet led to other features of human NASH, including hypercholesterolemia and obesity. Hepatic and metabolic effects induced by dietary fat and cholesterol together were more than twice as great as the sum of the separate effects of each dietary component alone, demonstrating significant positive interaction. CONCLUSION: Dietary fat and dietary cholesterol interact synergistically to induce the metabolic and hepatic features of NASH, whereas neither factor alone is sufficient to cause NASH in mice. PMID- 22508246 TI - Sexuality after treatment of head and neck cancer: findings based on modification of sexual adjustment questionnaire. AB - OBJECTIVES/HYPOTHESIS: Evaluate sexual dysfunction in patients after treatment for head and neck cancer. STUDY DESIGN: Single-institution cross-sectional study. METHODS: Our modified Sexual Adjustment Questionnaire was administered to 42 patients (mean age, 55.1 years) and included seven questions (total score, 7-35). Based on sexual satisfaction ratings, we categorized three groups as unsatisfied (7-16), satisfied (17-25), and very satisfied (26-35). Clinical information was obtained by reviewing medical records. Bivariate analysis tested associations between sexual satisfaction and patient-related factors (e.g., sex, age, site/cancer stage, treatment, time between treatment and survey, partner, alcohol/tobacco consumption). Pearson correlation was used to analyze two continuous variables, and multivariate logistic regression analysis was used to evaluate the independent impact of each factor. RESULTS: All 42 patients rated that head and neck cancer negatively impacted their sexual relationships, including 21 (50%) rating effects as negative or extremely negative. Men reported higher satisfaction scores with sexual function (mean +/- standard deviation) than women (19.9 +/- 5.0 vs. 16.3 +/- 6.5, respectively; P = .06). Respondents with partners reported higher scores than those without partners (19.9 +/- 5.3 vs. 14.1 +/- 4.4, respectively; P = .01). When the survey was administered (median, 12 months; range, 4-33 months) after the first treatment, mean score was 19; 57% of respondents were sexually satisfied, 31% were unsatisfied, and 12% were very satisfied. Instrument reliability was .82 (Cronbach alpha). CONCLUSIONS: Patients who are male and <= 60 years have a higher probability of sexual satisfaction during recovery. Our sexual dysfunction questionnaire will be administered in further prospective studies in patients with head and neck cancer. PMID- 22508248 TI - Management of articular cartilage defects of the knee. AB - Articular cartilage injuries of the knee present a difficult clinical dilemma and their treatment is controversial. Hyaline articular cartilage is an avascular, low-friction, and wear-resistant weightbearing surface that has limited capacity for self-repair. The optimal treatment for cartilage lesions has yet to be established. Various treatment methods are employed to reestablish a stable cartilage surface, including microfracture, autologous and allograft osteochondral transplantation, autologous chondrocyte implantation, matrix associated chondrocyte implantation, and scaffold-assisted methods. Treatment algorithms help to guide physicians' decision making in the care of these injuries. In this article, results from outcomes studies as well as prospective randomized clinical trials comparing treatment methods are reviewed, and current practice guidelines are summarized. PMID- 22508249 TI - Effect of timing of ACL reconstruction in surgery and development of meniscal and chondral lesions. AB - PURPOSE: To investigate whether a delay in the timing of surgery of > 6 months compared with performing the surgery <= 6 months after the anterior cruciate ligament (ACL) injury leads to an increased risk of injuries or degenerative changes in the ACL-deficient knee. METHODS: Patients who underwent primary ACL reconstruction at an academic tertiary care center, and had preoperative magnetic resonance imaging (MRI) performed within 2 months of the time of the ACL injury were included. The prevalence of degenerative changes at the time of surgery was assessed and related to the timing of ACL surgery, with "early reconstruction" defined as a surgery performed <= 6 months and "delayed reconstruction" defined as surgery performed > 6 months after ACL injury. "New" meniscal tears were defined as lesions detected at the time of surgery that were not detected by MRI. RESULTS: Of 195 patients who were selected based on inclusion criteria, 171 patients underwent surgery <= 6 months after their ACL injury, and 24 patients underwent surgery > 6 months after their ACL injury. The prevalence of new medial meniscal tears in the early reconstruction group was 4.1%, while in the delayed reconstruction group, the prevalence was 16.7% (P = 0.012). CONCLUSION: A delay in the timing of ACL reconstruction from <= 6 months to > 6 months following injury is associated with a significant increase in the prevalence of medial meniscal tears (P = 0.012), with a relative risk of 4.07 (CI, 1.29-12.88). PMID- 22508247 TI - Is body composition associated with an increased risk of developing anterior knee pain in adolescent female athletes? AB - OBJECTIVE: To determine the relationship between relative body composition and body mass to height, anterior knee pain, or patellofemoral pain (PFP) in adolescent female athletes. BACKGROUND: Patellofemoral pain is common in female athletes and has an undefined etiology. The purpose of this study was to examine whether there was an association among higher body mass index (BMI), BMI z scores, and relative body fat percentage in the development of PFP in an adolescent female athlete population. We hypothesized that female athletes who developed PFP over the course of a competitive basketball season had higher relative body mass or body fat percentage compared with those who did not develop PFP. METHODS: Fifteen middle school basketball teams that consisted of 248 basketball players (mean age, 12.76 +/- 1.13 years; height, 158.43 +/- 7.78 cm; body mass, 52.35 +/- 12.31 kg; BMI, 20.73 +/- 3.88 kg/m(2)) agreed to participate in this study over the course of 2 basketball seasons, resulting in 262 athlete seasons. Testing included the completion of the Anterior Knee Pain Scale (AKPS), International Knee Documentation Committee (IKDC) form, standardized history, physician-administered physical examination, maturational estimates, and anthropometrics. RESULTS: Of the 262 athlete-seasons monitored, 39 athletes developed PFP over the course of the study. The incidence rate of new PFP was 1.57 per 1000 athlete-exposures. The cumulative incidence of PFP was 14.9%. There was no difference in BMI between those who developed PFP (mean body mass, 20.2 kg/m(2); 95% CI,18.9-21.4) and those who did not develop PFP (mean body mass, 20.8 kg/m(2); 95% CI, 20.3-21.3;P > 0.05). Body mass index z-scores were not different between those who developed PFP (mean, 0.3; 95% CI, 0.7-0.6) and those who did not develop PFP (mean, 0.4; 95% CI, 0.3-0.6;P > 0.05). A similar trend was noted in relative body fat percentage, with mean scores of similar ranges in those who developed PFP (mean body fat percentage, 22.2%; 95% CI, 19.4-24.9) to the referent group who did not (mean body fat percentage, 22.9%; 95% CI, 21.8 24.1;P > 0.05). CONCLUSIONS: Our results do not indicate a relationship between relative body composition or relative body mass to height to the propensity to develop PFP in middle school-aged female basketball players. Although previous data indicate a relationship between higher relative body mass and overall knee injury, these data did not support this association with PFP specifically. These data suggest the underlying etiology of PFP may be neuromuscular in nature. Further research is needed to understand the predictors, etiology, and ultimate prevention of this condition. PMID- 22508250 TI - Approach to the active patient with chronic anterior knee pain. AB - The diagnosis and management of chronic anterior knee pain in the active individual can be frustrating for both the patient and physician. Pain may be a result of a single traumatic event or, more commonly, repetitive overuse. "Anterior knee pain," "patellofemoral pain syndrome," and "chondromalacia" are terms that are often used interchangeably to describe multiple conditions that occur in the same anatomic region but that can have significantly different etiologies. Potential pain sources include connective or soft tissue irritation, intra-articular cartilage damage, mechanical irritation, nerve-mediated abnormalities, systemic conditions, or psychosocial issues. Patients with anterior knee pain often report pain during weightbearing activities that involve significant knee flexion, such as squatting, running, jumping, and walking up stairs. A detailed history and thorough physical examination can improve the differential diagnosis. Plain radiographs (anteroposterior, anteroposterior flexion, lateral, and axial views) can be ordered in severe or recalcitrant cases. Treatment is typically nonoperative and includes activity modification, nonsteroidal anti-inflammatory drugs, supervised physical therapy, orthotics, and footwear adjustment. Patients should be informed that it may take several months for symptoms to resolve. It is important for patients to be aware of and avoid aggravating activities that can cause symptom recurrence. Patients who are unresponsive to conservative treatment, or those who have an underlying systemic condition, should be referred to an orthopedic surgeon or an appropriate medical specialist. PMID- 22508251 TI - A primer for physical examination of the elbow. AB - The elbow is a complex joint consisting of 3 separate but important articulations: the ulnohumeral, radiohumeral, and proximal radioulnar joints. The elbow assists in positioning the hand in space through 2 important motions, flexion-extension and pronation-supination. Although the elbow is not a weightbearing joint, it is subjected to significant loads, especially in overhead and throwing athletes. An accurate knowledge of the anatomy and physiology of the elbow joint is critical for conducting a focused physical examination and arriving at an accurate diagnosis. The goal of this article is to review general and focused physical examination of the elbow in a systematic manner based on medial, lateral, anterior, and posterior aspects. PMID- 22508252 TI - Simple elbow dislocations: evaluation, management, and outcomes. AB - Elbow dislocations are common athletic injuries and occur during a fall onto an outstretched hand as a combination of axial-compressive and rotational-shear forces are conducted across the elbow joint. Simple dislocations are those that involve purely ligamentous injury, while complex dislocations include periarticular fractures. The initial assessment, radiographic evaluation, and on field treatment of these injuries is discussed. Multiple reduction techniques are described with the patient positioned both supine and prone. Definitive management involves primarily nonoperative treatment with limited immobilization and early active range of motion to minimize joint contracture and hasten return to pre-injury activities. For unstable elbows, surgical treatment is usually appropriate. Operative management may involve exploration, lateral ligament repair or reconstruction, and assessment of the need for medial ligament repair or reconstruction. The role of arthroscopic and arthroscopically assisted surgery for elbow dislocation is evolving. Clinical series have shown that extended periods of immobilization (> 3 weeks) are associated with poor outcomes. Early active range of motion should be initiated as early as possible because late or recurrent instability is uncommon. Contracture is the most common adverse sequela of elbow dislocation. The literature indicates an average of 3 degrees to 8 degrees of extension loss with standard management of simple elbow dislocations. PMID- 22508253 TI - Suprascapular neuropathy: diagnosis and management. AB - Although historically considered a diagnosis of exclusion, suprascapular neuropathy may be more common than once believed, as more recent reports are describing the condition as a cause of substantial pain and weakness in patients with and without concomitant shoulder pathology. The etiology is traction or compression of the suprascapular nerve. This can result from a space-occupying lesion, such as a ganglion cyst, or a traction injury as a result of repetitive overhead activities. More recent studies have cited cases of traction injuries occurring with retraction of a large rotator cuff tear. Atrophy of the infraspinatus and/or supraspinatus rotator cuff muscles with resultant weakness in forward flexion and/or external rotation of the shoulder on physical examination may be demonstrated. Magnetic resonance imaging (MRI) is the preferred modality to assess atrophy of the rotator cuff muscles as well as assess potential causes of suprascapular nerve compression. Electromyography and nerve conduction velocity studies remain the gold standard for confirmation of the diagnosis of suprascapular neuropathy; however, nerve pain may occur even in the setting of a negative electromyography. Initial management is usually nonoperative, consisting of activity modification, physical therapy, and nonsteroidal anti-inflammatory drugs. Surgical intervention is considered for patients with nerve compression by an external source or for symptoms refractory to conservative measures. Decompression of the suprascapular nerve may be accomplished through an open approach, although arthroscopic surgical approaches have become more common in the past several years. PMID- 22508254 TI - Shoulder injuries in the throwing athlete. AB - Shoulder injuries in the throwing athlete are becoming more frequent. Sports specialization at a younger age, playing multiple seasons, increased awareness of injury and injury prevention, advances in diagnosis, and surgical treatment all play a part in the increase in diagnosis of these injuries. Understanding the biomechanics of throwing and pathologies that are encountered in the throwing athlete can aid the clinician in successful diagnosis and nonoperative/operative treatment of the throwing athlete. This article discusses the relevant anatomy, biomechanics, and pathoanatomy of the throwing shoulder. Additionally, understanding the kinetic chain can assist in the nonoperative rehabilitation of the injured shoulder. Surgical reconstruction is indicated when nonoperative efforts have been exhausted and is directed based on the extent of the pathology to the capsuloligamentous structures, labrum, and rotator cuff. PMID- 22508255 TI - A physician's guide to the physical examination of the shoulder. AB - Shoulder pain is the third most frequent musculoskeletal complaint presented to physicians. Often considered a benign entity by patients and even their physicians, shoulder disorders can have a devastating effect on a patient's ability to function, as well as serve as an indicator of poor general health. For these reasons, it is important for the physician to be able to identify the etiology of a patient's shoulder problem(s). However, making a correct diagnosis is often difficult because there can be many causes for a patient's shoulder pain, weakness, or loss of function. Moreover, the shoulder girdle is an intricate group of structures that work together to allow for the largest range of motion in the body. This complexity makes it difficult to diagnose a patient's condition(s) based on history alone. A thorough and well-performed physical examination is the key to making a correct diagnosis and helping to distinguish different etiologies of shoulder dysfunction. In this article, we review relevant shoulder anatomy and biomechanics, and general shoulder examinations with special tests for various shoulder pathologies. We provide an effective and methodical approach to the physical examination of the shoulder. PMID- 22508256 TI - Combined lesions of the glenoid labrum. AB - Advances in shoulder arthroscopy and improved understanding of the pathoanatomy following shoulder instability have led to increased recognition of combined lesions of the glenoid labrum. Although the diagnosis of combined labral tears is often made with physical examination and magnetic resonance imaging, combined tears can be discovered intraoperatively. A high index of suspicion is necessary, especially in the setting of chronic recurrent shoulder instability or previous failed labral repair. Over a 6-year period at a military institution, combined labral repairs comprised 37% of all patients undergoing any labral repair. With accurate identification of all labral pathology and a systematic approach to labral repair, successful outcomes can be achieved. PMID- 22508257 TI - Therapeutic lifestyle changes for cardiovascular disease. AB - Cardiovascular disease, including hypertension, coronary artery disease, and heart failure, is common in the general US population. The mainstay of treatment for this cohort is implementing therapeutic lifestyle changes (TLCs). Therapeutic lifestyle changes include a reduced-sodium diet, the Dietary Approaches to Stop Hypertension (DASH) diet, weight loss, moderation of alcohol consumption, and increased aerobic exercise. It is important to emphasize that exercise should be recommended to all patients, even for those who historically were told not do so, such as those with heart failure. When prescribing harmacotherapy, physical activity should be taken into account. Athletes competing at the top level warrant adherence to the restrictions of the World Anti-Doping Agency. PMID- 22508258 TI - Deep-water running: a practical review of the literature with an emphasis on biomechanics. AB - Deep-water running (DWR) is used as an adjunct to training and conditioning, and as an injury-rehabilitation technique. It is important for the physician or sports medicine practitioner to focus on the underlying physics and biomechanics of running in water in order to better produce the desired physiological, metabolic, and psychological outcomes. Deep-water running maximal heart rate and oxygen consumption values have been consistently shown to be lower than those found during treadmill running. However, recent evidence reveals that there is less of a difference between these maximal values relative to treadmill running and DWR with increased DWR experience. Submaximal values have been shown to be strikingly similar. The skill level of DWR technique, psychological comfort, perception of work, muscular recruitment patterns, and running kinematics are all affected by the physics (ie, temperature, buoyancy, hydrostatic pressure, specific gravity, and drag) of running in water. Therefore, the relationship between the biomechanics and the corollary practical physiological indicators of workload found in DWR must be factored into the appropriate prescription of training and conditioning workloads and rehabilitation protocols. PMID- 22508259 TI - [Presentation of the Salomon-Neumann Medal in 2011]. PMID- 22508260 TI - [Evidence-based policy and sustainable translation of knowledge: a perspective for health promotion in Germany]. AB - This article proposes to shift the focus of our view on evidence-based policy towards a comprehensive "policy orientation". While previous contributions on policy making in public health have already recognised that the evidence-based medicine paradigm is inappropriate for the specificities of the policy context, they still have primarily dealt with evidence of the policy content, i. e. with research to inform policy makers about "what works" in public health (e. g. evidence-based interventions on health determinants). However, they have widely neglected issues pertaining to the policy process, i. e. knowledge concerning "what works" in policy making (e. g. key determinants of policy development and policy implementation in order to build policy capacities and to improve policy outcomes). A broader perspective including the policy process will allow us to contextualise theory and research in a way more appropriate to the process of policy making and will help improve approaches of applied science and knowledge translation in public health. We will illustrate the differences be-tween a content orientation and a policy process orientation in public health by reviewing previous discourses on 3 closely related topics: (1) the production of evidence for policy making, (2) the conditions for the utilisation of evidence in policy making, and (3) the translation of evidence into policy making. We conclude that future public health theory and research, while continuing to broaden the evidence base on health determinants and health interventions, should increasingly focus on research concerning processes of public health policy development and implementation, building frameworks, developing methodologies, and conducting the necessary empirical research. PMID- 22508261 TI - [Prevention at the interface between politics and practice]. AB - Disease prevention and health promotion can be understood as being complementary to each other in the context of stress reduction (disease prevention) and strengthening of resources (health promotion). This implies change. The desired improvement aims at personal behaviour, concomitant resources and conditions and political processes. In line with this aim, there is exchange and transfer at the interfaces science-practice, science-politics and politics-practice, which are often not successful. With reference to results of the working groups on practice transfer and policy transfer of the cooperation for sustainable prevention research, 10 theses are formulated for an effective transfer management. An explicit and explicitly funded transfer research in disease prevention and health promotion is advisable. PMID- 22508262 TI - An elusive goal? Gender equity and gender equality in health policy. AB - Variations in the health of men and women are well known: men have poorer life expectancy than women in virtually every country, and there are differences between women and men in patterns of morbidity across the life course. These variations reflect both biology and gender, and health systems play a part through the services they offer. In recent years a number of national governments and international bodies have paid increasing attention to gender inequalities, and gender mainstreaming has been adopted by as a key policy objective at various levels of governance. While gender mainstreaming has resulted in some successes, analysis of the depth of change suggests a less optimistic view, reflecting the persistence of barriers to gender mainstreaming in health, which include a lack of resources, uncertainty over the goals of gender mainstreaming, and notional rather than genuine adoption of gender mainstreaming principles. Underlying these barriers however, is the use of bureaucratic and systems-based approaches to gender mainstreaming. The failure to challenge underlying gender relations of power allows gender strategies to become technocratic exercises which achieve results in terms of the boxes ticked, but not in relation to what matters: the health and health opportunities of both women and men. PMID- 22508263 TI - Bilateral quadruple renal arteries. AB - Variation in the number of renal arteries (RAs) constitutes the most common and clinically important renal vascular variation. In this study, the authors describe a rare case of a 58-year-old male with eight RAs (bilateral quadruple) as revealed by routine multidetector computed tomography angiography. All the eight RAs originated from the abdominal aorta and penetrated the renal parenchyma at the level of renal sinus. The main RAs had the intraluminal diameter larger than the diameter of the additional renal arteries (AdRAs) at the origin. All the AdRAs had a greater length than the main RAs. These aspects are particularly important in planning microsurgical procedures. PMID- 22508264 TI - Pro-inflammatory cytokines produced by growth plate chondrocytes may act locally to modulate longitudinal bone growth. AB - INTRODUCTION: Interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF alpha), both cytokines upregulated during chronic inflammation, are known to suppress bone growth. So far no role of these cytokines in modulation of normal bone growth has been established. METHODOLOGY: Applying RT-PCR and immunohistochemistry, expression of IL-1beta and TNF-alpha was studied in cultured fetal (E20) rat metatarsal bones. Anakinra (500 MUg/ml; IL-1 receptor antagonist) and/or etanercept (500 MUg/ml; soluble TNF-alpha receptor) were used to block cytokine actions. RESULTS: The local expression of IL-1beta and TNF alpha was confirmed in the rat metatarsal growth plate. When cultured for 12 days and compared to control, the length of bones exposed to anakinra, etanercept, or anakinra plus etanercept increased by 7.7 +/- 2.0 (p < 0.05), 11.7 +/- 2.8 (p < 0.01) and 20.3 +/- 1.9% (p < 0.001), respectively, while the height of the hypertrophic growth plate zone (collagen X staining) increased by 11.0 +/- 6.7, 17.4 +/- 7.1 and 43.1 +/- 5.0% (p < 0.01), respectively. Moreover, etanercept increased chondrocyte proliferation (BrdU incorporation). CONCLUSION: Our findings that IL-1beta and TNF-alpha are produced by growth plate chondrocytes and that their antagonists improve growth of cultured metatarsal bones suggest that these cytokines play a physiological role in the normal regulation of longitudinal bone growth. PMID- 22508265 TI - Cep57, a NEDD1-binding pericentriolar material component, is essential for spindle pole integrity. AB - Formation of a bipolar spindle is indispensable for faithful chromosome segregation and cell division. Spindle integrity is largely dependent on the centrosome and the microtubule network. Centrosome protein Cep57 can bundle microtubules in mammalian cells. Its related protein (Cep57R) in Xenopus was characterized as a stabilization factor for microtubule-kinetochore attachment. Here we show that Cep57 is a pericentriolar material (PCM) component. Its interaction with NEDD1 is necessary for the centrosome localization of Cep57. Depletion of Cep57 leads to unaligned chromosomes and a multipolar spindle, which is induced by PCM fragmentation. In the absence of Cep57, centrosome microtubule array assembly activity is weakened, and the spindle length and microtubule density decrease. As a spindle microtubule-binding protein, Cep57 is also responsible for the proper organization of the spindle microtubule and localization of spindle pole focusing proteins. Collectively, these results suggest that Cep57, as a NEDD1-binding centrosome component, could function as a spindle pole- and microtubule-stabilizing factor for establishing robust spindle architecture. PMID- 22508266 TI - Will the real aging Sirtuin please stand up? AB - Initial studies linking Sirtuins to longevity in yeast initiated what is now a rich vein of aging research that is full of promise and fraught with controversy. Missing was a demonstration that enhanced Sirtuin expression extends lifespan in mammals. Now Kanfi et al. provide the evidence but with an interesting plot twist - the lesser known SIRT6 is the longevity factor. PMID- 22508267 TI - LATERAL ORGAN BOUNDARIES DOMAIN transcription factors direct callus formation in Arabidopsis regeneration. AB - The remarkable regeneration capability of plant tissues or organs under culture conditions has underlain an extensive practice for decades. The initial step in plant in vitro regeneration often involves the induction of a pluripotent cell mass termed callus, which is driven by the phytohormone auxin and occurs via a root development pathway. However, the key molecules governing callus formation remain unknown. Here we demonstrate that Arabidopsis LATERAL ORGAN BOUNDARIES DOMAIN (LBD)/ASYMMETRIC LEAVES2-LIKE (ASL) transcription factors are involved in the control of callus formation program. The four LBD genes downstream of AUXIN RESPONSE FACTORs (ARFs), LBD16, LBD17, LBD18 and LBD29, are rapidly and dramatically induced by callus-inducing medium (CIM) in multiple organs. Ectopic expression of each of the four LBD genes in Arabidopsis is sufficient to trigger spontaneous callus formation without exogenous phytohormones, whereas suppression of LBD function inhibits the callus formation induced by CIM. Moreover, the callus triggered by LBD resembles that induced by CIM by characteristics of ectopically activated root meristem genes and efficient regeneration capacity. These findings define LBD transcription factors as key regulators in the callus induction process, thereby establishing a molecular link between auxin signaling and the plant regeneration program. PMID- 22508268 TI - PKR in DSS-induced colitis: a matter of genetic background and maternal microflora? PMID- 22508269 TI - Pityriasis rubra pilaris: treatment with biologics - a new promising therapy? AB - Pityriasis rubra pilaris (PRP) includes a spectrum of rare chronic inflammatory disorders with papulosquamous eruptions of unknown cause. Different etiologies have been proposed such as vitamin A metabolism dysfunction, association with autoimmune disorders, infection or malignancies. However, PRP seems to be a polygenic skin disorder. Classical systemic treatment is empirical and includes retinoids and methotrexate; however, only few series on treatments exist. Recently there has been an increasing number of reports documenting that new biologicals and in particular TNF-alpha blockers are safe and effective. PMID- 22508270 TI - Self condensation of enamines mediated by acetylation. A novel approach to 1 (azol-5-yl)-(1E,3Z)-butadiene-4-N,N-dimethylamines. AB - Novel self-condensation of 3-(azol-5-yl)-1,1-dimethylenamines has been found to form new C-C bonds leading to 2,4-(1,2,3-triazole-1,2,3-thiadiazole-3 phenylisothiazole)-(1E,3Z)-5-yl-butadiene-1-amines. The discovered reaction represents a new example of C-H functionalization in unsaturated systems and can serve an efficient synthetic approach to rational design of new 2,4-(diazole-5 yl)-dieneamines. PMID- 22508272 TI - Systemically alendronate was incorporated into dental tissues but did not cause morphological or mechanical changes in rats teeth. AB - This study evaluated the effect of the systemic use of sodium alendronate in rats in vivo. Forty-five Wistar rats aged 36 to 42 days and weighing 200 to 230 g were randomly assigned to a control group (n = 20), which received distilled water, and an experimental group (n = 25), which received 2 weekly doses of 1 mg/kg of chemically pure sodium alendronate. The animals were killed after 60 days of treatment. The tibias were removed for analysis of bone mineral density by dual energy X-ray absorptiometry (DXA). Then, the maxillary incisors were extracted for analysis of the mineralized dental tissues using fluorescence spectroscopy (FS), scanning electron microscopy (SEM), bright field microscopy (BFM), and cross-sectional microhardness (CSMH) testing. DXA and CSMH data were subjected to statistical analysis by Kruskal-Wallis test (5% significance level). The experimental group presented higher bone mineral density than the control group by DXA. FS analysis revealed presence of alendronate in the mineralized dental tissues of the specimens of the experimental group. Significant morphological differences were not found by SEM and BFM. Enamel and dentin (100 and 300 MUm from the dentinoenamel junction) CSMH data did not show significant difference between the control and experimental groups. Based on the obtained results, we conclude that while alendronate increased the bone mineral density and was incorporated into the mineralized dental tissues it did not cause significant alterations in the morphology and microhardness of rat incisor enamel and dentin. PMID- 22508271 TI - Fasting glucose GWAS candidate region analysis across ethnic groups in the Multiethnic Study of Atherosclerosis (MESA). AB - Genetic variants associated with fasting glucose in European ancestry populations are increasingly well understood. However, the nature of the associations between these single nucleotide polymorphisms (SNPs) and fasting glucose in other racial and ethnic groups is unclear. We sought to examine regions previously identified to be associated with fasting glucose in Caucasian genome-wide association studies (GWAS) across multiple ethnicities in the Multiethnic Study of Atherosclerosis (MESA). Nondiabetic MESA participants with fasting glucose measured at the baseline exam and with GWAS genotyping were included; 2,349 Caucasians, 664 individuals of Chinese descent, 1,366 African Americans, and 1,171 Hispanics. Genotype data were generated from the Affymetrix 6.0 array and imputation in IMPUTE. Fasting glucose was regressed on SNP dosage data in each ethnic group adjusting for age, gender, MESA study center, and ethnic-specific principal components. SNPs from the three gene regions with the strongest associations to fasting glucose in previous Caucasian GWAS (MTNR1B / GCK / G6PC2) were examined in depth. There was limited power to replicate associations in other ethnic groups due to smaller allele frequencies and limited sample size; SNP associations may also have differed across ethnic groups due to differing linkage disequilibrium patterns with causal variants. rs10830963 in MTNR1B and rs4607517 in GCK demonstrated consistent magnitude and direction of association with fasting glucose across ethnic groups, although the associations were often not nominally significant. In conclusion, certain SNPs in MTNR1B and GCK demonstrate consistent effects across four racial and ethnic groups, narrowing the putative region for these causal variants. PMID- 22508273 TI - Winding up alkynes: a Pd-catalyzed tandem-domino reaction to chiral biphenyls. AB - Wrap it up! An intramolecular Pd-catalyzed tandem-domino process leading to highly sterically encumbered biphenyls is reported. The chirality of the newly formed axis is induced by the configuration of the carbohydrate backbone. PMID- 22508277 TI - Can we define "pre-motor" Parkinson's disease? PMID- 22508278 TI - Lewy pathology and neurodegeneration in premotor Parkinson's disease. AB - The foremost motor manifestations of Parkinson's disease are resting tremor, cogwheel rigidity, hypokinesia/bradykinesia, and postural instability. Epidemiological and clinical data reveal that a wide variety of additional complaints (nonmotor symptoms), also considerably impar patients' quality of life parallel to the chronic-progressive neurodegenerative disorder. This article reviews the neuropathology and anatomy of Lewy pathology-related neurodegeneration in relation to selected nonmotro and prodromal dysfunctions. PMID- 22508279 TI - Premotor Parkinson's disease: concepts and definitions. AB - Parkinson's disease (PD) has a prodromal phase during which nonmotor clinical features as well as physiological abnormalities may be present. These premotor markers could be used to screen for PD before motor abnormalities are present. The technology to identify PD before it reaches symptomatic Braak Stage 3 (substantia nigra compacta [SNc] involvement) already exists. The current challenge is to define the appropriate scope of use of predictive testing for PD. Imaging technologies such as dopamine transporter imaging currently offer the highest degree of accuracy for identifying premotor PD, but they are expensive as screening tools, and abnormalities on these studies would only be evident at Braak Stage 3 or higher. Efficiency is greatly enhanced by combining imaging with a prescreening test such as olfactory testing. This 2-step process has the potential to greatly reduce costs while retaining diagnostic accuracy. Alternatively, or in concert with this approach, evaluating high-risk populations (eg, patients with rapid eye movement behavior disorder or LRRK2 mutations) would enrich the sample for cases with underlying PD. Ultimately, the role of preclinical detection of PD will be determined by the ability of emerging therapies to influence clinical outcomes. As such, implementation of large-scale screening strategies awaits the arrival of clearly safe and effective therapies that address the underlying pathogenesis of PD. Future research will establish more definitive biomarkers capable of revealing the presence of disease in advance of SNc involvement with the promise of the potential for introducing disease-modifying therapy even before the development of evidence of dopamine deficiency. PMID- 22508280 TI - Identifying prodromal Parkinson's disease: pre-motor disorders in Parkinson's disease. AB - Increasing recognition that Parkinson's disease (PD) may start outside of the substantia nigra has led to a rapidly expanding effort to define prodromal stages of PD, before motor signs permit classical diagnosis. Many of these efforts center around the identification of clinical non-motor symptoms and signs of disease. There is now direct evidence that olfaction, rapid eye movement (REM) sleep behavior disorder (RBD), constipation, and depression can be present in prodromal PD. In addition, there is suggestive evidence that visual changes, other autonomic symptoms, and subtle cognitive changes may also be present at prodromal stages. A critical issue in utility of these prodromal markers will be assessment of sensitivity, specificity, and positive and negative predictive values. Although these have yet to be fully defined, olfactory deficits, some visual changes, and autonomic symptoms occur in the majority of PD patients at diagnosis, suggesting good potential sensitivity. However, with the exception of RBD and perhaps some specific autonomic measures, specificity, and positive predictive value of these markers may be insufficient to be used alone as identifiers of prodromal disease. The evidence for the utility of olfaction, RBD, autonomic markers, visual changes, mood disorders, and cognitive loss as markers of prodromal PD and the potential sensitivity and specificity of these markers are summarized. PMID- 22508281 TI - Neuroimaging: current role in detecting pre-motor Parkinson's disease. AB - Convergent evidence suggests a pre-motor period in Parkinson's disease (PD) during which typical motor symptoms have not yet developed although dopaminergic neurons in the substantia nigra have started to degenerate. Advances in different neuroimaging techniques have allowed the detection of functional and structural changes in early PD. This review summarizes the state of the art knowledge concerning structural neuroimaging techniques including magnetic resonance imaging (MRI) and transcranial B-mode-Doppler-sonography (TCS) as well as functional neuroimaging techniques using radiotracer imaging (RTI) with different radioligands in detecting pre-motor PD. PMID- 22508283 TI - Prerequisites to launch neuroprotective trials in Parkinson's disease: an industry perspective. AB - Realizing that 60% to 80% of dopaminergic nigrostriatal neurons are nonfunctional at the time of clinical diagnosis, there is an emerging consensus that disease modifying treatments should be initiated in the earliest stages of Parkinson's disease (PD). To date, clinical trial designs and metrics in PD have been focused on motor symptoms as the core feature of the clinical disease. To identify earlier or "pre-motor" populations in PD, new markers have been proposed. We address the prerequisites needed to use these pre-motor markers in clinical trials for the selection of subjects, definition of populations, and monitoring of disease progression. This may require the development of new diagnostic criteria potentially based on non-motor clinical signs, imaging techniques, or biological features, all requiring discussion in a regulatory framework. Questions addressed include: Which steps must be taken to gain a broad consensus in the field from academic opinion leaders, patient advocacy groups, regulatory bodies, and industry? How do we prevent the selection of subgroups, which may not be representative of the full disease spectrum? Is there a way forward in personalized medicine? How do we balance risk and benefit in an at-risk population? While many tools are available, a concerted effort is required to develop integrated data sets, as well as to achieve the necessary standardization for multicenter clinical trials. To this end, public-private consortia (including academic centers, patient advocacy groups, and industry) will be of crucial importance to prospectively investigate and define the best tools and treatment paradigms. PMID- 22508282 TI - Biochemical premotor biomarkers for Parkinson's disease. AB - A biomarker is a biological characteristic that is objectively measured and evaluated as an indicator of normal biological or pathologic processes or of pharmacologic responses to a therapeutic intervention. We reviewed the current status of target protein biomarkers (eg, total/oligomeric alpha-synuclein and DJ 1) in cerebrospinal fluid, as well as on unbiased processes that can be used to discover novel biomarkers. We have also provide details about strategies toward potential populations/models and technologies, including the need for standardized sampling techniques, to pursue the identification of new biochemical markers in the premotor stage of Parkinson's disease in the future. PMID- 22508284 TI - Defining at-risk populations for Parkinson's disease: lessons from ongoing studies. AB - It is currently widely acknowledged that the natural history of PD includes a preclinical phase, and there are increasing efforts to identify markers that would allow the identification of individuals at risk for PD. Here, we discuss the issues related to defining at-risk populations for PD and review findings of current population-based cohorts that have reported potential biomarkers for PD, such as the Honolulu-Asia Aging Study (HAAS) and the PRIPS (Prospective Validation of Risk factors for the development of Parkinson Syndromes) study. We also discuss enriched risk cohorts designed to evaluate specificity and predictive value of markers exemplified by the PARS (Parkinson Associated Risk Study) and the TREND (Tubinger evaluation of Risk factors for the Early detection of NeuroDegeneration) study. Although there is still a long way to go, studies designed according to these concepts might eventually provide sufficient data to form the basis for future screening programs for PD risk to be applied at a population level. PMID- 22508285 TI - The significance of defining preclinical or prodromal Parkinson's disease. AB - A body of clinical and pathologic evidence supports the concept that there a pre Parkinson state exists prior to the time when Parkinson's disease (PD) can be formally diagnosed. The ability to define a the preclinical or prodromal PD state has many important implications. First, understanding the timing and sequence of pathologic change that occurs in PD could provide important clues as to the etiology and pathogenesis of PD, and provide insight into cell vulnerability factors. Second, defining a population of patients with preclinical PD would provide a potentially important group of subjects for clinical trials attempting to define disease-modifying therapies. And, finally, being able to determine that a person has PD at an earlier time point than is currently possible would permit the introduction of a putative disease-modifying therapy at a time when it could have more profound and long-lasting effects. This paper reviews the clinical significance of defining preclinical PD. PMID- 22508286 TI - Reply to: relationship of the lumbar lordosis angle to the abdominal aortic bifurcation and inferior vena cava confluence levels. PMID- 22508288 TI - Recruitment mechanisms of primary and malignant B cells to the human liver. AB - B cells are present within chronically inflamed liver tissue and recent evidence implicates them in the progression of liver disease. In addition, a large proportion of hepatic lymphomas are of B-cell origin. The molecular signals that regulate normal and malignant B-cell recruitment into peripheral tissue from blood are poorly understood, leading us to study human B-cell migration through hepatic sinusoidal endothelial cells in flow-based adhesion assays. In such assays, human blood-derived B cells were captured from shear flow without a previous rolling phase and underwent firm adhesion mediated by vascular cell adhesion molecule-1 (VCAM-1). Unlike T cells, which displayed vigorous crawling behavior on the endothelium, B cells remained static before a proportion underwent transendothelial migration mediated by a combination of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion protein-1, common lymphatic endothelial and vascular endothelial receptor-1/stabilin-1, and the chemokine receptors, CXCR3 and CXCR4. B-cell lymphoma cell lines and primary malignant B cells from patients with chronic lymphocytic leukemia and marginal zone B cell lymphoma also underwent integrin-mediated firm adhesion involving ICAM-1 and/or VCAM-1 and demonstrated ICAM-1-dependent shape-change and crawling behavior. Unlike primary lymphocytes, the malignant cells did not undergo transendothelial migration, which could explain why lymphomas are frequently characterized by the intravascular accumulation of malignant cells in the hepatic sinusoids. CONCLUSION: Our findings demonstrate that distinct combinations of signals promote B-cell recruitment to the liver, suggesting the possibility of novel targets to modulate liver inflammation in disease. Certain features of lymphocyte homing are maintained in lymphoma recruitment to the liver, suggesting that therapeutic targets for lymphocyte recruitment may also prevent hepatic lymphoma dissemination. PMID- 22508289 TI - Ex vivo functional analysis, expansion and adoptive transfer of cytomegalovirus specific T-cells in patients with glioblastoma multiforme. AB - The frequent detection of human cytomegalovirus (CMV) antigens in glioblastoma multiforme (GBM) has raised the possibility of exploiting CMV-specific T-cell immunotherapy to control this disease in CMV--seropositive patients. Here, we have conducted a comprehensive ex vivo profiling of CMV-specific CD8(+) T-cell responses in a cohort of GBM patients. Of the patients analyzed, approximately half exhibited serological evidence of past infection with CMV. Although no CMV specific CD8(+) T-cell responses could be detected in the serologically negative GBM patients, virus-specific CD8(+) T-cell responses were detected in all seropositive GBM patients. Using major histocompatibility complex-peptide multimers, the frequency of CMV-specific T-cells in the patients detected ranged from 0.1 to 22% of CD8(+) T-cells and a high proportion of these cells were positive for the human natural killer-1 glycoprotein CD57. Furthermore, ex vivo polychromatic functional analysis of the CMV-specific T-cells from GBM patients revealed that large proportions of these cells were unable to produce multiple cytokines (macrophage inflammatory protein (MIP)-1beta, tumor necrosis factor (TNF)alpha and interferon (IFN)gamma) and displayed limited cytolytic function (CD107a mobilization) following stimulation with CMV peptide epitopes. However, in vitro stimulation with CMV peptide epitopes in the presence of gammaC cytokine dramatically reversed the polyfunctional profile of these antigen-specific T cells with high levels of MIP-1beta, TNFalpha, IFNgamma and CD107a mobilization. Most importantly, adoptive transfer of these in vitro-expanded T-cells in combination with temozolomide (TMZ) therapy into a patient with recurrent GBM was coincident with a long-term disease-free survival. These studies provide an important platform for a formal assessment of combination therapies based on CMV specific T-cells and TMZ for recurrent GBM. PMID- 22508290 TI - Prognostic significance of left ventricular diastolic function in burn patients. AB - Severe inflammation leads to cardiac diastolic dysfunction, an independent prognostic marker for the mortality of critically ill patients. We investigated the possible molecular mechanism from inflammatory cytokines (tumor necrosis factor alpha [TNF-alpha] and interleukin 6 [IL-6]) causing left ventricular (LV) diastolic dysfunction in critically burned patients. We consecutively enrolled 56 critically burned patients who were admitted to the intensive care unit and performed transthoracic echocardiography to evaluate LV diastolic function. Sarcoplasmic reticulum Ca2+-ATPase 2 (SERCA2) gene expression in HL-1 cardiomyocytes was used as a molecular phenotype of diastolic heart failure. Soluble plasma levels of TNF-alpha and IL-6 were measured in all subjects. The effect of serum from the burned patients on SERCA2 gene expression of HL-1 cardiomyocytes was investigated. The total body surface area of burned patients was proportional to serum level of IL-6 and TNF-alpha (P < 0.001 for each). Significant correlations were found for TNF-alpha and decelerating time, E/A, and E/Em (r2 = 0.59, 0.45, and 0.52; P <0.001 for each) and for IL-6 and decelerating time, E/A, and E/Em (r2 = 0.63, 0.60, and 0.62; P < 0.001 for each). Diastolic function improved significantly in association with decrease in cytokines after burned patients were transferred to general ward (P < 0.001). Tumor necrosis factor alpha, IL-6, and sera from critically burned patients downregulated the expression of the SERCA2 gene in HL-1 cardiomyocytes. There was a significant correlation between LV diastolic dysfunction and in-hospital mortality in critically burned patients (hazard ratio, 3.92; P = 0.034) after risk factors were adjusted. Inflammatory cytokines may be associated with cardiac diastolic, which could be an independent prognostic factor in burn patients. Novel therapeutic strategies may be applied in critically burned patients with LV diastolic dysfunction by modulating inflammatory reactions. PMID- 22508291 TI - Molecular hydrogen ameliorates lipopolysaccharide-induced acute lung injury in mice through reducing inflammation and apoptosis. AB - Acute lung injury (ALI) is still a leading cause of morbidity and mortality in critically ill patients. Recently, our and other studies have found that hydrogen gas (H2) treatment can ameliorate the lung injury induced by sepsis, ventilator, hyperoxia, and ischemia-reperfusion. However, the molecular mechanisms by which H2 ameliorates lung injury remain unclear. In the current study, we investigated whether H2 or hydrogen-rich saline (HS) could exert protective effects in a mouse model of ALI induced by intratracheal administration of lipopolysaccharide (LPS) via inhibiting the nuclear factor kappaB (NF-kappaB) signaling pathway-mediated inflammation and apoptosis. Two percent of H2 was inhaled for 1 h beginning at 1 and 6 h after LPS administration, respectively. We found that LPS-challenged mice exhibited significant lung injury characterized by the deterioration of histopathology and histologic scores, wet-to-dry weight ratio, and oxygenation index (PaO2/FIO2), as well as total protein in the bronchoalveolar lavage fluid (BALF), which was attenuated by H2 treatment. Hydrogen gas treatment inhibited LPS-induced pulmonary early and late NF-kappaB activation. Moreover, H2 treatment dramatically prevented the LPS-induced pulmonary cell apoptosis in LPS-challenged mice, as reflected by the decrease in TUNEL (deoxynucleotidyl transferase dUTP nick end labeling) staining-positive cells and caspase 3 activity. Furthermore, H2 treatment markedly attenuated LPS-induced lung neutrophil recruitment and inflammation, as evidenced by downregulation of lung myeloperoxidase activity, total cells, and polymorphonuclear neutrophils in BALF, as well as proinflammatory cytokines (tumor necrosis factor alpha, interleukin 1beta, interleukin 6, and high-mobility group box 1) and chemokines (keratinocyte derived chemokine, macrophage inflammatory protein [MIP] 1alpha, MIP-2, and monocyte chemoattractant protein 1) in BALF. In addition, i.p. injection of 10 mL/kg hydrogen-rich saline also significantly attenuated the LPS-induced ALI. Collectively, these results demonstrate that molecular hydrogen treatment ameliorates LPS-induced ALI through reducing lung inflammation and apoptosis, which may be associated with the decreased NF-kappaB activity. Hydrogen gas may be useful as a novel therapy to treat ALI. munosorbent assay; H2-hydrogen gas; HMGB1-high-mobility group box 1; HS-hydrogen-rich saline; i.t.-intratracheal; KC keratinocyte-derived chemokine; LPS-lipopolysaccharide; MCP-1-monocyte chemoattractant protein 1; MIP-1alpha-macrophage inflammatory protein 1alpha; MIP 2-macrophage inflammatory protein 2; MPO-myeloperoxidase; PBS-phosphate-buffered saline; PMNs-polymorphonuclear neutrophils; TUNEL-deoxynucleotidyl transferase dUTP nick end labeling; W/D-wet-to-dry. PMID- 22508292 TI - Anti-TNF therapy is associated with decreased imaging and radiation exposure in patients with Crohn's disease. AB - BACKGROUND: Diagnostic imaging is frequently used in Crohn's disease (CD) for diagnosis, evaluation of complications, and determination of response to treatment. Patients with CD are at risk for high radiation exposure in their lifetime. The aim of our study was to compare the effective dose of radiation in CD patients the year prior to and the year after initiation of anti-tumor necrosis factor (anti-TNF) agents or corticosteroids. METHODS: We conducted a retrospective review of 99 CD patients initiated on anti-TNF therapy or corticosteroids between 2004 and 2009 in a tertiary care center. RESULTS: Sixty five patients were initiated on anti-TNF agents and 34 were initiated on corticosteroids. The anti-TNF cohort was significantly younger at diagnosis and at the time of initiation of anti-TNF or steroid therapy. The anti-TNF group had significantly more stricturing, penetrating, and perianal disease than the corticosteroid group. The anti-TNF cohort had a significant reduction in number of radiologic exams (5.5 vs. 3.7, P < 0.01) as well as a significant reduction in the cumulative radiation dose (28.1 vs. 15.0 mSv, P < 0.01) the year after initiation of therapy. This reduction was largely attributable to decreased use of computed tomography (CT) scans. In contrast, there was no significant change in radiation exposure in the corticosteroid cohort. Logistic regression analysis showed a strong trend toward higher exposure in patients with complicated disease behavior (stricturing or penetrating phenotype) (odds ratio [OR] 2.87, 95% confidence interval [CI] 0.98-8.38). CONCLUSIONS: Initiation of anti-TNF therapy for treatment of CD is associated with a significant reduction in diagnostic radiation exposure. Conversely, steroid treatment does not reduce diagnostic radiation exposure. PMID- 22508293 TI - Diisocyanoarene-linked pentacarbonylvanadate(I-) ions as building blocks in a supramolecular charge-transfer framework assembled through noncovalent pi-pi and contact ion interactions. AB - Three synthetic routes to the unusual supramolecular complex ([Cp(2)Co](2)[{(OC)(5)V}(2)(MU-1,4-CNC(6)Me(4)NC)])(infinity), which was crystallographically characterized, are presented. The dianion [{(OC)(5)V}(2)(MU 1,4-CNC(6)Me(4)NC)](2-) constitutes the first subvalent organometallics featuring a diisocyanoarene linker. PMID- 22508294 TI - Hematologic safety of breast cancer chemotherapies in patients with hepatitis B or C virus infection. AB - BACKGROUND: Information regarding hematological toxicities in breast cancer chemotherapy patients with hepatitis B (HBV) or C virus (HCV) infection is limited. METHODS: We retrospectively reviewed the presence of hepatotoxicities (i.e. aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin elevation) and hematotoxicities (i.e. leukopenia and thrombocytopenia) among breast cancer patients with HBV or HCV infection who received chemotherapy from 1999 to 2010. All of the patients included in this analysis were classified as Child-Pugh A. RESULTS: Among 32 patients with HBV infection who underwent chemotherapy (total cycles, 378), 3 experienced grade 3/4 hepatotoxicities, requiring 2 treatment delays and 1 treatment revision. Further, 9 patients experienced grade 3/4 hematotoxicities; of these, 2 required treatment delays and 3 required treatment revisions. Fifty-two HCV patients underwent a total of 570 cycles of chemotherapy. Five patients experienced grade 3/4 hepatotoxicities and required treatment delays, whereas 10 patients experienced grade 3 hematotoxicities; 3 of these patients required treatment delays. CONCLUSION: Hematotoxicities requiring chemotherapy dose or treatment revision were not highly prevalent among breast cancer chemotherapy patients with HBV or HCV infection and a normal range of liver function. Under careful monitoring, chemotherapy dosage or schedule adjustments may not be necessary in similar patients positive for HBV or HCV. PMID- 22508295 TI - First identification of OXA-72 carbapenemase from Acinetobacter pittii in Colombia. AB - OXA-72 has been reported in few countries around the world. We report the first case in Colombia in an Acinetobacter pittii clinical isolate. The arrival of a new OXA, into a country with high endemic resistance, poses a significant threat, especially because the potential for widespread dissemination is considerable. PMID- 22508296 TI - Decreased susceptibility to noncarbapenem antimicrobials in extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae isolates in Toronto, Canada. AB - Retrospective review from 11 Canadian hospitals showed increasing incidence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae from 0.12 per 1,000 inpatient days during 2005 to 0.47 per 1,000 inpatient days during 2009. By 2009, susceptibility rates of ESBL-positive E. coli/K. pneumoniae were as follows: ciprofloxacin, 12.8%/9.0%; TMP/SMX, 32.9%/12.2%; and nitrofurantoin, 83.8%/10.3%. Nosocomial and nonnosocomial ESBL producing E. coli isolates had similar susceptibility profiles, while nonnosocomial ESBL-producing K. pneumoniae was associated with decreased ciprofloxacin (P = 0.03) and nitrofurantoin (P < 0.001) susceptibilities. PMID- 22508297 TI - Resistance analysis of the hepatitis C virus NS3 protease inhibitor asunaprevir. AB - Asunaprevir (BMS-650032) is a potent hepatitis C virus (HCV) NS3 protease inhibitor demonstrating efficacy in alfa interferon-sparing, direct-acting antiviral dual-combination regimens (together with the NS5A replication complex inhibitor daclatasvir) in patients chronically infected with HCV genotype 1b. Here, we describe a comprehensive in vitro genotypic and phenotypic analysis of asunaprevir-associated resistance against genotypes 1a and 1b using HCV replicons and patient samples obtained from clinical studies of short-term asunaprevir monotherapy. During genotype 1a resistance selection using HCV replicons, the primary NS3 protease substitutions identified were R155K, D168G, and I170T, which conferred low- to moderate-level asunaprevir resistance (5- to 21-fold) in transient-transfection susceptibility assays. For genotype 1b, a higher level of asunaprevir-associated resistance was observed at the same selection pressures, ranging from 170- to 400-fold relative to the wild-type control. The primary NS3 protease substitutions identified occurred predominantly at amino acid residue D168 (D168A/G/H/V/Y) and were associated with high-level asunaprevir resistance (16- to 280-fold) and impaired replication capacity. In asunaprevir single ascending-dose and 3-day multiple-ascending-dose studies in HCV genotype 1a- or 1b-infected patients, the predominant pre-existing NS3 baseline polymorphism was NS3-Q80K. This substitution impacted initial virologic response rates in a single ascending-dose study, but its effects after multiple doses were more ambiguous. Interestingly, for patient NS3 protease sequences containing Q80 and those containing K80, susceptibilities to asunaprevir were comparable when tested in an enzyme assay. No resistance-associated variants emerged in these clinical studies that significantly impacted susceptibility to asunaprevir. Importantly, asunaprevir-resistant replicons remained susceptible to an NS5A replication complex inhibitor, consistent with a role for asunaprevir in combination therapies. PMID- 22508298 TI - Biochemical and genetic characterization of carbapenem-hydrolyzing beta-lactamase OXA-229 from Acinetobacter bereziniae. AB - Acinetobacter bereziniae (formerly Acinetobacter genomospecies 10) isolate Nec was recovered from a skin sample of a patient hospitalized in Paris, France. It was resistant to penicillins, penicillin-inhibitor combinations, and carbapenems. Cloning and expression in Escherichia coli identified the carbapenem-hydrolyzing class D beta-lactamase OXA-229, which is weakly related to other oxacillinases (66% amino acid identity with the closest oxacillinase, OXA-58). It hydrolyzed penicillins, oxacillin, and imipenem but not expanded-spectrum cephalosporins. Sequencing of the genetic context of the bla(OXA-229) gene did not identify an insertion sequence but did identify mutations in the promoter sequences in comparison to the fully susceptible A. bereziniae reference strain. The overexpression of bla(OXA-229) in A. bereziniae Nec as a source of carbapenem resistance was identified by quantitative real-time PCR. PMID- 22508299 TI - Characterizations of clinical isolates of clostridium difficile by toxin genotypes and by susceptibility to 12 antimicrobial agents, including fidaxomicin (OPT-80) and rifaximin: a multicenter study in Taiwan. AB - A total of 403 nonduplicate isolates of Clostridium difficile were collected at three major teaching hospitals representing northern, central, and southern Taiwan from January 2005 to December 2010. Of these 403 isolates, 170 (42.2%) were presumed to be nontoxigenic due to the absence of genes for toxins A or B or binary toxin. The remaining 233 (57.8%) isolates carried toxin A and B genes, and 39 (16.7%) of these also had binary toxin genes. The MIC(90) of all isolates for fidaxomicin and rifaximin was 0.5 MUg/ml (range, <= 0.015 to 0.5 MUg/ml) and >128 MUg/ml (range, <= 0.015 to >128 MUg/ml), respectively. All isolates were susceptible to metronidazole (MIC(90) of 0.5 MUg/ml; range, <= 0.03 to 4 MUg/ml). Two isolates had reduced susceptibility to vancomycin (MICs, 4 MUg/ml). Only 13.6% of isolates were susceptible to clindamycin (MIC of <= 2 MUg/ml). Nonsusceptibility to moxifloxacin (n = 81, 20.1%) was accompanied by single or multiple mutations in gyrA and gyrB genes in all but eight moxifloxacin nonsusceptible isolates. Two previously unreported gyrB mutations might independently confer resistance (MIC, 16 MUg/ml), Ser416 to Ala and Glu466 to Lys. Moxifloxacin-resistant isolates were cross-resistant to ciprofloxacin and levofloxacin, but some moxifloxacin-nonsusceptible isolates remained susceptible to gemifloxacin or nemonoxacin at 0.5 MUg/ml. This study found the diversity of toxigenic and nontoxigenic strains of C. difficile in the health care setting in Taiwan. All isolates tested were susceptible to metronidazole and vancomycin. Fidaxomicin exhibited potent in vitro activity against all isolates tested, while the more than 10% of Taiwanese isolates with rifaximin MICs of >= 128 MUg/ml raises concerns. PMID- 22508301 TI - Characterization of extended-spectrum-beta-lactamase-producing Vibrio parahaemolyticus. PMID- 22508300 TI - Antiviral effects of small interfering RNA simultaneously inducing RNA interference and type 1 interferon in coxsackievirus myocarditis. AB - Antiviral therapeutics are currently unavailable for treatment of coxsackievirus B3, which can cause life-threatening myocarditis. A modified small interfering RNA (siRNA) containing 5'-triphosphate, 3p-siRNA, was shown to induce RNA interference and interferon activation. We aimed to develop a potent antiviral treatment using CVB3-specific 3p-siRNA and to understand its underlying mechanisms. Virus-specific 3p-siRNA was superior to both conventional virus specific siRNA with an empty hydroxyl group at the 5' end (OH-siRNA) and nonspecific 3p-siRNA in decreasing viral replication and subsequent cytotoxicity. A single administration of 3p-siRNA dramatically attenuated virus-associated pathological symptoms in mice with no signs of toxicity, and their body weights eventually reached the normal range. Myocardial inflammation and fibrosis were rare, and virus production was greatly reduced. A nonspecific 3p-siRNA showed relatively less protective effect under identical conditions, and a virus specific OH-siRNA showed no protective effects. We confirmed that virus-specific 3p-siRNA simultaneously activated target-specific gene silencing and type I interferon signaling. We provide a clear proof of concept that coxsackievirus B3 specific 3p-siRNA has 2 distinct modes of action, which significantly enhance antiviral activities with minimal organ damage. This is the first direct demonstration of improved antiviral effects with an immunostimulatory virus specific siRNA in coxsackievirus myocarditis, and this method could be applied to many virus-related diseases. PMID- 22508302 TI - The anthelmintic triclabendazole and its metabolites inhibit the membrane transporter ABCG2/BCRP. AB - ABCG2/BCRP is an ATP-binding cassette transporter that extrudes compounds from cells in the intestine, liver, kidney, and other organs, such as the mammary gland, affecting pharmacokinetics and milk secretion of antibiotics, anticancer drugs, and other compounds and mediating drug-drug interactions. In addition, ABCG2 expression in cancer cells may directly cause resistance by active efflux of anticancer drugs. The development of ABCG2 modulators is critical in order to improve drug pharmacokinetic properties, reduce milk secretion of xenotoxins, and/or increase the effective intracellular concentrations of substrates. Our purpose was to determine whether the anthelmintic triclabendazole (TCBZ) and its main plasma metabolites triclabendazole sulfoxide (TCBZSO) and triclabendazole sulfone (TCBZSO(2)) inhibit ABCG2 activity. ATPase assays using human ABCG2 enriched membranes demonstrated a clear ABCG2 inhibition exerted by these compounds. Mitoxantrone accumulation assays using murine Abcg2- and human ABCG2 transduced MDCK-II cells confirmed that TCBZSO and TCBZSO(2) are ABCG2 inhibitors, reaching inhibitory potencies between 40 and 55% for a concentration range from 5 to 25 MUM. Transepithelial transport assays of ABCG2 substrates in the presence of both TCBZ metabolites at 15 MUM showed very efficient inhibition of the Abcg2/ABCG2-mediated transport of the antibacterial agents nitrofurantoin and danofloxacin. TCBZSO administration also inhibited nitrofurantoin Abcg2 mediated secretion into milk by more than 2-fold and increased plasma levels of the sulfonamide sulfasalazine by more than 1.5-fold in mice. These results support the potential role of TCBZSO and TCBZSO(2) as ABCG2 inhibitors to participate in drug interactions and modulate ABCG2-mediated pharmacokinetic processes. PMID- 22508303 TI - In vitro susceptibility of Pythium insidiosum isolates to aminoglycoside antibiotics and tigecycline. AB - This study evaluated the in vitro activity of aminoglycoside antibiotics and tigecycline against Pythium insidiosum. The susceptibility tests were carried out using the broth microdilution method in accordance with the CLSI document M38-A2. MIC values for gentamicin, neomycin, paromomycin, and streptomycin ranged from 32 to 64 mg/liter, and the minimal fungicidal concentration (MFC) ranged from 32 to 128 mg/liter, which are incompatible with safe concentrations of these drugs in plasma in vivo. Tigecycline showed the lowest MIC (0.25 to 2 mg/liter) and MFC (1 to 8 mg/liter) range values. The in vitro susceptibility observed to tigecycline makes this drug a good option in future tests in vitro and in vivo for the management of pythiosis. PMID- 22508304 TI - Worldwide appraisal and update (2010) of telavancin activity tested against a collection of Gram-positive clinical pathogens from five continents. AB - A total of 15,480 Gram-positive pathogens were collected from 89 sites in the United States, Europe, the Asia-Pacific region, and Latin America in 2010. Telavancin was active against indicated Staphylococcus aureus (MIC(50/90), 0.12/0.25 MUg/ml), vancomycin-susceptible Enterococcus faecalis (MIC(50/90), 0.5/0.5 MUg/ml), and beta-hemolytic (MIC(50/90), 0.06/0.12 MUg/ml) and viridans group streptococcus (MIC(50/90), 0.03/0.06 MUg/ml) isolates. These MIC results showed potency for telavancin equal to or greater than that of comparators. These in vitro data confirm a continued potent activity of telavancin when tested against contemporary Gram-positive clinical isolates. PMID- 22508305 TI - Sontochin as a guide to the development of drugs against chloroquine-resistant malaria. AB - Sontochin was the original chloroquine replacement drug, arising from research by Hans Andersag 2 years after chloroquine (known as "resochin" at the time) had been shelved due to the mistaken perception that it was too toxic for human use. We were surprised to find that sontochin, i.e., 3-methyl-chloroquine, retains significant activity against chloroquine-resistant strains of Plasmodium falciparum in vitro. We prepared derivatives of sontochin, "pharmachins," with alkyl or aryl substituents at the 3 position and with alterations to the 4 position side chain to enhance activity against drug-resistant strains. Modified with an aryl substituent in the 3 position of the 7-chloro-quinoline ring, Pharmachin 203 (PH-203) exhibits low-nanomolar 50% inhibitory concentrations (IC(50)s) against drug-sensitive and multidrug-resistant strains and in vivo efficacy against patent infections of Plasmodium yoelii in mice that is superior to chloroquine. Our findings suggest that novel 3-position aryl pharmachin derivatives have the potential for use in treating drug resistant malaria. PMID- 22508306 TI - Evaluation of arylimidamides DB1955 and DB1960 as candidates against visceral leishmaniasis and Chagas' disease: in vivo efficacy, acute toxicity, pharmacokinetics, and toxicology studies. AB - Arylimidamides (AIAs) have shown outstanding in vitro potency against intracellular kinetoplastid parasites, and the AIA 2,5-bis[2-(2-propoxy)-4-(2 pyridylimino)aminophenyl]furan dihydrochloride (DB766) displayed good in vivo efficacy in rodent models of visceral leishmaniasis (VL) and Chagas' disease. In an attempt to further increase the solubility and in vivo antikinetoplastid potential of DB766, the mesylate salt of this compound and that of the closely related AIA 2,5-bis[2-(2-cyclopentyloxy)-4-(2-pyridylimino)aminophenyl]furan hydrochloride (DB1852) were prepared. These two mesylate salts, designated DB1960 and DB1955, respectively, exhibited dose-dependent activity in the murine model of VL, with DB1960 inhibiting liver parasitemia by 51% at an oral dose of 100 mg/kg/day * 5 and DB1955 reducing liver parasitemia by 57% when given by the same dosing regimen. In a murine Trypanosoma cruzi infection model, DB1960 decreased the peak parasitemia levels that occurred at 8 days postinfection by 46% when given orally at 100 mg/kg/day * 5, while DB1955 had no effect on peak parasitemia levels when administered by the same dosing regimen. Distribution studies revealed that these compounds accumulated to micromolar levels in the liver, spleen, and kidneys but to a lesser extent in the heart, brain, and plasma. A 5 day repeat-dose toxicology study with DB1960 and DB1955 was also conducted with female BALB/c mice, with the compounds administered orally at 100, 200, and 500 mg/kg/day. In the high-dose groups, DB1960 caused changes in serum chemistry, with statistically significant increases in serum blood urea nitrogen, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase levels, and a 21% decrease in body weight was observed in this group. These changes were consistent with microscopic findings in the livers and kidneys of the treated animals. The incidences of observed clinical signs (hunched posture, tachypnea, tremors, and ruffled fur) were more frequent in DB1960-treated groups than in those treated with DB1955. However, histopathological examination of tissue samples indicated that both compounds had adverse effects at all dose levels. PMID- 22508307 TI - UC781 microbicide gel retains anti-HIV activity in cervicovaginal lavage fluids collected following twice-daily vaginal application. AB - The potent nonnucleoside reverse transcriptase inhibitor UC781 has been safety tested as a vaginal microbicide gel formulation for prevention of HIV-1 sexual transmission. To investigate whether UC781 retained anti-infective activity following exposure to the female genital tract, we conducted an ex vivo analysis of the UC781 levels and antiviral activity in cervicovaginal lavage (CVL) fluids from 25 Thai women enrolled in a 14-day safety trial of twice-daily vaginal application of two concentrations of the UC781 microbicide gel. CVL samples were collected from women in the 0.1% (n = 5), 0.25% (n = 15), and placebo (n = 5) gel arms following the first application of gel (T(15 min)) and 8 to 24 h after the final application (T(8-24 h)) and separated into cell-free (CVL-s) and pelletable (CVL-p) fractions. As UC781 is highly hydrophobic, there were significantly higher levels of UC781 in the CVL-p samples than in the CVL-s samples for the UC781 gel arms. In T(8-24 h) CVL-p samples, 2/5 and 13/15 samples collected from the 0.1% and 0.25% UC781 gel arms, respectively, efficiently blocked infection with >= 4 log(10) 50% tissue culture infective dose (TCID(50)) of a CCR5-tropic CRF01_AE HIV-1 virus stock. Independent of the arm, the 11 CVL-p samples with UC781 levels of >= 5 MUg/CVL sample reduced infectious HIV by >= 4 log(10) TCID(50). Our results suggest that the levels and anti-infective activities of UC781 gel formulations are likely to be associated with a cellular or pelletable component in CVL samples. Therefore, cellular and pelletable fractions should be assayed for drug levels and anti-infective activity in preclinical studies of candidate microbicides. PMID- 22508308 TI - Activity of human immunodeficiency virus type 1 protease inhibitors against the initial autocleavage in Gag-Pol polyprotein processing. AB - Inhibitors of HIV protease have proven to be important drugs in combination anti HIV therapy. These inhibitors were designed to target mature protease and prevent viral particle maturation by blocking Gag and Gag-Pol processing by mature protease. Currently there are few data assessing the ability of these protease inhibitors to block the initial step in autoproteolytic processing of Gag-Pol. This unique step involves the dimerization of two Gag-Pol polyproteins and autocleavage of the Gag-Pol polyprotein by the embedded dimeric protease. We developed a plasmid encoding a modified form of Gag-Pol that can undergo autoprocessing only at the initial cleavage site between p2 and nucleocapsid. Using an in vitro transcription/translation system, we assessed the ability of six different approved protease inhibitors (darunavir, indinavir, nelfinavir, ritonavir, saquinavir, and tipranavir) to block this initial autocleavage step. Of these inhibitors, darunavir and saquinavir were the most effective. Darunavir and saquinavir were also the most effective at blocking the initial autoprocessing of full-length Gag-Pol in HIV-1-infected T cells. Thus, we have identified at least two HIV-1 protease inhibitors that have activity against the primary autocatalytic step of the embedded HIV-1 protease in Gag-Pol at concentrations that may be attained in HIV-1-infected patients. Due to unique aspects of the initial processing step, it may be possible to develop inhibitors with greater potency against this step, thus halting viral maturation at the earliest stages. The transcription/translation assay could be used to develop more potent inhibitors of this essential first step in viral maturation. PMID- 22508309 TI - The spiroindolone drug candidate NITD609 potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to anopheles mosquito vector. AB - The global malaria agenda has undergone a reorientation from control of clinical cases to entirely eradicating malaria. For that purpose, a key objective is blocking transmission of malaria parasites from humans to mosquito vectors. The new antimalarial drug candidate NITD609 was evaluated for its transmission reducing potential and compared to a few established antimalarials (lumefantrine, artemether, primaquine), using a suite of in vitro assays. By the use of a microscopic readout, NITD609 was found to inhibit the early and late development of Plasmodium falciparum gametocytes in vitro in a dose-dependent fashion over a range of 5 to 500 nM. In addition, using the standard membrane feeding assay, NITD609 was also found to be a very effective drug in reducing transmission to the Anopheles stephensi mosquito vector. Collectively, our data suggest a strong transmission-reducing effect of NITD609 acting against different P. falciparum transmission stages. PMID- 22508310 TI - The antidepressant sertraline provides a promising therapeutic option for neurotropic cryptococcal infections. AB - Therapeutic treatment for systemic mycoses is severely hampered by the extremely limited number of antifungals. The difficulty of treatment of fungal infections in the central nervous system is further compounded by the poor central nervous system (CNS) penetration of most antifungals due to the blood-brain barrier. Only a few fungistatic azole drugs, such as fluconazole, show reasonable CNS penetration. Here we demonstrate that sertraline (Zoloft), the most frequently prescribed antidepressant, displays potent antifungal activity against Cryptococcus neoformans, the major causative agent of fungal meningitis. In in vitro assays, this neurotropic drug is fungicidal to all natural Cryptococcus isolates tested at clinically relevant concentrations. Furthermore, sertraline interacts synergistically or additively with fluconazole against Cryptococcus. Importantly, consistent with our in vitro observations, sertraline used alone reduces the brain fungal burden at an efficacy comparable to that of fluconazole in a murine model of systemic cryptococcosis. It works synergistically with fluconazole in reducing the fungal burden in brain, kidney, and spleen. In contrast to its potency against Cryptococcus, sertraline is less effective against strains of Candida species and its interactions with fluconazole against Candida strains are often antagonistic. Therefore, our data suggest the unique application of sertraline against cryptococcosis. To understand the antifungal mechanisms of sertraline, we screened a whole-genome deletion collection of Saccharomyces cerevisiae for altered sertraline susceptibility. Gene ontology analyses of selected mutations suggest that sertraline perturbs translation. In vitro translation assays using fungal cell extracts show that sertraline inhibits protein synthesis. Taken together, our findings indicate the potential of adopting this antidepressant in treating cryptococcal meningitis. PMID- 22508311 TI - In vitro anti-Trypanosoma cruzi activity of dronedarone, a novel amiodarone derivative with an improved safety profile. AB - Amiodarone, a commonly used antiarrhythmic, is also a potent and selective anti Trypanosoma cruzi agent. Dronedarone is an amiodarone derivative in which the 2,5 diiodophenyl moiety of the parental drug has been replaced with an unsubstituted phenyl group aiming to eliminate the thyroid toxicity frequently observed with amiodarone treatment. Dronedarone has been approved by the Food and Drug Administration (FDA), and its use as a safe antiarrhythmic has been extensively documented. We show here that dronedarone also has potent anti-T. cruzi activity, against both extracellular epimastigotes and intracellular amastigotes, the clinically relevant form of the parasite. The 50% inhibitory concentrations against both proliferative stages are lower than those previously reported for amiodarone. The mechanism of action of dronedarone resembles that of amiodarone, as it induces a large increase in the intracellular Ca(2+) concentration of the parasite, which results from the release of this ion from intracellular storage sites, including a direct effect of the drug on the mitochondrial electrochemical potential, and through alkalinization of the acidocalcisomes. Our results suggest a possible future repurposed use of dronedarone for the treatment of Chagas' disease. PMID- 22508313 TI - Dogs of nomadic pastoralists in northern Kenya are reservoirs of plasmid-mediated cephalosporin- and quinolone-resistant Escherichia coli, including pandemic clone B2-O25-ST131. AB - Resistance in Escherichia coli isolates colonizing gastrointestinal tracts of dogs, cats, and their owners in Northern Kenya was investigated with an emphasis on extended-spectrum beta-lactamases (ESBLs). Totals of 47 (22%, n = 216), 2 (4%, n = 50), and 4 (17%, n = 23) CTX-M-15-producing E. coli isolates were obtained from dogs, cats, and humans, respectively. CTX-M-15-producing E. coli isolates with identical PFGE profiles were detected in animals and humans living in the same area. PMID- 22508312 TI - Antimalarial activity of the anticancer histone deacetylase inhibitor SB939. AB - Histone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, the in vitro and in vivo antiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth of Plasmodium falciparum asexual-stage parasites in vitro (50% inhibitory concentration [IC(50)], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited the in vitro growth of exoerythrocytic-stage Plasmodium parasites in liver cells (IC(50), ~150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimental in vivo murine model of cerebral malaria, orally administered SB939 significantly inhibited P. berghei ANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria. PMID- 22508314 TI - Nonspecific effect of Mycograb on amphotericin B MIC. AB - Mycograb C28Y is a recombinant human antibody fragment thought to target HSP-90 and potentiate amphotericin B (AMB). Absence of in vivo efficacy led us to reevaluate its in vitro activity. Interactions between AMB and Mycograb were investigated using a checkerboard design. Addition of Mycograb or various unrelated proteins, including human serum, resulted in similar decreases in the MIC of AMB. Potentiation of AMB by Mycograb appears to be a nonspecific protein effect. PMID- 22508316 TI - Progesterone receptor isoform expression in response to in utero growth restriction in the fetal guinea pig brain. AB - Intra-uterine growth restriction (IUGR) is a significant in utero complication that can have profound effects on brain development including reduced myelination and deficits that can continue into adulthood. Progesterone increases oligodendrocyte proliferation and myelin expression, an action that may depend on the expression of progesterone receptor (PR) isoforms A (PRA) and B (PRB). The objective of this study was to determine the effect of IUGR on PR isoform expression in the brain of male and female fetuses and whether effects were associated with a reduction in myelination. We used a guinea pig model that involves selective reduction in maternal perfusion to the placenta at midgestation (35 days, term 70 days). This resulted in a significant reduction in body weight with marked sparing of brain weight. PRA, PRB and myelin basic protein (MBP) expression were measured in the brains of male and female growth restricted and control fetuses at late gestation. MBP, as a measure of myelination, was found to decrease in association with IUGR in the CA1 hippocampal region with no change observed in the cortical white matter. There was a marked increase in PRA, PRB and total PR expression in the IUGR fetal brain. Control female fetuses demonstrated significantly higher PRA:PRB ratios than males; however, this sex difference was abolished with IUGR. These data suggest the central nervous system effects of clinical use of progesterone augmentation therapy in late pregnancy should be carefully evaluated. The overall upregulation of PR isoforms in association with IUGR suggests increased progesterone action and a possible neuroprotective mechanism. PMID- 22508315 TI - pfmdr1 amplification is related to increased Plasmodium falciparum in vitro sensitivity to the bisquinoline piperaquine. AB - The 4-aminoquinoline bisquinoline piperaquine is an important partner drug in one of the presently recommended artemisinin combination therapies. Recent clinical trials have confirmed its high efficacy in combination with dihydroartemisinin. Resistance to piperaquine alone has, however, been documented. Amplification in copy number of the Plasmodium falciparum multidrug resistance locus on chromosome 5, containing the pfmdr1 gene, has been shown to confer resistance to structurally unrelated antimalarials. Through the determination of the 50% inhibitory concentrations (IC(50)s) and IC(90)s for piperaquine and chloroquine in a set of 46 adapted P. falciparum cultures originating from the Thai-Burmese border, we have characterized the regions around the pfmdr1 gene and identified a significant association between the presence of pfmdr1 duplications and enhanced sensitivity to piperaquine (P = 0.005 for IC(50) and P = 0.002 for IC(90)) and chloroquine, reaching statistical significance at IC(90)s (P = 0.026). These results substantiate the potential importance of pfmdr1 copy number amplifications in the efficacy of the combination therapy piperaquine dihydroartemisinin. It supports the rational use of 4-aminoquinolines and artemisinin-based compounds, as they independently select for mutually incompatible combinations of mutations. PMID- 22508317 TI - Gender influences short-term growth hormone treatment response in children. AB - BACKGROUND: Gender may affect growth hormone (GH) treatment outcome. This study assessed gender-related differences in change from baseline height standard deviation scores (DeltaHSDS) after 2 years' GH treatment. METHODS: Data from two observational databases were analyzed - the NordiNet(r) International Outcome Study (NordiNet(r) IOS) and the American Norditropin Studies: Web Enabled Research Program (ANSWER Program(r)). Of all the evaluated patients (n = 5,880; age 0 to <18 years), 4,471 were diagnosed with GH deficiency (GHD), 422 with multiple pituitary hormone deficiency, and 987 were born small for gestational age (SGA). Data were analyzed by indication, gender and pubertal status (total population/prepubertal). RESULTS: In the total population, after correcting for dose, mean baseline age and HSDS, DeltaHSDS was significantly greater in boys than in girls born SGA (p = 0.0261). In the prepubertal cohort, DeltaHSDS was significantly greater for boys versus girls with GHD (p = 0.0004) and SGA (p = 0.0019). No between-gender difference in DeltaIGF-I SDS was found. CONCLUSIONS: A significant gender difference was found in the 2-year response to GH treatment in the total population of SGA children as well as in the prepubertal cohorts of SGA and GHD children. PMID- 22508318 TI - Comparing dry ashing and wet oxidation methods. The case of the rice husk (Oryza sativa L.). AB - Experiments were conducted to determine the effects that different methods for the preparation of modern plant samples have on the resulting phytoliths using rice husks (Oryza sp.). The methods that are commonly used in phytolith extraction include (1) dry ashing, (2) acid extraction (3) a combination of both techniques. The results showed that processing methods have an impact on the morphology of two subspecies of rice phytoliths, dry ashing producing more conjoined cell phytoliths or multicells phytoliths than acid extraction. Using a combination of both methods resulted in the presence of fewer conjoined cells than dry ashing alone, but more conjoined cells than acid extraction. Alternative explanations are proposed to explain the formation of conjoined phytolith cells. PMID- 22508320 TI - High-output cardiac failure in a fetus with thanatophoric dysplasia associated with large placental chorioangioma: case report. AB - Placental chorioangioma is an angioma arising from chorionic tissue. Fetal thanatophoric dysplasia is a lethal skeletal dysplasia due to mutation of fibroblast growth factor receptor 3 gene. These two conditions are rare and their coexistence in a given fetus is even rarer. We present a case of a fetus with thanatophoric dysplasia having high-output cardiac failure due to a large placental chorioangioma. PMID- 22508321 TI - Tumour-associated trypsin inhibitor TATI is a prognostic marker in colorectal cancer. AB - BACKGROUND: The tumour-associated trypsin inhibitor TATI is expressed together with trypsin in many cancer forms, and an elevated serum level associates with poor prognosis. TATI can reduce tissue destruction by inhibiting trypsin and other proteinases, and in some cancer forms, its high tissue expression is associated with favourable prognosis. We analyzed the prognostic values of TATI, trypsinogen-1 and trypsinogen-2 immunoexpression from tissue array blocks constructed from surgical specimens of 592 colorectal cancer patients. RESULTS: TATI positivity correlated negatively with differentiation (p < 0.001) and positively with the histological type of adenocarcinoma (p < 0.001). Trypsinogen 1 and trypsinogen-2 positivity correlated with Dukes' stage (p = 0.045, p = 0.050); the percentage of trypsinogen-1- and trypsinogen-2-positive tumours was lower in metastasized (Dukes' stage C-D) than in local (Dukes' stage A-B) disease. In addition, trypsinogen-2 correlated inversely with differentiation (p = 0.012). In univariate analysis, the expression of TATI associated with more favourable cancer-specific survival (p = 0.010). In multivariate analysis, low TATI (p = 0.044), age (p < 0.001), Dukes' stage (p < 0.001), tumour differentiation (p = 0.020) and location in the rectum (p = 0.006) were independent prognostic factors for adverse outcome. Furthermore, TATI expression was an independent prognostic factor in a subgroup of trypsinogen-1- (p = 0.007) and trypsinogen-2-positive (p = 0.006) tumours. CONCLUSION: TATI tissue expression is an independent prognostic marker in colorectal cancer. PMID- 22508319 TI - Examining markers in 8q24 to explain differences in evidence for association with cleft lip with/without cleft palate between Asians and Europeans. AB - In a recent genome-wide association study (GWAS) from an international consortium, evidence of linkage and association in chr8q24 was much stronger among nonsyndromic cleft lip/palate (CL/P) case-parent trios of European ancestry than among trios of Asian ancestry. We examined marker information content and haplotype diversity across 13 recruitment sites (from Europe, United States, and Asia) separately, and conducted principal components analysis (PCA) on parents. As expected, PCA revealed large genetic distances between Europeans and Asians, and a north-south cline from Korea to Singapore in Asia, with Filipino parents forming a somewhat distinct Southeast Asian cluster. Hierarchical clustering of SNP heterozygosity revealed two major clades consistent with PCA results. All genotyped SNPs giving P < 10(-6) in the allelic transmission disequilibrium test (TDT) showed higher heterozygosity in Europeans than Asians. On average, European ancestry parents had higher haplotype diversity than Asians. Imputing additional variants across chr8q24 increased the strength of statistical evidence among Europeans and also revealed a significant signal among Asians (although it did not reach genome-wide significance). Tests for SNP-population interaction were negative, indicating the lack of strong signal for 8q24 in families of Asian ancestry was not due to any distinct genetic effect, but could simply reflect low power due to lower allele frequencies in Asians. PMID- 22508323 TI - Management of low-grade dysplasia in Barrett's esophagus. AB - PURPOSE OF REVIEW: This article discusses the various controversies that surround the management of low-grade dysplasia (LGD) in Barrett's esophagus. RECENT FINDINGS: Data on the clinical course of LGD patients with regards to rates of progression to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) are highly variable. Recent data suggest that the rate of progression to EAC may be similar to that of patients with nondysplastic Barrett's esophagus (0.4-0.5% per year). There is significant interobserver variability in the diagnosis of LGD even among expert gastrointestinal pathologists. Data on various endoscopic eradication therapies (EET) specifically in this patient population are limited. Eradication of LGD and intestinal metaplasia can be achieved by radiofrequency ablation as demonstrated in a randomized controlled trial. Although treatment appears to be durable for up to 3 years, progression to HGD and EAC can occur, highlighting the need for close endoscopic surveillance even after EET. SUMMARY: There is a need to risk stratify Barrett's esophagus patients with LGD to identify patients most likely to progress using a reliable and objective system that incorporates clinical features, advanced imaging techniques and biomarkers. If such a high risk group could be identified, they may benefit from EET, whereas, the majority may be managed conservatively. PMID- 22508322 TI - Hepatic steatosis and steatohepatitis in human immunodeficiency virus/hepatitis C virus-coinfected patients. AB - Hepatic steatosis (HS) is frequent in human immunodeficiency virus (HIV)- and hepatitis C virus (HCV)-coinfected patients. Antiretroviral therapy (ART) and metabolic alterations could induce HS. However, a protective effect of ART has been reported in a paired biopsy study. Thus, our aim was to examine the changes and predictors of HS progression among HIV/HCV-coinfected patients with sequential biopsies. We also evaluated the rates of steatohepatitis and factors associated thereof. HIV-infected patients with detectable serum HCV RNA, who underwent two biopsies, separated at least by 1 year, were included in this retrospective study. HS progression was defined as increase in one or more HS grades. The median (interquartile range) time between biopsies was 3.3 (2.0-5.2) years. Among 146 individuals, HS at baseline was observed in 86 (60%) patients and in 113 (77%) in the follow-up biopsy (P < 0.001). Progression of HS was observed in 60 (40%) patients. HS regressed in 11 (8%) patients. Factors associated with HS progression were changes in fasting plasma glucose (FPG) between biopsies (per 10 mg/dL increase; odds ratio [OR] [95% confidence interval; CI] = 1.4 [1.04-1.8]; P = 0.024) and cumulative use of dideoxynucleoside analogs (per year; OR [95% CI] = 1.5 [1.2-1.8]; P = 0.001). Persistent steatohepatitis or progression to steatohepatitis between biopsies was observed in 27 (18%) patients. Persistence of or progression to steatohepatitis was associated with progression >= 1 fibrosis stages between biopsies (OR [95% CI] = 2.4 [1.01-5.7]; P = 0.047). CONCLUSIONS: HS progresses frequently and regression is rarely observed in HIV/HCV-coinfected patients, including in those on ART. Cumulative exposure to dideoxynucleoside analogs and increases in FPG are related with HS progression. Stetatohepatitis is frequently observed in these patients and is linked to fibrosis progression. PMID- 22508324 TI - Treatment of the patient with achalasia. AB - PURPOSE OF REVIEW: In recent years, several studies on the treatment and follow up of achalasia have been published. This review aims at highlighting interesting publications from the recent years. RECENT FINDINGS: Treatment of achalasia aims at relieving functional obstruction at the level of the esophagogastric junction. Several treatment options such as pneumodilation and laparoscopic Heller myotomy (LHM) are available for this purpose. A large prospective randomized trial comparing pneumodilation and LHM demonstrated comparable success rates and quality of life for the two treatment options. Long-term data demonstrate comparable treatment success rates, when redilation in case of recurrent symptoms after pneumodilation is accepted. The most important risk factor for treatment failure is the manometric subtype, with a worse outcome for type I and type III compared with type II achalasia. Recently, peroral endoscopic myotomy (POEM) has been described with high success rates. Comparative studies with longer follow-up are awaited. A prospective study assessing the risk of esophageal carcinoma in patients with achalasia showed a 28-fold increased risk to develop carcinoma. SUMMARY: Either LHM or pneumodilation have high comparable short-term clinical success rates. Based on the increased risk to develop esophageal carcinoma, a screening program may be indicated. POEM is a new interesting treatment but longer follow-up data are awaited. PMID- 22508325 TI - Screening and surveillance for Barrett's esophagus: current issues and future directions. AB - PURPOSE OF REVIEW: Our article discusses the current understanding of screening and surveillance options for Barrett's esophagus and emerging concepts that have the potential to improve the effectiveness and cost-effectiveness of surveillance. RECENT FINDINGS: Although endoscopic surveillance of patients with Barrett's esophagus is commonly practiced in order to detect high-grade dysplasia and early esophageal adenocarcinoma (EAC), the reported incidence of EAC in Barrett's esophagus patients varies widely. Recent studies found the risk of progression from Barrett's esophagus to EAC to be significantly lower than previously reported, raising concerns regarding the limitations of current surveillance strategies. Advances in imaging techniques and their enhanced diagnostic accuracy may improve the value of endoscopic surveillance. Additionally, various efforts are ongoing to identify biomarkers that identify individuals at higher risk of cancer, possibly allowing for individual risk stratification. SUMMARY: These new data highlight some of the opportunities to revise and improve surveillance in patients with Barrett's esophagus. The incorporation of new advances such as imaging techniques and biomarkers has the potential to improve the effectiveness and cost-effectiveness of new surveillance regimens. PMID- 22508327 TI - Gender and location of CRC in IBD: implications for surveillance protocols. PMID- 22508326 TI - Lack of sequence variations in THAP1 gene and THAP1-binding sites in TOR1A promoter of DYT1 patients. PMID- 22508328 TI - Nickel-catalyzed regio- and stereoselective reductive coupling between methylenecyclopropanes, aldehydes, and triethylborane with retention of the cyclopropane ring. AB - Running rings: The first regio- and stereoselective reductive coupling between methylenecyclopropanes, aldehydes, and triethylborane with retention of the cyclopropane ring was achieved using a nickel-phosphine catalyst (see scheme). The reductive coupling reaction constructed a stereo-defined cyclopropane ring with formation of a quaternary stereogenic carbon center. PMID- 22508329 TI - Resolution of 2-chloromandelic acid with (R)-(+)-N-benzyl-1-phenylethylamine: chiral discrimination mechanism. AB - During the resolution of 2-chloromandelic acid with (R)-(+)-N-benzyl-1 phenylethylamine, the crystals of the less soluble salt were grown, and their structure were determined and presented. The chiral discrimination mechanism was investigated by examining the weak intermolecular interactions (such as hydrogen bond, CH/pi, and van der Waals interactions) and molecular packing mode in crystal structure of the less soluble diastereomeric salt. A one-dimensional double-chain hydrogen-bonding network and a "lock-and-key" supramolecular packing mode are disclosed. The investigation demonstrates that hydrophobic layers with corrugated surfaces can fit into the grooves of one another to realize a compact packing, when the molecular structure of resolving agent is much larger than that of the racemate. This "lock-and-key" assembly is recognized to be another characteristic of molecular packing contributing to the chiral discrimination, in addition to the well-known sandwich-like packing by hydrophobic layers with planar boundary surfaces. PMID- 22508330 TI - Regioselectivity in the ring opening of epoxides for the synthesis of aminocyclitols from D-(-)-quinic acid. AB - Efficient syntheses of four aminocyclitols are reported. Each synthesis is accomplished in eight steps starting from D-(-)-quinic acid. The key step involves a highly regioselective ring opening of epoxides by sodium azide. PMID- 22508331 TI - The Suzuki reaction applied to the synthesis of novel pyrrolyl and thiophenyl indazoles. AB - The paper describes the Suzuki cross-coupling of a variety of N and C-3 substituted 5-bromoindazoles with N-Boc-2-pyrrole and 2-thiopheneboronic acids. The reactions, performed in the presence of K(2)CO(3), dimethoxyethane and Pd(dppf)Cl(2) as catalyst, gave the corresponding adducts in good yields. The methodology allows the facile production of indazole-based heteroaryl compounds, a unique architectural motif that is ubiquitous in biologically active molecules. PMID- 22508332 TI - Gene cloning, expression and activity analysis of manganese superoxide dismutase from two strains of Gracilaria lemaneiformis (Gracilariaceae, Rhodophyta) under heat stress. AB - Manganese superoxide dismutase (Mn-SOD) plays a crucial role in antioxidant responses to environmental stress. To determine whether Mn-SOD affects heat resistance of Gracilaria lemaneiformis, we cloned Mn-SOD cDNA sequences of two strains of this red alga, wild type and cultivar 981. Both cDNA sequences contained an ORF of 675 bp encoding 224 amino acid residues. The cDNA sequences and the deduced amino acid sequences of the two strains shared relatively high identity (more than 99%). No intron existed in genomic DNA of Mn-SOD in G. lemaneiformis. Southern blotting indicated that there were multiple copies, possibly four, of Mn-SOD in both strains. Both in the wild type and cultivar 981, SOD mRNA transcription and SOD activity increased under high temperature stress, while cultivar 981 was more heat resistant based on its SOD activity. This research suggests that there may be a direct relationship between SOD activity and the heat resistance of G. lemaneiformis. PMID- 22508333 TI - Large-scale solvent-free chlorination of hydroxy-pyrimidines, -pyridines, pyrazines and -amides using equimolar POCl3. AB - Chlorination with equimolar POCl3 can be efficiently achieved not only for hydroxypyrimidines, but also for many other substrates such as 2-hydroxy pyridines, -quinoxalines, or even -amides. The procedure is solvent-free and involves heating in a sealed reactor at high temperatures using one equivalent of pyridine as base. It is suitable for large scale (multigram) batch preparations. PMID- 22508334 TI - 1,25-Dihydroxyvitamin D3 inhibits the cytokine-induced secretion of MCP-1 and reduces monocyte recruitment by human preadipocytes. AB - BACKGROUND: Adipose tissue expansion during obesity is associated with a state of low-grade inflammation and an increase in macrophage infiltration, which predisposes to insulin resistance and vascular malfunction. Growing evidence suggests that vitamin D3 has immunoregulatory effects and adipose tissue could be a target for vitamin D3 action. Preadipocytes, one of the major cell types in adipose tissue, are actively involved in inflammatory processes. OBJECTIVES: This study investigated whether the active form of vitamin D3 (1,25(OH)2D3) affects the production of proinflammatory chemokines/cytokines and the monocyte recruitment by human preadipocytes. METHODS/RESULTS: The secretion levels of monocyte chemoattractant proteint-1 (MCP-1), IL-8 and IL-6 were significantly higher in preadipocytes than in differentiated adipocytes, suggesting that preadipocytes could be a major source of proinflammatory mediators. Cytokine profile analysis revealed that 1,25(OH)2D3 (10 nM) markedly reduced the release of MCP-1, IL-6 and IL-8 by preadipocytes. The involvement of NFkappaB signalling was shown by the upregulation of IkappaBalpha protein abundance by 1,25(OH)2D3 in preadipocytes. In addition, 1,25(OH)2D3 was able to decrease the migration of THP 1 monocytes. Treatment with proinflammatory stimuli, including macrophage conditioned (MC) medium, TNFalpha and IL-1beta, led to a marked increase in protein release of MCP-1 and IL-6 by preadipocytes. Pretreatment with 1,25(OH)2D3 (10 nM and 100 nM) significantly decreased the stimulatory effects of MC medium, TNFalpha and IL-1beta on MCP-1 expression and protein release, although the effect on stimulated release of IL-6 was less potent. CONCLUSIONS: These results demonstrate that 1,25(OH)2D3 decreases the production of MCP-1 and other proinflammatory mediators by preadipocytes and reduces monocyte migration. Thus, vitamin D3 may protect against adipose tissue inflammation by disrupting the deleterious cycle of macrophage recruitment. PMID- 22508335 TI - Unraveling the adipocyte inflammomodulatory pathways activated by North American ginseng. AB - BACKGROUND: North American (NA) ginseng (Panax quinquefolius) is a popular natural health product (NHP) that has been demonstrated to regulate immune function, inflammatory processes and response to stress and fatigue. Recent evidence suggests that various extracts of NA ginseng may have different bioactivities because of distinct profiles of ginsenosides and polysaccharides. To date, the bioactive role of ginseng on adipocytes remains relatively unexplored. OBJECTIVE: The goal of this work was to study the extract-specific bioactivity of NA ginseng on differentiated preadipocyte gene expression and adipocytokine secretion. METHODS: In vitro differentiated 3T3-L1 preadipocytes were treated with 25 and 50 MUg ml of either crude ethanol (EtOH) or aqueous (AQ) NA ginseng extracts, or polysaccharide and ginsenoside extracts isolated from the AQ extract. Global gene expression was studied with microarrays and the resulting data were analyzed with functional pathway analysis. Adipocytokine secretion was also measured in media. RESULTS: Pathway analysis indicated that the AQ extract, and in particular the polysaccharide extract, triggered a global inflammomodulatory response in differentiated preadipocytes. Specifically, the expression of Il-6 (interleukin 6), Ccl5 (chemokine (C-C motif) ligand 5), Nfkappab (nuclear factor-kappaB) and Tnfalpha (tumor necrosis factor alpha) was increased. These effects were also reflected at the protein level through the increased secretion of IL-6 and CCL5. No effect was seen with the EtOH extract or ginsenoside extract. Using a specific toll-like receptor 4 (TLR4) inhibitor reduced the upregulation of inflammatory gene expression, indicating the relevance of this pathway for the signaling capacity of NA ginseng polysaccharides. CONCLUSION: This work emphasizes the distinct bioactivities of different ginseng extracts on differentiated preadipocyte signaling pathways, and highlights the importance of TLR4 for mediating the inflammomodulatory role of ginseng polysaccharides. PMID- 22508336 TI - Diet-induced obesity promotes depressive-like behaviour that is associated with neural adaptations in brain reward circuitry. AB - BACKGROUND: The biological mechanisms that link the development of depression to metabolic disorders such as obesity and diabetes remain obscure. Dopamine- and plasticity-related signalling in mesolimbic reward circuitry is implicated in the pathophysiology and aetiology of depression. OBJECTIVE: To determine the impact of a palatable high-fat diet (HFD) on depressive-like behaviour and biochemical alterations in brain reward circuitry in order to understand the neural processes that may contribute to the development of depression in the context of diet induced obesity (DIO). METHODS: Adult male C57Bl6 mice were placed on a HFD or ingredient-matched, low-fat diet for 12 weeks. At the end of the diet regimen, we assessed anxiety and depressive-like behaviour, corticosterone levels and biochemical changes in the midbrain and limbic brain regions. Nucleus accumbens (NAc), dorsolateral striatum (DLS) and ventral tegmental area dissections were subjected to SDS-PAGE and immunoblotting using antibodies against D1A receptor, D2 receptor, brain-derived neurotrophic factor (BDNF), phospho-DARPP-32(thr75), phospho-CREB and DeltaFosB. RESULTS: HFD mice showed significant decreases in open arm time and centre time activity in elevated plus maze and open field tasks, respectively, and increased immobility (behavioural despair) in the forced swim test. Corticosterone levels following acute restraint stress were substantially elevated in HFD mice. HFD mice had significantly higher D2R, BDNF and DeltaFosB, but reduced D1R, protein expression in the NAc. Notably, the expression of BDNF in both the NAc and DLS and phospho-CREB in the DLS was positively correlated with behavioural despair. CONCLUSIONS: Our results demonstrate that chronic consumption of high-fat food and obesity induce plasticity-related changes in reward circuitry that are associated with a depressive-like phenotype. As increases in striatal BDNF and CREB activity are well implicated in depressive behaviour and reward, we suggest these signalling molecules may mediate the effects of high-fat feeding and DIO to promote negative emotional states and depressive-like symptomology. PMID- 22508337 TI - Pre-bariatric surgery weight loss requirements and the effect of preoperative weight loss on postoperative outcome. AB - Pre-bariatric surgery requirements vary between surgeons and surgical centers, with standards of practice not yet established. The goal of this systematic review was to summarize and evaluate the available literature on pre-bariatric surgery weight loss requirements and the relation between preoperative weight loss and postoperative outcome. Major databases, including Medline, PubMed and PsychINFO were searched for relevant articles. Case studies, studies>20 years old and studies that utilized self-reported body weight data were excluded. Data on the effect of the following was summarized: (1) preoperative requirements on preoperative weight loss; (2) insurance-mandated preoperative requirements; (3) the contingency of receipt of surgery; (4) preoperative weight loss on postoperative weight loss and (5) preoperative weight loss on perioperative and postoperative complication and comorbidity rates. The majority of studies suggest that: (1) current preoperative requirements held by the majority of third party payer organizations in the United States are ineffective in fostering preoperative weight loss; (2) making receipt of surgery contingent upon achieving preoperative weight loss, and meal-replacement diets, may be particularly effective in fostering preoperative weight loss and (3) preoperative weight loss may lead to improvements in at least some relevant postoperative outcomes. However, a preoperative weight loss mandate may lead to the denial of surgery and subsequent health benefits to individuals who are unable to achieve a prespecified amount of weight. Overall, the limited number and quality of prospective studies in this area prohibits the much-needed establishment of standards of practice for pre-bariatric requirements. PMID- 22508338 TI - Relation of chemokines to BMI and insulin resistance at ages 18-21. AB - OBJECTIVE: In obesity, adipose tissue becomes a significant source of chemokines and inflammatory cytokines that are associated with chronic systemic low-grade inflammation and may lead to insulin resistance. Studies in children have mainly focused on inflammatory cytokines and there are limited data for chemokines in adolescents and young adults. We studied the relation of chemokines to cardiovascular (CV)-risk factors, insulin resistance and adipocytokines in 18-21 year-old individuals. SUBJECTS AND DESIGN: Cross-sectional data collected in a cohort originally enrolled at mean age 13, with data for the present study obtained from 252 examined at age 18.7+/-0.1 years. METHODS: Multiple linear regression models were used to analyze the associations among chemokines (monocyte chemotactic protein-1, macrophage inflammatory protein-1beta (MIP 1beta), visfatin and interleukin-8 (IL-8)) and between chemokines and body mass index (BMI), glucose, lipids, blood pressure (BP), insulin resistance (euglycemic hyperinsulinemic clamp) and adipocytokines (IL-6, TNF-alpha and adiponectin). RESULTS: Chemokine levels were significantly intercorrelated. Significant associations (P<0.05) with adjustment for age, race and sex included: MIP-1beta with waist circumference and IL-6, IL-8 with systolic BP and visfatin with IL-6. No other significant relations were found between the chemokines and the other variables. Further adjustment for BMI did not alter these conclusions. CONCLUSION: Considered in the context of prior studies in children and adults, these results suggest that in large part, the association between chemokines and CV risk or inflammatory factors does not appear to develop until adult life. PMID- 22508339 TI - A longitudinal analysis of gross motor coordination in overweight and obese children versus normal-weight peers. AB - BACKGROUND: The relationship of childhood overweight (OW) and obesity (OB) with motor skill and coordination is gaining due attention; however, longitudinal evidence is currently lacking. OBJECTIVE: The dual purpose of this study was (1) to investigate the short-term evolution in the level of gross motor coordination according to children's weight status, and (2) to identify those factors predicting their gross motor coordination performance over a 2-year interval. SUBJECTS: Participants were 50 children with OW, including 8 with OB (aged 6-10 years at baseline, with 52% boys), and 50 with normal-weight (NW) matched for gender and age. MEASUREMENTS: Anthropometrics (body height, body weight, body mass index (BMI), %body fat) and level of gross motor coordination (Korperkoordinationstest fur Kinder, KTK) were assessed in 2007 (baseline) and 2 years later in 2009 (follow-up). At baseline, participants completed a survey based on the Flemish Physical Activity Questionnaire (FPAQ) to obtain socio demographic information and to determine physical activity levels in diverse domains. RESULTS: The evolution in the level of gross motor coordination over time was strongly related to children's weight status. Participants in the NW group showed more progress than their OW/OB peers, who demonstrated significantly poorer performances. Accordingly, between-group differences in KTK outcomes (that is, raw item scores and total motor quotient) became more evident over time. Multiple linear regression analysis further indicated that, in addition to BMI per se (negative predictor), participation in organized sports within a sports club (positive predictor) determines gross motor coordination performance(s) 2 years later. CONCLUSION: Our results provide conclusive evidence for an increasingly widening gap of OW/OB children's gross motor coordination relative to NW peers across developmental time in the absence of targeted initiatives. Special attention is thus needed for OW/OB children, especially for those not practicing sports in a club environment, in terms of motor skill improvement to promote regular participation in physical activity. PMID- 22508340 TI - Psychological burden in adult neurofibromatosis type 1 patients: impact of disease visibility on body image. AB - AIM: To evaluate the impact of disease visibility on psychological stress factors in neurofibromatosis type 1 (NF1) and to explore the body image of NF1 patients. METHODS: 228 adult NF1 patients participated in this cross-sectional survey. The questionnaire assessed perceived disease visibility and patients' body image. Outcome parameters were depression, distress and quality of life. Mediation models were performed to test if body experience mediated the effect of disease visibility on outcome parameters. RESULTS: Adult NF1 patients had a negative body image, expressed by bodily insecurity/uneasiness and fewer feelings of attractiveness and self-confidence. Compared to the body image of patients with other disfiguring diseases, patients with NF1 felt less attractive, displayed less self-confidence (women: p < 0.001; men: p < 0.001) and were more insecure/uneasy and sexually dissatisfied with their bodies (men: p < 0.001; women: p <= 0.12, d = 0.28). The found effect of disease visibility on psychological stress was completely mediated by how patients experienced their bodies. CONCLUSIONS: Our study shed light on the importance of how NF1 patients experience and appraise their own bodies. We revealed that body image is an important link between disease visibility and psychological well-being. The body image of patients can be improved with psychotherapeutic interventions. PMID- 22508341 TI - Association between glycosylated hemoglobin and intentional weight loss in overweight and obese patients with type 2 diabetes mellitus: a retrospective cohort study. AB - PURPOSE: The purpose of this study is to assess the relationship between magnitude of weight loss and improvement in percentage A1C (A1C%) among overweight and obese patients with type 2 diabetes mellitus (DM) undergoing weight reduction. METHODS: Case records of patients enrolled in 2 university based weight management programs were reviewed. Patients were sampled if they had a diagnosis of DM and had at least 1 documented A1C% reduction from their baseline value. Weight loss treatment was individualized and consisted of a calorie-restricted diet, a behavior modification plan, and a plan for increasing physical activity. Patient weights were measured at bimonthly visits. A1C% was measured every 3 months. RESULTS: Seventy-two patients formed the study cohort. Mean baseline body mass index was 35.1 kg/m(2), mean age was 52.6 years, and 59% were males. Mean starting A1C% was 8.6. Patients achieved significant mean weight loss (10.7 kg) at study exit. Weight loss of 6.5 kg (4.5% of baseline body weight), 12.2 kg (8.7%), and 15.9 kg (10.3%) was required to reduce A1C% by 0.5, 1, and 1.5, respectively, and it took a mean of 5.6, 8.7, and 10.1 months, respectively, to achieve this. After adjustment for antidiabetic medication intake, for every 10% weight loss, the predicted reduction in A1C% was 0.81. CONCLUSIONS: Intentional weight loss of 10% can potentially decrease A1C% by 0.81 among patients with type 2 DM. This finding may be clinically useful in encouraging and counseling a patient attempting weight loss. PMID- 22508342 TI - Electrochemotherapy for disseminated superficial metastases from malignant melanoma. AB - BACKGROUND: The aim of the study was to determine predictive factors for effectiveness, toxicity and local disease control in patients with malignant melanoma treated with bleomycin-based electrochemotherapy (ECT). METHODS: Electrochemotherapy was offered to patients with superficially disseminated melanoma metastases unsuitable for resection and unresponsive to chemotherapy. RESULTS: Eighty-five patients were treated with up to six ECT cycles with minimal, mainly dermatological, toxicity. One month after the first ECT, an objective response was observed in 80 patients (94 per cent). After retreatment because of a partial response in 39 patients, a complete response was achieved in 19 patients. Among the 41 (48 per cent) complete responders at first ECT, 19 patients received a second cycle because of new lesions after a median of 6 (range 2-14) months. After a median follow-up of 26 months, six patients experienced local recurrence with a 2-year local progression-free survival rate of 87 per cent. In multivariable analysis, significant predictive factors for response were tumour size (odds ratio (OR) 0.23, 95 per cent confidence interval (c.i.) 0.19 to 0.86; P = 0.003) and number of lesions (OR 0.38, 0.28 to 0.88; P = 0.002). An increasing number of electrode applications (hazard ratio (HR) 2.18, 95 per cent c.i. 1.22 to 3.44; P = 0.041) and ECT cycles (HR 0.46, 0.22 to 0.95; P = 0.005) were predictors of local control. There were no predictors of toxicity. Melanoma thickness and lower limb location of metastases were prognostic for survival. CONCLUSION: The most suitable candidates for ECT were patients with few and small metastases on the lower limb treated with multiple electrode applications and ECT cycles. PMID- 22508343 TI - Mobile monitoring along a street canyon and stationary forest air monitoring of formaldehyde by means of a micro-gas analysis system. AB - A micro-gas analysis system (MUGAS) was developed for mobile monitoring and continuous measurements of atmospheric HCHO. HCHO gas was trapped into an absorbing/reaction solution continuously using a microchannel scrubber in which the microchannels were patterned in a honeycomb structure to form a wide absorbing area with a thin absorbing solution layer. Fluorescence was monitored after reaction of the collected HCHO with 2,4-pentanedione (PD) in the presence of acetic acid/ammonium acetate. The system was portable, battery-driven, highly sensitive (limit of detection = 0.01 ppbv) and had good time resolution (response time 50 s). The results revealed that the PD chemistry was subject to interference from O(3). The mechanism of this interference was investigated and the problem was addressed by incorporating a wet denuder. Mobile monitoring was performed along traffic roads, and elevated HCHO levels in a street canyon were evident upon mapping of the obtained data. The system was also applied to stationary monitoring in a forest in which HCHO formed naturally via reaction of biogenic compounds with oxidants. Concentrations of a few ppbv-HCHO and several tens of ppbv of O(3) were then simultaneously monitored with the MUGAS in forest air monitoring campaigns. The obtained 1 h average data were compared with those obtained by 1 h impinger collection and offsite GC-MS analysis after derivatization with o-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine (PFBOA). From the obtained data in the forest, daily variations of chemical HCHO production and loss are discussed. PMID- 22508344 TI - Translation of molecular pathways into clinical trials of neuroendocrine tumors. AB - Current treatment options for neuroendocrine tumors (NET) include somatostatin analogs, interferon-alpha, peptide receptor-targeted therapy and cytotoxic chemotherapy. Most patients undergo sequential therapies since these drugs are active only in subpopulations of patients and for a limited period of time. There is a need for novel drugs that are capable of amelioration of symptomatology (syndromic control) and/or tumor growth control. A number of diverse signaling pathways are involved in the pathogenesis of NET and tumor growth, thus many potential targets are available for drug targeting. Targeted therapies therefore represent an appropriate developmental therapeutic strategy given the multiplicity of potential targets in NET. These include but are not limited to: inhibitory or activating G protein-coupled receptors, receptor tyrosine kinases, ligands, and intracellular targets such as the mammalian target of rapamycin (mTOR). Numerous drugs that utilize single or multiple targets are currently in clinical development. Recently, two target-directed agents, the multiple tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus, have been approved for the treatment of progressive pancreatic NET. This review provides a broad overview of established and potential molecular targets in NET, summarizes data from phase II and III clinical trials with targeted drugs and outlines future therapeutic directions. PMID- 22508346 TI - Development of strong Bronsted base catalysis: catalytic direct-type Mannich reactions of non-activated esters via a product-base mechanism. AB - A catalytic Mannich reaction of a simple ester with no activating functionality at the alpha-position via a product-base mechanism was reported. The desired Mannich adducts were obtained in high yields using a catalytic amount of KH. This is a rare example of a Bronsted base-catalyzed Mannich reaction of unactivated esters as substrates. PMID- 22508345 TI - Neonatal screening: identification of children with 11beta-hydroxylase deficiency by second-tier testing. AB - BACKGROUND: 21-Hydroxylase deficiency (21-OHD) is the target disease of newborn screening for congenital adrenal hyperplasia (CAH). We describe the additional detection of patients suffering from 11beta-hydroxylase deficiency (11-OHD) by second-tier testing. METHOD: Over a period of 5 years, screening for CAH was done in a total of 986,098 newborns by time-resolved immunoassay (DELFIA(r)) for 17alpha-hydroxyprogesterone (17-OHP). Positive samples were subsequently analyzed in an LC-MS/MS second-tier test including 17-OHP, cortisol, 11-deoxycortisol, 4 androstenedione and 21-deoxycortisol. RESULTS: In addition to 78 cases of 21-OHD, 5 patients with 11-OHD were identified. Diagnostic parameters were a markedly elevated concentration of 11-deoxycortisol in the presence of a low level of cortisol. Androstenedione was also increased. In contrast to 21-OHD, concentrations of 21-deoxycortisol were normal. CONCLUSION: Steroid profiling in newborn blood samples showing positive results in immunoassays for 17-OHP allows for differentiating 21-OHD from 11-OHD. This procedure may not detect all cases of 11-OHD in the newborn population because there may be samples of affected newborns with negative results for 17-OHP in the immunoassay. PMID- 22508347 TI - A new phenotype of brain iron accumulation with dystonia, optic atrophy, and peripheral neuropathy. AB - BACKGROUND: Neurodegeneration with brain iron accumulation is clinically and genetically heterogeneous because of mutations in at least 7 nuclear genes. METHODS: We performed homozygosity mapping and whole-exome sequencing in 2 brothers with brain iron accumulation from a consanguineous family. RESULTS: We identified a homozygous missense mutation in both brothers in the very recently identified chromosome 19 open-reading frame 12 gene. The disease presented before age 10 with slowly progressive tremor, dystonia, and spasticity. Additional features were optic atrophy, peripheral neuropathy, and learning difficulties. A raised serum creatine kinase indicated neuromuscular involvement, and compensatory mitochondrial proliferation implicated mitochondrial dysfunction as a pathological mechanism. CONCLUSIONS: Further studies are needed to explore the function of the chromosome 19 open-reading frame 12 gene, and extended genetic analysis on larger patient cohorts will provide more information about the presentation and frequency of this disease. PMID- 22508348 TI - [Respect]. PMID- 22508349 TI - [Emergency compulsory admission in crisis situations; the Amsterdam Study of Acute Psychiatry]. AB - BACKGROUND: This article presents initial data from the Amsterdam Study of Acute Psychiatry (ASAP) which investigated the factors that play a role in the decision to admit a patient compulsorily to a psychiatric clinic in the Amsterdam area. AIM: To find out how socio-demographic factors, a patient's psychiatric history and pathway to care influence a patient's chance of being served with an emergency compulsory admission order during emergency consultation. METHODS: We conducted a prospective cohort study of 1970 consecutive patients who consecutively came into contact with the Psychiatric Emergency Service Amsterdam (PESA) in the period September 2004 to September 2006. RESULTS: A patient who had been admitted compulsorily once in the previous five years ran an increased risk of compulsorily admission (or 3.9). Referral by the police or by the mental health services also implied a high risk of a compulsorily admission (or 2.2 and or 2.6 respectively). CONCLUSION: A previous compulsorily admission and referral by the police or mental health services were found to be predictors of emergency compulsory admission, irrespective of possible danger to the patient himself and others and irrespective of the patient's lack of motivation for treatment. PMID- 22508350 TI - [Risk assessment of violent women: development of the 'Female Additional Manual' (FAM)]. AB - BACKGROUND: Violence perpetrated by women is a growing problem. Research has shown that the risk factors associated with women differ from those associated with men and that the risk assessments currently in use are not adequate for predicting violence in women. AIM: To develop a clinically relevant, useful tool for an accurate, gender-sensitive assessment of risk of violent behaviour in women and to offer guidelines for risk management in women. METHOD: On the basis of literature research, clinical expertise and the results of a pilot study, we adapted the much-used 'Historical Clinical Risk management-20 (HCR-20) for use with female (forensic) psychiatric patients who have a record of violence towards other people. RESULTS: The 'Female Additional Manual (FAM) supplemented and added value to the HCR-20 for assessing the risk of violent behaviour by women. CONCLUSION: The fam is a valuable addition to the currently available risk assessment tools in that it provides a more accurate gender-specific risk assessment with regard to female (forensic) psychiatric patients. Future research will have to further demonstrate the value of the FAM. PMID- 22508351 TI - [Are men really from Mars and women from Venus?]. PMID- 22508352 TI - [Suicide prevention via the internet and the telephone: 113Online]. AB - BACKGROUND: 113Online is a combination of a website and a telephone help-line for suicidal persons, their relatives and bereaved next of kin. The services it provides include crisis intervention, self-tests and brief psychotherapy. aim: To discover whether 113Online can in fact prevent suicidal behaviour - since it has now been in operation for more than a year. METHOD: We were able to obtain information about the visitors of the website, check on the usage of services provided by 113Online and study the results of the self-tests. RESULTS: The results for the first year indicated that there was a great need for anonymous online help for persons contemplating suicide. Scores for the self-tests showed that the website was visited by severely suicidal persons. It is surprising that so few of the users thereafter sought assistance from the conventional mental health care services. CONCLUSION: The 113Online seems to be a promising approach to suicide prevention. The online assistance reaches its target population and seems to fulfil needs that are not being met by the regular health care services. PMID- 22508353 TI - [Pathological hoarding by children and adolescents]. AB - BACKGROUND: There is a dearth of knowledge and understanding concerning hoarding by children and adolescents. Psychiatrists need to know more about the phenomenon of hoarding since it can be a marker of psychopathology and it sometimes is symptomatic of a psychiatric disorder. AIM: To review hoarding from an epidemiological and psychopathological perspective and to discuss it in relation to the developmental aspect of the first object acquisition: the transitional object. METHOD: We conducted a literature search in PubMed, Medline, PsycINFO and the Cochranedatabase using primarily the search term 'hoarding', but also in combination with the terms: primates, child, adolescent, psych*, klepto*, transitional object, obsessive-compulsive disorder, collecting and attachment. RESULTS: Both animals and humans engage frequently in collecting and hoarding. Up to 60% of normally functioning children and adolescents are involved in collecting. A strong emotional attachment to possessions may be a response to an attachment problem. Hoarding combined with psychopathology is seen in persons of all ages but the prevalence rates for children and adults are unknown. CONCLUSION: Hoarding is a worrisome type of behaviour which must be regarded as an indication of serious comorbid psychopathology. It can occur either as a symptom of an existing disorder or as a separate disorder. Finally we recommend that hoarding be included in the diagnostic criteria of the dsm and icd. PMID- 22508354 TI - [Neurotoxicity in elderly patients being treated with lithium: is there a reason to adjust the dosage administered?]. AB - BACKGROUND: Neurotoxicity can occur in patients being treated with lithium. Features are cognitive dysfunctioning and motor symptoms. Some results of research performed on adults up to the age of 65 indicate that lithium can cause mild cognitive dysfunctioning. It is not clear, however, whether elderly patients are more susceptible than young adults to this form of neurotoxicity or, if this is the case, whether the dosage of lithium should be reduced. AIM: To determine whether elderly patients treated with lithium run an increased risk of neurotoxicity, and to discuss the pharmacodynamic aspects of lithium use in the elderly which may cause neurotoxicity. METHOD: Literature review in Cochrane (all EBM), Embase, PsycINFO, Medline and PubMed, with cross-checked references. RESULTS: Few studies described possible neurotoxic effects of lithium. We found no indications for cognitive dysfunctioning in elderly patients being treated with lithium. However, a lithiumassociated tremor was seen more often in elderly patients than in younger adults. Pharmacodynamic effects of aging, such as an increase in the lithium concentration in the brain with no change in the serum level, may give rise to side-effects. More research is needed into the relationship between the serum level and the neurotoxic effects of lithium in the elderly. CONCLUSION: There are no indications that lithium causes more neurotoxicity in the elderly than in younger adults. If the use of lithium is indicated, it can be safely prescribed for the elderly, provided age-related pharmacodynamics are taken into account. PMID- 22508355 TI - [Pills for the Psyche. Neuro-enhancement among psychiatrists, trainees and other doctors in the Netherlands -- an explanatory study]. AB - BACKGROUND: Psychotropic drugs are being used increasingly for the purpose of neuroenhancement. A survey conducted by Nature revealed that neuro-enhancing drugs were also being used quite widely by non-medical academics. AIM: To investigate the extent to which psychiatrists and other doctors working in psychiatry in the Netherlands actually take neuro-enhancing drugs themselves, and to record their views on the use of such drug. The findings form a basis for an ethical debate about the use of neuro-enhancing drugs in the Netherlands. METHOD: We transmitted an online questionnaire, based on the survey conducted by Nature, to as many as possible psychiatrists, trainees and other doctors working in psychiatry in the Netherlands. RESULTS: 11% of the respondents reported that they had occasionally taken neuro-enhancing medication without any medical reason in order to improve their own mental functioning. 66% of respondents felt that no one should be allowed to take psychotropic drugs unless these have been prescribed for a strictly medical reason. CONCLUSION: Compared to those who responded to the Nature survey, respondents to the Dutch survey seemed to have considerably more reservations about the private use of neuroenhancing drugs and seemed to be more critical about their use in general. PMID- 22508356 TI - [An inpatient version of mentalisation-based treatment for patients with cluster A personality disorders]. AB - BACKGROUND: Despite the severity of their disorder, only a few patients suffering from cluster A personality problems are admitted to mental health care facilities for appropriate treatment. A review of the international literature on the treatment of cluster A patients does not reveal any description of non pharmaceutical treatment for this group of patients, nor does it mention any research into the effectiveness of treatment for the group. AIM: To describe the development of a step-down inpatient treatment model for patients suffering from severe cluster A problems. METHOD: We reviewed the sparse research and the limited reports of clinical experience. RESULTS: The arguments supporting a step down inpatient version of mentalisation-based treatment and its application in clinical practice are discussed. CONCLUSION: A step-down inpatient treatment model has been developed and will be tested in research. PMID- 22508358 TI - [Reaction on 'Reorganisation of the mental health services in Belgium in 2011. Will this lead to better care for patients with a serious mental illness?']. PMID- 22508357 TI - [Clinical treatment of posttraumatic stress disorder in patients with serious dual diagnosis problems]. AB - Three patients with severe addiction problems, early sexual trauma, posttraumatic stress disorder PTSD comorbid psychotic vulnerability and personality problems received integrated treatment following admission to a clinic specialising in the care of patients with a dual diagnosis. Treatment was administered in accordance with current guidelines and involved either imaginal exposure or eye movement desensitization and reprocessing EMDR, integrated with relapse management of addiction problems. It is concluded that the current evidence-based guidelines regarding PTSD and addiction can also be applied successfully and effectively to an extremely vulnerable patient population. PMID- 22508359 TI - Antiobesity effects of Chinese black tea (Pu-erh tea) extract and gallic acid. AB - The antiobesity effects of Chinese black tea (Pu-erh tea) and of gallic acid (GA) were investigated using in vitro and in vivo assays. Chinese black tea extract (BTE) and GA inhibited pancreatic lipase activity in a dose-dependent manner in vitro; the IC(inhibitory concentration)(50) values were 101.6 and 9.2 ug/mL, respectively. Black tea extract (50, 100 mg/kg body weight (b.w.)) and GA (15, 45 mg/kg b.w.) significantly suppressed the elevation of blood triglyceride after oral administration of a corn oil emulsion (8 mL oil/kg b.w.) to male ddY mice. Moreover, the antiobesity effects of BTE and GA were also evaluated in a mouse model of diet-induced obesity. Female ddY mice were divided into seven groups; normal diet (ND) group, high fat diet (HFD) group, BTE (0.2% and 0.6% of diets) groups, and GA (0.007%, 0.02% and 0.1% of diets) groups; the experimental groups were fed the test diets for 12 weeks. The BTE 0.6% and GA 0.1% groups showed significant suppression of weight gain. The weight of parametrial adipose tissue was strongly correlated with the body weight. These results suggest that GA contributes to the antiobesity effect of BTE as an active constituent by inhibiting pancreatic lipase activity. PMID- 22508360 TI - Honey prophylaxis reduces the risk of endophthalmitis during perioperative period of eye surgery. AB - Endophthalmitis following eye surgery remains a rare but serious complication. Topical fluoroquinolones have been used as prophylactic agents against endophthalmitis. However, the emerging resistance of ocular pathogens to fluoroquinolones may preclude their routine use. Honey, a natural antimicrobial product with wound healing properties, is a promising candidate for the prophylaxis of endophthalmitis. The goal of this study was to determine whether 25% (w/v) honey solution is effective in eradicating bacterial ocular pathogens in the perioperative period in patients scheduled for cataract surgery or vitrectomy, and to compare its efficacy to 0.3% ofloxacin. In this pilot study, 101 patients were randomized to honey (n = 49) or ofloxacin (n = 52) treatment. In both groups, eye drops were administered five times a day for 7 days before and 5 days after surgery. Before administration of the antibacterial agents, 18 and 25 isolates were detected in the ofloxacin and honey group, respectively. After 7 days of administration, four isolates (coagulase-negative Staphylococcus) were detected in each therapeutic group. No significant difference in antibacterial effect was found between groups. These results indicate that honey may act as a prophylactic agent of endophthalmitis; however, further studies are needed to characterize its ocular penetration properties. PMID- 22508362 TI - Pairwise interaction enthalpies of enantiomers of beta-amino alcohols in DMSO + H2O mixtures at 298.15 K. AB - The dilution enthalpies of enantiomers of six beta-amino alcohols, namely (R)-(-) 2-amino-1-propanol versus (S)-(+)-2-amino-1-propanol, (R)-(-)-2-amino-1-butanol versus (S)-(+)-2-amino-1-butanol, and (R)-(-)-2-amino-1-pentanol versus (S)-(+)-2 amino-1-pentanol in dimethylsulfoxide (DMSO) + H(2)O mixtures (mass fractions of DMSO w = 0 to 0.3) have been determined respectively using an isothermal titration calorimeter (MicroCal ITC200, Northampton, MA, USA) at 298.15 K. According to the McMillan-Mayer theory, the corresponding homochiral enthalpic pairwise interaction coefficients (h(XX)) of the six amino alcohols have been calculated. It is found that across the whole studied composition range of mixed solvent, values of h(XX) for S-enantiomer are almost universally higher than those of R-enantiomer for each amino alcohol and that the variations of h(XX) depend largely on the composition of mixed solvent. The results were interpreted from the point of view of solute-solute interaction mediated by cosolvent DMSO, as well as competition equilibrium between hydrophobic-hydrophobic, hydrophilic hydrophilic, and hydrophobic-hydrophilic interactions. PMID- 22508361 TI - The influence of obesity on the assessment of carotid intima-media thickness. AB - BACKGROUND: The assessment of carotid intima-media thickness (CIMT) may improve cardiovascular risk prediction. The optimal protocol for CIMT measurement is unclear. CIMT may be measured in the common carotid artery (CCA), carotid bifurcation (CB), and internal carotid artery (ICA), but measurements from CB and ICA are more difficult to obtain. We studied the influence of body mass index (BMI) and atheroma plaques on the capacity to obtain CIMT measurements at different carotid sites. METHODS: Using an automatic system, CIMT was measured in 700 subjects aged 45-75, in the near and far walls of CCA, CB, and ICA bilaterally. The presence of atheroma plaques, BMI and vascular risk factors were recorded. RESULTS: CIMT measurements in CCA were possible in all except one subject. It was not possible to obtain CIMT measurements at CB or ICA in 24.1% of normal weight and 58.8% of obese subjects. The likelihood of obtaining CIMT measurement at all carotid sites decreased as the BMI increased. Atheroma plaques in a carotid segment did not preclude CIMT measurement at this site. CONCLUSIONS: CIMT measurements in distal carotid segments are more challenging in obese subjects. Measuring CIMT at CCA remains feasible in obese subjects and should be the primary endpoint in these subjects. Nevertheless, CB and ICA measurements, when feasible, would improve risk classification. PMID- 22508363 TI - Concentration of metabolites from low-density planktonic communities for environmental metabolomics using nuclear magnetic resonance spectroscopy. AB - Environmental metabolomics is an emerging field that is promoting new understanding in how organisms respond to and interact with the environment and each other at the biochemical level. Nuclear magnetic resonance (NMR) spectroscopy is one of several technologies, including gas chromatography-mass spectrometry (GC-MS), with considerable promise for such studies. Advantages of NMR are that it is suitable for untargeted analyses, provides structural information and spectra can be queried in quantitative and statistical manners against recently available databases of individual metabolite spectra. In addition, NMR spectral data can be combined with data from other omics levels (e.g. transcriptomics, genomics) to provide a more comprehensive understanding of the physiological responses of taxa to each other and the environment. However, NMR is less sensitive than other metabolomic techniques, making it difficult to apply to natural microbial systems where sample populations can be low-density and metabolite concentrations low compared to metabolites from well-defined and readily extractable sources such as whole tissues, biofluids or cell-cultures. Consequently, the few direct environmental metabolomic studies of microbes performed to date have been limited to culture-based or easily defined high density ecosystems such as host-symbiont systems, constructed co-cultures or manipulations of the gut environment where stable isotope labeling can be additionally used to enhance NMR signals. Methods that facilitate the concentration and collection of environmental metabolites at concentrations suitable for NMR are lacking. Since recent attention has been given to the environmental metabolomics of organisms within the aquatic environment, where much of the energy and material flow is mediated by the planktonic community, we have developed a method for the concentration and extraction of whole-community metabolites from planktonic microbial systems by filtration. Commercially available hydrophilic poly-1,1-difluoroethene (PVDF) filters are specially treated to completely remove extractables, which can otherwise appear as contaminants in subsequent analyses. These treated filters are then used to filter environmental or experimental samples of interest. Filters containing the wet sample material are lyophilized and aqueous-soluble metabolites are extracted directly for conventional NMR spectroscopy using a standardized potassium phosphate extraction buffer. Data derived from these methods can be analyzed statistically to identify meaningful patterns, or integrated with other omics levels for comprehensive understanding of community and ecosystem function. PMID- 22508364 TI - Long-term clinical outcomes of Crohn's disease and intestinal Behcet's disease. AB - BACKGROUND: Crohn's disease (CD) and intestinal Behcet's disease (BD) are transmural inflammatory diseases with fluctuating courses characterized by repeated episodes of relapse and remission that often require operation or reoperation. However, no study has directly compared the long-term prognoses of these two diseases. METHODS: We reviewed the medical records of 332 patients with CD and 276 patients with intestinal BD who were regularly followed up at a single tertiary academic medical center in Korea between March 1986 and July 2010. The clinical outcomes after diagnosis and surgery were analyzed using the Kaplan Meier method and log-rank test. RESULTS: There were no significant differences in the cumulative probabilities of surgery (29.4% and 36.0% vs. 31.6% and 44.4% at 5 and 10 years, respectively: P = 0.287) or admission (66.1% and 73.8% vs. 59.0% and 69.2%, P = 0.259) between CD and intestinal BD. Furthermore, no differences were observed between the two diseases for the cumulative probabilities of postoperative clinical recurrence (P = 0.724) and reoperation (P = 0.770). However, the cumulative probabilities of corticosteroid use (63.8% and 76.6% vs. 42.6% and 59.4% at 5 and 10 years, respectively: P < 0.001) and immunosuppressant use (49.1% and 65.5% vs. 27.1% and 37.7%, P < 0.001) were significantly higher in CD patients than in intestinal BD patients. CONCLUSIONS: There were no significant differences in the long-term clinical outcomes and postoperative prognoses between CD and intestinal BD, although CD patients required corticosteroid or immunosuppressant therapy more often than intestinal BD patients. PMID- 22508365 TI - A two-platform design for next generation genome-wide association studies. AB - Genome-wide association studies (GWAS) have been successful in their search for common genetic variants associated with complex traits and diseases. With new advances in array technologies together with available genetic reference sets, the next generation of GWAS will extend the search for associations with uncommon SNPs (1% <= MAF <= 10%). Two possible approaches are genotyping all participants, a prohibitively expensive option for large GWAS, or using a combination of genotyping and imputation. Here, we consider a two platform method that genotypes all participants on a standard genotyping array, designed to identify common variants, and then supplements that data by genotyping only a small proportion of the participants on a platform that has higher coverage for uncommon SNPs. This subset of the study population is then included as part of the imputation reference set. To demonstrate the use of this two-platform design, we evaluate its potential efficiency using a newly available dataset containing 756 individuals genotyped on both the Illumina Human OmniExpress and Omni2.5 Quad. Although genotyping all individuals on the denser array would be ideal, we find that genotyping only 100 individuals on this array, in combination with imputation, leads to only a modest loss of power for detecting associations. However, the loss of power due to imputation can be more substantial if the relative risks for rare variants are significantly larger than those previously observed for common variants. PMID- 22508366 TI - Food cues do not modulate the neuroendocrine response to a prolonged fast in healthy men. AB - INTRODUCTION: Dietary restriction benefits health and increases lifespan in several species. Food odorants restrain the beneficial effects of dietary restriction in Drosophila melanogaster. We hypothesized that the presence of visual and odorous food stimuli during a prolonged fast modifies the neuroendocrine and metabolic response to fasting in humans. SUBJECTS AND METHODS: In this randomized, crossover intervention study, healthy young men (n = 12) fasted twice for 60 h; once in the presence and once in the absence of food related visual and odorous stimuli. At baseline and on the last morning of each intervention, an oral glucose tolerance test (OGTT) was performed. During the OGTT, blood was sampled and a functional MRI scan was made. RESULTS: The main effects of prolonged fasting were: (1) decreased plasma thyroid stimulating hormone and triiodothyronine levels; (2) downregulation of the pituitary-gonadal axis; (3) reduced plasma glucose and insulin concentrations, but increased glucose and insulin responses to glucose ingestion; (4) altered hypothalamic blood oxygenation level-dependent (BOLD) signal in response to the glucose load (particularly during the first 20 min after ingestion); (5) increased resting energy expenditure. Exposure to food cues did not affect these parameters. CONCLUSION: This study shows that 60 h of fasting in young men (1) decreases the hypothalamic BOLD signal in response to glucose ingestion; (2) induces glucose intolerance; (3) increases resting energy expenditure, and (4) downregulates the pituitary-thyroid and pituitary-gonadal axes. Exposure to visual and odorous food cues did not alter these metabolic and neuroendocrine adaptations to nutrient deprivation. PMID- 22508367 TI - In vitro identification of DNA-binding motif for the new zinc finger protein AtYY1. AB - The functional characterization of novel transcription factors identified by systematic analysis remains a major challenge due to insufficient data to interpret their specific roles in signaling networks. Here we present a DNA binding sequence discovery method to in vitro identify a G-rich, 11-bp DNA binding motif of a novel potential transcription factor AtYY1, a zinc finger protein in Arabidopsis, by using polymerase chain reaction-assisted in vitro selection and surface plasmon resonance analysis. Further mutational analysis of the conserved G bases of the potential motif confirmed that AtYY1 specifically bound to these conserved G sites. Additionally, genome-wide target gene analysis revealed that AtYY1 was involved in diverse cellular pathways, including glucose metabolism, photosynthesis, phototropism, and stress response. PMID- 22508368 TI - Waldenstrom macroglobulinemia: 2012 update on diagnosis, risk stratification, and management. AB - DISEASE OVERVIEW: Waldenstrom macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy. DIAGNOSIS: Presence of IgM monoclonal protein associated with >=10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. RISK STRATIFICATION: Age, hemoglobin level, platelet count, beta(2) microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis. RISK ADAPTED THERAPY: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-based therapy is used in virtually all US patients with WM and can be combined with alkylating agent or purine nucleoside analog (or both). The preferred Mayo Clinic nonstudy therapeutic induction is rituximab, cyclophosphamide, and dexamethasone. Future stem-cell transplantation should be considered in induction therapy selection. MANAGEMENT OF REFRACTORY DISEASE: Bortezomib, thalidomide, lenalidomide, and bendamustine have all been shown to have activity in WM. Given WM's natural history, reduction of complications will be a priority for future treatment trials. PMID- 22508369 TI - The aggressive peripheral T-cell lymphomas: 2012 update on diagnosis, risk stratification, and management. AB - BACKGROUND: T-cell lymphomas make up approximately 10-15% of lymphoid malignancies. The frequency of these lymphomas varies geographically, with the highest incidence in parts of Asia. DIAGNOSIS: The diagnosis of aggressive peripheral T-cell lymphoma (PTCL) is usually made using the WHO classification. The ability of hematopathologists to reproducibly diagnose aggressive PTCL is lower than for aggressive B-cell lymphomas, with a range of 72-97% for the aggressive PTCLs. RISK STRATIFICATION: Patients with aggressive PTCL are staged using the Ann Arbor Classification. Although somewhat controversial, positron emission tomography (PET) scans appear to be useful as they are in aggressive B cell lymphomas. The most commonly used prognostic index is the International Prognostic Index. The specific subtype of aggressive PTCL is an important risk factor, with the best survival seen in anaplastic large-cell lymphoma particularly young patients with the anaplastic lymphoma kinase positive subtype. RISK ADAPTED THERAPY: Anaplastic large-cell lymphoma is the only subgroup to have a good response to a cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-like regimen. Angioimmunoblastic T-cell lymphoma has a prolonged disease free survival in only ~20% of patients, but younger patients who have an autotransplant in remission seem to do better. PTCL-not otherwise specified (NOS) is not one disease. Anthracycline containing regimens have disappointing results and a new approach is needed. NK/T-cell lymphoma localized to the nose and nasal sinuses seems to be best treated with radiotherapy containing regimens. Enteropathy associated PTCL and hepatosplenic PTCL are rare disorders with a generally poor response to therapy, although selected patients with enteropathy associated PTCL seem to benefit from intensive therapy. PMID- 22508370 TI - Giant Mongolian macules with bilateral ocular involvement: case report and review. AB - Dermal melanocytosis is characterized by the presence of spindle-shaped melanocytes in the dermis. The most common form is Mongolian spots. A 15-month old girl from Azerbaijan had a systematized dark blue-gray hyperpigmentation on her shoulder, back and extremities. The hyperpigmentation was also found on both sclera and choroidal areas, without any other facial involvement. On histopathological examination, dense melanocytes were found on the intermediate and deep dermis. Her physical and mental development was normal. This association of blue macules and involvement of both sclerae does not represent a distinct entity and cannot be categorized as an example of nevus of Ota. PMID- 22508371 TI - Hepatic venous pressure gradient in the assessment of portal hypertension before liver resection in patients with cirrhosis. AB - BACKGROUND: Preoperative measurement of hepatic venous pressure gradient (HVPG) is not performed routinely before hepatectomy in patients with cirrhosis, although it has been suggested to be useful. This study investigated whether preoperative HVPG values and indirect criteria of portal hypertension (PHT) predict the postoperative course in these patients. METHODS: Between January 2007 and December 2009, consecutive patients with resectable hepatocellular carcinoma (HCC) in a cirrhotic liver were included in this prospective study. PHT was assessed by transjugular HVPG measurement and by classical indirect criteria (oesophageal varices, splenomegaly and thrombocytopenia). The main endpoints were postoperative liver dysfunction and 90-day mortality. RESULTS: Forty patients were enrolled. A raised HVPG was associated with postoperative liver dysfunction (median 11 and 7 mmHg in those with and without dysfunction respectively; P = 0.017) and 90-day mortality (12 and 8 mmHg in those who died and survivors respectively; P = 0.026). Oesophageal varices, splenomegaly and thrombocytopenia were not associated with any of the endpoints. In multivariable analysis, body mass index, remnant liver volume ratio and preoperative HVPG were the only independent predictors of postoperative liver dysfunction. CONCLUSION: An increased HVPG was associated with postoperative liver dysfunction and mortality after liver resection in patients with HCC and liver cirrhosis, whereas indirect criteria of PHT were not. This study suggests that preoperative HVPG measurement should be measured routinely in these patients. PMID- 22508372 TI - Label-free quantitation of peptide release from neurons in a microfluidic device with mass spectrometry imaging. AB - Microfluidic technology allows the manipulation of mass-limited samples and when used with cultured cells, enables control of the extracellular microenvironment, making it well suited for studying neurons and their response to environmental perturbations. While matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) provides for off-line coupling to microfluidic devices for characterizing small-volume extracellular releasates, performing quantitative studies with MALDI is challenging. Here we describe a label-free absolute quantitation approach for microfluidic devices. We optimize device fabrication to prevent analyte losses before measurement and then incorporate a substrate that collects the analytes as they flow through a collection channel. Following collection, the channel is interrogated using MS imaging. Rather than quantifying the sample present via MS peak height, the length of the channel containing appreciable analyte signal is used as a measure of analyte amount. A linear relationship between peptide amount and band length is suggested by modeling the adsorption process and this relationship is validated using two neuropeptides, acidic peptide (AP) and alpha-bag cell peptide [1-9] (alphaBCP). The variance of length measurement, defined as the ratio of standard error to mean value, is as low as 3% between devices. The limit of detection (LOD) of our system is 600 fmol for AP and 400 fmol for alphaBCP. Using appropriate calibrations, we determined that an individual Aplysia bag cell neuron secretes 0.15 +/- 0.03 pmol of AP and 0.13 +/- 0.06 pmol of alphaBCP after being stimulated with elevated KCl. This quantitation approach is robust, does not require labeling, and is well suited for miniaturized off-line characterization from microfluidic devices. PMID- 22508373 TI - A phase I study of infusional 5-fluorouracil, leucovorin, oxaliplatin and irinotecan in Japanese patients with advanced colorectal cancer who harbor UGT1A1*1/*1,*1/*6 or *1/*28. AB - OBJECTIVE: To evaluate the safety and efficacy of combination chemotherapy with 5 fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin (FOLFOXIRI) in Japanese patients with advanced colorectal cancer. METHODS: This phase I dose finding study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD) or both of FOLFOXIRI. Patients with UDP glucuronosyltransferase (UGT) 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded, because these UGT1A1 genotypes are linked to severe neutropenia in Japanese. RESULTS: A total of 10 Japanese patients with advanced colorectal cancer were studied. The MTD of FOLFOXIRI in these Japanese patients was 165 mg/m(2) irinotecan, 85 mg/m(2) oxaliplatin and 2,400 mg/m(2) 5-FU. Accordingly, the RD of FOLFOXIRI was determined to be 150 mg/m(2) irinotecan, 85 mg/m(2) oxaliplatin and 2,400 mg/m(2) 5-FU. Toxic effects, evaluated until the completion of 4 cycles, were manageable. Grade 3-4 neutropenia occurred in 27% of cycles, but there was no febrile neutropenia. Among the 9 assessable patients, the objective response rate was 89%. CONCLUSIONS: We thus determined the RD of FOLFOXIRI in Japanese patients with advanced colorectal cancer who do not have UGT1A1*28/*28, *6/*6 or *6/*28 genotypes. Our results indicate that FOLFOXIRI is a well-tolerated regimen for these Japanese patients. PMID- 22508375 TI - Reclassification of giant viruses composing a fourth domain of life in the new order Megavirales. AB - Interest in giant viruses has risen sharply since 2003, following the discovery of the Mimivirus and four other protist-infecting giant viruses that are linked to the nucleocytoplasmic large DNA viruses (NCLDVs). Despite considerable heterogeneity in hosts and genome sizes, the NCLDVs have been shown to be monophyletic based on analyses of their sequences and gene repertoires and recent studies have proposed that these viruses share a common ancient ancestor and compose a fourth domain of life. In addition, several characteristics of these giant viruses contradict or do not match the criteria used for the canonical definition of viruses, and the NCLDV denomination is not completely appropriate. We propose here to define a new viral order named Megavirales. PMID- 22508374 TI - Analgesic properties of loperamide differ following systemic and local administration to rats after spinal nerve injury. AB - BACKGROUND: The analgesic properties and mechanisms of loperamide hydrochloride, a peripherally acting opioid receptor agonist, in neuropathic pain warrant further investigation. METHODS: We examined the effects of systemic or local administration of loperamide on heat and mechanical hyperalgesia in rats after an L5 spinal nerve ligation (SNL). RESULTS: (1) Systemic loperamide (0.3-10 mg/kg, subcutaneous in the back) dose dependently reversed heat hyperalgesia in SNL rats, but did not produce thermal analgesia. Systemic loperamide (3 mg/kg) did not induce thermal antinociception in naive rats; (2) systemic loperamide-induced anti-heat hyperalgesia was blocked by pretreatment with intraperitoneal naloxone methiodide (5 mg/kg), but not by intraperitoneal naltrindole (5 mg/kg) or intrathecal naltrexone (20 MUg/10 MUL); (3) local administration of loperamide (150 MUg), but not vehicle, into plantar or dorsal hind paw tissue induced thermal analgesia in SNL rats and thermal antinociception in naive rats; (4) the analgesic effect of intraplantar loperamide (150 MUg/15 MUL) in SNL rats at 45 min, but not 10 min, post-injection was blocked by pretreatment with an intraplantar injection of naltrexone (75 MUg/10 MUL); (5) systemic (3.0 mg/kg) and local (150 MUg) loperamide reduced the exaggerated duration of hind paw elevation to noxious pinprick stimuli in SNL rats. Intraplantar injection of loperamide also decreased the frequency of pinprick-evoked response in naive rats. CONCLUSIONS: These findings suggest that both systemic and local administration of loperamide induce an opioid receptor-dependent inhibition of heat and mechanical hyperalgesia in nerve-injured rats, but that local paw administration of loperamide also induces thermal and mechanical antinociception. PMID- 22508376 TI - Are high doses of carbidopa a concern? A randomized, clinical trial in Parkinson's disease. AB - Recommended doses of carbidopa are 75-200 mg/day. Higher doses could inhibit brain aromatic amino-acid decarboxylase and reduce clinical effects. We compared 4-week outpatient treatments with carbidopa (75 and 450 mg/day) administered with L-dopa on the subjects' normal schedule. After each treatment phase, subjects had two 2-hour L-dopa infusions. The first infusion examined the effects of carbidopa doses administered the preceding 4 weeks, and the second infusion determined the acute effects of the two dosages of carbidopa. The antiparkinsonian effects and L dopa and carbidopa plasma concentrations were monitored during the infusions. Twelve subjects completed the study. Carbidopa concentrations were eight times higher after the high-carbidopa phase. Area under the curve (AUC) for clinical ratings did not differ for the four L-dopa infusions, although AUC for plasma L dopa was modestly increased with 450 mg of carbidopa. Nine subjects reported that the high-carbidopa outpatient phase was associated with greater response to L dopa. Doses of 450 mg/day of carbidopa did not reduce the responses to L-dopa infusion, extending the safe range of carbidopa to 450 mg/day. PMID- 22508377 TI - Packaging HIV- or FIV-based lentivector expression constructs and transduction of VSV-G pseudotyped viral particles. AB - As with standard plasmid vectors, it is possible to transfect lentivectors in plasmid form into cells with low-to-medium efficiency to obtain transient expression of effectors. Packaging lentiviral expression constructs into pseudoviral particles, however, enables up to 100% transduction, even with difficult-to-transfect cells, such as primary, stem, and differentiated cells. Moreover, the lentiviral delivery does not produce the specific cellular responses typically associated with chemical transfections, such as cell death resulting from toxicity of the transfection reagent. When transduced into target cells, the lentiviral construct integrates into genomic DNA and provides stable expression of the small hairpin RNA (shRNA), cDNA, microRNA or reporter gene. Target cells stably expressing the effector molecule can be isolated using a selectable marker contained in the expression vector construct such as puromycin or GFP. After pseudoviral particles infect target cells, they cannot replicate within target cells because the viral structural genes are absent and the long terminal repeats (LTRs) are designed to be self-inactivating upon transduction. There are three main components necessary for efficient lentiviral packaging. 1. The lentiviral expression vector that contains some of the genetic elements required for packaging, stable integration of the viral expression construct into genomic DNA, and expression of the effector or reporter. 2. The lentiviral packaging plasmids that provide the proteins essential for transcription and packaging of an RNA copy of the expression construct into recombinant pseudoviral particles. This protocol uses the pPACK plasmids (SBI) that encode for gag, pol, and rev from the HIV or FIV genome and Vesicular Stomatitis Virus g protein (VSV G) for the viral coat protein. 3. 293TN producer cells (derived from HEK293 cells) that express the SV40 large T antigen, which is required for high-titer lentiviral production and a neomycin resistance gene, useful for reselecting the cells for maintenance. An overview of the viral production protocol can be seen in Figure 1. Viral production starts by co-transfecting 293TN producer cells with the lentiviral expression vector and the packaging plasmids. Viral particles are secreted into the media. After 48-72 hours the cell culture media is harvested. Cellular debris is removed from the cell culture media, and the viral particles are precipitated by centrifugation with PEG-it for concentration. Produced lentiviral particles are then titered and can be used to transduce target cells. Details of viral titering are not included in this protocol, but can be found at: http://www.systembio.com/downloads/global_titer_kit_web_090710.pdf. This protocol has been optimized using the specific products indicated. Other reagents may be substituted, but the same results cannot be guaranteed. PMID- 22508378 TI - Ultraviolet, circular dichroism, fluorescence, and circularly polarized luminescence spectra of regioregular poly-[3-((S)-2-methylbutyl)-thiophene] in solution. AB - Ultraviolet (UV), Circular Dichroism (CD), Fluorescence, and Circularly Polarized Luminescence (CPL) spectra were recorded for mixed chloroform/methanol and chloroform/butanol solutions of regioregular poly[3-((S)-2-methylbutyl) thiophene]. An evaluation of the chiral and nonchiral components in solution is proposed on the basis of the UV and CD spectra. The fluorescence and CPL spectra are observed in a wavelength range where some UV and CD activity still appears. For this reason, the observed CPL features are strongly influenced by CD. A general procedure for evaluating true CPL spectra is proposed, when absorption and emission coexist. PMID- 22508379 TI - Adherence to gastroprotection during cyclooxygenase 2 inhibitor treatment and the risk of upper gastrointestinal tract events: a population-based study. AB - OBJECTIVE: Guidelines recommend coprescription of gastroprotective agents (GPAs) in patients receiving cyclooxygenase 2 inhibitors (coxibs) who are at high risk of upper gastrointestinal (UGI) tract complications (i.e., patients with a previous complicated ulcer or with multiple risk factors). Suboptimal GPA adherence has been shown to diminish the gastroprotective effect during use of nonselective nonsteroidal antiinflammatory drugs, but little is known about the effect of GPA adherence during coxib treatment. We undertook this study to determine the association between GPA adherence and UGI tract events among patients receiving coxibs. METHODS: Using primary care data from 3 databases, we conducted a case-control study in a cohort of patients age >=50 years who were newly starting treatment with coxibs and concomitantly taking GPAs. Patients who had a UGI tract event (bleeding or symptomatic ulcer) were matched to event-free controls for age, sex, database, and calendar date. Coxib treatment intervals were defined as consecutive coxib prescriptions with intervening gaps not exceeding the duration of the previous coxib prescription. Adherence to GPAs was calculated as the proportion of days of coxib treatment covered by a GPA prescription. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated using conditional logistic regression analysis. RESULTS: The coxib plus GPA-treated cohort consisted of 14,416 coxib-treated patients who received GPAs for at least 1 day, yielding 16,442 coxib treatment intervals in which a GPA was coprescribed. Most patients were treated with coxibs for <30 days. Seventy four patients had a UGI tract event during or shortly after a coxib treatment interval in which a GPA was coprescribed, with an incidence rate of 11.9 (95% CI 9.4-14.8) per 1,000 years of coxib treatment. The risk of UGI tract events was 1.97 (95% CI 0.84-4.60) for patients with <20% adherence to GPAs compared to patients with >80% adherence to GPAs. For every 10% decrease in GPA adherence, the risk of UGI tract events increased by 9% (OR 1.09 [95% CI 1.00-1.18]). CONCLUSION: Decreasing GPA adherence among coxib-treated patients is associated with an increased risk of UGI tract events. PMID- 22508380 TI - Detailed ultrasound screening in the second trimester: pictorial essay of normal fetal anatomy. AB - Today, ultrasound is the main diagnostic tool in the prenatal detection of congenital abnormalities. Therefore, ultrasound examination should be offered to all pregnant women. A detailed sonographic examination of the fetus is usually performed between 18 and 22 weeks of pregnancy. The accurate recognition of normal fetal anatomy is very important for the detection of both minor and major defects. The purpose of this pictorial essay is to show fetal anatomic structures, which have to be examined between the 18(th) and 22(nd) weeks of pregnancy, and present their standard measurements systematically and thoroughly in accordance with sonographically obtained ideal sections. PMID- 22508381 TI - The introduction of arrays in prenatal diagnosis: a special challenge. AB - Genome-wide arrays are rapidly replacing conventional karyotyping in postnatal cytogenetic diagnostics and there is a growing request for arrays in the prenatal setting. Several studies have documented 1-3% additional abnormal findings in prenatal diagnosis with arrays compared to conventional karyotyping. A recent meta-analysis demonstrated that 5.2% extra diagnoses can be expected in fetuses with ultrasound abnormalities. However, no consensus exists as to whether the use of genome-wide arrays should be restricted to pregnancies with ultrasound abnormalities, performed in all women undergoing invasive prenatal testing or offered to all pregnant women. Moreover, the interpretation of array results in the prenatal situation is challenging due to the large numbers of copy number variants with no major phenotypic effect. This also raises the question of what, or what not to report, for example, how to deal with unsolicited findings. These issues were discussed at a working group meeting that preceded the European Society of Human Genetics 2011 Conference in Amsterdam. This article is the result of this meeting and explores the introduction of genome-wide arrays into routine prenatal diagnosis. We aim to give some general recommendations on how to develop practical guidelines that can be implemented in the local setting and that are consistent with the emerging international consensus. PMID- 22508382 TI - Outcomes of cardiac involvement in patients with late-stage Duchenne muscular dystrophy under management in the pulmonary rehabilitation center of a tertiary referral hospital. AB - OBJECTIVES: The purpose of this study was to investigate the clinical outcome as well as the sequential changes of cardiac function in late-stage Duchenne muscular dystrophy (DMD) patients by 2-dimensional echocardiography. METHODS: A total of 31 individuals (initial age: 21.6 +/- 5.0 years, range: 15-35 years) with late-stage DMD (Swinyard-Deaver's stage 7 or 8) were enrolled. All of these patients had respiratory insufficiency and were on ventilator support. Sequential echocardiographic data were collected over at least 3 years. Repeated measures analysis of variance was used to compare changes in left ventricular ejection fraction (LVEF) over time. RESULTS: The sequential change in the mean LVEF showed no significant differences with initial, 1-, 2-, and 3-year follow-up LVEFs which were 42.2, 42.9, 43.8 and 42.6%, respectively (p = 0.320). In terms of the clinical outcome, all but 1 patient survived during the follow-up period of 46.5 +/- 9.1 months. CONCLUSIONS: The cardiac function in late-stage DMD patients showed a stabilization of LVEF on adequate ventilatory support and optimal cardiac medication therapy until their mid-30s. In addition, considering the favorable clinical outcome in our study, the process of cardiac involvement in late-stage DMD may demonstrate that in some patients it is nonprogressive. PMID- 22508383 TI - IL-33 attenuates development and perpetuation of chronic intestinal inflammation. AB - BACKGROUND: Interleukin-33 (IL-33) is a member of the IL-1 family. Recent evidence shows the importance of IL-33 in autoimmune and inflammatory diseases. To elucidate its impact on inflammatory bowel disease we studied the effects of exogenous IL-33 during the induction of acute dextran sodium sulfate (DSS) induced colitis, the induction period of chronic DSS colitis, and after establishment of chronic inflammation. METHODS: For induction of acute colitis mice received DSS in their drinking water for 7 days and were killed at day 8 or 14 after first DSS administration. Chronic colitis was induced by four cycles of DSS. Animals were treated with IL-33 between the DSS cycles (intermediate treatment) or after onset of chronic disease (posttreatment). Colons and mesenteric lymph nodes were isolated for histology and cytokine secretion, flow cytometric analysis, determination of myeloperoxidase, and transcription factor activity. RESULTS: While IL-33 in acute colitis led to slight aggravation of inflammation, both chronic colitis approaches resulted in a significant reduction of inflammatory colon contraction, amelioration of disease scores, suppression of interferon-gamma (IFN-gamma), and a shift to T helper (Th)2-associated cytokines. Examination of colon tissue revealed increased Ly6g-mRNA levels and myeloperoxidase (MPO) activity in IL-33-treated animals. Evaluation of bacterial translocation revealed decreased translocation incidence in IL-33-treated mice. CONCLUSIONS: In summary, IL-33 has extenuating effects in chronic DSS-induced colitis: Excessive Th1-directed cytokine responses are shifted toward Th2-like immune reactions and general inflammation parameters are reduced. IL-33-induced neutrophil influx during chronic inflammation reduced translocation of pathogenic bacteria across damaged epithelium. PMID- 22508384 TI - The validation of international consultation on incontinence questionnaires in the Greek language. AB - AIMS: The objective of this study was to validate four specific International Consultation on Incontinence Questionnaires (ICIQ) modules in the Greek language: (i) the ICIQ-FLUTS long form (ICIQ-FLUTS-LF), (ii) the ICIQ-FLUTS, (iii) the ICIQ FLUTS-SEX, and (iv) the ICIQ-Vaginal Symptoms Questionnaire (ICIQ-VS), originally validated in English. METHODS: The English questionnaires were initially translated into Greek, then back-translated into English and final modifications were made after testing the questionnaires on a sample of patients. To validate the translated questionnaires, the following tests were undertaken: Content/face validity, internal consistency (reliability) and stability (test-retest reliability). RESULTS: A total of 122 women participated in the study. Eighty nine presented with pelvic organ prolapse (POP) and/or urinary incontinence (UI) symptoms and 33 attended an outpatient gynecological clinic without POP/UI symptoms. All modules showed excellent content/face validity (missing values 0 2.5%). Cronbach's alpha test for internal consistency showed satisfactory to excellent reliability (0.876 for ICIQ-FLUTS-LF, 0.85 for ICIQ-FLUTS, and 0.83 for ICIQ-VS), with the exception ICIQ-FLUTS-SEX which was 0.69. The test-retest reliability showed moderate to near-perfect agreement (weighted kappa value 0.52 0.99). CONCLUSIONS: The Greek versions of the ICIQ-FLUTS-LF, ICIQ-FLUTS, and ICIQ VS questionnaires were successfully validated. Our data showed that the ICIQ FLUTS-SEX questionnaire, as it stands in its current English version, cannot be reliably used to assess sex symptoms in the Greek female population. PMID- 22508386 TI - International collaboration in the use of registries for new devices and procedures. PMID- 22508387 TI - Pretherapeutic expression of the hOCT1 gene predicts a complete molecular response to imatinib mesylate in chronic-phase chronic myeloid leukemia. AB - In this retrospective study we evaluated the pretherapeutic mRNA expression of the hOCT1 (human organic cation transporter 1) gene in patients with chronic phase (CP) chronic myeloid leukemia (CML) who varied in terms of their response to imatinib (IM). hOCT1 mRNA was quantified by real-time PCR. Patients were classified as expressing either high (n = 44) or low hOCT1 mRNA (n = 44). The complete cytogenetic response rates observed at 6, 12 and 18 months were 47.7, 84.1 and 91%, respectively, in patients with high hOCT1 mRNA and 47.5, 81.8 and 86.3%, respectively, in patients with low hOCT1 transcripts. The major molecular response rates were not significantly different between patients with high and low hOCT1 mRNA after 6 months of therapy (22.7 vs. 9.1%; p = 0.07), but they were significantly different after 12 months (54.5 vs. 31.8%; p = 0.026) and 18 months (77.2 vs. 56.8%; p = 0.034). Complete molecular responses were observed in 5 patients with low and 17 patients with high hOCT1 mRNA (p = 0.003). The 5-year event-free and overall survival analyses revealed no significant differences between the groups. These data imply that knowledge of the pretherapeutic level of hOCT1 could be a useful marker to predict IM therapy outcome in treatment naive CP CML patients. PMID- 22508388 TI - Link functions in multi-locus genetic models: implications for testing, prediction, and interpretation. AB - "Complex" diseases are, by definition, influenced by multiple causes, both genetic and environmental, and statistical work on the joint action of multiple risk factors has, for more than 40 years, been dominated by the generalized linear model (GLM). In genetics, models for dichotomous traits have traditionally been approached via the model of an underlying, normally distributed, liability. This corresponds to the GLM with binomial errors and a probit link function. Elsewhere in epidemiology, however, the logistic regression model, a GLM with logit link function, has been the tool of choice, largely because of its convenient properties in case-control studies. The choice of link function has usually been dictated by mathematical convenience, but it has some important implications in (a) the choice of association test statistic in the presence of existing strong risk factors, (b) the ability to predict disease from genotype given its heritability, and (c) the definition, and interpretation of epistasis (or epistacy). These issues are reviewed, and a new association test proposed. PMID- 22508389 TI - Gene silencing of EREG mediated by DNA methylation and histone modification in human gastric cancers. AB - Epiregulin (EREG) induces cell growth by binding to the epidermal growth factor receptor (EGFR). Expression of EREG affects sensitivity to cetuximab a chimeric monoclonal antibody that inhibits the EGFR signaling pathway. The mechanism through which EREG is regulated is largely unknown, but a methyl-array study previously performed by our group revealed that EREG is methylated in gastric cancer cells. In this study, we found that EREG gene expression was low in 7 out of 11 gastric cancer cells and this downregulation was mediated by aberrant CpG methylation of the EREG promoter. Treatment with 5-aza-CdR restored EREG expression and demethylated CpG sites in the EREG promoter. Compared with DNA methyltransferase 1 (DNMT1), knock-down of DNA methyltransferase 3b (DNMT3b) significantly increased the expression of EREG and led to the demethylation of specific CpG sites in the EREG promoter, suggesting that DNMT3b primarily regulates CpG methylation and silencing of the EREG gene. EREG methylation was observed in 30% (4/13) of human primary gastric tumor tissues we evaluated. In addition to DNA methylation, results from a chromatin immunoprecipitation assay demonstrated that transcriptional levels of EREG were associated with the enrichment of active histone marks (H3K4me3 and AcH3) and of a repressive mark (H3K27me2). Treatment with 5-aza-CdR dynamically increased the low occupancy of H3K4me3 and AcH3, while decreasing the high enrichment of H3K27me2, indicating that dynamic histone modifications contribute to EREG regulation in addition to DNA methylation. Finally, the combination of 5-aza-CdR and cetuximab exerted a synergistic anti-proliferative effect on gastric cancer cells. Taken together, the results of our study showed for the first time that EREG is epigenetically silenced in gastric cancer cells by aberrant DNA methylation and histone modification. PMID- 22508390 TI - Controllable gas/liquid/liquid double emulsions in a dual-coaxial microfluidic device. AB - This article presents a simple and novel approach to prepare monodispersed gas-in oil-in-water (G/O/W) and gas-in-water-in-oil (G/W/O) double-emulsions in the same dual-coaxial microfluidic device. The effects of three phase flow rates on the sizes of microbubbles and droplets and the number of the encapsulated microbubbles were systematically studied. We successfully synthesized two different types of gas/liquid/liquid (G/L/L) double emulsions with different inner structures in the same geometry by adjusting the flow rates sequentially. Mathematical models were developed to predict the size and structures of the double emulsions. This simple approach gives a new idea for preparing hollow and porous microspheres with microbubbles as the direct core/pores templates. PMID- 22508391 TI - Synthesis of luminescent covalent-organic polymers for detecting nitroaromatic explosives and small organic molecules. AB - Three porous luminescent covalent--organic polymers (COPs) have been synthesized through self-polycondensation of the monomers of tris(4-bromophenyl)amine, 1,3,5 tris(4-bromophenyl)benzene, and 2,4,6-tris-(4-bromo-phenyl)-[1,3,5]triazine by using Ni-catalyzed Yamamoto reaction. All the COP materials possess not only high Brunauer-Emmett-Teller (BET) specific surface area of about 2000 m(2) g(-1) , high hydrothermal stability, but also graphene-like layer texture. Interestingly, COP-3 and COP-4 show very fast responses and high sensitivity to the nitroaromatic explosives, and also high selectivity for tracing picric acid (PA) and 2,4,6-trinitrotoluene (TNT) at low concentration (<1 ppm). In short, the COPs may be a new kind of material for detecting explosives and small organic molecules. PMID- 22508392 TI - Effects of benzalkonium chloride and potassium sorbate on airway ciliary activity. AB - OBJECTIVES: Preservatives are indispensable components of aqueous multidose topical formulations. The purpose of our study was to investigate the effects of two representative preservatives, benzalkonium chloride (BKC) and potassium sorbate (PS), on rabbit tracheal ciliary beat frequency (CBF). METHODS: Rabbit tracheal ciliated cell culture was established and CBF was determined using high speed digital imaging methods. The effects of preservatives at different concentrations on CBF were observed over a 10-min exposure period. RESULTS: BKC induced inhibition of CBF in a concentration-dependent manner. Ciliary beating was stopped by 0.01% BKC after 5 min of exposure. A low concentration of PS (0.12%) only resulted in a mild decrease in CBF during a 10-min exposure. The CBF decreased by 13.0% from baseline after 10 min. However, there was no statistically significant difference compared with the corresponding control condition. Application of 0.24, 0.48 and 0.96% of PS to rabbit tracheal cells resulted in an increase in CBF, with an increase of 105 +/- 9.8, 107.6 +/- 4.0, and 117.1 +/- 9.5% relative to baseline CBF after 10 min of exposure, respectively. CONCLUSIONS: PS could be considered as a safer and more promising preservative than BKC for use in topical formulations. PMID- 22508394 TI - Microelectrode targeting of the subthalamic nucleus for deep brain stimulation surgery. AB - Though microelectrode recordings likely increase the risks and costs of DBS, incremental improvement in accuracy may translate into improved outcomes that justify these risks and costs. Clinically based, controlled studies to resolve these issues are problematic. Until such studies are reported, physicians must rely on indirect evidence. The spatial variability of physiologically defined optimal targets, as determined by microelectrode recording (MER), necessary for targeting the STN was calculated. Study of the effectiveness of a MER algorithm was based on the number of penetrations required. The radius of the volume with a 99% chance of including the physiologically defined optimal target, based on 108 cases, was 4.5 mm. This is larger than the estimated radius of the DBS effect, which is variously estimated to be 2 to 3.9 mm. The 99% confidence radius in the plane orthogonal to the lead was 3.2 mm. In 70% of cases, the imaging-based trajectories corresponded to the physiologically defined optimal target. For the remaining 30% of cases, 70% required only a single additional MER tract. The radii of the 99% confidence volume and area may be larger than the effective radius of stimulation. Surveying within those volumes or areas is therefore necessary to assure that at least 99% of cases will cover the physiologically defined target. The MER algorithm was robust in detecting the physiologically defined optimal target. However, there are significant caveats in interpretation of the data. PMID- 22508396 TI - Gene polymorphisms and high-altitude pulmonary edema susceptibility: a 2011 update. AB - High-altitude pulmonary edema (HAPE) is a severe disease caused by high-altitude hypoxia. Since some individuals are more susceptible to high altitude than others, the incidence is variable and cannot be predicted. Furthermore, multiple genes can contribute to the occurrence of HAPE, making it even more difficult to predict. The genes associated with HAPE include those in the renin-angiotensin aldosterone system pathway, the nitric oxide pathway and the hypoxia-inducible factor pathway. Other genes associated with HAPE include tyrosine hydroxylase (TH), vascular endothelial growth factor (VEGF), pulmonary surfactant proteins and beta(2)-adrenergic receptor. The association of the polymorphisms of these genes with HAPE susceptibility has previously been investigated. Among the genes evaluated, polymorphisms of NOS3, ACE, CYP11B2, Hsp70 and endothelin-1 and pulmonary surfactant proteins A1 and A2 were shown to be associated with HAPE incidence, while associations between TH, VEGF and HAPE remain to be fully elucidated. Novel technological approaches, including genome-wide association studies and next-generation sequencing, are currently being used to identify new HAPE susceptibility genes. The goal of this review article is to summarize the current literature and to define the outstanding areas of research that need to be explored to advance our ability to predict when HAPE will occur. PMID- 22508393 TI - Child intellectual development in relation to cytokine levels in umbilical cord blood. AB - Although cytokines play a dual role in the developing neurologic system and in prenatal immune reactions, relations between fetal cytokine levels and child intellectual development remain unknown. The authors investigated associations between umbilical cord serum cytokine concentrations and intellectual outcomes in 369 children within a prospective cohort study, the Eunice Kennedy Shriver National Institute of Child Health and Human Development-University of Alabama Infant Growth Study (1985-1988). Concentrations of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukins 4, 10, and 12p70 were determined. The Wechsler Preschool and Primary Scale of Intelligence-Revised was administered at age 5 years, producing verbal and performance intelligence quotients (VIQ and PIQ); associations with each cytokine were evaluated using linear and logistic regression. Log-unit increases in IFN-gamma (adjusted odds ratio (aOR) = 0.67, 95% confidence interval (CI): 0.46, 0.98) and interleukin 12p70 (aOR = 0.43, 95% CI: 0.21, 0.87) were inversely associated with low PIQ (score <70). One log-unit increase in TNF-alpha was associated with a reduced odds ratio for low VIQ (score <70) among preterm children (aOR = 0.11, 95% CI: 0.01, 0.94) and an elevated odds ratio for low VIQ among small-for-gestational age children (aOR = 3.96, 95% CI: 0.99, 15.9). IFN-gamma, which is involved in neurogenesis and perinatal adaptive immunity, may be related to fetal neurologic development overall, while TNF-alpha may be a marker of intellectual development in vulnerable subgroups. PMID- 22508397 TI - Cytotoxicity of different sized TiO2 nanoparticles in mouse macrophages. AB - With large-scale production and wide application of nano-titanium oxide (TiO2), its health hazard has attracted extensive attention worldwide. In this study, mouse macrophages (Ana-1 and MH-S cells) were used to evaluate the cytotoxicity of different sized TiO2 nanoparticles. The results showed that TiO2 nanoparticles caused low toxicity, especially in MH-S cells. There was a difference in the cytotoxicity induced by different sized TiO2 particles. The 25 nm anatase particles induced the strongest cytotoxicity and oxidative stress, followed by 5 and 100 nm anatase particles; in contrast, 100 nm rutile particles induced the lowest toxicity. Although TiO2 nanoparticles induced high levels of intracellular reactive oxygen species (ROS), the determination of ROS demonstrated that the inherent oxidative capacity of TiO2 nanoparticles was lower in the absence of photoactivation. Therefore, the generation of intracellular ROS could not completely depend on inherent oxidative capacity of TiO2 nanoparticles. Toxicity of TiO2 nanoparticles could mainly depend on the structural characteristics. PMID- 22508398 TI - Expressions of P53 and CD68 in mouse liver with Schistosoma mansoni infection and the protective role of silymarin. AB - Schistosomiasis is one of the major human parasitic diseases in many developing countries and is one of the causes of morbidity and mortality in the human population. The present work has been planned to study the histopathological and immunohistochemical expression of P53 and CD68 in mouse liver tissues experimentally infected with Schistosoma mansoni, in addition to the ameliorating role of silymarin. A total of 50 adult male mice were divided into 5 groups (10 animals each). Groups 1 and 2 were the control and silymarin groups, respectively, while group 3 was the infected group in which the mice were infected with S. mansoni live cercariae for 6 weeks. Groups 4 and 5 were the cotreated and posttreated groups, respectively, in which mice were infected with cercariae of S. mansoni and treated with silymarin during and after Schistosoma infection, respectively. The major histopathological lesions were variable numbers of perioval granulomas, diffuse infiltration of inflammatory cells, mainly eosinophils and small mononuclear cells, and fibrosis of portal areas and interlobular septa. Treatment with silymarin led to a significant reduction in granuloma area in all treated infected mice compared with nontreated infected mice. Immunohistochemical observations of the liver tissues showed a significant increase in the apoptotic proteins P53 and CD68 after the infection with the cercariae of Schistosoma, compared with the control group. The expression of the cytoplasmic P53 and CD68 was very low in the control liver sections. A significant decrease in the expression of the cytoplasmic P53 and CD68 was observed after silymarin treatment. PMID- 22508399 TI - Acute toxic effects of fenpyroximate acaricide on Guppy (Poecilia reticulata Peters, 1859). AB - Fenpyroximate (FP), an acaricide, is widely used in the prevention of acarids (mites) in fruit plant gardens. In this study, the acute toxic effects of different concentrations of FP were investigated using adult guppy (Poecilia reticulata Peters, 1859). Guppy adults were exposed to a range of FP concentrations (25, 50, 75, 100, 125, and 150 ug/L) during 48 h. Static method, which is one of the acute toxicity experiments, has been used in this study. According to probit analysis, the 48-h median lethal concentration (LC50) value of FP at 26 degrees C was found to be 72.821 ug/L. Sublethal exposures were predetermined based on 48-h LC50 value. Guppies were exposed to low concentrations (15, 25, and 50 ug/L) of FP for 48 h. Signs of paralysis and behavior deformations were monitored every 12 h in a number of live and dead adults. Low concentrations of FP were also responsible for erratic swimming, loss of equilibrium, and being lethargic. Liver histology revealed several pathological damages including congestion, picnotic nucleus, sinusoidal dilatation, increase in melanomacrophagic centers, and endothelial degeneration. Finally, the toxicity test results provided 48-h LC50 value for FP, and low concentrations of FP can be highly detrimental to guppy adults with clear evidence of behavioral and histologic effects. PMID- 22508401 TI - Acute and chronic tactile sensory testing after spinal cord injury in rats. AB - Spinal cord injury (SCI) impairs sensory systems causing allodynia. To identify cellular and molecular causes of allodynia, sensitive and valid sensory testing in rat SCI models is needed. However, until recently, no single testing approach had been validated for SCI so that standardized methods have not been implemented across labs. Additionally, available testing methods could not be implemented acutely or when severe motor impairments existed, preventing studies of the development of SCI-induced allodynia(3). Here we present two validated sensory testing methods using von Frey Hair (VFH) monofilaments which quantify changes in tactile sensory thresholds after SCI. One test is the well-established Up-Down test which demonstrates high sensitivity and specificity across different SCI severities when tested chronically. The other test is a newly-developed dorsal VFH test that can be applied acutely after SCI when allodynia develops, prior to motor recovery. Each VFH monofilament applies a calibrated force when touched to the skin of the hind paw until it bends. In the up-down method, alternating VFHs of higher or lower forces are used on the plantar L5 dermatome to delineate flexor withdrawal thresholds. Successively higher forces are applied until withdrawal occurs then lower force VFHs are used until withdrawal ceases. The tactile threshold reflects the force required to elicit withdrawal in 50% of the stimuli. For the new test, each VFH is applied to the dorsal L5 dermatome of the paw while the rat is supported by the examiner. The VFH stimulation occurs in ascending order of force until at least 2 of 3 applications at a given force produces paw withdrawal. Tactile sensory threshold is the lowest force to elicit withdrawal 66% of the time. Acclimation, testing and scoring procedures are described. Aberrant trials that require a retest and typical trials are defined. Animal use was approved by Ohio State University Animal Care and Use Committee. PMID- 22508400 TI - Meta-analysis of genetic polymorphisms in granulomatosis with polyangiitis (Wegener's) reveals shared susceptibility loci with rheumatoid arthritis. AB - OBJECTIVE: To examine the association of previously identified autoimmune disease susceptibility loci with granulomatosis with polyangiitis (Wegener's) (GPA), and to determine whether the genetic susceptibility profiles of other autoimmune diseases are associated with those of GPA. METHODS: Genetic data from 2 cohorts were meta-analyzed. Genotypes for 168 previously identified single-nucleotide polymorphisms (SNPs) associated with susceptibility to different autoimmune diseases were ascertained in a total of 880 patients with GPA and 1,969 control subjects of European descent. Single-marker associations were identified using additive logistic regression models. Associations of multiple SNPs with GPA were assessed using genetic risk scores based on susceptibility loci for Crohn's disease, type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis (RA), celiac disease, and ulcerative colitis. Adjustment for population substructure was performed in all analyses, using ancestry-informative markers and principal components analysis. RESULTS: Genetic polymorphisms in CTLA4 were significantly associated with GPA in the single-marker meta-analysis (odds ratio [OR] 0.79, 95% confidence interval [95% CI] 0.70-0.89, P = 9.8 * 10(-5) ). The genetic risk score for RA susceptibility markers was significantly associated with GPA (OR 1.05 per 1-unit increase in genetic risk score, 95% CI 1.02-1.08, P = 5.1 * 10(-5) ). CONCLUSION: RA and GPA may arise from a similar genetic predisposition. Aside from CTLA4, other loci previously found to be associated with common autoimmune diseases were not statistically significantly associated with GPA in this study. PMID- 22508402 TI - Prospective study of the progression of low-grade dysplasia in ulcerative colitis using current cancer surveillance guidelines. AB - BACKGROUND: The goal of this study was to assess the natural history of low-grade dysplasia (LGD) and its risk of progression in ulcerative colitis (UC) patients by prospective endoscopic surveillance. METHODS: Forty-two UC patients with LGD were followed prospectively using a uniform approach to surveillance colonoscopy with an average of 43 biopsies per exam. The interval between colonoscopies ranged from 3-12 months. Progression was defined as development of high-grade dysplasia (HGD) or cancer at subsequent colonoscopy or at colectomy. Univariate and multivariate analysis were performed to identify risk factors associated with progression. RESULTS: Patients were followed for an average of 3.9 years (range 1 13). Over that period 19% (8/42) of patients progressed to advanced neoplasia (two cancer, six HGD) while 17% (7/42) had persistent LGD and 64% (27/42) had indefinite dysplasia or no dysplasia at the end of follow-up. Multivariate analysis demonstrated that the number of biopsies with LGD at baseline was associated with an increased risk of progression to advanced neoplasia (relative risk [RR] 5.8, 95% confidence interval [CI]: (1.29-26.04). Among the 15 patients who underwent colectomy, four were found to have higher-grade neoplasia on their colectomy specimen than their preoperative colonoscopy, and these patients were more likely to be nonadherent with recommendations for colectomy. CONCLUSIONS: The majority (81%) of UC patients with LGD did not progress to higher grades of dysplasia during a 4-year follow-up. Patients with three or more biopsies demonstrating LGD at a single colonoscopy were at increased risk for progression to advanced neoplasia. PMID- 22508403 TI - The effects of aging on quantitative sonographic features of rotator cuff tendons. AB - PURPOSE: Grayscale analysis is a practical, objective, and easy way to quantify echogenicity during ultrasonography. The purpose of the current study was to measure the changes in thickness and echogenicity that result from aging of the rotator cuff and long head of the biceps tendons. METHODS: The study comprised 45 volunteers, aged between 20 and 84 years and without history of shoulder pain. Participants were divided into three groups: young, middle-aged, and old. All subjects underwent standard ultrasonography of both shoulders. Tendon thickness and tear were recorded, and images in both transverse and longitudinal scans were taken for grayscale analysis. To reduce the attenuation effect from skin and subcutaneous fat, we used the ratio of echogenicity of the tendon to that of the reference muscle and compared the tendon echogenicity among the different age groups. Sonographic findings were also correlated with age. RESULTS: The supraspinatus tendon was significantly thicker in elderly participants and this was positively correlated with age. Moreover, the echogenicity ratio of the supraspinatus tendon decreased in the elderly group and showed a negative correlation with age. There was a higher prevalence of supraspinatus tendon tears in the older participants. CONCLUSIONS: Our results indicate that supraspinatus tendons became thickened, hypoechogenic, and more likely to tear with age. The study presents a simple and useful method to investigate the echogenicity of the rotator cuff quantitatively. PMID- 22508404 TI - Copeptin in mitral balloon valvuloplasty: a new approach in valvular interventions? PMID- 22508405 TI - Analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex in neuropathic pain: influence of theta burst stimulation priming. AB - BACKGROUND: 'Conventional' protocols of high-frequency repetitive transcranial magnetic stimulation (rTMS) delivered to M1 can produce analgesia. Theta burst stimulation (TBS), a novel rTMS paradigm, is thought to produce greater changes in M1 excitability than 'conventional' protocols. After a preliminary experiment showing no analgesic effect of continuous or intermittent TBS trains (cTBS or iTBS) delivered to M1 as single procedures, we used TBS to prime a subsequent session of 'conventional' 10 Hz-rTMS. METHODS: In 14 patients with chronic refractory neuropathic pain, navigated rTMS was targeted over M1 hand region, contralateral to painful side. Analgesic effects were daily assessed on a visual analogue scale for the week after each 10 Hz-rTMS session, preceded or not by TBS priming. In an additional experiment, the effects on cortical excitability parameters provided by single- and paired-pulse TMS paradigms were studied. RESULTS: Pain level was reduced after any type of rTMS procedure compared to baseline, but iTBS priming produced greater analgesia than the other protocols. Regarding motor cortex excitability changes, the analgesic effects were associated with an increase in intracortical inhibition, whatever the type of stimulation, primed or non-primed. CONCLUSIONS: The present results show that the analgesic effects of 'conventional' 10 Hz-rTMS delivered to M1 can be enhanced by TBS priming, at least using iTBS. Interestingly, the application of cTBS and iTBS did not produce opposite modulations, unlike previously reported in other systems. It remains to be determined whether the interest of TBS priming is to generate a simple additive effect or a more specific process of cortical plasticity. PMID- 22508406 TI - Program fidelity and beyond: multiple strategies and criteria for ensuring quality of assertive community treatment. AB - OBJECTIVE: In most public mental health systems, assertive community treatment (ACT) is a key service for people with severe mental illness. Although considerable research supports the effectiveness of ACT as an evidence-based practice, other research indicates a failure to adequately implement or sustain ACT, resulting in a diminishing quality of services over time. There have been relatively few attempts to develop and test strategies for implementing new ACT teams and for ensuring their operational and service quality over time. The authors provide a heuristic model for administrators and providers seeking to implement and sustain high-quality ACT programs. METHODS: The authors conducted a selected review of literature about implementation and sustainability of ACT published between January 2000 and May 2011. The review was supplemented by the authors' experiences as researchers, administrators, trainers and consultants, and practitioners. RESULTS: A total of 57 articles were found by searches in PsycINFO and PubMed. The authors propose four major approaches for assessing and ensuring the quality of ACT programs--policy and administrative, training and consultation, team operational, and program evaluation--and identify strategies for achieving the goals in each category. CONCLUSIONS: Although a scarcity of rigorous research makes firm conclusions difficult, the authors conclude that no single strategy is sufficient for ensuring adequate ACT implementation and services of consistently good quality. Rather, it is useful to implement a blend of policy and administrative, training and consultation, team operational, and program evaluation strategies. Additional rigorous research on implementing and sustaining the quality of ACT and other evidence-based practices is needed. PMID- 22508407 TI - Excessive running induces cartilage degeneration in knee joints and alters gait of rats. AB - The goal of this study was to develop an aggressive running regimen for modeling osteoarthritis (OA) in rats. Twelve Wistar rats were randomly placed into either a running group or a non-running group to serve as the control. The running rats used a motorized treadmill to run either 30 km in 3 weeks or 55 km in 6 weeks. Each week, the prints of hind paws were obtained when rats were made to walk through a tunnel. The resulting prints were digitalized for analyses of stride length and step angle. The histology of the knees was examined at 3 and 6 weeks and the OA pathology in the knees was quantified by Mankin's score. Osteoarthritic pathology developed in the knees of the running rats, including decreased proteoglycan content, uneven type II collagen distribution in the cartilage matrix, increased MMP-13 expression, expanded calcified cartilage zone, and clefts and defects in articular cartilage. The pathology worsened from running for 3 to 6 weeks. Gait analysis revealed an inverse correlation between paw angle and the grades of OA pathology. In conclusion, excessive running induces joint degeneration and a unique gait pattern in rats. PMID- 22508408 TI - Primary plasma cell leukemia: clinical and laboratory presentation, gene expression profiling and clinical outcome with Total Therapy protocols. AB - To determine whether primary plasma cell leukemia (PPCL) remains a high-risk multiple myeloma feature in the context of contemporary therapy and gene expression profiling (GEP), we reviewed records of 1474 patients with myeloma, who were enrolled in Total Therapy protocols or treated identically off protocol. A total of 27 patients (1.8%) were classified as having PPCL. As a group, these patients more often had low hemoglobin, high beta-2-microglobulin, high lactate dehydrogenase, low albumin and cytogenetic abnormalities. Among 866 patients with GEP results, the PPCL group more often had disease that was classified as high risk, and in CD-1 and MF molecular subgroups. Regardless of the therapeutic protocol, patients with PPCL had shorter median overall survival (OS; 1.8 years), progression-free survival (PFS; 0.8 years) and complete response duration (CRD; 1.3 years) than the remainder, whose clinical outcomes had improved markedly with successive protocols. Multivariate analyses of pretreatment parameters showed that PPCL was a highly significant independent adverse feature linked to OS, PFS and CRD. In GEP analyses, 203 gene probes distinguished PPCL from non-PPCL; the identified genes were involved in the LXR/RXR activation, inositol metabolism, hepatic fibrosis/hepatic stellate-cell activation and lipopolysaccharide/interleukin-1-mediated inhibition of RXR function pathways. Different treatment approaches building on these genomic differences may improve the grave outcome of patients with PPCL. PMID- 22508409 TI - Amino-acid-based block copolymers by RAFT polymerization. AB - This review summarizes recent advances in the design and synthesis of amino-acid based block copolymers by reversible addition-fragmentation chain transfer (RAFT) polymerization of amino-acid-bearing monomers. We will mainly focus on stimuli responsive block copolymers, such as pH-, thermo-, and dual-stimuli-responsive block copolymers, and self-assembled block copolymers, including amphiphilic and double-hydrophilic block copolymers having tunable chiroptical properties. We will also highlight recent results in RAFT synthesis of amino-acid-based copolymers having various properties, such as catalytic and optoelectronic properties, cross-linked block copolymer micelles, unimolecular micelles, and organic-inorganic hybrids. PMID- 22508410 TI - High levels of tumor necrosis factor-alpha downregulate antimicrobial iron transport protein, Nramp1, in chronic hemodialysis patients: a key factor for infection risk. AB - BACKGROUND/AIMS: The susceptibility of patients on maintenance hemodialysis (MHD) to infections is a major cause of mortality and morbidity. Natural resistance associated macrophage protein 1 (Nramp1) regulates intracellular pathogen proliferation, and its mRNA expression is highest in polymorphonuclear leukocytes (PMNLs). The purpose of this study was to determine the level of Nramp1 in PMNLs from MHD patients and the factors affecting its expression. METHODS: Twenty MHD patients and 24 healthy volunteers (controls) were recruited. Relative quantitative PCR was used to measure Nramp1 mRNA, and protein levels were semiquantified by means of real-time PCR and Western blot analysis or immunohistochemistry. The effect of tumor necrosis factor-alpha (TNF-alpha) or interleukin-6 (IL-6) on Nramp1 expression in PMNLs from controls was also examined. RESULTS: Nramp1 mRNA and protein levels were substantially lower in PMNLs from MHD than control subjects. Serum TNF-alpha levels were significantly higher in the MHD group and were inversely correlated with Nramp1 mRNA levels. The addition of TNF-alpha to PMNLs from control subjects decreased mRNA and protein levels of Nramp1. IL-6 did not alter Nramp1 mRNA or protein expression. CONCLUSION: We found that Nramp1 was downregulated in the PMNLs of MHD patients, which constitute the first defense barrier against bacterial challenges. High levels of TNF-alpha may be associated with the downregulation of Nramp1. Our findings indicate that the susceptibility to infection observed in MHD patients could be partly due to the impairment of the intracellular handling of iron and the donation of more iron to the bacteria. PMID- 22508411 TI - Increase of meningococcal serogroup Y cases in Europe: a reason for concern? AB - Neisseria meningitidis is differentiated into 12 distinct serogroups of which A, B, C, W-135, X and Y are medically most important and represent a major health problem in one or more parts of the world. The epidemiology of N. meningitidis is unpredictable over time and across geographic regions. A sudden increase or decrease of IMD or meningococcal carriage may occur anywhere at any time. Recent epidemiological surveillance indicates an increase of serogroup Y IMD in some parts of Europe and data from various European countries are presented. PMID- 22508412 TI - Long-term anti-HBs antibody persistence and immune memory in children and adolescents who received routine childhood hepatitis B vaccination. AB - This paper presents data from two studies that evaluated 5-y and 10-y persistence of antibodies against hepatitis B (HBV) surface antigen (anti-HBs) and immune response to an HBV vaccine challenge in children and adolescents who had received three doses of a HBV vaccine in infancy as part of routine clinical practice [NCT00519649/NCT00984139]. Anti-HBs antibody concentrations >= 10 mIU/ml persisted in 83.3% (95% confidence interval [CI]: 78.5-87.5) and 78.3% (95% CI: 73.1-83.0) of subjects aged 7-8 y and 12-13 y, respectively 5-10 y after infant vaccination. One month postchallenge dose, 98.2% (95% CI: 95.9-99.4) and 93.7% (95% CI: 90.2-96.2) of subjects in the two age groups, respectively had anti-HBs antibody concentrations >= 100 mIU/ml. Overall, 99.6% (95% CI: 98-100) and 97.2% (95% CI: 94.5-98.8) of subjects aged 7-8 y and 12-13 y mounted an anamnestic response to the HBV challenge dose, which was well-tolerated. Healthy children aged 7-8 y and adolescents aged 12-13 y received three doses of a monovalent pediatric HBV vaccine (10 MUg of HBsAg) before 18 mo of age. Serum samples collected before and one month post-HBV vaccine challenge dose were tested for anti-HBs antibody concentrations. Safety assessments were made for the HBV vaccine challenge dose. A three-dose childhood HBV immunization regimen induced persistence of antibodies against HBV infection for 10 y, up to adolescence. This vaccination regimen also conferred long-term immune memory against HBV as evidenced by the strong anamnestic response to the HBV vaccine challenge, despite waning anti-HBs antibody levels. PMID- 22508413 TI - Retrospective analysis of the results of acellular pertussis vaccine toxicity tests performed in Korea. AB - Specific toxicity test is a major quality control test for acellular pertussis (aP) vaccines performed by manufacturers and regulatory authorities. The 'mouse body weight gain test (MWGT)', the 'leukocytosis-promoting test (LPT)' and the 'histamine sensitization test (HIST)' have been conducted to check the specific toxicity of all batches of aP vaccines used in Korea through the national quality control program, which requires a lot of animals, labor and time. In this study, test results obtained in the past 9 y from a total of 258 lots of aP vaccines were examined retrospectively to evaluate the three test methods. A pairwise comparison of the test results indicated a good correlation between LPT and HIST, whereas MWGT showed no correlation with either LPT or HIST. Moreover, the reversion to toxicity was higher than the residual toxicity in the majority of lots tested by HIST, which indicated that the histamine-sensitizing toxicity, although rated within a safe range, increased during the vaccine storage. Thus, the vaccine safety test results accumulated in the past might be useful for the improvement of test protocols. PMID- 22508414 TI - Implications of philosophical and personal belief exemptions on re-emergence of vaccine-preventable disease: the role of spatial clustering in under-vaccination. AB - Vaccine exemption policies vary by state, and it has been demonstrated that easier protocols for personal/philosophical belief exemptions are associated with lower vaccine coverage at the state level. However, this does not lead to ubiquitously lower immunization rates across the state, as shown by variability in county-level exemption rates. Rather, there is geographical clustering of areas which are then more vulnerable to outbreaks of vaccine-preventable diseases. Understanding both state and local patterns of vaccine exemptions and developing policies and public health interventions to increase coverage in high risk areas is critical. At all levels of healthcare, efforts must be made to encourage vaccination education and legislation to protect the public's health. PMID- 22508416 TI - Immunogenicity of a hexavalent vaccine co-administered with 7-valent pneumococcal conjugate vaccine. Findings from the National Immunisation Programme in The Netherlands. AB - The hexavalent vaccine Infanrix hexa was introduced into the national childhood vaccination schedule in the Netherlands in 2006. It is offered, concomitantly with pneumococcal vaccine (Prevenar), to children at increased risk of hepatitis B, administered in a 4-dose schedule at 2, 3, 4 and 11 months of age. We assessed the immunogenicity of the HBV component of Infanrix hexa co-administered with Prevenar, and compared pertussis and Hib components in Infanrix hexa with the standard Infanrix-IPV+Hib vaccine. Target thresholds for immune responses were achieved for all antigens studied. Over 99% (163/164) of children vaccinated with Infanrix hexa achieved an adequate immune response (>= 10 mIU/ml) to the HBV component and peak anti-HBs geometric mean concentration (GMC) was 2264 mIU/ml (95%CI:1850-2771 mIU/ml). The GMC of a pertussis component, filamentous hemagglutinin (FHA), of Infanrix-hexa was significantly lower in children vaccinated with Infanrix hexa and Prevenar than in children vaccinated with Infanrix-IPV+Hib. Universal infant HBV vaccination using Infanrix hexa was introduced in The Netherlands in 2011. Despite very high rates of seroconversion for the HBV component of Infanrix hexa, its long term immunogenicity and effectiveness should be monitored after concomitant vaccination. PMID- 22508417 TI - Laryngeal chondrosarcoma with unusual dissemination to the humerus. AB - We report the case of an 81-year-old woman admitted to our clinic with a 16-month history of hoarseness due to unilateral vocal cord immobilization, slowly progressive dysphagia and an episode of painless swelling of the right arm. Radiological and histological workup revealed a medium-grade conventional chondrosarcoma of the cricoid cartilage with paratracheal spread and dissemination to the lung and the humeral bone. To our knowledge, this is the first humeral bone metastasis of laryngeal chondrosarcoma reported in the literature. The course of the presented case underlines the need for an early and detailed clinical and radiological workup of vocal cord immobilization. PMID- 22508418 TI - The art in science of microTAS. PMID- 22508415 TI - Can growth inhibition assays (GIA) predict blood-stage malaria vaccine efficacy? AB - An effective vaccine against P. falciparum malaria remains a global health priority. Blood-stage vaccines are an important component of this effort, with some indications of recent progress. However only a fraction of potential blood stage antigens have been tested, highlighting a critical need for efficient down selection strategies. Functional in vitro assays such as the growth/invasion inhibition assays (GIA) are widely used, but it is unclear whether GIA activity correlates with protection or predicts vaccine efficacy. While preliminary data in controlled human malaria infection (CHMI) studies indicate a possible association between in vitro and in vivo parasite growth rates, there have been conflicting results of immunoepidemiology studies, where associations with exposure rather than protection have been observed. In addition, GIA-interfering antibodies in vaccinated individuals from endemic regions may limit assay sensitivity in heavily malaria-exposed populations. More work is needed to establish the utility of GIA for blood-stage vaccine development. PMID- 22508419 TI - Activation of -N=CH- bond in a Schiff base by divalent nickel monitored by NMR evidence. AB - The Schiff base, 2-salicylidene-4-aminophenyl benzimidazole in ethanol undergoes activation of -N=CH- bond by Ni(2+) in the presence of ammonia or primary alkyl amine to produce nickel complexes of the formula Ni{o-C(6)H(4)(O)CH NR}(2) . n H(2)O [R = H, Me; n = 0; R = Et, n = 0.5] and 4-aminophenyl benzimidazole. The products have been identified by elemental analysis, magnetic susceptibility measurements and IR, ESR, mass and extensive NMR spectral studies. The possible mechanism for the activation of -N=CH- bond has also been proposed. PMID- 22508421 TI - Paroxysmal kinesigenic dyskinesias of epileptic origin abolished by temporal lobectomy. PMID- 22508420 TI - Development of diffuse alopecia with psoriasis-like eruptions during administration of infliximab for Crohn's disease. PMID- 22508422 TI - Pain treatment: a new approach to link bench to bedside--the SIMPAR meeting 2011. PMID- 22508423 TI - Endothelial function, oxidative stress and inflammatory studies in chronic coronary slow flow phenomenon patients. AB - The coronary slow flow phenomenon (CSFP) is associated with coronary microvascular dysfunction although the responsible mechanisms are unknown. This study compared endothelial function assessed by changes in augmentation index (AIx) following endothelium-independent (glyceryl trinitrate, GTN) and endothelium-dependent vasodilators (salbutamol), in 40 stable CSFP patients and 23 age-matched healthy controls. Plasma concentrations of inflammatory proteins (myeloperoxidase and high-sensitivity C-reactive protein), oxidative stress biomarkers (malondialdehyde and homocysteine), and asymmetric dimethylarginine levels were also determined. There were no differences between CSFP and controls in response to salbutamol (AIx: -2.28 +/- 0.88% vs. -3.22 +/- 0.70%, p = 0.4) or GTN (AIx: -11.30 +/- 0.75% vs. -13.30 +/- 1.00%, p = 0.12). Similarly, there were no differences in the measured biomarkers. Thus, alternate mechanisms to the assessed endothelial function, inflammatory and oxidative stress processes should be explored to explain the microvascular dysfunction in CSFP patients. PMID- 22508424 TI - Influence of smoking cessation on carotid artery wall elasticity evaluated by echo-tracking. AB - OBJECTIVE: Exploring the use of echo-tracking (ET) for evaluating changes in carotid artery wall elasticity after smoking cessation. METHODS: Carotid artery ultrasound examination was performed in 67 male patients before and after smoking cessation treatment, for measurement of intimal media thickness (IMT), and ET measurement of wall elasticity variables, ie, wall stiffness index (beta), pressure-strain elastic modulus (Ep), compliance (AC), augmentation index (AI), and local pulse wave velocity (PWVbeta). We also measured heart rate (HR), systolic pressure (Ps), diastolic pressure (Pd), total cholesterol (TC), triglyceride level (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). RESULTS: Hyperlipemia and/or arterial hypertension and/or hyperglycemia were absent in 22 (group A1) and 12 (group B1) and present in 19 (group A2) and 14 (group B2) of the patients with successful (group A, n = 41) and unsuccessful (group B, n = 26) treatment, respectively. In the A1 group, there was no significant difference in AI before and after smoking cessation, whereas beta, Ep, and PWVbeta decreased, and AC increased (p < 0.05). None of these variables changed after smoking cessation in groups A2, B1, and B2. There was no change in IMT in either group. HR decreased and HDL increased in the A1 group, without change in Ps, Pd, TC, TG, and LDL. There was no change in HR, Ps, Pd, TC, TG, LDL, and HDL in groups A2, B1, and B2. CONCLUSIONS: ET can be used to evaluate quantitatively the impact of smoking cessation on common carotid artery wall elasticity. PMID- 22508425 TI - Characterizing the presence and sensitivity of the P2X7 receptor in different compartments of the gut. AB - Purinergic signaling has been established as an important feature of inflammation and homeostasis. The expression of a number of P2 receptor subtypes in the gut has been reported. In this study, using a well-known permeabilization method that is assessed by flow cytometry, we show that lymphocytes and macrophages from the mesenteric lymph nodes (MLN) and the peritoneal cavity exhibit different sensitivities to extracellular ATP. Compared with the macrophages, the lymphocytes are more sensitive to ATP in the MLN compartment, whereas in the peritoneal cavity the macrophages are more sensitive to ATP than the lymphocytes. In addition, we have shown that the epithelial cells from the small bowel are more resistant to the ATP effects than the cells from the colon. These cells, however, become susceptible after exposure to IFN-gamma. Furthermore, by examining parameters such as pH manipulation, the exposure to divalent cations and the P2X7 antagonist Brilliant Blue G, and the use of cells from P2X7(-/-) mice, we have shown that the P2X7 receptors are the ATP-activated receptors responsible for the permeabilization phenomenon. In addition, using Western blot analysis, we have demonstrated the changes in the P2X7 receptor expression in immune cells isolated from different sites in the gut and in the gut-associated lymphoid tissues. Our findings suggest the existence of the site-specific modulation of P2X7 receptors on epithelial and immune cells, and we define purinergic signaling as a new regulatory element in the control of inflammation and cell fate in the gut and in the gut-associated lymphoid tissues. PMID- 22508426 TI - Novel chiral selector based on mefloquine--a comparative NMR study to elucidate intermolecular interactions with acidic chiral selectands. AB - The synthesis, ab initio calculations, and a comparative nuclear magnetic resonance study of a novel chiral mefloquine-based selector (SO) are presented. On a series of variously N-acyl protected leucine selectands (SAs), a feasibility study of mefloquine carbamate as a basic chiral solvating agent, and potential fluorophilic high-performance liquid chromatography selector has been undertaken and evaluated. An analogy is drawn between the new SO and tert-butylcarbamoyl quinidine as a reference. PMID- 22508427 TI - Patellar stress fracture after transosseous extensor mechanism repair: report of 3 cases. PMID- 22508428 TI - Development of a decision support system to predict physicians' rehabilitation protocols for patients with knee osteoarthritis. AB - To design a medical decision support system (MDSS) that would accurately predict the rehabilitation protocols prescribed by the physicians for patients with knee osteoarthritis (OA) using only their demographic and clinical characteristics. The demographic and clinical variables for 170 patients receiving one of three treatment protocols for knee OA were entered into the MDSS. Demographic variables in the model were age and sex. Clinical variables entered into the model were height, weight, BMI, affected side, severity of knee OA, and severity of pain. All patients in the study received one of three treatment protocols for patients with knee OA: (a) hot packs, followed by electrotherapy and exercise, (b) ice packs, followed by ultrasound and exercise and (c) exercise alone. The resilient back propagation artificial neural network algorithm was used, with a ten-fold cross-validation. It was estimated that the MDSS is able to accurately predict the treatment prescribed by the physician for 87% of the patients. We developed an artificial neural network-based decision support system that can viably aid physicians in determining which treatment protocol would best match the anthropometric and clinical characteristics of patients with knee OA. PMID- 22508430 TI - Diagnosis. Severity scoring system for paediatric FMF. AB - Severity scoring systems for adult familial Mediterranean fever (FMF) are established and used as important clinical and analytical tools in disease management and research. A recent paper highlights the need for a paediatric FMF severity measure. How should such a score be built and what challenges might be faced? PMID- 22508429 TI - The transition of acute to chronic bowel inflammation in spondyloarthritis. AB - That gut and joint inflammation are linked in spondyloarthritis (SpA) has been recognized for almost three decades. Intriguingly, microscopic gut inflammation, which occurs frequently in patients with SpA, is an important risk factor for clinically overt Crohn's disease and ankylosing spondylitis. This Review describes current insights into the underlying mechanisms that lead to chronic gut inflammation in patients with SpA. We propose that the development of chronic bowel inflammation in these individuals occurs through a transition phase, in which inflammation evolves from an acute into a chronic state. Our transition model implies that different cell types are involved at different stages during disease progression, with stromal cells having an important role in chronicity. In addition, deficient regulatory feedback mechanisms or genetically determined alterations in antigen presentation, endoplasmic reticulum stress, autophagy or cytokine signaling might also favor a transition from self-limiting acute inflammation to chronic inflammation. We anticipate that this transition phase might be an important window for therapeutic intervention. PMID- 22508431 TI - Connective tissue diseases. Unravelling aetiology in male SLE--the X chromosome dose effect. AB - New evidence suggesting an X chromosome effect underlies the development and progression of male systemic lupus erythematosus comes from a study of sex chromosome aneuploidy in men with this disease. The description of a number of immunoregulatory mechanisms encoded on the X chromosome support this hypothesis; however, further studies are warranted. PMID- 22508432 TI - Osteoarthritis. Omega-3 fatty acids and synovitis in osteoarthritic knees. PMID- 22508433 TI - Impaired myogenic tone in isolated cerebral and coronary resistance arteries from the goto-kakizaki rat model of type 2 diabetes. AB - AIM: Type 2 diabetes is associated with stroke and cardiac dysfunction. We therefore investigated isolated middle cerebral arteries and coronary septal arteries from the diabetic Goto-Kakizaki (GK) rat model of nonobese type 2 diabetes. METHODS: Myogenic tone and agonist-induced responses were investigated under isobaric conditions with simultaneous recording of [Ca2+]i. Rho-kinase and NO pathways were investigated using specific pharmacological tools. RESULTS: Arteries from GK rats developed less tone at pressures from 20 to 100 mm Hg than arteries from control Wistar (CW) rats while [Ca2+]i was similar. Blocking the Rho-kinase pathway decreased the pressure-induced development of tone and after blockade no difference in myogenic tone between arteries from GK and CW rats was seen. Cerebral arteries had similar tone to a maximal concentration of U46619 (GK: 35.5+/-2% vs. CW: 31.6+/-5%), while coronary arteries from GK rats developed less tone than arteries from CW rats (12+/-3 vs. 26.1+/-3%). Endothelium dependent vasodilation to A23187 (cerebral) and to acetylcholine (coronary) was not different between arteries from GK and CW rats. CONCLUSION: Our data suggest that in resistance arteries from the brain and the heart of GK rats the myogenic tone is decreased due to impaired calcium sensitivity likely due to a defective Rho-kinase pathway. PMID- 22508434 TI - Genome-wide screen for miRNA targets using the MISSION target ID library. AB - The Target ID Library is designed to assist in discovery and identification of microRNA (miRNA) targets. The Target ID Library is a plasmid-based, genome-wide cDNA library cloned into the 3'UTR downstream from the dual-selection fusion protein, thymidine kinase-zeocin (TKzeo). The first round of selection is for stable transformants, followed with introduction of a miRNA of interest, and finally, selecting for cDNAs containing the miRNA's target. Selected cDNAs are identified by sequencing (see Figure 1-3 for Target ID Library Workflow and details). To ensure broad coverage of the human transcriptome, Target ID Library cDNAs were generated via oligo-dT priming using a pool of total RNA prepared from multiple human tissues and cell lines. Resulting cDNA range from 0.5 to 4 kb, with an average size of 1.2 kb, and were cloned into the p3I"TKzeo dual-selection plasmid (see Figure 4 for plasmid map). The gene targets represented in the library can be found on the Sigma-Aldrich webpage. Results from Illumina sequencing (Table 3), show that the library includes 16,922 of the 21,518 unique genes in UCSC RefGene (79%), or 14,000 genes with 10 or more reads (66%). PMID- 22508435 TI - A randomized controlled trial of effects of Wellness Recovery Action Planning on depression, anxiety, and recovery. AB - OBJECTIVE: The purpose of this study was to test the effectiveness of the Wellness Recovery Action Planning (WRAP) self-management intervention in reducing depression and anxiety and in increasing self-perceived recovery among individuals with a serious mental illness. METHODS: Participants were recruited from outpatient community mental health settings in six Ohio communities: Canton, Cleveland, Columbus, Dayton, Lorain, and Toledo. With a single-blind, randomized controlled trial design, 519 individuals were assigned to WRAP or to services as usual and assessed at baseline and at two- and eight-month follow-ups. The intervention consisted of eight weekly 2.5-hour sessions delivered by peers in recovery from serious mental illness who were certified WRAP educators. RESULTS: The mean number of WRAP sessions attended was five, and fidelity ranged from 90% to 92%. Analysis using mixed-effects random regression revealed interactions of study condition by time in each outcome area. Compared with the control group, intervention participants reported significantly greater reduction over time in Brief Symptom Inventory depression and anxiety subscales and significantly greater improvement in total Recovery Assessment Scale scores as well as the subscales measuring personal confidence and goal orientation. CONCLUSIONS: Training in mental illness self-management reduced depression and anxiety and improved participants' self-perceived recovery over time. Results confirmed the importance of WRAP as part of a group of evidence-based, recovery-oriented interventions. PMID- 22508436 TI - Long-term amelioration of established collagen-induced arthritis achieved with short-term therapy combining anti-CD3 and anti-tumor necrosis factor treatments. AB - OBJECTIVE: The goal of rheumatoid arthritis (RA) treatment is to achieve clinical remission in order to limit structural damage and physical disability. To this end, recent emphasis has been placed on aggressive treatment early in the course of disease with drugs such as anti-tumor necrosis factor (anti-TNF) agents. As T cells are also thought to play an important role in the initiation of RA, we hypothesized that targeting both TNF and T cells would result in better outcomes. The aim of this study was to examine the efficacy of combined therapy with anti CD3 and anti-TNF in experimental RA. METHODS: Two anti-mouse antibodies were developed as surrogate reagents for anti-TNF and anti-CD3 therapies. Collagen induced arthritis (CIA) was induced in DBA/1 mice, and antibodies were injected intraperitoneally, either alone on in combination, at predetermined subtherapeutic doses. The frequency and number of pathogenic and regulatory CD4+ T cell subsets in the draining lymph nodes were determined in order to investigate the mechanisms of action. RESULTS: Strikingly, the combination of the two antibodies demonstrated a potent synergy in established CIA, with long-term inhibition of disease progression and protection from joint destruction. The results did not demonstrate any enhancement of CD25+FoxP3+ regulatory T cells, but a profound depletion of pathogenic T cells from the draining lymph nodes was associated with reduced numbers of T cells in the joints. CONCLUSION: A short course of combination therapy with anti-CD3 and anti-TNF efficiently depletes pathogenic T cells from the draining lymph nodes, reducing the numbers of T cells in the joints and affording long-lasting inhibition of established CIA. PMID- 22508437 TI - Multi-investigator collaboration in orthopaedic surgery research compared to other medical fields. AB - An increasing emphasis has been placed across health care on evidence-based medicine with higher level studies, such as randomized trials and prospective cohort studies. Historically, clinical research in orthopaedic surgery has been dominated by studies with low patient numbers from a limited number of surgeons. The purpose of this study was to test our hypothesis that orthopaedics has fewer multi-center collaborative studies as compared to other medical disciplines. We chose three leading journals from general medicine, a leading journal from the surgical subspecialties of obstetrics and gynecology, ophthalmology and otolaryngology, and three leading journals from orthopaedic surgery based on highest impact factor. We compared the percentage of collaborative studies and the number of contributing institutions and authors in original research manuscripts published in 2009 between general medical, surgical subspecialty and orthopaedic surgery journals. A significantly higher percentage of manuscripts resulted from multicenter collaborative efforts in the general medical literature (p < 0.000001) and the other surgical subspecialty literature (p < 0.000001) compared to the orthopaedic surgery literature. Manuscripts published in the general medical journals came from more institutions (p < 0.0001) and had significantly more authors (p < 0.000001) than those published in the orthopaedic surgery journals. There is an opportunity to stimulate greater multicenter collaborative research, which correlates with increased patient numbers, a higher level of evidence and more generalizable findings, in the orthopaedic surgery community. These efforts can be supported through increased funding, surgeon participation, and appropriate expansion of authorship for multicenter studies in orthopaedic journals. PMID- 22508439 TI - Advances in WNK signaling of salt and potassium metabolism: clinical implications. AB - Recent evidence due to the discovery of a family of kinases implicated in arterial hypertension now points to the underlying molecular mechanisms that dictate Na(+), K(+) and water handling in the nephron. These new key players need to be understood in order to fully comprehend the pathophysiology, manifestations, and treatment of common clinical entities such as hypovolemic shock, congestive heart failure, primary hyperaldosteronism, nephrotic syndrome and hypertension. It is through the analysis of the volume status and electrolyte abnormalities that commonly present with these diseases that we can begin to create a link between the abstract concept of a kinase regulation and how a patient will respond to a particular treatment. This review is an attempt to bridge that gap. PMID- 22508440 TI - Giant magnetoresistance in silicene nanoribbons. AB - By performing first-principle quantum transport calculations, we predict a giant magnetoresistance in zigzag silicene nanoribbons (ZSiNRs) connecting two semi infinite silicene electrodes through switch of the edge spin direction of ZSiNRs. Spin-filter efficiency of both the antiferromagnetic and ferromagnetic ZSiNRs is sign-changeable with the bias voltage. Therefore, potential application of silicene in spintronics devices is suggested. PMID- 22508441 TI - A methyl-deficient diet modifies early B cell development. AB - A functional methyl group donor is essential for the epigenetic regulation of all biological events due to the importance of DNA methylation and histone methylation as an epigenetic marker. However, the epigenetic alterations in the immune system due to methyl donor deficiency are not well known. In this study, we tried to address this question by studying the lymphocyte development and DNA methylation changes caused by a methyl-deficient diet (MDD). We fed one group of C57BL/6J mice with a methyl-sufficient diet (MSD) and the other group with an MDD for 5 months. Flow cytometry analyses of their immune systems showed a decrease in B220+ IgM+ (immature B) cells and an increase in B220+ IgM- (pro/pre-B) cells in the bone marrow of mice fed an MDD. By means of an in vitro OP9 coculture system, we recognized that this B220+ IgM- cell fraction from the MDD has an intrinsic developmental defect. When we quantitatively measured the mRNA expression levels of transcription factors and recombination machinery related to B cell development in the B220+ IgM- cell fraction of their bone marrow, we found that ADA, EBF1, DNTT and Pax5 mRNA expression levels were significantly downregulated in mice fed with an MDD. In addition, there was a drastic decrease in histone methylation profile H3K4me3 in the Pax5 and EBF1 promoters in these B220+ IgM- B cells. However, CpG-DNA methylation profiles had not changed and this revealed that these two promoters are demethylated even under an MSD condition. We also found changed expression levels of the Polycomb group genes (mel18, bmi1, Pc1, Pc2, Ring1A, Ring1B, Ph1) on semi-quantitative RT-PCR. These results indicate that under an MDD condition, early B cell development in bone marrow is easily affected by epigenetic alterations. PMID- 22508442 TI - Percutaneous coronary revascularization in coronary artery disease: lessons from a single center experience. AB - OBJECTIVES: To determine the role of percutaneous coronary intervention (PCI) and its impact on mortality in coronary artery disease (CAD). BACKGROUND: It's unclear whether PCI provides benefit in patients with CAD outside of acute settings. We sought to determine the role of PCI and its effect on mortality in patients with similar entry criteria to prior RCTs and compare outcomes with medical treatment. METHODS: Using institutional diagnostic catheterization database of consecutive patients undergoing coronary angiography from 1/2004 to 1/2010, we examined records for patients with a positive stress test and >70% coronary stenosis or symptoms of angina and >80% coronary stenosis. We excluded those with acute coronary syndromes, low ejection fraction (EF), history of CABG, and CABG following index catheterization. We stratified patients by treatment and performed unadjusted and propensity matched analyses. The outcome was all-cause mortality obtained from the social security death index. RESULTS: We identified 3,375 patients using study inclusion criteria. Mean age was 65 +/- 11 years and 69% (n = 2,332) were men. Mean EF was 55% +/- 8%. In the unadjusted cohort, 1,265 patients received medical management and 2,110 received PCI. The unadjusted analysis revealed significantly better survival in PCI patients (P < 0.0001) (HR: 0.51; 95% confidence interval (CI), 0.41-0.63). Propensity matching was performed for 1,580 patients and analysis showed better survival among patients receiving PCI (0 = 0.04) (HR: 0.74; 95% CI, 0.55-0.98). PCI continued to show better survival after excluding patients with malignancy (P = 0.03) and unstable angina (P = 0.007). CONCLUSIONS: This single center registry analysis demonstrated better survival in stable CAD patients undergoing PCI compared to medical management alone. These data suggest there may be a benefit of PCI beyond symptom relief. Future randomized trials are needed to further understand the role of PCI in broader patient populations. PMID- 22508443 TI - Validation of the first quality-of-life measurement for patients with Huntington's disease: the Huntington Quality of Life Instrument. AB - Health-related quality-of-life instruments are critical for assessing disease burdens. Generic tools allow comparison between diseases but do not discriminate between disease severities. Specific tools also tend to be more sensitive. No specific tool is available to assess quality of life in patients with Huntington's disease (HD). In the context of the European study on HD burden, a specific tool was created: the Huntington Quality of Life Instrument (H-QoL-I). The aim of this study was to optimize the content and validate the H-QoL-I. After a semistructured interview with patients, caregivers and HD specialists, we conducted a patient focus group. A self-reported questionnaire was then developed in French and Italian. A total of 252 patients were recruited to answer the questionnaire. Face, internal and external validities were examined using a variety of methods. The shortened H-QoL-I that resulted from the successive analyses comprises 11 items, which are divided into three dimensions: motor functioning (four items), psychology (four items) and socializing (three items). These three domains were identified as being essential to cover the full domain of the quality of life for patients affected by HD. The H-QoL-I showed an acceptable reliability (Cronbach's alpha>0.84). Factor analyses demonstrated satisfactory construct validity. Moreover, the item internal consistency and item discriminant validity criteria were fulfilled. No differential item functioning was detected. External validity supported the scale's robustness. These data support the validity of the H-QoL-I in patients with HD. PMID- 22508444 TI - Liquid chromatographic resolution of 3-amino-1,4-benzodiazepin-2-ones on crown ether-based chiral stationary phases. AB - 3-Amino-5-phenyl (or 5-methyl)-1,4-benzodiazepin-2-ones, which are chiral precursors of anti-respiratory syncytial virus active agents, were resolved on three different chiral stationary phases (CSPs) based on (+)-(18-crown-6) 2,3,11,12-tetracarboxylic acid or (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6. Among the three CSPs, the CSP that is based on (3,3'-diphenyl-1,1'-binaphthyl)-20 crown-6 and containing residual silanol group-protecting n-octyl groups on the silica surface was found to be most effective with the use of 80% ethanol in water containing perchloric acid (10 mM) and ammonium acetate (1.0 mM) as a mobile phase. The separation factors (alpha) and resolutions (R(S) ) were in the range of 1.90-3.21 and 2.79-5.96, respectively. From the relationship between the analyte structure and the chromatographic resolution behavior, the chiral recognition mechanism on the CSP based on (+)-(18-crown-6)-2,3,11,12 tetracarboxylic acid was proposed to be different from that on the CSP based on (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6. In addition, the chromatographic resolution behavior of the most effective CSP was investigated as a function of the composition of aqueous mobile phase containing organic and acidic modifier and ammonium acetate. PMID- 22508445 TI - Nanomaterials for ocular drug delivery. AB - Efficient drug delivery to the eye remains a challenging task for pharmaceutical scientists. Due to the various anatomical barriers and the clearance mechanisms prevailing in the eye, conventional drug delivery systems, such as eye drop solutions, suffer from low bioavailability. More invasive methods, such as intravitreal injections and implants, cause adverse effects in the eye. Recently, an increasing number of scientists have turned to nanomaterial-based drug delivery systems to address the challenges faced by conventional methods. This paper highlights recent applications of various nanomaterials, such as polymeric micelles, hydrogels, liposomes, niosomes, dendrimers, and cyclodextrins as ocular drug delivery systems to enhance the bioavailability of ocular therapeutic agents. PMID- 22508446 TI - Determination of lipid raft partitioning of fluorescently-tagged probes in living cells by Fluorescence Correlation Spectroscopy (FCS). AB - In the past fifteen years the notion that cell membranes are not homogenous and rely on microdomains to exert their functions has become widely accepted. Lipid rafts are membrane microdomains enriched in cholesterol and sphingolipids. They play a role in cellular physiological processes such as signalling, and trafficking but are also thought to be key players in several diseases including viral or bacterial infections and neurodegenerative diseases. Yet their existence is still a matter of controversy. Indeed, lipid raft size has been estimated to be around 20 nm, far under the resolution limit of conventional microscopy (around 200 nm), thus precluding their direct imaging. Up to now, the main techniques used to assess the partition of proteins of interest inside lipid rafts were Detergent Resistant Membranes (DRMs) isolation and co-patching with antibodies. Though widely used because of their rather easy implementation, these techniques were prone to artefacts and thus criticized. Technical improvements were therefore necessary to overcome these artefacts and to be able to probe lipid rafts partition in living cells. Here we present a method for the sensitive analysis of lipid rafts partition of fluorescently-tagged proteins or lipids in the plasma membrane of living cells. This method, termed Fluorescence Correlation Spectroscopy (FCS), relies on the disparity in diffusion times of fluorescent probes located inside or outside of lipid rafts. In fact, as evidenced in both artificial membranes and cell cultures, probes would diffuse much faster outside than inside dense lipid rafts. To determine diffusion times, minute fluorescence fluctuations are measured as a function of time in a focal volume (approximately 1 femtoliter), located at the plasma membrane of cells with a confocal microscope (Fig. 1). The auto-correlation curves can then be drawn from these fluctuations and fitted with appropriate mathematical diffusion models. FCS can be used to determine the lipid raft partitioning of various probes, as long as they are fluorescently tagged. Fluorescent tagging can be achieved by expression of fluorescent fusion proteins or by binding of fluorescent ligands. Moreover, FCS can be used not only in artificial membranes and cell lines but also in primary cultures, as described recently. It can also be used to follow the dynamics of lipid raft partitioning after drug addition or membrane lipid composition change. PMID- 22508447 TI - Sonographic features of histopathologically benign solid breast lesions that have been classified as BI-RADS 4 on sonography. AB - PURPOSE: To describe the sonographic (US) features associated with ultrasonography BI-RADS category 4 lesions that have a benign histopathological outcome. METHODS: One hundred seventy-two histopathologically proven benign lesions in 169 patients, which had been classified as BI-RADS category 4 with ultrasonography, were retrospectively evaluated. Ultrasonography and histopathology findings were analyzed. The frequency of sonographic findings according to the histopathological diagnosis was determined. RESULTS: Among the 172 lesions, there were 66 (38%) fibroadenomas, 31 (18%) sclerosing adenoses, 24 (14%) fibrocystic changes, 16 (9%) mastitis/inflammations, 9 (5.5%) intraductal papillomas, 8 (5%) focal fibroses, 4 (2.5%) atypical ductal hyperplasias, 4 (2.5%) fat necroses, 2 (1%) phyllodes tumors, 1 (0.5%) tubular adenomas, 1 (0.5%) epidermal inclusion cysts, and 6 (3.5%) "other benign lesions." The most frequent sonographic findings were heterogeneity, indistinct margin, microlobulation in fibroadenomas; heterogeneity, irregular-indefinite margin, and antiparallel orientation in sclerosing adenosis; heterogeneity, microlobulation, and acoustic shadowing in fibrocystic changes. CONCLUSIONS: BI-RADS category 4 lesions demonstrate more than one suspicious ultrasonography feature, and biopsy is necessary to diagnose malignancy captured in 33% of lesions in this study. At this time, any lesion with more than one suspicious BI-RADS US feature cannot avoid a diagnostic biopsy. PMID- 22508448 TI - Peculiarities of intramolecular exchange and valence tautomerism in metal semiquinolates determined by high-resolution NMR spectroscopy. AB - The (1)H NMR spectra of semiquinalate cobalt complex have been analyzed in a wide range of temperatures. It has been established that the intramolecular exchange requires the obligatory presence of a paramagnetic structure containing non compensated electron spin localized on the carbon atom of the ligand aromatic ring, the cobalt atom being trivalent. The presence of such a structure leads to the appearance of satellite signals in the NMR spectra because of the superfine interactions. PMID- 22508449 TI - An in vitro comparison of detection methods for approximal carious lesions in primary molars. AB - BACKGROUND/AIMS: This study aimed to compare and contrast in vitro six methods to determine the most accurate method for detecting approximal carious lesions in primary molars. METHODS: Extracted primary molars (n = 140) were stored in 0.02% chlorhexidine solution and mounted in light-cured resin in pairs. The six carious lesion detection methods used by the three examiners to assess approximal carious lesions were visual inspection, digital radiography, two transillumination lights (SDI and NSK), and two laser fluorescence instruments (CDD and DDP). Five damaged teeth were discarded. The teeth (n = 135) were sectioned, serially ground, and examined under light microscopy using Downer's histological (HST) criteria as the gold standard. Intra- and inter-examiner reliability, agreement with HST, specificity, sensitivity, receiver operating characteristic (ROC) curves, and areas under the curve were calculated. RESULTS: This study found visual inspection to be the most accurate method when validated by histology. Transillumination with NSK light had the highest specificity, and digital radiography had the highest sensitivity for detecting enamel and/or dentinal carious lesions. Combining specificity and sensitivity into the area under ROC curves, enamel plus dentinal lesions were detected most accurately by visual inspection followed by digital radiography; dentinal lesions were detected most accurately by digital radiography followed by visual inspection. CONCLUSIONS: None of the four newly developed methods can be recommended as suitable replacements for visual inspection and digital radiography in detecting carious lesions on approximal surfaces of primary molars, and further developmental work is needed. PMID- 22508450 TI - Regulation of sodium-glutamine cotransport in villus and crypt cells by glucocorticoids during chronic enteritis. AB - BACKGROUND: Assimilation of the preferred nutrient of enterocytes is mediated primarily by sodium (Na)-dependent cotransport (NGct) in the intestine. The predominant NGcT in villus cells, B0AT1, is inhibited secondary to a decrease in cotransporter numbers during chronic intestinal inflammation. In contrast, NGcT mediated by SN2 in crypt cells is stimulated secondary to increased affinity of the cotransporter for glutamine during chronic ileitis. Glucocorticoid is a mainstay of treatment for inflammatory bowel disease. However, its effect on NGcT is not known. METHODS: The inhibition of B0AT1 in villus cells during chronic intestinal inflammation was reversed back to normal by methylprednisolone (MP). This was secondary to the restoration of the cotransporter numbers in the brush border membrane rather than an alteration in the affinity. The stimulation of NGcT in crypt cells during chronic ileitis was also restored back to its normal levels by MP treatment. This reversal was secondary to the restoration of the altered affinity of the cotransporter SN2 for glutamine. RESULTS: Kinetic studies and western blot analysis were consistent with functional studies for both cotransporters. Thus, glucocorticoids restore two uniquely altered Na-glutamine cotransporters, B0AT1 in villus and SN2 in crypt cells during chronic enteritis. CONCLUSIONS: These data indicate that glucocorticoids function as an upstream broad spectrum immune modulator in the chronically inflamed intestine. PMID- 22508451 TI - Experimental and modeling analysis of Synechocystis sp. PCC 6803 growth. AB - BACKGROUND/AIMS: The influence of different parameters such as temperature, irradiance, nitrate concentration, pH, and an external carbon source on Synechocystis PCC 6803 growth was evaluated. METHODS: 4.5-ml cuvettes containing 2 ml of culture, a high-throughput system equivalent to batch cultures, were used with gas exchange ensured by the use of a ParafilmTM cover. The effect of the different variables on maximum growth was assessed by a multi-way statistical analysis. RESULTS: Temperature and pH were identified as the key factors. It was observed that Synechocystis cells have a strong influence on the external pH. The optimal growth temperature was 33 degrees C while light-saturating conditions were reached at 40 uE.m-2.s-1. CONCLUSION: It was demonstrated that Synechocystis exhibits a marked difference in behavior between autotrophic and glucose-based mixotrophic conditions, and that nitrate concentrations did not have a significant influence, probably due to endogenous nitrogen reserves. Furthermore, a dynamic metabolic model of Synechocystis photosynthesis was developed to gain insights on the underlying mechanism enabling this cyanobacterium to control the levels of external pH. The model showed a coupled effect between the increase of the pH and ATP production which in turn allows a higher carbon fixation rate. PMID- 22508454 TI - Prostate cancer: Smoothened inhibition reduces tumor cell proliferation. PMID- 22508452 TI - Prostate cancer: the future of TRUS-guided biopsy antibiotic prophylaxis? PMID- 22508457 TI - Testicular cancer: Underestimating radiotherapy toxicity for stage I seminoma. PMID- 22508458 TI - Bladder cancer: New insight into the mechanisms of lung metastasis. PMID- 22508461 TI - BPH: Hormone antagonists for two-pronged attack on BPH. PMID- 22508459 TI - Adolescent and adult risk factors for testicular cancer. AB - The incidence of testicular cancer has been increasing over the past several decades in many developed countries. The reasons for the increases are unknown because the risk factors for the disease are poorly understood. Some research suggests that in utero exposures, or those in early childhood, are likely to be important in determining an individual's level of risk. However, other research suggests that exposure to various factors in adolescence and adulthood is also linked to the development of testicular cancer. Of these, two adult occupational exposures-fire fighting and aircraft maintenance--and one environmental exposure (to organochlorine pesticides) are likely to be associated with increased risk of developing testicular cancer. By contrast, seven of the identified factors--diet, types of physical activity, military service, police work as well as exposure to ionizing radiation, electricity and acrylamide--are unlikely to increase the risk of developing testicular cancer. Finally, seven further exposures--to heat, polyvinyl chloride, nonionizing radiation, heavy metals, agricultural work, pesticides and polychlorinated biphenyls as well as marijuana use--require further study to determine their association with testicular cancer. PMID- 22508463 TI - Knowledge and attitudes about mental illness: a survey of middle school students. AB - OBJECTIVES: Despite the many studies of public attitudes toward mental illnesses, relatively few have examined the views of the youngest generation of citizens. This study was intended to increase understanding of youths' views of mental illness by developing and administering measures of knowledge and attitudes of middle school students toward mental illnesses. METHODS: Self-report questionnaires concerning knowledge, attitudes, and social distance related to mental illness were developed and pilot-tested to create an assessment tool appropriate for a juvenile sample. The measures were administered to 193 students at four middle schools in different parts of the United States between November 2008 and April 2009. RESULTS: The students' knowledge about mental illness was inconsistent, but important gaps were evident, particularly with respect to the symptoms of specific disorders. Attitudes toward individuals with a mental illness were generally positive, but substantial numbers of students had less favorable attitudes. Social distance scores revealed considerable reluctance to interact closely with a person with mental illness. Most (65%) students were uncertain whether mental illnesses have a biological cause, and 37% believed that medication to treat mental illness is useful. CONCLUSIONS: Attitudes toward individuals with mental illnesses may be more favorable among students than among adults. Nevertheless, stigma may persist as a problem for the next generation of citizens, and youths with a mental illness remain likely to experience misunderstanding and exclusion by peers. There is a need to educate children about specific disorders and about acceptance of individuals with mental illness. PMID- 22508462 TI - New strategies to prevent catheter-associated urinary tract infections. AB - Catheter-associated urinary tract infection (CAUTI) is the most common health care-associated infection worldwide. Although not all cases of bacteriuria result in clinical infection, several hundred thousand episodes of CAUTI occur each year in the USA alone. The milieu in which the catheter is placed is highly conducive to bacterial colonization, biofilm formation on the catheter surface, and inevitable catheter-associated bacteriuria. A multitude of novel methods of CAUTI prevention have been described, including established approaches that are routinely recommended, such as the use of a secured, closed, silicone urinary catheter drainage system that mimics normal voiding, and newer strategies focusing on biocompatible catheter materials that cause minimal host inflammatory response and retard biofilm formation. Much recent research has focused on modification of the catheter surface by either coating or impregnation with antimicrobials or antiseptics. However, clinical trials that analyse cost effectiveness and rates of antimicrobial resistance are awaited. More recently, innovative use of iontophoresis, vibroacoustic stimulation, bacterial interference and bacteriophage cocktails has been reported. PMID- 22508466 TI - Comparative safety and efficiency of five percutaneous kidney biopsy approaches of native kidneys: a multicenter study. AB - BACKGROUND: Renal biopsy (RB) is necessary for the diagnosis, prognosis, and therapy guidance of native kidney diseases. Few studies have compared outcomes of RB procedures. We retrospectively compared the safety and efficiency of five biopsy procedures. METHODS: The number of glomeruli on light microscopy (LM) and on immunofluorescence (IF) and serious adverse events following RB performed in five nephrology units (C1-C5) were collected. C1 performed ultrasound (US) assessment before RB and used a 14-gauge core-cutting needle biopsy gun, C2 US guidance and a 14-gauge needle, C3 tomodensitometry guidance and a 14-gauge needle, C4 US guidance and a 16-gauge needle, and C5 tomodensitometry guidance and a 16-gauge needle. RESULTS: RB was performed in 943 adults between January 2006 and July 2010. Serious adverse events occurred in 1.5% of biopsies. The complication rate was not different between nephrology units. The mean number of glomeruli on biopsy was 14.2 +/- 8.6 with LM and 4.4 +/- 3.3 on IF. It was different according to the nephrology unit for LM (p = 0.01) and for IF (p < 0.001). The number of failed biopsies was influenced by the nephrology unit and radiological guidance technique, favoring real-time US guidance. Failed biopsies using US or tomodensitometry assessment before RB was certainly due to kidney imprecise localization since it was often non-renal tissue sampling. At least 10 glomeruli were found in 69% of biopsies on LM. This rate varied according to the nephrology unit (p = 0.004) and was higher when 14-gauge needles were used in comparison with 16-gauge needles. CONCLUSION: RB is safe regardless of the technical procedure, but radiological guidance and needle size influence the efficiency of biopsies. PMID- 22508465 TI - The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development. AB - Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, increased impulsivity and emotion dysregulation. Linkage analysis followed by fine-mapping identified variation in the gene coding for Latrophilin 3 (LPHN3), a putative adhesion-G protein-coupled receptor, as a risk factor for ADHD. In order to validate the link between LPHN3 and ADHD, and to understand the function of LPHN3 in the etiology of the disease, we examined its ortholog lphn3.1 during zebrafish development. Loss of lphn3.1 function causes a reduction and misplacement of dopamine-positive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype can be rescued by the ADHD treatment drugs methylphenidate and atomoxetine. Together, our results implicate decreased Lphn3 activity in eliciting ADHD-like behavior, and demonstrate its correlated contribution to the development of the brain dopaminergic circuitry. PMID- 22508464 TI - Increased vulnerability of the brain norepinephrine system of females to corticotropin-releasing factor overexpression. AB - Stress-related psychiatric disorders are more prevalent in women than men. As hypersecretion of the stress neuromediator, corticotropin-releasing factor (CRF) has been implicated in these disorders, sex differences in CRF sensitivity could underlie this disparity. Hyperarousal is a core symptom that is shared by stress related disorders and this has been attributed to CRF regulation of the locus ceruleus (LC)-norepinephrine arousal system. We recently identified sex differences in CRF(1) receptor (CRF(1)) signaling and trafficking that render LC neurons of female rats more sensitive to CRF and potentially less able to adapt to excess CRF compared with male rats. The present study used a genetic model of CRF overexpression to test the hypothesis that females would be more vulnerable to LC dysregulation by conditions of excess CRF. In both male and female CRF overexpressing (CRF-OE) mice, the LC was more densely innervated by CRF compared with wild-type controls. Despite the equally dense CRF innervation of the LC in male and female CRF-OE mice, LC discharge rates recorded in slices in vitro were selectively elevated in female CRF-OE mice. Immunoelectron microscopy revealed that this sex difference resulted from differential CRF(1) trafficking. In male CRF-OE mice, CRF(1) immunolabeling was prominent in the cytoplasm of LC neurons, indicative of internalization, a process that would protect cells from excessive CRF. However, in female CRF-OE mice, CRF(1) labeling was more prominent on the plasma membrane, suggesting that the compensatory response of internalization was compromised. Together, the findings suggest that the LC-norepinephrine system of females will be particularly affected by conditions resulting in elevated CRF because of differences in receptor trafficking. As excessive LC activation has been implicated in the arousal components of stress-related psychiatric disorders, this may be a cellular mechanism that contributes to the increased incidence of these disorders in females. PMID- 22508467 TI - Lower-limb joint mechanics after total hip arthroplasty during sitting and standing tasks. AB - While the effect of total hip arthroplasty on the operated limb mechanics is well documented, little is known on its effect on the contralateral limb. The purpose of this study was to measure the joint mechanics of both lower limbs during the tasks of sit-to-stand and stand-to-sit. Twenty total hip arthroplasty patients and 20 control participants performed three trials of each task from which 3D lower-limb joint kinematics and kinetics were obtained. Total hip arthroplasty patients exhibited lower operated-hip joint flexion, extension moments, and power, occurring most frequently near seat-on and seat-off. Despite these reduced kinetic variables in the operated hip, the joints of the non-operated limb generated similar joint kinetics as the matched control participants. These results indicated the patients who underwent total hip arthroplasty could adopt a strategy that allowed them to reduce moments and power generated at the operated lower-limb joints without overcompensating with the non-operated leg. Although such a strategy may be desirable given that higher loads can increase friction and accelerate wear of the prosthesis, reduced loading may be an indication of inadequate muscle strength that needs to be addressed. PMID- 22508469 TI - Alkene metathesis - a tool for the synthesis of conjugated polymers. AB - Alkene metathesis is a superb methodology. We report the progress using alkene metathesis in the synthesis of polymeric organic semiconductors. Three classes of polymers have been synthesized using acyclic diene metathesis (ADMET) or ring opening metathesis polymerization (ROMP), viz., poly(acetylene)s (PA), poly(arylene-vinylene)s (PAV), and organometallic polymers. For PAs, ROMP of cyclooctatetraenes is best, whereas for PAV, both ADMET and indirect and direct ROMP are viable. Metathesis performs flawlessly with the correct monomers, as molybdenum and particularly the robust Ru carbenes demonstrate. When performing ROMP, one is often rewarded with structurally uniform polymers that can display very low polydispersities. Overall, metathesis is a powerful tool for the preparation of semiconducting polymers. PMID- 22508470 TI - Cerebral excitability is abnormal in patients with painful chronic pancreatitis. AB - BACKGROUND: We investigated whether patients with painful chronic pancreatitis (CP) present abnormalities in the cerebral response to experimental pain stimuli. METHODS: Contact heat-evoked potentials (CHEPS) were recorded in 15 patients with CP and in 15 healthy volunteers during repetitive stimulation of the upper abdominal region (pancreatic 'viscerotome') and the right forearm (heterologous area). Three sequences of painful stimuli were applied at each site. Subjective pain scores were assessed by a visual analogue scale. Habituation was calculated as the relative change in CHEPS amplitudes between the first and the third stimulation sequence. RESULTS: As expected pain scores decreased in healthy volunteers during successive stimulations at both sites (i.e., habituation), while in the CP group, they remained unchanged. The cerebral response consisted of an early-latency, low-amplitude response (N1, contralateral temporal region) followed by a late, high-amplitude, negative-positive complex (N2/P2, vertex). During successive stimulation of the pancreatic area, N2/P2 amplitude increased 25% in CP patients, while they decreased 20% in healthy volunteers (p = 0.006). After stimulation of the forearm, N2/P2 amplitudes increased 3% in CP patients compared to a decrease of 20% in healthy volunteers (p = 0.06). CONCLUSIONS: Taken together, CP patients had an abnormal cerebral response to repetitive thermal stimuli. This was most prominent after stimulation of the upper abdominal area. As this area share spinal innervation with the pancreatic gland, these findings likely mirror distinctive abnormalities in cerebral pain processing. PMID- 22508468 TI - A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. AB - OBJECTIVE: To assess whether it is better to intensively treat all patients with early rheumatoid arthritis (RA) using combinations of drugs or to reserve this approach for patients who do not have an appropriate response (as determined by a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR] of >= 3.2 at week 24) to methotrexate (MTX) monotherapy, and to assess whether combination therapy with MTX plus etanercept is superior to the combination of MTX plus sulfasalazine plus hydroxychloroquine. METHODS: The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study is a 2-year, randomized, double-blind trial. A 2 * 2 factorial design was used to randomly assign subjects to 1 of 4 treatment arms: immediate treatment with MTX plus etanercept, immediate oral triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or step-up from MTX monotherapy to one of the combination therapies (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine) at week 24 if the DAS28-ESR was >= 3.2. All treatment arms included matching placebos. The primary outcome was an observed-group analysis of DAS28-ESR values from week 48 to week 102. RESULTS: At week 24 (beginning of the step-up period), subjects in the 2 immediate-treatment groups demonstrated a greater reduction in the DAS28-ESR compared with those in the 2 step-up groups (3.6 versus 4.2; P < 0.0001); no differences between the combination-therapy regimens were observed. Between week 48 and week 102, subjects randomized to the step-up arms had a DAS28 ESR clinical response that was not different from that of subjects who initially received combination therapy, regardless of the treatment arm. There was no significant difference in the DAS28-ESR between subjects randomized to oral triple therapy and those randomized to receive MTX plus etanercept. By week 102, there was a statistically significant difference in the change in radiographic measurements from baseline between the group receiving MTX plus etanercept and the group receiving oral triple therapy (0.64 versus 1.69; P = 0.047). CONCLUSION: There were no differences in the mean DAS28-ESR during weeks 48-102 between subjects randomized to receive MTX plus etanercept and those randomized to triple therapy, regardless of whether they received immediate combination treatment or step-up from MTX monotherapy. At 102 weeks, immediate combination treatment with either strategy was more effective than MTX monotherapy prior to the initiation of step-up therapy. Initial use of MTX monotherapy with the addition of sulfasalazine plus hydroxychloroquine (or etanercept, if necessary, after 6 months) is a reasonable therapeutic strategy for patients with early RA. Treatment with the combination of MTX plus etanercept resulted in a statistically significant radiographic benefit compared with oral triple therapy. PMID- 22508471 TI - Genistein attenuated allergic airway inflammation by modulating the transcription factors T-bet, GATA-3 and STAT-6 in a murine model of asthma. AB - BACKGROUND: Genistein, a flavonoid in legumes and some herbal medicines, has various biological actions. Previous studies have shown that genistein decreased airway inflammation in allergic asthma. However, studies on how genistein affects immunoreactions in asthma are very limited. OBJECTIVE: It was the aim of this study to investigate the effect of genistein on T helper 1 (Th1)/Th2 cytokines in a murine asthma model and to explore its underlying mechanisms. METHODS: The asthma model was set up both in vivo and in vitro: the mice were divided into four groups in vivo, i.e. control group, ovalbumin-sensitized (OVA) group, Gen20 group (20 mg/kg genistein) and Gen40 group (40 mg/kg genistein), and into three groups in vitro, i.e. control group, OVA group, genistein group. Changes in lung histology were observed and concentrations of interleukin-4, interleukin-5 and interferon-gamma in bronchoalveolar lavage fluid and serum were measured by enzyme-linked immunosorbent assay. The mRNA expression of GATA binding protein 3 (GATA-3), signal transducer and activator of transcription 6 (STAT-6) and T-box transcription factor (T-bet) in the lungs and CD4+ T cells of each group were detected by real-time PCR and the corresponding proteins were detected by Western blot. RESULTS: The results showed that genistein attenuated OVA-induced airway inflammation, decreased Th2-type cytokines and increased Th1-type cytokines. Additionally, our data suggested that genistein may modulate the Th1/Th2 reaction by inhibiting GATA-3 and STAT-6 production while increasing T-bet production. CONCLUSION: Genistein may modulate the immunomodulatory actions caused by Th1/Th2 cytokines in asthma, at least partially, by the down-regulation of GATA-3 and STAT-6 and the up-regulation of T-bet. PMID- 22508472 TI - Facile backbone (1H, 15N, 13Ca, and 13C') assignment of 13C/15N-labeled proteins using orthogonal projection planes of HNN and HN(C)N experiments and its automation. AB - Recently, we introduced an efficient high-throughput protocol for backbone assignment of small folded proteins based on two-dimensional (2D) projections of HN(C)N suite of experiments and its automation [Borkar et al., J. Biomol. NMR 2011, 50(3), 285-297]. This strategy provides complete sequence-specific assignment of backbone ((1)H, (15)N, (13)C(alpha), and (13)C') resonances in less than a day; thus, it has great implications for high-throughput structural proteomics. However, in cases when such small folded protein exhibits substantial amide (1)H shift degeneracy (typically seen in alpha-helical proteins), the strategy may fail or lead to ambiguities. Another limitation is with respect to the identification of checkpoints from the variants of 2D-hncNH spectrum. For example, a protein with many GG, GA, AA, SS, TS, TT, and TS types of dipeptide stretches along its sequence, thus the identification of NH cross-peak corresponding to second G, A, S, or T becomes difficult. In this backdrop, we present here two improvements to enhance the utility of the proposed high throughput AUTOmatic Backbone Assignment protocol: (i) use of 2D-hNnH spectrum and its variants that display additional (1)H-(15)N correlations and thus help to resolve ambiguities arising because of amide (1)H shift degeneracy and (ii) optimization of the tau(CN) delay in the 2D-hncNH experiment that, when properly adjusted, is observed to help remove ambiguities in the identification of the checkpoints. These improvements have also been incorporated in the automation program AUTOmatic Backbone Assignment. Finally, the performance of the strategy and the automation has been demonstrated using the chicken SH3 domain protein. PMID- 22508473 TI - The personal meaning of recovery among individuals treated for a first episode of psychosis. AB - OBJECTIVE: There is little understanding of service users' conceptions of recovery in the early phase of psychotic disorders. An enhanced understanding of personal notions of recovery may help with the development and evaluation of interventions that address the concerns of service users. This study examined personal definitions of recovery among individuals recently treated in a specialized early-intervention service in Canada. METHODS: Semistructured interviews were carried out with 30 individuals three to five years after initial treatment of a first episode of psychosis. Interpretative phenomenological analysis was used to examine participants' personal meanings of recovery. A typology of recovery definitions was constructed. RESULTS: A majority of individuals considered themselves to be recovered. Responses indicated that recovery is a multidimensional experience and is often a personalized and achievable goal at this early stage in treatment. Individuals described recovery as improvement in one or more of three domains: illness recovery, psychological and personal recovery, and social and functional recovery. There was variation in the extent to which individuals perceived that recovery involved alleviation of symptoms and elimination of underlying vulnerability to illness. CONCLUSIONS: There were several components of the personal meanings of recovery from a first episode of psychosis and variations in the emphasis that individuals placed on each component. An overall positive outlook may be a function of younger age, shorter duration of illness, and receipt of client-centered comprehensive and phase-specific treatment. Improved understanding of personal notions of recovery can guide clinical practices to address service users' recovery goals. PMID- 22508474 TI - Implementing collaborative care for late-life depression in community long-term care. PMID- 22508475 TI - Does combining cognitive and functional scales facilitate the diagnosis of dementia? PMID- 22508476 TI - Are the interactions between recombinant prion proteins and polymeric surfaces related to the hydrophilic/hydrophobic balance? AB - New non-fouling tubes are developed and their influence on the adhesion of neuroproteins is studied. Recombinant prion proteins are considered as a single component representative of hydrophobic proteins. Samples are stored for 24 h at 4 degrees C in tubes coated with two different coatings: poly(N isopropylacrylamide) as a hydrophilic surface and a plasma-fluorinated coating as a hydrophobic one. The protein adhesion is monitored by ELISA tests, XPS and confocal microscopy. It appears that the highest recovery of recombinant prion protein in the liquid phase is obtained with the hydrophilic surface while the hydrophobic character of the storage tube induces an important amount of biological loss. However, the recovery is not complete even for tubes coated with poly(N-isopropylacrylamide). PMID- 22508477 TI - Ligand-exchange synthesis of selenophenolate-capped Au25 nanoclusters. AB - We report the synthesis and characterization of selenophenolate-capped 25-gold atom nanoclusters via a ligand-exchange approach. In this method, phenylethanethiolate (PhCH(2)CH(2)S) capped Au(25) nanoclusters are utilized as the starting material, which is subject to ligand-exchange with selenophenol (PhSeH). The as-obtained cluster product is confirmed to be selenophenolate protected Au(25) nanoclusters through characterization by electrospray ionization (ESI) and matrix-assisted laser desorption ionization mass spectrometry (MALDI MS), thermogravimetric analysis (TGA), elemental analysis (EA), UV-Vis and (1)H/(13)C NMR spectroscopies. The ligand-exchange synthesis of [Au(25)(SePh)(18)](-)[(C(8)H(17))(4)N](+) nanoclusters demonstrates that the core size of gold nanoclusters is retained in the thiolate-to-selenolate exchange process and that the 18 surface thiolate ligands can be completely exchanged by selenophenolate, rather than giving rise to a mixed ligand shell on the cluster. The two types of Au(25)L(18) (L = thiolate or selenolate) nanoclusters also show some differences in stability and optical properties. PMID- 22508479 TI - Re-expression of microRNA-375 reverses both tamoxifen resistance and accompanying EMT-like properties in breast cancer. AB - Epithelial-mesenchymal transition (EMT) is an initiating event in tumor cell invasion and metastasis. It has been shown to occur in resistance to a range of cancer therapies, including tamoxifen. MicroRNAs (miRNAs) have been associated with EMT as well as resistance to standard therapies. To investigate the role of miRNAs in the development of resistance to tamoxifen as well as accompanying EMT like properties, we established a tamoxifen-resistant (TamR) model by continually exposing MCF-7 breast cancer cells to tamoxifen. In addition to the molecular changes known to be involved in acquired tamoxifen resistance, TamR cells displayed mesenchymal features and had increased invasiveness. Genome-wide miRNA microarray analysis revealed that miRNA-375 was among the top downregulated miRNAs in resistant cells. Re-expression of miR-375 was sufficient to sensitize TamR cells to tamoxifen and partly reversed EMT. A combination of mRNA profiling, bioinformatics analysis and experimental validation identified metadherin (MTDH) as a direct target of miR-375. Knockdown of MTDH partially phenocopied the effects of miR-375 on the sensitivity to tamoxifen and the reversal of EMT. We observed an inverse correlation between the expression of miR-375 and its target MTDH in primary breast cancer samples, implying the pathological relevance of targeting. Finally, tamoxifen-treated patients with higher expression of MTDH had a shorter disease-free survival and higher risk of relapse. As most cancer related deaths occur because of resistance to standard therapies and metastasis, re-expression of miR-375 or targeting MTDH might serve as potential therapeutic approaches for the treatment of TamR breast cancer. PMID- 22508480 TI - Fas signaling promotes motility and metastasis through epithelial-mesenchymal transition in gastrointestinal cancer. AB - Fas signaling was reported to participate in cell apoptosis. However, this pathway has also been shown to promote tumor cell motility, leading to the hypothesis that Fas signaling may induce epithelial-mesenchymal transition (EMT) to promote metastasis. The effects of Fas-ligand (FasL) treatment and inhibition of Fas signaling on colorectal and gastric cancer cells were tested using motility assay, immunofluorescence, RT-PCR and immunoblot analyses. Fas signaling downregulated epithelial markers, upregulated mesenchymal markers and promoted motility in gastrointestinal (GI) cancer cells. FasL treatment also increased the expression of EMT transcriptional factors in the nucleus and induced a spindle shape cell morphology in these cells. Knockdown of Snail or Twist expression significantly decreased FasL-induced motility. The ERK1/2 pathway was activated by Fas signaling and is required for FasL-induced EMT and motility. Moreover, oxaliplatin, a chemotherapeutic agent, induced EMT partly through Fas signaling. Evaluation of human GI clinical specimens showed that FasL expression increased whereas E-cadherin expression decreased during GI cancer progression. Both markers were significantly inversely correlated. Tissue samples with a non-EMT phenotype were mainly distributed in patients with early cancer stages, whereas samples with an EMT phenotype were mostly distributed in patients with advanced cancer stages. A non-EMT phenotype significantly correlated with better prognosis. Altogether, these data indicate that Fas signaling may induce EMT to promote tumor motility and metastasis in GI cancer in vivo and in vitro. PMID- 22508478 TI - The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. AB - Cancer progression is characterized by rapidly proliferating cancer cells that are in need of increased protein synthesis. Therefore, enhanced endoplasmic reticulum (ER) activity is required to facilitate the folding, assembly and transportation of membrane and secretory proteins. These functions are carried out by ER chaperones. It is now becoming clear that the ER chaperones have critical functions outside of simply facilitating protein folding. For example, cancer progression requires glucose regulated protein (GRP) 78 for cancer cell survival and proliferation, as well as angiogenesis in the microenvironment. GRP78 can translocate to the cell surface acting as a receptor regulating oncogenic signaling and cell viability. Calreticulin, another ER chaperone, can translocate to the cell surface of apoptotic cancer cells and induce immunogenic cancer cell death and antitumor responses in vivo. Tumor-secreted GRP94 has been shown to elicit antitumor immune responses when used as antitumor vaccines. Protein disulfide isomerase is another ER chaperone that demonstrates pro oncogenic and pro-survival functions. Because of intrinsic alterations of cellular metabolism and extrinsic factors in the tumor microenvironment, cancer cells are under ER stress, and they respond to this stress by activating the unfolded protein response (UPR). Depending on the severity and duration of ER stress, the signaling branches of the UPR can activate adaptive and pro-survival signals, or induce apoptotic cell death. The protein kinase RNA-like ER kinase signaling branch of the UPR has a dual role in cancer proliferation and survival, and is also required for ER stress-induced autophagy. The activation of the inositol-requiring kinase 1alpha branch promotes tumorigenesis, cancer cell survival and regulates tumor invasion. In summary, perturbance of ER homeostasis has critical roles in tumorigenesis, and therapeutic modulation of ER chaperones and/or UPR components presents potential antitumor treatments. PMID- 22508481 TI - Prox1 suppresses the proliferation of neuroblastoma cells via a dual action in p27-Kip1 and Cdc25A. AB - Neuroblastoma is a pediatric tumor that originates from precursor cells of the sympathetic nervous system with less than 40% long-term survival in children diagnosed with high-risk disease. These clinical observations underscore the need for novel insights in the mechanisms of malignant transformation and progression. Accordingly, it was recently reported that Prox1, a homeobox transcription regulator, is expressed in higher levels in human neuroblastoma with favorable prognosis. Consistently, we have recently shown that Prox1 exerts a strong antiproliferative effect on neural precursor cells during embryonic development. Thus, Prox1 is a candidate gene with a critical role in suppressing malignant neuroblastoma transformation. Here, we provide evidence that Prox1 strongly suppresses the proliferation of mouse and human neuroblastoma cell lines and blocks the growth of neuroblastoma tumors in SCID mice. Conversely, short hairpin RNA (shRNA) -mediated knockdown of basal Prox1 expression significantly induces proliferation, genomic instability and the ability of neuroblastoma cells to form tumors. Mechanistically, analysis of an inducible Prox1-overexpressing Neuro2A cell line indicates that Prox1 is sufficient to suppress CyclinD1, CyclinA and CyclinB1, consistent with a role in cell cycle arrest. Surprisingly, Prox1 strongly induces CyclinE1 expression in the same system despite its action on blocking cell cycle progression, which could account for the context dependent oncogenic function of Prox1. Most importantly, Prox1 was sufficient to decrease Cdc25A and induce p27-Kip1, but not p21-Cip1 or p53. By alleviating the Prox1 action in Cdc25A and p27-Kip1 expression, we were able to rescue its effect on cell cycle arrest. Together these data suggest that Prox1 negatively regulates neuroblastoma carcinogenesis through suppression of Cdc25A and induction of p27 Kip1 to counteract CyclinE1 overexpression and block cell cycle progression. Furthermore, these observations render Prox1 a candidate target for the treatment of neuroblastoma tumors. PMID- 22508482 TI - Egr-1 mediates epidermal growth factor-induced downregulation of E-cadherin expression via Slug in human ovarian cancer cells. AB - Loss of the cell adhesion protein E-cadherin increases the invasive capability of ovarian cancer cells. We have previously shown that epidermal growth factor (EGF) downregulates E-cadherin and induces ovarian cancer cell invasion through the H(2)O(2)/p38 MAPK-mediated upregulation of the E-cadherin transcriptional repressor Snail. However, the molecular mechanisms underlying the EGF-induced downregulation of E-cadherin are not fully understood. In the current study, we demonstrated that treatment of two ovarian cancer cell lines, SKOV3 and OVCAR5, with EGF induced the expression of the transcription factor Egr-1, and this induction was abolished by small interfering RNA (siRNA)-mediated depletion of the EGF receptor. EGF-induced Egr-1 expression required the activation of the ERK1/2 and PI3K/Akt signaling pathways and was unrelated to EGF-induced H(2)O(2) production and activation of the p38 MAPK pathway. Moreover, depletion of Egr-1 with siRNA abolished the EGF-induced downregulation of E-cadherin and increased cell invasion. Interestingly, siRNA depletion of Egr-1 attenuated the EGF-induced expression of Slug, but not that of Snail. Moreover, chromatin immunoprecipitation (ChIP) analysis showed that Slug is a target gene of Egr-1. These results provide evidence that Egr-1 is a mediator that is involved in the EGF-induced downregulation of E-cadherin and increased cell invasion. Our results also demonstrate that EGF activates two independent signaling pathways, which are the H(2)O(2)/p38 MAPK-mediated upregulation of Snail expression and the Egr-1 mediated upregulation of Slug expression. These two signaling pathways contribute to the EGF-induced downregulation of E-cadherin, which subsequently increases the invasive capability of ovarian cancer cells. PMID- 22508483 TI - Anti-oncogenic potential of the eIF4E-binding proteins. AB - The eIF4E-binding proteins (4E-BPs) are inhibitors of protein synthesis that sequester the mRNA cap-binding protein eIF4E and consequently block cell growth and proliferation. In most tumors however, their inhibitory function is compromised by major oncogenic signaling pathways. Recently, thanks to the generation of mouse genetic models, considerable progress has been made in elucidating the involvement of 4E-BPs and their unique target, eIF4E, in the process of carcinogenesis. Increasing evidence indicates that an 'addiction' to protein synthesis emerges in cancer cells, highlighting the potential that 4E-BPs have as targets for therapeutics. In this review, we summarize the biochemical function, regulation and anti-oncogenic activity of the 4E-BPs. PMID- 22508484 TI - Clostridium difficile infection in the inflammatory bowel disease patient. AB - Clostridium difficile infection (CDI) has been increasing in frequency and severity in patients with inflammatory bowel disease (IBD). Population based and single center studies have shown worse clinical outcomes in concomitant CDI and IBD, with several reporting longer length of hospital stay, higher colectomy rates and increased mortality. Clinically, CDI may be difficult to distinguish from an IBD flare and may range from an asymptomatic carrier state to severe life threatening colitis. The traditional risk factors for CDI have included hospitalization, antibiotic use, older age and severe co-morbid disease but IBD patients have several distinct characteristics including younger age, community acquisition, lack of antibiotic exposure, colonic IBD and steroid use. CDI can occur in the small bowel and specifically in ulcerative colitis patients who have had a colectomy and an ileal pouch anal anastomosis. PCR based assays and combination Elisa algorithms have improved the sensitivity and specificity of testing, though in IBD patients have raised clinical questions about how to best manage diarrhea in the setting of possible C. difficile colonization. Treatment modalities for CDI have not been examined in randomized clinical trials in the IBD population. Newer antibiotics, immunotherapy and fecal microbiota transplantation may alter current treatment strategies. This review will focus on the unique epidemiology of CDI in IBD patients, detail clinical disease states, and provide updated diagnostic strategies, prevention and treatment options. PMID- 22508485 TI - Diagnosing pulmonary tuberculosis with the Xpert MTB/RIF test. AB - Tuberculosis (TB) due to Mycobacterium tuberculosis (MTB) remains a major public health issue: the infection affects up to one third of the world population(1), and almost two million people are killed by TB each year. Universal access to high-quality, patient-centered treatment for all TB patients is emphasized by WHO's Stop TB Strategy. The rapid detection of MTB in respiratory specimens and drug therapy based on reliable drug resistance testing results are a prerequisite for the successful implementation of this strategy. However, in many areas of the world, TB diagnosis still relies on insensitive, poorly standardized sputum microscopy methods. Ineffective TB detection and the emergence and transmission of drug-resistant MTB strains increasingly jeopardize global TB control activities. Effective diagnosis of pulmonary TB requires the availability - on a global scale - of standardized, easy-to-use, and robust diagnostic tools that would allow the direct detection of both the MTB complex and resistance to key antibiotics, such as rifampicin (RIF). The latter result can serve as marker for multidrug-resistant MTB (MDR TB) and has been reported in > 95% of the MDR-TB isolates. The rapid availability of reliable test results is likely to directly translate into sound patient management decisions that, ultimately, will cure the individual patient and break the chain of TB transmission in the community. Cepheid's (Sunnyvale, CA, U.S.A.) Xpert MTB/RIF assay meets the demands outlined above in a remarkable manner. It is a nucleic-acids amplification test for 1) the detection of MTB complex DNA in sputum or concentrated sputum sediments; and 2) the detection of RIF resistance-associated mutations of the rpoB gene. It is designed for use with Cepheid's GeneXpert Dx System that integrates and automates sample processing, nucleic acid amplification, and detection of the target sequences using real-time PCR and reverse transcriptase PCR. The system consists of an instrument, personal computer, barcode scanner, and preloaded software for running tests and viewing the results. It employs single-use disposable Xpert MTB/RIF cartridges that hold PCR reagents and host the PCR process. Because the cartridges are self-contained, cross-contamination between samples is eliminated. Current nucleic acid amplification methods used to detect MTB are complex, labor intensive, and technically demanding. The Xpert MTB/RIF assay has the potential to bring standardized, sensitive and very specific diagnostic testing for both TB and drug resistance to universal-access point-of-care settings, provided that they will be able to afford it. In order to facilitate access, the Foundation for Innovative New Diagnostics (FIND) has negotiated significant price reductions. Current FIND-negotiated prices, along with the list of countries eligible for the discounts, are available on the web. PMID- 22508486 TI - Effects of glycyrrhizin on biliary transport and hepatic levels of glutathione in rats. AB - The purpose of the current study was to determine whether glycyrrhizin (GL) maintains hepatic glutathione (GSH) levels by inhibiting GSH biliary secretion in normal rats. The effects of glycyrrhizin on hepatic glutathione content, bile flow and biliary secretion of glutathione were examined. Because glutathione is a substrate for multidrug resistance associated protein-2 (Mrp2/ABCC2), the inhibitory effects of GL on Mrp2 in isolated perfused rat liver and in Mrp2 expressing Sf9 membrane vesicles were also examined using the Mrp2 substrate methotrexate (MTX) and estradiol-17-beta-glucuronide (E2 17G). The hepatic content of glutathione in rats following GL perfusion (43.7 umol/l) in isolated liver perfusion and GL intravenous treatment (25 mg/kg) was significantly higher than that for the control. A marked and dose-dependent decrease in the excretion of glutathione was observed. In addition, the secretion rate of MTX was decreased by 57% in isolated liver perfusion in GL-treated rats. Moreover the ATP-dependent uptake of E2 17G by Mrp2 membrane vesicles was decreased by 75.9% in the 20 um GL group and by 60.5% in the 2 um GL group. In conclusion, glycyrrhizin increases hepatic glutathione content possibly through inhibition of Mrp2 which then reduces the biliary excretion of glutathione. PMID- 22508488 TI - Cardiovascular health promotion and risk reduction in children and adolescents: the new integrated guidelines. PMID- 22508489 TI - Lentivirus mediated delivery of neurosin promotes clearance of wild-type alpha synuclein and reduces the pathology in an alpha-synuclein model of LBD. AB - Neurosin is a predominant serine protease in the central nervous system (CNS) and has been shown to play a role in the clearance of alpha-synuclein (alpha-syn) which is centrally involved in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Although it has been previously shown that neurosin and alpha-syn colocalize and that neurosin degrades alpha-syn aggregates in vitro, it is not clear if neurosin is dysregulated in the brains of patients with PD/DLB and to what extent delivery of neurosin into the CNS might ameliorate the deficits associated with alpha-syn accumulation in vivo. We analyzed the levels of neurosin in the brains of patients with PD/DLB and in alpha-syn transgenic (tg) models. With increased accumulation of alpha-syn, we observed decreased neurosin expression. Lentiviral vector (LV) driven expression of neurosin in neuronal cell cultures reduced the accumulation of wild type but not A53T alpha-syn and prevented alpha-syn associated toxicity. Neuropathological analysis following delivery of LV-Neurosin to alpha-syn tg mice resulted in reduced accumulation of alpha-syn and reversal of neurodegenerative alterations in wild type but not A53T alpha-syn tg mice. Therefore, viral vector driven expression of neurosin may warrant further investigation as a potential therapeutic tool for DLB. PMID- 22508490 TI - DNA vaccination in the skin using microneedles improves protection against influenza. AB - In this study, we tested the hypothesis that DNA vaccination in the skin using microneedles improves protective immunity compared to conventional intramuscular (i.m.) injection of a plasmid DNA vaccine encoding the influenza hemagglutinin (HA). In vivo fluorescence imaging demonstrated the expression of a reporter gene delivered to the skin using a solid microneedle patch coated with plasmid DNA. Vaccination at a low dose (3 ug HA DNA) using microneedles generated significantly stronger humoral immune responses and better protective responses post-challenge compared to i.m. vaccination at either low or high (10 ug HA DNA) dose. Vaccination using microneedles at a high (10 ug) dose further generated improved post-challenge protection, as measured by survival, recall antibody secreting cell responses in spleen and bone marrow, and interferon (IFN)-gamma cytokine T-cell responses. This study demonstrates that DNA vaccination in the skin using microneedles induces higher humoral and cellular immune responses as well as improves protective immunity compared to conventional i.m. injection of HA DNA vaccine. PMID- 22508492 TI - Urine cytology in paroxysmal nocturnal hemoglobinuria. PMID- 22508491 TI - RNA interference inhibits DUX4-induced muscle toxicity in vivo: implications for a targeted FSHD therapy. AB - No treatment exists for facioscapulohumeral muscular dystrophy (FSHD), one of the most common inherited muscle diseases. Although FSHD can be debilitating, little effort has been made to develop targeted therapies. This lack of focus on targeted FSHD therapy perpetuated because the genes and pathways involved in the disorder were not understood. Now, more than 2 decades after efforts to decipher the root cause of FSHD began, this barrier to translation is finally lowering. Specifically, several recent studies support an FSHD pathogenesis model involving overexpression of the myopathic DUX4 gene. DUX4 inhibition has therefore emerged as a promising therapeutic strategy for FSHD. In this study, we tested a preclinical RNA interference (RNAi)-based DUX4 gene silencing approach as a prospective treatment for FSHD. We found that adeno-associated viral (AAV) vector delivered therapeutic microRNAs corrected DUX4-associated myopathy in mouse muscle. These results provide proof-of-principle for RNAi therapy of FSHD through DUX4 inhibition. PMID- 22508493 TI - Genetic and environmental factors associated with dental caries in children: the Iowa Fluoride Study. AB - Dental caries remains the most common chronic childhood disease. Despite strong evidence of genetic components, there have been few studies of candidate genes and caries. In this analysis we tried to assess genetic and environmental factors contributing to childhood caries in the Iowa Fluoride Study. Environmental factors (age, sex, race, tooth-brushing frequencies and water fluoride level) and three dental caries scores (d(2)fs-total, d(2)fs-pit/fissure, and d(2)fs-smooth surface) were assessed in 575 unrelated children (mean age 5.2 years). Regression analyses were applied to assess environmental correlates. The Family-Based Association Test was used to test genetic associations for 23 single nucleotide polymorphism (SNP) markers in 7 caries candidate genes on 333 Caucasian parent child trios. We evaluated the associations between caries status and the level of both single and multiple SNPs (haplotype) respectively. Permutation procedure was performed for correction of inflated type I errors due to multiple testing. Age, tooth-brushing frequency and water fluoride level were significantly correlated to at least one carious score. Caries on pit and fissure surfaces was substantially higher than on smooth surfaces (61 vs. 39%). SNPs in three genes (DSPP, KLK4 and AQP5) showed consistent associations with protection against caries. Of note, KLK4 and AQP5 were also highlighted by subsequent haplotype analysis. Our results support the concept that genes can modify the susceptibility of caries in children. Replication analysis in independent cohorts is highly needed in order to verify the validity of our findings. PMID- 22508494 TI - miR-21 expression is related to particle-induced osteolysis pathogenesis. AB - Previous studies have found that microRNA-21 (miR-21) is an important functional factor during osteoclast differentiation. Abnormal osteoclastogenesis induced by wear particles is the main cause of aseptic loosening in joint replacements. The aim of the present study is to investigate the possible role of miR-21 in the pathogenesis of particle-induced osteolysis (PIO). miR-21 expression was examined in a PIO mouse model using real-time (RT-PCR). Osteoclastogenesis was determined by a tartrate resistant acid phosphatase (TRAP) quantification method. A toluidine blue staining assay was used to examine calvarial osteolysis. The results demonstrated that miR-21 was significantly upregulated in the PIO animal model. Knocking out miR-21 in the particle-stimulated tissue could ameliorate osteolysis symptoms. Additionally, through our analysis of PDCD4 and AP-1 expression, we suggest that the feedback loop of AP-1, miR-21, and PDCD4 might have an important influence on the development of PIO and that miR-21 is a potential target for implant loosening therapies. PMID- 22508495 TI - Three-dimensional charge transport in organic semiconductor single crystals. AB - Three-dimensional charge transport anisotropy in organic semiconductor single crystals - both plates and rods (above and below, respectively, in the figure) - is measured in well-performing organic field-effect transistors for the first time. The results provide an excellent model for molecular design and device preparation that leads to good performance. PMID- 22508496 TI - High-performance ambipolar transistors and inverters from an ultralow bandgap polymer. AB - High mobility ambipolor organic thin-film transistors based on an ultralow bandgap polymer are presented together with their morphological and optical properties. Hole and electron mobilities of this polymer are of 1.0 cm(2) V(-1) s(-1) and 0.7 cm(2) V(-1) s(-1), respectively. The inverter based on two identical ambipolar transistors exhibits a gain around 35. PMID- 22508497 TI - High efficiency quantum dot heterojunction solar cell using anatase (001) TiO2 nanosheets. AB - This is the first report of using anatase TiO(2) nanosheets with exposed (001) facets in a high-efficiency PbS quantum dot/TiO(2) heterojunction solar cell. The TiO(2) nanosheets have higher conduction band, and surface energy compared to normal anatase (101) TiO(2) nanoparticles. This PbS QD/TiO(2) heterojunction solar cell produces power conversion efficiency of 4.7% which is one of the highest reported in literature. PMID- 22508499 TI - Combining modular ligation and supramolecular self-assembly for the construction of star-shaped macromolecules. AB - A well-defined random copolymer of styrene (S) and chloromethylstyrene (CMS) featuring lateral chlorine moieties with an alkyne terminal group is prepared (P(S-co-CMS), M(n) = 5500 Da, PDI = 1.13). The chloromethyl groups are converted into Hamilton wedge (HW) entities (P(S-co-HWS), M(n) = 6200 Da, PDI = 1.13). The P(S-co-HWS) polymer is subsequently ligated with tetrakis(4-azidophenyl)methane to give HW-functional star-shaped macromolecules (P(S-co-HWS))(4), M(n) = 25,100 Da, PDI = 1.08). Supramolecular star-shaped copolymers are then prepared via self assembly between the HW-functionalized four-arm star-shaped macromolecules (P(S co-HW))(4) and cyanuric acid (CA) end-functionalized PS (PS-CA, M(n) = 3700 Da, PDI = 1.04), CA end-functionalized poly(methyl methacrylate) (PMMA-CA, M(n) = 8500 Da, PDI = 1.13) and CA end-functionalized polyethylene glycol (PEG-CA, M(n) = 1700 Da, PDI = 1.05). The self-assembly is monitored by (1)H NMR spectroscopy and light scattering analyses. PMID- 22508498 TI - Synergistic action of fibroblast growth factor-2 and transforming growth factor beta1 enhances bioprinted human neocartilage formation. AB - Bioprinting as a promising but unexplored approach for cartilage tissue engineering has the advantages of high throughput, digital control, and highly accurate placement of cells and biomaterial scaffold to the targeted 3D locations with simultaneous polymerization. This study tested feasibility of using bioprinting for cartilage engineering and examined the influence of cell density, growth, and differentiation factors. Human articular chondrocytes were printed at various densities, stimulated transiently with growth factors and subsequently with chondrogenic factors. Samples were cultured for up to 4 weeks to evaluate cell proliferation and viability, mechanical properties, mass swelling ratio, water content, gene expression, ECM production, DNA content, and histology. Bioprinted samples treated with FGF-2/TGF-beta1 had the best chondrogenic properties among all groups apparently due to synergistic stimulation of cell proliferation and chondrogenic phenotype. ECM production per chondrocyte in low cell density was much higher than that in high cell seeding density. This finding was also verified by mechanical testing and histology. In conclusion, cell seeding density that is feasible for bioprinting also appears optimal for human neocartilage formation when combined with appropriate growth and differentiation factors. PMID- 22508500 TI - Retrospective cohort study of the risk of impaired glucose tolerance among shift workers. AB - OBJECTIVES: The aim of this study was to investigate the effect of shift working on the risk of developing impaired glucose tolerance (IGT). METHODS: This study comprised 6413 male employees (5608 daytime workers, 512 3-shift workers and 293 2-shift workers) whose work schedules remained constant during the follow-up period (mean follow-up period 9.9 years). IGT was defined as Hemoglobin A1c >= 5.9%. The Cox proportional hazards model was used to estimate the risk of developing IGT, after making adjustments for age, smoking, alcohol consumption, leisure-time physical activity, body mass index (BMI) and Hemoglobin A1c (HbA1c) at baseline. Analysis was additionally performed for a sub-cohort of 1625 workers with BMI of 20.0-25.0 kg/m2 that did not change by >2.0 kg/m2 during the follow up period. RESULTS: The risk of developing IGT was significantly elevated among both 3-shift workers [hazard ratio (HR) 1.78, 95% confidence interval (95% CI) 1.49- 2.14] and 2-shift workers (HR 2.62, 95% CI 2.17-3.17). Significant elevations of the risk were still observed at the additional analysis on the sub cohort (3-shift work: HR 3.55, 95% CI 2.02-6.25; 2-shift work: HR 4.86, 95% CI 2.62-9.01). CONCLUSIONS: Both 2- and 3-shift workers were associated with a high risk factor of developing IGT compared to day workers. Moreover, 2-shift workers had a higher risk than 3-shift workers. The risk was observed even among workers whose body mass remained within the normal range. PMID- 22508501 TI - Combined experimental-theoretical NMR study on 2,5-bis(5-aryl-3-hexylthiophen-2 yl)-thiazolo[5,4-d]thiazole derivatives for printable electronics. AB - Four 2,5-bis(5-aryl-3-hexylthiophen-2-yl)thiazolo[5,4-d]thiazole derivatives have been synthesized and thoroughly characterized. The extended aromatic core of the molecules was designed to enhance the charge transport characteristics, and solubilizing hexyl side chains were introduced on the thiophene subunits to enable possible integration of these semiconducting small molecules in printable electronics. Complete elucidation of the chemical structures by detailed one dimensional/two-dimensional NMR spectroscopy is described, providing interesting input for chemical shift prediction software as well, because limited experimental data on these types of compounds are currently available. Furthermore, theoretical calculations have assisted experimental observations- giving support for the chemical shift assignment and providing a springboard for future screening and predictions--demonstrating the benefits of a coordinated theoretical-experimental approach. PMID- 22508502 TI - Design of serum compatible tetrary complexes for gene delivery. AB - A novel gene delivery system, called PoSC, consisting of PEI, PSP, and HA is described. In contrast to the DNA/PEI/HA ternary system whose transfection efficiency decreases significantly with increasing serum concentration, PoSC exhibits a high transfection efficiency of about 51 and 87% for NIH3T3 and HCT116 cells, respectively, at 50% serum concentration. Furthermore, PoSC shows no cytotoxic effect at its working concentration. The overall results suggest that HA adsorption on cationic complexes enhances the transfection efficiency, while PSP is essential for high transfection efficiency at higher serum concentration. PMID- 22508504 TI - Response to preeclampsia and hypertensive disease in pregnancy: their contributions to cardiovascular risk. PMID- 22508503 TI - Development of viral nanoparticles for efficient intracellular delivery. AB - Viral nanoparticles (VNPs) based on plant viruses such as Cowpea mosaic virus (CPMV) can be used for a broad range of biomedical applications because they present a robust scaffold that allows functionalization by chemical conjugation and genetic modification, thereby offering an efficient drug delivery platform that can target specific cells and tissues. VNPs such as CPMV show natural affinity to cells; however, cellular uptake is inefficient. Here we show that chemical modification of the CPMV surface with a highly reactive, specific and UV traceable hydrazone linker allows bioconjugation of polyarginine (R5) cell penetrating peptides (CPPs), which can overcome these limitations. The resulting CPMV-R5 particles were taken up into a human cervical cancer cell line (HeLa) more efficiently than native particles. Uptake efficiency was dependent on the density of R5 peptides on the surface of the VNP; particles displaying 40 R5 peptides per CPMV (denoted as CPMV-R5H) interact strongly with the plasma membrane and are taken up into the cells via an energy-dependent mechanism whereas particles displaying 10 R5 peptides per CPMV (CPMV-R5L) are only slowly taken up. The fate of CPMV-R5 versus native CPMV particles within cells was evaluated in a co-localization time course study. It was indicated that the intracellular localization of CPMV-R5 and CPMV differs; CPMV remains trapped in Lamp-1 positive endolysosomes over long time frames; in contrast, 30-50% of the CPMV-R5 particles transitioned from the endosome into other cellular vesicles or compartments. Our data provide the groundwork for the development of efficient drug delivery formulations based on CPMV-R5. PMID- 22508505 TI - Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis. AB - Osteoporosis is a complex disease with various causes, such as estrogen loss, genetics, and aging. Here we show that a dominant-negative form of aldehyde dehydrogenase 2 (ALDH2) protein, ALDH2*2, which is produced by a single nucleotide polymorphism (rs671), promotes osteoporosis due to impaired osteoblastogenesis. Aldh2 plays a role in alcohol-detoxification by acetaldehyde detoxification; however, transgenic mice expressing Aldh2*2 (Aldh2*2 Tg) exhibited severe osteoporosis with increased levels of blood acetaldehyde without alcohol consumption, indicating that Aldh2 regulates physiological bone homeostasis. Wild-type osteoblast differentiation was severely inhibited by exogenous acetaldehyde, and osteoblastic markers such as osteocalcin, runx2, and osterix expression, or phosphorylation of Smad1,5,8 induced by bone morphogenetic protein 2 (BMP2) was strongly altered by acetaldehyde. Acetaldehyde treatment also inhibits proliferation and induces apoptosis in osteoblasts. The Aldh2*2 transgene or acetaldehyde treatment induced accumulation of the lipid-oxidant 4 hydroxy-2-nonenal (4HNE) and expression of peroxisome proliferator-activated receptor gamma (PPARgamma), a transcription factor that promotes adipogenesis and inhibits osteoblastogenesis. Antioxidant treatment inhibited acetaldehyde-induced proliferation-loss, apoptosis, and PPARgamma expression and restored osteoblastogenesis inhibited by acetaldehyde. Treatment with a PPARgamma inhibitor also restored acetaldehyde-mediated osteoblastogenesis inhibition. These results provide new insight into regulation of osteoporosis in a subset of individuals with ALDH2*2 and in alcoholic patients and suggest a novel strategy to promote bone formation in such osteopenic diseases. PMID- 22508506 TI - Yoshinori Ohsumi: autophagy from beginning to end. Interview by Caitlin Sedwick. PMID- 22508508 TI - DNA damage-inducible SUMOylation of HERC2 promotes RNF8 binding via a novel SUMO binding Zinc finger. AB - Nonproteolytic ubiquitylation of chromatin surrounding deoxyribonucleic acid (DNA) double-strand breaks (DSBs) by the RNF8/RNF168/HERC2 ubiquitin ligases facilitates restoration of genome integrity by licensing chromatin to concentrate genome caretaker proteins near the lesions. In parallel, SUMOylation of so-far elusive upstream DSB regulators is also required for execution of this ubiquitin dependent chromatin response. We show that HERC2 and RNF168 are novel DNA damage dependent SUMOylation targets in human cells. In response to DSBs, both HERC2 and RNF168 were specifically modified with SUMO1 at DSB sites in a manner dependent on the SUMO E3 ligase PIAS4. SUMOylation of HERC2 was required for its DSB induced association with RNF8 and for stabilizing the RNF8-Ubc13 complex. We also demonstrate that the ZZ Zinc finger in HERC2 defined a novel SUMO-specific binding module, which together with its concomitant SUMOylation and T4827 phosphorylation promoted binding to RNF8. Our findings provide novel insight into the regulatory complexity of how ubiquitylation and SUMOylation cooperate to orchestrate protein interactions with DSB repair foci. PMID- 22508507 TI - Cell biology of spinocerebellar ataxia. AB - Ataxia is a neurological disorder characterized by loss of control of body movements. Spinocerebellar ataxia (SCA), previously known as autosomal dominant cerebellar ataxia, is a biologically robust group of close to 30 progressive neurodegenerative diseases. Six SCAs, including the more prevalent SCA1, SCA2, SCA3, and SCA6 along with SCA7 and SCA17 are caused by expansion of a CAG repeat that encodes a polyglutamine tract in the affected protein. How the mutated proteins in these polyglutamine SCAs cause disease is highly debated. Recent work suggests that the mutated protein contributes to pathogenesis within the context of its "normal" cellular function. Thus, understanding the cellular function of these proteins could aid in the development of therapeutics. PMID- 22508509 TI - The dynamin-like GTPase Sey1p mediates homotypic ER fusion in S. cerevisiae. AB - The endoplasmic reticulum (ER) forms a network of tubules and sheets that requires homotypic membrane fusion to be maintained. In metazoans, this process is mediated by dynamin-like guanosine triphosphatases (GTPases) called atlastins (ATLs), which are also required to maintain ER morphology. Previous work suggested that the dynamin-like GTPase Sey1p was needed to maintain ER morphology in Saccharomyces cerevisiae. In this paper, we demonstrate that Sey1p, like ATLs, mediates homotypic ER fusion. The absence of Sey1p resulted in the ER undergoing delayed fusion in vivo and proteoliposomes containing purified Sey1p fused in a GTP-dependent manner in vitro. Sey1p could be partially replaced by ATL1 in vivo. Like ATL1, Sey1p underwent GTP-dependent dimerization. We found that the residual ER-ER fusion that occurred in cells lacking Sey1p required the ER SNARE Ufe1p. Collectively, our results show that Sey1p and its homologues function analogously to ATLs in mediating ER fusion. They also indicate that S. cerevisiae has an alternative fusion mechanism that requires ER SNAREs. PMID- 22508510 TI - Human telomeres replicate using chromosome-specific, rather than universal, replication programs. AB - Telomeric and adjacent subtelomeric heterochromatin pose significant challenges to the DNA replication machinery. Little is known about how replication progresses through these regions in human cells. Using single molecule analysis of replicated DNA (SMARD), we delineate the replication programs-i.e., origin distribution, termination site location, and fork rate and direction-of specific telomeres/subtelomeres of individual human chromosomes in two embryonic stem (ES) cell lines and two primary somatic cell types. We observe that replication can initiate within human telomere repeats but was most frequently accomplished by replisomes originating in the subtelomere. No major delay or pausing in fork progression was detected that might lead to telomere/subtelomere fragility. In addition, telomeres from different chromosomes from the same cell type displayed chromosome-specific replication programs rather than a universal program. Importantly, although there was some variation in the replication program of the same telomere in different cell types, the basic features of the program of a specific chromosome end appear to be conserved. PMID- 22508511 TI - 53BP1 deficiency combined with telomere dysfunction activates ATR-dependent DNA damage response. AB - TRF1 protects mammalian telomeres from fusion and fragility. Depletion of TRF1 leads to telomere fusions as well as accumulation of gamma-H2AX foci and activation of both the ataxia telangiectasia mutated (ATM)- and the ataxia telangiectasia and Rad3 related (ATR)-mediated deoxyribonucleic acid (DNA) damage response (DDR) pathways. 53BP1, which is also present at dysfunctional telomeres, is a target of ATM that accumulates at DNA double-strand breaks and favors nonhomologous end-joining (NHEJ) repair over ATM-dependent resection and homology directed repair (homologous recombination [HR]). To address the role of 53BP1 at dysfunctional telomeres, we generated mice lacking TRF1 and 53BP1. 53BP1 deficiency significantly rescued telomere fusions in mouse embryonic fibroblasts (MEFs) lacking TRF1, but they showed evidence of a switch from the NHEJ- to HR mediated repair of uncapped telomeres. Concomitantly, double-mutant MEFs showed evidence of hyperactivation of the ATR-dependent DDR. In intact mice, combined 53BP1/TRF1 deficiency in stratified epithelia resulted in earlier onset of DNA damage and increased CHK1 phosphorylation during embryonic development, leading to aggravation of skin phenotypes. PMID- 22508512 TI - Munc13-4 reconstitutes calcium-dependent SNARE-mediated membrane fusion. AB - Munc13-4 is a widely expressed member of the CAPS/Munc13 protein family proposed to function in priming secretory granules for exocytosis. Munc13-4 contains N- and C-terminal C2 domains (C2A and C2B) predicted to bind Ca(2+), but Ca(2+) dependent regulation of Munc13-4 activity has not been described. The C2 domains bracket a predicted SNARE-binding domain, but whether Munc13-4 interacts with SNARE proteins is unknown. We report that Munc13-4 bound Ca(2+) and restored Ca(2+)-dependent granule exocytosis to permeable cells (platelets, mast, and neuroendocrine cells) dependent on putative Ca(2+)-binding residues in C2A and C2B. Munc13-4 exhibited Ca(2+)-stimulated SNARE interactions dependent on C2A and Ca(2+)-dependent membrane binding dependent on C2B. In an apparent coupling of membrane and SNARE binding, Munc13-4 stimulated SNARE-dependent liposome fusion dependent on putative Ca(2+)-binding residues in both C2A and C2B domains. Munc13 4 is the first priming factor shown to promote Ca(2+)-dependent SNARE complex formation and SNARE-mediated liposome fusion. These properties of Munc13-4 suggest its function as a Ca(2+) sensor at rate-limiting priming steps in granule exocytosis. PMID- 22508513 TI - Drosophila chibby is required for basal body formation and ciliogenesis but not for Wg signaling. AB - Centriole-to-basal body conversion, a complex process essential for ciliogenesis, involves the progressive addition of specific proteins to centrioles. CHIBBY (CBY) is a coiled-coil domain protein first described as interacting with beta catenin and involved in Wg-Int (WNT) signaling. We found that, in Drosophila melanogaster, CBY was exclusively expressed in cells that require functional basal bodies, i.e., sensory neurons and male germ cells. CBY was associated with the basal body transition zone (TZ) in these two cell types. Inactivation of cby led to defects in sensory transduction and in spermatogenesis. Loss of CBY resulted in altered ciliary trafficking into neuronal cilia, irregular deposition of proteins on spermatocyte basal bodies, and, consequently, distorted axonemal assembly. Importantly, cby(1/1) flies did not show Wingless signaling defects. Hence, CBY is essential for normal basal body structure and function in Drosophila, potentially through effects on the TZ. The function of CBY in WNT signaling in vertebrates has either been acquired during vertebrate evolution or lost in Drosophila. PMID- 22508515 TI - Acute and specific modulation of presynaptic aromatization in the vertebrate brain. AB - Estrogens affect a diversity of peripheral and central physiological endpoints. Traditionally, estrogens were thought to be peripherally derived transcription regulators (i.e. slow acting). More recently, we have learned that estrogens are also synthesized in neuronal cell bodies and synaptic terminals and have potent membrane effects, which modulate brain function. However, the mechanisms that control local steroid concentrations in a temporal and spatial resolution compatible with their acute actions are poorly understood. Here, using differential centrifugation followed by enzymatic assay, we provide evidence that estrogen synthesis within synaptosomes can be modulated more dramatically by phosphorylating conditions, relative to microsomes. This is the first demonstration of a rapid mechanism that may alter steroid concentrations within the synapse and may represent a potential mechanism for the acute control of neurophysiology and behavior. PMID- 22508514 TI - Arcuate kisspeptin/neurokinin B/dynorphin (KNDy) neurons mediate the estrogen suppression of gonadotropin secretion and body weight. AB - Estrogen withdrawal increases gonadotropin secretion and body weight, but the critical cell populations mediating these effects are not well understood. Recent studies have focused on a subpopulation of hypothalamic arcuate neurons that coexpress estrogen receptor alpha, neurokinin 3 receptor (NK(3)R), kisspeptin, neurokinin B, and dynorphin for the regulation of reproduction. To investigate the function of kisspeptin/neurokinin B/dynorphin (KNDy) neurons, a novel method was developed to ablate these cells using a selective NK(3)R agonist conjugated to the ribosome-inactivating toxin, saporin (NK(3)-SAP). Stereotaxic injections of NK(3)-SAP in the arcuate nucleus ablated KNDy neurons, as demonstrated by the near-complete loss of NK(3)R, NKB, and kisspeptin-immunoreactive (ir) neurons and depletion of the majority of arcuate dynorphin-ir neurons. Selectivity was demonstrated by the preservation of proopiomelanocortin, neuropeptide Y, and GnRH ir elements in the arcuate nucleus and median eminence. In control rats, ovariectomy (OVX) markedly increased serum LH, FSH, and body weight, and these parameters were subsequently decreased by treatment with 17beta-estradiol. KNDy neuron ablation prevented the rise in serum LH after OVX and attenuated the rise in serum FSH. KNDy neuron ablation did not completely block the suppressive effects of E(2) on gonadotropin secretion, a finding consistent with redundant pathways for estrogen negative feedback. However, regardless of estrogen status, KNDy-ablated rats had lower levels of serum gonadotropins compared with controls. Surprisingly, KNDy neuron ablation prevented the dramatic effects of OVX and 17beta-estradiol (E(2)) replacement on body weight and abdominal girth. These data provide evidence that arcuate KNDy neurons are essential for tonic gonadotropin secretion, the rise in LH after removal of E(2), and the E(2) modulation of body weight. PMID- 22508516 TI - A humanized pattern of aromatase expression is associated with mammary hyperplasia in mice. AB - Aromatase is essential for estrogen production and is the target of aromatase inhibitors, the most effective endocrine treatment for postmenopausal breast cancer. Peripheral tissues in women, including the breast, express aromatase via alternative promoters. Female mice lack the promoters that drive aromatase expression in peripheral tissues; thus, we generated a transgenic humanized aromatase (Arom(hum)) mouse line containing a single copy of the human aromatase gene to study the link between aromatase expression in mammary adipose tissue and breast pathology. Arom(hum) mice expressed human aromatase, driven by the proximal human promoters II and I.3 and the distal promoter I.4, in breast adipose fibroblasts and myoepithelial cells. Estrogen levels in the breast tissue of Arom(hum) mice were higher than in wild-type mice, whereas circulating levels were similar. Arom(hum) mice exhibited accelerated mammary duct elongation at puberty and an increased incidence of lobuloalveolar breast hyperplasia associated with increased signal transducer and activator of transcription-5 phosphorylation at 24 and 64 wk. Hyperplastic epithelial cells showed remarkably increased proliferative activity. Thus, we demonstrated that the human aromatase gene can be expressed via its native promoters in a wide variety of mouse tissues and in a distribution pattern nearly identical to that of humans. Locally increased tissue levels, but not circulating levels, of estrogen appeared to exert hyperplastic effects on the mammary gland. This novel mouse model will be valuable for developing tissue-specific aromatase inhibition strategies. PMID- 22508517 TI - The inflammatory response in acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy). AB - Among several peroxisomal neurodegenerative disorders, the pseudoneonatal adrenoleukodystrophy (P-NALD) is characterized by the acyl-coenzyme A oxidase 1 (ACOX1) deficiency, which leads to the accumulation of very-long-chain fatty acids (VLCFA) and inflammatory demyelination. However, the components of this inflammatory process in P-NALD remain elusive. In this study, we used transcriptomic profiling and PCR array analyses to explore inflammatory gene expression in patient fibroblasts. Our results show the activation of IL-1 inflammatory pathway accompanied by the increased secretion of two IL-1 target genes, IL-6 and IL-8 cytokines. Human fibroblasts exposed to very-long-chain fatty acids exhibited increased mRNA expression of IL-1alpha and IL-1beta cytokines. Furthermore, expression of IL-6 and IL-8 cytokines in patient fibroblasts was down-regulated by MAPK, p38MAPK, and Jun N-terminal kinase inhibitors. Thus, the absence of acyl-coenzyme A oxidase 1 activity in P-NALD fibroblasts triggers an inflammatory process, in which the IL-1 pathway seems to be central. The use of specific kinase inhibitors may permit the modulation of the enhanced inflammatory status. PMID- 22508519 TI - Zoocin A and lauricidin in combination reduce Streptococcus mutans growth in a multispecies biofilm. AB - Dental caries is the most prevalent human infection. It is a multifactorial disease in which the microbial composition of dental plaque plays a major role in the development of clinical symptoms. The bacteria most often implicated in the development of caries are that group of streptococci referred to as the mutans streptococci, in particular Streptococcus mutans and Streptococcus sobrinus. One approach to the prevention of caries is to reduce the numbers of mutans streptococci in plaque to a level insufficient to support demineralization of the tooth. In this study, zoocin A, a peptidoglycan hydrolase, combined with lauricidin, a cell membrane active lipid, was shown over a 72 h period to selectively suppress the growth of S. mutans in a triple species biofilm. Growth of the non-target species Streptococcus oralis and Actinomyces viscosus was not inhibited. In treated systems the amount of extracellular polysaccharide matrix produced was much reduced as determined by use of fluorescein isothiocyanate conjugated wheat germ agglutinin. The pH of treated biofilms remained above neutral as opposed to a value of 4.3 in untreated controls. We conclude that use of antimicrobial compounds that specifically target cariogenic bacteria should be further explored. PMID- 22508518 TI - CCK-induced reduction of food intake and hindbrain MAPK signaling are mediated by NMDA receptor activation. AB - The dorsal vagal complex of the hindbrain, including the nucleus of the solitary tract (NTS), receives neural and humoral afferents that contribute to the process of satiation. The gut peptide, cholecystokinin (CCK), promotes satiation by activating gastrointestinal vagal afferents that synapse in the NTS. Previously, we demonstrated that hindbrain administration of N-methyl-D-aspartate (NMDA)-type glutamate receptor antagonists attenuate reduction of food intake after ip CCK-8 injection, indicating that these receptors play a necessary role in control of food intake by CCK. However, the signaling pathways through which hindbrain NMDA receptors contribute to CCK-induced reduction of food intake have not been investigated. Here we report CCK increases phospho-ERK1/2 in NTS neurons and in identified vagal afferent endings in the NTS. CCK-evoked phospho-ERK1/2 in the NTS was attenuated in rats pretreated with capsaicin and was abolished by systemic injection of a CCK1 receptor antagonist, indicating that phosphorylation of ERK1/2 occurs in and is mediated by gastrointestinal vagal afferents. Fourth ventricle injection of a competitive NMDA receptor antagonist, prevented CCK induced phosphorylation of ERK1/2 in hindbrain neurons and in vagal afferent endings, as did direct inhibition of MAPK kinase. Finally, fourth ventricle administration of either a MAPK kinase inhibitor or NMDA receptor antagonist prevented the reduction of food intake by CCK. We conclude that activation of NMDA receptors in the hindbrain is necessary for CCK-induced ERK1/2 phosphorylation in the NTS and consequent reduction of food intake. PMID- 22508520 TI - The glycopolymer code: synthesis of glycopolymers and multivalent carbohydrate lectin interactions. AB - Glycopolymers are becoming more and more important in understanding biological interactions due to their unique recognition properties. Macromolecules with different chain lengths, compositions and architectures provide enormous diversity in the formation of primary and secondary structures that have a major effect on multivalent binding to lectins. It is crucial to control the precise structure of macromolecules to achieve specific and selective carbohydrate-lectin binding. The use of advanced synthesis techniques to prepare well-defined glycopolymers and selected advanced analytical techniques to study multivalent interactions are highlighted in this Feature Article. PMID- 22508521 TI - XIAP inhibition and generation of reactive oxygen species enhances TRAIL sensitivity in inflammatory breast cancer cells. AB - We recently identified superoxide dismutase (SOD) overexpression and decreased induction of reactive oxygen species (ROS)-mediated apoptosis in models of inflammatory breast cancer (IBC) cells with acquired therapeutic resistance. This population of cells has high expression of X-linked inhibitor of apoptosis protein (XIAP), which inhibits both extrinsic and intrinsic apoptosis pathways. We therefore wanted to evaluate the effect of classical apoptosis-inducing agent TRAIL, a proapoptotic receptor agonist that selectively triggers death receptor (DR)-mediated apoptosis in cancer cells, in the IBC acquired resistance model. XIAP levels and subsequent inhibition of caspase activity inversely correlated with TRAIL sensitivity in our models of IBC. These include SUM149, a basal-type cell line isolated from primary IBC tumors and isogenic SUM149-derived lines rSUM149 and SUM149 wtXIAP, models of acquired therapeutic resistance with endogenous and exogenous XIAP overexpression, respectively. Inhibition of XIAP function using embelin, a plant-derived cell permeable small molecule, in combination with TRAIL caused a synergistic decrease in cell viability. Embelin treatment resulted in activation of extracellular signal-regulated kinase (ERK)1/2 and ROS accumulation, which correlated with downregulation of antioxidant protein SOD1 and consumption of redox modulator reduced glutathione in the XIAP-overexpressing cells. Simultaneous treatment with an SOD mimic, which protects against ROS accumulation, reversed the decrease in cell viability caused by embelin + TRAIL treatment. Embelin primes IBC cells for TRAIL-mediated apoptosis by its direct action on the anti-caspase activity of XIAP and by shifting the cellular redox balance toward oxidative stress-mediated apoptosis. Thus, ROS modulators represent a novel approach to enhance efficacy of TRAIL based treatment protocols in IBC. PMID- 22508522 TI - Enhancement in the performance of ultrathin hematite photoanode for water splitting by an oxide underlayer. AB - A 2-nm thick Nb(2)O(5) underlayer deposited by atomic layer deposition increases the charge separation efficiency and the photovoltage of ultrathin hematite films by suppressing electron back injection. Absorbed photon-to-current efficiencies (APCE) as high as 40%, which are one of the highest ever reported with hematite photoanodes, are obtained at 400 nm at +1.43 V vs. RHE. PMID- 22508523 TI - Cryptococcal lymphadenitis in HIV: a chance diagnosis by FNAC. AB - Cryptococcosis is a life threatening, opportunistic fungal disease in human immunodeficiency virus-infected individual. Lymph node involvement as a presenting feature in Cryptococcosis is not a common manifestation. A prompt diagnosis is of utmost importance in this disseminated form of cryptococcosis. There are very few reports, however, of cryptococcal lymphadenitis as a presenting feature. We report here a case of cryptococcal lymphadenitis that was diagnosed by fine-needle aspiration cytology of the involved cervical lymph node. PMID- 22508524 TI - Segmentation and measurement of fat volumes in murine obesity models using X-ray computed tomography. AB - Obesity is associated with increased morbidity and mortality as well as reduced metrics in quality of life. Both environmental and genetic factors are associated with obesity, though the precise underlying mechanisms that contribute to the disease are currently being delineated. Several small animal models of obesity have been developed and are employed in a variety of studies. A critical component to these experiments involves the collection of regional and/or total animal fat content data under varied conditions. Traditional experimental methods available for measuring fat content in small animal models of obesity include invasive (e.g. ex vivo measurement of fat deposits) and non-invasive (e.g. Dual Energy X-ray Absorptiometry (DEXA), or Magnetic Resonance (MR)) protocols, each of which presents relative trade-offs. Current invasive methods for measuring fat content may provide details for organ and region specific fat distribution, but sacrificing the subjects will preclude longitudinal assessments. Conversely, current non-invasive strategies provide limited details for organ and region specific fat distribution, but enable valuable longitudinal assessment. With the advent of dedicated small animal X-ray computed tomography (CT) systems and customized analytical procedures, both organ and region specific analysis of fat distribution and longitudinal profiling may be possible. Recent reports have validated the use of CT for in vivo longitudinal imaging of adiposity in living mice. Here we provide a modified method that allows for fat/total volume measurement, analysis and visualization utilizing the Carestream Molecular Imaging Albira CT system in conjunction with PMOD and Volview software packages. PMID- 22508525 TI - Donor-specific human leukocyte antigen antibodies of the immunoglobulin G3 subclass are associated with chronic rejection and graft loss after liver transplantation. AB - In a previous study, we found that 92% of patients with chronic rejection had donor-specific human leukocyte antigen antibodies (DSAs), but surprisingly, 61% of comparator patients without rejection also had DSAs. We hypothesized that immunoglobulin G (IgG) subclasses were differentially distributed between the 2 groups. A modified single-antigen bead assay was used to detect the presence of individual IgG subclasses against human leukocyte antigen in 39 chronic rejection patients and 66 comparator patients. DSAs of the IgG1 subclass were most common and were found in 45% of all patients; they were followed by IgG3 DSAs (21%), IgG4 DSAs (14%), and IgG2 DSAs (13%). The percentage of patients with multiple IgG subclasses was significantly higher in the chronic rejection group versus the comparator group (50% versus 14%, P < 0.001). Patients with normal graft function in the presence of DSAs mostly had isolated IgG1, whereas patients with chronic rejection had a combination of IgG subclasses. Patients who developed DSAs of the IgG3 subclass showed an increased risk of graft loss (hazard ratio = 3.35, 95% confidence interval = 1.39-8.05) in comparison with patients with DSAs of other IgG subclasses or without DSAs. Although further study is needed, the determination of the IgG subclass in DSA-positive patients may help us to identify patients with a higher risk of chronic rejection and graft loss. PMID- 22508526 TI - What's the next best cytokine target in IBD? AB - In the gut of patients with inflammatory bowel disease (IBD), immune and nonimmune cells produce large amounts of cytokines that drive the inflammatory process leading to the tissue damage. Cytokine blockers, such as anti-tumor necrosis factor alpha (TNF-alpha), have been used with some success in IBD. However, not all patients respond, and the therapeutic effects wane with time, demonstrating the need for more effective and long-lasting antiinflammatory strategies. A key question is whether neutralizing other proinflammatory cytokines such as interleukin (IL)-12, IL-21, IL-27, or IL-33 will lead to a better clinical response than with anti-TNF-alpha antibodies. Equally, we now know that IBD-related inflammation is marked by defective production/activity of antiinflammatory cytokines, and there are strategies to correct these defects. An alternative approach is to try to target individual therapies to individual patients, to improve clinical efficacy in subsets of patients, but this has proven difficult. Here we try to evaluate the potential of each of these choices. PMID- 22508527 TI - Does perceived work ability improve after a multidisciplinary preventive program in a population with no severe medical problems? The Finnish Public Sector Study. AB - OBJECTIVES: This study examines the short- and long-term effects of a multidisciplinary preventive program on perceived work ability in a population with no severe medical problems. METHODS: Altogether 859 public sector employees who participated in the program in 1997-2005 and their 2426 propensity-score matched controls were studied prospectively. Propensity scores for probability of being granted participation in the program were calculated based on the data on health, health-risk behaviors, and work-related characteristics that were gathered from repeat responses to a survey, national health registers, and employers' records. Mean scores of perceived work ability (PWA) and prevalence ratios (PR) of suboptimal PWA were calculated after a short-term (mean 1.7 years, up to 4.6 years) and a long-term (mean 5.8 years, up to 9.2 years) follow-up. RESULTS: No beneficial effects were observed with respect to work ability. In comparison to controls, the participants' risk of suboptimal PWA was actually slightly higher after both the short-term [PR 1.23, 95% confidence interval (95% CI) 1.10-1.39] and long-term (PR 1.18, 95% CI 1.06-1.31) follow-ups. CONCLUSIONS: These data suggest that the vocationally oriented multidisciplinary preventive program was ineffective in improving work ability among participants with no severe medical problems. PMID- 22508528 TI - Cellular interactions of surface modified nanoporous silicon particles. AB - In this study, the self-assembly of hydrophobin class II (HFBII) on the surface of thermally hydrocarbonized porous silicon (THCPSi) nanoparticles was investigated. The HFBII-coating converted the hydrophobic particles into more hydrophilic ones, improved the particles' cell viability in both HT-29 and Caco-2 cell lines compared to uncoated particles, and enhanced the particles' cellular association. The amount of HFBII adsorbed onto the particles was also successfully quantified by both the BCA assay and a HPLC method. Importantly, the permeation of a poorly water-soluble drug, indomethacin, loaded into THCPSi particles across Caco-2 monolayers was not affected by the protein coating. In addition, (125)I-radiolabelled HFBII did not extensively permeate the Caco-2 monolayer and was found to be stably adsorbed onto the THCPSi nanoparticles incubated in pH 7.4, which renders the particles the possibility for further track-imaging applications. The results highlight the potential of HFBII coating for improving wettability, increasing biocompatibility and possible intestinal association of PSi nanoparticulates for drug delivery applications. PMID- 22508529 TI - Strongly enhanced levels of sclerostin during human fracture healing. AB - Sclerostin (SOST), an antagonist of Wnt signaling, is an important negative regulator of bone formation. However, no data on the role of SOST in the human fracture healing have been published so far. This study addressed this issue. Seventy-five patients with long bone fractures were included into the study and divided in two groups. The first group contained 69 patients with normal fracture healing. Six patients with impaired fracture healing formed the second group. Thirty-four volunteers donated blood samples as control. Serum samples were collected over a period of 1 year following a standardized time schedule. In addition, SOST levels were measured in fracture hematoma and serum of 16 patients with bone fractures. Fracture hematoma contained significantly higher SOST concentrations compared to patient's serum. SOST levels in fracture hematoma and in patient's serum were both significantly higher than in the serum of controls. Highly elevated SOST serum concentrations were found in patients with physiological fracture healing. SOST levels were decreased in patients with impaired fracture healing. However, this difference was not statistically significant. This is the first study to provide evidence of strongly enhanced SOST levels in patients with bone fracture. The results indicate local and systemic involvement of SOST in humans during fracture healing. PMID- 22508533 TI - International spinal cord injury endocrine and metabolic basic data set (version 1.2). PMID- 22508530 TI - Development of channeled nanofibrous scaffolds for oriented tissue engineering. AB - A tissue-engineering scaffold resembling the structure of the natural extracellular matrix can often facilitate tissue regeneration. Nerve and tendon are oriented micro-scale tissue bundles. In this study, a method combining injection molding and thermally induced phase separation techniques is developed to create single- and multiple-channeled nanofibrous poly(L-lactic acid) scaffolds. The overall shape, the number and spatial arrangement of channels, the channel wall matrix architecture, the porosity and mechanical properties of the scaffolds are all tunable. The porous NF channel wall matrix provides an excellent microenvironment for protein adsorption and the attachment of PC12 neuronal cells and tendon fibroblast cells, showing potential for neural and tendon tissue regeneration. PMID- 22508534 TI - Effects of resistance training on strength, pain and shoulder functionality in paraplegics. AB - STUDY DESIGN: Time series design. OBJECTIVES: To determine the effects of a shoulder resistance training programme on isokinetic and isometric strength, body composition, pain and functionality in paraplegic subjects. SETTING: University of Valencia, Valencia, Spain. METHODS: A total of 15 subjects with thoracic spinal cord injury (SCI) performed three testing sessions with an 8-week period between the sessions. Subjects were not disturbed between the first and the second testing sessions. Subjects performed an 8-week resistance training programme after the second testing session. Variations in isometric and isokinetic shoulder muscle strength, body composition, reported pain and shoulder functionality were evaluated. RESULTS: The training programme produced a significant increase (P<0.05) in the isometric and isokinetic strength of several shoulder movements as well as an increase (P<0.05) in arm fat-free mass and a decrease in arm fat mass (FM). Furthermore, reported pain was decreased, (P<0.05) and upper-limb functionality was increased (P<0.05). CONCLUSION: Implementing resistance training programmes as physical therapy in SCI subjects effectively increases strength, muscle mass and upper-limb functionality, whereas decreasing FM and pain perception. PMID- 22508536 TI - Design and rationale of a Prospective, Observational European Multicenter study on the efficacy of acute surgical decompression after traumatic Spinal Cord Injury: the SCI-POEM study. AB - OBJECTIVES: Despite many years of research, there is currently no treatment available that results in major neurological or functional recovery after traumatic spinal cord injury (tSCI). In particular, no conclusive data related to the role of the timing of decompressive surgery, and the impact of injury severity on its benefit, have been published to date. This paper presents a protocol that was designed to examine the hypothesized association between the timing of surgical decompression and the extent of neurological recovery in tSCI patients. STUDY DESIGN: The SCI-POEM study is a Prospective, Observational European Multicenter comparative cohort study. This study compares acute (<12 h) versus non-acute (>12 h, <2 weeks) decompressive surgery in patients with a traumatic spinal column injury and concomitant spinal cord injury. The sample size calculation was based on a representative European patient cohort of 492 tSCI patients. During a 4-year period, 300 patients will need to be enrolled from 10 trauma centers across Europe. The primary endpoint is lower-extremity motor score as assessed according to the 'International standards for neurological classification of SCI' at 12 months after injury. Secondary endpoints include motor, sensory, imaging and functional outcomes at 3, 6 and 12 months after injury. CONCLUSION: In order to minimize bias and reduce the impact of confounders, special attention is paid to key methodological principles in this study protocol. A significant difference in safety and/or efficacy endpoints will provide meaningful information to clinicians, as this would confirm the hypothesis that rapid referral to and treatment in specialized centers result in important improvements in tSCI patients. PMID- 22508535 TI - Dysfunctional sleep in persons with spinal cord injuries and disorders. AB - STUDY DESIGN: Cross-sectional survey of veterans with spinal cord injuries and disorders (SCI/D). OBJECTIVES: To describe sleep dysfunction (independent of sleep apnea) in persons with traumatic and non-traumatic SCI/D, and to examine characteristics and health outcomes independently associated with sleep dysfunction unrelated to sleep apnea. SETTING: Seven Veterans Affairs SCI care facilities in the United States. METHODS: Mailed cross-sectional survey with follow-up calls completed by end of 2008. Bivariate analyses to compare measures outcomes in persons with SCI/D who were dysfunctional sleepers vs those who were not. Multivariate logistic regression used to identify variables independently associated with dysfunctional sleep in veterans with SCI/D. RESULTS: Overall, 49% of the sample had sleep dysfunction unrelated to sleep apnea. In this subgroup, bivariate analyses showed that a greater proportion of dysfunctional sleepers than non-dysfunctional sleepers were current smokers, had problems with drinking alcohol, hypertension, asthma, chronic obstructive pulmonary disease (COPD) and problematic weight gain. Variables independently associated with higher odds of dysfunctional sleep included white race, being a current smoker, problems with drinking alcohol, asthma, COPD and problematic weight gain. CONCLUSION: Consistent with epidemiological evidence for the general population, we found significant associations of sleep dysfunction with weight gain, smoking, alcohol misuse and select chronic conditions (COPD, asthma). Sustained sleep dysfunction may contribute to health deterioration and mortality, highlighting the need to address the high prevalence of sleep dysfunction (independent of sleep apnea) in persons with SCI/D. In particular, efforts aimed at modifying problematic weight gain, alcohol misuse and smoking are warranted in this cohort to improve sleep. PMID- 22508537 TI - Could motor imagery be effective in upper limb rehabilitation of individuals with spinal cord injury? A case study. AB - STUDY DESIGN: A case study. OBJECTIVE: The aim was to investigate whether motor imagery (MI) could be successfully incorporated into conventional therapy among individuals with spinal cord injury (SCI) to improve upper limb (UL) function. SETTING: The Physical Medicine and Rehabilitation Unit at the Henry Gabrielle Hospital in Lyon, France. METHODS: The participant was an individual with a complete C6 SCI. MI content was focused on functional UL movements, to improve hand transport to reach out and grasp with tenodesis. The participant was tested before and after 15 MI training sessions (45 min each, three times a week during 5 consecutive weeks). MI ability and program compliance were used as indicators of feasibility. The Minnesota and Box and Blocks tests, as well as movement time and hand trajectory during targeted movements were the dependent variables, evaluating motor performance before and after MI training. RESULTS: The participant's ability to generate MI was checked and compliance with the rehabilitation program was confirmed. The time needed to complete the Minnesota test decreased by 1 min 25 s. The Box and Blocks score was improved by three units after MI program. Decreased movement time and enhanced hand trajectory smoothness were still observed 3 months later, despite a slight decrease in performance. CONCLUSIONS: This study supports the feasibility for introducing MI in conventional therapy. Further studies should confirm the potential role of MI in motor recovery with a larger sample. PMID- 22508538 TI - Meal provision in a UK National Spinal Injury Centre: a qualitative audit of service users and stakeholders. AB - STUDY DESIGN: A single centre survey. OBJECTIVES: The objective of this study is to (1) assess patients' food intake and (2) measure satisfaction with current food provision, as judged by patients and by stakeholders (medical and nursing staff, managers and catering staff). METHODS: Standardised questionnaires were used to record food intake over a 24-h period, and to evaluate the quality, ordering, delivery and overall acceptability of food provided. RESULTS: The food intake of 67 patients with spinal cord injury (SCI) was recorded (64% response rate) and 166 evaluations (50% response rate) were returned. Twenty-nine patients (48%) consumed three full meals a day, 17 (26%) received oral nutritional supplements, 22 (34%) received vitamin/mineral supplements, and 23 (35%) required assistance to eat. Some patients and stakeholders expressed satisfaction with the current food provision: taste good: 25 versus 17% (for patients and stakeholders, respectively); appropriate texture: 22 versus 21%; appropriate temperature: 55 versus 72% (P = 0.002); well presented: 43 versus 28%; good choice: 49 versus 59%; received meal ordered: 65 versus 37% (P < 0.001); meal served on time: 71 versus 58%; and no interruption during mealtimes: 62 versus 46%. Principal component analyses of item scores identified three main factors (food quality, food presentation and food delivery (logistics). CONCLUSION: The present study identified some areas where there appeared to have been improvement in SCI hospital catering, but with much still to be achieved. Hospital-catering systems should be tailored to meet the demands of the different patient groups to optimise nutritional intake. Periodic quality control is essential to meet recommendations and patients' expectations. PMID- 22508539 TI - Cytologic and histologic findings of iron pill-induced injury of the lower respiratory tract. AB - In the airways, iron pill-induced mucosal injury is uncommon and can lead to necrosis and stricture of the respiratory tracts. The process is characterized by mucosal ulceration with deposition of crystalline iron particles, and the diagnosis is usually made on tissue biopsies. We report a case of iron-sulfate induced mucosal injury in the bronchial washing and biopsy of a patient receiving therapeutic oral iron supplementation with no known aspiration event. Clinically, the patient presented with hemoptysis, and bronchoscopy detected ulcerated main stem bronchus mucosa clinically suspicious for a neoplastic process. Bronchial washings revealed reactive epithelial cells and numerous histiocytes with both intracellular and extracellular refractile brown crystalline material, which was positive on iron stain. The histologic findings on biopsy showed mucosal ulceration with deposits of extracellular crystalline iron particles. These histologic changes are similar to those seen in iron pill-induced mucosal injury of the upper gastrointestinal tract in patients with "iron pill" gastritis. The cytologic and histologic features of iron pill-induced airway injury clinically can mimic cancer. The presence of extracellular and intracellular crystalline iron in the airway lumen and/or mucosa with associated varying degrees of ulceration and inflammation confirms the diagnosis. PMID- 22508540 TI - Effects of chemotherapy during pregnancy on the maternal and fetal heart. AB - OBJECTIVE: The co-occurrence of cancer and pregnancy is more frequently diagnosed. The effects of cancer treatment on maternal and fetal outcomes are less well known. The cardiotoxic effects of chemotherapy are a specific concern for the mother and fetus. We wanted to review the existing literature, mainly consisting of case reports, case studies, and retrospective data. RESULTS: Maternal effects Overall, the published data indicate that pregnancy is not an independent risk factor influencing cancer survival. There is no indirect evidence for an increased risk for maternal chemotherapy-related cardiotoxicity. Fetal effects During the first trimester chemotherapy needs to be avoided because of teratogenic risks. The risks of chemotherapy during the second and third trimester are more controversial. It has been associated with intrauterine growth restriction and preterm delivery in some studies, while others did not find the same effect. Cardiotoxic fetal effects have been reported despite the limited transplacental passage of chemotherapy. In most patients this was transient and long-term data are generally reassuring. CONCLUSION: A specific strategy for monitoring fetal and maternal chemotherapy-induced cardiotoxicity is suggested. Prospective data are needed on the long-term effects of chemotherapy in both mother and child. PMID- 22508541 TI - Highly efficient ring-opening reaction of azlactone-based copolymer platforms for the design of functionalized materials. AB - Azlactone-based homopolymers and copolymers were successfully synthesized using the reversible addition-fragmentation chain transfer (RAFT) process. The functional monomer 2-styryl-4,4-dimethylazlactone (SDA) was first homopolymerized in bulk then copolymerized with styrene, leading to (co)polymers with low polydispersity indices (PDI = 1.10-1.20). The reactive azlactone rings, located along the backbone of the copolymers were subjected to highly efficient ring opening reactions with functionalized primary amine derivatives incorporating a fluorescent (naphthalene) or an electrochemical (ferrocene) probes, a biological fragment (glutathione), a sugar unit (beta-cyclodextrin), or an oligomeric fluorinated moiety, leading to materials with various interesting properties. PMID- 22508543 TI - Relationship among salivary carbonic anhydrase VI activity and flow rate, biofilm pH and caries in primary dentition. AB - This study aimed to determine the activity of carbonic anhydrase isoenzyme VI (CAVI) in the saliva of preschool children with caries and to investigate the relationship between caries and salivary CAVI activity, salivary flow rate and biofilm pH before and after a 20% sucrose rinse. Thirty preschool children aged 45.3-80.3 months were divided into two groups: a caries-free group and a caries group. Clinical examinations were conducted by one examiner (kappa = 0.95) according to WHO criteria (dmfs) and early caries lesions. From each subject, CAVI activity, salivary flow rate and plaque pH were determined before and after a sucrose rinse. The results were submitted to Wilcoxon, Mann-Whitney and Spearman correlation tests (alpha = 0.05). The results showed that prerinse CAVI activity and its variation were higher in the saliva from caries children than from caries-free children. No difference was found between the two groups in postrinse salivary CAVI activity. After rinsing, biofilm pH differences were lower in both groups (p = 0.0012 and p = 0.0037 for the caries and caries-free groups, respectively). Also, after the sucrose rinse, salivary flow rate significantly increased in caries and caries-free groups (p = 0.0003, p = 0.0037). The variation of salivary CAVI activity was negatively correlated with caries (r = -0.501, p = 0.005). Child's age showed a positive correlation with caries (r = 0.456, p = 0.011). These results suggest that variation of salivary CAVI activity and child's age are associated with dental caries in preschool children. PMID- 22508542 TI - Transcriptional repression of the Dspp gene leads to dentinogenesis imperfecta phenotype in Col1a1-Trps1 transgenic mice. AB - Dentinogenesis imperfecta (DGI) is a hereditary defect of dentin, a calcified tissue that is the most abundant component of teeth. Most commonly, DGI is manifested as a part of osteogenesis imperfecta (OI) or the phenotype is restricted to dental findings only. In the latter case, DGI is caused by mutations in the DSPP gene, which codes for dentin sialoprotein (DSP) and dentin phosphoprotein (DPP). Although these two proteins together constitute the majority of noncollagenous proteins of the dentin, little is known about their transcriptional regulation. Here we demonstrate that mice overexpressing the Trps1 transcription factor (Col1a1-Trps1 mice) in dentin-producing cells, odontoblasts, present with severe defects of dentin formation that resemble DGI. Combined micro-computed tomography (uCT) and histological analyses revealed tooth fragility due to severe hypomineralization of dentin and a diminished dentin layer with irregular mineralization in Col1a1-Trps1 mice. Biochemical analyses of noncollagenous dentin matrix proteins demonstrated decreased levels of both DSP and DPP proteins in Col1a1-Trps1 mice. On the molecular level, we demonstrated that sustained high levels of Trps1 in odontoblasts lead to dramatic decrease of Dspp expression as a result of direct inhibition of the Dspp promoter by Trps1. During tooth development Trps1 is highly expressed in preodontoblasts, but in mature odontoblasts secreting matrix its expression significantly decreases, which suggests a Trps1 role in odontoblast development. In these studies we identified Trps1 as a potent inhibitor of Dspp expression and the subsequent mineralization of dentin. Thus, we provide novel insights into mechanisms of transcriptional dysregulation that leads to DGI. PMID- 22508544 TI - Fibroblast growth factor receptors in breast cancer: expression, downstream effects, and possible drug targets. AB - Cancer treatments are increasingly focusing on the molecular mechanisms underlying the oncogenic processes present in tumors of individual patients. Fibroblast growth factor receptors (FGFRs) are among the many molecules that are involved in oncogenesis and are currently under investigation for their potential as drug targets in breast cancer patients. These receptor tyrosine kinases play a role in several processes including proliferation, angiogenesis, and migration. Alterations in these basal processes can contribute to the development and progression of tumors. Among breast cancer patients, several subgroups have been shown to harbor genetic aberrations in FGFRs, including amplifications of FGFR1, FGFR2, and FGFR4 and mutations in FGFR2 and FGFR4. Here, we review in vitro and in vivo models that have partly elucidated the molecular implications of these different genetic aberrations, the resulting tumor characteristics, and the potential of FGFRs as therapeutic targets for breast cancer treatment. PMID- 22508545 TI - Self-organized liquid-crystalline nanostructured membranes for water treatment: selective permeation of ions. AB - A membrane with ordered 3D ionic nanochannels constructed by in situ photopolymerization of a thermotropic liquid-crystalline monomer shows high filtration performance and ion selectivity. The nanostructured membrane exhibits water-treatment performance superior to that of an amorphous membrane prepared from the isotropic melt of the monomer. Self-organized nanostructured membranes have great potential for supplying high-quality water. PMID- 22508546 TI - Methemoglobin formation by triapine, di-2-pyridylketone-4,4-dimethyl-3 thiosemicarbazone (Dp44mT), and other anticancer thiosemicarbazones: identification of novel thiosemicarbazones and therapeutics that prevent this effect. AB - Thiosemicarbazones are a group of compounds that have received comprehensive investigation as anticancer agents. The antitumor activity of the thiosemicarbazone, 3-amino-2-pyridinecarboxaldehyde thiosemicarbazone (3-AP; triapine), has been extensively assessed in more than 20 phase I and II clinical trials. These studies have demonstrated that 3-AP induces methemoglobin (metHb) formation and hypoxia in patients, limiting its usefulness. Considering this problem, we assessed the mechanism of metHb formation by 3-AP compared with that of more recently developed thiosemicarbazones, including di-2-pyridylketone-4,4 dimethyl-3-thiosemicarbazone (Dp44mT). This was investigated using intact red blood cells (RBCs), RBC lysates, purified oxyhemoglobin, and a mouse model. The chelation of cellular labile iron with the formation of a redox-active thiosemicarbazone-iron complex was found to be crucial for oxyhemoglobin oxidation. This observation was substantiated using a thiosemicarbazone that cannot ligate iron and also by using the chelator, desferrioxamine, that forms a redox-inactive iron complex. Of significance, cellular copper chelation was not important for metHb generation in contrast to its role in preventing tumor cell proliferation. Administration of Dp44mT to mice catalyzed metHb and cardiac metmyoglobin formation. However, ascorbic acid administered together with the drug in vivo significantly decreased metHb levels, providing a potential therapeutic intervention. Moreover, we demonstrated that the structure of the thiosemicarbazone is of importance in terms of metHb generation, because the DpT analog, di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), does not induce metHb generation in vivo. Hence, DpC represents a next-generation thiosemicarbazone that possesses markedly superior properties. This investigation is important for developing more effective thiosemicarbazone treatment regimens. PMID- 22508547 TI - Fine control of polyester properties via epoxide ROP using monomers carrying diverse functional groups. AB - Synthetic biodegradable polymers are important biomaterials. However, most of them are biologically inert. Free functional groups can allow easy biofunctionalization. Efficient introduction of functional groups to biodegradable polymers is still a challenge. Here, a practical strategy is presented to synthesize various functional polyesters with free hydroxyl groups polymerized via epoxide ring-opening polymerization between dicarboxylic acids and diglycidyl dicarboxylates without protection and deprotection. The polymers exhibit a wide range of physical, thermal, and mechanical properties, and good cytocompatibilities. This synthetic platform is expected to lead to functional polymers useful for a wide variety of biomedical applications. PMID- 22508548 TI - Template-free synthesis of large anisotropic gold nanostructures on reduced graphene oxide. AB - The morphologies/dimensions of Au nanostructures can be tailored by merely controlling the reduction degree of graphene oxide surface. Au nanoparticles, long Au nanowires, and semicircular-shaped Au nanoplates are in situ synthesized on slightly, moderately, and highly reduced graphene oxide films respectively, without the need of any templating agent. PMID- 22508549 TI - Is it safe to use a liver graft from a Chagas disease-seropositive donor in a human immunodeficiency virus-positive recipient? A case report addressing a novel challenge in liver transplantation. AB - This is the first report presenting a human immunodeficiency virus (HIV)-positive patient with fulminant hepatic failure receiving a liver graft from a Chagas disease-seropositive deceased donor. We describe the history of a 38-year-old HIV positive female patient who developed fulminant hepatic failure of an autoimmune etiology with rapid deterioration of her clinical status and secondary multiorgan failure and, therefore, needed emergency liver transplantation (LT) as a lifesaving procedure. Because of the scarcity of organs and the high mortality rate for emergency status patients on the LT waiting list, we decided to accept a Chagas disease-seropositive deceased donor liver graft for this immunocompromised Chagas disease-seronegative patient. The recipient had a rapid postoperative recovery and was discharged on postoperative day 9 without prophylactic treatment for Chagas disease. Fifteen months after LT, she was still alive and had never experienced seroconversion on periodic screening tests for Chagas detection. Although there is an inherent risk of acute Chagas disease developing in seronegative recipients, our report suggests that these infected organs can be safely used as a lifesaving strategy for HIV patients with a high need for LT. PMID- 22508550 TI - Effects of endothelial cells on proliferation and survival of human mesenchymal stem cells and primary osteoblasts. AB - Angiogenesis is a fundamental process in bone formation, remodeling, and regeneration. Moreover, for the regeneration of bone in tissue engineering applications, it is essential to support neovascularization. This can be achieved by cell-based therapies using primary endothelial cells, which are able to form functional blood vessels upon implantation. In bone composite grafts, coimplanted endothelial cells do not only support neovascularization but also support osteogenic differentiation of osteoblasts and osteoprogenitor cells. In this study, we investigated the effect of endothelial cells on proliferation and cell survival of human primary osteoblasts (hOBs) and human mesenchymal stem cells (MSCs). Human umbilical vein endothelial cells (HUVECs) stimulated hOB and MSC proliferation, whereas proliferation of HUVECs was unaffected by cocultured hOBs or MSCs. The effect of HUVEC cocultivation on hOB and MSC proliferation was more pronounced in direct cocultures than in indirect cocultures, indicating that this effect is at least partially dependent on the formation of heterotypic cell contacts between HUVECs and hOBs or MSCs. Furthermore, HUVEC cocultivation reduced low-serum induced apotosis of hOBs and MSCs by a mechanism involving increased phosphorylation and inactivation of the proapoptotic protein Bad. In summary, our experiments have shown that cocultured HUVECs increase the proliferation and reduce low-serum induced apoptosis of hOBs and MSCs. PMID- 22508551 TI - DNA-mediated silver nanoclusters: synthesis, properties and applications. AB - Fluorescent DNA-AgNCs have emerged as an alternative to standard emitters because of their unique properties: high fluorescent quantum yield, photostability, a broad pallet of colors (blue to near-IR), and the fact that their properties are easily modulated by the DNA sequence and environment. Applications as gene, ion, or small-molecule sensors have been reported. PMID- 22508555 TI - Coup d'oeil of sperm. PMID- 22508552 TI - Relationship of first-trimester uterine artery Doppler to late stillbirth. AB - OBJECTIVE: The aim of this study was to investigate if increased first-trimester uterine artery Doppler resistance indices (RI) are related to stillbirth. METHOD: Uterine artery Doppler indices were assessed prospectively during a routine first trimester ultrasound scan. Patients were categorised as having a high uterine artery mean Doppler RI if the index was above the 90th centile for gestation. Stillbirth outcomes were ascertained from a mandatory national register of pregnancy losses. RESULTS: High RI uterine artery Doppler (>90th centile) was an independent risk factor for late (>= 34 weeks) but not early stillbirth, with a hazard ratio of 2.61 (95% CI 1.13-6.03). The inclusion of uterine artery Doppler indices into Cox proportional hazard model negated the influence of conventional risk factors for stillbirth, such as parity, maternal age and body mass index (BMI), but not Afro-Caribbean ethnicity or smoking. CONCLUSION: High first trimester uterine artery Doppler RI is associated with late stillbirth after 34 weeks' gestation. This association supersedes those of conventional risk factors such as maternal age, parity and BMI, implying that these factors result in an increased risk of stillbirth by causing placental dysfunction. PMID- 22508557 TI - Post-synthetic modification of Zr-metal-organic frameworks through cycloaddition reactions. AB - Cycloaddition reactions are highly attractive for post-synthetic modification of metal-organic frameworks (MOFs). We report herein on cycloaddition reactions with PIZOF(R(1),R(2))s, which are porous interpenetrated Zr-based MOFs with Zr(6)O(4)(OH)(4)(CO(2))(12) as the nodes and the dicarboxylates (-)O(2)C[PE P(R(1),R(2))-EP]CO(2)(-) (P: phenylene, E: ethynylene; R(1), R(2): side chains at the central phenylene unit) as the linkers. 1,3-Dipolar cycloaddition between the pendant ethyne moieties of PIZOF(OMe,OCH(2)C=CH) and 4-methylbenzyl azide resulted in 98% conversion of the ethyne groups. Reactions of PIZOF(OMe,O(CH(2))(3)furan) with maleimide, N-methylmaleimide, and N phenylmaleimide converted 98, 99, and 89% of the furan moieties into the Diels Alder adducts. However, no reaction occurred with maleic anhydride. High resolution (1)H NMR spectra were crucial in determining the conversion and identifying the reaction products. Of all the reagents (NaOD/D(2)O, D(2)SO(4), Bu(4)NF, CsF, CsF/DCl, and KHF(2)) tested for the disassembly of the PIZOFs in [D(6)]DMSO, the combination of CsF and DCl was found to be the best. The disassembly at room temperature was fast (5-15 min), and after the addition of K(2)CO(3) the (1)H NMR data were identical to those of the diacids (=protonated linkers) dissolved in pure DMSO. This allowed for simple structure elucidation through data comparison. CsF/DCl dissolves not only PIZOFs but also the hydrolytically very stable UiO-66. PMID- 22508558 TI - Renal artery stenosis: an innocent bystander or an independent predictor of worse outcome in patients with chronic heart failure? A magnetic resonance imaging study. AB - AIMS: To investigate the prognostic impact of atherosclerotic renovascular disease in patients with chronic heart failure. METHODS AND RESULTS: Patients with heart failure due to left ventricular systolic dysfunction underwent cardiac magnetic resonance imaging and contrast-enhanced magnetic resonance angiography. Renal artery stenosis (RAS) was defined as a luminal narrowing >50%. Of the 366 patients investigated, 112 (31%) had RAS, of whom 41 had bilateral RAS. Patients with RAS were older (P < 0.001), had higher blood pressure (P < 0.001), and worse renal function (P = 0.001). In addition, these patients had more admissions and more prolonged hospital stays because of vascular events (0.09 +/- 0.26 vs. 0.02 +/- 0.16 admissions/per patient/year; P < 0.001; and 1.26 +/- 5.79 vs. 0.31 +/- 2.54 days/per patient/year; P < 0.001, respectively) and worse prognosis (hazard ratio 1.60, 95% confidence interval 1.10-2.34, P = 0.015). However, in multivariable analysis, a history of diabetes mellitus, decreasing haemoglobin, and increasing left ventricular end-systolic volume index, but not age and RAS, were independently related to outcome. CONCLUSIONS: RAS is a common finding in patients suffering from heart failure. Although it is associated with an increased vascular morbidity, it is not an independent predictor of mortality. PMID- 22508559 TI - Solution structure studies of monomeric human TIP47/perilipin-3 reveal a highly extended conformation. AB - Tail-interacting protein of 47 kDa (TIP47) has two putative functions: lipid biogenesis and mannose 6-phosphate receptor recycling. Progress in understanding the molecular details of these two functions has been hampered by the lack of structural data on TIP47, with a crystal structure of the C-terminal domain of the mouse homolog constituting the only structural data in the literature so far. Our studies have first provided a strategy to obtain pure monodisperse preparations of the full-length TIP47/perilipin-3 protein, as well as a series of N-terminal truncation mutants with no exogenous sequences. These constructs have then enabled us to obtain the first structural characterization of the full length protein in solution. Our work demonstrates that the N-terminal region of TIP47/perilipin-3, in contrast to the largely helical C-terminal region, is predominantly beta-structure with turns and bends. Moreover, we show that full length TIP47/perilipin-3 adopts an extended conformation in solution, with considerable spatial separation of the N- and C-termini that would likely translate into a separation of functional domains. PMID- 22508560 TI - Retraction: Nanoporous PdCu near-surface alloy for nonenzymatic glucose biosensing. PMID- 22508561 TI - A simple approach towards uniform spherical Ag-like nanoparticles. AB - A facile method was employed to synthesize uniform spherical Ag-like nanoparticles using gold nanorods as a template through a cycling reaction. As synthesized Ag-like nanoparticles displayed a narrow size distribution. PMID- 22508562 TI - Bismuth hexagons: facile mass synthesis, stability and applications. AB - A unique direct electrodeposition technique involving very high current densities, high voltages and high electrolyte concentrations is applied for highly selective mass synthesis of stable, isolable, surfactant-free, single crystalline Bi hexagons on a Cu wire at room temperature. A formation mechanism of the hexagons is proposed. The morphology, phase purity, and crystallinity of the material are well characterized by FESEM, AFM, TEM, SAED, EDX, XRD, and Raman spectroscopy. The thermal stability of the material under intense electron beam and intense laser light irradiation is studied. The chemical stability of elemental Bi in nitric acid shows different dissolution rates for different morphologies. This effect enables a second way for the selective fabrication of Bi hexagons. Bi hexagons can be oxidized exclusively to alpha-Bi(2)O(3) hexagons. The Bi hexagons are found to be promising for thermoelectric applications. They are also catalytically active, inducing the reduction of 4-nitrophenol to 4 aminophenol. This electrodeposition methodology has also been demonstrated to be applicable for synthesis of bismuth-based bimetallic hybrid composites for advanced applications. PMID- 22508565 TI - An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva. AB - Fibrodysplasia ossificans progressiva (FOP; MIM #135100) is a debilitating genetic disorder of dysregulated cellular differentiation characterized by malformation of the great toes during embryonic skeletal development and by progressive heterotopic endochondral ossification postnatally. Patients with these classic clinical features of FOP have the identical heterozygous single nucleotide substitution (c.617G > A; R206H) in the gene encoding ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor. Gene targeting was used to develop an Acvr1 knock-in model for FOP (Acvr1(R206H/+)). Radiographic analysis of Acvr1(R206H/+) chimeric mice revealed that this mutation induced malformed first digits in the hind limbs and postnatal extraskeletal bone formation, recapitulating the human disease. Histological analysis of murine lesions showed inflammatory infiltration and apoptosis of skeletal muscle followed by robust formation of heterotopic bone through an endochondral pathway, identical to that seen in patients. Progenitor cells of a Tie2(+) lineage participated in each stage of endochondral osteogenesis. We further determined that both wild-type (WT) and mutant cells are present within the ectopic bone tissue, an unexpected finding that indicates that although the mutation is necessary to induce the bone formation process, the mutation is not required for progenitor cell contribution to bone and cartilage. This unique knock-in mouse model provides novel insight into the genetic regulation of heterotopic ossification and establishes the first direct in vivo evidence that the R206H mutation in ACVR1 causes FOP. PMID- 22508566 TI - BMP-2 but not VEGF or PDGF in fibrin matrix supports bone healing in a delayed union rat model. AB - Treatment of delayed bone healing and non-unions after fractures, osteotomies or arthrodesis still is a relevant clinical challenge. Artificially applied growth factors can increase bone healing and progressively gain importance in clinical routine. The aim of this study was to determine the effects of rhPDGF-BB, rhVEGF 165, and rhBMP-2 in fibrin matrix on bone healing in a delayed-union rat model. Thirty-seven rats underwent a first operation where a standardized femoral critical size defect was created. A silicone spacer was implanted to impair vascularization within the defect. At 4 weeks the spacer was removed in a second operation and rhPDGF-BB, rhVEGF-165, or rhBMP-2 were applied in a fibrin clot. Animals in a fourth group received a fibrin clot without growth factors. At 8 weeks fibrin bound rhBMP-2 treated animals showed a significantly increased union rate and bone volume within the defect compared to the other groups. Single application of fibrin bound rhPDGF-BB and rhVEGF-165 failed to increase bone healing in our atrophic non-union model. PMID- 22508567 TI - Sphenoidal fontanelle area measurement on rendered three-dimensional ultrasound. AB - OBJECTIVE: Rendered three-dimensional images of the fetal cranial vault permit the identification of sutures and measurement of the fontanelle surface area. The objective of this study was to establish the feasibility and repeatability of sphenoidal fontanelle area measurement. METHOD: Head volumes were obtained using the biparietal diameter as the reference plane. These were displayed with maximum rendering and the surface area of the sphenoidal fontanelle was measured by one operator. Feasibility was expressed as the percentage of scans with a successful measurement at different gestational ages. Repeatability was expressed as coefficient of variation (CV), intraclass correlation coefficient (ICC) and Bland Altman plots. RESULTS: Thirty women underwent 141 scans. Feasibility of sphenoidal fontanelle measurement is over 90% before 26 weeks, but drops gradually thereafter and becomes 0% at 34 weeks. Intraobserver repeatability of measurement on the same scan image demonstrated CV = 17.5% and ICC = 0.883; however, when measuring a newly acquired volume, the repeatability is poor, CV = 30.7% and ICC = 0.649. CONCLUSION: Although it is feasible to visualize the sphenoidal fontanelle on rendered three dimensions, its surface area measurement is not reliable for clinical use. There is potential to overestimate repeatability when remeasuring the same volume. PMID- 22508568 TI - Does Alzheimer's disease with early onset progress faster than with late onset? A case-control study of clinical progression and cerebrospinal fluid biomarkers. AB - BACKGROUND: Early-onset Alzheimer's disease (EOAD) is generally thought to have a more rapid course compared to late-onset Alzheimer's disease (LOAD). The faster progression of EOAD observed in some studies has also been thought to correlate with cerebrospinal fluid (CSF) biomarkers. Our clinical experience has not been suggestive of any difference in disease progression; therefore, we decided to investigate whether differences in clinical progression and CSF biomarkers between EOAD and LOAD could be demonstrated. METHODS: Case-control study with 42 patients, 21 EOAD and 21 matched LOAD patients. Rates of progression were calculated and these, as well as CSF biomarker levels, were statistically compared. RESULTS: There were no statistically significant differences in clinical progression between the EOAD group and the LOAD group. There was no significant difference in the absolute values of CSF biomarkers, but a tendency towards lower levels of beta-amyloid in patients with EOAD was observed. CONCLUSIONS: Our findings did not converge with results from the majority of previous studies, which have been suggestive of a faster clinical progression in EOAD. Possibly, the very strict algorithm by which our patients were matched explains our findings. However, the findings should be repeated in a larger study population. PMID- 22508569 TI - Influence of arylamine N-acetyltransferase, sex, and age on 4-aminobiphenyl induced in vivo mutant frequencies and spectra in mouse liver. AB - One model for cancer initiation by 4-aminobiphenyl (ABP) involves N-oxidation by cytochrome P450 CYP1A2 followed by O-conjugation by N-acetyltransferase(s) NAT1 and/or NAT2 and decomposition to a DNA-binding nitrenium ion. We recently observed that neonatal ABP exposure produced liver tumors in male but not in female mice, and that NAT deficiency reduced liver tumor incidence. However, ABP induced liver tumor incidence did not correlate with liver levels of N (deoxyguanosin-8-yl)-ABP adducts 24 hr after exposure. In this study, we compared in vivo ABP-induced DNA mutant frequencies and spectra between male and female wild-type and NAT-deficient MutaTMMouse using both the tumor-inducing neonatal exposure protocol and a 28-day repetitive dosing adult exposure protocol. ABP produced an increase in liver DNA mutant frequencies in both neonates and adults. However, we observed no sex or strain differences in mutant frequencies in neonatally exposed mice, and higher frequencies in adult females than males. Neonatal ABP exposure of wild-type mice increased the proportion of G-T transversions in both males and females, while exposure of Nat1/2(-/-) mice produced increased G-T transversions in males and a decrease in females, even though females had higher levels of N-(deoxyguanosin-8-yl)-4-ABP adducts. There was no correlation of mutant frequencies or spectra between mice dosed as neonates or as adults. These results suggest that observed sex- and NAT-dependent differences in ABP-induced liver tumor incidence in mice are not due to differences in either mutation rates or mutational spectra, and that mechanisms independent of carcinogen bioactivation, covalent DNA binding and mutation may be responsible for these differences. PMID- 22508571 TI - Tribute: the American Society of Pediatric Hematology/Oncology (ASPHO) 2012 distinguished career award goes to Dr. Victor Blanchette. PMID- 22508570 TI - Non-orthogonal tool/flange and robot/world calibration. AB - BACKGROUND: For many robot-assisted medical applications, it is necessary to accurately compute the relation between the robot's coordinate system and the coordinate system of a localisation or tracking device. Today, this is typically carried out using hand-eye calibration methods like those proposed by Tsai/Lenz or Daniilidis. METHODS: We present a new method for simultaneous tool/flange and robot/world calibration by estimating a solution to the matrix equation AX = YB. It is computed using a least-squares approach. Because real robots and localisation are all afflicted by errors, our approach allows for non-orthogonal matrices, partially compensating for imperfect calibration of the robot or localisation device. We also introduce a new method where full robot/world and partial tool/flange calibration is possible by using localisation devices providing less than six degrees of freedom (DOFs). The methods are evaluated on simulation data and on real-world measurements from optical and magnetical tracking devices, volumetric ultrasound providing 3-DOF data, and a surface laser scanning device. We compare our methods with two classical approaches: the method by Tsai/Lenz and the method by Daniilidis. RESULTS: In all experiments, the new algorithms outperform the classical methods in terms of translational accuracy by up to 80% and perform similarly in terms of rotational accuracy. Additionally, the methods are shown to be stable: the number of calibration stations used has far less influence on calibration quality than for the classical methods. CONCLUSION: Our work shows that the new method can be used for estimating the relationship between the robot's and the localisation device's coordinate systems. The new method can also be used for deficient systems providing only 3 DOF data, and it can be employed in real-time scenarios because of its speed. PMID- 22508573 TI - Chemical surface modification of poly-epsilon-caprolactone improves Schwann cell proliferation for peripheral nerve repair. AB - Poly-epsilon-caprolactone (PCL) is a biodegradable and biocompatible polymer used in tissue engineering for various clinical applications. Schwann cells (SCs) play an important role in nerve regeneration and repair. SCs attach and proliferate on PCL films but cellular responses are weak due to the hydrophobicity and neutrality of PCL. In this study, PCL films were hydrolysed and aminolysed to modify the surface with different functional groups and improve hydrophilicity. Hydrolysed films showed a significant increase in hydrophilicity while maintaining surface topography. A significant decrease in mechanical properties was also observed in the case of aminolysis. In vitro tests with Schwann cells (SCs) were performed to assess film biocompatibility. A short-time experiment showed improved cell attachment on modified films, in particular when amino groups were present on the material surface. Cell proliferation significantly increased when both treatments were performed, indicating that surface treatments are necessary for SC response. It was also demonstrated that cell morphology was influenced by physico-chemical surface properties. PCL can be used to make artificial conduits and chemical modification of the inner lumen improves biocompatibility. PMID- 22508574 TI - Transcriptomic and proteomic analyses in bone tumor cells: Deciphering parathyroid hormone-related protein regulation of the cell cycle and apoptosis. AB - Giant cell tumor of bone (GCT) is an aggressive skeletal tumor characterized by local bone destruction, high recurrence rates, and metastatic potential. Previous works in our laboratory, including functional assays, have shown that neutralization of parathyroid hormone-related protein (PTHrP) in the cell environment inhibits cell proliferation and induces cell death in GCT stromal cells, indicating a role for PTHrP in cell propagation and survival. The objective of this study was to investigate the global gene and protein expression patterns of GCT cells in order to identify the underlying pathways and mechanisms of neoplastic proliferation provided by PTHrP in the bone microenvironment. Primary stromal cell cultures from 10 patients with GCT were used in this study. Cells were exposed to optimized concentrations of either PTHrP peptide or anti PTHrP neutralizing antiserum and were analyzed with both cDNA microarray and proteomic microarray assays in triplicate. Hierarchical clustering and principal component analyses confirmed that counteraction of PTHrP in GCT stromal cells results in a clear-cut gene expression pattern distinct from all other treatment groups and the control cell line human fetal osteoblast (hFOB). Multiple bioinformatics tools were used to analyze changes in gene/protein expression and identify important gene ontologies and pathways common to this anti-PTHrP-induced regulatory gene network. PTHrP neutralization interferes with multiple cell survival and apoptosis signaling pathways by triggering both death receptors and cell cycle-mediated apoptosis, particularly via the caspase pathway, TRAIL pathway, JAK-STAT signaling pathway, and cyclin E/CDK2-associated G1/S cell cycle progression. These findings indicate that PTHrP neutralization exhibits anticancer potential by regulating cell-cycle progression and apoptosis in bone tumor cells, with the corollary being that PTHrP is a pro-neoplastic factor that can be targeted in the treatment of bone tumors. PMID- 22508575 TI - Maternal serum human chorionic gonadotropin and pregnancy-associated plasma protein-A in pregnancies with fetal homozygous alpha-thalassemia-1 disease. AB - OBJECTIVE: To compare the levels of maternal serum free beta-hCG and PAPP-A between pregnancies with fetal homozygous alpha-thalassemia-1 disease and unaffected pregnancies. MATERIALS AND METHODS: One hundred and forty eight pregnancies at risk for fetal homozygous alpha-thalassemia-1 disease scheduled for cordocentesis at 18 to 22 weeks were recruited into the study. Maternal serum free beta-hCG and PAPP-A concentrations were measured before cordocentesis, and the final fetal diagnosis of homozygous alpha-thalassemia-1 disease was based on fetal Hb typing using high-performance liquid chromatography. RESULTS: Maternal serum concentration of free beta-hCG was significantly higher in women with fetal homozygous alpha-thalassemia-1 disease than those with unaffected fetuses (P = 0.018), whereas the concentrations of PAPP-A was not significantly different (P = 0.184). The median MoM of free beta-hCG in the affected group was 1.38 MoM and in the unaffected group was 0.88 MoM (P = 0.020). CONCLUSION: At midpregnancy, maternal serum free beta-hCG levels are significantly higher in pregnancies with fetal homozygous alpha-thalassemia-1 disease, signifying that the disease could be a confounder for interpretation free beta-hCG level in Down syndrome screening program. Nevertheless PAPP-A level seems to be similar in both groups. PMID- 22508576 TI - Decreased JH biosynthesis is related to precocious metamorphosis in recessive trimolter (rt) mutants of the silkworm, Bombyx mori. AB - In recessive trimolter (rt) mutants of the silkworm, Bombyx mori, that have four larval instars rather than five larval instars of normal B. mori, a decrease after a small increase in the hemolymph ecdysteroid titer during the early stages of the last (fourth) larval instar appeared to be a prerequisite for larvae to undergo precocious metamorphosis. The present study was carried out to investigate the possible mechanism underlying this decrease in the ecdysteroid titer. It was found that juvenile hormone (JH) biosynthetic activity of the corpora allata (CA) increased during the first day of the last larval instar, but its absolute JH biosynthesis activity was relatively lower compared to that of normal fourth-instar larvae in tetramolters. This lowered JH biosynthetic activity appeared to be related to a decrease in prothoracic gland ecdysteroidogenesis during the second day of the last instar, because hydroprene application prevented this decrease in prothoracic gland ecdysteroidogenesis, leading to the induction of a supernumerary larval molt. The in vitro incubation of prothoracic glands with hydroprene showed that hydroprene did not directly exert its action on prothoracicotropic hormone (PTTH) release. Further study showed that the application of hydroprene enhanced the competency of the glands to respond to PTTH. From these results, it was supposed that the lowered JH biosynthesis of the CA during the first day of last instar in rt mutants was related to decreased ecdysteroidogenesis in the prothoracic glands during the second day, thus playing a role in leading to precocious metamorphosis. PMID- 22508577 TI - Comparative proteomic analysis of proteins involved in oocyte meiotic maturation in mice. AB - After birth, oocytes stay at the diplotene stage in prophase of meiosis I. Meiosis resumes about 1 day before ovulation, and arrests in metaphase II (MII) after ovulation. The mature, MII oocytes are then ready for fertilization and to provide materials for early embryonic development. Proteomic characterization of oocytes can help identify proteins that are important for female meiotic maturation and early embryonic development. In this study, we compared the proteomic profiles between the germinal vesicle and MII mouse oocytes by two dimensional electrophoresis; 95 differentially expressed protein spots corresponding to 63 proteins were identified. Many of these proteins are known to be essential for oocyte meiosis and early embryonic development, such as adenylosuccinate synthetase, nucleoplasmin-2, and protein-arginine deiminase type 6. Of the 12 proteins that were identified and are highly expressed in oocytes, a novel protein, E330034G19Rik, was found to be oocyte-specific. According to analysis by bioinformatics, it may regulate chromosome segregation during meiosis or cleavage. An in-depth study of these proteins will help us better understand the mechanisms of oocyte meiotic maturation, fertilization, and early embryogenesis. It will also help us understand the mechanisms of diseases that stem from abnormal oocyte maturation, such as polycystic ovary syndrome and premature ovary failure. PMID- 22508578 TI - Mini-Cog and Mini-Mental State Examination: agreement in a cross-sectional study with an elderly sample. AB - BACKGROUND/AIMS: We aimed to compare the Mini-Mental State Examination (MMSE) with the Mini-Cog, measuring agreement in participants' classification, using a general population sample. METHODS: Cross-sectional evaluation of 609 community dwellers aged >=60 years was performed by trained interviewers. Cohen's kappa and 95% confidence intervals (CI) were calculated to assess overall agreement, and Cronbach alphas computed to assess reliability. Two-parameter Item Response Theory models (difficulty and discrimination parameters) were used to assess discrimination. RESULTS: Considering MMSE cut-point for scores <24, 3.1% of the participants would be 'cognitive impaired' and 6.2% considering cut-point scores <25. Following Mini-Cog's cut-point score <3, 11.3% would be impaired. For MMSE cut-point <24 and Mini-Cog <3, we observed a Cohen's kappa of 0.116 (95% CI: 0.073 to 0.305), and of 0.258 (95% CI: 0.101-0.415) for cut-point <25. The highest kappa was obtained for cut-point <26 on the MMSE and Mini-Cog <3 (kappa = 0.413). MMSE Cronbach alpha was 0.6108 and Mini-Cog's alpha was 0.2776. Co calibration according to inherent ability is graphically presented. CONCLUSIONS: Agreement between scales seems fragile in our sample. The discriminative and reliability analysis suggests a better performance for subsets of the MMSE compared with the Mini-Cog. Usefulness of calibrated scores is discussed. PMID- 22508579 TI - Three-dimensional vascularization of electrospun PCL/collagen-blend nanofibrous scaffolds in vivo. AB - Nanofiber scaffolds have proven their various advantages for tissue engineering and have been analyzed extensively. However, to date the three-dimensional pattern of vascularization inside nanofibrous scaffolds is unknown. This study introduces a novel method to visualize and quantify vascularization of electrospun nanofibrous PCL/collagen scaffolds in 3D in vivo. Randomly spun PCL/collagen blend and parallel aligned PCL/collagen blend/PEO scaffolds were analyzed for numbers and patterns of sprouting vessels inside the constructs using microCT scans at different time points. The image data derived from the microCT scans was converted into three-dimensional vessel trees. The aligned scaffold showed a significantly smaller number of sprouting vessels but vascularization in the center of the constructs occurred considerably earlier than in the nonwoven scaffold. Thus, for the first time the actual pattern of vascularization in nanofibrous scaffolds can be visualized three-dimensionally. These results demonstrate that the 3D pattern of vessel trees could be an essential parameter to evaluate nanofiber scaffolds for their suitability for tissue engineering as well as in vivo applications in general. PMID- 22508580 TI - The optimization of wireless power transmission: design and realization. AB - BACKGROUND: A wireless power transmission system is regarded as a practical way of solving power-shortage problems in multifunctional active capsule endoscopes. METHODS: The uniformity of magnetic flux density, frequency stability and orientation stability are used to evaluate power transmission stability, taking into consideration size and safety constraints. Magnetic field safety and temperature rise are also considered. Test benches are designed to measure the relevent parameters. Finally, a mathematical programming model in which these constraints are considered is proposed to improve transmission efficiency. To verify the feasibility of the proposed method, various systems for a wireless active capsule endoscope are designed and evaluated. RESULTS: The optimal power transmission system has the capability to supply continuously at least 500 mW of power with a transmission efficiency of 4.08%. CONCLUSIONS: The example validates the feasibility of the proposed method. Introduction of novel designs enables further improvement of this method. PMID- 22508581 TI - The involvement of cytochrome P450 monooxygenases in methanol elimination in Drosophila melanogaster larvae. AB - Methanol is one of the most common short-chain alcohols in fermenting fruits, the natural food of the fruit fly, Drosophila melanogaster. The larvae cope continuously with methanol at various concentrations in order to survive and develop. In the present article, we found toxicities of dietary methanol and formaldehyde were enhanced by piperonyl butoxide, but not by 3-amino-1, 2, 4 triazole, 4-methylpyrazole, diethylmeleate, and triphenyl phosphate, when assessing by the combination index method. These results reveal that cytochrome P450 monooxygenases (CYPs), rather than catalases, alcohol dehydrogenases, glutathione S-transferases, and esterases, participate in methanol metabolism. Moreover, methanol exposure dramatically increased CYP activity. The ratios of the CYP activities in treated larvae to those in control reached, respectively, up to 3.0-, 3.9-, and 2.7-fold, at methanol concentrations of 22.6, 27.9, and 34.5 mg/g diet. In addition, methanol exposure greatly up-regulated the mRNA expression level of five Cyp genes, which were Cyp304a1, Cyp9f2, Cyp28a5, Cyp4d2, and Cyp4e2. Their resulting proteins were suggested as the candidate enzymes for methanol metabolism in D. melanogaster larvae. PMID- 22508582 TI - Who donates their body to science? An international, multicenter, prospective study. AB - The altruistic act of body donation provides a precious resource for both teaching and researching human anatomy. However, relatively little is known about individuals who donate their bodies to science (donors), and in particular whether donors in different geographical locations share similar characteristics. A multicenter prospective survey of donors registering during 2010 in three different geographical locations, New Zealand, Ireland, and the Republic of South Africa, was conducted to identify donor characteristics. The 28-question survey included sections on body donation program awareness, reasons for donating, giving tendency, education, ethnicity, relationship status, occupation, religion, and political preference. Two hundred surveys (81%) were returned [New Zealand 123 (85% response rate), Republic of South Africa 41 (67%), and Ireland 36 (92%)]. Results indicate that donors share certain characteristics including reason for donating (80% cited a desire to aid medical science as the main reason for wishing to donate their body); family structure (most donors are or have been in long-term partnerships and >= 85% have siblings); and a higher proportion with no religious affiliation compared to their reference population. Some variations between locations were noted including donor age, the mode of program awareness, occupation, relationship status, political preference, organ donor status and with whom donors had discussed their decision to donate. This information could be important for assisting the identification of potential body donors in new and established bequest programs. PMID- 22508583 TI - Beneficial effects of Trigonella foenum graecum and sodium orthovanadate on metabolic parameters in experimental diabetes. AB - Oxidative stress in diabetic tissues is accompanied by high-level of free radicals with simultaneously declined antioxidant enzymes status leading to cell membrane damage. The present study was carried out to observe the effect of sodium orthovanadate (SOV) and Trigonella foenum graecum seed powder (TSP) administration on blood glucose and insulin levels, antioxidant enzymes, lipid peroxidation, pyruvate kinase, lactate dehydrogenase and protein kinase C in heart, muscle and brain of the alloxan-induced diabetic rats to see whether the treatment with SOV and TSP was capable of reversing the diabetic effects. Diabetes was induced by administration of alloxan monohydrate (15 mg/100 g body weight), and rats were treated with 2 IU insulin, 0.6 mg/ml SOV, 5% TSP in the diet and a combination of 0.2 mg/ml SOV and 5% TSP separately for 21 days. Blood glucose levels increased markedly in diabetic rats, animals treated with a combined dose of SOV and TSP had glucose levels almost comparable with controls, similar results were obtained in the activities of pyruvate kinase, lactate dehydrogenase, antioxidant enzymes and protein kinase C in diabetic animals. Our results showed that lower doses of SOV (0.2 mg/ml) could be used in combination with TSP to effectively reverse diabetic alterations in experimental diabetes. PMID- 22508584 TI - ANZJP this month. PMID- 22508585 TI - Bipolar antidepressant agents: shaken not stirred. PMID- 22508586 TI - Antidepressants for major depressive episodes: a modest proposal. PMID- 22508587 TI - Antidepressants in bipolar depression: much confusion, many questions, few answers. PMID- 22508588 TI - Antidepressants in bipolar depression: the clinical debate. PMID- 22508589 TI - Antidepressants: the scapegoat of poor outcome bipolar disorder? PMID- 22508590 TI - From mania and melancholia to the bipolar disorders spectrum: a brief history of controversy. PMID- 22508591 TI - Truth and reality in early intervention. PMID- 22508592 TI - Effectiveness of interventions to improve medication adherence in bipolar disorder. AB - OBJECTIVE: To identify interventions that improve medication adherence in bipolar disorder. METHOD: A review of the literature from 2004 to 2011 was conducted using Medline and manual searching. RESULTS: Eleven studies were identified as meeting inclusion criteria. Five studies demonstrated improved medication adherence. No characteristics of the interventions, clinical characteristics of the groups or methodological factors distinguished those psychosocial interventions that demonstrated improvement from those that did not. CONCLUSIONS: While only a few interventions improved adherence, most improved clinical outcomes. Issues were also identified about the way in which adherence is defined. It is proposed that incorporating patient preferences into measures of adherence within the context of a disorder-specific psychosocial intervention may provide an approach that demonstrates both improved adherence and improved clinical outcomes. However this requires further research. PMID- 22508593 TI - Borderline personality disorder and bipolar affective disorder. Spectra or spectre? A review. AB - OBJECTIVE: Bipolar affective disorder and borderline personality disorder have long been considered to have significant similarities and comorbidity. This review endeavours to clarify the similarities and differences between these disorders, with an effort to determine whether they reflect different forms of the same illness or separate illness clusters. METHOD: The published literature relating to bipolar affective disorders, borderline personality disorders, and related areas of knowledge was reviewed using searches of several electronic databases (AMED, CINHAL, Embase, Ovid, ProQuest, MEDLINE, Web of Science, ScienceDirect) and published texts. These findings were combined with the personal clinical experience of the author, and information gathered from colleagues, to create a review of this topic. RESULTS: Bipolar affective disorders and borderline personality disorders differ with respect to sense of self, disruption of relationships, family history of bipolar disorders, the benefits of medications, the extent of cognitive deficits, the form of affective dysregulation and mood cycling, the incidence of suicide and suicide attempts, the form of psychotic episodes, the incidence of early sexual abuse but not early trauma in general, the loss of brain substance, alterations in cortical activity, glucocorticoid receptor sensitivity, and mitochondrial dysfunction. They are similar with respect to non-specific features of affective dysregulation, the incidence of atypical depressive features, the incidence of self-mutilation, the incidence of transporter polymorphisms, possible genetic linkages, overall reduction in limbic modulation, reduction in the size of hippocampi and amygdala, and the incidence of sleep disruption. CONCLUSIONS: This review concludes that bipolar affective disorders and borderline personality disorder are separate disorders, but have significant elements in common. PMID- 22508594 TI - Changes in psychological distress in Australian adults between 1995 and 2011. AB - OBJECTIVE: To monitor changes in psychological distress in Australia over a 16 year period during which the availability of mental health services was increasing. METHOD: Data on psychological distress using the 4-NS scale were analysed from national surveys of adults carried out in 1995, 2003-04 and 2011. RESULTS: No change in psychological distress was found. CONCLUSIONS: The data show no improvement in adult mental health during a period when the availability of pharmacological, psychological and population interventions increased. Regular population monitoring of mental health is needed in the future in order to identify emerging needs and to evaluate the impact of service improvements and preventive programmes. PMID- 22508595 TI - Mania, homicide and severe violence. AB - BACKGROUND: Mania has been reported to be a risk factor for aggression and violence in psychiatric hospitals, but the extent of any association between mania and severe interpersonal violence in community settings is not known. AIM: To examine the association between mania and severe violence in a series of patients found not guilty by reason of mental illness (NGMI). METHODS: A review of the court documents of those found NGMI of offences involving severe violence, including homicide, attempted homicide and assault causing wounding or serious injury, in New South Wales between 1992 and 2008. RESULTS: Twelve of 272 people found NGMI were in a manic state when they committed a severe violence offence. Ten were diagnosed with schizo-affective disorder and two with bipolar disorder. Three patients were in the depressed phase of schizo-affective disorder and there were no patients in the depressed phase of bipolar disorder. CONCLUSION: Mania, in particular the manic phase of bipolar disorder, is not strongly associated with severe violence. PMID- 22508596 TI - The role of hardship in the association between socio-economic position and depression. AB - OBJECTIVE: It is well established that socio-economic position is associated with depression. The experience of financial hardship, having to go without the essentials of daily living due to limited financial resources, may explain the effect. However, there are few studies examining the link between financial hardship and diagnosable depression at a population level. The current paper addresses this gap and also evaluates the moderating effect of age. METHOD: Data were from 8841 participants aged 16-85 years in Australia's 2007 National Survey of Mental Health and Wellbeing. The 12-month prevalence of depressive episode was assessed using the Composite International Diagnostic Interview. Measures of socio-economic position included: financial hardship, education, labour-force status, occupational skill, household income, main source of income, and area level disadvantage. RESULTS: Financial hardship was more strongly associated with depression than other socio-economic variables. Hardship was more strongly associated with current depression than with prior history of depression. The relative effect of hardship was strongest in late adulthood but the absolute effect of hardship was greatest in middle age. CONCLUSIONS: The results demonstrate the critical role of financial hardship in the association between socio-economic disadvantage and 12-month depressive episode, and suggest that social and economic policies that address inequalities in living standards may be an appropriate way to reduce the burden attributable to depression. PMID- 22508597 TI - The impact of depression heterogeneity on inhibitory control. AB - OBJECTIVE: Major depressive disorder (MDD) is associated with deficits in executive cognitive function, including inhibitory control. However, inconsistencies have been found across studies. Depression is a heterogeneous disorder and these inconsistencies may therefore relate to heterogeneity in relatively small samples. METHOD: Here we sought to examine event-related potentials (ERPs) during a cognitive Go/No-Go task in melancholic (n = 60) and non-melancholic depressed patients (n = 54) relative to controls (n = 114). RESULTS: Behavioural responses indicate that inhibitory control processes are differentially affected by subtypes of depression such that melancholic patients exhibit a greater number of commission errors and more variable response rates in comparison to non-melancholic patients and controls respectively. However, ERPs do not differ during a cognitive Go/No-Go task when ERPs associated with correct responses are examined. CONCLUSIONS: These findings indicate that while patients with melancholia differ from patients without melancholia and controls, no neurophysiological differences are observed when controlling for observable behavioural impairment. PMID- 22508598 TI - Time to move on? Commentary on the early intervention in psychosis debate. PMID- 22508599 TI - Isn't it a bit risky to dismiss suicide risk assessment? PMID- 22508601 TI - Successful ultrabrief ECT for a mixed episode of bipolar disorder. PMID- 22508602 TI - Manic exacerbation induced by nicotine patch. PMID- 22508603 TI - A pathognomonic symptom of bipolar disorder. PMID- 22508604 TI - Depolarising bipolar disorder: a contribution. PMID- 22508605 TI - [Integrated public health]. PMID- 22508606 TI - [Pay for performance in primary care]. AB - Pay for Performance is a tool that links payment of healthcare professionals to the quality of health outcomes and processes. In this article the authors discuss the results of a literature review on the subject, highlighting the importance of introducing a Pay for Performance system in primary care, and the advantages and critical issues associated with the system. The experience of the British National Health Service and possible uses of the described payment system in Italy are also briefly discussed. PMID- 22508607 TI - [Overcrowding in emergency departments: the case of the San Giovanni Battista (Molinette) university hospital in Turin (Italy)]. AB - Overcrowding in Emergency Departments (ED) is a common phenomenon worldwide, especially in metropolitan areas. The main reason for overcrowding is not inappropriate emergency department use by patients but rather a shortage of available hospital beds which results in extended ED stays for patients who need emergency admission. The aims of this study, conducted at the San Giovanni Battista (Molinette) University hospital in Turin (Italy), were a) to verify the existence of overcrowding in the hospital ED and b) to test whether, as stated in the literature, overcrowding is due to restricted access to hospital beds for patients needing emergency admission, and to identify contributing factors. Results show the existence of overcrowding and confirm the hypothesized cause. PMID- 22508608 TI - [Knowledge, attitudes and beliefs of nurses regarding the prevention of Aspergillus spp. infections]. AB - In this article, the authors describe the results of a survey conducted in selected hospitals in the Piedmont region (Italy), using two questionnaires designed to evaluate knowledge, beliefs, opinions and attitudes of nursing staff about the risks and possible prevention of infections caused by Aspergillus spp. PMID- 22508609 TI - [A cross- sectional study to evaluate the effects of introducing a Bachelor of Science in Nursing and Midwifery in Italy]. AB - The effects of advanced nursing education have been documented at the international level but there is little information available in the Italian context. In Italy, the university nursing degree was introduced almost ten years ago and is facing its first reform. The aim of this study was to describe the effects of the Bachelor of Science in Nursing and Midwifery on skills as perceived by graduates of the school, and on professional and career development. A cross-sectional study design was used. All students who attended the nursing/midwifery program of the University of Udine and Trieste from 2005/2006 to 2008/2009 (n= 114) were considered eligible to participate. Participating students completed a self-assessment portfolio a few months after registering in the program and again upon completion of the program. Effects on professional and career development were assessed through a questionnaire. All participants reported having received one or more positive effects on their professional development. Only 19% of participants obtained a career advancement within 12 months of completing the program. PMID- 22508610 TI - [Do critical pathways improve outcomes of patients with cardiac failure?]. AB - Cardiac failure represents an important public health problem and despite recent clinical, diagnostic and therapeutic advances, the incidence and prevalence of this syndrome show a steady increase. In view of this, the authors conducted a meta-analysis to evaluate the effect of critical pathways in the management of patients with cardiac failure when compared with standard care. The impact of critical pathways on the following outcomes were evaluated: hospital mortality, mortality at six months, mean length of hospital stay, direct costs, readmission rates at one, three and six months. METHODS: The following databases were consulted: Medline, Embase, CINAHL, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. The research was limited to articles published between January 1975 and June 2010. Methodological quality of studies was evaluated by the Jadad method (for RCTs, cRCT, CCT) and the New Castle Ottawa Scale for case-control and cohort studies. Data analysis was performed by using the statistical methods described in the Cochrane Collaboration guidelines. Meta-analyses were performed using RevMan software version 5. RESULTS: Eleven studies were included in the meta-analysis (5,460 patients). A lower mortality (hospital mortality and mortality at 6 months) was observed in the critical pathways group compared to the group treated with standard care. A positive impact of critical pathways was also observed in length of stay, direct costs, readmission after one, three and six months. CONCLUSIONS: Critical pathways can improve the quality of care provided to patients with cardiac failure. Further studies are needed to evaluate which mechanisms within the care pathways can truly improve the quality of care. PMID- 22508611 TI - [Institutional changes for the future of Hygiene and Preventive Medicine in Italy]. AB - Following a brief overview of the initiatives undertaken since 2005 by the Italian Society of Hygiene (SitI) regarding he future of Hygiene and Public Health in Italy, the authors examine the latest proposals for renewing the organizational structure of the departments of Prevention, as well as for training programs and function of public health physicians. These changes, however, may be insufficient for a real renewal of public health, in the absence of institutional changes which would allocate administrative management of healthcare functions to local government, with community participation in health promotion. The planned establishment of "metropolitan cities" in 2012 is an opportunity for the SItI to show that the management of health administrative functions by the new local government organs is compatible with the institutional framework, is useful for achieving the objectives of health promotion and disease prevention, and facilitates health policy in local governments. PMID- 22508612 TI - [Integrated local health services for Alzheimer's disease in Umbria (Italy)]. AB - To improve the quality of healthcare for patients affected by dementia (Alzheimer's and other types of dementia) and provide support to family caregivers, a health district in Umbria (Italy) has developed a network of social and health services integrated with third-sector and voluntary sector activities and has worked on addressing both the health and social needs of patients and their caregivers. In this article the authors describe the implemented activities which include educational activities, forming a self-help group for caregivers of Alzheimer patients, opening a counseling center and an outpatient clinic for Alzheimer's disease and cognitive disorders. PMID- 22508613 TI - [The Italian Hygiene Society from the 19th to the 21st century: successes, difficulties, and future objectives]. PMID- 22508614 TI - The cultivation of the mushroom Agaricus bisporus (Champignon): micro-organisms and preservability. AB - Cultivation of Agaricus bisporus mushrooms requires the use of substrates that are potentially dangerous from the microbiological point of view, such as chicken and horse manure. Microorganisms can pose risks to consumers and workers, and generate lower profits. Packaging of fresh mushrooms with impermeable films is used to extend their shelf life but creates anaerobic and humidity conditions that could favour the growth of microorganisms such as Listeria monocytogenes and Clostridium botulinum. This paper examines some alternatives for packaging fresh mushrooms and the resulting potential microbiological hazards. PMID- 22508615 TI - [History of compulsory immunization]. AB - Mandatory vaccination was introduced for the first time in the nineteenth century in some European countries following the then sweeping smallpox epidemics. Compulsory vaccination for some diseases is still extant in some countries like Italy, France, Greece, Portugal and Belgium; in other countries, like the United Kingdom and Finland, vaccinations are voluntary but the state pursues a policy of active promotion. In 2007, the Veneto Region of Italy government approved a law allowing the experimentation of the abolition of mandatory vaccination. This experimentation caused an important debate among healthcare workers and scientific society of public health. PMID- 22508616 TI - Evaluation of flow cytometric assessment of myeloid nuclear differentiation antigen expression as a diagnostic marker for myelodysplastic syndromes in a series of 269 patients. AB - BACKGROUND: Myeloid nuclear differentiation antigen (MNDA) is expressed in myelomonocytic cells with highest levels in mature granulocytes and monocytes. It is suggested to be expressed more weakly in patients with myelodysplastic syndromes (MDS). The analysis of MNDA therefore may improve diagnostic capabilities of multiparameter flow cytometry (MFC) in MDS. METHODS: We used MFC for detection of MNDA expression in 269 patients with suspected or known MDS, acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML), cytopenia of unknown cause or without malignancy (negative controls). Results were compared with the diagnoses revealed by cytomorphology (CM) and cytogenetics (CG). RESULTS: Percentages of granulocytes and monocytes with diminished MNDA expression (dimG and dimM) were higher in patients with MDS (mean +/- SD, 20% +/- 20%, P < 0.001 and 31% +/- 24%, P < 0.001) and AML (27% +/- 27%, P = 0.007 and 45% +/- 31%, P = 0.001) diagnosed by CM, vs. patients without MDS (8% +/- 10% and 16% +/- 11%), respectively. Significant differences were also found for mean fluorescence intensity (MFI) of MNDA in monocytes which was lower in MDS (mean +/ SD, 71 +/- 36, P = 0.004) and AML (55 +/- 39, P < 0.001) vs. no MDS samples (85 +/- 28), respectively. Within patients with MDS, cases with cytogenetic aberrations showed a trend to higher %dimG (24% +/- 18%, P = 0.083) compared with those without (16% +/- 21%). Cut-off values for %dimG (12%) and %dimM (22%) as well as for MFI in monocytes (72) were defined capable of discriminating between MDS and non-MDS. CONCLUSION: MNDA expression in bone marrow cells can be assessed reliably by MFC and may facilitate evaluation of dyspoiesis when added to a standard MDS MFC panel. PMID- 22508617 TI - Percutaneous coronary intervention for acute coronary syndrome due to graft failure: use of bare-metal and drug-eluting stents and subsequent long-term clinical outcome. AB - OBJECTIVES: To describe clinical outcome after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) due to graft failure. BACKGROUND: Limited data are available on outcome after PCI for graft failure-induced ACS in the drug eluting stent (DES) era. METHODS: Patients were identified who underwent PCI either with DES or BMS for ACS due to graft failure between January 2003 and December 2008. Follow-up was performed at 1 year and April 2011. The primary endpoint was the composite of death, myocardial infarction (MI), or target vessel revascularization (TVR). Kaplan-Meier estimates were calculated at 1 and 5-year follow-up. Predictors were identified by backward selection in Cox proportional hazards models. RESULTS: A total of 92 patients underwent PCI, of which 77 were treated with bare metal stents (BMS) and 15 with DES. Patient and procedural characteristics were similar in both groups. Mean follow-up was 3.2 years. Five year composite event rate was 65.9% after BMS vs. 43.4% after DES implantation (P = 0.17). Individual endpoints were comparable in both groups. Recurrence of angina, hospitalization, and repeat interventions were similar. After multivariable adjustment, the use of DES was not associated with a significant reduction in the primary endpoint (HR = 0.44, 0.18-1.04, p = 0.06). CONCLUSION: In patients presenting with ACS due to acute graft failure, long-term outcomes remain poor. In a nonrandomized comparison with BMS, DES use was not associated with significant improved long-term clinical outcomes. PMID- 22508619 TI - A new blended learning concept for medical students in otolaryngology. AB - OBJECTIVE: To evaluate students' overall assessment and effectiveness of the web based blended learning conception "Unified Patient Project" (UPP) for medical students rotating on their otolaryngology internship (ear, nose, and throat [ENT] tertiary). DESIGN: Prospective comparison group design of the quasiexperimental type. SETTING: Medical education. SUBJECTS: The experimental group (preintervention test [pretest], intervention, and postintervention test [posttest]) comprised 117 students, and the comparison group (pretest, alternative intervention, and posttest), 119. INTERVENTIONS: In the experimental group, lecturing of case studies was replaced by the blended learning concept UPP. A standardized questionnaire evaluated students' overall assessment of teaching otolaryngology. A pretest and posttest using multiple choice questions was administered to clarify whether the UPP has led to a knowledge gain. RESULTS: The comparison group was more satisfied with their teaching; however, this was not statistically significant (P = .26) compared with the UPP. Students with higher preknowledge benefitted from the UPP, while students with lower preknowledge did not (P = .01). On average, posttest results in the experimental group exceeded those of the comparison group by 8.7 percentage points for a 75% preknowledge of the maximum attainable score, while they fell below those of the comparison group by 8.1 percentage points for a 25% preknowledge. CONCLUSIONS: Students' satisfaction with the blended learning concept UPP was lower than in the face-to-face teaching, although this was not statistically significant. The new web-based UPP leads to an improved knowledge in clinical otolaryngology for all students. Students with lower preknowledge benefitted more from face-to-face teaching than from the UPP, while students with higher preknowledge benefitted more from the UPP. This implies students with poor preknowledge need special promotion programs. PMID- 22508621 TI - Prophylactic swallowing exercises in patients with head and neck cancer undergoing chemoradiation: a randomized trial. AB - OBJECTIVE: To assess the efficacy of prophylactic swallowing exercises on swallowing function in patients undergoing chemoradiation therapy (CRT) for head and neck cancer. DESIGN: Randomized controlled trial. SETTING: Tertiary care, academic medical center. PATIENTS: Twenty-six patients with head and neck cancer receiving CRT. INTERVENTION: Patients performed 5 targeted swallowing exercises throughout their CRT and participated in weekly swallowing therapy sessions to promote adherence and accurate technique. Controls had no prophylactic exercises and were referred for swallowing treatment after completion of CRT if indicated. MAIN OUTCOME MEASURES: Swallowing function was assessed with the Functional Oral Intake Scale (FOIS) and the Performance Status Scale for Head and Neck Cancer Patients (PSS-H&N) at baseline, immediately after CRT, and at 3, 6, 9, and 12 months after CRT. RESULTS: There were no statistically significant differences in FOIS scores between intervention and control patients immediately after CRT (immediately after CRT: intervention group median score, 3 [range, 1-7], vs median control score, 4 [range, 1-6] (P = .88). However, intervention patients had significantly better scores at months 3 and 6 (median 3-month intervention score, 7 [range, 5-7], vs median control score, 5 [range, 3-7] [P = .03]; median 6-month intervention score, 7 [range, 6-7], vs median control score, 6 [range, 3 7] [P = .009]). There was no significant difference in scores at months 9 and 12 (P = .24 and P = .93, respectively). The same pattern between intervention and control patients was observed for scores on the PSS-H&N. CONCLUSIONS: Patients who performed prophylactic swallowing exercises had improved swallowing function at 3 and 6 months after CRT but not immediately after CRT or at 9 and 12 months after CRT. The small sample size may have limited our ability to detect significant differences beyond 6 months of observation as well as additional significant differences in our study. PMID- 22508620 TI - Pediatric cervicofacial necrotizing fasciitis: a case report and review of a 10 year national pediatric database. AB - OBJECTIVE: To present a case of a pediatric cervicofacial necrotizing fasciitis (NF), a rapidly progressive infection, and a review of a 10-year pediatric inpatient database. DESIGN: Case report and review. SETTING: Pediatric intensive care unit. PATIENTS: A healthy 5-year-old male who developed NF of the lower lip 36 hours following minor trauma. International Classification of Diseases, Ninth Revision, code 728.86 (NF), was the inclusion criteria for the Kids' Inpatient Database (KID) in 1997 and 2006. RESULTS: A pediatric case is presented with a thorough photographic record demonstrating the need for rapid diagnosis and treatment. In a review of the KID from 1997 and 2006, the relative risk of being discharged with NF in 2006 vs 1997 was 1.4 (95% CI, 9.95-2.28). Age at diagnosis of NF was older in 2006 compared with 1997 (11.5 years vs 8.05 years; P < .001). Deaths with a diagnosis of NF increased from 1997 compared with 2006: from 3.9% to 5.4%. In 2006, the odds of death were 15.1 times higher in pediatric discharges with a diagnosis of NF compared with discharges without a diagnosis of NF (P < .001; 95% CI, 9.3-23.1). CONCLUSIONS: Even with the advent of new treatments and antibiotics, the incidence and death rates of NF have changed little over the past 10 years. While it is still a rare diagnosis, knowledge and awareness of necrotizing fasciitis with aggressive medical and surgical treatment are still the foundation in disease survival. PMID- 22508622 TI - Frequent association of cochlear nerve canal stenosis with pediatric sensorineural hearing loss. AB - OBJECTIVE: To examine the association between cochlear nerve canal (CNC) dimensions and sensorineural hearing loss (SNHL). DESIGN: Retrospective review. SETTING: Tertiary pediatric hospital. PATIENTS: Children with SNHL and CNC stenosis. INTERVENTION: The CNCs measured in axial and 45 degrees oblique planes on temporal bone computed tomography (TBCT) in children with SNHL were compared with TBCT from children with normal hearing and 100 normal temporal bone specimens. Additional inner ear abnormalities were recorded. Hearing was measured using 4 frequency pure-tone averages (PTAs). MAIN OUTCOME MEASURE: The degree of CNC stenosis related to the degree of SNHL. RESULTS: Fifty-three patients (32 female) with SNHL had CNC stenosis in 85 ears (32 bilateral, 21 unilateral). The mean (SD) axial CNC measurement for 85 ears was 0.98 (0.57) mm (range, 0-1.75 mm). The mean (SD) Poschl CNC measurement was 1.30 (0.69) mm (range, 0-2.80 mm). Of 85 ears, 64 had at least 1 additional inner ear abnormality. The mean (SD) PTA was 56.2 (40.8) dB. For each ear separately axial and Poschl plane CNC measurements were highly correlated (P < .001). The degree of CNC stenosis was significantly (P = .02) related to degree of hearing loss, and PTA decreased in the CNC stenosis population by 1.4 dB per year (P = .054). In addition, PTA and additional inner ear abnormalities were found to be significantly correlated (P = .002). CONCLUSIONS: Cochlear nerve canal stenosis is associated with SNHL, and the degree of stenosis predicted the degree of SNHL. In addition, the presence of CNC stenosis with additional inner ear abnormalities may affect the severity of SNHL. PMID- 22508624 TI - Pulse transit time and assessment of childhood sleep disordered breathing. AB - OBJECTIVES: To compare nocturnal polysomnography (PSG) with pulse transit time (PTT) recordings and structured clinical assessments and assess the reliability of these methods as a surrogate for the apnea-hypopnea index (AHI; calculated as the number of apneas/hypopneas per hour of total sleep time) and to test the associations between the clinical assessments and sleep disordered breathing (SDB). DESIGN: Prospective observational study. The parents of 51 children and adolescents filled out a questionnaire on SDB and the participants underwent examination. Scores from questionnaire and examination items were weighted according to their association with SDB. A total clinical score was assigned combining questionnaire and examination scores. SETTING: Hospital pediatrics department. PATIENTS: Children and adolescents aged 5 to 17 years undergoing standard PSG with the addition of PTT as part of a clinical investigation for SDB. MAIN OUTCOME MEASURES: The AHI and associations between the AHI and PTT arousal index (PTT-AI) and questionnaire, examination, and total clinical scores. RESULTS: We found a significant correlation between the AHI and PTT-AI (r = 0.55; P < .001). The relationship between the AHI and PTT-AI was stronger when the AHI was greater than 3. We also found significant correlations between the PTT-AI and the total clinical score (r = 0.38; P = .008) and the examination score (r = 0.44; P = .002) but not the questionnaire score (r = 0.23; P = .12). There was an association between the AHI and examination score in particular when the AHI was greater than 3. CONCLUSIONS: Pulse transit time shows promise as a screening test for SDB associated with an AHI greater than 3. For less severe SDB, the validity of using the PTT to separate these conditions from primary snoring has not been demonstrated in a clinical setting. PMID- 22508623 TI - Localization of inflammatory mediators in pediatric sinus mucosa. AB - OBJECTIVES: Microarray analyses of sinus mucosa in pediatric patients with chronic rhinosinusitis (CRS) have recently demonstrated increased messenger RNA expression of the inflammatory chemokines CXCL5 and CXCL13 and of the innate immune mediators beta-defensin 1 (DEFB1), serum amyloid A2 (SAA2), and serpin B4. The objectives of this study were to determine whether these gene products were expressed at the protein level in pediatric sinus mucosa and to determine their localization. DESIGN: Immunohistochemical analysis was used to identify protein expression and cellular localization of CXCL5, CXCL13, DEFB1, SAA2, and serpin B4. Coimmunofluorescence staining of inflammatory cells was performed to further evaluate expression of CXCL5 and CXCL13. SETTING: Pediatric tertiary care facility. PATIENTS: Fifteen children with CRS who underwent endoscopic sinus surgery and 8 children who underwent craniofacial or neurosurgical procedures for abnormalities other than sinusitis. MAIN OUTCOME MEASURES: Protein expression and cellular localization of CXCL5, CXCL13, DEFB1, SAA2, and serpin B4 in pediatric sinus mucosa. RESULTS: Ciliated and basal cells in the pseudostratified epithelium stained positively for the 5 mediators examined in both cohorts. Except for serpin B4, goblet cells did not stain for any mediators in either cohort. Glandular cells stained positively for all 5 mediators in both cohorts. Coimmunofluorescence staining of inflammatory cells showed that CXCL13 was expressed in macrophages, T and B cells but not in neutrophils. CXCL5 was detected only in T cells. CONCLUSIONS: CXCL5, CXCL13, DEFB1, SAA2, and serpin B4 were expressed at the protein level in the sinus mucosa of controls and pediatric patients with CRS and exhibited cell-specific localization. These mediators, not typically associated with pediatric CRS, may be involved in the inflammatory response and mucus hypersecretion seen in pediatric CRS. PMID- 22508625 TI - Systematic intraoperative application of confocal endomicroscopy for early detection and resection of squamous cell carcinoma of the head and neck: a preliminary report. AB - OBJECTIVE: To use intraoperative confocal endomicroscopy for early detection and resection of squamous cell carcinoma (SCC) of the head and neck. A preliminary report. DESIGN: Prospective case series. SETTING: Tertiary referral hospital. PATIENTS: Fifteen consecutive patients with SCC of the oral cavity, hypopharynx, and larynx were included from the Department of Otolaryngology-Head and Neck Surgery, HSK Dr Horst Schmidt Kliniken GmbH, Wiesbaden, Germany INTERVENTIONS: Confocal endomicroscopy was performed during diagnostic and therapeutic procedures with a prototype of a rigid laser endoscope in combination with the already available technology of autofluorescence. MAIN OUTCOME MEASURES: Real time visualization of cellular and subcellular details during endoscopy. Diagnostic scores were applied to differentiate dysplastic and malignant mucosal changes of SCC of the head and neck from normal squamous cell mucosa using this method. Results were correlated with the well-established gold standard, histologic analysis. RESULTS: Dysplastic and malignant changes of head and neck squamous cell mucosa were endoscopically determined by this unique in vivo application of confocal laser endomicroscopy using a rigid probe. CONCLUSIONS: We present preliminary and descriptive data using this novel technology in vivo. Considering the impact of a virtual real-time histologic analysis, this technology points to a very promising development. It may carry potential for quicker intraoperative diagnosis, less need for multiple frozen sections, and more precise resection margins. PMID- 22508627 TI - An unusual complication of vocal fold lipoinjection: case report and review of the literature. PMID- 22508626 TI - A novel modular polymer platform for the treatment of head and neck squamous cell carcinoma in an animal model. AB - OBJECTIVE: To evaluate the therapeutic efficacy of a novel modular polymer platform in the treatment of head and neck squamous cell carcinoma (HNSCC). DESIGN: In vivo study. SETTING: Academic research laboratory. Subjects and METHODS: C3H/HeJ mice and SCID/beige mice were randomized to receive implantation of no polymer, plain polymer, plain polymer with local cisplatin injection, or cisplatin polymer. The 2 groups of mice implanted with cisplatin polymer or no polymer were further randomized to receive 4 Gy of external beam radiation for 4 days or no radiation. Tumor size was measured until the mice were humanely killed. At necropsy, the tumors were excised and weighed. RESULTS: There was a significant reduction in tumor growth using this novel polymer platform. The cisplatin-secreting polymer effectively reduced human head and neck tumor growth in SCID mice by 17-fold and SCC VII/SF tumors in C3H/HeJ mice by more than 16 fold compared with the control, plain polymer, and plain polymer + intratumoral cisplatin injection groups (P = .01 for both). We also observed a statistically significant lower tumor weight in mice treated with cisplatin polymer and concomitant radiation compared with the radiation alone and control groups. CONCLUSIONS: We demonstrate the efficacy of a novel polymer platform in delivering cisplatin to a partially resected SCC in a murine model. This polymer may represent a new therapeutic modality for patients with HNSCC. Once this polymer platform is optimized, we will plan for validation in the context of a prospective trial in patients with unresectable advanced or recurrent HNSCC. PMID- 22508628 TI - Objective tinnitus from middle ear myoclonus. PMID- 22508629 TI - Radiology quiz case 1. Myositis ossificans of the bilateral medial and lateral pterygoid muscles. PMID- 22508630 TI - Radiology quiz case 2. Retropharyngeal prevertebral lipoma. PMID- 22508631 TI - Pathology quiz case 1. Allergic fungal rhinosinusitis (AFRS). PMID- 22508632 TI - Pathology quiz case 2. Metastatic calcium phosphate deposition secondary to chronic kidney disease (CKD). PMID- 22508633 TI - The need for further evaluation of objective parameters of swallowing function after transoral robotic surgery. PMID- 22508634 TI - Rethinking cultural competence. PMID- 22508635 TI - Organizational cultural competence consultation to a mental health institution. AB - Cultural competence is increasingly recognized as an essential component of effective mental health care delivery to address diversity and equity issues. Drawing from the literature and our experience in providing cultural competence consultation and training, the paper will discuss our perspective on the foundational concepts of cultural competence and how it applies to a health care organization, including its programs and services. Based on a recent consultation project, we present a methodology for assessing cultural competence in health care organizations, involving mixed quantitative and qualitative methods. Key findings and recommendations from the resulting cultural competence plan are discussed, including core principles, change strategies, and an Organizational Cultural Competence Framework, which may be applicable to other health care institutions seeking such changes. This framework, consisting of eight domains, can be used for organizational assessment and cultural competence planning, ultimately aiming at enhancing mental health care service to the diverse patients, families, and communities. PMID- 22508636 TI - Issues of clinical and cultural competence in Caribbean migrants. AB - The level of out-migration from the Caribbean is very high, with migration of tertiary-level educated populations from Caribbean countries being the highest in the world. Many clinicians in receiving countries have had limited diagnostic and therapeutic experience with Caribbean migrants, resulting in diagnostic and therapeutic controversies. There is an urgent need for better understanding of these cultural differences. The paper explores issues of clinical and cultural competence relevant to assessing, diagnosing, and treating Caribbean migrants with a focus on three areas: cultural influences on illness phenomenology; the role of language differences in clinical misunderstandings; and the complexities of culture and migration. Clinical issues are illustrated with case studies culled from four decades of clinical experience of the first author, an African Jamaican psychiatrist who has worked in the Caribbean, North America, Europe, and New Zealand. PMID- 22508637 TI - More than being against it: anti-racism and anti-oppression in mental health services. AB - Anti-racism and anti-oppression frameworks of practice are being increasingly advocated for in efforts to address racism and oppression embedded in mental health and social services, and to help reduce their impact on mental health and clinical outcomes. This literature review summarizes how these two philosophies of practice are conceptualized and the strategies used within these frameworks as they are applied to service provision toward racialized groups. The strategies identified can be grouped in seven main categories: empowerment, education, alliance building, language, alternative healing strategies, advocacy, social justice/activism, and fostering reflexivity. Although anti-racism and anti oppression frameworks have limitations, they may offer useful approaches to service delivery and would benefit from further study. PMID- 22508638 TI - Use of the Cultural Formulation in Stockholm: a qualitative study of mental illness experience among migrants. AB - This paper explores the contributions of the Cultural Formulation (CF) interview to an overall understanding of patients, and focuses on the narratives of 23 newly referred patients with migrant backgrounds seeking help at a psychiatric outpatient clinic in Stockholm. Through text content analysis methods we identified five themes: displacement in space and time; mental illness as a physical disability; life events as etiological factors; concealing as a coping strategy; and being lost in a fragmented health care system. Findings indicate the need to contextualize symptoms for an in-depth comprehension of patients' phenomenology. Both clinical and policy implications are discussed. The findings suggest that a section on migration and acculturation should be added to the cultural formulation in the next edition of DSM. PMID- 22508639 TI - Adapting CBT for traumatized refugees and ethnic minority patients: examples from culturally adapted CBT (CA-CBT). AB - In this article, we illustrate how cognitive behavioral therapy (CBT) can be adapted for the treatment of PTSD among traumatized refugees and ethnic minority populations, providing examples from our treatment, culturally adapted CBT, or CA CBT. CA-CBT has a unique approach to exposure (typical exposure is poorly tolerated in these groups), emphasizes the treatment of somatic sensations (a particularly salient part of the presentation of PTSD in these groups), and addresses comorbid anxiety disorders and anger. To accomplish these treatment goals, CA-CBT emphasizes emotion exposure and emotion regulation techniques such as meditation and aims to promote emotional and psychological flexibility. We describe 12 key aspects of adapting CA-CBT that make it a culturally sensitive treatment of traumatized refugee and ethnic minority populations. We discuss three models that guide our treatment and that can be used to design culturally sensitive treatments: (a) the panic attack-PTSD model to illustrate the many processes that generate PTSD in these populations, highlighting the role of arousal and somatic symptoms; (b) the arousal triad to demonstrate how somatic symptoms are produced and the importance of targeting comorbid anxiety conditions and psychopathological processes; and (c) the multisystem network (MSN) model of emotional state to reveal how some of our therapeutic techniques (e.g., body focused techniques: bodily stretching paired with self-statements) bring about psychological flexibility and improvement. PMID- 22508640 TI - Toward new insights on the white blood cell differential by flow cytometry: a proof of concept study on the sepsis model. AB - BACKGROUND: We sought to evaluate, on a model of sepsis, the clinical relevance of new parameters obtained on a white blood cell (WBC) differential by flow cytometry, implemented in the routine workflow of our hematology laboratory. METHODS: A WBC with differential by flow cytometry was done on 459 patients at admission in intensive care unit. They were retrospectively categorized in having (i) infection or not or (ii) a high gravity score (severe sepsis or septic shock) or not. We analyzed by hierarchical clustering, in a multidimensional manner, 50 parameters provided by the flow cytometric platform in place of the standard seven parameters for a standard differential. RESULTS: Our approach allows to discriminate on the basis of a WBC differential (i) infected patients at admission based on a 16 parameter signature, with a concordance rate of 72.7% and a specificity of 79.9% and (ii) patients with high gravity score (septic shock or severe sepsis) at admission with a signature of eight parameters, with a concordance rate of 74.7% and a specificity of 75.9%. CONCLUSIONS: This study shows the clinical relevance of an extended WBC differential to obtain by a flow cytometer integrated into a routine hematology laboratory workflow. Development of such approach implicates the redefinition of the WBC differential by integrating new parameters. PMID- 22508641 TI - [Education for change in public health]. PMID- 22508642 TI - [Evaluation of the efficacy of a school-based program to prevent tobacco smoking among adolescents in Lombardy (Italy)]. AB - The program "Free to choose" was a school-based program aimed at encouraging secondary school students to lead healthy lifestyles and free from tobacco smoke. The project was part of a wider project named "Free from tobacco smoke", implemented in kindergarten, elementary and secondary schools in Lombardy (Italy). The "Free to choose" program was a controlled, non randomized study involving 2,145 subjects aged 16 years, of whom 1,063 participated in the activities laid out by the program (treatment group) and 1,082 only completed the questionnaires (control group). The program did not achieve the aim of reducing the number of subjects who start smoking. However, an increased awareness of the risks of smoking was observed among "treated" subjects as well as an increased number of non smokers who intend to refuse a cigarette if they were offered one. PMID- 22508643 TI - [Antibiotic resistance as a public health problem: the case of genital mycoplasmoses]. AB - Antibiotic resistance is an emerging public health problem especially due to the continuous use of antibiotics that selects more aggressive and resistant species. In the present study the authors determined the antibiotic sensitivity of 128 Mycoplasma hominis strains obtained from urethral swabs of male patients (mean age 36 years). The Mycoplasma IST 2 strip was used to test antibiotic susceptibility: 88% of analysed strains were found to be resistant to erythromycin and azithromycin, 75% to clarithromycin, 50% to ofloxacin and ciprofloxacin, and 12% to tetracycline. All strains were susceptible to josamycin, doxycycline and pristinamycin. Results were comparable to those of a recent study by Savarino-Mattei which also showed high resistance of M hominis to macrolide antibiotics and to ciprofloxacin and susceptibility to tetracyclines. Doxycycline is currently the antibiotic of first choice for treating M hominis infections. PMID- 22508644 TI - [When health "sells": presence and characteristics of health-related advertising in the Italian press]. AB - The authors evaluated the amount of health-related advertising that appeared in major Italian newspapers and magazines during the months of July 2009 and November 2009. Advertisements related to health (as defined by the World Health Organization) were found to be widely present in the Italian press. Health promotion messages given by health institutions must therefore compete with the above advertisements that deal with health issues usually for purely commercial purposes. PMID- 22508645 TI - Foodborne outbreaks surveillance in the Piedmont Region, Italy (2002-2009). AB - BACKGROUND: this article summarises the results of eight years (2002-2009) of investigations on food borne disease outbreaks carried out the Regional Agency for Public Health in Piedmont, which is an Italian Region (4,432,571 citizens, 2008). METHODS: the investigations were conducted as cohort studies supported by laboratory analysis of: food and patients. The data were reported by general practitioners and hospital physicians, and were collected, evaluated and recorded in 22 Hospitals. RESULTS: it recorded 803 outbreaks of food borne disease, of which 177 mushroom outbreaks with 318 ill people and 499 outbreaks for all the others agents with 3,381 ill people. The maximum prevalence was 15.7/100,000 (2004). The most important causes for numbers of ill people have been (2002 2009): salmonellosis (34%, 1,250/3,699), mushroom poisoning (9%, 318/3,699), Escherichia coli (8%, 228/3,699), Staphyilococcus (6%, 209/3,699), virus (5%, 198/3,699), Clostridium perfringens (4%, 154/3,699), Bacillus cereus (2.1%, 76/3,699), scombrotoxin (1.8%, 65/3,699). 303 out of 304 mushrooms outbreaks occurred from consumers that picking mushrooms themselves to eat in private homes and for all others agents: 57% of 499 the outbreaks occurred in private homes, 27% in restaurants, 6% in canteens, but 39% of 3,381 ill people had eaten in restaurants and other public food facilities, 32% in private homes and 24% in canteens. After mushrooms the eggs (75 outbreaks) were the most important food recognized. CONCLUSION: the theoretical maximum prevalence which can be hypothesized with this data in Piedmont (2002-2009) is 141/100,000 (sum of the maximum prevalence recorded at least in one Piedmont Hospital district). PMID- 22508646 TI - [Mortality among the population living near the municipal solid waste landfill site in Barengo (Italy)]. AB - A municipal solid waste landfill site is present in Barengo (northern Italy). The site is located in the centre of an area that includes eight towns: Barengo, Cavaglietto, Momo, Cavaglio, Briona, Vaprio and Fara Sizzano. The total population of the area is 11,122. The authors carried out an analysis of routine mortality data in order to identify any excess mortality in the area. Standardised mortality ratios by sex and cause of death were calculated. The Piemonte regional population and the population of the province of Novara were used as standard populations. Overall mortality data for the years 2000 to 2009 showed excess mortality in both sexes for cardiovascular disease, gastrointestinal disease, nervous system and respiratory system disorders. The frequency of Alzheimer's disease, amyotrophic lateral sclerosis and certain tumours should be monitored. PMID- 22508647 TI - [Online communication regarding health promotion and protection: the public health perspective]. AB - Currently web health portals are moving away from providing institutional and administrative types of information towards a more interactive type of communication focused on providing citizens and health care professionals various services associated with health promotion and on facilitating access to healthcare services. The aim of this study was to provide guidance in the planning and conduction of online health promotion and protection communication activities that will contribute to the process of community empowerment repeatedly called upon by the WHO. For this purpose, the authors conducted an analysis of the epidemiology of the determinants of health and disease in Italy as well as two systematic revisions of the literature regarding web-based health information needs of citizens and the efficacy of health promotion and preventative interventions administered via the internet. Although current scientific evidence suggests that some interventions (e.g. expert systems or tailored interventions) are more effective with respect to others (e.g. online support groups or other types of interventions), common sense suggests that public health computer platforms such as the " citizens' channel" of the Ministry of Health web portal should implement hybrid models, i.e. models that contain various types of interventions, and should provide access to both general information and to interactive and personalized programs. PMID- 22508648 TI - [Recommendations and Italian standards for setting safe staff nursing levels in hospitals: results of a consensus conference]. AB - Nurse staffing levels have always been an issue and the optimal level and mix of nurses required to deliver quality care as cost-effectively as possible continues to be discussed at both national and international levels. In Italy, a network of experts rom ten local health and hospital authorities was set up in June 2010. The, main objectives of the network were to define, validate and approve a panel of relevant indicators, identify minimum standards of safety and develop recommendations to guide decision-making regarding hospital nurse staffing levels. The indicators and recommendations developed by the network are presented in this paper. PMID- 22508649 TI - [Tuberculosis and immigration: criticality and possible remedial actions]. AB - The conditions of social and environmental degradation of immigrants in the host country cause an increase of tuberculosis disease and infectivity risk. Without an effective vaccine, difficulties in accessing treatment and diagnosis services represent the emergency to face. Present world situation imposes a revision of the guidelines for disease control, looking at the critical aspects, by implementing surveillance systems, with the aim of identifying and treating tuberculosis cases in order to reduce the risk of spreading. PMID- 22508650 TI - Flow cytometry-based assessment of mitoxantrone efflux from leukemic blasts varies with response to induction chemotherapy in acute myeloid leukemia. AB - BACKGROUND: Accurate prediction of chemotherapy drug resistance would aid treatment decisions in acute myeloid leukemia (AML). The aim of this study was to determine if mitoxantrone efflux from AML blasts would correlate with response to induction chemotherapy. METHODS: Flow cytometry was used to measure the median fluorescence intensity (MFI) for AML blasts incubated with mitoxantrone [an ATP binding cassette (ABC) transporter substrate] with or without coincubation with cyclosporine A (a broad-spectrum inhibitor of ABC transporters) and a ratio (MFIR) between the inhibited and uninhibited MFI was calculated. RESULTS: Among 174 AML patient blast samples, the mean MFIR for complete remission (CR) patients was lower than that obtained for induction failure (IF) patients (mean MFIR +/- SD 1.62 +/- 0.53 for CR after one cycle of chemotherapy vs. 2.22 +/- 1.29 for CR after two cycles and 2.59 +/- 0.98 for IF, P < 0.001). Logistic regression analysis determined 2.45 as the MFIR threshold above which 29% of patients achieved CR vs. a CR rate of 84% when the MFIR was <= 2.45 (P < 0.0001). In AML patients with normal karyotype (n = 80), CR was obtained for 33% of patients with an MFIR > 2.45 vs. 89% of those with MFIR <= 2.45 (P < 0.0001). In patients > age 60 (n = 77), 30% vs. 87% of those with MFIR > vs. <= 2.45 achieved CR (P < 0.0001). CONCLUSIONS: This assay of ABC transporter function can potentially predict response to induction chemotherapy in AML. PMID- 22508651 TI - Erythropoietin and erythropoiesis stimulating agents. AB - Erythropoietin (EPO) is the main hormonal regulator of red blood cell production. Recombinant EPO has become the leading drug for treatment of anaemia from a variety of causes; however, it is sometimes misused in sport with the aim of improving performance and endurance. This paper presents an introductory overview of EPO, its receptor, and a variety of recombinant human EPOs/erythropoiesis stimulating agents (ESAs) available on the market (e.g. epoetins and their long acting analogs--darbepoetin alfa and continuous erythropoiesis receptor activator). Recent efforts to improve on EPO's pharmaceutical properties and to develop novel replacement products are also presented. In most cases, these efforts have emphasized a reduction in frequency of injections or complete elimination of intravenous or subcutaneous injections of the hormone (biosimilars, EPO mimetic peptides, fusion proteins, endogenous EPO gene activators and gene doping). Isoelectric focusing (IEF) combined with double immunoblotting can detect the subtle differences in glycosylation/sialylation, enabling differentiation among endogenous and recombinant EPO analogues. This method, using the highly sensitive anti-EPO monoclonal antibody AE7A5, has been accepted internationally as one of the methods for detecting misuse of ESAs in sport. PMID- 22508652 TI - Comparison of patients' and clinicians' views of the therapeutic relationship: a pilot project. AB - OBJECTIVE: Our aim was to find out whether psychiatrists' views of the quality of the therapeutic relationship were shared by their patients, and to ascertain a feasible way to explore these relationships routinely. METHOD: Sixty-one outpatients selected by two receptionists completed the Helping Alliance Scale (HAS), client version and the Relationship Questionnaire. The two participating psychiatrists were not involved in patient selection and were blind to patients' responses. They recorded their view of the relationships using the clinician version of HAS. The Big Five Inventory and Relationship Questionnaire were also utilized. Without identifying patients, each psychiatrist analysed the data of the other clinician. RESULTS: Both clinicians had an agreement rate above 75%. The differences in the details reflected gender and personality differences. There was no benchmark with which to compare these results. CONCLUSIONS: Assessing and recording the therapeutic relationship in community practice is feasible and provides invaluable knowledge. The next challenge is to consider whether and how this could be done routinely. PMID- 22508653 TI - An Acute Recovery Unit: the first 18 months. AB - OBJECTIVES: To describe a new type of acute inpatient unit, the Acute Recovery Unit, at the Concord Centre for Mental Health, Sydney and to report patient characteristics and outcome data for the first 18 months of operation. METHODS: The mission, values, principles of care and operation of the Acute Recovery Unit are presented, including the lessons from a review of the first 18 months of operation. The specialist assessment procedure, academic detailing and range of specialist interventions are described. RESULTS: Clinical outcome measures including the Health of the Nation Outcome Scale, Multidimensional Incomplete Recovery - Clinical Global Index and community tenure time post-discharge are presented. CONCLUSIONS: The Acute Recovery Unit is an important component of the range of services required at a regional level to respond to those who will develop treatment refractory mental illness. PMID- 22508654 TI - Detection of EPO gene doping in blood. AB - Gene doping--or the abuse of gene therapy--will continue to threaten the sports world. History has shown that progress in medical research is likely to be abused in order to enhance human performance. In this review, we critically discuss the progress and the risks associated with the field of erythropoietin (EPO) gene therapy and its applicability to EPO gene doping. We present typical vector systems that are employed in ex vivo and in vivo gene therapy trials. Due to associated risks, gene doping is not a feasible alternative to conventional EPO or blood doping at this time. Nevertheless, it is well described that about half of the elite athlete population is in principle willing to risk its health to gain a competitive advantage. This includes the use of technologies that lack safety approval. Sophisticated detection approaches are a prerequisite for prevention of unapproved and uncontrolled use of gene therapy technology. In this review, we present current detection approaches for EPO gene doping, with a focus on blood-based direct and indirect approaches. Gene doping is detectable in principle, and recent DNA-based detection strategies enable long-term detection of transgenic DNA (tDNA) following in vivo gene transfer. PMID- 22508658 TI - Quantification of active ingredients in suppositories by FT-Raman spectroscopy. AB - An efficient method for the quantitative determination of acetaminophen (AAP) and diclofenac sodium (DS) in commercial suppositories based on partial least squares (PLS) treatment of FT-Raman spectra is described. The relative standard errors of prediction (RSEP) were calculated for calibration and validation data sets to evaluate the quality of the constructed models. In the case of DS determination, RSEP error values of 1.9 % and 2.3 % for the calibration and validation data sets, respectively, were found. For AAP these errors amounted to 1.6-2.3 % and 1.8-2.8 %, respectively, for the different calibration models. Four commercial preparations containing 5, 12.5, 16.7 and 33.3 % (w/w) AAP and one containing 5 % (w/w) DS were successfully quantified using the developed models. Concentrations derived from the developed models correlated strongly with the declared values and yielded recoveries of 99.4-100.2 % and 99.6 % for AAP and DS, respectively. The proposed procedure can be used as a fast, economic and reliable method for quantification of the active pharmaceutical ingredients in suppositories. PMID- 22508659 TI - Thirty-femtogram detection of iron in mammalian cells. AB - Inorganic nanomaterials and particles with enhanced optical, mechanical, or magnetic attributes are currently being developed for a wide range of applications. Safety issues have developed however concerning their potential cyto- and genotoxicity. For in vivo and in vitro experimentations, recent developments have heightened the need for simple and facile methods to measure the amount of nanoparticles taken up by cells or tissues. In this work, a rapid and highly sensitive method for quantifying the uptake of iron oxide nanoparticles in mammalian cells is reported. The approach exploits the digestion of incubated cells with concentrated hydrochloric acid reactant and a colorimetric-based UV-visible absorption technique. The technique allows the detection of iron in cells over 4 decades in masses from 0.03 to 300 picograms per cell. Applied on particles of different surface chemistry and sizes, the protocol demonstrates that the coating is the key parameter in the nanoparticle/cell interactions. The data are corroborated by scanning and transmission electron microscopy, and the results stress the importance of resiliently adsorbed nanoparticles at the plasma membrane. PMID- 22508660 TI - Resonant laser-induced formation of double-walled carbon nanotubes from peapods under ambient conditions. AB - The selective excitation of fullerenes encapsulated in single-walled carbon nanotubes (SWCNTs) is carried out by irradiating them using a UV laser, the wavelength of which corresponds exactly to their maximum of absorption. Under such conditions, fullerenes strongly absorb the laser energy, open, and break, while the containing SWCNT merely acts as both a nanoreactor and a mold which is only weakly heated by the laser. The containing tube confines the fullerene fragments, promotes their reconstruction into an inner tube, and protects them from air oxidation. This leads to the overall formation of double-walled carbon nanotubes (DWCNTs). The transformation is found to strongly depend on the laser irradiance and dose. This proves that the related mechanism is a multiphoton photolysis, different from the previous heat-induced transformation attempts found in the literature, whether the heat is produced by means of a thermostat, infrared laser, or nonresonant UV laser. The actual peapod-to-DWCNT transformation is monitored by Raman spectroscopy and high-resolution transmission electron microscopy. PMID- 22508661 TI - Impaired expression of genes involved in the butyrate oxidation pathway in Crohn's disease patients. PMID- 22508662 TI - Gynecologic cytology on conventional and liquid-based preparations: a comprehensive review of similarities and differences. AB - Liquid-based preparations (LBPs) have largely replaced conventional Papanicolaou smears (CPS) for cervical samples in the United States and in many other industrialized countries. The two FDA-approved LBP currently in use include ThinPrep (TP), (Hologic Inc., Bedford, MA) and SurePath (SP), (BD Diagnostic, Burlington, NC). Split-sample and direct-to-vial studies have shown that LBPs show an overall improvement in sample collection and processing, reduce artifacts that interfere in diagnosis, are more sensitive, can be utilized for ancillary tests and are a cost-effective replacement for CPS. Comparative analyses of diagnostic accuracy indicate that LBPs perform at least as well as CPS. However, the added advantages of standardized, automated preparations and screening, reduced unsatisfactory rate, improved specimen adequacy and ability to perform human papillomavirus (HPV) test, are enough to continue use of LBP. The cytologic features in LBP are similar to CPS with subtle differences, particularly in background information. There are also subtle differences between the two LBPs, SP and TP, which are reflective of different sampling devices, collection media, and processing techniques. Architecturally, LBP shows smaller cell clusters and sheets and more dyscohesion. Cytologically, enhanced nuclear features and smaller cell size are more prominent. Advances in liquid-based Papanicolaou's (Pap) test have lead to well-defined patient management guidelines by the American Society for Colposcopy and Cervical Pathology. Herein, we review these aspects of Pap test including, morphology, automation, ancillary tests (HPV and immunochemistry), pertinent QA/QC monitors, patient management guidelines, and review of pertinent literature. PMID- 22508663 TI - Impact of Medicare Part D for Medicare-age adults with arthritis: prescription use, prescription expenditures, and medical spending from 2005 to 2008. AB - OBJECTIVE: To evaluate the impact of Medicare Part D on medication utilization, drug expenditures, and medical expenditures in patients with arthritis. METHODS: This was a retrospective study using a national sample of 2,484 Medicare-eligible beneficiaries with arthritis from the pooled Medical Expenditure Panel Survey 2005-2008 data. Quantile regression was used to estimate the following outcomes: 1) number of prescription fills, 2) total drug expenditures, 3) out-of-pocket (OOP) drug expenditures, 4) Medicare-paid drug expenditures, 5) total medical expenditures (including all payments for inpatient/outpatient care, prescription drugs, and other medical services), 6) OOP medical expenditures, and 7) Medicare paid medical expenditures. For each outcome variable, the 50th, 75th, and 90th percentiles were estimated, adjusting for demographics and comorbidity. All expenditures were inflation adjusted to 2008 dollars. RESULTS: From 2005 to 2008, the adjusted median annual number of prescription fills increased by 4.2 (14.6% change), from 28.4 to 32.6. The adjusted median OOP drug expenditures and OOP medical expenditures decreased by $151 (25.2% change) and $197 (17.3% change), respectively. The adjusted median Medicare-paid drug and medical expenditures increased by $366 and $896 (39.5% change), respectively. The adjusted total prescription expenditures increased by $845 (25.3% change) at the 75th percentile and by $1,194 (22.0% change) at the 90th percentile. The adjusted total medical expenditures did not change significantly. CONCLUSION: Medicare Part D resulted in increased medication utilization and significant reductions in OOP drug and OOP medical expenditures among beneficiaries with arthritis 3 years after its implementation. Part D was not associated with significant differences in total medical spending. PMID- 22508664 TI - Improved photodynamic cancer treatment by folate-conjugated polymeric micelles in a KB xenografted animal model. AB - Photodynamic therapy (PDT) is a light-induced chemical reaction that produces localized tissue damage for the treatment of cancers and various nonmalignant conditions. In the clinic, patients treated with PDT should be kept away from direct sunlight or strong indoor lighting to avoid skin phototoxicity. In a previous study, it was demonstrated that the skin phototoxicity of meta tetra(hydroxyphenyl)chlorin (m-THPC), a photosensitizer used in the clinic, can be significantly reduced after micellar encapsulation; however, no improvement in antitumor efficacy was observed. In this work, a folate-conjugated polymeric m THPC delivery system is developed for improving tumor targeting of the photosensitizer, preventing photodamage to the healthy tissue, and increasing the effectiveness of the photosensitizers. The results demonstrate that folate conjugated m-THPC-loaded micelles with particle sizes around 100 nm are taken up and accumulated by folate receptor-overexpressed KB cells in vitro and in vivo, and their PDT has no significant adverse effects on the body weight of mice. After an extended delivery time, a single dose of folate-conjugated m-THPC-loaded micelles has higher antitumor effects (tumor growth inhibition = 92%) through inhibition of cell proliferation and reduction of vessel density than free m-THPC or m-THPC-loaded micelles at an equivalent m-THPC concentration of 0.3 mg kg(-1) after irradiation. Furthermore, folate-conjugated m-THPC-loaded micelles at only 0.2 mg kg(-1) m-THPC have a similar antitumor efficacy to m-THPC or m-THPC loaded micelles with the m-THPC concentration at 0.3 mg kg(-1) , which indicates that the folate conjugation on the micellar photosensitizer apparently reduces the requirement of m-THPC for PDT. Thus, folate-conjugated m-THPC-loaded micelles with improved selectivity via folate-folate receptor interactions have the potential to reduce, not only the skin photosensitivity, but also the drug dose requirement for clinical PDT. PMID- 22508665 TI - Multidrug resistance is common in Escherichia coli associated with ileal Crohn's disease. AB - BACKGROUND: Escherichia coli is increasingly implicated in the pathogenesis of ileal Crohn's disease (ICD), offering a potential therapeutic target for disease management. Empirical antimicrobial targeting of ileal E. coli has advantages of economy and speed of implementation, but relies on uniform susceptibility of E. coli to routinely selected antimicrobials to avoid apparent treatment failure. Therefore, we examined the susceptibility of ileal E. coli to such antimicrobials. METHODS: E. coli from 32 patients with ICD and 28 with normal ileum (NI) were characterized by phylogroup, pathotype, antimicrobial susceptibility, and presence of antimicrobial resistance genes. RESULTS: In all, 17/32 ICD and 12/28 NI patients harbored >= 1 E. coli strain; 10/24 E. coli strains from ICD and 2/14 from NI were nonsuscepti-ble to >= 1 antimicrobial in >= 3 categories (multidrug-resistant). Resistance to amoxicillin/clavulanic-acid, cefoxitin, chloramphenicol, ciprofloxa-cin, gentamicin, and rifaximin was restricted to ICD, with 10/24 strains from 8/17 patients resistant to ciprofloxacin or rifaximin (P < 0.01). Adherent-invasive E. coli (AIEC) were isolated from 8/32 ICD and 5/28 NI, and accounted for 54% and 43% of E. coli strains in these groups. In all, 8/13 AIEC strains from ICD (6/8 patients) versus 2/6 NI (2/5 patients) showed resistance to the macrophage-penetrating antimicrobials ciprofloxacin, clarithromycin, rifampicin, tetracycline, and trimethoprim/sulfamethoxazole. Resistance was associated with tetA, tetB, tetC, bla-(TEM), bla(oxa)-1, sulI, sulII, dhfrI, dhfrVII, ant(3")-Ia, and catI genes and prior use of rifaximin (P < 0.01). CONCLUSIONS: ICD-associated E. coli frequently manifest resistance to commonly used antimicrobials. Clinical trials of antimicrobials against E. coli in ICD that are informed by susceptibility testing, rather than empirical selection, are more likely to demonstrate valid outcomes of such therapy. PMID- 22508666 TI - Site-specific cytomorphology of disseminated PC-3 prostate cancer cells visualized in vivo with fluorescent proteins. AB - Circulating tumor cells (CTC) may reach multiple organ sites. However, CTC seeding and growth in distant organs is not random. Each metastatic site may contain a specific subpopulation of the original metastatic tumor capable of growing at that site. The fluorescent orthotopic prostate cancer model (PC-3-GFP) model was used for immunomagnetic capture of CTC. The captured CTC were efficiently cultivated in vitro. PC-3-GFP cells were also isolated from various metastatic sites, grown in vitro and examined under fluorescence microscopy. The differential morphology was compared of primary tumor cells, CTC and disseminated (DTC) from multiple metastatic sites, from nude mice with orthotopic PC-3-GFP. The cultured captured CTC and DTC from various organs have distinctive morphologies. Distinct cancer cell morphologies were observed at different metastatic sites as well as among CTC. The distinct morphologies were maintained during in vitro culture. The results demonstrate extensive tumor heterogeneity that could account for the widely different behavior of cancer cells in a single tumor. Further hetereogeneity testing would be a big promise for personalizing the cancer treatment in the future. PMID- 22508667 TI - Laparoscopic colorectal surgery: a better look into the latest trends. AB - BACKGROUND: The latest trends of laparoscopic colorectal surgery (LCRS) after the introduction of International Classification of Diseases, Ninth Revision laparoscopic procedure codes in 2008 remains unknown. This study evaluates LCRS trends before and after the application of specific codes for LCRS. DESIGN: Retrospective analysis of elective surgery for colon cancer, rectal cancer, and diverticulitis using Nationwide Inpatient Sample data from 2007 and 2009. MAIN OUTCOME MEASURE: Primary outcome measures included in-hospital mortality, length of stay, and total charge. RESULTS: A total of 126 921 patients in 2007 and 117 177 patients in 2009 underwent colorectal surgery. Laparoscopic colorectal surgery increased dramatically from 13.8% in 2007 to 42.6% in 2009 (P.01). This trendwas disease and procedure specific. When compared with 2007, patients who underwent LCRS in 2009 had lower conversion rates (14.8% vs 32.1%, P.001). In 2009, LCRS had lower in-hospital mortality (0.5% vs 1.1%, P.001) and a shorter length of hospital stay (5 vs 6 days, P.001) compared with open surgery. In 2009, when compared with successful LCRS, conversion to open surgery was associated with a longer length of hospital stay (6 vs 5 days, P.01), increased hospital charges, and increased mortality (0.7% vs 0.5%, P.01). CONCLUSION: The marked increase in LCRS when comparing these 2 years is unlikely only due to the changing practice of colorectal surgery but brings into question the accuracy of data prior to 2009. Our report of Nationwide Inpatient Sample 2009 data represents the most accurate reflection of the use of LCRS in the United States. These data can serve as a benchmark for future comparative studies. PMID- 22508668 TI - Perioperative risk assessment in robotic general surgery: lessons learned from 884 cases at a single institution. AB - OBJECTIVE: To assess factors associated with morbidity and mortality following the use of robotics in general surgery. DESIGN: Case series. SETTING: University of Illinois at Chicago. PATIENTS AND INTERVENTION: Eight hundred eighty-four consecutive patients who underwent a robotic procedure in our institution between April 2007 and July 2010. MAIN OUTCOMES MEASURES: Perioperative morbidity and mortality. RESULTS: During the study period, 884 patients underwent a robotic procedure. The conversion rate was 2%, the mortality rate was 0.5%, and the overall postoperative morbidity rate was 16.7%. The reoperation rate was 2.4%. Mean length of stay was 4.5 days (range, 0.2-113 days). In univariate analysis, several factors were associated with increased morbidity and included either patient-related (cardiovascular and renal comorbidities, American Society of Anesthesiologists score >= 3, body mass index [calculated as weight in kilograms divided by height in meters squared] <30, age >= 70 years, and malignant disease) or procedure-related (blood loss >= 500 mL, transfusion, multiquadrant operation, and advanced procedure) factors. In multivariate analysis, advanced procedure, multiquadrant surgery, malignant disease, body mass index of less than 30, hypertension, and transfusion were factors significantly associated with a higher risk for complications. American Society of Anesthesiologists score of 3 or greater, age 70 years or older, cardiovascular comorbidity, and blood loss of 500 mL or more were also associated with increased risk for mortality. CONCLUSIONS: Use of the robotic approach for general surgery can be achieved safely with low morbidity and mortality. Several risk factors have been identified as independent causes for higher morbidity and mortality. These can be used to identify patients at risk before and during the surgery and, in the future, to develop a scoring system for the use of robotic general surgery PMID- 22508670 TI - Bariatric surgery as a highly effective intervention for diabetes: news flash or preaching to the choir?: comments on "obesity, type 2 diabetes mellitus, and other comorbidities". PMID- 22508669 TI - Overcoming the challenges of single-incision cholecystectomy with robotic single site technology. AB - OBJECTIVE: To analyze the preliminary experience with the new da Vinci single site technology for cholecystectomy. HYPOTHESIS: Single-incision laparoscopic cholecystectomy is technically challenging and a related learning curve clearly exists. A novel approved robotic single-port platform has recently been introduced. This technology may help overcome some of the limitations of manual single-incision surgery relating to triangulation of instruments, ergonomics, and surgical exposure. DESIGN: A prospective longitudinal observational study was conducted on 100 consecutive da Vinci single-site cholecystectomies. SETTING: Five Italian centers of robotic general surgery. MAIN OUTCOME MEASURES: Primary end points were feasibility without conversion and the absence of major complications. Operative times were analyzed to define the learning curve using a mixed regression model.A questionnaire collected the opinions of the surgeons involved in using the new technique. RESULTS: Two patients underwent conversion. No major intraoperative complications occurred, but there were 12 minor incidents (7 ruptures of the gallbladder and 5 cases of minor bleeding from the gallbladder bed). Mean (SD) total operative time was 71 (19) minutes, with a mean (SD) console time of 32 (13) minutes. No significant reduction in the operative times was observed with the increasing of each surgeon's experience. The technique was judged more complex than standard 4-port laparoscopy but easier than single incision laparoscopy. CONCLUSIONS: Da Vinci single-site cholecystectomy is an easy and safe procedure for expert robotic surgeons. It allows the quick overcoming of the learning curve typical of single-incision laparoscopic surgery and may potentially increase the safety of this approach. PMID- 22508671 TI - Obesity, type 2 diabetes mellitus, and other comorbidities: a prospective cohort study of laparoscopic sleeve gastrectomy vs medical treatment. AB - OBJECTIVE: To compare the effect of sleeve gastrectomy vs medical therapy on type 2 diabetes mellitus and other obesity-related comorbidities (obstructive sleep apnea syndrome, hypertension, and dyslipidemia) in prospectively enrolled and matched obese patients with type 2 diabetes. DESIGN: A prospective cohort study. Morbidly obese patients with type 2 diabetes who either underwent sleeve gastrectomy or conventional therapy were followed up and assessed for their diabetic state and other comorbidities every 3 months for 18 months. SETTING: Centre for the Surgical-Medical Treatment of Morbid Obesity, Policlinico "Umberto I," University of Rome "Sapienza," Italy. PATIENTS: A total of 30 morbidly obese patients with type 2 diabetes who underwent sleeve gastrectomy (group A) and a total of 30 morbidly obese patients with type 2 diabetes who underwent conventional therapy (group B). RESULTS: In group A, the preoperative mean (SD) body mass index, fasting plasma glucose level, and hemoglobin A1c level were 41.3 (6.0), 166.6 (68.1) mg/dL, and 7.9% (2.1%), respectively, and, at 18 months, these values were 28.3 (5.4), 96.2 (29.4) mg/dL, and 6.0% (1.5%), respectively. For 80% of patients, diabetes was resolved. With regard to other comorbidities, the prevalence of obstructive sleep apnea syndrome dropped from 50% to 10%, and patients reduced significantly their use of medication for hypertension and dyslipidemia. In group B, the preoperative mean (SD) body mass index, fasting plasma glucose level, and hemoglobin A1c level were 39.0 (5.5), 183.7 (63.5) mg/dL, and 8.1% (1.7%), respectively, and, at 18 months, these values were 39.8 (5.0), 150 (48) mg/dL, and 7.1% (1.3%), respectively. All patients remained diabetic and continued or increased their level of hypoglycemic therapy. With regard to other comorbidities, we observed an increase in the use of medication for hypertension and dyslipidemia, and the prevalence of obstructive sleep apnea syndrome did not change. CONCLUSIONS: This study confirms the efficacy of sleeve gastrectomy in the treatment of morbidly obese type 2 diabetic patients when compared with conventional medical treatment. PMID- 22508673 TI - Adenomatoid nodules are the main cause for discrepant histology in 234 thyroid fine-needle aspirates reported as follicular neoplasm. AB - According to several large studies, the surgical pathologist renders a non neoplastic diagnosis in ~20-40% of thyroid fine-needle aspiration (FNA) cases reported as follicular neoplasm. This study analyzes the cause of this poor correlation between cytology and histology. Cases consisting of oncocytic (Hurthle) cells were excluded from study. During the study period from January 1996 to April 2010, histologic follow-up was available for 234 of 670 cases (34.9%) reported as follicular neoplasm on ultrasound-guided thyroid FNA. Sonographic and Doppler data were available in all cases and included nodule location, size, echogenicity, and vascularity. Of the 234 aspirates with follow up, surgical pathology reported 130 cases (55.6%) of follicular adenoma, 15 cases (6.4%) of follicular carcinoma, 14 cases (6.1%) of follicular variant of papillary carcinoma, and 75 cases (32.3%) of nodular goiter. Recuts of those index nodules reported as nodular goiter were examined independently by two pathologists using the 2* objective lens. Adenomatoid nodule was defined as an insufficiently encapsulated "blue" nodule of increased nuclear density when compared with the surrounding thyroid. Of the 75 cases reported as nodular goiter, 60 index nodules (80%) fulfilled the described criteria for adenomatoid nodule, while 15 did not. In conclusion, adenomatoid nodules are the main cause of poor histologic correlation with follicular neoplasm reported by FNA. If "increased nuclear density at scanning magnification" were adopted by surgical pathologists as the major diagnostic criterion for follicular adenoma rather than encapsulation, noncorrelated cases would be reduced from 32 to 6.4%. PMID- 22508674 TI - Cytological cell blocks: Predictors of squamous cell carcinoma and adenocarcinoma subtypes. AB - Fine needle aspirations biopsies, CT-guided and endobronchial ultrasound-guided, as a mode of diagnosing and/or staging lung carcinoma, are becoming more frequent. Also, there is greater necessity for classification of lung cancers into subcategories of squamous cell carcinoma and adenocarcinoma for appropriate management. Cytomorphology, based on smears alone, allows this classification in many instances. The aim of the current study was to explore the potential of cell blocks to increase the specificity of diagnosis. The morphological characteristics of sixty-two lung carcinomas were examined. Less well differentiated squamous cell carcinomas were more readily classified as such on cell blocks. Likewise, cell block sections with architectural patterns including strips of cells, papillae and nests of cells correlated with bronchioalveolar, papillary and acinar/mixed subtypes of adenocarcinoma on follow-up histology. In conclusion, cell blocks provide additional morphological clues and material for ancillary studies for classification of lung carcinomas. PMID- 22508672 TI - Predictors of lymph node count in colorectal cancer resections: data from US nationwide prospective cohort studies. AB - OBJECTIVE: To identify factors that influence the total and negative lymph node counts in colorectal cancer resection specimens independent of pathologists and surgeons. DESIGN: We used multivariate negative binomial regression. Covariates included age, sex, body mass index, family history of colorectal carcinoma, year of diagnosis, hospital setting, tumor location, resected colorectal length (specimen length), tumor size, circumferential growth, TNM stage, lymphocytic reactions and other pathological features, and tumor molecular features (microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element 1 [LINE-1] methylation, and BRAF, KRAS, and PIK3CA mutations). SETTING: Two US nationwide prospective cohort studies. PATIENTS: Patients with rectal and colon cancer (N=918). MAIN OUTCOME MEASURES: The negative and total node counts (continuous). RESULTS: Specimen length, tumor size, ascending colon location, T3N0M0 stage, and year of diagnosis were positively associated with the negative node count (all P.002). Mutation of KRAS might also be positively associated with the negative node count (P=.03; borderline significance considering multiple hypothesis testing). Among node-negative (stages I and II) cases, specimen length, tumor size, and ascending colon location remained significantly associated with the node count (all P.002), and PIK3CA and KRAS mutations might also be positively associated (P=.03 and P=.049, respectively, with borderline significance). CONCLUSIONS: This molecular pathological epidemiology study shows that specimen length, tumor size, tumor location, TNM stage, and year of diagnosis are operator-independent predictors of the lymph node count. These crucial variables should be examined in any future evaluation of the adequacy of lymph node harvest and nodal staging when devising individualized treatment plans for patients with colorectal cancer. PMID- 22508675 TI - Thyroid follicular lesion of undetermined significance: Evaluation of the risk of malignancy using the two-tier sub-classification. AB - The Bethesda 2007 Thyroid Cytology Classification defines follicular lesion of undetermined significance as a heterogeneous category of cases that are not convincingly benign nor sufficiently atypical for a diagnosis of follicular neoplasm or suspicious for malignancy. In our institution, we refer to these cases as indeterminate, and they are further sub-classified into two: (1) low cellularity with predominant microfollicular architecture and absence of colloid (IN(a)) and (2) nuclear features not characteristic of benign lesions (nuclear atypia) (IN(b)). We reviewed these indeterminate cases to document the follow-up trend using this two-tier classification. A search of the cytology records was performed for the period between January 2008 and June 2009. All thyroid fine needle aspiration (FNA) cases were reviewed and the ones diagnosed as indeterminate were identified. Correlating follow-up FNA and/or surgical pathology reports were reviewed. The percentage of cases showing a malignancy was calculated. One hundred and seventy-one indeterminate cases were identified, representing 2.8% of the 6,205 thyroid FNA cases examined during the time under review (107 IN(a), 64 IN(b)). Records of follow-up procedures were available in 106 (61%) cases. Malignancy was identified in 27% of all indeterminate cases. This was disproportionately more in the IN(b) (56%) compared to the IN(a) (7%) cases. A diagnosis of "IN(a)" does not carry the same implication as that of "IN(b)". The IN(b) category needs a more aggressive follow-up than the IN(a) category and may justify an immediate referral for lobectomy. Despite the vague morphologic criteria for this diagnostic category, the indeterminate rate remains relatively low and falls within the NCI recommendation (<7%). PMID- 22508676 TI - Controlling the formation of DNA origami structures with external signals. AB - Degradable Newkome-type and polylysine dendrons functionalized with spermine surface units are used to control the formation of DNA origami structures. The intact dendrons form polyelectrolyte complexes with the scaffold strands, therefore blocking the origami formation. Degradation of the dendron with an optical trigger or chemical reduction leads to the release of the DNA scaffold and efficient formation of the desired origami structure. These results provide new insights towards realizing responsive materials with DNA origami. PMID- 22508677 TI - Associations between genetic variants in the IRGM gene and inflammatory bowel diseases in the Korean population. AB - BACKGROUND: Recent European ancestry genome-wide association studies have identified genetic variants of IRGM as significant susceptibility loci for Crohn's disease (CD). Therefore, we investigated whether genetic variants of IRGM confer genetic susceptibility to CD or ulcerative colitis (UC) and evaluated the genotype-phenotype associations in the Korean population. METHODS: This study included 510 inflammatory bowel disease (IBD) patients (253 patients with CD and 257 with UC) and 520 healthy controls in Koreans. Initially, we performed direct sequencing analysis to identify unique IRGM single nucleotide polymorphisms (SNPs). Three selected haplotype-tagging SNPs and one risk locus (rs72553867, rs10065172, rs4958847, and rs12654043) within the IRGM were then geno-typed in patients and controls. RESULTS: IRGM SNP rs10065172 was significantly associated with CD susceptibility in terms of allelic frequency (P = 0.004; odds ratio [OR] = 1.42) and genotype frequency (dominant model, P = 0.008; OR = 1.62). We also found a relationship between SNP rs72553867 and CD susceptibility in the analysis of allelic frequency (P = 0.0117; OR = 0.67) and genotype frequency (dominant model, P = 0.002; OR = 0.55). In addition, we observed that the association of CD with rs10065172 became stronger in patients with younger age at diagnosis (<= 20 years) or male gender. However, there was no significant association between the four SNPs and UC susceptibility. CONCLUSIONS: This is the first study to identify SNP rs10065172 and rs72553867 in IRGM as principal CD susceptibility loci in an Asian population. PMID- 22508678 TI - FNA of thyroid granular cell tumor. AB - Granular cell tumor rarely occurs in the thyroid. This case report describes the cytologic features of a granular cell tumor seen in a fine needle aspirate obtained from a 27-year-old woman with a gradually enlarging thyroid nodule. The aspirate showed single as well as syncytial clusters of cells with abundant granular cytoplasm. The differential diagnosis in this case included granular cell tumor, Hurthle cell lesion/neoplasm, and a histiocytic reparative process. Immunohistochemical studies, including S-100 protein and CD68, performed on a cell block preparation were helpful in supporting the diagnosis. PMID- 22508679 TI - Rapid preparation of multifunctional surfaces for orthogonal ligation by microcontact chemistry. AB - Microcontact chemistry has been applied to patterned glass and silicon substrates by successive reaction of unprotected and monoprotected heterobifunctional linkers with alkene-terminated self-assembled monolayers (SAMs) to produce bi-, tri-, and tetrafunctional surfaces. Photochemical microcontact printing of an azide thiol linker followed by immobilization of an acid thiol linker on an undecenyl-terminated SAM results in a well-defined, micropatterned surface with terminal azide, acid, and alkene groups. Biologically relevant molecules (biotin, carbohydrates) have been selectively attached to the surface by means of orthogonal ligation chemistry, and the resulting microarrays display selective binding to fluorescently labeled proteins. An orthogonally addressable, tetrafunctional surface (azide, acid, alkene, and amine) can be prepared by an additional printing step of a tert-butyloxycarbonyl (Boc)-protected alkyne amine linker on the azide structures by using the copper(I)-catalyzed azide-alkyne Huisgen cycloaddition and subsequent removal of the protective group. PMID- 22508680 TI - Structural effect and mechanism of C70-carboxyfullerenes as efficient sensitizers against cancer cells. AB - Carboxyfullerenes with different adduct numbers and cage sizes are tested as photosensitizers for photodynamic therapy (PDT). The photodynamic efficiency of these carboxyfullerenes depends mainly on the cage size, C(60) versus C(70) , and to a lesser extent on the adduct numbers. In particular, malonic acid modified C(70) fullerenes are more efficient than their C(60) counterparts as photosensitizers, and the mechanism of cell death induced by C(70) carboxyfullerene under light irradiation is investigated in detail. The results indicate that cell death occurs via necrosis accompanied by membrane blebbing, which is a unique phenomenon for photosensitizer-induced cell death. Since C(70) carboxyfullerene displays an efficient PDT property and negligible dark cytotoxicity, it is promising for use in PDT applications, especially in vascular capillary diseases usually occurring under the surface. PMID- 22508681 TI - PKR-signaling in DSS-induced colitis: detrime-N-tal or prote-C-tive? PMID- 22508682 TI - Fine needle aspiration cytology in two cases of chondromyxoid fibroma of bone and review of literature. AB - We report the cytological features of two cases of chondromyxoid fibroma (CMF) confirmed by histopathology examination. First case was a 40-year-old male who presented with a foot swelling, and the second case was a 16-year-old male with a lesion at the angle of jaw. A fine needle aspiration cytology (FNAC) was performed in both the cases. In first case, a correct diagnosis of CMF could be offered on FNAC. In the second case, though the cytology diagnosis was a sarcoma considering the cytological, radiological and clinical features, the histopathological examination confirmed the same to be a CMF. The cases are being discussed to highlight the usefulness of FNAC to diagnose these uncommon benign bone lesions and the potential pitfalls in the cytological diagnosis of chondroid lesions. PMID- 22508684 TI - Following the steps of Abu al-Qasim to Bethesda and beyond: the continuing deliberations in thyroid fine-needle aspiration. PMID- 22508683 TI - Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase. AB - Copper (Cu) is a trace metal that readily gains and donates electrons, a property that renders it desirable as an enzyme cofactor but dangerous as a source of free radicals. To regulate cellular Cu metabolism, an elaborate system of chaperones and transporters has evolved, although no human Cu chaperone mutations have been described to date. We describe a child from a consanguineous family who inherited homozygous mutations in the SLC33A1, encoding an acetyl CoA transporter, and in CCS, encoding the Cu chaperone for superoxide dismutase. The CCS mutation, p.Arg163Trp, predicts substitution of a highly conserved arginine residue at position 163, with tryptophan in domain II of CCS, which interacts directly with superoxide dismutase 1 (SOD1). Biochemical analyses of the patient's fibroblasts, mammalian cell transfections, immunoprecipitation assays, and Lys7Delta (CCS homolog) yeast complementation support the pathogenicity of the mutation. Expression of CCS was reduced and binding of CCS to SOD1 impaired. As a result, this mutation causes reduced SOD1 activity and may impair other mechanisms important for normal Cu homeostasis. CCS-Arg163Trp represents the primary example of a human mutation in a gene coding for a Cu chaperone. PMID- 22508685 TI - Enteropathogenic viruses: triggers for exacerbation in IBD? A prospective cohort study using real-time quantitative polymerase chain reaction. AB - BACKGROUND: While the role of bacteria as an etiological factor triggering relapse in inflammatory bowel disease (IBD) has been studied extensively, little is known of the role of enteric viruses. We aimed to prospectively study the prevalence and risk factors for common enteropathogenic viruses in IBD patients in relation to disease activity. METHODS: IBD patients visiting the outpatient clinic of the Maastricht University Medical Center were included in a prospective cohort with a follow-up of 1 year. Every 3 months and during relapses, fecal samples, demographic, and clinical data were collected and disease activity was scored. A fecal sample from patients at baseline (Crohn's disease [CD] n = 170, ulcerative colitis [UC] n = 116) and an additional sample from a subgroup with changing disease activity during follow-up (CD n = 57, UC n = 31) were analyzed for the presence of rotavirus, norovirus GI and GII, human astrovirus, and adenovirus using quantitative polymerase chain reaction (qPCR). RESULTS: Overall viral pathogen detection, defined by the detection of at least one of the studied viruses, at baseline was 5.2% and differed neither between CD (6.5%) or UC patients (3.4%) (P = 0.20), nor between active disease (4.7%) and remission (5.5%) (P = 0.79). Within the subgroup of patients with changing disease activity no association was found between overall viral pathogen detection and disease activity (P = 0.39). Using multivariate logistic regression, age, gender, disease subtype, disease activity, medication, and season of sampling were not associated with overall viral pathogen detection. CONCLUSIONS: Enteropathogenic viruses are not frequently observed in a consecutive cohort of IBD patients and are not a common trigger for active disease in daily clinical practice. PMID- 22508686 TI - Strategies for selecting measures for pediatric and maternal child research. PMID- 22508688 TI - Technology of building an expert system based on a set of quantitative features of tumor cell nuclei for diagnosing breast cancer. AB - The technology of building an expert system for diagnosing malignant nature of invasive tumors of the mammary gland based on a set of quantitative features of the cell nuclei has been developed. Its peculiarity was the presence of weighting coefficients in all the features. Quantitative features were obtained by transforming the initial morphometric data with the help of simple (evaluation of mean values and building of histograms) and complex (regression analysis) mathematical operations. The expert system consisted of one-dimensional X-matrix used for investigations and two-dimensional standard S-matrix. The X-matrix elements were assigned for filling with the quantitative features of the studied sample with a nonestablished diagnosis. The S-matrix elements contained threshold values of quantitative features from the system of diagnostic decision criteria for malignant forms of diseases and their weighting coefficients. Threshold values of nuclear features (larger or smaller) were determined taking into account the range of their values in the groups of malignant and benign pathology. Significance of quantitative features in diagnosing diseases has been assessed. The presence of weighting coefficients allowed diagnosing malignant and benign pathology in a quantitative form by the diagnostic index value. Diagnostic index was calculated by the sum of weighting coefficients of features of the studied sample, which fell within the range of system of the S-matrix diagnostic decision criteria. Clinical trials revealed high efficiency of the developed approach while diagnosis of breast cancer invasive forms at a preoperative stage. PMID- 22508689 TI - Upregulation of proteasome activity in muscle RING finger 1-null mice following denervation. AB - Deletion of muscle RING finger 1 (MuRF1), an E3 ubiquitin ligase, leads to sparing of muscle mass following denervation. The purpose of this study was to test the hypothesis that muscle sparing in mice with a deletion of MuRF1 is due to the selective inhibition of the ubiquitin proteasome system. Activities of the 20S and 26S proteasomes, calpain and cathepsin L, were measured in the triceps surae muscles of wild-type (WT) and MuRF1-knockout (KO) mice at 3 and 14 d following denervation. In addition, fractional protein synthesis rates and differential gene expression were measured in WT and KO muscle. The major finding was that 20S and 26S proteasome activities were significantly elevated (1.5- to 2.5-fold) after 14 d of denervation in both WT and KO mice relative to control, but interestingly, the activities of both the 20S and 26S proteasome were significantly higher in KO than WT mice. Further, mRNA expression of MAFbx was elevated after 14 d of denervation in KO, but not WT, mice. These data challenge the conventional dogma that MuRF1 is controlling the degradation of only contractile proteins and suggest a role for MuRF1 in the global control of the ubiquitin proteasome system and protein turnover. PMID- 22508690 TI - Abnormal cross-talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis. AB - Mutations in the presenilin 1 (PS1) gene are associated with early onset familial Alzheimer's disease (FAD). In this study, we found that the expression of mutant PS1 in stable transfectants of SH-SY5Y neuroblastoma cells results in a reduction of the biosynthesis and steady-state levels of glucosylceramide. As an in vivo corroboration of these data, there was a significant reduction of brain glucosylceramide and gangliosides in an animal model of FAD. In mutant-PS1 transfectants (I143T, G384A), immunocytochemistry disclosed a remarkable reduction of glucosylceramide synthase (GlcT-1)-like immunoreactivity in the cells when compared with those of mock- and wild-PS1 transfectants. Immunoprecipitation of GlcT-1 protein from mutant-PS1 transfectants demonstrated a marked reduction in GlcT-1 protein, but there was no reduction in the levels of GlcT-1 mRNA. Both coprecipitation and gamma-secretase inhibition experiments suggest that mutant-PS1 seems to form a complex with GlcT-1 protein and to be involved in GlcT-1 degradation, which was never found in other cell types. Thus, mutations in the PS1 gene result in profound glycosphingolipids abnormalities by abnormal molecular interaction with GlcT-1. PMID- 22508691 TI - Selective separation of biobutanol from acetone-butanol-ethanol fermentation broth by means of sorption methodology based on a novel macroporous resin. AB - The traditional distillation method for recovery of butanol from fermentation broth is an energy-intensive process. Separation of butanol based on adsorption methodology has advantages in terms of biocompatibility and stability, as well as economy, and therefore gains much attention. However, the application of the commercial adsorbents in the integrated acetone-butanol-ethanol (ABE) fermentation process is restricted due to the low recovery (less than 85%) and the weak capability of enrichment in the eluent (3-4 times). In this study, we investigated the sorption properties of butanol onto three kinds of adsorbents with different polarities developed in our laboratory, that is, XD-41, H-511, and KA-I resin. The sorption behaviors of single component and ABE ternary mixtures presented in the fermentation broths on KA-I resin were investigated. KA-I resin had higher affinity for butanol than for acetone, ethanol, glucose, acetic acid, and butyric acid. Multicomponent ABE sorption on KA-I resin was modeled using a single site extended Langmuir isotherm model. In a desorption study, all the adsorbed components were desorbed in one bed volume of methanol, and the recovery of butanol from KA-I resin was 99.7%. The concentration of butanol in the eluent was increased by a factor of 6.13. In addition, KA-I resin was successfully regenerated by two bed volumes of water. Because of its quick sorption, high sorption capacity, low cost, and ease of desorption and regeneration, KA-I resin exhibits good potential for compatibility with future ABE fermentation coupled with in situ recovery product removal techniques. PMID- 22508692 TI - Social inequality in awareness of cardiovascular risk factors in patients undergoing coronary angiography. AB - BACKGROUND: In order to improve their risk profile, individuals need to be aware of the existence of cardiovascular (CV) risk factors. The awareness of CV risk factors has not yet been studied in patients undergoing coronary angiography. PATIENTS AND METHODS: A total of 4,500 patients undergoing coronary angiography were asked to complete a questionnaire before the procedure. The patients were asked about their economic status, their education, their source of health information and were also asked to name CV risk factors. RESULTS: The prevalence of coronary artery disease (CAD) (87%) and CV risk factors was high. Hypertension and hypercholesterolemia were the two most common CV risk factors and were found in two thirds of the patients. There were significant differences in the awareness of risk factors across the different levels of education. Only 8% of the men and 7% of the women could cite at least three risk factors. This percentage ranged from 4% of the patients with primary level of education to 11% and 20% of the patients with secondary and university levels of education, respectively (p < 0.001). More than 1 out of 10 patients did not know any CV risk factor. Smoking and hypercholesterolemia were the best identified CV risk factors in contrast to diabetes and hypertension. The primary care physician was the major source of information across all levels of education. CONCLUSION: Awareness of CV risk factors is low in this high-risk population and associated with strong social inequalities. This information is alarming and will have to be addressed in order to improve outcomes in patients with CAD. PMID- 22508693 TI - Outpatient cardiac rehabilitation: the Austrian model. AB - Over the past decades undisputable evidence has accumulated identifying the panoply of beneficial effects of exercise training, smoking cessation, blood pressure lowering, glycaemic and lipid control, as well as psycho-social interventions on cardiovascular risk factors, the well-being, morbidity and mortality of patients with cardiac diseases with or without acute events. Nevertheless, despite all the evidence, insurance companies are more than hesitant to provide patients with an adequate infrastructure to allow outpatient cardiac rehabilitation in their community. Whereas some countries still favour in hospital rehabilitation, others are on the verge of introducing cardiac rehabilitation for the first time. Thanks to the efforts of the Working Group of Outpatient Cardiac Rehabilitation of the Austrian Cardiac Society, detailed guidelines for outpatient cardiac rehabilitation have been introduced, which not only include aims, contents and duration of outpatient cardiac rehabilitation, but also requirements for staff, quality of care and infrastructure. As a result cardiac rehabilitation in Austria is currently undergoing a transition process from exclusive in-hospital cardiac rehabilitation to a more open approach of granting patients a choice between in-hospital and outpatient rehabilitation. Experience gained appears relevant to a great number of colleagues in many countries Europe - as well as worldwide. Since these guidelines were and still are the basis for implementing outpatient cardiac rehabilitation, they are presented in great detail, so that they may either be applied as is or simply stimulate discussion. PMID- 22508695 TI - Anti-VEGF/VEGFR therapy for cancer: reassessing the target. AB - Judah Folkman recognized that new blood vessel formation is important for tumor growth and proposed antiangiogenesis as a novel approach to cancer therapy. Discovery of vascular permeability factor VEGF-A as the primary tumor angiogenesis factor prompted the development of a number of drugs that targeted it or its receptors. These agents have often been successful in halting tumor angiogenesis and in regressing rapidly growing mouse tumors. However, results in human cancer have been less impressive. A number of reasons have been offered for the lack of greater success, and, here, we call attention to the heterogeneity of the tumor vasculature as an important issue. Human and mouse tumors are supplied by at least 6 well-defined blood vessel types that arise by both angiogenesis and arterio-venogenesis. All 6 types can be generated in mouse tissues by an adenoviral vector expressing VEGF-A(164). Once formed, 4 of the 6 types lose their VEGF-A dependency, and so their responsiveness to anti-VEGF/VEGF receptor therapy. If therapies directed against the vasculature are to have a greater impact on human cancer, targets other than VEGF and its receptors will need to be identified on these resistant tumor vessels. PMID- 22508696 TI - Nodal expression and detection in cancer: experience and challenges. AB - Nodal is a TGF-beta-related embryonic morphogen that is expressed in multiple human cancers. Detection of Nodal expression in these tissues can be challenging if issues related to Nodal transcription and protein processing are not considered. Here, we discuss certain characteristics related to Nodal expression and function and how these can facilitate acquisition and interpretation of expression data, contributing to our understanding of the potential role of Nodal in human cancer. We also discuss how Nodal could be exploited clinically as a novel biomarker for cancer progression and therapeutic target. PMID- 22508698 TI - Primary and secondary prevention of cardiovascular disease in diabetes with aspirin. AB - Diabetes is associated with an increased cardiovascular risk. The role for aspirin in diabetes is of high clinical interest. Guidelines recommend that primary prevention of cardiovascular disease (CVD) in diabetes with aspirin should be based on the individual risk for CVD. New mechanistic studies suggest that enhanced platelet turnover may partly contribute to the fact the primary prevention studies found unequivocal results in diabetes. There is initial evidence that a potential future modification of dosages in diabetes may counteract the enhancement in platelet turnover in diabetes. The use of aspirin in diabetic patients for secondary prevention of CVD is supported by key evidence. The aim of the review is to present recent studies on aspirin for prevention of CVD in diabetes and to highlight its role also in view of new mechanistic and clinical studies with aspirin. Novel aspects of aspirin, e.g. its potential role for the prevention of cancer, are also presented. PMID- 22508697 TI - INT6/EIF3E interacts with ATM and is required for proper execution of the DNA damage response in human cells. AB - Altered expression of the INT6 gene, encoding the e subunit of the translational initiation factor eIF3, occurs in human breast cancers, but how INT6 relates to carcinogenesis remains unestablished. Here, we show that INT6 is involved in the DNA damage response. INT6 was required for cell survival following gamma irradiation and G(2)-M checkpoint control. RNA interference-mediated silencing of INT6 reduced phosphorylation of the checkpoint kinases CHK1 and CHK2 after DNA damage. In addition, INT6 silencing prevented sustained accumulation of ataxia telangiectasia mutated (ATM) at DNA damage sites in cells treated with gamma radiation or the radiomimetic drug neocarzinostatin. Mechanistically, this result could be explained by interaction of INT6 with ATM, which together with INT6 was recruited to the sites of DNA damage. Finally, INT6 silencing also reduced ubiquitylation events that promote retention of repair proteins at DNA lesions. Accordingly, accumulation of the repair factor BRCA1 was defective in the absence of INT6. Our findings reveal unexpected and striking connections of INT6 with ATM and BRCA1 and suggest that the protective action of INT6 in the onset of breast cancers relies on its involvement in the DNA damage response. PMID- 22508699 TI - Alpha-glucosidase inhibitors 2012 - cardiovascular considerations and trial evaluation. AB - Alpha-glucosidase inhibitors have been available for clinical use for about 20 years. They have shown reasonably good efficacy comparable to other oral blood glucose lowering drugs and in some parts of the world are the most commonly prescribed oral diabetes medication, especially in Asian countries. Unlike as has been observed with some other blood glucose lowering agents, however, no adverse signals of potential cardiovascular harm have emerged in relation to their use. On the contrary, significant beneficial cardiovascular outcome results have been observed in the post-hoc analyses of randomised placebo-controlled trials with the alpha-glucosidase inhibitor acarbose. Targeting mainly postprandial hyperglycaemia, alpha-glucosidase inhibitors favourably affect several cardiovascular risk factors, such as obesity, hypertension and high glycaemic variability with little to no risk for hypoglycaemia. Furthermore, acarbose favourably affects endothelial dysfunction and carotid intima media thickening in humans and, in animal models, improves cardiac interstitial fibrosis and hypertrophy of cardiomyocytes. The ultimate determination of the cardiovascular effects of alpha-glucosidase inhibitors in terms of clinical outcomes awaits the results of ongoing long-term, randomised, placebo-controlled trials. PMID- 22508700 TI - Purkinje cell heterotopy with cerebellar hypoplasia in two free-living American kestrels (Falco sparverius). AB - Two wild fledgling kestrels exhibited lack of motor coordination, postural reaction deficits, and abnormal propioception. At necropsy, the cerebellum and brainstem were markedly underdeveloped. Microscopically, there was Purkinje cells heterotopy, abnormal circuitry, and hypoplasia with defective foliation. Heterotopic neurons were identified as immature Purkinje cells by their size, location, immunoreactivity for calbindin D-28 K, and ultrastructural features. The authors suggest that this cerebellar abnormality was likely due to a disruption of molecular mechanisms that dictate Purkinje cell migration, placement, and maturation in early embryonic development. The etiology of this condition remains undetermined. Congenital central nervous system disorders have rarely been reported in birds. PMID- 22508701 TI - An ocular infection model using suckling hamsters inoculated with equine herpesvirus 9 (EHV-9): kinetics of the virus and time-course pathogenesis of EHV 9-induced encephalitis via the eyes. AB - By using a new member of the neurotropic equine herpesviruses, EHV-9, which induced encephalitis in various species via various routes, an ocular infection model was developed in suckling hamsters. The suckling hamsters were inoculated with EHV-9 via the conjunctival route and were sacrificed after 6, 12, 24, 36, 48, 72, 96, 120, and 144 hours (h) post inoculation (PI). Three horizontal sections of the brains, including the eyes and cranial cavity, were examined histologically to assess the viral kinetics and time-course neuropathological alterations using a panoramic view. At 6 to 24 h PI, there were various degrees of necrosis in the conjunctival epithelial cells, as well as frequent mononuclear cell infiltrations in the lamina propria and the tarsus of the eyelid, and frequent myositis of the eyelid muscles. At 96 h PI, encephalitis was observed in the brainstem at the level of the pons and cerebellum. EHV-9 antigen immunoreactivity was detected in the macrophages circulating in the eyelid and around the fine nerve endings supplying the eyelid, the nerves of the extraocular muscles, and the lacrimal glands from 6 h to 144 h PI. At 96 h PI, the viral antigen immunoreactivity was detected in the brainstem at the level of the pons and cerebellum. These results suggest that EHV-9 invaded the brain via the trigeminal nerve in addition to the abducent, oculomotor, and facial nerves. This conjunctival EHV-9 suckling hamster model may be useful in assessing the neuronal spread of neuropathogenic viruses via the eyes to the brain. PMID- 22508702 TI - A community-driven intervention for prostate cancer screening in African Americans. AB - The purpose of the study was to assess the impact of an educational intervention on prostate cancer screening behavior and knowledge. Participants were 104 African American men, 45 years and older, who had not been screened for prostate cancer with a prostate-specific antigen and/or digital rectal exam within the past year. All participants received an intervention delivered by trained lay community educators using a prostate cancer educational brochure developed in collaboration with the community, with structured interviews preintervention and 3 months postintervention. The main study outcomes included prostate-specific antigen screening rates during the 3-month interval and knowledge, barriers to screenings, and decisional conflict around screening. Compared with the 46 men who did not get screened, the 58 participants who got screened were more likely to have greater than a high school education, annual household incomes >=$25,000, and a family history of non-prostate cancer (p < .05). Average knowledge scores increased, and barriers to screening scores decreased, from preintervention to postintervention only for participants who had been screened (p < .05). The results of this study demonstrate the feasibility and efficacy of an academic institution collaborating with the African American community to develop a successful prostate cancer educational intervention, an approach that can be expanded to other cancers and other chronic diseases. PMID- 22508703 TI - Decidual endovascular trophoblast invasion in women with polycystic ovary syndrome: an experimental case-control study. AB - CONTEXT: Previous experimental and clinical data suggest impaired decidual trophoblast invasion in patients with polycystic ovarian syndrome (PCOS). OBJECTIVE: The objective of the study was to test the hypothesis that decidual endovascular trophoblast invasion in pregnant patients with PCOS is impaired and to clarify the potential mechanisms involved. DESIGN: This was an experimental case-control study. SETTING: The study was conducted at the academic Departments of Obstetrics and Gynecology and the Unit of Pathology (Italy). PATIENTS: Forty five pregnant subjects screened from a wide population of women waiting for legal pregnancy termination were included in the final analysis. Specifically, 15 pregnant patients with PCOS were enrolled as cases and another 30 age- and body mass index (BMI)-matched healthy pregnant women without any feature of PCOS were enrolled as the controls. INTERVENTION: Interventions included the collection of trophoblastic and decidual tissue at the 12th week of gestation. MAIN OUTCOME MEASURES: Clinical, ultrasonographic, and biochemical data as well as the histological analysis of decidual endovascular trophoblast invasion. RESULTS: The rate of implantation site vessels with endovascular trophoblast invasion (ratio between total number of implantation site vessels and total number of vessels with endovascular trophoblast invasion) and the extent of endovascular trophoblast invasion (proportion between immunoreactive areas to cytokeratin 7 and to CD34) were significantly lower in patients with PCOS compared with healthy non-PCOS controls. Endovascular trophoblast invasion data were significantly and indirectly related to the markers of insulin resistance and testosterone concentrations in PCOS patients. CONCLUSIONS: Pregnant patients with PCOS patients have impaired decidual trophoblast invasion. Further studies are needed to evaluate the exact mechanisms through which insulin resistance and hyperandrogenemia exert this effect. PMID- 22508704 TI - Crosstalk between advanced glycation and endoplasmic reticulum stress: emerging therapeutic targeting for metabolic diseases. AB - CONTEXT: Advanced glycation, the major posttranslational modification of proteins, DNA, and lipids, is accelerated under conditions of increased oxidative stress, hyperglycemia, and hypoxia contributing to a variety of metabolic diseases such as diabetes mellitus, obesity, inflammation, polycystic ovarian syndrome, ischemic cardiovascular disease, and neurodegenerative disorders. The potential role of advanced glycation in endoplasmic reticulum (ER) homeostasis is largely unknown. EVIDENCE ACQUISITION: Basic and clinical peer-reviewed articles on advanced glycation and ER stress related to metabolic regulation were searched in PubMed from 2000-2011. The resulting articles as well as relevant cited references were reviewed. EVIDENCE SYNTHESIS: Recent evidence indicates that hyperglycemia, hypoxia, and oxidative stress, apart of triggering advanced glycation, can also adversely affect ER function, leading to pathogenic ER stress, followed by the unfolded protein response. The concomitant presence of advanced glycation in the same conditions with ER stress suggests their crosstalk in the progression of diseases associated with hypoxic and oxidative stress. CONCLUSION: Current data support the direct or indirect induction of ER stress response by advanced glycation end products or advanced glycation end product precursors in the pathogenesis of metabolic diseases. Inhibitors of advanced glycation acting as potent ER stress modulators with beneficial effects in restoring ER homeostasis and adjusting physiological unfolded protein response level present an emerging therapeutic approach with significant applications, especially in the context of metabolic dysfunction. PMID- 22508705 TI - Neuroendocrine ACTH-producing tumor of the thymus--experience with 12 patients over 25 years. AB - CONTEXT: ACTH-producing neuroendocrine tumor (NET) of the thymus is a rare cause of Cushing's syndrome (CS). The literature consists mainly of isolated case reports. PATIENTS: We studied 12 cases (eight males and four females) diagnosed between 1986 and 2010 with CS and thymic NET who underwent surgical resection. MAIN OUTCOME MEASURES: We measured time from onset of CS to diagnosis of thymic NET, tumor size, histological grade, time to recurrence, and survival and performed a meta-analysis of other published cases of CS associated with thymic NET. RESULTS: Eleven of 12 patients presented with classic features of CS at a median age of 21 yr (range, 7-51). Four were children. The 24-h urine free cortisol was greater than 16-fold of normal, and biochemical testing was consistent with ectopic ACTH production in all 11. Another patient presenting with pulmonary embolus had a thymic mass and was later diagnosed with CS. All patients underwent thymectomy, and nine of 10 tumors exhibited positive ACTH immunochemistry. Median tumor diameter was 5 cm (range, 1-11.5). Six patients recurred 20-28 months after surgery with metastases to mediastinal lymph nodes (n = 5), bone (n = 5), liver (n = 1), parotid gland (n = 1), and breast (n = 1). Four of five patients treated with radiation therapy also received chemotherapy. All recurrent patients received ketoconazole; four later underwent bilateral adrenalectomy. Six recurrent patients died 22-90 months (median, 57) after thymectomy. At last review, six patients were alive 14-90 months (median, 49) after thymectomy. These data are similar to those from the meta-analysis. CONCLUSIONS: Thymic ACTH-producing NET is an aggressive disease that should be considered in CS with ectopic ACTH secretion, particularly in younger patients. PMID- 22508706 TI - A high percentage of BRAFV600E alleles in papillary thyroid carcinoma predicts a poorer outcome. AB - CONTEXT: BRAF(V600E) is considered a negative prognostic marker in papillary thyroid carcinoma (PTC), but unexplained conflicting results are present in the literature. In light of the new finding that most PTC consist of a mixture of tumor cells with wild-type and mutant BRAF, we examined the associations between the percentage of BRAF(V600E) alleles and both the clinicopathological parameters at time of diagnosis and the disease outcome in a large series of PTCs. STUDY DESIGN: Tumors from 168 patients with PTC were genotyped for BRAF(V600E) using BigDye Terminator sequencing and pyrosequencing, and the clinical parameters were analyzed. The associations between clinicopathological characteristics, including disease recurrence at follow-up (median 5.1 yr) and the percentage of mutant BRAF alleles were assessed. RESULTS: The observed prevalence of BRAF(V600E) was higher when using pyrosequencing then when using BigDye Terminator sequencing (53.6 vs. 36.9%). In the PTC positive for BRAF(V600E), the percentage of mutant alleles ranged from 5.1 to 44.7% of the total BRAF alleles, with a median of 20.6%. The presence or the percentage of BRAF(V600E) alleles did not correlate significantly with sex, multicentricity, lymph node metastasis, or tumor stage. The percentage of BRAF(V600E) alleles directly correlated with age at diagnosis and tumor volume (R(2) = 0.223, P = 0.039, and R(2) = 0.166, P < 0.001, respectively). The percentage of BRAF(V600E) alleles (P = 0.014), tumor volume (P = 0.012), and lymph node metastasis (P = 0.008) predicted the disease outcome. The odds ratio of recurrence for PTC with BRAF(V600E) alleles of 30% or greater, compared with that for PTC with BRAF(V600E) alleles of less than 30%, was 5.31 (P = 0.002). CONCLUSIONS: A high percentage of BRAF(V600E) alleles defines a PTC molecular subtype and predicts a poorer disease outcome. The analysis of BRAF mutations by pyrosequencing is useful to refine the risk stratification of patients with PTC. PMID- 22508707 TI - Beneficial effects of growth hormone treatment on cognition in children with Prader-Willi syndrome: a randomized controlled trial and longitudinal study. AB - BACKGROUND: Knowledge about the effects of GH treatment on cognitive functioning in children with Prader-Willi syndrome (PWS) is limited. METHODS: Fifty prepubertal children aged 3.5 to 14 yr were studied in a randomized controlled GH trial during 2 yr, followed by a longitudinal study during 4 yr of GH treatment. Cognitive functioning was measured biennially by short forms of the WPPSI-R or WISC-R, depending on age. Total IQ (TIQ) score was estimated based on two subtest scores. RESULTS: During the randomized controlled trial, mean sd scores of all subtests and mean TIQ score remained similar compared to baseline in GH-treated children with PWS, whereas in untreated controls mean subtest sd scores and mean TIQ score decreased and became lower compared to baseline. This decline was significant for the Similarities (P = 0.04) and Vocabulary (P = 0.03) subtests. After 4 yr of GH treatment, mean sd scores on the Similarities and Block design subtests were significantly higher than at baseline (P = 0.01 and P = 0.03, respectively), and scores on Vocabulary and TIQ remained similar compared to baseline. At baseline, children with a maternal uniparental disomy had a significantly lower score on the Block design subtest (P = 0.01) but a larger increment on this subtest during 4 yr of GH treatment than children with a deletion. Lower baseline scores correlated significantly with higher increases in Similarities (P = 0.04) and Block design (P < 0.0001) sd scores. CONCLUSIONS: Our study shows that GH treatment prevents deterioration of certain cognitive skills in children with PWS on the short term and significantly improves abstract reasoning and visuospatial skills during 4 yr of GH treatment. Furthermore, children with a greater deficit had more benefit from GH treatment. PMID- 22508708 TI - Metabolically healthy obesity and risk of all-cause and cardiovascular disease mortality. AB - CONTEXT: Previous studies have identified an obese phenotype without the burden of adiposity-associated cardiometabolic risk factors, although the health effects remain unclear. OBJECTIVE: We examined the association between metabolically healthy obesity and risk of cardiovascular disease (CVD) and all-cause mortality. DESIGN AND SETTING: This was an observational study with prospective linkage to mortality records in community-dwelling adults from the general population in Scotland and England. PARTICIPANTS: A total of 22,203 men and women [aged 54.1 (SD 12.7 yr), 45.2% men] without known history of CVD at baseline. INTERVENTIONS: Based on blood pressure, high-density lipoprotein-cholesterol, diabetes diagnosis, waist circumference, and low-grade inflammation (C-reactive protein >= 3 mg/liter), participants were classified as metabolically healthy (0 or 1 metabolic abnormality) or unhealthy (two or more metabolic abnormalities). Obesity was defined as a body mass index of 30 kg/m(2) or greater. MAIN OUTCOME MEASURE: Study members were followed up, on average, more than 7.0 +/- 3.0 yr for cause-specific mortality. Cox proportional hazards models were used to examine the association of metabolic health/obesity categories with mortality. RESULTS: There were 604 CVD and 1868 all-cause deaths, respectively. Compared with the metabolically healthy nonobese participants, their obese counterparts were not at elevated risk of CVD [hazard ratio (HR) 1.26, 95% confidence interval (CI) 0.74 2.13], although both nonobese (HR 1.59, 95% CI 1.30-1.94) and obese (HR 1.64, 95% CI 1.17-2.30) participants with two or more metabolic abnormalities were at elevated risk. Metabolically unhealthy obese participants were at elevated risk of all-cause mortality compared with their metabolically healthy obese counterparts (HR 1.72, 95% CI 1.23-2.41). CONCLUSION: Metabolically healthy obese participants were not at increased risk of CVD and all-cause mortality over 7 yr. PMID- 22508709 TI - Intramyocellular lipid is associated with visceral adiposity, markers of insulin resistance, and cardiovascular risk in prepubertal children: the EPOCH study. AB - CONTEXT: The intramyocellular deposition of lipid associates with metabolic dysregulation in adolescents and adults. Relatively little is known about the deposition of fat in muscle before the onset of puberty. OBJECTIVE: Our objective was to describe the relationship between intramyocellular lipid (IMCL) accumulation and 1) visceral adiposity and 2) markers of insulin resistance and cardiovascular disease risk in a cohort of prepubertal and early pubertal children. STUDY DESIGN: Data were collected as part of a retrospective cohort study, Exploring Perinatal Outcomes among Children (EPOCH). Multiple linear regression models were constructed for data analysis. RESULTS: A total of 441 children participated in the study (226 prepubertal, 215 early pubertal). In prepubertal children, there was a significant relationship between IMCL and visceral fat (parameter estimate 0.019, P = 0.002) that remained after controlling for body mass index. Independent of overall adiposity, in all children, IMCL was associated with the triglyceride to high-density lipoprotein ratio (parameter estimate 0.1418, P = 0.002). CONCLUSIONS: This study demonstrates a concerning and related pattern of IMCL and visceral fat deposition in prepubertal children. Intramuscular fat deposition is linked to markers of insulin resistance and cardiovascular disease risk. PMID- 22508710 TI - Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low risk prostate cancer under active surveillance. AB - CONTEXT: We wanted to investigate vitamin D in low-risk prostate cancer. OBJECTIVES: The objective of the study was to determine whether vitamin D(3) supplementation at 4000 IU/d for 1 yr is safe and would result in a decrease in serum levels of prostate-specific antigen (PSA) or in the rate of progression. DESIGN: In this open-label clinical trial (Investigational New Drug 77,839), subjects were followed up until repeat biopsy. SETTING: All subjects were enrolled through the Medical University of South Carolina and the Ralph H. Johnson Veterans Affairs Medical Center, both in Charleston, SC. PATIENTS AND OTHER PARTICIPANTS: All subjects had a diagnosis of low-risk prostate cancer. Fifty-two subjects were enrolled in the study, 48 completed 1 yr of supplementation, and 44 could be analyzed for both safety and efficacy objectives. INTERVENTION: The intervention included vitamin D(3) soft gels (4000 IU). MAIN OUTCOME MEASURES: Adverse events were monitored throughout the study. PSA serum levels were measured at entry and every 2 months for 1 yr. Biopsy procedures were performed before enrollment (for eligibility) and after 1 yr of supplementation. RESULTS: No adverse events associated with vitamin D(3) supplementation were observed. No significant changes in PSA levels were observed. However, 24 of 44 subjects (55%) showed a decrease in the number of positive cores or decrease in Gleason score; five subjects (11%) showed no change; 15 subjects (34%) showed an increase in the number of positive cores or Gleason score. CONCLUSION: Patients with low-risk prostate cancer under active surveillance may benefit from vitamin D(3) supplementation at 4000 IU/d. PMID- 22508711 TI - Candesartan acutely recruits skeletal and cardiac muscle microvasculature in healthy humans. AB - CONTEXT: Angiotensin II type 1 receptor (AT(1)R) tone restricts muscle microvascular blood volume (MBV) and decreases muscle insulin delivery and glucose use. OBJECTIVE: The objective of the study was to examine whether acute AT(1)R blockade alters microvascular perfusion in skeletal and cardiac muscle in humans. SETTING: The study was conducted at the General Clinical Research Center at the University of Virginia. METHODS: Eight overnight-fasted healthy young adults were studied thrice in random order. In study 1, each subject received candesartan (32 mg) orally at time 0. In study 2, each subject received placebo at time 0 and a 1 mU/min . kg euglycemic insulin clamp from time 240 to 360 min. In study 3, each subject received candesartan (32 mg) orally at time 0 and insulin infusion from 240 to 360 min. Forearm skeletal and cardiac muscle MBV, microvascular flow velocity, and microvascular blood flow (MBF) were determined at baseline and at 240 and 360 min. RESULTS: Candesartan treatment acutely recruited microvasculature in both skeletal and cardiac muscle by significantly increasing MBV (P < 0.03 and P = 0.02, respectively) and MBF (P < 0.03 for both) without altering microvascular flow velocity. Insulin infusion significantly increased cardiac MBV (P = 0.02) and MBF (P < 0.02). Superimposing insulin infusion 4 h after candesartan ingestion did not further recruit microvasculature. Insulin-mediated whole-body glucose disposal did not differ with or without candesartan pretreatment. CONCLUSIONS: Acute AT(1)R blockade with candesartan recruits skeletal as well as cardiac muscle microvasculature in healthy humans without altering insulin-mediated whole-body glucose disposal. This may contribute to the observed improvement in the cardiovascular outcomes in patients receiving prolonged treatment with AT(1)R blockers. PMID- 22508713 TI - The level of serum anti-Mullerian hormone correlates with vitamin D status in men and women but not in boys. AB - CONTEXT: Anti-Mullerian hormone (AMH) is a gonad-specific hormone, which is extensively used as a marker of gonadal status. The level of serum AMH has a high variance in similar individuals for reasons that are unknown. The AMH gene promoter contains a vitamin D response element that may cause vitamin D status to influence serum AMH levels. AIM: The objective of the study was to determine whether serum levels of AMH are related to 25-hydroxyitamin D [25(OH)D)] status. SETTING: This was a correlative and intervention study. PARTICIPANTS: Three cohorts of participants were analyzed; mature men (n = 113), premenopausal women (n = 33), and 5- to 6-yr-old boys (n = 74). Women were given a daily supplement of ergocalciferol, cholecalciferol, or a placebo for 6 months and provided baseline and posttreatment blood samples. MAIN OUTCOME MEASURES: Serum AMH and 25(OH)D were measured and analyzed for covariation. RESULTS: Serum AMH positively correlated with 25(OH)D in men (r = 0.22, P = 0.02) but not boys. Both 25(OH)D and AMH levels exhibited seasonal variation in women, with an 18% decrease in AMH levels in winter compared with summer (P = 0.01). Change in AMH level correlated with the initial AMH level and the magnitude of change in vitamin D levels (r = 0.36, P = 0.004). Cholecalciferol supplementation prevented seasonal AMH change. CONCLUSION: Vitamin D may be a positive regulator of AMH production in adults, and vitamin D deficiency may confound clinical decisions based on AMH. Vitamin D deficiency should be considered when serum AMH levels are obtained for diagnosis. PMID- 22508712 TI - Sleeping parathyroid tumor: rapid hyperfunction after removal of the dominant tumor. AB - CONTEXT: Due to frequent multiplicity of tumors in multiple endocrine neoplasia type 1, it may be difficult to decide when to stop a parathyroid exploration. A fall of intraoperative serum PTH by a certain percentage during parathyroid surgery is often used as one criterion for ending the operation. RESULTS: We report two patients with primary hyperparathyroidism due to multiple endocrine neoplasia type 1 who had their first parathyroidectomy at the National Institutes of Health. In both cases, two and a half glands were removed, an extensive search was done for an occult parathyroid tumor, and intraoperative PTH decreased markedly to the lower limits of normal, suggesting a successful operation. Despite this, both patients became hypercalcemic within 3 d after the operation and showed persistent primary hyperparathyroidism. Detailed findings suggest the following course: chronic hypercalcemia had caused near total suppression of PTH secretion by an undiscovered parathyroid tumor (sleeping parathyroid tumor). When the hypercalcemia decreased after surgery due to the removal of the dominant parathyroid tumor(s), the abnormal yet previously suppressed tumor rapidly began to oversecrete PTH and thus caused postoperative hypercalcemia. CONCLUSIONS: Even a fall of the intraoperative PTH to the lower limits of the normal range cannot guarantee that removal of all parathyroid tumors has been complete in cases with multiple tumors. These findings likely reflect strikingly differing PTH secretory functions among distinct tumors in the same patient, with hypercalcemia at least from a dominant tumor suppressing PTH secretion by one or more other parathyroid tumors. PMID- 22508714 TI - Gender differences in VLDL1 and VLDL2 triglyceride kinetics and fatty acid kinetics in obese postmenopausal women and obese men. AB - CONTEXT: High plasma triglycerides (TG) have been shown to be independent and better predictors of cardiovascular disease than low-density lipoprotein (LDL) cholesterol in women. This may be due to gender differences in very-low-density lipoprotein 1 (VLDL(1))- and VLDL(2)-TG and fatty acid kinetics. OBJECTIVE: Our objective was to investigate whether there are differences in VLDL(1)- and VLDL(2)-TG and fatty acid kinetics in obese men and postmenopausal women, a high risk group for cardiovascular disease. RESEARCH DESIGN AND METHODS: Stable isotopes techniques were used to measure fasting palmitate rate of appearance, metabolic clearance rate, oxidation rate, and nonoxidative disposal rate, VLDL(1) TG and VLDL(2)-TG fractional catabolic rate (FCR) and production rate (PR). Whole body fat distribution was measured by magnetic resonance imaging. PARTICIPANTS: Participants included 10 postmenopausal obese women and eight obese men matched for age, body mass index, and fasting plasma TG. RESULTS: The women had lower visceral fat and higher sc fat than the men (P < 0.001 and P < 0.002). Palmitate rate of appearance, metabolic clearance rate, nonoxidative disposal rate, and oxidation rate corrected for resting energy expenditure were greater in the women than the men (all P < 0.03). VLDL(2)-TG PR corrected for fat-free mass was higher in the women (P < 0.001). VLDL(2)-TG and VLDL(2)-cholesterol pools were higher in the women (P < 0.001 and P < 0.008). VLDL(1)-TG FCR and PR and VLDL(2)-TG FCR were not different between genders. CONCLUSION: Fatty acid and VLDL(2)-TG flux is higher in postmenopausal obese women than in obese men matched for fasting plasma TG levels. PMID- 22508716 TI - The helicase domain and C-terminus of human RecQL4 facilitate replication elongation on DNA templates damaged by ionizing radiation. AB - The vertebrate RECQL4 (RECQ4) gene is thought to be the ortholog of budding yeast SLD2. However, RecQL4 contains within its C-terminus a RecQ-like helicase domain, which is absent in Sld2. We established human pre-B lymphocyte Nalm-6 cells, in which the endogenous RECQL4 gene was homozygously targeted such that the entire C terminus would not be expressed. The RECQL4(DeltaC/DeltaC) cells behaved like the parental cells during unperturbed DNA replication or after treatment with agents that induce stalling of DNA replication forks, such as hydroxyurea (HU). However, after exposure to ionizing radiation (IR), the RECQL4(DeltaC/DeltaC) cells exhibited hypersensitivity, inability to complete S phase and prematurely terminated or paused DNA replication forks. Deletion of BLM, a gene that also encodes a RecQ helicase, had the opposite phenotype; an almost wild-type response to IR, but hypersensitivity to HU. Targeting both RECQL4 and BLM resulted in viable cells, which exhibited mostly additive phenotypes compared with those exhibited by the RECQL4(DeltaC/DeltaC) and the BLM(-/-) cells. We propose that RecQL4 facilitates DNA replication in cells that have been exposed to IR. PMID- 22508715 TI - Reduction in inflammation and the expression of amyloid precursor protein and other proteins related to Alzheimer's disease following gastric bypass surgery. AB - OBJECTIVE: Obesity and type 2 diabetes are associated with an increase in the incidence and prevalence of Alzheimer's disease (AD) and an impaired cognitive function. Because peripheral blood mononuclear cells (MNC) express amyloid precursor protein (APP), the precursor of beta-amyloid, which forms the pathognomonic plaques in the brain, we hypothesized that APP expression diminishes after the marked caloric restriction and weight loss associated with Roux-en-Y gastric bypass (RYGB) surgery. RESEARCH DESIGN AND METHODS: Fifteen type 2 diabetic patients with morbid obesity (body mass index, 52.1 +/- 13 kg/m(2)) underwent RYGB, and the expression of inflammatory and AD-related genes was examined before and after 6 months in plasma and in MNC. RESULTS: Body mass index fell to 40.4 +/- 11.1 kg/m(2) at 6 months after RYGB. There was a significant fall in plasma concentrations of glucose and insulin and in homeostasis model of assessment for insulin resistance. The expression of APP mRNA fell by 31 +/- 9%, and that of protein fell by 36 +/- 14%. In addition, there was a reduction in the expression of other AD-related genes including presinilin-2, ADAM-9, GSK-3beta, PICALM, SORL-1, and clusterin (P < 0.05 for all). Additionally, the expression of c-Fos, a subunit of the proinflammatory transcription factor AP-1, was also suppressed after RYGB. These changes occurred in parallel with reductions in other proinflammatory mediators including C reactive protein and monocyte chemoattractant protein-1. CONCLUSIONS: Thus, the reversal of the proinflammatory state of obesity is associated with a concomitant reduction in the expression of APP and other AD-related genes in MNC. We conclude that obesity and caloric intake modulate the expression of APP in MNC. If indeed, this effect also occurs in the brain, this may have implications for the pathogenesis and the treatment of AD. It is relevant that cognitive function has been shown to improve with weight loss following bariatric surgery. PMID- 22508717 TI - Exploring the relevance of autonomy and relatedness for mental health in healthy and depressed women from two different cultures: when does culture matter? AB - BACKGROUND: It is well known that the absence of both autonomy and social support (relatedness) are two important etiologic pathways to major depressive disorder (MDD). However, cross-cultural researchers state that the implications of autonomy and relatedness for mental health vary across cultures. AIM: To test these assumptions, the current study investigated the relevance of autonomy and relatedness for mental health in healthy and depressed women from two different cultures (Germans and Turkish immigrants in Germany). METHODS: One hundred and eight (108) women were evaluated for their levels of autonomy/relatedness satisfaction, for overall psychopathological complaints including depression, for affectivity and for perceived loneliness through self-report measures. RESULTS: Among healthy groups, relatedness satisfaction predicted better mental health in Turkish women, whereas in German women, autonomy satisfaction was the better mental health predictor. Within depressed groups however, cultural differences in mental health outcomes regarding autonomy were no longer evident. Autonomy was associated with higher levels of mental health in Turkish as well as in German patients. CONCLUSIONS: Our findings indicate that the relationship between autonomy and mental health is culture-specific in healthy women, but disappears in depressed women. These findings are discussed with consideration of clinical implications and an outlook regarding further research. PMID- 22508718 TI - Trends in alcohol-related deaths in the EU countries in 1980-2003. AB - AIMS: To explore temporal trends since 1980 in alcohol-related death for people resident in the European Union (EU) and to examine differences between EU members admitted prior to 2004 and new EU members admitted since 2004. METHODS: The data were extracted from the World Health Organization's European mortality database and the European Health for All database. RESULTS: New EU members had higher rates of alcohol-related deaths (135.0 +/- 18.48 vs 88.9 +/- 18.93; t = -8.55 (d.f. = 46), p < .001) and higher death rates from alcohol abuse (whole population: 3.4 +/- 1.24 vs 2.6 +/- 0.12; t = -2.98 (d.f. = 23.45), p < .01; male population: 6.1 +/- 2.17 vs 4.4 +/- 0.19; t = -3.87 (d.f. = 23.35), p < .001) than early EU countries. However, a mortality gradient between groups of countries was visible only for female alcohol-related deaths when controlling for mortality rates from all causes. Multivariate regression analyses also indicated that alcohol-related deaths and alcohol consumption were associated negatively with the gross national product (GNP) of EU countries and positively with levels of urbanization. CONCLUSIONS: Alcohol-related deaths represent more than 10% of all EU mortality and confirm the importance of national prevention strategies for alcohol problems. PMID- 22508719 TI - Peptidomics-based phylogeny and biogeography of Mantophasmatodea (Hexapoda). AB - The insect order Mantophasmatodea was described in 2002. Prior to that time, several generations of entomologists had assumed that all major insect taxa were known; thus, its description was a sensation for zoologists. Since then, a surprising abundance and species diversity of this taxon have been found, particularly in the winter rainfall region of South Africa. To learn more about the evolutionary lineages, speciation, and biogeography of Mantophasmatodea, we applied an unusual peptidomics approach. We collected specimens of almost all known and novel taxa of these insects, developed methods for immediate sample preparation in the field, introduced peptide mass fingerprints for the unambiguous identification of taxa, and subsequently analyzed the most extensive data set on peptide hormones ever compiled for insect taxa. To account for intraspecific variation, we analyzed several individuals per putative species. Increased taxon sampling was preferred over a further increase in the number of characters to optimize the accuracy of phylogenetic analyses. The large data set made it possible to test the validity of using neuropeptide sequences, which coevolve with their respective receptors, to analyze phylogenetic relationships among closely related taxa. Altogether, the data from 71 populations of Mantophasmatodea were sufficient to clearly separate the major clades of Mantophasmatodea, including previously undescribed taxa such as Pachyphasma, Striatophasma, and Austrophasmatidae gen. et sp. nov. "RV." The data confirm the monophyly of Austrophasmatidae and show a relatively recent and extensive radiation in the winter rainfall region of South Africa but also suggest that the species-level diversification of Namibian Mantophasma is less marked than previously thought. We discuss the biogeographical and ecological factors that may have resulted in different regional patterns of endemism and species diversity in Mantophasmatodea. The unique development of the neuroendocrine capa neurons in the ventral nervous system is described as synapomorphy of Mantophasmatodea + Grylloblattodea and is a further argument for a close relationship between these insect taxa. PMID- 22508720 TI - Fitting nonstationary general-time-reversible models to obtain edge-lengths and frequencies for the barry-hartigan model. AB - Among models of nucleotide evolution, the Barry and Hartigan (BH) model (also known as the General Markov Model) is very flexible as it allows separate arbitrary substitution matrices along edges. For a given tree, the estimates of the BH model are a set of joint probability matrices, each giving the pairwise frequencies of nucleotides at the ends of the edge. We have previously shown that, due to an identifiability problem, these cannot be expected to consistently estimate the actual pairwise frequencies. A further consequence is that internal node frequency estimates are likely to be incorrect. Here we define a nonstationary GTR model for each edge that we refer to as the NSGTR model. We fit the NSGTR model by minimizing the sums of squares between the estimates of transition probabilities under the NSGTR model and the estimates provided by a fitted BH model. This NSGTR model provides estimates that avoid the identifiability difficulties of the BH model while closely fitting it. With the best-fitting NSGTR estimates, we are able to get interpretable frequency vectors at internal nodes as well as edge length estimates that are otherwise not yielded by the BH model. These edge lengths are interpretable as the expected number of substitutions along an edge for the model. We also show that for a nonstationary continuous-time model these are not the same as the edge length parameters for conventional substitution matrices that are output by nonstationary model phylogenetic estimation programs such as nhPhyML. PMID- 22508721 TI - RNAi in fission yeast finds new targets and new ways of targeting at the nuclear periphery. AB - RNAi in Schizosaccharomyces pombe is critical for centromeric heterochromatin formation. It has remained unclear, however, whether RNAi also regulates the expression of protein-coding loci. In the April 1, 2012, issue of Genes & Development, Woolcock and colleagues (pp. 683-667) reported an elegant mechanism for the conditional RNAi-mediated repression of stress response genes involving association with Dcr1 at the nuclear pore. Unexpectedly, the initial targeting of RNAi components to these genes does not require small RNA guides. PMID- 22508722 TI - Developing S-phase control. AB - The duration of S phase in early embryos is often short, and then increases as development proceeds because of the appearance of late-replicating regions of the genome. In the April 1, 2012, issue of Genes & Development, Farrell and colleagues (pp. 714-725) demonstrate that the down-regulation of cyclin-dependent kinase 1 (Cdk1) activity triggers the onset of late-replicating DNA and an increase in S-phase length in Drosophila embryos, revealing an unexpected role for Cdk1 in replication control during development. PMID- 22508723 TI - A complex Polycomb issue: the two faces of EZH2 in cancer. AB - In the April 1, 2012, issue of Genes & Development, Simon and colleagues (pp. 651 656) demonstrated that the disruption of Ezh2 in mice is sufficient to cause T acute lymphoblastic leukemia (T-ALL). Moreover, in concert with concurrent studies, the authors revealed that similar mechanisms are involved in human T ALL. These data contrast with previous findings showing that increased EZH2 activity promotes cancer. PMID- 22508725 TI - Linking photoreceptor excitation to changes in plant architecture. AB - Plants sense neighbor proximity as a decrease in the ratio of red to far-red light, which triggers a series of developmental responses. In Arabidopsis, phytochrome B (PHYB) is the major sensor of shade, but PHYB excitation has not been linked directly to a growth response. We show that the basic helix-loop helix (bHLH) transcription factor PIF7 (phytochrome-interacting factor 7), an interactor of PHYB, accumulates in its dephosphorylated form in shade, allowing it to bind auxin biosynthetic genes and increase their expression. New auxin synthesized through a PIF7-regulated pathway is required for shade-induced growth, linking directly the perception of a light quality signal to a rapid growth response. PMID- 22508726 TI - The ubiquitin ligase mLin41 temporally promotes neural progenitor cell maintenance through FGF signaling. AB - How self-renewal versus differentiation of neural progenitor cells is temporally controlled during early development remains ill-defined. We show that mouse Lin41 (mLin41) is highly expressed in neural progenitor cells and its expression declines during neural differentiation. Loss of mLin41 function in mice causes reduced proliferation and premature differentiation of embryonic neural progenitor cells. mLin41 was recently implicated as the E3 ubiquitin ligase that mediates degradation of Argonaute 2 (AGO2), a key effector of the microRNA pathway. However, our mechanistic studies of neural progenitor cells indicate mLin41 is not required for AGO2 ubiquitination or stability. Instead, mLin41 deficient neural progenitors exhibit hyposensitivity for fibroblast growth factor (FGF) signaling. We show that mLin41 promotes FGF signaling by directly binding to and enhancing the stability of Shc SH2-binding protein 1 (SHCBP1) and that SHCBP1 is an important component of FGF signaling in neural progenitor cells. Thus, mLin41 acts as a temporal regulator to promote neural progenitor cell maintenance, not via the regulation of AGO2 stability, but through FGF signaling. PMID- 22508727 TI - Mutant p53 cooperates with ETS2 to promote etoposide resistance. AB - Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms, including disabling proapoptotic proteins and regulating gene expression. Comparison of genome wide analysis of mtp53 binding revealed that the ETS-binding site motif (EBS) is prevalent within predicted mtp53-binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5'-tyrosyl DNA phosphodiesterase involved in the repair of DNA damage caused by etoposide, as a transcriptional target of mtp53. We demonstrate that suppression of TDP2 sensitizes mtp53-expressing cells to etoposide and that mtp53 and TDP2 are frequently overexpressed in human lung cancer; thus, our analysis identifies a potentially "druggable" component of mtp53's gain-of-function activity. PMID- 22508728 TI - The RDE-10/RDE-11 complex triggers RNAi-induced mRNA degradation by association with target mRNA in C. elegans. AB - The molecular mechanisms for target mRNA degradation in Caenorhabditis elegans undergoing RNAi are not fully understood. Using a combination of genetic, proteomic, and biochemical approaches, we report a divergent RDE-10/RDE-11 complex that is required for RNAi in C. elegans. Genetic analysis indicates that the RDE-10/RDE-11 complex acts in parallel to nuclear RNAi. Association of the complex with target mRNA is dependent on RDE-1 but not RRF-1, suggesting that target mRNA recognition depends on primary but not secondary siRNA. Furthermore, RDE-11 is required for mRNA degradation subsequent to target engagement. Deep sequencing reveals a fivefold decrease in secondary siRNA abundance in rde-10 and rde-11 mutant animals, while primary siRNA and microRNA biogenesis is normal. Therefore, the RDE-10/RDE-11 complex is critical for amplifying the exogenous RNAi response. Our work uncovers an essential output of the RNAi pathway in C. elegans. PMID- 22508729 TI - In vivo Polycomb kinetics and mitotic chromatin binding distinguish stem cells from differentiated cells. AB - Epigenetic memory mediated by Polycomb group (PcG) proteins must be maintained during cell division, but must also be flexible to allow cell fate transitions. Here we quantify dynamic chromatin-binding properties of PH::GFP and PC::GFP in living Drosophila in two cell types that undergo defined differentiation and mitosis events. Quantitative fluorescence recovery after photobleaching (FRAP) analysis demonstrates that PcG binding has a higher plasticity in stem cells than in more determined cells and identifies a fraction of PcG proteins that binds mitotic chromatin with up to 300-fold longer residence times than in interphase. Mathematical modeling examines which parameters best distinguish stem cells from differentiated cells. We identify phosphorylation of histone H3 at Ser 28 as a potential mechanism governing the extent and rate of mitotic PC dissociation in different lineages. We propose that regulation of the kinetic properties of PcG chromatin binding is an essential factor in the choice between stability and flexibility in the establishment of cell identities. PMID- 22508730 TI - Xylem hydraulic adjustment and growth response of Quercus canariensis Willd. to climatic variability. AB - Global change challenges forest adaptability at the distributional limit of species. We studied ring-porous Quercus canariensis Willd. xylem traits to analyze how they adjust to spatio-temporal variability in climate. Trees were sampled along altitudinal transects, and annual time series of radial growth (ring width (RW)) and several earlywood vessel (EV) traits were built to analyze their relationships with climate. The trees responded to increasing water constraints with decreasing altitude and changes in climate in the short term but the analyses showed that xylem did not acclimate in response to long-term temperature increase during the past 30 years. The plants' adjustment to climate variability was expressed in a different but complementary manner by the different xylem traits. At low elevations, trees exhibited higher correlations with water stress indices and trees acclimated to more xeric conditions at low elevations by reducing radial growth and hydraulic diameter (D(H)) but increasing the density of vessels (DV). Average potential conductivity (K(H)) was similar for trees at different altitudes. However, inter-tree differences in xylem traits were higher than those between altitudes, suggesting a strong influence of individual genetic features or micro-site conditions. Trees exhibited higher RW those years with larger D(H) and particularly the linear density of vessels (DV(l)), but partly, climatic signals expressed in RW differed from those in EVs. Trees produced larger D(H) after cold winters and wet years. Ring width responded positively to wet and cool weather in fall and spring, whereas the response to climate of DV and K(H) was generally opposite to that of RW. These relationships likely expressed the negative impact of high respiration rates in winter on the carbon pools used to produce the EVs in the next spring and the overall positive influence of water availability for trees. Our results showed that trees at different sites were able to adjust their hydraulic architecture to climatic variability and temperature increase during recent decades coordinating several complementary traits. Nonetheless, it should be monitored whether they will succeed to acclimate to future climatic scenarios of increasing water stress. PMID- 22508724 TI - Emerging insights into the molecular and cellular basis of glioblastoma. AB - Glioblastoma is both the most common and lethal primary malignant brain tumor. Extensive multiplatform genomic characterization has provided a higher-resolution picture of the molecular alterations underlying this disease. These studies provide the emerging view that "glioblastoma" represents several histologically similar yet molecularly heterogeneous diseases, which influences taxonomic classification systems, prognosis, and therapeutic decisions. PMID- 22508732 TI - Epidural steroids, etanercept, or saline in subacute sciatica: a multicenter, randomized trial. AB - BACKGROUND: Perineural inhibitors of tumor necrosis factor have recently generated intense interest as an alternative to epidural steroid injections for lumbosacral radiculopathy. OBJECTIVE: To evaluate whether epidural steroids, etanercept, or saline better improves pain and function in adults with lumbosacral radiculopathy. DESIGN: A multicenter, 3-group, randomized, placebo controlled trial conducted from 2008 to 2011. Randomization was computer generated and stratified by site. Pharmacists prepared the syringes. Patients, treating physicians, and nurses assessing outcomes were blinded to treatment assignment. (ClinicalTrials.gov registration number: NCT00733096) SETTING: Military and civilian treatment centers. PATIENTS: 84 adults with lumbosacral radiculopathy of less than 6 months' duration. INTERVENTION: 2 epidural injections of steroids, etanercept, or saline, mixed with bupivacaine and separated by 2 weeks. MEASUREMENTS: The primary outcome measure was leg pain 1 month after the second injection. All patients had 1-month follow-up visits; patients whose condition improved remained blinded for the 6-month study period. RESULTS: The group that received epidural steroids had greater reductions in the primary outcome measure than those who received saline (mean difference, -1.26 [95% CI, -2.79 to 0.27]; P = 0.11) or etanercept (mean difference, -1.01 [CI, 2.60 to 0.58]; P = 0.21). For back pain, smaller differences favoring steroids compared with saline (mean difference, -0.52 [CI, -1.85 to 0.81]; P = 0.44) and etanercept (mean difference, -0.92 [CI,-2.28 to 0.44]; P = 0.18) were observed. The largest differences were noted for functional capacity, in which etanercept fared worse than the other treatments: steroids vs. etanercept (mean difference, 16.16 [CI, -26.05 to -6.27]; P = 0.002), steroids vs. saline (mean difference, 5.87 [CI, -15.59 to 3.85]; P = 0.23), and etanercept vs. saline (mean difference, 10.29 [CI, 0.55 to 20.04]; P = 0.04). More patients treated with epidural steroids (75%) reported 50% or greater leg pain relief and a positive global perceived effect at 1 month than those who received saline (50%) or etanercept (42%) (P = 0.09). LIMITATION: Short-term follow-up, small sample size, and a possibly subtherapeutic dose of etanercept. CONCLUSION: Epidural steroid injections may provide modest short-term pain relief for some adults with lumbosacral radiculopathy, but larger studies with longer follow-up are needed to confirm their benefits. PRIMARY FUNDING SOURCE: The John P. Murtha Neuroscience and Pain Institute, International Spinal Intervention Society, and Center for Rehabilitation Sciences Research. PMID- 22508733 TI - New fibrate use and acute renal outcomes in elderly adults: a population-based study. AB - BACKGROUND: Fibric acid derivatives (fibrates) have been shown to increase serum creatinine level in randomized trials. OBJECTIVE: To assess renal outcomes in elderly adults within 90 days of a new fibrate prescription. DESIGN: Population based cohort study. SETTING: Ontario, Canada. PATIENTS: Patients aged 66 years or older with a new outpatient prescription for a fibrate or ezetimibe (comparator drug) between January 2004 and December 2008. MEASUREMENTS: Hospitalization for an increase in serum creatinine level (primary outcome) and consultation with a nephrologist, receipt of dialysis for severe acute kidney injury, all-cause mortality, and increases in serum creatinine level (secondary outcomes). All outcomes were assessed within 90 days of a new prescription for ezetimibe or a fibrate. RESULTS: Compared with ezetimibe users (n = 61,831), fibrate users (n = 19,072) were more likely to be hospitalized for an increase in serum creatinine level (adjusted odds ratio, 2.4 [95% CI, 1.7 to 3.3]) and were more likely to consult a nephrologist (absolute risk difference, 0.15% [CI, 0.01% to 0.29%]; adjusted odds ratio, 1.3 [CI, 1.0 to 1.6]). There were no differences between groups in the risk for all-cause mortality or receiving dialysis for severe acute kidney injury. In a subpopulation of 1110 patients (fibrates, n = 220; ezetimibe, n = 890), 9.1% of fibrate users and 0.3% of ezetimibe users had an increase in serum creatinine level of 50% or more (absolute difference, 8.8% [CI, 4.5% to 13.1%]; odds ratio, 29.6 [CI, 8.7 to 100.5]). Risks were greater among fibrate users with chronic kidney disease. LIMITATIONS: Because hospitalizations for an increase in serum creatinine level were underestimated, absolute differences may be misleading. Most patients (91%) were prescribed fenofibrate. Serum creatinine levels were measured as part of routine care and were not available for everyone or at predefined times. CONCLUSION: New fibrate use in elderly adults was associated with an increase in serum creatinine level and a small 90-day absolute increase in hospitalizations and nephrologist consultations. There was no detectable effect on dialysis for severe acute kidney injury or on mortality. The mechanism and clinical significance of the increase in serum creatinine level with fibrates is unclear. PRIMARY FUNDING SOURCE: Ontario Ministry of Health and Long-Term Care Drug Innovation Fund. PMID- 22508734 TI - Screening for, monitoring, and treatment of chronic kidney disease stages 1 to 3: a systematic review for the U.S. Preventive Services Task Force and for an American College of Physicians Clinical Practice Guideline. AB - BACKGROUND: Screening and monitoring for chronic kidney disease (CKD) could lead to earlier interventions that improve clinical outcomes. PURPOSE: To summarize evidence about the benefits and harms of screening for and monitoring and treatment of CKD stages 1 to 3 in adults. DATA SOURCES: MEDLINE (1985 through November 2011), reference lists, and expert suggestions. STUDY SELECTION: English language, randomized, controlled trials that evaluated screening for or monitoring or treatment of CKD and that reported clinical outcomes. DATA EXTRACTION: Two reviewers assessed study characteristics and rated quality and strength of evidence. DATA SYNTHESIS: No trials evaluated screening or monitoring, and 110 evaluated treatments. Angiotensin-converting enzyme inhibitors (relative risk, 0.65 [95% CI, 0.49 to 0.88]) and angiotensin II receptor blockers (relative risk, 0.77 [CI, 0.66 to 0.90]) reduced end-stage renal disease versus placebo, primarily in patients with diabetes who have macroalbuminuria. Angiotensin-converting enzyme inhibitors reduced mortality versus placebo (relative risk, 0.79 [CI, 0.66 to 0.96]) in patients with microalbuminuria and cardiovascular disease or high-risk diabetes. Statins and beta-blockers reduced mortality and cardiovascular events versus placebo or control in patients with impaired estimated glomerular filtration rate and either hyperlipidemia or congestive heart failure, respectively. Risks for mortality, end-stage renal disease, or other clinical outcomes did not significantly differ between strict and usual blood pressure control. The strength of evidence was rated high for angiotensin II-receptor blockers and statins, moderate for angiotensin-converting enzyme inhibitors and beta-blockers, and low for strict blood pressure control. LIMITATIONS: Evidence about outcomes was sometimes scant and derived from post hoc analyses of subgroups of patients enrolled in trials. Few trials reported or systematically collected information about adverse events. Selective reporting and publication bias were possible. CONCLUSION: The role of CKD screening or monitoring in improving clinical outcomes is uncertain. Evidence for CKD treatment benefit is strongest for angiotensin-converting enzyme inhibitors and angiotensin II-receptor blockers, and in patients with albuminuria combined with diabetes or cardiovascular disease. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 22508731 TI - The cost-effectiveness of preexposure prophylaxis for HIV prevention in the United States in men who have sex with men. AB - BACKGROUND: A recent randomized, controlled trial showed that daily oral preexposure chemoprophylaxis (PrEP) was effective for HIV prevention in men who have sex with men (MSM). The Centers for Disease Control and Prevention recently provided interim guidance for PrEP in MSM at high risk for HIV. Previous studies did not reach a consistent estimate of its cost-effectiveness. OBJECTIVE: To estimate the effectiveness and cost-effectiveness of PrEP in MSM in the United States. DESIGN: Dynamic model of HIV transmission and progression combined with a detailed economic analysis. DATA SOURCES: Published literature. TARGET POPULATION: MSM aged 13 to 64 years in the United States. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: PrEP was evaluated in both the general MSM population and in high-risk MSM and was assumed to reduce infection risk by 44% on the basis of clinical trial results. OUTCOME MEASURES: New HIV infections, discounted quality-adjusted life-years (QALYs) and costs, and incremental cost effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS: Initiating PrEP in 20% of MSM in the United States would reduce new HIV infections by an estimated 13% and result in a gain of 550,166 QALYs over 20 years at a cost of $172,091 per QALY gained. Initiating PrEP in a larger proportion of MSM would prevent more infections but at an increasing cost per QALY gained (up to $216,480 if all MSM receive PrEP). Preexposure chemoprophylaxis in only high-risk MSM can improve cost-effectiveness. For MSM with an average of 5 partners per year, PrEP costs approximately $50,000 per QALY gained. Providing PrEP to all high-risk MSM for 20 years would cost $75 billion more in health care-related costs than the status quo and $600,000 per HIV infection prevented, compared with incremental costs of $95 billion and $2 million per infection prevented for 20% coverage of all MSM. RESULTS OF SENSITIVITY ANALYSIS: PrEP in the general MSM population would cost less than $100,000 per QALY gained if the daily cost of antiretroviral drugs for PrEP was less than $15 or if PrEP efficacy was greater than 75%. LIMITATION: When examining PrEP in high-risk MSM, the investigators did not model a mix of low- and high-risk MSM because of lack of data on mixing patterns. CONCLUSION: PrEP in the general MSM population could prevent a substantial number of HIV infections, but it is expensive. Use in high-risk MSM compares favorably with other interventions that are considered cost-effective but could result in annual PrEP expenditures of more than $4 billion. PRIMARY FUNDING SOURCE: National Institute on Drug Abuse, Department of Veterans Affairs, and National Institute of Allergy and Infectious Diseases. PMID- 22508735 TI - Consent for research with biological samples: one-time general consent versus a gift model. AB - This analysis suggests that one-time general consent is better than a gift model for addressing 5 central challenges that arise in the context of obtaining and storing human biological samples for future research. This conclusion supports the suggestion made in a recent Advance Notice of Proposed Rulemaking to incorporate one-time general consent for research with human biological samples into any revisions of the federal regulations. PMID- 22508736 TI - Developing guidelines for chronic kidney disease: we should include all of the outcomes. PMID- 22508737 TI - The watchman. PMID- 22508738 TI - Screening for cervical cancer. PMID- 22508739 TI - Defining patient complexity. PMID- 22508740 TI - Defining patient complexity. PMID- 22508741 TI - Inviting patients to read doctors' notes. PMID- 22508742 TI - ACP Journal Club. Review: PSA-based screening does not reduce prostate cancer mortality or all-cause mortality. PMID- 22508743 TI - ACP Journal Club. Radical prostatectomy and watchful waiting for localized prostate cancer did not differ for quality of life. PMID- 22508744 TI - ACP Journal Club. Review: Androgen deprivation therapy does not increase CV mortality in prostate cancer. PMID- 22508745 TI - ACP Journal Club. Radiation plus androgen deprivation therapy reduced mortality in locally advanced prostate cancer. PMID- 22508746 TI - ACP Journal Club. Enoxaparin thrombophylaxis did not reduce mortality in acutely ill medical patients. PMID- 22508747 TI - ACP Journal Club. Review: Statins reduce mortality and cardiovascular (CV) morbidity in patients with low CV risk. PMID- 22508748 TI - ACP Journal Club. Adding niacin to simvastatin did not improve clinical outcomes in patients with CV disease and dyslipidemia. PMID- 22508749 TI - ACP Journal Club. Review: Fidaxomicin is better than vancomycin for Clostridium difficile recurrence. PMID- 22508750 TI - ACP Journal Club. Ivacaftor improved lung function in cystic fibrosis with G551D mutation. PMID- 22508751 TI - ACP Journal Club. Thiazides increased hyponatremia, but not hospitalizations, in patients with hypertension. PMID- 22508752 TI - ACP Journal Club. The simplified Pulmonary Embolism Severity Index and high sensitivity troponin T predicted prognosis in PE. PMID- 22508753 TI - ACP Journal Club. CHADS2 score predicted bleeding and death in atrial fibrillation treated with anticoagulants. PMID- 22508754 TI - Impact of PNKP mutations associated with microcephaly, seizures and developmental delay on enzyme activity and DNA strand break repair. AB - Microcephaly with early-onset, intractable seizures and developmental delay (MCSZ) is a hereditary disease caused by mutations in polynucleotide kinase/phosphatase (PNKP), a DNA strand break repair protein with DNA 5'-kinase and DNA 3'-phosphatase activity. To investigate the molecular basis of this disease, we examined the impact of MCSZ mutations on PNKP activity in vitro and in cells. Three of the four mutations currently associated with MCSZ greatly reduce or ablate DNA kinase activity of recombinant PNKP at 30 degrees C (L176F, T424Gfs48X and exon15Deltafs4X), but only one of these mutations reduces DNA phosphatase activity under the same conditions (L176F). The fourth mutation (E326K) has little impact on either DNA kinase or DNA phosphatase activity at 30 degrees C, but is less stable than the wild-type enzyme at physiological temperature. Critically, all of the MCSZ mutations identified to date result in ~ 10-fold reduced cellular levels of PNKP protein, and reduced rates of chromosomal DNA strand break repair. Together, these data suggest that all four known MCSZ mutations reduce the cellular stability and level of PNKP protein, with three mutations likely ablating cellular DNA 5'-kinase activity and all of the mutations greatly reducing cellular DNA 3'-phosphatase activity. PMID- 22508756 TI - Developmental delays in children with ADHD. AB - OBJECTIVE: ADHD is often comorbid with other disorders, but it is often assumed that academic, language, or motor c skills problems are secondary to ADHD rather than that attention problems are secondary to the other disorder or both disorders have a shared etiology. We assessed for comorbid developmental disorders and which cognitive processes were impaired in children with ADHD. METHOD: Measures of intelligence, language, motor skills, social cognition, and executive functions were administered to children with ADHD (n = 53) and age/sex matched typical children. RESULTS: Clinically significant deficits were 2 to 7 times as common in children with ADHD as in typical children, and the structure of ability differed in the two groups. Abilities were less differentiated in children with ADHD. CONCLUSION: The results indicate a need for comprehensive screening for developmental disorders in children with ADHD and imply that research needs to focus on how ADHD and developmental disorders may share an etiology. PMID- 22508755 TI - Oxidative stress during mitochondrial biogenesis compromises mtDNA integrity in growing hearts and induces a global DNA repair response. AB - Cardiomyocyte development in mammals is characterized by a transition from hyperplastic to hypertrophic growth soon after birth. The rise of cardiomyocyte cell mass in postnatal life goes along with a proportionally bigger increase in the mitochondrial mass in response to growing energy requirements. Relatively little is known about the molecular processes regulating mitochondrial biogenesis and mitochondrial DNA (mtDNA) maintenance during developmental cardiac hypertrophy. Genome-wide transcriptional profiling revealed the activation of transcriptional regulatory circuits controlling mitochondrial biogenesis in growing rat hearts. In particular, we detected a specific upregulation of factors involved in mtDNA expression and translation. More surprisingly, we found a specific upregulation of DNA repair proteins directly linked to increased oxidative damage during heart mitochondrial biogenesis, but only relatively minor changes in the mtDNA replication machinery. Our study paves the way for improved understanding of mitochondrial biogenesis, mtDNA maintenance and physiological adaptation processes in the heart and provides the first evidence for the recruitment of nucleotide excision repair proteins to mtDNA in cardiomyocytes upon DNA damage. PMID- 22508757 TI - Association between ADHD symptoms and anxiety symptoms in Taiwanese adolescents. AB - OBJECTIVE: The aims of this cross-sectional study were to examine the association between significant ADHD symptoms and the four domains of anxiety symptoms on the Taiwanese version of Multidimensional Anxiety Scale for Children (MASC-T) and to examine the moderating effects of sociodemographic characteristics on this association among Taiwanese adolescents in the community. METHOD: A total of 4,716 adolescents in Grades 7 through 12 in southern Taiwan completed the MASC-T, the ADHD Self-Rated Scale, the Mandarin Chinese version of the Center for Epidemiological Studies Depression Scale, the Rosenberg Self-Esteem Scale, and a questionnaire about sociodemographic characteristics. Multiple regression analysis was used to examine both the association of significant ADHD symptoms with four domains of anxiety symptoms on the MASC-T and the moderating effects of sociodemographic characteristics on this association. RESULTS: The adolescents with significant ADHD symptoms had more severe total anxiety symptoms, physical symptoms, social anxiety symptoms, and separation/panic symptoms for three domains of the MASC-T but less harm avoidance than did those without significant ADHD symptoms. Age, gender, and low self-esteem had moderating effects on the association between significant ADHD symptoms and anxiety symptoms for some domains of the MASC-T. CONCLUSION: The results of this study suggest a significant association between significant ADHD symptoms and the severity of anxiety symptoms in adolescents. Clinicians must evaluate anxiety symptoms among adolescents with ADHD and arrange comprehensive treatment programs. PMID- 22508758 TI - The influence of parent behaviors on positive illusory bias in children with ADHD. AB - OBJECTIVE: To explore the relationship between parental feedback and the accuracy of children's self-perceptions. Children with ADHD have been demonstrated to overestimate their own competence, a phenomenon known as positive illusory bias (PIB). METHOD: Participants were families of 56 children (41 male) ages 7 to 10, half of whom had clinical diagnoses of ADHD. PIB was assessed by comparing children's self-ratings of their competence relative to teachers' ratings. Laboratory interactions were observed where parental feedback to children was coded. RESULTS: Parental warmth was associated with lower PIB about social competence in children with ADHD, but greater PIB in comparison children. Parent criticism was positively correlated with greater PIB about social competence in children with ADHD, but the relationship was nonsignificant for comparison children. Parent praise was associated with lower PIB about behavioral conduct in comparison children. CONCLUSION: Results support the self-protective hypothesis of PIB, and implications for interventions are discussed. PMID- 22508759 TI - Increased response-time variability across different cognitive tasks in children with ADHD. AB - OBJECTIVE: Increased response-time (RT) fluctuations below 0.2 Hz have been reported as characteristic of ADHD in some but not all studies, possibly due to methodological differences. Accordingly, We contrasted two tasks and two analytical approaches in the same sample of children with ADHD. METHOD: Fifty-two children with ADHD and 49 typically developing children completed an Eriksen Flanker Task and a fixed-sequence version of the sustained attention to response task. RT fluctuations with two different frequency analyses were examined. RESULTS: Robust ADHD-related increases of slow RT fluctuations within all frequencies were found in both tasks. Tasks were significantly correlated in both groups for frequencies above 0.07 Hz. RT fluctuations across all frequencies were greatest in children with ADHD with abnormally elevated omissions. CONCLUSION: We observed significantly increased fluctuations of RT in children with ADHD across two different tasks and methods supporting the hypothesis that slow frequency RT fluctuations reflect neurophysiological processes underlying ADHD. PMID- 22508760 TI - A pilot study of lis-dexamfetamine dimesylate (LDX/SPD489) to facilitate smoking cessation in nicotine-dependent adults with ADHD. AB - OBJECTIVE: The goal of this study was to assess the efficacy and tolerability of lis-dexamfetamine dimesylate (LDX) as an adjunct to nicotine replacement therapy in adult smokers with ADHD who were undergoing a quit attempt. METHODS: Thirty two regular adult smokers with ADHD were randomized to receive LDX (n = 17) or placebo (n = 15) in addition to nicotine patch concurrent with a quit attempt. RESULTS: There were no differences between smokers assigned to LDX versus placebo in any smoking outcomes. Participants treated with LDX demonstrated significant reductions in self-reported and clinician-rated ADHD symptoms. LDX was well tolerated in smokers attempting to quit. DISCUSSION: In general, LDX does not facilitate smoking cessation in adults with ADHD more than does placebo, though both groups significantly reduced smoking. LDX demonstrated efficacy for reducing ADHD symptoms in adult smokers engaging in a quit attempt. PMID- 22508761 TI - Caveolin-1, caveolae, and glioblastoma. AB - Glioblastoma multiforme (GBM) is the most common malignant brain tumor and is characterized by high invasiveness, poor prognosis, and limited therapeutic options. Biochemical and morphological experiments have shown the presence of caveolae in glioblastoma cells. Caveolae are flask-shaped plasma membrane subdomains that play trafficking, mechanosensing, and signaling roles. Caveolin-1 is a membrane protein that participates in the formation of caveolae and binds a multitude of signaling proteins, compartmentalizing them in caveolae and often directly regulating their activity via binding to its scaffolding domain. Caveolin-1 has been proposed to behave either as a tumor suppressor or as an ongogene depending on the tumor type and progress. This review discusses the existing information on the expression and function of caveolin-1 and caveolae in GBM and the role of this organelle and its defining protein on cellular signaling, growth, and invasiveness of GBM. We further analyze the available data suggesting caveolin-1 could be a target in GBM therapy. PMID- 22508762 TI - Early measures of cognitive function predict survival in patients with newly diagnosed glioblastoma. AB - Cognitive dysfunction is a common manifestation of primary brain tumors. We evaluated the association between early cognitive dysfunction and prognosis in a cohort of patients with newly diagnosed glioblastoma. Ninety-one patients who completed neuropsychological assessment after tumor resection but before further treatment were identified in the MD Anderson Neuropsychology database. The relationship between performance on cognitive testing and survival was evaluated using not only Cox proportional hazards models that included clinical factors such as age and KPS but also the Kaplan-Meier method. Median survival time from surgery was 20.7 months. Rates of impairment on cognitive testing ranged from 7.1% for Similarities, to 60.0% for Hopkins Verbal Learning Test-Revised Total Recall. As continuous variables, the Clinical Trial Battery Composite, Trail Making Test Part B, and Controlled Oral Word Association test were associated with survival. Impairment on the Trail Making Test Part B, Controlled Oral Word Association, Similarities, and Digit Span were associated with mortality. Kaplan Meier analysis demonstrated the survival impact of these tests on the group as a whole and in select patient subgroups defined by classification by the Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA). Cognitive impairment as measured by specific neuropsychological tests is independently associated with poor prognosis in patients with newly diagnosed glioblastoma, and this effect remains significant even within patient subgroups defined by RTOG RPA class. Executive function and attention are the cognitive domains most closely associated with prognosis in this analysis. PMID- 22508763 TI - Multidimensional regulation of gene expression in the C. elegans embryo. AB - How cells adopt different expression patterns is a fundamental question of developmental biology. We quantitatively measured reporter expression of 127 genes, primarily transcription factors, in every cell and with high temporal resolution in C. elegans embryos. Embryonic cells are highly distinct in their gene expression; expression of the 127 genes studied here can distinguish nearly all pairs of cells, even between cells of the same tissue type. We observed recurrent lineage-regulated expression patterns for many genes in diverse contexts. These patterns are regulated in part by the TCF-LEF transcription factor POP-1. Other genes' reporters exhibited patterns correlated with tissue, position, and left-right asymmetry. Sequential patterns both within tissues and series of sublineages suggest regulatory pathways. Expression patterns often differ between embryonic and larval stages for the same genes, emphasizing the importance of profiling expression in different stages. This work greatly expands the number of genes in each of these categories and provides the first large scale, digitally based, cellular resolution compendium of gene expression dynamics in live animals. The resulting data sets will be a useful resource for future research. PMID- 22508764 TI - Genome-wide phosphoacetylation of histone H3 at Drosophila enhancers and promoters. AB - Transcription regulation is mediated by enhancers that bind sequence-specific transcription factors, which in turn interact with the promoters of the genes they control. Here, we show that the JIL-1 kinase is present at both enhancers and promoters of ecdysone-induced Drosophila genes, where it phosphorylates the Ser10 and Ser28 residues of histone H3. JIL-1 is also required for CREB binding protein (CBP)-mediated acetylation of Lys27, a well-characterized mark of active enhancers. The presence of these proteins at enhancers and promoters of ecdysone induced genes results in the establishment of the H3K9acS10ph and H3K27acS28ph marks at both regulatory sequences. These modifications are necessary for the recruitment of 14-3-3, a scaffolding protein capable of facilitating interactions between two simultaneously bound proteins. Chromatin conformation capture assays indicate that interaction between the enhancer and the promoter is dependent on the presence of JIL-1, 14-3-3, and CBP. Genome-wide analyses extend these conclusions to most Drosophila genes, showing that the presence of JIL-1, H3K9acS10ph, and H3K27acS28ph is a general feature of enhancers and promoters in this organism. PMID- 22508765 TI - Differential DNase I hypersensitivity reveals factor-dependent chromatin dynamics. AB - Transcription factor cistromes are highly cell-type specific. Chromatin accessibility, histone modifications, and nucleosome occupancy have all been found to play a role in defining these binding locations. Here, we show that hormone-induced DNase I hypersensitivity changes (DeltaDHS) are highly predictive of androgen receptor (AR) and estrogen receptor 1 (ESR1) binding in prostate cancer and breast cancer cells, respectively. While chromatin structure prior to receptor binding and nucleosome occupancy after binding are strikingly different for ESR1 and AR, DeltaDHS is highly predictive for both. AR binding is associated with changes in both local nucleosome occupancy and DNase I hypersensitivity. In contrast, while global ESR1 binding is unrelated to changes in nucleosome occupancy, DNase I hypersensitivity dynamics are also predictive of the ESR1 cistrome. These findings suggest that AR and ESR1 have distinct modes of interaction with chromatin and that DNase I hypersensitivity dynamics provides a general approach for predicting cell-type specific cistromes. PMID- 22508767 TI - Neural bases of the interactions between spatial attention and conscious perception. AB - Recent behavioral observations suggest that some forms of attentional orienting have the ability to modulate access to perceptual consciousness. However, the neural structures subserving such processes remain uncertain. We used functional magnetic resonance imaging during a visual discrimination task with near threshold targets preceded by peripheral cues to identify the neural bases of the interactions between spatial attention and conscious visual perception. During the cue-target period critical for spatial orienting, regions within a frontoparietal network, including nodes of the dorsal attentional system, were more strongly engaged for consciously perceived targets than for nonperceived targets at attended locations. Moreover, activation increased for "unseen" targets in more ventral frontoparietal regions, known to be part of a system involved in attentional reorienting. Functional connectivity analyses revealed tighter coupling between frontoparietal nodes for valid cues leading to "seen" reports and for invalid cues leading to unseen reports. We conclude that spatial orienting to peripheral stimuli, subserved by frontoparietal attentional networks, plays a major role in determining the content of our conscious experience. PMID- 22508766 TI - Visual and audiovisual effects of isochronous timing on visual perception and brain activity. AB - Understanding how the brain extracts and combines temporal structure (rhythm) information from events presented to different senses remains unresolved. Many neuroimaging beat perception studies have focused on the auditory domain and show the presence of a highly regular beat (isochrony) in "auditory" stimulus streams enhances neural responses in a distributed brain network and affects perceptual performance. Here, we acquired functional magnetic resonance imaging (fMRI) measurements of brain activity while healthy human participants performed a visual task on isochronous versus randomly timed "visual" streams, with or without concurrent task-irrelevant sounds. We found that visual detection of higher intensity oddball targets was better for isochronous than randomly timed streams, extending previous auditory findings to vision. The impact of isochrony on visual target sensitivity correlated positively with fMRI signal changes not only in visual cortex but also in auditory sensory cortex during audiovisual presentations. Visual isochrony activated a similar timing-related brain network to that previously found primarily in auditory beat perception work. Finally, activity in multisensory left posterior superior temporal sulcus increased specifically during concurrent isochronous audiovisual presentations. These results indicate that regular isochronous timing can modulate visual processing and this can also involve multisensory audiovisual brain mechanisms. PMID- 22508768 TI - Exploration of the neural correlates of ticklish laughter by functional magnetic resonance imaging. AB - The burst of laughter that is evoked by tickling is a primitive form of vocalization. It evolves during an early phase of postnatal life and appears to be independent of higher cortical circuits. Clinicopathological observations have led to suspicions that the hypothalamus is directly involved in the production of laughter. In this functional magnetic resonance imaging investigation, healthy participants were 1) tickled on the sole of the right foot with permission to laugh, 2) tickled but asked to stifle laughter, and 3) requested to laugh voluntarily. Tickling that was accompanied by involuntary laughter activated regions in the lateral hypothalamus, parietal operculum, amygdala, and right cerebellum to a consistently greater degree than did the 2 other conditions. Activation of the periaqueductal gray matter was observed during voluntary and involuntary laughter but not when laughter was inhibited. The present findings indicate that hypothalamic activity plays a crucial role in evoking ticklish laughter in healthy individuals. The hypothalamus promotes innate behavioral reactions to stimuli and sends projections to the periaqueductal gray matter, which is itself an important integrative center for the control of vocalization. A comparison of our findings with published data relating to humorous laughter revealed the involvement of a common set of subcortical centers. PMID- 22508769 TI - Cutaneous B-cell neoplasms mimicking granulomatous rosacea or rhinophyma. AB - BACKGROUND: Unlike T-cell neoplasms, B-cell lymphoproliferative disorders have a limited clinical spectrum of skin involvement. Cutaneous B-cell neoplasms mimicking rosacea or rhinophyma are rare. OBSERVATIONS: We described 12 patients with B-cell lymphoproliferative neoplasms presenting with a facial eruption clinically mimicking rosacea or rhinophyma. Eleven patients were women; ages ranged from 36 to 81 years. The clinical presentation included small papules on the nose and cheeks and around the eyes mimicking granulomatous rosacea; nodules on the nose, cheeks, chin, or forehead mimicking phymatous rosacea; or a combination of both. Three patients had preexisting erythematotelangiectatic rosacea and 1 had rhinophyma. Based on a clinicopathologic correlation and B-cell clonality analysis, the diagnosis was primary cutaneous follicular center B-cell lymphoma in 4 cases, primary cutaneous marginal zone lymphoma in 6, and skin involvement of chronic lymphocytic leukemia in 2. All patients had an indolent course as expected for their disease. CONCLUSIONS: Cutaneous involvement of B cell neoplasms may mimic granulomatous rosacea or rhinophyma. This unusual clinical presentation is more common in women and appears in the setting of preexisting rosacea or as a new eruption. Proliferative B-cell disorders should be added to the differential diagnosis of symmetric papular or papulonodular eruptions of the face. PMID- 22508770 TI - Primary cutaneous follicular helper T-cell lymphoma: a new subtype of cutaneous T cell lymphoma reported in a series of 5 cases. AB - BACKGROUND: Peripheral nodal follicular T-cell lymphomas expressing follicular helper T-cell (T(FH)) markers have recently been identified. Such lymphomas are characterized by a nodal neoplastic T-cell proliferation accompanied by numerous reactive B cells and demonstrate some overlap with nodal angioimmunoblastic T cell lymphoma (AITL). We identified 5 cases of cutaneous T-cell lymphoma with a peculiar pathologic aspect and expression of T(FH) markers. OBSERVATIONS: The mean age of the patients was 61 years (range, 33-78 years). Four patients had multiple papules, plaques, and nodules predominating on the trunk and the head. One had a nodular plaque on the face. Lesional T-cell clonality was found in all 5 patients, and blood T-cell clonality in 4 of the 5. Nodal involvement was never found. Patients had no systemic symptoms and no biological signs of AITL. In 3 cases, findings from skin biopsy specimens were initially misdiagnosed as primary cutaneous follicle B-cell lymphoma due to major B-cell infiltrate and CD10 positivity. Rituximab-containing therapies were ineffective in these cases, and biopsy specimens after treatment with rituximab showed medium- to large-sized atypical T-cell skin infiltrate expressing T(FH) markers (CD10, Bcl-6, PD-1, CXCL13, and ICOS). The final diagnosis proposed for all patients was cutaneous T(FH) lymphoma. The patient with localized disease was successfully treated with radiotherapy. Patients with diffuse disease showed marked resistance to treatments, with only 1 case of complete remission after allogeneic hematopoietic stem cell transplantation followed by bortezomib and donor-lymphocyte infusion. Bexarotene, methotrexate, thalidomide, interferon alfa, gemcitabine, liposomal doxorubicin, or multiagent chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) were either ineffective or induced transitory partial remission. CONCLUSIONS: We describe an original clinicopathologic series of primary cutaneous lymphomas with T(FH) phenotype, suggesting the existence of a new entity among cutaneous T-cell lymphomas. Relations of these lymphomas with the provisional entity of primary cutaneous small to medium CD4 pleomorphic T cell lymphoma need to be further addressed. PMID- 22508771 TI - Ocular adverse effects of systemic treatment with isotretinoin. AB - OBJECTIVE: To examine whether isotretinoin therapy could result in deleterious ocular effects, as previously described in case report studies. DESIGN: Retrospective cohort study. SETTING: The study was conducted using the electronic medical databases of a large health maintenance organization in Israel. PATIENTS: The study population consisted of 14 682 adolescents and young adults who were new users of isotretinoin for acne and 2 age- and sex-matched comparison groups (isotretinoin-naive patients with acne and acne-free patients). MAIN OUTCOME MEASURES: Ocular adverse effects (AEs) or purchases of ophthalmic medications within 1 year after the first dispensed isotretinoin prescription. RESULTS: In total, 13.8% of the isotretinoin group experienced ocular AEs vs 9.6% of the isotretinoin-naive group and 7.1% of the acne-free group. During a 1-year follow up period, the isotretinoin group had significantly higher risk for any ocular AEs (hazard ratio, 1.70; P.001) compared with the acne-free group. No such increased risk was observed for the isotretinoin-naive group. The isotretinoin group had higher relative risks for inflammatory and structural AEs. CONCLUSION: Isotretinoin use may be associated with short-term ocular events, especially conjunctivitis, underscoring the importance of educating patients and caregivers about these potentially important AEs of the therapy. PMID- 22508772 TI - A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. AB - OBJECTIVE: To investigate the preliminary safety and efficacy of apremilast, an oral phosphodiesterase 4 inhibitor, for atopic dermatitis. DESIGN: This investigator-initiated, open-label pilot study evaluated 2 doses of apremilast in patients with atopic dermatitis. Differential gene analysis was performed from peripheral whole blood using data before and after treatment. SETTING: University based dermatology clinical research unit. PATIENTS: Sixteen adult patients with atopic dermatitis. INTERVENTION: A specific phosphodiesterase 4 inhibitor, apremilast. MAIN OUTCOME MEASURES: The primary outcome was incidence of adverse events. Secondary outcomes included the differences in pruritus, Dermatology Life Quality Index (DLQI), and Eczema Area and Severity Index (EASI) scores between the baseline visit and end-ofstudy visit for each cohort. RESULTS: The group receiving apremilast, 20 mg twice daily, displayed a significant reduction from baseline of pruritus (P=.02) and the DLQI (P=.003) at 3 months. The group receiving apremilast, 30 mg twice daily, displayed a significant reduction of the EASI (P=.008) and the DLQI (P=.01) at 3 months. At 6 months, there was a significant reduction of the EASI (P=.002), the visual analog scale (P=.03), and the DLQI (P=.03). Gene ontologic analyses comparing baseline with samples during treatment revealed alterations in immune response pathways, especially those related to cyclic adenosine monophosphate-mediated signaling. CONCLUSIONS: These results support further development of apremilast for treatment of atopic dermatitis. Larger randomized controlled studies are needed to more adequately evaluate both safety and efficacy. Limitations include the small sample size and absence of a control. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01393158. PMID- 22508773 TI - Pronounced allelic imbalance at D9S162 in skin squamous cell carcinoma of organ transplant recipients. AB - OBJECTIVE: To evaluate chromosomal instability at 9p21-22 with p16 protein expression in organ transplant recipients (OTRs) compared with immunocompetent patients with squamous cell carcinoma (SCC). DESIGN: In a select population of intraepithelial and subsequent invasive SCC from the same anatomic region of the same patient at different times, we assessed loss of heterozygosity at 3 microsatellites-IFNA, D9S162, and D9S925-in the course of carcinogenesis in OTRs and immunocompetent patients. SETTING: Department of Dermatology, University Hospital Zurich. PATIENTS: Immunocompetent patients and OTRs with SCC on sun damaged skin. MAIN OUTCOME MEASURE: Chromosomal allelic balance in SCC of OTRs and immunocompetent patients. RESULTS: Reduced allelic balance at IFNA, D9S162, and D9S925 in intraepithelial forms of SCC and similar allelic imbalance in invasive forms of SCC were found. Allelic balance at D9S162 was reduced for SCC in OTRs compared with SCC in immunocompetent patients. The study revealed broadly reduced allelic balance at 9p21-22 in all cutaneous SCCs, and OTRs presented a further reduced allelic balance for D9S162, suggesting a common trait for SCC in OTRs. Actinic keratosis and Bowen disease differed in allelic balance at D9S162, suggesting substantial differences in their carcinogenesis. CONCLUSION: Reduced allelic balance around locus D9S162 is a genomic correlate for enhanced carcinogenesis in OTRs. PMID- 22508774 TI - Early depth assessment of local burns by dermoscopy: a new frontier of dermoscopic evaluation. AB - This article has been retracted. See Notice of Retraction. OBJECTIVE: To investigate the effectiveness of early depth assessment of local burns, the depth of which is difficult to assess with the naked eye, by dermoscopy. DESIGN: The morphological findings of burn wounds were prospectively evaluated by dermoscopy and videomicroscopy. Prior to dermoscopic and videomicroscopic measurement, clinical assessment was performed. All patients received conservative treatment for 21 days after injury. SETTING: A burns unit at a primary care hospital. PARTICIPANTS: Thirty-two patients with 41 intermediate-depth local burn wounds were included. Inclusion criteria were time to presentation greater than 24 hours after injury and total burn size greater than 1% and less than 10% of the total body surface area. MAIN OUTCOME MEASURES: Primary healing within 21 days (superficial partial thickness) and failure of primary healing within 21 days (deep partial thickness). The accuracy, sensitivity, and specificity of the assessment according to the algorithm proposed in this study were evaluated by dermoscopy, and the accuracy of the dermoscopic measurements was compared with videomicroscopic measurements and clinical assessments. RESULTS: The results of dermoscopic measurements according to the proposed algorithm showed an accuracy of 93%, sensitivity of 86%, and specificity of 100%. The dermoscopic measurements were significantly more accurate compared with clinical assessment (P = .01). CONCLUSIONS: Dermoscopy is a noninvasive, portable, relatively inexpensive, and effective approach for assessment of the burn wound healing potential. It is more accurate if compared with clinical observation in burn depth assessment. It has a broader utility and is equally or more accurate compared with the more expensive videomicroscopy. PMID- 22508775 TI - Cell therapy limits myofibroblast differentiation and structural cardiac remodeling: basic fibroblast growth factor-mediated paracrine mechanism. AB - BACKGROUND: Experimental cell therapy attenuates maladaptive cardiac remodeling and improves heart function. Paracrine mechanisms have been proposed. The effect of cell therapy on post infarction cardiac fibroblast and extracellular matrix (ECM) regulation was examined. METHODS AND RESULTS: Vascular smooth muscle cells (VSMC) were injected into the border zone of subacute infarcted syngeneic Fischer rat hearts and compared with medium-injected controls. Twelve weeks post injection, cell-treated hearts showed preserved ECM content and attenuated structural chamber remodeling. Myofibroblast activation (alpha-smooth muscle actin expression) was decreased significantly, while basic fibroblast growth factor (bFGF) expression, a known inhibitor of transforming growth factor beta-1 induced fibroblast differentiation, was increased. Matrix metalloproteinase-2 expression and activation by gelatin zymography was unchanged between groups, while its endogenous inhibitor, tissue inhibitors of matrix metalloproteinase (TIMP)-2, showed both increased expression and enhanced inhibitory capacity in cell-treated hearts. To define paracrine mechanisms, in vitro effects of VSMC conditioned media on myofibroblast activation were assessed by 3-D collagen gel contraction assay. VSMC conditioned media significantly inhibited collagen contraction, while a specific bFGF inhibitor abolished this paracrine response. TIMP-2 induced collagen contraction, but the effect was suppressed in the presence of bFGF. CONCLUSIONS: Extracellular matrix dysregulation post myocardial infarction is improved by cell therapy. These data suggest that cell transplantation attenuates myofibroblast activation and subsequent maladaptive structural chamber remodeling through paracrine mechanisms involving bFGF and TIMP-2. PMID- 22508776 TI - Health policy update: making sense of accountable care organizations. PMID- 22508777 TI - "Selective rather than routine": using sound clinical judgment. PMID- 22508779 TI - Effects of large hiatal hernias on esophageal peristalsis. AB - HYPOTHESIS: Anatomic changes induced by large hiatal hernia may alter esophageal pressure topography measurements made during high-resolution manometry. DESIGN: Retrospective study. SETTING: Single-institution tertiary hospital. PATIENTS: Ninety patients with large (>5 cm) hiatal hernias on endoscopy were compared with a control group of 46 patients without hernia selected from the same database of 2000 consecutive clinical high-resolution manometry studies. INTERVENTION: High resolution manometry with at least 7 evaluable swallows for analysis. MAIN OUTCOMES MEASURES: Esophageal pressure topography was analyzed for lower esophageal sphincter pressure, distal contractile integral, contraction amplitude, contractile front velocity, and distal latency time. Esophageal length was measured on esophageal pressure topography from the distal border of the upper esophageal sphincter to the proximal border of the lower esophageal sphincter. Esophageal pressure topography diagnosis was based on the Chicago Classification. RESULTS: The manometry catheter was coiled in the hernia and did not traverse the diaphragm in 44 patients (49%) with large hernia. Patients with large hernias had lower average lower esophageal sphincter pressures, a lower distal contractile integral, slower contractile front velocity, and shorter distal latency time than patients without hernia. They also exhibited a shorter mean esophageal length. However, the distribution of peristaltic abnormalities was not different in patients with and without large hernia. CONCLUSIONS: Patients with large hernias had an alteration of esophageal pressure topography measurements and a shortened esophagus. However, the distribution of peristaltic disorders was unaffected by the presence of hernia. PMID- 22508778 TI - Routine leak testing in colorectal surgery in the Surgical Care and Outcomes Assessment Program. AB - OBJECTIVE: To evaluate the effect of routine anastomotic leak testing (performed to screen for leaks) vs selective testing (performed to evaluate for a suspected leak in a higher-risk or technically difficult anastomosis) on outcomes in colorectal surgery because the value of provocative testing of colorectal anastomoses as a quality improvement metric has yet to be determined. DESIGN: Observational, prospectively designed cohort study. SETTING: Data from Washington state's Surgical Care and Outcomes Assessment Program (SCOAP). PATIENTS: Patients undergoing elective left-sided colon or rectal resections at 40 SCOAP hospitals from October 1, 2005, to December 31, 2009. INTERVENTIONS: Use of leak testing, distinguishing procedures that were performed at hospitals where leak testing was selective (<90% use) or routine (>= 90% use) in a given calendar quarter. MAIN OUTCOME MEASURE: Adjusted odds ratio of a composite adverse event (CAE) (unplanned postoperative intervention and/or in-hospital death) at routine testing hospitals. RESULTS: Among 3449 patients (mean [SD] age, 58.8 [14.8] years; 55.0% women), the CAE rate was 5.5%. Provocative leak testing increased (from 56% in the starting quarter to 76% in quarter 16) and overall rates of CAE decreased (from 7.0% in the starting quarter to 4.6% in quarter 16; both P <= .01) over time. Among patients at hospitals that performed routine leak testing, we found a reduction of more than 75% in the adjusted risk of CAEs (odds ratio, 0.23; 95% CI, 0.05-0.99). CONCLUSION: Routine leak testing of left-sided colorectal anastomoses appears to be associated with a reduced rate of CAEs within the SCOAP network and meets many of the criteria of a worthwhile quality improvement metric. PMID- 22508780 TI - What do the esophagus and a jump rope have in common? The functional importance of anchoring at both ends. PMID- 22508781 TI - Effect of laparoscopy on the risk of small-bowel obstruction: a population-based register study. AB - OBJECTIVE: To investigate the incidence and risk factors for small-bowel obstruction (SBO) after certain surgical procedures. DESIGN: A population-based retrospective register study. SETTING: Small-bowel obstruction causes considerable patient suffering. Risk factors for SBO have been identified, but the effect of surgical technique (open vs laparoscopic) on the incidence of SBO has not been fully elucidated. PATIENTS: The Inpatient Register held by the Swedish National Board of Health and Welfare was used. The hospital discharge diagnoses and registered performed surgical procedures identified data for cholecystectomy, hysterectomy, salpingo-oophorectomy, bowel resection, anterior resection, abdominoperineal resection, rectopexy, appendectomy, and bariatric surgery performed from January 1, 2002, through December 31, 2004. Data on demographic characteristics, comorbidity, previous abdominal surgery, and death were collected. MAIN OUTCOME MEASURES: Episodes of hospital stay and surgery for SBO within 5 years after the index surgery. RESULTS: A total of 108,141 patients were included. The incidence of SBO ranged from 0.4% to 13.9%. Multivariate analysis revealed age, previous surgery, comorbidity, and surgical technique to be risk factors for SBO. Laparoscopy exceeded other risk factors in reduction of the risk of SBO for most of the surgical procedures. CONCLUSIONS: Open surgery seems to increase the risk of SBO at least 4 times compared with laparoscopy for most of the abdominal surgical procedures studied. Other factors such as age, previous abdominal surgery, and comorbidity are also of importance. PMID- 22508782 TI - Minimal invasion and maximal benefit. PMID- 22508783 TI - Prognostic significance of tumor-infiltrating lymphocytes for patients with colorectal cancer. AB - OBJECTIVE: To evaluate the prognostic significance of tumor-infiltrating lymphocytes (TILs) in patients with colorectal cancer. DESIGN: A retrospective review of prospectively collected data. SETTING: Tertiary care hospital. PATIENTS: A total of 546 patients who underwent curative surgery for primary nonmetastatic colorectal cancers from May 1, 2004, through December 31, 2007. MAIN OUTCOME MEASURES: The prognostic value of macroscopic ulceration, tumor border configuration, and TILs at the invasive margin was assessed. RESULTS: The low TIL group was significantly correlated with a poorly differentiated status and perineural invasion. During the median 54-month follow-up period, the low TIL group had significantly lower 5-year overall survival and disease-free survival rates than the high TIL group of patients with stage III colorectal cancer (P = .005 and P = .03, respectively); however, for patients with stage I and II cancers, the survival rates did not differ between the 2 groups. The 5-year overall survival and 5-year disease-free survival rates were significantly different between the high and low TIL groups of patients with rectal cancer (P = .003 and P = .01, respectively). The multivariate analysis confirmed that the TIL grade was significantly and independently associated with a worse prognosis for overall survival but not for disease-free survival. CONCLUSIONS: An inflammatory cell reaction at the tumor invasive border is considered a useful predictor of survival after colorectal cancer surgery, particularly for patients with stage III disease or rectal cancer. PMID- 22508784 TI - Survival prediction for patients with colorectal carcinoma incorporating tumor infiltrating lymphocyte grade. PMID- 22508785 TI - Wound healing and infection in surgery. The clinical impact of smoking and smoking cessation: a systematic review and meta-analysis. AB - OBJECTIVES: To clarify the evidence on smoking and postoperative healing complications across surgical specialties and to determine the impact of perioperative smoking cessation intervention. DATA SOURCES: Cohort studies and randomized controlled trials. STUDY SELECTION: Selected studies were identified through electronic databases (CENTRAL, MEDLINE, and EMBASE) and by hand searching. DATA EXTRACTION: Multiple data on study characteristics were extracted. Risk of bias was assessed by means of the Newcastle-Ottawa Scale and Jadad score. Healing outcome was classified as necrosis, healing delay and dehiscence, surgical site infection, wound complications, hernia, and lack of fistula or bone healing. Mantel-Haenszel and inverse variance methods for meta analysis (fixed- and random-effects models) were used. DATA SYNTHESIS: Smokers and nonsmokers were compared in 140 cohort studies including 479,150 patients. The pooled adjusted odds ratios (95% CI) were 3.60 (2.62-4.93) for necrosis, 2.07 (1.53-2.81) for healing delay and dehiscence, 1.79 (1.57-2.04) for surgical site infection, 2.27 (1.82-2.84) for wound complications, 2.07 (1.23-3.47) for hernia, and 2.44 (1.66-3.58) for lack of fistula or bone healing. Former smokers and patients who never smoked were compared in 24 studies including 47,764 patients, and former smokers and current smokers were compared in 20 studies including 40,629 patients. The pooled unadjusted odds ratios were 1.30 (1.07-1.59) and 0.69 (0.56-0.85), respectively, for healing complications combined. In 4 randomized controlled trials, smoking cessation intervention reduced surgical site infections (odds ratio, 0.43 [95% CI, 0.21-0.85]), but not other healing complications (0.51 [0.22-1.19]). CONCLUSIONS: Postoperative healing complications occur significantly more often in smokers compared with nonsmokers and in former smokers compared with those who never smoked. Perioperative smoking cessation intervention reduces surgical site infections, but not other healing complications. PMID- 22508786 TI - Kicking society's tobacco habit: does the butt stop here? PMID- 22508787 TI - In vitro and ex vivo delivery of short hairpin RNAs for control of hepatitis C viral transcript expression. AB - Recurrent hepatitis C virus (HCV) infection is the most common cause of graft loss and patient death after transplantation for HCV cirrhosis. Transplant surgeons have access to uninfected explanted livers before transplantation and an opportunity to deliver RNA interference-based protective gene therapy to uninfected grafts. Conserved HCV sequences were used to design short interfering RNAs and test their ability to knockdown HCV transcript expression in an in vitro model, both by transfection and when delivered via an adeno-associated viral vector. In a rodent model of liver transplantation, portal venous perfusion of explanted grafts with an adeno-associated viral vector before transplantation produced detectable short hairpin RNA transcript expression after transplantation. The ability to deliver anti-HCV short hairpin RNAs to uninfected livers before transplantation and subsequent exposure to HCV offers hope for the possibility of preventing the currently inevitable subsequent infection of liver grafts with HCV. PMID- 22508788 TI - Image of the month. Right paraduodenal hernia. PMID- 22508789 TI - Image of the month. Send serum for coagulation studies and obtain computed tomographic imaging of the brain. PMID- 22508790 TI - Positive and negative staining of hepatic segments by use of fluorescent imaging techniques during laparoscopic hepatectomy. PMID- 22508791 TI - A unifying framework for bivalent multilocus linkage analysis of allotetraploids. AB - An allotetraploid has four paired sets of chromosomes derived from different diploid species, whose meiotic behavior is qualitatively different from the underlying diploids. According to a traditional view, meiotic pairing occurs only between homologous chromosomes, but new evidence indicates that homoeologous chromosomes may also pair to a lesser extent compared with homolog pairing. Here, we describe and assess a unifying analytical framework that incorporates differential chromosomal pairing into a multilocus linkage model. The preferential pairing factor is used to quantify the probability difference of pairing occurring between homologous chromosomes and homoeologous chromosomes. The unifying framework allows simultaneous estimation of the linkage, genetic interference and preferential pairing factor using commonly existing multiplex markers. We compared the unifying approach and traditional approaches assuming random chromosomal pairing by analyzing marker data collected in a full-sib family of tetraploid switchgrass, a bioenergy species whose diploid origins are undefined, but with subgenomes that are genetically well differentiated. The unifying framework provides a better tool for estimating the meiotic linkage and constructing a genetic map for allotetraploids. PMID- 22508792 TI - Case report of apoptosis in testis of four AZFc-deleted patients: increased DNA fragmentation during meiosis, but decreased apoptotic markers in post-meiotic germ cells. AB - AZFc deletions of the Y chromosome are the major known genetic cause of spermatogenetic failure. Meiotic studies have shown a prevalence of synaptonemal complex fragmentation and an excess of early-stage sperm cells, suggesting that the maturation block could involve apoptosis. We present a prospective and observational study of apoptotic markers in the sperm of four AZFc-deleted patients and two non-obstructive azoospermic controls without an AZFc deletion. Polycaspases assays and terminal deoxynucleotidyl transferase dUDP nick-end labelling (TUNEL) assays were combined to evaluate the incidence of apoptosis in pre-meiotic, meiotic and post-meiotic germs cells identified, respectively, using anti-melanoma-associated antigen A4 (MAGE-A4), anti-synaptonemal complex protein 3 (SCP3) and anti-sperm acrosome membrane-associated protein 1 (SPACA1) antibodies. We detected apoptosis at all stages of AZFc-deletion spermatogenesis. Using the caspase assay, the incidence of positive cells was found to be heterogeneous for pre-meiotic (from 4.8 to 84.5%) and meiotic stages (from 7.9 to 57.6%), while for post-meiotic cells, the mean incidence was 6% in AZFc-deleted patients compared with 26.5% in controls (P < 0.05). Using the TUNEL assay, the mean percentage with DNA fragmentation for meiotic cells was 54.0% in AZFc deleted patients compared with 20.3% in controls (P < 0.05), while the percentage of TUNEL-positive post-meiotic cells ranged from 5.3 to 44.7%. Spermatocyte loss in AZFc-deleted patients occurs via the apoptotic pathway. In post-meiotic cells, the lower incidence of apoptosis in testis from three of the four AZFc-deleted patients, compared with controls, is consistent with AZFc deletions having little negative impact on sperm quality. PMID- 22508794 TI - pIRS: Profile-based Illumina pair-end reads simulator. AB - MOTIVATION: The next-generation high-throughput sequencing technologies, especially from Illumina, have been widely used in re-sequencing and de novo assembly studies. However, there is no existing software that can simulate Illumina reads with real error and quality distributions and coverage bias yet, which is very useful in relevant software development and study designing of sequencing projects. RESULTS: We provide a software package, pIRS (profile-based Illumina pair-end reads simulator), which simulates Illumina reads with empirical Base-Calling and GC%-depth profiles trained from real re-sequencing data. The error and quality distributions as well as coverage bias patterns of simulated reads using pIRS fit the properties of real sequencing data better than existing simulators. In addition, pIRS also comes with a tool to simulate the heterozygous diploid genomes. AVAILABILITY: pIRS is written in C++ and Perl, and is freely available at ftp://ftp.genomics.org.cn/pub/pIRS/. PMID- 22508795 TI - Long-Term (>10 Years) clinical outcomes of first-in-human biodegradable poly-l lactic acid coronary stents: Igaki-Tamai stents. AB - BACKGROUND: The purpose of this study was to evaluate the long-term safety of the Igaki-Tamai stent, the first-in-human fully biodegradable coronary stent made of poly-l-lactic acid. METHODS AND RESULTS: Between September 1998 and April 2000, 50 patients with 63 lesions were treated electively with 84 Igaki-Tamai stents. Overall clinical follow-up (>10 years) of major adverse cardiac events and rates of scaffold thrombosis was analyzed together with the results of angiography and intravascular ultrasound. Major adverse cardiac events included all-cause death, nonfatal myocardial infarction, and target lesion revascularization/target vessel revascularization. During the overall clinical follow-up period (121 +/- 17 months), 2 patients were lost to follow-up. There were 1 cardiac death, 6 noncardiac deaths, and 4 myocardial infarctions. Survival rates free of all-cause death, cardiac death, and major adverse cardiac events at 10 years were 87%, 98%, and 50%, respectively. The cumulative rates of target lesion revascularization (target vessel revascularization) were 16% (16%) at 1 year, 18% (22%) at 5 years, and 28% (38%) at 10 years. Two definite scaffold thromboses (1 subacute, 1 very late) were recorded. The latter case was related to a sirolimus-eluting stent, which was implanted for a lesion proximal to an Igaki-Tamai stent. From the analysis of intravascular ultrasound data, the stent struts mostly disappeared within 3 years. The external elastic membrane area and stent area did not change. CONCLUSION: Acceptable major adverse cardiac events and scaffold thrombosis rates without stent recoil and vessel remodeling suggested the long-term safety of the Igaki-Tamai stent. PMID- 22508796 TI - The disappearing stent: when plastic replaces metal. PMID- 22508799 TI - Mini-abdominal flaps for preservation of digital length in an 18-month old child. PMID- 22508800 TI - Pyrolytic carbon arthroplasty for the proximal interphalangeal joint: results after minimum 3 years of follow-up. AB - A retrospective study was undertaken to review the outcomes of a consecutive series of patients treated using pyrocarbon surface replacement arthroplasty by the same surgeon. We analyzed the results of this procedure in 24 proximal interphalangeal (PIP) joints in 19 hands of 16 patients. The minimum follow-up was 3 years. The study showed that pyrocarbon PIP joint replacements provided excellent pain relief and high patient satisfaction. More than two-thirds of patients subjectively rated postoperative range of motion and functional outcomes as better than preoperatively. Objective assessment showed a modest improvement in the active range of motion, which did not achieve statistical significance, although we did observe a statistically significant increase in passive range of motion. The results are encouraging for those surgeons who seek an alternative to silicone implant PIP joint arthroplasty in high-demand patients. PMID- 22508801 TI - Ganglions of the hand and wrist: determinants of treatment choice. AB - The aim of this study was to determine whether psychological factors (depression, catastrophic thinking, and pain anxiety) and pain intensity are associated with choice of operative treatment. Ninety new patients with a ganglion cyst on their hand or wrist completed psychological questionnaires (Pain Catastrophizing Scale, Pain Anxiety Symptoms Scale, and Center for the Epidemiological Study of Depression instrument) and an ordinal measure of pain intensity. After a minimum of 4 months, patients were contacted to determine if they chose operative treatment, to rate their pain intensity, and to complete the Disabilities of the Arm, Shoulder, and Hand questionnaire. Younger patients were more likely to choose operative treatment. Psychological factors were associated with pain intensity at enrolment, but not with treatment choice. Operative treatment did not result in less pain intensity or disability, or higher satisfaction compared with non-operative treatment. PMID- 22508802 TI - Oxidative stress and fatigue in systemic lupus erythematosus. AB - OBJECTIVE: The objective of this study is to investigate the relationship of oxidative stress to fatigue in systemic lupus erythematosus (SLE). METHODS: Patients with a confirmed diagnosis of SLE by ACR criteria and healthy controls completed validated questionnaires to assess depression and fatigue. Fatigue was measured with the Fatigue Severity Scale (FSS) and the Profile of Fatigue (Prof F). Visual analogue scales (VAS) were also used to assess fatigue and pain. Depression was measured with the Center for Epidemiologic Studies Depression Scale (CES-D). Plasma F(2)-isoprostane was measured with gas chromatography/mass spectroscopy to assess oxidative stress. Evaluation included medical record review, physical exam and calculation of body mass index (BMI), disease activity (SLEDAI) and damage (SLICC) in the SLE patients. RESULTS: Seventy-one SLE patients with low disease activity (mean SLEDAI = 1.62 standard error (SE) 0.37, range 0-8) were compared to 51 controls. Fatigue-limiting physical activity (defined as FSS >= 4) was present in 56% of patients and 12% of controls. F(2) isoprostane was higher in SLE patients with fatigue compared to not-fatigued SLE subjects (p = .0076) who were otherwise similar in ethnicity, disease activity and cardiovascular risk factors. Plasma F(2)-isoprostane was strongly correlated with FSS and Profile of Somatic Fatigue (Prof-S) (p < .0001), VAS fatigue (p = .005), CES-D (p = .008) and with BMI (p = .0001.) In a multivariate model, F(2) isoprostane was a significant predictor of FSS after adjustment for age, BMI, pain and depression (p = .0002). CONCLUSION: Fatigue in SLE patients with low disease activity is associated with increased F(2)-isoprostane. F2-isoprostane could provide a useful biomarker to explore mitochondrial function and the regulation of oxidative pathways in patients with SLE in whom fatigue is a debilitating symptom. PMID- 22508803 TI - Otolaryngology resident in-service examination scores predict passage of the written board examination. AB - OBJECTIVE: The purpose of this study was to assess the association between the Otolaryngology Training Examination (OTE) and the passage rate of first-time examinees on the American Board of Otolaryngology (ABOto) Written Qualifying Examination (WQE). STUDY DESIGN: Historical cohort study. SETTING: De-identified database containing information on examinees who took the WQE in 2007 to 2011 and the OTE in 2005 to 2011. SUBJECTS AND METHODS: One thousand three hundred nine otolaryngology residents took the WQE for the first time in 2007 to 2011 and the OTE in their final and penultimate years of training in 2005 to 2011. Data were analyzed using 1-way frequencies and table analysis. Logistic regression was used to model the relationship between the pass/fail WQE result and the OTE percentile score in the final and penultimate years of training. Data transformation was used to analyze WQE passage as a function of OTE scores by deciles and quartiles. RESULTS: There is a significant relationship between OTE score and passage of the WQE on the first attempt. The probability of passing the WQE on the first attempt is 97% if the resident scores in the upper 3 quartiles of the OTE in the final and penultimate years of training compared with 70% if the examinee scores in the bottom quartile both years. CONCLUSION: Residents who score in the bottom quartile in both their final and penultimate years of training are at significantly higher risk of failing the WQE on the first attempt. Remediation efforts should be focused on these individuals. PMID- 22508804 TI - A selective cytopheretic inhibitory device for use during cardiopulmonary bypass surgery. AB - BACKGROUND: Systemic inflammatory response syndrome (SIRS) can occur in association with cardiopulmonary bypass (CPB) surgery, resulting in multiple organ dysfunction (MOD). Activated neutrophils have been implicated as major inciting factors in this process. Neutrophil-depleting filters incorporated within the extracorporeal blood circuit during CPB have been developed and evaluated, with inconsistent clinical results. METHODS: A novel, biomimetic, selective cytopheretic device (SCD) was tested in vitro within a blood circuit to assess safety and interactions with blood components and further evaluated ex vivo in a bovine model of CPB surgery during ventricular assist device implantation. RESULTS: In vitro blood circuit studies demonstrated that the SCD reduces circulating neutrophils while maintaining low rates of hemolysis compared to current leukocyte-reduction filters. In the bovine CPB model, animals without SCD treatment (No SCD) demonstrated an increase in circulating white blood cell (WBC) and neutrophil counts, steadily increasing throughout CPB. SCD with only systemic heparin anticoagulation (SCD-H) acutely reduced neutrophils for the first 2 hrs of CPB, but followed with a greater than 6-fold increase in neutrophil counts. SCD treatment with regional citrate anticoagulation along the SCD circuit (SCD-C) reduced systemic neutrophil counts throughout 4 hrs of CPB despite lower amounts of eluted cells from the SCD. When analyzed for immature neutrophils, the control and SCD-H showed increasing counts at later time-points, not seen in the SCD-C group, suggesting a more complex mechanism of action than simple leukoreduction. CONCLUSIONS: These results suggest that SCD-C therapy may disrupt the systemic leukocyte response during CPB, leading to improved outcomes for CPB-mediated MOD. PMID- 22508805 TI - Wal's story: reflections on presence. PMID- 22508806 TI - Predictors of early death risk in older patients treated with first-line chemotherapy for cancer. AB - PURPOSE: Objective factors for making choices about the treatment of elderly patients with cancer are lacking. This investigation aimed to help physicians select appropriate treatments through the identification of factors that predict early death (< 6 months) after initiation of chemotherapy treatment. PATIENTS AND METHODS: Previously untreated patients greater than 70 years of age who were scheduled for first-line chemotherapy for various types of cancer were included. Baseline abbreviated comprehensive geriatric assessment (aCGA), including the Mini-Mental State Exam, Timed Get Up and Go (GUG), Activities of Daily Living (ADL), Instrumental Activities in Daily Living (IADL), Mini Nutritional Assessment (MNA), Geriatric Depression Scale (GDS15), and comorbidities index (Cumulative Index Rating Scale-Geriatric), was carried out. Prognostic factors of early death were sought from aCGA results and traditional oncology measures. RESULTS: A total of 348 patients were included across 12 centers in Southwest France (median age, 77.45 years; ratio of men to women, 1.47; advanced disease, 65%). Abnormal aCGA scores were observed for 18.1% of patients on the ADL, 73.0% of patients on the IADL, 24.1% of patients on the GUG, 19.0% of patients on the MMS, 44.0% of patients on the GDS15, and 64.9% of patients on the MNA. Advanced disease (odds ratio [OR], 3.9; 95% CI, [1.58 to 9.73]), a low MNA score (OR 2.77; 95% CI, [1.24 to 6.18]), male sex (OR, 2.40; 95% CI, [1.2 to 4.82]), and long GUG (OR, 2.55; 95% CI, [1.32 to 4.94] were associated with higher risk of early death. CONCLUSION: In patients greater than 70 years of age with cancer, advanced disease, a low MNA score, and poor mobility predicted early death. We recommend that the MNA and GUG, performed by a trained nurse, be maintained as part of routine pretreatment workup in these patients to identify at-risk patients and to inform the decision-making process for chemotherapy. PMID- 22508807 TI - Cancer-related fatigue in women with breast cancer: outcomes of a 5-year prospective cohort study. AB - PURPOSE: Prolonged and disabling fatigue is prevalent after cancer treatment, but the early natural history of cancer-related fatigue (CRF) has not been systematically examined to document consistent presence of symptoms. Hence, relationships to cancer, surgery, and adjuvant therapy are unclear. PATIENTS AND METHODS: A prospective cohort study of women receiving adjuvant treatment for early-stage breast cancer was conducted. Women (n = 218) were enrolled after surgery and observed at end treatment and at 1, 3, 6, 9, and 12 months as well as 5 years. Structured interviews and self-report questionnaires were used to record physical and psychologic health as well as disability and health care utilization. Patients with CRF persisting for 6 months were assessed to exclude alternative medical and psychiatric causes of fatigue. Predictors of persistent fatigue, mood disturbance, and health care utilization were sought by logistic regression. RESULTS: The case rate for CRF was 24% (n = 51) postsurgery and 31% (n = 69) at end of treatment; it became persistent in 11% (n = 24) at 6 months and 6% (n = 12) at 12 months. At each time point, approximately one third of the patients had comorbid mood disturbance. Persistent CRF was predicted by tumor size but not demographic, psychologic, surgical, or hematologic parameters. CRF was associated with significant disability and health care utilization. CONCLUSION: CRF is common but generally runs a self-limiting course. Much of the previously reported high rates of persistent CRF may be attributable to factors unrelated to the cancer or its treatment. PMID- 22508808 TI - High frequency of germline SUFU mutations in children with desmoplastic/nodular medulloblastoma younger than 3 years of age. AB - PURPOSE: Germline mutations of the SUFU gene have been shown to be associated with genetic predisposition to medulloblastoma, mainly in families with multiple cases of medulloblastoma and/or in patients with symptoms similar to those of Gorlin syndrome. To evaluate the contribution of these mutations to the genesis of sporadic medulloblastomas, we screened a series of unselected patients with medulloblastoma for germline SUFU mutations. PATIENTS AND METHODS: A complete mutational analysis of the SUFU gene was performed on genomic DNA in all 131 consecutive patients treated for medulloblastoma in the pediatrics department of the Institut Gustave Roussy between 1972 and 2009 and for whom a blood sample was available. RESULTS: We identified eight germline mutations of the SUFU gene: one large genomic duplication and seven point mutations. Mutations were identified in three of three individuals with medulloblastoma with extensive nodularity, four of 20 with desmoplastic/nodular medulloblastomas, and one of 108 with other subtypes. All eight patients were younger than 3 years of age at diagnosis. The mutations were inherited from the healthy father in four of six patient cases in which the parents accepted genetic testing; de novo mutations accounted for the other two patient cases. Associated events were macrocrania in six patients, hypertelorism in three patients, and multiple basal cell carcinomas in the radiation field after age 18 years in one patient. CONCLUSION: These data indicate that germline SUFU mutations were responsible for a high proportion of desmoplastic medulloblastoma in children younger than 3 years of age. Genetic testing should be offered to all children diagnosed with sonic hedgehog-driven medulloblastoma at a young age. PMID- 22508809 TI - Why is management of cancer pain still a problem? PMID- 22508810 TI - Defining the benefits of neoadjuvant chemotherapy for breast cancer. PMID- 22508811 TI - Elusive goal of targeting tumor hypoxia for therapeutic gain. PMID- 22508812 TI - Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. AB - PURPOSE: The exact definition of pathologic complete response (pCR) and its prognostic impact on survival in intrinsic breast cancer subtypes is uncertain. METHODS: Tumor response at surgery and its association with long-term outcome of 6,377 patients with primary breast cancer receiving neoadjuvant anthracycline taxane-based chemotherapy in seven randomized trials were analyzed. RESULTS: Disease-free survival (DFS) was significantly superior in patients with no invasive and no in situ residuals in breast or nodes (n = 955) compared with patients with residual ductal carcinoma in situ only (n = 309), no invasive residuals in breast but involved nodes (n = 186), only focal-invasive disease in the breast (n = 478), and gross invasive residual disease (n = 4,449; P < .001). Hazard ratios for DFS comparing patients with or without pCR were lowest when defined as no invasive and no in situ residuals (0.446) and increased monotonously when in situ residuals (0.523), no invasive breast residuals but involved nodes (0.623), and focal-invasive disease (0.727) were included in the definition. pCR was associated with improved DFS in luminal B/human epidermal growth factor receptor 2 (HER2) -negative (P = .005), HER2-positive/nonluminal (P < .001), and triple-negative (P < .001) tumors but not in luminal A (P = .39) or luminal B/HER2-positive (P = .45) breast cancer. pCR in HER2-positive (nonluminal) and triple-negative tumors was associated with excellent prognosis. CONCLUSION: pCR defined as no invasive and no in situ residuals in breast and nodes can best discriminate between patients with favorable and unfavorable outcomes. Patients with noninvasive or focal-invasive residues or involved lymph nodes should not be considered as having achieved pCR. pCR is a suitable surrogate end point for patients with luminal B/HER2-negative, HER2-positive (nonluminal), and triple-negative disease but not for those with luminal B/HER2 positive or luminal A tumors. PMID- 22508813 TI - Prevention of pegfilgrastim-induced bone pain: a phase III double-blind placebo controlled randomized clinical trial of the university of rochester cancer center clinical community oncology program research base. AB - PURPOSE: Pegfilgrastim-induced bone pain is a significant clinical problem that may result in discontinuation of pegfilgrastim and lead to less effective chemotherapy dosing. Interventions for pegfilgrastim-induced bone pain are needed. PATIENTS AND METHODS: The University of Rochester Cancer Center Clinical Community Oncology Program Research Base randomly assigned 510 patients at 17 sites to receive either naproxen (500 mg two times per day) or placebo on the day of pegfilgrastim administration, continuing for 5 to 8 days after pegfilgrastim. Patients recorded pain severity (using a scale of 0 to 10) and duration in daily diaries. The primary outcome measure was the area under the curve (AUC) for pain for days 1 through 5. Secondary outcome measures included the identification of risk factors for the development of pain and response to naproxen. RESULTS: Patients' mean age was 55.6 years and 86% were female. Sixty-eight percent of patients had breast cancer and 10% had lung cancer. Pain reached its peak at 3 days for both groups. The mean AUC for pain was 7.71 for the placebo group and 6.04 for the naproxen group (P = .037). Naproxen reduced maximum pain from 3.40 to 2.59 (P = .005). Naproxen also reduced overall pain incidence from 71.3% to 61.1% (P = .020) and duration from 2.40 to 1.92 days (P = .009). The reduction in severe pain (> 5 on a scale of 1 to 10) from 27.0% to 19.2% was also significant (P = .048). Risk factors could not be identified to predict incidence, severity, or ability to prevent pegfilgrastim-induced bone pain. CONCLUSION: Our phase III randomized placebo-controlled clinical trial demonstrated that naproxen at a dose of 500 mg twice per day is effective in reducing the incidence and severity of pegfilgrastim-induced bone pain. PMID- 22508814 TI - Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomized trial. AB - PURPOSE: To report the results from a randomized trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen inhalation and nicotinamide (ARCON) in laryngeal cancer. PATIENTS AND METHODS: Patients with cT2 4 squamous cell laryngeal cancer were randomly assigned to AR (68 Gy within 36 to 38 days) or ARCON. To limit the risk of laryngeal necrosis, ARCON patients received 64 Gy on the laryngeal cartilage. The primary end point was local control. Secondary end points were regional control, larynx preservation, toxicity, disease-free survival, and overall survival. In a translational side study, the hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. RESULTS: From April 2001 to February 2008, 345 patients were accrued. After a median follow-up of 44 months, local tumor control rate at 5 years was 78% for AR versus 79% for ARCON (P = .80), with larynx preservation rates of 84% and 87%, respectively (P = .48). The 5-year regional control was significantly better with ARCON (93%) compared with AR (86%, P = .04). The improvement in regional control was specifically observed in patients with hypoxic tumors and not in patients with well-oxygenated tumors (100% v 55%, respectively; P = .01). AR and ARCON produced equal levels of toxicity. CONCLUSION: Despite lack of benefit in local tumor control for advanced laryngeal cancers, a significant gain in regional control rate, with equal levels of toxicity, was observed in favor of ARCON. The poor regional control of patients with hypoxic tumors is specifically countered by ARCON treatment. PMID- 22508815 TI - Bilateral ear swelling and erythema after chemotherapy: a case of ara-C ears. PMID- 22508816 TI - Validating the interval to biochemical failure for the identification of potentially lethal prostate cancer. AB - PURPOSE: To validate the interval to biochemical failure (IBF) as a prognostic factor at the time of biochemical failure for prostate cancer mortality (PCM) following radiotherapy (RT). PATIENTS AND METHODS: From a collaborative data set of men with clinically localized prostate cancer treated with RT from four institutions in three countries, we identified 1,722 men with biochemical failure (BF; prostate-specific antigen nadir + 2 ng/mL). The IBF was defined as the time interval from completion of treatment to the date of BF. The primary outcome measure was discriminatory power in the form of the concordance index (c-index). RESULTS: Seventeen percent of men had an IBF <= 18 months. Median potential follow-up beyond the time of BF was 67 months. There were 290 deaths from prostate cancer. The IBF was the most discriminating individual prognostic factor overall, with a sensitivity of IBF <= 18 months to predict PCM within 10 years of 48.4% (95% CI, 43.3% to 54.1%); the specificity was 86.1% (95% CI, 84.5% to 87.7%), equating to a c-index of 0.611 (95% CI, 0.578 to 0.647). The 5-year cumulative incidence of PCM for IBF more than 18 months versus IBF <= 18 months was 9.4% (95% CI, 7.7% to 11.5%) versus 26.3% (95% CI, 21.2% to 31.8%); corresponding 10-year estimates were 26.2% (95% CI, 21.5% to 30.8%) versus 55.9% (95% CI, 48.9% to 63.0%), respectively (P < .001 for both). IBF exhibited minimal change in performance across various follow-up durations. CONCLUSION: IBF is the single most robust prognostic factor for PCM following RT without androgen deprivation therapy. This external validation demonstrates that patients and clinicians can use this information to make decisions about subsequent treatments. PMID- 22508817 TI - Parallel lives diverge. PMID- 22508818 TI - Need to improve communication in breast cancer care. PMID- 22508820 TI - A balancing act. PMID- 22508819 TI - Prospective, observational study of pain and analgesic prescribing in medical oncology outpatients with breast, colorectal, lung, or prostate cancer. AB - PURPOSE: Pain is prevalent among patients with cancer, yet pain management patterns in outpatient oncology are poorly understood. PATIENTS AND METHODS: A total of 3,123 ambulatory patients with invasive cancer of the breast, prostate, colon/rectum, or lung were enrolled onto this prospective study regardless of phase of care or stage of disease. At initial assessment and 4 to 5 weeks later, patients completed a 25-item measure of pain, functional interference, and other symptoms. Providers recorded analgesic prescribing. The pain management index was calculated to assess treatment adequacy. RESULTS: Of the 3,023 patients we identified to be at risk for pain, 2,026 (67%) reported having pain or requiring analgesics at initial assessment; of these 2,026 patients, 670 (33%) were receiving inadequate analgesic prescribing. We found no difference in treatment adequacy between the initial and follow-up visits. Multivariable analysis revealed that the odds of a non-Hispanic white patient having inadequate pain treatment were approximately half those of a minority patient after adjusting for other explanatory variables (odds ratio, 0.51; 95% CI, 0.37 to 0.70; P = .002). Other significant predictors of inadequate pain treatment were having a good performance status, being treated at a minority treatment site, and having nonadvanced disease without concurrent treatment. CONCLUSION: Most outpatients with common solid tumors must confront issues related to pain and the use of analgesics. There is significant disparity in pain treatment adequacy, with the odds of undertreatment twice as high for minority patients. These findings persist over 1 month of follow-up, highlighting the complexity of these problems. PMID- 22508821 TI - Hedgehog-GLI pathway in medulloblastoma. PMID- 22508823 TI - Complex role of histone deacetylase inhibitors in the treatment of non-small-cell lung cancer. PMID- 22508822 TI - Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. AB - PURPOSE: Ganitumab is a fully human monoclonal antibody against type-1 insulin like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT). PATIENTS AND METHODS: Patients >=16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] >= 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated. RESULTS: Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD >= 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed. CONCLUSION: Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT. PMID- 22508824 TI - Remarkable tumor response to crizotinib in a 14-year-old girl with ALK-positive non-small-cell lung cancer. PMID- 22508825 TI - Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. AB - PURPOSE: The goal of this study was to evaluate whether the addition of a purine analog, cladribine or fludarabine, to the standard induction regimen affects the outcome of adult patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: A cohort of 652 untreated AML patients with median age 47 years (range, 17 to 60 years) were randomly assigned to receive one of three induction regimens: DA (daunorubicin plus cytarabine), DAC (DA plus cladribine), or DAF (DA plus fludarabine). Postremission treatment was the same for all arms. RESULTS: Complete remission rate in the DAC arm was higher compared with the DA arm (67.5% v 56%; P = .01) as a consequence of reduced incidence of resistant disease (21% v 34%; P = .004). There was no significant difference in early outcome between the DAF and DA arms. The probability of overall survival was improved for the DAC arm (45% +/- 4% at 3 years) compared with the DA arm (33% +/- 4%; P = .02), and leukemia-free survival was comparable. Long-term outcome did not differ significantly for the comparison of the DAF and DA arms. A survival advantage of the DAC arm over the DA arm was observed among patients age 50 years or older (P = .005), those with initial leukocyte count above 50 * 10(9)/L (P = .03), and those with unfavorable karyotype (P = .03). DAF revealed a significant advantage over DA in patients with adverse karyotype (P = .02). CONCLUSION: The addition of cladribine to the standard induction regimen is associated with increased rate of complete remission and improved survival of adult patients with AML. PMID- 22508826 TI - Acquired angioedema and marginal zone lymphoma. PMID- 22508827 TI - Gene modules and response to neoadjuvant chemotherapy in breast cancer subtypes: a pooled analysis. AB - PURPOSE: To investigate the association between chemotherapy response and gene expression modules describing important biologic processes and druggable oncogenic pathways in breast cancer (BC) subtypes. PATIENTS AND METHODS: We searched for publicly available gene expression studies evaluating anthracycline with or without taxane-based neoadjuvant chemotherapy and identified eight studies with 996 patients. We computed 17 gene modules and calculated odds ratios (ORs) for pathologic complete response (pCR) for one-unit increases in scaled modules with and without adjustment for clinicopathologic characteristics. Added predictive accuracy was evaluated using the area under the receiver operating characteristic curve (AUC) and integrated discrimination index (IDI). We used the false discovery rate (FDR) to adjust for multiple testing. RESULTS: High immune module scores were associated with increased pCR probability in all BC subtypes. High module scores of chromosomal instability, phosphatase and tensin homolog (PTEN) loss, and E2F3 transcription factor were associated with increased pCR probability in estrogen receptor (ER) -negative/human epidermal growth factor receptor 2 (HER2) -negative and ER-positive/HER2-negative but not in HER2 positive tumors (interactions between HER2 and each of these modules for their association with pCR: P < .05; FDR, 0.17; trend for interaction between HER2 and PTEN). High values of insulin-like growth factor 1 activation module were associated with increased pCR probability only in ER-positive/HER2-negative tumors (interaction between insulin-like growth factor 1 and ER: P = .002; FDR, 0.03). When adding the immune module to clinicopathologic characteristics, we observed substantial increases in predictive accuracy for pCR in the HER2 positive subtype (IDI, 0.093; P = .004; increase in AUC from 0.760 to 0.836). CONCLUSION: Different processes and pathways are associated with pCR in different BC subtypes. PMID- 22508829 TI - Assessing the clinical relevance of oncogenic pathways in neoadjuvant breast cancer. PMID- 22508828 TI - Toward patient-centered cancer care: patient perceptions of problematic events, impact, and response. AB - PURPOSE: Cancer treatments are complex, involving multiple clinicians, toxic therapies, and uncertain outcomes. Consequently, patients are vulnerable when breakdowns in care occur. This study explored cancer patients' perceptions of preventable, harmful events; the impact of these events; and interactions with clinicians after such events. PATIENTS AND METHODS: In-depth telephone interviews were conducted with cancer patients from three clinical sites. Patients were eligible if they believed: something "went wrong" during their cancer care; the event could have been prevented; and the event caused, or could have caused, significant harm. Interviews focused on patients' perceptions of the event, its impact, and clinicians' responses to the event. RESULTS: Ninety-three of 416 patients queried believed something had gone wrong in their care that was preventable and caused or could have caused harm. Seventy-eight patients completed interviews. Of those interviewed, 28% described a problem with medical care, such as a delay in diagnosis or treatment; 47% described a communication problem, including problems with information exchange or manner; and 24% described problems with both medical care and communication. Perceived harms included physical and emotional harm, disruption of life, effect on family members, damaged physician-patient relationship, and financial expense. Few clinicians initiated discussion of the problematic events. Most patients did not formally report their concerns. CONCLUSION: Cancer patients who believe they experienced a preventable, harmful event during their cancer diagnosis or care often do not formally report their concerns. Systems are needed to encourage patients to report such events and to help physicians and health care systems respond effectively. PMID- 22508830 TI - Randomized phase II trial of erlotinib with and without entinostat in patients with advanced non-small-cell lung cancer who progressed on prior chemotherapy. AB - PURPOSE: Histone deacetylase inhibitors (HDACis) have been shown to overcome resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) linked to epigenetic changes and epithelial-mesenchymal transition (EMT) state. This randomized phase II study evaluated the outcome of erlotinib with and without the isoform selective HDACi, entinostat. PATIENTS AND METHODS: Previously treated patients with stage IIIB/IV non-small-cell lung cancer, no prior EGFR TKIs, and performance status <= 2 were randomly administered erlotinib 150 mg on days 1 through 28 plus entinostat 10 mg orally on days 1 and 15 every 28 days (EE) or erlotinib plus placebo (EP). The primary end point was 4-month progression-free survival (PFS) rate with additional end points including 6-month PFS rate, PFS, and overall survival (OS). Exploratory analyses included EMT- and EGFR-related biomarker analysis on archival tissue. RESULTS: One hundred thirty two patients were enrolled (EE, 67; EP, 65). The 4-month PFS rate was comparable for both groups (EE, 18% v EP, 20%; P = .7). In the subset of patients with high E-cadherin levels, OS was longer in the EE group compared with the EP group (9.4 v 5.4 months; hazard ratio, 0.35; 95% CI, 0.13 to 0.92; P = .03) with a corresponding trend toward increased PFS. The adverse event (AE) profile was acceptable, with rash, fatigue, diarrhea, and nausea the most common AEs in both groups. CONCLUSION: Erlotinib combined with entinostat did not improve the outcomes of patients in the overall study population when compared with erlotinib monotherapy. High E-cadherin expression levels at time of diagnosis indicate an increased sensitivity to HDACi/EGFR-TKI inhibition providing the basis for a biomarker-driven validation study. PMID- 22508831 TI - Cardioprotective effects mediated by angiotensin II type 1 receptor blockade and enhancing angiotensin 1-7 in experimental heart failure in angiotensin-converting enzyme 2-null mice. AB - Loss of angiotensin (Ang)-converting enzyme 2 (ACE2) and inability to metabolize Ang II to Ang 1-7 perpetuate the actions of Ang II after biomechanical stress and exacerbate early adverse myocardial remodeling. Ang receptor blockers are known to antagonize the effect of Ang II by blocking Ang II type 1 receptor (AT(1)R) and also by upregulating the ACE2 expression. We directly compare the benefits of AT(1)R blockade versus enhancing Ang 1-7 action in pressure-overload-induced heart failure in ACE2 knockout mice. AT(1)R blockade and Ang 1-7 both resulted in marked recovery of systolic dysfunction in pressure-overloaded ACE2-null mice. Similarly, both therapies attenuated the increase in NADPH oxidase activation by downregulating the expression of Nox2 and p47(phox) subunits and also by limiting the p47(phox) phosphorylation. Biomechanical stress-induced increase in protein kinase C-alpha expression and phosphorylation of extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3, Akt, and glycogen synthase kinase 3beta were normalized by irbesartan and Ang 1-7. Ang receptor blocker and Ang 1-7 effectively reduced matrix metalloproteinase 2 activation and matrix metalloproteinase 9 levels. Ang II-mediated cellular effects in cultured adult cardiomyocytes and cardiofibrolasts isolated from pressure-overloaded ACE2 null hearts were inhibited to similar degree by AT(1)R blockade and stimulation with Ang 1-7. Thus, treatment with the AT(1)R blocker irbesartan and Ang 1-7 prevented the cardiac hypertrophy and improved cardiac remodeling in pressure overloaded ACE2-null mice by suppressing NADPH oxidase and normalizing pathological signaling pathways. PMID- 22508832 TI - Left ventricular failure produces profound lung remodeling and pulmonary hypertension in mice: heart failure causes severe lung disease. AB - Chronic left ventricular failure causes pulmonary congestion with increased lung weight and type 2 pulmonary hypertension. Understanding the molecular mechanisms for type 2 pulmonary hypertension and the development of novel treatments for this condition requires a robust experimental animal model and a good understanding of the nature of the resultant pulmonary remodeling. Here we demonstrate that chronic transverse aortic constriction causes massive pulmonary fibrosis and remodeling, as well as type 2 pulmonary hypertension, in mice. Thus, aortic constriction-induced left ventricular dysfunction and increased left ventricular end-diastolic pressure are associated with a <=5.3-fold increase in lung wet weight and dry weight, pulmonary hypertension, and right ventricular hypertrophy. Interestingly, the aortic constriction-induced increase in lung weight was not associated with pulmonary edema but resulted from profound pulmonary remodeling with a dramatic increase in the percentage of fully muscularized lung vessels, marked vascular and lung fibrosis, myofibroblast proliferation, and leukocyte infiltration. The aortic constriction-induced left ventricular dysfunction was also associated with right ventricular hypertrophy, increased right ventricular end-diastolic pressure, and right atrial hypertrophy. The massive lung fibrosis, leukocyte infiltration, and pulmonary hypertension in mice after transverse aortic constriction clearly indicate that congestive heart failure also causes severe lung disease. The lung fibrosis and leukocyte infiltration may be important mechanisms in the poor clinical outcome in patients with end-stage heart failure. Thus, the effective treatment of left ventricular failure may require additional efforts to reduce lung fibrosis and the inflammatory response. PMID- 22508833 TI - Low-dose spironolactone prevents apoptosis repressor with caspase recruitment domain degradation during myocardial infarction. AB - Low-dose mineralocorticoid receptor antagonists reduce morbidity and mortality in patients with heart failure and myocardial infarction, despite normal plasma aldosterone levels. Since apoptosis plays an important role in heart failure and postinfarction left ventricular remodeling, we examined whether low-dose mineralocorticoid receptor antagonists modulate cardiomyocyte death by regulating the apoptosis repressor protein apoptosis repressor with caspase recruitment domain to lessen the extent of apoptosis. Hearts from adult male Sprague-Dawley rats were subjected to regional ischemia followed by reperfusion ex vivo, with mineralocorticoid receptor antagonists added to perfusates before ischemia. Low dose spironolactone (10 nmol/L) or eplerenone (100 nmol/L) significantly reduced infarct size. Spironolactone also prevented cleavage of the apoptotic chromatin condensation inducer in the nucleus and of the inhibitor of caspase-activated DNAse induced by ischemia-reperfusion, thereby abolishing chromatin condensation and internucleosomal cleavage. Ischemia-reperfusion-induced activation of caspases 2, 3, and 9, but not caspase 8, was prevented by spironolactone, suggesting targeted regulation of the intrinsic pathway. Low-dose spironolactone and eplerenone prevented loss of the apoptosis repressor with the caspase recruitment domain and reduced myocyte death. In H9c2 cells, mineralocorticoid receptor activation by aldosterone resulted in apoptosis repressor with caspase recruitment domain degradation and enhanced apoptosis; these actions were prevented by coadministration of spironolactone. Using a triple lysine mutant we identified that aldosterone enhances posttranscriptional degradation of the apoptosis repressor with a caspase recruitment domain via the ubiquitin proteasomal pathway. Our data demonstrate that low-dose mineralocorticoid receptor antagonists reduce infarct size and apoptosis in the reperfused myocardium by preventing the apoptosis repressor with caspase recruitment domain degradation. PMID- 22508834 TI - Mechanisms of carbon monoxide attenuation of tubuloglomerular feedback. AB - Carbon monoxide (CO) is a physiological messenger with diverse functions in the kidney, including controlling afferent arteriole tone both directly and via tubuloglomerular feedback (TGF). We have reported that CO attenuates TGF, but the mechanisms underlying this effect remain unknown. We hypothesized that CO, acting via cGMP, cGMP-dependent protein kinase, and cGMP-stimulated phosphodiesterase 2, reduces cAMP in the macula densa, leading to TGF attenuation. In vitro, microdissected rabbit afferent arterioles and their attached macula densa were simultaneously perfused. TGF was measured as the decrease in afferent arteriole diameter elicited by switching macula densa NaCl from 10 to 80 mmol/L. Adding a CO-releasing molecule (CORM-3, 5 * 10(-5) mol/L) to the macula densa blunted TGF from 3.3 +/- 0.3 to 2.0 +/- 0.3 MUm (P<0.001). The guanylate cyclase inhibitor LY 83583 (10(-6) mol/L) enhanced TGF (5.8 +/- 0.6 MUm; P<0.001 versus control) and prevented the effect of CORM-3 on TGF (LY-83583+CORM-3, 5.5 +/- 0.3 MUm). Similarly, the cGMP-dependent protein kinase inhibitor KT-5823 (2 * 10(-6) mol/L) enhanced TGF and prevented the effect of CORM-3 on TGF (KT-5823, 6.0 +/- 0.7 MUm; KT-5823+CORM-3, 5.9 +/- 0.8 MUm). However, the phosphodiesterase 2 inhibitor BAY 60-7550 (10(-6) mol/L) did not prevent the effect of CORM-3 on TGF (BAY-60-7550, 4.07 +/- 0.31 MUm; BAY-60-7550+CORM-3, 1.84 +/- 0.31 MUm; P<0.001). Finally, the degradation-resistant cAMP analog dibutyryl-cAMP (10(-3) mol/L) prevented the attenuation of TGF by CORM-3 (dibutyryl-cAMP, 4.6 +/- 0.5 MUm; dibutyryl cAMP+CORM-3, 5.0 +/- 0.6 MUm). We conclude that CO attenuates TGF by reducing cAMP via a cGMP-dependent pathway mediated by cGMP-dependent protein kinase rather than phosphodiesterase 2. Our results will lead to a better understanding of the mechanisms that control the renal microcirculation. PMID- 22508835 TI - Human invariant natural killer T cells acquire transient innate responsiveness via histone H4 acetylation induced by weak TCR stimulation. AB - Invariant NKT cells (iNKT cells) are innate T lymphocytes that are thought to play an important role in producing an early burst of IFN-gamma that promotes successful tumor immunosurveillance and antimicrobial immunity. The cellular activation processes underlying innate IFN-gamma production remain poorly understood. We show here that weak T cell receptor (TCR) stimulation that does not directly activate iNKT cell IFN-gamma messenger RNA transcription nevertheless induces histone H4 acetylation at specific regions near the IFNG gene locus. This renders the iNKT cells able to produce IFN-gamma in an innate manner (i.e., not requiring concurrent TCR stimulation) upon exposure to IL-12 and IL-18. The iNKT cells retain the capacity for innate activation for hours to days after the initial weak TCR stimulation, although their innate responsiveness gradually declines as a function of histone deacetylation. These results explain how iNKT cells are able to mediate rapid innate IFN-gamma secretion in a manner that does not require them to undergo permanent T(H1) differentiation. Moreover, our results also indicate that iNKT cell motility is maintained during activation by IL-12 and IL-18. Therefore, iNKT cells activated through this pathway can continue to migrate and may thus disseminate the IFN-gamma that they produce, which may amplify its impact. PMID- 22508837 TI - A role for GPx3 in activity of normal and leukemia stem cells. AB - The determinants of normal and leukemic stem cell self-renewal remain poorly characterized. We report that expression of the reactive oxygen species (ROS) scavenger glutathione peroxidase 3 (GPx3) positively correlates with the frequency of leukemia stem cells (LSCs) in Hoxa9+Meis1-induced leukemias. Compared with a leukemia with a low frequency of LSCs, a leukemia with a high frequency of LSCs showed hypomethylation of the Gpx3 promoter region, and expressed high levels of Gpx3 and low levels of ROS. LSCs and normal hematopoietic stem cells (HSCs) engineered to express Gpx3 short hairpin RNA (shRNA) were much less competitive in vivo than control cells. However, progenitor cell proliferation and differentiation was not affected by Gpx3 shRNA. Consistent with this, HSCs overexpressing Gpx3 were significantly more competitive than control cells in long-term repopulation experiments, and overexpression of the self-renewal genes Prdm16 or Hoxb4 boosted Gpx3 expression. In human primary acute myeloid leukemia samples, GPX3 expression level directly correlated with adverse prognostic outcome, revealing a potential novel target for the eradication of LSCs. PMID- 22508836 TI - Chikungunya virus-induced autophagy delays caspase-dependent cell death. AB - Autophagy is an important survival pathway and can participate in the host response to infection. Studying Chikungunya virus (CHIKV), the causative agent of a major epidemic in India, Southeast Asia, and southern Europe, we reveal a novel mechanism by which autophagy limits cell death and mortality after infection. We use biochemical studies and single cell multispectral assays to demonstrate that direct infection triggers both apoptosis and autophagy. CHIKV-induced autophagy is mediated by the independent induction of endoplasmic reticulum and oxidative stress pathways. These cellular responses delay apoptotic cell death by inducing the IRE1alpha-XBP-1 pathway in conjunction with ROS-mediated mTOR inhibition. Silencing of autophagy genes resulted in enhanced intrinsic and extrinsic apoptosis, favoring viral propagation in cultured cells. Providing in vivo evidence for the relevance of our findings, Atg16L(HM) mice, which display reduced levels of autophagy, exhibited increased lethality and showed a higher sensitivity to CHIKV-induced apoptosis. Based on kinetic studies and the observation that features of apoptosis and autophagy were mutually exclusive, we conclude that autophagy inhibits caspase-dependent cell death but is ultimately overwhelmed by viral replication. Our study suggests that inducers of autophagy may limit the pathogenesis of acute Chikungunya disease. PMID- 22508838 TI - We hear you. PMID- 22508839 TI - Intracerebral inoculation of pathological alpha-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice. AB - The accumulation of misfolded proteins is a fundamental pathogenic process in neurodegenerative diseases. However, the factors that trigger aggregation of alpha-Synuclein (alpha-Syn), the principal component of the intraneuronal inclusions known as Lewy bodies (LBs), and Lewy neurites (LNs), which characterize Parkinson's disease (PD) and dementia with LBs (DLB), are poorly understood. We show here that in young asymptomatic alpha-Syn transgenic (Tg) mice, intracerebral injections of brain homogenates derived from older Tg mice exhibiting alpha-Syn pathology accelerate both the formation of intracellular LB/LN-like inclusions and the onset of neurological symptoms in recipient animals. Pathological alpha-Syn propagated along major central nervous system (CNS) pathways to regions far beyond injection sites and reduced survival with a highly reproducible interval from injection to death in inoculated animals. Importantly, inoculation with alpha-Syn amyloid fibrils assembled from recombinant human alpha-Syn induced identical consequences. Furthermore, we show for the first time that synthetic alpha-Syn fibrils are wholly sufficient to initiate PD-like LBs/LNs and to transmit disease in vivo. Thus, our data point to a prion-like cascade in synucleinopathies whereby cell-cell transmission and propagation of misfolded alpha-Syn underlie the CNS spread of LBs/LNs. These findings open up new avenues for understanding the progression of PD and for developing novel therapeutics. PMID- 22508841 TI - Pseudoaneurysms of the heart. PMID- 22508842 TI - Claudication due to cystic adventitial degeneration: a classical differential diagnosis of atherosclerotic peripheral artery disease. PMID- 22508840 TI - Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. PMID- 22508843 TI - Three-dimensional blood flow alterations after transcatheter aortic valve implantation. PMID- 22508845 TI - Letter by Charitos et al regarding article, "Reoperation of left heart valve bioprostheses according to age at implantation". PMID- 22508846 TI - Identification of a novel post-hydrolytic state in CFTR gating. AB - Adenosine triphosphate (ATP)-binding cassette (ABC) transporters, ubiquitous proteins found in all kingdoms of life, catalyze substrates translocation across biological membranes using the free energy of ATP hydrolysis. Cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of this superfamily in that it functions as an ATP-gated chloride channel. Despite difference in function, recent studies suggest that the CFTR chloride channel and the exporter members of the ABC protein family may share an evolutionary origin. Although ABC exporters harness the free energy of ATP hydrolysis to fuel a transport cycle, for CFTR, ATP-induced dimerization of its nucleotide-binding domains (NBDs) and subsequent hydrolysis-triggered dimer separation are proposed to be coupled, respectively, to the opening and closing of the gate in its transmembrane domains. In this study, by using nonhydrolyzable ATP analogues, such as pyrophosphate or adenylyl-imidodiphosphate as baits, we captured a short-lived state (state X), which distinguishes itself from the previously identified long lived C2 closed state by its fast response to these nonhydrolyzable ligands. As state X is caught during the decay phase of channel closing upon washout of the ligand ATP but before the channel sojourns to the C2 closed state, it likely emerges after the bound ATP in the catalysis-competent site has been hydrolyzed and the hydrolytic products have been released. Thus, this newly identified post hydrolytic state may share a similar conformation of NBDs as the C2 closed state (i.e., a partially separated NBD and a vacated ATP-binding pocket). The significance of this novel state in understanding the structural basis of CFTR gating is discussed. PMID- 22508848 TI - Blood-brain barrier: recent developments and clinical correlations. PMID- 22508847 TI - Analysis of high-affinity assembly for AMPA receptor amino-terminal domains. AB - Analytical ultracentrifugation (AUC) and steady-state fluorescence anisotropy were used to measure the equilibrium dissociation constant (Kd) for formation of dimers by the amino-terminal domains (ATDs) of the GluA2 and GluA3 subtypes of AMPA receptor. Previous reports on GluA2 dimerization differed in their estimate of the monomer-dimer Kd by a 2,400-fold range, with no consensus on whether the ATD forms tetramers in solution. We find by sedimentation velocity (SV) analysis performed using absorbance detection a narrow range of monomer-dimer Kd values for GluA2, from 5 to 11 nM for six independent experiments, with no detectable formation of tetramers and no effect of glycosylation or the polypeptide linker connecting the ATD and ligand-binding domains; for GluA3, the monomer-dimer Kd was 5.6 uM, again with no detectable tetramer formation. For sedimentation equilibrium (SE) experiments, a wide range of Kd values was obtained for GluA2, from 13 to 284 nM, whereas for GluA3, the Kd of 3.1 uM was less than twofold different from the SV value. Analysis of cell contents after the ~1-week centrifuge run by silver-stained gels revealed low molecular weight GluA2 breakdown products. Simulated data for SE runs demonstrate that the apparent Kd for GluA2 varies with the extent of proteolysis, leading to artificially high Kd values. SV experiments with fluorescence detection for GluA2 labeled with 5,6 carboxyfluorescein, and fluorescence anisotropy measurements for GluA2 labeled with DyLight405, yielded Kd values of 5 and 11 nM, consistent with those from SV with absorbance detection. However, the sedimentation coefficients measured by AUC using absorbance and fluorescence systems were strikingly different, and for the latter are not consistent with hydrodynamic protein models. Thus, for unknown reasons, the concentration dependence of sedimentation coefficients obtained with fluorescence detection SV may be unreliable, limiting the usefulness of this technique for quantitative analysis. PMID- 22508849 TI - Scheuermann disease presenting as compressive myelopathy. PMID- 22508850 TI - Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama study. PMID- 22508851 TI - Thrombomodulin and the brain: past, present, and future. PMID- 22508852 TI - Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging. PMID- 22508854 TI - Pearls & oy-sters: treatment of central sleep apnea with topiramate. PMID- 22508855 TI - Serum cholesterol and mTOR inhibitors: surrogate biomarker or epiphenomenon? AB - Lee and colleagues report that increase in serum cholesterol is associated with improved clinical outcomes in patients with renal cell carcinoma treated with temsirolimus. Although these findings must be validated prospectively, it should also be determined if this marker is a true mechanism-based toxicity or an epiphenomenon associated with therapy. PMID- 22508856 TI - Members of the Francisella tularensis phagosomal transporter subfamily of major facilitator superfamily transporters are critical for pathogenesis. AB - Francisella tularensis is the causative agent of tularemia. Due to its aerosolizable nature and low infectious dose, F. tularensis is classified as a category A select agent and, therefore, is a priority for vaccine development. Survival and replication in macrophages and other cell types are critical to F. tularensis pathogenesis, and impaired intracellular survival has been linked to a reduction in virulence. The F. tularensis genome is predicted to encode 31 major facilitator superfamily (MFS) transporters, and the nine-member Francisella phagosomal transporter (Fpt) subfamily possesses homology with virulence factors in other intracellular pathogens. We hypothesized that these MFS transporters may play an important role in F. tularensis pathogenesis and serve as good targets for attenuation and vaccine development. Here we show altered intracellular replication kinetics and attenuation of virulence in mice infected with three of the nine Fpt mutant strains compared with wild-type (WT) F. tularensis LVS. The vaccination of mice with these mutant strains was protective against a lethal intraperitoneal challenge. Additionally, we observed pronounced differences in cytokine profiles in the livers of mutant-infected mice, suggesting that alterations in in vivo cytokine responses are a major contributor to the attenuation observed for these mutant strains. These results confirm that this subset of MFS transporters plays an important role in the pathogenesis of F. tularensis and suggest that a focus on the development of attenuated Fpt subfamily MFS transporter mutants is a viable strategy toward the development of an efficacious vaccine. PMID- 22508857 TI - Loss of meningococcal PilU delays microcolony formation and attenuates virulence in vivo. AB - Neisseria meningitidis is a major cause of sepsis and bacterial meningitis worldwide. This bacterium expresses type IV pili (Tfp), which mediate important virulence traits such as the formation of bacterial aggregates, host cell adhesion, twitching motility, and DNA uptake. The meningococcal PilT protein is a hexameric ATPase that mediates pilus retraction. The PilU protein is produced from the pilT-pilU operon and shares a high degree of homology with PilT. The function of PilT in Tfp biology has been studied extensively, whereas the role of PilU remains poorly understood. Here we show that pilU mutants have delayed microcolony formation on host epithelial cells compared to the wild type, indicating that bacterium-bacterium interactions are affected. In normal human serum, the pilU mutant survived at a higher rate than that for wild-type bacteria. However, in a murine model of disease, mice infected with the pilT mutant demonstrated significantly reduced bacterial blood counts and survived at a higher rate than that for mice infected with the wild type. Infection of mice with the pilU mutant resulted in a trend of lower bacteremia, and still a significant increase in survival, than that of the wild type. In conclusion, these data suggest that PilU promotes timely microcolony formation and that both PilU and PilT are required for full bacterial virulence. PMID- 22508858 TI - Toll-like receptor- and filarial antigen-mediated, mitogen-activated protein kinase- and NF-kappaB-dependent regulation of angiogenic growth factors in filarial lymphatic pathology. AB - Filarial lymphatic pathology is of multifactorial origin, with inflammation, lymphangiogenesis, and innate immune responses all playing important roles. The role of Toll-like receptors (TLRs) in the development of filarial pathology is well characterized. Similarly, the association of pathology with elevated levels of plasma angiogenic factors has also been documented. To examine the association between TLR function and the development of lymphangiogenesis in filarial infections, we examined TLR- and filarial antigen-induced expression and production of various angiogenic growth factors. We demonstrate that TLR ligands (specifically TLR2, -3, and -5 ligands) induce significantly increased expression/production of vascular endothelial growth factor A (VEGF-A) and angiopoietin-1 (Ang-1) in the peripheral blood mononuclear cells of individuals with lymphatic pathology (CP individuals) compared to that in cells of asymptomatic infected (INF) individuals. Similarly, filarial antigens induce significantly enhanced production of VEGF-C in CP compared with INF individuals. TLR2-mediated enhancement of angiogenic growth factor production in CP individuals was shown to be dependent on mitogen-activated protein kinase (MAPK) and NF-kappaB signaling, as pharmacologic inhibition of either extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK, or NF-kappaB signaling resulted in significantly diminished production of VEGF-A and Ang-1. Our data therefore strongly suggest an important association between TLR signaling and lymphangiogenesis in the development of pathology in human lymphatic filariasis. PMID- 22508859 TI - Invasive potential of nonencapsulated disease isolates of Neisseria meningitidis. AB - The capsule of Neisseria meningitidis is the major virulence factor that enables this bacterium to overcome host immunity elicited by complement and phagocytes, rendering it capable of surviving in blood. As such, nonencapsulated N. meningitidis isolates are generally considered nonpathogenic. Here, we consider the inherent virulence of two nonencapsulated N. meningitidis isolates obtained from our national surveillance of infected blood cultures in Canada. Capsule deficiency of both strains was confirmed by serology and PCR for the ctrA to ctrD genes and siaA to siaC genes, as well as siaD genes specific to serogroups B, C, Y, and W135. In both strains, the capsule synthesis genes were replaced by the capsule null locus, cnl-2. In accordance with a lack of capsule, both strains were fully susceptible to killing by both human and baby rabbit complement. However, in the presence of cytidine-5' monophospho-N-acetylneuraminic acid (CMP NANA), allowing for lipooligosaccharide (LOS) sialylation, a significant increase of resistance to complement killing was observed. Mass spectrometry of purified LOS did not reveal any uncommon modifications that would explain their invasive phenotype. Finally, in a mouse intraperitoneal challenge model, these nonencapsulated isolates displayed enhanced virulence relative to an isogenic mutant of serogroup B strain MC58 lacking capsule (MC58DeltasiaD). Virulence of all nonencapsulated isolates tested was below that of encapsulated serogroup B strains MC58 and B16B6. However, whereas no mortality was observed with MC58DeltasiaD, 5/10 mice succumbed to infection with strain 2275 and 2/11 mice succumbed to strain 2274. Our results suggest the acquisition of a new virulence phenotype by these nonencapsulated strains. PMID- 22508860 TI - Listeria monocytogenes strain-specific impairment of the TetR regulator underlies the drastic increase in cyclic di-AMP secretion and beta interferon-inducing ability. AB - Among a number of laboratory strains of Listeria monocytogenes used in experimental infection, strain LO28 is highly capable of inducing robust beta interferon (IFN-beta) production in infected macrophages. In this study, we investigated the molecular mechanism of the IFN-beta-inducing ability of LO28 by comparing it with that of strain EGD, a low-IFN-beta-inducing strain. It was found that LO28 secretes a large amount of IFN-beta-inducing factor, which turned out to be cyclic di-AMP. The secretion of cyclic di-AMP was dependent on MdrT, a multidrug resistance transporter, and LO28 exhibited a very high level of mdrT expression. The introduction of a null mutation into mdrT abolished the ability of LO28 to induce IFN-beta production. Examination of genes responsible for the regulation of mdrT expression revealed a spontaneous 188-bp deletion in tetR of LO28. By constructing recombinant strains of LO28 and EGD in which tetR from each strain was replaced, it was confirmed that the distinct ability of LO28 is attributable mostly to tetR mutation. We concluded that the strong IFN-beta inducing ability of LO28 is due to a genetic defect in tetR resulting in the overexpression of mdrT and a concomitant increase in the secretion of cyclic di AMP through MdrT. PMID- 22508861 TI - Cj1136 is required for lipooligosaccharide biosynthesis, hyperinvasion, and chick colonization by Campylobacter jejuni. AB - Campylobacter jejuni is a major cause of bacterial food-borne enteritis worldwide, and invasion into intestinal epithelial cells is an important virulence mechanism. Recently we reported the identification of hyperinvasive C. jejuni strains and created a number of transposon mutants of one of these strains, some of which exhibited reduced invasion into INT-407 and Caco-2 cells. In one such mutant the transposon had inserted into a homologue of cj1136, which encodes a putative galactosyltransferase according to the annotation of the C. jejuni NCTC11168 genome. In the current study, we investigated the role of cj1136 in C. jejuni virulence, lipooligosaccharide (LOS) biosynthesis, and host colonization by targeted mutagenesis and complementation of the mutation. The cj1136 mutant showed a significant reduction in invasion into human intestinal epithelial cells compared to the wild-type strain 01/51. Invasion levels were partially restored on complementing the mutation. The inactivation of cj1136 resulted in the production of truncated LOS, while biosynthesis of a full-length LOS molecule was restored in the complemented strain. The cj1136 mutant showed an increase in sensitivity to the bile salts sodium taurocholate and sodium deoxycholate and significantly increased sensitivity to polymyxin B compared to the parental strain. Importantly, the ability of the mutant to colonize 1-day-old chicks was also significantly impaired. This study confirms that a putative galactosyltransferase encoded by cj1136 is involved in LOS biosynthesis and is important for C. jejuni virulence, as disruption of this gene and the resultant truncation of LOS affect both colonization in vivo and invasiveness in vitro. PMID- 22508862 TI - Borrelia burgdorferi needs chemotaxis to establish infection in mammals and to accomplish its enzootic cycle. AB - Borrelia burgdorferi, the causative agent of Lyme disease, can be recovered from different organs of infected animals and patients, indicating that the spirochete is very invasive. Motility and chemotaxis contribute to the invasiveness of B. burgdorferi and play important roles in the process of the disease. Recent reports have shown that motility is required for establishing infection in mammals. However, the role of chemotaxis in virulence remains elusive. Our previous studies showed that cheA2, a gene encoding a histidine kinase, is essential for the chemotaxis of B. burgdorferi. In this report, the cheA2 gene was inactivated in a low-passage-number virulent strain of B. burgdorferi. In vitro analyses (microscopic observations, computer-based bacterial tracking analysis, swarm plate assays, and capillary tube assays) showed that the cheA2 mutant failed to reverse and constantly ran in one direction; the mutant was nonchemotactic to attractants. Mouse needle infection studies showed that the cheA2 mutant failed to infect either immunocompetent or immunodeficient mice and was quickly eliminated from the initial inoculation sites. Tick-mouse infection studies revealed that although the mutant was able to survive in ticks, it failed to establish a new infection in mice via tick bites. The altered phenotypes were completely restored when the mutant was complemented. Collectively, these data demonstrate that B. burgdorferi needs chemotaxis to establish mammalian infection and to accomplish its natural enzootic cycle. PMID- 22508865 TI - Measuring the prevalence of questionable research practices with incentives for truth telling. AB - Cases of clear scientific misconduct have received significant media attention recently, but less flagrantly questionable research practices may be more prevalent and, ultimately, more damaging to the academic enterprise. Using an anonymous elicitation format supplemented by incentives for honest reporting, we surveyed over 2,000 psychologists about their involvement in questionable research practices. The impact of truth-telling incentives on self-admissions of questionable research practices was positive, and this impact was greater for practices that respondents judged to be less defensible. Combining three different estimation methods, we found that the percentage of respondents who have engaged in questionable practices was surprisingly high. This finding suggests that some questionable practices may constitute the prevailing research norm. PMID- 22508863 TI - The Spx regulator modulates stress responses and virulence in Enterococcus faecalis. AB - The ability to cope with endogenous or host-generated reactive oxygen species is considered a key virulence attribute of the opportunistic pathogen Enterococcus faecalis, a leading cause of hospital-acquired infections. In this study, we used in silico and mutational analyses to identify and characterize the role of the Spx global regulator in oxidative stress tolerance and virulence in E. faecalis. While the Deltaspx strain grew as well as the wild-type strain under anaerobic conditions, the mutant strain exhibited impaired growth under aerobic conditions and was highly sensitive to oxidative stress agents. The spx mutant strain was also sensitive to a variety of other stressful conditions, including antibiotic stress and killing by the mouse-derived macrophage cell line J774. Using a murine model of foreign body-associated peritonitis, we demonstrated that the ability of the Deltaspx strain to colonize the peritoneum and disseminate in the bloodstream was significantly reduced compared to that of the parent strain. Transcriptional analysis revealed that a large number of known oxidative stress genes are under positive control by Spx. Collectively, our results show that Spx is a major stress gene regulator and is implicated in the pathophysiology of E. faecalis. The relationship of Spx to other oxidative stress regulators is also discussed. PMID- 22508864 TI - E-selectin mediates Porphyromonas gingivalis adherence to human endothelial cells. AB - Porphyromonas gingivalis, a major periodontal pathogen, may contribute to atherogenesis and other inflammatory cardiovascular diseases. However, little is known about interactions between P. gingivalis and endothelial cells. E-selectin is a membrane protein on endothelial cells that initiates recruitment of leukocytes to inflamed tissue, and it may also play a role in pathogen attachment. In the present study, we examined the role of E-selectin in P. gingivalis adherence to endothelial cells. Human umbilical vein endothelial cells (HUVECs) were stimulated with tumor necrosis factor alpha (TNF-alpha) to induce E selectin expression. Adherence of P. gingivalis to HUVECs was measured by fluorescence microscopy. TNF-alpha increased adherence of wild-type P. gingivalis to HUVECs. Antibodies to E-selectin and sialyl Lewis X suppressed P. gingivalis adherence to stimulated HUVECs. P. gingivalis mutants lacking OmpA-like proteins Pgm6 and -7 had reduced adherence to stimulated HUVECs, but fimbria-deficient mutants were not affected. E-selectin-mediated P. gingivalis adherence activated endothelial exocytosis. These results suggest that the interaction between host E selectin and pathogen Pgm6/7 mediates P. gingivalis adherence to endothelial cells and may trigger vascular inflammation. PMID- 22508866 TI - Barnacles and biofouling. AB - Biofouling, the attachment and growth of organisms on submerged, man-made surfaces, has plagued ship operators for at least 2500 years. Accumulation of biofouling, including barnacles and other sessile marine invertebrates, increases the frictional resistance of ships' hulls, resulting in an increase in power and in fuel consumption required to make speed. Scientists and engineers recognized over 100 years ago that in order to solve the biofouling problem, a deeper understanding of the biology of the organisms involved, particularly with regard to larval settlement and metamorphosis and adhesives and adhesion, would be required. Barnacles have served as an important tool in pursuing this research. Over the past 20 years, the pace of these studies has accelerated, likely driven by the introduction of environmental regulations banning the most effective biofouling control products from the market. Research has largely focused on larval settlement and metamorphosis, the development of new biocides, and materials/surface science. Increased research has so far, however, failed to result in commercial applications. Two recent successes (medetomidine/Selektope((r)), surface-bound noradrenaline) build on our improving understanding of the role of the larval nervous system in mediating settlement and metamorphosis. New findings with regard to the curing of barnacle adhesives may pave the way to additional successes. Although the development of most current biofouling control technologies remains largely uninfluenced by basic research on, for example, the ability of settling larvae to perceive surface cues, or the nature of the interaction between organismal adhesives and the substrate, newly-developed materials can serve as useful probes to further our understanding of these processes. PMID- 22508867 TI - Botulinum toxin-A for the treatment of Raynaud syndrome. PMID- 22508869 TI - Risk of serious adverse events associated with biologic and nonbiologic psoriasis systemic therapy: patients ineligible vs eligible for randomized controlled trials. AB - OBJECTIVE: To describe the use of systemic therapy for psoriasis (biologic and nonbiologic [classic] drugs) in patients not adequately represented in randomized controlled trials (RCTs) and the risk of serious adverse events (SAEs) in these patients. DESIGN: A registry inception cohort was used. SETTING: Thirteen dermatology departments in Spain participated. PATIENTS: A consecutive sample of patients treated with biologics and a systematic sample of patients treated with classic systemic therapy were evaluated. A total of 1042 patients (2179 person years) were included. EXPOSURE: Inadequate representation in trials was defined as the presence of any of the following factors: elderly age (>70 years); type of psoriasis other than chronic plaque psoriasis; history of infection caused by hepatitis B, hepatitis C, or human immunodeficiency virus; history of cancer (excluding nonmelanoma skin cancer); and chronic renal or hepatic disease. MAIN OUTCOME MEASURES: Serious adverse events as defined by the International Conference on Harmonization were evaluated. RESULTS: In all, 29.8% of patients receiving systemic therapy for psoriasis would not have been eligible for RCTs. These individuals had an increased risk of SAEs (incidence rate ratio, 2.7; 95% CI, 1.5-4.7). Patients exposed to biologics had an adjusted increased risk of SAEs (incidence rate ratio, 2.3; 95% CI, 1.1-4.8) that was similar in patients eligible and ineligible for RCTs. CONCLUSIONS: Patients ineligible for RCTs are an important proportion (30%) of those receiving systemic therapy for psoriasis. These patients have a higher risk of SAEs and should be closely monitored. Patients exposed to biologics (whether these patients are eligible for RCTs or ineligible) are susceptible to the same increase in risk of SAEs, but biologics add to a higher baseline risk in patients who are ineligible for RCTs. The risk benefit ratio in ineligible patients receiving biologics might be different from the ratio in eligible patients. PMID- 22508870 TI - Mohs micrographic surgery and surgical excision for nonmelanoma skin cancer treatment in the Medicare population. AB - OBJECTIVES: To identify Medicare use rates of Mohs micrographic surgery (MMS) and surgical excision for the treatment of nonmelanoma skin cancer (NMSC) and to identify patient, lesion, and geographic characteristics associated with treatment type. DESIGN: A retrospective analysis of Medicare beneficiaries. SETTING: Surveillance, Epidemiology, and End Results database. PATIENTS: Patients undergoing MMS or other surgical intervention for the treatment of NMSC from January 1, 2001, through December 31, 2006. MAIN OUTCOME MEASURES: Surgical treatment, patient, and lesion characteristics. RESULTS: A total of 26,931 operations were performed for the treatment of NMSC from 2001 through 2006, of which 36.4% were MMS. Although the rate of surgical excision slightly increased during this period (1.8 vs 2.1 per 100 Medicare beneficiaries), the rate of MMS doubled (0.75 vs 1.5 per 100 Medicare beneficiaries). In 46.9% of facial lesions, MMS was performed, whereas MMS was used to treat 14.7% of total body lesions. Atlanta, Georgia, had the highest proportion of patients treated with MMS (45.1%); Louisiana had the lowest (11.0%). Age, race, lesion location, and area of country for patient treatment were significantly associated with MMS use (all P < .001). CONCLUSIONS: Surgical treatment of NMSC increased substantially from 2001 through 2006, primarily because of a doubling in the rate of MMS procedures. Significant differences in surgical rates, depending on patient age, race, lesion location, and geographic region, of treatment were found. PMID- 22508871 TI - Practice gaps. Use of Mohs micrographic surgery for the treatment of nonmelanoma skin cancer. PMID- 22508872 TI - Low blood concentration of hydroxychloroquine in patients with refractory cutaneous lupus erythematosus: a French multicenter prospective study. AB - OBJECTIVE: To study the relation between blood concentration of hydroxychloroquine and the clinical efficacy of hydroxychloroquine sulfate in a series of patients with cutaneous lupus erythematosus (CLE). DESIGN: Prospective multicenter study. A staff dermatologist blinded to blood hydroxychloroquine concentrations performed a standardized review of medical records and assessment of hydroxychloroquine efficacy in the following 3 categories: complete remission, partial remission (clearing of >50% of skin lesions), or treatment failure. Whole blood samples were collected for measurement of blood hydroxychloroquine concentration. SETTING: Fourteen French university hospitals. PATIENTS: Three hundred consecutive patients with subacute or chronic CLE who had been treated with hydroxychloroquine for at least 3 months. MAIN OUTCOME MEASURES: The statistical significance of correlation between blood hydroxychloroquine concentration and efficacy of hydroxychloroquine and the statistical associations in univariate and multivariate analyses of complete remission with several variables. RESULTS: The study included 300 patients with discoid lupus erythematosus (n = 160), subacute CLE (n = 86), lupus erythematosus tumidus (n = 52), chilblain lupus (n = 26), and lupus panniculitis (n = 16); 38 of these patients had 2 or more associated forms. Median blood hydroxychloroquine concentration was significantly higher in patients with complete remission (910 [range, <50 to 3057] ng/mL) compared with partial remission (692 [<50 to 2843] ng/mL) and treatment failure (569 [<50 to 2242] ng/mL) (P = .007). In the multivariate analysis, complete remission was associated with higher blood hydroxychloroquine concentrations (P = .005) and the absence of discoid lesions (P = .004). Thirty patients (10.0%) had very low blood hydroxychloroquine concentrations (<200 ng/mL) and may be considered nonadherent to the treatment regimen. CONCLUSION: Monitoring hydroxychloroquine blood concentrations might improve the management of refractory CLE. PMID- 22508874 TI - Comparative effectiveness of commonly used systemic treatments or phototherapy for moderate to severe plaque psoriasis in the clinical practice setting. AB - OBJECTIVE: To compare the effectiveness of biologic systemic therapy, nonbiologic systemic therapy, and phototherapy for treatment of psoriasis. DESIGN: A cross sectional design was used. SETTING: Ten outpatient dermatology sites across the United States participating in the Dermatology Clinical Effectiveness Research Network contributed to the study. PARTICIPANTS: A total of 713 patients with plaque psoriasis receiving systemic monotherapy (ie, methotrexate sodium, adalimumab, etanercept, or ustekinumab) or narrowband UV-B phototherapy. MAIN OUTCOME MEASURES: The primary outcome of the study was clear or almost clear skin on the Physician Global Assessment scale. Secondary outcomes were score on the Psoriasis Area and Severity Index, affected body surface area, and score on the Dermatology Life Quality Index. RESULTS: The proportion of patients with clear or almost clear ratings on the Physician Global Assessment scale differed among treatments: methotrexate (23.8%), adalimumab (47.7%), etanercept (34.2%), ustekinumab (36.1%), and narrowband UV-B (27.6%) (P < .001). In adjusted analyses, patients receiving adalimumab (relative response rate, 2.15; 95% CI, 1.60-2.90), etanercept (1.45; 1.06-1.97), and ustekinumab (1.57; 1.06-2.32) were more likely to have clear or almost clear skin vs patients receiving methotrexate. Patients receiving phototherapy showed no significant difference (1.35; 95% CI, 0.93-1.96) compared with those receiving methotrexate. No response difference was observed with respect to quality of life. Treatment doses were double the recommended doses in 36.1% of patients taking etanercept and 11.8% of those taking adalimumab;10.6% of patients undergoing phototherapy received the recommended treatment frequency. CONCLUSIONS: The effectiveness of psoriasis therapies in clinical practice may be lower than that reported in previous trials. Although relative differences in objective response rates among therapies may exist, absolute differences are small and may not be clinically significant. Dosing of common therapies varied from trial recommendations. These results provide novel benchmarks emphasizing the critical importance of studying effectiveness in real-world practice. PMID- 22508876 TI - Halo nevi association in nonsegmental vitiligo affects age at onset and depigmentation pattern. AB - OBJECTIVE: To compare factors associated with halo nevi with nonsegmental vitiligo (NSV) vs NSV alone. DESIGN: Prospective observational study in 553 patients with a confirmed diagnosis of NSV attending a vitiligo clinic between January 1, 2006, and July 1, 2010. SETTING: Vitiligo Clinic at the Department of Dermatology, University Hospital Center of Bordeaux, Bordeaux, France. PATIENTS: The Vitiligo European Task Force questionnaire was informed for each patient attending the clinic with a confirmed diagnosis of NSV after the exclusion of other forms of vitiligo (focal, mucosal, and not classifiable). Thyroid function and antithyroid antibodies were screened if not obtained in the previous year. MAIN OUTCOME MEASURES: Extent of disease and markers of autoimmunity or autoinflammation. RESULTS: Of the 553 patients, 130 had halo nevi-NSV and 423 had NSV. Family history of premature hair graying (odds ratio, 1.74; P < .01) was positively associated with halo nevi-NSV by univariate analysis. Using multivariate analysis, age at onset younger than 18 years, phototype, total body area, localization on the trunk, involvement of hands and feet, and total staging were found to be independent factors. Age at onset younger than 18 years; phototypes I, II, and III; trunk involvement; and staging were positively associated with halo nevi-NSV, whereas this association was negative for total affected area and involvement of hands and feet. CONCLUSIONS: Halo nevi association in NSV affects age at onset and depigmentation pattern and has a stronger link with familial premature hair graying, suggesting that premature hair graying may involve, at least partly, an autoimmune pathway. PMID- 22508877 TI - An unusual variant of confluent and reticulated papillomatosis masquerading as tinea versicolor. AB - BACKGROUND: Confluent and reticulated papillomatosis (CARP), also known as Gougerot-Carteaud syndrome, is a rare disorder. It usually presents as hyperkeratotic brown papules that coalesce into plaques with a reticulated periphery on the central trunk of young adults. Confluent and reticulated papillomatosis is most often clinically confused with tinea versicolor and usually does not respond to therapy with antifungals. Minocycline is the treatment of choice. OBSERVATIONS: Four cases of CARP with the unusual presentation of hypopigmented lesions masquerading as tinea versicolor in dark skinned (Fitzpatrick skin types IV-V) patients are presented. All cases exhibited characteristic features of CARP on biopsy results and responded to minocycline of several months' duration. Two of the cases were also treated with adjuvant topical tazarotene. CONCLUSIONS: The hypopigmented variant of CARP in dark skinned patients makes the clinical differentiation from tinea versicolor extremely challenging. Physicians encountering darkly pigmented individuals with hypopigmented plaques unresponsive to antifungals should have a high clinical suspicion for the hypopigmented variant of CARP. PMID- 22508878 TI - Safety of topical corticosteroid use during pregnancy. PMID- 22508879 TI - Pitfalls of evidence-based medicine: the example of actinic keratosis therapy. PMID- 22508880 TI - A generalized annular eruption with occasional vesicles. PMID- 22508881 TI - Erythematous annular plaques on the trunk. PMID- 22508882 TI - Plaques on a butcher's fingers. PMID- 22508883 TI - Multiple brown macules and papules on a female teenager. PMID- 22508884 TI - Dermatologist preferences for treatments to compare in future randomized controlled comparative effectiveness trials for moderate to severe psoriasis. PMID- 22508885 TI - Poor benefit/risk balance of intravenous immunoglobulins in DRESS. PMID- 22508886 TI - Recurrent blistering of the fingertips as a sign of carpal tunnel syndrome: an effect of nerve compression. PMID- 22508887 TI - Topical psoralen plus UV-A therapy for tyrosine kinase inhibitor-induced hand foot syndrome. PMID- 22508888 TI - In vivo confocal microscopic pattern of fibroepithelioma of pinkus. PMID- 22508889 TI - Practice gaps. The need to examine the risks and benefits of intravenous immunoglobulin therapy in severe cutaneous adverse reactions. PMID- 22508891 TI - Epithelioid haemangioendothelioma of the superior vena cava. AB - Primary calcified tumours of major central veins are extremely rare. Epithelioid haemangioendotheliomas (EHs) are malignant tumours of vascular origin with very limited reports in the literature. The aetiology is unknown. Immunohistochemically, tumours are often positive for at least one endothelial marker. We present a unique presentation of an EA in the superior vena cava. PMID- 22508890 TI - Successful surgical repair of platypnea-orthodeoxia syndrome in a patient with cerebral infarction. AB - Platypnea-orthodeoxia syndrome is a rare condition characterized by hypoxaemia in the upright position and arterial hypoxaemia induced by the upright position, and the syndrome is relieved by recumbency. We encountered a cerebral infarction patient who presented with low SpO(2) levels in the upright position. The patient was diagnosed with platypnea-orthodeoxia syndrome caused by the patent foramen ovale and mechanical compression of the heart due to an elongated aorta. The surgical closure of the foramen and shortening of the ascending aorta improved the patient's clinical condition. To our knowledge, there have been few reports of clinical conditions of this kind. PMID- 22508892 TI - Challenging management of a complex distal aortic arch pseudoaneurysm following previous aortic dissection repair. AB - The primary goals of surgery for acute aortic dissection are to resect or control the intimal flap, prevent distal malperfusion, protect the brain and have a viable patient. However, several technical measures are important to prevent early and late sequalae, including adequate aortic resection, creating a stable anastamotic suture line, appropriate graft measurement and tailoring and completely resecting inciting aortic aneurysms. Utilizing simultaneous sternotomy and thoracotomy incisions, we report the re-operative management of a patient with an expanding distal aortic arch pseudoaneurysm, extending into the left pleural space, superimposed upon severely kinked proximal ascending aortic grafts and an aneurysmal aortic root only 6 months after initial repair. PMID- 22508894 TI - Motor nerve to the vastus lateralis. AB - Objective To further delineate the anatomy of the motor nerve to the vastus lateralis (MNVL) in the context of its use as a possible interpositional nerve graft in facial nerve rehabilitation.Methods Twelve fresh human cadaveric thighs were dissected to investigate the anatomic location and branching pattern of the MNVL muscle.Results There were 3 to 6 primary nerve branches (mean, 4.4) supplying the vastus lateralis. The mean primary branch length was 93.8 mm (range, 51-196 mm), and each primary branch had a mean of 2.3 subsequent branches. There were 2 larger caliber branches (>2 mm in diameter) supplying the proximal and distal muscle. The nerve branches are variable in their relation to the vascular pedicle and perforating vessels of the descending branch of the lateral circumflex femoral artery.Conclusion The nerve to the vastus lateralis is a readily available, redundant motor nerve suitable for facial nerve cable grafting. PMID- 22508893 TI - Conservative treatment of post-lobectomy bronchopleural fistula. AB - Post-lobectomy bronchopleural fistula is a rare complication of lung resection surgery, and proper management is essential for its successful resolution. Most published papers deal with endoscopic and surgical treatment. We report our experience with conservative management. Data were collected by reviewing the clinical charts of patients diagnosed with post-lobectomy bronchopleural fistula at the University Hospitals Marques de Valdecilla, Santander, and Puerta de Hierro, Majadahonda-Madrid, Spain, from June 2003 to December 2010. Bronchopleural fistula was diagnosed by means of endoscopic visualization. Treatment included the insertion of a thoracostomy drainage tube in the pleural cavity. In patients under mechanical ventilation, independent pulmonary ventilation was also applied. Seven cases of post-lobectomy bronchopleural fistula were collected. Three of them occurred within the first week, another three within the first month and the remaining case after 10 months. The fistula size ranged between 6 mm and complete suture dehiscence. Two patients died due to causes unrelated to the treatment. The period of time elapsed for the resolution of this complication varied between 5 and 36 days. We conclude that conservative treatment of post-lobectomy bronchopleural fistula is a safe and simple option that must be taken into account in the management of this problem. PMID- 22508895 TI - Toward a universal, automated facial measurement tool in facial reanimation. AB - OBJECTIVE: To describe a highly quantitative facial function-measuring tool that yields accurate, objective measures of facial position in significantly less time than existing methods. METHODS: Facial Assessment by Computer Evaluation (FACE) software was designed for facial analysis. Outputs report the static facial landmark positions and dynamic facial movements relevant in facial reanimation. Fifty individuals underwent facial movement analysis using Photoshop-based measurements and the new software; comparisons of agreement and efficiency were made. Comparisons were made between individuals with normal facial animation and patients with paralysis to gauge sensitivity to abnormal movements. RESULTS: Facial measurements were matched using FACE software and Photoshop-based measures at rest and during expressions. The automated assessments required significantly less time than Photoshop-based assessments.FACE measurements easily revealed differences between individuals with normal facial animation and patients with facial paralysis. CONCLUSIONS: FACE software produces accurate measurements of facial landmarks and facial movements and is sensitive to paralysis. Given its efficiency, it serves as a useful tool in the clinical setting for zonal facial movement analysis in comprehensive facial nerve rehabilitation programs. PMID- 22508896 TI - Role of virtual surgery in preoperative planning: assessing the individual components of functional nasal airway surgery. AB - OBJECTIVES: To demonstrate the effect of individual components of functional nasal airway surgery in a patient with multifactorial obstruction and to discuss the potential benefit of computational fluid dynamics (CFD)-aided virtual surgery. METHODS: A 53-year-old woman underwent septoplasty,turbinate reduction, and nasal valve repair. Presurgery and postsurgery digital nasal models were created from computed tomographic images, and nasal resistance was calculated using CFD techniques. The digital models were then manipulated to isolate the effects of the components of the surgery, creating a nasal valverepair alone model and a septoplasty/turbinate reduction alone model. RESULTS: Bilateral nasal resistance in the postsurgery model was approximately 25% less than presurgery values.Similarly, CFD analysis showed reductions in nasal resistance of the virtual models: 19% reduction with intranasal surgery alone and 6% reduction with nasal valve repair alone. CONCLUSIONS: Most of the reduction in nasal resistance was accomplished with performance of septoplasty and inferior turbinate reduction. The contribution of nasal valve repair was less in comparison but not insignificant.This pilot study implies that CFD-aided virtual surgery may be useful as part of preoperative planning inpatients with multifactorial anatomical nasal airwayobstruction PMID- 22508897 TI - Impact of cleft width in clefts of secondary palate on the risk of velopharyngeal insufficiency. AB - Objective To investigate the association between velopharyngeal insufficiency (VPI), a common finding after cleft palate repair, and various risk factors, including cleft width.Methods We performed a retrospective cohort study of patients with isolated cleft palates repaired from 2003 to 2008 at a tertiary children's hospital. Patients were observed postoperatively for development of VPI and palatal fistula. The primary risk factor was cleft width. Covariates included cleft length, age at surgery, and presence of associated syndrome. Logistic regression analysis was used to calculate adjusted and unadjusted odds ratios (ORs).Results The cohort comprised 61 patients. Mean (SD) patient age at the time of cleft repair was 13 (3) months. Fistula rate was 3%. Overall rate of postoperative VPI was 32%. We found significant associations between VPI diagnosis and increasing age in months at the time of palate repair (OR, 1.4 [95% CI, 1.2-1.7]) and between VPI and cleft width greater than 10 mm (OR, 5.3 [95% CI, 1.8-15.6]). The association between VPI and cleft width was similar after adjustment for cleft length, patient age, and syndrome presence (OR, 4.5 [95% CI, 1.1-18.7]).Conclusions Our results suggest that increased palatal cleft width is associated with a greater risk of postoperative VPI. Clinicians should consider this when counseling patient families for cleft palate repair. PMID- 22508898 TI - Admissible Diffusion Wavelets and Their Applications in Space-Frequency Processing. AB - As signal processing tools, diffusion wavelets and biorthogonal diffusion wavelets have been propelled by recent research in mathematics. They employ diffusion as a smoothing and scaling process to empower multiscale analysis. However, their applications in graphics and visualization are overshadowed by nonadmissible wavelets and their expensive computation. In this paper, our motivation is to broaden the application scope to space-frequency processing of shape geometry and scalar fields. We propose the admissible diffusion wavelets (ADW) on meshed surfaces and point clouds. The ADW are constructed in a bottom-up manner that starts from a local operator in a high frequency, and dilates by its dyadic powers to low frequencies. By relieving the orthogonality and enforcing normalization, the wavelets are locally supported and admissible, hence facilitating data analysis and geometry processing. We define the novel rapid reconstruction, which recovers the signal from multiple bands of high frequencies and a low-frequency base in full resolution. It enables operations localized in both space and frequency by manipulating wavelet coefficients through space frequency filters. This paper aims to build a common theoretic foundation for a host of applications, including saliency visualization, multiscale feature extraction, spectral geometry processing, etc. PMID- 22508899 TI - Rich Intrinsic Image Decomposition of Outdoor Scenes from Multiple Views. AB - Intrinsic images aim at separating an image into its reflectance and illumination components to facilitate further analysis or manipulation. This separation is severely ill posed and the most successful methods rely on user indications or precise geometry to resolve the ambiguities inherent to this problem. In this paper, we propose a method to estimate intrinsic images from multiple views of an outdoor scene without the need for precise geometry and with a few manual steps to calibrate the input. We use multiview stereo to automatically reconstruct a 3D point cloud of the scene. Although this point cloud is sparse and incomplete, we show that it provides the necessary information to compute plausible sky and indirect illumination at each 3D point. We then introduce an optimization method to estimate sun visibility over the point cloud. This algorithm compensates for the lack of accurate geometry and allows the extraction of precise shadows in the final image. We finally propagate the information computed over the sparse point cloud to every pixel in the photograph using image-guided propagation. Our propagation not only separates reflectance from illumination, but also decomposes the illumination into a sun, sky, and indirect layer. This rich decomposition allows novel image manipulations as demonstrated by our results. PMID- 22508900 TI - Abstracting Attribute Space for Transfer Function Exploration and Design. AB - Currently, user centered transfer function design begins with the user interacting with a one or two-dimensional histogram of the volumetric attribute space. The attribute space is visualized as a function of the number of voxels, allowing the user to explore the data in terms of the attribute size/magnitude. However, such visualizations provide the user with no information on the relationship between various attribute spaces (e.g., density, temperature, pressure, x, y, z) within the multivariate data. In this work, we propose a modification to the attribute space visualization in which the user is no longer presented with the magnitude of the attribute; instead, the user is presented with an information metric detailing the relationship between attributes of the multivariate volumetric data. In this way, the user can guide their exploration based on the relationship between the attribute magnitude and user selected attribute information as opposed to being constrained by only visualizing the magnitude of the attribute. We refer to this modification to the traditional histogram widget as an abstract attribute space representation. Our system utilizes common one and two-dimensional histogram widgets where the bins of the abstract attribute space now correspond to an attribute relationship in terms of the mean, standard deviation, entropy, or skewness. In this manner, we exploit the relationships and correlations present in the underlying data with respect to the dimension(s) under examination. These relationships are often times key to insight and allow us to guide attribute discovery as opposed to automatic extraction schemes which try to calculate and extract distinct attributes a priori. In this way, our system aids in the knowledge discovery of the interaction of properties within volumetric data. PMID- 22508901 TI - Visuo-Haptic Mixed Reality with Unobstructed Tool-Hand Integration. AB - Visuo-haptic mixed reality consists of adding to a real scene the ability to see and touch virtual objects. It requires the use of see-through display technology for visually mixing real and virtual objects, and haptic devices for adding haptic interaction with the virtual objects. Unfortunately, the use of commodity haptic devices poses obstruction and misalignment issues that complicate the correct integration of a virtual tool and the user's real hand in the mixed reality scene. In this work, we propose a novel mixed reality paradigm where it is possible to touch and see virtual objects in combination with a real scene, using commodity haptic devices, and with a visually consistent integration of the user's hand and the virtual tool. We discuss the visual obstruction and misalignment issues introduced by commodity haptic devices, and then propose a solution that relies on four simple technical steps: color-based segmentation of the hand, tracking-based segmentation of the haptic device, background repainting using image-based models, and misalignment-free compositing of the user's hand. We have developed a successful proof-of-concept implementation, where a user can touch virtual objects and interact with them in the context of a real scene, and we have evaluated the impact on user performance of obstruction and misalignment correction. PMID- 22508902 TI - Efficient Boundary Extraction of BSP Solids Based on Clipping Operations. AB - We present an efficient algorithm to extract the manifold surface that approximates the boundary of a solid represented by a Binary Space Partition (BSP) tree. Our polygonization algorithm repeatedly performs clipping operations on volumetric cells that correspond to a spatial convex partition and computes the boundary by traversing the connected cells. We use point-based representations along with finite-precision arithmetic to improve the efficiency and generate the B-rep approximation of a BSP solid. The core of our polygonization method is a novel clipping algorithm that uses a set of logical operations to make it resistant to degeneracies resulting from limited precision of floating-point arithmetic. The overall BSP to B-rep conversion algorithm can accurately generate boundaries with sharp and small features, and is faster than prior methods. At the end of this paper, we use this algorithm for a few geometric processing applications including Boolean operations, model repair, and mesh reconstruction. PMID- 22508903 TI - Linear Correlations between Spatial and Normal Noise in Triangle Meshes. AB - We study the relationship between the noise in the vertex coordinates of a triangle mesh and normal noise. First, we compute in closed form the expectation for the angle theta between the new and the old normal when uniform noise is added to a single vertex of a triangle. Next, we propose and experimentally validate an approximation and lower and upper bounds for theta when uniform noise is added to all three vertices of the triangle. In all cases, for small amounts of spatial noise that do not severely distort the mesh, there is a linear correlation between theta and simple functions of the heights of the triangles and thus, theta can be computed efficiently. The addition of uniform spatial noise to a mesh can be seen as a dithered quantization of its vertices. We use the obtained linear correlations between spatial and normal noise to compute the level of dithered quantization of the mesh vertices when a tolerance for the average normal distortion is given. PMID- 22508904 TI - Poisson Coordinates. AB - Harmonic functions are the critical points of a Dirichlet energy functional, the linear projections of conformal maps. They play an important role in computer graphics, particularly for gradient-domain image processing and shape-preserving geometric computation. We propose Poisson coordinates, a novel transfinite interpolation scheme based on the Poisson integral formula, as a rapid way to estimate a harmonic function on a certain domain with desired boundary values. Poisson coordinates are an extension of the Mean Value coordinates (MVCs) which inherit their linear precision, smoothness, and kernel positivity. We give explicit formulas for Poisson coordinates in both continuous and 2D discrete forms. Superior to MVCs, Poisson coordinates are proved to be pseudoharmonic (i.e., they reproduce harmonic functions on n-dimensional balls). Our experimental results show that Poisson coordinates have lower Dirichlet energies than MVCs on a number of typical 2D domains (particularly convex domains). As well as presenting a formula, our approach provides useful insights for further studies on coordinates-based interpolation and fast estimation of harmonic functions. PMID- 22508905 TI - Visualization and visual analysis of multifaceted scientific data: a survey. AB - Visualization and visual analysis play important roles in exploring, analyzing, and presenting scientific data. In many disciplines, data and model scenarios are becoming multifaceted: data are often spatiotemporal and multivariate; they stem from different data sources (multimodal data), from multiple simulation runs (multirun/ensemble data), or from multiphysics simulations of interacting phenomena (multimodel data resulting from coupled simulation models). Also, data can be of different dimensionality or structured on various types of grids that need to be related or fused in the visualization. This heterogeneity of data characteristics presents new opportunities as well as technical challenges for visualization research. Visualization and interaction techniques are thus often combined with computational analysis. In this survey, we study existing methods for visualization and interactive visual analysis of multifaceted scientific data. Based on a thorough literature review, a categorization of approaches is proposed. We cover a wide range of fields and discuss to which degree the different challenges are matched with existing solutions for visualization and visual analysis. This leads to conclusions with respect to promising research directions, for instance, to pursue new solutions for multirun and multimodel data as well as techniques that support a multitude of facets. PMID- 22508906 TI - Real-time GPU surface curvature estimation on deforming meshes and volumetric data sets. AB - Surface curvature is used in a number of areas in computer graphics, including texture synthesis and shape representation, mesh simplification, surface modeling, and nonphotorealistic line drawing. Most real-time applications must estimate curvature on a triangular mesh. This estimation has been limited to CPU algorithms, forcing object geometry to reside in main memory. However, as more computational work is done directly on the GPU, it is increasingly common for object geometry to exist only in GPU memory. Examples include vertex skinned animations and isosurfaces from GPU-based surface reconstruction algorithms. For static models, curvature can be precomputed and CPU algorithms are a reasonable choice. For deforming models where the geometry only resides on the GPU, transferring the deformed mesh back to the CPU limits performance. We introduce a GPU algorithm for estimating curvature in real time on arbitrary triangular meshes. We demonstrate our algorithm with curvature-based NPR feature lines and a curvature-based approximation for an ambient occlusion. We show curvature computation on volumetric data sets with a GPU isosurface extraction algorithm and vertex-skinned animations. We present a graphics pipeline and CUDA implementation. Our curvature estimation is up to ~18x faster than a multithreaded CPU benchmark. PMID- 22508907 TI - Enhanced Spatial Stability with Hilbert and Moore Treemaps. AB - Treemaps are a well known and powerful space-filling visualisation method for displaying hierarchical data. Many alternative treemap algorithms have been proposed, often with the aim being to optimise performance across several criteria, including spatial stability to assist users in locating and monitoring items of interest. In this paper, we demonstrate that spatial stability is not fully captured by the commonly used "distance change" (DC) metric, and we introduce a new "location drift" (LD) metric to more fully capture spatial stability. An empirical study examines the validity and usefulness of the location drift metric, showing that it explains some effects on user performance that distance change does not. Next, we introduce "Hilbert" and "Moore" treemap algorithms, which are designed to achieve high spatial stability. We assess their performance in comparison to other treemaps, showing that Hilbert and Moore treemaps perform well across all stability metrics. PMID- 22508908 TI - Reduced false positives in PDZ binding prediction using sequence and structural descriptors. AB - Abstract-Identifying the binding partners of proteins is a problem of fundamental importance in computational biology. The PDZ is one of the most common and well studied protein binding domains, hence it is a perfect model system for designing protein binding predictors. The standard approach to identifying the binding partners of PDZ domains uses multiple sequence alignments to infer the set of contact residues that are used in a predictive model. We expand on the sequence alignment approach by incorporating structural information to generate descriptors of the binding site geometry. Furthermore, we generate a real-value score for binary predictions by applying a filter based on models that predict the probability distributions of contact residues at each of the canonical PDZ ligand binding positions. Under training cross validation, our model produced an order of magnitude more predictions at a false positive proportion (FPP) of 10 percent than our benchmark model chosen from the literature. Evaluated using an independent cross validation, with computationally predicted structures, our model was able to make five times as many predictions as the benchmark model, with a Matthews' correlation coefficient (MCC) of 0.33. In addition, our model achieved a false positive proportion of 0.14, while the benchmark model had a 0.25 false positive proportion. PMID- 22508909 TI - An evolutionary algorithm approach for feature generation from sequence data and its application to DNA splice site prediction. AB - Associating functional information with biological sequences remains a challenge for machine learning methods. The performance of these methods often depends on deriving predictive features from the sequences sought to be classified. Feature generation is a difficult problem, as the connection between the sequence features and the sought property is not known a priori. It is often the task of domain experts or exhaustive feature enumeration techniques to generate a few features whose predictive power is then tested in the context of classification. This paper proposes an evolutionary algorithm to effectively explore a large feature space and generate predictive features from sequence data. The effectiveness of the algorithm is demonstrated on an important component of the gene-finding problem, DNA splice site prediction. This application is chosen due to the complexity of the features needed to obtain high classification accuracy and precision. Our results test the effectiveness of the obtained features in the context of classification by Support Vector Machines and show significant improvement in accuracy and precision over state-of-the-art approaches. PMID- 22508910 TI - A computational model for predicting protein interactions based on multidomain collaboration. AB - Recently, several domain-based computational models for predicting protein protein interactions (PPIs) have been proposed. The conventional methods usually infer domain or domain combination (DC) interactions from already known interacting sets of proteins, and then predict PPIs using the information. However, the majority of these models often have limitations in providing detailed information on which domain pair (single domain interaction) or DC pair (multidomain interaction) will actually interact for the predicted protein interaction. Therefore, a more comprehensive and concrete computational model for the prediction of PPIs is needed. We developed a computational model to predict PPIs using the information of intraprotein domain cohesion and interprotein DC coupling interaction. A method of identifying the primary interacting DC pair was also incorporated into the model in order to infer actual participants in a predicted interaction. Our method made an apparent improvement in the PPI prediction accuracy, and the primary interacting DC pair identification was valid specifically in predicting multidomain protein interactions. In this paper, we demonstrate that 1) the intraprotein domain cohesion is meaningful in improving the accuracy of domain-based PPI prediction, 2) a prediction model incorporating the intradomain cohesion enables us to identify the primary interacting DC pair, and 3) a hybrid approach using the intra/interdomain interaction information can lead to a more accurate prediction. PMID- 22508911 TI - Who forgot? The challenges of family responsibility for adherence in vulnerable pediatric populations. PMID- 22508912 TI - Birth asphyxia: a major cause of early neonatal mortality in a Tanzanian rural hospital. AB - OBJECTIVE: Early neonatal mortality within the first 24 hours contributes substantially to overall neonatal mortality rates. The definition of birth asphyxia (BA) is imprecise, and reliable cause-specific mortality data are limited; thus the estimated proportion of BA-related deaths globally remains questionable. The objective was to determine the presumed causes of neonatal death within the first 24 hours in a rural hospital in Northern Tanzania. METHODS: This is a prospective descriptive observational study conducted in the delivery room and adjacent neonatal area. Research assistants were trained to observe and record events related to labor, neonatal resuscitation, and 24-hour postnatal course. BA was defined as failure to initiate spontaneous respirations and/or 5-minute Apgar score <7, prematurity as gestational age <36 weeks, and low birth weight (LBW) as birth weight <3rd centile for gestational age. Data were analyzed with chi(2) and Student's t tests. RESULTS: Over 1 year, 4720 infants were born and evaluated. Of these, 256 were admitted to the neonatal area. Forty nine infants died secondary to BA (61%), prematurity (18%), LBW (8%), infection (2%), congenital abnormalities (8%), and unclear reason (2%). The 5-minute Apgar score was >=7 in 50% of the infants who died secondary to BA. CONCLUSIONS: Most cases of early neonatal mortality were related to BA, and prematurity and LBW are additional important considerations. Reducing perinatal mortality requires a multifaceted approach with attention to issues related to BA, potential complications of prematurity, and LBW. The 5-minute Apgar score is a poor surrogate of BA. PMID- 22508913 TI - Health risks of Oregon eighth-grade participants in the "choking game": results from a population-based survey. AB - OBJECTIVE: To examine the risk behaviors associated with participation in the "choking game" by eighth-graders in Oregon. METHODS: We obtained data from the 2009 Oregon Healthy Teens survey, a cross-sectional weighted survey of 5348 eighth-graders that questioned lifetime prevalence and frequency of choking game participation. The survey also included questions about physical and mental health, gambling, sexual activity, nutrition, physical activity/body image, exposure to violence, and substance use. RESULTS: Lifetime prevalence of choking game participation was 6.1% for Oregon eighth-graders, with no differences between males and females. Of the eighth-grade choking game participants, 64% had engaged in the activity more than once and 26.6% >5 times. Among males, black youth were more likely to participate than white youth. Among both females and males, Pacific Islander youth were much more likely to participate than white youth. Multivariate logistic regression revealed that sexual activity and substance use were significantly associated with choking game participation for both males and females. CONCLUSIONS: At >6%, the prevalence of choking game participation among Oregon youth is consistent with previous findings. However, we found that most of those who participate will put themselves at risk more than once. Participants also have other associated health risk behaviors. The comprehensive adolescent well visit, as recommended by the American Academy of Pediatrics, is a good opportunity for providers to conduct a health behavior risk assessment and, if appropriate, discuss the dangers of engaging in this activity. PMID- 22508914 TI - Comparison of mercury and aneroid blood pressure measurements in youth. AB - OBJECTIVE: Because of concerns about the safety and environmental impact of mercury, aneroid sphygmomanometers have replaced mercury-filled devices for blood pressure (BP) measurements. Despite this change, few studies have compared BP measurements between the 2 devices. METHODS: The SEARCH for Diabetes in Youth Study conducted a comparison of aneroid and mercury devices among 193 youth with diabetes (48% boys, aged 12.9 +/- 3.7 years; 89% type 1). Statistical analyses included estimating Pearson correlation coefficients, Bland-Altman plots, paired t tests, and fitting regression models, both overall and stratified by age (<10 vs >=10-18 years). RESULTS: Mean mercury and aneroid systolic and diastolic BPs were highly correlated. For the entire group, there was no significant difference in mean systolic BP using the aneroid device, but there was a -1.53 +/- 5.06 mm Hg difference in mean diastolic BP. When stratified by age, a lower diastolic BP (-1.78 +/- 5.2 mm Hg) was seen in those >=10 to 18 years using the aneroid device. No differences in systolic BP were observed, and there were no differences in BP by device in individuals <10 years. Regression analyses did not identify any explanatory variables. CONCLUSIONS: Although a small discrepancy between diastolic BP measurements from aneroid versus mercury devices exists, this variation is unlikely to be clinically significant, suggesting that either device could be used in research or clinical settings. PMID- 22508916 TI - Reference ranges for lymphocyte counts of neonates: associations between abnormal counts and outcomes. AB - BACKGROUND AND OBJECTIVE: Both high and low lymphocyte counts at birth have been associated with adverse outcomes. However, the validity of defining a lymphocyte count as "abnormal" depends on having an accurate reference range. We established a reference range for neonatal lymphocyte counts by using multihospital data and used this to assess previously reported relationships between abnormal counts and early onset sepsis (EOS), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), periventricular leukomalacia, and birth asphyxia. METHODS: We first created a data set that excluded counts from neonates with diagnoses previously associated with abnormal lymphocyte counts. Then the complete data (counts excluded plus included in the reference range) were used to test associations between abnormal counts and EOS, IVH, ROP, periventricular leukomalacia, and outcomes after birth asphyxia. RESULTS: Lymphocyte counts were retrieved from 40 487 neonates, 10 860 of which were excluded from the reference range. A count >95th percentile was associated with EOS (2.07; 95% confidence interval [CI]: 1.80-2.38) and IVH >=grade 3 (2.93; 95% CI: 1.83-4.71). A count <5th percentile was associated with EOS (odds ratio:1.24; 95% CI: 1.04-1.48), IVH >=grade 3 (3.23; 95% CI: 1.95-5.36), and ROP >=stage 3 (4.80: 95% CI: 2.38-9.66). Among 120 meeting criteria for birth asphyxia, those with a low count and a high nucleated red cell count had higher mortality (37% vs 11%, P = .001), more transfusions (P = .000), and more neurology referrals (P < .01). CONCLUSIONS: A reference range for lymphocytes can identify neonates with abnormal counts, which can be useful because these neonates are at higher risk for certain adverse outcomes. PMID- 22508915 TI - Barriers to medication adherence in HIV-infected children and youth based on self and caregiver report. AB - OBJECTIVE: Nonadherence to antiretroviral therapy among children/youth with HIV often is associated with disease progression. This study examined the agreement between child and caregiver perceptions of barriers to adherence and factors associated with these barriers. METHODS: Children/youth with perinatally acquired HIV and their parents/caregivers (n = 120 dyads) completed a questionnaire about 19 potential barriers to adherence to the child's antiretroviral therapy regimen. Agreement between the 2 reports was measured via the kappa statistic. Factors associated with the barriers were assessed by using multiple logistic regression. RESULTS: Of the 120 children, 55% were African American, 54% were boys, and the average age was 12.8 years. The most frequently reported barrier by either the caregiver or youth was "forgot." There were varying degrees of agreement between child and caregiver on the following barriers: "forgot," "taste," "child was away from home," "child refused," and "child felt good." Children who knew their HIV status were more likely to report logistical barriers, such as scheduling issues. Children with a biological parent as their caregiver were more likely to report regimen or fear of disclosure as a barrier. CONCLUSIONS: Lack of agreement was observed for more than half of the studied barriers, indicating discrepancies between children's and caregivers' perceptions of factors that influence medication-taking. The findings suggest a need for interventions that involve both child and caregiver in the tasks of remembering when to administer the child's medications, sustaining adherence, and appropriately transitioning medication responsibility to the youth. PMID- 22508917 TI - Antenatal glucocorticoid exposure and long-term alterations in aortic function and glucose metabolism. AB - OBJECTIVE: Animal studies have demonstrated long-term effects of in utero glucocortcoid exposure on vascular development and glucose metabolism. We hypothesized that there would be a similar impact in humans. METHODS: One hundred and two young adults born preterm aged 23 to 28 years, with prospective data collection from birth, and 95 adults born term after uncomplicated pregnancies underwent cardiovascular MRI. We compared cardiac and aortic structure and function, as well as cardiovascular risk profile, in a nested case-control study of 16 participants exposed to antenatal steroids and 32 who were not, but with otherwise similar perinatal care. Outcomes were compared with normal ranges in those born term. RESULTS: Adults whose mothers had received antenatal steroids had decreased ascending aortic distensibility (9.88 +/- 3.21 vs 13.62 +/- 3.88 mm Hg(-1) * 10(3), P = .002) and increased aortic arch pulse wave velocity (5.45 +/- 1.41 vs 4.47 +/- 0.91 m/s, P = .006). The increase in stiffness was equivalent to that of term adults a decade older. Those who had in utero exposure to antenatal steroids also had significant differences in homeostatic model assessments for beta-cell function (P = .010), but in multiple regression analysis this did not explain the impact of steroids on aortic function. CONCLUSIONS: Antenatal glucocorticoid exposure in preterm infants is associated with increased aortic arch stiffness and altered glucose metabolism in early adulthood. PMID- 22508919 TI - Risk factors for hospitalization with lower respiratory tract infections in children in rural Alaska. AB - OBJECTIVE: Lower respiratory tract infections (LRTIs) are a major cause of morbidity for children worldwide and particularly for children from developing and indigenous populations. In this study, we evaluated risk factors for hospitalization with LRTI in a region in southwest Alaska. METHODS: The study was conducted from October 1, 2006, to September 30, 2007, in the Yukon Kuskokwim Delta region of Alaska. Cases were recruited from children <3 years of age hospitalized with LRTI. Controls were recruited during visits to the surrounding communities in the region and matched posthoc to cases on the basis of subregion, season, and age. Parents were interviewed for potential risk factors, and medical records were reviewed. Participants had a nasopharyngeal swab sample taken for polymerase chain reaction (PCR) testing for a panel of respiratory viruses. Samples positive for respiratory syncytial virus, human metapneumovirus, or parainfluenza type 3 were quantitated by reverse transcriptase real-time quantitative PCR. RESULTS: One hundred twenty-eight cases were matched to 186 controls. In a multivariable conditional logistic regression model, significantly (P < .05) increased risk of hospitalization was associated with medically high risk status, having a woodstove in the house, being bottle fed, and vomiting after feeding; living in a house that had 2 or more rooms with sinks was a protective factor. Viral loads in hospitalized cases were significantly higher than those in controls, but a strict cutoff level was not observed. CONCLUSIONS: Several risk factors for LRTI hospitalization were identified in this high risk population. Some factors are amenable to environmental and behavioral interventions. PMID- 22508918 TI - Factors related to voluntary parental decision-making in pediatric oncology. AB - OBJECTIVE: The aim of the current study was to examine demographic and contextual correlates of voluntariness in parents making research or treatment decisions for their children with cancer. METHODS: Participants included 184 parents of children with cancer who made a decision about enrolling the child in a research or treatment protocol within the previous 10 days. Parents completed questionnaires that assessed voluntariness, external influence by others, concern that the child's care would be negatively affected if the parent did not agree, time pressure, information adequacy, and demographics. RESULTS: Lower perceived voluntariness was associated with lower education, male gender, minority status, and not having previous experience with a similar decision. Parents who reported lower voluntariness also perceived more external influence and time pressure, had more concern about the child's care being negatively affected if they declined, and perceived that they had either too much or not enough information about the decision. In a multivariate regression, education, minority status, gender, external influence, and too little information remained significantly associated with voluntariness. CONCLUSIONS: Several groups of parents appear to be at risk for decreased voluntariness when making research or treatment decisions for their seriously ill children, including fathers, nonwhite parents, and those with less education. Parental voluntariness may be enhanced by helping parents to mitigate the effects of unhelpful or unwanted influences by others and ensuring that their information needs are met. PMID- 22508920 TI - Diagnostic imaging and negative appendectomy rates in children: effects of age and gender. AB - BACKGROUND AND OBJECTIVES: Diagnostic imaging is often used in the evaluation of children with possible appendicitis. The utility of imaging may vary according to a patient's age and gender. The objectives of this study were (1) to examine the use of computed tomography (CT) and ultrasound for age and gender subgroups of children undergoing an appendectomy; and (2) to study the association between imaging and negative appendectomy rates (NARs) among these subgroups. METHODS: Retrospective review of children presenting to 40 US pediatric emergency departments from 2005 to 2009 (Pediatric Health Information Systems database). Children undergoing an appendectomy were stratified by age and gender for measuring the association between ultrasound and CT use and the outcome of negative appendectomy. RESULTS: A total of 8 959 155 visits at 40 pediatric emergency departments were investigated; 55 227 children had appendicitis. The NAR was 3.6%. NARs were highest for children younger than 5 years (boys 16.8%, girls 14.6%) and girls older than 10 years (4.8%). At the institutional level, increased rates of diagnostic imaging (ultrasound and/or CT) were associated with lower NARs for all age and gender subgroups other than children younger than 5 years, The NAR was 1.2% for boys older than 5 years without any diagnostic imaging. CONCLUSIONS: The impact of diagnostic imaging on negative appendectomy rate varies by age and gender. Diagnostic imaging for boys older than 5 years with suspected appendicitis has no meaningful impact on NAR. Diagnostic strategies for possible appendicitis should incorporate the risk of negative appendectomy by age and gender. PMID- 22508921 TI - Cumulative social risk and obesity in early childhood. AB - OBJECTIVES: The goal of this study was to examine the relationship between cumulative social adversity and childhood obesity among preschool-aged children (N = 1605) in the Fragile Families and Child Wellbeing Study. METHODS: Maternal reports of intimate partner violence, food insecurity, housing insecurity, maternal depressive symptoms, maternal substance use, and father's incarceration were obtained when the child was 1 and 3 years of age. Two cumulative social risk scores were created by summing the 6 factors assessed at ages 1 and 3 years. Child height and weight were measured at 5 years of age. Logistic regression models stratified according to gender were used to estimate the association between cumulative social risk and obesity, adjusting for sociodemographic factors. RESULTS: Seventeen percent of children were obese at age 5 years, and 57% had at least 1 social risk factor. Adjusting for sociodemographic factors, girls experiencing high cumulative social risk (>=2 factors) at age 1 year only (odds ratio [OR]: 2.1 [95% confidence interval [CI]: 1.1-4.1]) or at 3 years only (OR: 2.2 [95% CI: 1.2-4.2]) were at increased odds of being obese compared with girls with no risk factors at either time point. Those experiencing high cumulative risk at age 1 and 3 years were not at statistically significant odds of being obese (OR: 1.9 [95% CI: 0.9-4.0]). No significant associations were noted among boys. CONCLUSIONS: There seems to be gender differences in the effects of cumulative social risk factors on the prevalence of obesity at 5 years of age. Understanding the social context of families could make for more effective preventive efforts to combat childhood obesity. PMID- 22508922 TI - Magnesium use in asthma pharmacotherapy: a Pediatric Emergency Research Canada study. AB - OBJECTIVES: To examine the use of intravenous magnesium in Canadian pediatric emergency departments (EDs) in children requiring hospitalization for acute asthma and association of administration of frequent albuterol/ipratropium and timely corticosteroids with hospitalization. METHODS: Retrospective medical record review at 6 EDs of otherwise healthy children 2 to 17 years of age with acute asthma. Data were extracted on history, disease severity, and timing of ED stabilization treatments with inhaled albuterol, ipratropium, corticosteroids, and magnesium. Primary outcome was the proportion of hospitalized children given magnesium in the ED. Secondary outcome was the ED use of "intensive therapy" in hospitalized children, defined as 3 albuterol inhalations with ipratropium and corticosteroids within 1 hour of triage. RESULTS: A total of 19 (12.3%) of 154 hospitalized children received magnesium (95% confidence interval 7.1, 17.5) versus 2 of 962 discharged patients. Children given magnesium were more likely to have been previously admitted to ICU (odds ratio [OR] 11.2), hospitalized within the past year (OR 3.8), received corticosteroids before arrival (OR 4.0), presented with severe exacerbation (OR 6.1), and to have been treated at 1 particular center (OR 14.9). Forty-two (53%) of 90 hospitalized children were not given "intensive therapy." Children receiving "intensive therapy" were more likely to present with severe disease to EDs by using asthma guidelines (ORs 8.9, 3.0). Differences in the frequencies of all stabilization treatments were significant across centers. CONCLUSIONS: Magnesium is used infrequently in Canadian pediatric EDs in acute asthma requiring hospitalization. Many of these children also do not receive frequent albuterol and ipratropium, or early corticosteroids. Significant variability in the use of these interventions was detected. PMID- 22508923 TI - Neonatal Sweet syndrome: a potential marker of serious systemic illness. AB - Sweet syndrome is an inflammatory disease characterized by fever and painful erythematous plaques with a dermal neutrophilic infiltrate. It is most common in adults, where it is often parainflammatory or paraneoplastic, but is rare in children. We describe 3 cases of neonatal Sweet syndrome, including 1 patient who had myelodysplastic syndrome and immunodeficiency, the first report of a premalignancy underlying infantile Sweet syndrome. We reviewed the literature on patients presenting with neutrophilic dermatosis in the first 6 months of life. Of 20 cases, 6 had a probable viral etiology, 4 primary immunodeficiencies, 3 neonatal lupus syndrome, 1 gastrointestinal involvement, 1 HIV, and 5 probable genetic cases. Three of these had chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome, caused by mutations in the PSMB8 gene. Most children who presented within the first 6 weeks of life had either a serious underlying condition, such as primary immunodeficiency, or a genetic Sweet syndrome, with 2 fatalities among this latter group. The outcome of postinfective cases was good. Extracutaneous involvement was unusual, whereas postinflammatory scarring and cutis laxa occurred in a minority of patients. In conclusion, Sweet syndrome in the neonatal period often heralds a serious underlying disorder and requires thorough investigation. PMID- 22508924 TI - Effective analgesia using physical interventions for infant immunizations. AB - BACKGROUND: To measure the analgesic effectiveness of the 5 S's (swaddling, side/stomach position, shushing, swinging, and sucking) alone and combined with sucrose, during routine immunizations at 2 and 4 months. METHODS: We conducted a prospective, randomized, placebo-controlled trial with 2- and 4-month-old infants during well-child visits. Patients were assigned into 4 groups (2 * 2) receiving either 2 mL of water or 2 mL of 24% oral sucrose and then either standard-of-care comfort measures by parents or intervention with the 5 S's immediately postvaccination. The Modified Riley Pain Score was used to score the infants' pain at 15-second intervals for 2 minutes, then every 30 seconds up to 5 minutes postvaccination. Repeated-measures analysis of variance examined between group differences and within-subject variability of treatment effect on overall pain scores and length of crying. RESULTS: Two hundred thirty infants were enrolled. Results revealed significantly different mean pain scores between study groups with the exception of the 5S's and 5S's with sucrose groups. These 2 groups had lower similar mean scores over time, followed by sucrose alone, then control. The same trend was found with the proportion of children crying as with the mean pain score outcome measure. CONCLUSIONS: Physical intervention of the 5 S's (swaddling, side/stomach position, shushing, swinging, and sucking) provided decreased pain scores on a validated pain scale and decreased crying time among 2 and 4-month-old infants during routine vaccinations. The use of 5S's did not differ from 5S's and sucrose. PMID- 22508926 TI - Nonequilibrium mesoscopic transport: a genealogy. AB - Models of nonequilibrium quantum transport underpin all modern electronic devices, from the largest scales to the smallest. Past simplifications such as coarse graining and bulk self-averaging served well to understand electronic materials. Such particular notions become inapplicable at mesoscopic dimensions, edging towards the truly quantum regime. Nevertheless a unifying thread continues to run through transport physics, animating the design of small-scale electronic technology: microscopic conservation and nonequilibrium dissipation. These fundamentals are inherent in quantum transport and gain even greater and more explicit experimental meaning in the passage to atomic-sized devices. We review their genesis, their theoretical context, and their governing role in the electronic response of meso- and nanoscopic systems. PMID- 22508925 TI - Automated primary care screening in pediatric waiting rooms. AB - BACKGROUND AND OBJECTIVE: Implementing US Preventive Services Task Force and American Academy of Pediatrics preventive service guidelines within the short duration of a visit is difficult because identifying which of a large number of guidelines apply to a particular patient is impractical. Clinical decision support system integrated with electronic medical records offer a good strategy for implementing screening in waiting rooms. Our objective was to determine rates of positive risk screens during typical well-care visits among children and adolescents in a primary care setting. METHODS: Child Health Improvement through Computer Automation (CHICA) is a pediatric clinical decision support system developed by our research group. CHICA encodes clinical guidelines as medical logic modules to generate scanable paper forms: the patient screening form to collect structured data from patient families in the waiting room and the physician worksheet to provide physician assessments at each visit. By using visit as a unit of analysis from CHICA's database, we have determined positive risk screen rates in our population. RESULTS: From a cohort of 16 963 patients, 408 601 questions were asked in 31 843 visits. Of the questions asked, 362 363 (89%) had a response. Of those, 39 176 (11%) identified positive risk screens in both the younger children and the adolescent age groups. CONCLUSIONS: By automating the process of screening and alerting the physician to those who screened positive, we have significantly decreased the burden of identifying relevant guidelines and screening of patient families in our clinics. PMID- 22508927 TI - Immunogenicity and cross-reactivity of a representative ancestral sequence in hepatitis C virus infection. AB - Vaccines designed to prevent or to treat hepatitis C viral infection must achieve maximum cross-reactivity against widely divergent circulating strains. Rational approaches for sequence selection to maximize immunogenicity and minimize genetic distance across circulating strains may enhance vaccine induction of optimal cytotoxic T cell responses. We assessed T cell recognition of potential hepatitis C virus (HCV) vaccine sequences generated using three rational approaches: combining epitopes with predicted tight binding to the MHC, consensus sequence (most common amino acid at each position), and representative ancestral sequence that had been derived using bayesian phylogenetic tools. No correlation was seen between peptide-MHC binding affinity and frequency of recognition, as measured by an IFN-gamma T cell response in HLA-matched HCV-infected individuals. Peptides encoding representative, consensus, and natural variant sequences were then tested for the capacity to expand CD8 T cell populations and to elicit cross reactive CD8 T cell responses. CD8(+) T cells expanded with representative sequence HCV generally more broadly and robustly recognized highly diverse circulating HCV strains than did T cells expanded with either consensus sequence or naturally occurring sequence variants. These data support the use of representative sequence in HCV vaccine design. PMID- 22508928 TI - Novel role for surfactant protein A in gastrointestinal graft-versus-host disease. AB - Graft-versus-host disease (GVHD) is a severe and frequent complication of allogeneic bone marrow transplantation (BMT) that involves the gastrointestinal (GI) tract and lungs. The pathobiology of GVHD is complex and involves immune cell recognition of host Ags as foreign. We hypothesize a central role for the collectin surfactant protein A (SP-A) in regulating the development of GVHD after allogeneic BMT. C57BL/6 (H2b; WT) and SP-A-deficient mice on a C57BL/6 background (H2b; SP-A(-/-)) mice underwent allogeneic or syngeneic BMT with cells from either C3HeB/FeJ (H2k; SP-A-deficient recipient mice that have undergone an allogeneic BMT [SP-A(-/-)alloBMT] or SP-A-sufficient recipient mice that have undergone an allogeneic BMT) or C57BL/6 (H2b; SP-A-deficient recipient mice that have undergone a syngeneic BMT or SP-A-sufficient recipient mice that have undergone a syngeneic BMT) mice. Five weeks post-BMT, mice were necropsied, and lung and GI tissue were analyzed. SP-A(-/-) alloBMT or SP-A-sufficient recipient mice that have undergone an allogeneic BMT had no significant differences in lung pathology; however, SP-A(-/-)alloBMT mice developed marked features of GI GVHD, including decreased body weight, increased tissue inflammation, and lymphocytic infiltration. SP-A(-/-)alloBMT mice also had increased colon expression of IL 1beta, IL-6, TNF-alpha, and IFN-gamma and as well as increased Th17 cells and diminished regulatory T cells. Our results demonstrate the first evidence, to our knowledge, of a critical role for SP-A in modulating GI GVHD. In these studies, we demonstrate that mice deficient in SP-A that have undergone an allogeneic BMT have a greater incidence of GI GVHD that is associated with increased Th17 cells and decreased regulatory T cells. The results of these studies demonstrate that SP-A protects against the development of GI GVHD and establishes a role for SP-A in regulating the immune response in the GI tract. PMID- 22508929 TI - Autoregulation of MARCH1 expression by dimerization and autoubiquitination. AB - Some members of the membrane-associated RING-CH family of E3 ubiquitin ligases (MARCHs) are membrane-bound and target major players of the immune response. MARCH1 ubiquitinates and downregulates MHC class II expression in APCs. It is induced by IL-10 and despite a strong increase in mRNA expression in human primary monocytes, the protein remains hardly detectable. To gain insights into the posttranslational regulation of MARCH1, we investigated whether its expression is itself regulated by ubiquitination. Our results demonstrate that MARCH1 is ubiquitinated in transfected human cell lines. Polyubiquitin chain specific Abs revealed the presence of K48-linked polyubiquitin chains. A mutant devoid of lysine residues in the N- and C-terminal regions was less ubiquitinated and had a prolonged half-life. Reduced ubiquitination was also observed for an inactive mutated form of the molecule (M1WI), suggesting that MARCH1 is capable of autoubiquitination. Immunoprecipitation and energy transfer experiments demonstrated that MARCH1 homodimerizes and also forms heterodimers with others family members. Coexpression of MARCH1 decreased the protein levels of the inactive M1WI, suggesting a transubiquitination process. Taken together, our results suggest that MARCH1 may regulate its own expression through dimerization and autoubiquitination. PMID- 22508930 TI - Functional specialization of islet dendritic cell subsets. AB - Dendritic cells (DC) play important roles in both tolerance and immunity to beta cells in type 1 diabetes. How and why DC can have diverse and opposing functions in islets remains elusive. To answer these questions, islet DC subsets and their specialized functions were characterized. Under both homeostatic and inflammatory conditions, there were two main tissue-resident DC subsets in islets, defined as CD11b(lo/-)CD103(+)CX3CR1(-) (CD103(+) DC), the majority of which were derived from fms-like tyrosine kinase 3-dependent pre-DC, and CD11b(+)CD103(-)CX3CR1(+) (CD11b(+) DC), the majority of which were derived from monocytes. CD103(+) DC were the major migratory DC and cross-presented islet-derived Ag in the pancreatic draining lymph node, although this DC subset displayed limited phagocytic activity. CD11b(+) DC were numerically the predominant subset (60-80%) but poorly migrated to the draining lymph node. Although CD11b(+) DC had greater phagocytic activity, they poorly presented Ag to T cells. CD11b(+) DC increased in numbers and percentage during T cell-mediated insulitis, suggesting that this subset might be involved in the pathogenesis of diabetes. These data elucidate the phenotype and function of homeostatic and inflammatory islet DC, suggesting differential roles in islet immunity. PMID- 22508933 TI - Structural ordering in a silica glass matrix under Mn ion implantation. AB - Mn(+)-implanted, amorphous SiO(2) samples were synthesized using pulsed-ion implantation without thermal annealing. The crystal and electronic structures have been studied using x-ray diffraction and synchrotron-based soft x-ray absorption and emission spectroscopy at the Si and Mn L(2,3) edges. We find a combination of small MnO clusters and Si crystallites at shallow depths while tetrahedral Mn coordination is found deeper in the host target. Through a combination of techniques, we find that the implantation process simultaneously decreases the long-range order in the near-surface region and increases order deeper in the SiO(2) host. Our results suggest Mn substitution into Si sites at deep levels catalyzes the formation of alpha-quartz, providing insight into the complex interactions that determine the local structure around the impurities as well as the overall changes to the crystallinity of implanted SiO(2). PMID- 22508934 TI - The spin dynamics in distorted kagome lattices: a comparative Raman study. AB - Despite the conceptional importance of realizing spin liquids in solid states only few compounds are known. On the other hand the effect of lattice distortions and anisotropies on the magnetic exchange topology and the fluctuation spectrum is an interesting problem. We compare the excitation spectra of the two s = 1/2 kagome lattice compounds, volborthite and vesignieite, using Raman scattering. We demonstrate that even small modifications of the crystal structure may have a huge effect on the phonon spectrum and low-temperature properties. PMID- 22508935 TI - Local moment ferromagnetism in CeRu2Ga2B. AB - Magnetization, specific heat, and electrical resistivity measurements for polycrystalline specimens of CeRu(2)Ga(2)B reveal local moment ferromagnetic order at a Curie temperature T(C) = 16.3 K. Specific heat measurements show that the phase transition is second order and the low temperature behavior indicates that the Ce f-electron states do not hybridize strongly with the conduction electron states. Electrical resistivity measurements demonstrate large spin disorder scattering of conduction electrons for T >= T(C). Results for a single crystal are also reported, where T(C) = 15.4 K. While results for the polycrystal and single crystal specimens are qualitatively similar, the differences between them suggest that crystalline disorder plays a role in how the magnetism develops. PMID- 22508931 TI - IL-27 production and STAT3-dependent upregulation of B7-H1 mediate immune regulatory functions of liver plasmacytoid dendritic cells. AB - Plasmacytoid dendritic cells (pDCs) are highly specialized APCs that, in addition to their well-recognized role in anti-viral immunity, also regulate immune responses. Liver-resident pDCs are considerably less immunostimulatory than those from secondary lymphoid tissues and are equipped to promote immune tolerance/regulation through various mechanisms. IL-27 is an IL-12 family cytokine that regulates the function of both APCs and T cells, although little is known about its role in pDC immunobiology. In this study, we show that mouse liver pDCs express higher levels of IL-27p28 and EBV-induced protein 3 (Ebi3) compared with those of splenic pDCs. Both populations of pDCs express the IL 27Ralpha/WSX-1; however, only liver pDCs significantly upregulate expression of the coregulatory molecule B7 homolog-1 (B7-H1) in response to IL-27. Inhibition of STAT3 activation completely abrogates IL-27-induced upregulation of B7-H1 expression on liver pDCs. Liver pDCs treated with IL-27 increase the percentage of CD4(+)Foxp3(+) T cells in MLR, which is dependent upon expression of B7-H1. pDCs from Ebi3-deficient mice lacking functional IL-27 show increased capacity to stimulate allogeneic T cell proliferation and IFN-gamma production in MLR. Liver but not spleen pDCs suppress delayed-type hypersensitivity responses to OVA, an effect that is lost with Ebi3(-/-) and B7-H1(-/-) liver pDCs compared with wild type liver pDCs. These data suggest that IL-27 signaling in pDCs promotes their immunoregulatory function and that IL-27 produced by pDCs contributes to their capacity to regulate immune responses in vitro and in vivo. PMID- 22508932 TI - Uncovering small RNA-mediated responses to cold stress in a wheat thermosensitive genic male-sterile line by deep sequencing. AB - The male sterility of thermosensitive genic male sterile (TGMS) lines of wheat (Triticum aestivum) is strictly controlled by temperature. The early phase of anther development is especially susceptible to cold stress. MicroRNAs (miRNAs) play an important role in plant development and in responses to environmental stress. In this study, deep sequencing of small RNA (smRNA) libraries obtained from spike tissues of the TGMS line under cold and control conditions identified a total of 78 unique miRNA sequences from 30 families and trans-acting small interfering RNAs (tasiRNAs) derived from two TAS3 genes. To identify smRNA targets in the wheat TGMS line, we applied the degradome sequencing method, which globally and directly identifies the remnants of smRNA-directed target cleavage. We identified 26 targets of 16 miRNA families and three targets of tasiRNAs. Comparing smRNA sequencing data sets and TaqMan quantitative polymerase chain reaction results, we identified six miRNAs and one tasiRNA (tasiRNA-ARF [for Auxin-Responsive Factor]) as cold stress-responsive smRNAs in spike tissues of the TGMS line. We also determined the expression profiles of target genes that encode transcription factors in response to cold stress. Interestingly, the expression of cold stress-responsive smRNAs integrated in the auxin-signaling pathway and their target genes was largely noncorrelated. We investigated the tissue-specific expression of smRNAs using a tissue microarray approach. Our data indicated that miR167 and tasiRNA-ARF play roles in regulating the auxin signaling pathway and possibly in the developmental response to cold stress. These data provide evidence that smRNA regulatory pathways are linked with male sterility in the TGMS line during cold stress. PMID- 22508936 TI - Definitions, methodological and statistical issues for phase 3 clinical trials in chronic myeloid leukemia: a proposal by the European LeukemiaNet. AB - The treatment policy of chronic myeloid leukemia (CML), particularly with tyrosine kinase inhibitors, has been influenced by several recent studies that were well designed and rapidly performed, but their interpretation is of some concern because different end points and methodologies were used. To understand and compare the results of the previous and future studies and to translate their conclusion into clinical practice, there is a need for common definitions and methods for analyses of CML studies. A panel of experts was appointed by the European LeukemiaNet with the aim of developing a set of definitions and recommendations to be used in design, analyses, and reporting of phase 3 clinical trials in this disease. This paper summarizes the consensus of the panel on events and major end points of interest in CML. It also focuses on specific issues concerning the intention-to-treat principle and longitudinal data analyses in the context of long-term follow-up. The panel proposes that future clinical trials follow these recommendations. PMID- 22508937 TI - Mouse background and IVIG dosage are critical in establishing the role of inhibitory Fcgamma receptor for the amelioration of experimental ITP. AB - A recognized paradigm for the therapeutic action of intravenous immunoglobulin (IVIG) in immune thrombocytopenia (ITP) involves up-regulation of the inhibitory Fcgamma receptor (FcgammaRIIB) in splenic macrophages. However, published data have indicated that opposing results are obtained when using FcgammaRIIB deficient mice on different strain backgrounds. Herein we show BALB/c FcgammaRIIB(-/-) and wild-type, with or without spleens, all recover ITP with similar dynamics after IVIG (1 g/kg) treatment; however, this was not the case for C57BL/6 (B6) FcgammaRIIB(-/-). In investigating this conundrum, we found that wild-type B6 mice are much less sensitive than BALB/c to IVIG-mediated amelioration of ITP, requiring approximately 2- to 2.5-fold more IVIG than BALB/c. When using 2.5 g/kg IVIG in FcgammaRIIB(-/-) B6 mice, amelioration of ITP was as in wild-type in all animals. Our findings led us to the conclusion that different strains of mice respond differently to IVIG and that FcgammaRIIB plays no role in the mechanism of effect of IVIG in experimental ITP. PMID- 22508939 TI - Tears from children with chronic hepatitis B virus (HBV) infection are infectious vehicles of HBV transmission: experimental transmission of HBV by tears, using mice with chimeric human livers. AB - BACKGROUND: Body fluids such as saliva, urine, sweat, and tears from hepatitis B virus (HBV) carriers are potential sources of HBV transmission. METHODS: Thirty nine children and 8 adults who were chronically infected with HBV were enrolled. Real-time polymerase chain reaction was used for the quantification of HBV DNA. RESULTS: HBV DNA was detected in 73.7% of urine samples (14 of 19), 86.8% of saliva samples (33 of 38), 100% of tear samples (11 of 11), and 100% of sweat samples (9 of 9). Mean HBV DNA levels (+/-SD) in urine, saliva, tears, and sweat were 4.3 +/- 1.1 log copies/mL, 5.9 +/- 1.2 log copies/mL, 6.2 +/- 0.7 log copies/mL, and 5.2 +/- 0.6 log copies/mL, respectively. A statistically significant correlation was observed between the HBV DNA level in serum specimens and HBV DNA levels in saliva and tear specimens (r = 0.88; P < .001). Tear specimens from a child were injected intravenously into 2 human hepatocyte transplanted chimeric mice. One week after inoculation, both chimeric mice had serum positive for HBV DNA. CONCLUSIONS: The levels of HBV DNA in tear specimens from young children were high. Tears were confirmed to be infectious, using chimeric mice. Strict precautions should be taken against direct contact with body fluids from HBV carriers with high-level viremia. PMID- 22508938 TI - Spry1 as a novel regulator of erythropoiesis, EPO/EPOR target, and suppressor of JAK2. AB - Sprouty proteins are established modifiers of receptor tyrosine kinase (RTK) signaling and play important roles in vasculogenesis, bone morphogenesis, and renal uteric branching. Little is understood, however, concerning possible roles for these molecular adaptors during hematopoiesis. Within erythroid lineage, Spry1 was observed to be selectively and highly expressed at CFU-e to erythroblast stages. In analyses of possible functional roles, an Mx1-Cre approach was applied to conditionally delete Spry1. At steady state, Spry1 deletion selectively perturbed erythroid development and led to reticulocytosis plus heightened splenic erythropoiesis. When challenged by hemolysis, Spry1-null mice exhibited worsened anemia and delayed recovery. During short-term marrow transplantation, Spry1-null donor marrow also failed to efficiently rescue the erythron. In each anemia model, however, hyperexpansion of erythroid progenitors was observed. Spry function depends on phosphorylation of a conserved N-terminal PY motif. Through an LC-MS/MS approach, Spry1 was discovered to be regulated via the erythropoietin receptor (EPOR), with marked EPO-induced Spry1-PY53 phosphorylation observed. When EPOR signaling pathways were analyzed within Spry1 deficient erythroid progenitors, hyperactivation of not only Erk1,2 but also Jak2 was observed. Studies implicate Spry1 as a novel regulator of erythropoiesis during anemia, transducer of EPOR signals, and candidate suppressor of Jak2 activity. PMID- 22508940 TI - Interleukin 15 mediates joint destruction in Staphylococcus aureus arthritis. AB - BACKGROUND: Staphylococcus aureus arthritis causes severe and rapid joint damage despite antibiotics. Thus, there is a need to identify new treatment targets in addition to antibiotics. Lately, interleukin 15 (IL-15) has been implicated both in osteoclastogenesis and in bacterial clearance-2 important issues in S. aureus induced joint destruction. This has prompted us to investigate the importance of IL-15 in S. aureus-induced arthritis. METHODS: Toxic shock syndrome toxin-1 producing S. aureus was intravenously inoculated in IL-15 knockout and wildtype mice and in wildtype mice treated with anti-IL-15 antibodies (aIL-15ab) or isotype control antibody. RESULTS: Absence of IL-15, either in knockout mice or after treatment with aIL-15ab, significantly reduced weight loss compared with controls during the infection. The severity of synovitis and joint destruction was significantly decreased in IL-15 knockout and aIL-15ab treated mice compared with controls. In IL-15 knockout mice there was a reduced number of osteoclasts in the joints. The host's ability to clear bacteria was not influenced in the IL 15 knockout mice, but significantly increased after treatment with aIL-15ab. CONCLUSIONS: IL-15 is a mediator of joint destruction in S. aureus-induced arthritis and contributes to general morbidity, which makes this cytokine an interesting treatment target in addition to conventional antibiotics. PMID- 22508942 TI - Cone-beam reconstruction for the two-circles-plus-one-line trajectory. AB - The Kodak Image Station In-Vivo FX has an x-ray module with cone-beam configuration for radiographic imaging but lacks the functionality of tomography. To introduce x-ray tomography into the system, we choose the two-circles-plus-one line trajectory by mounting one translation motor and one rotation motor. We establish a reconstruction algorithm by applying the M-line reconstruction method. Numerical studies and preliminary physical phantom experiment demonstrate the feasibility of the proposed design and reconstruction algorithm. PMID- 22508941 TI - Horizontal transmission of hepatitis B virus--why discuss when we can vaccinate? PMID- 22508943 TI - Determining the influence of Korean population variation on whole-body average SAR. AB - Compliance of the ICNIRP reference and IEEE action levels with the basic restrictions on whole-body average (WBA) SAR was investigated based on age, physique, and posture under isolated and grounded conditions. First, Korean male models 1, 3, 5, 7, and 20 years of age with body sizes in the 50th percentile were developed and used as the test subjects: 1y(50th), 3y(50th), 5y(50th), 7y(50th), and 20y(50th). The effects of age-dependent dielectric properties due to the water content of the tissue on WBA SAR were analysed, and showed that the changes in WBA SAR are marginal. At the ages of 1, 5, and 20, thin models 1y(10th), 5y(10th), and 20y(10th) with body sizes in the 10th percentile for the horizontal plane were added in order to determine the influence of physical variations of the population. We considered standing postures with arms up and arms down. The WBA SAR for each human model was calculated when exposed to a vertically polarized plane wave in the frequency range of 10 MHz-3 GHz using the finite-difference time-domain method. The evaluated WBA SAR-based safety factor of each model is discussed for exposure to the ICNIRP reference and IEEE action levels. Finally, the lowest external electric field strength required to produce the basic restrictions on the WBA SAR, 0.08 W kg(-1), was obtained. The results showed that the ICNIRP public reference level is not conservative in the frequency range of 20-200 MHz for an arms-up posture, in the range of 40-200 MHz for an arms-down posture, and above 1 GHz for both postures. The IEEE action level is different from the ICNIRP reference level below 30 MHz, where most cases showed a safety factor of less than 50, which is the minimum value compliant with the basic restrictions for exposure to the general public. PMID- 22508944 TI - Peptide mimotopes of malondialdehyde epitopes for clinical applications in cardiovascular disease. AB - Autoantibodies specific for malondialdehyde-modified LDL (MDA-LDL) represent potential biomarkers to predict cardiovascular risk. However, MDA-LDL is a high variability antigen with limited reproducibility. To identify peptide mimotopes of MDA-LDL, phage display libraries were screened with the MDA-LDL-specific IgM monoclonal Ab LRO4, and the specificity and antigenic properties of MDA mimotopes were assessed in vitro and in vivo. We identified one 12-mer linear (P1) and one 7-mer cyclic (P2) peptide carrying a consensus sequence, which bound specifically to murine and human anti-MDA monoclonal Abs. Furthermore, MDA mimotopes were found to mimic MDA epitopes on the surface of apoptotic cells. Immunization of mice with P2 resulted in the induction of MDA-LDL-specific Abs, which strongly immunostained human atherosclerotic lesions. We detected IgG and IgM autoAbs to both MDA mimotopes in sera of healthy subjects and patients with myocardial infarction and stable angina pectoris undergoing percutaneous coronary intervention, and the titers of autoAbs correlated significantly with respective Ab titers against MDA-LDL. In conclusion, we identified specific peptides that are immunological mimotopes of MDA. These mimotopes can serve as standardized and reproducible antigens that will be useful for diagnostic and therapeutic applications in cardiovascular disease. PMID- 22508946 TI - Haiti launches vaccination campaign against cholera after much debate. PMID- 22508945 TI - Studying fatty aldehyde metabolism in living cells with pyrene-labeled compounds. AB - The lack of fatty aldehyde dehydrogenase function in Sjogren Larsson Syndrome (SLS) patient cells not only impairs the conversion of fatty aldehydes into their corresponding fatty acid but also has an effect on connected pathways. Alteration of the lipid profile in these cells is thought to be responsible for severe symptoms such as ichtyosis, mental retardation, and spasticity. Here we present a novel approach to examine fatty aldehyde metabolism in a time-dependent manner by measuring pyrene-labeled fatty aldehyde, fatty alcohol, fatty acid, and alkylglycerol in the culture medium of living cells using HPLC separation and fluorescence detection. Our results show that in fibroblasts from SLS patients, fatty aldehyde is not accumulating but is converted readily into fatty alcohol. In control cells, in contrast, exclusively the corresponding fatty acid is formed. SLS patient cells did not display a hypersensitivity toward hexadecanal or hexadecanol, but 3-fold lower concentrations of the fatty alcohol than the corresponding fatty aldehyde were needed to induce toxicity in SLS patient and in control cells. PMID- 22508947 TI - New report highlights obstacles for migrants in accessing healthcare in European Union. PMID- 22508948 TI - GPs and charity draw up plan to improve cancer diagnosis in primary care. PMID- 22508949 TI - Zic3 induces conversion of human fibroblasts to stable neural progenitor-like cells. PMID- 22508950 TI - Enhanced detection efficiency of genetically encoded tag allows the visualization of monomeric proteins by electron microscopy. AB - A cadmium-binding, genetically encoded protein tag, consisting of three repeats of metallothionein (3MT), can be used in electron microscopy for the visualization of multimeric- but not monomeric-tagged proteins due to insufficient electron density in monomeric proteins. Here, we present a technique for detecting monomeric 3MT-tagged green fluorescent protein (GFP-3MT) using a platinum compound to intensify the electron density. Substitution of cadmium by platinum as a result of incubating purified cadmium-binding 3MT-tagged GFP (GFP Cd-3MT) with cis-diamminedichloroplatinum(II) (cisDDP) was assessed by a UV absorption band centered at 284 nm thereby indicating platinum-sulfhydryl bonds. The incubation time and the concentration of cisDDP to reach maximal absorption were 2 h and 36-fold molar equivalent of cisDDP, respectively. GFP-Pt-3MT isolated by gel filtration chromatography contained 29 platinum atoms per single GFP-3MT molecule. Electron-dense particles were observed in a GFP-Pt-3MT sample by electron microscopy without negative staining. Further image processing and image analysis demonstrated that particles with higher density relative to their surroundings were detectable in both GFP-Cd-3MT and GFP-Pt-3MT samples. These results demonstrate that replacement of cadmium with platinum, together with proper image analyses, improve detection efficiency and enable the visualization of 3MT-tagged monomeric protein by electron microscopy. PMID- 22508951 TI - Doctors' preference for branded version of cholesterol drug costs US healthcare system $700m a year, study shows. PMID- 22508952 TI - US judge fines Johnson & Johnson $1.1bn for misleading marketing of risperidone. PMID- 22508953 TI - The color constancy of three-dimensional objects. AB - Human color constancy has been studied for over 100 years, and there is extensive experimental data for the case where a spatially diffuse light source illuminates a set of flat matte surfaces. In natural viewing, however, three-dimensional objects are viewed in three-dimensional scenes. Little is known about color constancy for three-dimensional objects. We used a forced-choice task to measure the achromatic chromaticity of matte disks, matte spheres, and glossy spheres. In all cases, the test stimuli were viewed in the context of stereoscopically viewed graphics simulations of three-dimensional scenes, and we varied the scene illuminant. We studied conditions both where all cues were consistent with the simulated illuminant change (consistent-cue conditions) and where local contrast was silenced as a cue (reduced-cue conditions). We computed constancy indices from the achromatic chromaticities. To first order, constancy was similar for the three test object types. There was, however, a reliable interaction between test object type and cue condition. In the consistent-cue conditions, constancy tended to be best for the matte disks, while in the reduced-cue conditions constancy was best for the spheres. The presence of this interaction presents an important challenge for theorists who seek to generalize models that account for constancy for flat tests to the more general case of three-dimensional objects. PMID- 22508954 TI - To CD or not to CD: Is there a 3D motion aftereffect based on changing disparities? AB - Recently, T. B. Czuba, B. Rokers, K. Guillet, A. C. Huk, and L. K. Cormack, (2011) and Y. Sakano, R. S. Allison, and I. P. Howard (2012) published very similar studies using the motion aftereffect to probe the way in which motion through depth is computed. Here, we compare and contrast the findings of these two studies and incorporate their results with a brief follow-up experiment. Taken together, the results leave no doubt that the human visual system incorporates a mechanism that is uniquely sensitive to the difference in velocity signals between the two eyes, but--perhaps surprisingly--evidence for a neural representation of changes in binocular disparity over time remains elusive. PMID- 22508955 TI - Do pacifiers increase the risk of nosocomial diarrhoea? A cohort study. AB - DESIGN: Prospective cohort study. SETTING: Teaching paediatric hospital-Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Northeast Brazil. PARTICIPANTS: 378 of 536 infants admitted in paediatric wards from April to October 2009 were daily assessed during hospital stay until the first episode of nosocomial diarrhoea (ND), death or discharge. Infants with community-acquired diarrhoea, respiratory or haemodynamic instability and who stayed in hospital for <24 h were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: Incidence and risk factors for ND and rates of pacifier faecal contamination. RESULTS: 33 ND episodes occurred in 378 infants, with a cumulative incidence of 8.7% and density of 11.25/1000 patients-day. ND occurred in 8.2% (16/194) of pacifier users compared with 9.2% (17/184) in non-users (adjusted OR=0.88, 95% CI 0.43 to 1.80). In multivariate logistic regression analysis, duration of oxygen use (OR=1.61; 95% CI 1.18 to 2.20) and days of antimicrobial use (OR=1.62, 95% CI 1.34 to 1.94) were associated with higher risk of ND, whereas being breast fed (OR=0.40, 95% CI 0.17 to 0.93) and each day of hospital stay (OR=0.65, 95% CI 0.53 to 0.80) were protective factors. Faecal coliforms were isolated in 16% (27/169) of tested pacifiers, 77.8% of which had more than 100 000 CFU/ml. The probability of a child remaining free of an episode of diarrhoea up to the seventh day of hospitalisation in the ward was 91.2% (95% CI 87.7% to 94.9%). The log-rank test showed no statistical difference between pacifier users and non-users. CONCLUSIONS: ND is a frequent healthcare-associated infection in paediatric wards, but the use of pacifiers during the stay in hospital does not seem to affect the incidence of ND in infants in many settings where the burden of diarrhoea is still high. PMID- 22508956 TI - Enhanced involvement of general practitioners in cancer rehabilitation: a randomised controlled trial. AB - OBJECTIVE: To test the hypothesis that a multimodal intervention giving the general practitioner (GP) an enhanced role in cancer rehabilitation improves patients' health-related quality of life and psychological distress. DESIGN: Cluster randomised controlled trial. All general practices in Denmark were randomised to an intervention group or to a control group. Patients were subsequently allocated to intervention or control (usual procedures) based on the randomisation status of their GP. SETTING: All clinical departments at a public regional hospital treating cancer patients and all general practices in Denmark. PARTICIPANTS: Adult patients treated for incident cancer at Vejle Hospital, Denmark, between 12 May 2008 and 28 February 2009. A total of 955 patients (486 to the intervention group and 469 to the control group) registered with 323 general practices were included. INTERVENTION: The intervention included an interview about rehabilitation needs with a rehabilitation coordinator at the regional hospital, information from the hospital to the GP about individual needs for rehabilitation and an encouragement of the GP to contact the patient to offer his support with rehabilitation. MAIN OUTCOME MEASURES: The primary outcome was health-related quality of life measured 6 months after inclusion using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Secondary outcomes included quality of life at 14 months and additional subscales of the EORTC QLQ-C30 at 6 and 14 months and psychological distress at 14 months using the Profile of Mood States Scale. RESULTS: No effect of the intervention was observed on primary and/or secondary outcomes after 6 and 14 months. CONCLUSION: A multimodal intervention aiming to give the GP an enhanced role in cancer patients' rehabilitation did not improve quality of life or psychological distress. TRIAL REGISTRATION: ClinicalTrials.gov, registration ID number NCT01021371. PMID- 22508957 TI - Do adverts increase the probability of finding online cognitive behavioural therapy for depression? Cross-sectional study. AB - OBJECTIVE: To estimate the effect of online adverts on the probability of finding online cognitive behavioural therapy (CBT) for depression. DESIGN: Exploratory online cross-sectional study of search experience of people in the UK with depression in 2011. (1) The authors identified the search terms over 6 months entered by users who subsequently clicked on the advert for online help for depression. (2) A panel of volunteers across the UK recorded websites presented by normal Google search for the term 'depression'. (iii) The authors examined these websites to estimate probabilities of knowledgeable and naive internet users finding online CBT and the improved probability by addition of a Google advert. PARTICIPANTS: (1) 3868 internet users entering search terms related to depression into Google. (2) Panel, recruited online, of 12 UK participants with an interest in depression. MAIN OUTCOME MEASURES: Probability of finding online CBT for depression with/without an advert. RESULTS: The 3868 users entered 1748 different search terms but the single keyword 'depression' resulted in two-thirds of the presentations of, and over half the 'clicks' on, the advert. In total, 14 different websites were presented to our panel in the first page of Google results for 'depression'. Four of the 14 websites had links enabling access to online CBT in three clicks for knowledgeable users. Extending this approach to the 10 most frequent search terms, the authors estimated probabilities of finding online CBT as 0.29 for knowledgeable users and 0.006 for naive users, making it unlikely CBT would be found. Adding adverts that linked directly to online CBT increased the probabilities to 0.31 (knowledgeable) and 0.02 (naive). CONCLUSIONS: In this case, online CBT was not easy to find and online adverts substantially increased the chance for naive users. Others could use this approach to explore additional impact before committing to long-term Google AdWords advertising budgets. TRIAL REGISTRATION: This exploratory case study was a substudy within a cluster randomised trial, registered on http://www.clinicaltrials.gov (reference: NCT01469689). (The trial will be reported subsequently). PMID- 22508959 TI - Subthalamic stimulation in Parkinson's disease: restoring the balance of motivated behaviours. AB - Addictions to dopaminergic drugs or to pleasant behaviours are frequent and potentially devastating neuropsychiatric disorders observed in Parkinson's disease. They encompass impulse control disorders, punding and dopamine dysregulation syndrome. A relationship with dopaminergic treatment is strongly suggested. Subthalamic stimulation improves motor complications and allows for drastic reductions in medication. This treatment might, therefore, be considered for patients with behavioural addictions, when attempts to reduce dopaminergic medication have failed. However, conflicting data have reported suppression, alleviation, worsening or new onset of behavioural addictions after subthalamic stimulation. Non-motor fluctuations are also a disabling feature of the disease. We prospectively investigated behaviour in a cohort of 63 patients with Parkinson's disease, before and 1 year after subthalamic stimulation using the Ardouin scale, with systematic evaluation of functioning in overall appetitive or apathetic modes, non-motor fluctuations, dopaminergic dysregulation syndrome, as well as behavioural addictions (including impulse control disorders and punding) and compulsive use of dopaminergic medication. Defined drug management included immediate postoperative discontinuation of dopamine agonists and reduction in levodopa. Motor and cognitive statuses were controlled (Unified Parkinson's Disease Rating Scale, Mattis Dementia Rating Scale, frontal score). After surgery, the OFF medication motor score improved (-45.2%), allowing for a 73% reduction in dopaminergic treatment, while overall cognitive evaluation was unchanged. Preoperative dopamine dysregulation syndrome had disappeared in 4/4, behavioural addictions in 17/17 and compulsive dopaminergic medication use in 9/9 patients. New onset of levodopa abuse occurred in one patient with surgical failure. Non-motor fluctuations were significantly reduced with improvements in off-dysphoria (P <= 0.001) and reduction in on-euphoria (P <= 0.001). There was an inversion in the number of patients functioning in an overall appetitive mode (29 before versus 2 after surgery, P <= 0.0001) to an overall apathetic mode (3 before versus 13 after surgery, P < 0.05). Two patients attempted suicide. Improvement in motor fluctuations is linked to the direct effect of stimulation on the sensory-motor subthalamic territory, while improvement in dyskinesias is mainly explained by an indirect effect related to the decrease in dopaminergic drugs. Our data suggest that non-motor fluctuations could similarly be directly alleviated through stimulation of the non-motor subthalamic territories, and hyperdopaminergic side effects might improve mainly due to the decrease in dopaminergic medication. We show an overall improvement in neuropsychiatric symptomatology and propose that disabling non-motor fluctuations, dopaminergic treatment abuse and drug-induced behavioural addictions in Parkinson's disease may be considered as new indications for subthalamic stimulation. PMID- 22508958 TI - Dopamine and performance in a reinforcement learning task: evidence from Parkinson's disease. AB - The role dopamine plays in decision-making has important theoretical, empirical and clinical implications. Here, we examined its precise contribution by exploiting the lesion deficit model afforded by Parkinson's disease. We studied patients in a two-stage reinforcement learning task, while they were ON and OFF dopamine replacement medication. Contrary to expectation, we found that dopaminergic drug state (ON or OFF) did not impact learning. Instead, the critical factor was drug state during the performance phase, with patients ON medication choosing correctly significantly more frequently than those OFF medication. This effect was independent of drug state during initial learning and appears to reflect a facilitation of generalization for learnt information. This inference is bolstered by our observation that neural activity in nucleus accumbens and ventromedial prefrontal cortex, measured during simultaneously acquired functional magnetic resonance imaging, represented learnt stimulus values during performance. This effect was expressed solely during the ON state with activity in these regions correlating with better performance. Our data indicate that dopamine modulation of nucleus accumbens and ventromedial prefrontal cortex exerts a specific effect on choice behaviour distinct from pure learning. The findings are in keeping with the substantial other evidence that certain aspects of learning are unaffected by dopamine lesions or depletion, and that dopamine plays a key role in performance that may be distinct from its role in learning. PMID- 22508960 TI - Hydrogen sulfide activates Ca2+ sparks to induce cerebral arteriole dilatation. AB - Hydrogen sulfide (H2S) is a gaseous vasodilator produced by endothelial cells. Mechanisms by which H2S induces vasodilatation are unclear. We tested the hypothesis that H2S dilates cerebral arterioles by modulating local and global intracellular Ca2+ signals in smooth muscle cells. High-speed confocal imaging revealed that Na2S, an H2S donor, increased Ca2+ spark frequency ~1.43-fold and decreased global intracellular Ca2+ concentration ([Ca2+]i) by ~37 nM in smooth muscle cells of intact piglet cerebral arterioles. In contrast, H2S did not alter Ca2+ wave frequency. In voltage-clamped (-40 mV) cells, H2S increased the frequency of iberiotoxin-sensitive, Ca2+ spark-induced transient Ca2+-activated K+ (KCa) currents ~1.83-fold, but did not alter the amplitude of these events. H2S did not alter the activity of single KCa channels recorded in the absence of Ca2+ sparks in arteriole smooth muscle cells. H2S increased SR Ca2+ load ([Ca2+]SR), measured as caffeine (10 and 20mM)-induced [Ca2+]i transients, ~1.5 fold. H2S hyperpolarized (by ~18 mV) and dilated pressurized (40 mmHg) cerebral arterioles. Iberiotoxin, a KCa channel blocker, reduced H2S-induced hyperpolarization by ~51%. Iberiotoxin and ryanodine, a ryanodine receptor channel inhibitor, reduced H2S-induced vasodilatation by ~38 and ~37%, respectively. In summary, our data indicate that H2S elevates [Ca2+]SR, leading to Ca2+ spark activation in cerebral arteriole smooth muscle cells. The subsequent elevation in transient KCa current frequency leads to membrane hyperpolarization, a reduction in global [Ca2+]i and vasodilatation. PMID- 22508961 TI - A genome resource to address mechanisms of developmental programming: determination of the fetal sheep heart transcriptome. AB - The pregnant sheep has provided seminal insights into reproduction related to animal and human development (ovarian function, fertility, implantation, fetal growth, parturition and lactation). Fetal sheep physiology has been extensively studied since 1950, contributing significantly to the basis for our understanding of many aspects of fetal development and behaviour that remain in use in clinical practice today. Understanding mechanisms requires the combination of systems approaches uniquely available in fetal sheep with the power of genomic studies. Absence of the full range of sheep genomic resources has limited the full realization of the power of this model, impeding progress in emerging areas of pregnancy biology such as developmental programming. We have examined the expressed fetal sheep heart transcriptome using high-throughput sequencing technologies. In so doing we identified 36,737 novel transcripts and describe genes, gene variants and pathways relevant to fundamental developmental mechanisms. Genes with the highest expression levels and with novel exons in the fetal heart transcriptome are known to play central roles in muscle development. We show that high-throughput sequencing methods can generate extensive transcriptome information in the absence of an assembled and annotated genome for that species. The gene sequence data obtained provide a unique genomic resource for sheep specific genetic technology development and, combined with the polymorphism data, augment annotation and assembly of the sheep genome. In addition, identification and pathway analysis of novel fetal sheep heart transcriptome splice variants is a first step towards revealing mechanisms of genetic variation and gene environment interactions during fetal heart development. PMID- 22508962 TI - Reduction of motion artifacts during in vivo two-photon imaging of brain through heartbeat triggered scanning. AB - Two-photon imaging of fluorescence in brain enables analysis of the structure and dynamic activity of neurons and glial cells in living animals. However, vital functions such as beating of the heart cause pulsations in brain tissue, leading to image distortion and loss of resolution. We find that synchronizing imaging scans to the cardiac cycle reduces motion artifacts, significantly improving the resolution of cellular structures. By interlacing multiple heartbeat triggered imaging scans, it was possible to image large brain volumes with negligible distortion. This approach can be readily incorporated into conventional microscopes to achieve substantial reductions in motion artifacts during two photon imaging. PMID- 22508963 TI - Pro-arrhythmogenic effects of the S140G KCNQ1 mutation in human atrial fibrillation - insights from modelling. AB - Functional analysis has shown that the missense gain-in-function KCNQ1 S140G mutation associated with familial atrial fibrillation produces an increase of the slow delayed rectifier potassium current (I(Ks)). Through computer modelling, this study investigated mechanisms by which the KCNQ1 S140G mutation promotes and perpetuates atrial fibrillation. In simulations, Courtemanche et al.'s model of human atrial cell action potentials (APs) was modified to incorporate experimental data on changes of I(Ks) induced by the KCNQ1 S140G mutation. The cell models for wild type (WT) and mutant type (MT) I(Ks) were incorporated into homogeneous multicellular 2D and 3D tissue models. Effects of the mutation were quantified on AP profile, AP duration (APD) restitution, effective refractory period (ERP) restitution, and conduction velocity (CV) restitution.Temporal and spatial vulnerabilities of atrial tissue to genesis of re-entry were computed. Dynamic behaviours of re-entrant excitation waves (lifespan (LS), tip meandering patterns and dominant frequency) in 2D and 3D models were characterised. It was shown that the KCNQ1 S140G mutation abbreviated atrial APD and ERP and flattened APD and ERP restitution curves. It reduced atrial CV at low excitation rates, but increased it at high excitation rates that facilitated the conduction of high rate atrial excitation waves. Although it increased slightly tissue temporal vulnerability for initiating re-entry, it reduced markedly the minimal substrate size necessary for sustaining re-entry (increasing the tissue spatial vulnerability). In the 2D and 3D models, the mutation also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. In the 3D model, scroll waves under the mutation condition MT conditions also degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, increased I(Ks) due to the KCNQ1 S140G mutation increases atrial susceptibility to arrhythmia due to increased tissue vulnerability, shortened ERP and altered atrial conduction velocity, which, in combination, facilitate initiation and maintenance of re-entrant excitation waves. PMID- 22508964 TI - Effects of an intraoperative infusion of 4% succinylated gelatine (Gelofusine(R)) and 6% hydroxyethyl starch (Voluven(R)) on blood volume. AB - BACKGROUND: This study aims to study changes in blood volume after 1 litre infusions of Gelofusine((r)) [4% succinylated gelatine in 0.7% saline, weight average molecular weight (MWw) 30 kDa] and Voluven((r)) (6% hydroxyethyl starch in 0.9% saline, MWw 130 kDa) in the presence of increased capillary permeability. METHODS: In this randomized double-blind study, adults undergoing laparoscopic cholecystectomy received 1 litre of Gelofusine((r)) (n=12) or Voluven((r)) (n=13) over 1 h at the induction of anaesthesia. No other fluids were given. Haematocrit, serum electrolytes, and osmolality were measured before infusion and hourly thereafter for 4 h. Changes in blood volume were calculated from changes in haematocrit. The urinary albumin:creatinine ratio (ACR) was measured before and after operation. RESULTS: Baseline parameters before the two infusions were similar (P>0.050). The urinary ACR increased significantly after operation after Gelofusine((r)) (P=0.011) and Voluven((r)) (P=0.002), indicating increased capillary permeability. Voluven((r)) produced a greater increase in serum chloride concentration (P=0.028) and a larger decrease in strong ion difference (P=0.009) than Gelofusine((r)). There were no significant differences in changes in haematocrit (P=0.523) and blood volume (P=0.404) over the study period when the two infusions were compared, nor were there any differences in serum sodium, potassium, bicarbonate, and albumin concentrations (P>0.050). Urine output, sodium concentration, and osmolality were similar after the two infusions (P>0.050). CONCLUSIONS: The blood volume-expanding effects of the two colloids were not significantly different, despite the increase in postoperative urinary ACR and the 100 kDa difference in MWw. PMID- 22508967 TI - Journal of the Royal Society of Medicine. Welcome from the Chairman. PMID- 22508966 TI - The CDK4/6 inhibitor PD0332991 reverses epithelial dysplasia associated with abnormal activation of the cyclin-CDK-Rb pathway. AB - Loss of normal growth control is a hallmark of cancer progression. Therefore, understanding the early mechanisms of normal growth regulation and the changes that occur during preneoplasia may provide insights of both diagnostic and therapeutic importance. Models of dysplasia that help elucidate the mechanisms responsible for disease progression are useful in highlighting potential targets for prevention. An important strategy in cancer prevention treatment programs is to reduce hyperplasia and dysplasia. This study identified abnormal upregulation of cell cycle-related proteins cyclin D1, cyclin-dependent kinase (CDK)4, CDK6, and phosphorylated retinoblastoma protein (pRb) as mechanisms responsible for maintenance of hyperplasia and dysplasia following downregulation of the initiating viral oncoprotein Simian virus 40 (SV40) T antigen. Significantly, p53 was not required for successful reversal of hyperplasia and dysplasia. Ligand induced activation of retinoid X receptor and PPARgamma agonists attenuated cyclin D1 and CDK6 but not CDK4 or phosphorylated pRb upregulation with limited reversal of hyperplasia and dysplasia. PD0332991, an orally available CDK4/6 inhibitor, was able to prevent upregulation of cyclin D1 and CDK6 as well as CDK4 and phosphorylated pRb and this correlated with a more profound reversal of hyperplasia and dysplasia. In summary, the study distinguished CDK4 and phosphorylated pRb as targets for chemoprevention regimens targeting reversal of hyperplasia and dysplasia. PMID- 22508968 TI - Regulation of medical devices outside the European Union. PMID- 22508969 TI - Journal of the Royal Society of Medicine. Foreward by the Director of the Centre for Health Technology Evaluation. PMID- 22508970 TI - How are medical devices regulated in the European Union? PMID- 22508971 TI - Journal of the Royal Society of Medicine. Foreword from the medical technology industries. PMID- 22508972 TI - The NICE Medical Technologies Evaluation Programme (MTEP): manufacturer submission challenges. PMID- 22508973 TI - Hockey concussion: is it child abuse? PMID- 22508974 TI - Melatonin. PMID- 22508975 TI - Young women with breast cancer genes face tough choices. PMID- 22508976 TI - The downside of genetic screening. PMID- 22508977 TI - Sex ratios among Canadian liveborn infants of mothers from different countries. AB - BACKGROUND: There has been much discussion about whether female feticide occurs in certain immigrant groups in Canada. We examined data on live births in Ontario and compared sex ratios in different groups according to the mother's country or region of birth and parity. METHODS: We completed a population-based study of 766,688 singleton live births between 2002 and 2007. We used birth records provided by Ontario Vital Statistics for live births in the province between 23 and 41 weeks' gestation. We categorized each newborn according to the mother's country or region of birth, namely Canada (n = 486,599), Europe (n = 58,505), South Korea (n = 3663), China (n = 23,818), Philippines (n = 15,367), rest of East Asia (n = 18,971), Pakistan (n = 18,018), India (n = 31,978), rest of South Asia (n = 20,695) and other countries (n = 89,074). We calculated male:female ratios and 95% confidence intervals (CIs) for all live births by these regions and stratified them by maternal parity at the time of delivery (0, 1, 2 or >= 3). RESULTS: Among infants of nulliparous women, the male:female ratio was about 1.05 overall. As parity increased, the ratio remained unchanged among infants of Canadian-born women. In contrast, the male:female ratio was significantly higher among infants of primiparous women born in South Korea (1.20, 95% CI 1.09-1.34) and India (1.11, 95% CI 1.07-1.15) than among infants of Canadian-born primiparous women. Among multiparous women, those born in India were significantly more likely than Canadian-born women to have a male infant (parity 2, ratio 1.36, 95% CI 1.27-1.46; parity >= 3, ratio 1.25, 95% CI 1.09-1.43). INTERPRETATION: Our study of male:female ratios in Ontario showed that multiparous women born in India were significantly more likely than multiparous women born in Canada to have a male infant. PMID- 22508978 TI - The variability of reported salt levels in fast foods across six countries: opportunities for salt reduction. AB - BACKGROUND: Several fast food companies have made commitments to reduce the levels of salt in the foods they serve, but technical issues are often cited as a barrier to achieving substantial reductions. Our objective was to examine the reported salt levels for products offered by leading multinational fast food chains. METHODS: Data on salt content for products served by six fast food chains operating in Australia, Canada, France, New Zealand, the United Kingdom and the United States were collected by survey in April 2010. Mean salt contents (and their ranges) were calculated and compared within and between countries and companies. RESULTS: We saw substantial variation in the mean salt content for different categories of products. For example, the salads we included in our survey contained 0.5 g of salt per 100 g, whereas the chicken products we included contained 1.6 g. We also saw variability between countries: chicken products from the UK contained 1.1 g of salt per 100 g, whereas chicken products from the US contained 1.8 g. Furthermore, the mean salt content of food categories varied between companies and between the same products in different countries (e.g., McDonald's Chicken McNuggets contain 0.6 g of salt per 100 g in the UK, but 1.6 g of salt per 100 g in the US). INTERPRETATION: The salt content of fast foods varies substantially, not only by type of food, but by company and country in which the food is produced. Although the reasons for this variation are not clear, the marked differences in salt content of very similar products suggest that technical reasons are not a primary explanation. In the right regulatory environment, it is likely that fast food companies could substantially reduce the salt in their products, translating to large gains for population health. PMID- 22508979 TI - Hand-foot syndrome related to chemotherapy. PMID- 22508980 TI - Management of suspected stones in the common bile duct. PMID- 22508982 TI - Caught in lead recall limbo. PMID- 22508983 TI - p73 expression is regulated by RNPC1, a target of the p53 family, via mRNA stability. AB - p73, a p53 family tumor suppressor, is expressed as TA and DeltaN isoforms. Due to the role of p73 in tumor suppression and neural development, its expression and activity are tightly regulated by multiple mechanisms, including transcription and posttranslational modifications. Here, we found that p73 mRNA stability is regulated by RNPC1, an RNA binding protein and a target of the p53 family. We also showed that a CU-rich element in the 3' untranslated region of p73 is recognized by and responsive to RNPC1. To explore the physiological significance of RNPC1-regulated p73 expression, we showed that the loss of RNPC1 in p53-null mouse embryonic fibroblasts leads to reduced expression of p73, along with decreased expression of p21, p130, and gamma-H2A.X, and consequently a decreased number of senescent cells. Furthermore, we observed that knockdown of TAp73 or p21, another target of RNPC1, attenuates the inhibitory effect of RNPC1 on cell proliferation and premature senescence, whereas combined knockdown of TAp73 and p21 completely abolishes it. Due to the fact that RNPC1 is a target of p73, the mutual regulation between p73 and RNPC1 constitutes a novel feed-forward loop, which might be explored as a target for tumors without a functional p53. PMID- 22508984 TI - CREB binding protein (CBP) activation is required for luteinizing hormone beta expression and normal fertility in mice. AB - Normal function of the hypothalamic-pituitary-gonadal axis is dependent on gonadotropin-releasing hormone (GNRH)-stimulated synthesis and secretion of luteinizing hormone (LH) from the pituitary gonadotroph. While the transcriptional coactivator CREB binding protein (CBP) is known to interact with Egr-1, the major mediator of GNRH action on the Lhb gene, the role of CBP in Lhb gene expression has yet to be characterized. We show that in the LbetaT2 gonadotroph cell line, overexpression of CBP augmented the response to GNRH and that knockdown of CBP eliminated GNRH responsiveness. While GNRH-mediated phosphorylation of CBP at Ser436 increased the interaction with Egr-1 on the Lhb promoter, loss of this phosphorylation site eliminated GNRH-mediated Lhb expression in LbetaT2 cells. In vivo, loss of CBP phosphorylation at Ser436 rendered female mice subfertile. S436A knock-in mice had disrupted estrous cyclicity and reduced responsiveness to GNRH. Our results show that GNRH-mediated phosphorylation of CBP at Ser436 is required for Egr-1 to activate Lhb expression and is a requirement for normal fertility in female mice. As CBP can be phosphorylated by other factors, such as insulin, our studies suggest that CBP may act as a key regulator of Lhb expression in the gonadotroph by integrating homeostatic information with GNRH signaling. PMID- 22508985 TI - Nucleosome remodeler SNF2L suppresses cell proliferation and migration and attenuates Wnt signaling. AB - ISWI is an evolutionarily conserved ATPase that catalyzes nucleosome remodeling in different macromolecular complexes. Two mammalian ISWI orthologs, SNF2H and SNF2L, are thought to have specialized functions despite their high sequence similarity. To date, the function of SNF2L in human cells has not been a focus of research. Newly established specific monoclonal antibodies and selective RNA interference protocols have now enabled a comprehensive characterization of loss of-function phenotypes in human cells. In contrast to earlier results, we found SNF2L to be broadly expressed in primary human tissues. Depletion of SNF2L in HeLa cells led to enhanced proliferation and increased migration. These phenomena were explained by transcriptome profiling, which identified SNF2L as a modulator of the Wnt signaling network. The cumulative effects of SNF2L depletion on gene expression portray the cell in a state of activated Wnt signaling characterized by increased proliferation and chemotactic locomotion. Accordingly, high levels of SNF2L expression in normal melanocytes contrast with undetectable expression in malignant melanoma. In summary, our data document an inverse relationship between SNF2L expression and features characteristic of malignant cells. PMID- 22508986 TI - The extracellular signal-regulated kinase 3 (mitogen-activated protein kinase 6 [MAPK6])-MAPK-activated protein kinase 5 signaling complex regulates septin function and dendrite morphology. AB - Mitogen-activated protein kinase-activated protein (MAPKAP) kinase 5 (MK5) deficiency is associated with reduced extracellular signal-regulated kinase 3 (ERK3) (mitogen-activated protein kinase 6) levels, hence we utilized the MK5 knockout mouse model to analyze the physiological functions of the ERK3/MK5 signaling module. MK5-deficient mice displayed impaired dendritic spine formation in mouse hippocampal neurons in vivo. We performed large-scale interaction screens to understand the neuronal functions of the ERK3/MK5 pathway and identified septin7 (Sept7) as a novel interacting partner of ERK3. ERK3/MK5/Sept7 form a ternary complex, which can phosphorylate the Sept7 regulators Binders of Rho GTPases (Borgs). In addition, the brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. In transfected primary neurons, Sept7-dependent dendrite development and spine formation are stimulated by the ERK3/MK5 module. Thus, the regulation of neuronal morphogenesis is proposed as the first physiological function of the ERK3/MK5 signaling module. PMID- 22508987 TI - Regulation of a novel androgen receptor target gene, the cyclin B1 gene, through androgen-dependent E2F family member switching. AB - The malignant transformation of human prostatic epithelium is associated with the loss of androgen receptor (AR) in the surrounding stroma. However, the function and mechanisms of AR signaling in prostate cancer (PCa) stroma remain elusive. Here we report, by using proteomics pathway array analysis (PPAA), that androgen and its receptor inhibit the proliferation of prostate stromal cells through transcriptional suppression of cyclin B1, and we confirmed our findings at mRNA and protein levels using AR-negative or -positive primary prostate stromal cells. Furthermore, AR showed a negative correlation with cyclin B1 expression in stroma of human PCa samples in vivo. Mechanistically, we identify cyclin B1 as a bona fide AR target gene in prostate stromal cells. The negative regulation of cyclin B1 by AR is mediated through switching between E2F1 and E2F4 on the promoter of cyclin B1. E2F1 binds to the cyclin B1 promoter and maintains its expression and subsequent cell cycle progression in AR-negative stromal cells or AR-positive stromal cells when androgens are depleted. Upon stimulation with androgen in AR positive stromal cells, E2F1 is displaced from the binding site by AR and replaced with E2F4, leading to the recruitment of the silencing mediator for retinoid and thyroid hormone receptor (SMRT)/histone deacetylase 3 (HDAC3) corepressor complex and repression of cyclin B1 at the chromatin level. The switch between E2F1 and E2F4 at the E2F binding site of the cyclin B1 promoter coincides with an androgen-dependent interaction between AR and E2F1 as well as the cytoplasmic-to-nuclear translocation of E2F4. Thus, we identified a novel mechanism for E2F factors in the regulation of cell cycle gene expression and cell cycle progression under the control of AR signaling. PMID- 22508988 TI - Separate domains of fission yeast Cdk9 (P-TEFb) are required for capping enzyme recruitment and primed (Ser7-phosphorylated) Rpb1 carboxyl-terminal domain substrate recognition. AB - In fission yeast, discrete steps in mRNA maturation and synthesis depend on a complex containing the 5'-cap methyltransferase Pcm1 and Cdk9, which phosphorylates the RNA polymerase II (Pol II) carboxyl-terminal domain (CTD) and the processivity factor Spt5 to promote transcript elongation. Here we show that a Cdk9 carboxyl-terminal extension, distinct from the catalytic domain, mediates binding to both Pcm1 and the Pol II CTD. Removal of this segment diminishes Cdk9/Pcm1 chromatin recruitment and Spt5 phosphorylation in vivo and leads to slow growth and hypersensitivity to cold temperature, nutrient limitation, and the IMP dehydrogenase inhibitor mycophenolic acid (MPA). These phenotypes, and the Spt5 phosphorylation defect, are suppressed by Pcm1 overproduction, suggesting that normal transcript elongation and gene expression depend on physical linkage between Cdk9 and Pcm1. The extension is dispensable, however, for recognition of CTD substrates "primed" by Mcs6 (Cdk7). On defined peptide substrates in vitro, Cdk9 prefers CTD repeats phosphorylated at Ser7 over unmodified repeats. In vivo, Ser7 phosphorylation depends on Mcs6 activity, suggesting a conserved mechanism, independent of chromatin recruitment, to order transcriptional CDK functions. Therefore, fission yeast Cdk9 comprises a catalytic domain sufficient for primed substrate recognition and a multivalent recruitment module that couples transcription with capping. PMID- 22508992 TI - Statins for primary prevention. PMID- 22508989 TI - The arginine attenuator peptide interferes with the ribosome peptidyl transferase center. AB - The fungal arginine attenuator peptide (AAP) is encoded by a regulatory upstream open reading frame (uORF). The AAP acts as a nascent peptide within the ribosome tunnel to stall translation in response to arginine (Arg). The effect of AAP and Arg on ribosome peptidyl transferase center (PTC) function was analyzed in Neurospora crassa and wheat germ translation extracts using the transfer of nascent AAP to puromycin as an assay. In the presence of a high concentration of Arg, the wild-type AAP inhibited PTC function, but a mutated AAP that lacked stalling activity did not. While AAP of wild-type length was most efficient at stalling ribosomes, based on primer extension inhibition (toeprint) assays and reporter synthesis assays, a window of inhibitory function spanning four residues was observed at the AAP's C terminus. The data indicate that inhibition of PTC function by the AAP in response to Arg is the basis for the AAP's function of stalling ribosomes at the uORF termination codon. Arg could interfere with PTC function by inhibiting peptidyltransferase activity and/or by restricting PTC A site accessibility. The mode of PTC inhibition appears unusual because neither specific amino acids nor a specific nascent peptide chain length was required for AAP to inhibit PTC function. PMID- 22508990 TI - Cks1 promotion of S phase entry and proliferation is independent of p27Kip1 suppression. AB - Cks1 is an activator of the SCF(Skp2) ubiquitin ligase complex that targets the cell cycle inhibitor p27(Kip1) for degradation. The loss of Cks1 results in p27(Kip1) accumulation and decreased proliferation and inhibits tumorigenesis. We identify here a function of Cks1 in mammalian cell cycle regulation that is independent of p27(Kip1). Specifically, Cks1(-/-); p27(Kip1-/-) mouse embryonic fibroblasts retain defects in the G(1)-S phase transition that are coupled with decreased Cdk2-associated kinase activity and defects in proliferation that are associated with Cks1 loss. Furthermore, concomitant loss of Cks1 does not rescue the tumor suppressor function of p27(Kip1) that is manifest in various organs of p27(Kip1-/-) mice. In contrast, defects in mitotic entry and premature senescence manifest in Cks1(-/-) cells are p27(Kip1) dependent. Collectively, these findings establish p27(Kip1)-independent functions of Cks1 in regulating the G(1)-S transition. PMID- 22508995 TI - Working through disaster: re-establishing mental health care after Hurricane Katrina. AB - OBJECTIVE: Our research explored how mental health care providers continued to work during and after Hurricane Katrina. METHODS: We interviewed 32 practitioners working in the New Orleans mental health care community during and after Hurricane Katrina. Through qualitative data analysis, we developed three temporal periods of disruption: the evacuation period, the surreal period, and the new normal period. We analyzed the actions informants took during these time periods. RESULTS: The mental health care providers adapted to disruption by displaying two forms of flexibility: doing different tasks and doing tasks differently. How much and how they engaged in these forms of flexibility varied during the three periods. CONCLUSIONS: Informants' actions helped to create system resilience by adjusting the extent to which they were doing different tasks and the ways in which they were doing tasks differently during the three time periods. Their flexibility allowed them to provide basic care and adapt to changed circumstances. Their flexibility also contributed to maintaining a skilled workforce in the affected region. PMID- 22508994 TI - The PRINTS database: a fine-grained protein sequence annotation and analysis resource--its status in 2012. AB - The PRINTS database, now in its 21st year, houses a collection of diagnostic protein family 'fingerprints'. Fingerprints are groups of conserved motifs, evident in multiple sequence alignments, whose unique inter-relationships provide distinctive signatures for particular protein families and structural/functional domains. As such, they may be used to assign uncharacterized sequences to known families, and hence to infer tentative functional, structural and/or evolutionary relationships. The February 2012 release (version 42.0) includes 2156 fingerprints, encoding 12 444 individual motifs, covering a range of globular and membrane proteins, modular polypeptides and so on. Here, we report the current status of the database, and introduce a number of recent developments that help both to render a variety of our annotation and analysis tools easier to use and to make them more widely available. Database URL: www.bioinf.manchester.ac.uk/dbbrowser/PRINTS/. PMID- 22508996 TI - A brief report of surveillance of traumatic experiences and exposures after the earthquake-tsunami in American Samoa, 2009. AB - CONTEXT: Rapid mental health surveillance during the acute phase of a disaster response can inform the allocation of limited clinical resources and provide essential household-level risk estimates for recovery planning. OBJECTIVE: To describe the use of the PsySTART Rapid Mental Health Triage and Incident Management System for individual-level clinical triage and traumatic exposure assessment in the aftermath of a large-scale disaster. METHODS: We conducted a cross-sectional, comparative review of mental health triage data collected with the PsySTART system from survivors of the September 2009 earthquake-tsunami in American Samoa. Data were obtained from two sources--secondary triage of patients and a standardized community assessment survey-and analyzed descriptively. The main outcome measures were survivor-reported traumatic experiences and exposures- called triage factors--associated with risk for developing severe distress and new mental health disorders following disasters. RESULTS: The most common triage factors reported by survivors referred for mental health services were "felt extreme panic/fear" (93%) and "felt direct threat to life" (93%). The most common factor reported by persons in tsunami-affected communities was "felt extreme panic or fear" (75%). Proportions of severe triage factors reported by persons living in the community were consistently lower than those reported by patients referred for mental health services. CONCLUSIONS: The combination of evidence based mental health triage and community assessment gave hospital-based providers, local public health officials, and federal response teams a strategy to match limited clinical resources with survivors at greatest risk. Also, it produced a common operating picture of acute and chronic mental health needs among disaster systems of care operating in American Samoa. PMID- 22508997 TI - Paleolithic cave rock art, animal coloration, and specific animal habitats. PMID- 22508998 TI - Genetic, molecular, and biochemical basis of fungal tropolone biosynthesis. AB - A gene cluster encoding the biosynthesis of the fungal tropolone stipitatic acid was discovered in Talaromyces stipitatus (Penicillium stipitatum) and investigated by targeted gene knockout. A minimum of three genes are required to form the tropolone nucleus: tropA encodes a nonreducing polyketide synthase which releases 3-methylorcinaldehyde; tropB encodes a FAD-dependent monooxygenase which dearomatizes 3-methylorcinaldehyde via hydroxylation at C-3; and tropC encodes a non-heme Fe(II)-dependent dioxygenase which catalyzes the oxidative ring expansion to the tropolone nucleus via hydroxylation of the 3-methyl group. The tropA gene was characterized by heterologous expression in Aspergillus oryzae, whereas tropB and tropC were successfully expressed in Escherichia coli and the purified TropB and TropC proteins converted 3-methylorcinaldehyde to a tropolone in vitro. Finally, knockout of the tropD gene, encoding a cytochrome P450 monooxygenase, indicated its place as the next gene in the pathway, probably responsible for hydroxylation of the 6-methyl group. Comparison of the T. stipitatus tropolone biosynthetic cluster with other known gene clusters allows clarification of important steps during the biosynthesis of other fungal compounds including the xenovulenes, citrinin, sepedonin, sclerotiorin, and asperfuranone. PMID- 22508999 TI - Agulhas leakage as a key process in the modes of Quaternary climate changes. AB - Heat and salt transfer from the Indian Ocean to the Atlantic Ocean (Agulhas leakage) has an important effect on the global thermohaline circulation and climate. The lack of long transfer record prevents elucidation of its role on climate changes throughout the Quaternary. Here, we present a 1,350-ka accumulation rate record of the planktic foraminiferal species Globorotalia menardii. We demonstrate that, according to previous assumptions, the presence and reseeding of this fauna in the subtropical southeast Atlantic was driven by interocean exchange south of Africa. The Agulhas transfer strengthened at glacial ice-volume maxima for every glacial-interglacial transition, with maximum reinforcements organized according to a 400-ka periodicity. The long-term dynamics of Agulhas leakage may have played a crucial role in regulating meridional overturning circulation and global climate changes during the Mid Brunhes event and the Mid-Pleistocene transition, and could also play an important role in the near future. PMID- 22509000 TI - Designing biomimetic pores based on carbon nanotubes. AB - Biomimetic nanopores based on membrane-spanning single-walled carbon nanotubes have been designed to include selectivity filters based on combinations of anionic and cationic groups mimicking those present in bacterial porins and in voltage-gated sodium and calcium channels. The ion permeation and selectivity properties of these nanopores when embedded in a phospholipid bilayer have been explored by molecular dynamics simulations and free energy profile calculations. The interactions of the nanopores with sodium, potassium, calcium, and chloride ions have been explored as a function of the number of anionic and cationic groups within the selectivity filter. Unbiased molecular dynamics simulations show that the overall selectivity is largely determined by the net charge of the filter. Analysis of distribution functions reveals considerable structuring of the distribution of ions and water within the nanopores. The distributions of ions along the pore axis reveal local selectivity for cations around filter, even in those nanopores (C0) where the net filter charge is zero. Single ion free energy profiles also reveal clear evidence for cation selectivity, even in the C0 nanopores. Detailed analysis of the interactions of the C0 nanopore with Ca(2+) ions reveals that local interactions with the anionic (carboxylate) groups of the selectivity filter lead to (partial) replacement of solvating water as the ion passes through the pore. These studies suggest that a computational biomimetic approach can be used to evaluate our understanding of the design principles of nanopores and channels. PMID- 22509001 TI - Uniform hexagonal graphene flakes and films grown on liquid copper surface. AB - Unresolved problems associated with the production of graphene materials include the need for greater control over layer number, crystallinity, size, edge structure and spatial orientation, and a better understanding of the underlying mechanisms. Here we report a chemical vapor deposition approach that allows the direct synthesis of uniform single-layered, large-size (up to 10,000 MUm(2)), spatially self-aligned, and single-crystalline hexagonal graphene flakes (HGFs) and their continuous films on liquid Cu surfaces. Employing a liquid Cu surface completely eliminates the grain boundaries in solid polycrystalline Cu, resulting in a uniform nucleation distribution and low graphene nucleation density, but also enables self-assembly of HGFs into compact and ordered structures. These HGFs show an average two-dimensional resistivity of 609 +/- 200 Omega and saturation current density of 0.96 +/- 0.15 mA/MUm, demonstrating their good conductivity and capability for carrying high current density. PMID- 22509002 TI - On the origin of the hierarchy of color names. AB - One of the fundamental problems in cognitive science is how humans categorize the visible color spectrum. The empirical evidence of the existence of universal or recurrent patterns in color naming across cultures is paralleled by the observation that color names begin to be used by individual cultures in a relatively fixed order. The origin of this hierarchy is largely unexplained. Here we resort to multiagent simulations, where a population of individuals, subject to a simple perceptual constraint shared by all humans, namely the human Just Noticeable Difference, categorizes and names colors through a purely cultural negotiation in the form of language games. We found that the time needed for a population to reach consensus on a color name depends on the region of the visible color spectrum. If color spectrum regions are ranked according to this criterion, a hierarchy with [red, (magenta)-red], [violet], [green/yellow], [blue], [orange], and [cyan], appearing in this order, is recovered, featuring an excellent quantitative agreement with the empirical observations of the WCS. Our results demonstrate a clear possible route to the emergence of hierarchical color categories, confirming that the theoretical modeling in this area has now attained the required maturity to make significant contributions to the ongoing debates concerning language universals. PMID- 22509003 TI - Intrinsic disorder modulates protein self-assembly and aggregation. AB - Protein molecules have evolved to adopt distinctive and well-defined functional and soluble states under physiological conditions. In some circumstances, however, proteins can self-assemble into fibrillar aggregates designated as amyloid fibrils. In vivo these processes are normally associated with severe pathological conditions but can sometimes have functional relevance. One such example is the hydrophobins, whose aggregation at air-water interfaces serves to create robust protein coats that help fungal spores to resist wetting and thus facilitate their dispersal in the air. We have performed multiscale simulations to address the molecular determinants governing the formation of functional amyloids by the class I fungal hydrophobin EAS. Extensive samplings of full-atom replica-exchange molecular dynamics and coarse-grained simulations have allowed us to identify factors that distinguish aggregation-prone from highly soluble states of EAS. As a result of unfavourable entropic terms, highly dynamical regions are shown to exert a crucial influence on the propensity of the protein to aggregate under different conditions. More generally, our findings suggest a key role that specific flexible structural elements can play to ensure the existence of soluble and functional states of proteins under physiological conditions. PMID- 22509004 TI - Pressure tunes electrical resistivity by four orders of magnitude in amorphous Ge2Sb2Te5 phase-change memory alloy. AB - Ge-Sb-Te-based phase-change memory is one of the most promising candidates to succeed the current flash memories. The application of phase-change materials for data storage and memory devices takes advantage of the fast phase transition (on the order of nanoseconds) and the large property contrasts (e.g., several orders of magnitude difference in electrical resistivity) between the amorphous and the crystalline states. Despite the importance of Ge-Sb-Te alloys and the intense research they have received, the possible phases in the temperature-pressure diagram, as well as the corresponding structure-property correlations, remain to be systematically explored. In this study, by subjecting the amorphous Ge(2)Sb(2)Te(5) (a-GST) to hydrostatic-like pressure (P), the thermodynamic variable alternative to temperature, we are able to tune its electrical resistivity by several orders of magnitude, similar to the resistivity contrast corresponding to the usually investigated amorphous-to-crystalline (a-GST to rock salt GST) transition used in current phase-change memories. In particular, the electrical resistivity drops precipitously in the P = 0 to 8 GPa regime. A prominent structural signature representing the underlying evolution in atomic arrangements and bonding in this pressure regime, as revealed by the ab initio molecular dynamics simulations, is the reduction of low-electron-density regions, which contributes to the narrowing of band gap and delocalization of trapped electrons. At P > 8 GPa, we have observed major changes of the average local structures (bond angle and coordination numbers), gradually transforming the a GST into a high-density, metallic-like state. This high-pressure glass is characterized by local motifs that bear similarities to the body-centered-cubic GST (bcc-GST) it eventually crystallizes into at 28 GPa, and hence represents a bcc-type polyamorph of a-GST. PMID- 22509005 TI - Evidence of a large-scale mechanosensing mechanism for cellular adaptation to substrate stiffness. AB - Cell migration plays a major role in many fundamental biological processes, such as morphogenesis, tumor metastasis, and wound healing. As they anchor and pull on their surroundings, adhering cells actively probe the stiffness of their environment. Current understanding is that traction forces exerted by cells arise mainly at mechanotransduction sites, called focal adhesions, whose size seems to be correlated to the force exerted by cells on their underlying substrate, at least during their initial stages. In fact, our data show by direct measurements that the buildup of traction forces is faster for larger substrate stiffness, and that the stress measured at adhesion sites depends on substrate rigidity. Our results, backed by a phenomenological model based on active gel theory, suggest that rigidity-sensing is mediated by a large-scale mechanism originating in the cytoskeleton instead of a local one. We show that large-scale mechanosensing leads to an adaptative response of cell migration to stiffness gradients. In response to a step boundary in rigidity, we observe not only that cells migrate preferentially toward stiffer substrates, but also that this response is optimal in a narrow range of rigidities. Taken together, these findings lead to unique insights into the regulation of cell response to external mechanical cues and provide evidence for a cytoskeleton-based rigidity-sensing mechanism. PMID- 22509006 TI - Amorfrutins are potent antidiabetic dietary natural products. AB - Given worldwide increases in the incidence of obesity and type 2 diabetes, new strategies for preventing and treating metabolic diseases are needed. The nuclear receptor PPARgamma (peroxisome proliferator-activated receptor gamma) plays a central role in lipid and glucose metabolism; however, current PPARgamma targeting drugs are characterized by undesirable side effects. Natural products from edible biomaterial provide a structurally diverse resource to alleviate complex disorders via tailored nutritional intervention. We identified a family of natural products, the amorfrutins, from edible parts of two legumes, Glycyrrhiza foetida and Amorpha fruticosa, as structurally new and powerful antidiabetics with unprecedented effects for a dietary molecule. Amorfrutins bind to and activate PPARgamma, which results in selective gene expression and physiological profiles markedly different from activation by current synthetic PPARgamma drugs. In diet-induced obese and db/db mice, amorfrutin treatment strongly improves insulin resistance and other metabolic and inflammatory parameters without concomitant increase of fat storage or other unwanted side effects such as hepatoxicity. These results show that selective PPARgamma activation by diet-derived ligands may constitute a promising approach to combat metabolic disease. PMID- 22509008 TI - Rethinking the purinergic neuron-glia connection. PMID- 22509007 TI - Robustness and accuracy of cell division in Escherichia coli in diverse cell shapes. AB - Cell division in typical rod-shaped bacteria such as Escherichia coli shows a remarkable plasticity in being able to adapt to a variety of irregular cell shapes. Here, we investigate the roles of the Min system and the nucleoid occlusion factor SlmA in supporting this adaptation. We study "squeezed" E. coli in narrow nanofabricated channels where these bacteria exhibit highly irregular shapes and large volumes. Despite the severely anomalous morphologies we find that most of these bacteria maintain their ability to divide into two equally sized daughters with an accuracy comparable to that of normal rod-shaped cells (about 4%). Deletion of either slmA or minC shows that the molecular systems associated with these genes are largely dispensable for accurate cell division in these irregular cell shapes. Using fluorescence time-lapse microscopy, we determine that the functionality of the Min system is affected by the cell shape, whereas the localization of a nucleoid relative to the cell division proteins (the divisome) remains unperturbed in a broad spectrum of morphologies, consistent with nucleoid occlusion. The observed positioning of the nucleoid relative to the divisome appears not to be affected by the nucleoid-occlusion factor SlmA. The current study underscores the importance of nucleoid occlusion in positioning the divisome and shows that it is robust against shape irregularities. PMID- 22509009 TI - General anesthesia alters time perception by phase shifting the circadian clock. AB - Following general anesthesia, people are often confused about the time of day and experience sleep disruption and fatigue. It has been hypothesized that these symptoms may be caused by general anesthesia affecting the circadian clock. The circadian clock is fundamental to our well-being because it regulates almost all aspects of our daily biochemistry, physiology, and behavior. Here, we investigated the effects of the most common general anesthetic, isoflurane, on time perception and the circadian clock using the honeybee (Apis mellifera) as a model. A 6-h daytime anesthetic systematically altered the time-compensated sun compass orientation of the bees, with a mean anticlockwise shift in vanishing bearing of 87 degrees in the Southern Hemisphere and a clockwise shift in flight direction of 58 degrees in the Northern Hemisphere. Using the same 6-h anesthetic treatment, time-trained bees showed a delay in the start of foraging of 3.3 h, and whole-hive locomotor-activity rhythms were delayed by an average of 4.3 h. We show that these effects are all attributable to a phase delay in the core molecular clockwork. mRNA oscillations of the central clock genes cryptochrome-m and period were delayed by 4.9 and 4.3 h, respectively. However, this effect is dependent on the time of day of administration, as is common for clock effects, and nighttime anesthesia did not shift the clock. Taken together, our results suggest that general anesthesia during the day causes a persistent and marked shift of the clock effectively inducing "jet lag" and causing impaired time perception. Managing this effect in humans is likely to help expedite postoperative recovery. PMID- 22509010 TI - Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine binding domain in complex with the LDL-receptor tail. AB - Hypercholesterolemia, high serum cholesterol in the form of LDL, is a major risk factor for atherosclerosis. LDL is mostly degraded in the liver after its cellular internalization with the LDL receptor (LDLR). This clathrin-mediated endocytosis depends on the protein autosomal recessive hypercholesterolemia (ARH), which binds the LDLR cytoplasmic tail. Mutations in either the LDLR tail or in ARH lead to hypercholesterolemia and premature atherosclerosis. Despite the significance of this interaction for cholesterol homeostasis, no structure of either ARH or the LDLR tail is available to determine its molecular basis. We report the crystal structure at 1.37-A resolution of the phosphotyrosine-binding (PTB) domain of ARH in complex with an LDLR tail peptide containing the FxNPxY(0) internalization signal. Surprisingly, ARH interacts with a longer portion of the tail than previously recognized, which extends to I(-7)xF(-5)xNPxY(0)QK(+2). The LDLR tail assumes a unique "Hook"-like structure with a double beta-turn conformation, which is accommodated in distinctive ARH structural determinants (i.e., an extended backbone hydrogen-bonding platform, three hydrophobic helical grooves, and a hydrophobic pocket for Y(0)). This unique complementarity differs significantly in related PTB proteins and may account for the unique physiological role of these partners in the hepatic uptake of cholesterol LDL. Moreover, the unusual hydrophobic pocket for Y(0) explains the distinctive ability of ARH to internalize proteins containing either FxNPxY(0) or FxNPxF(0) sequences. Biophysical measurements reveal how mutations associated with hypercholesterolemia destabilize ARH and its complex with LDLR and illuminate LDL internalization defects seen in patients. PMID- 22509011 TI - Facial expressions of emotion are not culturally universal. AB - Since Darwin's seminal works, the universality of facial expressions of emotion has remained one of the longest standing debates in the biological and social sciences. Briefly stated, the universality hypothesis claims that all humans communicate six basic internal emotional states (happy, surprise, fear, disgust, anger, and sad) using the same facial movements by virtue of their biological and evolutionary origins [Susskind JM, et al. (2008) Nat Neurosci 11:843-850]. Here, we refute this assumed universality. Using a unique computer graphics platform that combines generative grammars [Chomsky N (1965) MIT Press, Cambridge, MA] with visual perception, we accessed the mind's eye of 30 Western and Eastern culture individuals and reconstructed their mental representations of the six basic facial expressions of emotion. Cross-cultural comparisons of the mental representations challenge universality on two separate counts. First, whereas Westerners represent each of the six basic emotions with a distinct set of facial movements common to the group, Easterners do not. Second, Easterners represent emotional intensity with distinctive dynamic eye activity. By refuting the long standing universality hypothesis, our data highlight the powerful influence of culture on shaping basic behaviors once considered biologically hardwired. Consequently, our data open a unique nature-nurture debate across broad fields from evolutionary psychology and social neuroscience to social networking via digital avatars. PMID- 22509012 TI - Agricultural legacies, food production and its environmental consequences. PMID- 22509013 TI - Promiscuous restriction is a cellular defense strategy that confers fitness advantage to bacteria. AB - Most bacterial genomes harbor restriction-modification systems, encoding a REase and its cognate MTase. On attack by a foreign DNA, the REase recognizes it as nonself and subjects it to restriction. Should REases be highly specific for targeting the invading foreign DNA? It is often considered to be the case. However, when bacteria harboring a promiscuous or high-fidelity variant of the REase were challenged with bacteriophages, fitness was maximal under conditions of catalytic promiscuity. We also delineate possible mechanisms by which the REase recognizes the chromosome as self at the noncanonical sites, thereby preventing lethal dsDNA breaks. This study provides a fundamental understanding of how bacteria exploit an existing defense system to gain fitness advantage during a host-parasite coevolutionary "arms race." PMID- 22509014 TI - MHC class I antigen processing distinguishes endogenous antigens based on their translation from cellular vs. viral mRNA. AB - To better understand the generation of MHC class I-associated peptides, we used a model antigenic protein whose proteasome-mediated degradation is rapidly and reversibly controlled by Shield-1, a cell-permeant drug. When expressed from a stably transfected gene, the efficiency of antigen presentation is ~2%, that is, one cell-surface MHC class I-peptide complex is generated for every 50 folded source proteins degraded upon Shield-1 withdrawal. By contrast, when the same protein is expressed by vaccinia virus, its antigen presentation efficiency is reduced ~10-fold to values similar to those reported for other vaccinia virus encoded model antigens. Virus infection per se does not modify the efficiency of antigen processing. Rather, the efficiency difference between cellular and virus encoded antigens is based on whether the antigen is synthesized from transgene- vs. virus-encoded mRNA. Thus, class I antigen-processing machinery can distinguish folded proteins based on the precise details of their synthesis to modulate antigen presentation efficiency. PMID- 22509015 TI - Link between orientation and retinotopic maps in primary visual cortex. AB - Maps representing the preference of neurons for the location and orientation of a stimulus on the visual field are a hallmark of primary visual cortex. It is not yet known how these maps develop and what function they play in visual processing. One hypothesis postulates that orientation maps are initially seeded by the spatial interference of ON- and OFF-center retinal receptive field mosaics. Here we show that such a mechanism predicts a link between the layout of orientation preferences around singularities of different signs and the cardinal axes of the retinotopic map. Moreover, we confirm the predicted relationship holds in tree shrew primary visual cortex. These findings provide additional support for the notion that spatially structured input from the retina may provide a blueprint for the early development of cortical maps and receptive fields. More broadly, it raises the possibility that spatially structured input from the periphery may shape the organization of primary sensory cortex of other modalities as well. PMID- 22509016 TI - Midlife gene expressions identify modulators of aging through dietary interventions. AB - Dietary interventions are effective ways to extend or shorten lifespan. By examining midlife hepatic gene expressions in mice under different dietary conditions, which resulted in different lifespans and aging-related phenotypes, we were able to identify genes and pathways that modulate the aging process. We found that pathways transcriptionally correlated with diet-modulated lifespan and physiological changes were enriched for lifespan-modifying genes. Intriguingly, mitochondrial gene expression correlated with lifespan and anticorrelated with aging-related pathological changes, whereas peroxisomal gene expression showed an opposite trend. Both organelles produce reactive oxygen species, a proposed causative factor of aging. This finding implicates a contribution of peroxisome to aging. Consistent with this hypothesis, lowering the expression levels of peroxisome proliferation genes decreased the cellular peroxide levels and extended the lifespan of Drosophila melanogaster and Caenorhabditis elegans. These findings show that transcriptional changes resulting from dietary interventions can effectively reflect causal factors in aging and identify previously unknown or under-appreciated longevity pathways, such as the peroxisome pathway. PMID- 22509017 TI - Snapshot of virus evolution in hypersaline environments from the characterization of a membrane-containing Salisaeta icosahedral phage 1. AB - The multitude of archaea and bacteria inhabiting extreme environments has only become evident during the last decades. As viruses apply a significant evolutionary force to their hosts, there is an inherent value in learning about viruses infecting these extremophiles. In this study, we have focused on one such unique virus-host pair isolated from a hypersaline environment: an icosahedral, membrane-containing double-stranded DNA virus--Salisaeta icosahedral phage 1 (SSIP-1) and its halophilic host bacterium Salisaeta sp. SP9-1 closely related to Salisaeta longa. The architectural principles, virion composition, and the proposed functions associated with some of the ORFs of the virus are surprisingly similar to those found in viruses belonging to the PRD1-adenovirus lineage. The virion structure, determined by electron cryomicroscopy, reveals that the bulk of the outer protein capsid is composed of upright standing pseudohexameric capsomers organized on a T = 49 icosahedral lattice. Our results give a comprehensive description of a halophilic virus-host system and shed light on the relatedness of viruses based on their virion architecture. PMID- 22509018 TI - Langerhans cells down-regulate inflammation-driven alveolar bone loss. AB - Excessive bone resorption is frequently associated with chronic infections and inflammatory diseases. Whereas T cells were demonstrated to facilitate osteoclastogenesis in such diseases, the role of dendritic cells, the most potent activators of naive T cells, remains unclear. Using a model involving inflammation-driven alveolar bone loss attributable to infection, we showed that in vivo ablation of Langerhans cells (LCs) resulted in enhanced bone loss. An increased infiltration of B and T lymphocytes into the tissue surrounding the bone was observed in LC-ablated mice, including receptor activator of NF-kappaB ligand (RANKL)-expressing CD4(+) T cells with known capabilities of altering bone homeostasis. In addition, the absence of LCs significantly reduced the numbers of CD4(+)Foxp3(+) T-regulatory cells in the tissue. Further investigation revealed that LCs were not directly involved in presenting antigens to T cells. Nevertheless, despite their low numbers in the tissue, the absence of LCs resulted in an elevated activation of CD4(+) but not CD8(+) T cells. This activation involved elevated production of IFN-gamma but not IL-17 or IL-10 cytokines. Our data, thus, reveal a protective immunoregulatory role for LCs in inflammation-induced alveolar bone resorption, by inhibiting IFN-gamma secretion and excessive activation of RANKL(+)CD4(+) T cells with a capability of promoting osteoclastogenesis. PMID- 22509019 TI - Crafting a system-wide response to healthcare-associated infections. PMID- 22509020 TI - Representation of stable social dominance relations by human infants. AB - What are the origins of humans' capacity to represent social relations? We approached this question by studying human infants' understanding of social dominance as a stable relation. We presented infants with interactions between animated agents in conflict situations. Studies 1 and 2 targeted expectations of stability of social dominance. They revealed that 15-mo-olds (and, to a lesser extent, 12-mo-olds) expect an asymmetric relationship between two agents to remain stable from one conflict to another. To do so, infants need to infer that one of the agents (the dominant) will consistently prevail when her goals conflict with those of the other (the subordinate). Study 3 and 4 targeted the format of infants' representation of social dominance. In these studies, we found that 12- and 15-mo-olds did not extend their expectations of dominance to unobserved relationships, even when they could have been established by transitive inference. These results suggest that infants' expectation of stability originates from their representation of social dominance as a relationship between two agents rather than as an individual property. Infants' demonstrated understanding of social dominance reflects the cognitive underpinning of humans' capacity to represent social relations, which may be evolutionarily ancient, and may be shared with nonhuman species. PMID- 22509021 TI - Induction of microRNA-155 is TLR- and type IV secretion system-dependent in macrophages and inhibits DNA-damage induced apoptosis. AB - Helicobacter pylori is a gastric pathogen responsible for a high disease burden worldwide. Deregulated inflammatory responses, possibly involving macrophages, are implicated in H. pylori-induced pathology, and microRNAs, such as miR-155, have recently emerged as crucial regulators of innate immunity and inflammatory responses. miR-155 is regulated by Toll-like receptor (TLR) ligands in monocyte derived cells and has been shown to be induced in macrophages during H. pylori infection. Here, we investigated the regulation of miR-155 expression in primary murine bone marrow-derived macrophages (BMMs) during H. pylori infection and examined the downstream mRNA targets of this microRNA using microarray analysis. We report TLR2/4- and NOD1/2-independent up-regulation of miR-155, which was found to be dependent on the major H. pylori pathogenicity determinant, the type IV secretion system (T4SS). miR-155 expression was dependent on NF-kappaB signaling but was independent of CagA. Microarray analysis identified known gene targets of miR-155 in BMMs during H. pylori infection that are proapoptotic. We also identified and validated miR-155 binding sites in the 3' UTRs of the targets, Tspan14, Lpin1, and Pmaip1. We observed that H. pylori-infected miR-155( /-) BMMs were significantly more susceptible to cisplatin DNA damage-induced apoptosis than were wild-type BMMs. Thus, our data suggest a function for the prototypical H. pylori pathogenicity factor, the T4SS, in the up-regulation of miR-155 in BMMs. We propose the antiapoptotic effects of miR-155 could enhance macrophage resistance to apoptosis induced by DNA damage during H. pylori infection. PMID- 22509022 TI - Nest-building orangutans demonstrate engineering know-how to produce safe, comfortable beds. AB - Nest-building orangutans must daily build safe and comfortable nest structures in the forest canopy and do this quickly and effectively using the branches that surround them. This study aimed to investigate the mechanical design and architecture of orangutan nests and determine the degree of technical sophistication used in their construction. We measured the whole nest compliance and the thickness of the branches used and recorded the ways in which the branches were fractured. Branch samples were also collected from the nests and subjected to three-point bending tests to determine their mechanical properties. We demonstrated that the center of the nest is more compliant than the edges; this may add extra comfort and safety to the structure. During construction orangutans use the fact that branches only break half-way across in "greenstick" fracture to weave the main nest structure. They choose thicker branches with greater rigidity and strength to build the main structure in this way. They then detach thinner branches by following greenstick fracture with a twisting action to make the lining. These results suggest that orangutans exhibit a degree of technical knowledge and choice in the construction of nests. PMID- 22509023 TI - Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. AB - Despite the fact that most cancer cells display high glycolytic activity, cancer cells selectively express the less active M2 isoform of pyruvate kinase (PKM2). Here we demonstrate that PKM2 expression makes a critical regulatory contribution to the serine synthetic pathway. In the absence of serine, an allosteric activator of PKM2, glycolytic efflux to lactate is significantly reduced in PKM2 expressing cells. This inhibition of PKM2 results in the accumulation of glycolytic intermediates that feed into serine synthesis. As a consequence, PKM2 expressing cells can maintain mammalian target of rapamycin complex 1 activity and proliferate in serine-depleted medium, but PKM1-expressing cells cannot. Cellular detection of serine depletion depends on general control nonderepressible 2 kinase-activating transcription factor 4 (GCN2-ATF4) pathway activation and results in increased expression of enzymes required for serine synthesis from the accumulating glycolytic precursors. These findings suggest that tumor cells use serine-dependent regulation of PKM2 and GCN2 to modulate the flux of glycolytic intermediates in support of cell proliferation. PMID- 22509024 TI - The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia. AB - Pancreatic cancer is an almost uniformly lethal disease, characterized by late diagnosis, early metastasis, resistance to chemotherapy, and early mutation of the Kras oncogene. Here we show that the receptor for advanced glycation endproducts (RAGE) is required for the activation of interleukin 6 (IL-6) mediated mitochondrial signal transducers and activators of transcription 3 (STAT3) signaling in pancreatic carcinogenesis. RAGE expression correlates with elevated levels of autophagy in pancreatic cancer in vivo and in vitro, and this heightened state of autophagy is required for IL-6-induced STAT3 activation. To further explore the intersection of RAGE, autophagy, and pancreatic carcinogenesis, we created a transgenic murine model, backcrossing RAGE-null mice to a spontaneous mouse model of pancreatic cancer, Pdx1-Cre:Kras(G12D/+) (KC). Targeted ablation of Rage in KC mice delayed neoplasia development, decreased levels of autophagy, and inhibited mitochondrial STAT3 activity and subsequent ATP production. Our results suggest a critical role for RAGE expression in the earliest stages of pancreatic carcinogenesis, potentially acting as the "autophagic switch," regulating mitochondrial STAT3 signaling. PMID- 22509025 TI - Selective recruitment of G protein-coupled receptor kinases (GRKs) controls signaling of the insulin-like growth factor 1 receptor. AB - beta-Arrestins are multifunctional proteins that play central roles in G protein coupled receptor (GPCR) trafficking and signaling. beta-Arrestin1 is also recruited to the insulin-like growth factor-1 receptor (IGF-1R), a receptor tyrosine kinase (RTK), mediating receptor degradation and signaling. Because GPCR phosphorylation by GPCR-kinases (GRKs) governs interactions of the receptors with beta-arrestins, we investigated the regulatory roles of the four widely expressed GRKs on IGF-1R signaling/degradation. By suppressing GRK expression with siRNA, we demonstrated that lowering GRK5/6 abolishes IGF1-mediated ERK and AKT activation, whereas GRK2 inhibition increases ERK activation and partially inhibits AKT signaling. Conversely, beta-arrestin-mediated ERK signaling is enhanced by overexpression of GRK6 and diminished by GRK2. Similarly, we demonstrated opposing effects of GRK2 and -6 on IGF-1R degradation: GRK2 decreases whereas GRK6 enhances ligand-induced degradation. GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting beta-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated beta-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R, and subsequent mutation analysis demonstrated clear effects on IGF-1R signaling and degradation, mirroring alterations by GRKs. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation, consistent with GRK isoform-specific serine phosphorylation. This study demonstrates distinct roles for GRK isoforms in IGF-1R signaling through beta-arrestin binding with divergent functional outcomes. PMID- 22509026 TI - Lysocardiolipin acyltransferase 1 (ALCAT1) controls mitochondrial DNA fidelity and biogenesis through modulation of MFN2 expression. AB - Oxidative stress causes mitochondrial fragmentation and dysfunction in age related diseases through unknown mechanisms. Cardiolipin (CL) is a phospholipid required for mitochondrial oxidative phosphorylation. The function of CL is determined by its acyl composition, which is significantly altered by the onset of age-related diseases. Here, we examine a role of acyl-CoA:lysocardiolipin acyltransferase lysocardiolipin acyltransferase 1 (ALCAT1), a lysocardiolipin acyltransferase that catalyzes pathological CL remodeling, in mitochondrial biogenesis. We show that overexpression of ALCAT1 causes mitochondrial fragmentation through oxidative stress and depletion of mitofusin mitofusin 2 (MFN2) expression. Strikingly, ALCAT1 overexpression also leads to mtDNA instability and depletion that are reminiscent of MFN2 deficiency. Accordingly, expression of MFN2 completely rescues mitochondrial fusion defect and respiratory dysfunction. Furthermore, ablation of ALCAT1 prevents mitochondrial fragmentation from oxidative stress by up-regulating MFN2 expression, mtDNA copy number, and mtDNA fidelity. Together, these findings reveal an unexpected role of CL remodeling in mitochondrial biogenesis, linking oxidative stress by ALCAT1 to mitochondrial fusion defect. PMID- 22509027 TI - Dynamic reciprocity of sodium and potassium channel expression in a macromolecular complex controls cardiac excitability and arrhythmia. AB - The cardiac electrical impulse depends on an orchestrated interplay of transmembrane ionic currents in myocardial cells. Two critical ionic current mechanisms are the inwardly rectifying potassium current (I(K1)), which is important for maintenance of the cell resting membrane potential, and the sodium current (I(Na)), which provides a rapid depolarizing current during the upstroke of the action potential. By controlling the resting membrane potential, I(K1) modifies sodium channel availability and therefore, cell excitability, action potential duration, and velocity of impulse propagation. Additionally, I(K1) I(Na) interactions are key determinants of electrical rotor frequency responsible for abnormal, often lethal, cardiac reentrant activity. Here, we have used a multidisciplinary approach based on molecular and biochemical techniques, acute gene transfer or silencing, and electrophysiology to show that I(K1)-I(Na) interactions involve a reciprocal modulation of expression of their respective channel proteins (Kir2.1 and Na(V)1.5) within a macromolecular complex. Thus, an increase in functional expression of one channel reciprocally modulates the other to enhance cardiac excitability. The modulation is model-independent; it is demonstrable in myocytes isolated from mouse and rat hearts and with transgenic and adenoviral-mediated overexpression/silencing. We also show that the post synaptic density, discs large, and zonula occludens-1 (PDZ) domain protein SAP97 is a component of this macromolecular complex. We show that the interplay between Na(v)1.5 and Kir2.1 has electrophysiological consequences on the myocardium and that SAP97 may affect the integrity of this complex or the nature of Na(v)1.5 Kir2.1 interactions. The reciprocal modulation between Na(v)1.5 and Kir2.1 and the respective ionic currents should be important in the ability of the heart to undergo self-sustaining cardiac rhythm disturbances. PMID- 22509028 TI - BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain. AB - The bromodomain protein, BRD4, has been identified recently as a therapeutic target in acute myeloid leukemia, multiple myeloma, Burkitt's lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease; its loss is a prognostic signature for metastatic breast cancer. BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papilloma virus (HPV). Despite its role in a broad range of biological processes, the precise molecular mechanism of BRD4 function remains unknown. We report that BRD4 is an atypical kinase that binds to the carboxyl-terminal domain (CTD) of RNA polymerase II and directly phosphorylates its serine 2 (Ser2) sites both in vitro and in vivo under conditions where other CTD kinases are inactive. Phosphorylation of the CTD Ser2 is inhibited in vivo by a BRD4 inhibitor that blocks its binding to chromatin. Our finding that BRD4 is an RNA polymerase II CTD Ser2 kinase implicates it as a regulator of eukaryotic transcription. PMID- 22509029 TI - Differentiation of vascular smooth muscle cells from local precursors during embryonic and adult arteriogenesis requires Notch signaling. AB - Vascular smooth muscle cells (VSMC) have been suggested to arise from various developmental sources during embryogenesis, depending on the vascular bed. However, evidence also points to a common subpopulation of vascular progenitor cells predisposed to VSMC fate in the embryo. In the present study, we use binary transgenic reporter mice to identify a Tie1(+)CD31(dim)vascular endothelial (VE) cadherin(-)CD45(-) precursor that gives rise to VSMC in vivo in all vascular beds examined. This precursor does not represent a mature endothelial cell, because a VE-cadherin promoter-driven reporter shows no expression in VSMC during murine development. Blockade of Notch signaling in the Tie1(+) precursor cell, but not the VE-cadherin(+) endothelial cell, decreases VSMC investment of developing arteries, leading to localized hemorrhage in the embryo at the time of vascular maturation. However, Notch signaling is not required in the Tie1(+) precursor after establishment of a stable artery. Thus, Notch activity is required in the differentiation of a Tie1(+) local precursor to VSMC in a spatiotemporal fashion across all vascular beds. PMID- 22509030 TI - Kaposi's sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection. AB - Kaposi's sarcoma-associated herpesvirus (KSHV), etiologically associated with Kaposi's sarcoma, uses integrins (alpha3beta1, alphaVbeta3, and alphaVbeta5) and associated signaling to enter human dermal microvascular endothelial cells (HMVEC d), an in vivo target of infection. KSHV infection activated c-Cbl, which induced the selective translocation of KSHV into lipid rafts (LRs) along with the alpha3beta1, alphaVbeta3, and xCT receptors, but not alphaVbeta5. LR-translocated receptors were monoubiquitinated, leading to productive macropinocytic entry, whereas non-LR-associated alphaVbeta5 was polyubiquitinated, leading to clathrin mediated entry that was targeted to lysosomes. Because the molecule(s) that integrate signal pathways and productive KSHV macropinocytosis were unknown, we immunoprecipitated KSHV-infected LR fractions with anti-alpha3beta1 antibodies and analyzed them by mass spectrometry. The tyrosine kinase EphrinA2 (EphA2), implicated in many cancers, was identified in this analysis. EphA2 was activated by KSHV. EphA2 was also associated with KSHV and integrins (alpha3beta1 and alphaVbeta3) in LRs early during infection. Preincubation of virus with soluble EphA2, knockdown of EphA2 by shRNAs, or pretreatment of cells with anti-EphA2 monoclonal antibodies or tyrosine kinase inhibitor dasatinib significantly reduced KSHV entry and gene expression. EphA2 associates with c-Cbl-myosin IIA and augmented KSHV-induced Src and PI3-K signals in LRs, leading to bleb formation and macropinocytosis of KSHV. EphA2 shRNA ablated macropinocytosis associated signaling events, virus internalization, and productive nuclear trafficking of KSHV DNA. Taken together, these studies demonstrate that the EphA2 receptor acts as a master assembly regulator of KSHV-induced signal molecules and KSHV entry in endothelial cells and suggest that the EphA2 receptor is an attractive target for controlling KSHV infection. PMID- 22509032 TI - Global changes in diets and the consequences for land requirements for food. AB - Provision of food is a prerequisite for the functioning of human society. Cropland where food and feed are grown is the central, limiting resource for food production. The amount of cropland needed depends on population numbers, average food consumption patterns, and output per unit of land. Around the globe, these factors show large differences. We use data from the Food and Agriculture Organization to consistently assess subcontinental dynamics of how much land was needed to supply the prevailing diets during a span of 46 y, from 1961 to 2007. We find that, in most regions, diets became richer while the land needed to feed one person decreased. A decomposition approach is used to quantify the contributions of the main drivers of cropland requirements for food: changes in population, agricultural technology, and diet. We compare the impact of these drivers for different subcontinents and find that potential land savings through yield increases were offset by a combination of population growth and dietary change. The dynamics of the three factors were the largest in developing regions and emerging economies. The results indicate an inverse relationship between the two main drivers behind increased land requirements for food: with socioeconomic development, population growth decreases and, at the same time, diets become richer. In many regions, dietary change may override population growth as major driver behind land requirements for food in the near future. PMID- 22509031 TI - Chronic restraint stress attenuates p53 function and promotes tumorigenesis. AB - Epidemiological studies strongly suggest that chronic psychological stress promotes tumorigenesis. However, its direct link in vivo and the underlying mechanisms that cause this remain unclear. This study provides direct evidence that chronic stress promotes tumorigenesis in vivo; chronic restraint, a well established mouse model to induce chronic stress, greatly promotes ionizing radiation (IR)-induced tumorigenesis in p53(+/-) mice. The tumor suppressor protein p53 plays a central role in tumor prevention. Loss or attenuation of p53 function contriubutes greatly to tumorigenesis. We found that chronic restraint decreases the levels and function of p53 in mice, and furthermore, promotes the growth of human xenograft tumors in a largely p53-dependent manner. Our results show that glucocorticoids elevated during chronic restraint mediate the effect of chronic restraint on p53 through the induction of serum- and glucocorticoid induced protein kinase (SGK1), which in turn increases MDM2 activity and decreases p53 function. Taken together, this study demonstrates that chronic stress promotes tumorigenesis in mice, and the attenuation of p53 function is an important part of the underlying mechanism, which can be mediated by glucocortcoids elevated during chronic restraint. PMID- 22509033 TI - Tempo of trophic evolution and its impact on mammalian diversification. AB - Mammals are characterized by the complex adaptations of their dentition, which are an indication that diet has played a critical role in their evolutionary history. Although much attention has focused on diet and the adaptations of specific taxa, the role of diet in large-scale diversification patterns remains unresolved. Contradictory hypotheses have been proposed, making prediction of the expected relationship difficult. We show that net diversification rate (the cumulative effect of speciation and extinction), differs significantly among living mammals, depending upon trophic strategy. Herbivores diversify fastest, carnivores are intermediate, and omnivores are slowest. The tempo of transitions between the trophic strategies is also highly biased: the fastest rates occur into omnivory from herbivory and carnivory and the lowest transition rates are between herbivory and carnivory. Extant herbivore and carnivore diversity arose primarily through diversification within lineages, whereas omnivore diversity evolved by transitions into the strategy. The ability to specialize and subdivide the trophic niche allowed herbivores and carnivores to evolve greater diversity than omnivores. PMID- 22509034 TI - Superessential reactions in metabolic networks. AB - The metabolic genotype of an organism can change through loss and acquisition of enzyme-coding genes, while preserving its ability to survive and synthesize biomass in specific environments. This evolutionary plasticity allows pathogens to evolve resistance to antimetabolic drugs by acquiring new metabolic pathways that bypass an enzyme blocked by a drug. We here study quantitatively the extent to which individual metabolic reactions and enzymes can be bypassed. To this end, we use a recently developed computational approach to create large metabolic network ensembles that can synthesize all biomass components in a given environment but contain an otherwise random set of known biochemical reactions. Using this approach, we identify a small connected core of 124 reactions that are absolutely superessential (that is, required in all metabolic networks). Many of these reactions have been experimentally confirmed as essential in different organisms. We also report a superessentiality index for thousands of reactions. This index indicates how easily a reaction can be bypassed. We find that it correlates with the number of sequenced genomes that encode an enzyme for the reaction. Superessentiality can help choose an enzyme as a potential drug target, especially because the index is not highly sensitive to the chemical environment that a pathogen requires. Our work also shows how analyses of large network ensembles can help understand the evolution of complex and robust metabolic networks. PMID- 22509035 TI - Refactoring the nitrogen fixation gene cluster from Klebsiella oxytoca. AB - Bacterial genes associated with a single trait are often grouped in a contiguous unit of the genome known as a gene cluster. It is difficult to genetically manipulate many gene clusters because of complex, redundant, and integrated host regulation. We have developed a systematic approach to completely specify the genetics of a gene cluster by rebuilding it from the bottom up using only synthetic, well-characterized parts. This process removes all native regulation, including that which is undiscovered. First, all noncoding DNA, regulatory proteins, and nonessential genes are removed. The codons of essential genes are changed to create a DNA sequence as divergent as possible from the wild-type (WT) gene. Recoded genes are computationally scanned to eliminate internal regulation. They are organized into operons and placed under the control of synthetic parts (promoters, ribosome binding sites, and terminators) that are functionally separated by spacer parts. Finally, a controller consisting of genetic sensors and circuits regulates the conditions and dynamics of gene expression. We applied this approach to an agriculturally relevant gene cluster from Klebsiella oxytoca encoding the nitrogen fixation pathway for converting atmospheric N(2) to ammonia. The native gene cluster consists of 20 genes in seven operons and is encoded in 23.5 kb of DNA. We constructed a "refactored" gene cluster that shares little DNA sequence identity with WT and for which the function of every genetic part is defined. This work demonstrates the potential for synthetic biology tools to rewrite the genetics encoding complex biological functions to facilitate access, engineering, and transferability. PMID- 22509036 TI - Transformational adaptation when incremental adaptations to climate change are insufficient. AB - All human-environment systems adapt to climate and its natural variation. Adaptation to human-induced change in climate has largely been envisioned as increments of these adaptations intended to avoid disruptions of systems at their current locations. In some places, for some systems, however, vulnerabilities and risks may be so sizeable that they require transformational rather than incremental adaptations. Three classes of transformational adaptations are those that are adopted at a much larger scale, that are truly new to a particular region or resource system, and that transform places and shift locations. We illustrate these with examples drawn from Africa, Europe, and North America. Two conditions set the stage for transformational adaptation to climate change: large vulnerability in certain regions, populations, or resource systems; and severe climate change that overwhelms even robust human use systems. However, anticipatory transformational adaptation may be difficult to implement because of uncertainties about climate change risks and adaptation benefits, the high costs of transformational actions, and institutional and behavioral actions that tend to maintain existing resource systems and policies. Implementing transformational adaptation requires effort to initiate it and then to sustain the effort over time. In initiating transformational adaptation focusing events and multiple stresses are important, combined with local leadership. In sustaining transformational adaptation, it seems likely that supportive social contexts and the availability of acceptable options and resources for actions are key enabling factors. Early steps would include incorporating transformation adaptation into risk management and initiating research to expand the menu of innovative transformational adaptations. PMID- 22509040 TI - Predator-induced macroevolutionary trends in Mesozoic crinoids. AB - Sea urchins are a major component of recent marine communities where they exert a key role as grazers and benthic predators. However, their impact on past marine organisms, such as crinoids, is hard to infer in the fossil record. Analysis of bite mark frequencies on crinoid columnals and comprehensive genus-level diversity data provide unique insights into the importance of sea urchin predation through geologic time. These data show that over the Mesozoic, predation intensity on crinoids, as measured by bite mark frequencies on columnals, changed in step with diversity of sea urchins. Moreover, Mesozoic diversity changes in the predatory sea urchins show a positive correlation with diversity of motile crinoids and a negative correlation with diversity of sessile crinoids, consistent with a crinoid motility representing an effective escape strategy. We contend that the Mesozoic diversity history of crinoids likely represents a macroevolutionary response to changes in sea urchin predation pressure and that it may have set the stage for the recent pattern of crinoid diversity in which motile forms greatly predominate and sessile forms are restricted to deep-water refugia. PMID- 22509038 TI - Allosteric gating mechanism underlies the flexible gating of KCNQ1 potassium channels. AB - KCNQ1 (Kv7.1) is a unique member of the superfamily of voltage-gated K(+) channels in that it displays a remarkable range of gating behaviors tuned by coassembly with different beta subunits of the KCNE family of proteins. To better understand the basis for the biophysical diversity of KCNQ1 channels, we here investigate the basis of KCNQ1 gating in the absence of beta subunits using voltage-clamp fluorometry (VCF). In our previous study, we found the kinetics and voltage dependence of voltage-sensor movements are very similar to those of the channel gate, as if multiple voltage-sensor movements are not required to precede gate opening. Here, we have tested two different hypotheses to explain KCNQ1 gating: (i) KCNQ1 voltage sensors undergo a single concerted movement that leads to channel opening, or (ii) individual voltage-sensor movements lead to channel opening before all voltage sensors have moved. Here, we find that KCNQ1 voltage sensors move relatively independently, but that the channel can conduct before all voltage sensors have activated. We explore a KCNQ1 point mutation that causes some channels to transition to the open state even in the absence of voltage sensor movement. To interpret these results, we adopt an allosteric gating scheme wherein KCNQ1 is able to transition to the open state after zero to four voltage sensor movements. This model allows for widely varying gating behavior, depending on the relative strength of the opening transition, and suggests how KCNQ1 could be controlled by coassembly with different KCNE family members. PMID- 22509042 TI - ATP-independent substrate reduction by nitrogenase P-cluster variant. AB - The P-cluster of nitrogenase is largely known for its function to mediate electron transfer to the active cofactor site during catalysis. Here, we show that a P-cluster variant (designated P*-cluster), which consists of paired [Fe(4)S(4)]-like clusters, can catalyze ATP-independent substrate reduction in the presence of a strong reductant, europium(II) diethylenetriaminepentaacetate [Eu(II)-DTPA]. The observation of a decrease of activity in the rank DeltanifH, DeltanifBDeltanifZ, and DeltanifB MoFe protein, which corresponds to a decrease of the amount of P*-clusters in these cofactor-deficient proteins, firmly establishes P*-cluster as a catalytically active metal center in Eu(II)-DTPA driven reactions. More excitingly, the fact that P*-cluster is not only capable of catalyzing the two-electron reduction of proton, acetylene, ethylene, and hydrazine, but also capable of reducing cyanide, carbon monoxide, and carbon dioxide to alkanes and alkenes, points to a possibility of developing biomimetic catalysts for hydrocarbon production under ambient conditions. PMID- 22509043 TI - Different agonists recruit different stromal interaction molecule proteins to support cytoplasmic Ca2+ oscillations and gene expression. AB - Stimulation of cells with physiological concentrations of calcium-mobilizing agonists often results in the generation of repetitive cytoplasmic Ca(2+) oscillations. Although oscillations arise from regenerative Ca(2+) release, they are sustained by store-operated Ca(2+) entry through Ca(2+) release-activated Ca(2+) (CRAC) channels. Here, we show that following stimulation of cysteinyl leukotriene type I receptors in rat basophilic leukemia (RBL)-1 cells, large amplitude Ca(2+) oscillations, CRAC channel activity, and downstream Ca(2+) dependent nuclear factor of activated T cells (NFAT)-driven gene expression are all exclusively maintained by the endoplasmic reticulum Ca(2+) sensor stromal interaction molecule (STIM) 1. However, stimulation of tyrosine kinase-coupled FCepsilonRI receptors evoked Ca(2+) oscillations and NFAT-dependent gene expression through recruitment of both STIM2 and STIM1. We conclude that different agonists activate different STIM proteins to sustain Ca(2+) signals and downstream responses. PMID- 22509044 TI - Regulation of selective autophagy onset by a Ypt/Rab GTPase module. AB - The key regulators of intracellular trafficking, Ypt/Rab GTPases, are stimulated by specific upstream activators and, when activated, recruit specific downstream effectors to mediate membrane-transport events. The yeast Ypt1 and its human functional homolog hRab1 regulate both endoplasmic reticulum (ER)-to-Golgi transport and autophagy. However, it is not clear whether the mechanism by which these GTPases regulate autophagy depends on their well-documented function in ER to-Golgi transport. Here, we identify Atg11, the preautophagosomal structure (PAS) organizer, as a downstream effector of Ypt1 and show that the Ypt1-Atg11 interaction is required for PAS assembly under normal growth conditions. Moreover, we show that Ypt1 and Atg11 colocalize with Trs85, a Ypt1 activator subunit, and together they regulate selective autophagy. Finally, we show that Ypt1 and Trs85 interact on Atg9-containing membranes, which serve as a source for the membrane component of the PAS. Together our results define a Ypt/Rab module- comprising an activator, GTPase, and effector--that orchestrates the onset of selective autophagy, a process vital for cell homeostasis. Furthermore, because Atg11 does not play a role in ER-to-Golgi transport, we demonstrate here that Ypt/Rabs can regulate two independent membrane-transport processes by recruiting process-specific effectors. PMID- 22509045 TI - Membrane binding of Escherichia coli RNase E catalytic domain stabilizes protein structure and increases RNA substrate affinity. AB - RNase E plays an essential role in RNA processing and decay and tethers to the cytoplasmic membrane in Escherichia coli; however, the function of this membrane protein interaction has remained unclear. Here, we establish a mechanistic role for the RNase E-membrane interaction. The reconstituted highly conserved N terminal fragment of RNase E (NRne, residues 1-499) binds specifically to anionic phospholipids through electrostatic interactions. The membrane-binding specificity of NRne was confirmed using circular dichroism difference spectroscopy; the dissociation constant (K(d)) for NRne binding to anionic liposomes was 298 nM. E. coli RNase G and RNase E/G homologs from phylogenetically distant Aquifex aeolicus, Haemophilus influenzae Rd, and Synechocystis sp. were found to be membrane-binding proteins. Electrostatic potentials of NRne and its homologs were found to be conserved, highly positive, and spread over a large surface area encompassing four putative membrane-binding regions identified in the "large" domain (amino acids 1-400, consisting of the RNase H, S1, 5'-sensor, and DNase I subdomains) of E. coli NRne. In vitro cleavage assay using liposome-free and liposome-bound NRne and RNA substrates BR13 and GGG-RNAI showed that NRne membrane binding altered its enzymatic activity. Circular dichroism spectroscopy showed no obvious thermotropic structural changes in membrane-bound NRne between 10 and 60 degrees C, and membrane-bound NRne retained its normal cleavage activity after cooling. Thus, NRne membrane binding induced changes in secondary protein structure and enzymatic activation by stabilizing the protein-folding state and increasing its binding affinity for its substrate. Our results demonstrate that RNase E-membrane interaction enhances the rate of RNA processing and decay. PMID- 22509048 TI - Cardiac troponin I: a case study in rational antibody design for human diagnostics. AB - In vitro diagnostic (IVD) platforms provide rapid and accurate determination of disease status. The clinical performance of antibody-based diagnostic platforms is paramount as the information provided often informs the medical intervention taken and, ultimately, the patient's outcome. Breaking down such an immuno-IVD device into its component elements, the biorecognition entity is key to the analytical specificity of the test. Furthermore, tailored optimisation of the antibody is often necessary to impart the desired biophysical properties for the specific application. This tailoring is now widely facilitated by advances in combinatorial approaches to antibody generation, molecular evolution strategies and the availability of truly high-throughput (HT), refined surface plasmon resonance-based screening tools. In this paper, we demonstrate a rational, knowledge-driven approach to the generation of epitope-specific antibodies for the early detection of cardiovascular disease, discuss the merits of the approaches taken and offer a perspective on HT strategies to mining large antibody libraries. These results highlight the expedience of such methodologies for the development of truly superior cardiovascular disease biorecognition elements. PMID- 22509046 TI - Immunotoxin resistance via reversible methylation of the DPH4 promoter is a unique survival strategy. AB - HA22 is a recombinant immunotoxin composed of an anti-CD22 Fv fused to a portion of Pseudomonas exotoxin A. HA22 produced a high rate of complete remissions in drug-resistant hairy cell leukemia and has a lower response rate in pediatric acute lymphoblastic leukemia (ALL). To understand why patients with ALL have poorer responses, we isolated an ALL cell line that is resistant to killing by HA22. The resistance is unstable; without HA22 the cells revert to HA22 sensitivity in 4 mo. We showed that in the resistant cell line, HA22 is unable to ADP ribosylate and inactivate elongation factor-2 (EF2), owing to a low level of DPH4 mRNA and protein, which prevents diphthamide biosynthesis and renders EF2 refractory to HA22. Analysis of the promoter region of the DPH4 gene shows that the CpG island was hypomethylated in the HA22-sensitive cells, heavily methylated in the resistant cells, and reverted to low methylation in the revertant cells. Our data show that immunotoxin resistance is associated with reversible CpG island methylation and silencing of DPH4 gene transcription. Incubation of sensitive cells with the methylation inhibitor 5-azacytidine prevented the emergence of resistant cells, suggesting that this agent in combination with HA22 may be useful in the treatment of some cases of ALL. PMID- 22509047 TI - Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. AB - Although circulating memory T cells provide enhanced protection against pathogen challenge, they often fail to do so if infection is localized to peripheral or extralymphoid compartments. In those cases, it is T cells already resident at the site of virus challenge that offer superior immune protection. These tissue resident memory T (T(RM)) cells are identified by their expression of the alpha chain from the integrin alpha(E)(CD103)beta(7), and can exist in disequilibrium with the blood, remaining in the local environment long after peripheral infections subside. In this study, we demonstrate that long-lived intraepithelial CD103(+)CD8(+) T(RM) cells can be generated in the absence of in situ antigen recognition. Local inflammation in skin and mucosa alone resulted in enhanced recruitment of effector populations and their conversion to the T(RM) phenotype. The CD8(+) T(RM) cells lodged in these barrier tissues provided long-lived protection against local challenge with herpes simplex virus in skin and vagina challenge models, and were clearly superior to the circulating memory T-cell cohort. The results demonstrate that peripheral T(RM) cells can be generated and survive in the absence of local antigen presentation and provide a powerful means of achieving immune protection against peripheral infection. PMID- 22509049 TI - Effect of antioxidants on X-ray-induced gamma-H2AX foci in human blood lymphocytes: preliminary observations. AB - PURPOSE: To investigate the effect of a radioprotective oral agent containing a formulation of antioxidants and glutathione-elevating compounds on the extent of x-ray-induced gamma-H2AX foci formation. MATERIALS AND METHODS: The study was approved by local ethics committee and informed consent was obtained from each subject. In vitro experiments with blood lymphocytes of 25 healthy volunteers were performed without antioxidants and with antioxidants added either before or immediately after irradiation (10 mGy). For in vivo/in vitro tests, blood samples were obtained before, 15, 30, and 60 minutes (n=17) after, and 2, 3, and 5 hours (n=11) after oral ingestion of antioxidant pills and were irradiated (10 mGy). DNA double-strand breaks (DSBs) were quantified in isolated lymphocytes 5 minutes (in vitro and in vivo/in vitro) and 15 minutes (in vitro) after irradiation by enumerating gamma-H2AX foci. To validate the data, additional in vitro experiments with use of 53BP1 as another independent marker for DSBs were performed. Nonirradiated samples served as controls. Statistical analyses were performed by using Wilcoxon rank-sum tests (in vitro), repeated-measures test, and Dunnett test (in vivo/in vitro). RESULTS: In the in vitro experiments, 15 minute preincubation with antioxidants significantly reduced mean gamma-H2AX foci levels by 23% (P<.0001), whereas addition of antioxidants immediately after irradiation did not lead to a reduction of x-ray-induced foci (P=.6905). Mean 53BP1 foci were also reduced by preincubation with the radioprotectant. In the in vivo/in vitro tests, oral pretreatment with antioxidants also led to a significant reduction of gamma-H2AX foci formation; administration 60 minutes before irradiation resulted in a mean foci reduction of 58% (P<.0001). CONCLUSION: The tested formulation of antioxidants significantly reduced formation of gamma-H2AX and 53BP1 foci after irradiation at a radiologic radiation dose typical for computed tomographic imaging; administration 60 minutes prior to irradiation seems to be appropriate and leads to a significant reduction in foci. PMID- 22509051 TI - Hyperkalemic periodic paralysis and permanent weakness: 3-T MR imaging depicts intracellular 23Na overload--initial results. AB - PURPOSE: To assess whether myoplasmic ionic sodium (Na+) is increased in muscles of patients with hyperkalemic periodic paralysis (HyperPP) with 3-T sodium 23 (23Na) magnetic resonance (MR) imaging and to evaluate the effect of medical treatment on sodium-induced muscle edema. MATERIALS AND METHODS: This study received institutional review board approval; written informed consent was obtained. Proton (hydrogen 1 [1H]) and 23Na MR of both calves were performed in 12 patients with HyperPP (mean age, 48 years+/-14 [standard deviation]) and 12 healthy volunteers (mean age, 38 years+/-12) before and after provocation (unilateral cooling, one calf). 23Na MR included spin-density, T1-weighted, and inversion-recovery (IR) sequences. Total sodium concentration and normalized signal intensities (SIs) were evaluated within regions of interest (ROIs). Muscle strength was measured with the British Medical Research Council (MRC) grading scale. Five patients underwent follow-up MR after diuretic treatment. RESULTS: During rest, mean myoplasmic Na+ concentration was significantly higher in HyperPP with permanent weakness (40.7 MUmol/g+/-3.9) compared with HyperPP with transient weakness (31.3 MUmol/g+/-4.8) (P=.004). Mean SI in 23Na IR MR was significantly higher in HyperPP with permanent weakness (0.83+/-0.04; median MRC, grade 4; range, 3-5) compared with HyperPP without permanent weakness (0.67+/ 0.05; median MRC, grade 5; range, 4-5) (P=.002). Provocation reduced muscle strength in HyperPP (before provocation, median MRC, 5; range, 3-5; after provocation, median MRC, 3; range, 1-4) and increased SI in 23Na IR from 0.75+/ 0.09 to 0.86+/-0.10 (P=.004). Spin-density and T1-weighted sequences were less sensitive, particularly to cold-induced Na+ changes. 23Na IR SI remained unchanged in volunteers (0.53+/-0.06 before and 0.54+/-0.06 after provocation, P=.3). Therapy reduced mean SI in 23Na IR sequence from 0.85+/-0.04 to 0.64+/ 0.11. CONCLUSION: 23Na MR imaging depicts increased myoplasmic Na+ in HyperPP with permanent weakness. Na+ overload may cause muscle degeneration developing with age. 23Na MR imaging may have potential to aid monitoring of medical treatment that reduces this overload. PMID- 22509050 TI - Pulmonary arterial hypertension: MR imaging-derived first-pass bolus kinetic parameters are biomarkers for pulmonary hemodynamics, cardiac function, and ventricular remodeling. AB - PURPOSE: To prospectively compare contrast material-enhanced (CE) magnetic resonance (MR) imaging-derived right-to-left ventricle pulmonary transit time (PTT), left ventricular (LV) full width at half maximum (FWHM), and LV time to peak (TTP) between patients with pulmonary arterial hypertension (PAH) and healthy volunteers and to correlate these measurements with survival markers in patients with PAH. MATERIALS AND METHODS: This HIPAA-compliant study received institutional review board approval. Written informed consent was obtained from all participants. Forty-three patients (32 with PAH [29 women; median age, 55.4 years], 11 with scleroderma but not PAH [seven women; median age, 58.9 years]) underwent right-sided heart catheterization and 3-T CE cardiac MR imaging. Eighteen age- and sex-matched healthy control subjects (12 women; median age, 51.7 years) underwent only CE MR imaging. A short-axis saturation-recovery gradient-echo section was acquired in the basal third of both ventricles, and right-to-left-ventricle PTT, LV FWHM, and LV TTP were calculated. Statistical analysis included Kruskal-Wallis test, Wilcoxon rank sum test, Spearman correlation coefficient, multiple linear regression analysis, and Lin correlation coefficient analysis. RESULTS: Patients had significantly longer PTT (median, 8.2 seconds; 25th-75th percentile, 6.9-9.9 seconds), FWHM (median, 8.2 seconds; 25th 75th percentile, 5.7-11.4 seconds), and TTP (median, 4.8 seconds; 25th-75th percentile, 3.9-6.5 seconds) than did control subjects (median, 6.4 seconds; 25th 75th percentile, 5.7-7.1 seconds; median, 5.2 seconds; 25th-75th percentile, 4.1 6.1 seconds; median, 3.2 seconds; 25th-75th percentile, 2.8-3.8 seconds, respectively; P < .01 for each) and subjects with scleroderma but not PAH (median, 6.5 seconds; 25th-75th percentile, 5.6-7.0 seconds; median, 5.0 seconds; 25th-75th percentile, 4.0-7.3 seconds; median, 3.6 seconds; 25th-75th percentile, 2.7-4.0 seconds, respectively; P < .02 for each). PTT, LV FWHM, and LV TTP correlated with pulmonary vascular resistance index (P < .01), right ventricular stroke volume index (P <= .01), and pulmonary artery capacitance (P <= .02). In multiple linear regression models, PTT, FWHM, and TTP were associated with mean pulmonary arterial pressure and cardiac index. CONCLUSION: CE MR-derived PTT, LV FWHM, and LV TTP are noninvasive compound markers of pulmonary hemodynamics and cardiac function in patients with PAH. Their predictive value for patient outcome warrants further investigation. PMID- 22509053 TI - Review: depression is associated with an increased risk of developing stroke. PMID- 22509052 TI - Altered resting-state brain activity at functional MR imaging during the progression of hepatic encephalopathy. AB - PURPOSE: To explore the spatial patterns of the amplitude of low-frequency fluctuation (ALFF) in patients with hepatic encephalopathy (HE) of varying severity and to correlate these fluctuations with clinical markers of HE. MATERIALS AND METHODS: This study was approved by the local ethics committee, and written informed consent was obtained from all participants. Twenty-nine patients with HE (15 with overt and 14 with minimal HE) and 17 healthy control subjects underwent resting-state functional magnetic resonance (MR) imaging. The ALFF, an index reflecting the amplitudes of spontaneous brain activity, was compared among patients with overt HE, patients with minimal HE, and control subjects with analysis of variance tests and t tests between each pair. Pearson correlation analysis was performed between the ALFF and the venous blood ammonia level and Child-Pugh score of all patients with HE. RESULTS: Compared with control subjects, patients with overt and minimal HE showed decreased ALFF mainly in regions within the default-mode network (DMN) and increased ALFF in the cerebellum and middle temporal gyrus. Compared with patients with minimal HE, those with overt HE showed decreased ALFF in DMN regions and increased ALFF in the posterior insular cortex (P<.05, corrected for multiple comparisons). Both the venous blood ammonia levels and Child-Pugh scores of individual patients with HE showed negative correlation with ALFF within some DMN regions, whereas they showed positive correlation with ALFF in the posterior insular cortex (P<.05, corrected for multiple comparisons). CONCLUSION: Patients with HE have diffuse abnormalities in intrinsic brain activity. The levels of decreased ALFF in the DMN and increased ALFF in the posterior insular cortex are dependent on the severity of HE, suggesting continuous impairment of the DMN and a compensatory role of the insula during the progression of HE. Resting-state functional MR imaging with ALFF analysis may be a noninvasive modality with which to detect the progression of HE. PMID- 22509054 TI - Review: premorbid IQ is inversely associated with future risk of schizophrenia. PMID- 22509055 TI - Children with social phobia have distinct social skills deficit and vocal characteristics to children with Asperger's disorder and typically developing children. PMID- 22509056 TI - The risk of suicide attempt by a child or adolescent is highest after a contact with a psychiatric department. PMID- 22509058 TI - Biosensors: surface structures and materials. PMID- 22509059 TI - Theory, fabrication and applications of microfluidic and nanofluidic biosensors. AB - Biosensors are a broad array of devices that detect the type and amount of a biological species or biomolecule. Several different types of biosensors have been developed that rely on changes to mechanical, chemical or electrical properties of the transduction or sensing element to induce a measurable signal. Often, a biosensor will integrate several functions or unit operations such as sample extraction, manipulation and detection on a single platform. This review begins with an overview of the current state-of-the-art biosensor field. Next, the review delves into a special class of biosensors that rely on microfluidics and nanofluidics by presenting the underlying theory, fabrication and several examples and applications of microfluidic and nanofluidic sensors. PMID- 22509060 TI - Measurement of slip length on superhydrophobic surfaces. AB - In this paper, a review of different techniques used to measure the slip length on superhydrophobic surfaces with large slip length is presented. First, we present the theoretical models used to calculate the effective slip length on superhydrophobic surfaces in different configurations of liquid flow. Then, we present the different techniques used to measure the slip past these superhydrophobic surfaces: rheometry, particle image velocimetry, pressure drop, surface force apparatus and atomic force microscopy. PMID- 22509061 TI - Bioadhesion: a review of concepts and applications. AB - Bioadhesion refers to the phenomenon where natural and synthetic materials adhere to biological surfaces. An understanding of the fundamental mechanisms that govern bioadhesion is of great interest for various researchers who aim to develop new biomaterials, therapies and technological applications such as biosensors. This review paper will first describe various examples of the manifestation of bioadhesion along with the underlying mechanisms. This will be followed by a discussion of some of the methods for the optimization of bioadhesion. Finally, nanoscale and macroscale characterization techniques for the efficacy of bioadhesion and the analysis of failure surfaces are described. PMID- 22509062 TI - Designing nanostructured block copolymer surfaces to control protein adhesion. AB - The profile and conformation of proteins that are adsorbed onto a polymeric biomaterial surface have a profound effect on its in vivo performance. Cells and tissue recognize the protein layer rather than directly interact with the surface. The chemistry and morphology of a polymer surface will govern the protein behaviour. So, by controlling the polymer surface, the biocompatibility can be regulated. Nanoscale surface features are known to affect the protein behaviour, and in this overview the nanostructure of self-assembled block copolymers will be harnessed to control protein behaviour. The nanostructure of a block copolymer can be controlled by manipulating the chemistry and arrangement of the blocks. Random, A-B and A-B-A block copolymers composed of methyl methacrylate copolymerized with either acrylic acid or 2-hydroxyethyl methacrylate will be explored. Using atomic force microscopy (AFM), the surface morphology of these block copolymers will be characterized. Further, AFM tips functionalized with proteins will measure the adhesion of that particular protein to polymer surfaces. In this manner, the influence of block copolymer morphology on protein adhesion can be measured. AFM tips functionalized with antibodies to fibronectin will determine how the surfaces will affect the conformation of fibronectin, an important parameter in evaluating surface biocompatibility. PMID- 22509063 TI - Biofouling: lessons from nature. AB - Biofouling is generally undesirable for many applications. An overview of the medical, marine and industrial fields susceptible to fouling is presented. Two types of fouling include biofouling from organism colonization and inorganic fouling from non-living particles. Nature offers many solutions to control fouling through various physical and chemical control mechanisms. Examples include low drag, low adhesion, wettability (water repellency and attraction), microtexture, grooming, sloughing, various miscellaneous behaviours and chemical secretions. A survey of nature's flora and fauna was taken in order to discover new antifouling methods that could be mimicked for engineering applications. Antifouling methods currently employed, ranging from coatings to cleaning techniques, are described. New antifouling methods will presumably incorporate a combination of physical and chemical controls. PMID- 22509064 TI - Towards biodegradable wireless implants. AB - A new generation of partially or even fully biodegradable implants is emerging. The idea of using temporary devices is to avoid a second surgery to remove the implant after its period of use, thereby improving considerably the patient's comfort and safety. This paper provides a state-of-the-art overview and an experimental section that describes the key technological challenges for making biodegradable devices. The general considerations for the design and synthesis of biodegradable components are illustrated with radiofrequency-driven resistor inductor-capacitor (RLC) resonators made of biodegradable metals (Mg, Mg alloy, Fe, Fe alloys) and biodegradable conductive polymer composites (polycaprolactone polypyrrole, polylactide-polypyrrole). Two concepts for partially/fully biodegradable wireless implants are discussed, the ultimate goal being to obtain a fully biodegradable sensor for in vivo sensing. PMID- 22509066 TI - A new approach to gas sensing with nanotechnology. AB - Nanosized gas sensor elements are potentially faster, require lower power, come with a lower limit of detection, operate at lower temperatures, obviate the need for expensive catalysts, are more heat shock resistant and might even come at a lower cost than their macro-counterparts. In the last two decades, there have been important developments in two key areas that might make this promise a reality. First is the development of a variety of very good performing nanostructured metal oxide semiconductors (MOSs), the most commonly used materials for gas sensing; and second are advances in very low power loss miniaturized heater elements. Advanced nano- or micro-nanogas sensors have attracted much attention owing to a variety of possible applications. In this article, we first discuss the mechanism underlying MOS-based gas sensor devices, then we describe the advances that have been made towards MOS nanostructured materials and the progress towards low-power nano- and microheaters. Finally, we attempt to design an ideal nanogas sensor by combining the best nanomaterial strategy with the best heater implementation. In this regard, we end with a discussion of a suspended carbon nanowire-based gas sensor design and the advantages it might offer compared with other more conventional gas sensor devices. PMID- 22509065 TI - Monitoring the progression of metastatic breast cancer on nanoporous silica chips. AB - Breast cancer accounted for 15 per cent of total cancer deaths in female patients in 2010. Although significant progress has been made in treating early-stage breast cancer patients, there is still no effective therapy targeting late-stage metastatic breast cancers except for the conventional chemotherapy interventions. Until effective therapy for later-stage cancers emerges, the identification of biomarkers for the early detection of tumour metastasis continues to hold the key to successful management of breast cancer therapy. Our study concentrated on the low molecular weight (LMW) region of the serum protein and the information it contains for identifying biomarkers that could reflect the ongoing physiological state of all tissues. Owing to technical difficulties in harvesting LMW species, studying these proteins/peptides has been challenging until now. In our study, we have recently developed nanoporous chip-based technologies to separate small proteins/peptides from the large proteins in serum. We used nanoporous silica chips, with a highly periodic nanostructure and uniform pore size distribution, to isolate LMW proteins and peptides from the serum of nude mice with MDA-MB-231 human breast cancer lung metastasis. By matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and biostatistical analysis, we were able to identify protein signatures unique to different stages of cancer development. The approach and results reported in this study possess a significant potential for the discovery of proteomic biomarkers that may significantly enhance personalized medicine targeted at metastatic breast cancer. PMID- 22509067 TI - ImmunoFET feasibility in physiological salt environments. AB - Field-effect transistors (FETs) are solid-state electrical devices featuring current sources, current drains and semiconductor channels through which charge carriers migrate. FETs can be inexpensive, detect analyte without label, exhibit exponential responses to surface potential changes mediated by analyte binding, require limited sample preparation and operate in real time. ImmunoFETs for protein sensing deploy bioaffinity elements on their channels (antibodies), analyte binding to which modulates immunoFET electrical properties. Historically, immunoFETs were assessed infeasible owing to ion shielding in physiological environments. We demonstrate reliable immunoFET sensing of chemokines by relatively ion-impermeable III-nitride immunoHFETs (heterojunction FETs) in physiological buffers. Data show that the specificity of detection follows the specificity of the antibodies used as receptors, allowing us to discriminate between individual highly related protein species (human and murine CXCL9) as well as mixed samples of analytes (native and biotinylated CXCL9). These capabilities demonstrate that immunoHFETs can be feasible, contrary to classical FET-sensing assessment. FET protein sensors may lead to point-of-care diagnostics that are faster and cheaper than immunoassay in clinical, biotechnological and environmental applications. PMID- 22509068 TI - Radiation dose reduction in CT of the brain: can advanced noise filtering compensate for loss of image quality? AB - BACKGROUND: Computed tomography (CT) of the brain is performed with high local doses due to high demands on low contrast resolution. Advanced algorithms for noise reduction might be able to preserve critical image information when reducing radiation dose. PURPOSE: To evaluate the effect of advanced noise filtering on image quality in brain CT acquired with reduced radiation dose. MATERIAL AND METHODS: Thirty patients referred for non-enhanced CT of the brain were examined with two helical protocols: normal dose (ND, CTDI(vol) 57 mGy) and low dose (LD, CTDI(vol) 40 mGy) implying a 30% radiation dose reduction. Images from the LD examinations were also postprocessed with a noise reduction software with non-linear filters (SharpView CT), creating filtered low dose images (FLD) for each patient. The three image stacks for each patient were presented side by side in randomized order. Five radiologists, blinded for dose level and filtering, ranked these three axial image stacks (ND, LD, FLD) as best to poorest (1 to 3) regarding three image quality criteria. Measurements of mean Hounsfield units (HU) and standard deviation (SD) of the HU were calculated for large region of interest in the centrum semiovale as a measure for noise. RESULTS: Ranking results in pooled data showed that the advanced noise filtering significantly improved the image quality in FLD as compared to LD images for all tested criteria. No significant differences in image quality were found between ND examinations and FLD. However, there was a notable inter-reader spread of the ranking. SD values were 15% higher for LD as compared to ND and FLD. CONCLUSION: The advanced noise filtering clearly improves image quality of CT examinations of the brain. This effect can be used to significantly lower radiation dose. PMID- 22509069 TI - Slow light for deep tissue imaging with ultrasound modulation. AB - Slow light has been extensively studied for applications ranging from optical delay lines to single photon quantum storage. Here, we show that the time delay of slow-light significantly improves the performance of the narrowband spectral filters needed to optically detect ultrasound from deep inside highly scattering tissue. We demonstrate this capability with a 9 cm thick tissue phantom, having 10 cm(-1) reduced scattering coefficient, and achieve an unprecedented background free signal. Based on the data, we project real time imaging at video rates in even thicker phantoms and possibly deep enough into real tissue for clinical applications like early cancer detection. PMID- 22509070 TI - Photo-thermal polymerization of nanotube/polymer composites: Effects of load transfer and mechanical strength. AB - The authors report a method where in-situ photon assisted heating of multi-wall carbon nanotubes was utilized for enhanced polymerization of the nanotube/polydimethylsiloxane interface that resulted in significant load transfer and improved mechanical properties. Large Raman shifts (20 cm(-1) wavenumbers) of the 2D bands were witnessed for near-infrared light polymerized samples, signifying increased load transfer to the nanotubes for up to ~80% strains. An increase in elastic modulus of ~130% for 1 wt. % composites is reported for photon assisted crosslinking. PMID- 22509071 TI - High-throughput biological small-angle X-ray scattering with a robotically loaded capillary cell. AB - With the rise in popularity of biological small-angle X-ray scattering (BioSAXS) measurements, synchrotron beamlines are confronted with an ever-increasing number of samples from a wide range of solution conditions. To meet these demands, an increasing number of beamlines worldwide have begun to provide automated liquid handling systems for sample loading. This article presents an automated sample loading system for BioSAXS beamlines, which combines single-channel disposable tip pipetting with a vacuum-enclosed temperature-controlled capillary flow cell. The design incorporates an easily changeable capillary to reduce the incidence of X-ray window fouling and cross contamination. Both the robot-control and the data processing systems are written in Python. The data-processing code, RAW, has been enhanced with several new features to form a user-friendly BioSAXS pipeline for the robot. The flow cell also supports efficient manual loading and sample recovery. An effective rinse protocol for the sample cell is developed and tested. Fluid dynamics within the sample capillary reveals a vortex ring pattern of circulation that redistributes radiation-damaged material. Radiation damage is most severe in the boundary layer near the capillary surface. At typical flow speeds, capillaries below 2 mm in diameter are beginning to enter the Stokes (creeping flow) regime in which mixing due to oscillation is limited. Analysis within this regime shows that single-pass exposure and multiple-pass exposure of a sample plug are functionally the same with regard to exposed volume when plug motion reversal is slow. The robot was tested on three different beamlines at the Cornell High-Energy Synchrotron Source, with a variety of detectors and beam characteristics, and it has been used successfully in several published studies as well as in two introductory short courses on basic BioSAXS methods. PMID- 22509072 TI - Beyond Depression: Towards a Process-Based Approach to Research, Diagnosis, and Treatment. AB - Despite decades of research on the etiology and treatment of depression, a significant proportion of the population is affected by the disorder, fails to respond to treatment and is plagued by relapse. Six prominent scientists, Aaron Beck, Richard Davidson, Fritz Henn, Steven Maier, Helen Mayberg, and Martin Seligman, gathered to discuss the current state of scientific knowledge on depression, and in particular on the basic neurobiological and psychopathological processes at play in the disorder. These general themes were addressed: 1) the relevance of learned helplessness as a basic process involved in the development of depression; 2) the limitations of our current taxonomy of psychological disorders; 3) the need to work towards a psychobiological process-based taxonomy; and 4) the clinical implications of implementing such a process-based taxonomy. PMID- 22509073 TI - Pancreatic cancer: translational research aspects and clinical implications. AB - Despite improvements in surgical techniques and adjuvant chemotherapy, the overall mortality rates in pancreatic cancer have generally remained relatively unchanged and the 5-year survival rate is actually below 2%. This paper will address the importance of achieving an early diagnosis and identifying markers for prognosis and response to therapy such as genes, proteins, microRNAs or epigenetic modifications. However, there are still major hurdles when translating investigational biomarkers into routine clinical practice. Furthermore, novel ways of secondary screening in high-risk individuals, such as artificial neural networks and modern imaging, will be discussed. Drug resistance is ubiquitous in pancreatic cancer. Several mechanisms of drug resistance have already been revealed, including human equilibrative nucleoside transporter-1 status, multidrug resistance proteins, aberrant signaling pathways, microRNAs, stromal influence, epithelial-mesenchymal transition-type cells and recently the presence of cancer stem cells/cancer-initiating cells. These factors must be considered when developing more customized types of intervention ("personalized medicine"). In the future, multifunctional nanoparticles that combine a specific targeting agent, an imaging probe, a cell-penetrating agent, a biocompatible polymer and an anti-cancer drug may become valuable for the management of patients with pancreatic cancer. PMID- 22509074 TI - Worldwide epidemiology of liver hydatidosis including the Mediterranean area. AB - The worldwide incidence and prevalence of cystic echinococcosis have fallen dramatically over the past several decades. Nonetheless, infection with Echinococcus granulosus (E. granulosus) remains a major public health issue in several countries and regions, even in places where it was previously at low levels, as a result of a reduction of control programmes due to economic problems and lack of resources. Geographic distribution differs by country and region depending on the presence in that country of large numbers of nomadic or semi nomadic sheep and goat flocks that represent the intermediate host of the parasite, and their close contact with the final host, the dog, which mostly provides the transmission of infection to humans. The greatest prevalence of cystic echinococcosis in human and animal hosts is found in countries of the temperate zones, including several parts of Eurasia (the Mediterranean regions, southern and central parts of Russia, central Asia, China), Australia, some parts of America (especially South America) and north and east Africa. Echinococcosis is currently considered an endemic zoonotic disease in the Mediterranean region. The most frequent strain associated with human cystic echinococcosis appears to be the common sheep strain (G1). This strain appears to be widely distributed in all continents. The purpose of this review is to examine the distribution of E. granulosus and the epidemiology of a re-emerging disease such as cystic echinococcosis. PMID- 22509075 TI - Multidisciplinary imaging of liver hydatidosis. AB - Liver hydatidosis is a parasitic endemic disease affecting extensive areas in our planet, a significant stigma within medicine to manage because of its incidence, possible complications, and diagnostic involvements. The diagnosis of liver hydatidosis should be as fast as possible because of the relevant complications that may arise with disease progression, involving multiple organs and neighboring structures causing disruption, migration, contamination. The aim of this essay is to illustrate the role of imaging as ultrasonography (US), multi detector row computed tomography, and magnetic resonance imaging (MRI) in the evaluation of liver hydatidosis: the diagnosis, the assessment of extension, the identification of possible complications and the monitoring the response to therapy. US is the screening method of choice. Computed tomography (CT) is indicated in cases in which US is inadequate and has high sensitivity and specificity for calcified hydatid cysts. Magnetic resonance is the best imaging procedure to demonstrate a cystic component and to show a biliary tree involvement. Diagnostic tests such as CT and MRI are mandatory in liver hydatidosis because they allow thorough knowledge regarding lesion size, location, and relations to intrahepatic vascular and biliary structures, providing useful information for effective treatment and decrease in post operative morbidity. Hydatid disease is classified into four types on the basis of their radiologic appearance. PMID- 22509077 TI - Increased presence of effector lymphocytes during Helicobacter hepaticus-induced colitis. AB - AIM: To identify and characterize drosophila mothers against decapentaplegic (SMAD)3-dependent changes in immune cell populations following infection with Helicobacter hepaticus (H. hepaticus). METHODS: SMAD3(-/-) (n = 19) and colitis resistant SMAD3(+/-) (n = 24) mice (8-10 wk of age) were infected with H. hepaticus and changes in immune cell populations [T lymphocytes, natural killer (NK) cells, T regulatory cells] were measured in the spleen and mesenteric lymph nodes (MsLNs) at 0 d, 3 d, 7 d and 28 d post-infection using flow cytometry. Genotype-dependent changes in T lymphocytes and granzyme B(+) cells were also assessed after 28 d in proximal colon tissue using immunohistochemistry. RESULTS: As previously observed, SMAD3(-/-), but not SMAD3(+/-) mice, developed colitis, peaking at 4 wk post-infection. No significant changes in T cell subsets were observed in the spleen or in the MsLNs between genotypes at any time point. However, CD4(+) and CD8(+)/CD62L(lo) cells, an effector T lymphocyte population, as well as NK cells (NKp46/DX5(+)) were significantly higher in the MsLNs of SMAD3(-/-) mice at 7 d and 28 d post-infection. In the colon, a higher number of CD3(+) cells were present in SMAD3(-/-) compared to SMAD3(+/-) mice at baseline, which did not significantly change during infection. However, the number of granzyme B(+) cells, a marker of cytolytic lymphocytes, significantly increased in SMAD3(-/-) mice 28 d post-infection compared to both SMAD3(+/-) mice and to baseline values. This was consistent with more severe colitis development in these animals. CONCLUSION: Data suggest that defects in SMAD3 signaling increase susceptibility to H. hepaticus-induced colitis through aberrant activation and/or dysregulation of effector lymphocytes. PMID- 22509076 TI - Hepatic echinococcosis: clinical and therapeutic aspects. AB - Echinococcosis or hydatid disease (HD) is a zoonosis caused by the larval stages of taeniid cestodes belonging to the genus Echinococcus. Hepatic echinococcosis is a life-threatening disease, mainly differentiated into alveolar and cystic forms, associated with Echinoccus multilocularis (E. multilocularis) and Echinococcus granulosus (E. granulosus) infection, respectively. Cystic echinococcosis (CE) has a worldwide distribution, while hepatic alveolar echinococcosis (AE) is endemic in the Northern hemisphere, including North America and several Asian and European countries, like France, Germany and Austria. E. granulosus young cysts are spherical, unilocular vesicles, consisting of an internal germinal layer and an outer acellular layer. Cyst expansion is associated with a host immune reaction and the subsequent development of a fibrous layer, called the pericyst; old cysts typically present internal septations and daughter cysts. E. multilocularis has a tumor-like, infiltrative behavior, which is responsible for tissue destruction and finally for liver failure. The liver is the main site of HD involvement, for both alveolar and cystic hydatidosis. HD is usually asymptomatic for a long period of time, because cyst growth is commonly slow; the most frequent symptoms are fatigue and abdominal pain. Patients may also present jaundice, hepatomegaly or anaphylaxis, due to cyst leakage or rupture. HD diagnosis is usually accomplished with the combined use of ultrasonography and immunodiagnosis; furthermore, the improvement of surgical techniques, the introduction of minimally invasive treatments [such as puncture, aspiration, injection, re-aspiration (PAIR)] and more effective drugs (such as benzoimidazoles) have deeply changed life expectancy and quality of life of patients with HD. The aim of this article is to provide an up-to-date review of biological, diagnostic, clinical and therapeutic aspects of hepatic echinococcosis. PMID- 22509078 TI - Immunological milieu in the peritoneal cavity at laparotomy for gastric cancer. AB - AIM: To investigate the immunological repertoire in the peritoneal cavity of gastric cancer patients. METHODS: The peritoneal cavity is a compartment in which immunological host-tumor interactions can occur. However, the role of lymphocytes in the peritoneal cavity of gastric cancer patients is unclear. We observed 64 patients who underwent gastrectomy for gastric cancer and 11 patients who underwent laparoscopic cholecystectomy for gallstones and acted as controls. Lymphocytes isolated from both peripheral blood and peritoneal lavage were analyzed for surface markers of lymphocytes and their cytokine production by flow cytometry. CD4(+)CD25(high) T cells isolated from the patient's peripheral blood were co-cultivated for 4 d with the intra-peritoneal lymphocytes, and a cytokine assay was performed. RESULTS: At gastrectomy, CCR7(-) CD45RA(-) CD8(+) effector memory T cells were observed in the peritoneal cavity. The frequency of CD4(+) CD25 (high) T cells in both the peripheral blood and peritoneal cavity was elevated in patients at advanced stage [control vs stage IV in the peripheral blood: 6.89 (3.39-10.4) vs 15.34 (11.37-19.31), P < 0.05, control vs stage IV in the peritoneal cavity: 8.65 (5.28-12.0) vs 19.56 (14.81-24.32), P < 0.05]. On the other hand, the suppression was restored with CD4(+) CD25(high) T cells from their own peripheral blood. This study is the first to analyze lymphocyte and cytokine production in the peritoneal cavity in patients with gastric cancer. Immune regulation at advanced stage is reversible at the point of gastrectomy. CONCLUSION: The immunological milieu in the peritoneal cavity of patients with advanced gastric cancer elicited a Th2 response even at gastrectomy, but this response was reversible. PMID- 22509079 TI - Curcumin prevents indomethacin-induced gastropathy in rats. AB - AIM: To investigate the effects of curcumin on gastric microcirculation and inflammation in rats with indomethacin-induced gastric damage. METHODS: Male Sprague-Dawley rats were randomly divided into three groups. Group 1 (control group, n = 5) was fed with olive oil and 5% NaHCO(3) (-) (vehicle). Group 2 [indomethacin (IMN) group, n = 5] was fed with olive oil 30 min prior to indomethacin 150 mg/kg body weight (BW) dissolved in 5% NaHCO(3) (-) at time 0th and 4th h. Group 3 (IMN + Cur group, n = 4) was fed with curcumin 200 mg/kg BW dissolved in olive oil 0.5 mL, 30 min prior to indomethacin at 0th and 4th h. Leukocyte-endothelium interactions at postcapillary venules were recorded after acridine orange injection. Blood samples were determined for intercellular adhesion molecule (ICAM)-1 and tumor necrosis factor (TNF)-alpha levels using enzyme linked immunosorbent assay method. Finally, the stomach was removed for histopathological examination for gastric lesions and grading for neutrophil infiltration. RESULTS: In group 2, the leukocyte adherence in postcapillary venules was significantly increased compared to the control group (6.40 +/- 2.30 cells/frame vs 1.20 +/- 0.83 cells/frame, P = 0.001). Pretreatment with curcumin caused leukocyte adherence to postcapillary venule to decline (3.00 +/- 0.81 cells/frame vs 6.40 +/- 2.30 cells/frame, P = 0.027). The levels of ICAM-1 and TNF-alpha increased significantly in the indomethacin-treated group compared with the control group (1106.50 +/- 504.22 pg/mL vs 336.93 +/- 224.82 pg/mL, P = 0.011 and 230.92 +/- 114.47 pg/mL vs 47.13 +/- 65.59 pg/mL, P = 0.009 respectively). Pretreatment with curcumin significantly decreased the elevation of ICAM-1 and TNF-alpha levels compared to treatment with indomethacin alone (413.66 +/- 147.74 pg/mL vs 1106.50 +/- 504.22 pg/mL, P = 0.019 and 58.27 +/- 67.74 pg/mL vs 230.92 +/- 114.47 pg/mL, P = 0.013 respectively). The histological appearance of the stomach in the control group was normal. In the indomethacin-treated group, the stomachs showed a mild to moderate neutrophil infiltration score. Gastric lesions were erosive and ulcerative. In rats treated with indomethacin and curcumin, stomach histopathology improved and showed only a mild neutrophil infiltration score and fewer erosive lesions in the gastric mucosa. CONCLUSION: The results indicate that curcumin prevents indomethacin-induced gastropathy through the improvement of gastric microcirculation by attenuating the level of ICAM-1 and TNF-alpha. PMID- 22509080 TI - HBx activates FasL and mediates HepG2 cell apoptosis through MLK3-MKK7-JNKs signal module. AB - AIM: To investigate the possible mechanism by which hepatitis B virus X protein (HBx) mediates apoptosis of HepG2 cells. METHODS: HBx expression vector pcDNA3.1 X was transfected into HepG2 cells to establish an HBx high-expression cellular model as pcDNA3.1-X transfected group. The pcDNA3.1-X and pSilencer3.1-shHBX (HBx antagonist) were cotransfected into HepG2 cells to establish an HBx low expression model as RNAi group. Untransfected HepG2 cells and HepG2 cells transfected with negative control plasmid were used as controls. Apoptosis rate, the expression of Fas/FasL signaling pathway-related proteins and the phosphorylation levels of MLK3, MKK7 and JNKs, which are upstream molecules of death receptor pathways and belong to the family of mitogen-activated protein kinases (MAPKs), were measured in each group. RESULTS: Compared with HepG2 cell group and RNAi group, apoptosis rate, the expression of Fas and FasL proteins, and the activation of MLK3, MKK7 and JNKs were increased in the pcDNA3.1-X transfected group. The activation of JNKs and expression of FasL protein were inhibited in the pcDNA3.1-X transfected group when treated with a known JNK inhibitor, SP600125. When authors treated pcDNA3.1-X transfected group with K252a, a known MLK3 inhibitor, the activation of MLK3, MKK7 and JNKs as well as expression of FasL protein was inhibited. Furthermore, cell apoptosis rate was also significantly declined in the presence of K252a in the pcDNA3.1-X transfected group. CONCLUSION: HBx can induce HepG2 cell apoptosis via a novel active MLK3-MKK7-JNKs signaling module to upregulate FasL protein expression. PMID- 22509081 TI - Magnetic resonance imaging: a new tool for diagnosis of acute ischemic colitis? AB - AIM: To define the evolution of ischemic lesions with 7T magnetic resonance imaging (7T-MRI) in an animal model of acute colonic ischemia. METHODS: Adult Sprague-Dawley rats were divided into two groups. Group I underwent inferior mesenteric artery (IMA) ligation followed by macroscopic observations and histological analysis. In group II, 7T-MRI was performed before and after IMA ligation and followed by histological analysis. RESULTS: Morphological alterations started to develop 1 h after IMA ligation, when pale areas became evident in the splenic flexure mesentery and progressively worsened up to 8 h thereafter, when the mesentery was less pale, and the splenic flexure loop appeared very dark. The 7T-MRI results reflected these alterations, showing a hyperintense signal in both the intraperitoneal space and the colonic loop wall 1 h after IMA ligation; the latter progressively increased to demonstrate a reduction in the colonic loop lumen at 6 h. Eight hours after IMA ligation, MRI showed a persistent colonic mural hyperintensity associated with a reduction in peritoneal free fluid. The 7T-MRI findings were correlated with histological alterations, varying from an attenuated epithelium with glandular apex lesions at 1 h to coagulative necrosis and loss of the surface epithelium detected 8 h after IMA ligation. CONCLUSION: MRI may be used as a substitute for invasive procedures in diagnosing and grading acute ischemic colitis, allowing for the early identification of pathological findings. PMID- 22509082 TI - Diagnostic yield of small bowel capsule endoscopy depends on the small bowel transit time. AB - AIM: To investigate whether the small bowel transit time (SBTT) influences the diagnostic yield of capsule endoscopy (CE). METHODS: Six hundred and ninety-one consecutive CE procedures collected in a database were analyzed. SBTT and CE findings were recorded. A running mean for the SBTT was calculated and correlated to the diagnostic yield with a Spearman's correlation test. Subgroup analyses were performed for the various indications for the procedure. RESULTS: There was a positive correlation between the diagnostic yield and SBTT (Spearman's rho 0.58, P < 0.01). Positive correlations between diagnostic yield and SBTT were found for the indication obscure gastrointestinal bleeding (r = 0.54, P < 0.01), for polyposis and carcinoid combined (r = 0.56, P < 0.01) and for the other indications (r = 0.90, P <0.01), but not for suspected Crohn's disease (r = 0.40). CONCLUSION: The diagnostic yield in small bowel capsule endoscopy is positively correlated with the small bowel transit time. This is true for all indications except for suspected Crohn's disease. PMID- 22509083 TI - Identification of individuals with non-alcoholic fatty liver disease by the diagnostic criteria for the metabolic syndrome. AB - AIM: To clarify the efficiency of the criterion of metabolic syndrome to detecting non-alcoholic fatty liver disease (NAFLD). METHODS: Authors performed a cross-sectional study involving participants of a medical health checkup program including abdominal ultrasonography. This study involved 11 714 apparently healthy Japanese men and women, 18 to 83 years of age. NAFLD was defined by abdominal ultrasonography without an alcohol intake of more than 20 g/d, known liver disease, or current use of medication. The revised criteria of the National Cholesterol Education Program Adult Treatment Panel III were used to characterize the metabolic syndrome. RESULTS: NAFLD was detected in 32.2% (95% CI: 31.0% 33.5%) of men (n = 1874 of 5811) and in 8.7% (95% CI: 8.0%-9.5%) of women (n = 514 of 5903). Among obese people, the prevalence of NAFLD was as high as 67.3% (95% CI: 64.8%-69.7%) in men and 45.8% (95% CI: 41.7%-50.0%) in women. Although NAFLD was thought of as being the liver phenotype of metabolic syndrome, the prevalence of the metabolic syndrome among subjects with NAFLD was low both in men and women. 66.8% of men and 70.4% of women with NAFLD were not diagnosed with the metabolic syndrome. 48.2% of men with NAFLD and 49.8% of women with NAFLD weren't overweight [body mass index (BMI) >= 25 kg/m(2)]. In the same way, 68.6% of men with NAFLD and 37.9% of women with NAFLD weren't satisfied with abdominal classification (>= 90 cm for men and >= 80 cm for women). Next, authors defined it as positive at screening for NAFLD when participants satisfied at least one criterion of metabolic syndrome. The sensitivity of the definition "at least 1 criterion" was as good as 84.8% in men and 86.6% in women. Separating subjects by BMI, the sensitivity was higher in obese men and women than in non-obese men and women (92.3% vs 76.8% in men, 96.1% vs 77.0% in women, respectively). CONCLUSION: Authors could determine NAFLD effectively in epidemiological study by modifying the usage of the criteria for metabolic syndrome. PMID- 22509084 TI - Comparison of PPIs and H2-receptor antagonists plus prokinetics for dysmotility like dyspepsia. AB - AIM: To compare efficacy of proton pump inhibitors (PPIs) with H(2)-receptor antagonists (H(2)RAs) plus prokinetics (Proks) for dysmotility-like symptoms in functional dyspepsia (FD). METHODS: Subjects were randomized to receive open label treatment with either rabeprazole 10 mg od (n = 57) or famotidine 10 mg bid plus mosapride 5 mg tid (n = 57) for 4 wk. The primary efficacy endpoint was change (%) from baseline in total dysmotility-like dyspepsia symptom score. The secondary efficacy endpoint was patient satisfaction with treatment. RESULTS: The improvement in dysmotility-like dyspepsia symptom score on day 28 was significantly greater in the rabeprazole group (22.5% +/- 29.2% of baseline) than the famotidine + mosapride group (53.2% +/- 58.6% of baseline, P < 0.0001). The superior benefit of rabeprazole treatment after 28 d was consistent regardless of Helicobacter pylori status. Significantly more subjects in the rabeprazole group were satisfied or very satisfied with treatment on day 28 than in the famotidine + mosapride group (87.7% vs 59.6%, P = 0.0012). Rabeprazole therapy was the only significant predictor of treatment response (P < 0.0001), defined as a total symptom score improvement >= 50%. CONCLUSION: PPI monotherapy improves dysmotility-like symptoms significantly better than H(2)RAs plus Proks, and should be the treatment of first choice for Japanese FD. PMID- 22509085 TI - Noninvasive parameters and hepatic fibrosis scores in children with nonalcoholic fatty liver disease. AB - AIM: To evaluate the noninvasive parameters and hepatic fibrosis scores in obese children with nonalcoholic fatty liver disease (NAFLD). METHODS: A total of 77 children diagnosed with NAFLD via liver biopsy were included and divided into 2 subgroups according to the histopathologic staging of hepatic fibrosis: mild (stage 0-1) vs significant fibrosis (stage 2-4). Clinical and laboratory parameters were evaluated in each patient. The aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, AST/platelet ratio index (APRI), PGA index, Forns index, FIB-4, NAFLD fibrosis score, and pediatric NAFLD fibrosis index (PNFI) were calculated. RESULTS: No clinical or biochemical parameter exhibited a significant difference between patients with mild and significant fibrosis. Among noninvasive hepatic fibrosis scores, only APRI and FIB4 revealed a significant difference between patients with mild and significant fibrosis (APRI: 0.67 +/- 0.54 vs 0.78 +/- 0.38, P = 0.032 and FIB4: 0.24 +/- 0.12 vs 0.31 +/- 0.21, P = 0.010). The area under the receiving operating characteristic curve of FIB4 was 0.81, followed by Forns index (0.73), APRI (0.70), NAFLD fibrosis score (0.58), AST/ALT ratio (0.53), PGA score (0.45), and PNFI (0.41). CONCLUSION: APRI and FIB4 might be useful noninvasive hepatic fibrosis scores for predicting hepatic fibrosis in children with NAFLD. PMID- 22509086 TI - Clinical implication of 14-3-3 epsilon expression in gastric cancer. AB - AIM: To evaluate for the first time the protein and mRNA expression of 14-3 3epsilon in gastric carcinogenesis. METHODS: 14-3-3epsilon protein expression was determined by western blotting, and mRNA expression was examined by real-time quantitative RT-PCR in gastric tumors and their matched non-neoplastic gastric tissue samples. RESULTS: Authors observed a significant reduction of 14-3 3epsilon protein expression in gastric cancer (GC) samples compared to their matched non-neoplastic tissue. Reduced levels of 14-3-3epsilon were also associated with diffuse-type GC and early-onset of this pathology. Our data suggest that reduced 14-3-3epsilon may have a role in gastric carcinogenesis process. CONCLUSION: Our results reveal that the reduced 14-3-3epsilon expression in GC and investigation of 14-3-3epsilon interaction partners may help to elucidate the carcinogenesis process. PMID- 22509087 TI - Pancreatic schwannoma: Case report and an updated 30-year review of the literature yielding 47 cases. AB - Pancreatic schwannomas are rare neoplasms. Authors briefly describe a 64-year-old female patient with cystic pancreatic schwannoma mimicking other cystic tumors and review the literature. Databases for PubMed were searched for English language articles from 1980 to 2010 using a list of keywords, as well as references from review articles. Only 41 articles, including 47 cases, have been reported in the English literature. The mean age was 55.7 years (range 20-87 years), with 45% of patients being male. Mean tumor size was 6.2 cm (range 1-20 cm). Tumor location was the head (40%), head and body (6%), body (21%), body and tail (15%), tail (4%), and uncinate process (13%). Thirty-four percent of patients exhibited solid tumors and 60% of patients exhibited cystic tumors. Treatment included pancreaticoduodenectomy (32%), distal pancreatectomy (21%), enucleation (15%), unresectable (4%), refused operation (2%) and the detail of resection was not specified in 26% of patients. No patients died of disease with a mean follow-up of 15.7 mo (range 3-65 mo), although 5 (11%) patients had a malignancy. The tumor size was significantly related to malignant tumor (13.8 +/- 6.2 cm for malignancy vs 5.5 +/- 4.4 cm for benign, P = 0.001) and cystic formation (7.9 +/- 5.9 cm for cystic tumor vs 3.9 +/- 2.4 cm for solid tumor, P = 0.005). The preoperative diagnosis of pancreatic schwannoma remains difficult. Cystic pancreatic schwannomas should be considered in the differential diagnosis of cystic neoplasms and pseudocysts. In our case, intraoperative frozen section confirmed the diagnosis of a schwannoma. Simple enucleation may be adequate, if this is possible. PMID- 22509088 TI - Esophageal combined carcinomas: Immunohoistochemical and molecular genetic studies. AB - Primary esophageal combined carcinoma is very rare. The authors herein report 2 cases. Case 1 was a combined squamous cell carcinoma and small cell carcinoma, and case 2 was a combined squamous cell carcinoma, adenocarcinoma, and small cell carcinoma. Case 1 was a 67-year-old man with complaints of dysphagia. Endoscopic examination revealed an ulcerated tumor in the middle esophagus, and 6 biopsies were obtained. All 6 biopsies revealed a mixture of squamous cell carcinoma and small cell carcinoma. Both elements were positive for cytokeratin, epithelial membrane antigen, and p53 protein, and had high Ki-67 labeling. The small cell carcinoma element was positive for synaptophysin, CD56, KIT, and platelet-derived growth factor-alpha (PDGFRA), while the squamous cell carcinoma element was not. Genetically, no mutations of KIT and PDGFRA were recognized. The patient died of systemic carcinomatosis 15 mo after presentation. Case 2 was a 74-year-old man presenting with dysplasia. Endoscopy revealed a polypoid tumor in the distal esophagus. Seven biopsies were taken, and 6 showed a mixture of squamous cell carcinoma, small cell carcinoma, and adenocarcinoma. The 3 elements were positive for cytokeratins, epithelial membrane antigen, and p53 protein, and had high Ki 67 labeling. The adenocarcinoma element was positive for mucins. The small cell carcinoma element was positive for CD56, synaptophysin, KIT, and PDGFRA, but the other elements were not. Mutations of KIT and PDGFRA were not recognized. The patient died of systemic carcinomatosis 7 mo after presentation. These combined carcinomas may arise from enterochromaffin cells or totipotential stem cell in the esophagus or transdifferentiation of one element to another. A review of the literature was performed. PMID- 22509089 TI - Esophageal space-occupying lesion caused by Ascaris lumbricoides. AB - Ascaris lumbricoides is the largest intestinal nematode parasite of man, which can lead to various complications because of its mobility. As the esophagus is not normal habitat of Ascaris, the report of esophageal ascariasis is rare. An old female presented with dysphagia after an intake of several red bean buns and haw jellies. The barium meal examination revealed a spherical defect in the lower esophagus. Esophageal bezoar or esophageal carcinoma was considered at the beginning. The patient fasted, and received fluid replacement treatment as well as some oral drugs such as proton pump inhibitor and sodium bicarbonate. Then upper gastrointestinal endoscopy was done to further confirm the diagnosis and found a live Ascaris lumbricoides in the gastric antrum and two in the duodenal bulb. The conclusive diagnosis was ascariasis. The esophageal space-occupying lesion might be the entangled worm bolus. Anthelmitnic treatment with mebendazole improved patient's clinical manifestations along with normalization of the radiological findings during a 2-wk follow-up. Authors report herein this rare case of Ascaris lumbricoides in the esophagus, emphasizing the importance of awareness of this parasitic infection as it often presents with different and unspecific symptoms. PMID- 22509090 TI - Comparison of anomalous Doppler resonance effects with molybdenum and graphite limiters on HT-7. AB - The material of limiter in HT-7 tokamak was changed from graphite to molybdenum in the last experimental campaign. The pitch angle scattering of runaway electrons due to anomalous Doppler resonance effects was observed. The experimental results agree very well with the stable boundary condition expected from the linear resistive theory but only agree with that from the nonlinear evolutionary of runaway-electron distribution theory in low electric field region. The current carried by runaway electrons is the same under different limiter conditions. PMID- 22509091 TI - Are medical students accepted by patients in teaching hospitals? AB - BACKGROUND: Worldwide, patients are the cornerstone of bedside teaching of medical students. In this study, the authors aimed to assess patients' acceptability toward medical students in teaching hospitals of the Faculty of Medicine of Kuwait University. METHODS: Ninehundred and ninety five patients were approached in 14 teaching hospitals; 932 patients agreed to participate (refusal rate is 6.3%). A self-administered questionnaire was used to collect data. RESULTS: In general, higher acceptance of students by patients was found when there is no direct contact between the patient and the student (e.g., reading patients' files, presenting in outpatient clinic, observing doctors performing examination or procedures) compared to other situations (e.g., performing physical examination or procedures). Pediatrics patients showed higher acceptance of students compared to patients in other specialties, while Obstetrics/Gynecology patients showed the highest refusal of students. Gender of patients (especially females) and students appeared to affect the degree of acceptance of medical students by patients. Majority of the patients (436; 46.8%) believed that the presence of medical students in hospitals improves the quality of health care. CONCLUSION: Patients are an important factor of bedside teaching. Clinical tutors must take advantage of patients who accept medical students. Clinical tutors and medical students should master essential communication skills to convince patients in accepting students, thus improving bedside teaching. Also, using simulation and standardization should be considered to address scenarios that most patients are unwilling to allow students to participate. PMID- 22509092 TI - Aqueous cytokine and chemokine analysis in uveitis associated with tuberculosis. AB - PURPOSE: The aim of this study was to study the aqueous cytokine and chemokine composition in patients with uveitis associated with tuberculosis (TAU). METHODS: We present a prospective case series of consecutive new patients with active uveitis presenting at a single tertiary center (January 1, 2008-January 1, 2010). Patients with no ocular pathology other than cataracts were enrolled as non inflammatory controls. Aqueous samples were taken from all study subjects and analyzed using a magnetic color-bead-based multiplex assay for cytokine and chemokine concentrations. RESULTS: Twenty-five eyes of 25 patients with active uveitis with suspected tuberculosis (TB) and 23 non-inflammatory controls were enrolled. Ten patients tested positive on a tuberculin skin test and interferon gamma release assay; all ten patients responded to anti-TB treatment with no recurrences (TAU). The remaining 15 eyes were negative for the above tests and had no other underlying causes for uveitis found on clinical evaluation and investigations; therefore, they were classified as "idiopathic uveitis" (IU). The TAU group showed significantly higher levels of interleukin-6 (IL-6; p=0.047), interleukin-8 (CXCL8; p=0.001), monokine induced by interferon-gamma (CXCL9; p=0.001), and interferon-gamma-induced protein 10 (IP-10 or CXCL10; p=0.002), compared to the controls. The IU group showed significantly higher levels of IL-6 (p=0.008), monocyte chemotactic protein-1 (CCL2; p=0.036), CXCL8 (p=0.001), and IL-9 (p=0.045), and significantly lower levels of IL-2 (p=0.011), IL-12 (p=0.001), and tumor necrosis factor (TNF)-alpha (p=0.001), compared to the controls. Heat map analysis revealed significant differences in aqueous cytokine and chemokine concentrations among the TAU patients, the IU patients, and the controls. CONCLUSIONS: In our study population, aqueous cytokine and chemokine analyses suggest that subjects with uveitis associated with TB who respond to anti-TB therapy do not have an active ocular tuberculous infection, but rather an autoimmune-related ocular inflammation that may be triggered by TB. PMID- 22509093 TI - NOD2/CARD15 gene mutation identified in a Chinese family with Blau syndrome. AB - PURPOSE: To characterize the clinical features of a Chinese pedigree with Blau syndrome and to identify mutations in the NOD2/CARD15 (nucleotide-binding oligomerization domain containing 2/caspase recruitment domain family, member 15) gene. METHODS: Clinical features of this family were evaluated. Genomic DNA was obtained from blood samples, and all exons of NOD2/CARD15 were amplified by polymerase chain reaction (PCR) and direct DNA sequencing of PCR products was performed for mutations in NOD2/CARD15. RESULTS: Granulomatous arthritis, uveitis, and skin granulomas were found in all affected members. Sequencing analysis demonstrated a heterozygous C>T mutation in exon 4 of NOD2/CARD15 in all patients of this pedigree, which resulted in an amino acid substitution at position 334 (p.R334W). CONCLUSIONS: The R334W mutation in NOD2/CARD15 caused Blau syndrome in a Chinese pedigree. This is the first report of R334W mutation in NOD2/CARD15 in a Chinese pedigree of this disease. PMID- 22509095 TI - Association of insulin-like growth factor-1 polymorphisms with high myopia in the Chinese population. AB - PURPOSE: The purpose of this study was to determine whether genetic variants in the insulin-like growth factor-1 (IGF-1) gene were associated with high myopia in the Chinese population. METHODS: A case-control association study of 421 unrelated Chinese patients with high myopia and 401 control subjects matched in ethnicity and gender was undertaken. Genomic DNA was prepared from peripheral blood. All individuals were genotyped for 7 tag single nucleotide polymorphisms (tSNPs) across the IGF-1 gene region. Genotypic distribution was tested for Hardy Weinberg equilibrium. The genotype and allele frequencies were evaluated using the chi(2) tests. Bonferroni corrections for multiple comparisons were performed. RESULTS: The polymorphism of rs12423791 showed positive association with extreme myopia (p(allel)=0.006 and p(allel1 recessive model)=0.004, respectively) after Bonferroni correction for multiple testing and the haplotype GC of rs5742629 rs12423791 was also associated with extreme myopia (p=0.033) after 50,000 permutations for multiple comparisons. CONCLUSIONS: The polymorphism of rs12423791 in IGF-1 may be associated with extreme myopia in the Chinese population and should be investigated further. PMID- 22509094 TI - Topical application of FTY720 and cyclosporin A prolong corneal graft survival in mice. AB - PURPOSE: To investigate the effects of topical FTY720 and cyclosporin A (CsA) on allogeneic corneal transplantation in mice. METHODS: A total of 75 BALB/c mice received corneal grafts from C57BL/6 donors. Recipients were treated with 0.1%, 0.3%, or 0.5% FTY720 ophthalmic gel or 1% CsA eye-drops after the graft (controls received no treatment). The number of cluster of differentiation (CD)4+ T cells and CD4+CD25+forkhead box P3 (Foxp3)+ regulatory (Treg) cell phenotypes were measured by flow cytometry. Cytokine mRNA expression in corneal grafts was analyzed by real-time quantitative PCR. CD4 + T cells and cytokines in corneal samples were identified by immunohistochemical staining. RESULTS: Corneal graft survival was prolonged by treatment with topical 0.5% FTY720 (mean survival time [MST], 24.1+/-1.6 days) or 1% CsA eye-drops (MST 25.0+/-1.9 days) compared with controls (MST, 13.4+/-0.5 days; n=9, both p<0.01). Topical 0.5% FTY720 treatment significantly increased the percentages of CD4 + T (p<0.05) and Treg cells (p<0.01; n=5) in the cervical lymph nodes compared with controls. Transforming growth factor-beta1 (TGF-beta1) mRNA transcription in corneal grafts after topical 0.5% FTY720 increased (p<0.05, n=3), while interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) mRNA expression in corneal grafts treated with 1% CsA decreased (p<0.01, p<0.05, respectively). These cytokine results were paralleled by similar immunohistochemical staining. Topical 0.5% FTY720 and 1% CsA treatment reduced the infiltration of CD4+ Tcells in the grafts. CONCLUSIONS: Topical 0.5% FTY720 and 1% CsA can effectively prolong allogeneic corneal graft survival in mice. Treatment with topical 0.5% FTY720 increases the percentage of CD4+ T cells and the percentage of Treg cells in cervical lymph nodes. The 0.5% FTY720 increased TGF-beta1 mRNA expression and decreases infiltration of CD4+ T cells in corneal grafts, while topical 1% CsA down-regulated the expression of IL 2 and IFN-gamma. PMID- 22509096 TI - Identification of Wnt/beta-catenin modulated genes in the developing retina. AB - PURPOSE: During mammalian eye development, the restriction of Wnt/beta-catenin signaling at the junction of the neural retina and the retinal pigment epithelium in the peripheral eyecup is required for the development of the ciliary margin, a non-neural region of the eyecup that is the precursor of the ciliary body and iris of the adult eye. METHODS: To identify genes that are modulated by beta catenin activity in the embryonic retina, we performed gene expression profiling in Li(+)-treated retinal explants, a pharmacological model of beta-catenin activation. The Li(+)-modulated gene data set was searched for beta-catenin/T cell specific transcription factor binding sites. RESULTS: Functional annotations of this data set revealed significant enrichments for genes involved in chromatin organization, neurogenesis, and cell motion/migration. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis confirmed the modulation of 12 genes in Li(+)-treated explants and retinas of mice with Cre-mediated induction of constitutively active beta-catenin (beta-cat(act)). In situ hybridization revealed beta-catenin-specific upregulation of cyclin-dependent kinase inhibitor 1A (P21) [Cdkn1a] and tumor necrosis factor receptor superfamily, member 19 (Tnfrsf19) in the developing retina consistent with the antineurogenic and proliferation changes associated with ectopic Wnt/beta-catenin signaling in the eyecup. CONCLUSIONS: This data set of Li(+)-modulated genes provides a valuable resource for characterizing the Wnt/ beta-catenin regulated gene network in eyecup patterning. PMID- 22509097 TI - Multicenter cohort association study of SLC2A1 single nucleotide polymorphisms and age-related macular degeneration. AB - PURPOSE: Age-related macular degeneration (AMD) is a major cause of blindness in older adults and has a genetically complex background. This study examines the potential association between single nucleotide polymorphisms (SNPs) in the glucose transporter 1 (SLC2A1) gene and AMD. SLC2A1 regulates the bioavailability of glucose in the retinal pigment epithelium (RPE), which might influence oxidative stress-mediated AMD pathology. METHODS: Twenty-two SNPs spanning the SLC2A1 gene were genotyped in 375 cases and 199 controls from an initial discovery cohort (the Amsterdam-Rotterdam-Netherlands study). Replication testing was performed in The Rotterdam Study (the Netherlands) and study populations from Wurzburg (Germany), the Age Related Eye Disease Study (AREDS; United States), Columbia University (United States), and Iowa University (United States). Subsequently, a meta-analysis of SNP association was performed. RESULTS: In the discovery cohort, significant genotypic association between three SNPs (rs3754219, rs4660687, and rs841853) and AMD was found. Replication in five large independent (Caucasian) cohorts (4,860 cases and 4,004 controls) did not yield consistent association results. The genotype frequencies for these SNPs were significantly different for the controls and/or cases among the six individual populations. Meta-analysis revealed significant heterogeneity of effect between the studies. CONCLUSIONS: No overall association between SLC2A1 SNPs and AMD was demonstrated. Since the genotype frequencies for the three SLC2A1 SNPs were significantly different for the controls and/or cases between the six cohorts, this study corroborates previous evidence that population dependent genetic risk heterogeneity in AMD exists. PMID- 22509098 TI - Retinal compensatory changes after light damage in albino mice. AB - PURPOSE: To investigate the anatomic and functional changes triggered by light exposure in the albino mouse retina and compare them with those observed in the albino rat. METHODS: BALB/c albino mice were exposed to 3,000 lx of white light during 24 h and their retinas analyzed from 1 to 180 days after light exposure (ALE). Left pupil mydriasis was induced with topical atropine. Retinal function was analyzed by electroretinographic (ERG) recording. To assess retinal degeneration, hematoxylin and eosin staining, the TdT-mediated dUTP nick-end labeling (TUNEL) technique, and quantitative immunohistofluorescence for synaptophysin and protein kinase Calpha (PKCalpha) were used in cross sections. Intravenous injection of horseradish peroxidase and Fluoro-GoldTM tracing were used in whole-mounted retinas to study the retinal vasculature and the retinal ganglion cell (RGC) population, respectively. RESULTS: Light exposure caused apoptotic photoreceptor death in the central retina. This death was more severe in the dorsal than in the ventral retina, sparing the periphery. Neither retinal vascular leakage nor retinal ganglion cell death was observed ALE. The electroretinographic a-wave was permanently impaired, while the b-wave decreased but recovered gradually by 180 days ALE. The scotopic threshold responses, associated with the inner retinal function, diminished at first but recovered completely by 14 days ALE. This functional recovery was concomitant with the upregulation of protein kinase Calpha and synaptophysin. Similar results were obtained in both eyes, irrespective of mydriasis. CONCLUSIONS: In albino mice, light exposure induces substantial retinal damage, but the surviving photoreceptors, together with compensatory morphological/molecular changes, allow an important restoration of the retinal function. PMID- 22509099 TI - Proteomic analysis of SRA01/04 transfected with wild-type and mutant HSF4b identified from a Chinese congenital cataract family. AB - PURPOSE: Congenital cataracts account for about 10% of cases of childhood blindness. Heat shock transcription factor 4 (HSF4) is related with human autosomal dominant lamellar and Marner cataracts; a T->C transition at nucleotide 348 was found in a large Chinese cataract family. The aim of this study was to analyze the unique role of HSF4b and the mutation of HSF4b. METHODS: The isobaric tags for relative and absolute quantification (iTRAQ), coupled with the two dimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS) technique, was used to identify and quantify differential proteomes in human lens epithelial cell lines SRA 01/04 expressing wild-type and mutant HSF4b. RESULTS: A total of 104 unique proteins were identified from the human lens epithelial cell lines SRA 01/04. Apart from the proteins due to the effect of the pcDNA3.1 vector, the wild-type and mutant HSF4b led to 23 differentially expressed proteins, of which four were histone proteins and three were ribosomal proteins. The T->C transition at nucleotide 348 in HSF4b led to 18 differentially expressed proteins in SRA 01/04, among which serpin H1 precursor, heat shock protein beta 1, and stress-70 protein belong to heat shock protein families. The up- or down regulated proteins were functionally analyzed using Ingenuity Pathways Analysis (IPA) to interpret the interaction network and predominant canonical pathways involved in these differentially expressed proteins. CONCLUSIONS: A multitude of differentially expressed proteins was found to be associated with HSF4b and a T >C transition at nucleotide 348 in HSF4b. The proteins interacted directly or indirectly with each other, and they may provide clues as to how HSF4b modulates protein expression in the lens epithelial cells of SRA 01/04. Although further investigation is required, the results may provide some new clues to the transcriptional mechanism of HSF4b and cataract formation. PMID- 22509100 TI - Localization of SH3PXD2B in human eyes and detection of rare variants in patients with anterior segment diseases and glaucoma. AB - PURPOSE: Analysis of mutant mouse strains and linkage analysis with human families have both demonstrated that mutations influencing the podosomal adaptor protein SH3 and PX domains 2B (SH3PXD2B) can result in a congenital form of glaucoma. Here, we use immunohistochemistry to describe localization of the SH3PXD2B protein throughout the adult human eye and test whether sequence variants in SH3PXD2B occur in multiple other forms of glaucoma. METHODS: In immunohistochemical experiments, cryosections of human donor eyes were evaluated for SH3PXD2B immunoreactivity with a polyclonal antibody. In genetic experiments, exon sequences of SH3PXD2B from patients with primary congenital glaucoma (n=21), Axenfeld-Rieger syndrome (n=30), and primary open angle glaucoma (n=127) were compared to control subjects (n=89). The frequency of non-synonymous SH3PXD2B coding sequence variants were compared between patient cohorts and controls using Fisher's exact test. RESULTS: Varying intensities of SH3PXD2B immunoreactivity were detected in almost all ocular tissues. Among tissues important to glaucoma, immunoreactivity was detected in the drainage structures of the iridocorneal angle, ciliary body, and retinal ganglion cells. Intense immunoreactivity was present in photoreceptor inner segments. From DNA analysis, a total of 11 non synonymous variants were detected. By Fisher's Exact test, there was not a significant skew in the overall frequency of these changes in any patient cohort versus controls (p-value >0.05). Each cohort contained unique variants not detected in other cohorts or patients. CONCLUSIONS: SH3PXD2B is widely distributed in the adult human eye, including several tissues important to glaucoma pathogenesis. Analysis of DNA variants in three forms of glaucoma detected multiple variants unique to each patient cohort. While statistical analysis failed to support a pathogenic role for these variants, some of them may be rare disease-causing variants whose biologic significance warrants investigation in follow up replication studies and functional assays. PMID- 22509101 TI - Bleb morphology and histology in a rabbit model of glaucoma filtration surgery using Ozurdex(r) or mitomycin-C. AB - PURPOSE: To determine the effect of a sustained-release dexamethasone implant (Ozurdex((r))) on wound healing after glaucoma filtration surgery in a rabbit model. METHODS: Twelve new zealand white rabbits were divided into three groups: filtration surgery with intraoperative subconjunctival implantation of Ozurdex((r)) (n=6), filtration surgery with intraoperative topical application of mitomycin-C (MMC; n=6), and filtration surgery with intraoperative topical application of balanced salt solution (BSS; n=12). A standard scale was used to grade bleb vascularity at three and six weeks after the initial operation. Bleb survival was also recorded for comparison between the three groups. Histologic analysis was performed with attention to cellularity and collagen deposition. RESULTS: MMC-treated blebs demonstrated decreased numbers of goblet cells compared to all other groups. Blebs treated with Ozurdex((r)) maintained a near normal number of goblet cells with modest collagen deposition. The control eyes treated with only BSS had significant collagen deposition and increased cellularity compared to both the Ozurdex((r)) and MMC groups. Bleb vascularity was not significantly different among groups at the three and six week post operative evaluations. MMC-treated and Ozurdex((r))-treated blebs had significantly prolonged bleb survival compared to blebs treated with only BSS. In addition, MMC-treated blebs had significantly longer survival compared to Ozurdex((r))-treated blebs. CONCLUSIONS: The results of this study support the utility of extended-release dexamethasone (Ozurdex((r))) as a wound modulating agent in a rabbit model of filtration surgery. Further animal and human studies are needed to better characterize a possible role for Ozurdex((r)) in filtration surgery. PMID- 22509102 TI - An international collaborative family-based whole genome quantitative trait linkage scan for myopic refractive error. AB - PURPOSE: To investigate quantitative trait loci linked to refractive error, we performed a genome-wide quantitative trait linkage analysis using single nucleotide polymorphism markers and family data from five international sites. METHODS: Genomic DNA samples from 254 families were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel IVb. Quantitative trait linkage analysis was performed on 225 Caucasian families and 4,656 markers after accounting for linkage disequilibrium and quality control exclusions. Two refractive quantitative phenotypes, sphere (SPH) and spherical equivalent (SE), were analyzed. The SOLAR program was used to estimate identity by descent probabilities and to conduct two-point and multipoint quantitative trait linkage analyses. RESULTS: We found 29 markers and 11 linkage regions reaching peak two point and multipoint logarithms of the odds (LODs)>1.5. Four linkage regions revealed at least one LOD score greater than 2: chromosome 6q13-6q16.1 (LOD=1.96 for SPH, 2.18 for SE), chromosome 5q35.1-35.2 (LOD=2.05 for SPH, 1.80 for SE), chromosome 7q11.23-7q21.2 (LOD=1.19 for SPH, 2.03 for SE), and chromosome 3q29 (LOD=1.07 for SPH, 2.05 for SE). Among these, the chromosome 6 and chromosome 5 regions showed the most consistent results between SPH and SEM. Four linkage regions with multipoint scores above 1.5 are near or within the known myopia (MYP) loci of MYP3, MYP12, MYP14, and MYP16. Overall, we observed consistent linkage signals across the SPH and SEM phenotypes, although scores were generally higher for the SEM phenotype. CONCLUSIONS: Our quantitative trait linkage analyses of a large myopia family cohort provided additional evidence for several known MYP loci, and identified two additional potential loci at chromosome 6q13 16.1 and chromosome 5q35.1-35.2 for myopia. These results will benefit the efforts toward determining genes for myopic refractive error. PMID- 22509103 TI - Microarray analysis of gene expression in West Nile virus-infected human retinal pigment epithelium. AB - PURPOSE: To identify key genes differentially expressed in the human retinal pigment epithelium (hRPE) following low-level West Nile virus (WNV) infection. METHODS: Primary hRPE and retinal pigment epithelium cell line (ARPE-19) cells were infected with WNV (multiplicity of infection 1). RNA extracted from mock infected and WNV-infected cells was assessed for differential expression of genes using Affymetrix microarray. Quantitative real-time PCR analysis of 23 genes was used to validate the microarray results. RESULTS: Functional annotation clustering of the microarray data showed that gene clusters involved in immune and antiviral responses ranked highly, involving genes such as chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 5 (CCL5), chemokine (C-X-C motif) ligand 10 (CXCL10), and toll like receptor 3 (TLR3). In conjunction with the quantitative real-time PCR analysis, other novel genes regulated by WNV infection included indoleamine 2,3-dioxygenase (IDO1), genes involved in the transforming growth factor-beta pathway (bone morphogenetic protein and activin membrane-bound inhibitor homolog [BAMBI] and activating transcription factor 3 [ATF3]), and genes involved in apoptosis (tumor necrosis factor receptor superfamily, member 10d [TNFRSF10D]). WNV-infected RPE did not produce any interferon-gamma, suggesting that IDO1 is induced by other soluble factors, by the virus alone, or both. CONCLUSIONS: Low-level WNV infection of hRPE cells induced expression of genes that are typically associated with the host cell response to virus infection. We also identified other genes, including IDO1 and BAMBI, that may influence the RPE and therefore outer blood-retinal barrier integrity during ocular infection and inflammation, or are associated with degeneration, as seen for example in aging. PMID- 22509104 TI - Novel RPE65 mutations associated with Leber congenital amaurosis in Chinese patients. AB - PURPOSE: Retinal pigment epithelium-specific protein 65 kDa (RPE65) plays an essential role in vitamin A metabolism necessary for synthesizing the visual pigment 11-cis-retinal chromophore. Mutations in RPE65 cause the childhood blindness disorder known as Leber congenital amaurosis (LCA), as well as autosomal recessive retinitis pigmentosa (RP). The purpose of this study was to identify RPE65 mutations in Chinese patients with LCA, determine the prevalence of RPE65 mutations in this cohort, and assess the clinical features of those patients with RPE65 mutations. METHODS: Detailed ocular examinations were performed, and genomic DNA was isolated with standard methods for genetic diagnosis. All 14 exons of RPE65 were amplified with PCR and screened for mutation with direct DNA sequencing. Two hundred unrelated healthy Chinese subjects were screened to exclude nonpathogenic polymorphisms. Multiple alignments of eight eukaryotic RPE65 orthologs were performed. RESULTS: A total of 101 LCA patients, drawn from 100 unrelated families, were selected for mutation screening in the RPE65 gene. Compound heterozygous missense mutations Leu67Arg and Tyr368Cys were identified in two affected sisters and segregated with their family. Four previously reported polymorphisms were identified in this study. No other disease-related mutation was detected. The frequency spectrum of variations in the RPE65 gene was estimated to be 1% (1/100) in this cohort of Chinese patients with LCA. The two patients showed classical signs of LCA with relatively preserved central vision and retinal structure. CONCLUSIONS: The RPE65 mutation is a rare cause of LCA in the Chinese population. Compound heterozygous missense mutations Leu67Arg and Tyr368Cys are related to a relatively mild LCA phenotype. Genetic characterization of patients with RPE65 mutations is important for future rational therapies. PMID- 22509105 TI - A splice site mutation in the PAX6 gene which induces exon skipping causes autosomal dominant inherited aniridia. AB - PURPOSE: To identify the underlying genetic cause in a two generation German family diagnosed with isolated aniridia. METHODS: All patients underwent full ophthalmic examination. Mutation screening of the paired box gene 6 (PAX6) was performed by bidirectional Sanger sequencing. A minigene assay was applied to analyze transcript processing of mutant and wildtype PAX6 variants in HEK293 cells. RESULTS: We identified a PAX6 sequence variant at the splice donor site (+5) of intron 12. This variant has been described before in another family with aniridia but has not been characterized at the transcript level. We could demonstrate that the mutant allele causes the skipping of exon 12 during transcript processing. The mutation is predicted to result in a 'run on' translation past the normal translational stop codon. CONCLUSIONS: A splice site mutation resulting in exon skipping was found in a family with autosomal dominant aniridia. The mutation is predicted to result in an enlarged protein with an extra COOH-terminal domain. This very likely affects the transactivation properties of the PAX6 protein. PMID- 22509106 TI - NGF promotes cell cycle progression by regulating D-type cyclins via PI3K/Akt and MAPK/Erk activation in human corneal epithelial cells. AB - PURPOSE: Nerve growth factor (NGF) plays an important role in promoting the healing of corneal wounds. However, the molecular mechanism by which NGF functions is unknown. We investigated the possible effects of NGF on phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) pathways and cell growth in human corneal epithelial cells (HCECs). METHODS: We examined the effect of NGF on cell cycle and proliferation in HCECs by flow cytometry and cell proliferation assay, respectively. The levels of D-type cyclins in NGF-treated HCECs were determined by western blot. The tyrosine kinase A (TrkA), PI3K/Akt and MAPK/Erk pathways were then checked in cells stimulated with NGF for different time periods or cells undergoing a dose-dependent treatment. Furthermore, HCECs were treated with pathway inhibitors, LY294002 or PD98059, to confirm NGF-induced activations. RESULTS: We found that NGF had a positive effect on the growth of HCECs, and D-type cyclins, and it was correlated with the percentage of the G(1) to S progression. We also observed a time-dependent and dose-dependent effect of NGF on the PI3K/Akt and MAPK/Erk pathways. Furthermore, NGF affected cell cycle progression of HCECs by regulating cyclin D through Akt and Erk activation upon treatment with the pathway inhibitors, LY294002 for Akt or PD98059 for Erk pathways. CONCLUSIONS: NGF stimulation could promote cell proliferation and cell cycle progression of HCECs by activation of cyclin D via the PI3K/Akt and MAPK/Erk signaling pathways. PMID- 22509107 TI - Endophenotyping reveals differential phenotype-genotype correlations between myopia-associated polymorphisms and eye biometric parameters. AB - PURPOSE: To investigate the association with ocular biometric parameters in myopia-associated single nucleotide polymorphisms (SNPs) of the gap junction protein delta 2 (GJD2), insulin-like growth factor-1 (IGF1) and hepatocyte growth factor (HGF) genes in two geographically different Chinese cohorts. METHODS: In 814 unrelated Han Chinese individuals aged above 50 years including 362 inland residents and 432 island dwellers, comprehensive ophthalmic examinations were performed. Three SNPs, including GJD2 rs634990, IGF1 rs6214, and HGF rs3735520, were genotyped. Genetic association with ocular biometric parameters was analyzed in individual cohorts, using linear regression controlled for sex and age. Common associations shared by the two cohorts were revealed by meta-analysis. RESULTS: Meta-analysis showed that GJD2 rs634990 alone was not associated with any biometric parameters (adjusted p>0.645). The T allele of IGF1 rs6214 was specifically associated with thicker lens (beta+/-SE=0.055+/-0.022, adjusted p=0.034). The A allele of HGF rs3735520 was associated with longer vitreous chamber depth (beta+/-SE=0.143+/-0.060, adjusted p=0.050). Significant interaction between HGF rs3735520 and GJD2 rs634990 was found in association with axial length and vitreous chamber depth (adjusted p=0.003 and 0.033, respectively), and possibly with spherical error (adjusted p=0.056). CONCLUSIONS: Our endophenotyping analysis showed differential association between selected myopia-associated genes and ocular biometric parameters in our Chinese cohorts, which may underline substantial but diversified effects of these genes and their interaction on the development of eye structure and etiology of myopia. PMID- 22509108 TI - Polymorphism in the TNF-alpha(-863) locus associated with reduced risk of primary open angle glaucoma. AB - PURPOSE: Tumor necrosis factor-alpha (TNF-alpha), an important proinflammatory cytokine, exerts a variety of physiologic and pathogenic effects that lead to tissue destruction. Recent laboratory evidence indicates that TNF-alpha have either protective or adverse effects on primary open angle glaucoma (POAG). Inheritance of the TNF-alpha (-863) C allele has been associated with an elevated risk of Alzheimer disease. The neuronal injuries associated with Alzheimer disease have several similarities with the optic nerve changes often seen with POAG. In this study we investigated the possible association between the TNF alpha (-863) polymorphism and the development of POAG. METHODS: A total of 234 patients with POAG were recruited and compared with 230 healthy controls in a Chinese population. Sequence-specific primers with 3' end mismatches were used to identify the presence of specific allelic variants by polymerase chain reaction (PCR) amplification. Patients and controls were genotyped for the A/C polymorphism at position -863 of the TNF-alpha gene promoter region. RESULTS: The frequency of the TNF-alpha (-863)A allele (22% versus 30%, respectively; p=0.007) and the carriers of the TNF-alpha (-863)A allele (37% versus 48%; p=0.017, OR 0.63, 95% CI 0.44-0.92) were lower in POAG patients compared with those in controls. There is a reduced risk of POAG associated with homozygosity for the TNF-alpha (-863)A allele (AA genotype) compared with that in the control population (AA genotype; 7% versus 11%, respectively, p=0.037; OR 0.5, 95% CI 0.26-0.98). CONCLUSIONS: The TNF-alpha (-863)A allele polymorphism may be a protective factor in the development of POAG. PMID- 22509109 TI - No association of genetic polymorphisms in CYP1B1 with primary open-angle glaucoma: a meta- and gene-based analysis. AB - PURPOSE: To examine the effects of genetic polymorphisms in cytochrome P450, subfamily 1, polypeptide 1 (C1P1B1) on primary open-angle glaucoma (POAG). METHODS: A systematic literature search was performed, and random-effects meta analyses were used to evaluate genetic polymorphisms in CYP1B1 with POAG. A gene based analysis was conducted to investigate the cumulative effects of genetic polymorphisms in CYP1B1. RESULTS: A total of six studies from published papers were included in our analysis. Random-effects meta-analyses failed to detect any significant association of POAG with genetic polymorphisms in CYP1B1, including rs180040, rs1056836, rs10012, rs1056827, rs1056837, and rs2567206. The gene-based analysis indicated that the cumulative effect of genetic polymorphisms in CYP1B1 is not associated with POAG (p>0.50). CONCLUSIONS: We did not find any evidence of strong association of POAG with CYP1B1 genetic polymorphisms and their cumulative effect. PMID- 22509110 TI - Cytokines in tear fluid of patients with ocular graft-versus-host disease after allogeneic stem cell transplantation. AB - PURPOSE: To investigate the profile of cytokines in tear fluid of patients after allogeneic stem cell transplantation (allo-SCT) and determine their relation to the presence and manifestations of ocular graft-versus-host disease (GvHD). METHODS: In this cross sectional study tear fluid was collected in 34 consecutive adult patients that previously underwent allo-SCT (16 with ocular GvHD and 18 without) and 16 age- and gender-matched healthy controls using the Schirmer test under local anesthesia. Tear fluid was analyzed by multiplex immunoassay for the presence of interleukin (IL)-2, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. Levels of measured cytokines were correlated with the findings in slit lamp examination and the Ocular Surface Disease Index (OSDI). RESULTS: The levels of IL-6 and IFN-gamma in tear fluid in ocular GvHD patients were significantly elevated in comparison to patients without ocular GvHD and healthy controls (p<0.005 for each) The levels of IFN gamma correlated with the Schirmer score (r=-0.48, p<0.0001) and tear break up time (TBUT; r=-0.38, p=0.03). Tear IL-6 levels correlated with complaints of dry eyes (r=0.39, p=0.02), tear production (r=-0.59, p<0.0001), fluorescent staining of the cornea (r=0.42, p=0.01), and with the OSDI score (r=0.40, p=0.005). CONCLUSIONS: IL-6 and IFN-gamma were elevated in tear fluid of patients with ocular GvHD and correlated with different symptoms of dry eye disease, suggesting that IFN-gamma is elevated during the early stages and IL-6 is involved in later stages of ocular GVHD and exhibits moreover an association with its severity. PMID- 22509111 TI - High expression of p16INK4a and low expression of Bmi1 are associated with endothelial cellular senescence in the human cornea. AB - PURPOSE: Determine cyclin-dependent kinase inhibitor 2A (p16(Ink4a)) and polycomb ring finger oncogene (Bmi1) expression in corneal endothelium samples from different age groups and test whether the expression of p16(INK4a) and Bmi1 are associated with endothelial cellular senescence in human cornea. METHODS: Samples were selected from an eyebank of healthy human corneal endothelial cells (HCECs). Donor human corneas were divided into three age-groups: age <=30 years, 30-50 years and >=50 years. The expression of p16(INK4a) and Bmil were analyzed by real time PCR, immunohistochemistry, and immunofluorescence. RESULTS: Through real time PCR, we detected less than threefold decreases in Bmi1 expression and greater than fivefold increases in p16(INK4a) expression associated with aging. Bmi1 expression was significantly down-regulated with increasing donor age. The number of p16(INK4a)-positive cells was significantly higher and the number of Bmi1-positive cells was significantly lower in older donors compared to the younger age groups. Our immunohistochemistry experiments showed that the expression of p16(INK4a) in older donors was stronger than that in younger donors and the expression of Bmi1 in older donors was weaker than that in younger donors. Results from both the immunohistochemistry and real-time PCR experiments confirmed increased expression of p16(INK4a) and decreased expression of Bmi1 with age in HCECs. Additionally, the results of immunofluorescence double staining for p16(INK4a) and Bmi1 further validated the immunocytochemistry and real-time PCR results. CONCLUSIONS: Our data are the first to demonstrate that high expression of p16(INK4a) and low expression of Bmi1 are associated with endothelial cellular senescence in human cornea. Our findings are not just for cornea transplantation but also for a better understanding of the cornea senescence and the process of aging in this specific human organ. PMID- 22509113 TI - Radiopacity evaluation of composite restorative resins and bonding agents using digital and film x-ray systems. AB - OBJECTIVE: The purpose of this in vitro study was to explore the radiopacity of composite resins and bonding materials using film and phosphor plates. METHODS: Nine composite dental resin specimens and human tooth slices were exposed together with an aluminium stepwedge using dental film and phosphor plates. Eight dentin bonding specimens were prepared and exposed in a similar manner. Their radiopacity on film was assessed using a transmission densitometer, and the radiopacity with phosphor plates was assessed digitally using the system's own software (Digora). Data were analysed using one-way analysis of variance (ANOVA) and post-hoc Tukey tests (P<.05). Film and phosphor plate radiopacity values were compared using simple regression analysis. RESULTS: Excellent linear correlation was found between film and phosphor plates for both composite resins and bonding agents. The composite materials Spectrum Tph and Natural Look exhibited the highest radiopacity with film and with phosphor plates, respectively. All the dentin bonding agents tested exhibited lower radiopacity than dentin. CONCLUSION: Synergy, Ice, Filtek Silorane, Filtek Z250, Clearfil Majesty Posterior, Herculite Classic, Spectrum Tph, and Natural Look composite materials exhibited greater radiopacity than dentin, and all the dentin bonding agents tested exhibited lower radiopacity than either enamel or dentin. PMID- 22509112 TI - Genetic associations in polypoidal choroidal vasculopathy: a systematic review and meta-analysis. AB - PURPOSE: To investigate the genetic associations of polypoidal choroidal vasculopathy (PCV), the genetic difference between PCV and age-related macular degeneration (AMD), and the genotype-phenotype correlation of PCV. METHODS: A systematic review and meta-analysis were performed. Published articles about genetic associations of PCV identified from a literature search were reviewed. The following data from individual studies were extracted and analyzed: 1) comparison of genetic polymorphisms between PCV and controls; 2) comparison of genetic polymorphisms between PCV and AMD; and 3) comparison of phenotypes between different genotype groups. RESULTS: A total of 33 articles fulfilled the inclusion criteria. With meta-analyses, variants in four genes were found to be significantly associated with PCV: LOC387715 rs10490924 (n=9, allelic odds ratio [OR]=2.27, p<0.00001), HTRA1 rs11200638 (n=4, OR=2.72, p<0.00001), CFH rs1061170 (n=4, OR=1.72, p<0.00001), CFH rs800292 (n=5, OR=2.10, p<0.00001), and C2 rs547154 (n=3, OR=0.56, p=0.01). LOC387715 rs10490924 was the only variant showing a significant difference between PCV and wet AMD (n=5, OR=0.66, p<0.00001). The risk genotypes of rs10490924 were associated with larger lesion size, greater chance of vitreous hemorrhage, and worse therapeutic response in PCV. CONCLUSIONS: LOC387715 rs10490924 was associated with PCV and its clinical manifestations, and showed a discrepant distribution between PCV and AMD. Variants in HTRA1, CFH, and C2 were also associated with PCV. PMID- 22509114 TI - Alveolar and symphysis regions of patients with skeletal class II division 1 anomalies with different vertical growth patterns. AB - OBJECTIVES: The aim of this study was to investigate the alveolar and symphysis region properties in hyper-, hypo-, and normodivergent Class II division 1 anomalies. METHODS: Pretreatment lateral cephalograms of 111 young adult female patients with skeletal Class II division 1 anomalies were compared to those of 54 Class I normal subjects (control group). Class II cases were divided into hyperdivergent (n = 58), hypodivergent (n = 19), and normodivergent groups (n = 34). The heights and widths of the symphysis and alveolus and the depth of maxillary palate were measured on the lateral cephalograms. RESULTS: Mean symphysis width was wider in the hypodivergent Class II group than in the other groups, while mean symphysis height was similar among all groups. Maxillary palatal depth, upper incisor angle, upper and lower molar alveolar heights, and Id-Id' width were also similar among groups. CONCLUSION: Symphysis width is the main factor in the differential diagnosis of Class II division 1 anomaly rather than symphysis height and hypodivergent Class II Division 1 anomaly is more suitable for mandibular incisors movements. PMID- 22509115 TI - Hardness, polymerization depth, and internal adaptation of Class II silorane composite restorations as a function of polymerization protocol. AB - OBJECTIVES: To evaluate the influence of various photoactivation techniques on the internal gap, Knoop-hardness, and polymerization depth of silorane- and methacrylate-based composites in Class II restorations. METHODS: Preparations were made in third molars (n = 10), according to composites (Filtek P60: methacrylate; Filtek P90: silorane) and photoactivation techniques (OC: occlusal photoactivation (control); OBL: occlusal+buccal+lingual photoactivation; and BLO: buccal+lingual+occlusal photoactivation (transdental)). Composites were inserted in two increments, both individually photoactivated for 20s. After 24h, specimens were sectioned and the ratio of internal gaps to interface length (%) recorded. Hardness was tested across the transversal section of restorations (1-4 mm below the surface). RESULTS: Silorane restorations showed significantly lower gaps compared with methacrylate, regardless of polymerization technique (P<.05). Supplementary energy dose in OBL and BLO protocols caused significant increase in gaps in silorane restorations (P<.05). For methacrylate restorations, OBL activation caused significantly higher gap formation (P<.05). Significantly lower hardness values were seen for silorane than for methacrylate composites (P<.05), regardless of depth and photoactivation. Significantly higher hardness values were seen in BLO activation for methacrylate restorations compared with control (P<.05); for silorane, no differences were observed. Significantly higher hardness values were observed at 1 and 3 mm compared to 2 and 4 mm for both composites. CONCLUSIONS: Internal gaps and hardness are affected by composite type and photoactivation. Despite the reduced values, hardness of silorane is not influenced by photoactivation or by depth. Internal gaps are dependent on the energy dose for both composites, with silorane showing lower internal gaps. PMID- 22509116 TI - Prevalence of early childhood caries and associated risk factors in preschool children of urban Bangalore, India: A cross-sectional study. AB - OBJECTIVES: Early childhood caries (ECC) is a devastating form of dental decay with multi-factorial origin. The aim of this cross-sectional study is to investigate the prevalence and related risk factors of ECC in preschool children of urban Bangalore (India). METHODS: A random sample of 1,500 children aged between 8 and 48 months were selected from various parts of urban Bangalore. The status of dental caries was recorded according to the World Health Organization (WHO) criteria. Information regarding oral hygiene practices, feeding habits, socio-economic status, birth weight, and educational status of the mother was obtained through a structured questionnaire given to mothers of preschool children. The data was subjected to statistical analysis using the Statistical package for social sciences (SPSS) version 12. RESULTS: The prevalence of ECC in preschool children was 27.5%, while the mean deft was 0.854. ECC increased significantly with age. Children whose mothers had no schooling and those who belonged to low socioeconomic group showed higher caries prevalence. A significant increase in caries prevalence was found in children accustomed to the practice of on-demand breast feeding and bottle feeding at night. Caries also increased significantly when snacks were consumed between meals. However, increased frequency of tooth-brushing, parental supervision, use of a baby toothbrush, and fluoridated dentifrice significantly decreased caries prevalence. CONCLUSION: ECC is a serious public health problem in this population and measures to increase awareness should be undertaken. The target candidates for oral health promotion programs should include mothers, general dentists, pediatricians, nurses, primary care health workers, care-takers at day-care centers and gynecologists. PMID- 22509117 TI - Influence of light source and extended time of curing on microhardness and degree of conversion of different regions of a nanofilled composite resin. AB - OBJECTIVES: The aim of this study was to evaluate the effects of different light sources and curing time on the degree of conversion and microhardness of two surfaces within a nanofilled composite resin. METHODS: Four experimental groups (n=10) were formed in accordance with the light source (quartz-tungsten halogen (QTH - 600mW/cm(2)), or light-emitting-diode (LED - 800mW/cm(2))) and the time of curing (20 s or 40 s). The specimens were prepared with a circular mould (5 mm ? and 2 mm thick), according to the respective protocol, and the Knoop microhardness and degree of conversion was measured at the top and the base of the specimens. The degree of conversion was evaluated by the Fourier transform infrared spectrometer (FTIR). The results were analyzed by ANOVA two-way repeated measures and Tukey's test (alpha=,05). RESULTS: Both the degree of conversion and microhardness were higher at the top than at the bottom of the specimens. The QTH light source presented better values on the degree of conversion evaluation, but this result was not observed in the microhardness evaluation. Although forty seconds of curing promotes an increased level of microhardness, it did not influence the degree of conversion. CONCLUSION: It could be concluded that increasing the time of curing to 40 s promotes an increase in microhardness, but it does not influence the degree of conversion of a nanofilled composite resin. QTH promote better monomeric conversion; however, the microhardness values are similar to LED curing. For all situations tested, the bottom of the specimens presented lower results than the top. PMID- 22509118 TI - Searching for Helicobacter pylori and Chlamydia pneumoniae in primary endodontic infections. AB - OBJECTIVES: The purpose of this study was to search samples from primary endodontic infections for the presence of two common human bacterial pathogens - Helicobacter pylori and Chlamydia pneumoniae. METHODS: Genomic DNA isolated from samples taken from 25 root canals of teeth with asymptomatic (chronic) apical periodontitis and 25 aspirates from acute apical abscess was initially amplified by the multiple displacement amplification approach and then used as template in species-specific polymerase chain reaction (PCR) for detection of H. pylori and C. pneumoniae. RESULTS: All clinical samples were positive for the presence of bacterial DNA. However, no clinical sample was positive for either H. pylori or C. pneumoniae. CONCLUSIONS: Neither H. pylori nor C. pneumoniae were found in samples from primary endodontic infections. These findings suggest that these species are not candidate endodontic pathogens and that the necrotic root canal does not serve as a reservoir for these human pathogens in healthy patients. PMID- 22509119 TI - Evaluation of marginal fit of two all-ceramic copings with two finish lines. AB - OBJECTIVES: This in-vitro study investigated the marginal fit of two all-ceramic copings with 2 finish line designs. METHODS: Forty machined stainless steel molar die models with two different margin designs (chamfer and rounded shoulder) were prepared. A total of 40 standardized copings were fabricated and divided into 4 groups (n=10 for each finish line-coping material). Coping materials tested were IPS e.max Press and Zirkonzahn; luting agent was Variolink II. Marginal fit was evaluated after cementation with a stereomicroscope (Leica MZ16). Two-way analysis of variance and Tukey-HSD test were performed to assess the influence of each finish line design and ceramic type on the marginal fit of 2 all-ceramic copings (alpha =.05). RESULTS: Two-way analysis of variance revealed no statistically significant differences for marginal fit relative to finish lines (P=.362) and ceramic types (P=.065). CONCLUSION: Within the limitations of this study, both types of all-ceramic copings demonstrated that the mean marginal fit was considered acceptable for clinical application (?120 MUm). PMID- 22509120 TI - Interfacial integrity of bonded restorations with self-etching adhesives: Water storage and thermo-mechanical cycling. AB - OBJECTIVES: OBJECTIVE: To evaluate the effect of thermo-mechanical cycling (TMC) on the microleakage (MUL) and axial gap width (AG) of Class V bonded restorations in premolars using self-etching adhesive systems. The bond strength of composite restorations to dentin (MUTBS) using the same adhesives was also evaluated in third molars after water storage: 24 h and 6 months. The research hypotheses were tested for the results of two self-etching adhesives in comparison when a conventional two-step adhesive was used: (1) the MUL and AG would be lower, regardless of TMC; (2) the MUTBS of self-etching adhesives would be higher, irrespective of evaluation times. METHODS: Sixty Class V composite restorations were made in 30 premolars and bonded with Adper Single Bond 2 (ASB2), AdheSE (ASE), and Adper Prompt L-Pop (APL-P) (n=20). Dentin MUL and AG were immediately measured for half of the sample. The other half was evaluated after TMC. Eighteen third molars were also selected and bonded using the same adhesives to test the MUTBS to dentin. Specimens were evaluated after 24 h and 6 months of water storage. RESULTS: No differences in MUL and AG were found among the groups (P>.05). The MUTBS mean values were: ASB2>ASE>APL-P (P<.05); only Adper Single Bond 2 presented a significantly lower MUTBS after water storage (P<.05). CONCLUSIONS: The bonding approach does not influence the microleakage and interfacial gap extension. Despite the decrease in the mean values, the bond strength to dentin of the conventional, two-step adhesive remains high after 6 months of water storage. PMID- 22509121 TI - Dental anomalies in the primary dentition of Turkish children. AB - OBJECTIVE: The aim of this study was to determine the prevalence of double teeth, hypodontia, microdontia, and hyperdontia of primary teeth in Turkish children. METHODS: The study group comprised 1149 children (554 girls, 595 boys). The children were examined in twelve local nurseries in Sivas, Turkiye. Clinical data were collected by four dentists according to Kreiborg criteria; which includes double teeth, hypodontia, microdontia, and supernumerary teeth. Statistical analysis of the data was performed using the chi-square test. RESULTS: Dental anomalies were found in 2.0% of children. The distribution of dental anomalies were significantly more frequent (P=.023) in boys (2.9%, n=17) than in girls (1.1%, n=6). In relation to anomaly frequencies at different ages, no difference was found (P = .760). CONCLUSION: Double teeth were the most frequently (1.3%) observed anomaly. The other anomalies followed as; 0.3% supernumerary teeth, 0.3% microdontia, 0.2% hypodontia. Identification of dental anomalies in the anterior region at an early age is of great importance for esthetic and orthodontic treatment planning. PMID- 22509122 TI - Study of thyroid hormones free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) in subjects with dental fluorosis. AB - OBJECTIVE: Apart from its well-known deleterious dental and skeletal effects, fluoride excess can have toxic effects on many other tissues. Fluoride, when in excess, is known to interfere with thyroid gland function. Fluoride-induced thyroid disturbances similar to those observed in iodine deficiency state in spite of adequate iodine intake have been documented. Similar thyroid disturbances in individuals with dental fluorosis have not been well studied in populations with endemic fluorosis. This work was undertaken to study the effects of fluoride-induced thyroid disturbances in individuals with dental fluorosis. METHODS: The study group included 65 subjects with dental fluorosis from endemic fluorosis populations. An additional control group was comprised of 10 subjects without dental fluorosis. The drinking water fluoride levels of the study populations were analyzed. Serum free FT3, FT4, and TSH levels of both groups were assessed. RESULTS: All subjects with dental fluorosis had serum levels of thyroid hormones (FT3, FT4, and TSH) within the normal range, with the exception of 1 individual, who had elevated levels of TSH. Statistical significance was found when FT3 and TSH values were compared with different Dean's index groups by a 1-way ANOVA test: FT3 (F = 3.4572; P=.0377) and TSH (F = 3.2649 and P=.0449). CONCLUSIONS: Findings of this study did not show any significant alterations in the levels of the thyroid hormones FT3, FT4, and TSH in subjects with dental fluorosis. Our observations suggest that thyroid hormone levels were not altered in subjects with dental fluorosis. Hence, future studies of this kind, along with more detailed investigations are needed. PMID- 22509123 TI - Evaluation of oral health status and salivary flow rate in obese patients after bariatric surgery. AB - OBJECTIVES: The aim of this study was to identify the prevalence of dental caries, periodontal diseases and tooth wear in bariatric patients, and relate the oral health conditions to saliva flow. METHODS: Fifty-two patients who had undergone bariatric surgery (Roux-en-Y gastric bypass) and 50 severely obese patients indicated for bariatric surgery were submitted to clinical examinations with regard to dental caries (DMFT index), periodontal condition (CPI index), dental wear (DWI index - Dental wear index) and saliva flow. The data were statistically analyzed by the Student's-t, Mann-Whitney, Spearman Correlation and Chi-square (chi(2)) tests at 5% significance level. RESULTS: The DMFT index was 16.11+/-5.19 in the surgical group and 16.06+/-6.29 in the control group (P>.05). The mean CPI was 3.05+/-0.84 for the operated group and 2.66+/-1.25 for the obese patients with no significant difference between them (P>.05). There was statistically significant difference between the groups for the presence of periodontal pockets (P=.021). All the patients presented some degree of tooth wear, however, with no significant difference between the two groups (P=.82). The mean saliva flow values of the surgical group and control group were 0.64+/-0.46 mL/min and 0.66+/-0.49 mL/min, respectively. There was no significant difference in saliva flow and all oral conditions analyzed (P>.05). CONCLUSION: The prevalence of oral diseases was similar in severely obese patients who were candidates for bariatric surgery and in patients who had been submitted to bariatric surgery. Nevertheless, there was higher prevalence of periodontal pockets in the operated group. PMID- 22509124 TI - The effect of one-step and multi-step polishing systems on the surface roughness and microhardness of novel resin composites. AB - OBJECTIVES: The objective of this in vitro study was to evaluate the surface roughness and micro-hardness of three novel resin composites containing nanoparticles after polishing with one-step and conventional multi-step polishing systems. METHODS: A total of 126 specimens (10 X 2 mm) were prepared in a metal mold using three nano-composites (Filtek Supreme XT, Ceram-X, and Grandio), 21 specimens of each resin composite for both tests (n=63 for each test). Following light curing, seven specimens from each group received no polishing treatment and served as controls for both tests. The specimens were randomly polished using PoGo and Sof-Lex systems for 30 seconds after being wet-ground with 1200-grit silicon carbide paper. The mean surface roughness of each polished specimen was determined with a profilometer. The microhardness was determined using a Vickers hardness measuring instrument with a 200-g load and 15 seconds dwell time. The data were analyzed using the Kruskal-Wallis test and the post hoc Dunn's multiple comparison tests at a significance level of .05. RESULTS: Among all materials, the smoothest surfaces were obtained under a matrix strip (control) (P<.05). There were no statistically significant differences among polishing systems in the resin composites for surface roughness (P>.05). The lowest hardness values for the three resin composites were obtained with a matrix strip, and there was a statistically significant difference compared with other polishing systems (P<.05) whereas no statistically significant differences were observed between the polishing systems (P>.05). CONCLUSION: The current one-step polishing system appears to be as effective as multi-step systems and may be preferable for polishing resin composite restorations. PMID- 22509125 TI - Maxillary protraction in adult cleft lip and palate by a rigid external distraction device with dentoskeletal anchorage. AB - OBJECTIVE: The objective is to evaluate the effects of maxillary distraction osteogenesis (DO) in an adult patient with unilateral cleft lip and palate (UCLP) by using a rigid external distraction (RED) device with dentoskeletal anchorage. METHOD: 31-year-old male patient with UCLP with severe maxillary hypoplasia, dolichofacial growth pattern, negative overjet and 1.5 mm openbite. After pre surgical orthodontic treatment, an intra-oral appliance was modified to prevent extrusion of the molars and clockwise rotation of the mandible. Stainless steel plates were soldered bilaterally to the intra oral appliance at the level of canines. During surgery, miniplates were inserted in the maxillary segment and fixed to the plates of the intra oral appliance with screws. RESULTS: The mean distraction length was 12 mm immediately after DO. SNA increased from 73o to 82o after distraction. A significant advancement of the maxilla and correction of the sagittal Class III skeletal relationship was achieved. The vertical position of the mandible and the face was kept stable, and the soft tissue profile became more balanced. CONCLUSION: This intra oral appliance design achieved desired skeletal changes during maxillary protraction with RED device in dolichofacial CLP patient. Occlusion and facial profile changes was found to be stable in 1 year follow-up. PMID- 22509126 TI - Enhanced retention of a maxillofacial prosthetic obturator using precision attachments: Two case reports. AB - The majority of maxillary defects can be rehabilitated with conventional simple obturator prosthesis. However, inadequate retention, stability and support may be associated with the use of an obturator. Precision attachments have been used to retain obturators for some time. The use of precision attachments in a dentate maxillectomy patient can yield significant functional improvement while maintaining the obturator's aesthetic advantages. This clinical report describes the prosthetic rehabilitation of two maxillary defects with an obturator retained using extracoronal resilient precision attachments. PMID- 22509127 TI - Multidisciplinary treatment of non-syndromic oligodontia. AB - Oligodontia is the agenesis of 6 or more teeth, excluding third molars. The etiology of congenital absence of teeth is believed to be rooted in heredity or developmental anomalies. The absence of teeth in patients can cause aesthetic, functional, and psychological problems, particularly if the anterior region is involved. This case report describes the multidisciplinary treatment approach toward a patient 17 years of age with non-syndromic oligodontia, with absence of 11 permanent teeth. Genetic counseling revealed non-syndromic, autosomal recessive-linked oligodontia. The objectives of the first phase of therapy were pre-prosthetic orthodontic space opening for proper positioning of the missing teeth and correction of inter-maxillary relations, as a prerequisite for proper prosthetic restoration. The second phase of therapy was prosthetic restoration of the missing teeth and provision of occlusion with full-mouth porcelain fused to metal crowns and bridges after increasing occlusal vertical dimension by 2 mm. PMID- 22509128 TI - Reattachment of fractured maxillary incisors using fiber-reinforced post: Two case reports. AB - OBJECTIVE: The reattachment of the crown fragment to a fractured tooth is a conservative treatment that should be considered for young patients with crown root fractures to the maxillary incisors if the subgingival fracture can be exposed to provide isolation. Gingivectomy, the surgical or orthodontic extrusion of the apical fragment is necessary to expose the subgingival fracture. This report demonstrates the treatment of two cases with the combination of gingivectomy or resective osseous surgery, reattachment of coronal fracture and fiber-reinforced polymer posts and shows three years long term follow-up. Subgingivally extended crown-root fractures of maxillary incisors were restored with a combination of chemically cured resin material, light cured resin material and polyethylene fiber. CONCLUSION: Within the limitations of this case report, it was demonstrated that reattachment of tooth fragments can successfully benefit periodontal health, aesthetic needs and normal functioning after three years. PMID- 22509129 TI - How to make epidemiological training infectious. AB - Modern infectious disease epidemiology builds on two independently developed fields: classical epidemiology and dynamical epidemiology. Over the past decade, integration of the two fields has increased in research practice, but training options within the fields remain distinct with few opportunities for integration in the classroom. The annual Clinic on the Meaningful Modeling of Epidemiological Data (MMED) at the African Institute for Mathematical Sciences has begun to address this gap. MMED offers participants exposure to a broad range of concepts and techniques from both epidemiological traditions. During MMED 2010 we developed a pedagogical approach that bridges the traditional distinction between classical and dynamical epidemiology and can be used at multiple educational levels, from high school to graduate level courses. The approach is hands-on, consisting of a real-time simulation of a stochastic outbreak in course participants, including realistic data reporting, followed by a variety of mathematical and statistical analyses, stemming from both epidemiological traditions. During the exercise, dynamical epidemiologists developed empirical skills such as study design and learned concepts of bias while classical epidemiologists were trained in systems thinking and began to understand epidemics as dynamic nonlinear processes. We believe this type of integrated educational tool will prove extremely valuable in the training of future infectious disease epidemiologists. We also believe that such interdisciplinary training will be critical for local capacity building in analytical epidemiology as Africa continues to produce new cohorts of well-trained mathematicians, statisticians, and scientists. And because the lessons draw on skills and concepts from many fields in biology--from pathogen biology, evolutionary dynamics of host--pathogen interactions, and the ecology of infectious disease to bioinformatics, computational biology, and statistics--this exercise can be incorporated into a broad array of life sciences courses. PMID- 22509130 TI - Nonheritable cellular variability accelerates the evolutionary processes of cancer. AB - Recent cancer studies emphasize that genetic and heritable epigenetic changes drive the evolutionary rate of cancer progression and drug resistance. We discuss the ways in which nonheritable aspects of cellular variability may significantly increase evolutionary rate. Nonheritable variability arises by stochastic fluctuations in cells and by physiological responses of cells to the environment. New approaches to drug design may be required to control nonheritable variability and the evolution of resistance to chemotherapy. PMID- 22509131 TI - Immunity in society: diverse solutions to common problems. AB - Understanding how organisms fight infection has been a central focus of scientific research and medicine for the past couple of centuries, and a perennial object of trial and error by humans trying to mitigate the burden of disease. Vaccination success relies upon the exposure of susceptible individuals to pathogen constituents that do not cause (excessive) pathology and that elicit specific immune memory. Mass vaccination allows us to study how immunity operates at the group level; denser populations are more prone to transmitting disease between individuals, but once a critical proportion of the population becomes immune, "herd immunity" emerges. In social species, the combination of behavioural control of infection--e.g., segregation of sick individuals, disposal of the dead, quality assessment of food and water--and aggregation of immune individuals can protect non-immune members from disease. While immune specificity and memory are well understood to underpin immunisation in vertebrates, it has been somewhat surprising to find similar phenomena in invertebrates, which lack the vertebrate molecular mechanisms deemed necessary for immunisation. Indeed, reports showing alternative forms of immune memory are accumulating in invertebrates. In this issue of PLoS Biology, Konrad et al. present an example of fungus-specific immune responses in social ants that lead to the active immunisation of nestmates by infected individuals. These findings join others in showing how organisms evolved diverse mechanisms that fulfil common functions, namely the discrimination between pathogens, the transfer of immunity between related individuals, and the group-level benefits of immunisation. PMID- 22509132 TI - Cytoneme-mediated delivery of hedgehog regulates the expression of bone morphogenetic proteins to maintain germline stem cells in Drosophila. AB - Stem cells reside in specialised microenvironments, or niches, which often contain support cells that control stem cell maintenance and proliferation. Hedgehog (Hh) proteins mediate homeostasis in several adult niches, but a detailed understanding of Hh signalling in stem cell regulation is lacking. Studying the Drosophila female germline stem cell (GSC) niche, we show that Hh acts as a critical juxtacrine signal to maintain the normal GSC population of the ovary. Hh production in cap cells, a type of niche support cells, is regulated by the Engrailed transcription factor. Hh is then secreted to a second, adjacent population of niche cells, the escort cells, where it activates transcription of the GSC essential factors Decapentaplegic (Dpp) and Glass bottom boat (Gbb). In wild-type niches, Hh protein decorates short filopodia that originate in the support cap cells and that are functionally relevant, as they are required to transduce the Hh pathway in the escort cells and to maintain a normal population of GSCs. These filopodia, reminiscent of wing disc cytonemes, grow several fold in length if Hh signalling is impaired within the niche. Because these long cytonemes project directionally towards the signalling-deficient region, cap cells sense and react to the strength of Hh pathway transduction in the niche. Thus, the GSC niche responds to insufficient Hh signalling by increasing the range of Hh spreading. Although the signal(s) perceived by the cap cells and the receptor(s) involved are still unknown, our results emphasise the integration of signals necessary to maintain a functional niche and the plasticity of cellular niches to respond to challenging physiological conditions. PMID- 22509133 TI - ROP GTPase-dependent actin microfilaments promote PIN1 polarization by localized inhibition of clathrin-dependent endocytosis. AB - Cell polarization via asymmetrical distribution of structures or molecules is essential for diverse cellular functions and development of organisms, but how polarity is developmentally controlled has been poorly understood. In plants, the asymmetrical distribution of the PIN-FORMED (PIN) proteins involved in the cellular efflux of the quintessential phytohormone auxin plays a central role in developmental patterning, morphogenesis, and differential growth. Recently we showed that auxin promotes cell interdigitation by activating the Rho family ROP GTPases in leaf epidermal pavement cells. Here we found that auxin activation of the ROP2 signaling pathway regulates the asymmetric distribution of PIN1 by inhibiting its endocytosis. ROP2 inhibits PIN1 endocytosis via the accumulation of cortical actin microfilaments induced by the ROP2 effector protein RIC4. Our findings suggest a link between the developmental auxin signal and polar PIN1 distribution via Rho-dependent cytoskeletal reorganization and reveal the conservation of a design principle for cell polarization that is based on Rho GTPase-mediated inhibition of endocytosis. PMID- 22509135 TI - Stitching together multiple data dimensions reveals interacting metabolomic and transcriptomic networks that modulate cell regulation. AB - Cells employ multiple levels of regulation, including transcriptional and translational regulation, that drive core biological processes and enable cells to respond to genetic and environmental changes. Small-molecule metabolites are one category of critical cellular intermediates that can influence as well as be a target of cellular regulations. Because metabolites represent the direct output of protein-mediated cellular processes, endogenous metabolite concentrations can closely reflect cellular physiological states, especially when integrated with other molecular-profiling data. Here we develop and apply a network reconstruction approach that simultaneously integrates six different types of data: endogenous metabolite concentration, RNA expression, DNA variation, DNA protein binding, protein-metabolite interaction, and protein-protein interaction data, to construct probabilistic causal networks that elucidate the complexity of cell regulation in a segregating yeast population. Because many of the metabolites are found to be under strong genetic control, we were able to employ a causal regulator detection algorithm to identify causal regulators of the resulting network that elucidated the mechanisms by which variations in their sequence affect gene expression and metabolite concentrations. We examined all four expression quantitative trait loci (eQTL) hot spots with colocalized metabolite QTLs, two of which recapitulated known biological processes, while the other two elucidated novel putative biological mechanisms for the eQTL hot spots. PMID- 22509134 TI - Social transfer of pathogenic fungus promotes active immunisation in ant colonies. AB - Due to the omnipresent risk of epidemics, insect societies have evolved sophisticated disease defences at the individual and colony level. An intriguing yet little understood phenomenon is that social contact to pathogen-exposed individuals reduces susceptibility of previously naive nestmates to this pathogen. We tested whether such social immunisation in Lasius ants against the entomopathogenic fungus Metarhizium anisopliae is based on active upregulation of the immune system of nestmates following contact to an infectious individual or passive protection via transfer of immune effectors among group members--that is, active versus passive immunisation. We found no evidence for involvement of passive immunisation via transfer of antimicrobials among colony members. Instead, intensive allogrooming behaviour between naive and pathogen-exposed ants before fungal conidia firmly attached to their cuticle suggested passage of the pathogen from the exposed individuals to their nestmates. By tracing fluorescence labelled conidia we indeed detected frequent pathogen transfer to the nestmates, where they caused low-level infections as revealed by growth of small numbers of fungal colony forming units from their dissected body content. These infections rarely led to death, but instead promoted an enhanced ability to inhibit fungal growth and an active upregulation of immune genes involved in antifungal defences (defensin and prophenoloxidase, PPO). Contrarily, there was no upregulation of the gene cathepsin L, which is associated with antibacterial and antiviral defences, and we found no increased antibacterial activity of nestmates of fungus exposed ants. This indicates that social immunisation after fungal exposure is specific, similar to recent findings for individual-level immune priming in invertebrates. Epidemiological modeling further suggests that active social immunisation is adaptive, as it leads to faster elimination of the disease and lower death rates than passive immunisation. Interestingly, humans have also utilised the protective effect of low-level infections to fight smallpox by intentional transfer of low pathogen doses ("variolation" or "inoculation"). PMID- 22509137 TI - The role of public health institutions in global health system strengthening efforts: the US CDC's perspective. PMID- 22509136 TI - Medical evidence of human rights violations against non-Arabic-speaking civilians in Darfur: a cross-sectional study. AB - BACKGROUND: Ongoing conflict in the Darfur region of Sudan has resulted in a severe humanitarian crisis. We sought to characterize the nature and geographic scope of allegations of human rights violations perpetrated against civilians in Darfur and to evaluate their consistency with medical examinations documented in patients' medical records. METHODS AND FINDINGS: This was a retrospective review and analysis of medical records from all 325 patients seen for treatment from September 28, 2004, through December 31, 2006, at the Nyala-based Amel Centre for Treatment and Rehabilitation of Victims of Torture, the only dedicated local provider of free clinical and legal services to civilian victims of torture and other human rights violations in Darfur during this time period. Among 325 medical records identified and examined, 292 (89.8%) patients from 12 different non-Arabic-speaking tribes disclosed in the medical notes that they had been attacked by Government of Sudan (GoS) and/or Janjaweed forces. Attacks were reported in 23 different rural council areas throughout Darfur. Nearly all attacks (321 [98.8%]) were described as having occurred in the absence of active armed conflict between Janjaweed/GoS forces and rebel groups. The most common alleged abuses were beatings (161 [49.5%]), gunshot wounds (140 [43.1%]), destruction or theft of property (121 [37.2%]), involuntary detainment (97 [29.9%]), and being bound (64 [19.7%]). Approximately one-half (36 [49.3%]) of all women disclosed that they had been sexually assaulted, and one-half of sexual assaults were described as having occurred in close proximity to a camp for internally displaced persons. Among the 198 (60.9%) medical records that contained sufficient detail to enable the forensic medical reviewers to render an informed judgment, the signs and symptoms in all of the medical records were assessed to be consistent with, highly consistent with, or virtually diagnostic of the alleged abuses. CONCLUSIONS: Allegations of widespread and sustained torture and other human rights violations by GoS and/or Janjaweed forces against non-Arabic-speaking civilians were corroborated by medical forensic review of medical records of patients seen at a local non-governmental provider of free clinical and legal services in Darfur. Limitations of this study were that patients seen in this clinic may not have been a representative sample of persons alleging abuse by Janjaweed/GoS forces, and that most delayed presenting for care. The quality of documentation was similar to that available in other conflict/post-conflict, resource-limited settings. PMID- 22509138 TI - Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta analysis of randomised controlled trials. AB - BACKGROUND: The UK Prospective Diabetes Study showed that metformin decreases mortality compared to diet alone in overweight patients with type 2 diabetes mellitus. Since then, it has been the first-line treatment in overweight patients with type 2 diabetes. However, metformin-sulphonylurea bitherapy may increase mortality. METHODS AND FINDINGS: This meta-analysis of randomised controlled trials evaluated metformin efficacy (in studies of metformin versus diet alone, versus placebo, and versus no treatment; metformin as an add-on therapy; and metformin withdrawal) against cardiovascular morbidity or mortality in patients with type 2 diabetes. We searched Medline, Embase, and the Cochrane database. Primary end points were all-cause mortality and cardiovascular death. Secondary end points included all myocardial infarctions, all strokes, congestive heart failure, peripheral vascular disease, leg amputations, and microvascular complications. Thirteen randomised controlled trials (13,110 patients) were retrieved; 9,560 patients were given metformin, and 3,550 patients were given conventional treatment or placebo. Metformin did not significantly affect the primary outcomes all-cause mortality, risk ratio (RR)=0.99 (95% CI: 0.75 to 1.31), and cardiovascular mortality, RR=1.05 (95% CI: 0.67 to 1.64). The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR=0.90 (95% CI: 0.74 to 1.09); all strokes, RR=0.76 (95% CI: 0.51 to 1.14); heart failure, RR=1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR=0.90 (95% CI: 0.46 to 1.78); leg amputations, RR=1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR=0.83 (95% CI: 0.59 to 1.17). For all-cause mortality and cardiovascular mortality, there was significant heterogeneity when including the UK Prospective Diabetes Study subgroups (I(2)=41% and 59%). There was significant interaction with sulphonylurea as a concomitant treatment for myocardial infarction (p=0.10 and 0.02, respectively). CONCLUSIONS: Although metformin is considered the gold standard, its benefit/risk ratio remains uncertain. We cannot exclude a 25% reduction or a 31% increase in all-cause mortality. We cannot exclude a 33% reduction or a 64% increase in cardiovascular mortality. Further studies are needed to clarify this situation. PMID- 22509144 TI - The effect of alpha- or beta-casein addition to waxy maize starch on postprandial levels of glucose, insulin, and incretin hormones in pigs as a model for humans. AB - BACKGROUND: Starch is a main source of glucose and energy in the human diet. The extent to which it is digested in the gastrointestinal tract plays a major role in variations in postprandial blood glucose levels. Interactions with other biopolymers, such as dairy proteins, during processing can influence both the duration and extent of this postprandial surge. OBJECTIVE: To evaluate the effect of the addition of bovine alpha- or beta-casein to waxy maize starch on changes in postprandial blood glucose, insulin, and incretin hormones [glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1)] in 30 kg pigs used as an animal model for humans. DESIGN: Gelatinised starch, starch gelatinised with alpha-casein, and starch gelatinised with beta-casein were orally administered to trained pigs (n = 8) at a level of 60 g of available carbohydrate. Pre- and postprandial glucose measurements were taken every 15 min for the first hour and every 30 min thereafter up to 180 min. Insulin, GIP, and GLP-1 levels were measured in plasma samples up to 90 min postprandial. RESULTS: Starch gelatinised with alpha-casein had a significantly (p < 0.05) lower peak viscosity on pasting and resulted in significantly lower glucose release at 15, 30, and 90 min postprandial compared to starch gelatinised with beta-casein. During the first 45-min postprandial, the area under the glucose curve (AUC) for starch gelatinised with alpha-casein was significantly (p < 0.05) lower than that for starch gelatinised with beta-casein. There was also a significant (p < 0.05) difference at T30 in GIP levels in response to the control compared to starch gelatinised with alpha- or beta-casein. Significant (p < 0.05) increases in several free amino acid concentrations were observed on ingestion of either alpha or beta-casein gelatinised with starch at 30 and 90 min postprandial compared to starch alone. In addition, plasma levels of six individual amino acids were increased on ingestion of starch gelatinised with alpha-casein compared to ingestion of starch gelatinised with beta-casein. CONCLUSION: The presence of casein fractions (alpha- or beta-casein) in gelatinised waxy maize starch affects swelling characteristics, viscosity, and subsequent in vivo digestion as determined by glucose levels in blood postprandial. PMID- 22509143 TI - Homocysteine as a potential biochemical marker for depression in elderly stroke survivors. AB - BACKGROUND: Elderly stroke survivors have been reported to be at risk of malnutrition and depression. Vitamin B-related metabolites such as methylmalonic acid and homocysteine have been implicated in depression. OBJECTIVE: We conducted a study exploring the relationship between homocysteine and post-stroke depression. DESIGN: THREE METHODOLOGIES WERE USED: Observational cohort study of elderly Swedish patients (n=149) 1.5 years post-stroke, assessed using Diagnostic and Statistical Manual of Mental Disorders, Montgomery Asberg Depression Rating Scale and serum blood levels of methylmalonic acid and homocysteine. RESULTS: Homocysteine significantly correlated with depressive symptomatology in stroke survivors (beta=0.18*). Individuals with abnormal levels of methylmalonic acid and homocysteine were almost twice more likely to show depressive symptomatology than those with normal levels (depressive symptoms 22%; no depressive symptoms 12%). Comparison of methylmalonic acid and homocysteine levels with literature data showed fewer stroke survivors had vitamin deficiency than did reference individuals (normal range 66%; elevated 34%). CONCLUSIONS: Homocysteine is significantly associated with depressive symptomatology in elderly Swedish stroke survivors. PMID- 22509142 TI - Fine-scale mapping of natural variation in fly fecundity identifies neuronal domain of expression and function of an aquaporin. AB - To gain insight into the molecular genetic basis of standing variation in fitness related traits, we identify a novel factor that regulates the molecular and physiological basis of natural variation in female Drosophila melanogaster fecundity. Genetic variation in female fecundity in flies derived from a wild orchard population is heritable and largely independent of other measured life history traits. We map a portion of this variation to a single QTL and then use deficiency mapping to further refine this QTL to 5 candidate genes. Ubiquitous expression of RNAi against only one of these genes, an aquaporin encoded by Drip, reduces fecundity. Within our mapping population Drip mRNA level in the head, but not other tissues, is positively correlated with fecundity. We localize Drip expression to a small population of corazonin producing neurons located in the dorsolateral posterior compartments of the protocerebrum. Expression of Drip-RNAi using both the pan-neuronal ELAV-Gal4 and the Crz-Gal4 drivers reduces fecundity. Low-fecundity RILs have decreased Crz expression and increased expression of pale, the enzyme encoding the rate-limiting step in the production of dopamine, a modulator of insect life histories. Taken together these data suggest that natural variation in Drip expression in the corazonin producing neurons contributes to standing variation in fitness by altering the concentration of two neurohormones. PMID- 22509145 TI - Invited commentary to the paper 'Zinc status and its association with the health of adolescents: a review of studies in India'. AB - We are pleased to view the article based on Dr. Rama Kawade's thesis illustrating the importance of micronutrient adequacy, especially zinc, and associated health implications in Indian adolescent girls. This brief commentary addresses three major aspects in which Kawade's work has made a significant contribution; nutrition and health issues of adolescents, rising importance of zinc in terms of deficiency problems being addressed, and development of dietary interventions to alleviate micronutrient deficiencies. PMID- 22509146 TI - Ethanol Activation of Protein Kinase A Regulates GABA(A) Receptor Subunit Expression in the Cerebral Cortex and Contributes to Ethanol-Induced Hypnosis. AB - Protein kinases are implicated in neuronal cell functions such as modulation of ion channel function, trafficking, and synaptic excitability. Both protein kinase C (PKC) and A (PKA) are involved in regulation of gamma-aminobutyric acid type A (GABA(A)) receptors through phosphorylation. However, the role of PKA in regulating GABA(A) receptors (GABA(A)-R) following acute ethanol exposure is not known. The present study investigated the role of PKA in the effects of ethanol on GABA(A)-R alpha1 subunit expression in rat cerebral cortical P2 synaptosomal fractions. Additionally, GABA-related behaviors were examined. Rats were administered ethanol (2.0-3.5 g/kg) or saline and PKC, PKA, and GABA(A)-R alpha1 subunit levels were measured by western blot analysis. Ethanol (3.5 g/kg) transiently increased GABA(A)-R alpha1 subunit expression and PKA RIIbeta subunit expression at similar time points whereas PKA RIIalpha was increased at later time points. In contrast, PKC isoform expression remained unchanged. Notably, lower ethanol doses (2.0 g/kg) had no effect on GABA(A)-R alpha1 subunit levels, although PKA type II regulatory subunits RIIalpha and RIIbeta were increased at 10 and 60 min when PKC isozymes are also known to be elevated. To determine if PKA activation was responsible for the ethanol-induced elevation of GABA(A)-R alpha1 subunits, the PKA antagonist H89 was administered to rats prior to ethanol exposure. H89 administration prevented ethanol-induced increases in GABA(A)-R alpha1 subunit expression. Moreover, increasing PKA activity intracerebroventricularly with Sp-cAMP prior to a hypnotic dose of ethanol increased ethanol-induced loss of righting reflex (LORR) duration. This effect appears to be mediated in part by GABA(A)-R as increasing PKA activity also increased the duration of muscimol-induced LORR. Overall, these data suggest that PKA mediates ethanol-induced GABA(A)-R expression and contributes to behavioral effects of ethanol involving GABA(A)-R. PMID- 22509147 TI - Alteration of forebrain neurogenesis after cervical spinal cord injury in the adult rat. AB - Spinal cord injury (SCI) triggers a complex cellular response at the injury site, leading to the formation of a dense scar tissue. Despite this local tissue remodeling, the consequences of SCI at the cellular level in distant rostral sites (i.e., brain), remain unknown. In this study, we asked whether cervical SCI could alter cell dynamics in neurogenic areas of the adult rat forebrain. To this aim, we quantified BrdU incorporation and determined the phenotypes of newly generated cells (neurons, astrocytes, or microglia) during the subchronic and chronic phases of injury. We find that subchronic SCI leads to a reduction of BrdU incorporation and neurogenesis in the olfactory bulb and in the hippocampal dentate gyrus. By contrast, subchronic SCI triggers an increased BrdU incorporation in the dorsal vagal complex of the hindbrain, where most of the newly generated cells are identified as microglia. In chronic condition 90 days after SCI, BrdU incorporation returns to control levels in all regions examined, except in the hippocampus, where SCI produces a long-term reduction of neurogenesis, indicating that this structure is particularly sensitive to SCI. Finally, we observe that SCI triggers an acute inflammatory response in all brain regions examined, as well as a hippocampal-specific decline in BDNF levels. This study provides the first demonstration that forebrain neurogenesis is vulnerable to a distal SCI. PMID- 22509150 TI - Regenerating wnts. PMID- 22509148 TI - Cause or Effect: Misregulation of microRNA Pathways in Neurodegeneration. AB - During normal aging or neurodegenerative diseases, neuronal survival and function depend on protein homeostasis, which is regulated by multiple mechanisms, including the microRNA (miRNA) pathway. In different cells types, the absence of Dicer, a key miRNA processing enzyme, leads to neurodegeneration through cell autonomous and non-cell-autonomous mechanisms. Loss of certain miRNAs also causes neurodegeneration in some model organisms. On the other hand, miRNA expression is misregulated in patients with different neurodegenerative diseases. Thus, the miRNA pathway appears to be essential in the pathogenesis of several age dependent neurodegenerative conditions; however, our understanding of the underlying mechanism remains rudimentary. The precise causal relationships between specific miRNAs and neurodegeneration in humans need to be further investigated. PMID- 22509151 TI - Antithetical modes of and the Ca(2+) sensors targeting in ANF-RGC and ROS-GC1 membrane guanylate cyclases. AB - THE MEMBRANE GUANYLATE CYCLASE FAMILY HAS BEEN BRANCHED INTO THREE SUBFAMILIES: natriuretic peptide hormone surface receptors, Ca(2+)-modulated neuronal ROS-GC, and Ca(2+)-modulated odorant surface receptor ONE-GC. The first subfamily is solely modulated by the extracellularly generated hormonal signals; the second, by the intracellularly generated sensory and sensory-linked signals; and the third, by combination of these two. The present study defines a new paradigm and a new mechanism of Ca(2+) signaling. (1) It demonstrates for the first time that ANF-RGC, the prototype member of the surface receptor subfamily, is stimulated by free [Ca(2+)](i). The stimulation occurs via myristoylated form of neurocalcin delta, and both the guanylate cyclase and the calcium sensor neurocalcin delta are present in the glomerulosa region of the adrenal gland. (2) The EF-2, EF-3 and EF-4 hands of GCAP1 sense the progressive increment of [Ca(2+)](i) and with a K(1/2) of 100 nM turn ROS-GC1 "OFF." In total reversal, the same EF hands upon sensing the progressive increment of [Ca(2+)](i) with K(1/2) turn ONE-GC "ON." The findings suggest a universal Ca(2+)-modulated signal transduction theme of the membrane guanylate cyclase family; demonstrate that signaling of ANF-RGC occurs by the peptide hormones and also by [Ca(2+)](i) signals; that for the Ca(2+) signal transduction, ANF-RGC functions as a two-component transduction system consisting of the Ca(2+) sensor neurocalcin delta and the transducer ANF RGC; and that the neurocalcin delta in this case expands beyond its NCS family. Furthermore, the study shows a novel mechanism of the [Ca(2+)](i) sensor GCAP1 where it acts as an antithetical NCS for the signaling mechanisms of ROS-GC1 and ONE-GC. PMID- 22509152 TI - Neurological functions of the masterswitch protein kinase - gsk-3. PMID- 22509149 TI - Ca(2+)-sensors and ROS-GC: interlocked sensory transduction elements: a review. AB - From its initial discovery that ROS-GC membrane guanylate cyclase is a mono-modal Ca(2+)-transduction system linked exclusively with the photo-transduction machinery to the successive finding that it embodies a remarkable bimodal Ca(2+) signaling device, its widened transduction role in the general signaling mechanisms of the sensory neuron cells was envisioned. A theoretical concept was proposed where Ca(2+)-modulates ROS-GC through its generated cyclic GMP via a nearby cyclic nucleotide gated channel and creates a hyper- or depolarized sate in the neuron membrane (Ca(2+) Binding Proteins 1:1, 7-11, 2006). The generated electric potential then becomes a mode of transmission of the parent [Ca(2+)](i) signal. Ca(2+) and ROS-GC are interlocked messengers in multiple sensory transduction mechanisms. This comprehensive review discusses the developmental stages to the present status of this concept and demonstrates how neuronal Ca(2+) sensor (NCS) proteins are the interconnected elements of this elegant ROS-GC transduction system. The focus is on the dynamism of the structural composition of this system, and how it accommodates selectivity and elasticity for the Ca(2+) signals to perform multiple tasks linked with the SENSES of vision, smell, and possibly of taste and the pineal gland. An intriguing illustration is provided for the Ca(2+) sensor GCAP1 which displays its remarkable ability for its flexibility in function from being a photoreceptor sensor to an odorant receptor sensor. In doing so it reverses its function from an inhibitor of ROS-GC to the stimulator of ONE-GC membrane guanylate cyclase. PMID- 22509153 TI - Potentials of endogenous neural stem cells in cortical repair. AB - In the last few decades great thrust has been put in the area of regenerative neurobiology research to combat brain injuries and neurodegenerative diseases. The recent discovery of neurogenic niches in the adult brain has led researchers to study how to mobilize these cells to orchestrate an endogenous repair mechanism. The brain can minimize injury-induced damage by means of an immediate glial response and by initiating repair mechanisms that involve the generation and mobilization of new neurons to the site of injury where they can integrate into the existing circuit. This review highlights the current status of research in this field. Here, we discuss the changes that take place in the neurogenic milieu following injury. We will focus, in particular, on the cellular and molecular controls that lead to increased proliferation in the Sub ventricular Zone (SVZ) as well as neurogenesis. We will also concentrate on how these cellular and molecular mechanisms influence the migration of new cells to the affected area and their differentiation into neuronal/glial lineage that initiate the repair mechanism. Next, we will discuss some of the different factors that limit/retard the repair process and highlight future lines of research that can help to overcome these limitations. A clear understanding of the underlying molecular mechanisms and physiological changes following brain damage and the subsequent endogenous repair should help us develop better strategies to repair damaged brains. PMID- 22509154 TI - Interactions between noradrenaline and corticosteroids in the brain: from electrical activity to cognitive performance. AB - One of the core reactions in response to a stressful situation is the activation of the hypothalamus-pituitary-adrenal axis which increases the release of glucocorticoid hormones from the adrenal glands. In concert with other neuro modulators, such as (nor)adrenaline, these hormones enable and promote cognitive adaptation to stressful events. Recent studies have demonstrated that glucocorticoid hormones and noradrenaline, via their receptors, can both rapidly and persistently regulate the function of excitatory synapses which are critical for storage of information. Here we will review how glucocorticoids and noradrenaline alone and in synergy dynamically tune these synapses in the hippocampus and amygdala, and discuss how these hormones interact to promote behavioral adaptation to stressful situations. PMID- 22509156 TI - Recovery of neurofilament following early monocular deprivation. AB - Postnatal development of the mammalian geniculostriate visual pathway is partly guided by visually driven activity. Disruption of normal visual input during certain critical periods can alter the structure of neurons, as well as their connections and functional properties. Within the layers of the dorsal lateral geniculate nucleus (dLGN), a brief early period of monocular deprivation can alter the structure and soma size of neurons within deprived-eye-receiving layers. This modification of structure is accompanied by a marked reduction in labeling for neurofilament protein, a principle component of the stable cytoskeleton. This study examined the extent of neurofilament recovery in monocularly deprived cats that either had their deprived eye opened (binocular recovery), or had the deprivation reversed to the fellow eye (reverse occlusion). The loss of neurofilament and the reduction of soma size caused by monocular deprivation were ameliorated equally and substantially in both recovery conditions after 8 days. The degree to which this recovery was dependent on visually driven activity was examined by placing monocularly deprived animals in complete darkness. Though monocularly deprived animals placed in darkness showed recovery of soma size in deprived layers, the manipulation catalyzed a loss of neurofilament labeling that extended to non-deprived layers as well. Overall, these results indicate that both recovery of soma size and neurofilament labeling is achieved by removal of the competitive disadvantage of the deprived eye. However, while the former occurred even in the absence of visually driven activity, recovery of neurofilament did not. The finding that a period of darkness produced an overall loss of neurofilament throughout the dLGN suggests that this experiential manipulation may cause the visual pathways to revert to an earlier more plastic developmental stage. It is possible that short periods of darkness could be incorporated as a component of therapeutic measures for treatment of deprivation-induced disorders such as amblyopia. PMID- 22509155 TI - Neuroimaging and neuromodulation: complementary approaches for identifying the neuronal correlates of tinnitus. AB - An inherent limitation of functional imaging studies is their correlational approach. More information about critical contributions of specific brain regions can be gained by focal transient perturbation of neural activity in specific regions with non-invasive focal brain stimulation methods. Functional imaging studies have revealed that tinnitus is related to alterations in neuronal activity of central auditory pathways. Modulation of neuronal activity in auditory cortical areas by repetitive transcranial magnetic stimulation (rTMS) can reduce tinnitus loudness and, if applied repeatedly, exerts therapeutic effects, confirming the relevance of auditory cortex activation for tinnitus generation and persistence. Measurements of oscillatory brain activity before and after rTMS demonstrate that the same stimulation protocol has different effects on brain activity in different patients, presumably related to interindividual differences in baseline activity in the clinically heterogeneous study cohort. In addition to alterations in auditory pathways, imaging techniques also indicate the involvement of non-auditory brain areas, such as the fronto-parietal "awareness" network and the non-tinnitus-specific distress network consisting of the anterior cingulate cortex, anterior insula, and amygdale. Involvement of the hippocampus and the parahippocampal region putatively reflects the relevance of memory mechanisms in the persistence of the phantom percept and the associated distress. Preliminary studies targeting the dorsolateral prefrontal cortex, the dorsal anterior cingulate cortex, and the parietal cortex with rTMS and with transcranial direct current stimulation confirm the relevance of the mentioned non-auditory networks. Available data indicate the important value added by brain stimulation as a complementary approach to neuroimaging for identifying the neuronal correlates of the various clinical aspects of tinnitus. PMID- 22509157 TI - Proton- and ammonium-sensing by histaminergic neurons controlling wakefulness. AB - The histaminergic neurons in the tuberomamillary nucleus (TMN) of the posterior hypothalamus are involved in the control of arousal. These neurons are sensitive to hypercapnia as has been shown in experiments examining c-Fos expression, a marker for increased neuronal activity. We investigated the mechanisms through which TMN neurons respond to changes in extracellular levels of acid/CO(2). Recordings in rat brain slices revealed that acidification within the physiological range (pH from 7.4 to 7.0), as well as ammonium chloride (5 mM), excite histaminergic neurons. This excitation is significantly reduced by antagonists of type I metabotropic glutamate receptors and abolished by benzamil, an antagonist of acid-sensing ion channels (ASICs) and Na(+)/Ca(2+) exchanger, or by ouabain which blocks Na(+)/K(+) ATPase. We detected variable combinations of 4 known types of ASICs in single TMN neurons, and observed activation of ASICs in single dissociated TMN neurons only at pH lower than 7.0. Thus, glutamate, which is known to be released by glial cells and orexinergic neurons, amplifies the acid/CO(2)-induced activation of TMN neurons. This amplification demands the coordinated function of metabotropic glutamate receptors, Na(+)/Ca(2+) exchanger and Na(+)/K(+) ATPase. We also developed a novel HDC-Cre transgenic reporter mouse line in which histaminergic TMN neurons can be visualized. In contrast to the rat, the mouse histaminergic neurons lacked the pH 7.0-induced excitation and displayed only a minimal response to the mGluR I agonist DHPG (0.5 MUM). On the other hand, ammonium-induced excitation was similar in mouse and rat. These results are relevant for the understanding of the neuronal mechanisms controlling acid/CO(2)-induced arousal in hepatic encephalopathy and obstructive sleep apnoea. Moreover, the new HDC-Cre mouse model will be a useful tool for studying the physiological and pathophysiological roles of the histaminergic system. PMID- 22509158 TI - Spatiotemporal properties of sensory responses in vivo are strongly dependent on network context. AB - Sensory responses in neocortex are strongly modulated by changes in brain state, such as those observed between sleep stages or attentional levels. However, the specific effects of network state changes on the spatiotemporal properties of sensory responses are poorly understood. The slow oscillation, which is observed in neocortex under ketamine-xylazine anesthesia and is characterized by alternating depolarizing (up-states) and hyperpolarizing (down-states) phases, provides an opportunity to study the state-dependence of primary sensory responses in large networks. Here we used voltage sensitive dye (VSD) imaging to record the spatiotemporal properties of sensory responses and local field potential (LFP) and multiunit activity (MUA) recordings to monitor the ongoing brain state in which the sensory responses occurred. Despite a rich variability of slow oscillation patterns, sensory responses showed a consistent relationship with the ongoing oscillation and triggered a new up-state only after the termination of the refractory period that followed the preceding oscillatory cycle. We show that spatiotemporal properties of whisker-evoked responses are highly dependent on their timing with regard to the ongoing oscillation. In both the up- and down-states, responses spread across large portions of the barrel field, although the up-state responses were reduced in total area due to their sparseness. The depolarizing response in the up-state showed a tendency to propagate along the rows, with an amplitude and slope favoring the higher numbered arcs. In the up-state, but not in the down-state, the depolarizing response was followed by a hyperpolarizing wave with a consistent spatial structure. We measured the suppression of whisker-evoked responses by a preceding response at 100 ms, and found that suppression showed the same spatial asymmetry as the depolarization. Because the resting level of cells in the up-state is likely to be closer to that in the awake animal, we suggest that the polarities in signal propagation which we observed in the up-state could be used as computational mechanisms in the behaving animal. These results demonstrate the critical importance of ongoing network activity on the dynamics of sensory responses and their integration. PMID- 22509160 TI - On-line social interactions and executive functions. AB - A successful social interaction often requires on-line and active construction of an ever-changing mental-model of another person's beliefs, expectations, emotions, and desires. It also requires the ability to maintain focus, problem solve, and flexibly pursue goals in a distraction-rich environment, as well as the ability to take-turns and inhibit inappropriate behaviors. Many of these tasks rely on executive functions (EF) - working memory, attention/cognitive control, and inhibition. Executive functioning has long been viewed as relatively static. However, starting with recent reports of successful cognitive interventions, this view is changing and now EFs are seen as much more open to both short- and long-term "training," "warm-up," and "exhaustion" effects. Some of the most intriguing evidence suggests that engaging in social interaction enhances performance on standard EF tests. Interestingly, the latest research indicates these EF benefits are selectively conferred by certain on-line, dynamic social interactions, which require participants to mentally engage with another person and actively construct a model of their mind. We review this literature and highlight its connection with evolutionary and cultural theories emphasizing links between intelligence and sociality. PMID- 22509159 TI - Multisensory stimulation in stroke rehabilitation. AB - The brain has a large capacity for automatic simultaneous processing and integration of sensory information. Combining information from different sensory modalities facilitates our ability to detect, discriminate, and recognize sensory stimuli, and learning is often optimal in a multisensory environment. Currently used multisensory stimulation methods in stroke rehabilitation include motor imagery, action observation, training with a mirror or in a virtual environment, and various kinds of music therapy. Non-invasive brain stimulation has showed promising preliminary results in aphasia and neglect. Patient heterogeneity and the interaction of age, gender, genes, and environment are discussed. Randomized controlled longitudinal trials starting earlier post-stroke are needed. The advance in brain network science and neuroimaging enabling longitudinal studies of structural and functional networks are likely to have an important impact on patient selection for specific interventions in future stroke rehabilitation. It is proposed that we should pay more attention to age, gender, and laterality in clinical studies. PMID- 22509162 TI - Acute tryptophan depletion attenuates brain-heart coupling following external feedback. AB - External and internal performance feedback triggers neural and visceral modulations such as reactions in the medial prefrontal cortex and insulae or changes of heart period (HP). The functional coupling of neural and cardiac responses following feedback (cortico-cardiac connectivity) is not well understood. While linear time-lagged within-subjects correlations of single-trial EEG and HP (cardio-electroencephalographic covariance tracing, CECT) indicate a robust negative coupling of EEG magnitude 300 ms after presentation of an external feedback stimulus with subsequent alterations of heart period (the so called N300H phenomenon), the neurotransmitter systems underlying feedback-evoked cortico-cardiac connectivity are largely unknown. Because it has been shown that acute tryptophan depletion (ATD), attenuating brain serotonin (5-HT), decreases cardiac but not neural correlates of feedback processing, we hypothesized that 5 HT may be involved in feedback-evoked cortico-cardiac connectivity. In a placebo controlled double-blind cross-over design, 12 healthy male participants received a tryptophan-free amino-acid drink at one session (TRP-) and a balanced amino acid control-drink (TRP+) on another and twice performed a time-estimation task with feedback presented after each trial. N300H magnitude and plasma tryptophan levels were assessed. Results indicated a robust N300H after TRP+, which was significantly attenuated following TRP-. Moreover, plasma tryptophan levels during TRP+ were correlated with N300H amplitude such that individuals with lower tryptophan levels showed reduced N300H. Together, these findings indicate that 5 HT is important for feedback-induced covariation of cortical and cardiac activity. Because individual differences in anxiety have previously been linked to 5-HT, cortico-cardiac coupling and feedback processing, the present findings may be particularly relevant for futures studies on the relationship between 5-HT and anxiety. PMID- 22509161 TI - Training the developing brain: a neurocognitive perspective. AB - DEVELOPMENTAL TRAINING STUDIES ARE IMPORTANT TO INCREASE OUR UNDERSTANDING OF THE POTENTIAL OF THE DEVELOPING BRAIN BY PROVIDING ANSWERS TO QUESTIONS SUCH AS: "Which functions can and which functions cannot be improved as a result of practice?," "Is there a specific period during which training has more impact?," and "Is it always advantageous to train a particular function?"In addition, neuroimaging methods provide valuable information about the underlying mechanisms that drive cognitive plasticity. In this review, we describe how neuroscientific studies of training effects inform us about the possibilities of the developing brain, pointing out that childhood is a special period during which training may have different effects. We conclude that there is much complexity in interpreting training effects in children. Depending on the type of training and the level of maturation of the individual, training may influence developmental trajectories in different ways. We propose that the immature brain structure might set limits on how much can be achieved with training, but that the immaturity can also have advantages, in terms of flexibility for learning. PMID- 22509163 TI - Targets for a comparative neurobiology of language. AB - One longstanding impediment to progress in understanding the neural basis of language is the development of model systems that retain language-relevant cognitive behaviors yet permit invasive cellular neuroscience methods. Recent experiments in songbirds suggest that this group may be developed into a powerful animal model, particularly for components of grammatical processing. It remains unknown, however, what a neuroscience of language perception may look like when instantiated at the cellular or network level. Here we deconstruct language perception into a minimal set of cognitive processes necessary to support grammatical processing. We then review the current state of our understanding about the neural mechanisms of these requisite cognitive processes in songbirds. We note where current knowledge is lacking, and suggest how these mechanisms may ultimately combine to support an emergent mechanism capable of processing grammatical structures of differing complexity. PMID- 22509164 TI - Quality Difference Study of Six Varieties of Ganoderma lucidum with Different Origins. AB - The quality difference of six varieties Ganoderma lucidum with different origins was investigated in this study by comparing the contents of ganoderic acid A and B, polysaccharide, and triterpenoids. The contents of ganoderic acid A and B in G. lucidum were analyzed by ultra performance liquid chromatography (UPLC). There was higher content of ganoderic acid A in G. lucidum of Dabie Mountain and Longquan. The G. lucidum from Longquan has the highest content of ganoderic acid B. The content of polysaccharide was determined by Anthrone-sulfuric acid method. The highest of polysaccharide content is G. lucidum from Liaocheng. The content of triterpenoid in G. lucidum was quantified by ultraviolet spectrophotometer at 548.1 nm using Ursolic acid as standard. The G. lucidum from Dabie Mountain has the highest content of triterpenoids. In summary, the content of ganoderic acid A and B, polysaccharide, and triterpenoids in G. lucidum with different origins are remarkably different, which may be caused by the conditions of cultivation and geographic environment. PMID- 22509165 TI - The ketogenic diet as a treatment paradigm for diverse neurological disorders. AB - Dietary and metabolic therapies have been attempted in a wide variety of neurological diseases, including epilepsy, headache, neurotrauma, Alzheimer disease, Parkinson disease, sleep disorders, brain cancer, autism, pain, and multiple sclerosis. The impetus for using various diets to treat - or at least ameliorate symptoms of - these disorders stems from both a lack of effectiveness of pharmacological therapies, and also the intrinsic appeal of implementing a more "natural" treatment. The enormous spectrum of pathophysiological mechanisms underlying the aforementioned diseases would suggest a degree of complexity that cannot be impacted universally by any single dietary treatment. Yet, it is conceivable that alterations in certain dietary constituents could affect the course and impact the outcome of these brain disorders. Further, it is possible that a final common neurometabolic pathway might be influenced by a variety of dietary interventions. The most notable example of a dietary treatment with proven efficacy against a neurological condition is the high-fat, low carbohydrate ketogenic diet (KD) used in patients with medically intractable epilepsy. While the mechanisms through which the KD works remain unclear, there is now compelling evidence that its efficacy is likely related to the normalization of aberrant energy metabolism. The concept that many neurological conditions are linked pathophysiologically to energy dysregulation could well provide a common research and experimental therapeutics platform, from which the course of several neurological diseases could be favorably influenced by dietary means. Here we provide an overview of studies using the KD in a wide panoply of neurologic disorders in which neuroprotection is an essential component. PMID- 22509168 TI - The benefit of enhanced contractility in the infarct borderzone: a virtual experiment. AB - OBJECTIVES: Contractile function in the normally perfused infarct borderzone (BZ) is depressed. However, the impact of reduced BZ contractility on left ventricular (LV) pump function is unknown. As a consequence, there have been no therapies specifically designed to improve BZ contractility. We tested the hypothesis that an improvement in borderzone contractility will improve LV pump function. METHODS: From a previously reported study, magnetic resonance imaging (MRI) images with non-invasive tags were used to calculate 3D myocardial strain in five sheep 16 weeks after anteroapical myocardial infarction. Animal-specific finite element (FE) models were created using MRI data and LV pressure obtained at early diastolic filling. Analysis of borderzone function using those FE models has been previously reported. Chamber stiffness, pump function (Starling's law) and stress in the fiber, cross fiber, and circumferential directions were calculated. Animal specific FE models were performed for three cases: (a) impaired BZ contractility (INJURED); (b) BZ-contractility fully restored (100% BZ IMPROVEMENT); or (c) BZ contractility partially restored (50% BZ IMPROVEMENT). RESULTS: 100% BZ IMPROVEMENT and 50% BZ IMPROVEMENT both caused an upward shift in the Starling relationship, resulting in a large (36 and 26%) increase in stroke volume at LVP(ED) = 20 mmHg (8.0 ml, p < 0.001). Moreover, there were a leftward shift in the end-systolic pressure volume relationship, resulting in a 7 and 5% increase in LVP(ES) at 110 mmHg (7.7 ml, p < 0.005). It showed that even 50% BZ IMPROVEMENT was sufficient to drive much of the calculated increase in function. CONCLUSION: Improved borderzone contractility has a beneficial effect on LV pump function. Partial improvement of borderzone contractility was sufficient to drive much of the calculated increase in function. Therapies specifically designed to improve borderzone contractility should be developed. PMID- 22509166 TI - Molecular pathways of notch signaling in vascular smooth muscle cells. AB - Notch signaling in the cardiovascular system is important during embryonic development, vascular repair of injury, and vascular pathology in humans. The vascular smooth muscle cell (VSMC) expresses multiple Notch receptors throughout its life cycle, and responds to Notch ligands as a regulatory mechanism of differentiation, recruitment to growing vessels, and maturation. The goal of this review is to provide an overview of the current understanding of the molecular basis for Notch regulation of VSMC phenotype. Further, we will explore Notch interaction with other signaling pathways important in VSMC. PMID- 22509167 TI - Gasotransmitters: novel regulators of epithelial na(+) transport? AB - The vectorial transport of Na(+) across epithelia is crucial for the maintenance of Na(+) and water homeostasis in organs such as the kidneys, lung, or intestine. Dysregulated Na(+) transport processes are associated with various human diseases such as hypertension, the salt-wasting syndrome pseudohypoaldosteronism type 1, pulmonary edema, cystic fibrosis, or intestinal disorders, which indicate that a precise regulation of epithelial Na(+) transport is essential. Novel regulatory signaling molecules are gasotransmitters. There are currently three known gasotransmitters: nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H(2)S). These molecules are endogenously produced in mammalian cells by specific enzymes and have been shown to regulate various physiological processes. There is a growing body of evidence which indicates that gasotransmitters may also regulate Na(+) transport across epithelia. This review will summarize the available data concerning NO, CO, and H(2)S dependent regulation of epithelial Na(+) transport processes and will discuss whether or not these mediators can be considered as true physiological regulators of epithelial Na(+) transport biology. PMID- 22509169 TI - Unraveling the Influence of Arbuscular Mycorrhizal Colonization on Arsenic Tolerance in Medicago: Glomus mosseae is More Effective than G. intraradices, Associated with Lower Expression of Root Epidermal Pi Transporter Genes. AB - We used medic (Medicago truncatula) to investigate effects of inoculation with two arbuscular mycorrhizal (AM) fungi and application of arsenate (AsV) and phosphate (Pi) on mechanisms underlying increased tolerance (in terms of growth) of AM plants to AsV. We tested the hypotheses that (1) inoculation with AM fungi results in down-regulation of MtPht1;1 and MtPht1;2 genes (encoding high-affinity Pi and AsV uptake systems in the direct root epidermal pathway) and up-regulation of the AM-induced MtPht1;4 (responsible for transfer of Pi from the arbuscular interface to cortical cells), and (2) these changes are involved in decreased As uptake relative to P uptake and hence increased As tolerance. We also measured expression of MtMT4, a Pi starvation-inducible gene, other genes encoding Pi uptake systems (MtPht 1;5 and MtPht1;6) and arsenate reductase (MtACR) and phytochelatin synthase (MtPCS), to gain insights into broader aspects of P transfers in AM plants and possible detoxification mechanisms. Medic responded slightly to AM colonization in terms of growth in the absence of As, but positively in terms of P uptake. Both growth and P responses in AM plants were positive when As was applied, indicating As tolerance relative to non-mycorrhizal (NM) plants. All AM plants showed high expression of MtPT4 and those inoculated with Glomus mosseae showed higher selectivity against As (shown by P/As molar ratios) and much lower expression of MtPht1;1 (and to some extent MtPht1;2) than Glomus intraradices-inoculated or NM plants. Results are consistent with increased P/As selectivity in AM plants (particularly those inoculated with G. mosseae) as a consequence of high P uptake but little or no As uptake via the AM pathway. However, the extent to which selectivity is dependent on down-regulation of direct Pi and AsV uptake through epidermal cells is still not clear. Marked up regulation of a PCS gene and an ACR gene in AM plants may also be involved and requires further investigation. PMID- 22509170 TI - Dopamine pathology in schizophrenia: analysis of total and phosphorylated tyrosine hydroxylase in the substantia nigra. AB - INTRODUCTION: Despite the importance of dopamine neurotransmission in schizophrenia, very few studies have addressed anomalies in the mesencephalic dopaminergic neurons of the substantia nigra/ventral tegmental area (SN/VTA). Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the production of dopamine, and a possible contributor to the anomalies in the dopaminergic neurotransmission observed in schizophrenia. OBJECTIVES: In this study, we had three objectives: (1) Compare TH expression (mRNA and protein) in the SN/VTA of schizophrenia and control postmortem samples. (2) Assess the effect of antipsychotic medications on the expression of TH in the SN/VTA. (3) Examine possible regional differences in TH expression anomalies within the SN/VTA. METHODS: To achieve these objectives three independent studies were conducted: (1) A pilot study to compare TH mRNA and TH protein levels in the SN/VTA of postmortem samples from schizophrenia and controls. (2) A chronic treatment study was performed in rodents to assess the effect of antipsychotic medications in TH protein levels in the SN/VTA. (3) A second postmortem study was performed to assess TH and phosphorylated TH protein levels in two types of samples: schizophrenia and control samples containing the entire rostro-caudal extent of the SN/VTA, and schizophrenia and control samples containing only mid-caudal regions of the SN/VTA. RESULTS AND CONCLUSION: Our studies showed impairment in the dopaminergic system in schizophrenia that could be mainly (or exclusively) located in the rostral region of the SN/VTA. Our studies also showed that TH protein levels were significantly abnormal in schizophrenia, while mRNA expression levels were not affected, indicating that TH pathology in this region may occur posttranscriptionally. Lastly, our antipsychotic animal treatment study showed that TH protein levels were not significantly affected by antipsychotic treatment, indicating that these anomalies are an intrinsic pathology rather than a treatment effect. PMID- 22509171 TI - Word class and context affect alpha-band oscillatory dynamics in an older population. AB - Differences in the oscillatory EEG dynamics of reading open class (OC) and closed class (CC) words have previously been found (Bastiaansen et al., 2005) and are thought to reflect differences in lexical-semantic content between these word classes. In particular, the theta-band (4-7 Hz) seems to play a prominent role in lexical-semantic retrieval. We tested whether this theta effect is robust in an older population of subjects. Additionally, we examined how the context of a word can modulate the oscillatory dynamics underlying retrieval for the two different classes of words. Older participants (mean age 55) read words presented in either syntactically correct sentences or in a scrambled order ("scrambled sentence") while their EEG was recorded. We performed time-frequency analysis to examine how power varied based on the context or class of the word. We observed larger power decreases in the alpha (8-12 Hz) band between 200-700 ms for the OC compared to CC words, but this was true only for the scrambled sentence context. We did not observe differences in theta power between these conditions. Context exerted an effect on the alpha and low beta (13-18 Hz) bands between 0 and 700 ms. These results suggest that the previously observed word class effects on theta power changes in a younger participant sample do not seem to be a robust effect in this older population. Though this is an indirect comparison between studies, it may suggest the existence of aging effects on word retrieval dynamics for different populations. Additionally, the interaction between word class and context suggests that word retrieval mechanisms interact with sentence-level comprehension mechanisms in the alpha-band. PMID- 22509172 TI - Negative emotion does not modulate rapid feature integration effects. AB - Emotional arousal at encoding is known to facilitate later memory recall. In the present study, we asked whether this emotion-modulation of episodic memory is also evident at very short time scales, as measured by "feature integration effects," the moment-by-moment binding of relevant stimulus and response features in episodic memory. This question was motivated by recent findings that negative emotion appears to potentiate first-order trial sequence effects in classic conflict tasks, which has been attributed to emotion-modulation of conflict driven cognitive control processes. However, these effects could equally well have been carried by emotion-modulation of mnemonic feature binding processes, which were perfectly confounded with putative control processes in these studies. In the present experiments, we tried to shed light on this question by testing explicitly whether feature integration processes, assessed in isolation of conflict-control, are in fact susceptible to negative emotion-modulation. For this purpose, we adopted a standard protocol for assessing the rapid binding of stimulus and response features in episodic memory (Experiment 1) and paired it with the presentation of either neutral or fearful background face stimuli, shown either at encoding only (Experiment 2), or at both encoding and retrieval (Experiment 3). Whereas reliable feature integration effects were observed in all three experiments, no evidence for emotion-modulation of these effects was detected, in spite of significant effects of emotion on response times. These findings suggest that rapid feature integration of foreground stimulus and response features is not subject to modulation by negative emotional background stimuli and further suggest that previous reports of emotion-modulated trial transition effects are likely attributable to the effects of emotion on cognitive control processes. PMID- 22509173 TI - Glucoregulatory consequences and cardiorespiratory parameters in rats exposed to chronic-intermittent hypoxia: effects of the duration of exposure and losartan. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with glucose intolerance. Both chronic sleep disruption and recurrent blood oxygen desaturations (chronic intermittent hypoxia, CIH) may cause, or exacerbate, metabolic derangements. METHODS: To assess the impact of CIH alone, without accompanying upper airway obstructions, on the counter-regulatory response to glucose load and cardiorespiratory parameters, we exposed adult male Sprague-Dawley rats to CIH or sham room air exchanges for 10 h/day for 7, 21, or 35 days and then, 1 day after conclusion of CIH exposure, conducted intravenous glucose-tolerance tests (ivgtt) under urethane anesthesia. Additional rats underwent 35 days of CIH followed by 35 days of regular housing, or had 35 day-long CIH exposure combined with daily administration of the type 1 angiotensin II receptor antagonist, losartan (15 mg/kg, p.o.), and then were also subjected to ivgtt. RESULTS: Compared with the corresponding control groups, CIH rats had progressively reduced glucose stimulated insulin release and impaired glucose clearance, only mildly elevated heart rate and/or arterial blood pressure and slightly reduced respiratory rate. The differences in insulin release between the CIH and sham-treated rats disappeared in the rats normally housed for 35 days after 35 days of CIH/sham exposure. The losartan-treated rats had improved insulin sensitivity, with no evidence of suppressed insulin release in the CIH group. CONCLUSION: In adult rats, the glucose-stimulated insulin release is gradually suppressed with the duration of exposure to CIH, but the effect is reversible. Elimination of the detrimental effect of CIH on insulin release by losartan suggests that CIH disrupts glucoregulation through angiotensin/catecholaminergic pathways. Accordingly, treatment with continuous positive airway pressure may ameliorate pre-diabetic conditions in OSA patients, in part, by reducing sympathoexcitatory effects of recurrent nocturnal hypoxia. PMID- 22509174 TI - A Streamlined Strategy for Biohydrogen Production with Halanaerobium hydrogeniformans, an Alkaliphilic Bacterium. AB - Biofuels are anticipated to enable a shift from fossil fuels for renewable transportation and manufacturing fuels, with biohydrogen considered attractive since it could offer the largest reduction of global carbon budgets. Currently, lignocellulosic biohydrogen production remains inefficient with pretreatments that are heavily fossil fuel-dependent. However, bacteria using alkali-treated biomass could streamline biofuel production while reducing costs and fossil fuel needs. An alkaliphilic bacterium, Halanaerobiumhydrogeniformans, is described that is capable of biohydrogen production at levels rivaling neutrophilic strains, but at pH 11 and hypersaline conditions. H. hydrogeniformans ferments a variety of 5- and 6-carbon sugars derived from hemicellulose and cellulose including cellobiose, and forms the end products hydrogen, acetate, and formate. Further, it can also produce biohydrogen from switchgrass and straw pretreated at temperatures far lower than any previously reported and in solutions compatible with growth. Hence, this bacterium can potentially increase the efficiency and efficacy of biohydrogen production from renewable biomass resources. PMID- 22509175 TI - Integron involvement in environmental spread of antibiotic resistance. AB - The spread of antibiotic-resistant bacteria is a growing problem and a public health issue. In recent decades, various genetic mechanisms involved in the spread of resistance genes among bacteria have been identified. Integrons - genetic elements that acquire, exchange, and express genes embedded within gene cassettes (GC) - are one of these mechanisms. Integrons are widely distributed, especially in Gram-negative bacteria; they are carried by mobile genetic elements, plasmids, and transposons, which promote their spread within bacterial communities. Initially studied mainly in the clinical setting for their involvement in antibiotic resistance, their role in the environment is now an increasing focus of attention. The aim of this review is to provide an in-depth analysis of recent studies of antibiotic-resistance integrons in the environment, highlighting their potential involvement in antibiotic-resistance outside the clinical context. We will focus particularly on the impact of human activities (agriculture, industries, wastewater treatment, etc.). PMID- 22509178 TI - Clarifying the Relationship between Average Excesses and Average Effects of Allele Substitutions. AB - Fisher's concepts of average effects and average excesses are at the core of the quantitative genetics theory. Their meaning and relationship have regularly been discussed and clarified. Here we develop a generalized set of one locus two allele orthogonal contrasts for average excesses and average effects, based on the concept of the effective gene content of alleles. Our developments help understand the average excesses of alleles for the biallelic case. We dissect how average excesses relate to the average effects and to the decomposition of the genetic variance. PMID- 22509176 TI - Methicillin-Resistant Staphylococcus aureus Associated with Animals and Its Relevance to Human Health. AB - Staphylococcus aureus is a typical human pathogen. Some animal S. aureus lineages have derived from human strains following profound genetic adaptation determining a change in host specificity. Due to the close relationship of animals with the environmental microbiome and resistome, animal staphylococcal strains also represent a source of resistance determinants. Methicillin-resistant S. aureus (MRSA) emerged 50 years ago as a nosocomial pathogen but in the last decade it has also become a frequent cause of infections in the community. The recent finding that MRSA frequently colonizes animals, especially livestock, has been a reason for concern, as it has revealed an expanded reservoir of MRSA. While MRSA strains recovered from companion animals are generally similar to human nosocomial MRSA, MRSA strains recovered from food animals appear to be specific animal-adapted clones. Since 2005, MRSA belonging to ST398 was recognized as a colonizer of pigs and human subjects professionally exposed to pig farming. The "pig" MRSA was also found to colonize other species of farmed animals, including horses, cattle, and poultry and was therefore designated livestock-associated (LA)-MRSA. LA-MRSA ST398 can cause infections in humans in contact with animals, and can infect hospitalized people, although at the moment this occurrence is relatively rare. Other animal-adapted MRSA clones have been detected in livestock, such as ST1 and ST9. Recently, ST130 MRSA isolated from bovine mastitis has been found to carry a novel mecA gene that eludes detection by conventional PCR tests. Similar ST130 strains have been isolated from human infections in UK, Denmark, and Germany at low frequency. It is plausible that the increased attention to animal MRSA will reveal other strains with peculiar characteristics that can pose a risk to human health. PMID- 22509177 TI - Vpu and BST2: Still Not There Yet? AB - Extensive investigations have identified two cellular proteins in humans that potently inhibit HIV type 1 (HIV-1) replication and are widely accepted as "restriction factors." APOBEC3G was identified as a restriction factor that diminishes HIV-1 replication by inducing G-to-A hypermutation in the viral genome, while BST2 has been identified as another restriction factor that impairs the release of nascent virions by tethering them on the surface of infected cells. To counter these restriction factors, HIV-1 has equipped itself with its own weapons: viral infectivity factor (Vif) degrades APOBEC3G, while viral protein U (Vpu) antagonizes BST2. These findings have allowed us to further our understanding of virus-host interaction, namely, the interplay between viral factors versus host restriction factors. In the first case, the interplay between APOBEC3G and Vif is clear: vif-deficient HIV-1 is incapable of replicating in APOBEC3G-expressing cells. This insight directly indicates that APOBEC3G is a bona fide restriction factor and has intrinsic immunity against HIV-1, and that Vif is a prerequisite for HIV-1 infection. In other words, the relationship between Vif and APOBEC3G has already "matured," and Vif has highly evolved to overcome APOBEC3G. On the other hand, although BST2 drastically impairs the release of vpu-deficient HIV-1 virions, it is puzzling that vpu-deficient HIV-1 is still able to replicate in BST2-expressing cells. These insights imply that BST2-mediated anti-HIV-1 activity is vulnerable, and that Vpu is dispensable for HIV-1 infection. If so, why has Vpu acquired the counteracting potential against BST2? Was it necessary or important for HIV-1? Or is the relationship between Vpu and BST2 still "immature"? In this review, we particularly focus on the interplay between Vpu and BST2. We discuss the possibility that Vpu has evolved as a potent antagonist against BST2, and finally, propose a hypothesis that Vpu has evolved as a promoter of human-to-human HIV-1 transmission. Since the first report of acquired immunodeficiency syndrome patients in 1981, HIV-1 has spread explosively worldwide and is currently a pandemic. This review proposes a concept suggesting that the current HIV-1 pandemic may be partly attributed by Vpu. PMID- 22509179 TI - New array approaches to explore single cells genomes. AB - Microarray analysis enables the genome-wide detection of copy number variations and the investigation of chromosomal instability. Whereas array techniques have been well established for the analysis of unamplified DNA derived from many cells, it has been more challenging to enable the accurate analysis of single cell genomes. In this review, we provide an overview of single cell DNA amplification techniques, the different array approaches, and discuss their potential applications to study human embryos. PMID- 22509181 TI - Why we still need HBV population-based epidemiologic studies. PMID- 22509180 TI - Cigarette smoke exposure-associated alterations to non-coding RNA. AB - Environmental exposures vary by timing, severity, and frequency and may have a number of deleterious effects throughout the life course. The period of in utero development, for example, is one of the most crucial stages of development during which adverse environmental exposures can both alter the growth and development of the fetus as well as lead to aberrant fetal programming, increasing disease risk. During fetal development and beyond, the plethora of exposures, including nutrients, drugs, stress, and trauma, influence health, development, and survival. Recent research in environmental epigenetics has investigated the roles of environmental exposures in influencing epigenetic modes of gene regulation during pregnancy and at various stages of life. Many relatively common environmental exposures, such as cigarette smoking, alcohol consumption, and drug use, may have consequences for the expression and function of non-coding RNA (ncRNA), important post-transcriptional regulators of gene expression. A number of ncRNA have been discovered, including microRNA (miRNA), Piwi-interacting RNA (piRNA), and long non-coding RNA (long ncRNA). The best-characterized species of ncRNA are miRNA, the mature forms of which are ~22 nucleotides in length and capable of post-transcriptionally regulating target mRNA utilizing mechanisms based largely on the degree of complementarity between miRNA and target mRNA. Because miRNA can still negatively regulate gene expression when imperfectly base paired with a target mRNA, a single miRNA can have a large number of potential mRNA targets and can regulate many different biological processes critical for health and development. The following review analyzes the current literature detailing links between cigarette smoke exposure and aberrant expression and function of ncRNA, assesses how such alterations may have consequences throughout the life course, and proposes future directions for this intriguing field of research. PMID- 22509182 TI - Autoimmune hepatitis in Iran: what we know, what we don't know and requirements for better management. PMID- 22509183 TI - Clinical features of hepatitis C virus carriers with persistently normal alanine aminotransferase levels. AB - Hepatitis C virus (HCV) infection causes chronic hepatitis, which frequently leads to hepatic fibrosis and hepatocellular carcinoma (HCC). Alanine aminotransferase (ALT) is a biomarker of hepatocyte injury and is associated with the progression of hepatic fibrosis. Advanced hepatic fibrosis also predisposes HCV carriers to a risk of HCC. In contrast, some cases with persistent HCV infection have normal ALT levels that persist for a long time, and these HCV carriers have no or mild hepatitis and hepatic fibrosis. These HCV carriers are defined as persistent normal ALT (PNALT) cases and their risk of HCC is low compared to HCV carriers with abnormal ALT. However, there are various definitions of normal ALT and PNALT, and advanced hepatic fibrosis may be missed without a liver biopsy. In addition, there is also a risk of ALT elevation in HCV carriers with PNALT, which increases the risk of progression to hepatic fibrosis and HCC. Most HCV carriers with PNALT have asymptomatic or nonspecific symptoms. HCV carriers with PNALT are also considered to be responsive to interferon-based treatment. Thus, assessment of hepatic fibrosis is important in HCV carriers, and the eradication of HCV infection is more likely in HCV carriers with evidence of hepatic fibrosis, regardless of their ALT levels. PMID- 22509185 TI - Clinical features and long term outcome of 102 treated autoimmune hepatitis patients. AB - BACKGROUND: There is limited data on the natural history of autoimmune hepatitis (AIH) and on the long-term follow-up of AIH patients who have been referred for regular medical attention. OBJECTIVES: We evaluated the clinical presentation and natural history of AIH in a large cohort of type I AIH patients from Iran. PATIENTS AND METHODS: Between 1997 and 2008, 102 patients were enrolled in the study. Patients were diagnosed using the International Autoimmune Hepatitis Group criteria and were followed up for an average of 60 months. Clinical and biochemical data were gathered from all the patients at both the beginning and the end of the follow-up period. Liver biopsy was performed in all patients before treatment, and the biopsies were performed in 28 patients after treatment. RESULTS: Biochemical remission was achieved by 80 (79.4%) patients. Of these, 53 (66.5%) showed near-normal liver histology or liver function test results and sonogram. The remaining 27 (33.5%) patients also achieved clinical and biochemical remission, but developed compensated cirrhosis. After a period of remission, 24 patients (32.5%) relapsed. Among the 22 (21.6%) patients who showed ultimate treatment failure, 6 underwent orthotopic liver transplantation and 3 died of liver failure while awaiting a transplant. Sixteen (72.7%) of the 22 patients who did not respond to therapy were non-compliant with medications and had irregular follow-up. The overall 10-year survival rate in the cohort was 96%. CONCLUSIONS: Long-term survival in AIH patients is very good. Prompt diagnosis and appropriate first-line and salvage therapy that includes close follow-up will make liver transplantation a rare necessity in the treatment of this disease. PMID- 22509184 TI - Hepatitis C virus cryoglobulinemia and non-hodgkin lymphoma. AB - CONTEXT: On the strength of epidemiological data,biological studies, and clinical findings, hepatitis C virus appears to be involved in the pathogenesis of a proportion of patients with non-Hodgkin lymphoma and cryoglobulinemia. OBJECTIVES: The aim of this paper is to review the published literature focused on the current knowledge concerning hepatitis C virus and its potential role in the production of non-Hodgkin lymphoma and cryoglobulinemia in susceptible individuals. EVIDENCE ACQUISITION: In this review, databases such as pubMed, embase, ISI, and Iranian databases including Iranmedex, and SID were searched. RESULTS: The results of this review indicate that HCV infection may be a likely cause of various B cell dysregulation disorders such as non-Hodgkin lymphoma and cryoglobulinemia. CONCLUSION: Based on current findings, it has been hypothesized that NHL and cryoglobulinemia in HCV infection may have an immune-mediated pathogenesis. In HCV infected patients, we showed an elevated risk of these two diseases. These finding suggested a possible role for chronic hepatitis C in the pathogenesis of NHL and cryoglobulinemia. PMID- 22509186 TI - Era of vaccination heralds a decline in incidence of hepatitis A in high-risk groups in China. AB - BACKGROUND: Hepatitis A was ranked first among all of the different types of viral hepatitis in China, which occurred an average of 500,000 cases annually during the 1980's. A live attenuated hepatitis A vaccine was applied in preventing of the disease in 1992, large scale used in vaccination program in 1995, and incorporated in the Expanded Program of Immunization in 2008 in China. OBJECTIVE: The objective of this study was to determine whether, and to what extent, the decline in the incidence of hepatitis A in China was the result of hepatitis A (HA) vaccination. MATERIALS AND METHODS: Official documents and longitudinal serological follow-up studies were reviewed to compare the incidence of HA before and after the introduction of the vaccine. RESULTS: National trends in the incidence of HA in China saw rates decrease by 92.7% in 2009, compared to the levels seen in 1992. A mass vaccination program was carried out in 3-18 year old children (Wuhan City, China), and its protective efficacy was 85.4%. In a mass vaccination program of an entire population (Shenshi County, China), the annual HA incidence decreased from 359.7/100,000 to 17.7/100,000 (almost 20.3 times). There was a significant relationship found between vaccine coverage and the incidence of HA, the correlation of the negative regression was significant at the 1% (Kendall rank correlation, significant level P < 0.05). CONCLUSIONS: In summary, this study highlights the important role of implementing a vaccination program in decreasing the incidence of HA, and the large protective efficacy of such a strategy, as demonstrated in China. PMID- 22509187 TI - Impact of hepatitis C on survival of HIV-infected individuals in Shiraz; South of Iran. AB - BACKGROUND: HIV and HCV infections are basic issues of many health systems. Since HIV and HCV are transmitted similarly, it is common to become infected by them simultaneously. No consensus exists on the effect of HCV infection on the survival of HIV-infected patients. OBJECTIVES: This study aimed to investigate the issue in a relatively large cohort of patients who had a high prevalence of this coinfection in Shiraz (South of Iran). PATIENTS AND METHODS: In this historical cohort study, we evaluated the survival time of 1338 HIV-infected individuals who had been referred to a behavioral consultation center in Shiraz over 10 years (from April 2001 to July 2011). Kaplan-Meier method and log-rank test were used to investigate patient survival and compare their survival curves, respectively. Moreover, Cox proportional hazards model was used to examine the effect of HCV infection on patient survival after control for age, sex, having the injection drug use (IDU) risk factor, CD4 count at baseline, more than a 30% decline in CD4 cell count, and highly active antiretroviral therapy (HAART). RESULTS: In our cohort, 1044 patients (78.03%) were infected by HCV. The median follow-up was 43.48 months (95% CI = 61.18-26.63). The median survival time in HCV-infected and uninfected patients was 163.8 and 194.8 months, respectively (P = 0.039). After controlling for other covariates, HCV infection increased the mortality rate 2.13 times more in HCV-infected patients than HCV -uninfected patients (CI: 95%; 1.1-4.52). CONCLUSIONS: HCV infection increases AIDS-related deaths. To control HCV infection and transmission and eliminate HCV, timely diagnosis and treatment and serious harm reduction programs must be implemented. PMID- 22509188 TI - Distribution and risk factors of hepatitis B virus infection in the general population of Central Iran. AB - BACKGROUND: Hepatitis B is the most common chronic viral infection in humans and the most common cause of death among viral hepatitis. As 70% to 80% of chronic hepatitis cases are caused by HBV in Iran, this virus alone is considered the most important cause of liver diseases and the major cause of mortality arising from viral hepatitis cases in Iran. OBJECTIVES: We planned this study to determine the prevalence of hepatitis B in the general population of Qom, central Iran. PATIENTS AND METHODS: The present study is a cross-sectional study. A total of 3690 samples were collected from 7 rural clusters and 116 urban clusters. Ten teams, each consisting of 2 trained members, were assigned to conduct the sampling and fill the questionnaires. The data were analyzed using SPSS. RESULTS: The prevalence rate of hepatitis B infection in Qom Province was 1.3%. The mean age of the patients with hepatitis B was 44.17 years. The prevalence of hepatitis B was 1.6% in men and 1.1% in women. Moreover, the prevalence of hepatitis B correlated positively with age, tattooing, and literacy level. CONCLUSIONS: The prevalence rate of hepatitis B in Qom is 1.3%. It is possible to prevent the disease by increasing public awareness. Further investigation on clinical presentations and a determination of the genotype of the virus are suggested. PMID- 22509189 TI - Hepatitis B virus genotype G infection in a Turkish patient undergoing hemodialysis therapy. AB - BACKGROUND: Genotype G is the least common of all the hepatitis B virus (HBV) genotypes. The existence of the genotype G strain of HBV was first noted in 2000 and little information is available on its global geographical distribution. Previous studies have demonstrated the dominance of genotype D in patients with HBV infections in Turkey. OBJECTIVES: To report for the first time in Turkey, the case of a 61 year old male patient who developed the HBV genotype G infection. CASE REPORT: According to HBV genotyping using phylogenetic analysis and an INNO LiPA assay, the patient was infected with genotype G and G+A, respectively. CONCLUSIONS: The present clinical study suggests that the transmission of an HBV genotype other than genotype D, namely HBV genotype G, is possible in Turkey. Epidemiological and clinical information on genotype G infection is currently limited, and this is most likely due to its low prevalence throughout the world. Therefore, it may be important to determine the epidemiologic and molecular characteristics of the HBV genotype G as it relates to chronic hepatitis, to enable better understanding of its circulation and progression around the world. PMID- 22509190 TI - Sustained viral response and hematological adverse events during chronic hepatitis C infection treatment. PMID- 22509191 TI - The evolving incidence of hepatitis C virus infection in Italy. PMID- 22509192 TI - Iron overload and HFE mutations: are they relevant in cryptogenic cirrhosis? PMID- 22509193 TI - Applications of functionalized fullerenes in tumor theranostics. AB - Functionalized fullerenes with specific physicochemical properties have been developed for cancer diagnosis and therapy. Notably, metallofullerene is a new class of magnetic resonance imaging (MRI) contrast-enhancing agent, and may have promising applications for clinical diagnosis. Polyhydroxylated and carboxyl fullerenes have been applied to photoacoustic imaging. Moreover, in recent years, functionalized fullerenes have shown potential in tumor therapies, such as photodynamic therapy, photothermal treatment, radiotherapy and chemotherapeutics. Their antitumor effects may be associated with the modulation of oxidative stress, anti-angiogenesis, and immunostimulatory activity. While various types of novel nanoparticle agents have been exploited in tumor theranostics, their distribution, metabolism and toxicity in organisms have also been a source of concern among researchers. The present review summarizes the potential of fullerenes as tumor theranostics agents and their possible underlying mechanisms are discussed. PMID- 22509194 TI - Multiwalled carbon nanotubes interact with macrophages and influence tumor progression and metastasis. AB - Macrophages are one of the most important types of immune effector cells and are closely associated with tumor progression and metastasis. In this work, we investigated the influences of oxidized multiwalled carbon nanotubes (o-MWCNT) on macrophages that are resting in the normal subcutis tissue or in the tumor microenvironment in vivo as well as on the macrophage cell line of RAW 264.7 treated with combination of IL4, IL10 and IL13 in vitro. The o-MWCNT were characterized with SEM, DLS, FTIR, TGA, and UV-vis-NIR spectroscopy, and their effects on the RWA 264.7 cell line and breast cancer tumor-bearing mice were analyzed using the MTS assay, flow cytometry analysis, and histological and immunohistochemical observations. Our experimental results showed that subcutaneously injected o-MWCNT not only induced phagocytosis of the local resident macrophages, but also competitively recruited macrophages from other tissues. These interactions resulted in macrophage reduction and decreased vessel density around the tumor mass, which together inhibited tumor progression and metastasis in the lung. In the cell line model, the o-MWCNT inhibited the ability of the interleukin treated RAW macrophages to promote tumor cell migration as well as decreased their proliferation rate. PMID- 22509195 TI - Pharmacokinetics, metabolism and toxicity of carbon nanotubes for biomedical purposes. AB - Carbon nanotubes (CNTs) have attracted great interest of the nano community and beyond. However, the biomedical applications of CNTs arouse serious concerns for their unknown in vivo consequence, in which the information of pharmacokinetics, metabolism and toxicity of CNTs is essential. In this review, we summarize the updated data of CNTs from the biomedical view. The information shows that surface chemistry is crucial in regulating the in vivo behaviors of CNTs. Among the functionalization methods, PEGylation is the most efficient one to improve the pharmacokinetics and biocompatibility of CNTs. The guiding effects of the pharmacokinetics, metabolism and toxicity information on the biomedical applications of CNTs are discussed. PMID- 22509196 TI - The biocompatibility of nanodiamonds and their application in drug delivery systems. AB - Nanodiamonds (NDs), as a new member of the carbon nanoparticles family, have attracted more and more attention in biomedicine recently due to their excellent physical and chemical properties. This paper summarizes the main results from the in vitro and in vivo safety assessments of NDs and reports the application of NDs in the development of drug delivery systems. In view of the NDs' characteristics of easy formation of a porous cluster structure in solution, an adsorption model for a variety of functional molecules on the ND clusters is proposed, which provides new ideas for developing a novel smart drug with various features such as sustained-release, targeting, and fluorescence imaging. PMID- 22509197 TI - Molecular imaging of stem cells: tracking survival, biodistribution, tumorigenicity, and immunogenicity. AB - Being able to self-renew and differentiate into virtually all cell types, both human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) have exciting therapeutic implications for myocardial infarction, neurodegenerative disease, diabetes, and other disorders involving irreversible cell loss. However, stem cell biology remains incompletely understood despite significant advances in the field. Inefficient stem cell differentiation, difficulty in verifying successful delivery to the target organ, and problems with engraftment all hamper the transition from laboratory animal studies to human clinical trials. Although traditional histopathological techniques have been the primary approach for ex vivo analysis of stem cell behavior, these postmortem examinations are unable to further elucidate the underlying mechanisms in real time and in vivo. Fortunately, the advent of molecular imaging has led to unprecedented progress in understanding the fundamental behavior of stem cells, including their survival, biodistribution, immunogenicity, and tumorigenicity in the targeted tissues of interest. This review summarizes various molecular imaging technologies and how they have advanced the current understanding of stem cell survival, biodistribution, immunogenicity, and tumorigenicity. PMID- 22509198 TI - Bioluminescence imaging of stem cell-based therapeutics for vascular regeneration. AB - Stem cell-based therapeutics show promise for treatment of vascular diseases. However, the survival of the cells after in vivo injection into diseased tissues remains a concern. In the advent of non-invasive optical imaging techniques such as bioluminescence imaging (BLI), cell localization and survival can be easily monitored over time. This approach has recently been applied towards monitoring stem cell treatments for vascular regeneration of the coronary or peripheral arteries. In this review, we will describe the application of BLI for tracking transplanted stem cells and associating their viability with therapeutic efficacy, in preclinical disease models of vascular disease. PMID- 22509199 TI - Reporter gene imaging of immune responses to cancer: progress and challenges. AB - Immune responses to cancer are dynamic processes which take place through the concerted activity of innate and adaptive cell populations. In order to fully understand the efficacy of immune therapies for cancer, it is critical to understand how the treatment modulates the function of each cell type involved in the anti-tumor immune response. Molecular imaging is a versatile method for longitudinal studies of cellular localization and function. The development of reporter genes for tracking cell movement and function was a powerful addition to the immunologist's toolbox. This review will highlight the advances and challenges in the use of reporter gene imaging to track immune cell localization and function in cancer. PMID- 22509202 TI - Synthesis and photooxidation of styrene copolymer bearing camphorquinone pendant groups. AB - (+/-)-10-Methacryloyloxycamphorquinone (MCQ) was synthesized from (+/-)-10 camphorsulfonic acid either by a known seven-step synthetic route or by a novel, shorter five-step synthetic route. MCQ was copolymerized with styrene (S) and the photochemical behavior of the copolymer MCQ/S was compared with that of a formerly studied copolymer of styrene with monomers containing the benzil (BZ) moiety (another 1,2-dicarbonyl). Irradiation (lambda > 380 nm) of aerated films of styrene copolymers with monomers containing the BZ moiety leads to the insertion of two oxygen atoms between the carbonyl groups of BZ and to the formation of benzoyl peroxide (BP) as pendant groups on the polymer backbone. An equivalent irradiation of MCQ/S led mainly to the insertion of only one oxygen atom between the carbonyl groups of camphorquinone (CQ) and to the formation of camphoric anhydride (11) covalently bound to the polymer backbone. While the decomposition of pendant BP groups formed in irradiated films of styrene copolymers with pendant BZ groups leads to crosslinking, only small molecular weight changes in irradiated MCQ/S were observed. PMID- 22509200 TI - Theranostic potential of oncolytic vaccinia virus. AB - Biological cancer therapies, such as oncolytic, or replication-selective viruses have advantages over traditional therapeutics as they can employ multiple different mechanisms to target and destroy cancers (including direct cell lysis, immune activation and vascular collapse). This has led to their rapid recent clinical development. However this also makes their pre-clinical and clinical study complex, as many parameters may affect their therapeutic potential and so defining reason for treatment failure or approaches that might enhance their therapeutic activity can be complicated. The ability to non-invasively image viral gene expression in vivo both in pre-clinical models and during clinical testing will considerably enhance the speed of oncolytic virus development as well as increasing the level and type of useful data produced from these studies. Further, subsequent to future clinical approval, imaging of reporter gene expression might be used to evaluate the likelihood of response to oncolytic viral therapy prior to changes in tumor burden. Here different reporter genes used in conjunction with oncolytic viral therapy are described, along with the imaging modalities used to measure their expression, while their applications both in pre-clinical and clinical testing are discussed. Possible future applications for reporter gene expression from oncolytic viruses in the phenotyping of tumors and the personalizing of treatment regimens are also discussed. PMID- 22509203 TI - Organic synthesis using (diacetoxyiodo)benzene (DIB): Unexpected and novel oxidation of 3-oxo-butanamides to 2,2-dihalo-N-phenylacetamides. AB - A novel and reliable method for the direct preparation of 2,2-dihalo-N phenylacetamides is reported. The key transformation involves the cleavage of a carbon-carbon bond in the presence of DIB and a Lewis acid as the halogen source, and thus this method significantly expands the value of DIB as a unique and powerful tool in chemical synthesis. This protocol not only adds a new aspect to reactions that use other hypervalent iodine reagents but also provides a wide space for the synthesis of disubstituted acetamides. PMID- 22509201 TI - Positron emission tomography reporter genes and reporter probes: gene and cell therapy applications. AB - Positron emission tomography (PET) imaging reporter genes (IRGs) and PET reporter probes (PRPs) are amongst the most valuable tools for gene and cell therapy. PET IRGs/PRPs can be used to non-invasively monitor all aspects of the kinetics of therapeutic transgenes and cells in all types of living mammals. This technology is generalizable and can allow long-term kinetics monitoring. In gene therapy, PET IRGs/PRPs can be used for whole-body imaging of therapeutic transgene expression, monitoring variations in the magnitude of transgene expression over time. In cell or cellular gene therapy, PET IRGs/PRPs can be used for whole-body monitoring of therapeutic cell locations, quantity at all locations, survival and proliferation over time and also possibly changes in characteristics or function over time. In this review, we have classified PET IRGs/PRPs into two groups based on the source from which they were derived: human or non-human. This classification addresses the important concern of potential immunogenicity in humans, which is important for expansion of PET IRG imaging in clinical trials. We have then discussed the application of this technology in gene/cell therapy and described its use in these fields, including a summary of using PET IRGs/PRPs in gene and cell therapy clinical trials. This review concludes with a discussion of the future direction of PET IRGs/PRPs and recommends cell and gene therapists collaborate with molecular imaging experts early in their investigations to choose a PET IRG/PRP system suitable for progression into clinical trials. PMID- 22509204 TI - Liquid-crystalline nanoparticles: Hybrid design and mesophase structures. AB - Liquid-crystalline nanoparticles represent an exciting class of new materials for a variety of potential applications. By combining supramolecular ordering with the fluid properties of the liquid-crystalline state, these materials offer the possibility to organise nanoparticles into addressable 2-D and 3-D arrangements exhibiting high processability and self-healing properties. Herein, we review the developments in the field of discrete thermotropic liquid-crystalline nanoparticle hybrids, with special emphasis on the relationship between the nanoparticle morphology and the nature of the organic ligand coating and their resulting phase behaviour. Mechanisms proposed to explain the supramolecular organisation of the mesogens within the liquid-crystalline phases are discussed. PMID- 22509205 TI - Synthesis and mesomorphic properties of calamitic malonates and cyanoacetates tethered to 4-cyanobiphenyls. AB - 4-Cyano-1,1'-biphenyl derivatives bearing omega-hydroxyalkyl substituents were reacted with methyl 3-chloro-3-oxopropionate or cyanoacetic acid, giving liquid crystalline linear malonates and cyanoacetates. These compounds formed monotropic nematic phases at 62 degrees C down to ambient temperature upon cooling from the isotropic liquid. The mesomorphic properties were investigated by differential scanning calorimetry, polarizing optical microscopy and X-ray diffraction (WAXS). PMID- 22509206 TI - Syntheses and applications of furanyl-functionalised 2,2':6',2''-terpyridines. AB - Different synthetic routes leading to terpyridines functionalised with furan heterocycles are reviewed. The methodologies used to prepare such compounds include the ring closure of 1,5-diketones and cross-coupling reactions. These versatile terpyridines and their derived metal complexes find applications in various fields including coordination chemistry, medicinal chemistry and material sciences. PMID- 22509207 TI - Synthesis of mesomeric betaine compounds with imidazolium-enolate structure. AB - The synthesis of a heterocyclic mesomeric betaine by quaternization reaction of 1 butylimidazole and tetrabromo-1,4-benzoquinone is presented. The structure was verified by means of X-ray single-crystal analysis, NMR and IR spectroscopy. Inclusion complexes of the heterocyclic mesomeric betaine with randomly methylated (1.8) beta-cyclodextrin were investigated by UV-vis spectroscopy. Furthermore, the reaction conditions were applied to poly(vinylimidazole) and 1,4 bis(1H-imidazol-1-yl)butane to obtain functionalized polymer networks and condensate polymers, respectively. PMID- 22509208 TI - N-Heterocyclic carbene/Bronsted acid cooperative catalysis as a powerful tool in organic synthesis. AB - The interplay between metals and N-heterocyclic carbenes (NHCs) has provided a window of opportunities for the development of novel catalytic strategies within the past few years. The recent successful combination of Bronsted acids with NHCs has added a new dimension to the field of cooperative catalysis, enabling the stereoselective synthesis of functionalized pyrrolidin-2-ones as valuable scaffolds in heterocyclic chemistry. This Commentary will briefly highlight the concept of N-heterocyclic carbene/Bronsted acid cooperative catalysis as a new and powerful methodology in organic chemistry. PMID- 22509209 TI - Perhydroazulene-based liquid-crystalline materials with smectic phases. AB - New liquid-crystalline materials with a perhydroazulene core were synthesized and the stereochemistry of these compounds was investigated. The mesomorphic properties of the new LC compounds were investigated by differential scanning colorimetry, polarizing optical microscopy and X-ray diffraction. We report here on the LC properties of nonchiral materials, which predominantly exhibit smectic phases and display nematic phases only within narrow temperature ranges. The dependence of the mesogenic behavior of the new materials on the stereochemistry of the core system was also investigated. All newly synthesized compounds were fully characterized by the usual spectroscopic and analytical methods. PMID- 22509210 TI - Synthesis in the glycosciences II. PMID- 22509211 TI - Acceptor-influenced and donor-tuned base-promoted glycosylation. AB - Base-promoted glycosylation is a recently established stereoselective and regioselective approach for the assembly of di- and oligosaccharides by using partially protected acceptors and glycosyl halide donors. Initial studies were performed on partially methylated acceptor and donor moieties as a model system in order to analyze the key principles of oxyanion reactivities. In this work, extended studies on base-promoted glycosylation are presented by using benzyl protective groups in view of preparative applications. Emphases are placed on the influence of the acceptor anomeric configuration and donor reactivities. PMID- 22509212 TI - Synthesis of heteroglycoclusters by using orthogonal chemoselective ligations. AB - Synthetic heteroglycoclusters are being subjected to increasing interest due to their potential to serve as selective ligands for carbohydrate-binding proteins. In this paper, we describe an expedient strategy to prepare cyclopeptides displaying well-defined distributions and combinations of carbohydrates. By using both oxime ligation and copper(I)-catalyzed alkyne-azide cycloaddition, two series of compounds bearing binary combinations of alphaMan, alphaFuc or betaLac in an overall tetravalent presentation, and either 2:2 or 3:1 relative proportions, have been prepared. PMID- 22509213 TI - Facile synthesis of nitrophenyl 2-acetamido-2-deoxy-alpha-D-mannopyranosides from ManNAc-oxazoline. AB - The synthetic procedures for a large-scale preparation of o- and p-nitrophenyl 2 acetamido-2-deoxy-alpha-D-mannopyranoside are described. The synthetic pathway employs the glycosylation of phenol with ManNAc oxazoline, followed by nitration of the aromatic moiety yielding a separable mixture of the o- and p-nitrophenyl derivative in a 2:3 ratio. PMID- 22509214 TI - Intramolecular carbenoid ylide forming reactions of 2-diazo-3-keto-4 phthalimidocarboxylic esters derived from methionine and cysteine. AB - Methionine, S-benzylcysteine and S-allylcysteine were converted into 2-diazo-3 oxo-4-phthalimidocarboxylic esters 8a-c in three steps. Upon rhodium-catalysed dediazoniation, two intramolecular carbenoid reactions competed, namely the formation of a cyclic sulfonium ylide and that of a six-ring carbonyl ylide. The S-methyl and S-benzyl ylides 12a and b could be isolated, while S-allyl ylide 12c underwent a [2,3]-sigmatropic rearrangement. The short-lived carbonyl ylides derived from methionine and S-benzylcysteine formed head-to-tail dimers by a [3 + 3]-cycloaddition and could be trapped with external dipolarophiles, while the S allyl derivative 14c yielded the pentacyclic compound 17 by an intramolecular [3 + 2]-cycloaddition reaction. PMID- 22509215 TI - Enaminones in a multicomponent synthesis of 4-aryldihydropyridines for potential applications in photoinduced intramolecular electron-transfer systems. AB - An efficient three component reaction with enaminones, primary amines and aldehydes resulted in easy access to 1,4-dihydropyridines with different substituents at the 1-, 3-, 4- and 5-positions. Microwaves improved the reaction yield, reducing also considerably the reaction time and the amount of solvent used. Chiral primary amines gave chiral 1-substituted-1,4-dihydropyridines. The 4 (1-naphthyl) and 4-(phenanthren-9-yl)dihydropyridine derivatives exhibited an interesting photoluminescence behavior, which suggests their potential application as suitable photoinduced intramolecular electron-transfer systems. PMID- 22509216 TI - Synthesis of fluorinated maltose derivatives for monitoring protein interaction by (19)F NMR. AB - A novel reporter system, which is applicable to the (19)F NMR investigation of protein interactions, is presented. This approach uses 2-F-labeled maltose as a spy ligand to indirectly probe protein-ligand or protein-protein interactions of proteins fused or tagged to the maltose-binding protein (MBP). The key feature is the simultaneous NMR observation of both (19)F NMR signals of gluco/manno-type-2 F-maltose-isomers; one isomer (alpha-gluco-type) binds to MBP and senses the protein interaction, and the nonbinding isomers (beta-gluco- and/or alpha/beta manno-type) are utilized as internal references. Moreover, this reporter system was used for relative affinity studies of fluorinated and nonfluorinated carbohydrates to the maltose-binding protein, which were found to be in perfect agreement with published X-ray data. The results of the NMR competition experiments together with the established correlation between (19)F chemical shift data and molecular interaction patterns, suggest valuable applications for studies of protein-ligand interaction interfaces. PMID- 22509217 TI - Electrochemical generation of 2,3-oxazolidinone glycosyl triflates as an intermediate for stereoselective glycosylation. AB - Glycosyl triflates with a 2,3-oxazolidinone protecting group were generated from thioglycosides by low-temperature electrochemical oxidation. The glycosyl triflates reacted with alcohols to give the corresponding glycosides beta selectively at low temperatures. However, alpha-selectivity was observed in the absence of base at elevated reaction temperatures. In situ generated triflic acid promotes the isomerization of beta-products to alpha-products. PMID- 22509218 TI - Discovery of practical production processes for arylsulfur pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides): Beginning of a new era of "super-trifluoromethyl" arene chemistry and its industry. AB - Various arylsulfur pentafluorides, ArSF(5), have long been desired in both academic and industrial areas, and ArSF(5) compounds have attracted considerable interest in many areas such as medicines, agrochemicals, and other new materials, since the highly stable SF(5) group is considered a "super-trifluoromethyl group" due to its significantly higher electronegativity and lipophilicity. This article describes the first practical method for the production of various arylsulfur pentafluorides and their higher homologues, bis- and tris(sulfur pentafluorides), from the corresponding diaryl disulfides or aryl thiols. The method consists of two steps: (Step 1) treatment of a diaryl disulfide or an aryl thiol with chlorine in the presence of an alkali metal fluoride, and (step 2) treatment of the resulting arylsulfur chlorotetrafluoride with a fluoride source, such as ZnF(2), HF, and Sb(III/V) fluorides. The intermediate arylsulfur chlorotetrafluorides were isolated by distillation or recrystallization and characterized. The aspects of these new reactions are revealed and reaction mechanisms are discussed. As the method offers considerable improvement over previous methods in cost, yield, practicality, applicability, and large-scale production, the new processes described here can be employed as the first practical methods for the economical production of various arylsulfur pentafluorides and their higher homologues, which could then open up a new era of "super-trifluoromethyl" arene chemistry and its applications in many areas. PMID- 22509219 TI - Liquid-crystalline heterodimesogens and ABA-heterotrimesogens comprising a bent 3,5-diphenyl-1,2,4-oxadiazole central unit. AB - Three new types of terminally connected ABA-heterotrimesogens and heterodimesogens, composed of a bent 3,5-diphenyl-1,2,4-oxadiazole central unit and one or two rod-shaped 4-cyanobiphenyl cores or one 2-phenyl-1,3,4-thiadiazole core, connected by flexible spacers, have been synthesized, and their mesomorphic behavior was studied by optical polarizing microscopy (PM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). All dimesogens exhibit broad ranges of cybotactic nematic phases (N(cybA) and N(cybC)), in some cases accompanied by additional mesophases (CybA or SmC) at lower temperature. The combination of the 3,5-diphenyl-1,2,4-oxadiazole unit with one cyanobiphenyl core leads to the removal of tilted smectic and cybotactic nematic phases (SmC, N(cybC)), which are replaced by the nontilted CybA phases and nematic phases composed of SmA-type clusters (N(cybA)). The orthogonal cybotactic nematic phases of bent-core mesogens are of special interest for achieving biaxial nematic phases of the orthorhombic type. The orthogonal (N(cybA)) and skewed (N(cybC)) cybotactic nematic phases were distinguished by XRD and optical observations. PMID- 22509220 TI - Azobenzene dye-coupled quadruply hydrogen-bonding modules as colorimetric indicators for supramolecular interactions. AB - The facile coupling of azobenzene dyes to the quadruply hydrogen-bonding modules 2,7-diamido-1,8-naphthyridine (DAN) and 7-deazaguanine urea (DeUG) is described. The coupling of azobenzene dye 2 to mono-amido DAN units 4, 7, and 9 was effected by classic 4-(dimethylamino)pyridine (DMAP)-catalyzed peptide synthesis with N-(3 dimethylaminopropyl)-N'-ethyl carbodiimide hydrochloride (EDC) as activating agent, affording the respective amide products 5, 8, and 10 in 60-71% yield. The amide linkage was formed through either the aliphatic or aromatic ester group of 2, allowing both the flexibility and absorption maximum to be tuned. Azobenzene dye 1 was coupled to the DeUG unit 11 by Steglich esterification to afford the product amide 12 in 35% yield. Alternatively, azobenzene dye 16 underwent a room temperature copper-catalyzed azide-alkyne Huisgen cycloaddition with DeUG alkyne 17 to give triazole 18 in 71% yield. Azobenzene coupled DAN modules 5, 8, and 10 are bright orange-red in color, and azobenzene coupled DeUG modules 12 and 18 are orange-yellow in color. Azobenzene coupled DAN and DeUG modules were successfully used as colorimetric indicators for specific DAN-DeUG and DAN-UPy (2-ureido-4(1H) pyrimidone) quadruply hydrogen-bonding interactions. PMID- 22509221 TI - Regio- and stereoselective oxidation of unactivated C-H bonds with Rhodococcus rhodochrous. AB - The ability of Rhodococcus rhodochrous (NCIMB 9703) to catalyse the regio- and stereoselective hydroxylation of a range of benzyloxy-substituted heterocycles has been investigated. Incubation of 2-benzyloxytetrahydropyrans with resting cell suspensions of the organism yielded predominantly a mixture of 5 hydroxylated isomers in combined yields of up to 40%. Exposure of the corresponding 2-benzyloxytetrahydrofuran derivatives to the cell suspensions gave predominantly the 4-hydroxylated isomers in yields of up to 26%. Most interestingly, 2-(4-nitrobenzyloxy)tetrahydrofuran and 2-(4 nitrobenzyloxy)tetrahydropyran were transformed in high yields to the 4 hydroxylated and 5-hydroxylated products, respectively. PMID- 22509222 TI - Mutational analysis of a phenazine biosynthetic gene cluster in Streptomyces anulatus 9663. AB - The biosynthetic gene cluster for endophenazines, i.e., prenylated phenazines from Streptomyces anulatus 9663, was heterologously expressed in several engineered host strains derived from Streptomyces coelicolor M145. The highest production levels were obtained in strain M512. Mutations in the rpoB and rpsL genes of the host, which result in increased production of other secondary metabolites, had no beneficial effect on the production of phenazines. The heterologous expression strains produced, besides the known phenazine compounds, a new prenylated phenazine, termed endophenazine E. The structure of endophenazine E was determined by high-resolution mass spectrometry and by one- and two-dimensional NMR spectroscopy. It represented a conjugate of endophenazine A (9-dimethylallylphenazine-1-carboxylic acid) and L-glutamine (L-Gln), with the carboxyl group of endophenazine A forming an amide bond to the alpha-amino group of L-Gln. Gene inactivation experiments in the gene cluster proved that ppzM codes for a phenazine N-methyltransferase. The gene ppzV apparently represents a new type of TetR-family regulator, specifically controlling the prenylation in endophenazine biosynthesis. The gene ppzY codes for a LysR-type regulator and most likely controls the biosynthesis of the phenazine core. A further putative transcriptional regulator is located in the vicinity of the cluster, but was found not to be required for phenazine or endophenazine formation. This is the first investigation of the regulatory genes of phenazine biosynthesis in Streptomyces. PMID- 22509223 TI - Synthesis and biological evaluation of nojirimycin- and pyrrolidine-based trehalase inhibitors. AB - A small set of nojirimycin- and pyrrolidine-based iminosugar derivatives has been synthesized and evaluated as potential inhibitors of porcine and insect trehalases. Compounds 12, 13 and 20 proved to be active against both insect and porcine trehalases with selectivity towards the insect glycosidase, while compounds 10, 14 and 16 behaved as inhibitors only of insect trehalase. Despite the fact that the activity was found in the micromolar range, these findings may help in elucidating the structural features of this class of enzymes of different origin, which are still scarcely characterised. PMID- 22509224 TI - Branching out at C-2 of septanosides. Synthesis of 2-deoxy-2-C-alkyl/aryl septanosides from a bromo-oxepine. AB - This paper deals with the synthesis of 2-deoxy-2-C-alkyl/aryl septanosides. A range of such septanoside derivatives was synthesized by using a common bromo oxepine intermediate, involving C-C bond forming organometallic reactions. Unsaturated, seven-membered septanoside vinyl bromides or bromo-oxepines, obtained through a ring expansion methodology of the cyclopropane derivatives of oxyglycals, displayed a good reactivity towards several acceptor moieties in C-C bond forming Heck, Suzuki and Sonogashira coupling reactions, thus affording 2 deoxy-2-C-alkyl/aryl septanosides. Whereas Heck and Sonogashira coupling reactions afforded 2-deoxy-2-C-alkenyl and -alkynyl derivatives, respectively, the Suzuki reaction afforded 2-deoxy-2-C-aryl septanosides. Deprotection and reduction of the 2-deoxy-2-alkenyl derivative afforded the corresponding 2-deoxy 2-C-alkyl septanoside free of protecting groups. The present study illustrates the reactivity of bromo-oxepine in the synthesis of hitherto unknown septanosides, branching out at C-2, through C-C bond formation with alkyl and aryl substituents. PMID- 22509225 TI - Satisfaction and depression in German primary care doctors. PMID- 22509226 TI - Job satisfaction among primary care physicians: results of a survey. AB - BACKGROUND: A shortage of primary care physicians (PCPs) seems likely in Germany in the near future and already exists in some parts of the country. Many currently practicing PCPs will soon reach retirement age, and recruiting young physicians for family practice is difficult. The attractiveness of primary care for young physicians depends on the job satisfaction of currently practicing PCPs. We studied job satisfaction among PCPs in Lower Saxony, a large federal state in Germany. METHODS: In 2009, we sent a standardized written questionnaire on overall job satisfaction and on particular aspects of medical practice to 3296 randomly chosen PCPs and internists in family practice in Lower Saxony (50% of the entire target population). RESULTS: 1106 physicians (34%) responded; their mean age was 52, and 69% were men. 64% said they were satisfied or very satisfied with their job overall. There were particularly high rates of satisfaction with patient contact (91%) and working atmosphere (87% satisfied or very satisfied). In contrast, there were high rates of dissatisfaction with administrative tasks (75% dissatisfied or not at all satisfied). The results were more indifferent concerning payment and work life balance. Overall, younger PCPs and physicians just entering practice were more satisfied than their older colleagues who had been in practice longer. CONCLUSION: PCPs are satisfied with their job overall. However, there is significant dissatisfaction with administrative tasks. Improvements in this area may contribute to making primary care more attractive to young physicians. PMID- 22509227 TI - The mental health of primary care physicians in Rhineland-Palatinate, Germany: the prevalence of problems and identification of possible risk factors. AB - BACKGROUND: The generally high job-related stress level among physicians may lead to various health impairments in the long run. Apart from job-related stress, stress during leisure time and certain personality traits might be risk factors for health impairments. However, very little research on the health situation of primary care physicians (PCPs) in Germany is available. Therefore, the objective of the present study was to systematically assess the stress experience and the health situation of German PCPs. One main focus was on mental health. METHODS: In 2009, a state-wide survey among practice-based PCPs in the federal German state of Rhineland-Palatinate (cross-sectional study, n = 2092) was carried out in order to assess stress and strain as well as the health situation. RESULTS: 790 participants (37.7%) were eligible for the analyses. One in four PCPs exceeded the cut-off value >= 3 for depression in the PHQ-2 (PHQ, Patient Health Questionaire). Moreover, approximately one in six PCPs stated that he or she had used psychotropic drugs or other psychoactive substances at least once in the preceding year. Stress during leisure time, type D personality and low job satisfaction were associated with the presence of mental health impairments in the binary logistic regression analyses. CONCLUSION: All in all, it appears that mental health impairments are a common health problem among the PCPs. Target group-specific measures should be taken in order to reduce the subjective stress level, and to foster mental hygiene. Furthermore, the development of favorable personality profiles and the corresponding behavioral patterns should be supported. PMID- 22509228 TI - Ovarian cancer: diagnosis and treatment. PMID- 22509230 TI - Percutaneous tennis elbow release under local anaesthesia. AB - INTRODUCTION: When the non-operative treatment of tennis elbow fails to improve the symptoms a surgical procedure can be performed. Many different techniques are available. The percutaneous release of the common extensor origin was first presented by Loose at a meeting in 1962. Despite the simplicity of the operation and its effectiveness in relieving pain with minimal scarring this procedure is still not widely accepted. This study presents the long-term results of percutaneous tennis elbow release in patients when conservative measures including local steroid injections have failed to relieve the symptoms. PATIENTS AND METHODS: Percutaneous release of the extensor origin was performed in 24 consecutive patients (seven male and seventeen female), providing 30 elbows for this study. The age of the patients ranged from 26 to 71 years with mean age of 55 years. The technique involved a day case procedure in the operating theatre using local anaesthesia without the need for a tourniquet. The lateral elbow was infiltrated with 5mls 1% lignocaine and 5mls 0.5% bupivicaine with 1:200,000 adrenaline. All operations were performed by the senior author. The patients were assessed post operatively by using DASH (disabilities of arm, shoulder and hand) score and Oxford elbow scores. The mean follow up period was 36 months (1 71months). RESULTS: Twenty one patients returned the DASH and Oxford elbow questionnaires. Four patients were lost in the follow up. The post operative outcome was good to excellent in most patients. Eighty seven percent of patients had complete pain relief. The mean post-op DASH score was 8.47 (range 0 to 42.9) and the mean Oxford elbow score was 42.8 (range 16 to 48). There were no complications reported. All the patients returned to their normal jobs, hobbies such as gardening, horse riding and playing musical instruments. CONCLUSION: In our experience Percutaneous release of the epicondylar muscles for humeral epicondylitis has a high rate of success, is relatively simple to perform, is done as a day case procedure and has been without complications. Percutaneous release is a viable treatment option after failed conservative management of tennis elbow. PMID- 22509231 TI - Relationship between brassiere cup size and shoulder-neck pain in women. AB - There are very few reports in regard to relationship between breast size and shoulder-neck pain. The purpose of this study is to examine the correlations among breast size, brassiere cup size, and moment-in-time reporting of shoulderneck pain in a group of adult women. Three hundred thirty nine female volunteers from the hospital staff answered the questionnaire. Breast size, brassiere cup size, and shoulder-neck pain were self-reported by each participant. The relationship among breast size, brassiere cup size and shoulder neck pain was investigated. Spearman's test showed no significant relationship between shoulder-neck pain and brassiere cup size. However, after participants were classified into two groups (small brassiere cup size and large brassiere cup size with 219 and 120 participants, respectively), there was a significant positive correlation between shoulder-neck pain and large brassiere cup size (p<0.05). There was no significant relationship between shoulder-neck pain and breast size. In conclusion, large brassiere cup size is an important cause of shoulder-neck pain. PMID- 22509232 TI - Professional Caregivers' Perceptions on how Persons with Mild Dementia Might Experience the Usage of a Digital Photo Diary. AB - Cognitive impairments influence the possibility of persons with dementia to remember daily events and maintain a sense of self. In order to address these problems a digital photo diary was developed to capture information about events in daily life. The device consisted of a wearable digital camera, smart phone with Global Positioning System (GPS) and a home memory station with computer for uploading the photographs and touch screen. The aim of this study was to describe professional caregiver's perceptions on how persons with mild dementia might experience the usage of this digital photo diary from both a situation when wearing the camera and a situation when viewing the uploaded photos, through a questionnaire with 408 respondents. In order to catch the professional caregivers' perceptions a questionnaire with the semantic differential technique was used and the main question was "How do you think Hilda (the fictive person in the questionnaire) feels when she is using the digital photo diary?". The factor analysis revealed three factors; Sense of autonomy, Sense of self-esteem and Sense of trust. An interesting conclusion that can be drawn is that professional caregivers had an overall positive view of the usage of digital photo diary as supporting autonomy for persons with mild dementia. The meaningfulness of each situation when wearing the camera and viewing the uploaded pictures to be used in two different situations and a part of an integrated assistive device has to be considered separately. Individual needs and desires of the person who is living with dementia and the context of each individual has to be reflected on and taken into account before implementing assistive digital devices as a tool in care. PMID- 22509233 TI - Self-reported non-adherence and beliefs about medication in a Swedish kidney transplant population. AB - BACKGROUND: Patients' non-adherence to immunosuppressant treatment after organ transplantation may lead to organ failure, graft loss and death. Non-adherence among Swedish kidney transplant recipients has not previously been studied. Hence the aim of this study was to explore non-adherence among Swedish kidney transplant recipients by using self-report instruments as well as testing the hypothesis that there is a difference in self-reported symptoms, beliefs about medicine and social support between respondents with or without self reported non adherence. MATERIALS AND METHODOLOGY: In the present cross sectional study 250 renal transplant recipients participated by replying to a questionnaire. Two validated instruments were included, one on beliefs about medicine (the BMQ(c)), the other on nonadherence (the BAASIS(c)). RESULTS: Only 46 % never failed to follow the medical treatment with respect to taking the drugs, dosage or timing (>2 hrs from prescribed time). Timing was the most frequently reported deviation (48 %). Forty-seven patients (16 %) had failed taking at least one dose of the prescribed immunosuppressants during the past four weeks. Four individuals had reduced the prescribed doses. Only one reported taking a 'drug holiday'. Nine participants reported stronger concerns than necessities for immunosuppressive medication. For the BMQ the necessity scores were extremely high while the scores for concern were low. Risk behaviour identified by the BAASIS had no association in risk attitudes as identified in the BMQ. The only factor relating to non adherence was lack of social support (p=0.022). CONCLUSION: In general adherence was high. Identification of the exceptions remains a challenge. PMID- 22509241 TI - The role of natural killer (NK) cells and NK cell receptor polymorphisms in the assessment of HIV-1 neutralization. AB - The importance of innate immune cells in HIV-1 pathogenesis and protection has been highlighted by the role of natural killer (NK) cells in the containment of viral replication. Use of peripheral blood mononuclear cells (PBMC) in immunologic studies provides both HIV-1 target cells (ie. CD4+ T cells), as well as anti-HIV-1 effector cells, such as NK cells. In this study, NK and other immune cell populations were analyzed in HIV-negative donor PBMC for an impact on the anti-HIV activity of polyclonal and monoclonal antibodies. NK cell percentages were significantly higher in donor PBMC that supported lower levels of viral replication. While the percentage of NK cells was not directly associated with neutralization titers, NK cell-depletion significantly diminished the antiviral antibody activity by up to three logs, and polymorphisms in NK killer immunoglobulin receptor (KIR) and FcgammaRIIIa alleles appear to be associated with this affect. These findings demonstrate that NK cells and NK cell receptor polymorphisms may influence assessment of traditional HIV-1 neutralization in a platform where antibody is continuously present. This format appears to simultaneously assess conventional entry inhibition (neutralization) and non-neutralizing antibody-dependent HIV inhibition, which may provide the opportunity to delineate the dominant antibody function(s) in polyclonal vaccine responses. PMID- 22509242 TI - Anatomy and cranial functional morphology of the small-bodied dinosaur Fruitadens haagarorum from the Upper Jurassic of the USA. AB - BACKGROUND: Heterodontosaurids are an important but enigmatic and poorly understood early radiation of ornithischian dinosaurs. The late-surviving heterodontosaurid Fruitadens haagarorum from the Late Jurassic (early Tithonian) Morrison Formation of the western USA is represented by remains of several small (<1 metre total body length, <1 kg body mass) individuals that include well preserved but incomplete cranial and postcranial material. Fruitadens is hypothesized to represent one of the smallest known ornithischian dinosaurs. METHODOLOGY/PRINCIPAL FINDINGS: We describe the cranial and postcranial anatomy of Fruitadens in detail, providing comparisons to all other known heterodontosaurid taxa. High resolution micro-CT data provides new insights into tooth replacement and the internal anatomy of the tooth-bearing bones. Moreover, we provide a preliminary functional analysis of the skull of late-surviving heterodontosaurids, discuss the implications of Fruitadens for current understanding of heterodontosaurid monophyly, and briefly review the evolution and biogeography of heterodontosaurids. CONCLUSIONS/SIGNIFICANCE: The validity of Fruitadens is supported by multiple unique characters of the dentition and hindlimb as well as a distinct character combination. Fruitadens shares highly distinctive appendicular characters with other heterodontosaurids, strengthening monophyly of the clade on the basis of the postcranium. Mandibular morphology and muscle moment arms suggest that the jaws of late-surviving heterodontosaurids, including Fruitadens, were adapted for rapid biting at large gape angles, contrasting with the jaws of the stratigraphically older Heterodontosaurus, which were better suited for strong jaw adduction at small gapes. The lack of wear facets and plesiomorphic dentition suggest that Fruitadens used orthal jaw movements and employed simple puncture-crushing to process food. In combination with its small body size, these results suggest that Fruitadens was an ecological generalist, consuming select plant material and possibly insects or other invertebrates. PMID- 22509243 TI - Gender dimorphism in aspartame-induced impairment of spatial cognition and insulin sensitivity. AB - Previous studies have linked aspartame consumption to impaired retention of learned behavior in rodents. Prenatal exposure to aspartame has also been shown to impair odor-associative learning in guinea pigs; and recently, aspartame-fed hyperlipidemic zebrafish exhibited weight gain, hyperglycemia and acute swimming defects. We therefore investigated the effects of chronic lifetime exposure to aspartame, commencing in utero, on changes in blood glucose parameters, spatial learning and memory in C57BL/6J mice. Morris Water Maze (MWM) testing was used to assess learning and memory, and a random-fed insulin tolerance test was performed to assess glucose homeostasis. Pearson correlation analysis was used to investigate the associations between body characteristics and MWM performance outcome variables. At 17 weeks of age, male aspartame-fed mice exhibited weight gain, elevated fasting glucose levels and decreased insulin sensitivity compared to controls (P<0.05). Females were less affected, but had significantly raised fasting glucose levels. During spatial learning trials in the MWM (acquisition training), the escape latencies of male aspartame-fed mice were consistently higher than controls, indicative of learning impairment. Thigmotactic behavior and time spent floating directionless was increased in aspartame mice, who also spent less time searching in the target quadrant of the maze (P<0.05). Spatial learning of female aspartame-fed mice was not significantly different from controls. Reference memory during a probe test was affected in both genders, with the aspartame-fed mice spending significantly less time searching for the former location of the platform. Interestingly, the extent of visceral fat deposition correlated positively with non-spatial search strategies such as floating and thigmotaxis, and negatively with time spent in the target quadrant and swimming across the location of the escape platform. These data suggest that lifetime exposure to aspartame, commencing in utero, may affect spatial cognition and glucose homeostasis in C57BL/6J mice, particularly in males. PMID- 22509244 TI - Discrimination training with multimodal stimuli changes activity in the mushroom body of the hawkmoth Manduca sexta. AB - BACKGROUND: The mushroom bodies of the insect brain play an important role in olfactory processing, associative learning and memory. The mushroom bodies show odor-specific spatial patterns of activity and are also influenced by visual stimuli. METHODOLOGY/PRINCIPAL FINDINGS: Functional imaging was used to investigate changes in the in vivo responses of the mushroom body of the hawkmoth Manduca sexta during multimodal discrimination training. A visual and an odour stimulus were presented either together or individually. Initially, mushroom body activation patterns were identical to the odour stimulus and the multimodal stimulus. After training, however, the mushroom body response to the rewarded multimodal stimulus was significantly lower than the response to the unrewarded unimodal odour stimulus, indicating that the coding of the stimuli had changed as a result of training. The opposite pattern was seen when only the unimodal odour stimulus was rewarded. In this case, the mushroom body was more strongly activated by the multimodal stimuli after training. When no stimuli were rewarded, the mushroom body activity decreased for both the multimodal and unimodal odour stimuli. There was no measurable response to the unimodal visual stimulus in any of the experiments. These results can be explained using a connectionist model where the mushroom body is assumed to be excited by olfactory stimulus components, and suppressed by multimodal configurations. CONCLUSIONS: Discrimination training with multimodal stimuli consisting of visual and odour cues leads to stimulus specific changes in the in vivo responses of the mushroom body of the hawkmoth. PMID- 22509245 TI - Phylogenetic reconstruction and DNA barcoding for closely related pine moth species (Dendrolimus) in China with multiple gene markers. AB - Unlike distinct species, closely related species offer a great challenge for phylogeny reconstruction and species identification with DNA barcoding due to their often overlapping genetic variation. We tested a sibling species group of pine moth pests in China with a standard cytochrome c oxidase subunit I (COI) gene and two alternative internal transcribed spacer (ITS) genes (ITS1 and ITS2). Five different phylogenetic/DNA barcoding analysis methods (Maximum likelihood (ML)/Neighbor-joining (NJ), "best close match" (BCM), Minimum distance (MD), and BP-based method (BP)), representing commonly used methodology (tree-based and non tree based) in the field, were applied to both single-gene and multiple-gene analyses. Our results demonstrated clear reciprocal species monophyly for three relatively distant related species, Dendrolimus superans, D. houi, D. kikuchii, as recovered by both single and multiple genes while the phylogenetic relationship of three closely related species, D. punctatus, D. tabulaeformis, D. spectabilis, could not be resolved with the traditional tree-building methods. Additionally, we find the standard COI barcode outperforms two nuclear ITS genes, whatever the methods used. On average, the COI barcode achieved a success rate of 94.10-97.40%, while ITS1 and ITS2 obtained a success rate of 64.70-81.60%, indicating ITS genes are less suitable for species identification in this case. We propose the use of an overall success rate of species identification that takes both sequencing success and assignation success into account, since species identification success rates with multiple-gene barcoding system were generally overestimated, especially by tree-based methods, where only successfully sequenced DNA sequences were used to construct a phylogenetic tree. Non-tree based methods, such as MD, BCM, and BP approaches, presented advantages over tree based methods by reporting the overall success rates with statistical significance. In addition, our results indicate that the most closely related species D. punctatus, D. tabulaeformis, and D. spectabilis, may be still in the process of incomplete lineage sorting, with occasional hybridizations occurring among them. PMID- 22509247 TI - Weapons make the man (larger): formidability is represented as size and strength in humans. AB - In order to determine how to act in situations of potential agonistic conflict, individuals must assess multiple features of a prospective foe that contribute to the foe's resource-holding potential, or formidability. Across diverse species, physical size and strength are key determinants of formidability, and the same is often true for humans. However, in many species, formidability is also influenced by other factors, such as sex, coalitional size, and, in humans, access to weaponry. Decision-making involving assessments of multiple features is enhanced by the use of a single summary variable that encapsulates the contributions of these features. Given both a) the phylogenetic antiquity of the importance of size and strength as determinants of formidability, and b) redundant experiences during development that underscore the contributions of size and strength to formidability, we hypothesize that size and strength constitute the conceptual dimensions of a representation used to summarize multiple diverse determinants of a prospective foe's formidability. Here, we test this hypothesis in humans by examining the effects of a potential foe's access to weaponry on estimations of that individual's size and strength. We demonstrate that knowing that an individual possesses a gun or a large kitchen knife leads observers to conceptualize him as taller, and generally larger and more muscular, than individuals who possess only tools or similarly mundane objects. We also document that such patterns are not explicable in terms of any actual correlation between gun ownership and physical size, nor can they be explained in terms of cultural schemas or other background knowledge linking particular objects to individuals of particular size and strength. These findings pave the way for a fuller understanding of the evolution of the cognitive systems whereby humans--and likely many other social vertebrates--navigate social hierarchies. PMID- 22509246 TI - Specific roles of Akt iso forms in apoptosis and axon growth regulation in neurons. AB - Akt is a member of the AGC kinase family and consists of three isoforms. As one of the major regulators of the class I PI3 kinase pathway, it has a key role in the control of cell metabolism, growth, and survival. Although it has been extensively studied in the nervous system, we have only a faint knowledge of the specific role of each isoform in differentiated neurons. Here, we have used both cortical and hippocampal neuronal cultures to analyse their function. We characterized the expression and function of Akt isoforms, and some of their substrates along different stages of neuronal development using a specific shRNA approach to elucidate the involvement of each isoform in neuron viability, axon development, and cell signalling. Our results suggest that three Akt isoforms show substantial compensation in many processes. However, the disruption of Akt2 and Akt3 significantly reduced neuron viability and axon length. These changes correlated with a tendency to increase in active caspase 3 and a decrease in the phosphorylation of some elements of the mTORC1 pathway. Indeed, the decrease of Akt2 and more evident the inhibition of Akt3 reduced the expression and phosphorylation of S6. All these data indicate that Akt2 and Akt3 specifically regulate some aspects of apoptosis and cell growth in cultured neurons and may contribute to the understanding of mechanisms of neuron death and pathologies that show deregulated growth. PMID- 22509249 TI - Interactions of hydroxyapatite with proteins and its toxicological effect to zebrafish embryos development. AB - The increased application of nanomaterials has raised the level of public concern regarding possible toxicities caused by exposure to nanostructures. The interactions of nanosized hydroxyapatite (HA) with cytochrome c and hemoglobin were investigated by zeta-potential, UV-vis, fluorescence and circular dichroism. The experimental results indicated that the interactions were formed via charge attraction and hydrogen bond and obeyed Langmuir adsorption isotherm. The two functional proteins bridged between HA particles to aggregate into the coralloid form, where change of the secondary structure of proteins occurred. From effects of nanosized HA, SiO(2) and TiO(2) particles on the zebrafish embryos development, they were adsorbed on the membrane surface confirmed by the electronic scanning microscopy. Nano-HA aggregated into the biggest particles around the membrane protein and then caused a little toxicity to development of zebrafish embryos. The SiO(2) particles were distributed throughout the outer surface and caused jam of membrane passage, delay of the hatching time and axial malformation. Maybe owing to the oxygen free radical activity, TiO(2) caused some serious deformity characters in the cardiovascular system. PMID- 22509248 TI - Sinusoidal endothelial dysfunction precedes inflammation and fibrosis in a model of NAFLD. AB - Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Most morbidity associated with the metabolic syndrome is related to vascular complications, in which endothelial dysfunction is a major pathogenic factor. However, whether NAFLD is associated with endothelial dysfunction within the hepatic vasculature is unknown. The aims of this study were to explore, in a model of diet-induced overweight that expresses most features of the metabolic syndrome, whether early NAFLD is associated with liver endothelial dysfunction. Wistar Kyoto rats were fed a cafeteria diet (CafD; 65% of fat, mostly saturated) or a control diet (CD) for 1 month. CafD rats developed features of the metabolic syndrome (overweight, arterial hypertension, hypertryglyceridemia, hyperglucemia and insulin resistance) and liver steatosis without inflammation or fibrosis. CafD rats had a significantly higher in vivo hepatic vascular resistance than CD. In liver perfusion livers from CafD rats had an increased portal perfusion pressure and decreased endothelium-dependent vasodilation. This was associated with a decreased Akt-dependent eNOS phosphorylation and NOS activity. In summary, we demonstrate in a rat model of the metabolic syndrome that shows features of NAFLD, that liver endothelial dysfunction occurs before the development of fibrosis or inflammation. PMID- 22509250 TI - The risks we dread: a social circle account. AB - What makes some risks dreadful? We propose that people are particularly sensitive to threats that could kill the number of people that is similar to the size of a typical human social circle. Although there is some variability in reported sizes of social circles, active contact rarely seems to be maintained with more than about 100 people. The loss of this immediate social group may have had survival consequences in the past and still causes great distress to people today. Therefore we hypothesize that risks that threaten a much larger number of people (e.g., 1000) will not be dreaded more than those that threaten to kill "only" the number of people typical for social circles. We found support for this hypothesis in 9 experiments using different risk scenarios, measurements of fear, and samples from different countries. Fear of risks killing 100 people was higher than fear of risks killing 10 people, but there was no difference in fear of risks killing 100 or 1000 people (Experiments 1-4, 7-9). Also in support of the hypothesis, the median number of deaths that would cause maximum level of fear was 100 (Experiments 5 and 6). These results are not a consequence of lack of differentiation between the numbers 100 and 1000 (Experiments 7 and 8), and are different from the phenomenon of "psychophysical numbing" that occurs in the context of altruistic behavior towards members of other communities rather than in the context of threat to one's own community (Experiment 9). We discuss several possible explanations of these findings. Our results stress the importance of considering social environments when studying people's understanding of and reactions to risks. PMID- 22509251 TI - Socially anxious and confident men interact with a forward virtual woman: an experimental study. AB - BACKGROUND: Male volunteers entered an immersive virtual reality that depicted a party, where they were approached by a lone virtual woman who initiated a conversation. The goal was to study how socially anxious and socially confident men would react to this event. Interest focused on whether the socially anxious participants would exhibit sustained anxiety during the conversation or whether this would diminish over time, and differ from the responses of the more socially confident men. METHODOLOGY: The scenario was a party with five virtual characters, four sitting at a distance from the participant and talking amongst themselves and one lone woman standing closer. The woman approached the participant, introduced herself and initiated a conversation that was first about mundane matters and then became more personal and intimate. Participants were men who were either relatively socially confident (18) or socially anxious in their relationships with women (18). A second experimental factor was whether or not the other four characters occasionally looked towards the participant. There was a post-trial questionnaire about social anxiety in relation to the experience, and skin conductance and ECG physiological measures were recorded. Our expectation was that the socially anxious participants would show greater anxiety throughout. CONCLUSIONS: Compared to baseline readings both socially confident and socially anxious groups on average showed signs of significantly increased stress at the initial approach of the virtual woman. The stress then diminished once the conversation entered into the mundane phase and then did not significantly change. Comparing pre- and post-questionnaire anxiety scores there was no change for the more confident participants but a significant decrease in average score amongst the anxious group. The methodology of placing socially anxious participants in a virtual reality where they can gain experience of how to act in a stressful situation promises a novel way forward for treating social anxiety. PMID- 22509252 TI - Complexity of the Mycoplasma fermentans M64 genome and metabolic essentiality and diversity among mycoplasmas. AB - Recently, the genomes of two Mycoplasma fermentans strains, namely M64 and JER, have been completely sequenced. Gross comparison indicated that the genome of M64 is significantly bigger than the other strain and the difference is mainly contributed by the repetitive sequences including seven families of simple and complex transposable elements ranging from 973 to 23,778 bps. Analysis of these repeats resulted in the identification of a new distinct family of Integrative Conjugal Elements of M. fermentans, designated as ICEF-III. Using the concept of "reaction connectivity", the metabolic capabilities in M. fermentans manifested by the complete and partial connected biomodules were revealed. A comparison of the reported M. pulmonis, M. arthritidis, M. genitalium, B. subtilis, and E. coli essential genes and the genes predicted from the M64 genome indicated that more than 73% of the Mycoplasmas essential genes are preserved in M. fermentans. Further examination of the highly and partly connected reactions by a novel combinatorial phylogenetic tree, metabolic network, and essential gene analysis indicated that some of the pathways (e.g. purine and pyrimidine metabolisms) with partial connected reactions may be important for the conversions of intermediate metabolites. Taken together, in light of systems and network analyses, the diversity among the Mycoplasma species was manifested on the variations of their limited metabolic abilities during evolution. PMID- 22509253 TI - Cacospongionolide and scalaradial, two marine sesterterpenoids as potent apoptosis-inducing factors in human carcinoma cell lines. AB - Apoptosis, a form of programmed cell death, is a critical defence mechanism against the formation and progression of cancer and acts by eliminating potentially deleterious cells without causing such adverse effects, as inflammatory response and ensuing scar formation. Therefore, targeting apoptotic pathways becomes an intriguing strategy for the development of chemotherapeutic agents. In last decades, marine natural products, such as sesterterpenoids, have played an important role in the discovery and development of new drugs. Interestingly, many of these compounds have a strong potential as anticancer drugs by inhibiting cell proliferation and/or inducing cell death. In the present study, we investigated the effects of scalaradial and cacospongionolide, two sesterterpenoids from Cacospongia scalaris and Fasciospongia cavernosa marine sponges, on the apoptotic signalling pathway in three different human tumoral cells. Results were obtained by using DNA fragmentation, comet and viability assays, quantification of the mitochondrial transmembrane potential and Western blot. The T47D (human breast carcinoma), A431 (human epidermoid carcinoma), HeLa (human cervix carcinoma) and HCT116 (human colon carcinoma) cells were incubated for 24 h with scalaradial or cacospongionolide. Treatment of T47D cells with scalaradial or cacospongionolide for 24 h brought about a significant increase in DNA migration as well as fragmentation. Moreover, incubation of HCT116 and HeLa cells with scalaradial or cacospongionolide for 24 h caused an increased expression of pro-apoptotic proteins. Furthermore, scalaradial or cacospongionolide, added to HCT116 and HeLa cells overnight, induced a significant and concentration-dependent loss of mitochondrial transmembrane potential, an early apoptosis signalling event. These effects paralleled with those achieved with p50 and p65, NF-kappaB subunits, nuclear level. In conclusion, scalaradial and cacospongionolide, by determining human cancer cell apoptosis, may represent new promising compounds to inhibit cancer cell proliferation. PMID- 22509255 TI - A temperature-precipitation based leafing model and its application in Northeast China. AB - Plant phenology models, especially leafing models, play critical roles in evaluating the impact of climate change on the primary production of temperate plants. Existing models based on temperature alone could not accurately simulate plant leafing in arid and semi-arid regions. The objective of the present study was to test the suitability of the existing temperature-based leafing models in arid and semi-arid regions, and to develop a temperature-precipitation based leafing model (TP), based on the long-term (i.e., 12-27 years) ground leafing observation data and meteorological data in Northeast China. The better simulation of leafing for all the plant species in Northeast China was given by TP with the fixed starting date (TPn) than with the parameterized starting date (TPm), which gave the smallest average root mean square error (RMSE) of 4.21 days. Tree leafing models were validated with independent data, and the coefficient of determination (R(2)) was greater than 0.60 in 75% of the estimates by TP and the spring warming model (SW) with the fixed starting date. The average RMSE of herb leafing simulated by TPn was 5.03 days, much lower than other models (>9.51 days), while the average R(2) of TPn and TPm were 0.68 and 0.57, respectively, much higher than the other models (<0.22). It indicates that TPn is a universal model and more suitable for simulating leafing of trees and herbs than the prior models. Furthermore, water is an important factor determining herb leafing in arid and semi-arid temperate regions. PMID- 22509254 TI - Exhaled aerosol transmission of pandemic and seasonal H1N1 influenza viruses in the ferret. AB - Person-to-person transmission of influenza viruses occurs by contact (direct and fomites) and non-contact (droplet and small particle aerosol) routes, but the quantitative dynamics and relative contributions of these routes are incompletely understood. The transmissibility of influenza strains estimated from secondary attack rates in closed human populations is confounded by large variations in population susceptibilities. An experimental method to phenotype strains for transmissibility in an animal model could provide relative efficiencies of transmission. We developed an experimental method to detect exhaled viral aerosol transmission between unanesthetized infected and susceptible ferrets, measured aerosol particle size and number, and quantified the viral genomic RNA in the exhaled aerosol. During brief 3-hour exposures to exhaled viral aerosols in airflow-controlled chambers, three strains of pandemic 2009 H1N1 strains were frequently transmitted to susceptible ferrets. In contrast one seasonal H1N1 strain was not transmitted in spite of higher levels of viral RNA in the exhaled aerosol. Among three pandemic strains, the two strains causing weight loss and illness in the intranasally infected 'donor' ferrets were transmitted less efficiently from the donor than the strain causing no detectable illness, suggesting that the mucosal inflammatory response may attenuate viable exhaled virus. Although exhaled viral RNA remained constant, transmission efficiency diminished from day 1 to day 5 after donor infection. Thus, aerosol transmission between ferrets may be dependent on at least four characteristics of virus-host relationships including the level of exhaled virus, infectious particle size, mucosal inflammation, and viral replication efficiency in susceptible mucosa. PMID- 22509256 TI - From forest to farm: systematic review of cultivar feeding by chimpanzees- management implications for wildlife in anthropogenic landscapes. AB - Crop-raiding is a major source of conflict between people and wildlife globally, impacting local livelihoods and impeding conservation. Conflict mitigation strategies that target problematic wildlife behaviours such as crop-raiding are notoriously difficult to develop for large-bodied, cognitively complex species. Many crop-raiders are generalist feeders. In more ecologically specialised species crop-type selection is not random and evidence-based management requires a good understanding of species' ecology and crop feeding habits. Comprehensive species-wide studies of crop consumption by endangered wildlife are lacking but are important for managing human-wildlife conflict. We conducted a comprehensive literature search of crop feeding records by wild chimpanzees (Pan troglodytes), a ripe-fruit specialist. We assessed quantitatively patterns of crop selection in relation to species-specific feeding behaviour, agricultural exposure, and crop availability. Crop consumption by chimpanzees is widespread in tropical Africa. Chimpanzees were recorded to eat a considerable range of cultivars (51 plant parts from 36 species). Crop part selection reflected a species-typical preference for fruit. Crops widely distributed in chimpanzee range countries were eaten at more sites than sparsely distributed crops. We identified 'high' and 'low' conflict crops according to their attractiveness to chimpanzees, taking account of their importance as cash crops and/or staple foods to people. Most (86%) high conflict crops were fruits, compared to 13% of low conflict crops. Some widely farmed cash or staple crops were seldom or never eaten by chimpanzees. Information about which crops are most frequently consumed and which are ignored has enormous potential for aiding on-the-ground stakeholders (i.e. farmers, wildlife managers, and conservation and agricultural extension practitioners) develop sustainable wildlife management schemes for ecologically specialised and protected species in anthropogenic habitats. However, the economic and subsistence needs of local people, and the crop-raiding behaviour of sympatric wildlife, must be considered when assessing suitability of particular crops for conflict prevention and mitigation. PMID- 22509257 TI - Effects of culture on musical pitch perception. AB - The strong association between music and speech has been supported by recent research focusing on musicians' superior abilities in second language learning and neural encoding of foreign speech sounds. However, evidence for a double association--the influence of linguistic background on music pitch processing and disorders--remains elusive. Because languages differ in their usage of elements (e.g., pitch) that are also essential for music, a unique opportunity for examining such language-to-music associations comes from a cross-cultural (linguistic) comparison of congenital amusia, a neurogenetic disorder affecting the music (pitch and rhythm) processing of about 5% of the Western population. In the present study, two populations (Hong Kong and Canada) were compared. One spoke a tone language in which differences in voice pitch correspond to differences in word meaning (in Hong Kong Cantonese, /si/ means 'teacher' and 'to try' when spoken in a high and mid pitch pattern, respectively). Using the On line Identification Test of Congenital Amusia, we found Cantonese speakers as a group tend to show enhanced pitch perception ability compared to speakers of Canadian French and English (non-tone languages). This enhanced ability occurs in the absence of differences in rhythmic perception and persists even after relevant factors such as musical background and age were controlled. Following a common definition of amusia (5% of the population), we found Hong Kong pitch amusics also show enhanced pitch abilities relative to their Canadian counterparts. These findings not only provide critical evidence for a double association of music and speech, but also argue for the reconceptualization of communicative disorders within a cultural framework. Along with recent studies documenting cultural differences in visual perception, our auditory evidence challenges the common assumption of universality of basic mental processes and speaks to the domain generality of culture-to-perception influences. PMID- 22509258 TI - A human PrM antibody that recognizes a novel cryptic epitope on dengue E glycoprotein. AB - Dengue virus (DENV) is a major mosquito-borne pathogen infecting up to 100 million people each year; so far no effective treatment or vaccines are available. Recently, highly cross-reactive and infection-enhancing pre-membrane (prM)-specific antibodies were found to dominate the anti-DENV immune response in humans, raising concern over vaccine candidates that contain native dengue prM sequences. In this study, we have isolated a broadly cross-reactive prM-specific antibody, D29, during a screen with a non-immunized human Fab-phage library against the four serotypes of DENV. The antibody is capable of restoring the infectivity of virtually non-infectious immature DENV (imDENV) in FcgammaR bearing K562 cells. Remarkably, D29 also cross-reacted with a cryptic epitope on the envelope (E) protein located to the DI/DII junction as evidenced by site directed mutagenesis. This cryptic epitope, while inaccessible to antibody binding in a native virus particle, may become exposed if E is not properly folded. These findings suggest that generation of anti-prM antibodies that enhance DENV infection may not be completely avoided even with immunization strategies employing E protein alone or subunits of E proteins. PMID- 22509259 TI - Off-label biologic regimens in psoriasis: a systematic review of efficacy and safety of dose escalation, reduction, and interrupted biologic therapy. AB - OBJECTIVES: While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and safety of these off-label dosing regimens. The aim of this systematic review is to evaluate efficacy and safety of off-label dosing regimens (dose escalation, dose reduction, and interrupted treatment) with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for psoriasis treatment. DATA SOURCES AND STUDY SELECTION: We searched OVID Medline from January 1, 1990 through August 1, 2011 for prospective clinical trials that studied biologic therapy for psoriasis treatment in adults. Individual articles were screened for studies that examined escalated, reduced, or interrupted therapy with etanercept, adalimumab, infliximab, ustekinumab, or alefacept. DATA SYNTHESIS: A total of 23 articles with 12,617 patients matched the inclusion and exclusion criteria for the systematic review. Data were examined for primary and secondary efficacy outcomes and adverse events including infections, malignancies, cardiovascular events, and anti-drug antibodies. The preponderance of data suggests that continuous treatment with anti-TNF agents and anti-IL12/23 agent was necessary for maintenance of disease control. Among non-responders, dose escalation with etanercept, adalimumab, ustekinumab, and alefacept typically resulted in greater efficacy than standard dosing. Dose reduction with etanercept and alefacept resulted in reduced efficacy. Withdrawal of the examined biologics led to an increase in disease activity; efficacy from retreatment did not result in equivalent initial response rates for most biologics. Safety data on off-label dosing regimens are limited. CONCLUSION: Dose escalation in non-responders generally resulted in increased efficacy in the examined biologics used to treat moderate-to-severe psoriasis. Continuous treatment with anti-TNF agents and anti IL12/23 agent results in superior efficacy over interrupted therapy. The decision to use off-label dosing needs to account for both benefits and risks and be individualized to patients' disease severity, quality of life, and existence of comorbidities. PMID- 22509260 TI - GAMETOPHYTE DEFECTIVE 1, a putative subunit of RNases P/MRP, is essential for female gametogenesis and male competence in Arabidopsis. AB - RNA biogenesis, including biosynthesis and maturation of rRNA, tRNA and mRNA, is a fundamental process that is critical for cell growth, division and differentiation. Previous studies showed that mutations in components involved in RNA biogenesis resulted in abnormalities in gametophyte and leaf development in Arabidopsis. In eukaryotes, RNases P/MRP (RNase mitochondrial RNA processing) are important ribonucleases that are responsible for processing of tRNA, and transcription of small non-coding RNAs. Here we report that Gametophyte Defective 1 (GAF1), a gene encoding a predicted protein subunit of RNases P/MRP, AtRPP30, plays a role in female gametophyte development and male competence. Embryo sacs were arrested at stages ranging from FG1 to FG7 in gaf1 mutant, suggesting that the progression of the gametophytic division during female gametogenesis was impaired in gaf1 mutant. In contrast, pollen development was not affected in gaf1. However, the fitness of the mutant pollen tube was weaker than that of the wild-type, leading to reduced transmission through the male gametes. GAF1 is featured as a typical RPP30 domain protein and interacts physically with AtPOP5, a homologue of RNases P/MRP subunit POP5 of yeast. Together, our data suggest that components of the RNases P/MRP family, such as RPP30, play important roles in gametophyte development and function in plants. PMID- 22509261 TI - Preparation and characterization of the extracellular domain of human Sid-1. AB - In C. elegans, the cell surface protein Sid-1 imports extracellular dsRNA into the cytosol of most non-neuronal cells, enabling systemic spread of RNA interference (RNAi) throughout the worm. Sid-1 homologs are found in many other animals, although for most a function for the protein has not yet been established. Sid-1 proteins are composed of an N-terminal extracellular domain (ECD) followed by 9-12 predicted transmembrane regions. We developed a baculovirus system to express and purify the ECD of the human Sid-1 protein SidT1. Recombinant SidT1 ECD is glycosylated and spontaneously assembles into a stable and discrete tetrameric structure. Electron microscopy (EM) and small angle x-ray scattering (SAXS) studies reveal that the SidT1 ECD tetramer is a compact, puck-shaped globular particle, which we hypothesize may control access of dsRNA to the transmembrane pore. These characterizations provide inroads towards understanding the mechanism of this unique RNA transport system from structural prospective. PMID- 22509262 TI - Genes involved in systemic and arterial bed dependent atherosclerosis--Tampere Vascular study. AB - BACKGROUND: Atherosclerosis is a complex disease with hundreds of genes influencing its progression. In addition, the phenotype of the disease varies significantly depending on the arterial bed. METHODOLOGY/PRINCIPAL FINDINGS: We characterized the genes generally involved in human advanced atherosclerotic (AHA type V-VI) plaques in carotid and femoral arteries as well as aortas from 24 subjects of Tampere Vascular study and compared the results to non atherosclerotic internal thoracic arteries (n=6) using genome-wide expression array and QRT-PCR. In addition we determined genes that were typical for each arterial plaque studied. To gain a comprehensive insight into the pathologic processes in the plaques we also analyzed pathways and gene sets dysregulated in this disease using gene set enrichment analysis (GSEA). According to the selection criteria used (>3.0 fold change and p-value <0.05), 235 genes were up regulated and 68 genes down-regulated in the carotid plaques, 242 genes up regulated and 116 down-regulated in the femoral plaques and 256 genes up regulated and 49 genes down-regulated in the aortic plaques. Nine genes were found to be specifically induced predominantly in aortic plaques, e.g., lactoferrin, and three genes in femoral plaques, e.g., chondroadherin, whereas no gene was found to be specific for carotid plaques. In pathway analysis, a total of 28 pathways or gene sets were found to be significantly dysregulated in atherosclerotic plaques (false discovery rate [FDR] <0.25). CONCLUSIONS: This study describes comprehensively the gene expression changes that generally prevail in human atherosclerotic plaques. In addition, site specific genes induced only in femoral or aortic plaques were found, reflecting that atherosclerotic process has unique features in different vascular beds. PMID- 22509263 TI - The impact of adherence to screening guidelines and of diabetes clinics referral on morbidity and mortality in diabetes. AB - Despite the heightened awareness of diabetes as a major health problem, evidence on the impact of assistance and organizational factors, as well as of adherence to recommended care guidelines, on morbidity and mortality in diabetes is scanty. We identified diabetic residents in Torino, Italy, as of 1st January 2002, using multiple independent data sources. We collected data on several laboratory tests and specialist medical examinations to compare primary versus specialty care management of diabetes and the fulfillment of a quality-of-care indicator based on existing screening guidelines (GCI). Then, we performed regression analyses to identify associations of these factors with mortality and cardiovascular morbidity over a 4 year-follow-up. Patients with the lowest degree of quality of care (i.e. only cared for by primary care and with no fulfillment of GCI) had worse RRs for all-cause (1.72 [95% CI 1.57-1.89]), cardiovascular (1.74 [95% CI 1.50-2.01]) and cancer (1.35 [95% CI 1.14-1.61]) mortality, compared with those with the highest quality of care. They also showed increased RRs for incidence of major cardiovascular events up to 2.03 (95% CI 1.26-3.28) for lower extremity amputations. Receiving specialist care itself increased survival, but was far more effective when combined with the fulfillment of GCI. Throughout the whole set of analysis, implementation of guidelines emerged as a strong modifier of prognosis. We conclude that management of diabetic patients with a pathway based on both primary and specialist care is associated with a favorable impact on all cause mortality and CV incidence, provided that guidelines are implemented. PMID- 22509264 TI - White matter atrophy and cognitive dysfunctions in neuromyelitis optica. AB - Neuromyelitis optica (NMO) is an inflammatory disease of central nervous system characterized by optic neuritis and longitudinally extensive acute transverse myelitis. NMO patients have cognitive dysfunctions but other clinical symptoms of brain origin are rare. In the present study, we aimed to investigate cognitive functions and brain volume in NMO. The study population consisted of 28 patients with NMO and 28 healthy control subjects matched for age, sex and educational level. We applied a French translation of the Brief Repeatable Battery (BRB-N) to the NMO patients. Using SIENAx for global brain volume (Grey Matter, GM; White Matter, WM; and whole brain) and VBM for focal brain volume (GM and WM), NMO patients and controls were compared. Voxel-level correlations between diminished brain concentration and cognitive performance for each tests were performed. Focal and global brain volume of NMO patients with and without cognitive impairment were also compared. Fifteen NMO patients (54%) had cognitive impairment with memory, executive function, attention and speed of information processing deficits. Global and focal brain atrophy of WM but not Grey Matter (GM) was found in the NMO patients group. The focal WM atrophy included the optic chiasm, pons, cerebellum, the corpus callosum and parts of the frontal, temporal and parietal lobes, including superior longitudinal fascicle. Visual memory, verbal memory, speed of information processing, short-term memory and executive functions were correlated to focal WM volumes. The comparison of patients with, to patients without cognitive impairment showed a clear decrease of global and focal WM, including brainstem, corticospinal tracts, corpus callosum but also superior and inferior longitudinal fascicles. Cognitive impairment in NMO patients is correlated to the decreased of global and focal WM volume of the brain. Further studies are needed to better understand the precise origin of cognitive impairment in NMO patients, particularly in the WM. PMID- 22509265 TI - The immune cell composition in Barrett's metaplastic tissue resembles that in normal duodenal tissue. AB - BACKGROUND AND OBJECTIVE: Barrett's esophagus (BE) is characterized by the transition of squamous epithelium into columnar epithelium with intestinal metaplasia. The increased number and types of immune cells in BE have been indicated to be due to a Th2-type inflammatory process. We tested the alternative hypothesis that the abundance of T-cells in BE is caused by a homing mechanism that is found in the duodenum. PATIENTS AND METHODS: Biopsies from BE and duodenal tissue from 30 BE patients and duodenal tissue from 18 controls were characterized by immmunohistochemistry for the presence of T-cells and eosinophils(eos). Ex vivo expanded T-cells were further phenotyped by multicolor analysis using flowcytometry. RESULTS: The high percentage of CD4(+)-T cells (69+/-3% (mean+/-SEM/n = 17, by flowcytometry)), measured by flowcytometry and immunohistochemistry, and the presence of non-activated eosinophils found in BE by immunohistochemical staining, were not different from that found in duodenal tissue. Expanded lymphocytes from these tissues had a similar phenotype, characterized by a comparable but low percentage of alphaE(CD103) positive CD4(+)cells (44+/-5% in BE, 43+/-4% in duodenum of BE and 34+/-7% in duodenum of controls) and a similar percentage of granzyme-B(+)CD8(+) cells(44+/-5% in BE, 33+/-6% in duodenum of BE and 36+/-7% in duodenum of controls). In addition, a similar percentage of alpha4beta7(+) T-lymphocytes (63+/-5% in BE, 58+/-5% in duodenum of BE and 62+/-8% in duodenum of controls) was found. Finally, mRNA expression of the ligand for alpha4beta7, MAdCAM-1, was also similar in BE and duodenal tissue. No evidence for a Th2-response was found as almost no IL-4(+)-T cells were seen. CONCLUSION: The immune cell composition (lymphocytes and eosinophils) and expression of intestinal adhesion molecule MAdCAM-1 is similar in BE and duodenum. This supports the hypothesis that homing of lymphocytes to BE tissue is mainly caused by intestinal homing signals rather than to an active inflammatory response. PMID- 22509266 TI - Expression of odorant receptor family, type 2 OR in the aquatic olfactory cavity of amphibian frog Xenopus tropicalis. AB - Recent genome wide in silico analyses discovered a new family (type 2 or family H) of odorant receptors (ORs) in teleost fish and frogs. However, since there is no evidence of the expression of these novel OR genes in olfactory sensory neurons (OSN), it remains unknown if type 2 ORs (OR2) function as odorant receptors. In this study, we examined expression of OR2 genes in the frog Xenopus tropicalis. The overall gene expression pattern is highly complex and differs depending on the gene and developmental stage. RT-PCR analysis in larvae showed that all of the OR2eta genes we identified were expressed in the peripheral olfactory system and some were detected in the brain and skin. Whole mount in situ hybridization of the larval olfactory cavity confirmed that at least two OR2eta genes so far tested are expressed in the OSN. Because tadpoles are aquatic animals, OR2eta genes are probably involved in aquatic olfaction. In adults, OR2eta genes are expressed in the nose, brain, and testes to different degrees depending on the genes. OR2eta expression in the olfactory system is restricted to the medium cavity, which participates in the detection of water-soluble odorants, suggesting that OR2etas function as receptors for water-soluble odorants. Moreover, the fact that several OR2etas are significantly expressed in non-olfactory organs suggests unknown roles in a range of biological processes other than putative odorant receptor functions. PMID- 22509267 TI - Quality indicators for colonoscopy procedures: a prospective multicentre method for endoscopy units. AB - BACKGROUND AND AIMS: Healthcare professionals are required to conduct quality control of endoscopy procedures, and yet there is no standardised method for assessing quality. The topic of the present study was to validate the applicability of the procedure in daily practice, giving physicians the ability to define areas for continuous quality improvement. METHODS: In ten endoscopy units in France, 200 patients per centre undergoing colonoscopy were enrolled in the study. An evaluation was carried out based on a prospectively developed checklist of 10 quality-control indicators including five dependent upon and five independent of the colonoscopy procedure. RESULTS: Of the 2000 procedures, 30% were done at general hospitals, 20% at university hospitals, and 50% in private practices. The colonoscopies were carried out for a valid indication for 95.9% (range 92.5-100). Colon preparation was insufficient in 3.7% (range 1-10.5). Colonoscopies were successful in 95.3% (range 81-99). Adenoma detection rate was 0.31 (range 0.17-0.45) in successful colonoscopies. CONCLUSION: This tool for evaluating the quality of colonoscopy procedures in healthcare units is based on standard endoscopy and patient criteria. It is an easy and feasible procedure giving the ability to detect suboptimal practice and differences between endoscopy-units. It will enable individual units to assess the quality of their colonoscopy techniques. PMID- 22509268 TI - HLA-DRB1-DQB1 haplotypes confer susceptibility and resistance to multiple sclerosis in Sardinia. AB - INTRODUCTION: Genetic predisposition to multiple sclerosis (MS) in Sardinia (Italy) has been associated with five DRB1*-DQB1* haplotypes of the human leukocyte antigen (HLA). Given the complexity of these associations, an in-depth re-analysis was performed with the specific aims of confirming the haplotype associations; establishing the independence of the associated haplotypes; and assessing patients' genotypic risk of developing MS. METHODS AND RESULTS: A transmission disequilibrium test (TDT) of the DRB1*-DQB1* haplotypes in 943 trio families, confirmed a higher than expected transmission rate (over-transmission) of the *13:03-*03:01 (OR = 2.9, P = 7.6*10(-3)), *04:05-*03:01 (OR = 2.4, P = 4.4*10(-6)) and *03:01-*02:01 (OR = 2.1, P = 1.0*10(-15)) haplotype. In contrast, the *16:01-*05:02 (OR = 0.5, P = 5.4*10(-11)) and the *15:02-*06:01 (OR = 0.3, P = 1.5*10(-3)) haplotypes exhibited a lower than expected transmission rate (under transmission). The independence of the transmission of each positively and negatively associated haplotype was confirmed relative to all positively associated haplotypes, and to the negatively associated *16:01-*05:02 haplotype. In patients, carriage of two predisposing haplotypes, or of protective haplotypes, respectively increased or decreased the patient's risk of developing MS. The risk of MS followed a multiplicative model of genotypes, which was, in order of decreasing ORs: *04:05-*0301/*03:01-*02:01 (OR = 4.5); *03:01 *02:01/*03:01-*02:01 (OR = 4.1); and the *16:01-*05:02/*16:01-*0502 (OR = 0.2) genotypes. Analysis of DRB1 and DQB1 protein chain residues showed that the Val/Gly residue at position 86 of the DRB1 chain was the only difference between the protective *16:01- *15:02 alleles and the predisposing *15:01 one. Similarly, the Ala/Val residue at position 38 of the DQB1 chain differentiated the positively associated *06:02 allele and the negatively associated *05:02, *06:01 alleles. CONCLUSIONS: These findings show that the association of specific, independent DRB1*-DQB1* haplotypes confers susceptibility or resistance to MS in the MS-prone Sardinian population. The data also supports a functional role for specific residues of the DRB1 and DQB1 proteins in predisposing patients to MS. PMID- 22509269 TI - Governing the global commons with local institutions. AB - Most problems faced by modern human society have two characteristics in common- they are tragedy-of-the-commons type of problems, and they are global problems. Tragedy-of-the-commons type of problems are those where a commonly shared resource is overexploited by free riders at the expense of everyone sharing the resource. The exploitation of global resources such as clean air and water, political stability and peace, etc. underlies many of the most pressing human problems. Punishment of free riding behavior is one of the most frequently used strategies to combat the problem, but the spatial reach of sanctioning institutions is often more limited than the spatial effects of overexploitation. Here, we analyze a general game theoretical model to assess under what circumstances sanctioning institutions with limited reach can maintain the larger commons. We find that the effect of the spatial reach has a strong effect on whether and how the commons can be maintained, and that the transitions between those outcomes are characterized by phase transitions. The latter indicates that a small change in the reach of sanctioning systems can profoundly change the way the global commons can be managed. PMID- 22509270 TI - A versatile PhiC31 based reporter system for measuring AP-1 and Nrf2 signaling in Drosophila and in tissue culture. AB - This paper describes the construction and characterization of a system of transcriptional reporter genes for monitoring the activity of signaling pathways and gene regulation mechanisms in intact Drosophila, dissected tissues or cultured cells. Transgenic integration of the reporters into the Drosophila germline was performed in a site-directed manner, using PhiC31 integrase. This strategy avoids variable position effects and assures low base level activity and high signal responsiveness. Defined integration sites furthermore enable the experimenter to compare the activity of different reporters in one organism. The reporter constructs have a modular design to facilitate the combination of promoter elements (synthetic transcription factor binding sites or natural regulatory sequences), reporter genes (eGFP, or DsRed.T4), and genomic integration sites. The system was used to analyze and compare the activity and signal response profiles of two stress inducible transcription factors, AP-1 and Nrf2. To complement the transgenic reporter fly lines, tissue culture assays were developed in which the same synthetic ARE and TRE elements control the expression of firefly luciferase. PMID- 22509271 TI - Demographic and phenotypic effects of human mediated trophic subsidy on a large Australian lizard (Varanus varius): meal ticket or last supper? AB - Humans are increasingly subsidizing and altering natural food webs via changes to nutrient cycling and productivity. Where human trophic subsidies are concentrated and persistent within natural environments, their consumption could have complex consequences for wild animals through altering habitat preferences, phenotypes and fitness attributes that influence population dynamics. Human trophic subsidies conceptually create both costs and benefits for animals that receive increased calorific and altered nutritional inputs. Here, we evaluated the effects of a common terrestrial human trophic subsidies, human food refuse, on population and phenotypic (comprising morphological and physiological health indices) parameters of a large predatory lizard (~2 m length), the lace monitor (Varanus varius), in southern Australia by comparison with individuals not receiving human trophic subsidies. At human trophic subsidies sites, lizards were significantly more abundant and their sex ratio highly male biased compared to control sites in natural forest. Human trophic subsidies recipient lizards were significantly longer, heavier and in much greater body condition. Blood parasites were significantly lower in human trophic subsidies lizards. Collectively, our results imply that human trophic subsidized sites were especially attractive to adult male lace monitors and had large phenotypic effects. However, we cannot rule out that the male-biased aggregations of large monitors at human trophic subsidized sites could lead to reductions in reproductive fitness, through mate competition and offspring survival, and through greater exposure of eggs and juveniles to predation. These possibilities could have negative population consequences. Aggregations of these large predators may also have flow on effects to surrounding food web dynamics through elevated predation levels. Given that flux of energy and nutrients into food webs is central to the regulation of populations and their communities, we advocate further studies of human trophic subsidies be undertaken to evaluate the potentially large ecological implications of this significant human environmental alteration. PMID- 22509272 TI - Corticosterone induces rapid spinogenesis via synaptic glucocorticoid receptors and kinase networks in hippocampus. AB - BACKGROUND: Modulation of dendritic spines under acute stress is attracting much attention. Exposure to acute stress induces corticosterone (CORT) secretion from the adrenal cortex, resulting in rapid increase of CORT levels in plasma and the hippocampus. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrated the mechanisms of rapid effect (~1 h) of CORT on the density and morphology of spines by imaging neurons in adult male rat hippocampal slices. The application of CORT at 100-1000 nM induced a rapid increase in the density of spines of CA1 pyramidal neurons. The density of small-head spines (0.2-0.4 um) was increased even at low CORT levels (100-200 nM). The density of middle-head spines (0.4-0.5 um) was increased at high CORT levels between 400-1000 nM. The density of large-head spines (0.5 1.0 um) was increased only at 1000 nM CORT. Co-administration of RU486, an antagonist of glucocorticoid receptor (GR), abolished the effect of CORT. Blocking a single kinase, such as MAPK, PKA, PKC or PI3K, suppressed CORT-induced enhancement of spinogenesis. Blocking NMDA receptors suppressed the CORT effect. CONCLUSIONS/SIGNIFICANCE: These results imply that stress levels of CORT (100 1000 nM) drive the spinogenesis via synaptic GR and multiple kinase pathways. PMID- 22509273 TI - Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice. AB - The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Delta(9)-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT(2A) receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABA(A) receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT(2A) binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes. PMID- 22509274 TI - Prevention of wear particle-induced osteolysis by a novel V-ATPase inhibitor saliphenylhalamide through inhibition of osteoclast bone resorption. AB - Wear particle-induced peri-implant loosening (Aseptic prosthetic loosening) is one of the most common causes of total joint arthroplasty. It is well established that extensive bone destruction (osteolysis) by osteoclasts is responsible for wear particle-induced peri-implant loosening. Thus, inhibition of osteoclastic bone resorption should prevent wear particle induced osteolysis and may serve as a potential therapeutic avenue for prosthetic loosening. Here, we demonstrate for the first time that saliphenylhalamide, a new V-ATPase inhibitor attenuates wear particle-induced osteolysis in a mouse calvarial model. In vitro biochemical and morphological assays revealed that the inhibition of osteolysis is partially attributed to a disruption in osteoclast acidification and polarization, both a prerequisite for osteoclast bone resorption. Interestingly, the V-ATPase inhibitor also impaired osteoclast differentiation via the inhibition of RANKL induced NF-kappaB and ERK signaling pathways. In conclusion, we showed that saliphenylhalamide affected multiple physiological processes including osteoclast differentiation, acidification and polarization, leading to inhibition of osteoclast bone resorption in vitro and wear particle-induced osteolysis in vivo. The results of the study provide proof that the new generation V-ATPase inhibitors, such as saliphenylhalamide, are potential anti-resorptive agents for treatment of peri-implant osteolysis. PMID- 22509275 TI - Multi-level interactions between the nuclear receptor TRalpha1 and the WNT effectors beta-catenin/Tcf4 in the intestinal epithelium. AB - Intestinal homeostasis results from complex cross-regulation of signaling pathways; their alteration induces intestinal tumorigenesis. Previously, we found that the thyroid hormone nuclear receptor TRalpha1 activates and synergizes with the WNT pathway, inducing crypt cell proliferation and promoting tumorigenesis. Here, we investigated the mechanisms and implications of the cross-regulation between these two pathways in gut tumorigenesis in vivo and in vitro. We analyzed TRalpha1 and WNT target gene expression in healthy mucosae and tumors from mice overexpressing TRalpha1 in the intestinal epithelium in a WNT-activated genetic background (vil-TRalpha1/Apc mice). Interestingly, increased levels of beta catenin/Tcf4 complex in tumors from vil-TRalpha1/Apc mice blocked TRalpha1 transcriptional activity. This observation was confirmed in Caco2 cells, in which TRalpha1 functionality on a luciferase reporter-assay was reduced by the overexpression of beta-catenin/Tcf4. Moreover, TRalpha1 physically interacted with beta-catenin/Tcf4 in the nuclei of these cells. Using molecular approaches, we demonstrated that the binding of TRalpha1 to its DNA target sequences within the tumors was impaired, while it was newly recruited to WNT target genes. In conclusion, our observations strongly suggest that increased beta-catenin/Tcf4 levels i) correlated with reduced TRalpha1 transcriptional activity on its target genes and, ii) were likely responsible for the shift of TRalpha1 binding on WNT targets. Together, these data suggest a novel mechanism for the tumor-promoting activity of the TRalpha1 nuclear receptor. PMID- 22509276 TI - A novel intracellular isoform of matrix metalloproteinase-2 induced by oxidative stress activates innate immunity. AB - BACKGROUND: Experimental and clinical evidence has pinpointed a critical role for matrix metalloproteinase-2 (MMP-2) in ischemic ventricular remodeling and systolic heart failure. Prior studies have demonstrated that transgenic expression of the full-length, 68 kDa, secreted form of MMP-2 induces severe systolic failure. These mice also had unexpected and severe mitochondrial structural abnormalities and dysfunction. We hypothesized that an additional intracellular isoform of MMP-2, which affects mitochondrial function is induced under conditions of systolic failure-associated oxidative stress. METHODOLOGY AND PRINCIPAL FINDINGS: Western blots of cardiac mitochondria from the full length MMP-2 transgenics, ageing mice and a model of accelerated atherogenesis revealed a smaller 65 kDa MMP-2 isoform. Cultured cardiomyoblasts subjected to transient oxidative stress generated the 65 kDa MMP-2 isoform. The 65 kDa MMP-2 isoform was also induced by hypoxic culture of cardiomyoblasts. Genomic database analysis of the MMP-2 gene mapped transcriptional start sites and RNA transcripts induced by hypoxia or epigenetic modifiers within the first intron of the MMP-2 gene. Translation of these transcripts yields a 65 kDa N-terminal truncated isoform beginning at M(77), thereby deleting the signal sequence and inhibitory prodomain. Cellular trafficking studies demonstrated that the 65 kDa MMP-2 isoform is not secreted and is present in cytosolic and mitochondrial fractions, while the full length 68 kDa isoform was found only in the extracellular space. Expression of the 65 kDa MMP-2 isoform induced mitochondrial-nuclear stress signaling with activation of the pro-inflammatory NF-kappaB, NFAT and IRF transcriptional pathways. By microarray, the 65 kDa MMP-2 induces an innate immunity transcriptome, including viral stress response genes, innate immunity transcription factor IRF7, chemokines and pro-apoptosis genes. CONCLUSION: A novel N-terminal truncated intracellular isoform of MMP-2 is induced by oxidative stress. This isoform initiates a primary innate immune response that may contribute to progressive cardiac dysfunction in the setting of ischemia and systolic failure. PMID- 22509277 TI - Distribution and habitat associations of billfish and swordfish larvae across mesoscale features in the Gulf of Mexico. AB - Ichthyoplankton surveys were conducted in surface waters of the northern Gulf of Mexico (NGoM) over a three-year period (2006-2008) to determine the relative value of this region as early life habitat of sailfish (Istiophorus platypterus), blue marlin (Makaira nigricans), white marlin (Kajikia albida), and swordfish (Xiphias gladius). Sailfish were the dominant billfish collected in summer surveys, and larvae were present at 37.5% of the stations sampled. Blue marlin and white marlin larvae were present at 25.0% and 4.6% of the stations sampled, respectively, while swordfish occurred at 17.2% of the stations. Areas of peak production were detected and maximum density estimates for sailfish (22.09 larvae 1000 m(-2)) were significantly higher than the three other species: blue marlin (9.62 larvae 1000 m(-2)), white marlin (5.44 larvae 1000 m(-2)), and swordfish (4.67 larvae 1000 m(-2)). The distribution and abundance of billfish and swordfish larvae varied spatially and temporally, and several environmental variables (sea surface temperature, salinity, sea surface height, distance to the Loop Current, current velocity, water depth, and Sargassum biomass) were deemed to be influential variables in generalized additive models (GAMs). Mesoscale features in the NGoM affected the distribution and abundance of billfish and swordfish larvae, with densities typically higher in frontal zones or areas proximal to the Loop Current. Habitat suitability of all four species was strongly linked to physicochemical attributes of the water masses they inhabited, and observed abundance was higher in slope waters with lower sea surface temperature and higher salinity. Our results highlight the value of the NGoM as early life habitat of billfishes and swordfish, and represent valuable baseline data for evaluating anthropogenic effects (i.e., Deepwater Horizon oil spill) on the Atlantic billfish and swordfish populations. PMID- 22509279 TI - Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats. AB - Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW) was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR) were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(P)H and GSH (56% and 74% respectively; P<0.001), increased superoxide and secondary ROS/RNS generation along with oxidative damage to cellular macromolecules. Nimesulide reduced mitochondrial activity, depolarized mitochondria and caused membrane permeability transition (MPT) followed by release of apoptotic proteins (AIF; apoptosis inducing factor, EndoG; endonuclease G, and Cyto c; cytochrome c). It also significantly activated caspase-9 and caspase-3 and increased oxidative DNA damage (level of 8-Oxoguanine glycosylase; P<0.05). A combination of camphene and geraniol (CG; 1:1), when pre-administered in rats (10 mg/kg BW), accorded protection against nimesulide hepatotoxicity in vivo, as evident from normalized serum biomarkers and histopathology. mRNA expression and activity of key antioxidant and redox enzymes along with oxidative stress were also normalized due to CG pre-treatment. Downstream effects like decreased mitochondrial swelling, inhibition in release of apoptotic proteins, prevention of mitochondrial depolarization along with reduction in oxidized NAD(P)H and increased mitochondrial electron flow further supported protective action of selected terpenes against nimesulide toxicity. Therefore CG, a combination of natural terpenes prevented nimesulide induced cellular damage and ensuing hepatotoxicity. PMID- 22509280 TI - Glucocorticoid-treated mice are an inappropriate positive control for long-term preclinical studies in the mdx mouse. AB - BACKGROUND: Dmd(mdx) (mdx) mice are used as a genetic and biochemical model of dystrophin deficiency. The long-term consequences of glucocorticoid (GC) treatment on dystrophin-deficient skeletal and heart muscle are not yet known. Here we used systematic phenotyping to assess the long-term consequences of GC treatment in mdx mice. Our investigation addressed not only the effects of GC on the disease phenotype but also the question of whether GCs can be used as a positive control for preclinical drug evaluations. METHODS AND FINDINGS: We performed nine pre-clinical efficacy trials (treated N = 129, untreated N = 106) of different durations in 9-to-50-week-old dystrophic mdx mice over a 3-year time period using standardized methods. In all these trials, we used either 1 mg/kg body weight of prednisone or 5 mg/kg body weight of prednisolone as positive controls to compare the efficacy of various test drugs. Data from untreated controls and GC-treated mice in the various trials have been pooled and analyzed to assess the effects of GCs on dystrophin-deficient skeletal and cardiac muscles of mdx mice. Our results indicate that continuous GC treatment results in early (e.g., at 50 days) improvements in normalized parameters such as grip strength, motor coordination and maximal in vitro force contractions on isolated EDL muscle, but these initial benefits are followed by a progressive loss of muscle strength after 100 days. We also found a significant increase in heart fibrosis that is reflected in a significant deterioration in cardiac systolic function after 100 days of treatment. CONCLUSION: Continuous administration of prednisone to mdx mice initially improves skeletal muscle strength, but further therapy result in deterioration of muscle strength and cardiac function associated with enhanced cardiac fibrosis. These results suggest that GCs may not serve as an appropriate positive control for long-term mdx mouse preclinical trials. PMID- 22509281 TI - Unique cell type-specific junctional complexes in vascular endothelium of human and rat liver sinusoids. AB - Liver sinusoidal endothelium is strategically positioned to control access of fluids, macromolecules and cells to the liver parenchyma and to serve clearance functions upstream of the hepatocytes. While clearance of macromolecular debris from the peripheral blood is performed by liver sinusoidal endothelial cells (LSECs) using a delicate endocytic receptor system featuring stabilin-1 and -2, the mannose receptor and CD32b, vascular permeability and cell trafficking are controlled by transcellular pores, i.e. the fenestrae, and by intercellular junctional complexes. In contrast to blood vascular and lymphatic endothelial cells in other organs, the junctional complexes of LSECs have not yet been consistently characterized in molecular terms. In a comprehensive analysis, we here show that LSECs express the typical proteins found in endothelial adherens junctions (AJ), i.e. VE-cadherin as well as alpha-, beta-, p120-catenin and plakoglobin. Tight junction (TJ) transmembrane proteins typical of endothelial cells, i.e. claudin-5 and occludin, were not expressed by rat LSECs while heterogenous immunreactivity for claudin-5 was detected in human LSECs. In contrast, junctional molecules preferentially associating with TJ such as JAM-A, B and C and zonula occludens proteins ZO-1 and ZO-2 were readily detected in LSECs. Remarkably, among the JAMs JAM-C was considerably over-expressed in LSECs as compared to lung microvascular endothelial cells. In conclusion, we show here that LSECs form a special kind of mixed-type intercellular junctions characterized by co-occurrence of endothelial AJ proteins, and of ZO-1 and -2, and JAMs. The distinct molecular architecture of the intercellular junctional complexes of LSECs corroborates previous ultrastructural findings and provides the molecular basis for further analyses of the endothelial barrier function of liver sinusoids under pathologic conditions ranging from hepatic inflammation to formation of liver metastasis. PMID- 22509278 TI - Culture and end of life care: a scoping exercise in seven European countries. AB - AIM: Culture is becoming increasingly important in relation to end of life (EoL) care in a context of globalization, migration and European integration. We explore and compare socio-cultural issues that shape EoL care in seven European countries and critically appraise the existing research evidence on cultural issues in EoL care generated in the different countries. METHODS: We scoped the literature for Germany, Norway, Belgium, The Netherlands, Spain, Italy and Portugal, carrying out electronic searches in 16 international and country specific databases and handsearches in 17 journals, bibliographies of relevant papers and webpages. We analysed the literature which was unearthed, in its entirety and by type (reviews, original studies, opinion pieces) and conducted quantitative analyses for each country and across countries. Qualitative techniques generated themes and sub-themes. RESULTS: A total of 868 papers were reviewed. The following themes facilitated cross-country comparison: setting, caregivers, communication, medical EoL decisions, minority ethnic groups, and knowledge, attitudes and values of death and care. The frequencies of themes varied considerably between countries. Sub-themes reflected issues characteristic for specific countries (e.g. culture-specific disclosure in the southern European countries). The work from the seven European countries concentrates on cultural traditions and identities, and there was almost no evidence on ethnic minorities. CONCLUSION: This scoping review is the first comparative exploration of the cultural differences in the understanding of EoL care in these countries. The diverse body of evidence that was identified on socio-cultural issues in EoL care, reflects clearly distinguishable national cultures of EoL care, with differences in meaning, priorities, and expertise in each country. The diverse ways that EoL care is understood and practised forms a necessary part of what constitutes best evidence for the improvement of EoL care in the future. PMID- 22509282 TI - Assessment of the red cell proteome of young patients with unexplained hemolytic anemia by two-dimensional differential in-gel electrophoresis (DIGE). AB - Erythrocyte cytosolic protein expression profiles of children with unexplained hemolytic anemia were compared with profiles of close relatives and controls by two-dimensional differential in-gel electrophoresis (2D-DIGE). The severity of anemia in the patients varied from compensated (i.e., no medical intervention required) to chronic transfusion dependence. Common characteristics of all patients included chronic elevation of reticulocyte count and a negative workup for anemia focusing on hemoglobinopathies, morphologic abnormalities that would suggest a membrane defect, immune-mediated red cell destruction, and evaluation of the most common red cell enzyme defects, glucose-6-phosphate dehydrogenase and pyruvate kinase deficiency. Based upon this initial workup and presentation during infancy or early childhood, four patients classified as hereditary nonspherocytic hemolytic anemia (HNSHA) of unknown etiology were selected for proteomic analysis. DIGE analysis of red cell cytosolic proteins clearly discriminated each anemic patient from both familial and unrelated controls, revealing both patient-specific and shared patterns of differential protein expression. Changes in expression pattern shared among the four patients were identified in several protein classes including chaperons, cytoskeletal and proteasome proteins. Elevated expression in patient samples of some proteins correlated with high reticulocyte count, likely identifying a subset of proteins that are normally lost during erythroid maturation, including proteins involved in mitochondrial metabolism and protein synthesis. Proteins identified with patient-specific decreased expression included components of the glutathione synthetic pathway, antioxidant pathways, and proteins involved in signal transduction and nucleotide metabolism. Among the more than 200 proteins identified in this study are 21 proteins not previously described as part of the erythrocyte proteome. These results demonstrate the feasibility of applying a global proteomic approach to aid characterization of red cells from patients with hereditary anemia of unknown cause, including the identification of differentially expressed proteins as potential candidates with a role in disease pathogenesis. PMID- 22509283 TI - Finding a needle in the virus metagenome haystack--micro-metagenome analysis captures a snapshot of the diversity of a bacteriophage armoire. AB - Viruses are ubiquitous in the oceans and critical components of marine microbial communities, regulating nutrient transfer to higher trophic levels or to the dissolved organic pool through lysis of host cells. Hydrothermal vent systems are oases of biological activity in the deep oceans, for which knowledge of biodiversity and its impact on global ocean biogeochemical cycling is still in its infancy. In order to gain biological insight into viral communities present in hydrothermal vent systems, we developed a method based on deep-sequencing of pulsed field gel electrophoretic bands representing key viral fractions present in seawater within and surrounding a hydrothermal plume derived from Loki's Castle vent field at the Arctic Mid-Ocean Ridge. The reduction in virus community complexity afforded by this novel approach enabled the near-complete reconstruction of a lambda-like phage genome from the virus fraction of the plume. Phylogenetic examination of distinct gene regions in this lambdoid phage genome unveiled diversity at loci encoding superinfection exclusion- and integrase-like proteins. This suggests the importance of fine-tuning lyosgenic conversion as a viral survival strategy, and provides insights into the nature of host-virus and virus-virus interactions, within hydrothermal plumes. By reducing the complexity of the viral community through targeted sequencing of prominent dsDNA viral fractions, this method has selectively mimicked virus dominance approaching that hitherto achieved only through culturing, thus enabling bioinformatic analysis to locate a lambdoid viral "needle" within the greater viral community "haystack". Such targeted analyses have great potential for accelerating the extraction of biological knowledge from diverse and poorly understood environmental viral communities. PMID- 22509284 TI - Phosphorylation of Ubc9 by Cdk1 enhances SUMOylation activity. AB - Increasing evidence has pointed to an important role of SUMOylation in cell cycle regulation, especially for M phase. In the current studies, we have obtained evidence through in vitro studies that the master M phase regulator CDK1/cyclin B kinase phosphorylates the SUMOylation machinery component Ubc9, leading to its enhanced SUMOylation activity. First, we show that CDK1/cyclin B, but not many other cell cycle kinases such as CDK2/cyclin E, ERK1, ERK2, PKA and JNK2/SAPK1, specifically enhances SUMOylation activity. Second, CDK1/cyclin B phosphorylates the SUMOylation machinery component Ubc9, but not SAE1/SAE2 or SUMO1. Third, CDK1/cyclin B-phosphorylated Ubc9 exhibits increased SUMOylation activity and elevated accumulation of the Ubc9-SUMO1 thioester conjugate. Fourth, CDK1/cyclin B enhances SUMOylation activity through phosphorylation of Ubc9 at serine 71. These studies demonstrate for the first time that the cell cycle-specific kinase CDK1/cyclin B phosphorylates a SUMOylation machinery component to increase its overall SUMOylation activity, suggesting that SUMOylation is part of the cell cycle program orchestrated by CDK1 through Ubc9. PMID- 22509285 TI - Cryptic distant relatives are common in both isolated and cosmopolitan genetic samples. AB - Although a few hundred single nucleotide polymorphisms (SNPs) suffice to infer close familial relationships, high density genome-wide SNP data make possible the inference of more distant relationships such as 2(nd) to 9(th) cousinships. In order to characterize the relationship between genetic similarity and degree of kinship given a timeframe of 100-300 years, we analyzed the sharing of DNA inferred to be identical by descent (IBD) in a subset of individuals from the 23andMe customer database (n = 22,757) and from the Human Genome Diversity Panel (HGDP-CEPH, n = 952). With data from 121 populations, we show that the average amount of DNA shared IBD in most ethnolinguistically-defined populations, for example Native American groups, Finns and Ashkenazi Jews, differs from continentally-defined populations by several orders of magnitude. Via extensive pedigree-based simulations, we determined bounds for predicted degrees of relationship given the amount of genomic IBD sharing in both endogamous and 'unrelated' population samples. Using these bounds as a guide, we detected tens of thousands of 2(nd) to 9(th) degree cousin pairs within a heterogenous set of 5,000 Europeans. The ubiquity of distant relatives, detected via IBD segments, in both ethnolinguistic populations and in large 'unrelated' populations samples has important implications for genetic genealogy, forensics and genotype/phenotype mapping studies. PMID- 22509286 TI - Genome-wide gene expression analysis in cancer cells reveals 3D growth to affect ECM and processes associated with cell adhesion but not DNA repair. AB - Cell morphology determines cell behavior, signal transduction, protein-protein interaction, and responsiveness to external stimuli. In cancer, these functions profoundly contribute to resistance mechanisms to radio- and chemotherapy. With regard to this aspect, this study compared the genome wide gene expression in exponentially growing cell lines from different tumor entities, lung carcinoma and squamous cell carcinoma, under more physiological three-dimensional (3D) versus monolayer cell culture conditions. Whole genome cDNA microarray analysis was accomplished using the Affymetrix HG U133 Plus 2.0 gene chip. Significance analysis of microarray (SAM) and t-test analysis revealed significant changes in gene expression profiles of 3D relative to 2D cell culture conditions. These changes affected the extracellular matrix and were mainly associated with biological processes like tissue development, cell adhesion, immune system and defense response in contrast to terms related to DNA repair, which lacked significant alterations. Selected genes were verified by semi-quantitative RT-PCR and Western blotting. Additionally, we show that 3D growth mediates a significant increase in tumor cell radio- and chemoresistance relative to 2D. Our findings show significant gene expression differences between 3D and 2D cell culture systems and indicate that cellular responsiveness to external stress such as ionizing radiation and chemotherapeutics is essentially influenced by differential expression of genes involved in the regulation of integrin signaling, cell shape and cell-cell contact. PMID- 22509288 TI - A molecular model for the differential activation of STAT3 and STAT6 by the herpesviral oncoprotein tip. AB - Constitutive STAT signaling provides growth promoting signals in many forms of malignancy. We performed molecular modeling and molecular dynamics studies of the interaction between the regulatory Src homology 2 (SH2) domains of STAT3 and 6 with phosphorylated peptides of the herpesviral oncoprotein Tip, which facilitates Src kinase mediated STAT-activation and T cell proliferation. The studies give insight into the ligand binding specificity of the STAT SH2 domains and provide the first model for the differential activation of STAT3 or STAT6 by two distinct regions of the viral Tip protein. The biological relevance of the modeled interactions was then confirmed by activation studies using corresponding recombinant oncoproteins, and finally by respective recombinant viruses. The functional data give experimental validation of the molecular dynamics study, and provide evidence for the involvement of STAT6 in the herpesvirus induced T cell proliferation. PMID- 22509289 TI - A prompt to the web: the media and health information seeking behaviour. AB - OBJECTIVE, DESIGN, SETTING AND PARTICIPANTS: The objective was to investigate media influence on consumers' health related behaviours. A cross-sectional survey of randomly selected adults (18+ years) residing in the Hunter Region of New South Wales Australia was conducted. The sample was selected using a combination of the white pages and random digit dialling. MAIN OUTCOME MEASURES: The proportions of respondents who recalled seeing or hearing about conditions or treatments in the media over the 12 months prior to interview (August 2009-August 2010) and their subsequent health related behaviour. RESULTS: Although most survey participants reported seeking health information from their doctors, around two-thirds of survey participants (551, 68.8%) recalled hearing, seeing or reading about one or more medical conditions (total = 1097 instances) in the mainstream media over the past 12 months. Almost 40% of respondents (307, 38.4%) stated that they had looked for more information about a condition as a result of hearing about it in the media, and most used the internet (269, 87.4%). More than a quarter of respondents (215, 26.9%) indicated that they had asked their doctor about a condition they had heard about in the media. Around half of those who asked their doctor (109, 50.6%) reported that their inquiry resulted in them receiving treatment, of whom almost half (53, 48.3%) reported being prescribed a medicine. CONCLUSION: The survey results show that consumers become aware of medicines through traditional media and then to learn more often turn to the internet where quality of information may be poor. PMID- 22509287 TI - A combined synthetic-fibrin scaffold supports growth and cardiomyogenic commitment of human placental derived stem cells. AB - AIMS: A potential therapy for myocardial infarction is to deliver isolated stem cells to the infarcted site. A key issue with this therapy is to have at one's disposal a suitable cell delivery system which, besides being able to support cell proliferation and differentiation, may also provide handling and elastic properties which do not affect cardiac contractile function. In this study an elastic scaffold, obtained combining a poly(ether)urethane-polydimethylsiloxane (PEtU-PDMS) semi-interpenetrating polymeric network (s-IPN) with fibrin, was used as a substrate for in vitro studies of human amniotic mesenchymal stromal cells (hAMSC) growth and differentiation. METHODOLOGY/PRINCIPAL FINDINGS: After hAMSC seeding on the fibrin side of the scaffold, cell metabolic activity and proliferation were evaluated by WST-1 and bromodeoxyuridine assays. Morphological changes and mRNAs expression for cardiac differentiation markers in the hAMSCs were examined using immunofluorescence and RT-PCR analysis. The beginning of cardiomyogenic commitment of hAMSCs grown on the scaffold was induced, for the first time in this cell population, by a nitric oxide (NO) treatment. Following NO treatment hAMSCs show morphological changes, an increase of the messenger cardiac differentiation markers [troponin I (TnI) and NK2 transcription factor related locus 5 (Nkx2.5)] and a modulation of the endothelial markers [vascular endothelial growth factor (VEGF) and kinase insert domain receptor (KDR)]. CONCLUSIONS/SIGNIFICANCE: The results of this study suggest that the s-IPN PEtU PDMS/fibrin combined scaffold allows a better proliferation and metabolic activity of hAMSCs cultured up to 14 days, compared to the ones grown on plastic dishes. In addition, the combined scaffold sustains the beginning of hAMSCs differentiation process towards a cardiomyogenic lineage. PMID- 22509290 TI - Distinct effects of unfractionated heparin versus bivalirudin on circulating angiogenic peptides. AB - BACKGROUND: Human studies of therapeutic angiogenesis, stem-cell, and progenitor cell therapy have failed to demonstrate consistent clinical benefit. Recent studies have shown that heparin increases circulating levels of anti-angiogenic peptides. Given the widely prevalent use of heparin in percutaneous and surgical procedures including those performed as part of studies examining the benefit of therapeutic angiogenesis and cell-based therapy, we compared the effects of unfractionated heparin (UFH) on angiogenic peptides with those of bivalirudin, a relatively newer anticoagulant whose effects on angiogenic peptides have not been studied. METHODOLOGY/PRINCIPAL FINDINGS: We measured soluble fms-like tyrosine kinase-1 (sFLT1), placental growth factor (PlGF), vascular endothelial growth factor (VEGF), and soluble Endoglin (sEng) serum levels by enzyme linked immunosorbent assays (ELISA) in 16 patients undergoing elective percutaneous coronary intervention. Compared to baseline values, sFLT1 and PlGF levels increased by 2629+/-313% and 253+/-54%, respectively, within 30 minutes of UFH therapy (p<0.01 for both; n = 8). VEGF levels decreased by 93.2+/-5% in patients treated with UFH (p<0.01 versus baseline). No change in sEng levels were observed after UFH therapy. No changes in sFLT1, PlGF, VEGF, or sEng levels were observed in any patients receiving bivalirudin (n = 8). To further explore the direct effect of anticoagulation on circulating angiogenic peptides, adult, male wild type mice received venous injections of clinically dosed UFH or bivalirudin. Compared to saline controls, sFLT1 and PlGF levels increased by >500% (p<0.01, for both) and VEGF levels increased by 221+/-101% (p<0.05) 30 minutes after UFH treatment. Bivalirudin had no effect on peptide levels. To study the cellular origin of peptides after anticoagulant therapy, human coronary endothelial cells were treated with UFH and demonstrated increased sFLT1 and PlGF levels (ANOVA p<0.01 for both) with reduced VEGF levels (ANOVA p<0.05). Bivalirudin had no effect on peptide levels in vitro. CONCLUSIONS/SIGNIFICANCE: Circulating levels of sFLT1, PlGF, and VEGF are significantly altered by UFH, while bivalirudin therapy has no effect. These findings may have significant implications for clinical studies of therapeutic angiogenesis, stem-cell and progenitor-cell therapy. PMID- 22509291 TI - Dimer formation enhances structural differences between amyloid beta-protein (1 40) and (1-42): an explicit-solvent molecular dynamics study. AB - Amyloid beta-protein (Abeta) is central to the pathology of Alzheimer's disease. A 5% difference in the primary structure of the two predominant alloforms, Abeta(1-40) and Abeta(1-42), results in distinct assembly pathways and toxicity properties. Discrete molecular dynamics (DMD) studies of Abeta(1-40) and Abeta(1 42) assembly resulted in alloform-specific oligomer size distributions consistent with experimental findings. Here, a large ensemble of DMD-derived Abeta(1-40) and Abeta(1-42) monomers and dimers was subjected to fully atomistic molecular dynamics (MD) simulations using the OPLS-AA force field combined with two water models, SPCE and TIP3P. The resulting all-atom conformations were slightly larger, less compact, had similar turn and lower beta-strand propensities than those predicted by DMD. Fully atomistic Abeta(1-40) and Abeta(1-42) monomers populated qualitatively similar free energy landscapes. In contrast, the free energy landscape of Abeta(1-42) dimers indicated a larger conformational variability in comparison to that of Abeta(1-40) dimers. Abeta(1-42) dimers were characterized by an increased flexibility in the N-terminal region D1-R5 and a larger solvent exposure of charged amino acids relative to Abeta(1-40) dimers. Of the three positively charged amino acids, R5 was the most and K16 the least involved in salt bridge formation. This result was independent of the water model, alloform, and assembly state. Overall, salt bridge propensities increased upon dimer formation. An exception was the salt bridge propensity of K28, which decreased upon formation of Abeta(1-42) dimers and was significantly lower than in Abeta(1-40) dimers. The potential relevance of the three positively charged amino acids in mediating the Abeta oligomer toxicity is discussed in the light of available experimental data. PMID- 22509292 TI - Natriuretic peptides for the detection of paroxysmal atrial fibrillation in patients with cerebral ischemia--the Find-AF study. AB - BACKGROUND AND PURPOSE: Diagnosis of paroxysmal atrial fibrillation (AF) can be challenging, but it is highly relevant in patients presenting with sinus rhythm and acute cerebral ischemia. We aimed to evaluate prospectively whether natriuretic peptide levels and kinetics identify patients with paroxysmal AF. METHODS: Patients with acute cerebral ischemia were included into the prospective observational Find-AF study. N-terminal pro brain-type natriuretic peptide (NT proBNP), brain-type natriuretic peptide (BNP) and N-terminal pro atrial-type natriuretic peptide (NT-proANP) plasma levels were measured on admission, after 6 and 24 hours. Patients free from AF at presentation received 7 day Holter monitoring. We prospectively hypothesized that patients presenting in sinus rhythm with NT-proBNP>median were more likely to have paroxysmal AF than patients with NT-proBNPmedian (239 pg/ml), 17.9% had paroxysmal AF in contrast to 7.4% with NT-proBNP<239 pg/ml (p = 0.025). The ratio of early (0 h) to late (24 h) plasma levels of NT-proBNP showed no difference between both groups. For the detection of paroxysmal atrial fibrillation, BNP, NT-proBNP and NT-proANP at admission had an area under the curve in ROC analysis of 0.747 (0.663-0.831), 0.638 (0.531-0.744) and 0.663 (0.566-0.761), respectively. In multivariate analysis, BNP was the only biomarker to be independently predictive for paroxysmal atrial fibrillation. CONCLUSIONS: BNP is independently predictive of paroxysmal AF detected by prolonged ECG monitoring in patients with cerebral ischemia and may be used to effectively select patients for prolonged Holter monitoring. PMID- 22509293 TI - Prevalence, distribution and functional significance of the -237C to T polymorphism in the IL-12Rbeta2 promoter in Indian tuberculosis patients. AB - Cytokine/cytokine receptor gene polymorphisms related to structure/expression could impact immune response. Hence, the -237 polymorphic site in the 5' promoter region of the IL-12Rbeta2 (SNP ID: rs11810249) gene associated with the AP-4 transcription motif GAGCTG, was examined. Amplicons encompassing the polymorphism were generated from 46 pulmonary tuberculosis patients, 35 family contacts and 28 miscellaneous volunteers and sequenced. The C allele predominated among patients, (93.4%, 43/46), and in all volunteers and contacts screened, but the T allele was exclusively limited to patients, (6.5%, 3/46). The functional impact of this polymorphism on transcriptional activity was assessed by Luciferase-reporter and electrophoretic mobility shift assays (EMSA). Luciferase-reporter assays showed a significant reduction in transcriptional efficiency with T compared to C allele. The reduction in transcriptional efficiency with the T allele construct (pGIL 12Rb2-T), in U-87MG, THP-1 and Jurkat cell lines, were 53, 37.6, and 49.8% respectively, compared to the C allele construct (pGIL-12Rb2-C). Similarly, densitometric analysis of the EMSA assay showed reduced binding of the AP-4 transcription factor, to T compared to the C nucleotide probe. Reduced mRNA expression in all patients (3/3) harboring the T allele was seen, whereas individuals with the C allele exhibited high mRNA expression (17/25; 68%, p = 0.05). These observations were in agreement with the in vitro assessment of the promoter activity by Luciferase-reporter and EMSA assays. The reduced expression of IL-12Rbeta2 transcripts in 8 patients despite having the C allele was attributed to the predominant over expression of the suppressors (IL-4 and GATA 3) and reduced expression of enhancers (IFN-alpha) of IL-12Rbeta2 transcripts. The 17 high IL-12Rbeta2 mRNA expressers had significantly elevated IFN-alpha mRNA levels compared to low expressers and volunteers. Notwithstanding the presence of high levels of IL-12Rbeta2 mRNA in these patients elevated IFN-alpha expression could modulate their immune responses to Mycobacterium tuberculosis. PMID- 22509294 TI - Somatostatin modulates insulin-degrading-enzyme metabolism: implications for the regulation of microglia activity in AD. AB - The deposition of beta-amyloid (Abeta) into senile plaques and the impairment of somatostatin-mediated neurotransmission are key pathological events in the onset of Alzheimer's disease (AD). Insulin-degrading-enzyme (IDE) is one of the main extracellular protease targeting Abeta, and thus it represents an interesting pharmacological target for AD therapy. We show that the active form of somatostatin-14 regulates IDE activity by affecting its expression and secretion in microglia cells. A similar effect can also be observed when adding octreotide. Following a previous observation where somatostatin directly interacts with IDE, here we demonstrate that somatostatin regulates Abeta catabolism by modulating IDE proteolytic activity in IDE gene-silencing experiments. As a whole, these data indicate the relevant role played by somatostatin and, potentially, by analogue octreotide, in preventing Abeta accumulation by partially restoring IDE activity. PMID- 22509295 TI - Does the integration of haptic and visual cues reduce the effect of a biased visual reference frame on the subjective head orientation? AB - BACKGROUND: The selection of appropriate frames of reference (FOR) is a key factor in the elaboration of spatial perception and the production of robust interaction with our environment. The extent to which we perceive the head axis orientation (subjective head orientation, SHO) with both accuracy and precision likely contributes to the efficiency of these spatial interactions. A first goal of this study was to investigate the relative contribution of both the visual and egocentric FOR (centre-of-mass) in the SHO processing. A second goal was to investigate humans' ability to process SHO in various sensory response modalities (visual, haptic and visuo-haptic), and the way they modify the reliance to either the visual or egocentric FORs. A third goal was to question whether subjects combined visual and haptic cues optimally to increase SHO certainty and to decrease the FORs disruption effect. METHODOLOGY/PRINCIPAL FINDINGS: Thirteen subjects were asked to indicate their SHO while the visual and/or egocentric FORs were deviated. Four results emerged from our study. First, visual rod settings to SHO were altered by the tilted visual frame but not by the egocentric FOR alteration, whereas no haptic settings alteration was observed whether due to the egocentric FOR alteration or the tilted visual frame. These results are modulated by individual analysis. Second, visual and egocentric FOR dependency appear to be negatively correlated. Third, the response modality enrichment appears to improve SHO. Fourth, several combination rules of the visuo-haptic cues such as the Maximum Likelihood Estimation (MLE), Winner-Take-All (WTA) or Unweighted Mean (UWM) rule seem to account for SHO improvements. However, the UWM rule seems to best account for the improvement of visuo-haptic estimates, especially in situations with high FOR incongruence. Finally, the data also indicated that FOR reliance resulted from the application of UWM rule. This was observed more particularly, in the visual dependent subject. CONCLUSIONS: Taken together, these findings emphasize the importance of identifying individual spatial FOR preferences to assess the efficiency of our interaction with the environment whilst performing spatial tasks. PMID- 22509297 TI - The frequency of malaria is similar among women receiving either lopinavir/ritonavir or nevirapine-based antiretroviral treatment. AB - HIV protease inhibitors (PIs) show antimalarial activity in vitro and in animals. Whether this translates into a clinical benefit in HIV-infected patients residing in malaria-endemic regions is unknown. We studied the incidence of malaria, as defined by blood smear positivity or a positive Plasmodium falciparum histidine rich protein 2 antigen test, among 444 HIV-infected women initiating antiretroviral treatment (ART) in the OCTANE trial (A5208; ClinicalTrials.gov: NCT00089505). Participants were randomized to treatment with PI-containing vs. PI sparing ART, and were followed prospectively for >=48 weeks; 73% also received cotrimoxazole prophylaxis. PI-containing treatment was not associated with protection against malaria in this study population. PMID- 22509296 TI - Variability of intensive care admission decisions for the very elderly. AB - Although increasing numbers of very elderly patients are requiring intensive care, few large sample studies have investigated ICU admission of very elderly patients. Data on pre triage by physicians from other specialities is limited. This observational cohort study aims at examining inter-hospital variability of ICU admission rates and its association with patients' outcomes. All patients over 80 years possibly qualifying for ICU admission who presented to the emergency departments (ED) of 15 hospitals in the Paris (France) area during a one-year period were prospectively included in the study. Main outcome measures were ICU eligibility, as assessed by the ED and ICU physicians; in-hospital mortality; and vital and functional status 6 months after the ED visit. 2646 patients (median age 86; interquartile range 83-91) were included in the study. 94% of participants completed follow-up (n = 2495). 12.4% (n = 329) of participants were deemed eligible for ICU admission by ED physicians and intensivists. The overall in-hospital and 6-month mortality rates were respectively 27.2% (n = 717) and 50.7% (n = 1264). At six months, 57.5% (n = 1433) of patients had died or had a functional deterioration. Rates of patients deemed eligible for ICU admission ranged from 5.6% to 38.8% across the participating centers, and this variability persisted after adjustment for patients' characteristics. Despite this variability, we found no association between level of ICU eligibility and either in-hospital death or six-month death or functional deterioration. In France, the likelihood that a very elderly person will be admitted to an ICU varies widely from one hospital to another. Influence of intensive care admission on patients' outcome remains unclear. TRIAL REGISTRATION: ClinicalTrials.gov NCT00912600. PMID- 22509298 TI - The tri-trophic interactions hypothesis: interactive effects of host plant quality, diet breadth and natural enemies on herbivores. AB - Several influential hypotheses in plant-herbivore and herbivore-predator interactions consider the interactive effects of plant quality, herbivore diet breadth, and predation on herbivore performance. Yet individually and collectively, these hypotheses fail to address the simultaneous influence of all three factors. Here we review existing hypotheses, and propose the tri-trophic interactions (TTI) hypothesis to consolidate and integrate their predictions. The TTI hypothesis predicts that dietary specialist herbivores (as compared to generalists) should escape predators and be competitively dominant due to faster growth rates, and that such differences should be greater on low quality (as compared to high quality) host plants. To provide a preliminary test of these predictions, we conducted an empirical study comparing the effects of plant (Baccharis salicifolia) quality and predators between a specialist (Uroleucon macolai) and a generalist (Aphis gossypii) aphid herbivore. Consistent with predictions, these three factors interactively determine herbivore performance in ways not addressed by existing hypotheses. Compared to the specialist, the generalist was less fecund, competitively inferior, and more sensitive to low plant quality. Correspondingly, predator effects were contingent upon plant quality only for the generalist. Contrary to predictions, predator effects were weaker for the generalist and on low-quality plants, likely due to density dependent benefits provided to the generalist by mutualist ants. Because the TTI hypothesis predicts the superior performance of specialists, mutualist ants may be critical to A. gossypii persistence under competition from U. macolai. In summary, the integrative nature of the TTI hypothesis offers novel insight into the determinants of plant-herbivore and herbivore-predator interactions and the coexistence of specialist and generalist herbivores. PMID- 22509299 TI - Protein tyrosine phosphatase 1B deficiency potentiates PERK/eIF2alpha signaling in brown adipocytes. AB - BACKGROUND: Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of glucose homeostasis and body mass, and has been implicated in endoplasmic reticulum (ER) stress. Herein, we assess the role of PTP1B in ER stress in brown adipocytes, which are key regulators of thermogenesis and metabolic response. METHODOLOGY/PRINCIPAL FINDINGS: To determine the role of PTP1B in ER stress, we utilized brown adipose tissue (BAT) from mice with adipose-specific PTP1B deletion, and brown adipocytes deficient in PTP1B and reconstituted with PTP1B wild type (WT) or the substrate-trapping PTP1B D181A (D/A) mutant. PTP1B deficiency led to upregulation of PERK-eIF2alpha phosphorylation and IRE1alpha XBP1 sub-arms of the unfolded protein response. In addition, PTP1B deficiency sensitized differentiated brown adipocytes to chemical-induced ER stress. Moreover, PERK activation and tyrosine phosphorylation were increased in BAT and adipocytes lacking PTP1B. Increased PERK activity resulted in the induction of eIF2alpha phosphorylation at Ser51 and better translatability of ATF4 mRNA in response to ER stress. At the molecular level, we demonstrate direct interaction between PTP1B and PERK and identify PERK Tyr615 as a mediator of this association. CONCLUSIONS: Collectively, the data demonstrate that PTP1B is a physiologically-relevant modulator of ER stress in brown adipocytes and that PTP1B deficiency modulates PERK-eIF2alpha phosphorylation and protein synthesis. PMID- 22509300 TI - Statistical inference of selection and divergence from a time-dependent Poisson random field model. AB - We apply a recently developed time-dependent Poisson random field model to aligned DNA sequences from two related biological species to estimate selection coefficients and divergence time. We use Markov chain Monte Carlo methods to estimate species divergence time and selection coefficients for each locus. The model assumes that the selective effects of non-synonymous mutations are normally distributed across genetic loci but constant within loci, and synonymous mutations are selectively neutral. In contrast with previous models, we do not assume that the individual species are at population equilibrium after divergence. Using a data set of 91 genes in two Drosophila species, D. melanogaster and D. simulans, we estimate the species divergence time t(div) = 2.16 N(e) (or 1.68 million years, assuming the haploid effective population size N(e) = 6.45 x 10(5) years) and a mean selection coefficient per generation MU(gamma) = 1.98/N(e). Although the average selection coefficient is positive, the magnitude of the selection is quite small. Results from numerical simulations are also presented as an accuracy check for the time-dependent model. PMID- 22509301 TI - Modulators of prostate cancer cell proliferation and viability identified by short-hairpin RNA library screening. AB - There is significant need to identify novel prostate cancer drug targets because current hormone therapies eventually fail, leading to a drug-resistant and fatal disease termed castration-resistant prostate cancer. To functionally identify genes that, when silenced, decrease prostate cancer cell proliferation or induce cell death in combination with antiandrogens, we employed an RNA interference based short hairpin RNA barcode screen in LNCaP human prostate cancer cells. We identified and validated four candidate genes (AKT1, PSMC1, STRADA, and TTK) that impaired growth when silenced in androgen receptor positive prostate cancer cells and enhanced the antiproliferative effects of antiandrogens. Inhibition of AKT with a pharmacologic inhibitor also induced apoptosis when combined with antiandrogens, consistent with recent evidence for PI3K and AR pathway crosstalk in prostate cancer cells. Recovery of hairpins targeting a known prostate cancer pathway validates the utility of shRNA library screening in prostate cancer as a broad strategy to identify new candidate drug targets. PMID- 22509302 TI - Mapping molecular agents distributions in whole mice hearts using born-normalized optical projection tomography. AB - To date there is a lack of tools to map the spatio-temporal dynamics of diverse cells in experimental heart models. Conventional histology is labor intensive with limited coverage, whereas many imaging techniques do not have sufficiently high enough spatial resolution to map cell distributions. We have designed and built a high resolution, dual channel Born-normalized near-infrared fluorescence optical projection tomography system to quantitatively and spatially resolve molecular agents distribution within whole murine heart. We validated the use of the system in a mouse model of monocytes/macrophages recruitment during myocardial infarction. While acquired, data were processed and reconstructed in real time. Tomographic analysis and visualization of the key inflammatory components were obtained via a mathematical formalism based on left ventricular modeling. We observed extensive monocyte recruitment within and around the infarcted areas and discovered that monocytes were also extensively recruited into non-ischemic myocardium, beyond that of injured tissue, such as the septum. PMID- 22509303 TI - Comparison of CATs, CURB-65 and PMEWS as triage tools in pandemic influenza admissions to UK hospitals: case control analysis using retrospective data. AB - Triage tools have an important role in pandemics to identify those most likely to benefit from higher levels of care. We compared Community Assessment Tools (CATs), the CURB-65 score, and the Pandemic Medical Early Warning Score (PMEWS); to predict higher levels of care (high dependency--Level 2 or intensive care- Level 3) and/or death in patients at or shortly after admission to hospital with A/H1N1 2009 pandemic influenza. This was a case-control analysis using retrospectively collected data from the FLU-CIN cohort (1040 adults, 480 children) with PCR-confirmed A/H1N1 2009 influenza. Area under receiver operator curves (AUROC), sensitivity, specificity, positive predictive values and negative predictive values were calculated. CATs best predicted Level 2/3 admissions in both adults [AUROC (95% CI): CATs 0.77 (0.73, 0.80); CURB-65 0.68 (0.64, 0.72); PMEWS 0.68 (0.64, 0.73), p<0.001] and children [AUROC: CATs 0.74 (0.68, 0.80); CURB-65 0.52 (0.46, 0.59); PMEWS 0.69 (0.62, 0.75), p<0.001]. CURB-65 and CATs were similar in predicting death in adults with both performing better than PMEWS; and CATs best predicted death in children. CATs were the best predictor of Level 2/3 care and/or death for both adults and children. CATs are potentially useful triage tools for predicting need for higher levels of care and/or mortality in patients of all ages. PMID- 22509304 TI - Efficacy of a non-hypercalcemic vitamin-D2 derived anti-cancer agent (MT19c) and inhibition of fatty acid synthesis in an ovarian cancer xenograft model. AB - BACKGROUND: Numerous vitamin-D analogs exhibited poor response rates, high systemic toxicities and hypercalcemia in human trials to treat cancer. We identified the first non-hypercalcemic anti-cancer vitamin D analog MT19c by altering the A-ring of ergocalciferol. This study describes the therapeutic efficacy and mechanism of action of MT19c in both in vitro and in vivo models. METHODOLOGY/PRINCIPAL FINDING: Antitumor efficacy of MT19c was evaluated in ovarian cancer cell (SKOV-3) xenografts in nude mice and a syngenic rat ovarian cancer model. Serum calcium levels of MT19c or calcitriol treated animals were measured. In-silico molecular docking simulation and a cell based VDR reporter assay revealed MT19c-VDR interaction. Genomewide mRNA analysis of MT19c treated tumors identified drug targets which were verified by immunoblotting and microscopy. Quantification of cellular malonyl CoA was carried out by HPLC-MS. A binding study with PPAR-Y receptor was performed. MT19c reduced ovarian cancer growth in xenograft and syngeneic animal models without causing hypercalcemia or acute toxicity. MT19c is a weak vitamin-D receptor (VDR) antagonist that disrupted the interaction between VDR and coactivator SRC2-3. Genome-wide mRNA analysis and western blot and microscopy of MT19c treated xenograft tumors showed inhibition of fatty acid synthase (FASN) activity. MT19c reduced cellular levels of malonyl CoA in SKOV-3 cells and inhibited EGFR/phosphoinositol-3kinase (PI-3K) activity independently of PPAR-gamma protein. SIGNIFICANCE: Antitumor effects of non-hypercalcemic agent MT19c provide a new approach to the design of vitamin-D based anticancer molecules and a rationale for developing MT19c as a therapeutic agent for malignant ovarian tumors by targeting oncogenic de novo lipogenesis. PMID- 22509305 TI - Design and validation of a novel method to measure cross-sectional area of neck muscles included during routine MR brain volume imaging. AB - INTRODUCTION: Low muscle mass secondary to disease and ageing is an important cause of excess mortality and morbidity. Many studies include a MR brain scan but no peripheral measure of muscle mass. We developed a technique to measure posterior neck muscle cross-sectional area (CSA) on volumetric MR brain scans enabling brain and muscle size to be measured simultaneously. METHODS: We performed four studies to develop and test: feasibility, inter-rater reliability, repeatability and external validity. We used T1-weighted MR brain imaging from young and older subjects, obtained on different scanners, and collected mid-thigh MR data. RESULTS: After developing the technique and demonstrating feasibility, we tested it for inter-rater reliability in 40 subjects. Intraclass correlation coefficients (ICC) between raters were 0.99 (95% confidence intervals (CI) 0.98 1.00) for the combined group (trapezius, splenius and semispinalis), 0.92 (CI 0.85-0.96) for obliquus and 0.92 (CI 0.85-0.96) for sternocleidomastoid. The first unrotated principal component explained 72.2% of total neck muscle CSA variance and correlated positively with both right (r = 0.52, p = .001) and left (r = 0.50, p = .002) grip strength. The 14 subjects in the repeatability study had had two MR brain scans on three different scanners. The ICC for between scanner variation for total neck muscle CSA was high at 0.94 (CI 0.86-0.98). The ICCs for within scanner variations were also high, with values of 0.95 (CI 0.86 0.98), 0.97 (CI 0.92-0.99) and 0.96 (CI 0.86-0.99) for the three scanners. The external validity study found a correlation coefficient for total thigh CSA and total neck CSA of 0.88. DISCUSSION: We present a feasible, valid and reliable method for measuring neck muscle CSA on T1-weighted MR brain scans. Larger studies are needed to validate and apply our technique with subjects differing in age, ethnicity and geographical location. PMID- 22509306 TI - Multimodality imaging in vivo for preclinical assessment of tumor-targeted doxorubicin nanoparticles. AB - This study presents a new multimodal imaging approach that includes high frequency ultrasound, fluorescence intensity, confocal, and spectral imaging to improve the preclinical evaluation of new therapeutics in vivo. Here we use this approach to assess in vivo the therapeutic efficacy of the novel chemotherapy construct, HerDox during and after treatment. HerDox is comprised of doxorubicin non-covalently assembled in a viral-like particle targeted to HER2+ tumor cells, causing tumor cell death at over 10-fold lower dose compared to the untargeted drug, while sparing the heart. Whereas our initial proof-of-principle studies on HerDox used tumor growth/shrinkage rates as a measure of therapeutic efficacy, here we show that multimodal imaging deployed during and after treatment can supplement traditional modes of tumor monitoring to further characterize the particle in tissues of treated mice. Specifically, we show here that tumor cell apoptosis elicited by HerDox can be monitored in vivo during treatment using high frequency ultrasound imaging, while in situ confocal imaging of excised tumors shows that HerDox indeed penetrated tumor tissue and can be detected at the subcellular level, including in the nucleus, via Dox fluorescence. In addition, ratiometric spectral imaging of the same tumor tissue enables quantitative discrimination of HerDox fluorescence from autofluorescence in situ. In contrast to standard approaches of preclinical assessment, this new method provides multiple/complementary information that may shorten the time required for initial evaluation of in vivo efficacy, thus potentially reducing the time and cost for translating new drug molecules into the clinic. PMID- 22509307 TI - The 5HT1a receptor agonist 8-Oh DPAT induces protection from lipofuscin accumulation and oxidative stress in the retinal pigment epithelium. AB - Age-related macular degeneration (AMD), a major cause of blindness in the elderly, is associated with oxidative stress, lipofuscin accumulation and retinal degeneration. The aim of this study was to determine if a 5-HT(1A) receptor agonist can reduce lipofuscin accumulation, reduce oxidative damage and prevent retinal cell loss both in vitro and in vivo. Autophagy-derived and photoreceptor outer segment (POS)-derived lipofuscin formation was assessed using FACS analysis and confocal microscopy in cultured retinal pigment epithelial (RPE) cells in the presence or absence of the 5-HT(1A) receptor agonist, 8-OH DPAT. 8-OH DPAT treatment resulted in a dose-dependent reduction in both autophagy- and POS derived lipofuscin compared to control. Reduction in autophagy-induced lipofuscin was sustained for 4 weeks following removal of the drug. The ability of 8-OH DPAT to reduce oxidative damage following exposure to 200 uM H(2)O(2) was assessed. 8 OH DPAT reduced superoxide generation and increased mitochondrial superoxide dismutase (MnSOD) levels and the ratio of reduced glutathione to the oxidized form of glutathione in H(2)O(2)-treated cells compared to controls and protected against H(2)O(2)-initiated lipid peroxidation, nitrotyrosine levels and mitochondrial damage. SOD2 knockdown mice, which have an AMD-like phenotype, received daily subcutaneous injections of either saline, 0.5 or 5.0 mg/kg 8-OH DPAT and were evaluated at monthly intervals. Systemic administration of 8-OH DPAT improved the electroretinogram response in SOD2 knockdown eyes of mice compared to knockdown eyes receiving vehicle control. There was a significant increase in the ONL thickness in mice treated with 8-OH DPAT at 4 months past the time of MnSOD knockdown compared to untreated controls together with a 60% reduction in RPE lipofuscin. The data indicate that 5-HT(1A) agonists can reduce lipofuscin accumulation and protect the retina from oxidative damage and mitochondrial dysfunction. 5-HT(1A) receptor agonists may have potential as therapeutic agents in the treatment of retinal degenerative disease. PMID- 22509308 TI - Erythropoietin receptor signaling is membrane raft dependent. AB - Upon erythropoietin (Epo) engagement, Epo-receptor (R) homodimerizes to activate JAK2 and Lyn, which phosphorylate STAT5. Although recent investigations have identified key negative regulators of Epo-R signaling, little is known about the role of membrane localization in controlling receptor signal fidelity. Here we show a critical role for membrane raft (MR) microdomains in creation of discrete signaling platforms essential for Epo-R signaling. Treatment of UT7 cells with Epo induced MR assembly and coalescence. Confocal microscopy showed that raft aggregates significantly increased after Epo stimulation (mean, 4.3+/-1.4(SE) vs. 25.6+/-3.2 aggregates/cell; p<=0.001), accompanied by a >3-fold increase in cluster size (p<=0.001). Raft fraction immunoblotting showed Epo-R translocation to MR after Epo stimulation and was confirmed by fluorescence microscopy in Epo stimulated UT7 cells and primary erythroid bursts. Receptor recruitment into MR was accompanied by incorporation of JAK2, Lyn, and STAT5 and their activated forms. Raft disruption by cholesterol depletion extinguished Epo induced Jak2, STAT5, Akt and MAPK phosphorylation in UT7 cells and erythroid progenitors. Furthermore, inhibition of the Rho GTPases Rac1 or RhoA blocked receptor recruitment into raft fractions, indicating a role for these GTPases in receptor trafficking. These data establish a critical role for MR in recruitment and assembly of Epo-R and signal intermediates into discrete membrane signaling units. PMID- 22509309 TI - A common role for various human truncated adenomatous polyposis coli isoforms in the control of beta-catenin activity and cell proliferation. AB - The tumour suppressor gene adenomatous polyposis coli (APC) is mutated in most colorectal cancer cases, leading to the synthesis of truncated APC products and the stabilization of beta-catenin. Truncated APC is almost always retained in tumour cells, suggesting that it serves an essential function. Here, RNA interference has been used to down-regulate truncated APC in several colorectal cancer cell lines expressing truncated APCs of different lengths, thereby performing an analysis covering most of the mutation cluster region (MCR). The consequences on proliferation in vitro, tumour formation in vivo and the level and transcriptional activity of beta-catenin have been investigated. Down regulation of truncated APC results in an inhibition of tumour cell population expansion in vitro in 6 cell lines out of 6 and inhibition of tumour outgrowth in vivo as analysed in one of these cell lines, HT29. This provides a general rule explaining the retention of truncated APC in colorectal tumours and defines it as a suitable target for therapeutic intervention. Actually, we also show that it is possible to design a shRNA that targets a specific truncated isoform of APC without altering the expression of wild-type APC. Down-regulation of truncated APC is accompanied by an up-regulation of the transcriptional activity of beta catenin in 5 out of 6 cell lines. Surprisingly, the increased signalling is associated in most cases (4 out of 5) with an up-regulation of beta-catenin levels, indicating that truncated APC can still modulate wnt signalling through controlling the level of beta-catenin. This control can happen even when truncated APC lacks the beta-catenin inhibiting domain (CiD) involved in targeting beta-catenin for proteasomal degradation. Thus, truncated APC is an essential component of colorectal cancer cells, required for cell proliferation, possibly by adjusting beta-catenin signalling to the "just right" level. PMID- 22509310 TI - Fused traditional and geometric morphometrics demonstrate pinniped whisker diversity. AB - Vibrissae (whiskers) are important components of the mammalian tactile sensory system, and primarily function as detectors of vibrotactile information from the environment. Pinnipeds possess the largest vibrissae among mammals and their vibrissal hair shafts demonstrate a diversity of shapes. The vibrissae of most phocid seals exhibit a beaded morphology with repeating sequences of crests and troughs along their length. However, there are few detailed analyses of pinniped vibrissal morphology, and these are limited to a few species. Therefore, we comparatively characterized differences in vibrissal hair shaft morphologies among phocid species with a beaded profile, phocid species with a smooth profile, and otariids with a smooth profile using traditional and geometric morphometric methods. Traditional morphometric measurements (peak-to-peak distance, crest width, trough width and total length) were collected using digital photographs. Elliptic Fourier analysis (geometric morphometrics) was used to quantify the outlines of whole vibrissae. The traditional and geometric morphometric datasets were subsequently combined by mathematically scaling each to true rank, followed by a single eigendecomposition. Quadratic discriminant function analysis demonstrated that 79.3, 97.8 and 100% of individuals could be correctly classified to their species based on vibrissal shape variables in the traditional, geometric and combined morphometric analyses, respectively. Phocids with beaded vibrissae, phocids with smooth vibrissae, and otariids each occupied distinct morphospace in the geometric morphometric and combined data analyses. Otariids split into two groups in the geometric morphometric analysis and gray seals appeared intermediate between beaded- and smooth-whiskered species in the traditional and combined analyses. Vibrissal hair shafts modulate the transduction of environmental stimuli to the mechanoreceptors in the follicle sinus complex (F-SC), which results in vibrotactile reception, but it is currently unclear how the diversity of shapes affects environmental signal modulation. PMID- 22509312 TI - Reduced polymorphism in domains involved in protein-protein interactions. AB - Genome sequencing of various individuals or isolates of the same species allows studying the polymorphism level of specific proteins and protein domains. Here we ask whether domains that are known to be involved in mediating protein-protein interactions show lower polymorphism than other domains. To this end we take advantage of a recent genome sequence dataset of 39 Saccahromyces cerevisiae strains and the experimentally determined protein interaction network of the laboratory strain. We analyze the polymorphism in domain residues involved in interactions at various levels of resolution, depending on their likelihood to be interaction mediators. We find that domains involved in interactions are less polymorphic than other domains. Furthermore, as the likelihood of a residue to be involved in interaction increases, its polymorphism decreases. Our results suggest that purifying selection operates on domains capable of mediating protein interactions to maintain their function. PMID- 22509313 TI - In situ monitoring of intracellular glucose and glutamine in CHO cell culture. AB - The development of processes to produce biopharmaceuticals industrially is still largely empirical and relies on optimizing both medium formulation and cell line in a product-specific manner. Current small-scale (well plate-based) process development methods cannot provide sufficient sample volume for analysis, to obtain information on nutrient utilization which can be problematic when processes are scaled to industrial fermenters. We envision a platform where essential metabolites can be monitored non-invasively and in real time in an ultra-low volume assay in order to provide additional information on cellular metabolism in high throughput screens. Towards this end, we have developed a model system of Chinese Hamster Ovary cells stably expressing protein-based biosensors for glucose and glutamine. Herein, we demonstrate that these can accurately reflect changing intracellular metabolite concentrations in vivo during batch and fed-batch culture of CHO cells. The ability to monitor intracellular depletion of essential nutrients in high throughput will allow rapid development of improved bioprocesses. PMID- 22509311 TI - Vascular dysfunction induced in offspring by maternal dietary fat involves altered arterial polyunsaturated fatty acid biosynthesis. AB - Nutrition during development affects risk of future cardiovascular disease. Relatively little is known about whether the amount and type of fat in the maternal diet affect vascular function in the offspring. To investigate this, pregnant and lactating rats were fed either 7%(w/w) or 21%(w/w) fat enriched in either 18:2n-6, trans fatty acids, saturated fatty acids, or fish oil. Their offspring were fed 4%(w/w) soybean oil from weaning until day 77. Type and amount of maternal dietary fat altered acetylcholine (ACh)-mediated vaso-relaxation in offspring aortae and mesenteric arteries, contingent on sex. Amount, but not type, of maternal dietary fat altered phenylephrine (Pe)-induced vasoconstriction in these arteries. Maternal 21% fat diet decreased 20:4n-6 concentration in offspring aortae. We investigated the role of Delta6 and Delta5 desaturases, showing that their inhibition in aortae and mesenteric arteries reduced vasoconstriction, but not vaso-relaxation, and the synthesis of specific pro constriction eicosanoids. Removal of the aortic endothelium did not alter the effect of inhibition of Delta6 and Delta5 desaturases on Pe-mediated vasoconstriction. Thus arterial smooth muscle 20:4n-6 biosynthesis de novo appears to be important for Pe-mediated vasoconstriction. Next we studied genes encoding these desaturases, finding that maternal 21% fat reduced Fads2 mRNA expression and increased Fads1 in offspring aortae, indicating dysregulation of 20:4n-6 biosynthesis. Methylation at CpG -394 bp 5' to the Fads2 transcription start site predicted its expression. This locus was hypermethylated in offspring of dams fed 21% fat. Pe treatment of aortae for 10 minutes increased Fads2, but not Fads1, mRNA expression (76%; P<0.05). This suggests that Fads2 may be an immediate early gene in the response of aortae to Pe. Thus both amount and type of maternal dietary fat induce altered regulation of vascular tone in offspring though differential effects on vaso-relaxation, and persistent changes in vasoconstriction via epigenetic processes controlling arterial polyunsaturated fatty acid biosynthesis. PMID- 22509314 TI - Experimental beetle metapopulations respond positively to dynamic landscapes and reduced connectivity. AB - Interactive effects of multiple environmental factors on metapopulation dynamics have received scant attention. We designed a laboratory study to test hypotheses regarding interactive effects of factors affecting the metapopulation dynamics of red flour beetle, Tribolium castaneum. Within a four-patch landscape we modified resource level (constant and diminishing), patch connectivity (high and low) and patch configuration (static and dynamic) to conduct a 2(3) factorial experiment, consisting of 8 metapopulations, each with 3 replicates. For comparison, two control populations consisting of isolated and static subpopulations were provided with resources at constant or diminishing levels. Longitudinal data from 22 tri-weekly counts of beetle abundance were analyzed using bayesian Poisson generalized linear mixed models to estimate additive and interactive effects of factors affecting abundance. Constant resource levels, low connectivity and dynamic patches yielded greater levels of adult beetle abundance. For a given resource level, frequency of colonization exceeded extinction in landscapes with dynamic patches when connectivity was low, thereby promoting greater patch occupancy. Negative density dependence of pupae on adults occurred and was stronger in landscapes with low connectivity and constant resources; these metapopulations also demonstrated greatest stability. Metapopulations in control landscapes went extinct quickly, denoting lower persistence than comparable landscapes with low connectivity. When landscape carrying capacity was constant, habitat destruction coupled with low connectivity created asynchronous local dynamics and refugia within which cannibalism of pupae was reduced. Increasing connectivity may be counter-productive and habitat destruction/recreation may be beneficial to species in some contexts. PMID- 22509315 TI - Validation of bacterial replication termination models using simulation of genomic mutations. AB - In bacterial circular chromosomes and most plasmids, the replication is known to be terminated when either of the following occurs: the forks progressing in opposite directions meet at the distal end of the chromosome or the replication forks become trapped by Tus proteins bound to Ter sites. Most bacterial genomes have various polarities in their genomic structures. The most notable feature is polar genomic compositional asymmetry of the bases G and C in the leading and lagging strands, called GC skew. This asymmetry is caused by replication associated mutation bias, and this "footprint" of the replication machinery suggests that, in contrast to the two known mechanisms, replication termination occurs near the chromosome dimer resolution site dif. To understand this difference between the known replication machinery and genomic compositional bias, we undertook a simulation study of genomic mutations, and we report here how different replication termination models contribute to the generation of replication-related genomic compositional asymmetry. Contrary to naive expectations, our results show that a single finite termination site at dif or at the GC skew shift point is not sufficient to reconstruct the genomic compositional bias as observed in published sequences. The results also show that the known replication mechanisms are sufficient to explain the position of the GC skew shift point. PMID- 22509316 TI - PORCN moonlights in a Wnt-independent pathway that regulates cancer cell proliferation. AB - Porcupine (PORCN) is a membrane-bound O-acyl transferase that is required for the palmitoylation of Wnt proteins, and that is essential in diverse Wnt pathways for Wnt-Wntless (WLS) binding, Wnt secretion, and Wnt signaling activity. We tested if PORCN was required for the proliferation of transformed cells. Knockdown of PORCN by multiple independent siRNAs results in a cell growth defect in a subset of epithelial cancer cell lines. The growth defect is transformation-dependent in human mammary epithelial (HMEC) cells. Additionally, inducible PORCN knockdown by two independent shRNAs markedly reduces the growth of established MDA-MB-231 cancers in orthotopic xenografts in immunodeficient mice. Unexpectedly, the proliferation defect resulting from loss of PORCN occurs in a Wnt-independent manner, as it is rescued by re-expression of catalytically inactive PORCN, and is not seen after RNAi-mediated knockdown of the Wnt carrier protein WLS, nor after treatment with the PORCN inhibitor IWP. Consistent with a role in a Wnt independent pathway, knockdown of PORCN regulates a distinct set of genes that are not altered by other inhibitors of Wnt signaling. PORCN protein thus appears to moonlight in a novel signaling pathway that is rate-limiting for cancer cell growth and tumorigenesis independent of its enzymatic function in Wnt biosynthesis and secretion. PMID- 22509317 TI - The transition between stochastic and deterministic behavior in an excitable gene circuit. AB - We explore the connection between a stochastic simulation model and an ordinary differential equations (ODEs) model of the dynamics of an excitable gene circuit that exhibits noise-induced oscillations. Near a bifurcation point in the ODE model, the stochastic simulation model yields behavior dramatically different from that predicted by the ODE model. We analyze how that behavior depends on the gene copy number and find very slow convergence to the large number limit near the bifurcation point. The implications for understanding the dynamics of gene circuits and other birth-death dynamical systems with small numbers of constituents are discussed. PMID- 22509318 TI - Improved cellular specificity of plasmonic nanobubbles versus nanoparticles in heterogeneous cell systems. AB - The limited specificity of nanoparticle (NP) uptake by target cells associated with a disease is one of the principal challenges of nanomedicine. Using the threshold mechanism of plasmonic nanobubble (PNB) generation and enhanced accumulation and clustering of gold nanoparticles in target cells, we increased the specificity of PNB generation and detection in target versus non-target cells by more than one order of magnitude compared to the specificity of NP uptake by the same cells. This improved cellular specificity of PNBs was demonstrated in six different cell models representing diverse molecular targets such as epidermal growth factor receptor, CD3 receptor, prostate specific membrane antigen and mucin molecule MUC1. Thus PNBs may be a universal method and nano agent that overcome the problem of non-specific uptake of NPs by non-target cells and improve the specificity of NP-based diagnostics, therapeutics and theranostics at the cell level. PMID- 22509319 TI - Efficacy of oral metronidazole with vaginal clindamycin or vaginal probiotic for bacterial vaginosis: randomised placebo-controlled double-blind trial. AB - BACKGROUND: To determine if oral metronidazole (MTZ-400 mg bid) with 2% vaginal clindamycin-cream (Clind) or a Lactobacillus acidophilus vaginal-probiotic containing oestriol (Prob) reduces 6-month bacterial vaginosis (BV) recurrence. METHODS: Double-blind placebo-controlled parallel-group single-site study with balanced randomization (1:1:1) conducted at Melbourne Sexual Health Centre, Australia. Participants with symptomatic BV [Nugent Score (NS) = 7-10 or >=3 Amsel's criteria and NS = 4-10], were randomly allocated to MTZ-Clind, MTZ-Prob or MTZ-Placebo and assessed at 1,2,3 and 6 months. MTZ and Clind were administered for 7 days and Prob and Placebo for 12 days. Primary outcome was BV recurrence (NS of 7-10) on self-collected vaginal-swabs over 6-months. Cumulative BV recurrence rates were compared between groups by Chi-squared statistics. Kaplan-Meier, log rank and Cox regression analyses were used to compare time until and risk of BV recurrence between groups. RESULTS: 450 18-50 year old females were randomized and 408 (91%), equally distributed between groups, provided >=1 NS post-randomization and were included in analyses; 42 (9%) participants with no post-randomization data were excluded. Six-month retention rates were 78% (n = 351). One-month BV recurrence (NS 7-10) rates were 3.6% (5/140), 6.8% (9/133) and 9.6% (13/135) in the MTZ-Clind, MTZ-Prob and MTZ Placebo groups respectively, p = 0.13. Hazard ratios (HR) for BV recurrence at one-month, adjusted for adherence to vaginal therapy, were 0.43 (95%CI 0.15-1.22) and 0.75 (95% CI 0.32-1.76) in the MTZ-Clind and MTZ-Prob groups compared to MTZ Plac respectively. Cumulative 6-month BV recurrence was 28.2%; (95%CI 24.0-32.7%) with no difference between groups, p = 0.82; HRs for 6-month BV recurrence for MTZ-Clind and MTZ-Prob compared to MTZ-Plac, adjusted for adherence to vaginal therapy were 1.09(95% CI = 0.70-1.70) and 1.03(95% CI = 0.65-1.63), respectively. No serious adverse events occurred. CONCLUSION: Combining the recommended first line therapies of oral metronidazole and vaginal clindamycin, or oral metronidazole with an extended-course of a commercially available vaginal L.acidophilus probiotic, does not reduce BV recurrence. TRIAL REGISTRATION: ANZCTR.org.au ACTRN12607000350426. PMID- 22509320 TI - Analysis of microsatellite polymorphism in inbred knockout mice. AB - Previously, we found that the genotype of 42 out of 198 mouse microsatellite loci, which are distributed among all chromosomes except the Y chromosome, changed from monomorphism to polymorphism (CMP) in a genetically modified inbred mouse strain. In this study, we further examined whether CMP also relates to the homologous recombination in gene knockout (KO) mouse strains. The same 42 microsatellite loci were analyzed by polymerase chain reaction (PCR) in 29 KO inbred mouse strains via short tandem sequence repeat (STR) scanning and direct sequence cloning to justify microsatellite polymorphisms. The C57BL/6J and 129 mouse strains, from which these 29 KO mice were derived, were chosen as the background controls. The results indicated that 10 out of 42 (23.8%) loci showed CMP in some of these mouse strains. Except for the trinucleotide repeat locus of D3Mit22, which had microsatellite CMP in strain number 9, the core sequences of the remaining 41 loci were dinucleotide repeats, and 9 out of 41 (21.95%) showed CMPs among detected mouse strains. However, 11 out of 29 (37.9%) KO mice strains were recognized as having CMPs. The popular dinucleotide motifs in CMP were (TG)(n) (50%, 2/4), followed by (GT)(n) (27.27%, 3/11) and (CA)(n) (23.08%, 3/13). The microsatellite CMP in (CT)(n) and (AG)(n) repeats were 20% (1/5). According to cloning sequencing results, 6 KO mouse strains showed insertions of nucleotides whereas 1 showed a deletion. Furthermore, 2 loci (D13Mit3 and D14Mit102) revealed CMP in 2 strains, and mouse strain number 9 showed CMPs in two loci (D3Mit22 and D13Mit3) simultaneously. Collectively, these results indicated that microsatellite polymorphisms were present in the examined inbred KO mice. PMID- 22509321 TI - Lmo4 in the basolateral complex of the amygdala modulates fear learning. AB - Pavlovian fear conditioning is an associative learning paradigm in which mice learn to associate a neutral conditioned stimulus with an aversive unconditioned stimulus. In this study, we demonstrate a novel role for the transcriptional regulator Lmo4 in fear learning. LMO4 is predominantly expressed in pyramidal projection neurons of the basolateral complex of the amygdala (BLC). Mice heterozygous for a genetrap insertion in the Lmo4 locus (Lmo4gt/+), which express 50% less Lmo4 than their wild type (WT) counterparts display enhanced freezing to both the context and the cue in which they received the aversive stimulus. Small hairpin RNA-mediated knockdown of Lmo4 in the BLC, but not the dentate gyrus region of the hippocampus recapitulated this enhanced conditioning phenotype, suggesting an adult- and brain region-specific role for Lmo4 in fear learning. Immunohistochemical analyses revealed an increase in the number of c-Fos positive puncta in the BLC of Lmo4gt/+ mice in comparison to their WT counterparts after fear conditioning. Lastly, we measured anxiety-like behavior in Lmo4gt/+ mice and in mice with BLC-specific downregulation of Lmo4 using the elevated plus maze, open field, and light/dark box tests. Global or BLC-specific knockdown of Lmo4 did not significantly affect anxiety-like behavior. These results suggest a selective role for LMO4 in the BLC in modulating learned but not unlearned fear. PMID- 22509322 TI - Solubility and permeation of hydrogen sulfide in lipid membranes. AB - Hydrogen sulfide (H(2)S) is mainly known for its toxicity but has recently been shown to be produced endogenously in mammalian tissues and to be associated with physiological regulatory functions. To better understand the role of biomembranes in modulating its biological distribution and effects; we measured the partition coefficient of H(2)S in models of biological membranes. The partition coefficients were found to be 2.1+/-0.2, 1.9+/-0.5 and 2.0+/-0.6 in n-octanol, hexane and dilauroylphosphatidylcholine liposome membranes relative to water, respectively (25 degrees C). This two-fold higher concentration of H(2)S in the membrane translates into a rapid membrane permeability, P(m) = 3 cm s(-1). We used a mathematical model in three dimensions to gain insight into the diffusion of total sulfide in tissues. This model shows that the sphere of action of sulfide produced by a single cell expands to involve more than 200 neighboring cells, and that the resistance imposed by lipid membranes has a significant effect on the diffusional spread of sulfide at pH 7.4, increasing local concentrations. These results support the role of hydrogen sulfide as a paracrine signaling molecule and reveal advantageous pharmacokinetic properties for its therapeutic applications. PMID- 22509323 TI - Determinants of bacteriophage 933W repressor DNA binding specificity. AB - We reported previously that 933W repressor apparently does not cooperatively bind to adjacent sites on DNA and that the relative affinities of 933W repressor for its operators differ significantly from that of any other lambdoid bacteriophage. These findings indicate that the operational details of the lysis-lysogeny switch of bacteriophage 933W are unique among lambdoid bacteriophages. Since the functioning of the lysis-lysogeny switch in 933W bacteriophage uniquely and solely depends on the order of preference of 933W repressor for its operators, we examined the details of how 933W repressor recognizes its DNA sites. To identify the specificity determinants, we first created a molecular model of the 933W repressor-DNA complex and tested the predicted protein-DNA interactions. These results of these studies provide a picture of how 933W repressor recognizes its DNA sites. We also show that, opposite of what is normally observed for lambdoid phages, 933W operator sequences have evolved in such a way that the presence of the most commonly found base sequences at particular operator positions serves to decrease, rather than increase, the affinity of the protein for the site. This finding cautions against assuming that a consensus sequence derived from sequence analysis defines the optimal, highest affinity DNA binding site for a protein. PMID- 22509324 TI - Multiple episodes of convergence in genes of the dim light vision pathway in bats. AB - The molecular basis of the evolution of phenotypic characters is very complex and is poorly understood with few examples documenting the roles of multiple genes. Considering that a single gene cannot fully explain the convergence of phenotypic characters, we choose to study the convergent evolution of rod vision in two divergent bats from a network perspective. The Old World fruit bats (Pteropodidae) are non-echolocating and have binocular vision, whereas the sheath tailed bats (Emballonuridae) are echolocating and have monocular vision; however, they both have relatively large eyes and rely more on rod vision to find food and navigate in the night. We found that the genes CRX, which plays an essential role in the differentiation of photoreceptor cells, SAG, which is involved in the desensitization of the photoactivated transduction cascade, and the photoreceptor gene RH, which is directly responsible for the perception of dim light, have undergone parallel sequence evolution in two divergent lineages of bats with larger eyes (Pteropodidae and Emballonuroidea). The multiple convergent events in the network of genes essential for rod vision is a rare phenomenon that illustrates the importance of investigating pathways and networks in the evolution of the molecular basis of phenotypic convergence. PMID- 22509325 TI - Invasion genetics of the Western flower thrips in China: evidence for genetic bottleneck, hybridization and bridgehead effect. AB - The western flower thrips, Frankliniella occidentalis (Pergande), is an invasive species and the most economically important pest within the insect order Thysanoptera. F. occidentalis, which is endemic to North America, was initially detected in Kunming in southwestern China in 2000 and since then it has rapidly invaded several other localities in China where it has greatly damaged greenhouse vegetables and ornamental crops. Controlling this invasive pest in China requires an understanding of its genetic makeup and migration patterns. Using the mitochondrial COI gene and 10 microsatellites, eight of which were newly isolated and are highly polymorphic, we investigated the genetic structure and the routes of range expansion of 14 F. occidentalis populations in China. Both the mitochondrial and microsatellite data revealed that the genetic diversity of F. occidentalis of the Chinese populations is lower than that in its native range. Two previously reported cryptic species (or ecotypes) were found in the study. The divergence in the mitochondrial COI of two Chinese cryptic species (or ecotypes) was about 3.3% but they cannot be distinguished by nuclear markers. Hybridization might produce such substantial mitochondrial-nuclear discordance. Furthermore, we found low genetic differentiation (global F(ST) = 0.043, P<0.001) among all the populations and strong evidence for gene flow, especially from the three southwestern populations (Baoshan, Dali and Kunming) to the other Chinese populations. The directional gene flow was further supported by the higher genetic diversity of these three southwestern populations. Thus, quarantine and management of F. occidentalis should focus on preventing it from spreading from the putative source populations to other parts of China. PMID- 22509326 TI - The glass is half-full: overestimating the quality of a novel environment is advantageous. AB - According to optimal foraging theory, foraging decisions are based on the forager's current estimate of the quality of its environment. However, in a novel environment, a forager does not possess information regarding the quality of the environment, and may make a decision based on a biased estimate. We show, using a simple simulation model, that when facing uncertainty in heterogeneous environments it is better to overestimate the quality of the environment (to be an "optimist") than underestimate it, as optimistic animals learn the true value of the environment faster due to higher exploration rate. Moreover, we show that when the animal has the capacity to remember the location and quality of resource patches, having a positively biased estimate of the environment leads to higher fitness gains than having an unbiased estimate, due to the benefits of exploration. Our study demonstrates how a simple model of foraging with incomplete information, derived directly from optimal foraging theory, can produce well documented complex space-use patterns of exploring animals. PMID- 22509327 TI - Reasons for (non)participating in a telephone-based intervention program for families with overweight children. AB - OBJECTIVE: Willingness to participate in obesity prevention programs is low; underlying reasons are poorly understood. We evaluated reasons for (non)participating in a novel telephone-based obesity prevention program for overweight children and their families. METHOD: Overweight children and adolescents (BMI>90(th) percentile) aged 3.5-17.4 years were screened via the CrescNet database, a representative cohort of German children, and program participation (repetitive computer aided telephone counseling) was offered by their local pediatrician. Identical questionnaires to collect baseline data on anthropometrics, lifestyle, eating habits, sociodemographic and psychosocial parameters were analyzed from 433 families (241 participants, 192 nonparticipants). Univariate analyses and binary logistic regression were used to identify factors associated with nonparticipation. RESULTS: The number of overweight children (BMI>90(th) percentile) was higher in nonparticipants than participants (62% vs. 41.1%,p<0.001), whereas the number of obese children (BMI>97(th) percentile) was higher in participants (58.9% vs.38%,p<0.001). Participating girls were younger than boys (8.8 vs.10.4 years, p<0.001). 87.3% and 40% of participants, but only 72.2% and 24.7% of nonparticipants, respectively, reported to have regular breakfasts (p = 0.008) and 5 regular daily meals (p = 0.003). Nonparticipants had a lower household-net-income (p<0.001), but higher subjective physical wellbeing than participants (p = 0.018) and believed that changes in lifestyle can be made easily (p = 0.05). CONCLUSION: An important reason for nonparticipation was non-awareness of their child's weight status by parents. Nonparticipants, who were often low-income families, believed that they already perform a healthy lifestyle and had a higher subjective wellbeing. We hypothesize that even a low-threshold intervention program does not reach the families who really need it. PMID- 22509328 TI - RLIP76 regulates PI3K/Akt signaling and chemo-radiotherapy resistance in pancreatic cancer. AB - PURPOSE: Pancreatic cancer is an aggressive malignancy with characteristic metastatic course of disease and resistance to conventional chemo-radiotherapy. RLIP76 is a multi-functional cell membrane protein that functions as a major mercapturic acid pathway transporter as well as key regulator of receptor-ligand complexes. In this regard, we investigated the significance of targeting RLIP76 on PI3K/Akt pathway and mechanisms regulating response to chemo-radiotherapy. RESEARCH DESIGN AND METHODS: Cell survival was assessed by MTT and colony forming assays. Cellular levels of proteins and phosphorylation was determined by Western blot analyses. The impact on apoptosis was determined by TUNEL assay. The anti cancer effects of RLIP76 targeted interventions in vivo were determined using mice xenograft model of the pancreatic cancer. The regulation of doxorubicin transport and radiation sensitivity were determined by transport studies and colony forming assays, respectively. RESULTS: Our current studies reveal an encompassing model for the role of RLIP76 in regulating the levels of fundamental proteins like PI3K, Akt, E-cadherin, CDK4, Bcl2 and PCNA which are of specific importance in the signal transduction from critical upstream signaling cascades that determine the proliferation, apoptosis and differentiation of pancreatic cancer cells. RLIP76 depletion also caused marked and sustained regression of established human BxPC-3 pancreatic cancer tumors in nude mouse xenograft model. RLIP76 turned out to be a major regulator of drug transport along with contributing to the radiation resistance in pancreatic cancer. CONCLUSIONS/SIGNIFICANCE: RLIP76 represents a mechanistically significant target for developing effective interventions in aggressive and refractory pancreatic cancers. PMID- 22509329 TI - Thrombospondin-1 type 1 repeats in a model of inflammatory bowel disease: transcript profile and therapeutic effects. AB - Thrombospondin-1 (TSP-1) is a matricellular protein with regulatory functions in inflammation and cancer. The type 1 repeats (TSR) domains of TSP-1 have been shown to interact with a wide range of proteins that result in the anti angiogenic and anti-tumor properties of TSP-1. To ascertain possible functions and evaluate potential therapeutic effects of TSRs in inflammatory bowel disease, we conducted clinical, histological and microarray analyses on a mouse model of induced colitis. We used dextran sulfate sodium (DSS) to induce colitis in wild type (WT) mice for 7 days. Simultaneously, mice were injected with either saline or one form of TSP-1 derived recombinant proteins, containing either (1) the three type 1 repeats of the TSP-1 (3TSR), (2) the second type 1 repeat (TSR2), or (3) TSR2 with the RFK sequence (TSR2+RFK). Total RNA isolated from the mice colons were processed and hybridized to mouse arrays. Array data were validated by real-time qPCR and immunohistochemistry. Histological and disease indices reveal that the mice treated with the TSRs show different patterns of leukocytic infiltration and that 3TSR treatment was the most effective in decreasing inflammation in DSS-induced colitis. Transcriptional profiling revealed differentially expressed (DE) genes, with the 3TSR-treated mice showing the least deviation from the WT-water controls. In conclusion, this study shows that 3TSR treatment is effective in attenuating the inflammatory response to DSS injury. In addition, the transcriptomics work unveils novel genetic data that suggest beneficial application of the TSR domains in inflammatory bowel disease. PMID- 22509331 TI - Animal or plant: which is the better fog water collector? AB - Occasional fog is a critical water source utilised by plants and animals in the Namib Desert. Fog basking beetles (Onymacris unguicularis, Tenebrionidae) and Namib dune bushman grass (Stipagrostris sabulicola, Poaceae) collect water directly from the fog. While the beetles position themselves optimally for fog water collection on dune ridges, the grass occurs predominantly at the dune base where less fog water is available. Differences in the fog-water collecting abilities in animals and plants have never been addressed. Here we place beetles and grass side-by-side in a fog chamber and measure the amount of water they collect over time. Based on the accumulated amount of water over a two hour period, grass is the better fog collector. However, in contrast to the episodic cascading water run-off from the grass, the beetles obtain water in a steady flow from their elytra. This steady trickle from the beetles' elytra to their mouth could ensure that even short periods of fog basking--while exposed to predators- will yield water. Up to now there is no indication of specialised surface properties on the grass leafs, but the steady run-off from the beetles could point to specific property adaptations of their elytra surface. PMID- 22509330 TI - Estrogen prevents oxidative damage to the mitochondria in Friedreich's ataxia skin fibroblasts. AB - Estrogen and estrogen-related compounds have been shown to have very potent cytoprotective properties in a wide range of disease models, including an in vitro model of Friedreich's ataxia (FRDA). This study describes a potential estrogen receptor (ER)-independent mechanism by which estrogens act to protect human FRDA skin fibroblasts from a BSO-induced oxidative insult resulting from inhibition of de novo glutathione (GSH) synthesis. We demonstrate that phenolic estrogens, independent of any known ER, are able to prevent lipid peroxidation and mitochondrial membrane potential (DeltaPsim) collapse, maintain ATP at near control levels, increase oxidative phosphorylation and maintain activity of aconitase. Estrogens did not, however, prevent BSO from depleting GSH or induce an increased expression level of GSH. The cytoprotective effects of estrogen appear to be due to a direct overall reduction in oxidative damage to the mitochondria, enabling the FRDA fibroblast mitochondria to generate sufficient ATP for energy requirements and better survive oxidative stress. These data support the hypothesis that phenol ring containing estrogens are possible candidate drugs for the delay and/or prevention of FRDA symptoms. PMID- 22509332 TI - Proteomic candidate biomarkers of drug-induced nephrotoxicity in the rat. AB - Improved biomarkers of acute nephrotoxicity are coveted by the drug development industry, regulatory agencies, and clinicians. In an effort to identify such biomarkers, urinary peptide profiles of rats treated with two different nephrotoxins were investigated. 493 marker candidates were defined that showed a significant response to cis-platin comparing a cis-platin treated cohort to controls. Next, urine samples from rats that received three consecutive daily doses of 150 or 300 mg/kg gentamicin were examined. 557 potential biomarkers were initially identified; 108 of these gentamicin-response markers showed a clear temporal response to treatment. 39 of the cisplatin-response markers also displayed a clear response to gentamicin. Of the combined 147 peptides, 101 were similarly regulated by gentamicin or cis-platin and 54 could be identified by tandem mass spectrometry. Most were collagen type I and type III fragments up regulated in response to gentamicin treatment. Based on these peptides, classification models were generated and validated in a longitudinal study. In agreement with histopathology, the observed changes in classification scores were transient, initiated after the first dose, and generally persistent over a period of 10-20 days before returning to control levels. The data support the hypothesis that gentamicin-induced renal toxicity up-regulates protease activity, resulting in an increase in several specific urinary collagen fragments. Urinary proteomic biomarkers identified here, especially those common to both nephrotoxins, may serve as a valuable tool to investigate potential new drug candidates for the risk of nephrotoxicity. PMID- 22509333 TI - PolysacDB: a database of microbial polysaccharide antigens and their antibodies. AB - Vaccines based on microbial cell surface polysaccharides have long been considered as attractive means to control infectious diseases. To realize this goal, detailed systematic information about the antigenic polysaccharide is necessary. However, only a few databases that provide limited knowledge in this area are available. This paper describes PolysacDB, a manually curated database of antigenic polysaccharides. We collected and compiled comprehensive information from literature and web resources about antigenic polysaccharides of microbial origin. The current version of the database has 1,554 entries of 149 different antigenic polysaccharides from 347 different microbes. Each entry provides comprehensive information about an antigenic polysaccharide, i.e., its origin, function, protocols for its conjugation to carriers, antibodies produced, details of assay systems, specificities of antibodies, proposed epitopes involved and antibody utilities. For convenience to the user, we have integrated web interface for searching, advanced searching and browsing data in database. This database will be useful for researchers working on polysaccharide-based vaccines. It is freely available from the URL: http://crdd.osdd.net/raghava/polysacdb/. PMID- 22509334 TI - Global DNA hypomethylation in peripheral blood leukocytes as a biomarker for cancer risk: a meta-analysis. AB - BACKGROUND: Good biomarkers for early detection of cancer lead to better prognosis. However, harvesting tumor tissue is invasive and cannot be routinely performed. Global DNA methylation of peripheral blood leukocyte DNA was evaluated as a biomarker for cancer risk. METHODS: We performed a meta-analysis to estimate overall cancer risk according to global DNA hypomethylation levels among studies with various cancer types and analytical methods used to measure DNA methylation. Studies were systemically searched via PubMed with no language limitation up to July 2011. Summary estimates were calculated using a fixed effects model. RESULTS: The subgroup analyses by experimental methods to determine DNA methylation level were performed due to heterogeneity within the selected studies (p<0.001, I(2): 80%). Heterogeneity was not found in the subgroup of %5-mC (p = 0.393, I(2): 0%) and LINE-1 used same target sequence (p = 0.097, I(2): 49%), whereas considerable variance remained in LINE-1 (p<0.001, I(2): 80%) and bladder cancer studies (p = 0.016, I(2): 76%). These results suggest that experimental methods used to quantify global DNA methylation levels are important factors in the association study between hypomethylation levels and cancer risk. Overall, cancer risks of the group with the lowest DNA methylation levels were significantly higher compared to the group with the highest methylation levels [OR (95% CI): 1.48 (1.28-1.70)]. CONCLUSIONS: Global DNA hypomethylation in peripheral blood leukocytes may be a suitable biomarker for cancer risk. However, the association between global DNA methylation and cancer risk may be different based on experimental methods, and region of DNA targeted for measuring global hypomethylation levels as well as the cancer type. Therefore, it is important to select a precise and accurate surrogate marker for global DNA methylation levels in the association studies between global DNA methylation levels in peripheral leukocyte and cancer risk. PMID- 22509335 TI - 3D Morphometric and posture study of felid scapulae using statistical shape modelling. AB - We present a three dimensional (3D) morphometric modelling study of the scapulae of Felidae, with a focus on the correlations between forelimb postures and extracted scapular shape variations. Our shape modelling results indicate that the scapular infraspinous fossa becomes larger and relatively broader along the craniocaudal axis in larger felids. We infer that this enlargement of the scapular fossa may be a size-related specialization for postural support of the shoulder joint. PMID- 22509336 TI - The SNP rs961253 in 20p12.3 is associated with colorectal cancer risk: a case control study and a meta-analysis of the published literature. AB - BACKGROUND: Colorectal cancer (CRC) is the third common cancer and the fourth leading cause of cancer death worldwide. A single nucleotide polymorphism (SNP), rs961253 located in 20p12, was firstly described to be associated with the increased risk of CRC in a genome-wide association study; however, more recent replication studies yielded controversial results. METHODOLOGY/PRINCIPAL FINDINGS: A hospital-based case-control study in a Chinese population was firstly performed, and then a meta-analysis combining the current and previously published studies were conducted to explore the real effect of rs961253 in CRC susceptibility. In the Chinese population including 641 cases and 1037 controls, per-A-allele conferred an OR of 1.60 (95% CI = 1.26-2.02) under additive model. In the meta-analysis including 29859 cases and 29696 controls, per-A-allele have an OR of 1.13 (95% CI = 1.09-1.18) under a random-effects model due to heterogeneity (P = 0.019). Nevertheless, the heterogeneity can be totally explained by ethnicity, with the tau(2) reduced to 0 after including ethnicity in meta-regression model. In stratified analysis by ethnicity, per-A-allele had ORs of 1.34 (95% CI = 1.20-1.50) and 1.11 (95% CI = 1.08-1.14) for Asian and European, respectively, without heterogeneity. Modest influence of each study was observed on overall estimate in sensitive analysis, and evident tendency to significant association was seen in cumulative analysis over time, together indicating the robust stability of the current results. CONCLUSIONS/SIGNIFICANCE: The results from our study and the meta-analysis provided firm evidence that rs961253 significantly contributed to CRC risk in both Asian and European population. PMID- 22509337 TI - Infant safety during and after maternal valacyclovir therapy in conjunction with antiretroviral HIV-1 prophylaxis in a randomized clinical trial. AB - BACKGROUND: Maternal administration of the acyclovir prodrug valacyclovir is compatible with pregnancy and breastfeeding. However, the safety profile of prolonged infant and maternal exposure to acyclovir in the context of antiretrovirals (ARVs) for prevention of mother-to-child HIV-1 transmission (PMTCT) has not been described. METHODS: Pregnant Kenyan women co-infected with HIV-1/HSV-2 with CD4 counts > 250 cells/mm(3) were enrolled at 34 weeks gestation and randomized to twice daily 500 mg valacyclovir or placebo until 12 months postpartum. Women received zidovudine from 28 weeks gestation and single dose nevirapine was given to women and infants at the time of delivery for PMTCT. Infant blood was collected at 6 weeks for creatinine and ALT. Breast milk specimens were collected at 2 weeks postpartum from 71 women in the valacyclovir arm; acyclovir levels were determined for a random sample of 44 (62%) specimens. Fisher's Exact and Wilcoxon rank-sum tests were used for analysis. RESULTS: One hundred forty-eight women were randomized and 146 mother-infant pairs were followed postpartum. PMTCT ARVs were administered to 98% of infants and all mothers. Valacyclovir was not associated with infant or maternal toxicities or adverse events, and no congenital malformations were observed. Infant creatinine levels were all normal (< 0.83 mg/dl) and median creatinine (median 0.50 mg/dl) and infant growth did not differ between study arms. Acyclovir was detected in 35 (80%) of 44 breast milk samples collected at 2 weeks postpartum. Median and maximum acyclovir levels were 2.62 and 10.15 mg/ml, respectively (interquartile range 0.6-4.19). CONCLUSIONS: Exposure to PMTCT ARVs and acyclovir after maternal administration of valacyclovir during pregnancy and postpartum to women co infected with HIV-1/HSV-2 was not associated with an increase in infant or maternal toxicities or adverse events. TRIAL REGISTRATION: ClinicalTrials.gov NCT00530777. PMID- 22509338 TI - Computational modeling-based discovery of novel classes of anti-inflammatory drugs that target lanthionine synthetase C-like protein 2. AB - BACKGROUND: Lanthionine synthetase component C-like protein 2 (LANCL2) is a member of the eukaryotic lanthionine synthetase component C-Like protein family involved in signal transduction and insulin sensitization. Recently, LANCL2 is a target for the binding and signaling of abscisic acid (ABA), a plant hormone with anti-diabetic and anti-inflammatory effects. METHODOLOGY/PRINCIPAL FINDINGS: The goal of this study was to determine the role of LANCL2 as a potential therapeutic target for developing novel drugs and nutraceuticals against inflammatory diseases. Previously, we performed homology modeling to construct a three dimensional structure of LANCL2 using the crystal structure of lanthionine synthetase component C-like protein 1 (LANCL1) as a template. Using this model, structure-based virtual screening was performed using compounds from NCI (National Cancer Institute) Diversity Set II, ChemBridge, ZINC natural products, and FDA-approved drugs databases. Several potential ligands were identified using molecular docking. In order to validate the anti-inflammatory efficacy of the top ranked compound (NSC61610) in the NCI Diversity Set II, a series of in vitro and pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate (DSS)-induced colitis. Our findings showed that the lead compound, NSC61610, activated peroxisome proliferator-activated receptor gamma in a LANCL2- and adenylate cyclase/cAMP dependent manner in vitro and ameliorated experimental colitis by down-modulating colonic inflammatory gene expression and favoring regulatory T cell responses. CONCLUSIONS/SIGNIFICANCE: LANCL2 is a novel therapeutic target for inflammatory diseases. High-throughput, structure-based virtual screening is an effective computational-based drug design method for discovering anti-inflammatory LANCL2-based drug candidates. PMID- 22509339 TI - Body size evolution in extant Oryzomyini rodents: Cope's rule or miniaturization? AB - At the macroevolutionary level, one of the first and most important hypotheses that proposes an evolutionary tendency in the evolution of body sizes is "Cope's rule". This rule has considerable empirical support in the fossil record and predicts that the size of species within a lineage increases over evolutionary time. Nevertheless, there is also a large amount of evidence indicating the opposite pattern of miniaturization over evolutionary time. A recent analysis using a single phylogenetic tree approach and a bayesian based model of evolution found no evidence for Cope's rule in extant mammal species. Here we utilize a likelihood-based phylogenetic method, to test the evolutionary trend in body size, which considers phylogenetic uncertainty, to discern between Cope's rule and miniaturization, using extant Oryzomyini rodents as a study model. We evaluated body size trends using two principal predictions: (a) phylogenetically related species are more similar in their body size, than expected by chance; (b) body size increased (Cope's rule)/decreased (miniaturization) over time. Consequently the distribution of forces and/or constraints that affect the tendency are homogenous and generate this directional process from a small/large sized ancestor. Results showed that body size in the Oryzomyini tribe evolved according to phylogenetic relationships, with a positive trend, from a small sized ancestor. Our results support that the high diversity and specialization currently observed in the Oryzomyini tribe is a consequence of the evolutionary trend of increased body size, following and supporting Cope's rule. PMID- 22509340 TI - Estimating long-term survival temperatures at the assemblage level in the marine environment: towards macrophysiology. AB - Defining ecologically relevant upper temperature limits of species is important in the context of environmental change. The approach used in the present paper estimates the relationship between rates of temperature change and upper temperature limits for survival in order to evaluate the maximum long-term survival temperature (Ts). This new approach integrates both the exposure time and the exposure temperature in the evaluation of temperature limits. Using data previously published for different temperate and Antarctic marine environments, we calculated Ts in each environment, which allowed us to calculate a new index: the Warming Allowance (WA). This index is defined as the maximum environmental temperature increase which an ectotherm in a given environment can tolerate, possibly with a decrease in performance but without endangering survival over seasonal or lifetime time-scales. It is calculated as the difference between maximum long-term survival temperature (Ts) and mean maximum habitat temperature. It provides a measure of how close a species, assemblage or fauna are living to their temperature limits for long-term survival and hence their vulnerability to environmental warming. In contrast to data for terrestrial environments showing that warming tolerance increases with latitude, results here for marine environments show a less clear pattern as the smallest WA value was for the Peru upwelling system. The method applied here, relating upper temperature limits to rate of experimental warming, has potential for wide application in the identification of faunas with little capacity to survive environmental warming. PMID- 22509341 TI - Major cellular and physiological impacts of ocean acidification on a reef building coral. AB - As atmospheric levels of CO(2) increase, reef-building corals are under greater stress from both increased sea surface temperatures and declining sea water pH. To date, most studies have focused on either coral bleaching due to warming oceans or declining calcification due to decreasing oceanic carbonate ion concentrations. Here, through the use of physiology measurements and cDNA microarrays, we show that changes in pH and ocean chemistry consistent with two scenarios put forward by the Intergovernmental Panel on Climate Change (IPCC) drive major changes in gene expression, respiration, photosynthesis and symbiosis of the coral, Acropora millepora, before affects on biomineralisation are apparent at the phenotype level. Under high CO(2) conditions corals at the phenotype level lost over half their Symbiodinium populations, and had a decrease in both photosynthesis and respiration. Changes in gene expression were consistent with metabolic suppression, an increase in oxidative stress, apoptosis and symbiont loss. Other expression patterns demonstrate upregulation of membrane transporters, as well as the regulation of genes involved in membrane cytoskeletal interactions and cytoskeletal remodeling. These widespread changes in gene expression emphasize the need to expand future studies of ocean acidification to include a wider spectrum of cellular processes, many of which may occur before impacts on calcification. PMID- 22509342 TI - Roles of the Drosophila SK channel (dSK) in courtship memory. AB - A role for SK channels in synaptic plasticity has been very well-characterized. However, in the absence of simple genetic animal models, their role in behavioral memory remains elusive. Here, we take advantage of Drosophila melanogaster with its single SK gene (dSK) and well-established courtship memory assay to investigate the contribution of this channel to memory. Using two independent dSK alleles, a null mutation and a dominant negative subunit, we show that while dSK negatively regulates the acquisition of short-term memory 30 min after a short training session, it is required for normal long-term memory 24 h after extended training. These findings highlight important functions for dSK in courtship memory and suggest that SK channels can mediate multiple forms of behavioral plasticity. PMID- 22509343 TI - Stimulus variability affects the amplitude of the auditory steady-state response. AB - In this study we investigate whether stimulus variability affects the auditory steady-state response (ASSR). We present cosinusoidal AM pulses as stimuli where we are able to manipulate waveform shape independently of the fixed repetition rate of 4 Hz. We either present sounds in which the waveform shape, the pulse width, is fixed throughout the presentation or where it varies pseudo-randomly. Importantly, the average spectra of all the fixed-width AM stimuli are equal to the spectra of the mixed-width AM. Our null hypothesis is that the average ASSR to the fixed-width AM will not be significantly different from the ASSR to the mixed-width AM. In a region of interest beamformer analysis of MEG data, we compare the 4 Hz component of the ASSR to the mixed-width AM with the 4 Hz component of the ASSR to the pooled fixed-width AM. We find that at the group level, there is a significantly greater response to the variable mixed-width AM at the medial boundary of the Middle and Superior Temporal Gyri. Hence, we find that adding variability into AM stimuli increases the amplitude of the ASSR. This observation is important, as it provides evidence that analysis of the modulation waveform shape is an integral part of AM processing. Therefore, standard steady state studies in audition, using sinusoidal AM, may not be sensitive to a key feature of acoustic processing. PMID- 22509344 TI - Epigenetic factors in cancer risk: effect of chemical carcinogens on global DNA methylation pattern in human TK6 cells. AB - In the current study, we assessed the global DNA methylation changes in human lymphoblastoid (TK6) cells in vitro in response to 5 direct and 10 indirect acting genotoxic agents. TK6 cells were exposed to the selected agents for 24 h in the presence and/or absence of S9 metabolic mix. Liquid chromatography-mass spectrometry was used for quantitative profiling of 5-methyl-2'-deoxycytidine. The effect of exposure on 5-methyl-2'-deoxycytidine between control and exposed cultures was assessed by applying the marginal model with correlated residuals on % global DNA methylation data. We reported the induction of global DNA hypomethylation in TK6 cells in response to S9 metabolic mix, under the current experimental settings. Benzene, hydroquinone, styrene, carbon tetrachloride and trichloroethylene induced global DNA hypomethylation in TK6 cells. Furthermore, we showed that dose did not have an effect on global DNA methylation in TK6 cells. In conclusion we report changes in global DNA methylation as an early event in response to agents traditionally considered as genotoxic. PMID- 22509346 TI - Glucose and fatty acid metabolism in a 3 tissue in-vitro model challenged with normo- and hyperglycaemia. AB - Nutrient balance in the human body is maintained through systemic signaling between different cells and tissues. Breaking down this circuitry to its most basic elements and reconstructing the metabolic network in-vitro provides a systematic method to gain a better understanding of how cross-talk between the organs contributes to the whole body metabolic profile and of the specific role of each different cell type. To this end, a 3-way connected culture of hepatocytes, adipose tissue and endothelial cells representing a simplified model of energetic substrate metabolism in the visceral region was developed. The 3-way culture was shown to maintain glucose and fatty acid homeostasis in-vitro. Subsequently it was challenged with insulin and high glucose concentrations to simulate hyperglycaemia. The aim was to study the capacity of the 3-way culture to maintain or restore normal circulating glucose concentrations in response to insulin and to investigate the effects these conditions on other metabolites involved in glucose and lipid metabolism. The results show that the system's metabolic profile changes dramatically in the presence of high concentrations of glucose, and that these changes are modulated by the presence of insulin. Furthermore, we observed an increase in E-selectin levels in hyperglycaemic conditions and increased IL-6 concentrations in insulin-free-hyperglycaemic conditions, indicating, respectively, endothelial injury and proinflammatory stress in the challenged 3-way system. PMID- 22509345 TI - RAGE expression in human T cells: a link between environmental factors and adaptive immune responses. AB - The Receptor for Advanced Glycation Endproducts (RAGE) is a scavenger ligand that binds glycated endproducts as well as molecules released during cell death such as S100b and HMGB1. RAGE is expressed on antigen presenting cells where it may participate in activation of innate immune responses but its role in adaptive human immune responses has not been described. We have found that RAGE is expressed intracellularly in human T cells following TCR activation but constitutively on T cells from patients with diabetes. The levels of RAGE on T cells from patients with diabetes are not related to the level of glucose control. It co-localizes to the endosomes. Its expression increases in activated T cells from healthy control subjects but bystander cells also express RAGE after stimulation of the antigen specific T cells. RAGE ligands enhance RAGE expression. In patients with T1D, the level of RAGE expression decreases with T cell activation. RAGE+ T cells express higher levels of IL-17A, CD107a, and IL-5 than RAGE- cells from the same individual with T1D. Our studies have identified the expression of RAGE on adaptive immune cells and a role for this receptor and its ligands in modulating human immune responses. PMID- 22509347 TI - Bacterial symbiosis maintenance in the asexually reproducing and regenerating flatworm Paracatenula galateia. AB - Bacteriocytes set the stage for some of the most intimate interactions between animal and bacterial cells. In all bacteriocyte possessing systems studied so far, de novo formation of bacteriocytes occurs only once in the host development, at the time of symbiosis establishment. Here, we present the free-living symbiotic flatworm Paracatenula galateia and its intracellular, sulfur-oxidizing bacteria as a system with previously undescribed strategies of bacteriocyte formation and bacterial symbiont transmission. Using thymidine analogue S-phase labeling and immunohistochemistry, we show that all somatic cells in adult worms including bacteriocytes - originate exclusively from aposymbiotic stem cells (neoblasts). The continued bacteriocyte formation from aposymbiotic stem cells in adult animals represents a previously undescribed strategy of symbiosis maintenance and makes P. galateia a unique system to study bacteriocyte differentiation and development. We also provide morphological and immunohistochemical evidence that P. galateia reproduces by asexual fragmentation and regeneration (paratomy) and, thereby, vertically transmits numerous symbiont containing bacteriocytes to its asexual progeny. Our data support the earlier reported hypothesis that the symbiont population is subjected to reduced bottleneck effects. This would justify both the codiversification between Paracatenula hosts and their Candidatus Riegeria symbionts, and the slow evolutionary rates observed for several symbiont genes. PMID- 22509348 TI - Chemerin and adiponectin contribute reciprocally to metabolic syndrome. AB - Obesity and metabolic syndrome (MetS) are considered chronic inflammatory states. Chemerin, a novel adipokine, may play an important role in linking MetS and inflammation. We investigated the association of chemerin with inflammatory markers and with characteristics of MetS in apparently healthy overweight and obese adults. We studied 92 adults; 59 men and 33 women whose average body mass index (BMI) was 28.15 +/- 5.08 kg/m(2). Anthropometric parameters, insulin resistance indices, lipid profiles, and inflammatory markers including high sensitivity C-reactive protein (hsCRP), pentraxin 3 (PTX3), adiponectin, and chemerin were measured. Controlling for age, gender, and BMI, serum chemerin level was positively correlated with body fat and serum triglyceride, and negatively correlated with adiponectin and high density lipoprotein cholesterol (HDL- C), and was not correlated with altered hsCRP or PTX3 levels. Among the low, moderate and high chemerin groups, high chemerin individuals are more likely to have lower HDL-C. Conversely, individuals in the low adiponectin group are more likely to have lower HDL-C and show more MetS phenotypic traits than moderate and high adiponectin subjects. To determine the relationships of chemerin and adiponectin to MetS and its components, participants were stratified into four groups based on their chemerin and adiponectin levels (high chemerin/high adiponectin, high chemerin/low adiponectin, low chemerin/high adiponectin, or low chemerin/low adiponectin). Participants who were in the high chemerin/low adiponectin group more likely to have dyslipidemia and MetS (OR: 5.79, 95% CI:1.00-33.70) compared to the other three group. Our findings suggest that chemerin and adiponectin may reciprocally participate in the development of MetS. PMID- 22509349 TI - Chitosan-graft-branched polyethylenimine copolymers: influence of degree of grafting on transfection behavior. AB - BACKGROUND: Successful non-viral gene delivery currently requires compromises to achieve useful transfection levels while minimizing toxicity. Despite high molecular weight (MW) branched polyethylenimine (bPEI) is considered the gold standard polymeric transfectant, it suffers from high cytotoxicity. Inversely, its low MW counterpart is less toxic and effective in transfection. Moreover, chitosan is a highly biocompatible and biodegradable polymer but characterized by very low transfection efficiency. In this scenario, a straightforward approach widely exploited to develop effective transfectants relies on the synthesis of chitosan-graft-low MW bPEIs (Chi-g-bPEI(x)) but, despite the vast amount of work that has been done in developing promising polymeric assemblies, the possible influence of the degree of grafting on the overall behavior of copolymers for gene delivery has been largely overlooked. METHODOLOGY/PRINCIPAL FINDINGS: With the aim of providing a comprehensive evaluation of the pivotal role of the degree of grafting in modulating the overall transfection effectiveness of copolymeric vectors, we have synthesized seven Chi-g-bPEI(x) derivatives with a variable amount of bPEI grafts (minimum: 0.6%; maximum: 8.8%). Along the Chi-g-bPEI(x) series, the higher the degree of grafting, the greater the zeta-potential and the cytotoxicity of the resulting polyplexes. Most important, in all cell lines tested the intermediate degree of grafting of 2.7% conferred low cytotoxicity and higher transfection efficiency compared to other Chi-g-bPEI(x) copolymers. We emphasize that, in transfection experiments carried out in primary articular chondrocytes, Chi-g-bPEI(2.7%) was as effective as and less cytotoxic than the gold standard 25 kDa bPEI. CONCLUSIONS/SIGNIFICANCE: This work underlines for the first time the pivotal role of the degree of grafting in modulating the overall transfection effectiveness of Chi-g-bPEI(x) copolymers. Crucially, we have demonstrated that, along the copolymer series, the fine tuning of the degree of grafting directly affected the overall charge of polyplexes and, altogether, had a direct effect on cytotoxicity. PMID- 22509350 TI - Altering an artificial Gagpolnef polyprotein and mode of ENV co-administration affects the immunogenicity of a clade C HIV DNA vaccine. AB - HIV-1 candidate vaccines expressing an artificial polyprotein comprising Gag, Pol and Nef (GPN) and a secreted envelope protein (Env) were shown in recent Phase I/II clinical trials to induce high levels of polyfunctional T cell responses; however, Env-specific responses clearly exceeded those against Gag. Here, we assess the impact of the GPN immunogen design and variations in the formulation and vaccination regimen of a combined GPN/Env DNA vaccine on the T cell responses against the various HIV proteins. Subtle modifications were introduced into the GPN gene to increase Gag expression, modify the expression ratio of Gag to PolNef and support budding of virus-like particles. I.m. administration of the various DNA constructs into BALB/c mice resulted in an up to 10-fold increase in Gag- and Pol-specific IFNgamma(+) CD8(+) T cells compared to GPN. Co-administering Env with Gag or GPN derivatives largely abrogated Gag-specific responses. Alterations in the molar ratio of the DNA vaccines and spatially or temporally separated administration induced more balanced T cell responses. Whereas forced co expression of Gag and Env from one plasmid induced predominantly Env-specific T cells responses, deletion of the only H-2(d) T cell epitope in Env allowed increased levels of Gag-specific T cells, suggesting competition at an epitope level. Our data demonstrate that the biochemical properties of an artificial polyprotein clearly influence the levels of antigen-specific T cells, and variations in formulation and schedule can overcome competition for the induction of these responses. These results are guiding the design of ongoing pre-clinical and clinical trials. PMID- 22509351 TI - Ocean acidification-induced food quality deterioration constrains trophic transfer. AB - Our present understanding of ocean acidification (OA) impacts on marine organisms caused by rapidly rising atmospheric carbon dioxide (CO(2)) concentration is almost entirely limited to single species responses. OA consequences for food web interactions are, however, still unknown. Indirect OA effects can be expected for consumers by changing the nutritional quality of their prey. We used a laboratory experiment to test potential OA effects on algal fatty acid (FA) composition and resulting copepod growth. We show that elevated CO(2) significantly changed the FA concentration and composition of the diatom Thalassiosira pseudonana, which constrained growth and reproduction of the copepod Acartia tonsa. A significant decline in both total FAs (28.1 to 17.4 fg cell(-1)) and the ratio of long-chain polyunsaturated to saturated fatty acids (PUFA:SFA) of food algae cultured under elevated (750 uatm) compared to present day (380 uatm) pCO(2) was directly translated to copepods. The proportion of total essential FAs declined almost tenfold in copepods and the contribution of saturated fatty acids (SFAs) tripled at high CO(2). This rapid and reversible CO(2)-dependent shift in FA concentration and composition caused a decrease in both copepod somatic growth and egg production from 34 to 5 eggs female(-1) day(-1). Because the diatom copepod link supports some of the most productive ecosystems in the world, our study demonstrates that OA can have far-reaching consequences for ocean food webs by changing the nutritional quality of essential macromolecules in primary producers that cascade up the food web. PMID- 22509352 TI - High proportion of 22q13 deletions and SHANK3 mutations in Chinese patients with intellectual disability. AB - Intellectual disability (ID) is a heterogeneous disorder caused by chromosomal abnormalities, monogenic factors and environmental factors. 22q13 deletion syndrome is a genetic disorder characterized by severe ID. Although the frequency of 22q13 deletions in ID is unclear, it is believed to be largely underestimated. To address this issue, we used Affymetrix Human SNP 6.0 array to detect the 22q13 deletions in 234 Chinese unexplained ID patients and 103 controls. After the Quality Control (QC) test of raw data, 22q13 deletions were found in four out of 230 cases (1.7%), while absent in parents of the cases and 101 controls. A review of genome-wide microarray studies in ID was performed and the frequency of 22q13 deletions from the literatures was 0.24%, much lower than our report. The overlapping region shared by all 4 cases encompasses the gene SHANK3. A heterozygous de novo nonsense mutation Y1015X of SHANK3 was identified in one ID patient. Cortical neurons were prepared from embryonic mice and were transfected with a control plasmid, shank3 wild-type (WT) or mutant plasmids. Overexpression of the Y1015 mutant in neurons significantly affected neurite outgrowth compared with shank3 WT. These findings suggest that 22q13 deletions may be a more frequent cause for Chinese ID patients than previously thought, and the SHANK3 gene is involved in the neurite development. PMID- 22509353 TI - Variation of serine-aspartate repeats in membrane proteins possibly contributes to staphylococcal microevolution. AB - Tandem repeats (either as microsatellites or minisatellites) in eukaryotic and prokaryotic organisms are mutation-prone DNA. While minisatellites in prokaryotic genomes are underrepresented, the cell surface adhesins of bacteria often contain the minisatellite SD repeats, encoding the amino acid pair of serine-asparatate, especially in Staphylococcal strains. However, their relationship to biological functions is still elusive. In this study, effort was made to uncover the copy number variations of SD repeats by bioinformatic analysis and to detect changes in SD repeats during a plasmid-based assay, as a first step to understand its biological functions. The SD repeats were found to be mainly present in the cell surface proteins. The SD repeats were genetically unstable and polymorphic in terms of copy numbers and sequence compositions. Unlike SNPs, the change of its copy number was reversible, without frame shifting. More significantly, a rearrangement hot spot, the ATTC/AGRT site, was found to be mainly responsible for the instability and reversibility of SD repeats. These characteristics of SD repeats may facilitate bacteria to respond to environmental changes, with low cost, low risk and high efficiency. PMID- 22509354 TI - Expression and subcellular localization of mammalian formin Fhod3 in the embryonic and adult heart. AB - The formin family proteins play pivotal roles in actin filament assembly via the FH2 domain. The mammalian formin Fhod3 is highly expressed in the heart, and its mRNA in the adult heart contains exons 11, 12, and 25, which are absent from non muscle Fhod3 isoforms. In cultured neonatal cardiomyocytes, Fhod3 localizes to the middle of the sarcomere and appears to function in its organization, although it is suggested that Fhod3 localizes differently in the adult heart. Here we show, using immunohistochemical analysis with three different antibodies, each recognizing distinct regions of Fhod3, that Fhod3 localizes as two closely spaced bands in middle of the sarcomere in both embryonic and adult hearts. The bands are adjacent to the M-line that crosslinks thick myosin filaments at the center of a sarcomere but distant from the Z-line that forms the boundary of the sarcomere, which localization is the same as that observed in cultured cardiomyocytes. Detailed immunohistochemical and immuno-electron microscopic analyses reveal that Fhod3 localizes not at the pointed ends of thin actin filaments but to a more peripheral zone, where thin filaments overlap with thick myosin filaments. We also demonstrate that the embryonic heart of mice specifically expresses the Fhod3 mRNA isoform harboring the three alternative exons, and that the characteristic localization of Fhod3 in the sarcomere does not require a region encoded by exon 25, in contrast to an essential role of exons 11 and 12. Furthermore, the exon 25-encoded region appears to be dispensable for actin-organizing activities both in vivo and in vitro, albeit it is inserted in the catalytic FH2 domain. PMID- 22509355 TI - Covariation in plant functional traits and soil fertility within two species-rich forests. AB - The distribution of plant species along environmental gradients is expected to be predictable based on organismal function. Plant functional trait research has shown that trait values generally vary predictably along broad-scale climatic and soil gradients. This work has also demonstrated that at any one point along these gradients there is a large amount of interspecific trait variation. The present research proposes that this variation may be explained by the local-scale sorting of traits along soil fertility and acidity axes. Specifically, we predicted that trait values associated with high resource acquisition and growth rates would be found on soils that are more fertile and less acidic. We tested the expected relationships at the species-level and quadrat-level (20 * 20 m) using two large forest plots in Panama and China that contain over 450 species combined. Predicted relationships between leaf area and wood density and soil fertility were supported in some instances, but the majority of the predicted relationships were rejected. Alternative resource axes, such as light gradients, therefore likely play a larger role in determining the interspecific variability in plant functional traits in the two forests studied. PMID- 22509356 TI - Modulation of astrocytic mitochondrial function by dichloroacetate improves survival and motor performance in inherited amyotrophic lateral sclerosis. AB - Mitochondrial dysfunction is one of the pathogenic mechanisms that lead to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). Astrocytes expressing the ALS-linked SOD1(G93A) mutation display a decreased mitochondrial respiratory capacity associated to phenotypic changes that cause them to induce motor neuron death. Astrocyte-mediated toxicity can be prevented by mitochondria-targeted antioxidants, indicating a critical role of mitochondria in the neurotoxic phenotype. However, it is presently unknown whether drugs currently used to stimulate mitochondrial metabolism can also modulate ALS progression. Here, we tested the disease-modifying effect of dichloroacetate (DCA), an orphan drug that improves the functional status of mitochondria through the stimulation of the pyruvate dehydrogenase complex activity (PDH). Applied to astrocyte cultures isolated from rats expressing the SOD1(G93A) mutation, DCA reduced phosphorylation of PDH and improved mitochondrial coupling as expressed by the respiratory control ratio (RCR). Notably, DCA completely prevented the toxicity of SOD1(G93A) astrocytes to motor neurons in coculture conditions. Chronic administration of DCA (500 mg/L) in the drinking water of mice expressing the SOD1(G93A) mutation increased survival by 2 weeks compared to untreated mice. Systemic DCA also normalized the reduced RCR value measured in lumbar spinal cord tissue of diseased SOD1(G93A) mice. A remarkable effect of DCA was the improvement of grip strength performance at the end stage of the disease, which correlated with a recovery of the neuromuscular junction area in extensor digitorum longus muscles. Systemic DCA also decreased astrocyte reactivity and prevented motor neuron loss in SOD1(G93A) mice. Taken together, our results indicate that improvement of the mitochondrial redox status by DCA leads to a disease-modifying effect, further supporting the therapeutic potential of mitochondria-targeted drugs in ALS. PMID- 22509357 TI - Combinatorial expression rules of ion channel genes in juvenile rat (Rattus norvegicus) neocortical neurons. AB - The electrical diversity of neurons arises from the expression of different combinations of ion channels. The gene expression rules governing these combinations are not known. We examined the expression of twenty-six ion channel genes in a broad range of single neocortical neuron cell types. Using expression data from a subset of twenty-six ion channel genes in ten different neocortical neuronal types, classified according to their electrophysiological properties, morphologies and anatomical positions, we first developed an incremental Support Vector Machine (iSVM) model that prioritizes the predictive value of single and combinations of genes for the rest of the expression pattern. With this approach we could predict the expression patterns for the ten neuronal types with an average 10-fold cross validation accuracy of 87% and for a further fourteen neuronal types not used in building the model, with an average accuracy of 75%. The expression of the genes for HCN4, Kv2.2, Kv3.2 and Cabeta3 were found to be particularly strong predictors of ion channel gene combinations, while expression of the Kv1.4 and Kv3.3 genes has no predictive value. Using a logic gate analysis, we then extracted a spectrum of observed combinatorial gene expression rules of twenty ion channels in different neocortical neurons. We also show that when applied to a completely random and independent data, the model could not extract any rules and that it is only possible to extract them if the data has consistent expression patterns. This novel strategy can be used for predictive reverse engineering combinatorial expression rules from single-cell data and could help identify candidate transcription regulatory processes. PMID- 22509358 TI - Environmental enrichment promotes plasticity and visual acuity recovery in adult monocular amblyopic rats. AB - Loss of visual acuity caused by abnormal visual experience during development (amblyopia) is an untreatable pathology in adults. In some occasions, amblyopic patients loose vision in their better eye owing to accidents or illnesses. While this condition is relevant both for its clinical importance and because it represents a case in which binocular interactions in the visual cortex are suppressed, it has scarcely been studied in animal models. We investigated whether exposure to environmental enrichment (EE) is effective in triggering recovery of vision in adult amblyopic rats rendered monocular by optic nerve dissection in their normal eye. By employing both electrophysiological and behavioral assessments, we found a full recovery of visual acuity in enriched rats compared to controls reared in standard conditions. Moreover, we report that EE modulates the expression of GAD67 and BDNF. The non invasive nature of EE renders this paradigm promising for amblyopia therapy in adult monocular people. PMID- 22509359 TI - Microbial activities and dissolved organic matter dynamics in oil-contaminated surface seawater from the Deepwater Horizon oil spill site. AB - The Deepwater Horizon oil spill triggered a complex cascade of microbial responses that reshaped the dynamics of heterotrophic carbon degradation and the turnover of dissolved organic carbon (DOC) in oil contaminated waters. Our results from 21-day laboratory incubations in rotating glass bottles (roller bottles) demonstrate that microbial dynamics and carbon flux in oil-contaminated surface water sampled near the spill site two weeks after the onset of the blowout were greatly affected by activities of microbes associated with macroscopic oil aggregates. Roller bottles with oil-amended water showed rapid formation of oil aggregates that were similar in size and appearance compared to oil aggregates observed in surface waters near the spill site. Oil aggregates that formed in roller bottles were densely colonized by heterotrophic bacteria, exhibiting high rates of enzymatic activity (lipase hydrolysis) indicative of oil degradation. Ambient waters surrounding aggregates also showed enhanced microbial activities not directly associated with primary oil-degradation (beta glucosidase; peptidase), as well as a twofold increase in DOC. Concurrent changes in fluorescence properties of colored dissolved organic matter (CDOM) suggest an increase in oil-derived, aromatic hydrocarbons in the DOC pool. Thus our data indicate that oil aggregates mediate, by two distinct mechanisms, the transfer of hydrocarbons to the deep sea: a microbially-derived flux of oil-derived DOC from sinking oil aggregates into the ambient water column, and rapid sedimentation of the oil aggregates themselves, serving as vehicles for oily particulate matter as well as oil aggregate-associated microbial communities. PMID- 22509360 TI - Access rate to the emergency department for venous thromboembolism in relationship with coarse and fine particulate matter air pollution. AB - Particulate matter (PM) air pollution has been associated with cardiovascular and respiratory disease. Recent studies have proposed also a link with venous thromboembolism (VTE) risk. This study was aimed to evaluate the possible influence of air pollution-related changes on the daily flux of patients referring to the Emergency Department (ED) for VTE, dissecting the different effects of coarse and fine PM. From July 1(st), 2007, to June 30(th), 2009, data about ED accesses for VTE and about daily concentrations of PM air pollution in Verona district (Italy) were collected. Coarse PM (PM(10-2.5)) was calculated by subtracting the finest PM(2.5) from the whole PM(10). During the index period a total of 302 accesses for VTE were observed (135 males and 167 females; mean age 68.3 +/- 16.7 years). In multiple regression models adjusted for other atmospheric parameters PM(10-2.5), but not PM(2.5), concentrations were positively correlated with VTE (beta-coefficient = 0.237; P = 0.020). During the days with high levels of PM(10-2.5) (>= 75(th) percentile) there was an increased risk of ED accesses for VTE (OR 1.69 with 95%CI 1.13-2.53). By analysing days of exposure using distributed lag non-linear models, the increase of VTE risk was limited to PM(10-2.5) peaks in the short-term period. Consistently with these results, in another cohort of subjects without active thrombosis (n = 102) an inverse correlation between PM(10-2.5) and prothrombin time was found (R = 0.247; P = 0.012). Our results suggest that short-time exposure to high concentrations of PM(10-2.5) may favour an increased rate of ED accesses for VTE through the induction of a prothrombotic state. PMID- 22509361 TI - Polymorphisms of -174G>C and -572G>C in the interleukin 6 (IL-6) gene and coronary heart disease risk: a meta-analysis of 27 research studies. AB - OBJECTIVE: Elevated serum IL-6 level is a risk factor for coronary heart disease (CHD). The -174 G>C and -572 G>C polymorphisms in the IL-6 gene have previously been shown to modulate IL-6 levels. But the association between the -174 G>C and 572 G>C polymorphisms and the risk of CHD is still unclear. A meta-analysis of all eligible studies was carried out to clarify the role of IL-6 gene polymorphisms in CHD. METHODS AND RESULTS: PubMed, EMBASE, Vip, CNKI and CBM-disc were searched for eligible articles in English and Chinese that were published before October 2010. 27 studies involving 11580 patients with CHD and 17103 controls were included. A meta-analysis was performed for the included articles using the RevMan 5.0 and Stata 10.0 softwares. Overall, the -174 C allele was not significantly associated with CHD risk (ORs = 1.04, 95%CI = 0.98 to 1.10) when compared with the -174 G allele in the additive model, and meta-analysis under other genetic models (dominant, recessive, CC versus GG, and GC versus GG) also did not reveal any significant association. On the contrary, the -572 C allele was associated with a decreased risk of CHD when compared with the -572 G allele (ORs = 0.79, 95%CI = 0.68 to 0.93). Furthermore, analyses under the recessive model (ORs = 0.69, 95% = 0.59 to 0.80) and the allele contrast model (genotype of CC versus GG, ORs = 0.49, 95% = 0.35 to 0.70) yielded similar results. However, statistical significance was not found when the meta-analysis was restricted to studies focusing on European populations, studies with large sample size, and cohort studies by using subgroup analysis. CONCLUSIONS: The -174 G>C polymorphism in the IL-6 gene is not significantly associated with increased risks of CHD. However, The -572 G>C polymorphism may contribute to CHD development. Future investigations with better study design and large number of subjects are needed. PMID- 22509363 TI - Miz1 is a critical repressor of cdkn1a during skin tumorigenesis. AB - The transcription factor Miz1 forms repressive DNA-binding complexes with the Myc, Gfi-1 and Bcl-6 oncoproteins. Known target genes of these complexes encode the cyclin-dependent kinase inhibitors (CKIs) cdkn2b (p15(Ink4)), cdkn1a (p21(Cip1)), and cdkn1c (p57(Kip2)). Whether Miz1-mediated repression is important for control of cell proliferation in vivo and for tumor formation is unknown. Here we show that deletion of the Miz1 POZ domain, which is critical for Miz1 function, restrains the development of skin tumors in a model of chemically induced, Ras-dependent tumorigenesis. While the stem cell compartment appears unaffected, interfollicular keratinocytes lacking functional Miz1 exhibit a reduced proliferation and an accelerated differentiation of the epidermis in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Tumorigenesis, proliferation and normal differentiation are restored in animals lacking cdkn1a, but not in those lacking cdkn2b. Our data demonstrate that Miz1 mediated attenuation of cell cycle arrest pathways via repression of cdkn1a has a critical role during tumorigenesis in the skin. PMID- 22509362 TI - Deregulation of CREB signaling pathway induced by chronic hyperglycemia downregulates NeuroD transcription. AB - CREB mediates the transcriptional effects of glucose and incretin hormones in insulin-target cells and insulin-producing beta-cells. Although the inhibition of CREB activity is known to decrease the beta-cell mass, it is still unknown what factors inversely alter the CREB signaling pathway in beta-cells. Here, we show that beta-cell dysfunctions occurring in chronic hyperglycemia are not caused by simple inhibition of CREB activity but rather by the persistent activation of CREB due to decreases in protein phophatase PP2A. When freshly isolated rat pancreatic islets were chronically exposed to 25 mM (high) glucose, the PP2A activity was reduced with a concomitant increase in active pCREB. Brief challenges with 15 mM glucose or 30 uM forskolin after 2 hour fasting further increased the level of pCREB and consequently induced the persistent expression of ICER. The excessively produced ICER was sufficient to repress the transcription of NeuroD, insulin, and SUR1 genes. In contrast, when islets were grown in 5 mM (low) glucose, CREB was transiently activated in response to glucose or forskolin stimuli. Thus, ICER expression was transient and insufficient to repress those target genes. Importantly, overexpression of PP2A reversed the adverse effects of chronic hyperglycemia and successfully restored the transient activation of CREB and ICER. Conversely, depletion of PP2A with siRNA was sufficient to disrupt the negative feedback regulation of CREB and induce hyperglycemic phenotypes even under low glucose conditions. Our findings suggest that the failure of the negative feedback regulation of CREB is the primary cause for beta-cell dysfunctions under conditions of pathogenic hyperglycemia, and PP2A can be a novel target for future therapies aiming to protect beta-cells mass in the late transitional phase of non-insulin dependent type 2 diabetes (NIDDM). PMID- 22509364 TI - Don'T fall off the adaptation cliff: when asymmetrical fitness selects for suboptimal traits. AB - The cliff-edge hypothesis introduces the counterintuitive idea that the trait value associated with the maximum of an asymmetrical fitness function is not necessarily the value that is selected for if the trait shows variability in its phenotypic expression. We develop a model of population dynamics to show that, in such a system, the evolutionary stable strategy depends on both the shape of the fitness function around its maximum and the amount of phenotypic variance. The model provides quantitative predictions of the expected trait value distribution and provides an alternative quantity that should be maximized ("genotype fitness") instead of the classical fitness function ("phenotype fitness"). We test the model's predictions on three examples: (1) litter size in guinea pigs, (2) sexual selection in damselflies, and (3) the geometry of the human lung. In all three cases, the model's predictions give a closer match to empirical data than traditional optimization theory models. Our model can be extended to most ecological situations, and the evolutionary conditions for its application are expected to be common in nature. PMID- 22509365 TI - Associations of type 2 diabetes with common variants in PPARD and the modifying effect of vitamin D among middle-aged and elderly Chinese. AB - BACKGROUND: Previous studies have identified that variants in peroxisome proliferator-activated receptor PPAR-delta (PPARD), a target gene of vitamin D, were significantly associated with fasting glucose and insulin sensitivity in European populations. This current study sought to determine (1) whether the genetic associations of PPARD variants with type 2 diabetes and its related traits could be replicated in Chinese Han population, and (2) whether the associations would be modified by the effect of vitamin D status. METHODS AND FINDINGS: We genotyped 9 tag single nucleotide polymorphisms (SNPs) that cover the gene of PPARD (rs2267664, rs6902123, rs3798343, rs2267665, rs2267668, rs2016520, rs2299869, rs1053049, and rs9658056) and tested their associations with type 2 diabetes risk and its related traits, including fasting glucose, insulin and HbA1c in 3,210 Chinese Hans. Among the 9 PPARD tag SNPs, rs6902123 was significantly associated with risk of type 2 diabetes (odds ratio 1.75 [95%CI 1.22-2.53]; P = 0.0025) and combined type 2 diabetes and impaired fasting glucose (IFG) (odds ratio 1.47 [95%CI 1.12-1.92]; P = 0.0054). The minor C allele of rs6902123 was associated with increased levels of fasting glucose (P = 0.0316) and HbA1c (P = 0.0180). In addition, we observed that vitamin D modified the effect of rs6902123 on HbA1c (P for interaction = 0.0347). CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that common variants in PPARD contribute to the risk of type 2 diabetes in Chinese Hans, and provided suggestive evidence of interaction between 25(OH)D levels and PPARD-rs6902123 on HbA1c. PMID- 22509366 TI - Very small embryonic-like stem cells purified from umbilical cord blood lack stem cell characteristics. AB - Very small embryonic-like (VSEL) cells have been described as putatively pluripotent stem cells present in murine bone marrow and human umbilical cord blood (hUCB) and as such are of high potential interest for regenerative medicine. However, there remain some questions concerning the precise identity and properties of VSEL cells, particularly those derived from hUCB. For this reason, we have carried out an extensive characterisation of purified populations of VSEL cells from a large number of UCB samples. Consistent with a previous report, we find that VSEL cells are CXCR4(+), have a high density, are indeed significantly smaller than HSC and have an extremely high nuclear/cytoplasmic ratio. Their nucleoplasm is unstructured and stains strongly with Hoechst 33342. A comprehensive FACS screen for surface markers characteristic of embryonic, mesenchymal, neuronal or hematopoietic stem cells revealed negligible expression on VSEL cells. These cells failed to expand in vitro under a wide range of culture conditions known to support embryonic or adult stem cell types and a microarray analysis revealed the transcriptional profile of VSEL cells to be clearly distinct both from well-defined populations of pluripotent and adult stem cells and from the mature hematopoietic lineages. Finally, we detected an aneuploid karyotype in the majority of purified VSEL cells by fluorescence in situ hybridisation. These data support neither an embryonic nor an adult stem cell like phenotype, suggesting rather that hUCB VSEL cells are an aberrant and inactive population that is not comparable to murine VSEL cells. PMID- 22509367 TI - Factors affecting occupational exposure to needlestick and sharps injuries among dentists in Taiwan: a nationwide survey. AB - BACKGROUND: Although the risks of needlestick and sharps injuries (NSIs) for dentists are well recognized, most papers published only described the frequency of occupational exposure to NSIs. Less has been reported assessing factors contributing to exposure to NSIs. The purpose of this study was to update the epidemiology of NSIs among dentists in Taiwan and identify factors affecting NSIs in order to find preventive strategies. METHODOLOGY/PRINCIPAL FINDINGS: A nationwide survey was conducted in dentists at 60 hospitals and 340 clinics in Taiwan. The survey included questions about factors supposedly affecting exposure to NSIs, such as dentist and facility characteristics, knowledge and attitudes about infectious diseases, and practices related to infection control. Univariate and multivariate logistic regression analyses were conducted to determine the association between risk factors and exposure to NSIs. In total, 434 (74.8%) of 580 dentists returned the survey questionnaires, and 100 (23.0%) reported that they had experienced more than one NSI per week. Our data showed that the risk of occupational NSIs is similarly heightened by an older age (odds ratio [OR], 3.18; 95% confidence interval [CI], 1.62-6.25), more years in practice (OR, 2.57; 95% CI, 1.41-4.69), working in clinics (OR, 1.73; 95% CI, 1.08-2.77), exhibiting less compliance with infection-control procedures (OR, 1.82; 95% CI, 1.04-3.18), having insufficient knowledge of blood-borne pathogens (OR, 1.67; 95% CI, 1.04 2.67), and being more worried about being infected by blood-borne pathogens (OR, 1.82; 95% CI, 1.05-3.13). CONCLUSIONS/SIGNIFICANCE: High rates of NSIs and low compliance with infection-control procedures highly contribute to the chance of acquiring a blood-borne pathogen infection and threaten occupational safety. This study reveals the possible affecting factors and helps in designing prevention strategies for occupational exposure to NSIs. PMID- 22509368 TI - Regulation of p53 stability and apoptosis by a ROR agonist. AB - Activation of p53 function leading to cell-cycle arrest and/or apoptosis is a promising strategy for development of anti-cancer therapeutic agents. Here, we describe a novel mechanism for stabilization of p53 protein expression via activation of the orphan nuclear receptor, RORalpha. We demonstrate that treatment of cancer cells with a newly described synthetic ROR agonist, SR1078, leads to p53 stabilization and induction of apoptosis. These data suggest that synthetic ROR agonists may hold utility in the treatment of cancer. PMID- 22509369 TI - Axin1 prevents Salmonella invasiveness and inflammatory response in intestinal epithelial cells. AB - BACKGROUND: Axin1 and its homolog Axin2 are scaffold proteins essential for regulating Wnt signaling. Axin-dependent regulation of Wnt is important for various developmental processes and human diseases. However, the involvement of Axin1 and Axin2 in host defense and inflammation remains to be determined. METHODS/PRINCIPAL FINDINGS: Here, we report that Axin1, but not Axin2, plays an essential role in host-pathogen interaction mediated by the Wnt pathway. Pathogenic Salmonella colonization greatly reduces the level of Axin1 in intestinal epithelial cells. This reduction is regulated at the posttranslational level in early onset of the bacterial infection. Further analysis reveals that the DIX domain and Ser614 of Axin1 are necessary for the Salmonella-mediated modulation through ubiquitination and SUMOylation. CONCLUSION/SIGNIFICANCE: Axin1 apparently has a preventive effect on bacterial invasiveness and inflammatory response during the early stages of infection. The results suggest a distinct biological function of Axin1 and Axin2 in infectious disease and intestinal inflammation while they are functionally equivalent in developmental settings. PMID- 22509370 TI - Antibiotic resistance is prevalent in an isolated cave microbiome. AB - Antibiotic resistance is a global challenge that impacts all pharmaceutically used antibiotics. The origin of the genes associated with this resistance is of significant importance to our understanding of the evolution and dissemination of antibiotic resistance in pathogens. A growing body of evidence implicates environmental organisms as reservoirs of these resistance genes; however, the role of anthropogenic use of antibiotics in the emergence of these genes is controversial. We report a screen of a sample of the culturable microbiome of Lechuguilla Cave, New Mexico, in a region of the cave that has been isolated for over 4 million years. We report that, like surface microbes, these bacteria were highly resistant to antibiotics; some strains were resistant to 14 different commercially available antibiotics. Resistance was detected to a wide range of structurally different antibiotics including daptomycin, an antibiotic of last resort in the treatment of drug resistant Gram-positive pathogens. Enzyme mediated mechanisms of resistance were also discovered for natural and semi synthetic macrolide antibiotics via glycosylation and through a kinase-mediated phosphorylation mechanism. Sequencing of the genome of one of the resistant bacteria identified a macrolide kinase encoding gene and characterization of its product revealed it to be related to a known family of kinases circulating in modern drug resistant pathogens. The implications of this study are significant to our understanding of the prevalence of resistance, even in microbiomes isolated from human use of antibiotics. This supports a growing understanding that antibiotic resistance is natural, ancient, and hard wired in the microbial pangenome. PMID- 22509371 TI - A protective role by interleukin-17F in colon tumorigenesis. AB - Interleukin-17F (IL-17F), produced by Th17 cells and other immune cells, is a member of IL-17 cytokine family with highest homology to IL-17A. IL-17F has been shown to have multiple functions in inflammatory responses. While IL-17A plays important roles in cancer development, the function of IL-17F in tumorigenesis has not yet been elucidated. In the current study, we found that IL-17F is expressed in normal human colonic epithelial cells, but this expression is greatly decreased in colon cancer tissues. To examine the roles of IL-17F in colon cancer, we have used IL-17F over-expressing colon cancer cell lines and IL 17F-deficient mice. Our data showed decreased tumor growth of IL-17F-transfected HCT116 cells comparing to mock transfectants when transplanted in nude mice. Conversely, there were increased colonic tumor numbers and tumor areas in Il-17f( /-) mice than those from wild-type controls after colon cancer induction. These results indicate that IL-17F plays an inhibitory role in colon tumorigenesis in vivo. In IL-17F over-expressing tumors, there was no significant change in leukocyte infiltration; instead, we found decreased VEGF levels and CD31(+) cells. While the VEGF levels were increased in the colon tissues of Il-17f(-/-) mice with colon cancer. Together, our findings demonstrate a protective role for IL-17F in colon cancer development, possibly via inhibiting tumor angiogenesis. PMID- 22509372 TI - Gastrin-releasing peptide signaling plays a limited and subtle role in amygdala physiology and aversive memory. AB - Links between synaptic plasticity in the lateral amygdala (LA) and Pavlovian fear learning are well established. Neuropeptides including gastrin-releasing peptide (GRP) can modulate LA function. GRP increases inhibition in the LA and mice lacking the GRP receptor (GRPR KO) show more pronounced and persistent fear after single-trial associative learning. Here, we confirmed these initial findings and examined whether they extrapolate to more aspects of amygdala physiology and to other forms of aversive associative learning. GRP application in brain slices from wildtype but not GRPR KO mice increased spontaneous inhibitory activity in LA pyramidal neurons. In amygdala slices from GRPR KO mice, GRP did not increase inhibitory activity. In comparison to wildtype, short- but not long-term plasticity was increased in the cortico-lateral amygdala (LA) pathway of GRPR KO amygdala slices, whereas no changes were detected in the thalamo-LA pathway. In addition, GRPR KO mice showed enhanced fear evoked by single-trial conditioning and reduced spontaneous firing of neurons in the central nucleus of the amygdala (CeA). Altogether, these results are consistent with a potentially important modulatory role of GRP/GRPR signaling in the amygdala. However, administration of GRP or the GRPR antagonist (D-Phe(6), Leu-NHEt(13), des-Met(14))-Bombesin (6-14) did not affect amygdala LTP in brain slices, nor did they affect the expression of conditioned fear following intra-amygdala administration. GRPR KO mice also failed to show differences in fear expression and extinction after multiple-trial fear conditioning, and there were no differences in conditioned taste aversion or gustatory neophobia. Collectively, our data indicate that GRP/GRPR signaling modulates amygdala physiology in a paradigm-specific fashion that likely is insufficient to generate therapeutic effects across amygdala-dependent disorders. PMID- 22509373 TI - Soil respiration in Tibetan alpine grasslands: belowground biomass and soil moisture, but not soil temperature, best explain the large-scale patterns. AB - The Tibetan Plateau is an essential area to study the potential feedback effects of soils to climate change due to the rapid rise in its air temperature in the past several decades and the large amounts of soil organic carbon (SOC) stocks, particularly in the permafrost. Yet it is one of the most under-investigated regions in soil respiration (Rs) studies. Here, Rs rates were measured at 42 sites in alpine grasslands (including alpine steppes and meadows) along a transect across the Tibetan Plateau during the peak growing season of 2006 and 2007 in order to test whether: (1) belowground biomass (BGB) is most closely related to spatial variation in Rs due to high root biomass density, and (2) soil temperature significantly influences spatial pattern of Rs owing to metabolic limitation from the low temperature in cold, high-altitude ecosystems. The average daily mean Rs of the alpine grasslands at peak growing season was 3.92 umol CO(2) m(-2) s(-1), ranging from 0.39 to 12.88 umol CO(2) m(-2) s(-1), with average daily mean Rs of 2.01 and 5.49 umol CO(2) m(-2) s(-1) for steppes and meadows, respectively. By regression tree analysis, BGB, aboveground biomass (AGB), SOC, soil moisture (SM), and vegetation type were selected out of 15 variables examined, as the factors influencing large-scale variation in Rs. With a structural equation modelling approach, we found only BGB and SM had direct effects on Rs, while other factors indirectly affecting Rs through BGB or SM. Most (80%) of the variation in Rs could be attributed to the difference in BGB among sites. BGB and SM together accounted for the majority (82%) of spatial patterns of Rs. Our results only support the first hypothesis, suggesting that models incorporating BGB and SM can improve Rs estimation at regional scale. PMID- 22509374 TI - LAPTM4B allele *2 is a marker of poor prognosis following hepatic tumor resection for hepatocellular carcinoma. AB - BACKGROUND: Lysosomal protein transmembrane 4 beta (LAPTM4B) is a gene related to hepatocellular carcinoma that has two alleles designated LAPTM4B*1 and LAPTM4B*2. This study aimed to investigate the correlation of LAPTM4B genotype with prognosis and clinicopathologic features in patients who have undergone resection for hepatocellular carcinoma (HCC). METHODOLOGY/PRINCIPAL FINDINGS: The LAPTM4B genotype was analyzed by PCR in 68 patients who had undergone curative hepatic resection for hepatocellular carcinoma. The correlation of LAPTM4B genotype with clinicopathologic parameters was assessed with the Chi-squared test. Differences in patient survival were determined by the Kaplan-Meier method. Multivariate analysis of prognostic factors was carried out with Cox regression analysis. Patients with LAPTM4B *2 had both significantly shorter overall survival (OS) and shorter disease-free survival (DFS) (both P<0.001). Multivariate analysis showed that LAPTM4B genotype is an independent prognostic factor for OS and DFS (both P<0.001). CONCLUSIONS/SIGNIFICANCE: Allele *2 of LAPTM4B is a risk factor associated with poor prognosis in patients with resected HCC. LAPTM4B status may be useful preoperatively as an adjunct in evaluation of the operability of HCC. PMID- 22509375 TI - Housing conditions differentially affect physiological and behavioural stress responses of zebrafish, as well as the response to anxiolytics. AB - Zebrafish are a widely utilised animal model in developmental genetics, and owing to recent advances in our understanding of zebrafish behaviour, their utility as a comparative model in behavioural neuroscience is beginning to be realised. One widely reported behavioural measure is the novel tank-diving assay, which has been often cited as a test of anxiety and stress reactivity. Despite its wide utilisation, and various validations against anxiolytic drugs, reporting of pre test housing has been sparse in the literature. As zebrafish are a shoaling species, we predicted that housing environment would affect their stress reactivity and, as such, their response in the tank-diving procedure. In our first experiment, we tested various aspects of housing (large groups, large groups with no contact, paired, visual contact only, olfactory contact only) and found that the tank diving response was mediated by visual contact with conspecifics. We also tested the basal cortisol levels of group and individually housed fish, and found that individually housed individuals have lower basal cortisol levels. In our second experiment we found ethanol appeared to have an anxiolytic effect with individually housed fish but not those that were group housed. In our final experiment, we examined the effects of changing the fishes' water prior to tank diving as an additional acclimation procedure. We found that this had no effect on individually housed fish, but appeared to affect the typical tank diving responses of the group housed individuals. In conclusion, we demonstrate that housing represents an important factor in obtaining reliable data from this methodology, and should be considered by researchers interested in comparative models of anxiety in zebrafish in order to refine their approach and to increase the power in their experiments. PMID- 22509376 TI - Detailed analysis of Japanese population substructure with a focus on the southwest islands of Japan. AB - Uncovering population structure is important for properly conducting association studies and for examining the demographic history of a population. Here, we examined the Japanese population substructure using data from the Japan Multi Institutional Collaborative Cohort (J-MICC), which covers all but the northern region of Japan. Using 222 autosomal loci from 4502 subjects, we investigated population substructure by estimating F(ST) among populations, testing population differentiation, and performing principal component analysis (PCA) and correspondence analysis (CA). All analyses revealed a low but significant differentiation between the Amami Islanders and the mainland Japanese population. Furthermore, we examined the genetic differentiation between the mainland population, Amami Islanders and Okinawa Islanders using six loci included in both the Pan-Asian SNP (PASNP) consortium data and the J-MICC data. This analysis revealed that the Amami and Okinawa Islanders were differentiated from the mainland population. In conclusion, we revealed a low but significant level of genetic differentiation between the mainland population and populations in or to the south of the Amami Islands, although genetic variation between both populations might be clinal. Therefore, the possibility of population stratification must be considered when enrolling the islander population of this area, such as in the J-MICC study. PMID- 22509377 TI - Candidate gene sequencing of SLC11A2 and TMPRSS6 in a family with severe anaemia: common SNPs, rare haplotypes, no causative mutation. AB - BACKGROUND: Iron-refractory iron deficiency anaemia (IRIDA) is a rare disorder which was linked to mutations in two genes (SLC11A2 and TMPRSS6). Common polymorphisms within these genes were associated with serum iron levels. We identified a family of Serbian origin with asymptomatic non-consanguineous parents with three of four children presenting with IRIDA not responding to oral but to intravenous iron supplementation. After excluding all known causes responsible for iron deficiency anaemia we searched for mutations in SLC11A2 and TMPRSS6 that could explain the severe anaemia in these children. METHODOLOGY/RESULTS: We sequenced the exons and exon-intron boundaries of SLC11A2 and TMPRSS6 in all six family members. Thereby, we found seven known and fairly common SNPs, but no new mutation. We then genotyped these seven SNPs in the population-based SAPHIR study (n = 1,726) and performed genetic association analysis on iron and ferritin levels. Only two SNPs, which were top-hits from recent GWAS on iron and ferritin, exhibited an effect on iron and ferritin levels in SAPHIR. Six SAPHIR participants carrying the same TMPRSS6 genotypes and haplotype-pairs as one anaemic son showed lower ferritin and iron levels than the average. One individual exhibiting the joint SLC11A2/TMPRSS6 profile of the anaemic son had iron and ferritin levels lying below the 5(th) percentile of the population's iron and ferritin level distribution. We then checked the genotype constellations in the Nijmegen Biomedical Study (n = 1,832), but the profile of the anaemic son did not occur in this population. CONCLUSIONS: We cannot exclude a gene-gene interaction between SLC11A2 and TMPRSS6, but we can also not confirm it. As in this case candidate gene sequencing did not reveal causative rare mutations, the samples will be subjected to whole exome sequencing. PMID- 22509378 TI - A genome-wide association study of female sexual dysfunction. AB - BACKGROUND: Female sexual dysfunction (FSD) is an important but controversial problem with serious negative impact on women's quality of life. Data from twin studies have shown a genetic contribution to the development and maintenance of FSD. METHODOLOGY/PRINCIPAL FINDINGS: We performed a genome-wide association study (GWAS) on 2.5 million single-nucleotide polymorphisms (SNPs) in 1,104 female twins (25-81 years of age) in a population-based register and phenotypic data on lifelong sexual functioning. Although none reached conventional genome-wide level of significance (10 * -8), we found strongly suggestive associations with the phenotypic dimension of arousal (rs13202860, P = 1.2 * 10(-7); rs1876525, P = 1.2 * 10(-7); and rs13209281 P = 8.3 * 10(-7)) on chromosome 6, around 500 kb upstream of the locus HTR1E (5-hydroxytryptamine receptor 1E) locus, related to the serotonin brain pathways. We could not replicate previously reported candidate SNPs associated with FSD in the DRD4, 5HT2A and IL-1B loci. CONCLUSIONS/SIGNIFICANCE: We report the first GWAS of FSD symptoms in humans. This has pointed to several "risk alleles" and the implication of the serotonin and GABA pathways. Ultimately, understanding key mechanisms via this research may lead to new FSD treatments and inform clinical practice and developments in psychiatric nosology. PMID- 22509379 TI - Gender based within-household inequality in childhood immunization in India: changes over time and across regions. AB - BACKGROUND AND OBJECTIVES: Despite India's substantial economic growth in the past two decades, girls in India are discriminated against in access to preventive healthcare including immunizations. Surprisingly, no study has assessed the contribution of gender based within-household discrimination to the overall inequality in immunization status of Indian children. This study therefore has two objectives: to estimate the gender based within-household inequality (GWHI) in immunization status of Indian children and to examine the inter-regional and inter-temporal variations in the GWHI. DATA AND METHODS: The present study used households with a pair of male-female siblings (aged 1-5 years) from two rounds of National Family Health Survey (NFHS, 1992-93 and 2005 06). The overall inequality in the immunization status (after controlling for age and birth order) of children was decomposed into within-households and between households components using Mean log deviation to obtain the GWHI component. The analysis was conducted at the all-India level as well as for six specified geographical regions and at two time points (1992-93 and 2005-06). Household fixed-effects models for immunization status of children were also estimated. RESULTS AND CONCLUSIONS: Findings from household fixed effects analysis indicated that the immunization scores of girls were significantly lower than that of boys. The inequality decompositions revealed that, at the all-India level, the absolute level of GWHI in immunization status decreased from 0.035 in 1992-93 to 0.023 in 2005-06. However, as a percentage of total inequality, it increased marginally (15.5% to 16.5%). In absolute terms, GWHI decreased in all the regions except in the North-East. But, as a percentage of total inequality it increased in the North-Eastern, Western and Southern regions. The main conclusions are the following: GWHI contributes substantially to the overall inequality in immunization status of Indian children; and though the overall inequality in immunization status declined in all the regions, the changes in GWHI were mixed. PMID- 22509380 TI - Cellular cytoskeleton dynamics modulates non-viral gene delivery through RhoGTPases. AB - Although it is well accepted that the constituents of the cellular microenvironment modulate a myriad of cellular processes, including cell morphology, cytoskeletal dynamics and uptake pathways, the underlying mechanism of how these pathways influence non-viral gene transfer have not been studied. Transgene expression is increased on fibronectin (Fn) coated surfaces as a consequence of increased proliferation, cell spreading and active engagement of clathrin endocytosis pathway. RhoGTPases mediate the crosstalk between the cell and Fn, and regulate cellular processes involving filamentous actin, in-response to cellular interaction with Fn. Here the role of RhoGTPases specifically Rho, Rac and Cdc42 in modulation of non-viral gene transfer in mouse mesenchymal stem (mMSCs) plated in a fibronectin microenvironment was studied. More than 90% decrease in transgene expression was observed after inactivation of RhoGTPases using difficile toxin B (TcdB) and C3 transferase. Expression of dominant negative RhoA (RhoAT19N), Rac1(Rac1T17N) and Cdc42 (Cdc42T17N) also significantly reduced polyplex uptake and transgene expression. Interactions of cells with Fn lead to activation of RhoGTPases. However, further activation of RhoA, Rac1 and Cdc42 by expression of constitutively active genes (RhoAQ63L, Rac1Q61L and Cdc42Q61L) did not further enhance transgene expression in mMSCs, when plated on Fn. In contrast, activation of RhoA, Rac1 and Cdc42 by expression of constitutively active genes for cells plated on collagen I, which by itself did not increase RhoGTPase activation, resulted in enhanced transgene expression. Our study shows that RhoGTPases regulate internalization and effective intracellular processing of polyplexes that results in efficient gene transfer. PMID- 22509381 TI - NEDD9 stabilizes focal adhesions, increases binding to the extra-cellular matrix and differentially effects 2D versus 3D cell migration. AB - The speed of cell migration on 2-dimensional (2D) surfaces is determined by the rate of assembly and disassembly of clustered integrin receptors known as focal adhesions. Different modes of cell migration that have been described in 3D environments are distinguished by their dependence on integrin-mediated interactions with the extra-cellular matrix. In particular, the mesenchymal invasion mode is the most dependent on focal adhesion dynamics. The focal adhesion protein NEDD9 is a key signalling intermediary in mesenchymal cell migration, however whether NEDD9 plays a role in regulating focal adhesion dynamics has not previously been reported. As NEDD9 effects on 2D migration speed appear to depend on the cell type examined, in the present study we have used mouse embryo fibroblasts (MEFs) from mice in which the NEDD9 gene has been depleted (NEDD9 -/- MEFs). This allows comparison with effects of other focal adhesion proteins that have previously been demonstrated using MEFs. We show that focal adhesion disassembly rates are increased in the absence of NEDD9 expression and this is correlated with increased paxillin phosphorylation at focal adhesions. NEDD9-/- MEFs have increased rates of migration on 2D surfaces, but conversely, migration of these cells is significantly reduced in 3D collagen gels. Importantly we show that myosin light chain kinase is activated in 3D in the absence of NEDD9 and is conversely inhibited in 2D cultures. Measurement of adhesion strength reveals that NEDD9-/- MEFs have decreased adhesion to fibronectin, despite upregulated alpha5beta1 fibronectin receptor expression. We find that beta1 integrin activation is significantly suppressed in the NEDD9-/-, suggesting that in the absence of NEDD9 there is decreased integrin receptor activation. Collectively our data suggest that NEDD9 may promote 3D cell migration by slowing focal adhesion disassembly, promoting integrin receptor activation and increasing adhesion force to the ECM. PMID- 22509382 TI - Surfactant protein d deficiency in mice is associated with hyperphagia, altered fat deposition, insulin resistance, and increased basal endotoxemia. AB - Pulmonary surfactant protein D (SP-D) is a host defence lectin of the innate immune system that enhances clearance of pathogens and modulates inflammatory responses. Recently it has been found that systemic SP-D is associated with metabolic disturbances and that SP-D deficient mice are mildly obese. However, the mechanism behind SP-D's role in energy metabolism is not known.Here we report that SP-D deficient mice had significantly higher ad libitum energy intake compared to wild-type mice and unchanged energy expenditure. This resulted in accumulation but also redistribution of fat tissue. Blood pressure was unchanged. The change in energy intake was unrelated to the basal levels of hypothalamic Pro opiomelanocortin (POMC) and Agouti-related peptide (AgRP) gene expression. Neither short time systemic, nor intracereberoventricular SP-D treatment altered the hypothalamic signalling or body weight accumulation.In ad libitum fed animals, serum leptin, insulin, and glucose were significantly increased in mice deficient in SP-D, and indicative of insulin resistance. However, restricted diets eliminated all metabolic differences except the distribution of body fat. SP-D deficiency was further associated with elevated levels of systemic bacterial lipopolysaccharide.In conclusion, our findings suggest that lack of SP-D mediates modulation of food intake not directly involving hypothalamic regulatory pathways. The resulting accumulation of adipose tissue was associated with insulin resistance. The data suggest SP-D as a regulator of energy intake and body composition and an inhibitor of metabolic endotoxemia. SP-D may play a causal role at the crossroads of inflammation, obesity, and insulin resistance. PMID- 22509383 TI - Behavioral and neuronal investigations of hypervigilance in patients with fibromyalgia syndrome. AB - Painful stimuli are of utmost behavioral relevance and thereby affect attentional resources. In health, variable effects of pain on attention have been observed, indicating alerting as well as distracting effects of pain. In the human brain, these effects are closely related to modulations of neuronal gamma oscillations. As hypervigilance as an abnormal increase of attention to external stimuli has been implicated in chronic pain states, we assumed both attentional performance and pain-induced gamma oscillations to be altered in patients with fibromyalgia syndrome (FMS). We recorded electroencephalography from healthy subjects (n = 22) and patients with FMS (n = 19) during an attention demanding visual reaction time task. In 50% of the trials we applied painful laser stimuli. The results of self assessment questionnaires confirm that patients with FMS consider themselves hypervigilant towards pain as compared to healthy controls. However, the experimental findings indicate that the effects of painful stimuli on attentional performance and neuronal gamma oscillations do not differ between patients and healthy subjects. We further found a significant correlation between the pain induced modulation of visual gamma oscillations and the pain-induced modulation of reaction times. This relationship did not differ between groups either. These findings confirm a close relationship between gamma oscillations and the variable attentional effects of pain, which appear to be comparable in health and disease. Thus, our results do not provide evidence for a behavioral or neuronal manifestation of hypervigilance in patients with FMS. PMID- 22509384 TI - Effects of NFKB1 and NFKBIA gene polymorphisms on susceptibility to environmental factors and the clinicopathologic development of oral cancer. AB - BACKGROUND: Oral cancer, which is the fourth most common cancer in Taiwanese men, is associated with environmental carcinogens. The possibility that genetic predisposition in nuclear factor-kappa B (NF-kappaB)-signaling pathways activation is linked to the development of oral squamous cell carcinoma (OSCC) requires investigation. The current study examines associations between polymorphisms within promoter regions of NFKB1 encoding NF-kappaB1 and NFKBIA encoding IkappaBalpha (IkappaBalpha) with both the susceptibility to develop OSCC and the clinicopathological characteristics of the tumors. METHODOLOGY/PRINCIPAL FINDINGS: Genetic polymorphisms of NFKB1 and NFKBIA were analyzed by a real-time polymerase chain reaction (real-time PCR) for 462 patients with oral cancer and 520 non-cancer controls. We found that NFKB1 -94 ATGG1/ATGG2, -94 ATGG2/ATGG2, and the combination of -94 ATGG1/ATGG2 and ATGG2/ATGG2 genotypes NFKBIA -826 T (CT+TT) and -881 G (AG+GG) allelic carriages, were more prevalent in OSCC patients than in non-cancer participants. Moreover, we found that NFKB1 or NFKBIA gene polymorphisms seem to be related to susceptibility to develop oral cancer linked to betel nut and tobacco consumption. Finally, patients with oral cancer who had at least one -519 T allele of the NFKBIA gene were at higher risk for developing distant metastasis (P<.05), compared with those patients CC homozygotes. CONCLUSIONS: Our results suggest that NFKB1 -94 ATTG2, NFKBIA -826 T, and -881 G alleles are associated with oral carcinogenesis. The combination of NFKB1 or NFKBIA gene polymorphisms and environmental carcinogens appears related to an increased risk of oral cancer. More importantly, the genetic polymorphism of NFKBIA -519 might be a predictive factor for the distal metastasis of OSCC in Taiwanese. PMID- 22509385 TI - Mixed adjuvant formulations reveal a new combination that elicit antibody response comparable to Freund's adjuvants. AB - Adjuvant formulations capable of inducing high titer and high affinity antibody responses would provide a major advance in the development of vaccines to viral infections such as HIV-1. Although oil-in-water emulsions, such as Freund's adjuvant (FCA/FIA), are known to be potent, their toxicity and reactogenicity make them unacceptable for human use. Here, we explored different adjuvants and compared their ability to elicit antibody responses to FCA/FIA. Recombinant soluble trimeric HIV-1 gp140 antigen was formulated in different adjuvants, including FCA/FIA, Carbopol-971P, Carbopol-974P and the licensed adjuvant MF59, or combinations of MF59 and Carbopol. The antigen-adjuvant formulation was administered in a prime-boost regimen into rabbits, and elicitation of antigen binding and neutralizing antibodies (nAbs) was evaluated. When used individually, only FCA/FIA elicited significantly higher titer of nAbs than the control group (gp140 in PBS (p<0.05)). Sequential prime-boost immunizations with different adjuvants did not offer improvements over the use of FCA/FIA or MF59. Remarkably however, the concurrent use of the combination of Carbopol-971P and MF59 induced potent adjuvant activity with significantly higher titer nAbs than FCA/FIA (p<0.05). This combination was not associated with any obvious local or systemic adverse effects. Antibody competition indicated that the majority of the neutralizing activities were directed to the CD4 binding site (CD4bs). Increased antibody titers to the gp41 membrane proximal external region (MPER) and gp120 V3 were detected when the more potent adjuvants were used. These data reveal that the combination of Carbopol-971P and MF59 is unusually potent for eliciting nAbs to a variety of HIV-1 nAb epitopes. PMID- 22509386 TI - Proinsulin atypical maturation and disposal induces extensive defects in mouse Ins2+/Akita beta-cells. AB - Because of its low relative folding rate and plentiful manufacture in beta-cells, proinsulin maintains a homeostatic balance of natively and plentiful non-natively folded states (i.e., proinsulin homeostasis, PIHO) through the integration of maturation and disposal processes. PIHO is susceptible to genetic and environmental influences, and its disorder has been critically linked to defects in beta-cells in diabetes. To explore this hypothesis, we performed polymerase chain reaction (PCR), metabolic-labeling, immunoblotting, and histological studies to clarify what defects result from primary disorder of PIHO in model Ins2(+/Akita) beta-cells. We used T antigen-transformed Ins2(+/Akita) and control Ins2(+/+) beta-cells established from Akita and wild-type littermate mice. In Ins2(+/Akita) beta-cells, we found no apparent defect at the transcriptional and translational levels to contribute to reduced cellular content of insulin and its precursor and secreted insulin. Glucose response remained normal in proinsulin biosynthesis but was impaired for insulin secretion. The size and number of mature insulin granules were reduced, but the size/number of endoplasmic reticulum, Golgi, mitochondrion, and lysosome organelles and vacuoles were expanded/increased. Moreover, cell death increased, and severe oxidative stress, which manifested as increased reactive oxygen species, thioredoxin-interacting protein, and protein tyrosine nitration, occurred in Ins2(+/Akita) beta-cells and/or islets. These data show the first clear evidence that primary PIHO imbalance induces severe oxidative stress and impairs glucose-stimulated insulin release and beta-cell survival as well as producing other toxic consequences. The defects disclosed/clarified in model Ins2(+/Akita) beta-cells further support a role of the genetic and stress-susceptible PIHO disorder in beta-cell failure and diabetes. PMID- 22509387 TI - Cloning and characterization of genes involved in nostoxanthin biosynthesis of Sphingomonas elodea ATCC 31461. AB - Most Sphingomonas species synthesize the yellow carotenoid nostoxanthin. However, the carotenoid biosynthetic pathway of these species remains unclear. In this study, we cloned and characterized a carotenoid biosynthesis gene cluster containing four carotenogenic genes (crtG, crtY, crtI and crtB) and a beta carotene hydroxylase gene (crtZ) located outside the cluster, from the gellan-gum producing bacterium Sphingomonas elodea ATCC 31461. Each of these genes was inactivated, and the biochemical function of each gene was confirmed based on chromatographic and spectroscopic analysis of the intermediates accumulated in the knockout mutants. Moreover, the crtG gene encoding the 2,2'-beta-hydroxylase and the crtZ gene encoding the beta-carotene hydroxylase, both responsible for hydroxylation of beta-carotene, were confirmed by complementation studies using Escherichia coli producing different carotenoids. Expression of crtG in zeaxanthin and beta-carotene accumulating E. coli cells resulted in the formation of nostoxanthin and 2,2'-dihydroxy-beta-carotene, respectively. Based on these results, a biochemical pathway for synthesis of nostoxanthin in S. elodea ATCC 31461 is proposed. PMID- 22509388 TI - Fossil fishes from china provide first evidence of dermal pelvic girdles in osteichthyans. AB - BACKGROUND: The pectoral and pelvic girdles support paired fins and limbs, and have transformed significantly in the diversification of gnathostomes or jawed vertebrates (including osteichthyans, chondrichthyans, acanthodians and placoderms). For instance, changes in the pectoral and pelvic girdles accompanied the transition of fins to limbs as some osteichthyans (a clade that contains the vast majority of vertebrates--bony fishes and tetrapods) ventured from aquatic to terrestrial environments. The fossil record shows that the pectoral girdles of early osteichthyans (e.g., Lophosteus, Andreolepis, Psarolepis and Guiyu) retained part of the primitive gnathostome pectoral girdle condition with spines and/or other dermal components. However, very little is known about the condition of the pelvic girdle in the earliest osteichthyans. Living osteichthyans, like chondrichthyans (cartilaginous fishes), have exclusively endoskeletal pelvic girdles, while dermal pelvic girdle components (plates and/or spines) have so far been found only in some extinct placoderms and acanthodians. Consequently, whether the pectoral and pelvic girdles are primitively similar in osteichthyans cannot be adequately evaluated, and phylogeny-based inferences regarding the primitive pelvic girdle condition in osteichthyans cannot be tested against available fossil evidence. METHODOLOGY/PRINCIPAL FINDINGS: Here we report the first discovery of spine-bearing dermal pelvic girdles in early osteichthyans, based on a new articulated specimen of Guiyu oneiros from the Late Ludlow (Silurian) Kuanti Formation, Yunnan, as well as a re-examination of the previously described holotype. We also describe disarticulated pelvic girdles of Psarolepis romeri from the Lochkovian (Early Devonian) Xitun Formation, Yunnan, which resemble the previously reported pectoral girdles in having integrated dermal and endoskeletal components with polybasal fin articulation. CONCLUSIONS/SIGNIFICANCE: The new findings reveal hitherto unknown similarity in pectoral and pelvic girdles among early osteichthyans, and provide critical information for studying the evolution of pelvic girdles in osteichthyans and other gnathostomes. PMID- 22509389 TI - Spontaneous eosinophilic nasal inflammation in a genetically-mutant mouse: comparative study with an allergic inflammation model. AB - BACKGROUND: Eosinophilic inflammation is a hallmark of chronic rhinosinusitis with nasal polyps. To model this disease process experimentally, nasal sensitization of mice with ovalbumin or aspergillus has been described. Here, we describe a genetically mutant mouse that develops robust spontaneous nasal eosinophilic inflammation. These mice lack the enzyme SHP-1 that down-regulates the IL-4Ralpha/stat6 signaling pathway. We compared nasal inflammation and inflammatory mediators in SHP-1 deficient mice (mev) and an ovalbumin-induced nasal allergy model. METHODS: A novel technique of trans-pharyngeal nasal lavage was developed to obtain samples of inflammatory cells from the nasal passages of allergic and mev mice. Total and differential cell counts were performed on cytospin preparations. Expression of tissue mRNA for IL-4, IL-13, and mouse beta defensin-1 (MBD-1) was determined by quantitative PCR. Eotaxin in the lavage fluid was assessed by ELISA. RESULTS: Allergic and mev mice had increased total cells and eosinophils compared with controls. Expression of IL-4 was similarly increased in both allergic and mev mice, but expression of IL-13 and eotaxin was significantly greater in the allergic mice than mev mice. Eotaxin was significantly up-regulated in both allergic rhinitis and mev mice. In both models of eosinophilic inflammation, down-regulation of the innate immune marker MBD-1 was observed. CONCLUSIONS: The mev mice display spontaneous chronic nasal eosinophilic inflammation with potential utility for chronic rhinosinusitis with nasal polyps research. The eosinophilic infiltrate is more robust in the mev mice than allergic mice, but Th2 cytokine expression is not as pronounced. Decreased MBD-1 expression in both models supports the concept that Th2-cytokines down regulate sinonasal innate immunity in humans, and suggests a role for mouse models in investigating the interaction between adaptive and innate immunity in the sinonasal mucosa. PMID- 22509390 TI - Regulation of progranulin expression in human microglia and proteolysis of progranulin by matrix metalloproteinase-12 (MMP-12). AB - BACKGROUND: The essential role of progranulin (PGRN) as a neurotrophic factor has been demonstrated by the discovery that haploinsufficiency due to GRN gene mutations causes frontotemporal lobar dementia. In addition to neurons, microglia in vivo express PGRN, but little is known about the regulation of PGRN expression by microglia. GOAL: In the current study, we examined the regulation of expression and function of PGRN, its proteolytic enzyme macrophage elastase (MMP 12), as well as the inhibitor of PGRN proteolysis, secretory leukocyte protease inhibitor (SLPI), in human CNS cells. METHODS: Cultures of primary human microglia and astrocytes were stimulated with the TLR ligands (LPS or poly IC), Th1 cytokines (IL-1/IFNgamma), or Th2 cytokines (IL-4, IL-13). Results were analyzed by Q-PCR, immunoblotting or ELISA. The roles of MMP-12 and SLPI in PGRN cleavage were also examined. RESULTS: Unstimulated microglia produced nanogram levels of PGRN, and PGRN release from microglia was suppressed by the TLR ligands or IL-1/IFNgamma, but increased by IL-4 or IL-13. Unexpectedly, while astrocytes stimulated with proinflammatory factors released large amounts of SLPI, none were detected in microglial cultures. We also identified MMP-12 as a PGRN proteolytic enzyme, and SLPI as an inhibitor of MMP-12-induced PGRN proteolysis. Experiments employing PGRN siRNA demonstrated that microglial PGRN was involved in the cytokine and chemokine production following TLR3/4 activation, with its effect on TNFalpha being the most conspicuous. CONCLUSIONS: Our study is the first detailed examination of PGRN in human microglia. Our results establish microglia as a significant source of PGRN, and MMP-12 and SLPI as modulators of PGRN proteolysis. Negative and positive regulation of microglial PGRN release by the proinflammatory/Th1 and the Th2 stimuli, respectively, suggests a fundamentally different aspect of PGRN regulation compared to other known microglial activation products. Microglial PGRN appears to function as an endogenous modulator of innate immune responses. PMID- 22509391 TI - Revised selection criteria for candidate restriction enzymes in genome walking. AB - A new method to improve the efficiency of flanking sequence identification by genome walking was developed based on an expanded, sequential list of criteria for selecting candidate enzymes, plus several other optimization steps. These criteria include: step (1) initially choosing the most appropriate restriction enzyme according to the average fragment size produced by each enzyme determined using in silico digestion of genomic DNA, step (2) evaluating the in silico frequency of fragment size distribution between individual chromosomes, step (3) selecting those enzymes that generate fragments with the majority between 100 bp and 3,000 bp, step (4) weighing the advantages and disadvantages of blunt-end sites vs. cohesive-end sites, step (5) elimination of methylation sensitive enzymes with methylation-insensitive isoschizomers, and step (6) elimination of enzymes with recognition sites within the binary vector sequence (T-DNA and plasmid backbone). Step (7) includes the selection of a second restriction enzyme with highest number of recognition sites within regions not covered by the first restriction enzyme. Step (8) considers primer and adapter sequence optimization, selecting the best adapter-primer pairs according to their hairpin/dimers and secondary structure. In step (9), the efficiency of genomic library development was improved by column-filtration of digested DNA to remove restriction enzyme and phosphatase enzyme, and most important, to remove small genomic fragments (<100 bp) lacking the T-DNA insertion, hence improving the chance of ligation between adapters and fragments harbouring a T-DNA. Two enzymes, NsiI and NdeI, fit these criteria for the Arabidopsis thaliana genome. Their efficiency was assessed using 54 T(3) lines from an Arabidopsis SK enhancer population. Over 70% success rate was achieved in amplifying the flanking sequences of these lines. This strategy was also tested with Brachypodium distachyon to demonstrate its applicability to other larger genomes. PMID- 22509392 TI - Terrestrialization, miniaturization and rates of diversification in African puddle frogs (Anura: Phrynobatrachidae). AB - Terrestrialization, the evolution of non-aquatic oviposition, and miniaturization, the evolution of tiny adult body size, are recurring trends in amphibian evolution, but the relationships among the traits that characterize these phenomena are not well understood. Furthermore, these traits have been identified as possible "key innovations" that are predicted to increase rates of speciation in those lineages in which they evolve. We examine terrestrialization and miniaturization in sub-Saharan puddle frogs (Phrynobatrachidae) in a phylogenetic context to investigate the relationship between adaptation and diversification through time. We use relative dating techniques to ascertain if character trait shifts are associated with increased diversification rates, and we evaluate the likelihood that a single temporal event can explain the evolution of those traits. Results indicate alternate reproductive modes evolved independently in Phrynobatrachus at least seven times, including terrestrial deposition of eggs and terrestrial, non-feeding larvae. These shifts towards alternate reproductive modes are not linked to a common temporal event. Contrary to the "key innovations" hypothesis, clades that exhibit alternate reproductive modes have lower diversification rates than those that deposit eggs aquatically. Adult habitat, pedal webbing and body size have no effect on diversification rates. Though these traits putatively identified as key innovations for Phrynobatrachus do not seem to be associated with increased speciation rates, they may still provide opportunities to extend into new niches, thus increasing overall diversity. PMID- 22509393 TI - Linking hydrogen (delta2H) isotopes in feathers and precipitation: sources of variance and consequences for assignment to isoscapes. AB - BACKGROUND: Tracking small migrant organisms worldwide has been hampered by technological and recovery limitations and sampling bias inherent in exogenous markers. Naturally occurring stable isotopes of H (delta(2)H) in feathers provide an alternative intrinsic marker of animal origin due to the predictable spatial linkage to underlying hydrologically driven flow of H isotopes into foodwebs. This approach can assess the likelihood that a migrant animal originated from a given location(s) within a continent but requires a robust algorithm linking H isotopes in tissues of interest to an appropriate hydrological isotopic spatio temporal pattern, such as weighted-annual rainfall. However, a number of factors contribute to or alter expected isotopic patterns in animals. We present results of an extensive investigation into taxonomic and environmental factors influencing feather delta(2)H patterns across North America. PRINCIPAL FINDINGS: Stable isotope data were measured from 544 feathers from 40 species and 140 known locations. For delta(2)H, the most parsimonious model explaining 83% of the isotopic variance was found with amount-weighted growing-season precipitation delta(2)H, foraging substrate and migratory strategy. CONCLUSIONS/SIGNIFICANCE: This extensive H isotopic analysis of known-origin feathers of songbirds in North America and elsewhere reconfirmed the strong coupling between tissue delta(2)H and global hydrologic delta(2)H patterns, and accounting for variance associated with foraging substrate and migratory strategy, can be used in conservation and research for the purpose of assigning birds and other species to their approximate origin. PMID- 22509394 TI - Plant 45S rDNA clusters are fragile sites and their instability is associated with epigenetic alterations. AB - Our previous study demonstrated that 45S ribosomal DNA (45S rDNA) clusters were chromosome fragile sites expressed spontaneously in Lolium. In this study, fragile phenotypes of 45S rDNA were observed under aphidicolin (APH) incubation in several plant species. Further actinomycin D (ActD) treatment showed that transcriptional stress might interfere with chromatin packaging, resulting in 45S rDNA fragile expression. These data identified 45S rDNA sites as replication dependent as well as transcription-dependent fragile sites in plants. In the presence of ActD, a dramatic switch to an open chromatin conformation and accumulated incomplete 5' end of the external transcribed spacer (5'ETS) transcripts were observed, accompanied by decreased DNA methylation, decreased levels of histone H3, and increased histone acetylation and levels of H3K4me2, suggesting that these epigenetic alterations are associated with failure of 45S rDNA condensation. Furthermore, the finding that gamma-H2AX was accumulated at 45S rDNA sites following ActD treatment suggested that the DNA damage signaling pathway was associated with the appearance of 45S rDNA fragile phenotypes. Our data provide a link between 45S rDNA transcription and chromatin-packaging defects and open the door for further identifying the molecular mechanism involved. PMID- 22509395 TI - Tumor-targeted delivery of IL-2 by NKG2D leads to accumulation of antigen specific CD8+ T cells in the tumor loci and enhanced anti-tumor effects. AB - Interleukin-2 (IL-2) has been shown to promote tumor-specific T-cell proliferation and differentiation but systemic administration of IL-2 results in significant toxicity. Therefore, a strategy that can specifically deliver IL-2 to the tumor location may alleviate concerns of toxicity. Because NKG2D ligands have been shown to be highly expressed in many cancer cells but not in healthy cells, we reason that a chimeric protein consisting of NKG2D linked to IL-2 will lead to the specific targeting of IL-2 to the tumor location. Therefore, we created chimeric proteins consisting of NKG2D linked to Gaussia luciferase (GLuc; a marker protein) or IL-2 to form NKG2D-Fc-GLuc and NKG2D-Fc-IL2, respectively. We demonstrated that NKG2D linked to GLuc was able to deliver GLuc to the tumor location in vivo. Furthermore, we showed that TC-1 tumor-bearing mice intramuscularly injected with DNA encoding NKG2D-Fc-IL2, followed by electroporation, exhibited an increased number of luciferase-expressing E7 specific CD8+ T cells at the tumor location. More importantly, treatment with the DNA construct encoding NKG2D-Fc-IL2 significantly enhanced the therapeutic anti tumor effects generated by intradermal vaccination with therapeutic HPV DNA in tumor-bearing mice. Therefore, by linking NKG2D to IL2, we are able to specifically deliver IL-2 to the tumor location, enhancing antigen-specific T cell immune response and controlling tumor growth. Our approach represents a platform technology to specifically deliver proteins of interest to tumor loci. PMID- 22509396 TI - Prostate cancer-specific and potent antitumor effect of a DD3-controlled oncolytic virus harboring the PTEN gene. AB - Prostate cancer is a major health problem for men in Western societies. Here we report a Prostate Cancer-Specific Targeting Gene-Viro-Therapy (CTGVT-PCa), in which PTEN was inserted into a DD3-controlled oncolytic viral vector (OV) to form Ad.DD3.E1A.E1B(Delta55)-(PTEN) or, briefly, Ad.DD3.D55-PTEN. The woodchuck post transcriptional element (WPRE) was also introduced at the downstream of the E1A coding sequence, resulting in much higher expression of the E1A gene. DD3 is one of the most prostate cancer-specific genes and has been used as a clinical bio diagnostic marker. PTEN is frequently inactivated in primary prostate cancers, which is crucial for prostate cancer progression. Therefore, the Ad.DD3.D55-PTEN has prostate cancer specific and potent antitumor effect. The tumor growth rate was almost completely inhibited with the final tumor volume after Ad.DD3.D55-PTEN treatment less than the initial volume at the beginning of Ad.DD3.D55-PTEN treatment, which shows the powerful antitumor effect of Ad.DD3.D55-PTEN on prostate cancer tumor growth. The CTGVT-PCa construct reported here killed all of the prostate cancer cell lines tested, such as DU145, 22RV1 and CL1, but had a reduced or no killing effect on all the non-prostate cancer cell lines tested. The mechanism of action of Ad.DD3.D55-PTEN was due to the induction of apoptosis, as detected by TUNEL assays and flow cytometry. The apoptosis was mediated by mitochondria-dependent and -independent pathways, as determined by caspase assays and mitochondrial membrane potential. PMID- 22509397 TI - Protein signature of lung cancer tissues. AB - Lung cancer remains the most common cause of cancer-related mortality. We applied a highly multiplexed proteomic technology (SOMAscan) to compare protein expression signatures of non small-cell lung cancer (NSCLC) tissues with healthy adjacent and distant tissues from surgical resections. In this first report of SOMAscan applied to tissues, we highlight 36 proteins that exhibit the largest expression differences between matched tumor and non-tumor tissues. The concentrations of twenty proteins increased and sixteen decreased in tumor tissue, thirteen of which are novel for NSCLC. NSCLC tissue biomarkers identified here overlap with a core set identified in a large serum-based NSCLC study with SOMAscan. We show that large-scale comparative analysis of protein expression can be used to develop novel histochemical probes. As expected, relative differences in protein expression are greater in tissues than in serum. The combined results from tissue and serum present the most extensive view to date of the complex changes in NSCLC protein expression and provide important implications for diagnosis and treatment. PMID- 22509399 TI - Terminal investment: individual reproduction of ant queens increases with age. AB - The pattern of age-specific fecundity is a key component of the life history of organisms and shapes their ecology and evolution. In numerous animals, including humans, reproductive performance decreases with age. Here, we demonstrate that some social insect queens exhibit the opposite pattern. Egg laying rates of Cardiocondyla obscurior ant queens increased with age until death, even when the number of workers caring for them was kept constant. Cardiocondyla, and probably also other ants, therefore resemble the few select organisms with similar age specific reproductive investment, such as corals, sturgeons, or box turtles (e.g., [1]), but they differ in being more short-lived and lacking individual, though not social, indeterminate growth. Furthermore, in contrast to most other organisms, in which average life span declines with increasing reproductive effort, queens with high egg laying rates survived as long as less fecund queens. PMID- 22509398 TI - Specific in vivo staining of astrocytes in the whole brain after intravenous injection of sulforhodamine dyes. AB - Fluorescent staining of astrocytes without damaging or interfering with normal brain functions is essential for intravital microscopy studies. Current methods involved either transgenic mice or local intracerebral injection of sulforhodamine 101. Transgenic rat models rarely exist, and in mice, a backcross with GFAP transgenic mice may be difficult. Local injections of fluorescent dyes are invasive. Here, we propose a non-invasive, specific and ubiquitous method to stain astrocytes in vivo. This method is based on iv injection of sulforhodamine dyes and is applicable on rats and mice from postnatal age to adulthood. The astrocytes staining obtained after iv injection was maintained for nearly half a day and showed no adverse reaction on astrocytic calcium signals or electroencephalographic recordings in vivo. The high contrast of the staining facilitates the image processing and allows to quantify 3D morphological parameters of the astrocytes and to characterize their network. Our method may become a reference for in vivo staining of the whole astrocytes population in animal models of neurological disorders. PMID- 22509400 TI - An epithelial serine protease, AgESP, is required for Plasmodium invasion in the mosquito Anopheles gambiae. AB - BACKGROUND: Plasmodium parasites need to cross the midgut and salivary gland epithelia to complete their life cycle in the mosquito. However, our understanding of the molecular mechanism and the mosquito genes that participate in this process is still very limited. METHODOLOGY/PRINCIPAL FINDINGS: We identified an Anopheles gambiae epithelial serine protease (AgESP) that is constitutively expressed in the submicrovillar region of mosquito midgut epithelial cells and in the basal side of the salivary glands that is critical for Plasmodium parasites to cross these two epithelial barriers. AgESP silencing greatly reduces Plasmodium berghei and Plasmodium falciparum midgut invasion and prevents the transcriptional activation of gelsolin, a key regulator of actin remodeling and a reported Plasmodium agonist. AgESP expression is highly induced in midgut cells invaded by Plasmodium, suggesting that this protease also participates in the apoptotic response to invasion. In salivary gland epithelial cells, AgESP is localized on the basal side--the surface with which sporozoites interact. AgESP expression in the salivary gland is also induced in response to P. berghei and P. falciparum sporozoite invasion, and AgESP silencing significantly reduces the number of sporozoites that invade this organ. CONCLUSION: Our findings indicate that AgESP is required for Plasmodium parasites to effectively traverse the midgut and salivary gland epithelial barriers. Plasmodium parasites need to modify the actin cytoskeleton of mosquito epithelial cells to successfully complete their life cycle in the mosquito and AgESP appears to be a major player in the regulation of this process. PMID- 22509401 TI - Pdx1 is post-translationally modified in vivo and serine 61 is the principal site of phosphorylation. AB - Maintaining sufficient levels of Pdx1 activity is a prerequisite for proper regulation of blood glucose homeostasis and beta cell function. Mice that are haploinsufficient for Pdx1 display impaired glucose tolerance and lack the ability to increase beta cell mass in response to decreased insulin signaling. Several studies have shown that post-translational modifications are regulating Pdx1 activity through intracellular localization and binding to co-factors. Understanding the signaling cues converging on Pdx1 and modulating its activity is therefore an attractive approach in diabetes treatment. We employed a novel technique called Nanofluidic Proteomic Immunoassay to characterize the post translational profile of Pdx1. Following isoelectric focusing in nano capillaries, this technology relies on a pan specific antibody for detection and it therefore allows the relative abundance of differently charged protein species to be examined simultaneously. In all eukaryotic cells tested we find that the Pdx1 protein separates into four distinct peaks whereas Pdx1 protein from bacteria only produces one peak. Of the four peaks in eukaryotic cells we correlate one of them to a phosphorylation Using alanine scanning and mass spectrometry we map this phosphorylation to serine 61 in both Min6 cells and in exogenous Pdx1 over-expressed in HEK293 cells. A single phosphorylation is also present in cultured islets but it remains unaffected by changes in glucose levels. It is present during embryogenesis but is not required for pancreas development. PMID- 22509402 TI - Effect on adherence to nicotine replacement therapy of informing smokers their dose is determined by their genotype: a randomised controlled trial. AB - BACKGROUND: The behavioural impact of pharmacogenomics is untested. We tested two hypotheses concerning the behavioural impact of informing smokers their oral dose of NRT is tailored to analysis of DNA. METHODS AND FINDINGS: We conducted an RCT with smokers in smoking cessation clinics (N = 633). In combination with NRT patch, participants were informed that their doses of oral NRT were based either on their mu-opioid receptor (OPRM1) genotype, or their nicotine dependence questionnaire score (phenotype). The proportion of prescribed NRT consumed in the first 28 days following quitting was not significantly different between groups: (68.5% of prescribed NRT consumed in genotype vs 63.6%, phenotype group, difference = 5.0%, 95% CI -0.9,10.8, p = 0.098). Motivation to make another quit attempt among those (n = 331) not abstinent at six months was not significantly different between groups (p = 0.23). Abstinence at 28 days was not different between groups (p = 0.67); at six months was greater in genotype than phenotype group (13.7% vs 7.9%, difference = 5.8%, 95% CI 1.0,10.7, p = 0.018). CONCLUSIONS: Informing smokers their oral dose of NRT was tailored to genotype not phenotype had a small, statistically non-significant effect on 28-day adherence to NRT. Among those still smoking at six months, there was no evidence that saying NRT was tailored to genotype adversely affected motivation to make another quit attempt. Higher abstinence rate at six months in the genotype arm requires investigation. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN14352545. PMID- 22509403 TI - AAV-mediated cone rescue in a naturally occurring mouse model of CNGA3 achromatopsia. AB - Achromatopsia is a rare autosomal recessive disorder which shows color blindness, severely impaired visual acuity, and extreme sensitivity to bright light. Mutations in the alpha subunits of the cone cyclic nucleotide-gated channels (CNGA3) are responsible for about 1/4 of achromatopsia in the U.S. and Europe. Here, we test whether gene replacement therapy using an AAV5 vector could restore cone-mediated function and arrest cone degeneration in the cpfl5 mouse, a naturally occurring mouse model of achromatopsia with a CNGA3 mutation. We show that gene therapy leads to significant rescue of cone-mediated ERGs, normal visual acuities and contrast sensitivities. Normal expression and outer segment localization of both M- and S-opsins were maintained in treated retinas. The therapeutic effect of treatment lasted for at least 5 months post-injection. This study is the first demonstration of substantial, relatively long-term restoration of cone-mediated light responsiveness and visual behavior in a naturally occurring mouse model of CNGA3 achromatopsia. The results provide the foundation for development of an AAV5-based gene therapy trial for human CNGA3 achromatopsia. PMID- 22509404 TI - Contrast enhanced micro-computed tomography resolves the 3-dimensional morphology of the cardiac conduction system in mammalian hearts. AB - The general anatomy of the cardiac conduction system (CCS) has been known for 100 years, but its complex and irregular three-dimensional (3D) geometry is not so well understood. This is largely because the conducting tissue is not distinct from the surrounding tissue by dissection. The best descriptions of its anatomy come from studies based on serial sectioning of samples taken from the appropriate areas of the heart. Low X-ray attenuation has formerly ruled out micro-computed tomography (micro-CT) as a modality to resolve internal structures of soft tissue, but incorporation of iodine, which has a high molecular weight, into those tissues enhances the differential attenuation of X-rays and allows visualisation of fine detail in embryos and skeletal muscle. Here, with the use of a iodine based contrast agent (I(2)KI), we present contrast enhanced micro-CT images of cardiac tissue from rat and rabbit in which the three major subdivisions of the CCS can be differentiated from the surrounding contractile myocardium and visualised in 3D. Structures identified include the sinoatrial node (SAN) and the atrioventricular conduction axis: the penetrating bundle, His bundle, the bundle branches and the Purkinje network. Although the current findings are consistent with existing anatomical representations, the representations shown here offer superior resolution and are the first 3D representations of the CCS within a single intact mammalian heart. PMID- 22509405 TI - The GPI anchor signal sequence dictates the folding and functionality of the Als5 adhesin from Candida albicans. AB - BACKGROUND: Proteins destined to be Glycosylphosphatidylinositol (GPI) anchored are translocated into the ER lumen completely before the C-terminal GPI anchor attachment signal sequence (SS) is removed by the GPI-transamidase and replaced by a pre-formed GPI anchor precursor. Does the SS have a role in dictating the conformation and function of the protein as well? METHODOLOGY/PRINCIPAL FINDINGS: We generated two variants of the Als5 protein without and with the SS in order to address the above question. Using a combination of biochemical and biophysical techniques, we show that in the case of Als5, an adhesin of C. albicans, the C terminal deletion of 20 amino acids (SS) results in a significant alteration in conformation and function of the mature protein. CONCLUSIONS/SIGNIFICANCE: We propose that the locking of the conformation of the precursor protein in an alternate conformation from that of the mature protein is one probable strategy employed by the cell to control the behaviour and function of proteins intended to be GPI anchored during their transit through the ER. PMID- 22509406 TI - Propofol prevents autophagic cell death following oxygen and glucose deprivation in PC12 cells and cerebral ischemia-reperfusion injury in rats. AB - BACKGROUND: Propofol exerts protective effects on neuronal cells, in part through the inhibition of programmed cell death. Autophagic cell death is a type of programmed cell death that plays elusive roles in controlling neuronal damage and metabolic homeostasis. We therefore studied whether propofol could attenuate the formation of autophagosomes, and if so, whether the inhibition of autophagic cell death mediates the neuroprotective effects observed with propofol. METHODOLOGY/PRINCIPAL FINDINGS: The cell model was established by depriving the cells of oxygen and glucose (OGD) for 6 hours, and the rat model of ischemia was introduced by a transient two-vessel occlusion for 10 minutes. Transmission electron microscopy (TEM) revealed that the formation of autophagosomes and autolysosomes in both neuronal PC12 cells and pyramidal rat hippocampal neurons after respective OGD and ischemia/reperfusion (I/R) insults. A western blot analysis revealed that the autophagy-related proteins, such as microtubule associated protein 1 light chain 3 (LC3-II), Beclin-1 and class III PI3K, were also increased accordingly, but cytoprotective Bcl-2 protein was decreased. The negative effects of OGD and I/R, including the formation of autophagosomes and autolysosomes, the increase in LC3-II, Beclin-1 and class III PI3K expression and the decline in Bcl-2 production were all inhibited by propofol and specific inhibitors of autophagy, such as 3-methyladenine (3-MA), LY294002 and Bafilomycin A1 (Baf),. Furthermore, in vitro OGD cultures and in vivo I/R rats showed an increase in cell survival following the administration of propofol, as assessed by an MTT assay or histochemical analyses. CONCLUSIONS/SIGNIFICANCE: Our data suggest that propofol can markedly attenuate autophagic processes via the decreased expression of autophagy-related proteins in vitro and in vivo. This inhibition improves cell survival, which provides a novel explanation for the pleiotropic effects of propofol that benefit the nervous system. PMID- 22509407 TI - Mapping of gene expression reveals CYP27A1 as a susceptibility gene for sporadic ALS. AB - Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 * 10(-51)) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS. PMID- 22509409 TI - Scientific publications on primary biliary cirrhosis from 2000 through 2010: an 11-year survey of the literature. AB - BACKGROUND: Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by intrahepatic bile-duct destruction, cholestasis, and fibrosis. It can lead to cirrhosis and eventually liver failure. PBC also shows some regional differences with respect to incidence and prevalence that are becoming more pronounced each year. Recently, researchers have paid more attention to PBC. To evaluate the development of PBC research during the past 11 years, we determined the quantity and quality of articles on this subject. We also compared the contributions of scientists from the US, UK, Japan, Italy, Germany, and China. METHODS: The English-language papers covering PBC published in journals from 2000 through 2010 were retrieved from the PubMed database. We recorded the number of papers published each year, analyzed the publication type, and calculated the accumulated, average impact factors (IFs) and citations from every country. The quantity and quality of articles on PBC were compared by country. We also contrasted the level of PBC research in China and other countries. RESULTS: The total number of articles did not significantly increase during the past 11 years. The number of articles from the US exceeded those from any other country; the publications from the US also had the highest IFs and the most citations. Four other countries showed complex trends with respect to the quantity and quality of articles about PBC. CONCLUSION: The researchers from the US have contributed the most to the development of PBC research. They currently represent the highest level of research. Some high-level studies, such as RCTs, meta analyses, and in-depth basic studies should be launched. The gap between China and the advanced level is still enormous. Chinese investigators still have a long way to go. PMID- 22509408 TI - Prediction of phenotype-associated genes via a cellular network approach: a Candida albicans infection case study. AB - Candida albicans is the most prevalent opportunistic fungal pathogen in humans causing superficial and serious systemic infections. The infection process can be divided into three stages: adhesion, invasion, and host cell damage. To enhance our understanding of these C. albicans infection stages, this study aimed to predict phenotype-associated genes involved during these three infection stages and their roles in C. albicans-host interactions. In light of the principles that proteins that lie closer to one another in a protein interaction network are more likely to have similar functions, and that genes regulated by the same transcription factors tend to have similar functions, a cellular network approach was proposed to predict the phenotype-associated genes in this study. A total of 4, 12, and 3 genes were predicted as adhesion-, invasion-, and damage-associated genes during C. albicans infection, respectively. These predicted genes highlight the facts that cell surface components are critical for cell adhesion, and that morphogenesis is crucial for cell invasion. In addition, they provide targets for further investigations into the mechanisms of the three C. albicans infection stages. These results give insights into the responses elicited in C. albicans during interaction with the host, possibly instrumental in identifying novel therapies to treat C. albicans infection. PMID- 22509410 TI - Early treatment with fumagillin, an inhibitor of methionine aminopeptidase-2, prevents Pulmonary Hypertension in monocrotaline-injured rats. AB - Pulmonary Hypertension (PH) is a pathophysiologic condition characterized by hypoxemia and right ventricular strain. Proliferation of fibroblasts, smooth muscle cells, and endothelial cells is central to the pathology of PH in animal models and in humans. Methionine aminopeptidase-2 (MetAP2) regulates proliferation in a variety of cell types including endothelial cells, smooth muscle cells, and fibroblasts. MetAP2 is inhibited irreversibly by the angiogenesis inhibitor fumagillin. We have previously found that inhibition of MetAP2 with fumagillin in bleomycin-injured mice decreased pulmonary fibrosis by selectively decreasing the proliferation of lung myofibroblasts. In this study, we investigated the role of fumagillin as a potential therapy in experimental PH. In vivo, treatment of rats with fumagillin early after monocrotaline injury prevented PH and right ventricular remodeling by decreasing the thickness of the medial layer of the pulmonary arteries. Treatment with fumagillin beginning two weeks after monocrotaline injury did not prevent PH but was associated with decreased right ventricular mass and decreased cardiomyocyte hypertrophy, suggesting a direct effect of fumagillin on right ventricular remodeling. Incubation of rat pulmonary artery smooth muscle cells (RPASMC) with fumagillin and MetAP2-targeting siRNA inhibited proliferation of RPASMC in vitro. Platelet derived growth factor, a growth factor that is important in the pathogenesis of PH and stimulates proliferation of fibroblasts and smooth muscle cells, strongly increased expression of MetP2. By immunohistochemistry, we found that MetAP2 was expressed in the lesions of human pulmonary arterial hypertension. We propose that fumagillin may be an effective adjunctive therapy for treating PH in patients. PMID- 22509411 TI - Cellular imaging of human atherosclerotic lesions by intravascular electric impedance spectroscopy. AB - BACKGROUND: Newer techniques are required to identify atherosclerotic lesions that are prone to rupture. Electric impedance spectroscopy (EIS) is able to provide information about the cellular composition of biological tissue. The present study was performed to determine the influence of inflammatory processes in type Va (lipid core, thick fibrous cap) and Vc (abundant fibrous connective tissue while lipid is minimal or even absent) human atherosclerotic lesions on the electrical impedance of these lesions measured by EIS. METHODS AND RESULTS: EIS was performed on 1 aortic and 3 femoral human arteries at 25 spots with visually heavy plaque burden. Severely calcified lesions were excluded from analysis. A highly flexible micro-electrode mounted onto a balloon catheter was placed on marked regions to measure impedance values at 100 kHz. After paraffin embedding, visible marked cross sections (n = 21) were processed. Assessment of lesion types was performed by Movats staining. Immunostaining for CD31 (marker of neovascularisation), CD36 (scavenger cells) and MMP-3 (matrix metalloproteinase 3) was performed. The amount of positive cells was assessed semi-quantitatively. 15 type Va lesions and 6 type Vc lesions were identified. Lesions containing abundant CD36-, CD31- and MMP-3-positive staining revealed significantly higher impedance values compared to lesions with marginal or without positive staining (CD36 + 455 +/- 50 Omega vs. CD36- 346 +/- 53 Omega, p = 0.001; CD31 + 436 +/- 43 Omega vs. CD31- 340 +/- 55 Omega, p = 0.001; MMP-3 + 400 +/- 68 Omega vs. MMP-3- 323 +/- 33 Omega, p = 0.03). CONCLUSIONS: Atherosclerotic lesions with abundant neovascularisation (CD31), many scavenger receptor class B expressing cells (CD36) or high amount of MMP-3 immunoreactivity reveal significantly higher impedance values compared to lesions with marginal or no detection of immunoreactivity. Findings suggest that inflammatory processes in vulnerable plaques affect the impedance of atherosclerotic lesions and might therefore be detected by EIS. PMID- 22509412 TI - Continuous production of prions after infectious particles are eliminated: implications for Alzheimer's disease. AB - Rat septal cells, induced to enter a terminal differentiation-like state by temperature shift, produce prion protein (PrP) levels 7x higher than their proliferative counterparts. Host PrP accumulates on the plasma membrane, newly elaborated nanotubes, and cell-to-cell junctions, important conduits for viral spread. To find if elevated PrP increased susceptibility to FU-CJD infection, we determined agent titers under both proliferating and arresting conditions. A short 5 day arrest and a prolonged 140 day arrest increased infectivity by 5x and 122x (>2 logs) respectively as compared to proliferating cells. Total PrP rapidly increased 7x and was even more elevated in proliferating cells that escaped chronic arrest conditions. Amyloid generating PrP (PrP-res), the "infectious prion" form, present at ~100,000 copies per infectious particle, also increased proportionately by 140 days. However, when these highly infectious cells were switched back to proliferative conditions for 60 days, abundant PrP-res continued to be generated even though 4 logs of titer was lost. An identical 4 log loss was found with maximal PrP and PrP-res production in parallel cells under arresting conditions. While host PrP is essential for TSE agent spread and replication, excessive production of all forms of PrP can be inappropriately perpetuated by living cells, even after the initiating infectious agent is eliminated. Host PrP changes can start as a protective innate immune response that ultimately escapes control. A subset of other neurodegenerative and amyloid diseases, including non transmissible AD, may be initiated by environmental infectious agents that are no longer present. PMID- 22509413 TI - Human and canine echinococcosis infection in informal, unlicensed abattoirs in Lima, Peru. AB - Echinococcus granulosus infections are a major public health problem in livestock raising regions around the world. The life cycle of this tapeworm is sustained between dogs (definitive host, canine echinococcosis), and herbivores (intermediary host, cystic hydatid disease). Humans may also develop cystic hydatid disease. Echinococcosis is endemic in rural areas of Peru; nevertheless, its presence or the extension of the problem in urban areas is basically unknown. Migration into Lima, an 8-million habitant's metropolis, creates peripheral areas where animals brought from endemic areas are slaughtered without veterinary supervision. We identified eight informal, unlicensed abattoirs in a peripheral district of Lima and performed a cross-sectional study in to assess the prevalence of canine echinococcosis, evaluated by coproELISA followed by PCR evaluation and arecoline purge. Eight of 22 dogs (36%) were positive to coproELISA, and four (18%) were confirmed to be infected with E. granulosus tapeworms either by PCR or direct observation (purge). Later evaluation of the human population living in these abattoirs using abdominal ultrasound, chest X rays and serology, found 3 out of 32 (9.3%) subjects with echinococcal cysts in the liver (two viable, one calcified), one of whom had also lung involvement and a strongly positive antibody response. Autochthonous transmission of E. granulosus is present in Lima. Informal, unlicensed abattoirs may be sources of infection to neighbouring people in this urban environment. PMID- 22509414 TI - Investigation of the proteolytic functions of an expanded cercarial elastase gene family in Schistosoma mansoni. AB - BACKGROUND: Cercarial elastase is the major invasive larval protease in Schistosoma mansoni, a parasitic blood fluke, and is essential for host skin invasion. Genome sequence analysis reveals a greatly expanded family of cercarial elastase gene isoforms in Schistosoma mansoni. This expansion appears to be unique to S. mansoni, and it is unknown whether gene duplication has led to divergent protease function. METHODS: Profiling of transcript and protein expression patterns reveals that cercarial elastase isoforms are similarly expressed throughout the S. mansoni life cycle. Computational modeling predicts key differences in the substrate-binding pockets of various cercarial elastase isoforms, suggesting a diversification of substrate preferences compared with the ancestral gene of the family. In addition, active site labeling of SmCE reveals that it is activated prior to exit of the parasite from its intermediate snail host. CONCLUSIONS: The expansion of the cercarial gene family in S. mansoni is likely to be an example of gene dosage. In addition to its critical role in human skin penetration, data presented here suggests a novel role for the protease in egress from the intermediate snail host. This study demonstrates how enzyme activity-based analysis complements genomic and proteomic studies, and is key in elucidating proteolytic function. PMID- 22509415 TI - Detection of Mycobacterium ulcerans by the loop mediated isothermal amplification method. AB - BACKGROUND: Buruli ulcer (BU) caused by Mycobacterium ulcerans (M. ulcerans) has emerged as an important public health problem in several rural communities in sub Saharan Africa. Early diagnosis and prompt treatment are important in preventing disfiguring complications associated with late stages of the disease progression. Presently there is no simple and rapid test that is appropriate for early diagnosis and use in the low-resource settings where M. ulcerans is most prevalent. METHODOLOGY: We compared conventional and pocket warmer loop mediated isothermal amplification (LAMP) methods (using a heat block and a pocket warmer respectively as heat source for amplification reaction) for the detection of M. ulcerans in clinical specimens. The effect of purified and crude DNA preparations on the detection rate of the LAMP assays were also investigated and compared with that of IS2404 PCR, a reference assay for the detection of M. ulcerans. Thirty clinical specimens from suspected BU cases were examined by LAMP and IS2404 PCR. PRINCIPAL FINDINGS: The lower detection limit of both LAMP methods at 60 degrees C was 300 copies of IS2404 and 30 copies of IS2404 for the conventional LAMP at 65 degrees C. When purified DNA extracts were used, both the conventional LAMP and IS2404 PCR concordantly detected 21 positive cases, while the pocket warmer LAMP detected 19 cases. Nine of 30 samples were positive by both the LAMP assays as well as IS2404 PCR when crude extracts of clinical specimens were used. CONCLUSION/SIGNIFICANCE: The LAMP method can be used as a simple and rapid test for the detection of M. ulcerans in clinical specimens. However, obtaining purified DNA, as well as generating isothermal conditions, remains a major challenge for the use of the LAMP method under field conditions. With further improvement in DNA extraction and amplification conditions, the pwLAMP could be used as a point of care diagnostic test for BU. PMID- 22509416 TI - Population structure and transmission dynamics of Plasmodium vivax in the Republic of Korea based on microsatellite DNA analysis. AB - BACKGROUND: In order to control malaria, it is important to understand the genetic structure of the parasites in each endemic area. Plasmodium vivax is widely distributed in the tropical to temperate regions of Asia and South America, but effective strategies for its elimination have yet to be designed. In South Korea, for example, indigenous vivax malaria was eliminated by the late 1970s, but re-emerged from 1993. We estimated the population structure and temporal dynamics of transmission of P. vivax in South Korea using microsatellite DNA markers. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed 255 South Korean P. vivax isolates collected from 1994 to 2008, based on 10 highly polymorphic microsatellite DNA loci of the P. vivax genome. Allelic data were obtained for the 87 isolates and their microsatellite haplotypes were determined based on a combination of allelic data of the loci. In total, 40 haplotypes were observed. There were two predominant haplotypes: H16 and H25. H16 was observed in 9 isolates (10%) from 1996 to 2005, and H25 in 27 (31%) from 1995 to 2003. These results suggested that the recombination rate of P. vivax in South Korea, a temperate country, was lower than in tropical areas where identical haplotypes were rarely seen in the following year. Next, we estimated the relationships among the 40 haplotypes by eBURST analysis. Two major groups were found: one composed of 36 isolates (41%) including H25; the other of 20 isolates (23%) including H16. Despite the low recombination rate, other new haplotypes that are genetically distinct from the 2 groups have also been observed since 1997 (H27). CONCLUSIONS/SIGNIFICANCE: These results suggested a continual introduction of P. vivax from other population sources, probably North Korea. Molecular epidemiology using microsatellite DNA of the P. vivax population is effective for assessing the population structure and transmission dynamics of the parasites--information that can assist in the elimination of vivax malaria in endemic areas. PMID- 22509417 TI - The Schistosoma mansoni tegumental-allergen-like (TAL) protein family: influence of developmental expression on human IgE responses. AB - BACKGROUND: A human IgE response to Sm22.6 (a dominant IgE target in Schistosoma mansoni) is associated with the development of partial immunity. Located inside the tegument, the molecule belongs to a family of proteins from parasitic platyhelminths, the Tegument-Allergen-Like proteins (TALs). In addition to containing dynein-light-chain domains, these TALs also contain EF-hand domains similar to those found in numerous EF-hand allergens. METHODOLOGY/PRINCIPAL FINDINGS: S. mansoni genome searches revealed 13 members (SmTAL1-13) within the species. Recent microarray data demonstrated they have a wide range of life-cycle transcriptional profiles. We expressed SmTAL1 (Sm22.6), SmTAL2, 3, 4, 5 and 13 as recombinant proteins and measured IgE and IgG4 in 200 infected males (7-60 years) from a schistosomiasis endemic region in Uganda. For SmTAL1 and 3 (transcribed in schistosomula through adult-worms and adult-worms, respectively) and SmTAL5 (transcribed in cercariae through adult-worms), detectable IgE responses were rare in 7-9 year olds, but increased with age. At all ages, IgE to SmTAL2 (expressed constitutively), was rare while anti-SmTAL2 IgG4 was common. Levels of IgE and IgG4 to SmTAL4 and 13 (transcribed predominantly in the cercariae/skin stage) were all low. CONCLUSIONS: We have not measured SmTAL protein abundance or exposure in live parasites, but the antibody data suggests to us that, in endemic areas, there is priming and boosting of IgE to adult-worm SmTALs by occasional death of long-lived worms, desensitization to egg SmTALs through continuous exposure to dying eggs and low immunogenicity of larval SmTALs due to immunosuppression in the skin by the parasite. Of these, it is the gradual increase in IgE to the worm antigens that parallels age-dependent immunity seen in endemic areas. PMID- 22509418 TI - IFN-gamma plays a unique role in protection against low virulent Trypanosoma cruzi strain. AB - BACKGROUND: T. cruzi strains have been divided into six discrete typing units (DTUs) according to their genetic background. These groups are designated T. cruzi I to VI. In this context, amastigotes from G strain (T. cruzi I) are highly infective in vitro and show no parasitemia in vivo. Here we aimed to understand why amastigotes from G strain are highly infective in vitro and do not contribute for a patent in vivo infection. METHODOLOGY/PRINCIPAL FINDINGS: Our in vitro studies demonstrated the first evidence that IFN-gamma would be associated to the low virulence of G strain in vivo. After intraperitoneal amastigotes inoculation in wild-type and knockout mice for TNF-alpha, Nod2, Myd88, iNOS, IL-12p40, IL-18, CD4, CD8 and IFN-gamma we found that the latter is crucial for controlling infection by G strain amastigotes. CONCLUSIONS/SIGNIFICANCE: Our results showed that amastigotes from G strain are highly infective in vitro but did not contribute for a patent infection in vivo due to its susceptibility to IFN-gamma production by host immune cells. These data are useful to understand the mechanisms underlying the contrasting behavior of different T. cruzi groups for in vitro and in vivo infection. PMID- 22509419 TI - Genetic and anatomic determinants of enzootic Venezuelan equine encephalitis virus infection of Culex (Melanoconion) taeniopus. AB - Venezuelan equine encephalitis (VEE) is a re-emerging, mosquito-borne viral disease with the potential to cause fatal encephalitis in both humans and equids. Recently, detection of endemic VEE caused by enzootic strains has escalated in Mexico, Peru, Bolivia, Colombia and Ecuador, emphasizing the importance of understanding the enzootic transmission cycle of the etiologic agent, VEE virus (VEEV). The majority of work examining the viral determinants of vector infection has been performed in the epizootic mosquito vector, Aedes (Ochlerotatus) taeniorhynchus. Based on the fundamental differences between the epizootic and enzootic cycles, we hypothesized that the virus-vector interaction of the enzootic cycle is fundamentally different from that of the epizootic model. We therefore examined the determinants for VEEV IE infection in the enzootic vector, Culex (Melanoconion) taeniopus, and determined the number and susceptibility of midgut epithelial cells initially infected and their distribution compared to the epizootic virus-vector interaction. Using chimeric viruses, we demonstrated that the determinants of infection for the enzootic vector are different than those observed for the epizootic vector. Similarly, we showed that, unlike A. taeniorhynchus infection with subtype IC VEEV, C. taeniopus does not have a limited subpopulation of midgut cells susceptible to subtype IE VEEV. These findings support the hypothesis that the enzootic VEEV relationship with C. taeniopus differs from the epizootic virus-vector interaction in that the determinants appear to be found in both the nonstructural and structural regions, and initial midgut infection is not limited to a small population of susceptible cells. PMID- 22509420 TI - Second external quality assurance study for the serological diagnosis of hantaviruses in Europe. AB - Hantaviruses are endemic throughout the world and hosted by rodents and insectivores. Two human zoonoses, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), are caused by hantaviruses and case fatality rates have reached 12% for HFRS and 50% for HPS in some outbreaks. Symptomatic hantavirus infections in Europe are summarised as HFRS mainly due to Puumala, Dobrava-Belgrade and Saaremaa virus. While HFRS has an overall low incidence in Europe, the number of cases varies from 100 per year in all Eastern and Southern Europe up to 1,000 per year only in Finland. To assess the quality of hantavirus diagnostics, the European Network for the Diagnostics of "Imported" Viral Diseases (ENIVD) organised a first external quality assurance (EQA) in 2002. The purpose of this second EQA study is to collect updated information on the efficiency and accurateness of hantavirus serological methods applied by expert laboratories. A serum panel of 14 samples was sent to 28 participants in Europe of which 27 sent results. Performance in hantavirus diagnosis varied not only on the method used but also on the laboratories and the subclass of antibodies tested. Commercial and in-house assays performed almost equally. Enzyme immunoassays were mainly used but did not show the best performances while immunoblot assays were the less employed and showed overall better performances. IgM antibodies were not detected in 61% of the positive IgM samples and IgM detection was not performed by 7% of the laboratories indicating a risk of overlooking acute infections in patients. Uneven performances using the same method is indicating that there is still a need for improving testing conditions and standardizing protocols. PMID- 22509421 TI - Increased birth weight associated with regular pre-pregnancy deworming and weekly iron-folic acid supplementation for Vietnamese women. AB - BACKGROUND: Hookworm infections are significant public health issues in South East Asia. In women of reproductive age, chronic hookworm infections cause iron deficiency anaemia, which, upon pregnancy, can lead to intrauterine growth restriction and low birth weight. Low birth weight is an important risk factor for neonatal and infant mortality and morbidity. METHODOLOGY: We investigated the association between neonatal birth weight and a 4-monthly deworming and weekly iron-folic acid supplementation program given to women of reproductive age in north-west Vietnam. The program was made available to all women of reproductive age (estimated 51,623) in two districts in Yen Bai Province for 20 months prior to commencement of birth weight data collection. Data were obtained for births at the district hospitals of the two intervention districts as well as from two control districts where women did not have access to the intervention, but had similar maternal and child health indicators and socio-economic backgrounds. The primary outcome was low birth weight. PRINCIPAL FINDINGS: The birth weights of 463 infants born in district hospitals in the intervention (168) and control districts (295) were recorded. Twenty-six months after the program was started, the prevalence of low birth weight was 3% in intervention districts compared to 7.4% in control districts (adjusted odds ratio 0.29, 95% confidence interval 0.10 to 0.81, p = 0.017). The mean birth weight was 124 g (CI 68 - 255 g, p<0.001) greater in the intervention districts compared to control districts. CONCLUSIONS/SIGNIFICANCE: The findings of this study suggest that providing women with regular deworming and weekly iron-folic acid supplements before pregnancy is associated with a reduced prevalence of low birth weight in rural Vietnam. The impact of this health system-integrated intervention on birth outcomes should be further evaluated through a more extensive randomised-controlled trial. PMID- 22509422 TI - Incrimination of Phlebotomus kandelakii and Phlebotomus balcanicus as vectors of Leishmania infantum in Tbilisi, Georgia. AB - A survey of potential vector sand flies was conducted in the neighboring suburban communities of Vake and Mtatsminda districts in an active focus of visceral Leishmaniasis (VL) in Tbilisi, Georgia. Using light and sticky-paper traps, 1,266 male and 1,179 female sand flies were collected during 2006-2008. Five Phlebotomus species of three subgenera were collected: Phlebotomus balcanicus Theodor and Phlebotomus halepensis Theodor of the subgenus Adlerius; Phlebotomus kandelakii Shchurenkova and Phlebotomus wenyoni Adler and Theodor of the subgenus Larroussius; Phlebotomus sergenti Perfil'ev of the subgenus Paraphlebotomus. Phlebotomus sergenti (35.1%) predominated in Vake, followed by P. kandelakii (33.5%), P. balcanicus (18.9%), P. halepensis (12.2%), and P. wenyoni (0.3%). In Mtatsminda, P. kandelakii (76.8%) comprised over three fourths of collected sand flies, followed by P. sergenti (12.6%), P. balcanicus (5.8%), P. halepensis (3.7%), and P. wenyoni (1.1%). The sand fly season in Georgia is exceptionally short beginning in early June, peaking in July and August, then declining to zero in early September. Of 659 female sand flies examined for Leishmania, 12 (1.8%) specimens without traces of blood were infected including 10 of 535 P. kandelakii (1.9%) and two of 40 P. balcanicus (5.0%). Six isolates were successfully cultured and characterized as Leishmania by PCR. Three isolates from P. kandelakii (2) and P. balcanicus (1) were further identified as L. infantum using sequence alignment of the 70 kDa heat-shock protein gene. Importantly, the sand fly isolates showed a high percent identity (99.8%-99.9%) to human and dog isolates from the same focus, incriminating the two sand fly species as vectors. Blood meal analysis showed that P. kandelakii preferentially feeds on dogs (76%) but also feeds on humans. The abundance, infection rate and feeding behavior of P. kandelakii and the infection rate in P. balcanicus establish these species as vectors in the Tbilisi VL focus. PMID- 22509423 TI - KSAC, a defined Leishmania antigen, plus adjuvant protects against the virulence of L. major transmitted by its natural vector Phlebotomus duboscqi. AB - BACKGROUND: Recombinant KSAC and L110f are promising Leishmania vaccine candidates. Both antigens formulated in stable emulsions (SE) with the natural TLR4 agonist MPL(r) and L110f with the synthetic TLR4 agonist GLA in SE protected BALB/c mice against L. major infection following needle challenge. Considering the virulence of vector-transmitted Leishmania infections, we vaccinated BALB/c mice with either KSAC+GLA-SE or L110f+GLA-SE to assess protection against L. major transmitted via its vector Phlebotomus duboscqi. METHODS: Mice receiving the KSAC or L110f vaccines were challenged by needle or L. major-infected sand flies. Weekly disease progression and terminal parasite loads were determined. Immunological responses to KSAC, L110f, or soluble Leishmania antigen (SLA) were assessed throughout vaccination, three and twelve weeks after immunization, and one week post-challenge. RESULTS: Following sand fly challenge, KSAC-vaccinated mice were protected while L110f-vaccinated animals showed partial protection. Protection correlated with the ability of SLA to induce IFN-gamma-producing CD4(+)CD62L(low)CCR7(low) effector memory T cells pre- and post-sand fly challenge. CONCLUSIONS: This study demonstrates the protective efficacy of KSAC+GLA-SE against sand fly challenge; the importance of vector-transmitted challenge in evaluating vaccine candidates against Leishmania infection; and the necessity of a rapid potent Th1 response against Leishmania to attain true protection. PMID- 22509424 TI - Elevated adaptive immune responses are associated with latent infections of Wuchereria bancrofti. AB - In order to guarantee the fulfillment of their complex lifecycle, adult filarial nematodes release millions of microfilariae (MF), which are taken up by mosquito vectors. The current strategy to eliminate lymphatic filariasis as a public health problem focuses upon interrupting this transmission through annual mass drug administration (MDA). It remains unclear however, how many rounds of MDA are required to achieve low enough levels of MF to cease transmission. Interestingly, with the development of further diagnostic tools a relatively neglected cohort of asymptomatic (non-lymphedema) amicrofilaremic (latent) individuals has become apparent. Indeed, epidemiological studies have suggested that there are equal numbers of patent (MF(+)) and latent individuals. Since the latter represent a roadblock for transmission, we studied differences in immune responses of infected asymptomatic male individuals (n = 159) presenting either patent (n = 92 MF(+)) or latent (n = 67 MF(-)) manifestations of Wuchereria bancrofti. These individuals were selected on the basis of MF, circulating filarial antigen in plasma and detectable worm nests. Immunological profiles of either Th1/Th17, Th2, regulatory or innate responses were determined after stimulation of freshly isolated PBMCs with either filarial-specific extract or bystander stimuli. In addition, levels of total and filarial-specific antibodies, both IgG subclasses and IgE, were ascertained from plasma. Results from these individuals were compared with those from 22 healthy volunteers from the same endemic area. Interestingly, we observed that in contrast to MF(+) patients, latent infected individuals had lower numbers of worm nests and increased adaptive immune responses including antigen-specific IL-5. These data highlight the immunosuppressive status of MF(+) individuals, regardless of age or clinical hydrocele and reveal immunological profiles associated with latency and immune mediated suppression of parasite transmission. PMID- 22509426 TI - Donor-derived peripheral mononuclear cell DNA is associated with stable kidney allograft function: a randomized controlled trial. AB - A large body of literature has documented an inconsistent relationship of peripheral donor cell chimerism with alloimmune tolerance following kidney transplantation. We revisit this association with assays capable of quantifying cellular microchimerism with 150-1500-fold greater sensitivity than previously utilized allo-antibody based flow cytometric approaches. Forty renal transplant patients, 20 with concurrent donor bone marrow infusion (DBMI) and 20 control participants without infusion were prospectively monitored for peripheral blood microchimerism using donor polymorphism-specific quantitative real-time PCR. Thirty-eight patients were evaluated for microchimerism, 19 in each group. The frequency of testing positive for (95% vs. 58%, p = 0.02) and mean concentrations of microchimerism (115 +/- 66 vs. 13 +/- 3 donor genomes/million recipient genomes, p = 0.007), respectively, were higher in infused patients compared with controls. Thirty-one patients maintained stable graft function; 17 in the DBMI group vs. 14 in controls. Patients with stable graft function in the DBMI group compared with control patients harbored microchimerism more frequently (94 vs. 50%, p = 0.01) and at higher concentrations (123 +/- 67 vs. 11 +/- 4, p = 0.007), respectively. Significant correlation between dose of infused cells and microchimerism levels was found post-transplant (p = 0.01). Using very sensitive assays, our findings demonstrate associations between the presence and quantity of microchimerism with stable graft function in infused patients. PMID- 22509428 TI - HLA-targeted cell sorting of microchimeric cells opens the way to phenotypical and functional characterization. AB - Microchimerism refers to the presence of less than 1% of non-host cells in a person. Our group developed a reliable method for separating viable microchimeric cells from the host environment. Optimal separation of microchimeric cells at proportions as low as 0.01% could be established with two monoclonal antibodies directed against different HLA antigens, one targeting the microchimeric cells and the other the host cells. Purity of separated cell populations was validated by HLA-allele-specific and Y-chromosome directed real-time qPCR assays. The methodology was used successfully to separate microchimeric maternal cells from child umbilical cord mononuclear cells after pregnancy. Cell sorting with HLA monoclonal antibodies targeting allelic differences enables reliable microchimeric cell detection and separation in blood specimens. With this approach, maximal enrichment of potentially viable microchimeric cells from a background cell population is reached, which opens the way to phenotypical and functional characterization of microchimeric cells. PMID- 22509427 TI - Layers of regulation in induction of mixed chimerism by anti-CD40L. AB - The pathways regulating immunological tolerance are complex and overlapping. Here, we comment on our findings that the PD-1, CTLA-4, LAG-3 and TGFbeta inhibitory molecules are all involved in mediating peripheral CD8 T-cell tolerance induced by anti-CD40L and allogeneic bone marrow transplantation in mice. These observations suggest the possibility of targeted manipulation of these pathways for induction of mixed hematopoietic chimerism for donor-specific transplantation tolerance. PMID- 22509429 TI - Th2 alloimmunity counteracts Th17-type response in the neonatal establishment of lymphoid chimerism. AB - The neonatal period of life is described as particularly susceptible to develop tolerance. This status of neonatal tolerance has been studied for decades since the discovery that semiallogeneic spleen cells inoculated at birth can induce donor-type graft acceptance. The host neonatal T-cell compartment that may account for this propensity to develop tolerance is mostly characterized by a Th2 type polarized response and a default in the cytotoxic T lymphocyte (CTL) functions that allow the establishment of lymphoid chimerism and promote donor type graft survival. We highlighted a new role of alloreactive Th17 cells as a critical barrier to neonatal tolerance that prevents this lymphoid chimerism and further demonstrated that the Th2 immune deviation is essential to control this Th17-type response. We discuss here the potential impact of breaking the tolerizing effects of exposure of the developing offspring to alloantigens in the induction of Th17-type immunity. PMID- 22509425 TI - Mixed chimerism and split tolerance: mechanisms and clinical correlations. AB - Establishing hematopoietic mixed chimerism can lead to donor-specific tolerance to transplanted organs and may eliminate the need for long-term immunosuppressive therapy, while also preventing chronic rejection. In this review, we discuss central and peripheral mechanisms of chimerism induced tolerance. However, even in the long-lasting presence of a donor organ or donor hematopoietic cells, some allogeneic tissues from the same donor can be rejected; a phenomenon known as split tolerance. With the current goal of creating mixed chimeras using clinically feasible amounts of donor bone marrow and with minimal conditioning, split tolerance may become more prevalent and its mechanisms need to be explored. Some predisposing factors that may increase the likelihood of split tolerance are immunogenicity of the graft, certain donor-recipient combinations, prior sensitization, location and type of graft and minimal conditioning chimerism induction protocols. Additionally, split tolerance may occur due to a differential susceptibility of various types of tissues to rejection. The mechanisms involved in a tissue's differential susceptibility to rejection include the presence of polymorphic tissue-specific antigens and variable sensitivity to indirect pathway effector mechanisms. Finally, we review the clinical attempts at allograft tolerance through the induction of chimerism; studies that are revealing the complex relationship between chimerism and tolerance. This relationship often displays split tolerance, and further research into its mechanisms is warranted. PMID- 22509430 TI - Host stem cells repopulate liver allografts: reverse chimerism. AB - Liver transplant has become life-saving therapy for thousands of patients with end stage liver disease in the United States, but chronic rejection and the toxicities of immunosuppression remain significant obstacles to the further expansion of this modality and "transplant tolerance" remains a central goal in the field. So we and others are looking for alternative post-transplant strategies. We set out to 'engineer' repopulation after transplantation in a strain combination [dark agouti (DA) to Lewis green fluorescent protein+ (LEW GFP+)] which rejects liver grafts strongly, a model that more closely resembles the situation in humans. Our central finding is purposeful manipulation of the immune response with low dose immunosuppression and liberation of stem cells for a very short period after transplantation results in long-term transplant acceptance by two mechanisms: transforming the liver (donor) to self (host) phenotype, and auto-suppression of the specific allograft response. PMID- 22509431 TI - Ductopenia related liver sarcoidosis. AB - Sarcoidosis is a systemic granulomatous disease which may involve many organs. In approximately 95% of patients there is liver involvement, with noncaseating hepatic granulomas occurring in 21 to 99% of patients with sarcoidosis. Liver involvement is usually asymptomatic and limited to mild to moderate abnormalities in liver biochemistry. The occurrence of jaundice in sarcoidosis is rare; extensive imaging procedures and the examination of liver biopsies permit a precise diagnostic. Ductopenia associated with sarcoidosis has been reported in less than 20 cases and can lead to biliary cirrhosis and liver- related death. We report here on a case of ductopenia-related sarcoidosis in which primary biliary cirrhosis and extrahepatic cholestasis have been carefully excluded. The patient follow up was 8 years. Although ursodesoxycholic acid appears to improve liver biochemistry it does not preclude the rapid occurrence of extensive fibrosis. A review of the literature of reported cases of ductopenia related to sarcoidosis is provided. PMID- 22509432 TI - Design of substituted bis-Tetrahydrofuran (bis-THF)-derived Potent HIV-1 Protease Inhibitors, Protein-ligand X-ray Structure, and Convenient Syntheses of bis-THF and Substituted bis-THF Ligands. AB - We investigated substituted bis-THF-derived HIV-1 protease inhibitors in order to enhance ligand-binding site interactions in the HIV-1 protease active site. In this context, we have carried out convenient syntheses of optically active bis THF and C4-substituted bis-THF ligands using a [2,3]-sigmatropic rearrangement as the key step. The synthesis provided convenient access to a number of substituted bis-THF derivatives. Incorporation of these ligands led to a series of potent HIV 1 protease inhibitors. Inhibitor 23c turned out to be the most potent (K(i) = 2.9 pM; IC(50) = 2.4 nM) among the inhibitors. An X-ray structure of 23c-bound HIV-1 protease showed extensive interactions of the inhibitor with the protease active site, including a unique water-mediated hydrogen bond to the Gly-48 amide NH in the S2 site. PMID- 22509434 TI - Ankylosing spondylitis and cardiac abnormalities. PMID- 22509433 TI - Current clinical applications of transthoracic three-dimensional echocardiography. AB - The advent of three-dimensional echocardiography (3DE) has significantly improved the impact of non-invasive imaging on our understanding and management of cardiac diseases in clinical practice. Transthoracic 3DE enables an easier, more accurate and reproducible interpretation of the complex cardiac anatomy, overcoming the intrinsic limitations of conventional echocardiography. The availability of unprecedented views of cardiac structures from any perspective in the beating heart provides valuable clinical information and new levels of confidence in diagnosing heart disease. One major advantage of the third dimension is the improvement in the accuracy and reproducibility of chamber volume measurement by eliminating geometric assumptions and errors caused by foreshortened views. Another benefit of 3DE is the realistic en face views of heart valves, enabling a better appreciation of the severity and mechanisms of valve diseases in a unique, noninvasive manner. The purpose of this review is to provide readers with an update on the current clinical applications of transthoracic 3DE, emphasizing the incremental benefits of 3DE over conventional two-dimensional echocardiography. PMID- 22509435 TI - Left Atrial Volume Index as Indicator of Left Ventricular Diastolic Dysfunction: Comparation between Left Atrial Volume Index and Tissue Myocardial Performance Index. AB - BACKGROUND: To point out a possible correlation between left atrial volume index (LAVI) and left ventricular (LV) diastolic time interval to better define LV diastolic dysfunction, this study was performed. METHODS: In 62 hypertensive hypertrophic patients without LV systolic dysfunction, LV volumes, myocardial mass index, ejection fraction% (EF%) and LAVI were measured by two-dimensional echocardiography. Instead, tissue Doppler echocardiography (TDE) was used to measure myocardial performance index (MPI) and its systo-diastolic time intervals, such as: iso-volumetric contraction time (IVCT); iso-volumetric relaxation time (IVRT); ejection time. LAVI, TDE-MPI and time intervals where also measured in 15 healthy controls, to obtain the reference values. RESULTS: Results shown a significant increase of LV volumes in hypertensives in comparison to the control group (p < 0.05). LV mass index also augmented (p < 0.001). Instead, EF% not significantly changed in hypertrophic patients in comparison with healthy controls. LAVI raised in hypertensives wih left ventricular hypertrophy, whereas IVCT resulted within the normal limits. On the contrary, IVRT significantly raised. Accordingly, MPI resulted higher in controls. CONCLUSION: LAVI, MPI and its time intervals appear as reliable tools to non invasively individualize LV diastolic dysfunction in systemic hypertension, in absence of mitral valve disease. PMID- 22509436 TI - Early cardiac valvular changes in ankylosing spondylitis: a transesophageal echocardiography study. AB - BACKGROUND: This study was conducted to determine the early cardiac valvular changes in young male ankylosing spondylitis (AS) patients. METHODS: A total of 70 AS patients on treatment without clinical cardiac symptoms were divided into group I (< 10 years, n = 50) and group II (>= 10 years, n = 20) depending on their disease duration after first diagnosis. Twenty-five healthy volunteers were selected as control subjects. All the subjects underwent transthoracic and transesophageal echocardiography, electrocardiography, and rheumatologic evaluation for AS patients. RESULTS: The thickness of both the aortic and mitral valve was more increased in AS patients than in controls. Aortic valve thickness over 1.3 mm could predict AS with a sensitivity of 73% and specificity of 76%. The prevalence of aortic valve thickening was higher in the AS group compared to the controls. The prevalence of aortic and mitral regurgitation was very low and there was no difference between the controls and the patients. The aortic valve thickening was related to longer disease duration, high blood pressure, disease activity and inflammatory markers. CONCLUSION: Thickening of the aortic and mitral valve was observed without regurgitation in male AS patients early in the course of their disease without clinical cardiac manifestations. This subclinical change of aorto-mitral valve in early AS should be considered and followed up to determine its prognostic implication and evolution. PMID- 22509437 TI - Correlation of right atrial appendage velocity with left atrial appendage velocity and brain natriuretic Peptide. AB - BACKGROUND: Left atrial appendage (LAA) anatomy and function have been well characterized both in healthy and diseased people, whereas relatively little attention has been focused on the right atrial appendage (RAA). We sought to evaluate RAA flow velocity and to compare these parameters with LAA indices and with a study of biomarkers, such as brain natriuretic peptide, among patients with sinus rhythm (SR) and atrial fibrillation (AF). METHODS: In a series of 79 consecutive patients referred for transesophageal echocardiography, 43 patients (23 with AF and 20 controls) were evaluated. RESULTS: AF was associated with a decrease in flow velocity for both LAA and RAA [LAA velocity-SR vs. AF: 61 +/- 22 vs. 29 +/- 18 m/sec (p < 0.01), RAA velocity-SR vs. AF: 46 +/- 20 vs. 19 +/- 8 m/sec (p < 0.01)]. Based on simple linear regression analysis, LAA velocity and RAA velocity were positively correlated, and RAA velocity was inversely correlated with brain natriuretic peptide (BNP). CONCLUSION: AF was associated with decreased RAA and LAA flow velocities. RAA velocity was found to be positively correlated with LAA velocity and negatively correlated with BNP. The plasma BNP concentration may serve as a determinant of LAA and RAA functions. PMID- 22509438 TI - Impact of right ventricular apical pacing and its frequency on left atrial function. AB - BACKGROUND: Right ventricular apical (RVA) pacing induces left ventricular (LV) dyssynchrony, increases the risk of persistent atrial fibrillation in the long term. The aim was to investigate the effects of RVA pacing on left atrial (LA) function, which are unknown. METHODS: Echocardiographic evaluation including LV dyssynchrony based on conventional Doppler, tissue Doppler imaging and speckle tracking strain echocardiography was done before and after (12 months) single chamber ventricular pacemaker implantation in 40 patients with sick sinus syndrome. Patients were divided to 2 groups, according to the RVA pacing frequency (group I had higher pacing rate of more than 50% and group II, less than 50%). RESULTS: There was no significant difference in LV ejection fraction, however, mean global LV strain, myocardial performance index, and parameters of LV dyssynchrony had shown significant changes after 12 months of RVA pacing. There were also significant increase in the LA volume index and the reduction of peak systolic LA strain and strain rate (SR), peak early and late diastolic SR after RVA pacing. Moreover, there was significant deterioration of LV dyssynchrony and both LA and LV longitudinal function in even group II. LA functional deterioration and LA volume was significantly correlated with the frequency of RVA pacing. CONCLUSION: LV dyssynchrony, induced by RVA pacing, significantly impaired active LA contraction and passive stretching, and these findings were shown in the patients with even less than 50% of RVA pacing. Impairment of LA strain/SR was significantly correlated with the frequency of RVA pacing. PMID- 22509439 TI - Role of echocardiography in sinus venosus atrial septal defect combined with systemic and pulmonary vascular disease. AB - We present a case of persistent left superior vena cava, anomalous right pulmonary venous connection to the right-sided superior vena cava and sinus venosus atrial septal defect detected by computed tomography (CT) pulmonary angiography and echocardiography. These defects were surgically corrected using a double-patch technique. In fact, CT can provide anatomical information about a complex anomaly in the systemic and pulmonary vasculatures. Though modern imaging techniques are useful for detecting complex cardiovascular disease, careful echocardiographic examination should be performed to diagnose complex cardiac anomalies. PMID- 22509440 TI - Cases of hemolytic anemia with periprosthetic leaks evaluated by real-time 3 dimensional transesophageal echocardiography. AB - Hemolytic anemia is recognized as a rare complication of mitral valve replacement or repair. We report on a 44-year-old man with shortness of breath and hemolytic anemia, 23 years after mitral valve replacement (Hall-Kaster), and a 63-year-old woman diagnosed of hemolytic anemia, 4 years after mitral and tricuspid annuloplasty (Tailor ring, An-core ring). Routine 2-dimensional transthoracic echocardiography revealed paravalvular leakage around the prosthesis. Subsequent real-time 3-dimensional (3D)transesophageal echocardiography helped the perceptional appreciation of the leakage and the measuring of the regurgitant orifice area using the anatomically correct plane. Surgical findings of each case fit those of 3D volumetric images. PMID- 22509441 TI - Primary malignant pericardial mesothelioma presenting as acute pericarditis. AB - We report on a 21-year-old man with fever, dyspnea, and pleuritic chest pain. An electrocardiography showed ST elevation in multiple lead and thoracic echocardiography revealed moderate pericardial effusion. He was initially diagnosed with acute pericarditis, and treated with nonsteroidal anti inflammatory drugs and colchicines with clinical and laboratory improvement. After 1 month of medication, his symptoms recurred. An echocardiography showed constrictive physiology and the patient was treated with steroid on the top of current medication. The patient had been well for 7 months until dyspnea and edema developed, when an echocardiography showed marked increased pericardial thickness and constriction. Pericardial biopsy was performed and primary malignant pericardial mesothelioma was diagnosed. Malignancy should be considered in the differential diagnosis of recurrent pericarditis. PMID- 22509442 TI - A giant unruptured right coronary sinus of valsalva aneurysm. AB - There have been few case reports on giant sinus of Valsalva aneurysm (SVA). We report a case of a giant unruptured right coronary SVA that was confused with a pericardial cyst by transthoracic echocardiography. PMID- 22509443 TI - A remnant mitral subvalvular apparatus mimicking aortic valve vegetation after mitral valve replacement. AB - Preservation of the subvalvular apparatus has the merits of postoperative outcomes during mitral valve replacement for mitral regurgitation. We performed mitral valve replacement with anterior and posterior leaflet chordal preservation in a 65-year-old woman. On the 2nd postoperative day, routine postoperative trans thoracic echocardiography showed an unknown aortic subvalvular mobile mass. We report a case of a remnant mitral subvalvular apparatus detected by echocardiography after chordal preserving mitral valve replacement which was confused with postoperative aortic valve vegetation. PMID- 22509444 TI - Massive left ventricular pseudoaneurysm. PMID- 22509446 TI - Interaction Between Persistent Organic Pollutants and C-reactive Protein in Estimating Insulin Resistance Among Non-diabetic Adults. AB - OBJECTIVES: Chronic inflammation is now thought to play a key pathogenetic role in the associations of obesity with insulin resistance and diabetes. Based on our recent findings on persistent organic pollutants (POPs) including the lack of an association between obesity and either insulin resistance or diabetes prevalence among subjects with very low concentrations of POPs, we hypothesized that POP concentrations may be associated with inflammation and modify the associations between inflammation and insulin resistance in non-diabetic subjects. METHODS: Cross-sectional associations among serum POPs, C-reactive protein (CRP), and homeostasis model assessment of insulin resistance (HOMA-IR) were investigated in 748 non-diabetic participants aged >=20 years. Nineteen types of POPs in 5 subclasses were selected because the POPs were detectable in >=60% of the participants. RESULTS: Among the five subclasses of POPs, only organochlorine (OC) pesticides showed positive associations with CRP concentrations, while polychlorinated biphenyls (PCBs) showed inverse associations with CRP concentrations. There were statistically significant interactions between CRP and OC pesticides and between CRP and PCBs, in estimating HOMA-IR (P for interaction <0.01 and <0.01, respectively). CRP was not associated with HOMA-IR among subjects with low concentrations of OC pesticides or PCBs, while CRP was strongly associated with HOMA-IR among subjects with high concentrations of these POPs. CONCLUSIONS: In the current study, OC pesticides were associated with increased levels of CRP, a marker of inflammation, and both OC pesticides and PCBs may also modify the associations between CRP and insulin resistance. PMID- 22509447 TI - Suicide rate differences by sex, age, and urbanicity, and related regional factors in Korea. AB - OBJECTIVES: Identify the characteristics related to the suicide rates in rural and urban areas of Korea and discover the factors that influence the suicide rate of the rural and urban areas. METHODS: Using the data on causes of death from 2006 to 2008, the suicide rates were calculated and compared after age standardization based on gender, age group and urbanicity. And, in order to understand the factors that influence suicide rate, total 10 local characteristics in four domains--public service, social integration, residential environment, and economic status--were selected for multiple regression analysis. RESULTS: The suicide rates were higher in men than women, in rural areas than urban, and in older people than the younger. Generally, although there were variations according to age group and urbanicity, suicide rates were significantly related to residential environment and regional economic status but not related to regional welfare spending and social integration. In addition, the population over the age of 65 years, only regional economic status has significantly influence on their suicide rates. CONCLUSIONS: The influence of characteristics of regions on suicide rate is various by age-group, gender, and urbanicity. Therefore, in order to lower suicide rate and reduce the gap between regions, various approaches must be adopted by taking into account the socioeconomic characteristics of the regions. PMID- 22509448 TI - Vaccine storage practices and the effects of education in some private medical institutions. AB - OBJECTIVES: Although vaccination rates have increased, problems still remain in the storage and handling of vaccines. This study focused on inspecting actual vaccine storage status and awareness, and comparing them before and after education was provided. METHODS: In the primary inspection, a status survey checklist was completed by visual inspection. A questionnaire on the awareness of proper vaccine storage and handling was also administered to vaccine administrators in private medical institutions in 4 regions in Gyeongsangbuk province. One-on-one education was then carried out, and our self-produced manual on safe vaccine storage and management methods was provided. In the secondary inspection, the investigators visited the same medical institutions and used the same questionnaire and checklist used during the primary inspection. The results before and after education were compared, by treating each appropriate answer as 1 point. RESULTS: The average checklists score was 9.74 (out of 15 points), which increased significantly after education was provided (by 0.84, p<0.001). The participants demonstrated improved practices in recording storage temperatures (p=0.016), storing vaccines in the center of the refrigerator (p=0.004), storing vaccines with other medication and non-medical items (p=0.031) after education. The average score calculated from the questionnaires was 10.48 (out of 14 points), which increased after education (by 1.03, p<0.001). CONCLUSIONS: This study suggests that vaccine storage practices and awareness are inadequate, but can be partially improved by providing relevant education. Repetitive education and policy-making are required to store vaccines safely because one-off education and unenforced guidelines offer limited efficacy. PMID- 22509449 TI - Factors affecting public prejudice and social distance on mental illness: analysis of contextual effect by multi-level analysis. AB - OBJECTIVES: While there have been many quantitative studies on the public's attitude towards mental illnesses, it is hard to find quantitative study which focused on the contextual effect on the public's attitude. The purpose of this study was to identify factors that affect the public's beliefs and attitudes including contextual effects. METHODS: We analyzed survey on the public's beliefs and attitudes towards mental illness in Korea with multi-level analysis. We analyzed the public's beliefs and attitudes in terms of prejudice as an intermediate outcome and social distance as a final outcome. Then, we focused on the associations of factors, which were individual and regional socio-economic factors, familiarity, and knowledge based on the comparison of the intermediate and final outcomes. RESULTS: Prejudice was not explained by regional variables but was only correlated with individual factors. Prejudice increased with age and decreased by high education level. However, social distance controlling for prejudice increased in females, in people with a high education level, and in regions with a high education level and a high proportion of the old. Therefore, social distance without controlling for prejudice increased in females, in the elderly, in highly educated people, and in regions with a high education and aged community. CONCLUSIONS: The result of the multi-level analysis for the regional variables suggests that social distance for mental illness are not only determined by individual factors but also influenced by the surroundings so that it could be tackled sufficiently with appropriate considering of the relevant regional context with individual characteristics. PMID- 22509451 TI - Cigarette smoking and serum bilirubin subtypes in healthy Korean men: the Korea Medical Institute study. AB - OBJECTIVES: Cigarette smoking is a modifiable risk factor for cardiovascular disease. Bilirubin is a potent antioxidant and its concentration decreases in smokers. However, studies about the association between cigarette smoking and bilirubin are scarce and most are limited to total bilirubin. Additionally, bilirubin is highly related to hemoglobin. Therefore, this study evaluates the association between bilirubin subtypes and cigarette smoking in healthy Korean men independently of hemoglobin. METHODS: This study included 48 040 Korean men aged 30 to 87 years who visited the Korea Medical Institute for routine health examinations from January to December, 2007. The association of smoking with total, direct, and indirect bilirubin was assessed by logistic regression analysis taking into consideration differences in subjects and smoking characteristics. RESULTS: Current smokers had lower bilirubin concentrations than never-smokers and ex-smokers. Smoking amount and duration were inversely significantly associated with total, direct, and indirect bilirubin. In a multivariable adjusted model, compared to never-smokers, the odds ratios (ORs) and 95% confidence intervals (CIs) of current smokers with the highest number of pack-years were 1.7 (1.6 to 1.9) for total, 1.5 (1.4 to 1.6) for direct, and 1.7 (1.6 to 1.9) for indirect bilirubin. After further adjustment for hemoglobin, this association became stronger (OR [95% CI], 2.1 [1.9 to 2.2] for total; 1.9 [1.8 to 2.0] for direct; 2.0 [1.9 to 2.2] for indirect bilirubin). CONCLUSIONS: In this study, bilirubin subtypes are inversely associated with smoking status, smoking amount, and smoking duration in healthy Korean men independently of hemoglobin. Further studies are needed to investigate this association in healthy Korean women. PMID- 22509450 TI - The association between serum albumin levels and metabolic syndrome in a rural population of Korea. AB - OBJECTIVES: A positive association between serum albumin levels and metabolic syndrome has been reported in observation studies, but it has not been established in the Korean population. The purpose of this study was to evaluate the association between serum albumin levels and the presence of metabolic syndrome among a sample of apparently healthy Korean adults. METHODS: This cross sectional study analyzed data of 3189 community-dwelling people (1189 men and 2000 women) who were aged 40 to 87 years and were living in a rural area in Korea. Serum albumin levels were classified into quartile groups for each sex. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III guidelines with an adjusted waist circumference cut-off value (>=90 cm for men and >=85 cm for women). An independent association between serum albumin levels and metabolic syndrome was assessed by multiple logistic regression analysis. RESULTS: Higher serum albumin levels were associated with increased prevalence of metabolic syndrome. The odds ratio (95% confidence interval) of the prevalence of metabolic syndrome for the highest versus the lowest serum albumin quartiles was 2.81 (1.91 to 4.14) in men and 1.96 (1.52 to 2.52) in women, after adjusting for age, smoking status, alcohol consumption, and physical activity. When each metabolic abnormality was analyzed separately, higher serum albumin levels were significantly associated with hypertriglyceridemia and hyperglycemia in both sexes, and with abdominal obesity in men. CONCLUSIONS: These results suggest that higher serum albumin levels are positively associated with an increased risk of metabolic syndrome in Korean adults. PMID- 22509452 TI - Trends in gender-based health inequality in a transitional society: a historical analysis of South Korea. AB - OBJECTIVES: This study examined the trends in gender disparity in the self-rated health of people aged 25 to 64 in South Korea, a rapidly changing society, with specific attention to socio-structural inequality. METHODS: Representative sample data were obtained from six successive, nationwide Social Statistics Surveys of the Korean National Statistical Office performed during 1992 to 2010. RESULTS: The results showed a convergent trend in poor self-rated health between genders since 1992, with a sharper decline in gender disparity observed in younger adults (aged 25 to 44) than in older adults (aged 45 to 64). The diminishing gender gap seemed to be attributable to an increase in women's educational attainment levels and to their higher status in the labor market. CONCLUSIONS: The study indicated the importance of equitable social opportunities for both genders for understanding the historical trends in the gender gap in the self-reported health data from South Korea. PMID- 22509453 TI - Ankle-brachial index, peripheral arterial disease, and diabetic retinopathy. PMID- 22509454 TI - SEM Analysis of MTAD Efficacy for Smear Layer Removal from Periodontally Affected Root Surfaces. AB - OBJECTIVE: Biopure(r) MTAD (Dentsply Tulsa Dental, USA) has been developed as a final irrigant following root canal shaping to remove intracanal smear layer. Many of the unique properties of MTAD potentially transfer to the conditioning process of tooth roots during periodontal therapy. The aim of this ex vivo study was to evaluate the effect of MTAD on the removal of smear layer from root surfaces. MATERIALS AND METHODS: Thirty two longitudinally sectioned specimens from 16 freshly extracted teeth diagnosed with advanced periodontal disease were divided into four groups. In group 1 and 2, the root surfaces were scaled using Gracey curettes. In group 3 and 4, 0.5 mm of the root surface was removed using a fissure bur. The specimens in group 1 and 3 were then irrigated by normal saline. The specimens in groups 2 and 4 were irrigated with Biopure MTAD. All specimens were prepared for SEM and scored according to the presence of smear layer. RESULTS: MTAD significantly increased (P=0.001) the smear layer removal in both groups 2 and 4 compared to the associated control groups, in which only saline was used. CONCLUSION: MTAD increased the removal of the smear layer from periodontally affected root surfaces. Use of MTAD as a periodontal conditioner may be suggested. PMID- 22509455 TI - Saliva secretion and efficacy of helicobacter pylori eradication in peptic ulcer patients. AB - OBJECTIVE: It has been noted that the presence of Helicobacter pylori (H. pylori) in the oral cavity may affect the outcome of eradication therapy. This condition is associated with the recurrence of gastric infection. The optimum secretion of saliva promotes oral health consequently influencing H. pylori eradication. The purpose of this study was to investigate the relation between salivary secretion and the efficacy of H. pylori eradication from the stomach. MATERIALS AND METHODS: Forty five patients with gastric H. pylori infection were enrolled in this study. Diagnosis of H. pylori infection was confirmed by endoscopy, biopsy, urease test and histological examination. Salivary secretion of all participants was determined under standard condition before the beginning of antibacterial treatment. Then the patients were treated with a 14-day course anti-H. pylori regimen consisting of amoxicillin, omeprazole, metronidazole and bismuth. The efficacy of eradication therapy was evaluated 4 weeks after the end of the treatment course. Mann-Whitney U test was used to analyze the variables. RESULTS: The median of salivary secretion among successful and unsuccessful H. pylori eradication groups was 0.48 ml/min and 0.24 ml/min, respectively (p=0.005). CONCLUSION: Although the type of drug regimens is challenging, the efficacy of H. pylori eradication from the stomach might be reduced by lower salivary secretion. PMID- 22509457 TI - Microleakage and Micrographic Evaluation of Composite Restorations with Various Bases over ZOE Layer in Pulpotomized Primary Molars. AB - OBJECTIVE: Zinc oxide eugenol (ZOE) under composite restorations should be covered with a suitable material in order to prevent the harmful effect of ZOE on the composite. The aim of this in vitro study was to evaluate microleakage of composite restorations in pulpotomized primary molars with different bases for covering the ZOE layer and to assess the distance between different layers. MATERIALS AND METHODS: Proximo-occlusal cavities were prepared in 78 extracted second primary molars. Carious lesions were removed and pulpotomy was carried out. Zinc oxide eugenol paste was placed in 2-mm thickness. The teeth were randomly divided in 6 groups and restored as follows: 1. Light-cured composite; 2. Resin-modified glass-ionomer and composite resin; 3. Glass-ionomer and composite resin; 4. Light-cured calcium hydroxide and composite resin; 5. Calcium hydroxide and composite resin; 6. Amalgam and composite resin. The restored specimens were thermocycled for 500 cycles (5 degrees C/55 degrees C) and microleakage was assessed by dye penetration technique. Three specimens from each group were processed for scanning electron microscope evaluation to determine the distance between the layers. The results were analyzed by Kruskal-Wallis and Dunn tests. RESULTS: Microleakage assessment revealed significant differences between the groups (P=0.04), with the amalgam group exhibiting the lowest microleakage values. In SEM micrographs no significant differences were observed in the distance between ZOE base layers (P=0.94) and base-composite layers (P=0.47); however, the amalgam group had the lowest distances. CONCLUSION: The use of amalgam over zinc oxide eugenol layer in pulpotomized primary molars decreases microleakage. PMID- 22509456 TI - Association between dental caries and body mass index among hamedan elementary school children in 2009. AB - OBJECTIVE: Excessive weight in children is a major public health concern. The intake of refined carbohydrates, especially sugars and the prevalence of dental caries are well documented in the literature. The purpose of this study was to investigate the relationship between dental caries and BMI in elementary school children. MATERIALS AND METHODS: The sampling technique used in the present study was a cluster random sampling. A total of 1000 pupils (500 girls, 500 boys) aged 6-11 years from 20 private and state elementary schools (10 boys, 10 girls). The weight status was measured in children by assessment of body mass index (BMI) (=body weight/body height(2) kg/m(2)) corresponding to gender and age-ranked percentages. To assess the caries frequency the decayed filled teeth (DFT) index for permanent dentition and the dft index for primary dentition were used since they give good perception about the situation of tooth caries in young patients. RESULTS: The highest mean total dft/DFT was seen in normal weight and lowest average in at risk of overweight children. There was not a statistically significant relationship found between high weight and caries frequency in the first (p=0.08) and permanent dentitions (p=0.06). CONCLUSION: The results of this preliminary study do not support an association between dental caries and obesity. PMID- 22509458 TI - Evaluation of stability changes in tapered and parallel wall implants: a human clinical trial. AB - OBJECTIVE: To determine the pattern of stability changes as a reflection of early healing around single-stage roughened-surface implants in humans utilizing resonance frequency analysis (RFA). MATERIALS AND METHODS: Hundred twenty-five patients who demanded dental implants were treated with two different implant (Nobel Biocare ReplaceTM and StrummanTM ITI) systems. Bone type was classified into four groups. RFA was used for direct measurement of implant stability on the day of implant placement and consecutively at 14, 30 and 60 days after placement. The data were analyzed with Student t test and regression analysis. RESULTS: Three-hundred four roughened surface implants placed in the maxilla and mandible were evaluated. In ReplaceTM implants the lowest mean stability measurement was at 30 days for all bone types and the stability did not change significantly in any of the bone types (p>0.05). ITITM implants demonstrated the lowest stability at 60 days for type 1 and 30 days and baseline for type 2, 3 and 4 bones. In addition, there was significant differences in implant stability between bone types 1 and 4 (P<0.001), 2 and 3 (p<0.05), and bone types 3 and 4 (P=0.07) at all aforementioned times in ITITM implants. In ReplaceTM implants, regarding the implant diameter, contrary to ITI implants, no significant stability changes were detected (p>0.05). No significant difference was observed regarding gender, age and lengths in both systems. CONCLUSION: In comparison to ITITM implants, ReplaceTM implants revealed no significant difference in the pattern of stability changes among different bone types. PMID- 22509459 TI - Tensile bond strength of metal bracket bonding to glazed ceramic surfaces with different surface conditionings. AB - OBJECTIVE: The objective of this study was to compare the tensile bond strength of metal brackets bonding to glazed ceramic surfaces using three various surface treatments. MATERIALS AND METHODS: Forty two glazed ceramic disks were assigned to three groups. In the first and second groups the specimens were etched with 9.5% hydrofluoric acid (HFA). Subsequently in first group, ceramic primer and adhesive were applied, but in second group a bonding agent alone was used. In third group, specimens were treated with 35% phosphoric acid followed by ceramic primer and adhesive application. Brackets were bonded with light cure composites. The specimens were stored in distilled water in the room temperature for 24 hours and thermocycled 500 times between 5 degrees C and 55 degrees C. The universal testing machine was used to test the tensile bond strength and the adhesive remenant index scores between three groups was evaluated. The data were subjected to one-way ANOVA, Tukey and Kruskal-Wallis tests respectively. RESULTS: The tensile bond strength was 3.69+/-0.52 MPa forfirst group, 2.69+/-0.91 MPa for second group and 3.60+/-0.41 MPa for third group. Group II specimens showed tensile strength values significantly different from other groups (P<0.01). CONCLUSION: In spite of limitations in laboratory studies it may be concluded that in application of Scotch bond multipurpose plus adhesive, phosphoric acid can be used instead of HFA for bonding brackets to the glazed ceramic restorations with enough tensile bond strength. PMID- 22509460 TI - A composite buccal flap for alar based defect reconstruction: a technical note. AB - It is difficult to reconstruct an alar defect with cartilage involvement. Here in the authors report a case of traumatic alar loss during childhood in which an alar reconstruction was carried out with a composite auricular graft put over the pedicle buccal flap which was rotated and passed through the intraoral side. The lining skin and auricular cartilage for the flap was obtained from the auricular region which was acceptable for the patient. All procedures were performed under general anesthesia. One year follow up revealed satisfactory results with minimal contracture of the graft. PMID- 22509461 TI - Radicular cyst associated with a primary first molar: A case report. AB - Radicular cysts arising from deciduous teeth are rare. This report presents a case of radicular cyst associated with a primary molar following pulp therapy and discusses the relationship between pulp therapy and the rapid growth of the cyst. The treatment consisted of enucleation of the cyst sac and extraction of the involved primary teeth and 20 months follow up of the patient. Early diagnosis of the lesion would have lead to a less aggressive treatment plan. PMID- 22509462 TI - Genome size in Anthurium evaluated in the context of karyotypes and phenotypes. AB - BACKGROUND AND AIMS: Anthurium is an important horticultural crop from the family Araceae, order Alismatales, a lineage considered to have diverged from other monocots prior to the cereals. Genome size and its distribution in Anthurium were investigated to gain a basic understanding of genome organization in this large genus and to forge a firm foundation for advancement of molecular approaches for the study of Anthurium. Currently, genome size estimates have been reported for only two Anthurium samples. METHODOLOGY: Bulk nuclear DNA content estimates were obtained by flow cell cytometry using leaf tissue collected from Anthurium species of different subgeneric groups and from commercial cultivars. The most current and well-supported topology of subgeneric, sectional relationships was applied to present genome size estimates in the context of reported chromosome counts, karyotypes, putative phylogenetic relationships, observed phenotypes and pedigree. PRINCIPAL RESULTS: Genome size estimates based on bulk nuclear DNA content for 77 accessions representing 34 species and 9 cultivars were obtained, including initial estimates for 33 Anthurium species, and both the smallest (Anthurium obtusum; Tetraspermium) and largest (Anthurium roseospadix; Calomystrium) Anthurium genome sizes reported to date. Genome size did not distinguish any subgeneric section, but ranged 5-fold (4.42-20.83 pg/2 C) despite consistent 2N= 30 chromosome counts. Intraspecies genome size variation >20 % is reported for Anthurium ravenii, A. watermaliense and A. gracile. CONCLUSIONS: Genome size estimates for Anthurium species spanning 13 recognized subgeneric sections indicate that genome size does not generally correlate with chromosome count or phylogenetic relationships. Mechanisms of genome expansion and contraction, including amplification and reduction of repetitive elements, polyploidy, chromosome reorganization/loss, may be involved in genome evolution in Anthurium as in other species. The new information on Anthurium genome sizes provides a platform for molecular studies supporting further research on genome evolution as well as cultivar development. PMID- 22509463 TI - Covalently bonded three-dimensional carbon nanotube solids via boron induced nanojunctions. AB - The establishment of covalent junctions between carbon nanotubes (CNTs) and the modification of their straight tubular morphology are two strategies needed to successfully synthesize nanotube-based three-dimensional (3D) frameworks exhibiting superior material properties. Engineering such 3D structures in scalable synthetic processes still remains a challenge. This work pioneers the bulk synthesis of 3D macroscale nanotube elastic solids directly via a boron doping strategy during chemical vapour deposition, which influences the formation of atomic-scale "elbow" junctions and nanotube covalent interconnections. Detailed elemental analysis revealed that the "elbow" junctions are preferred sites for excess boron atoms, indicating the role of boron and curvature in the junction formation mechanism, in agreement with our first principle theoretical calculations. Exploiting this material's ultra-light weight, super hydrophobicity, high porosity, thermal stability, and mechanical flexibility, the strongly oleophilic sponge-like solids are demonstrated as unique reusable sorbent scaffolds able to efficiently remove oil from contaminated seawater even after repeated use. PMID- 22509464 TI - The eye limits the brain's learning potential. AB - The concept of a critical period for visual development early in life during which sensory experience is essential to normal neural development is now well established. However recent evidence suggests that a limited degree of plasticity remains after this period and well into adulthood. Here, we ask the question, "what limits the degree of plasticity in adulthood?" Although this limit has been assumed to be due to neural factors, we show that the optical quality of the retinal image ultimately limits the brain potential for change. We correct the high-order aberrations (HOAs) normally present in the eye's optics using adaptive optics, and reveal a greater degree of neuronal plasticity than previously appreciated. PMID- 22509465 TI - High susceptibility to lipopolysaccharide-induced lethal shock in encephalomyocarditis virus-infected mice. AB - Secondary bacterial infection in humans is one of the pathological conditions requiring clinical attention. In this study, we examined the effect of lipopolysaccharide (LPS) on encephalomyocarditis virus (EMCV) infected mice. All mice inoculated with EMCV at 5 days before LPS challenge died within 24 h. LPS induced TNF-alpha mRNA expression was significantly increased in the brain and heart at 5 days after EMCV infection. CD11b(+)/TLR4(+) cell population in the heart was remarkably elevated at 5 days after EMCV infection, and sorted CD11b(+) cells at 5 days after EMCV infection produced a large amount of TNF-alpha on LPS stimulation in vivo and in vitro. In conclusion, we found that the infiltration of CD11b(+) cells into infected organs is involved in the subsequent LPS-induced lethal shock in viral encephalomyocarditis. This new experimental model can help define the mechanism by which secondary bacterial infection causes a lethal shock in viral encephalomyocarditis. PMID- 22509466 TI - High Electrocatalytic Activity of Vertically Aligned Single-Walled Carbon Nanotubes towards Sulfide Redox Shuttles. AB - Vertically aligned single-walled carbon nanotubes (VASWCNTs) have been successfully transferred onto transparent conducting oxide glass and implemented as efficient low-cost, platinum-free counter electrode in sulfide -mediated dye sensitized solar cells (DSCs), featuring notably improved electrocatalytic activity toward thiolate/disulfide redox shuttle over conventional Pt counter electrodes. Impressively, device with VASWCNTs counter electrode demonstrates a high fill factor of 0.68 and power conversion efficiency up to 5.25%, which is significantly higher than 0.56 and 3.49% for that with a conventional Pt electrode. Moreover, VASWCNTs counter electrode produces a charge transfer resistance of only 21.22 Omega towards aqueous polysulfide electrolyte commonly applied in quantum dots-sensitized solar cells (QDSCs), which is several orders of magnitude lower than that of a typical Pt electrode. Therefore, VASWCNTs counter electrodes are believed to be a versatile candidate for further improvement of the power conversion efficiency of other iodine-free redox couple based DSCs and polysulfide electrolyte based QDSCs. PMID- 22509467 TI - Publication Ethics in HIR. PMID- 22509468 TI - Medical image retrieval: past and present. AB - With the widespread dissemination of picture archiving and communication systems (PACSs) in hospitals, the amount of imaging data is rapidly increasing. Effective image retrieval systems are required to manage these complex and large image databases. The authors reviewed the past development and the present state of medical image retrieval systems including text-based and content-based systems. In order to provide a more effective image retrieval service, the intelligent content-based retrieval systems combined with semantic systems are required. PMID- 22509469 TI - The Development of Medical Record Items: a User-centered, Bottom-up Approach. AB - OBJECTIVES: Clinical documents (CDs) have evolved from traditional paper documents containing narrative text information into the electronic record sheets composed of itemized records, where each record is expressed as an item with a specific value. We defined medical record (MR) items to be information entities with a specific value. These entities were then used to compile form-based clinical documents as part of an electronic health record system (EHR-s). METHODS: We took a reusable bottom-up developmental approach for the MR items, which provided three things: efficient incorporation of the local needs and requirements of the medical professionals from various departments in the hospital, comprehensive inclusion of the essential concepts of the basic elements required in clinical documents, and the provision of a structured means for meaningful data entry and retrieval. This paper delineates our experiences in developing and managing medical records at a large tertiary university hospital in Korea. RESULTS: We collected 63,232 MR items from paper records scanned into 962 CDs. The MR item database was constructed using 13,287 MR items after removing redundant items. During the first year of service users requested changes to be made to 235 (1.8%) attributes of the MR items and also requested the additional 9,572 new MR items. In the second year, the attributes of 70 (0.5%) of the existing MR items were changed and 3,704 new items were added. The number of registered MR items increased by 72.0% in the first year and 27.9% in the second year. CONCLUSIONS: The MR item concept provides an easier and more structured means of data entry within an EHR-s. By using these MR items, various kinds of clinical documents can be easily constructed and allows for medical information to be reused and retrieved as data. The success of the use of MR items in a large tertiary university hospital system provides evidence that verifies our approach as being an efficient means of user-oriented and structured data entry, enabling the easy reuse of medical records. PMID- 22509470 TI - Improving the Performance of Text Categorization Models used for the Selection of High Quality Articles. AB - OBJECTIVES: Machine learning systems can considerably reduce the time and effort needed by experts to perform new systematic reviews (SRs). This study investigates categorization models, which are trained on a combination of included and commonly excluded articles, which can improve performance by identifying high quality articles for new procedures or drug SRs. METHODS: Test collections were built using the annotated reference files from 19 procedure and 15 drug systematic reviews. The classification models, using a support vector machine, were trained by the combined even data of other topics, excepting the desired topic. This approach was compared to the combination of included and commonly excluded articles with the combination of included and excluded articles. Accuracy was used for the measure of comparison. RESULTS: On average, the performance was improved by about 15% in the procedure topics and 11% in the drug topics when the classification models trained on the combination of articles included and commonly excluded, were used. The system using the combination of included and commonly excluded articles performed better than the combination of included and excluded articles in all of the procedure topics. CONCLUSIONS: Automatically rigorous article classification using machine learning can reduce the workload of experts when they perform systematic reviews when the topic specific data are scarce. In particular, when the combination of included and commonly excluded articles is used, this system will be more effective. PMID- 22509471 TI - A mixture of experts model for the diagnosis of liver cirrhosis by measuring the liver stiffness. AB - OBJECTIVES: The mixture-of-experts (ME) network uses a modular type of neural network architecture optimized for supervised learning. This model has been applied to a variety of areas related to pattern classification and regression. In this research, we applied a ME model to classify hidden subgroups and test its significance by measuring the stiffness of the liver as associated with the development of liver cirrhosis. METHODS: The data used in this study was based on transient elastography (Fibroscan) by Kim et al. We enrolled 228 HBsAg-positive patients whose liver stiffness was measured by the Fibroscan system during six months. Statistical analysis was performed by R-2.13.0. RESULTS: A classical logistic regression model together with an expert model was used to describe and classify hidden subgroups. The performance of the proposed model was evaluated in terms of the classification accuracy, and the results confirmed that the proposed ME model has some potential in detecting liver cirrhosis. CONCLUSIONS: This method can be used as an important diagnostic decision support mechanism to assist physicians in the diagnosis of liver cirrhosis in patients. PMID- 22509472 TI - A Study on User Satisfaction regarding the Clinical Decision Support System (CDSS) for Medication. AB - OBJECTIVES: Many medication errors can occur when ordering and dispensing medicine in hospitals. The clinical decision support system (CDSS) is widely used in an effort to reduce medication errors. This study focused on the evaluation of user satisfaction with the CDSS for medication at a university hospital. Specifically, this study aimed to identify the factors influencing user satisfaction and to examine user requirements in order to further improve user satisfaction and drug safety. METHODS: The study was based on survey data from 218 users (103 doctors, 103 nurses, and 15 pharmacists) at a university hospital that uses the CDSS. In order to identify the factors influencing user satisfaction with the CDSS, a multiple linear regression was performed. In order to compare the satisfaction level among the professional groups, an analysis of variance (ANOVA) was performed. RESULTS: The reliability of information, decision supporting capability, and departmental support were significant factors in influencing user satisfaction. In addition, nurses were the most satisfied group, followed by pharmacists and doctors according to the ANOVA. Areas for further improvement in enhancing drug safety were real time information searching and decision supporting capabilities to prevent adverse drug events (ADE) in a timely manner. CONCLUSIONS: We found that the CDSS users were generally satisfied with the system and that it complements the nationwide drug utilization review (DUR) system in reducing ADE. Further CDSS evaluation in other hospitals is needed to improve user satisfaction and drug safety. PMID- 22509473 TI - Application of social network analysis to health care sectors. AB - OBJECTIVES: This study aimed to examine the feasibility of social network analysis as a valuable research tool for indicating a change in research topics in health care and medicine. METHODS: Papers used in the analysis were collected from the PubMed database at the National Library of Medicine. After limiting the search to papers affiliated with the National Institutes of Health, 27,125 papers were selected for the analysis. From these papers, the top 100 non-duplicate and most studied Medical Subject Heading terms were extracted. NetMiner V.3 was used for analysis. Weighted degree centrality was applied to the analysis to compare the trends in the change of research topics. Changes in the core keywords were observed for the entire group and in three-year intervals. RESULTS: The core keyword with the highest centrality value was "Risk Factor," followed by "Molecular Sequence Data," "Neoplasms," "Signal Transduction," "Brain," and "Amino Acid Sequence." Core keywords varied between time intervals, changing from "Molecular Sequence Data" to "Risk Factors" over time. "Risk Factors" was added as a new keyword and its social network was expanded. The slope of the keywords also varied over time: "Molecular Sequence Data," with a high centrality value, had a decreasing slope at certain intervals, whereas "SNP," with a low centrality value, had an increasing slope at certain intervals. CONCLUSIONS: The social network analysis method is useful for tracking changes in research topics over time. Further research should be conducted to confirm the usefulness of this method in health care and medicine. PMID- 22509474 TI - Comparing the Certification Criteria for CCHIT-Certified Ambulatory EHR with the SNUBH's EHR Functionalities. AB - OBJECTIVES: This study aims to investigate the suitability of electronic health record (EHR) systems in Korea for global certification and to propose functions for future global systems by comparing and analyzing the certification criteria for Certification Commission for Health Information Technology (CCHIT) Certified Ambulatory EHR with BESTCare, which is the EHR system at Seoul National University Bundang hospital. METHODS: Domain expert groups were formed to analyze the inclusion of BESTCare functions and the types of differences for each of the CCHIT Certified 2011 Ambulatory EHR Certification Criteria. The types of differences were divided into differences in functions (F), differences in business processes (B), and differences in government policies (P). RESULTS: Generally, the criteria that showed differences in functions pertained to the connection between the diagnosis/problem list and order, the alert and warning functions for medication-diagnosis interactions, and the reminder/instruction/notification messages related to the patient's immunization status; these absent functions were enhanced clinical decision support system (CDSS) functions related to patient safety and healthcare quality. Differences in government policies were found in the pharmacy's electronic prescription functions, while differences in business processes were found in the functions constrained by the local workflow or internal policy, which require some customization. CONCLUSIONS: Functions that differed between the CCHIT certification criteria and the BESTCare system in this study should be considered when developing a global EHR system. Such a system will need to be easily customizable to adapt to various government policies and local business processes. These functions should be considered when developing a global EHR system certified by CCHIT in the future. PMID- 22509475 TI - An Evaluation of Multiple Query Representations for the Relevance Judgments used to Build a Biomedical Test Collection. AB - OBJECTIVES: The purpose of this study is to validate a method that uses multiple queries to create a set of relevance judgments used to indicate which documents are pertinent to each query when forming a biomedical test collection. METHODS: The aspect query is the major concept of this research; it can represent every aspect of the original query with the same informational need. Manually generated aspect queries created by 15 recruited participants where run using the BM25 retrieval model in order to create aspect query based relevance sets (QRELS). In order to demonstrate the feasibility of these QRELSs, The results from a 2004 genomics track run supported by the National Institute of Standards and Technology (NIST) were used to compute the mean average precision (MAP) based on Text Retrieval Conference (TREC) QRELSs and aspect-QRELSs. The rank correlation was calculated using both Kendall's and Spearman's rank correlation methods. RESULTS: We experimentally verified the utility of the aspect query method by combining the top ranked documents retrieved by a number of multiple queries which ranked the order of the information. The retrieval system correlated highly with rankings based on human relevance judgments. CONCLUSIONS: Substantial results were shown with high correlations of up to 0.863 (p < 0.01) between the judgment-free gold standard based on the aspect queries and the human-judged gold standard supported by NIST. The results also demonstrate that the aspect query method can contribute in building test collections used for medical literature retrieval. PMID- 22509476 TI - Smart information system for gachon university gil hospital. AB - OBJECTIVES: In this research, the hospital information system of Gachon University Gil hospital is introduced and a future strategy for hospital information systems is proposed. METHODS: This research introduces the development conditions of hospital information system at Gachon University Gil hospital, information about the development of the enterprise resource planning (ERP), a medical service process improvement system, and the personal health record (PHR) system. RESULTS: The medical service process and work efficiency were improved through the medical service process improvement system, which is the most common hospital information system at Gachon University Gil hospital and which includes an emergency medical service system, an online evaluation system and a round support system. CONCLUSIONS: Gachon University Gil hospital developed medical service improvement systems to increase work efficiency of medical team and optimized the systems to prove the availability of high-quality medical services for patients and their families. The PHR-based personalized health care solution is under development and will provide higher quality medical service for more patients in the future. PMID- 22509478 TI - Rapamycin induces the anti-apoptotic protein survivin in neuroblastoma. AB - Neuroblastoma is the most common solid tumor of infancy, accounting for 15% of all cancer cell deaths in children. Expression of the anti-apoptotic protein survivin in these tumors correlates with poor prognostic features and resistance to therapy. The mammalian target of rapamycin (mTOR) protein is being explored as a potential therapeutic target in patients with this disease. The objective of this study was to test the hypothesis that rapamycin regulates survivin expression and function in neuroblastoma cells. To explore this hypothesis, we treated two different neuroblastoma lines (NB7, NB8) and a well-characterized control lung cancer cell line, A549, with varying doses of rapamycin (0.1-10MUM) for serial time points (2-48 hours). RNA and protein expression levels were then evaluated by quantitative RT-PCR and western blotting, respectively. Cell proliferation and apoptosis were assayed by WST-1 and Annexin V. The results showed a rapamycin-dependent increase in survivin mRNA and protein levels in the neuroblastoma cell lines in a dose- and time-dependent fashion, while a decrease in these levels was observed in control cells. Rapamycin inhibited cell proliferation in both A549 and neuroblastoma cells however neuroblastoma cells had less apoptosis than A549 cells (9% vs. 20%). In summary, our results indicate that rapamycin induces expression of the anti-apoptotic protein survivin in neuroblastoma cells which may protect these cells from programmed cell death. Induction of survivin by rapamycin could therefore be a potential mechanism of neuroblastoma tumor cell resistance and rapamycin may not be an effective therapeutic agent for these tumors. PMID- 22509479 TI - Multiple protein-protein interactions within the DNA-PK complex are mediated by the C-terminus of Ku 80. AB - DNA double strand breaks (DSB) are among the most lethal forms of DNA damage and, in humans, are repaired predominantly by the non-homologous end joining (NHEJ) pathway. NHEJ is initiated by the Ku70/80 heterodimer binding free DNA termini and then recruiting the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the catalytically active DNA-PK holoenzyme. The extreme C-terminus of Ku80 (Ku80CTD) has been shown to be important for in vitro stimulation of DNA-PK activity and NHEJ in vivo. To better define the mechanism by which the Ku80CTD elicits these activities, we assessed its functional and physical interactions with DNA-PKcs and Ku70/80. The results demonstrate that DNA-PKcs activity could not be complemented by addition of a Ku80CTD suggesting that the physical connection of the C-terminus to the DNA binding domain of Ku70/80 is required for DNA -PKcs activation. Analysis of protein-protein interactions revealed a low but measurable binding of the Ku80CTD for Ku70/80DeltaC and for DNA-PKcs while dimer formation and the formation of higher ordered structures of the Ku80CTD was readily apparent. Ku has been shown to tether DNA termini possibly due to protein/protein interactions. Results demonstrate that the presence of the Ku80CTD stimulates this activity possibly through Ku80CTD/Ku80CTD interactions. PMID- 22509480 TI - Hedgehog signaling activation in the development of squamous cell carcinoma and adenocarcinoma of esophagus. AB - Hedgehog (Hh) signaling is frequently activated in human cancer, including esophageal cancer. Most esophageal cancers are diagnosed in the advanced stages, therefore, identifying the very alterations that drive esophageal carcinogenesis may help designing novel strategies to diagnose and treat the disease. Analysis of Hh signaling in precancerous lesions is a critical first step in determining the significance of this pathway for carcinogenesis. Here we report our data on Hh target gene expression in 174 human esophageal specimens [28 esophageal adenocarcinomas (EAC), 19 Barrett's esophagus, 103 cases of esophageal squamous cell carcinoma (ESCC), and 24 of squamous dysplastic lesions], and in two rat models of esophageal cancer. We found that 96% of human EAC express Hh target genes. We showed that PTCH1 expression is the most reliable biomarker. In contrast to EAC, only 38% of ESCC express Hh target genes. We found activation of Hh signaling in precancerous lesions of ESCCs and EACs in different degrees (21% and 58% respectively). Expression of Hh target genes is frequently detected in severe squamous dysplasia/ carcinoma in situ (p=0.04) and Barrett's esophagus (p=0.01). Unlike EAC, sonic hedgehog (Shh) expression was rare in ESCCs. Consistent with the human specimen data, we found a high percentage of Hh signaling activation in precancerous lesions in rat models. These data indicate that Hh signaling activation is an early molecular event in the development of esophageal cancer, particularly EAC. PMID- 22509481 TI - Crystal structure of peptidyl-tRNA hydrolase from mycobacterium smegmatis reveals novel features related to enzyme dynamics. AB - Peptidyl-tRNA hydrolase from Mycobacterium smegmatis is a single domain 21 kDa protein involved in the hydrolysis of prematurely produced peptidyl-tRNAs to ensure the viability of cells in bacteria, thus making it a potentially important drug target. In order to aid the development of potent drugs for controlling bacterial infections, the three-dimensional structure of peptidyl-tRNA hydrolase from Mycobacterium smegmatis has been determined. The protein adopts a compact alpha/beta globular fold with a twisted beta-sheet surrounded by alpha-helices. The functionally important C-terminal stretch has been unambiguously modeled for the first time in the unliganded structure of peptidyl-tRNA hydrolase. The segment, Gly138 - Val150 is mobile because it lacks significant interactions with the rest of the protein molecule. This conformational flexibility is reflected through different values of distances between a reference atom Ala147 C(alpha) of the segment Gly138 - Val150 to Gly114 C(alpha) from another segment from opposite side of the substrate binding channel in Mycobacterium smegmatis (7.8 A), Mycobacterium tuberculosis (9.5 A) and Escherichia coli (11.8 A). Similarly, the conformation of loop Gly109 - Gly117 with respect to another loop Asp95 - Asp100 also shows variability of the substrate binding cleft as the distance between Asp98 O(delta2) to Gly113 C(alpha) in Mycobacterium smegmatis is 4.5 A while the corresponding distances in Mycobacterium tuberculosis and Escherichia coli are 3.1 A and 6.7 A respectively. The hydrogen bonded interactions between Asn116, His22 and Asp95 indicate a stereochemically favorable arrangement of these residues for catalytic action. PMID- 22509477 TI - Human ABCG2: structure, function, and its role in multidrug resistance. AB - Human ABCG2 is a member of the ATP-binding cassette (ABC) transporter superfamily and is known to contribute to multidrug resistance (MDR) in cancer chemotherapy. Among ABC transporters that are known to cause MDR, ABCG2 is particularly interesting for its potential role in protecting cancer stem cells and its complex oligomeric structure. Recent studies have also revealed that the biogenesis of ABCG2 could be modulated by small molecule compounds. These modulators, upon binding to ABCG2, accelerate the endocytosis and trafficking to lysosome for degradation and effectively reduce the half-life of ABCG2. Hence, targeting ABCG2 stability could be a new venue for therapeutic discovery to sensitize drug resistant human cancers. In this report, we review recent progress on understanding the structure, function, biogenesis, as well as physiological and pathophysiological functions of ABCG2. PMID- 22509483 TI - Structural basis of heparin binding to camel peptidoglycan recognition protein-S. AB - Short peptidoglycan recognition protein (PGRP-S) is a member of the innate immunity system in mammals. PGRP-S from Camelus dromedarius (CPGRP-S) is found to be highly potent against bacterial infections. It is capable of binding to a wide range of pathogen-associated molecular patterns (PAMPs) including lipopolysaccharide (LPS), lipoteichoic acid (LTA) and peptidoglycan (PGN). The heparin-like polysaccharides have also been observed in some bacteria such as the capsule of K5 Escherichia coli thus making them relevant for determining the nature of their interactions with CPGRP-S. The binding studies of CPGRP-S with heparin disaccharide in solution using surface plasmon resonance gave a value 3.3*10(-7) M for the dissociation constant (Kd). The structure of the heparin bound CPGRP-S determined at 2.8A resolution revealed the presence of a bound heparin molecule in the binding pocket of CPGRP-S. It was found anchored tightly to the protein with the help of several ionic and hydrogen bonded interactions. Three sulphate groups of heparin S1, S2 and S3 have been found to interact with residues, Arg-31, Lys-90, Thr- 97, Asn-99 Asn-140, Gln-150 and Arg-170 of CPGRP S. The binding site includes two subsites, S-I and S-II with cleft-like structures. Heparin disaccharide is bound in subsite S-I. Previously determined structures of the complexes of CPGRP-S with LPS, LTA and PGN also showed that their glycan moieties were also held in subsite S-I indicating that heparin disaccharide also represents an important element for the recognition by CPGRP-S. PMID- 22509484 TI - HTLV-I Tax regulates the cellular proliferation through the down-regulation of PIP3-phosphatase expressions via the NF-kappaB pathway. AB - An oncogenic retrovirus, human T-cell leukemia virus type I (HTLV-I), encodes an oncoprotein, Tax, which plays critical roles in leukemogenesis of adult T-cell leukemia/lymphoma (ATLL) through the pleiotropic actions such as transcriptional regulation, cell cycle control, and transformation. We have previously reported that PTEN and SHIP- 1, PIP3 inositol phosphatases that negatively regulate the PI3-kinase signaling cascade, are disrupted in ATLL neoplasias. Overactivation of PI3-kinase signaling has an essential role in onset of ATLL. We report here that both PTEN and SHIP-1 are downregulated by Tax through the NF-kappaB signaling pathway. Tax expression upregulated phosphorylated Akt, a downstream serine/threonine kinase in the PI3-kinase signaling cascade. Activation of NF kappaB pathway also suppressed these phosphatases. An IkappaBDeltaN mutant which inhibits the activation of NF-kappaB prevented PIP3 phosphatase downregulation by Tax. The underlying mechanism of NF-kappaB mediated suppression of PIP3 phosphatases involved sequestration of the coactivator p300 by p65. These down regulations of PIP3 phosphatases were found to be essential for the Tax-induced cell proliferation. Thus, our results suggest that HTLV-I Tax downregulates PIP3 phosphatases through the NF-kappaB pathway, resulting in increased activation of the PI3-kinase signaling cascade in human T-cells and contributing to leukemogenesis. PMID- 22509482 TI - The HIV-1 passage from cytoplasm to nucleus: the process involving a complex exchange between the components of HIV-1 and cellular machinery to access nucleus and successful integration. AB - The human immunodeficiency virus 1 (HIV-1) synthesizes its genomic DNA in cytoplasm as soon as it enters the cell. The newly synthesized DNA remains associated with viral/cellular proteins as a high molecular weight pre integration complex (PIC), which precludes passive diffusion across intact nuclear membrane. However, HIV-1 successfully overcomes nuclear membrane barrier by actively delivering its DNA into nucleus with the help of host nuclear import machinery. Such ability allows HIV-1 to productively infect non-dividing cells as well as dividing cells at interphase. Further, HIV-1 nuclear import is also found important for the proper integration of viral DNA. Thus, nuclear import plays a crucial role in establishment of infection and disease progression. While several viral components, including matrix, viral protein R, integrase, capsid, and central DNA flap are implicated in HIV-1 nuclear import, their molecular mechanism remains poorly understood. In this review, we will elaborate the role of individual viral factors and some of current insights on their molecular mechanism(s) associated with HIV-1 nuclear import. In addition, we will discuss the importance of nuclear import for subsequent step of viral DNA integration. Hereby we aim to further our understanding on molecular mechanism of HIV-1 nuclear import and its potential usefulness for anti-HIV-1 strategies. PMID- 22509485 TI - Common micro RNAs (miRNAs) target complement factor H (CFH) regulation in Alzheimer's disease (AD) and in age-related macular degeneration (AMD). AB - Alzheimer's disease (AD) and age-related macular degeneration (AMD) are complex and progressive inflammatory degenerations of the human neocortex and retina. Recent molecular, genetic and epigenetic evidence indicate that at least 4 micro RNAs (miRNAs) - including the NF-kB-regulated miRNA-9, miRNA-125b, miRNA-146a and miRNA-155 - are progressively up-regulated in both AD and AMD. This quartet of up regulated miRNAs in turn down-regulate a small brain- and retinal-cell-relevant family of target mRNAs, including that encoding complement factor H (CFH), a major negative regulator of the innate immune and inflammatory response. Together miRNA-146a and miRNA-155 recognize an overlapping miRNA regulatory control (MiRC) region in the CFH 3'-untranslated region (3'- UTR; 5'-TTTAGTATTAA-3') to which either of these miRNAs may interact. Progressive, pathogenic increases in specific miRNA binding to the entire 232 nucleotide CFH 3'-UTR appears to be a major regulator of CFH expression down-regulation, and the inflammatory pathology that characterizes both AMD and AD. The data presented in this report provides evidence that up-regulation of brain- and retinal- abundant miRNAs, including miRNA-9, miRNA-125b, miRNA-146a and miRNA-155, are common to the pathogenetic mechanism of CFH deficiency that drives inflammatory neurodegeneration, and for the first time indicates multiple, independent miRNA-mediated regulation of the CFH mRNA 3'-UTR. PMID- 22509486 TI - Assembly stoichiometry of the GluK2/GluK5 kainate receptor complex. AB - Ionotropic glutamate receptors assemble as homo- or heterotetramers. One well studied heteromeric complex is formed by the kainate receptor subunits GluK2 and GluK5. Retention motifs prevent trafficking of GluK5 homomers to the plasma membrane, but coassembly with GluK2 yields functional heteromeric receptors. Additional control over GluK2/GluK5 assembly seems to be exerted by the aminoterminal domains, which preferentially assemble into heterodimers as isolated domains. However,the stoichiometry of the full-length GluK2/GluK5 receptor complex has yet to be determined, as is the case for all non-NMDA glutamate receptors. Here, we address this question, using a single-molecule imaging technique that enables direct counting of the number of each GluK subunit type in homomeric and heteromeric receptors in the plasma membranes of live cells. We show that GluK2 and GluK5 assemble with 2:2 stoichiometry. This is an important step toward understanding the assembly mechanism, architecture, and functional consequences of heteromer formation in ionotropic glutamate receptors. PMID- 22509488 TI - A novel method for preparing silver nanoparticle-hydrogel nanocomposites via pH induced self-assembly. AB - We present a novel and facile method to fabricate the silver nanoparticle (AgNP) sodium deoxycholate (NaDOC) hybrid hydrogel from the NaDOC-stablized AgNP colloidal hydrosol via the pH-induced self-assembly. PMID- 22509487 TI - FoldEco: a model for proteostasis in E. coli. AB - To gain insight into the interplay of processes and species that maintain a correctly folded, functional proteome, we have developed a computational model called FoldEco. FoldEco models the cellular proteostasis network of the E. coli cytoplasm, including protein synthesis, degradation, aggregation, chaperone systems, and the folding characteristics of protein clients. We focused on E. coli because much of the needed input information--including mechanisms, rate parameters, and equilibrium coefficients--is available, largely from in vitro experiments; however, FoldEco will shed light on proteostasis in other organisms. FoldEco can generate hypotheses to guide the design of new experiments. Hypothesis generation leads to system-wide questions and shows how to convert these questions to experimentally measurable quantities, such as changes in protein concentrations with chaperone or protease levels, which can then be used to improve our current understanding of proteostasis and refine the model. A web version of FoldEco is available at http://foldeco.scripps.edu. PMID- 22509489 TI - Toward aceneporphyrinoids: synthesis and transformations of palladium(II) meso anthriporphyrin. AB - meso-Anthriporphyrin is a carbaporphyrinoid with an anthracene ring embedded in the tripyrrolic framework. The coordination of palladium(II) results in a specific intramacrocyclic metal(II)-eta(2)-CC interaction which facilitates the cleavage to palladium(II) acyclic oligopyrrole with the appended anthracene moiety. PMID- 22509490 TI - Multi-scale structured, superhydrophobic and wide-angle, antireflective coating in the near-infrared region. AB - Superhydrophobic self-cleaning surfaces were produced with simultaneous wide angle optical transmittance in the near-infrared region and antireflection properties from combination of multi-scale surface topology based on silica nanoparticles, index grading and interference. PMID- 22509491 TI - Alkali earth metal (Ca, Sr, Ba) based thermostable metal-organic frameworks (MOFs) for proton conduction. AB - Three new alkaline earth metal based MOFs have been synthesized by using 4,4' sulfobisbenzoic acid (SBBA) and alkaline earth metal salts M(NO(3))(2), M = Ca, Sr, Ba. These MOFs exhibit interesting structural diversity, variable chemical stability as well as proton conductivity. PMID- 22509492 TI - Intercalation of magnesium into a graphite-like layered material of composition BC2N. AB - Magnesium was intercalated into a graphite-like layered material with an approximate composition of BC(2)N. The obtained material was a second-stage compound with a d-spacing of 0.367 nm for the intercalated layers. This is the first example of magnesium intercalation into a graphite-network-based material. PMID- 22509493 TI - Organocatalytic asymmetric oxy-Michael addition to a gamma-hydroxy-alpha,beta unsaturated thioester via hemiacetal intermediates. AB - We report an asymmetric oxy-Michael addition to a gamma-hydroxy-alpha,beta unsaturated thioester via hemiacetal intermediates in the presence of Cinchona alkaloid-thiourea-based bifunctional organocatalysts. This method provides a novel enantioselective route to beta-hydroxy carboxyl compounds, which in turn can be used to synthesize valuable chiral building blocks. PMID- 22509494 TI - Matrix-assisted polymer pen lithography induced Staudinger Ligation. AB - The Staudinger Ligation has been combined with Polymer Pen Lithography to create patterns of fluorescent and redox-active inks with 1-micrometer scale feature diameters over centimeter-scale areas. This report presents a straightforward strategy to expand the scope of organic reactions employed in surface science. PMID- 22509495 TI - Flavin as a photo-active acceptor for efficient energy and charge transfer in a model donor-acceptor system. AB - A donor-acceptor dyad model system using a flavin moiety as a photo-active acceptor has been synthesized for an energy and photo-induced electron transfer study. The photophysical investigations of the dyad revealed a multi-path energy and electron transfer process with a very high transfer efficiency. The photo activity of flavin was believed to play an important role in the process, implying the potential application of flavin as a novel acceptor molecule for photovoltaics. PMID- 22509496 TI - Hydration of hydrophilic thiolate monolayers visualized by atomic force microscopy. AB - Monolayers of mercaptoundecanol and mercaptoundecanoic acid were prepared on Au(111) films, immersed in aqueous solutions, and probed by frequency-modulation atomic force microscopy. The pN-order tip-surface force was observed over the monolayers as a function of vertical and lateral coordinates, together with the topography of the monolayers. The observed force distribution was modulated between adjacent OH endgroups in the mercaptoundecanol monolayer, as opposed to on top of COOH and COO(-) endgroups in the mercaptoundecanoic acid monolayer. Models of the interfacial hydrogen bond between water and the endgroups were proposed. The force distribution was insensitive to the electrolyte composition. There was no qualitative sign of tip-induced confinement of water. PMID- 22509497 TI - Cyborg cells: functionalisation of living cells with polymers and nanomaterials. AB - Living cells interfaced with a range of polyelectrolyte coatings, magnetic and noble metal nanoparticles, hard mineral shells and other complex nanomaterials can perform functions often completely different from their original specialisation. Such "cyborg cells" are already finding a range of novel applications in areas like whole cell biosensors, bioelectronics, toxicity microscreening, tissue engineering, cell implant protection and bioanalytical chemistry. In this tutorial review, we describe the development of novel methods for functionalisation of cells with polymers and nanoparticles and comment on future advances in this technology in the light of other literature approaches. We review recent studies on the cell viability and function upon direct deposition of nanoparticles, coating with polyelectrolytes, polymer assisted assembly of nanomaterials and hard shells on the cell surface. The cell toxicity issues are considered for many practical applications in terms of possible adverse effects of the deposited polymers, polyelectrolytes and nanoparticles on the cell surface. PMID- 22509498 TI - Coherent electric field characterization of molecular chirality in the time domain. AB - Intrinsic handedness encountered in molecular sciences plays an essential role in diverse physical, chemical and biological processes. Optical activity spectroscopy has enabled one to characterize such molecular handedness (chirality) and demonstrated its unique ability to provide stereo-specific structural insight into chiral molecular systems including biopolymers, chiral drugs, and superchiral materials. However, more extended applications including time-resolved studies have often been hindered by inherent limitations of conventional differential methods utilizing both left- and right-handed radiations. The latest methodological advance is heterodyned detection methods measuring wave interferences between signal and reference fields, which allowed direct characterizations of coherent chiroptical signals in a flash. With its ultimate sensitivity, the heterodyned chiroptical method promises to open new possibilities of transient electronic or vibrational optical activity measurements in the ultrafast time domain. PMID- 22509499 TI - Recent advances in transition metal-catalyzed enantioselective hydrogenation of unprotected enamines. AB - Transition metal-catalyzed enantioselective hydrogenation of enamines is undoubtedly a useful and environment-friendly method for the preparation of optically pure chiral amines and amine derivatives. Over the last few decades, the use of transition metal catalysts containing chiral phosphorus or phosphine oxazoline ligands attracted much attention for the hydrogenation of unprotected enamines. A number of efficient chiral catalysts have been developed, and some of them have shown high potential for the application in the synthesis of optical chiral amines in both laboratory and industry. This tutorial review focuses on the contributions concerning the transition metal-catalyzed enantioselective hydrogenation of unprotected enamines for the synthesis of chiral amines and amine derivatives. PMID- 22509500 TI - Subtle issues in model specification and estimation of marginal structural models. AB - We review the concept of time-dependent confounding by using the example in paper "Comparative effectiveness of individual angiotensin receptor blockers on risk of mortality in patients with chronic heart failure" by Desai et al. and illustrate how to adjust for it by using inverse probability of treatment weighting through a simulated example. We discuss a few subtle issues that arise in specification of the model for treatment required to fit marginal structural models (MSMs) and in specification of the structural model for the outcome. We discuss the differences between the effects estimated in MSMs and intention-to-treat effects estimated in randomized trials, followed by an outline of some limitations of MSMs. PMID- 22509501 TI - Photocurrent generation from hierarchical zinc-substituted hemoprotein assemblies immobilized on a gold electrode. AB - All connected: a protein-immobilized electrode comprising hierarchical assemblies of photoactive cytochrome b(562) reconstituted with zinc protoporphyrin IX exhibits remarkably enhanced photocurrent generation relative to an electrode bearing a single zinc-substituted hemoprotein layer. The protein oligomers, which bear a covalently linked protoporphyrin group, assemble by a supramolecular heme/heme pocket interaction. PMID- 22509502 TI - Multiple sclerosis. PMID- 22509503 TI - Aetiology: The X factor. PMID- 22509504 TI - Genomics: A complex code. PMID- 22509505 TI - Drugs: An injection of hope. PMID- 22509506 TI - Stem cells: Don't believe the hype. PMID- 22509507 TI - Perspective: Deconstructing a disease. PMID- 22509508 TI - Diagnostics: Getting a clear picture. PMID- 22509509 TI - Perspective: Let the sunshine in! PMID- 22509510 TI - Animal models: Not close enough. PMID- 22509511 TI - Progressive multiple sclerosis: The treatment gap. PMID- 22509512 TI - Alternative therapies: Desperate measures. PMID- 22509513 TI - Proceedings of the Joint Proceedings of the High Blood Pressure Research 2011 Scientific Sessions and the Inter-American Society of Hypertension Meeting, September 20-24, 2011, Orlando, Florida. PMID- 22509515 TI - Proceedings of the Neurocomp 2010 International Meeting,October 6-8, 2011, Lyon, France. PMID- 22509514 TI - Proceedings of the 13th International Winter Eicosanoid Conference, March 13-16, 2011, Baltimore, Maryland. PMID- 22509516 TI - People with mental retardation are dying, legally: at least 44 have been executed. PMID- 22509517 TI - Proceedings of the 2010 MidSouth Computational Biology and Bioinformatics Society (MCBIOS) Conference, April 1-2, 2011, College Station, Texas. PMID- 22509518 TI - Japanese studies on attitudes towards persons with mental retardation. PMID- 22509519 TI - Social role valorization and, or versus, "empowerment". PMID- 22509520 TI - Special issue dedicated to Sung Wan Kim. PMID- 22509521 TI - Proceedings of the Fusion Summit, March 23-25, 2011, Oxford, England. PMID- 22509522 TI - The Hunterian Museum (Glasgow). PMID- 22509524 TI - Sostdc1 defines the size and number of skin appendage placodes. AB - Mammary glands and hair follicles develop as ectodermal organs sharing common features during embryonic morphogenesis. The molecular signals controlling the initiation and patterning of skin appendages involve the bone morphogenetic proteins and Wnt family members, which are commonly thought to serve as inhibitory and activating cues, respectively. Here, we have examined the role of the Bmp and Wnt pathway modulator Sostdc1 in mammary gland, and hair and vibrissa follicle development using Sostdc1-null mice. Contrary to previous speculations, loss of Sostdc1 did not affect pelage hair cycling. Instead, we found that Sostdc1 limits the number of developing vibrissae and other muzzle hair follicles, and the size of primary hair placodes. Sostdc1 controls also the size and shape of mammary buds. Furthermore, Sostdc1 is essential for suppression of hair follicle fate in the normally hairless nipple epidermis, but its loss also promotes the appearance of supernumerary nipple-like protrusions. Our data suggest that functions of Sostdc1 can be largely attributed to its ability to attenuate Wnt/beta-catenin signaling. PMID- 22509523 TI - Analysis of lipolysis underlying lactation in the tsetse fly, Glossina morsitans. AB - Female tsetse flies undergo viviparous reproduction, generating one larva each gonotrophic cycle. Larval nourishment is provided by the mother in the form of milk secretions. The milk consists mostly of lipids during early larval development and shifts to a balanced combination of protein and lipids in the late larval instars. Provisioning of adequate lipids to the accessory gland is an indispensable process for tsetse fecundity. This work investigates the roles of Brummer lipase (Bmm) and the adipokinetic hormone (AKH)/adipokinetic hormone receptor (AKHR) systems on lipid metabolism and mobilization during lactation in tsetse. The contributions of each system were investigated by a knockdown approach utilizing siRNA injections. Starvation experiments revealed that silencing of either system results in prolonged female lifespan. Simultaneous suppression of bmm and akhr prolonged survival further than either individual knockdown. Knockdown of akhr and bmm transcript levels resulted in high levels of whole body lipids at death, indicating an inability to utilize lipid reserves during starvation. Silencing of bmm resulted in delayed oocyte development. Respective reductions in fecundity of 20 and 50% were observed upon knockdown of akhr and bmm, while simultaneous knockdown of both genes resulted in 80% reduction of larval production. Omission of one bloodmeal during larvigenesis (nutritional stress) after simultaneous knockdown led to almost complete suppression of larval production. This phenotype likely results from tsetse's inability to utilize lipid reserves as loss of both lipolysis systems leads to accumulation and retention of stored lipids during pregnancy. This shows that both Bmm lipolysis and AKH/AKHR signaling are critical for lipolysis required for milk production during tsetse pregnancy, and identifies the underlying mechanisms of lipid metabolism critical to tsetse lactation. The similarities in the lipid metabolic pathways and other aspects of milk production between tsetse and mammals indicate that this fly could be used as a novel model for lactation research. PMID- 22509525 TI - Cis-regulatory logic driving glial cells missing: self-sustaining circuitry in later embryogenesis. AB - The glial cells missing (gcm) regulatory gene of the sea urchin Strongylocentrotus purpuratus is first expressed in veg2 daughter cells as the genomic target of late cleavage stage Delta-Notch signaling from the skeletogenic mesoderm precursors. Gcm is required in veg2 progeny during late cleavages for the early phase of pigment cell precursor specification. Here we report on a later acting cis-regulatory module that assumes control of gcm expression by the early mesenchyme blastula stage and maintains it through pigment cell differentiation and dispersal. Cis-perturbation analyses reveal that the two critical elements within this late module are consensus matches to Gcm and Six1 binding sites. Significantly, six1 mRNA localizes to gcm+cells from the mesenchyme blastula stage onwards. Trans-perturbations with anti-sense morpholinos reveal a co-dependency between six1 and gcm. Six1 mRNA levels fall sharply after Gcm is depleted, while depleting Six1 leads to significant reductions in output of endogenous gcm or modular-reporters. These results support the conclusion gcm and six1 comprise a positive intergenic feedback loop in the mesodermal GRN. This often employed cross regulatory GRN feature here ensures self-sustaining gcm output in a cohort of fully specified pigment cell precursors at a relatively early developmental stage. PMID- 22509527 TI - Not all that glitters: mercury poisoning in Colombia. PMID- 22509526 TI - WHO plans new yaws eradication campaign. PMID- 22509529 TI - Breast cancer incidence rates in US women are no longer declining. PMID- 22509528 TI - Bitter medicine: gout and the birth of the cocktail. PMID- 22509530 TI - Effect of nitroglycerin ointment on bone density. PMID- 22509531 TI - Female sexual dysfunction is more than just a hormonal problem. PMID- 22509532 TI - Direct association of 25-hydroxyvitamin D insufficiency, a preventable condition, with prior vertebral fractures. PMID- 22509534 TI - Soy for bone protection and vasomotor symptoms. PMID- 22509535 TI - Coventina's Column. Polyimplant prosthese (PIP) breast implants. PMID- 22509533 TI - Interrelationships between spontaneous and low-level stimulus-frequency otoacoustic emissions in humans. AB - It has been proposed that OAEs be classified not on the basis of the stimuli used to evoke them, but on the mechanisms that produce them (Shera and Guinan, 1999). One branch of this taxonomy focuses on a coherent reflection model and explicitly describes interrelationships between spontaneous emissions (SOAEs) and stimulus frequency emissions (SFOAEs). The present study empirically examines SOAEs and SFOAEs from individual ears within the context of model predictions, using a low stimulus level (20 dB SPL) to evoke SFOAEs. Emissions were recorded from ears of normal-hearing young adults, both with and without prominent SOAE activity. When spontaneous activity was observed, SFOAEs demonstrated a localized increase about the SOAE peaks. The converse was not necessarily true though, i.e., robust SFOAEs could be measured where no SOAE peaks were observed. There was no significant difference in SFOAE phase-gradient delays between those with and without observable SOAE activity. However, delays were larger for a 20 dB SPL stimulus level than those previously reported for 40 dB SPL. The total amount of SFOAE phase accumulation occurring between adjacent SOAE peaks tended to cluster about an integral number of cycles. Overall, the present data appear congruous with predictions stemming from the coherent reflection model and support the notion that such comparisons ideally are made with emissions evoked using relatively lower stimulus levels. PMID- 22509536 TI - Nuclear war in the Middle East: where is the voice of medicine and public health. AB - Once again, the politically volatile Middle East and accompanying rhetoric has escalated the risk of a major nuclear exchange. Diplomatic efforts have failed to make the medical consequences of such an exchange a leading element in negotiations. The medical and academic communities share this denial. Without exaggeration, the harsh reality of the enormous consequences of an imminently conceivable nuclear war between Iran and Israel will encompass an unprecedented millions of dead and an unavoidable decline in public health and environmental devastation that would impact major populations in the Middle East for decades to come. Nuclear deterrence and the uncomfortable but real medical and public health consequences must become an integral part of a broader global health diplomacy that emphasizes health security along with poverty reduction and good governance. PMID- 22509537 TI - [Peroxisome proliferator activated receptor gamma Pro12Ala: old topic of conversation and new question]. AB - Comments concerning Meta analysis for relationship between peroxisome proliferator activated receptor gamma Pro12Ala polymorphism and type 2 diabetes susceptibility in different cohorts in this mini review were given. The comments pointed out existent problems and presented suggestions for genetic analysis of diseases in Chinese populations. PMID- 22509538 TI - [Meta-analysis of the association of Pro12Ala polymorphism of peroxisome proliferator activated receptor gamma gene with type 2 diabetes in Chinese Han population]. AB - OBJECTIVE: To evaluate the association of Pro12Ala polymorphism of peroxisome proliferator activated receptor gamma (PPARgamma) gene with type 2 diabetes (T2DM) in Chinese Han population. METHODS: The present investigation was carried out using the keywords "PPARgamma", "pparg", "Pro12Ala", "type 2 diabetes", and "Chinese. The odds ratios (OR) for Ala12 used as the metric of choice were calculated in the dominant and additive model separately. The Meta-analysis was conducted by software STATA 11.0. RESULTS: (1) We identified 22 studies, of which 17 studies involving 3927 type 2 diabetes cases and 3364 controls fell into the inclusion criteria. The analysis indicated no significant inter-study heterogeneity and publication bias. (2) The frequencies of the minor allele Ala12 in type 2 diabetes and control groups were 4.8% and 4.6% respectively. (3) The combined overall OR of dominant and additive model calculated by fix-effects meta analysis for type 2 diabetes and the Pro12Ala polymorphism, were 0.95 (95% CI: 0.80, 1.12) and 0.93 (95% CI: 0.79, 1.09) respectively. CONCLUSION: In this meta analysis, the Pro12Ala gene variant (rs1801282) is not found to be associated with the susceptibility for type 2 diabetes in Chinese Han population. PMID- 22509539 TI - [Activation of transient receptor potential vanilloid 1 inhibits RhoA/Rho kinase and improves vasorelaxation dysfunction mediated by high-fat diet in mice]. AB - OBJECTIVE: To investigate the role of dietary capsaicin in activating transient receptor potential vanilloid 1 (TRPV1) and thus influencing the vascular dysfunction mediated by high-fat diet and the potential mechanisms. METHODS: A total of 80 male C57BL/6J mice aged 10 weeks were equally divided into four groups, in which the mice were fed with normal diet (ND), normal diet plus capsaicin (NC), high-fat diet (HD), or high-fat diet plus capsaicin (HC) for 20 weeks. Tail-cuff blood pressure (BP), vascular function of mice aortic rings, expressions of voltage-gated potassium-channel Kv1.4, RhoA and Rho kinase in aorta were examined. RESULTS: Compared with ND group, both nitroglycerin [(18.9 +/- 13)% vs. 100%, P < 0.01] and acetylcholine [(26 +/- 12)% vs. 100%, P < 0.01] induced vasorelaxation of aortic rings were significantly reduced in HD group. Both endothelium dependent and independent aortic rings vasorelaxation in HC group were significantly improved compared with that in HD group [acetylcholine: (69 +/- 15)%; nitroglycerin: (46.5 +/- 6)%, P < 0.05], but still reduced compared with that in ND group (P < 0.05, P < 0.01). High fat diet induced the expression of RhoA and Rho kinase. Dietary capsaicin down-regulated the expression of RhoA and Rho kinase but up-regulated the expression of Kv1.4 in aorta in mice fed with normal or high fat diet (all P < 0.05). CONCLUSION: Dietary capsaicin can ameliorate vasorelaxation dysfunction mediated by high-fat diet. The potential mechanisms may be related with TRPV1 activation, which in turn stimulates potassium channel and inhibits RhoA and Rho kinase in the vasculature. PMID- 22509540 TI - [Effect of epidermal growth factor on migration of human amniotic mesenchymal stem cells]. AB - OBJECTIVE: To explore the mechanism via which the epidermal growth factor (EGF) affects the migration of human amnion-derived mesenchymal stem cells (hAMSCs). METHODS: In vitro cultured hAMSCs were divided into control (untreated), EGF group, inhibitor AG1478 + EGF group, inhibitor LY294002 + EGF group, and inhibitor U0126 + EGF group. The migration ability of hAMSCs in each group was measured using Transwell chamber. The expressions of phosphorylated EGFR (P EGFR), phosphorylated AKT (P-AKT), and phosphorylated ERK1/2 (P-ERK1/2) as well as the expressions of metalloproteinase (MMP) -2 and MMP-9 were detected using Western blot analysis. The differentially expressed genes in the culture solutions in EGF groups and control group were analyzed with RNA-Seq technique. RESULTS: Cells in EGF group had significantly stronger migration ability than in control group (P = 0.0361), inhibitor AG1478 + EGF group (P = 0.0113), inhibitor LY294002 + EGF group (P = 0.0169), and inhibitor U0126 + EGF group (P = 0.0293). EGF increased the phosphorylation levels of EGFR, AKT and ERK, and increased the expression of MMP-2. However, the increased expressions of P-AKT and P-ERK could be suppressed by AG1478 and LY294002. As shown by GO functional enrichment analysis and KEGG pathway analysis, EGF increased the transcription of genes, which were mainly involved in transcriptional regulation, protein modification, and apoptosis inhibition. Genes that were involved in the MARK pathway included DUSP5, IL1B, DUSP6, NGF, and HSPA2. CONCLUSION: EGF-induced migration of hAMSCs may be mediated by the signaling pathways of PI3K and ERK, which needs MMP-2 expression and the co-expression of genes involved in transcriptional regulation, protein modification, and apoptosis inhibition. PMID- 22509541 TI - [Effect of the human amniotic membrane loaded with human amniotic mesenchymal stem cells on the skin wounds of SD rats]. AB - OBJECTIVE: To observe the effect of the human amniotic membrane (HAM) loaded with human amniotic mesenchymal stem cells (hAMSCs) on the skin wounds of SD rats. METHODS: The amniotic epithelial cells were removed by trypsin digestion, hAMSCs were loaded onto HAM and then covered on rats' skin defects. The wound healing was observed by HE staining and immunohistochemistry, and the results were compared with the amniotic membrane group and blank control group. RESULTS: The average wound healing time was (18.3 +/- 0.9) d in the HAM load with hAMSCs group, which was significantly faster than those in the blank control group [(26.4 +/- 0.7) d, P < 0.01] and the amniotic membrane group [(21.5 +/- 1.2) d, P < 0.05]. After 11 d and 14 d, the wound healing rates in the HAM load with hAMSCs group were (81.5 +/- 7.2)% and (94.3 +/- 3.6)%, respectively, which were significantly higher than those in the blank control group [(48.5 +/- 3.2)% and (74.3 +/- 4.3 )%] and the amniotic membrane group [(68.5 +/- 4.5)% and (86.8 +/- 4.8)%] (all P < 0.01). Skin biopsy/HE staining confirmed that the quality of wound healing in the HAM load with hAMSCs group was significantly better than in the amniotic membrane group and the blank control group. Immunohistochemical staining showed that the number of CK19-positive epidermal stem cells in the HAM load with hAMSCs group (48.2 +/- 3.2) was significantly larger than those in the amniotic membrane group (37.7 +/- 3.1) (P < 0.05) and the blank control group (29.6 +/- 2.4) (P < 0.01). Furthermore, the vascular endothelial growth factor expression (64.5 +/- 4.5) in the HAM load with hAMSCs group was also significantly higher than those in the amniotic membrane group (52.6 +/- 3.8) (P < 0.05) and the blank control group (40.7 +/- 3.1) (P < 0.01). CONCLUSION: HAM loaded with hAMSCs may promote the repair of skin wounds by promoting the regeneration of epidermal stem cells and capillaries. PMID- 22509542 TI - [Role of extracellular signal-regulated protein kinase 5 in the biosynthesis of follicle-stimulating hormone-stimulated progesterone in primary granulosa cells]. AB - OBJECTIVE: To study the role of extracellular signal-regulated protein kinase 5 (ERK5) during the biosynthesis of follicle-stimulating hormone (FSH)-mediated progesterone in primary granulosa cells. METHODS: The expressions of phosphorylated and general forms of ERKS in primary granulosa cells after the treatment of FSH were detected by Western blot analysis. The subcellular localization of ERK5 was observed by confocal microscopy. The effect of ERK5 on FSH-mediated progesterone biosynthesis in primary granulosa cells was analyzed using recombinant adenovirus vectors. RESULTS: ERK5 activation was induced by FSH in a time-dependent manner in primary cultured granulosa cells, although the general ERK5 protein level decreased also in a time-dependent manner. The treatment of FSH showed no remarkable effect on the subcellular distribution of endogenous ERK5, which was mainly in the cytoplasm of granulosa cells. The co infection of Ad-caMEK5 and Ad-wtERK5 increased the progesterone production and StAR expression in primary cultured granulosa cells, whereas inhibition of ERK5 activation suppressed the FSH-stimulated progesterone production. CONCLUSION: ERK5 may stimulate FSH-mediated progesterone production in primary cultured granulosa cells. PMID- 22509543 TI - [Screening and identification of natural antisense transcript in mouse cerebral cortex]. AB - OBJECTIVE: To screen and identify the possible existence of natural antisense transcript (NAT) within the mouse neocortex. METHODS: Sixty-three cerebral cortex layer-specific genes were screened by bioinformatics prediction in mice, among which 31 mice with potential NATs were screened. NAT was identified using reverse transcription polymerase chain reaction (RT-PCR) and then cloned in pGEM-T Vector System for sequencing. RESULTS: Among 31 genes predicted using bioinformatics, 8 were proved to be NAT positive by RT-PCR. CONCLUSIONS: NATs exist in the mouse neocortex tissue during the development of cerebral cortex. NATs may influence mouse cortical development by regulating the related coding genes. PMID- 22509545 TI - [Separation and morphological observation of mouse testis seminiferous tubule epithelium]. AB - OBJECTIVE: To explore a simple and feasible technique to locate proteins during spermatogenesis. METHODS: Various germ cells and somatic cells were separated by collagenase I and DNase I after the albuginea was removed. The cells were then smeared, dyed, and observed directly under fluorescence and confocal microscopy. RESULTS: Germ cells at different steps were successfully identified by specific dyestuffs for acrosome and nucleolus. CONCLUSION: A simple method for locating proteins during spermatogenesis was successfully developed. PMID- 22509544 TI - [Establishment of a targeting protein for Xenopus kinesin-like protein 2 C' terminal SBP-3 x Flag tagged HCT 116 colorectal cancer cell model]. AB - OBJECTIVE: To develop a targeting protein for Xenopus kinesin-like protein 2 (TPX2) C' terminal SBP-3 x Flag-tagged HCT 116 cell model. METHODS: Homologous arms were amplified by polymerase chain reaction (PCR), and then the adeno associated virus (AAV) -targeting vector of TPX2 was constructed. HCT 116 cells were targeted after the viruses were packaged. Positive cell clones with neomycin resistance gene were obtained by G418 and PCR screening. Finally, the neomycin gene cassette was excised after the targeted clones were infected with adenovirus expressing Cre-recombinase, and the TPX2 C' terminal SBP and 3 x Flag endogenous double-tagged HCT 116 cells were obtained by PCR screening. RESULTS: Two positive cell clones with neomycin resistance gene were obtained by PCR screening. The positive clones with neomycin resistance gene excised were obtained by Cre adenovirus infection, and the knock-in of SBP-3 x Flag gene was verified by Western blot analysis. CONCLUSION: The TPX2 C' terminal SBP-3 x Flag tagged HCT 116 cell model was successfully established. PMID- 22509546 TI - [Construction and identification of nemo-like kinase gene recombinant adenovirus vector]. AB - OBJECTIVE: To construct the nemo-like kinase (NLK) gene recombinant adenovirus vector. METHODS: The AdEasy system was used to construct the recombinant adenovirus vector. Using reverse transcriptase polymerase chain reaction (RT PCR), the full-length gene of NLK and its mutants (K155M, T286V, and C425Y) were amplified from HEK293 cells. The FLAG tag was appended at the C-terminal of NLK. After ligation and transformation, the NLK gene and its mutants were cloned into the pAdTrack-CMV vector. It was detected by PCR, sequencing, and Western blot analysis. Using DNA recombination and homogenous recombination, the normally expressed plasmids were linearized by the restriction enzyme-PmeI and PacI, then the enzyme-digested products were recycled by using ethanol precipitation. The purified product was transfected to HEK293A packaging cells with FuGENE HD transfection reagent. After amplification of the recombinant adenovirus, Western blot analysis was performed to detect the expression of NLK gene and its mutants. RESULTS: The successful construction of pAdtrack-CMV-NLK (and mutants) was confirmed by PCR and sequencing. Western blot analysis showed that the target genes and the recombinant adenovirus were obtained. This recombinant virus was able to express NLK protein and its mutants correctly in HCT 116 cells. CONCLUSION: The NLK gene recombinant adenovirus vector was successfully constructed and identified. PMID- 22509547 TI - [Prokaryotic expression and purification of mitochondrial transcription complex proteins]. AB - OBJECTIVE: To obtain human mitochondrial transcription factor A (TFAM), mitochondrial transcription factor B1 (TFB1M), and mitochondrial transcription factor B2 (TFB2M) that were expressed efficiently in E. coli BE21 and to purify the target proteins. METHODS: TFAM, TFB1M, and TFB2M segments were designed and synthesized. After having been sequenced, the reconstructed expression vectors were constructed by enzyme digestion and by cloning into an expression vector pET42a. Then the reconstructed vectors were transformed into E. coli BL21. Recombinant glutathione S transferase (GST) fusion proteins were expressed via the induction of IsoPropyl beta-D-ThioGalactoside (IPTG) and purified by glutathione Sepharose 4B. RESULTS: The expression plasmids of pET42a-TFAM, pET42a TFB1M, and pET42a-TFB1M were successfully constructed. The sequences of the cloned gene segments were identical with GenBank reported. The protein bands with relative molecular masses of 56 000, 67 000, and 69 000 appeared on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) after the expressed GST-TFAM, GST-TFB1M, and GST-TFB2M fusion proteins were separated by SDS-PAGE. The expressed fusion proteins were purified to high purity. CONCLUSION: The recombinant plasmids pET42a-TFAM, pET42a-TFB1M, and pET42a-TFB2M were successfully constructed, and the GST-fused target proteins were prepared. PMID- 22509548 TI - [Selection of culture media for the mass production of gamma delta T cells used in adoptive immunotherapy]. AB - OBJECTIVE: To select the optimal culture media for the mass production of gamma delta T cells used in adoptive immunotherapy. METHODS: Three different culture media (RPMI-1640, AIM-V, and OpTmizer, with or without autologous serum) were used to culture gamma delta T cells. The survival rate, purity, proliferation efficiency, and biological functions of the expanded gamma delta T cells were examined and compared. RESULTS: The survival rate of gamma delta T cells expanded in RPMI-1640 decreased over culture time. The purities of gamma delta T cells cultured in AIM-V or OpTmizer with or without serum were higher than those cultured in RPMI-1640. After two weeks of culture in the absence of serum, the purity and proliferation efficiency of gamma delta T cells cultured in OpTmizer were significantly higher than those cultured in RPMI-1640 (P < 0.05) and AIM-V (P < 0.05). gamma delta T cells in different culture media had similar CD107a expression and tumor necrosis factor-alpha production (P > 0.05). However, cells expanded in RPMI-1640 exhibited significantly weaker cytotoxicity against Daudi lymphoma cells than those expanded in OpTmizer (P < 0.05) and AIM-V (P < 0.05). CONCLUSION: Due to low serum-dependence, high proliferation efficiency, and favorable biology function of expanded cells, OpTmizer is the most suitable medium for the mass production of gamma delta T cells used in adoptive immunotherapy. PMID- 22509549 TI - [Adenovirus construction of expression and its function of connective tissue growth factor]. AB - OBJECTIVE: To construct and identify a adenovirus vector of the expression of connective tissue growth factor (CTGF) and to explore the role of CTGF in the metabolism of glucose and lipid. METHODS: The over-expressed plasmid of CTGF was cloned, and then the CTGF sequences were cloned into pAdTrack-CMW vector. The reformed E. coli BJ5183-sensitive bacteria that contain pAdEasy-1 were transformed with lined vector cut by Pme I enzyme. The recombinant adenovirus vector was cut with Pac I enzyme and obtained, then transfected 293A cells to produce virus. Through three times of amplification, the adenovirus infected the primary hepatocytes to determine the infection efficiency and CTGF expression. The mice were starved for several time periods, and then the liver RNA was extracted for real-time PCR to detect the expressions of CTGF under different nutritional conditions. RESULTS: The adenovirus of CTGF was successfully produced with an infection efficiency of 90%. The expressions of the CTGF were different under different nutritional conditions and showed a coincidence with the expression of peroxisome proliferators-activated receptor gamma coactivator 1 alpha. After the mice were starved for 24h, the expression of CTGF increased by (2.38 +/- 0.51) folds; after the mice were starved for 48 h, the expression of CTGF increased by (2.95 +/- 0.57) folds (P < 0.05). CONCLUSION: CTGF is speculated to be involved in the metabolism of glucose and lipids. PMID- 22509550 TI - [Effects of sodium selenite on the expressions of beta-catenin and its target cyclin D1 in colorectal cancer cells HCT 116 and SW480]. AB - OBJECTIVE: To explore the effects of sodium selenite on the expressions of beta catenin and cyclin D1 in colorectal cancer cells HCT 116 and SW480. METHODS: HCT 116 and SW480 cells were treated by 10 micromol/L sodium selenite at different time points. The expressions and transcription of beta-catenin and cyclin D1 were detected by Western blot analysis and reverse transcriptase polymerase chain reaction (RT-PCR), respectively. Meanwhile, the impact of MG132 (a proteasome inhibitor) pretreatment on the expressions of beta-catenin and cyclin D1 was observed through Western blot analysis. The interaction between beta-catenin and T cell factor 4 (TCF4) after selenite treatment was evaluated using co immunoprecipitation assay. RESULTS: Sodium selenite inhibited the expression of beta-catenin and transcription of its target such as cyclin D1. MG132 pretreatment prevented the inhibition of beta-catenin signaling triggered by selenite in HCT 116 and SW480 cells. Furthermore, selenite treatment disrupted the interaction between beta-catenin and TCF4 in HCT 116 and SW480 cells. CONCLUSIONS: Sodium selenite can lower the expression levels of beta-catenin and its target cyclin D1, during which the proteasome-mediated degradative pathway may be involved. The decreased interaction between beta-catenin and TCF4 due to sodium selenite may be also involved in the regulation of beta-catenin signaling. PMID- 22509551 TI - [Role of beta-catenin in the pathogenesis of mesial temporal lobe epilepsy]. AB - OBJECTIVE: To explore the role of beta-catenin in the pathogenesis of mesial temporal lobe epilepsy. METHODS: Kainic acid-induced rat models of medial temporal lobe epilepsy was established. The expression of beta-catenin in the normal mice and the model mice were detected using Western blot analysis. The expression of beta-catenin at human hippocampus was detected using immunohistochemical analysis and immunofluorescence and compared between patients with non-hippocampal sclerosis temporal lobe epilepsy and those with hippocampal sclerosis epilepsy. RESULTS: The pathologies of model mice were similar with those in mice with hippocampal sclerosis temporal lobe epilepsy, demonstrating that the mice model was successfully established. Western blot analysis showed no significant difference of beta-catenin expression between normal mice and model mice. As shown by immunohistochemical analysis and immunofluorescence, beta catenin expression in human hippocampus was also not significantly different between patients with temporal lobe epilepsy without hippocampal sclerosis and those with hippocampal sclerosis. CONCLUSION: Beta-catenin may not be involved in the development of hippocampal sclerosis of mesial temporal lobe epilepsy. PMID- 22509552 TI - [Association between protein tyrosine phosphatase receptor type R gene and major depressive disorder]. AB - OBJECTIVE: To explore the genetic association between protein tyrosine phosphatase receptor type R (PTPRR) gene polymorphism and major depressive disorder (MDD) and its endophenotype. METHODS: A total of 517 unrelated MDD patients and 455 unrelated healthy subjects were recruited in this study to detect 11 single nucleotide polymorphisms (SNPs) in the PTPRR locus. They all were of the Chinese Han origin. Genotyping of SNPs was performed by matrix assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) -based genotyping approach. The UNPHASED program was applied to analyze the genotyping data. RESULTS: Of the 11 selected SNPs, no significant allelic and genotypic association was found between MDD patients and the normal controls (corrected P > 0.05). However, analysis of haplotypes showed that the three SNPs haplotype rs1398599 (C) -rs2175711 (A) - rs4489789 (T) (P = 0.0023, OR = 1.334, 95% CI = 1.104-1.612) and four SNPs haplotype rs11178391 (C) -rs1398599 (C) rs2175711 (A)-rs4489789(T) (P = 0.0063, OR = 1.281, 95% CI = 1.059-1.549) were associated with increased risk of MDD. Quantitative trait analysis revealed that rs2203231 in the PTPRR locus had strong allelic and genotypic association with the raw score of long-term memory (P = 0.0038 for allelic association, P = 0.0024 for genotypic association), the scaled score of long-term memory (P = 0.0057 for allelic association, P = 0.0038 for genotypic association), the raw score of short-term memory (P = 0.0027 for allelic association, P = 0.0015 for genotypic association), and the scaled score of short-term memory (P = 0.0035 for allelic association, P = 0.002 for genotypic association) in MDD patients. CONCLUSION: The polymorphism of PTPRR gene rs2203231 may be associated with the impairment of long-term and short-term memories in MDD patients. PMID- 22509553 TI - [Expression of manganese superoxide dismutase in colorectal carcinoma and its relationship with clinicopathological findings]. AB - OBJECTIVE: To explore the expression of manganese superoxide dismutase (MnSOD) in colorectal carcinoma and its relationship with the clinicopathological findings. METHODS: The expressions of MnSOD in colorectal carcinoma, adenoma, and adjacent corresponding intestinal mucosal tissues were detected by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). The relationship between MnSOD expression level in colorectal adenoma and clinical parameters was analyzed. RESULTS: The expression of MnSOD was negative in adjacent corresponding colorectal tissues. The positive expression rate of MnSOD was 44% (11/25) in colorectal adenoma and 76% (19/25) in colorectal carcinoma (P < 0.05 when compared with the colorectal adenoma and its adjacent tissues). The expression of MnSOD was positively correlated with histopathological grades (P < 0.05) but not with other clinicopathological findings (P > 0.05). CONCLUSION: The expression of MnSOD may be associated with the carcinogenesis and progression of colorectal carcinoma, and therefore may be used as a new biomarker. PMID- 22509554 TI - [Virus free induction of umbilical cord derived mesenchymal stem cells into islet like cells]. AB - OBJECTIVE: To explore the feasibility of using a virus-free system in the induction of umbilical cord derived mesenchymal stem cells (UC-MSCs) into insulin secreting cells. METHODS: MSCs were isolated from human umbilical cord and induced into insulin-secreting cells with a three-stage method. The mRNA expression levels of foxa2, sox17, pdx1, ngn3, pax4, insulin, and glut-2 were compared between induced and non-induced groups by RT-PCR in each stage. The distribution pattern of insulin and c-peptide were detected by immunofluorescence staining and observed by fluorescence microscopy. Insulin and c-peptide secretion and glucose responsiveness were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Transcription factors foxa2, sox17, pdx1, ngn3, pax4, insulin, and glut-2 were expressed in the induced cells. The mRNA expression levels of foxa2 and sox17 were significantly higher in the induced group than those in non induced group in the first stage (all P < 0.05), pdx1, ngn3, and pax4 were significantly higher in the induced cells than those in non-induced cells in the second stage (all P < 0.05), and insulin and glut-2 expressions were significantly up-regulated in the induced group at last stage (all P < 0.05). Immunofluorescence staining showed that insulin and c-peptide were located in the cytoplasm of more than 90% of induced cells. ELISA showed that total intracellular insulin content of the induced cells contained up to (346.3 739 +/- 32.5 149) microU/ml, which was significantly higher than insulin in non-induced cells (17.69 +/- 1.46) microU/ml (P < 0.01). C-peptide content of the induced cells measured up to (195.10 +/- 8.88) pmol/L/h (P < 0.01), when exposed to 5.5 mmol/L glucose (P < 0.01). When stimulated with 22 mmol/L glucose, the c-peptide content of the induced cells increased to (340.99 +/- 7.91) pmol/L/h (P < 0.01 ). CONCLUSION: The umbilical cord derived MSCs can be efficiently induced into insulin-secreting cells via a virus-free system. PMID- 22509555 TI - [Application of adrenocorticotropic hormone receptor determination and ultrastructural observation of tumor cells in the subtyping of adrenocortical neoplasms]. AB - OBJECTIVE: To explore the values of adrenocorticotropic hormone receptor (ACTH-R) determination and ultrastructural observation of tumor cells in the subtyping of adrenocortical neoplasms (ANs). METHODS: The expression of ACTH-R in 87 AN tissues were determined with Polymer immunohistochemical staining, with 10 normal adrenal tissues as the controls. The ultrastructure of the tumor cells was observed using electron microscopy. RESULTS: The positive expression rate of ACTH R was (80.1 +/- 8.2)%, (53.2 +/- 10.3)%, (63.2 +/- 10.1)%, (83.3 +/- 6.5)%, and (70.1 +/- 7.3)% in the sub-CPA group, CPA group, APA group, NFA group, and NC group, respectively. ACTH-R expression was significantly higher in NFA and sub CPA groups than in NC group (P = 0.001, P = 0.000), APA group (P = 0.000, P = 0.000), and CPA group (P = 0.000, P = 0.000), and was also significantly different between NC group and APA group (P = 0.039) and between APA group and CPA group (P = 0.037). However, no significant difference was found between NFA group and sub-CPA group (P = 0.325). As shown by the electron microscopy, ANs had some partially similar microscopic features, while different AN subtypes showed differences in the type and amount of secretory granules. CONCLUSION: ACTH-R determination and ultrastructural observation of tumor cells may be helpful for subtyping ANs. PMID- 22509556 TI - [Development of a nomogram for predicting positive initial prostate biopsy among Chinese patients]. AB - OBJECTIVE: To develop a predictive nomogram for predicting the prostate carcinoma among Chinese population. METHODS: Totally 556 Chinese male patients who had undergone an initial prostate biopsy in our hospital from July 2004 to February 2009 were enrolled in this study. Variables including age, volume, prostate specific antigen (PSA) level, and free PSA (f-PSA)/total PSA (t-PSA) were collected. Logistic regression analysis was performed to estimate the relative risk. Regression equation was established for variables via stepwise regression, via which a nomogram for assessing the positive biopsy results was established, and then the predictive value of this nomogram was evaluated using receiver area under curve (ROC) analysis. RESULTS: Of these 556 patients, cancer was detected in 205 patients (36.87%) via biopsies. Univariate analysis showed that age, prostate volume, PSA levels, and f-PSA/t-PSA were the influencing factors of the nomogram. The risk model performed well in an independent sample, with an AUC(ROC) of 0.8767, which was significantly larger than that of the prediction based on age (AUC(ROC) : 0.6397), prostate volume (AUC(ROC) : 0.7255), PSA (AUC(ROC) : 0.7111), or f-PSA/t-PSA (AUC(ROC) : 0.6973) alone. CONCLUSION: A preliminary nomogram with high predictive value for Chinese population was successfully established. PMID- 22509557 TI - [Cell reprogramming: control key genes to obtain needed cells]. AB - Cell reprogramming is a progress in which the memory of a mature cell is erased and then the cell develops novel phenotype and function; ultimately, the fate of the cell changes. Cell reprogramming usually occurs at genes expression levels that no genomic DNA sequence change will be involved. By changing the programs of the genetic expressions of cells in terms of space and time, cell reprogramming alters the differentiation of cells and thus produces the required cells. Further research on cells reprogramming will elucidate the mechanisms that govern the cell development, and thus provides more information of the sources of seed cells used for regeneration medicine. More cells differentiated from many terminally differentiated cells will be obtained, which is extremely important for the understanding of molecular differentiation and for the development of cell replacement therapy. This article summarizes the classification, influencing factors, approaches and latest advances of cells reprogramming. PMID- 22509558 TI - [Osmotic demyelination syndrome in patients with hyponatremia caused by neurologic disorders]. AB - Hyponatremia is relatively common in patients with neurologic disorders, while its diagnosis and treatment remain controversial. Osmotic demyelination syndrome (ODS) has shown to be closely associated with hyponatremia. ODS patients often present as central pontine myelinolysis, extrapontine myelinolysis, or both. This article reviews the clinical manifestations, pathogenesis, and risk factors of ODS in patients with hyponatremia caused by neurologic disorders. PMID- 22509559 TI - [Application of endovascular embolization for brain arteriovenous malformation]. AB - Endovascular embolization has increasingly been applied for brain arteriovenous malformation (BAVM). With our better understanding of BAVM and the continuous improvement of micro-catheter technology and embolic materials, the therapeutic effectiveness has constantly increased. This paper reviews recent advances in research on BAVM and the application of endovascular embolization. PMID- 22509560 TI - [Early effectiveness of total hip arthroplasty in treating protrusion acetabuli]. AB - OBJECTIVE: To evaluate the method and the early effectiveness of total hip arthroplasty in the treatment of protrusion acetabuli. METHODS: Between January 2006 and February 2010, 16 cases (16 hips) of protrusion acetabuli were treated, including 6 males and 10 females with an average age of 56.5 years (range, 39-72 years). The median disease duration was 6.4 years (range, 1 year and 6 months to 35 years). Involved hips included 7 left hips and 9 right hips; 3 patients had primary protrusion acetabuli and 13 patients had secondary protrusion acetabuli. The preoperative Harris score was 49.5 +/- 5.5. According to Dunlop et al. classification criterion, there were 3 cases of mild, 9 cases of moderate, and 4 cases of severe. All patients received total hip arthroplasty with bone graft and cementless prosthesis for recovery of femoral offset and acetabular center of rotation. RESULTS: All incisions healed by first intention without complication of infection, deep venous thrombosis, or nerve injury. All patients were followed up 12-62 months with an average of 37 months. The Harris score at last follow-up was 90.5 +/- 4.5, showing significant difference (t = 49.578, P = 0.000) when compared with preoperative score. The X-ray films showed that no prosthesis loosening or subsidence was observed, and bone graft healed with no sign of re protrusion. CONCLUSION: In treatment of protrusion acetabuli, total hip arthroplasty with bone graft and cementless prosthesis can recover the femoral offset and acetabular center of rotation and provide satisfactory early effectiveness. PMID- 22509561 TI - Deceased heart beating donor and organ transplantation in Saudi Arabia. PMID- 22509562 TI - [Historical recurrences in psychiatry: somatic therapies]. PMID- 22509563 TI - Combination of chlorhexidine gluconate and PVP in surgical site antisepsis. PMID- 22509564 TI - [Safety value of contaminant in water pollution accident based on human health risk]. AB - The acute human health risk assessment of contaminant in water pollution accident is a new study field of environmental sciences. This study established a model for calculating acute safety value of contaminant in water pollutant. The acute safety value of contaminant in mainly water pollution during 2000-2010 was calculated by this model. The safety value of sodium cyanide, cadmium, formaldehyde, ammonia, toluene, nitrobenzene, microcystin-LR were 0.1, 0.6, 8, 20, 6, 0.07, 0.004 mg x L(-1), respectively. The differences of safety value calculate methods between acute and chronic exposure were compared from the following aspects, the toxicology exposure end-point, allocation of intake, exposure sensitive subpopulation. PMID- 22509565 TI - [Safety concentration of genotoxic carcinogens in water pollution accident based on human health risk]. AB - It was an urgent problem to determine short-term exposure safety concentration of genetic carcinogens in water pollution accident in China. Based on the hypothesis that the relationship between exposure dosage and carcinogenic risk was linear, the calculation process of genetic carcinogens safety concentration was put forwarded, and the method using life-time exposed safety concentration to calculate short-term exposure safety concentration was set up. Based on the statistical result of water pollution accident occurred in china during 2000 2010, arsenic was a major characteristic contaminate in water pollution accident. According to the method of short-term exposure safety concentration of genotoxic carcinogens, the safety concentration of arsenic was 0.5 mg x L(-1), it showed that the method was feasible in emergence management of water pollution accident. PMID- 22509566 TI - [A quantitative method and case analysis for assessing water health]. AB - Water is the basis of wetland, the degree of water health directly determines the function of wetland ecosystem. The theory and method of water health were established in the study. Water health included both water status health and water process health. Water status health was reflected by hydrologic condition and water quality. Water process health was calculated by water elasticity, water stability and resilience. Xixi Wetland Park was taken as the case study. The results indicated that: 1) Seasonal variations of water health were apparent in Xixi Wetland. Water health index was the highest (46.36) and stayed under the sub health condition in summer. In contrast, water health index was the lowest (37.35) and unhealth in winter; 2) the degrees of water health were obviously different between ponds and creeks. Water health index in ponds was 42.72, which was higher than that of creeks (37.99); 3) Water in Xixi Wetland Park was sub health with 53.80 as its water health index. Based on the result of study, to enhance water health of creeks in winter is an effective measure to improve water health in Xixi Wetland Park. PMID- 22509567 TI - [Temporal and spatial variation of nitrogen and phosphorus and eutrophication assessment in downstream river network areas of North Canal River Watershed]. AB - Based on the water quality survey for one year in the downstream river network areas of North Canal River Watershed, variation features of inorganic nitrogen (N) and phosphorus (P) were analyzed, and water eutrophication degree of river network areas was also assessed. The results showed that the average concentration of TN was 12.50 mg x L(-1) (NH4(+)-N, 67.41%); TP was 1.45 mg x L( 1) (SRP, 80.81%). The temporal and spatial variations of N and P in the river network areas were obvious. Various forms of TN and NO3(-)-N concentrations almost had a similar change by month; NH4(+)-N was a little different; TP and SRP also had a similar change. The concentrations of N and P all decreased gradually from water coming region to water leaving region, TN, NH4(+)-N and NO3(-)-N decreased from 19.30, 13.22 and 2.19 mg x L(-1) to 7.98, 4.45 and 1.50 mg x L(-1) on average, respectively; TP and SRP were from 1.95 and 1.59 mg x L(-1) to 1.11 and 0.91 mg x L(-1). Water eutrophication degrees of river network areas were all the highest level at both temporal and spatial scale. PMID- 22509568 TI - [Spatiotemporal variation analysis and identification of water pollution sources in the Zhangweinan River basin]. AB - In this study, several statistical methods including cluster analysis, seasonal Kendall test, factor analysis/principal component analysis and principal component regression were used to evaluate the spatiotemporal variation of water quality and identify the sources of water pollution in the Zhangweinan River basin. Results of spatial cluster analysis and principal component analysis indicated that the Zhangweinan River basin can be classified into two regions. One is the Zhang River upstream located in the northwest of the Zhangweinan River basin where water quality is good. The other one covers the Wei River and eastern plain of the Zhangweinan River basin, where water is seriously polluted. In this region, pollutants from point sources flow into the river and the water quality changes greatly. Results of temporal cluster analysis and seasonal Kendall test indicated that the study periods may be classified into three periods and two different trends were detected during the period of 2002-2009. The first period was the year of 2002-2003, during which water quality had deteriorated and serious pollution was observed in the Wei river basin and eastern plain of the Zhangweinan River basin. The second period was the year of 2004-2006, during which water quality became better. The year of 2007-2009 is the third period, during which water quality had been improved greatly. Despite that water quality in the Zhangweinan River basin had been improved during the period of 2004-2009, the water quality in the Wei River (southwestern part of the basin), the Wei Canal River and the Zhangweixin River (eastern plain of the basin) is still poor. Principal component analysis and multi-linear regression of the absolute principal component scores showed that the main pollutants of the Zhangweinan River basin came from point source discharge such as heavy industrial wastewater, municipal sewage, chemical industries wasterwater and mine drainage in upstream. Non-point source pollution such as agricultural pollution and runoff pollution caused by heavy rainfalls also showed considerable impact on water quality in the Zhangweinan River basin during flood seasons. These results provide useful information for better pollution control strategies in the Zhangweinan River basin. PMID- 22509569 TI - [Hydrochemical characteristics and formation mechanism of shallow groundwater in the Yellow River Delta]. AB - Understanding the chemical characteristics of groundwater in the Yellow River Delta is very important. It can provide a useful reference for the development and construction of the Yellow River Delta High-efficiency Ecological Economic Zone and ecological regulation in the lower Yellow River. Based on partitioning the sediment environment and the recharge-runoff-discharge system, we studied the hydrochemical features and causes of shallow groundwater in the Yellow River Delta by mathematical statistics and geostatistics, Piper diagram, ion ratios and so on. Following results are obtained: 1) Major cations and anions such as Na+, Mg2+, Ca2+, Cl(-), SO4(2-), HCO3(-) and TDS concentrations range from 0.1-25.0 g x L(-1), 3.6-3 815.0 mg x L(-1), 5.6-3 377.0 mg x L(-1), 0.1-45.1 g x L(-1), 24.2 4 947.0 mg x L(-1), 62.6-850.0 mg x L(-1) and 0.4-80.7 g x L(-1). Average ion concentrations further indicate that Cl(-), Na+ and TDS concentrations are high while HCO3(-), CO3(2-) and K+ concentrations are very low in the study area. 2) The Cl(-) and TDS concentrations of shallow groundwater possess conspicuous directional spatial variability and gradually increase along the groundwater flow direction, showing that Cl(-) is the most critical ion of shallow groundwater. 3) From the recharge area to the discharge area, shallow groundwater changes from the Na+ -Mg2+ -Ca2+ -Cl(-) -SO4(2-) facies to the Na -Mg2 + -Ca2+ -Cl(-), Mg2+ Na+ -Ca2+ -Cl(-) and Na+ -Mg2+ -Cl(-) facies, finally evolves into Na+ -Cl(-) facies in the coast. 4) Ion ratios indicate that the following main hydrochemical processes are inferred to control the shallow groundwater chemical composition: mixing, evaporation concentrating, mineral dissolution, cation exchange and adsorption and human activities. These findings strongly suggest that changes of the Yellow River water course and seawater intrusion are key drivers to form the chemical characteristics of shallow groundwater in the region. PMID- 22509570 TI - [Impacts of sediment disturbance time on the distribution of phosphorus forms in suspended solids]. AB - To examine the impact of sediment disturbance time (disturbance 10 min and 9h, respectively) on the transformation of phosphorus forms in suspended solids, the microcosm experiment was carried out with sediment and lake water from Yueliang estuary in Taihu Lake. The transformation of phosphorus forms in suspended solids was analyzed. The longer disturbance time, the greater of dissolved total phosphorus (DTP) in the overlying water was observed. However, in the control experiment, the concentration of DTP was higher than that in the disturbance experiment. Sequential fractionations indicted that mass fraction of Fe/Al-P to Tot-P in the suspended solids decreased gradually under disturbance conditions (10 min, 9 h) with increasing the experiment time, and then, the values decreased to 42.5% (10 min) and 38.1% (9 h) at 10 d, respectively. At the end, they increased slightly, compared with the values at 10d. However, mass fraction of HCl-P to Tot-P in the suspended solids increased gradually with time, and then went up to the highest (48.9%, 10 min and 53.7%, 9 h) value at 10 d. It suggested that sediment disturbance promoted the transformation of phosphorus forms in the suspended solids, especially from mobile phosphorus forms to refractory forms. PMID- 22509571 TI - [Influence of submerged macrophytes on phosphorus transference between sediment and overlying water in the growth period]. AB - In order to study the process of phosphorus transfer between sediment and overlying water, Hydrilla verticillata and Vallisneria natans were cultured in spring, Potamogeton crispus was cultured in winter. Changes of environmental factors and phosphorus concentrations in water and sediment were investigated. The results indicated that: submerged macrophytes could reduce all phosphorus fractions in the overlying water. Phosphorus concentrations in overlying water maintained in a relative low level in the growth period of submerged macrophytes. The concentrations of total phosphorus (TP) in overlying water of H. verticillata, V. natans and P. crispus were 0.03-0.05, 0.04-0.12, 0.02-0.11 mg x L(-1), respectively. All phosphorus fractions in sediment were reduced. The maximum value between submerged macrophyte and control of H. verticillata, V. natans and P. crispus were 35.34, 60.67 and 25.92 mg x kg(-1), respectively. Dissolved oxygen (DO), redox potential (Eh) and pH in overlying water increased (DO 10.0-14.0 mg x L(-1), Eh 185-240 mV, pH 8.0-11.0) in the submerged macrophytes groups. Submerged macrophytes increased Eh( -140 - -23 mV) and maintained pH(7.2-8.0) in neutral range. The results indicated that submerged macrophytes affected phosphorus transferring between sediment and overlying water through increasing DO, Eh and pH in overlying water, and Eh in sediment. PMID- 22509572 TI - [Pollution characteristics and evaluation of nitrogen, phosphorus and organic matter in surface sediments of Lake Changshouhu in Chongqing, China]. AB - In order to reveal spatial distribution characteristics of nutrient in the surface sediments of Lake Changshouhu, contents of total nitrogen (TN), total phosphorus (TP) and organic matter (OM) of 62 surface sediments samples were determined and compared with other urban (suburban) lakes in China. C/N and the correlation of TN, TP and OM had also been analyzed. The results showed that the average contents of TN and TP were 2 255.89 mg x kg(-1) and 622.03 mg x kg(-1) respectively. Nitrogen and phosphorus pollution were very serious all over the lake, with a significantly different spatial distribution. The average content of OM was 2.80%. So the contents of TN, TP and OM were in the middle level compared with other lakes. 87.10% of C/N was between 5 and 14 (72.58% within which was between 6 and 13) and 3.23% of C/N was between 2.8 and 3.4, which showed that OM came from algae, phytoplankton and zooplankton. Besides, a small part of OM came from aquatic organisms. OM and TN were significantly correlated (Pearson coefficient was 0.849), but with less significant correlation to TP. The spatial distribution characteristics of OM were very similar with that of TN. The content of OM in water samples collected from western and middle waterbody was higher than that in eastern waterbody, which was the same as TN. By evaluating pollution situation with organic index and organic nitrogen, the average organic index was 0.386 which was on the III level still belonged to clean category. However, the average number of organic nitrogen was up to 0.214% which was on the IV level indicated the pollution degree. This showed that the lake Changshouhu was in a serious pollution situation especially in nitrogen pollution. PMID- 22509573 TI - [Vertical distribution characteristics of nutrients and heavy metals in sediments of Lake Hongze]. AB - In order to understand the vertical distribution characteristics of nutrients and heavy metals in sediments of Lake Hongze, three core sediment samples at 3 sites (one near the Huaihe River inlet of Lake Hongze, one at the western part of the lake and one at the lake center) were collected in June of 2008. By measurement of total nitrogen (TN), total phosphorus (TP) and heavy metals (Cu, Zn, Pb, Cd, Fe, Al, Cr, Hg, Mn, As) and by analyzing of their vertical characteristics, investigation revealed the nutrient evolution processes and pollution history. Sediment near Huaihe river mouth was more polluted by the Huaihe River watershed. The nutrients TN, TP and organic matter (OM) concentrations in this core sample were 390.8-643.7, 428.6-538.6, 5 194.3-9 164.9 mg x kg(-1) respectively. Zn, Cd, Al, Fe and Mn in the sediment in this area were affected by human activities less than other heavy metals. Western Lake sediment was affected by the Huaihe River, inlet river and human activities in cities along western lake shoreline. TN, TP and OM concentrations in this core sample were 633.4-2 677.3, 480.0-1115.9, 7 140.8-47 849.7 mg x kg(-1) respectively. The pollution extents of TN, OM and heavy metals in sediment were exacerbated since the late of 1970s, but the situation was improved since the 1990s. As and Cr in the sediments were influenced by human activities more than other heavy metals. Main pollution source in sediment at the lake center were detritus from the lake watershed. TN, TP and OM concentrations in this core sample were 904.7-1 585.4, 526.3-750.1, 10 635.6-19 020.6 mg x kg(-1) respectively. The correlations among nutrients and heavy metals in sediment are significant, and their vertical distribution patterns were similar. The concentrations of nutrients and heavy metals increased from bottom to surface. Nutrients and heavy metal pollution in sediment had the same vertical distribution characteristics which coincided with the lake watershed economic development stage. The sediment in Lake Hongze can be described by the Turbidity Flood Model. PMID- 22509574 TI - [Effects of rainfall on nitrogen and phosphorus loss from courtyard compost and its risk of nonpoint source pollution]. AB - The in situ 120 days experiment was conducted to investigate effects of rainfall on nitrogen and phosphorus loss from courtyard composting with four kinds of coverage, involving no coverage, rice straw, thin film and soil, and their risks of nonpoint source pollution were discussed. The results showed that, with decomposing of the manure and increasing of runoff, the concentration of total nitrogen (TN), ammoniac nitrogen (NH4(+)-N), nitrate nitrogen (NO3(-)-N), total phosphorus (TP) and dissolved phosphorus (DP) from courtyard composting decreased. Especially, the concentration variation of TN, NH4(+)-N, NO3(-)-N with time fit for I kinetic equation, while TP and DP fit for linear equation. The concentration order of nitrogen and phosphorus in runoff observed as follows: no coverage > coverage by rice straw > coverage by soil > coverage by thin film. As a result, the coverage by thin film could be used as a recommended mode to decrease the loss of nitrogen and phosphorus in runoff resulting from its low risks for nonpoint source pollution. PMID- 22509575 TI - [Effects of hydrodynamic process on bio-optical properties in algal-dominated lake region of shallow lake]. AB - An in situ field high-frequency bio-optical measurement was carried out in the littoral region in Meiliang Bay of Lake Taihu, a large shallow lake of China from 24 July to 1 August in 2010. The underwater irradiance, beam attenuation coefficient and absorption coefficient, the related physical-chemical and meteorological parameters were measured and analyzed, in order to determine the relationship between water bio-optical properties and wind waves process. The absorption coefficients of particles a(p) (440), non-phytoplankton a(d) (440), phytoplankton a(ph) (440) and chromophoric dissolved organic matter (CDOM) a(CDOM) (440) were 3.97, 3.97, 6.58 m(-1); 1.69, 2.17, 4.20 m(-1); 2.28, 1.80, 1.33 m(-1); 1.05, 1.04, 1.08 m(-1) with the corresponding 30-minute average wind speed of <3, 3-5 and >5 m x s(-1) under small, middle and large wind and waves, respectively. Phytoplankton particles contributed the most to total absorption coefficient integrated over a range of photosynthetically active radiation (PAR) (400-700 nm) with a value of 42.5% during small wind waves. With the increase of wind speed, the relative contributions of phytoplankton, CDOM and pure water deceased but the relative contribution of non-phytoplankton significantly increased with the values of 33.0%, 41.7% and 52.0% during small, middle and large wind waves, respectively. A significantly positive linear relationship was found between PAR diffuse attenuation coefficients and the mean wind speed within 10 minutes. Sediment resuspension caused by wind waves had a significant effect on PAR diffuse attenuation coefficient. From small wind waves to large wind waves, PAR diffuse attenuation increased 80.0% but the euphotic depth decreased 42.2%. Significant linear relationships were found between PAR diffuse attenuation coefficient, the beam attenuation coefficients at 750 nm, total suspended solid concentration and wind speed, wave height, wave shear stress, in which the correlation between PAR attenuation coefficients and meteorological hydrology factors was most significant. High-frequency bio-optical measurement showed that hydrodynamic process significantly affected the short-term variation of bio-optical properties in algal-dominated lake region of shallow lake through sediment resuspension, mixing and migration of phytoplankton. PMID- 22509576 TI - [Estimation and remote sensing inversion of diffuse attenuation coefficient Kd(490) in Lake Taihu in spring based on semi-analytical model]. AB - Diffuse attenuation coefficient is not only an important optical parameter, but also an important factor of water ecological system. Two datasets measured in April 2009 and May 2010 were firstly used to calculate absorption coefficient [a (490)] and backscattering coefficient [b(b) (490)] at 490 nm, and then, the relationship between b(b) (490) and simulated remote sensing reflectance at different bands of HJ-1 was studied. The semi-analytical model of Kd (490) in Lake Taihu in spring was constructed based on this basis, and it was used to estimate Kd (490) of Lake Taihu via an image of HJ-1 finally. The results show that: 1) The values of a(490) and b(b)(490) can be calculated accurately based on optical closure principle, and the mean absolute percent error (MAPE) of a(490) between calculated and measured is 17.1%. In addition, the backscattering coefficient at 490 nm [b(b) (490)] exponentially relate with the simulated remote sensing reflectance at the fourth band of HJ-1; 2) The semi-analytical model constructed in this study has good accuracy and stability. The MAPE is 21.6% and RMSE is 1.68 m(-1) by comparing inversion result and quasi-synchronous measured data; 3) Kd (490) of Lake Taihu in spring differs a lot in space distribution. The values are relatively smaller in north and east part of Lake Taihu, but larger in west and south part. PMID- 22509577 TI - [Monitoring the total suspended matter of Lake Chaohu based on quasi-analytical algorithm]. AB - There has been some effort by using quasi-analytical algorithm (QAA), which is based on radiative transfer theory to calculate backscattering coefficients of waters. A field investigation in Lake Chaohu was carried out in June, 2009, and a dataset including many parameters such as remote sensing reflectance, absorption and attenuation coefficients, concentration of total suspended matter (c(TSM)), had been obtained. Thereafter, a model for estimating c(TSM), was built, and in order to improve the accuracy, we employed the QAA algorithm to simulate backscattering ratio of Lake Chaohu. The results show that: 1) 807 nm and 834 nm are determined as optimum bands for the Two Near-Infrared Bands Method in Lake Chaohu, and the average specific scattering coefficient of suspended matters at the wavelength of 807 nm and 834 nm is 0.411 m2 x g(-1) and 0.395 m2 x g(-1) respectively; 2) The backscattering ratio of Lake Chaohu is 0.029, and better accuracy is achieved by using this value rather than other empirical values. The root mean square error (RMSE) and mean absolute percentage error (MAPE) of the estimated c(TSM) with calculated backscattering ratio are 12. 143 mg x L(-1) and 24.378%; 3) It is found that stations with high c(TSM) (nearly greater than 30 mg x L(-1)) can have more stable and reliable estimated results. PMID- 22509578 TI - [Optimization of aerobic/anaerobic subsurface flow constructed wetlands]. AB - Previous studies showed that setting aerobic and anaerobic paragraph segments in the subsurface constructed wetlands (SFCWs) can improve the COD, NH4(+)-N, and TN removal rate, whereas the oxygen enrichment environment which produced by the artificial aeration could restrain the NO3(-)-N and NO2(-)-N removal process, and to a certain extent, inhibit the denitrification in SFCWs Therefore, in this research the structure and technology of SFCW with aerobic and anaerobic paragraph segments were optimized, by using the multi-point water inflow and setting the corresponding section for the extra pollutant removal. Results showed that with the hydraulic load of 0.06 m3 x (m2 x d)(-1), the COD, NH4(+)-N and TN removal efficiencies in the optimized SFCW achieved 91.6%, 100% and 87.7% respectively. COD/N increased to 10 speedily after the inflow supplement. The multi-point water inflow could add carbon sources, and simultaneously maximum utilization of wetland to remove pollutants. The optimized SFCW could achieve the purposes of purification process optimization, and provide theoretical basis and application foundation for improving the total nitrogen removal efficiency. PMID- 22509579 TI - [Effects of allelochemical dibutyl phthalate on Gymnodinium breve reactive oxygen species]. AB - The purpose of this study was to investigate the mechanism of inhibitory action of dibutyl phthalate (DBP) on red tide algae Gymnodinium breve. Reactive oxygen species (ROS) level, contents of *OH and H2O2, and O2*(-) production rate were investigated, and also for the effects of electron transfer inhibitors on the ROS induction of DBP. The results showed that DBP triggered the synthesis of reactive oxygen species ROS, and with the increase of concentration of DBP, *OH and H2O2 contents in cells accumulated, as for the 3 mg x L(-1) DBP treated algae cultures, OH showed a peak of 33 U x mL(-1) at 48 h, which was about 2. 4 times higher than that in the controlled, and H2O2 contents was about 250 nmol x (10(7) cells)(-1) at 72 h, which was about 5 times higher and also was the highest during the whole culture. Rotenone (an inhibitor of complex I in the mitochondria electron transport chain) decreased the DBP induced ROS production, and dicumarol (an inhibitor of the redox enzyme system in the plasma membrane) stimulated the DBP induced ROS production. Taken all together, the results demonstrated DBP induced over production of reactive oxygen species in G. breve, which is the main inhibitory mechanism, and mitochondria and plasma membrane seem to be the main target site of DBP. These conclusions were of scientific meaning on uncovering the inhibitory mechanism of allelochemical on algae. PMID- 22509580 TI - [Toxicity effects of Rac- and S-metolachlor on two algaes]. AB - The enantioselective toxicity of the chiral herbicides Rac- and S-metolachlor to Scenedesmus obliquus and Chlorella vulgaris was determined, and the effect of humic acid was studied by using acute toxicity testing method. The results indicated that the toxicity of Rac- and S-metolachlor increased with increasing concentration and exposure time. The EC(50, 96 h) ratio of Rac-metolachlor to S metolachlor was 2.25 for C. vulgaris and 1.81 for S. obliquus, indicating that S metolachlor had higher effect on two algaes, and S. obliquus was more sensitive to Rac- and S-metolachlor. Linear correlation between toxicity on S. obliquus and C. vulgaris was observed. The toxicity of Rac- and S-metolachlor changed with humic acid, with more significant change was observed in S-metolachlor (P<0.05). PMID- 22509581 TI - [Studies for killing the oceanic harmful organisms in ship's ballast water using hydroxyl radicals]. AB - With a physical method of strong electric-field discharge, O2 in air and H2O at gas state are ionized and dissociated into a number of activated particles such as *OH, O2+, H2O+, etc, which are injected into a part of ballast water to form the dissolved *OH. High concentration of *OH solution was injected into the main pipe of discharge ballast water to effectively and fast kill the oceanic harmful organisms and bacteria in the course of conveying ship's ballast water. In the 10 t x h(-1) experimental system of ship's ballast water, the experiments were carried out for killing the plankton and bacteria using *OH radicals. The *OH concentration is 0.65 mg x L(-1) for 100% killing efficiency. At the same time, cell morphology changes of Chaetoceros muelleri and Nitzschia closterium were observed by a microscope. The cells of algae in their cellular wall, cellular membrane or cell protoplasm were greatly destroyed using *OH radicals. PMID- 22509582 TI - [Modification of natural siderite and enhanced adsorption of arsenic]. AB - Groundwater with high arsenic concentration has widely been found in China. More attention has been paid to economic and efficient arsenic removal technology. Natural siderite, which was abundant and relatively cheap, was used as the main raw material for arsenic adsorption by batch methods. Modified conditions of natural siderite, including temperature and time of calcination and adhesive addition, were carried out for arsenic removal. Results showed that the maximum removal efficiency was reached with the calcination temperature of 350 degrees C for 90 minutes and an adhesive dosage of 10 mg x g(-1). With the ratio of solid to liquid of 0.5 g: 50 mL and the initial concentration of 5 mg x L(-1) for either As(III) or As(V) at 25 degrees C, arsenic concentrations at equilibrium time were lower than 10 microg x L(-1). Characteristics of adsorption kinetics and adsorption isotherm on the optimal modified adsorbent were also evaluated. It was found that the arsenic adsorption kinetics fitted pseudo-second order kinetics equation, and the adsorption achieved equilibrium at about 12 h. The adsorption isotherm could be well described by Langmuir and Freundlich models. The maximum adsorption capacity was 1039 microg x g(-1) for As(III) and 1 026 microg x g(-1) for As(V). Furthermore, X-ray diffraction (XRD), scanning electron microscopy (SEM), and BET method were used to investigate main mechanisms of arsenic removal. Results showed that modified adsorbent had higher specific surface area and contained the spherical coating of Fe(II) and Fe(III) on the surface, in comparison with pristine material, which were believed to contribute to the high adsorption capacity of the modified material. The modified natural siderite appears to be a promising adsorbent that is worthy of further studies and practical application for arsenic removal. PMID- 22509583 TI - [Kinetic study of 4-chloronitrobenzene degradation by zero-valent iron]. AB - 4-chloronitrobenzene as a representative material of nitroaromatic compounds was used in this study to investigate the degradation reaction rate and products by different concentrations of zero-valent iron (ZVI) under anoxic condition. According to stoichiometry, different reaction rates of products were obtained by fitting the experimental data. Products of ZVI were measured by Mossbauer technique. The results show that reduction of 4-chloronitrobenzene corresponds to the concentration of ZVI. The production and transformation rates of intermediate products, 4-chloronitrosobenzene and 4-chloro phenyl hydroxylamine, can be achieved. The 4-chloronitrobenzene reduction reaction is the fastest when the ZVI concentration is 1.04 g x L(-1). The reaction rate constant is 0.189 min(-1). Ferrous iron ions generated during reaction are sorbed on the ZVI surfaces in the early age of the reaction. Formation and reduction reaction rates of different products depend on the reactive sites of ZVI and the mass transfer between each other. PMID- 22509584 TI - [Photochemical degradation of ofloxacin in aqueous solution]. AB - The photodegradation of ofloxacin (OFLX) was investigated in distilled water, artificial seawater and natural seawater exposed to high-pressure mercury lamp and xeon lamp. The photolysis of OFLX was affected by various factors including light sources, initial concentrations, acetone and surfactants. The photoreaction rate of OFLX under high pressure mercury lamp was much faster than that under xeon lamp, conforming to the first-order kinetics behavior. Expose to the same light intensity, The photodegradation rate of OFLX was the quickest in natural seawater, followed by artificial seawater. The initial concentrations of OFLX were 2, 4 and 6 mg x L(-1), the rate constants were 0.163, 0.140 and 0.132 min( 1), respectively. The photodegradation rates of OFLX in seawater decreased along with its initial concentration. The addition of acetone could accelerate the photoreactions of OFLX, The constants of the reaction rate range from 0.084 2 0.102 min(-1). A positive correlation was found between the photosensitive efficiency and the added concentration of acetone. On the contrary, the addition of cetyl trimethyl ammonium bromide (CTAB), sodium dodecyl benzene sulfonate(SDBS) and Tween-20 (TW-20) inhibited the photodegradation of OFLX, of which concentrations were all 5 mg x L(-1). In addition, toxicity tests with Isochrysis galbana 8701 showed higher risk of intermediate products generated from photolysis of OFLX. The toxicity of products decreased along with the reaction. PMID- 22509585 TI - [Photodegradation of atenolol in aqueous nitrate solution]. AB - The aqueous photolysis of beta-blocker atenolol (ATL) using Xe lamp as simulated solar irradiation source was investigated in the presence of nitrate ions. The effects of nitrate ion concentration, solution pH value, and concentration of bicarbonate and humic substance on the photodegradation of ATL were studied. The results showed that photodegradation of ATL in nitrate solution followed pseudo first-order kinetics. The increasing concentration of nitrate ion promoted the photodegradation rate of ATL. The first-order rate constant increased from 0.002 26 min(-1) to 0.009 4 min(-1) with nitrate concentration increasing from 0 to 5 mmol x L(-1). Acidic or alkaline condition of the solution favored the photodegradation of ATL. Different concentration of bicarbonate showed insignificant effect of the degradation while the increasing concentration of fulvic acid showed inhibiting effect. Hydroxyl radical was determined to be formed during the photolysis process of ATL using isopropanol as molecular probe. The main photoproducts of ATL were identified by using SPE-LC-MS techniques and possible photoinduced degradation pathways in nitrate solution were proposed. PMID- 22509586 TI - [Biodegradation of pyridine under UV irradiation]. AB - Pyridine, a complex nitrogen-containing heterocyclic compounds, is usually difficult to degrade by means of single biological method. The internal loop photobiodegradation reactor (ILPBR) was used for degradation of pyridine in batch and continuous experiments following three protocols: photolysis alone (P), biodegradation alone (B), and intimately coupled photolysis and biodegradation (P&B) to investigate the regularity of pyridine degradation. The experimental results indicated that pyridine removal rate by P&B was fastest among three protocols in batch experiment, in which protocol B was faster than P. For initial pyridine concentration of 100 mg L(-1), the pyridine removal rates were respectively 4.95, 10.2 and 14.58 mg (L x h)(-1) corresponding to protocol P, B and P&B. Pyridine degradation kinetic equations were established based on Monod model, and the saturation constants decreased from 1920.4 mg x L(-1) for protocol B to 1094.1 mg x L(-1) for protocol P&B. Protocols P, B and P&B were also used for pyridine degradation in continuous flow and influent pyridine concentration increased from 50 to 300 mg x L(-1), and their average removal rates were respectively 15.8 mg (L x h)(-1) for protocol P, 23.1 mg x (L x h)(-1) for protocol B and 24.9 mg x (L x h)(-1) for protocol P&B, in which the removal rates were higher than that in batch. Experiments suggested that the inhibition of pyridine to biofilm could be relieved due to UV irradiation in process of intimately coupled UV photolysis and biodegradation, and biofilm had kept its bioactivity degrading pyridine and enhanced pyridine removal rates. PMID- 22509587 TI - [Optimization on decoloration conditions of anthraquinone dyes by laccase from Amillariella mellea]. AB - Laccase extracted from the Amillariella mellea fermentation catalytic decolored on two common anthraquinone dyes: Reactive Brilliant Blue KN-R and Reactive Brilliant Blue X-BR which is broadly used in the printing and dyeing industry and obtained the optimal catalytic decolorizing conditions. The results showed that optimum temperature of Reactive Brilliant Blue KN-R decolorization was 30 degrees C, the optimum dye concentrations was 80 mg x L(-1), the optimum enzyme dosage was 0.25 U x mL(-1), and the optimum pH was 5. Under this optimal conditions, the maximum decolorization rate of Reactive Brilliant Blue KN-R was over 90%. The optimum temperature Reactive Brilliant Blue X-BR decolorization was 30 degrees C, the optimum dye concentrations was 50 mg x L(-1), the optimum enzyme dosage was 0.5 U x mL(-1), and the optimum was pH 4. Under the optimal conditions, the maximum decolorization rate of Reactive Brilliant Blue X-BR was over 70%. The decolorization on the two common industrial dyes by crude enzyme from Amillariella mellea fermentation obtained a good results. The results indicated that the decoloration on anthraquinone dyes by laccase from Amillariella mellea has a potential value in the printing and dyeing industry. PMID- 22509588 TI - [Biosorption of chromium (VI) by waste biomass of epsilon-poly-L-lysine fermentation]. AB - The sorption of hexavalent chromium by waste biomass of epsilon-Poly-L-lysine fermentation strains (Streptomyces albulus) PD-1 was studied. Effects of pretreatment ways, pH, initial concentration of Cr(VI), contact time and temperature on biosorption were determined. It was found that homogenization in HCl was the best way to pretreat mycelia, having an increased rate of Cr(VI) biosorption at 22.7%, the optimum pH was about 2.0, while no significant impact of temperature on the biosorption was observed. The fitness of the experimental data for the Langmuir and Freundlich adsorption models was further examined and good correlations with R2 of 0.979 4 and 0.979 8 were observed, indicating the presence of both monolayer biosorption and heterogeneous surface condition. The maximum adsorption capacity of the Streptomyces albulus PD-1 for Cr(VI) was 23.92 mg x g(-1). FT-IR analysis demonstrates that the major functional groups (amide and hydroxyl) may contribute to the absorption of Cr(VI). PMID- 22509589 TI - [Investigation on enhanced conditions for the densification of filamentous sludge]. AB - A new approach was investigated for controlling sludge bulking by using enhanced conditions for densification of filamentous sludge. Several methods, including elevated dissolved oxygen, increased superficial velocity, elevated calcium concentration, extended starvation time, have been employed to reveal when and how filamentous sludge could be denser in terms of settleability. It showed that increased superficial velocity improved the settleability and event triggered filamentous granulation in a short term, i. e., sludge volumetric index (SVI) decreased from 800 mL/g to 350 mL/g, and it became less effective in a long term, as the SVI increased to approximately 800 mL/g after a short period of stable operation. Elevated calcium concentration also improved the settleability by clustering the mycelium of filamentous microorganisms, and then SVI decreased to 300 mL/g gradually, but no granulation was observed. However, negligible changes were observed by elevated dissolved oxygen or extended starvation time, as the decrease of SVI value could not be significantly observed. Additionally, relationship between ovality of filamentous mesh and sludge volumetric index was also examined. It was found that the clustered growth that brought about high ovality (approximately 1.5) could improve the settleability. Additionally, acidic condition may damage the mycelium aggregation, and alkaline condition and divalent cation concentration were insignificant for mycelium aggregation. PMID- 22509590 TI - [Effect of temperature on the response characteristics of shortcut nitrification granular sludge]. AB - The experiment was carried out in a sequencing batch reactor (SBR), using granular sludge with 90% shortcut nitrification accumulation ratio, which had been cultivated by the laboratory to seed the reactor. The effects of temperature on characteristics, stability, nitrogen conversion properties and activity of short-cut nitrification granular sludge were investigated. The results show that the temperature has a significant influence on structure and short-cut nitrification performance of short-cut nitrification granular sludge. 30 degrees C was the optimum temperature for shortcut nitrification granular sludge cultivation, and the granules were more compact which led better flocculation and settleability. SVI and average diameter of sludge reached up to 39 mL x g(-1) and 3.03 mm, respectively. The nitrification accumulation was maintained at 96.17% during this period. When the temperature was at 25 degrees C, the granules changed to a loose-structure along with the electronegativity increased as well as the hydrophobicity decreased, which was due to the increase of EPS and decreased ratio of protein to polysaccharide. The granules disintegrated during this period, at the same time, the nitrification accumulation ratio was below 35%. It can be seen that the shortcut nitrification performance was destroyed. At 15 degrees C, the shortcut nitrification sludge also disintegrated and had a looser structure. However, the oxygen penetration depth increased at a lower temperature, which made the relative quantity of ammonia oxidizing bacteria (AOB) in reactor increased, the nitrification accumulation was around 68% ultimately. PMID- 22509591 TI - [Fuel consumption and emission inventory of typical construction equipments in China]. AB - Developing emission inventory for nonroad mobile equipments is the initiating step of nonroad mobile source emission control. NONROAD model developed by U. S. EPA was studied, and methods based on actual fuel consumption rate were established to calculate fuel consumption and emission inventory of excavators and loaders in China. Surveys were conducted on key emission parameters of typical construction equipments in China, including equipment inventory, annual activity, actual fuel consumption rate, and emission factor. Results show that diesel consumption of excavators and loaders was 1.21 x 10(7) t, accounting for 9.7% of total consumption of all sectors in China in 2007. Total emissions of NO, and PM from excavators and loaders were 6.81 x 10(5) t and 5.31 x 10(4) t, respectively. The data indicates construction equipments are important emission sources compared with motor vehicles. According to the results, it is necessary to tighten limits of exhaust pollutants for construction equipments in China and to bring them into effect. PMID- 22509592 TI - [Optimization of PM10 monitoring network in Beijing]. AB - PM10 monitoring network in Beijing was classified using a new technique, positive matrix factorization (PMF). And then the removal bias of each cluster was calculated by GIS system and sites with redundant information were identified. The daily average mass concentrations of PM10 from July 2007 to June 2008 were analyzed at 26 sites. The result showed that PM10 monitoring network of Beijing was separated into 10 clusters. Tongzhou, Yanqing, Miyunshuiku, Fangshan, and Pinggu formed five separate clusters. The five clusters with more than one site each were Cluster 4, which included sites Fengtaihuayuan, Fengtaiyungang, Mentougou, Haidianbeibuxinqu, and Shijingshan, located within the west developing urban area; Cluster 7, which included Dongchengdongsi, Dongchengtiantan, Xichengwanshouxigong, Xichengguanyuan, Chaoyangaotizhongxin, Chaoyangnongzhanguan, and Shunyi, located mainly within the developed area and the east developing area; Cluster 8, which included Daxingyizhuang, Daxinghuangcun, and Daxingyufa, located within the southern suburban industrial area; Cluster 9, which included Miyunzhen and Huairou, located within the north remote rural area; and Cluster 10, which included Haidianxiangshan, Changpingdingling, Haidianwanliu, and Changpingzhen, located within the northwest suburban area. All the 10 clusters had unique seasonal variations. According to the removal criteria, two scenarios were constructed. The criterion of scenario 1 was the uncertainty of the PM10 monitoring network, and the optimization result in which 12-18 sites should be retained was equal to the original monitoring network included 26 sites. The criterion of scenario 2 was two times of the uncertainty, and 10-13 sites needed to be retained. PMID- 22509593 TI - [Effect of greenbelt on pollutant dispersion in street canyon]. AB - The effect feature of greenbelt on flow field and pollutant dispersion in urban street canyon was researched. The greenbelt was assumed as uniform porous media and its aerodynamics property defined by the pressure loss coefficient. Subsequently, the pollutant dispersion in the street canyon of which there was greenbelt in the middle was simulated with the steady-state standard kappa epsilon turbulence model and species transport equation. The simulated results agreed well with the wind-tunnel data. Compared with the treeless case, it finds that the street canyon contain a clockwise vortex, the pollutant concentration of the leeward was several times than the windward and the growth rate of pollutant concentration was 46.0%. The further simulation for the impact of tree crown position on the airflow and pollutant dispersion finds that the height of major vortex center in the street canyon increases with the height of tree crown and gradually closes the top of windward building This causes that the average wind speed in the street canyon decreases. Especially when the top of tree crown over the roof and hinder the air flow above the street canyon, the average pollutant concentration increases with the height of tree crown rapidly. PMID- 22509594 TI - [Investigation of effect and process of nitric oxide removal in rotating drum biofilter coupled with absorption by Fe(II) (EDTA)]. AB - In order to accelerate the NO removal efficiency, a novel and effective system was developed for the complete treatment of NO from flue gases. The system features NO absorption by Fe(II) (EDTA) and biological denitrification in a rotating drum biofilter (RDB) so as to promote biological reduction. The experimental results show that a moderate amount of Fe(II) (EDTA) was added to the nutrient solution to improve the mass transfer efficiency of NO from gas to liquid, with the concomitant formation of nitrosyl complex Fe(II) (EDTA)-NO. Under the experimental conditions of rotational speed was at 0.5 r x min(-1), EBRT of 57.7 s, temperature was at 30 degrees C, pH was 7-8, with the increasing concentration of Fe(II) (EDTA) was from 0 mg x L(-1) to 500 mg x L(-1), the NO removal efficiency was improved from 61.1% to 97.6%, and the elimination capacity was from 16.2 g (m3 x h)(-1) to 26.7 g (m3 x h)(-1). In order to simulate the denitrifying process of waste gas containing NO by using RDB coupled with Fe(II) (EDTA) absorption, a tie-in equation of NO removal and the Fe(II) (EDTA) concentration added in RDB was established. The experimental NO removal efficiency change tendency agrees fairly with that predicted by the proposed equation. PMID- 22509595 TI - [Effect of UV-B radiation on release of nitrogen and phosphorus from leaf litter in subtropical region in China]. AB - The release of nitrogen and phosphorus from leaf litter of six representative species, Cunninghamia lanceolata, Pinus massoniana, Schima superba, Cinnamanun camphora, Cyclobalanopsis glauca and Castanopsis eyeri, was investigated with litterbag method under ambient and reduced UV-B radiation (22.1% below ambient) treatments in subtropical region. The results showed that, the N dynamics exhibited three patterns: immobilization, mineralization-immobilization and mineralization-immobilization-mineralization. P dynamics also exhibited three different patterns: mineralization, immobilization-mineralization-immobilization and no large change. Compared with ambient treatment, the reduced treatment significantly delayed the N release from C. eyeri and P release from both C. glanca and C. eyeri (P<0.05), but significantly stimulated P release from C. camphora (P<0.05). The initial N contents and C: N ratios can not account for the N dynamics during leaf litter decomposition. The C: P ratios can partly explain the P dynamics during decomposition. The more works need to be done to better understand the role of UV-B radiation in the forest ecosystem in humid subtropical China under global environment change. PMID- 22509596 TI - [Characteristics of carbon sequestration and apparent stability of new sequestered carbon in forested torrid red soil at dry-hot valley]. AB - Great concerns about potential for carbon (C) sequestration in forested soil and the stability of the sequestered C have been exerted under the background of global climate change. Organic C density in soil and in soil physical and biochemical fractions at various stages (1991, 1997, 2003 and 2010) in Acacia auriculiformis stand afforested in 1991 were investigated at Dry-Hot Valley via density fractionation and acid hydrolysis. The results showed that organic C density at surface (0-15 cm) and subsurface (15-30 cm) soil layers was 1.40 kg x m(-2) and 0.99 kg x m(-2) after 19 years of afforestation, respectively. The annual C sequestration rates of surface and subsurface soil layers were 37.89 g x (m2 x a)(-1) and 16.84 g x (m2 x a)(-1) during 1991-2010, respectively, and the sequestration was accelerating. The ratio of organic C in heavy fraction to in surface soil was 71.44% in 2003, which was significantly higher than that in 2010 (67.99%). The recalcitrant carbon index (I(RC)) in light fraction was significantly higher than that in heavy fraction at surface or subsurface layers in 2003, but both decreased with aging of plantation, especially I(RC) in light fraction. Approximately 57% - 70% of new sequestered C was protected by physical mechanism and 33-49 percent was biochemical recalcitrant C during the stage from 12 to 19 years after afforestation. The results reveal that forested torrid red soil at Dry-Hot Valley may have a considerable capability of C sequestration. The biochemical stability of physically protected C is lower than the unprotected. Both the stability, however, decreases with the plantation age. PMID- 22509597 TI - [Spatial distribution of methane in surface water and sediment of Jiulongjiang estuary and the effect environment factors of it]. AB - Distribution of methane in surface water and sediment of Jiulongjiang Estuary was investigated during July, 2009 through head-space method. The concentration of methane varies from 10.7 to 456.7 nmol x L(-1) in the surface water at 56 sampled stations, and supersaturates relative to equilibrium with atmospheric methane. The concentration of methane decreases rapidly from estuarine upside margin to the open coastal ocean, resulting from mixing between high CH4-containing fresh water and low CH4-containing seawater. The sediment cores are situated in the upper estuarine coast and seaward boundary along the estuarine salinity gradient, representing the freshwater, half-brackish and marine water environment. Distribution of methane in porewater is consistent with that of surface water, which decreases rapidly from B1, B2, B3 to B4 stations, from 2 212 micromol x L( 1) to 5 micromol x L(-1). The concentration of sulfate in porewater increases gradually from B1, B2, B3 to B4 stations, with average value of 0.13, 0.64, 5.3 and 16.3 mmol x L(-1) respectively. The trends of methane in surface water and porewater have illustrated a large amount of methane is generated via the process of organic matter degradation mediated by methanogens, moved across sediment water interface, and entered to overlying water. In seaward boundary sediment with an abundance of sulphate in sediment, and sulphate in porewater inhibits the methanogenesis, the methane input from the sediment rapidly decreases. Depth profiles of methane in porewater B2 and B3 stations show an increase in concentration from 43 and 10 micromol x L(-1) near the sediment-water interface to about 1 051 and 57 micromol L(-1) at core end. According to the vertical profile of methane, total organic carbon (TOC) and sulfate trend, a large amount of methane is depleted via anoxic oxidation in methane-sulfate transition. The methane released from the low concentration of sulfate sediment intertidal wetland situated in upper estuarine could be the most important source in Jiulongjiang estuary. PMID- 22509598 TI - [Methane fluxes and controlling factors in the intertidal zone of the Yellow River estuary in autumn]. AB - The characteristics of methane (CH4) fluxes from tidal wetlands of the Yellow River estuary were observed in situ with static-chamber and GC methods in September and October 2009, and the key factors affecting CH4 fluxes were discussed. From the aspect of space, the CH4 flux ranges in high tidal wetland, middle tidal wetland, low tidal wetland, bare flat are - 0.206-1.264, -0.197 0.431, -0.125-0.659 and -0.742-1.767 mg x (m2 x h)(-1), the day average fluxes are 0.089, 0.038, 0.197 and 0.169 mg x (m2 x h)(-1), respectively, indicating that the tidal wetlands are the sources of CH4 and the source function of CH4 differed among the four study sites, in the order of low tidal wetland > bare flat > high tidal wetland > middle tidal wetland. From the aspect of time, the ranges of CH4 fluxes from the tidal wetland ecosystems are -0.444-1.767 and - 0.742- 1.264 mg x (m2 x h)(-1), and the day average fluxes are 0.218 and 0.028 mg x (m2 x h)(-1) in September and October, respectively. The CH4 fluxes in each tidal wetland in September are higher than those in October except that the high tidal wetland acts as weak sink in September. Further studies indicate that the changes of environmental factors in the Yellow River estuary are complicated, and the CH4 fluxes are affected by multiple factors. The differences of CH4 fluxes characteristics among different tidal wetlands in autumn are probably related to temperature (especially atmospheric temperature) and vegetation growth status, while the effects of water or salinity condition and tide status on the CH4 flux characteristics might not be ignored. PMID- 22509599 TI - [Study on dioxin emission for typical non-wood pulp making in China]. AB - Based on the requirement of National Implementation Plan for the Stockholm Convention on Persistent Organic Pollutants (NIP), six industries including pulp and paper industry have been set as the priority key sectors to implement the best available technology and best environmental practice (BAT/BEP) within a specific time for UPOPs reduction. Non-wood pulping has always played important role in virgin pulp production in China, its elemental chlorinated bleaching process has been confirmed as main source of Dioxin emission for the sector. As the signature party of Stockholm Convention and long time existing country of non wood pulping, identification of Dioxin emission situation is significant importance to China to committee the obligation of Stockholm Convention. The Dioxin concentrations in outflow water of bamboo, straw, reed, and bagasse pulping processes (chlorination alkaline extraction hypochlorite, CEH) are 41.8 pg x L(-1), 72.7 pg x L(-1), 7.46 pg x L(-1), and 19.7 pg x L(-1) respectively, which are all around the national waste water discharge standard (30 pg x L(-1)). But relevant data will easily exceed national standard while the limitation of unit water consumption for pulp making is decreased. So the application of best available techniques/best environmental practices (BAT/BEP) is very necessary to improve relevant mills up to the above standard, and proceed the sector meeting the national and international requirements for Dioxin emission. At the same time, the text calculates emission factors on bamboo, straw, reed and bagasse pulp making process through whole process monitoring, which will provide meaningful reference for increasing relevant factors in UNEP Toolkit. PMID- 22509600 TI - [Horizontal and vertical distribution of polybrominated diphenyl ethers (PBDEs) in river sediment from a typical electrical equipment industrial area]. AB - Polybrominated diphenyl ethers (PBDEs) were determined in sediment collected from a river in a typical electrical equipment industrial area, Ronggui, Foshan. Eight samples were collected from river sediment. The results indicated that PBDEs were presented in all samples. Spatial trends showed that the concentrations of PBDEs in all sediment samples were ranged from 62 ng x g(-1) to 349 ng x g(-1), with an average of 178 ng x g(-1). The predominant congener was BDE-209 (90% - 99%), which ranged from 56-337 ng x g(-1), with an average of 171 ng x g(-1). Some of congeners such as BDE-196, 197 and 203 may be were the degradation product of BDE 209. Vertically, the concentrations of PBDEs were increased with the depth, whereas the concentrations were 147 ng x g(-1) in layer 0-10 cm and 260 ng x g( 1) in layer 30-40 cm, respectively. Distribution profile of PBDEs in vertical direction was similar in different depths. The commercial deca-BDE (94%), which contained BDE-209, 208, 207 and 206, was the dominate pollutant with minor contributions from penta-and octa-BDEs. The results suggested that this area was polluted by PBDEs and BDE-209 was the most dominate congener, which is related with the manufacturing activities for electrical equipment. PMID- 22509601 TI - [Characteristics of polychlorinated biphenyls in soils from an electronic waste recycling area]. AB - The concentrations of 144 polychlorinated biphenyls (PCBs) in the soils from Luqiao were analyzed by GC-microECD. The objectives of this study were to understand the contents, spatial distribution and sources. The sigma PCBs concentrations in soils samples were in the range of 0.779 ng x g(-1) to 937 ng x g(-1), with a mean of 75.7 ng x g(-1), and the relatively high level of PCBs were mainly distributed in the south central area. Penta-CBs, hexa-CBs and tetra-CBs were the primary homologues in 38 samples, with the range of 13.0% - 61.1%, 4.59% - 48.8% and 10.1% - 31.5%, respectively. Di-CBs was the most predominant homologues in other samples, with the range of 47.1% - 75.2%. The hierarchical cluster analysis (HCA) showed that most of samples were mainly polluted by Ar1254, few samples were polluted by Ar1221. Significant correlations were observed between sigma PCBs and TOC, which suggested PCBs were affected by TOC in soils. The correlation analysis also showed significant correlation among the PCBs homologues (except di-CBs and nona-CBs), which suggested PCBs might have the similar sources. Compared to other studies from different countries and regions, the PCBs concentrations in the present study were at an upper-middle level. PMID- 22509602 TI - [Characterization and potential risks of polycyclic aromatic hydrocarbons in green space soils of educational areas in Beijing]. AB - Pollution of green space by polycyclic aromatic hydrocarbons (PAHs) in education area may pose a potential impact on the faculty, students, and staffs. To study the characterization, influencing factors, sources and risks of soil PAHs in Beijing educational areas, the concentrations of 16 priority PAH identified by United States Environmental Protection Agency (USEPA) in green spaces of 20 schools and academies were determined. The total PAHs concentration ranged from 194 microg x kg(-1) to 6 988 microg x kg(-1), with a mean of 1 637 microg x kg( 1). Middle and high molecular weight PAHs (4-6 rings) accounted for 85% of the total PAHs concentration. Coal combustion for winter heating and food supply were the main sources of PAHs in Beijing educational areas. Based on the Cluster analysis, the transportation and accumulation of NAP were distinguished from other 15 PAH congeners. No significant correlation between PAHs and soil organic matter (SOM) was found except for NAP, suggesting that most of the PAH congeners were derived from direct deposition of urban sources. The integrated lifetime cancer risks (ILCRs) associated with exposure to soil PAHs in Beijing educational areas were acceptable, but the indirect effects should not be ignored. PMID- 22509603 TI - [Spatial variability and evaluation of soil heavy metal contamination in the urban-transect of Shanghai]. AB - Soil heavy metal concentrations along the typical urban-transect in Shanghai were analyzed to indicate the effect of urbanization and industrialization on soil environment quality. Spatial variation structure and distribution of 5 heavy metals (Cu, Cr, Mn, Pb and Zn) in the top soil of urban-transect were analyzed. The single pollution index and the composite pollution index were used to evaluate the soil heavy metal pollution. The results showed that the average concentrations of the Cu, Pb, Zn, Cr, Mn were 27.80, 28.86, 99.36, 87.72, 556.97 mg x kg(-1), respectively. Cu, Cr, Mn, Pb and Zn were medium in variability, Mn was distributed lognormally, while Cu, Cr, Pb and Zn were distributed normally. The results of semivariance analysis showed that Mn was fit for the exponential model, Cr, Pb, Cu and Zn were fit for the linear model. The spatial distribution maps of heavy metal content of the topsoil in this city-transect were produced by means of the universal kriging interpolation. Cu was spatially distributed in ribbon, Cr and Mn were distributed in island, while the spatial distribution of Pb and Zn showed the mixed characteristic of ribbon and island. With the result of soil pollution evaluation, it showed that the pollution of Cr, Zn and Pb was relatively severe. Cr, Zn, Pb, Mn and Cu were significantly correlated, and heavy metal co-contamination existed in soil. Difference of soil heavy metals pollution along "Urban-suburban-rural" was obvious, the special variation of heavy metal concentrations in the soil closely related to the degree of industrialization and urbanization of the city. PMID- 22509604 TI - [Assessment of heavy metal pollution in surface sediments of rivers in northern area of Haihe River Basin, China]. AB - Using Hakanson potential ecological risk index, the paper assesses heavy metal risk levels in northern parts of Haihe River basin based on 39 sampling sites. The results indicate that, the concentrations of Cu, Zn, Cd, and Cr in Haihe River basin are higher than the background values of heavy metals in China mainland, while the concentration of Pb is close to the background value in China mainland. Based on the potential ecological risk index for single heavy metal, the risk of Cu, Pb, Zn and Cr belongs to the "slight" level, while Cd has various risk levels at different sampling sites. Generally, the risk order of the heavy metals is Cd > Pb > Cu > Cr > Zn. According to Hakanson potential ecological risk index, 32 monitoring sites belong to "slight" level, 5 sampling sites belong to "middle" level, and 2 monitoring sites belong to "very strong" level. The most polluted sites are Tang River and Dashi River of Beijing, Juma River in Baoding. Therefore, these rivers should be taken more considerations in the river management. PMID- 22509605 TI - [Concentrations and pollution assessment of soil heavy metals at different water level altitudes in the draw-down areas of the Three Gorges Reservoir]. AB - To investigate the effect of 175 m trial impounding (2008 and 2009) of the Three Gorges Reservoir on soil heavy metals, three draw-down areas with similar geological environment and history of land-use in Zhongxian County were chosen. Altogether 36 surface soil samples (including 0-10 cm and 10-20 cm soil layer) from water-level altitude of 160 m and 170 m were obtained, and their heavy metals concentrations (As, Cd, Cr, Cu, Ni, Pb and Zn) were measured by the X-ray fluorescence spectrometric method. Geoaccumulation index (I(geo)) and Hakanson potential ecological risk index were applied to assess the heavy metals pollution status and potential ecological risk, respectively. Results indicated that although the inundation period of 160 m was 224 d longer than that of 170 m, significant difference in concentrations of heavy metals were not found between the two water-level altitudes. Except for Cd, most of the heavy metals highly related with each other positively. According to the geoaccumulation index, the pollution extent of the heavy metals followed the order: As > Cd > Cu > Ni > Zn = Pb > Cr. The I(geo) value of As, Cd and Cu were 0.45, 0.39 and 0.06, respectively, indicating that the soil was only lightly polluted by these heavy metals. Hakanson single potential ecological risk index followed the order: Cd > As > Cu > Pb > Ni > Cr > Zn. Cd with E(i) values of 59.10, had a medium potential for ecological risk,while As, Cr, Cu, Pb, Ni and Zn only had a light potential. Consequently, although As, Cd and Cu were the major heavy metals with potential ecological risk for surface soil pollution in the draw-down areas in Zhongxian County, the Three Gorges Reservoir. PMID- 22509606 TI - [Analysis of community structure on sludge aerobic/anoxic digestion after ultrasonic pretreatment]. AB - The microbial community structure of sludge aerobic/anoxic digestion after ultrasonic pretreatment was studied by PCR amplification and DGGE based on 16S rDNA. The genomic DNA of sludge at different stages was extracted with SDS cell lysate method. After purification of DNA, the 16S rDNA genes (V3 region) were amplified by using the universal primers (F357GC and R518). The results of agarose gel (1.5%) electrophoresis showed that the PCR products were about 190 bp in length. The amplified DNA fragments were separated by paralleled DGGE with the denaturant (urea and acrylamide) from 30% to 60%. The sequences were used for homology analysis and phylogenetic trees were constructed. The DGGE profiles showed that the change of microbial diversity was in correspondence to different periods. Compared with 0 d, the diversities of microorganisms were 61.2%, 48.2%, 46.4%, 42.6% and 41.7%, respectively after 5 d, 10 d, 15 d, 20 d, 25 d. Shannon density index of bacteria experienced a process from a gradual reduction to stable state. This suggested that ultrasonic pretreatment had a significant impact on bacterial community structures. Cluster analysis of DGGE by UPGMA (unweighted air group method, arithmetic mean) divided all lanes into three clusters, which corresponded to different periods during the whole experiment. The sequences indicated that Firmicute, Genuscitrobacter, Bacilli, alpha Proteobacteria, beta-Proteobacteria were the predominant microbial populations in the process of sludge aerobic/anoxic digestion after ultrasonic pretreatment. PMID- 22509607 TI - [Research on population structure and distribution characteristic of indigenous microorganism in post-polymer-flooding oil reservoir]. AB - Denaturing gradient gel electrophoresis (DGGE) method and principal component analysis (PCA) method were used to analyze the structures of microorganism population in injection wells and production wells of a post-polymer-flooding oil reservoir in Daqing oil field. The results showed that the dominant species in injection wellhead were aerobic bacteria Pseudomonas and Acinenobacter. Facultative anaerobic bacteria Enterbacter was the dominant bacteria in near area of injection wells. Bacteria detected in production wells included Thauera, Clostridia, Pseudomonas, Petrobacter and some uncultured bacteria. Methanosaeta turned out to be the only archaea detected in injection wells, which was an aceticlastic methane-producing archaeon. Archaea detected in production wells consisted of Methanomicrobium, Methanospirillum and Methanobacterium. In general, aerobic bacteria, facultative anaerobe, and strictly anaerobic bacteria distributed successively from injection wells to production wells in this block. The dominant populations of archaea were different between injection wells and production wells, while were influenced by different environments and microbial metabolism products. PMID- 22509608 TI - [Study on degradation of polycyclic aromatic hydrocarbons (PAHs) with different additional carbon sources in aged contaminated soil]. AB - This study was conducted with different additional carbon sources (such as: glucose, DL-malic acid, citrate, urea and ammonium acetate) to elucidate the degradation of polycyclic aromatic hydrocarbons (PAHs) in aged contaminated soil under an indoor simulation experiment. The results showed that the quantity of CO2 emission in different additional carbon sources treatments was obviously much more than that of check treatment in the first week, and the quantity of CO2 emission in DL-malic acid treatment was the largest. The average CO2 production decreased in an order urea > glucose approximately citrate approximately DL-malic acid approximately ammonium acetate > check. Meanwhile, the amount of volatized PAHs in applied carbon sources treatments was significantly less than that in check treatment. The amount of three volatized PAHs decreased in an order phenanthrene > fluoranthene > benzo(b)fluoranthene. Compared with the check treatment, the average degradation rates of the three PAHs were significantly augmented in the supplied carbon sources treatments, in which rates of the three PAHs were much higher in DL-malic acid and urea treatments than those in other treatments. The largest proportion of residual was benzo(b)fluoranthene (from 72% to 81%) among three PAHs compounds, followed by fluoranthene (from 53% to 70% ) and phenanthrene (from 27% to 44%). PMID- 22509609 TI - [Detection of Prorocentrum minimum (Pavillard) Schiller with the electrochemiluminescence-molecular probe]. AB - In this study, the electrochemiluminescence-molecular probe (ECL-MP) was established based on the sandwich hybridization integrated with nuclease protection assay (NPA-SH) improved by electrochemiluminescence (ECL). It can be used for detecting Prorocentrum minimum (Pavillard) Schiller qualitatively and quantitatively. NPA probes of P. minimum were designed based on the NPA-SH. After labeled with Ru (bpy)3(2+) and biotin, they bounded with streptavidin-coupled magnetic beads and generated electrochemiluminescence in an ECL analyzer. The ECL counts per second (CPS) was drawn against the cell number obtained from microscopy to establish a calibration curve of P. minimum. The results showed that the labeled NPA probes had good specificity and practicability, the optimal usage of magnetic beads was 4 microg for detecting 20 microL hybridization mixture, the detection range of P. minimum cell numbers was 6.25 x 10(2) - 4 x 10(4), and there was no significant difference between the data gained from ECL MP and microscopy with 95% confidence level (t-test) when treated with cultured and mixed samples. ECL-MP was a convenient new tool for rapid assessment of P. minimum in marine environment. PMID- 22509610 TI - [Development of direct competitive enzyme-linked immunosorbent assay for the determination of domoic acid]. AB - To develop a direct competitive enzyme-linked immunosorbent assay (ELISA) for rapid detection of domoic acid concentrations, HRP (horse radish peroxidase) was successfully linked to DA using EDC. The concentration of DA was quantitatively analyzed on the basic of the specific immune responses between the DA- HRP and the monoclonal antibodies made in advance. Calibration curve were established after the optimization of reaction conditions such as the type of blocking solution, the blocking time and the incubation temperature. The results show that, the best reaction condition of the direct competitive ELISA is 1% gelatin, blocking 1 h at 37 degrees C, incubating 1 h at 37 degrees C after the monoclonal antibodies added. The detect limit is 3.58 ng x mL(-1), the coefficient of variation between the holes is below 15%, and the recovery is 80% - 120%. The whole analysis process could be completed within 1.5 h. It meets the requirements of rapid and batch detection of domoic acid. The method will have broad development prospects. PMID- 22509611 TI - [Simultaneous determination of 10 sulfonamide antibiotics in water by solid-phase extraction and high performance liquid chromatography]. AB - A solid-phase extraction (SPE)-high performance liquid chromatography (HPLC) method has been developed for simultaneous determination of 10 sulfonamide antibiotics in water. The analytes were first enriched and purified through a PEP solid-phase extraction column, and eluted with acetonitrile-dichloromethane solution (2: 1, V/V), then detected by a HPLC with a UV detector. The detection wavelength was 268 nm and the column temperature was 33 degrees C, using gradient elution process with acetonitrile - 0.4% acetic acid/water (V/V) as the mobile phase to achieve baseline separations of these 10 analytes. The linearity range was 10 - 2 000 microg x L(-1). The recovery ranges of standard addition for deionized water and real water samples were 73.4% - 95.6% and 70.2% - 92.5%, respectively (except for sulfonamide, were 8.5% and 8.0%). The limit of detection was 1.42-7.25 ng x L(-1). Application of this method for parts of Huangpu River in Shanghai, surface water and groundwater in Chongming Island showed that sulfonamide antibiotics were detected in different frequencies in different aqueous environments, with the concentration range of 13.3 - 241.5 ng x L(-1), proving this method is easy, rapid, sensitive and efficient to meet the needs of actual work. PMID- 22509612 TI - [Effects of pentachlorophenol on DNA damage and cytotoxicity of HeLa cells]. AB - Using human cervical carcinoma HeLa cells, the cell viability was determined by MTT assay after pentachlorophenol (PCP) treatment, the cytotoxicity of PCP was evaluated by detecting lactate dehydrogenase (LDH) leakage rate and total superoxide dismutase (SOD) activity in cell culture medium; DNA damage was detected by comet assay. The results indicated that HeLa cells proliferation was inhibited by PCP and the median inhibitory concentration (IC50) was 66.59 micromol x L(-1); PCP did not induce DNA damage in the concentration range from 6.25 micromol x L(-1) to 50 micromol L(-1); LDH leakage rate increased gradually with the increasing of exposure time when HeLa cells were treated by PCP in the concentration range from 12.5 micromol x L(-1) to 200 micromol x L(-1); SOD activity decreased gradually as the increasing of exposure time when HeLa cells were treated by PCP at lower concentration of 12.25 micromol x L(-1), 17.5 micromol x L(-1), 25 micromol x L(-1) respectively, LDH leakage rate increased significantly at 25 micromol x L(-1) and activity of SOD decreased markedly at 12.25 micromol x L(-1) in HeLa cells following PCP-treatment respectively. Results suggested that SOD and LDH might be regarded as candidate sensitive biomarkers for evaluating toxicity of PCP at low concentration on human and wildlife. PMID- 22509613 TI - [Modeling of carbon dioxide measurement and optimization on building ceramic industry]. AB - Input-output model and low carbon programming model on building ceramic industry were established. Carbon dioxide emissions of key steps and carbon footprint of products were calculated and predicted using the input-output model. While products planning was optimized using the low carbon programming model. The results showed that CO2 emission in the enterprise reached 182 543.9 t a year and CO2 emission per unit product was 10% more than advanced level in the world. 80% of the total CO2 was emitted during the processes of firing and drying. As a result, we should focus on these two steps in order to reduce carbon dioxide emission of building ceramic industry. Carbon footprint of blank tile, polished tile, and glazed tile were 150.2 t, 168.0 t, 159.6 t respectively. Optimized by the low carbon model, The ceramic enterprise could reduce carbon dioxide emission by 5.4% while not sacrificing any profit, and also could obtain profit 5.6% higher than before while unrise the carbon dioxide emission. PMID- 22509615 TI - [Experimental project for the accreditation of Hospital Directions in the Lazio hospitals]. AB - A system of quality management of one organization can differ from that of another organization, for many aspects: activity, function, complexity of procedures and ability of the employees. Based on the above is the experimental project of ANMDO, in collaboration with Laziosanita-ASP whose goal was to accredit Hospital Directions towards a continuous quality improvement. To assist in the process of adaptation to the standards and to get certification, ANMDO proposes the method of benchmarking. In total, 30 structures of the Lazio Region took part in this project. The ASL Roma H included all her 8 hospitals. From February 2009 Laziosanita-ASP's representatives have begun to make checks on the place. The first evaluations took place at the Frascati Hospital. PMID- 22509614 TI - [The scientific contributions by the Roman School of Hygiene on the microbiological quality of the surface waters of Rome and her County from 1890 to 2010. A systemic review]. AB - Research on quality of surface waters has been performed also in Italy during the development of the large urban areas, and in Rome this has been the duty of the Istituto di Igiene of the Sapienza University since 1890. Using MedLine--and also traditional consultation for papers printed before 1968--we identified 100 articles printed in the period 1890-2010. Thirty of them met the inclusion criteria (to have been written by researchers belonging to the Rome universities and to contain microbiological informations about the surface waters of Rome). The majority of papers identified (46.6%) were produced during the years Sixties and Seventies of the 20th century, and 30% in the twenty years to follow (1980 1999). The most frequent microbiological descriptors were "Total coliforms" and "Streptococci". The waterbodies most investigated were the Tiber river and the coastal waters around Fiumicino, where the Tiber flows into the Tyrrhenian sea. The quality of surface waters has always been a central interest of the research performed by the Hygienists of the Roman School. The good quality of the past research and the renovated interest of International Organizations and of the European Union should encourage the public health researchers toward a strategic field of investigation which has strong interconnections with the protection of the individual and community health and also with the protection of the environment. PMID- 22509616 TI - [Revision of the behavior of Italian universities towards the HBV vaccination and tuberculosis prophylaxis]. AB - Diagnostic screening for hepatitis B and tuberculosis infection bears a very important role for health care professionals even considering the decreasing epidemiological trends. According to the WHO predictions in 2030 these diseases will remain at third and fourth places among the causes of death for infectious diseases in industrial countries. The aim of this study is to verify the presence of hepatitis B and tuberculosis prophylaxis among the entry requirements for Medical Schools (MED) and Healthcare Professions Degree (PS) courses in 2011/2012 enrollment announcements. We examined 39 websites of Italian Public and Private Universities and we discovered 38 different announcements for MED and PS courses looking for any reference about hepatitis B and tuberculosis vaccinations and Mantoux skin test. The statistical analysis is descriptive (frequency tables). Hepatitis B vaccination was required in 7 (18.4%) enrollment announcements for MED and 6 (13.6%) for PS, respectively. Tuberculosis vaccination and/or Mantoux skin test were found among requirements of only 10 announcements for MED and 7 for PS, respectively. According to this study there is a great and unexpected variability among the different universities. A homologation of these requirements would be strongly desirable among Italian regions and on the entire national territory. PMID- 22509617 TI - [Abolishing mandatory routine medical and laboratory examination of food handlers may have influenced the reporting trends of foodborne diseases? Frequency of notified foodborne illnesses in Southern Italy from 1996 to 2009]. AB - The aim of this study is to compare notifications of foodborne diseases in Southern Italy, before and after abolishing mandatory medical and laboratory examination routine. Data were obtained from the National Epidemiological Report of Health Ministry, that includes the annual summaries of foodborne infectious illnesses notified in Italy. The average number of foodborne diseases per million inhabitants per year decreased after the abolishment of health card for all examined conditions. There was a statistically significant reduction in all Regions for Salmonellosis and in Basilicata, Calabria, Campania and Sicily for Brucellosis. Abolishing health card of food handlers workers did not increase trends of foodborne illnesses and foodborne epidemics in Southern Italy. Examined data confirm the substantial effectiveness of food handlers self-control and training as essentials instruments of Evidence Based Prevention. PMID- 22509618 TI - [Biogenic amines in epigeal spontaneous mushrooms: indicators of quality and freshness?]. AB - Purpose of the present study is to determine the qualitative and quantitative composition of nine biogenic amines (BA) in 153 samples of epigeal spontaneous mushrooms (Boletus edulis and Amanita Caesarea), sampled at large and small food retail shops in the Florence area. Each BA has been identified and quantified using a liquid chromatography system with a reversed phase, C18 column and post column derivatization with o-oftalaldeide. The results have shown a widespread presence of each amine, although with varying frequency and concentration, and an increasing concentration of tyramine and putrescine in samples with poor organoleptic quality than those in good conditions. PMID- 22509619 TI - [Strategies for prevention and control of healthcare related infections by Acinetobacter baumannii]. AB - The frequent development of acquired antibiotics resistance in bacteria represents a challenge for Public Health in terms of healthcare associated infections control. Apart from the appropriate use of drugs, in particular the choice of proper antimicrobial therapy, increasing interest is, therefore, given to the non-pharmacological prevention of these infections. Acinetobacter (A.) baumannii is a micoorganism that commonly causes infections for patients hospitalized in critical hospital wards (intensive care units, burn centers, surgery, neonatology, etc) potentially severe and difficult to treat, because A. baumannii is resistant to many or sometimes all, available antibiotics (PDR - pan drug resistant). The aim of the present paper was to review the available measures for preventing and controlling the contamination and the spread of these types of bacterial infections in health care scenarios, with particular attention to two methods that stand out for efficiency and safety: hand hygiene and environmental disinfection. PMID- 22509620 TI - [Pilot study to assess and compare the eating habits and nutrition knowledge in school-age Italians and Finns, using specific questionnaires]. AB - In recent decades, the American diet has emerged in our country as a reference model food, particularly among young people, to the detriment of the Mediterranean diet, an healthy eating pattern rich in fruits and vegetables, olive oil, whole grains and fish. Even in Europe, North American habits are widespread at the expense of traditional northern nutritional powers, characterized by a lot of fish, wild game meat that are much thinner than from farm animals, rye, oats, cabbage, root vegetables. Given this background, in Pavia (Italy) and Tampere (Finland) we conducted a pilot study with the objective to assess and compare the eating habits and nutrition knowledge in school-age children using 2 questionnaires entitled "what do you eat?" and "what do you know about diet and health?". The results of the first questionnaire clearly shows that, among young people of both countries, there is the loss of traditional food: the Mediterranean and the Finnish diet. All the boys wear it with a low frequency fish, fruit and vegetables, and instead a high frequency of adverse health foods, such as potato chips and sweet drinks. The answers to questions which relate to nutrients and their properties, show that children of all groups have little knowledge about these topics. The use of questionnaires, such as those administered by us, can be easily performed to investigate the dietary habits and the nutritional level of culture, due to make nutrition education interventions aimed at correcting poor eating habits. PMID- 22509621 TI - [Nutrition prevention intervention for cancers: "Med-Food Anticancer Program"]. AB - Several studies recommend the Mediterranean diet and daily physical activity to prevent cancer development. These recommendations, however must be transformed into public health structured programmes, so that they assume operational effectiveness. The aim of the diet and lifestyle intervention called Med-Food Anticancer Program (MFAP) is to promote the Mediterranean diet and physical activity in the adult population. In particular; the target for participants in the intervention is the increased consumption of legumes, fish, whole grain bread and cereals, fruits and vegetables, and the decreased consumption of meat, cheese and foods of animal origin. At the same time, it is recommended to make at least ten thousand steps a day. Two studies have shown the effectiveness of MFAP. PMID- 22509622 TI - Joint Commission Center for Transforming Healthcare launches second targeted solutions tool. Tool focuses on reducing the risk of wrong site surgery. PMID- 22509623 TI - ACCEPTED: new and revised laboratory requirements to meet relevant CLIA regulations. PMID- 22509624 TI - CMS selects JCR to serve as a Hospital Engagement Network. PMID- 22509625 TI - Joint Commission International aims to improve health care delivery in developing countries. PMID- 22509626 TI - Sentinel Event alert: new alert warns of risks associated with health care worker fatigue. PMID- 22509627 TI - The Joint Commission and JCR announce 2012 Board appointments. Behavioral health care, home care, and long-term care representatives gain full membership. PMID- 22509628 TI - Revisions to California law for outpatient surgery settings. PMID- 22509629 TI - CLARIFICATION: requirements for an endoscopy equipment processing room. PMID- 22509630 TI - [Treatment of distal humeral shaft fractures at Polanco Mexican Red Cross]. AB - OBJECTIVE: To determine which is the most effective treatment for the management of soft tissues, the functional recovery and the healing of distal third humeral shaft fractures at the Mexican Red Cross trauma center. MATERIAL AND METHODS: This is a retrospective, longitudinal, comparative study of patients with a diagnosis of distal third humeral shaft fractures; clinical and radiographic follow-up was done with the MEPI, UCLA and Montoya functional scales at week 24. RESULTS: The results of patient follow-up using the MEPI in Group I were: 2 poor, 3 fair, 1 excellent; in Group II: 8 excellent; in Group III: 3 poor, 2 fair, 4 excellent; in Group IV: 1 poor, 5 fair and 2 excellent. The UCLA results were: Group I, 3 poor, 2 good, 2 excellent; Group II: 5 excellent, 2 good; Group III, 4 poor, 1 partial, 2 good and 2 excellent; Group IV, 4 partial, 2 good, 2 excellent. The results of the Montoya scale were: Group I, 3 stage II, 1 stage III, 2 stage IV; Group II, 3 stage III, 5 stage IV; Group III, 3 stage II, 5 stage III, 1 stage IV; Group IV, 2 stage II, 2 stage III, 4 stage IV. DISCUSSION: This paper shows that the anterior 4.5 mm LCP MI plate has been the best treatment for distal third humeral shaft fractures. PMID- 22509631 TI - [Periprosthetic femur fractures. Experience at hospital Espanol de Mexico with a 2-year follow-up]. AB - Periprosthetic fractures have had an increasing incidence in the past decades; their resolution is a difficult challenge even for the most experienced orthopedist surgeons. The Vancouver classification has contributed to a great extent to their better characterization and therapeutic guidance. The purpose of this paper is to make a review of the most recent advances on the topic and present our experience in the treatment of these fractures. MATERIAL AND METHODS: We describe the characteristics of a sample of 20 patients with periprosthetic femur fractures treated at our hospital from March 2008 to March 2010 and typed according to the Vancouver classification. RESULTS: Mean age was 74.5 years with a range of 65-87 years. Females were predominant (70%). Five cases were type A in the classification, 10 cases type B, and 5 cases type C. Nineteen underwent surgical treatment. The mean total length of stay was 7 days, with a range of 5 12. The mean healing time for types B and C was 4 months (range 3-6 months). Four patients had complications. The resolution was assessed as excellent in 5 cases (25%), good in 11 cases (55%), and poor in 4 cases (20%). CONCLUSIONS: A thorough individual assessment based on the Vancouver classification, age and the patient's functional requirements are the major parameters for treatment success. PMID- 22509632 TI - [The most frequent organisms in open fractures in Mexico]. AB - An open fracture is one in which the bone segments penetrate into the skin leaving the bone in contact with the outer environment. Many microorganisms may cause wound infection in open fractures; the most common one is Staphyloccocus aureus. METHODS: This study included a group of 75 patients of both genders seen from November 1st, 2009 to April 30, 2010. A sample for culture was taken upon admission and incubated for 48 hours. RESULTS: A total of 75 patients were included, 62 males and 13 females. The age range was 18 to 83 years. The tibia and the fibula were the most commonly affected bones. The most common mechanisms of injury resulted from high energy. The most frequent grade of exposure was III B. Forty-six percent of the culture results were negative at 48 hours; the most frequent organisms found in the positive cultures were Staphylococcus aureus and Candida albicans. CONCLUSIONS: Males are the gender most affected by open fractures. This kind of condition occurs at productive ages. The time elapsed between the injury and the onset of treatment was significant. The culture results showed that the most frequent organism was Staphylococcus aureus, together with Candida albicans. PMID- 22509633 TI - [Clinical and radiologic skills for fracture management. Multicenter study at orthopedics residents]. AB - BACKGROUND: There is a shortcoming in the diagnostic integration of the mechanism of injury and the radiographic findings. This leads to diagnostic errors and a poor surgical planning with labor and legal repercussions. The purpose is to find out which is the prevailing clinical skill in various Orthopedics residencies by applying a measurement tool prepared ex profeso. MATERIAL AND METHODS: This is an exploratory study conducted in nine Orthopedics residency sites; a measurement tool was designed with theoretical and empirical adequacy with 0.96 reliability (Kuder-Richardson). It includes ten clinical cases with 200 questions providing only X-ray images of a traumatic event exploring the following aspects: I. Kinematics of trauma, II. Clinical diagnosis, III. Radiographic interpretation, IV. Treatment, and V. Prognosis. It was applied to residents of all grades at each of the participating sites. RESULTS: Most of the sites had a low to intermediate level of clinical skills. Upon assessing the results (82 residents) differences were found in indicators I, II, IV and in the overall skills. No significant differences were seen at the sites in indicators III and V. The assessment of sites by indicators showed that site one had more refined skills for clinical diagnosis, while site six for radiographic interpretation. CONCLUSIONS: There are differences in the development level of the clinical skills studied. The low to intermediate skills may be explained by the different educational strategies applied at the sites studied without ruling out the experience acquired in each academic grade. It is possible to improve the results by implementing participative strategies. PMID- 22509634 TI - [Evolution of the treatment of distal radius fractures in Spain. Is this the right way to go?]. AB - OBJECTIVE: To assess the changes in the treatment of distal radius fractures that have occurred in recent years at our center. To analyze the changes that have occurred and their possible causes. MATERIAL AND METHODS: We analyzed the hospital admission data from our center, both total admissions and those due to distal radius fractures. Surgical activity records show the evolution of the surgical treatment of distal radius fractures throughout time. Using the data from 2 research works done at our center we assessed the radiological and functional results obtained with an external fixator and nails and with buttress plates. We reviewed the updated bibliography trying to identify new evidence leading to treatment changes. RESULTS: Objective evidence shows a marked evolution towards the use of open reduction and internal fixation to treat distal radius fractures. We did not identify data in our studies that show poor results with the use of external fixators and nails or a clear superiority of the open reduction methods. These data are not available in the current bibliography. CONCLUSION: The treatment of distal radius fractures is being modified. This change is not based on contrasted clinical or bibliographic data. We need to ask whether this is due to commercial pressure or to a perception of surgeons that is yet to be proven in quality studies. PMID- 22509635 TI - [Femoral lengthening with a uniplanar external fixator in pediatric patients]. AB - Pelvic limb length discrepancies > 4 cm are a challenge that some orthopedists face and multiple methods and procedures have been proposed; among them, callotasis facilitates the management of these discrepancies. This paper reports the experience obtained with 133 femoral lengthenings divided into "and" 14 years of age with acquired or congenital conditions. Lengthening variables and complications were analyzed (with Velasquez' criteria). This study has favorable factors for case analysis, such as the use of a single type of fixator and the use of the same treatment method in pediatric patients. Our results are no different from the world literature concerning the incidence rate of complications by age and diagnosis as well as the healing rate. PMID- 22509636 TI - [Arthroscopy-assisted ankle arthrodesis with MIPF. An alternative proposal]. AB - The ankle is a loading joint with a small contact surface and it is therefore very vulnerable to trauma, as it is an exposed region. It is a unique joint because it forms several joints. In this joint the load falls on the contact area, which is one third of the knee or the hip, and it is the most important part of our musculo-skeletal system designed for ambulation and bipedestation. In case of ankle injuries, arthrodesis is a procedure performed to relieve pain, decrease deformity and provide stability. An optimum result of this procedure may be easily achieved if the ankle is fixed in the right position, so this technique will continue to be a treatment alternative. With "minimally invasive percutaneous fixation (MIPF)" fixation is safe, it relieves pain and stops the progression of regeneration, it is a minimally invasive method performed through a small posteromedial incision on the ventral surface of the distal tibial metaphysis, which minimizes soft tissue dissection thus eliminating wound complications. In this study we included patients with severe joint damage and pain, with a physically demanding type of work, in whom other treatments had previously failed and in whom total arthroplasty was not possible (due to questionable results). Patients with a varus-valgus > 15 degrees, talar necrosis, bone defects requiring a graft or subtalar arthrosis were excluded. Our results are no different from the world literature concerning the incidence rate of complications by age and diagnosis as well as the healing rate. Postoperative patient management was better as no rigid immobilization was required. Even though weight bearing was not immediate, at two weeks they could use an unloading boot for partial weight bearing, and total weight bearing was possible by week six. Therefore, there were less complications and in failed cases salvage surgery was possible. PMID- 22509637 TI - [Diagnosis and treatment of osteoporosis. Position of the Mexican College of Orthopedics and Traumatology]. AB - Our current in Mexico is that it represents a serious health problem not yet recognized as low-energy fractures in older adults account for approximately 10% of subjects over 65 years (compared with 29% in Japan) about 4.4 million fractures in patients over 70 years, taking into account that we are a nation of 112 million, the problem is minor compared with other diseases in this and other population groups. In the Mexican health system, orthopedic services instead share with other health priorities, so that the authorities do not understand osteoporosis as a health problem, not observe increased morbidity and mortality that implicitly leads, there are few centers to support the diagnosis of osteoporosis (densitometers do not have), and recruitment, diagnosis and management of patients who have suffered a broken ground mechanically compromised. Have increased the frequency of fractures in osteoporotic ground, and institutional level has only treatments based on calcitriol and calcium to maintain bone mineral density. In the Mexican health system, orthopedic services instead share with other health priorities, so that the authorities do not understand osteoporosis as a health problem, not observe increased morbidity and mortality that implicitly leads, there are few centers to support the diagnosis of osteoporosis (we don't count with densitometers), and recruitment, diagnosis and management of patients who have suffered a broken ground mechanically compromised. Have increased the frequency of fractures in osteoporotic ground, and institutional level has only treatments based on calcitriol and calcium to maintain bone mineral density. PMID- 22509638 TI - [Early diagnosis of hip dysplasia. Crippling disease for life. Consensus of the Mexican College of Orthopedics and Traumatology]. AB - The developmental dysplasia of the hip (DDH), where the spectrum of deformity varies from a slight mismatch in the articular surfaces between the ilium and femur, which will bring a premature wear of the joint, until the situation more serious when the femoral head is out of the acetabulum, causing a host of disorders side as curvature of the spine, significant shortening of the limb deformities in the knee and the contralateral hip, as well as causing pain and loss of joint mobility mentioned. All this makes the spectrum of abnormalities in a person being disabled with a social and economic burden for the family and society. "Preventing" a clinical entity such as developmental dysplasia of the hip does not mean to anticipate the presentation, because children continue to be born with this problem, but to have a program for early detection and early treatment and thus prevent the occurrence. The goal of this study was to provide the medical community that timely tool for prevention. When diagnosed and treated in a timely and favorable prognosis qualified for motor function and quality of life. PMID- 22509639 TI - [Cemented stems in hip arthroplasty: history and evolution]. AB - Despite the favorable results in cemented femoral fixation, there is a growing tendency to use uncemented stems. Due to the successful results of cementless acetabular fixation, the most versatile and easy implantation technique, to the misinformation about the "cement disease" and the poor performance of cemented stems with a rough surface. However, the advantages of cemented femoral fixation are numerous: it can be implemented successfully in femurs of diverse morphology and quality of bone, the surgeon can position the implant with the desired femoral anteversion, without it being determined by th natural femoral anteversion, very low incidence of intraoperative and postoperative fractures, allows the addition of antibiotics in patients with a history or predisposition to infection and minimal risk of postoperative leg pain during walking. PMID- 22509640 TI - [Lorenz Bohler (1885-1973)]. PMID- 22509641 TI - [Quo vadis: wither medicine?]. PMID- 22509642 TI - [Effectiveness of sodium hyaluronate in patients with gonarthrosis: randomized comparative study]. AB - INTRODUCTION: Hyaluronic acid is a major component of synovial fluid and cartilage; it plays an essential role in joint function. This concept is based on the hypothesis that intraarticular sodium hyaluronate injections improve articular function upon restoring synovial fluid viscosupplementation and promoting endogenous synthesis. MATERIAL AND METHODS: Forty randomly selected patients older than 50 years of age, with a diagnosis of gonarthrosis, standard treatment-naive, were divided into two 20-patient groups. The first group was treated with five 2.5 ml doses of hyaluronic acid, at one dose per week. The second group was treated with a single 2 ml dose of intraarticular methylprednisolone. A survey containing the Womac functional scale and the pain visual analogue scale was applied to both groups before and 3 months after treatment. RESULTS: A statistically significant reduction in pain (visual analogue scale) was observed 3 months after treatment in group H (1.6 +/- 0.88) and group M (2.95 +/- 1.84), as well as a functional post-treatment improvement in the Womac scale. Results for post-treatment pain were 5.43 +/- 1.05 for group H and 7.86 +/- 0.77 for group M; results for post-treatment stiffness were 3.05 +/- 0.82 for group H and 3.7 +/- 0.85 for group M; and finally for post-treatment functional capacity the results were 12.25 +/- 0.82 for group H and 18.95 +/- 0.85 for group M. CONCLUSION: Intraarticular sodium hyaluronate is more effective for pain and function than methylprednisolone. However, it involves higher costs than conservative treatment and fewer costs than surgical treatment, as well as the discomfort resulting from repeated intraarticular injections and the possibility of anaphylactic reaction. PMID- 22509643 TI - [Joint position statement of the Mexican College of Orthopedics and Traumatology: prophylaxis for venous thromboembolic disease in high-risk orthopedic surgery]. AB - Venous thromboembolic disease (VTED) is a public health problem worldwide. In the United States it causes 2 million annual cases. Its annual incidence is 1-2 cases per 1,000 individuals in the general population. It is a disease frequently associated with life threatening complications and its mortality rate is 1-5% of cases. Due to its high complication rate, its slow recovery, and the need for prolonged disability, it is considered as a high-cost disease. VTED may occur in both surgical and medical patients; the known associated risk factors include prolonged rest, active cancer, congestive heart failure, atrial fibrillation, and stroke, among the major medical conditions. Orthopedic surgery represents the main surgical risk factor for VTED, including mainly hip and knee replacements, as well as polytraumatized patients with severe spinal lesions, and major fractures. VTED may be prevented with the appropriate use of antithrombotics. The participants in this consensus defined thromboprophylaxis as the strategy and actions undertaken to reduce the risk of VTED in patients undergoing high risk orthopedic surgery. The position of the Mexican College of Orthopedics and Traumatology regarding the prevention of VTED in orthopedic surgery is described herein. PMID- 22509644 TI - [Arthroscopic removal of an intraarticular projectile from the knee]. AB - OBJECTIVE: We present the case of a patient who sustained a gunshot wound; the projectile was located in the knee and was arthroscopically removed. CLINICAL CASE: A 31 year-old patient sustained a gunshot wound in the right thigh, right hand and left knee. X-rays revealed the presence of a projectile in the knee, thigh and hand. The projectile was arthroscopically removed. DISCUSSION: Traumas causing articular wounds of the knee are infrequent. Excluding the most frequent causes of articular wounds, a small percentage of them are due to gunshot wounds. There is consensus around arthroscopy as a technique useful to remove articular foreign bodies; it has advantages over open surgery. This procedure minimizes surgical morbidity, reduces the risk of septic arthritis, synovitis, arthropathy or systemic lead toxicity, and it also hastens the patient's functional recovery. Knee arthroscopy allows physicians to provide a definitive treatment of these injuries, explore the joint, diagnose associated injuries and perform debridement and articular lavage. CONCLUSION: Arthroscopy is an effective tool for the extraction of articular projectiles; it also allows diagnosing and treating associated lesions. PMID- 22509645 TI - [Inveterate unilateral lumbosacral dislocation in children. Case report and literature review]. AB - Lumbosacral facet dislocation, whether associated with a fracture or not, is an infrequent lesion in children. The mechanism is hyperflexion due to high energy trauma. We present the case of an 8 year-old patient whose condition began when a soccer goal collapsed and fell on her lumbar area. She was seen at the emergency room and the diagnosis was lumbar sprain. At month 3 she went to the emergency room with persistent pain, lumbosacral deformity and functional impairment. The spine AP and lateral X-rays showed traumatic spondylolisthesis secondary to facet dislocation and fracture of L4 and L5 transverse processes. The neurologic exam was normal. Instrumentation with L4-S1 posterolateral arthrodesis was performed and her postoperative course was appropriate. Proper fusion was achieved at 3 months. At postoperative month 13 the patient was asymptomatic. PMID- 22509646 TI - [Multicenter osteoblastic osteosarcoma in a preschooler. Case report]. AB - Osteoblastic osteosarcoma is the most frequent malignant bone neoplasia in pediatric patients. It accounts for 50% of primary bone tumors and the most frequent age at presentation is adolescence, particularly during the growth spurts. Cases of children younger than 8 years of age have been reported in the literature. The purpose of this article is to report the case of a male, 19 month old patient with osteoblastic osteosarcoma of the left distal femur and proximal tibia. It is considered as a special case due both to the age at presentation and to the multicenter feature of the tumor. This suggests that this entity may be more aggressive and rapidly growing in younger children. At the National Pediatrics Institute, in 35 years we only had three cases of children younger than 5 years. PMID- 22509647 TI - [Fibrodysplasia ossificans progressiva syndrome. Report of three cases]. AB - Fibrodysplasia ossificans gressiva (FOP) syndrome is a very rare connective tissue disease characterized clinically by the progressive ossification of the soft tissues, usually with hallux malformation. MATERIAL AND METHODS: Three patients diagnosed with FOP during 2006 were clinically, radiographically and tomographically assessed. RESULTS: Three female patients ages 4, 6 and 12 years old with hallux deformity and indurated tumors of the trunk, neck and shoulders. CONCLUSION: FOP is a rare autosomal dominant genetic disease that manifests itself with ossification of the soft tissues, which progressively limits joint and trunk mobility. PMID- 22509648 TI - [Inclusion bone cyst in the distal phalanx. Report of three cases]. AB - Inclusion bone cysts are cysts of an epidermal lineage containing keratin. They are commonly found in the subcutaneous tissue, occasionally in intratendinous, subungueal or intraosseous tissue. The diagnosis is usually clinical. The most frequent symptom is pain, which may be associated with ungueal deformity. Plain X rays in two views allow identifying the bone location. The treatment recommended for all cases of epidermoid cyst of the distal phalanx is curettage of the lesion. MATERIAL AND METHODS: The clinical charts of patients with inclusion cysts of the distal phalanx from 1983 to 2010 were reviewed. RESULTS: Three cases were found; 2 males and one female, ages 23, 28 and 47 years. The most frequent symptom was pain with ungueal deformity in 2 cases. In 2 cases the X-rays show the characteristics of the epidermoid cyst. Curettage was performed in the 3 cases; a bone graft was used in 2 cases. The follow-up ranged between 120 and 324 months (mean of 222 months). No relapses or complications were reported. DISCUSSION: Inclusion bone cysts are infrequent tumors of the distal phalanx and have particular characteristics that the orthopedist surgeon should be familiar with. PMID- 22509649 TI - [Synovial sarcoma in a patient with metal-on-polyethylene total hip replacement. A case report]. AB - We present the case of a synovial sarcoma five years after primary total hip arthroplasty in a male 65 year-old patient who was surgically treated for left hip pain due to coxarthrosis. A 32 mm uncemented prosthesis with metal-on polyethylene tribology was placed in the patient. The latter developed synovial sarcoma that caused lung metastasis. The association between total hip arthroplasty and malignancy is discussed, as well as its frequency worldwide. PMID- 22509650 TI - [Magnetic resonance imaging elbow anatomy]. AB - Knowledge of the anatomy of the elbow joint has become intricate due to the advent of magnetic resonance imaging (MRI) techniques, as they are superior to represent the different soft tissues. This advantage allows evaluating in detail the increasingly frequent pathologic processes that occur in high performance athletes. The ideal MRI technique includes having the patient in a comfortable position, using an appropriate surface antenna and the right sequences in the appropriate planes depending on the entity. Being familiar with the normal elbow anatomy is crucial to properly identify the pathology and avoid potential diagnostic errors. PMID- 22509651 TI - [Professor Mario Mercuri]. PMID- 22509652 TI - [Modern oncologic surgery and multidisciplinary team code]. PMID- 22509654 TI - [Sacral nerve stimulation in the treatment of fecal incontinence--initial experience in the Czech Republic and assessment of functional outcomes]. AB - INTRODUCTION: During the last decade, sacral nerve stimulation (SNS) has become a new perspective and effective method in the treatment of fecal incontinence. In the Czech Republic, SNSs have been used since 2010. METHODS: From May 2010 to August 2011, sacral nerve stimulation was performed in 15 patients in FN Na Bulovce Surgical Clinic in Prague. All of the subjects were female patients and their mean age was 59 (46-68 years of age). The first phase of the treatment included the following procedures: percutaneous sacral nerve (S2-S4) examination, electrode implantation and subchronic stimulation. Permanent neurostimulator implantation was indicated in 14 out of the 15 subjects and over 50% of them experienced reduction in incontinence episodes. The following neurostimulators were used: Medtronic InterStim 3023 or InterStim II 3058. Stimulation parameters included 15 Hz frequency, pulse width of 210 micros and the stimulation range was between 1-3 V. The patients' follow up period was 1-15 months after the procedure. OUTCOMES: After the first phase of SNS, the morbidy rate was 7%. The morbidity rate after the permanent neurostimulator implantation was 0 %. Permanent neurostimulators were implanted in 14 out of the total of 15 subjects, i.e. the success rate was 93 %. Based on the incontinence recording sheet (diary) data collected from all the 14 subjects, the mean number of incontinence epizodes was 24 epizodes/week (+/- 13.0) before the stimulation and 4 epizodes/week (+/- 3.8) after the stimulation procedure. Cleveland Clinic Incontinence Score was assessed in the first 8 subjects and its mean value was 20 (+/- 0.7) before the procedure, vs. 7 (+/- 1.2) after the stimulation procedure. The both values were significantly lower after the stimulation procedure (p <0.05). No significant differences between the manometric values before the procedure and after the stimulation procedure were detected. SF-36 showed improvement in the quality of life, in particular in the parameters assessing social and mental functions. Nevertheless, there were no significant differences in any of the studied parameters. CONCLUSION: The initial experience with SNS in the Czech Republic showed over 50% improvement in continence rates in 93% of the subjects with introduction of stimulation electrodes and subchronic stimulation and over 50% improvement in 100% of the subjects, who underwent permanent neurostimulator implantations, and full continence was achieved in 33% of the subjects. PMID- 22509653 TI - Trends in the treatment for liver metastasis of colorectal cancer in Japan. AB - The rate of liver metastasis before surgery of colorectal cancer is 11% in Japan. The survival rate of radical surgery with D-3 lymph node adenectomy is 83.7% in colon cancer and 77.1% in rectal cancer. The percentage of recurrent liver metastasis after curative surgery with D-3 lymph node extent resection is 7.1% within 5 years. Hepatectomy has the best survival rate: 52.8% after 3 years, 39.2% after 5 years. There is no difference in patients' survival rate between systemic anatomical hepatectomy and non-anatomical limited resection. For recurrent hepatic metastasis after curative surgery, hepatectomy should be done if no other metastasis is found in any other organ and the patient is suitable for surgery. Hepatic artery infusion chemotherapy (HAI) for metastasis of the liver is no longer used today. Radiofrequency ablation or microwave coagulation therapy may prolong the survival time but is not a curative procedure. PMID- 22509655 TI - [Incidence and risk factors of ischemic colitis after AAA repair in our cohort of patients from 2005 through 2009]. AB - INTRODUCTION: Using retrospective analysis, we sought to investigate the incidence, risk factors and therapeutic outcomes of ischemic colitis in patients after surgical and endovascular repair of abdominal aortic aneurysms (AAA). MATERIAL AND METHODS: The complete inpatient and outpatient medical records of all patients undergoing surgical or endovascular AAA repair in our Department from January 2005 to December 2009 were retrospectively reviewed. We selected all patients who had developed an acute or chronic form of postoperative large or small bowel ischemia. We carried out data analysis and focused on determining the incidence and risk factors of this complication and the outcomes of its treatment. RESULTS: Two hundred and seven AAA repairs were performed in the 2nd Department of Surgery of St. Anne's University Hospital in Brno and the Faculty of Medicine of Masaryk University in Brno during the studied period. This number includes endovascular AAA repairs (13 patients; 6.3%) as well as one robot assisted operation, and also the whole clinical spectrum of AAA manifestations, from non-symptomatic forms to ruptured aneurysm forms. The rest of the patients underwent open operation. Bowel ischemia developed in a total of 11 patients (5.3 %), who all underwent open AAA repair. Six of these patients presented with non ruptured AAA and the remaining 5 with ruptured AAA. In 3 patients, bowel ischemia was diagnosed with a delay of several months from the original revascularization operation in the clinical form of postischemic stricture of the large bowel (2 patients) or postischemic colitis (1 patient). 8 patients were diagnosed with acute ischemic colitis affecting an isolated segment of the small bowel in one patient, extended segments of the large bowel (descending colon + sigmoid colon + rectum) in 2 patients, and typically the descending and sigmoid colon in 5 patients. None of the three patients with late manifestation of ischemic colitis died. Of the 8 patients with acute presentation, resection of the ischemic bowel +/- the rectum was performed in 6 patients. 3 of them died and 3 survived the operation and have been followed up in our outpatient department. 2 patients with acute manifestation did not undergo bowel resection. Both of them died. The overall mortality of all patients with ischemic colitis was 45.5% (5 patients out of 11 died) in our study. When considering only patients suffering from the acute form of ischemic colitis, the mortality rate in our studied cohort amounts to 62.5% (5 patients out of 8 died). CONCLUSION: Bowel ischemia after AAA repair remains to be a serious complication. Besides the acute form of ischemic colitis, its possible late clinical manifestation in the form of postischemic stricture of the large bowel or postischemic large bowel colitis must also be kept in mind when following up patients. The analysis of our patient's data shows that conditions requiring the use of vasopressors and an increased need of transfusions (more than 7 units of packed red blood cells) intraoperatively represent important predictors of colon ischemia after AAA repair. PMID- 22509656 TI - [IGF1 and tumor markers in different breast cancer stages]. AB - INTRODUCTION: In our work we asked ourselves whether it would be possible to use growth factors for a quick orientation in the clinical status of patients prior to biopsy and histological examination. MATERIAL AND METHODS: Our patient group included 82 patients with breast cancer. Serum samples were collected preoperatively. Histological examination findings were available for each patient. Our set was divided into three groups based on the disease stage. The values of analytes in different tumor stages were statistically evaluated and statistical comparisons of Stage I and II, and then of Stage II and III were performed. RESULTS: Tumor markers CEA, CA 15-3, TK, TPA-M and MonoTotal correlate with the disease severity. Serum levels of the growth factor IGFI negatively correlated with the severity of cancer. There was aa statistically significant increase in the EGF growth factor serum levels between Stage I and II. No statistically significant differences between Stage I vs. II and Stage II vs. III were detected when HGF and VEGF growth factor serum levels were assessed. CONCLUSION: The growth factor EGF is one of the candidates to become a tumor growth marker in early disease stages. The IGFI, HGF and VEGF growth factors can not be used for quick and correct orientation in the clinical condition of patients in the early stages of tumor growth. PMID- 22509657 TI - [Transrectal hybrid NOTES versus laparoscopic cholecystectomy--a randomized prospective study in a large laboratory animal]. AB - INTRODUCTION: NOTES (Natural Orifice Transluminal Endoscopic Surgery) technique was developed to achieve less invasive surgery with the aim to lower frequency of postoperative complications. Cholecystectomy is one of the most frequent elective surgical procedures and is relevant for evaluation of NOTES. The aim of the experimental study was to compare hybrid transrectal and laparoscopic cholecystectomy regarding feasibility and inflammatory response. MATERIAL AND METHODS: A total of 20 pigs weighing 26-56 kg were randomized to laparoscopic or NOTES group. Transrectal approach (15-18 cm from anal edge) was created by needle knife, followed by balloon dilatation and two-channel endoscope was introduced into the abdominal cavity. Cystic artery and duct were clipped and dissected. After extirpation of the gall bladder the colostomy was closed by occlusion loop and-clip (King' closure) technique. In the laparoscopic group, cholecystectomy was performed by three-port access. Blood samples for evaluation of inflammatory response markers (leukocytes, CRP, interleukin 6) were taken 0, 2nd, 7th and 30th postoperative day, when the experiment ended and pig was euthanized. RESULTS: Two pigs were excluded (1 died early postoperatively for pneumonia, 1 for the rectal closure impossibility after it's laceration during of the gall bladder extirpation). Other pigs survived without complications. Procedure time was significantly longer in NOTES group (134 +/- 27 minutes versus 60 +/- 22 minutes, p < 0.05). White blood cells count and CRP level increased significantly in both groups 2nd and 7th postoperative day and then normalized. Differences between groups were not significant in any of the measured laboratory markers. Sectional finding of exudate and adhesions was comparable in both groups and all transrectal closures were healed. Small subhepatal abscess was found in one pig from NOTES group. CONCLUSION: Transrectal hybrid cholecystectomy is a safe and feasible method with comparable inflammatory responses and longer operating time compared to laparoscopy. A novel loop-and-clip technique was verified as a safe and simple rectal closure. PMID- 22509658 TI - [Torsion of dystopic spleen--possible solutions]. AB - Early diagnosis the torsion of wandering spleen and surgical intervention are necessary to preserve the spleen, because persistant torsion can lead to splenic infarction. We present two cases with torsion of wandering spleen and different disease process and result. Diagnosis was by ultrasonography and CT angiography found. The 7-year-old boy with recurrent abdominal pain was admitted early and operated with spleenpreserving splenopexy. The 8-year-old girl with acute torsion of a wandering spleen was sent of after an initial misdiagnosis too late. Patient was managed by urgent laparotomy and splenectomy, because of splenic vessels thrombosis and splenic infarction. No complications occurred during two year postoperative follow up period of both patients. PMID- 22509661 TI - [Vaccination program after HPV?]. PMID- 22509662 TI - [Global Health Watch 3--an alternative health report. Health care through global eyeglasses]. PMID- 22509663 TI - [Alcohol ignition interlock after driving under the influence. New possibility to help patients drink less and drive sober!]. PMID- 22509664 TI - [Screening--balancing between advantages and disadvantages]. PMID- 22509665 TI - [The pathologist's role: to diagnose prostatic cancer and determine prognosis]. PMID- 22509666 TI - [Radical prostatectomy--the optimal surgical treatment]. PMID- 22509667 TI - [New prospects for curative radiotherapy of local advanced prostatic cancer]. PMID- 22509669 TI - [Ethics Committee of the Swedish Society of Medicine: no to compulsory sterilization in gender identity determination]. PMID- 22509668 TI - [Promising on advanced cancer, several new drugs coming]. PMID- 22509670 TI - [Henrietta Lack's immortal legacy to humanity]. PMID- 22509671 TI - Planning the future of private duty: the experts weigh in. PMID- 22509672 TI - Private duty homecare association legislative update. PMID- 22509673 TI - Bathing, dressing, grooming, and beyond! PMID- 22509674 TI - Private duty and long-term care insurance: a primer for caregivers. PMID- 22509676 TI - Strike a balance: employee vs. independent contractor model. PMID- 22509675 TI - Necessary sacrifices: a new tribute to Frederick Douglass. PMID- 22509677 TI - The Private Duty Homecare Association: A NAHC affiliate organization. PMID- 22509678 TI - The unintended consequences of the Department of Labor's move to change the companionship exemption for third-party employers. PMID- 22509679 TI - Hospices and private duty agencies: working together to fill the gap. PMID- 22509680 TI - Customer forensics. PMID- 22509681 TI - Are we there yet? Driving with someone with Alzheimer's disease. PMID- 22509682 TI - Short on ADHD drugs. PMID- 22509683 TI - Medicare home health patients suffer a disproportionate $77 billion in cuts from 2009-2019. PMID- 22509684 TI - [Clinical classification of osteoradionecrosis of temporal bone and the treatment of massive osteonecrosis]. AB - OBJECTIVE: To explore the effective treatment regimen for osteoradionecrosis of temporal bone. METHOD: Twenty-seven patients with massive osteoradionecrosis in temporal bone were included and retrospectively analyzed, in which, 15 cases received surgery and the other 12 cases adopted non-surgical treatment. RESULT: In the surgery group, three cases died one year postoperatively and died of massive hemorrhage due to internal carotid blowout. One case died four years after surgery without clear cause of death, and two cases were lost to follow up. Out of the nine survivors, the follow up period ranged from four months to eight years (one was followed up eight years, one was followed up over four years, four were followed up two-three years, one was followed up over one year, one was followed up nine months, and one was followed up four months, respectively). Patients classified as the type III received best outcome, and patients of type V and IV without invasion of the internal carotid artery received good surgical effects, while patients classified as the type IV with internal carotid artery invasion presented low survival rate. Two cases in the non-surgical group died of internal carotid rupture, and the other ten cases presented with repeated infection and expansion of the osteoradionecrosis lesion. CONCLUSION: The new classification criteria is helpful in diagnosis of location of lesions,and can serve as a guide for clinical therapy. Massive osteoradionecrosis in temporal bone responded unfavorably to conservative treatment, compared to that, surgery can effectively control the expansion of the lesion and markedly improve patient quality of life. Long-term follow up is necessary because of the slow development of osteoradionecrosis after surgery. PMID- 22509685 TI - [Analyzing the relationship between genotype and phenotype of common deafness genic in two hereditary hearing loss families]. AB - OBJECTIVE: To investigate the relationship between genotype and phenotype of common deafness genes by analyzing genotype and degree of hearing loss in deaf patients from deafness pedigrees. METHOD: Two small deafness pedigrees were selected. Nine locus mutations of four deafness genes were detected, and pure tone audiometry on family members were conducted simultaneously. RESULT: In LGR-1 pedigree, I :1, I :2, I :4, and II :5 carried single heterozygous mutation, which manifested by mild-moderate deafness in phenotype; while II :3 and II :4 genotype were double heterozygous mutation, and II :2 and III :1 genotype were composite mutation, both manifested by severe or profound deafness in phenotype. In HXL-2 pedigree, I :1 and I :2 carried single heterozygous mutation, which manifested by mild-moderate deafness while II :2, II :3, II :5 and III :2 presented with severe or profound deafness in phenotype, and II-1 genotype was double heterozygous, which manifested by profound deafness. CONCLUSION: Patients who suffer from single heterozygous mutation mostly manifest with mild-moderate deafness in phenotype, and severe or profound deafness may be caused by other undetected mutations. Those who suffer from double or composite heterozygous mutations manifest with severe or profound deafness. Thus, there exists certain positive correlation between genotype and phenotype. PMID- 22509686 TI - [Compare NRT value of straight electrode and contour electrode in Nucleus 24 cochlear implant system]. AB - OBJECTIVE: To learn the neural response of spiral ganglion cell to electrical stimulus by comparing the neural response telemetry(NRT) value between straight electrode and contour electrode in Nucleus 24 cochlear implant system. METHOD: Fourty-six patients with Nucleus 24 cochlear implants were paired into two groups: 23 with contour electrode and 23 with straight electrode respectively. NRT value of each group were tested and compared. RESULT: The NRT value of straight electrode fell in the range of 160 microV to 170 microV and contour electrode 150 microV to 160 microV. The NRT were going up higher a little bit from electrode twenty to electrode one. CONCLUSION: The contour electrode requires less power consumption than straight electrode in Nucleus 24 cochlear implant system. PMID- 22509687 TI - [Clinical approach of trans-horizontal semicircular canal and vestibule for treatment of Mondini dysplasia with cerebrospinal fluid leakage]. AB - OBJECTIVE: To evaluate the clinical manifestation of Mondini dysplasia with cerebrospinal fluid leakage and investigate the effect of the surgical repair through trans-horizontal semicircular canal and vestibule approach. METHOD: Four cases which were operated by the approach of trans-horizontal semicircular canal and vestibule in our hospital were analyzed retrospectively. RESULT: The leakages were all stopped by the primary surgical closure after six-month follow up. CONCLUSION: Mondini dysplasia should be considered in children or teenagers with recurrent bacterial meningitis whether or not with otorhinorrhea. Pure tone audiometry and a temporal bone CT or MRI will confirm the diagnosis. A trans horizontal semicircular canal and vestibule approach is an effective and simple way for the treatment. PMID- 22509688 TI - [Diagnosis and treatment of 318 benign paroxysmal positional vertigo cases]. AB - OBJECTIVE: To investigate the diagnosis, treatment and therapeutic effect of various types of BPPV. METHOD: Three hundred and eighteen BPPV patients were retrospectively analyzed. After the types of BPPV were determined by nystagmus characteristics provoked by positioning test, the appropriate repositioning maneuvers were performed. For patients unresponsive to initial treatment, a repetitive treatment was given after seven days. If patients failed after three continuous treatments, other therapeutic methods were chosen and performed. Overall effectiveness in the next three months after treatment was observed. RESULT: Of 318 patients, 221 (69.5%) with posterior semicircular canal involvement, Epley repositioning maneuver was performed; 62 (19.5%) with horizontal semicircular canal involvement, Barbecue maneuver combined forced prolonged position maneuver were applied; 23 (7.2%) with anterior canal involvement were treated with Epley maneuver; 12 (3.8%) had the mixed type and were treated with corresponding repositioning maneuvers. After one week the total improvement rate was 82.1% (261/318) and 91.8% three months later (292/318). CONCLUSION: The different BPPV variants can be diagnosed according to the nystagmus characteristics during the appropriate provoking maneuvers, and appropriate repositioning maneuvers is a very effective method which can shorten disease period and relieve the symptoms. The method is easy to apply and could be widely performed clinically. PMID- 22509689 TI - [The diagnostic value of labyrinthine fistula with multi-planar reconstruction in chronic otitis media by HRCT]. AB - OBJECTIVE: To study the ability of HRCT to delineate the semicircular canals and the diagnostic value of HRCT in identifying labyrinthine fistula in chronic otitis media (COM) by means of multiplanar reconstruction. METHOD: Eighty-six patients (79 healthy ear and 93 failed ears) with chronic otitis media were scanned with HRCT, and the original data was processed with MPR. In the normal ears the semicircular canals form were individually observed and the canal geometry were compared in axial and coronal and s-MPR. In COM the destruction of the canal were observed and compared with the intraoperative findings. RESULT: The full length of horizontal semicircular canal can be displayed in some cases and the full length of the three canals can't be displayed in any single coronal image but they can be individually displayed in one image in s-MPR. In the COM, six ears labyrinthine fistula were found in the axial and five ears in coronal images; six ears were located at the horizontal semicircular canal and two ears at the superior semicircular canal in the s-MPR, which corresponded with the intraoperative findings. CONCLUSIONS: MPR can display the full path of individual semicircular canal in one image and is promising in identifying labyrinthine fistula. PMID- 22509690 TI - [Outcome in patients with acute low-tone sensorineural hearing loss by administration of different doses of glucocorticoids]. AB - OBJECTIVE: Aimed to compare the outcome in patients with acute low-tone sensorineural hearing loss (ALHL) treated with different doses of glucocorticoids. METHOD: Fifty-four ALHL patients were randomly divided into no prednisone group (n = ten), low-dose prednisone group (n = 22) and high-dose prednisone group (n = 22). All patients were treated for ten days and followed up for six months from the initial examination. RESULT: The cure rates(complete recovery)were 30.0%, 59.1%, 90.9% respectively and the improved rates (complete recovery and partial recovery) were 40.0%, 86.4%, 95.5% respectively in the three groups of no prednisone group, low-dose prednisone group and high-dose prednisone group. The low-dose prednisone group therapy for ALHL showed significant improved rates than the no prednisone group (P < 0.05). The high-dose prednisone group therapy for ALHL showed significant cure rates than the low-dose prednisone group (P < 0.05). CONCLUSION: High-dose glucocorticoids is more effective than low dose. It is suggested that the etiology of ALHL is related with both an endolymphatic hydrops and an autoimmunological mechanism. PMID- 22509691 TI - [Investigation of SLC26A4 mutations associated with inner ear malformations]. AB - OBJECTIVE: To study the molecular pathogenesis of SLC26A4 mutations associated with inner ear malformations including large vestibular aqueduct syndrome (LVAS), Mondini dysplasia and inner ear malformations but not accompanied with LVAS. METHOD: DNA sample and clinical material were obtained from 14 sporadic LVAS probands, six Mondini dysplasia probands and seven inner ear malformations excluding IVAS probands. SLC26A4 gene mutation was analyzed by direct sequencing for its 20 coding exons. GJB2 gene and also mt12SrRNA were analyzed by direct sequencing. RESULT: In 14 cases of LVAS, two mutations were detected in 12 patients (85.7%, either homozygous or compound heterozygous mutations), and one mutation was found in two patients (14.3%). In six cases of Mondini dysplasia, two mutations were detected in all of patients (100%). No mutation could be found in the seven cases of other inner ear abnormalities not accompanied with LVAS. No pathogenic mutation was detected in all of these 27 probands in GJB2 gene and mt12SrRNA 1555/1494T. CONCLUSION: We have shown that LVAS and Mondini dysplasia closely correlate with SLC26A4 gene. No mutation was detected in seven probands of inner ear malformations not accompanied with LVAS. We should study the molecular pathogenesis of this disease in depth. PMID- 22509692 TI - [Endoscopic orbital decompression for thyroid-associated ophthalmopathy]. AB - OBJECTIVE: To evaluate the therapeutic results of endoscopic orbital decompression for thyroid-associated ophthalmopathy. METHOD: The records of nine patients (twelve orbits) received endoscopic orbital decompression for thyroid associated ophthalmopathy were analyzed for changes in visual acuity, intraocular pressure, proptosis, corneal ulceration and movement. The follow-ups ranged from two months to thirty-six months. RESULT: Twelve orbits (100%) had improvement in visual acuity (range 0.1-0.7). Ten orbits (83.3%) decreased in intraocular pressure (range 0.2-21.4 mm Hg). Eight orbits (66.70%) decreased in proptosis (one-five mm). The orbit with corneal ulcer was healed after decompression. Diplopia was cured in one of four patients. CONCLUSION: Endoscopic orbital decompression is a safe and effective procedure for the treatment of thyroid associated ophthalmopathy. PMID- 22509693 TI - [Formation characteristics and significance of bacteria biofilm in middle ear mucosa of rats with chronic suppurative otitis]. AB - OBJECTIVE: To establish the rat model of chronic suppurative otitis media and observe the formation of bacterial biofilm in middle ear mucosa of animal models and discuss the role of bacterial biofilm in the pathogenesis of chronic suppurative otitis media. METHOD: Twenty-eight rats were divided into six experimental groups and a control group evenly. All rats in experimental groups were infected with pseudomonas aeruginosa solution in 1 X 10(6) cfu/ml concentration through the tympanic membrane puncture approach to bilateral middle ear cavity. On the first, sixth, tenth, fifteenth and twenty-first st day after inoculation respectively, four rats in one experimental group were narcotized, then two-sided tympanic membrane of each rat were observed by using electric otoscope. We rated on the severity of the inflammation from the general pathology level (0 for normal, four for the most serious). After the execution, the two sided otocysts were obtained. The left was made to SEM specimen and the shape of bacterial biofilm in middle ear mucous was observed. The right was observed by CLSM. Control group were executed at the beginning of the experiment. RESULT: (1) Bacterial biofilm in line with their respective criteria were found at the six days after the inoculation, and were more typical in shape after ten days. Then the states maintained stably within three weeks. (2) By observing tympanic membrane under electric otoscope, it can be seen that the inflammation severity of otitis media aggravated gradually in the first ten days and achieved the peak, then the state continued to the third week. The differences of tympanic membrane rating between one day group and six day group, six day group and ten day group were statistically significant (P < 0.05, P < 0.01). CONCLUSION: (1) In this experiment, the process of bacterial biofilm development in rats model is: from beginning to the five days, the bacteria adhere and accumulates. After six days, the 3D structure of bacterial biofilm preliminary formatted. After ten days, the bacterial biofilm achieves the mature and steady state. (2) With the growth and maturity of bacterial biofilm in middle ear mucosa, the inflammation of otitis media is gradually increasing, which suggests that the inflammation severity of otitis media and the maturation of bacterial biofilm in middle ear mucosa are closely related. PMID- 22509694 TI - [Use of topical nonsteroidal anti-inflammatory drugs in intraocular surgeries: its past, present and future]. PMID- 22509695 TI - [Prevalence of sleep-disordered breathing in patients with retinal vein occlusion]. AB - PURPOSE: To investigate the prevalence of sleep-disordered breathing (SDB) in retinal vein occlusion (RVO) patients. SUBJECT AND METHOD: Forty RVO patients who had undergone either vitreous surgery or anti-coagulation therapy were included in this study. Pulse oximetry was conducted during the night and 4% oxygen desaturation index (4% ODI times/hour) and mean SpO2 (%) were calculated. If 4% ODI > or = 5, SDB was diagnosed. The results were compared between branch retinal vein occlusion (BRVO), and central retinal vein occlusion (CRVO). In addition, simple linear regression analyses were conducted to investigate whether 4% ODI related to systemic factors for RVO patients, i.e., incidences of hypertension and diabetes and body mass index(BMI kg/m2). RESULTS: Forty two percent of the men, 33% of the women and 37% of all the RVO patients were diagnosed as having SDB. The prevalence of SDB and 4% ODI, and the mean SpO2 were not significantly different between the BRVO and CRVO cases. The incidences of diabetes tended to correlate to the 4% ODI, however, neither proved significant. The BMI had a statistic correlation with the 4% ODI. CONCLUSION: The results of our study suggested that RVO cases have a high frequency of SDB. We believe that at the time of ophthalmic medical examinations or during the treatment of RVO, ophthalmologists should be aware of the possibility of SDB. PMID- 22509696 TI - [Phase III open-label study of nepafenac ophthalmic suspension 0.1% for inflammation and ocular pain following ophthalmic surgery]. AB - PURPOSE: To examine the efficacy and safety of nepafenac ophthalmic suspension 0.1% on postoperative inflammation and eye pain with intraocular surgery, other than cataract surgery. PATIENTS AND METHODS: Patients scheduled to undergo vitreous surgery, trabeculectomy, laser iridotomy, laser trabeculoplasty and laser posterior capsulotomy were investigated in a multicenter, open-label study. RESULTS: The total rate of patients cured in all the intraocular surgery methods was 85.6% (95/111), and that of the patients who were pain free was 91.0% (101/111). The rate cured by vitreous surgery was 80.4% (45/56), by laser iridotomy 93.3% (14/15) and by laser posterior capsulotomy was 94.6% (35/37). The rate of patients free from pain following vitreous surgery was 85.7% (48/56), laser iridotomy 100.0% (15/15) and by laser posterior capsulotomy was 94.6% (35/37). A total of 23 adverse events were reported in 22 patients (19.6%). Allergic conjunctivitis was observed in one patient (0.9%) as an adverse event, in which the relationship cannot be denied. This allergic conjunctivitis was mild and resolved after treatment. CONCLUSION: Nepafenac ophthalmic suspension 0.1% is considered safe and efficious not only following cataract surgery but also for postoperative inflammation and eye pain in intraocular surgery. PMID- 22509697 TI - [Relationship between birth month and ocular refraction noted during eye disease checkups for three-and-a-half-year-old children in Japan]. AB - PURPOSE: To examine the relationship between birth month and ocular refraction in three-and-a-half-year-old children. METHODS: A total of 487 children were examined during eye disease checkups performed in three-anda-half-year-old children in Kishiwada, Japan. Using left eye data, mean refractive values were calculated and graphically analyzed for each birth month. The relationship between refraction and birth season was evaluated by ANOVA. RESULTS: A slight shift in the mean refraction to the hyperopic side was found for subjects born in September and October. The mean refractions +/- SE were: -0.058 +/- 0.057 D in spring (n = 118), -0.001 0.052D in summer (n = 124), +0.133 +/- 0.064D in autumn (n = 112), and -0.143 +/- 0.055 D in winter (n = 111). Comparisons of refraction for each birth season proved to be significantly different, with subjects born in autumn found to be more hyperopic (p = 0.008). CONCLUSION: A relationship between refraction and birth season was found in three-and-a-half-year-old children, with children born in the autumn tending to be more hyperopic. PMID- 22509698 TI - [Retrospective comparison of 25-gauge vitrectomy with 20-gauge vitrectomy in the repair of retinal detachment complicated with proliferative vitreoretinopathy]. AB - PURPOSE: To compare the surgical outcomes of 25-gauge vitrectomy with that of 20 gauge vitrectomy for the repair of retinal detachment complicated with proliferative vitreoretinopathy (PVR). METHODS: Forty-one eyes of 40 patients (17 women, 23 men), who underwent vitrectomy for grade C PVR and had at least 6 months of follow-up period, were investigated retrospectively. The mean age of the patients was 44.6 years (range; 13-78 years). Twenty eyes underwent vitrectomy with a 25-gauge system (25 G Group, including 5 cases with hybrid surgery, i.e., vitrectomy conducted mostly with a 25-gauge and partially with 20 gauge instruments) and 21 eyes had vitrectomy with a 20-gauge system(20 G Group). The intraoperative technique used for vitreous surgery, the number of vitrectomy procedures, the length of the surgery, the surgical success rate, the best corrected visual acuity (BCVA) and intraocular pressure (IOP) both before and after the vitrectomy were compared between the two groups. RESULTS: There was no significant difference in preoperative background between the two groups. The number patients with inner limiting membrane peeling was significantly higher in the 25 G Group than in the 20 G Group (p = 0.020). There were no significant differences in the number of vitrectomies, surgical time and the rate of retinal reattachment between the two groups (25 G Group; 95.0%, 20 G Group; 85.7%). The BCVAs 6 months after the surgery were significantly better than preoperative BCVAs in both 25 G (p < 0.001) and 20 G Group (p = 0.003). In the 25 G Group, the BCVA was significantly improved 1, 3, and 6 month(s) after the surgery compared to before surgery (p < 0.05), while, in the 20 G Group, the BCVA was significantly improved 3 and 6 months after the surgery (p < 0.05). In addition, the BCVA 6 months after the surgery was significantly (p = 0.010) better in the 25 G Group than in the 20 G Group. There was no significant difference in either the pre- or the postoperative IOP between the two groups, while the rate of the cases with hypotony of less than 5 mmHg was significantly higher (p = 0.048) in the 20 G Group than in the 25 G Group. CONCLUSIONS: These results suggest that, although vitrectomy only with 25-gauge system proved insufficient, 25-gauge vitrectomy may achieve the surgical outcomes for the repair of retinal detachment complicated with PVR equal to or higher than 20-gauge vitrectomy. PMID- 22509699 TI - [Macular ischemia following intravitreal bevacizumab therapy for diabetic macular edema]. AB - PURPOSE: To examine the effects of macular ischemia after intravitreal bevacizumab (IVB) in patients with diabetic macular edema(DME). METHODS: Thirty three eyes of 33 patients with DME were treated with IVB. Fluorescein angiography (FA) was conducted before and 3 months after IVB, the pretreatment sizes of the foveal avascular zone (FAZ) calculated by FA were compared to the values at 3 months after IVB. This study was approved by the Chiba University Hospital Clinical Research Ethics Committee. RESULTS: After IVB, the size of the FAZ enlarged significantly (p = 0.03). Among the 33 patients treated with IVB, 2 patients (6%) had advanced macular ischemia with an FAZ enlarged by 50% or more. In both patients, the visual acuity did not worsen and the foveal thickness decreased. CONCLUSIONS: It is possible that IVB led to macular ischemia. PMID- 22509700 TI - [Prader-Willi syndrome case with proliferative diabetic retinopathy in both eyes treated by early vitrectomy under local anesthesia]. AB - BACKGROUND: Although patients with Prader-Willi syndrome have a high rate of diabetes, to date, there have been only 4 reported cases (6 eyes) undergoing vitrectomy for proliferative diabetic retinopathy. Herein, we report a case of Prader-Willi syndrome with proliferative diabetic retinopathy that was treated by early vitrectomy OU under local anesthesia. CASE: A 30-year-old man was diagnosed as having Prader-Willi syndrome at the age of 2 years and diabetes at age 17. He was referred to our hospital as diabetic retinopathy had been detected in his first ophthalmological examination at age 29. Visual acuity was 0.6 bilaterally. Proliferative retinopathy, with cataract and macular edema, was identified in both eyes. Panretinal photocoagulation was performed on both eyes. However, proliferative membranes developed bilaterally, and vitreous hemorrhage occurred OS. Visual acuity decreased to 0.3 OU. The patient was hospitalized at our internal medicine department for blood glucose control. Subsequently, with an anesthesiologist on standby, a hypnotic sedative was injected intramuscularly, achieving retro-bulbar anesthesia. Combined cataract and vitreous surgery was performed on the left eye. One week later, a similar operation was performed on the right eye. The patient was discharged four days later. In the two years since these operation, visual acuity has been maintained at 0.8 OU. CONCLUSION: Patients with Prader-Willi syndrome should be examined for early detection and treatment of diabetic retinopathy. PMID- 22509702 TI - ["And I ask the patient, what do you need now"]. PMID- 22509701 TI - [Patient with recurrent central serous chorioretinopathy who developed multiple evanescent white dots and serous retinal detachment immediately following bevacizumab administration]. AB - BACKGROUND: A patient developed choroidal neovascularization (CNV) in one eye during treatment for bilateral recurrent central serous chorioretinopathy (CSC) and was intravitreously injected with bevacizumab; she developed multiple evanescent white dots and serous retinal detachment(SRD). CASE: A 50-year-old women had a history of CSC OD at the age of 29 years. On initial examination, CSC OD was noted, and multiple detachments of the retinal pigment epithelium OU were observed. While the CSC in the right eye was successfully treated by laser photocoagulation, it spread to both eyes following this episode. Examination of the right eye by optical coherence tomography (OCT) following the recurrence of the CSC showed slight elevation of the retinal pigment epithelial layer in the central fovea, but this finding disappeared with the resolution of the CSC. However, as the CSC combined with CNV (Gass type 2) recurred within 1 year, the patient was intravitreously injected with bevacizumab. On the day following the injection, SRD OD occurred, and on the 7th day following the injection many white lesions varying in size appeared in the deep layer of the retina, but they healed 3 weeks later, leaving only the CNV. The CNV was cured later by additional photodynamic therapy. CONCLUSION: Since the lesions of the fundus observed immediately after the bevacizumab administration resolved spontaneously without sequelae, they were retrospectively diagnosed as a white dot syndrome-like disease. The white dot syndrome-like disease is suggested as a rare complication of bevacizumab. PMID- 22509703 TI - [Admission requirements for nursing education: VPU president Torsten Rantzsch takes a position in conflict with the Federal Minister of Health. "The self image of nursing is changing dramatically"]. PMID- 22509704 TI - [Effectiveness of measures to prevent falls in the elderly. Many questions remain open]. PMID- 22509705 TI - [Nursing oasis for persons with severe dementia. Cared for in the community]. PMID- 22509706 TI - [Mittelhessen Technical College will start the "hospital hygiene" study concentration in the winter semester: risks and infection prevention]. PMID- 22509707 TI - [Residence for the elderly with nursing care needs. "Under no circumstances into a nursing home"!]. PMID- 22509708 TI - [Spirituality and terminal care. The patients hand us the key]. PMID- 22509709 TI - [A plea for respect for patients with dementia. The good fortune of the Alzheimer patient]. PMID- 22509710 TI - [Therapeutic touch for demented patients with pain. Healing with the hands]. PMID- 22509711 TI - [Promoting continence with assertive nursing. Impersonal diaper rounds]. PMID- 22509712 TI - [Experiences of nurses in assessment of contractures in the nursing home. "Something is going on!"]. PMID- 22509713 TI - [Nurses end-of-life decision making. Professional nurses about the application of complementary care for patients with breathlessness]. AB - Aim of this study was to explore the nursing professionals' experiences and handling of decisions to provide complementary care for patients with breathlessness at the end of life. Therefore, it presents one of the first studies in the German speaking area addressing genuine nursing decisions belonging to their responsibility. Based on Grounded Theory Methodology the data were collected and analysed synchronously. Results show a high professional and emphatic decision making process always focussing on the patient. "To consider the patient" emanates from their general attitude and is influenced by the possibility to be human themselves and by reflecting ones limitations. At the same time participants described a repertoire of complementary care procedures which they use in their daily nursing routine. This study illustrates the decision making process and outlines the general attitude influencing all decisions and actions of nurses to relieve breathlessness. Furthermore, it shows for the first time a range of currently used complementary care procedures to treat patients with breathlessness at the end of life. PMID- 22509714 TI - [Project to reduce preventable hospital transfer from homes for the aged and nursing home. Is it really always necessary?]. PMID- 22509715 TI - [Communication in routine nursing care. Displaying understanding]. PMID- 22509716 TI - [Promoting physical activity and incontinence in the elderly. Weak bladder and unsteady gait]. PMID- 22509717 TI - Highly efficient inverted type-I CdS/CdSe core/shell structure QD-sensitized solar cells. AB - Presynthesized high-quality CdS/CdSe inverted type-I core/shell structure QDs have been deposited onto TiO(2) electrodes after first coating with bifunctional linker molecules, mercaptopropionic acid (MPA), and the resulting quantum dot sensitized solar cells (QDSCs) exhibited record conversion efficiency of 5.32% (V(oc) = 0.527 V, J(sc) = 18.02 mA/cm(2), FF = 0.56) under simulated AM 1.5, 100 mW cm(-2) illumination. CdS/CdSe QDs with different CdSe shell thicknesses and different corresponding absorption onsets were prepared via the well-developed organometallic high-temperature injection method. MPA-capped water-dispersible QDs were then obtained via ligand exchange from the initial organic ligand capped oil-dispersible QDs. The QD-sensitized TiO(2) electrodes were facilely prepared by pipetting the MPA-capped CdS/CdSe QD aqueous solution onto the TiO(2) film, followed by a covering process with a ZnS layer and a postsintering process at 300 degrees C. Polysulfide electrolyte and Cu(2)S counterelectrode were used to provide higher photocurrents and fill factors of the constructed cell devices. The characteristics of these QDSCs were studied in more detail by optical measurements, incidental photo-to-current efficiency measurements, and impedance spectroscopy. With the combination of the modified deposition technique with use of linker molecule MPA-capped water-soluble QDs and well-developed inverted type I core/shell structure of the sensitizer together with the sintering treatment of QD-bound TiO(2) electrodes, the resulting CdS/CdSe-sensitized solar cells show a record photovoltaic performance with a conversion efficiency of 5.32%. PMID- 22509718 TI - High-risk clonal evolution in chronic B-lymphocytic leukemia: single-center interphase fluorescence in situ hybridization study and review of the literature. AB - BACKGROUND: We studied the relation of clonal evolution (CE) in Chronic B lymphocytic leukemia (CLL) with prognostic factors and the correlation between CE and disease progression and overall survival. METHODS: With interphase fluorescence in situ hybridization (FISH) analysis, we looked for 11q22 deletion, 17p13 deletion, and trisomy 12. A second FISH was performed approximately 3 yr after the first one or earlier in case of disease progression. RESULTS: High-risk CE, defined as the acquisition of a new 11q or 17p deletion, was observed in 11.5% (11/95) of patients with CLL. The relative risk of CE was not influenced by CD38 and ZAP-70 expression, mutational status of the immunoglobulin heavy chain gene (IgVH), lymphocyte doubling time, and genomic aberrations observed with the first FISH or by treatment given between the sequential genetic analyses. Patients with high-risk CE had a significant shorter survival time (59 months vs. not reached, P = 0.0367). Multivariate analysis identified CE as the strongest independent prognostic marker regarding survival [hazard ratio (HR) 4.1, P = 0.01]. Clonal fluctuation, defined as disappearance of the 11q or 17p deletion, was seen in 11.5% (11/95) of patients. Most patients lost the high-risk clone after treatment despite persistence of a malignant clone. The disappearance of these genomic aberrations did not ameliorate outcome. A few patients have lost spontaneously a small 17p clone. CONCLUSION: This study confirms that CE and clonal fluctuation are common phenomena in CLL. CE was not limited to patients with pre-existing adverse prognostic factors. Acquiring high-risk CE was identified as the strongest independent prognostic factor for impaired survival. PMID- 22509719 TI - Enhanced sample multiplexing for nitrotyrosine-modified proteins using combined precursor isotopic labeling and isobaric tagging. AB - Current strategies for identification and quantification of 3-nitrotyrosine (3NT) post-translationally modified proteins (PTM) generally rely on biotin/avidin enrichment. Quantitative approaches have been demonstrated which employ isotopic labeling or isobaric tagging in order to quantify differences in the relative abundances of 3NT-modified proteins in two or potentially eight samples, respectively. Here, we present a novel strategy which uses combined precursor isotopic labeling and isobaric tagging (cPILOT) to increase the multiplexing capability of quantifying 3NT-modified proteins to 12 or 16 samples using commercially available tandem mass tags (TMT) or isobaric tags for relative and absolute quantification (iTRAQ), respectively. This strategy employs "light" and "heavy" labeled acetyl groups to block both N-termini and lysine residues of tryptic peptides. Next, 3NT is reduced to 3-aminotyrosine (3AT) using sodium dithionite followed by derivatization of light and heavy labeled 3AT-peptides with either TMT or iTRAQ multiplex reagents. We demonstrate the proof-of principle utility of cPILOT with in vitro nitrated bovine serum albumin (BSA) and mouse splenic proteins using TMT(0), TMT(6), and iTRAQ(8) reagents and discuss limitations of the strategy. PMID- 22509720 TI - Interpretation of stochastic events in single-molecule measurements of conductance and transition voltage spectroscopy. AB - The first simultaneous measurements of transition voltage (V(t)) spectroscopy (TVS) and conductance (G) histograms (Guo et al., J. Am. Chem. Soc. 2011, 133, 19189) form a great case for studying stochastic effects, which are ubiquitous in molecular junctions. Here an interpretation of those data is proposed that emphasizes the different physical content of V(t) and G and reveals that fluctuations in the molecular orbital alignment have a significantly larger impact on G than initially claimed. The present study demonstrates the usefulness of corroborating statistical information on different transport properties and gives support to TVS as a valuable investigative tool. PMID- 22509721 TI - In vitro analysis of bacterial morphology by atomic force microscopy of low level laser therapy 660, 830 and 904 nm. AB - OBJECTIVE: The objective of this study was to analyze the bacterial morphology by atomic force microscopy (AFM) after the application of low-level laser therapy (LLLT) in in vitro culture of Staphylococcus aureus ATCC 29213. BACKGROUND DATA: Infections caused by S. aureus are among the highest occurring in hospitals and can often colonize pressure ulcers. LLLT is among the methods used to accelerate the healing of ulcers. However, there is no consensus on its effect on bacteria. MATERIALS AND METHODS: After being cultivated and seeded, the cultures were irradiated using wavelengths of 660, 830, and 904 nm at fluences of 0, 1, 2, 3, 4, 5, and 16 J/cm(2). Viable cells of S. aureus strain were counted after 24 h incubation. To analyze the occurrence of morphological changes, the topographical measurement of bacterial cells was analyzed using the AFM. RESULTS: The overall assessment revealed that the laser irradiation reduced the S. aureus growth using 830 and 904 nm wavelengths; the latter with the greatest inhibition of the colony forming units (CFU/mL) (331.1+/-38.19 and 137.38+/-21.72). Specifically with 660 nm, the statistical difference occurred only at a fluence of 3 J/cm(2). Topographical analysis showed small changes in morphological conformity of the samples tested. CONCLUSIONS: LLLT reduced the growth of S. aureus with 830 and 904 nm wavelengths, particularly with 904 nm at a fluence of 3 J/cm(2), where the greatest topographical changes of the cell structure occurred. PMID- 22509722 TI - Laser GaAlAs (lambda860 nm) photobiomodulation for the treatment of bisphosphonate-induced osteonecrosis of the jaw. AB - OBJECTIVE: The aim of this article is to report a case of bisphosphonate-induced osteonecrosis (ONJ-BP) of the jaw treated by curettage of the necrotic bone, low level laser therapy (LLLT), and antibiotic therapy. BACKGROUND DATA: ONJ-BP is characterized by painful ulcerations of the oral mucosa, is prone to bone necrosis that does not heal within 8 weeks after diagnosis, and is often difficult to treat. No definitive standard of care has been established for ONJ BP. LLLT improves wound healing, relieves pain, and appears to be a promising treatment modality for patients with ONJ-BP. MATERIALS AND METHODS: An 82-year old man taking intravenous bisphosphonate presented with ONJ-BP after tooth extraction. The patient was treated by LLLT using a GaAlAs diode laser with the following settings: wavelength, 860 nm; 70 mW; continuous wave; and spot size 4 mm(2). An energy density of 4.2 J/cm(2) per point was applied in a punctual contact manner every 48 h for 10 days, in association with antibiotic therapy and curettage of the necrotic bone. Reduction in painful symptoms was reported after the second irradiation session, and tissue healing was complete at the end of the third week following oral curettage. The patient was followed up for 12 months and exhibited good oral healt and quality of life. CONCLUSIONS: The therapeutic protocol used in this study had a positive effect on tissue healing and remission of painful symptoms, resulting in better oral health and quality of life for the patient. PMID- 22509723 TI - Overall stability for the ibuprofen racemate: experimental and topological results leading to the pressure-temperature phase relationships between its racemate and conglomerate. AB - Enantiomer resolution is much sought after for pharmaceutical applications, because many optically active drug molecules have only one pharmaceutically active enantiomer. Although it is always possible to force separation, it will come at a cost. The present method, based on thermodynamics, provides a relatively easy approach to investigate whether separation can be thermodynamically spontaneous. A topological phase diagram of the binary enantiomer system at 0.5 mol-fraction is constructed as a function of temperature and pressure after analysis of pressure and heat related quantities. It is demonstrated that for ibuprofen, an optically active analgesic, the racemate is the only stable solid form; the phase relationship between the racemate and the conglomerate is analogous to dimorphism with overall monotropy in pure chemical compounds. PMID- 22509725 TI - 3-Alkenylation or 3-alkylation of indole with propargylic alcohols: construction of 3,4-dihydrocyclopenta[b]indole and 1,4-dihydrocyclopenta[b]indole in the presence of different catalysts. AB - 3-Alkenylation or 3-alkylation of indole with propargylic alcohols could be efficiently controlled by the catalyst. In the presence of triflic acid, 3 alkenylation of indole occurred and a 3,4-dihydrocyclopenta[b]indole skeleton was effectively constructed in moderate to excellent yields via a cascade process. In the presence of Cu(OTf)(2), 3-alkylation of indole resulted in the formation of 3 propargylic indole, which could be further converted into 2-iodo-1,4 dihydrocyclopenta[b]indoles in the presence of N-iodosuccinimide and boron trifluoride etherate. Possible mechanisms related to the 3-alkenylation or 3 alkylation of indole and their extension to the formation of 3,4 dihydrocyclopenta[b]indoles or 1,4-dihydrocyclopenta[b]indoles are postulated and discussed. PMID- 22509724 TI - Defining the needs of ICU patient families in a suburban/rural Greek population: a prospective cohort study. AB - AIM: To define the needs of intensive care unit patients' families in the specific suburban/rural population of Crete Island. BACKGROUND: Families of intensive care unit patients have specific needs that should also be addressed by the intensive care unit-care team. Current research has mostly concentrated on families from an urban setting, therefore may not be applicable to other populations. DESIGN: Prospective cohort study. METHODS: Family members of patients admitted in the intensive care unit for >= 48 hours over 18 months, in a mixed medical-surgical, 11 bed closed intensive care unit. Questionnaire: The Greek translation of Critical Care Family Need Inventory, which consists of 45 need items covering the information, reassurance, proximity, support and comfort domains. Each item was scored on a four-point scale (1 = very important to 4 = not important). Participants were also asked to single out the most important need from the Critical Care Family Need Inventory and complete a questionnaire on basic demographic characteristics. RESULTS: Two hundred and thirty (65%) family members completed the questionnaire. Mean score for each of the 45 items ranged from 1.03-3 (scale from 1: very important-4: not important). Fourteen items were rated by responders as very important (mean score <1.25). Reassurance need items were consistently singled out as most important regardless of the participant's background. Participants with a lower educational and socio-economical status rated support need items as more important than those with a higher status. CONCLUSION: In this particular suburban/rural population, both 'universal' reassurance needs and specific support needs related to responders' educational or socio-economical background were identified. RELEVANCE TO CLINICAL PRACTICE: Enhanced recognition of these needs may improve quality of care offered by intensive care unit-care team to families of their patients. PMID- 22509726 TI - The effect of hemolysis on plasma oxidation and nitration in patients with sickle cell disease. AB - This study aimed to determine the effect of haemolysis on plasma oxidation and nitration in sickle cell disease (SCD) patients. Blood was collected from haemoglobin (Hb)A volunteers and homozygous HbSS patients who had not received blood transfusions in the last 3 months. Haemolysis was characterised by low levels of haemoglobin and haptoglobin and high levels of reticulocyte, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), plasma cell-free haemoglobin, bilirubin, total lactate dehydrogenase (LDH) and dominance of LDH-1 isoenzyme. Plasma 8-isoprostane, protein carbonyl and nitrotyrosine levels were measured to evaluate oxidised lipids, oxidised and nitrated proteins, respectively. Plasma nitrite-nitrate levels were also determined to assess nitric oxide (NO) production in both SCD patients and controls. Markers of haemolysis were significantly evident in SCD patients compared to controls. Plasma 8 isoprostane, protein carbonyl and nitrotyrosine levels were markedly elevated in SCD patients compared to controls. Linear regression analysis revealed a significant inverse correlation between haemoglobin and reticulocyte counts and a significant positive correlation of plasma cell-free haemoglobin with protein carbonyl and nitrotyrosine levels. The obtained data shows that increased haemolysis in SCD increases plasma protein oxidation and nitration. PMID- 22509727 TI - Unbiased approach to profile the variety of small non-coding RNA of human blood plasma with massively parallel sequencing technology. AB - OBJECTIVE: Understanding structures of circulating RNA expands fundamental knowledge of cell communications and signaling pathways as well as allows developing new molecular diagnostic approaches. The aim of this study was to deploy a new approach to sequencing cDNA library construction which expands the capabilities of high-throughput sequencing analysis of small non-coding RNAs. With the approach, we performed massively parallel sequencing of human blood plasma RNA to document profile of common and peculiar RNA species normally circulating in blood of healthy individuals. METHODS: Total RNA was extracted from blood plasma samples of eight apparently healthy individuals. To obtain comprehensive cDNA libraries RNA was dephosphorylated and then 5'-phosphorylated. 5'-Phosphorylated total plasma RNA was ligated with adapters, reverse transcribed and eight personalized cDNA libraries were constructed. Libraries were sequenced with SOLiD(TM) technology. RESULTS/CONCLUSION: Fragments of rRNA, mitochondrial transcripts, microRNAs, fragments of scRNAs, snRNA and snoRNA, fragments of several mRNAs as well as the set of newly discovered transcripts were found to be permanent representatives of human blood plasma RNAs. Advanced mapping allowed to identify circulating herpes virus and enterobacterial transcripts. Documented profile of circulating RNA of healthy individuals provides basis for development of new approaches in research and diagnosis of human pathology. PMID- 22509728 TI - Novel and uncommon antimicrobial resistance genes in livestock-associated methicillin-resistant Staphylococcus aureus. AB - Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) isolates have been the subject of numerous studies during recent years. The characterization of such isolates has usually also included the determination of their resistance phenotypes and associated resistance genotypes. Analysis of the resistance genes present in LA-MRSA isolates has revealed a number of genes commonly found in S. aureus and coagulase-negative staphylococci of humans and animals. In addition, novel resistance genes and/or resistance genes that have been rarely detected in staphylococci so far have been encountered. These include the phenicol exporter gene fexA, the multiresistance gene cfr, the tetracycline resistance gene tet(L), the trimethoprim resistance gene dfrK, the macrolide lincosamide-streptogramin B resistance gene erm(T), the lincosamide-streptogramin A-pleuromutilin resistance genes vga(C) and vga(E), and the apramycin resistance gene apmA. Most of these genes were located on multiresistance plasmids in LA MRSA. The co-localization of these resistance genes with other resistance genes enables their co-selection and persistence. LA-MRSA can therefore act as a donor and a recipient of antimicrobial resistance genes within the Gram-positive gene pool. PMID- 22509729 TI - Role of a conserved arginine residue in linkers between the ketosynthase and acyltransferase domains of multimodular polyketide synthases. AB - The role of interdomain linkers in modular polyketide synthases is poorly understood. Analysis of the 6-deoxyerythronolide B synthase (DEBS) has yielded a model in which chain elongation is governed by interactions between the acyl carrier protein domain and the ketosynthase domain plus an adjacent linker. Alanine scanning mutagenesis of the conserved residues of this linker in DEBS module 3 led to the identification of the R513A mutant with a markedly reduced rate of chain elongation. Limited proteolysis supported a structural role for this Arg. Our findings highlight the importance of domain-linker interactions in assembly line polyketide biosynthesis. PMID- 22509730 TI - Size-dependent interaction of the poly(N-vinyl-2-pyrrolidone) capping ligand with Pd nanocrystals. AB - Pd nanocrystals were prepared by the reduction of a H(2)PdCl(4) aqueous solution with C(2)H(4) in the presence of different amounts of poly(N-vinyl-2-pyrrolidone) (PVP). Their average size decreases monotonically as the PVP monomer/Pd molar ratio increases up to 1.0 and then does not vary much at higher PVP monomer/Pd molar ratios. Infrared spectroscopy and X-ray photoelectron spectroscopy results reveal the interesting size-dependent interaction of PVP molecules with Pd nanocrystals. For fine Pd nanocrystals capped with a large number of PVP molecules, each PVP molecule chemisorbs with its oxygen atom in the ring; for large Pd nanocrystals capped by a small number of PVP molecules, each PVP molecule chemisorbs with both the oxygen atom and nitrogen atom in the ring, which obviously affects the structure of chemisorbed PVP molecules and even results in the breaking of involved C-N bonds of some chemisorbed PVP molecules. Charge transfer always occurs from a chemisorbed PVP ligand to Pd nanocrystals. These results provide novel insights into the PVP-metal nanocrystal interaction, which are of great importance in the fundamental understanding of surface mediated properties of PVP-capped metal nanocrystals. PMID- 22509731 TI - Short-term secular change in height, body mass and Tanner-Whitehouse 3 skeletal maturity of Madeira youth, Portugal. AB - BACKGROUND: Secular trends in height and weight are reasonably well documented in Europe. Corresponding observations for skeletal maturation are lacking. AIM: To assess secular trends in height, body mass and skeletal maturity of Portuguese children and adolescents and to provide updated reference values for skeletal maturity scores (SMSs). SUBJECTS AND METHODS: Data for 2856 children and adolescents of 4-17 years, 1412 boys and 1444 girls, from The 'Madeira Growth Study' (MGS; 1996-1998) and from the'Healthy Growth of Madeira Children Study' (CRES; 2006) were used. Height and body mass were measured. Skeletal maturity was assessed with the Tanner-Whitehouse 2 and 3 methods. RESULTS: Children from CRES were taller and heavier than peers from MGS. Differences in height reached 5.8 cm in boys and 5.5 cm in girls. RUS SMSs did not differ consistently between surveys boys, while higher RUS scores were observed in CRES girls. Adult RUS SMSs for MGS and CRES combined were attained at 15.8 years in boys and 14.8 years in girls. Corresponding ages for adult Carpal SMSs were 14.4 and 14.0, respectively. CONCLUSION: The short-term trends for height and mass were not entirely consistent with the trends in RUS and Carpal SMSs and SAs. PMID- 22509732 TI - Sulthiame add-on therapy in children with focal epilepsies associated with encephalopathy related to electrical status epilepticus during slow sleep (ESES). AB - PURPOSE: In children with symptomatic or idiopathic focal epilepsies, their disease may evolve into an epileptic encephalopathy related to continuous spike and wave during slow sleep (CSWS) or electrical status epilepticus during slow sleep (ESES). ESES syndrome implies serious risks of neuropsychologic impairment, and its treatment has frequently been disappointing. The aim of this study is to present our experience using sulthiame as add-on treatment in 53 patients with ESES syndrome that was refractory to other antiepileptic drugs (AEDs). METHODS: Neurologic examinations, cerebral magnetic resonance imaging (MRI), and repeated prolonged sleep electroencephalography (EEG) studies were performed in all cases. Data about school achievements and or neuropsychological evaluations were obtained repeatedly during the follow-up of 1.5-16 years. Sulthiame was added in doses ranging between 5 and 30 mg/kg/day. KEY FINDINGS: Since add-on of sulthiame, 10 of 28 patients in the symptomatic group became seizure free: 4 patients with normal EEG studies and 6 with residual spikes. Nine of 28 patients showed a significant reduction in number of seizures and presented spikes but no ESES on EEG. The other nine cases showed neither clinical nor EEG improvement. A striking result was that 3 of 11 children with unilateral polymicrogyria and ESES syndrome became seizure free, and in another six a significant improvement in frequency of seizures and in EEG abnormalities seemed to be related to the add-on of sulthiame. Twenty-one of the 25 patients in the idiopathic group became seizure free and without ESES in <3 months after add on of sulthiame. In two of the patients the changes were seen in a few days. SIGNIFICANCE: We understand that sulthiame may be effective as add-on treatment in children with ESES syndrome. PMID- 22509733 TI - Diosmin protects rat retina from ischemia/reperfusion injury. AB - OBJECTIVE: Diosmin, a natural flavone glycoside, possesses antioxidant activity and has been used to alleviate ischemia/reperfusion (I/R) injury. The aim of this study was to clarify whether the administration of diosmin has a protective effect against I/R injury induced using the high intraocular pressure (IOP) model in rat retina, and to determine the possible antioxidant mechanisms involved. METHODS: Retinal I/R injury was induced in the rats by elevating the IOP to 110 mmHg for 60 min. Diosmin (100 mg/kg) or vehicle solution was administered intragastrically 30 min before the onset of ischemia and then daily after I/R injury until the animals were sacrificed. The levels of malondialdehyde (MDA) and the activities of total-superoxide dismutase (T-SOD), glutathione peroxidase (GSH Px), and catalase (CAT) in the retinal tissues were determined 24 h after I/R injury. At 7 days post-I/R injury, electroretinograms (ERGs) were recorded, and the density of surviving retinal ganglion cells (RGCs) was estimated by counting retrograde tracer-labeled cells in whole-mounted retinas. Retinal histological changes were also examined and quantified using light microscopy. RESULTS: Diosmin significantly decreased the MDA levels and increased the activities of T SOD, GSH-Px, and CAT in the retina of rats compared with the ischemia group (P<0.05), and suppressed the I/R-induced reduction in the a- and b-wave amplitudes of the ERG (P<0.05). The thickness of the entire retina, inner nuclear layer, inner plexiform layer, and outer retinal layer and the number of cells in the ganglion cell layer were significantly less after I/R injury (P<0.05), and diosmin remarkably ameliorated these changes on retinal morphology. Diosmin also attenuated the I/R-induced loss of RGCs of the rat retina (P<0.05). CONCLUSION: Diosmin protected the retina from I/R injury, possibly via a mechanism involving the regulation of oxidative parameters. PMID- 22509734 TI - Ethinyl estradiol-drospirenone vs ethinyl estradiol-drospirenone plus metformin in the treatment of lean women with polycystic ovary syndrome. AB - OBJECTIVE: Oral contraceptive use might be associated with cardiometabolic risk in PCOS. We aimed to compare the effects of ethinyl estradiol-drospirenone (EE/DRSP) alone vs EE/DRSP plus metformin on clinical and cardiometabolic parameters in PCOS. DESIGN: Prospective observational study. PATIENTS: Forty-five lean patients with PCOS who received EE/DRSP (30 MUg/3 mg) (n = 25) or EE/DRSP plus metformin (1700 mg/day) (n = 20) and 45 BMI-matched healthy controls. MEASUREMENT: BMI, waist-to-hip ratio (WHR), hirsutism scores, androgens, lipids, glucose and insulin levels during an OGTT were measured before and after 6 months of treatment in patients and compared to controls. RESULTS: At baseline, patients with PCOS showed similar glucose, insulin and lipids but increased 2 h glucose values compared to controls. Hirsutism scores and free androgen index decreased in both treatment groups. BMI and WHR did not show any change in the EE/DRSP group, while metformin addition resulted in a decrease in BMI. Lipid levels increased in both groups. Glucose and insulin parameters did not change in any group, but metformin addition compared to EE/DRSP alone significantly decreased waist circumference, fasting insulin and HOMA-IR. After-treatment values for both EE/DRSP alone and in combination with metformin compared to the control group showed increased 2 h glucose and increased lipids in patients with PCOS. CONCLUSION: EE/DRSP alone or in combination with metformin improves clinical and biochemical hyperandrogenism in lean PCOS. Both treatments similarly alter lipid profile. EE/DRSP alone does not affect insulin sensitivity, whereas combining EE/DRSP with metformin might improve it. PMID- 22509735 TI - On the disruption of biochemical and biological assays by chemicals leaching from disposable laboratory plasticware. AB - Plastic consumables, used universally in bioscience laboratories, are presumed inert with respect to bioassay outcomes. However, it is clear that many pipette tips, microfuge tubes, and other plastic disposables leach bioactive compounds into assay solutions, profoundly affecting data and experimental interpretation. In this paper we discuss the nature and sources of leachates and review several examples of compromised bioassay data that speak to the probable widespread nature of this largely unrecognised source of error. Strategies for minimizing leachate interferences are discussed. PMID- 22509736 TI - Rapid tomato volatile profiling by using proton-transfer reaction mass spectrometry (PTR-MS). AB - The availability of rapid and accurate methods to assess fruit flavor is of utmost importance to support quality control especially in the breeding phase. Breeders need more information and analytical tools to facilitate selection for complex multigenic traits such as flavor quality. In this study, it is shown that proton-transfer reaction mass spectrometry (PTR-MS) is a suitable method to monitor at high sensitivity the emission of volatiles determining the tomato aromatic profile such as hexanal, hexenals, methanol, ethanol, and acetaldehyde. The volatiles emitted by 14 tomato varieties (at red stage) were analyzed by 2 solvent-free headspace methods: solid-phase microextraction/gas chromatography MS and PTR-MS. Multivariate statistics (principal component analysis and cluster analysis) of the PTR-MS results allow an unambiguous separation between varieties, especially with a clear fingerprinting separation between the different tomato types: round truss, cocktail, and cherry tomatoes. PTR-MS was also successfully used to monitor the changes in volatile profiles during postharvest ripening and storage. PMID- 22509738 TI - Er:YAG laser versus systemic metronidazole as an adjunct to nonsurgical periodontal therapy: a clinical and microbiological study. AB - OBJECTIVE: The objective of this randomized clinical trial was to describe the clinical and microbiological results obtained by treatment with Er:YAG laser and systemic metronidazole used as adjuncts to mechanical subgingival debridement in chronic periodontitis. METHODS: Twenty-seven chronic periodontitis (CP) patients were randomly divided into three parallel groups each comprising nine individuals with at least four teeth having at least one approximal site with a probing depth (PD) of >=5 mm and gingival index (GI) of >=2 in each quadrant. Groups of patients received: (1) Scaling and root planing (SRP)+ Er:YAG laser (10 hz, 30 mJ/pulse, 1 min per pocket, apico-coronal direction in parallel paths with 30 degree angle tips, under water irrigation), (2) SRP+ systemic metronidazole, or (3) SRP alone. In all treatment groups, SRP was performed at 1 week intervals in two sessions. The microbiological and clinical effects of the treatments were evaluated after 90 days. RESULTS: At the end of the experimental period, statistically significant improvements in plaque index, GI, PD and attachment level, as well as reductions in the number of total bacteria and proportions of obligately anaerobic microorganisms were observed within each group. Although intergroup comparisons revealed no significant microbiological differences, clinical parameters as attachment gain and PD reduction were found significantly higher in Group 1 compared with the other groups. CONCLUSIONS: Within its limits, this study demonstrated the possibility of better resolution of infection with combined SRP+Er:YAG laser treatment. However, microbiological results failed to demonstrate significant advantages of this combination in comparison with SRP alone or SRP+systemic metronidazole. PMID- 22509739 TI - Optically stable biocompatible flame-made SiO2-coated Y2O3:Tb3+ nanophosphors for cell imaging. AB - Nanophosphors are light-emitting materials with stable optical properties that represent promising tools for bioimaging. The synthesis of nanophosphors, and thus the control of their surface properties, is, however, challenging. Here, flame aerosol technology is exploited to generate Tb-activated Y(2)O(3) nanophosphors (~25 nm) encapsulated in situ by a nanothin amorphous inert SiO(2) film. The nanocrystalline core exhibits a bright green luminescence following the Tb(3+) ion transitions, while the hermetic SiO(2)-coating prevents any unspecific interference with cellular activities. The SiO(2)-coated nanophosphors display minimal photobleaching upon imaging and can be easily functionalized through surface absorption of biological molecules. Therefore, they can be used as bionanoprobes for cell detection and for long-term monitoring of cellular activities. As an example, we report on the interaction between epidermal growth factor (EGF)-functionalized nanophosphors and mouse melanoma cells. The cellular uptake of the nanophosphors is visualized with confocal microscopy, and the specific activation of EGF receptors is revealed with biochemical techniques. Altogether, our results establish SiO(2)-coated Tb-activated Y(2)O(3) nanophosphors as superior imaging tools for biological applications. PMID- 22509740 TI - Cellular antioxidant activity of feijoada whole meal coupled with an in vitro digestion. AB - Consumption of plant food rich meals, such as feijoada, a traditional meal in Brazil, is associated with the reduction of chronic disease. The objectives of this study were to determine phytochemical content and antioxidant activity by chemical and cellular antioxidant assays (CAA) of feijoada with or without in vitro digestion. Feijoada showed no difference in phenolics and flavonoids after digestion. Bound and residue contributions to total phenolics were 20.9% and 32.2%, respectively, suggesting that phenolics reach the colon after intake. Flavonoids in residue and bound fractions represented 50% of total flavonoids. Antioxidant activity of feijoada without digestion was higher than that with digestion; however, it showed lower antiproliferative activity and CAA. Feijoada with in vitro digestion also yielded phenolics with higher CAA. Analyses of whole meals should be used to evaluate phytochemicals present in food mixtures consumed, especially with digestion models coupled with CAA resulting in information similar to those in physiological conditions. PMID- 22509741 TI - Chip-calorimetry provides real time insights into the inactivation of biofilms by predatory bacteria. AB - Control or removal of undesired biofilms has frequently been found to be quite difficult. In addition to biocidal or antibiotic chemicals or materials designed to prevent biofouling, biological control agents appear to be promising. Reports of bacterial predators eradicating biofilms or eliminating pathogens motivate a more systematic screening of biofilm-eliminating bacterial predators. Unfortunately, the analysis of the eradication process is demanding. In the present study, chip-calorimetry was applied to monitor the elimination of Pseudomonas sp. biofilms by Bdellovibrio bacteriovorus. The method uses metabolic heat as a real-time parameter for biofilm activity. The method is non-invasive, fast and convenient due to real-time data acquisition. In addition, heat production data can reveal information about the energetics of the predator-prey interaction. The calorimetric results were validated by confocal laser scanning microscopy. The approach described may be useful for the screening of biofilm susceptibility to different predators. PMID- 22509743 TI - Transformation of non-tumor host cells during tumor progression: theories and evidence. AB - INTRODUCTION: Most cancer deaths are due to the development of metastases and this phenomenon is still a hard challenge for researchers. A number of theories have tried to unravel the metastatic machinery, but definitive results that link the evidence with conventional concepts of metastatic disease remain to be reported. AREAS COVERED: Considerable evidence suggests interactions between tumor cells and host cells that might be essential for tumor progression and metastasis. Most such evidence is suggestive of fusion phenomena, but some suggest the transfer of cell-free DNA (cfDNA). Such evidence is often ignored or overlooked in the assessment and management of malignancy. In this article, we review the available evidence for the importance of cell fusion and cfDNA in metastasis, and we present some preliminary data that support the hypothesis that tumor progression might be based not only on the division of tumor cells but also on the transformation of normal cells. EXPERT OPINION: Future success in the search for cancer therapies will surely require advances in our knowledge of the pathways of tumor invasion by unexpected mechanisms. Thus, no well supported evidence for roles of cell-free nucleic acids and fusion of cells or of cells with vesicles should be ignored. PMID- 22509742 TI - Defining intact protein primary structures from saliva: a step toward the human proteome project. AB - Top-down mass spectrometry has been used to investigate structural diversity within some abundant salivary protein families. In this study, we report the identification of two isoforms of protein II-2 which differed in mass by less than 1 Da, the determination of a sequence for protein IB8a that was best satisfied by including a mutation and a covalent modification in the C-terminal part, and the assignment of a sequence of a previously unreported protein of mass 10433 Da. The final characterization of Peptide P-J was achieved, and the discovery of a truncated form of this peptide was reported. The first sequence assignment was done at low resolution using a hybrid quadrupole time-of-flight instrument to quickly identify and characterize proteins, and data acquisition was switched to Fourier-transform ion cyclotron resonance (FTICR) for proteins that required additional sequence coverage and certainty of assignment. High resolution and high mass accuracy mass spectrometry on a FTICR-mass spectrometry (MS) instrument combined with electron-capture dissociation (ECD) provided the most informative data sets, with the more frequent presence of "unique" ions that unambiguously define the primary structure. A mixture of predictable and unusual post-translational modifications in the protein sequence precluded the use of shotgun-annotated databases at this stage, requiring manual iterations of sequence refinement in many cases. This led us to propose guidelines for an iterative processing workflow of MS and MSMS data sets that allow researchers to completely assign the identity and the structure of a protein. PMID- 22509744 TI - Autocrine and paracrine actions of ATP in rat carotid body. AB - Carotid bodies are peripheral chemoreceptors that detect lowering of arterial blood O(2) level. The carotid body comprises clusters of glomus (type I) cells surrounded by glial-like sustentacular (type II) cells. Hypoxia triggers depolarization and cytosolic [Ca(2+)] ([Ca(2+)](i)) elevation in glomus cells, resulting in the release of multiple transmitters, including ATP. While ATP has been shown to be an important excitatory transmitter in the stimulation of carotid sinus nerve, there is considerable evidence that ATP exerts autocrine and paracrine actions in carotid body. ATP acting via P2Y(1) receptors, causes hyperpolarization in glomus cells and inhibits the hypoxia-mediated [Ca(2+)](i) rise. In contrast, adenosine (an ATP metabolite) triggers depolarization and [Ca(2+)](i) rise in glomus cells via A(2A) receptors. We suggest that during prolonged hypoxia, the negative and positive feedback actions of ATP and adenosine may result in an oscillatory Ca(2+) signal in glomus cells. Such mechanisms may allow cyclic release of transmitters from glomus cells during prolonged hypoxia without causing cellular damage from a persistent [Ca(2+)](i) rise. ATP also stimulates intracellular Ca(2+) release in sustentacular cells via P2Y(2) receptors. The autocine and paracrine actions of ATP suggest that ATP has important roles in coordinating chemosensory transmission in the carotid body. PMID- 22509745 TI - Dissecting chemical interactions governing RNA polymerase II transcriptional fidelity. AB - Maintaining high transcriptional fidelity is essential to life. For all eukaryotic organisms, RNA polymerase II (Pol II) is responsible for messenger RNA synthesis from the DNA template. Three key checkpoint steps are important in controlling Pol II transcriptional fidelity: nucleotide selection and incorporation, RNA transcript extension, and proofreading. Some types of DNA damage significantly reduce transcriptional fidelity. However, the chemical interactions governing each individual checkpoint step of Pol II transcriptional fidelity and the molecular basis of how subtle DNA base damage leads to significant losses of transcriptional fidelity are not fully understood. Here we use a series of "hydrogen bond deficient" nucleoside analogues to dissect chemical interactions governing Pol II transcriptional fidelity. We find that whereas hydrogen bonds between a Watson-Crick base pair of template DNA and incoming NTP are critical for efficient incorporation, they are not required for efficient transcript extension from this matched 3'-RNA end. In sharp contrast, the fidelity of extension is strongly dependent on the discrimination of an incorrect pattern of hydrogen bonds. We show that U:T wobble base interactions are critical to prevent extension of this mismatch by Pol II. Additionally, both hydrogen bonding and base stacking play important roles in controlling Pol II proofreading activity. Strong base stacking at the 3'-RNA terminus can compensate for loss of hydrogen bonds. Finally, we show that Pol II can distinguish very subtle size differences in template bases. The current work provides the first systematic evaluation of electrostatic and steric effects in controlling Pol II transcriptional fidelity. PMID- 22509748 TI - Elderly sexual offenders: two unusual cases. AB - The aim of this case report is to describe two cases of sexual abuse by elderly subjects for which the Judge commissioned an expert psychiatric-forensic opinion. The elderly are generally believed to commit nonviolent crimes, whereas the two cases we observed feature forcible rape committed by elderly offenders, who showed no form of mental disease and had rationally planned their offense. They had never previously committed similar acts and had no history of homosexuality; both had been married for many years before the death of their wives and had adult children. Finally, no previous episodes of rape emerged in their personal histories during interrogations. The sociocultural context in which the crimes were committed was identical and arouses interest as regards both the method employed and how the crimes were discovered. The legal authorities then commissioned accurate investigations including medicolegal and psychiatric forensic evaluations of the offenders and their victims. PMID- 22509749 TI - Mast cell degranulation in human periodontitis. AB - BACKGROUND: Mast cells are tissue-resident immune cells that participate in a variety of allergic and inflammatory conditions. Limited attention has been given to the role of mast cells in periodontal diseases, and the effects of mast cell degranulation on the chronic stages of non-allergic inflammation, particularly in periodontitis, are not known. The present study analyzes the relationship between the mast cell degranulation and human periodontal disease progression. METHODS: A total of 50 clinical specimens including moderate periodontitis (n = 17), advanced periodontitis (n = 18), and healthy control tissues (n = 15) were used in this study. All specimens were fixed in 10% buffered formalin and stained with hematoxylin and eosin for histopathology, with toluidine blue for identifying mast cells, and by immunohistochemistry for the expressions of mast cell tryptase in periodontal tissues. The total and degranulated mast cell densities (per high power field) were quantified in the specimens. RESULTS: Compared with healthy controls, there were significantly increased both total and degranulated mast cell densities in human moderate (P <0.01) and advanced (P <0.01) periodontitis groups by toluidine blue staining, and there were significantly higher densities of both total and degranulated tryptase-positive mast cell subpopulation in the moderate periodontitis group (P <0.01) and even significantly higher subpopulation densities in the advanced periodontitis group by immunohistochemical staining, in which both total and degranulated mast cell densities were significantly higher in the advanced periodontitis group than those in the moderate periodontitis group (P <0.01) by both toluidine blue staining and immunohistochemical staining. There was significantly more severe periodontal inflammatory pathology in the advanced periodontitis group than in the moderate periodontitis group (P <0.01). CONCLUSION: These findings indicate a significant correlation among tryptase-positive mast cell density, the degree of their degranulation, and the human periodontitis severity, and the results of this study further indicate that mast cell degranulation appears to be associated with human periodontal disease. PMID- 22509746 TI - Single-step inline hydroxyapatite enrichment facilitates identification and quantitation of phosphopeptides from mass-limited proteomes with MudPIT. AB - Herein we report the characterization and optimization of single-step inline enrichment of phosphopeptides directly from small amounts of whole cell and tissue lysates (100-500 MUg) using a hydroxyapatite (HAP) microcolumn and Multidimensional Protein Identification Technology (MudPIT). In comparison to a triplicate HILIC-IMAC phosphopeptide enrichment study, ~80% of the phosphopeptides identified using HAP-MudPIT were unique. Similarly, analysis of the consensus phosphorylation motifs between the two enrichment methods illustrates the complementarity of calcium- and iron-based enrichment methods and the higher sensitivity and selectivity of HAP-MudPIT for acidic motifs. We demonstrate how the identification of more multiply phosphorylated peptides from HAP-MudPIT can be used to quantify phosphorylation cooperativity. Through optimization of HAP-MudPIT on a whole cell lysate we routinely achieved identification and quantification of ca. 1000 phosphopeptides from a ~1 h enrichment and 12 h MudPIT analysis on small quantities of material. Finally, we applied this optimized method to identify phosphorylation sites from a mass limited mouse brain region, the amygdala (200-500 MUg), identifying up to 4000 phosphopeptides per run. PMID- 22509750 TI - Efficacy of varying concentrations of subgingivally delivered metformin in the treatment of chronic periodontitis: a randomized controlled clinical trial. AB - BACKGROUND: Metformin (MF), a second-generation biguanide, is a commonly used oral antidiabetic drug that has been shown recently to stimulate osteoblasts and reduce alveolar bone loss. The present study aims to explore the efficacy of 0.5%, 1%, and 1.5% MF gel as a local drug delivery system in adjunct to scaling and root planing (SRP) for treatment of intrabony defects (IBDs) in patients with chronic periodontitis. METHODS: A total of 118 IBDs were treated with 0.5%, 1%, or 1.5% MF gel or placebo gel. Clinical parameters (modified sulcus bleeding index, plaque index, probing depth [PD], and clinical attachment level [CAL]) were recorded at baseline, 3 months, and 6 months, whereas radiographic parameters were recorded at baseline and 6 months. IBD depth at baseline and 6 months was calculated on standardized radiographs by using the image analysis software. The mean concentration of MF in gingival crevicular fluid was estimated by reverse-phase high-performance liquid chromatography. RESULTS: Mean PD reduction and mean CAL gain was found to be greater in MF groups than the placebo group at both 3 and 6 months. Furthermore, significantly greater reduction of IBD depth was found in the MF groups compared to the placebo group, with greatest reduction in 1% MF. CONCLUSIONS: The results of the present study show that local delivery of MF into the periodontal pocket stimulated significant increase in the PD reduction, CAL gain, and improved IBD depth reduction compared to placebo in adjunct to SRP. This can provide a new direction in the field of periodontal healing. PMID- 22509751 TI - Is there an interaction between polycystic ovary syndrome and gingival inflammation? AB - BACKGROUND: The aim of this study is to evaluate the gingival crevicular fluid (GCF), saliva, and serum concentrations of tumor necrosis factor-alpha (TNF alpha), TNF-alpha receptor-1 (TNF-alphaR1), TNF-alphaR2, and interleukin-6 (IL-6) in non-obese females with polycystic ovary syndrome (PCOS) and either clinically healthy periodontium or gingivitis. METHODS: Thirty-one females with PCOS and healthy periodontium, 30 females with PCOS and gingivitis, and 12 systemically and periodontally healthy females were included in the study. GCF, saliva, and serum samples were collected, and clinical periodontal measurements, body mass index, and Ferriman-Gallwey score (FGS) were recorded. Sex hormones, cortisol, and insulin levels were measured. TNF-alpha, TNF-alphaR1, TNF-alphaR2, and IL-6 were determined by enzyme-linked immunosorbent assay. Kruskal-Wallis followed by Bonferroni-corrected post hoc Mann-Whitney U tests were used to analyze the data. RESULTS: The PCOS + gingivitis group revealed significantly higher GCF, saliva, and serum IL-6 concentrations than the PCOS + healthy group (P <0.0001). The two PCOS groups exhibited significantly higher saliva TNF-alpha concentrations than the control group (P = 0.024 and P = 0.013, respectively). The FGS index was significantly higher in the PCOS + gingivitis group than the PCOS + healthy group (P = 0.030). The PCOS + gingivitis group revealed significantly higher insulin concentration than the PCOS + healthy and control groups (P = 0.014 and P <0.0001, respectively). Serum TNF-alpha, TNF-alphaRs, and serum, GCF, and salivary IL-6 levels correlated with the clinical periodontal measurements. CONCLUSIONS: PCOS and gingival inflammation appear to act synergistically on the proinflammatory cytokines IL-6 and TNF-alpha. Thus, PCOS may have an impact on gingival inflammation or vice versa. Additional studies are warranted to clarify the possible relationship between PCOS and periodontal disease. PMID- 22509753 TI - Quality assessment of systematic reviews on periodontal regeneration in humans. AB - BACKGROUND: Systematic reviews represent the highest form of evidence in the current hierarchy of evidence-based dentistry. Critical analysis of published systematic reviews may help to analyze their strengths and weaknesses and to identify areas that need future improvement. The aim of this overview is to determine and compare the quality of systematic reviews published in the field of periodontal regeneration using established checklists, such as the Assessment of Multiple Systematic Reviews (AMSTAR) guidelines. METHODS: A systematic search was conducted to retrieve reviews on periodontal regeneration in humans. A total of 14 systematic reviews were selected using a set of inclusion and exclusion criteria. Two independent reviewers appraised the quality of the selected reviews using AMSTAR guidelines. Each article was given an AMSTAR total score, based on the number of AMSTAR criteria that were fulfilled. The quality of included reviews was further assessed using a checklist proposed in 2003. RESULTS: Only one of the selected systematic reviews satisfied all the AMSTAR guidelines, whereas two reviews satisfied just two of the 11 items. This study shows that published systematic reviews on periodontal regeneration exhibit significant structural and methodologic variability. Quality assessment using the additional checklist further confirmed the variability in the way systematic reviews were conducted and/or reported. CONCLUSION: Consideration of guidelines for quality assessment, such as AMSTAR, when designing and conducting systematic reviews may increase the validity and clinical applicability of future reviews. PMID- 22509752 TI - Severe preeclampsia and maternal self-report of oral health, hygiene, and dental care. AB - BACKGROUND: Maternal periodontal disease diagnosed by a detailed oral health examination is associated with preeclampsia. Our objective was to measure the association between maternal self-report of oral symptoms/problems, oral hygiene practices, and/or dental service use before or during pregnancy and severe preeclampsia. METHODS: A written questionnaire was administered to pregnant females at the time of prenatal ultrasound and outcomes were ascertained by chart abstraction. The chi(2) test compared maternal oral symptoms/problems, hygiene practices, and dental service use between females with severe preeclampsia versus normotensive females. Multivariable logistic regression was used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for severe preeclampsia. RESULTS: A total of 48 (10%) of 470 females reported >=2 oral symptoms/problems in the 6 months before pregnancy and 77 (16%) since pregnancy. Fifty-one (11%) reported previous periodontal treatment. Twenty-eight (6%) of 470 developed severe preeclampsia. Females with a history of periodontal treatment were more likely to develop severe preeclampsia (aOR = 3.71; 95% CI = 1.40 to 9.83) than females without a history of periodontal treatment. Self-reported oral health symptoms/problems, oral hygiene practices, or dental service use before or during pregnancy were not associated with severe preeclampsia when considered in the context of other maternal risk factors. CONCLUSION: Maternal self-report of previous periodontal treatment before pregnancy is associated with severe preeclampsia. PMID- 22509754 TI - Effect of a collagen membrane combined with a porous titanium membrane on exophytic new bone formation in a rabbit calvarial model. AB - BACKGROUND: Previous studies showed that the use of a porous titanium membrane (TM) for exophytic bone regeneration does not effectively inhibit the infiltration of undesired tissue. Therefore, this study examines the effect of resorbable collagen membranes, such as cross-linked type I collagen membrane (BA) and double-layered porcine collagen membrane (BG), on the promotion of exophytic bone formation in guided bone regeneration when used in conjunction with a porous TM. METHODS: Thirty-six male New Zealand white rabbits were used in this study. Six rabbits were allotted to each test group. After decorticating the parietal bone, with or without filling the inner space with a freeze-dried cortical bone allograft (OG), the collagen membranes were fixed with metal pins. The experimental groups were divided into the following six groups: TM only, TM + OG, TM + BA, TM + BG, TM + OG + BA, and TM + OG + BG. The experimental animals were sacrificed at 8 and 16 weeks after surgery. Non-decalcified specimens were prepared and processed for histologic observations. The newly formed bone (percentage) was measured histomorphometrically. RESULTS: BG combined with TM promoted new bone formation and maturation by inhibiting the infiltration of connective tissue. However, BA had no significant effect on new bone formation. The amount of new bone formation was higher at 16 weeks than at 8 weeks, but the difference was not significant. At 16 weeks, the best result for newly formed bone was with TM + OG + BG, with a significant difference from TM alone and TM + BA. CONCLUSIONS: Regardless of the use of graft materials, BG combined with TM promoted more bone formation than BA combined with TM or TM alone. Thus, using a commercial collagen membrane to cover a TM can promote new exophytic bone formation. PMID- 22509755 TI - Effect of the timing of restoration on implant marginal bone loss: a systematic review. AB - BACKGROUND: The advancement in implant dentistry has allowed shortened treatment time by restoring the implants earlier. Whether the timing of restoration has an impact on implant marginal bone level has not been systematically analyzed. The aim of this study is to compare marginal bone loss (MBL) between implants that were restored with the following protocols: 1) immediate restoration/loading (IR/L); 2) early loading (EL); and 3) conventional loading (CL). METHODS: An electronic literature search from three databases (until November 2011) and a hand search in implant-related journals were conducted. Clinical human studies in English language that had reported a comparison of MBL between implants with IR/L, EL, or CL with >=12-month follow-up were included. In addition, the minimal number of implants had to be 10 for each group. Implants with both immediate placement (IP) and delayed placement (DP) were included and analyzed separately. An assessment of the publication bias for the included randomized clinical trials (RCTs) was performed. RESULTS: The initial search resulted in 1,640 articles, of which 27 articles in full text were further evaluated for eligibility. Finally, 11 studies (eight RCTs, two controlled clinical trials, and one retrospective study) were qualified and classified into four groups: 1) IR/L + DP versus CL + DP (n = 6 articles); 2) IR + DP versus EL + DP (n = 2 articles); 3) EL + DP versus CL + DP (n = 1 article); and (4) IL + IP versus CL + IP (n = 2 articles). A meta-analysis performed for group 1 showed 0.09 mm (95% confidence interval = 0.27 to 0.09 mm) difference in the mean MBL, favoring the IR/L protocol but without significant difference (P = 0.33). No significant difference in MBL was found for groups 2 through 4 after adjusting for the implant placement level. The eight RCTs were determined to be at moderate-to-high risk of publication bias. CONCLUSIONS: This meta-analysis does not show an effect of the timing of restorations on implant MBL. The selection of restoration protocols should be based on factors other than MBL. PMID- 22509756 TI - Immediate implant placement in infected sites: a case series. AB - BACKGROUND: Immediate implant placement has several advantages, such as reduction in the number of surgical treatments and reduction of the time between tooth extraction and the placement of the definitive prosthesis. However, there are still some situations that could jeopardize the success of the aforesaid therapy, such as the presence of an infection caused by periodontal disease or periapical lesions. The aim of this case series is to evaluate the clinical success of implants placed in fresh extraction sockets that showed clinical signs of periodontal disease. METHODS: Thirteen patients (six males and seven females, 24 to 65 years old) are included in this case series. After initial examination and treatment planning, all patients underwent the periodontal treatment deemed necessary to facilitate wound healing. Twenty teeth were extracted as a result of an infection. Second-stage surgery was performed 4 months after the initial procedure. The following clinical parameters were evaluated for each patient at the time of implant placement and at the end of the 12-month follow-up period: 1) clinical attachment level (CAL); 2) presence or absence of mobility; 3) presence or absence of pain; and 4) presence or absence of suppuration. The bone level was measured as the distance from the implant shoulder to the first bone-implant contact (distance bone-implant [DIB]) by periapical radiographs. The stability and health of the soft tissue were clinically evaluated by means of the plaque score. RESULTS: The healing period was uneventful for all the patients. All the implants were osseointegrated. At the end of the 12-month follow-up period, patients were asymptomatic and showed no signs of infection or bleeding when probed. The mean CAL at the mid-buccal location per implant was 0.8 mm at baseline and 0.9 mm at the end of the follow-up. The mean width of keratinized mucosa measured at the mid-buccal location per implant at baseline and 1-year visits was 3.2 +/- 0.4 mm and 3.3 +/- 0.5 mm, respectively. The periapical radiographs, obtained in a standardized manner, revealed a mean increase of 0.5 mm in the DIB value. At the 12-month follow-up, the presence of plaque was observed in 44 of the 80 sites analyzed. CONCLUSION: Based on the results of this case series, placement of implants in fresh extraction sockets affected by infection may be a valid operative technique that leads to predictable results if adequate preoperative and postoperative care is taken. PMID- 22509757 TI - Control of cell adhesion by mechanical reinforcement of soft polyelectrolyte films with nanoparticles. AB - Chemical cross-linking is the standard approach to tune the mechanical properties of polymer coatings for cell culture applications. Here we show that the elastic modulus of highly swollen polyelectrolyte films composed of poly(L-lysine) (PLL) and hyaluronic acid (HA) can be changed by more than 1 order of magnitude by addition of gold nanoparticles (AuNPs) in a one-step procedure. This hydrogel nanoparticle architecture has great potential as a platform for advanced cell engineering application, for example remote release of drugs. As a first step toward utilization of such films for biomedical applications we identify the most favorable polymer/nanoparticle composition for optimized cell adhesion on the films. Using atomic force microscopy (AFM) we determine the following surface parameters that are relevant for cell adhesion, i.e., stiffness, roughness, and protein interactions. Optimized cell adhesion is observed for films with an elastic modulus of about 1 MPa and a surface roughness on the order of 30 nm. The analysis further shows that AuNPs are not incorporated in the HA/PLL bulk but form clusters on the film surface. Combined studies of the elastic modulus and surface topography indicate a cluster percolation threshold at a critical surface coverage above which the film stiffness drastically increases. In this context we also discuss changes in film thickness, material density and swelling ratio due to nanoparticle treatment. PMID- 22509759 TI - Peanut sensitization during the first 5 yr of life is associated with elevated levels of peanut-specific IgG. AB - BACKGROUND: Allergen-specific IgE antibodies are implicated in allergic diseases while allergen-specific IgG antibodies have been proposed to prevent allergic reactions. The objective for this study was to study whether the immune response (IgG and IgG4) to peanut differs in IgE-sensitized and non-sensitized young children. METHODS: A total of 239 children have been followed prospectively from birth to 5 yr of age. The levels of IgG and IgG4 to peanut, Ara h 2, and Ara h 8 were analyzed at 2 and 5 yr of age and related to IgE sensitization and peanut consumption. RESULTS: The levels of peanut-specific IgG and IgG4 were significantly higher in peanut-sensitized children at 2 and 5 yr of age when compared with non-sensitized children and children sensitized to other food/inhalant allergens. A strong correlation was seen between levels of peanut-specific IgG/IgG4-ratios and peanut-specific IgE at 5 yr of age. Children avoiding peanuts, a subgroup of the peanut sensitized, had statistically significant higher levels of IgE to peanut and a tendency of higher IgG and IgG4 levels to peanut. In the avoidance group, significant correlations between IgE and IgG/IgG4 to peanut were found compared with children eating peanuts. CONCLUSION: Peanut-specific IgG or IgG4 levels were elevated in peanut sensitized children especially those avoiding peanuts. In our study, IgG and IgG4 do not seem to indicate tolerance or protection from sensitization. PMID- 22509762 TI - The reality of pediatric allergy and immunology in Spain. PMID- 22509760 TI - IL-31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis. AB - Recently, we could show that IL-31 serum levels are significantly increased in adult patients with atopic dermatitis compared with skin healthy controls. However, the regulation of IL-31 in children with atopic dermatitis so far is not clear. Thus, we analyzed IL-31 serum levels together with IL-4, IL-13, ECP, and total IgE levels in 60 children with extrinsic, in five children with intrinsic atopic dermatitis, and 20 non-atopic healthy children. Further, we determined the SCORAD score, sleeplessness, and pruritus severity in all children with atopic dermatitis. IL-31 was significantly increased in children with the intrinsic and extrinsic type of atopic dermatitis compared with non-atopic healthy children (p < 0.05-0.001). Further, IL-31 serum levels significantly correlated with SCORAD score (p < 0.01), sleeplessness (p < 0.05), IL-4, and IL-13 levels (p < 0.01) in children with extrinsic atopic dermatitis. There was no correlation of IL-31 with pruritus, total IgE Ab, and ECP levels, whereas ECP levels significantly correlated with the SCORAD score in children with extrinsic atopic dermatitis. Together, IL-31 represents an interesting cytokine especially with regard to the severity of the inflammatory process indicated by the correlation of IL-31 with SCORAD score and Th2 cytokines including IL-4 and IL-13 in children with extrinsic atopic dermatitis. PMID- 22509763 TI - Multivalent peptidomimetic conjugates: a versatile platform for modulating androgen receptor activity. AB - We introduce a family of multivalent peptidomimetic conjugates that modulate the activity of the androgen receptor (AR). Bioactive ethisterone ligands were conjugated to a set of sequence-specific peptoid oligomers. Certain multivalent peptoid conjugates enhance AR-mediated transcriptional activation. We identify a linear and a cyclic conjugate that exhibit potent anti-proliferative activity in LNCaP-abl cells, a model of therapy-resistant prostate cancer. The linear conjugate blocks AR action by competing for ligand binding. In contrast, the cyclic conjugate is active despite its inability to compete against endogenous ligand for binding to AR in vitro, suggesting a non-competitive mode of action. These results establish a versatile platform to design competitive and non competitive AR modulators with potential therapeutic significance. PMID- 22509764 TI - Novel 1,2,4-triazolo[1,5-a]pyridines and their fused ring systems attenuate oxidative stress and prolong lifespan of Caenorhabiditis elegans. AB - In this paper we report the synthesis of some novel 1,2,4-triazolo[1,5-a]pyridine and azolotriazolopyridine ring systems. The products were screened for various types of activity like antibacterial, antifungal, and antioxidative activity. Compound 13 was found to pose an antioxidative activity. In addition, this compound was found to extend the life span of Caenorhabiditis elegans under standard laboratory conditions and reduces both heat and chemical induced oxidative stress in C. elegans in a dose-dependent manner. Furthermore, treatment of worms with compound 13 was found to significantly attenuate the formation of advanced glycation end products and malondialdehyde in a dose dependent manner. PMID- 22509765 TI - Triangulating the genetic basis of adaptation to multifarious selection. AB - Understanding how natural populations adapt to their local environments is a major research theme for ecological genomics. This endeavour begins by sleuthing for shared genetic similarities among unrelated natural populations sharing adaptive traits to documented selective pressures. When the selective pressures have low dimensionality, and the genetic response is localized to a few genes of major effect, this detective work is relatively straightforward. However, in the real world, populations face a complex mixture of selective pressures and many adaptive responses are the result of changes in quantitative traits that have a polygenic genetic basis. This complex relationship between environment and adaptation presents a significant challenge. How can we begin to identify drivers of adaptation in natural settings? In this issue of Molecular Ecology, Orsini et al. (2012) take advantage of the biological attributes of the freshwater microcrustacean Daphnia (Fig. 1) to disentangle multidimensional selection's signature on the genome of populations that have repeatedly evolved adaptive responses to isolated selective pressures including predation, parasitism and anthropogenic changes in land use. Orsini et al. (2012) leverage a powerful combination of spatially structured populations in a geographic mosaic of environmental stressors, the historical archive of past genotypes preserved in lake-bottom sediments and selection experiments to identify sets of candidate genomic regions associated with adaptation in response to these three environmental stressors. This study provides a template for future investigation in ecological genomics, combining multiple experimental approaches with the genomic investigation of a well-studied ecological model species. PMID- 22509766 TI - Behind every great ant, there is a great gut. AB - Ants are quite possibly the most successful insects on Earth, with an estimated 10,000 species worldwide, making up at least a third of the global insect biomass, and comprising several times the biomass of all land vertebrates combined. Ant species have diverse trophic habits, including herbivory, hunting/gathering, scavenging and predation and are distributed in diverse habitats, performing a variety of important ecosystem functions. Often they exert these functions while engaging in symbiotic associations with other insects, plants or microbes; however, remarkably little work has focused on the potential contribution of the ants' gut symbionts. This issue of Molecular Ecology contains a study by Anderson et al. (2012), who take a comparative approach to explore the link between trophic levels and ant microbiomes, specifically, to address three main questions: (i) Do closely related herbivorous ants share similar bacterial communities? (ii) Do species of predatory ants share similar bacterial communities? (iii) Do distantly related herbivorous ants tend to share similar bacterial communities? By doing so, the authors demonstrate that ants with similar trophic habits appear to have relatively conserved gut microbiomes, suggesting symbiont functions that directly relate to dietary preference of the ant host. These findings suggest an ecological role of gut symbionts in ants, for example, in metabolism and/or protection, and the comparative approach taken supports a model of co-evolution between ant species and specific core symbiont microbiomes. This study, thereby, highlights the omnipresence and importance of gut symbioses-also in the Hymenoptera-and suggests that these hitherto overlooked microbes likely have contributed to the ecological success of the ants. PMID- 22509767 TI - Primary hyperoxaluria presenting with early renal allograft dysfunction. PMID- 22509768 TI - Mega-oesophagus in a young woman with encapsulating peritoneal sclerosis. PMID- 22509769 TI - Rationale and methods of discovering hormetins as drugs for healthy ageing. AB - INTRODUCTION: Mild stress-induced hormesis is becoming increasingly attractive as an ageing interventional strategy and is leading to the discovery of hormesis inducing compounds called hormetins. Almost 50 years of modern biogerontolgical research has established a clear framework regarding the biological basis of ageing and longevity, and it is now generally accepted that ageing occurs in spite of the presence of complex pathways of maintenance, repair and defense, and there is no 'enemy within.' This viewpoint makes modulation of ageing different from the treatment of one or more age-related diseases. A promising strategy to slow down ageing and prevent or delay the onset of age-related diseases is that of mild stress-induced hormesis by using hormetins. AREAS COVERED: The article presents the rationale and a strategy for discovering novel hormetins as potential drugs for ageing intervention by elucidating multiple stress responses of normal human cells. Furthermore, it discusses the first steps in identifying prospective hormetin drugs and provides a recent example of successful product development, based on the ideas of hormesis and by following the strategy described here. EXPERT OPINION: As a biomedical issue, the biological process of ageing underlies several major diseases, and although the optimal treatment of every disease, irrespective of age, is a social and moral necessity, preventing the onset of age-related diseases by intervening in the basic process of ageing is the best approach for achieving healthy ageing and for extending the healthspan. PMID- 22509770 TI - Printed carbon microelectrodes for electrochemical detection of single vesicle release from PC12 cells. AB - We present a disposable system for recording neurotransmitter release from individual cells in vitro. A simple yet reliable microelectrode fabrication process is introduced using screen-printed carbon paste. It allows rapid fabrication of devices at low costs without standard clean-room technology. We demonstrate functionality of the system by real-time observation of vesicle release from single PC12 (rat pheochromocytoma) cells. The cells are cultured directly on the chip and can be used for immediate or long-term in vitro experiments. Thus, our approach may serve as a platform for pharmacological cell culture studies. PMID- 22509771 TI - NMR characterization of saccharides in Italian honeys of different floral sources. AB - The saccharide profiles of 5 different botanical species in 86 Italian honey samples were investigated by 1H and 1H-13C NMR spectroscopy. Nineteen saccharides were identified in the aqueous extracts, namely, fructose, glucose, gentiobiose, isomaltose, kojibiose, maltose, maltulose, melibiose, nigerose, palatinose, sucrose, turanose, erlose, isomaltotriose, kestose, maltotriose, melezitose, raffinose, and maltotetraose. PCA performed on NMR spectral regions, in particular between 4.400 and 5.700 ppm and the fructose signal at 4.050 ppm, revealed a partial sample grouping. The score contribution plots derived from PCA performed using the mean values for the buckets of the anomeric region for each floral source allowed the identification of saccharides characterizing different honeys. OPLS-DA models were further evaluated to confirm the previous findings. OPLS-DA models were also built to highlight differences between polyfloral and high mountain polyfloral honeys and between high mountain polyfloral and rhododendron honeys, both collected at high altitude; S-plots highlighted the characteristic saccharides. PMID- 22509772 TI - Pulmonary vein antral isolation and nonpulmonary vein trigger ablation without additional substrate modification for treating longstanding persistent atrial fibrillation. AB - INTRODUCTION: Effectiveness of antral pulmonary vein isolation (PVAI) and ablation of non-PV triggers (non-PVTA) in controlling longstanding persistent atrial fibrillation (AF) has not been reported. We sought to describe clinical outcomes with this ablation strategy in patients (pts) followed for at least 1 year. METHODS: Two hundred pts underwent PVAI for longstanding persistent AF and were followed for recurrence. Thirty-three pts with <1-year follow-up and 37 pts with additional RF atrial ablation were excluded, leaving 130 pts for analysis. RESULTS: All 130 pts (108 men, mean LA 4.7 +/- 0.6 cm, mean AF duration of 38 +/- 44 months) underwent PVAI with entrance/exit block. In addition, 24 pts (15 pts during the initial procedure and 9 additional pts at repeat ablations) had 40 non PVTA, including 3 with AVNRT. During follow-up, atrial flutter (AFL) was noted in 7 (5%) pts. The AF-free survival after single procedure without antiarrhythmic drugs (AAD) was 38%. Repeat AF or AFL ablation was performed in 37 pts (28%) with PV reconnection uniformly identified (3.7 +/- 0.5 veins/pt). During mean follow up of 41.1 +/- 23.8 months (range 12-103 months), 85/130 pts (65%) were in sinus rhythm with 65 pts (50%) off AAD, 20 pts (15%) on AAD. Additionally, 9 pts (7%) have had rare episodes of AF such that 72% of pts have had good long-term clinical outcome. Of the 36 pts with recurrent AF, 20 pts have not had a repeat procedure. CONCLUSIONS: PVAI with non-PVTA for longstanding persistent AF provides good long-term AF control in over 70% of patients with infrequent (5%) AFL. AAD therapy and repeat PVAI may be required for this optimal outcome. PMID- 22509773 TI - New conjugated polymers for photoinduced unwinding of DNA supercoiling and gene regulation. AB - Three cationic polythiophene derivatives (P1, P2, P3) were synthesized and characterized. Under white light irradiation (400-800 nm), they sensitize oxygen molecule in the surrounding to generate reactive oxygen species (ROS) that can efficiently unwind the supercoiled DNA in vitro. Further study shows that this relaxation of the DNA supercoiling results in the decrease of gene (pCX-EGFP plasmid) expression level. The ability of these conjugated polymers for regulating gene expression will add a new dimension to the function of conjugated polymers. PMID- 22509774 TI - A nationwide population-based study on the association between chronic periodontitis and erectile dysfunction. AB - AIM: To explore the association between chronic periodontitis (CP) and erectile dysfunction (ED) by using a nationwide, population-based dataset with a retrospective case-control design in Taiwan. MATERIAL AND METHODS: We identified 32,856 patients with ED as cases and randomly selected 162,480 patients as controls. Conditional logistic regression analyses were performed to investigate the association between ED and having been previously diagnosed with CP. RESULTS: Of the sampled patients 24,294 (12.3%) had been diagnosed with CP prior to the index date; this included 8825 cases (26.9% of the patients with ED) and 15,469 controls (9.4% of the comparison cohort). After adjusting for patient monthly income, age, geographic location, hypertension, diabetes, hyperlipidaemia, coronary heart disease, obesity, and alcohol abuse/alcohol dependence syndrome, patients with ED were more likely to have been diagnosed with CP prior to the index date than controls (OR = 3.35, 95% CI = 3.25-3.45, p < 0.001). In addition, the association was much stronger among the population aged less than 30 years (OR = 4.54, 95% CI = 3.81-5.40) and the group aged over than 69 years (OR = 4.84, 95% CI = 4.35-5.39). CONCLUSIONS: Our study demonstrated an association between ED and having been previously diagnosed with CP. PMID- 22509775 TI - A cost-utility analysis of pregabalin versus duloxetine for the treatment of painful diabetic neuropathy. AB - The objective of the current study was to determine the cost-utility of pregabalin versus duloxetine for treating painful diabetic neuropathy (PDN) using a decision tree analysis. Literature searches identified clinical trials and real world studies reporting the efficacy, tolerability, safety, adherence, opioid usage, health care utilization, and costs of pregabalin and duloxetine. The proportions of patients reported in the included studies were used to determine probabilities in the decision tree model. The base-case model included the Food and Drug Administration (FDA)-approved doses of pregabalin (300 mg/day) and duloxetine (60 mg/day), whereas "real-world" sensitivity analyses explored the effects over a range of doses (pregabalin 75-600 mg/day, duloxetine 20-120 mg/day). A 6-month time horizon and a US third-party payer perspective were chosen for the study. Outcomes from the model were expressed as cost per quality adjusted life-year (QALY). In the base-case model, duloxetine cost less and was more effective than pregabalin (incremental cost -$187, incremental effectiveness 0.011 QALYs). Results from two real-world sensitivity analyses indicated that duloxetine cost $16,300 and $20,667 more per additional QALY than pregabalin. Using a decision tree model that incorporated both clinical trial and real-world data, duloxetine was a more cost-effective option than pregabalin in the treatment of PDN from the perspective of third-party payers. PMID- 22509776 TI - Phototriggered DNA complexation and compaction using poly(vinyl alcohol) carrying a malachite green moiety. AB - Photoinduced DNA compaction was performed using the interaction of DNA with a photoresponsive random copolymer of poly(vinyl alcohol) carrying a malachite green moiety (PVAMG). Although PVAMG does not have any affinity for DNA under dark conditions, it undergoes photoionization upon exposure to UV light, consequently resulting in a cationic binding site for DNA. Electrophoresis results demonstrated that irradiation of PVAMG retarded the DNA bands due to their complexation, whereas the bands remained unchanged under dark conditions. The binding of PVAMG to DNA occurs at a cationic site/DNA phosphate ratio of approximately 0.036. Single-molecule observations of DNA by fluorescence microscopy revealed that irradiation of PVAMG induced a coil-globule transition in the DNA molecule. Complete compaction of DNA has been accomplished at a cationic site/DNA phosphate ratio >8.0, indicating that PVAMG offers an effective system to photochemically trigger DNA compaction. PMID- 22509777 TI - Characterization of microorganisms isolated from counterfeit toothpaste. AB - The appearance of potentially counterfeit "Colgate" toothpaste on the American market prompted a criminal investigation by the United States Food and Drug Administration (FDA), including the collection of c. 60,000 tubes of toothpaste from retail outlets and product distributors. Microbiological testing was performed based on the FDA Bacteriological Analytical Manual, which determined the presence and number of bacteria present in the products. Bacteria were isolated from each "Colgate" variety; up to 2 * 10(6) cfu/g were isolated from some of the product units. Using conventional microscopic and biochemical bacterial identification methods, most of the bacteria isolated from these samples were Gram-negative rods of several genera, including Pseudomonas, Serratia, and Klebsiella. Most of the organisms isolated represent opportunistic pathogens, and therefore, counterfeit "Colgate" toothpaste containing high levels of bacteria pose a human health hazard. PMID- 22509778 TI - Novel whole cell adhesion assays of three isolates of the fouling diatom Amphora coffeaeformis reveal diverse responses to surfaces of different wettability. AB - Whole cell, strength of adhesion assays of three different isolates of the fouling diatom Amphora coffeaeformis were compared using a hydrophilic surface viz. acid washed glass (AWG), and a hydrophobic surface viz. a self assembled monolayer (SAM) of undecanethiol (UDT). Assays were performed using a newly designed turbulent flow channel that permits direct observation and recording of cell populations on a test surface. Exposure to continuous shear stress over 3 h revealed that the more motile isolate, WIL2, adhered much more strongly to both test surfaces compared to the other two strains. When the response of the isolates to shear stress after 3 h was compared, there was no significant difference in the percentage of cells removed, irrespective of surface wettability. Cells of the three isolates of A. coffeaeformis varied significantly in their response to different surfaces during initial adhesion, indicating the presence of a wide range of 'physiological races' within this species. PMID- 22509779 TI - LB3D: a protein three-dimensional substructure search program based on the lower bound of a root mean square deviation value. AB - Searching for protein structure-function relationships using three-dimensional (3D) structural coordinates represents a fundamental approach for determining the function of proteins with unknown functions. Since protein structure databases are rapidly growing in size, the development of a fast search method to find similar protein substructures by comparison of protein 3D structures is essential. In this article, we present a novel protein 3D structure search method to find all substructures with root mean square deviations (RMSDs) to the query structure that are lower than a given threshold value. Our new algorithm runs in O(m + N/m(0.5)) time, after O(N log N) preprocessing, where N is the database size and m is the query length. The new method is 1.8-41.6 times faster than the practically best known O(N) algorithm, according to computational experiments using a huge database (i.e., >20,000,000 C-alpha coordinates). PMID- 22509780 TI - Shared care between specialised psychiatric services and primary care: the experiences and expectations of General Practitioners in Ireland. AB - Objective. The study aims to explore the views of General Practitioners in Ireland on shared care between specialised psychiatric services and primary care. Method. A self-administered questionnaire was designed and posted to 400 randomly selected General Practitioners working in Ireland. Results. Of the respondents, 189 (94%) reported that they would support a general policy on shared care between primary care and specialised psychiatric services for patients who are stable on their treatment. However, 124 (61.4%) reported that they foresaw difficulties for patients in implementing such a policy including: a concern that primary care is not adequately resourced with allied health professionals to support provision of psychiatric care (113, 53.2%); a concern this would result in increased financial burden on some patients (89, 48.8%); a lack of adequate cooperation between primary care and specialised mental health services (84, 41.8%); a concern that some patients may lack confidence in GP care (55, 27.4%); and that primary care providers are not adequately trained to provide psychiatric care (29, 14.4% ). Conclusion. The majority of GPs in Ireland would support a policy of shared care of psychiatric patients; however they raise significant concerns regarding practical implications of such a policy in Ireland. PMID- 22509781 TI - Neurofilament heavy chain and heat shock protein 70 as markers of seizure-related brain injury. AB - PURPOSE: Status epilepticus (SE) has deleterious effects on brain tissue, but whether brief recurrent seizures may also damage neurons represents a matter of controversy. Therefore, it remains a central area of epilepsy research to identify individuals at risk where disease progression can be potentially prevented. Biomarkers may serve as tools for such identification. Thus the present study aimed at analyzing the levels of heat shock protein 70 (HSP-70, also designated as HSPA1A) and neurofilament heavy chain protein (NfH(SMI35) ) in cerebrospinal fluid (CSF) of patients with seizures of different severity. METHODS: Forty-one patients were included, of whom 20 patients had a single generalized tonic-clonic seizure (GTCS) episode (SS), 11 had repetitive GTCS (RS), and 10 experienced convulsive SE. The control group consisted of 18 subjects. HSP-70 levels were measured using a conventional enzyme-linked immunosorbent assay (ELISA), whereas the NfH(SMI35) protein levels were detected by an electrochemiluminescence (ECL) immunoassay. KEY FINDINGS: Patients with SE (p < 0.001) and RS (p < 0.05) had significantly higher NfH(SMI35) levels than controls, and SE was associated with increased concentrations when compared with SS (p < 0.001). NfH(SMI35) levels in SS did not differ from controls. Patients with SE had significantly raised HSP-70 levels compared to RS (p < 0.05), SS (p < 0.05), and controls (p < 0.001). SS and RS did not differ from each or from controls. Levels of NfH(SMI35) and HSP-70 showed a significant correlation (r = 0.34; p = 0.007) in the group of all study subjects, which was not apparent when controls and patients with seizures were considered separately. The correlation between NfH(SMI35) and HSP-70 tended to be inverse in patients with SE, but it did not reach statistical significance (r = -0.3; p > 0.05). SIGNIFICANCE: Studying biochemical markers as additional quantitative tools for the measurement of neuronal damage (especially subclinical), complementary to available techniques of imaging, and clinical assessment might prove useful for identifying patients at risk of accumulating neuronal injury resulting from uncontrolled seizures. NfH(SMI35) and HSP-70 are of potential value as sensitive and specific biomarkers of seizure-related pathologic events. Future longitudinal studies are needed to monitor such patients by correlating biochemical, neuroimaging, and clinical methods of assessment. PMID- 22509782 TI - Bone healing around titanium implants in two rat colitis models. AB - OBJECTIVE: Crohn's disease is a chronic inflammatory process that has recently been associated with a higher risk of early implant failure. Herein we provide information on the impact of colitis on peri-implant bone formation using preclinical models of chemically induced colitis. METHODS: Colitis was induced by intrarectal instillation of 2,4,6-trinitro-benzene-sulfonic-acid (TNBS). Colitis was also induced by feeding rats dextran-sodium-sulfate (DSS) in drinking water. One week after disease induction, titanium miniscrews were inserted into the tibia. Four weeks after implantation, peri-implant bone volume per tissue volume (BV/TV) and bone-to-implant contacts (BIC) were determined by histomorphometric analysis. RESULTS: Cortical histomorphometric parameters were similar in the control (n = 10), DSS (n = 10) and TNBS (n = 8) groups. Cortical BV/TV was 92.2 +/- 3.7%, 92.0 +/- 3.0% and 92.6 +/- 2.7%. Cortical BIC was 81.3 +/- 8.8%, 83.2 +/- 8.4% and 84.0 +/- 7.0%, respectively. No significant differences were observed when comparing the medullary BV/TV and BIC (19.5 +/- 6.4%, 16.2 +/- 5.6% and 15.4 +/- 9.0%) and (48.8 +/- 12.9%, 49.2 +/- 6.2 and 41.9 +/- 11.7%), respectively. Successful induction of colitis was confirmed by loss of body weight and colon morphology. CONCLUSIONS: The results suggest bone regeneration around implants is not impaired in chemically induced colitis models. Considering that Crohn's disease can affect any part of the gastrointestinal tract including the mouth, our model only partially reflects the clinical situation. PMID- 22509783 TI - Monodisperse gas-filled microparticles from reactions in double emulsions. AB - We present a strategy for preparing size-controlled gas-filled microparticles using two aqueous components that chemically react to produce the gas. We use a dual-bore microfluidic device to isolate the reactants of two gas-producing reactions until they are encapsulated in the outer droplet. The reactants in the monodisperse droplets merge and produce the gas bubbles, which are stabilized with a surfactant and form the core of the microparticles. The number and size of the generated gas bubbles are governed by the gas-forming reaction used. Our versatile strategy can be applied to a wide range of gas-producing reactions. PMID- 22509786 TI - Pharmacokinetics of Py-Im polyamides depend on architecture: cyclic versus linear. AB - The pharmacokinetic properties of three pyrrole-imidazole (Py-Im) polyamides of similar size and Py-Im content but different shape were studied in the mouse. Remarkably, hairpin and cyclic oligomers programmed for the same DNA sequence 5' WGGWWW-3' displayed distinct pharmacokinetic properties. Furthermore, the hairpin 1 and cycle 2 exhibited vastly different animal toxicities. These data provide a foundation for design of DNA binding Py-Im polyamides to be tested in vivo. PMID- 22509787 TI - Partial anomalous pulmonary venous connection and pulmonary arterial hypertension. AB - BACKGROUND AND OBJECTIVE: Isolated partial anomalous pulmonary venous connection (PAPVC) has been implicated as a cause of pulmonary arterial hypertension (PAH); however this condition is often overlooked in the diagnostic work up of patients with PH. We studied the prevalence of PAH both in patients with isolated PAPVC or associated with other congenital heart diseases (CHD) such as atrial septal defect (ASD). We also aimed to identify factors related to the presence of PAH in these patients. METHODS: We retrospectively analyzed data from the Adult CHD database at the Cleveland Clinic, U.S.A. between October 2005-2010. We included all patients diagnosed with PAPVC with or without other CHD. We excluded all patients with previous corrective surgeries. RESULTS: We identified 14 (2.5%) patients with PAPVC. Group I included patients with PAPVC (with or without patent foramen ovale (PFO)). Group II included patients with PAPVC associated with other CHD. PAH was seen in six (6/14, 42.8%) patients, two (2/7, 28.5%) in group I and four (4/7, 57.1%) in group II (P = 0.3). The mean pulmonary artery pressure in all patients (n = 14) was 29.5 +/- 13.8 mm Hg. group I had a mean PAP of 23.6 +/- 6.6 mm Hg as compared to 33.7 +/- 16.5 mm Hg for group II (P = 0.34). The two patients in group I with PAH had either two anomalous pulmonary veins or a condition (sickle cell disease) that could potentially explain the haemodynamic findings. CONCLUSIONS: Patients with PAPVC (with or without PFO) in the absence of other CHD had normal pulmonary arterial pressure (PAP) unless they have two pulmonary veins with anomalous return or associated conditions known to cause PAH. PMID- 22509788 TI - Lewis acid-catalyzed, copper(II)-mediated synthesis of heteroaryl thioethers under base-free conditions. AB - A Lewis acid (Ag(I), Ni(II), or Fe(II)) catalyzed, Cu(II)-mediated thiolation reaction between heteroarenes and thiols was achieved with good yield under base free conditions. DMSO could serve as an effective methylthiolation reagent for the synthesis of heterocyclic methyl thioethers. PMID- 22509789 TI - Aerosol-based fabrication of biocompatible organic-inorganic nanocomposites. AB - Several novel nanoparticle composites were conveniently obtained by appropriately reacting freshly produced aerosol metal nanoparticles with soluble organic components. A serial reactor consisting of a spark particle generator coupled to a collison atomizer was used to fabricate the new materials, which included nanomagnetosols (comprising iron nanoparticles, the drug ketoprofen, and a Eudragit shell), hybrid nanogels (comprising iron nanoparticles and an N isopropylacrylamide, NIPAM, gel), and nanoinorganics (gold immobilized silica). A fourth hybrid material, consisting of iron-gold nanoparticles and NIPAM) was obtained via an aerosol into liquid configuration, in which aerosol iron-gold particles were collected into a NIPAM/ethanol solution and then formed into nanogels with NIPAM under ultrasonic treatment. The strategy outlined in this work is potentially generalizable as a new platform for creating biocompatible nanocomposites, using only clinically approved starting materials in a single pass and under low-temperature conditions. PMID- 22509790 TI - Profile of trans fatty acids (FAs) including trans polyunsaturated FAs in representative fast food samples. AB - The content of trans fat in foods is most commonly determined by summing the levels of individual trans fatty acids (FAs), analyzed as FA methyl esters (FAME) by gas chromatography. Current Official Methods of the American Oil Chemists' Society (AOCS) enable quantitation of total trans fat in foods but were not designed for the determination of transFA isomeric compositions. In the present study, the content of trans fat in 32 representative fast food samples ranged from 0.1 to 3.1 g per serving, as determined according to AOCS Official Method Ce 1j-07. Further analysis of FAME using the 200 m SLB-IL111 ionic liquid column yielded quantitative results of total, trans, saturated, and cis unsaturated fat that were comparable to those of Method Ce 1j-07 and also allowed for the complementary determination of individual trans 18:1, trans 18:2, and trans 18:3 FA isomeric compositions under conditions suitable for routine sample analysis. PMID- 22509791 TI - A clinical report on the use of closed tray, hex-lock-friction-fit implant impression copings. AB - Abstract AbstractThe precision of an impression determines the subsequent accuracy and fit of thefinal restoration. Therefore, the ultimate search is for the most accurate impressionmaterial and technique that is also the most efficient and least time consuming. One ofthe major debates in implant dentistry has been between the pick up versus the transferimpression technique. The pick up technique is widely accepted as the more accurate.However, the conventional transfer technique is simpler and less time consuming. TheHex-Lock-Friction-Fit impression coping (AB Dental Devices(r)) combines theadvantages of both the transfer impression technique and the pick up impressiontechnique. In this article we will review the relevant literature, discuss the advantages ofthis unique implant impression technique and present some related clinical cases. PMID- 22509792 TI - A minimally invasive technique for the detection and analysis of pulmonary fat embolism: a feasibility study. AB - We investigated the feasibility of postmortem percutaneous needle biopsy (PNB) for obtaining pulmonary samples adequate for the study of pulmonary fat embolism (PFE). Samples of both lungs were obtained from 26 cadavers via two different methods: (i) PNB and (ii) the double-edged knife technique, the gold standard at our institute. After water storage and Sudan III staining, six forensic pathologists independently examined all samples for the presence and severity of PFE. The results were compared and analyzed in each case regarding the vitality of the PFE and its relationship to the cause of death. The results showed that PFE was almost identically diagnosed and graded on the samples obtained via both methods. The discrepancies between the two techniques did not affect the diagnoses of vitality or cause of death related to PFE. This study demonstrates the feasibility of the PNB sampling method for the diagnosis and interpretation of PFE in the postmortem setting. PMID- 22509793 TI - QT interval and the risk of myocardial infarction and all-cause death: a cohort study. AB - INTRODUCTION: The relationship between QT interval and cardiovascular disease is controversial. METHODS: All male residents aged 20-61 years and female residents aged 20-56 years were invited to the Tromso Study in 1986-1987. A total of 15,558 participants free of heart disease were prospectively followed over 20 years for myocardial infarction and death. QT interval at baseline was measured on lead I of the electrocardiogram. Hazard ratios (HRs) with 95% confidence intervals (CIs) per standard deviation change in QT interval were calculated using a Cox regression model. RESULTS: We identified 756 cases of myocardial infarction and 1,183 all-cause deaths. Prolonged QT interval was present in 792 (5%) participants. QT interval was not associated with increased risk of myocardial infarction (HR: 0.95, 95% CI: 0.84-1.07, after adjustment for potential confounders). Heart-rate-corrected QT interval was a significant predictor for all-cause death in men (HR: 1.15, 95% CI: 1.03-1.29), but not in women (HR: 1.04, 95% CI: 0.91-1.18), after adjustment for potential confounders. CONCLUSIONS: The findings suggest that the previously observed relationship between QT interval and increased risk of cardiovascular death is not mediated by increased risk of myocardial infarction. The clinical utility of the QT interval to identify individuals at high risk for coronary events is limited in a general population without prior heart disease. PMID- 22509794 TI - A systematic review on the frequency of advanced recession following single immediate implant treatment. AB - PURPOSE: It has been stated that midfacial recession is common following immediate implant treatment (IIT). The objective of this systematic review was to assess the frequency of advanced recession (>1 mm) following single IIT. MATERIAL AND METHODS: An electronic search in Pubmed, Web of Science and the Cochrane Oral Health Group Specialized Trials Register database was performed using a search algorithm. Reference lists of relevant articles were also scrutinized to identify prospective studies on >=10 implants installed in patients with an intact buccal bone wall and followed for >=12 months. Study eligibility and quality were independently assessed by two investigators. Primary outcome variables were advanced inter-proximal and midfacial recession defined as soft tissue loss surpassing 1 mm between the pre- or postoperative status and the final re assessment. RESULTS: Thirteen of 171 papers were selected. Inter-examiner agreement on eligibility (kappa = 0.879; p < 0.001) and quality (kappa = 0.788; p < 0.001) was high. Advanced inter-proximal recession was described in 0-27% of the cases. However, these data were only based on two studies. Mean inter proximal recession was frequently reported (11/13) and was <1 mm in all studies suggesting limited risk for advanced inter-proximal recession. Advanced midfacial recession was described in 0-64% of the cases. Again, few papers provided such information (4/13). Only one of these studies demonstrated high risk for advanced midfacial recession (>10%). This could be attributed to the fact that implants had not been restored with an immediate implant crown, which seems of pivotal importance given the results of a randomized controlled trial reporting on the preserving effect of immediate provisionalization on midfacial mucosa level. There is limited evidence to support an increased risk for midfacial recession following flap surgery and in patients with a thin-scalloped gingival biotype. The impact of implant-specific parameters on inter-proximal and midfacial soft tissue level seems conflicting. CONCLUSIONS: Soft tissue recession may be expected following IIT and multiple factors seem to contribute to the phenomenon. Taking into account the paucity of papers, patients with an intact buccal bone wall and thick gingival biotype, treated by means of flapless surgery and an immediate implant crown may demonstrate limited risk for advanced midfacial recession (<10%). Proper risk assessment addressing diagnostic, surgical and restorative aspects is mandatory to avoid compromised outcome of IIT. PMID- 22509795 TI - Mitogenome sequencing reveals shallow evolutionary histories and recent divergence time between morphologically and ecologically distinct European whitefish (Coregonus spp.). AB - The advent of second-generation sequencing has made it possible to quickly and economically generate whole mitochondrial genome (mitogenome) sequences. To date, mitogenome studies of nonmodel organisms have demonstrated increased power for resolving interspecies relationships. We explored an alternate use of such data to recover relationships and population history of closely related lineages with a shallow evolutionary history. Using a GS-FLX platform, we sequenced 106 mitogenomes from the Coregonus lavaretus (Europe) and Coregonus clupeaformis (North America) species complexes to investigate the evolutionary history of the endangered Danish North Sea houting (NSH) and other closely related Danish and Baltic European lake whitefish (ELW). Two well-supported clades were found within both ELW and NSH, probably reflecting historical introgression via Baltic migrants. Although ELW and NSH are not reciprocally monophyletic, they share no haplotypes, suggesting recent, but strong, reproductive isolation. The divergence time between NSH and the geographically closest ELW population was estimated using IMa, assuming isolation with migration and a new mutation rate estimate chosen to avoid time-dependency effects. The estimate of c. 2700 bp was remarkably similar to results obtained using microsatellite markers. Within North American C. clupeaformis, the divergence time between the two lineages (Atlantic and Acadian) was estimated as between 20,000 and 60,000 bp. Under the assumption that NSH and ELW colonized Denmark following the last glacial maximum, Bayesian Serial SimCoal analysis showed consistency with a scenario of long-term stability, resulting from a rapid initial sixfold population expansion. The findings illustrate the utility of mitogenome data for resolving recent intraspecific divergence events and provide evidence for recent reproductive isolation of the phenotypically divergent NSH. PMID- 22509796 TI - Impact of drug transporter pharmacogenomics on pharmacokinetic and pharmacodynamic variability - considerations for drug development. AB - INTRODUCTION: Drug transporter proteins are expressed on the cell membrane, regulating substrate exposure in systemic circulation and/or peripheral tissues. Genetic polymorphism of drug transporter genes encoding these proteins could alter the functional activity and/or protein expression, having effects on absorption, distribution, metabolism and excretion (ADME), efficacy and adverse effects. AREAS COVERED: The authors provide the reader with an overview of the pharmacogenetics (PGx) of 12 membrane transporters. The clinical literature is summarized as to the quantitative significance on pharmacokinetics (PK) and implications on pharmacodynamics (PD) and adverse effects, due to transporter influence on intracellular drug concentrations. EXPERT OPINION: Unlike polymorphisms for cytochrome P450s (CYPs) resulting in large magnitude of PK variation, genetic mutations for membrane transporters are typically less than threefold alteration in systemic PK for drugs with a few exceptions. However, substantially greater changes in intracellular drug levels may result. We are aware of 1880 exome variants in 12 of the best-studied transporters to date, and nearly 40% of these change the amino acid. However, the functional consequences of most of these variants remain to be determined, and have only been empirically evaluated for a handful. To the extent that genetic polymorphisms impact ADME, it is a variable that will contribute to ethnic differences due to substantial frequency differences for the known variants. PMID- 22509797 TI - Impact of diabetes mellitus and metabolic control on bone healing around osseointegrated implants: removal torque and histomorphometric analysis in rats. AB - OBJECTIVES: To evaluate bone healing around dental implants with established osseointegration in experimental diabetes mellitus (DM) and insulin therapy by histomorphometric and removal torque analysis in a rat model. MATERIALS AND METHODS: A total of 80 male Wistar rats received a titanium implant in the tibiae proximal methaphysis. After a healing period of 60 days, the rats were divided into four groups of 20 animals each: a 2-month control group, sacrificed at time (group A), a diabetic group (group D), an insulin group (group I), and a 4-month control group (group C), subdivided half for removal torque and half for histomorphometric analysis. In the D and I groups the DM was induced by a single injection of 40 mg/kg body weight streptozotocin (STZ). Two days after DM induction, group I received subcutaneous doses of insulin twice a day, during 2 months. Groups C and D received only saline. Two months after induction of DM, the animals of groups D, C and I were sacrificed. The plasmatic levels of glucose (GPL) were monitored throughout the experiment. Evaluation of the percentages of bone-to-implant contact and bone area within the limits of the implant threads was done by histomorphometric and mechanical torque analysis. Data were analyzed by anova at significant level of 5%. RESULTS: The GPL were within normal range for groups A, C and I and higher for group D. The means and standard deviations (SD) for histomorphometric bone area showed significant difference between group D (69.34 +/- 5.00%) and groups C (78.20 +/- 4.88%) and I (79.63 +/- 4.97%). Related to bone-to-implant contact there were no significant difference between the groups D (60.81 + 6.83%), C (63.37 + 5.88%) and I (66.97 + 4.13%). The means and SD for removal torque showed that group D (12.91 +/- 2.51 Ncm) was statistically lower than group I (17.10 +/- 3.06 Ncm) and C (16.95 +/- 5.39 Ncm). CONCLUSIONS: Diabetes mellitus impaired the bone healing around dental implants with established osseointegration because the results presented a lower percentage of bone area in group D in relation to groups C and I resulting in a lowest torque values for implant removal. Moreover, insulin therapy prevents the occurrence of bone abnormalities found in diabetic animals and osseointegration was not compromised. PMID- 22509799 TI - Formation of CO(x)-free H2 and cup-stacked carbon nanotubes over nano-Ni dispersed single wall carbon nanohorns. AB - Transitional metals (M) were dispersed on single-wall carbon nanohorns (M/SWCNHs, M = Fe, Co, Ni, Cu) by simple thermal treatment of the deposited metal nitrate without H(2) reduction. Nanometallic Ni particles on SWCNH were evidenced by high resolution transmission electron microscopic observation and X-ray photoelectron spectroscopy. The nano-Ni dispersed on SWCNH showed the highest CH(4) decomposition activity; the activity of used transitional metals decreases in the order Ni ? Co > Fe ? Cu. On the other hand, the reaction rate over Ni/SWCNH was much larger than that over Ni/Al(2)O(3), and the former provided CO(x)-free H(2) and cup-stacked carbon nanotubes, while Ni/Al(2)O(3) produced CO(x) in addition to H(2). SWCNH was superior to Al(2)O(3) as the catalyst support of Ni for the CH(4) decomposition reaction. PMID- 22509798 TI - A rare fraction of drug-resistant follicular lymphoma cancer stem cells interacts with follicular dendritic cells to maintain tumourigenic potential. AB - Follicular lymphoma (FL) comprises nearly 25% of non-Hodgkin lymphoma cases and is clinically characterized by initial sensitivity to chemotherapy followed by relapse. FL stroma contains a special type of stromal cell found in the germinal centre of lymph nodes-the follicular dendritic cell (FDC). We first isolated tumourigenic cells from the FL cell line FLK-1 by side population (SP) technique, and found that SP cells, which express ABCG2, were enriched by chemotherapy and radiation treatments. In vitro, SP cells were attracted by and adhered to FDCs through chemokine (C-X-C motif) ligand 12/chemokine (C-X-C motif) receptor 4 (CXCL12/CXCR4) signalling. In vivo, limiting dilution assays showed SP cells were highly enriched in cancer stem cells (CSC), but required FDC for tumour formation in non-obese diabetic/severe combined immunodeficiency mice. Treatment with AMD3100, a specific CXCL12/CXCR4 inhibitor, eliminated tumour growth. These findings were then verified with FL cells isolated from an FL patient's ascitic fluid (FLA-1). Finally, we detected the ABCG2 expressing lymphoma cells in FL clinical specimens. Thus, we found that the highly tumourigenic FL cells having CSC-like activities (FL-SC) interact with FDCs in a CXCL12/CXCR4 dependent manner to resist chemotherapy. Our results indicate the importance of FL-SC and niche cell signalling in maintaining tumourigenicity. These signals represent novel targets for CSC eradication. PMID- 22509800 TI - Polysaccharide-coated thermosets for orthopedic applications: from material characterization to in vivo tests. AB - The long-term stability and success of orthopedic implants depend on the osseointegration process, which is strongly influenced by the biomaterial surface. A promising approach to enhance implant integration involves the modification of the surface of the implant by means of polymers that mimic the natural components of the extracellular matrix, for example, polysaccharides. In this study, methacrylate thermosets (bisphenol A glycidylmethacrylate/triethyleneglycol dimethacrylate), a widely used composition for orthopedic and dental applications, have been coated by electrostatic deposition of a bioactive chitosan-derivative. This polysaccharide was shown to induce osteoblasts aggregation in vitro, to stimulate cell proliferation and to enhance alkaline phosphatase activity. The coating deposition was studied by analyzing the effect of pH and ionic strength on the grafting of the polysaccharide. Contact angle studies show that the functionalized material displays a higher hydrophilic character owing to the increase of surface polar groups. The mechanical properties of the coating were evaluated by nanoindentation studies which point to higher values of indentation hardness and modulus (E) of the polysaccharide surface layer, while the influence of cyclic stress on the construct was assessed by fatigue tests. Finally, in vivo tests in minipigs showed that the polysaccharide-based implant showed a good biocompatibility and an ability for osseointegration at least similar to that of the titanium Ti6Al4V alloy with roughened surface. PMID- 22509801 TI - Statistical parametric mapping reveals regional alterations in cannabinoid CB1 receptor distribution and G-protein activation in the 3D reconstructed epileptic rat brain. AB - PURPOSE: The endocannabinoid system is known to modulate seizure activity in several in vivo and in vitro models, and CB(1) -receptor activation is anticonvulsant in the rat pilocarpine model of acquired epilepsy (AE). In these epileptic rats, a unique redistribution of the CB(1) receptor occurs within the hippocampus; however, an anatomically inclusive analysis of the effect of status epilepticus (SE)-induced AE on CB(1) receptors has not been thoroughly evaluated. Therefore, statistical parametric mapping (SPM), a whole-brain unbiased approach, was used to study the long-term effect of pilocarpine-induced SE on CB(1) receptor binding and G-protein activation in rats with AE. METHODS: Serial coronal sections from control and epileptic rats were cut at equal intervals throughout the neuraxis and processed for [(3) H]WIN55,212-2 (WIN) autoradiography, WIN-stimulated [(35) S]GTPgammaS autoradiography, and CB(1) receptor immunohistochemistry (IHC). The autoradiographic techniques were evaluated with both region of interest (ROI) and SPM analyses. KEY FINDINGS: In rats with AE, regionally specific increases in CB(1) -receptor binding and activity were detected in cortex, discrete thalamic nuclei, and other regions including caudate-putamen and septum, and confirmed by IHC. However, CB(1) receptors were unaltered in several brain regions, including substantia nigra and cerebellum, and did not exhibit regional decreases in rats with AE. SIGNIFICANCE: This study provides the first comprehensive evaluation of the regional distribution of changes in CB(1) -receptor expression, binding, and G-protein activation in the rat pilocarpine model of AE. These regions may ultimately serve as targets for cannabinomimetic compounds or manipulation of the endocannabinoid system in epileptic brain. PMID- 22509802 TI - Increased neutrophil migration in smokers with or without chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: The number of airway neutrophils is increased in chronic obstructive pulmonary disease (COPD), and this may have a central pathophysiological role in the disease. In addition, activation of neutrophils increases their migration into sites of injury. We hypothesize that circulating neutrophils are activated in smokers. METHODS: Peripheral blood neutrophils were isolated from healthy non-smokers (n = 15), and smokers with (n = 15) or without COPD (n = 15), who were matched with regard to cumulative tobacco exposure, and chemotactic responses to N-formyl-methionyl-leucyl-phenylalanine (fMLP), interleukin-8 (IL-8, CXCL8) and leukotriene B(4) (LTB(4)) were assessed using the ChemoTx System (Neuro Probe Inc., Gaithersburg, MD, USA). Serum tumour necrosis factor-alpha (TNF-alpha) concentrations were measured by ELISA. Surface expression of the neutrophil activation marker, CD11b, was measured by flow cytometry. RESULTS: The chemotactic response to CXCL8 was increased in smokers with or without COPD (P < 0.05). Migration towards LTB(4) was increased in smokers without COPD compared with non-smokers (P < 0.05), whereas there was no difference in fMLP-induced chemotaxis between the groups. There was a correlation between serum TNF-alpha levels and migration induced by IL-8 (Rho = 0.442; P = 0.038) and LTB(4) (Rho = 0.428; P = 0.044) in the smokers. Furthermore, there was a tendency towards higher CD11b expression in the COPD group (P = 0.057). CONCLUSIONS: Chemotaxis of circulating neutrophils towards CXCL8, and partly towards LTB(4), is increased in smokers, indicating a systemic influence of smoking on cell activation, irrespective of the presence of airflow limitation. The relationship between TNF-alpha and chemotactic response suggests that TNF alpha is involved in neutrophil activation, resulting in enhanced migration. PMID- 22509803 TI - A modified system for analyzing ionizing radiation-induced chromosome abnormalities. AB - The analysis of dicentric chromosomes in human peripheral blood lymphocytes (PBLs) by Giemsa staining is the most established method for biological dosimetry. However, this method requires a well-trained person because of the difficulty in detecting aberrations rapidly and accurately. Here, we applied a fluorescence in situ hybridization (FISH) technique, using telomere and centromere peptide nucleic acid (PNA) probes, to solve the problem of biological dosimetry in radiation emergency medicine. A comparison by a well-trained observer found that FISH analysis of PBLs for the dose estimation was more accurate than the conventional Giemsa analysis, especially in samples irradiated at high doses. These results show that FISH analysis with centromeric/telomeric PNA probes could become the standard method for biological dosimetry in radiation emergency medicine. PMID- 22509805 TI - Fibroblasts--a key host cell type in tumor initiation, progression, and metastasis. AB - Tumor initiation, growth, invasion, and metastasis occur as a consequence of a complex interplay between the host environment and cancer cells. Fibroblasts are now recognized as a key host cell type involved in host-cancer signaling. This review discusses some recent studies that highlight the roles of fibroblasts in tumor initiation, early progression, invasion, and metastasis. Some clinical studies describing the prognostic significance of fibroblast-derived markers and signatures are also discussed. PMID- 22509806 TI - Dynamic kinetic resolution of alpha-keto esters via asymmetric transfer hydrogenation. AB - The dynamic kinetic resolution of beta-aryl alpha-keto esters has been accomplished using a newly designed (arene)RuCl(monosulfonamide) transfer hydrogenation catalyst. This dynamic process generates three contiguous stereocenters with remarkable diastereoselectivity through a reduction/lactonization sequence. The resulting enantioenriched, densely functionalized gamma-butyrolactones are of high synthetic utility, as highlighted by several secondary derivatizations. PMID- 22509804 TI - PDGF and PDGF receptors in glioma. AB - The family of platelet-derived growth factors (PDGFs) plays a number of critical roles in normal embryonic development, cellular differentiation, and response to tissue damage. Not surprisingly, as it is a multi-faceted regulatory system, numerous pathological conditions are associated with aberrant activity of the PDGFs and their receptors. As we and others have shown, human gliomas, especially glioblastoma, express all PDGF ligands and both the two cell surface receptors, PDGFR-alpha and -beta. The cellular distribution of these proteins in tumors indicates that glial tumor cells are stimulated via PDGF/PDGFR-alpha autocrine and paracrine loops, while tumor vessels are stimulated via the PDGFR-beta. Here we summarize the initial discoveries on the role of PDGF and PDGF receptors in gliomas and provide a brief overview of what is known in this field. PMID- 22509807 TI - Proteomics insight into the biological safety of transgenic modification of rice as compared with conventional genetic breeding and spontaneous genotypic variation. AB - The potential of unintended effects caused by transgenic events is a key issue in the commercialization of genetically modified (GM) crops. To investigate whether transgenic events cause unintended effects, we used comparative proteomics approaches to evaluate proteome differences in seeds from 2 sets of GM indica rice, herbicide-resistant Bar68-1 carrying bar and insect-resistant 2036-1a carrying cry1Ac/sck, and their respective controls D68 and MH86, as well as indica variety MH63, a parental line for breeding MH86, and japonica variety ZH10. This experimental design allowed for comparing proteome difference caused by transgenes, conventional genetic breeding, and natural genetic variation. Proteomics analysis revealed the maximum numbers of differentially expressed proteins between indica and japonica cultivars, second among indica varieties with relative small difference between MH86 and MH63, and the minimum between GM rice and respective control, thus indicating GM events do not substantially alter proteome profiles as compared with conventional genetic breeding and natural genetic variation. Mass spectrometry analysis revealed 234 proteins differentially expressed in the 6 materials, and these proteins were involved in different cellular and metabolic processes with a prominent skew toward metabolism (31.2%), protein synthesis and destination (25.2%), and defense response (22.4%). In these seed proteomes, proteins implicated in the 3 prominent biological processes showed significantly different composite expression patterns and were major factors differentiating japonica and indica cultivars, as well as indica varieties. Thus, metabolism, protein synthesis and destination, and defense response in seeds are important in differentiating rice cultivars and varieties. PMID- 22509808 TI - Cardiovascular drift and cerebral and muscle tissue oxygenation during prolonged cycling at different pedalling cadences. AB - We hypothesized that a faster cycling cadence could exaggerate cardiovascular drift and affect muscle and cerebral blood volume and oxygenation. Twelve healthy males (mean age, 23.4 +/- 3.8 years) performed cycle ergometry for 90 min on 2 separate occasions, with pedalling frequencies of 40 and 80 r.min(-1), at individual workloads corresponding to 60% of their peak oxygen consumption. The main measured variables were heart rate, ventilation, cardiac output, electromyographic activity of the vastus lateralis, and regional muscle and cerebral blood volume and oxygenation. Cardiovascular drift developed at both cadences, but it was more pronounced at the faster than at the slower cadence, as indicated by the drop in cardiac output by 1.0 +/- 0.2 L.min(-1), the decline in stroke volume by 9 +/- 3 mL.beat(-1), and the increase in heart rate by 9 +/- 1 beats.min(-1) at 80 r.min(-1). At the faster cadence, minute ventilation was higher by 5.0 +/- 0.5 L.min(-1), and end-tidal CO(2) pressure was lower by 2.0 +/ 0.1 torr. Although higher electromyographic activity in the vastus lateralis was recorded at 80 r.min(-1), muscle blood volume did not increase at this cadence, as it did at 40 r.min(-1). In addition, muscle oxygenation was no different between cadences. In contrast, cerebral regional blood volume and oxygenation at 80 r.min(-1) were not as high as at 40 r.min(-1) (p < 0.05). Faster cycling cadence exaggerates cardiovascular drift and seems to influence muscle and cerebral blood volume and cerebral oxygenation, without muscle oxygenation being radically affected. PMID- 22509809 TI - Genistein ameliorates hyperglycemia in a mouse model of nongenetic type 2 diabetes. AB - While peripheral insulin resistance is common during obesity and aging in mice and people, the progression to type 2 diabetes (T2D) is largely due to loss of beta-cell mass and function through apoptosis. We recently reported that genistein, a soy derived isoflavone, can improve glycemic control and beta-cell function in insulin-deficient diabetic mice. However, whether it can prevent beta cell loss and diabetes in T2D mice is unknown. Our current study aimed to investigate the effect of dietary supplemented genistein in a nongenetic T2D mouse model. Nongenetic, middle-aged obese diabetic mice were generated by high fat diet and a low dose of streptozotocin injection. The effect of dietary supplementation of genistein on glycemic control and beta-cell mass and function was determined. Dietary intake of genistein (250 mg.kg(-1) diet) improved hyperglycemia, glucose tolerance, and blood insulin level in obese diabetic mice, whereas it did not affect body weight gain, food intake, fat deposit, plasma lipid profile, and peripheral insulin sensitivity. Genistein increased the number of insulin-positive beta-cell in islets, promoted islet beta-cell survival, and preserved islet mass. In conclusion, dietary intake of genistein could prevent T2D via a direct protective action on beta-cells without alteration of periphery insulin sensitivity. PMID- 22509810 TI - Beneficial effects of cod protein on skeletal muscle repair following injury. AB - This study examined the effect of peanut and cod proteins on post-damage skeletal muscle repair, compared with casein. We hypothesized that because of their high arginine content, these proteins would improve the resolution of inflammation and muscle mass recovery following injury. One hundred and twenty-eight male Wistar rats were assigned to isoenergetic diets composed of casein and peanut (experiment 1) or cod protein (experiment 2). After 21 days of feeding, one tibialis anterior muscle (TA) was injured with bupivacaine, while the contralateral TA was injected with saline (sham muscle). Measurements were taken at days 0, 3, 14, and 24 post-injury. Compared with casein, peanut protein reduced muscle mass at days 0 (-12%, p = 0.005) and 14 post-injury in the injured muscle (-13%, p = 0.04), and lowered myofiber cross-sectional area in both the sham (-21%, p = 0.008) and injured muscles (-26%, p = 0.05) at day 24 post injury, showing that peanut protein has a weak potential to support muscle growth. At day 14 post-injury, muscle mass in the sham (13%, p = 0.02) and injured muscles (12%, p = 0.01) was higher in cod-protein-fed rats, indicating better muscle mass recovery, than in casein-fed rats. Cod protein tended (p = 0.06) to decrease the density of neutrophils (-24%) at day 14 post-injury in the injured muscle, and to decrease the density of ED1(+) macrophages at day 24 post injury in both sham (-29%, p = 0.03) and injured (-40%, p = 0.01) muscles. No effects were observed for peanut protein. These data indicate that cod protein is better for promoting growth and regeneration of skeletal muscle after trauma, partly because of the improved resolution of inflammation. PMID- 22509811 TI - mTORC1 and the regulation of skeletal muscle anabolism and mass. AB - The mass and integrity of skeletal muscle is vital to whole-body substrate metabolism and health. Indeed, defects in muscle metabolism and functions underlie or exacerbate diseases like diabetes, rheumatoid arthritis, and cancer. Physical activity and nutrition are the 2 most important environmental factors that can affect muscle health. At the molecular level, the mammalian target of rapamycin complex 1 (mTORC1) is a critical signalling complex that regulates muscle mass. In response to nutrition and resistance exercise, increased muscle mass and activation of mTORC1 occur in parallel. In this review, we summarize recent findings on mTORC1 and its regulation in skeletal muscle in response to resistance exercise, alone or in combination with intake of protein or amino acids. Because increased activity of the complex is implicated in the development of muscle insulin resistance, obesity, and some cancers (e.g., ovarian, breast), drugs that target mTORC1 are being developed or are in clinical trials. However, various cancers are associated with extensive muscle wasting, due in part to tumour burden and malnutrition. This muscle wasting may also be a side effect of anticancer drugs. Because loss of muscle mass is associated not only with metabolic abnormalities but also dose limiting toxicity, we review the possible implications for skeletal muscle of long-term inhibition of mTORC1, especially in muscle wasting conditions. PMID- 22509813 TI - Association of killer cell immunoglobulin-like receptor and human leukocyte antigen-C genotype with dry eye disease in a Chinese Han population. AB - Dry eye is one of the most prevalent eye diseases and dry eye disease (DED) is associated with ocular surface inflammation. The interaction between killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigens (HLAs) regulates the activation of natural killer (NK) cells and certain T cell subsets in response to inflammation. The objective of this study was to explore whether KIR gene and HLA-C allele polymorphisms were associated with DED in a Chinese Han population. Polymerase chain reaction with sequence-specific primers method was used to genotype KIR genes and HLA-C alleles in 106 DED patients and 220 healthy controls. Framework genes KIR2DL4, KIR3DL2, KIR3DL3, and KIR3DP1 were present in all individuals. There were no significant differences in the frequencies of inhibitory KIR genes between the two groups. However, the frequency of KIR2DS2 was significantly higher in severe DED patients than that in healthy controls (p=0.031, odds ratio [OR]=1.828, 95% confidence interval [CI]=1.05-3.17). Significantly different distributions of HLA-C allele groups were not observed in severe DED patients and controls. The frequency of the combination of HLA-C1 allele group with KIR2DS2 was significantly higher in severe DED patients compared with controls (p=0.013, OR=2.083, 95% CI=1.16-3.74). These data suggested that this genotype combination was associated with susceptibility to severe DED and that NK cells might have a role in the pathogenesis of DED. The results led to an interesting future research question of whether or not KIR and HLA-C genotypes were involved in the predisposition to or pathogenesis of DED. PMID- 22509814 TI - Frequency of IL28B rs12979860 single-nucleotide polymorphism alleles in newborn infants and in patients with chronic hepatitis C in Morocco. AB - BACKGROUND: Epidemiological and experimental evidence support the role of host genetics in treatment response and viral clearance in chronic hepatitis C (CHC). Recently, the CC genotype of IL28B single-nucleotide polymorphism (SNP) rs12979860 has been associated with spontaneous viral clearance and a better treatment response. The distribution of this polymorphism varies according to populations. Frequency of rs12979860 SNP alleles in the Moroccan population is unknown. The aim of our study was to estimate the frequency of the C allele of this SNP in the Moroccan population and, in parallel, in a cohort of Moroccan patients with CHC treated with pegylated interferon-alpha and ribavirin. METHODS: We used real-time polymerase chain reaction assay based on TaqMan technology to determine the allele frequency of the rs12979860 SNP in 100 Moroccan newborn infants. We also compared the frequency of the CC genotype between two groups of patients with genotype 1-CHC treated by combination therapy: group1, n=30 patients, responders who achieved sustained viral response (SVR) and group2, n=30 patients, nonresponders. RESULTS: The rs12979860 C allele frequency was estimated to be 73% in the Moroccan population. The frequency of this allele in the group of patients with CHC was only 58.3%, and the CC genotype is more prevalent in group1 (62.5%) than in group 2. CONCLUSIONS: This is the first report providing genetic data related to the frequency of genetic polymorphisms of IL28B in Morocco. The C-allele frequency of the IL28B gene SNP rs12979860 in Morocco is higher than in the African populations. Distribution of this SNP distinguishes in a population of CHC between SVR and nonresponders. This result merits consideration and should be studied by analyzing a larger sample size of patients. PMID- 22509815 TI - Altering the static dipole on surfaces through chemistry: molecular films of zwitterionic quinonoids. AB - The adsorption of molecular films made of small molecules with a large intrinsic electrical dipole has been explored. The data indicate that such dipolar molecules may be used for altering the interface dipole screening at the metal electrode interface in organic electronics. More specifically, we have investigated the surface electronic spectroscopic properties of zwitterionic molecules containing 12pi electrons of the p-benzoquinonemonoimine type, C(6)H(2)(...NHR)(2)(...O)(2)(R = H (1), n-C(4)H(9) (2), C(3)H(6)-S-CH(3) (3), C(3)H(6)-O-CH(3) (4), CH(2)-C(6)H(5) (5)), adsorbed on Au. These molecules are stable zwitterions by virtue of the meta positions occupied by the nitrogen and oxygen substituents on the central ring, respectively. The structures of 2-4 have been determined by single crystal X-ray diffraction and indicate that in these molecules, two chemically connected but electronically not conjugated 6pi electron subunits are present, which explains their strong dipolar character. We systematically observed that homogeneous molecular films with thickness as small as 1 nm were formed on Au, which fully cover the surface, even for a variety of R substituents. Preferential adsorption toward the patterned gold areas on SiO(2) substrates was found with 4. Optimum self-assembling of 2 and 5 results in ordered close packed films, which exhibit n-type character, based on the position of the Fermi level close to the conduction band minimum, suggesting high conductivity properties. This new type of self-assembled molecular films offers interesting possibilities for engineering metal-organic interfaces, of critical importance for organic electronics. PMID- 22509816 TI - State-specific reactions of Cu(+)(1S, 3D) with CH3X and CF3X (X = Cl, Br, I): exploring the influence of dipole orientation on association and C-X bond activation. AB - The reactions of gas-phase Cu(+)((1)S) and Cu(+)((3)D) with CF(3)X and CH(3)X (X = Cl, Br, and I) have been examined experimentally using the drift cell technique at 3.5 Torr in He at room temperature. State-specific product channels and overall bimolecular rate constants for depletion of the two Cu(+) states were determined using electronic state chromatography. The results showed that Cu(+)((1)S) participates exclusively in association with all of these neutrals, whereas, depending on the neutral, Cu(+)((3)D) initiates up to three bimolecular processes, resulting in the formation of CuX(+), CuC(H/F)(3)(+), and C(H/F)(3)X(+). Possible structures for the singlet association products were explored using density functional methods. These calculations indicated that Cu(+) preferentially associates with the labile halogen (Cl, Br, I) with all neutrals except CF(3)Cl, for which a "backside" geometry occurs in which Cu(+)((1)S) is weakly bound to the -CF(3) end of the molecule. All products observed on the triplet reaction surface can be understood in terms of either known or calculated thermochemical requirements. Product distributions and overall reaction efficiencies for C-X bond activation (X = Br, I) through Cu(+)((3)D) suggest that the orientation of the neutral dipole has little or no effect in controlling access to specific product channels. Likewise, second-order rate constants for reactions with X = Br and I indicate efficient depletion of Cu(+)((3)D) and do not exhibit the dramatic variations in reaction efficiency previously observed with CH(3)Cl and CF(3)Cl. These results suggest that C-X bond activation proceeds through a bond-insertion mechanism as opposed to direct abstraction. PMID- 22509817 TI - Recent colonization of the Galapagos by the tree Geoffroea spinosa Jacq. (Leguminosae). AB - This study puts together genetic data and an approximate bayesian computation (ABC) approach to infer the time at which the tree Geoffroea spinosa colonized the Galapagos Islands. The genetic diversity and differentiation between Peru and Galapagos population samples, estimated using three chloroplast spacers and six microsatellite loci, reveal significant differences between two mainland regions separated by the Andes mountains (Inter Andean vs. Pacific Coast) as well as a significant genetic differentiation of island populations. Microsatellites identify two distinct geographical clusters, the Galapagos and the mainland, and chloroplast markers show a private haplotype in the Galapagos. The nuclear distinctiveness of the Inter Andean populations suggests current restricted pollen flow, but chloroplast points to cross-Andean dispersals via seeds, indicating that the Andes might not be an effective biogeographical barrier. The ABC analyses clearly point to the colonization of the Galapagos within the last 160,000 years and possibly as recently as 4750 years ago (475 generations). Founder events associated with colonization of the two islands where the species occurs are detected, with Espanola having been colonized after Floreana. We discuss two nonmutually exclusive possibilities for the colonization of the Galapagos, recent natural dispersal vs. human introduction. PMID- 22509818 TI - One-pot noninjection route to CdS quantum dots via hydrothermal synthesis. AB - Water-dispersible CdS quantum dots (QDs) emitting from 510 to 650 nm were synthesized in a simple one-pot noninjection hydrothermal route using cadmium chloride, thiourea, and 3-mercaptopropionic acid (MPA) as starting materials. All these chemicals were loaded at room temperature in a Teflon sealed tube and the reaction mixture heated at 100 degrees C. The effects of CdCl(2)/thiourea/MPA feed molar ratios, pH, and concentrations of precursors affecting the growth of the CdS QDs, was monitored via the temporal evolution of the optical properties of the CdS nanocrystals. High concentration of precursors and high MPA/Cd feed molar ratios were found to lead to an increase in the diameter of the resulting CdS nanocrystals and of the trap state emission of the dots. The combination of moderate pH value, low concentration of precursors and slow growth rate plays the crucial role in the good optical properties of the obtained CdS nanocrystals. The highest photoluminescence achieved for CdS@MPA QDs of average size 3.5 nm was 20%. As prepared colloids show rather narrow particle size distribution, although all reactants were mixed at room temperature. CdS@MPA QDs were characterized by UV-vis and photoluminescence spectroscopy, powder X-ray diffraction, transmission electron microscopy, energy-dispersive X-ray spectrometry and MALDI TOF mass spectrometry. This noninjection one-pot approach features easy handling and large scale production with excellent synthetic reproducibility. Surface passivation of CdS@MPA cores by a wider bandgap material, ZnS, led to enhanced luminescence intensity. CdS@MPA and CdS/ZnS@MPA QDs exhibit high photochemical stability and hold a good potential to be applied in optoelectronic devices and biological applications. PMID- 22509819 TI - Severe efavirenz-induced vacuolar axonopathy complicated by fatal aspiration pneumonia. PMID- 22509820 TI - A new spirurid (Nematoda) parasite from mormoopid bats in Mexico. AB - A new nematode species, Spirura mexicana n. sp., is described from specimens recovered from the esophageal mucosa of the Parnell's mustached bat Pteronotus parnellii , Davy's naked-backed bat Pteronotus davyi, Wagner's mustached bat Pteronotus personatus, and the ghost-faced bat Mormoops megalophylla in the State of Morelos, Mexico. This nematode is characterized by having a relatively short prostoma, 5-6 pairs of caudal papillae, and a smooth distal end of the tail in females. This is the first species of Spirura described from bats in the New World. PMID- 22509821 TI - Pharmacokinetic and pharmacogenetic determinants and considerations in chemotherapy selection and dosing in infants. AB - INTRODUCTION: There is a lack of high-quality data regarding optimal chemotherapy dosage regimens among infants. Dosing regimens for chemotherapy during the first year of life are commonly based on empiric recommendations extrapolated from older children; however, balancing efficacy and toxicity is critical as severe adverse drug reactions may lead to treatment failure or reduced adherence to needed medications. AREAS COVERED: This review describes pharmacokinetic and pharmacogenetic considerations when administering chemotherapeutic agents to infants. Examples of commonly used agents are provided with practical recommendations for dosing adjustments. EXPERT OPINION: Optimal chemotherapy for children and infants in particular has lagged behind the remarkable progress in cancer treatment and it is clear that far more basic and clinical research are needed with respect to the mechanistic basis of age-dependent differences in pharmacokinetic parameters. More recent studies which have combined pharmacokinetic data with clinical toxicity and outcome data have resulted in a number of more evidence-based guidelines at least for the initial chemotherapy dosing; however, at present, the dosing of chemotherapy drugs in neonates and infants remains largely empiric. PMID- 22509823 TI - Hydrophilic anti-migraine triptans are substrates for OATP1A2, a transporter expressed at human blood-brain barrier. AB - OATP1A2 is expressed in the luminal membrane of human blood-brain barrier (BBB). The human tissue with the highest OATP1A2 mRNA expression is the brain. We have established a robust BacMam2-OATP1A2 transduced HEK293 system. Among the 36 central nervous system (CNS) marketed drugs tested, hydrophilic triptans, 5 HT(1B/1D) receptor agonists for the treatment of migraine attacks, were identified as OATP1A2 substrates. Kinetics (K(m) and V(max)) were determined for six marketed triptans. Structure-activity relationship (SAR) obtained from 18 triptan structural analogs revealed that the positively charged basic amine atom was essential for efficient OATP1A2-mediated triptan uptake and uptake rate was in the order of tertiary > secondary > primary. Preliminary quantitative SAR analysis of the triptan analogs demonstrated positive correlation between OATP1A2 mediated uptake rate and van der Waals volume (vdw_vol). OATP1A2 was specifically expressed on the apical side of MDCKII monolayer after BacMam2-OATP1A2 transduction and can facilitate transport of triptans across the MDCKII monolayer from apical to basolateral side. Involvement of OATP1A2 for brain penetration of triptans in human requires further investigation. PMID- 22509822 TI - AMP-activated protein kinase (AMPK)-dependent and -independent pathways regulate hypoxic inhibition of transepithelial Na+ transport across human airway epithelial cells. AB - BACKGROUND AND PURPOSE: Pulmonary transepithelial Na(+) transport is reduced by hypoxia, but in the airway the regulatory mechanisms remain unclear. We investigated the role of AMPK and ROS in the hypoxic regulation of apical amiloride-sensitive Na(+) channels and basolateral Na(+) K(+) ATPase activity. EXPERIMENTAL APPROACH: H441 human airway epithelial cells were used to examine the effects of hypoxia on Na(+) transport, AMP : ATP ratio and AMPK activity. Lentiviral constructs were used to modify cellular AMPK abundance and activity; pharmacological agents were used to modify cellular ROS. KEY RESULTS: AMPK was activated by exposure to 3% or 0.2% O(2) for 60 min in cells grown in submerged culture or when fluid (0.1 mL.cm(-2) ) was added to the apical surface of cells grown at the air-liquid interface. Only 0.2% O(2) activated AMPK in cells grown at the air-liquid interface. AMPK activation was associated with elevation of cellular AMP:ATP ratio and activity of the upstream kinase LKB1. Hypoxia inhibited basolateral ouabain-sensitive I(sc) (I(ouabain) ) and apical amiloride sensitive Na(+) conductance (G(Na+) ). Modification of AMPK activity prevented the effect of hypoxia on I(ouabain) (Na(+) K(+) ATPase) but not apical G(Na+) . Scavenging of superoxide and inhibition of NADPH oxidase prevented the effect of hypoxia on apical G(Na+) (epithelial Na(+) channels). CONCLUSIONS AND IMPLICATIONS: Hypoxia activates AMPK-dependent and -independent pathways in airway epithelial cells. Importantly, these pathways differentially regulate apical Na(+) channels and basolateral Na(+) K(+) ATPase activity to decrease transepithelial Na(+) transport. Luminal fluid potentiated the effect of hypoxia and activated AMPK, which could have important consequences in lung disease conditions. PMID- 22509824 TI - Practical use of the regression offset approach for the prediction of in vivo intrinsic clearance from hepatocytes. AB - Systematic under-prediction of clearance is frequently associated with in vitro kinetic data when extrapolated using physiological scaling factors, appropriate binding parameters and the well-stirred model. The present study describes a method of removing this systematic bias through application of empirical correction factors derived from regression analyses applied to the in vitro and in vivo data for a defined set of reference compounds. Linear regression lines were established with in vivo intrinsic clearance (CLint), derived from in vivo clearance data and scaled in vitro intrinsic clearance from isolated hepatocyte incubations. The scaled CLint was empirically corrected to a predicted in vivo CLint using the slope and intercept from a uniform weighted linear regression applied to the in vitro to in vivo extrapolation. Cross validation of human data demonstrated that 66% of the reference compounds had a predicted in vivo CLint within two-fold of the observed value. The average absolute fold error (AAFE) for the in vivo CLint predictions was 1.90. For rat, 54% of the compounds had a predicted value within two-fold of the observed and the AAFE was 1.98. Three AstraZeneca projects are used to exemplify how a two-sided prediction interval, applied to the rat regression corrected reference data, can form the basis for assessing the likelihood that, for a given chemical series, the in vitro kinetic data is predictive of in vivo clearance and is therefore appropriate to guide optimisation of compound metabolic stability. PMID- 22509826 TI - The role of the TRAF-interacting protein in proliferation and differentiation. AB - Ubiquitination of proteins is a post-translational modification, which decides on the cellular fate of the protein. Addition of ubiquitin moieties to proteins is carried out by the sequential action of three enzymes: E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; and E3, ubiquitin ligase. The TRAF interacting protein (TRAIP, TRIP, RNF206) functions as Really Interesting New Gene (RING)-type E3 ubiquitin ligase, but its physiological substrates are not yet known. TRAIP was reported to interact with TRAF [tumor necrosis factor (TNF) receptor-associated factors] and the two tumor suppressors CYLD and Syk (spleen tyrosine kinase). Ectopically expressed TRAIP was shown to inhibit nuclear factor kappa B (NF-kappaB) signalling. However, recent results suggested a role for TRAIP in biological processes other than NF-kappaB regulation. Knock-down of TRAIP in human epidermal keratinocytes repressed cellular proliferation and induced a block in the G1/S phase of the cell cycle without affecting NF-kappaB signalling. TRAIP is necessary for embryonal development as mutations affecting the Drosophila homologue of TRAIP are maternal effect-lethal mutants, and TRAIP knock-out mice die in utero because of aberrant regulation of cell proliferation and apoptosis. These findings underline the tight link between TRAIP and cell proliferation. In this review, we summarize the data on TRAIP and put them into a larger perspective regarding the role of TRAIP in the control of tissue homeostasis. PMID- 22509825 TI - Identification of human cytochrome P450 isoforms and esterases involved in the metabolism of mirabegron, a potent and selective beta3-adrenoceptor agonist. AB - 1. Human cytochrome P450 (CYP) enzymes and esterases involved in the metabolism of mirabegron, a potent and selective human beta(3)-adrenoceptor agonist intended for the treatment of overactive bladder, were identified in in vitro studies. 2. Incubations of mirabegron with recombinant human CYP enzymes showed significant metabolism of mirabegron by CYP2D6 and CYP3A4 only. Correlation analyses showed a significant correlation between mirabegron metabolism and testosterone 6beta hydroxylation (CYP3A4/5 marker activity). In inhibition studies using antiserum against CYP3A4, a strong inhibition (at maximum 80% inhibition) of the metabolism of mirabegron was observed, whereas the inhibitory effects of monoclonal antibodies against CYP2D6 were small (at maximum 10% inhibition). These findings suggest that CYP3A4 is the primary CYP enzyme responsible for in vitro oxidative metabolism of mirabegron, with a minor role of CYP2D6. 3. Mirabegron hydrolysis was catalyzed in human blood, plasma and butyrylcholinesterase (BChE) solution, but not in human liver microsomes, intestinal microsomes, liver S9, intestinal S9 and recombinant acetylcholinesterase solution. K(m) values of mirabegron hydrolysis in human blood, plasma and BChE solution were all similar (13.4-15.2 MUM). The inhibition profiles in human blood and plasma were also similar to those in BChE solution, suggesting that mirabegron hydrolysis is catalyzed by BChE. PMID- 22509827 TI - Cathelicidin LL-37: a defense molecule with a potential role in psoriasis pathogenesis. AB - Epidermal keratinocytes produce and secrete antimicrobial peptides (AMPs) that subsequently form a chemical shield on the skin surface. Cathelicidins are one family of AMPs in skin with various further immune functions. Consequently, dysfunction of these peptides has been implicated in the pathogenesis of inflammatory skin disease. In particular, the cathelicidin LL-37 is overexpressed in inflamed skin in psoriasis, binds to extracellular self-DNA released from dying cells and converts self-DNA in a potent stimulus for plasmacytoid dendritic cells (pDCs). Subsequently, pDCs secrete type I interferons and trigger an auto inflammatory cascade. Paradoxically, therapies targeting the vitamin D pathway such as vitamin D analogues or UVB phototherapy ameliorate cutaneous inflammation in psoriasis but strongly induce cathelicidin expression in skin at the same time. Current evidence now suggests that self-DNA present in the cytosol of keratinocytes is also pro-inflammatory active and triggers IL-1beta secretion in psoriatic lesions through the AIM2 inflammasome. This time, however, binding of LL-37 to self-DNA neutralizes DNA-mediated inflammation. Hence, cathelicidin LL 37 shows contrasting roles in skin inflammation in psoriasis and might serve as a target for novel therapies for this chronic skin disease. PMID- 22509828 TI - Periostin, a matricellular protein, accelerates cutaneous wound repair by activating dermal fibroblasts. AB - Cutaneous wound repair is a highly ordered and well-coordinated process involving various cell lineages and many molecular effectors. Cell-matrix interactions through integrin molecules provide key signals important for wound repair. Periostin is a matricellular protein that may provide signals important during tissue development and remodelling by interacting with several integrin molecules, via the phosphatidylinositol 3-kinase/Akt and MAP kinase pathways. In this study, we examined the role of periostin in the process of cutaneous wound repair using periostin-deficient mice and by analysing the effects of periostin on dermal fibroblasts. We first determined the expression profile and localization of periostin in a well-characterized wound repair model mice. Periostin was robustly deposited in the granulation tissues beneath the extended epidermal wound edges and at the dermal-epidermal junctions in wounded mice. Moreover, periostin-deficient mice exhibited delayed in vivo wound repair, which could be improved by direct administration of exogenous periostin. In vitro analyses revealed that loss of periostin impaired proliferation and migration of dermal fibroblasts, but exogenous supplementation or enforced periostin expression enhanced their proliferation. Combined, these results demonstrate that periostin accelerates the process of cutaneous wound repair by activating fibroblasts. PMID- 22509830 TI - Optimization of electron paramagnetic resonance imaging for visualization of human skin melanoma in various stages of invasion. AB - Malignant melanoma is a tumor characterized by the uncontrolled proliferation of melanocytes, mainly in skin, but also in eyes. Its incidence is rising each year. To improve the diagnosis and treatment of the tumor, it is essential to develop new effective methods to early detect and characterize melanoma. Previously, we demonstrated in a single-shot study that it was possible to map free radicals of melanin pigments using an electron paramagnetic resonance (EPR)-based method. Furthermore, we demonstrated that X-Band (9 GHz) EPR spectrometry was an accurate tool to assess the growth stage of a pigmented tumor. The aim of the present study was to investigate the ability of EPR imaging to detect and localize melanin pigments inside melanin phantoms, B16 melanoma tumor models and resected human melanomas. We show that EPR can provide an accurate image of synthetic samples, both in terms of shape and size, with errors always lower than 10% compared to the real size. Regarding melanoma studies, the ability of EPR imaging to map accurately the melanoma was depending on the concentration of melanin in the sample, which is proportional to the growth stage of the tumor and the consequent signal-to-noise ratio (SNR) provided by the EPR signal intensity. This led us to define an operational concept, considering SNR and interferences with other EPR signals, to determine when EPR imaging was feasible. PMID- 22509829 TI - Topical hesperidin improves epidermal permeability barrier function and epidermal differentiation in normal murine skin. AB - Orange peel extract appears to exhibit beneficial effects on skin whitening, inflammation, UVB protection, as well as keratinocyte proliferation. In the present study, we determine whether topical hesperidin influences epidermal permeability barrier function and its underlying mechanisms. Hairless mice were treated topically with 2% hesperidin or 70% ethanol alone twice daily for 6 days. At the end of treatment, basal transepidermal water loss (TEWL) was measured 2 and 4 h post barrier disruption. Epidermal proliferation and differentiation were evaluated by immunohistochemical staining and Western blot analysis. Additionally, lamellar body density and secretion were assessed by electron microscopy. Although there were no significant differences in basal barrier function, in comparison with control animals, topical hesperidin significantly accelerated barrier recovery at both 2 and 4 h after acute barrier abrogation. Enhanced barrier function in hesperidin-treated skin correlated with stimulation of both epidermal proliferation and differentiation, as well as enhanced lamellar body secretion. These results indicate that topical hesperidin enhances epidermal permeability barrier homeostasis at least in part due to stimulation of epidermal proliferation, differentiation, as well as lamellar body secretion. PMID- 22509831 TI - Zinc gluconate is an agonist of peroxisome proliferator-activated receptor-alpha in the epidermis. AB - Peroxisome proliferator-activated receptors-alpha (PPARs-alpha) are nuclear receptors with anti-inflammatory properties. Zinc gluconate is efficient in the treatment of several inflammatory dermatoses. The aim of our work was to determine whether the modulation of PPAR-alpha expression and activity could be one of the mechanisms of action of zinc gluconate anti-inflammatory activity in inflammatory dermatoses. Thus, we used ex vivo skin explants incubated with lipopolysaccharide (LPS), a pro-inflammatory molecule, with or without zinc gluconate. We evaluated PPAR-alpha protein expression using immunohistochemistry, PPAR-alpha DNA-binding activity using an ELISA-like technique, and PPAR-alpha mRNA levels using quantitative PCR. On the one hand, we found that PPAR-alpha epidermal protein expression was stimulated by LPS and that LPS suppressed PPAR alpha mRNA expression, without modifying its function. On the other hand, in inflammatory LPS-stimulated explants, zinc gluconate significantly upregulated PPAR-alpha function and mRNA expression level, without changing its epidermal protein expression. These results suggest that zinc gluconate may be a PPAR-alpha agonist, which might play a role in the anti-inflammatory activity of this molecule. PMID- 22509833 TI - Xenobiotic metabolism capacities of human skin in comparison with a 3D epidermis model and keratinocyte-based cell culture as in vitro alternatives for chemical testing: activating enzymes (Phase I). AB - Skin is important for the absorption and metabolism of exposed chemicals such as cosmetics or pharmaceuticals. The Seventh Amendment to the EU Cosmetics Directive prohibits the use of animals for cosmetic testing for certain endpoints, such as genotoxicity; therefore, there is an urgent need to understand the xenobiotic metabolizing capacities of human skin and to compare these activities with reconstructed 3D skin models developed to replace animal testing. We have measured Phase I enzyme activities of cytochrome P450 (CYP) and cyclooxygenase (COX) in ex vivo human skin, the 3D skin model EpiDermTM (EPI-200), immortalized keratinocyte-based cell lines and primary normal human epidermal keratinocytes. Our data demonstrate that basal CYP enzyme activities are very low in whole human skin and EPI-200 as well as keratinocytes. In addition, activities in monolayer cells differed from organotypic tissues after induction. COX activity was similar in skin, EPI-200 and NHEK cells, but was significantly lower in immortalized keratinocytes. Hence, the 3D model EPI-200 might represent a more suitable model for dermatotoxicological studies. Altogether, these data help to better understand skin metabolism and expand the knowledge of in vitro alternatives used for dermatotoxicity testing. PMID- 22509832 TI - Quantitative phosphoproteomics identifies filaggrin and other targets of ionizing radiation in a human skin model. AB - Our objective here was to perform a quantitative phosphoproteomic study on a reconstituted human skin tissue to identify low- and high-dose ionizing radiation dependent signalling in a complex three-dimensional setting. Application of an isobaric labelling strategy using sham and three radiation doses (3, 10, 200 cGy) resulted in the identification of 1052 unique phosphopeptides. Statistical analyses identified 176 phosphopeptides showing significant changes in response to radiation and radiation dose. Proteins responsible for maintaining skin structural integrity including keratins and desmosomal proteins (desmoglein, desmoplakin, plakophilin 1, 2 and 3) had altered phosphorylation levels following exposure to both low and high doses of radiation. Altered phosphorylation of multiple sites in profilaggrin linker domains coincided with altered profilaggrin processing suggesting a role for linker phosphorylation in human profilaggrin regulation. These studies demonstrate that the reconstituted human skin system undergoes a coordinated response to both low and high doses of ionizing radiation involving multiple layers of the stratified epithelium that serve to maintain tissue integrity and mitigate effects of radiation exposure. PMID- 22509834 TI - Xenobiotic metabolism capacities of human skin in comparison with a 3D-epidermis model and keratinocyte-based cell culture as in vitro alternatives for chemical testing: phase II enzymes. AB - The 7th Amendment to the EU Cosmetics Directive prohibits the use of animals in cosmetic testing for certain endpoints, such as genotoxicity. Therefore, skin in vitro models have to replace chemical testing in vivo. However, the metabolic competence neither of human skin nor of alternative in vitro models has so far been fully characterized, although skin is the first-pass organ for accidentally or purposely (cosmetics and pharmaceuticals) applied chemicals. Thus, there is an urgent need to understand the xenobiotic-metabolizing capacities of human skin and to compare these activities to models developed to replace animal testing. We have measured the activity of the phase II enzymes glutathione S-transferase, UDP glucuronosyltransferase and N-acetyltransferase in ex vivo human skin, the 3D epidermal model EpiDerm 200 (EPI-200), immortalized keratinocyte-based cell lines (HaCaT and NCTC 2544) and primary normal human epidermal keratinocytes. We show that all three phase II enzymes are present and highly active in skin as compared to phase I. Human skin, therefore, represents a more detoxifying than activating organ. This work systematically compares the activities of three important phase II enzymes in four different in vitro models directly to human skin. We conclude from our studies that 3D epidermal models, like the EPI-200 employed here, are superior over monolayer cultures in mimicking human skin xenobiotic metabolism and thus better suited for dermatotoxicity testing. PMID- 22509835 TI - Quercetin enhancement of arsenic-induced apoptosis via stimulating ROS-dependent p53 protein ubiquitination in human HaCaT keratinocytes. AB - In this study, QUE, but not the structurally related chemical, rutin, enhanced the cytotoxicity of arsenic trioxide (As(+3)) against the viability of normal human HaCaT keratinocytes via induction of apoptosis. QUE enhancement of As(+3) mediated apoptosis was accompanied by increased intracellular peroxide production according to a DCFH-DA analysis, and DNA ladders induced by QUE/As(+3) were inhibited by adding the antioxidative compound, N-acetyl cysteine (NAC). A loss of the mitochondrial membrane potential by QUE/As(+3) was observed according to DiOC(6) staining in concert with increased Bax protein and cytosolic cytochrome (Cyt) c protein expression in HaCaT cells, which was prevented by the addition of NAC. A decrease in the p53 protein with increased protein ubiquitination was detected in QUE/As(+3)-treated HaCaT cells, and this was prevented by the addition of NAC. The decrease in the p53 protein by QUE/As(+3) was reversed by adding the proteasome inhibitor, MG132. L-Buthionine sulphoximine (BSO) enhanced the cytotoxicity of As(+3) against the viability of HaCaT cells with reduced p53 protein through inducing protein ubiquitination and reactive oxygen species (ROS) production, and disrupting the mitochondrial membrane potential in HaCaT cells. Additionally, QUE and BSO enhanced the cytotoxic effects of monomethylarsonous acid (MMA(+3)) but not other arsenic compounds in accordance with increased p53 protein ubiquitination in HaCaT cells. QUE plus As(+3) stimulation of apoptosis in human HaCaT keratinocytes via activating ROS-dependent p53 protein ubiquitination may offer a rationale for the use of QUE to improve the clinical efficacy of arsenics in treating psoriasis. PMID- 22509836 TI - Long-term organ culture of keloid disease tissue. AB - Keloid disease (KD) is a common fibroproliferative disorder of unknown aetiopathogenesis, with highly unsatisfactory treatment. Therefore, it is crucial to have a robust and clinically relevant model for studying KD pathobiology as well as preclinical testing of potential KD therapeutics. However, the unique occurrence of KD in human skin and the corresponding lack of animal models pose a major challenge in KD research. Therefore, we developed a simplified assay for the serum-free, long-term organ culture of KD tissue that facilitates quantitative analyses of major KD read-out parameters. Four millimetre KD punches embedded in a collagen matrix and organ-cultured at the epidermis air-liquid interphase (ALI) in supplemented William's E medium showed optimal tissue, cell and RNA preservation for up to 6 weeks (as measured by H & E and Pyronin Y histochemistry as well as by MTT assay, lactate dehydrogenase release and quantitative Ki67/TUNEL immunohistomorphometry). The keloid phenotype persisted well during this period, as shown by collagen-I and -III synthesis (Herovici's histochemistry staining and ELISA), and analysis of the expression of significant KD markers (CD3, CD20, CD31, CD34, CD56, tryptase, Langerin, vimentin, neutrophil elastase, CTGF and Collagen). To functionally evaluate whether this assay can test the response to candidate therapeutics, dexamethasone, a glucocorticosteroid often used in KD therapy, was administered. Indeed, dexamethasone significantly reduced the keloid volume and cellularity plus induced epidermal shrinkage. Therefore, this novel assay provides a quantitative, clinically relevant model system for studying KD pathobiology and response to treatment. PMID- 22509837 TI - Contact dermatitis: from pathomechanisms to immunotoxicology. AB - Contact allergens are small reactive chemicals. They cause allergic contact dermatitis (ACD) by activating the innate and adaptive immune system. Contact allergens are very peculiar because of their built-in autoadjuvanticity that allows them to trigger sterile inflammation following skin penetration. The innate inflammatory response involves the triggering of pattern recognition receptors either by direct chemical interaction with such receptors or by induction of endogenous activators. I discuss here the recent findings regarding prevalence and predisposition, the identification of innate immune and stress response mechanisms relevant for sensitization and the orchestration of the innate and adaptive immune response to contact allergens. Despite still significant gaps of knowledge, recent advances in our understanding of the immunopathogenesis of ACD can now be used for the development of causative treatment strategies and of in vitro alternatives to animal testing for the identification of contact allergens in immunotoxicology. PMID- 22509838 TI - Selected variants of the steroid-5-alpha-reductase isoforms SRD5A1 and SRD5A2 and the sex steroid hormone receptors ESR1, ESR2 and PGR: no association with female pattern hair loss identified. AB - Female pattern hair loss (FPHL) is a common disorder with a complex mode of inheritance. Although understanding of its etiopathogenesis is incomplete, an interaction between genetic and hormonal factors is assumed to be important. The involvement of an androgen-dependent pathway and sex steroid hormones is the most likely hypothesis. We therefore selected a total of 21 variants from the steroid 5-alpha-reductase isoforms SRD5A1 and SRD5A2, the sex steroid hormone receptors ESR1, ESR2 (oestrogen receptor) and PGR (progesterone receptor) and genotyped these in a case-control sample of 198 patients (145 UK; 53 German patients) and 329 controls (179 UK; 150 German). None of these variants showed any significant association, either in the overall UK and German samples or in the subgroup analyses. In summary, the present results, while based on a limited selection of gene variants, do not point to the involvement of SRD5A1, SRD5A2, ESR1, ESR2 or PGR in FPHL. PMID- 22509839 TI - SZ95 sebocytes induce epidermal melanocyte dendricity and proliferation in vitro. AB - The regulatory effects of sebocytes on melanocytes (HMel) are unknown. In this study, SZ95 sebocytes co-cultured with HMel, whether in direct cell contact or with SZ95 sebocytes in inserts, resulted in epidermal HMel flattening with increase in surface area and multiple small dendrites formation. Only in high Ca(2+) level and direct cell contact co-culture, the HMel dendrites were remarkably long and preferentially targeted and attached to SZ95 sebocytes. Likewise, only high Ca(2+) SZ95 sebocyte conditioned medium stimulated HMel proliferation in a time-dependent manner at days 9 (142.9%, P < 0.01) and 12 (179.2%, P < 0.0001) of incubation when compared with day 0. In contrast, melanin contents significantly decreased on incubation with high Ca(2+) SZ95 sebocytes in comparison with low Ca(2+) SZ95 sebocytes at days 6 (P < 0.01) and 9 (P < 0.05) of incubation. These results denote that sebocytes also modulate HMel functions and may contribute to skin colour in sebaceous glands-rich body regions. PMID- 22509840 TI - Targeting of the hNC16A collagen domain to dendritic cells induces tolerance to human type XVII collagen. AB - Antibodies, specific to murine DEC205, can be used to target antigens to dendritic cells. The immunodominant domain of human type XVII collagen, hNC16A, was fused to this antibody (DEC-hNC16A) and was administered as expression plasmid by gene gun transfection with the aim of inducing tolerance to human type XVII collagen in a skin transplantation model. Mice transfected with DEC-hNC16A were challenged with skin grafts from transgenic mice engineered to express human type XVII collagen. Graft survival was either prolonged or grafts were accepted infinitely (33% and 16%, respectively) upon treatment with DEC-hNC16A while 100% of grafts were rejected in untreated controls. Graft acceptance was associated with the absence of a CD4+ infiltrate and a dense CD8+ T-cell infiltrate and was not strictly dependent on antibody production. Our results show that DEC-hNC16A targets dendritic cells in vivo leading to prolonged survival of transgenic skin grafts. This indicates that DEC205-targeting may be used for the induction of tolerance to skin antigens, which would increase the chances of successful skin gene therapy of epidermolysis bullosa patients. PMID- 22509841 TI - The anti-ageing potential of a new jasmonic acid derivative (LR2412): in vitro evaluation using reconstructed epidermis EpiskinTM. AB - Jasmonic acid is involved in plant wound repair and tissue regeneration, but no study has been reported in human skin. The effect of a jasmonic acid derivative, tetra-hydro-jasmonic acid (LR2412, 1 and 10 MUm) was investigated on an in vitro reconstructed skin model, EpiskinTM. Using real time RTQPCR studies, results showed an increase in hyaluronan synthase 2 (HAS2) and hyaluronase synthase 3 (HAS3) expression. Furthermore, an increase in hyaluronic acid (HA) deposits in basal and suprabasal layers of the epidermis was observed. The percentage of positive Ki67 keratinocytes in the basal layer as well as the epidermis thickness were seen to increase. Immunohistochemistry studies showed that the synthesis of late differentiation proteins filaggrin and transglutaminase 1 was not modified. The human epidermis is known to thin with age while HA content has been reported to decrease. These results illustrate the potential of LR2412 in counteracting signs of skin ageing. PMID- 22509842 TI - MALDI-TOF mass spectrometry: avoidance of artifacts and analysis of caffeine precipitated SII thearubigins from 15 commercial black teas. AB - Thearubigins are the quantitatively major phenolic compounds in black tea, accounting for some 60-70% of the solids in a typical black tea infusion. MALDI TOF mass spectra for caffeine-precipitated SII thearubigins (SII CTRs) from 15 different commercial teas support previous conclusions that SII CTRs are polyhydroxylated oligomers (rather than polymers) of catechins and catechin gallates in redox equilibrium with their quinone counterparts. Some 4500 peaks were revealed in a mass range from m/z 500 to 2100. Polyphenols are redox susceptible and readily generate artifacts during MALDI-TOF analysis when the matrix is also redox-susceptible. Of the nine matrices evaluated, 3',4',5' trihydroxyacetophenone (F) provided the best compromise between signal intensity and redox artifact formation. PMID- 22509843 TI - Dielectrophoretic growth of platinum nanowires: concentration and temperature dependence of the growth velocity. AB - The growth velocity of platinum nanowires in an aqueous solution of K(2)PtCl(4) is investigated as a function of the metal complex concentration and temperature. The solution is specially prepared to provide mainly the neutral complex cis [PtCl(2)(H(2)O)(2)] for growing nanowires by dielectrophoresis. The measured growth velocities indicate diffusion-limited nanowire growth at low concentration and high temperature in qualitative agreement with a theoretical analysis that includes the diffusion of metal complexes and the dielectrophoretic force on the complexes. At concentrations greater than 100 MUM and low temperature, different behavior is observed, suggesting the growth rate to be limited by the deposition reaction of platinum at the nanowire tip. The enhancement of the K(+) concentration is found to support nanowire growth. Possible reasons for a rate limitation and for the difference between observed and calculated nanowire growth velocities are discussed. PMID- 22509844 TI - Temporal analysis of the cocaine metabolite benzoylecgonine in wastewater to estimate community drug use. AB - Indirect estimation methods of cocaine consumption may not reflect the real extent of cocaine use. Another approach is sewage epidemiology. This direct approach is based on analysis of a stable cocaine metabolite, benzoylecgonine (BE), in wastewater. Influent to the Lubbock (Texas) Water Reclamation Plant was sampled twice a week to assess weekly variations in estimates of cocaine consumption over a 5-month period. BE was extracted from influent wastewater samples using solid phase extraction and analyzed using gas chromatography/mass spectrometry. Measured concentrations of BE were converted to cocaine equivalents; the estimated average daily consumption of cocaine during the study period was 1152 +/- 147 g. Based on BE concentrations and sewage epidemiology, higher cocaine consumption was observed on weekends compared to weekdays (p < 0.0003). This method was effective in monitoring BE in wastewater and could be used to complement survey data in estimating cocaine use at a local level. PMID- 22509845 TI - Analytical solution for well design with respect to discharge ratio. AB - For a well in the vicinity of a surface water body, a formula is developed that relates the share of bank filtrate on total pumpage, that is, the discharge ratio, on one side, to basic well and aquifer characteristics on the other. The application of the formula is demonstrated for solving the inverse problem: for an aimed discharge ratio, well characteristics (pumping rate, distance to shore) can be determined. Other useful applications of the formula are outlined. PMID- 22509846 TI - Direct enhancement of nuclear singlet order by dynamic nuclear polarization. AB - Hyperpolarized singlet order is available immediately after dissolution DNP, avoiding need for additional preparation steps. We demonstrate this procedure on a sample of [1,2-(13)C(2)]pyruvic acid. PMID- 22509847 TI - Process parameters study of alpha-amylase production in a packed-bed bioreactor under solid-state fermentation with possibility of temperature monitoring. AB - Production of alpha-amylase in a laboratory-scale packed-bed bioreactor by Bacillus sp. KR-8104 under solid-state fermentation (SSF) with possibility of temperature control and monitoring was studied using wheat bran (WB) as a solid substrate. The simultaneous effects of aeration rate, initial substrate moisture, and incubation temperature on alpha-amylase production were evaluated using response surface methodology (RSM) based on a Box-Behnken design. The optimum conditions for attaining the maximum production of alpha-amylase were 37 degrees C, 72% (w/w) initial substrate moisture, and 0.15 L/min aeration. The average enzyme activity obtained under the optimized conditions was 473.8 U/g dry fermented substrate. In addition, it was observed that the production of enzyme decreased from the bottom of the bioreactor to the top. PMID- 22509848 TI - Cell separation by countercurrent centrifugal elutriation: recent developments. AB - Countercurrent centrifugal elutriation (CCE) is a cell separation technique that separates particles predominantly according to their size, and to some degree according to their specific density, without a need for antibodies or ligands tagging cell surfaces. The principles of this technique have been known for half a century. Still, numerous recent publications confirmed that CCE is a valuable supplement to current cell separation technology. It is mainly applied when homogeneous populations of cells, which mirror an in vivo situation, are required for answering scientific questions or for clinical transplantation, while antibodies or ligands suitable for cell isolation are not available. Currently, new technical developments are expanding its application toward fractionation of healthy and malignant tissue cells and the preparation of dendritic cells for immunotherapy. PMID- 22509849 TI - Immobilization of cellulases on amine and aldehyde functionalized Fe2O3 magnetic nanoparticles. PMID- 22509850 TI - Microbial synthesis of rhamnolipids by Pseudomonas aeruginosa (ATCC 10145) on waste frying oil as low cost carbon source. AB - Vegetable edible oils and fats are mainly used for frying purposes in households and the food industry. The oil undergoes degradation during frying and hence has to be replaced from time to time. Rhamnolipids are produced by microbial cultivation using refined vegetable oils as a carbon source and Pseudomonas aeruginosa (ATCC 10145). The raw material cost accounts for 10-30% of the overall cost of biosurfactant production and can be reduced by using low-cost substrates. In this research, attention was focused on the preparation of rhamnolipids, which are biosurfactants, using potential frying edible oils as a carbon source via a microbial fermentation technique. The use of low-cost substrates as a carbon source was emphasized to tilt the cost of production for rhamnolipids. The yield was 2.8 g/L and 7.5 g/L from waste frying oil before and after activated earth treatment, respectively. The crude product contained mainly dirhamnolipids, confirmed by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LC-MS), and (1)H nuclear magnetic resonance (NMR). Hence, the treatment can be used to convert waste frying oil as a low-cost substrate into a cost-effective carbon source. PMID- 22509851 TI - Medium optimization of antifungal activity production by Bacillus amyloliquefaciens using statistical experimental design. AB - In order to overproduce biofungicides agents by Bacillus amyloliquefaciens BLB371, a suitable culture medium was optimized using response surface methodology. Plackett-Burman design and central composite design were employed for experimental design and analysis of the results. Peptone, sucrose, and yeast extract were found to significantly influence antifungal activity production and their optimal concentrations were, respectively, 20 g/L, 25 g/L, and 4.5 g/L. The corresponding biofungicide production was 250 AU/mL, corresponding to 56% improvement in antifungal components production over a previously used medium (160 AU/mL). Moreover, our results indicated that a deficiency of the minerals CuSO(4), FeCl(3) . 6H(2)O, Na(2)MoO(4), KI, ZnSO(4) . 7H(2)O, H(3)BO(3), and C(6)H(8)O(7) in the optimized culture medium was not crucial for biofungicides production by Bacillus amyloliquefaciens BLB371, which is interesting from a practical point of view, particularly for low-cost production and use of the biofungicide for the control of agricultural fungal pests. PMID- 22509852 TI - Effect of agitation and aeration on the citric acid production by Yarrowia lipolytica grown on glycerol. AB - The effects of agitation rates from 400 to 900 rpm and aeration rates ranging from 0.18 to 0.6 vvm on biomass and citric acid production on glycerol media by acetate-negative mutants of Yarrowia lipolytica, Wratislavia 1.31 and Wratislavia AWG7, in batch culture were studied. The agitation rates of 800 and 900 rpm (at a constant aeration rate of 0.36 vvm) and aeration rates within the range of 0.24 0.48 vvm (at a constant agitation rate of 800 rpm), which generated dissolved oxygen concentration (DO) higher than 40%, were found the best for citric acid biosynthesis from glycerol. An increase in agitation rate (higher than 800 rpm) and aeration rate (higher than 0.36 vvm) had no impact on DO and citric acid production. The highest citric acid concentration (92.8 g/L) and yield (0.63 g/g) were obtained with Wratislavia 1.31 strain at 0.24 vvm. The highest volumetric citric acid production rate (1.15 g/Lh) and specific citric acid production rate (0.071 g/gh) were reached at 0.48 vvm. PMID- 22509853 TI - Toward the reliable diagnosis of indeterminate thyroid lesions: a HRMAS NMR-based metabolomics case of study. AB - Cytological analysis of thyroid nodules detected using ultrasound-guided fine needle aspiration technique is an efficient method for the diagnosis of well differenciated tumors such as papillary thyroid carcinoma. However, for between 10 to 30% of all the nodules, the cytological analysis based on fine-needle aspiration biopsies leads to an "indeterminated" identification. Consequently, a surgical excision is then necessary for a definite histological diagnosis of the lesions, resulting in 85% of the patient with indeterminated nodules undergoing unnecessary surgery since their tumor is finally diagnosed as benign. In this work, we discuss how HRMAS (1)H NMR-based metabolomics could be a complementary tool for the diagnosis of these elusive cases. We first showed that our approach was able to discriminate clearly any types of thyroid lesions from healthy tissues. Then we proceeded to demonstrate that the information produced by (1)H HRMAS NMR spectra differentiate tumors according to their malignancy grade, even when they belong to the "indeterminate" category. Analysis of the discriminating spectral area in this last case points out toward a possible increase of phenylalanine, taurine, and lactate and a decrease of choline and choline derivatives, myo- and scyllo-inositol in the malignant tumors compared to the benign ones. PMID- 22509854 TI - What is stopping us from using flumazenil? PMID- 22509855 TI - 3-Nitropropionic acid induces autophagy by forming mitochondrial permeability transition pores rather than activating the mitochondrial fission pathway. AB - BACKGROUND AND PURPOSE: Huntington's disease is a neurodegenerative process associated with mitochondrial alterations. Inhibitors of the electron-transport channel complex II, such as 3-nitropropionic acid (3NP), are used to study the molecular and cellular pathways involved in this disease. We studied the effect of 3NP on mitochondrial morphology and its involvement in macrophagy. EXPERIMENTAL APPROACH: Pharmacological and biochemical methods were used to characterize the effects of 3NP on autophagy and mitochondrial morphology. SH SY5Y cells were transfected with GFP-LC3, GFP-Drp1 or GFP-Bax to ascertain their role and intracellular localization after 3NP treatment using confocal microscopy. KEY RESULTS: Untreated SH-SY5Y cells presented a long, tubular and filamentous net of mitochondria. After 3NP (5 mM) treatment, mitochondria became shorter and rounder. 3NP induced formation of mitochondrial permeability transition pores, both in cell cultures and in isolated liver mitochondria, and this process was inhibited by cyclosporin A. Participation of the mitochondrial fission pathway was excluded because 3NP did not induce translocation of the dynamin-related protein 1 (Drp1) to the mitochondria. The Drp1 inhibitor Mdivi-1 did not affect the observed changes in mitochondrial morphology. Finally, scavengers of reactive oxygen species failed to prevent mitochondrial alterations, while cyclosporin A, but not Mdivi-1, prevented the generation of ROS. CONCLUSIONS AND IMPLICATIONS: There was a direct correlation between formation of mitochondrial permeability transition pores and autophagy induced by 3NP treatment. Activation of autophagy preceded the apoptotic process and was mediated, at least partly, by formation of reactive oxygen species and mitochondrial permeability transition pores. PMID- 22509858 TI - Liquid-filled metal microcapsules. AB - A moisture-sensitive diisocyanate liquid is microencapsulated within a metal shell measuring less than 2 MUm thick and 50 MUm in diameter. This mild synthesis takes place through a series aqueous processing steps that occur at or near room temperature. Through a combination of emulsification, interfacial polymerization, and electroless plating, one can microencapsulate moisture- or air-sensitive chemicals within a metal seal. The liquid-filled metal microcapsules promise a number of advantages compared to conventional polymeric microencapsulation, including improved mechanical properties and improved barrier properties to gases and organic molecules. PMID- 22509857 TI - Prevalence of Hemoproteus iwa in Galapagos great frigatebirds (Fregata minor) and their obligate fly ectoparasite (Olfersia spinifera). AB - The prevalence of hemosporidian parasites varies among different host species, geographic locations, habitats, and host life histories, and yet we do not have a firm understanding of the ultimate causes of the variation. Seabirds are not typically found infected with hemosporidian parasites; however, frigatebird species have been repeatedly documented with Hemoproteus spp. infections. Hemoproteus iwa in Galapagos great frigatebirds (Fregata minor) is vectored by a hippoboscid fly, Olfersia spinifera , an obligate ectoparasite of the bird host. Five populations of Galapagos great frigatebirds, and flies collected from the birds, were sampled and tested for H. iwa . Prevalence did not differ across 4 yr or between 5 islands, but males were found to have a significantly higher prevalence of infection than did females. Additionally, juveniles were more likely to be infected than were adults and chicks. Because the invertebrate vector is an obligate parasite, we were able to estimate prevalence in the vector as well as in the particular host upon which it fed, a task that is impossible, or nearly impossible, in hemosporidian parasites vectored by midges or mosquitoes. We tested the correlation between the infection status of the bird host and the infection status of the fly collected from the bird. More often than not the 2 were correlated, but some mismatches were found. Using the occurrence of infected flies on uninfected birds (12/99) as a proxy for transmission potential, we can estimate the transmission rate to be between 5 and 20% (95% confidence intervals) among individual vertebrate hosts. PMID- 22509856 TI - The role of transporters in the toxicity of nucleoside and nucleotide analogs. AB - INTRODUCTION: Two families of nucleoside analogs have been developed to treat viral infections and cancer, but these compounds can cause tissue- and cell specific toxicity related to their uptake and subcellular activity, which are dictated by host enzymes and transporters. Cellular uptake of these compounds requires nucleoside transporters that share functional similarities but differ in substrate specificity. Tissue-specific cellular expression of these transporters enables nucleoside analogs to produce their tissue-specific toxic effects, a limiting factor in the treatment of retroviruses and cancer. AREAS COVERED: This review discusses the families of nucleoside transporters and how they mediate cellular uptake of nucleoside analogs. Specific focus is placed on examples of known cases of transporter-mediated cellular toxicity and classification of the toxicities resulting. Efflux transporters are also explored as a contributor to analog toxicity and cell-specific effects. EXPERT OPINION: Efforts to modulate transporter uptake/clearance remain long-term goals of oncologists and virologists. Accordingly, subcellular approaches that either increase or decrease intracellular nucleoside analog concentrations are eagerly sought and include transporter inhibitors and targeting transporter expression. However, additional understanding of nucleoside transporter kinetics, tissue expression and genetic polymorphisms is required to design better molecules and better therapies. PMID- 22509859 TI - Efficacy and safety of biphasic insulin aspart 70/30 in type 2 diabetes patients of different race or ethnicity (INITIATEplus trial). AB - OBJECTIVE: To determine if self-titration using biphasic insulin aspart 70/30 (BIAsp 30) had a different impact on efficacy and safety across different racial/ethnic subgroups. RESEARCH DESIGN/METHODS: This was an exploratory, post hoc analysis by race (White vs. Black/African-American) and ethnicity (Hispanic/Latino vs. non-Hispanic/Latino) of data from the INITIATEplus trial. Participants were treated twice-daily with BIAsp 30 over 24 weeks. TRIAL REGISTRATION: NCT00101751. MAIN OUTCOME MEASURES: Efficacy endpoints included reductions in mean glycated hemoglobin (A1C) and fasting plasma glucose (FPG). Safety endpoints included hypoglycemia rates (events/patient-year) and adverse events. Body weight changes were also measured. RESULTS: Glycemic control improved by a similar extent for all demographic groups. Observed mean decreases in A1C ranged from 2.4% to 2.6% after 24 weeks' treatment. Baseline-adjusted mean A1C decreases for White vs. Black/African-American subjects were 2.56% and 2.13% (p < 0.0001), and for Hispanic/Latino vs. non-Hispanic/Latino subjects were 2.45% and 2.42% (p = 0.677), respectively. Final FPG values were similar among all groups (141-146 mg/dL [7.83-8.10 m mol/L]), and baseline-adjusted FPG decreases were not significantly different (p > 0.025) between groups. Hypoglycemia was low for White, Black/African-American, Hispanic/Latino, and non-Hispanic/Latino subjects (0.08, 0.04, 0.03, and 0.07 major events/patient-year, with 0.60, 0.30, 0.37, and 0.52 minor events/patient-year, respectively). Body weight increases were 3.17 and 3.06 kg (White vs. African-American) and 2.69 and 3.19 kg (Hispanic/Latino vs. non-Hispanic/Latino). Final weight-adjusted total daily insulin doses were 0.60 U/kg for Black/African-American subjects vs. 0.78 U/kg for White subjects (p < 0.0001), and 0.71 U/kg for Hispanic/Latino subjects vs. 0.74 U/kg for non-Hispanic/Latino subjects (p = 0.42). LIMITATIONS: The trial was not designed or powered for comparisons across racial or ethnic groups, subjects were not stratified for pre-baseline medication regimens between each race and ethnic group, and unequal subject numbers and baseline A1C disparities existed between the pairs of groups being compared. CONCLUSIONS: Diabetes self-management with BIAsp 30 using an easily followed self-titration algorithm produced low hypoglycemia rates. All subgroups achieved A1C reductions >2.1% and FPG declines >82 mg/dL that were similar across groups, demonstrating that self-titration of BIAsp 30 can successfully be pursued in a primary care setting by patients who had previously failed to meet ADA A1C targets under oral antidiabetes therapy, with race or ethnicity not an obstacle to achieving better glycemic control. PMID- 22509860 TI - Distal protection devices in primary percutaneous coronary intervention of native coronary artery lesions: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: The use of embolic protection devices to decrease major adverse cardiac events (MACEs) in patients with saphenous vein graft lesions is considered class I therapy by the recent practice guidelines. However, the benefits of adjunctive protection devices to prevent distal embolization in patients with native coronary artery lesions are still a matter of debate. Therefore, we performed the meta-analysis to determine whether the use of distal protection devices during revascularization can improve myocardial perfusion and reduce the occurrence of MACEs compared with primary percutaneous coronary intervention (PCI) alone. METHODS AND RESULTS: Studies were identified in English language articles by search of Medline and Embase database (inception to December 2011). A total of 15 prospective randomized controlled trials involving 2783 patients were included for analysis (1378 patients in the distal protection device group and 1405 cases in the control group). Overall, adjunctive embolic protection was associated with significantly improved postprocedural TIMI 3 (thrombolysis in myocardial infarction 3) flow (OR 1.71; 95% CI 1.13-2.57; P = 0.01) and MBG 3 (myocardial blush grade 3) (OR 1.50; 95% CI 1.09-2.07; P = 0.01), whereas the overall MACEs analysis demonstrated that a nonsignificant trend was observed toward better clinical outcomes associated with adjunctive protection devices at 1 month (OR 0.80; 95% CI 0.55-1.15; P = 0.23) and at 6 months (OR 0.80; 95% CI 0.55-1.17; P = 0.24). When stratified by MACEs, no statistical differences were found among mortality, reinfarction, and target vessel revascularization (TVR), respectively. CONCLUSIONS: The meta-analysis indicated an improvement of myocardial perfusion in AMI patients treated with adjunctive protection devices. However, a nonsignificant trend was observed toward a lower risk of MACEs in the distal protection device group when compared with the control group. PMID- 22509861 TI - Managing conflicts of interest: who, and how? PMID- 22509862 TI - A call for national e-health clinical safety governance. PMID- 22509863 TI - Avoiding adverse events with dabigatran by careful selection of eligible patients. PMID- 22509864 TI - New medicines - urgent need to assess outcomes in special groups. PMID- 22509865 TI - Clinical software on personal mobile devices needs regulation. PMID- 22509866 TI - Towards sharing health-services data. PMID- 22509867 TI - Beyond evidence: reappraising use of CA-125 as post-therapy surveillance for ovarian cancer. PMID- 22509868 TI - Energy drinks: health risks and toxicity. Comment. PMID- 22509869 TI - Conflict of interest guidelines for clinical guidelines. Comment. PMID- 22509870 TI - How receptive are patients to medical students in Australian hospitals? A cross sectional survey of a public and a private hospital. PMID- 22509871 TI - Congenital toxoplasmosis over 10 years in a low-incidence population. PMID- 22509872 TI - Case series of four patients with strongyloides after occupational exposure. PMID- 22509873 TI - Human papillomavirus vaccination and cervical cancer screening by socioeconomic status, Victoria. PMID- 22509874 TI - Universal human papillomavirus vaccination of Australian boys - neither cost effective nor equitable. PMID- 22509875 TI - Upper limb tremor. AB - Tremor is a common clinical problem in middle-aged and older patients, and Parkinson disease (PD) is one of the commonest causes. Careful history-taking and physical examination is usually sufficient for diagnosis of PD; extensive investigation is generally not required. Treatment of PD should be individualised, taking into account the patient's age, lifestyle, severity of motor symptoms, level of disability, comorbidities, expectations of treatment and PD subtype (eg, akinetic rigid or tremor dominant). In PD, optimal medical therapy often involves a combination of dopaminergic medications, aiming for doses that provide adequate symptom relief without adverse effects such as dyskinesias and impulse-control disorders. Continuous dopaminergic stimulation and deep brain stimulation should be considered for patients with PD whose motor symptoms cannot be adequately controlled with oral medication, especially those aged less than 70 years. PMID- 22509876 TI - Policies and practices on competing interests of academic staff in Australian universities. AB - OBJECTIVES: To document the existence and provisions of Australian universities' policies on the competing interests of academic staff and university practices in recording, updating and making these declarations publicly accessible. DESIGN AND SETTING: A 14-item survey was sent to the vice-chancellors of 39 Australian universities and university websites were searched for relevant policies. RESULTS: Twelve universities declined to provide any information. Of the 27 that did, all had policies on staff competing interests. Fifteen did not require regular declarations from staff and only four required annual declarations. Eight universities maintained a centralised register of COIs of all staff and six had a mechanism in place that allowed members of the public to access information on COIs. None reported that they required that staff place their COI declarations on their website profiles and none had policies that indicated that staff should declare COIs when making a public comment. CONCLUSIONS: Australian universities vary significantly in their approaches to the declaration and management of competing interests. While two-thirds of Australian universities require staff to declare competing interests, this information is mostly inaccessible to the public. Australian universities should adopt a standard approach to the declaration and management of competing interests and commit to meaningful transparency and public accountability. This could include frequently updated declarations on website profiles of all staff. In addition, dialogue about what is needed to effectively deal with competing interests should be encouraged. PMID- 22509877 TI - Eligibility for medical thromboprophylaxis based on risk-factor weights, and clinical thrombotic event rates. AB - OBJECTIVES: To measure eligibility for medical thromboprophylaxis using two Australasian guidelines - the Australia and New Zealand Working Party Guidelines [WPG] and the National Health and Medical Research Council Guidelines [NHMRCG]) - and proposed new guidelines based on risk-factor weights; and to measure the incidence of clinical venous thromboembolism (VTE) events in medical patients ("ensuing VTE"). DESIGN, SETTING AND PATIENTS: Prospective case-note audit in an acute medical ward of Southland Hospital, a regional hospital in Invercargill, New Zealand, among all 595 patients who were discharged consecutively from 21 November 2010 to 7 March 2011. Of these, 245 were excluded on clinical grounds or because they were under the care of the authors. MAIN OUTCOME MEASURES: The primary outcome was eligibility for prophylaxis under each guideline. Secondary outcomes included incidence of ensuing VTEs, use of thromboprophylaxis, drug acquisition costs with each guideline, and bedside practicability of a guideline based on risk-factor weights. RESULTS: Nineteen per cent of patients were eligible under the new guidelines, compared with 80%, 88% and 36% under the WPG and two interpetations of the NHMRCG, respectively. One patient had an ensuing VTE. The new guideline had lower drug acquisition costs and was suitable for bedside use. CONCLUSIONS: Clinical VTE events are rare in medical patients, and medical VTE thromboprophylaxis needs to be more focused. The new guideline has performance characteristics th@satisfy this need. PMID- 22509878 TI - Prothrombinex-VF use in warfarin reversal and other indications. AB - OBJECTIVE: To assess the use of Prothrombinex-VF powder for injection (PTX-VF) at Royal Perth Hospital and analyse the efficacy and safety profile of PTX-VF. DESIGN, SETTING AND PATIENTS: A prospective observational audit of PTX-VF use, conducted by reviewing medical records and laboratory and imaging results for all patients prescribed PTX-VF from 1 November 2009 to 1 May 2010. MAIN OUTCOME MEASURES: Data on indication, diagnosis, comorbidities, dose of PTX-VF, fresh frozen plasma (FFP) and vitamin K, coagulation parameters before and after PTX-VF administration, and adverse effects. RESULTS: 334 vials of PTX-VF were administered to 84 patients over 107 prescriptions. Indications were warfarin reversal, intraoperative bleeding and coagulopathy (66, 20 and 21 prescriptions, respectively). PTX-VF with FFP was compared with PTX-VF alone for warfarin reversal and there was a significant decrease in international normalised ratio (INR) that was independent of group (P < 0.001). Lower doses of PTX-VF (< 25 IU/kg) were compared with higher doses (25-50 IU/kg) for warfarin reversal and decrease in INR was significant, independent of group (P = 0.002). PTX-VF was administered for intraoperative bleeding in 18 patients who had not been treated with warfarin. No hypersensitivity reactions, thrombotic complications or worsening of disseminated intravascular coagulation occurred during 7-day follow up. CONCLUSION: For warfarin reversal, lower doses of PTX-VF (< 25 IU/kg) and PTX VF without FFP were effective. PTX-VF was also used in intraoperative bleeding and non-warfarin coagulopathy. No adverse events were associated with PTX-VF. PMID- 22509879 TI - Incidence of vitamin D deficiency rickets among Australian children: an Australian Paediatric Surveillance Unit study. AB - OBJECTIVE: To determine the incidence of and factors associated with vitamin D deficiency rickets in Australian children. DESIGN: 18-month questionnaire-based prospective observational study, using Australian Paediatric Surveillance Unit (APSU) data. SETTING: Australian paediatricians and child health workers, January 2006 - July 2007. PARTICIPANTS: Children aged <= 15 years with vitamin D deficiency rickets (25-hydroxyvitamin D [25OHD] <= 50 nmol/L, and elevated alkaline phosphatase levels [> 229 IU/L] and/or radiological rickets). MAIN OUTCOME MEASURES: Incidence of vitamin D deficiency rickets. Description of demographics, clinical presentation, identification and further analysis of overrepresented groups, and treatment regimens compared with best-practice guidelines. RESULTS: We identified 398 children with vitamin D deficiency (55% male; median age, 6.3 years [range, 0.2-15 years]). The overall incidence in children <= 15 years of age in Australia was 4.9/100 000/year. All had a low 25OHD level (median, 28 nmol/L [range, 5-50 nmol]) and an elevated alkaline phosphatase level (median, 407 IU/L [range, 229-5443 IU/L]), and 48 (12%) were hypocalcaemic. Ninety-five children had wrist x-rays, of whom 67 (71%) had rachitic changes. Most (98%) had dark or intermediate skin colour and 18% of girls were partially or completely veiled. Most children were born in Africa (252; 63%) and 75% of children were refugees. Duration of exclusive breastfeeding was inversely related to serum vitamin D levels in children < 3 years of age. Empirical vitamin D treatment was given to 4% of children before diagnosis. CONCLUSIONS: Vitamin D deficiency rickets is a significant problem in Australia among known high-risk groups. Public health campaigns to prevent, identify and tre@vitamin D deficiency, especially in high-risk groups, are essential. PMID- 22509880 TI - Endovascular therapy after stroke in a patient treated with dabigatran. PMID- 22509881 TI - The context of clinical teaching and learning in Australia. AB - Gaining clinical experience for an extended period of time in teaching hospitals is one of the enduring strengths of medical education. Teaching hospitals have recently faced significant challenges, with increasing specialisation of services and workload pressures reducing clinical learning opportunities. New clinical teaching environments have been established in Australia, particularly in rural and regional areas; these are proving to be ideal contexts for student learning. The new clinical teaching environments have shown the importance of developing symbiotic relationships between universities and health services. Symbiotic clinical learning is built around longitudinal, patient-based learning emphasising priority health concerns. The symbiotic framework provides a basis for reconstructing clinical teaching in teaching hospitals so th@they continue to play a vital role in Australian medical education, with additional clinical experience provided by primary care and community, rural and regional hospitals. PMID- 22509882 TI - The Indian camp. PMID- 22509884 TI - Tattoos, piercings, and alcohol consumption. AB - OBJECTIVE: Previous studies have found a link between body tattoos or piercings and risky behavior. However, these studies only examined survey data but not real behavior. METHODS: Young men (mean = 20.6 years) and women (mean = 20.2 years) leaving a bar were asked whether they wore tattoos and piercings or not and were requested to breathe into a breathalyzer in order to evaluate their alcohol consumption. RESULTS: It was found that participants with piercings and/or tattoos as well as combined piercings and tattoos revealed higher levels of alcohol consumption. CONCLUSIONS: Piercings and tattoos could serve as signs of alcohol consumption for educators, parents, and physicians. PMID- 22509885 TI - e-Learning initiatives to support prescribing. AB - Preparing medical students to prescribe is a major challenge of undergraduate education. They must develop an understanding of clinical pharmacology and acquire knowledge about drugs and therapeutics, as well as the skills to prescribe for individual patients in the face of multiple variables. The task of delivering the learning required to achieve these attributes relies upon limited numbers of teachers, who have increasingly busy clinical commitments. There is evidence that training is currently insufficient to meet the demands of the workplace. e-Learning provides an opportunity to improve the learning experience. The advantages for teachers are improved distribution of learning content, ease of update, standardization and tracking of learner activities. The advantages for learners are ease of access, greater interactivity and individual choice concerning the pace and mix of learning. Important disadvantages are the considerable resource required to develop e-Learning projects and difficulties in simulating some aspects of the real world prescribing experience. Pre-requisites for developing an e-Learning programme to support prescribing include academic expertise, institutional support, learning technology services and an effective virtual learning environment. e-Learning content might range from complex interactive learning sessions through to static web pages with links. It is now possible to simulate and provide feedback on prescribing decisions and this will improve with advances in virtual reality. Other content might include a student formulary, self-assessment exercises (e.g. calculations), a glossary and an on line library. There is some evidence for the effectiveness of e-Learning but better research is required into its potential impact on prescribing. PMID- 22509886 TI - Worldwide experience with the robotic navigation system in catheter ablation of atrial fibrillation: methodology, efficacy and safety. AB - INTRODUCTION: The Hansen Robotic system has been utilized in ablation procedures for atrial fibrillation (AF). However, because of the lack of tactile feedback and the rigidity of the robotic sheath, this approach could result in higher risk of complications. This worldwide survey reports a multicenter experience on the methodology, efficacy, and safety of the Hansen system in AF ablations. METHODS AND RESULTS: A questionnaire addressing questions on patient's demographics, procedural parameters, ablation success rate and safety information was sent to all centers where more than 50 robotic AF ablation cases have been performed. From June 2007 to December 2009, 1,728 procedures were performed at 12 centers utilizing the Hansen robotic navigation technology. The overall complication rate was 4.7% and the success rate was 67.1% after 18 +/- 4 months of follow-up. In 5 low volume centers there appeared to be a learning curve of about 50 cases (complication rate 11.2% for the first 50 cases vs 3.7% for the 51-100 cases; P = 0.044) and a trend showing a decrease of complication rate with increasing case volume. However, in the remaining 7 centers no learning curve was present and the complication rate was stable over time (3.7% for the first 50 cases vs 3.6% for the 51st case thereafter; P = 0.942). CONCLUSION: The Hansen robotic system can be used for AF ablation safely. In low volume centers, there appeared to be a learning curve of the first 50 cases after which the complication rate decreased. With a higher case volume, the success rate increased. PMID- 22509887 TI - Transient convection, diffusion, and adsorption in surface-based biosensors. AB - This paper presents a theoretical and computational investigation of convection, diffusion, and adsorption in surface-based biosensors. In particular, we study the transport dynamics in a model geometry of a surface plasmon resonance (SPR) sensor. The work, however, is equally relevant for other microfluidic surface based biosensors, operating under flow conditions. A widely adopted approximate quasi-steady theory to capture convective and diffusive mass transport is reviewed, and an analytical solution is presented. An expression of the Damkohler number is derived in terms of the nondimensional adsorption coefficient (Biot number), the nondimensional flow rate (Peclet number), and the model geometry. Transient dynamics is investigated, and we quantify the error of using the quasi steady-state assumption for experimental data fitting in both kinetically limited and convection-diffusion-limited regimes for irreversible adsorption, in specific. The results clarify the conditions under which the quasi-steady theory is reliable or not. In extension to the well-known fact that the range of validity is altered under convection-diffusion-limited conditions, we show how also the ratio of the inlet concentration to the maximum surface capacity is critical for reliable use of the quasi-steady theory. Finally, our results provide users of surface-based biosensors with a tool for correcting experimentally obtained adsorption rate constants. PMID- 22509888 TI - Plant sterols and antioxidant parameters in enriched beverages: storage stability. AB - Plant sterols (PS) stability, antioxidant parameters, and color were studied during 6 months of storage at 4, 24, and 37 degrees C in three PS-enriched functional beverages. Beverages were skimmed milk with fruit juice and PS (MFJPS), fruit juice and PS (FJPS), and skimmed milk with PS (MPS). No loss in total PS content occurred during storage observing the same values at any given storage time point. Total carotenoids decreased 36% with storage at two months and then remained stable. Total polyphenols showed fluctuations throughout the storage, remaining stable at 6 months and reaching initial values. The antioxidant capacity (TEAC method) increased 18% at 6 months, and there was an increase in color over time and temperature, probably due to Maillard reaction compound formation. The increase in total antioxidant capacity might have helped PS maintenance throughout storage, these beverages being a good PS source even after 6 months of storage. PMID- 22509889 TI - Revisiting community-scale greenhouse gas inventories. PMID- 22509890 TI - Overexpression of DNA polymerase iota (Poliota) in esophageal squamous cell carcinoma. AB - The present study investigated the transcriptional regulation of low-fidelity translesion DNA synthesis (TLS) polymerases in human esophageal carcinoma. Significantly higher mRNA expression of polymerase zeta (Polxi), RAD18, polymerase iota (Poliota), and polymerase kappa (Polkappa) was found in esophageal carcinomas. The increased expression of Poliota in tumor samples was further confirmed by immunohistochemistry. The promoter of POLI that encodes Poliota was found to be hypomethylated, although the overexpression of this gene was unlikely to be associated with methylation in tumors. We further identified Sp1 and Oct-1 binding sites present in the POLI promoter. We observed that the binding affinity of Sp1 to the POLI promoter was significantly increased in cancerous tissues and that Sp1 activated POLI gene transcription in cultured cell lines. The present study demonstrates overexpression of the TLS genes in esophageal carcinoma and identifies a key role for Sp1 in upregulating POLI gene expression. PMID- 22509891 TI - Assembling photoluminescent silicon nanocrystals into periodic mesoporous organosilica. AB - A contemporary question in the intensely active field of periodic mesoporous organosilica (PMO) materials is how large a silsesquioxane precursor can be self assembled under template direction into the pore walls of an ordered mesostructure. An answer to this question is beginning to emerge with the ability to synthesize dendrimer, buckyball, and polyhedral oligomeric silsesquioxane PMOs. In this paper, we further expand the library of large-scale silsesquioxane precursors by demonstrating that photoluminescent nanocrystalline silicon that has been surface-capped with oligo(triethoxysilylethylene), denoted as ncSi:(CH(2)CH(2)Si(OEt)(3))(n)H, can be self-assembled into a photoluminescent nanocrystalline silicon periodic mesoporous organosilica (ncSi-PMO). A comprehensive multianalytical characterization of the structural and optical properties of ncSi-PMO demonstrates that the material gainfully combines the photoluminescent properties of nanocrystalline silicon with the porous structure of the PMO. This integration of two functional components makes ncSi-PMO a promising multifunctional material for optoelectronic and biomedical applications. PMID- 22509892 TI - Ultraviolet induction of antifungal activity in plants. AB - Ultraviolet-C irradiation as a method to induce the production of plant compounds with antifungal properties was investigated in the leaves of 18 plant species. A susceptibility assay to determine the antifungal susceptibility of filamentous fungi was developed based on an agar dilution series in microtiter plates. UV irradiation strongly induced antifungal properties in five species against a clinical Fusarium solani strain that was responsible for an onychomycosis case that was resistant to classic pharmacological treatment. The antifungal properties of three additional plant species were either unaffected or reduced by UV-C irradiation. This study demonstrates that UV-C irradiation is an effective means of modulating the antifungal activity of very diverse plants from a screening perspective. PMID- 22509893 TI - Twelve tips for running teaching programmes for newly qualified doctors. AB - A teaching programme for newly qualified doctors is necessary for their continuing professional development and education. However, guidelines for the logistics and content of such teaching programmes are limited. These 12 tips provide advice and guidance for the creation and development of a successful programme. This article is intended for readers who are involved in teaching; programme directors, administrators, tutors and trainee doctors themselves. The principles included will also be useful for those involved in developing other types of teaching programmes. Engagement of trainees, the education department and other staff in the hospital is crucial for the success of teaching programmes. A culture of attendance and feedback may take time and effort to establish but is absolutely essential for long-term programme viability. Innovative approaches to teaching, a range of teaching staff and coverage of varied clinical and non-clinical topics, all contribute to a strong programme. PMID- 22509894 TI - The misinterpretation of the standard error of measurement in medical education: a primer on the problems, pitfalls and peculiarities of the three different standard errors of measurement. AB - BACKGROUND: In high-stakes assessments in medical education, such as final undergraduate examinations and postgraduate assessments, an attempt is frequently made to set confidence limits on the probable true score of a candidate. Typically, this is carried out using what is referred to as the standard error of measurement (SEM). However, it is often the case that the wrong formula is applied, there actually being three different formulae for use in different situations. AIMS: To explain and clarify the calculation of the SEM, and differentiate three separate standard errors, which here are called the standard error of measurement (SEmeas), the standard error of estimation (SEest) and the standard error of prediction (SEpred). RESULTS: Most accounts describe the calculation of SEmeas. For most purposes, though, what is required is the standard error of estimation (SEest), which has to be applied not to a candidate's actual score but to their estimated true score after taking into account the regression to the mean that occurs due to the unreliability of an assessment. A third formula, the standard error of prediction (SEpred) is less commonly used in medical education, but is useful in situations such as counselling, where one needs to predict a future actual score on an examination from a previous actual score on the same examination. CONCLUSIONS: The various formulae can produce predictions that differ quite substantially, particularly when reliability is not particularly high, and the mark in question is far removed from the average performance of candidates. That can have important, unintended consequences, particularly in a medico-legal context. PMID- 22509895 TI - Comparative analysis of the chemical profiles of 3,4 methylenedioxymethamphetamine based on comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC * GC-TOFMS). AB - The chemical profiling of illicit drugs is an important analytical tool to support the work of investigating and law enforcement authorities. In our work, comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC * GC-TOFMS) combined with nontargeted, pixel-based data analysis was adapted for the chemical profiling of 3,4-methylenedioxymethamphetamine (MDMA). The validity and benefit of this approach was evaluated by analyzing a well investigated set of MDMA samples. Samples were prepared according to a harmonized extraction protocol to ensure the comparability of the chemical signatures. The nontargeted approach comprises preprocessing followed by analysis of variances as a fast filter algorithm for selection of a variable subset followed by partial least squares discriminant analysis for reduction to promising marker compounds for discrimination of the samples according to their chemical profile. Forty seven potential marker compounds were determined, covering most of the target impurities known from the harmonized one-dimensional profiling as well as other compounds not previously elucidated. PMID- 22509896 TI - The Kozeny-Carman equation with a percolation threshold. AB - A procedure has been developed for calculating permeability (k) from the Kozeny Carman equation, a procedure that links ideas from percolation theory with the ideas of Koltermann and Gorelick (1995) and Esselburn et al. (2011). The approach focuses on the proportion of coarser pores that are occupied by finer sediments relative to a percolation threshold proportion (omega(c)). If the proportion occupied is below omega(c), then the unoccupied coarser pores percolate. Otherwise they do not percolate. Following the ideas of Koltermann and Gorelick (1995), the effective grain-size term in the Kozeny-Carman equation is calculated using the geometric mean if the unoccupied coarse pores percolate, and using the harmonic mean if otherwise. Following ideas of Esselburn et al. (2011), this approach is implemented by evaluating the potential for grains in each size category to occupy pores among sediment of each larger-size category. Application of these ideas to physical sediment models for sands and gravels, which have known k, indicates that a threshold does indeed exist. Results also suggest that the Kozeny-Carman equation is robust and gives representative values for k, even though omega(c) is not precisely known. PMID- 22509898 TI - Condensation of excitons in a trap. AB - Condensation is observed in a gas of indirect excitons confined in an electrostatic trap. Imaging and interferometric measurements detect that excitons condense at the trap bottom and exciton spontaneous coherence emerges with lowering temperature. Below a temperature of about 1 K, the direct signature of Bose-Einstein condensation, the extension of coherence over the entire cloud, is observed. PMID- 22509897 TI - JTV519 (K201) reduces sarcoplasmic reticulum Ca2+ leak and improves diastolic function in vitro in murine and human non-failing myocardium. AB - BACKGROUND AND PURPOSE: Ca2+ leak from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyR2s) contributes to cardiomyocyte dysfunction. RyR2 Ca2+ leak has been related to RyR2 phosphorylation. In these conditions, JTV519 (K201), a 1,4-benzothiazepine derivative and multi-channel blocker, stabilizes RyR2s and decrease SR Ca2+ leak. We investigated whether JTV519 stabilizes RyR2s without increasing RyR2 phosphorylation in mice and in non-failing human myocardium and explored underlying mechanisms. EXPERIMENTAL APPROACH: SR Ca2+ leak was induced by ouabain in murine cardiomyocytes. [Ca2+]-transients, SR Ca2+ load and RyR2-mediated Ca2+ leak (sparks/waves) were quantified, with or without JTV519 (1 umol.L-1). Contribution of Ca2+ -/calmodulin-dependent kinase II (CaMKII) was assessed by KN-93 and Western blot (RyR2-Ser(2814) phosphorylation). Effects of JTV519 on contractile force were investigated in non-failing human ventricular trabeculae. KEY RESULTS: Ouabain increased systolic and diastolic cytosolic [Ca2+](i) , SR [Ca2+], and SR Ca2+ leak (Ca2+ spark (SparkF) and Ca2+ wave frequency), independently of CaMKII and RyR-Ser(2814) phosphorylation. JTV519 decreased SparkF but also SR Ca2+ load. At matched SR [Ca2+], Ca2+ leak was significantly reduced by JTV519, but it had no effect on fractional Ca2+ release or Ca2+ wave propagation velocity. In human muscle, JTV519 was negatively inotropic at baseline but significantly enhanced ouabain-induced force and reduced its deleterious effects on diastolic function. CONCLUSIONS AND IMPLICATIONS: JTV519 was effective in reducing SR Ca2+ leak by specifically regulating RyR2 opening at diastolic [Ca2+](i) in the absence of increased RyR2 phosphorylation at Ser(2814) , extending the potential use of JTV519 to conditions of acute cellular Ca2+ overload. PMID- 22509899 TI - The effects of green tea polyphenols on drug metabolism. AB - INTRODUCTION: Tea, made from the dried leaves of the plant Camellia sinensis Theaceae, is a very popular beverage consumed worldwide. Recently, green tea extract-based dietary supplements have also been widely consumed for the acclaimed beneficial health effects, such as weight reduction. Although tea consumption is considered to be innocuous, the potential interactions between tea polyphenols and drugs have been demonstrated in studies in vitro and in vivo. AREAS COVERED: This article reviews the current literature on the chemistry and biotransformation of tea constituents, mainly catechins from green tea. The article also provides a review of their effects on the absorption, efflux, metabolism and elimination of different drugs. EXPERT OPINION: Tea catechins may bind to certain drugs to affect their absorption and bioactivities. Tea catechins may inhibit the activities of drug-metabolizing enzymes and drug transporters or affect the expression of these proteins, either upregulation or downregulation. Although these effects have been demonstrated in studies in vitro and in animal models, such effects have only been observed in limited cases in humans at common doses of human tea consumption. The ingestion of tea catechins from dietary supplements, which could be in large bullet doses, may produce more profound effects on drug metabolism, and such effects with drugs need to be further investigated. PMID- 22509900 TI - Ocean-atmosphere interactions in the emergence of complexity in simple chemical systems. AB - The prebiotic conversion of simple organic molecules into complex biopolymers necessary for life can only have emerged on a stage set by geophysics. The transition between "prebiotic soup," the diverse mixture of small molecules, and complex, self-replicating organisms requires passing through the bottleneck of fundamental chemistry. In this Account, we examine how water-air interfaces, namely, the surfaces of lakes, oceans, and atmospheric aerosols on ancient Earth, facilitated the emergence of complex structures necessary for life. Aerosols are liquid or solid suspensions in air with a broad, power law size distribution. Collectively, these globally distributed atmospheric particles have an enormous surface area. Organic films at the interface between water and air offer advantages for biomolecular synthesis compared with the bulk and can simultaneously participate in the folding of biopolymers into primitive enclosed structures. We survey the advantages of the water-air interface for prebiotic chemistry in a geophysical context from three points of view. We examine the formation of biopolymers from simple organic precursors and describe the necessity and availability of enclosures. In addition, we provide a statistical mechanical approach to natural selection and emergence of complexity that proposes a link between these molecular mechanisms and macroscopic scales. Very large aerosol populations were ubiquitous on ancient Earth, and the surfaces of lakes, oceans, and atmospheric aerosols would have provided an auspicious environment for the emergence of complex structures necessary for life. These prebiotic reactors would inevitably have incorporated the products of chemistry into their anhydrous, two-dimensional organic films in the three-dimensional fluids of the gaseous atmosphere and the liquid ocean. The untrammeled operation of natural selection on these aerosols provided the likely location where condensation reactions could form biopolymers by elimination of water. The fluctuating exposure of the large, recycling aerosol populations to radiation, pressure, temperature, and humidity over geological time allows complexity to emerge from simple molecular precursors. We propose an approach that connects chemical statistical thermodynamics and the macroscopic world of the planetary ocean and atmosphere. PMID- 22509901 TI - Neisseria meningitidis and Neisseria gonorrhoeae are differently adapted in the regulation of denitrification: single nucleotide polymorphisms that enable species-specific tuning of the aerobic-anaerobic switch. AB - The closely related pathogenic Neisseria species N. meningitidis and N. gonorrhoeae are able to respire in the absence of oxygen, using nitrite as an alternative electron acceptor. aniA (copper-containing nitrite reductase) is tightly regulated by four transcriptional regulators: FNR (fumarate and nitrate reductase), NarP, FUR (Ferric uptake regulator) and NsrR. The four regulators control expression of aniA in N. meningitidis by binding to specific and distinct regions of the promoter. We show in the present study that FUR and NarP are both required for the induction of expression of aniA in N. meningitidis, and that they bind adjacent to one another in a non-co-operative manner. Activation via FUR/NarP is dependent on their topological arrangement relative to the RNA polymerase-binding site. Analysis of the sequence of the aniA promoters from multiple N. meningitidis and N. gonorrhoeae strains indicates that there are species-specific single nucleotide polymorphisms, in regions predicted to be important for regulator binding. These sequence differences alter both the in vitro DNA binding and the promoter activation in intact cells by key activators FNR (oxygen sensor) and NarP (which is activated by nitrite in N. meningitidis). The weak relative binding of FNR to the N. gonorrhoeae aniA promoter (compared to N. meningitidis) is compensated for by a higher affinity of the gonococcal aniA promoter for NarP. Despite containing nearly identical genes for catalysing and regulating denitrification, variations in the promoter for the aniA gene appear to have been selected to enable the two pathogens to tune differentially their responses to environmental variables during the aerobic-anaerobic switch. PMID- 22509902 TI - Droplet shape analysis and permeability studies in droplet lipid bilayers. AB - We apply optical manipulation to prepare lipid bilayers between pairs of water droplets immersed in an oil matrix. These droplet pairs have a well-defined geometry allowing the use of droplet shape analysis to perform quantitative studies of the dynamics during bilayer formation and to determine time-dependent values for the droplet volumes, bilayer radius, bilayer contact angle, and droplet center-line approach velocity. During bilayer formation, the contact angle rises steadily to an equilibrium value determined by the bilayer adhesion energy. When there is a salt concentration imbalance between droplets, there is a measurable change in the droplet volume. We present an analytical expression for this volume change and use this expression to calculate the bilayer permeability to water. PMID- 22509903 TI - Conversation with Lorraine Midanik. PMID- 22509904 TI - Youth recovery contexts: the incremental effects of 12-step attendance and involvement on adolescent outpatient outcomes. AB - BACKGROUND: A major barrier to youth recovery is finding suitable sobriety supportive social contexts. National studies reveal most adolescent addiction treatment programs link youths to community 12-step fellowships to help meet this challenge, but little is known empirically regarding the extent to which adolescents attend and benefit from 12-step meetings or whether they derive additional gains from active involvement in prescribed 12-step activities (e.g., contact with a sponsor and other fellowship members). Greater knowledge in this area would enhance the efficiency of clinical continuing care recommendations. METHODS: Adolescent outpatients (N = 127; M age 16.7; 75% male; 87% white) enrolled in a naturalistic study of treatment effectiveness were assessed at intake and 3, 6, and 12 months later using standardized assessments. Mixed effects models, controlling for static and time-varying confounds, examined the concurrent and lagged effects of 12-step attendance and active involvement on abstinence over time. RESULTS: The proportion attending 12-step meetings was relatively low across follow-up (24 to 29%), but more frequent attendance was independently associated with greater abstinence in concurrent and, to a lesser extent, lagged models. An 8-item composite measure of 12-step involvement did not enhance outcomes over and above attendance, but separate components did; specifically, greater contact with a 12-step sponsor outside of meetings and more verbal participation during meetings. CONCLUSIONS: The benefits of 12-step participation observed among adult samples extend to adolescent outpatients. Community 12-step fellowships appear to provide a useful sobriety-supportive social context for youths seeking recovery, but evidence-based youth-specific 12 step facilitation strategies are needed to enhance outpatient attendance rates. PMID- 22509905 TI - Detecting improvements in dyspnea in COPD using a three-minute constant rate shuttle walking protocol. AB - RATIONALE: We examined the responsiveness of a 3-minute constant rate shuttle walking protocol to detect improvements in exertional dyspnea following acute bronchodilation in COPD. Our hypothesis was that the 3-minute constant rate shuttle walking protocol would be able to adequately put forth improvements in exertional dyspnea following acute bronchodilation in this population. METHODS: Using a placebo controlled, double-blind cross-over design, 39 patients with moderate to severe COPD performed a 3-min constant rate shuttle walking test during which they were asked to walk on a flat corridor at a speed that was externally imposed by an audio signal. During the test, dyspnea was graded using the 10-point modified Borg scale. The test was performed twice, following the administration of saline placebo or of 500 MUg nebulized ipratropium bromide. RESULTS: Improvements of respiratory pattern (respiratory rate and tidal volume) and statistically and clinically significant reductions in Borg dyspnea scores (? dyspnea score = 1.0 +/- 0.2, p < 0.01) were seen during the 3-min shuttle walking protocol with ipratropium bromide compared to placebo. CONCLUSION: This 3-minute shuttle walking protocol adequately detected dyspnea and breathing pattern improvements following acute bronchodilation in COPD. PMID- 22509906 TI - Variable microsatellite loci for population genetic analysis of Old World monkey lice (Pedicinus sp.). AB - Parasitic lice have been valuable informants of their host's evolutionary history because they complete their entire life cycle on the host and move between hosts primarily through direct host-to-host contact. Therefore, lice are confined to their hosts both in ecological and evolutionary time. Lice on great apes have been studied to examine details of their host's evolutionary history; however, species of Pedicinus, which parasitize the Old World monkeys, are less well known. We sampled lice from 2 groups of red colobus (Procolobus spp.) in Kibale National Park in Uganda and from red colobus and black and white colobus (Procolobus polycomos) in Tai National Park in Cote d'Ivoire. We used next generation sequencing data analysis and the human body louse (Pediculus humanus humanus) genome to search for microsatellites for population genetic studies of Pedicinus lice. The 96 primer sets for microsatellite loci designed from the human body louse genome failed to amplify microsatellites in Pedicinus sp., perhaps due to the fast rate of evolution in parasitic lice. Of 63 microsatellites identified by next-generation sequencing data analysis of Pedicinus sp., 12 were variable among populations and 9 were variable within a single population. Our results suggest that these loci will be useful across the genus Pedicinus. We found that the lice in Uganda are not structured according to their hosts' social group; rather, 2 non-interbreeding populations of lice were found on both groups of red colobus. Because direct host-to-host contact is usually required for lice to move among hosts, these lice could be useful for identification and study of behavioral interactions between primate species. PMID- 22509907 TI - What are the public policy implications of a neurobiological view of addiction? PMID- 22509908 TI - Potential contaminant pathways from hydraulically fractured shale to aquifers. AB - Hydraulic fracturing of deep shale beds to develop natural gas has caused concern regarding the potential for various forms of water pollution. Two potential pathways-advective transport through bulk media and preferential flow through fractures-could allow the transport of contaminants from the fractured shale to aquifers. There is substantial geologic evidence that natural vertical flow drives contaminants, mostly brine, to near the surface from deep evaporite sources. Interpretative modeling shows that advective transport could require up to tens of thousands of years to move contaminants to the surface, but also that fracking the shale could reduce that transport time to tens or hundreds of years. Conductive faults or fracture zones, as found throughout the Marcellus shale region, could reduce the travel time further. Injection of up to 15,000,000 L of fluid into the shale generates high pressure at the well, which decreases with distance from the well and with time after injection as the fluid advects through the shale. The advection displaces native fluids, mostly brine, and fractures the bulk media widening existing fractures. Simulated pressure returns to pre injection levels in about 300 d. The overall system requires from 3 to 6 years to reach a new equilibrium reflecting the significant changes caused by fracking the shale, which could allow advective transport to aquifers in less than 10 years. The rapid expansion of hydraulic fracturing requires that monitoring systems be employed to track the movement of contaminants and that gas wells have a reasonable offset from faults. PMID- 22509909 TI - The MaBwana Black men's study: community and belonging in the lives of African, Caribbean and other Black gay men in Toronto. AB - In Canada, there is a paucity of research aimed at understanding Black gay men and the antecedents to risk factors for HIV. This study is an attempt to move beyond risk factor analysis and explore the role of sexual and ethnic communities in the lives of these men. The study utilized a community-based research and critical race theory approach. Semi-structured interviews were conducted with eight key informants to augment our understanding of Black gay men and to facilitate recruitment of participants. In-depth interviews were done with 24 Black gay men. Our data showed that the construction of community for Black gay men is challenged by their social and cultural environment. However, these men use their resilience to navigate gay social networks. Black gay men expressed a sense of abjuration from both gay and Black communities because of homophobia and racism. It is essential for health and social programmers to understand how Black gay men interact with Black and gay communities and the complexities of their interactions in creating outreach educational, preventive and support services. PMID- 22509910 TI - The p53 target gene TRIM22 directly or indirectly interacts with the translation initiation factor eIF4E and inhibits the binding of eIF4E to eIF4G. AB - BACKGROUND INFORMATION: The interferon (IFN)-inducible protein TRIM22 (Staf50) is a member of the tripartite motif protein family and has been suggested a role in the regulation of viral replication as well as of protein ubiquitylation. In addition, we have previously shown that TRIM22 is a direct target gene for the tumour suppressor p53. Consistently, over-expression of TRIM22 inhibits the clonogenic growth of monoblastic U937 cells, suggesting anti-proliferative or cell death-inducing effects. RESULTS: Here, we demonstrate that TRIM22 directly or indirectly interacts with the eukaryotic translation initiation factor (eIF)4E, and inhibits the binding of eIF4E to eIF4G, thus disturbing the assembly of the eIF4F complex, which is necessary for cap-dependent translation. Furthermore, TRIM22 exerts a repressive effect on luciferase reporter protein levels and to some extent on radiolabelled methionine incorporation. Even though all nuclear mRNAs are capped, some are more dependent on eIF4F than others for translation. The translation of one of these mRNAs, IRF-7C, was indeed found to be repressed in the presence of TRIM22. CONCLUSIONS: Our data suggest TRIM22 to repress protein translation preferably of some specific mRNAs. Taken together, we show that TRIM22 represses translation by inhibiting the binding of eIF4E to eIF4G, suggesting a mechanism for regulation of protein translation, which may be of importance in response to p53 and/or IFN signalling. PMID- 22509911 TI - Anti-caveolin-1 antibodies as anti-prostate cancer therapeutics. AB - Caveolae are critical cell surface structures important in coordinated cell signaling and endocytosis. One of the major proteins of caveolae is caveolin 1 (Cav-1). Cellular levels of Cav-1 are associated with cancer progression. In prostate cancer cells, levels of Cav-1 are positively correlated with tumor progression and metastasis. Cav-1 can be secreted by prostate cancer cells into the microenvironment and triggers proliferation and anti-apoptosis of the tumor and tumor endothelial cells. Clinical studies have shown increased serum Cav-1 levels in patients with poor prognosis. In tissue culture and animal model experiments, blocking secreted Cav-1 by polyclonal antibodies inhibits tumor cell growth. Cav-1 is therefore a potential therapeutic target for prostate cancer treatment. In this study, we used Cav-1 knock-out mice as hosts to produce monoclonal anti-Cav-1 antibodies. A total of 11 hybridoma cell lines were selected for their ability to produce antibodies that bound GST-Cav-1 but not GST on glutathione-coated ELISA plates. Further screening with ELISAs using GST-Cav-1 fragments on GSH-coated plates classified these antibodies into four groups: N1 31 with five antibodies binds the far N-terminus between amino acids 1 and 31; N32-80 with three antibodies binds between amino acids 32 and 80; CSD with two antibodies potentially bind the scaffolding domain (amino acids 80-101); and Cav 1-C with 1 antibody binds parts of the C-terminal half. Binding affinities (Kd) of these antibodies to soluble Cav-1 ranged from 10(-11) to 10(-8) M. Binding competition experiments revealed that these antibodies recognized a total of six different epitopes on Cav-1. Potency of these antibodies to neutralize Cav-1 mediated signaling pathways in cultured cells and in animal models will be tested. A selected monoclonal antibody will then be humanized and be further developed into a potential anti-prostate cancer therapeutic. PMID- 22509913 TI - Recombinant Fc-IL-18BPc isoform inhibits IL-18-induced cytokine production. AB - IL-18 is a pro-inflammatory cytokine that is produced from T cells and NK cells. IL-18 has been implicated in the pathogenesis of various inflammatory and cardiovascular diseases. IL-18 binding protein (IL-18BP) is a natural inhibitor of IL-18 that possesses higher affinity to IL-18 than that of the IL-18 receptor alpha chain on the cell surface. Human isoform a and c among four isoforms of IL 18BPs have an inhibitory effect on IL-18-induced cytokines whereas mouse IL-18BP isoforms exist only in two isoforms: c and d. Fc-fusion protein is a molecule in which the immunoglobulin Fc is fused genetically to a protein of interest, such as an extracellular domain of a receptor, ligand, or enzyme. In this study, we expressed and purified human Fc-IL-18BPa and c isoforms from CHO-DG44 cells and their biological activities were compared to each other. This is the first time that expressed recombinant human Fc-IL-18BPc has been examined for its biological activity on IL-18-induced IFNgamma in human PBMC and IL-6 in A549/IL-18Rbeta. PMID- 22509912 TI - Model IgG monoclonal autoantibody-anti-idiotype pair for dissecting the humoral immune response to oxidized low density lipoprotein. AB - Increasing evidence implicates IgG autoantibodies against oxidized forms of low density lipoprotein (oxLDL) in the pathophysiology of atherosclerotic arterial disease. However, insufficient knowledge of their structure and function is a key gap. Using an elderly LDL receptor-deficient atherosclerotic mouse, we isolated a novel IgG3k against oxLDL (designated MAb LO1). LO1 reacts with copper-oxidized LDL, but minimally with native LDL. Further analysis showed that MAb LO1 also reacts in vitro with malondialdehyde-conjugated LDL (MDA-LDL), a known key epitope in copper-oxidized LDL preparations. By screening a phage library expressing single chain variable region antibodies (scFv), we selected an anti idiotype scFv (designated H3) that neutralizes MAb LO1 binding to MDA-LDL. Amino acid substitutions between H3 and an irrelevant control scFv C12 showed that residues in the H3 CDRH2, CDRH3, and CDRL2 are all critical for MAb LO1 binding, consistent with a conformational epitope on H3 involving both heavy and light chains. Comparison of amino acids in H3 CDRH2 and CDRL2 with apoB, the major LDL protein, showed homologous sequences, suggesting H3 has structural similarities to the MAb LO1 binding site on MDA-LDL. Immunocytochemical staining showed that MAb LO1 binds epitopes in mouse and human atherosclerotic lesions. The MAb LO1-H3 combination therefore provides a very promising model for analyzing the structure and function of an individual IgG autoantibody in relation to atherosclerosis. PMID- 22509914 TI - Production of human anti-glycophorin-A monoclonal antibodies and their purification by pseudoaffinity chromatography using a convective interaction media monolithic column. AB - Monoclonal antibodies (MAbs) against glycophorin-A (GPA) could be used in identifying MN blood groups, detecting specific markers of erythroid differentiation, and studying parasite interactions. Large-scale production of MAbs in bioreactors demands an efficient and rapid separation technology. The present study describes the production of a human anti-GPA monoclonal antibody and its purification using a pseudo-bioaffinity L-histidine-convective interaction media (CIM) monolithic column. Hybridomas were generated by fusion of mouse myeloma cell line (Sp2/0) and spleen cells from the mouse immunized with Triton X-100 solubilized RBC membrane proteins. Hybridomas producing antibodies specific to commercial glycophorin-A were screened by indirect enzyme-linked immunosorbent assay (ELISA). The antibodies produced by the stable clones were found to be IgG1 with kappa light chain. Purification of IgG1 MAbs from the cell culture supernatant carried out with a CIM-EDA-histidine disk resulted in high specific activity with purification fold of 8.3 in the fraction eluted with MOPS buffer containing 0.2 M NaCl. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and ELISA showed that the antibodies obtained were highly pure, with high antigen-binding efficiency. The results indicate that faster separation and efficient recovery of high-purity anti-GPA MAbs could be achieved by using CIM-EDA-histidine disk. PMID- 22509915 TI - Functional characterization of an IgE-class monoclonal antibody specific for the bullous pemphigoid autoantigen, BP180. AB - BP180 (collagen XVII) is the target antigen in several autoimmune diseases including bullous pemphigoid (BP). Both IgE and IgG class autoantibodies have been shown to be pathogenic in BP; however, studies designed to elucidate the patho-mechanisms mediated specifically by the IgE-class autoantibodies are limited by the low levels (ng/mL) of IgE in human sera. In this report, we developed mouse IgE class monoclonal antibodies (MAbs) against the immunodominant NC16A domain of the human BP180 protein and characterized two of the resultant MAbs, designated 395A5 and 395D2. Epitope mapping studies revealed that both MAbs target segment 2 of NC16A, as was described for IgE and IgG class BP autoantibodies. Also similar to BP IgE, MAb 395A5 showed indirect immunofluorescence labeling of the basement membrane zone (BMZ) of human skin, stimulated histamine release from mast cells when triggered with NC16A, and induced keratinocyte production of IL-8. The 395D2 MAb was also able to trigger antigen-specific histamine release from mast cells; however, in contrast to BP IgE and 395A5, 395D2 did not label the cutaneous BMZ, nor did it induce IL-8 production in keratinocytes. In summary, these studies underscore the importance of functionally characterizing MAbs generated for use in human disease models. The 395A5 IgE class murine MAb was shown to share several key functional properties with the pathogenically active IgE produced by BP patients. We therefore expect that this MAb will prove to be a useful tool for dissecting the mechanisms used by BP180-NC16A-specific IgE antibodies in the induction of BP skin lesions. PMID- 22509916 TI - Monoclonal antibodies against recombinant AtHOS15. AB - Histone modifications are important components of transcriptional regulation and chromatin-based regulatory processes. In addition, WD40-repeat protein and several other components are involved in these functions. Here we present the development of monoclonal antibodies (MAbs) against Arabidopsis HOS15, a WD40 repeat protein. Mice were immunized with recombinant HOS15 (rHOS15) protein for generating MAbs via the classic hybridoma production technique. We confirmed the specific activity of anti-HOS15 MAbs by tobacco transient expression assays. Based on immunoprecipitation assays, the anti-HOS15 MAb was able to detect endogenous HOS15 in Arabidopsis wild-type plants, but not in hos15 mutant plants. Finally, the anti-HOS15 MAbs are highly sensitive for detecting endogenous HOS15 protein. They can be used for immunological and immunoprecipitation assays to support other experimental strategies. In particular, the anti-HOS15 MAbs will be essential tools to investigate the role of HOS15 in the regulation of tolerance to environmental stresses in plants. PMID- 22509917 TI - Monoclonal antibodies against NS1 protein of Goose parvovirus. AB - In the present study, monoclonal antibodies (MAbs) against NS1 protein of Goose parvovirus (GPV) were generated. The secreted MAbs were obtained by fusing mouse myeloma cells and spleen cells of BALB/c mice, which were immunized with the plasmid pcDNA3.1-GPV-NS1 and recombinant protein of GPV-NS1. With indirect ELISA, six hybridoma cell lines against GPV-NS1 were screened. The subtypes of the two MAbs were IgG2a; the others were IgM. The light chain was kappa. Western blot analysis showed that six MAbs reacted with recombinant protein GPV-NS1. GPV-NS1 was dissected into 15 overlapping epitopes, which were used to react with MAbs in Western blot. Results showed that six MAbs recognized NS1 protein linear B-cell epitopes located at the C-terminus 453-514 aa, 485-542 aa, and 533-598 aa. PMID- 22509918 TI - A novel monoclonal antibody against cannabinoid receptor 1. AB - The cannabinoid receptor 1 (CBR1) is being widely investigated because of its specific structure and functions compared with other cannabinoid receptors. In this study, we immunized BALB/c mice with synthesized human CBR1 polypeptide and obtained a novel monoclonal antibody (MAb) against human CBR1. Analysis through enzyme-linked immunosorbent assay (ELISA), spot-ELISA, Western blot, and immunohistochemistry revealed that the MAb was specifically against recombinant human CBR1 protein, and its subtype and affinity constant (Kaff) were IgG2b/k and 7.85 * 10(8) M/L, respectively. Using this MAb we found that CBR1 is expressed on HL-7702 cells and lipid tissue, raising the possibility that the CBR1 may take a role in glucose and lipid metabolism. Thus, this antibody might facilitate studies for pathophysiology of diseases associated with glucose and lipid metabolism abnormality. PMID- 22509919 TI - Monoclonal antibodies against NS3 and NS5 proteins of Japanese encephalitis virus. AB - Non-structural proteins NS3 and NS5 of Japanese encephalitis virus (JEV) were expressed in Escherichia coli and purified by dialysis. Two monoclonal antibodies (MAbs) named 1H7 and 2D4 against NS3 protein and three MAbs named 3C4, 3H7, and 3F10 against NS5 protein were generated by fusing mouse myeloma cell line SP2/0 with spleen lymphocytes from NS3 or NS5 protein immunized mice. Then activity of MAbs was characterized by enzyme-linked immunosorbent assay (ELISA), Western blot analysis, and indirect immunofluorescent assays (IFA). Our results demonstrated that all the MAbs showed high specificity and sensitivity in IFA at 1:100 dilution and in Western blot analysis at 1:500 dilution, which indicated that these MAbs against NS3 and NS5 proteins of JEV may be used as valuable tools for analysis of the protein functions and pathogenesis of JEV. PMID- 22509920 TI - Immunocytochemical and immunohistochemical application of monoclonal antibodies against peroxisomal biogenesis factor 14. AB - PEX14 is an integral membrane protein essential for protein docking onto the peroxisomes and is a bi-functional protein capable of acting as a transcriptional co-repressor and a polypeptide transport modulator. Further studies showed that PEX14 is the sole peroxin that has a unique dual function in peroxisome formation and selective degradation. Its RNA transcripts are ubiquitously expressed; there is, however, no data on the expression profiles of PEX14 at the protein level due to a lack of MAbs suitable for immunohistochemical staining, thus hindering studies on its functions. In the present study, we generated one MAb that could be used in immunocytochemistry and immunohistochemistry and investigated PEX14 expression in normal and malignant human tissues. In contrast to the ubiquitous expression of its RNA transcripts, there is no PEX14 protein expression in normal human tissue, including liver, spleen, lung, rectum, brain, prostate, breast, ovary, and stomach. Protein expression of PEX14 was dramatically upregulated in some malignancies. Presented here are the first data on the expression profiles of PEX14 at the protein level, which will further our understanding of its functions. PMID- 22509921 TI - Monoclonal antibody BP180 against bullous pemphigoid antigen-2 type XVII collagen. PMID- 22509923 TI - Highly efficient (R-X-R)-type carbamates as molecular transporters for cellular delivery. AB - The (R-X-R) motif-containing arginine-rich peptides are among the most effective cell-penetrating peptides. The replacement of amide linkages in the (R-X-R) motif by carbamate linkages as in (r-ahx-r)(4) or (r-ahx-r-r-apr-r)(2) increases the efficacy of such oligomers several-fold. Internalization of these oligomers in mammalian cell lines occurs by an energy-independent process. These oligomers show efficient delivery of biologically active plasmid DNA into CHO-K1 cells. PMID- 22509924 TI - Clinical usefulness of BK virus plasma quantitative PCR to prevent BK virus associated nephropathy. AB - The present study investigated the clinical usefulness of plasma real-time polymerase chain reaction (PCR) (plasma-PCR) in the prevention of BK virus associated nephropathy (BKVAN). First, we investigated the diagnostic value of plasma BK-PCR, urine BK-PCR, and urine cytology for the prediction of BKVAN retrospectively. Then we designed a prospective study of regular plasma-PCR monitoring and pre-emptive immunosuppression (IS) reduction based on the result. In the retrospective cohort, the prevalence of BKVAN was 3.7% (14/379) and the positive rate of decoy cells, urine-PCR (>1 * 10(10) copies/ml), and plasma-PCR (>1 * 10(4) copies/ml) was 18.6%, 11.1%, and 5.5%, respectively. Plasma-PCR was superior to urine-PCR or urine cytology in specificity and positive predictive value for detection of BKVAN. In prospective study, regular monitoring of plasma PCR detected significant BKV viremia in 8.3% (12/145) and BKVAN in 1 patient (0.6%). After IS reduction, BKV viremia was eliminated in 91.6% (11/12) within 103 days (25-254). In patients with viremia, the frequency of acute rejection did not increase and allograft function did not differ significantly compared with those in patients without viremia during the first year post-transplant (P > 0.05, in both). Plasma-PCR is useful to predict an increased risk for BKVAN, and regular monitoring is effective to prevent the development of BKVAN. PMID- 22509925 TI - Altered brain activation to colorectal distention in visceral hypersensitive maternal-separated rats. AB - BACKGROUND: Early life trauma can predispose to increased visceral pain perception. Human neuroimaging studies emphasize that altered brain processing may contribute to increased visceral sensitivity. The aim of our study was to evaluate brain responses to painful visceral stimuli in maternal-separated rats before and after acute stress exposure in vivo. METHODS: H(2)(15)O microPET scanning was performed during colorectal distention in maternal-separated rats before and after water avoidance stress. Brain images were anatomically normalized to Paxinos space and analyzed by voxel-based statistical parametric mapping (SPM2). Colorectal induced visceral pain was assessed by recording of the visceromotor response using abdominal muscle electromyography. KEY RESULTS: Colorectal distention (1.0-2.0 mL) evoked a volume-dependent increase in visceromotor response in maternal-separated rats. Stress [water avoidance (WA)] induced an increased visceromotor response to colorectal distention in awake and anesthetized rats. In pre-WA rats, colorectal distention evoked significant increases in regional blood flow in the cerebellum and periaquaductal gray (PAG). Colorectal distention post-WA revealed activation clusters covering the PAG as well as somatosensory cortex and hippocampus. At maximal colorectal distention, the frontal cortex was significantly deactivated. CONCLUSIONS & INFERENCES: WA stress induced increased pain perception as well as activation of the somatosensory cortex, PAG, and hippocampus in maternal-separated rats. These findings are in line with human studies and provide indirect evidence that the maternal separation model mimics the cerebral response to visceral hypersensitivity in humans. PMID- 22509927 TI - Thermal degradation kinetics of neoxanthin, violaxanthin, and antheraxanthin in virgin olive oils. AB - A first-order kinetic mechanism was appropriate for describing the thermal degradation of epoxy xanthophylls in virgin olive oil (VOO). Consecutive reactions that involve reorganization of 5,6-epoxide groups to 5,8-furanoxide groups and subsequent rupture of the polyene chain occurred in the degradation pathways. Thermal stability was significantly affected by changes in the chemical structure (epoxy to furanoid structure), being the greatest stability for neoxanthin. A true kinetic compensation effect was found in a series of similar reactions, that is, the degradation of 5,8-furanoxides into colorless products. An isokinetic study in different VOO matrices showed that the oily medium did not significantly affect the reaction mechanisms. Consequently, the kinetic parameters obtained as temperature functions according to the Arrhenius model can be used to develop a prediction mathematical model for 5,8-furanoxide xanthophylls in VOO over time. The potential usefulness of the parameter neoxanthin/neochrome ratio is discussed as a chemical marker of heat treatment in VOO. PMID- 22509926 TI - EO9 (Apaziquone): from the clinic to the laboratory and back again. AB - EO9 (Apaziquone) is a bioreductive drug that has a chequered history. It underwent clinical trial but failed to show activity in phase II clinical trials when administered i.v. Poor drug delivery to tumours caused by a combination of rapid pharmacokinetic elimination and poor penetration through avascular tissue were the major factors responsible for EO9's poor efficacy. Based upon an understanding of why EO9 failed, a further clinical trial against patients with superficial transitional cell carcinoma of the bladder was conducted. The rationale for this was that intravesical administration directly into the bladder would circumvent the drug delivery problem, and any drug reaching the blood supply would be rapidly cleared thereby reducing the risk of systemic exposure. EO9 was well tolerated, and clinical activity against marker lesions was recorded in both phase I and II clinical trials. This article charts the pharmacological history of EO9 and discusses the potential implications that 'the EO9 story' has for the development of other loco-regional therapies. PMID- 22509928 TI - Short double-stranded RNA with immunostimulatory activity: sequence dependence. AB - Small interfering RNAs (siRNA) are able to activate the mammalian innate immune system depending on their structure, sequence, and method of delivery. The immunostimulatory activity of double-stranded RNA can be applied to antiviral and antitumor therapy. Here we identified a set of 19-bp RNA duplexes with 3 nucleotid overhangs in the 3' ends that display immunostimulating activity (here and after immunostimulating RNA, or isRNA) and studied their sequence/activity relationships. It was found that the introduction of substitutions in the middle part of the isRNA sequence (10-16 positions counting from the 5' end of strand 1) does not alter the antiproliferative activity, while substitutions in the 3' end region of isRNA substantially reduce it. isRNAs efficiently inhibit the proliferation of human oral epidermoid carcinoma cells [half-maximal inhibitory concentration (IC(50)) values varied from 10 to 100 nM]. Our research demonstrated that antiproliferative effects of isRNAs are related to cell growth arrest, rather than the induction of apoptosis. These isRNAs strongly stimulate the synthesis of interferon-alpha (IFN-alpha), and to a lesser extent the synthesis of tumor necrosis factor (TNF-alpha) and interleukin-6 (IL-6), in adherent peripheral blood mononuclear cells. An intravenous injection of isRNA/Lipofectamine complexes into C57BL mice increases IFN-alpha and IL-6 levels in the blood serum up to 15-fold and 3-fold, respectively, compared to the control mice. The results obtained clearly demonstrate the pronounced immunostimulatory and antiproliferative properties of the isRNAs under study. Hence, these short double-stranded RNAs can be considered as potential agents for the therapy of oncological and viral diseases. PMID- 22509929 TI - Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56(+) cells. AB - PROBLEM: Natural killer (NK, CD3(-)CD56(+)/CD16(+)) and NKT-like cells (CD3(+)CD56(+)/CD16(+)) activity is considered among the key factors for reproductive success. In the absence of immunological screening, beneficial effects of intravenous immunoglobulin (IVIG) in preventing recurrent reproductive failure (RRF) have not been reported. Here, we analyse the IVIG influence on pregnancy success in women with RRF and circulating NK or/and NKT-like cells expansion. METHOD OF STUDY: One hundred fifty-seven women with previous recurrent miscarriage and/or recurrent implantation failure after in vitro fertilization were consecutively studied. Sixty-four patients with CD56(+) cell expansion, no apparent underlying disease and who maintained their desire to conceive were selected. Forty of them received IVIG during pregnancy. RESULTS: Overall, the clinical pregnancy rate for the women under IVIG therapy was 92.5% and the live birth rate was 82.5%. Significantly lower pregnancy and live birth rates (25% and 12.5%, respectively) were observed for the patients with recurrent pregnancy loss and NK/NKT-like cells expansion without IVIG. After three cycles of IVIG, NK cell percentages decreased significantly and these values persisted throughout gestation. CONCLUSION: Intravenous immunoglobulin therapy for women with RRF and NK or NKT-like cell expansion was a safe and beneficial therapeutic strategy that associated with high clinical pregnancy and live birth rates. PMID- 22509931 TI - Roles of surface chemistry on safety and electrochemistry in lithium ion batteries. AB - Motivated by new applications including electric vehicles and the smart grid, interest in advanced lithium ion batteries has increased significantly over the past decade. Therefore, research in this field has intensified to produce safer devices with better electrochemical performance. Most research has focused on the development of new electrode materials through the optimization of bulk properties such as crystal structure, ionic diffusivity, and electric conductivity. More recently, researchers have also considered the surface properties of electrodes as critical factors for optimizing performance. In particular, the electrolyte decomposition at the electrode surface relates to both a lithium ion battery's electrochemical performance and safety. In this Account, we give an overview of the major developments in the area of surface chemistry for lithium ion batteries. These ideas will provide the basis for the design of advanced electrode materials. Initially, we present a brief background to lithium ion batteries such as major chemical components and reactions that occur in lithium ion batteries. Then, we highlight the role of surface chemistry in the safety of lithium ion batteries. We examine the thermal stability of cathode materials: For example, we discuss the oxygen generation from cathode materials and describe how cells can swell and heat up in response to specific conditions. We also demonstrate how coating the surfaces of electrodes can improve safety. The surface chemistry can also affect the electrochemistry of lithium ion batteries. The surface coating strategy improved the energy density and cycle performance for layered LiCoO2, xLi2MnO3.(1 - x)LiMO2 (M = Mn, Ni, Co, and their combinations), and LiMn2O4 spinel materials, and we describe a working mechanism for these enhancements. Although coating the surfaces of cathodes with inorganic materials such as metal oxides and phosphates improves the electrochemical performance and safety properties of batteries, the microstructure of the coating layers and the mechanism of action are not fully understood. Therefore, researchers will need to further investigate the surface coating strategy during the development of new lithium ion batteries. PMID- 22509930 TI - A Y-chromosomal haplotype with two short tandem repeat mutations. AB - The male-specific Y-chromosomal short tandem repeat (STR) is a useful tool in forensic casework. The Y haplotype comprised of 16 loci, which is amplified simultaneously by AmpFlSTR((r)) Yfiler(TM) PCR kit and provides strong exculpatory evidence in individual identification. We reported a rare Y-STR profile with a null allele at the DYS448 locus and an off-ladder allele at the DYS456 locus, when genotyping material from a vaginal swab in an alleged rape case. Sequence analysis revealed that the DYS448 null allele was a true type of null allele because of a total deletion of 11 upstream repeats and 9bp of the N(42) region, and there were numerous primer binding site mutations as well. The amplicon of the DYS456 locus was a small 92-bp fragment that was off-ladder, and sequencing analysis showed that there were only 10 repeats (AGAT)(10). This Y chromosome haplotype that was comprised of two variations provided helpful evidence for personal identification. PMID- 22509932 TI - Prediction of psychological symptoms in family members of patients with burns 1 year after injury. AB - AIM: To report a study of predictors of psychological symptoms in family members of patients with burns. BACKGROUND: Family members are important as a source of social support for patients undergoing prolonged rehabilitation. Little is known about psychological symptoms of family members of patients with burns, especially in the long term. DESIGN: The design of the study was prospective and longitudinal. METHODS: Forty-four family members of adult patients treated in a burn centre between 2000-2007 completed questionnaires during care and at 3, 6, and 12 months after injury. Psychological symptoms were assessed with the Hospital Anxiety and Depression Scale. Predictors for anxiety and depression were explored in regression analyses. RESULTS: The mean scores indicated normal to mild symptoms in general. Moderate and severe symptom levels during care and at 12 months were demonstrated on the anxiety subscale by 15/44 and 5/39, respectively, and on the depression subscale by 5/44 and 0/39 of the family members, respectively. In the final regression models, the primary predictor was psychological symptoms at the previous assessment. Other predictors were previous life events, age, and the coping strategy avoidance. CONCLUSION: Family members of patients with burns demonstrate normal to mild levels of psychological symptoms that decrease over time. One-third show moderate to severe anxiety symptoms during care and may benefit from counselling. Previous symptoms predict later symptoms, indicating that screening with a validated instrument is useful. The results provide guidance for nurses in assessing and planning adequate interventions for family members. PMID- 22509933 TI - Re: Staghorn morphometry: a new tool for clinical classification and prediction model for percutaneous nephrolithotomy monotherapy. (From: Mishra S, Sabnis RB, Desai M. J Endourol 2012;26:6-14). PMID- 22509934 TI - A novel bispecific single-chain antibody for ADAM17 and CD3 induces T-cell mediated lysis of prostate cancer cells. AB - ADAM17 (A disintegrin and metalloproteinase 17) is a membrane-bound protease that cleaves various cell surface proteins, including cytokines and cytokine receptors. Recently it was shown that ADAM17 is highly expressed on the surface of many cancer cells, whereas normal cells express low levels of ADAM17, implying that ADAM17 is a potential immunotherapeutic target. We have generated a monoclonal antibody against human ADAM17, which recognized the membrane proximal cysteine-rich extension of the ADAM17 protein. Unlike normal cells, tumour cell lines, such as a prostate cancer cell line, pancreatic cancer cell lines, a breast cancer cell line and a non-small lung cancer cell line, expressed ADAM17 on the cell surface. Using the sequence of the antibody we generated an ADAM17 specific scFv (single-chain variable fragment) and fused this to a CD3-specific scFv to generate a bispecific T-cell engager antibody [A300E-BiTE (bispecific T cell engager antibody)]. Specificity was demonstrated on cells in which ADAM17 was knocked down with a specific shRNA (short hairpin RNA). A300E-BiTE recognized ADAM17 and CD3 on the cell surface of tumour cells and T-cells respectively. In the presence of primary human peripheral blood mononuclear cells or human T-cells the addition of A300E-BiTE led to ADAM17-specific killing of prostate tumour cells indicating a novel strategy for the treatment of cancer. PMID- 22509936 TI - Bandlike transport in strongly coupled and doped quantum dot solids: a route to high-performance thin-film electronics. AB - We report bandlike transport in solution-deposited, CdSe QD thin-films with room temperature field-effect mobilities for electrons of 27 cm(2)/(V s). A concomitant shift and broadening in the QD solid optical absorption compared to that of dispersed samples is consistent with electron delocalization and measured electron mobilities. Annealing indium contacts allows for thermal diffusion and doping of the QD thin-films, shifting the Fermi energy, filling traps, and providing access to the bands. Temperature-dependent measurements show bandlike transport to 220 K on a SiO(2) gate insulator that is extended to 140 K by reducing the interface trap density using an Al(2)O(3)/SiO(2) gate insulator. The use of compact ligands and doping provides a pathway to high performance, solution-deposited QD electronics and optoelectronics. PMID- 22509935 TI - Engineering Streptomyces tenebrarius to synthesize single component of carbamoyl tobramycin. AB - AIMS: To engineer Streptomyces tenebrarius for producing carbamoyl tobramycin as a main component. METHODS AND RESULTS: The aprH-M gene fragment (apramycin biosynthetic gene from GenBank) in S. tenebrarius Tt49 was knocked out by genetic engineering to form S. tenebrarius T106 (DeltaaprH-M). Compared to the wild-type strain, mutant strain T106 (DeltaaprH-M) no longer produced apramycin, while mainly synthesize carbamoyl tobramycin. TLC and HPLC-MS analyses indicated that the mutant strain significantly increased the production of carbamoyl tobramycin. CONCLUSIONS: The metabolic flow for the apramycin and its analogues biosynthesis was blocked by disrupting the aprH-M gene clusters. The aprH-M gene clusters might be essential for the biosynthesis of apramycin. The mutant strain T106 mainly synthesized carbamoyl tobramycin. SIGNIFICANCE AND IMPACT OF STUDY: The mutant T106 mainly produces carbamoyl tobramycin without synthesizing apramycin, which will reduce cost of postextraction from fermentation products. Therefore, it has good prospects for industrial application. PMID- 22509938 TI - Effective porosity implies effective bulk density in sorbing solute transport. PMID- 22509937 TI - Adolescents' conformity to their peers' pro-alcohol and anti-alcohol norms: the power of popularity. AB - BACKGROUND: Research on adolescent development suggests that peer influence may play a key role in explaining adolescents' willingness to drink, an important predictor of drinking initiation. However, experiments that thoroughly examine these peer influence effects are scarce. This study experimentally examined whether adolescents adapted their willingness to drink when confronted with the pro-alcohol and anti-alcohol norms of peers in a chat room session and whether these effects were moderated by the social status of peers. METHODS: We collected survey data on drinking behavior, social status, and willingness to drink among five hundred thirty-two 14- to 15-year-olds. Of this sample, 74 boys participated in a simulated Internet chat room session in which participants were confronted with preprogrammed pro-alcohol or anti-alcohol norms of "grade-mates" which were in fact preprogrammed e-confederates. Accordingly, we tested whether participants adapted their willingness to drink to the norms of these grade-mates. To test whether adaptations in participants' willingness to drink would depend on grade mates' social status, we manipulated their level of popularity. RESULTS: The results indicated that adolescents adapted their willingness to drink substantially to the pro-alcohol (i.e., more willing to drink) as well as anti alcohol (i.e., less willing to drink) norms of these peers. Adolescents were more influenced by high-status than low-status peers. Interestingly, the anti-alcohol norms of the popular peers seemed most influential in that adolescents were less willing to drink when they were confronted with the anti-alcohol norms of popular peers. Additionally, the adolescents internalized these anti-alcohol norms. CONCLUSIONS: This study gives more insight into peer influence processes that encourage or discourage alcohol use. These results could be fundamental for the development of prevention and intervention programs to reduce alcohol use among the adolescents. PMID- 22509939 TI - Elucidating driving forces for liposome rupture: external perturbations and chemical affinity. AB - Atomic force microscopy (AFM) studies under aqueous buffer probed the role of chemical affinity between liposomes, consisting of large unilamellar vesicles, and substrate surfaces in driving vesicle rupture and tethered lipid bilayer membrane (tLBM) formation on Au surfaces. 1,2-Distearoyl-sn-glycero-3 phosphoethanolamine-N-poly(ethylene glycol)-2000-N-[3-(2-pyridyldithio) propionate] (DSPE-PEG-PDP) was added to 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC) vesicles to promote interactions via Au-thiolate bond formation. Forces induced by an AFM tip leading to vesicle rupture on Au were quantified as a function of DSPE-PEG-PDP composition with and without osmotic pressure. The critical forces needed to initiate rupture of vesicles with 2.5, 5, and 10 mol % DSPE-PEG-PDP are approximately 1.1, 0.8, and 0.5 nN, respectively. The critical force needed for tLBM formation decreases from 1.1 nN (without osmotic pressure) to 0.6 nN (with an osmotic pressure due to 5 mM of CaCl(2)) for vesicles having 2.5 mol % DSPE-PEG-PDP. Forces as high as 5 nN did not lead to LBM formation from pure POPC vesicles on Au. DSPE-PEG-PDP appears to be important to anchor and deform vesicles on Au surfaces. This study demonstrates how functional lipids can be used to tune vesicle-surface interactions and elucidates the role of vesicle-substrate interactions in vesicle rupture. PMID- 22509940 TI - A new species of Eimeria (Apicomplexa: Eimeriidae) from the northern myotis, Myotis septentrionalis (Chiroptera: Vespertilionidae), in Oklahoma. AB - During September 2004, 4 adult northern myotis, Myotis septentrionalis, were collected from LeFlore County, Oklahoma (n = 2), and Logan (n = 1) and Yell (n = 1) counties, Arkansas, and their feces examined for coccidian parasites. Three of 4 bats (75%) were passing oocysts of Eimeria spp. Oocysts of Eimeria tumlisoni n. sp. were subspherical, 17.6 * 16.8 (16-19 * 14-18) um with a shape index of 1.0 (1.0-1.1). A micropyle and oocyst residuum were absent, although 1-2 bilobed polar granules were often present. Sporocysts were ovoidal, 10.5 * 5.9 (9 12 * 5-7) um with a shape index of 1.8 (1.6-2.0). A Stieda body was present, but substieda and parastieda bodies were absent. A sporocyst residuum was present consisting of compact to dispersed granules between the sporozoites. The sporozoites were elongate, with subspherical anterior refractile body and spherical posterior refractile body; a nucleus was not discernable. This is the second coccidian reported from this host and the first instance of a bat coccidian reported from Oklahoma. We also document a new geographic record for Eimeria catronensis in Oklahoma and provide an emended description. PMID- 22509941 TI - The association between endometriosis and polymorphisms in the interleukin-1 family genes in Korean women. AB - PROBLEM: To investigate the association between polymorphisms of the interleukin 1 (IL-1) family genes and endometriosis in Korean women. METHOD OF STUDY: In this case-control study, the IL-1alpha -889C>T, IL-1 receptor antagonist (IL-1RA) 86 bp microsatellite, IL-1 receptor 1 (IL-1R1) 52C>A, 294C>T, 1498T>C, 1632A>G, IL 1R2 rs2072472 C>T and rs7561460 C>T polymorphisms were analyzed in women with (n = 138) and without (n = 214) endometriosis using restriction fragment length polymorphism (RFLP) analysis, TaqMan assay, or DNA sequencing. Serum IL-1alpha, soluble IL-1RA (sIL-1RA), and sIL-1R2 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Among the polymorphisms measured, the 1498T>C polymorphisms in the IL-1R1 gene were found to be related with early stage endometriosis but not with advanced-stage endometriosis. The genotypes with at least one T allele (CT + TT) were less frequently observed in early-stage endometriosis compared with normal controls (OR = 0.44, 95% CI = 0.22-0.87, P = 0.02). Serum sIL-1R2 levels were significantly lower (P < 0.01) in women with endometriosis than in normal controls, whereas no difference in serum sIL-1RA levels between these two groups was noted. The single and haplotype genotypes of the IL-1R2 and IL-1RA microsatellite polymorphisms were not related with these serum levels. CONCLUSION: The IL-1R1 1498T>C polymorphism is associated with early-stage endometriosis in Korean women. PMID- 22509942 TI - Induction of senescence in cancer cells by the G-quadruplex stabilizer, BMVC4, is independent of its telomerase inhibitory activity. AB - BACKGROUND AND PURPOSE: Telomerase is the enzyme responsible for extending G strand telomeric DNA and represents a promising target for treatment of neoplasia. Inhibition of telomerase can be achieved by stabilization of G quadruplex DNA structures. Here, we characterize the cellular effects of a novel G-quadruplex stabilizing compound, 3,6-bis(4-methyl-2-vinylpyrazinium iodine) carbazole (BMVC4). EXPERIMENTAL APPROACH: The cellular effects of BMVC4 were characterized in both telomerase-positive and alternative lengthening of telomeres (ALT) cancer cells. The molecular mechanism of how BMVC4 induced senescence is also addressed. KEY RESULTS: BMVC4-treated cancer cells showed typical senescence phenotypes. BMVC4 induced senescence in both ALT and telomerase-overexpressing cells, suggesting that telomere shortening through telomerase inhibition might not be the cause for senescence. A large fraction of DNA damage foci was not localized to telomeres in BMVC4-treated cells and BMVC4 suppressed c-myc expression through stabilizing the G-quadruplex structure located at its promoter. These results indicated that the cellular targets of BMVC4 were not limited to telomeres. Further analyses showed that BMVC4 induced DNA breaks and activation of ataxia telangiectasia-mutated mediated DNA damage response pathway. CONCLUSIONS AND IMPLICATIONS: BMVC4, a G-quadruplex stabilizer, induced senescence by activation of pathways of response to DNA damage that was independent of its telomerase inhibitory activity. Thus, BMVC4 has the potential to be developed as a chemotherapeutic agent against both telomerase positive and ALT cancer cells. PMID- 22509943 TI - Contribution of ion binding affinity to ion selectivity and permeation in KcsA, a model potassium channel. AB - Ion permeation and selectivity, key features in ion channel function, are believed to arise from a complex ensemble of energetic and kinetic variables. Here we evaluate the contribution of pore cation binding to ion permeation and selectivity features of KcsA, a model potassium channel. For this, we used E71A and M96V KcsA mutants in which the equilibrium between conductive and nonconductive conformations of the channel is differently shifted. E71A KcsA is a noninactivating channel mutant. Binding of K(+) to this mutant reveals a single set of low-affinity K(+) binding sites, similar to that seen in the binding of K(+) to wild-type KcsA that produces a conductive, low-affinity complex. This seems consistent with the observed K(+) permeation in E71A. Nonetheless, the E71A mutant retains K(+) selectivity, which cannot be explained on the basis of just its low affinity for this ion. At variance, M96V KcsA is a rapidly inactivating mutant that has lost selectivity for K(+) and also conducts Na(+). Here, low affinity binding and high-affinity binding of both cations are detected, seemingly in agreement with both being permeating species in this mutant channel. In conclusion, binding of the ion to the channel protein seemingly explains certain gating, ion selectivity, and permeation properties. Ion binding stabilizes greatly the channel and, depending upon ion type and concentration, leads to different conformations and ion binding affinities. High-affinity states guarantee binding of specific ions and mediate ion selectivity but are nonconductive. Conversely, low-affinity states would not discriminate well among different ions but allow permeation to occur. PMID- 22509944 TI - Standardization of egg collection from aquatic birds for biomonitoring--a critical review. AB - Collecting bird eggs is an established method of biomonitoring for specific pollution hazards. One of the most critical problems with this method is the extreme biological variability in bird eggs, but standardizing the collection and preservation of eggs can reduce these problems. Furthermore, standard practices are required so that the results can be compared among studies because mistakes cannot be corrected by laboratory analysis. Therefore, a standard procedure for collecting and preserving bird eggs may be necessary. The objective of this review is to investigate the current standard of quality assurance in the field by analyzing 86 peer-reviewed papers describing egg collection and use for aquatic birds. We show that little attention has been paid to standardizing how eggs are collected and stored in the field. Important information is often absent, including crucial aspects of sample collection and preservation, such as the freshness of the eggs, the position of the eggs in the laying sequence, the selection criteria, random sampling, and the duration and temperature of transport. Potential standards are suggested and discussed as a foundation for the development of quality assurance standards in the field. PMID- 22509945 TI - Multiscale modeling of the nanomechanics of microtubule protofilaments. AB - Large-size biomolecular systems that spontaneously assemble, disassemble, and self-repair by controlled inputs play fundamental roles in biology. Microtubules (MTs), which play important roles in cell adhesion and cell division, are a prime example. MTs serve as "tracks" for molecular motors, and their biomechanical functions depend on dynamic instability-a stochastic switching between periods of rapid growing and shrinking. This process is controlled by many cellular factors so that growth and shrinkage periods are correlated with the life cycle of a cell. Resolving the molecular basis for the action of these factors is of paramount importance for understanding the diverse functions of MTs. We employed a multiscale modeling approach to study the force-induced MT depolymerization by analyzing the mechanical response of a MT protofilament to external forces. We carried out self-organized polymer (SOP) model based simulations accelerated on Graphics Processing Units (GPUs). This approach enabled us to follow the mechanical behavior of the molecule on experimental time scales using experimental force loads. We resolved the structural details and determined the physical parameters that characterize the stretching and bending modes of motion of a MT protofilament. The central result is that the severing action of proteins, such as katanin and kinesin, can be understood in terms of their mechanical coupling to a protofilament. For example, the extraction of tubulin dimers from MT caps by katanin can be achieved by pushing the protofilament toward the axis of the MT cylinder, while the removal of large protofilaments curved into "ram's horn" structures by kinesin is the result of the outward bending of the protofilament. We showed that, at the molecular level, these types of deformations are due to the anisotropic, but homogeneous, micromechanical properties of MT protofilaments. PMID- 22509946 TI - Anatomicohistological characteristics of the tubular genital organs of the female red brocket deer (Mazama americana) in the Peruvian Amazon. AB - This study examined the anatomical and histological characteristics of tubular genital organs of 51 adult female red brocket deer in the wild in different reproductive stages, collected by rural hunters in the north-eastern Peruvian Amazon. The infundibulum was characterized by a large diameter and the presence of a highly folded and ciliated epithelium, and the isthmus has a growing secretor epithelium and a thicker muscular layer. Whereas ciliated cells are more frequent in the infundibulum, epithelial secretory cells showing abundant apical secretory blebs are more frequent in the isthmus. In non-pregnant females in luteal phase, the endometrium transforms from a proliferative to a secretory type, showing a significant proliferation of endometrial uterine glands. The red brocket deer has four large circular folds in the cervix. The epithelium of the cervix is composed primarily of secretory cells. In pregnant females, the lumen of the endocervical canal is occupied by abundant mucous secretion. All pregnant females had one embryo or fetus, with a fetal sex ratio of 54.0% females to 46.0% males. This species has a cotyledonary, syndesmochorial and partially deciduate placenta, with 6-7 dome-shaped caruncles per female. The red brocket deer does not present a true cornification of the vaginal epithelial cells, and no vaginal epithelial pattern was determined according the reproductive state of the female. PMID- 22509947 TI - Does mirror imaging a radiograph affect reliability of age assessment using the Greulich and Pyle atlas? AB - Age estimation is routinely undertaken by comparing radiographs of the individual in question to published reference samples of individuals of known age. This study examines the reliability of age estimation utilizing the Greulich and Pyle atlas in relation to both left- and right-hand/wrist radiographs and explores whether reversing right-hand/wrist radiographs, so that they are in the same anatomical orientation as those images used in the atlas affects reliability. A total of 403 left-hand/wrist radiographs and 415 right-hand/wrist radiographs were age assessed using the Greulich and Pyle atlas. Analysis showed that there is no significant loss in reliability when radiographs of the right hand (women R(2) = 0.887 and men R(2) = 0.907) are utilized instead of the left (women R(2) = 0.939 and men R(2) = 0.940) or when they are assessed as mirror images to those printed in the reference atlas (reversed female left hand R(2) = 0.929 and reversed male left hand R(2) = 0.931). PMID- 22509948 TI - Auditory skills, language development, and adaptive behavior of children with cochlear implants and additional disabilities. AB - OBJECTIVE: The objective of this study was to evaluate the development of functional auditory skills, language, and adaptive behavior in deaf children with cochlear implants (CI) who also have additional disabilities (AD). DESIGN: A two group, pre-test versus post-test design was used. STUDY SAMPLE: Comparisons were made between 23 children with CIs and ADs, and an age-matched comparison group of 23 children with CIs without ADs (No-AD). Assessments were obtained pre-CI and within 12 months post-CI. RESULTS: All but two deaf children with ADs improved in auditory skills using the IT-MAIS. Most deaf children in the AD group made progress in receptive but not expressive language using the preschool language scale, but their language quotients were lower than the No-AD group. Five of eight children with ADs made progress in daily living skills and socialization skills; two made progress in motor skills. Children with ADs who did not make progress in language, did show progress in adaptive behavior. CONCLUSIONS: Children with deafness and ADs made progress in functional auditory skills, receptive language, and adaptive behavior. Expanded assessment that includes adaptive functioning and multi-center collaboration is recommended to best determine benefits of implantation in areas of expected growth in this clinical population. PMID- 22509949 TI - Computed tomography assessment of pharmacological lung volume reduction induced by bronchodilators in COPD. AB - Pharmacological lung volume reduction in COPD is an important goal in treatment with long-acting bronchodilators because in addition to airflow limitation, lung hyperinflation considerably affects COPD symptoms. Quantitative computed tomography (CT) simultaneously provides structural information about airway dimensions, emphysematous changes, and lung volumes, some of which are difficult to be evaluated by pulmonary function. Here, we evaluated changes in CT parameters and pulmonary function in 30 patients with COPD who underwent CT scans before and one year after starting tiotropium treatment and in 12 patients with COPD who were not treated with long-acting bronchodilators. Baseline pulmonary function and CT parameters did not differ between the two groups. One-year tiotropium therapy improved physiological-indices including residual volume (RV) and ratio of RV to total lung capacity (RV/TLC) (-235 mL, p = 0.005, and -2.9%, p = 0.0001, respectively), and CT-indices including wall area percent (WA%) and inner luminal area in right upper lobe apical and lower lobe basal segmental bronchi (-1.59%, p = 0.01, 2.27 mm(2), p = 0.0005; and -1.33%, p = 0.0008, 3.42 mm(2), p < 0.0001, respectively), low attenuation volume (LAV) and total lung volume (CT-TLV) (-92 mL, p = 0.0003, and -211 mL, p = 0.002, respectively). Changes in LAV, CT-TLV, RV, and RV/TLC were significantly greater in the tiotropium, than the non-bronchodilator group. The tiotropium-induced reduction in LAV correlated with the decrease in RV (rho = 0.45, p = 0.01). Our findings not only indicate the value of the comprehensive CT measurements in assessing the effects of bronchodilators, including pharmacological lung volume reduction, but also further understanding of the structural changes underlying physiological improvements induced by bronchodilators. PMID- 22509950 TI - Estradiol levels predict short-term adverse health outcomes in postmenopausal acute stroke women. AB - BACKGROUND: Data on the role of endogenous sex steroids in cerebrovascular disease are sparse. Estradiol is a hormone with diverse actions on the central nervous system. Our aim was to investigate the role of circulating estradiol levels in a postmenopausal acute stroke population. METHODS: During a time-period of 2 years, we prospectively studied 302 postmenopausal female patients hospitalized for an acute stroke in two tertiary hospitals. We addressed the question whether endogenous estradiol is associated with stroke severity on admission and functional outcome 1 month after stroke, as assessed by the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS), respectively. RESULTS: Estradiol levels were significantly related to stroke severity on admission, as expressed by NIHSS, even after correcting for confounding factors in the multivariate analysis (beta 0.353, P < 0.001). Estradiol was an independent determinant of 1-month mortality and adverse functional outcome (mRS >= 4), [odds ratio (OR) with 95% confidence intervals (CI): 3.341 (1.617-6.902), P = 0.001 and 2.277 (1.273-4.074), P = 0.006, respectively]. CONCLUSIONS: We identified an independent association of endogenous estradiol levels with stroke severity and short-term mortality and outcome. These findings suggest challenging the role of estradiol as a neuroprotective agent. PMID- 22509951 TI - Fat mass and obesity-associated (fto) gene and alcohol intake. PMID- 22509952 TI - Burden of caregivers of patients in Vegetative state and minimally conscious state. AB - OBJECTIVES: To assess differences in the burden of caregivers of patients in Vegetative state (VS) and minimally conscious state (MCS). MATERIALS AND METHODS: The Family Strain Questionnaire, Coping Orientations to Problem Experiences, Caregiver Needs Assessment, Short Form-12, Beck Depression Inventory and State Trait Anxiety Inventory were used. Differences in psychological condition between caregivers of VS and MCS patients, with different disease duration and hosting facility were assessed with Kruskall-Wallis test and factors associated with the overall levels of burden with UNIANOVA. RESULTS: In total, 487 participants were enrolled. Daily hours of care-giving is significantly associated with the overall level of burden perceived by caregivers (F = 4.099; P = 0.018). Strain, needs and frequency of use of coping strategies are substantially similar regardless of the patient's condition and distance from the acute event. Caregivers of post-acute patients reported low scores in mental health (median = 33.8; IQR = 23.1-47.6) and higher state of anxiety (median = 54; IQR = 45-62), whereas caregivers of long-term patients expressed more needs in social involvement (median = 19; IQR = 15-22). CONCLUSIONS: Burden and distress were high for all caregivers of VS and MCS patients. As care-giving is a long-term commitment process, support to the caregiver should be guaranteed throughout the duration of the relative's disease despite the patient's diagnosis or place where the patient is hosted. PMID- 22509953 TI - A genome-wide scan for quantitative trait loci affecting respiratory disease and immune capacity in Landrace pigs. AB - Respiratory disease is the most important health concern for the swine industry. Genetic improvement for disease resistance is challenging because of the difficulty in obtaining good phenotypes related with disease resistance; however, identification of genes or markers associated with disease resistance can help in the genetic improvement of pig health. The purpose of our study was to investigate whether quantitative trait loci (QTL) associated with disease resistance were segregated in a purebred population of Landrace pigs that had been selected for meat production traits and mycoplasmal pneumonia of swine (MPS) scores over five generations. We analysed 1395 pigs from the base to the fifth generation of this population. Two respiratory disease traits [MPS scores and atrophic rhinitis (AR) scores] and 11 immune-capacity traits were measured in 630 1332 animals at 7 weeks of age and when the animal's body weight reached 105 kg. Each of the pigs, except sires in the base population, was genotyped using 109 microsatellite markers, and then, QTL analysis of the full-sib family population with a multi-generational pedigree structure was performed. Variance component analysis was used to detect QTL associated with MPS or AR scores, and the logarithm of odds (LOD) score and genotypic heritability of the QTL were estimated. Five significant (LOD > 2.51) and 18 suggestive (LOD > 1.35) QTL for respiratory disease traits and immune-capacity traits were detected. The significant QTL for Log-MPS score, located on S. scrofa chromosome 2, could explain 87% of the genetic variance of this score in this analysis. This is the first report of QTL associated with respiratory disease lesions. PMID- 22509955 TI - Enhancement of motor imagery-related cortical activation during first-person observation measured by functional near-infrared spectroscopy. AB - It is known that activity in secondary motor areas during observation of human limbs performing actions is affected by the observer's viewpoint, with first person views generally leading to stronger activation. However, previous neuroimaging studies have displayed limbs in front of the observer, providing an offset view of the limbs without a truly first-person viewpoint. It is unknown to what extent these pseudo-first-person viewpoints have affected the results published to date. In this experiment, we used a horizontal two-dimensional mirrored display that places virtual limbs at the correct egocentric position relative to the observer. We compared subjects using the mirrored and conventional displays while recording over the premotor cortex with functional near-infrared spectroscopy. Subjects watched a first-person view of virtual arms grasping incoming balls on-screen; they were instructed to either imagine the virtual arm as their own [motor imagery during observation (MIO)] or to execute the movements [motor execution (ME)]. With repeated-measures anova, the hemoglobin difference as a direct index of cortical oxygenation revealed significant main effects of the factors hemisphere (P = 0.005) and condition (P <= 0.001) with significant post hoc differences between MIO-mirror and MIO conventional (P = 0.024). These results suggest that the horizontal mirrored display provides a more accurate first-person view, enhancing subjects' ability to perform motor imagery during observation. Our results may have implications for future experimental designs involving motor imagery, and may also have applications in video gaming and virtual reality therapy, such as for patients following stroke. PMID- 22509956 TI - Asymmetric synthesis of chiral 9,10-dihydrophenanthrenes using Pd-catalyzed asymmetric intramolecular Friedel-Crafts allylic alkylation of phenols. AB - We developed a novel asymmetric synthetic method for multisubstituted 9,10 dihydrophenanthrenes based on the Pd-catalyzed asymmetric intramolecular Friedel Crafts allylic alkylation of phenols, which produces 10-vinyl or 10-isopropenyl chiral 9,10-dihydrophenanthrene derivatives in high yield with up to 94% ee. PMID- 22509954 TI - Face-name association learning and brain structural substrates in alcoholism. AB - BACKGROUND: Associative learning is required for face-name association and is impaired in alcoholism, but the cognitive processes and brain structural components underlying this deficit remain unclear. It is also unknown whether prompting alcoholics to implement a deep level of processing during face-name encoding would enhance performance. METHODS: Abstinent alcoholics and controls performed a levels-of-processing face-name learning task. Participants indicated whether the face was that of an honest person (deep encoding) or that of a man (shallow encoding). Retrieval was examined using an associative (face-name) recognition task and a single-item (face or name only) recognition task. Participants also underwent 3T structural MRI. RESULTS: Compared with controls, alcoholics had poorer associative and single-item learning and performed at similar levels. Level of processing at encoding had little effect on recognition performance but affected reaction time (RT). Correlations with brain volumes were generally modest and based primarily on RT in alcoholics, where the deeper the processing at encoding, the more restricted the correlations with brain volumes. In alcoholics, longer control task RTs correlated modestly with smaller tissue volumes across several anterior to posterior brain regions; shallow encoding correlated with calcarine and striatal volumes; deep encoding correlated with precuneus and parietal volumes; and associative recognition RT correlated with cerebellar volumes. In controls, poorer associative recognition with deep encoding correlated significantly with smaller volumes of frontal and striatal structures. CONCLUSIONS: Despite prompting, alcoholics did not take advantage of encoding memoranda at a deep level to enhance face-name recognition accuracy. Nonetheless, conditions of deeper encoding resulted in faster RTs and more specific relations with regional brain volumes than did shallow encoding. The normal relation between associative recognition and corticostriatal volumes was not present in alcoholics. Rather, their speeded RTs occurred at the expense of accuracy and were related most robustly to cerebellar volumes. PMID- 22509957 TI - Cryoablation for AVNRT: importance of ablation endpoint criteria. AB - BACKGROUND: For ablation of atrioventricular nodal reentrant tachycardia (AVNRT), cryoablation has been shown to be a safe alternative to radiofrequency ablation. However, previous studies have shown a higher recurrence rate with cryoablation compared to radiofrequency ablation. OBJECTIVE: This study reviewed our experience using cryoablation for typical AVNRT using stringent endpoint criteria for slow pathway ablation, yet preserving the desirable safety profile of cryoablation. METHODS: Seventy-five consecutive cases of typical AVNRT underwent cryoablation. Ablation of the AV nodal slow pathway was performed with the goal of eliminating tachycardia, AH jump, and retrograde atrial echo beats. The primary efficacy endpoint was freedom of recurrent supraventricular tachycardia at follow-up. Analysis of AVN characteristics, number of lesions, and complications was performed. RESULTS: Seventy-two (96%) patients met the primary efficacy endpoint over an average follow-up of 34.6 (12.6-68.3) months. In patients who had complete elimination of the slow pathway, there were no recurrences. The presence of an AH jump with a single retrograde echo was highly associated with a recurrence (P = 0.0001). There were no complications, including AV conduction block. CONCLUSION: The efficacy of cryoablation for management of AVNRT can be comparable to radiofrequency energy if the suggested endpoint of elimination of tachycardia, AH jump with retrograde atrial beats, is met. Prior studies evaluating cryoablation in this setting did not require this endpoint, which could have contributed to the relatively higher rate of late recurrences. PMID- 22509958 TI - Abundance of adult ticks (Acari: Ixodidae) in the Chernobyl nuclear power plant exclusion zone. AB - The Chernobyl nuclear disaster resulted in contamination of vast areas in Europe. To date, there is little knowledge about the effects of radioactive contamination on tick species. We sampled ticks from vegetation and large-sized wild mammals belonging to orders Carnivora and Artiodactyla at sites with 0.76, 1.91, and 4.50 mSv/hr ionizing radiation background values in the Polesky State Radio-Ecological Reserve of the Chernobyl nuclear disaster zone in spring 2010. Altogether, 122 questing ticks were collected from vegetation. Among collected ticks, Dermacentor reticulatus (Fabricius) was, by far, the most abundant species (99.2%), followed by Ixodes ricnus (L.) (0.8%), which was collected only at the 0.76 mSv/hr site. The average sex ratio female?male was 2.9?1.0. In parallel with the present study, we examined 3 Sus scrofa (L.), 2 Nyctereutes procyonoides (Gray), and 1 Alces alces (L.) at the 4.50 mSv/hr site; 96 D. reticulatus ticks were found on 2 N. procyonoides specimens. The mean density and the intensity of infestation were 16 ticks per animal and 48 ticks per infested animal, respectively. Future investigations are warranted to further characterize the role of various tick vectors, vertebrate reservoirs, and diversity of tick-borne pathogens in the Chernobyl exclusion zone. PMID- 22509961 TI - Comparison of population level and individual level endpoints to evaluate ecological risk of chemicals. AB - Ecological risk assessments (ERA) of chemicals are often based on mortality and reproduction of individuals. To protect populations, fixed safety factors are applied to the data. However, the relationship between individuals and populations cannot easily be described by predefined numbers. The use of population models may reduce uncertainty and, hence, the risk for erroneous assessments. However, introducing models also introduces additional complexity. Therefore, it is desirable to keep the models as simple as possible. The objective of the present study was to determine whether simple risk equations or matrix models can improve ERA compared to traditional endpoints. To examine this, complex models that included environmental stochasticity and density dependence were used to simulate population level risk based on dose-response data for five chemicals. The risk, measured as probability for pseudo extinction and recovery time, was then compared to risk estimates based on individual level data (acute and chronic), risk equations, and simple matrix models. The results showed that the simple matrix models reduced uncertainty by more than 88% and 76% compared to acute and chronic data, respectively. Also the simple risk equation reduced uncertainty considerably (80% and 61% compared to acute and chronic data, respectively). PMID- 22509959 TI - Marked differences in CCR5 expression and activation levels in two South African populations. AB - The chemokine receptor CCR5 is pivotal in determining an individual's susceptibility to HIV-1 infection and rate of disease progression. To establish whether population-based differences exist in cell surface expression of CCR5 we evaluated the extent of CCR5 expression across all peripheral blood cell types in individuals from two populations, South African Africans (SAA) and South African Caucasians (SAC). Significant differences in CCR5 expression, both in number of CCR5 molecules per cell (density) and the percentage of CCR5-expressing cells, were observed between the two study groups, within all cell subsets. Most notably, the percentage of all CCR5(+) cell subsets was significantly lower in SAC compared with SAA individuals (P < 0.01) among natural killer (NK) -cell subsets (CD56(+) , CD16(+) CD56(+) and CD56(dim) ) whereas CCR5 density was significantly higher in SAC compared with SAA individuals in CCR5(+) CD8(+) T cell subsets and CCR5(+) NK-cell subsets (CD56(+) , CD16(+) CD56(+) and CD56(dim) ) (all P < 0.05). These relationships were maintained after exclusion of CCR5Delta32 heterozygous individuals (n = 7) from the SAC dataset. The SAA individuals exhibited significantly higher cell activation levels, as measured by HLA-DR expression, than SAC individuals in CD4(+) T-cell subsets (P = 0.002) and CD56(+) NK-cell subsets (P < 0.001). This study serves to demonstrate that ethnically divergent populations show marked differences in both cell activation and CCR5 expression, which are likely to impact on both susceptibility to HIV-1 infection and the rate of HIV-1 disease progression. PMID- 22509960 TI - Comparative neuropharmacology of three psychostimulant cathinone derivatives: butylone, mephedrone and methylone. AB - BACKGROUND AND PURPOSE: Here, we have compared the neurochemical profile of three new cathinones, butylone, mephedrone and methylone, in terms of their potential to inhibit plasmalemmal and vesicular monoamine transporters. Their interaction with 5-HT and dopamine receptors and their psychostimulant effect was also studied. EXPERIMENTAL APPROACH: Locomotor activity was recorded in mice following different doses of cathinones. Monoamine uptake assays were performed in purified rat synaptosomes. Radioligand-binding assays were carried out to assess the affinity of these compounds for monoamine transporters or receptors. KEY RESULTS: Butylone, mephedrone and methylone (5-25 mg.kg(-1) ) caused hyperlocomotion, which was prevented with ketanserin or haloperidol. Methylone was the most potent compound inhibiting both [(3) H]5-HT and [(3) H]dopamine uptake with IC(50) values that correlate with its affinity for dopamine and 5-HT transporter. Mephedrone was found to be the cathinone derivative with highest affinity for vesicular monoamine transporter-2 causing the inhibition of dopamine uptake. The affinity of cathinones for 5-HT(2A) receptors was similar to that of MDMA. CONCLUSIONS AND IMPLICATIONS: Butylone and methylone induced hyperlocomotion through activating 5-HT(2A) receptors and increasing extra-cellular dopamine. They inhibited 5-HT and dopamine uptake by competing with substrate. Methylone was the most potent 5-HT and dopamine uptake inhibitor and its effect partly persisted after withdrawal. Mephedrone-induced hyperlocomotion was dependent on endogenous 5-HT. Vesicular content played a key role in the effect of mephedrone, especially for 5-HT uptake inhibition. The potency of mephedrone in inhibiting noradrenaline uptake suggests a sympathetic effect of this cathinone. PMID- 22509962 TI - Multinomial Bayesian learning for modeling classical and nonclassical receptive field properties. AB - We study the interplay of Bayesian inference and natural image learning in a hierarchical vision system, in relation to the response properties of early visual cortex. We particularly focus on a Bayesian network with multinomial variables that can represent discrete feature spaces similar to hypercolumns combining minicolumns, enforce sparsity of activation to learn efficient representations, and explain divisive normalization. We demonstrate that maximal likelihood learning using sampling-based Bayesian inference gives rise to classical receptive field properties similar to V1 simple cells and V2 cells, while inference performed on the trained network yields nonclassical context dependent response properties such as cross-orientation suppression and filling in. Comparison with known physiological properties reveals some qualitative and quantitative similarities. PMID- 22509963 TI - An efficient learning procedure for deep Boltzmann machines. AB - We present a new learning algorithm for Boltzmann machines that contain many layers of hidden variables. Data-dependent statistics are estimated using a variational approximation that tends to focus on a single mode, and data independent statistics are estimated using persistent Markov chains. The use of two quite different techniques for estimating the two types of statistic that enter into the gradient of the log likelihood makes it practical to learn Boltzmann machines with multiple hidden layers and millions of parameters. The learning can be made more efficient by using a layer-by-layer pretraining phase that initializes the weights sensibly. The pretraining also allows the variational inference to be initialized sensibly with a single bottom-up pass. We present results on the MNIST and NORB data sets showing that deep Boltzmann machines learn very good generative models of handwritten digits and 3D objects. We also show that the features discovered by deep Boltzmann machines are a very effective way to initialize the hidden layers of feedforward neural nets, which are then discriminatively fine-tuned. PMID- 22509964 TI - Learning where to attend with deep architectures for image tracking. AB - We discuss an attentional model for simultaneous object tracking and recognition that is driven by gaze data. Motivated by theories of perception, the model consists of two interacting pathways, identity and control, intended to mirror the what and where pathways in neuroscience models. The identity pathway models object appearance and performs classification using deep (factored)-restricted Boltzmann machines. At each point in time, the observations consist of foveated images, with decaying resolution toward the periphery of the gaze. The control pathway models the location, orientation, scale, and speed of the attended object. The posterior distribution of these states is estimated with particle filtering. Deeper in the control pathway, we encounter an attentional mechanism that learns to select gazes so as to minimize tracking uncertainty. Unlike in our previous work, we introduce gaze selection strategies that operate in the presence of partial information and on a continuous action space. We show that a straightforward extension of the existing approach to the partial information setting results in poor performance, and we propose an alternative method based on modeling the reward surface as a gaussian process. This approach gives good performance in the presence of partial information and allows us to expand the action space from a small, discrete set of fixation points to a continuous domain. PMID- 22509965 TI - Chaotic exploration and learning of locomotion behaviors. AB - We present a general and fully dynamic neural system, which exploits intrinsic chaotic dynamics, for the real-time goal-directed exploration and learning of the possible locomotion patterns of an articulated robot of an arbitrary morphology in an unknown environment. The controller is modeled as a network of neural oscillators that are initially coupled only through physical embodiment, and goal directed exploration of coordinated motor patterns is achieved by chaotic search using adaptive bifurcation. The phase space of the indirectly coupled neural-body environment system contains multiple transient or permanent self-organized dynamics, each of which is a candidate for a locomotion behavior. The adaptive bifurcation enables the system orbit to wander through various phase-coordinated states, using its intrinsic chaotic dynamics as a driving force, and stabilizes on to one of the states matching the given goal criteria. In order to improve the sustainability of useful transient patterns, sensory homeostasis has been introduced, which results in an increased diversity of motor outputs, thus achieving multiscale exploration. A rhythmic pattern discovered by this process is memorized and sustained by changing the wiring between initially disconnected oscillators using an adaptive synchronization method. Our results show that the novel neurorobotic system is able to create and learn multiple locomotion behaviors for a wide range of body configurations and physical environments and can readapt in realtime after sustaining damage. PMID- 22509966 TI - Neural dynamics, bifurcations, and firing rates in a quadratic integrate-and-fire model with a recovery variable. I: Deterministic behavior. AB - We study the dynamics of a quadratic integrate-and-fire model of a single compartment neuron with a slow recovery variable, as input current and parameters describing timescales, recovery variable, and postspike reset change. Analysis of a codimension 2 bifurcation reveals that the domain of attraction of a stable hyperpolarized rest state interacts subtly with reset parameters, which reposition the system state after spiking. We obtain explicit approximations of instantaneous firing rates for fixed values of the recovery variable, and use the averaging theorem to obtain asymptotic firing rates as a function of current and reset parameters. Along with the different phase-plane geometries, these computations provide explicit tools for the interpretation of different spiking patterns and guide parameter selection in modeling different cortical cell types. PMID- 22509968 TI - Strictly positive-definite spike train kernels for point-process divergences. AB - Exploratory tools that are sensitive to arbitrary statistical variations in spike train observations open up the possibility of novel neuroscientific discoveries. Developing such tools, however, is difficult due to the lack of Euclidean structure of the spike train space, and an experimenter usually prefers simpler tools that capture only limited statistical features of the spike train, such as mean spike count or mean firing rate. We explore strictly positive-definite kernels on the space of spike trains to offer both a structural representation of this space and a platform for developing statistical measures that explore features beyond count or rate. We apply these kernels to construct measures of divergence between two point processes and use them for hypothesis testing, that is, to observe if two sets of spike trains originate from the same underlying probability law. Although there exist positive-definite spike train kernels in the literature, we establish that these kernels are not strictly definite and thus do not induce measures of divergence. We discuss the properties of both of these existing nonstrict kernels and the novel strict kernels in terms of their computational complexity, choice of free parameters, and performance on both synthetic and real data through kernel principal component analysis and hypothesis testing. PMID- 22509967 TI - A framework for evaluating pairwise and multiway synchrony among stimulus-driven neurons. AB - Several authors have previously discussed the use of log-linear models, often called maximum entropy models, for analyzing spike train data to detect synchrony. The usual log-linear modeling techniques, however, do not allow time varying firing rates that typically appear in stimulus-driven (or action-driven) neurons, nor do they incorporate non-Poisson history effects or covariate effects. We generalize the usual approach, combining point-process regression models of individual neuron activity with log-linear models of multiway synchronous interaction. The methods are illustrated with results found in spike trains recorded simultaneously from primary visual cortex. We then assess the amount of data needed to reliably detect multiway spiking. PMID- 22509969 TI - Competition through selective inhibitory synchrony. AB - Models of cortical neuronal circuits commonly depend on inhibitory feedback to control gain, provide signal normalization, and selectively amplify signals using winner-take-all (WTA) dynamics. Such models generally assume that excitatory and inhibitory neurons are able to interact easily because their axons and dendrites are colocalized in the same small volume. However, quantitative neuroanatomical studies of the dimensions of axonal and dendritic trees of neurons in the neocortex show that this colocalization assumption is not valid. In this letter, we describe a simple modification to the WTA circuit design that permits the effects of distributed inhibitory neurons to be coupled through synchronization, and so allows a single WTA to be distributed widely in cortical space, well beyond the arborization of any single inhibitory neuron and even across different cortical areas. We prove by nonlinear contraction analysis and demonstrate by simulation that distributed WTA subsystems combined by such inhibitory synchrony are inherently stable. We show analytically that synchronization is substantially faster than winner selection. This circuit mechanism allows networks of independent WTAs to fully or partially compete with other. PMID- 22509970 TI - Information recall using relative spike timing in a spiking neural network. AB - We present a neural network that is capable of completing and correcting a spiking pattern given only a partial, noisy version. It operates in continuous time and represents information using the relative timing of individual spikes. The network is capable of correcting and recalling multiple patterns simultaneously. We analyze the network's performance in terms of information recall. We explore two measures of the capacity of the network: one that values the accurate recall of individual spike times and another that values only the presence or absence of complete patterns. Both measures of information are found to scale linearly in both the number of neurons and the period of the patterns, suggesting these are natural measures of network information. We show a smooth transition from encodings that provide precise spike times to flexible encodings that can encode many scenes. This makes it plausible that many diverse tasks could be learned with such an encoding. PMID- 22509971 TI - Bayesian community detection. AB - Many networks of scientific interest naturally decompose into clusters or communities with comparatively fewer external than internal links; however, current Bayesian models of network communities do not exert this intuitive notion of communities. We formulate a nonparametric Bayesian model for community detection consistent with an intuitive definition of communities and present a Markov chain Monte Carlo procedure for inferring the community structure. A Matlab toolbox with the proposed inference procedure is available for download. On synthetic and real networks, our model detects communities consistent with ground truth, and on real networks, it outperforms existing approaches in predicting missing links. This suggests that community structure is an important structural property of networks that should be explicitly modeled. PMID- 22509972 TI - A computational feedforward model predicts categorization of masked emotional body language for longer, but not for shorter, latencies. AB - Given the presence of massive feedback loops in brain networks, it is difficult to disentangle the contribution of feedforward and feedback processing to the recognition of visual stimuli, in this case, of emotional body expressions. The aim of the work presented in this letter is to shed light on how well feedforward processing explains rapid categorization of this important class of stimuli. By means of parametric masking, it may be possible to control the contribution of feedback activity in human participants. A close comparison is presented between human recognition performance and the performance of a computational neural model that exclusively modeled feedforward processing and was engineered to fulfill the computational requirements of recognition. Results show that the longer the stimulus onset asynchrony (SOA), the closer the performance of the human participants was to the values predicted by the model, with an optimum at an SOA of 100 ms. At short SOA latencies, human performance deteriorated, but the categorization of the emotional expressions was still above baseline. The data suggest that, although theoretically, feedback arising from inferotemporal cortex is likely to be blocked when the SOA is 100 ms, human participants still seem to rely on more local visual feedback processing to equal the model's performance. PMID- 22509973 TI - Geophysical monitoring of simulated clandestine graves using electrical and ground-penetrating radar methods: 0-3 years after burial. AB - This study provides forensic search teams with systematic geophysical monitoring data over simulated clandestine graves for comparison to active cases. Simulated "wrapped" and "naked" burials were created. Multigeophysical surveys were collected over a 3-year monitoring period. Bulk ground resistivity, electrical resistivity imaging, multifrequency ground-penetrating radar (GPR), and grave and background "soil-water" conductivity data were collected. Resistivity surveys revealed the naked burial had consistently low-resistivity anomalies, whereas the wrapped burial had small, varying high-resistivity anomalies. GPR 110- to 900-MHz frequency surveys showed the wrapped burial could be detected throughout, with the "naked" burial mostly resolved. Two hundred and twenty-five megahertz frequency GPR data were optimal. "Soil-water" analyses showed rapidly increasing (year 1), slowly increasing (year 2), and decreasing (year 3) conductivity values. Results suggest resistivity and GPR surveys should be collected if target "wrapping" is unknown, with winter to spring surveys optimal. Resistivity surveys should be collected in clay-rich soils. PMID- 22509974 TI - A kinetic approach to determining the conformational stability of a protein that dimerizes after folding. AB - A strongly stabilized form of the beta1 domain of the streptococcal protein G, termed Gbeta1-M2, was previously obtained by an in vitro selection method for stabilized protein variants. It contains four substitutions, but how they contribute to the Gibbs free energy of denaturation (DeltaG(D)) could not be determined, because, unlike the wild-type protein, Gbeta1-M2 dimerizes in a spectroscopically silent reaction. Here we determined the DeltaG(D) of the folded Gbeta1-M2 monomer by using a kinetic approach that uncouples the folding of the monomer from dimerization. The conformational equilibration of the monomer is faster than dimer formation, and therefore, its stability constant could be determined from the ratio of the rate constants for monomer unfolding and refolding. In this approach, double-mixing experiments were essential for uncovering the unfolding kinetics of the transient Gbeta1-M2 monomer and the association of the monomers after their folding. The analysis revealed that the selected substitutions stabilize the Gbeta1-M2 monomer by 15 kJ mol(-1) in an additive fashion. The combination of single- and double-mixing kinetic experiments thus allowed us to determine the thermodynamic stability of a transient species that is inaccessible in equilibrium experiments. It can be applied for proteins in which monomer folding and oligomerization are kinetically uncoupled. PMID- 22509975 TI - Relationship of SNP of H2BFWT gene to male infertility in a Chinese population with idiopathic spermatogenesis impairment. AB - The H2B family, member W, testis specific (H2BFWT) gene encodes a testis specific histone that plays a crucial role in reorganization and remodeling of chromatin and epigenetic regulation during spermatogenesis, suggesting that the gene may be involved in spermatogenesis impairment. To test the speculation, the allele and haplotype frequencies of two single-nucleotide polymorphism loci in this gene, 9C>T and 368A>G, were investigated in 409 infertile patients with idiopathic azoospermia or oligozoospermia and 209 fertile men as controls using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. As the results, the frequencies of -9T (52.8% vs. 41.6%, p = 0.009) and 368G (43.0% vs. 32.5%, p = 0.012) were significantly higher in patients than those in controls; after stratifying patients, the significant higher frequencies were still detected in allele -9T for azoospermia (57.4% vs. 41.6%, p = 0.001) and allele 368G for oligozoospermia (45.4% vs. 32.5%, p = 0.007). The haplotype CA was significantly decreased (22.8% vs. 33.0%, p = 0.006) whereas TG was significantly increased (18.3% vs. 7.2%, p < 0.001) in infertile patients compared with controls. These results indicated that the polymorphism -9C>T and 368A>G in H2BFWT gene are associated with male infertility with idiopathic azoospermia or oligozoospermia, suggesting that H2BFWT gene might be contribute to susceptibility to spermatogenesis impairment in Chinese population. PMID- 22509976 TI - Suicidal ideation in anxiety-disordered youth. AB - Evidence is mixed regarding an independent association between anxiety and suicidality in youth. Study 1 examined suicidal ideation in treatment-referred, anxiety-disordered youth (N = 312, aged 7-17). Forty-one percent of anxiety disordered youth endorsed suicidal ideation. Anxiety disorder severity, global impairment, and current depressive symptoms predicted suicidal ideation in a multivariate model. Study 2 compared youth (N = 216, aged 7-14) with and without anxiety disorders. Higher rates of suicidal ideation were associated with anxiety diagnosis, and levels of anxiety predicted suicidal ideation after controlling for comorbid depressive disorders, current depressive symptoms, and global impairment. Results support an association between anxiety disorders and suicidal ideation in treatment-referred youth and recommend routine screening for suicidal ideation in this population. PMID- 22509977 TI - Inhibition of type I interferon-mediated antiviral action in human glioma cells by the IKK inhibitors BMS-345541 and TPCA-1. AB - The nuclear factor-kappa B (NFkappaB) signal transduction pathway plays an important role in immunity, inflammation, cell growth, and survival. Since dysregulation of this pathway results in high, constitutive NFkappaB activation in various cancers and immune disorders, the development of specific drugs to target this pathway has become a focus for treating these diseases. NFkappaB regulates various aspects of the cellular response to interferon (IFN). However, the role of the upstream regulator of the NFkappaB signaling pathway, the inhibitor of kappaB kinase (IKK) complex, on IFN function has not been examined. In the present study, we examined the effects of 2 IKK inhibitors, N-(1,8 Dimethylimidazo[1,2-a]quinoxalin-4-yl)-1,2-ethanediamine hydrochloride (BMS 345541) and 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), on IFN action in several human glioma cell lines. IKK inhibitors inhibit glioma cell proliferation, as well as TNF-induced RelA (p65) nuclear translocation and NFkappaB-dependent IL8 gene expression. Importantly, BMS-345541 and TPCA-1 differentially inhibit IFN-induced gene expression, completely suppressing MX1 and GBP1 gene expression, while having only a minor effect on ISG15 expression. Furthermore, these IKK inhibitors displayed marked differences in blocking IFN-induced antiviral action against cytopathic effects and replication of vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV). Our results show that the IKK complex plays an important function in IFN induced gene expression and antiviral activity. Since VSV and EMCV are oncolytic viruses used in cancer therapy, our results indicate the potential synergy in combining IKK inhibitors with oncolytic viruses. PMID- 22509980 TI - Improved mechanical properties of zwitterionic hydrogels with hydroxyl groups. AB - Molecular dynamics simulations were performed to examine the mechanical properties of poly(carboxybetaine methacrylate) (pCBMA) hydrogels. pCBMA hydrogels with additional hydroxyl groups as physical cross-linkers (OH-pCBMA hydrogels) were studied for comparison. Results show that OH-pCBMA hydrogels have higher elastic modulus than pCBMA hydrogels. This improvement can be explained by hydrogen bond formation between hydroxyl groups and carboxylate groups in the OH pCBMA hydrogel, which result in an enhanced polymer network within the hydrogel. The enhancement of the polymer work is also suggested by a smaller value of root mean-square deviation of zwitterionic side chain pairs in the OH-pCBMA hydrogel than that in the pCBMA hydrogel. Additionally, the presence of hydrogen bonds leads to a lower equilibrium water content for the OH-pCBMA hydrogel compared to the pCBMA hydrogel, which is another reason for the greater mechanical modulus of the OH-pCBMA hydrogel. PMID- 22509979 TI - B-cell activating factor levels in rheumatoid arthritis patients in response to treatment with biologics. AB - The B-cell-activating factor (BAFF), a member of the tumor necrosis factor (TNF) family, has recently attracted attention as a potent cytokine, involved in B-cell stimulation and survival of autoimmune cells. Despite its significance in the pathogenesis of autoimmune diseases, data is limited and inconclusive regarding its expression in different stages of rheumatoid arthritis (RA). The aim of this study was to assess BAFF in biologic-naive RA patients with early versus established disease and monitor its levels in response to anti-TNF treatment in seronegative- and seropositive patients. Based on our results, B-cell-activating factor (BAFF) did not appear to be overexpressed or differentially expressed early (<=2 years duration) in comparison to established rheumatoid arthritis (RA). Moreover, tumor necrosis factor (TNF) blockade did not appear to affect BAFF levels in either seropositive or seronegative RA patients, despite the association of anti-TNF treatment with the development of autoantibodies and the known anti-apoptotic effects of BAFF. As expected, BAFF became induced after B cell depletion. Investigation of the effect of different biologics on the expression of BAFF and other cytokines will help elucidate the interconnecting immune pathways involved in the initiation and perpetuation of the inflammatory process. PMID- 22509978 TI - Update on the immunological pathway of negative regulation in acute insults and sepsis. AB - Sepsis with subsequent multiple organ dysfunction is a distinctly systemic inflammatory response to concealed or known infection and is a leading cause of death in intensive care units. In the initial stage of sepsis, a phase of immune activation can be evident, but a marked apoptosis-induced depletion of lymphocytes and a nonspecific anergy of immune function after severe trauma and burns might be responsible for the increased susceptibility of the host to subsequent septic complications. Recent studies indicated that negative regulation of immune function plays a pivotal role in the maintenance of peripheral homeostasis and regulation of immune responses; therefore, an understanding of the basic pathways might give rise to novel insights into the mechanisms of sepsis and immune homeostasis. This review is an attempt to provide a summary of the different pathways of negative regulation that are involved in the pathogenesis of sepsis, secondary to acute insults. PMID- 22509981 TI - Understanding changes in heroin availability in Europe over time: emerging evidence for a slide, a squeeze and a shock. PMID- 22509982 TI - Optimizing clozapine through clinical decision making. AB - OBJECTIVE: Recognizing and incorporating the patient's own perspective into treatment recommendations are essential to optimizing clozapine use. The study describes how the patient's perspective influences clinicians' decision strategies and affects their clozapine recommendations. METHOD: Psychiatric trainees examined six case vignettes of varying complexity that included clinical and patient perspective information. They made treatment recommendations guided by a well-known switching guideline and rated the factors that influenced their recommendations. RESULTS: The decision to follow the guideline's switch recommendation was influenced principally by the importance of the patient's positive symptom profile. The decision to recommend clozapine in lieu of another treatment was influenced principally by the importance of patient's perspective and patient-specific clinical information. These factors had a significant combined influence on the clozapine recommendation rate: When clinical factors were moderately important, the rate was 8%. When clinical factors were extremely important, the rate was 22% when the patient's perspective was moderately important, but 80% when the patient's perspective was very or extremely important. CONCLUSION: A clozapine optimization strategy requires skill in advanced decision making, and specifically in prioritizing the patient's perspective without diminishing the importance of clinical information. This skill can be developed through practice-based learning. PMID- 22509983 TI - Association between genetic variations in surfactant protein d and emphysema, interstitial pneumonia, and lung cancer in a Japanese population. AB - Surfactant protein D (SFTPD) is a lung-specific anti-inflammatory factor that antagonizes inflammation by inhibiting oxidative stress and stimulating innate immunity. Variations in SFTPA2 and SFTPB, genes for other surfactant proteins, have been associated with lung cancer. We therefore investigated associations between SFTPD variations and lung cancer as well as emphysema and interstitial pneumonia, which are characterized by chronic inflammation from which lung cancer often arises. DNA from 1342 autopsy samples, including those from 140 subjects with lung cancer, was investigated. The single nucleotide polymorphism (SNP) rs721917, which results in methionine being exchanged for threonine at amino acid 11 (the Met11Thr variation), tended to be associated with emphysema and was associated with interstitial pneumonia and lung cancer. A haplotype analysis revealed that the haplotypes associated with emphysema and lung cancer differed from that associated with interstitial pneumonia, suggesting a differential role for SFTPD in the development of these diseases. A mediating analysis did not reveal a mediating effect exerted by emphysema or interstitial pneumonia on lung cancer. Our results suggested that SFTPD plays a role in the development of lung cancer and that the role for lung cancer may differ from that for interstitial pneumonia. PMID- 22509984 TI - Advances in the management of multiple sclerosis-related spasticity. PMID- 22509985 TI - Clinical efficacy and effectiveness of Sativex, a combined cannabinoid medicine, in multiple sclerosis-related spasticity. AB - Multiple sclerosis (MS) is associated with a wide range of disease symptoms and amongst these, spasticity is one of the most disabling and has the greatest impact on patient well-being and quality of life. Until now, available drug therapies for spasticity appear to have limited benefit and are often associated with poor tolerability. In a recent Spanish survey it was noted that multidrug therapy and a low control rate were common features for a large proportion of patients with MS-related spasticity, suggesting that currently available monotherapies lack significant activity. Sativex is a 1:1 mixture of delta-9 tetrahydrocannabinol and cannabidiol derived from Cannabis sativa chemovars, which is available as an oromucosal spray. Clinical experience with Sativex in patients with MS-related spasticity is steadily accumulating. Results from randomized, controlled trials have reported a reduction in the severity of symptoms associated with spasticity, leading to a better ability to perform daily activities and an improved perception of patients and their carers regarding functional status. These are highly encouraging findings that provide some much needed optimism for the treatment of this disabling and often painful symptom of MS. PMID- 22509986 TI - Evaluation of the safety and tolerability profile of Sativex: is it reassuring enough? AB - The adoption of new drug therapies involves an assessment of risk:benefit based upon the best clinical evidence, including clinical trials but also everyday clinical practice data collection. However, in the case of Sativex, a cannabinoid medicine containing the two main active ingredients of cannabis, delta-9 tetrahydrocannabinol and cannabidiol, the picture is somewhat clouded by preconceived views regarding the world's most widely used illicit drug, herbal cannabis. In this review, I aim to look beyond these preconceptions and evaluate the body of published data concerning this medicine currently approved in different countries for the management of one of the most frequent and disabling symptoms associated with multiple sclerosis, spasticity. In particular, data relevant to areas of concern such as tolerability, safety, psychoactivity, effects on withdrawal (including possible drug tolerance) and finally the potential for abuse/dependence are evaluated. Balancing these risk factors, the main positive clinical data published over the years by the Oxford Centre for Enablement, following on from the first pilot study in 2004, are presented. Based upon our experience, the benefits that are seen initially with Sativex when treating multiple sclerosis spasticity patients are generally maintained during long-term treatment. Furthermore, following withdrawal of Sativex, symptoms often return, but, beyond this, sudden cessation is generally safe with no evidence of physiological or psychological dependence. Dose escalation has not usually been observed in clinical trials or clinical practice after the first titration weeks. Adverse effects occur relatively frequently, but they are usually mild to moderate in intensity and rarely require drug discontinuation. Overall, Sativex appears to be well-tolerated and a useful addition for patients who have failed treatment with traditional antispastic agents. PMID- 22509987 TI - COMT Val158Met modulates the effect of childhood adverse experiences on the risk of alcohol dependence. AB - Genetic factors and childhood adverse experiences contribute to the vulnerability to alcohol dependence. However, empirical data on the interplay between specific genes and adverse experiences are few. The COMT Val158Met and DRD2/ANKK1 Taq1A genotypes have been suggested to affect both stress sensitivity and the risk for alcohol dependence. This study tested the hypothesis that genetic variation in COMT Val158Met and DRD2/ANKK1 Taq1A interacts with childhood adverse experiences to predict alcohol dependence. Male abstinent alcohol-dependent patients (n = 110) and age-matched healthy male controls (n = 99) were genotyped for the COMT Val158Met and the DRD2/ANKK1 Taq1A genotypes. Childhood adverse events were measured using three self-report questionnaires. Alcohol dependence severity, age of onset and duration of alcohol dependence were analyzed as secondary outcome measures. Statistical analysis involved logistic regression analysis and analysis of variance. Alcohol-dependent patients reported increased childhood adversity. The interaction between childhood adversity and the COMT Val158Met genotype added significantly to the prediction model. This gene-environment interaction was confirmed in the analysis of the secondary outcome measures, i.e. alcohol dependence severity, age of onset and duration of alcohol dependence. The DRD2/ANKK1 Taq1A genotype was not related to alcohol dependence, nor did it interact with childhood adversity in predicting alcohol dependence. This study provides evidence for a gene-environment interaction in alcohol dependence, in which an individual's sensitivity to childhood adverse experience is moderated by the COMT genotype. Exposed carriers of a low-activity Met allele have a higher risk to develop severe alcohol dependence than individuals homozygous for the Val allele. PMID- 22509988 TI - Stem cells in the reproductive system. AB - This review article summarizes current knowledge on regulation, functions, and capacities of stem cells in the female and male reproductive tract. Major locations in which pluripotent cells reside and from where they can be isolated are the ovaries, the endometrium, the decidua, and the testis. They include oocytes, embryonic stem cells, trophoblast stem cells, and spermatogonial stem cells, but also several side populations, which can be obtained after certain isolation and culture procedures. The potential of pluripotent cells in the reproductive tract to differentiate is manifold, but heterogenous, depending upon their respective origin. As stem cells have a potential for future application in transplantation and regenerative medicine, this article also reviews the literature on major histocompatibility complex expression on stem cells of the reproductive tract, because of its immunogenic effects, but also because of its potential expression of HLA-G, a potent immunomodulator mainly associated with trophoblast cells. PMID- 22509989 TI - Short-term crossmodal plasticity of the auditory steady-state response in blindfolded sighted individuals. AB - This study investigated the effect of short-term visual deprivation on auditory steady-state response (ASSR) to amplitude-modulated tones. Magnetoencephalography data were acquired while subjects performed an auditory detection task under both monaural and dichotic presentation conditions. Analyses were performed on the spectral power, mean amplitudes and dipole positions of the ASSR at the onset of blindfolding, as well as after 2, 4 and 6 h of visual deprivation. Results show a modulation of the spectral power of the ASSR at the frequencies that were present in the stimulus after 6 h of sensory deprivation, and this was especially true for the dichotic condition. Moreover, participants showed two spectral peaks in the occipital cortex at the end of the visual deprivation period, a phenomenon normally observed in the auditory cortex. Our results shed light not only on the timeline associated with short-term crossmodal recruitment of input-deprived sensory cortices but also demonstrate that the visual cortex can display auditory cortex-like functioning in response to the ASSR. Importantly, our results also highlight the importance of taking into consideration individual differences when investigating crossmodal plastic phenomena. Indeed, the occipital spectral peaks were only observed in half the subjects following short-term deprivation. PMID- 22509991 TI - A two-step approach to map quantitative trait loci for meat quality in connected porcine F(2) crosses considering main and epistatic effects. AB - The aim of this study was to map QTL for meat quality traits in three connected porcine F(2) crosses comprising around 1000 individuals. The three crosses were derived from the founder breeds Chinese Meishan, European Wild Boar and Pietrain. The animals were genotyped genomewide for approximately 250 genetic markers, mostly microsatellites. They were phenotyped for seven meat quality traits (pH at 45 min and 24 h after slaughter, conductivity at 45 min and 24 h after slaughter, meat colour, drip loss and rigour). QTL mapping was conducted using a two-step procedure. In the first step, the QTL were mapped using a multi-QTL multi-allele model that was tailored to analyse multiple connected F(2) crosses. It considered additive, dominance and imprinting effects. The major gene RYR1:g.1843C>T affecting the meat quality on SSC6 was included as a cofactor in the model. The mapped QTL were tested for pairwise epistatic effects in the second step. All possible epistatic effects between additive, dominant and imprinting effects were considered, leading to nine orthogonal forms of epistasis. Numerous QTL were found. The most interesting chromosome was SSC6. Not all genetic variance of meat quality was explained by RYR1:g.1843C>T. A small confidence interval was obtained, which facilitated the identification of candidate genes underlying the QTL. Epistasis was significant for the pairwise QTL on SSC12 and SSC14 for pH24 and for the QTL on SSC2 and SSC5 for rigour. Some evidence for additional pairwise epistatic effects was found, although not significant. Imprinting was involved in epistasis. PMID- 22509990 TI - Choline supplementation and DNA methylation in the hippocampus and prefrontal cortex of rats exposed to alcohol during development. AB - BACKGROUND: Some of the most frequent deficits seen in children with fetal alcohol spectrum disorders (FASD) and in animal models of FASD are spatial memory impairments and impaired executive functioning, which are likely related to alcohol-induced alterations of the hippocampus and prefrontal cortex (PFC), respectively. Choline, a nutrient supplement, has been shown in a rat model to ameliorate some of alcohol's teratogenic effects, and this effect may be mediated through choline's effects on DNA methylation. METHODS: Alcohol was given by intragastric intubation to rat pups during the neonatal period (postnatal days 2 to 10) (ET group), which is equivalent to the third trimester in humans and a period of heightened vulnerability of the brain to alcohol exposure. Control groups included an intubated control group given the intubation procedure without alcohol (IC) and a nontreated control group (NC). Choline or saline was administered subcutaneously to each subject from postnatal days 2 to 20. On postnatal day 21, the brains of the subjects were removed and assayed for global DNA methylation patterning as measured by chemiluminescence using the cpGlobal assay in both the hippocampal region and PFC. RESULTS: Alcohol exposure caused hypermethylation in the hippocampus and PFC, which was significantly reduced after choline supplementation. In contrast, control animals showed increases in DNA methylation in both regions after choline supplementation, suggesting that choline supplementation has different effects depending upon the initial state of the brain. CONCLUSIONS: This study is the first to show changes in global DNA methylation of the hippocampal region and PFC after neonatal alcohol exposure. Choline supplementation impacts global DNA methylation in these 2 brain regions in alcohol-exposed and control animals in a differential manner. The current findings suggest that both alcohol and choline have substantial impact on the epigenome in the PFC and hippocampus, and future studies will be needed to describe which gene families are impacted in such a way that function of the nervous system is changed. PMID- 22509992 TI - Direct palladium(II)-catalyzed synthesis of arylamidines from aryltrifluoroborates. AB - A fast and convenient synthesis of arylamidines starting from readily available potassium aryltrifluoroborates and cyanamides is reported. The coupling was achieved by Pd(II)-catalysis in a one step 20 min microwave protocol using Pd(O(2)CCF(3)), 6-methyl-2,2'-bipyridyl, TFA, and MeOH, providing the corresponding arylamidines in moderate to excellent yields. PMID- 22509994 TI - Development of predictive models for the growth of Escherichia coli O157:H7 on cabbage in Korea. AB - Cabbage is the main material of coleslaw, a popular side dish in Korea as well as many other countries. In the present study, the combined effect of temperature (15, 25, and 35 degrees C) and relative humidity (60%, 70%, and 80%) on the growth of Escherichia coli O157:H7 on cabbage was investigated. The polynomial models for growth rate (GR), lag time (LT), and maximum population density (MPD) estimated from the Baranyi model were conducted with high coefficients of determination (R(2)> 0.98). Subsequently, performance and reliability of the models were assessed through external validation, employing three indices as bias factor (B(f)), accuracy factor (A(f)), and the standard error of prediction expressed in percentage (%SEP). The B(f), A(f), and %SEP values of the predictive models for GR were 1.008, 1.127 and 18.70%, while 1.033, 1.187 and 20.79% for LT and 0.960, 1.044 and 5.22% for MPD, respectively. The results demonstrated that the developed secondary models showed a good agreement between the observed and predicted values. Therefore, the established models can be suitable to estimate and control E. coli O157:H7 growth risk on cabbage at some steps from farm to table in Korea as a valuable tool. PMID- 22509993 TI - Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss. AB - Distal renal tubular acidosis (dRTA) is characterized by the inability to excrete acid in the renal collecting ducts resulting in inappropriately alkaline urine and hyperchloremic (normal anion gap) metabolic acidosis in the context of a normal (or near-normal) glomerular filtration rate. Inborn dRTA can be due to autosomal dominant or recessive gene defects. Clinical symptoms vary from mild acidosis, incidental detection of kidney stones or renal tract calcification to severe findings such as failure to thrive, severe metabolic acidosis, and nephrocalcinosis. The majority of patients with recessive dRTA present with sensorineural hearing loss (SNHL). Few cases with abnormal widening of the vestibular aqueduct have been described with dRTA. Mutations in three different genes have been identified, namely SLC4A1, ATP6V1B1, and ATP6V0A4. Patients with mutations in the ATP6V1B1 proton pump subunit develop dRTA and in most of the cases sensorineural hearing loss early in childhood. We present two patients from two different and non-consanguineous families with dRTA and SNHL. Direct sequencing of the ATP6V1B1 gene revealed that one patient harbors two homozygous mutations and the other one is a compound heterozygous. To our knowledge, this is the first case in the literature describing homozygosity in the same dRTA gene on both alleles. PMID- 22509995 TI - Gas-phase and transpiration-driven mechanisms for volatilization through wetland macrophytes. AB - Natural and constructed wetlands have gained attention as potential tools for remediation of shallow sediments and groundwater contaminated with volatile organic compounds (VOCs). Wetland macrophytes are known to enhance rates of contaminant removal via volatilization, but the magnitude of different volatilization mechanisms, and the relationship between volatilization rates and contaminant physiochemical properties, remain poorly understood. Greenhouse mesocosm experiments using the volatile tracer sulfur hexafluoride were conducted to determine the relative magnitudes of gas-phase and transpiration-driven volatilization mechanisms. A numerical model for vegetation-mediated volatilization was developed, calibrated with tracer measurements, and used to predict plant-mediated volatilization of common VOCs as well as quantify the contribution of different volatilization pathways. Model simulations agree with conclusions from previous work that transpiration is the main driver for volatilization of VOCs, but also demonstrate that vapor-phase transport in wetland plants is significant, and can represent up to 50% of the total flux for compounds with greater volatility like vinyl chloride. PMID- 22509996 TI - Radioiodinated folic acid conjugates: evaluation of a valuable concept to improve tumor-to-background contrast. AB - Folic acid radioconjugates can be used for targeting folate receptor positive (FR(+)) tumors. However, the high renal uptake of radiofolates is a drawback of this strategy, particularly with respect to a therapeutic application due to the risk of damage to the kidneys by particle radiation. The goal of this study was to develop and evaluate radioiodinated folate conjugates as a novel class of folate-based radiopharmaceuticals potentially suitable for therapeutic application. Two different folic acid conjugates, tyrosine-folate (1) and tyrosine-click-folate (3), were synthesized and radioiodinated using the Iodogen method resulting in [(125)I]-2 and [(125/131)I]-4. Both radiofolates were highly stable in mouse and human plasma. Determination of FR binding affinities using (3)H-folic acid and FR(+) KB tumor cells revealed affinities in the nanomolar range for 2 and 4. The cell uptake of [(125)I]-2 and [(125/131)I]-4 proved to be FR specific as it was blocked by the coincubation of folic acid. 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) in vitro assays were employed for the determination of tumor cell viability upon exposure to [(131)I] 4. Compared to untreated control cells, significantly reduced cell viability was observed for FR(+) cancer cells (KB, IGROV-1, SKOV-3), while FR(-) cells (PC-3) were not affected. Biodistribution studies performed in tumor bearing nude mice showed the specific accumulation of both radiofolates in KB tumor xenografts ([(125)I]-2: 3.43 +/- 0.28% ID/g; [(125)I]-4: 2.28 +/- 0.46% ID/g, 4 h p.i.) and increasing tumor-to-kidney ratios over time. The further improvement of the tumor to-background contrast was achieved by preinjection of the mice with pemetrexed allowing excellent imaging via single-photon emission computed tomography (SPECT/CT). These findings confirmed the hypothesis that the application of radioiodinated folate conjugates may be a valuable concept to improve tumor-to background contrast. The inhibitory effect of [(131)I]-4 on FR(+) cancer cells in vitro indicates the potential of this class of radiofolates for therapeutic application. PMID- 22509998 TI - Linguistic production and syntactic comprehension in schizophrenia and bipolar disorder. AB - OBJECTIVE: To explore linguistic abilities in schizophrenia and bipolar disorder. Specifically, the aims of this study were to: i) investigate microlinguistic (lexicon, morphology, syntax) and macrolinguistic (discourse coherence, pragmatics) dimensions of speech production and ii) evaluate syntactic comprehension skills in both schizophrenia and bipolar disorder. METHOD: Linguistic performance of 30 Italian-speaking patients with schizophrenia, 30 participants with bipolar disorder and 30 healthy controls comparable for age and educational level has been assessed using a story-telling task and a computer based test of syntactic comprehension. RESULTS: In narrative production, compared with healthy participants, those with schizophrenia had slight problems in speech rate and deficits at both local and global discourse coherence, whereas patients with bipolar disorder showed reduced mean length of utterance. As regards syntactic comprehension, both groups of patients collected more grammatical errors than controls, but they differed with regard to the number and kind of grammatical construction they missed. CONCLUSION: Linguistic deficits have been detected in both groups of patients, being, however, more severe and generalized in schizophrenia than in bipolar disorder. Such results help us in improving our understanding of the potential psychopathological overlapping between these disorders. PMID- 22509997 TI - Identification of novel genes conferring altered azole susceptibility in Aspergillus fumigatus. AB - Azoles are currently the mainstay of antifungal treatment both in agricultural and in clinical settings. Although the target site of azole action is well studied, the basis of azole resistance and the ultimate mode of action of the drug in fungi are poorly understood. To gain a deeper insight into these aspects of azole action, restriction-mediated plasmid integration (REMI) was used to create azole sensitive and resistant strains of the clinically important fungus Aspergillus fumigatus. Four azole sensitive insertions and four azole-resistant insertions were characterized. Three phenotypes could be re-created in wild-type AF210 by reintegration of rescued plasmid and a further four could be confirmed by complementation of the mutant phenotype with a copy of the wild-type gene predicted to be disrupted by the original insertional event. Six insertions were in genes not previously associated with azole sensitivity or resistance. Two insertions occur in transporter genes that may affect drug efflux, whereas others may affect transcriptional regulation of sterol biosynthesis genes and NADH metabolism in the mitochondrion. Two insertions are in genes of unknown function. PMID- 22509999 TI - Building a three-dimensional model of CYP2C9 inhibition using the Autocorrelator: an autonomous model generator. AB - In modern day drug discovery campaigns, computational chemists have to be concerned not only about improving the potency of molecules but also reducing any off-target ADMET activity. There are a plethora of antitargets that computational chemists may have to consider. Fortunately many antitargets have crystal structures deposited in the PDB. These structures are immediately useful to our Autocorrelator: an automated model generator that optimizes variables for building computational models. This paper describes the use of the Autocorrelator to construct high quality docking models for cytochrome P450 2C9 (CYP2C9) from two publicly available crystal structures. Both models result in strong correlation coefficients (R2 > 0.66) between the predicted and experimental determined log(IC50) values. Results from the two models overlap well with each other, converging on the same scoring function, deprotonated charge state, and predicted the binding orientation for our collection of molecules. PMID- 22510000 TI - A hybrid mechanism in chiral discrimination induced by crystallization of supramolecular compounds. AB - Host-guest complexes formed in aqueous medium between permethylated beta cyclodextrin (TMbeta-CD) and racemic 1-(p-fluorophenyl)ethanol (p-F-PE) are studied. The crystalline complexes are characterized and their crystal structures are determined, revealing two sets of solid phases with specific abilities for chiral discrimination: on the one hand, a stable complete solid solution with two independent complexes per asymmetric unit exhibits a limited chiral recognition, and on the other hand, two metastable partial solid solutions with unusual 1:2 host-guest stoichiometries behave as diastereomeric complexes. The structural features of the 1:2 complexes and their study by means of molecular modeling show that these solid phases, described as cocrystals formed between one host-guest inclusion complex and one non-engulfed p-F-PE molecule, present a significant chiral discrimination occurring both inside the cyclodextrin and outside the macrocycle in a crystal lattice cavity. Therefore, the enantioselectivity observed in this system results from an interplay between molecular inclusion in the cyclodextrin and lattice inclusion. To our knowledge, it is the first report of such a hybrid mechanism. An overview of the crystal structures of the literature containing TMbeta-CD is also achieved and allows their classification in four structural groups in relation to their crystal packing features. PMID- 22510001 TI - Therapeutic targeting of the angiotensin-converting enzyme 2/Angiotensin-(1 7)/Mas cascade in the renin-angiotensin system: a patent review. AB - INTRODUCTION: The renin-angiotensin system (RAS) is a main therapeutic target for cardiovascular diseases. Within the last two decades, novel components of the RAS have been discovered, opening new opportunities to interfere with its activity. Angiotensin(Ang)-(1-7) is synthesized by angiotensin-converting enzyme 2 (ACE2), and interacts with the G-protein-coupled receptor Mas. The axis formed by ACE2/Ang-(1-7)/Mas represents an endogenous counter regulatory pathway within the RAS. AREAS COVERED: In this review, the authors discuss patents and recent initiatives to develop therapeutic strategies based on the ACE2/Ang-(1-7)/Mas axis. EXPERT OPINION: Many publications and patents support a strategy to interfere with the activity of the RAS by stimulating its counter-regulatory axis mainly in two different ways: i) To increase the activity of ACE2, which will impact the system by increasing the inactivation of Ang II and the production of Ang-(1-7); ii) To stimulate Mas, taking advantage of nanostructured formulations of the natural peptide or analogues of Ang-(1-7). Although the preclinical studies are compelling, the possible impact of these novel therapeutic tools for the treatment of cardiometabolic diseases will only be known after completion of the ongoing clinical studies. PMID- 22510002 TI - Gold(I)-catalyzed synthesis of 1,5-benzodiazepines directly from o phenylenediamines and alkynes. AB - A unique gold(I)-catalyzed highly atom-economic synthesis of 1,5-benzodiazepines directly from o-phenylenediamines and alkynes has been achieved for the first time. PMID- 22510003 TI - Heart rate recovery in epilepsy. AB - Autonomic manifestations regarding cardiac function in epilepsy are not rare and are being recognized with increasing frequency. The aim of this study was to assess autonomic function by measuring heart rate recovery (HRR), an index of vagal activity, in patients with epilepsy who were not taking any medication. Fourteen patients (eight with primary generalized epilepsy, four with secondary generalized epilepsy, and two with complex partial epilepsy) and 14 control subjects underwent exercise tolerance tests according to the modified Bruce protocol. HRR at 1 and 3 min (HRR1 and HRR3) were calculated. HRR1 and HRR3 were increased in patients with epilepsy. These results suggest increased parasympathetic function in epilepsy and support results of previous studies indicating autonomic dysfunction in epilepsy. PMID- 22510004 TI - Advances in ocular drug delivery. AB - Eye drops have long been the primary ocular drug delivery dosage form used to treat ocular disorders ranging from superficial conditions to intravitreal diseases. The ocular anatomical structure and physiological protective mechanisms are one of the most formidable barriers to drug penetration that have significantly reduced the drug's efficacy and target selectivity while sometimes causing ocular tissue damage. There are many new and innovative advances in ocular drug delivery due to better understanding of the structure and function of the eye, the nature of its diseases, and how to overcome or utilize its protective barrier(s), which resulted in increased bioavailability and longer duration of action of the administered drugs, therefore, more effective disease management. We seek in this article to present a comprehensive overview of the basic required knowledge about the barriers for drug delivery to the eye and the major breakthroughs and advances in ocular drug delivery to the anterior, posterior and intravitreal segments of the eye. PMID- 22510005 TI - Item by item analysis strategy of the relationship between symptoms and signs in early dry eye. AB - PURPOSE: The present study aimed at analyzing the relationship between several particular symptoms, risk factors or global questionnaire scores and some tear clinical signs in early dry eye patients. MATERIAL AND METHODS: A total of 77 volunteers were enrolled in the study without any prior classification, although patients with severe dry eye were excluded. Two questionnaires were used to assess ocular symptoms and risk factors, and clinical tear signs were evaluated with four tests (osmolarity, ferning, break-up time and the phenol red thread test). Multiple linear regression analysis was performed to determine the relative predictive value of each particular ocular symptom and risk factor, for each clinical sign. This analysis was repeated using symptoms and risk factors global scores. RESULTS: The symptom "eyes stuck shut in the morning" was the only predictor variable for the sign "ferning crystallization" (R = 0.228, p < 0.05) and "dryness" for "break-up time" (R = -0.315, p < 0.01). "Burning sensation" and "computer use for more than 3 h" were predictor variables for "tear osmolarity" (R = 0.342, p < 0.01), while "itching" and "female gender" were found to predict the outcomes of the "phenol red thread test" (R = -0.462, p < 0.05). Global questionnaire scores were not found to predict any tear clinical sign. CONCLUSIONS: The present findings support the informative value of exploring the associations between clinical signs, ocular symptoms and risk factors by following an item by item strategy rather than opting for global questionnaire scores. PMID- 22510006 TI - Histopathology and immunohistochemical profile in idiopathic dacryoadenitis. AB - PURPOSE: This study deduced the pathological and immunophenotypic features of idiopathic dacryoadenitis, and researched into the possible immune mechanism of this lesion. METHODS: Here are 23 lesions of idiopathic lacrimal gland inflammation collected retrospectively, whose histopathologic types were classified based on different characteristics, while the fibrosis degrees were measured. The immunohistochemical staining was performed on tissue sections using monoclonal antibodies against CD20, CD45RO, IL-4 and IFN-gamma, the percentages of mononuclear inflammatory cells staining for CD20, CD45RO and the quantities of cells staining positively for IL-4 and IFN-gamma were enumerated. RESULTS: Lymphoid follicular and sclerosing lesions are two most common pathological types with different lymphocyte and fibrosis pattern. The proportions of CD20 cells have significant difference between lymphoid follicular (48.6 +/- 14.9%) and sclerosing lesions (21.8 +/- 12.2%), and the proportions of CD45RO cells are also different in the two types (27.2 +/- 6.5% and 43.5 +/- 15.1%, respectively). The quantities of lacrimal inflammatory cells staining positively for IL-4 are significantly different in lymphoid follicular (43 +/- 27) and sclerosing lesions (11 +/- 9), and for IFN-gamma are also different (13 +/- 8 and 22 +/- 16 respectively). CONCLUSION: Different immune processes exist in idiopathic dacryoadenitis: Th2 mediated B-cell humoral immune response presents in lymphoid follicular type and Th1 mediated cellular immune response presents in sclerosing type. PMID- 22510007 TI - Corneal hysteresis is correlated with reduction in axial length after trabeculectomy. AB - BACKGROUND: We sought to determine whether corneal biomechanical parameters are predictive of reduction in axial length after anti-metabolite trabeculectomy. METHODS: Chinese subjects undergoing trabeculectomy with mitomycin C by a single experienced surgeon underwent the following measurements: Corneal hysteresis (CH, Ocular Response Analyzer, Reichert Ophthalmic Instruments), Goldmann intra-ocular pressure (IOP), central corneal thickness (CCT) and axial length (AL, IOLMaster, Carl Zeiss Meditec, Dublin, CA) were measured pre-operatively, and AL, CH and IOP were measured 1 day and 1 week post-operatively. RESULTS: Mean age of 31 subjects was 52.0 +/- 15.2 years, and 15 (48.4%) were female. The mean pre-operative IOP of 21.4 +/- 9.3 mmHg was reduced to 8.2 +/- 4.6 mmHg 1 day and 11.0 +/- 4.4 mmHg 1 week post-operatively (p < 0.001). AL declined from 22.99 +/- 0.90 to 22.76 +/- 0.87 mm at 1 day and 22.74 +/- 0.9 mm at 1 week; 30/31 (%) eyes had a decline in AL (p < 0.001, sign test). In multivariate linear regression models including post-operative data from 1 day and 1 week, greater decline in Goldmann IOP (p < 0.0001, greater pre-op axial length (p < 0.001) and lower pre-operative CH (p = 0.03), were all associated with greater decline in post-operative axial length. CONCLUSIONS: Eyes with lesser ability of the ocular coat to absorb energy (lower CH) had significantly greater decrease in axial length after trabeculectomy induced IOP-lowering. PMID- 22510008 TI - Changes in anterior chamber parameters with the Pentacam rotating Scheimpflug and axial length measurements by ultrasound in patients who use isotretinoin. AB - PURPOSE: Evaluation of changes in anterior chamber parameters with the Pentacam rotating Scheimpflug and axial length measurements (Alx) by ultrasound in patients who use isotretinoin for the treatment of acne vulgaris. METHODS: Twenty nine eyes of 29 patients (15 men, 14 women) were evaluated with the Pentacam before the treatment, and at the 3rd and 6th months of treatment. The axial length was evaluated by ultrasound biometry. The non-parametric paired t-test was used to compare pretreatment and 3rd and 6th month anterior chamber depth (ACD), anterior chamber volume (ACV), anterior chamber angle (ACA) width, central corneal thickness (CCT), lens thickness (LT), pupil size, axial length measurement (Alx) and mean keratometry values (K). RESULTS: The mean age of the patients was 21.82 +/- 4.14 years. The differences between the pretreatment and 3rd and 6th month ACD, ACV, CCT, Alx, LT and mean K values were statistically significant (p < 0.05). The differences between the pretreatment and 3rd and 6th month pupil size measurements were not statistically significant (p > 0.05). The differences between the pretreatment and 3rd month ACA measurements were statistically significant (p > 0.05), but there was no statistically significant difference with 6th month values (p < 0.05). CONCLUSIONS: Isotretinoin treatment causes statistically significant changes in most anterior segment parameters during treatment. PMID- 22510009 TI - Retinal function and morphology in rabbit after intravitreal injection of VEGF inhibitors. AB - PURPOSE/AIM: To explore changes in morphology and function in the rabbit retina after intravitreal high-dose injection of three commonly used VEGF inhibitors. MATERIALS AND METHODS: Forty-eight rabbits of mixed strain (6 months of age, body weight ~ 3 kg) were randomized into four groups (n = 12). They were examined with full-field electroretinography (ERG) and with multifocal electroretinography (mf ERG) prior to drug exposure. The rabbits were then injected intravitreally with bevacizumab, ranibizumab, pegaptanib, or with a balanced saline solution. The dose of VEGF inhibitor was chosen to achieve a vitreous concentration approximately three times higher than the one clinically used in the adult human eye. ERG was then performed 8 weeks postinjection, and mf ERG 9 weeks postinjection. After 9 weeks, the rabbits were sacrificed and the sectioned retina was studied. Immunohistochemical analysis was performed of rods, cones, rod bipolar cells, horizontal cells, and amacrine cells. RESULTS: Rabbits injected with VEGF inhibitors all showed significantly lower amplitude of the dark-adapted b-wave rod-mediated response to dim light, compared to the rabbits injected with BSS. The a wave (reflecting photoreceptor function) in the response to single flash white light was however not affected. Immunohistochemistry revealed a significant reduction in PKC labeling of rod bipolar cells in pegaptanib and ranibizumab injected eyes whereas bevacizumab injected eyes displayed normal PKC labeling. No apparent morphological change was seen with markers for remaining retinal cells. CONCLUSIONS: Our results indicate that the use of high-dose intravitreal VEGF inhibitors in the rabbit eye affects rod mediated retinal function and PKC expression in rod bipolars cells for at least 9 weeks after drug administration. The three VEGF inhibitors influence the retina slightly differently. These results are important for the understanding of drug action and when devising therapeutical strategies in new areas such as retinopathy of prematurity where vitreous volume is significantly lower compared to the adult eye. PMID- 22510010 TI - Effect of curcumin on miRNA expression in human Y79 retinoblastoma cells. AB - PURPOSE: Retinoblastoma (RB) is the most common intraocular malignancy in children. Deregulation of several miRNAs has been identified in RB, suggesting a potential role in tumorigenesis. Recent evidence suggests that many dietary components like folate, retinoids and curcumin act as potential anticancer/antiproliferative agents by regulating the expression of miRNA. In this study, we investigated the effect of phenolic compound curcumin on miRNA expression in Y79 RB cells. MATERIALS AND METHODS: We analyzed the expression profile of miRNA by microarray analysis and quantitative real-time polymerase chain reaction (qRT-PCR) in curcumin-treated Y79 RB cells. Transfection of miR-22 was performed using Lipofectamine 2000. Cell viability, in vitro scratch migration assay, prediction of miRNA targets and Western blot analysis were performed to determine the biological function of miR-22 in Y79 RB cells. RESULTS: In Y79 RB cells treated with curcumin, 5 human miRNAs were upregulated and 16 were downregulated as detected with the miRNA microarray analysis. miR-22, a tumor-suppressor miRNA was one of the miRNA which was upregulated by curcumin. Transfected miR-22 Y79 cells inhibited the cell proliferation and reduced the migration, and erythoblastic leukemia viral oncogene homolog 3 (Erbb3) was confirmed to be the target gene of miR-22. CONCLUSION: These observations suggest that curcumin modulate the miRNA expression profile, thereby exerting its anticancer effects on RB cells. PMID- 22510011 TI - Evaluation of changes in choroidal neovascularization secondary to age-related macular degeneration after anti-VEGF therapy using spectral domain optical coherence tomography. AB - PURPOSE: To evaluate the changes in choroidal neovascularization (CNV) after anti VEGF therapy for treatment of age-related macular degeneration (AMD) using spectral domain optical coherence tomography (SD OCT). MATERIALS AND METHODS: This retrospective study included 65 eyes of 65 patients with CNV secondary to AMD. All patients underwent SD OCT before and 4 weeks after three intravitreal injections of bevacizumab (bevacizumab group) or ranibizumab (ranibizumab group). The diameter and thickness of CNV were measured from SD OCT images. RESULTS: Retinal edema was completely resolved in 57%, partially resolved in 28% and unchanged in 15% of all post-injection SD OCTs. The resolution rate of retinal edema was not significantly different between the bevacizumab and ranibizumab group (p = 0.960). In all CNV types, the diameter of CNV did not show significant change after treatment; the average diameter changed from 2923 to 2888 MUm in classic CNV and from 2378 to 2338 MUm in occult CNV in bevacizumab group; from 2691 to 2580 MUm in classic CNV and from 2731 to 2337 MUm in occult CNV in ranibizumab group. However, the thickness of CNV showed a significant reduction in classic CNV of both the bevacizumab group (from 301 to 233 MUm, p = 0.012, reduction rate 22%) and the ranibizumab group (from 258 to 213 MUm, p = 0.025, reduction rate 17%). In occult CNV, the thickness of CNV showed a significant reduction only in the ranibizumab group (from 163 to 146 MUm, p = 0.033, reduction rate 10%). CONCLUSIONS: Anti-VEGF therapy for the treatment of AMD may reduce the thickness of CNV and thus result in morphologic stability of CNV. Although morphologic regression of CNV is not achieved, further CNV growth could be arrested with anti-VEGF therapy. PMID- 22510012 TI - Association between diabetic retinopathy and flow-mediated vasodilation in type 2 DM. AB - OBJECTIVE: Retinal endothelial dysfunction is a key in the etiogenesis of diabetic retinopathy (DR), in patients with type 2 diabetes mellitus (DM). Brachial artery flow-mediated vasodilation (FMD) is a marker of endothelial function associated with production of endogenous nitric oxide. Using FMD, we investigated the relationship between macrovascular function and DR. METHODS: We studied 74 patients with type 2 DM, including non-DR (NDR) (n = 30); mild nonproliferative DR (NPDR) (n = 16); moderate NPDR (n = 10); severe NPDR (n = 10); and proliferative DR (PDR) (n = 8); and 21 age-matched controls. We measured FMD in each group. Retinal blood flow and pulsatility ratios were measured using laser Doppler velocimetry. RESULTS: FMD decreased significantly in patients with DM compared with healthy control subjects. No significant differences were found in FMD among the NDR, mild NPDR, and moderate NPDR groups. FMD decreased significantly in the severe NPDR and PDR groups compared with the NDR group. FMD was significantly and negatively correlated with duration of DM and pulsatility ratio. CONCLUSION: Systemic endothelial dysfunction appears to be associated with DR and vascular abnormalities in patients with type 2 DM. PMID- 22510013 TI - The frequency of peripheral blood CD4+ CD25high FoxP3+ and CD4+ CD25- FoxP3+ regulatory T cells in normal pregnancy and pre-eclampsia. AB - PROBLEM: Regulatory T cells (Tregs) play an important role in the development of pregnancy-specific immune tolerance. We aimed to determine the peripheral frequency of a recently described Treg subpopulation, the CD4+ CD25- FoxP3+ Treg subset, and its correlation with the conventional CD4+ CD25high FoxP3+ Tregs in normal pregnancy (NP) and pre-eclampsia (PE) compared to non-pregnant (non-P) women. We also examined the proportion of the activated CD4+ CD25high FoxP3high Treg subset within conventional Treg cells. METHOD: We took peripheral blood samples from 20 PE, 20 NP, and 12 non-P women and determined the frequency of the above Treg subsets using flow cytometry. RESULTS: The frequency of conventional CD4+ CD25high FoxP3+ Tregs and activated CD4+ CD25high FoxP3high Tregs, but also that of non-conventional CD4+ CD25- FoxP3+ Tregs was higher in NP compared to non P women, but lower again in PE, reaching comparable levels to the non-P group. The ratios of CD4+ CD25high FoxP3+ and CD4+ CD25- FoxP3+ Treg subsets were constant in all three investigated groups. CONCLUSION: Our results indicate that the frequency of conventional and non-conventional Tregs alters simultaneously, and the presence in circulation of both of these Treg subsets is similarly important in the adequate development of pregnancy-specific immune tolerance. PMID- 22510014 TI - The influence of subclinical hyperthyroidism on blood pressure, heart rate variability, and prevalence of arrhythmias. AB - BACKGROUND: The impact of subclinical hyperthyroidism (sHT) on the cardiovascular system still needs to be elucidated. The aim of the study was to prospectively assess blood pressure (BP), variability in heart rate, and the prevalence of arrhythmias in patients with sHT, both before and after they are restored to the euthyroid state. METHODS: The study group consisted of 44 normotensive patients (37 women, 7 men), aged 22-65 years (mean+/-SD: 45.9+/-11.0) with sHT. Enrolled patients were drawn from 1080 patients referred to our department for treatment of hyperthyroidism. Study patients were treated with radioiodine treatment to restore the euthyroid state. Ambulatory BP monitoring and Holter electrocardiography were performed (i) when sHT was diagnosed and (ii) at least 6 months after they became euthyroid. RESULTS: sHT in comparison to the euthyroid state was associated with higher (109.3+/-7.1 vs. 107.1+/-7.7 mmHg) nocturnal systolic mean BP (p=0.035) and BP load (14.8 vs. 10.2%, p=0.033), mean diastolic BP (66.4+/-6.6 vs. 64.8+/-6.6 mmHg, p=0.047), and mean arterial pressure (80.8+/ 43.1 vs. 79.3+/-43.6 mmHg, p=0.049). Moreover, significant changes in both the time and frequency domain measures of heart rate variability (HRV) were observed: decrease of the square root of the mean squared differences of successive NN intervals (rMSSD) (45.68+/-34.1 vs. 65.09+/-50.6 ms, p=0.03) and the low frequency power (LF) (5.71+/-0.99 vs. 6.0+/-1.01 ms(2), p=0.049) as well as increase of QT interval dispersion (58.25+/-28.5 vs. 46.90+/-12.1 ms, p=0.020). This was accompanied by a clinically insignificant increase in the frequency of ventricular extrasystoles (VES) (3.1+/-7.4 vs. 0.6+/-1.2 per hour, p=0.048) and increased mean heart rate (78.4+/-6.8 vs. 76.0+/-8.0 beats/min, p=0.004). Some of the parameters correlated positively with thyroid hormones: nocturnal diastolic BP with free triiodothyronine (FT(3)) (r=0.397, p=0.008), rMSSD with free thyroxine (FT(4)) (r=0.389, p=0.013), and QT interval dispersion with FT(4) (r=0.450, p=0.004). CONCLUSIONS: The study suggests that sHT in comparison to euthyroid status may be associated with a statistically significant but probably clinically insignificant increase of QT interval dispersion, prevalence of VES, elevated nocturnal arterial BP, and changes in HRV. These findings broaden our understanding of the cardiovascular effects of sHT. PMID- 22510015 TI - Insights into the different catalytic activities of Clostridium neurotoxins. AB - The clostridial neurotoxins are among the most potent protein toxins for humans and are responsible for botulism, a flaccid paralysis elicited by the botulinum toxins (BoNT), and spastic paralysis elicited by tetanus toxin (TeNT). Seven serotypes of botulinum neurotoxins (A-G) and tetanus toxin showed different toxicities and cleave their substrates with different efficiencies. However, the molecular basis of their different catalytic activities with respect to their substrates is not clear. BoNT/B light chain (LC/B) and TeNT light chain (LC/T) cleave vesicle-associated membrane protein 2 (VAMP2) at the same scissile bond but possess different catalytic activities and substrate requirements, which make them the best candidates for studying the mechanisms of their different catalytic activities. The recognition of five major P sites of VAMP2 (P7, P6, P1, P1', and P2') and fine alignment of sites P2 and P3 and sites P2 and P4 by LC/B and LC/T, respectively, contributed to their substrate recognition and catalysis. Significantly, we found that the S1 pocket mutation LC/T(K(168)E) increased the rate of native VAMP2 cleavage so that it approached the rate of LC/B, which explains the molecular basis for the lower k(cat) that LC/T possesses for VAMP2 cleavage relative to that of LC/B. This analysis explains the molecular basis underlying the VAMP2 recognition and cleavage by LC/B and LC/T and provides insight that may extend the pharmacologic utility of these neurological reagents. PMID- 22510016 TI - Resource utilization and cost of heart failure associated with reduced ejection fraction in Swedish patients. AB - AIM: The purpose of this study was to assess healthcare utilization and costs for heart failure patients with reduced ejection fraction (HF-REF) in Sweden. METHODS AND RESULTS: This was a retrospective, population-based cohort study of patients diagnosed with HF-REF during a period of 18 months at 31 primary care centers in Uppsala County, Sweden. Data was obtained from computerized records from these centers, the Swedish Patient Registry, the Swedish Prescription Registry, the Cause of Death Registry, and a local echocardiography registry maintained by the Department of Physiology, Uppsala University Hospital. Main outcome measures were cardiovascular and heart-failure-related hospitalizations, outpatient visits, medication utilization, mortality (all-cause, cardiovascular, and heart-failure), and healthcare costs for HF-REF patients. During the index period, 252 heart failure patients had a left ventricular ejection fraction measurement <= 40% and were categorized as having HF-REF. More than half of the patients had >= 1 cardiovascular or heart failure-related hospitalization. On average, patients had >2 such hospitalizations annually. They also averaged ~1 cardiovascular or heart failure-related outpatient visit per year. All-cause mortality was high: 15.9% patients died within 1 year after the index date. The mean annual cost per patient for heart-failure-related hospitalizations was SEK 72,613 (EUR 7610). In contrast, annual prescription costs were low, on average 3% of total cost (SEK 3503, EUR 367 per patient) LIMITATIONS: The main limitations of this study include a short follow-up time and small sample size. Also, certain data were missing, such as echocardiograms (available for only 28% of patients), and information on patients' New York Heart Association (NYHA) functional class, validity period for prescriptions or the units of medication prescribed, and medication dosing. Furthermore, the overall mortality could have been under estimated, as only the primary cause of death was included in the analysis. CONCLUSIONS: The main burden associated with HF-REF is related to hospitalizations for heart-failure events. Effective treatment options that decrease hospitalization rates could reduce patients' suffering and potentially offer considerable cost savings. PMID- 22510017 TI - The impact of non-severe hypoglycemic events on daytime function and diabetes management among adults with type 1 and type 2 diabetes. AB - OBJECTIVES: To describe daytime non-severe hypoglycemic events (NSHEs), assess their impact on patient functioning and diabetes self-management, and examine if these impacts differ by diabetes type or country. METHODS: Internet survey to adults with diabetes in the US, UK, Germany, and France. RESULTS: Of 6756 screened respondents, 2439 reported a daytime NSHE in the past month. NSHEs occurred while active (e.g., running errands) (45.1%), 29.6% while not active (e.g., watching TV), and 23.8% at work. On average, it took half a day to respond and recover from NSHE. Respondents monitored their glucose 5.7 extra times on average over the following week. On the day of event, type 1 respondents tested significantly more often than type 2 (p<0.05). Type 2 were less likely to confirm NSHE with glucose test (p<0.001). Following NSHE, 12.6% of respondents reduced total insulin by an average of 7.6 units (SD=8.3). Total units and days with reduced dosing was significantly less, whilst number of additional glucose tests and time to recover was significantly longer if NSHE occurred at work (p<0.001). Type 1 decreased insulin doses more often (p<0.001); however, type 2 decreased a greater number of units (p<0.01). Compared with other countries, US respondents were more likely to eat a light or full meal and respondents in France took significantly longer than all other countries to recognize (p<0.05), respond to (p<0.001), and recover from (p<0.001) NSHE, used significantly more monitoring tests the day of (p<0.05) and over the subsequent week (p<0.001), and decreased their normal insulin dose more (p<0.001). Limitations of the study include potential recall bias and selection bias. CONCLUSIONS: NSHEs are associated with a significant impact on patient functioning and diabetes management. PMID- 22510018 TI - Properties of an alkaline-tolerant, thermostable xylanase from Streptomyces chartreusis L1105, suitable for xylooligosaccharide production. AB - An extracellular xylanase was purified to homogeneity from a culture of Streptomyces chartreusis L1105 by a 2-step method of ammonium sulfate precipitation and carboxymethyl sepharose fast-flow chromatography (CMSFF). The xylanase was purified by 6.86-fold, with a recovery yield of 31.96%. The purified xylanase appeared as a single protein band on SDS-PAGE with a molecular mass of about 34.2 kDa. The optimum temperature and pH of the purified xylanase activity were 70 degrees C and 7.2 respectively. The xylanase was more stable under alkaline conditions and retained more than 80% activity after 30 min incubation at pH 6 to 10. It also showed specific activity towards different xylans. Hydrolysis of oat-spelt and corn-cob xylans by the xylanase yielded xylobiose and xylotriose as principle products without the formation of xylose. These properties indicate that the purified xylanase may potentially be useful in biotechnological applications, such as xylooligosaccharide preparation. This is the first report about the purification and characterization of a xylanase from S. chartreusis. PMID- 22510019 TI - Genetic and cellular basis of cerebral cavernous malformations: implications for clinical management. AB - Cerebral cavernous malformations (CCMs) are a diffuse cerebrovascular disease affecting approximately 0.5% of the population. A CCM is characterized by abnormally enlarged and leaky capillaries arranged in mulberry-like structures with no clear flow pattern. The lesion might predispose to seizures, focal neurological deficits or fatal intracerebral hemorrhage. However, a CCM can also remain neurologically silent. It might either occur sporadically or as an inherited disorder with incomplete penetrance and variable expressivity. Due to advances in imaging techniques, the incidence of CCM diagnoses are increasing, and the patient must be managed on a multidisciplinary basis: genetic counselling, treatment if needed, and follow-up. Advances have been made using radiological and pathological correlates of CCM lesions adding to the accumulated knowledge of this disease, although management of these patients is very variable among centers. This review is aimed at providing an update in genetic and molecular insights of this condition. Included are implications for genetic counselling, and possible approaches to prevention and treatment that derive from the understanding of pathogenetic mechanisms. PMID- 22510020 TI - Implementing a diet and exercise program for limiting maternal weight gain in obese pregnant women: a pilot study. AB - BACKGROUND: Thirty-four per cent of Australian women having a baby are overweight or obese. Excessive gestational weight gain leads to significant complications for mother and baby, not only during the pregnancy but in the long term. Limiting weight gain in pregnancy is thought to reduce complications, but there is limited evidence to guide practice. AIM: To test the feasibility and acceptance of an intervention aimed at limiting gestational weight gain in obese pregnant women. METHODS: A low-cost multidisciplinary program, comprised of four individual dietary education sessions and three exercise classes, was developed and implemented at a tertiary hospital in metropolitan Melbourne, Australia. The Maternal Weight Management program was offered to obese women at their pregnancy booking visit. Program uptake and women's views of the program were explored via telephone survey, and pregnancy and birth outcomes collected. RESULTS: Seventy four women participated in this pilot study; 95% attended at least one session of the program and the attrition rates were high. Fifty-three per cent completed the postnatal survey. Women confirmed their preference for individual appointments and felt it was important for the hospital to offer a weight management program. CONCLUSIONS: The program we designed had poor uptake and cannot be recommended in its current format. Future studies and considerations could look at more acceptable program design and recruitment strategies and should include formative work with women who would be eligible for such intervention. PMID- 22510021 TI - Cyclic AMP-response element modulator inhibits the promoter activity of the sodium iodide symporter gene in thyroid cancer cells. AB - BACKGROUND: Comprehension of the regulatory mechanism involved in the sodium iodide symporter (NIS) expression is of great relevance for thyroid cancer. In fact, restoration of NIS expression would be a strategy to treat undifferentiated thyroid cancer. Previous in vitro findings suggest that the cyclic AMP-response element (CRE) modulator (CREM) is involved in control of NIS expression. In this work, we examined the expression of CREM in a series of thyroid cancer tissues and its action on NIS promoter in human thyroid cancer cells. METHODS: Expression of mRNA levels for CREM, PAX8 and NIS was measured by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in 6 normal thyroid tissues, 22 papillary, 12 follicular and 4 anaplastic thyroid cancers. The effect of CREM on transcriptional activity of the NIS promoter was investigated by transient transfection of human thyroid cell lines. RESULTS: Compared to normal tissues, NIS and PAX8 mRNA levels were significantly reduced in all types of thyroid cancer. As expected, the maximal decrease was detected in anaplastic thyroid cancer. Conversely, CREM mRNA levels were increased in all types of thyroid cancer, reaching statistical significance for follicular and anaplastic thyroid carcinoma (p=0.0157 and 0.0045, respectively). Transfection experiments showed an inhibitory effect of CREM on NIS promoter activity in various thyroid cancer cell lines. CONCLUSIONS: These data demonstrate that CREM expression is increased in thyroid cancer tissue and may play a role in the downregulation of NIS expression in thyroid cancer acting at the transcriptional level. PMID- 22510022 TI - Use of thermal imagery for estimation of core body temperature during precooling, exertion, and recovery in wildland firefighter protective clothing. AB - BACKGROUND: Monitoring core body temperature to identify heat stress in first responders and in individuals participating in mass gatherings (e.g., marathons) is difficult. OBJECTIVE: This study utilized high-sensitivity thermal imaging technology to predict the core temperature of human subjects at a distance while performing simulated field operations wearing thermal protective garments. METHODS: Six male subjects participating in a study of precooling prior to exertion in wildland firefighter thermal protective clothing had thermal images of the face captured with a high-resolution thermal imaging camera concomitant with measures of core and skin temperature before, during, and after treadmill exercise in a heated room. Correlations and measures of agreement between core temperature and thermal imaging-based temperature were performed. RESULTS: The subjects walked an average (+/- standard deviation) of 42.6 (+/-5.9) minutes and a distance of 4.2 (+/-0.6) km on the treadmill. Mean heart rate at the end of exercise was 152 (+/-33) bpm and core body temperature at the end of exercise was 38.3 degrees C (+/-0.7 degrees C). A visual relationship and a strong correlation between core temperature and thermal imaging of the face were identified in all subjects, with the closest relationship and best agreement occurring during exercise. The Bland-Altman test of agreement during exercise revealed the majority of measurement pairs to be within two standard deviations of the measured temperature. CONCLUSIONS: High-resolution thermal imaging in the middle wave infrared spectrum (3-5 MUm) can be used to accurately estimate core body temperature during exertion in a hot room while participants are wearing wildland firefighting garments. Although this technology is promising, it must be refined. Using alternative measurement sites such as the skin over the carotid artery, using multiple measurement sites, or adding pulse detection may improve the estimation of body temperature by thermal imagery. PMID- 22510023 TI - Screening for pre-diabetes to predict future diabetes using various cut-off points for HbA(1c) and impaired fasting glucose: the Toranomon Hospital Health Management Center Study 4 (TOPICS 4). AB - AIM: To evaluate various screening criteria for pre-diabetes to identify which combination of impaired fasting glucose and elevated HbA(1c) values performs most effectively in predicting future diabetes in a large cohort of Japanese individuals. METHODS: The study included 4670 men and 1571 women without diabetes (diabetes: fasting plasma glucose >= 7.0 mmol/l, HbA(1c) >= 48 mmol/mol (>= 6.5%), or self-reported clinician-diagnosed diabetes). Pre-diabetes was diagnosed by a combination of impaired fasting glucose (fasting plasma glucose 5.6-6.9 mmol/l or 6.1-6.9 mmol/l) and elevated HbA(1c) [39-46 mmol/mol (5.7-6.4%) or 42 46 mmol/mol (6.0-6.4%)]. RESULTS: During a 5-year follow-up, 338 incident cases of diabetes occurred. The combination of HbA(1c) 39-46 mmol/mol (5.7-6.4%) and fasting plasma glucose 5.6-6.9 mmol/l yielded the highest sensitivity (86%) and generated a large population-attributable per cent risk (78%) for predicting development of diabetes. Among individuals classified as having pre-diabetes by any of the four combined criteria, 20.5-32.0% reverted to the normoglycaemic state as having neither elevated HbA(1c) nor impaired fasting glucose at the last follow-up examination. At 5.6 years after the baseline examination, however, pre diabetic individuals who fulfilled both HbA(1c) 42-46 mmol/mol (6.0-6.4%) and fasting plasma glucose 6.1-6.9 mmol/l had a 100% cumulative risk of developing diabetes. CONCLUSIONS: The combination of HbA(1c) 39-46 mmol/mol (5.7-6.4%) and fasting plasma glucose 5.6-6.9 mmol/l would have the best performance in reducing the likelihood of missing future cases of diabetes. Identifying pre-diabetic individuals who strictly fulfil HbA(1c) 42-46 mmol/mol (6.0-6.4%) and fasting plasma glucose 6.1-6.9 mmol/l would predict definite progression to diabetes. PMID- 22510024 TI - Still looking for the right mechanism as a target during ablation of atrial fibrillation. PMID- 22510025 TI - Direct healthcare costs of osteoporosis-related fractures in managed care patients receiving pharmacological osteoporosis therapy. AB - BACKGROUND: Osteoporosis is a common condition and the economic burden of osteoporosis-related fractures is significant. While studies have reported the incremental or attributable costs of osteoporosis-related fracture, data on the economic impact of osteoporosis-related fractures in commercial health plan populations are limited. OBJECTIVE: To estimate the direct costs of osteoporosis related fractures among pharmacologically treated patients in a large, commercially insured population between 2005 and 2008. METHODS: In this retrospective cohort study, patients were identified from a large, commercially insured population with integrated pharmacy and medical claims. Inclusion criteria were age 45-64 years; one or more osteoporosis medication claim(s) with first (index) claim between 1 January 2005 and 30 April 2008; and continuous insurance coverage for >=12 months pre-index and >=6 months post-index. Patients with pre-index Paget's disease or malignant neoplasm; skilled nursing facility stay; combination therapy at index; or fracture <=6 months post-index were excluded. A generalized linear model compared differences in 6-month pre-/post event costs for patients with and without fracture. Propensity score weighting was used to ensure comparability of fracture and non-fracture patients. Generalized estimating equations accounted for repeated measures. RESULTS: The study included 49,680 patients (2613 with fracture) with a mean (SD) age of 56.4 (4.7) years; 95.9% were female. Mean differences between pre- and post-event direct costs were $US14,049 (95% CI 7670, 20,428) for patients with vertebral fractures, $US16,663 (95% CI 11,690, 21,636) for patients with hip fractures, and $US7582 (95% CI 6532, 8632) for patients with other fractures. After adjusting for covariates, osteoporosis-related fractures were associated with an additional $US9996 (95% CI 8838, 11,154; p < 0.0001) in direct costs per patient across all fracture types during the 6 months following fracture. CONCLUSION: Patients with osteoporosis-related fractures were found to incur nearly $US10,000 in estimated additional direct healthcare costs in the 6 months post-fracture, compared with patients with no fracture. Reduced fracture risk may lower associated direct healthcare costs. PMID- 22510026 TI - Phosphino hydrazones as suitable ligands in the asymmetric Suzuki-Miyaura cross coupling. AB - Phosphino hydrazones derived from C(2)-symmetric hydrazines exhibit excellent catalytic activity and provide good enantioselectivities in the asymmetric Suzuki Miyaura cross-coupling to axially chiral biaryls, in particular for the most challenging reactions of monocyclic, functionalized aryl bromides and triflates. X-ray analysis of preformed [Pd(P/N)Cl(2)] precatalysts [(P/N) = phosphino hydrazone] revealed a strong n-pi conjugation in the hydrazone moiety, identified by a high planarity degree at the pyrrolidine N(sp(3)) atom, that makes rotations around N-N bonds inconsequential. The complexes are also characterized by an envelope-like conformation with the Pd atom placed at the opposite side to the 2 phenyl group on the nearest stereogenic center of the pyrrolidine group. The isolation and structural analysis of oxidative addition intermediates indicate that the configurational stability of Pd-C(Ar) bonds is dependent on the substitution pattern in the aryl bromide. PMID- 22510027 TI - Randomised clinical trial: a comparison between a GerdQ-based algorithm and an endoscopy-based approach for the diagnosis and initial treatment of GERD. AB - BACKGROUND: The diagnosis of gastro-oesophageal reflux disease (GERD) remains challenging. An algorithm, facilitated by a questionnaire, may provide a more structured and cost-effective care of patients. AIM: To compare symptom control achieved with empirical therapy for GERD, in an algorithm based on the GerdQ (new structured pathway, NSP), with that of current care after endoscopy (ordinary clinical pathway, OCP). METHODS: Patients with symptoms of GERD, but without alarm features, were randomised in an open, parallel-group study and followed for 4-8 weeks. In the NSP, GerdQ score was used as a basis for both diagnosis and a treatment algorithm. Patients with high likelihood of GERD were treated empirically with a PPI whereas patients with low likelihood of GERD received therapy chosen by the clinician. In the OCP, diagnosis and treatment were based on endoscopy or pH-metry findings. The statistical hypothesis was non-inferiority of NSP to OCP. RESULTS: A total of 147 patients (86.5%) in the NSP and 133 patients (80.1%) in the OCP arm were responders. Overall, NSP was non-inferior to OCP, but not superior (P = 0.14). Patients with high likelihood of GERD had significantly better symptom relief in the NSP (P = 0.03), whereas those with low likelihood of GERD showed a numerical difference in favour of an endoscopy-based approach (OCP). NSP saved 146 ? per patient. CONCLUSIONS: A symptom-based approach using GerdQ reduced health care costs without loss in efficacy. Patients with high likelihood GERD benefited from empirical treatment. An algorithm based on GerdQ may provide physicians with a tool for a more structured care of patients (ClinicalTrials.gov NCT00842387). PMID- 22510028 TI - Letter to the editor: melanocortin 4 receptor antagonists and their emerging role in pain management. PMID- 22510029 TI - Potential use of lactosylated dendrimer (G3)/alpha-cyclodextrin conjugates as hepatocyte-specific siRNA carriers for the treatment of familial amyloidotic polyneuropathy. AB - To reveal the potential use of lactosylated-dendrimer (G3) conjugates with alpha cyclodextrin (Lac-alpha-CDE (G3)) as novel hepatocyte-specific siRNA carriers in order to treat transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP), we evaluated the RNAi effect of siRNA complexes with Lac-alpha-CDE (G3) both in vitro and in vivo. Herein, we targeted TTR gene expression because TTR related FAP was often caused by amyloidogenic TTR (ATTR), which mainly expresses in hepatocytes. Lac-alpha-CDE (G3, average degree of substitution of lactose (DSL) 1.2)/siRNA complex had a potent RNAi effect against TTR gene expression through adequate physicochemical properties, asialoglycoprotein receptor (ASGP-R) mediated cellular uptake, efficient endosomal escape and the delivery of the siRNA complex to cytoplasm, but not nucleus, with negligible cytotoxicity. Lac alpha-CDE (G3, DSL 1.2)/siRNA complex had the potential to induce the in vivo RNAi effect after intravenous administration in the liver of mice. The blood chemistry values in the alpha-CDE (G3) and Lac-alpha-CDE (G3, DSL 1.2) systems were almost equivalent to those in the control system (5% mannitol solution). Taken together, these results suggest that Lac-alpha-CDE (G3, DSL 1.2) has the potential for a novel hepatocyte-selective siRNA carrier in vitro and in vivo, and has a possibility as a therapeutic tool for FAP to the liver transplantation. PMID- 22510030 TI - Stomach wall evaluation using helical hydro-computed tomography. AB - In helical hydro-computed tomography (helical hydro-CT), water is used as a neutral luminal contrast medium together with intravenous iodine contrast medium for the diagnosis and staging of human gastric neoplasia. We evaluated the feasibility of helical hydro-CT in 11 healthy animals (nine dogs and two cats). Adequate uniform gastric distension was obtained with 30 ml water/kg body weight. Fourteen client-owned dogs and four cats with suspected or diagnosed gastric neoplasia then underwent helical hydro-CT followed by intravenous contrast medium administration. Focal thickening with moderate contrast enhancement was found in 10 dogs and 3 cats. The extent of the lesion was assessed easily in all these patients. Three dogs and one cat had a normal stomach wall. One dog had multifocal thickening of the antrum but no histopathologic diagnosis was made. Helical hydro-CT, followed by intravenous contrast medium administration, is a simple technique for assessing the stomach wall. PMID- 22510031 TI - Real refractive indices and formation yields of secondary organic aerosol generated from photooxidation of limonene and alpha-pinene: the effect of the HC/NO(x) ratio. AB - The refractive index is an important property affecting aerosol optical properties, which in turn help determine the aerosol direct effect and satellite retrieval results. Here, we investigate the real refractive indices (m(r)) of secondary organic aerosols (SOA) generated from the photooxidation of limonene and alpha-pinene with different HC/NO(x) ratios. Refractive indices were obtained from polar nephelometer data using parallel and perpendicular polarized 532 nm light combined with measured size distributions, and retrievals were performed using a genetic algorithm and Mie-Lorenz scattering theory. The absolute error associated with the m(r) retrieval is +/-0.03, and reliable retrievals are possible for mass concentrations above 5-20 MUg/m(3) depending on particle size. The limonene SOA data suggest the most important factor controlling the refractive index is the HC/NO(x) ratio; the refractive index is much less sensitive to the aerosol age or mass concentration. The refractive index ranges from about 1.34 to 1.56 for limonene and from 1.36 to 1.52 for alpha-pinene, and generally decreases as the HC/NO(x) ratio increases. Especially for limonene, the particle diameter is also inversely related to the HC/NO(x) ratio; the final size mode increases from 220 to 330 nm as the HC/NO(x) ratio decreases from 33 to 6. In an effort to explore the ability of models from the literature to explain the observed refractive indices, a recent limonene oxidation mechanism was combined with SOA partitioning and a structure-property relationship for estimating refractive indices of condensing species. The resulting refractive indices fell in a much narrower range (1.475 +/- 0.02) of m(r) than observed experimentally. We hypothesize the experimentally observed high m(r) values are due to oligomerization and the low values to water uptake, small soluble molecules such as glyoxal and other factors, each of which is not included in the oxidation mechanism. Aerosol formation yields were measured over the mass concentration range from 6 to ~150 MUg/m(3), over which they increased steadily, and were higher for high HC/NO(x) ratio experiments. PMID- 22510032 TI - Novel molecular targets for the therapy of urothelial carcinoma. AB - INTRODUCTION: First-line platinum-based combinations are active in locally advanced and metastatic urothelial carcinoma; however, long-term outcomes including disease-specific and overall survival remain suboptimal. In addition, approximately 40 - 50% of patients with advanced urothelial carcinoma have coexisting medical issues that preclude the use of cisplatin-based therapy. Improvements in our understanding of the molecular mechanisms of urothelial tumorigenesis have led to first-generation clinical trials evaluating novel agents targeting molecular pathways. These are particularly relevant in regard to subpopulations. Novel trial designs warrant consideration to accelerate accrual. AREAS COVERED: In this review, novel molecular targets for the therapy of urothelial carcinoma, as well as recently completed and ongoing clinical trials utilizing novel targeted agents, are discussed. A Medline search with key words, abstracts reported at national conferences on urothelial carcinoma and NCI clinical trial identifiers was used for this review. EXPERT OPINION: Improved understanding of molecular biology has identified a number of new molecular targets, but there is a seeming absence of one dominant molecular driver for urothelial cancer. An adaptive and biomarker-derived strategy may be warranted. Clinical trials utilizing targeted agents are ongoing and results are awaited. PMID- 22510033 TI - Balanced efficacy, safety, and tolerability recommendations for the clinical management of bipolar disorder. AB - OBJECTIVE: To provide practical and clinically meaningful treatment recommendations that amalgamate clinical experience and research findings for each phase of bipolar disorder. METHODS: A comprehensive search of the literature was undertaken using electronic database search engines (Medline, PubMed, Cochrane reviews) using key words (e.g., bipolar depression, mania, treatment). All relevant randomised controlled trials were examined, along with review papers, meta-analyses, and book chapters known to the authors. In addition, the recommendations from accompanying papers in this supplement have been distilled and captured in the form of summary boxes. The findings, in conjunction with the clinical experience of international researchers and clinicians who are practiced in treating mood disorders, formed the basis of the treatment recommendations within this paper. RESULTS: Balancing clinical experience with evidence informed and lead to the development of practical clinical recommendations that emphasise the importance of safety and tolerability alongside efficacy in the clinical management of bipolar disorder. CONCLUSIONS: The current paper summarises the treatment recommendations relating to each phase of bipolar disorder while providing additional, evidence-based, practical insights. Medication-related side effects and monitoring strategies highlight the importance of safety and tolerability considerations, which, along with efficacy information, should be given equal merit. PMID- 22510034 TI - Efficacy of antimanic treatments in mixed states. AB - OBJECTIVE: To review the efficacy of pharmacological agents in bipolar mixed states. METHODS: We conducted a PubMed search of all English-language articles involving Food and Drug Administration (FDA)-approved agents for manic/mixed states in adults with bipolar I disorder. We also included names of agents established as efficacious in acute mania/mixed states that have not received FDA approval for bipolar disorder. Bibliographies from relevant articles were also searched. The efficacy of each agent in the mixed state subpopulation was reviewed, as evidenced by change from baseline on total scores of mania [e.g., Young Mania Rating Scale (YMRS)] and depression [e.g., Montgomery-Asberg Depression Rating Scale (MADRS)] measures. RESULTS: No available study is dedicated exclusively to the evaluation of mixed state populations. Although key inclusion and exclusion criteria are similar across treatment studies, mixed states have been variably defined and measured. The use of conventional manic and depressive metrics in bipolar mixed states perpetuates the unproven notion that mixed states are the consequence of coexisting depression and mania. Notwithstanding the methodological limitations, there are numerically more studies that exist for atypical antipsychotic agents than for any other class. On the basis of symptomatic improvement, recommendations for and/or strong admonishments against any established antimanic agents (e.g., lithium) cannot be made. An emergent signal supports combination treatment strategies (e.g., atypical antipsychotic plus divalproex) over mood stabilizer monotherapy (e.g., divalproex). Available evidence does not empirically support the hypothesis that conventional antipsychotics engender and/or amplify depressive symptoms in bipolar mixed states. CONCLUSIONS: All proven antimanic agents (including lithium), can be recommended in the treatment of mixed/dysphoric states. The totality of evidence with attention paid to the therapeutic index of each agent would suggest that atypical antipsychotics and divalproex be considered as first line treatment, with lithium and carbamazepine as second-line. Most individuals will require combination therapy for the treatment of mixed states; variable combinations of atypical antipsychotics and conventional mood stabilizers have the most replicated evidence. PMID- 22510035 TI - Treatment options for acute depression in bipolar disorder. AB - OBJECTIVE: The burden of depression represents the most debilitating dimension for the majority of patients with bipolar disorder and dominates the long-term course of the illness. The purpose of this manuscript is to review the evidence base of the available treatment options for bipolar depression within two frequent clinical scenarios. METHODS: The evidence is largely based on a systematic literature search and appraisal that was part of the development of the German Guideline for Bipolar Disorders. All relevant randomized controlled trials were critically evaluated. RESULTS: Overall, the number of suitably controlled studies for the treatment of bipolar depression is relatively low. There are two common scenarios. Scenario A, if a patient with bipolar depression is currently not being treated with a mood-stabilizing agent (de novo depression, first or subsequent episode), then quetiapine or olanzapine are options, or alternatively, carbamazepine and lamotrigine can be considered. Antidepressants are an option for short-term use, but whether they are best administered as monotherapy or in combination with mood-stabilizing agents is still controversial. In practice, most clinicians use antidepressants in combination with an antimanic agent. Scenario B, if a patient is already being treated optimally with a mood-stabilizing agent (good adherence and appropriate dose) such as lithium, lamotrigine is an option. There is no evidence for additional benefit from antidepressants where a patient is already being treated with a mood stabilizer; however, in practice an antidepressant is often trialled. Efficient psychotherapy is an important part of the treatment regimen and should span all phases of the illness. CONCLUSIONS: Treatment decisions in bipolar depression involve a range of different pharmacological and non-pharmacological options. Monitoring potential unwanted effects and the appropriateness of treatment can help to effectively balance benefits and risks in individual situations. However, the quality of the assessment and reporting of risks in clinical trials need to be improved to better inform treatment decisions. PMID- 22510036 TI - Maintenance therapies in bipolar disorders. AB - OBJECTIVE: Bipolar disorder is an inherently recurrent disorder, requiring maintenance preventive treatments in the vast majority of patients. The authors review the data on maintenance treatments in bipolar disorder, highlighting the controlled trial literature. METHODS: Literature review using PubMed, Medline, and a hand search of relevant literature. RESULTS: Over the last decade, a number of effective maintenance treatments for bipolar disorder have been developed with an evidence base for second-generation antipsychotics and some anticonvulsants. Increasing numbers of patients, therefore, are appropriately treated with multiple medications as a maintenance regimen. For some medications, maintenance treatment has been demonstrated in randomized controlled trials for both monotherapy and in combination with other mood stabilizers. Lithium continues as our oldest well-established maintenance treatment in bipolar disorder with somewhat better efficacy in preventing mania than depression. Lamotrigine, olanzapine, and quetiapine have bimodal efficacy in preventing both mania and depression, although lamotrigine's efficacy is more robust in preventing depression and olanzapine's efficacy is greater in preventing mania. Aripiprazole, ziprasidone, and risperidone long-acting injection all prevent mania, but not depression. Less controlled investigations have suggested some evidence of maintenance mood stabilization with carbamazepine, oxcarbazepine, and adjunctive psychotherapy. CONCLUSIONS: Despite the number of agents with demonstrated efficacy as maintenance treatments in bipolar disorder, optimal treatment regimens are still a combination of evidence-based therapy in combination with individualized creative treatment algorithms. PMID- 22510037 TI - The clinical management of bipolar disorder complexity using a stratified model. AB - OBJECTIVE: To provide practical and clinically meaningful treatment recommendations that amalgamate clinical and research considerations for several common, and as yet understudied, bipolar disorder complex presentations, within the framework of a proposed stratified model. METHODS: A comprehensive search of the literature was undertaken using electronic database search engines (Medline, PubMed, Web of Science) using key words (e.g., bipolar disorder, anxiety, rapid cycling, and subsyndromal). All relevant randomised controlled trials were examined, in addition to review papers, meta-analyses, and book chapters known to the authors. The findings formed the basis of the treatment recommendations within this paper. RESULTS: In light of the many broad presentations of bipolar disorder, a stratified model of bipolar disorder complexity was developed to facilitate consideration of the myriad of complexities that can occur during the longitudinal course of illness and the appropriate selection of treatment. Evidence-based treatment recommendations are provided for the following bipolar disorder presentations: bipolar II disorder, subsyndromal symptoms, mixed states, rapid cycling, comorbid anxiety, comorbid substance abuse, and for the following special populations: young, elderly, and bipolar disorder around the time of pregnancy and birth. In addition, some key strategies for countering treatment non-response and alternative medication recommendations are provided. CONCLUSIONS: Treatment recommendations for the more challenging presentations of bipolar disorder have historically received less attention, despite their prevalence. This review acknowledges the weaknesses in the current evidence base on which treatment recommendations are generally formulated, and additionally emphasises the need for high-quality research in this area. The stratified model provides a means for conceptualizing the complexity of many bipolar disorder presentations and considering their management. PMID- 22510039 TI - Water dynamics in water/DMSO binary mixtures. AB - The dynamics of dimethyl sulfoxide (DMSO)/water solutions with a wide range of water concentrations are studied using polarization selective infrared pump-probe experiments, two-dimensional infrared (2D IR) vibrational echo spectroscopy, optical heterodyne detected optical Kerr effect (OHD-OKE) experiments, and IR absorption spectroscopy. Vibrational population relaxation of the OD stretch of dilute HOD in H(2)O displays two vibrational lifetimes even at very low water concentrations that are associated with water-water and water-DMSO hydrogen bonds. The IR absorption spectra also show characteristics of both water-DMSO and water-water hydrogen bonding. Although two populations are observed, water anisotropy decays (orientational relaxation) exhibit single ensemble behavior, indicative of concerted reorientation involving water and DMSO molecules. OHD-OKE experiments, which measure the orientational relaxation of DMSO, reveal that the DMSO orientational relaxation times are the same as orientational relaxation times found for water over a wide range of water concentrations within experimental error. The fact that the reorientation times of water and DMSO are basically the same shows that the reorientation of water is coupled to the reorientation of DMSO itself. These observations are discussed in terms of a jump reorientation model. Frequency-frequency correlation functions determined from the 2D IR experiments on the OD stretch show both fast and slow spectral diffusion. In analogy to bulk water, the fast component is assigned to very local hydrogen bond fluctuations. The slow component, which is similar to the slow water reorientation time at each water concentration, is associated with global hydrogen bond structural randomization. PMID- 22510038 TI - Biochemical and structural basis for inhibition of Enterococcus faecalis hydroxymethylglutaryl-CoA synthase, mvaS, by hymeglusin. AB - Hymeglusin (1233A, F244, L-659-699) is established as a specific beta-lactone inhibitor of eukaryotic hydroxymethylglutaryl-CoA synthase (HMGCS). Inhibition results from formation of a thioester adduct to the active site cysteine. In contrast, the effects of hymeglusin on bacterial HMG-CoA synthase, mvaS, have been minimally characterized. Hymeglusin blocks growth of Enterococcus faecalis. After removal of the inhibitor from culture media, a growth curve inflection point at 3.1 h is observed (vs 0.7 h for the uninhibited control). Upon hymeglusin inactivation of purified E. faecalis mvaS, the thioester adduct is more stable than that measured for human HMGCS. Hydroxylamine cleaves the thioester adduct; substantial enzyme activity is restored at a rate that is 8 fold faster for human HMGCS than for mvaS. Structural results explain these differences in enzyme-inhibitor thioester adduct stability and solvent accessibility. The E. faecalis mvaS-hymeglusin cocrystal structure (1.95 A) reveals virtually complete occlusion of the bound inhibitor in a narrow tunnel that is largely sequestered from bulk solvent. In contrast, eukaryotic (Brassica juncea) HMGCS binds hymeglusin in a more solvent-exposed cavity. PMID- 22510040 TI - Microbial activity inhibition in chilled mackerel (Scomber scombrus) by employment of an organic acid-icing system. AB - The present study concerns Atlantic mackerel (Scomber scombrus) traded as a chilled product. The study was aimed to investigate the effect of including a mixture of organic acids (citric, ascorbic, and lactic) in the icing medium employed during the fish chilled storage. To this end and according to preliminary trials results, an aqueous solution including 0.050% (w/v) of each acid was employed as icing medium; its effect on the microbial activity development in mackerel muscle was monitored for up to 13 d of chilled storage and compared to a counterpart-fish batch kept under traditional water ice considered as control. Results indicated a lower bacterial growth in mackerel muscle subjected to storage in the organic acid-icing system by comparison with control fish. Thus, statistically-significant (P < 0.05) differences between both batches for all 6 microbial groups investigated (aerobes, anaerobes, psychrotrophes, Enterobacteriaceae, lipolytics, and proteolytics) and for 2 chemical indices related to microbial activity development (total volatile bases and trimethylamine) were obtained. The surface wash caused by the melting of the ice during storage and the subsequent antimicrobial effect of such acids on skin microflora of the fish can be invoked as the main reasons for the limited bacterial growth found in the corresponding mackerel muscle. PMID- 22510041 TI - Phenolic antioxidants inhibit the triplet-induced transformation of anilines and sulfonamide antibiotics in aqueous solution. AB - Recent studies have shown that dissolved organic matter (DOM) may inhibit the excited triplet-induced oxidation of several aromatic water contaminants, in particular those containing an aniline functionality. Such an inhibition was ascribed to antioxidant moieties of DOM. The present study was conducted with the aim of verifying whether well-defined antioxidants could act as inhibitors in analogy to DOM. Various substituted phenols exhibiting antioxidant character were able, at micromolar concentration, to slow down the photoinduced depletion of several anilines and sulfonamides in aerated aqueous solution containing 2 acetonaphthone as the photosensitizer. A concomitant accelerated degradation of the phenols in the presence of such contaminants was observed. This reinforces the hypothesis of reduction of oxidation intermediates of the contaminants by the phenols. Phenol (unsubstituted) was found to be a useful inhibitor even in the case of DOM-photosensitized transformations. Phenolic antioxidants are proposed as diagnostic tools to investigate the aquatic photochemistry of aromatic amines. PMID- 22510042 TI - Further characterization and determination of the single amino acid change in the tsI138 reovirus thermosensitive mutant. AB - Many temperature-sensitive mutants have been isolated in early studies of mammalian reovirus. However, the biological properties and nature of the genetic alterations remain incompletely explored for most of these mutants. The mutation harbored by the tsI138 mutant was already assigned to the L3 gene encoding the lambda1 protein. In the present study, this mutant was further studied as a possible tool to establish the role of the putative lambda1 enzymatic activities in viral multiplication. It was observed that synthesis of viral proteins is only marginally reduced, while it was difficult to recover viral particles at the nonpermissive temperature. A single nucleotide substitution resulting in an amino acid change was found; the position of this amino acid is consistent with a probable defect in assembly of the inner capsid at the nonpermissive temperature. PMID- 22510043 TI - Premacular hemorrhage due to isotretinoin use. AB - Isotretinoin is a vitamin A derivative used for serious acne that is refractory to other modes of treatment. The most common side effects include dryness of the skin and mucous membranes. Itching as a result of neurological, hematological and ocular side effects has also been reported. Here, we present a 19-year-old female patient who developed premacular hemorrhage and consequent loss of vision in the left eye after oral use of isotretinoin. To the best of our knowledge, this is the first report of the development of premacular hemorrhage as a result of isotretinoin use. PMID- 22510044 TI - Yacon flour and Bifidobacterium longum modulate bone health in rats. AB - Yacon flour has been considered a food with prebiotic potential because of the high levels of fructooligosaccharides, which allows for its use in formulating synbiotic foods. The purpose of this study was to evaluate the effect of yacon flour and probiotic (Bifidobacterium longum) on the modulation of variables related to bone health. Thirty-two Wistar rats were divided into 4 groups: control, yacon flour, diet+B. longum, and yacon flour+B. longum. After euthanasia, the bones were removed for analysis of biomechanical properties (thickness, length, and strength of fracture) and mineral content (Ca, Mg, and P); the cecum was removed for analysis of the microbiota and short-chain fatty acids. Tibia Ca, P, and Mg content was significantly (P<.05) higher in groups fed diet+B. longum, yacon flour+B. longum than in the control group. An increase in fracture strength was observed in the yacon flour (8.1%), diet+B. longum (8.6%), and yacon flour+B. longum (14.6%) in comparison to the control group. Total anaerobe and weight of the cecum were higher (P<.05) in rats consuming the yacon flour diet compared with the other groups. Cecal concentration of propionate was higher in all experimental groups compared with the control (P<.05). Yacon flour in combination with B. longum helped increase the concentration of minerals in bones, an important factor in the prevention of diseases such as osteoporosis. PMID- 22510045 TI - Effect of scaling and root planing on interleukin-1beta, interleukin-8 and MMP-8 levels in gingival crevicular fluid from chronic periodontitis patients. AB - BACKGROUND AND OBJECTIVE: There are few data concerning the effect of scaling and root planing on the levels of immune and inflammatory mediators in gingival crevicular fluid from patients with chronic periodontitis. Therefore, in this study the influence of scaling and root planing was determined on amounts of interleukin (IL)-1beta, IL-8 and MMP-8 in gingival crevicular fluid from patients with chronic periodontitis, in relation to clinical parameters. MATERIAL AND METHODS: A total of 51 patients were enrolled in this study. The study population consisted of 30 patients with generalized advanced chronic periodontitis, while 21 periodontally healthy subjects were recruited for the control group. The clinical parameters included approximal plaque index, gingival index, pocket depth and clinical attachment loss. The amounts of IL-1beta, IL-8 and MMP-8 in gingival crevicular fluid were measured by ELISA. Periodontal parameters as well as gingival crevicular fluid humoral factor amounts were evaluated in the control group and in chronic periodontitis patients at baseline and at 1 and 4 wk after scaling and root planing treatment. RESULTS: At baseline, there were significant differences between control subjects and chronic periodontitis patients in terms of clinical attachment loss, pocket depth, gingival index (p < 0.001) and approximal plaque index (p < 0.01). The amounts of IL-1beta, MMP-8 (p < 0.001) and IL-8 (p < 0.01) in gingival crevicular fluid were significantly lower in healthy subjects than in chronic periodontitis patients. Scaling and root planing led to improvement in all examined clinical parameters, apart from clinical attachment loss. Periodontal treatment also resulted in a significant decrease in the amounts of IL-1beta, IL-8 and MMP-8 in comparison to baseline, especially 4 wk after scaling and root planing (p < 0.001); however, the amounts of these humoral factors were still higher than those in control group. CONCLUSION: Our observations indicated that short-term nonsurgical therapy resulted in a significant improvement in periodontal indices and in a marked decrease of IL-1beta, IL-8 and MMP-8 gingival crevicular fluid levels. Nevertheless, no significant correlations were found between clinical parameters and amounts of humoral factors after therapy. PMID- 22510047 TI - Postoperative adverse outcomes in surgical patients with epilepsy: a population based study. AB - PURPOSE: People with epilepsy are more likely than healthy people to experience comorbidities and complications in various medical situations. However, the prevalence of postoperative complications, mortality, and use of medical resources in surgical patients with epilepsy has not been studied. The purpose of this study is to examine whether epilepsy is an independent risk factor for postoperative adverse outcomes of patients receiving major surgery. METHODS: Retrospective cohort study using the National Health Insurance Research Database to identify patients with epilepsy who underwent major surgery in Taiwan between the years 2004 and 2007. For each case, four age- and sex-matched participants without epilepsy were included. Preoperative comorbidities in the 24 months before surgery were identified. Eight major postoperative complications, overall 30-day mortality, and in-hospital utilization of medical resources (including length of hospital stay, percentage of postoperative intensive care unit admissions, and in-hospital medical expenditures) served as the major outcome measurements. Comorbidities, status of receiving renal dialysis, teaching hospital status, types of surgery, and patients living in urban or rural areas were adjusted by multivariate logistic regression. KEY FINDINGS: A total of 13,103 participants with epilepsy and 52,412 without were included. Patients with epilepsy have significantly more preoperative comorbidities and demonstrated more risks of any postoperative complications (odds ratio 2.02, 95% confidence interval 1.90-2.14). Consumption of in-hospital medical resources was also significantly higher in patients with epilepsy, but no significant differences in postoperative mortality rates between the two groups were noted. SIGNIFICANCE: Stroke was identified as the most significant postoperative complication for surgical patients with epilepsy. Patients, especially those with previous hospitalization or emergency visits due to the disease, confronted significantly higher postoperative complication rates, and consumed more in-hospital medical resources without differences in overall mortality rates. Further revision of health care standards to provide early recognition of postoperative complications and better management for surgical patients with epilepsy is needed. PMID- 22510046 TI - Hemorrhagic pseudoaneurysm in a patient receiving aflibercept for metastatic thyroid cancer. AB - BACKGROUND: Agents such as aflibercept, which target the angiogenic pathway, are of great interest as candidates for the management of metastatic differentiated thyroid cancer. Here, we report a patient who developed a hemorrhagic abdominal pseudoaneurysm shortly after being started on this drug. PATIENT FINDINGS: The patient was a 67-year-old woman being treated with single agent aflibercept (VEGF Trap) for metastatic thyroid cancer. She had no history of intra-abdominal pathology or vascular disease but had been previously treated with sorafenib. Twelve days after receiving her second dose of aflibercept, she developed vague abdominal pain, which increased in severity and was accompanied by nausea and vomiting. Her symptoms progressed along with a decline in her hematocrit and signs of internal hemorrhaging. An angiogram identified an occluded celiac artery with increased collaterals and a bleeding pseudoaneurysm in the inferior pancreaticoduodenal artery. After the pseudoaneurysm was coiled, the patient stabilized. SUMMARY AND CONCLUSIONS: Anti-angiogenic agents, usually well tolerated, can disrupt the delicate balance of normal endothelium, leading to hemorrhagic and thrombotic complications. The hemorrhage of aberrant vasculature should be included in the differential diagnosis in patients presenting with vague complaints while being treated with anti-angiogenic agents. PMID- 22510048 TI - Hyperglycaemia monitoring and management in stroke care: policy vs. practice. AB - AIM: To evaluate the extent to which hyperglycaemia was monitored and managed among patients admitted to hospital with acute stroke and transient ischaemic attack. METHODS: We conducted a retrospective cohort study involving a review of the records of 112 patients consecutively admitted with acute stroke or transient ischaemic attack to all three district general hospitals in one Health and Social Care Trust in Northern Ireland from 1 January to 15 April 2008. Glucose results for each of the first 5 days of hospital admission were ascertained. We compared interventions, clinical outcome and discharge planning between patients who experienced glucose >= 7.8 mmol/l in the first 5 days, and patients with lower glucose results. RESULTS: The daily prevalence rate of hyperglycaemia > 7.8 mmol/l across the first 5 days ranged from 24 to 34%. A total of 41 (37%) patients experienced hyperglycaemia on at least one occasion during the first 5 days. A history of diabetes mellitus prompted near patient glucose testing, but, among patients without diagnosed diabetes, glycaemia was under-monitored. Hyperglycaemia was a persisting trend, was under-treated and under-reported to general practitioners. Elevated glucose results failed to influence higher rates of fasting plasma glucose tests and BMI assessment. CONCLUSIONS: There is a need for greater vigilance in the detection of hyperglycaemia and undiagnosed diabetes mellitus among patients admitted to hospital with stroke or transient ischaemic attack. PMID- 22510049 TI - Paramedic-performed digital nerve block to facilitate field reduction of a dislocated finger. AB - This short report describes the use of digital nerve block by a paramedic to facilitate the reduction of a dislocated finger in the prehospital setting. The finger was successfully reduced at the scene without requiring administration of parenteral opioids. The patient was reluctant to visit an emergency department, but was able to be referred to a local primary care practice for postreduction imaging and further care. Paramedic-performed local and regional anesthesia has not been previously described in the emergency medicine or emergency medical services literature. With appropriate training, prehospital digital nerve blocks may be a feasible option to supplement existing paramedic analgesic options. PMID- 22510050 TI - A review of the contemporary management of fetal and neonatal alloimmune thrombocytopenia in an Australian tertiary obstetric hospital. AB - BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is the most common cause of severe perinatal thrombocytopenia, arising from the transplacental passage of maternal antibodies directed at paternally inherited antigens on fetal platelets. AIM: To review the occurrence, management and perinatal outcomes of pregnancies complicated by FNAIT from a single tertiary obstetric hospital in Western Australia. MATERIALS AND METHODS: The study was conducted as a retrospective review of cases with prenatally recognised FNAIT between 2001 and 2011, with the treatment modalities and outcomes analysed. RESULTS: Over the 10-year period, 20 cases of clinically significant FNAIT in 13 women were managed at our centre. Three cases were complicated by antenatal intracranial haemorrhage (15%), and in all 3, this was the presenting feature leading to diagnosis. In 17/20 (85%) cases, anti-HPA 1a was the responsible antibody, with the remainder being anti-HPA 5b. In 16/17 cases with pre-pregnancy recognition, intravenous gammaglobulin (IVGG) was administered antenatally (gestation at commencement ranging from 13 to 26 weeks) with adjuvant prednisolone in three cases. Postnatal treatment (IVGG or platelet transfusion) was provided in 4/16 cases. There was no intracranial haemorrhage or demise in any case receiving prenatal therapy. CONCLUSIONS: FNAIT is a rare and serious condition. In our small single-centre study, there was variability in the therapeutic strategies, although IVGG was central to all prenatally managed pregnancies. None of the treated pregnancies was complicated by intracranial haemorrhage or fetal death. There is a need for ongoing refinement of FNAIT management protocols, both in the prenatal and in the postnatal period. PMID- 22510051 TI - Cognitive testing and readability of an item bank for measuring the impact of headache on health-related quality of life. AB - BACKGROUND: Patient-reported outcomes (PRO) measures should be valid and accessible to a wide audience. OBJECTIVE: Cognitive item testing and readability studies were conducted to evaluate how adult headache sufferers (N = 9) understood and responded to the Headache Impact Test (HITTM) item bank, a PRO measure for headache that serves as the source of item content for the HIT-6TM (a widely used six-item short-form measure of headache impact with more than 30 language translations), and the Dynamic Health Assessment Headache Impact Test (DYNHA(r) HITTM) [a computerized adaptive test (CAT) of headache impact]. METHODS: During cognitive interviews, participants were asked to 'think aloud' as they read survey instructions, completed items, and formulated responses. Data analyses evaluated item comprehension, memory recall of relevant information, and decision and response processes; compared various item attributes; and tested shortened item versions. RESULTS: Survey readability was at the seventh-grade level. Respondents understood most revised items as intended, and found shorter items comparable to longer items with some exceptions. When recall period was included in instructions but not within the items themselves, respondents often expanded the recall period to answer the item. Some response scales (e.g. "Never" to "Always") were more readily understood than others (e.g. "Definitely true" to "Definitely false"). CONCLUSION: Qualitative research can improve the validity and accessibility of PRO measures that are used to monitor health conditions and aid patient-provider communication. PMID- 22510053 TI - Premature ventricular contractions from the outflow tract: 2 sides of the same coin! PMID- 22510052 TI - Designing family-centered male circumcision services: a conjoint analysis approach. AB - BACKGROUND: Male circumcision (MC) has become an important weapon in the fight against HIV/AIDS in many Sub-Saharan African countries. The successful implementation of a national MC program requires the design of circumcision services that are attractive to young men of various ages. For many potential clients, mothers and/or fathers will play an important role in the decision to be circumcised, and hence services will need to be designed with the preferences of mothers, fathers, and sons in mind. OBJECTIVE: Our objective was to value multiple design characteristics of potential community-based MC services from the perspectives of mothers, fathers, and sons in Johannesburg, South Africa, and to test for concordance between their values for the design characteristics. METHODS: Potential design characteristics of MC services were identified through open-ended interviews with key informants (n = 25). Preferences were estimated using conjoint analysis implemented as part of a cluster randomized household survey. Each participant was randomized to receive one of two possible blocks of conjoint analysis, each consisting of six forced-choice tasks comparing two possible MC services varying on 11 design characteristics. With only two levels for each attribute, our experimental design utilized a main effects orthogonal array. Data were analyzed using linear probability models, with tests of concordance of values using Wald tests generated from stratified estimates calculated using restricted least square estimation. RESULTS: A racially and geographically diverse sample consisting of 204 fathers, 204 mothers, and 237 sons completed the survey. In aggregate, requiring a follow-up visit was the most valued design factor (p < 0.001), followed by having a lower infection rate (p < 0.001), having less pain (p = 0.001), and a private waiting room (p = 0.001). Based on stratified analysis, sons also valued having the risks and benefits of MC explained (p = 0.01) and mothers valued requiring an HIV test as part of the procedure. Requiring an HIV test was the most significant difference between the respondents (p = 0.03), with sons finding it somewhat repulsive (p = 0.30). CONCLUSION: Our findings suggest that valuation of aspects of MC clinic design can diverge by decision maker. To better ensure utilization of services, these variations should be taken into account to prior to implementation of a national strategy in South Africa. PMID- 22510054 TI - Bone mineral density (BMD) in male patients with Parkinson's disease. AB - Patients with Parkinson's disease (PD) are at risk for osteoporosis. We aimed to compare male PD subjects with short disease duration (less than 5 years) to those with longer disease duration (5 to 10 years) in bone health characteristics and in bone mineral density (BMD). This current case series included male idiopathic PD patients ages 18-90 at an outpatient academic center. Outcome measures were bone mineral density and the Unified Parkinson Disease Rating Scale Motor Section (UPDRS III). Thirty-six PD patients received DEXA scans. Seventy-two percent had osteopenia or osteoporosis in at least one bone site. Reduced BMD was observed in 58.8% of the 0-5 years PD group, and in 84.2% of the 5-10 years PD group. There was no difference in the spine BMD between the 0 to 5 years and the 5 to 10 years PD groups, and no difference in femoral neck BMD between PD disease duration groups. There were no differences in UPDRS Part III scores between 0 to 5 years and the 5 to 10 years groups. Prevalence of osteoporosis and osteopenia was high in male PD subjects regardless of disease duration. Bone-health promoting/screening behaviors were found to be low. As PD patients are prone to falls, fractures, and associated comorbidities, more research should be performed to determine if a screening regimen is appropriate. PMID- 22510055 TI - Dentists' attitude to provision of care for people with learning disabilities in Udaipur, India. AB - This study determines and compares the attitudes of dentists to the provision of care for people with learning disabilities according to gender, qualification, previous experience of treating patients with learning disabilities and work experience of dentists. A cross-sectional study was conducted among 247 dentists (166 men and 81 women) using a pretested structured questionnaire. This questionnaire assessed the respondent's attitude towards learning-disabled patients in five categories: beliefs about treating them, their capabilities, discrimination against these patients, their social behaviour and quality of care to be received by these patients. The information on dentist's gender, qualification, work experience and previous experience of treating patients with learning disabilities was also collected through questionnaire. The Student's t test and anova test were used for statistical analysis. The mean attitude score was found to be 71.13 +/- 8.97. A statistically significant difference was found in the mean attitude scores of dentists with work experience (p = 0.000). Study subjects with postgraduate qualification and previous experience of treating patients with learning disabilities had significantly greater mean attitude score than their counterparts (p = 0.000). The overall attitude of dentists towards provision of care for people with learning disabilities was favourable, which increased with higher qualification and past experience. PMID- 22510056 TI - Lipase is essential for the study of in vitro release kinetics from organogels. AB - In vitro drug release studies remain indispensable in the development of drug delivery systems, even if correlations between in vitro and in vivo results are often imperfect. In this work, an improved in vitro analysis method for studying in situ-forming lipid-based implants was developed. More specifically, lipase was found to be an essential additive for evidencing differences in drug release kinetics from organogels of different amino acid-based organogelators, organogelator concentrations, drug loadings, and volumes. Lipases are thought to participate in the degradation of and release from amino acid-based organogel implants in vivo. Our experimental conditions allowed for the rapid and reliable screening of in vitro parameters that may be optimized to slow or accelerate drug release, once preliminary in vivo data are available. PMID- 22510057 TI - The interaction between importin-alpha and Nup153 promotes importin-alpha/beta mediated nuclear import. AB - Nuclear transport is mediated by transport factors, including the importin beta family members. The directionality of nuclear transport is governed by the asymmetrical distribution of the small GTPase Ran. Of note, importin alpha/beta mediated import of classical nuclear localization signal (cNLS)--containing cargo is more efficient than other Ran-dependent import pathways that do not require importin alpha. In this study, we characterized the role of importin alpha in nuclear transport by examining import efficiencies of cNLS-cargo/importin alpha/beta complexes. We first depleted digitonin-permeabilized semi-intact cells of endogenous importin alpha and used the cells to show that the interaction between importin alpha and Nup153--a component of the nuclear pore complex (NPC)- is essential for efficient import of importin beta-binding domain containing substrates, but not other cargoes that directly bind to importin beta. Moreover, we found that the binding of importin alpha to Nup153 facilitates cNLS-mediated import, and demonstrated that importin alpha in import complexes and cargo-free importin alpha prebound to Nup153 promote efficient import of cNLS-containing proteins. This is the first in vitro study showing that in conjunction with Nup153, importin alpha contributes to directionally biased exit of cNLS containing cargo to the nuclear side of NPCs. PMID- 22510058 TI - Trend analysis of antimicrobial resistance in Campylobacter jejuni and Campylobacter coli isolated from Belgian pork and poultry meat products using surveillance data of 2004-2009. AB - The purpose of this study was to analyze and compare antimicrobial resistance in Campylobacter spp. isolated from pork and poultry carcasses, and pork and poultry meat (at slaughterhouse level, during meat cutting, and at retail) in Belgium, using available surveillance data over the period 2004-2009. The susceptibilities of 1724 Campylobacter isolates for ampicillin, ciprofloxacin, nalidixic acid, tetracycline, erythromycin, and gentamicin were tested by E-test. Gentamicin resistance was low (near 0%) until 2007, with an increase to over 20% by 2009 for all species-matrix combinations. Resistance to tetracycline fluctuated around the same level during the entire study period and was significantly higher (p-value of <0.05) in C. coli than in C. jejuni. Erythromycin resistance was low and showed a slight decrease between 2004 and 2007, but increased from 2007 until 2009. Fluoroquinolone and ampicillin resistance was significantly higher in isolates derived from poultry, compared to pork-related isolates. This correlates with the higher use of these antimicrobials in poultry husbandry. A total of 25% of C. coli isolates from poultry showed the most apparent multiresistance (resistance to four or more antimicrobials). Approximately 1% of the poultry derived isolates (both C. coli and C. jejuni) showed resistance to all tested antimicrobials, while none was found in pork products. PMID- 22510060 TI - Probing electron-induced bond cleavage at the single-molecule level using DNA origami templates. AB - Low-energy electrons (LEEs) play an important role in nanolithography, atmospheric chemistry, and DNA radiation damage. Previously, the cleavage of specific chemical bonds triggered by LEEs has been demonstrated in a variety of small organic molecules such as halogenated benzenes and DNA nucleobases. Here we present a strategy that allows for the first time to visualize the electron induced dissociation of single chemical bonds within complex, but well-defined self-assembled DNA nanostructures. We employ atomic force microscopy to image and quantify LEE-induced bond dissociations within specifically designed oligonucleotide targets that are attached to DNA origami templates. In this way, we use a highly selective approach to compare the efficiency of the electron induced dissociation of a single disulfide bond with the more complex cleavage of the DNA backbone within a TT dinucleotide sequence. This novel technique enables the fast and parallel determination of DNA strand break yields with unprecedented control over the DNA's primary and secondary structure. Thus the detailed investigation of DNA radiation damage in its most natural environment, e.g., DNA nucleosomes constituting the chromatin, now becomes feasible. PMID- 22510059 TI - A nuptially transmitted ichthyosporean symbiont of Tenebrio molitor (Coleoptera: Tenebrionidae). AB - The yellow mealworm, Tenebrio molitor, harbors a symbiont that has spores with a thick, laminated wall and infects the fat body and ventral nerve chord of adult and larval beetles. In adult males, there is heavy infection of the epithelial cells of the testes and between testes lobes with occasional penetration of the lobes. Spores are enveloped in the spermatophores when they are formed at the time of mating and transferred to the female's bursa copulatrix. Infection has not been found in the ovaries. The sequence of the nuclear small subunit rDNA indicates that the symbiont is a member of the Ichthyosporea, a class of protists near the animal-fungi divergence. PMID- 22510061 TI - Analysis of lunasin in commercial and pilot plant produced soybean products and an improved method of lunasin purification. AB - Lunasin is a bioactive peptide present in soybean. It is important to quantify lunasin concentration in soy products to assess its potential impact as functional food. The objectives of this study were to analyze lunasin in commercial soymilk products and implement an efficient method to isolate and purify it from defatted soybean flour. Defatted soybean flour was suspended in water, and the extract was loaded in a pre-equilibrated diethylaminoethyl column and bound proteins eluted using a step gradient of salt. Most lunasin was eluted from the column at 0.2 to 0.4M NaCl as quantified by immunoassays and purified using ultracentrifugation and ultrafiltration techniques. Lunasin purity was >=90% and a standard curve was used to quantify its concentration in soymilk products. Concentration of lunasin in soy products, including organic soymilk, soy protein shakes, and soy infant formulas, ranged from 1.78 to 9.26 mg lunasin/100 g product. The concentration per serving ranged from 1.59 +/- 0.01 to 22.23 +/- 0.74 mg lunasin with variability depending on brand and size per serving. Steam-ground-cooked soy had the highest concentration of lunasin (22.23 +/- 0.74 mg/serving), similar to some commercial products. Ground-cooked soymilk contained roughly half the concentration of lunasin (14.39 +/- 1.4 mg/serving). Soy infant formulas that used soy protein isolate revealed lower concentrations of lunasin (P < 0.05). It was concluded that all soymilk products analyzed contained lunasin, and a more efficient method to isolate lunasin with higher purity was developed. PMID- 22510062 TI - Motifs Q and I are required for ATP hydrolysis but not for ATP binding in SWI2/SNF2 proteins. AB - Active DNA-dependent ATPase A Domain (ADAAD) is a SWI2/SNF2 protein that hydrolyzes ATP in the presence of stem-loop DNA that contains both double stranded and single-stranded regions. ADAAD possesses the seven helicase motifs that are a characteristic feature of all the SWI2/SNF2 proteins present in yeast as well as mammalian cells. In addition, these proteins also possess the Q motif ~17 nucleotides upstream of motif I. Using site-directed mutagenesis, we have sought to define the role of motifs Q and I in ATP hydrolysis mediated by ADAAD. We show that in ADAAD both motifs Q and I are required for ATP catalysis but not for ATP binding. In addition, the conserved glutamine present in motif Q also dictates the catalytic rate. The ability of the conserved glutamine present in motif Q to dictate the catalytic rate has not been observed in helicases. Further, the SWI2/SNF2 proteins contain a conserved glutamine, one amino acid residue downstream of motif I. This conserved glutamine, Q244 in ADAAD, also directs the rate of catalysis but is not required either for hydrolysis or for ligand binding. Finally, we show that the adenine moiety of ATP is sufficient for interaction with SWI2/SNF2 proteins. The gamma-phosphate of ATP is required for inducing the conformational change that leads to ATPase activity. Thus, the SWI2/SNF2 proteins despite sequence conservation with helicases appear to behave in a manner distinct from that of the helicases. PMID- 22510063 TI - Enantioselective total synthesis and absolute configuration of apiosporic acid. AB - The first total synthesis of the polyketide apiosporic acid is presented. Key steps are a Julia-Kocienski olefination, a Suzuki-Miyaura cross-coupling, and an intramolecular Diels-Alder reaction. The absolute configuration of the natural product was determined. PMID- 22510064 TI - Physicochemical, pharmacokinetic and pharmacodynamic evaluations of novel ternary solid dispersion of rebamipide with poloxamer 407. AB - This study was conducted primarily to improve the solubility of rebamipide, a poorly water-soluble anti-ulcer drug, using novel ternary solid dispersion (SD) systems and secondly to evaluate the effect of solubility enhancement on its pharmacokinetic (PK) and pharmacodynamic (PD) profile. After dissolving the three components in aqueous medium, ternary SD containing the drug, sodium hydroxide (NaOH) and PVP-VA 64 was achieved by spray drying method, which was used as primary SD. Poloxamer 407, a surfactant polymer, was incorporated in this primary SD by four different methods: co-grinding, physical mixing, melting or spray drying. SD was then characterized by dissolution test, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR). The spray dried SD of poloxamer 407 together with primary SD displayed highest dissolution rate of the drug of about 70% after 2 h. DSC, PXRD and FT-IR characterized the amorphous state and molecular dispersion of the drug in the SD. PK and PD studies in Sprague-Dawley rats revealed that the bioavailability of the drug using optimal SD was about twofold higher than that of reference product, and the irritation area of stomach was significantly reduced in the ulcer-induced rat model using optimal SD as compared to the reference product. PMID- 22510065 TI - Intriguing H-aggregate and H-dimer formation of coumarin-481 dye in aqueous solution as evidenced from photophysical studies. AB - Photophysical properties of coumarin-481 (C481) dye in aqueous solution show intriguing presence of multiple emitting species. Concentration and wavelength dependent fluorescence decays and time-resolved emission spectra and area normalized emission spectra suggest the coexistence of dye monomers, dimers, and higher aggregates (mostly trimers) in the solution. Because of the efficient intramolecular charge transfer (ICT) state to twisted intramolecular charge transfer (TICT) state conversion, the dye monomers show very short fluorescence lifetime of ~0.2 ns. Fluorescence lifetimes of dimers (~4.1 ns) and higher aggregates (~1.4 ns) are relatively longer due to steric constrain toward ICT to TICT conversion. Observed results indicate that the emission spectra of the aggregates are substantially blue-shifted compared to monomers, suggesting H aggregation of the dye in the solution. Temperature-dependent fluorescence decays in water and time-resolved fluorescence results in water-acetonitrile solvent mixtures are also in support of the dye aggregation in the solution. Though dynamic light scattering studies could not recognize the dye aggregates in the solution due to their small size and low concentration, fluorescence up conversion measurements show a relatively higher decay tail in water than in water-acetonitrile solvent mixture, in agreement with higher dye aggregation in aqueous solution. Time-resolved fluorescence results with structurally related non-TICT dyes, especially those of coumarin-153 dye, are also in accordance with the aggregation behavior of these dyes in aqueous solution. To the best of our knowledge, this is the first report on the aggregation of coumarin dyes in aqueous solution. Present results are important because coumarin dyes are widely used as fluorescent probes in various microheterogeneous systems where water is always a solvent component, and the dye aggregation in these systems, if overlooked, can easily lead to a misinterpretation of the observed results. PMID- 22510066 TI - Overexpression of MtCAS31 enhances drought tolerance in transgenic Arabidopsis by reducing stomatal density. AB - * Dehydrins are a type of late embryogenesis abundant protein. Some dehydrins are involved in the response to various abiotic stresses. Accumulation of dehydrins enhances the drought, cold and salt tolerances of transgenic plants, although the underlying mechanism is unclear. MtCAS31 (Medicago Truncatula cold-acclimation specific protein 31) is a Y(2)K(4)-type dehydrin that was isolated from Medicago truncatula. * We analyzed the subcellular and histochemical localization of MtCAS31, and the expression patterns of MtCAS31 under different stresses. Transgenic Arabidopsis that overexpressed MtCAS31 was used to determine the function of MtCAS31. A yeast two-hybrid assay was used to screen potential proteins that could interact with MtCAS31. The interaction was confirmed by bimolecular fluorescence complementation (BiFC) assay. * After a 3-h drought treatment, the expression of MtCAS31 significantly increased 600-fold. MtCAS31 overexpression dramatically reduced stomatal density and markedly enhanced the drought tolerance of transgenic Arabidopsis. MtCAS31 could interact with AtICE1 (inducer of CBF expression 1) and the AtICE1 homologous protein Mt7g083900.1, which was identified from Medicago truncatula both in vitro and in vivo. * Our findings demonstrate that a dehydrin induces decreased stomatal density. Most importantly, the interaction of MtCAS31 with AtICE1 plays a role in stomatal development. We hypothesize that the interaction of MtCAS31 and AtICE1 caused the decrease in stomatal density to enhance the drought resistance of transgenic Arabidopsis. PMID- 22510067 TI - Tactical emergency medical support programs: a comprehensive statewide survey. AB - BACKGROUND: Specially trained tactical emergency medical support (TEMS) personnel provide support to law enforcement special weapons and tactics (SWAT) teams. These programs benefit law enforcement agencies, officers, suspects, and citizens. TEMS programs are increasingly popular, but there are wide variations in their organization and operation and no recent data on their prevalence. OBJECTIVE: We sought to measure the current prevalence and specific characteristics of TEMS programs in a comprehensive fashion in a single southeastern state. METHODS: North Carolina emergency medical services (EMS) systems have county-based central EMS oversight; each system was surveyed by phone and e-mail. The presence and selected characteristics of TEMS programs were recorded. U.S. Census data were used to measure the population impact of the programs. RESULTS: All of the 101 EMS systems statewide were successfully contacted. Thirty-three counties (33%) have TEMS programs providing medical support to 56 local law enforcement agencies as well as state and federal agencies. TEMS programs tend to be located in more populated urban and suburban areas, serving a population base of 5.9 million people, or 64% of the state's population. Tactical medics in the majority of these programs (29/33; 88%) are not sworn law enforcement officers. CONCLUSIONS: Approximately one-third of county-based EMS systems in North Carolina have TEMS programs. These programs serve almost two-thirds of the state's population base, using primarily nonsworn tactical medics. Comparison with other regions of the country will be useful to demonstrate differences in prevalence and program characteristics. Serial surveillance will help track trends and measure the growth and impact of this growing subspecialty field. PMID- 22510068 TI - Tacticity influence on the electrochemical reactivity of group transfer polymerization-synthesized PTMA. AB - Spectroscopic, thermal, and electrochemical characterization results are presented for the redox active polymer poly(2,2,6,6-tetramethyl-1-piperinidyloxy 4-yl methacrylate) or PTMA, synthesized by group transfer polymerization (GTP), and its precursors 4-hydroxy-tetramethylpiperidine-N-oxyl (HO-TEMPO) and 4 methacryloyloxy-tetramethylpiperidine-N-oxyl (MO-TEMPO). DSC analysis of synthesized PTMA showed that the glass transition temperature (T(g)) of the polymer structure occurs at 155 degrees C, corroborated by dynamic mechanical analysis (DMA), which is higher when compared with T(g) data for PTMA synthesized by other methods. Also, the amount of radical species present in PTMA synthesized by GTP reactions (100%) is higher than the values typically upon synthesizing PTMA by radical polymerization. Electrochemical and spectroelectrochemical electron spin resonance studies in acetonitrile revealed two redox events in the PTMA polymer, one of which is reversible, accounting for ca. 80% of the spins in the polymer and giving rise to the battery behavior. The other redox event is irreversible, accounting for the remaining ca. 20% of spins, which has not previously been reported. These two redox events are linked to a structural property associated with the tacticity of the polymer, where the reversible feature (responsible for cathode behavior) is the dominant species. This corresponds to a number of isotactic domains of the polymer (determined by high temperature (1)H NMR). The second feature accounts for the three-line impurity observed in the ESR, which has been reported previously but poorly explained, associated to the number of heterotactic/syndiotactic triads. PMID- 22510069 TI - Determination of pharmaceutical residues in fish bile by solid-phase microextraction couple with liquid chromatography-tandem mass spectrometry (LC/MS/MS). AB - The present study investigates possible uptake and bioconcentration of different classes of pharmaceuticals residues (organic contaminants) in fish bile using a simplified analytical methodology based on solid phase microextration (SPME). The use of solid phase microextraction (SPME), as a simple analytical tool, to screen for target pharmaceuticals in fish bile samples was validated in rainbow trout (Oncorhynchus mykiss) following short-term laboratory exposures to carbamazepine and fluoxetine. While fish bioconcentrated both fluoxetine and carbamazepine from exposure water, fluoxetine accumulated to a greater degree in bile than carbamazepine. Good agreement was obtained for both analytes in bile samples between SPME and traditional liquid (solvent) extraction approaches (R(2) > 0.99). The field application of SPME sampling was further demonstrated in fathead minnow (Pimephales promelas), a small-bodied fish caged upstream and downstream of a local wastewater treatment plant where fluoxetine, atorvastatin, and sertraline were detected in fish bile at the downstream location. SPME is a promising analytical tool for investigating the bioconcentration of trace contaminants in fish bile, facilitating detection of trace environmental contaminants otherwise undetectable due to low concentrations in the environment and biological tissues as well as the complexity of the sample matrices. PMID- 22510070 TI - Combined thyroidectomy and cardiac surgery. AB - A combination of cardiac surgery and thyroidectomy as a single stage operation has rarely been reported in the literature. We report on the management of a 64 year-old female undergoing a combined aortic valve replacement and excision of a primary (ectopic) intrathoracic goiter. The literature on combined cardiac surgery and thyroidectomy is also reviewed. PMID- 22510071 TI - Carbohydrate- and lipid-enriched meals acutely disrupt glycemic homeostasis by inducing transient insulin resistance in rats. AB - Chronic intake of high-carbohydrate or high-lipid diets is a well-known insulin resistance inducer. This study investigates the immediate effect (1-6 h) of a carbohydrate- or lipid-enriched meal on insulin sensitivity. Fasted rats were refed with standard, carbohydrate-enriched (C), or lipid-enriched (L) meal. Plasma insulin, glucose, and non-esterified fatty acids (NEFA) were measured at 1, 2, 4, and 6 h of refeeding. The glucose-insulin index showed that either carbohydrates or lipids decreased insulin sensitivity at 2 h of refeeding. At this time point, insulin tolerance tests (ITTs) and glucose tolerance tests (GTTs) detected insulin resistance in C rats, while GTT confirmed it in L rats. Reduced glycogen and phosphorylated AKT and GSK3 content revealed hepatic insulin resistance in C rats. Reduced glucose uptake in skeletal muscle subjected to the fatty acid concentration that mimics the high NEFA level of L rats suggests insulin resistance in these animals is mainly in muscle. In conclusion, carbohydrate- or lipid-enriched meals acutely disrupt glycemic homeostasis, inducing a transient insulin resistance, which seems to involve liver and skeletal muscle, respectively. Thus, the insulin resistance observed when those types of diets are chronically consumed may be an evolution of repeated episodes of this transient insulin resistance. PMID- 22510074 TI - Prevalence of breech-strike in mulesed, clipped and unmulesed Merino hoggets in south-eastern Australia. AB - OBJECTIVE: To compare the prevalence of breech flystrike ('breech-strike') on 12 20-month-old Merino hoggets that were mulesed, had breech and tail clips applied ('clipped') or were left unmulesed but treated strategically with long-acting insecticide. DESIGN: A cohort study on three farms in southern Victoria. METHODS: Three treatment groups were established at lamb marking on each farm. The unmulesed group was treated with dicyclanil when 12 months old in September or October ('early-season treatment'). The prevalence of breech-strike and key risk factors, including soiling of the breech with faeces ('dag') and urine ('stain'), and breech wrinkle, were compared between the groups. RESULTS: Over all the farms, breech-strike occurred on 1.1% of mulesed sheep and 7.7% of clipped sheep. Clipped sheep had a relative risk of breech-strike of 18.2-, 16.8- and 3.0-fold that of mulesed sheep on the three farms. Unmulesed sheep treated with dicyclanil had a similar prevalence of breech-strike to that of mulesed sheep (overall 0.9%, range 0-2.5%), but had significantly more dag, stain and wrinkle. CONCLUSION: Early-season treatment of unmulesed sheep prevented most breech-strikes during the spring and early summer, and offers a short- to medium-term option for the control of breech-strike in south-eastern Australia. There were some benefits associated with using clips, namely less dag and stain, and a shorter time spent crutching. However, to control breech-strike the clipped sheep should be treated the same as unmulesed sheep. Reducing the prevalence and severity of dag will be a major component of strategies to control breech-strike of Merinos in this region. PMID- 22510075 TI - Quarter-milking-, quarter-, udder- and lactation-level risk factors and indicators for clinical mastitis during lactation in pasture-fed dairy cows managed in an automatic milking system. AB - OBJECTIVES: To identify risk factors and indicators at quarter-milking and other levels for clinical mastitis during lactation in pasture-fed cows managed in an automatic milking system. DESIGN: A retrospective nested case-control study using data collected over a 31-month period. A total of 803,948 quarter milkings from 249 cows were available for analysis, of which 245 were selected as clinical mastitis quarter-milking cases and 2450 unaffected quarter-milkings were selected as controls. Most of the diagnoses of clinical mastitis had been made after clinical assessments of quarters following automated alerts by the milking system. Potential risk factors and indicators were assessed using univariable and multivariable multilevel logistic models. RESULTS: Quarters that are milked infrequently and have low yield, fast peak milk flow rates, blood in the milk and/or elevated milk conductivity are at increased risk of clinical mastitis. Quarters were also at increased risk between days 10 and 29 of lactation, and during higher parity lactations. Milk fat and protein concentrations and the fat:protein ratio were not significantly associated with the development of clinical mastitis. Neither quarter position (fore or rear) nor side (left or right) was associated with clinical mastitis occurrence. Quarters that had been clinically affected more than 30 days previous in the current lactation were not at increased risk of redeveloping clinical mastitis. CONCLUSIONS: Under the study conditions, the risk of clinical mastitis increased for quarter-milkings in quarters that were milked less frequently in the previous 7 days, were low yielding, had fast peak milk flow rates and had more milkings in which blood was detected in milk and/or the milk conductivity was elevated. Risk was also increased in days 10-29 of lactation and in higher parity lactations. PMID- 22510076 TI - Retrospective study of 103 presumed cases of tick (Ixodes holocyclus) envenomation in the horse. AB - OBJECTIVE: Review 103 cases of presumed tick envenomation in horses. DESIGN: Retrospective study. METHOD: Variables, including date of presentation, age, breed, weight, presence of ticks, gait and respiration scores, duration of recumbency, treatment, outcome and complications were recorded. A series of univariable screening tests were performed and used in a multivariable logistic regression model. RESULTS: There were a total of 103 cases affecting 10 breeds, aged between 1 week and 18 years of age. Horses >6 months old and weighing >100 kg had a higher odds of death than those <6 months old and <100 kg. Cases were seen from North Queensland to the central coast of New South Wales and were more likely to present in the warmer months. There was no association between the number of ticks found on an animal and death. Horses with a higher respiratory score had higher odds of dying, but there was no association between gait score and survival. Horses recumbent >120 h after presentation had higher odds of dying. Complications were reported in 35% of horses. The odds ratio for survival was higher for horses receiving >0.5 mL/kg of tick antiserum. Overall, 74% of horses survived. Multivariable modelling was limited by the small sample size. CONCLUSION: In general, tick envenomation in horses follows the geographic distribution of Ixodes holocyclus. Tick antiserum administered at >0.5 mL/kg increases the odds of survival. It would appear that the complications associated with managing a recumbent horse increase the odds of death. PMID- 22510077 TI - Suspected tick paralysis (Ixodes holocyclus) in a Miniature Horse. AB - A 9-year-old Miniature Horse gelding infested with ticks (Ixodes holocyclus) was presented with flaccid motor paralysis causing recumbency. Neurological examination and other diagnostic tests did not identify an alternative aetiology, leading to a presumptive diagnosis of tick paralysis. The gelding was treated with tick antiserum and intensive supportive care. He made a gradual recovery over the 48 h following presentation and was discharged without further complications. This case report describes in detail the clinical signs and successful treatment of a Miniature Horse with flaccid paralysis caused by suspected envenomation by Ixodes holocyclus. PMID- 22510078 TI - Postoperative pain and perioperative analgesic administration in dogs: practices, attitudes and beliefs of Queensland veterinarians. AB - OBJECTIVE: The aim of this study was to describe the practices, attitudes and beliefs of Queensland veterinarians in relation to postoperative pain and perioperative analgesia in dogs. METHODS: One veterinarian from each of the 50 randomly selected Queensland veterinary practices was enrolled after selection by convenience sampling. RESULTS: The study response rate was 94.3%. Demeanour, vocalisation and heart rate were the most common postoperative pain assessment tools used, even though the most sensitive tools were considered to be demeanour, heart rate and respiratory rate. Only 20% of respondents used formalised pain scoring systems. Preoperative analgesic administration was always used by 72% of respondents. There was marked variability in the frequency with which analgesia was administered perioperatively for ovariohysterectomy. Only 24% of veterinarians discharged animals with ongoing analgesia even though 38% agreed that pain is still present 7 days postoperatively. Multimodal analgesia was used by 82% of respondents. Epidural and local anaesthetic analgesic techniques were not being utilised by any respondents. Conclusions These results indicate that management of postoperative pain in dogs in Queensland is frequently suboptimal and, at times, is not consistent with the veterinarian's attitudes and beliefs. Continuing education into analgesic use and pain evaluation may be effective in addressing this. PMID- 22510080 TI - Waterbird movement across the Great Dividing Range and implications for arbovirus irruption into southern Victoria. AB - BACKGROUND: Waterbirds are the major hosts of various arboviruses. Murray Valley encephalitis virus (MVEV) is an arbovirus native to northern Australia, the major hosts of which are Phalacrocoraciformes (cormorants), Ciconiiformes (herons) and other waterbirds. MVEV is transmitted to humans by mosquitoes and can cause acute encephalomyelitis. In Victoria, MVEV is restricted to the northern side of the Great Dividing Range (GDR), suggesting that waterbirds cannot cross the high country. METHODS AND RESULTS: We tested this hypothesis by analysing data on waterbird banding and recovery and discovered that 12 species can cross the GDR. CONCLUSION: Waterbirds have the potential to carry arboviruses, including MVEV, into southern Victoria. PMID- 22510079 TI - Comparison of the use of cabergoline and gonadotrophin to treat primary and secondary anoestrus in bitches. AB - OBJECTIVE: To determine the efficacy and reliability of cabergoline and pregnant mare's serum gonadotrophin (PMSG) for induction of oestrus in bitches with primary or secondary anoestrus. PROCEDURES: We studied 39 healthy bitches of various breeds aged 2-6 years and in primary or secondary anoestrus: 20 bitches were administered 5 ug/kg/day cabergoline orally until day 2 after the onset of pro-oestrus or for a maximum of 42 days, and 19 bitches were administered 20 IU/kg/day PMSG intramuscularly for 5 consecutive days, followed by an additional single injection of 25 IU/kg of human chorionic gonadotrophin on the fifth day. RESULTS: The rates of oestrus induction in the primary and secondary anoestrous bitches treated with cabergoline and PMSG were found to be similar. Pregnancy and whelping rates in the cabergoline group were statistically different from the rates in the PMSG group (P < 0.001). CONCLUSION: Cabergoline is more effective and reliable for the induction of a fertile oestrus in bitches with primary or secondary anoestrous. PMID- 22510081 TI - Mixed methods study of management of health conditions in rural low-income families: implications for health care policy in the USA. AB - INTRODUCTION: The purpose of this mixed methods study was to examine the health issues and health management strategies utilized by rural low-income women and their families to inform the design, implementation, and evaluation of health reform in rural areas of the USA. METHODS; Quantitative data was analyzed from 271 rural, low-income women and their families and qualitative data from a sub sample of 44. Specifically explored were the: (1) types and perceived severity of health conditions rural, low-income individuals report; (2) perceived value and utilization of a usual source of care; and (3) strategies these individuals employ to manage their health. RESULTS: Rural American families manage multiple healthcare needs with limited resources; 42.1% reported 1-4 chronic conditions in the family, 31.4% reported 5-8 conditions, and 17.7% reported 9 or more conditions. The majority of participants (79.0%) reported having a doctor or other healthcare professional that they usually see; 61.3% reported their partners had a usual provider, and 91.7% reported their children had a usual provider. Analysis of the qualitative data revealed two main themes regarding management of health conditions: (1) lack of engagement in managing overall health; and (2) ineffective utilization of health care. CONCLUSIONS: Rural low income individuals in the US may benefit from new policies that promote patient centered, personalized care. However, any policy change must be carefully designed to consider the ways in which rural American families manage their health in order to improve individual health status and reduce rural health disparities. PMID- 22510082 TI - The role of voxel-based morphometry in the detection of cortical dysplasia within the temporal pole in patients with intractable mesial temporal lobe epilepsy. AB - PURPOSE: To determine whether voxel-based morphometry (VBM) might contribute to the detection of cortical dysplasia within the temporal pole in patients with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE/HS). METHODS: Eighteen patients with intractable MTLE/HS and 30 sex- and age-matched healthy controls were included in the study. All of the patients fulfilled the diagnostic criteria for MTLE/HS and underwent anteromedial temporal resection. VBM without a modulation step was applied to the magnetic resonance (MR) images of the brain. Statistical parametric maps were used to compare structural characteristics such as gray matter concentration (GMC) within the temporal pole among patients and controls separately. The acquired data were then statistically analyzed to determine the congruency between visually inspected MR imaging (MRI) scans and VBM results in the detection of morphologic abnormalities in the temporal pole compared to postoperative histopathologic findings of cortical dysplasia. KEY FINDINGS: Histopathologic examination revealed cortical dysplasia within the temporal pole in 11 patients. In detail, according to Palmini's classification, mild malformations of cortical development (mMCDs) were disclosed in three patients, focal cortical dysplasia (FCD) type Ia in three patients, and FCD type Ib in five patients. Some type of structural temporal pole abnormality was suggested by VBM in 14 patients and by visually inspected MRI scans in 11 patients. The results of VBM were in agreement with the presence/absence of cortical dysplasia in 13 patients (72.2%); this correspondence was significant (p = 0.047). In one case, VBM was false negative and in four cases it was false positive. There was congruence between the results of visual analysis and histologic proof in 55.6% of examined patients, which was not significant. SIGNIFICANCE: We found that VBM made a superior contribution to the detection of temporopolar structural malformations (cortical dysplasia) compared to visual inspection. The agreement with postoperative histopathologic proof was clearly significant for VBM results and nonsignificant for visual inspection. PMID- 22510084 TI - Acceptability of the consumer-centric u-health services for patients with chronic obstructive pulmonary disease. AB - OBJECTIVES: We developed and implemented a system for u-health (ubiquitous healthcare) services for patients with chronic obstructive pulmonary disease (COPD) and studied the level of acceptability by the patients in the context of home visits and telephone education. SUBJECTS AND METHODS: To determine its effectiveness, the u-health service system was used for 2 years with 144 COPD patients in a clinical environment. Patients were provided with the u-healthcare service. RESULTS: Patients with COPD were highly satisfied with the u-healthcare service, which incorporated telemonitoring, teleconsultation, and tele-education along with home visits. The average acceptable fees (in USD) of the service system are as follows: u-health device, $421.28; home visit, $21.53/visit; tele education, $0.53/min or $26.57/month; and total service fee, $44.26/month. CONCLUSIONS: COPD patients accepted u-health services with a high satisfaction rate, promising a new paradigm of consumer-centric healthcare services. PMID- 22510083 TI - Effects of parboiled rice diet on oxidative stress parameters in kidney of rats with streptozotocin-induced diabetes. AB - The effect of parboiled rice (PR) and white rice (WR) diets on oxidative stress (OS) parameters was investigated in the kidneys of rats with streptozotocin induced diabetes (40 mg kg(-1), iv). The experimental groups (n=8) were control fed with PR (CPR), control fed with WR, diabetic fed with PR, and diabetic fed with WR. After 30 days of treatment, all animals were anesthetized and exsanguinated before removal of kidneys, which were used to determine thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides, carbonyl protein, superoxide dismutase, catalase, glutathione peroxidase (GPx), glutathione reductase, glutathione-S-transferase activities, and levels of glutathione (GSH). Total phenolic compounds were determined in WR and PR grains. Our data indicated that diabetes induced increase in TBARS and lipid hydroperoxides levels. Although PR has not prevented the rise in the levels of these measurements, its consumption by our animals resulted in higher GPx activity and GSH content than that of the CPR. Moreover, PR also presented concentration of total phenolic compounds 127% higher than WR grains. Thus, its consumption in this diabetic condition is suggested because this seems to confer greater protection against OS in the renal tissue of diabetic animals. PMID- 22510085 TI - Longitudinal changes of nerve conduction velocity, distal motor latency, compound motor action potential duration, and skin temperature during prolonged exposure to cold in a climate chamber. AB - Changes of nerve conduction velocity (NCV), distal motor latency (DML), compound motor action potential (CMAP) duration, and skin temperature with regard to cold have been investigated by use of ice packs or cold water baths, but not after cooling of environmental temperature which has higher ecological validity. The aim of this study was to investigate these parameters during cooled room temperature. NCV, DML, and CMAP duration of the common fibular nerve, and skin temperature were measured in 20 healthy young females during exposure to 15 degrees C room temperature, coming from 25 degrees C room. We found that NCV decreased and DML increased linearly during 45 min observation time, in contrast to CMAP duration and skin temperature which changes followed an exponential curve. To the best of our knowledge, this is the first study investigating changes of these parameters during exposure to environmental cold. The results may pilot some new hypotheses and studies on physiological and pathological changes of the peripheral nervous system and skin to environmental cold, e.g., in elderly with peripheral neuropathies. PMID- 22510087 TI - Comparative review of family-professional communication: what mental health care can learn from oncology and nursing home care. AB - Because family members take on caring tasks and also suffer as a consequence of the illness of the patient, communication between health-care professionals and family members of the patient is important. This review compares communication practices between these two parties in three different parts of health care: oncology, nursing home care, and mental health care. It shows that there are important differences between sectors. Mental health stands out because contacts between family members and professionals are considered problematic due to the autonomy and confidentiality of the patient. The article explores several explanations for this, and, by comparing the three health sectors, distils lessons to improve the relationship between family members and health-care professionals. PMID- 22510086 TI - Myosin Ia is required for CFTR brush border membrane trafficking and ion transport in the mouse small intestine. AB - In enterocytes of the small intestine, endocytic trafficking of CFTR channels from the brush border membrane (BBM) to the subapical endosomes requires the minus-end motor, myosin VI (Myo6). The subapical localization of Myo6 is dependent on myosin Ia (Myo1a) the major plus-end motor associated with the BBM, suggestive of functional synergy between these two motors. In villus enterocytes of the Myo1a KO mouse small intestine, CFTR accumulated in syntaxin-3 positive subapical endosomes, redistributed to the basolateral domain and was absent from the BBM. In colon, where villi are absent and Myo1a expression is low, CFTR exhibited normal localization to the BBM in the Myo1a KO similar to WT. cAMP stimulated CFTR anion transport in the small intestine was reduced by 58% in the KO, while anion transport in the colon was comparable to WT. Co immunoprecipitation confirmed the association of CFTR with Myo1a. These data indicate that Myo1a is an important regulator of CFTR traffic and anion transport in the BBM of villus enterocytes and suggest that Myo1a may power apical CFTR movement into the BBM from subapical endosomes. Alternatively, it may anchor CFTR channels in the BBM of villus enterocytes as was proposed for Myo1a's role in BBM localization of sucrase-isomaltase. PMID- 22510089 TI - Vasodepressor cough syncope masked by sleep apnea-induced asystole. AB - Vasodepressor Cough Syncope. Cough syncope is classified among the neural-reflex "situational" faints, but whether the clinical consequences in affected individuals result from reflex triggered bradyarrhythmia or vasodepressor-induced hypotension, or both, is often unknown. In this report we describe findings in a patient with a clinical history consistent with cough syncope, and in whom documented multiple asystolic spells were at first believed to be responsible for symptoms. However, pacemaker therapy initiated at an outside facility failed to suppress symptoms, and subsequent referral for more detailed autonomic study revealed the asystole to be due to sleep apnea, whereas cough-induced vasodepressor hypotension was the basis of syncope in this individual; the latter provided a pathophysiologic target for prevention of recurring symptoms. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1024-1027, September 2012). PMID- 22510088 TI - Catalysis by a de novo zinc-mediated protein interface: implications for natural enzyme evolution and rational enzyme engineering. AB - Here we show that a recent computationally designed zinc-mediated protein interface is serendipitously capable of catalyzing carboxyester and phosphoester hydrolysis. Although the original motivation was to design a de novo zinc mediated protein-protein interaction (called MID1-zinc), we observed in the homodimer crystal structure a small cleft and open zinc coordination site. We investigated if the cleft and zinc site at the designed interface were sufficient for formation of a primitive active site that can perform hydrolysis. MID1-zinc hydrolyzes 4-nitrophenyl acetate with a rate acceleration of 10(5) and a k(cat)/K(M) of 630 M(-1) s(-1) and 4-nitrophenyl phosphate with a rate acceleration of 10(4) and a k(cat)/K(M) of 14 M(-1) s(-1). These rate accelerations by an unoptimized active site highlight the catalytic power of zinc and suggest that the clefts formed by protein-protein interactions are well suited for creating enzyme active sites. This discovery has implications for protein evolution and engineering: from an evolutionary perspective, three coordinated zinc at a homodimer interface cleft represents a simple evolutionary path to nascent enzymatic activity; from a protein engineering perspective, future efforts in de novo design of enzyme active sites may benefit from exploring clefts at protein interfaces for active site placement. PMID- 22510090 TI - Bullying or violence during training and the risk of dropout from the eldercare sector 2 years later. AB - BACKGROUND: The proportion of old people in need of care is growing rapidly in most western societies, and there is a rising demand for qualified eldercare workers in the years to come. Hence, solutions to high turnover in the eldercare sector are becoming increasingly important. AIM: To test whether bullying, violence and/or threats of violence (violence) among health care trainees are predictors of subsequent dropout from the eldercare sector 2 years after graduation from college. METHODS: A questionnaire was given to all health care trainees in Denmark approximately 2 weeks before their graduation in 2004. Female respondents (N = 5000) were followed in national employment registers to see whether they had dropped out of the eldercare sector by the end of 2006. Logistic regression was used to model the outcome. RESULTS: Among the respondents, 5.5% had been bullied during the training period, 9.1% had been subjected to violence. Hereof, 1% reported exposure to both bullying and violence. At follow-up, 37% had dropped out of the eldercare sector. The odds of dropout were significantly associated with bullying, OR = 1.39 (95% CI: 1.08-1.79), but not with violence, OR = 0.89 (95% CI: 0.72-1.09). CONCLUSION: Being bullied while in training as a health care worker is a predictor of subsequent dropout from the eldercare sector. PMID- 22510091 TI - Electrochemical boron-doped diamond film microcells micromachined with femtosecond laser: application to the determination of water framework directive metals. AB - Planar electrochemical microcells were micromachined in a microcrystalline boron doped diamond (BDD) thin layer using a femtosecond laser. The electrochemical performances of the new laser-machined BDD microcell were assessed by differential pulse anodic stripping voltammetry (DPASV) determinations, at the nanomolar level, of the four heavy metal ions of the European Water Framework Directive (WFD): Cd(II), Ni(II), Pb(II), Hg(II). The results are compared with those of previously published BDD electrodes. The calculated detection limits are 0.4, 6.8, 5.5, and 2.3 nM, and the linearities go up to 35, 97, 48, and 5 nM for, respectively, Cd(II), Ni(II) Pb(II), and Hg(II). The detection limits meet with the environmental quality standard of the WFD for three of the four metals. It was shown that the four heavy metals could be detected simultaneously in the concentration ratio usually measured in sewage or runoff waters. PMID- 22510092 TI - Enhanced release of anticancer agents from nanoliposomes in response to diagnostic ultrasound energy levels. AB - The efficacy of diagnostic ultrasound is explored for the release of anticancer agents loaded inside liposomes. Diagnostic ultrasound energy levels employed in the study were at a frequency of 7.5 MHz and the highest power intensity which is a function of the pulse repetition time. Design of Experiments was used to formulate the Ultrasound sensitive nanoliposome (USNL) by varying the lipid ratios and the intensity settings of ultrasound energy. Doxorubicin was loaded into the USNL and the release was compared to conventional Doxil liposomes. The USNLs released increasing amounts of drug in response to increasing irradiation times while the drug release was not significant when the Non-USNLs (Doxil liposomes) were exposed to ultrasound energy levels. In vitro studies to test the cytotoxicity of the formulations showed that the USNLs significantly inhibited cell survival of SCC9, squamous oral cancer cells, as compared to the Non-USNLs. We hypothesize that the drug is released due to increased membrane permeability during exposure to ultrasound energy levels, where the lipid composition and energy levels play a key role in determining the efficacy of diagnostic ultrasound energy as a tool for drug delivery. PMID- 22510093 TI - A synthetic approach to diverse 3-acyltetramic acids via O- to C-acyl rearrangement and application to the total synthesis of penicillenol series. AB - For the efficient approach to medicinally important alpha-branched 3-acyltetramic acids, the key reaction of O- to C- acyl rearrangement using alpha-amino-acid derived 4-O-acyltetramic acids was extensively examined in the presence of various metal salts. Use of CaCl(2) or NaI dramatically changed the results in the reaction efficiency and rapidly brought about the desired alpha-branched 3 acyltetramic acids in markedly improved yields. We also discuss an epimerization at C5 stereocenter under the rearrangement conditions as well as the tolerance for structural variation at C3 and C5. In addition to the preceding success in the total synthesis of new cytotoxic tetramic acid, penicillenol A(1), this methodology could be also applied to the first total synthesis of penicillenol A(2). PMID- 22510094 TI - Membrane-based energy efficient dewatering of microalgae in biofuels production and recovery of value added co-products. AB - The objective of this paper is to describe the use of membranes for energy efficient biomass harvesting and dewatering. The dewatering of Nannochloropsis sp. was evaluated with polymeric hollow fiber and tubular inorganic membranes to demonstrate the capabilities of a membrane-based system to achieve microalgal biomass of >150 g/L (dry wt.) and ~99% volume reduction through dewatering. The particle free filtrate containing the growth media is suitable for recycle and reuse. For cost-effective processing, hollow fiber membranes can be utilized to recover 90-95% media for recycle. Tubular membranes can provide additional media and water recovery to achieve target final concentrations. Based on the operating conditions used in this study and taking into scale-up considerations, an integrated hollow fiber-tubular membrane system can process microalgal biomass with at least 80% lower energy requirement compared to traditional processes. Backpulsing was found to be an effective flux maintenance strategy to minimize flux decline at high biomass concentration. An effective chemical cleaning protocol was developed for regeneration of fouled membranes. PMID- 22510095 TI - Effects of enzymatic hydrolysis of protein on the pasting properties of different types of wheat flour. AB - As one of the most effective methods to modify proteins, enzymatic hydrolysis is used widely in the preparation of wheat products in the food industry. During the same process, starch pasting occurs frequently. The effects of wheat protein hydrolysis with papain, pepsin, and trypsin on the pasting properties of 3 different kinds of flour were investigated in 5 concentrations. Results showed that the peak viscosity, trough, final, and integral area of pasting curve of these flours decreased with increasing enzymatic hydrolysis of protein, and decreased significantly with the increasing enzyme concentrations. Medium-gluten flour was the least sensitive to enzymatic activity and weak-gluten the most sensitive. Downtrends appeared with increasing papain and trypsin concentrations in the form of breakdown. Enzymes had no significant different effect on the peak times of strong- and medium-gluten flour, but prolonged peak time slightly in weak-gluten flour. The pasting time and temperature of strong- and medium-gluten flour were significantly increased in a concentration-dependent manner. However, there were no significant effects on the pasting times of weak-gluten flour. These results could supply a basis for utilization of enzymatic hydrolysis of wheat protein in food industry and for further studies into the interactions between hydrolyzed protein and starch in food or processing industries. PMID- 22510096 TI - HIV-HCV co-infection facing HCV protease inhibitor licensing: implications for clinicians. AB - With the licensing of the first hepatitis C (HCV) protease inhibitors (PI), telaprevir (TVR) and boceprevir (BOC), cure rates for chronic HCV infection will substantially improve. Human immunodeficiency virus- chronic hepatitis C (HIV HCV) co-infected patients are in urgent need for these new drugs, because they are facing both severe liver disease and lower response rates than HCV monoinfected patients. The currently available efficacy data are however, limited to two phase II trials. Fortunately, TVR and BOC appear to be able to improve cure rates in co-infected patients. A major challenge for clinicians will be the management of drug-drug interactions of antiretroviral drugs and new PI. As HCV PI are also metabolized by the cytochrome P450 3A4 system interactions are probable as well with non-nucleoside reverse transcriptase inhibitors as with HIV PI. To our knowledge, TVR can only be safely used with one protease inhibitor, boosted atazanavir, and also with efavirenz (EFV), although this combination requires TVR dose adjustments. Boceprevir should not be combined with HIV PI and should not be combined with EFV. The approval of TVR and BOC will create new chances of cure also for HIV-HCV co-infected patients. However, the decision who to treat or not has to be taken carefully on the basis of fibrosis stage and previous treatment outcomes. In addition, HIV therapy needs to be optimized according to the available drug-drug interaction data. PMID- 22510097 TI - Asymmetric cortical surface area and morphology changes in mesial temporal lobe epilepsy with hippocampal sclerosis. AB - PURPOSE: To date, magnetic resonance imaging (MRI)-based studies of the cerebral cortex in mesial temporal lobe epilepsy (MTLE) have focused primarily on investigating cortical volume and thickness. However, volume is a composite of surface area and thickness, each reflecting distinct neurobiologic and genetic processes. The goal of this study was to investigate cerebral cortex (1) surface area, (2) surface geometric distortion, and (3) thickness in MTLE with hippocampal sclerosis (HS). METHODS: Seventy patients with "sporadic" unilateral MTLE + HS and 40 healthy controls underwent T(1) -weighted MRI. Processing MR images using an automated cortical surface reconstruction method (FreeSurfer), we quantified cortical surface area, surface geometric distortion (metric distortion), and thickness at each vertex across the entire cortex. Differences between patients and controls were determined using generalized linear models. Separate linear regression models were employed to assess the relationship between cortical surface area and hippocampal volume as well as a series of important clinical features of the condition. KEY FINDINGS: We detected an asymmetric reduction in cortical surface area, predominantly in ipsilateral mesial and anterior temporal lobe subregions, of patients with MTLE + HS. Changes in surface geometric features were also evident and closely mirrored surface area patterns. In contrast, cortical thinning appeared dispersed across the cortex bilaterally. The regression models revealed that ipsilateral hippocampal volume was a significant predictor of temporal lobe surface area changes. SIGNIFICANCE: Our findings indicate that contraction in surface area, rather than cortical thinning, explains ipsilateral mesial and anterior temporal lobe atrophy in patients with MTLE with HS. Furthermore, the alterations in surface geometry indicate folding abnormality involving the same regions. Cortical surface changes may represent sequelae of the disease or deviant cortical development. PMID- 22510098 TI - Complex evolutionary history and diverse domain organization of SET proteins suggest divergent regulatory interactions. AB - * Plants and animals possess very different developmental processes, yet share conserved epigenetic regulatory mechanisms, such as histone modifications. One of the most important forms of histone modification is methylation on lysine residues of the tails, carried out by members of the SET protein family, which are widespread in eukaryotes. * We analyzed molecular evolution by comparative genomics and phylogenetics of the SET genes from plant and animal genomes, grouping SET genes into several subfamilies and uncovering numerous gene duplications, particularly in the Suv, Ash, Trx and E(z) subfamilies. * Domain organizations differ between different subfamilies and between plant and animal SET proteins in some subfamilies, and support the grouping of SET genes into seven main subfamilies, suggesting that SET proteins have acquired distinctive regulatory interactions during evolution. We detected evidence for independent evolution of domain organization in different lineages, including recruitment of new domains following some duplications. * More recent duplications in both vertebrates and land plants are probably the result of whole-genome or segmental duplications. The evolution of the SET gene family shows that gene duplications caused by segmental duplications and other mechanisms have probably contributed to the complexity of epigenetic regulation, providing insights into the evolution of the regulation of chromatin structure. PMID- 22510099 TI - DNA-binding studies of fluoxetine antidepressant. AB - Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) antidepressant that is widely prescribed. The DNA-binding behavior of fluoxetine antidepressant and calf thymus DNA was investigated in Tris-HCl buffer at physiological pH 7.4 with a series of techniques, including UV-Vis and circular dichroism spectroscopies, competitive study with Hoechst 33258, viscometry, and cyclic voltammetry. Fluoxetine molecules bind to DNA via groove mode as illustrated by hypochromism with no red shift in the UV absorption band of fluoxetine, decrease in Hoechst DNA solution fluorescence, and no significant changes in viscosity of DNA. The CD spectra of DNA molecules show a little change in stacking mode of base pair but no modification changes in DNA conformation, for example, from B-DNA to A or C DNA. The binding constant (K(b)) of DNA with fluoxetine was calculated to be 6.7 * 10(4) M(-1), which is in the range of reported and known groove binders, such as distamycin. All results showed the groove-binding mode of interaction of fluoxetine with DNA. PMID- 22510100 TI - Polycyclic aromatic triptycenes: oxygen substitution cyclization strategies. AB - The cyclization and planarization of polycyclic aromatic hydrocarbons with concomitant oxygen substitution was achieved through acid catalyzed transetherification and oxygen-radical reactions. The triptycene scaffold enforces proximity of the alcohol and arene reacting partners and confers significant rigidity to the resulting pi-system, expanding the tool set of iptycenes for materials applications. PMID- 22510101 TI - Fraction of macroporous resin from Smilax china L. inhibits testosterone propionate-induced prostatic hyperplasia in castrated rats. AB - The present study was conducted to evaluate the effect of a fraction of macroporous resin (FMR), a bioactive component of Smilax china L., on benign prostatic hyperplasia (BPH) in castrated rats induced by testosterone propionate. Rats were randomly divided into five groups: the negative control group (sham operated), the model group, two FMR-treated groups (at doses of 300 mg/kg and 600 mg/kg of body weight), and the positive control group (treated with finasteride at the dose of 3 mg/kg). Drugs were administered once a day for three consecutive weeks by gastric gavage. Prostates were weighed, testosterone and dihydrotestosterone (DHT) levels in serum were determined, and histopathological examinations were carried out. FMR treatment inhibited prostatic hyperplasia, reducing the DHT level in serum and improving the prostate gland morphology compared with the model group. The overall results of this study suggest that FMR is effective at inhibiting experimentally induced prostate enlargement, and it presents a valuable resource for the treatment of human BPH. PMID- 22510102 TI - Serum and liver tissue bio-element levels, and antioxidant enzyme activities in carbon tetrachloride-induced hepatotoxicity: protective effects of royal jelly. AB - The liver is a vital organ, and its function is generally impaired by chemicals. Some natural compounds have a protective role against liver diseases such as royal jelly (RJ). To our knowledge, there are no data available on the effect of RJ therapy on the levels of bio-element metabolisms and antioxidant enzyme activities in the carbon tetrachloride (CCl(4))-induced liver damage. Therefore, in the present study, we have investigated the role of RJ therapy in the trace and major elements and antioxidant enzymes in CCl(4)-induced hepatotoxicity in rats. Antioxidant enzyme activities decreased in the CCl(4)-treated group more than they did in the sham and RJ-administered groups. Many bio-element levels were also reduced in only the CCl(4)-treated group. This showed that the depletion of trace elements was related to erythrocyte antioxidant enzyme activities. RJ administration clearly increased the trace and major element levels and antioxidant enzyme activities in RJ groups. RJ may be used as functional foods because of their naturally high antioxidant potential and rich element content. PMID- 22510103 TI - Bioinspired synthesis of multifunctional inorganic and bio-organic hybrid materials. AB - Owing to their physical and chemical properties, inorganic functional materials have tremendous impacts on key technologies such as energy generation and storage, information, medicine, and automotive engineering. Nature, on the other hand, provides evolution-optimized processes, which lead to multifunctional inorganic-bio-organic materials with complex structures. Their formation occurs under physiological conditions, and is goverened by a combination of highly regulated biological processes and intrinsic chemical properties. Nevertheless, insights into the molecular mechanisms of biomineralization open up promising perspectives for bioinspired and biomimetic design and the development of inorganic-bio-organic multifunctional hybrids. Therefore, biomimetic approaches may disclose new synthetic routes under ambient conditions by integrating the concept of gene-regulated biomineralization principles. The skeletal structures of marine sponges provide an interesting example of biosilicification via enzymatically controlled and gene-regulated silica metabolism. Spicule formation is initiated intracellularly by a fine-tuned genetic mechanism, which involves silica deposition in vesicles (silicassomes) under the control of the enzyme silicatein, which has both catalytic and templating functions. In this review, we place an emphasis on the fabrication of biologically inspired materials with silicatein as a biocatalyst. PMID- 22510104 TI - Sex-specific associations between soft tissue body composition and bone mineral density among older adults. AB - AIM: This paper examines sex specific associations between soft tissue body composition (lean and fat mass) and bone mineral density among older adults. SUBJECTS AND METHODS: Two hundred and eighty-two subjects (152 females and 130 males) aged 60-92 years ((x))= 71.9 +/- 7.9) were enrolled. Body composition of the whole body and bone density (BMD) of the whole body and the femoral neckwere measured by dual energy x-ray absorptiometry. Body mass index (BMI), relative appendicular skeletal muscle mass (RASM) and relative total muscle mass (RTSM) were calculated. Subjects were categorized based on sarcopenia, i.e. reduced appendicular skeletal muscle mass, osteopenia and osteoporosis. BMD of the femoral neck was used to categorize osteopenia and osteoporosis. RESULTS: Sex specific correlation patterns between soft tissue body composition and bone density were observed. Lean body mass (RASM and RTSM) correlated significantly with total and femoral neck bone density in men, absolute and relative fat mass were significantly related to whole and femoral neck bone density among women only. Sarcopenic men suffered significantly more frequently from osteopenia and osteoporosis than their non-sarcopenic counterparts. Among females sarcopenia was not related to reduced bone density. CONCLUSIONS: The impact of soft tissue body composition on bone density is different among men and women at older ages. A significant relation between muscle mass and bone density is found among elderly males only. PMID- 22510105 TI - The interaction of leukocytes and adhesion molecules in mesenteric microvessel endothelial cells after internal capsule hemorrhage. AB - OBJECTIVE: To explore the correlation between hemorheological variations and the expression of cell adhesion molecules in mesenteric microvessel endothelial cells after internal capsule hemorrhage. METHODS: We established an internal capsule hemorrhage model. Then leukocyte-endothelium interaction was observed and hemorheological variations in mesenteric microvessels were evaluated in the following aspects: blood flow volume, diameter of microvessels, blood flow rate, and shear rate. We also measured the expression of vascular cell adhesion molecule-l and intercellular adhesion molecule-1 (ICAM-1) in mesenteric microvessel endothelial cells with immunohistochemistry stain. RESULTS: Leukocyte endothelium interaction intensified after internal capsule hemorrhage. Besides, blood flow volume and velocity decreased, diameter narrowed, and shear rate reduced. Immunohistochemical staining of vascular cell adhesion molecule-l and ICAM-1in mesenteric microvessel endothelial cells was stronger. CONCLUSIONS: VCAM 1 and ICAM-1 expression in mesenteric microvessels increased as a result of decreased wall shear stress in stress state following internal capsule hemorrhage, and then further shear stress change from interaction of enhanced production of CAMs and leukocytes created a vicious cycle of leukocytes margination, adhesion, and transmigration that could ultimately result in stress gastrointestinal ulcer. PMID- 22510106 TI - On the interaction of aliphatic amines and ammonium ions with carboxylic acids in solution and in receptor pockets. AB - Association energies of the acetate ion with cationic amines bearing one to three methyl groups were calculated in the range of -14 to -17 kcal/mol in aqueous solution by means of the IEF-PCM method at the CCSD(T)/CBS//MP2/aug-cc-pvdz and DFT/B97D/CBS//B97D/aug-cc-pvtz levels. The main stabilization factor for the association is the possibility for the formation of an ionic intermolecular hydrogen bond between the elements of the complex. For a quaternary ammonium ion, the favorable electrostatic interaction energy is the only driving force, and the stabilization energy for the complex is reduced to -4 kcal/mol. The internal free energies of the ion-pair tautomers of the studied species are higher by 10-15 kcal/mol in water than those for the neutral, hydrogen-bonded forms. Monte Carlo free energy perturbation calculations at T = 298 K and p = 1 atm predict -11 to 16 kcal/mol relative solvation free energy in favor of the corresponding ionic form. As a result, the ion-pair tautomer is the prevailing form in aqueous solution and on the extracellular surface of a receptor. Modeling the complex of a protonated ligand interacting with an Asp/Glu carboxylate side-chain in the binding cavity of a receptor, two strongly bound water molecules were considered so as to form hydrogen-bonded water bridges between the elements of the ion-pair. Nonetheless, the low polarity environment mimicked by a chloroform solvent cannot stabilize the ionic tautomer. A proton jump was predicted, which suggests that acetylcholine, an inherent cation by structure, might have evolved as the natural agonist for muscarinic receptors because a quaternary ammonium system assures the maintenance of the ion-pair form with a carboxylate side-chain in a protein cavity, the latter perhaps then being needed for receptor activation. PMID- 22510107 TI - Conformational control of hydrogen-bonded aromatic bis-ureas. AB - The phenylurea moiety is a ubiquitous synthon in supramolecular chemistry because it contains strong complementary hydrogen bonding groups and is synthetically very accessible. Here we investigate the possibility to strengthen self association by conformational preorganization of the phenylurea moiety. In fact, we show that it is possible to strongly enhance intermolecular interactions between hydrogen bonded aromatic bis-ureas by substitution at the ortho positions of the phenylurea groups. Ortho substituents enforce a noncoplanar conformation of the urea and phenyl moieties better suited for hydrogen bonding. Substitution by methyl groups is more efficient than with larger groups, probably because of reduced steric hindrance. These effects have been demonstrated in the case of two different supramolecular architectures, which points to the probable generality of the phenomenon. In addition, this study has led to the discovery of a new bis urea able to form very stable self-assembled nanotubes in toluene up to high temperatures (boiling point) or low concentrations (10(-7) M) and in chloroform down to 3 * 10(-4) M. PMID- 22510108 TI - Therapeutic strategies to protect the immature newborn myocardium during resuscitation following asphyxia. AB - Perinatal asphyxia contributes to over one million newborn deaths worldwide annually, and may progress to multiorgan failure. Cardiac dysfunction, of varying severity, is seen in 50%-70% of asphyxiated newborns. Resuscitation is necessary to restore oxygenation to deprived tissues, including the heart. However, reoxygenation of asphyxiated newborns may lead to generation of reactive oxygen species (ROS) and further myocardial damage, termed reperfusion injury. The newborn heart is especially vulnerable to oxidative stress and reperfusion injury due to immature antioxidant defense mechanisms and increased vulnerability to apoptosis. Currently, newborn myocardial protective strategies are aimed at reducing the generation of ROS through controlled reoxygenation, boosting antioxidant defenses, and attenuating cellular injury via mitochondrial stabilization. PMID- 22510109 TI - Ethanol, glutamate, and the ventral tegmental area--a commentary on: Ding, Engleman, Rodd, and McBride, "ethanol increases glutamate neurotransmission in the posterior ventral tegmental area of female wistar rats". AB - The recent study by Ding and colleagues (2012) utilized in vivo microdialysis to demonstrate that acute and repeated alcohol administration produces dose dependent effects on extracellular levels of the glutamate in the posterior ventral tegmental area. These findings have important implications for interactions between glutamatergic and dopaminergic mediation of alcohol reinforcement in the ventral midbrain. PMID- 22510110 TI - Heterogeneous glyoxal oxidation: a potential source of secondary organic aerosol. AB - Laboratory studies are described that suggest reactive uptake of glyoxal on particulate containing HNO(3) could contribute to the formation of secondary organic aerosol (SOA) in the upper troposphere (UT). Using a Knudsen cell flow reactor, glyoxal is observed to react on supercooled H(2)O/HNO(3) surfaces to form condensed-phase glyoxylic acid. This product was verified by derivatization and GC-MS analysis. The reactive uptake coefficient, gamma, of glyoxal varies only slightly with the pressure of nitric acid, from gamma = 0.5 to 3.0 * 10(-3) for nitric acid pressures between 10(-8) and 10(-6) Torr. The data do not show any dependence on temperature (181-201 K) or pressure of glyoxal (10(-7) to 10( 5) Torr). Using the determined reactive uptake kinetics in a simple model shows that glyoxal uptake to supercooled H(2)O/HNO(3) may account for 4-53% of the total organic mass fraction of aerosol in the UT. PMID- 22510111 TI - Biodiversity, metabolism and applications of acidophilic sulfur-metabolizing microorganisms. AB - Extremely acidic, sulfur-rich environments can be natural, such as solfatara fields in geothermal and volcanic areas, or anthropogenic, such as acid mine drainage waters. Many species of acidophilic bacteria and archaea are known to be involved in redox transformations of sulfur, using elemental sulfur and inorganic sulfur compounds as electron donors or acceptors in reactions involving between one and eight electrons. This minireview describes the nature and origins of acidic, sulfur-rich environments, the biodiversity of sulfur-metabolizing acidophiles, and how sulfur is metabolized and assimilated by acidophiles under aerobic and anaerobic conditions. Finally, existing and developing technologies that harness the abilities of sulfur-oxidizing and sulfate-reducing acidophiles to extract and capture metals, and to remediate sulfur-polluted waste waters are outlined. PMID- 22510113 TI - 'Growing up' with laparoscopic radical prostatectomy makes a difference in early independent surgical practice. PMID- 22510114 TI - The Australasian Vascular Audit: where there is a web, there is a way. PMID- 22510117 TI - Results from the Australasian Vascular Surgical Audit: the inaugural year. AB - The Australian and New Zealand Society for Vascular Surgery has incorporated a constitutional change to administer a self-funded compulsory vascular surgery audit since January 2010. This is a bi-national quality assurance activity that captures all procedures performed in both countries. Data is collected at two points in the clinical admission; at operation and at discharge and data entry is via the Internet. Security is stringent and confidentiality is guaranteed by Commonwealth privilege. Data privacy is maximized by encryption. The application is flexible and administered by a dedicated administrator with a help-desk facility. Reports are available to provide real-time feedback of user performance compared with the peer group data in key categories of arterial surgery. A structured hierarchy for data management has been established to assess four main categories of performance: mortality after aortic surgery, stroke and death after carotid surgery, patency and limb salvage after infrainguinal bypass and patency after arteriovenous access for haemodialysis. Data is analysed using risk adjustment techniques and an algorithm for management of underperformance has been followed. Data validation has been performed. The outcomes in all categories have been of a high standard and correction of erroneous data in a single statistical outlier has negated underperformance. The audit has captured only 65% of the estimated procedures in Australia in the first year, but data quality is good. The feasibility of a complete compulsory bi-national audit has now been established and will be the benchmark for other craft groups in the current environment of accountability. PMID- 22510118 TI - Meta-analysis of robot-assisted versus conventional laparoscopic Nissen fundoplication for gastro-oesophageal reflux disease. AB - BACKGROUND: Conventional laparoscopic Nissen fundoplication (CLF) is generally considered the surgical approach of choice for gastro-oesophageal reflux disease. Robotic-assisted laparoscopic fundoplication (RALF) has recently been introduced into laparoscopic clinical practice with the aim of improving surgical performance by eliminating tremors and fatigue. A meta-analysis of randomized clinical trials (RCTs) was performed to compare RALF and CLF. METHODS: Medline, Embase, ISI Web of Knowledge CPCI-S and The Cochrane Library were searched and the methodological quality of included trials was evaluated. Outcomes evaluated were intraoperative, dysphagia, flatulence, antisecretory medication, satisfaction with intervention, operation time, hospital stay and total cost. Results were pooled in meta-analyses as risk ratios and weighted mean differences (WMD). RESULTS: Of 221 patients in six RCTs, 111 were allocated to CLF and 110 to RALF. RALF prolonged total time necessary to carry out fundoplication (WMD 3.17 (95% confidence interval. 2.33-4.00) min; P < 0.00001, chi(2) P = 0.25, I(2) = 24%). Operation complication, antisecretory medication, satisfaction with intervention, the time needed for hiatal dissection, the time from incision to completion of sutures, the total operation time and total cost were similar in both groups. CONCLUSION: Clinical outcomes from RALF were comparable to CLF approach, but RALF prolonged the operation time. Currently, CLF should be routinely used as costs are lower. PMID- 22510119 TI - Review of treatment of acute scaphoid fractures: R1. AB - Scaphoid fractures are common. Clinical suspicion and early diagnosis and treatment are vital in order to avoid complications such as avascular necrosis. The management of these fractures depends on fracture characteristics, specifically the degree of displacement. With consideration of patient factors, such as occupation, the treatment can be non-operative or operative. There has been much debate in the recent literature regarding the best management of these fractures. The purpose of this review was to identify the current evidence for non-operative and operative treatment. Undisplaced and minimally displaced fractures can be managed non-operatively with a scaphoid cast. Surgical treatment is used for fractures with displacement of >1 mm. PMID- 22510120 TI - Extended endoscopic endonasal skull base surgery: from the sella to the anterior and posterior cranial fossa. AB - Skull base surgery has gone through significant changes with the development of extended endoscopic endonasal approaches over the last decade. Initially used for the transphenoidal removal of hypophyseal adenomas, the endoscopic transnasal approach gradually evolved into a way of accessing the whole ventral skull base. Improved visualization, avoidance of brain retraction, the ability to access directly tumours with minimal damage to critical neurosurgical structures as well lack of external scars are among its obvious benefits. However, it presents the surgeons with a number of challenges, including the need to deal endoscopically with potential arterial bleeding, complicated reconstruction requirements as well as the need for a true team approach. In this review drawing from our experience as well as published series, we present an overview of current indications, challenges and limitations of the expanded endonasal approaches to the skull base. PMID- 22510121 TI - Laparoscopic radical prostatectomy: introduction of training during our first 50 cases. AB - BACKGROUND: The study aims to assess the initial experience of laparoscopic radical prostatectomy (LRP) in a regional centre in Australia which includes Fellowship training during our first 50 cases. METHODS: Data were collected prospectively from our first 50 consecutive patients who underwent LRP for localized prostate cancer between September 2009 and October 2010. All cases were performed or supervised by the primary surgeon. Patient details, operative details, complications, early oncological and functional outcomes were analysed. RESULTS: The median age was 65 (45-76) years and median preoperative prostate specific antigen was 7.5 (2.5-23) ng/mL, with palpable disease present in 48%. Using D'Amico's risk stratification, 14%, 74% and 12% were in low, intermediate and high-risk categories, respectively. Forty percent of cases were training cases with a median of 5 (2-8) of 10 operative steps performed by the Fellow. There was one open conversion and no rectal injuries. Mean operative time was 288 (175-440) min and with blood transfusion rate of 6%. Mean length of stay was 2.5 (1-6) days. Positive surgical margin rates for pT2 and pT3 disease were 14% and 52%, respectively, although for the last 25 cases they were 7% and 30%, respectively. Continence rate was 86% at 6 months, and 45% and 33% of preoperatively potent patients were potent after bilateral and unilateral nerve preservation at 6 months. CONCLUSION: LRP has been safely introduced in a regional centre with establishment of a Fellowship training programme, with early results comparable with other open, laparoscopic and robotic series. PMID- 22510122 TI - Follicular thyroid cancer: minimally invasive tumours can give rise to metastases. AB - BACKGROUND: The histological characteristics of follicular thyroid carcinomas (FTCs) are important predictors of prognosis, and lesions can be classified as either minimally invasive follicular carcinoma (MIFC) or widely invasive follicular carcinoma (WIFC) based on histopathological characteristics. There has been controversy surrounding the histological classification of FTC, which can present challenges to clinicians attempting to deliver accurate prognostic information to their patients. The aim of the present study was to examine cases of metastatic FTC for characteristics that may predict aggressive tumour behaviour. METHODS: The Monash University Endocrine Surgery Unit database was searched for patients with FTC. The histopathology reports were collated for these patients to confirm the diagnosis of FTC, classify patients into MIFC versus WIFC, and examine for key characteristics such as the capsular and/or vascular invasion. The thyroid specimens from patients with metastatic FTC were examined by reviewing pathologists. It was hypothesized that patients with metastatic disease would likely have WIFC as their primary lesion. RESULTS: There were 64 patients with FTC identified during the period of 1997-2009. Of these, 10 patients were found to have metastatic disease. On review of the histopathology, three patients were found to have WIFC,four patients had MIFC and three patients did not have definite features of FTC found in the thyroid gland. CONCLUSION: Currently accepted histological classification of FTC is inadequate and fails to accurately predict patients with distant metastatic disease and a more aggressive clinical course. It is thus the policy of our unit to recommend total thyroidectomy and radioactive iodine ablation for all patients with FTC. PMID- 22510123 TI - Impact of F18-fluorodeoxyglycose positron emission tomography/computed tomography on the management of resectable pancreatic tumours. AB - BACKGROUND: Positron emission tomography/computed tomography (PET/CT) using F18 fluorodeoxyglucose has been shown to be valuable in the management of malignant disease. The aim of this study is to investigate the impact of this technique on the management of patients with resectable pancreatic tumours. METHODS: Thirty six patients with 37 potentially resectable pancreatic tumours on diagnostic CT imaging underwent PET/CT scans. Operative findings, histological reports and/or clinical follow-up served as standard of reference. The impact of PET/CT on patient management was estimated by calculating the percentage of patients whose treatment plan was altered due to PET/CT. RESULTS: Pancreatic adenocarcinoma was diagnosed in 30 patients, neuroendocrine tumours in 3, mass-forming pancreatitis in 3 and serous cystadenoma in 1. The median standard uptake (max) value was 5.0 (range 2.2-12.0). Sensitivity and specificity of detecting extrapancreatic metastatic disease were 73% and 100%, respectively. Three occult liver metastases were detected at laparotomy following negative PET/CT. PET/CT findings influenced the management of 8 (22%) patients - 3 with liver metastases, 3 with bone metastases, 1 with lymph node metastases and 1 by identifying the benign appearance of the pancreatic tumour. CONCLUSION: PET/CT achieves a significant diagnostic impact in detecting extrapancreatic metastatic disease. F18 fluorodeoxyglucose PET/CT appears to be useful in assessing suspicious pancreatic masses. PMID- 22510124 TI - Lost opportunity cost of surgical training in the Australian private sector. AB - BACKGROUND: To meet Australia's future demands, surgical training in the private sector will be required. The aim of this study was to estimate the time and lost opportunity cost of training in the private sector. METHODS: A literature search identified studies that compared the operation time required by a supervised trainee with a consultant. This time was costed using a business model. RESULTS: In 22 studies (34 operations), the median operation duration of a supervised trainee was 34% longer than the consultant. To complete a private training list in the same time as a consultant list, one major case would have to be dropped. A consultant's average lost opportunity cost was $1186 per list ($106,698 per year). Training in rooms and administration requirements increased this to $155,618 per year. To train 400 trainees in the private sector to college standards would require 54,000 training lists per year. The consultants' national lost opportunity cost would be $137 million per year. The average lost hospital case payment was $5894 per list, or $330 million per year nationally. The total lost opportunity cost of surgical training in the private sector would be about $467 million per year. When trainee salaries, other specialties and indirect expenses are included, the total cost will be substantially greater. CONCLUSION: It is unlikely that surgeons or hospitals will be prepared to absorb these costs. There needs to be a public debate about the funding implications of surgical training in the private sector. PMID- 22510125 TI - Efficacy of patient information concerning casts applied post-fracture. AB - INTRODUCTION: Serious complications can result when casts are used for bone immobilization following fracture. Adequate patient information regarding cast care and possible complications is vital for prevention. This study examines the effectiveness of verbal and written patient information regarding cast safety. METHODS: Patients (n= 109; age >=18 years) from three Western Australian teaching hospitals were interviewed using a custom-designed questionnaire. Patients' understanding of cast care and possible complications were tested by recall of seven categories of information, notably: pain, swelling, cast care, itching, neural signs, vascular signs/symptoms, exercise/rest. A follow-up phone call (3-8 weeks after initial interview) was conducted to elicit complications and determine information recall. RESULTS: Written information was received by 62% of patients; however, overall, only 35% claimed to have read the information provided. Of these, the highest recall was in four of seven information categories. A high proportion of those given only verbal information had poor recall (<=2 categories, defined a priori). In contrast, patients who also received written information had better recall (three or more categories, defined a priori, P= 0.031). Four of the 109 patients developed complications attributable to the cast (three had pressure ulcers and one had a deep vein thrombosis). CONCLUSION: Patient recall of information concerning cast care and possible complications was no more than 60%. The provision of written information was associated with a significantly higher awareness of possible complications. The results indicate that for fracture care, the delivery and use of information protocols can be greatly improved. PMID- 22510126 TI - Modular acute system for general surgery: hand over the operation, not the patient. AB - INTRODUCTION: Various models have been proposed to effectively provide acute surgical care in Australasia. Recently, General Surgeons Australia (GSA) has published a 12-point plan with guiding principles on this matter. This study describes a model of providing acute general surgical care in a high-volume institution, evaluates clinical outcomes and critically appraises the system against the GSA 12-point plan. METHODS: The acute care system is qualitatively described with quantitative measures of workload. The outcomes of acute laparoscopic cholecystectomy were used as a proxy of system performance. The system was critically appraised against the GSA 12-point plan. RESULTS: Teams are on call once per week with each surgeon on call once per fortnight. The three key elements of acute management - collecting patients, post-acute ward round and operating - are treated as modules. The patient remains under the care of the admitting consultant but is often operated on by another team. From June 2009 to 2010, there were 7429 acute general surgical admissions (mean: 20.4 patients per day) with 2999 acute operations (mean: 8.4 operations per day). The other activities of the department were not compromised. In that time, 388 acute laparoscopic cholecystectomies were performed with a conversion rate of 1.3% and no major bile duct injury. The system is compatible with the GSA 12-point plan. CONCLUSION: This study describes an efficient and safe system for providing acute general surgical care in a high-volume setting with satisfactory clinical outcomes. It is compatible with the GSA 12-point plan. PMID- 22510127 TI - Massive transfusion in trauma: blood product ratios should be measured at 6 hours. AB - BACKGROUND: Most potentially preventable haemorrhagic deaths occur within 6 h of injury. Conventionally, blood component therapy delivery is measured by 24-h cumulative totals and ratios. The study aim was to examine the effect of a massive transfusion protocol (MTP) on early (6 h) balanced component therapy. METHODS: An 88-month retrospective clinical study at a level 1 trauma centre was undertaken, examining consecutive trauma patients receiving >=10 units of packed red blood cells (PRBCs) within 24 h, before (pre-MTP) and after implementation of MTP. Demographic data, injury severity score (ISS), abbreviated injury scale (AIS), shock parameters, coagulation profile, the need for surgical intervention (<24 h), mortality and intensive care unit length of stay were collected. The ratios of blood products given by 6 h, by 24 h and the time between administrations of components was collected and analysed. RESULTS: Pre-MTP and MTP patients had similar demographics, shock severity and initial laboratory findings. Despite MTP patients having had a higher ISS (42 +/- 12 versus 36 +/- 12, P < 0.05) and AIS head score (2.6 +/- 1.8 versus 1.6 +/- 2.0, P < 0.05), there was no difference in mortality. Area under the curve (AUC) of the MTP period showed earlier delivery of higher median ratios of fresh frozen plasma (FFP)/PRBC (P= 0.004). Similar findings were found for cryoprecipitate/PRBC and platelet/PRBC ratios. By 24 h, the AUC for FFP/PRBC ratios were no different. DISCUSSION: Implementation of MTP resulted in earlier balanced transfusion. The difference between the FFP/PRBC ratios of the two types of resuscitations levelled by 24 h. The efficacy of component therapy delivery should be measured earlier than 24 h. PMID- 22510128 TI - Surgical excision of intraductal breast papilloma diagnosed on core biopsy. AB - BACKGROUND: The need for surgical excision of benign papillary lesions diagnosed on core biopsy remains debatable. This lack of consensus arises because although there is a possibility of histological underestimation, there are as yet no reliable predictors of malignancy. We therefore aimed to evaluate the incidence of histological underestimation in our practice, and to identify factors that predict for this, in order to reduce unnecessary surgery without missing out on possible malignancy. METHODS: Retrospective review of 106 patients diagnosed with a papillary lesion on percutaneous image-guided core biopsy was performed between 1 January 2005 and 31 December 2008. The presence of atypia on core biopsy and the presence of malignancy in the surgical specimen were correlated with standard clinical, radiological and pathological features. RESULTS: Histological underestimation occurred in 15 of 81 patients (19%). Malignancy was more likely when atypia was present in the core biopsy (P= 0.04, OR 5.17). Otherwise, a final diagnosis of malignancy was not correlated with any clinical or radiological features (P > 0.05). The presence of atypia was also not correlated with any clinical or radiological features. CONCLUSION: In our study, 19% of patients with a benign papillary lesion diagnosed on core biopsy were found to have atypical ductal hyperplasia or malignancy following surgery. In view of this, together with the absence of reliable predictive factors for malignancy, we recommend surgical excision of all papillary lesions diagnosed on core biopsy. PMID- 22510129 TI - Long-term changes in body composition after pancreaticoduodenectomy. AB - BACKGROUND: The Whipple's procedure (WP) is a major operation that adds a further demand on the body's nutritional reserves and therefore body composition after the effect of pancreatic cancer. The aim was to document changes in body composition changes that occur during the first six months after a WP for a pancreatic cancer malignancy. METHODS: Twenty-seven (14 males, 13 females) consecutive WP patients had body composition measured at baseline and then at 2, 5, 14 and 26 weeks after surgery. These included; anthropometric measure (weight, skin folds and arm muscle area (AMA)), total body measures of protein (TBP), potassium (TBK), water (TBW) and fat mass (FM). Changes were compared using repeated measures analysis of variance. RESULTS: Hospital nutritional care maintained TBP and TBK but at 2 weeks there was a loss of FM (P= 0.037). The nadir of weight loss (P < 0.001) occurred at 5 weeks because of losses of protein (P= 0.007), fat (P < 0.001) and potassium (P= 0.045) but not water. Although weight and FM were still significantly less than baseline measures at 26 weeks weight, TBP, TBK and AMA were not significantly different to preoperative values. CONCLUSIONS: Although at 6 months, important measures of the metabolically functioning tissue, TBP and TBK, have returned to preoperative values significant losses occurred during the first 3 weeks after discharge from hospital and FM did not return to preoperative values. These results suggest the need to improve post discharge nutritional care. PMID- 22510130 TI - Great auricular nerve perineural spread of squamous cell carcinoma. PMID- 22510131 TI - Don't sit on chronic inflammation. PMID- 22510132 TI - Hepatic artery aneurysm. PMID- 22510133 TI - ABC approach to history taking in the bariatric patient. PMID- 22510134 TI - Suction tip: a potential source of infection in clean orthopaedic procedures. PMID- 22510135 TI - Use of loupes in urology. PMID- 22510136 TI - Survival of patient after aorto-oesophageal fistula following button battery ingestion. PMID- 22510137 TI - Renal cell carcinoma in tuberous sclerosis. PMID- 22510138 TI - Superior non-migration of radioactive seed for impalpable breast lesion localization. PMID- 22510139 TI - Post-thyroidectomy hoarseness caused by arytenoid cartilage subluxation. PMID- 22510140 TI - Human papilloma virus in oropharyngeal cancers (Re: ANZ J. Surg. 2011; 81: 581 3). PMID- 22510141 TI - Foregut cyst associated with thyroid cancer. PMID- 22510142 TI - Operative experience of general surgeons in a rural hospital (Re: ANZ J. Surg. 2011; 81: 601-3). PMID- 22510144 TI - GH levels and insulin sensitivity are differently associated with biomarkers of cardiovascular disease in active acromegaly. AB - CONTEXT: Acromegaly is characterized by GH excess and insulin resistance. It is not known which of these disorders is responsible for the increased atherogenic risk in these patients. OBJECTIVE: To analyse the associations of GH and homoeostasis model assessment (HOMA) with biomarkers of cardiovascular disease and to compare the above-mentioned variables between patients with active acromegaly and controls. DESIGN AND SETTING: This open cross-sectional study was conducted at a University Hospital. PATIENTS: Twenty-two outpatients were compared with sex- and age-matched control subjects. MAIN OUTCOMES: Included clinical features, hormonal status, markers of insulin resistance, lipoprotein profile and biomarkers of cardiovascular disease. RESULTS: Patients presented higher triglyceride (median [IQR]) (1.2[1.1-1.6] vs 0.9[0.6-1.1] mm, P < 0.05), low-density lipoprotein-cholesterol (LDL-C) (mean +/- SD) (3.5 +/- 0.9 vs 3.0 +/- 0.7mm, P < 0.05), apoB (0.98 +/- 0.23 vs 0.77 +/- 0.22 g/l, P < 0.05), free fatty acid (0.69 +/- 0.2 vs 0.54 +/- 0.2 mM, P < 0.05), oxidized-LDL (120 +/- 22 vs 85 +/- 19 U/l, P < 0.05) and endothelin-1 (0.90 +/- 0.23 vs 0.72 +/- 0.17 ng/l, P < 0.05) levels, increased cholesteryl ester transfer protein (CETP) activity (179 +/- 27 vs 138 +/- 30%/ml/h, P < 0.01) and lower C reactive protein (CRP) (0.25[0.1-0.9] vs 0.85[0.4-1.4] mg/l; P < 0.05) levels than control subjects. Vascular cell adhesion molecule (VCAM-1) concentration was not different. By multiple linear regression analyses, HOMA explained the variability of triglycerides (25%), high-density lipoprotein-cholesterol (HDL-C) (30%) and CETP activity (28%), while GH independently predicted LDL-C (18%), oxidized-LDL (40%) and endothelin-1 levels (19%). CONCLUSIONS: In patients with active acromegaly, GH excess contributes to the development of insulin resistance, and the interaction between both disturbances would be responsible for the appearance of atherogenic pro-oxidative and pro-inflammatory factors. Insulin resistance would be preferably associated with an atherogenic lipoprotein profile and to high CETP activity, while high GH levels would independently predict the increase in LDL-C, ox-LDL and endothelin-1. PMID- 22510143 TI - BactQuant: an enhanced broad-coverage bacterial quantitative real-time PCR assay. AB - BACKGROUND: Bacterial load quantification is a critical component of bacterial community analysis, but a culture-independent method capable of detecting and quantifying diverse bacteria is needed. Based on our analysis of a diverse collection of 16 S rRNA gene sequences, we designed a broad-coverage quantitative real-time PCR (qPCR) assay--BactQuant--for quantifying 16 S rRNA gene copy number and estimating bacterial load. We further utilized in silico evaluation to complement laboratory-based qPCR characterization to validate BactQuant. METHODS: The aligned core set of 4,938 16 S rRNA gene sequences in the Greengenes database were analyzed for assay design. Cloned plasmid standards were generated and quantified using a qPCR-based approach. Coverage analysis was performed computationally using >670,000 sequences and further evaluated following the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. RESULTS: A bacterial TaqMan(r) qPCR assay targeting a 466 bp region in V3-V4 was designed. Coverage analysis showed that 91% of the phyla, 96% of the genera, and >80% of the 89,537 species analyzed contained at least one perfect sequence match to the BactQuant assay. Of the 106 bacterial species evaluated, amplification efficiencies ranged from 81 to 120%, with r2-value of >0.99, including species with sequence mismatches. Inter- and intra-run coefficient of variance was <3% and <16% for Ct and copy number, respectively. CONCLUSIONS: The BactQuant assay offers significantly broader coverage than a previously reported universal bacterial quantification assay BactQuant in vitro performance was better than the in silico predictions. PMID- 22510145 TI - Natural history of chronic hepatitis B: what exactly has REVEAL revealed? AB - Chronic hepatitis B virus (HBV) infection is a serious public health problem because of its worldwide prevalence and potential to cause adverse consequences. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer Hepatitis B Virus (REVEAL-HBV) study carried out in Taiwan was used to investigate the natural history of chronic hepatitis B. The REVEAL-HBV study has established an HBV viral load paradigm in the natural history of chronic hepatitis B (CHB). Serum HBV DNA level has been shown to be significantly and independently associated with incidence of hepatocellular carcinoma (HCC) and cirrhosis and liver-related mortality across a biological gradient. It is also a major predictor of HBsAg seroclearance. Genetic features including HBV genotype and basal core promoter A1762T/G1764A mutant, and precore G1896A mutant were documented as predictors of HCC risk. Inactive HBV carriers still had an increased risk on HCC development and liver-related mortality compared with HBsAg -seronegatives. Nomograms focusing on facilitating risk communication between patients and clinicians were developed incorporating non-invasive clinical parameters to predict long-term HCC risk. These will hopefully contribute to evidence-based decisions in the clinical management of CHB patients. A somewhat provocative and novel finding from the REVEAL-HBV study is the association of chronic HBV infection in active replication with an increased pancreatic cancer risk especially in women less than 50 years old. This finding will hopefully spur further research in this area seeking confirmatory evidence. Finally, we hope that the REVEAL-HBV study will continue to be a source of data to answer other important questions in chronic hepatitis B research going forward. PMID- 22510146 TI - Microwave-assisted synthesis and antioxidant properties of hydrazinyl thiazolyl coumarin derivatives. AB - BACKGROUND: Coumarin derivatives exhibit a wide range of biological properties including promising antioxidant activity. Furthermore, microwave-assisted organic synthesis has delivered rapid routes to N- and O-containing heterocycles, including coumarins and thiazoles. Combining these features, the use of microwave assisted processes will provide rapid access to a targeted coumarin library bearing a hydrazino pharmacophore for evaluation of antioxidant properties RESULTS: Microwave irradiation promoted 3 of the 4 steps in a rapid, convergent synthesis of a small library of hydrazinyl thiazolyl coumarin derivatives, all of which exhibited significant antioxidant activity comparable to that of the natural antioxidant quercetin, as established by DPPH and ABTS radical assays CONCLUSIONS: Microwave dielectric heating provides a rapid and expedient route to a series of hydrazinyl thiazolyl coumarins to investigate their radical scavenging properties. Given their favourable properties, in comparison with known antioxidants, these coumarin derivatives are promising leads for further development and optimization. PMID- 22510147 TI - Novel mouse mammary cell lines for in vivo bioluminescence imaging (BLI) of bone metastasis. AB - BACKGROUND: Tumor cell lines that can be tracked in vivo during tumorigenesis and metastasis provide vital tools for studying the specific cellular mechanisms that mediate these processes as well as investigating therapeutic targets to inhibit them. The goal of this study was to engineer imageable mouse mammary tumor cell lines with discrete propensities to metastasize to bone in vivo. Two novel luciferase expressing cell lines were developed and characterized for use in the study of breast cancer metastasis to bone in a syngeneic mouse model. RESULTS: The 4 T1.2 luc3 and 66c14 luc2 cell lines were shown to have high levels of bioluminescence intensity in vitro and in vivo after orthotopic injection into mouse mammary fat pads. The 4 T1.2 luc3 cell line was found to closely model the sites of metastases seen in human patients including lung, liver, and bone. Specifically, 4 T1.2 luc3 cells demonstrated a high incidence of metastasis to spine, with an ex-vivo BLI intensity three orders of magnitude above the commercially available 4 T1 luc2 cells. 66c14 luc2 cells also demonstrated metastasis to spine, which was lower than that of 4 T1.2 luc3 cells but higher than 4 T1 luc2 cells, in addition to previously unreported metastases in the liver. High osteolytic activity of the 4 T1.2 luc3 cells in vivo in the bone microenvironment was also detected. CONCLUSIONS: The engineered 4 T1.2 luc3 and 66c14 luc2 cell lines described in this study are valuable tools for studying the cellular events moderating the metastasis of breast tumor cells to bone. PMID- 22510148 TI - Natural variation in GA1 associates with floral morphology in Arabidopsis thaliana. AB - * The genetic architecture of floral traits is evolutionarily important due to the fitness consequences of quantitative variation in floral morphology. Yet, little is known about the genes underlying these traits in natural populations. Using Arabidopsis thaliana, we examine molecular variation at GIBBERELLIC ACID REQUIRING 1 (GA1) and test for associations with floral morphology. * We examined full-length sequence in 32 accessions and describe two haplotypes (comprising four nonsynonymous polymorphisms) in GA1 that segregate at intermediate frequencies. In 133 A. thaliana accessions, we test for genotype-phenotype associations and corroborate these findings in segregating progenies. * The two common GA1 haplotypes were associated with the length of petals, stamens, and to a lesser extent style-stigma length. Associations were confirmed in a segregating progeny developed from 19 accessions. We find analogous results in recombinant inbred lines of the Bayreuth * Shahdara cross, which differ only at one of 4 SNPs, suggesting that this SNP may contribute to the observed association. * Assuming GA1 causally affects floral organ size, it is interesting that adjacent petal and stamen whorls are most strongly affected. This pattern suggests that GA1 could contribute to the greater strength of petal-stamen correlations relative to other floral-length correlations observed in some Brassicaceous species. PMID- 22510149 TI - Double-hit BCL2/MYC translocations in a consecutive cohort of patients with large B-cell lymphoma - a single centre's experience. AB - Concurrent BCL2 and MYC translocations, so called double hit (DH), are a rare finding in large B-cell lymphoma (LBCL). Based on data from retrospective series, DH has been correlated with aggressive clinical behaviour and poor outcome. We conducted a consecutive study of DH incidence and correlation with pathologic and clinical characteristics, including response to Rituximab-containing chemotherapy and survival, in an unselected cohort of patients with LBCL. Translocations involving BCL2 and MYC loci were examined with fluorescent in situ hybridization (FISH) in 157 patients with diffuse large B-cell lymphoma (DLBCL) or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BCLU). The incidence of DH was 11% in the total cohort, 7% of primary LBCL and 21% of transformed LBCL. DH lymphomas were all GCB immunophenotype and were more often BCLU. No clinical characteristics were correlated with the presence of DH, which also had no impact on overall response rate (ORR), relapse rate or overall survival (OS). However, sub-stratification of DH lymphomas by FISH indicated a possible inferior survival related to immunoglobulin MYC translocation partner gene. Screening of patients with BCLU and DLBCL of GCB type for DH BCL2/MYC translocation including MYC translocation partner gene may provide important prognostic information. PMID- 22510150 TI - Two new Dy3 triangles with trinuclear circular helicates and their single molecule magnet behavior. AB - Self-assembly of polydentate Schiff base 2,6-diformyl-4-methylphenol di(benzoy1hydrazone) (H(3)L), with dysprosium thiocyanate and sodium azide, affords two novel trinuclear triangular circular helicate dysprosium(III) complexes, [Dy(3)(MU(3)-OCH(3))(2)(HL)(3)(SCN)].4CH(3)OH.2CH(3)CN.2H(2)O (1) or [Dy(3)(MU(3)-N(3))(MU(3)-OH)(H(2)L)(3)(SCN)(3)](SCN).3CH(3)OH.H(2)O (2), depending on the presence or absence of base. Single-crystal X-ray analyses show that two MU(3)-methoxy oxygens cap the Dy(3) triangle in complex 1 and that one MU(3)-OH and one MU(3)-N(3)(-) cap the Dy(3) triangle of complex 2, representing the first example of a MU(3)-N(3)(-)-capped lanthanide complex reported to date. Ac susceptibility measurements reveal that multiple relaxation processes and the onset of slow magnetization relaxation occur for complex 1 and 2, respectively. Theoretical calculations are required to elucidate the underlying mechanism; however, the different magnetic anisotropy of the respective structures, which is dictated by the coordination environment of Dy(III) ions and structural parameters of the triangles, is mostly responsible for the distinctive relaxation dynamics observed. PMID- 22510151 TI - Exposure to probiotic Lactobacillus acidophilus L-92 modulates gene expression profiles of epithelial Caco-2 cells. AB - To understand host gastrointestinal response after exposure to probiotic Lactobacillus acidophilus L-92, microarray analysis of cultured epithelial Caco-2 cells was performed. Of the 187 genes down-regulated after 4 h treatment with L 92, 25 were involved in RNA splicing; 12, in cell cycle; 8 were transcriptional regulators; 2 were involved in ubiquitin proteolysis; 2, in adhesion; 2, in meiosis; 2, in splicing; and 2 encoding cytokines. In the RNA splicing group, genes encoding small nuclear RNAs, nuclear pore complex interacting proteins, RNA binding motif proteins, and SMG1 homologs (phosphatidylinositol 3-kinase-related kinase) were identified. Among the only 13 genes up-regulated by the treatment, 5 were involved in histone structure, and 2 were involved in metabolism. Genes belonging to cell adhesion, transmembrane proteins, mitogen-activated protein kinase, immune response, DNA binding, inflammation, and protein synthesis groups were mainly up-regulated after 20 h of treatment, whereas no significantly down regulated genes were observed. In the present transcriptome analysis, during the early stage of treatment (four hours of treatment) with L-92, genes involved in cell growth and cell meiosis were mainly repressed. During the late phase of treatment (20 h of treatment), the expression of the genes linked to cell adhesion activity and metabolism for cell growth was enhanced. From the present transcriptome analysis, we suggest that Caco-2 cells slow down cell death and turnover of RNA synthesis as an early response to L-92 treatment; at the late stage of treatment, the genes involved in cell proliferation, transcriptional activity, and apoptosis are activated. PMID- 22510152 TI - 2,5-dihydroxyacetophenone isolated from Rehmanniae Radix Preparata inhibits inflammatory responses in lipopolysaccharide-stimulated RAW264.7 macrophages. AB - Rehmanniae Radix Preparata, the steamed root of Rehmannia glutinosa Libosch, has been widely used for the treatment of inflammatory conditions in Oriental medicines. In this study we evaluated the effects of 2,5-dihydroxyacetophenone (DHAP) isolated from Rehmanniae Radix Preparata on inflammatory responses in lipopolysaccharide (LPS)-stimulated RAW264.7 mouse macrophages. LPS-stimulated RAW264.7 cells were used to investigate the anti-inflammatory activity of DHAP on the production of inflammatory mediators such as nitric oxide (NO), inducible NO synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-6. DHAP significantly inhibited NO production via the suppression of iNOS expression and significantly decreased levels of the pro-inflammatory cytokines TNF-alpha and IL-6 via the down-regulation of their mRNA expression in LPS-stimulated RAW264.7 cells. DHAP potently inhibited the phosphorylation of extracellular signal-related kinase (ERK) 1/2 and the nuclear translocation of nuclear factor kappaB (NF-kappaB) p65 in LPS-stimulated cells. These results indicate that DHAP inhibits the production of inflammatory mediators in activated macrophages by blocking the ERK1/2 and NF-kappaB signaling pathways. Our results suggest that DHAP from Rehmanniae Radix Preparata has anti-inflammatory activity in activated macrophages, raising the possibility that this compound has a therapeutic potential for inflammatory conditions. PMID- 22510153 TI - Dynamic windowing algorithm for the fast and accurate determination of luminescence lifetimes. AB - An algorithm for the accurate calculation of luminescence lifetimes in near-real time is described. The dynamic rapid lifetime determination (DRLD) method uses a window-summing technique and dynamically selects the appropriate window width for each lifetime decay such that a large range of lifetimes can be accurately calculated. The selection of window width is based on an optimal range of window sum ratios. The algorithm was compared to alternative approaches for rapid lifetime determination as well as nonlinear least-squares (NLLS) fitting in both simulated and real experimental conditions. A palladium porphyrin was used as a model luminophore to quantitatively evaluate the algorithm in a dynamic situation, where oxygen concentration was modulated to induce a change in lifetime. Unlike other window-summing techniques, the new algorithm calculates lifetimes that are not significantly different than the slower, traditional NLLS. In addition, the computation time required to calculate the lifetime is 4 orders of magnitude less than NLLS and 2 orders less than other iterative methods. This advance will improve the accuracy of real-time measurements that must be made on samples that are expected to exhibit widely varying lifetimes, such as sensors and biosensors. PMID- 22510155 TI - Mesenchymal stromal cell therapy and treatment of ischaemic disease. PMID- 22510154 TI - Illuminating the diversity of aromatic polyketide synthases in Aspergillus nidulans. AB - Genome sequencing has revealed that fungi have the ability to synthesize many more natural products (NPs) than are currently known, but methods for obtaining suitable expression of NPs have been inadequate. We have developed a successful strategy that bypasses normal regulatory mechanisms. By efficient gene targeting, we have replaced, en masse, the promoters of nonreducing polyketide synthase (NR PKS) genes, key genes in NP biosynthetic pathways, and other genes necessary for NR-PKS product formation or release. This has allowed us to determine the products of eight NR-PKSs of Aspergillus nidulans, including seven novel compounds, as well as the NR-PKS genes required for the synthesis of the toxins alternariol (8) and cichorine (19). PMID- 22510157 TI - Value of matrix-assisted laser desorption ionization-time of flight for routine identification of viridans group streptococci causing bloodstream infections. AB - Phenotypic tests do not always unequivocally identify some species of viridans group streptococci (VGS). sodA sequence analysis is the most accurate method for identification, although it requires specialized personnel and has not been applied systematically in clinical microbiology laboratory routines. Matrix assisted laser desorption ionization-time of flight (MALDI-TOF) is emerging as a rapid alternative for bacterial identification. This study assesses the ability of MALDI-TOF and the API 20 Strep system to identify VGS isolates recovered from blood cultures using sodA sequence analysis as the reference method. All clinically significant VGS isolates recovered from blood cultures between January 2007 and January 2010 were identified by sodA sequence analysis and API 20 Strep. The strains were then tested by MALDI-TOF. Agreement between API 20 Strep/MALDI TOF and sodA sequence analysis was determined. We examined 124 clinical isolates. Sensitivities of API 20 strep and MALDI-TOF for the species level identification of VGS isolates were, respectively, as follows: 60.5% and 73.4%. Sensitivities of API 20 strep and MALDI-TOF for the group level identification were, respectively, as follows: 70% and 94.3%. The turnaround times to identify VGS isolates by sodA sequence analysis, API 20 Strep and MALDI-TOF were 12-24, 24-48 h and 15 min, respectively. API 20 Strep cannot accurately identify all isolates of VGS. MALDI TOF appeared to be a rapid and reliable alternative for identification of VGS strains to group level, but was not able to discriminate closely related species of certain groups. PMID- 22510158 TI - Electron-induced elimination of the bromide anion from brominated nucleobases. A computational study. AB - The enhancement of radiodamage to DNA labeled with halonucleobases is attributed to the reactive radical produced from a halonucleobase by the attachment of an electron. We examined at the B3LYP/6-31++G** level electron capture by four brominated nucleobases (BrNBs): 8-bromo-9-methyladenine, 8-bromo-9-methylguanine, 5-bromo-1-methylcytosine, and 5-bromo-1-methyluracil followed by the release of the bromide anion and a nucleobase radical. We demonstrate that neutral BrNBs in both gas and aqueous phases are better electron acceptors than unsubstituted NBs and that resulting anion radicals, BrNBs(*-), can easily transform into the product complex of the bromide anion and the nucleobase radical ([Br( )...NB(*)]). The overall thermodynamic stimulus for the process starting with the neutral BrNB and ending with the isolated bromide anion and the NB(*) radical is similar in the case of all four BrNBs studied, which suggests their comparable radiosensitizing capabilities. PMID- 22510159 TI - Impact of e-resources on learning in biochemistry: first-year medical students' perceptions. AB - BACKGROUND: E-learning resources (e-resources) have been widely used to facilitate self-directed learning among medical students. The Department of Biochemistry at Christian Medical College (CMC), Vellore, India, has made available e-resources to first-year medical students to supplement conventional lecture-based teaching in the subject. This study was designed to assess students' perceptions of the impact of these e-resources on various aspects of their learning in biochemistry. METHODS: Sixty first-year medical students were the subjects of this study. At the end of the one-year course in biochemistry, the students were administered a questionnaire that asked them to assess the impact of the e-resources on various aspects of their learning in biochemistry. RESULTS: Ninety-eight percent of students had used the e-resources provided to varying extents. Most of them found the e-resources provided useful and of a high quality. The majority of them used these resources to prepare for periodic formative and final summative assessments in the course. The use of these resources increased steadily as the academic year progressed. Students said that the extent to which they understood the subject (83%) and their ability to answer questions in assessments (86%) had improved as a result of using these resources. They also said that they found biochemistry interesting (73%) and felt motivated to study the subject (59%). CONCLUSIONS: We found that first-year medical students extensively used the e-resources in biochemistry that were provided. They perceived that these resources had made a positive impact on various aspects of their learning in biochemistry. We conclude that e-resources are a useful supplement to conventional lecture-based teaching in the medical curriculum. PMID- 22510160 TI - Catheter ablation utilizing remote magnetic navigation: a review of applications and outcomes. AB - The utilization of the NIOBETM magnetic navigation system (MNS, Stereotaxis, St. Louis, MO, USA) has increased significantly since the first published report in 2002. There has been much enthusiasm for this technology as a means to reduce radiation exposure to the patient and physician alike, and potentially decrease risks associated with catheter manipulation by less experienced operators. However, there are limited data regarding the acute, intermediate, and long-term results and procedural characteristics from ablation procedures utilizing this system. We present a review of the outcomes and procedural data available to date. PMID- 22510161 TI - Looking to the future: adolescents with cerebral palsy talk about their aspirations--a narrative study. AB - PURPOSE: To explore the future hopes and aspirations of adolescents with cerebral palsy (CP) with a particular focus on their reflections on engagement in leisure activities. METHOD: This qualitative study used narrative inquiry methodology. Ten adolescents, aged 14-16 years with CP and Manual Ability Classification System levels ranging from I-IV, were purposively sampled from a longitudinal study of leisure participation. Data were gathered during two face-face interviews conducted approximately 1 month apart. Between interviews, photographs were taken by the adolescents to represent their visions of their future aspirations. In accordance with narrative inquiry methodology, the results were presented as individual stories constructed by the researcher. These narratives were subsequently analysed to produce themes representing the participants' reflections on their future. RESULTS: Three themes were developed: (i) Keeping close relationships, (ii) Choosing a future life of one's own, (iii) Leisure in the years ahead. All the adolescents had aspirations for education, work, leisure and living situation. CONCLUSION: This study highlights the value of seeking information from adolescents with CP and suggests clinicians be aware of, and work to support their expectations for future study, employment and recreational engagement. PMID- 22510162 TI - The FeSTivaLS trial protocol: a randomized evaluation of the efficacy of functional strength training on enhancing walking and upper limb function later post stroke. AB - RATIONALE: Functional Strength Training may enhance motor function of people who are more than six months post stroke. AIMS: to evaluate the clinical efficacy of enhancing upper and lower limb motor function with FST to explore participants' views (expectations and experiences) of FST, and to determine what cost effectiveness data to collect in a subsequent Phase III trial. DESIGN: Randomized, observer-blind trial with embedded qualitative investigation of participants' views of FST (n = 6, purposive sampling). STUDY: Participants (n = 58), six months to five years after stroke with difficulty using their paretic upper (UL) and lower limbs (LL) for everyday functional activity. All will be randomized to either FST-UL or FST-LL delivered in their own homes for four days each week for six weeks. FST involves repetitive progressive resisted exercise during goal directed functional activities. The therapist's main input is to provide verbal prompting and feedback. OUTCOMES: Measures will be undertaken before randomization (baseline), after the six-week intervention (outcome) and six weeks thereafter (follow-up). Primary outcomes for clinical efficacy will be the Functional Ambulation Categories (FAC) and the Action Research Arm Test (ARAT). Clinical efficacy analysis will use the proportional odds model for FAC and a Mann-Whitney test for ARAT. Participants' views of FST will be explored at baseline and outcome through audiotaped, semi-structured, narrative approach, interviews. The analytic process for interviews will sort transcribed data thematically and seek categories to inform conceptualization (theory-building). A purpose-designed cost questionnaire will identify what cost resource items are likely to be affected by FST. PMID- 22510163 TI - The IHF regulon of exponentially growing Pseudomonas putida cells. AB - Integration host factor (IHF) sites are largely absent from intergenic regions of ORFs encoding central metabolic functions in Pseudomonas putida mt-2. To gain an insight into this unequal distribution of otherwise abundant IHF-binding sequences, the transcriptome of IHF-plus and IHF-minus cells growing exponentially on glucose as sole carbon source was examined. In parallel, the cognate metabolic fluxes of the wild-type P. putida strain and its ihfA derivative were determined by culturing cells to a steady-state physiological regime with (13)C-labelled glucose. While expression of many transcripts was altered by the lack of IHF, flux balance analysis revealed that the ihfA mutation did not influence central carbon metabolism. Identification of multiple IHF sites adjacent to genes responsive to the factor allowed a refinement of the consensus and the mapping of the preferred binding positions for activation or repression of associated promoters. That few (if any) of the genes affected by IHF involved core pathways suggested that the central carbon metabolism tolerates the loss of the factor. Instead, IHF controlled various cell surface-related functions and downregulated genes encoding ribosomal proteins, the alpha subunit of RNA polymerase and components of the ATP synthase. These results were confirmed with lacZ fusions to a suite of promoters detected in the transcriptome as affected by IHF. Taken together, the data suggest that IHF plays a role in the physiological shift that sets P. putida for entering stationary phase. PMID- 22510164 TI - First observation of ultrafast intramolecular proton transfer rate between electronic ground states in solution. AB - Despite the importance of ultrafast (time scale exceeding 10(-11) s) intramolecular proton transfer (PT) events between electronic ground states in solution, experimental determination of the rates of such reactions has not yet been accomplished because of the limitations of the utilized methods. The objective of this study was to evaluate the PT rates of intramolecular O...H...O hydrogen-bonded systems in solution through the (1)H spin-lattice relaxation times of the hydroxyl protons, induced by the (1)H-(17)O dipolar interactions (T(1dd)(OH)), taking into account the contribution of the OH reorientational motion to T(1dd)(OH). Solutions of the benzoic acid dimer (BA dimer), 1-benzoyl-6 hydroxy-6-phenylfulvene (Fulvene), and dibenzoylmethane (DBM) were chosen as test systems. For Fulvene in CCl(4), the PT time, tau(PT), was deduced to be 7 * 10( 11) s. In the case of the BA dimer in CCl(4), the tau(PT) value was considerably greater than the OH reorientational correlation time, tau(R(OH)) = 4.3 * 10(-11) s. In contrast, the experimental results for DBM in CCl(4) indicated that the proton is located about midway between the two oxygen atoms, that is, the PT potential energy surface is a single well or a double well with a PT barrier near or below the zero-point energy. PMID- 22510165 TI - Direct-to-consumer genetic testing for addiction susceptibility: a premature commercialisation of doubtful validity and value. AB - Genetic research on addiction liability and pharmacogenetic research on treatments for addiction have identified some genetic variants associated with disease risk and treatment. Genetic testing for addiction liability and treatment response has not been used widely in clinical practice because most of the genes identified only modestly predict addiction risk or treatment response. However, many of these genetic tests have been commercialized prematurely and are available direct to the consumer (DTC). The easy availability of DTC tests for addiction liability and lack of regulation over their use raises a number of ethical concerns. Of paramount concern is the limited predictive power and clinical utility of these tests. Many DTC testing companies do not provide the consumer with the necessary genetic counselling to assist them in interpreting and acting on their test results. They may also engage in misleading marketing to entice consumers to purchase their products. Consumers' genetic information may be vulnerable to misuse by third parties, as there are limited standards to protect the privacy of the genetic information. Non-consensual testing and inappropriate testing of minors may also occur. The United States Food and Drug Administration plans to regulate DTC genetic tests. Based on the ethical concerns we discuss below, we believe there is a strong case for regulation of DTC genetic tests for addiction liability and treatment response. We argue that until this occurs, these tests have more potential to cause harm than to contribute to improved prevention and treatment of addiction. PMID- 22510166 TI - Predictors of steal syndrome in hemodialysis patients. AB - Steal syndrome is a feared complication of dialysis vascular access in a population becoming older and frailer. The aim of this study was to determine the predictor factors of steal syndrome. All proximal arteriovenous fistulas (AVFs), patent at day 30, inserted between January 2008 and December 2009 were studied. Data on age, gender, diabetes mellitus (DM) status, presence of coronary or peripheral artery disease, date of initiation of renal replacement therapy, date of access construction, localization, type of anastomosis, previous interventions, and outcome for AVF and patients were analyzed. There were 324 AVFs placed into 309 individual patients. The mean age was 66.7 +/- 15.3 years, and the majority (53.7%) of the patients was male. Mean follow-up of all 324 fistulas was 18.6 +/- 8.5 months. During follow-up, steal syndrome occurred in 26 (8%) of the AVFs. Univariate analysis revealed correlations between steal syndrome and DM (P = 0.002), brachiomedian fistulas (P = 0.016), and side-to-side (STS) anastomosis (P = 0.003). However, in multivariate analysis, the presence of DM, STS anastomosis, and female gender were found to be the independent risk factors. The strongest predictive factor was DM (odds ratio: 6.7; 95% confidence interval: 2.5-17.9). Being diabetic is the factor most predictive of having steal syndrome. In diabetic women, with a proximal access, it seems preferable to construct fistulas with end-to-side anastomosis to minimize the risk. PMID- 22510167 TI - Transseptal puncture through Amplatzer septal occluder device for catheter ablation of atrial fibrillation: use of balloon dilatation technique. AB - Transseptal puncture is required for catheter ablation of atrial fibrillation. We report on a 59-year-old woman presenting with atrial fibrillation after transcatheter closure of a large-sized secundum atrial septal defect with an Amplatzer septal occluder. Direct transseptal access through the device was achieved with the aid of an angioplasty balloon and atrial fibrillation was successfully ablated. Such an approach of transseptal puncture can facilitate obtaining left atrial access in complicated intervention procedures. PMID- 22510168 TI - Genetic polymorphism of glutathione S-transferase T1 and the risk of rheumatoid arthritis: a meta-analysis. AB - OBJECTIVES: Reports investigating the association between the genetic polymorphism of glutathione S-transferase T1 (GSTT1) and the risk of rheumatoid arthritis (RA) have revealed conflicting results. To clarify the effect of GSTT1 polymorphism on the risk of developing RA, we carried out a meta-analysis using published data. METHODS: Electronic searches were conducted to select studies. Reports were included if they were observational studies investigating the link between GSTT1 genotype and the risk of RA. The principal outcome measure was the odds ratio (OR) with 95% confidence interval (CI) for the risk of RA with GSTT1 null genotype. RESULTS: We identified 7 eligible studies including 2652 cases and 4117 controls. The combined results showed that there was not a statistically significant link between GSTT1 null genotype and RA. However, we observed an increased risk in heavy smokers (cigarette consumption >10 pack-years) with GSTT1 null polymorphism compared with never or light smokers (cigarette consumption <=10 pack-years) with GSTT1 present. Moreover, compared to GSTT1 positive polymorphism with seronegative results, there was an increased risk in GSTT1 null polymorphism with seropositive results. CONCLUSIONS: The results from this meta analysis suggested that GSTT1 null genotype is not association with an increased susceptibility to RA. However, GSTT1 null polymorphism may increase the risk of RA in relation to heavy smokers or seropositive results. Whether GSTT1 polymorphism may act in synergy with other genes or environmental factors remains to be studied more in depth. PMID- 22510169 TI - Urgent parathyroidectomy. PMID- 22510170 TI - Life insurance and genetic testing for prostate cancer: what advice for patients? PMID- 22510171 TI - Mastering the totally extraperitoneal technique is a prerequisite for successful inguinal hernia repair. PMID- 22510174 TI - Inguinal hernia: aetiology, diagnosis, post-repair pain and compensation. AB - BACKGROUND: Inguinal hernia compensation depends on aetiology, diagnosis and complications, particularly post-hernia pain. New studies in these three areas bring confusion to claims. METHODS: A comprehensive research of the literature using Medline: in aetiology, in diagnoses, the use of ultrasound and/or other investigations, in chronic post-hernia pain and the understanding of the pathogenesis of hernia and post-hernia pain. Using the above data, a creation of a protocol for acceptance of compensation claim. RESULTS: Although intra abdominal pressure has been accepted for 200 years as a significant aetiological factor in inguinal hernia, tissue studies and prospective studies suggest an inevitability. In diagnosis, the clinical detection of a lump is the gold standard; investigations are not required. An ultrasonic detection of a hernia without clinical correlation does not require surgery. Post-hernia chronic pain is not singular to hernia, is now considered neuropathic pain and treatment is conservative. CONCLUSIONS: The work scene is possibly an aggravating factor but not a prime aetiological factor. The diagnosis does not require ultrasound. Chronic pain is neuropathic. A protocol for claim acceptance is presented. PMID- 22510175 TI - Impact of regional and local anaesthetics on length of stay in knee arthroplasty. AB - BACKGROUND: Regional and local anaesthetic techniques are thought to improve postoperative pain control and functional outcomes following total knee arthroplasty, potentially leading to a reduction in hospital length of stay. OBJECTIVES: The objective of this study was to evaluate the reporting quality and discuss the clinical findings of the available literature on these modalities that included length of stay as a study outcome. DATA SOURCES: The electronic databases Pubmed, Scopus, Medline, Web of Science and Cochrane library were searched using key words. REVIEW METHODS: Eight-hundred and forty-three papers were identified in the search. Fifteen of these met the inclusion criteria. Eight further studies were identified from their reference lists to give a final total of 23 studies that were reported against the consolidated standards of reporting trials (CONSORT) 2001 statement checklist. RESULTS: The mean criteria CONSORT score was 17.3/22 (79%). The majority of studies that compared femoral nerve blocks with placebo or conventional pain management modalities failed to demonstrate a significant reduction in length of stay. All studies that compared femoral nerve blocks with epidurals found no significant difference in length of stay. Only half of the studies comparing local anaesthetic techniques to placebo or conventional pain management methods found a significant reduction in length of stay. CONCLUSIONS: The reporting quality has specific deficiencies in the areas of sample size calculation, randomization whilst there was under-reporting of blinding. Regional and local anaesthetic techniques have not demonstrated a clear reduction in hospital length of stay. Epidurals and femoral nerve blocks have similar impacts on length of stay. PMID- 22510176 TI - Malignant potential in incidental pancreatic cysts. AB - Although pancreatic cysts are being diagnosed with greater frequency, a uniform agreement on management is still lacking. This is mainly because accurate and reliable preoperative determination of the exact pathology of a pancreatic cyst remains elusive. Although ultrasound-guided fine needle aspiration represents a significant advancement in our ability to characterize pancreatic cysts preoperatively, significant limitations persist. In this article, we review the roles of clinical characteristics, imaging features and biochemical markers in the correct classification of incidental pancreatic cysts. The correct diagnosis and management of these cysts still hinges, to a large extent, on clinical experience and multidisciplinary cooperation. PMID- 22510177 TI - Sticking to the facts: a systematic review of fibrin glue for pilonidal disease. AB - BACKGROUND: Pilonidal disease occurs when hair invading the natal cleft causes inflammation and abscess formation. Opinions vary on best practice, and most procedures have considerable morbidity and high recurrence rates of 6-40%. OBJECTIVES: This study systematically reviews the use of fibrin glue in the treatment of pilonidal disease. Outcomes measured were healing time and recurrence rate. DATA SOURCE: ScienceDirect and PubMed databases were searched for relevant literature, yielding seven papers including five small trials. The total number of patients receiving fibrin glue treatments across all trials was 85. There were no exclusion criteria in this review. RESULTS: Fibrin glue treatments had equivalent or better reported healing times than conventional therapies at an average of 2-6 weeks, and low recurrence rates between 0 and 17% at follow-up periods between 4 and 28 months. Considerable heterogeneity in study methodologies and surgical techniques prevented statistical significance or aggregate figures from being determined. CONCLUSIONS: There appears to be early promise for the use of fibrin glue in the treatment of pilonidal disease and an impetus for definitive research. PMID- 22510178 TI - Appropriate working hours for surgical training according to Australasian trainees. AB - BACKGROUND: The demands of surgical training, learning and service delivery compete with the need to minimize fatigue and maintain an acceptable lifestyle. The optimal balance of working hours is uncertain. This study aimed to define the appropriate hours to meet these requirements according to trainees. METHODS: All Australian and New Zealand surgical trainees were surveyed. Roster structures, weekly working hours and weekly 'sleep loss hours' (<8 per night) because of 24-h calls were defined. These work practices were then correlated with sufficiency of training time, time for study, fatigue and its impacts, and work-life balance preferences. Multivariate and univariate analyses were performed. RESULTS: The response rate was 55.3% with responders representative of the total trainee body. Trainees who worked median 60 h/week (interquartile range: 55-65) considered their work hours to be appropriate for 'technical' and 'non-technical' training needs compared with 55 h/week (interquartile range: 50-60) regarded as appropriate for study/research needs. Working >=65 h/week, or accruing >=5.5 weekly 'sleep loss hours', was associated with increased fatigue, reduced ability to study, more frequent dozing while driving and impaired concentration at work. Trainees who considered they had an appropriate work-life balance worked median 55 h/week. CONCLUSIONS: Approximately, 60 h/week proved an appropriate balance of working hours for surgical training, although study and lifestyle demands are better met at around 55 h/week. Sleep loss is an important determinant of fatigue and its impacts, and work hours should not be considered in isolation. PMID- 22510179 TI - Risk stratification for metastasis from cutaneous squamous cell carcinoma of the head and neck. AB - BACKGROUND: The purpose of the study was to develop a system of risk stratification, based on clinical and histological factors that would aid prediction of metastasis from cutaneous squamous cell carcinoma (SCC) of the head and neck. METHOD: The method used was a retrospective case control study comparing clinical and histological parameters of 78 patients who developed metastasis with 92 patients who did not develop metastasis over a 5-year period. RESULTS: The two 'absolute' (highest) risk factors for development of metastatic disease are poor histological differentiation and perineural/lymphovascular infiltration. The three 'relative' risk factors are moderate histological differentiation, diameter >=20 mm and Clark level 5. RISK STRATIFICATION: High risk lesions have either one of the absolute risk factors or all three of the relative risk factors with a predicted incidence of metastasis of 37%. Intermediate risk lesions have two of three relative risk factors and a predicted incidence of metastasis of 5%. Low-risk lesions have one or none of the relative risk factors and a predicted incidence of metastasis of 0.3%. CONCLUSION: Ongoing management of patients with histo-pathologically proven invasive SCC of the head and neck should be based upon risk stratification for metastasis. PMID- 22510180 TI - Use of trastuzumab in Australia and New Zealand: results from the National Breast Cancer Audit. AB - BACKGROUND: Trastuzumab increases disease-free and overall survival in HER-2 positive, early breast cancer. In 2007, the National Breast and Ovarian Cancer Centre recommended that patients with HER-2 positive cancers (node positive or node negative tumours >1 cm) be offered adjuvant trastuzumab with chemotherapy. The aim of this study was to evaluate recent trends in trastuzumab therapy in Australia and New Zealand. METHODS: Following data were obtained from the National Breast Cancer Audit for patients treated between 2006 and 2008: tumour size, number of cases recorded per surgeon per year, location of hospital, HER-2 receptor status, age, lymph node status, chemotherapy and trastuzumab treatment. RESULTS: Data were available from 23,290 patients. During the study period, the percentage of breast cancers tested for HER-2 rose from 77% to 91%. Patients over 70 had fewer HER-2 tests than their younger counterparts. Fourteen percent of tumours were HER-2 positive; the proportion treated with trastuzumab in 2006, 2007 and 2008 was 50%, 66% and 74%, respectively. Significantly more node positive patients (77%) were given trastuzumab than node-negative patients (52%). All the patients prescribed trastuzumab also received chemotherapy. Patients under 70 years, patients treated in Australia and patients treated by higher caseload surgeons were more likely to be prescribed trastuzumab than those over 70, patients in New Zealand and patients treated by lower caseload surgeons. CONCLUSIONS: Trastuzumab-prescribing trends conform to the published guidelines. However, older patients and those with HER-2 positive, node-negative tumours >1 cm may be undertreated in some cases. PMID- 22510181 TI - Gunpowder, the Prince of Wales's feathers and the origins of modern military surgery. AB - BACKGROUND: The history of military surgery claims many forebears. The first surgeon-soldiers were Homer's Machaon and Podalirius, followed a thousand years later by the Roman surgeons-general, Antonius Musa and Euphorbus; and later, e.g. Ambrose Pare, John Hunter and Sir John Pringle; and the 19th century innovators, Dominique-Jean Larrey (France), Friedrich von Esmarch (Prussia) and the Russian, Nikolai Pirogoff. The singular feature that distinguished modern military surgery from its earlier practice was the use of gunpowder. It was one of two inventions (the other was printing) that by the empowerment of individuals, lifted Western humankind from the medieval to the modern era. METHODS: Research of primary and secondary archives. RESULTS AND CONCLUSION: Gunpowder was first used in European warfare at Algeceras (1344-1368). Hitherto, the destruction of tissue had been the result of (relative) low-energy wounding with tissue damage caused by incisional or crushing wounds. The founder of modern surgery, Master John of Arderne (1307-1380), wrote of his experience gained as a military surgeon on the battlefield at Crecy (1346). Following Crecy, Arderne was the only chronicler who described the origins of the Prince of Wales's feathers as a royal and later commercial symbol, and the motto 'Ich Dien', 'I serve', as that of hospitals in the Western World. Later advances in military surgery incorporated both clinical experimentation and the innovation of new systems of pre-hospital battlefield care. PMID- 22510182 TI - Indications for conversion of thoracoscopic to open thoracotomy in video-assisted thoracoscopic lobectomy. AB - BACKGROUND: The study aims to discuss indications for conversion to thoracotomy in completely thoracoscopic lobectomy. METHODS: From September 2006 to April 2010, 306 patients (164 men, 142 women, median age 58.1 years, range 15 to 86 years) underwent completely thoracoscopic lobectomy. There were 223 cases of primary lung cancer, 11 other malignant diseases and 72 cases of benign disease. The steps of the thoracoscopic procedures are almost identical to those of traditional open lobectomy, which requires standard mediastinal lymph node dissection for primary lung cancer patients. When conversion to an open procedure is necessary, such as in the presence of lymph node adhesions or metastases and bleeding, operative incisions are extended 12-15 cm towards lower angle of the scapula, retractors are used to separate the ribs, and the procedure is completely under direct visualization. RESULTS: All procedures were performed without significant complications or intraoperative deaths. The average surgical duration was 195 min, and average blood loss was 256 mL with no blood transfusions required. The average chest tube drainage duration was 7.45 days. The average post-operative hospital stay was 10.34 days. There were 27 cases (8.8%) of conversion to open thoracotomy, for the reasons of interference by lymph nodes (n = 18), bleeding (n = 4), inflammatory adhesions of arteries (n = 3) and large size tumours (n = 2). CONCLUSION: Adhesions or lymph node metastases and bleeding were the most important causes of conversion to thoracotomy in completely thoracoscopic lobectomy. Large tumours, fused fissures and dense pleural adhesions can always be managed thoracoscopically. PMID- 22510183 TI - Safety and efficacy of extended-release bupivacaine local anaesthetic in open hernia repair: a randomized controlled trial. AB - BACKGROUND: Pain relief remains a major problem in hernia surgery. SABER Bupivacaine is an investigational extended-release formulation of bupivacaine in a resorbable matrix, which may provide up to 72 h of local pain relief. METHODS: A double-blinded, randomized controlled trial was undertaken to evaluate the safety and efficacy of SABER-Bupivacaine. Consented patients (n = 124) undergoing open inguinal hernia repair at five sites in Australia and New Zealand were randomized to receive either 2.5 (330 mg) or 5.0 mL (660 mg) of SABER-Bupivacaine or SABER-Placebo administered to the surgical wound at the end of the procedure. Analgesic efficacy and safety was evaluated. RESULTS: SABER-Bupivacaine appeared safe with no difference in the incidence of side effects compared with SABER Placebo. The 5.0 mL dose of SABER-Bupivacaine reduced the mean area under the curve of pain intensity on movement compared with SABER-Placebo (2.47 versus 3.60; P = 0.0033) and decreased the number of patients requiring supplemental opioids by 26% (although not statistically significant; P = 0.0909). Normal wound healing was reported throughout the trial and at 3- and 6-month follow-up in every treatment group. CONCLUSION: After open inguinal hernia repair, SABER Bupivacaine administered at the surgical site was safe and provided pain relief, reduced the need for supplemental (oral and parenteral) analgesia and did not impair wound healing. PMID- 22510184 TI - Trends in colorectal cancer incidence rates in New Zealand, 1981-2004. AB - BACKGROUND: Incidence rates of colorectal cancer (CRC) in New Zealand rank among the highest worldwide. Internationally, there has been evidence of a shift in colon cancer from left- to right-sided. The objective of this study was to determine trends in left- and right-sided colon and rectal cancers incidence by sex, age and ethnicity. METHODS: Using datasets created by linking data from the New Zealand Cancer Registry to the census data, we analysed a total of 47,694 CRCs from 1981 to 2004. Cancers were divided into right-sided colon (cecum to the splenic flexure); left-sided colon (descending and sigmoid colon); and rectal (rectosigmoid junction and rectum). RESULTS: Left- and right-sided colon, and rectal cancer incidence rates increased by 13-20% among men. In women, colon cancer rates increased by 25% for right-sided cancers, decreased by 8% for left sided cancers and remained unchanged for rectal cancers. This corresponds with an increase in right-sided cancers from 57% to 65% of total colon cancers in women. The incidence of all CRCs increased at a faster rate among Maori than non-Maori. CONCLUSION: We identified a left- to right-sided shift in colon cancer limited to women over the age of 65. While Maori trends in site distribution parallel those of their non-Maori counterparts, the rapid increase in Maori incidence rates is noteworthy. It is unclear why such shifts in CRC site distribution are occurring. PMID- 22510185 TI - Laparoscopic management of the median arcuate ligament syndrome. AB - BACKGROUND: The median arcuate ligament syndrome (MALS) is an infrequent cause of abdominal pain. This diagnosis is made after exclusion of other more common causes of upper abdominal symptoms. Mesenteric duplex and a computerized tomography mesenteric angiography demonstrate dynamic compression of the coeliac axis during expiration. METHODS: Retrospective analysis of presenting symptoms, preoperative findings and postoperative outcomes. RESULTS: Five consecutive patients who underwent laparoscopic division of the median arcuate ligament over a 4-year period (2006-2010) are presented. This procedure was associated with low morbidity and complete relief of symptoms in all patients. CONCLUSION: A minimally invasive procedure is the treatment of choice in selected patients with MALS. PMID- 22510186 TI - Bimodal electric tissue ablation (BETA) compared with the Cool-Tip RFA system. AB - BACKGROUND: Bimodal electric tissue ablation (BETA) incorporates the process of electrolysis into radiofrequency ablation (RFA) to increase the size of tissue ablation. This study investigated whether BETA could increase the efficacy of the Cool-Tip RF system (Covidien, Boulder, CO, USA) to produce larger ablations. It also investigated whether applying electrolysis only during the pretreatment phase (called electrochemical treatment (ECT)/RFA group) is as effective as BETA (where electrolysis was used during both the pretreatment and RFA phases). METHODS: A Cool-Tip RF system (Covidien) was used to test three types of ablations (RFA, BETA, and ECT/RFA) in a pig liver model. In BETA, 9 V of direct current was provided for 10 min, after which the RF generator was started and both electrical circuits were allowed to run concurrently. In ECT/RFA, however, the direct current circuit was switched off after 10 min of pretreatment and only RFA was performed as described above. Ablation sizes were measured in three dimensions. RESULTS: The size of ablations (transverse diameter A and B) produced by BETA and ECT/RFA was significantly larger compared with standard RFA (P < 0/001). BETA also created larger ablations compared with ECT/RFA (P < 0.001). CONCLUSION: BETA could improve the efficacy of the Cool-Tip RF system (Covidien) to achieve larger ablations. The increased tissue hydration improved delivery of electrical energy to the tissues and delayed the process of desiccation, thus allowing the ablation process to continue for longer periods of time to produce larger ablations. BETA could be used to treat larger liver tumours more effectively than standard RFA. PMID- 22510187 TI - Currarinot triade. PMID- 22510188 TI - Rib fixation for a traumatic 'stove-in chest': an option to consider. PMID- 22510189 TI - Vesicovaginal fistula with large bladder calculus. PMID- 22510190 TI - There is still the best of reasons for all of us to be grateful to Sir Kenelm Digby. PMID- 22510191 TI - Endoscopic ultrasound-guided fine needle aspirate: a useful method in the diagnosis of pancreatic tuberculosis. PMID- 22510192 TI - Spontaneous bacterial peritonitis: a rare mimic of acute appendicitis. PMID- 22510193 TI - Re: Cardiac surgery in the Pacific Islands. PMID- 22510194 TI - University of Tasmania student's foray into surgical research (Re: ANZ J. Surg. 2011; 81: 851-2). PMID- 22510195 TI - Carolinas Comfort Scale for mesh repair of inguinal hernia. PMID- 22510196 TI - Re: Local recurrence of an oral squamous cell carcinoma confined to a free flap. PMID- 22510197 TI - Chondroepitrochlearis: an abnormal muscle that may affect axillary lymphadenectomy. PMID- 22510198 TI - Serratia marcescens: a historical tale forged in blood? PMID- 22510199 TI - Operating theatre: the unacknowledged classroom of the modern medical degree. PMID- 22510201 TI - Deficiency of Sbds in the mouse pancreas leads to features of Shwachman-Diamond syndrome, with loss of zymogen granules. AB - BACKGROUND & AIMS: Shwachman-Diamond syndrome (SDS) is the second leading cause of hereditary exocrine pancreatic dysfunction. More than 90% of patients with SDS have biallelic loss-of-function mutations in the Shwachman-Bodian Diamond syndrome (SBDS) gene, which encodes a factor involved in ribosome function. We investigated whether mutations in Sbds lead to similar pancreatic defects in mice. METHODS: Pancreas-specific knock-out mice were generated using a floxed Sbds allele and bred with mice carrying a null or disease-associated missense Sbds allele. Cre recombinase, regulated by the pancreatic transcription factor 1a promoter, was used to disrupt Sbds specifically in the pancreas. Models were assessed for pancreatic dysfunction and growth impairment. RESULTS: Disruption of Sbds in the mouse pancreas was sufficient to recapitulate SDS phenotypes. Pancreata of mice with Sbds mutations had decreased mass, fat infiltration, but general preservation of ductal and endocrine compartments. Pancreatic extracts from mutant mice had defects in formation of the 80S ribosomal complex. The exocrine compartment of mutant mice was hypoplastic and individual acini produced few zymogen granules. The null Sbds allele resulted in an earlier onset of phenotypes as well as endocrine impairment. Mutant mice had reduced serum levels of digestive enzymes and overall growth impairment. CONCLUSIONS: We developed a mouse model of SDS with pancreatic phenotypes similar to those of the human disease. This model could be used to investigate organ-specific consequences of Sbds-associated ribosomopathy. Sbds genotypes correlated with phenotypes. Defects developed specifically in the pancreata of mice, reducing growth of mice and production of digestive enzymes. SBDS therefore appears to be required for normal pancreatic development and function. PMID- 22510200 TI - Induced Mist1 expression promotes remodeling of mouse pancreatic acinar cells. AB - BACKGROUND & AIMS: Early embryogenesis involves cell fate decisions that define the body axes and establish pools of progenitor cells. Development does not stop once lineages are specified; cells continue to undergo specific maturation events, and changes in gene expression patterns lead to their unique physiological functions. Secretory pancreatic acinar cells mature postnatally to synthesize large amounts of protein, polarize, and communicate with other cells. The transcription factor MIST1 is expressed by only secretory cells and regulates maturation events. MIST1-deficient acinar cells in mice do not establish apical basal polarity, properly position zymogen granules, or communicate with adjacent cells, disrupting pancreatic function. We investigated whether MIST1 directly induces and maintains the mature phenotype of acinar cells. METHODS: We analyzed the effects of Cre-mediated expression of Mist1 in adult Mist1-deficient (Mist1(KO)) mice. Pancreatic tissues were collected and analyzed by light and electron microscopy, immunohistochemistry, real-time polymerase chain reaction analysis, and chromatin immunoprecipitation. Primary acini were isolated from mice and analyzed in amylase secretion assays. RESULTS: Induced expression of Mist1 in adult Mist1(KO) mice restored wild-type gene expression patterns in acinar cells. The acinar cells changed phenotypes, establishing apical-basal polarity, increasing the size of zymogen granules, reorganizing the cytoskeletal network, communicating intercellularly (by synthesizing gap junctions), and undergoing exocytosis. CONCLUSIONS: The exocrine pancreas of adult mice can be remodeled by re-expression of the transcription factor MIST1. MIST1 regulates acinar cell maturation and might be used to repair damaged pancreata in patients with pancreatic disorders. PMID- 22510202 TI - Identification of pancreatic cancer stem cells and selective toxicity of chemotherapeutic agents. AB - BACKGROUND & AIMS: Identification and purification of cancer stem cells (CSCs) could lead to new therapeutic targets, but their heterogeneous expansion is an obstacle to their study. We investigated whether it is possible to monitor pancreatic CSCs in real time, based on their intrinsic low level of proteasome activity. METHODS: We engineered human pancreatic adenocarcinoma cells (PANC1, MIAPaCa2, BxPC3, and KLM1) to express a green fluorescent molecule fused to the degron of ornithine decarboxylase (Gdeg) from a retroviral vector; the fluorescent Gdeg accumulates in CSCs as a result of low activity of the 26S proteasome. Cells with high and low levels of fluorescence (Gdeg(high) and Gdeg(low)) were isolated by flow cytometry; tumor growth was analyzed in immunocompromised mice. We performed a screen for agents that were specifically toxic to pancreatic CSCs, in a synthetic lethal manner. RESULTS: Gdeg(high) cells, but not Gdeg(low) cells, formed spheres and underwent asymmetric division features of CSCs. Injection of as few as 10 Gdeg(high) cells led to tumor formation in mice. Gemcitabine was toxic to cultured Gdeg(low) cells, whereas Gdeg(high) cells were resistant. We observed that quercetin was toxic to Gdeg(high) cells in culture and in pre-established tumors grown from these cells in mice. Nuclear accumulation of beta-catenin was detected in Gdeg(high), but not Gdeg(low), and lost after exposure to quercetin. CONCLUSIONS: We used a fluorescence marker system for level of proteasome activity to identify pancreatic cancer cells with features of cancer stem cells. We identified quercetin as a compound that is specifically toxic to pancreatic CSCs. PMID- 22510203 TI - Dystonia in Costello syndrome. AB - BACKGROUND: Costello Syndrome is a rare multiple congenital anomaly disorder caused by de novo heterozygous mutations in the v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) gene. Recent studies seem to support apparent autosomal dominant inheritance and somatic mosaicism and an association with advanced parental age. Abnormal hand posture has been reported as a typical feature of Costello Syndrome but the pathophysiology of this is unclear. METHODS: We evaluated and described posture and movement in six consecutive subjects with genetically proven Costello Syndrome, in order to better characterize the phenomenology of the associated postural abnormalities and any related motor abnormalities. We also evaluated motor cortex plasticity by applying Paired Associative Stimulation. RESULTS: All the patients presented the typical postural abnormalities reported in Costello Syndrome, in particular the ulnar deviation of fingers. The latter was reducible and not fixed. In addition, patients exhibited more explicit dystonic features of the face, limbs and trunk and altered sensorimotor plasticity consistent with generalized dystonia. CONCLUSIONS: These findings suggest that dystonia may underlie the abnormal postures described in Costello Syndrome patients. PMID- 22510204 TI - Resting-state brain connectivity in patients with Parkinson's disease and freezing of gait. AB - BACKGROUND: Freezing of gait is a common cause of disability and falls in patients with Parkinson's disease. We studied brain functional connectivity, by means of resting-state functional magnetic resonance imaging, in patients with Parkinson's disease and freezing of gait. METHODS: Resting-state functional magnetic resonance imaging at 3 T was collected in 29 patients with Parkinson's disease, of whom 16 presented with freezing of gait as determined by a validated freezing of gait questionnaire, and 15 matched healthy controls. Single-subject and group-level independent component analysis was used to identify the main resting-state networks differing between Parkinson's disease patients with and without freezing of gait. Statistical analysis was performed using BrainVoyager QX. RESULTS: Between-group differences in resting-state networks revealed that patients with freezing of gait exhibit significantly reduced functional connectivity within both "executive-attention" (in the right middle frontal gyrus and in the angular gyrus) and visual networks (in the right occipito-temporal gyrus) [p < 0.05 corrected for multiple comparisons]. Freezing of gait clinical severity was significantly correlated with decreased connectivity within the two networks. Consistent with their "executive-attention" network impairment, patients with freezing of gait scored lower on tests of frontal lobe functions (phonemic verbal fluency: p = 0.005; frontal assessment battery: p < 0.001; ten point clock test: p = 0.04). CONCLUSIONS: Our findings suggest that a resting state functional connectivity disruption of "executive-attention" and visual neural networks may be associated with the development of freezing of gait in patients with Parkinson's disease. PMID- 22510205 TI - The validity and reliability of the Italian Olfactory Identification Test (IOIT) in healthy subjects and in Parkinson's disease patients. AB - BACKGROUND: Olfactory function can be rapidly evaluated by means of standardized olfactory tests. Multiple-choice smell identification tests can be conditioned by cultural background. To investigate a new tool for detecting olfactory deficit in Italian subjects we developed a multiple-choice identification test prepared with odorants belonging to the Italian culture. METHODS: The Italian Olfactory Identification Test (IOIT) was developed with 33 microencapsulated odorants with intensity of odors and headspace Gas Chromatography being tested. Test-retest reliability of the IOIT was evaluated. The IOIT was administered to 511 controls and 133 Parkinson's patients. RESULTS: In healthy subjects the number of IOIT errors increased with age for both females (p < 0.0001) and males (p < 0.0001), while in the Parkinson's disease group the number of IOIT errors was significantly greater where compared to healthy subjects (p < 0.0001 in all age groups). The reference limits applied to all age groups revealed an IOIT sensitivity of 93% and a specificity of 99%. The test-retest reliability was excellent. CONCLUSION: The IOIT is highly reliable, disposable, easy to administer, not fragile, and has a long shelf-life. All these features make the IOIT suitable for clinical use as well as for population screening and to discriminate Parkinson's patients from healthy subjects. PMID- 22510206 TI - Adaptation of the Amsterdam Inventory for Auditory Disability and Handicap into Spanish. AB - PURPOSE: Self-report questionnaires have been suggested as valuable assessment tools in audiology, especially when investigating the effect of hearing impairment on the everyday lives of adults. Many self-report questionnaires have been developed for English-speaking populations; however, there is a lack of this type of questionnaire for Spanish-speaking patients. The aim of the present research was to adapt the Amsterdam Inventory for Auditory Disability and Handicap (AIADH) into Spanish. METHODS: The AIADH consists of 30 questions that deal with real-life listening situations. Each question is accompanied by a picture representing the situation being addressed. Six Spanish-English bilingual speakers and one Spanish-English bilingual speaker participated in the translations and back translations of the English version of the AIADH. Once the adaptation was finalized, 189 normal-hearing and hearing-impaired Spanish speaking participants completed the Spanish version of the AIADH (S-AIADH). RESULTS: Statistical analysis showed a high Cronbach's alpha coefficient, indicating good internal reliability. Test-retest scores were highly correlated. Also, the S-AIADH showed good criterion validity. Statistically significant differences for all questionnaire item responses were observed between normal hearing and hearing-impaired respondents. CONCLUSIONS: The AIADH has been adapted into Spanish. Normative data in percentiles have been obtained for clinical use with Spanish-speaking populations, to explore self-reported performance for the hearing functions proposed by the ICF. [Box: see text]. PMID- 22510207 TI - [Comparison of epidemiological factors between serous and mucinous borderline ovarian tumors: therapeutic implications]. AB - The goals of this multicenter French retrospective study were to compare epidemiological factors within borderline ovarian tumors (BOT) according to their serous (SBOT) or mucinous (MBOT) type and according to the presence of pejorative histological criteria. We analysed 224 SBOT and 164 MBOT diagnosed between 1990 and 2009. The patients mean age was not different according to serous or mucinous type (46.9 +/- 16.7 years and 44.6 +/- 17.6 years). Women with SBOT, had more frequently history of infertility (17.2% versus 3.9%, P < 0.0001) than women with MBOT. SBOT were more often asymptomatic (52.3% versus 33.5%, P < 0.001), bilateral (26.4% versus 4.3%, P = 0.0001), smaller (9.1 cm versus 14.5 cm, P = 0.0001) and diagnosed at advanced stage (81.2% of stage I versus 95.1%, P < 0.0001) than MBOT. The micropapillary pattern found in 10.3% of SBOT was observed at younger age (38 +/- 15.4 years versus 47.9 +/- 16.6 years, P = 0.007) and was more often associated with peritoneal implants (26.1% versus 6.5%, P = 0.02). The intraepithelial carcinoma found in 6.7% of MBOT, was more often associated with micro-invasion (36.4% versus 4.6%, P = 0.003). The existence of epidemiologic differences between SBOT and MBOT underlines that the BOT series analysis can not be considered without taking into account this parameter. PMID- 22510208 TI - Highly sensitive multiple microRNA detection based on fluorescence quenching of graphene oxide and isothermal strand-displacement polymerase reaction. AB - A simple, highly sensitive, and selective multiple microRNA (miRNA) detection method based on the graphene oxide (GO) fluorescence quenching and isothermal strand-displacement polymerase reaction (ISDPR) was proposed. The capability to discriminate ssDNA and double-stranded nucleic acid structure coupled with the extraordinary fluorescence quenching of GO on multiple organic dye allows the proposed strategy to simultaneously and selectively detect several miRNA labeled with different dyes in the same solution, while the ISDPR amplification endows the detection method with high sensitivity. The strong interaction between ssDNA and GO led to the fluorescent ssDNA probe exhibiting minimal background fluorescence. Upon the recognition of specific target miRNA, an ISDPR was triggered to produce numerous massive specific DNA-miRNA duplex helixes, and a strong emission was observed due to the weak interaction between the DNA-miRNA duplex helix and GO. A miRNA biosensor down to 2.1 fM with a linear range of 4 orders of magnitude was obtained. Furthermore, the large planar surface of GO allows simultaneous quenching of several DNA probes with different dyes and produces a multiple biosensing platform with high sensitivity and selectivity, which has promising application in profiling the pattern of miRNA expression and biomedical research. PMID- 22510209 TI - Loss of genetic diversity as a signature of apricot domestication and diffusion into the Mediterranean Basin. AB - BACKGROUND: Domestication generally implies a loss of diversity in crop species relative to their wild ancestors because of genetic drift through bottleneck effects. Compared to native Mediterranean fruit species like olive and grape, the loss of genetic diversity is expected to be more substantial for fruit species introduced into Mediterranean areas such as apricot (Prunus armeniaca L.), which was probably primarily domesticated in China. By comparing genetic diversity among regional apricot gene pools in several Mediterranean areas, we investigated the loss of genetic diversity associated with apricot selection and diffusion into the Mediterranean Basin. RESULTS: According to the geographic origin of apricots and using Bayesian clustering of genotypes, Mediterranean apricot (207 genotypes) was structured into three main gene pools: 'Irano-Caucasian', 'North Mediterranean Basin' and 'South Mediterranean Basin'. Among the 25 microsatellite markers used, only one displayed deviations from the frequencies expected under neutrality. Similar genetic diversity parameters were obtained within each of the three main clusters using both all SSR loci and only 24 SSR loci based on the assumption of neutrality. A significant loss of genetic diversity, as assessed by the allelic richness and private allelic richness, was revealed from the 'Irano Caucasian' gene pool, considered as a secondary centre of diversification, to the northern and southwestern Mediterranean Basin. A substantial proportion of shared alleles was specifically detected when comparing gene pools from the 'North Mediterranean Basin' and 'South Mediterranean Basin' to the secondary centre of diversification. CONCLUSIONS: A marked domestication bottleneck was detected with microsatellite markers in the Mediterranean apricot material, depicting a global image of two diffusion routes from the 'Irano-Caucasian' gene pool: North Mediterranean and Southwest Mediterranean. This study generated genetic insight that will be useful for management of Mediterranean apricot germplasm as well as genetic selection programs related to adaptive traits. PMID- 22510210 TI - Overexpression of Hsp90 from grass carp (Ctenopharyngodon idella) increases thermal protection against heat stress. AB - With homologous DNA probes, we had screened a grass carp heat shock protein 90 gene (CiHsp90). The full sequence of CiHsp90 cDNA was 2793 bp, which could code a 798 amino acids peptide. The phylogenetic analysis demonstrated that CiHsp90 shared the high homology with Zebrafish Grp94. Quantitative RT-PCR analysis showed that CiHsp90 was ubiquitously expressed at lower levels in all detected tissues and up-regulated after heat shock at 34 degrees C or cold stress at 4 degrees C. To understand the function of CiHsp90 involving in thermal protection, an expression vector containing coding region cDNA was expressed in E. coli BL21 (DE3) plysS. Upon transfer from 37 degrees C to 42 degrees C, these cells that accumulated CiHsp90 peptides displayed greater thermoresistance than the control cells. While incubated at 4 degrees C for different periods, it could also improve the cell viability. After transient transfected recombinant plasmid pcDNA3.1/CiHsp90 into mouse myeloma cell line SP2/0, we found that CiHsp90 could contribute to protecting cells against both thermal and cold extremes. On the contrary, the mutant construct DeltaN-CiHsp90 (256-798aa) could abolish the protection activity both in prokaryotic cells and eukaryotic cells. Additionally, both CiHsp90 and DeltaN-CiHsp90 peptides could reduce the level of citrate synthase aggregation at the high temperature. PMID- 22510211 TI - BIRC7 gene in channel catfish (Ictalurus punctatus): identification and expression analysis in response to Edwardsiella tarda, Streptococcus iniae and Channel catfish Hemorrhage Reovirus. AB - A family member of inhibitor of apoptosis protein (IAP) termed baculoviral IAP repeat-containing 7 (BIRC7) from channel catfish (Ictalurus punctatus) was identified, the full length cDNA sequence of channel catfish BIRC7 (CcBIRC7) was 1686 bp, containing a 5'UTR of 93 bp, a 3'UTR of 399 bp with a poly (A) tail and an ORF of 1194 bp encoding a putative protein of 398 amino acids. The putative CcBIRC7 protein contains two BIR super-family conservative domains and a C terminal RING finger motif. Phylogenetic analysis showed that catfish CcBIRC7 was moderately conserved with other BIRC7. Quantitative real-time PCR was conducted to examine the expression profiles of CcBIRC7 in healthy tissues and responding to different pathogens (Edwardsiella tarda, Streptococcus iniae and Channel catfish Hemorrhage Reovirus (CCRV)). CcBIRC7 was widely expressed in healthy tissues of channel catfish and with the highest 37.28-fold expression in blood. E. tarda and S. iniae could induce CcBIRC7 gene expression drastically in head kidney, liver and spleen, which the peak value reached 31.6-fold, 613.9-fold and 34.4-fold increase by E. tarda infection, and 248.3-fold, 1540.3-fold and 120.4 fold increase post S. iniae challenge, respectively. While, CCRV virus could slightly induce CcBIRC7 expression in head kidney and liver but reduce it in spleen. The result suggested BIRC7 may play a potential role in channel catfish innate immune system against bacterial and virus infections, especially as the anti-bacteria immune gene. This is the first report of BIRC7 gene identification and its expression in fish. PMID- 22510212 TI - Role of perferryl-oxo oxidant in alkane hydroxylation catalyzed by cytochrome P450: a hybrid density functional study. AB - We have performed hybrid density functional theory (DFT) calculations on the reactivities of low-lying doublet and quartet ferryl-oxo [Fe(IV)?O] oxidants and a doublet perferryl-oxo [Fe(V)?O] oxidant as a new key active species in cytochrome P450. Several aspects of the mechanism of hydrogen-atom abstraction from propane by the above active species of compound I models have been addressed in detail. The results, based on fully optimized structures, demonstrate that the perferryl-oxo oxidant can contribute to the reactivity of compound I owing to the presence of a highly reactive ppi atomic radical character of the oxo ligand. The perferryl-oxo species can abstract a hydrogen atom from propane with an activation barrier of only 0.6-2.5 kcal mol(-1), which is substantially smaller than that for the ferryl-oxo species (13.4-17.8 kcal mol(-1)). The role of the doublet perferryl species in the heterolytic and homolytic O-O bond cleavage in precursor (protonated) compound 0 coupled with the subsequent C-H bond activation has also been explored by grid search of ferryl and perferryl potential surfaces using two parameters. Our calculations suggest that the perferryl-oxo oxidant is catalytically competent, if the O-O bond cleaves heterolytically. The interplay between the accessible ferryl and perferryl states of compound I with quite different reactivities could be a possible reason for elusiveness of compound I in native P450 catalysis on the one hand and various degrees of detection in shunt reactions using peroxy acids on the other hand. PMID- 22510213 TI - Quality of ICD-10 colorectal cancer diagnosis codes in the Danish National Registry of Patients. AB - This study examined the quality of International Classification of Diseases-10 colorectal cancer (CRC) diagnosis coding in the Danish National Registry of Patients (DNRP), using the Danish Cancer Registry (DCR) as a reference. We included all patients in Denmark with a CRC diagnosis in the DNRP and/or in the DCR from 2001 through 2006. Data quality was evaluated by estimating completeness and positive predictive value (PPV) of data in different subcategories of patients. We estimated mortality and date of diagnosis, to evaluate the effect of potential differences in data quality. Overall completeness of data in the DNRP for CRC was 93.4% [95% confidence interval (CI): 93.1-93.7] and the PPV was 88.9% (95% CI: 88.5-89.2). Completeness and PPV improved during the study period. However, the completeness of data for patients >75 years in the 2001-2003 period [88.8% (95% CI: 87.8-89.6)] was lower than average, and cancers in more unspecific locations and cancers in the colorectal junction also had lower estimates (below 90%). There were no differences in survival estimates in the DNRP compared to the DCR. In conclusion, this study shows high CRC data quality in the DNRP measured by completeness and PPV, except in a few subgroups. PMID- 22510214 TI - Paenibacillus larvae 16S-23S rDNA intergenic transcribed spacer (ITS) regions: DNA fingerprinting and characterization. AB - Paenibacillus larvae is the causative agent of American foulbrood in honey bee (Apis mellifera) larvae. PCR amplification of the 16S-23S ribosomal DNA (rDNA) intergenic transcribed spacer (ITS) regions, and agarose gel electrophoresis of the amplified DNA, was performed using genomic DNA collected from 134 P. larvae strains isolated in Connecticut, six Northern Regional Research Laboratory stock strains, four strains isolated in Argentina, and one strain isolated in Chile. Following electrophoresis of amplified DNA, all isolates exhibited a common migratory profile (i.e., ITS-PCR fingerprint pattern) of six DNA bands. This profile represented a unique ITS-PCR DNA fingerprint that was useful as a fast, simple, and accurate procedure for identification of P. larvae. Digestion of ITS PCR amplified DNA, using mung bean nuclease prior to electrophoresis, characterized only three of the six electrophoresis bands as homoduplex DNA and indicating three true ITS regions. These three ITS regions, DNA migratory band sizes of 915, 1010, and 1474 bp, signify a minimum of three types of rrn operons within P. larvae. DNA sequence analysis of ITS region DNA, using P. larvae NRRL B 3553, identified the 3' terminal nucleotides of the 16S rRNA gene, 5' terminal nucleotides of the 23S rRNA gene, and the complete DNA sequences of the 5S rRNA, tRNA(ala), and tRNA(ile) genes. Gene organization within the three rrn operon types was 16S-23S, 16S-tRNA(ala)-23S, and l6S-5S-tRNA(ile)-tRNA(ala)-23S and these operons were named rrnA, rrnF, and rrnG, respectively. The 23S rRNA gene was shown by I-CeuI digestion and pulsed-field gel electrophoresis of genomic DNA to be present as seven copies. This was suggestive of seven rrn operon copies within the P. larvae genome. Investigation of the 16S-23S rDNA regions of this bacterium has aided the development of a diagnostic procedure and has helped genomic mapping investigations via characterization of the ITS regions. PMID- 22510215 TI - Seroprevalence of anti-Leptospira spp. antibodies in dogs in Bahia, Brazil. AB - The aim of this study was to determine the prevalence of anti-Leptospira spp. antibodies in dogs living in the urban area of the city of Ilheus, Bahia, Brazil using the microscopic agglutination test (MAT) to investigate 24 serovars. A semi structured questionnaire was administered to dog owners to collect data about demography, husbandry and environmental factors. The prevalence of anti Leptospira spp. antibodies in the population of 282 dogs was 7.1% (95% confidence interval: 4.4-10.7%). Serovar Copenhageni was the most prevalent, followed by serovars Bratislava, Canicola and Gryppotyphosa. No risk factor was detected with regard to demography (age, gender and breed), husbandry (Leptospira vaccinations, food and water exposure through their environment, hunting habits, contact with other animals and contact with rats) and environmental factors (sewage network, garbage collection, history of flooding, river proximity and wastelands). Despite the low prevalence found in this study, the seroprevalence of Leptospira spp. in healthy dogs in Ilheus indicates the presence of this agent in the environment, which may be a source of human infection. Knowledge of the serovars present in this environment is important for understanding the epidemiology of leptospirosis and establishing public health policies aimed at its control. PMID- 22510216 TI - Wake-up or unclear-onset strokes: are they waking up to the world of thrombolysis therapy? AB - Wake-up or unclear-onset strokes occur in up to one-fourth of patients with ischemic stroke. Although stroke severity and clinical outcomes appear to be poorer in wake-up strokes than nonwake-up strokes, many patients with wake-up strokes do not receive thrombolytic therapy because stroke onset time cannot be determined. Recent studies have suggested, however, that the actual onset time of wake-up stroke is close to the wake-up time. Furthermore, advanced imaging technologies may enable us to identify patients with favorable risk-benefit profiles for thrombolysis. Indeed, empirical thrombolytic treatments have suggested safety and feasibility of such therapy in these patients. Based on these promising results and the development of multimodal imaging methods, prospective thrombolysis trials using predefined imaging criteria are currently under way to test the safety and efficacy of thrombolysis in patients with wake up or unclear-onset strokes. The establishment of optimal acute treatment strategies in this important yet so far neglected group of patients is eagerly awaited. PMID- 22510217 TI - Plasma BNP, a useful marker of fluid overload in hospitalized hemodialysis patients. PMID- 22510218 TI - Comparative drug dose and drug combinations in patients that present to hospital due to self-poisoning. AB - Self-poisoning is a common reason for acute presentation to hospital. Commonly involved drugs have been reported, but few data exist concerning the different combinations of agents or comparative doses ingested. The present study sought to better characterise the typical patterns of drug overdose that may present via the emergency department. Consecutive adults >=16 years of age that presented to York Hospital owing to self-poisoning were studied for 2010-2011 inclusive. The primary outcome measure was reported dose, expressed as a multiple of the defined daily dose (DDD) to allow comparison between different agents. There were 1024 patients, including 622 women (60.7%), and median age was 32 years (range, 16 to 92 years). Overdose in men was associated with a higher overall quantity of drugs: arithmetic mean of 20 DDD multiples (95% CI, 15-26) versus 13 (11-15), p = 0.001. Overdose involved a single agent only in 538 patients (52.5%). The mean paracetamol dose was 4.0 (95% CI, 3.7-4.3) DDD multiples; the doses of antidepressants (19.4, 17.0-21.7, p < 0.0001) and benzodiazepines (18.0, 12.8 23.2, p < 0.0001) were comparatively higher. The types of agents involved in self poisoning and common combinations of agents are characterised. Psychotropic medications were ingested in comparatively larger quantities than analgesic agents and had worse clinical outcome. Further work is required to understand the factors that determine the quantity of drug ingested in patients at risk of drug overdose so as to minimise the risk of significant toxicity. PMID- 22510219 TI - Nepalese origin of cholera epidemic in Haiti. AB - Cholera appeared in Haiti in October 2010 for the first time in recorded history. The causative agent was quickly identified by the Haitian National Public Health Laboratory and the United States Centers for Disease Control and Prevention as Vibrio cholerae serogroup O1, serotype Ogawa, biotype El Tor. Since then, >500 000 government-acknowledged cholera cases and >7000 deaths have occurred, the largest cholera epidemic in the world, with the real death toll probably much higher. Questions of origin have been widely debated with some attributing the onset of the epidemic to climatic factors and others to human transmission. None of the evidence on origin supports climatic factors. Instead, recent epidemiological and molecular-genetic evidence point to the United Nations peacekeeping troops from Nepal as the source of cholera to Haiti, following their troop rotation in early October 2010. Such findings have important policy implications for shaping future international relief efforts. PMID- 22510220 TI - Cardiovascular magnetic resonance characterization of peri-infarct zone remodeling following myocardial infarction. AB - BACKGROUND: Clinical studies implementing late gadolinium-enhanced (LGE) cardiovascular magnetic resonance (CMR) studies suggest that the peri-infarct zone (PIZ) contains a mixture of viable and non-viable myocytes, and is associated with greater susceptibility to ventricular tachycardia induction and adverse cardiac outcomes. However, CMR data assessing the temporal formation and functional remodeling characteristics of this complex region are limited. We intended to characterize early temporal changes in scar morphology and regional function in the PIZ. METHODS AND RESULTS: CMR studies were performed at six time points up to 90 days after induction of myocardial infarction (MI) in eight minipigs with reperfused, anterior-septal infarcts. Custom signal density threshold algorithms, based on the remote myocardium, were applied to define the infarct core and PIZ region for each time point. After the initial post-MI edema subsided, the PIZ decreased by 54% from day 10 to day 90 (p = 0.04). The size of infarct scar expanded by 14% and thinned by 56% from day 3 to 12 weeks (p = 0.004 and p < 0.001, respectively). LVEDV increased from 34.7. +/- 2.2 ml to 47.8 +/- 3.0 ml (day 3 and week 12, respectively; p < 0.001). At 30 days post-MI, regional circumferential strain was increased between the infarct scar and the PIZ (-2.1 +/- 0.6 and -6.8 +/- 0.9, respectively;* p < 0.05). CONCLUSIONS: The PIZ is dynamic and decreases in mass following reperfused MI. Tensile forces in the PIZ undergo changes following MI. Remodeling characteristics of the PIZ may provide mechanistic insights into the development of life-threatening arrhythmias and sudden cardiac death post-MI. PMID- 22510221 TI - An observational study of compliance with the Scandinavian guidelines for management of minimal, mild and moderate head injury. AB - BACKGROUND: The Scandinavian guidelines for management of minimal, mild and moderate head injuries were developed to provide safe and cost effective assessment of head injured patients. In a previous study conducted one year after publication and implementation of the guidelines (2003), we showed low compliance, involving over-triage with computed tomography (CT) and hospital admissions. The aim of the present study was to investigate guideline compliance after an educational intervention. METHODS: We evaluated guideline compliance in the management of head injured patients referred to the University Hospital of Stavanger, Norway. The findings from the previous study in 2003 were communicated to the hospitals physicians, and a feed-back loop training program for guideline implementation was conducted. All patients managed during the months January through June in the years 2005, 2007 and 2009 were then identified with an electronic search in the hospitals patient administrative database, and the patient files were reviewed. Patients were classified according to the Head Injury Severity Scale, and the management was classified as compliant or not with the guideline. RESULTS: The 1 180 patients were 759 (64%) males and 421 (36%) females with a mean age of 31.5 (range 0-97) years. Over all, 738 (63%) patients were managed in accordance with the guidelines and 442 (37%) were not. Compliance was not significantly different between minimal (56%) and mild (59%) injuries, while most moderate (93%) injuries were managed in accordance with the guidelines (p < 0.05). Noncompliance was caused by overtriage in 362 cases (30%) and undertriage in 80 (7%). Guideline compliance was 54% in 2005, 71% in 2007, and 64% in 2009. CONCLUSIONS: This study shows higher guideline compliance after an educational intervention involving feed-back on performance. A substantial number of patients are exposed to over-triage, involving unnecessary radiation from CT examinations, and unnecessary costs from hospital admissions. PMID- 22510222 TI - Abnormal spatial QRS-T angle, a marker of ventricular repolarisation, predicts serious ventricular arrhythmia in systemic sclerosis. AB - OBJECTIVES: Cardiac involvement may be under-diagnosed in asymptomatic patients with systemic sclerosis (SSc). Standard electrocardiography-derived spatial QRS-T angle (spQRS-Ta) is an established marker of ventricular repolarisation heterogeneity, and a strong independent predictor of cardiac morbidity and mortality, including sudden death, in the general population. We examined whether spQRS-Ta is abnormal in asymptomatic SSc patients and assessed its predictive value for possibly concurrent, serious ventricular arrhythmia. METHODS: SpQRS-Ta and 24-hour Holter recordings were obtained from 69 SSc patients (aged 51+/-13 years, 63 women) without clinically evident cardiac involvement and having left ventricular ejection fraction at least 50% by echocardiography. 'Healthy' subjects matched 1:1 with patients for age, gender and body mass index served as controls. RESULTS: SpQRS-Ta was wider in SSc (median value 15.6 degrees , interquartile range 10.6-24.3 degrees ) than controls (10.5 degrees , 7.3-13.5 degrees , p=0.0001) and not associated with skin fibrosis extent or specific clinical manifestations and autoantibodies. Twenty-four-hour Holter recordings revealed couplets of ventricular beats in six (Lown class IVa) and non-sustained ventricular tachycardia in five patients (Lown class IVb); spQRS-Ta was wider in those eleven patients with serious ventricular arrhythmia than the remaining patients (24.9 degrees , 14.9-31.3 degrees vs. 14.4 degrees , 9.6-22.3 degrees ; p=0.02). A spQRS-Ta>19.3 degrees demonstrated 80% sensitivity and 68% specificity (area under the curve 0.81, p=0.02) to predict the presence of non sustained ventricular tachycardia in Holter monitoring. CONCLUSIONS: Ventricular repolarisation heterogeneity, as reflected by wider spQRS-Ta, is common in SSc. Increased spQRS-Ta could serve as a simple screening test for further investigation to identify patients at risk or prone to develop life-threatening ventricular arrhythmia. PMID- 22510224 TI - [Monitoring and evaluation tools for irinotecan and bevacizumab in glioblastoma: from prescription to patient's information]. AB - In 2007, the use of a new therapeutic association that included two expensive drugs (bevacizumab and irinotecan), used in second line treatment for progressive glioblastoma, led to the increase of the monitoring and self-evaluation of the medical prescriptions. Methodological tools have been designed by neuro oncologists together with pharmacists of the Pitie-Salpetriere Hospital in order to be consistent with the "good use economic contract". Those drugs have not been approved by European authorities in this indication and, moreover, this combination presents adverse effects and contraindications that need to be known by the professionals, the patient and his family. Some documents have been created in order to facilitate prescriptions for neuro-oncologists and others provide monitoring tools for the physicians and nurses. A letter of information targets the patient and his family, another one targets the general practitioner. This is useful for a better coordination between these ones and the hospital. The patient receives a document and a monitoring book in order to inform him about his treatment and help him to prevent and react in time in case of side effects occurrence. Those measures have been designed to put a frame around the prescriptions and to decrease iatrogenic events as well as the economic costs. PMID- 22510225 TI - Dithizone modified gold nanoparticles films for potentiometric sensing. AB - For the first time, application of a membrane composed of gold nanoparticles decorated with complexing ligand for potentiometric sensing is shown. Gold nanoparticles drop cast from a solution form a porous structure on a substrate electrode surface. Sample cations can penetrate the gold nanoparticles layer and interact with ligand acting as a charged ionophore, resulting in Nernstian potentiometric responses. Anchoring of complexing ligand on the gold surface abolishes the necessity of ionophore application. Moreover, it opens the possibility of preparation of potentiometric sensors using chelators of significantly different selectivity patterns further enhanced by the absence of polymeric membrane matrix. This was clearly seen, for example, for gold nanoparticles stabilizing the applied ligand-dithizone-thiol conformation leading to a high potentiometric selectivity toward copper ions, much higher than that of ionophores typically used to induce selectivity for polymeric ion-selective membranes. PMID- 22510223 TI - Cost-effectiveness analysis of neonatal hearing screening program in China: should universal screening be prioritized? AB - BACKGROUND: Neonatal hearing screening (NHS) has been routinely offered as a vital component of early childhood care in developed countries, whereas such a screening program is still at the pilot or preliminary stage as regards its nationwide implementation in developing countries. To provide significant evidence for health policy making in China, this study aims to determine the cost effectiveness of NHS program implementation in case of eight provinces of China. METHODS: A cost-effectiveness model was conducted and all neonates annually born from 2007 to 2009 in eight provinces of China were simulated in this model. The model parameters were estimated from the established databases in the general hospitals or maternal and child health hospitals of these eight provinces, supplemented from the published literature. The model estimated changes in program implementation costs, disability-adjusted life years (DALYs), average cost-effectiveness ratio (ACER), and incremental cost-effectiveness ratio (ICER) for universal screening compared to targeted screening in eight provinces. RESULTS AND DISCUSSION: A multivariate sensitivity analysis was performed to determine uncertainty in health effect estimates and cost-effectiveness ratios using a probabilistic modeling technique. Targeted strategy trended to be cost effective in Guangxi, Jiangxi, Henan, Guangdong, Zhejiang, Hebei, Shandong, and Beijing from the level of 9%, 9%, 8%, 4%, 3%, 7%, 5%, and 2%, respectively; while universal strategy trended to be cost-effective in those provinces from the level of 70%, 70%, 48%, 10%, 8%, 28%, 15%, 4%, respectively. This study showed although there was a huge disparity in the implementation of the NHS program in the surveyed provinces, both universal strategy and targeted strategy showed cost effectiveness in those relatively developed provinces, while neither of the screening strategy showed cost-effectiveness in those relatively developing provinces. This study also showed that both strategies especially universal strategy achieve a good economic effect in the long term costs. CONCLUSIONS: Universal screening might be considered as the prioritized implementation goal especially in those relatively developed provinces of China as it provides the best health and economic effects, while targeted screening might be temporarily more realistic than universal screening in those relatively developing provinces of China. PMID- 22510226 TI - Transferability of National Institute for Health and Clinical Excellence recommendations for pharmaceutical therapies in oncology to Central-Eastern European countries. AB - The health burden of malignancies is greater in Central-Eastern Europe than in Western Europe. Furthermore, these countries have more limited healthcare resources, and therefore transparent decision criteria for innovative cancer therapies, including the assessment of cost-effectiveness, are an absolute necessity. Transferability of good-quality technology assessment reports, especially those prepared by National Institute for Health and Clinical Excellence (NICE) in the UK, could be highly beneficial to prevent duplication of efforts and save resources for local technology assessment. Our objective was to summarise key factors influencing the transferability of NICE recommendations in oncology for policy makers and oncologists in Central-Eastern Europe without personal experience in health technology assessment. In general, NICE recommendations are not transferable without adjustment of the analyses to local data. Even if the recommendation is positive, the conclusion can still be negative in lower-income countries, mainly due to relative price differences and the significance of the local budget impact. Technologies with negative NICE recommendations can still be cost-effective in Central-Eastern Europe due to the worse health status and therefore the greater potential health gain of the targeted population. The appropriateness of reimbursement decisions must be improved in Central-Eastern Europe, but copying NICE recommendations without local adjustment may do more harm than good. PMID- 22510227 TI - Method for appraising model validity of randomised controlled trials of homeopathic treatment: multi-rater concordance study. AB - BACKGROUND: A method for assessing the model validity of randomised controlled trials of homeopathy is needed. To date, only conventional standards for assessing intrinsic bias (internal validity) of trials have been invoked, with little recognition of the special characteristics of homeopathy. We aimed to identify relevant judgmental domains to use in assessing the model validity of homeopathic treatment (MVHT). We define MVHT as the extent to which a homeopathic intervention and the main measure of its outcome, as implemented in a randomised controlled trial (RCT), reflect 'state-of-the-art' homeopathic practice. METHODS: Using an iterative process, an international group of experts developed a set of six judgmental domains, with associated descriptive criteria. The domains address: (I) the rationale for the choice of the particular homeopathic intervention; (II) the homeopathic principles reflected in the intervention; (III) the extent of homeopathic practitioner input; (IV) the nature of the main outcome measure; (V) the capability of the main outcome measure to detect change; (VI) the length of follow-up to the endpoint of the study. Six papers reporting RCTs of homeopathy of varying design were randomly selected from the literature. A standard form was used to record each assessor's independent response per domain, using the optional verdicts 'Yes', 'Unclear', 'No'. Concordance among the eight verdicts per domain, across all six papers, was evaluated using the kappa (kappa) statistic. RESULTS: The six judgmental domains enabled MVHT to be assessed with 'fair' to 'almost perfect' concordance in each case. For the six RCTs examined, the method allowed MVHT to be classified overall as 'acceptable' in three, 'unclear' in two, and 'inadequate' in one. CONCLUSION: Future systematic reviews of RCTs in homeopathy should adopt the MVHT method as part of a complete appraisal of trial validity. PMID- 22510228 TI - Stroke units and stroke care services in Korea. AB - Organized stroke care systems improve stroke outcomes, but require resources and quality-improvement programs. This study was aimed at understanding the current status of stroke care services and stroke units in Korea. An on-line survey to investigate stroke services was conducted using a structured questionnaire for physicians who were in charge of stroke services or neurology departments of Korean hospitals that had neurology resident training programs. Of the 86 neurology training hospitals in Korea, 67 (78.0%) participated in this study. Brain computed tomography and computed tomography angiography were available 24 h a day and seven days a week (24/7) in all hospitals. More than 95% of hospitals offered transcranial Doppler, carotid duplex sonography, echocardiography, and conventional catheter angiography. Intravenous thrombolysis and hemicraniectomy for ischemic brain edema were provided 24/7 in all hospitals, and 50 hospitals (74.6%) were capable of intra-arterial thrombolysis. Stent or angioplasty was more frequently performed than endarterectomy. Performance measures were monitored in 57 hospitals (85.1%). Twenty-nine (43.3%) hospitals had stroke units. Stroke units were more common as the number of beds in the hospital increased (P = 0.001). When compared with hospitals without stroke units, stroke coordinators, use of general management protocol and education program for stroke team were more frequently available in the hospitals with stroke units. Most neurology training hospitals in Korea offered competent acute stroke care services. However, stroke units have not been widely implemented. Encouragement and support at the government or national stroke society level would promote the implementation of stroke units with little additional effort. PMID- 22510229 TI - Oral contraceptive containing chlormadinone acetate and ethinylestradiol reduces plasma concentrations of matrix metalloproteinase-2 in women with polycystic ovary syndrome. AB - Biochemical markers of cardiovascular disease, including matrix metalloproteinases (MMPs), are altered in women with polycystic ovary syndrome (PCOS), with many of these alterations thought to be due to excess androgen concentrations. Despite oral contraceptives (OCs) being the first-line pharmacological treatment in women with PCOS and the importance of MMPs in many physiological conditions and pathological states, including cardiovascular diseases, no study has yet evaluated whether OCs alter plasma concentrations of MMPs. We therefore assessed whether treatment with an OC containing the anti androgenic progestogen alters MMP profiles in women with PCOS. We analysed 20 women with PCOS who wanted hormonal contraception (OC-PCOS group), 20 ovulatory women who required hormonal contraception (OC-control group) and 20 ovulatory women who wanted non-hormonal contraception (non-OC-control group). OC consisted of cyclic use of 2 mg chlormadinone acetate/30 MUg ethinylestradiol for 6 months. Plasma concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 were measured by gelatin zymography or enzyme-linked immunoassays. OC treatment for 6 months significantly reduced plasma MMP-2 concentrations in the OC-control and OC-PCOS groups and TIMP 2 and TIMP-1 concentrations levels in the OC-control group (all p < 0.05), but had no effects on MMP-9 concentrations or on MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios in any group (all p > 0.05). These findings indicated that long-term treatment with an OC containing chlormadinone acetate plus ethinylestradiol reduced plasma MMP-2 concentrations in both healthy and PCOS women. As the latter have imbalances in circulating matrix MMPs, treatment of these women with an OC may be beneficial. PMID- 22510231 TI - Dehydration and drinking responses in a pelagic sea snake. AB - Recent investigations of water balance in sea snakes demonstrated that amphibious sea kraits (Laticauda spp.) dehydrate in seawater and require fresh water to restore deficits in body water. Here, we report similar findings for Pelamis platurus, a viviparous, pelagic, entirely marine species of hydrophiine ("true") sea snake. We sampled snakes at Golfo de Papagayo, Guanacaste, Costa Rica and demonstrated they do not drink seawater but fresh water at variable deficits of body water incurred by dehydration. The threshold dehydration at which snakes first drink fresh water is -18.3 +/- 1.1 % (mean +/- SE) loss of body mass, which is roughly twice the magnitude of mass deficit at which sea kraits drink fresh water. Compared to sea kraits, Pelamis drink relatively larger volumes of water and make up a larger percentage of the dehydration deficit. Some dehydrated Pelamis also were shown to drink brackish water up to 50% seawater, but most drank at lower brackish values and 20% of the snakes tested did not drink at all. Like sea kraits, Pelamis dehydrate when kept in seawater in the laboratory. Moreover, some individuals drank fresh water immediately following capture, providing preliminary evidence that Pelamis dehydrate at sea. Thus, this widely distributed pelagic species remains subject to dehydration in marine environments where it retains a capacity to sense and to drink fresh water. In comparison with sea kraits, however, Pelamis represents a more advanced stage in the evolutionary transition to a fully marine life and appears to be less dependent on fresh water. PMID- 22510230 TI - Prognostic implications of left ventricular dilation in patients with nonischemic heart failure: interactions with restrictive filling pattern and mitral regurgitation. AB - The aim of this study was to evaluate whether small left ventricular (LV) volumes increase the negative prognostic impact of a restrictive filling pattern (RFP) and that of mitral regurgitation (MR) in patients with nonischemic heart failure (HF). The Meta-analysis Research Group in Echocardiography (MeRGE) is a meta analysis that collated individual patient data from several prospective echocardiography outcome studies. This analysis was restricted to 10 studies and 601 patients with nonischemic HF. The role of MR was tested in a subgroup of 252 patients. A total of 106 deaths occurred during a median follow-up of 32 months. At multivariate analysis, RFP (hazard ratio [HR], 4.16; 95% confidence interval [CI], 1.54-11.23; P=.005) and New York Heart Association class III or IV (HR, 2.15; 95% CI, 1.33-3.47; P=.001) were the independent predictors of poor prognosis, and there was no statistically significant interaction between LV dilation and RFP. Moderate/severe MR was associated with poorer outcome in the group of patients with normal volumes, whereas it was not a significant predictor of mortality in patients with any degree of LV dilation. In patients with nonischemic HF, RFP is the most important indicator of poor prognosis, irrespective of the degree of LV dilation. Normal LV volumes increase the negative prognostic impact of moderate to severe MR. PMID- 22510232 TI - Chest wall TB and low 25-hidroxy-vitamin D levels in a 15-month-old girl. AB - Parietal chest wall tuberculosis is an extremely rare manifestation of tuberculosis (TB) in children. We present the case of a 15 month-old girl presenting with a chest wall lesion initially thought to be of neoplastic origin and eventually diagnosed as chest wall TB, which was treated with surgical debridement and specific antitubercular therapy. The girl had not-measurable 25 hidroxy-vitamin D levels, an increasingly recognized risk factor for the development of active TB. To our knowledge, in the English literature there are no similar described cases in such young infants. This case highlight the possibility of dealing with TB and its different manifestations also in low TB burden countries, due to continuously increasing migration flows. A detailed history is a key point to reach the diagnosis. Moreover, our case confirm the possible non casual relationship between TB and low 25-hidroxy-vitamin D levels, pointing out the importance of measuring its levels in all TB patients and considering its supplementation in addition to specific antitubercular therapy. PMID- 22510233 TI - Expression profiles of carnosine synthesis-related genes in mice after ingestion of carnosine or beta-alanine. AB - BACKGROUND: Carnosine is a dipeptide that improves exercise performance. The carnosine synthesis mechanism through carnosine and beta-alanine ingestion remains unclear. Therefore, we investigated the tissue distribution of carnosine synthase, ATP-grasp domain-containing protein-1 (ATPGD1) mRNA, and ATPGD1 and carnosine specific dipeptidase (CN1) gene expression profiles in mice that were given carnosine or beta-alanine orally. METHODS: ddY mice (7-week-old) were randomly divided into three groups (n = 6 to 8 animals per group) and were orally given 2 g/kg body weight of carnosine, beta-alanine, or water. After 15, 30, 60, 120, 180, or 360 min of treatment, the tissues (brain, blood, liver, kidneys, olfactory bulbs, hindleg muscles) were collected. The obtained tissues measured the expression of ATPGD1 and CN1 genes using quantitative PCR methods. RESULTS: The ATPGD1 gene was expressed in muscle and to a lesser extent in brain. The expression of ATPGD1 in the vastus lateralis muscle increased significantly at 180 min (P = 0.023) after carnosine ingestion and 60 (P = 0.023) and 180 min (P = 0.025) after beta-alanine ingestion. Moreover, the carnosine group showed a significantly increased renal expression of the CN1 gene 60 min after ingestion (P = 0.0015). CONCLUSIONS: The ATPGD1 gene showed high expression levels in brain and muscle. The beta-alanine or carnosine administration significantly increased ATPGD1 and CN1 expression in mice. PMID- 22510234 TI - Immune cells and bone formation in ankylosing spondylitis. AB - OBJECTIVES: The aims of this study were to examine immune cell proportions in peripheral blood of patients with ankylosing spondylitis (AS) and to investigate relationships between immune cells, level of bone formation related molecules, and radiographic changes. METHODS: Forty-nine AS patients and 53 age- and sex matched healthy controls (HCs) were enrolled in this study. Clinical parameters were extensively evaluated in the study subjects. CD4+ T-cells, CD8+ T-cells, CD56+ T-cells, natural killer cells, and natural killer T (NKT) cells in peripheral blood were measured by flow cytometry. Serum levels of Dickkopf-1 and bone morphogenic proteins were determined using enzyme linked immunosorbent assays. Modified Stokes AS spinal scores were used to assess radiographic changes. RESULTS: Patients were found to have a significantly higher percentages of CD56+T-cells than healthy controls (median 1.31% vs. 0.53%, p<0.001), whereas percentages of peripheral blood natural killer T (NKT) cell were lower in patients than in controls (median 0.07 % vs. 0.10%, p=0.010). Moreover, mean CD 56+T to NKT cell ratio was markedly higher in patients. Although no significant correlations were observed between the immune cell percentages and bone formation related molecule levels, interestingly, patients with a higher CD56+T to NKT cell ratio at baseline were found to develop greater radiographic changes (r=0.79, p=0.007, age and disease duration adjusted) during 3 years of radiographic follow up. CONCLUSIONS: An altered T-cell compartment, particularly with respect to CD56+ T and NKT cells, was observed in AS patients and could contribute to radiographic changes in AS. PMID- 22510235 TI - Unintentional non-adherence to chronic prescription medications: how unintentional is it really? AB - BACKGROUND: Unintentional non-adherence has been characterized as passively inconsistent medication-taking behavior (forgetfulness or carelessness). Our objectives were to: (1) study the prevalence and predictors of unintentional non adherence; and (2) explore the interrelationship between intentional and unintentional non-adherence in relation to patients' medication beliefs. METHODS: We conducted a cross-sectional survey of adults with asthma, hypertension, diabetes, hyperlipidemia, osteoporosis, or depression from the Harris Interactive Chronic Illness Panel. The analytic sample for this study included 24,017 adults who self-identified themselves as persistent to prescription medications for their index disease. They answered three questions on unintentional non-adherence (forgot, ran out, being careless), 11 questions on intentional non-adherence, and three multi-item scales assessing perceived need for medication (k = 10), perceived medication concerns (k = 6), and perceived medication affordability (k = 4). Logistic regression was used to model predictors of each unintentional non adherence behavior. Baron and Kenny's regression approach was used to test the mediational effect of unintentional non-adherence on the relationship between medication beliefs and intentional non-adherence. Bootstrapping was employed to confirm the statistical significance of these results. RESULTS: For the index disease, 62% forgot to take a medication, 37% had run out of the medication, and 23% were careless about taking the medication. Common multivariate predictors (p < .001) of the three behaviors were: (1) lower perceived need for medications; (2) more medication affordability problems; (3) worse self-rated health; (4) diabetes or osteoporosis (relative to hypertension); and (5) younger age. Unique statistically-significant predictors of the three behaviors were: (a) 'forgot to take medications' - greater concerns about the index medication and male gender; (b) 'run out of medications' - non-white race, asthma, and higher number of total prescription medications; (c) 'being careless' - greater medication concerns. Mediational tests confirmed the hypothesis that the effect of medication beliefs (perceived need, concerns, and affordability) on intentional non-adherence is mediated through unintentional non-adherence. CONCLUSIONS: For our study sample, unintentional non-adherence does not appear to be random and is predicted by medication beliefs, chronic disease, and sociodemographics. The data suggests that the importance of unintentional non-adherence may lie in its potential prognostic significance for future intentional non-adherence. Health care providers may consider routinely inquiring about unintentional non-adherence in order to proactively address patients' suboptimal medication beliefs before they choose to discontinue therapy all together. PMID- 22510236 TI - Computational analysis of microfluidic immunomagnetic rare cell separation from a particulate blood flow. AB - We describe a computational analysis method to evaluate the efficacy of immunomagnetic rare cell separation from non-Newtonian particulate blood flow. The core procedure proposed here is calculation of local viscosity distributions induced by red blood cell (RBC) sedimentation. Numerical calculation methods have previously been introduced to simulate particulate behavior of individual RBCs. However, due to the limitation of the computational power, those studies are typically capable of calculating only a very small number (less than 100) of RBCs and are not suitable to analyze many practical separation methods for rare cells such as circulating tumor cells (CTCs). We introduce a sedimentation and viscosity model based on our experimental measurements. The computational field is divided into small unit control volumes, where the local viscosity distribution is dynamically calculated based on the experimentally found sedimentation model. For analysis of rare cell separation, the local viscosity distribution is calculated as a function of the volume RBC rate. The direction of gravity has an important role in such a sedimentation-involved cell separation system. We evaluated the separation efficacy with multiple design parameters including the channel design, channel operational orientations (inverted and upright), and flow rates. The results showed excellent agreement with real experiments to demonstrate the effectiveness of our computational analytical method. We demonstrated higher capture efficiency with the inverted microchannel configuration.We conclude that proper direction of blood sedimentation significantly enhances separation efficiency in microfluidic devices. PMID- 22510237 TI - Utility of non-high-density lipoprotein cholesterol in assessing incident type 2 diabetes risk. AB - AIMS: Traditional lipid indices have been associated with type 2 diabetes, but limited data are available regarding non-high-density lipoprotein (non-HDL) cholesterol. In view of recent guidelines for the clinical management of dyslipidemia recommending the monitoring of non-HDL cholesterol as a secondary target after achieving the low-density lipoprotein (LDL) cholesterol goal, we aimed to assess the association of non-HDL cholesterol with incident type 2 diabetes and compare its utility as a risk predictor with traditional lipid variables in Aboriginal Canadians. METHODS: Of 606 diabetes-free participants at baseline, 540 (89.1%) returned for 10-year follow-up assessments. Baseline anthropometry, blood pressure, fasting insulin and serum lipids were measured. Fasting and 2-h postload glucose were obtained at baseline and follow-up to determine the incidence of type 2 diabetes. RESULTS: The cumulative incidence of type 2 diabetes was 17.5%. Higher non-HDL cholesterol, total-to-HDL cholesterol ratio, apolipoprotein B, triglyceride and LDL cholesterol and lower HDL cholesterol concentrations were individually associated with incident type 2 diabetes in univariate analyses (all p < 0.05). Non-HDL cholesterol was a superior determinant of incident diabetes compared with LDL cholesterol (comparing C-statistics of univariate models p = 0.01) or HDL cholesterol (p = 0.004). With multivariate adjustment including waist circumference, non-HDL cholesterol remained associated with incident diabetes [odds ratio (OR) 1.42 (95% confidence interval, CI 1.07-1.88)], while LDL cholesterol and HDL cholesterol became non-significant. CONCLUSIONS: Non-HDL cholesterol was associated with incident type 2 diabetes and was superior to LDL cholesterol as a risk predictor in this population. Further studies are required to establish the utility of non HDL cholesterol in non-Aboriginal populations. PMID- 22510238 TI - A randomized, placebo-controlled study to assess safety and efficacy of vardenafil 10 mg and tamsulosin 0.4 mg vs. tamsulosin 0.4 mg alone in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. AB - INTRODUCTION: Safety and efficacy of tamsulosin and vardenafil are well established: however, there is no report regarding combined therapy with these drugs for lower urinary tract symptoms (LUTSs) secondary to benign prostatic hyperplasia (BPH). AIM: To compare the safety and efficacy of tamsulosin 0.4 mg/day vs. tamsulosin 0.4 mg/day plus vardenafil 10 mg/day in patients with LUTS/BPH in a randomized trial with 12-week follow-up. METHODS: We conducted a randomized, double-blind, placebo-controlled study on 60 men with persistent storage LUTS after 2-week run-in with tamsulosin. MAIN OUTCOME MEASURES: International Prostate Symptom Score (IPSS), IPSS-bother, International Index of Erectile Function, Version 5 (IIEF-5) and Over Active Bladder questionnaire (OAB q) scores, uroflowmetry data (Qmax, Qave), and postvoiding residual urine were recorded after run-in (baseline), and 2 and 12 weeks after treatment. Differences between vardenafil and placebo at different times were calculated with unpaired samples t-test. Between-group differences in change from baseline to 2 and 12 weeks were evaluated with analysis of variance. RESULTS: We found a between-group significant difference from baseline to 12 weeks in the following: (i) Qmax (placebo: +0.07, vardenafil: +2.56, P = 0.034); (ii) Qave (placebo: -0.15, vardenafil: +1.02, P = 0.031); (iii) irritative-IPSS subscores (placebo: -1.67, vardenafil: -3.11, P = 0.039); and (iv) IIEF (placebo: +0.06, vardenafil: +2.61, P = 0.030). No patient reported any serious (grade >= 2) adverse event (AE). There were no differences in the incidence of common, treatment-related AEs between men undergoing combined therapy or tamsulosin alone. CONCLUSIONS: The combination of tamsulosin and vardenafil for 12 weeks was well tolerated and more effective to improve both LUTS and erectile function, as compared with tamsulosin alone. Further studies are needed to assess the role of combined therapy of phosphodiesterase type 5 inhibitors and alpha blockers in treating LUTS/BPH. PMID- 22510239 TI - Definitions and methods of measuring and reporting on injurious falls in randomised controlled fall prevention trials: a systematic review. AB - BACKGROUND: The standardisation of the assessment methodology and case definition represents a major precondition for the comparison of study results and the conduction of meta-analyses. International guidelines provide recommendations for the standardisation of falls methodology; however, injurious falls have not been targeted. The aim of the present article was to review systematically the range of case definitions and methods used to measure and report on injurious falls in randomised controlled trials (RCTs) on fall prevention. METHODS: An electronic literature search of selected comprehensive databases was performed to identify injurious falls definitions in published trials. Inclusion criteria were: RCTs on falls prevention published in English, study population >= 65 years, definition of injurious falls as a study endpoint by using the terms "injuries" and "falls". RESULTS: The search yielded 2089 articles, 2048 were excluded according to defined inclusion criteria. Forty-one articles were included. The systematic analysis of the methodology applied in RCTs disclosed substantial variations in the definition and methods used to measure and document injurious falls. The limited standardisation hampered comparability of study results. Our results also highlight that studies which used a similar, standardised definition of injurious falls showed comparable outcomes. CONCLUSIONS: No standard for defining, measuring, and documenting injurious falls could be identified among published RCTs. A standardised injurious falls definition enhances the comparability of study results as demonstrated by a subgroup of RCTs used a similar definition. Recommendations for standardising the methodology are given in the present review. PMID- 22510240 TI - Adenosine 5'-triphosphate (ATP) supplements are not orally bioavailable: a randomized, placebo-controlled cross-over trial in healthy humans. AB - BACKGROUND: Nutritional supplements designed to increase adenosine 5' triphosphate (ATP) concentrations are commonly used by athletes as ergogenic aids. ATP is the primary source of energy for the cells, and supplementation may enhance the ability to maintain high ATP turnover during high-intensity exercise. Oral ATP supplements have beneficial effects in some but not all studies examining physical performance. One of the remaining questions is whether orally administered ATP is bioavailable. We investigated whether acute supplementation with oral ATP administered as enteric-coated pellets led to increased concentrations of ATP or its metabolites in the circulation. METHODS: Eight healthy volunteers participated in a cross-over study. Participants were given in random order single doses of 5000 mg ATP or placebo. To prevent degradation of ATP in the acidic environment of the stomach, the supplement was administered via two types of pH-sensitive, enteric-coated pellets (targeted at release in the proximal or distal small intestine), or via a naso-duodenal tube. Blood ATP and metabolite concentrations were monitored by HPLC for 4.5 h (naso-duodenal tube) or 7 h (pellets) post-administration. Areas under the concentration vs. time curve were calculated and compared by paired-samples t-tests. RESULTS: ATP concentrations in blood did not increase after ATP supplementation via enteric coated pellets or naso-duodenal tube. In contrast, concentrations of the final catabolic product of ATP, uric acid, were significantly increased compared to placebo by ~50% after administration via proximal-release pellets (P = 0.003) and naso-duodenal tube (P = 0.001), but not after administration via distal-release pellets. CONCLUSIONS: A single dose of orally administered ATP is not bioavailable, and this may explain why several studies did not find ergogenic effects of oral ATP supplementation. On the other hand, increases in uric acid after release of ATP in the proximal part of the small intestine suggest that ATP or one of its metabolites is absorbed and metabolized. Uric acid itself may have ergogenic effects, but this needs further study. Also, more studies are needed to determine whether chronic administration of ATP will enhance its oral bioavailability. PMID- 22510241 TI - Autonomic reactions and peri-interventional alterations in body weight as potential supplementary outcome parameters for thromboembolic stroke in rats. AB - BACKGROUND: Since several neuroprotectives failed to reproduce promising preclinical results under clinical conditions, efforts emerged to implement clinically relevant endpoints in animal stroke studies. Thereby, insufficient attention was given on autonomic reactions due to experimental stroke, although clinical trials reported on high functional and prognostic impact. This study focused on autonomic consequences and body weight changes in a translational relevant stroke model and investigated interrelations to different outcome measurements. METHODS: Forty-eight rats underwent thromboembolic middle cerebral artery occlusion (MCAO) while recording heart rate (HR) and mean arterial pressure (MAP). After assessing early functional impairment (Menzies score), animals were assigned to control procedure or potentially neuroprotective treatment with normobaric (NBO) or hyperbaric oxygen (HBO). Four or 24 hours after ischemia onset, functional impairment was re-assessed and FITC-albumin administered intravenously obtaining leakage-related blood-brain barrier (BBB) impairment. Body weight was documented prior to MCAO and 4 or 24 hours after ischemia onset. RESULTS: During MCAO, HR was found to increase significantly while MAP decreased. The amount of changes in HR was positively correlated with early functional impairment (P = 0.001): Severely affected animals provided an increase of 15.2 compared to 0.8 beats/minute in rats with low impairment (P = 0.048). Regarding body weight, a decrease of 9.4% within 24 hours after MCAO occurred, but treatment-specific alterations showed no significant correlations with respective functional or BBB impairment. CONCLUSIONS: Future studies should routinely include autonomic parameters to allow inter-group comparisons and better understanding of autonomic reactions due to experimental stroke. Prospectively, autonomic consequences might represent a useful outcome parameter enhancing the methodological spectrum of preclinical stroke studies. PMID- 22510242 TI - Stroke complicating transcatheter aortic valve implantation: incidence, risk factors and outcome. AB - BACKGROUND: Transcatheter aortic valve implantation is a novel therapeutic option for patients at high risk for surgical heart valve replacement that carries a risk for periprocedural stroke. PATIENTS AND METHODS: Consecutive patients undergoing transcatheter aortic valve implantation with the self-expandable Medtronic-Corevalve Revalving system were included in a single-centre prospective database. Strokes complicating transcatheter aortic valve implantation in the first five-days following the procedure were documented, and the differences between patients with and without stroke were studied. RESULTS: Seventy-two patients (32 men, mean age 80.5 +/- 6.2) underwent transcatheter aortic valve implantation from September 2008 to April 2011. Of these, eight (11%) had focal neurological deficits in the periprocedural period (three transient ischaemic attacks, five strokes of which three were minor, one moderate, and one major). Patients with stroke/transient ischaemic attacks did not differ from those without cerebral ischaemia in baseline criteria or procedural variables. Six of the events were believed to be embolic resulting from dislodgement of calcific material from the aortic valve, and one transient ischaemic attack was secondary to hypoperfusion during severe bradycardia. One patient with basilar occlusion died, but the remaining six patients survived and all had a modified Rankin score <=2 at 90 days. None of the patients had a recurrent stroke during follow-up. DISCUSSION: Periprocedural cerebral ischaemia following transcatheter aortic valve implantation is not uncommon, but most patients have good outcomes. There was no particular pre-transcatheter aortic valve implantation or procedural risk factor profile that increased the risk for periprocedural stroke. Further studies are warranted to examine whether patients that are at higher risk for developing stroke after transcatheter aortic valve implantation can be identified. PMID- 22510243 TI - Syringocystadenocarcinoma papilliferum in situ of the penis. PMID- 22510244 TI - Nurses' practice environments, error interception practices, and inpatient medication errors. AB - PURPOSE: Medication errors remain a threat to patient safety. Therefore, the purpose of this study was to determine the relationships among characteristics of the nursing practice environment, nurse staffing levels, nurses' error interception practices, and rates of nonintercepted medication errors in acute care hospitals. DESIGN: This study, using a nonexperimental design, was conducted in a sample of 82 medical-surgical units recruited from 14 U.S. acute care hospitals. Registered nurses (RNs) on the 82 units were surveyed, producing a sample of 686 staff nurses. METHODS: Data collected for the 8-month study period included the number of medication errors per 1,000 patient days and the number of RN hours per patient day. Nurse survey data included the Practice Environment Scale of the Nursing Work Index as a measure of environmental characteristics; a metric of nurses' interception practices was developed for the study. All survey measures were aggregated to the unit level prior to analysis with hierarchical linear modeling. FINDINGS: A supportive practice environment was positively associated with error interception practices among nurses in the sample of medical-surgical units. Importantly, nurses' interception practices were inversely associated with medication error rates. CONCLUSIONS: A supportive practice environment enhances nurses' error interception practices. These interception practices play a role in reducing medication errors. CLINICAL RELEVANCE: When supported by their practice environments, nurses employ practices that can assist in interrupting medication errors before they reach the patients. PMID- 22510245 TI - Forced residential mobility and social support: impacts on psychiatric disorders among Somali migrants. AB - BACKGROUND: Somali migrants fleeing the civil war in their country face punishing journeys, the loss of homes, possessions, and bereavement. On arrival in the host country they encounter poverty, hostility, and residential instability which may also undermine their mental health. METHODS: An in-depth and semi-structured interview was used to gather detailed accommodation histories for a five year period from 142 Somali migrants recruited in community venues and primary care. Post-codes were verified and geo-mapped to calculate characteristics of residential location including deprivation indices, the number of moves and the distances between residential moves. We asked about the reasons for changing accommodation, perceived discrimination, asylum status, traumatic experiences, social support, employment and demographic factors. These factors were assessed alongside characteristics of residential mobility as correlates of ICD-10 psychiatric disorders. RESULTS: Those who were forced to move homes were more likely to have an ICD-10 psychiatric disorder (OR = 2.64, 1.16-5.98, p = 0.02) compared with those moving through their own choice. A lower risk of psychiatric disorders was found for people with larger friendship networks (0.35, 0.14-0.84, p = 0.02), for those with more confiding emotional support (0.42, 0.18-1.0, p = 0.05), and for those who had not moved during the study period (OR = 0.21, 0.07 0.62, p = 0.01). CONCLUSIONS: Forced residential mobility is a risk factor for psychiatric disorder; social support may contribute to resilience against psychiatric disorders associated with residential mobility. PMID- 22510246 TI - The role of left superior parietal lobe in male sexual behavior: dynamics of distinct components revealed by FMRI. AB - INTRODUCTION: Despite the interest for the brain correlates of male sexual arousal, few studies investigated neural mechanisms underlying psychogenic erectile dysfunction (ED). Although these studies showed several brain regions active in ED patients during visual erotic stimulation, the dynamics of inhibition of sexual response is still unclear. AIM: This study investigated the dynamics of brain regions involved in the psychogenic ED. METHODS: Functional magnetic resonance imaging (fMRI) and simultaneous penile tumescence (PT) were used to study brain activity evoked in 17 outpatients with psychogenic ED and 19 healthy controls during visual erotic stimulation. Patterns of brain activation related to different phases of sexual response in the two groups were compared. MAIN OUTCOME MEASURES: Simultaneous recording of blood oxygen level-dependent fMRI responses and PT during visual erotic stimulation. RESULTS: During visual erotic stimuli, a larger activation was observed for the patient group in the left superior parietal lobe, ventromedial prefrontal cortex, and posterior cingulate cortex, whereas the control group showed larger activation in the right middle insula and dorsal anterior cingulate cortex and hippocampus. Moreover, the left superior parietal lobe showed a larger activation in patients than controls especially during the later stage of sexual response. CONCLUSION: Our results suggest that, among regions more active in patient group, the left superior parietal lobe plays a crucial role in inhibition of sexual response. Previous studies showed that left superior parietal lobe is involved in monitoring of internal body representation. The larger activation of this region in patients during later stages of sexual response suggests a high monitoring of the internal body representation, possibly affecting the behavioral response. These findings provide insight on brain mechanisms involved in psychogenic ED. PMID- 22510247 TI - The effect of intravenous immunoglobulin (IVIG) treatment on patients with dermatomyositis: a 4-year follow-up study. AB - OBJECTIVES: The aim of this study is to evaluate the short- and long-term outcome of patients with dermatomyositis treated with IVIG. METHODS: Forty-two dermatomyositis patients (43 +/- 19 yrs, 40.5% males) were studied; 24 of them received IVIG as an add-on treatment, while the rest received conventional immunosupression. The first follow-up point was 6 months following the initiation of treatment. Muscular and cutaneous involvement, as well as demographical and baseline data of the IVIG treated patients, were documented for a median period of 76 months (1st, 3rd quartiles 48, 108). RESULTS: Muscular remission rate was higher for IVIG treated patients at 6 months after the onset of treatment (p=0.007). During long-term follow-up, IVIG treated patients presented with low muscular and cutaneous involvement, as well as low percentages of muscular relapses. The total number of muscular relapses was inversely associated with the number of pulses (p=0.03). CONCLUSIONS: This study is a retrospective one, consisting of a small patient sample, and both muscle and skin involvement scores were developed on the basis of the clinical data provided in the patients' records. Nevertheless, it manages to demonstrate that IVIG may improve the short term prognosis of dermatomyositis patients as compared to the classical therapies. During long-term follow-up, IVIG treated patients experienced relapses, but their muscular and cutaneous involvement scores were significantly better than their pre-treatment ones. A larger number of IVIG infusions could maintain disease remission for a longer period of time, reducing the total number of muscular relapses. PMID- 22510248 TI - Patient preferences for the allocation of deceased donor kidneys for transplantation: a mixed methods study. AB - BACKGROUND: Deceased donor kidneys are a scarce health resource, yet patient preferences for organ allocation are largely unknown. The aim of this study was to determine patient preferences for how kidneys should be allocated for transplantation. METHODS: Patients on dialysis and kidney transplant recipients were purposively selected from two centres in Australia to participate in nominal/focus groups in March 2011. Participants identified and ranked criteria they considered important for deceased donor kidney allocation. Transcripts were thematically analysed to identify reasons for their rankings. RESULTS: From six groups involving 37 participants, 23 criteria emerged. Most agreed that matching, wait-list time, medical urgency, likelihood of surviving surgery, age, comorbidities, duration of illness, quality of life, number of organs needed and impact on the recipient's life circumstances were important considerations. Underpinning their rankings were four main themes: enhancing life, medical priority, recipient valuation, and deservingness. These were predominantly expressed as achieving equity for all patients, or priority for specific sub groups of potential recipients regarded as more "deserving". CONCLUSIONS: Patients believed any wait-listed individual who would gain life expectancy and quality of life compared with dialysis should have access to transplantation. Equity of access to transplantation for all patients and justice for those who would look after their transplant were considered important. A utilitarian rationale based on maximizing health gains from the allocation of a scarce resource to avoid "wastage," were rarely expressed. Organ allocation organisations need to seek input from patients who can articulate preferences for allocation and advocate for equity and justice in organ allocation. PMID- 22510250 TI - Fasting hyperglycaemia blunts the reversal of impaired glucose tolerance after exercise training in obese older adults. AB - AIM: Lifestyle modification, consisting of exercise and weight loss, delays the progression from prediabetes to type 2 diabetes (T2D). However, no study has determined the efficacy of exercise training on glucose metabolism in the different prediabetes subtypes. METHODS: Seventy-six older (65.1 +/- 0.6 years) obese adults with impaired fasting glucose (IFG; n = 12), impaired glucose tolerance (IGT; n = 9) and combined glucose intolerance (IFG + IGT = CGI; n = 22) were compared with normal glucose tolerant (NGT; n = 15) and T2D (n = 18) groups after 12 weeks of exercise training (60 min/day for 5 days/week at ~85% HR(max)). An oral glucose tolerance test was used to assess glucose levels. Insulin sensitivity (IS; euglycaemic hyperinsulinaemic clamp at 40 mU/m(2)/min), beta cell function (glucose-stimulated insulin secretion corrected for IS), body composition (hydrostatic weighing/computed tomography scan) and cardiovascular fitness (treadmill VO(2) max) were also assessed. RESULTS: Exercise training reduced weight and increased cardiovascular fitness (p < 0.05). Exercise training lowered fasting glucose levels in IFG, CGI and T2D (p < 0.05) and 2-h glucose levels in IGT, CGI and T2D (p < 0.05). However, 2-h glucose levels were not normalized in adults with CGI compared with IGT (p < 0.05). beta-Cell function improved similarly across groups (p < 0.05). Although not statistically significant, IS increased approximately 40% in IFG and IGT, but only 17% in CGI. CONCLUSION: The magnitude of improvement in glucose metabolism after 12 weeks of exercise training is not uniform across the prediabetes subtypes. Given the high risk of progressing to T2D, adults with CGI may require more aggressive therapies to prevent diabetes. PMID- 22510249 TI - Expression of the pair-rule gene homologs runt, Pax3/7, even-skipped-1 and even skipped-2 during larval and juvenile development of the polychaete annelid Capitella teleta does not support a role in segmentation. AB - BACKGROUND: Annelids and arthropods each possess a segmented body. Whether this similarity represents an evolutionary convergence or inheritance from a common segmented ancestor is the subject of ongoing investigation. METHODS: To investigate whether annelids and arthropods share molecular components that control segmentation, we isolated orthologs of the Drosophila melanogaster pair rule genes, runt, paired (Pax3/7) and eve, from the polychaete annelid Capitella teleta and used whole mount in situ hybridization to characterize their expression patterns. RESULTS: When segments first appear, expression of the single C. teleta runt ortholog is only detected in the brain. Later, Ct-runt is expressed in the ventral nerve cord, foregut and hindgut. Analysis of Pax genes in the C. teleta genome reveals the presence of a single Pax3/7 ortholog. Ct Pax3/7 is initially detected in the mid-body prior to segmentation, but is restricted to two longitudinal bands in the ventral ectoderm. Each of the two C. teleta eve orthologs has a unique and complex expression pattern, although there is partial overlap in several tissues. Prior to and during segment formation, Ct eve1 and Ct-eve2 are both expressed in the bilaterial pair of mesoteloblasts, while Ct-eve1 is expressed in the descendant mesodermal band cells. At later stages, Ct-eve2 is expressed in the central and peripheral nervous system, and in mesoderm along the dorsal midline. In late stage larvae and adults, Ct-eve1 and Ct-eve2 are expressed in the posterior growth zone. CONCLUSIONS: C. teleta eve, Pax3/7 and runt homologs all have distinct expression patterns and share expression domains with homologs from other bilaterians. None of the pair-rule orthologs examined in C. teleta exhibit segmental or pair-rule stripes of expression in the ectoderm or mesoderm, consistent with an independent origin of segmentation between annelids and arthropods. PMID- 22510251 TI - Altered re-excitation thresholds and conduction of extrasystolic action potentials contribute to arrhythmogenicity in murine models of long QT syndrome. AB - AIM: QT interval prolongation reflecting delayed action potential (AP) repolarization is associated with polymorphic ventricular tachycardia and early after depolarizations potentially initiating extrasystolic APs if of sufficient amplitude. The current experiments explored contributions of altered re excitation thresholds for, and conduction of, such extrasystolic APs to arrhythmogenesis in Langendorff-perfused, normokalaemic, control wild-type hearts and two experimental groups modelling long QT (LQT). The two LQT groups consisted of genetically modified, Scn5a(+/DeltaKPQ) and hypokalaemic wild-type murine hearts. METHODS: Hearts were paced from their right ventricles and monophasic AP electrode recordings obtained from their left ventricular epicardia, with recording and pacing electrodes separated by 1 cm. An adaptive programmed electrical stimulation protocol applied pacing (S1) stimulus trains followed by premature (S2) extrastimuli whose amplitudes were progressively increased with progressive decrements in S1S2 interval to maintain stimulus capture. Such protocols culminated in either arrhythmic or refractory endpoints. RESULTS: Arrhythmic outcomes were associated with (1) lower conduction velocities in their initiating extrasystolic APs than refractory outcomes and (2) higher conduction velocities in the LQT groups than in controls. Furthermore, (3) the endpoints were reached at longer S1S2 coupling intervals and with smaller stimulus amplitudes in the LQT groups compared with controls. This was despite (4) similar relationships between conduction velocity and S1S2 coupling interval and between re-excitation thresholds and S1S2 coupling interval in all three experimental groups. CONCLUSIONS: Arrhythmias induced by extrasystolic APs in the LQT groups thus occur under conditions of higher conduction velocity and greater sensitivity to extrastimuli than in controls. PMID- 22510252 TI - Sustained safety and efficacy of once-daily hydromorphone extended-release (OROS(r) hydromorphone ER) compared with twice-daily oxycodone controlled-release over 52 weeks in patients with moderate to severe chronic noncancer pain. AB - Once-daily hydromorphone extended-release (OROS((r)) hydromorphone ER) and oxycodone controlled-release (CR) are semisynthetic, ER opioid analgesics with established efficacy. An open-label, randomized, 24-week, parallel group, flexible-dose study demonstrated noninferiority of OROS hydromorphone ER vs. twice-daily oxycodone CR in patients with chronic noncancer pain. In total, 112 patients were enrolled in a 28-week, open-label extension study; 60 patients received OROS hydromorphone ER and 52 received oxycodone CR. The primary efficacy measure was the change from baseline to Weeks 38 and 52 in Brief Pain Inventory item "pain right now." Global assessments of efficacy, dosing convenience, and tolerability were secondary endpoints. Mean change in "pain right now" from baseline to Week 38 was -3.0 (OROS hydromorphone ER) vs. -2.8 (oxycodone CR), and from baseline to Week 52 was -2.9 vs. -2.8; these changes were similar to the changes in the core phase (-2.1 vs. -2.1). Similar improvements were demonstrated for secondary assessments, including pain, pain interference, and quality of life. At Week 52, global assessment of efficacy was rated as "very good" or "good" by the majority of patients (OROS hydromorphone ER, 91.7%; oxycodone CR, 86.5%). More patients in the OROS hydromorphone ER group (35.0% vs. 21.2%) assessed mode of drug intake as "very convenient." The majority of patients receiving OROS hydromorphone ER (88.3%) and oxycodone CR (88.5%) rated tolerability as "good" or "very good" at Week 52; few patients discontinued treatment because of an adverse event (1.6% vs. 0.4%, respectively). The effectiveness of OROS hydromorphone ER and oxycodone CR was maintained through 1 year. PMID- 22510253 TI - Acute L-arginine alpha ketoglutarate supplementation fails to improve muscular performance in resistance trained and untrained men. AB - BACKGROUND: Dietary supplements containing L-arginine are marketed to improve exercise performance, but the efficacy of such supplements is not clear. Therefore, this study examined the efficacy of acute ingestion of L-arginine alpha-ketoglutarate (AAKG) muscular strength and endurance in resistance trained and untrained men. METHODS: Eight resistance trained and eight untrained healthy males ingested either 3000mg of AAKG or a placebo 45 minutes prior to a resistance exercise protocol in a randomized, double-blind crossover design. One repetition maximum (1RM) on the standard barbell bench press and leg press were obtained. Upon determination of 1RM, subjects completed repetitions to failure at 60% 1RM on both the standard barbell bench press and leg press. Heart rate was measured pre and post exercise. One week later, subjects ingested the other supplement and performed the identical resistance exercise protocol. RESULTS: Our data showed statistical significant differences (p<0.05) between resistance trained and untrained males for both 1RM and total load volume (TLV; multiply 60% of 1RM times the number of repetitions to failure) for the upper body. However, 1RM and TLV were not statistically different (p>0.05) between supplementation conditions for either resistance trained or untrained men in the bench press or leg press exercises. Heart rate was similar at the end of the upper and lower body bouts of resistance exercise with AAKG vs. placebo. CONCLUSION: The results from our study indicate that acute AAKG supplementation provides no ergogenic benefit on 1RM or TLV as measured by the standard barbell bench press and leg press, regardless of the subjects training status. PMID- 22510255 TI - Epileptogenic networks of type II focal cortical dysplasia: a stereo-EEG study. AB - In the context of focal and drug-resistant epilepsy, surgical resection of the epileptogenic zone may be the only therapeutic option for reducing or suppressing seizures. In many such patients, intracranial stereo-EEG recordings remain the gold standard for the epilepsy surgery work-up. Assessing the extent of the epileptogenic zone and its organisation is a crucial objective, and requires advanced methods of signal processing. Over the last ten years, considerable efforts have been made to develop signal analysis techniques for characterising the connectivity between spatially distributed regions. The aim of this study was to evaluate the changes in dynamic connectivity pattern under inter-ictal, pre ictal and ictal conditions using signals derived from stereo-EEG recordings of 10 patients with Taylor-type focal cortical dysplasia. A causal linear multivariate method - partial directed coherence - and indices derived from graph theory were used to characterise the synchronisation property of the lesional zone (corresponding to the epileptogenic zone in our patients) and to distinguish it from other regions involved in ictal activity or not. The results show that a significantly different connectivity pattern (mainly in the gamma band) distinguishes the epileptogenic zone from other cortical regions not only during the ictal event, but also during the inter- and pre-ictal periods. This indicates that the lesional nodes play a leading role in generating and propagating ictal EEG activity by acting as the hubs of the epileptic network originating and sustaining seizures. Our findings also indicate that the cortical regions beyond the dysplasia involved in the ictal activity essentially act as "secondary" generators of synchronous activity. The leading role of the lesional zone may account for the good post-surgical outcome of patients with type II focal cortical dysplasia as resecting the dysplasia removes the epileptogenic zone responsible for seizure organisation. Furthermore, our findings strongly suggest that advanced signal processing techniques aimed at studying synchronisation and characterising brain networks could substantially improve the pre-surgical evaluation of patients with focal epilepsy, even in cases without an associated anatomically detectable lesion. PMID- 22510254 TI - Quantitative tract-based white matter development from birth to age 2years. AB - Few large-scale studies have been done to characterize the normal human brain white matter growth in the first years of life. We investigated white matter maturation patterns in major fiber pathways in a large cohort of healthy young children from birth to age two using diffusion parameters fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (RD). Ten fiber pathways, including commissural, association and projection tracts, were examined with tract-based analysis, providing more detailed and continuous spatial developmental patterns compared to conventional ROI based methods. All DTI data sets were transformed to a population specific atlas with a group-wise longitudinal large deformation diffeomorphic registration approach. Diffusion measurements were analyzed along the major fiber tracts obtained in the atlas space. All fiber bundles show increasing FA values and decreasing radial and axial diffusivities during development in the first 2years of life. The changing rates of the diffusion indices are faster in the first year than the second year for all tracts. RD and FA show larger percentage changes in the first and second years than AD. The gender effects on the diffusion measures are small. Along different spatial locations of fiber tracts, maturation does not always follow the same speed. Temporal and spatial diffusion changes near cortical regions are in general smaller than changes in central regions. Overall developmental patterns revealed in our study confirm the general rules of white matter maturation. This work shows a promising framework to study and analyze white matter maturation in a tract-based fashion. Compared to most previous studies that are ROI-based, our approach has the potential to discover localized development patterns associated with fiber tracts of interest. PMID- 22510256 TI - Resting state FDG-PET functional connectivity as an early biomarker of Alzheimer's disease using conjoint univariate and independent component analyses. AB - Imaging cerebral glucose metabolism with positron emission tomography (PET) in Alzheimer's disease (AD) has allowed for improved characterisation of this pathology. Such patterns are typically analysed using either univariate or multivariate statistical techniques. In this work we combined voxel-based group analysis and independent component analysis to extract differential characteristic patterns from PET data of glucose metabolism in a large cohort of normal elderly controls and patients with AD. The patterns were used in conjunction with a support vector machine to discriminate between subjects with mild cognitive impairment (MCI) at risk or not of converting to AD. The method was applied to baseline fluoro-deoxyglucose (FDG)-PET images of subjects from the ADNI database. Our approach achieved improved early detection and differentiation of typical versus pathological metabolic patterns in the MCI population, reaching 80% accuracy (85% sensitivity and 75% specificity) when using selected regions. The method has the potential to assist in the advance diagnosis of Alzheimer's disease, and to identify early in the development of the disease those individuals at high risk of rapid cognitive decline who could be candidates for new therapeutic approaches. PMID- 22510258 TI - A brief review on the history of human functional near-infrared spectroscopy (fNIRS) development and fields of application. AB - This review is aimed at celebrating the upcoming 20th anniversary of the birth of human functional near-infrared spectroscopy (fNIRS). After the discovery in 1992 that the functional activation of the human cerebral cortex (due to oxygenation and hemodynamic changes) can be explored by NIRS, human functional brain mapping research has gained a new dimension. fNIRS or optical topography, or near infrared imaging or diffuse optical imaging is used mainly to detect simultaneous changes in optical properties of the human cortex from multiple measurement sites and displays the results in the form of a map or image over a specific area. In order to place current fNIRS research in its proper context, this paper presents a brief historical overview of the events that have shaped the present status of fNIRS. In particular, technological progresses of fNIRS are highlighted (i.e., from single-site to multi-site functional cortical measurements (images)), introduction of the commercial multi-channel systems, recent commercial wireless instrumentation and more advanced prototypes. PMID- 22510257 TI - Brain structural complexity and life course cognitive change. AB - Fractal measures such as fractal dimension (FD) can quantify the structural complexity of the brain. These have been used in clinical neuroscience to investigate brain development, ageing and in studies of psychiatric and neurological disorders. Here, we examined associations between the FD of white matter and cognitive changes across the life course in the absence of detectable brain disease. The FD was calculated from segmented cerebral white matter MR images in 217 subjects aged about 68years, in whom archived intelligence scores from age 11years were available. Cognitive test scores of fluid and crystallised intelligence were obtained at the time of MR imaging. Significant differences were found (intracranial volume, brain volume, white matter volume and Raven's Progressive Matrices score) between men and women at age 68years and novel associations were found between FD and measures of cognitive change over the life course from age 11 to 68years. Those with greater FD were found to have greater than expected fluid abilities at age 68years than predicted by their childhood intelligence and less cognitive decline from age 11 to 68years. These results are consistent with other reports that FD measures of cortical structural complexity increase across the early life course during maturation of the cerebral cortex and add new data to support an association between FD and cognitive ageing. PMID- 22510259 TI - Biosimilar, biobetter, and next generation antibody characterization by mass spectrometry. AB - This Feature will introduce the strategies of therapeutic antibodies (mAbs) in depth characterization by mass spectrometry (MS) and discuss analytical comparison of biosimilar to originator mAbs, with the cases of trastuzumab and cetuximab. In addition, the structural and functional insights gained both by state-of-the art and emerging MS methods used for biobetters and next generation antibodies design and optimization will also be highlighted. PMID- 22510260 TI - Statin hepatotoxicity and the dilemma of causality in rare hepatic adverse drug reactions. PMID- 22510261 TI - Biliary atresia: does ethnicity matter? PMID- 22510262 TI - Which is the real efficacy of pegylated interferon alpha 2a or 2b plus ribavirin in HCV infected patients with advanced fibrosis? PMID- 22510264 TI - Why 88% of US military veterans with HCV are not treated. PMID- 22510266 TI - Accuracy of abbreviated indirect calorimetry protocols for energy expenditure measurement in critically ill children. AB - BACKGROUND: Accurate measurement of resting energy expenditure (REE) using indirect calorimetry (IC) facilitates optimal energy prescription. Steady-state (SS) REE obtained using a 5-minute protocol (SS5) has been used as a surrogate for 24-hour REE measurement. However, SS5 conditions are difficult to achieve in critically ill children on mechanical ventilatory support. METHODS: The authors prospectively examined factors associated with successful IC testing using the standard SS5 protocol in mechanically ventilated children. They examined the agreement of REE between SS5 and 2 abbreviated SS protocols: 4-minute (SS4) and 3 minute (SS3) protocols as well as the Schofield prediction equation, using Bland Altman analysis. RESULTS: IC testing (n = 45) was completed in 34 children. SS was achieved during 25 (56%), 31 (69%), and 42 (93%) tests, using the SS5, SS4, and SS3 protocols, respectively. Intratest variability in respiratory rate, endotracheal tube leak, and inspiratory time was associated with failed IC by the SS5 protocol. The mean bias (limits of agreement) for REE was 2.8 (-47 to 65), 5.8 (-71 to 72), and -127 (-418 to 1176) kcal/d using SS4, SS3, and Schofield, respectively. A stronger agreement was observed when means of all abbreviated SS REE values during a 30-minute test were used. CONCLUSION: In mechanically ventilated children, 4-minute and 3-minute SS protocols allowed REE measurements to be obtained in most patients with reasonable accuracy. Abbreviated protocols may decrease the need to rely on inaccurate equations when assessing energy expenditure in children who fail IC testing by standard SS criteria. PMID- 22510268 TI - Evidence that RNA polymerase II and not TFIIB is responsible for the difference in transcription initiation patterns between Saccharomyces cerevisiae and Schizosaccharomyces pombe. AB - The basal eukaryotic transcription machinery for protein coding genes is highly conserved from unicellular yeast to higher eukaryotes. Whereas TATA-containing promoters in human cells usually contain a single transcription start site (TSS) located ~ 30 bp downstream of the TATA element, transcription in the yeast Schizosaccharomyces pombe and Saccharomyces cerevisiae typically initiates at multiple sites within a window ranging from 30 to 70 bp or 40 to 200 bp downstream of a TATA element, respectively. By exchanging highly purified factors between reconstituted S. pombe and S. cerevisiae transcription systems, we confirmed previous observations that the dual exchange of RNA polymerase II (RNAPII) and transcription factor IIB (TFIIB) confer the distinct initiation patterns between these yeast species. Surprisingly, however, further genetic and biochemical assays of TFIIB chimeras revealed that TFIIB and the proposed B finger/reader domain do not play a role in determining the distinct initiation patterns between S. pombe and S. cerevisiae, but rather, these patterns are solely due to differences in RNAPII. These results are discussed within the context of a proposed model for the mechanistic coupling of the efficiency of early phosphodiester bond formation during productive TSS utilization and intrinsic elongation proficiency. PMID- 22510267 TI - Sequence and expression analysis of gaps in human chromosome 20. AB - The finished human genome-assemblies comprise several hundred un-sequenced euchromatic gaps, which may be rich in long polypurine/polypyrimidine stretches. Human chromosome 20 (chr 20) currently has three unfinished gaps remaining on its q-arm. All three gaps are within gene-dense regions and/or overlap disease associated loci, including the DLGAP4 locus. In this study, we sequenced ~ 99% of all three unfinished gaps on human chr 20, determined their complete genomic sizes and assessed epigenetic profiles using a combination of Sanger sequencing, mate pair paired-end high-throughput sequencing and chromatin, methylation and expression analyses. We found histone 3 trimethylated at Lysine 27 to be distributed across all three gaps in immortalized B-lymphocytes. In one gap, five novel CpG islands were predominantly hypermethylated in genomic DNA from peripheral blood lymphocytes and human cerebellum. One of these CpG islands was differentially methylated and paternally hypermethylated. We found all chr 20 gaps to comprise structured non-coding RNAs (ncRNAs) and to be conserved in primates. We verified expression for 13 candidate ncRNAs, some of which showed tissue specificity. Four ncRNAs expressed within the gap at DLGAP4 show elevated expression in the human brain. Our data suggest that unfinished human genome gaps are likely to comprise numerous functional elements. PMID- 22510269 TI - How effective is microwave ablation for atrial fibrillation during concomitant cardiac surgery? AB - A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was whether performing microwave ablative procedures during concomitant cardiac surgical procedures is effective for the treatment of atrial fibrillation (AF). In total, 200 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Major exclusion criteria included studies exclusively using bipolar ablation, ambiguous or unspecified ablation technique, other energy modalities and studies with highly variable or undisclosed follow-up time. One study reported that 66% of patients were in sinus rhythm (SR) with follow-ups ranging from 1 to 14 months and suggested that the risk of AF recurrence was significantly increased with a larger left atrial diameter (OR = 1.21, P = 0.02) and an increased duration of preoperative AF (OR = 2.14, P = 0.03). A separate study found no significant difference in the success rate on the basis of the concomitant procedure (coronary artery bypass grafting or mitral valve surgery, P > 0.5). In the only randomized trial identified, microwave ablation delivered significantly inferior SR restoration rates to radiofrequency (RF) ablation at all time points from discharge to 24 months. There is a large degree of heterogeneity in the studies, with patients' characteristics, for example type of AF, and patient management postoperatively, for example administration of anti arrhythmias, being inconsistent. Of the 12 studies, nine assessed SR at a mean of 6-12 months and found postoperative success rates between 62 and 87%. One study looked at the medium range follow-up of 24 months with SR restoration at 71%. Two studies looked at the long-term follow-up (5 and 5.37 years) with SR restoration at 39 and 61%, respectively. We conclude that microwave ablation, as an intervention for the treatment of AF during concomitant surgery, is not currently recommended on the limited available evidence. This is because the success rates in the longer term are less clear and the only randomized study to date has found inferior outcomes compared with RF-based ablation. PMID- 22510270 TI - Assessment of endothelin-A receptor expression in subcutaneous and orthotopic thyroid carcinoma xenografts in vivo employing optical imaging methods. AB - Endothelin (ET) receptor dysregulation has been described in a number of pathophysiological processes, including cardiovascular disorders, renal failure, and cancer. The aim of this study was to evaluate the expression of the ET-A receptor (ET(A)R) in murine models of thyroid carcinoma using optical imaging methods. A recently developed near-infrared fluorescent tracer was first assessed in isolated artery preparations for its functional performance in comparison with known ET(A)R antagonists BQ123 and PD156707. Before evaluation of the tracer in vivo, different thyroid carcinoma cell lines were characterized with respect to their ET receptor expression by RT-PCR and autoradiography. In vivo, sc and orthotopic papillary thyroid tumor xenografts were clearly visualized by fluorescence reflectance imaging and fluorescence-mediated tomography up to 48 h after injection of the tracer. Binding specificity of the probe was demonstrated by predosing with PD156707 as a competing inhibitor. In conclusion, optical imaging with a fluorescent ET(A)R tracer allows the noninvasive imaging of tumor associated ET(A)R expression in vivo. In the future, this technique may help surgeons to evaluate lesion dimensions in intraoperative settings (e.g. thyroidectomy). PMID- 22510271 TI - Glutamatergic and GABAergic innervation of human gonadotropin-releasing hormone-I neurons. AB - Amino acid (aa) neurotransmitters in synaptic afferents to hypothalamic GnRH-I neurons are critically involved in the neuroendocrine control of reproduction. Although in rodents the major aa neurotransmitter in these afferents is gamma aminobutyric acid (GABA), glutamatergic axons also innervate GnRH neurons directly. Our aim with the present study was to address the relative contribution of GABAergic and glutamatergic axons to the afferent control of human GnRH neurons. Formalin-fixed hypothalamic samples were obtained from adult male individuals (n = 8) at autopsies, and their coronal sections processed for dual label immunohistochemical studies. GABAergic axons were labeled with vesicular inhibitory aa transporter antibodies, whereas glutamatergic axons were detected with antisera against the major vesicular glutamate transporter (VGLUT) isoforms, VGLUT1 and VGLUT2. The relative incidences of GABAergic and glutamatergic axonal appositions to GnRH-immunoreactive neurons were compared quantitatively in two regions, the infundibular and paraventricular nuclei. Results showed that GABAergic axons established the most frequently encountered type of axo-somatic apposition. Glutamatergic contacts occurred in significantly lower numbers, with similar contributions by their VGLUT1 and VGLUT2 subclasses. The innervation pattern was different on GnRH dendrites where the combined incidence of glutamatergic (VGLUT1 + VGLUT2) contacts slightly exceeded that of the GABAergic appositions. We conclude that GABA represents the major aa neurotransmitter in axo-somatic afferents to human GnRH neurons, whereas glutamatergic inputs occur somewhat more frequently than GABAergic inputs on GnRH dendrites. Unlike in rats, the GnRH system of the human receives innervation from the VGLUT1, in addition to the VGLUT2, subclass of glutamatergic neurons. PMID- 22510272 TI - Novel genes of visceral adiposity: identification of mouse and human mesenteric estrogen-dependent adipose (MEDA)-4 gene and its adipogenic function. AB - Visceral adiposity represents a high risk factor for type 2 diabetes, metabolic syndrome, and cardiovascular disease as well as various cancers. While studying sex hormone imbalance-induced early obesity and late onset of insulin resistance in FSH receptor knock out female mice, we identified a novel mesenteric estrogen dependent adipose gene (MEDA-4) selectively up-regulated in a depot-specific manner in mesenteric adipose tissue. Meda-4 cloned from both mouse and human adipose tissue codes for a 34-kDa cytosolic protein with 91% homology. Mouse Meda 4 mRNA is expressed highest in visceral adipose tissue and localizes predominantly in the adipocyte fraction. Human MEDA-4 is also more abundant in omental fat than sc depot in obese patients. In 3T3-L1 cells endogenous Meda-4 expression increases early during differentiation, and its overexpression promotes differentiation of preadipocytes into adipocytes and enhances glucose uptake. Conversely, short hairpin RNA-mediated knockdown of Meda-4 reduces both adipogenic and glucose uptake potential. In promoting adipogenesis, Meda-4 up regulates transcription factor peroxisome proliferator-activated receptor-gamma2. Meda-4 promotes lipid accumulation in adipocytes, regulating adipocyte fatty acid binding protein 2, CD36, lipoprotein lipase, hormone-sensitive lipase, acyl Coenzyme A oxidase-1, perilipin-1, and fatty acid synthase expression. 17beta Estradiol reduced Meda-4 expression in mesenteric adipose tissue of ovariectomized mice and in 3T3-L1 adipocytes. Thus our study identifies Meda-4 as a novel adipogenic gene, capable of promoting differentiation of preadipocytes into adipocytes, increasing lipid content and glucose uptake in adipocytes. Therefore it might play an important role in adipose tissue expansion in normal and aberrant hormonal conditions and pathophysiological states. PMID- 22510274 TI - Adjusting for confounding by neighborhood using a proportional odds model and complex survey data. AB - In social epidemiology, an individual's neighborhood is considered to be an important determinant of health behaviors, mediators, and outcomes. Consequently, when investigating health disparities, researchers may wish to adjust for confounding by unmeasured neighborhood factors, such as local availability of health facilities or cultural predispositions. With a simple random sample and a binary outcome, a conditional logistic regression analysis that treats individuals within a neighborhood as a matched set is a natural method to use. The authors present a generalization of this method for ordinal outcomes and complex sampling designs. The method is based on a proportional odds model and is very simple to program using standard software such as SAS PROC SURVEYLOGISTIC (SAS Institute Inc., Cary, North Carolina). The authors applied the method to analyze racial/ethnic differences in dental preventative care, using 2008 Florida Behavioral Risk Factor Surveillance System survey data. The ordinal outcome represented time since last dental cleaning, and the authors adjusted for individual-level confounding by gender, age, education, and health insurance coverage. The authors compared results with and without additional adjustment for confounding by neighborhood, operationalized as zip code. The authors found that adjustment for confounding by neighborhood greatly affected the results in this example. PMID- 22510273 TI - Early mitochondrial adaptations in skeletal muscle to diet-induced obesity are strain dependent and determine oxidative stress and energy expenditure but not insulin sensitivity. AB - This study sought to elucidate the relationship between skeletal muscle mitochondrial dysfunction, oxidative stress, and insulin resistance in two mouse models with differential susceptibility to diet-induced obesity. We examined the time course of mitochondrial dysfunction and insulin resistance in obesity-prone C57B and obesity-resistant FVB mouse strains in response to high-fat feeding. After 5 wk, impaired insulin-mediated glucose uptake in skeletal muscle developed in both strains in the absence of any impairment in proximal insulin signaling. Impaired mitochondrial oxidative capacity preceded the development of insulin resistant glucose uptake in C57B mice in concert with increased oxidative stress in skeletal muscle. By contrast, mitochondrial uncoupling in FVB mice, which prevented oxidative stress and increased energy expenditure, did not prevent insulin resistant glucose uptake in skeletal muscle. Preventing oxidative stress in C57B mice treated systemically with an antioxidant normalized skeletal muscle mitochondrial function but failed to normalize glucose tolerance and insulin sensitivity. Furthermore, high fat-fed uncoupling protein 3 knockout mice developed increased oxidative stress that did not worsen glucose tolerance. In the evolution of diet-induced obesity and insulin resistance, initial but divergent strain-dependent mitochondrial adaptations modulate oxidative stress and energy expenditure without influencing the onset of impaired insulin-mediated glucose uptake. PMID- 22510276 TI - Differential associations between the food environment near schools and childhood overweight across race/ethnicity, gender, and grade. AB - Epidemiologic studies have observed influences of the food environment near schools on children's overweight status but have not systematically assessed the associations by race, sex, and grade. The authors examined whether the associations between franchised fast food restaurant or convenience store density near schools and overweight varied by these factors using data for 926,018 children (31.3% white, 55.1% Hispanic, 5.7% black, and 8% Asian) in fifth, seventh, or ninth grade, nested in 6,362 schools. Cross-sectional data were from the 2007 California physical fitness test (also known as "Fitnessgram"), InfoUSA, the California Department of Education, and the 2000 US Census. In adjusted models, the overweight prevalence ratio comparing children in schools with 1 or more versus 0 fast food restaurants was 1.02 (95% confidence interval (CI): 1.01, 1.03), with a higher prevalence ratio among girls compared with boys. The association varied by student's race/ethnicity (P = 0.003): Among Hispanics, the prevalence ratio = 1.02 (95% CI: 1.01, 1.03); among blacks, the prevalence ratio = 1.03 (95% CI: 1.00, 1.06), but among Asians the prevalence ratio = 0.94 (95% CI: 0.91, 0.97). For each additional convenience store, the prevalence ratio was 1.01 (95% CI: 1.00, 1.01), with a higher prevalence ratio among fifth grade children. Nuanced understanding of the impact of food environments near schools by race/ethnicity, sex, and grade may help to elucidate the etiology of childhood overweight and related race/ethnic disparities. PMID- 22510275 TI - A meta-analysis and multisite time-series analysis of the differential toxicity of major fine particulate matter constituents. AB - Health risk assessments of particulate matter less than 2.5 MUm in diameter (PM(2.5)) often assume that all constituents of PM(2.5) are equally toxic. While investigators in previous epidemiologic studies have evaluated health risks from various PM(2.5) constituents, few have conducted the analyses needed to directly inform risk assessments. In this study, the authors performed a literature review and conducted a multisite time-series analysis of hospital admissions and exposure to PM(2.5) constituents (elemental carbon, organic carbon matter, sulfate, and nitrate) in a population of 12 million US Medicare enrollees for the period 2000-2008. The literature review illustrated a general lack of multiconstituent models or insight about probabilities of differential impacts per unit of concentration change. Consistent with previous results, the multisite time-series analysis found statistically significant associations between short term changes in elemental carbon and cardiovascular hospital admissions. Posterior probabilities from multiconstituent models provided evidence that some individual constituents were more toxic than others, and posterior parameter estimates coupled with correlations among these estimates provided necessary information for risk assessment. Ratios of constituent toxicities, commonly used in risk assessment to describe differential toxicity, were extremely uncertain for all comparisons. These analyses emphasize the subtlety of the statistical techniques and epidemiologic studies necessary to inform risk assessments of particle constituents. PMID- 22510277 TI - Comparison of instrumental variable analysis using a new instrument with risk adjustment methods to reduce confounding by indication. AB - Confounding by indication is a vexing problem, especially in evaluating treatment effects using observational data, since treatment decisions are often related to disease severity, prognosis, and frailty. To compare the ability of the instrumental variable (IV) approach with a new instrument based on the local-area practice style and risk adjustment methods, including conventional multivariate regression and propensity score adjustment, to reduce confounding by indication, the authors investigated the effects of long-term control (LTC) therapy on the occurrence of acute asthma exacerbation events among children and young adults with incident and uncontrolled persistent asthma, using Iowa Medicaid claims files from 1997-1999. Established evidence from clinical trials has demonstrated the protective benefits of LTC therapy for persistent asthma. Among patients identified (n = 4,275), those with higher asthma severity at baseline were more likely to receive LTC therapy. The multivariate regression and propensity score adjustment methods suggested that LTC therapy had no effect on the occurrence of acute exacerbation events. Estimates from the new IV approach showed that LTC therapy significantly decreased the occurrence of acute exacerbation events, which is consistent with established clinical evidence. The authors discuss how to interpret estimates from the risk adjustment and IV methods when the treatment effect is heterogeneous. PMID- 22510278 TI - Association of particulate air pollution with daily mortality: the China Air Pollution and Health Effects Study. AB - China is one of the few countries with some of the highest particulate matter levels in the world. However, only a small number of particulate matter health studies have been conducted in China. The study objective was to examine the association of particulate matter with an aerodynamic diameter of less than 10 MUm (PM(10)) with daily mortality in 16 Chinese cities between 1996 and 2008. Two stage Bayesian hierarchical models were applied to obtain city-specific and national average estimates. Poisson regression models incorporating natural spline smoothing functions were used to adjust for long-term and seasonal trends of mortality, as well as other time-varying covariates. The averaged daily concentrations of PM(10) in the 16 Chinese cities ranged from 52 MUg/m(3) to 156 MUg/m(3). The 16-city combined analysis showed significant associations of PM(10) with mortality: A 10-MUg/m(3) increase in 2-day moving-average PM(10) was associated with a 0.35% (95% posterior interval (PI): 0.18, 0.52) increase of total mortality, 0.44% (95% PI: 0.23, 0.64) increase of cardiovascular mortality, and 0.56% (95% PI: 0.31, 0.81) increase of respiratory mortality. Females, older people, and residents with low educational attainment appeared to be more vulnerable to PM(10) exposure. Conclusively, this largest epidemiologic study of particulate air pollution in China suggests that short-term exposure to PM(10) is associated with increased mortality risk. PMID- 22510279 TI - Sexual function and quality of life of women with stress urinary incontinence: a randomized controlled trial comparing the Paula method (circular muscle exercises) to pelvic floor muscle training (PFMT) exercises. AB - AIM: To compare the effectiveness of the Paula method (circular muscle exercises) vs. pelvic floor muscle training (PFMT) exercises on sexual function (SF) and quality of life (QoL) of women with stress urinary incontinence (SUI). METHODS: A randomized controlled trial (RCT) was conducted in outpatient urban community clinics serving diverse socioeconomic populations between September 2004 and July 2005. The intervention included two exercise regimens: Paula method--12 weeks of private 45 minutes sessions; PFMT--12 weeks of group (up to 10 participants) sessions of 30 minutes in length once a week, for 4 weeks plus two additional sessions, 3 weeks apart. MAIN OUTCOME MEASURES: The Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire; the Incontinence Quality of Life Questionnaire; 1-hour clinic pad test; gynecological examination; demographic/health history. RESULTS: Sixty-six women in the Paula group and 60 women in the PFMT group. The mean SF scores post interventions were 38.72 (5.35) in the Paula group and 38.07 (5.80) in the PFMT group. SF score improvement was found to be significant in both groups (Paula, P = 0.01; PFMT, P = 0.05), as was in the QoL scores (Paula, P < 0.001; PFMT, P <= 0.001), with no significant difference between groups. There was a significant correlation between the mean SF score and the mean QoL score after the intervention (Paula: r = 0.4, P = 0.002; PFMT: r = 0.4, P = 0.009). A mild to moderate significant correlation was also found between the SF score and pad test results in both groups post intervention (r = -0.3, P = 0.02; r = -0.3, P = 0.04, respectively). CONCLUSION: This RCT study demonstrated the effectiveness of two exercise methods on SF and QoL in women suffering from SUI. The Paula method of exercise was presented for the first time in the literature as a conservative noninvasive treatment for SUI and SF. PMID- 22510281 TI - MicroRNA-153 negatively regulates the expression of amyloid precursor protein and amyloid precursor-like protein 2. AB - Increased expression of the amyloid precursor protein (APP) is a crucial risk factor of Alzheimer's disease (AD). Amyloid precursor-like protein 2 (APLP2), a homologue of APP, is also suggested to participate in AD pathogenesis. Accumulating evidence suggest the regulatory role of microRNA on AD-related genes. Here we showed that the levels of miR-153 were significantly decreased at early- and late-stage of AD in APPswe/PSDeltaE9 murine model. Moreover, a binding site of miR-153 on APP and APLP2-3'UTR was identified, respectively, by luciferase assay. Gain and loss of function experiments demonstrated that miR-153 suppressed the expression of APP and APLP2. Using miR-153 transgenic mouse model, we testified that miR-153 downregulated the expression of APP and APLP2 protein in vivo. Furthermore, closely related expression patterns of miR-153 and APP/APLP2 during brain development indicated a physiological regulation role of miR-153 on the two genes. In a neuronal cell line treated with Abeta(42) peptides and H(2)O(2,) the levels of miR-153 varied during time-course leading to corresponding changes of APLP2 protein, indicating Abeta peptides and oxidative stress influence the expression of miR-153. Thus, miR-153 contributes to post transcriptional regulation of APP/APLP2, suggesting a possible role for miR-153 in neuro-pathological conditions. PMID- 22510280 TI - Identification of somatic mutations in non-small cell lung carcinomas using whole exome sequencing. AB - Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole-exome sequencing in 31 NSCLCs and their matched normal tissue samples. We identified both common and unique mutation spectra and pathway activation in lung adenocarcinomas and squamous cell carcinomas, two major histologies in NSCLC. In addition to identifying previously known lung cancer genes (TP53, KRAS, EGFR, CDKN2A and RB1), the analysis revealed many genes not previously implicated in this malignancy. Notably, a novel gene CSMD3 was identified as the second most frequently mutated gene (next to TP53) in lung cancer. We further demonstrated that loss of CSMD3 results in increased proliferation of airway epithelial cells. The study provides unprecedented insights into mutational processes, cellular pathways and gene networks associated with lung cancer. Of potential immediate clinical relevance, several highly mutated genes identified in our study are promising druggable targets in cancer therapy including ALK, CTNNA3, DCC, MLL3, PCDHIIX, PIK3C2B, PIK3CG and ROCK2. PMID- 22510282 TI - Distribution of bacterial contamination in a teaching hospital in Tehran - a special focus on Staphylococcus aureus. AB - There are documents that confirm the cycle of bacterial transmission between patients, staff, and the inanimate environment. The environment may have more effect on intensive care units (ICUs), because the patients who require intensive care have unstable clinical conditions and are more sensitive to infections. The aim of this study was to determine the prevalence of bacteria in air and inanimate surface in the ICUs and to compare the microbial levels to standard levels.Air and inanimate surface in the four ICUs of a teaching hospital underwent weekly surveillance by means of air sampler and swabs for a period of six-month. Total bacterial counts were evaluated onto trypticase soy agar and mannitol salt agar (MSA).A total of 725 samples [air (168) and inanimate surfaces (557)] were collected. The total mean +/- SD CFU/m3 of airborne bacteria in all of the ICUs were 115.93 +/- 48.04. The most common bacteria in air of the ICUs were Gram-positive cocci (84.2%). The total mean +/- SD airborne of Staphylococcus aureus was 12.10+/-8.11 CFU/m3. The highest levels of S. aureus contamination were found in ventilators and bed ledges. More suitable disinfection of hospital environments and monthly rotation in utilization of the various disinfectant agents are needed for the prevention of airborne and inanimate transmission of S. aureus. PMID- 22510283 TI - Interaction of methylxanthines and gentamicin against Staphylococcus aureus and Pseudomonas aeruginosa: role of phosphodiesterase inhibition. AB - Previous studies showed that methylxanthines increased the antimicrobial activity of gentamicin against Staphylococcus aureus and Pseudomonas aeruginosa. In this study, the effect of non-selective phosphodiesterase (PDE) inhibitors (methylxanthines: aminophylline and caffeine) and partially selective PDE inhibitors, dipyridamole and sildenafil, was evaluated on the antimicrobial activity of gentamicin using checkerboard method. Aminophylline at concentrations of 0.5 and 1 mg/ml reduced the minimal inhibitory concentration (MIC) of gentamicin (2 MUg/ml) 2 and 4 times against S. aureus, and at concentrations of 0.5 and 2 mg/ml reduced the MIC of gentamicin (4 MUg/ml) 2 and 4 times, respectively, against P. aeruginosa. Caffeine at concentrations of 1 and 2 mg/ml reduced the MIC of gentamicin (2 MUg/ml) 4 and 32 times against S. aureus, and at concentrations of 0.12 and 2 mg/ml reduced the MIC of gentamicin (4 MUg/ml) 2 and 4 times, respectively, against P. aeruginosa. However, dipyridamole and sildenafil (32 MUg/ml) did not show any effect on MIC of gentamicin against S. aureus and P. aeruginosa. These results suggest that methylxanthines could increase gentamicin effects against S. aureus and P. aeruginosa but this effect is not mediated by inhibition of PDE 5, 6, 8, 10 and 11. PMID- 22510284 TI - Clinical streptococci and their sensitivity to enterocins produced by different strains of the species Enterococcus faecium (short communication). AB - In children, acute otitis media (AOM) is one of the most frequently occurring infections caused by Streptococcus pneumoniae and Str. pyogenes. The standard treatment of AOMis provided by antibiotics; however, an increased resistance of the causative agents to antibiotics requires the need to search for innovations. This study was focused on in vitro testing sensitivity of streptococci isolated from AOM to enterocins produced by 9 different origin strains of E. faecium. Enterocins (Ent) represent ribosomally synthesized proteinaceous substances with antimicrobial activity against Gram-positive and/or Gram-negative bacteria which are produced mostly by strains of the species Enterococcus faecium. Str. pneumoniae were sensitive at least to 1 Ent. Str. pneumoniae SPn 754 was sensitive to 5 Ent. Five Str. pyogenes were sensitive to enterocins. Ent A (P) inhibited the growth of 3 Str. pneumoniae, and 4 Str. pyogenes (activity between 100 and 3,200 AU/ml). Most of Ent inhibited the growth of streptococci tested (100-3,200 AU/ml). Str. pyogenes were more sensitive to Ent than Str. pneumoniae. Although more detailed further studies are required, our results indicate a new possibility for enterocin use. PMID- 22510285 TI - Evaluation of fungaemia infections in a Hungarian university hospital between 1996 and 2009. AB - The incidence of Candida species causing bloodstream infections in the University Hospital of Szeged, Hungary, between 1996 and 2009, and the susceptibilities of these isolates to antifungal agents were evaluated.Automated blood culture systems (Vital, bioMerieux, Marcy-l'Etoile, France; and BACTEC 9120, Becton Dickinson Diagnostic Systems, Sparks, USA) were used. The in vitro susceptibilities of the yeast isolates to antifungal agents were determined by the Etest method (AB Biodisk, Solna, Sweden).Bloodstream infections were caused by yeast strains in 231 cases during this period, and 226 Candida strains were cultured from 216 candidaemia patients. Bloodstream infections caused by multiple Candida spp. were diagnosed almost every year. Of the 216 patients, 67 were children; and 55 infants needed intensive care. In 2005, C. glabrata caused an increase in the incidence of invasive fungal infections in the Neonatal Intensive Care Unit. The PFGE analysis of 12 isolates distinguished 4 different karyotypes. The incidence of bloodstream infections caused by fungi did not change during the 14-year study period. The most frequent species cultured from blood samples were C. albicans and C. glabrata. The incidence of resistant isolates remained constant. The local trends of fungaemia must be monitored and compared with global reports. PMID- 22510286 TI - Serum level of specific IgG antibody for aspergillus and its association with severity of asthma in asthmatic children. AB - Aspergillosis is one of the frequent causes of exacerbation of asthma depending on the geographical regions. The specific serum IgG level for aspergillus is a major diagnostic criterion in aspergillosis.Ninety-six asthmatic patients, with mean age of 5.4 +/- 3.0 years who were referred to the asthma clinic of the Mofid Children's Hospital, were enrolled in this study. Serum specific IgG for aspergillus was measured and its association with severity of asthma was evaluated.Nineteen asthmatic patients (10 females and 9 males) had aspergillus IgG antibody. Among them, severe persistent asthma and moderate persistent asthma were detected in 5 and 13 cases, respectively, whereas only one patient suffered from mildpersistent asthma. A total of 36.5% of the 96 patients had a history of atopy, while 26% had allergic rhinitis. There was an association between the severity of asthma and the presence of aspergillus IgG antibody. Moreover, the positivity for aspergillus IgG antibody was higher in older patients.Our results indicated an association between aspergillus antibody level and severity of asthma. It could be recommended that the IgG titer for aspergillus is measured in pediatric patients with asthma, whereas co-morbidity of aspergillosis and asthma increases the risk of asthma exacerbation. PMID- 22510287 TI - Effect of caries preventive products on the growth of bacterial biofilm on titanium surface. AB - Fluorides may affect the oxide layer on titanium surface. Caries preventive mouthwashes or gels contain fluorides and are applied at low pH. The aim of the present work was to study whether various concentrations of fluoride at acidic pH cause changes in the surface structure on the polished region of Ti implants, and alter the adherence and colonization of bacteria. Commercially pure Ti grade 4 discs with a polished surface were treated with a mouthwash containing 0.025% fluoride, a gel containing 1.25% fluoride or a 1% aqueous solution of NaF (pH 4.5). The change of surface roughness of the samples and the colonization of Porphyromonas gingivalis strains were studied by scanning electron microscopy after 5 days of anaerobic incubation. The quantity of the bacterial protein was determined by protein assay analysis. Agents with high fluoride concentration at acidic pH increased the roughness of the Ti surface. A slight increase in the amount of bacteria was found on the surfaces treated with 1% NaF and gel in comparison with the control surface. This study suggested that a high fluoride concentration at acidic pH may hinder the development of a healthy transgingival epithelial junction on Ti implants, due to bacterial colonization. PMID- 22510288 TI - Attempted immunotherapy for Mycobacterium tuberculosis with viral and protein vaccines based on Ag85B-ESAT6 in a mouse model. AB - The increasing threat of drug-resistant strains of Mycobacterium tuberculosis (M. tb) and co-infection with human immunodeficiency virus (HIV) has worsened the international public health crisis and challenged conventional chemotherapy. Therapeutic vaccines, which possess the capacity to stimulate the immune system and affect the disease progression, deserve reconsideration to aid chemotherapy. Vaccines based on Ag85B-ESAT6 fusion protein were tested as potential immunotherapeutic vaccines against ongoing intravenous infection in a mouse model. Therapeutic efficacy was evaluated by enumeration of bacilli in infected tissues and by histological examination of the lungs. Ag85B-ESAT6 with the adjuvant dimethyl dioctadecylammonium bromide (DDA) - monophosphoryl lipid A (MPL) did not reduce bacterial load, however induced a sharp weight loss and worsened pathology. Recombinant virus-based vaccines failed to protect mice against tuberculosis either. More efforts should be taken to search for protective candidates and elucidate the mechanism for immunotherapy. PMID- 22510289 TI - Drug resistance in Vibrio cholerae strains isolated from clinical specimens. AB - Cholera is a serious epidemic and endemic disease caused by the Gram-negative bacterium Vibrio cholerae. SXT is an integrative conjugation element (ICE) that was isolated from a V. cholerae; it encodes resistance to the antibiotics chloramphenicol, streptomycin and sulfamethoxazole/trimethoprim. One hundred seven V. cholerae O1 strains were collected from cholera patients in Iran from 2005 to 2007 in order to study the presence of SXT constin and antibiotic resistance.The study examined 107 Vibrio cholerae strains isolated from cholera prevalent in some Iranian provinces. Bacterial isolation and identification were carried out according to standard bacteriological methods. Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) to four antibiotics (chloramphenicol, streptomycin, sulfamethoxazole, and trimethoprim) were determined by broth microdilution method. PCR was employed to evaluate the presence of established antibiotic resistance genes and SXT constin using specific primer sets.The resistance of the clinical isolates to sulfamethoxazole, trimethoprime, chloramphenicol, and streptomycin was 97%, 99%, 99%, and 90%, respectively. The data obtained by PCR assay showed that the genes sulII, dfrA1, floR, strB, and sxt element were present in 95.3%, 95.3%, 81.3%, 95.3%, and 95.3% of the V. cholerae isolates.The Vibrio strains showed the typical multidrug resistance phenotype of an SXT constin. They were resistant to sulfamethoxazole, trimethoprime, chloramphenicol, and streptomycin. The detected antibiotic resistance genes included dfrA for trimethoprim and floR, strB, sulII and int, respectively, for chloramphenicol, streptomycin, sulfamethoxazole, as well as the SXT element. PMID- 22510290 TI - A case of urinary tract infection due to Salmonella enterica serovar Virchow and review of the related literature. AB - Nontyphoid salmonella (NTS) serotypes can cause gastroenteritis, bacteriemia, and focal infections. However, these focal infections, including urinary tract infections (UTI), are occasionally observed; in particular, the presence of several predisposing factors, such as immunodeficiency and structural abnormality in the urinary tract, increase the possibility of the occurrence of infection. We present a case of UTI caused by Salmonella enterica serovar Virchow in an elderly and debilitated patient with benign prostatic hyperplasia (BPH). Administration of appropriate antibiotic treatment resulted in recovery of the patient's clinical course. PMID- 22510291 TI - Comparison of soil microbial communities from two distinct karst areas in Hungary. AB - Karst areas belong to the most exposed terrestrial ecosystems, therefore their study have a priority task in Hungary, as well. The aim of this study was to compare the structure, activity and diversity of soil microbial communities from two distinct Hungarian karst areas (Aggtelek NP and Tapolca-basin). Soil samples were taken three times from 6 distinct sites, from different depths. Soil microbial biomass C (MBC), microbial biomass N (MBN), basal respiration (BRESP) and substrate induced respiration (SIR) were measured. The phylogenetic diversity of bacterial communities was compared by Denaturing Gradient Gel Electrophoresis (DGGE). The highest MBC, MBN, BRESP and SIR values were measured in the rendzina soil from Aggtelek. On the basis of biomass and respiration measurements, microbial communities differentiated mainly according to soil depths whereas DGGE profiles of bacterial communities resulted in groups mainly according to sampling sites. PMID- 22510292 TI - Nasal carriage of Streptococcus pneumoniae among Hungarian children before the wide use of the conjugate vaccine. AB - Streptococcus pneumoniae is responsible for a significant amount of morbidity and mortality worldwide, especially among children <5 years. Healthy carriers are the most important sources of infections and the carriage also peaks in the first years of life, especially among children attending communities. In this study, for the first time in Hungary, we surveyed the nasal carriage of healthy children, just before the use of the conjugate vaccine started increasing.Nasal specimens of 358 children were cultured and pneumococci isolated. The strains were serotyped with antisera and PCR, genotyped by PFGE and their antibiotic sensitivity determined by agar dilution method.The carriage rate was 37.71%. The isolates were sensitive to most tested antibiotics, except for macrolides. In this cohort of specimens still the widespread, so-called "pediatric serotypes" dominated (14, 19F, 23F, 6A, 6B in ranking order), but three of the previously rare types: 15B, 11A and 13 were represented already by 21.5% of all strains and also a few other rare non-vaccine types (e.g. 10A or 37) were detected.The calculated vaccine coverage was 55.6% for PCV-7, 69.6% for PCV-13 and 86.7% for Pneumovax. In this cohort, only 15.9% of the children (n = 57) were vaccinated. The carriage rate of PCV-7 vaccinated children was significantly lower (30.4%) than that of the non-vaccinated group (39.2%). The clonality of the isolates was significant within each group, revealing the extensive bacterium exchange among children. PMID- 22510293 TI - Are we protected? Imported measles - on the way to eradication. AB - In accordance with the 2015 regional goal for measles and rubella elimination of the WHO European Region, only a few imported cases have been documented of both diseases in Hungary for years.This paper presents a case of a Hungarian woman, born in 1975, who received measles vaccination at age of 12 months and later at age of 11 years, according to her certificate of vaccination. In 2009, after arriving home from a vacation in Ireland, she developed acute measles infection with clinical symptoms. It was confirmed by the detection of measles specific IgM, IgA and IgG antibodies, and by detection of viral nucleic acid from throat swab in virus transport medium.Additionally, an outbreak occurred in December of 2011 among a family emigrated from Romania to Hungary. No new measles cases were diagnosed among the contact persons of neither the young Hungarian woman returning from Ireland, nor the family emigrated from Romania. This observation refers to the effectiveness of the Hungarian vaccination program. PMID- 22510294 TI - Variability of plasma and urine betaine in diabetes mellitus and its relationship to methionine load test responses: an observational study. AB - BACKGROUND: Since betaine is an osmolyte and methyl donor, and abnormal betaine loss is common in diabetes mellitus (>20% patients), we investigated the relationship between betaine and the post-methionine load rise in homocysteine, in diabetes and control subjects. The post-methionine load test is reported to be both an independent vascular risk factor and a measure of betaine sufficiency. METHODS: Patients with type 2 diabetes (n = 34) and control subjects (n = 17) were recruited. We measured baseline fasting plasma and 4-hour post-methionine load (L-methionine, 0.1 mg/kg body weight) concentrations of homocysteine, betaine, and the betaine metabolite N,N-dimethylglycine. Baseline urine excretions of betaine, dimethylglycine and glucose were measured on morning urine samples as the ratio to urine creatinine. Statistical determinants of the post methionine load increase in homocysteine were identified in multiple linear regression models. RESULTS: Plasma betaine concentrations and urinary betaine excretions were significantly (p < 0.001) more variable in the subjects with diabetes compared with the controls. Dimethylglycine excretion (p = 0.00014) and plasma dimethylglycine concentrations (p = 0.039) were also more variable. In diabetes, plasma betaine was a significant negative determinant (p < 0.001) of the post-methionine load increase in homocysteine. However, it was not conclusive that this was different from the relationship in the controls. In the patients with diabetes, a strong relationship was found between urinary betaine excretion and urinary glucose excretion (but not with plasma glucose). CONCLUSIONS: Both high and low plasma betaine concentrations, and high and low urinary betaine excretions, are more prevalent in diabetes. The availability of betaine affects the response in the methionine load test. The benefits of increasing betaine intake should be investigated. PMID- 22510296 TI - Atorvastatin synergizes with IFN-gamma in treating human non-small cell lung carcinomas via potent inhibition of RhoA activity. AB - Interferon-gamma (IFN-gamma) has been widely used to treat various malignant tumors including human non-small-cell-lung carcinomas (NSCLCs). However, the tumor-inhibitory effect of IFN-gamma displays not satisfactory in NSCLC treatment due to the lack of immunogenicity of NSCLCs. This study demonstrated that inhibition of RhoA activity led to significant inhibition of NSCLC cell growth accompanied by decreased expression of c-myc and cyclin D1 and increased levels of major histocompatibility complex (MHC) class I and peptide transporter protein 1 (TAP1) which are involved in tumor immunity. Combination treatment of atorvastatin and IFN-gamma resulted in a synergistic inhibition of NSCLC cell growth both in vitro and in vivo. Though IFN-gamma alone exerted minimal inhibitory effect on RhoA activity, additional administration of atorvastatin could result in a significant inhibition of RhoA activity, thus substantially suppressing NSCLC cell growth. Specifically, atorvastatin could induce specific deposition of endogenous IFN-gamma in tumors while not in other normal tissues in LLC-harbored mice. In conclusion, atorvastatin can enhance IFN-gamma sensitivity in NSCLCs both in vitro and in vivo, probably through induction of a synergistic inhibitory effect on RhoA activity. This study also suggests a potential alternative of combination of atorvastatin and IFN-gamma in clinical therapy against NSCLCs. PMID- 22510295 TI - Pregnancy related back pain, is it related to aerobic fitness? A longitudinal cohort study. AB - BACKGROUND: Low back pain with onset during pregnancy is common and approximately one out of three women have disabling pain. The pathogenesis of the pain condition is uncertain and there is no information on the role of physical fitness. Whether poorer physical conditioning is a cause or effect of back pain is also disputed and information from prospective studies needed. METHODS: A cohort of pregnant women, recruited from maternal health care centers in central Sweden, were examined regarding estimated peak oxygen uptake by cycle ergometer test in early pregnancy, reported physical activity prior to pregnancy, basic characteristics, back pain during pregnancy and back pain postpartum. RESULTS: Back pain during the current pregnancy was reported by nearly 80% of the women. At the postpartum appointment this prevalence was 40%. No association was displayed between estimated peak oxygen uptake and incidence of back pain during and after pregnancy, adjusted for physical activity, back pain before present pregnancy, previous deliveries, age and weight. A significant inverse association was found between estimated peak oxygen uptake and back pain intensity during pregnancy and a direct association post partum, in a fully adjusted multiple linear regression analysis. CONCLUSIONS: Estimated peak oxygen uptake and reported physical activity in early pregnancy displayed no influence on the onset of subsequent back pain during or after pregnancy, where the time sequence support the hypothesis that poorer physical deconditioning is not a cause but a consequence of the back pain condition. The mechanism for the attenuating effect of increased oxygen uptake on back pain intensity is uncertain. PMID- 22510297 TI - The signaling mechanisms mediating the inhibitory effect of TCH-1116 on formyl peptide-stimulated superoxide anion generation in neutrophils. AB - In fMLP (formyl-Met-Leu-Phe)-stimulated rat neutrophils, a mixture of regioisomers benzo[a]furo[2,3-c]phenazine-10-carboxylic acid and benzo[a]furo[2,3 c]phenazine-11-carboxylic acid (TCH-1116) inhibited O(2)(-) (superoxide anion) generation, which was not mediated by scavenging the generated O(2)(-) or by a cytotoxic effect on neutrophils. TCH-1116 had no effect on the arachidonic acid induced NADPH oxidase activation in a cell-free system, whereas it effectively attenuated the phosphorylation of Ser residues in p47(phox) and the association between p47(phox) and p22(phox) in fMLP-stimulated neutrophils. The interaction of p47(phox) with PKC (protein kinase C) isoforms (alpha, betaI, betaII, delta and zeta) was attenuated by TCH-1116, whereas TCH-1116 did not affect the PKC isoforms membrane translocation, phosphorylation (Ser660) and kinase activity. TCH-1116 effectively attenuated the association between PKB/Akt (protein kinase B) and p47(phox), Akt phosphorylation (Thr308/Ser473) and kinase activities of Akt and human recombinant PDK (3-phosphoinositide-dependent kinase) 1, whereas it had no effect on recruitment of Akt, phospho-PDK1 (Ser241) and p110gamma to membrane. Moreover, the interaction of p21-activated kinase (PAK) 1 with p47(phox) and the phosphorylation of PAK1 (Thr423 but not Ser144) were inhibited by TCH-1116, but without affecting the membrane recruitment of PAK1. The cellular cyclic AMP level was not changed by TCH-1116. Taken together, these results suggest that TCH-1116 inhibits fMLP-stimulated O(2)(-) generation in rat neutrophils through the blockade of PKC, Akt and PAK signaling pathways. PMID- 22510298 TI - Diagnosis and management of neonatal leukaemia. AB - Leukaemia in neonates (infants <1 month) is rare, whereby neonatal acute myeloid leukaemia (AML) is more frequent than neonatal acute lymphoblastic leukaemia (ALL). High mortality rates are observed, though AML has a better prognosis than ALL. Neonatal leukaemia is typically presented with hepatosplenomegaly, leukaemia cutis and/or hyperleucocytosis. Congenital infections should be ruled out before diagnosis. Rearrangement of the MLL gene is the most frequently occurring genetic aberration. Treatment includes intensive multi-agent chemotherapy, usually with age-related dose adjustments next to supportive care. Treatment intensification for ALL could be indicated in the future as the dismal prognosis is subject to high relapse rates in ALL. PMID- 22510299 TI - Patients with psoriatic arthritis may show differences in their clinical and genetic profiles depending on their age at psoriasis onset. AB - OBJECTIVES: The age of psoriasis onset has an important impact on the clinical expression and heritability of psoriasis. Psoriasis characteristics according to the age at disease onset have been extensively studied. However, the impact of the age of psoriasis onset on psoriatic arthritis (PsA) features has not been analysed in depth. The aim of the present paper is to analyse whether the age of psoriasis onset may have an impact on the clinical and genetic characteristics in a cohort of PsA patients. METHODS: The study included 110 PsA patients classified in accordance with the CASPAR criteria. Patients were divided into early (onset age <30 years) and late (onset age >30 years) onset psoriasis, and clinical features were studied in accordance to this stratification. Distribution of several genes within the MHC region were analysed in accordance with the prior stratification, and their frequencies compared to that of 110 healthy matched blood donors. RESULTS: Compared to patients with late-onset disease, PsA patients with early-onset psoriasis showed more frequently: a longer psoriasis-arthritis latency period (9.9+/-6 years vs. 3.8+/-4 years, p=0.0001), a positive family history of disease (60.3% vs. 20.5%, OR 6.1, 95% CI: 2.5-15.0, p=0.0001), severe psoriasis (PASI 8.2+/-4 vs. 3.6+/-2.2, p=0.0001), clinical enthesitis (37.7% vs. 22.4%, OR 2.09, 95% CI: 0.9-4.9, p=0.08), and oligoarthritis (47.5% vs. 28.6%, OR 2.26, 95% CI: 1.02-5.02, p=0.04). MICA-A9 was associated with susceptibility in both early-onset (60.7% vs. 30%, p=0.0002) and late-onset patients (59.2% vs. 30%, p=0.0008). However, HLA-Cw*0602 was significantly increased in patients with early-onset psoriasis (73.8% vs. 17%, p<0.0001), whereas the allele 384 of the microsatellite C1_4_4, located 34 kb telomeric to HLA-C locus, was increased only in late-onset cases (49% vs. 21%, p=0.001). CONCLUSIONS: Clinical and genetic features of PsA may differ depending on the age at psoriasis onset. This type of stratification should be considered in future genetic and epidemiological studies of PsA. PMID- 22510300 TI - The effect of various intensities of physical activity and chronic inflammation in men and women by diabetes status in a national sample. AB - Moderate-to-vigorous physical activity (MVPA) has been shown to be inversely associated with C-reactive protein (CRP); however, the association between light intensity physical activity (LPA), and CRP is unknown. Our findings suggest that focusing on increasing MVPA, relative to LPA, may have a greater impact on inflammation regardless of diabetes status. PMID- 22510301 TI - Sexual and cardiovascular correlates of male unfaithfulness. AB - INTRODUCTION: Definitions of unfaithfulness and its consequences vary across different cultures, religions, and legal jurisdictions; however, having extramarital affairs is associated in most societies with a stigma. Therefore, the study of this sensitive topic is extremely complex, and its prevalence is often underestimated. AIM: To offer a summary of available data in literature about unfaithfulness. METHOD: An extensive Medline search was performed including the following words "unfaithfulness,""extramarital affairs,""infidelity,""men." The search, up to December 4, 2011, was restricted to English-language articles. MAIN OUTCOME MEASURES: We reported literature data on the prevalence of unfaithfulness and on related psychobiological, sexual, and risk factors. RESULTS: Some surveys reported that 1.5-4% of married men had extramarital coitus in any given year, others that 23.2% of men have cheated during their current relationship. Different studies reported a lifetime prevalence of unfaithfulness between 15% and 50%. With respect to factors related to unfaithfulness, several authors reported that men with extramarital affairs more frequently have a dysfunctional primary relationship, in both relational and sexual terms. In addition, parenthood, as well as conflicts within the family, seem to be associated with a higher risk of having an affair. Furthermore, unfaithful men display a higher androgenization, larger testis volume, lower prevalence of hypoactive sexual desire, and better sexual functioning. Only few studies have evaluated the correlation between infidelity and cardiovascular risk, reporting that having an extramarital affair could have a negative impact on cardiac morbidity and mortality. CONCLUSIONS: Several interpersonal, sexual, and biological factors are associated with having extramarital affairs. Unfaithfulness in men seems to be associated with a higher risk of major cardiovascular events. PMID- 22510302 TI - Distributed network organization underlying feeding behavior in the mollusk Lymnaea. AB - The aim of the work reviewed here is to relate the properties of individual neurons to network organization and behavior using the feeding system of the gastropod mollusk, Lymnaea. Food ingestion in this animal involves sequences of rhythmic biting movements that are initiated by the application of a chemical food stimulus to the lips and esophagus. We investigated how individual neurons contribute to various network functions that are required for the generation of feeding behavior such as rhythm generation, initiation ('decision making'), modulation and hunger and satiety. The data support the view that feeding behavior is generated by a distributed type of network organization with individual neurons often contributing to more than one network function, sharing roles with other neurons. Multitasking in a distributed type of network would be 'economically' sensible in the Lymnaea feeding system where only about 100 neurons are available to carry out a variety of complex tasks performed by millions of neurons in the vertebrate nervous system. Having complementary and potentially alternative mechanisms for network functions would also add robustness to what is a 'noisy' network where variable firing rates and synaptic strengths are commonly encountered in electrophysiological recording experiments. PMID- 22510303 TI - Measuring complete isotopomer distribution of aspartate using gas chromatography/tandem mass spectrometry. AB - We have developed a simple and accurate method for determining the complete positional isotopomer distribution of aspartate carbon atoms by gas chromatography/tandem mass spectrometry for (13)C-metabolic flux analysis. First, we screened tandem mass spectrometry (MS) spectra of the tert-butyldimethylsilyl (TBDMS) derivative of aspartate for daughter fragments with the necessary carbon atom fragmentations to fully resolve all 16 isotopomers of aspartate. Tandem MS scanning parameters were optimized for each daughter fragment, and the accuracy of tandem MS measurements were evaluated. We selected five accurate fragments that provided a redundant set of 47 labeling measurements to quantify the complete isotopomer distribution of aspartate by least-squares regression. The validity of the approach was demonstrated using six (13)C-labeled aspartate standards and natural aspartate. PMID- 22510304 TI - Endocannabinoids modulate non-adrenergic, non-cholinergic inhibitory neurotransmission in strips from the mouse gastric fundus. AB - AIM: To investigate the effects of endocannabinoids on non-adrenergic, non cholinergic (NANC) relaxant responses in gastric strips from mice. METHODS: Gastric longitudinal strips from the fundus region were mounted in organ baths for isometric recording. RESULTS: In carbachol-precontracted strips, electrical field stimulation (EFS) elicited tetrodotoxin (TTX)-sensitive fast nitrergic relaxant responses that were followed, at the highest stimulation frequency, by sustained relaxations. The latter were abolished by alpha-chymotrypsin. Anandamide caused a TTX-sensitive relaxation that was abolished by alpha chymotrypsin but unaffected by the nitric oxide (NO) synthesis inhibitor, Nomega nitro-L-arginine (L-NNA). Anandamide reduced the amplitude of EFS-induced fast relaxations, whereas increased that of sustained ones. Relaxation to the nicotinic receptor agonist dimethylphenyl piperazinium iodide (DMPP) was decreased in amplitude by either anandamide or L-NNA, whereas, surprisingly, it was increased by alpha-chymotrypsin and abolished by L-NNA plus alpha chymotrypsin. Relaxation to vasoactive intestinal polypeptide (VIP) was not influenced by anandamide or L-NNA and was abolished by alpha-chymotrypsin. Following VIP desensitization, fast relaxant responses to EFS were reduced and the sustained ones abolished. The CB1 receptor antagonist AM251 increased, only at the highest stimulation frequency, the amplitude of the EFS-induced fast relaxation and reduced the sustained one. AM251 increased the response to DMPP and abolished that to anandamide. The CB2 receptor antagonist AM630 had no effects. CONCLUSION: These results indicate that endocannabinoids modulate, via prejunctional CB1 receptors, the NANC peptidergic neurotransmission that, in turn, affects the nitrergic one. PMID- 22510305 TI - Effects of HbA1c and weight reduction on blood pressure in patients with type 2 diabetes mellitus treated with exenatide*. AB - AIM: Treatment of patients with type 2 diabetes with glucagon-like peptide-1 (GLP 1) receptor agonist exenatide has showed improvements in glycaemic control coupled with weight loss and lowered blood pressure (BP). We examined the synergy between improved glycaemia and weight loss on BP reduction in patients treated with either exenatide twice daily (BID) or once weekly (QW). METHODS: Combining data from three controlled trials, 686 (53% male) patients [baseline mean +/- SD: age 55 +/- 10 years, weight 95 +/- 20 kg, systolic blood pressure (SBP)/diastolic blood pressure (DBP) 130/79 +/- 15/9 mmHg, HbA(1c) 8.3 +/- 1.1%] treated with exenatide QW (n = 541) or BID (n = 145) were observed over 26 weeks. Using weighted means (WMs) of the longitudinal measures of HbA(1c) and weight, patients were subdivided into four groups at each visit by glycaemic and weight responses; patients who failed to reduce both HbA(1c) and weight below WMs became the reference group (R). The other three groups corresponded to patients with HbA(1c) reduction (A), weight reduction (W) and both HbA(1c) and weight reduction (AW). RESULTS: Compared with R, patients in AW, A and W groups had a significantly higher likelihood of improving SBP <130 mmHg by 88, 30 and 61%, respectively. Compared with R, patients in AW, A and W had 63, 13 and 45% higher likelihood of improving DBP <80 mmHg. CONCLUSION: Although the mechanism of BP-lowering effect of exenatide is not established, it appears that the short-term dynamics of BP is related to concomitant effects on glycaemia and body weight. These data offer a preliminary insight into the possible cardiometabolic effects of GLP-1 receptor agonism. PMID- 22510307 TI - Differential susceptibility to plasticity: a 'missing link' between gene-culture co-evolution and neuropsychiatric spectrum disorders? AB - Brune's proposal that erstwhile 'vulnerability' genes need to be reconsidered as 'plasticity' genes, given the potential for certain environments to yield increased positive function in the same domain as potential dysfunction, has implications for psychiatric nosology as well as a more dynamic understanding of the relationship between genes and culture. In addition to validating neuropsychiatric spectrum disorder nosologies by calling for similar methodological shifts in gene-environment-interaction studies, Brune's position elevates the importance of environmental contexts - inclusive of socio-cultural variables - as mechanisms that contribute to clinical presentation. We assert that when models of susceptibility to plasticity and neuropsychiatric spectrum disorders are concomitantly considered, a new line of inquiry emerges into the co evolution and co-determination of socio-cultural contexts and endophenotypes. This presents potentially unique opportunities, benefits, challenges, and responsibilities for research and practice in psychiatry. Please see related manuscript: http://www.biomedcentral.com/1741-7015/10/38. PMID- 22510308 TI - Biogeography of Old World emballonurine bats (Chiroptera: Emballonuridae) inferred with mitochondrial and nuclear DNA. AB - Extant bats of the genus Emballonura have a trans-Indian Ocean distribution, with two endemic species restricted to Madagascar, and eight species occurring in mainland southeast Asia and islands in the western Pacific Ocean. Ancestral Emballonura may have been more widespread on continental areas, but no fossil identified to this genus is known from the Old World. Emballonura belongs to the subfamily Emballonurinae, which occurs in the New and Old World. Relationships of all Old World genera of this subfamily, including Emballonura and members of the genera Coleura from Africa and western Indian Ocean islands and Mosia nigrescens from the western Pacific region, are previously unresolved. Using 1833 bp of nuclear and mitochondrial genes, we reconstructed the phylogenetic history of Old World emballonurine bats. We estimated that these lineages diverged around 30 million years ago into two monophyletic sister groups, one represented by the two taxa of Malagasy Emballonura, Coleura and possibly Mosia, and the other by a radiation of Indo-Pacific Emballonura, hence, rendering the genus Emballonura paraphyletic. The fossil record combined with these phylogenetic relationships suggest at least one long-distance dispersal event across the Indian Ocean, presumably of African origin, giving rise to all Indo-Pacific Emballonura species (and possibly Mosia). Cladogenesis of the extant Malagasy taxa took place during the Quaternary giving rise to two vicariant species, E. atrata in the humid east and E. tiavato in the dry west. PMID- 22510309 TI - Phylogenetic relationships among the Caribbean members of the Cliona viridis complex (Porifera, Demospongiae, Hadromerida) using nuclear and mitochondrial DNA sequences. AB - Species complexes - groups of closely related species in which intraspecific and interspecific variability overlap - have generated considerable interest and study. Frequently, members of a species complex do not have complete reproductive isolation; therefore, the complex may go through extensive gene flow. In the Caribbean Sea, some encrusting and excavating sponges of the genus Cliona (Porifera, Hadromerida, Clionaidae) are grouped within the great "Cliona viridis" complex because of their morphological similarities. This study examined the evolutionary relationships of the Caribbean members of this complex (C. caribbaea, C. tenuis, C. aprica and C. varians) and related taxa based on nuclear (ITS1 and ITS2) and mitochondrial (3' end of ND6) DNA sequences. The intragenomic ITS variation and its secondary structures were evaluated using a mixed approach of Denaturing Gradient Gel Electrophoresis (DGGE), DNA sequencing and secondary structure prediction. Considerable intragenomic variation was found in all the species, with apparently functional ITS1 and ITS2 secondary structures. Despite the subtle but clear morphological differentiation in these excavating sponges, the intragenomic copies of C. caribbaea, C. tenuis and C. aprica had a polyphyletic placement in the ITS1 and ITS2 genealogies and very low divergence. Therefore, it is clear that these species constitute a species complex (herein called Ct-complex). Genetic distances within the Ct-complex revealed that an important part of the interspecific variation overlapped with intraspecific variation, suggesting either incomplete lineage sorting or extensive gene flow. In contrast, C. varians and an unidentified "Pione" species emerged as monophyletic clades, being the closest sister groups to the Ct-complex. Additionally, our results support that C. laticavicola and C. delitrix conform a monophyletic group, but absence of reciprocal monophyly in these species suggests they may be life stages or ecophenotypes of a single species or they have diverged recently. Our work showed that the 3' end of the ND6 mitochondrial gene was highly conserved and not suitable for phylogenetic analysis at the interspecific level. PMID- 22510310 TI - Biocompatibility and biomineralization assessment of a new root canal sealer and root-end filling material. AB - OBJECTIVE: This study investigated the short-term subcutaneous tissue reaction and biomineralization ability of two epoxy-based root canal sealers containing calcium hydroxide (MBP and MBPc) and ProRoot MTA. MATERIALS AND METHODS: Polyethylene tubes containing the materials were implanted into the dorsal connective tissue of Wistar rats (n = 52) for 7 or 30 days; empty implanted tubes served as controls. Specimens were stained with hematoxylin-eosin and von Kossa stain or left unstained for observation under polarized light. Qualitative and quantitative evaluations of all tissue reactions were performed. One-way anova and the Kruskal-Wallis test were used for statistical analysis (P < 0.05). RESULTS: No significant differences were observed among the groups. All three materials induced mild-to-moderate tissue reactions at 7 days, which decreased over time. Dystrophic mineralization and birefringent structures were observed only in the ProRoot MTA ((r)) group. CONCLUSION: Both MBP and MBPc appear to be biocompatible but do not stimulate biomineralization. PMID- 22510306 TI - Consequences of oxidative stress in age-related macular degeneration. AB - The retina resides in an environment that is primed for the generation of reactive oxygen species (ROS) and resultant oxidative damage. The retina is one of the highest oxygen-consuming tissues in the human body. The highest oxygen levels are found in the choroid, but this falls dramatically across the outermost retina, creating a large gradient of oxygen towards the retina and inner segments of the photoreceptors which contain high levels of polyunsaturated fatty acids. This micro-environment together with abundant photosensitizers, visible light exposure and a high energy demand supports a highly oxidative milieu. However, oxidative damage is normally minimized by the presence of a range of antioxidant and efficient repair systems. Unfortunately, as we age oxidative damage increases, antioxidant capacity decreases and the efficiency of reparative systems become impaired. The result is retinal dysfunction and cell loss leading to visual impairment. It appears that these age-related oxidative changes are a hallmark of early age-related macular degeneration (AMD) which, in combination with hereditary susceptibility and other retinal modifiers, can progress to the pathology and visual morbidity associated with advanced AMD. This review reassesses the consequences of oxidative stress in AMD and strategies for preventing or reversing oxidative damage in retinal tissues. PMID- 22510311 TI - Factor structure of the Emotional Eating Scale in overweight and obese adults seeking treatment. AB - The purpose of this study was to examine the factor structure and anthropometric correlates of the Emotional Eating Scale in overweight and obese adults presenting for weight loss. Participants were 217 men and women with a mean body mass index of 33.1 (+/-3.4) kg/m2. Results indicated a four factor structure: depression, anger, anxiety, and somatic arousal. These factors demonstrated strong internal consistency, and together accounted for approximately 60% of the total variance. Women had significantly higher depression and total scores than did men. There were no significant correlations between the Emotional Eating Scale scores and anthropometric measures. This work begins to add to the literature base regarding the applicability of the original design of the Emotional Eating Scale for samples consisting of men and African Americans. PMID- 22510312 TI - Novel application of a fecal management system for vaginal use in radiotherapy associated rectovaginal fistula. AB - While highly effective for treating certain gynecologic malignancies, radiotherapy carries known risks, including fistula formation. We report a 75 year-old female with advanced cervical carcinoma who was provided a vaginally placed fecal management system after developing a rectovaginal fistula following primary treatment with chemoradiation. This report presents and discusses a novel method to palliate symptomatic RVFs in advanced-stage cancer. PMID- 22510313 TI - Characterization of physicochemical properties of hydroxypropyl methylcellulose (HPMC) type 2208 and their influence on prolonged drug release from matrix tablets. AB - The key physicochemical properties of functional excipients should be identified, and the influence of their variability on the properties of the final dosage form should be evaluated during the development phase. Excipients produced by different manufacturers and/or by different manufacturing processes should have comparable properties. Hydroxypropyl methylcellulose (HPMC) with a high molecular weight is a functional excipient often used in solid matrix systems with prolonged release of active pharmaceutical ingredients (API). This study investigates whether HPMC manufactured by two manufacturers using different chemical procedures differs in particle-size distribution, particle shape, particle morphology, chemical composition, and dissolution of diclofenac sodium as a model drug. NIR spectroscopy was introduced and calibration models were developed to detect physical differences among HPMC batches from two different origins. The physical differences between HPMC samples were additionally confirmed with scanning electron microscopy (SEM), gas chromatography (GC) measurements, and dissolution testing of hydrophilic matrix tablets. Our results prove that, even if HPMC polymers manufactured from two different sources comply with the pharmacopeial specification, they significantly differ in physicochemical properties and thus influence the properties of the formulated dosage forms. PMID- 22510314 TI - A novel ion-pair RP-HPLC method for determination of five components in compound alpha-ketoacid tablets. AB - A sensitive and reliable ion-pair reversed-phase high-performance liquid chromatographic (RP-HPLC) method has been developed and validated for the simultaneous determination of D,L-alpha-hydroxymethionine calcium (HMACa), D,L alpha-ketoisoleucine calcium (KILCa), alpha-ketovaline calcium (KVCa), alpha ketoleucine calcium (KLCa) and alpha-ketophenylalanine calcium (KPACa) in the compound alpha-ketoacid tablets using tetrabutylammonium hydroxide as an ion-pair reagent. The analytes were separated on a C(18) column (250 mm * 4.6 mm, 5 MUm) with the mobile phase of methanol-potassium dihydrogen phosphate buffer (pH 3.0; 50mM) (37:63, v/v) at a flow rate of 0.6 mL min(-1). The UV detection wavelength was set at 210 nm. Good linearity with correlation coefficients larger than 0.9990 (n=6) for all analytes were achieved. The average recoveries were within the range of 99.6-100.9%, and the RSDs of the results were within the acceptable limit of 2.0%, which showed that this method was accurate and precise. The limits of detection were 10.44, 5.94, 3.44, 3.60 and 1.63 ng mL(-1), and the limits of quantification were 34.80, 19.80, 10.32, 12.00 and 5.44 ng mL(-1) for HMACa, KILCa, KVCa, KLCa and KPACa, respectively. The method is simple and accurate for quality control of the compound alpha-ketoacid tablets. PMID- 22510315 TI - [Current issues in pulmonary hypertension]. AB - Pulmonary hypertension is a multietiological disease. Other forms have to be excluded to establish this diagnosis. Pulmonary hypertension is classified into five categories. One of these forms is pulmonary arterial hypertension with special treatment options. There are three main pathophysiological pathways and corresponding treatment includes the administration phosphodiesterase-5 inhibitors, endothelin receptor antagonists and prostacyclin derivates. Novel therapeutic options are under development. Patients with pulmonary hypertension need regular care and their treatment has to be conducted in specified centres. PMID- 22510316 TI - [Neuropathy in the gut. Gastrointestinal motility disorders in patients with diabetes mellitus]. AB - The extent and severity of motility disorders remains heterogeneous in the different parts of the gut, and in most cases failures in gut motility do not correspond with the severity of the symptoms. If diarrhea or fecal incontinence is the leading symptom, or the blood glucose level varies frequently and considerably despite the treatment efforts, the motility of the stomach and bowels is seriously disturbed. The clinical aspects, detailed pathogenesis, diagnostic approach and treatment modalities of gastrointestinal motility disorders in diabetes mellitus are reviewed to help and improve the everyday medical practice. PMID- 22510317 TI - [Summaries of papers at the 43rd Scientific Inservice Training of the South Hungary Section of the Hungarian Internists' Society]. PMID- 22510318 TI - [Doctors, druggists and the ones who appear to be -- on the musical stage]. PMID- 22510319 TI - [Caesarean section in ancient India]. PMID- 22510321 TI - Clinical features and outcome of multiple primary malignancies involving hepatocellular carcinoma: a long-term follow-up study. AB - BACKGROUND: The prolonged survival of individuals diagnosed with cancer has led to an increase in the number of secondary primary malignancies. We undertook to perform a definitive study to characterize and predict prognosis of multiple primary malignancies (MPM) involving hepatocellular carcinoma (HCC), due to the scarcity of such reports. METHODS: Clinicopathological data were analyzed for 68 MPM patients involving HCC, with 35 (target group) underwent curative liver resection. Additional 140 HCC-alone patients with hepatectomy were selected randomly during the same period as the control group. RESULTS: Of the 68 patients with extrahepatic primary malignancies (EHPM), 22 were diagnosed synchronously with HCC, and 46 metachronously. The most frequent EHPM was nasophageal carcinoma, followed by colorectal and lung cancer. Univariate analysis demonstrated that synchronous (P = 0.008) and non-radical treatment for EHPM (P < 0.001) were significant risk factors associated with poorer overall survival (OS). While, Cox modeling revealed that the treatment modality for EHPM, but not the synchronous/metachronous determinant, was an independent factor for OS, and that therapeutic option for HCC was an independent factor for HCC-specific OS. Moreover, no HCC-specific overall and recurrence-free survival benefit were observed in the control group when compared with that of the target group (P = 0.607, P = 0.131, respectively). CONCLUSIONS: Curative treatment is an independent predictive factor for OS and HCC-specific OS, and should been taken into account both for synchronous and metachronous patients. MPM patients involving HCC should not be excluded from radical resection for HCC. PMID- 22510322 TI - Expression and purification of the p75 neurotrophin receptor transmembrane domain using a ketosteroid isomerase tag. AB - BACKGROUND: Receptors with a single transmembrane (TM) domain are essential for the signal transduction across the cell membrane. NMR spectroscopy is a powerful tool to study structure of the single TM domain. The expression and purification of a TM domain in Escherichia coli (E.coli) is challenging due to its small molecular weight. Although ketosteroid isomerase (KSI) is a commonly used affinity tag for expression and purification of short peptides, KSI tag needs to be removed with the toxic reagent cyanogen bromide (CNBr). RESULT: The purification of the TM domain of p75 neurotrophin receptor using a KSI tag with the introduction of a thrombin cleavage site is described herein. The recombinant fusion protein was refolded into micelles and was cleaved with thrombin. Studies showed that purified protein could be used for structural study using NMR spectroscopy. CONCLUSIONS: These results provide another strategy for obtaining a single TM domain for structural studies without using toxic chemical digestion or acid to remove the fusion tag. The purified TM domain of p75 neurotrophin receptor will be useful for structural studies. PMID- 22510323 TI - Baseline serum immunoglobulin levels in patients with rheumatoid arthritis: relationships with clinical parameters and with B-cell dynamics following rituximab. AB - OBJECTIVES: To investigate whether levels of serum immunoglobulins (sIgs) at baseline were associated with clinical parameters or B-cell dynamics following rituximab (RTX) in patients with rheumatoid arthritis (RA). METHODS: Baseline Ig levels, C-reactive protein (CRP), DAS28 and CD19+ve B-cell count (baseline, 1, 3 and 5 months) in 112 patients with RA after 1 cycle of RTX were included. All showed adequate B-cell depletion (<5 CD19+B cells/MUl) after 1 month. Normal sIg ranges were for IgA (0.7-4.0 g/L), IgG (7.0-16.0 g/L), and IgM (0.4-2.3 g/L). RESULTS: Baseline IgA levels were raised in 29 patients, IgG in 18 and IgM in 11. CRP levels were significantly higher in patients with raised IgA and IgG compared to patients with normal levels (p=0.0002; p=0.03). At nadir after RTX, median levels of all sIgs decreased significantly although 16 patients (55%) remained with raised IgA, 28% IgG (5/18) and 27% IgM (3/11). Patients with raised IgA had higher minimum levels reached of CRP and of DAS28 (p=0.002; p=05). After 5 months, a higher percentage of patients with raised baseline sIgA had repopulated and were found to have shorter clinical responses than those with sIgs within normal limits. CONCLUSIONS: sIgA levels in RA patients remained raised in a higher proportion of patients than other sIg after RTX. Raised sIgA was associated with a less robust clinical response to RTX and with B-cell repopulation coincident with relapse. Expanded or more permissive microenvironments for long-lived IgA plasma cells may be related to the presence of disease more refractive to B-cell depletion therapy. PMID- 22510324 TI - Perioperative prevention of penile prosthesis infection: practice patterns among surgeons of SMSNA and ISSM. AB - INTRODUCTION: Anecdotally, there is great variation in the use of strategies to prevent postoperative penile implant infection. AIM: To evaluate the perioperative practice patterns of surgeons who insert penile prostheses focusing on their respective infection control routines. METHOD: An anonymous Web-based survey was sent to members of the Sexual Medicine Society of North America (SMSNA) and the International Society of Sexual Medicine (ISSM). MAIN OUTCOME MEASURES: Thirty-nine questions were asked pertaining to the strategies used during the pre-, intra-, and postoperative phases of penile implant surgery to prevent infection. RESULTS: One hundred twenty-nine surgeons responded to the survey (SMSNA 84; ISSM 45). Most surgeons considered themselves sexual medicine specialists. More SMSNA respondents had inserted >100 prosthesis (SMSNA 69%, ISSM 50%). Routine urine culture is not performed by 40% and 50% of SMSNA and ISSM members, respectively. Similar percentages of surgeons from each society request a daily preoperative antimicrobial scrub. About two-thirds of ISSM members use razors for the preoperative shave compared with one-third of SMSNA members. Most ISSM surgeons preferred povidone-iodine for hand and skin preparation while most SMSNA surgeons chose this only for skin preparation. Two-thirds of SMSNA members prepared the skin for at least 10 minutes compared with 34% of ISSM surgeons. There were considerable differences in all aspects of antibiotic usage not only between members of both societies but also among individual members of each society. Most surgeons prefer not to place a drain (SMSNA 70%, ISSM 81%). Discharge timing differs between the two groups. CONCLUSIONS: There is great variation in perioperative strategies utilized to prevent penile implant infections including some key differences between surgeons from SMSNA and ISSM. It is unknown if these variations result in changes in the postoperative infection rate; however, the study data may assist in the formation of practice guidelines and form the basis of future prospective studies. PMID- 22510325 TI - Cochrane and non-Cochrane systematic reviews in leading orthodontic journals: a quality paradigm? AB - The aims of this study were to assess and compare the methodological quality of Cochrane and non-Cochrane systematic reviews (SRs) published in leading orthodontic journals and the Cochrane Database of Systematic Reviews (CDSR) using AMSTAR and to compare the prevalence of meta-analysis in both review types. A literature search was undertaken to identify SRs that consisted of hand-searching five major orthodontic journals [American Journal of Orthodontics and Dentofacial Orthopedics, Angle Orthodontist, European Journal of Orthodontics, Journal of Orthodontics and Orthodontics and Craniofacial Research (February 2002 to July 2011)] and the Cochrane Database of Systematic Reviews from January 2000 to July 2011. Methodological quality of the included reviews was gauged using the AMSTAR tool involving 11 key methodological criteria with a score of 0 or 1 given for each criterion. A cumulative grade was given for the paper overall (0-11); an overall score of 4 or less represented poor methodological quality, 5-8 was considered fair and 9 or greater was deemed to be good. In total, 109 SRs were identified in the five major journals and on the CDSR. Of these, 26 (23.9%) were in the CDSR. The mean overall AMSTAR score was 6.2 with 21.1% of reviews satisfying 9 or more of the 11 criteria; a similar prevalence of poor reviews (22%) was also noted. Multiple linear regression indicated that reviews published in the CDSR (P < 0.01); and involving meta-analysis (beta = 0.50, 95% confidence interval 0.72, 2.07, P < 0.001) showed greater concordance with AMSTAR. PMID- 22510327 TI - Presenilin-1 L166P mutant human pluripotent stem cell-derived neurons exhibit partial loss of gamma-secretase activity in endogenous amyloid-beta generation. AB - Alzheimer's disease (AD) is the most frequent cause of dementia. There is compelling evidence that the proteolytic processing of the amyloid precursor protein (APP) and accumulation of amyloid-beta (Abeta) peptides play critical roles in AD pathogenesis. Due to limited access to human neural tissue, pathogenetic studies have, so far, mostly focused on the heterologous overexpression of mutant human APP in non-human cells. In this study, we show that key steps in proteolytic APP processing are recapitulated in neurons generated from human embryonic and induced pluripotent stem cell-derived neural stem cells (NSC). These human NSC-derived neurons express the neuron-specific APP(695) splice variant, BACE1, and all members of the gamma-secretase complex. The human NSC-derived neurons also exhibit a differentiation-dependent increase in Abeta secretion and respond to the pharmacotherapeutic modulation by anti amyloidogenic compounds, such as gamma-secretase inhibitors and nonsteroidal anti inflammatory drugs. Being highly amenable to genetic modification, human NSCs enable the study of mechanisms caused by disease-associated mutations in human neurons. Interestingly, the AD-associated PS1(L166P) variant revealed a partial loss of gamma-secretase function, resulting in the decreased production of endogenous Abeta40 and an increased Abeta42/40 ratio. The PS1(L166P) mutant is also resistant to gamma-secretase modulation by nonsteroidal anti-inflammatory drugs. Pluripotent stem cell-derived neurons thus provide experimental access to key steps in AD pathogenesis and can be used to screen pharmaceutical compounds directly in a human neuronal system. PMID- 22510326 TI - Combined in silico/in vivo analysis of mechanisms providing for root apical meristem self-organization and maintenance. AB - BACKGROUND AND AIMS: The root apical meristem (RAM) is the plant stem cell niche which provides for the formation and continuous development of the root. Auxin is the main regulator of RAM functioning, and auxin maxima coincide with the sites of RAM initiation and maintenance. Auxin gradients are formed due to local auxin biosynthesis and polar auxin transport. The PIN family of auxin transporters plays a critical role in polar auxin transport, and two mechanisms of auxin maximum formation in the RAM based on PIN-mediated auxin transport have been proposed to date: the reverse fountain and the reflected flow mechanisms. METHODS: The two mechanisms are combined here in in silico studies of auxin distribution in intact roots and roots cut into two pieces in the proximal meristem region. In parallel, corresponding experiments were performed in vivo using DR5::GFP Arabidopsis plants. KEY RESULTS: The reverse fountain and the reflected flow mechanism naturally cooperate for RAM patterning and maintenance in intact root. Regeneration of the RAM in decapitated roots is provided by the reflected flow mechanism. In the excised root tips local auxin biosynthesis either alone or in cooperation with the reverse fountain enables RAM maintenance. CONCLUSIONS: The efficiency of a dual-mechanism model in guiding biological experiments on RAM regeneration and maintenance is demonstrated. The model also allows estimation of the concentrations of auxin and PINs in root cells during development and under various treatments. The dual-mechanism model proposed here can be a powerful tool for the study of several different aspects of auxin function in root. PMID- 22510329 TI - Retention challenge in an MSM cohort in Suzhou, China. PMID- 22510328 TI - Are volatile anesthetics neuroprotective or neurotoxic? AB - Volatile anesthetics are one class of the most commonly used drugs. However, the mechanisms for these drugs to induce anesthesia are not fully understood and have been under intensive investigation. Two other effects of these anesthetics on the central nervous system, volatile anesthetics-induced neuroprotection and neurotoxicity, currently are hot research fields. Although data from animal studies for these two effects are extensive and convincing, clinical data for volatile anesthetics-induced neuroprotection are relatively weak. There is essentially lack of evidence to suggest volatile anesthetics-induced neurotoxicity in humans. In this regard, the contribution of general anesthesia/anesthetics to postoperative cognitive decline, a clinical entity whose existence has been supported by substantial evidence, also has not been established. This paper will be focused on reviewing the evidence, especially the clinical evidence, for volatile anesthetics-induced neuroprotection and neurotoxicity. Efforts will be devoted to facilitating the understanding of the two seemingly contradictory effects of these important drugs on the brain. PMID- 22510330 TI - Young persons' access to genitourinary medicine clinics in the UK: a cross sectional survey. AB - STUDY DESIGN: This service evaluation of genitourinary medicine (GUM) clinics in the UK was designed to quantify access for young people requesting to be seen and to establish whether they could be seen outside school hours. METHODS: In December 2009 postal questionnaires were sent to all lead clinicians in UK GUM clinics asking when they expected a young person would be offered an appointment and whether it could be outside school hours. Between January and March 2010 trained male and female medical students posing as 16 year olds telephoned all GUM clinics listed on the British Association for Sexual Health and HIV website with symptomatic and asymptomatic scenarios and requested an appointment after school hours. RESULTS: 99% of the 152 responding clinicians estimated that an appointment would be offered within 48 h for both male and female contacts and over 90% could be seen outside school hours whether symptomatic or not. Of the 666 clinic telephone contacts, 88% were offered an appointment within two working days, and 66% were offered an after school appointment within 2 days. There was no significant difference whether the 'patient' was symptomatic or not (87% vs 86%, respectively, p=0.784) in being offered an appointment within two working days. There was variation between countries, with England performing significantly better; 94% were offered an appointment within 2 days versus 58%, 55% and 67% for Wales, Scotland and Northern Ireland, respectively. CONCLUSION: The findings would support the impact and value of process targets on service delivery. PMID- 22510331 TI - Where do young men want to access STI screening? A stratified random probability sample survey of young men in Great Britain. AB - OBJECTIVES: Rates of sexually transmitted infections (STIs) in UK young people remain high in men and women. However, the National Chlamydia Screening Programme has had limited success in reaching men. The authors explored the acceptability of various medical, recreational and sports venues as settings to access self collected testing kits for STIs and HIV among men in the general population and those who participate in sport. METHODS: A stratified random probability survey of 411 (weighted n=632) men in Great Britain aged 18-35 years using computer assisted personal and self-interviews. RESULTS: Young men engaged well with healthcare with 93.5% registered with, and 75.3% having seen, a general practitioner in the last year. 28.7% and 19.8% had previously screened for STIs and HIV, respectively. Willingness to access self-collected tests for STIs (85.1%) and HIV (86.9%) was high. The most acceptable pick-up points for testing kits were general practice 79.9%, GUM 66.8% and pharmacy 65.4%. There was a low acceptability of sport venues as pick-up points in men as a whole (11.7%), but this was greater among those who participated in sport (53.9%). CONCLUSIONS: Healthcare settings were the most acceptable places for accessing STI and HIV self-testing kits. Although young men frequently access general practice, currently little STI screening occurs in this setting. There is considerable potential to screen large numbers of men and find high rates of infection through screening in general practice. While non-clinical settings are acceptable to a minority of men, more research is needed to understand how these venues could be used most effectively. PMID- 22510332 TI - Knowing your HIV/AIDS epidemic and tailoring an effective response: how did India do it? AB - Tremendous global efforts have been made to collect data on the HIV/AIDS epidemic. Yet, significant challenges remain for generating and analysing evidence to allocate resources efficiently and implement an effective AIDS response. India offers important lessons and a model for intelligent and integrated use of data on HIV/AIDS for an evidence-based response. Over the past 15 years, the number of data sources has expanded and the geographical unit of data generation, analysis and use for planning has shifted from the national to the state, district and now subdistrict level. The authors describe and critically analyse the evolution of data sets in India and how they have been utilised to better understand the epidemic, advance policy, and plan and implement an increasingly effective, well-targeted and decentralised national response to HIV and AIDS. The authors argue that India is an example of how 'know your epidemic, know your response' message can effectively be implemented at scale and presents important lessons to help other countries design their evidence generation systems. PMID- 22510334 TI - Young people, mental illness and suicidal behaviours. PMID- 22510333 TI - Robots in human biomechanics--a study on ankle push-off in walking. AB - In biomechanics, explanatory template models are used to identify the basic mechanisms of human locomotion. However, model predictions often lack verification in a realistic environment. We present a method that uses template model mechanics as a blueprint for a bipedal robot and a corresponding computer simulation. The hypotheses derived from template model studies concerning the function of heel-off in walking are analysed and discrepancies between the template model and its real-world anchor are pointed out. Neither extending the ground clearance of the swinging leg nor an impact reduction at touch-down as an effect of heel lifting was supported by the experiments. To confirm the relevance of the experimental findings, a comparison of robot data to human walking data is discussed and we speculate on an alternative explanation of heel-off in human walking, i.e. that the push-off powers the following leg swing. PMID- 22510335 TI - Markers of vulnerability to obsessive-compulsive disorder in an ultra-high risk sample of patients who developed psychosis. AB - AIMS: The study aims to identify markers of vulnerability to obsessive-compulsive disorder (OCD) in an ultra-high risk sample of patients who developed psychosis. METHODS: Three hundred and eleven patients at ultra-high risk for psychosis were examined at baseline and after a mean of 7.4 years follow-up. Patients who developed psychosis with OCD (PSY + OCD; n = 13) and psychosis without OCD (PSY - OCD; n = 45) were compared in terms of socio-demographic and clinical features. RESULTS: PSY + OCD patients displayed greater severity of depression before and after conversion to PSY + OCD, and increased rates of depressive disorders before exhibiting PSY + OCD. However, they only displayed greater severity of anxiety and increased rates of non-OCD anxiety disorders after psychosis. Further, PSY + OCD patients were more likely to report a positive family history for anxiety disorders than PSY - OCD. CONCLUSION: Although depression and a family history of anxiety disorder may act as vulnerability markers for OCD in psychosis, the resulting anxiety may be a correlate or a consequence of PSY + OCD. PMID- 22510336 TI - Establishing and operating an early intervention service for psychosis in a defined catchment area of northwestern Greece within the context of the local mental health network. AB - AIM: The study aims to present briefly the development of an early intervention service (EIS) for psychosis in a rural catchment area of north-western Greece within the context of the local mental health network, its structure and procedures, and the results of its operation 2 years after its establishment. METHOD: Established in December 2007, our EIS is the first service in Greece for patients with a first-episode psychosis. The context and the local mental health network are described, and the EIS operation, including clinical, educational, community and research activities, is outlined. Assessment measures are presented to evaluate the EIS progress 2 years after its establishment. RESULTS: Between December 2007 and December 2009, EIS received 45 referrals, retaining 38 patients in its caseload. The mean duration of untreated psychosis was 26.6 +/- 41.0 months (median = 12 months). Thirty-seven patients (82.2%) were hospitalized after their first referral, 14 under a compulsory order (31.1%). The duration of hospitalization ranged from 2 to 69 days, with a median of 13 days. Mean (+/-SD) duration of the follow-up was 14.8 +/- 8.5 months, indicating adequate adherence to EIS, with particularly low relapse rates (20%). CONCLUSIONS: Our EIS seems to be successfully established within the local mental health network. Our collaboration with the local mobile mental health unit enabled our communication with rural primary healthcare centers. The collaboration of patients' family and the participation of the mobile mental health unit to the continuity of care contributed greatly to the brief duration of hospitalization and the high adherence to follow-up rates. PMID- 22510338 TI - How do the top 12 pharmaceutical companies operate safety pharmacology? AB - INTRODUCTION: How does safety pharmacology operate in large pharmaceutical companies today? By understanding our current position, can we prepare safety pharmacology to successfully navigate the complex process of drug discovery and development? METHODS: A short anonymous survey was conducted, by invitation, to safety pharmacology representatives of the top 12 pharmaceutical companies, as defined by 2009 revenue figures. A series of multiple choice questions was designed to explore group size, accountabilities, roles and responsibilities of group members, outsourcing policy and publication record. RESULTS: A 92% response rate was obtained. Six out of 11 companies have 10 to 30 full time equivalents in safety pharmacology, who hold similar roles and responsibilities; although the majority of members are not qualified at PhD level or equivalent. Accountabilities were similar across companies and all groups have accountability for core battery in vivo studies and problem solving activities but differences do exist for example with in vitro safety screening and pharmacodynamic/pharmokinetic modeling (PK/PD). The majority of companies outsource less than 25% of studies, with in vitro profiling being the most commonly outsourced activity. Finally, safety pharmacology groups are publishing 1 to 4 articles each year. CONCLUSION: This short survey has highlighted areas of similarity and differences in the way large pharmaceutical companies operate safety pharmacology. PMID- 22510337 TI - Expansion of polyreactive B cells cross-reactive to HLA and self in the blood of a patient with kidney graft rejection. AB - Antibody rejection is often accompanied by nondonor HLA specific antibodies (NDSA) and self-reactive antibodies that develop alongside donor-specific antibodies (DSA). To determine the source of these antibodies, we immortalized 107 B-cell clones from a kidney transplant recipient with humoral rejection. Two of these clones reacted to HLA class I or MICA. Both clones were also reactive to self-antigens and a lysate of a kidney cell line, hence revealing a pattern of polyreactivity. Monoclonality was verified by the identification of a single rearranged immunoglobulin heavy chain variable region (VH) sequence for each clone. By tracking their unique CDR3 sequence, we found that one such polyreactive clone was highly expanded in the patient blood, representing ~0.2% of circulating B cells. The VH sequence of this clone showed evidence of somatic mutations that were consistent with its memory phenotype and its expansion. Lastly, the reactivity of the expanded polyreactive B-cell clone was found in the patient serum at time of rejection. In conclusion, we provide here proof of principle at the clonal level that human antibodies can cross-react to HLA and self. Our findings strongly suggest that polyreactive antibodies contribute to DSA, NDSA as well as autoantibodies, in transplant recipients. PMID- 22510342 TI - Value of high-resolution ultrasound in the differential diagnosis of scaphocephaly and occipital plagiocephaly. AB - Secondary to the increase in deformational plagiocephaly a growing number of infants with cranial deformity present to craniofacial teams. Computed tomography (CT) is diagnostic, but uses ionizing radiation. The purpose of this study was to evaluate ultrasound as a screening test for the patency of cranial sutures in scaphocephaly and occipital plagiocephaly. The cranial sutures of 54 infants with this cranial deformity were assessed by ultrasound. Sutures were read as patent or fused if a hypoechoic gap could or could not be demonstrated between the hyperechoic clavarial bones, respectively. Seven children suffered from true craniosynostosis of either the sagittal or the lambdoid suture. In five cases the ultrasound findings were diagnostic for a fused suture, in two cases the results were inconclusive. Forty-seven infants presented with deformational plagiocephaly. Ultrasound examination demonstrated patent sutures in 45 cases and was inconclusive in two cases. Sonography of the cranial sutures is a good screening tool to distinguish fused from patent cranial sutures in scaphocephaly and occipital plagiocephaly and avoids the radiation exposure associated with CT examinations. PMID- 22510341 TI - Comparison of five different fixation techniques of sagittal split ramus osteotomy using three-dimensional finite elements analysis. AB - The aim of this study was to compare the mechanical stress over hemimandible substrate and hardware after sagittal split ramus osteotomy (SSRO) fixed with five different techniques using three-dimensional (3D) finite element analysis. A 3D finite element model of a hemimandible was created and a 5mm advancement SSRO was simulated on a computer model. The model was fixed with five different techniques: 3 linear 60 degrees screw arrangement; 3 linear 90 degrees screw arrangement; 3 inverted L screw arrangement; 1 conventional miniplate; and 1 locking miniplate with four monocortical screws. Load was applied until 3mm displacement was reached and the results were compared with previous mechanical and photoelastic tests, thus analysing the mechanical stresses developed in the proximity of miniplates and screws and within the fixation system itself. The maximum principal stress values demonstrate a lower mechanical stress rate in bone and in the fixation system with the inverted L arrangement, followed by the linear 90 degrees and linear 60 degrees arrangements. The locking miniplate/screw system presented lower maximum principal stress and better stress distribution compared with the conventional system. Under the conditions tested, the reversed L arrangement provided the most favourable stress dissipation behaviour. PMID- 22510340 TI - Inhibition of adenovirus multiplication by short interfering RNAs directly or indirectly targeting the viral DNA replication machinery. AB - Human adenoviruses are a common threat to immunocompromised patients, e.g., HIV positive individuals or solid-organ and, in particular, allogeneic stem cell transplant recipients. Antiviral drugs have a limited effect on adenoviruses, and existing treatment modalities often fail to prevent fatal outcome. Silencing of viral genes by short interfering RNAs (siRNAs) holds a great promise in the treatment of viral infections. The aim of the present study was to identify adenoviral candidate targets for RNA interference-mediated inhibition of adenoviral replication. We investigated the impact of silencing of a set of early, middle, and late viral genes on the replication of adenovirus 5 in vitro. Adenovirus replication was inhibited by siRNAs directed against the adenoviral E1A, DNA polymerase, preterminal protein (pTP), IVa2, hexon, and protease genes. Silencing of early and middle genes was more effective in inhibiting adenovirus multiplication than was silencing of late genes. A siRNA directed against the viral DNA polymerase mRNA decreased viral genome copy numbers and infectious virus progeny by several orders of magnitude. Since silencing of any of the early genes directly or indirectly affected viral DNA synthesis, our data suggest that reducing viral genome copy numbers is a more promising strategy for the treatment of adenoviral infections than is reducing the numbers of proteins necessary for capsid generation. Thus, adenoviral DNA replication was identified as a key target for RNAi-mediated inhibition of adenovirus multiplication. In addition, the E1A transcripts emerged as a second important target, because its knockdown markedly improved the viability of cells at late stages of infection. PMID- 22510343 TI - Long-term evaluation of the stability of reconstructed condyles by transport distraction osteogenesis. AB - This retrospective longitudinal study evaluated the long-term stability of reconstructed condyles by transport distraction osteogenesis of the mandibular ramus in patients with unilateral temporomandibular joint (TMJ) ankylosis. 7 patients were followed up for 16-92 months (mean 39.4 months). The mean age of the patients at the time of distraction was 22.9 years (range 7-44 years). Maximal mouth opening and panoramic radiographs were recorded preoperatively, at the time of device removal and several years after removal of distraction device. At follow-up, cone beam CT images of the TMJ were obtained to confirm the changes of the reconstructed condyle. Absolute height (Co-Inc) and relative height (Co Inc/Co-Go) of the reconstructed condyle and the asymmetric difference ratio (AR) were examined to assess the changes of condylar height and mandibular symmetry. The mean maximal mouth opening was stable during the period of follow-up. The mean absolute height and relative height of the reconstructed condyle decreased significantly (P<0.05). Although no significant difference was found, the mandibular asymmetry difference ratio increased by 16.7%. These results suggested that the heights of reconstructed condyles were not stable in the long-term, and the mandible tended to be asymmetrical. PMID- 22510344 TI - Modeling human hematopoietic cell development from pluripotent stem cells. AB - Understanding the steps and cues that allow hematopoietic cells to be generated during development holds great clinical as well as biological interest. Analysis of these events in mice has provided many important insights into the processes involved, but features that might be unique to humans remain challenging to elucidate because they cannot be studied directly in vivo. Human embryonic stem or induced pluripotent stem cells offer attractive in vitro alternatives to analyze the process. Here we review recent efforts to develop defined and quantitative systems to address outstanding developmental questions against a background of what we know about the development of hematopoietic cells in the fetus and derived from mouse embryonic stem cells. PMID- 22510345 TI - Changes in gene transcription underlying the aberrant citrate and choline metabolism in human prostate cancer samples. AB - PURPOSE: Low concentrations of citrate and high concentrations of choline containing compounds (ChoCC) are metabolic characteristics observed by magnetic resonance spectroscopy of prostate cancer tissue. The objective was to investigate the gene expression changes underlying these metabolic aberrations to find regulatory genes with potential for targeted therapies. EXPERIMENTAL DESIGN: Fresh frozen samples (n = 133) from 41 patients undergoing radical prostatectomy were included. Histopathologic evaluation was carried out for each sample before a metabolic profile was obtained with high-resolution magic angle spinning (HR MAS) spectroscopy. Following the HR-MAS, RNA was extracted from the same sample and quality controlled before carrying out microarray gene expression profiling. A partial least square statistical model was used to integrate the data sets to identify genes whose expression show significant covariance with citrate and ChoCC levels. RESULTS: Samples were classified as benign, n = 35; cancer of low grade (Gleason score 6), n = 24; intermediate grade (Gleason score 7), n = 41; or high grade (Gleason score >= 8), n = 33. RNA quality was high with a mean RNA Integrity Number score of 9.1 (SD 1.2). Gene products predicting significantly a reduced citrate level were acetyl citrate lyase (ACLY, P = 0.003) and m-aconitase (ACON, P < 0.001). The two genes whose expression most closely accompanied the increase in ChoCC were those of phospholipase A2 group VII (PLA2G7, P < 0.001) and choline kinase alpha (CHKA, P = 0.002). CONCLUSIONS: By integrating histologic, transcriptomic, and metabolic data, our study has contributed to an expanded understanding of the mechanisms underlying aberrant citrate and ChoCC levels in prostate cancer. PMID- 22510346 TI - Clinical outcomes in non-small cell lung cancers harboring different exon 19 deletions in EGFR. AB - PURPOSE: Several deletions in exon 19 of epidermal growth factor receptor (EGFR) gene have been reported in non-small cell lung cancer (NSCLC). It is unknown if deletions occurring at different amino acid positions or of different sizes are associated with different clinical outcome to EGFR tyrosine kinase inhibitors (TKI). EXPERIMENTAL DESIGN: This study enrolled NSCLC patients with deletions in EGFR exon 19. Patients who had received EGFR TKIs for advanced NSCLC were further evaluated for response rate (RR), progression-free survival (PFS), and overall survival (OS). RESULTS: In 308 patients with deletions in EGFR exon 19, 298 had deletions encompassing the entire amino acid string from L747 through E749 (LRE deletions). EGFR TKIs were used in 204 patients with advanced NSCLC. Patients with non-LRE deletions had the least RR, compared with those with deletions from E746 or L747 (42.9%, 68.2%, and 79.6%, respectively; P = 0.022). Patients with non-LRE deletions had relatively short median PFS, though not significantly different from those with deletions from E746 or L747 (5.9, 9.8, and 10.5 months, respectively; P = 0.665). The OS was not different among patients with deletions occurring at different amino acid positions (P = 0.776). Deletions in exon 19 of different sizes were not associated with different RR, PFS, or OS. CONCLUSIONS: Non-LRE deletions in exon 19 were associated with worse response to EGFR TKIs, compared with LRE deletions. Therefore, the expected clinical outcome under EGFR TKIs depends on not only the existence but also the types of deletions in exon 19. PMID- 22510347 TI - A phase I clinical trial of Ad5.SSTR/TK.RGD, a novel infectivity-enhanced bicistronic adenovirus, in patients with recurrent gynecologic cancer. AB - PURPOSE: Ad5.SSTR/TK.RGD is an infectivity-enhanced adenovirus expressing a therapeutic thymidine kinase suicide gene and a somatostatin receptor (SSTR) that allows for noninvasive gene transfer imaging. The purpose of this study was to identify the maximum tolerated dose (MTD), toxicities, clinical efficacy, and biologic effects of Ad5.SSTR/TK.RGD in patients with recurrent gynecologic cancer. EXPERIMENTAL DESIGN: Eligible patients were treated intraperitoneally for 3 days with 1 * 10(9) to 1 * 10(12) vp/dose of Ad5.SSTR/TK.RGD followed by intravenous ganciclovir for 14 days. Toxicity and clinical efficacy were assessed using Common Toxicity Criteria (CTC) Adverse Events grading and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Imaging using In-111 pentetreotide was obtained before and after treatment. Tissue samples were obtained to evaluate for gene transfer, generation of wild-type virus, viral shedding, and antibody response. RESULTS: Twelve patients were treated in three cohorts. The most common vector-related clinical toxicities were grade I/II constitutional or pain symptoms, experienced most often in patients treated at the highest dose. MTD was not identified. Five patients showed stable disease; all others experienced progressive disease. One patient with stable disease experienced complete resolution of disease and normalization of CA125 on further follow-up. Imaging detected increased In-111 pentetreotide retention in patients treated at the highest dose. Ancillary studies showed presence of Ad5.SSTR/TK.RGD virus and HSV1-tk expression in ascites samples collected at various time points in most patients treated within the higher dose cohorts. CONCLUSIONS: This study shows the safety, potential efficacy, and possible gene transfer imaging capacity of Ad5.SSTR/TK.RGD in patients with recurrent gynecologic cancer. Further development of this novel gene therapeutic appears to be warranted. PMID- 22510348 TI - Dendritic cell-activating vaccine adjuvants differ in the ability to elicit antitumor immunity due to an adjuvant-specific induction of immunosuppressive cells. AB - PURPOSE: We questioned whether the vaccine adjuvant combination of TLR-7 ligand agonist, imiquimod, with granulocyte macrophage colony-stimulating factor (GM CSF) would result in enhanced dendritic cell recruitment and activation with increased antigen-specific immunity as compared with either adjuvant used alone. EXPERIMENTAL DESIGN: The adjuvant effects of GM-CSF and imiquimod were studied in ovalbumin (OVA) and MMTVneu transgenic mice using peptide-based vaccines. Type I immunity, serum cytokines, myeloid-derived suppressive cells (MDSC), and regulatory T cells (Treg) levels were examined. RESULTS: Both GM-CSF and imiquimod equally induced local accumulation and activation of dendritic cells. Both adjuvants effectively enhanced OVA-specific T-cell responses. We further evaluated the antitumor efficacy of adjuvant GM-CSF and imiquimod immunizing against murine insulin-like growth factor-binding protein-2 (IGFBP-2), a nonmutated oncoprotein overexpressed in the tumors of MMTVneu transgenic mice. Tumor growth was significantly inhibited in the mice receiving IGFBP-2 peptides with GM-CSF (P = 0.000), but not in imiquimod vaccine-treated groups (P = 0.141). Moreover, the addition of imiquimod to GM-CSF negated the antitumor activity of the vaccine when GM-CSF was used as the sole adjuvant. While GM-CSF stimulated significant levels of antigen-specific T-helper cell (T(H))1, imiquimod induced elevated serum interleukin (IL)-10. Both MDSC and Tregs were increased in the imiquimod-treated but not GM-CSF-treated groups (P = 0.000 and 0.006, respectively). Depleting MDSC and Treg in animals immunized with imiquimod and IGFBP-2 peptides restored antitumor activity to the levels observed with vaccination using GM-CSF as the sole adjuvant. CONCLUSION: Adjuvants may induce regulatory responses in the context of a self-antigen vaccine. Adjuvant triggered immunosuppression may limit vaccine efficacy and should be evaluated in preclinical models especially when contemplating combination approaches. PMID- 22510349 TI - Safety and pharmacokinetics of ganitumab (AMG 479) combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with advanced solid tumors. AB - PURPOSE: This phase 1b dose-escalation study assessed safety, tolerability, and pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic chemotherapy in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with treatment-refractory advanced solid tumors were sequentially enrolled at 2 ganitumab dose levels (6 or 12 mg/kg i.v. every 2 weeks) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg every 2 weeks, erlotinib 150 mg once daily, or gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 of each 4-week cycle. The primary end points were safety and pharmacokinetics of ganitumab. RESULTS: Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events were generally mild and included fatigue, nausea, vomiting, and chills. Three patients had dose-limiting toxicities: grade 3 hyperglycemia (ganitumab 6 mg/kg and panitumumab), grade 4 neutropenia (ganitumab 6 mg/kg and gemcitabine), and grade 4 thrombocytopenia (ganitumab 12 mg/kg and erlotinib). Ganitumab-binding and panitumumab-binding antibodies were detected in 5 and 2 patients, respectively; neutralizing antibodies were not detected. The pharmacokinetics of ganitumab and each cotherapy did not appear affected by coadministration. Circulating total IGF1 and IGF binding protein 3 increased from baseline following treatment. Four patients (9%) had partial responses. CONCLUSIONS: Ganitumab up to 12 mg/kg was well tolerated, without adverse effects on pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents. PMID- 22510350 TI - The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. AB - CD8+ tumor-infiltrating lymphocytes (TIL) are associated with survival in a variety of cancers. A second subpopulation of TIL, defined by forkhead box protein P3 (FoxP3) expression, has been reported to inhibit tumor immunity, resulting in decreased patient survival. On the basis of this premise, several groups are attempting to deplete FoxP3+ T cells to enhance tumor immunity. However, recent studies have challenged this paradigm by showing that FoxP3+ T cells exhibit heterogeneous phenotypes and, in some cohorts, are associated with favorable prognosis. These discrepant results could arise from differences in study methodologies or the biologic properties of specific cancer types. Here, we conduct the first systematic review of the prognostic significance of FoxP3+ T cells across nonlymphoid cancers (58 studies from 16 cancers). We assessed antibody specificity, cell-scoring strategy, multivariate modeling, use of single compared with multiple markers, and tumor site. Two factors proved important. First, when FoxP3 was combined with one additional marker, double-positive T cells were generally associated with poor prognosis. Second, tumor site had a major influence. FoxP3+ T cells were associated with poor prognosis in hepatocellular cancer and generally good prognosis in colorectal cancer, whereas other cancer types were inconsistent or understudied. We conclude that FoxP3+ T cells have heterogeneous properties that can be discerned by the use of additional markers. Furthermore, the net biologic effects of FoxP3+ T cells seem to depend on the tumor site, perhaps reflecting microenvironmental differences. Thus, depletion of FoxP3+ T cells might enhance tumor immunity in some patient groups but be detrimental in others. PMID- 22510351 TI - Defining a gene promoter methylation signature in sputum for lung cancer risk assessment. AB - PURPOSE: To evaluate the methylation state of 31 genes in sputum as biomarkers in an expanded nested, case-control study from the Colorado cohort, and to assess the replication of results from the most promising genes in an independent case control study of asymptomatic patients with stage I lung cancer from New Mexico. EXPERIMENTAL DESIGN: Cases and controls from Colorado and New Mexico were interrogated for methylation of up to 31 genes using nested, methylation-specific PCR. Individual genes and methylation indices were used to assess the association between methylation and lung cancer with logistic regression modeling. RESULTS: Seventeen genes with ORs of 1.4 to 3.6 were identified and selected for replication in the New Mexico study. Overall, the direction of effects seen in New Mexico was similar to Colorado with the largest increase in case discrimination (ORs, 3.2-4.2) seen for the PAX5alpha, GATA5, and SULF2 genes. Receiver operating characteristic (ROC) curves generated from seven-gene panels from Colorado and New Mexico studies showed prediction accuracy of 71% and 77%, respectively. A 22-fold increase in lung cancer risk was seen for a subset of New Mexico cases with five or more genes methylated. Sequence variants associated with lung cancer did not improve the accuracy of this gene methylation panel. CONCLUSIONS: These studies have identified and replicated a panel of methylated genes whose integration with other promising biomarkers could initially identify the highest risk smokers for computed tomographic screening for early detection of lung cancer. PMID- 22510352 TI - Vocal fold mucus aggregation in persons with voice disorders. AB - Mucus aggregation on the vocal folds is a common finding from laryngeal endoscopy. Patients with voice disorders report the presence of mucus aggregation. Patients also report that mucus aggregation causes them to clear their throat, a behavior believed to be harmful to vocal fold mucosa. Even though clinicians and patients report and discuss mucus aggregation, we have a limited understanding of mucus aggregation in persons with voice disorders. The primary goal of this study was to provide an initial assessment of the presence and features of mucus aggregation in persons with voice disorders. The secondary goal of this study was to determine if there are differences in mucus aggregation between persons with and without voice disorders. To address these goals, four features of mucus aggregation were judged from laryngeal endoscopy recordings from 54 speakers with voice disorders and compared to judgments of these same features in persons without voice disorders. The results from this study showed: (1) 100% of dysphonic speakers had visible mucus aggregation on their vocal folds. (2) Persons with hyperfunctional voice disorders had different mucus characteristics than persons with hypofunctional voice disorders (p=0.002). (3) Dysphonic speakers did not differ in frequency of mucus identified on the vocal folds than non-dysphonic speakers. However, the two groups had different mucus characteristics (p=0.001). Future studies are warranted to determine if these differences in mucus aggregation between persons with and without voice disorders relate to specific aspects of laryngeal pathology or patient characteristics, such as age and gender. Once we understand these relationships, we may be able to use this information to improve our diagnosis and treatment of patients with atypical laryngeal mucus aggregation. LEARNING OUTCOMES: Readers will be able to: (1) describe why mucus aggregation may be an important feature to understand in persons with voice disorders, (2) describe the features of mucus aggregation that can be visually rated, and (3) explain the similarities and differences in mucus aggregation for persons with and without voice disorders. PMID- 22510353 TI - Liver toxicity of initial antiretroviral drug regimens including two nucleoside analogs plus one non-nucleoside analog or one ritonavir-boosted protease inhibitor in HIV/HCV-coinfected patients. AB - OBJECTIVE: To evaluate the incidence and risk factors for grade 3 or 4 ALT or AST elevations (TE) and grade 4 total bilirubin elevations (TBE) among HIV/HCV- coinfected treatment-naive patients with an initial regimen including 2 nucleoside analogs plus efavirenz (EFV), nevirapine (NVP), or a ritonavir-boosted protease inhibitor (PI/r). PATIENTS AND METHODS: This was a retrospective multicenter observational cohort study that recruited 745 HIV-infected drug-naive patients with detectable plasma HCV RNA who started a regimen including EFV, NVP, or PI/r. RESULTS: EFV was prescribed in 323 (43%), NVP in 126 (17%), and a PI/r in 296 (40%) patients. Grade 3 or 4 TE were observed in 19 (5.9%) individuals receiving EFV compared with 14 (11%) on NVP (P = .056) and 31 (10.5%) on PI/r (P = .036). Grade 4 TBE were identified in 7 (2.2%) patients on EFV, 1 (0.8%) on NVP, and 11 (3.7%) on PI/r (P = .19). Therapy was discontinued due to liver toxicity in 13 (4%) patients on EFV, 16 (13%) on NVP, and 17 (6%) on PI/r (P = .003). CONCLUSIONS: Regimens including EFV, NVP, or PI/r are generally safe in treatment-naive HIV/HCV-coinfected patients. Grade 3-4 TE are less commonly seen with EFV than with PI/r. Discontinuations due to hepatotoxicity were less frequent for patients receiving EFV than for those treated with NVP. PMID- 22510354 TI - Extended therapy with pegylated interferon and weight-based ribavirin for HCV-HIV coinfected patients. AB - BACKGROUND: It is unknown whether extended treatment with pegylated interferon (PEG) and weight-based ribavirin (WBR) results in higher rates of sustained viro logic response (SVR) among HCV-HIV coinfected patients compared with standard duration therapy. OBJECTIVE: The study aimed to measure rates of SVR among coinfected patients who received extended therapy with PEG plus WBR. METHODS: HCVHIV coinfected subjects were treated with PEG and WBR, and those who achieved early virologic response (EVR; >= 2 log decrease in HCV RNA from baseline or HCV RNA<600 IU/mL) at week 12 were eligible to continue treatment for 72 weeks. SVR (HCV RNA<60 IU/mL) was measured 24 weeks after treatment discontinuation. Predictors of SVR were assessed in simple and multivariate logistic regression. RESULTS: A total of 329 subjects enrolled at 36 sites. Of 184 subjects who achieved EVR, 169 entered Step 3: 89% male, 52% White, 29% Black, and 71% HCV treatment naive. The overall SVR rate was 27% (95% CI, 22%-32%) among all subjects, and 33% (95% CI, 27%-40%) among the 223 who were HCV treatment naive. In exploratory analyses, among 120 treatment-naive subjects who entered Step 3, the SVR rate was 62% (95% CI, 52%-70%). In this subgroup, predictors of SVR were HCV genotype 2 or 3 (P = .03), HCV RNA <800,000 IU/mL at study entry (P = .05), and achievement of complete EVR (HCV RNA<600 IU/mL at week 12;P < .0001). CONCLUSION: Among all subjects, we observed a comparable overall SVR rate to prior studies of subjects treated for 48 weeks. Extended treatment with PEG and WBR may be beneficial to subsets of coinfected patients, specifically those who are treatment naive and achieve complete EVR. PMID- 22510355 TI - Safety profile of maraviroc in patients coinfected with HIV-1 and hepatitis B or C included in the maraviroc expanded access program. AB - OBJECTIVE: To evaluate the safety of maraviroc with other antiretrovirals in patients with HIV-1 coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV). METHODS: This was a multicenter, noncomparative, open-label, expanded access program (EAP) initiated in February 2007. Patients with CCR5-tropic HIV-1 and HIV-1 RNA >= 1000 copies/mL on their current treatment received maraviroc 300 mg (150 mg with protease inhibitors) twice daily with optimized background therapy (OBT), which could include the newer agents raltegravir, etravirine, and darunavir. The adverse event (AE) profile was compared with the active and placebo arms of the maraviroc phase III clinical trials MOTIVATE 1 and 2, where the OBT did not include these agents. RESULTS: A total of 1,032 patients were enrolled: 51 HIV/HBV coinfected; 149 HIV/HCV coinfected, 9 HIV/HBV/HCV coinfected, and 823 HIV-1 monoinfected. Most (76%) received at least 1 newer agent. Overall AE frequency was comparable across coinfection groups (63%-72%). Hepatobiliary events were more common in HIV/HCV coinfection than in HIV monoinfection or HIV/HBV coinfection (10.0, 4.8, and 3.1 per 100 patient-years, respectively). Across all coinfection groups, there was a trend toward lower exposure-adjusted rates of serious and hepatobiliary AEs in the EAP than in the MOTIVATE studies. Grade 3/4 transaminase elevations in patients receiving maraviroc in the EAP and MOTIVATE were comparable with those seen in the MOTIVATE placebo arm. CONCLUSION: Maraviroc plus an OBT did not increase the incidence of AEs or severe laboratory liver abnormalities in HIV-1-infected patients coinfected with HBV or HCV. PMID- 22510357 TI - Longer prior exposure to zidovudine/lamivudine-containing combination antiretroviral therapy, age, and male gender are each associated with reduced subcutaneous adipose tissue. AB - OBJECTIVES: Whether zidovudine (AZT)-associated lipoatrophy occurrence differs by concomitant exposure to protease (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) remains unclear. Baseline body composition data from a randomized trial in subjects stable on first-line AZT-based therapy were used to explore this issue. METHODS: In this substudy of the PREPARE trial, centrally read baseline whole-body dual energy x-ray aborptiometry (DXA) and single-slice abdominal CT scans were analyzed with respect to duration and type of prior AZT/lamivudine (3TC) combination antiretroviral therapy (cART), including by multivariate linear regression adjusted for age, gender, ethnicity, body mass index (BMI), and nadir CD4. RESULTS: DXA and CT, from 134 and 136 patients, respectively [87% male; 82% Caucasian; mean (SD) age, 45.6 years (10); BMI, 24.3 kg/m2 (3.2)], were analyzed. Prior AZT/3TC cART exposure was 5.5 (2.2) years. Seventy-eight and 27 patients had concomitantly and exclusively used NNRTIs and PIs, respectively. AZT/3TC cART, AZT/3TC/NNRTI, and AZT/3TC/PI, respectively, were associated with the presence of a mean (95% CI) of 247 g (-438 to -56; P = .012), 267 g (-467 to -66; P = .010), and 216 g (-430 to -1.7; P = .048) less baseline limb fat per additional year of prior exposure. Although abdominal subcutaneous (SAT) adipose tissue was likewise less with longer AZT/3TC cART, this was only significant for AZT/3TC/ NNRTI but not AZT/3TC/PI. Visceral adipose tissue (VAT) amount was not clearly associated to prior treatment. Increased age and male gender were independently associated with lower limb fat and SAT, but more VAT. CONCLUSIONS: Longer exposure to AZT/3TC, regardless of whether in combination with PI or NNRTI, as well as increased age and male gender are independently associated with lower limb fat mass. PMID- 22510356 TI - Relationship of chronic hepatitis C infection to rates of AIDS-defining illnesses in a Canadian cohort of HIV seropositive individuals receiving highly active antiretroviral therapy. AB - BACKGROUND: The influence of chronic hepatitis C virus (HCV) infection on the risk, timing, and type of AIDS-defining illnesses (ADIs) is not well described. To this end, rates of ADIs were evaluated in a Canadian cohort of HIV seropositive individuals receiving highly active antiretroviral therapy (HAART). METHODS: ADIs were classified into 6 Centers for Disease Control and Prevention (CDC)-defined etiological subgroups: non-Hodgkin lymphoma, viral infection, bacterial infection, HIV-related disease, protozoal infection, and mycotic infection. Generalized estimating equation (GEE) Poisson regression models were used to estimate the effect of HCV on rates of ADIs after adjusting for covariates. RESULTS: Among 2,706 HAART recipients, 768 (28%) were HCV coinfected. Rates of all ADIs combined and of bacterial infection, HIV-related disease, and mycotic infection were increased in HCV-coinfected persons and among those with CD4 counts <200 cells/mm3 HCV was associated with an increased risk of ADIs (rate ratio [RR], 1.38; 95% CI, 1.01-1.88) and a 2-fold increased risk of mycotic infections (RR, 2.21; 95% CI, 1.35-3.62) in univariate analyses and after adjusting for age, baseline viral load, baseline CD4 count, and region of Canada. However, after further adjustment for HAART interruptions, HCV was no longer associated with an increased rate of ADIs overall (RR, 1.13; 95% CI, 0.80-1.59), but remained associated with an increased rate of mycotic infections (RR, 1.97, 95% CI, 1.08-3.61). CONCLUSION: Although HCV coin-fected individuals are at increased risk of developing ADIs overall, our analysis suggests that behavioral variables associated with HCV (including rates of retention on HAART), and not biological interactions with HCV itself, are primarily responsible. PMID- 22510358 TI - Impact of baseline virologic, immunologic, and demographic characteristics on virologic responses in the Gemini study. AB - PURPOSE: To determine the impact of baseline viral load (VL) and CD4+ cell count, race/ethnicity, and gender on response in a post hoc analysis of the Gemini study. METHODS: In this 48-week study, treatment-naive, HIV-infected participants received as initial therapy twice-daily saquinavir/ritonavir (SQV/r) 1000/100 mg (n=167) or lopinavir/ritonavir (LPV/r) 400/100 mg (n=170), each with emtricitabine 200 mg/tenofovir 300 mg daily. The proportion of participants achieving HIV RNA<50 copies/mL (primary endpoint) and median change from baseline in CD4+ cell count were compared by baseline VL (>100,000 vs <= 100,000 copies/ mL) and CD4+ cell count (>100 vs <= 100 cells/uL). The impact of baseline and demographic variables on virologic response was assessed by logistic regression analysis. RESULTS: Responses were similar between arms (SQV/r vs LPV/r) with or without stratification. In a pooled analysis of SQV/r and LPV/r arms, CD4+ cell count >100 cells/uL (odds ratio [OR], 1.628;P = .0416), non-Thai/non-Black versus Black race (OR, 1.518;P = .0023), and non-Thai/non-Black versus Thai (OR, 0.467;P = .0046) were significant predictors of virologic response. CONCLUSIONS: Treatment groups had similar efficacy. Baseline CD4+ cell count and race/ethnicity were independent predictors of virologic response, whereas baseline VL and gender were not. PMID- 22510359 TI - Does the oxytocin receptor (OXTR) polymorphism (rs2254298) confer 'vulnerability' for psychopathology or 'differential susceptibility'? Insights from evolution. AB - The diathesis-stress model of psychiatric conditions has recently been challenged by the view that it might be more accurate to speak of 'differential susceptibility' or 'plasticity' genes, rather than one-sidedly focusing on individual vulnerability. That is, the same allelic variation that predisposes to a psychiatric disorder if associated with (developmentally early) environmental adversity may lead to a better-than-average functional outcome in the same domain under thriving (or favourable) environmental conditions. Studies of polymorphic variations of the serotonin transporter gene, the monoamino-oxidase-inhibitor A coding gene or the dopamine D4 receptor gene indicate that the early environment plays a crucial role in the development of favourable versus unfavourable outcomes. Current evidence is limited, however, to establishing a link between genetic variation and behavioural phenotypes. In contrast, little is known about how plasticity may be expressed at the neuroanatomical level as a 'hard-wired' correlate of observable behaviour. The present review article seeks to further strengthen the argument in favour of the differential susceptibility theory by incorporating findings from behavioural and neuroanatomical studies in relation to genetic variation of the oxytocin receptor gene. It is suggested that polymorphic variation at the oxytocin receptor gene (rs2254298) is associated with sociability, amygdala volume and differential risk for psychiatric conditions including autism, depression and anxiety disorder, depending on the quality of early environmental experiences. Seeing genetic variation at the core of developmental plasticity can explain, in contrast to the diathesis-stress perspective, why evolution by natural selection has maintained such 'risk' alleles in the gene pool of a population. PMID- 22510360 TI - Ankylosing spondylitis: how diagnostic and therapeutic delay have changed over the last six decades. AB - OBJECTIVES: Ankylosing spondylitis (AS) is a chronic, progressive, and disabling disease, but the diagnosis is often missed and markedly delayed. An early diagnosis is important to establish a treatment to reduce disability and modify the natural course of disease. The aim of this study was to investigate the diagnostic (DD) and therapeutic (TD) delay according to the decade of diagnosis. The DD and TD correlation with radiological severity score and the new imaging techniques used in diagnosis (magnetic resonance [MRI], computerised tomography, scintigraphy for sacroiliac joints) were also investigated. METHODS: 135 AS patients (45 female and 90 male, 36.5+/-10.2 years old at diagnosis) with disease onset between 1950 and 2008, were investigated; the time from onset to diagnosis (DD) and treatment (TD), the New York and ASAS criteria fulfilment, the New York sacroiliac radiological score, bamboo spine presence at first visit and the new imaging technique used at diagnosis were recorded and their correlations were analysed. RESULTS: The New York and ASAS criteria were met at the first visit, by 87% and 96%, respectively. The delay from onset of symptoms to diagnosis and treatment was 9+/-8 and 12+/-11 years, respectively, but decreased significantly between different decades (p<0.001). The severity of sacroiliitis (mean 2+/-1; 17/135, 12.5% - IV grade sacroiliitis at diagnosis) and bamboo spine (3.7% at diagnosis) correlated with DD and TD (p<0.001). Sacroiliac MRI use at diagnosis significantly decreased both DD and TD (p>0.001 and p<0.05, respectively). CONCLUSIONS: DD and TD were correlated to radiological severity; they progressively decreased over 6 decades. PMID- 22510362 TI - Concepts of contraception for adolescent and young adult women with chronic illness and disability. AB - Sexual behavior is common in adolescents and young adults with or without chronic illness or disability, resulting in high levels of unplanned pregnancy and STDs. Individuals with chronic illness or disability should not receive suboptimal preventive health care. These individuals have a need for counseling regarding issues of sexuality and contraception. Sexually active adolescent and young adult women can be offered safe and effective contraception if they wish to avoid pregnancy. Women with chronic illnesses and disabilities who are sexually active should also be offered contraception based on their specific medical issues. Condoms are also recommended to reduce STD risks. Table 36 summarizes basic principles of contraception application for specific illnesses, which have been identified since the release of the combined OC in 1960. Clinicians should also consider the noncontraceptive benefits of this remarkable and life-changing technology that allows all reproductive age women to improve their lives, including those with chronic illnesses and disabilities. PMID- 22510363 TI - See your friends close and your enemies closer: social identity and identity threat shape the representation of physical distance. AB - Three studies demonstrated that collective identity and identity threat shape representations of the physical world. In Study 1, New York Yankees fans estimated Fenway Park, the stadium of a threatening out-group (but not Camden Yards, the stadium of a neutral out-group) to be closer than did non-Yankees fans. In Study 2, the authors manipulated identity threat among people affiliated (or not) with New York University (NYU). When Columbia University was portrayed as threatening to NYU, NYU affiliates estimated Columbia as closer than did non affiliates, compared with when Columbia was nonthreatening. In Study 3, Americans who perceived more symbolic threats from Mexican immigration estimated Mexico City as closer. Collective identification with the in-group moderated effects of threat on distance estimations. These studies suggest that social categorization, collective identification, and identity threat work in concert to shape the representations of the physical world. PMID- 22510364 TI - A stereochemical switch in the aDrs model system, a candidate for a functional amyloid. AB - Amyloid fibrils are commonly observed to adopt multiple distinct morphologies, which eventually can have significantly different neurotoxicities, as e.g. demonstrated in case of the Alzheimer peptide. The architecture of amyloid deposits is apparently also determined by the stereochemistry of amino acids. Post-translational changes of the chirality of certain residues may thus be a factor in controlling the formation of functional or disease-related amyloids. Anionic dermaseptin (aDrs), an unusual peptide from the skin secretions of the frog Pachymedusa dacnicolor, assembles to amyloid-like fibrils in a pH-dependent manner, which could play a functional role in defense. aDrs can be enzymatically converted into the diastereomer [d-Leu2]-aDrs by an l/d-isomerase. EM and AFM on fibrils formed by these isomers have shown that their predominant morphology is controlled by the stereochemistry of residue 2, whereas kinetic and thermodynamic parameters of aggregation are barely affected. When fibrils were grown from preformed seeds, backbone stereochemistry rather than templating-effects apparently dominated the superstructural organization of the isomers. Interestingly, MD indicated small differences in the conformational propensities between the isomers. Our results demonstrate how d-amino acid substitutions could take active part in the formation of functional or disease-related amyloid. Moreover, these findings contribute to the development of amyloid-based nanomaterials. PMID- 22510365 TI - Body mass index and survival after breast cancer diagnosis in Japanese women. AB - BACKGROUND: Body mass index (BMI) may be an important factor affecting breast cancer outcome. Studies conducted mainly in Western countries have reported a relationship between higher BMI and a higher risk of all-cause death or breast cancer-specific death among women with breast cancer, but only a few studies have been reported in Japan so far. In the present prospective study, we investigated the associations between BMI and the risk of all-cause and breast cancer-specific death among breast cancer patients overall and by menopausal status and hormone receptor status. METHODS: The study included 653 breast cancer patients admitted to a single hospital in Japan, between 1997 and 2005. BMI was assessed using a self-administered questionnaire. The patients were completely followed up until December, 2008. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated according to quartile points of BMI categories, respectively: <21.2, >=21.2 to <23.3 (reference), >=23.3 to <25.8 and >=25.8 kg/m2. RESULTS: During the follow-up period, 136 all-cause and 108 breast cancer-specific deaths were observed. After adjustment for clinical and confounding factors, higher BMI was associated with an increased risk of all-cause death (HR = 2.61; 95% CI: 1.01 6.78 for BMI >=25.8 vs. >=21.2 to <23.3 kg/m2) among premenopausal patients. According to hormonal receptor status, BMI >=25.8 kg/m2 was associated with breast cancer-specific death (HR = 4.95; 95% CI: 1.05-23.35) and BMI <21.2 kg/m2 was associated with all-cause (HR = 2.91; 95% CI: 1.09-7.77) and breast cancer specific death (HR = 7.23; 95% CI: 1.57-33.34) among patients with ER + or PgR + tumors. Analysis by hormonal receptor status also showed a positive association between BMI and mortality risk among patients with ER + or PgR + tumors and with BMI >=21.2 kg/m2 (p for trend: 0.020 and 0.031 for all-cause and breast cancer specific death, respectively). CONCLUSIONS: Our results suggest that both higher BMI and lower BMI are associated with an increased risk of mortality, especially among premenopausal patients or among patients with hormonal receptor positive tumors. Breast cancer patients should be informed of the potential importance of maintaining an appropriate body weight after they have been diagnosed. PMID- 22510366 TI - Analysis for genotyping Duffy blood group in inhabitants of Sudan, the fourth cataract of the Nile. AB - BACKGROUND: Genetic polymophisms of the Duffy antigen receptor for the chemokines (DARC) gene successfully protected against blood stage infection by Plasmodium vivax infection. The Fy (a-, b-) phenotype is predominant among African populations, particularly those originating from West Africa, and it is rare among non-African populations. The aim of this study was to analyse the frequency of four Duffy blood groups based on SNPs (T-33C, G125A, G298A and C5411T) in two local tribes of Sudanese Arabs, the Shagia and Manasir, which are both from the region of the Fourth Nile cataract in Sudan. METHODS: An analysis of polymorphisms was performed on 217 individuals (126 representatives of the Shagia tribe and 91 of the Manasir). Real-time PCR and TaqMan Genotyping Assays were used to study the prevalence of alleles and genotypes. RESULTS: The analysis of allelic and genotype frequency in the T-33C polymorphisms demonstrated a significant dominance of the C allele and CC genotype (OR = 0.53 [0.32-0.88]; p = 0.02) in both tribes. The G125A polymorphism is associated with phenotype Fy(a-, b-) and was identified in 83% of Shagia and 77% of Manasir. With regard to G298A polymorphisms, the genotype frequencies were different between the tribes (p = 0,002) and no single AA homozygote was found. Based on four SNPs examined, 20 combinations of genotypes for the Shagia and Manasir tribes were determined. The genotype CC/AA/GG/CT occurred most often in Shagia tribe (45.9%) but was rare in the Manasir tribe (6.6%) (p < 0.001 Shagia versus Manasir). The FY*AES allele was identified in both analysed tribes. The presence of individuals with the FY*A/FY*A genotype was demonstrated only in the Shagia tribe. CONCLUSION: This is probably the first report showing genotypically Duffy-negative people who carry both FY*BES and FY*AES. The identification of the FY*AES allele in both tribes may be due to admixture of the non-African genetic background. Taken as a whole, allele and genotype frequencies between the Shagia and the Manasir were statistically different. However, the presence of individuals with the FY*A/FY*A genotype was demonstrated only in the Shagia tribe. PMID- 22510367 TI - High-throughput microsatellite marker development in two sparid species and verification of their transferability in the family Sparidae. AB - Recently, 454 sequencing has emerged as a popular method for isolating microsatellites owing to cost-effectiveness and time saving. In this study, repeat-enriched libraries from two southern African endemic sparids (Pachymetopon blochii and Lithognathus lithognathus) were 454 GS-FLX sequenced. From these, 7370 sequences containing repeats (SCRs) were identified. A brief survey of 23 studies showed a significant difference between the number of SCRs when enrichment was performed first before 454 sequencing. We designed primers for 302 unique fragments containing more than five repeat units and suitable flanking regions. A fraction (<11%) of these loci were characterized with 18 polymorphic microsatellite loci (nine in each of the focal species) being described. Sanger sequencing of alleles confirmed that size variation was because of differences in the number of tandem repeats. However, a case of homoplasy and sequencing errors in the 454 sequencing were identified. These newly developed and four previously isolated loci were successfully used to identify polymorphic markers in nine other economically important species, representative of sparid diversity. The combination of newly developed markers with data from previous sparid cross species studies showed a significant negative correlation between genetic divergence to focal species and microsatellite transferability. The high level of transferability we described (48% amplification success and 32% polymorphism) suggests that the 302 microsatellite loci identified represent an excellent resource for future studies on sparids. Microsatellite marker development should commonly include tests of transferability to reduce costs and increase feasibility of population genetics studies in nonmodel organisms. PMID- 22510369 TI - Transformative learning during nursing education: a model of interconnectivity. AB - Higher education strives to transform students by opening their minds to different world views. This study investigated the transformative experiences of students using narrative analysis methodology to describe the experience of learning during nursing education. Phases of Transformative Learning Theory guided the analysis of narratives. The study yielded 5 narrative threads: 1) the multi-faceted process of learning, 2) experiential learning, 3) human interactions as central to defining nursing and caring, 4) personal life experiences intertwining with nursing, and 5) transformative learning. Results indicated that students perceived the greatest learning and transformation through experiential learning with humans. Such experiences included caring for immigrants, children in lower socioeconomic environments, and patients with a variety of physical and mental health needs in numerous settings. Other participants described personal experiences that took on new meaning or contributed to learning as a result of academic experiences. Some students entered with a personal history of service and charity work that provided a foundation for their educational experiences. PMID- 22510368 TI - Translational behaviour-genetic studies of alcohol: are we there yet? AB - In biomedical research, one key stage of translating basic science knowledge to clinical practice is the reconciliation of phenotypes employed for laboratory animal studies with those important for the clinical condition. Alcohol dependence (AD) is a prototypic complex genetic trait. There is a long history of behaviour-genetic studies of AD in both human subjects and various genetic animal models. This review assesses the state of the art in our understanding of the genetic contributions to AD. In particular, it primarily focuses on the phenotypes studied in mouse genetic animal models, comparing them to the aspects of the human condition they are intended to target. It identifies several features of AD where genetic animal models have been particularly useful, and tries to identify understudied areas where there is good promise for further genetic animal model work. PMID- 22510371 TI - RBM24: a 'regional business manager' in charge of the maintenance of sarcomeric protein expression 24 h a day? PMID- 22510370 TI - Evolutionary patterns of carbohydrate transport and metabolism in Halomonas boliviensis as derived from its genome sequence: influences on polyester production. AB - BACKGROUND: Halomonas boliviensis is a halophilic bacterium that is included in the gamma-Proteobacteria sub-group, and is able to assimilate different types of carbohydrates. H. boliviensis is also able to produce poly(3-hydroxybutyrate) (PHB) in high yields using glucose as the carbon precursor. Accumulation of PHB by microorganisms is induced by excess of intracellular NADH.The genome sequences and organization in microorganisms should be the result of evolution and adaptation influenced by mutation, gene duplication, horizontal gen transfer (HGT) and recombination. Furthermore, the nearly neutral theory of evolution sustains that genetic modification of DNA could be neutral or selected, albeit most mutations should be at the border between neutrality and selection, i.e. slightly deleterious base substitutions in DNA are followed by a slightly advantageous substitutions. RESULTS: This article reports the genome sequence of H. boliviensis. The chromosome size of H. boliviensis was 4 119 979 bp, and contained 3 863 genes. A total of 160 genes of H. boliviensis were related to carbohydrate transport and metabolism, and were organized as: 70 genes for metabolism of carbohydrates; 47 genes for ABC transport systems and 43 genes for TRAP-type C4-dicarboxylate transport systems. Protein sequences of H. boliviensis related to carbohydrate transport and metabolism were selected from clusters of orthologous proteins (COGs). Similar proteins derived from the genome sequences of other 41 archaea and 59 bacteria were used as reference. We found that most of the 160 genes in H. boliviensis, c.a. 44%, were obtained from other bacteria by horizontal gene transfer, while 13% of the genes were acquired from haloarchaea and thermophilic archaea, only 34% of the genes evolved among Proteobacteria and the remaining genes encoded proteins that did not cluster with any of the proteins obtained from the reference strains. Furthermore, the diversity of the enzymes derived from these genes led to polymorphism in glycolysis and gluconeogenesis. We found further that an optimum ratio of glucose and sucrose in the culture medium of H. boliviensis favored cell growth and PHB production. CONCLUSIONS: Results obtained in this article depict that most genetic modifications and enzyme polymorphism in the genome of H. boliviensis were mainly influenced by HGT rather than nearly neutral mutations. Molecular adaptation and evolution experienced by H. boliviensis were also a response to environmental conditions such as the type and amount of carbohydrates in its ecological niche. Consequently, the genome evolution of H. boliviensis showed to be strongly influenced by the type of microorganisms, genetic interaction among microbial species and its environment. Such trend should also be experienced by other prokaryotes. A system for PHB production by H. boliviensis that takes into account the evolutionary adaptation of this bacterium to the assimilation of combinations of carbohydrates suggests the feasibility of a bioprocess economically viable and environmentally friendly. PMID- 22510372 TI - The shape of things to come: mitochondrial fusion and fission in the adult heart. PMID- 22510373 TI - Relaxin improves TNF-alpha-induced endothelial dysfunction: the role of glucocorticoid receptor and phosphatidylinositol 3-kinase signalling. AB - AIMS: Human relaxin-2 influences renal and cardiovascular functions. We investigated its effects on experimental endothelial dysfunction. METHODS AND RESULTS: Acetylcholine-mediated vasodilation of rat aortic rings, impaired by 48 h tumour necrosis factor-alpha (TNF-alpha) treatment, was dose-dependently improved by relaxin co-incubation, an effect sensitive to phosphatidylinositol 3 kinase (PI3K) inhibition and the glucocorticoid receptor (GR) antagonist RU-486. TNF increased endothelial nitric oxide synthase (eNOS) phosphorylation at Thr495 and decreased total eNOS expression and both basal and stimulated eNOS activity. Relaxin co-incubation did not affect eNOS expression but improved its activity via PI3K-dependent Thr495 dephosphorylation and Ser1177 phosphorylation, and additional Ser633 phosphorylation. Via GR, relaxin attenuated the TNF-related stimulation of endothelin-1 expression, superoxide and nitrotyrosine formation, and arginase II expression. Relaxin restored, via GR-CCAAT/enhancer-binding protein-beta (c/EBP-beta)-mediated promoter stimulation, the compromised expression of superoxide dismutase-1 (SOD1). In rat aortic endothelial cells, relaxin activated protein kinase B (Akt) and repressed TNF-induced nuclear factor kappaB and activator protein-1. Finally, the relevance of the different findings to the model used was proved by pharmacological interventions. CONCLUSION: Relaxin improved endothelial dysfunction by promoting eNOS activity, suppressing endothelin-1 and arginase-II expression, and up-regulating SOD1 via GR, GR-c/EBP beta, and PI3K-Akt pathways. This corroborates the notion that it functions as an endogenous and potentially therapeutic vasoprotector. PMID- 22510374 TI - Learning from toxicity patterns in phase I trials during the era of mechanism targeted agents. PMID- 22510375 TI - Recording evoked potentials during deep brain stimulation: development and validation of instrumentation to suppress the stimulus artefact. AB - The clinical efficacy of deep brain stimulation (DBS) for the treatment of movement disorders depends on the identification of appropriate stimulation parameters. Since the mechanisms of action of DBS remain unclear, programming sessions can be time consuming, costly and result in sub-optimal outcomes. Measurement of electrically evoked compound action potentials (ECAPs) during DBS, generated by activated neurons in the vicinity of the stimulating electrode, could offer insight into the type and spatial extent of neural element activation and provide a potential feedback signal for the rational selection of stimulation parameters and closed-loop DBS. However, recording ECAPs presents a significant technical challenge due to the large stimulus artefact, which can saturate recording amplifiers and distort short latency ECAP signals. We developed DBS ECAP recording instrumentation combining commercial amplifiers and circuit elements in a serial configuration to reduce the stimulus artefact and enable high fidelity recording. We used an electrical circuit equivalent model of the instrumentation to understand better the sources of the stimulus artefact and the mechanisms of artefact reduction by the circuit elements. In vitro testing validated the capability of the instrumentation to suppress the stimulus artefact and increase gain by a factor of 1000 to 5000 compared to a conventional biopotential amplifier. The distortion of mock ECAP (mECAP) signals was measured across stimulation parameters, and the instrumentation enabled high fidelity recording of mECAPs with latencies of only 0.5 ms for DBS pulse widths of 50 to 100 us/phase. Subsequently, the instrumentation was used to record in vivo ECAPs, without contamination by the stimulus artefact, during thalamic DBS in an anesthetized cat. The characteristics of the physiological ECAP were dependent on stimulation parameters. The novel instrumentation enables high fidelity ECAP recording and advances the potential use of the ECAP as a feedback signal for the tuning of DBS parameters. PMID- 22510376 TI - Molecular responses to environmental stresses. PMID- 22510377 TI - Atypical Atm-p53 genetic interaction in osteogenesis is mediated by Smad1 signaling. PMID- 22510379 TI - Pre-hypertension as a significant predictor of chronic kidney disease in a general population: the Ohasama Study. AB - BACKGROUND: Hypertension is associated with an increased risk of development of chronic kidney disease (CKD). However, it is unclear whether pre-hypertension is related to the incidence of CKD. METHODS: The incidence of CKD defined as positive proteinuria or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) was examined in 2150 inhabitants without pre-existing CKD from the general Japanese population. The association of blood pressure and CKD incidence was examined using a Cox regression model adjusted for age, sex, habitual smoking and drinking, obesity, history of cardiovascular disease, diabetes mellitus or hypercholesterolemia, eGFR at baseline, number of follow-up examinations and year of baseline examination. Participants were categorized according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. RESULTS: Participants were categorized into normotension (n = 586, 27.3 % ), pre-hypertension (n = 815, 37.9 % ), Stage 1 hypertension (n = 386, 18.0 % ) and Stage 2 hypertension (n = 363, 16.9 % ). During a mean follow-up of 6.5 years (14 023 person-years), 461 incidences of CKD were recorded. Compared to normotension, adjusted hazard ratios of CKD were significantly higher for pre-hypertension (1.49, P < 0.003), Stage 1 (1.83, P < 0.001) and Stage 2 (2.55, P < 0.001) hypertension. The population attributable fraction of pre-hypertension (12.1 % ) was considered to be compatible to that of Stage 1 (8.6 % ) and Stage 2 (14.9 % ) hypertension. CONCLUSION: This was the first study to demonstrate that pre-hypertension was significantly associated with an increased risk of CKD and was one of the considerable causes of CKD in the general population. PMID- 22510380 TI - Human RAGE antibody protects against AGE-mediated podocyte dysfunction. AB - BACKGROUND: Residual renal function (RRF) contributes to better patient survival in peritoneal dialysis (PD). It is known that glucose degradation products (GDP) and advanced glycation end-products (AGE) resorbed from the peritoneal cavity do not only cause local peritoneal toxicity but also systemic damage resulting in a loss of RRF. We hypothesize that GDP and AGE affect the structure and function of podocytes and investigate whether these effects can be rescued by human RAGE antibody (hRAGEab) to prevent AGE/RAGE interaction and podocyte damage. METHODS: Differentiated human podocytes were pre-incubated with +/-hRAGEab to block the AGE/RAGE interaction and incubated afterwards either with control solution (control), PD fluid (PDF) or a GDP mixture (GDP) for 48 h. We analysed podocyte damage and rescue by hRAGEab using immunofluorescence, western blot, enzyme linked immunosorbent assay and a functional migration assay. For quantitation, a semiquantitative score was used. RESULTS: When pre-incubating podocytes with hRAGEab, damage mediated by PDF and GDP was reduced. We observed lower expression of AGE in PDF and GDP as well as decreased levels of inflammation as shown by activation of nuclear factor kappa B and interleukin-6 release. The reorganization of the podocyte actin cytoskeleton was reduced in the presence of hRAGEab as well as ameliorated synaptopodin expression could be observed, both functionally associated with normal podocyte motility. Finally, podocytes underwent less apoptosis. CONCLUSIONS: It has been investigated that GDP containing PDF causes a loss of RRF in PD. Our findings suggest that hRAGEab confers protection against PDF- and GDP-induced podocyte dysfunction. Blocking the AGE/RAGE interaction provides specific protective effects against PDF- and GDP-induced cytoskeletal reorganization, dynamics and stabilizes podocyte survival; this might be an implication for the preservation of RRF in PD. PMID- 22510381 TI - Nephrological abnormalities in patients with transaldolase deficiency. AB - BACKGROUND: Transaldolase deficiency (OMIM 606003) is a multisystem disorder first described in 2001. Transaldolase is an enzyme of the reversible part of the pentose phosphate pathway. Affected patients have abnormal polyol concentrations in body fluids, mostly in urine. The clinical presentation is variable. The leading symptoms are coagulopathy, thrombocytopenia, hepatosplenomegaly, hepatic fibrosis and dysmorphic features. The objective of our study was to attempt to characterize the renal phenotype of patients with transaldolase deficiency. METHODS: Clinical and laboratory data of all nine patients with transaldolase deficiency presently known were gathered by retrospective chart analysis. RESULTS: Nephrological abnormalities were present in seven of the nine patients. The most common findings were low molecular weight (LMW) proteinuria and hypercalciuria. The two oldest patients had moderate chronic kidney failure. In two patients, generalized aminoaciduria was found, two patients had renal phosphate wasting and three patients had hyperchloremic metabolic acidosis. Three patients had anatomical abnormalities. CONCLUSIONS: Renal tubular dysfunction is present in the majority of patients with transaldolase deficiency and may lead to chronic renal failure. The combination of unexplained liver dysfunction with LMW proteinuria should prompt metabolic screening for transaldolase deficiency by measuring urinary polyols. In patients with transaldolase deficiency, monitoring of kidney function is mandatory. PMID- 22510382 TI - ERK and p38 inhibitors attenuate memory deficits and increase CREB phosphorylation and PGC-1alpha levels in Abeta-injected rats. AB - In this study, we investigated the effect of intracerebroventricular administration of ERK and p38 specific inhibitors, U0126 and PD169316, respectively, on learning and memory deficits induced by amyloid beta (Abeta) in rats. To investigate the effects of these compounds on learning and memory, we performed Morris water maze (MWM) test. U0126 and/or PD169316 improved spatial learning in MWM in Abeta-injected rats, 20 days after Abeta-injection. To determine the mechanisms of action of U0126 and PD169316, we studies their effect on some intracellular signaling pathways such as Ca(+)/cAMP-response element binding protein (CREB), c-fos, and transcription factors that regulate mitochondrial biogenesis. Based on our data, CREB and c-fos levels decreased 7 days after Abeta-injection, while U0126 and/or PD169316 pretreatments significantly increased these levels. Moreover, U0126 and PD169316 activated peroxisome proliferator-activated receptor gamma coactivator-1a, nuclear respiratory factor 1, and mitochondrial transcription factor A, 7 days after Abeta-injection. Surprisingly, these factors were returned to vehicle level, 20 days after Abeta-injection. Our findings reinforce the potential neuroprotective effect of these inhibitors against the Abeta toxicity. PMID- 22510383 TI - Secondary treatment of acute graft-versus-host disease: a critical review. AB - Management of steroid-resistant or steroid-refractory acute graft-versus-host disease (aGVHD) poses one of the most vexing and difficult problems faced by transplantation physicians. In the current study, we used 10 criteria to evaluate 67 reports describing secondary treatment of patients with aGVHD. The goal of this exercise was not only to provide a critical summary of the literature but also to offer suggestions that could improve future studies. Areas especially in need of improvement include the use of a consistent treatment regimen, the assessment of response at a consistent prespecified time point, consideration of concomitant treatment in assessing response, documentation that selection bias was minimized, and the use of methods that test a formal statistical hypothesis based on a contemporaneous or historical benchmark. Our results suggest that previous published reports collectively offer little guidance in discerning the most effective treatments for patients with steroid-resistant or steroid refractory aGVHD. Adherence to the proposed criteria in future reports would enable meaningful comparisons across studies and thereby accelerate progress in evaluating new treatments for patients with aGVHD. PMID- 22510384 TI - First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. AB - Despite prophylaxis with immunosuppressive agents or a variety of other approaches, many patients suffer from acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation. Although consensus has emerged supporting the use of high-dose methylprednisolone or prednisone for initial treatment of aGVHD, practices differ among centers with respect to the initial glucocorticoid dose, the use of additional immunosuppressive agents, and the approach to withdrawal of treatment after initial improvement. Despite many studies, practices vary considerably with respect to the selection of agents for treatment of glucocorticoid-resistant or refractory GVHD. Investigators and clinicians have recognized the lack of progress and lamented the absence of an accepted standard of care for secondary treatment of aGVHD. The American Society of Blood and Marrow Transplantation has developed recommendations for treatment of aGVHD to be considered by care providers, based on a comprehensive and critical review of published reports. Because the literature provides little basis for a definitive guideline, this review also provides a framework for the interpretation of previous results and the design of future studies. PMID- 22510385 TI - Pattern of tissue invasion by Propionibacterium acnes in acne vulgaris. PMID- 22510386 TI - The effect of disinfecting solutions on the dimensional stability of dental alginate impression materials. AB - OBJECTIVES: Dimensional changes occur in set dental alginate impression materials when immersed in disinfecting solutions. In this contribution the dimensional changes of two alginates in two disinfecting solutions, and for two specimen thicknesses, have been studied. The results were analyzed theoretically. METHODS: The dimensional changes of two commercial alginates (Blueprint Cremix and Hydrogum), have been measured, in distilled water and two disinfecting solutions (Perform ID/sodium hypochlorite), using a traveling microscope, at 5 min intervals over a period of 1h. Samples of simple geometry have been studied, namely rectangular strips with thicknesses of 1.5 and 3mm, respectively. RESULTS: In all cases, both alginates continuously shrank with time, in the three immersion liquids, over the hour of measurement, indicating transfer of water from the alginate into the external water or disinfecting solution. The t(1/2) shrinkage plots were generally linear, but with an intercept on the t(1/2) axis, indicating the possibility of an initial expansion at very short times. In most cases, the ratios of slopes for both thicknesses were 1.33-1.54, in contrast to the theoretical value of 2. Perform ID however gave anomalous results for the 1.5mm thick samples. At 10 min their shrinkage was 1.34-1.72%, compared with 0.42% to 0.67% in the other two media. SIGNIFICANCE: The effects of thickness observed were not in accord with simple Fickian theory because of the various ions diffusing into and out of the alginate. Moreover, the water content of the alginate decreased consequent on the cross-linking process. PMID- 22510387 TI - Prevalence and correlates of cancer survivors' supportive care needs 6 months after diagnosis: a population-based cross-sectional study. AB - BACKGROUND: An understanding of the nature and magnitude of the impact of cancer is critical to planning how best to deliver supportive care to the growing population of cancer survivors whose need for care may span many years. This study aimed to describe the prevalence of and factors associated with moderate to high level unmet supportive care needs among adult cancer survivors six months after diagnosis. METHODS: A population-based sample of adult cancer survivors diagnosed with one of the eight most incident cancers in Australia was recruited from two state-based cancer registries. Data for 1323 survivors were obtained by self-report questionnaire and linkage with cancer registry data. Unmet needs were assessed by the 34-item Supportive Care Needs Survey (SCNS-SF34). The data were examined using chi-square and multiple logistic regression analyses. RESULTS: A total of 444 (37%) survivors reported at least one 'moderate to high' level unmet need and 496 (42%) reported 'no need' for help. Moderate to high level unmet needs were most commonly reported in the psychological (25%) and physical aspects of daily living (20%) domains. The five most frequently endorsed items of moderate to high unmet need were concerns about the worries of those close to them (15%), fears about the cancer spreading (14%), not being able to do the things they used to do (13%), uncertainty about the future (13%) and lack of energy/tiredness (12%). Survivors' psychological characteristics were the strongest indicators of unmet need, particularly caseness for anxious preoccupation coping which was associated (OR = 2.2-5.9) with unmet need for help across all domains. CONCLUSIONS: Unmet supportive care needs are prevalent among a subgroup of survivors transitioning from active treatment to survivorship, although lower than previously reported. In addition to coping support, valuable insight about how to prevent or address survivors' unmet needs could be gained by examining the substantial proportion of survivors who report no unmet needs. PMID- 22510388 TI - From in silico to in spectro kinetics of respiratory complex I. AB - An enzyme's activity is the consequence of its structure. The stochastic approach we developed to study the functioning of the respiratory complexes is based upon their 3D structure and their physical and chemical properties. Consequently it should predict their kinetic properties. In this paper we compare the predictions of our stochastic model derived for the complex I with a number of experiments performed with a large range of complex I substrates and products. A good fit was found between the experiments and the prediction of our stochastic approach. We show that, due to the spatial separation of the two half redox reactions (NADH/NAD and Q/QH(2)), the kinetics cannot necessarily obey a simple mechanism (ordered or ping-pong for instance). A plateau in the kinetics is observed at high substrates concentrations, well evidenced in the double reciprocal plots, which is explained by the limiting rate of quinone reduction as compared with the oxidation of NADH at the other end of complex I. Moreover, we show that the set of the seven redox reactions in between the two half redox reactions (NADH/NAD and Q/QH(2)) acts as an electron buffer. An inhibition of complex I activity by quinone is observed at high concentration of this molecule, which cannot be explained by a simple stochastic model based on the known structure. We hypothesize that the distance between the catalytic site close to N2 (iron/sulfur redox center that transfers electrons to quinone) and the membrane forces the quinone/quinol to take several positions in between these sites. We represent these possible positions by an extra site necessarily occupied by the quinone/quinol molecules on their way to the redox site. With this hypothesis, we are able to fit the kinetic experiments over a large range of substrates and products concentrations. The slow rate constants derived for the transition between the two sites could be an indication of a conformational change of the enzyme during the quinone/quinol movement. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012). PMID- 22510389 TI - Track record? PMID- 22510390 TI - Caspofungin for treatment of invasive aspergillosis in Germany: results of a pre planned subanalysis of an international registry. AB - BACKGROUND: This study is a pre-planned country-specific subanalysis of results in Germany from a multinational multicenter registry to prospectively assess real world experience with caspofungin administered for treatment of proven or probable invasive aspergillosis (IA). METHODS: Data from patients treated with caspofungin for a single episode of IA were collected. Effectiveness was determined by the local investigator as favorable (complete or partial response) or unfavorable (stable disease, failure or death) at the end of caspofungin therapy. Descriptive statistics with binomial exact confidence intervals were employed. RESULTS: Forty-two consecutive patients were identified in three German centers. Three patients (7%) had proven IA and 39/42 (93%) had probable IA (modified European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria). Forty-one patients had pulmonary IA and one had tracheal IA. Caspofungin monotherapy was received by 36/42 patients (86%); of these, 26/36 (72%) received salvage therapy. A favorable response was observed in 29/42 patients (69%; 95% CI 53 to 82%); of these, 21/29 (72%) had a complete and 8/29 (28%) a partial response. Favorable response rate was 69% in patients with monotherapy (95% CI 52% to 84%; 25/36 patients), and 67% in patients receiving combination therapy (95% CI 22% to 96%; 4/6 patients). Favorable response rate in patients with first line therapy was 64% (95% CI 31% to 89%; 7/11 patients), and 73% in patients with second line therapy (95% CI 54% to 88%; 20/30 patients). No adverse events were reported. In total, 35/42 patients (83%; 95% CI 69 to 93%) survived seven days after completion of caspofungin therapy. CONCLUSIONS: These real-life findings in Germany are consistent with the international findings from this registry and with findings from randomized studies. PMID- 22510391 TI - Elaboration and validation of a questionnaire (Qualisex) to assess the impact of rheumatoid arthritis on sexuality with patient involvement. AB - OBJECTIVES: Rheumatoid arthritis (RA) may have consequences on sexual life. The objective was to develop and validate a questionnaire assessing the impact of RA on sexuality. METHODS: First, 6 patients (5 women, 1 man) with RA, 2 rheumatologists and 1 sexologist elaborated during a one-day focus-group type meeting an exhaustive list of issues relating to impact of RA on sexuality. The list was reduced by merging similar issues, then according to the relative importance for patients of each issue. A questionnaire was developed with input from these patients, with particular attention on phrasing. Psychometric properties (missing data, correlations with other disease aspects, reliability) were assessed in a multi-centre study. RESULTS: The list of 33 issues related to impact of RA on sexuality included psychological issues (9), couple/relationship issues (9), physical issues (7), and general aspects (5). A 10-question numeric rating scale questionnaire was constructed. Preliminary validation was obtained on 53 patients (44 women, mean age 50.7 years; mean disease duration 14.4 years). The mean score was 3.3+/-2.5, missing data were acceptable (13%). Qualisex results were correlated with disease activity and symptoms (r=0.50-0.65, p< 0.001); but not with demographics, depression or coping. Qualisex was reliable in 40 patients: the intra-class correlation coefficient was 0.83 (95% CI: 0.70 0.91). CONCLUSIONS: A simple (10 questions) and valid tool investigating impact of RA on sexuality has been developed with the involvement of patients. This tool can be useful to assess this important aspect of quality of life. PMID- 22510393 TI - From neural responses to population behavior: neural focus group predicts population-level media effects. AB - Can neural responses of a small group of individuals predict the behavior of large-scale populations? In this investigation, brain activations were recorded while smokers viewed three different television campaigns promoting the National Cancer Institute's telephone hotline to help smokers quit (1-800-QUIT-NOW). The smokers also provided self-report predictions of the campaigns' relative effectiveness. Population measures of the success of each campaign were computed by comparing call volume to 1-800-QUIT-NOW in the month before and the month after the launch of each campaign. This approach allowed us to directly compare the predictive value of self-reports with neural predictors of message effectiveness. Neural activity in a medial prefrontal region of interest, previously associated with individual behavior change, predicted the population response, whereas self-report judgments did not. This finding suggests a novel way of connecting neural signals to population responses that has not been previously demonstrated and provides information that may be difficult to obtain otherwise. PMID- 22510394 TI - Efficacy and feasibility of radiofrequency ablation for hepatocellular carcinoma patients. AB - BACKGROUND/AIMS: Radiofrequency ablation (RFA) is a new treatment which is used to treat hepatocellular carcinoma (HCC). We performed this clinical trial to investigate whether it could reduce the damage of residual liver function. METHODOLOGY: We studied 40 hepatitis-related chronic patients who underwent RFA for hepatocellular carcinoma. Indocyanine green (ICG) test was performed pre and postoperatively. RESULTS: There were 32 males and 8 females with an average age of 53.98+12.59 years who underwent RFA for HCC. The mean preoperative ICGR15 value of 40 of the patients was (10.17+9.54) lower than the postoperative ICG retention rate at 15 min (ICGR15) value (14.95+12.71).Differences between the preoperative ICGR15 and the postoperative ICGR15 values were not significantly different (p=0.074). The 1-, 2- and 3-year survival rates were 98.7%, 88.8% and 76.4%, respectively. CONCLUSIONS: The results indicate that RFA is a minimally invasive treatment which provides a possible treatment modality for HCC patients with poor liver function and the efficacy is as well as the surgical treatment for HCC patients within the Milan criteria. PMID- 22510392 TI - Aging, cancer, and cancer vaccines. AB - World population has experienced continuous growth since 1400 A.D. Current projections show a continued increase - but a steady decline in the population growth rate - with the number expected to reach between 8 and 10.5 billion people within 40 years. The elderly population is rapidly rising: in 1950 there were 205 million people aged 60 or older, while in 2000 there were 606 million. By 2050, the global population aged 60 or over is projected to expand by more than three times, reaching nearly 2 billion people 1. Most cancers are age-related diseases: in the US, 50% of all malignancies occur in people aged 65-95. 60% of all cancers are expected to be diagnosed in elderly patients by 2020 2. Further, cancer related mortality increases with age: 70% of all malignancy-related deaths are registered in people aged 65 years or older 3. Here we introduce the microscopic aspects of aging, the pro-inflammatory phenotype of the elderly, and the changes related to immunosenescence. Then we deal with cancer disease and its development, the difficulty of treatment administration in the geriatric population, and the importance of a comprehensive geriatric assessment. Finally, we aim to analyze the complex interactions of aging with cancer and cancer vaccinology, and the importance of this last approach as a complementary therapy to different levels of prevention and treatment. Cancer vaccines, in fact, should at present be recommended in association to a stronger cancer prevention and conventional therapies (surgery, chemotherapy, radiation therapy), both for curative and palliative intent, in order to reduce morbidity and mortality associated to cancer progression. PMID- 22510395 TI - Investigations on anopheline mosquitoes close to the nest sites of chimpanzees subject to malaria infection in Ugandan highlands. AB - BACKGROUND: Malaria parasites (Plasmodium sp.), including new species, have recently been discovered as low grade mixed infections in three wild chimpanzees (Pan troglodytes schweinfurthii) sampled randomly in Kibale National Park, Uganda. This suggested a high prevalence of malaria infection in this community. The clinical course of malaria in chimpanzees and the species of the vectors that transmit their parasites are not known. The fact that these apes display a specific behaviour in which they consume plant parts of low nutritional value but that contain compounds with anti-malarial properties suggests that the apes health might be affected by the parasite. The avoidance of the night-biting anopheline mosquitoes is another potential behavioural adaptation that would lead to a decrease in the number of infectious bites and consequently malaria. METHODS: Mosquitoes were collected over two years using suction-light traps and yeast-generated CO(2) traps at the nesting and the feeding sites of two chimpanzee communities in Kibale National Park. The species of the female Anopheles caught were then determined and the presence of Plasmodium was sought in these insects by PCR amplification. RESULTS: The mosquito catches yielded a total of 309 female Anopheles specimens, the only known vectors of malaria parasites of mammalians. These specimens belonged to 10 species, of which Anopheles implexus, Anopheles vinckei and Anopheles demeilloni dominated. Sensitive DNA amplification techniques failed to detect any Plasmodium-positive Anopheles specimens. Humidity and trap height influenced the Anopheles capture success, and there was a negative correlation between nest numbers and mosquito abundance. The anopheline mosquitoes were also less diverse and numerous in sites where chimpanzees were nesting as compared to those where they were feeding. CONCLUSIONS: These observations suggest that the sites where chimpanzees build their nests every night might be selected, at least in part, in order to minimize contact with anopheline mosquitoes, which might lead to a reduced risk in acquiring malaria infections. PMID- 22510396 TI - Decreased levels of nucleotide pyrophosphatase phosphodiesterase 1 are associated with cartilage calcification in osteoarthritis and trigger osteoarthritic changes in mice. AB - OBJECTIVE: To analyse the function of nucleotide pyrophosphatase phosphodiesterase (NPP1), a member of the pyrophosphate pathway, in osteoarthritis (OA). METHODS: mRNA expression of NPP1, ANK ankylosing protein and tissue non-specific alkaline phosphatase was assessed by quantitative PCR. NPP1 protein levels were analysed in mouse and human cartilage samples. Bone metabolism was analysed by F18-positron emission tomography-scanning and uCT in ttw/ttw mice. Ttw/ttw mice are mice carrying a loss-of-function mutation in NPP1. Calcification of articular cartilage was assessed using von Kossa staining and OA severity using the Mankin score. Cartilage remodelling was investigated by type X collagen immunohistochemistry. RESULTS: Expression of NPP1, but not the other members of this pathway, inversely correlated with cartilage calcification and OA severity in mouse and humans. Proinflammatory cytokines downregulated the expression of NPP1, demonstrating an influence of inflammation on matrix calcification. Ttw/ttw mutant mice, carrying a loss-of-function mutation in NPP1, exhibit increased bone formation process in joints compared with wild types. Ttw/ttw mice also developed spontaneous OA-like changes, evaluated by histological analysis and in vivo imaging. Ectopic calcifications were associated with increased expression of collagen X in the cartilage. CONCLUSION: The authors conclude that OA is characterised by the reactivation of molecular signalling cascades involving proinflammatory cytokines, thereby regulating the pyrophosphate pathway which consequently leads to cartilage ossification, at least in part resembling endochondral ossification. PMID- 22510397 TI - The initial health-system response to the earthquake in Christchurch, New Zealand, in February, 2011. AB - At 1251 h on Feb 22, 2011, an earthquake struck Christchurch, New Zealand, causing widespread destruction. The only regional acute hospital was compromised but was able to continue to provide care, supported by other hospitals and primary care facilities in the city. 6659 people were injured and 182 died in the initial 24 h. The massive peak ground accelerations, the time of the day, and the collapse of major buildings contributed to injuries, but the proximity of the hospital to the central business district, which was the most affected, and the provision of good medical care based on careful preparation helped reduce mortality and the burden of injury. Lessons learned from the health response to this earthquake include the need for emergency departments to prepare for: patients arriving by unusual means without prehospital care, manual registration and tracking of patients, patient reluctance to come into hospital buildings, complete loss of electrical power, management of the many willing helpers, alternative communication methods, control of the media, and teamwork with clear leadership. Additionally, atypical providers of acute injury care need to be integrated into response plans. PMID- 22510398 TI - Primary brain tumours in adults. AB - Important advances have been made in the understanding and management of adult gliomas and primary CNS lymphomas--the two most common primary brain tumours. Progress in imaging has led to a better analysis of the nature and grade of these tumours. Findings from large phase 3 studies have yielded some standard treatments for gliomas, and have confirmed the prognostic value of specific molecular alterations. High-throughput methods that enable genome-wide analysis of tumours have improved the knowledge of tumour biology, which should lead to a better classification of gliomas and pave the way for so-called targeted therapy trials. Primary CNS lymphomas are a group of rare non-Hodgkin lymphomas. High dose methotrexate-based regimens increase survival, but the standards of care and the place of whole-brain radiotherapy remain unclear, and are likely to depend on the age of the patient. The focus now is on the development of new polychemotherapy regimens to reduce or defer whole-brain radiotherapy and its delayed complications. PMID- 22510399 TI - Universal lipid screening in children and adolescents: a baby step toward primordial prevention? PMID- 22510400 TI - Homocysteine and the risk of dementia. PMID- 22510401 TI - Biomedical coatings on magnesium alloys - a review. AB - This review comprehensively covers research carried out in the field of degradable coatings on Mg and Mg alloys for biomedical applications. Several coating methods are discussed, which can be divided, based on the specific processing techniques used, into conversion and deposition coatings. The literature review revealed that in most cases coatings increase the corrosion resistance of Mg and Mg alloys. The critical factors determining coating performance, such as corrosion rate, surface chemistry, adhesion and coating morphology, are identified and discussed. The analysis of the literature showed that many studies have focused on calcium phosphate coatings produced either using conversion or deposition methods which were developed for orthopaedic applications. However, the control of phases and the formation of cracks still appear unsatisfactory. More research and development is needed in the case of biodegradable organic based coatings to generate reproducible and relevant data. In addition to biocompatibility, the mechanical properties of the coatings are also relevant, and the development of appropriate methods to study the corrosion process in detail and in the long term remains an important area of research. PMID- 22510402 TI - Bilayered constructs aimed at osteochondral strategies: the influence of medium supplements in the osteogenic and chondrogenic differentiation of amniotic fluid derived stem cells. AB - The development of osteochondral tissue engineered interfaces would be a novel treatment for traumatic injuries and aging associated diseases that affect joints. This study reports the development of a bilayered scaffold, which consists of both bone and cartilage regions. On the other hand, amniotic fluid derived stem cells (AFSCs) could be differentiated into either osteogenic or chondrogenic cells, respectively. In this study we have developed a bilayered scaffolding system, which includes a starch/polycaprolactone (SPCL) scaffold for osteogenesis and an agarose hydrogel for chondrogenesis. AFSC-seeded scaffolds were cultured for 1 or 2 weeks in an osteochondral-defined culture medium containing both osteogenic and chondrogenic differentiation factors. Additionally, the effect of the presence or absence of insulin-like growth factor 1 (IGF-1) in the culture medium was assessed. Cell viability and phenotypic expression were assessed within the constructs in order to determine the influence of the osteochondral differentiation medium. The results indicated that, after osteogenic differentiation, AFSCs that had been seeded onto SPCL scaffolds did not require osteochondral medium to maintain their phenotype, and they produced a protein-rich, mineralized extracellular matrix (ECM) for up to 2 weeks. However, AFSCs differentiated into chondrocyte-like cells appeared to require osteochondral medium, but not IGF-1, to synthesize ECM proteins and maintain the chondrogenic phenotype. Thus, although IGF-1 was not essential for creating osteochondral constructs with AFSCs in this study, the osteochondral supplements used appear to be important to generate cartilage in long-term tissue engineering approaches for osteochondral interfaces. In addition, constructs generated from agarose-SPCL bilayered scaffolds containing pre-differentiated AFSCs may be useful for potential applications in regeneration strategies for damaged or diseased joints. PMID- 22510403 TI - Acceleration of new bone formation by an electrically polarized hydroxyapatite microgranule/platelet-rich plasma composite. AB - We have developed a technology for the electrical polarization and electrical characterization of hydroxyapatite (HA) microgranules. In order to improve handling of ceramic powders to fulfill complex geometrical demands, platelet-rich plasma (PRP) containing many growth factors was chosen as a carrier of HA microgranules. In this study, the effects of this electrically polarized HA microgranule/PRP composite on new bone formation were examined. To compare osteoconductivity, HA microgranules with or without electrical polarization/PRP composite gel, HA microgranules alone with or without electrical polarization, or PRP gel were implanted into holes in the medial femoral condyles of rabbits. As a control, some of the bone holes were left empty (n=6 in each group). Histological examination was performed 3 and 6 weeks after the surgical operation. It was suggested that PRP alone could not induce new bone formation until 6 weeks after implantation. HA microgranules with or without electrical polarization/PRP composite, especially the former, activated osteogenic cells, resulting in enhanced bone formation. It was confirmed that electrical polarization treatment of HA microgranules can accelerate new bone formation, and that this effect is enhanced by forming a complex within the PRP. PMID- 22510404 TI - Interplay of cell adhesion matrix stiffness and cell type for non-viral gene delivery. AB - Non-viral gene delivery has the potential to treat a wide array of diseases but has been hindered by limited expression in vivo, possibly due to complex cellular microenvironments at delivery sites. Previous studies have reported that extracellular matrix properties, including stiffness, influence non-viral gene transfection efficiencies. This study reports that the effect of matrix stiffness on non-viral gene delivery differs among cell types due to varying sensitivities to matrix rigidity. Plasmid DNA encoding bone morphogenetic protein (BMP)-2 was delivered to fibroblasts, bone marrow stromal cells, and myoblasts cultured on fibronectin-conjugated poly(ethylene glycol) diacrylate hydrogels with varied elastic moduli, and the cellular uptake and subsequent expression of plasmid DNA were examined. While exogenous BMP-2 expression increased with increasing matrix stiffness for all three cell types, the effects of matrix stiffness were most pronounced for fibroblasts. Mechanistic studies conducted in parallel indicate that matrix stiffness influenced the projected area and nuclear aspect ratio for fibroblasts but had minimal effects on the morphology of bone marrow stromal cells and myoblasts. Overall, we believe that the results of this study will be useful for developing advanced non-viral gene delivery strategies for improved therapeutic efficacy. PMID- 22510406 TI - Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells. AB - The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs promote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Recent studies have identified that a portion of cancer cells, called "cancer stem cells", within the entire cancer tissue harbor highly tumorigenic and chemo resistant phenotypes, which lead to the recurrence after surgery or re-growth of the tumor. The mechanisms that maintain the "stemness" of these cells remain largely unknown. We hypothesized that PSCs might enhance the cancer stem cell like phenotypes in pancreatic cancer cells. Indirect co-culture of pancreatic cancer cells with PSCs enhanced the spheroid-forming ability of cancer cells and induced the expression of cancer stem cell-related genes ABCG2, Nestin and LIN28. In addition, co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. These results suggested a novel role of PSCs as a part of the cancer stem cell niche. PMID- 22510405 TI - Vap (Vascular Associated Protein): a novel factor involved in erythropoiesis and angiogenesis. AB - Both endothelial and erythroid cells are generated in the intermediate cell mass (ICM) during zebrafish embryogenesis, but the nature of the genes that contribute to the processes of erythrocyte maturation and blood vessel network formation is not fully understood. From our in situ-based screening, we have identified a novel factor, Vap (Vascular Associated Protein) that is predominantly expressed in the ICM, and subsequently enriched in endothelial cells. Vap expression in the ICM was drastically suppressed in the cloche mutant that has defects in both vasculogenesis and hematopoiesis, whereas Vap expression was not affected in the vlad tepes/gata1 mutant. Knockdown of Vap using anti-sense morpholinos (VAP-MO) not only resulted in decreased numbers of erythrocytes but also in the strong suppression of hemoglobin production. Further, we found that Vap knockdown caused the disorganization of the intersegmental vessels (ISVs), which show irregular branching. We propose that Vap plays an important role in the maturation of endothelial and erythroid cells in zebrafish. PMID- 22510407 TI - Hepatitis B virus X protein inhibits p53-mediated upregulation of mitofusin-2 in hepatocellular carcinoma cells. AB - The hepatitis B virus X (HBx) protein has many significant roles in hepatocellular carcinoma (HCC). Our previous research demonstrated that mitofusion-2 (Mfn2), a potential tumor suppressor gene in HCC, is a novel direct target of p53 that exerts apoptotic effects via the mitochondrial apoptotic pathway. However, the relationship between HBx and Mfn2 expression in the development of HCC is unknown. We found that HBx had little direct effect on the expression of Mfn2 or p53 in HCC cells not treated with doxorubicin. However, HBx inhibited the upregulation of Mfn2 in HBx-transfected HCC cells simultaneously treated with doxorubicin or cotransfected with p53 plasmid, as evidenced by Western Blot and real-time PCR. Through electrophoretic mobility shift analysis, we confirmed that HBx interfered with the binding event of the p53 protein and the p53 binding site-oligo of the Mfn2 promoter. Moreover, luciferase assays revealed that the activity of the Mfn2 promoter did not increase when transfected with HBx plasmid in doxorubicin-treated HepG2 cells. These results indicate that HBx impacts p53-mediated transcription of Mfn2, providing insight into the negative effect of HBx against p53-dependent chemotherapeutic agents, such as doxorubicin, used in the treatment of HCC. PMID- 22510408 TI - Ribosomal protein S3 interacts with TRADD to induce apoptosis through caspase dependent JNK activation. AB - It has been reported that ribosomal protein S3 (rpS3) functions as a ribosomal protein, a DNA repair endonuclease, a proapoptotic protein, and an essential subunit of the native NF-kappaB complex. However, it is unknown how rpS3 induces apoptosis in response to extracellular stresses. We report here that rpS3 sensitizes genotoxic stress-induced apoptosis by activating JNK through a caspase dependent manner. This apoptotic effect was shown to result from the physical interaction between rpS3 and TRADD, as assessed by coimmunoprecipitation. Moreover, GFP-rpS3 colocalized with TRADD around the plasma membrane and in the cytoplasm during apoptosis. Thus, rpS3 appears to be recruited to the death inducing signaling complex (DISC) to induce apoptosis by interacting TRADD in response to extracellular stresses. Based on the findings of this study, we concluded that rpS3 is recruited to the DISC and plays a critical role in both genotoxic stress and cytokine induced apoptosis. PMID- 22510409 TI - Molecular dissection of the interaction between HIC1 and SIRT1. AB - HIC1 (Hypermethylated in Cancer 1) is a tumor suppressor gene frequently epigenetically silenced in human cancers. HIC1 encodes a transcriptional repressor involved in the regulation of growth control, cell survival and DNA damage response. The deacetylase SIRT1 regulates the repressive capacity of HIC1 in several fashions. First SIRT1 interacts with the BTB/POZ domain of HIC1 to form a transcriptional repression complex that prevents the transcription of SIRT1 itself. SIRT1 is also responsible of the deacetylation of the lysine 314 of HIC1 that allows its subsequent SUMOylation which in turn favors its interaction with the NuRD complex. To better understand the interplay between HIC1 and SIRT1, we performed co-immunoprecipitation experiments to define the domains essential for the HIC1/SIRT1 interaction. We demonstrated that the isolated four last zinc fingers of HIC1 were capable to interact with SIRT1 and that the amino-acids 610 677 of SIRT1 encompassing the ESA region of the deacetylase were crucial for the HIC1/SIRT1 interaction and HIC1 deacetylation. Finally we demonstrated that this interaction mainly depends on CKII-mediated phosphorylation of SIRT1 serine 659/661 which occurs upon DNA damage. Therefore, our results demonstrate that the activating acetylation to SUMOylation switch of HIC1 is favored by genotoxic stresses to regulate the DNA damage response. PMID- 22510410 TI - Regulation of the bovine SCD5 promoter by EGR2 and SREBP1. AB - In rodents, the transcription factors early growth response 2 (EGR2) and sterol regulatory element binding protein 1a (SREBP1a) regulate transcription of the stearoyl-CoA desaturase 2 (SCD2) gene during peripheral nerve myelination, which may be important for synthesis of the lipid component of myelin. Most non-rodent genomes do not contain the SCD2 gene, but rather express SCD5 in brain and nervous tissues. In this paper, we asked whether bovine SCD5 is regulated in a similar manner to rodent SCD2. Expression of EGR2 did not result in an increase in endogenous SCD5 mRNA expression in JEG3 cells, but did result in activation of truncated bovine SCD5 promoter luciferase reporter constructs. Similar results were obtained with expression of the active form of SREBP1a; however, unlike rodent SCD2, there was no synergistic activation of the bovine SCD5 promoter reporters when EGR2 and SREBP1a were co-expressed. Mutation of the putative EGR2 binding site in the SCD5 promoter abolished activation by SREBP1a, suggesting that EGR2 and SREBP1a bind to the same site in the SCD5 promoter. Finally, we have identified a region of the bovine SCD5 promoter between 505 and 305 base pairs upstream of the transcriptional start site that appears to be important for maintaining basal levels of transcription of this gene. While it appears that there are some differences between the regulation of rodent SCD2 and bovine SCD5, the promoters of both genes can be activated by EGR2 and SREBP1a. This is the first report of potential regulators of SCD5 transcription. PMID- 22510411 TI - A defect in cell death of macrophages is a conserved feature of nonobese diabetic mouse. AB - Impaired apoptosis in immune effector cells such as macrophages has been implicated in the development of autoimmune disease by promoting the breakdown of self-tolerance and the sustained production of cytotoxic molecules. Macrophages from nonobese diabetic (NOD) mouse, an animal model of human autoimmune diabetes, exhibit several defects that are causally linked to the onset and progression of the disease. In this context, we investigated whether NOD macrophages have a defect in a cell death pathway, and if that is the case, the mechanism underlying such dysregulation of cell death. We found that NOD macrophages were resistant to treatment with a broad spectrum of cell death stimuli, triggering both apoptotic and non-apoptotic death. Through analysis of intracellular signaling pathways along with the expression of apoptosis-related proteins, we found that atypical resistance to cell death was associated with an elevated expression of anti apoptotic Bcl-X(L) but not the NF-kappaB signaling pathway in NOD macrophages. Further, ABT-737, which can inhibit Bcl-X(L) function, sensitized NOD macrophages to apoptosis induced by diverse apoptotic stimuli, thus restoring sensitivity to cell death. Taken together, our results suggest a macrophage-intrinsic defect in cell death as a potential mechanism that promotes an immune attack towards pancreatic beta-cells and the development of autoimmune diabetes in NOD mice. PMID- 22510412 TI - The tyrosine phosphatase HD-PTP (PTPN23) is degraded by calpains in a calcium dependent manner. AB - HD-PTP (PTPN23) is a non-transmembrane protein tyrosine phosphatase which contributes to the signal transduction pathways involved in the regulation of cell migration and invasion. We here demonstrate in T24 bladder carcinoma cells that HD-PTP undergoes calcium-dependent degradation which can be prevented by specific calpain inhibitors. In addition, treatment of the cells with the calpain inhibitor calpeptin results in the redistribution of endogenous HD-PTP to the periphery of the cells. Since (i) calpains are overexpressed in some tumors and (ii) the downregulation of HD-PTP enhances cell migration and invasion, we propose that HD-PTP degradation by calpains might result in the acquisition of a more aggressive phenotype in neoplastic cells. PMID- 22510413 TI - Confinement and deconfinement in the potential of antidot arrays of a massless Dirac electron in magnetic fields. AB - We have investigated the effect of inter-Landau level mixing on confinement/deconfinement in antidot potentials of states with energies less than the potential height of the antidot array. We find that, depending on the ratio between the size of the antidot R and the magnetic length [Formula: see text], probability densities display confinement or deconfinement in antidot potentials (B is the magnetic field). When R/l < 1 inter-Landau level mixing is strong and probability densities with energy less than the potential height are non-chiral and localized inside antidot potentials. However, in the strong magnetic field limit R/l ? 1, where inter-Landau level mixing is small, they are delocalized outside antidot potentials, and are chiral for N = 0 Landau level (LL) states while non-chiral for N = 1. In the non-trivial crossover regime R/l ~ 1 localized and delocalized probability densities coexist. States that are delocalized outside antidots when R/l > 1 form a nearly degenerate band and their probability densities are independent of k, in contrast to the case of R/l < 1. PMID- 22510414 TI - [Mortality following elective surgery for abdominal aorta aneurysm]. AB - OBJECTIVE: Assessment of postoperative mortality in patients undergoing elective surgery for asymptomatic abdominal aorta aneurysm (AAA) in the Academic Medical Center (AMC), Amsterdam, the Netherlands. This is compared with national statistical information and data in the literature. DESIGN: Retrospective cohort study. METHOD: Retrospective analysis of all patients who underwent an elective open or endovascular intervention in connection with asymptomatic aneurysm of the infrarenal abdominal aorta >= 5.5 cm in the period 2004-2010. RESULTS: In the study period 234 patients were electively operated for an abdominal aorta aneurysm (129 conventional and 104 endovascular interventions). In this period, 3 (1.3%) patients died in hospital or within 30 days of the intervention. Of the 73 patients >= 75 years of age, 2 (2.7%) died. None of the deceased patients were treated endovascularly. CONCLUSION: The figures presented for elective aneurysm surgery in the AMC are favourable in comparison with the published national mortality statistics of over 10% morality in patients >= 75 years of age. Because of the lack of randomized trials for treatment of aneurysms >= 5.5 cm there are many uncertainties concerning survival benefit obtained by operation. It is important for each clinic to arrange the care for elective aneurysm surgery in such a way that mortality is minimal. Important factors to achieve this are a well-attuned treatment team and careful patient selection. PMID- 22510415 TI - [Withdrawal in newborns after exposure to psychotropic medications during pregnancy]. AB - The use of psychotropic medications during pregnancy causes withdrawal symptoms in 20-30% of the newborns. The literature on withdrawal symptoms is not unanimous concerning their recognition and treatment. A search of PubMed and Embase revealed 198 articles in which potential withdrawal symptoms in newborns were described following exposure to psychotropic medications during pregnancy. Commonly occurring withdrawal symptoms are mostly mild, including restlessness and sleeping and feeding difficulties. Severe symptoms such as convulsions are rare. It can sometimes be difficult to differentiate between symptoms of intoxication and symptoms of withdrawal. The Finnegan scale is widely used to recognise withdrawal from psychotropic medication. An observation period of at least 48 h post-partum is advised. Recognition of withdrawal is important to prevent needless additional tests. In withdrawal symptoms supportive measures such as feeding on demand and swaddling are usually sufficient. If withdrawal symptoms are severe, phenobarbital is a therapeutic option. PMID- 22510416 TI - [Dutch language area definition of chronic fatigue]. AB - Chronic fatigue is a frequent but unspecific characteristic of many diseases. However, a clear definition of 'chronic fatigue' is still lacking. The Flemish Dutch Research Group - Chronic Fatigue (VNO-CHROVER) has taken the opportunity to formulate such a definition that can be widely applied. This definition is not only beneficial to researchers conducting, reporting and comparing scientific studies on chronic fatigue in diverse patient populations, but also to clinicians of various disciplines in order to improve patient care. VNO-CHROVER proposes to define chronic fatigue as 'a self-reported reduction of physical and/or mental well-being that persists longer than 6 months and is manifested as exhaustion by which one fails to function at the desired level.' PMID- 22510417 TI - [Snellen and his optotypes]. AB - Herman Snellen (1834-1908) studied medicine in Utrecht and wrote a thesis under the guidance of Franciscus Donders (1818-1889). In 1858 he became assistant and a few years later first physician at Donders' newly-founded eye hospital. In 1862 he published his optotypes, letters of different sizes, constructed in squares with 5 x 5 subdivisions. For each row of letters of a given size there is an indication of the distance D at which a normal eye can just distinguish these (corresponding with 5 minutes of arc). If the eye of the subject being examined can just make out letters of a given size at distance d, the visual acuity V for that eye is d/D. Snellen was a gifted surgeon for a variety of ophthalmologic disorders. In 1877 he was appointed Professor of Ophthalmology at Utrecht and in 1884 he succeeded Donders as director of the eye hospital. PMID- 22510418 TI - [Autoimmune limbic encephalitis: importance of early diagnosis and treatment]. AB - BACKGROUND: Autoimmune limbic encephalitis is a rare disorder, characterised by the subacute onset of seizures, short-term memory loss, and psychiatric and behavioural symptoms. Initially, it was recognised as a paraneoplastic disorder, but recently a subgroup of patients without systemic cancer was identified. This type of limbic encephalitis is associated with voltage-gated potassium channel (VGKC) or N-methyl-D-aspartate receptor (NMDAR) antibodies. CASE DESCRIPTION: We describe a 69-year-old man with anti-VGKC limbic encephalitis suffering from generalised tonic-clonic seizures, severe insomnia, increasing memory deficits, visual hallucinations and depression. We also describe a 22-year-old woman, suffering from complex partial seizures and dysphasia, and displaying inappropriate behaviour. She was diagnosed with anti-NMDAR limbic encephalitis. Both showed marked improvement after starting prednisone and intravenous immunoglobulin therapy. CONCLUSION: These case descriptions emphasise the importance of timely recognition of autoimmune limbic encephalitis in order to rule out malignancy and to quickly initiate treatment. This potentially life threatening disease responds well to immunomodulatory therapy. PMID- 22510419 TI - [Actinomycosis resembling an ovarian malignancy]. AB - BACKGROUND: Actinomyces is an uncommon cause of infection which can occur in the lower pelvic area in women using an intrauterine device (IUD). The clinical presentation of actinomycosis can easily be confounded with a malignancy. CASE DESCRIPTION: In a 53-year-old woman with abdominal pain and fluctuating temperature, ovarian carcinoma was strongly suspected. She underwent a laparotomy in which both adnexae were removed. Histopathological examination of the specimens revealed, however, a rare Actinomyces infection. The patient received long-term antibiotic therapy in the postoperative period, upon which her condition improved. CONCLUSION: Differentiation between actinomycosis (mycetoma) and a malignancy is difficult. There are few diagnostic tools to demonstrate an Actinomyces infection, and the diagnosis is therefore often not made until during or after operation. The treatment of actinomycosis consists of long-term administration of antibiotics, although combined surgery and antibiotic therapy is often necessary due to the extent of the infection. PMID- 22510420 TI - [No end to selective publication yet]. AB - Selective publication of complete studies or outcomes within studies hampers unbiased medical decision making. If the available body of evidence does not offer a fair representation of all existing evidence, the true effect of an intervention cannot be judged, possible harmful effects cannot be identified and unnecessary costs for healthcare may be invoked. Prospective registration of studies at their inception and public disclosure of all study results via result databases should be enforced on a worldwide scale in accordance with the fundamental and ethical obligations of the investigators towards study participants who were subjected to potential harm in the belief that they contributed to medical progress. These regulations will ensure a solid basis for fully evidence-based decision making in health care. PMID- 22510421 TI - Can we treat fluid overload with fluid? Role of peritoneal dialysis in management of heart failure. PMID- 22510422 TI - Double jeopardy: the influence of excessive daytime sleepiness and impaired cognition on health-related quality of life in adults with heart failure. AB - AIMS: To determine how excessive daytime sleepiness (EDS) and impaired cognition contribute to health-related quality of life (HRQL) in heart failure (HF). METHODS AND RESULTS: Adults with chronic HF were enrolled into a prospective cohort study. Data were obtained from 280 subjects enrolled from three sites in the northeastern USA; 242 completed the 6-month study. At baseline, cohorts with and without EDS were identified using the Epworth Sleepiness Scale. Each EDS group was further subdivided into those with and without impaired cognition using a battery of five neuropsychological tests. Two disease-specific measures, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Functional Outcomes of Sleep Questionnaire (FOSQ), were used to measure HRQL. General linear modelling of square-transformed variables was used to test the hypothesis that cohort membership was a significant predictor of HRQL. At 6 months the remaining sample was 62.5 [standard deviation (SD) 12] years old, mostly male (63%), white (65%), and functionally compromised [72% New York Heart Association (NYHA) class III/IV]. The cohort with both EDS and impaired cognition had the lowest KCCQ overall summary score (60.5 +/- 22.5) compared with the cohort without EDS or impaired cognition (74.6 +/- 17.4, P <= 0.001). A similar effect was seen on the FOSQ (16.0 +/- 2.8 vs. 18.5 +/- 2.2, P < 0.001). CONCLUSION: Impaired cognition alone did not explain poor HRQL, but the addition of EDS poses a significant risk for poor HRQL. Interventions designed to influence EDS may improve HRQL in this population. PMID- 22510423 TI - Meta-analysis of randomized controlled trials evaluating left ventricular vs. biventricular pacing in heart failure: effect on all-cause mortality and hospitalizations. AB - AIM: Randomized controlled trials (RCTs) showed that biventricular (BiV) pacing reduces heart failure (HF) hospitalizations and mortality in patients with New York Heart Association (NYHA) class III-IV HF, left ventricular (LV) dysfunction, and wide QRS. We performed a systematic review and meta-analysis of the RCTs comparing LV-only vs. biventricular (BiV) pacing in candidates for cardiac resynchronization therapy (CRT). METHODS AND RESULTS: The systematic review selected five RCTs (out of 1888 analysed reports) with a cumulative number of 372 patients randomized to BiV pacing and 258 to LV-only pacing. The meta-analysis shows that BiV pacing is not superior to LV-only pacing and that these two pacing modalities do not differ with regard to death or heart transplantation [LV-only vs. BiV pacing odds ratio (OR) 1.24, 95% confidence interval (CI) 0.57-2.70 with the fixed effect model, OR 1.25, 95% CI 0.48-3.24 with the random effect model]. Specific data on hospitalizations were available only in two RCTs with a cumulative number of 127 patients randomized to BiV and 123 to LV-only pacing. The meta-analysis shows that BiV pacing is not superior to LV-only pacing and that these two pacing modalities do not differ with regard to this outcome (LV only vs. BiV pacing OR 0.86, 95% CI 0.49-1.50 with the fixed effect model, OR 0.86, 95% CI 0.49-1.50 with the random effect model). CONCLUSIONS: Biventricular pacing is not superior to LV-only pacing, and these two pacing modalities appear to achieve similar efficacy in candidates for CRT for moderate to severe HF, in terms of all-cause mortality and hospitalizations during follow-up. PMID- 22510424 TI - The efficacy and safety of lixivaptan in outpatients with heart failure and volume overload: results of a multicentre, randomized, double-blind, placebo controlled, parallel-group study. AB - AIMS: Volume overload is the dominant feature of decompensated heart failure (HF) and it often results in adverse clinical outcomes. Vasopressin receptor antagonists such as lixivaptan may provide effective volume unloading. This study assessed weight loss after 1 day and 8 weeks of treatment with lixivaptan in outpatients with HF and volume overload. METHODS AND RESULTS: This phase II, 8 week, multicentre, double-blind, parallel-group study randomized participants (2:1) to receive lixivaptan 100 mg or placebo once daily (in addition to standard HF therapy). Body weight and cardiovascular assessments were made at baseline, Day 1 (not cardiovascular), Weeks 1, 2, 4, and 8, and 7 days post-treatment. The Trail-making Test, part B (TMT-B) and the Medical Outcomes Survey 6-item cognitive function scale (MOS-6) were assessed at baseline and Week 4. The study randomized 170 participants (lixivaptan, n = 111; placebo, n = 59). Most (97.1%) were receiving pharmacological therapy for HF at baseline. Demographic characteristics were generally similar between the two groups. Body weight decreased significantly from baseline to Day 1 with lixivaptan vs. placebo (least square mean change +/- standard error: - 0.38 +/- 0.08 kg vs. +0.13 +/- 0.11 kg; P < 0.001) and at Weeks 1, 2, and 4 (P < 0.01). Cardiovascular changes were generally similar in both groups, though orthopnoea and dyspnoea improved in the lixivaptan group vs. placebo. The TMT-B and MOS-6 showed no significant differences between groups. Lixivaptan was well tolerated-thirst and polyuria occurred more frequently vs. placebo. CONCLUSIONS: In outpatients with HF and volume overload, lixivaptan 100 mg once daily, when added to standard therapy, reduced body weight, improved dyspnoea and orthopnoea, and was well tolerated. TRIAL REGISTRATION: NCT01055912. PMID- 22510425 TI - Circulating and synovial antibody profiling of juvenile arthritis patients by nucleic acid programmable protein arrays. AB - INTRODUCTION: Juvenile idiopathic arthritis (JIA) is a heterogeneous disease characterized by chronic joint inflammation of unknown cause in children. JIA is an autoimmune disease and small numbers of autoantibodies have been reported in JIA patients. The identification of antibody markers could improve the existing clinical management of patients. METHODS: A pilot study was performed on the application of a high-throughput platform, the nucleic acid programmable protein array (NAPPA), to assess the levels of antibodies present in the systemic circulation and synovial joint of a small cohort of juvenile arthritis patients. Plasma and synovial fluid from 10 JIA patients was screened for antibodies against 768 proteins on NAPPAs. RESULTS: Quantitative reproducibility of NAPPAs was demonstrated with > 0.95 intra-array and inter-array correlations. A strong correlation was also observed for the levels of antibodies between plasma and synovial fluid across the study cohort (r = 0.96). Differences in the levels of 18 antibodies were revealed between sample types across all patients. Patients were segregated into two clinical subtypes with distinct antibody signatures by unsupervised hierarchical cluster analysis. CONCLUSION: The NAPPAs provide a high throughput quantitatively reproducible platform to screen for disease-specific autoantibodies at the proteome level on a microscope slide. The strong correlation between the circulating antibody levels and those of the inflamed joint represents a novel finding and provides confidence to use plasma for discovery of autoantibodies in JIA, thus circumventing the challenges associated with joint aspiration. We expect that autoantibody profiling of JIA patients on NAPPAs could yield antibody markers that can act as criteria to stratify patients, predict outcomes and understand disease etiology at the molecular level. PMID- 22510427 TI - Baculovirus expression and antigenic characterization of classical swine fever virus E2 proteins. AB - Genes encoding a major structural glycoprotein, E2, of classical swine fever viruses (CSFV) Brescia (subgroup 1.2), Paderborn (subgroup 2.1) and Kanagawa (subgroup 3.4) were constructed by removing the transmembrane domain and adding a C-terminal 6 histidine (His) tag. All the E2 constructs were efficiently expressed in a baculovirus system as 53-kDa glycosylated proteins that were identified in Western blots by their reaction with anti-His and CSFV-specific antibodies. These proteins were used as ELISA antigens to confirm the existence of an antigenic relationship between the viruses using group-specific polyclonal antisera. Antigenic differences were identified by Western blot and ELISA reactivity of the E2 proteins with a panel of monoclonal antibodies. Specifically, one monoclonal antibody (WH303) reacted with all three proteins, two monoclonal antibodies (M1660 and M1665) reacted with only the Brescia E2 protein, and three monoclonal antibodies (M1654, M1664 and M1669) reacted equally well with only Brescia and Kanagawa E2 proteins. Therefore, antibody reactivity profiles, established using recombinant E2 proteins, could be used to quickly identify novel CSFV strains as illustrated in this report with only a limited number of monoclonal antibodies. These proteins could also have added utility in the production of monoclonal antibodies and as critical reagents in diagnostic assays. PMID- 22510428 TI - Adult-onset Still's disease: still a diagnosis of exclusion. A nested case control study in patients with fever of unknown origin. AB - OBJECTIVES: Several sets of criteria have been proposed to classify adult-onset Still's disease (AOSD), those of Yamaguchi being the most commonly used. The Yamaguchi criteria demand the exclusion of other conditions. A clinical scale, recently proposed by Crispin et al., but not yet validated, would allow a positive diagnosis of AOSD in a majority of patients, without the need of thorough diagnostic procedures. METHODS: From a database of 447 patients with classical fever of unknown origin (FUO), collected over a 10-year period (2000 2009) at a general internal medicine department of a university hospital, 22 patients with AOSD according to the Yamaguchi criteria were extracted and compared with 44 controls, matched to index year. Clinical and laboratory parameters were recorded. Sensitivity, specificity and accuracy of the Yamaguchi criteria and of the clinical score were assessed. RESULTS: Lower age, joint symptoms, rash, throat ache, neutrophilic leukocytosis, and elevated erythrocyte sedimentation rate were the principal characteristics supporting a diagnosis of AOSD in patients with FUO. Sensitivity, specificity, and accuracy of the Yamaguchi criteria were 95% or more. The clinical scale, while being specific (98%), lacked sensitivity (55%) and had lower accuracy (83%). CONCLUSIONS: In patients with FUO, the Yamaguchi criteria are a time honored and reliable guide to a diagnosis of AOSD. The clinical scale may serve to rule in, rather than to rule out, AOSD. In many patients, Still's disease is still a diagnosis of exclusion. PMID- 22510426 TI - Preventing mood and anxiety disorders in youth: a multi-centre RCT in the high risk offspring of depressed and anxious patients. AB - BACKGROUND: Anxiety and mood disorders are highly prevalent and pose a huge burden on patients. Their offspring is at increased risk of developing these disorders as well, indicating a clear need for prevention of psychopathology in this group. Given high comorbidity and non-specificity of intergenerational transmission of disorders, prevention programs should target both anxiety and depression. Further, while the indication for preventive interventions is often elevated symptoms, offspring with other high risk profiles may also benefit from resilience-based prevention programs. METHOD/DESIGN: The current STERK-study (Screening and Training: Enhancing Resilience in Kids) is a randomized controlled clinical trial combining selected and indicated prevention: it is targeted at both high risk individuals without symptoms and at those with subsyndromal symptoms. Individuals without symptoms meet two of three criteria of the High Risk Index (HRI; female gender, both parents affected, history of a parental suicide (attempt). This index was developed in an earlier study and corresponds with elevated risk in offspring of depressed patients. Children aged 8-17 years (n = 204) with subthreshold symptoms or meeting the criteria on the HRI are randomised to one of two treatment conditions, namely (a) 10 weekly individual child CBT sessions and 2 parent sessions or (b) minimal information. Assessments are held at pre-test, post-test and at 12 and 24 months follow-up. Primary outcome is the time to onset of a mood or anxiety disorder in the offspring. Secondary outcome measures include number of days with depression or anxiety, child and parent symptom levels, quality of life, and cost-effectiveness. Based on models of aetiology of mood and anxiety disorders as well as mechanisms of change during interventions, we selected potential mediators and moderators of treatment outcome, namely coping, parent-child interaction, self-associations, optimism/pessimism, temperament, and emotion processing. DISCUSSION: The current intervention trial aims to significantly reduce the risk of intergenerational transmission of mood and anxiety disorders with a short and well targeted intervention that is directed at strengthening the resilience in potentially vulnerable children. We plan to evaluate the effectiveness and cost-effectiveness of such an intervention and to identify mechanisms of change. TRIAL REGISTRATION: NTR2888. PMID- 22510429 TI - Caloric restriction may reverse age-related autonomic decline in humans. AB - Caloric restriction (CR) retards aging in laboratory rodents. No information is available on the effects of long-term CR on physiologic markers of aging and longevity in humans. Heart rate variability (HRV) is a marker for cardiac autonomic functioning. The progressive decline in HRV with aging and the association of higher HRV with better health outcomes are well established. Heart rate variability assessment is a reliable tool by which the effects of CR on autonomic function can be assessed. Time- and frequency-domain analyses compared 24-h HRV in 22 CR individuals aged 35-82 years and 20 age-matched controls eating Western diets (WD). The CR group was significantly leaner than the WD group. Heart rate was significantly lower, and virtually, all HRV values were significantly higher in the CR group than in the WD group (P < 0.002). Heart rate variability in the CR individuals was comparable with published norms for healthy individuals 20 years younger. In addition, when differences in heart rate (HR) and HRV between CR and WD were compared with previously published changes in HRV induced in healthy adults given atenolol, percent differences in each measure were generally similar in direction and magnitude and suggested declines in sympathetic and increases in parasympathetic modulation of HR and increased circadian variability associated with CR. These findings provide evidence that CR has direct systemic effects that counter the expected age-associated changes in autonomic function so that HRV indexes in CR individuals are similar to those of individuals 20 years younger eating WDs. PMID- 22510430 TI - Long-term stability of biochemical markers in pediatric serum specimens stored at -80 degrees C: a CALIPER Substudy. AB - OBJECTIVES: Pediatric serum samples collected from healthy children in the CALIPER (Canadian Laboratory Initiative in Pediatric Reference Interval) project are stored at -80 degrees C for various periods of time. This study aimed to determine the stability of chemistry, protein, and hormone analytes under these conditions. DESIGN AND METHODS: Serum samples collected from children of 0-18 years of age attending outpatient clinics were pooled into a single pool or into age-group specific pools. Following baseline measurement, each pool was aliquoted and kept frozen at -80 degrees C until analysis. Samples were analyzed for 57 biochemical markers at monthly intervals over a 10-13 month period and each aliquot was subject to one freeze-thaw cycle before analysis. The analysis was performed on VITROS Chemistry System, COBAS INTEGRA 400 Plus and IMMULITE 2500. Values obtained at monthly intervals were compared to baseline measurements and examined for trends over time. RESULTS: A majority of analytes measured in this study showed no significant time-dependent change relative to baseline or trend over time after up to 13 months of storage. PTH showed up to 27.2% decline after 10 months of storage with most of the decline evident after 2 months. Most analytes showed variability over time, which is thought to reflect assay variability rather than changes in analyte stability. CONCLUSIONS: The study shows stability for a majority of analytes stored in serum at -80 degrees C after up to 13 months of storage. Samples do not require immediate testing for reference interval determination for the selected analytes with possible exception of PTH. PMID- 22510431 TI - Chronic inflammatory diseases are stimulated by current lifestyle: how diet, stress levels and medication prevent our body from recovering. AB - Serhan and colleagues introduced the term "Resoleomics" in 1996 as the process of inflammation resolution. The major discovery of Serhan's work is that onset to conclusion of an inflammation is a controlled process of the immune system (IS) and not simply the consequence of an extinguished or "exhausted" immune reaction. Resoleomics can be considered as the evolutionary mechanism of restoring homeostatic balances after injury, inflammation and infection. Under normal circumstances, Resoleomics should be able to conclude inflammatory responses. Considering the modern pandemic increase of chronic medical and psychiatric illnesses involving chronic inflammation, it has become apparent that Resoleomics is not fulfilling its potential resolving capacity. We suggest that recent drastic changes in lifestyle, including diet and psycho-emotional stress, are responsible for inflammation and for disturbances in Resoleomics. In addition, current interventions, like chronic use of anti-inflammatory medication, suppress Resoleomics. These new lifestyle factors, including the use of medication, should be considered health hazards, as they are capable of long-term or chronic activation of the central stress axes. The IS is designed to produce solutions for fast, intensive hazards, not to cope with long-term, chronic stimulation. The never-ending stress factors of recent lifestyle changes have pushed the IS and the central stress system into a constant state of activity, leading to chronically unresolved inflammation and increased vulnerability for chronic disease. Our hypothesis is that modern diet, increased psycho-emotional stress and chronic use of anti-inflammatory medication disrupt the natural process of inflammation resolution ie Resoleomics. PMID- 22510434 TI - Enhancing the biological performance of synthetic polymeric materials by decoration with engineered, decellularized extracellular matrix. AB - Materials based on synthetic polymers can be extensively tailored in their physical properties but often suffer from limited biological functionality. Here we tested the hypothesis that the biological performance of 3D synthetic polymer based scaffolds can be enhanced by extracellular matrix (ECM) deposited by cells in vitro and subsequently decellularized. The hypothesis was tested in the context of bone graft substitutes, using polyesterurethane (PEU) foams and mineralized ECM laid by human mesenchymal stromal cells (hMSC). A perfusion-based bioreactor system was critically employed to uniformly seed and culture hMSC in the scaffolds and to efficiently decellularize (94% DNA reduction) the resulting ECM while preserving its main organic and inorganic components. As compared to plain PEU, the decellularized ECM-polymer hybrids supported the osteoblastic differentiation of newly seeded hMSC by up-regulating the mRNA expression of typical osteoblastic genes (6-fold higher bone sialoprotein; 4-fold higher osteocalcin and osteopontin) and increasing calcium deposition (6-fold higher), approaching the performance of ceramic-based materials. After ectopic implantation in nude mice, the decellularized hybrids induced the formation of a mineralized matrix positively immunostained for bone sialoprotein and resembling an immature osteoid tissue. Our findings consolidate the perspective of bioreactor-based production of ECM-decorated polymeric scaffolds as off-the-shelf materials combining tunable physical properties with the physiological presentation of instructive biological signals. PMID- 22510432 TI - Mirror neuron function, psychosis, and empathy in schizophrenia. AB - Processing of social and emotional information has been shown to be disturbed in schizophrenia. The biological underpinnings of these abnormalities may be explained by an abnormally functioning mirror neuron system. Yet the relationship between mirror neuron system activity in schizophrenia, as measured using an electroencephalography (EEG) paradigm, and socio-emotional functioning has not been assessed. The present research measured empathy and mirror neuron activity using an established EEG paradigm assessing the integrity of the Mu rhythm (8 13Hz) suppression over the sensorimotor cortex during observed and actual hand movement in 16 schizophrenia-spectrum disorder (SSD) participants (n=8 actively psychotic and n=8 in residual illness phase) and 16 age- and gender-matched healthy comparison participants. Actively psychotic SSD participants showed significantly greater mu suppression over the sensorimotor cortex of the left hemisphere than residual phase SSD and healthy comparison individuals. The latter two groups showed similar levels of mu suppression. Greater left-sided mu suppression was positively correlated with psychotic symptoms (i.e., greater mu suppression/mirror neuron activity was highest among subjects with the greater severity of psychotic symptoms). SSD subjects tended to have significantly higher levels of Personal Distress (as measured by the Interpersonal Reactivity Index) than healthy participants. The present study suggests that abnormal mirror neuron activity may exist among patients with schizophrenia during the active (psychotic) phase of the illness, and correlates with severity of psychosis. PMID- 22510435 TI - SPOC alert--when chromosomes get the wrong direction. AB - The asymmetrically dividing budding yeast relies upon the alignment of the mitotic spindle along the mother to daughter cell polarity axis for the fidelity of chromosome segregation during mitosis. In the case of spindle misalignment, a surveillance mechanism named the spindle position checkpoint (SPOC) prevents cells from exiting mitosis through the inhibition of the mitotic exit network (MEN). MEN is a signal transduction pathway that mediates mitotic exit through fully activation of the Cdk-counteracting phosphatase Cdc14. In this mini-review, we briefly describe the mechanisms leading to mitotic exit in budding yeast cells focusing on the control of MEN by the SPOC. In addition, we summarize the recent advances in the molecular understanding of SPOC regulation and discuss whether similar checkpoints may exist in higher eukaryotic cells that undergo asymmetric divisions. PMID- 22510433 TI - An fMRI study of attentional control in the context of emotional distracters in euthymic adults with bipolar disorder. AB - Inability to modulate attention away from emotional stimuli may be a key component of dysregulated emotion in bipolar disorder (BD). Previous studies of BD indicate abnormalities in neural circuitry underlying attentional control, yet few studies examined attentional control in the context of emotional distracters. We compared activity and connectivity in neural circuitry supporting attentional control and emotion processing among 22 individuals with BD type 1, currently remitted and euthymic, and 19 healthy controls. Participants performed an emotional n-back paradigm, comprising high and low attentional demand conditions, each with either emotional (happy, fearful), neutral or no face flanker distracters. During the high attentional control demand conditions without emotional distracters, BD individuals showed reduced activity relative to controls in dorsolateral prefrontal cortex, dorsal anterior cingulate cortex (dACC), and inferior parietal cortex. During the high attentional control demand conditions with fearful-face distracters, BD individuals showed greater activity than controls in these regions and amygdala and striatum. Relative to controls, BD individuals also showed abnormal patterns of effective connectivity between dACC and amygdala during high attentional control demand with emotional face distracters. Inter-episode bipolar disorder is characterized by abnormal recruitment of attentional control neural circuitry, especially in the context of emotionally distracting information. PMID- 22510436 TI - Suppression of rat Frizzled-2 attenuates hypoxia/reoxygenation-induced Ca2+ accumulation in rat H9c2 cells. AB - Growing evidence suggests that Ca(2+) overload is one of the major contributors of myocardial ischemia/reperfusion-induced injury. Since Frizzled-2 receptor, a seven transmembrane protein, transduces downstream signaling by specialized binding of Wnt5a to increase intracellular Ca(2+) release, this work aimed to investigate the effect of Frizzled-2 on Ca(2+) accumulation in H9c2 cells, which were subjected to hypoxia/reoxygenation to mimic myocardial ischemia/reperfusion. After exposing H9c2 cells to hypoxia/reoxygenation, we observed higher expression of Frizzled-2 and Wnt5a as compared to control group cells. Hypoxia/reoxygenation induced intracellular Ca(2+) accumulation approached that of cells transfected with frizzled-2 plasmid. In cells treated with RNAi specifically designed against frizzled-2, intracellular Ca(2+) in both hypoxia/reoxygenation-treated cells and plasmid-treated cells were decreased. Rats that underwent ischemia/reperfusion injury exhibited increased intracellular Ca(2+) with high expression levels of Frizzled-2 and Wnt5a as compared to the sham group. Our data indicates that upon binding to Wnt5a, increased Frizzled-2 expression after hypoxia/reoxygenation treatment activated intracellular calcium release in H9c2 cells. Our findings provide a new perspective in understanding calcium overload in myocardial ischemia/reperfusion. PMID- 22510437 TI - Direct conversion of tenocytes into chondrocytes by Sox9. AB - Sox9 is a high-mobility group box-containing transcription factor that functions as a key regulator of chondrogenesis. We here report that Sox9 mediates the direct conversion of tenocytes to chondrocytes through an intermediate state in which both differentiation programs are active. Sox9 is abundantly expressed in cartilage but is undetectable in limb tendons that express Scleraxis (Scx) and Tenomodulin (Tnmd), tendon-specific early and late molecular markers, respectively. Upon forced expression of Sox9 in the chick forelimb, ectopic cartilage formation is preferentially observed in fibrous tissues including the tendons, ligaments, perichondrium/periosteum, dermis, and muscle connective tissues. Tnmd expression in tenocytes isolated from leg tendons was markedly upregulated by forced expression of basic helix-loop-helix (b-HLH) activators including Scx, Paraxis, Twist1 and Twist2. In contrast, the overexpression of Sox9 in monolayer tenocytes resulted in the downregulation of Tnmd and Scx expressions during passaging in culture, and the induction of cartilage molecular markers such as type II collagen (Col2a1) and Chondromodulin-I (ChM-I). This Sox9 driven switching from a tenocytic to a chondrocytic gene expression profile was associated with a dramatic change from a spindle to a polygonal cellular morphology. The extracellular accumulation of cartilage-characteristic proteoglycans was also observed. These data suggest that tenocytes have a strong potential for conversion into chondrocytes through the activities of Sox9 both in vitro and in vivo. PMID- 22510439 TI - Electronic structure and elasticity of Z-phases in the Cr-Nb-V-N system. AB - Structural properties and energetics of Cr-based Z-phases (CrNbN, Cr(Nb,V)N and CrVN) were investigated using the Vienna ab initio simulation package (VASP) code employing the projector augmented wave (PAW) pseudopotentials by means of both local density approximation (LDA) and generalized gradient approximation (GGA) for the exchange and correlation term. The geometry of all studied phases including NbN, VN and elemental constituents (nonmagnetic bcc Nb and V and antiferromagnetic bcc Cr) was fully relaxed, providing the equilibrium structure parameters and total energies. The calculated lattice parameters of Z-phases correspond very well to the experimental data and decrease with increasing molar fraction of vanadium. Enthalpies of formation show that all three Z-phases are stable at T = 0 K. The electronic structures of Z-phases including densities of states and charge densities were analysed. The calculated bulk moduli and elastic constants were used to evaluate stability conditions and elastic anisotropy ratios. It was confirmed that Z-phases are mechanically stable. Additional information on ductility was obtained from Cauchy pressures, Pugh ratios, Young moduli, and Poisson ratios. The ductility evaluated using the Pugh ratio decreases with number of vanadium atoms. PMID- 22510438 TI - The health outcomes and physical activity in preschoolers (HOPP) study: rationale and design. AB - BACKGROUND: The early years are the period of growth for which we know the least about the impact of physical activity. In contrast, we know that more than 90 % of school-aged Canadian children, for example, are not meeting physical activity recommendations. Such an activity crisis is a major contributor to recent trends in childhood obesity, to which preschoolers are not immune. The World Health Organization estimated that more than 42 million children under the age of 5 years were overweight world-wide in 2010. If an activity crisis exists during the preschool years, we should also be concerned about its broader impact on health. Unfortunately, the relationship between physical activity and health during the early years is poorly understood. The goal of the Health Outcomes and Physical activity in Preschoolers (HOPP) study is to describe how the prevalence and patterns of physical activity in preschoolers are associated with indices of health. METHODS: The HOPP study is a prospective cohort study. We aim to recruit 400 3- to 5-year-old children (equal number of boys and girls) and test them once per year for 3 years. Each annual assessment involves 2 laboratory visits and 7 consecutive days of physical activity monitoring with protocols developed in our pilot work. At visit 1, we assess body composition, aerobic fitness, short-term muscle power, motor skills, and have the parents complete a series of questionnaires related to their child's physical activity, health-related quality of life and general behaviour. Over 7 consecutive days each child wears an accelerometer on his/her waist to objectively monitor physical activity. The accelerometer is programmed to record movement every 3 s, which is needed to accurately capture the intensity of physical activity. At visit 2, we assess vascular structure and function using ultrasound. To assess the associations between physical activity and health outcomes, our primary analysis will involve mixed-effects models for longitudinal analyses. DISCUSSION: The HOPP study addresses a significant gap in health research and our findings will hold the potential to shape public health policy for active living during the early years. PMID- 22510440 TI - Does the addition of a fundoplication improve outcomes for patients undergoing laparoscopic Heller's cardiomyotomy? AB - Laparoscopic Heller's cardiomyotomy is a well-established technique in the treatment of achalasia. However, the addition of a routine fundoplication as part of this procedure remains controversial. A best evidence topic in upper gastrointestinal surgery was written according to a structured protocol. The question addressed whether the addition of a fundoplication improved clinical outcomes. Two hundred and seven papers were found using the reported search and of these, 8 papers were identified using a pre-determined criteria as representing the best answer to this clinical question. There were 2 meta analyses, 3 randomised controlled trials and 3 prospective series. The author, journal, date and country of publication, patient group, study type, relevant outcomes, results, and study weaknesses of these papers are tabulated. Review of the data shows that the rates of gastro-oesophageal reflux both on pH monitoring and symptom reporting are all reduced when an anti-reflux procedure is added to a Heller's cardiomyotomy. In terms of the choice of the anti-reflux procedure, comparison between the Dor anterior and Toupet posterior fundoplications do not show any obvious clinical differences, however dysphagia appears to be lower in those undergoing partial fundoplication as compared to a Nissen fundoplication. PMID- 22510441 TI - Advanced endoscopic imaging in Barrett's oesophagus. AB - Barrett's oesophagus is a metaplastic condition with an inherent risk of progression to adenocarcinoma. It is essential to identify dysplastic changes within Barrett's oesophagus in order to individualise surveillance strategies and establish which patients warrant endoscopic treatment. There is a trend towards endoscopic resection of focal high-grade dysplasia followed by whole segment ablation. However, endoscopic identification of dysplastic lesions is unreliable and subjective making targeted therapy extremely difficult. In addition, the current practice of taking random quadrantic biopsies may miss dysplastic disease and intramucosal adenocarcinoma. Several advanced endoscopic imaging techniques have been described and tested in clinical trials in an effort to improve the detection of early lesions, although none are routinely used in clinical practice. In this article we will review these techniques and discuss their potential for clinical implementation. We will also discuss the potential benefits of multimodal imaging and highlight several newer techniques which have shown early promise for in vivo diagnosis. PMID- 22510442 TI - Interventional studies for preventing surgical site infections in sub-Saharan Africa - A systematic review. AB - BACKGROUND: There is a great need for safe surgical services in sub-Saharan Africa, but a major difficulty of performing surgery in this region is the high risk of post-operative surgical site infection (SSI). METHODS: We aimed to systematically review which interventions had been tested in sub-Saharan Africa to reduce the risk of SSI and to synthesize their findings. We searched Medline, Embase and Global Health databases for studies published between 1995 and 2010 without language restrictions and extracted data from full-text articles. FINDINGS: We identified 24 relevant articles originating from nine countries in sub-Saharan Africa. The methodological quality of these publications was diverse, with inconsistency in definitions used for SSI, period and method of post operative follow-up and classification of wound contamination. Although it was difficult to synthesise information between studies, there was consistent evidence that use of single-dose pre-operative antibiotic prophylaxis could reduce, sometimes dramatically, the risk of SSI. Several studies indicated that alcohol-based handrubs could provide a low-cost alternative to traditional surgical hand-washing methods. Other studies investigated the use of drains and variants of surgical technique. There were no African studies found relating to several other promising SSI prevention strategies, including use of checklists and SSI surveillance. CONCLUSIONS: There is extremely limited research from sub Saharan Africa on interventions to curb the occurrence of SSI. Although some of the existing studies are weak, several high-quality studies have been published in recent years. Standard methodological approaches to this subject are needed. PMID- 22510443 TI - Kinematic and dynamic gait compensations resulting from knee instability in a rat model of osteoarthritis. AB - INTRODUCTION: Osteoarthritis (OA) results in pain and disability; however, preclinical OA models often focus on joint-level changes. Gait analysis is one method used to evaluate both preclinical OA models and OA patients. The objective of this study is to describe spatiotemporal and ground reaction force changes in a rat medial meniscus transection (MMT) model of knee OA and to compare these gait measures with assays of weight bearing and tactile allodynia. METHODS: Sixteen rats were used in the study. The medial collateral ligament (MCL) was transected in twelve Lewis rats (male, 200 to 250 g); in six rats, the medial meniscus was transected, and the remaining six rats served as sham controls. The remaining four rats served as naive controls. Gait, weight-bearing as measured by an incapacitance meter, and tactile allodynia were assessed on postoperative days 9 to 24. On day 28, knee joints were collected for histology. Cytokine concentrations in the serum were assessed with a 10-plex cytokine panel. RESULTS: Weight bearing was not affected by sham or MMT surgery; however, the MMT group had decreased mechanical paw-withdrawal thresholds in the operated limb relative to the contralateral limb (P = 0.017). The gait of the MMT group became increasingly asymmetric from postoperative days 9 to 24 (P = 0.020); moreover, MMT animals tended to spend more time on their contralateral limb than their operated limb while walking (P < 0.1). Ground reaction forces confirmed temporal shifts in symmetry and stance time, as the MMT group had lower vertical and propulsive ground reaction forces in their operated limb relative to the contralateral limb, naive, and sham controls (P < 0.05). Levels of interleukin 6 in the MMT group tended to be higher than naive controls (P = 0.072). Histology confirmed increased cartilage damage in the MMT group, consistent with OA initiation. Post hoc analysis revealed that gait symmetry, stance time imbalance, peak propulsive force, and serum interleukin 6 concentrations had significant correlations to the severity of cartilage lesion formation. CONCLUSION: These data indicate significant gait compensations were present in the MMT group relative to medial collateral ligament (MCL) injury (sham) alone and naive controls. Moreover, these data suggest that gait compensations are likely driven by meniscal instability and/or cartilage damage, and not by MCL injury alone. PMID- 22510444 TI - Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet--Biedl syndrome with situs inversus and insertional polydactyly. AB - BACKGROUND: Bardet--Biedl Syndrome (BBS) is an emblematic recessive genetically highly heterogeneous ciliopathy characterised mainly by polydactyly, retinitis pigmentosa, obesity, cognitive impairment, and kidney dysfunction. The 16 BBS genes known to date are implied in the primary cilia related cellular pathways. METHODS AND RESULTS: Single nucleotide polymorphism (SNP) array analysis followed by exome sequencing was performed in a consanguineous family diagnosed with BBS with unusual developmental features, namely situs inversus and insertional polydactyly. A homozygous 5 bp deletion (NM_020347.2:c.402-406del, p.Pro136ThrfsX5) in LZTFL1 was identified. No LZTFL1 transcript was found in the patient's fibroblasts and no protein could be detected. The sonic hedgehog (Shh) pathway analysis conducted on the patient's fibroblast showed a significant increase in Smo. Patched1 as well as the downstream target GLI2 were also found to be upregulated, indicating an overall massive activation of the Shh signalling in the absence of LZTFL1. CONCLUSION: LZTFL1, encoding the human leucine zipper transcription factor like 1, has been recently shown to be an important negative regulator of BBSome ciliary trafficking and Shh signalling. This study shows that absence of LZTFL1 leads to a BBS phenotype with enhanced developmental abnormalities associated with cellular Shh dysfunction. LZTFL1 is a novel BBS gene (BBS17). PMID- 22510445 TI - Mutations in GRIP1 cause Fraser syndrome. AB - BACKGROUND: Fraser syndrome (FS) is a autosomal recessive malformation syndrome characterised by cryptophthalmos, syndactyly and urogenital defects. FS is a genetically heterogeneous condition. Thus far, mutations in FRAS1 and FREM2 have been identified as cause of FS. Both FRAS1 and FREM2 encode extracellular matrix proteins that are essential for the adhesion between epidermal basement membrane and the underlying dermal connective tissues during embryonic development. Mutations in murine Grip1, which encodes a scaffolding protein that interacts with Fras1/Frem proteins, result in FS-like defects in mice. OBJECTIVE: To test GRIP1 for genetic variants in FS families that do not have mutations in FRAS1 and FREM2. METHODS AND RESULTS: In three unrelated families with parental consanguinity, GRIP1 mutations were found to segregate with the disease in an autosomal recessive manner (donor splice site mutation NM_021150.3:c.2113+1G->C in two families and a 4-bp deletion, NM_021150.3:c.1181_1184del in the third). RT PCR analysis of the GRIP1 mRNA showed that the c.2113+1G->C splice mutation causes skipping of exon 17, leading to a frame shift and a premature stop of translation. CONCLUSION: Mutations in GRIP1 cause classic FS in humans. PMID- 22510446 TI - Enhanced neurotrophin-3 bioactivity and release from a nanoparticle-loaded composite hydrogel. AB - Neurotrophin-3 (NT-3) has shown promise in regenerative strategies after spinal cord injury; however, sustained local delivery is difficult to achieve by conventional methods. Controlled release from poly(lactic-co-glycolic acid) (PLGA) nanoparticles has been studied for numerous proteins, yet achieving sustained release of bioactive proteins remains a challenge. To address these issues, we designed a composite drug delivery system comprised of NT-3 encapsulated in PLGA nanoparticles dispersed in an injectable hydrogel of hyaluronan and methyl cellulose (HAMC). A continuum model was used to fit the in vitro release kinetics of an NT-3 analog from a nanoparticle formulation. Interestingly, the model suggested that the linear drug release observed from composite HAMC was due to a diffusion-limiting layer of methyl cellulose on the particle surface. We then studied the effects of processing parameters and excipient selection on NT-3 release, stability, and bioactivity. Trehalose was shown to be the most effective additive for stabilizing NT-3 during sonication and lyophilization and PLGA itself was shown to stabilize NT-3 during these processes. Of four excipients tested, 400g/mol poly(ethylene glycol) was the most effective during nanoparticle fabrication, with 74% of NT-3 detected by ELISA. Conversely, co-encapsulation of magnesium carbonate with NT-3 was the most effective in maintaining NT-3 bioactivity over 28 days according to a cell-based axonal outgrowth assay. Together, the modeling and optimized processing parameters provide insight critical to designing a controlled bioactive release formulation for ultimate testing in vivo. PMID- 22510447 TI - Influence of the relative composition of trace elements and vitamins in physicochemical stability of total parenteral nutrition formulations for neonatal use. AB - OBJECTIVE: The present study aimed to evaluate the influence of the relative composition of trace elements and vitamins in physicochemical stability of neonatal parenteral nutrition. MATERIAL AND METHODS: Three formulations for neonatal administration were selected; the main variable was the presence of trace elements and vitamins. The analyses where carried out immediately after preparation and at 24 h, 48 h, 72 h and 7 days after preparation. Three methods were selected to determine globule size: light obscuration, dynamic light scattering and optical microscopy. Complementary evaluation including visual inspection, determination of pH and osmolarity, peroxide levels and measurements of zeta potential were also performed. RESULTS: There was an observable alteration in color and phase separation in the PN stored at 25 degrees C and 40 degrees C. Neither globule size pattern, nor any other physicochemical characteristic evaluated appeared to be considerably altered in any of the analyzed formulations even after 7 days of storage at 5 degrees C. Globule size in all the PN studied was consistent with the established limit, below 500 nm by DLS measurement, and PFAT5 was below 0.05% under all storage temperatures. CONCLUSION: Concomitant presence of trace elements and vitamins in the same neonatal formulation did not alter the evaluated aspects of stability. PMID- 22510448 TI - Alcoholic hepatitis and liver transplantation:is an abstinence of six months necessary? PMID- 22510449 TI - Changes in neuronal DNA content variation in the human brain during aging. AB - The human brain has been proposed to represent a genetic mosaic, containing a small but constant number of neurons with an amount of DNA exceeding the diploid level that appear to be generated through various chromosome segregation defects initially. While a portion of these cells apparently die during development, neurons with abnormal chromosomal copy number have been identified in the mature brain. This genomic alteration might to lead to chromosomal instability affecting neuronal viability and could thus contribute to age-related mental disorders. Changes in the frequency of neurons with such structural genomic variation in the adult and aging brain, however, are unknown. Here, we quantified the frequency of neurons with a more than diploid DNA content in the cerebral cortex of normal human brain and analyzed its changes between the fourth and ninth decades of life. We applied a protocol of slide-based cytometry optimized for DNA quantification of single identified neurons, which allowed to analyze the DNA content of about 500 000 neurons for each brain. On average, 11.5% of cortical neurons showed DNA content above the diploid level. The frequency of neurons with this genomic alteration was highest at younger age and declined with age. Our results indicate that the genomic variation associated with DNA content exceeding the diploid level might compromise viability of these neurons in the aging brain and might thus contribute to susceptibilities for age-related CNS disorders. Alternatively, a potential selection bias of "healthy aging brains" needs to be considered, assuming that DNA content variation above a certain threshold associates with Alzheimer's disease. PMID- 22510450 TI - The role of muscarinic acetylcholine receptor type 3 polypeptide (M3RP205-220) antibody in the saliva of patients with primary Sjogren's syndrome. AB - BACKGROUND: Sjogren's syndrome (SS) is a chronic autoimmune disorder of unknown cause. Recent studies have shown that antimuscarinic acetylcholine type 3 receptor (M3R) antibodies can be detected in patients with Sjogren's syndrome (SS), but little is known about the diagnostic value of this antibody. OBJECTIVES: To assess the clinical correlations of anti-M3R (muscarinic acetylcholine receptor type 3) polypeptide (M3RP205-220) antibodies in saliva from patients of primary Sjogren's syndrome (pSS). METHODS: Serum samples and unstimulated mixed saliva from 100 patients with SS were collected and examined. Their mean (SD) age was 54.2 (13.4) years, and the mean (SD) disease duration was 6.2 (3.8) years. Serum samples from 40 patients with systemic lupus erythematosus (SLE), 40 with rheumatoid arthritis (RA), and 60 healthy subjects were analysed as controls. All the patients with SS were carefully evaluated according to European and American criteria. A circular M3RP205-220 peptide sequence was synthesized using solid-phase techniques on an applied biosytems peptide synthesizer. The correlation between anti-M3RP205-220 antibodies and clinical manifestations of pSS was analysed. RESULTS: The IgG of anti-M3RP205-220 antibodies was present in 69% of patients with pSS, 27.5% with SLE, 22.5% with RA, and 23.3% of normal saliva donors. The prevalence of anti-M3RP205-220 antibodies in pSS was significantly higher than in SLE, RA, and normal controls. The specificity of anti-M3RP205-220 antibodies in pSS was 75%. The salivary flow rate in the group positive for anti-M3RP205-220 was 436 MUl/10 min, compared to a rate of 658 MUl/10 min for the negative group (p<0.05). CONCLUSIONS: The anti M3RP205-220 antibody was detected in most patients with pSS. The presence of the antibody was closely associated with the salivary flow rate. This indicated that it may act as an autoantigen, with a role in the pathogenesis of pSS. PMID- 22510451 TI - Early plasma exchange improves outcome in PR3-ANCA-positive renal vasculitis. AB - OBJECTIVES: Plasma exchange (PE) has been shown to improve renal outcome in anti neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and severe renal failure; however the effect of PE in AAV with moderate renal impairment is controversial. METHODS: A single-centre, retrospective one-year follow-up study, including patients with renal AAV and eGFR <60 ml/min/1.73 m2. Since 2007, all patients with renal AAV and eGFR <60 ml/min/1.73 m2 had PE in addition to induction therapy with cyclophosphamide and prednisolone. Patients admitted from 1999 to 2007 that did not receive PE served as controls. The primary outcome was the combination of death, end-stage renal disease, and relapses after one year. RESULTS: A significant reduction in the primary endpoint was observed following the addition of PE (25% vs. 43%, p=0.04). Furthermore, a greater improvement in renal function after one year was observed among surviving PE treated patients not on dialysis (DeltaeGFR 36.1 vs. 19.7 ml/min, p=0.03). There was a significant reduction in serious adverse events in the PE treated group (4% vs. 30%, p=0.02) despite no differences in types and doses of induction immunosuppressive therapy. The advantageous effect of PE was related to the presence of anti-proteinase3 (PR3)-antibodies and also evident among patients with plasma creatinine less than 500 MUM. CONCLUSIONS: This study suggests the use of PE in addition to standard induction treatment with cyclophosphamide and glucocorticoids to patients with renal PR3-AAV and an estimated-GFR <60 ml/min/1.73m2. PMID- 22510452 TI - Inhibition of Ca2+/calmodulin-dependent protein kinase II reverses oxaliplatin induced mechanical allodynia in rats. AB - BACKGROUND: Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes severe peripheral neuropathy. We previously reported that oxaliplatin (4 mg/kg, i.p., twice a week) induces mechanical allodynia in the late phase in rats, and that spinal NR2B-containing N-methyl-D-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca(2+)/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca(2+) influx, in the oxaliplatin-induced mechanical allodynia in rats. RESULTS: An increase of CaMKII phosphorylation was found in the spinal cord (L(4-6)) of oxaliplatin-treated rats. This increased CaMKII phosphorylation was reversed by intrathecal injection of a selective CaMKII inhibitor KN-93 (50 nmol, i.t.) and a selective NR2B antagonist Ro 25-6981 (300 nmol, i.t.). Moreover, acute administration of KN-93 (50 nmol, i.t.) strongly reversed the oxaliplatin-induced mechanical allodynia in von Frey test, while it did not affect the oxaliplatin-induced cold hyperalgesia in acetone test. Similarly, oral administration of trifluoperazine (0.1 and 0.3 mg/kg, p.o.), which is an antipsychotic drug and inhibits calmodulin, reduced both mechanical allodynia and increased CaMKII phosphorylation. On the other hand, trifluoperazine at the effective dose (0.3 mg/kg) had no effect on the paw withdrawal threshold in intact rats. In addition, trifluoperazine at the same dose did not affect the motor coordination in rota-rod test in intact and oxaliplatin-treated rats. CONCLUSIONS: These results suggest that CaMKII is involved in the oxaliplatin induced mechanical allodynia, and trifluoperazine may be useful for the treatment of oxaliplatin-induced peripheral neuropathy in clinical setting. PMID- 22510453 TI - Assessment of financial impact of foot and mouth disease on smallholder cattle farmers in Southern Cambodia. AB - The financial impact of an outbreak of FMD in 2010 on 62 smallholder cattle farmers in four villages in southern Cambodia was investigated by a financial impact survey questionnaire. Financial losses associated with FMD infection were severe with variation depending on whether the animal survived or died or was used for draft. The average post-FMD loss varied from USD 216.32, a 54% reduction from the pre-FMD value because of weight loss and treatment costs, to USD 370.54, a 92% reduction from pre-FMD values if the animal was treated, died and a rental draft replacement was required. Partial budget analysis identified a strongly positive incentive for cattle to be vaccinated biannually for FMD, providing USD 31.48 per animal for each animal owned. However low vaccination rates suggest that farmers are mostly unaware of the need or averse to the practice of vaccinating their cattle for FMD. This may be due to poor understanding of preventative disease strategies such as vaccination, unavailable disposable income for purchase of vaccines, and failure to recognize the full costs that are incurred when the disease occurs. Enhancing smallholder cattle productivity through the introduction of forage growing systems has been suggested as a pathway for alleviating rural poverty in the Mekong region. As our financial analysis identified a net benefit of vaccination for smallholder farmer enterprises in an endemic FMD area in Cambodia, it is considered important that farmer education strategies aimed at improving cattle productivity, also include both access to vaccine and training in preventative disease risk management and biosecurity practices in Cambodia. PMID- 22510454 TI - Options available for labelling nucleic acid samples in DNA microarray-based detection methods. AB - DNA microarrays are considered by many researchers to be the platform of choice for the high-throughput analysis of nucleic acids. Since the past two decades, they have been used constantly as powerful tools in differential gene expression, SNP genotyping, DNA sequencing, gene discovery, disease diagnostic and pathways reconstruction. Several methods have been developed to enable samples of limited amounts of RNA to be quantified. Here we evaluate classical and up-to-date assays made available for labelling those samples. This review also sheds light on the recently developed strategies that ensure high sensitivity such as sample and signal amplification, quantum dot, surface plasmom resonance, nanoparticles and cationinc polythiophenes. PMID- 22510455 TI - Poly(N-vinylpyrrolidone)-modified poly(dimethylsiloxane) elastomers as anti biofouling materials. AB - A new method for the modification of poly(dimethylsiloxane) (PDMS) elastomer surfaces with hydrophilic poly(N-vinylpyrrolidone) (PVP) has been developed. PVP chains were grafted from the PDMS surface by surface-initiated atom transfer radical polymerization (SI-ATRP). The resulting surfaces were characterized by X ray photoelectron spectroscopy (XPS), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), atomic force microscopy (AFM) and water contact angle measurements. It was shown that the modified surfaces were strongly hydrophilic, indicating that the PVP grafts dominate the surface and define its properties. The anti-fouling properties of the grafted surfaces were demonstrated in protein adsorption and cell adhesion experiments. Both protein adsorption and cell adhesion were inhibited significantly on the PVP-modified PDMS surfaces compared to unmodified controls. It is concluded that modification by SI-ATRP grafting of PVP is an effective method for the preparation of anti biofouling PDMS materials. PMID- 22510456 TI - Automatic assessment of atrial pacing threshold in current medical practice. AB - AIMS: The aim of this study was to validate the ambulatory automatic atrial threshold monitoring algorithm by comparing the measurements assessed by the automatic system and those evaluated manually by the physician at discharge, 2- and 8-month follow-up sessions. METHODS AND RESULTS: This is an observational multicentric prospective study of 352 patients implanted with EnPulse((r)) DR pacemakers. Mean age was 76.3 +/- 9.4 years. Indications of pacing were atrio ventricular block (AVB) (64%) and sinus dysfunction (SD) or brady-tachy syndrome (36%). The automatic atrial threshold monitoring function was maintained at nominal programming state with daily measurement scheduled at 1:00 am. Ambulatory automatic atrial threshold assessment was possible for 91.5% of patients at discharge, 97.3% at 2 months, and 95.7% at 8 months. Causes of the unsuccessful attempts to perform automatic atrial threshold were atrial arrhythmias or permanent atrial and ventricular pacing. Feasibility is significantly better for AVB indication than SD indication due to more frequent occurrence of atrial fibrillation (AF). At each stage, there is a strict correlation between the automatic measurements and those conducted manually by the physician with a P < 0.001. CONCLUSION: Feasibility of ambulatory automatic atrial threshold is good. Results of the study show excellent correlation between the two methods for atrial threshold: there is no statistical difference between manual and automatic measurements during follow-up. PMID- 22510457 TI - De novo development of dural arteriovenous fistula after endovascular embolization of pial arteriovenous fistula. AB - BACKGROUND: The development of de novo dural arteriovenous fistula(s) following endovascular embolization of a prior high-flow pial arteriovenous fistula (PAVF) has not previously been reported and the natural history is unknown. The anatomic basis, pathophysiologic mechanism, management and outcome are discussed. METHODS: Treatment-completed congenital PAVFs treated at our center between January 2005 and August 2011 were analyzed retrospectively. Among 16 cases of PAVFs treated by endovascular embolization, four developed de novo dural arteriovenous fistulas during treatment or on follow-up that were not present before treatment. Information was collected from the clinical case records, imaging by MRI on presentation and during follow-up, all angiographic images and records during each of the procedures and during follow-up. RESULTS: The time interval between the last embolization and identification of a dural fistula ranged from 3 to 14 months. Ten fistulas were identified in four patients, seven of which were embolized, four with glue, two with Onyx18 and one with absolute alcohol. None recanalized, while one patient developed fistula in an adjacent location that was subsequently treated with radiosurgery. Not all fistulas need treatment; small fistulas with a minimal flow can safely be observed. CONCLUSIONS: De novo dural fistulas following endovascular embolization of high-flow PAVFs is not an uncommon development. They are mostly asymptomatic and develop anywhere along the drainage of the fistula, maturing over time and diagnosed during follow-up studies, emphasizing the need for follow-up angiography. They can be effectively treated by endovascular embolization. Localized refractory dural fistulas can be dealt with by radiosurgery. PMID- 22510458 TI - Flow diverters and a tale of two aneurysms. AB - Flow-diverting devices offer an exciting alternative for the management of large and giant intracranial aneurysms. However, the risk and mechanism of delayed aneurysmal rupture and hemorrhage following placement of these devices are not clearly understood. Two patients with similar symptomatic giant paraclinoid internal carotid artery aneurysms are described. Both patients were treated with SILK flow-diverting devices. In both patients the SILK device was placed without technical complication. The first patient continued to do well 1 year postoperatively with complete aneurysm occlusion. The second patient had a delayed subarachnoid hemorrhage despite markedly decreased filling of the aneurysm immediately following the procedure. Flow-diverting devices are an exciting technology which provide an alternative treatment modality in the management of giant intracranial aneurysms. However, caution must be exercised as the risks of delayed complications have yet to be fully elucidated. Similar aneurysms may have drastically different outcomes due to the unpredictability of this technology. PMID- 22510461 TI - Strain-induced changes to the electronic structure of germanium. AB - Density functional theory calculations (DFT) are used to investigate the strain induced changes to the electronic structure of biaxially strained (parallel to the (001), (110) and (111) planes) and uniaxially strained (along the [001], [110] and [111] directions) germanium (Ge). It is calculated that a moderate uniaxial strain parallel to the [111] direction can efficiently transform Ge to a direct bandgap material with a bandgap energy useful for technological applications. PMID- 22510459 TI - Wnt signaling in neuromuscular junction development. AB - Wnt proteins are best known for their profound roles in cell patterning, because they are required for the embryonic development of all animal species studied to date. Besides regulating cell fate, Wnt proteins are gaining increasing recognition for their roles in nervous system development and function. New studies indicate that multiple positive and negative Wnt signaling pathways take place simultaneously during the formation of vertebrate and invertebrate neuromuscular junctions. Although some Wnts are essential for the formation of NMJs, others appear to play a more modulatory role as part of multiple signaling pathways. Here we review the most recent findings regarding the function of Wnts at the NMJ from both vertebrate and invertebrate model systems. PMID- 22510460 TI - NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). AB - Long-term potentiation and long-term depression (LTP/LTD) can be elicited by activating N-methyl-d-aspartate (NMDA)-type glutamate receptors, typically by the coincident activity of pre- and postsynaptic neurons. The early phases of expression are mediated by a redistribution of AMPA-type glutamate receptors: More receptors are added to potentiate the synapse or receptors are removed to weaken synapses. With time, structural changes become apparent, which in general require the synthesis of new proteins. The investigation of the molecular and cellular mechanisms underlying these forms of synaptic plasticity has received much attention, because NMDA receptor-dependent LTP and LTD may constitute cellular substrates of learning and memory. PMID- 22510462 TI - Prenatal inflammation and neurodevelopment in schizophrenia: a review of human studies. AB - A confluence of evidence supports an association between prenatal inflammation and risk of schizophrenia. Outside of studies of prenatal infections and risk of schizophrenia, other relevant human studies of prenatal inflammation and neurodevelopment in schizophrenia have not been reviewed. In this paper, we review human studies of 1) prenatal inflammation and risk of schizophrenia, 2) inflammation as a potential common mediator of several prenatal risk factors for schizophrenia other than prenatal infections, 3) prenatal inflammation and immune function, neurocognition, brain morphology, and gene expression in adult offspring with schizophrenia, and 4) gene by environment and gene by gene interactions relevant to these associations. We suggest future areas for human studies research based on existing findings. PMID- 22510463 TI - Salutary effect of NFkappaB inhibitor and folacin in hyperhomocysteinemia hyperlipidemia induced vascular dementia. AB - Dementia of vascular origin or vascular dementia (VaD) is considered as the second commonest form of dementia after Alzheimer's disease (AD). In the last ten years various researchers have reported a strong association of hyperhomocysteinemia (HHcy), hyperlipidemia (HL) and dementia. This study investigates the salutary effect of natrium diethyl dithio carbamate trihydrate (NDDCT), a nuclear factor-kappaB (NF-kappaB) inhibitor as well as folacin (Vitamin-B(9)) in HHcy-HL induced VaD. l-methionone was used to induce HHcy-HL and associated VaD. Morris water-maze (MWM) was used for testing learning and memory. Vascular system assessment was done by testing endothelial function. Biochemical estimations were performed to assess HHcy (serum homocysteine), HL (serum cholesterol), oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species and brain glutathione), nitric oxide levels (serum nitrite/nitrate) and cholinergic activity (brain acetyl cholinesterase activity). L-methionine treated animals have shown HHcy-HL, endothelial dysfunction, impairment of learning, memory, reduction in serum nitrite/nitrate levels and brain glutathione (GSH) along with increase in serum and brain thiobarbituric acid reactive species (TBARS), and brain acetylcholinesterase activity. NDDCT, folacin and donepezil (positive control) significantly improved HHcy-HL induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. l-methionine induced HHcy-HL has caused VaD development in rats. NFkappa-B inhibitors and folacin may be considered as potential agents for the management of HHcy-HL induced VaD. PMID- 22510465 TI - Focus issue: Adding math to the signaling toolkit. AB - This issue of Science Signaling, which complements the 13 April issue of Science, showcases the application of computational approaches to signal transduction research. Research and commentary highlight how mathematical modeling combined with experimental data can yield new insights into how cells interpret, process, and respond to external and internal cues. PMID- 22510464 TI - The mediating effect of social relationships on the association between socioeconomic status and subjective health - results from the Heinz Nixdorf Recall cohort study. AB - BACKGROUND: Socioeconomic status (SES) is an important determinant of population health. Explanatory approaches on how SES determines health have so far included numerous factors, amongst them psychosocial factors such as social relationships. However, it is unclear whether social relationships can help explain socioeconomic differences in general subjective health. Do different aspects of social relationships contribute differently to the explanation? Based on a cohort study of middle and older aged residents (45 to 75 years) from the Ruhr Area in Germany our study tries to clarify the matter. METHODS: For the analyses data from the population-based prospective Heinz Nixdorf Recall (HNR) Study is used. As indicators of SES education, equivalent household income and occupational status were employed. Social relations were assessed by including structural as well as functional aspects. Structural aspects were estimated by the Social Integration Index (SII) and functional aspects were measured by availability of emotional and instrumental support. Data on general subjective health status was available for both baseline examination (2000-2003) and a 5-year follow-up (2006 2008). The sample consists of 4,146 men and women. Four logistic regression models were calculated: in the first model we controlled for age and subjective health at baseline, while in models 2 and 3, either functional or structural aspects of social relationships were introduced separately. Model 4 then included all variables. As former studies indicated different health effects of SES and social relations in men and women, analyses were conducted with the overall sample as well as for each gender alone. RESULTS: Prospective associations of SES and subjective health were reduced after introducing social relationships into the regression models. Percentage reductions between 2% and 30% were observed in the overall sample when all aspects of social relations were included. The percentage reductions were strongest in the lowest SES group. Gender specific analyses revealed mediating effects of social relationships in women and men. The magnitude of mediating effects varied depending on the indicators of SES and social relations. CONCLUSIONS: Social relationships substantially contribute to the explanation of SES differences in subjective health. Interventions for improving social relations which especially focus on socially deprived groups are likely to help reducing socioeconomic disparities in health. PMID- 22510466 TI - Understanding signaling dynamics through synthesis. AB - Tissue-scale organization emerges from the action of sophisticated multiscale developmental programs. But the design rules for composing elementary signaling and information processing modules into such functional systems and for integrating them into the noisy and convoluted living context remain incompletely addressed. The construction of a synthetic gene circuit encoding contact dependent signal propagation demonstrates one broadly applicable approach to this problem. The circuit comprises orthogonal signaling through the Delta ligand and the Notch receptor, multicellular positive feedback, and transcriptional signal amplification. Positive feedback and contact signaling proved sufficient for bistability and signal propagation across a population of mammalian cells, but only when combined with signal amplification. Thus, construction and characterization of synthetic gene circuits have made it possible to establish mechanistic sufficiency and the minimal requirements for the phenotype of interest. PMID- 22510467 TI - Unmasking functional motifs within disordered regions of proteins. AB - Eukaryotic proteins often possess long stretches that fail to adopt well-defined, three-dimensional structures. These intrinsically disordered regions are associated with cell signaling through the enrichment of hub proteins of networks and as targets for posttranslational modifications. Although disordered regions are readily identified because of their distinct sequence characteristics, it is difficult to predict the functions associated with these regions. This is because disordered regions often house short (two- to five-residue) linear motifs that mediate intermolecular interactions. Predicting their function requires the ability to identify the functionally relevant motifs. If one assumes that functional motifs are highly conserved as compared to background sequence contexts, then a suitable comparative genomics approach proves to be powerful in unmasking functional motifs that are part of disordered regions. This approach has successfully identified known functional motifs and predicted a set of new motifs that might yield important insights regarding previously unknown functionalities for disordered regions. Given knowledge of highly conserved motifs, one can assess whether the rapidly changing sequence contexts are actuators of the functionalities of short linear motifs within disordered regions. This should have important implications for engineering and targeting hub proteins in signaling networks. PMID- 22510468 TI - A systematic approach for analysis of peptide array kinome data. AB - The central roles of kinases in cellular processes and diseases make them highly attractive as indicators of biological responses and as therapeutic targets. Peptide arrays are emerging as an important means of characterizing kinome activity. Currently, the computational tools used to perform high-throughput kinome analyses are not specifically tailored to the nature of the data, which hinders extraction of biological information and overall progress in the field. We have developed a method for kinome analysis, which is implemented as a software pipeline in the R environment. Components and parameters were chosen to address the technical and biological characteristics of kinome microarrays. We performed comparative analysis of kinome data sets that corresponded to stimulation of immune cells with ligands of well-defined signaling pathways: bovine monocytes treated with interferon-gamma (IFN-gamma), CpG-containing nucleotides, or lipopolysaccharide (LPS). The data sets for each of the treatments were analyzed with our methodology as well as with three other commonly used approaches. The methods were evaluated on the basis of statistical confidence of calculated values with respect to technical and biological variability, and the statistical confidence (P values) by which the known signaling pathways could be independently identified by the pathway analysis of InnateDB (a Web-based resource for innate immunity interactions and pathways). By considering the particular attributes of kinome data, we found that our approach identified more of the peptides involved in the pathways than did the other compared methods and that it did so at a much higher degree of statistical confidence. PMID- 22510469 TI - Synthetic signal propagation through direct cell-cell interaction. AB - Contact-dependent cell communication has the potential to generate elaborate cell patterns, and this occurs in vivo. We used the Delta-Notch signaling system, consisting of the ligand Delta and the receptor Notch, to construct a positive feedback loop between adjacent cells to generate a propagating signal in cultured cells. To amplify the responses of Notch to Delta, we created a cell-cell positive feedback loop using an engineered transcriptional cascade and a Notch positive regulator, Lunatic fringe. We used mathematical modeling to determine the appropriate amount of amplification to enable the induction of Delta to propagate from one cell to its neighboring cells, which generated bistability within the local cell populations and resulted in discrete groups of cells that were either positive or negative for Delta. These results demonstrate the sufficiency of the cell-cell positive feedback loop to generate signal propagation and cell population-level bistability. This study represents a step in engineering more elaborate cell patterns in mammalian cells. PMID- 22510471 TI - Computational approaches for analyzing information flow in biological networks. AB - The advancements in "omics" (proteomics, genomics, lipidomics, and metabolomics) technologies have yielded large inventories of genes, transcripts, proteins, and metabolites. The challenge is to find out how these entities work together to regulate the processes by which cells respond to external and internal signals. Mathematical and computational modeling of signaling networks has a key role in this task, and network analysis provides insights into biological systems and has applications for medicine. Here, we review experimental and theoretical progress and future challenges toward this goal. We focus on how networks are reconstructed from data, how these networks are structured to control the flow of biological information, and how the design features of the networks specify biological decisions. PMID- 22510470 TI - Quantifying crosstalk among interferon-gamma, interleukin-12, and tumor necrosis factor signaling pathways within a TH1 cell model. AB - T helper (T(H)) cells integrate biochemical cues present in the tissue microenvironment and produce cytokines that orchestrate immune responses. Previous discoveries have revealed a qualitative understanding of how T(H) cells process this biochemical information; however, the lack of methods to quantify how well these depictions apply to a particular cell type limits our ability to translate our knowledge of the immune response from one biological system to another. We used model-based inference methods and quantitative flow cytometric analysis in mouse T(H)1 cells to determine the relative contributions of different putative branches in the signaling network that responds to the cytokine interleukin-12 (IL-12), which links innate and adaptive immunity. The response of T(H)1 cells to IL-12 exhibited hysteresis because it depended on both current and past exposure and engaged a positive feedback mechanism through the direct activation of signal transducer and activator of transcription 1. The hysteresis in the dose-response curve to IL-12 created a transient "memory" by sustaining cytokine secretion after the withdrawal of the stimulus. In summary, this combined experimental and computational approach illustrates how model-based inference can be used to better understand how cells process and act upon biochemical cues present in the tissue microenvironment. PMID- 22510472 TI - The "House Calls" trial: a randomized controlled trial to reduce racial disparities in live donor kidney transplantation: rationale and design. AB - Despite a substantially lower rate of live donor kidney transplantation among Black Americans compared to White Americans, there are few systematic efforts to reduce this racial disparity. This paper describes the rationale and design of a randomized controlled trial evaluating the comparative effectiveness of three different educational interventions for increasing live donor kidney transplantation in Black Americans. This trial is a single-site, urn-randomized controlled trial with a planned enrollment of 180 Black Americans awaiting kidney transplantation. Patients are randomized to receive transplant education in one of three education conditions: through group education at their homes (e.g., House Calls), or through group (Group-Based) or individual education (Individual Counseling) in the transplant center. The primary outcome of the trial is the occurrence of a live donor kidney transplant, with secondary outcomes including living donor inquiries and evaluations as well as changes in patient live donor kidney transplantation readiness, willingness, knowledge, and concerns. Sex, age, dialysis status, and quality of life are evaluated as moderating factors. Findings from this clinical trial have the potential to inform strategies for reducing racial disparities in live donor kidney transplantation. Similar trials have been developed recently to broaden the evaluation of House Calls as an innovative disparity-reducing intervention in kidney transplantation. PMID- 22510473 TI - Effect of age at disease onset in the clinical profile of spondyloarthritis: a study of 1424 Brazilian patients. AB - OBJECTIVES: To analyse demographic and clinical variables in patients with disease onset before and after 40, 45 and 50 years in a large series of Brazilian SpA patients. METHODS: A common protocol of investigation was prospectively applied to 1424 SpA patients in 29 centres distributed through the main geographical regions in Brazil. The mean age at disease onset was 28.56 +/- 12.34 years, with 259 patients (18.2%) referring disease onset after 40 years, 151 (10.6%) after 45 years and 81 (5.8%) after 50 years. Clinical and demographic variables and disease indices (BASDAI, BASFI, BASRI, MASES, ASQoL) were investigated. Ankylosing spondylitis was the most frequent disease (66.3%), followed by psoriatic arthritis (18%), undifferentiated SpA (6.7%), reactive arthritis (5.5%), and enteropathic arthritis (3.5%). RESULTS: Comparing the groups according to age of disease onset, those patients with later onset presented statistical association with female gender, peripheral arthritis, dactylitis, nail involvement and psoriasis, as well as negative statistical association with inflammatory low back pain, alternating buttock pain, radiographic sacroiliitis, hip involvement, positive familial history, HLA-B27 and uveitis. BASDAI, BASFI and quality of life, as well as physicians and patient's global assessment, were similar in all the groups. Radiographic indices showed worse results in the younger age groups. CONCLUSIONS: There are two different clinical patterns in SpA defined by age at disease onset: one with predominance of axial symptoms in the group with disease onset <= 40 years and another favouring the peripheral manifestations in those with later disease onset. PMID- 22510474 TI - Patient-oriented simulation based on Monte Carlo algorithm by using MRI data. AB - BACKGROUND: Although Monte Carlo simulations of light propagation in full segmented three-dimensional MRI based anatomical models of the human head have been reported in many articles. To our knowledge, there is no patient-oriented simulation for individualized calibration with NIRS measurement. Thus, we offer an approach for brain modeling based on image segmentation process with in vivo MRI T1 three-dimensional image to investigate the individualized calibration for NIRS measurement with Monte Carlo simulation. METHODS: In this study, an individualized brain is modeled based on in vivo MRI 3D image as five layers structure. The behavior of photon migration was studied for this individualized brain detections based on three-dimensional time-resolved Monte Carlo algorithm. During the Monte Carlo iteration, all photon paths were traced with various source-detector separations for characterization of brain structure to provide helpful information for individualized design of NIRS system. RESULTS: Our results indicate that the patient-oriented simulation can provide significant characteristics on the optimal choice of source-detector separation within 3.3 cm of individualized design in this case. Significant distortions were observed around the cerebral cortex folding. The spatial sensitivity profile penetrated deeper to the brain in the case of expanded CSF. This finding suggests that the optical method may provide not only functional signal from brain activation but also structural information of brain atrophy with the expanded CSF layer. The proposed modeling method also provides multi-wavelength for NIRS simulation to approach the practical NIRS measurement. CONCLUSIONS: In this study, the three dimensional time-resolved brain modeling method approaches the realistic human brain that provides useful information for NIRS systematic design and calibration for individualized case with prior MRI data. PMID- 22510475 TI - Effects of lipopolysaccharide exposure at different postnatal time points on the response of LH to homotypic stress in adulthood. AB - Early-life immune stress may have long-lasting effects, known as programming effects, on the physiological response to stress in adulthood. There may be a critical window after birth during which such a challenge can induce long-lasting alterations. However, there are few reports regarding the consequences of this phenomenon for later reproductive function. Here we report on induction by early life LPS injection of long-lasting alterations in the adult LH response to homotypic immune stress in male rats. First, we investigated developmental changes in the LH response to LPS, since immune challenge during the stress hyporesponsive period can induce long-lasting effects on physiological functions. Rat serum LH concentrations were decreased by LPS (100 MUg/kg) injection on postnatal day 15 or 25, but not day 10, suggesting that the period prior to postnatal day 10 is the stress hyporesponsive period for LH. Serum LH concentrations and body weight were decreased by adult LPS (400 MUg/kg) injection in rats given saline or LPS (100 MUg/kg) on postnatal day 25, but not in rats given LPS (100 MUg/kg) on postnatal day 10. Expression of hypothalamic IL-1beta and TNF-alpha mRNA, which suppress serum LH during immune stress, were equally increased in these groups by adult LPS (400 MUg/kg) injection. The present data suggest that the period prior to postnatal day 10 is the critical window in which immune stress can induce long-lasting alterations in the LH response, but that IL 1beta and TNF-alpha are not involved in mediating the altered response. PMID- 22510476 TI - miR-126 enhances the sensitivity of non-small cell lung cancer cells to anticancer agents by targeting vascular endothelial growth factor A. AB - Increasing evidence suggests that hsa-miR-126 (miR-126) is down-regulated in non small cell lung cancer (NSCLC) cell lines and the restoration of miR-126 impairs tumor cell proliferation, migration, invasion, and survival by targeting specific molecules. Here, we reported for the first time that miR-126 was involved in regulating the response of NSCLC cells to cancer chemotherapy. After transfected A549 cells with miR-126 mimic or inhibitor, we found that an elevated level of miR-126 was significantly associated with a decreased half maximal inhibitory concentration of adriamycin (ADM) and vincristine, an increased accumulation of ADM, down-regulation of vascular endothelial growth factor A (VEGFA) and multidrug resistance-associated protein 1 (MRP1), and inactivation of the Akt signaling pathway. Furthermore, enhanced expression of miR-126 suppressed the growth of A549 xenograft and inhibited the expression of VEGFA and MRP1. miR-126 could efficiently down-regulate VEGFA expression through the interaction with the VEGFA 3'-untranslated region, whereas restoration of VEGFA could partially attenuate the suppression of MRP1 by miR-126. However, LY294002, an inhibitor of the PI3K/Akt signaling pathway, diminished this effect, suggesting that enhanced expression of miR-126 increased the sensitivity of NSCLC cells to anticancer agents through negative regulation of a VEGF/PI3K/Akt/MRP1 signaling pathway. PMID- 22510477 TI - Acute leukemia classification by ensemble particle swarm model selection. AB - OBJECTIVE: Acute leukemia is a malignant disease that affects a large proportion of the world population. Different types and subtypes of acute leukemia require different treatments. In order to assign the correct treatment, a physician must identify the leukemia type or subtype. Advanced and precise methods are available for identifying leukemia types, but they are very expensive and not available in most hospitals in developing countries. Thus, alternative methods have been proposed. An option explored in this paper is based on the morphological properties of bone marrow images, where features are extracted from medical images and standard machine learning techniques are used to build leukemia type classifiers. METHODS AND MATERIALS: This paper studies the use of ensemble particle swarm model selection (EPSMS), which is an automated tool for the selection of classification models, in the context of acute leukemia classification. EPSMS is the application of particle swarm optimization to the exploration of the search space of ensembles that can be formed by heterogeneous classification models in a machine learning toolbox. EPSMS does not require prior domain knowledge and it is able to select highly accurate classification models without user intervention. Furthermore, specific models can be used for different classification tasks. RESULTS: We report experimental results for acute leukemia classification with real data and show that EPSMS outperformed the best results obtained using manually designed classifiers with the same data. The highest performance using EPSMS was of 97.68% for two-type classification problems and of 94.21% for more than two types problems. To the best of our knowledge, these are the best results reported for this data set. Compared with previous studies, these improvements were consistent among different type/subtype classification tasks, different features extracted from images, and different feature extraction regions. The performance improvements were statistically significant. We improved previous results by an average of 6% and there are improvements of more than 20% with some settings. In addition to the performance improvements, we demonstrated that no manual effort was required during acute leukemia type/subtype classification. CONCLUSIONS: Morphological classification of acute leukemia using EPSMS provides an alternative to expensive diagnostic methods in developing countries. EPSMS is a highly effective method for the automated construction of ensemble classifiers for acute leukemia classification, which requires no significant user intervention. EPSMS could also be used to address other medical classification tasks. PMID- 22510478 TI - The heat shock transcription factor Hsf1 is downregulated in DNA damage associated senescence, contributing to the maintenance of senescence phenotype. AB - Heat shock response (HSR) that protects cells from proteotoxic stresses is downregulated in aging, as well as upon replicative senescence of cells in culture. Here we demonstrate that HSR is suppressed in fibroblasts from the patients with segmental progerioid Werner Syndrome, which undergo premature senescence. Similar suppression of HSR was seen in normal fibroblasts, which underwent senescence in response to DNA damaging treatments. The major DNA-damage induced signaling (DDS) pathways p53-p21 and p38-NF-kB-SASP contributed to the HSR suppression. The HSR suppression was associated with inhibition of both activity and transcription of the heat shock transcription factor Hsf1. This inhibition in large part resulted from the downregulation of SIRT1, which in turn was because of decrease in the expression of the translation regulator HuR. Importantly, we uncovered a positive feedback regulation, where suppression of Hsf1 further activates the p38-NF-kappaB-SASP pathway, which in turn promotes senescence. Overexpression of Hsf1 inhibited the p38-NFkappaB-SASP pathway and partially relieved senescence. Therefore, downregulation of Hsf1 plays an important role in the development or in the maintenance of DNA damage signaling induced cell senescence. PMID- 22510479 TI - Nonlinear optical response in gapped graphene. AB - We present a formulation for the nonlinear optical response in gapped graphene, where the low-energy single-particle spectrum is modeled by massive Dirac theory. As a representative example of the formulation presented here, we obtain a closed form formula for the third harmonic generation in gapped graphene. It turns out that the covariant form of the low-energy theory gives rise to peculiar logarithmic singularities in the nonlinear optical spectra. The universal functional dependence of the response function on dimensionless quantities indicates that the optical nonlinearity can be largely enhanced by tuning the gap to smaller values. PMID- 22510480 TI - Domain enhanced lookup time accelerated BLAST. AB - BACKGROUND: BLAST is a commonly-used software package for comparing a query sequence to a database of known sequences; in this study, we focus on protein sequences. Position-specific-iterated BLAST (PSI-BLAST) iteratively searches a protein sequence database, using the matches in round i to construct a position specific score matrix (PSSM) for searching the database in round i + 1. Biegert and Soding developed Context-sensitive BLAST (CS-BLAST), which combines information from searching the sequence database with information derived from a library of short protein profiles to achieve better homology detection than PSI BLAST, which builds its PSSMs from scratch. RESULTS: We describe a new method, called domain enhanced lookup time accelerated BLAST (DELTA-BLAST), which searches a database of pre-constructed PSSMs before searching a protein-sequence database, to yield better homology detection. For its PSSMs, DELTA-BLAST employs a subset of NCBI's Conserved Domain Database (CDD). On a test set derived from ASTRAL, with one round of searching, DELTA-BLAST achieves a ROC5000 of 0.270 vs. 0.116 for CS-BLAST. The performance advantage diminishes in iterated searches, but DELTA-BLAST continues to achieve better ROC scores than CS-BLAST. CONCLUSIONS: DELTA-BLAST is a useful program for the detection of remote protein homologs. It is available under the "Protein BLAST" link at http://blast.ncbi.nlm.nih.gov. PMID- 22510481 TI - In vivo breast cancer characterization imaging using two monoclonal antibodies activatably labeled with near infrared fluorophores. AB - INTRODUCTION: The gene expression profiles of cancer cells are closely related to their aggressiveness and metastatic potential. Antibody-based immunohistochemistry (IHC) of tissue specimens is a common method of identifying expressed proteins in cancer cells and increasingly inform treatment decisions. Molecular imaging is a potential method of performing similar IHC studies in vivo without the requirement for biopsy or tumor excision. To date, antibody-based imaging has been limited by high background levels related to slow clearance, making such imaging practical. However, optically activatable imaging agents, which are only fluorescent when bound to their cognate receptor, open the possibility of doing in vivo multi-color IHC. METHODS: We describe the use of activatable, near infrared fluorescence-labeled AlexaFluor680 (Alexa680) conjugated panitumumab (Pan) targeted against human epidermal growth factor receptor (EGFR) (Pan-Alexa680) and Indocyanine Green (ICG) conjugated trastuzumab (Tra) targeted against human epidermal growth factor receptor type 2 (HER2) (Tra ICG) were synthesized and evaluated in cells in vitro and in an orthotopic breast cancer mouse model in vivo. RESULTS: Pan-Alexa680 (self-quenched; SQ) and Tra-ICG were initially quenched but demonstrated a 5.2- and 50- fold dequenching capacity under detergent treatment, respectively. In vitro microscopy and flow cytometry using MDA-MB-468 (EGFR+/HER2-) and 3T3/HER2 cells (EGFR-/HER2+), demonstrated specific fluorescence signal for each cell type based on binding to Pan Alexa680(SQ) or Tra-ICG. An in vivo imaging study employing a cocktail of Pan- Alexa680(SQ) and Tra-ICG (each 50 MUg) was injected into mice with orthotopic MDA MB-468 and 3T3/HER2 tumors in the breast. Each probe visualized only the target specific breast tumor. CONCLUSIONS: Multi-color target-specific fluorescence breast cancer imaging can be achieved in vivo by employing two activatable fluorescent probes administered as a cocktail. The images allowed us to see a specific receptor expression in each breast tumor without post-image processing. PMID- 22510482 TI - Association between polymorphism in the FTO gene and growth and carcass traits in pig crosses. AB - BACKGROUND: Independent studies have shown that several single nucleotide polymorphisms (SNP) in the human FTO (fat mass and obesity associated) gene are associated with obesity. SNP have also been identified in the pig FTO gene, among which some are associated with selected fat-deposition traits in F2 crosses and commercial populations. In this study, using both commercial pig populations and an experimental Meishan * Pietrain F2 population, we have investigated the association between one FTO SNP and several growth and carcass traits. Association analyses were performed with the FTO polymorphism either alone or in combination with polymorphisms in flanking loci. METHODS: SNP (FM244720:g.400C>G) in exon 3 of porcine FTO was genotyped by PCR-RFLP and tested for associations with some growth, carcass and fat-related traits. Proportions of genetic variance of four pig chromosome 6 genes (FTO, RYR1, LIPE and TGFB1) on selected traits were evaluated using single- and multi-locus models. RESULTS: Linkage analysis placed FTO on the p arm of pig chromosome 6, approximately 22 cM from RYR1. In the commercial populations, allele C of the FTO SNP was significantly associated with back fat depth and allele G with muscling traits. In the Meishan * Pietrain F2 pigs, heterozygotes with allele C from the Pietrain sows and allele G from the Meishan boar were more significantly associated with fat-related traits compared to homozygotes with allele G from the Pietrain and allele G from the Meishan breed. In single- and multi-locus models, genes RYR1, TGFB1 and FTO showed high associations. The contribution in genetic variance from the polymorphism in the FTO gene was highest for back fat depth, meat area on the musculus longissimus lumborum et thoracis tissues and metabolite glucose-6-phosphate dehydrogenase. CONCLUSIONS: Our results show that in pig, FTO influences back fat depth in the commercial populations, while in the Meishan * Pietrain F2 pigs with a CG genotype, heterosis occurs for several fat-related traits. PMID- 22510483 TI - Cryoglobulinaemic vasculitis: new aspects. PMID- 22510484 TI - Selective down-regulation of alpha4beta2 neuronal nicotinic acetylcholine receptors in the brain of uremic rats with cognitive impairment. AB - Cognitive impairment is common in patients with chronic kidney disease. Brain nicotinic acetylcholine receptors modulate cognitive functions, such as learning and memory. Pharmacological cholinergic enhancement is useful in patients with cognitive dysfunction. The major nicotinic acetylcholine receptor subtypes in the brain are heteromeric alpha4beta2 and homomeric alpha7 receptors. To study the involvement of neuronal acetylcholine receptors in cognitive impairment in uremic rats, bilateral nephrectomy was performed. 24 weeks after nephrectomy, memory was assessed using the one trial step-down inhibitory avoidance test. Neuronal nicotinic acetylcholine receptors in the brain were studied by radioligand binding, immunoprecipitation, Western blot and sucrose gradient experiments. We demonstrated that rats with severe renal failure show disorders of short term memory. Long term memory was not altered in these rats. The number of functional alpha4beta2 heteromeric neuronal nicotinic receptors was decreased in the brains of rats with severe renal failure. There was a significant correlation between the degree of renal impairment and the number of heteromeric nicotinic acetylcholine receptors in the brain. The down-regulation of functional alpha4beta2 receptors in the brains of rats with severe renal failure was not due to a reduction of alpha4 or beta2 subunit proteins. The number of alpha7 homomeric neuronal nicotinic acetylcholine receptors was not altered. These findings may have important clinical significance for the management of cognitive impairment in patients with chronic kidney disease. PMID- 22510485 TI - Collective phase-like mode and the role of lattice distortions at TN ~TC in RMn2O5 (R= Pr, Sm, Gd, Tb, Bi). AB - We report on electronic collective excitations in RMn(2)O(5) (R =Pr, Sm, Gd, Tb) showing condensation starting at and below ~T(N) ~T(C)~ 40-50 K. Their origin is understood as partial delocalized e(g) electron orbitals in the Jahn-Teller distortion of the pyramid dimer with strong hybridized Mn(3+)-O bonds. Our local probes, Raman, infrared, and x-ray absorption, back the conclusion that there is no structural phase transition at T(N)~T(C). Ferroelectricity is magnetically assisted by electron localization triggering lattice polarizability by unscreening. We have also found phonon hardening as the rare earth is sequentially replaced. This is understood as a consequence of lanthanide contraction. It is suggested that partially f-electron screened rare earth nuclei might be introducing a perturbation to e(g) electrons prone to delocalize as the superexchange interaction takes place. PMID- 22510486 TI - Geo-mapping of time trends in childhood caries risk--a method for assessment of preventive care. AB - BACKGROUND: Dental caries is unevenly distributed within populations with a higher burden in low socio-economy groups. Several attempts have been made to allocate resources to those that need them the most; there is a need for convenient approaches to population-based monitoring of caries risk over time. The aim of this study was to develop the geo-map concept, addressing time trends in caries risk, and demonstrate the novel approach by analyzing epidemiological data from preschool residents in the region of Halland, Sweden. METHODS: The study population consisted of 9,973 (2006) and 10,927 (2010) children between 3 to 6 years of age (~77% of the eligible population) from whom caries data were obtained. Reported dmfs>0 for a child was considered as the primary caries outcome. Each study individual was geo-coded with respect to his/her residence parish (66 parishes in the region). Smoothed caries risk geo-maps, along with corresponding statistical certainty geo-maps, were produced by using the free software Rapid Inquiry Facility and the ESRI(r) ArcGIS system. Parish-level socioeconomic data were available. RESULTS: The overall proportion of caries-free (dmfs=0) children improved from 84.0% in 2006 to 88.6% in 2010. The ratio of maximum and minimum (parish-level) smoothed relative risks (SmRRs) increased from 1.76/0.44=4.0 in 2006 to 2.37/0.33=7.2 in 2010, which indicated an increased geographical polarization of early childhood caries in the population. Eight parishes showed evidential, positional changes in caries risk between 2006 and 2010; their corresponding SmRRs and statistical certainty ranks changed markedly. No considerable parallel changes in parish-level socioeconomic characteristics were seen during the same time period. CONCLUSION: Geo-maps based on caries risk can be used to monitor changes in caries risk over time. Thus, geo-mapping offers a convenient tool for evaluating the effectiveness of tailored health promotion and preventive care in child populations. PMID- 22510487 TI - Cardiovascular disease and serum defensin levels in systemic lupus erythematosus. AB - OBJECTIVES: To analyse if defensins, immunomodulatory peptides involved in angiogenesis and elevated in the sera of systemic lupus erythematosus (SLE) patients, relate to cardiovascular disease in SLE. METHODS: Serum levels of the defensins human beta defensin 2 (hBD2) and human neutrophil peptide (HNP) of 72 SLE patients were determined by ELISA at baseline. Cardiovascular risk factors and the occurrence of cardiovascular events (CVE: stroke, claudication, angina pectoris, myocardial infarction) were recorded over 6 years. Intima media thickness of the carotid arteries (CIMT) was measured by ultrasound in 42 patients at baseline and at 4 years. Normally distributed log-transformed defensin levels (log-hBD2 and log-HNP) were used for statistical analysis. RESULTS: SLE patients who experienced a CVE had significantly higher log-hBD2 values and a likelihood-ratio for CVE of 2.23 when levels increased above 3.3 log(ng/ml). Using binary logistic regression analysis, log-hBD2 significantly contributed to a model also incorporating the number of traditional cardiovascular risk factors (dyslipidemia, hypertension, positive family history, age, smoking) as explanatory variables for the incidence of cardiovascular events. Moreover, SLE patients with progressive CIMT showed increased log-hBD2 and log-HNP values. Both defensin-levels also showed some correlation to the plaque stadium at baseline (hBD2: r2 0.10; HNP r2 0.12). Neither log-hBD2 nor log HNP were correlated to traditional cardiovascular risk factors. CONCLUSIONS: HNP and especially hBD2 may be indicators of progressive cardiovascular disease in SLE. PMID- 22510488 TI - The cytotoxicity of polycationic iron oxide nanoparticles: common endpoint assays and alternative approaches for improved understanding of cellular response mechanism. AB - BACKGROUND: Iron oxide magnetic nanoparticles (MNP's) have an increasing number of biomedical applications. As such in vitro characterisation is essential to ensure the bio-safety of these particles. Little is known on the cellular interaction or effect on membrane integrity upon exposure to these MNPs. Here we synthesised Fe(3)O(4) and surface coated with poly(ethylenimine) (PEI) and poly(ethylene glycol) (PEG) to achieve particles of varying surface positive charges and used them as model MNP's to evaluate the relative utility and limitations of cellular assays commonly applied for nanotoxicity assessment. An alternative approach, atomic force microscopy (AFM), was explored for the analysis of membrane structure and cell morphology upon interacting with the MNPs. The particles were tested in vitro on human SH-SY5Y, MCF-7 and U937 cell lines for reactive oxygen species (ROS) production and lipid peroxidation (LPO), LDH leakage and their overall cytotoxic effect. These results were compared with AFM topography imaging carried out on fixed cell lines. RESULTS: Successful particle synthesis and coating were characterised using FTIR, PCS, TEM and ICP. The particle size from TEM was 30 nm (-16.9 mV) which increased to 40 nm (+55.6 mV) upon coating with PEI and subsequently 50 nm (+31.2 mV) with PEG coating. Both particles showed excellent stability not only at neutral pH but also in acidic environment of pH 4.6 in the presence of sodium citrate. The higher surface charge MNP-PEI resulted in increased cytotoxic effect and ROS production on all cell lines compared with the MNP-PEI-PEG. In general the effect on the cell membrane integrity was observed only in SH-SY5Y and MCF-7 cells by MNP-PEI determined by LDH leakage and LPO production. AFM topography images showed consistently that both the highly charged MNP-PEI and the less charged MNP-PEI PEG caused cell morphology changes possibly due to membrane disruption and cytoskeleton remodelling. CONCLUSIONS: Our findings indicate that common in vitro cell endpoint assays do not give detailed and complete information on cellular state and it is essential to explore novel approaches and carry out more in-depth studies to elucidate cellular response mechanism to magnetic nanoparticles. PMID- 22510489 TI - Spectral characteristic investigation on complex of Ni (II) with captopril and its analytical application. AB - In this paper, Ni (II) reacting with captopril (CPT) can form complex in alkaline solution and the formed complex has a characteristic absorption peak at 340nm. The absorbance of the Ni-CPT complex increases linearly with the increased concentration of captopril. The study also shows that ammonia has an obvious sensitizing effect on the absorbance. Based on the study, a new method for the determination of captopril is established. Experimental results show that the linear range of this method under optimum condition is 1.0-60mg/L with correlation coefficient, detection limit and precision of 0.9999, 0.31mg/L and 0.87%, respectively. The method used to determine captopril in commercial captopril tablets has a satisfactory result with the recoveries in the range of 99.0-103.6% and the relative standard deviation (RSD) in the range of 0.8-3.7%. We preliminarily study the reaction mechanism and demonstrate that the complex ratio of Ni (II) with captopril is 1:2 and the formation constant is 6.3*10(9). PMID- 22510490 TI - Analysis of vibrational spectra (FT-IR and FT-Raman) and nonlinear optical properties of organic 2-chloro-p-xylene. AB - In this work, the vibrational spectral analysis was carried out by using FT-Raman and FT-IR spectroscopy in the range 100-4000cm(-1) and 400-4000cm(-1) respectively, for the title molecule. The molecular structure, fundamental vibrational frequencies and intensity of the vibrational bands are interpreted with the aid of structure optimizations and normal coordinate force field calculations based on Hartree-Fock (HF) and density functional theory (DFT) method with 6-311++G(d,p) basis set. The complete vibrational assignments of wavenumbers were made on the basis of potential energy distribution (PED). The scaled B3LYP/6-311++G(d,p) results show the best agreement with the experimental values over the other method. The influences due to the substitution of halogen bond and methyl group were investigated. The results of the calculations are applied to simulate the vibrational spectra of the title compound, which show excellent agreement with observed spectra. The absorption energy and oscillator strength are calculated by time-dependent density functional theory (TD-DFT). Besides, frontier molecular orbitals (FMOs), molecular electrostatic potential (MEP), and thermodynamic properties were performed. Mulliken charges of the title molecule were also calculated and interpreted. The dipole moment, linear polarizability and first hyperpolarizability values were also computed. PMID- 22510491 TI - A three generation study with high-lysine transgenic rice in Sprague-Dawley rats. AB - Lysine-rich rice (LR) is a transgenic rice produced by fusion protein expressed genes into the germline of rice seeds. Compositional analysis of LR showed that the absolute concentration of lysine was significantly higher as compared to a near-isogenic non-transgenic rice. Lysine is believed to be the first limiting essential amino acid in rice, it is important to improve lysine content on rice nutritional quality. Here we report the results of a three generation study comparing the outcome in rats fed the transgenic rice to those fed conventional, near-isogenic rice or a control diet. In the study, both clinical performance variables and pathological responses such as body weight, food consumption, reproductive data, hematological parameters, serum chemistry and relative organ weights were examined respectively. It was evident that there were no adverse effects observed in rats that were fed transgenic rice compared with non transgenic rice. There were significant differences in some hematology, serum chemistry parameters and relative organ weights in rats consuming the transgenic rice diet or non-transgenic rice diet compared with the control diet, but no macroscopic or histological adverse effects were observed. So the results from this study demonstrate that LR rice is as safe as near-isogenic non-transgenic rice. PMID- 22510492 TI - Fucoidan extract derived from Undaria pinnatifida inhibits angiogenesis by human umbilical vein endothelial cells. AB - In recent years, anti-angiogenic therapy has become an effective strategy for inhibiting tumor growth. Fucoidan is a class of fucose-enriched sulfated polysaccharides found in brown algae, and it is known to have strong anti-tumor property. Using a human umbilical vein endothelial cells (HUVEC)-based cell culture model, the present study investigated the anti-angiogenic activity of fucoidan extracted from the brown seaweed Undaria pinnatifida. Treatment of HUVECs with various concentrations of fucoidan resulted in significant inhibition of cell proliferation, cell migration, tube formation and vascular network formation. However, significant inhibition of cell proliferation only occurred with longer treatment time (48 h instead of 24h or less). About 40% of cell proliferation and cell migration and 61% of tube formation by HUVECs were inhibited by 400 MUg/ml fucoidan, the maximum concentration tested. These results appeared to suggest that modulation of angiogenesis by fucoidan might not occur through growth inhibition and apoptosis. Ex vivo angiogenesis assay demonstrated that at 100 MUg/ml, fucoidan caused significant reduction in microvessel outgrowth. Western blot and RT-PCR analyses indicated that at 400 MUg/ml, fucoidan significantly reduced the expression of the angiogenesis factor VEGF-A in the suppression of angiogenesis activity. Our results showed that fucoidan isolated from U. pinnatifida may have a new therapeutic potential in the prevention angiogenesis-related diseases. PMID- 22510493 TI - Inhibition of cholinesterase by essential oil from food plant. AB - Inhibition of cholinesterase has attracted much attention recently because of its potential for the treatment of Alzheimer's disease. In this work, the anticholinesterase activities of plant oils were investigated using Ellman's colorimetric method. The results indicate that essential oils obtained from Melissa officinalis leaf and Citrus aurantifolia leaf showed high acetylcholinesterase and butyrylcholinesterase co-inhibitory activities. C. aurantifolia leaf oil revealed in this study has an IC(50) value on acetylcholinesterase and butyrylcholinesterase of 139 +/- 35 and 42 +/- 5 MUg/ml, respectively. GC/MS analysis revealed that the major constituents of C. aurantifolia leaf oil are monoterpenoids including limonene, l-camphor, citronellol, o-cymene and 1,8-cineole. PMID- 22510494 TI - Acclimation increases freezing stress response of Arabidopsis thaliana at proteome level. AB - This study used 2DE to investigate how Arabidopsis thaliana modulates protein levels in response to freezing stress after sub-lethal exposure at -10 degrees C, both in cold-acclimated and in non-acclimated plants. A map was implemented in which 62 spots, corresponding to 44 proteins, were identified. Twenty-two spots were modulated upon treatments, and the corresponding proteins proved to be related to photosynthesis, energy metabolism, and stress response. Proteins demonstrated differences between control and acclimation conditions. Most of the acclimation-responsive proteins were either not further modulated or they were down-modulated by freezing treatment, indicating that the levels reached during acclimation were sufficient to deal with freezing. Anabolic metabolism appeared to be down-regulated in favor of catabolic metabolism. Acclimated plants and plants submitted to freezing after acclimation showed greater reciprocal similarity in protein profiles than either showed when compared both to control plants and to plants frozen without acclimation. The response of non-acclimated plants was aimed at re-modulating photosynthetic apparatus activity, and at increasing the levels of proteins with antioxidant-, molecular chaperone-, or post-transcriptional regulative functions. These changes, even less effective than the acclimation strategy, might allow the injured plastids to minimize the production of non-useful metabolites and might counteract photosynthetic apparatus injuries. PMID- 22510495 TI - Estimating treatment effects from a randomized clinical trial in the presence of a secondary treatment. AB - In randomized clinical trials involving survival time, a challenge that arises frequently, for example, in cancer studies (Manegold, Symanowski, Gatzemeier, Reck, von Pawel, Kortsik, Nackaerts, Lianes and Vogelzang, 2005. Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma. Annals of Oncology 16, 923--927), is that subjects may initiate secondary treatments during the follow-up. The marginal structural Cox model and the method of inverse probability of treatment weighting (IPTW) have been proposed, originally for observational studies, to make causal inference on time dependent treatments. In this paper, we adopt the marginal structural Cox model and propose an inferential method that improves the efficiency of the usual IPTW method by tailoring it to the setting of randomized clinical trials. The improvement in efficiency does not depend on any additional assumptions other than those required by the IPTW method, which is achieved by exploiting the knowledge that the study treatment is independent of baseline covariates due to randomization. The finite-sample performance of the proposed method is demonstrated via simulations and by application to data from a cancer clinical trial. PMID- 22510496 TI - Nb 1-y Fe 2+y thin film growth and characterization. AB - We report on the growth of c-axis oriented thin films of NbFe(2) prepared by pulsed laser deposition. Variation of the deposition conditions results in variation of the composition of the Nb(1-y)Fe(2+y) films in the range from Nb rich to Fe rich films. Films near the stoichiometric composition (y ~ 0) are the most interesting. However, microstructural investigations of these films reveal two kinds of grain, which exhibit different shape, epitaxial relation and chemical composition. The different chemical compositions of opposing doping character result in two magnetic phases confirmed by means of magnetization and Hall measurements. This investigation demonstrates the possibility of NbFe(2) thin film growth and discusses the microstructural inhomogeneities occurring. PMID- 22510497 TI - Molecular-spin dynamics study of electromagnons in multiferroic RMn2O5. AB - We investigate the electromagnon in magnetoferroelectrics RMn(2)O(5) using combined molecular-spin dynamics simulations. We confirm that the origin of the electromagnon modes observed in the optical spectra is due to the exchange striction interaction between the magnons and the phonons, and the dielectric step at the magnetic phase transition is due to the appearance of the electromagnon in the low-temperature phase in these materials. The magnetic anisotropy breaks the rotational symmetry of the magnetic structures and, as a result, the electromagnon splits into three modes in RMn(2)O(5). We find that the electromagnon frequencies are very sensitive to the magnetic wavevector along the a direction q(x). Therefore, the electromagnon frequencies of TmMn(2)O(5) (q(x) ~ 0.467) are expected to be much higher than those of other materials of the family, such as R= Tb, Y, Ho, etc (q(x) ~ 0.48). We further calculate the electromagnons in the magnetic field, and find a new mode appearing in the magnetic field. Although the modes' frequencies change significantly under magnetic field, the total static dielectric constant contributed from the electromagnons does not change much in the magnetic field, suggesting that the colossal magnetodielectric effects in these materials may not be caused by the electromagnons. PMID- 22510498 TI - How statins could be evaluated successfully in clinical trials for Alzheimer's disease? AB - Over the last decade, a large number of experimental observations have suggested a relationship between alterations in cholesterol homeostasis and Alzheimer's disease (AD). Moreover, epidemiological studies have pointed an association between statin treatment and a decrease in the risk of having AD. For these reasons, a large number of clinical trials have been carried out to determine whether the statins can prevent the progression of AD. However, these studies did not provide clear evidence for the therapeutic efficacy in AD. We consider that there are a number of explanations for this failure that may provide guidance for selecting and clinically developing statins with therapeutic efficacy in AD. PMID- 22510499 TI - Clinicopathological significance of SOX4 expression in primary gallbladder carcinoma. AB - AIM: SOX4, as a member of the SRY-related HMG-box (SOX) transcription factor family, has been demonstrated to be involved in tumorigenesis of many human malignancies; however, its role in primary gallbladder carcinoma (PGC) is still largely unknown. The aim of this study was to investigate SOX4 expression in PGC and its prognostic significance. METHODS: From 1997 to 2006, 136 patients underwent resection for PGC. The median follow-up was 12.8 months. Immunostainings for SOX4 were performed on these archival tissues. The correlation of SOX4 expression with clinicopathological features including survival was analyzed. RESULTS: SOX4 was expressed in 75.0% (102/136) of PGC but not in the normal epithelium of the gallbladder. In addition, the over-expression of SOX4 was significantly associated with low histologic grade (P = 0.02), low pathologic T stage (P = 0.02), and early clinical stage (P = 0.03). The levels of SOX4 immunostainings in PGC tissues with positive nodal metastasis were also significantly lower than those without (P = 0.01). Moreover, Kaplan-Meier curves showed that SOX4 over-expression was significantly related to better overall (P = 0.008) and disease-free survival (P = 0.01). Furthermore, multivariate analyses showed that SOX4 expression was an independent risk factor for both overall (P = 0.03, hazard ratio, 3.682) and disease-free survival (P = 0.04, hazard ratio, 2.215). CONCLUSION: Our data indicate for the first time that the over-expression of SOX4 in PGC was significantly correlated with favorable clinicopathologic features and was an independent prognostic factor for better overall and disease free survival in patients. Therefore, SOX4 might be an auxiliary parameter for predicting malignant behavior for PGC. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1534825818694957. PMID- 22510501 TI - Cerebral ganglioneuroblastoma of adult onset: two patients and a review of the literature. AB - Ganglioneuroblastoma is a rare tumor variant of neuroblastoma. Only five cases have been observed in the adult brain, and we report here on two more adult patients with cerebral ganglioneuroblastoma. Additionally, a review was carried out on all 50 published adult cases with ganglioneuroblastoma, located in the adrenal gland (9), mediastinum (8), retroperitoneal area (7), the brain parenchyma (7), or the spinal cord (3). Median age at onset was 39 years, and 52% of patients were female. For extracranial locations, treatment usually consisted of surgery followed by radiotherapy and adjuvant chemotherapy. Of the cases with cerebral involvement only one patient did not receive any treatment. The other six patients underwent surgical resection and radiation therapy, in four cases followed by chemotherapy with temozolomide. The median survival of cerebral ganglioneuroblastomas was 14 months and did not differ from the whole group of ganglioneuroblastomas (12 months). For cerebral ganglioneuroblastoma, the preferred regimen would seem to be neurosurgical removal, followed by chemoradiotherapy including temozolomide. PMID- 22510500 TI - Hepatitis C, porphyria cutanea tarda and liver iron: an update. AB - Porphyria cutanea tarda (PCT) is the most common form of porphyria across the world. Unlike other forms of porphyria, which are inborn errors of metabolism, PCT is usually an acquired liver disease caused by exogenous factors, chief among which are excess alcohol intake, iron overload, chronic hepatitis C, oestrogen therapy and cigarette smoking. The pathogenesis of PCT is complex and varied, but hereditary or acquired factors that lead to hepatic iron loading and increased oxidative stress are of central importance. Iron loading is usually only mild or moderate in degree [less than that associated with full-blown haemochromatosis (HFE)] and is usually acquired and/or mutations in HFE. Among acquired factors are excessive alcohol intake and chronic hepatitis C infection, which, like mutations in HFE, decrease hepcidin production by hepatocytes. The decrease in hepcidin leads to increased iron absorption from the gut. In the liver, iron loading and increased oxidative stress leads to the formation of non-porphyrin inhibitor(s) of uroporphyrinogen decarboxylase and to oxidation of porphyrinogens to porphyrins. The treatment of choice of active PCT is iron reduction by phlebotomy and maintenance of a mildly iron-reduced state without anaemia. Low dose antimalarials (cinchona alkaloids) are also useful as additional therapy or as alternative therapy for active PCT in those without haemochromatosis or chronic hepatitis C. In this review, we provide an update of PCT with special emphasis upon the important role often played by the hepatitis C virus. PMID- 22510502 TI - Expert validation of fit-for-purpose guidelines for designing programmes of assessment. AB - BACKGROUND: An assessment programme, a purposeful mix of assessment activities, is necessary to achieve a complete picture of assessee competence. High quality assessment programmes exist, however, design requirements for such programmes are still unclear. We developed guidelines for design based on an earlier developed framework which identified areas to be covered. A fitness-for-purpose approach defining quality was adopted to develop and validate guidelines. METHODS: First, in a brainstorm, ideas were generated, followed by structured interviews with 9 international assessment experts. Then, guidelines were fine-tuned through analysis of the interviews. Finally, validation was based on expert consensus via member checking. RESULTS: In total 72 guidelines were developed and in this paper the most salient guidelines are discussed. The guidelines are related and grouped per layer of the framework. Some guidelines were so generic that these are applicable in any design consideration. These are: the principle of proportionality, rationales should underpin each decisions, and requirement of expertise. Logically, many guidelines focus on practical aspects of assessment. Some guidelines were found to be clear and concrete, others were less straightforward and were phrased more as issues for contemplation. CONCLUSIONS: The set of guidelines is comprehensive and not bound to a specific context or educational approach. From the fitness-for-purpose principle, guidelines are eclectic, requiring expertise judgement to use them appropriately in different contexts. Further validation studies to test practicality are required. PMID- 22510504 TI - [Expressions and significance of TIMP-3 and mtp53 in non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Tissue inhibitor of metalloproteinase-3 (TIMP-3) can regulate tumor infiltration and metastasis through multiple channels and is likely associated with mutant-type p53 (mtp53). This study detected the expressions of TIMP-3 and mtp53 in non-small cell lung cancer (NSCLC) and lymph node metastasis using tissue microarray and evaluated their significance. METHODS: TIMP-3 and mtp53 expressions were detected in 288 cases of NSCLC (NSCLC group), 106 cases of metastatic carcinoma in lymph nodes (metastasis group), and 24 cases of benign lesions in the bronchial mucosa epithelium (control group) by immunohistochemical staining (LSAB and Elivision). RESULTS: The expression of TIMP-3 in the NSCLC and metastasis groups was lower than that in the control group (P<0.001), but the reverse was true for the expression of mtp53 (P<0.001). TIMP-3 and mtp53 expressions differed between NSCLC with (P=0.015) and without (P=0.030) lymph node metastasis. TIMP-3 expression correlated with NSCLC grade (P=0.030), whereas mtp53 expression correlated with TNM stage (P=0.016) and NSCLC histological type (P=0.004). Moreover, the expressions of TIMP-3 and mtp53 were negative in NSCLC cases (P=0.008) and correlated with patient survival (P=0.011 and P=0.003, respectively). CONCLUSIONS: Low expression of TIMP-3 and high expression of mtp53 in NSCLC can promote tumor metastasis and inhibit each other. TIMP-3 and mtp53 are promising targets for studying the metastatic mechanism of NSCLC. PMID- 22510503 TI - [Preliminary results of metabolite in serum and urine of lung cancer patients detected by metabolomics]. AB - BACKGROUND AND OBJECTIVE: Lung cancer is one of the most common cancers worldwide. Thus far, good tumor markers for diagnosing this disease have not been found. Therefore, the discovery of novel biomarkers through the application of new methods has become a hotspot in lung cancer research. The aim of this study is to analyze low-molecular-weight metabolites in the serum and urine samples of lung cancer patients and patients with other lung diseases through metabolomics and to explore potential tumor markers further. METHODS: Both serum and urine samples from 19 lung cancer patients and 15 patients with other lung diseases were subjected to metabolomic analysis using gas chromatography mass spectrometry. Orthogonal to partial least squares discriminant analysis was performed for modeling. Two sample t-test was used to identify differences in metabolite concentrations. RESULTS: A total of 57 metabolites were found in the serum, and 38 metabolites were found in the urine. Multivariate statistical analysis yielded a significant distinction in the metabolic profiles between lung cancer patients and patients with other lung diseases. The t-test results indicated a total of 13 metabolites in the serum and 7 metabolites in the urine with statistically significant differences. CONCLUSIONS: Metabolomics is useful in discriminating between lung cancer and other lung diseases. As a novel approach, it has potential in the diagnosis of lung cancer at molecular level. PMID- 22510505 TI - [A randomized trial of liposomal paclitaxel plus cisplatin as first-line therapy for advanced non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Paclitaxel plus cisplatin (TP) is used as the standard regimen for patients with advanced non-small cell lung cancer (NSCLC). In this study, we compared the response rate (RR), overall survival (OS), and toxicity of the combined chemotherapy regimen of liposomal paclitaxel plus cisplatin (LP) with those of TP as first-line treatments for advanced NSCLC. METHODS: A total of 100 patients were randomly selected to be treated with liposomal paclitaxel or paclitaxel at a dose of 150 mg/m(2) on day 1 plus cisplatin at a dose of 75 mg/m(2) on days 1 and 2 per cycle every 21 days. RESULTS: All 100 patients were eligible. The median progression free survival was 5.1 months vs 4.2 months, the median OS was 9.0 months vs 9.3 months, and RR was 26% vs 24% in the LP and TP arms, respectively. No significant difference was observed (P=0.110, 0.342 and 0.890, respectively). There was no significant difference between grades 3 and 4 toxicity of the arms (P>0.05). Peripheral neuritis observed in the LP arm was significantly lower than that in the TP arm (8% vs 28%), and the difference was statistically significant (P=0.030). CONCLUSIONS: The effects of LP and TP as first-line therapies for NSCLC are similar. However, peripheral neuritis in the LP arm is significantly lower than in the TP arm. PMID- 22510506 TI - [Study on the effect of Feiji Decoction for soothing the liver combined with psychotherapy on the quality of life for primary lung cancer patients]. AB - BACKGROUND AND OBJECTIVE: Lung cancer is the most common type among all malignant tumors, bringing huge pain and mood disorders to patients suffering from it. This study aims to evaluate the effect of the Feiji Decoction for soothing the liver combined with psychotherapy for depression and anxiety on patients with primary lung cancer. It also aims to further explore the relationship between depression and anxiety. METHODS: A total of 118 patients with primary non-small cell lung cancer were randomly divided into two groups. The combined therapy group consisted of 57 patients who were treated with Feiji Decoction for soothing the liver and psychotherapy combined with chemotherapy. The control group consisted of 61 patients who were treated with chemotherapy only. Both groups were observed for two treatment courses. The Zung Self-reported Depression Scales (SDS) and Zung Self-reported Anxiety Scales (SAS) were used to assess the patients' psychology status in both groups before and after treatment scales. RESULTS: After treatment, the depression and anxiety scores of the therapy group remarkably decreased compared with scores before treatment, indicating a statistical significance (P<0.01). In comparison, after treatment, the depression and anxiety scores of the control group significanfly increased compared with scores before treatment, indicating a statistical significance (P<0.01) as well. The depression and anxiety scores of the therapy group significanfly decreased compared with scores of the control group, showing statistical significance (P<0.01). Thus, depression and anxiety score has a close co-relationship, showing significant positive correlation (P<0.01). CONCLUSIONS: Feiji Decoction for soothing the liver combined with psychotherapy can alleviate depression and anxiety in patients with primary lung cancer. This therapy has good clinical therapeutic effect. PMID- 22510507 TI - [The evaluation of pneumonectomy and bronchoplasty lobectomy in the treatment of non-small cell lung cancer: a report of 64 cases]. AB - BACKGROUND AND OBJECTIVE: Pneumonectomy was the initial successful surgery to treat lung cancer, but there has been being a lot of controversy since its inception. The aim of this study is to evaluate its potential role in the treatment of lung cancer through analyzing the survival for 64 cases underwent pneumonectomy or bronchoplasty lobectomy out of 804 cases underwent lung resection. METHODS: Eight hundred and four cases of lung cancer underwent pulmonary surgery. We retrospectively reviewed the clinical data, especially foucused on the survival of 64 pneumonectomies or bronchoplasty lobectomies. RESULTS: Of the 64 patients, 25 underwent pneumonectomy (6 right, 19 left) due to involvement of ipsilateral pulmonary artery trunk. Owning to involving ipsilateral main bronchus with the distance of tumor from carina <2 cm, 4 pneumonectomies, 19 right upper bronchoplasty lobectomies, 1 left upper sleeve lobectomy and 1 left lower sleeve lobectomy were performed. Due to the ipsilateral main bronchus involvement with the distance of tumor from carina >=2 cm, 13 cases underwent main bronchus bronchoplasty. One performed right sleeve pneumonectomy because of carina involvement. Overall 1-, 3- and 5-year survival rates of 64 pneumonectomies or bronchoplasty lobectomies were 93.6%, 69.0% and 45.1%, respectively, and that of 489 standard lobectomies done by the same surgery team in the same period were 92.5%, 77.3% and 56.9%, respectively. There was no significant difference in 5-year cumulative survival rates between the two groups (P=0.226). CONCLUSIONS: Although standard lobectomy remains the main type of surgery, pneumonectomy or bronchoplasty lobectomy is still one of option for the highly selective patients combining the support of induction chemotherapy. PMID- 22510508 TI - [The diagnosis and surgical treatment for solitary pulmonary metastases: a report of 156 cases]. AB - BACKGROUND AND OBJECTIVE: In recent years, it has been proven that surgical treatment for solitary pulmonary metastases has achieved satisfactory results. Consequently, the study aims to investigate the diagnosis, indications for surgery, operative techniques, and prognostic factors of the surgical resection for solitary pulmonary metastases, and to improve the survival rate of patients with pulmonary metastases. METHODS: The medical records of 156 patients with surgical procedures at our institution were retrospectively reviewed. RESULTS: The primary tumors were verified as cancer in 134 cases, sarcoma in 21, and 1 contained unknown tissue. There was no perioperative mortality. A total of 153 patients returned for follow up. Follow-up time was 1 yr to 10 yr. The 5-year survival rates were 31.2%. The median survival time was 35.8 months. Systematic lymph node dissection was performed in 113 patients. The 5-year survival rates were 12.5% for lymph node-positive patients and 37.3% for lymph node-negative patients. The patients who underwent lobectomies had better survival rates, with a 5-year survival rate of 38.5%. CONCLUSIONS: Surgery is recommended for patients with solitary pulmonary metastasis if they fulfill the surgical indications and favorable outcomes can be achieved. VATS can be chosen for the patients. Hilar and mediastinal lymph node involvement and the surgical approach are potentially important prognostic factors. PMID- 22510509 TI - [Advances in the research of glycolysis and lung cancer]. PMID- 22510510 TI - [Advances of DNA methylation in early diagnosis of lung cancer]. AB - Lung cancer is the leading cause of cancer-related death and thus a major health problem nowadays. No early diagnostic method is ideal up to now. Changes in DNA methylation occur on early stage of lung cancer. Detection of DNA methylation is expected to be an important method in early diagosis of lung cancer. PMID- 22510511 TI - [The conceptual oligometastatic non-small cell lung cancer and therapeutic strategies]. AB - Non-small cell lung cancer (NSCLC) ranks among the most prevalent malignancies and is the major cause of cancer-related deaths worldwide. Nearly 20%-50% will accompany by metastatic disease and the most common extrapulmonary sites of distant metastases are the brain, bone, liver and adrenal gland. The oligometastatic state is a biologically mild tumor stage and a intermediate state in which spread may be limited to specific organs and metastases might be present in limited numbers. Oligometastases are thought to arise from micrometastases, which have been dormant for a period of time. Local control may be an crucial component of a curative therapeutic strategy in the following four clinical schemes: to prohibit metastases; to cure occult metastatic disease; to remedy oligometastases; and to deracinate any residual lesion after systemic therapy. This review aims to outline the concept of the oligometastatic NSCLC and its strategies of treatment. PMID- 22510512 TI - [One case of multiple inflammatory pseudotumor in both lungs]. AB - Inflammatory pseudotumor was a kind of rare benign tumor of the lung, whose incidence was only about 0.7% in all kinds of tumors of the lung. Multiple inflammatory pseudotumor in both lungs were rare, which were often misdiagnosed to metastatic tumor or disseminated pulmonary tuberculosis. The literature reports were scarce too. This report introduces one case of multiple inflammatory pseudotumor in both lungs that we met in clinical works, and discusses the diagnosis and treatment of it. PMID- 22510513 TI - [A case report of skeletal muscle metastasis in left arm and beck from lung adenocarcinoma]. PMID- 22510514 TI - Early disease activity suppression and younger age predict excellent outcome of recent-onset rheumatoid arthritis patients treated with conventional disease modifying anti-rheumatic drugs. AB - OBJECTIVES: Sustained remission (SR) is the target of treatment offered to patients with rheumatoid arthritis (RA). The objective of the present paper is to describe predictors of favourable outcomes in a cohort of early RA patients. METHODS: Data from 89 patients with 3 years of consecutive assessments and traditional treatment were analysed. SR was defined as >= 6 consecutive months with 2011 ACR/EULAR remission criteria. Excellent outcome (EO) was defined according to patient's perception. Descriptive statistics, logistic regression models and Cox regression were used. RESULTS: At baseline, patients were predominantly females (n=78), had rheumatoid factor (n=70) and (mean +/- SD) age of 38.8 +/- 13.6 years. After (mean +/- SD) 37.1 +/- 2.5 months, 75 patients achieved >= 1 SR state and 35 an EO. The former had lower disease activity, disability and comorbidity and better functional status at baseline than their counterparts (p <= 0.05); they also accumulated lesser disability (p <= 0.03). Lower C-reactive protein and disease activity and lesser comorbidity predict SR (p <= 0.04). Patients with EO were younger, better educated, had lower disease activity, better functional status and lesser comorbidity at baseline than their counterparts (p <= 0.05). They achieved a first sustained remission state (p <= 0.001) sooner and accumulated lesser disability and incident erosive disease (p <= 0.002). Younger age and lower disease activity were prognosticators of EO (p <= 0.02). When age, baseline disease activity and time to first SR were investigated as predictors of EO, younger age (HR:0.95, 95% CI: 0.91-0.98, p=0.003) and earlier SR (HR:0.49, 95% CI: 0.39-0.61, p <= 0.001) were relevant. CONCLUSIONS: Younger patients with lower disease activity achieved earlier SR which, in addition to age, was predictor of EO. PMID- 22510515 TI - Glia maturation factor gamma regulates the migration and adherence of human T lymphocytes. AB - BACKGROUND: Lymphocyte migration and chemotaxis are essential for effective immune surveillance. A critical aspect of migration is cell polarization and the extension of pseudopodia in the direction of movement. However, our knowledge of the underlying molecular mechanisms responsible for these events is incomplete. Proteomic analysis of the isolated leading edges of CXCL12 stimulated human T cell lines was used to identify glia maturation factor gamma (GMFG) as a component of the pseudopodia. This protein is predominantly expressed in hematopoietic cells and it has been shown to regulate cytoskeletal branching. The present studies were undertaken to examine the role of GMFG in lymphocyte migration. RESULTS: Microscopic analysis of migrating T-cells demonstrated that GMFG was distributed along the axis of movement with enrichment in the leading edge and behind the nucleus of these cells. Inhibition of GMFG expression in T cell lines and IL-2 dependent human peripheral blood T cells with shRNAmir reduced cellular basal and chemokine induced migration responses. The failure of the cells with reduced GMFG to migrate was associated with an apparent inability to detach from the substrates that they were moving on. It was also noted that these cells had an increased adherence to extracellular matrix proteins such as fibronectin. These changes in adherence were associated with altered patterns of beta1 integrin expression and increased levels of activated integrins as detected with the activation specific antibody HUTS4. GMFG loss was also shown to increase the expression of the beta2 integrin LFA-1 and to increase the adhesion of these cells to ICAM-1. CONCLUSIONS: The present studies demonstrate that GMFG is a component of human T cell pseudopodia required for migration. The reduction in migration and increased adherence properties associated with inhibition of GMFG expression suggest that GMFG activity influences the regulation of integrin mediated adhesion. PMID- 22510517 TI - Gender differences in care home admission risk: partner's age explains the higher risk for women. AB - BACKGROUND: older women have a higher risk of care home admission than men, this difference remains even after accounting for variations in health. A likely reason for this is the difference in social support provided by spouses. Older men may provide less care for their wives than women do for their husbands. OBJECTIVES: this study assessed two competing explanations for this. First, older men are less willing to undertake traditionally feminine caring roles; secondly, older men are less physically able to provide care. DESIGN: the Northern Ireland Longitudinal Study (NILS), a representative (c28%) sample of the Northern Ireland population. FINDINGS: a total of 20,830 couples were followed over 6 years, with 415 care home admissions among NILS cohort members. Women had a higher admission risk after controlling for cohort members' age and health; however, there was no gender difference after adjusting for partner's age. CONCLUSION: these results suggest that advanced age and physical frailty explain why men provide less care for their partners than women do; rather than being unwilling to undertake a caring role. The narrowing gap in life expectancy between men and women may have an effect on the future demand for formal care. PMID- 22510516 TI - Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer. AB - INTRODUCTION: Although human epidermal growth factor receptor 2 (HER2) positive or estrogen receptor (ER) positive breast cancers are treated with clinically validated anti-HER2 or anti-estrogen therapies, intrinsic and acquired resistance to these therapies appears in a substantial proportion of breast cancer patients and new therapies are needed. Identification of additional molecular factors, especially those characterized by aggressive behavior and poor prognosis, could prioritize interventional opportunities to improve the diagnosis and treatment of breast cancer. METHODS: We compiled a collection of 4,010 breast tumor gene expression data derived from 23 datasets that have been posted on the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. We performed a genome-scale survival analysis using Cox-regression survival analyses, and validated using Kaplan-Meier Estimates survival and Cox Proportional-Hazards Regression survival analyses. We conducted a genome-scale analysis of chromosome alteration using 481 breast cancer samples obtained from The Cancer Genome Atlas (TCGA), from which combined expression and copy number data were available. We assessed the correlation between somatic copy number alterations and gene expression using analysis of variance (ANOVA). RESULTS: Increased expression of each of the heat shock protein (HSP) 90 isoforms, as well as HSP transcriptional factor 1 (HSF1), was correlated with poor prognosis in different subtypes of breast cancer. High-level expression of HSP90AA1 and HSP90AB1, two cytoplasmic HSP90 isoforms, was driven by chromosome coding region amplifications and were independent factors that led to death from breast cancer among patients with triple-negative (TNBC) and HER2-/ER+ subtypes, respectively. Furthermore, amplification of HSF1 was correlated with higher HSP90AA1 and HSP90AB1 mRNA expression among the breast cancer cells without amplifications of these two genes. A collection of HSP90AA1, HSP90AB1 and HSF1 amplifications defined a subpopulation of breast cancer with up-regulated HSP90 gene expression, and up-regulated HSP90 expression independently elevated the risk of recurrence of TNBC and poor prognosis of HER2-/ER+ breast cancer. CONCLUSIONS: Up-regulated HSP90 mRNA expression represents a confluence of genomic vulnerability that renders HER2 negative breast cancers more aggressive, resulting in poor prognosis. Targeting breast cancer with up-regulated HSP90 may potentially improve the effectiveness of clinical intervention in this disease. PMID- 22510518 TI - Down-regulation of myosin light chain kinase expression in vascular smooth muscle cells accelerates cell proliferation: requirement of its actin-binding domain for reversion to normal rates. AB - Myosin light-chain kinase (MLCK) is a multi-domain protein with kinase and actin binding domains, among others. Deficiency of MLCK expression in GBaSM-4 vascular smooth muscle cells enhanced cell proliferation rate and shortened cell doubling time. Transient transfection of the MLCK-deficient cells with cDNA constructs of either wild-type MLCK or its mutant lacking the kinase activity reverted the cell proliferation rate to that of wild-type cells, whereas that of MLCK lacking the actin-binding domain maintained cell proliferation at an elevated rate similar to the MLCK-deficient cells. Thus, the actin-binding domain of MLCK seems to play a role in regulating cell proliferation. PMID- 22510519 TI - N-acetyl-L-cysteine inhibits marble-burying behavior in mice. AB - In the present study, we examined the effect of N-acetyl-L-cysteine (NAC), a glutamate-modulating agent, on marble-burying behavior in mice. Fluvoxamine (30 mg/kg, p.o.) and mirtazapine (3 mg/kg, i.p.) significantly inhibited marble burying behavior without affecting locomotor activity. Similarity, NAC (150 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity. On the other hand, the antioxidant alpha-tocopherol (10, 30, and 100 mg/kg, p.o.) had no effect on the marble-burying behavior. These results suggest that the glutamatergic system is involved in the marble-burying behavior, and NAC may be useful for treatment of OCD. PMID- 22510521 TI - Effect of spinally administered simvastatin on the formalin-induced nociceptive response in mice. AB - Clinical and experimental observations indicated that 3-hydroxy-3-methylglutaryl CoA reductase inhibitor statins have pleiotropic effects. The present study determined the antinociceptive property of centrally administered simvastatin on the formalin-induced nociception in the mouse. Intrathecal administration of simvastatin at doses of 0.5 - 50 nmol dose-dependently attenuated the second, but not the first, phase of the formalin-induced nociception, which was partially reversed by mevalonate (5 umol). Intracerebroventricular injection of simvastatin (50 nmol) did not affect the formalin-induced nociception. These results suggest that simvastatin-induced antinociception is mediated by attenuation of the sensitization of spinal nociceptive transmission. PMID- 22510520 TI - Effect of selective serotonin reuptake inhibitors via 5-HT1A receptors on L-DOPA induced rotational behavior in a hemiparkinsonian rat model. AB - L-Dihydroxyphenylalanine (L-DOPA) is considered the gold standard for the treatment of Parkinson's disease (PD). However, long-term administration of L DOPA can induce abnormal side effects. On the other hand, selective serotonin reuptake inhibitors (SSRIs) including fluoxetine have gained tremendous popularity in the treatment of depression in PD. SSRIs are thought to influence motor function in PD via pharmacological modification of interactions between serotonergic and dopaminergic networks, which are complex and not yet fully understand. In this study, intranigral injection of 6-hydroxydopamine (6-OHDA) in rats caused a significant loss of tyrosine hydroxylase immunoreactivity in the striatum and substantia nigra. However, tryptophan hydroxylase immunoreactivity of the striatum and raphe nucleus was unaffected by 6-OHDA. Immunohistochemical analysis reveal that the serotonergic system was unaffected by the injection of 6 OHDA. We demonstrated also that pre-treatment with fluoxetine significantly suppressed L-DOPA-induced rotational behavior. Additionally, fluoxetine suppressed L-DOPA-induced ERK1/2 and histone H3 phosphorylation. These effects of fluoxetine were abolished by pre-treatment with WAY 100135, a 5-HT(1A) antagonist. These results suggest that fluoxetine may influence motor function in PD via pharmacological modification of interactions between serotonergic and dopaminergic neuronal networks. PMID- 22510522 TI - Delayed mitochondrial membrane potential disruption by ATP in cultured rat hippocampal neurons exposed to N-methyl-D-aspartate. AB - Necrotic damage leads to a massive leakage from injured cells of different intracellular constituents such as glutamate (Glu) and ATP, which are believed to play a role in the neuronal survival in the brain. In this study, we evaluated pharmacological properties of ATP, which is shown to be an endogenous inhibitor of N-methyl-D-aspartate (NMDA) receptors, on the neurotoxicity relevant to mitochondrial membrane potential disruption in cultured rat hippocampal neurons. Exposure to Glu or NMDA significantly inhibited cellular viability determined 24 and 48 h later, while simultaneous addition of 1 mM ATP significantly ameliorated the decreased viability in neurons exposed to Glu and NMDA, but not in those exposed to other cytotoxins. Both Glu and NMDA markedly increased intracellular free Ca(2+) levels in a manner sensitive to blockade by the exposure to ATP, but not by that to adenosine. Exposure to ATP significantly delayed the rate of mitochondrial membrane potential disruption induced by Glu and NMDA. These results suggest that extracellular ATP would play a role as an endogenous antagonist endowed to protect rat hippocampal neurons from the excitotoxicity mediated by NMDA receptors in association with the delayed mitochondrial membrane potential disruption after the liberation from adjacent cells under necrotic death. PMID- 22510524 TI - Molecular cloning and characterization of the full-length cDNA encoding the porcine CD28. AB - CD28 is one of the most important co-stimulatory molecules required for effective activation of resting T cells in human and mouse. However, there are few studies on porcine CD28 (pCD28) until now. In the present study, we cloned and characterized the full-length cDNA of CD28 from the miniature pig. The open reading frame (ORF) sequence of pCD28 gene was organized into four exons, which were predicted to be in correspondence with the signal sequence, immunoglobulin variable-like (IgV) domain, transmembrane domain and cytoplasmic tail, respectively. We also identified the putative ligand binding site of CD28 within the IgV domain and the consensus motifs (one "YMNM" motif and two proline-rich motifs) within the cytoplasmic domain. Porcine CD28 was confirmed to be expressed on the cell membrane as indicated by indirect immunofluorescence assay (IFA). The putative promoter region of pCD28 was also cloned by the modified nested PCR and the cloned region could successfully drive the expression of yellow fluorescent protein (YFP) expression in porcine peripheral blood mononuclear cells (PBMCs). The present study is the first report of cloning and characterization of CD28 in porcine. Our work provided fundamental information for further researches on the structure and function of CD28 in porcine. PMID- 22510523 TI - Tubulobulbar complex: cytoskeletal remodeling to release spermatozoa. AB - Tubulobulbar complexes (TBCs) are actin-based structures that help establish close contact between Sertoli-Sertoli cells or Sertoli-mature germ cells (spermatids) in the seminiferous tubules of the testes. They are actin-rich push through devices that eliminate excess spermatid cytoplasm and prepare mature spermatids for release into the tubular lumen. Just prior to spermiation, the elongated spermatid interacts with the Sertoli cell via an extensive structure comprising various adhesion molecules called the apical ectoplasmic specialization which is partially replaced by the apical TBC, on the concave surface of the spermatid head. The sperm release process involves extensive restructuring, namely the disassembly and reassembly of junctions at the Sertoli spermatid interface in the seminiferous epithelium. Based on the presence of different classes of molecules in the TBCs or the defects observed in the absence of TBCs, the main functions attributed to TBCs are elimination of excess spermatid cytoplasm, endocytosis and recycling of junctional molecules, shaping of the spermatid acrosome, and forming transient anchoring devices for mature spermatids before they are released. This review summarizes the recent findings that focus on the role of TBCs in cell cytoskeleton restructuring during sperm release in the testes and the molecular mechanism involved. PMID- 22510525 TI - Evolution of structural and magnetic properties with varying oxygen content in low-bandwidth manganite Pr0.9Ca0.1MnO3 thin films. AB - The effects of ex situ vacuum and oxygen annealing treatments on thin films of the low-bandwidth compound Pr(1-x)Ca(x)MnO(3) (PCMO) are investigated. Structural and magnetic measurements reveal that increased ferromagnetism can be achieved by oxygen annealing treatment, which is linked to the increased Mn(4+) ion content, as observed from x-ray photoelectron spectroscopy (XPS) measurements, as well as relaxation of the substrate-induced tensile strain of the PCMO unit cell. The increased number of Mn(4+) ions and partial release of strain lead to stronger double-exchange interaction in the system. Vacuum annealing increases the ferromagnetic (FM) interaction as well; however, the increased FM ordering is not directly related to the improved double-exchange interaction, as XPS measurement reveals an indication of a slight increase in Mn(3+) ions in this case. Trapping of carriers in the oxygen vacancies and formation of magnetic polarons have been suggested as the causes of the increase in ferromagnetic ordering, and this is also supported by the large coercivity and longer spin memory in the vacuum annealed PCMO. PMID- 22510526 TI - 19q13 microdeletion syndrome: Further refining the critical region. AB - The 19q13 microdeletion syndrome is a recently identified disorder of which very few cases have been reported so far. Growth deficiency, microcephaly, ectodermal anomalies and intellectual disability are the major features reported in all the described cases. The critical region has been estimated to span 750 Kb. We report an Italian patient carrying a de novo 1.37 Mb deletion in chromosome 19q13, who presented all the cardinal features of the syndrome, and multiple pituitary hormone deficiency. Our findings might contribute to further refine the critical region to 460 Kb and restrict the list of candidate genes. PMID- 22510527 TI - Childhood apraxia of speech without intellectual deficit in a patient with cri du chat syndrome. AB - We report an 11-year-old girl for whom the diagnosis of cri du chat syndrome (CdCS) was made during a genetic investigation of childhood apraxia of speech. The patient presented with the classic chromosome 5 short arm deletion found in CdCS. The microdeletion, characterised using aCGH (array Comparative Genomic Hybridisation), was 12.85 Mb, overlapping the 5p15.2 and 5p15.3 critical regions. CdCS is typically associated with severe mental retardation while this patient had normal intellectual performance, confirmed by normal results from categorisation tasks. This mild phenotype was assessed using a comprehensive cognitive battery. Language evaluation showed normal receptive vocabulary scores, in contrast with obvious oro-facial dyspraxia. Disabled fine motor skills were confirmed as well as weak visuo-spatial reasoning abilities. In conclusion, fine cognitive assessment may be worthwhile for patients with CdCS since good intellectual functioning may be masked by severe speech and gestural dyspraxia, thus requiring specific teaching and rehabilitation strategies. PMID- 22510528 TI - The hermunculus: what is known about the representation of the female body in the brain? AB - The representation of the body in the brain, the homunculus, was posited by Wilder Penfield based on his studies of patients with intractable epilepsy. While he mapped both male and female patients, Penfield reports little about the females. The now iconic illustration of the map is clearly male with testicles, penis, and no breasts. In order to bring attention to this omission and to stimulate studies of female somatosensory cortex (SS), we discuss what is known about the map of the female body in the brain, including Penfield's findings in his female patients and subsequent work by others exploring the human female SS. We reveal that there is much we do not know about how the entire female body is represented in the brain or how it might change with different reproductive life stages, hormones, and experiences. Understanding what is and is not currently known about the female SS is a first step toward fully understanding neurological and physiological sex differences, as well as producing better-informed treatments for pain conditions related to mastectomy, hysterectomy, vulvodynia, and fibromyalgia. We suggest that the time is ripe for a full mapping of the female brain with the production of a hermunculus. PMID- 22510529 TI - An online neural substrate for sense of agency. AB - "Sense of agency" refers to the feeling of controlling an external event through one's own action. On one influential view, sense of agency is inferred after an action, by "retrospectively" comparing actual effects of actions against their intended effects. In contrast, a "prospective" component of agency, generated during action selection, and in advance of knowing the actual effect, has received less attention. Here, we used functional magnetic resonance imaging to investigate prospective contributions of action selection processes to sense of agency. To do so, we dissociated action selection processes from action-outcome matching, by subliminally priming responses to a target. We found that participants experienced greater control over action effects when the action was compatibly versus incompatibly primed. Thus, compatible primes facilitated action selection processing, in turn boosting sense of agency over a subsequent effect. This prospective contribution of action selection processes to sense of agency was accounted for by exchange of signals across a prefrontal-parietal network. Specifically, we found that the angular gyrus (AG) monitors signals relating to action selection in dorsolateral prefrontal cortex, to prospectively inform subjective judgments of control over action outcomes. Online monitoring of these signals by AG might provide the subject with a subjective marker of volition, prior to action itself. PMID- 22510530 TI - Independent effects of attentional gain control and competitive interactions on visual stimulus processing. AB - Attention filters behaviorally relevant stimuli from the constant stream of sensory information comprising our environment. Research into underlying neural mechanisms in humans suggests that visual attention biases mutual suppression between stimuli resulting from competition for limited processing resources. As a consequence, processing of an attended stimulus is facilitated. This account makes 2 assumptions: 1) An attended stimulus is released from mutual suppression with competing stimuli and 2) an attended stimulus experiences greater gain in the presence of competing stimuli than when it is presented alone. Here, we tested these assumptions by recording frequency-tagged potentials elicited in early visual cortex that index stimulus-specific processing. We contrasted the processing of a given stimulus when its location was attended or unattended and in the presence or the absence of a nearby competing stimulus. At variance with previous findings, competition similarly suppressed processing of attended and unattended stimuli. Moreover, the magnitude of attentional gain was comparable in the presence or the absence of competing stimuli. We conclude that visuospatial selective attention does not directly modulate mutual suppression between stimuli but instead acts as a signal gain, which biases processing toward attended stimuli independent of competition. PMID- 22510531 TI - Gray matter changes following limb amputation with high and low intensities of phantom limb pain. AB - Limb amputation and chronic phantom limb pain (PLP) are both associated with neural alterations at all levels of the neuraxis. We investigated gray matter volume of 21 upper limb amputees and 14 healthy control subjects. Results demonstrate that amputation is associated with reduced gray matter in areas in the motor cortex representing the amputated limb. Additionally, patients show an increase in gray matter in brain regions that belong to the dorsal and ventral visual stream. We subdivided the patient group into patients with medium to high PLP (HPLP; N = 11) and those with slight PLP (SPLP; N = 10). HPLP patients showed reduced gray matter in brain areas involved in pain processing. SPLP patients showed a significant gray matter increase in regions of the visual stream. Results indicate that all patients may have an enhanced need for visual control to compensate the lack of sensory feedback of the missing limb. As we found these alterations primarily in the SPLP patient group, successful compensation may have an impact on PLP development. Therefore, we hypothesize that visual adaptation mechanisms may compensate for the lack of sensorimotor feedback and may therefore function as a protection mechanism against high PLP development. PMID- 22510532 TI - Age-related differences in prefrontal cortex activity during retrieval monitoring: testing the compensation and dysfunction accounts. AB - Current theories of cognitive aging emphasize that the prefrontal cortex might not only be a major source of dysfunction but also a source of compensation. We evaluated neural activity associated with retrieval monitoring--or the selection and evaluation of recollected information during memory retrieval--for evidence of dysfunction or compensation. Younger and older adults studied pictures and words and were subsequently given criterial recollection tests during event related functional magnetic resonance imaging. Although memory accuracy was greater on the picture test than the word test in both groups, activity in right dorsolateral prefrontal cortex (DLPFC) was associated with greater retrieval monitoring demands (word test > picture test) only in younger adults. Similarly, DLPFC activity was consistently associated with greater item difficulty (studied > nonstudied) only in younger adults. Older adults instead exhibited high levels of DLPFC activity for all of these conditions, and activity was greater than younger adults even when test performance was naturally matched across the groups (picture test). Correlations also differed between DLPFC activity and test performance across the groups. Collectively, these findings are more consistent with accounts of DLPFC dysfunction than compensation, suggesting that aging disrupts the otherwise beneficial coupling between DLPFC recruitment and retrieval monitoring demands. PMID- 22510533 TI - NMDA-dependent switch of proBDNF actions on developing GABAergic synapses. AB - The brain-derived neurotrophic factor (BDNF) has emerged as an important messenger for activity-dependent development of neuronal network. Recent findings have suggested that a significant proportion of BDNF can be secreted as a precursor (proBDNF) and cleaved by extracellular proteases to yield the mature form. While the actions of proBDNF on maturation and plasticity of excitatory synapses have been studied, the effect of the precursor on developing GABAergic synapses remains largely unknown. Here, we show that regulated secretion of proBDNF exerts a bidirectional control of GABAergic synaptic activity with NMDA receptors driving the polarity of the plasticity. When NMDA receptors are activated during ongoing synaptic activity, regulated Ca(2+)-dependent secretion of proBDNF signals via p75(NTR) to depress GABAergic synaptic activity, while in the absence of NMDA receptors activation, secreted proBDNF induces a p75(NTR) dependent potentiation of GABAergic synaptic activity. These results revealed a new function for proBDNF-p75(NTR) signaling in synaptic plasticity and a novel mechanism by which synaptic activity can modulate the development of GABAergic synaptic connections. PMID- 22510535 TI - Genes encoding heterotrimeric G-proteins are associated with gray matter volume variations in the medial frontal cortex. AB - G-protein-coupled signal transduction mediates most cellular responses to hormones and neurotransmitters; this signaling system transduces a large variety of extracellular stimuli into neurons and is the most widely used mechanism for cell communication at the synaptic level. The heterotrimeric G-proteins have been well established as key regulators of neuronal growth, differentiation, and function. More recently, the heterotrimeric G-protein genes group was associated with general cognitive ability. Although heterotrimeric G-proteins are linked to both cognitive ability and neuron signaling, it is unknown whether heterotrimeric G-proteins are also important for brain structure. We tested for association between local cerebral gray matter volume and the heterotrimeric G-protein genes group in 294 subjects; a replication analysis was performed in an independent sample of 238 subjects. Voxel-based morphometry revealed a strong replicated association between 2 genes encoding heterotrimeric G-proteins with specific local increase in medial frontal cortex volume, an area known to be involved in cognitive control and negative affect. This finding suggests that heterotrimeric G-proteins might modulate medial frontal cortex gray matter volume. The differences in gray matter volume due to variations in genes encoding G-proteins may be explained by the role of G-proteins in prenatal and postnatal neocortex development. PMID- 22510534 TI - Different neural mechanisms within occipitotemporal cortex underlie repetition suppression across same and different-size faces. AB - Repetition suppression (RS) (or functional magnetic resonance imaging adaptation) refers to the reduction in blood oxygen level-dependent signal following repeated presentation of a stimulus. RS is frequently used to investigate the role of face selective regions in human visual cortex and is commonly thought to be a "localized" effect, reflecting fatigue of a neuronal population representing a given stimulus. In contrast, predictive coding theories characterize RS as a consequence of "top-down" changes in between-region modulation. Differentiating between these accounts is crucial for the correct interpretation of RS effects in the face-processing network. Here, dynamic causal modeling revealed that different mechanisms underlie different forms of RS to faces in occipitotemporal cortex. For both familiar and unfamiliar faces, repetition of identical face images (same size) was associated with changes in "forward" connectivity between the occipital face area (OFA) and the fusiform face area (FFA) (OFA-to-FFA). In contrast, RS across image size was characterized by altered "backward" connectivity (FFA-to-OFA). In addition, evidence was higher for models in which information projected directly into both OFA and FFA, challenging the role of OFA as the input stage of the face-processing network. These findings suggest "size invariant" RS to faces is a consequence of interactions between regions rather than being a localized effect. PMID- 22510536 TI - Spatial object recognition enables endogenous LTD that curtails LTP in the mouse hippocampus. AB - Although synaptic plasticity is believed to comprise the cellular substrate for learning and memory, limited direct evidence exists that hippocampus-dependent learning actually triggers synaptic plasticity. It is likely, however, that long term potentiation (LTP) works in concert with its counterpart, long-term depression (LTD) in the creation of spatial memory. It has been reported in rats that weak synaptic plasticity is facilitated into persistent plasticity if afferent stimulation is coupled with a novel spatial learning event. It is not known if this phenomenon also occurs in other species. We recorded from the hippocampal CA1 of freely behaving mice and observed that novel spatial learning triggers endogenous LTD. Specifically, we observed that LTD is enabled when test pulse afferent stimulation is given during the learning of object constellations or during a spatial object recognition task. Intriguingly, LTP is significantly impaired by the same tasks, suggesting that LTD is the main cellular substrate for this type of learning. These data indicate that learning-facilitated plasticity is not exclusive to rats and that spatial learning leads to endogenous LTD in the hippocampus, suggesting an important role for this type of synaptic plasticity in the creation of hippocampus-dependent memory. PMID- 22510537 TI - Low back pain subgroups using fear-avoidance model measures: results of a cluster analysis. AB - OBJECTIVES: The purpose of this secondary analysis was to test the hypothesis that an empirically derived psychological subgrouping scheme based on multiple Fear-Avoidance Model (FAM) constructs would provide additional capabilities for clinical outcomes in comparison with a single FAM construct. METHODS: Patients (n=108) with acute or subacute low back pain enrolled in a clinical trial comparing behavioral physical therapy interventions to classification-based physical therapy completed baseline questionnaires for Pain Catastrophizing Scale, fear-avoidance beliefs [Fear-Avoidance Beliefs Questionnaire (FABQ) physical activity scale (PA), FABQ work scale], and patient-specific fear (Fear of Daily Activities Questionnaire). Clinical outcomes included pain intensity and disability measured at baseline, 4 weeks, and 6 months. A hierarchical agglomerative cluster analysis was used to create distinct cluster profiles among the FAM measures and discriminant analysis was used to interpret clusters. Changes in clinical outcomes were investigated with repeated measures analysis of variance and differences in results based on cluster membership were compared with FABQ-PA subgrouping used in the original trial. RESULTS: Three distinct FAM subgroups (Low-Risk, High Specific Fear, and High Fear and Catastrophizing) emerged from cluster analysis. Subgroups differed on baseline pain and disability (P<0.01) with the High Fear and Catastrophizing subgroup associated with greater pain than the Low-Risk subgroup (P<0.01) and the greatest disability (P<0.05). Subgroup*time interactions were detected for both pain and disability (P<0.05) with the High Fear and Catastrophizing subgroup reporting greater changes in pain and disability than other subgroups (P<0.05). In contrast, FABQ-PA subgroups used in the original trial were not associated with interactions for clinical outcomes. DISCUSSION: These data suggest that subgrouping based on multiple FAM measures may provide additional information on clinical outcomes in comparison with determining subgroup status by FABQ-PA alone. Subgrouping methods for patients with low back pain should include multiple psychological factors to further explore if patients can be matched with appropriate interventions. PMID- 22510538 TI - The effects of low doses of pregabalin on morphine analgesia in advanced cancer patients. AB - OBJECTIVES: The aim of this study was to evaluate the opioid response in patients receiving morphine and pregabalin, independently from the presumed pain mechanisms, in comparison with patients receiving morphine treatment only. METHODS: A multicenter prospective randomized controlled study was carried out in a sample of 70 advanced cancer patients with pain requiring strong opioids. Thirty-five patients (group MO) were randomized to receive sustained-release morphine using initial doses of 60 mg/day. Thirty-five patients (group MO-PR) were randomized to start the same morphine doses and pregabalin in increasing doses, starting with 25 mg/day up to 150 mg/day in one week. The following data were also recorded before starting the treatments (T0) and then at week intervals for four weeks (W1-4): age, gender, primary cancer and known metastases, pain causes and mechanisms, symptoms associated with opioid therapy, pain intensity, Brief Pain Inventory (BPI), morphine doses and escalation indexes (OEIs), and quality of life. RESULTS: Forty-eight patients completed the study, twenty-eight and sixteen patients in group MO and MO-PR, respectively. Twenty patients were females, the mean age was 65.5 (+/- 10.3), and the mean Karnofsky status was 66.0 (+/- 18.9). No differences between groups were found in age (P = 0.839), Karnofsky status (P = 0.741), opioid doses as well as escalation indexes (OEI mg, P = 0.260, and OEI%, P = 0.270). No differences between the two groups were found in quality of life and all BPI items. CONCLUSION: The use of low doses of pregabalin added to morphine therapy in advanced cancer patients does not seem to provide advantageous analgesic effects, despite limitations of the present study due to the number of drop-outs. PMID- 22510539 TI - A clinical decision model identifies patients at risk for delayed diagnosed injuries after high-energy trauma. AB - OBJECTIVE: Tertiary trauma survey is widely implemented in trauma care to identify all injuries in trauma patients. However, various studies consistently show that some trauma patients have missed injuries. In this study, we developed a clinical decision model to identify patients who are at risk for delayed diagnosed injuries. METHODS: During a period of 18 months, we collected the medical records of all the adult patients who presented after a high-energy trauma at the emergency department of a Dutch trauma centre. The type of trauma, patient characteristics, the radiology studies performed, Glasgow Coma Scale, Revised Trauma Score, and Injury Severity Score (ISS) were registered. We thoroughly screened all medical records for delayed diagnosed injuries. Stepwise logistic regression analysis was used to identify the variables associated with the outcome delayed diagnosed injuries and to develop a clinical prediction model. RESULTS: We included 475 patients. Thirteen (2.7%) patients with delayed diagnosed injuries were identified. Stepwise logistic regression analysis revealed several models with the ISS, ICU admittance, and CT-head as predictive variables. The model we proposed with the ISS could identify patients who are at a risk for delayed diagnosed injuries with a sensitivity of 92.3% and a specificity of 86.4%. CONCLUSION: Our newly developed clinical decision model can identify patients who are at a risk for delayed diagnosed injuries and who should undergo an intensified search for potential unidentified injuries. PMID- 22510540 TI - Respiratory movement and pain thresholds in airway environmental sensitivity, asthma and COPD. AB - INTRODUCTION: Patients with "sensory hyperreactivity" (SHR) have airway environmental sensitivity, chronic cough and dyspnoea. Cough, chest discomfort and sense of difficulties getting air are some of the symptoms these patients seek medical attendance for. The patients have increased cough sensitivity to inhaled capsaicin, mediated by ion channel receptors on sensory nerves also known to react to pain stimuli. Whether a link exists between capsaicin airway sensitivity and pain sensitivity has not yet been evaluated. The aim was to investigate chest mobility, respiratory movement and pain sensitivity in SHR patients compared with patients with asthma, chronic obstructive pulmonary disease (COPD) and alleged healthy control subjects. METHODS: Thirty-five patients diagnosed with SHR, 19 with COPD, 32 with asthma and 28 control subjects were included. Chest expansion was measured with a measuring tape and thoracic and abdominal movement with light sensors. Pain sensitivity was assessed using a pressure algometer. RESULTS: Groups differed significantly in lung function, respiratory rate and pain sensitivity but also in chest expansion and abdominal breathing movement. In comparison with the control and asthma groups but not the COPD patients, SHR patients had an increased respiratory rate and reduced abdominal movement during deep breathing. All patient groups showed lower pain thresholds than the controls. CONCLUSION: Patients with SHR have evident signs of dysfunctional breathing and appeared to be most similar to the COPD group except for lung function. Lower pain thresholds among the patients indicate a general up regulation of the sensory nerve system. PMID- 22510541 TI - Root uptake and phytotoxicity of nanosized molybdenum octahedral clusters. AB - Here are examined the root uptake and phytotoxicity of octahedral hexamolybdenum clusters on rapeseed plants using the solid state compound Cs(2)Mo(6)Br(14) as cluster precursor. [Mo(6)Br(14)](2-) cluster units are nanosized entities offering a strong and stable emission in the near-infrared region with numerous applications in biotechnology. To investigate cluster toxicity on rapeseed plants, two different culture systems have been set up, using either a water sorbing suspension of cluster aggregates or an ethanol-sorbing solution of dispersed nanosized clusters. Size, shape, surface area and state of clusters in both medium were analyzed by FE-SEM, BET and XPS. The potential contribution of cluster dissolution to phytotoxicity was evaluated by ICP-OES and toxicity analysis of Mo, Br and Cs. We showed that the clusters did not affect seed germination but greatly inhibited plant growth. This inhibition was much more important when plants were treated with nanosized entities than with microsized cluster aggregates. In addition, nanosized clusters affected the root morphology in a different manner than microsized cluster aggregates, as shown by FE-SEM observations. The root penetration of the clusters was followed by secondary ion mass spectroscopy with high spatial resolution (NanoSIMS) and was also found to be much more important for treatments with nanosized clusters. PMID- 22510542 TI - Degradation of antibiotic norfloxacin in aqueous solution by visible-light mediated C-TiO2 photocatalysis. AB - A visible-light-mediated C-TiO(2) photocatalytic process (Vis/C-TiO(2)) was employed to degrade antibiotic norfloxacin. The influences of catalyst dosage, initial probe compound concentration and solution pH levels on the decay performance and reaction kinetics were investigated and optimized. Based on the experimental results, an equation was established to predict the observed rate constant under neutral pH. In addition, the decay rate was accelerated under weak alkali in the presence of moderate OH(-) anions. Hydroxyl radical was confirmed to play a major role in the Vis/TiO(2) process, where in the presence of OH quencher and electron acceptor, retardation and improvement were found respectively. Furthermore, an original schematic diagram describing the surface property of C-TiO(2) was built and further verified, in which, NH(4)(+) cations normally served as hole scavengers showed a negligible effect because the adsorbed OH(-) formed a barrier for NH(4)(+) ions to approach the holes, and the F(-) anions presented a significant suppression on norfloxacin decay due to the formation of hydrogen bond (OH?F) around the C-TiO(2) surface. Besides, the recycling and sedimentation tests justified that the Vis/C-TiO(2) process is a cost-effective and feasible way for wastewater treatment. PMID- 22510543 TI - Bronchial sleeve resection for early-stage squamous cell carcinoma. AB - A 75-year-old man complained of sputum and was referred to our department. His sputum cytology was class III. Chest X-ray and computed tomography showed no abnormalities, but bronchoscopy revealed an elevated lesion in the membranous portion of the left main bronchus, which was pathologically diagnosed as squamous cell carcinoma in situ. Since bronchoscopy revealed no other lesions in the visible parts of the airway, it was considered to be a solitary, early lung cancer, and sleeve resection of the left main bronchus was performed. The postoperative pathological diagnosis was squamous cell carcinoma in situ, pTisN0M0, stage 0. In recent years, an increasing number of studies have reported photodynamic therapy and brachytherapy for the treatment of early lung cancer. However, aggressive bronchoplastic surgery with emphasis on curability should be considered for lesions that are deemed resectable based on their number and extent of invasion. PMID- 22510544 TI - [Pregnancy in women who have undergone gastric bypass surgery - new challenge]. PMID- 22510545 TI - [Physician dual practice can have positive influence on their primary job]. PMID- 22510546 TI - [Pregnancy following bariatric surgery requires special attention]. AB - In the latest years the number of pregnant women having undergone bariatric surgery before pregnancy has increased rapidly. In pregnancy, they seem to have a reduced risk of obesity-related complications but an increased risk of mechanical complications causing small bowel obstruction and complications due to malabsorption. This article reviews the effect of bariatric surgery before pregnancy on obstetric and neonatal outcomes and provides, based on the limited available evidence, recommendations for the management of pregnancy in these women. PMID- 22510547 TI - [Obese pregnant women and complications in relation to pregnancy and birth]. AB - One third of the pregnant Danish women are overweight or obese. Maternal obesity is an independent risk factor for adverse maternal and foetal outcomes including infertility, miscarriage, congenital malformations, preeclampsia, gestational diabetes, complicated deliveries, caesarean section, macrosomia and childhood obesity. This article reviews the effect of maternal obesity on obstetric and neonatal outcomes and provides recommendations for management of obesity in pregnancy. PMID- 22510548 TI - [Internal herniation during pregnancy following gastric bypass surgery]. AB - In Denmark, the number of bariatric operations, including gastric bypass surgery, has increased dramatically in recent years. Internal herniation as a possible cause of acute abdominal pain, is a well-known complication after gastric bypass operation. We report two cases of internal herniation during pregnancy following gastric bypass operation. The diagnosis of internal herniation can be difficult as radiologic investigations may be inconclusive. Clinical suspicion alone should lead to surgical exploration due to the risks of morbidity and mortality if patients are not diagnosed properly. PMID- 22510549 TI - [Different attitudes among health-care professionals to late termination of pregnancy--a systematic review]. AB - International studies show that late termination of pregnancy causes more distress for the health-care professionals than early termination of pregnancy. The most commonly cited concern is the risk that the fetus will show signs of life after the abortion. Studies indicate that the cause of abortion, religious beliefs and profession influence the attitudes. The number of late terminations of pregnancy is increasing as the methods for prenatal diagnostics develop. As a result there is a need for research on Danish health-care professionals' attitudes towards late termination of pregnancy. PMID- 22510550 TI - [Cost-effective change in treatment after split skin grafting to lower leg defects]. AB - We present a clinical comparison of short stretch bandage versus a two-layer compression bandage and early mobilization after split skin grafting to lower leg defects. A total of 38 patients were included. The first group were immobilized for four days and given a short stretch support bandage. Group 2 were mobilized one day after the operation with a two-layer compression bandage (Pro-Guide). There was no difference in healing or frequency of complications. The patients treated with Pro-Guide had significantly fewer admission days and out-patient consultations. Larger randomized trials are warranted. PMID- 22510552 TI - [Malignant ovarian tumour as cause of virilisation in a 12 year-old girl]. AB - Virilisation in girls includes androgen dependent growth of terminal hair, acne, deepening of the voice and increased muscle mass. Sudden onset of symptoms, rapid progression, short duration and hyperandrogenaemia are ominous signs and the patient must be referred to a specialist as soon as possible to rule out cancer and avoid worsening of the irreversible virilisation. We describe a girl with severe virilisation as the sole symptom of an androgen producing Sertoli-Leydig cell tumour. Ovarian tumours are rare in children and malignant ovarian tumours account for less than 1% of childhood cancer. PMID- 22510551 TI - [Enteropathy associated T cell lymphoma mimicking an ACTH producing neuroendocrine tumour]. AB - We present a case of enteropathy associated T cell lymphoma mimicking an ACTH producing neuroendocrine tumour of the pancreas and duodenum on PET/CT because of symmetrical FDG avidity in the bilateral adrenal hyperplasia. Functional imaging with 18F-FDG PET depicts tumour metabolism, but may also visualise secondary endocrine hypersecretion. Therefore, as always, it is mandatory to perform a biopsy to ascertain the final diagnosis. The cause of FDG avidity in the adrenal hyperplasia was not found, but believed to be caused by a ''non-ACTH-mediated stimulant'' as reported earlier. PMID- 22510553 TI - [Serious infection with Lactococcus garvieae]. AB - Lactococcus garvieae are Gram-positive, facultative anaerobe cocci. The bacterium is a known pathogen in fish, but is also described in mastitis among ruminants. In recent years it has been found in a Danish fish farm. Only 15 cases documenting infection in humans are found in English literature. We present an 83 year-old female in antihypertensive treatment admitted to hospital because of hypothermia and sepsis. In two of two blood cultures L. garvieae were found. No infection site was found. The patient received ampicillin and ciprofloxacin and was discharged to her home after 18 days. PMID- 22510554 TI - [Lethal recurrent pulmonary embolism]. AB - An otherwise healthy 68 year-old man experienced three episodes of life threatening pulmonary embolism (PE) over a short period. The last episode had lethal outcome. After the first episode the patient was resuscitated and received embolectomy and after the second he received thrombolytic treatment. The last episode was not recognised until the autopsy. The second and the third episode occurred during anticoagulant therapy. Even in non-malignant patients recurrent PE may occur during anticoagulant therapy and implementing a prophylactic permanent filter in vena cava inferior in these patients in case of recurrent major PE could be considered. PMID- 22510555 TI - Bordering on bipolar: the overlap between borderline personality and bipolarity. AB - OBJECTIVE: There is much debate over whether borderline personality disorder (BPD) belongs to the bipolar spectrum. The diagnosis of bipolar disorder (BD) in BPD patients, and conversely, BPD in BD patients is common, indicating prevalent co-morbidity, as well as potential misdiagnosis in either group. BD and BPD are often indistinguishable given the core characteristics of emotional dysregulation and impulsivity that feature in both. However, it may be argued that the manifestation of these characteristics in the two groups is different, and that the symptoms are driven by distinct aetiological factors. The primary objective of this paper was to examine where potential areas of discrimination lie between BD and BPD. METHODS: A literature search was conducted using MEDLINE and PubMed databases to identify studies that have researched BD and BPD across the recognised domains of emotional dysregulation, impulsivity, childhood trauma, and their putative neurobiological substrates. RESULTS: Research comparing BD and BPD patients on self-report measures is limited, and no studies have examined their neurobiological underpinnings in the same design. One possible differentiating variable is childhood trauma which shapes the circumstances in which emotional dysregulation and impulsivity are triggered, the types of behaviours exhibited, and the frequency and duration of mood states. There is growing evidence that childhood trauma not only predisposes individuals to both disorders, but also modulates the clinical expression and course of bipolar illness, particularly rapid cycling BD, a form of bipolarity that resembles the clinical profile of BPD, yet presents quite distinctly from other BD subtypes. CONCLUSIONS: This paper provides an overview of BD and BPD with respect to emotional dysregulation, impulsivity, childhood factors, and neurobiological substrates. Based on findings predominantly within the independent areas of BD and BPD, it tentatively provides an integrated behavioural, aetiological and neurobiological approach for investigating the question of whether BPD belongs to the bipolar spectrum. PMID- 22510556 TI - A new tool for an old problem: synchronizing fission yeast cells during meiosis using an ATP analog-sensitive protein kinase. PMID- 22510557 TI - Peptidyl-prolyl isomerization for cytokinetic abscission: fold and cut. PMID- 22510558 TI - CHEKing out of mitosis. PMID- 22510559 TI - Tumor-stroma relationships: who's the driver? PMID- 22510561 TI - Evidence for cell cycle suppression and microRNA regulation of cyclin D1 during anoxia exposure in turtles. AB - The red-eared slider turtle (Trachemys scripta elegans) has a well-developed natural tolerance for oxygen deprivation that derives from biochemical adaptations, including anoxia-induced suppression of metabolic rate. We hypothesized that mechanisms that suppress ATP-expensive cell cycle activity would contribute significantly to establishing the hypometabolic state during anaerobiosis. Cyclin D1 is a critical regulator of the G 1 phase of the cell cycle and is regarded as key to initiating cell proliferation. The relative protein expression of cyclin D1 was analyzed in both whole-cell and nuclear fractions of liver, kidney and skeletal muscle from turtles exposed to 5 or 20 h of submergence anoxia. Expression of cyclin D1 in both total and nuclear fractions decreased significantly under anoxia in liver and kidney as compared with aerobic controls, but no significant change occurred in muscle. The relative phosphorylation state of cyclin D1 (threonine 286) was also unchanged during anoxia in all tissues. Since phosphorylation of threonine 286 is necessary for proteasomal degradation of cyclin D1, this implies that an alternative mechanism is responsible for cyclin D1 suppression in anoxia. Levels of cyclin D1 mRNA transcripts did not change under anoxia in any tissue, so a post-transcriptional method of regulation was implicated. Analysis of the 3'UTR of cyclin D1 showed the presence of both an AU-rich region and a conserved binding site for microRNA 16-1 and microRNA-15a. Levels of both microRNAs increased in liver and kidney (but not in muscle) under anoxic conditions, implicating microRNA inhibition of mRNA translation as the mechanism underlying the suppression of cyclin D1 protein levels in the anoxic turtle. PMID- 22510562 TI - Context-dependent dual and opposite roles of nemo-like kinase in the Wnt/beta catenin signaling. PMID- 22510560 TI - Decreased translation of p21waf1 mRNA causes attenuated p53 signaling in some p53 wild-type tumors. AB - DNA damage induces cell cycle arrest through both Chk1 and the p53 tumor suppressor protein, the latter arresting cells through induction of p21(waf1) protein. Arrest permits cells to repair the damage and recover. The frequent loss of p53 in tumor cells makes them more dependent on Chk1 for arrest and survival. However, some p53 wild type tumor cell lines, such as HCT116 and U2OS, are also sensitive to inhibition of Chk1 due to attenuated p21(waf1) induction upon DNA damage. The purpose of this study is to determine the cause of this attenuated p21(waf1) protein induction. We find that neither the induction of p21(waf1) mRNA nor protein half-life is sufficient to explain the low p21(waf1) protein levels in HCT116 and U2OS cells. The induced mRNA associates with polysomes but little protein is made suggesting these two cell lines have a reduced rate of p21(waf1) mRNA translation. This represents a novel mechanism for disruption of the p53 p21(waf1) pathway as currently known mechanisms involve either mutation of p53 or reduction of p53 protein levels. As a consequence, this attenuated p21(waf1) expression may render some p53 wild type tumors sensitive to a combination of DNA damage plus checkpoint inhibition. PMID- 22510563 TI - Delayed cell cycle pathway modulation facilitates recovery after spinal cord injury. AB - Traumatic spinal cord injury (SCI) causes tissue loss and associated neurological dysfunction through mechanical damage and secondary biochemical and physiological responses. We have previously described the pathobiological role of cell cycle pathways following rat contusion SCI by examining the effects of early intrathecal cell cycle inhibitor treatment initiation or gene knockout on secondary injury. Here, we delineate changes in cell cycle pathway activation following SCI and examine the effects of delayed (24 h) systemic administration of flavopiridol, an inhibitor of major cyclin-dependent kinases (CDKs), on functional recovery and histopathology in a rat SCI contusion model. Immunoblot analysis demonstrated a marked upregulation of cell cycle-related proteins, including pRb, cyclin D1, CDK4, E2F1 and PCNA, at various time points following SCI, along with downregulation of the endogenous CDK inhibitor p27. Treatment with flavopiridol reduced induction of cell cycle proteins and increased p27 expression in the injured spinal cord. Functional recovery was significantly improved after SCI from day 7 through day 28. Treatment significantly reduced lesion volume and the number of Iba-1(+) microglia in the preserved tissue and increased the myelinated area of spared white matter as well as the number of CC1(+) oligodendrocytes. Furthermore, flavopiridol attenuated expression of Iba-1 and glactin-3, associated with microglial activation and astrocytic reactivity by reduction of GFAP, NG2, and CHL1 expression. Our current study supports the role of cell cycle activation in the pathophysiology of SCI and by using a clinically relevant treatment model, provides further support for the therapeutic potential of cell cycle inhibitors in the treatment of human SCI. PMID- 22510564 TI - Chalcone-based small-molecule inhibitors attenuate malignant phenotype via targeting deubiquitinating enzymes. AB - The ubiquitin-proteasome system (UPS) is usurped by many if not all cancers to regulate their survival, proliferation, invasion, angiogenesis and metastasis. Bioflavonoids curcumin and chalcones exhibit anti-neoplastic selectivity through inhibition of the 26S proteasome-activity within the UPS. Here, we provide evidence for a novel mechanism of action of chalcone-based derivatives AM146, RA 9 and RA-14, which exert anticancer activity by targeting deubiquitinating enzymes (DUB) without affecting 20S proteasome catalytic-core activity. The presence of the alpha,beta-unsaturated carbonyl group susceptible to nucleophilic attack from the sulfhydryl of cysteines in the active sites of DUB determines the capacity of novel small-molecules to act as cell-permeable, partly selective DUB inhibitors and induce rapid accumulation of polyubiquitinated proteins and deplete the pool of free ubiquitin. These chalcone-derivatives directly suppress activity of DUB UCH-L1, UCH-L3, USP2, USP5 and USP8, which are known to regulate the turnover and stability of key regulators of cell survival and proliferation. Inhibition of DUB-activity mediated by these compounds downregulates cell-cycle promoters, e.g., cyclin D1 and upregulates tumor suppressors p53, p27(Kip1) and p16(Ink4A). These changes are associated with arrest in S-G 2/M, abrogated anchorage-dependent growth and onset of apoptosis in breast, ovarian and cervical cancer cells without noticeable alterations in primary human cells. Altogether, this work provides evidence of antitumor activity of novel chalcone-based derivatives mediated by their DUB-targeting capacity; supports the development of pharmaceuticals to directly target DUB as a most efficient strategy compared with proteasome inhibition and also provides a clear rationale for the clinical evaluation of these novel small-molecule DUB inhibitors. PMID- 22510565 TI - Manzamines: a potential for novel cures. AB - Manzamines are a unique class of beta-carboline marine alkaloids with an unusual tetra- or pentacyclic system. These alkaloids have shown a variety of bioactivities against infectious diseases, cancer and inflammatory diseases. The greatest potential for the manzamine alkaloids appears to be against malaria, with improved potency relative to chloroquine and artemisinin. Over 80 manzamine related alkaloids have been isolated from more than 16 species of marine sponges belonging to five families distributed from the Red Sea to Indonesia, which suggests a possible microbial origin for manzamine alkaloids. The current review summarizes marine literature, focusing on the biological activities of manzamines, the possible microbial origin of this class of compounds and the Red Sea as a possible source of manzamines from biosynthetic gene clusters of Red Sea microbes. PMID- 22510566 TI - Suspended animation, diapause and quiescence: arresting the cell cycle in C. elegans. AB - Developing organisms require nutrients to support cell division vital for growth and development. An adaptation to stress, used by many organisms, is to reversibly enter an arrested state by reducing energy-requiring processes, such as development and cell division. This "wait it out" approach to survive stress until the environment is conductive for growth and development is used by many metazoans. Much is known about the molecular regulation of cell division, metazoan development and responses to environmental stress. However, how these biological processes intersect is less understood. Here, we review studies conducted in Caenorhabditis elegans that investigate how stresses such as oxygen deprivation (hypoxia and anoxia), exogenous chemicals or starvation affect cellular processes in the embryo, larvae or adult germline. Using C. elegans to identify how stress signals biological arrest can help in our understanding of evolutionary pressures as well as human health-related issues. PMID- 22510568 TI - Hypometabolism and the cell cycle. PMID- 22510567 TI - Pro-apoptotic signaling pathway by CDK5 and MEKK1. PMID- 22510569 TI - Developmental decisions: balancing genetics and the environment by C. elegans. AB - The small nematode C. elegans is characterized by developing through a highly coordinated, reproducible cell lineage that serves as the basis of many studies focusing on the development of multi-lineage organisms. Indeed, the reproducible cell lineage enables discovery of developmental defects that occur in even a single cell. Only recently has attention been focused on how these animals modify their genetically programmed cell lineages to adapt to altered environments. Here, we summarize the current understanding of how C. elegans responds to food deprivation by adapting their developmental program in order to conserve energy. In particular, we highlight the AMPK-mediated and insulin-like growth factor signaling pathways that are the principal regulators of induced cell cycle quiescence. PMID- 22510570 TI - From oncogene to tumor suppressor: the dual role of Myc in leukemia. AB - The transcription factor c-Myc strongly stimulates cell proliferation but also regulates apoptosis, senescence, cell competition and cell differentiation, and its elevated activity is a hallmark for human tumorigenesis. c-Myc induces transcription by forming heterodimers with Max and then directly binding DNA at E box sequences. Conversely, transcription repression depends primarily on the inhibitory interaction of c-Myc/Max with Miz-1 at DNA initiator elements. We recently described a distinct mechanism of c-Myc gene regulation, in which c-Myc interacts with the retinoic acid receptor alpha (RARalpha) and is recruited to RAR DNA binding sequences (RAREs). In leukemia cells, this c-Myc/RARalpha complex functions either as an activator or a repressor of RARalpha-dependent targets through a phosphorylation switch. Unphosphorylated c-Myc interacts with RARalpha to repress the expression of RAR targets required for differentiation, thereby aggravating leukemia malignancy. However, if c-Myc is phosphorylated by the kinase Pak2, the c-Myc/RARalpha complex activates transcription of those same genes to stimulate differentiation, thus reducing tumor burden. Here, we discuss the role of c-Myc in balancing proliferation and differentiation and how modulating this previously unidentified c-Myc activity might provide alternative therapies against leukemia and possibly other types of tumors. PMID- 22510572 TI - Pattern of cellular quiescence over the hibernation cycle in liver of thirteen lined ground squirrels. AB - Mammalian hibernation is a state of seasonal heterothermy that consists of long periods of torpor at low body temperature interspersed with short periods of arousal back to euthermia. Entry into the hypometabolic state of torpor is achieved via a strong coordinated reduction of energy expenditures, particularly ATP-expensive activities, such as transcription and translation. The present study analyzes the status of the cell cycle during hibernation in liver of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) and examines the expression levels of cell cycle regulators over six stages of the torpor-arousal cycle. Immunoblot analysis showed that the protein expression levels of cyclin D1 and cyclin E were reduced in liver (by 31% and 48%, respectively) during long term torpor; however, during arousal from torpor, PCR analysis showed an upregulation of cyclin D1 transcript levels of about 1.5-fold. Protein expression of cyclin A and cyclin B1 were also elevated (1.57-fold and 2.44-fold, respectively) during early arousal from torpor, and in addition, cyclin A2 transcript levels increased by about 1.8-fold during arousal. Protein levels of two CKIs, p15(INK4b) and p21(CIP1), each increased by about 1.4-fold during torpor, and transcript levels of p15(INK4b) also rose by 1.7-2.1 fold during torpor, whereas p21(CIP1) transcripts increased by 1.5-1.7-fold. A reduction in cyclin D and E protein expression coupled with upregulation of p15(INK4b) and p21(CIP1) inhibitors during torpor reflects markers of cell cycle arrest during hibernation. Elevated expression of cyclin A and B protein expression during arousal stages of torpor suggests cell cycle progression is reversibly arrested during torpor and is reinitiated upon return to euthermia. PMID- 22510573 TI - Cell cycle regulation in the freeze tolerant wood frog, Rana sylvatica. AB - The wood frog (Rana sylvatica) is one of only a few vertebrate species that can survive extensive freezing of its body fluids during the winter. The mechanisms of natural freeze tolerance include metabolic rate depression to conserve energy and the implementation of cryoprotective strategies, especially the synthesis of huge amounts of glucose as a cryoprotectant. Liver is the main source of glucose production/export (and other cryoprotective actions) and plays a central role in freezing survival of the whole animal. Freezing is a multi-component stress that includes anoxia/ischemia due to the cessation of blood flow and dehydration of cells caused by ice accumulation in extracellular spaces. To help endure these stresses, cells need to suppress and reprioritize ATP-expensive cell functions. One of these is cell growth and proliferation, and we hypothesized that cell cycle arrest would be key to freezing survival. The present study examines the responses by key cell cycle components to freezing, anoxia and dehydration stresses in wood frog liver. Immunoblotting was used to investigate protein expression of Cdc 2, Cdks (2, 4, 6), and cyclins (A, B1, D1, E) as well as the phosphorylation states of Cdks (Thr14/Tyr15), the phosphatases Cdc25a (Ser76) and Cdc25c (Ser216) and the CIP/KIP Cdk inhibitors p21 (Thr145) and p27 (Thr187). Responses to 24 h freezing, 24 h anoxia and 40% dehydration as well as recovery from these stresses were analyzed. The results showed very similar responses by cell cycle components to anoxia or dehydration and were consistent with cell cycle suppression under stress and reversal during recovery. Freezing showed elements of cell cycle suppression, including reduced protein levels of Cdks and cyclins A and B1, but also showed unique responses by cyclin D1, Cdc25 phosphatases and p21/p27. These may be linked with alternative actions by these proteins that contribute to cryoprotection; e.g., an alternative action of cyclin D1 as a transcription factor may contribute to the upregulation of glucose-6 phosphatase, a key enzyme needed for the export of glucose cryoprotectant. PMID- 22510574 TI - Phase transitions and crystal-field and exchange interactions in TbFe3(BO3)4 as seen via optical spectroscopy. AB - High-resolution polarized broadband (1800-23 000 cm(-1)) optical absorption spectra of Tb(3+) in TbFe(3)(BO(3))(4) single crystals are studied between room temperature and 4.2 K. The spectral signatures of the structural (R32-P3(1)21, T(S ) = 192 K) and magnetic (T(N ) = 41 K) phase transitions are found and analyzed. Energies and symmetries of the Tb(3+) crystal-field (CF) levels were determined for both the high-temperature R32 and the low-temperature P3(1)21 structures of TbFe(3)(BO(3))(4) and compared with the calculated ones. It follows unambiguously from the spectral data that the ground state is the Gamma(1) + Gamma(2) quasi-doublet of the local D(3) point symmetry group for Tb(3+) in the R32 high-temperature structure. The CF calculations revealed the CF parameters and wavefunctions for Tb(3+) in TbFe(3)(BO(3))(4). The value of the Tb-Fe exchange integral and of the effective magnetic field created by the ordered Fe subsystem were estimated as J(fd) = 0.26 K and B(eff) = 3.92 T, using the observed splitting Delta = 32 cm(-1) of the Tb(3+) ground quasi-doublet at the temperature 5 K. The reliability of the obtained parameters was proven by modeling the literature data on the magnetic susceptibility of TbFe(3)(BO(3))(4). Lattice distortions below T(S) were evidenced by the observed changes of probabilities of the forced electric dipole transitions of Tb(3+). PMID- 22510575 TI - Community attitudes to deceased organ donation: a focus group study. AB - BACKGROUND: Despite broad community support for organ donation, there is a chronic shortage of donor organs for transplantation. This study elicited community attitudes on deceased organ donation and the current Australian organ donation system. METHODS: Thirteen focus groups with 114 participants aged between 18 and 75 years. Qualitative analysis using a grounded theory approach was used. RESULTS: Participants were generally positive toward deceased organ donation, but this did not always translate to decisions to be a donor. Three main categories of themes emerged. (1) Participants held core beliefs that both encouraged donation, such as "giving is good" and "saving lives," and discouraged donation, such as loss of body dignity, need for body wholeness, and differing medical care for donors. (2) A range of factors could influence how core beliefs were weighted in the decision-making process, including family, knowledge, information, media, grief, apathy, and fear. (3) Participants discussed the need for a simpler consent system where family members could not overrule their donation decision, greater public awareness for organ donation, and the availability of more information on the organ donation process. CONCLUSIONS: Opportunities exist to improve deceased organ donation rates by education to improve confidence in the donation process, positive media coverage, and clear information on each religion's stance on organ donation. Options for greater public recognition for organ donors should be explored. Finally, our findings suggest that aspects of the current donation consent system are not aligned with community values, and reforms should be debated publicly. PMID- 22510571 TI - Staying alive: metabolic adaptations to quiescence. AB - Quiescence is a state of reversible cell cycle arrest that can grant protection against many environmental insults. In some systems, cellular quiescence is associated with a low metabolic state characterized by a decrease in glucose uptake and glycolysis, reduced translation rates and activation of autophagy as a means to provide nutrients for survival. For cells in multiple different quiescence model systems, including Saccharomyces cerevisiae, mammalian lymphocytes and hematopoietic stem cells, the PI3Kinase/TOR signaling pathway helps to integrate information about nutrient availability with cell growth rates. Quiescence signals often inactivate the TOR kinase, resulting in reduced cell growth and biosynthesis. However, quiescence is not always associated with reduced metabolism; it is also possible to achieve a state of cellular quiescence in which glucose uptake, glycolysis and flux through central carbon metabolism are not reduced. In this review, we compare and contrast the metabolic changes that occur with quiescence in different model systems. PMID- 22510576 TI - Relationship of environmental tobacco smoke to otitis media (OM) in children. AB - INTRODUCTION: Many, but not all, studies have found a correlation between environmental tobacco smoke (ETS) and acute otitis media (AOM) and other adverse otologic outcomes. Given its high personal and societal costs and the divergent findings of the effect of ETS on middle ear disease, the aim of the current study was to assess the impact and possible determinant factors of ETS on recurrent (two or more) episodes of AOM. METHODS: The study was performed at Heim Pal Children's Hospital, Ear, Nose and Throat (ENT) Department, Budapest, Hungary. Caregivers of a convenience sample of 412 children attending the ENT outpatient clinic were surveyed via a 22-item questionnaire regarding demographics, socioeconomics, and smoking behaviours of the child's family; as well as care givers' self report of the number of AOM episodes of the child. RESULTS: Of the 412 participants, 155 (38%) children's parents smoked. In bivariate analysis, two or more episodes of AOM correlated with reported hearing problems, day care enrolment, parental employment and increased age of the child. In multivariate logistic regression, parental smoking more than doubled a child's risk for recurrent AOM while increased maternal employment (e.g. part-time or full-time versus unemployed) boosted risk up to fourfold. Among children whose parents smoked, half-packs of cigarettes smoked per day and day care attendance doubled or nearly tripled, respectively, the risk of recurrent AOM episodes. CONCLUSIONS: Childhood exposure to ETS is high among an ENT clinic population of Hungarian children. Such exposure correlates with AOM episodes, ENT operations and conductive hearing loss. Data such as these argue for strict laws smoke-free laws not only in Hungary, but also in Europe and around the world. PMID- 22510577 TI - Auditory screening concurrent deafness predisposing genes screening in 10,043 neonates in Gansu province, China. AB - OBJECTIVE: The aim of our study was to evaluate the effectiveness of combining newborn hearing screening with screening for genetic mutations associated with deafness. METHODS: Ten thousand forty-three newborn babies, born between December 2009 and April 2011 in Gansu province, China, were screened for hearing loss using the otoacoustic emissions test or automatic auditory brainstem response test and genetic mutations associated with deafness using a standard protocol. RESULTS: In the hearing screening, the referral rate for hearing loss in the first-step screening was 14.4% (1409/9786), decreasing significantly to 3.8% (362/9506) upon retesting. After the second-step screening, a total of 537 newborns were lost to follow-up. The genetic screening found that about 2.29% (230/10,043) individuals carried one or more recessive risk alleles or the mitochondrial mutation. Among them, 18 babies had the pathogenic mitochondrial DNA mutation, 92 babies were SLC26A4 heterozygote carriers, one case with both SLC26A4 and 12S rRNA 1555A>G mutation, 117 babies were GJB2 heterozygote carriers, and two babies were GJB2 homozygote carriers. However, 83.5% (192/230) neonates passed the conventional hearing screening among these carriers. CONCLUSIONS: It might be effective to complement the conventional hearing screening with gene screening for the purpose of early diagnosis and discovery of the late-onset hearing loss. PMID- 22510578 TI - Microbeam studies of soft X-ray induced bystander cell killing using microbeam X ray cell irradiation system at CRIEPI. AB - The radiation induced bystander response is defined as a response in cells which have not been directly targeted by radiation, but which are in the neighborhood of cells which have been directly exposed. In many cases, the bystander response is saturated with increasing dose and is observed when only one cell in a population is targeted by high-LET particle radiations or ultrasoft X-rays (278 eV). However, in our studies using synchrotron X-ray microbeams (5.35 keV), the bystander cell killing effect in normal human fibroblast WI-38 cells had a parabolic relationship to the irradiating dose and was detected if 5 or more cell nuclei were irradiated. To evaluate the feature of the X-ray-induced bystander cell killing effect at a wider dose range and the existence of photon energy dependence, the effects were assessed by irradiating cell nuclei in confluent WI 38 cells with AlK X-ray microbeams (1.49 keV). The surviving fraction decreased when only a single cell nucleus was irradiated, suggesting the minimal number of targeted cells to induce the effect may depend on the energy of photons used. In this study, we found that the bystander cell killing effect showed a biphasic relationship to the irradiating dose. The decrease in bystander cell survival at the doses higher than 0.23 Gy was partially suppressed between 2.3 and 7.0 Gy, followed by level-off around 90% above 14 Gy, suggesting that the X-ray-induced bystander response is dose dependent. In addition, NO is one of chief initiators/mediators of the effect at least 0.47 Gy. PMID- 22510579 TI - Heel pain in spondyloarthritis: results of a cross-sectional study of 275 patients. AB - OBJECTIVES: Heel pain is a common but poorly studied feature of spondyloarthritis (SpA). The aims of this study were to assess the prevalence and clinical features of heel pain in a cohort of patients with SpA. METHODS: This was a retrolective single centre observational study in 2010. Patients with SpA as defined by Amor's criteria were recruited. The data collected were: demographic and disease characteristics, history of heel pain, age at first heel pain, localisation, nature and intensity of pain and treatments. The analyses were descriptive. RESULTS: A total of 275 SpA patients (mean age 44.6+/-13.5 yrs, mean disease duration 16.7+/-11.8 yrs, 61.5% men) were assessed. A history of heel pain was reported in 130 patients (47.1%), and was the first symptom of SpA in 15.7% of all patients. Heel pain was frequent in both axial (89/201, 44.3%) and peripheral disease (27/56, 48.2%). Distribution was more frequently inferior (88, 69.3%) than posterior (61, 48.0%) (p<0.0001), and frequently bilateral: simultaneously (41.9%) rather than alternatively (29.1%) (p=0.03). Main clinical symptoms were: morning pain on weight bearing (83.6%), but also night pain (34.4%), and/or patient-described swelling (24.2%). Heel pain was frequently recurrent (74.2%), intense (70.3%), source of a limp (71.6%), and often resistant to non-steroidal anti-inflammatory drugs (NSAIDs) (54/108, 50%). Tumour necrosis factor blockers were efficacious on heel pain in 72/94 (76.6%) of cases. CONCLUSIONS: This study confirmed heel pain as a frequent symptom in both axial and peripheral SpA. It occurred early in the disease course and it was frequently recurrent and resistant to NSAIDs. PMID- 22510580 TI - HIV-1 mRNA electroporation of PBMC: a simple and efficient method to monitor T cell responses against autologous HIV-1 in HIV-1-infected patients. AB - Efficient monitoring of HIV-1-specific T-cells is crucial for the development of HIV-1 vaccines and immunotherapies. Currently, mainly peptides and vaccinia vectors are used for detection of HIV-1-specific cytotoxic T-lymphocytes (CTL), however, as HIV-1 is a variable virus, it is unknown to what extent the T-cell response against the autologous virus is under- or overestimated by using antigens from heterologous viral strains. Therefore, we established a new method for immunomonitoring of CTL using electroporation of peripheral blood mononuclear cells (PBMC) with mRNA derived from autologous viral strains. From six HIV-1 infected patients virus derived mRNA was produced after PCR-based cloning of autologous gag (n=5) and/or nef genes (n=3) from plasma and electroporated into PBMC from patients and healthy donors. Electroporation of PBMC with mRNA resulted in efficient protein expression with good induction of gamma-interferon (gamma IFN) release by specific T-cells comparable to peptide pools and better than recombinant vaccinia viruses. Three mRNA encoded autologous Gag proteins and one autologous mRNA encoded Nef protein were better recognized by autologous PBMC in comparison to heterologous mRNA encoded Gag or Nef proteins (SF2 or HXB2). However, in one case each, mRNA encoded autologous Gag or Nef, respectively, was recognized less efficiently due to the presence of CTL escape mutations. In summary, electroporation of PBMC with mRNA is a very efficient, easy and rapid method for immunomonitoring of HIV-1-specific T-cell responses against autologous viral strains. Our data demonstrate that patients' CTL responses against autologous viral strains may be under- or overestimated by using antigens from heterologous viral strains. PMID- 22510581 TI - Chianina beef tenderness investigated through integrated Omics. AB - In the present study we performed an integrated proteomics, interactomics and metabolomics analysis of Longissimus dorsi tender and tough meat samples from Chianina beef cattle. Results were statistically handled as to obtain Pearson's correlation coefficients of the results from Omics investigation in relation to canonical tenderness-related parameters, including Warner Bratzler shear force, myofibrillar degradation (at 48 h and 10 days after slaughter), sarcomere length and total collagen content. As a result, we could observe that the tender meat group was characterized by higher levels of glycolytic enzymes, which were over phosphorylated and produced accumulation of glycolytic intermediates. Oxidative stress promoted meat tenderness and elicited heat shock protein responses, which in turn triggered apoptosis-like cascades along with PARP fragmentation. Phosphorylation was found to be a key process in post mortem muscle conversion to meat, as it was shown not only to modulate glycolytic enzyme activities, but also mediate the stability of structural proteins at the Z-disk. On the other hand, phosphorylation of HSPs has been supposed to alter their functions through changing their affinity for target interactors. Analogies and breed-specific differences are highlighted throughout the text via a direct comparison of the present results against the ones obtained in a parallel study on Maremmana Longissimus dorsi. It emerges that, while the main cornerstones and the final outcome are maintained, post mortem metabolism in tender and tough meat yielding individuals is subtly modulated via specific higher levels of enzymes and amino acidic residue phosphorylation in a breed-specific fashion, and whether calcium homeostasis dysregulation was a key factor in Maremmana, higher early post mortem phosphocreatine levels in the Chianina tender group could favor a slower and prolonged glycolytic rate, prolonging the extent of the minimum hanging period necessary to obtain tender meat from this breed by a few days. PMID- 22510582 TI - Day-to-day variability in intraocular pressure in glaucoma and ocular hypertension. AB - AIMS: To investigate the day-to-day repeatability of intraocular pressure (IOP) measurements. METHODS: A prospective cohort study of untreated patients presenting with primary open-angle glaucoma or ocular hypertension presenting with IOP>21 mm Hg. IOP was measured by masked Goldmann tonometry at 08:00, 11:00 and 16:00 at each of the three weekly visits. After starting travaprost (0.004%) to both eyes, the measurements were repeated for a further three weekly visits. Day-to-day repeatability was estimated before and after commencing medication and reported as the coefficient of repeatability and coefficient of variability. RESULTS: At the 8:00 time point, mean IOPs were 26.1 and 17.9 mm Hg in the eye with higher pressure before and after starting treatment, respectively. Coefficient of repeatability and coefficient of variability were 6.8 mm Hg and 10.0%, respectively, before treatment, and 4.6 mm Hg and 10.5% on treatment. Therefore, before treatment and after starting medication the IOP lay within a range of +/-20% of the mean IOP with 95% confidence. CONCLUSIONS: The non therapeutic variability from day to day significantly undermines the precision of IOP estimation and of the estimation of medication effectiveness even when the time of day is standardised in patients with primary open-angle glaucoma/ocular hypertension. PMID- 22510583 TI - Resistance, not tachyphylaxis or tolerance. PMID- 22510584 TI - RKKY interaction in AB-stacked multilayer graphene. AB - The RKKY interaction between two magnetic impurities absorbed on the surface layer of half-filled AB-stacked multilayer graphene (ABSMLG) is theoretically studied based on the lattice Green's function technique. In comparison with the case of monolayer graphene, the RKKY interaction in such multilayer graphene presents distinct properties in some aspects. Firstly, from the numerical results, we find that the thickness of the ABSMLG influences the RKKY interaction in a complicated manner, depending on the odd/even parity of the number of layers and the sublattice attribution of the positions of the two magnetic impurities. Then, we derive the asymptotic expressions of the RKKY interactions in ABSMLG in the long-distance limit. For even-layered ABSMLG, we find that the RKKY interactions of the 1A-1A, 1B-1A and 1B-1B couplings fall off as 1/R(2), 1/R(4) and 1/R(6) (1A and 1B stand for, respectively, the sublattice points in the surface layer, which are positioned directly on the plaquette and on a lattice point of the layer underneath). On the other hand, in odd-layered ABSMLG, the decays of these interactions follow the 1/R(2), 1/R(3) and 1/R(3) power laws respectively. In addition, we also find that these analytical expressions are quantitatively valid to describe the RKKY interaction in ABSMLG when the distance between the two magnetic impurities is larger than the lattice constant of graphene by one order of magnitude. PMID- 22510585 TI - Preeclampsia serum upregulates CD40/CD40L expression and induces apoptosis in human umbilical cord endothelial cells. AB - BACKGROUND: The endothelial cell dysfunction observed in preeclampsia (PE) may be induced by CD40/CD40L signaling. This study investigated the role of CD40/CD40L in the pathogenesis of PE by comparing the effect of maternal serum obtained from healthy pregnant women and PE patients on HUVEC cell growth, apoptosis and CD40/CD40L expression. METHODS: Maternal serum was obtained from 20 patients with PE (PE group) as well as 20 healthy pregnant women (control group). The human umbilical endothelial cell line, CRL1730, was cultured in the presence of maternal serum for 24, 48, and 72 h after which cell growth and apoptosis were assessed by MTT and flow cytometry analysis, respectively. CD40/CD40L expression was determined using flow cytometry and RT-PCR analyses. RESULTS: As compared to CRL1730 cells treated with control sera, those treated with PE sera had altered morphology, decreased cell growth, increased apoptosis and greater CD40/CD40L protein and mRNA expression. Stimulation of CD40/CD40L protein and mRNA expression by PE sera was greatest at 24 h. CONCLUSIONS: PE sera may induce endothelial cell damage possibly through increased CD40/CD40L expression in early onset PE. Further studies are necessary to determine the factor(s) in PE sera responsible for the observed changes in endothelial cell viability. PMID- 22510586 TI - Tear film surface quality with rigid and soft contact lenses. AB - OBJECTIVES: The aim of this study was to measure tear film surface quality (TFSQ) using dynamic high-speed videokeratoscopy during short-term (8 hrs) use of rigid and soft contact lenses. METHODS: A group of 14 subjects wore 3 different types of contact lenses on 3 different nonconsecutive days (order randomized) in 1 eye only. The subjects were screened to exclude those with dry eye. The lenses included a polymethyl methacrylate (PMMA) hard, a rigid gas permeable (RGP; Boston XO), and a soft silicone hydrogel lens. Three 30-second long high-speed videokeratoscopy recordings were taken with contact lenses in situ, in the morning and again after 8 hrs of contact lens wear, both in normal and suppressed blinking conditions. Recordings were also made on a baseline day with no contact lens wear. RESULTS: The presence of a contact lens in the eye had a significant effect on the mean TFSQ in both natural and suppressed blinking conditions (P=0.001 and P=0.01, respectively, repeated-measures analysis of variance). The TFSQ was worse with all the lenses compared with no lens in the eye in the afternoon during both normal and suppressed blinking conditions (all P<0.05). In natural blinking conditions, the mean TFSQ for the PMMA and RGP lenses was significantly worse than the baseline day (no lens) for both morning and afternoon measures (P<0.05). CONCLUSIONS: This study shows that both rigid and soft contact lenses adversely affect the TFSQ in both natural and suppressed blinking conditions. No significant differences were found between the lens types and materials. PMID- 22510587 TI - GW quasiparticle bandgaps of anatase TiO2 starting from DFT + U. AB - We investigate the quasiparticle band structure of anatase TiO(2), a wide gap semiconductor widely employed in photovoltaics and photocatalysis. We obtain GW quasiparticle energies starting from density-functional theory (DFT) calculations including Hubbard U corrections. Using a simple iterative procedure we determine the value of the Hubbard parameter yielding a vanishing quasiparticle correction to the fundamental bandgap of anatase TiO(2). The bandgap (3.3 eV) calculated using this optimal Hubbard parameter is smaller than the value obtained by applying many-body perturbation theory to standard DFT eigenstates and eigenvalues (3.7 eV). We extend our analysis to the rutile polymorph of TiO(2) and reach similar conclusions. Our work highlights the role of the starting non interacting Hamiltonian in the calculation of GW quasiparticle energies in TiO(2) and suggests an optimal Hubbard parameter for future calculations. PMID- 22510588 TI - Millimeter wave-induced modulation of calcium dynamics in an engineered skin co culture model: role of secreted ATP on calcium spiking. AB - We have previously designed and characterized a 94 GHz exposure system that allows real-time monitoring of subcellular interactions induced by millimeter wave (MMW) stimulation. For example, studies of the calcium dynamics in neuronal cells in response to 94 GHz irradiation suggested that MMW stimulation increased calcium spiking. In this study, we engineered a 3D co-culture model that represents the major constituents of skin. We used this experimental model along with the custom-designed MMW exposure system to investigate the effects of 94 GHz irradiation in the skin-like tissue construct. Unlike typical non-excitable cells, keratinocytes exhibited calcium spikes in their resting state. Exposure to a 94 GHz irradiation induced a statistically significant increase in the calcium spiking. When co-cultured with neuronal cells in the 3D co-culture skin model, changes in the calcium spiking in neuronal cells depended on the MMW input power. Further, the 94 GHz irradiation caused ATP secretion by keratincytes. ATP is a major factor that modulates the calcium spiking in neuronal cells. Surprisingly, while a 5-fold increase in the ATP secretion enhanced the calcium spiking in neuronal cells, a 10-fold increase significantly hindered the calcium dynamics. Computational simulation of ATP-induced calcium dynamics was in general agreement with the experimental findings, suggesting the involvement of the ATP-sensitive purinergic receptors. The engineered co-culture skin model offers a physiologically relevant environment in which the calcium dynamics is regulated both by the cell-MMW and cell-cell interactions. PMID- 22510589 TI - Analysis of the cellular stress response in MCF10A cells exposed to combined radio frequency radiation. AB - Exposure to environmental stressors can be measured by monitoring the cellular stress response in target cells. Here, we used the cellular stress response to investigate whether single or combined radio frequency (RF) radiation could induce stress response in human cells. Cellular stress responses in MCF10A human breast epithelial cells were characterized after exposure to 4 h of RF radiation [code division multiple access (CDMA) or CDMA plus wideband CDMA (WCDMA)] or 2 h RF radiation on 3 consecutive days. Specific absorption rate (SAR) was 4.0 W/kg for CDMA signal alone exposure and 2.0 W/kg each, 4.0 W/kg in total for combined CDMA plus WCDMA signals. Expression levels and phosphorylation states of specific heat shock proteins (HSPs) and mitogen-activated protein kinases (MAPKs) were analyzed by Western blot. It was found that HSP27 and ERK1/2 phosphorylations are the most sensitive markers of the stress response in MCF10A cells exposed to heat shock or ionizing radiation. Using these markers, we demonstrated that neither one-time nor repeated single (CDMA alone) or combined (CDMA plus WCDMA) RF radiation exposure significantly altered HSP27 and ERK1/2 phosphorylations in MCF10A cells (p > 0.05). The lack of a statistically significant alteration in HSP27 and ERK1/2 phosphorylations suggests that single or combined RF radiation exposure did not elicit activation of HSP27 and ERK1/2 in MCF10A cells. PMID- 22510590 TI - Plutonium behavior after pulmonary administration according to solubility properties, and consequences on alveolar macrophage activation. AB - The physico-chemical form in which plutonium enters the body influences the lung distribution and the transfer rate from lungs to blood. In the present study, we evaluated the early lung damage and macrophage activation after pulmonary contamination of plutonium of various preparation modes which produce different solubility and distribution patterns. Whatever the solubility properties of the contaminant, macrophages represent a major retention compartment in lungs, with 42 to 67% of the activity from broncho-alveolar lavages being associated with macrophages 14 days post-contamination. Lung changes were observed 2 and 6 weeks post-contamination, showing inflammatory lesions and accumulation of activated macrophages (CD68 positive) in plutonium-contaminated rats, although no increased proliferation of pneumocytes II (TTF-1 positive cells) was found. In addition, acid phosphatase activity in macrophages from contaminated rats was enhanced 2 weeks post-contamination as compared to sham groups, as well as inflammatory mediator levels (TNF-alpha, MCP-1, MIP-2 and CINC-1) in macrophage culture supernatants. Correlating with the decrease in activity remaining in macrophages after plutonium contamination, inflammatory mediator production returned to basal levels 6 weeks post-exposure. The production of chemokines by macrophages was evaluated after contamination with Pu of increasing solubility. No correlation was found between the solubility properties of Pu and the activation level of macrophages. In summary, our data indicate that, despite the higher solubility of plutonium citrate or nitrate as compared to preformed colloids or oxides, macrophages remain the main lung target after plutonium contamination and may participate in the early pulmonary damage. PMID- 22510591 TI - Effects of ionizing radiation on proliferation and differentiation of mouse induced pluripotent stem cells. AB - The present study aimed to estimate the clonogenic and differentiation potential of induced pluripotent stem (iPS) cells exposed to ionizing radiation. Compared with mouse hematopoietic stem/progenitor cells, iPS cells were less sensitive to radiation. To examine the effect of ionizing radiation on the early differentiation pathway of iPS cells, we assessed embryoid body (EB) formation. Although EB formation was observed at all radiation doses, EB diameter decreased in a radiation dose-dependent manner. At the same time, we analyzed the expression of genes specific to differentiation in the initial iPS cells and cells of EB. The expression of the endoderm marker Afp increased remarkably in cells of EB derived from non-irradiated iPS cells; however, in irradiated cells, this expression significantly decreased in a radiation dose-dependent manner. Further, the expressions of the pluripotent stem cell markers Nanog and Oct-4 and the early mesoderm marker Brachyury significantly decreased. The results of the present study suggest that radiosensitivity with regard to gene expression differs at various stages in the early differentiation pathways of iPS cells that lead to the formation of the 3 germ layers; the sensitivity is the highest in the genes expressed during the differentiation pathways of iPS cells, leading to the formation of the endoderm. PMID- 22510592 TI - Combination of radiotherapy and adenovirus-mediated p53 gene therapy for MDM2 overexpressing hepatocellular carcinoma. AB - The p53 gene plays a determinant role in radiation-induced cell death and its protein product is negatively regulated by MDM2. We investigated whether adenovirus-mediated modified p53 gene transfer, which blocks p53-MDM2 binding, is effective for radiation-induced cell death in hepatocellular carcinoma (HCC) at different MDM2 cellular levels. Human hepatocellular carcinoma cell lines expressing MDM2 at low levels (Huh7) and high levels (SK-Hep1) were used. Ad-p53 and Ad-p53vp are replication-deficient adenoviral vectors containing human wild type or modified p53, respectively. The anti-tumor effect was highest for Ad-p53 + radiotherapy (RT) in the low-level MDM2 cells, whereas this effect was highest for Ad-p53vp + RT in the MDM2-overexpressing cells. In Huh-7 cells, Ad-p53 + RT decreased cell viability (32%) in vitro and inhibited tumor growth (enhancement factor, 1.86) in vivo. Additionally, p21 expression and apoptosis were increased. In contrast, in SK-Hep1 cells, Ad-p53vp + RT showed decreased cell viability (51%) in vitro and inhibition of tumor growth (enhancement factor, 3.07) in vivo. Caspase-3 expression and apoptosis were also increased. Adenovirus-expressing modified p53, which blocks p53-MDM2 binding, was effective in killing tumor cells overexpressing MDM2. Furthermore, the combination strategy for disruption of the p53-MDM2 interaction with RT demonstrated enhanced anti-tumor effects both in vitro and in vivo. PMID- 22510593 TI - Protection of mice against X-ray injuries by the post-irradiation administration of inosine-5'-monophosphate. AB - The aim of the present study was to investigate the radiation modulating properties of inosine-5'-monophosphate (IMP). Mice injected introperitoneally (i.p.) with IMP 15 minutes after irradiation with a lethal irradiation dose of 7 Gy have better survival rates comparative to irradiated mice non treated with IMP. The dose reduction factor of the IMP is 1.22. Using a hematologdical test we demonstrated that administration of IMP alleviates the symptoms of radiation induced leukopenia and thrombocytopenia. The DNA damage in bone marrow and thymus cells of irradiated mice was measured by flow cytofluorometry and micronucleus test (MN-test). The tests show that i.p. administration of IMP to irradiated animals leads to a significant reduction of the DNA damage level. In this paper we show that IMP substantially modulates the damaging effects of ionizing radiation protecting irradiated mice and it is a promising agent for a treatment of leukopenia. PMID- 22510594 TI - Long-term sequential changes of radiation proctitis and angiopathy in rats. AB - The purpose of the present study was to establish an experimental rat model for late radiation proctitis, and to examine the assessment strategy for late radiation proctitis. A total of 57 Wistar rats were used. Fourty-five of the rats were exposed to selective rectal irradiation with a single fraction of 25 Gy. These rats were sacrificed at the 4(th), 12(th), 24(th), and 37(th) week following irradiation. The remaining 12 rats comprised the control group without irradiation. The rectal mucosa of each rat was evaluated macroscopically and pathologically. The number of vessels in the rectal mucosa was counted microscopically. In addition, the vascular stenosis was evaluated. In the results, the degree of clinical and macroscopic findings decreased following acute proctitis and developed later. In the pathological examination, mucosal changes and microangiopathy were followed up, as well. The absolute number of vessels in the rectum was the greatest at the 12(th) week following irradiation and was the lowest in the control group. The severity of the microangiopathy was also well evaluated. To conclude, we established an animal experimental model of late radiation proctitis, and also established an assessment strategy to evaluate objectively the severity of late radiation proctitis with focusing on microangiopathy using an animal experimental model. This model can be used as an animal experimental model of radiation-induced microangiopathy. PMID- 22510595 TI - Cell killing and radiosensitizing effects of atorvastatin in PC3 prostate cancer cells. AB - Recent studies have indicated that autophagy may be one of the important pathways induced by ionizing radiation. Atorvastatin (statin), an inhibitor of 3-hydroxyl 3-methylglutaryl coenzyme A (HMG-CoA) reductase, may exhibit anticancer effects as an autophagy inducer. In our study, the cell killing and radiosensitizing effects of statin were analyzed in PC3 cell line. Activation of the autophagy pathway was analyzed using the GFP-LC3 assay and western blot to determine LC3-II expression. The radiosensitivity of PC3 cells was determined using the clonal survival assay, TUNEL assay, and the Annexin V apoptosis assay. The expression profiles of autophagy related genes were analyzed using a pathway specific real time polymerase chain reaction (PCR) array. Autophagic response was induced in PC3 cells after exposure to statin and/or gamma rays. Inhibition of the autophagic process using small interfering RNAs (siRNA) targeting Atg7 and/or Atg12 significantly reduced radiosensitivity of PC3 cells. Statin also exhibited a significant apoptosis-inducing effect in PC3 cells, which can be partially suppressed by Atg7 siRNA. Cells treated with statin and gamma irradiation showed significantly reduced colony forming efficiency and increased number of Annexin V positive early apoptotic cells. Analysis of autophagy and its regulatory gene profile showed that the expressions of 22 genes out of 86 genes assessed were significantly altered in the cells exposed to combined treatment or statin alone. The data indicate that activation of the autophagy pathway may be responsible for apoptosis inducing effect of statin. Furthermore, combined treatment with radiation and autophagic inducer, such as statin, may be synergistic in inducing cell death of PC3 cells. PMID- 22510596 TI - NEIL1 mRNA splicing variants are expressed in normal mouse organs. AB - Oxidized pyrimidines are mainly repaired by base excision repair, which is initiated by damage-specific DNA glycosylases. NEIL1, the mammalian homolog of Escherichia coli endonuclease VIII and a major DNA glycosylase, initiates repair of oxidized pyrimidines. Here, we investigated the expression of two putative variant mouse NEIL1 (mNEIL1) mRNAs--variant 1 ("Neil1 protein" mRNA; BC043297 in the NCBI database) and variant 2 ("unnamed protein" mRNA; AK040802 in the NCBI database)--in normal mouse organs. Reverse transcription-PCR showed that both mRNAs were expressed in total RNA samples from 9 organs. Immunoblot analysis of a nuclear extract from normal mouse liver revealed three bands corresponding to full-length mNEIL1 protein and the two predicted variant proteins. However, neither variant protein, which included an N-terminal enzymatic activity domain deduced from the mRNA variants, were enzymatically active under multiple reaction conditions when expressed as his-tagged recombinant proteins. Nevertheless, recombinant variant 1 protein influenced mNEIL1 activity, while recombinant variant 2 protein had no influence. These results suggest that mNEIL1 mRNA variants are expressed in a variety of organs in normal mice and that variant 1 protein may regulate mNEIL1 activity. PMID- 22510597 TI - Effects of depletion of dihydropyrimidine dehydrogenase on focus formation and RPA phosphorylation. AB - Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase (DPYD), partially inhibits homologous recombination (HR) repair and has a radiosensitizing effect as well as enhanced sensitivity to Camptothecin (CPT). DPYD is the target protein for radiosensitization by Gimeracil. We investigated the mechanisms of sensitization of radiation and CPT by DPYD inhibition using DLD-1 cells treated with siRNA for DPYD. We investigated the focus formation of various kinds of proteins involved in HR and examined the phosphorylation of RPA by irradiation using Western blot analysis. DPYD depletion by siRNA significantly restrained the formation of radiation-induced foci of Rad51 and RPA, whereas it increased the number of foci of NBS1. The numbers of colocalization of NBS1 and RPA foci in DPYD-depleted cells after radiation were significantly smaller than in the control cells. These results suggest that DPYD depletion is attributable to decreased single-stranded DNA generated by the Mre11/Rad50/NBS1 complex-dependent resection of DNA double-strand break ends. The phosphorylation of RPA by irradiation was partially suppressed in DPYD-depleted cells, suggesting that DPYD depletion may partially inhibit DNA repair with HR by suppressing phosphorylation of RPA. DPYD depletion showed a radiosensitizing effect as well as enhanced sensitivity to CPT. The radiosensitizing effect of DPYD depletion plus CPT was the additive effect of DPYD depletion and CPT. DPYD depletion did not have a cell killing effect, suggesting that DPYD depletion may not be so toxic. Considering these results, the combination of CPT and drugs that inhibit DPYD may prove useful for radiotherapy as a method of radiosensitization. PMID- 22510598 TI - Radiosensitization by inhibiting complex I activity in human hepatoma HepG2 cells to X-ray radiation. AB - The purpose of this study is to investigate the influence of mitochondrial respiratory chain complex I inhibition on the radiosensitivity of HepG2 cells. The complex I inhibitor rotenone was used to inhibit complex I activity on HepG2 cells before X-ray irradiation. The cytotoxicity of rotenone was analyzed by MTT assay at various doses. Rotenone induced dissipation of mitochondrial membrane potential and increase of intracellular ROS production were observed. Intracellular ATP production level was determined using luciferin-luciferase assay kit. We further analyzed cell survival and cell cycle distribution of a combined treatment which HepG2 cells underwent 0.5 uM rotenone pretreatment firstly and irradiated with different doses of X-ray radiation afterwards. Our results suggest rotenone pretreatment prior to X-ray irradiation could induce a sensitizing effect on HepG2 cells by enhancing X-ray radiation induced proliferation inhibition and cell apoptosis. PMID- 22510599 TI - Systematic measurement of lineal energy distributions for proton, He and Si ion beams over a wide energy range using a wall-less tissue equivalent proportional counter. AB - The frequency distributions of the lineal energy, y, of 160 MeV proton, 150 MeV/u helium, and 490 MeV/u silicon ion beams were measured using a wall-less tissue equivalent proportional counter (TEPC) with a site size of 0.72 um. The measured frequency distributions of y as well as the dose-mean values, y(D), agree with the corresponding data calculated using the microdosimetric function of the particle and heavy ion transport code system PHITS. The values of y(D) increase in the range of LET below ~10 keV um(-1) because of discrete energy deposition by delta rays, while the relation is reversed above ~10 keV um(-1) as the amount of energy escaping via delta rays increases. These results indicate that care should be taken with the difference between y(D) and LET when estimating the ionization density that usually relates to relative biological effectiveness (RBE) of energetic heavy ions. PMID- 22510600 TI - The effects of two HDR brachytherapy schedules in locally advanced cervical cancer treated with concurrent chemoradiation: a study from Chiang Mai, Thailand. AB - Efficacy of different schedules of HDR brachytherapy in concurrent chemoradiotherapy was evaluated. The study compared the effectiveness of the two HDR brachytherapy schedules which have the same Biological Effective Dose (BED) in locally advanced cervical carcinoma that was treated with concurrent chemoradiotherapy. Included in the study were 377 randomly selected patients with advanced carcinoma of the cervix uteri who were treated during the period 2004 2006. Patients were divided into Group I: 7.2 Gy * 3 fractions and Group II: 6 Gy * 4 fractions. With a median follow-up time of 35 months, local control, disease free survival and overall survival rates were 80.8%, 63.4%, 98.8% in group I and 86.7%, 63.8%, 97.3% in group II, respectively. There was no statistical significance in terms of local control, disease-free survival, overall survival and complication rates between the two treatment schedules which could be observed. Seven patients in group I developed acute grade 2-4 GI toxicities and two patients in group II. In GU toxicities, there were three patients in group I and three patients in group II who developed grade 2-4 toxicities. In late toxicity, no patient developed grade 3-4 GU toxicities in group I while two patients developed grade 3-4 GU toxicities in group II. In GI toxicities, there were five and six patients in group I and group II, respectively, who developed grade 3-4 severity. Both HDR schedules seem to be safe and effective for the treatment of locally advanced cervical cancer. PMID- 22510602 TI - International, multicenter randomized preclinical trials in translational stroke research: it's time to act. PMID- 22510601 TI - Anesthesia and the quantitative evaluation of neurovascular coupling. AB - Anesthesia has broad actions that include changing neuronal excitability, vascular reactivity, and other baseline physiologies and eventually modifies the neurovascular coupling relationship. Here, we review the effects of anesthesia on the spatial propagation, temporal dynamics, and quantitative relationship between the neural and vascular responses to cortical stimulation. Previous studies have shown that the onset latency of evoked cerebral blood flow (CBF) changes is relatively consistent across anesthesia conditions compared with variations in the time-to-peak. This finding indicates that the mechanism of vasodilation onset is less dependent on anesthesia interference, while vasodilation dynamics are subject to this interference. The quantitative coupling relationship is largely influenced by the type and dosage of anesthesia, including the actions on neural processing, vasoactive signal transmission, and vascular reactivity. The effects of anesthesia on the spatial gap between the neural and vascular response regions are not fully understood and require further attention to elucidate the mechanism of vascular control of CBF supply to the underlying focal and surrounding neural activity. The in-depth understanding of the anesthesia actions on neurovascular elements allows for better decision-making regarding the anesthetics used in specific models for neurovascular experiments and may also help elucidate the signal source issues in hemodynamic-based neuroimaging techniques. PMID- 22510603 TI - CD36 is involved in astrocyte activation and astroglial scar formation. AB - Inflammation is an essential component for glial scar formation. However, the upstream mediator(s) that triggers the process has not been identified. Previously, we showed that the expression of CD36, an inflammatory mediator, occurs in a subset of astcotyes in the peri-infarct area where the glial scar forms. This study investigates a role for CD36 in astrocyte activation and glial scar formation in stroke. We observed that the expression of CD36 and glial fibrillary acidic protein (GFAP) coincided in control and injured astrocytes and in the brain. Furthermore, GFAP expression was attenuated in CD36 small interfering RNA transfected astrocytes or in the brain of CD36 knockout (KO) mice, suggesting its involvement in GFAP expression. Using an in-vitro model of wound healing, we found that CD36 deficiency attenuated the proliferation of astrocytes and delayed closure of the wound gap. Furthermore, stroke-induced GFAP expression and scar formation were significantly attenuated in the CD36 KO mice compared with wild type. These findings identify CD36 as a novel mediator for injury-induced astrogliosis and scar formation. Targeting CD36 may serve as a potential strategy to reduce glial scar formation in stroke. PMID- 22510605 TI - Systematic evaluation of structure-activity relationships of the riminophenazine class and discovery of a C2 pyridylamino series for the treatment of multidrug resistant tuberculosis. AB - Clofazimine, a member of the riminophenazine class of drugs, is the cornerstone agent for the treatment of leprosy. This agent is currently being studied in clinical trials for the treatment of multidrug-resistant tuberculosis to address the urgent need for new drugs that can overcome existing and emerging drug resistance. However, the use of clofazimine in tuberculosis treatment is hampered by its high lipophilicity and skin pigmentation side effects. To identify a new generation of riminophenazines that is less lipophilic and skin staining, while maintaining efficacy, we have performed a systematic structure-activity relationship (SAR) investigation by synthesizing a variety of analogs of clofazimine and evaluating their anti-tuberculosis activity. The study reveals that the central tricyclic phenazine system and the pendant aromatic rings are important for anti-tuberculosis activity. However, the phenyl groups attached to the C2 and N5 position of clofazimine can be replaced by a pyridyl group to provide analogs with improved physicochemical properties and pharmacokinetic characteristics. Replacement of the phenyl group attached to the C2 position by a pyridyl group has led to a promising new series of compounds with improved physicochemical properties, improved anti-tuberculosis potency, and reduced pigmentation potential. PMID- 22510604 TI - Refining the mismatch concept in acute stroke: lessons learned from PET and MRI. AB - In ischemic stroke, positron-emission tomography (PET) established the imaging based concept of penumbra. It defines hypoperfused, but functionally impaired, tissue with preserved viability that can be rescued by timely reperfusion. Diffusion-weighted and perfusion-weighted (PW) magnetic resonance imaging (MRI) translated the concept of penumbra to the concept of mismatch. However, the use of mismatch-based patient stratification for reperfusion therapy remains a matter of debate. The equivalence of mismatch and penumbra, as well as the validity of the classical mismatch concept is questioned for several reasons. First, methodological differences between PET and MRI lead to different definitions of the tissue at risk. Second, the mismatch concept is still poorly standardized among imaging facilities causing relevant variability in stroke research. Third, relevant conceptual issues (e.g., the choice of the adequate perfusion measure, the best quantitative approach to perfusion maps, and the required size of the mismatch) need further refinement. Fourth, the use of single thresholds does not account for the physiological heterogeneity of the penumbra and probabilistic approaches may be more promising. The implementation of this current knowledge into an optimized state-of-the-art mismatch model and its validation in clinical stroke studies remains a major challenge for future stroke research. PMID- 22510606 TI - A support vector machine classification model for benzo[c]phenathridine analogues with toposiomerase-I inhibitory activity. AB - Benzo[c]phenanthridine (BCP) derivatives were identified as topoisomerase I (TOP I) targeting agents with pronounced antitumor activity. In this study, a support vector machine model was performed on a series of 73 analogues to classify BCP derivatives according to TOP-I inhibitory activity. The best SVM model with total accuracy of 93% for training set was achieved using a set of 7 descriptors identified from a large set via a random forest algorithm. Overall accuracy of up to 87% and a Matthews coefficient correlation (MCC) of 0.71 were obtained after this SVM classifier was validated internally by a test set of 15 compounds. For two external test sets, 89% and 80% BCP compounds, respectively, were correctly predicted. The results indicated that our SVM model could be used as the filter for designing new BCP compounds with higher TOP-I inhibitory activity. PMID- 22510607 TI - Isolation and identification of myo-inositol crystals from dragon fruit (Hylocereus polyrhizus). AB - Crystals isolated from Hylocereus polyrhizus were analyzed using four different approaches--X-ray Crystallography, High Performance Liquid Chromatography (HPLC), Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) and Nuclear Magnetic Resonance (NMR) and identified as myo-inositol. The X-ray crystallography analysis showed that the unit-cell parameters were: a = 6.6226 (3) A, b = 12.0462 (5) A, c = 18.8942 (8) A, alpha = 90.00, beta = 93.98, delta = 90.00. The purity of the crystals were checked using HPLC, whereupon a clean single peak was obtained at 4.8 min with a peak area of 41232 MUV*s. The LC-MS/MS technique, which is highly sensitive and selective, was used to provide a comparison of the isolated crystals with a myo-inositol standard where the results gave an identical match for both precursor and product ions. NMR was employed to confirm the molecular structure and conformation of the crystals, and the results were in agreement with the earlier results in this study. The discovery of myo-inositol crystals in substantial amount in H. polyrhizus has thus far not been reported and this is an important finding which will increase the marketability and importance of H. polyrhizus as a crop with a wide array of health properties. PMID- 22510608 TI - A new isorhamnetin glycoside and other phenolic compounds from Callianthemum taipaicum. AB - A new flavonol glycoside together with five known phenolic compounds were isolated from the whole herb of Callianthemum taipaicum. The compounds were identified as isorhamnetin-3-O-alpha-L-arabinoside-7-O-beta-D-glucoside (1), isorhamnetin-3-O-beta-D-glucoside (2), dibutyl phthalate (3), (+)-1 hydroxylpinoresinol-4'-beta-D-glucoside (4), pinoresinol-4'-O-beta-D-glucoside (5) and 2-phenylethyl-beta-primeveroside (6). Compound 1 was identified as a new flavonol glycoside. The compound 6 was isolated for the first time as natural product. All compounds were isolated for the first time from the Callianthemum genus. Furthermore, the 2D-NMR data of the four known compounds 2-5 are given for the first time in this paper. All the structures were identified on the basis of detailed spectral analysis. The compounds 1 and 4 exhibited certain antifungal activity. PMID- 22510609 TI - Extraction and characterization of chitin from the beetle Holotrichia parallela Motschulsky. AB - Insect chitin was isolated from adult Holotrichia parallela by treatment with 1 M HCl and 1 M NaOH, following by 1% potassium permanganate solution for decolorization. The yield of chitin from this species is 15%. This insect chitin was compared with the commercial a-chitin from shrimp, by infrared spectroscopy, X-ray diffraction, scanning electron microscopy, and elemental analysis. Both chitins exhibited similar chemical structures and physicochemical properties. Adult H. parallela is thus a promising alternative source of chitin. PMID- 22510611 TI - Editorial to accompany--training the brain: fact and fad in cognitive and behavioral remediation. PMID- 22510610 TI - A significant association of plasma serotonin to cardiovascular risk factors and changes in pulse wave velocity in patients with type 2 diabetes. PMID- 22510612 TI - Micellar catalysis in aqueous-ionic liquid systems. AB - We present the application of ionic liquid-aqueous micellar solutions as reaction media for Diels-Alder reaction and found that reaction rates could be significantly increased compared to the reaction in water. PMID- 22510614 TI - The influence of oestrous substances on cyclicity and oestrous behaviour in dairy heifers. AB - BACKGROUND: Declining fertility is a major concern for dairy farmers today. One explanation is shorter and weaker expression of oestrus in dairy cows making it difficult to determine optimal time for artificial insemination (AI). Chemical communication is of interest in the search for tools to detect oestrus or to synchronise or enhance oestrous periods. Pheromones, used in chemical communication within species, can influence reproduction in different ways. The aim here was to investigate whether oestrous cycle length, and duration and intensity of oestrous expression in dairy heifers could be manipulated through exposure to pheromones in oestrual substances from other females. METHODS: Beginning on day 16 of two consecutive control oestrous cycles, ten heifers of the Swedish Red Breed (SRB) were exposed to water. During the two following cycles the heifers were exposed to urine and vaginal mucus, obtained from cows in oestrus. Cyclicity parameters were monitored through hormone measurements, oestrus detection and ultrasonographic examination. RESULTS: We found no difference in cycle length or in duration of standing oestrus between control and treatment. We did, however, find a tendency of interaction between type of exposure (control or treatment) and cycle number within type of exposure for cycle length (p = 0.068), with the length differing less between the treatment cycles. We also found a tendency of effect of type of exposure on maximal concentration (p = 0.073) and sum of concentrations (p = 0.063) of LH during the LH surge, with values being higher for the control cycles. There were also significant differences in when the different signs of oestrus occurred and in the intensity of oestrous expression. The score for oedema and hyperaemia of external genitalia was significantly higher (p = 0.004) for the control cycles and there was also a significant interaction between type of exposure and time period for restlessness (p = 0.011), with maximum score occurring earlier for treatment cycles. CONCLUSIONS: No evidence of altered oestrous cycle length or duration of oestrus after exposure of females to oestrous substances from other females was found. Expression of oestrus, and maybe also LH secretion, however, seemed influenced by the exposure, with the effect of treatment being suppressive rather than enhancing. PMID- 22510613 TI - Activation of multiple cancer pathways and tumor maintenance function of the 3q amplified oncogene FNDC3B. AB - FNDC3B was recently identified in an oncogenomic screen for amplified oncogenes in hepatocellular carcinoma. It is located at 3q26 and is amplified in over 20% of cancers, usually as part of a broad amplified region encompassing the entire 3q arm. Consistent with an oncogenic role in multiple cancer types, we show here that overexpression of FNDC3B is capable of malignantly transforming mammary and kidney epithelial cells in addition to hepatocytes. To explore how FNDC3B transforms cells, we determined the cellular localization of its gene product and the cancer pathways that it activates. We found that the FNDC3B oncoprotein localizes to the Golgi network, and that its correct localization is essential for its transforming function. We found that overexpression of FNDC3B induces the epithelial-to-mesenchymal transition (EMT) and activates several cancer pathways, including PI3-kinase/Akt, Rb1 and TGFbeta signaling. For TGFbeta signaling, we analyzed the point in the pathway at which FNDC3B operates and obtained evidence that it induces expression of all three TGFbeta ligands and also promotes TGFBR1 cell-surface localization. We found that RNAi-mediated knockdown of FNDC3B in cancer cells with 3q amplification suppressed their clonogenicity and tumorigenicity, but that the same RNAi knockdown had no effect on single-copy 3q cancer cells. These results indicate that FNDC3B is an important oncogenic driver gene of the 3q amplicon, adding to the growing list of oncogenic drivers within this commonly amplified region. PMID- 22510616 TI - An electrocardiogram for a patient with Biobrane(r) dressing. PMID- 22510617 TI - Ectopic pregnancy. Foreword. PMID- 22510615 TI - Food intake profiles of children aged 12, 24 and 48 months from the 2004 Pelotas (Brazil) birth cohort: an exploratory analysis using principal components. AB - OBJECTIVES: To identify food intake profiles of children during their first four years of life and assess its variations according to sociodemographic and behavioral characteristics. METHODS: The Pelotas Birth Cohort Study (Brazil) recruited 4,231 liveborns, who were followed-up at ages 3, 12, 24 and 48 months. Food consumption data of children aged 12, 24 and 48 months was collected using a list of foods consumed during a 24-hour period prior to the interview. The food profiles were identified with the use of principal component analysis (PCA) for each age studied. RESULTS: Five components were identified at each age, four of them similar in all time points, namely: beverages, milks, staple, and snacks. A meat & vegetables component was identified at 12 and 24 months and a treats component at 48 months. The greatest nutritional differences were found among children from different socioeconomic levels. With regard to the milks component, higher breast milk intake compared to cow's milk was seen among poorer children (12- and 24-month old) and higher milk and chocolate powdered milk drink consumption was seen among more affluent children aged 48 months. Poorer children of less educated mothers showed higher adherence to the treats component (48 months). Regarding to the snack component, poorer children consumed more coffee, bread/cookies while more affluent children consumed proportionately more fruits, yogurt and soft drinks. Child care outside of the home was also a factor influencing food profiles more aligned with a healthier diet. CONCLUSIONS: The study results showed that very early in life children show food profiles that are strongly associated with social (maternal schooling, socioeconomic position and child care) and behavioral characteristics (breast-feeding duration, bottle feeding and pacifier use). PMID- 22510618 TI - Ectopic pregnancy: History, incidence, epidemiology, and risk factors. AB - Ectopic pregnancy is directly related to tubal infection, and so prevention of chlamydia and gonorrhea must be the watchword to lower its risk and incidence. With accurate determination of very low human chorionic gonadotropin concentrations and sonography, >85% of women are diagnosed before tubal rupture, which has led to medical therapy and laparoscopic surgery with tubal preservation and the potential for future fertility. Today, early intervention saves lives and reduces morbidity, but ectopic pregnancy still accounts for 4% to 10% of pregnancy-related deaths and leads to a high incidence of ectopic site gestations in subsequent pregnancies. PMID- 22510619 TI - Diagnosis of ectopic pregnancy. AB - The declining death rate from ectopic pregnancy over the last 30 years has resulted not from improvements in operative technique, anesthesia, or blood banking but primarily due to more rapid diagnosis that allows for earlier treatment. Algorithms have been developed to eliminate delays in ordering the various diagnostic tests in the appropriate order. Diagnostic tests include serum human chorionic gonadotropin and progesterone levels, culdocentesis, dilatation and curettage, transvaginal ultrasound, and laparoscopy. PMID- 22510620 TI - Ultrasound in the diagnosis of ectopic pregnancy. AB - The majority of ectopic pregnancies can be diagnosed on transvaginal scan before treatment. Diagnosis should be based on positive visualization of an ectopic pregnancy rather the inability to visualize an intrauterine pregnancy. The majority of ectopic pregnancies will be visible on the initial transvaginal scan performed. Those who do not have their ectopic pregnancies visualized on the first examination will be initially classified as having a pregnancy of unknown location. They will then need follow-up until a diagnosis of ectopic pregnancy is confirmed. This review discusses the use of ultrasound in the diagnosis of ectopic pregnancy and the specific criteria for diagnosis of the different types of ectopic pregnancy. PMID- 22510621 TI - Ectopic pregnancy: Ultrasound diagnosis in modern management. AB - Ectopic pregnancy (EP) continues to be the number one cause of maternal deaths in the first trimester of pregnancy. Over the past 30 years, several key developments including accurate and rapid serum human chorionic gonadotrophin assays, the introduction of high-resolution transvaginal probes and more recently tertiary hospital Early Pregnancy Units have changed the management of EPs. Early transvaginal ultrasound diagnosis of EP not only potentially decreases mortality and surgical intervention rates, but also promotes modern management options including expectant or medical management. The aim of this review is to demonstrate that transvaginal ultrasound is the new 'gold standard' diagnostic tool of choice for all forms of EP. PMID- 22510622 TI - hCG in ectopic pregnancy. AB - Ectopic pregnancies remain an important cause of morbidity and mortality in women of reproductive age. Management of these pregnancies has changed dramatically over the years. Human chorionic gonadotropin (hCG) is a glycoprotein hormone composed of 2 dissimilar subunits, alpha and beta, joined non-covalently. The free beta-subunit is the principal immuno-reactive agent in pregnancy serum samples. Improved diagnostic methods using hCG levels in combination with transvaginal ultrasound have lead to earlier detection rates, subsequent treatment and a reduction in mortality resulting from ectopic pregnancies. This chapter will describe current trends in ectopic pregnancy diagnosis based on hCG levels. PMID- 22510624 TI - Medical management of ectopic pregnancy. AB - The use of medical management of ectopic pregnancy has become an accepted alternative to surgical therapy. Methotrexate, a folic acid antagonist, is the most widely studied agent. The most commonly used protocol consists of methotrexate 50 mg/m of actual body weight. Assessment of human chorionic gonadotropin (hCG) levels is repeated on days 4 and 7. Repeat methotrexate dosing is performed for hCG drops < 15%. Contraindications include hemodynamically unstable patients or those with elevated liver enzymes, low white blood count, or abnormal renal function. hCG levels are most predictive of success. A success rate of above 90% is achievable. PMID- 22510623 TI - Serum biomarkers for detecting ectopic pregnancy. AB - Unless an ectopic pregnancy is visible by ultrasound, diagnosis can be a challenge. Differentiating ectopic pregnancies from intrauterine pregnancies can be impossible without intervention or follow-up. This poses a clinical dilemma to the practitioner given the inherent danger to the mother of tubal rupture of an ectopic pregnancy versus the fear of intervening in the case of a desired pregnancy without certainty of diagnosis. Early diagnostic modalities are clearly lacking, and serum biomarkers are currently being investigated as a solution to need for a rapid and accurate test for ectopic pregnancy. PMID- 22510625 TI - Methotrexate: the pharmacology behind medical treatment for ectopic pregnancy. AB - Previously established as a chemotherapeutic agent for decades, methotrexate has been adapted for use as a medical therapy for unruptured ectopic pregnancies. Its mechanism of action, competitive inhibition of folate-dependent steps in nucleic acid synthesis, effectively kills the rapidly dividing ectopic trophoblast. However, the same action on normal cells is the basis for many of its adverse effects. PMID- 22510627 TI - Surgical management of ectopic pregnancy. AB - Surgery remains an acceptable, and sometimes necessary, modality for the treatment of ectopic pregnancy. Laparoscopy is the preferred method of access, yet controversy remains regarding the optimal procedure and postoperative management. Generally, salpingostomy is employed with the goal of maintaining fertility, although data to support this tenet are lacking. In most cases, the decision to perform conservative versus radical surgery is on the basis of the patient's history, her desire for future fertility, and surgical findings. The procedures of salpingostomy and salpingectomy, techniques to prevent and control blood loss at the time of surgery, and surgical options for nontubal ectopic pregnancies are reviewed. PMID- 22510626 TI - Medical management of ectopic pregnancy: a comparison of regimens. AB - Medical management has become increasingly popular in the treatment of ectopic pregnancy. Given its convenience, for many it is used as a first-line treatment, however, this is not always the optimal choice for the patient. It is important to understand the options for medical treatment and when it is appropriate to treat a particular patient with medical management, or when one should opt for surgical management. This review outlines the different regimens for methotrexate administration and the associated risks and benefits to medical management. PMID- 22510628 TI - Reproductive outcomes after medical and surgical management of ectopic pregnancy. AB - Ectopic pregnancies have a negative impact on future fertility. Prompt diagnosis is paramount to preserve tubal function and reproductive potential. Expectant, medical, and surgical management of ectopic pregnancies have similar efficacy in properly selected patients. Medical management has emerged as a safe alternative to surgery and holds promise for preservation of future fertility. Laparoscopic salpingostomy or salpingectomy remains the preferred means of surgical removal of ectopic pregnancies. The most predictive factor of future fertility is the health of the contralateral tube. PMID- 22510629 TI - Expectant management of ectopic pregnancy. AB - This article will provide a review of the literature regarding expectant management of ectopic pregnancy. Detailed definitions and methods of evaluation are discussed, as well as pooled existing data on success rates of expectant management. A comparison of expectant management versus other treatment options is provided as well as a review of fertility outcomes after expectant management of ectopic pregnancy. PMID- 22510630 TI - Prevention of infection in the obstetric patient. Foreword. PMID- 22510631 TI - Vaccines in pregnant women and research initiatives. AB - Successful maternal immunization requires consideration of maternal and infant disease burden, biological factors affecting immune response and placental transport of antibodies, optimal timing of immunization, safety and acceptability. Tetanus, inactivated influenza and acellular pertussis vaccines are recommended during pregnancy; others are recommended when maternal risk of infection is high. The development of new conjugate vaccines for use in adults may reduce global maternal and infant disease burden. Maternal immunization against group B streptococcus is projected to be superior to current preventative strategies in decreasing disease. Further evaluation of maternal immunization strategies to prevent maternal and infant infections is needed. PMID- 22510632 TI - Influenza and pregnancy in the United States: before, during, and after 2009 H1N1. AB - Because pregnant women were recognized to be at increased risk for influenza associated complications, special considerations for this population were included as part of preparedness efforts before the 2009 H1N1 pandemic. We review data available before the pandemic on influenza and its treatment and prevention during pregnancy. We also review pandemic preparedness efforts aimed at pregnant women and how these efforts served as a foundation for recommendations during the pandemic. Data on 2009 H1N1 influenza in pregnant women and their infants are summarized, and the application of these data to recommendations for pregnant women in future influenza seasons and pandemics is discussed. PMID- 22510633 TI - Prevention of pertussis, tetanus, and diphtheria among pregnant, postpartum women, and infants. AB - Pertussis disease in the United States has been increasing since 1976 and many states are reporting epidemics. Pertussis is more severe in infants less than 3 months of age and is characterized by high hospital admission rates, apnea of the infant. The CDC recommends that Tdap be administered to all pregnant women after the 20th week of gestation to provide pertussis antibodies to the fetus which will offer protection against pertussis disease. Tdap is highly immunogenetic in the pregnant women and has an excellent safety profile. Tdap given to the postpartum patient and her cocoon family is an alternative strategy. PMID- 22510634 TI - Preventing neonatal transmission of herpes simplex virus. AB - Herpes simplex virus (HSV) infections are highly prevalent and may have devastating consequences if transmitted to newborns. The highest risk of transmission is when the mother has primary HSV infection (rather than recurrence of chronic infection) late in pregnancy. Clinicians should obtain a careful history, performing serologic testing and counseling as appropriate. Delayed diagnosis of neonatal HSV is associated with high mortality. Even with adequate treatment, permanent sequelae, such as cerebral palsy and developmental delay, may occur. Clinicians should develop prudent strategies to avoid primary HSV acquisition during pregnancy, and provide prophylaxis or treatment when indicated. PMID- 22510636 TI - Management of HIV in the pregnant woman. AB - The treatment of human immunodeficiency virus (HIV)-infected pregnant women is one of the most effective HIV-prevention interventions known. With prenatal testing, antiviral therapy, scheduled cesarean section when indicated, and formula feeding when feasible, rates of neonatal and perinatal HIV infection can diminish significantly. Although significant prevention is achievable, new cases of HIV in neonates continue to occur both worldwide and locally due to limited resources, delayed diagnosis, lack of linkage to care, and lack of timely effective therapy. Where those resources are available, the management of HIV infection in the pregnant woman requires a multidisciplinary expert approach to achieve optimal outcomes for both mother and child. PMID- 22510635 TI - Prevention of maternal and congenital cytomegalovirus infection. AB - Congenital cytomegalovirus (CMV) infection is an important cause of hearing impairment, mental retardation, and cerebral palsy. Principal sources of infection during pregnancy are young children and intimate contacts. Prevention of maternal and congenital CMV infection depends on counseling women regarding the sources of infection and hygienic measures that might prevent infection. There is currently insufficient evidence to support use of antiviral treatment or passive immunization for postexposure prophylaxis of pregnant women or as a maternal treatment aimed at preventing fetal infection. Vaccines for CMV are under development but it will be a number of years before one is licensed. PMID- 22510637 TI - Hepatitis B: Treatment to prevent perinatal transmission. AB - Hepatitis B remains a significant health issue and a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Transmission of the hepatitis B virus, despite the availability of the vaccine, still occurs, particularly in the perinatal setting. Studies have shown that mothers with active viremia especially those with very high viral levels (>108 copies/mL or >107 IU/mL) are at increased risk of hepatitis B virus transmission, even with appropriate immunoprophylaxis at birth. With the development of new and relatively safe oral antiviral therapies, assessment with the mother about the risks and benefits of antiviral therapy should be discussed in those with highest transmission risk. PMID- 22510638 TI - Measles, mumps, and rubella. AB - Measles, mumps, and rubella are viral diseases that may adversely affect nonimmune pregnant women and their fetuses/neonates. Prevention of these diseases and their complications can be achieved through measles-mumps-rubella (MMR) vaccination before pregnancy. The vaccine is contraindicated during pregnancy, because it contains live, attenuated viruses that pose a theoretical risk to the fetus. However, accidental receipt of MMR vaccination is not known to cause maternal/fetal complications. MMR immunization is recommended to nonimmune obstetric patients upon completion or termination of pregnancy. PMID- 22510640 TI - Infection control and postexposure prophylaxis for the pregnant healthcare worker. AB - Pregnant health care workers (HCW) may be exposed to pathogens during routine patient care duties. Although they do not seem to be at higher risk for infection compared with nonpregnant HCW, certain infections can be associated with increased maternal morbidity, mortality, and adverse perinatal outcomes. Primary prevention through vaccination is crucial. Medical providers must know which vaccines are safe during pregnancy and which should be postponed until after delivery. Pregnancy should not be a contraindication for certain postexposure prophylaxis regimens after an occupational exposure. Pregnant HCW need to be educated about specific occupational risks and the recommended infection control precautions. PMID- 22510639 TI - Varicella-zoster virus: Prevention through vaccination. AB - Widespread use of varicella vaccine in the United States has drastically changed the epidemiology of the disease. Although chickenpox is no longer a ubiquitous childhood infection, varicella-zoster virus continues to circulate in the community and nonimmune pregnant women remain at risk. Varicella can cause severe infection in pregnant women, often complicated by viral pneumonia. Maternal varicella occurring in the first half of pregnancy can cause the rare but devastating congenital varicella syndrome, whereas infection in the late stages of pregnancy may cause neonatal varicella. The best approach to avoiding the morbidity and mortality associated with chickenpox in pregnancy is to screen and vaccinate susceptible reproductive-age women. PMID- 22510644 TI - Neuroethology of prey capture in the barn owl (Tyto alba L.). AB - Barn owls are a model system for studying prey capture. These animals can catch mice by hearing alone, but use vision whenever light conditions allow this. The silent flight, the frontally oriented eyes, and the facial ruffs are specializations that evolved to optimize prey capture. The auditory system is characterized by high absolute sensitivity, a use of interaural time difference for azimuthal sound-localization over almost the total hearing range up to at least 9 kHz, and the use of interaural level difference for elevational sound localization in the upper frequency range. Response latencies towards auditory targets were shortened by covert attention, while overt attention helped to orient towards salient visual objects. However, only 20% of the fixation movements could be explained by the saliency of the fixated objects, suggesting a top-down control of attention. In a visual-search experiment the birds turned earlier and more often towards and spent more time at salient objects. The visual system also exhibits high absolute sensitivity, while the spatial resolution is not particularly high. Last but not least, head movements may be classified as fixations, translations, and rotations combined with translations. These motion primitives may be combined to complex head-movement patterns. With the expected easy availability of genetic techniques for specialists in the near future and the possibility to apply the findings in biomimetic devices prey capture in barn owls will remain an exciting field in the future. PMID- 22510645 TI - Mechanisms of traumatic shoulder injury in elite rugby players. AB - BACKGROUND: Shoulder injuries in rugby players are common, but the mechanisms of injury are less well understood. This study aims to elucidate common mechanisms of injury and identify the patterns of injury they produce. MATERIALS AND METHODS: Twenty-four elite rugby players, referred to the senior author for diagnosis and management of shoulder injuries, were selected. Videos of the injuries were independently reviewed by rugby-medical experts to describe the mechanisms of injury. The mechanisms reported were collated and analysed to determine the level of agreement between reviewers and conclude an overall description of injury mechanisms. RESULTS: The authors identified three mechanisms of shoulder injury from the video analysis. These are the 'Try Scorer', characterised by hyperflexion of the outstretched arm such as when scoring a try; the 'Tackler', extension of the abducted arm behind the player while tackling; and the 'Direct Impact', a direct blow to the arm or shoulder when held by the side in neutral or slight adduction. The Try Scorer and Tackler mechanisms both involve a levering force on the glenohumeral joint (GHJ). These mechanisms predominantly cause GHJ dislocation, with Bankart, reverse Bankart and superior labrum anterior-posterior tears. The Try-Scorer Mechanism also caused the majority (83%) of rotator cuff tears. The Direct Hit mechanism resulted in GHJ dislocation and labral injury in 37.5% of players and was most likely to cause acromioclavicular joint dislocation and scapula fractures, injuries that were not seen with the other mechanisms. CONCLUSION: Greater understanding of the mechanisms involved in rugby shoulder injury is useful in understanding the pathological injuries, guiding treatment and rehabilitation and aiding the development of injury-prevention methods. PMID- 22510646 TI - Microbial diversity in deep-sea methane seep sediments presented by SSU rRNA gene tag sequencing. AB - Microbial community structures in methane seep sediments in the Nankai Trough were analyzed by tag-sequencing analysis for the small subunit (SSU) rRNA gene using a newly developed primer set. The dominant members of Archaea were Deep-sea Hydrothermal Vent Euryarchaeotic Group 6 (DHVEG 6), Marine Group I (MGI) and Deep Sea Archaeal Group (DSAG), and those in Bacteria were Alpha-, Gamma-, Delta- and Epsilonproteobacteria, Chloroflexi, Bacteroidetes, Planctomycetes and Acidobacteria. Diversity and richness were examined by 8,709 and 7,690 tag sequences from sediments at 5 and 25 cm below the seafloor (cmbsf), respectively. The estimated diversity and richness in the methane seep sediment are as high as those in soil and deep-sea hydrothermal environments, although the tag-sequences obtained in this study were not sufficient to show whole microbial diversity in this analysis. We also compared the diversity and richness of each taxon/division between the sediments from the two depths, and found that the diversity and richness of some taxa/divisions varied significantly along with the depth. PMID- 22510647 TI - Radical gas-based DNA decontamination for ultra-sensitive molecular experiments. AB - In this study, we tested a radical gas-based decontamination technique to prevent possible DNA contamination by the air and/or equipment used in molecular experiments. We prepared 10(4) molecules of model DNA contaminant and placed the dried DNA into test tubes, which were then exposed to radical gas. Quantitative PCR analysis showed that, even after a short exposure time of 30 minutes, 99.54% of the model DNA contaminant was effectively decomposed to undetectable levels. Our results demonstrate that the radical gas-based treatment is a useful method for eliminating potential DNA contaminant in ultra-sensitive molecular experiments. PMID- 22510648 TI - Plant growth-promoting nitrogen-fixing enterobacteria are in association with sugarcane plants growing in Guangxi, China. AB - The current nitrogen fertilization for sugarcane production in Guangxi, the major sugarcane-producing area in China, is very high. We aim to reduce nitrogen fertilization and improve sugarcane production in Guangxi with the help of indigenous sugarcane-associated nitrogen-fixing bacteria. We initially obtained 196 fast-growing bacterial isolates associated with the main sugarcane cultivar ROC22 plants in fields using a nitrogen-deficient minimal medium and screened out 43 nitrogen-fixing isolates. Analysis of 16S rRNA gene sequences revealed that 42 of the 43 nitrogen-fixing isolates were affiliated with the genera Enterobacter and Klebsiella. Most of the nitrogen-fixing enterobacteria possessed two other plant growth-promoting activities of IAA production, siderophore production and phosphate solubilization. Two Enterobacter spp. strains of NN145S and NN143E isolated from rhizosphere soil and surface-sterilized roots, respectively, of the same ROC22 plant were used to inoculate micropropagated sugarcane plantlets. Both strains increased the biomass and nitrogen content of the sugarcane seedlings grown with nitrogen fertilization equivalent to 180 kg urea ha(-1), the recommended nitrogen fertilization for ROC22 cane crops at the seedling stage. (15)N isotope dilution assays demonstrated that biological nitrogen fixation contributed to plant growth promotion. These results suggested that indigenous nitrogen-fixing enterobacteria have the potential to fix N(2) associated with sugarcane plants grown in fields in Guangxi and to improve sugarcane production. PMID- 22510650 TI - Invest early and often. PMID- 22510649 TI - Chromatin as an expansive canvas for chemical biology. AB - Chromatin is extensively chemically modified and thereby acts as a dynamic signaling platform controlling gene function. Chromatin regulation is integral to cell differentiation, lineage commitment and organism development, whereas chromatin dysregulation can lead to age-related and neurodegenerative disorders as well as cancer. Investigating chromatin biology presents a unique challenge, as the issue spans many disciplines, including cell and systems biology, biochemistry and molecular biophysics. In recent years, the application of chemical biology methods for investigating chromatin processes has gained considerable traction. Indeed, chemical biologists now have at their disposal powerful chemical tools that allow chromatin biology to be scrutinized at the level of the cell all the way down to the single chromatin fiber. Here we present recent examples of how this rapidly expanding palette of chemical tools is being used to paint a detailed picture of chromatin function in organism development and disease. PMID- 22510660 TI - Immunology: Csk keeps LYP on a leash. PMID- 22510661 TI - Synthetic biology: Automated design of RNA devices. PMID- 22510663 TI - Resonant localized states and quantum percolation on random chains with power-law diluted long-range couplings. AB - We investigate the nature of one-electron eigenstates in power-law-diluted chains for which the probability of occurrence of a bond between sites separated by a distance r decays as p(r) = p/r(1+sigma). Using an exact diagonalization scheme and a phenomenological finite-size scaling analysis, we determine the quantum percolation transition phase diagram in the full parameter space (p,sigma). We show that the density of states displays singularities at some resonance energies associated with degenerate eigenstates localized in a pair of sites with special symmetries. This model is shown to present an intermediate phase for which there is classical percolation but no quantum percolation. Quantum percolation only takes place for sigma < 0.78, a value larger than the corresponding one for the Anderson transition in long-ranged coupled chains with random diagonal disorder. The fractality of critical wavefunctions is also characterized. PMID- 22510662 TI - Plant signaling: Deconstructing auxin sensing. PMID- 22510664 TI - An audit of the presurgical evaluation and patient selection for extratemporal resective epilepsy surgery in a resource-poor country. AB - PURPOSE: The selection of ideal candidates for extratemporal resective epilepsy surgery is a challenge in resource-poor countries because of the limited presurgical diagnostic facilities and their affordability. To audit the presurgical evaluation strategy and selection for extratemporal resective epilepsy surgery in a resource-poor region. METHODS: From the prospective database maintained at an epilepsy surgery center in southern India, we reviewed the data of consecutive patients who underwent presurgical evaluation from January 2005 through December 2008 for antiepileptic drug-resistant focal epilepsies emanating from the frontal, parietal and occipital lobes. Out of 285 patients, only 71 (24.9%) underwent resective surgery; the remaining 214 (75.1%) patients could not be selected for surgery. We inquired the reasons for their exclusion from surgery. RESULTS: The difference in the rates of seizure-free outcome between surgical and non-surgical groups was highly significant (73.2% vs. 7.7%, P<0.0005). The major reasons for exclusion from surgery were normal MRI in 107 (50%), inability to afford invasive EEG monitoring in 40 (18.7%) and lesion location adjacent to eloquent cortical areas in 27 (12.6%) patients. While clustering of seizures and presence of preoperative neurological deficits favored surgical selection, the presence of secondary generalized seizures and discordant interictal epileptiform abnormalities were associated with exclusion from surgery. CONCLUSIONS: We conclude that, in a resource-poor country, ideal candidates for extratemporal resective epilepsy surgery are those with well circumscribed lesions not adjoining eloquent cortical areas. In such patients, concordant EEG findings and absence of preoperative secondary generalized seizures reinforce selection for surgery. PMID- 22510665 TI - Comment: systematic review and meta-analysis of efficacy, safety, and tolerability data from randomized controlled trials of drugs used to treat postherpetic neuralgia. PMID- 22510666 TI - Psychometric properties of the Osteoporosis-specific Morisky Medication Adherence Scale in postmenopausal women with osteoporosis newly treated with bisphosphonates. AB - BACKGROUND: Poor adherence to oral osteoporosis medications is common. Strategies for improving adherence begin with identification of the problem. The 8-item Morisky Medication Adherence Scale for self-reported adherence to antihypertensive medications was modified for assessing adherence to oral osteoporosis medications. An evaluation of the measurement properties of the Osteoporosis-Specific Morisky Medication Adherence Scale (OS-MMAS) was needed. OBJECTIVE: To examine the psychometric properties of the OS-MMAS in women with postmenopausal osteoporosis. METHODS: Five hundred women aged 55 years and older with osteoporosis who were newly prescribed daily or weekly oral bisphosphonates between May 15, 2010, and August 15, 2010, were randomly selected from Kaiser Permanente Southern California, a large integrated health care delivery system, and mailed a self-administered survey that included the 8-item OS-MMAS, Self Efficacy for Appropriate Medication Use Scale (SEAMS), Beliefs about Medicines Questionnaire (BMQ), Treatment Satisfaction Questionnaire for Medication (TSQM), Gastrointestinal Symptom Rating Scale (GSRS), and 12-item Short-Form Health Survey (SF-12v2). OS-MMAS scores can range from 0 to 8, with higher scores indicating better medication adherence. Internal consistency reliability was evaluated using Cronbach alpha coefficient. Test-retest reliability was assessed using intraclass correlation coefficients (ICCs) in a subset of 102 participants. Construct validity was assessed using confirmatory factor analysis and correlations between OS-MMAS and related measures. RESULTS: Of 197 participants, 150 reported that they were still taking their bisphosphonate at the time of the survey and completed the OS-MMAS. Overall, 30.7%, 32.7%, and 36.7% had low, medium, and high OS-MMAS scores (<6, 6 to <8, and 8, respectively). Cronbach alpha was 0.82 and the ICC was 0.77. Convergent validity was supported by significant correlations with SEAMS, BMQ necessity, and TSQM scores. In confirmatory factor analysis, a single-factor scale was supported. CONCLUSIONS: The OS-MMAS showed strong psychometric properties with good reliability and construct validity and may provide a valuable assessment of self-reported medication adherence in women newly prescribed oral osteoporosis medications. PMID- 22510667 TI - Dantrolene sodium for the treatment of aldesleukin-induced rigors in a melanoma patient. AB - OBJECTIVE: To report the case of a 58-year-old male with melanoma who developed aldesleukin-induced rigors and was successfully treated with intravenous dantrolene sodium 20 mg and provide a review of the literature discussing other agents that have been used to treat drug-induced rigors. CASE SUMMARY: A 58-year old male was treated with 720,000 IU/kg of aldesleukin every 8 hours as part of his antimelanoma therapy. The patient developed rigors after aldesleukin administration and was successfully treated with 25 mg of meperidine. Later, he experienced renal dysfunction that was also linked to aldesleukin therapy and developed normeperidine-induced neurotoxicity requiring discontinuation of meperidine therapy. The rigors were treated with intravenous dantrolene sodium 20 mg every 4 hours, with complete resolution of symptoms. DISCUSSION: Several antineoplastic agents can cause rigors; many of these agents can also lead to renal failure. Several agents have been investigated for their use in the management of rigors but can cause adverse effects or are unsuitable in the setting of renal insufficiency or failure. Although meperidine remains the mainstay for the treatment and prevention of rigors, it can be associated with neurotoxicity in some patients, particularly those with impaired renal function. Given that dantrolene has been shown to be effective against rigors, it may be a useful alternative for patients who can not tolerate meperidine. Drugs with a more favorable adverse effect profile that are not eliminated through the kidneys are needed. CONCLUSIONS: In the oncology setting, severe rigors can result in the interruption of a patient's cancer therapy, which can increase the risk of treatment failure. Dantrolene may be a useful alternative for patients experiencing rigors who can not tolerate meperidine. PMID- 22510669 TI - Drug-drug interactions with glucagon-like peptide-1 receptor agonists. AB - OBJECTIVE: To review drug interaction studies of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and concurrent oral medications. DATA SOURCES: PubMed was searched (to December 5, 2011) using the terms exenatide, liraglutide, albiglutide, and lixisenatide. The search was limited to studies published in English and conducted in adults. Abstracts from the American Diabetes Association Scientific Sessions from 2004 through 2011 were also searched. STUDY SELECTION AND DATA EXTRACTION: All abstracts were screened for eligibility, which consisted of studies reporting the effects of GLP-1RA administration on the pharmacokinetics and pharmacodynamics of concurrent oral medications. Data extracted from eligible trials included study and population characteristics; pharmacokinetic parameters including maximum concentration (C(max)), time to maximum concentration (t(max)), and area under the concentration-time curve (AUC); and pharmacodynamic properties. DATA SYNTHESIS: Our search identified 254 potentially relevant articles; of those, 11 articles evaluating 15 drug interactions were reviewed. Only 1 study was conducted in patients with type 2 diabetes. Equivalence in AUC was demonstrated in the majority of drug interactions studied (11 of 15). The AUCs of acetaminophen and lovastatin were decreased after exenatide administration and those of lisinopril and digoxin were decreased after liraglutide administration. In 10 studies, GLP-1RAs decreased the C(max) and, in 14 studies, prolonged the t(max) of study drug. Pharmacokinetic properties of drugs and differences in study design can explain differences in interaction potential. CONCLUSIONS: GLP-1RAs may produce clinically significant interactions with drugs that require achievement of target peak concentrations or a rapid onset of action. Studies in patients with type 2 diabetes are needed to further assess and allow comparison of several GLP-1RA agents' impact on steady state pharmacokinetics and pharmacodynamics of concomitant oral medications. PMID- 22510670 TI - Factors associated with reported preventable adverse drug events: a retrospective, case-control study. AB - BACKGROUND: It has been reported that error occurs at some point during the medication use process in approximately 6% of medication doses administered in the inpatient setting. An estimated 1-10% of medication errors lead to patient harm; however, factors affecting the risk of harm from a medication error are undefined in the literature. OBJECTIVE: To identify independent factors affecting the risk of reported preventable adverse drug events (ADEs) (ie, medication errors contributing to patient harm) compared to medication errors that did not contribute to patient harm in a diverse patient population. METHODS: This was a retrospective, case-control study conducted at 3 hospitals within a large health system. Medication error reports from July 1, 2009, through June 30, 2010, were assessed. All reported medication errors determined to have contributed to patient harm were matched 1:1 with a medication error that did not contribute to harm. Data collected through review of the incident report and medical record included patient, provider, medication, and other related factors. Multivariable logistic regression was used to determine the relationship of potential factors to patient harm. RESULTS: Of 4321 medication errors reported at study sites, 182 (4%) contributed to patient harm. Factors associated with increased independent risk of harm were 30-day readmission, time of day 0300-0659, and Institute for Safe Medication Practices (ISMP) high-alert medications. Factors associated with decreased independent risk of harm were multiple medication errors, occurrence during February or April, dispensing errors, and pharmacist review of medication order. CONCLUSIONS: Health systems should develop programs to promote safe, conscientious use of ISMP high-alert medications, promote pharmacist review, control the use of cabinet overrides, and direct provider attention toward recently admitted patients. Efforts should be made to determine factors associated with risk of harm at local levels. PMID- 22510671 TI - Safety of low doses of quetiapine when used for insomnia. AB - OBJECTIVE: To evaluate the safety of low doses of quetiapine when used for insomnia. DATA SOURCES: A literature search was performed using PubMed and EMBASE (January 1990-November 2011) using the terms quetiapine, insomnia, sleep, low dose, subtherapeutic, safety, and weight gain. STUDY SELECTION AND DATA EXTRACTION: Two prospective trials were identified that evaluated the effect of quetiapine in primary insomnia. In addition, 2 retrospective cohort studies were identified that evaluated the safety of low doses of quetiapine when used for insomnia. Several case reports on adverse effects with low doses of the drug were also included. DATA SYNTHESIS: Quetiapine is commonly used off-label for treatment of insomnia. When used for sleep, doses typically seen are less than the Food and Drug Administration-recommended dosage of 150-800 mg/day; those evaluated in the studies reviewed here were 25-200 mg/day). At recommended doses, atypical antipsychotics such as quetiapine are associated with metabolic adverse events (diabetes, obesity, hyperlipidemia). Adverse effects in the prospective trials were patient-reported and were minor, including drowsiness and dry mouth; however, the trials were limited by their small sample size and short duration. The retrospective cohort studies found that quetiapine was associated with significant increases in weight compared to baseline. Serious adverse events identified from case reports included fatal hepatotoxicity, restless legs syndrome, akathisia, and weight gain. CONCLUSIONS: There are potential safety concerns when using low-dose quetiapine for treatment of insomnia. These concerns should be evaluated in further prospective studies. Based on limited data and potential safety concerns, use of low-dose quetiapine for insomnia is not recommended. PMID- 22510673 TI - Stereoselective amine-catalyzed carbohydrate chain elongation. AB - Aldol additions of unprotected carbohydrates to 1.3-dicarbonyl compounds have been described. This transformation is based on a dual activation by tertiary amines and 2-hydroxypyridine. PMID- 22510674 TI - Early rehabilitation reduces the onset of complications in the upper limb following breast cancer surgery. AB - BACKGROUND: Breast cancer (BC) is currently the most frequent tumor in women. Through the years, BC management has evolved towards conservative surgery. However, even minimally invasive surgery can cause neuromotor and/or articular impairments which can lead to permanent damage, if not adequately treated. AIM: To clinically evaluate upper ipsilateral limb function and the impact of certain post-surgical consequences arising after invasive or breast-conserving surgery for early BC, by intervening, or not intervening, with an early rehabilitation program. To investigate physical morbidity after sentinel (SLND) or axillary lymph node dissection (ALND) and after reconstructive surgery in the treatment of early BC. DESIGN: Observational prospective trial. SETTING: Inpatient and outpatient treatment. POPULATION: Eighty-three females participated in the study: 25 patients did not begin physiotherapy during hospitalization (Group A), 58 patients received early rehabilitation treatment (Group B). METHODS: The patients of Groups A and B were compared with respect to the following criteria: shoulder arm mobility, upper limb function, and presence of lymphedema. All patients were assessed at 15-30, 60 and 180 days after surgery. RESULTS: Statistically significant differences, in favor of Group B, were encountered at the 180-day follow-up visit, especially with respect to articular and functional limitation of the upper limb. CONCLUSION AND CLINICAL REHABILITATION IMPACT: The results of the present study show that early assisted mobilization (beginning on the first postoperative day) and home rehabilitation, in conjunction with written information on precautionary hygienic measures to observe, play a crucial role in reducing the occurrence of postoperative side-effects of the upper limb. PMID- 22510675 TI - Instrumental measures of spinal function: is it worth? A state-of-the art from a clinical perspective. AB - In the last decades, assessment of trunk posture and motion has gained importance in clinical practice, and several instrumental non-invasive techniques have been developed to overcome limitations of manual and radiological methods. Despite the large effort spent in improving the underlying technologies, the actual role of these measures in the clinical setting remains still undefined due to a variety of issues. The main question concerns the provision of parameters providing a significant contribution to the clinical decision making. In this paper, we review the available spine surface measurement techniques from a technical viewpoint, and point out their current and potential applications according to a clinical perspective. Conclusions are drawn on the basis of both the technical features and accessibility in daily clinical practice, as well as of the validity, reliability and clinical value of the provided parameters. A well defined clinical role is established for surface topography in the follow-up of spine sagittal plane deformities, adulthood scoliosis and spine disorders involving the spino-pelvic alignment. Conversely, further studies are required to identify reliable key parameters for use in the clinical (adolescent scoliosis, back and neck pain), occupational (measurement of spine exposure to mechanical loads) and forensic (assessment of segmental functional impairments) fields. PMID- 22510676 TI - Predicting the need for institutional care shortly after admission to rehabilitation: Rasch analysis and predictive validity of the BRASS Index. AB - BACKGROUND: Effective discharge planning is increasingly recognised as a critical component of hospital-based Rehabilitation. The BRASS index is a risk screening tool for identification, shortly after hospital admission, of patients who are at risk of post-discharge problems. AIM: To evaluate the internal construct validity and reliability of the Blaylock Risk Assessment Screening Score (BRASS) within the rehabilitation setting. DESIGN: Observational prospective study. SETTING: Rehabilitation ward of an Italian district hospital. POPULATION: One hundred and four consecutively admitted patients. METHODS: Using classical psychometric methods and Rasch analysis (RA), the internal construct validity and reliability of the BRASS were examined. Also, external and predictive validity of the Rasch modified BRASS (RMB) score were determined. RESULTS: Reliability of the original BRASS was low (Cronbach's alpha=0.595) and factor analyses showed that it was clearly multidimensional. A RA, based on a reduced 7-BRASS item set (RMB), satisfied model's expectations. Reliability was 0.777. The RMB scores strongly correlated with the original BRASS (rho=0.952; P<0.000) and with FIMTM admission scores (rho=-0.853; P<0.000). A RMB score of 12 was associated with an increased risk of nursing home admission (RR=2.1, 95%CI=1.7-2.5), whereas a score of 17 was associated to a higher risk of length of stay >28 days (RR=7.6, 95%CI=1.8-31.9). CONCLUSION: This study demonstrated that the original BRASS was multidimensional and unreliable. However, the RMB holds adequate internal construct validity and is sufficiently reliable as a predictor of discharge problems for group, but not individual use. CLINICAL REHABILITATION IMPACT: The application of tools and methods (such as the BRASS Index) developed under the biomedical paradigm in a Physical and Rehabilitation Medicine setting may have limitations. Further research is needed to develop, within the rehabilitation setting, a valid measuring tool of risk of post-discharge problems at the individual level. PMID- 22510677 TI - What do patients really know about cardiopulmonary rehabilitation: a cross sectional survey study. AB - BACKGROUND: Although it is known that cardiopulmonary rehabilitation (CPR) reduces mortality and morbidity, it is not widely implemented as is in Turkey. One factor might be lack of demand since the levels of knowledge and awareness among patients who are eligible for CPR seem to be insufficient. AIM: It is aimed to investigate the level of awareness and knowledge of CPR among patients with cardiopulmonary problems. DESIGN: Cross-sectional survey study. SETTING: Outpatient. METHODS: Knowledge regarding CPR was assessed by questionnaires given to 690 patients recruited in seven university hospitals and six training and research hospitals in which either comprehensive or limited CPR services are available. POPULATION: Patients who have cardiopulmonary problems RESULTS: Of the patients, 34.7% were given information on CPR by healthcare staff, and 25.3% reported that their source of information was physicians. Although 49.9% of the patients knew that they needed to exercise for their cardiac/pulmonary problems, only 23.4% and 32.1% of those were aware that fast walking and climbing stairs, respectively, would not pose a risk to their cardiac/pulmonary health. The majority of the patients believed that activities of daily living, which comprise the most important component of exercise-based CPR, were harmful for their cardiopulmonary health. We found that 31.1% of the patients exercised regularly. During their stay at the hospital, certain kinds of exercises were suggested to 62.7% of the patients, and 34.7% of these patients performed various exercises. Of the patients who were given detailed information on cardiopulmonary rehabilitation, 69% stated that they would be willing to participate in a similar program. CONCLUSION: Although nearly half of the patients stated that they needed CR, it was observed that the ratio of patients who had true knowledge of CPR was low among patients. It is imperative to furnish patients with information on CPR, both in the field of PMR and throughout Turkey, and to put more effort into running those services effectively. Furthermore, we should make an effort to increase the level of liaison between patients and physicians and other healthcare professionals who participate in the treatment of cardiac/pulmonary patients. PMID- 22510678 TI - Pulmonary rehabilitation for patients with bronchiectasis: case reports. AB - The effectiveness of pulmonary rehabilitation (PR) has been recognized in national and international guidelines and highlighted by the National Institute of Clinical Excellence as one of the six key priorities for improving the care of chronic obstructive pulmonary disease (COPD) patients. PR is likely to be effective in bronchiectasis as it is in COPD. We evaluated the efficacy of PR in the management of bronchiectasis. Three outpatients affected by bronchiectasis, with cough, sputum production, dyspnea, and decreased exercise tolerance, were submitted to five months of PR program consisting in treadmill walking, cycle ergometry, breathing exercises, and postural drainage with clapping percussion vibratory-shaking. In all patients, after PR, chest X-ray showed that the obstructive disease decreased with bronchial wall thickness reduction. This improvement facilitated the performance of breath actions increasing the exercise tolerance and quality of life, evaluated respectively with the 6-minute walk test, the SF36, and the RPE Borg scale. The improvements in both exercise capacity and health status observed at the end of the PR program were maintained in a 6-month follow-up after the cessation of training with also a reduction of acute bronchial exacerbations. These results highlighted the potential role of PR in patients with bronchiectasis, however further investigations are needed to identify the most eligible patients and to optimize the training programs to maintain long term benefit. Chest x-ray may represent a relevant instrument to observe the clinical improvement of these patients, also when spirometric values do not change significantly. PMID- 22510679 TI - Disability and human rights: the World Report on Disability as a unique opportunity to review and enrich European health policy. PMID- 22510680 TI - Structured interview to improve the reliability and psychometric integrity of the Disability Rating Scale. AB - OBJECTIVES: To (1) develop a standardized interview for telephone administration, (2) assess the psychometric properties of this interview format (Disability Rating Scale-Postacute Interview [DRS-PI]), and (3) identify additional items to reduce skew. DESIGN: Prospective cohort assessment study. SETTING: Not applicable. PARTICIPANTS: Participants (N=406; 287 individuals with traumatic brain injury [TBI], 119 caregivers) in the U.S. TBI Model Systems national database during 1- to 20-year telephone follow-up. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Original Disability Rating Scale (DRS) and DRS-PI variations. DRS-PI questions were developed by consensus of the study investigators; item scores were derived from responses to questions by algorithm. Unnecessary questions were pruned. RESULTS: The DRS-PI correlated highly with the original DRS (intraclass correlation, .91) and demonstrated satisfactory construct validity and internal consistency (person separation/reliability, 2.51/.86; item separation/reliability, 16.72/1.00; Cronbach alpha=.83). Both versions showed substantial skew. For the original DRS, 42% of scores were 0 or 1; for DRS-PI, 44%. Adding several items to the DRS-PI including actual employment status further improved its psychometric properties (person separation/reliability, 3.10/.91; item separation/reliability, 21.42/1.00; Cronbach alpha=.92) and reduced skew. For the Expanded DRS-PI, 18% of scores were 0 or 1. CONCLUSIONS: The DRS-PI provides an efficient method to ensure standardized administration of, and correlates highly with, the original DRS. The addition of several new items including actual employment status mitigates skew in postacute samples. PMID- 22510681 TI - Dietary-resistant starch and glucose metabolism. AB - PURPOSE OF REVIEW: Recent findings in animal models suggest that resistant starch is beneficial for both body weight regulation and glycaemic control. The purpose of this review is to summarize the current evidence and recommendations in humans. RECENT FINDINGS: When resistant starch replaces available carbohydrate in a meal, postprandial glycaemia is reduced. There are some data to suggest that resistant starch may affect glycaemia even when the available carbohydrate portion remains constant; however, there is inconsistency in the literature. Recent animal data suggest that chronic resistant starch feeding upregulates glucagon-like peptide 1 expression in the large bowel with concomitant increases in neuropeptide expression in the hypothalamus, combining to result in weight loss and improvements in glycaemic control. However, to date there is no evidence for this in humans. SUMMARY: Resistant starch may have a role in glycaemic control in healthy individuals and those with type 2 diabetes; however, there are limited interventional trials in humans to support this. There are no data concerning resistant starch feeding in human diabetes and as such no health recommendation can be made. PMID- 22510682 TI - Added sugar, glycemic index and load in colon cancer risk. AB - PURPOSE OF REVIEW: There is a growing body of in-vivo evidences that sucrose-rich diets cause mutations in the rat colon epithelium, with several biological mechanism hypothesized, but epidemiological studies have yielded conflicting results. In order to provide a quantification of the magnitude of the risk of colon cancer for high intake of added sugar, high dietary glycemic index and glycemic load, we performed a meta-analysis based on a systematic review of the literature to date. RECENT FINDINGS: Recent epidemiological data indicate a lack of association between high intake of added sugar, high-glycemic index and glycemic load diets and risk of colon cancer. SUMMARY: There is no consistent evidence from epidemiological studies, although a modest excess risk emerged in case-control studies, that added sugars, dietary glycemic index and glycemic load are associated with increased risk of colon cancer, independently from their effect on energy intake, overweight, obesity and diabetes, which are related to excess colon cancer risk. PMID- 22510683 TI - An investigation into the effectiveness of ELF protective clothing when exposed to RF fields between 65 MHz and 3 GHz. AB - Protective garments are worn by electric power workers to shield the body against electromagnetic fields. This paper uses the finite-difference time-domain method to calculate SAR in the heterogeneous human voxel model NORMAN, clad in a protective suit and exposed to radio-frequency (RF) electromagnetic fields between 65 MHz and 3 GHz. The representation of the suit was produced for this work by the modelling and voxelization of a surface-rendered object, based on the dimensions of the male voxel phantom. The calculations showed that the peak localized SAR in the head was higher than that calculated for a model without a protective suit for a number of exposure situations. These localized SAR values could be up to three times the values of those calculated for a model without a protective suit for a particular frequency. It is thought that the SAR hotspots in the head are caused by resonances in a cavity, which in this case is the conductive hood of the suit. This work shows that the increase in the peak localized SAR in the head due to wearing the suit meant that, in certain situations, the ICNIRP and IEEE reference levels were no longer conservative. Therefore, it is important that power line workers exposed to RF fields wear the correct high-frequency protective suits with conducting visors. PMID- 22510684 TI - The diagnostic and economic yield of neuroimaging in neuro-ophthalmology. AB - BACKGROUND: Diagnostic studies such as computed tomography scans (CT) and magnetic resonance imaging (MRI) are ordered frequently in neuro-ophthalmic practice, although the diagnostic yield and cost-effectiveness of these tests have been studied for only a few conditions. We assessed the diagnostic and economic yield of CT and MRI across all patients evaluated in a neuro ophthalmology practice. METHODS: This retrospective review included all patients referred by the division of neuro-ophthalmology at the Scheie Eye Institute for CT, CT angiography, MRI, MRA, or magnetic resonance venography over a 12-month period. Abnormal imaging findings were categorized as significant (one that elicited changes in management) and/or relevant (one that related to the patient's neuro-ophthalmic complaint or examination findings). The diagnostic yield of the test ordered was analyzed according to the patient's chief complaint, neuro-ophthalmic examination findings, and indication for imaging. The total costs for each diagnostic group and costs per significant finding were calculated using the global Resource-Based Relative Value Units for each examination from the Centers for Medicare and Medicaid Services Web site. RESULTS: Two hundred eleven imaging studies in 157 patients were evaluated. 28.9% (95% confidence interval, 22.5%-36.2%) of imaging studies had significant abnormalities relevant to the neuro-ophthalmic complaint. Imaging obtained for evaluation of progressive optic nerve dysfunction and cranial nerve palsy had statistically significant higher diagnostic yield than studies performed for other reasons. Total cost of all imaging studies performed was $107,615.72. Cost per clinically significant and relevant finding was $1,764.19. CONCLUSIONS: In comparison to the diagnostic yield of neuroimaging studies in other specialties, CT and MRI of the brain requested by neuro-ophthalmologists provide significant and relevant data at a reasonable cost. PMID- 22510685 TI - Broadband graphene terahertz modulators enabled by intraband transitions. AB - Terahertz technology promises myriad applications including imaging, spectroscopy and communications. However, one major bottleneck at present for advancing this field is the lack of efficient devices to manipulate the terahertz electromagnetic waves. Here we demonstrate that exceptionally efficient broadband modulation of terahertz waves at room temperature can be realized using graphene with extremely low intrinsic signal attenuation. We experimentally achieved more than 2.5 times superior modulation than prior broadband intensity modulators, which is also the first demonstrated graphene-based device enabled solely by intraband transitions. The unique advantages of graphene in comparison to conventional semiconductors are the ease of integration and the extraordinary transport properties of holes, which are as good as those of electrons owing to the symmetric conical band structure of graphene. Given recent progress in graphene-based terahertz emitters and detectors, graphene may offer some interesting solutions for terahertz technologies. PMID- 22510686 TI - miR-484 regulates mitochondrial network through targeting Fis1. AB - Mitochondria constantly undergo fusion and fission, two necessary processes for the maintenance of organelle fidelity. The abnormal mitochondrial fission participates in the pathogenesis of many diseases, but its regulation remains poorly understood. Here we show that miR-484 can suppress translation of mitochondrial fission protein Fis1, and inhibit Fis1-mediated fission and apoptosis in cardiomyocytes and in the adrenocortical cancer cells. We demonstrate that Fis1 is necessary for mitochondrial fission and apoptosis, and is upregulated during anoxia, whereas miR-484 is downregulated. miR-484 is able to attenuate Fis1 upregulation and mitochondrial fission, by binding to the amino acid coding sequence of Fis1 and inhibiting its translation. In exploring the underlying mechanism of miR-484 downregulation upon apoptosis, we observe that Foxo3a transactivates miR-484 expression. Foxo3a transgenic or knockout mice exhibit, respectively, a high or low level of miR-484 and a reduced or enhanced mitochondrial fission, apoptosis and myocardial infarction. Our data reveal a model of mitochondrial fission regulation by a microRNA. PMID- 22510687 TI - The structure of the FANCM-MHF complex reveals physical features for functional assembly. AB - Fanconi anaemia is a rare genetic disease characterized by chromosomal instability and cancer susceptibility. The Fanconi anaemia complementation group protein M (FANCM) forms an evolutionarily conserved DNA-processing complex with MHF1/MHF2 (histone-fold-containing proteins), which is essential for DNA repair in response to genotoxic stress. Here we present the crystal structures of the MHF1-MHF2 complex alone and bound to a fragment of FANCM (FANCM(661-800), designated FANCM-F). The structures show that MHF1 and MHF2 form a compact tetramer to which FANCM-F binds through a 'dual-V' shaped structure. FANCM-F and (MHF1-MHF2)(2) cooperate to constitute a new DNA-binding site that is coupled to the canonical L1L2 region. Perturbation of the MHF-FANCM-F structural plasticity changes the localization of FANCM in vivo. The MHF-FANCM interaction and its subcellular localization are altered by a disease-associated mutant of FANCM. These findings reveal the molecular basis of MHF-FANCM recognition and provide mechanistic insights into the pathway leading to Fanconi anaemia. PMID- 22510688 TI - Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels. AB - Tumour recurrence frequently occurs after radiotherapy, but the characteristics, intratumoural localization and post-irradiation behaviour of radioresistant cancer cells remain largely unknown. Here we develop a sophisticated strategy to track the post-irradiation fate of the cells, which exist in perinecrotic regions at the time of radiation. Although the perinecrotic tumour cells are originally hypoxia-inducible factor 1 (HIF-1)-negative, they acquire HIF-1 activity after surviving radiation, which triggers their translocation towards tumour blood vessels. HIF-1 inhibitors suppress the translocation and decrease the incidence of post-irradiation tumour recurrence. For the first time, our data unveil the HIF-1-dependent cellular dynamics during post-irradiation tumour recurrence and provide a rational basis for targeting HIF-1 after radiation therapy. PMID- 22510690 TI - Giant regular polyhedra from calixarene carboxylates and uranyl. AB - Self-assembly of large multi-component systems is a common strategy for the bottom-up construction of discrete, well-defined, nanoscopic-sized cages. Icosahedral or pseudospherical viral capsids, built up from hundreds of identical proteins, constitute typical examples of the complexity attained by biological self-assembly. Chemical versions of the so-called 5 Platonic regular or 13 Archimedean semi-regular polyhedra are usually assembled combining molecular platforms with metals with commensurate coordination spheres. Here we report novel, self-assembled cages, using the conical-shaped carboxylic acid derivatives of calix[4]arene and calix[5]arene as ligands, and the uranyl cation UO(2)2+ as a metallic counterpart, which coordinates with three carboxylates at the equatorial plane, giving rise to hexagonal bipyramidal architectures. As a result, octahedral and icosahedral anionic metallocages of nanoscopic dimensions are formed with an unusually small number of components. PMID- 22510689 TI - Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches. AB - Organ replacement regenerative therapy is purported to enable the replacement of organs damaged by disease, injury or aging in the foreseeable future. Here we demonstrate fully functional hair organ regeneration via the intracutaneous transplantation of a bioengineered pelage and vibrissa follicle germ. The pelage and vibrissae are reconstituted with embryonic skin-derived cells and adult vibrissa stem cell region-derived cells, respectively. The bioengineered hair follicle develops the correct structures and forms proper connections with surrounding host tissues such as the epidermis, arrector pili muscle and nerve fibres. The bioengineered follicles also show restored hair cycles and piloerection through the rearrangement of follicular stem cells and their niches. This study thus reveals the potential applications of adult tissue-derived follicular stem cells as a bioengineered organ replacement therapy. PMID- 22510691 TI - Strong-coupling d-wave superconductivity in PuCoGa5 probed by point-contact spectroscopy. AB - Superconductivity is due to an attractive interaction between electrons that, below a critical temperature, drives them to form Cooper pairs and to condense into a ground state separated by an energy gap from the unpaired states. In the simplest cases, the pairing is mediated by lattice vibrations and the wavefunction of the pairs is isotropic. Less conventional pairing mechanisms can favour more exotic symmetries of the Cooper pairs. Here, we report on point contact spectroscopy measurements in PuCoGa(5), a moderate heavy-fermion superconductor with a record high critical temperature T(c)=18.5 K. The results prove that the wavefunction of the paired electrons has a d-wave symmetry, with four lobes and nodes, and show that the pairing is likely to be mediated by spin fluctuations. Electronic structure calculations, which take into account the full structure of the f-orbital multiplets of Pu, provide a hint of the possible origin of these fluctuations. PMID- 22510692 TI - Ordinary percolation with discontinuous transitions. AB - Percolation on a one-dimensional lattice and fractals, such as the Sierpinski gasket, is typically considered to be trivial, because they percolate only at full bond density. By dressing up such lattices with small-world bonds, a novel percolation transition with explosive cluster growth can emerge at a non-trivial critical point. There, the usual order parameter, describing the probability of any node to be part of the largest cluster, jumps instantly to a finite value. Here we provide a simple example in the form of a small-world network consisting of a one-dimensional lattice which, when combined with a hierarchy of long-range bonds, reveals many features of this transition in a mathematically rigorous manner. PMID- 22510693 TI - Combinatorial targeting and discovery of ligand-receptors in organelles of mammalian cells. AB - Phage display screening allows the study of functional protein-protein interactions at the cell surface, but investigating intracellular organelles remains a challenge. Here we introduce internalizing-phage libraries to identify clones that enter mammalian cells through a receptor-independent mechanism and target-specific organelles as a tool to select ligand peptides and identify their intracellular receptors. We demonstrate that penetratin, an antennapedia-derived peptide, can be displayed on the phage envelope and mediate receptor-independent uptake of internalizing phage into cells. We also show that an internalizing phage construct displaying an established mitochondria-specific localization signal targets mitochondria, and that an internalizing-phage random peptide library selects for peptide motifs that localize to different intracellular compartments. As a proof-of-concept, we demonstrate that one such peptide, if chemically fused to penetratin, is internalized receptor-independently, localizes to mitochondria, and promotes cell death. This combinatorial platform technology has potential applications in cell biology and drug development. PMID- 22510695 TI - Pegylated magnetic nanocarriers for doxorubicin delivery: a quantitative determination of stealthiness in vitro and in vivo. AB - The aim of this work was to elucidate the impact of polyethylene glycol (PEG) polymeric coating on the in vitro and in vivo stealthiness of magnetic nanocarriers loaded or not with the anticancer drug doxorubicin. The comparison was made between aqueous suspensions of superparamagnetic iron oxide nanoparticles (SPIONs) stabilized by either citrate ions (C-SPIONs) or PEG(5000) (P-SPIONs), the latter being loaded or not with doxorubicin via the formation of a DOX-Fe(2+) complex (DLP-SPIONs). After determination of their relevant physico chemical properties (size and surface charge), nanoparticle (NP) stealthiness was studied in vitro (ability to activate the complement system and uptake by monocytes and macrophage-like cells) and in vivo in mice (blood half-life; t(1/2), and biodistribution in main clearance organs). These aspects were quantitatively assessed by atomic absorption spectrometry (AAS). Complement activation dramatically decreased for sterically stabilized P-SPIONs and DLP SPIONs in comparison with C-SPIONs stabilized by charge repulsion. Monocyte and macrophage uptake was also largely reduced for pegylated formulations loaded or not with doxorubicin. The t(1/2) in blood for P-SPIONs was estimated to be 76 +/- 6 min, with an elimination mainly directed to liver and spleen. Thanks to their small size (<80 nm) and a neutral hydrophilic polymer-extended surface, P-SPIONs exhibit prolonged blood circulation and thus potentially an increased level in tumor delivery suitable for magnetic drug targeting applications. PMID- 22510698 TI - Gene expression and immunoreactivity of elastolytic enzymes in the uterosacral ligaments from women with uterine prolapse. AB - Altered elastin metabolism has been documented in pelvic tissues from women with pelvic floor dysfunction. This study was conducted to quantify the expression of elastolytic enzymes in uterine cervix and uterosacral ligaments from women with uterine prolapse compared to asymptomatic normal controls. Paired tissues of uterosacral ligament and cervical tissues were obtained from 27 women with uterine prolapse and 14 normal controls. Steady state of matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinase 2 (TIMP-2), neutrophil elastase, alpha-1 antitrypsin immunoreactivity, and messenger RNA (mRNA) expression were analyzed by immunohistochemistry and real-time polymerase chain reaction, respectively. When compared with controls, women with uterine prolapse had a significantly greater level of MMP-2 immunoreactivity and mRNA expression, but less TIMP-2 and alpha-1 antitrypsin immunoreactivity and mRNA expression in their uterosacral ligaments. However, neutrophil elastase mRNA expression was similar between uterine prolapse and control tissue. Our results showed that there was a close relationship between expressions of MMP-2, TIMP-2, and alpha-1 antitrypsin in uterosacral ligament and the occurrence of uterine prolapse. PMID- 22510696 TI - Remobilization does not restore immobilization-induced adhesion of capsule and restricted joint motion in rat knee joints. AB - Joint immobilization, which is used in orthopaedic treatments and observed in bedridden people, usually causes restricted joint motion. Decreased joint motion diminishes activities of daily living and increases burden of nursing-care. The purpose of this study was to clarify the reversibility of immobilization-induced capsular changes and restricted joint motion in rat knee joints. The unilateral knee joints of adult male rats were immobilized with an internal fixator for 1, 2, 4, 8, and 16 weeks as a model of immobilization after surgery or disuse of the joint. After the fixation devices were removed, the rats were allowed to move freely for 16 weeks. Sham-operated rats were used as controls. Sagittal sections at medial midcondylar regions were made and assessed with histological, histomorphometric, and immunohistochemical methods. Joint motion was measured using a custom-made device under x-ray control after removal of the periarticular muscles. In the 1/16-week and 2/16-week immobilization-remobilization (Im-Rm) groups, cord-like structures connecting the superior and inferior portions of the posterior capsule (partial adhesion) were observed without restricted joint motion. In the 4/16-, 8/16-, and 16/16-week Im-Rm groups, global adhesion of the posterior capsule and restricted joint motion were observed. The restricted joint motion was not completely restored after incision of the posterior capsule. These data indicate that immobilization alone causes irreversible capsular changes and arthrogenic restricted joint motion. Besides the joint capsule, other arthrogenic factors such as ligaments might influence the restricted joint motion. Prolonged immobilization over 4 weeks should be avoided to prevent irreversible joint contracture. PMID- 22510699 TI - Sertraline alters multidrug resistance phosphoglycoprotein activity in the mouse placenta and fetal blood-brain barrier. AB - Phosphoglycoprotein (P-gp) is highly expressed in the placental syncytiotrophoblast and prevents xenobiotics from entering the fetus. In tumor cells, P-gp-mediated substrate efflux is inhibited by selective serotonin reuptake inhibitors (SSRIs). However, nothing is known regarding the effects of SSRIs on P-gp function in the placenta or fetal tissues. We hypothesized that the SSRI sertraline would decrease P-gp-mediated drug efflux at the placenta and fetal blood-brain barrier (BBB)-increasing P-gp substrate transfer from the mother to the fetus and fetal brain. In contrast to our hypothesis, this study presents the novel findings that sertraline (4 hours exposure) increases placental P-gp-mediated efflux (P < .001), resulting in decreased drug transfer to the fetus. Meanwhile, sertraline decreases fetal (P < .001) and maternal (P < .05) BBB P-gp-mediated efflux, resulting in increased drug transfer into the fetal and maternal brain from the circulation. This suggests that P-gp regulation by sertraline is tissue specific. These findings have important clinical implications with respect to fetal protection during maternal drug therapy in pregnancy. PMID- 22510694 TI - Convergence and coevolution of hepatitis B virus drug resistance. AB - Treatment with lamivudine of patients infected with hepatitis B virus (HBV) results in a high rate of drug resistance, which is primarily associated with the rtM204I/V substitution in the HBV reverse transcriptase domain. Here we show that the rtM204I/V substitution, although essential, is insufficient for establishing resistance against lamivudine. The analysis of 639 HBV whole-genome sequences obtained from 11 patients shows that rtM204I/V is independently acquired by more than one intra-host HBV variant, indicating the convergent nature of lamivudine resistance. The differential capacity of HBV variants to develop drug resistance suggests that fitness effects of drug-resistance mutations depend on the genetic structure of the HBV genome. An analysis of Bayesian networks that connect rtM204I/V to many sites of HBV proteins confirms that lamivudine resistance is a complex trait encoded by the entire HBV genome rather than by a single mutation. These findings have implications for public health and offer a more general framework for understanding drug resistance. PMID- 22510700 TI - Hyperfine structure of Ho3+ levels and electron-phonon coupling in YPO4 single crystals. AB - High resolution spectroscopy (the finest being 0.01 cm(-1)) was applied in the 75 25,000 cm(-1) and 9-300 K ranges to a 1 mol% holmium doped Y PO(4) single crystal with two purposes: (1) to study the hyperfine splitting of Ho(3+) energy levels of interest for possible quantum manipulation media and (2) to analyze the electron-phonon interaction. The hyperfine structure was clearly revealed for a high number of lines in a wide wavenumber range (up to ~21,500 cm(-1)) and for a large number of multiplets. Several hyperfine patterns were monitored, differing in the number of components (a maximum of 16 could be easily distinguished in a single beautiful pattern), in their separation, and in their relative statistical weight. These features were all understood in terms of a crystal-field model, whose results are in good agreement with experiments and account for the involved level symmetry, the type of transitions (electric and magnetic dipole allowed), and the contribution of a second-order (pseudoquadrupolar) hyperfine coupling between close levels. The electron-phonon interaction, investigated through the thermally induced line shift, was critically discussed in the framework of single phonon coupling and of two phonon Raman scattering models. PMID- 22510701 TI - Adsorption and separation of poly-aromatic hydrocarbons by a hydrogen-bonded coordination polymer. AB - A residual-host prepared by thermal removal of naphthalene (NA) from the inclusion compound [Ni(SCN)(2)(isonicotinic acid)(2)].(NA)(0.5) was found to function as an adsorbent for aromatic molecules and exhibit method-dependent selectivity. PMID- 22510702 TI - PET/CT and contrast enhanced CT in single vs. two separate sessions: a cost analysis study. AB - AIM: Aim of the study was to quantify the economic impact of PET/CT and contrast enhanced (c.e.) CT performed in a single session examination vs. stand-alone modalities in oncological patients. METHODS: One-hundred-forty-five cancer patients referred to both PET/CT and c.e. CT, to either stage (N.=46) or re-stage (N.=99) the disease, were included. Seventy-two/145 performed both studies in a single session (innovative method) and 73/145 in two different sessions (traditional method). The cost-minimization analysis was performed by evaluating: 1) institutional costs, data obtained by hospital accountability (staff, medical materials, equipment maintenance and depreciation, departments utilities); 2) patients costs, data obtained by a specific survey provided to patients (travel, food, accommodation costs, productivity loss). RESULTS: Economic data analysis showed that the costs for innovative method was lower than those of traditional method, both for Institution (106 ? less per test) and for patient (21 ? less per patient). The loss of productivity for patient and caregivers resulted lower for the innovative method than the traditional method (3 work-hour less per person). CONCLUSION: PET/CT and c.e. CT performed in a single session is more cost effective than stand-alone modalities, by reducing both Institutional and patients costs. These advantages are mainly due to lower Institutional cost (single procedure) and to lower cost related to travel and housing. PMID- 22510704 TI - Phylogroup and lpfA influence epithelial invasion by mastitis associated Escherichia coli. AB - Escherichia coli infection is one of the most common causes of bovine mastitis in well managed dairies. Although E. coli infections are usually transient, E. coli can also cause persistent intramammary infections. We sought to determine whether E. coli isolates recovered from either transient or persistent intramammary infections differed both genetically and in their ability to invade mammary epithelial cells. E. coli isolates from transient (EC(trans), n=16) and persistent (EC(pers), n=12) mastitis cases were compared for differences in overall genotype, virulence genes, serotype, phylogroup (A, B1, B2, D), and invasion of bovine mammary epithelial cells, MAC-T by microarray analysis, suppressive subtractive hybridization, PCR and gentamicin protection assays. EC(trans) and EC(pers) were diverse in overall genotype and serotype, and were predominantly of phylogroups A and B1. Both EC(trans) and EC(pers) contained genes encoding type II, IV and VI secretion systems, long polar fimbriae (lpfA) and iron acquisition, and lacked genes associated with virulence in diarrheagenic E. coli. EC(trans) had fewer virulence genes than EC(pers) (p<0.05), but no individual virulence genes were unique to either group. In phylogroup A, EC(pers) were more invasive than EC(trans) (p<0.05), but no difference was observed between them in phylogroup B1. Enhanced epithelial cell invasion was associated with lpfA (p<0.05). Our findings indicate that a genetically diverse group of E. coli is associated with transient and persistent mastitis. We did not identify a set of bacterial genes to account for phenotypic differences. However, we found that mastitis phenotype, phylogroup and presence of lpfA were associated with the ability to invade cultured bovine mammary epithelial cells. PMID- 22510705 TI - Effect of neonatal gene therapy on lumbar spine disease in mucopolysaccharidosis VII dogs. AB - Mucopolysaccharidosis VII (MPS VII) is due to deficient beta-glucuronidase (GUSB) activity, which leads to accumulation of chondroitin, heparan, and dermatan sulfate glycosaminoglycans in various tissues including those of the spine. Associated spine disease can be due to abnormalities in the vertebrae, the intervertebral disks, or other spine tissues. The goal of this study was to determine if neonatal gene therapy could prevent lumbar spine disease in MPS VII dogs. MPS VII dogs were injected intravenously with a retroviral vector (RV) expressing canine GUSB at 2 to 3 days after birth, which resulted in transduction of hepatocytes that secreted GUSB into blood. Expression was stable for up to 11 years, and mean survival was increased from 0.4 years in untreated dogs to 6.1 years in treated dogs. Despite a profound positive clinical effect, 6-month-old RV-treated MPS VII dogs still had hypoplastic ventral epiphyses with reduced calcification in the lumbar spine, which resulted in a reduced stiffness and increased range of motion that were not improved relative to untreated MPS VII dogs. At six to 11 years of age, ventral vertebrae remained hypoplastic in RV treated MPS VII dogs, and there was desiccation of the nucleus pulposus in some disks. Histochemical staining demonstrated that disks did not have detectable GUSB activity despite high serum GUSB activity, which is likely due to poor diffusion into this relatively avascular structure. Thus, neonatal gene therapy cannot prevent lumbar spine disease in MPS VII dogs, which predicts that enzyme replacement therapy (ERT) will similarly be relatively ineffective even if started at birth. PMID- 22510706 TI - Entropy of cellulose dissolution in water and in the ionic liquid 1-butyl-3 methylimidazolim chloride. AB - The entropic driving forces of cellulose dissolution in water and in the ionic liquid 1-butyl-3-methylimidazolium chloride (BmimCl) are investigated via molecular dynamics simulations and the two-phase thermodynamic model. An atomistic model of cellulose was simulated at a dissociated state and a microfibril state to represent dissolution. The calculated values of entropy and internal energy changes between the two states inform the interplay of energetic and entropic driving forces in cellulose dissolution. In both water and BmimCl, we found that the entropy associated with the solvent degrees of freedom (DOF) decreases upon cellulose dissolution. However, solvent entropy reduction in BmimCl is much smaller than that in water and counteracts the entropy gain from the solute DOF to a much lesser extent. Solvent entropy reduction in water also plays a major role in making the free energy change of cellulose dissolution unfavorable at room temperature. In BmimCl, the interaction energies between solvent molecules and glucan chains and the total entropy change both contribute favorably to the dissolution free energy of cellulose. Calculations at different temperatures in the two solvents indicate that changes in total internal energy are a good indicator of the sign of the free energy change of cellulose dissolution. PMID- 22510707 TI - Entrainment of peripheral clock genes by cortisol. AB - Circadian rhythmicity in mammals is primarily driven by the suprachiasmatic nucleus (SCN), often called the central pacemaker, which converts the photic information of light and dark cycles into neuronal and hormonal signals in the periphery of the body. Cells of peripheral tissues respond to these centrally mediated cues by adjusting their molecular function to optimize organism performance. Numerous systemic cues orchestrate peripheral rhythmicity, such as feeding, body temperature, the autonomic nervous system, and hormones. We propose a semimechanistic model for the entrainment of peripheral clock genes by cortisol as a representative entrainer of peripheral cells. This model demonstrates the importance of entrainer's characteristics in terms of the synchronization and entrainment of peripheral clock genes, and predicts the loss of intercellular synchrony when cortisol moves out of its homeostatic amplitude and frequency range, as has been observed clinically in chronic stress and cancer. The model also predicts a dynamic regime of entrainment, when cortisol has a slightly decreased amplitude rhythm, where individual clock genes remain relatively synchronized among themselves but are phase shifted in relation to the entrainer. The model illustrates how the loss of communication between the SCN and peripheral tissues could result in desynchronization of peripheral clocks. PMID- 22510708 TI - Early postnatal overnutrition increases adipose tissue accrual in response to a sucrose-enriched diet. AB - Both overnutrition and an incorrect nutrient balance have contributed to the rise in obesity. Moreover, it is now clear that poor nutrition during early life augments the possibility of excess weight gain in later years. Our aim was to determine how neonatal overnutrition affects later responses to a sucrose enriched diet and whether this varies depending upon when the diet is introduced in postnatal life. Male Wistar rats raised in litters of four or 12 pups were given a 33% sucrose solution instead of water from weaning (day 21) or postnatal day (PND) 65. All rats received normal chow ad libitum until they were euthanized on PND 80. Body weight (BW) and food and liquid intake were monitored throughout the study. Fat mass, adipocyte morphology, serum biochemical and hormonal parameters, and hypothalamic neuropeptide mRNA levels were measured at study termination. Neonatal overnutrition increased food intake, BW, and leptin levels, induced adipocyte hypertrophy, and decreased total ghrelin levels. The sucrose enriched diet increased total energy intake, adipose accrual, and leptin, adiponectin, and acylated ghrelin levels but decreased BW. Most of these responses were accentuated in neonatally overnourished rats, which also had increased insulin and triglyceride levels. However, long-term sucrose intake induced adipocyte hypertrophy in rats from normal-sized litters but not in neonatally overfed rats. The results reported here indicate that neonatal overnutrition increases the detrimental response to a diet rich in sucrose later in life. Moreover, the timing and duration of the exposure to a sucrose-enriched diet alter the adverse metabolic outcomes. PMID- 22510709 TI - Stress is a critical player in CYP3A, CYP2C, and CYP2D regulation: role of adrenergic receptor signaling pathways. AB - Stress is a critical player in the regulation of the major cytochrome P-450s (CYPs) that metabolize the majority of the prescribed drugs. Early in life, maternal deprivation (MD) stress and repeated restraint stress (RS) modified CYP expression in a stress-specific manner. In particular, the expression of CYP3A1 and CYP2C11 was increased in the liver of MD rats, whereas RS had no significant effect. In contrast, hepatic CYP2D1/2 activity was increased by RS, whereas MD did not affect it. The primary effectors of the stress system, glucocorticoids and epinephrine, highly induced CYP3A1/2. Epinephrine also induced the expression of CYP2C11 and CYP2D1/2. Further investigation indicated that AR-agonists may modify CYP regulation. In vitro experiments using primary hepatocyte cultures treated with the AR-agonists phenylephrine, dexmedetomidine, and isoprenaline indicated an AR-induced upregulating effect on the above-mentioned CYPs mediated by the cAMP/protein kinase A and c-Jun NH2-terminal kinase signaling pathways. Interestingly though, in vivo pharmacological manipulations of ARs using the same AR-agonists led to a suppressed hepatic CYP expression profile, indicating that the effect of the complex network of central and peripheral AR-linked pathways overrides that of the hepatic ARs. The AR-mediated alterations in CYP3A1/2, CYP2C11, and CYP2D1/2 expressions are potentially connected with those observed in the activation of signal transducer and activator of transcription 5b. In conclusion, stress and AR-agonists may modify the expression of the major CYP genes involved in the metabolism of drugs used in a wide range of diseases, thus affecting drug efficacy and toxicity. PMID- 22510710 TI - Body composition determines direct FFA storage pattern in overweight women. AB - Direct FFA storage in adipose tissue is a recently appreciated pathway for postabsorptive lipid storage. We evaluated the effect of body fat distribution on direct FFA storage in women with different obesity phenotypes. Twenty-eight women [10 upper body overweight/obese (UBO; WHR >0.85, BMI >28 kg/m(2)), 11 lower body overweight/obese (LBO; WHR <0.80, BMI >28 kg/m(2)), and 7 lean (BMI <25 kg/m(2))] received an intravenous bolus dose of [9,10-(3)H]palmitate- and [1-(14)C]triolein labeled VLDL tracer followed by upper body subcutaneous (UBSQ) and lower body subcutaneous (LBSQ) fat biopsies. Regional fat mass was assessed by combining DEXA and CT scanning. We report greater fractional storage of FFA in UBSQ fat in UBO women compared with lean women (P < 0.01). The LBO women had greater storage per 10(6) fat cells in LBSQ adipocytes compared with UBSQ adipocytes (P = 0.04), whereas the other groups had comparable storage in UBSQ and LBSQ adipocytes. Fractional FFA storage was significantly associated with fractional VLDL-TG storage in both UBSQ (P < 0.01) and LBSQ (P = 0.03) adipose tissue. In conclusion, UBO women store a greater proportion of FFA in the UBSQ depot compared with lean women. In addition, LBO women store FFA more efficiently in LBSQ fat cells compared with UBSQ fat cells, which may play a role in development of their LBO phenotype. Finally, direct FFA storage and VLDL-TG fatty acid storage are correlated, indicating they may share a common rate-limiting pathway for fatty acid storage in adipose tissue. PMID- 22510711 TI - Effect of acute exercise on glycogen synthase in muscle from obese and diabetic subjects. AB - Insulin stimulates glycogen synthase (GS) through dephosphorylation of serine residues, and this effect is impaired in skeletal muscle from insulin-resistant [obese and type 2 diabetic (T2DM)] subjects. Exercise also increases GS activity, yet it is not known whether the ability of exercise to affect GS is impaired in insulin-resistant subjects. The objective of this study was to examine the effect of acute exercise on GS phosphorylation and enzyme kinetic properties in muscle from insulin-resistant individuals. Lean normal glucose-tolerant (NGT), obese NGT, and obese T2DM subjects performed 40 min of moderate-intensity cycle exercise (70% of Vo(2max)). GS kinetic properties and phosphorylation were measured in vastus lateralis muscle before exercise, immediately after exercise, and 3.5 h postexercise. In lean subjects, GS fractional activity increased twofold after 40 min of exercise, and it remained elevated after the 3.5-h rest period. Importantly, exercise also decreased GS K(m) for UDP-glucose from ~0.5 to ~0.2 mM. In lean subjects, exercise caused significant dephosphorylation of GS by 50-70% (Ser(641), Ser(645), and Ser(645,649,653,657)), and phosphorylation of these sites remained decreased after 3.5 h; Ser7 phosphorylation was not regulated by exercise. In obese NGT and T2DM subjects, exercise increased GS fractional activity, decreased K(m) for UDP-glucose, and decreased GS phosphorylation as effectively as in lean NGT subjects. We conclude that the molecular regulatory process by which exercise promotes glycogen synthesis in muscle is preserved in insulin-resistant subjects. PMID- 22510712 TI - Effects of leptin replacement alone and with exendin-4 on food intake and weight regain in weight-reduced diet-induced obese rats. AB - Weight loss in obese humans produces a relative leptin deficiency, which is postulated to activate potent orexigenic and energy conservation mechanisms to restrict weight loss and promote weight regain. Here we determined whether leptin replacement alone or with GLP-1 receptor agonist exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced diet-induced obese (DIO) rats. Forty percent restriction in daily intake of a high-fat diet in DIO rats for 4 wk reduced body weight by 12%, body fat by 29%, and plasma leptin by 67% and normalized leptin sensitivity. When food restriction ended, body weight, body fat, and plasma leptin increased rapidly. Daily administration of leptin [3-h intraperitoneal (ip) infusions (4 nmol.kg(-1).h(-1))] at onset and end of dark period for 3 wk did not attenuate hyperphagia and weight regain, nor did it affect mean daily meal sizes or meal numbers. Exendin-4 (50 pmol.kg(-1).h(-1)) infusions during the same intervals prevented postrestriction hyperphagia and weight regain by normalizing meal size. Coadministration of leptin and exendin-4 did not reduce body weight more than exendin-4 alone. Instead, leptin began to attenuate the inhibitory effects of exendin-4 on food intake, meal size, and weight regain by the end of the second week of administration. Plasma leptin in rats receiving leptin was sevenfold greater than in rats receiving vehicle and 17 fold greater than in rats receiving exendin-4. Together, these results do not support the hypothesis that leptin replacement alone or with exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced DIO rats. PMID- 22510713 TI - Paramagnetic perfluorocarbon-filled albumin-(Gd-DTPA) microbubbles for the induction of focused-ultrasound-induced blood-brain barrier opening and concurrent MR and ultrasound imaging. AB - This paper presents new albumin-shelled Gd-DTPA microbubbles (MBs) that can concurrently serve as a dual-modality contrast agent for ultrasound (US) imaging and magnetic resonance (MR) imaging to assist blood-brain barrier (BBB) opening and detect intracerebral hemorrhage (ICH) during focused ultrasound brain drug delivery. Perfluorocarbon-filled albumin-(Gd-DTPA) MBs were prepared with a mean diameter of 2320 nm and concentration of 2.903*10(9) MBs ml(-1) using albumin-(Gd DTPA) and by sonication with perfluorocarbon (C(3)F(8)) gas. The albumin-(Gd DTPA) MBs were then centrifuged and the procedure was repeated until the free Gd(3+) ions were eliminated (which were detected by the xylenol orange sodium salt solution). The albumin-(Gd-DTPA) MBs were also characterized and evaluated both in vitro and in vivo by US and MR imaging. Focused US was used with the albumin-(Gd-DTPA) MBs to induce disruption of the BBB in 18 rats. BBB disruption was confirmed with contrast-enhanced T(1)-weighted turbo-spin-echo sequence MR imaging. Heavy T(2)*-weighted 3D fast low-angle shot sequence MR imaging was used to detect ICH. In vitro US imaging experiments showed that albumin-(Gd-DTPA) MBs can significantly enhance the US contrast in T(1)-, T(2)- and T(2)*-weighted MR images. The r(1) and r(2) relaxivities for Gd-DTPA were 7.69 and 21.35 s(-1)mM( 1), respectively, indicating that the MBs represent a positive contrast agent in T(1)-weighted images. In vivo MR imaging experiments on 18 rats showed that focused US combined with albumin-(Gd-DTPA) MBs can be used to both induce disruption of the BBB and detect ICH. To compare the signal intensity change between pure BBB opening and BBB opening accompanying ICH, albumin-(Gd-DTPA) MB imaging can provide a ratio of 5.14 with significant difference (p = 0.026), whereas Gd-DTPA imaging only provides a ratio of 2.13 and without significant difference (p = 0.108). The results indicate that albumin-(Gd-DTPA) MBs have potential as a US/MR dual-modality contrast agent for BBB opening and differentiating focused-US-induced BBB opening from ICH, and can monitor the focused ultrasound brain drug delivery process. PMID- 22510714 TI - Mindful of the gaps: enhancing psychiatry training through a trainee workshop. AB - OBJECTIVES: The aim of this study was to develop and pilot a workshop for basic trainees in psychiatry to address perceived gaps in the specialist training program and to foster a culture of mentorship. METHODS: A literature review and consultations with clinicians and managers determined interest in the workshop, preferences for content, and feasibility. Six psychiatrists met on several occasions to plan the workshop. Supervisors were surveyed prior to the workshop to ascertain their perceptions of their trainees' knowledge of particular topics and the content of supervision. Registrar self-evaluations and knowledge were assessed before and after the workshop. RESULTS: Twenty-four registrars attended the first session of the workshop and 22 the second. Following the workshop, self ratings of knowledge and confidence of trainees in topics including risk assessment and duty of care were significantly better. Registrars rated the program highly for collegiate interactions, format, originality and usefulness. Supervisors identified weaknesses in trainee knowledge corresponding to workshop topics. CONCLUSIONS: Trainee self-evaluations of key aspects of clinical psychiatry improved significantly after the workshop. The development process described here for implementing a service-based initiative in psychiatry trainee education tailored to local needs may be transferable to other services. PMID- 22510715 TI - Bipolar II disorder in rural New South Wales. AB - OBJECTIVE: To determine the frequency with which bipolar II disorder (BD II) was diagnosed in clinics held in four rural towns in New South Wales (NSW). METHOD: A retrospective case file audit was conducted for patients referred for psychiatric assessment and treatment in four towns in rural NSW over a period of two years and nine months. RESULTS: Of 559 patients seen for the first time during the study period, 113 (20.2%) were diagnosed with BD II, and of these this diagnosis was made for the first time in 69 patients (61%). Associated clinical findings in BD II patients are presented and a comparison is made with patients with non bipolar depression seen during the same period. CONCLUSION: BD II was commonly seen in these rural clinics, and appears to be often under-diagnosed in general practice, as has been found to be the case in urban centres. This is seen as a serious public health problem, which needs to be addressed by educational steps directed at general practitioners (GPs), mental health clinicians, and perhaps also the general public. PMID- 22510716 TI - Health behaviours of community-treated patients with psychosis. AB - OBJECTIVE: To assess physical health self-reports and health utilization behaviours of community dwelling persons with persistent psychosis. METHOD: A cross-sectional survey was conducted of 106 patients with persistent psychosis. Using self-reported measures, the prevalence of smoking, alcohol consumption and exercise, and body mass index were determined. Health utilization behaviour, especially with respect to general practice, was assessed. Data was compared with that derived from the general population and longitudinally with a historical cohort. RESULTS: Compared with the general population, those with psychosis were more likely to be smokers, overweight or obese, and less likely to be non/ex smokers. Compared with previous studies, smoking and obesity persisted as major modifiable risk factors. Over 7 years, some risks such as smoking increased, whereas moderating factors such as light exercise, improved. Three-quarters of patients would visit their GP if they had a physical illness but a third reported not having visited their GP or other doctor in the previous 12 months. CONCLUSIONS: Patients with persistent psychosis have increased rates of cardiometabolic risk yet seek medical attention infrequently. These findings have not improved despite an increased awareness of the enhanced risk of developing metabolic disease in this group. PMID- 22510717 TI - HK Fry: an early contributor to Australian psychiatry. AB - OBJECTIVE: To examine the contribution of HK Fry to early Australian psychiatry. METHOD: A brief biographical review and an examination of Fry's published work. RESULTS: Fry provided not only insightful research in to what he described as 'Aboriginal mentality', but he also promoted a consideration of psychological factors in general medical therapeutics. CONCLUSION: HK Fry warrants recognition as a significant contributor in the history of Australian psychiatry. PMID- 22510718 TI - Patterns of mental health service contact before and after forensic mental health contact in New Zealand. AB - OBJECTIVE: To describe patterns of mental health service contact before and after contact with a regional forensic mental health service (FMHS) to assist regional mental health service planning. METHOD: All new referrals to Auckland Regional FMHS in 2006 were audited for contact with mental health services in the three years before and three years after their contact in 2006. RESULTS: A total of 925 identified individuals were referred to the Auckland Regional FMHS in 2006, predominantly through the court (81%) or prison (17%). In the preceding three years, 30.2% of these service users had no mental health service contact, 41.4% had general adult mental health service (GAMHS) contact alone, 22.6% had both FMHS and GAMHS contact, and 5.8% had FMHS contact alone. In the three years after 2006, 13.4% had no further contact with either FMHS or GAMHS, 20.3% had GAMHS contact alone, 51.2% of the sample had contact with both FMHS and GAMHS, and 15% had only FMHS contact. CONCLUSIONS: The service utilization patterns of this population support the establishment of strong links between GAMHS and FMHS in courts and prisons. Further research is needed to determine the specific models most likely to improve clinical outcomes. PMID- 22510719 TI - Efficient determination of diffusion coefficients by monitoring transport during recovery delays in NMR. AB - A novel NMR approach allows one to efficiently determine translational diffusion coefficients of macromolecules in solution. This method for Signal Optimization with Recovery in Diffusion Delays (SORDID) monitors transport occurring during the recovery times between consecutive scans so that the duration of the measurements can be reduced approximately by a factor two. PMID- 22510720 TI - Photovoltaic characteristics and dye regeneration kinetics in D149-sensitized ZnO with varied dye loading and film thickness. AB - Porous ZnO electrodes on fluorine-doped tin oxide (FTO) were prepared by electrochemical deposition from an O(2)-saturated ZnCl(2) solution in the presence of eosin Y as a structure directing agent (SDA). Sensitization was reached by desorption of the SDA and subsequent adsorption of the indoline dye D149. The influence of film thickness and dye concentration in the films on their photovoltaic characteristics, recombination, and dye regeneration kinetics was investigated. The recombination kinetics was analyzed by time-resolved photovoltage measurements. The dye regeneration by iodide ions in the electrolyte was investigated using scanning electrochemical microscopy (SECM) feedback mode approach curves. Analysis of a SECM kinetic model shows strongly different effective D149 regeneration rate constants k'(ox) for D149-ZnO electrodes of systematically varied film thickness and dye loading. It was found that the short circuit current density J(sc) and k'(ox) correlated directly with the adsorbed dye concentration. k'(ox) was found to be independent of the dye loading but correlated strongly with the dye concentration in the film or inversely with the film thickness. Furthermore, we discussed the perspective of correlating macroscopic cell characteristics with SECM kinetics data. PMID- 22510722 TI - Disrupted regulation of social exclusion in alcohol-dependence: an fMRI study. AB - Alcohol-dependence is associated with cognitive and biological alterations, and also with interpersonal impairments. Although overwhelming in clinical settings and involved in relapse, these social impairments have received little attention from researchers. Particularly, brain alterations related to social exclusion have not been explored in alcohol-dependence. Our primary purpose was to determine the neural correlates of social exclusion feelings in this population. In all, 44 participants (22 abstinent alcohol-dependent patients and 22 paired controls) played a virtual game ('cyberball') during fMRI recording. They were first included by other players, then excluded, and finally re-included. Brain areas involved in social exclusion were identified and the functional connectivity between these areas was explored using psycho-physiological interactions (PPI). Results showed that while both groups presented dorsal anterior cingulate cortex (dACC) activations during social exclusion, alcohol dependent participants exhibited increased insula and reduced frontal activations (in ventrolateral prefrontal cortex) as compared with controls. Alcohol dependence was also associated with persistent dACC and parahippocampal gyrus activations in re-inclusion. PPI analyses showed reduced frontocingulate connectivity during social exclusion in alcohol-dependence. Alcohol-dependence is thus linked with increased activation in areas eliciting social exclusion feelings (dACC-insula), and with impaired ability to inhibit these feelings (indexed by reduced frontal activations). Altered frontal regulation thus appears implied in the interpersonal alterations observed in alcohol-dependence, which seem reinforced by impaired frontocingulate connectivity. This first exploration of the neural correlates of interpersonal problems in alcohol-dependence could initiate the development of a social neuroscience of addictive states. PMID- 22510721 TI - Predicting white matter integrity from multiple common genetic variants. AB - Several common genetic variants have recently been discovered that appear to influence white matter microstructure, as measured by diffusion tensor imaging (DTI). Each genetic variant explains only a small proportion of the variance in brain microstructure, so we set out to explore their combined effect on the white matter integrity of the corpus callosum. We measured six common candidate single nucleotide polymorphisms (SNPs) in the COMT, NTRK1, BDNF, ErbB4, CLU, and HFE genes, and investigated their individual and aggregate effects on white matter structure in 395 healthy adult twins and siblings (age: 20-30 years). All subjects were scanned with 4-tesla 94-direction high angular resolution diffusion imaging. When combined using mixed-effects linear regression, a joint model based on five of the candidate SNPs (COMT, NTRK1, ErbB4, CLU, and HFE) explained ~ 6% of the variance in the average fractional anisotropy (FA) of the corpus callosum. This predictive model had detectable effects on FA at 82% of the corpus callosum voxels, including the genu, body, and splenium. Predicting the brain's fiber microstructure from genotypes may ultimately help in early risk assessment, and eventually, in personalized treatment for neuropsychiatric disorders in which brain integrity and connectivity are affected. PMID- 22510723 TI - Muscarinic receptors modulate the intrinsic excitability of infralimbic neurons and consolidation of fear extinction. AB - There is considerable interest in identifying pharmacological compounds that could be used to facilitate fear extinction. Recently, we showed that the modulation of M-type K(+) channels regulates the intrinsic excitability of infralimbic (IL) neurons and fear expression. As muscarinic acetylcholine receptors inhibit M-type K(+) channels, cholinergic inputs to IL may have an important role in controlling IL excitability and, thereby, fear expression and extinction. To test this model, we combined whole-cell patch-clamp electrophysiology and auditory fear conditioning. In prefrontal brain slices, muscarine enhanced the intrinsic excitability of IL neurons by reducing the M current and the slow afterhyperpolarization, resulting in an increased number of spikes with shorter inter-spike intervals. Next, we examined the role of endogenous activation of muscarinic receptors in fear extinction. Systemic injected scopolamine (Scop) (muscarinic receptor antagonist) before or immediately after extinction training impaired recall of extinction 24-h later, suggesting that muscarinic receptors are critically involved in consolidation of extinction memory. Similarly, infusion of Scop into IL before extinction training also impaired recall of extinction 24-h later. Finally, we demonstrated that systemic injections of the muscarinic agonist, cevimeline (Cev), given before or immediately after extinction training facilitated recall of extinction the following day. Taken together, these findings suggest that cholinergic inputs to IL have a critical role in modulating consolidation of fear extinction and that muscarinic agonists such as Cev might be useful for facilitating extinction memory in patients suffering from anxiety disorders. PMID- 22510724 TI - Oxytocin modulates neural reactivity to children's faces as a function of social salience. AB - Oxytocin (OT) enhances social behaviors such as attachment and parental caretaking. Neural correlates of maternal attachment are found in reward-related brain regions, for example, in the globus pallidus (GP). The present work investigates the effects of OT on the neural correlates of parental attachment. Fathers viewed pictures of their own child (oC), a familiar child (fC), and an unfamiliar child (uC) after intranasal application of OT vs placebo. OT reduced activation and functional connectivity of the left GP with reward- and attachment related regions responsive to pictures of the oC and the uC. The present results emphasize the key role of OT in human parental attachment and suggest that OT reduces neural reactivity to social cues as a function of social salience. Our results together with previous findings speak to a selective reduction of neural reactivity to social stimuli, irrespective of their valence. We argue that one major pathway by which OT exerts its positive effects on affiliative and social behaviors is the attenuation of automatic neural responses, which in turn leads to increased approach behaviors and decreased social avoidance. PMID- 22510725 TI - Corticotropin-releasing factor acting at the locus coeruleus disrupts thalamic and cortical sensory-evoked responses. AB - Stress and stress-related psychiatric disorders, including post-traumatic stress disorder, are associated with disruptions in sensory information processing. The neuropeptide, corticotropin-releasing factor (CRF), coordinates the physiological and behavioral responses to stress, in part, by activating the locus coeruleus norepinephrine (LC-NE) projection system. Although the LC-NE system is an important modulator of sensory information processing, to date, the consequences of CRF activation of this system on sensory signal processing are poorly understood. The current study examined the dose-dependent actions of CRF at the LC on spontaneous and sensory-evoked discharge of neurons within the thalamus and cortex of the vibrissa somatosensory system in the awake, freely moving rat. Peri LC infusions of CRF resulted in a dose-dependent suppression of sensory-evoked discharge in ventral posterior medial thalamic and barrel field cortical neurons. A concurrent increase in spontaneous activity was observed. This latter action is generally not found with iontophoretic application of NE to target neurons or stimulation of the LC-NE pathway. Net decreases in signal-to-noise of sensory evoked responses within both regions suggest that under conditions associated with CRF release at the LC, including stress, the transfer of afferent information within sensory systems is impaired. Acutely, a suppression of certain types of sensory information may represent an adaptive response to an immediate unexpected stressor. Persistence of such effects could contribute to abnormalities of information processing seen in sensorimotor gating associated with stress and stress-related psychopathology. PMID- 22510727 TI - Focus on... Ubiquitin-related tumor suppressors. PMID- 22510726 TI - Norepinephrine and dopamine modulate impulsivity on the five-choice serial reaction time task through opponent actions in the shell and core sub-regions of the nucleus accumbens. AB - Impulsive behavior is a hallmark of several neuropsychiatric disorders (eg, attention-deficit/hyperactivity disorder, ADHD). Although dopamine (DA) and norepinephrine (NE) have a significant role in the modulation of impulsivity their neural loci of action is not well understood. Here, we investigated the effects of the selective NE re-uptake inhibitor atomoxetine (ATO) and the mixed DA/NE re-uptake inhibitor methylphenidate (MPH), both with proven clinical efficacy in ADHD, on the number of premature responses on a five-choice serial reaction time task, an operational measure of impulsivity. Microinfusions of ATO into the shell, but not the core, sub-region of the nucleus accumbens (NAcb) significantly decreased premature responding whereas infusions of MPH in the core, but not the shell, sub-region significantly increased premature responding. However, neither ATO nor MPH significantly altered impulsive behavior when infused into the prelimbic or infralimbic cortices. The opposing effects of ATO and MPH in the NAcb core and shell on impulsivity were unlikely mediated by ancillary effects on behavioral activation as locomotor activity was either unaffected, as in the case of ATO infusions in the core and shell, or increased when MPH was infused into either the core and shell sub-region. These findings indicate an apparently 'opponent' modulation of premature responses by NE and DA in the NAcb shell or core, respectively, and suggest that the symptom clusters of hyperactive-impulsive type ADHD may have distinct neural and neurochemical substrates. PMID- 22510730 TI - A priming role of local estrogen on exogenous estrogen-mediated synaptic plasticity and neuroprotection. AB - The localization of estrogen (E2) has been clearly shown in hippocampus, called local hippocampal E2. It enhanced neuronal synaptic plasticity and protected neuron form cerebral ischemia, similar to those effects of exogenous E2. However, the interactive function of hippocampal and exogenous E2 on synaptic plasticity activation and neuroprotection is still elusive. By using hippocampal H19-7 cells, we demonstrated the local hippocampal E2 that totally suppressed by aromatase inhibitor anastrozole. Anastrozole also suppressed estrogen receptor (ER)beta, but not ERalpha, expression. Specific agonist of ERalpha (PPT) and ERbeta (DPN) restored ERbeta expression in anastrozole-treated cells. In combinatorial treatment with anastrozole and phosphoinositide kinase-3 (PI-3K) signaling inhibitor wortmannin, PPT could not improve hippocampal ERbeta expression. On the other hand, DPN induced basal ERbeta translocalization into nucleus of anastrozole-treated cells. Exogenous E2 increased synaptic plasticity markers expression in H19-7 cells. However, exogenous E2 could not enhance synaptic plasticity in anastrozoletreated group. Exogenous E2 also increased cell viability and B-cell lymphoma 2 (Bcl2) expression in H(2)O(2)-treated cells. In combined treatment of anastrozole and H(2)O(2), exogenous E2 failed to enhance cell viability and Bcl2 expression in hippocampal H19-7 cells. Our results provided the evidence of the priming role of local hippocampal E2 on exogenous E2 enhanced synaptic plasticity and viability of hippocampal neurons. PMID- 22510731 TI - A facile synthesis of octa(carboxyphenyl)silsesquioxane. AB - A facile method was reported for a robust octa(carboxyphenyl) functionalized silsesquioxane (OCS), which offers excellent potential as a nanobuilding-block for the preparation of functional materials. OCS was fully characterized by FT IR, (1)H, (13)C, (29)Si-NMR, Maldi-TOF-MS spectra, and W-XRD analysis. PMID- 22510732 TI - Brain white matter lesions in HAM/TSP: do they have any special meaning? PMID- 22510733 TI - Cysticercosis and the immunossupression: what are the mechanisms involved? PMID- 22510734 TI - Tricks of the trade. PMID- 22510735 TI - HAM/TSP: association between white matter lesions on magnetic resonance imaging, clinical and cerebrospinal fluid findings. AB - OBJECTIVE: To investigate the association between clinical data, white matter lesions and inflammatory cerebrospinal fluid (CSF) findings in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). METHOD: We studied brain and cervical spinal cord on magnetic resonance imaging (MRI) and CSF examinations of 28 Brazilian HAM/TSP patients. RESULTS: The majority of patients had severe neurological incapacity with EDSS median of 6.5 (3-8). The brain MRI showed white matter lesions (75%) and atrophy (14%). The preferential brain location was periventricular. Cervical demyelination lesions occurred in 11% of the cases, and cervical atrophy in 3.5%. One patient had enhancement lesions on T1 cervical spinal cord MRI. Cases with spinal cord lesions had signs of acute CSF inflammation. The brain white matter lesions predominated in the patients with higher age. CONCLUSION: Our data suggest that an active inflammatory process is associated with the cervical spinal cord lesions in HAM/TSP. The brain abnormalities are not related to the clinical picture of HAM/TSP. PMID- 22510737 TI - Quantification of Fas protein in CSF of patients with neurocysticercosis. AB - Neurocysticercosis is a parasitic disease that affects the central nervous system. The objective of this study was to investigate the correlation between neuronal death evaluated by the quantification of Fas apoptotic factor and the different evolutive forms of neurocysticercosis accompanied or not by epileptic seizures. METHODS: Cerebrospinal fluid samples from 36 patients with a diagnosis of neurocysticercosis divided into the following groups: active cystic form (n=15), 9 patients with and 6 without seizures, and calcified form (=21), 9 with and 12 without seizures. Fourteen patients comprised the control group. Fas protein concentrations were determined by ELISA. RESULTS: Only the group of patients with calcified cysts without seizures presented cerebrospinal fluid levels of Fas similar to those of the control group. Higher levels were observed for the other groups. CONCLUSIONS: The present finding suggests high cerebrospinal fluid levels of soluble Fas protein, except for patients with calcified cysts without seizures. Significant differences were observed for the group with calcified cysts and seizures, suggesting greater neuronal damage in these patients. Replacement of the term inactive cyst with reactive inactive cyst is suggested. PMID- 22510736 TI - Neurological symptoms and signs in HTLV-1 patients with overactive bladder syndrome. AB - OBJECTIVE: To compare neurological symptoms and signs in HTLV-1 asymptomatic carriers and HTLV-1 patients with overactive bladder (OB) syndrome. METHODS: We studied 102 HTLV-1 positive individuals without HAM/TSP (HTLV-1 associated myelopathy/tropical spastic paraparesis) divided into two groups according to the presence or absence of OB syndrome. Clinical interview, neurological exam and proviral load was performed in all patients. RESULTS AND CONCLUSIONS: Individuals with OB were more commonly female (84.3 vs. 60.8% of asymptomatics, p=0.01). The prevalence of neurological complaints was higher in OB group, especially hand or foot numbness and arm or leg weakness. There was no difference between the groups in neurological strength and reflexes. Weakness complaint remained strongly associated with OB in multivariate logistic regression analysis adjusting for sex and age [adjusted odds ratio and 95%CI 3.59 (1.45-8.88) in arms and 6.68 (2.63 16.93) in legs]. Proviral load was also different between the two groups with higher level on OB individuals. PMID- 22510738 TI - Pediatric multiple sclerosis in Venezuela. AB - OBJECTIVE: To describe the epidemiological and clinical characteristics of Venezuelan pediatric patients with multiple sclerosis (MS). METHODS: Database records from the National Program for MS were searched for patients with an established diagnosis of MS whose first symptoms appeared before age 18. RESULTS: The national database held records of 1.710 patients; 3.8% had onset of the first symptoms before age 18. 46.7% were boys, yielding an F:M ratio of 1.13:1. Many children had a disease onset characterized by motor impairment (30.7%), brainstem/cerebellum and spinal cord affectation (27.6%), headache (26%). Less frequent symptoms were sensory symptoms (8%) and optic neuritis (7%). DISCUSSION: Pediatric MS patients in Venezuela represent a significant proportion of all MS cases. The clinical pattern is characterized by motor symptoms at onset, and predominantly monosymptomatic presentation with a relapsing-remitting pattern. This is the first systematic attempt to estimate the prevalence of pediatric MS in Venezuela. PMID- 22510740 TI - Neurosarcoidosis: guidance for the general neurologist. AB - Neurosarcoidosis (NS) more commonly occurs in the setting of systemic disease. The diagnosis is based on a clinical history suggestive of NS, presence of noncaseating granulomas, and supportive evidence of sarcoid pathology, laboratory, and imaging studies. NS could involve any part of the nervous system and often demands high doses of steroids for symptom control. It presents low response to isolated steroids administration and frequently requires immunosuppressive agents. In NS, lymphocytes are polarized toward an excessive Th1 response, leading to overproduction of TNF-alpha and INF-gama, as well as lL 2 and IL-15. Infliximab, a chimeric monoclonal antibody that neutralizes the biological activity of TNF-alpha, is a new option in the NS treatment. We revised pathophysiology, clinical manifestations, diagnostic work up, and treatment of NS as guidance for the general neurologist. PMID- 22510739 TI - Leprosy patients: neurotrophic factors and axonal markers in skin lesions. AB - Neurotrophins are growth factors with crucial roles in neural pathophysiology. These mediators functionally modulate nociceptive fibers, and changes in neurotrophins expression have been correlated with early loss of nociception in leprosy. This study investigated the expression of NGF, BDNF, and NT3 in dermal nerves of leprosy patients. Characterization of Remak bundles was achieved by p75(NTR), and axonal markers NF-L and PGP 9.5 immunostaining. Clinical parameters of neural impairment have been evaluated by Semmes-Wenstein monofilaments. Our findings demonstrated decrease of NGF in borderline leprosy, when compared to control specimens. Similar results were observed in PGP 9.5 expression (borderline: p<0.001 and lepromatous: p<0.05) and NF-L (lepromatous: p<0.05), suggesting advanced Remak bundles degeneration in multibacillary leprosy. It has also been observed positive correlation between p75(NTR) and PGP 9.5, indicating association between Schwann cells and axons in Remak bundles. Present data indicate that neurotrophins imbalance may participate in the establishment of peripheral nerve damage. PMID- 22510741 TI - The expanding spectrum of clinically-distinctive, immunotherapy-responsive autoimmune encephalopathies. AB - The autoimmune encephalopathies are a group of conditions that are associated with autoantibodies against surface neuronal proteins, which are likely to mediate the disease. They are established as a frequent cause of encephalitis. Characteristic clinical features in individual patients often allow the specificity of the underlying antibody to be confidently predicted. Antibodies against the VGKC-complex, mainly LGI1(leucine-rich glioma-inactivated 1), CASPR2 (contactin-associated protein 2), and contactin-2, and NMDA (N-methyl, D aspartate) -receptor are the most frequently established serological associations. In the minority of cases, an underlying tumour can be responsible. Early administration of immunotherapies, and tumour removal, where it is relevant, offer the greatest chance of improvement. Prolonged courses of immunotherapies may be required, and clinical improvements often correlate well with the antibody levels. In the present article, we have summarised recent developments in the clinical and laboratory findings within this rapidly expanding field. PMID- 22510742 TI - Charcot's son, commander Jean-Baptiste Charcot: from neurology to "Pourquoi Pas?". AB - Charcot name became very famous around the world, firstly because of the work of Professor Jean-Martin Charcot, the founder of Clinical Neurology, and, secondly, because of his son, Jean-Baptiste, the world famous maritime explorer. PMID- 22510743 TI - Penetrating cervical spine injury and spinal cord intramedullary abscess. PMID- 22510744 TI - Cerebellar ataxia as the first manifestation of Alexander's disease. PMID- 22510745 TI - A unique association: trigeminal and stapedial arteries in a patient harboring a meningioma. PMID- 22510746 TI - Transcranial sonography: Brazilian experience. PMID- 22510749 TI - Back to the future: molecular biology meets metabolism. PMID- 22510747 TI - Skeletal muscle anabolism is a side effect of therapy with the MEK inhibitor: selumetinib in patients with cholangiocarcinoma. AB - BACKGROUND: Cancer cachexia is characterised by skeletal muscle wasting; however, potential for muscle anabolism in patients with advanced cancer is unproven. METHODS: Quantitative analysis of computed tomography images for loss/gain of muscle in cholangiocarcinoma patients receiving selumetinib (AZD6244; ARRY 142886) in a Phase II study, compared with a separate standard therapy group. Selumetinib is an inhibitor of mitogen-activated protein/extracellular signal regulated kinase and of interleukin-6 secretion, a putative mediator of muscle wasting. RESULTS: Overall, 84.2% of patients gained muscle after initiating selumetinib; mean overall gain of total lumbar muscle cross-sectional area was 13.6 cm(2)/100 days (~2.3 kg on a whole-body basis). Cholangiocarcinoma patients who began standard treatment were markedly catabolic, with overall muscle loss of -7.3 cm(2)/100 days (~1.2 kg) and by contrast only 16.7% of these patients gained muscle. CONCLUSION: Our findings suggest that selumetinib promotes muscle gain in patients with cholangiocarcinoma. Specific mechanisms and relevance for cachexia therapy remain to be investigated. PMID- 22510748 TI - The cap-translation inhibitor 4EGI-1 induces apoptosis in multiple myeloma through Noxa induction. AB - BACKGROUND: Cancer cells are frequently addicted to deregulated oncogenic protein translation. The small molecule 4EG-I selectively inhibits the cap-dependent translation of mRNAs. As multiple myeloma is an incurable disease that requires new therapeutic approaches, we investigated whether targeting the translation initiation pathway could be a target for myeloma therapy. METHODS: Six myeloma cell lines and primary samples were included in this study. The 4EGI-1 effect was determined by AnnexinV staining and caspase activation. Modification of Bcl-2 protein expression was analysed, and the significance of modified proteins was analysed by knock-down experiments. RESULTS: We demonstrated that 4EGI-1 impaired the assembly of the eIF4F complex and decreased the expression of the eIF4E regulated proteins in myeloma cells. Furthermore, we showed that 4EGI-1 induced strong apoptosis in five out of six myeloma cell lines. Apoptosis is associated with the activation of the intrinsic mitochondrial pathway. The 4EGI-1 triggered Noxa induction only in cells undergoing apoptosis through endoplasmic reticulum (ER) stress. Furthermore, Noxa silencing prevented myeloma cells from 4EGI-1 induced apoptosis. Finally, Noxa induction led to a disruption of Mcl-1/Bim complexes in parallel to the generation of 'Mcl-1-free Noxa'. CONCLUSION: Our results suggested that the use of inhibitors that directly target the translation initiation complex eIF4F could represent a potential novel approach for multiple myeloma therapy. PMID- 22510750 TI - [Extracranial manifestations of tuberous sclerosis - characteristic findings in computed tomography]. PMID- 22510751 TI - Fluoranthene based fluorescent chemosensors for detection of explosive nitroaromatics. AB - A novel fluoranthene based fluorescent chemosensor for the detection of picric acid (PA) at the parts per billion (ppb) level was evaluated. Static fluorescence quenching was the dominant process by intercalative pi-pi interaction between fluoranthene (S(1)) and nitroaromatics. PMID- 22510752 TI - Interplay of low-energy phonons and magnetic excitations in the Kondo insulator YbB12. AB - Peculiarities in the lattice dynamics of the Kondo insulator Y bB(12) have been studied by inelastic neutron scattering. Selected phonon modes were traced above and below the temperature region (T ~ 50 K) where the gap opens in the electron density of states. The intensities of some low-energy modes exhibit an anomalous temperature dependence for q vectors close to the Brillouin zone boundary, suggesting a renormalization of the phonon eigenvectors. This effect is thought to arise from a coupling with magnetic excitations of the same symmetry, which exist at nearby energies. It is argued that this magnetovibrational coupling may in turn play a role in the steep temperature crossover existing in Y bB(12) between the low-temperature (Kondo insulator) and high-temperature (incoherent spin-fluctuation) regimes, which is rapidly suppressed by lighter Zr substitution. PMID- 22510753 TI - CT metal artifact reduction method correcting for beam hardening and missing projections. AB - We present and validate a computed tomography (CT) metal artifact reduction method that is effective for a wide spectrum of clinical implant materials. Projections through low-Z implants such as titanium were corrected using a novel physics correction algorithm that reduces beam hardening errors. In the case of high-Z implants (dental fillings, gold, platinum), projections through the implant were considered missing and regularized iterative reconstruction was performed. Both algorithms were combined if multiple implant materials were present. For comparison, a conventional projection interpolation method was implemented. In a blinded and randomized evaluation, ten radiation oncologists ranked the quality of patient scans on which the different methods were applied. For scans that included low-Z implants, the proposed method was ranked as the best method in 90% of the reviews. It was ranked superior to the original reconstruction (p = 0.0008), conventional projection interpolation (p < 0.0001) and regularized limited data reconstruction (p = 0.0002). All reviewers ranked the method first for scans with high-Z implants, and better as compared to the original reconstruction (p < 0.0001) and projection interpolation (p = 0.004). We conclude that effective reduction of CT metal artifacts can be achieved by combining algorithms tailored to specific types of implant materials. PMID- 22510754 TI - Ru-catalyzed highly chemo- and enantioselective hydrogenation of gamma-halo gamma,delta-unsaturated-beta-keto esters under neutral conditions. AB - Finely-tuned ruthenium-catalyzed highly chemoselective and enantioselective hydrogenation of gamma-halo-gamma,delta-unsaturated-beta-keto esters at the carbonyl group was achieved under neutral reaction conditions (ee up to 97%). Both olefin and alkenyl halogen moieties, which are labile under hydrogenation conditions, remained untouched during the reaction. PMID- 22510755 TI - Photosynthetic efficiency of Chlamydomonas reinhardtii in attenuated, flashing light. AB - As a result of mixing and light attenuation, algae in a photobioreactor (PBR) alternate between light and dark zones and, therefore, experience variations in photon flux density (PFD). These variations in PFD are called light/dark (L/D) cycles. The objective of this study was to determine how these L/D cycles affect biomass yield on light energy in microalgae cultivation. For our work, we used controlled, short light path, laboratory, turbidostat-operated PBRs equipped with a LED light source for square-wave L/D cycles with frequencies from 1 to 100 Hz. Biomass density was adjusted that the PFD leaving the PBR was equal to the compensation point of photosynthesis. Algae were acclimated to a sub-saturating incident PFD of 220 umol m(-2) s(-1) for continuous light. Using a duty cycle of 0.5, we observed that L/D cycles of 1 and 10 Hz resulted on average in a 10% lower biomass yield, but L/D cycles of 100 Hz resulted on average in a 35% higher biomass yield than the yield obtained in continuous light. Our results show that interaction of L/D cycle frequency, culture density and incident PFD play a role in overall PBR productivity. Hence, appropriate L/D cycle setting by mixing strategy appears as a possible way to reduce the effect that dark zone exposure impinges on biomass yield in microalgae cultivation. The results may find application in optimization of outdoor PBR design to maximize biomass yields. PMID- 22510756 TI - Effect of the vanadium(V) concentration on the spectroscopic properties of nanosized europium-doped yttrium phosphates. AB - Nanosized rare earth phosphovanadate phosphors (Y(P,V)O(4):Eu(3+)) have been prepared by applying the organic-inorganic polymeric precursors methodology. Luminescent powders with tetragonal structure and different vanadate concentrations (0%, 1%, 5%, 10%, 20%, 50%, and 100%, with regard to the phosphate content) were then obtained for evaluation of their structural and spectroscopic properties. The solids were characterized by scanning electron microscopy, X-ray diffractometry, vibrational spectroscopy (Raman and infrared), and electronic spectroscopy (emission, excitation, luminescence lifetimes, chromaticity, quantum efficiencies, and Judd-Ofelt intensity parameters). The solids exhibited very intense (5)D(0)->(7)F(J) Eu(3+) transitions, and it was possible to control the luminescent characteristics, such as excitation maximum, lifetime and emission colour, through the vanadium(V) concentration. The observed luminescent properties correlated to the characteristics of the chemical environments around the Eu(3+) ions with respect to the composition of the phosphovanadates. The Eu(3+) luminescence spectroscopy results indicated that the presence of larger vanadium(V) amounts in the phosphate host lattice led to more covalent and polarizable chemical environments. So, besides allowing for control of the luminescent properties of the solids, the variation in the vanadate concentration in the obtained YPO(4):Eu(3+) phosphors enabled the establishment of a strict correlation between the observable spectroscopic features and the chemical characteristics of the powders. PMID- 22510758 TI - The histopathology of lung allograft dysfunction associated with the development of donor-specific HLA alloantibodies. AB - The histopathology of antibody-mediated rejection in lung allografts, outside of classical hyperacute rejection, has been poorly defined, in part because of the difficulty in identifying potential alloantibodies and in separating alloreactive and nonspecific complement-mediated reactions. In this study, we looked at lung biopsies coinciding with the development of anti-human leukocyte antigen (anti HLA) antibodies and lung dysfunction in a diverse group of lung transplant recipients over a 3-year period. We identified 23 patients and found that 17 had coexistent high-grade acute cellular rejection, 5 had patchy acute lung injury, and 1 had bronchiolitis at the time that anti-HLA alloantibodies appeared. Capillaritis was seen in 4/22 (18%) cases, usually in the context of cellular rejection. When the 17 cases of acute cellular rejection with coexistent anti-HLA antibodies were compared with a matched group of 26 patients with equivalent cellular rejection grade without anti-HLA antibodies, the only morphologic feature that separated the 2 groups was capillaritis seen in a minority of cases. C4d deposits were seen in both groups, although more frequently in those cases with anti-HLA antibodies (76% vs. 24%). The development of anti-HLA alloantibodies often occurs in the setting of acute cellular rejection, which in only a minority of cases can be identified as likely having an antibody-mediated component. C4d staining does not consistently separate the 2 groups. Identifying and ascribing allograft dysfunction to antibody-mediated rejection related to the development of anti-HLA antibodies is a difficult task that cannot be solved exclusively by morphology and requires significant clinicopathologic correlation. PMID- 22510759 TI - Urothelial carcinoma involving the gynecologic tract: a morphologic and immunohistochemical study of 6 cases. AB - Spread of urothelial carcinoma (UC) to the female genital tract occurs in a small subset of women with UC. We studied 6 patients with involvement of various gynecologic (GYN) sites and detailed natural history and pathologic features. Four patients initially presented with bladder lesions, including 1 high-grade pTa tumor, 2 pT1 tumors, and 1 pT2 tumor; 1 patient presented with pT2 disease of the renal pelvis and 1 with GYN involvement in the form of vulvar Paget's disease. For the 5 patients presenting with UC, time to GYN involvement was 2 to 8 years; vaginal bleeding (n=4) was the main presenting symptom, and the first site of involvement was the vagina (n=4) or cervix (n=1). GYN sites displayed an array of morphologies and growth patterns that may be seen in both UC and GYN primary tumors. The presence or absence of invasion in the original UC did not dictate whether GYN sites would exhibit invasive disease or whether disease would present as continuous or "skip" lesions. Immunohistochemistry for at least 1 GYN site per patient revealed diffuse, strong CK7 and focal to diffuse strong CK20 positivity in all cases, as well as at least focal p16 positivity in 5 of 6 cases. HPV in situ hybridization was negative in all cases. At last follow-up, 3 patients had died from UC and 3 were alive with recurrent disease/documented metastasis. Our findings highlight the morphologic and immunohistochemical overlap between primary GYN squamous lesions and GYN involvement by UC and hence the importance of clinical history in ensuring an accurate diagnosis. PMID- 22510757 TI - Phenotype and polyp landscape in serrated polyposis syndrome: a series of 100 patients from genetics clinics. AB - Serrated polyposis syndrome (SPS), also known as hyperplastic polyposis, is a syndrome of unknown genetic basis defined by the occurrence of multiple serrated polyps in the large intestine and associated with an increased risk of colorectal cancer (CRC). There are a variety of SPS presentations, which may encompass a continuum of phenotypes modified by environmental and genetic factors. To explore the phenotype of SPS, we recorded the histologic and molecular characteristics of multiple colorectal polyps in patients with SPS recruited between 2000 and 2010 from genetics clinics in Australia, New Zealand, Canada, and the United States. Three specialist gastrointestinal pathologists reviewed the polyps, which they classified into conventional adenomas or serrated polyps, with various subtypes, according to the current World Health Organization criteria. Mutations in BRAF and KRAS and mismatch repair protein expression were determined in a subset of polyps. A total of 100 patients were selected for the study, of whom 58 were female and 42 were male. The total polyp count per patient ranged from 6 to 150 (median 30). The vast majority of patients (89%) had polyposis affecting the entire large intestine. From this cohort, 406 polyps were reviewed. Most of the polyps (83%) were serrated polyps: microvesicular hyperplastic polyps (HP) (n=156), goblet cell HP (n=25), sessile serrated adenoma/polyps (SSA/P) (n=110), SSA/P with cytologic dysplasia (n=28), and traditional serrated adenomas (n=18). A further 69 polyps were conventional adenomas. BRAF mutation was mainly detected in SSA/P with dysplasia (95%), SSA/P (85%), microvesicular HP (76%), and traditional serrated adenoma (54%), whereas KRAS mutation was present mainly in goblet cell HP (50%) and in tubulovillous adenoma (45%). Four of 6 SSA/Ps with high-grade dysplasia showed loss of MLH1/PMS2 expression. CRC was diagnosed in 39 patients who were more often found to have a conventional adenoma compared with patients without CRC (P=0.003). Patients with SPS referred to genetics clinics had a pancolonic disease with a high polyp burden and a high rate of BRAF mutation. The occurrence of CRC was associated with the presence of conventional adenoma. PMID- 22510760 TI - Pleomorphic dermal sarcoma: adverse histologic features predict aggressive behavior and allow distinction from atypical fibroxanthoma. AB - The behavior of atypical fibroxanthoma is benign, if strict diagnostic criteria are applied. Tumors with similar pathologic features but deep subcutaneous invasion, necrosis, and/or lymphovascular or perineural invasion are thought to be associated with adverse outcome and are better regarded as pleomorphic dermal sarcoma or undifferentiated pleomorphic sarcoma of skin. This tumor group is not well documented in the literature, and its characteristics are only poorly defined. To study the clinical and pathologic spectrum more comprehensively, we retrieved 32 pleomorphic dermal sarcomas from our departmental files. The tumors were large (median: 25 mm) and exclusively presented on sun-damaged skin with a strong predilection for the head. Typically, elderly men were affected (median age: 81 y). Histologically, these often ulcerated tumors were poorly marginated, asymmetrical, and deeply invasive into deep subcutaneous, muscular, and/or fascial tissues. The tumors were cellular and composed of pleomorphic epithelioid cells, atypical spindle cells, and multinucleated tumor giant cells in varying proportions. Mitotic count was brisk and often atypical. Tumor necrosis was observed in 53%, lymphovascular invasion in 26%, and perineural infiltration in 29%. The majority of tumors showed a predominance of atypical spindle cells in a fascicular arrangement. A sheet-like growth of pleomorphic epithelioid cells or mixed spindle and epithelioid cell features were less frequently observed. Myxoid and keloidal change, a desmoplastic stromal response, pseudoangiomatous and storiform growth patterns, and admixed osteoclast-like giant cells were additional morphologic features in some cases. No immunoreactivity was noted for multiple cytokeratins, S100, HMB-45, desmin, and CD34. Smooth muscle actin was expressed in 70%, CD31 in 48%, epithelial membrane antigen in 16%, Melan A in 6%, and p63 in 1 case. CD10 was expressed in all cases stained. Follow-up (available for 29 patients; median: 24 mo) showed local recurrence in 28% and a metastatic rate of 10%, mainly in the skin. Progressive metastatic disease was observed in 2 patients. Remission was achieved in 1 patient using systemic chemotherapy. The second patient died in the setting of advanced-stage non-Hodgkin lymphoma. No disease-related mortality was noted. Our data underscore the importance of recognizing adverse histologic features in tumors otherwise resembling atypical fibroxanthoma. Deep subcutaneous invasion, tumor necrosis, and perineural and/or lymphovascular invasion confers at least low-grade malignant potential. PMID- 22510761 TI - Invasive low-grade papillary urothelial carcinoma: a clinicopathologic analysis of 41 cases. AB - Typically in invasive papillary urothelial carcinoma both the overlying papillary and the invasive components are high grade. We describe a series of patients with invasive low-grade papillary urothelial carcinoma (LPUC) in which both the noninvasive and invasive components are low grade. A retrospective search from The Johns Hopkins Surgical Pathology Database and consult cases from one of the author's files from 1998 to 2011 found 54 cases of invasive LPUC, excluding the more common, unique, and already well-characterized nested variant of urothelial carcinoma. Slides were available for 41 cases and formed the basis of the current study. The mean patient age was 68.4 years, with a male predominance. The specimens consisted of 37 bladder biopsies, 1 renal pelvis biopsy, 1 cystoprostatectomy specimen, 1 nephrectomy specimen, and 1 nephroureterectomy specimen. In all cases, invasion was limited to the superficial lamina propria above the muscularis mucosae. None of the histologic features correlated with tumor recurrence. Follow-up information was available for 73% of cases, with an average time interval of 49 months. Recurrent tumor was identified in 10/29 (34%) cases; however, 34% of cases without recurrence had limited follow-up (<24 mo). Three patients showed progression in tumor grade, and 3 additional patients progressed in both grade and stage (60% stage/grade progression). Four patients developed recurrence with ureteral noninvasive LPUC (2 in the bladder and 2 in the ureter). All are alive without disease. As this lesion is being increasingly recognized, larger studies are needed to determine whether invasion arising in LPUC is a significant risk factor for future disease. PMID- 22510762 TI - Tumors with EWSR1-CREB1 and EWSR1-ATF1 fusions: the current status. AB - EWSR1-CREB1 and EWSR1-ATF1 are gene fusions of which one or both have now been consistently described in 5 histopathologically and behaviorally diverse neoplasms: angiomatoid fibrous histiocytoma, conventional clear cell sarcoma (of tendons and aponeuroses), clear cell sarcoma-like tumor of the gastrointestinal tract, hyalinizing clear cell carcinoma of the salivary gland, and primary pulmonary myxoid sarcoma. Some of the tumors in this group have been described only recently, and others have been the subject of recent genetic insights contributing to their characterization. These neoplasms are all rare; yet, the increasing frequency with which EWSR1-CREB1 and EWSR1-ATF1 fusions are being described in separate entities is noteworthy. The additional molecular mechanisms by which tumors with such variable morphologic, immunohistochemical, and clinical phenotypes are generated are yet to be understood. We review the clinicopathologic and molecular features of this group of neoplasms unified by the presence of EWSR1-CREB1 and EWSR1-ATF1 genetic fusions. PMID- 22510763 TI - Cancer genomics: Constructing a 'cancerpaedia'. PMID- 22510764 TI - A beginner's guide to eukaryotic genome annotation. AB - The falling cost of genome sequencing is having a marked impact on the research community with respect to which genomes are sequenced and how and where they are annotated. Genome annotation projects have generally become small-scale affairs that are often carried out by an individual laboratory. Although annotating a eukaryotic genome assembly is now within the reach of non-experts, it remains a challenging task. Here we provide an overview of the genome annotation process and the available tools and describe some best-practice approaches. PMID- 22510765 TI - MicroRNA profiling: approaches and considerations. AB - MicroRNAs (miRNAs) are small RNAs that post-transcriptionally regulate the expression of thousands of genes in a broad range of organisms in both normal physiological contexts and in disease contexts. miRNA expression profiling is gaining popularity because miRNAs, as key regulators in gene expression networks, can influence many biological processes and also show promise as biomarkers for disease. Technological advances have spawned a multitude of platforms for miRNA profiling, and an understanding of the strengths and pitfalls of different approaches can aid in their effective use. Here, we review the major considerations for carrying out and interpreting results of miRNA-profiling studies. PMID- 22510767 TI - Human immunodeficiency virus-associated plasmablastic lymphoma: poor prognosis in the era of highly active antiretroviral therapy. AB - BACKGROUND: Plasmablastic lymphoma (PBL) is a rare and aggressive B-cell lymphoma strongly associated with human immunodeficiency virus (HIV) infection. The authors conducted a multi-institutional, retrospective study to describe characteristics and determine prognostic factors in HIV-associated PBL. METHODS: For this study, the investigators included consecutive, HIV-positive patients diagnosed between the years 2000 and 2010 whose tumors had a plasmablastic morphology, were cluster of differentiation 20 (CD20)-negative, and expressed markers of plasmacytic differentiation. RESULTS: Fifty patients from 13 institutions were evaluated. The median age was 43 years, and there was a male predominance. The median count of cells that were positive for CD4 (a glycoprotein expressed on the surface of T-helper cells, monocytes, macrophages, and dendritic cells) was 206 cells/mm(3) . At presentation, 90% of patients had extranodal involvement, 69% presented with advanced stage disease, and 27% had oral involvement. Rearrangements of v-myc myelocytomatosis viral oncogene homolog (MYC) were detected in 41% of the tested patients. Eighty-five percent of patients received chemotherapy, with 63% receiving cyclophosphamide, doxorubicin, vincristine, and prednisone and 37% receiving more intensive regimens. The complete response (CR) rate was 66%. The median overall survival (OS) was 11 months regardless of the intensity of chemotherapy. In the survival analysis, an Eastern Cooperative Oncology Group performance status >=2, advanced stage, and MYC rearrangements were associated significantly with a worse outcome, whereas attaining a CR with chemotherapy was associated with a better outcome. CONCLUSIONS: The prognosis of PBL in HIV-infected individuals remains poor in the highly active antiretroviral therapy era. Intensive chemotherapy regimens do not seem to increase survival in patients with HIV-associated PBL. Cancer 2012. PMID- 22510769 TI - Spontaneous resolution of hypereosinophilic syndrome in an infant without treatment. AB - We report on a 4-month-old boy with hypereosinophilic syndrome (HES) and spontaneous progressive resolution without treatment. Differential diagnosis excluded myeloproliferative, lymphocytic, familiar, associated, and overlap HES. The final diagnosis was undefined HES. Repeated measurements of blood eosinophil counts, monitoring of clonal T cells, and observation of skin lesions and organ involvement were carefully performed as an outpatient. PMID- 22510770 TI - Risk factors for early death in transient myeloproliferative disorder without phenotypic features of Down syndrome: a case report and literature review. AB - Not only in newborns with Down syndrome, but newborns without phenotypic features of Down syndrome also develop transient myeloproliferative disorder (TMD). In these cases, trisomy 21 and related chromosomal abnormalities are either constitutionally mosaic or limited to blood cells. Risk factors for early death of these patients are unknown so far. We here report a fatal case of TMD without phenotypic features of Down syndrome and review literature to identify risk factors associated with early death. Not only are gestational age and white blood cell count risk factors for early death in TMD with Down syndrome, but they also appear to be risk factors in TMD without Down syndrome. PMID- 22510768 TI - Pattern of deposition of cell wall polysaccharides and transcript abundance of related cell wall synthesis genes during differentiation in barley endosperm. AB - Immunolabeling, combined with chemical analyses and transcript profiling, have provided a comprehensive temporal and spatial picture of the deposition and modification of cell wall polysaccharides during barley (Hordeum vulgare) grain development, from endosperm cellularization at 3 d after pollination (DAP) through differentiation to the mature grain at 38 DAP. (1->3)-beta-D-Glucan appears transiently during cellularization but reappears in patches in the subaleurone cell walls around 20 DAP. (1->3, 1->4)-beta-Glucan, the most abundant polysaccharide of the mature barley grain, accumulates throughout development. Arabino-(1-4)-beta-D-xylan is deposited significantly earlier than we previously reported. This was attributable to the initial deposition of the polysaccharide in a highly substituted form that was not recognized by antibodies commonly used to detect arabino-(1-4)-beta-D-xylans in sections of plant material. The epitopes needed for antibody recognition were exposed by pretreatment of sections with alpha-L-arabinofuranosidase; this procedure showed that arabino-(1-4)-beta-D xylans were deposited as early as 5 DAP and highlighted their changing structures during endosperm development. By 28 DAP labeling of hetero-(1->4)-beta-D-mannan is observed in the walls of the starchy endosperm but not in the aleurone walls. Although absent in mature endosperm cell walls we now show that xyloglucan is present transiently from 3 until about 6 DAP and disappears by 8 DAP. Quantitative reverse transcription-polymerase chain reaction of transcripts for GLUCAN SYNTHASE-LIKE, Cellulose Synthase, and CELLULOSE SYNTHASE-LIKE genes were consistent with the patterns of polysaccharide deposition. Transcript profiling of some members from the Carbohydrate-Active Enzymes database glycosyl transferase families GT61, GT47, and GT43, previously implicated in arabino-(1-4) beta-d-xylan biosynthesis, confirms their presence during grain development. PMID- 22510771 TI - Diagnostic and treatment challenges for the pediatric hematologist oncologist in endemic areas for coccidioidomycosis. AB - Coccidioidomycosis is a mycosis endemic to certain areas in the Southwest, mostly Arizona and California, Mexico, and parts of Central and South America. Disseminated coccidioidomycosis is much more common in immunocompromised hosts; therefore, it is frequently encountered by pediatric oncologists in endemic areas. Special attention is needed to diagnose, effectively treat the infection, and appropriately adjust chemotherapy treatment plans to minimize immunosuppression. We describe the presentation and course of 6 patients with coccidioidomycosis who were seen by the pediatric hematology-oncology service at the University of Arizona during the last 3 years. Coccidioidomycosis is a relatively common infection encountered by pediatric oncologists in the southwestern states and should be considered in the differential diagnosis of patients living or visiting these areas. PMID- 22510772 TI - Deferasirox therapy in children with Fanconi aplastic anemia. AB - Thirty-nine children with Fanconi aplastic anemia (FAA) have been followed up in our center between January 2008 and November 2010. Eight of these children (20%) with a transfusional iron overload had been undergoing deferasirox treatment during the study period. In the English literature, transfusional iron overload and the use of an iron chelator in children with FAA has not yet been evaluated. Here, we have presented the effectivity and tolerability of deferasirox in children with FAA and a transfusional iron overload. Before the deferasirox treatment, the mean serum ferritin level was 3377 +/- 2200 ng/mL. After a mean 13.6-month treatment duration, the mean ferritin level decreased to 2274 +/- 1300 ng/mL (P<0.05). In our series, 3 patients had renal and 3 had hepatic toxicity during the treatment. Two patients had peliosis hepatis and 2 had congenital renal abnormalities before the treatment. There may be differences in the side effect profiles of deferasirox treatment in patients with FAA. In our series, despite the low number of cases, nephrotoxicity and hepatotoxicity were common side effects instead of gastrointestinal disturbances reported in other studies. Deferasirox is an oral, easily applicable, and effective iron chelator; baseline hepatotoxicity and nephrotoxicity may increase the development of toxic side effects in children with FAA. Patients with FAA receiving deferasirox treatment should be followed up closely for these side effects. PMID- 22510773 TI - Hepatic hemangioendothelioma in an infant with severe congenital neutropenia. AB - Severe congenital neutropenia (SCN) is a rare disorder caused by heterogeneous genetic mutations. We describe here a rare association of SCN caused by a novel ELANE mutation and infantile hepatic hemangioendothelioma. In a 2-month-old infant, an abdominal ultrasound performed for omphalitis revealed a hepatic tumor, which was resected. Histopathology confirmed the diagnosis of hemangioendothelioma. Postoperatively, severe neutropenia was noted. Bone marrow examination showed myeloid maturation arrest, diagnostic of SCN. Mutation analysis for the neutrophil elastase gene identified a novel heterozygous de novo ELANE missense mutation in exon 2 (c.215T>A, p.Val72Glu). He was managed successfully with broad-spectrum antibiotics and high-dose granulocyte colony stimulating factor. PMID- 22510775 TI - A case report of simultaneous occurrence of Wilms tumor and acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most and Wilms tumor is the sixth most common malignancy in childhood. Genetic changes in WT1 or WT2 in Wilms tumor and a wide range of chromosomal mutations are reported in ALL that may predispose them to other congenital anomalies especially in Wilms tumor patients. Hospitalized patient was a 3-year-old girl with high-grade fever, petechia, and solid abdominal mass. The patient had anemia, thrombocytopenia, and leukocytosis in her initial homogram, and a large renal mass originated from left kidney in abdominal imagings. Bone marrow aspiration revealed ALL, and simultaneous kidney biopsy uncovered her Wilms tumor. Leukemia and Wilms tumor are 2 independent malignancies but occurred together in this patient. It is reasonable to investigate cellular and genetic relation of these 2 independent malignancies. PMID- 22510774 TI - A novel mutation of ribosomal protein S10 gene in a Japanese patient with diamond Blackfan anemia. AB - Diamond-Blackfan anemia (DBA) is an inherited bone marrow disease. The condition is characterized by anemia that usually presents during infancy or early childhood and congenital malformation. Several reports show that DBA is associated with mutations in the ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7. Recently, 5 and 12 patients with mutations in RPS10 and RPS26, respectively, were identified in a cohort of 117 DBA probands. Therefore, we screened the DBA patients who were negative for mutations in these DBA genes for mutations in RPS10 and RPS26. The present case report describes the identification of the first Japanese DBA patient with a novel mutation in RPS10. PMID- 22510776 TI - Cord blood transplants for SCID: better B-cell engraftment? AB - Hematopoietic stem-cell transplantation is the treatment of choice for severe combined immunodeficiency (SCID). Despite successful T-cell engraftment in transplanted patients, B-cell function is not always achieved; up to 58% of patients require immunoglobulin therapy after receiving haploidentical transplants. We report 2 half-sibling males with X-linked gamma-chain SCID treated with different sources of stem cells. Sibling 1 was transplanted with T cell-depleted haploidentical maternal bone marrow and sibling 2 was transplanted with 7/8 human leukocyte antigen-matched unrelated umbilical cord blood. Both patients received pretransplant conditioning and posttransplant graft-versus-host disease prophylaxis. B-cell engraftment and function was achieved in sibling 1 but not in sibling 2. This disparate result is consistent with a review of 19 other SCID children who received cord blood transplants. B-cell function, as indicated by no need for immunoglobulin therapy, was restored in 42% of patients given haploidentical transplants and in 68% of patients given matched unrelated donor transplants compared with 80% of patients given cord blood transplants. Cord blood is an alternative source of stem cells for transplantation in children with SCID and has a higher likelihood of B-cell reconstitution. PMID- 22510777 TI - Juvenile myelomonocytic leukemia in a 16-year-old with Noonan syndrome: case report. AB - A 16-year-old man with splenomegaly presented with ascites and bilateral leg eschars. Although he had intermittently elevated absolute monocyte counts, a diagnosis of juvenile myelomonocytic leukemia (JMML) was discounted because of his age and lack of persistent leukocytosis. Detailed examination demonstrated features consistent with Noonan syndrome (NS), including typical facies, growth retardation, a cardiac defect, and a history of a coagulopathy. He underwent a splenectomy where the surgeons encountered a rind of tissue composed of monocytes encasing the abdominal organs. After splenectomy, his leukocytes rose to over 100*10(9)/L with a monocytosis, suggesting JMML. On the basis of the clinical suspicion of NS, mutation analysis revealed a KRAS mutation, which is known to be common to both NS and JMML. Clinicians should have high index of suspicion for JMML in patients with Noonan features, regardless of a patient's age. PMID- 22510778 TI - PPARA: a novel genetic determinant of CYP3A4 in vitro and in vivo. AB - Interindividual variability in cytochrome P450 3A4 (CYP3A4) is believed to be largely heritable; however, predictive genetic factors have remained scarce. Using a candidate-gene approach in a human liver bank, we identified single nucleotide polymorphisms (SNPs) in the Ah-receptor nuclear translocator (ARNT), glucocorticoid receptor (GR), progesterone receptor membrane component 2 (PGRMC2), and peroxisome proliferator-activated receptor-alpha (PPARA) that are associated with CYP3A4 phenotype. Validation in atorvastatin-treated volunteers confirmed a decrease in atorvastatin-2-hydroxylation in carriers of PPARA SNP rs4253728. Homozygous carriers expressed significantly less PPAR-alpha protein in the liver. Moreover, shRNA-mediated PPARA gene knockdown in primary human hepatocytes decreased expression levels of the PPAR-alpha target ACOX1 and of CYP3A4 by more than 50%. In conclusion, this study identified novel genetic determinants of CYP3A4 that, together with nongenetic factors, explained 52, 55, and 33% of hepatic CYP3A4 mRNA, protein, and atorvastatin-2-hydroxylase activity, respectively. These findings have implications for variability in response to drug substrates of CYP3A4. PMID- 22510780 TI - Ion-recombination correction for different ionization chambers in high dose rate flattening-filter-free photon beams. AB - Recently, there has been an increased interest in flattening-filter-free (FFF) linear accelerators. Removal of the filter results in available dose rates up to 24 Gy min(-1) (for nominal energy 10 MV in depth of maximum dose, a source surface distance of 100 cm and a field size of 10*10 cm2). To guarantee accurate relative and reference dosimetry for the FFF beams, we investigated the charge collection efficiency of multiple air-vented and one liquid ionization chamber for dose rates up to 31.9 Gy min(-1). For flattened beams, the ion-collection efficiency of all air-vented ionization chambers (except for the PinPoint chamber) was above 0.995. By removing the flattening filter, we found a reduction in collection efficiency of approximately 0.5-0.9% for a 10 MV beam. For FFF beams, the Markus chamber showed the largest collection efficiency of 0.994. The observed collection efficiencies were dependent on dose per pulse, but independent of the pulse repetition frequency. Using the liquid ionization chamber, the ion-collection efficiency for flattened beams was above 0.990 for all dose rates. However, this chamber showed a low collection efficiency of 0.940 for the FFF 10 MV beam at a dose rate of 31.9 Gy min(-1). All investigated air vented ionization chambers can be reliably used for relative dosimetry of FFF beams. The order of correction for reference dosimetry is given in the manuscript. Due to their increased saturation in high dose rate FFF beams, liquid ionization chambers appear to be unsuitable for dosimetry within these contexts. PMID- 22510779 TI - Percent body fat is a better predictor of cardiovascular risk factors than body mass index. AB - The objective of the present study was to evaluate the predictive values of percent body fat (PBF) and body mass index (BMI) for cardiovascular risk factors, especially when PBF and BMI are conflicting. BMI was calculated by the standard formula and PBF was determined by bioelectrical impedance analysis. A total of 3859 ambulatory adult Han Chinese subjects (2173 males and 1686 females, age range: 18-85 years) without a history of cardiovascular diseases were recruited from February to September 2009. Based on BMI and PBF, they were classified into group 1 (normal BMI and PBF, N = 1961), group 2 (normal BMI, but abnormal PBF, N = 381), group 3 (abnormal BMI, but normal PBF, N = 681), and group 4 (abnormal BMI and PBF, N = 836). When age, gender, lifestyle, and family history of obesity were adjusted, PBF, but not BMI, was correlated with blood glucose and lipid levels. The odds ratio (OR) and 95% confidence interval (CI) for cardiovascular risk factors in groups 2 and 4 were 1.88 (1.45-2.45) and 2.06 (1.26-3.35) times those in group 1, respectively, but remained unchanged in group 3 (OR = 1.32, 95%CI = 0.92-1.89). Logistic regression models also demonstrated that PBF, rather than BMI, was independently associated with cardiovascular risk factors. In conclusion, PBF, and not BMI, is independently associated with cardiovascular risk factors, indicating that PBF is a better predictor. PMID- 22510781 TI - Facile synthesis of graphitic carbon quantum dots with size tunability and uniformity using reverse micelles. AB - Highly luminescent graphitic carbon quantum dots (GQDs) are synthesized employing reverse micelles as nanoreactors. This method offers size tunability and narrow size distribution without any unpractical size separation process. Also, high quantum yields of maximum 35% at the 360 nm excitation wavelength are achieved. PMID- 22510782 TI - Hydrogenation effects in metalloporphycenes: synthesis and redox behavior of Ni(II)-tetra(n-propyl)dihydroporphycene. AB - Hydrogenated tetrapropylporphycenes, 2,3-dihydro-2,7,12,17-tetrapropylporphycene 1 and its Ni(II) complex 2, have been prepared and the hydrogenation effects on their electronic structure characterized. A one-electron reduction of 2 promotes dehalogenation of organic halides whose observation is unprecedented for the porphycene compounds. PMID- 22510783 TI - Anderson lattice with explicit Kondo coupling revisited: metamagnetism and the field-induced suppression of the heavy fermion state. AB - We apply the extended (statistically consistent, SCA) Gutzwiller-type approach to the periodic Anderson model (PAM) in an applied magnetic field and in the strong correlation limit. The finite-U corrections are included systematically by transforming the PAM into the form with the Kondo-type interaction and the residual hybridization, both appearing at the same time and on equal footing. This effective Hamiltonian represents the essence of our Anderson-Kondo lattice model. We show that in ferromagnetic phases the low-energy single-particle states are strongly affected by the presence of the applied magnetic field. We also find that for large values of hybridization strength the system enters the so-called locked heavy fermion state introduced earlier. In this state the chemical potential lies in the majority-spin hybridization gap and, as a consequence, the system evolution is insensitive to further increase of the applied field. However, for a sufficiently strong magnetic field, the system transforms from the locked state to the fully spin-polarized phase. This is accompanied by a metamagnetic transition, as well as by a drastic reduction of the effective mass of the quasiparticles. In particular, we observe no effective mass enhancement in the fully polarized state. The findings are in overall agreement with experimental results for the Ce compounds in high magnetic fields. The mass enhancement for the spin-minority electrons may also diminish with the increasing field, unlike for the quasiparticle states in a single narrow band in the same limit of strong correlations. PMID- 22510784 TI - A co-crystal of polyoxometalates exhibiting single-molecule magnet behavior: the structural origin of a large magnetic anisotropy. AB - A polyoxometalate-based {Mn(III)(3)Mn(IV)} single-molecule magnet exhibits a large axial anisotropy (D = -0.86 cm(-1)) resulting from a near-parallel alignment of Jahn-Teller axes. Its rigorous three-fold symmetry (i.e. rhombicity E-> 0) and increased intercluster separation via co-crystallization effectively hamper quantum tunnelling of the magnetization. PMID- 22510785 TI - Singlet fission in rubrene single crystal: direct observation by femtosecond pump probe spectroscopy. AB - The excited state dynamics of rubrene in solution and in the single crystal were studied by femtosecond pump-probe spectroscopy under various excitation conditions. Singlet fission was demonstrated to play a predominant role in the excited state relaxation of the rubrene crystal in contrast to rubrene in solution. Upon 500 nm excitation, triplet excitons form on the picosecond time scale via fission from the lowest excited singlet state. Upon 250 nm excitation, fission from upper excited singlet states is observed within 200 fs. PMID- 22510786 TI - The influence of management and environment on local health department organizational structure and adaptation: a longitudinal network analysis. AB - OBJECTIVE: The nation's 2862 local health departments (LHDs) are the primary means for assuring public health services for all populations. The objective of this study is to assess the effect of organizational network analysis on management decisions in LHDs and to demonstrate the technique's ability to detect organizational adaptation over time. DESIGN AND SETTING: We conducted a longitudinal network analysis in a full-service LHD with 113 employees serving about 187,000 persons. Network survey data were collected from employees at 3 times: months 0, 8, and 34. At time 1 the initial analysis was presented to LHD managers as an intervention with information on evidence-based management strategies to address the findings. At times 2 and 3 interviews documented managers' decision making and events in the task environment. RESULTS: Response rates for the 3 network analyses were 90%, 97%, and 83%. Postintervention (time 2) results showed beneficial changes in network measures of communication and integration. Screening and case identification increased for chlamydia and for gonorrhea. Outbreak mitigation was accelerated by cross-divisional teaming. Network measurements at time 3 showed LHD adaptation to H1N1 and budget constraints with increased centralization. Task redundancy increased dramatically after National Incident Management System training. CONCLUSIONS: Organizational network analysis supports LHD management with empirical evidence that can be translated into strategic decisions about communication, allocation of resources, and addressing knowledge gaps. Specific population health outcomes were traced directly to management decisions based on network evidence. The technique can help managers improve how LHDs function as organizations and contribute to our understanding of public health systems. PMID- 22510789 TI - Small RNAs reach out for repair. PMID- 22510790 TI - Intercellular communication: diverse structures for exchange of genetic information. AB - An emerging concept is that cellular communication in mammals can be mediated by the exchange of genetic information, mainly in the form of microRNAs. This can occur when extracellular vesicles, such as exosomes, secreted by a donor cell are taken up by an acceptor cell. Transfer of genetic material can also occur through intimate membrane contacts between donor and acceptor cells. Specialized cell cell contacts, such as synapses, have the potential to combine these modes of genetic transfer. PMID- 22510791 TI - Effect of vitamin D supplementation of low birth weight term Indian infants from birth on cytokine production at 6 months. AB - BACKGROUND/OBJECTIVES: Vitamin D deficiency has been associated with impaired resistance to infection, which may be mediated by alterations in cytokine responses. We investigated the effect of vitamin D supplementation to infants on whole blood in-vitro cytokine production and on the inflammatory marker, plasma C reactive protein (CRP). SUBJECTS/METHODS: Blood samples were taken at 6 months of age from infants participating in the DIVIDS (Delhi Infant Vitamin D Supplementation) randomized controlled trial of weekly vitamin D supplements (1400 IU = recommended intake) from birth to 6 months with the aim of decreasing mortality and severe morbidity. We measured plasma CRP and whole blood in-vitro production of tumour necrosis factor-alpha (TNFalpha), interferon-gamma (INFgamma), interleukin (IL)-10 and IL-13 following no stimulation or stimulation with lipopolysaccharide or phytohemagglutinin. RESULTS: Although the intervention improved vitamin D status in a severely deficient population, there were no differences between treatment groups in plasma CRP or in the production of any of the cytokines in either unstimulated or stimulated cultures. Recent illness had limited association with immunological markers. Plasma 25-hydroxyvitamin D levels were not associated with CRP or production of any cytokines. CONCLUSIONS: Vitamin D supplementation did not affect plasma CRP or whole blood cytokine production of vitamin D-deficient low birth weight infants. This is consistent with the lack of effect of vitamin D on mortality and severe morbidity among infants in the DIVIDS trial. PMID- 22510794 TI - Indications for an alternative effective treatment of head and neck squamous cell carcinoma with temsirolimus plus bevacizumab: from bench to bedside? AB - Head and neck squamous cell carcinoma (HNSCC) is a group of tumors known to be sensitive to chemotherapy and radiotherapy in patients who are treatment naive. However, when recurrences do occur, these tumors generally become resistant and objective responses to therapy at that point tend to be less effective. There has been an increasing interest in developing novel molecular-targeted agents that specifically modulate growth factor and signaling pathways that are unregulated in HNSCC tumor cells. Combinations of vascular endothelial growth factor and mammalian target of rapamycin inhibitors have been used in some types of neoplasms, but no such efforts have been made in HNSCC. In this study, we investigated the in vitro, in vivo, and clinical effects of the temsirolimus (mammalian target of rapamycin inhibitor, Tem) and bevacizumab (antivascular endothelial growth factor antibody, Bev) combination. In-vitro studies were carried out on the A431 human squamous epidermoid carcinoma cell line and in-vivo studies were carried out on A431 tumor cells implanted on female Nu/Nu*nuBR (athymic nude) mice. Also, the effectiveness of the Tem and Bev combination was tested clinically in two separate clinical cases of chemoresistant HNSCC. The in vitro, in-vivo, and clinical results showed that this combination can be significantly effective. In conclusion, we discuss the theoretical basis of the molecular pharmacological interactions between Bev and Tem that could explain these good results. If the therapeutic index is ultimately well determined, the antitumor effect of Bev and Tem is very likely to yield fruitful results. PMID- 22510792 TI - Effects of higher- versus lower-protein diets on health outcomes: a systematic review and meta-analysis. AB - BACKGROUND/OBJECTIVES: Numerous randomised controlled trials (RCTs) published in first tier medical journals have evaluated the health effects of diets high in protein. We conducted a rigorous systematic review of RCTs comparing higher- and lower-protein diets. METHODS: We searched several electronic databases up to July 2011 for studies focusing on patient-important outcomes (for example, cardiovascular disease) and secondary outcomes such as risk factors for chronic disease (for example, adiposity). RESULTS: We identified 111 articles reporting on 74 trials. Pooled effect sizes using standardised mean differences (SMDs) were small to moderate and favoured higher-protein diets for weight loss (SMD -0.36, 95% confidence interval (CI) -0.56 to -0.17), body mass index (-0.37, CI -0.56 to 0.19), waist circumference (-0.43, CI -0.69 to -0.16), blood pressure (systolic: 0.21, CI -0.32 to -0.09 and diastolic: -0.18, CI -0.29 to -0.06), high-density lipoproteins (HDL 0.25, CI 0.07 to 0.44), fasting insulin (-0.20, CI -0.39 to 0.01) and triglycerides (-0.51, CI -0.78 to -0.24). Sensitivity analysis of studies with lower risk of bias abolished the effect on HDL and fasting insulin, and reduced the effect on triglycerides. We observed nonsignificant effects on total cholesterol, low-density lipoproteins, C-reactive protein, HbA1c, fasting blood glucose, and surrogates for bone and kidney health. Adverse gastrointestinal events were more common with high-protein diets. Multivariable meta-regression analysis showed no significant dose response with higher protein intake. CONCLUSIONS: Higher-protein diets probably improve adiposity, blood pressure and triglyceride levels, but these effects are small and need to be weighed against the potential for harms. PMID- 22510793 TI - Dietary intakes and food sources of phytoestrogens in the European Prospective Investigation into Cancer and Nutrition (EPIC) 24-hour dietary recall cohort. AB - BACKGROUND/OBJECTIVES: Phytoestrogens are estradiol-like natural compounds found in plants that have been associated with protective effects against chronic diseases, including some cancers, cardiovascular diseases and osteoporosis. The purpose of this study was to estimate the dietary intake of phytoestrogens, identify their food sources and their association with lifestyle factors in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. SUBJECTS/METHODS: Single 24-hour dietary recalls were collected from 36,037 individuals from 10 European countries, aged 35-74 years using a standardized computerized interview programe (EPIC-Soft). An ad hoc food composition database on phytoestrogens (isoflavones, lignans, coumestans, enterolignans and equol) was compiled using data from available databases, in order to obtain and describe phytoestrogen intakes and their food sources across 27 redefined EPIC centres. RESULTS: Mean total phytoestrogen intake was the highest in the UK health conscious group (24.9 mg/day in men and 21.1 mg/day in women) whereas lowest in Greece (1.3 mg/day) in men and Spain-Granada (1.0 mg/day) in women. Northern European countries had higher intakes than southern countries. The main phytoestrogen contributors were isoflavones in both UK centres and lignans in the other EPIC cohorts. Age, body mass index, educational level, smoking status and physical activity were related to increased intakes of lignans, enterolignans and equol, but not to total phytoestrogen, isoflavone or coumestan intakes. In the UK cohorts, the major food sources of phytoestrogens were soy products. In the other EPIC cohorts the dietary sources were more distributed, among fruits, vegetables, soy products, cereal products, non-alcoholic and alcoholic beverages. CONCLUSIONS: There was a high variability in the dietary intake of total and phytoestrogen subclasses and their food sources across European regions. PMID- 22510795 TI - Midterm results of the "sandwich technique" via a right ventricle incision to repair post-infarction ventricular septal defect. AB - BACKGROUND: Residual shunting and mortality are problems associated with current surgical repair techniques for post-infarction ventricular septal defects. METHODS: We describe the mid-term results of the "sandwich technique" to repair a post-infarction ventricular septal defect (VSD), performed via a right ventricle incision. Application of direct ultrasonography to the right ventricular wall enables a surgeon to visualize the region, perform an appropriate incision into the right ventricle, and perform a trabecula resection. One patch is placed on the left ventricular (LV) side and the other on the right ventricular (RV) side of the VSD. The VSD is sealed with gelatin-resorcin-formalin (GRF) glue between the two patches. RESULTS: We had seven consecutive patients. The sandwich technique resulted in geometric preservation of the LV shape. There were no significant leaks, no mortality within a thirty-day postoperative period, and no bleeding problems. Hospital mortality was 14.3% (1/7 cases). Late survival longer than a year was obtained in five cases (71%). The longest patient survival time was nine years. No tissue degeneration was noted. CONCLUSION: This technique may be useful for repairing a post-infarction VSD. PMID- 22510796 TI - Off pump coronary artery bypass versus mitral annuloplasty in moderate ischemic mitral regurgitation. AB - PURPOSE: To compare the outcomes of isolated off-pump coronary artery bypass grafting (OPCAB) to those of mitral annuloplasty (MAP) with revascularization in patients with moderate ischemic mitral regurgitation (MR). METHODS: Between April 2001 and December 2009, 140 patients with moderate ischemic MR who underwent isolated OPCAB (OPCAB group, n = 77) or MAP with revascularization (MAP group, n = 63) were analyzed. RESULTS: Freedom from cardiac-related death at eight years was similar between groups (78.4 +/- 5.5%, the OPCAB group versus 81.5 +/- 5.9%, the MAP group, p = 0.297). In patients with left ventricular ejection fraction (LVEF) >40%, the MAP group were similar to the OPCAB group in freedom from recurrent MR at eight years (85.7+/- 10.0% versus 84.9 +/- 8.3%, p = 0.738), but a significant difference was found in patients with LVEF <=40% (93.5+/- 4.5%, the MAP group versus 36.9 +/- 18.4%, the OPCAB group, p = 0.013). On multivariate analysis, emergency operation and low LVEF were predictive of recurrent MR. CONCLUSION: Concomitant MAP was more effective against recurrent MR than was OPCAB alone, in patients with LVEF <=40%. We suggest that MAP should be considered in moderate ischemic MR with low LVEF. PMID- 22510798 TI - Spring mass characteristics of the fastest men on Earth. AB - The spring mass model has widely been used to characterize the whole body during running and sprinting. However the spring mass characteristics of the world's fastest men are still unknown. Thus the aim of this study was to model these characteristics for currently the 3 fastest men on earth (Usain Bolt, Tyson Gay and Asafa Powell). This was done by using data collected during the 2009 World championships in Berlin and the modelling method of Morin et al. 21. Even though Bolt achieved the greatest velocity (12.3 m.s - 1) over the 60-80 m split compared to his competitors, his estimated vertical stiffness (355.8 kN.m - 1) and leg stiffness (21.0 kN.m - 1) were significantly lower than his competitors. This reduction in stiffness is a consequence of Bolt's longer contact time (0.091 s) [corrected] and lower step frequency (4.49 Hz).Thus Bolt is able to run at a greater velocity but with lower stiffness compared to his competitors. PMID- 22510797 TI - COL11A1 gene is associated with limbus vertebra in gymnasts. AB - Several studies have shown higher frequencies of radiological abnormalities among gymnasts. Recently, the gene encoding the alpha1 chain of type XI collagen, (COL11A1) (rs 1676486), was associated with lumbar disc herniation in the Japanese population. We hypothesized that there was a significant relationship between abnormal magnetic resonance imaging (MRI) findings of the lumbar spine and the COL11A1 4603C/T gene polymorphism in collegiate gymnasts. Our study participants included 103 Japanese collegiate gymnasts (70 men and 33 women). Radiological abnormalities were evaluated using T1- and T2-weighted MRI. Genotyping for COL11A1 was performed for all the participants. By using logistic regression analysis, we observed significant associations between limbus vertebra and age (adjusted odds ratio=0.51, 95% confidence interval: 0.27-0.96), sporting experience (adjusted odds ratio=1.49, 95% confidence interval: 1.14-1.94), and a TT genotype (adjusted odds ratio=7.83, 95% confidence interval: 1.33-46.03). We conclude that a TT genotype of COL11A1 polymorphism may be a significant risk factor for limbus vertebra in Japanese collegiate gymnasts. PMID- 22510799 TI - Comparison of ground reaction forces and contact times between 2 lateral plyometric exercises in professional soccer players. AB - There are no studies which have examined the differences in kinetics between lateral plyometric exercises and the selection of these exercises is largely based on the experience and observation of coaches. This study aimed to compare ground reaction forces (GRF) and contact times (GCT) between 2 lateral plyometric exercises: lateral alternative leg hopping (HOP), and speed lateral footwork (SPEED). 16 professional male soccer players (age: 24.6+/-5.5 years; and BMI: 21.7+/-2.2 kg.m - 2) participated in this within-participant repeated measures study. 3-dimensional GRF data were measured by force platform. Our study revealed significant differences between the 2 lateral plyometric exercises in all kinetics parameters (F=573.7, P<0.01). HOP produced significantly longer GCT (0.45 s vs. 0.23 s, P<0.01, large effect), significantly higher values (P<0.05, large effect) in peak force (3.31 vs. 2.47 Body Weight [BW]), peak rate of force development (0.94 vs. 0.29 BW/s), and impulse (0.76 vs. 0.31 BW.s) except for peak force in the medial-lateral (P<0.05, medium effect) and impulse in the anterio-posterior direction (not significant, small effect). Therefore, SPEED is an exercise that aims to increase step frequency because of its short GCT (< 0.25 s) while HOP increases leg strength and power. PMID- 22510800 TI - Validation of a real-time video analysis system for soccer. AB - The aim of the current study was to determine the validity of an automated multiple-camera tracking system (VenatrackTM), for the measurement of speed during soccer. 18 recreationally active males (mean age 27+/-8.6 years) performed a series of runs (total 391), representative of the movements made by soccer players, at given speeds. The speeds recorded by the automatic tracking system were compared statistically with speed measurements made using timing gates. For all the runs combined the mean speed recorded by the automated system was 15.4+/ 5.5 km.h - 1 compared with the recorded mean speed of 15.2+/-5.4 km.h - 1 and the mean difference and 95% limits of agreement were - 0.25+/-0.64 km.h - 1. Pearson correlations (r) among timing gate speed and automated tracking speed were >= 0.99 (P<0.001), except the 20 m sprint, with 90 degrees turn (r > 0.7). For the zig-zag shuttle the mean speed recorded by the automated system was 21.2+/-3.5 km.h - 1 compared with the recorded mean speed of 20.8+/-3.4 km.h - 1. The results demonstrate good validity over a range of soccer specific movements and speeds, up to and including sprinting. The results of this study suggest that the automated system (VenatrackTM) is a valid real-time motion analysis system for tracking player movements during soccer. PMID- 22510801 TI - Effect of exercise-induced muscle damage on neuromuscular function of the quadriceps muscle. AB - Exercise-induced muscle injury is commonly accompanied by a reduction of muscular strength. It has been suggested that this reduction in voluntary force is attributable to "peripheral" and "central" mechanisms within the neuromuscular system. The quadriceps muscle of 15 subjects was damaged with four bouts of 25 maximal voluntary concentric-eccentric contractions at a speed of 60 degrees /s. In a time period of 7 days, we investigated the contribution of agonist muscle activation and contractile properties (CP) to changes in isometric maximum voluntary torque (iMVT). In order to provide a comprehensive assessment, the neural drive to muscles was estimated with the interpolated twitch technique and root mean square of the EMG signal. CP were evaluated by analysing the twitch torque signal induced by single and doublet stimulation. Furthermore, we measured changes in alpha motoneuron excitability of vastus medialis at the spinal level due to muscle soreness using the H reflex technique. The iMVT was impaired at post, 24 h and 48 h, while rate of torque development and voluntary activation (VA) were only decreased immediately after the intervention. CP were impaired immediately after exercise and at 24 h. Maximal H reflex (Hmax), maximal M wave (Mmax) and the Hmax/Mmax-ratio were not affected. Sensation of muscle soreness assessment revealed impairments at 24 h, 48 h and 72 h. Data suggest that reduced VA and altered CP contribute to the force loss immediately after concentric eccentric exercise. Thereafter, the impairment of CP seems to be mainly responsible for the reduced iMVT. In addition, there is no evidence for an association between muscle soreness and VA as well as between muscle soreness and spinal excitability. PMID- 22510802 TI - Moxibustion attenuates inflammatory response to chronic exhaustive exercise in rats. AB - Exercise is recognized as an activator to elicit an inflammatory response whilst moxibustion in traditional Chinese medicine has been previously found to modulate immune functioning. However, whether moxibustion can alleviate the inflammatory cytokines response to chronic exhaustive exercise remains unknown. In the present study, rats were randomly assigned to a sedentary control group (Sed), a sedentary moxibustion group (Sed + Moxa), and 2 trained groups- one submitted to a 3-week exhaustive swimming (Trained), and the other a trained moxibustion group (Trained + Moxa). We found that chronic exhaustive exercise significantly increased the serum levels of pro-inflammatory cytokines (IL-1beta, TNF-alpha, IFN-gamma) and the IFN-gamma/IL-4 ratio, and decreased the anti-inflammatory cytokines (IL-4, IL-10). Moxibustion treatment markedly reduced the serum levels of IL-1beta, IFN-gamma and the IFN-gamma/IL-4 ratio, while elevated the IL-4 and IL-10 productions in trained rats. However, TNF-alpha level was not significantly affected. Our results suggested that an excessive inflammatory response and a potential inflammatory damage may be involved during chronic exhaustive exercise. Moxibustion could attenuate the inflammatory impairment and have an anti inflammatory effect. The beneficial effects of moxibustion might be mediated by reducing the pro-inflammatory cytokines, increasing the anti-inflammatory cytokines, and modulating the balance between pro- and anti-inflammatory cytokines. PMID- 22510803 TI - Exercise inhibits allergic lung inflammation. AB - Aerobic conditioning (AC) performed either during or after sensitization reduces allergic inflammation in mice; however, the effects of AC performed before and during allergic sensitization on airway inflammation are unknown. Mice were divided into Control, AC, OVA, and AC + OVA groups. Mice were trained in a treadmill followed by either ovalbumin (OVA) sensitization or saline administration. Peribronchial inflammation, OVA-specific IgE and IgG1 titers, the expression of Th1 and Th2 cytokines, and airway remodeling were evaluated, as well as the expression of Eotaxin, RANTES, ICAM-1, VCAM-1, TGF-beta and VEGF. Aerobic conditioning performed before and during allergic sensitization displayed an inhibitory effect on the OVA-induced migration of eosinophils and lymphocytes to the airways, a reduction of IgE and IgG1 titers and an inhibition of the expression of Th2 cytokines. The AC + OVA group also demonstrated reduced expression of ICAM-1, VCAM-1, RANTES, TGF-beta and VEGF, as well as decreased airway remodeling (p<0.05). The effects of AC before and during the sensitization process inhibit allergic airway inflammation and reduce the production of Th2 cytokines and allergen-specific IgE and IgG1. PMID- 22510804 TI - Activity patterns, body composition and muscle function during Ramadan in a Middle-East Muslim country. AB - This study investigated the effects of Ramadan on activity patterns, body composition and muscle function. 11 moderately active Muslim males were screened 1 month and 1 week before, in the last week of, and 1 month after Ramadan. Activity patterns were assessed during 72 h using a tri-axial accelerometer, body composition was evaluated via bio-electrical impedance and muscle function during maximal isometric contractions with EMG recordings. Data showed a modification of the activity pattern during Ramadan with a higher level of activity from 02:00 to 05:00 h (29+/-26, 364+/-323 and 27+/-22 steps.h - 1 before, during and after Ramadan, respectively, P<0.05). However, total daily energy expenditure was similar during all testing periods (506+/-156, 542+/-219 and 545+/-207 Kcal.day - 1, respectively), partly explaining the lack of influence of Ramadan on body mass (70.9+/-11, 70.0+/-9 and 70.8+/-9 Kg, respectively) and composition (all P>0.05). Maximal force, associated electrical activity and neuromuscular efficiency (torque/EMG ratio) were maintained during Ramadan (torque: 254.6+/-30 N.m - 1, Neuromuscular efficiency: 1.0+/-0.4 a.u.) to levels observed before (244.3+/-26 N.m, 1.1+/-0.5 a.u.) and after the holy month (252.5+/-31 N.m, 1.1+/-0.5 a.u.). In summary, our data suggest that the influence of Ramadan should be considered as a modification in the distribution of activity times during the day. PMID- 22510805 TI - Walking program of low or vigorous intensity during pregnancy confers an aerobic benefit. AB - Walking is the most popular activity during pregnancy and may confer an aerobic benefit. However, the minimum intensity threshold of a maternal walking program for an aerobic conditioning response is unknown. The purpose was to examine the effect of a walking program of a low-intensity (LI, 30% heart rate reserve, HRR) or vigorous-intensity (VI, 70%HRR) on maternal cardiorespiratory responses to a standard submaximal treadmill test. Normal weight pregnant women were randomized at study entry (16-20 weeks of gestation) to the LI (n=23) or VI (n=21) walking program, with nutritional control. Participants performed a steady-state treadmill exercise test at their prescribed intensity pre- and post-intervention (34-36 weeks) to evaluate changes in cardiorespiratory responses. Increasing body mass due to pregnancy was similar between the groups throughout the study. From pre- to post-intervention, relative (mL kg - 1 min - 1) VO2 and VCO2 during steady-state submaximal treadmill exercise did not change in the LI group but decreased in the VI group (- 1.25+/-2.71, p=0.02 and - 1.50+/-2.64, p=0.005, respectively). Both groups presented increases in oxygen pulse (p<=0.002). Our results showed that the energy cost of walking was not affected by the increase in maternal body weight in the LI group and was decreased in the VI group, suggesting an aerobic conditioning response in both groups, although the VI group presented a greater response. All women presented similar body mass throughout the intervention and delivered healthy babies, indicating that a prenatal walking program of low or vigorous intensity, combined with healthy eating habits, is safe and beneficial to the mother and fetus. PMID- 22510806 TI - Apolipoprotein C-III and hepatic triglyceride-rich lipoprotein production. AB - PURPOSE OF REVIEW: A strong positive correlation between plasma apolipoprotein (apo) C-III and triglyceride concentrations has been invariably observed in human and animal studies. The hypertriglyceridemic effect of apo C-III has been conventionally explained by its extracellular roles in inhibiting lipolysis catalysed by lipoprotein lipase and attenuating triglyceride-rich lipoprotein clearance through receptor-dependent and/or independent mechanisms. However, recent experimental evidence suggests that apo C-III may also play an intracellular role in promoting hepatic triglyceride-rich lipoprotein production. RECENT FINDINGS: Kinetic studies with humans and genetically modified mice have shown that apo C-III is linked with increased production of triglyceride-rich lipoproteins, such as very-low-density lipoprotein 1 (VLDL1). Mutational studies on human apo C-III variants (originally identified in humans with hypotriglyceridemia or hyperalphalipoproteinemia) provide the structure-function analysis of human apo C-III, demonstrating that loss-of-function mutations within human apo C-III impair the assembly and secretion of triglyceride-rich VLDL1 under lipid-rich conditions. SUMMARY: The current review summarizes recent experimental evidence for an intrahepatic role of human apo C-III in promoting mobilization and utilization of triglyceride during VLDL1 assembly/secretion. Understanding mechanisms by which hepatic apo C-III expression is regulated under insulin resistance and diabetic conditions will lead to better and more rational strategies for the prevention and treatment of diabetic hypertriglyceridemia that is closely related to premature atherosclerosis. PMID- 22510807 TI - Plasma noncholesterol sterols: current uses, potential and need for standardization. AB - PURPOSE OF REVIEW: Noncholesterol sterols (NCSs) in plasma encompass endogenous cholesterol precursors and exogenous phytosterols and cholesterol metabolites, which are used as surrogate measures of cholesterol synthesis and cholesterol absorption, respectively. The ratios of cholesterol synthesis to cholesterol absorption surrogates are also utilized to assess the overall balance of cholesterol metabolism, with higher values representing more synthesis and lower values more absorption. The objective of this review is to focus on recent findings using plasma NCSs and their potential in customizing dietary and pharmacological hypolipidemic therapies. RECENT FINDINGS: NCSs are often used to assess the impact of pharmacological and dietary interventions on cholesterol metabolism. Various forms of dyslipidemia have been characterized using NCSs, and NCSs may be a valuable tool in selecting appropriate treatment therapies. NCSs levels are affected by genetic, dietary and physiological factors and have been related to cardiovascular disease risk. SUMMARY: The expanded use of plasma NCSs is currently limited by the lack of standardized methodology. However, noncholesterol sterols are still a valuable research tool for the overall assessment of cholesterol metabolism and may have clinical potential in the personalization of diet and medicine. PMID- 22510808 TI - Post-transcriptional regulation of lipoprotein receptors by the E3-ubiquitin ligase inducible degrader of the low-density lipoprotein receptor. AB - PURPOSE OF REVIEW: The hepatic low-density lipoprotein receptor (LDLR) pathway is essential for clearing circulating LDL and is an important therapeutic target for treating cardiovascular disease. Abundance of the LDLR is subject to both transcriptional and nontranscriptional control. Here, we highlight a new post transcriptional mechanism for controlling LDLR function via ubiquitination of the receptor by the E3-ubiquitin ligase inducible degrader of the LDLR (IDOL). RECENT FINDINGS: IDOL is a recently identified transcriptional target of the liver X receptors. Acting as an E3-ubiquitin ligase IDOL promotes ubiquitination of the LDLR, thereby marking it for lysosomal degradation. The determinants required for degradation of the LDLR by IDOL have been largely identified. IDOL also targets two related lipoprotein receptors, the very low-density lipoprotein receptor and apolipoprotein E receptor 2. Despite several similarities, the IDOL, and PCSK9 pathways for controlling LDLR abundance seem independent of each other. Genome wide association studies have recently identified IDOL as a locus influencing variability in circulating levels of LDL, thereby highlighting the possible role of IDOL in human lipoprotein metabolism. SUMMARY: Transcriptional induction of IDOL by liver X receptor defines a new post-transcriptional pathway for controlling LDLR abundance and LDL uptake independent of sterol regulatory element binding proteins. Targeting IDOL activity may offer a novel therapeutic approach complementary to statins for treating cardiovascular disease. PMID- 22510809 TI - Reverse cholesterol transport in familial hypercholesterolemia. AB - PURPOSE OF REVIEW: Familial hypercholesterolemia is characterized by a major elevation in circulating LDL-cholesterol levels, cholesterol deposition within the arterial wall and an increased risk of premature coronary artery disease. The reverse cholesterol transport (RCT) is now considered as a key process that protects against development of atherosclerosis. The major antiatherogenic action of HDL particles is intimately linked to their determinant role in RCT pathway. However, the steady-sate of HDL-cholesterol levels does not represent the optimal marker to evaluate the efficiency of the RCT in all circumstances. RECENT FINDINGS: By using ex-vivo systems for the evaluation of the efficacy of RCT a strong inverse relationship between HDL efflux capacity from macrophages and atherosclerosis progression has been demonstrated. Low HDL-C phenotype observed in familial hypercholesterolemia patients is associated with defective capacities of HDL particles to mediate major steps of the centripetal movement of cholesterol from peripheral cells to feces. However, current available treatment used to reduce LDL-C to therapeutic goals does not correct altered functions of HDL particles in humans. SUMMARY: In the context of familial hypercholesterolemia, a growing body of evidence suggests that impaired efficacy of the RCT pathway contributes significantly to the progression of atherosclerosis. PMID- 22510811 TI - Acoustic startle responses and prepulse inhibition of acoustic startle responses in Warsaw alcohol high-preferring (WHP) and Warsaw alcohol low-preferring (WLP) rats. AB - AIMS: An assessment of the acoustic startle response (ASR) and prepulse inhibition (PPI) of ASR in laboratory animals is used to model human anxiety and psychotic states, respectively. The aim of the study was to evaluate ASR and PPI in alcohol-naive male and female Warsaw alcohol high-preferring (WHP) and Warsaw alcohol low-preferring (WLP) rats. METHODS: ASR and PPI were assessed in two separate experiments by using the SR-LAB apparatus (San Diego Instruments, San Diego, CA, USA). In the ASR session, animals (n = 13-16 rats per group) were exposed to startling stimuli of different intensities (72, 84, 98, 112 and 124 dB) in a random order. In the PPI session, prepulse stimuli (78, 81, 84 and 90 dB) preceded a pulse startling stimulus (120 dB) in a random order. The background white noise was set at 70 dB. PPI was calculated according to the formula: [(startle amplitude in pulse alone trials-startle amplitude in prepulse and-pulse trials)/startle amplitude in pulse alone trials] 100%. RESULTS: The WHP males exhibited higher startle amplitudes in response to 112 dB stimuli when compared with their WLP counterparts. The WHP females showed higher startle reactivity to 112 and 124 dB stimuli when compared with the WLP females. There were no differences between the WHPs and WLPs in PPI of ASR. CONCLUSION: The results of the present study suggest that exaggerated startle responses can be a physiological/behavioral marker of a propensity to abuse alcohol. PMID- 22510812 TI - TH-1 and TH-2 cytokines in stable chronic alcoholics. AB - In alcoholics, the activation of Kupffer cells by gram negative bacteriae leads to an inflammatory response and cytokine secretion, which in turn activate T lymphocytes. Possibly, Th-1 lymphocytes are activated first, followed by a Th-2 response. Th-2 cytokines, especially interleukin (IL)-13 (scarcely studied in alcoholics), may be involved in the progression to chronic stages. AIMS: The aim of the study was to analyze the relationship of Th-1 and Th-2 cytokines with liver function, alcohol consumption, nutritional status and survival. METHODS: Serum Th-1 [interferon-gamma (IFN-gamma)] and Th-2 cytokines (IL-4, IL-13), IL 10, IL-6 and tumor necrosis factor (TNF-alpha), were determined for 18 controls and 47 stable alcoholics with variable liver function impairment, who were followed-up during a median time of 90 months, a period during which 14 patients died. RESULTS: IL-4 was lower among patients; no differences were observed regarding IL-6, but the remaining ILs were higher among alcoholics. IL-10 and IL 13 were even higher in cirrhotics (Z = 2.88, P = 0.004, and Z = 2.09, P = 0.037, respectively). A significant, direct, correlation was observed between IL-13 and IL-10 (rho = 0.49, P = 0.001), and non-significant, inverse ones were observed between IFN-gamma and IL-13 (rho = -0.23), IL-4 (rho = -0.14) and IL-10 (rho = 0.09). IL-13 and IL-10 were inversely related with liver function and, directly with immunoglobulin A levels, but not with survival. CONCLUSION: Serum IFN-gamma values were increased in alcoholics, who also showed raised IL-13 and IL-10, but lower IL-4 levels. Given the immunomodulatory roles of IL-10 and IL-13, this increase may be interpreted as a compensatory rise of anti-inflammatory cytokines. We failed to find any relation with mortality. PMID- 22510813 TI - The effectiveness of a cue-reminder intervention to reduce adolescents' alcohol use in social contexts. AB - AIMS: To examine the use of a cue-reminder to target alcohol use among youth in social contexts. METHODS: Two experiments were conducted. First, among 92 late adolescents, we tested if a cue-reminder could be effectively associated with information about empowerment, awareness and monitoring of one's own limits with regard to alcohol use. Second, among 107 young adults, the effect of the cue in a real-life drinking setting was examined. RESULTS: The first study showed that adolescents in the experimental condition recalled more empowerment information compared with adolescents in the control condition (mean 2.00 +/- 0.92 vs mean 1.52 +/- 0.96, P = 0.017), indicating the possibility of creating an association between a symbol (cue-reminder) and empowerment information with regard to alcohol use. In the second study, significant interaction effects between general drinking frequency and condition were found in relation to having an alcoholic consumption (beta = -0.24; P = 0.027) and to the amount of alcoholic consumptions (beta = -0.24; P = 0.035), suggesting that the presence of the cue-reminder in a drinking situation may have an inhibitory effect on alcohol consumption among frequent drinkers. CONCLUSION: The cue-reminder seems to have the potential to function as an intervention to reduce excessive alcohol use in social settings. PMID- 22510814 TI - Sunlight-driven synthesis of gamma-diketones via oxidative coupling of enamines with silyl enol ethers catalyzed by [Ru(bpy)3]2+. AB - A photosensitizer [Ru(bpy)(3)](2+) catalyzes oxidative coupling reaction of enamines with silyl enol ethers under visible light irradiation by a Xe lamp or sunlight to produce gamma-diketones. A 2e-oxidation process involved in this reaction is achieved by a combination of the photoexcited [Ru(bpy)(3)](2+) species and duroquinone, a 2e-acceptor. PMID- 22510815 TI - Re: genome-wide association study of classical hodgkin lymphoma and epstein-barr virus status-defined subgroups. PMID- 22510816 TI - TiO2 nanotube fabrication with highly exposed (001) facets for enhanced conversion efficiency of solar cells. AB - We demonstrate that the use of poly(vinyl pyrrolidone) (PVP) and acetic acid during the synthesis of TiO(2) nanotubes may result in the synthesis of single crystal-like anatase TiO(2) with a mainly exposed and chemically active (001) facet. An enhancement in the overall conversion efficiency of dye-sensitized solar cells was observed in a photoanode consisting of TiO(2) single-crystal-like anatase exposed (001) facets. PMID- 22510817 TI - A non-self-consistent range-separated time-dependent density functional approach for large-scale simulations. AB - We propose an efficient method for carrying out time-dependent density functional theory (TDDFT) calculations using range-separated hybrid exchange-correlation functionals. Based on a non-self-consistent range-separated Hamiltonian, the method affords large-scale simulations at a fraction of the computational time of conventional hybrid TDDFT approaches. For typical benchmark molecules including N(2), CO, C(6)H(6), H(2)CO and the C(2)H(4)-C(2)F(4) dimer, the method possesses the same level of accuracy as the conventional approaches for the valence, Rydberg, and charge-transfer excitation energies when compared to the experimental results. The method is used to determine pi -> pi* excitations in both disordered and crystalline poly(3-hexylthiophene) (P3HT) conjugated polymers with more than six hundred atoms and it yields excitation energies and charge densities that are in excellent agreement with experiments. The simulation of the crystalline P3HT reveals that the phase of the wavefunctions could have an important effect on the excitation energy; a hypothesis based on pi-pi stacking is proposed to explain this novel effect in conjugated polymers. PMID- 22510818 TI - Orientations of polyoxometalate anions on gold nanoparticles. AB - Cryogenic transmission electron microscopy of polyoxometalate-protected gold nanoparticles reveals that the Preyssler ion, [NaP(5)W(30)O(110)](14-), lies "face down" with its C(5) axis perpendicular to the gold surface, while the Finke Droege ion, [P(4)W(30)Zn(4)(H(2)O)(2)O(112)](16-), is "tilted", with its long axis close to 60 degrees from the normal to the surface. PMID- 22510819 TI - A histological and clinical comparison of new and conventional integrated backscatter intravascular ultrasound (IB-IVUS). AB - BACKGROUND: While the utilization of integrated backscatter intravascular ultrasound (IB-IVUS) for the quantitative in vivo assessment of coronary plaque continues to grow, the validity of IB-IVUS images obtained from newly developed and conventional systems remains uncertain. METHODS AND RESULTS: To assess the accuracy and reliability of a newly developed IB-IVUS system (VISIWAVE) as compared to the conventional system (Clearview), we compared quantitative IB-IVUS plaque characteristics in the 2 systems using 125 post-mortem specimens from 26 coronary arteries in 11 cadavers, as well as using 200 clinical plaques in 32 patients undergoing coronary intervention. The overall agreement between the histological and IB-IVUS diagnoses using VISIWAVE (Cohen's kappa=0.82, 95%CI: 0.73-0.90) was similar to that using Clearview (Cohen's kappa=0.80, 95%CI: 0.71 0.89). The 2 systems also demonstrated comparably high sensitivity and specificity. In the direct comparison, the overall agreement between IB-IVUS diagnoses using VISIWAVE and Clearview was also excellent (Cohen's kappa=0.87, 95%CI: 0.78-0.95). In the clinical comparison, measured plaque dimensions were similar (VISIWAVE: 8.27+/-3.46 mm(2) vs. Clearview; 8.31+/-3.46 mm(2), P=0.44) and there was strong concordance between both greyscale and IB-IVUS parameters. CONCLUSIONS: There was close agreement of analyzed results in both systems when compared with the gold standard of histology. Both systems are able to reliably and accurately characterize coronary plaque and thereby make a valuable contribution to our understanding of atherosclerosis. PMID- 22510820 TI - Lipoprotein(a) and homocysteine potentiate the risk of coronary artery disease in male subjects. AB - BACKGROUND: Lipoprotein (Lp(a)) and homocysteine (Hcy) are independent risk factors for coronary artery disease (CAD). Hcy promotes the release of free apo(a) from Lp(a). The high fibrin affinity of free apo(a) inhibits plasminogen binding and plasmin generation. Hyperhomocysteinemia can result from a less active variant of methylene tetrahydrofolate reductase (variant C677T). Because the C677T genotype is estimated to be present in 32.2% of the Mexican population, we took advantage of this prevalence to determine the possible potentiating effect between high plasma Lp(a) and Hcy for increasing the risk of CAD in male patients. METHODS AND RESULTS: First, 222 male patients admitted for coronary angiography were recruited and classified as CAD+ or CAD-. Anthropometric measurements, traditional risk factors, and plasma total Hcy (tHcy) and Lp(a) levels were recorded in both groups. We performed a conditional logistic regression model adjusted for conventional risk factors of CAD and it became clear that Lp(a) >=30mg/dl was a risk factor for CAD (odds ratio [OR] 5.06, 95% confidence interval [CI] 1.88-13.51, P=0.001), whereas Hcy was not related to CAD (OR 0.44, 95% CI 0.63-2.90, P=0.44). However, when both factors were considered together in an interaction model, high tHcy and high Lp(a) plasma concentrations showed a potentiated effect (OR 10.52, 95% CI 2.18-50.71, P=0.003). CONCLUSIONS: The combination of high Lp(a) and Hcy levels synergistically increases the likelihood of developing CAD in male patients. PMID- 22510821 TI - Significance of measuring plasma vascular endothelial growth factor in patients with acute myocardial infarction. PMID- 22510822 TI - Prokaryotic cells: structural organisation of the cytoskeleton and organelles. AB - For many years, prokaryotic cells were distinguished from eukaryotic cells based on the simplicity of their cytoplasm, in which the presence of organelles and cytoskeletal structures had not been discovered. Based on current knowledge, this review describes the complex components of the prokaryotic cell cytoskeleton, including (i) tubulin homologues composed of FtsZ, BtuA, BtuB and several associated proteins, which play a fundamental role in cell division, (ii) actin like homologues, such as MreB and Mb1, which are involved in controlling cell width and cell length, and (iii) intermediate filament homologues, including crescentin and CfpA, which localise on the concave side of a bacterium and along its inner curvature and associate with its membrane. Some prokaryotes exhibit specialised membrane-bound organelles in the cytoplasm, such as magnetosomes and acidocalcisomes, as well as protein complexes, such as carboxysomes. This review also examines recent data on the presence of nanotubes, which are structures that are well characterised in mammalian cells that allow direct contact and communication between cells. PMID- 22510823 TI - Field optimisation of MosquiTRAP sampling for monitoring Aedes aegypti Linnaeus (Diptera: Culicidae). AB - A sticky trap designed to capture gravid Aedes (Stegomyia) aegypti mosquitoes, MosquiTRAP, has been evaluated for monitoring this species in Brazil. However, the effects of trap densities on the capture rate of Ae. aegypti females and the sensitivity of vector detection are still unknown. After a preliminary study has identified areas of high and low female mosquito abundance, a set of experiments was conducted in four neighbourhoods of Belo Horizonte (state of Minas Gerais, Brazil) using densities of 1, 2, 4, 8, 16, 32 and 64 traps per block. Trap sensitivity (positive MosquiTRAP index) increased significantly when 1-8 MosquiTRAPs were installed per block in both high and low abundance areas. A strong fit was obtained for the total number of mosquitoes captured with increasing trap densities through a non-linear function (Box-Lucas) (r2 = 0,994), which likely exhibits saturation towards an equilibrium level. The capacity of the Mean Female Aedes Index to distinguish between areas of high and low Ae. aegypti abundance was also investigated; the achieved differentiation was shown to be dependent on the MosquiTRAP density. PMID- 22510824 TI - Production of TNF-alpha, nitric oxide and hydrogen peroxide by macrophages from mice with paracoccidioidomycosis that were fed a linseed oil-enriched diet. AB - Omega-3 polyunsaturated fatty acids (n-3 PUFA) can modulate the immune system and their primary effect is on macrophage function. Paracoccidioidomycosis (PCM) is an endemic systemic mycosis in Latin America that is caused by the dimorphic fungus Paracoccidioides brasiliensis (Pb). Macrophages are the main defence against this pathogen and have microbicidal activity that is dependent on interferon-Gamma and tumour necrosis factor (TNF)-alpha. These cytokines stimulate the synthesis of nitric oxide (NO) and hydrogen peroxide (H2O2), leading to the death of the fungus. To study the effect of n-3 PUFA on the host immune response during experimental PCM, macrophages that were obtained from animals infected with Pb18 and fed a diet enriched by linseed (LIN) oil were cultured and challenged with the fungus in vitro. The macrophage function was analysed based on the concentrations of TNF-alpha, NO and H2O2. LIN oil seems to influence the production of TNF-alpha during the development of disease. A diet enriched with LIN oil influences the microbicidal activity of the macrophages by inducing the production of cytokines and metabolites such as NO and H2O2, predominantly in the chronic phase of infection. PMID- 22510825 TI - Distinct chitinases are expressed during various growth phases of the human pathogen Paracoccidioides brasiliensis. AB - The aim of this work was the partial purification and subsequent evaluation of chitinase expression during the various growth phases of Paracoccidioides brasiliensis. Initially, PbCTS1r was expressed as a recombinant protein and displayed enzymatic activity against 4-MU-[N-acetylglucosamine (GlcNAc)]3 and 4 MU-(GlcNAc)2. Two proteins, 45 kDa and 39 kDa in size, were partially purified from P. brasiliensis yeast crude extract using cation-exchange chromatography coupled with HPLC and were characterised as PbCTS1 and PbCTS2, respectively. Anti PbCTS1r antibody recognised two proteins in the crude extracts of yeast and the transitional stage between mycelial and yeast phases. In crude extracts of mycelium, only the 45 kDa protein was detected. However, quantitative real-time polymerase chain reaction led to the detection of small quantities of Pbcts2 transcript in the mycelial phase. In the yeast cell wall extract, only the 39 kDa protein was detected. Moreover, both proteins were secreted by the yeast parasitic phase, suggesting that these proteins participate in the modulation of the fungal environment. Phylogenetic analysis of the predicted PbCTS1 and PbCTS2 proteins indicated that they code for distinct chitinases in P. brasiliensis. During evolution, P. brasiliensis could have acquired the paralogues Pbcts1 and Pbcts2 for growth and survival in diverse environments in both saprophytic and parasitic phases. PMID- 22510826 TI - Antiviral therapy against chronic hepatitis B in Brazil: high rates of lamivudine resistance mutations and correlation with HBV genotypes. AB - The effectiveness of antiviral treatments of chronic hepatitis B has been poorly studied in Brazil. Here, hepatitis B virus (HBV) DNA positivity, drug resistance mutations and their association with HBV genotypes were evaluated in chronically HBV-infected patients under different drug regimens in Brazil. The study involved 129 patients under interferon or nucleos(t)ide analogue therapy for a median treatment time of 12 months. One hundred and five (81%) of these patients were treated with lamivudine (LAM), either in monotherapy or in combination with newer drugs, such as entecavir (ETV) or tenofovir (TDF). High (37.5-100%) rates of HBV DNA positivity were observed with all but one drug regimen (LAM + ETV). However, patients that were treated with ETV alone, TDF alone or with LAM combination therapies had a mean viral load that was 3-4 log lower than patients treated with LAM monotherapy. Of the patients treated with LAM, 47% developed resistance mutations. HBV genotypes A (59.1%), D (30.3%) and F (9.1%) were found. There was no association between the presence of LAM resistance mutations and genotypes, HBeAg status or treatment duration. Nevertheless, the rtM204V mutation was observed more frequently (12/13, 92%) in genotype A than in the others (p = 0.023). Six out of nine isolates that contained the rtM204I mutation belonged to genotype D and half of them displayed a single mutation. Genotype D isolates with the rtM204V variant preferentially displayed a triple mutation, while genotype A preferentially displayed a double mutation (p = 0.04). PMID- 22510827 TI - The relationship between genetic variability and the susceptibility of Biomphalaria alexandrina snails to Schistosoma mansoni infection. AB - In the present study, Biomphalaria snails collected from five Egyptian governorates (Giza, Fayoum, Kafr El-Sheikh, Ismailia and Damietta), as well as reference control Biomphalaria alexandrina snails from the Schistosome Biological Supply Center (SBSC) (Theodor Bilharz Research Institute, Egypt), were subjected to species-specific polymerase chain reaction (PCR) assays to identify the collected species. All of the collected snails were found to be B. alexandrina and there was no evidence of the presence of Biomphalaria glabrata. Randomly amplified polymorphic DNA (RAPD)-PCR assays showed different fingerprints with varying numbers of bands for the first generation (F1) of B. alexandrina snail populations (SBSC, Giza, Fayoum, Kafr El-Sheikh, Ismailia and Damietta). The primer OPA-1 produced the highest level of polymorphism and amplified the greatest number of specific bands. The estimated similarity coefficients among the B. alexandrina populations based on the RAPD-PCR profiles ranged from 0.56 (between SBSC and Ismailia snails) to 0.72 (between Ismailia and Kafr El-Sheikh snails). Experimental infection of the F1 of progeny from the collected snails with Schistosoma mansoni (SBSC strain) showed variable susceptibility rates ranging from 15% in the Fayoum snail group to 50.3% in SBSC snails. A negative correlation was observed between the infection rates in the different snail groups and the distances separating their corresponding governorates from the parasite source. The infection rates of the snail groups and their similarity coefficients with SBSC B. alexandrina snails were positively correlated. The variations in the rates of infection of different B. alexandrina groups with S. mansoni, as well as the differences in the similarity coefficients among these snails, are dependent not only on the geographical distribution of the snails and the parasite, but also on the genetic variability of the snails. Introduction of this variability into endemic areas may reduce the ability of the parasite to infect local hosts and consequently reduce schistosomiasis epidemiology. PMID- 22510828 TI - Prevalence of hepatitis E virus antibodies in individuals exposed to swine in Mato Grosso, Brazil. AB - This study was conducted to estimate the prevalence of hepatitis E antibodies (anti-HEV) among individuals exposed to swine in the rural areas of the state of Mato Grosso (MT) in Brazil. The study included 310 participants who had an average age of 39 years. Fifty-one per cent of the participants were female and 26 (8.4%) were anti-HEV-positive. Concomitantly, we studied 101 blood donors from the urban area of the state capital who had never lived in a rural area or handled swine. Four per cent (4%) of these individuals were anti-HEV-positive (p = 0.206). When we compared the anti-HEV-positive participants who had been exposed to swine with the anti-HEV-negative participants, we noticed associations between the presence of anti-HEV and increased age, a history of blood transfusions and contact with other farm animals. However, after a multivariate analysis was performed, this association was not confirmed. Finally, the ratio of anti-HEV-positive individuals who had been exposed to swine in rural MT was similar to that found in previous studies in Brazil. This prevalence did not characterise this type of exposure as a risk factor for HEV infection in this region. PMID- 22510829 TI - Early diagnosis of congenital toxoplasmosis in newborn infants using IgG subclasses against two Toxoplasma gondii recombinant proteins. AB - The aim of this work was to evaluate the utility of ELISA-based testing of total IgG (IgGt) antibodies and its subclasses (IgG1, IgG2, IgG3 and IgG4) against soluble (STAg) and recombinant (rSAG1 and rMIC3) antigens of Toxoplasma gondii for diagnosing congenital toxoplasmosis. Sera from 217 newborns initially testing positive for specific IgM in filter paper dried blood spots were tested for specific IgM and IgG by ELFA-VIDAS. Congenital toxoplasmosis was confirmed in 175 and ruled out in 42 infants. The validity of the ELISA tests was determined using the persistence of IgG antibodies (ELFA-VIDAS kit) at the end of 12 months, which is considered the reference test for the diagnosis of congenital toxoplasmosis. The frequency of positivity with IgGt against STAg, rSAG1 and rMIC3 was found in 97.2%, 96.3% and 80.2%, respectively, of the newborns with confirmed congenital toxoplasmosis. IgG1 reacted with all three antigens, while IgG3 and IgG4 reacted preferentially with rMIC3. Higher mean values of reactivity (sample optical density/cut-off) were found for all subclasses when using rMIC3. All of the antigens showed high sensitivity and low specificity in detecting anti-T. gondii IgGt and IgG1 and low sensitivity and high specificity in detecting IgG3 and IgG4. In conclusion, the combined detection of IgG antibody subclasses against recombinant toxoplasmic antigens may be useful for the early diagnosis of congenital toxoplasmosis. PMID- 22510830 TI - Distinct cytokine profiles of circulating mononuclear cells stimulated with Staphylococcus aureus enterotoxin A in vitro during early and late episodes of chronic osteomyelitis. AB - We investigated the cytokine profile of peripheral mononuclear cells from chronic osteomyelitis (OST) patients following in vitro stimulation with staphylococcal enterotoxin A (SEA). We demonstrate that stimulation with SEA induced prominent lymphocyte proliferation and high levels of tumour necrosis factor (TNF)-alpha, interleukin (IL)-4 and IL-10 secretion in both OST and non-infected individuals (NI). Even though stimulation with SEA had no impact on IL-6 production in either patient group, the baseline level of IL-6 production by cells from OST patients was always significantly less than that produced by cells from NI. After classifying the osteomyelitic episodes based on the time after the last reactivation event as "early" (1-4 months) or "late" osteomyelitis (5-12 months), we found that increased levels of TNF-alpha and IL-4 in combination with decreased levels of IL-6 were observed in the early episodes. By contrast, increased levels of IL-10, IL-2 and IL-6 were hallmarks of late episodes. Our data demonstrate that early osteomyelitic episodes are accompanied by an increased frequency of "high producers" of TNF-alpha and IL-4, whereas late events are characterised by increased frequencies of "high producers" of IL-10, IL-6 and IL-2. These findings demonstrate the distinct cytokine profiles in chronic osteomyelitis, with a distinct regulation of IL-6 production during early and late episodes. PMID- 22510831 TI - Parvovirus B19 seroconversion in a cohort of human immunodeficiency virus infected patients. AB - Erythrovirus B19 (B19V) infection may cause red cell aplasia in patients infected with human immunodeficiency virus (HIV). The introduction of highly active antiretroviral therapy (HAART) has improved the immune function of these patients by modifying the course of B19V infection. The purpose of this study was to estimate the frequency of B19 seroconversion in a cohort of HIV-infected patients and evaluate the occurrence of B19V-related anaemia during the seroconversion period. Adult HIV-infected patients were studied at a public hospital in Niteroi, state of Rio de Janeiro, Brazil. IgG and IgM antibodies against B19V were detected by an enzyme-linked immunosorbent assay and B19 viraemia was assayed by polymerase chain reaction. Medical records were reviewed for any clinical evaluation of anaemia. Seroconversion was detected in 31.8% of the 88 individuals who began the study as anti-B19V IgG-negative. No clinical manifestations of B19V infection were detected during the period of seroconversion. Patients who seroconverted were 5.40 times more likely to have anaemia than those who did not [odds ratio 5.40 (95% confidence interval: 1.33-22.93)]. Anaemia was detected in eight patients. All patients recovered from anaemia by either beginning or continuing HAART, without requiring blood transfusions. In the HAART era, B19V infection may only be associated with a course of disease characterised by less severe chronic anaemia. This milder course of B19V-associated disease is likely due to the increased immune function of HAART-treated patients. PMID- 22510832 TI - Diversity and microdistribution of black fly (Diptera: Simuliidae) assemblages in the tropical savanna streams of the Brazilian cerrado. AB - We describe the abiotic factors affecting the distribution of black flies at a microhabitat scale, rather than at the regional scale usually present in the literature on the Neotropics. Black fly larvae were sampled from the Tocantins River and three tributaries, located in the Brazilian savanna (state of Tocantins, Brazil) during six bi-monthly sampling periods from October 2004 August 2005. At each sampling site, 15 random quadrats (30 x 30 cm) were sampled each period and for each quadrat were determined mean water velocity, predominant substrate type (rocks, riffle litter or riparian vegetation) and depth detrended correspondence analysis (DCA) was used to determine associations with current velocity, whereas correspondence analysis (CA) was used to estimate site specific current velocity associations. Canonical correspondence analysis (CCA) was used to identify general microhabitat associations. The CCA showed that most species had a trend towards riffle litter, except for Simulium nigrimanum associated with rocky substrate and Simulium cuasiexiguum associated with riparian vegetation. The DCA showed a well defined pattern of water velocity associations. The CA revealed that the species showed different speed associations from one site to another, suggesting different competitive pressures resulting in the occurrence of different realized niches. PMID- 22510833 TI - In vitro evaluation of new terpenoid derivatives against Leishmania infantum and Leishmania braziliensis. AB - The activity of five (1-5) abietane phenol derivatives against Leishmania infantum and Leishmania braziliensis was studied using promastigotes and axenic and intracellular amastigotes. Infectivity and cytotoxicity tests were performed with J774.2 macrophage cells using Glucantime as a reference drug. The mechanisms of action were analysed by performing metabolite excretion and transmission electron microscopy ultrastructural studies. Compounds 1-5 were more active and less toxic than Glucantime. The infection rates and mean number of parasites per cell observed in amastigote experiments showed that derivatives 2, 4 and 5 were the most effective against both L. infantum and L. braziliensis. The ultrastructural changes observed in the treated promastigote forms confirmed that the greatest cell damage was caused by the most active compound (4). Only compound 5 caused changes in the nature and amounts of catabolites excreted by the parasites, as measured by 1H nuclear magnetic resonance spectroscopy. All of the assayed compounds were active against the two Leishmania species in vitro and were less toxic in mammalian cells than the reference drug. PMID- 22510834 TI - Characterization of anti-silencing factor 1 in Leishmania major. AB - Anti-silencing factor 1 (ASF1) is a histone chaperone that contributes to the histone deposition during nucleosome assembly in newly replicated DNA. It is involved in chromatin disassembly, transcription activation and in the cellular response to DNA damage. In Leishmania major the ASF1 gene (LmASF1) is located in chromosome 20 and codes for a protein showing 67% of identity with the Trypanosoma brucei TbASF1a. Compared to orthologous proteins, LmASF1 conserves the main residues relevant for its various biological functions. To study ASF1 in Leishmania we generated a mutant overexpressing LmASF1 in L. major. We observed that the excess of LmASF1 impaired promastigotes growth rates and had no impact on cell cycle progress. Differently from yeast, ASF1 overproduction in Leishmania did not affect expression levels of genes located on telomeres, but led to an upregulation of proteins involved in chromatin remodelling and physiological stress, such as heat shock proteins, oxidoreductase activity and proteolysis. In addition, we observed that LmASF1 mutant is more susceptible to the DNA damaging agent, methyl methane sulphonate, than the control line. Therefore, our study suggests that ASF1 from Leishmania pertains to the chromatin remodelling machinery of the parasite and acts on its response to DNA damage. PMID- 22510835 TI - The efficacy of a chitin synthesis inhibitor against field populations of organophosphate-resistant Aedes aegypti in Brazil. AB - The mosquito Aedes aegypti is the main focus of dengue control campaigns. Because of widespread resistance against conventional chemical insecticides, chitin synthesis inhibitors (CSIs) are considered control alternatives. We evaluated the resistance status of four Brazilian Ae. aegypti populations to both the organophosphate temephos and the pyrethroid deltamethrin, which are used in Brazil to control larvae and adults, respectively. All vector populations exhibited high levels of temephos resistance and varying rates of alterations in their susceptibility to pyrethroids. The effect of the CSI novaluron on these populations was also investigated. Novaluron was effective against all populations under laboratory conditions. Field-simulated assays with partial water replacement were conducted to evaluate novaluron persistence. Bioassays were continued until an adult emergence inhibition of at least 70% was attained. We found a residual effect of eight weeks under indoor conditions and novaluron persisted for five-six weeks in assays conducted in an external area. Our data show that novaluron is effective against the Ae. aegypti populations tested, regardless of their resistance to conventional chemical insecticides. PMID- 22510836 TI - Biotic factors and occurrence of Lutzomyia longipalpis in endemic area of visceral leishmaniasis, Mato Grosso do Sul, Brazil. AB - The relationships between environmental exposure to risk agents and health conditions have been studied with the aid of remote sensing imagery, a tool particularly useful in the study of vegetation cover. This study aims to evaluate the influence of environmental variables on the spatial distribution of the abundance of Lutzomyia longipalpis and the reported canine and human visceral leishmaniasis (VL) cases at an urban area of Campo Grande, state of Mato Grosso do Sul. The sandfly captures were performed in 13 residences that were selected by raffle considering four residences or collection station for buffer. These buffers were generated from the central house with about 50, 100 and 200 m from it in an endemic area of VL. The abundance of sandflies and human and canine cases were georreferenced using the GIS software PCI Geomatica. The normalized difference vegetation index (NDVI) and percentage of land covered by vegetation were the environmental variables extracted from a remote sensing IKONOS-2 image. The average NDVI was considered as the complexity of habitat and the standard deviation as the heterogeneity of habitat. One thousand three hundred sixty-seven specimens were collected during the catch. We found a significant positive linear correlation between the abundance of sandflies and the percentage of vegetation cover and average NDVI. However, there was no significant association between habitat heterogeneity and the abundance of these flies. PMID- 22510837 TI - A morphologically distinct Phlebotomus argentipes population from active cutaneous leishmaniasis foci in central Sri Lanka. AB - Although the reported aetiological agent of cutaneous leishmaniasis (CL) in Sri Lanka is Leishmania donovani, the sandfly vector remains unknown. Ninety-five sandflies, 60 females and 35 males, collected in six localities in the district of Matale, central Sri Lanka, close to current active transmission foci of CL were examined for taxonomically relevant characteristics. Eleven diagnostic morphological characters for female sandflies were compared with measurements described for Indian and Sri Lankan sandflies, including the now recognised Phlebotomus argentipes sensu lato species complex. The mean morphometric measurements of collected female sandflies differed significantly from published values for P. argentipes morphospecies B, now re-identified as Phlebotomus annandalei from Delft Island and northern Sri Lanka, from recently re-identified P. argentipes s.s. sibling species and from Phlebotomus glaucus. Furthermore, analysis of underlying variation in the morphometric data through principal component analysis also illustrated differences between the population described herein and previously recognised members of the P. argentipes species complex. Collectively, these results suggest that a morphologically distinct population, perhaps most closely related to P. glaucus of the P. argentipess. I. species complex, exists in areas of active CL transmission. Thus, research is required to determine the ability of this population of flies to transmit cutaneous leishmaniasis. PMID- 22510838 TI - Expression of non-TLR pattern recognition receptors in the spleen of BALB/c mice infected with Plasmodium yoelii and Plasmodium chabaudi chabaudi AS. AB - The spleen plays a crucial role in the development of immunity to malaria, but the role of pattern recognition receptors (PRRs) in splenic effector cells during malaria infection is poorly understood. In the present study, we analysed the expression of selected PRRs in splenic effector cells from BALB/c mice infected with the lethal and non-lethal Plasmodium yoelii strains 17XL and 17X, respectively, and the non-lethal Plasmodium chabaudi chabaudi AS strain. The results of these experiments showed fewer significant changes in the expression of PRRs in AS-infected mice than in 17X and 17XL-infected mice. Mannose receptor C type 2 (MRC2) expression increased with parasitemia, whereas Toll-like receptors and sialoadhesin (Sn) decreased in mice infected with P. chabaudi AS. In contrast, MRC type 1 (MRC1), MRC2 and EGF-like module containing mucin-like hormone receptor-like sequence 1 (F4/80) expression decreased with parasitemia in mice infected with 17X, whereas MRC1 an MRC2 increased and F4/80 decreased in mice infected with 17XL. Furthermore, macrophage receptor with collagenous structure and CD68 declined rapidly after initial parasitemia. SIGNR1 and Sn expression demonstrated minor variations in the spleens of mice infected with either strain. Notably, macrophage scavenger receptor (Msr1) and dendritic cell associated C-type lectin 2 expression increased at both the transcript and protein levels in 17XL-infected mice with 50% parasitemia. Furthermore, the increased lethality of 17X infection in Msr1 -/- mice demonstrated a protective role for Msr1. Our results suggest a dual role for these receptors in parasite clearance and protection in 17X infection and lethality in 17XL infection. PMID- 22510839 TI - The stepwise selection for ketoconazole resistance induces upregulation of C14 demethylase (CYP51) in Leishmania amazonensis. AB - Ketoconazole is a clinically safe antifungal agent that also inhibits the growth of Leishmania spp. A study was undertaken to determine whether Leishmania parasites are prone to becoming resistant to ketoconazole by upregulating C14 demethylase after stepwise pharmacological pressure. Leishmania amazonensis promastigotes [inhibitory concentration (IC)50 = 2 uM] were subjected to stepwise selection with ketoconazole and two resistant lines were obtained, La8 (IC50 = 8 uM) and La10 (IC50 = 10 uM). As a result, we found that the resistance level was directly proportional to the C14-demethylase mRNA expression level; we also observed that expression levels were six and 12 times higher in La8 and La10, respectively. This is the first demonstration that L. amazonensis can up-regulate C14-demethylase in response to drug pressure and this report contributes to the understanding of the mechanisms of parasite resistance. PMID- 22510840 TI - Changing the epidemiology of carbapenem-resistant Pseudomonas aeruginosa in a Brazilian teaching hospital: the replacement of Sao Paulo metallo-beta-lactamase producing isolates. AB - In Brazil, carbapenem-resistant Pseudomonas aeruginosa isolates are closely related to the Sao Paulo metallo-beta-lactamase (SPM) Brazilian clone. In this study, imipenem-resistant isolates were divided in two sets, 2002/2003 and 2008/2009, analysed by pulsed field gel electrophoresis and tested for the Ambler class B metallo-beta-lactamase (MBL) genes blaSPM-1, blaIMP and blaVIM. The results show a prevalence of one clone related to the SPM Brazilian clone in 2002/2003. In 2008/2009, P. aeruginosa isolates were mostly MBL negative, genetically diverse and unrelated to those that had been detected earlier. These findings suggest that the resistance to carbapenems by these recent P. aeruginosa isolates was not due to the spread of MBL-positive SPM-related clones, as often observed in Brazilian hospitals. PMID- 22510841 TI - Detection of the first incidence of Akodon paranaensis naturally infected with the Jabora virus strain (Hantavirus) in Brazil. AB - We characterised hantaviruses circulating in different Akodon rodent species collected in midwestern Santa Catarina (SC), southern Brazil, where the Jabora hantavirus (JABV) strain was first identified in Akodon montensis. Genetic and phylogenetic analyses based on a partial S segment indicated that, in SC, Akodon paranaensis and A. montensis carried the same type of hantavirus. Additionally, we conducted the first genomic characterisation of the complete S segment from the Brazilian JABV strain. This is the first report of A. paranaensis infected with the JABV. PMID- 22510842 TI - Incrimination of Anopheles (Anopheles) intermedius Peryassu, An. (Nyssorhynchus) nuneztovari Gabaldon, An. (Nys.) oswaldoi Peryassu as natural vectors of Plasmodium falciparum in French Guiana. AB - Anopheles darlingi Root is the major vector of human malaria in the Neotropics and has been considered to be the sole malaria vector in French Guiana. The presence of other potential vectors suggests that malaria may be transmitted by other species under certain conditions. From 2006-2011, all anopheline specimens collected from 11 localities were assayed to determine if the Plasmodium circumsporozoite protein was present. In addition to An. darlingi, we found Anopheles oswaldoi, Anopheles intermedius and Anopheles nuneztovari specimens that were infected with Plasmodium sp. Further investigations on the behaviour and ecology of An. oswaldoi, An. intermedius and An. nuneztovari are necessary to determine their role in malaria transmission in French Guiana. PMID- 22510843 TI - The activity of echinocandins, amphotericin B and voriconazole against fluconazole-susceptible and fluconazole-resistant Brazilian Candida glabrata isolates. AB - The extensive use of azole antifungal agents has promoted the resistance of Candida spp to these drugs. Candida glabrata is a problematic yeast because it presents a high degree of primary or secondary resistance to fluconazole. In Brazil, C. glabrata has been less studied than other species. In this paper, we compared the activity of three major classes of antifungal agents (azoles, echinocandins and polyenes) against fluconazole-susceptible (FS) and fluconazole resistant (FR) C. glabrata strains. Cross-resistance between fluconazole and voriconazole was remarkable. Among the antifungal agents, the echinocandins were the most effective against FS and FR C. glabrata and micafungin showed the lowest minimal inhibitory concentrations. PMID- 22510844 TI - Involvement of epidermal growth factor receptor overexpression in the promotion of breast cancer brain metastasis. AB - BACKGROUND: Brain-metastatic breast cancer (BMBC) is increasing and poses a severe clinical problem because of the lack of effective treatments and because the underlying molecular mechanisms are largely unknown. Recent work has demonstrated that deregulation of epidermal growth factor receptor (EGFR) may correlate with BMBC progression. However, the exact contribution that EGFR makes to BMBC remains unclear. METHODS: The role of EGFR in BMBC was explored by serial analyses in a brain-trophic clone of human MDA-MB-231 breast carcinoma cells (231 BR cells). EGFR expression was inhibited by stable short-hairpin RNA transfection or by the kinase inhibitor erlotinib, and it was activated by heparin-binding epidermal growth factor-like growth factor (HB-EGF). Cell growth and invasion activities also were analyzed in vitro and in vivo. RESULTS: EGFR inhibition or activation strongly affected 231-BR cell migration/invasion activities as assessed by an adhesion assay, a wound-healing assay, a Boyden chamber invasion assay, and cytoskeleton staining. Also, EGFR inhibition significantly decreased brain metastases of 231-BR cells in vivo. Surprisingly, changes to EGFR expression affected cell proliferation activities less significantly as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, an anchorage-independent growth assay, and cell cycle analysis. Immunoblot analysis suggested that EGFR drives cells' invasiveness capability mainly through phosphoinositide 3-kinase/protein kinase B and phospholipase C gamma downstream pathways. In addition, EGFR was involved less in proliferation because of the insensitivity of the downstream mitogen-activated protein kinase pathway. CONCLUSIONS: The current results indicated that EGFR plays more important roles in cell migration and invasion to the brain than in cell proliferation progression on 231-BR cells, providing new evidence of the potential value of EGFR inhibition in treating BMBC. PMID- 22510845 TI - Pathway-based genome-wide association analysis of coronary heart disease identifies biologically important gene sets. AB - Genome-wide association (GWA) studies of complex diseases including coronary heart disease (CHD) challenge investigators attempting to identify relevant genetic variants among hundreds of thousands of markers being tested. A selection strategy based purely on statistical significance will result in many false negative findings after adjustment for multiple testing. Thus, an integrated analysis using information from the learned genetic pathways, molecular functions, and biological processes is desirable. In this study, we applied a customized method, variable set enrichment analysis (VSEA), to the Framingham Heart Study data (404,467 variants, n=6421) to evaluate enrichment of genetic association in 1395 gene sets for their contribution to CHD. We identified 25 gene sets with nominal P<0.01; at least four sets are previously known for their roles in CHD: vascular genesis (GO:0001570), fatty-acid biosynthetic process (GO:0006633), fatty-acid metabolic process (GO:0006631), and glycerolipid metabolic process (GO:0046486). Although the four gene sets include 170 genes, only three of the genes contain a variant ranked among the top 100 in single variant association tests of the 404,467 variants tested. Significant enrichment for novel gene sets less known for their importance to CHD were also identified: Rac 1 cell-motility signaling pathway (h_rac1 Pathway, P<0.001) and sulfur amino acid metabolic process (GO:0000096, P<0.001). In summary, we showed that the pathway-based VSEA can help prioritize association signals in GWA studies by identifying biologically plausible targets for downstream searches of genetic variants associated with CHD. PMID- 22510846 TI - Comprehensive oligonucleotide array-comparative genomic hybridization analysis: new insights into the molecular pathology of the DMD gene. AB - We report on the effectiveness of a custom-designed oligonucleotide-based comparative genomic hybridization microarray (array-CGH) to interrogate copy number across the entire 2.2-Mb genomic region of the DMD gene and its applicability in diagnosis. The high-resolution array-CGH, we developed, successfully detected a series of 42 previously characterized large rearrangements of various size, localization and type (simple or complex deletions, duplications, triplications) and known intronic CNVs/Indels. Moreover, the technique succeeded in identifying a small duplication of only 191 bp in one patient previously negative for DMD mutation. Accurate intronic breakpoints localization by the technique enabled subsequent junction fragments identification by sequencing in 86% of cases (all deletion cases and 62.5% of duplication cases). Sequence examination of the junctions supports a role of microhomology-mediated processes in the occurrence of DMD large rearrangements. In addition, the precise knowledge of the sequence context at the breakpoints and analysis of the resulting consequences on maturation of pre-mRNA contribute to elucidating the cause of discrepancies in phenotype/genotype correlations in some patients. Thereby, the array-CGH proved to be a highly efficient and reliable diagnostic tool, and the new data it provides will have many potential implications in both, clinics and research. PMID- 22510847 TI - Afghanistan from a Y-chromosome perspective. AB - Central Asia has served as a corridor for human migrations providing trading routes since ancient times. It has functioned as a conduit connecting Europe and the Middle East with South Asia and far Eastern civilizations. Therefore, the study of populations in this region is essential for a comprehensive understanding of early human dispersal on the Eurasian continent. Although Y- chromosome distributions in Central Asia have been widely surveyed, present-day Afghanistan remains poorly characterized genetically. The present study addresses this lacuna by analyzing 190 Pathan males from Afghanistan using high-resolution Y-chromosome binary markers. In addition, haplotype diversity for its most common lineages (haplogroups R1a1a*-M198 and L3-M357) was estimated using a set of 15 Y specific STR loci. The observed haplogroup distribution suggests some degree of genetic isolation of the northern population, likely due to the Hindu Kush mountain range separating it from the southern Afghans who have had greater contact with neighboring Pathans from Pakistan and migrations from the Indian subcontinent. Our study demonstrates genetic similarities between Pathans from Afghanistan and Pakistan, both of which are characterized by the predominance of haplogroup R1a1a*-M198 (>50%) and the sharing of the same modal haplotype. Furthermore, the high frequencies of R1a1a-M198 and the presence of G2c-M377 chromosomes in Pathans might represent phylogenetic signals from Khazars, a common link between Pathans and Ashkenazi groups, whereas the absence of E1b1b1a2 V13 lineage does not support their professed Greek ancestry. PMID- 22510848 TI - Clinical utility gene card for: nemaline myopathy. PMID- 22510849 TI - Clinical utility gene card for: proximal spinal muscular atrophy. PMID- 22510850 TI - Clinical utility gene card for: Leri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD). PMID- 22510851 TI - Sampling strategies for rare variant tests in case-control studies. AB - Advances in sequencing technology allow assessing the impact of rare variation on common disorders. For this purpose, methods combine rare variants across a gene and compare an aggregate statistic between cases and controls. However, sequencing many individuals is costly. Hence, it is necessary to identify case samples that are most likely to result in powerful tests under realistic model assumptions. Power can be increased by selecting cases that are highly likely to carry risk variants. As rare variants that contribute to the heritability of a disease co-segregate among affected family members, selecting cases that have affected family members may increase the power of rare variant tests considerably. Here I compare sequencing random cases to cases ascertained to have affected family members. I quantify the power of the different approaches and provide criteria for sample selection under different models of inheritance. Under a model of multiplicative gene-gene interaction, a sample of random cases has to be 2-16-fold larger to achieve the same power as a sample of cases ascertained to have affected family members. However, in traits with high heritability this power gain can be reduced or even reversed under models of additive gene-gene interaction. Hence study designs should depend on the studied disease's heritability and on the available sample size. I also show that selecting cases that share both chromosomes identical by descent with an affected sibling at candidate regions can result in a further power gain. PMID- 22510852 TI - Quantifying harmful mutations in human populations. AB - A number of previous studies suggested the presence of deleterious amino acid altering nonsynonymous single-nucleotide polymorphisms (nSNPs) in human populations. However, the proportions of deleterious nSNPs among rare and common variants are not known. To estimate these, >77,000 SNPs from human protein-coding genes were analyzed. Based on two independent methods, this study reveals that up to 53% of rare nSNPs (minor allele frequency (MAF)<0.002) could be deleterious in nature. The fraction of deleterious nSNPs declines with the increase in their allele frequencies and only 12% of the common nSNPs (MAF>0.4) were found to be harmful. This shows that even at high frequencies significant fractions of deleterious polymorphisms are present in human populations. These results could be useful for genome-wide association studies in understanding the relative contributions of rare and common variants in causing human genetic diseases. PMID- 22510853 TI - How does bone marrow transplantation affect ovarian function and fertility? AB - PURPOSE OF REVIEW: This article sets out to review the literature on gonadal toxicity of bone marrow transplantation (BMT) in women, and preventive and curative actions available for girls and women facing BMT and infertility. FINDINGS: The real incidence of ovarian damage after BMT is difficult to assess. Series reporting ovarian function and pregnancies after BMT vary greatly in terms of endpoints, number of patients included, age at and indications for BMT, conditioning regimens and duration of follow-up. The risk of premature ovarian failure (POF) is very high, however, and increases with age and in case of BMT conditioning treatment with total body irradiation. Embryo, oocyte and ovarian cortex cryopreservation are effective fertility preservation methods that should be discussed with all girls and young women requiring BMT. SUMMARY: Despite a lack of literature on long-term follow-up of fertility after BMT in large populations, it is clear that the risk of ovarian damage and POF is very high. Fertility preservation options should therefore be discussed with all patients having to undergo BMT. PMID- 22510854 TI - Apicoaortic conduits: indications, complications, and imaging techniques. AB - Left ventricular apex to descending aorta conduits may be used as a last resort treatment of severe left ventricular outflow tract obstruction in cases in which alternative therapies are contraindicated. Although this technique is rarely used in current practice for congenital cases, its use in the elderly population is increasing, largely due to the expansion of this patient cohort and associated comorbidities precluding aortic valve replacement, the most common of which are a severely calcified "porcelain" aorta and/or previous coronary artery bypass grafts preventing aortic root manipulation. Diagnostic imaging is essential in the presurgical workup and subsequent follow-up of these patients, as complications of the procedure are potentially life threatening and are not rare. Several imaging modalities may be used, each with advantages and disadvantages. Both anatomic and functional assessments play a role in the comprehensive evaluation of both presurgical and postsurgical patients. PMID- 22510855 TI - Synthesis of Fe3O4@SnO2 core-shell nanorod film and its application as a thin film supercapacitor electrode. AB - Considerable areal capacitance (mF cm(-2) level) and long cycling stability (2000 cycles, the best ever for Fe(3)O(4)-based electrodes) are demonstrated for the first time for Fe(3)O(4)@SnO(2) core-shell nanorod film, which is grown directly on a current collector substrate. PMID- 22510856 TI - Prohemostatic Interventions: what's New? Preface. PMID- 22510857 TI - Prohemostatic treatment in cardiac surgery. AB - Cardiac surgical patients represent a unique group of patients where coagulopathy occurs due to multiple causes besides simple hemorrhagic blood loss. Hemodilution, inflammation, and hemostatic activation while on cardiopulmonary bypass all contribute to this problem and provide targets for therapeutic intervention. Current pharmacological strategies to reduce the need for allogeneic transfusions include both preemptive agents to decrease the potential for bleeding as well as prohemostatic agents to promote the coagulation process. This article will discuss pharmacological agents including antifibrinolytics, protamine, desmopressin, fibrinogen, purified protein concentrates, recombinant factor VIIa, factor XIII, and topical agents used in cardiac surgery. PMID- 22510858 TI - Prohemostatic interventions in liver surgery. AB - Surgical procedures of the liver, such as partial liver resections and liver transplantation, are major types of abdominal surgery. Liver surgery can be associated with excessive intraoperative blood loss, not only because the liver is a highly vascularized organ, but also because it plays a central role in the hemostatic system. Intraoperative blood loss and transfusion of blood products have been shown to be negatively associated with postoperative outcome after liver surgery. Dysfunction of the liver is frequently accompanied with a dysfunctional hemostatic system. However, in general, there is a poor correlation between preoperative coagulation tests and the intraoperative bleeding risk in patients undergoing liver surgery. Strategies to avoid excessive blood loss in liver surgery have been an active field of research and include three different areas: surgical methods, anesthesiological methods, and pharmacological agents.Surgeons can minimize blood loss by clamping the hepatic vasculature, by using specific dissection devices, and by using topical hemostatic agents. Anesthesiologists play an important role in minimizing blood loss by avoiding intravascular fluid overload. Maintaining a low central venous pressure has shown to be very effective in reducing blood loss during partial liver resections. Prophylactic transfusion of blood products such as fresh frozen plasma (FFP) has not been shown to reduce intraoperative bleeding and even seems counterproductive as it results in an increase of the intravascular filling status, which may enhance the bleeding risk. In patients with liver cirrhosis, there is increasing evidence that factors such as portal hypertension and the hyperdynamic circulation play a more important role in the bleeding tendency than changes in the coagulation system. Therefore, intravenous fluid restriction rather than prophylactic administration of large volumes of blood products (i.e., FFP) is recommended in patients undergoing major liver surgery. Pharmacological agents such as antifibrinolytic drugs or recombinant factor VIIa may be indicated in selected individual patients, but these agents do not have a routine role in the management of patients undergoing liver surgery. PMID- 22510859 TI - Prohemostatic interventions in obstetric hemorrhage. AB - Obstetric hemorrhage is a major cause of maternal morbidity and mortality. Pregnancy is associated with substantial hemostatic changes, resulting in a relatively hypercoagulable state. Acquired coagulopathy can, however, develop rapidly in severe obstetric hemorrhage. Therefore, prohemostatic treatments based on high fresh frozen plasma and red blood cell (FFP:RBC) ratio transfusion and procoagulant agents (fibrinogen concentrates, recombinant activated factor VII, and tranexamic acid) are crucial aspects of management. Often, evidence from trauma patients is applied to obstetric hemorrhage management, although distinct differences exist between the two situations. Therefore, until efficacy and safety are demonstrated in obstetric hemorrhage, clinicians should be cautious about wholesale adoption of high FFP:RBC ratio products. Applications of transfusion protocols, dedicated to massive obstetric hemorrhage and multidisciplinarily developed, currently remain the best available option. Similarly, while procoagulant agents appear promising in treatment of obstetric hemorrhage, caution is nonetheless warranted as long as clear evidence in the context of obstetric hemorrhage is lacking. PMID- 22510860 TI - Vatreptacog alfa from conception to clinical proof of concept. AB - Vatreptacog alfa is a genetically engineered variant of recombinant factor VIIa (rFVIIa) containing three amino acid changes. Aspartic acid, valine, and glutamine residues replace valine, glutamic acid, and methionine at positions 158, 296, and 298, respectively. These substitutions result in considerable enhancement of the intrinsic (tissue factor-independent) capability to activate factor X and the downstream hemostatic events are consequently augmented. The beneficial effects of vatreptacog alfa have been demonstrated in numerous in vitro systems attempting to mimic hemophilia and corroborated in in vivo models. Vatreptacog alfa has successfully passed through phase 1 and 2 clinical trials and the molecule is currently being explored in phase 3 clinical trial for the treatment of bleedings in hemophilia patients with inhibitors. This article describes the proposed mechanism behind the increased activity and action of vatreptacog alfa and reviews available data, which suggest that vatreptacog alfa could be a valuable addition to the existing portfolio of treatment options for hemophilia patients with inhibitors. PMID- 22510861 TI - Monitoring prohemostatic treatment in bleeding patients. AB - Acutely bleeding patients are commonly found in the trauma and major surgery scenarios. They require prompt and effective treatment to restore an adequate hemostatic pattern, to avoid serious and sometimes life-threatening complications.Different prohemostatic treatments are available, including allogeneic blood derivatives (fresh frozen plasma, platelet concentrates, and cryoprecipitates), prothrombin complex concentrates, specific coagulation factors (fibrinogen, recombinant factor XIII, recombinant activated factor VII), and drugs (protamine for patients under heparin treatment, desmopressin, antifibrinolytics).For decades, prohemostatic treatment of the acutely bleeding patient was based on empirical strategies and clinical judgment, both in terms of a correct diagnosis of the mechanism(s) leading to bleeding, and of an assessment of the effects of the treatment. This empirical strategy may lead to excessive or unnecessary use of allogeneic blood products, as well as to an incorrect, inefficacious, or even dangerous treatment. Different monitoring devices are nowadays available for guiding the diagnostic and therapeutic decision-making process in an acutely bleeding patient. This review addresses the available tools for monitoring prohemostatic treatment of the bleeding patient, with a specific respect for point-of-care tests (thromboelastography, thromboelastometry, platelet function tests, and heparin monitoring systems) at the light of the existing evidence. PMID- 22510862 TI - Safety of prohemostatic interventions. AB - Pharmacological prohemostatic agents may be useful adjunctive treatment options in patients with severe blood loss. The efficacy of these interventions has been established in a variety of clinical situations. However, the procoagulant effect of these interventions may tip the balance toward a higher risk of thrombotic complications. Several studies have shown that some prohemostatic interventions may indeed increase the risk of arterial and venous thromboembolism, although these complications are relatively rare. When considering the use of adjunctive prohemostatic agents to prevent or treat excessive blood loss, the risk of thrombotic complications should be taken into account. PMID- 22510864 TI - Predictors and clinical outcomes from failed Laryngeal Mask Airway UniqueTM: a study of 15,795 patients. AB - BACKGROUND: Although the estimated risk of life-threatening adverse respiratory events during supraglottic airway device use is rare, the reported rate of events leading to failure of the airway device is 0.2-8%. Little is known about the risk adjusted prediction of Laryngeal Mask Airway failure requiring rescue tracheal intubation and its impact on patient outcomes. METHODS: All adult patients in whom a laryngeal mask airway (LMA UniqueTM, uLMATM; LMA North America, Inc., San Diego, CA) was used in ambulatory and nonambulatory anesthesia settings were included. The primary outcome was uLMATM failure, defined as an airway event requiring uLMATM removal and tracheal intubation. The secondary outcomes were the incidence of difficult mask ventilation and unplanned hospital admissions. RESULTS: Of the 15,795 cases included in our study, 170 (1.1%) experienced the primary outcome of uLMATM failure. More than 60% of patients with uLMATM failure experienced significant hypoxia, hypercapnia, or airway obstruction, whereas 42% presented with inadequate ventilation related to leak. Four independent risk factors for failed uLMATM were identified: surgical table rotation, male sex, poor dentition, and increased body mass index. A 3-fold increased incidence of difficult mask ventilation was observed in patients with uLMATM failure. Among outpatients with uLMATM failure, 13.7% had unplanned hospital admission, 5.6% of whom needed intensive care for persistent hypoxemia. CONCLUSIONS: The study supports the use of the uLMATM as an effective supraglottic airway device with a relatively low failure rate. However, there are clinically relevant consequences of uLMATM failure, as evidenced by the high rate of acute respiratory events and need for unplanned hospital admissions. PMID- 22510863 TI - Solubility of haloether anesthetics in human and animal blood. AB - BACKGROUND: Anesthetic blood solubility predicts pharmacokinetics for inhaled agents and is essential for determination of blood anesthetic concentrations from end-tidal gas concentrations using Henry's Law. Though used to model anesthetic effects in humans, there are limited interspecies solubility comparisons that include modern haloethers. This study aimed to measure hematocrit-adjusted blood:gas anesthetic partition coefficients (lambda B:G) for desflurane, sevoflurane, isoflurane, and methoxyflurane in humans and animals. METHODS: Whole blood was collected from 20 rats, 8 horses, and 4 each of cats, cattle, humans, dogs, goats, pigs, rabbits, and sheep. Plasma or cell volume was removed to adjust all samples to a packed cell volume of 40%. A single-agent calibration gas headspace was added to blood in a glass syringe and was mixed and equilibrated at 37 degrees C for 2 h. Agent concentrations in the calibration gas and syringe headspace were measured using gas chromatography. Anesthetic solubility in saline, citrate-phosphate-dextrose-adenine, and olive oil were similarly measured. RESULTS: Except for goats, all animal species had at least one lambda B:G measurement that differed significantly from humans. For each agent, lambda B:G positively correlated with serum triglyceride concentrations, but this only explained 25% of interspecies variability. Desflurane was significantly less soluble in blood than sevoflurane in some species (e.g., humans) but not in others (e.g., rabbits). CONCLUSIONS: Anesthetic partition coefficients differ significantly between humans and most animals for haloether anesthetics. Because of their similar lambda B:G values, goats may be a better animal model for inhaled anesthetic pharmacokinetics in people. PMID- 22510865 TI - A novel environmental chamber for neuronal network multisite recordings. AB - Environmental stability is a critical issue for neuronal networks in vitro. Hence, the ability to control the physical and chemical environment of cell cultures during electrophysiological measurements is an important requirement in the experimental design. In this work, we describe the development and the experimental verification of a closed chamber for multisite electrophysiology and optical monitoring. The chamber provides stable temperature, pH and humidity and guarantees cell viability comparable to standard incubators. Besides, it integrates the electronics for long-term neuronal activity recording. The system is portable and adaptable for multiple network housings, which allows performing parallel experiments in the same environment. Our results show that this device can be a solution for long-term electrophysiology, for dual network experiments and for coupled optical and electrical measurements. PMID- 22510866 TI - Modest increase in risk of specific types of cancer types in type 2 diabetes mellitus patients. AB - Most studies associated diabetes mellitus (DM) with risk of cancer have focused on the Caucasian population and only a few types of cancer. Therefore, a large and comprehensive nationwide retrospective cohort study involving an Asian population was conducted to evaluate the risk of several major types of cancer among Type 2 DM patients. The study analyzed the nationwide population-based database from 1996 to 2009 released by the National Health Research Institute in Taiwan. Incidence and hazard ratios (HRs) were calculated for specific types of cancer. The overall risk of cancers was significantly greater in the DM cohort [N = 895,434; HR = 1.19, 95% confidence interval (CI) = 1.17-1.20], compared with non-DM controls (N = 895,434). Several organs in the digestive and urogenital systems showed increased risk of cancer. The three highest HRs were obtained from cancers of the liver (HR = 1.78, 95% CI = 1.73-1.84), pancreatic (HR = 1.52, 95% CI = 1.40-1.65), and uterus and corpus (HR = 1.38, 95% CI = 1.22-1.55). The risk increased with age, and men with DM aged >= 75 years exhibited the highest risk (HR = 7.76, 95% CI = 7.39-8.15). Subjects with DM in this population have a modest increased risk of cancer, similar to the Caucasian population for several specific types of cancer. Old men with DM have the highest risk of cancer. Careful screening for cancer in DM patients is important for early diagnosis and effective treatment. PMID- 22510868 TI - Renal tubular secretion of varenicline by multidrug and toxin extrusion (MATE) transporters. AB - Multidrug and toxin extrusion (MATE) 1 and MATE2-K, H(+)/organic cation antiporters, are located at the brush-border membrane of renal proximal tubules. The present study aimed to clarify the role of MATE transporters in tubular secretion of varenicline. Varenicline at a dose of 5 mg/kg was administered to wild-type and Mate1-knockout mice via the jugular vein, and its uptake was measured by high-performance liquid chromatography. The renal secretory clearance of and systemic exposure to varenicline were significantly decreased (54.6%, p < 0.05) and increased (116%, p < 0.05) respectively, by the genetic disruption of Mate1 in mice. Uptake of varenicline and [(14)C]tetraethylammonium (TEA) was examined in HEK293 cells transiently expressing the human (h) MATE1, hMATE2-K, mouse (m) MATE1, and hOCT2 basolateral organic cation transporter. [(14)C]TEA uptake in HEK293 cells expressing MATE transporters and hOCT2 was decreased in the presence of varenicline. The calculated IC(50) values for hMATE1, hMATE2-K, mMATE1, and hOCT2 were 62.2 +/- 6.5, 122.3 +/- 67.6, 255.0 +/- 37.9, and 1,003.9 +/- 135.8 (uM; mean +/- S.E. for three separate experiments), respectively. Varenicline uptake was significantly increased in HEK293 cells expressing mMATE1, hMATE1, or hMATE2-K cDNA as well as hOCT2 compared to empty vector-transfected cells. In conclusion, renal MATE transporters were found to be responsible for renal tubular secretion of varenicline. PMID- 22510869 TI - Enhancement effect of poly(amino acid)s on insulin uptake in alveolar epithelial cells. AB - In this study, we elucidated the effect of poly(amino acid)s such as poly-L ornithine (PLO) on FITC-insulin uptake in cultured alveolar type II epithelial cells, RLE-6TN. FITC-insulin uptake by RLE-6TN cells as well as its cell surface binding was markedly increased by PLO without cytotoxicity. The uptake of FITC insulin in the presence of PLO was shown to be mediated by endocytosis, but in contrast to the uptake in the absence of PLO, the contribution of macropinocytosis emerged. Colocalization of FITC-insulin and LysoTracker Red was observed by confocal laser scanning microscopy both in the absence and presence of PLO, indicating that FITC-insulin was partly targeted to lysosomes in the cells and degraded. The half-life of the intracellular degradation of FITC insulin was, however, prolonged by the presence of PLO. PLO also stimulated the uptake of other FITC-labeled compounds. Among them, the enhancement effects of PLO on FITC-albumin and FITC-insulin uptake were prominent. The effect of PLO on insulin absorption was also examined in in-vivo pulmonary administration in rats, and co-administration of PLO enhanced the hypoglycemic action of insulin. These findings suggest that co-administration of poly(amino acid)s such as PLO is a useful strategy for enhancing insulin uptake by alveolar epithelial cells and subsequent absorption from the lung. PMID- 22510870 TI - Nano-biphasic ionic liquid systems composed of hydrophobic phosphonium salts and a hydrophilic ammonium salt. AB - A combination of a phosphonium-type-zwitterions-lithium bis(trifluoromethanesulfonyl)imide complex and a hydrophilic ammonium salt provides a nanosegregated liquid-crystalline matrix consisting of hydrophilic ionic liquid (IL) domains and hydrophobic IL domains. PMID- 22510871 TI - Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. AB - Hodgkin lymphoma (HL) relapsing after allogeneic stem cell transplantation (alloSCT) presents a major clinical challenge. In the present investigation, we evaluated brentuximab vedotin, a CD30-directed Ab-drug conjugate, in 25 HL patients (median age, 32 years; range, 20-56) with recurrent disease after alloSCT (11 unrelated donors). Patients were > 100 days after alloSCT, had no active GVHD, and received a median of 9 (range, 5-19) prior regimens. Nineteen (76%) had refractory disease immediately before enrollment. Patients received 1.2 or 1.8 mg/kg of brentuximab vedotin IV every 3 weeks (median, 8 cycles; range, 1 16). Overall and complete response rates were 50% and 38%, respectively, among 24 evaluable patients. Median time to response was 8.1 weeks, median progression free survival was 7.8 months, and the median overall survival was not reached. Cough, fatigue, and pyrexia (52% each), nausea and peripheral sensory neuropathy (48% each), and dyspnea (40%) were the most frequent adverse events. The most common adverse events >= grade 3 were neutropenia (24%), anemia (20%), thrombocytopenia (16%), and hyperglycemia (12%). Cytomegalovirus was detected in 5 patients (potentially clinically significant in 1). These results support the potential utility of brentuximab vedotin for selected patients with HL relapsing after alloSCT. PMID- 22510872 TI - Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets. AB - The pathogenesis of hepatosplenic T-cell lymphoma (HSTL), a rare entity mostly derived from gammadelta T cells and usually with a fatal outcome, remains largely unknown. In this study, HSTL samples (7gammadelta and 2alphabeta) and the DERL2 HSTL cell line were subjected to combined gene-expression profiling and array based comparative genomic hybridization. Compared with other T-cell lymphomas, HSTL had a distinct molecular signature irrespective of TCR cell lineage. Compared with peripheral T-cell lymphoma, not otherwise specified and normal gammadelta T cells, HSTL overexpressed genes encoding NK-cell-associated molecules, oncogenes (FOS and VAV3), the sphingosine-1-phosphatase receptor 5 involved in cell trafficking, and the tyrosine kinase SYK, whereas the tumor suppressor gene AIM1 (absent in melanoma 1) was among the most down-expressed. We found highly methylated CpG islands of AIM1 in DERL2 cells, and decitabine treatment induced a significant increase in AIM1 transcripts. Syk was present in HSTL cells and DERL2 cells contained phosphorylated Syk and were sensitive to a Syk inhibitor in vitro. Genomic profiles confirmed recurrent isochromosome 7q (n = 6/9) without alterations at the SYK and AIM1 loci. Our results identify a distinct molecular signature for HSTL and highlight oncogenic pathways that offer rationale for exploring new therapeutic options such as Syk inhibitors and demethylating agents. PMID- 22510873 TI - An activating intragenic deletion in NOTCH1 in human T-ALL. AB - Oncogenic activating mutations in NOTCH1 occur in more than 50% of T-cell acute lymphoblastic leukemias (T-ALLs). In the present study, we describe a novel mechanism of NOTCH1 activation in T-ALL in which a deletion removing the 5' portion of NOTCH1 abolishes the negative regulatory control of the extracellular domain and leads to constitutively active NOTCH1 signaling. Polypeptides translated from truncated transcripts encoded by the NOTCH1 deletion allele retain the transmembrane domain of the receptor and are constitutively cleaved by the gamma-secretase complex, resulting in high levels of NOTCH1 signaling that can be effectively blocked by gamma-secretase inhibitors. Our results expand the spectrum of oncogenic lesions activating NOTCH1 signaling in human T-ALL. PMID- 22510874 TI - Osteopontin is a prognostic factor for survival of acute myeloid leukemia patients. AB - Osteopontin (OPN) is a glycoprotein that is secreted by osteoblasts and hematopoietic cells. OPN suppresses the proliferation of hematopoietic stem cells in vitro and may regulate the hematopoietic stem cell pool. Increased serum OPN concentrations occur in chronic myeloid leukemia, multiple myeloma, and acute myeloid leukemia (AML). In the present study, we analyzed the prognostic impact of OPN in AML by investigating the expression and relevance of OPN in newly diagnosed AML patients from 2 large study groups (the German AML Cooperative Group and the Dutch-Belgian Hematology Oncology Cooperative group). IHC (n = 84), ELISAs of blood/BM sera (n = 41), and microarray data for mRNA levels (n = 261) were performed. Expression of OPN protein was increased in AML patients both in BM blasts (IHC) and in BM serum (ELISA) compared with healthy controls. Patients expressing high levels of OPN within the BM (IHC) experienced shortened overall survival (OS; P = .025). Multivariate analysis identified karyotype, blast clearance (day 16), and the level of OPN expression as independent prognostic factors for OS. This prompted us to analyze microarray data from 261 patients from a third cohort. The analysis confirmed OPN as a prognostic marker. In summary, high OPN mRNA expression indicated decreased event-free survival (P = .0002) and OS (P = .001). The prognostic role of OPN was most prominent in intermediate-risk AML. These data provide evidence that OPN expression is an independent prognostic factor in AML. PMID- 22510875 TI - Unraveling the influence of endothelial cell density on VEGF-A signaling. AB - Vascular endothelial growth factor-A (VEGF) is the master determinant for the activation of the angiogenic program leading to the formation of new blood vessels to sustain solid tumor growth and metastasis. VEGF specific binding to VEGF receptor-2 (VEGFR-2) triggers different signaling pathways, including phospholipase C-gamma (PLC-gamma) and Akt cascades, crucial for endothelial proliferation, permeability, and survival. By combining biologic experiments, theoretical insights, and mathematical modeling, we found that: (1) cell density influences VEGFR-2 protein level, as receptor number is 2-fold higher in long confluent than in sparse cells; (2) cell density affects VEGFR-2 activation by reducing its affinity for VEGF in long-confluent cells; (3) despite reduced ligand-receptor affinity, high VEGF concentrations provide long-confluent cells with a larger amount of active receptors; (4) PLC-gamma and Akt are not directly sensitive to cell density but simply transduce downstream the upstream difference in VEGFR-2 protein level and activation; and (5) the mathematical model correctly predicts the existence of at least one protein tyrosine phosphatase directly targeting PLC-gamma and counteracting the receptor-mediated signal. Our data based mathematical model quantitatively describes VEGF signaling in quiescent and angiogenic endothelium and is suitable to identify new molecular determinants and therapeutic targets. PMID- 22510876 TI - Quantitative assessment of sensing and sequestration of spherocytic erythrocytes by the human spleen. AB - Splenic sequestration of RBCs with reduced surface area and cellular deformability has long been recognized as contributing to pathogenesis of several RBC disorders, including hereditary spherocytosis. However, the quantitative relationship between the extent of surface area loss and splenic entrapment remains to be defined. To address this issue, in the present study, we perfused ex vivo normal human spleens with RBCs displaying various degrees of surface area loss and monitored the kinetics of their splenic retention. Treatment with increasing concentrations of lysophosphatidylcholine resulted in a dose-dependent reduction of RBC surface area at constant volume, increased osmotic fragility, and decreased deformability. The degree of splenic retention of treated RBCs increased with increasing surface area loss. RBCs with a > 18% average surface area loss (> 27% reduced surface area-to-volume ratio) were rapidly and completely entrapped in the spleen. Surface-deficient RBCs appeared to undergo volume loss after repeated passages through the spleen and escape from splenic retention. The results of the present study for the first time define the critical extent of surface area loss leading to splenic entrapment and identify an adaptive volume regulation mechanism that allows spherocytic RBCs to prolong their life span in circulation. These results have significant implications for understanding the clinical heterogeneity of RBC membrane disorders. PMID- 22510878 TI - The transcription factor Spi-B regulates human plasmacytoid dendritic cell survival through direct induction of the antiapoptotic gene BCL2-A1. AB - Plasmacytoid dendritic cells (pDCs) selectively express Toll-like receptor (TLR) 7 and TLR-9, which allow them to rapidly secrete massive amounts of type I interferons after sensing nucleic acids derived from viruses or bacteria. It is not completely understood how development and function of pDCs are controlled at the transcriptional level. One of the main factors driving pDC development is the ETS factor Spi-B, but little is known about its target genes. Here we demonstrate that Spi-B is crucial for the differentiation of hematopoietic progenitor cells into pDCs by controlling survival of pDCs and its progenitors. In search for Spi B target genes, we identified the antiapoptotic gene Bcl2-A1 as a specific and direct target gene, thereby consolidating the critical role of Spi-B in cell survival. PMID- 22510877 TI - Human Langerhans cells use an IL-15R-alpha/IL-15/pSTAT5-dependent mechanism to break T-cell tolerance against the self-differentiation tumor antigen WT1. AB - Human CD34(+) progenitor-derived Langerhans-type dendritic cells (LCs) are more potent stimulators of T-cell immunity against tumor and viral antigens in vitro than are monocyte-derived DCs (moDCs). The exact mechanisms have remained elusive until now, however. LCs synthesize the highest amounts of IL-15R-alpha mRNA and protein, which binds IL-15 for presentation to responder lymphocytes, thereby signaling the phosphorylation of signal transducer and activator of transcription 5 (pSTAT5). LCs electroporated with Wilms tumor 1 (WT1) mRNA achieve sufficiently sustained presentation of antigenic peptides, which together with IL-15R-alpha/IL 15, break tolerance against WT1 by stimulating robust autologous, WT1-specific cytolytic T-lymphocytes (CTLs). These CTLs develop from healthy persons after only 7 days' stimulation without exogenous cytokines and lyse MHC-restricted tumor targets, which include primary WT1(+) leukemic blasts. In contrast, moDCs require exogenous rhuIL-15 to phosphorylate STAT5 and attain stimulatory capacity comparable to LCs. LCs therefore provide a more potent costimulatory cytokine milieu for T-cell activation than do moDCs, thus accounting for their superior stimulation of MHC-restricted Ag-specific CTLs without need for exogenous cytokines. These data support the use of mRNA-electroporated LCs, or moDCs supplemented with exogenous rhuIL-15, as vaccines for cancer immunotherapy to break tolerance against self-differentiation antigens shared by tumors. PMID- 22510879 TI - Long-term fate of polycyclic aromatic hydrocarbons (PAH) in sediments from Loch Leven after closure of an aluminium smelter. AB - An aluminium smelter discharged polycyclic aromatic hydrocarbons (PAHs) into Loch Leven on the west of Scotland from 1907 until it closed in 2000, resulting in elevated PAH concentrations in the sediment. A temporal monitoring programme to investigate any recovery in sediment concentrations began in 2004, with sampling each year until 2008 and again in 2010. Cores were also collected to investigate temporal trends over a longer time scale and to estimate the sedimentation rate in the loch. The loch is divided into two basins, and PAH concentrations were significantly higher in the upper basin, closer to the smelter, than in the lower basin. The PAH distribution and concentration ratios were consistent with a pyrolytic source of PAHs, with a high proportion of heavier parent PAHs. There was no evidence of any recovery in PAH concentrations, perhaps due to the mixing and disturbances of the sediment, and the persistence of PAHs. Concentrations of all PAHs were above the Background Assessment Concentrations (BACs) in both basins. In the lower basin only the 5- and 6-ring PAHs were above the Effects Range Low (ERL) values, but in the upper basin all but naphthalene were above the ERLs. There is therefore still an unacceptable risk of chronic effects in marine species. Concentrations decreased down the cores, falling below BACs in the deepest sections. However, ERLs were exceeded as far down the core as 30 cm for some PAHs. PMID- 22510881 TI - A new tumour suppressor enters the network of intestinal progenitor cell homeostasis. AB - In this issue of The EMBO Journal, Wilson et al (2012) elegantly discovered an important new axis for intestinal homeostasis and cancer, using an RNAi screen to enhance the RAS-induced multivulva (MUV) phenotype in Caenorhabditis elegans. PMID- 22510880 TI - Nuclear receptor binding protein 1 regulates intestinal progenitor cell homeostasis and tumour formation. AB - Genetic screens in simple model organisms have identified many of the key components of the conserved signal transduction pathways that are oncogenic when misregulated. Here, we identify H37N21.1 as a gene that regulates vulval induction in let-60(n1046gf), a strain with a gain-of-function mutation in the Caenorhabditis elegans Ras orthologue, and show that somatic deletion of Nrbp1, the mouse orthologue of this gene, results in an intestinal progenitor cell phenotype that leads to profound changes in the proliferation and differentiation of all intestinal cell lineages. We show that Nrbp1 interacts with key components of the ubiquitination machinery and that loss of Nrbp1 in the intestine results in the accumulation of Sall4, a key mediator of stem cell fate, and of Tsc22d2. We also reveal that somatic loss of Nrbp1 results in tumourigenesis, with haematological and intestinal tumours predominating, and that nuclear receptor binding protein 1 (NRBP1) is downregulated in a range of human tumours, where low expression correlates with a poor prognosis. Thus NRBP1 is a conserved regulator of cell fate, that plays an important role in tumour suppression. PMID- 22510883 TI - A bacterial actin unites to divide bacterial cells. PMID- 22510882 TI - Novel repressor regulates insulin sensitivity through interaction with Foxo1. AB - Forkhead box-containing protein o (Foxo) 1 is a key transcription factor in insulin and glucose metabolism. We identified a Foxo1-CoRepressor (FCoR) protein in mouse adipose tissue that inhibits Foxo1's activity by enhancing acetylation via impairment of the interaction between Foxo1 and the deacetylase Sirt1 and via direct acetylation. FCoR is phosphorylated at Threonine 93 by catalytic subunit of protein kinase A and is translocated into nucleus, making it possible to bind to Foxo1 in both cytosol and nucleus. Knockdown of FCoR in 3T3-F442A cells enhanced expression of Foxo target and inhibited adipocyte differentiation. Overexpression of FCoR in white adipose tissue decreased expression of Foxo target genes and adipocyte size and increased insulin sensitivity in Lepr(db/db) mice and in mice fed a high-fat diet. In contrast, Fcor knockout mice were lean, glucose intolerant, and had decreased insulin sensitivity that was accompanied by increased expression levels of Foxo-target genes and enlarged adipocytes. Taken together, these data suggest that FCoR is a novel repressor that regulates insulin sensitivity and energy metabolism in adipose tissue by acting to fine tune Foxo1 activity. PMID- 22510885 TI - Putting the brakes on FOXO1 in fat. PMID- 22510884 TI - Distinct requirement for an intact dimer interface in wild-type, V600E and kinase dead B-Raf signalling. AB - The dimerisation of Raf kinases involves a central cluster within the kinase domain, the dimer interface (DIF). Yet, the importance of the DIF for the signalling potential of wild-type B-Raf (B-Raf(wt)) and its oncogenic counterparts remains unknown. Here, we show that the DIF plays a pivotal role for the activity of B-Raf(wt) and several of its gain-of-function (g-o-f) mutants. In contrast, the B-Raf(V600E), B-Raf(insT) and B-Raf(G469A) oncoproteins are remarkably resistant to mutations in the DIF. However, compared with B-Raf(wt), B Raf(V600E) displays extended protomer contacts, increased homodimerisation and incorporation into larger protein complexes. In contrast, B-Raf(wt) and Raf-1(wt) mediated signalling triggered by oncogenic Ras as well as the paradoxical activation of Raf-1 by kinase-inactivated B-Raf require an intact DIF. Surprisingly, the B-Raf DIF is not required for dimerisation between Raf-1 and B Raf, which was inactivated by the D594A mutation, sorafenib or PLX4720. This suggests that paradoxical MEK/ERK activation represents a two-step mechanism consisting of dimerisation and DIF-dependent transactivation. Our data further implicate the Raf DIF as a potential target against Ras-driven Raf-mediated (paradoxical) ERK activation. PMID- 22510887 TI - Impaired mitochondrial function in psychiatric disorders. AB - Major psychiatric illnesses such as mood disorders and schizophrenia are chronic, recurrent mental illnesses that affect the lives of millions of individuals. Although these disorders have traditionally been viewed as 'neurochemical diseases', it is now clear that they are associated with impairments of synaptic plasticity and cellular resilience. Although most patients with these disorders do not have classic mitochondrial disorders, there is a growing body of evidence to suggest that impaired mitochondrial function may affect key cellular processes, thereby altering synaptic functioning and contributing to the atrophic changes that underlie the deteriorating long-term course of these illnesses. Enhancing mitochondrial function could represent an important avenue for the development of novel therapeutics and also presents an opportunity for a potentially more efficient drug-development process. PMID- 22510888 TI - Neurodegenerative networking. PMID- 22510886 TI - BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1alpha. AB - Adaptation to endoplasmic reticulum (ER) stress depends on the activation of the unfolded protein response (UPR) stress sensor inositol-requiring enzyme 1alpha (IRE1alpha), which functions as an endoribonuclease that splices the mRNA of the transcription factor XBP-1 (X-box-binding protein-1). Through a global proteomic approach we identified the BCL-2 family member PUMA as a novel IRE1alpha interactor. Immun oprecipitation experiments confirmed this interaction and further detected the association of IRE1alpha with BIM, another BH3-only protein. BIM and PUMA double-knockout cells failed to maintain sustained XBP-1 mRNA splicing after prolonged ER stress, resulting in early inactivation. Mutation in the BH3 domain of BIM abrogated the physical interaction with IRE1alpha, inhibiting its effects on XBP-1 mRNA splicing. Unexpectedly, this regulation required BCL-2 and was antagonized by BAD or the BH3 domain mimetic ABT-737. The modulation of IRE1alpha RNAse activity by BH3-only proteins was recapitulated in a cell-free system suggesting a direct regulation. Moreover, BH3-only proteins controlled XBP-1 mRNA splicing in vivo and affected the ER stress-regulated secretion of antibodies by primary B cells. We conclude that a subset of BCL-2 family members participates in a new UPR-regulatory network, thus assuming apoptosis-unrelated functions. PMID- 22510892 TI - Sourcing local produce. PMID- 22510894 TI - Immediate breast reconstruction in the previously augmented patient. AB - BACKGROUND: Women who had undergone previous breast augmentation represent a unique subset of patients presenting for breast reconstruction. Much of the literature on breast augmentation and breast cancer has focused on cancer detection, prognosis, and recurrence. There is a paucity of data describing this patient population from a breast reconstruction standpoint. METHODS: A review of a prospective institutional database of all patients who had previous breast augmentation undergoing immediate breast reconstruction (IBR) from 1996 to 2010 was performed. Patient demographics, operative techniques, reconstructive methods, and breast cancer data were collected. Data were compared with a control group of 591 patients without previous augmentation undergoing IBR from 2005 to 2009. RESULTS: Thirty-five patients treated by total mastectomy and IBR who had previous breast augmentation were identified. The median patient age was 51 (range, 32-80) years in the augmented group versus 50.1 (range, 24-84) years in the control group. The mean body mass indices of the augmented and the control groups were 24.1 and 27.5, respectively (P < 0.05). Implant-based reconstruction was performed in 94.3% the augmented group versus 62.4% in the control group (P < 0.01). Stage 0 and I breast cancer occurred in 57.6% of patients in the augmented group and 46.6% of patients in control group (P < 0.05). CONCLUSIONS: Patients with previous augmentation mammoplasty are more likely to undergo implant-based reconstruction compared with nonaugmented women. The presence of implants does not delay the detection of breast cancer when compared with a control group of patients who do not have breast implants. PMID- 22510895 TI - Changes in dermal histomorphology following surgical weight loss versus diet induced weight loss in the morbidly obese patient. AB - INTRODUCTION: Patients with postgastric bypass and diet-induced weight loss present to the plastic surgeon for various body contouring procedures. Gross differences in skin dermal elasticity may exist between these populations; however, studies evaluating histologic differences are lacking. This prospective study aims to evaluate histomorphologic differences in morbidly obese patients following surgical versus diet-induced (nonsurgical) weight loss. Further, we aim to elicit if postoperative complications are correlated with the mechanism of weight loss and potential histomorphologic differences. METHODS: Defined infraumbilical skin specimens were collected during abdominal contouring procedures following weight loss achieved through surgical or nonsurgical means. Specimens were stained for elastic fiber content and morphology, collagen deposition, and inflammation. All sections underwent evaluation for quality and quantity of elastic fibers, collagen architecture, and presence of inflammation in the context of age-matched controls. Histomorphological results were compared between the 2 groups and subanalyzed according to clinical variables and postbody contouring wound complications. RESULTS: Between July 2008 and December 2010, 30 consecutive patients with significant weight loss (17 surgical, 13 nonsurgical) underwent a panniculectomy (n = 15), abdominoplasty (n = 13), and lower body lift (n = 2), with an average age of 48.3 +/- 11.10 years and a body mass index of 39.23 +/- 13.65 kg/m. Demographic and clinical variables were not statistically significant between the 2 groups. Blinded histologic evaluation revealed a trend toward normal elastic fiber appearance (P = 0.255), increased wound complications (P = 0.546), and mild inflammation (P = 0.462) in the surgical group. Analysis of dermal histomorphology correlating with wound complications was not statistically significant at follow-up (4.76 +/- 5.55 months). Interestingly, there was a persistent inflammatory component in both groups when compared with age-matched controls. CONCLUSIONS: Although the differences in histomorphology between the surgical and nonsurgical weight loss groups did not reach statistical significance, the results demonstrated an existence of weight loss-induced histomorphological skin changes that may impact future studies. The study did not demonstrate a relationship between dermal histomorphology and postoperative wound complications, suggesting that aberrant healing in body contouring procedures involves a multifactorial process. PMID- 22510896 TI - Adipose-derived stromal cells accelerate wound healing in an organotypic raft culture model. AB - Adipose tissue is a known reservoir of multipotent mesenchymal stem cells, which can be manipulated in culture to produce cells with different phenotypes. The goal of this study was to determine whether the addition of these multipotential cells to organotypic, human skin equivalent cultures would accelerate wound healing after laser injury. For our initial studies, we were able to obtain 3 dimensional raft cultures from adult skin explanted directly onto the dermal equivalent containing human fibroblasts with or without adipose-derived stromal cells (ADSCs). Two days after laser injury, the raft cultures of skin explants that contained ADSCs had a completely healed multilayered epidermis, whereas the control raft culture without the adipose-derived cells still had areas of injury. With this encouraging outcome, these experiments were then repeated in a raft culture system initiated from dissociated primary adult human keratinocytes on the humanized dermal equivalent. Again, the cultures containing ADSCs healed faster than the control cultures. In conclusion, these data provide support to our hypothesis that ADSCs are an excellent and readily available source of factors necessary for accelerated wound healing and tissue regeneration. PMID- 22510898 TI - The use of autologous platelet-leukocyte-enriched plasma to minimize drain burden and prevent seroma formation in latissimus dorsi breast reconstruction. AB - INTRODUCTION: Seromas and drains are major sources of morbidity associated with latissimus dorsi breast reconstruction. Our goal was to look at an autologous platelet-leukocyte-enriched plasma spray and to assess its efficacy in reducing drain burden and seroma formation. METHODS: We performed a single surgeon, patient-controlled, blinded study on bilateral latissimus dorsi breast reconstruction patients in which we applied autologous platelet-leukocyte enriched plasma to one side and measured drain amounts, time to drain removal, and seroma rate. RESULTS: Twelve patients were included in this study. The average age was 41.1 years, and the average body mass index was 21.6 kg/m. Average volume of drain output showed neither difference (789 mL spray side vs. 790 mL control side) nor average time to drain removal (11.83 days spray side vs. 11.5 days control side). There were 2 complications reported: 1 hematoma (8.33%) and 1 seroma (8.33%) that required aspiration in a postoperative visit. CONCLUSIONS: It appears after 12 patients that there is no demonstrable difference regarding drain output, time to drain removal, or seroma incidence between the study and the control group. We feel a larger study population would add power and confirm these findings. PMID- 22510897 TI - Lack of emergency hand surgery: discrepancy between elective and emergency hand care. AB - Wrist, hand, and finger trauma are the most common injuries presenting to emergency departments. Shortage of emergency hand care is an emerging problem, as on-call hand coverage declines. This study evaluates the availability of elective and emergency hand surgery services in Tennessee, with the use of telephone surveys administered to emergency department and operating facility management. One hundred eleven Tennessee hospitals completed the surveys (93% response rate). In all, 77% of hospitals offer elective hand surgery, 58% offer basic emergency hand services, 18% offer occasional hand specialist call coverage and only 7% of hospitals have 24/7 hand specialist call coverage. Hospitals with hand specialists have significantly more payer charges from commercial insurance than hospitals without hand specialists (26.1% vs. 16.1%, P < 0.001). Our results strongly support the need for increased emergency hand coverage. Solutions include creating multihospital coordinated call schedules, increasing incentives for call coverage, and training more hand specialists. PMID- 22510899 TI - Cornu cutaneum in a patient of African descent: implications and management of an uncommon lesion. AB - Cornu cutaneum, or giant cutaneous horn (GCH), is an uncommon but disfiguring lesion that may cause the patient considerable distress. The aesthetic implications of such lesions are obvious. The etiology and treatment of GCH are more obscure, both to patients and physicians alike. We present a female patient of African descent with a GCH of the scalp, which represents the first such case to our knowledge outside Africa. The etiology and management of GCH in all races are reviewed. PMID- 22510900 TI - [Revista Peruana de Medicina Experimental y Salud Publica: 70 years of meeting its goals and aiming for the future]. PMID- 22510901 TI - [Violence and addiction problems in the Peruvian context]. PMID- 22510902 TI - [Efficacy of the therapeutic community model in the treatment of drug use-related problems: a systematic review]. AB - OBJECTIVE: To summarize the scientific evidence about the efficacy of therapeutic communities (TC) to reduce substance use and related problems among people with substance use disorders. METHODS: This systematic review builds from the work performed by Smith et al. (2006). We searched MEDLINE, EMBASE, Web of Science, Scielo, and LILACS for randomized trials that compare a TC with no treatment, a different type of treatment or another type of TC published from March 2004 to May 2011. RESULTS: 5 publications from 4 randomized trials were identified. All the studies had serious methodological limitations according to the CONSORT. The heterogeneity among studies did not allow for metaanalytic analysis to calculate pooled estimates. The primary analysis showed that, in prison, certain models of TC might be marginally superior to other types of treatments regarding levels of alcohol use, days in prison and re-incarceration rates. Also, evidence from a community setting (i.e., not in-prison) suggests that a community-based TC is not superior to an outpatient treatment model regarding levels of substance use, crime and unemployment at the 12-month follow-up. CONCLUSIONS: In general, there is no evidence to support superiority of TC over other more accessible and less costly types of treatment for drug use. However, in a prison context, TC might be of more benefit than other types of treatment. More research with solid experimental methodology is needed to add to the still weak body of evidence that supports the use of TC over other more affordable types of treatment for drug use disorders. PMID- 22510903 TI - [Barras bravas membership and its influence on drug use]. AB - OBJECTIVES: To identify the factors associated with barras bravas (soccer fans clubs) membership, the incidence in drug use and the association between membership and drug use. MATERIALS AND METHODS: This report analyzed data from 1303 adolescent scholars who participated in two stages (T1 and T2) of a longitudinal study done in 23 schools of Bogota during 2006- 2007, selected through a probabilistic sampling stratified by clusters. Logistic regression models were implemented in order to evaluate the associations of interest. RESULTS: In T1, 8,2% of the surveyed students reported barras bravas membership. After one year of follow-up, 14,2% of barras bravas members, and 4,6% of non members, initiated drug use. The association between barras bravas membership and drug use onset remained significant after adjusting for multiple confounding factors (ARR=2,4; 95%CI=1,2-4,7). Sex-stratified analysis indicated that this association remained statistically significant only for females (ARR=6,1; 95%CI=2,5-15,3). CONCLUSIONS: Barras bravas membership increases the risk of drug use onset, particularly among females. The findings imply that preventive efforts should be focused on females in these contexts. PMID- 22510904 TI - [Child and adolescent abuse recorded at a national referral hospital, 2006 - 2011]. AB - OBJECTIVES: To describe the records of child and adolescent abuse of the Instituto Nacional de Salud del Nino (INSN) from January 2006 to September 2011, characterizing the victim and perpetrator. MATERIALS AND METHODS: A secondary sources analysis was performed, based on the domestic violence and child abuse records, from froms administered by Child Abuse and Adolescent Health Unit (MAMIS) at the INSN. The records include data of the victim, offender and characteristics of the aggression. Types of aggression were categorized as: sexual, physical, psychological or neglection. Frequencies and percentages are presented. RESULTS: A total of 1798 records were included. From them 63.9% were girls, and 39.9% were adolescents. Males accounted for 60.6% of the offenders, and 65.8% of assaults occurred at home. Sexual assault was recorded in 48.6%, with more frequency among girls (73.2%) and adolescents (44.4%); and intercourse occurred in 9.6% of the cases. CONCLUSIONS: From the INSN MAMIS records, aggressions to girls was the most frequent type of report, the aggressor was often a male and most of the attacks occurred in the child's home. Sexual assault accounted for almost half of the series. PMID- 22510905 TI - [Factors associated to recent intimate partner physical violence against women in Peru, 2004-2007]. AB - OBJECTIVES: To identify factors associated to recent (during the last year) intimate partner physical violence against women in Peru. MATERIALS AND METHODS: Using the demographic and Family Health National Survey (ENDES) 2004- 2007 a secondary analysis was performed. 12,257 women married or living with a couple who answered the violence module were included, with this information they were assigned to a category according to the history of having been physically assaulted by their couples. Descriptive analysis and univariate and multivariate logistical regression for complex samples were done. RESULTS: Prevalence of physical violence at the national level was 14,5%, with variations according to the geographical areas (9,7% to 18,9%). The factor associated to a higher risk is having a couple who frequently gets drunk (OR: 7,2; 95%CI: 5,4-9,6) and having a couple controlling or limiting the woman's visits to family or friends (OR: 4,1; 95%CI: 3,3-5,0); other associated factors are history of physical aggression of the father to the mother, having had previous partners, be cohabiting, having a higher educational level than the partner and having a disbalanced decision taking in the couple. Among the factors associated with a lower risk are the communication and respect inside the couple (OR: 0,3; 95%CI: 0,2-0,3), and the fact that the woman has health insurance. CONCLUSIONS: Many individual factors, as well as factors of the couple relationship and others are associated with a higher probability of violence against the woman. Other agents, such as the communication and the respect in the couple, could have a protective character. PMID- 22510906 TI - [Who is the victim and who the offender in intimate partner physical violence? An epidemiological study in seven cities of Peru]. AB - OBJECTIVES: To identify factors associated to the probability of being the aggressor or the victim in cases of intimate partner physical violence. MATERIALS AND METHODS: A secondary data analysis was performed to an epidemiological survey done in seven cities in Peru (Lima, Arequipa, Huamanga, Trujillo, Cuzco, Callao and Maynas). 6399 men and women participated, of whom 3909 participants declared living together with an intimate partner at the time of the interview. Univariate and multivariate logistic regression models were used to identify associated factors to the roles of victim or aggressor. RESULTS: The likelihood of being aggressor or victim in cases of intimate partner physical violence was independent of sex (p<0,01) and the couple's time living together. Factors associated to a higher probability of both roles included a history of exposure to physical violence during childhood, having a favorable attitude towards violence, heavy alcohol drinking, and being younger than 45 years, as well as having a monthly family income of less than 750 USD or an educational attainment of less than complete tertiary school. Geographically, Cusco was the city where it was most likely to find an aggressor or a victim of intimate partner physical violence. Most of these associations obtained p-values of less than 0.001. CONCLUSIONS: In cases of intimate partner physical violence, the pattern of predictors is similar in both roles, i.e., aggressor and victim. Sex and the couple's span of time living together did not predict any of both roles. PMID- 22510907 TI - [Pneumococcal serotypes in carrier children prior to the introduction of anti pneumococcal vaccines in Peru]. AB - OBJECTIVES: To determine the carriage rate and serotype distribution of Streptococcus pneumoniae in the nasopharynx of healthy children younger than 2 years prior to the universal use of the pneumococcal conjugate vaccines in Peru. MATERIALS AND METHODS: Between 2007 and 2009 we collected nasopharyngeal swab samples from 2,123 healthy children aged 2 to 24 months in the vaccination and healthy children consultation offices of pediatric hospitals and health centers in 7 cities in Peru: on the coast (Lima, Piura), highlands (Cusco, Abancay, Arequipa and Huancayo) and amazon basin (Iquitos). The pneumococcal strains were isolated and identified at the central laboratory of the project in Lima, and serotyped by Quellung reaction in the pneumococcal reference laboratory at the Center for Diseases Control and Prevention (CDC). RESULTS: We found 27% (573/2123) of pneumococcal nasopharyngeal healthy carrier children. Among the 526 analyzed strains, we found 42 serotypes; the most common were: 19F (18.1%), 6B (14.3%); 23F (8.9%) and 14 (6.5%). CONCLUSIONS: The distribution of vaccine serotypes in the analyzed strains was of 50% for the serotypes present in the seven-valent vaccine, 50.2% for the serotypes present in the ten-valent vaccine and 57.2% for those present in the thirteen-valent vaccine. PMID- 22510908 TI - [The effect of the essential oil from Aloysia triphylla britton (lemon verbena) on Trypanosoma cruzi in mice]. AB - OBJECTIVES: To determine the in-vivo anti-Trypanosoma cruzi activity of the essential oil from Aloysia triphylla in mice. MATERIALS AND METHODS: The mice (n = 15) in the study were randomly assigned to the following groups: infected and untreated (G1), infected and treated with benznidazole 100 mg/kg (G2), infected and treated with of Aloysia triphylla essential oil 100 mg/kg (G3), infected and treated with of Aloysia triphylla essential oil 250 mg/kg (G4), uninfected and untreated (G5), and uninfected and treated with 250 mg/kg of Aloysia triphyla (G6). The infection was conducted using 104 blood T. cruzi trypomastigotes and the treatment began on the 8th day post-infection (dpi) through 28 dpi. The parasitemia was determined through optical microscopy every 2 days using 5 MUL of blood sampled from the tail. In dpi 14, 21 and 28, the blood sample was obtained from the queue for testing creatine kinase-MB, alanine aminotransferase and creatinine, then animals were euthanized and the heart was removed for histopathological study. RESULTS: The essential oil of lemon verbena produced a significant reduction of the parasitemia, 85.4% with the peak at a the dose of 250 mg/ kg. It was also observed a reduction in the number of amastigotes and inflammatory infiltrates in the heart. The creatine kinase-MB plasma levels also decreased at dpi 28 as a result of such treatment. CONCLUSIONS: Under experimental conditions, the essential oil of Aloysia triphylla (lemon verbena) has in vivo anti-Trypanosoma cruzi effect in mice. PMID- 22510909 TI - [Experimental efficacy of IgY antibodies produced in eggs against the venom of the Peruvian snake Bothrops atrox]. AB - OBJECTIVES: To develop an immunization protocol in order to produce avian IgY immunoglobulins against Bothrops atrox Peruvian snake venom and to evaluate its neutralizing capacity. MATERIALS AND METHODS: Six Hy Line Brown hens were immunized each two weeks using 500MUg/doses of B. atrox venom in a period of two months. Each week, eggs were collected for IgY isolation from yolk using two consecutive steps with caprilic acid and ammonium sulfate. Detection of IgY anti B. atrox were performed by double immunodiffusion, whereas title and cross reactivity were analyzed using ELISA and Western Blot technics, respectively. Furthermore, letal dose (DL(50)) and Medium Effective Dose (DE(50)) were obtained by Probit analysis. RESULTS: As a result of this protocol, chicken IgY's were obtained in a concentration of 8,5 +/- 1,35 mg/yolk mL. DE50 from avian antivenom was 575 MUL/venom mg. Cross-reactivity studies showed Bothrops atrox venom share more commom epitopes with Bothrops brazili (47%) than others Bothrops venoms showing Lachesis muta (19%) and Crotalus durissus (12%) venoms a low crossing reactivity, instead. CONCLUSIONS: Using this procedure, we could purify chicken IgY with a neutralizant capacity of B. atrox venom which is comparable to the antivenom of equine origin and demonstrate its capacity as a immunoanalitical tool to evaluate the cross reactivity with others peruvian snakes. PMID- 22510910 TI - [Evaluation of the quality of information about pregnancy found in webpages according to the Peruvian guidelines]. AB - OBJECTIVES: The objective of this study is to evaluate the information quality about pregnancy symptoms in Spanish available in the internet. MATERIALS AND METHODS: This is an analytic, cross-sectional study. In order to evaluate the selected websites, we used a methodology previously validated by Curro et al. The websites were selected from Google, MSN.com and Yahoo.com. The quality evaluation included three components: medical contents, accountability and usability of the website. The medical content was compared with the data available in the national guidelines for Comprehensive Sexual and Reproductive Health, from the Peruvian Ministry of Health. RESULTS: Ninety nine websites in Spanish were evaluated. From them, 26.3% had medium adherence to the gold standard document. In 37.4% the websites were of low quality. A total of 24.2% were blogs, they were associated (as a protrective factor) to sites of poor quality (OR: 0.1, 95% CI: 0.02 to 0.5). CONCLUSIONS: The majority of websites in Spanish related to pregnancy symptoms have low quality. These findings indicate the need to properly educate patients and general public, and a critical evaluation of the information quality found at the Internet as well. PMID- 22510911 TI - [Levels of quinolones resistance and other antimicrobial in non-pathogenic Escherichia coli strains in children from the periurban area of Lima, Peru]. AB - The main aim of this study was to establish the resistance levels to antimicrobial agents, in 222 non-pathogenic E. coli strains of fecal origin in Peru. The proportion of resistance found to the evaluated antimicrobials was ampicillin (62.6%), cotrimoxazole (48,6%), tetracycline (43,0%) and chloramphenicol (15,8%). We emphasize the high resistance levels found for quinolones: 32% for nalidixic acid (NAL) and 12% for ciprofloxacin (CIP). These high levels of quinoloneresistance in non-pathogenic strains isolated from children in this age group highlight the extensive use and the impact of the intake of this kind of antimicrobials in the community, showing the potential risk of the loss of their utility in the area. PMID- 22510912 TI - [Association between severe tuberculosis in children and previous BCG immunization in a national referral hospital, Peru 1990-2000]. AB - The objective of the study was to determine the association between BCG immunization and severe tuberculosis (TB). We performed a retrospective study, including medical records from patients of the pneumology department at the National Children's Institute in Peru, between the years 1990-2000. A total of 2106 TB cases were reviewed, from them 259 patients were severe (miliary TB or meningoencephalitic TB). From all, 497 cases did not have history of BCG vaccination, 202 had severe TB and 295 non-severe TB (OR = 0.05, 95% CI = 0.03 to 0.07). In conclusion, children diagnosed with TB and who have been immunized with BCG, has 94% lower risk of developing severe TB, compared to children with TB non immunized with BCG. PMID- 22510913 TI - [Molecular test Genotype(r) MTBDRplus, an alternative to rapid detection of multidrug resistance tuberculosis]. AB - The Genotype(r)MTBDRplus molecular test is a method that allows identification of the most frequent mutations associated with resistance to major first-line antituberculosis drugs, Isoniazid (INH) and Rifampicin (RFP). The aim of this study was to evaluate the performance of the molecular test with culture and smear- positive sputum samples. We evaluated 95 cultures and 100 sputum samples with resistance profiles previously determined by the reference method "Agar Plate Proportions" (APP). The molecular test from cultures showed a sensitivity of 100 %, 97,5 % and 96,97 % for RIF, INH and MDR respectively while from sputums the sensitivity was 95,65 %, 96,77 % and 95,24 % for RIF, INH and MDR respectively. We conclude that the molecular test Genotype(r)MTBDRplus is a very useful tool to detect resistance to isoniazid and rifampicin simultaneously (MDR TB) in up to 72 hours from sputum samples or cultures. PMID- 22510914 TI - [Violence and addictions: public health problems]. AB - Violence and addictions produce a great impact over persons, families, and communities. They impair their normal development and affect the possibility of individuals to fully grow. There are many different factors involved in their presentation, so proposed solutions must come from different sectors with an integrated point of view. The prospects of an adequate individual and collective development depend on the efficacy of the actions taken, from the public health point of view. PMID- 22510915 TI - [Risk/protective factors and prevention programs for drug dependence in Peru]. AB - Risk/ protective factors (RPF) are main elements for the analysis, understanding and formulation of answers for the prevention of drug dependences. The objective of this article is to present a literature review about the RPF and their implications in the design of preventive programs. It will focus on individual (genetic aspects, early experiences and psicosocial skills), family (parental control and monitoring, permissiveness, parenting styles), peer (group pressure and social norms) and communitarian (disorganization) RPF. On the other hand, the need of incorporating a multifactor conceptual framework for the preventive approach to drug dependences, articulating the intervention spaces (school, family and community), assuming and evolving perspective allowing the implementations of sustained actions is evidenced. On top, the implications for future research and public policy formulation are discussed. PMID- 22510916 TI - [Reducing the burden of disease caused by alcohol use in Peru: evidence- based approaches]. AB - Alcohol use is one the most important risk factors for illness and early death in Peru. Measures aimed at decreasing or controlling the great impact caused by alcohol in the Peruvian society are urgently needed. This article identifies and promotes the implementation of public health measures supported by sound scientific evidence of effectiveness or, in some cases, cost-effectiveness. The 10 evidence-based public health measures identified and described here represent a set if measures with high probability of success if implemented, as they are supported by scientific evidence. We recommend that governments, at the national or local levels, apply these measures not individually, but in combination, arranging them into a plan or roadmap, where the framework in which they will be applied must be established according to each context. Considering the available resources, some of these measures could be implemented in the short and medium term while the others can be set in the long-term. PMID- 22510917 TI - [Access and usability to medications: a proposal for an operational definition]. AB - Research about accessibility to medicines through household surveys is very important in order to verify the reality and effectiveness of interventions done to increase the access of the population to the medications. Unfortunately, such studies, on top of being very few, have methodological problems, which mostly result from a lack of uniformity in the operational definitions of access and the differentiation with the dimensions of accessibility. The aim of this paper is to propose setting a difference between both terms. We propose an operational definition of access to medications as the process of verification of the purchase of a drug by a patient, independently from many factors that can affect this process. The term "usability of drugs" is introduced, defining it operationally as aimed at measuring the dimensions of the accessibility to the medications: physical availability, affordability, geographical accessibility, acceptability (or satisfaction). PMID- 22510918 TI - [Effects of marijuana on cognition: a review form the neurobiological perspective]. AB - Marijuana is one of the most commonly used psychoactive substances in society, mainly among youths. Its use has been consistently associated with several health problems, many of which have in common an impairment in the cognitive processes of behavior, including the memory, attention, emotion and decision making. There is evidence suggesting that cannabinoids, marijuana's primary psychoactive substance, have a negative effect in short-term memory, working memory, and decision making. It has also been found that cannabinoids affect attention and the interaction between cognitive events and emotion. This information can be used as an argument of biological plausibility to assess clinical and epidemiological research findings that show that marijuana's use is associated to problems such as traffic accidents, psychosis, depression and poor academic records, among others. PMID- 22510919 TI - [Atypical presentation of diffuse tropical pyomiositis of the psoas due to methicillin resistant Staphylococcus aureus]. AB - Diffuse tropical primary pyomyositis is an infrequent entity in our country, with few cases associated to community-acquired Methicillin- resistant Staphylococcus aureus. There are no reported cases of Community-Acquired Methicillin- Resistant Staphylococcus aureus (CA- MRSA) in Peru. We present the case of a 70 year old male with a previous diagnosis of type 2 diabetes mellitus, receiving irregular treatment, who was admitted to the hospital with a history of 10 days of low back pain radiating to the left leg, fever and forced flexion of the right hip due to pain during movement. The diagnosis of diffuse pyomyositis of both psoas muscles was performed with MRI and culture of a posterior paravertebral collection, from which Staphylococcus aureus resistant to oxacillin, penicillin and dicloxacillin was isolated. PMID- 22510920 TI - [Recent traumatic lesions in cases of family violence]. PMID- 22510921 TI - [The stone of madness: starting points of the history of mental health]. AB - Addressing the relatively recent concern of public health in the issue of mental health problems, the evolution of the concept of mental illness in the occidental pre-modern history is revised, as well as the reasons why it remained outside the mainstream of the professional healing activity. The differences between the naturalist and the supernatural views are explored as well. PMID- 22510922 TI - [Comments to the article "ethics and research"]. PMID- 22510923 TI - [Comments to the article "ethics and research"]. PMID- 22510924 TI - [Comments to the article "ethics and research"]. PMID- 22510926 TI - [Over demand for medical students in clinical medicine]. PMID- 22510927 TI - [Differences in anemia detection in high altitude according to the World Health Organization]. PMID- 22510929 TI - [Hospitalized patients and the knowledge about their own illness]. PMID- 22510930 TI - [Application of rapid tests for syphilis diagnosis in rural areas]. PMID- 22510931 TI - [Morphological characterization of atypical and Ozzardi microfilariae of mansonella gender]. PMID- 22510932 TI - [Hepatitis B in blood donors at an hospital in Apurimac, Peru]. PMID- 22510933 TI - [Violence against medical doctors: an issue to consider in human resources for health]. PMID- 22510934 TI - [Knowledge of health professionals in the care of people with alcohol problems and family violence]. PMID- 22510935 TI - [Empirical management of addictions in Peru]. PMID- 22510937 TI - Association between kinase insert domain-containing receptor polymorphisms ( 604T>C, 1192G>A, 1719A>T) and premature ovarian failure in Korean women. AB - OBJECTIVE: The aim of the study was to investigate whether the -604T>C, 1192G>A, and 1719A>T polymorphisms in the kinase insert domain-containing receptor (KDR) gene confer risk for premature ovarian failure (POF) in Korean women. METHODS: DNA samples from 133 POF patients and 230 controls were genotyped for the three KDR single nucleotide polymorphisms by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The POF patients had significantly increased frequencies of the KDR -604TC and -604TC + CC genotypes (odds ratio [OR], 1.975; 95% CI, 1.219-3.201 and OR, 1.948; 95% CI, 1.221-3.109, respectively) and of the -604TC + CC/1192GG combined genotype (OR, 2.271; 95% CI, 1.359-3.795) and a decreased frequency of the 1192GA genotype (OR, 0.457; 95% CI, 0.231-0.905) compared with the controls. The genotype frequency of the 1719A>T polymorphism was not significantly different between the two groups. The frequencies of the KDR -604C/1192G/1719T, -604C/1192G, and -604C/1719T haplotypes (OR, 3.319; 95% CI, 1.564-7.041; OR, 2.083; 95% CI, 1.351-3.212; and OR, 1.979; 95% CI, 1.073-3.649, respectively) were significantly higher among POF patients than controls, whereas the -604T/1719T haplotype frequency (OR, 0.657; 95% CI, 0.472-0.915) was lower among POF patients. CONCLUSIONS: Carriers of the KDR -604C variant allele (-604TC and -604TC + CC genotypes; -604TC + CC/1192GG combined genotype; -604C/1192G/1719T haplotype, -604C/1192G haplotype, -604C/1719T haplotype) are consistently more prevalent among POF patients than among controls, suggesting that the KDR -604C allele may increase the risk of POF development in Korean women. PMID- 22510938 TI - Are there several kinds of palliative care? PMID- 22510936 TI - Association of past and recent major depression and menstrual characteristics in midlife: Study of Women's Health Across the Nation. AB - OBJECTIVE: The aim of this study was to examine the association of a history of major depression (MD) with menstrual problems in a multiethnic sample of midlife women. METHODS: Participants were 934 women enrolled in the Study of Women's Health Across the Nation, a multisite study of menopause and aging. The outcomes were menstrual bleeding problems and premenstrual symptoms in the year before study entry. The Structured Clinical Interview for the Diagnosis of DSM-IV Axis I Disorders was conducted to determine recent and past psychiatric diagnoses. Covariates included sociodemographic, behavioral, and gynecologic factors. RESULTS: One third of the participants reported heavy bleeding, 20% reported other abnormal bleeding, and 18% reported premenstrual symptoms. One third had past and 11% had recent MD. Past MD was associated with an increased likelihood of heavy bleeding (odds ratio, 1.89; 95% CI, 1.25-2.85), adjusting for recent MD, menopause status, and other covariates. Past MD was not associated with other abnormal bleeding or premenstrual symptoms in the final analysis that adjusted for recent MD. CONCLUSIONS: Midlife women with a history of MD are more likely to report heavy bleeding. PMID- 22510939 TI - Dermatofibrosarcoma protruberans treatment with platelet-derived growth factor receptor inhibitor: a review of clinical trial results. AB - PURPOSE OF REVIEW: Dermatofibrosarcoma protuberans (DFSP) is a rare mesenchymal neoplasm arising in the dermis, accounting for less than 0.1% of all cancers. Given its rarity, and paucity of randomized trials, the nuances of treatment are not widely understood. In this review we attempt to summarize the available data to guide treatment choices for physicians managing this disease. RECENT FINDINGS: DFSP carries a translocation of chromosomes 17 and 22 leading to juxtaposition of the collagen type-1alpha1 promoter to the platelet-derived growth factor (PDGF) gene. This results in unregulated expression of PDGF leading to autocrine or paracrine activation of its receptor (PDGFRbeta). This molecular pathway is the target of our current drug therapy for DFSP, imatinib, a tyrosine kinase inhibitor that interferes with the phosphorylation and activation of PDGFRbeta. In case reports and prospective studies, imatinib was noted to be an effective treatment for patients with unresectable or metastatic DFSP, associated with response rates approaching 50%. It has also been used preoperatively to improve the resectability of tumors. Since metastasis is rarely seen and local recurrences are uncommon following wide excision with pathologically negative margins, surgery remains the backbone of treatment. SUMMARY: Imatinib, a tyrosine kinase inhibitor, is the current preferred agent for treatment of unresectable or metastatic DFSP. Clinical trials evaluating broader-spectrum kinase inhibitors such as pazopanib are in development. PMID- 22510940 TI - Neuroendocrine tumors of the digestive tract: impact of new classifications and new agents on therapeutic approaches. AB - PURPOSE OF REVIEW: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) constitute a diverse group of neoplasms arising from the diffuse neuroendocrine cell system. During the last 2 years a new classification system, the WHO 2010, has come into clinical practice together with Tumor Nodes Metastases (TNM) staging and grading systems, developed by the European Neuroendocrine Tumor Society/American Joint Cancer Committee. At the same time new targeted agents have been developed for treatment of GEP-NETs and it is important discuss these new agents in relation to the classification and staging system. RECENT FINDINGS: The current article is reviewing the most important clinical trials of targeting agents within the field of neuroendocrine tumors. Tyrosine kinase inhibitors as well as PI3 kinase mTOR inhibitors have been applied in the treatment of neuroendocrine tumors. SUMMARY: Sunitinib and everolimus have recently been registered for treatment of pancreatic neuroendocrine tumors worldwide. The role of these new targeted agents in the treatment algorithm of neuroendocrine tumors will be discussed. A large number of phase I and phase II trials have been performed in GEP-NETs with rather limited results and no significant impact on the clinical management of patients with GEP-NETs. However, there are two phase III trials that have completely changed the treatment landscape for pancreatic neuroendocrine tumors, e.g., sunitinib and everolimus demonstrating an increased progression free survival of 11 vs. 5 months for the placebo group. PMID- 22510941 TI - A simulation study of the combined thermoelectric extracellular stimulation of the sciatic nerve of the Xenopus laevis: the localized transient heat block. AB - The electrical behavior of the Xenopus laevis nerve fibers was studied when combined electrical (cuff electrodes) and optical (infrared laser, low power sub 5 mW) stimulations are applied. Assuming that the main effect of the laser irradiation on the nerve tissue is the localized temperature increase, this paper analyzes and gives new insights into the function of the combined thermoelectric stimulation on both excitation and blocking of the nerve action potentials (AP). The calculations involve a finite-element model (COMSOL) to represent the electrical properties of the nerve and cuff. Electric-field distribution along the nerve was computed for the given stimulation current profile and imported into a NEURON model, which was built to simulate the electrical behavior of myelinated nerve fiber under extracellular stimulation. The main result of this study of combined thermoelectric stimulation showed that local temperature increase, for the given electric field, can create a transient block of both the generation and propagation of the APs. Some preliminary experimental data in support of this conclusion are also shown. PMID- 22510942 TI - Evaluating the noise in electrically evoked compound action potential measurements in cochlear implants. AB - Electrically evoked compound action potentials (ECAPs) are widely used to study the excitability of the auditory nerve and stimulation properties in cochlear implant (CI) users. However, ECAP detection can be difficult and very subjective at near-threshold stimulation levels or in spread of excitation measurements. In this study, we evaluated the statistical properties of the background noise (BN) and the postaverage residual noise (RN) in ECAP measurements in order to determine an objective detection criterion. For the estimation of the BN and the RN, a method currently used in auditory brainstem response measurements was applied. The potential benefit of using weighted (Bayesian) averages was also examined. All estimations were performed with a set of approximately 360 ECAP measurements recorded from five human CI users of the CII or HiRes90K device (advanced bionics). Results demonstrated that the BN was normally distributed and the RN decreased according to the square root of the number of averages. No additional benefit was observed by using weighted averaging. The noise was not significantly different either at different stimulation intensities or across recording electrodes along the cochlea. The analysis of the statistical properties of the noise indicated that a signal-to-noise ratio of 1.7 dB as a detection criterion corresponds to a false positive detection rate of 1% with the used measurement setup. PMID- 22510943 TI - Online 3-D tracking of suspension living cells imaged with phase-contrast microscopy. AB - Neural stem cells/neural progenitors (NSCs/NPs) are cells that give rise to the main cell types of the nervous system: oligodendrocytes, neurons, and astrocytes. Studying NSCs/NPs with time-lapse microscopy is critical to the understanding of the biology of these cells. However, NSCs/NPs are very sensitive to phototoxic damage, and therefore, fluorescent dyes cannot be used to follow these cells. Also, since in most of NSC/NP-related experiments, a large number of cells neesd to be monitored. Consequently, the acquisition of a huge amount of images is required. An additional difficulty is related to our original suspension living, tracking objective, behavior much closer to the natural, in vivo, way of development of the cells. Indeed, unlike adherent cells, suspension cells float freely in a liquid solution, thus, making their dynamics very different from that of adherent cells. As a result, existing visual tracking algorithms that have primarily been developed to track adherent cells are no longer adequate to tackle living cells in suspension. This paper presents a novel automated 3-D visual tracking of suspension living cells for time-lapse image acquisition using phase contrast microscopy. This new tracking method can potentially strongly impact on current 3-D video microscopy methods, paving the way for innovative analysis of NSCs/NPs and as a result, on the study of neurodegenerative diseases. PMID- 22510944 TI - Redundancy resolution of the human arm and an upper limb exoskeleton. AB - The human arm has 7 degrees of freedom (DOF) while only 6 DOF are required to position the wrist and orient the palm. Thus, the inverse kinematics of an human arm has a nonunique solution. Resolving this redundancy becomes critical as the human interacts with a wearable robot and the inverse kinematics solution of these two coupled systems must be identical to guarantee an seamless integration. The redundancy of the arm can be formulated by defining the swivel angle, the rotation angle of the plane defined by the upper and lower arm around a virtual axis that connects the shoulder and wrist joints. Analyzing reaching tasks recorded with a motion capture system indicates that the swivel angle is selected such that when the elbow joint is flexed, the palm points to the head. Based on these experimental results, a new criterion is formed to resolve the human arm redundancy. This criterion was implemented into the control algorithm of an upper limb 7-DOF wearable robot. Experimental results indicate that by using the proposed redundancy resolution criterion, the error between the predicted and the actual swivel angle adopted by the motor control system is less then 5 degrees . PMID- 22510946 TI - The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm arising from the mesothelial cells lining the parietal pleura and it exhibits poor prognosis. Although there has been significant progress in MPM treatment, development of more efficient therapeutic approaches is needed. BMAL1 is a core component of the circadian clock machinery and its constitutive overexpression in MPM has been reported. Here, we demonstrate that BMAL1 may serve as a molecular target for MPM. The majority of MPM cell lines and a subset of MPM clinical specimens expressed higher levels of BMAL1 compared to a nontumorigenic mesothelial cell line (MeT-5A) and normal parietal pleural specimens, respectively. A serum shock induced a rhythmical BMAL1 expression change in MeT-5A but not in ACC-MESO-1, suggesting that the circadian rhythm pathway is deregulated in MPM cells. BMAL1 knockdown suppressed proliferation and anchorage-dependent and independent clonal growth in two MPM cell lines (ACC-MESO-1 and H290) but not in MeT-5A. Notably, BMAL1 depletion resulted in cell cycle disruption with a substantial increase in apoptotic and polyploidy cell population in association with downregulation of Wee1, cyclin B and p21(WAF1/CIP1) and upregulation of cyclin E expression. BMAL1 knockdown induced mitotic catastrophe as denoted by disruption of cell cycle regulators and induction of drastic morphological changes including micronucleation and multiple nuclei in ACC-MESO-1 cells that expressed the highest level of BMAL1. Taken together, these findings indicate that BMAL1 has a critical role in MPM and could serve as an attractive therapeutic target for MPM. PMID- 22510947 TI - Growth stimulating antibody, as another predisposing factor of Graves' disease (GD): analysis using monoclonal TSH receptor antibodies derived from patients with GD. AB - TSH receptor antibody (TRAb) is clinically classified into thyroid stimulating antibody (TSAb) and thyroid-stimulation blocking antibody (TSBAb). Although the former is considered to cause Graves' disease (GD), its activity does not necessarily reflect hormone production and goiter size. Moreover, uptake of 99mTcO4(-), the best indicator for GD, is correlated with activity of TSH binding inhibitor immunoglobulin better than activity of TSAb. Because uptake of 99mTcO4( ) reflects thyroid volume, these observations suggest that there exist TRAb with thyrocyte growth stimulating activity (GSA) other than TSAb. In this study, we analyzed GSA of monoclonal TRAb established from patients with GD or idiopathic myxedema (IME). GSA was measured as the degree of FRTL-5 cell growth stimulated by each TRAb. The signaling pathways of the cell growth were pharmacologically analyzed. The cell growth stimulated by TSH was strongly suppressed by protein kinase A (PKA) inhibitor, but was not affected by extracellular signal regulated kinase kinase (MEK) inhibitor. Although TSAb from GD stimulated the cell growth, both inhibitors suppressed it. Surprisingly, the cell growth was also induced by TSBAb from GD and was only suppressed by MEK inhibitor. TSBAb from IME did not have GSA and attenuated the cell growth stimulated by TSH. We concluded that 1; in GD, not only TSAb but some TSBAb could stimulate thyrocyte growth. 2; TSBAb might be classified with respect to their effects on thyrocyte growth; i.e., thyrocyte growth stimulating antibody and thyrocyte growth-stimulation blocking antibody. PMID- 22510948 TI - A feature-based learning framework for accurate prostate localization in CT images. AB - Automatic segmentation of prostate in CT images plays an important role in medical image analysis and image guided radiation therapy. It remains as a challenging problem mainly due to three issues: First, the image contrast between the prostate and its surrounding tissues is low in prostate CT images and no obvious boundaries can be observed. Second, the unpredictable prostate motion causes large position variations of the prostate in the treatment images scanned at different treatment days. Third, the uncertainty of the existence of bowel gas in treatment images significantly changes the image appearance even for images taken from the same patient. To address these issues, in this paper we are motivated to propose a feature based learning framework for accurate prostate localization in CT images. The main contributions of the proposed method lie in the following aspects: (1) Anatomical features are extracted from input images and adopted as signatures for each voxel. The most robust and informative features are identified by the feature selection process to help localize the prostate. (2) Regions with salient features but irrelevant to the localization of prostate, such as regions filled with bowel gas are automatically filtered out by the proposed method. (3) An online update mechanism is adopted in this paper to adaptively combine both population information and patient-specific information to localize the prostate. The proposed method is evaluated on a CT prostate dataset of 24 patients to localize the prostate, where each patient has more than 10 longitudinal images scanned at different treatment times. It is also compared with several state-of- the-art prostate localization algorithms in CT images, and the experimental results demonstrate that the proposed method achieves the highest localization accuracy among all the methods under comparison. PMID- 22510949 TI - Archive film defect detection and removal: an automatic restoration framework. AB - In this paper, we present an automatic restoration system targeting on dirt and blotches in digitized archive films. The system is composed of mainly two modules: defect detection and defect removal. In defect detection, we locate the defects by combing temporal and spatial information across a number of frames. An HMM is trained for normal observation sequences and then applied within a framework to detect defective pixels. The resulting defect maps are refined in a two-stage false alarm elimination process and then passed over to the defect removal procedure. A labelled (degraded) pixels is restored in a multiscale framework by first searching the optimal replacement in its dynamically generated, random walk based region of candidate pixel-exemplars and then updating all its features (intensity, motion and texture). Finally, the proposed system is compared against state-of-the-art methods to demonstrate improved accuracy in both detection and restoration using synthetic and real degraded image sequences. PMID- 22510950 TI - Remote sensing image subpixel mapping based on adaptive differential evolution. AB - In this paper, a novel subpixel mapping algorithm based on an adaptive differential evolution (DE) algorithm, namely, adaptive-DE subpixel mapping (ADESM), is developed to perform the subpixel mapping task for remote sensing images. Subpixel mapping may provide a fine-resolution map of class labels from coarser spectral unmixing fraction images, with the assumption of spatial dependence. In ADESM, to utilize DE, the subpixel mapping problem is transformed into an optimization problem by maximizing the spatial dependence index. The traditional DE algorithm is an efficient and powerful population-based stochastic global optimizer in continuous optimization problems, but it cannot be applied to the subpixel mapping problem in a discrete search space. In addition, it is not an easy task to properly set control parameters in DE. To avoid these problems, this paper utilizes an adaptive strategy without user-defined parameters, and a reversible-conversion strategy between continuous space and discrete space, to improve the classical DE algorithm. During the process of evolution, they are further improved by enhanced evolution operators, e.g., mutation, crossover, repair, exchange, insertion, and an effective local search to generate new candidate solutions. Experimental results using different types of remote images show that the ADESM algorithm consistently outperforms the previous subpixel mapping algorithms in all the experiments. Based on sensitivity analysis, ADESM, with its self-adaptive control parameter setting, is better than, or at least comparable to, the standard DE algorithm, when considering the accuracy of subpixel mapping, and hence provides an effective new approach to subpixel mapping for remote sensing imagery. PMID- 22510951 TI - Polynomial fuzzy observer designs: a sum-of-squares approach. AB - This paper presents a sum-of-squares (SOS) approach to polynomial fuzzy observer designs for three classes of polynomial fuzzy systems. The proposed SOS-based framework provides a number of innovations and improvements over the existing linear matrix inequality (LMI)-based approaches to Takagi-Sugeno (T-S) fuzzy controller and observer designs. First, we briefly summarize previous results with respect to a polynomial fuzzy system that is a more general representation of the well-known T-S fuzzy system. Next, we propose polynomial fuzzy observers to estimate states in three classes of polynomial fuzzy systems and derive SOS conditions to design polynomial fuzzy controllers and observers. A remarkable feature of the SOS design conditions for the first two classes (Classes I and II) is that they realize the so-called separation principle, i.e., the polynomial fuzzy controller and observer for each class can be separately designed without lack of guaranteeing the stability of the overall control system in addition to converging state-estimation error (via the observer) to zero. Although, for the last class (Class III), the separation principle does not hold, we propose an algorithm to design polynomial fuzzy controller and observer satisfying the stability of the overall control system in addition to converging state estimation error (via the observer) to zero. All the design conditions in the proposed approach can be represented in terms of SOS and are symbolically and numerically solved via the recently developed SOSTOOLS and a semidefinite-program solver, respectively. To illustrate the validity and applicability of the proposed approach, three design examples are provided. The examples demonstrate the advantages of the SOS-based approaches for the existing LMI approaches to T-S fuzzy observer designs. PMID- 22510952 TI - Multichannel EEG compression: wavelet-based image and volumetric coding approach. AB - In this paper, lossless and near-lossless compression algorithms for multichannel electroencephalogram signals (EEG) are presented based on image and volumetric coding. Multichannel EEG signals have significant correlation among spatially adjacent channels; moreover, EEG signals are also correlated across time. Suitable representations are proposed to utilize those correlations effectively. In particular, multichannel EEG is represented either in the form of image (matrix) or volumetric data (tensor), next a wavelet transform is applied to those EEG representations. The compression algorithms are designed following the principle of lossy plus residual coding, consisting of a wavelet-based lossy coding layer followed by arithmetic coding on the residual. Such approach guarantees a specifiable maximum error between original and reconstructed signals. The compression algorithms are applied to three different EEG datasets, each with different sampling rate and resolution. The proposed multichannel compression algorithms achieve attractive compression ratios compared to algorithms that compress individual channels separately. PMID- 22510953 TI - Evolutionary approach to development of collaborative teleconsultation system for imaging medicine. AB - This paper presents an evolution of a modern collaborative teleconsultation system called TeleDICOM over the period of several years. We show how new features (required from a medical point of view) can be provided, which barriers have been identified, and how these factors influence the system's architecture. A turning point in the evolution of our system was the formulation of a new architecture, fully facilitating service-oriented architecture paradigm guidelines. We therefore show how the knowledge and experience gathered during utilization of previous versions of TeleDICOM positively stimulate procedures of service-based system decomposition and business processes definition. PMID- 22510954 TI - Evaluation of a MEMS-based dual metal-layer thin-film microelectrode array for suprachoroidal electrical stimulation. AB - A double metal-layer thin-film platinum microelectrode array was fabricated for implantation between sclera and choroid based on MEMS processing techniques and photosensitive polyimide material. The array was composed of 60 stimulating sites (6 * 10) and four selectable returning electrodes. The diameter of each stimulating electrode was 350 MU m with a center-to-center spacing of 750 MUm. The transient voltage responses of the electrode to current pulse stimulation indicated a charge-injection capacity greater than 52.1 MU C/cm (2) . Acute in vivo animal experiments showed that the implicit time of electrically evoked potentials (EEPs) was 17.09+/-1.45 ms at a threshold current of 25.55 +/-5.43 MUA for a full-row of simultaneously stimulated electrodes (i.e., current applied simultaneously to each of the 10 electrodes). Individual electrode stimulation threshold was 48.57 +/-6.90 MUA. The corresponding threshold charge densities were 13.28 +/-2.82 MUC/cm (2) and 25.24 +/-3.59 MUC/cm (2) , respectively. The spatial spread of the maximally recorded P1 response in the EEPs indicated a correspondence between the retinal stimulation site and the focal response location in the cortex. This method of array fabrication is suitable for acute suprachoroidal stimulation, and has a potential use for the fabrication of a visual prosthesis. PMID- 22510955 TI - A POMDP approach to optimizing P300 speller BCI paradigm. AB - To achieve high performance in brain-computer interfaces (BCIs) using P300, most of the work has been focused on feature extraction and classification algorithms. Although significant progress has been made in such signal processing methods in the lower layer, the issues in the higher layer, specifically determining the stimulus schedule in order to identify the target reliably and efficiently, remain relatively unexplored. In this paper, we propose a systematic approach to compute an optimal stimulus schedule in P300 BCIs. Our approach adopts the partially observable Markov decision process, which is a model for planning in partially observable stochastic environments. We show that the thus obtained stimulus schedule achieves a significant performance improvement in terms of the success rate, bit rate, and practical bit rate through human subject experiments. PMID- 22510956 TI - Overweight in adolescence is related to increased risk of future urothelial cancer. AB - Obesity has been linked to various malignancies, but a clear relation of overweight with urothelial cancer has not been established. We assessed the association between adolescent obesity and future risk for urothelial cancer. Medical data on 1,110,835 Israeli adolescents examined for fitness for military duty between 1967 and 2005 were linked to the National Cancer Registry in this nationwide population-based cohort study. We used Cox proportional hazards modeling to estimate the covariate-adjusted hazard ratio (HR) for urothelial cancer associated with BMI measured at age 17. The mean follow-up of 17.6 +/- 10.8 years reflected 19,576,635 person years, during which 661 examinees developed urothelial cancer of the bladder, ureter, or renal pelvis. BMI >= 85 th standard percentile in adolescence significantly predicted increased risk of urothelial cancer with a HR (adjusted for year of birth, education and religiosity) of 1.42 (95% confidence interval (CI), 1.13-1.77, P = 0.002). Similar results were observed using the >= 25 kg/m(2) definition of overweight (HR = 1.36 (95% CI, 1.08-1.72), P = 0.008). Incidence of urothelial cancer was significantly lower in the more educated and among those who attended religious schools. Overweight in adolescence is related to increased risk of future urothelial cancer. In view of the growing incidence of both urothelial cancer and adolescent obesity, our study suggests an avenue for possible prevention of urothelial cancer. PMID- 22510957 TI - The angiogenic inhibitor TNP-470 decreases caloric intake and weight gain in high fat fed mice. AB - The angiogenic inhibitor TNP-470 attenuates high-fat diet-induced obesity; however, it is not clear how the compound alters energy balance to prevent weight gain. Five-week-old C57BL/6J mice were fed high-fat diet (45% energy from fat) for 6.5 weeks and treated with TNP-470 (20 mg/kg body weight; n = 7) or vehicle (saline; n = 7). Control mice (n = 8) received standard chow and sham injection. TNP-470 mice initially gained weight, but by day 5 body weight was significantly less than high-fat fed (HFF) mice and not different from that of chow-fed mice, an effect maintained to the end of the study (28.6 +/- 0.6 vs. 22.4 +/- 0.6 and 22.2 +/- 0.5 g). Percent body fat was reduced in TNP-470 compared to HFF mice, but was greater than that of chow mice (34.0 +/- 1.5, 23.9 +/- 1.5, and 17.0 +/- 1.4%, P < 0.05). Food intake in TNP-470-treated mice was less (P < 0.05) than that in HFF mice by day 5 of treatment (2.5 +/- 0.1 vs. 2.8 +/- 0.1 g/mouse/day) and remained so to the end of the study. Twenty-four hours energy expenditure was greater (P < 0.05) in TNP-470 than HFF or chow mice (7.05 +/- 0.07 vs. 6.69 +/- 0.08 vs. 6.79 +/- 0.09 kcal/kg/h), an effect not explained by a difference in energy expended in locomotion. Despite normalization of body weight, TNP-470 mice exhibited impaired glucose tolerance (area under the curve 30,556 +/- 1,918 and 29,290 +/- 1,584 vs. 24,421 +/- 903 for TNP, HFF, and chow fed, P < 0.05). In summary, the angiogenic inhibitor TNP-470 attenuates weight gain in HFF mice via a reduction in caloric intake and an increase in energy expenditure. PMID- 22510959 TI - Adiponectin profile in Asian patients undergoing coronary revascularization and its association with plaque vulnerability: IDEAS-ADIPO study. AB - Despite potent insulin-sensitizing, anti-inflammatory, and antiatherogenic effects in animal studies, the relationship between serum adiponectin level and coronary artery disease in patients remains unclear. We determined the adiponectin profile in a cohort of multiethnic Asian patients with coronary artery disease, and the association between serum adiponectin level and culprit lesion necrotic core (NC) content. Ninety-four Asian patients (BMI, 25.3 +/- 3.7 kg/m(2)) undergoing percutaneous coronary intervention were recruited. The serum adiponectin level was measured (n = 94), and the baseline virtual histology intravascular ultrasound examination was analyzed (n = 88). The median level of adiponectin was 3.7 ug/ml (interquartile range, 2.8-4.5 ug/ml). The serum adiponectin level was below 10 ug/ml in 90 patients (95.7%) and below 6 ug/ml in 80 patients (85.1%). There was a significant association between ethnicity and serum adiponectin level (P = 0.048). The median adiponectin level was highest among the Chinese, followed by the Malay and the Indians. Serum adiponectin levels were positively associated with culprit lesion NC content. A 1-ug/ml increase in log adiponectin was associated with a 3.04% (95% confidence interval: 0.33-5.44) increase in culprit lesion NC content. This association remains significant after adjusting for age, sex, ethnicity, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and procedural indication. We found a low serum level of adiponectin in Asian patients and a significant ethnic effect on serum adiponectin level. Increased serum adiponectin levels were independently associated with increased culprit lesion NC burden, suggesting a role for adiponectin in modulating coronary plaque vulnerability. PMID- 22510960 TI - Development of a novel ER stress based selection system for the isolation of highly productive clones. AB - Most biotherapeutic drugs are recombinant monoclonal antibodies which are mostly produced in monoclonal cell lines derived from Chinese hamster ovary (CHO) cells. Various clones expressing a monoclonal recombinant antibody were analyzed and a correlation of the antibody concentration and the relative mRNA level of calreticulin (CALR), glucose-regulated protein 78 and 94 kDa (GRP78, GRP94) and spliced X-box binding protein 1 (XPB1) was observed. By means of these results we were motivated to establish a novel selection system based on endoplasmic reticulum (ER) stress, which allows the rapid identification and isolation of high-expressing clones out of a pool mainly consisting of low- and medium producing cells. Several ER stress responsive elements were tested with the aid of a recombinase mediated cassette exchange (RMCE) procedure. Very surprisingly, only GRP78 reporter constructs were strongly stimulated upon antibody expression. Furthermore we found that GRP78 reporter constructs are very suitable to reflect the level of antibody expression (IgG) in recombinant CHO cells. Based on these results, it is concluded, that the novel ER stress based selection system developed during this study is suitable to identify and isolate clones with a high level of antibody expression. PMID- 22510961 TI - Microfluidic synthesis of advanced microparticles for encapsulation and controlled release. AB - We describe droplet microfluidic strategies used to fabricate advanced microparticles that are useful structures for the encapsulation and release of actives; these strategies can be further developed to produce microparticles for advanced drug delivery applications. Microfluidics enables exquisite control in the fabrication of polymer vesicles and thermosensitive microgels from single and higher-order multiple emulsion templates. The strategies used to create the diversity of microparticle structures described in this review, coupled with the scalability of microfluidics, will enable fabrication of large quantities of novel microparticle structures that have potential uses in controlled drug release applications. PMID- 22510962 TI - Facile synthesis of metal-organic framework films via in situ seeding of nanoparticles. AB - A facile in situ nanoparticle seeding method is reported to prepare MIL-101(Cr) films on alumina supports. The in situ seeding of MIL-101(Cr) nanoparticles was promoted by use of dimethylacetamide (DMA). The generality of this approach is further demonstrated for Cu(3)(btc)(2) films by using a (poly)acrylate promoter. PMID- 22510964 TI - Integrated mechanism reviews. PMID- 22510965 TI - Yangonin blocks tumor necrosis factor-alpha-induced nuclear factor-kappaB dependent transcription by inhibiting the transactivation potential of the RelA/p65 subunit. AB - The nuclear factor-kappaB (NF-kappaB) transcription factors control many physiological processes including inflammation, immunity, and apoptosis. In our search for NF-kappaB inhibitors from natural resources, we identified yangonin from Piper methysticum as an inhibitor of NF-kappaB activation. In the present study, we demonstrate that yangonin potently inhibits NF-kappaB activation through suppression of the transcriptional activity of the RelA/p65 subunit of NF kappaB. This compound significantly inhibited the induced expression of the NF kappaB-reporter gene. However, this compound did not interfere with tumor necrosis factor-alpha (TNF-alpha)-induced inhibitor of kappaBalpha (IkappaBalpha) degradation, p65 nuclear translocation, and DNA-binding activity of NF-kappaB. Further analysis revealed that yangonin inhibited not only the induced NF-kappaB activation by overexpression of RelA/p65, but also transactivation activity of RelA/p65. Moreover, yangonin did not inhibit TNF-alpha-induced activation of p38, but it significantly impaired activation of extracellular signal-regulated kinase 1/2 and stress-activated protein kinase/c-Jun NH(2)-terminal kinase. We also demonstrated that pretreatment of cells with this compound prevented TNF-alpha induced expression of NF-kappaB target genes, such as interleukin 6, interleukin 8, monocyte chemotactic protein 1, cyclooxygenase-2 and inducible nitric oxide. Taken together, yangonin could be a valuable candidate for the intervention of NF kappaB-dependent pathological conditions such as inflammation. PMID- 22510966 TI - Anandamide induces endothelium-dependent vasoconstriction and CGRPergic nerve mediated vasodilatation in the rat mesenteric vascular bed. AB - An endogenous cannabinoid anandamide (N-arachidonoylethanolamide) has been shown to cause vasodilatation in vitro and a brief vasoconstriction followed by prolonged depressor response in vivo. This study investigated the vascular effects of anandamide and underlying mechanisms in rat mesenteric vascular beds. In preparations with an intact endothelium and active tone, anandamide at low concentrations (0.1 - 1 nM) caused a concentration-dependent decrease in perfusion pressure due to vasodilatation, but at high concentrations (10 nM - 1 uM) elicited an initial and sharp increase in perfusion pressure due to vasoconstriction followed by long-lasting vasodilatation in a concentration dependent manner. Treatment with SR141716A [cannabinoid-1 (CB(1))-receptor antagonist] blunted both the vasoconstrictor and vasodilator responses. Also, removal of the endothelium and indomethacin (cyclooxygenase inhibitor), but not adrenergic denervation with 6-hydoxydopamine (adrenergic neurotoxin), markedly inhibited the vasoconstrictor response to anandamide, while these treatments did not affect vasodilatation. The vasodilatation, but not vasoconstriction, in response to anandamide was markedly attenuated by capsazepine [selective antagonist for transient receptor potential vanilloid-1 (TRPV1)], pretreatment with capsaicin [calcitonin gene-related peptide (CGRP)ergic-nerve depletor], or cold-storage denervation. These results suggest that in rat mesenteric vascular beds, anandamide causes CB(1)-receptor- and prostanoid-mediated endothelium dependent vasoconstriction and perivascular capsaicin-sensitive CGRPergic nerve mediated vasodilatation. PMID- 22510967 TI - Involvement of guanylate cyclase and K+ channels in relaxation evoked by ferulate nitrate in rat aorta artery. AB - Vasorelaxant properties of N-2-(ferulamidoethyl)-nitrate (ferulate nitrate, FLNT), a newly synthesized nitrate, were compared with those of isosorbide dinitrate, nicorandil, nitroglycerin, and 8-bromoguanosine 3,5-cyclic monophosphate (8-Br-cGMP) in rat aorta pre-contracted by phenylephrine. FLNT produced vasorelaxation in a concentration-dependent manner (0.1 - 100 uM). The degree of relaxation induced by FLNT was similar to that induced by isosorbide dinitrate. In addition, removal of endothelium did not affect the relaxant effect of FLNT. FLNT caused a rightward shift of the cumulative concentration-response curves of phenylephrine and reduced the maximal efficacy of contraction. 1H [1,2,4]Oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 uM) and K(+)-channel blockers charybdotoxin (CHT, 0.1 uM) and BaCl(2) (1 uM) reduced the relaxant effect of FLNT in the endothelium-denuded arteries, whereas glibenclamide (1 uM) and 4 aminopyridine (1 mM) failed to influence FLNT-induced vasorelaxation. Furthermore, in the presence of ODQ, both CHT (0.1 uM) and BaCl(2) (1 uM) still significantly reduced the relaxation evoked by FLNT. Pretreatment of vessels with hydroxocobalamin, a nitric oxide scavenger, abolished the FLNT effect. These findings demonstrate that FLNT induces relaxation of the rat aorta rings endothelium-independently. Furthermore, we demonstrated that FLNT-induced vasorelaxation is related to its stimulation of soluble guanylate cyclase and activation of K(+) channels. PMID- 22510968 TI - Protective effect of sauchinone on methamphetamine-induced neurotoxicity in mice. AB - Sauchinone is a lignan isolated from Saururus chinensis known to suppress nitric oxide (NO) activity. Previous studies demonstrate that NO plays a key role in methamphetamine-induced neurotoxicity. Thus, we hypothesized that sauchinone could have a suppressive effect on the neurotoxicity induced by methamphetamine. Repeated injections of methamphetamine cause degeneration of dopaminergic nerve terminals, whereas sauchinone treatment significantly prevented this degeneration. Sauchinone treatment also inhibited the methamphetamine-induced activation of glia cells and the production of NO via a blockade of inducible NO synthase protein expression. Our results suggest that sauchinone can prevent methamphetamine-induced neurotoxicity through the suppression of NO production. PMID- 22510969 TI - Adrenergic stimulation-released histamine taken-up in adrenergic nerves induces endothelium-dependent vasodilation in rat mesenteric resistance arteries. AB - The present study investigated whether histamine was taken up by perivascular adrenergic nerves and released by periarterial nerve stimulation (PNS) to induce vascular responses. In rat mesenteric vascular beds treated with capsaicin to eliminate calcitonin gene-related peptide (CGRP)ergic vasodilation and with active tone, PNS (1 - 4 Hz) induced only adrenergic nerve-mediated vasoconstriction. Histamine treatment for 20 min induced PNS-induced vasoconstriction followed by vasodilation without affecting CGRP-induced vasodilation. Chlorpheniramine, guanethidine, combination of histamine and desipramine, and endothelium-removal abolished PNS-induced vasodilation in histamine-treated preparations. These results suggest that histamine taken up by and released from adrenergic nerves by PNS causes endothelium-dependent vasodilation in rat mesenteric arteries. PMID- 22510971 TI - Traditional knowledge for promotion of socioeconomic inclusion of local communities. AB - This paper discusses the key role played by public research institutes for promoting socioeconomic inclusion of local communities based on traditional knowledge and traditional medicine. Nongovernmental organizations and cooperatives have had an important role in raising financial resources, being involved with advocacy of local communities and advancing legislation changes. But strict best manufacturing practices regulations imposed by the Brazilian National Health Surveillance Agency on the requirements for approval and commercialization of drugs based on herbal medicine products call for the involvement of strong public research institutes capable of supporting community based pharmacies. Thus, public research institutes are pivotal as they can conduct scientific research studies to evidence the efficacy of herbal medicine products and help building the capacity of local communities to comply with current regulations. PMID- 22510972 TI - Severe acute maternal morbidity: use of the Brazilian Hospital Information System. AB - OBJECTIVE: To estimate the prevalence of severe acute maternal morbitidy and identify its associated hospital procedures. METHODS: Data from the Hospital Information System, obtained from the Municipal Secretariat of Health of the city of Juiz de Fora, Southeastern Brazil, for the years 2006 and 2007, were used. The studied women included those admitted to the hospital for obstetric procedures (n = 8,620), and whose primary diagnosis was included within chapter XV: pregnancy, childbirth and puerperium of the International Classification of Diseases, 10th revision. Codes for routine procedures, special procedures, and professional acts that fulfilled the World Health Organization's criteria for severe acute maternal morbidity were identified, as well as other procedures infrequently employed during pregnancy and the postnatal period. Logistic regression analysis was employed to identify associations between the outcome and selected variables. RESULTS: Prevalence of maternal morbidity was 37.8/1000 women, and that of mortality was 12/100,000 women. Hospitalization for more than 4 days was 13 times more frequent among women with some form of morbidity. After adjustment, predictors of severe acute maternal morbidity were: duration of hospitalization, number of hospitalizations, and still births, and the most frequent procedures and conditions were blood product transfusions (15.7/1,000), "extended stay" (9.5/1.000) and severe pre-eclampsia/eclampsia (8.2/1,000). CONCLUSIONS: Prevalence of severe acute maternal morbidity was high, and was related especially to hospitalization and to newborn variables. The criterion for identifying cases and the use of the National Hospital Information System proved to be useful for monitoring maternal morbidity and mortality and increasing our knowledge of its related aspects, contributing to the improvement of the quality of pregnancy and delivery care. PMID- 22510973 TI - Performance indicators and decision making for outsourcing public health laboratory services. AB - OBJECTIVE: To develop performance indicators for outsourcing clinical laboratory services, based on information systems and public administrative records. METHODS: In the municipality of Rio de Janeiro, Southern Brazil, the public health laboratory network comprised 33 laboratories with automated equipment (but no integrated information system), 90 primary care units (where sample collection was performed) and 983 employees. Information records were obtained from the administrative records of the Budget Information System for Public Health and the Outpatient and Hospital Information System of the Unified Health System. Performance indicators (production, productivity, usage and costs) were generated from data collected routinely from 2006 to 2008. The variations in production, costs and unit prices for tests were analyzed by Laspeyres and Paasche indices, which specifically measure laboratory activity, and by the Consumer Price Index from the Brazilian Institute of Geography and Statistics. RESULTS: A total of 10,359,111 tests were performed in 2008 (10.6% increase over 2006), and the test/employee ratio grew by 8.6%. The costs of supplies, wages and providers increased by 2.3%, 45.4% and 18.3%, respectively. The laboratory tests per visit and hospitalizations increased by 10% and 20%, respectively. The direct costs totaled R$ 63.2 million in 2008, representing an increase of 22.2% in current values during the period analyzed. The direct costs deflated by the Brazilian National Consumer Price Index (9.5% for the period) showed an 11.6% increase in production volumes. The activity-specific volume index, which considers changes in the mix of tests, showed increases of 18.5% in the test price and 3.1% in the production volume. CONCLUSIONS: The performance indicators, particularly the specific indices for volume and price of activity, constitute a baseline of performance potential for monitoring private laboratories and contractors. The economic performance indicators demonstrated the need for network information system integration prior to an outsourcing decision. PMID- 22510974 TI - Promotion, prevention and arterial hypertension care in Brazil. AB - OBJECTIVE: To estimate the prevalence of promotion, prevention and arterial hypertension care actions in adults and to identify their association with decompensated hypertension. METHODS: A population-based cross-sectional epidemiological study was conducted by interviewing 12,324 adults aged from 20 to 59 years, in 100 Brazilian cities. The independent variables considered as promotion, prevention and hypertension care were as follows: to have received guidance on ideal weight maintenance and physical activity practice; to have consulted a doctor; and to have had an electrocardiogram performed in the previous year. A blood pressure higher than 140/90 mm/Hg was considered to be decompensated, being the dependent variable adopted to assess quality of care. RESULTS: Of all participants, 16.3% (n = 2,004) reported a medical diagnosis of hypertension. The highest prevalences of hypertension were observed in the 50 to 59 year age group, primarily in the Southeast and Center-West regions. More than half (66.1%) of participants had a medical consultation about hypertension in the previous year, of which half (52.4%) had an electrocardiogram. Of all those with hypertension who had their blood pressure measured during interview (74.6%), less than half (42.4%) had decompensated values. CONCLUSIONS: There was no association between having consulted a doctor in the previous year and decompensated blood pressure values. The proportion of decompensated hypertensive participants was significantly lower among those who had received guidance on ideal weight maintenance and physical activity practice and those who had had an electrocardiogram performed. The following factors were associated with decompensated hypertension: to be male, to be aged more than 40 years and to live in the South region. PMID- 22510975 TI - Physical activity practice and associated factors in adolescents in Northeastern Brazil. AB - OBJECTIVE: To estimate the proportion of physically active adolescents and identify associated factors. METHODS: The sample was composed of 2,874 high school students (public and private schools) aged 14 to 19 years in the city of Joao Pessoa, Northeastern Brazil. Physical activity level was measured by means of a questionnaire and considered physically active if > 300 minutes/week. Sociodemographic variables were analyzed, as well as nutritional status, sedentary behavior, self-report of health status and participation in physical education classes. The prevalence ratio was used as association measure, estimated by means of Poisson regression. RESULTS: The prevalence of physical activity was 50.2% (95%CI: 47.3;53.1). Male adolescents were more physically active than female adolescents (66.3% vs. 38.5%; p<0.001). The factors directly associated with practice of physical activity were: father's higher level of schooling for the male sex and mother's higher level of schooling for the female sex, positive self-reported health status, and participation in physical education classes. CONCLUSIONS: The majority of the adolescents was classified as physically active, particularly the male youths. Adolescents with parents whose level of schooling was higher, with positive health status perception, and who participated in physical education classes were more likely to be physically active. PMID- 22510976 TI - Size-induced distortions in perceptual maps of visual space. AB - In order to interact with our environment, the human brain constructs maps of visual space. The orderly mapping of external space across the retinal surface, termed retinotopy, is maintained at subsequent levels of visual cortical processing and underpins our capacity to make precise and reliable judgments about the relative location of objects around us. While these maps, at least in the visual system, support high precision judgments about the relative location of objects, they are prone to significant perceptual distortion. Here, we ask observers to estimate the separation of two visual stimuli--a spatial interval discrimination task. We show that large stimulus sizes require much greater separation in order to be perceived as having the same separation as small stimulus sizes. The relationship is linear, task independent, and unrelated to the perceived position of object edges. We also show that this type of spatial distortion is not restricted to the object itself but can also be revealed by changing the spatial scale of the background, while object size remains constant. These results indicate that fundamental spatial properties, such as retinal image size or the scale at which an object is analyzed, exert a marked influence on spatial coding. PMID- 22510977 TI - Evidence for two distinct mechanisms directing gaze in natural scenes. AB - Various models have been proposed to explain the interplay between bottom-up and top-down mechanisms in driving saccades rapidly to one or a few isolated targets. We investigate this relationship using eye-tracking data from subjects viewing natural scenes to test attentional allocation to high-level objects within a mathematical decision-making framework. We show the existence of two distinct types of bottom-up saliency to objects within a visual scene, which disappear within a few fixations, and modification of this saliency by top-down influences. Our analysis reveals a subpopulation of early saccades, which are capable of accurately fixating salient targets after prior fixation within the same image. These data can be described quantitatively in terms of bottom-up saliency, including an explicit face channel, weighted by top-down influences, determining the mean rate of rise of a decision-making model to a threshold that triggers a saccade. These results are compatible with a rapid subcortical pathway generating accurate saccades to salient targets after analysis by cortical mechanisms. PMID- 22510979 TI - Small median tumor diameter at cure threshold (<20 mm) among aggressive non-small cell lung cancers in male smokers predicts both chest X-ray and CT screening outcomes in a novel simulation framework. AB - The effectiveness of population-wide lung cancer screening strategies depends on the underlying natural course of lung cancer. We evaluate the expected stage distribution in the Mayo CT screening study under an existing simulation model of non-small cell lung cancer (NSCLC) progression calibrated to the Mayo lung project (MLP). Within a likelihood framework, we evaluate whether the probability of 5-year NSCLC survival conditional on tumor diameter at detection depends significantly on screening detection modality, namely chest X-ray and computed tomography. We describe a novel simulation framework in which tumor progression depends on cellular proliferation and mutation within a stem cell compartment of the tumor. We fit this model to randomized trial data from the MLP and produce estimates of the median radiologic size at the cure threshold. We examine the goodness of model fit with respect to radiologic tumor size and 5-year NSCLC survival among incident cancers in both the MLP and Mayo CT studies. An existing model of NSCLC progression under-predicts the number of advanced-stage incident NSCLCs among males in the Mayo CT study (p-value = 0.004). The probability of 5 year NSCLC survival conditional on tumor diameter depends significantly on detection modality (p-value = 0.0312). In our new model, selected solution sets having a median tumor diameter of 16.2-22.1 mm at cure threshold among aggressive NSCLCs predict both MLP and Mayo CT outcomes. We conclude that the median lung tumor diameter at cure threshold among aggressive NSCLCs in male smokers may be small (<20 mm). PMID- 22510978 TI - Biosensor zebrafish provide new insights into potential health effects of environmental estrogens. AB - BACKGROUND: Environmental estrogens alter hormone signaling in the body that can induce reproductive abnormalities in both humans and wildlife. Available testing systems for estrogens are focused on specific systems such as reproduction. Crucially, however, the potential for significant health impacts of environmental estrogen exposures on a variety of body systems may have been overlooked. OBJECTIVE: Our aim was to develop and apply a sensitive transgenic zebrafish model to assess real-time effects of environmental estrogens on signaling mechanisms in a whole body system for use in integrated health assessments. METHODS: We created a novel transgenic biosensor zebrafish containing an estrogen inducible promoter derived with multiple tandem estrogen responsive elements (EREs) and a Gal4ff-UAS system for enhanced response sensitivity. RESULTS: Using our novel estrogen-responsive transgenic (TG) zebrafish, we identified target tissues for environmental estrogens; these tissues have very high sensitivity even at environmentally relevant concentrations. Exposure of the TG fish to estrogenic endocrine-disrupting chemicals (EDCs) induced specific expression of green fluorescent protein (GFP) in a wide variety of tissues including the liver, heart, skeletal muscle, otic vesicle, forebrain, lateral line, and ganglions, most of which have not been established previously as targets for estrogens in fish. Furthermore, we found that different EDCs induced GFP expression with different tissue response patterns and time trajectories, suggesting different potential health effects. CONCLUSION: We have developed a powerful new model for understanding toxicological effects, mechanisms, and health impacts of environmental estrogens in vertebrates. PMID- 22510980 TI - Acute lymphocytic leukemia with eosinophilia: a case report and review of the literature. AB - We present a 61-year-old man with marked peripheral blood eosinophilia, feature of hypereosinophilic syndrome, that later evolved into acute lymphocytic leukemia (ALL-L2). Initially the patient suffered from significant complications related to eosinophilic toxicity, including large urticarial hyperpigmented plaques, myocardial infarction, and eosinophilic pneumonia. He was treated with high dose of steroids resulting in a rapid suppression of the eosinophilia. Two weeks later, the eosinophilia had relapsed, so a bone marrow aspiration was performed. Cytomorphological examination of the bone marrow showed typical ALL features, while flow cytometric analysis revealed an My+pre-B-ALL immunophenotype, and chromosome analysis of bone marrow showed a normal karyotype. He received chemotherapy according to the standard protocol for ALL and died from refractory respiratory failure and congestive heart failure immediately after antileukemic therapy. We review the literature and compare the demographics, clinical features, and outcomes of several cases and reported studies. PMID- 22510981 TI - Capacitance-based droplet position estimator for digital microfluidic devices. AB - Digital microfluidic (DMF) devices manipulate minuscule droplets through basic fluidic operations including droplet transport, mixing and splitting commonly known as the building blocks for complete laboratory analyses on a single device. A DMF device can house various chemical species and confine chemical reactions within the volume of a droplet much like a micro-reactor. The automation of fluidic protocols requires a feedback controller whose sensor is capable of locating droplets independent of liquid composition (or previous knowledge of liquid composition). In this research, we present an estimator that tracks the continuous displacement of a droplet between electrodes of a DMF device. The estimator uses a dimensionless ratio of two electrode capacitances to approximate the position of a droplet, even, in the domain between two adjacent electrodes. This droplet position estimator significantly enhances the control precision of liquid handling in DMF devices compared to that of the techniques reported in the literature. It captures the continuous displacement of a droplet; valuable information for a feedback controller to execute intricate fluidic protocols including droplet positioning between electrodes, droplet velocity and acceleration control. We propose a state estimator for tracking the continuous droplet displacement between two adjacent electrodes. The dimensionless nature of this estimator means that any droplet composition can be sensed. Thus, no calibration for each chemical species within a single DMF device is required. We present theoretical and experimental results that demonstrate the efficacy of the position estimator in approximating the position of the droplet in the interval between two electrodes. PMID- 22510982 TI - Pathogenesis of the antiphospholipid syndrome. AB - The presence of pathogenic antiphospholipid antibodies (aPL) is the characterizing feature of the antiphospholipid syndrome (APS), mediating the recurrent pregnancy loss and thrombosis typical of the disease, through their action on various antigenic targets. Despite the available knowledge regarding the mechanisms by which aPL induce a procoagulant phenotype in the vasculature and abnormal cellular proliferation and differentiation in placental tissues to cause the typical clinical features, these processes still remain incompletely understood. It is also known that inflammation serves as a necessary link between the observed procoagulant phenotype and actual thrombus development, and is an important mediator of the placental injury in APS patients. Even less well understood are the processes underlying the ontogeny of these pathogenic antibodies. This review seeks to highlight what is known about the mechanisms that contribute to the origin of pathogenic aPL and to the action of these antibodies on target antigens that produce the pathological features of APS. We will also examine the feasibility of classifying patients in clinical phenotypes related to underlying pathophysiological mechanisms, and how this could impact the management of patients with novel "targeted" therapeutic strategies. PMID- 22510983 TI - Mechanisms of tissue fusion during development. AB - Tissue fusion events during embryonic development are crucial for the correct formation and function of many organs and tissues, including the heart, neural tube, eyes, face and body wall. During tissue fusion, two opposing tissue components approach one another and integrate to form a continuous tissue; disruption of this process leads to a variety of human birth defects. Genetic studies, together with recent advances in the ability to culture developing tissues, have greatly enriched our knowledge of the mechanisms involved in tissue fusion. This review aims to bring together what is currently known about tissue fusion in several developing mammalian organs and highlights some of the questions that remain to be addressed. PMID- 22510984 TI - Dual role for Insulin/TOR signaling in the control of hematopoietic progenitor maintenance in Drosophila. AB - The interconnected Insulin/IGF signaling (IlS) and Target of Rapamycin (TOR) signaling pathways constitute the main branches of the nutrient-sensing system that couples growth to nutritional conditions in Drosophila. Here, we addressed the influence of these pathways and of diet restriction on the balance between the maintenance of multipotent hematopoietic progenitors and their differentiation in the Drosophila lymph gland. In this larval hematopoietic organ, a pool of stem-like progenitor blood cells (prohemocytes) is kept undifferentiated in response to signaling from a specialized group of cells forming the posterior signaling center (PSC), which serves as a stem cell niche. We show that, reminiscent of the situation in human, loss of the negative regulator of IIS Pten results in lymph gland hyperplasia, aberrant blood cell differentiation and hematopoietic progenitor exhaustion. Using site-directed loss and gain-of-function analysis, we demonstrate that components of the IIS/TOR pathways control lymph gland homeostasis at two levels. First, they cell autonomously regulate the size and activity of the hematopoietic niche. Second, they are required within the prohemocytes to control their growth and maintenance. Moreover, we show that diet restriction or genetic alteration mimicking amino acid deprivation triggers progenitor cell differentiation. Hence, our study highlights the role of the IIS/TOR pathways in orchestrating hematopoietic progenitor fate and links blood cell fate to nutritional status. PMID- 22510985 TI - Hormonal activation of let-7-C microRNAs via EcR is required for adult Drosophila melanogaster morphology and function. AB - Steroid hormones and their nuclear receptors drive developmental transitions in diverse organisms, including mammals. In this study, we show that the Drosophila steroid hormone 20-hydroxyecdysone (20E) and its nuclear receptor directly activate transcription of the evolutionarily conserved let-7-complex (let-7-C) locus, which encodes the co-transcribed microRNAs miR-100, let-7 and miR-125. These small RNAs post-transcriptionally regulate the expression of target genes, and are required for the remodeling of the Drosophila neuromusculature during the larval-to-adult transition. Deletion of three 20E responsive elements located in the let-7-C locus results in reduced levels of let-7-C microRNAs, leading to neuromuscular and behavioral defects in adults. Given the evolutionary conservation of let-7-C microRNA sequences and temporal expression profiles, these findings indicate that steroid hormone-coupled control of let-7-C microRNAs is part of an ancestral pathway controlling the transition from larval-to reproductive animal forms. PMID- 22510986 TI - Functional interactions between Fat family cadherins in tissue morphogenesis and planar polarity. AB - The atypical cadherin fat (ft) was originally discovered as a tumor suppressor in Drosophila and later shown to regulate a form of tissue patterning known as planar polarity. In mammals, four ft homologs have been identified (Fat1-4). Recently, we demonstrated that Fat4 plays a role in vertebrate planar polarity. Fat4 has the highest homology to ft, whereas other Fat family members are homologous to the second ft-like gene, ft2. Genetic studies in flies and mice imply significant functional differences between the two groups of Fat cadherins. Here, we demonstrate that Fat family proteins act both synergistically and antagonistically to influence multiple aspects of tissue morphogenesis. We find that Fat1 and Fat4 cooperate during mouse development to control renal tubular elongation, cochlear extension, cranial neural tube formation and patterning of outer hair cells in the cochlea. Similarly, Fat3 and Fat4 synergize to drive vertebral arch fusion at the dorsal midline during caudal vertebra morphogenesis. We provide evidence that these effects depend on conserved interactions with planar polarity signaling components. In flies, the transcriptional co-repressor Atrophin (Atro) physically interacts with Ft and acts as a component of Fat signaling for planar polarity. We find that the mammalian orthologs of atro, Atn1 and Atn2l, modulate Fat4 activity during vertebral arch fusion and renal tubular elongation, respectively. Moreover, Fat4 morphogenetic defects are enhanced by mutations in Vangl2, a 'core' planar cell polarity gene. These studies highlight the wide range and complexity of Fat activities and suggest that a Fat-Atrophin interaction is a conserved element of planar polarity signaling. PMID- 22510988 TI - Identification of molecular compartments and genetic circuitry in the developing mammalian kidney. AB - Lengthy developmental programs generate cell diversity within an organotypic framework, enabling the later physiological actions of each organ system. Cell identity, cell diversity and cell function are determined by cell type-specific transcriptional programs; consequently, transcriptional regulatory factors are useful markers of emerging cellular complexity, and their expression patterns provide insights into the regulatory mechanisms at play. We performed a comprehensive genome-scale in situ expression screen of 921 transcriptional regulators in the developing mammalian urogenital system. Focusing on the kidney, analysis of regional-specific expression patterns identified novel markers and cell types associated with development and patterning of the urinary system. Furthermore, promoter analysis of synexpressed genes predicts transcriptional control mechanisms that regulate cell differentiation. The annotated informational resource (www.gudmap.org) will facilitate functional analysis of the mammalian kidney and provides useful information for the generation of novel genetic tools to manipulate emerging cell populations. PMID- 22510989 TI - The design of long-term effective uranium bioremediation strategy using a community metabolic model. AB - Acetate amendment at uranium contaminated sites in Rifle, CO. leads to an initial bloom of Geobacter accompanied by the removal of U(VI) from the groundwater, followed by an increase of sulfate-reducing bacteria (SRBs) which are poor reducers of U(VI). One of the challenges associated with bioremediation is the decay in Geobacter abundance, which has been attributed to the depletion of bio accessible Fe(III), motivating the investigation of simultaneous amendments of acetate and Fe(III) as an alternative bioremediation strategy. In order to understand the community metabolism of Geobacter and SRBs during artificial substrate amendment, we have created a genome-scale dynamic community model of Geobacter and SRBs using the previously described Dynamic Multi-species Metabolic Modeling framework. Optimization techniques are used to determine the optimal acetate and Fe(III) addition profile. Field-scale simulation of acetate addition accurately predicted the in situ data. The simulations suggest that batch amendment of Fe(III) along with continuous acetate addition is insufficient to promote long-term bioremediation, while continuous amendment of Fe(III) along with continuous acetate addition is sufficient to promote long-term bioremediation. By computationally minimizing the acetate and Fe(III) addition rates as well as the difference between the predicted and target uranium concentration, we showed that it is possible to maintain the uranium concentration below the environmental safety standard while minimizing the cost of chemical additions. These simulations show that simultaneous addition of acetate and Fe(III) has the potential to be an effective uranium bioremediation strategy. They also show that computational modeling of microbial community is an important tool to design effective strategies for practical applications in environmental biotechnology. PMID- 22510987 TI - The novel intestinal filament organizer IFO-1 contributes to epithelial integrity in concert with ERM-1 and DLG-1. AB - The nematode Caenorhabditis elegans is an excellent model system in which to study in vivo organization and function of the intermediate filament (IF) system for epithelial development and function. Using a transgenic ifb-2::cfp reporter strain, a mutagenesis screen was performed to identify mutants with aberrant expression patterns of the IF protein IFB-2, which is expressed in a dense network at the subapical endotube just below the microvillar brush border of intestinal cells. Two of the isolated alleles (kc2 and kc3) were mapped to the same gene, which we refer to as ifo-1 (intestinal filament organizer). The encoded polypeptide colocalizes with IF proteins and F-actin in the intestine. The apical localization of IFO-1 does not rely on IFB-2 but is dependent on LET 413, a basolateral protein involved in apical junction assembly and maintenance of cell polarity. In mutant worms, IFB-2 and IFC-2 are mislocalized in cytoplasmic granules and accumulate in large aggregates at the C. elegans apical junction (CeAJ) in a DLG-1-dependent fashion. Electron microscopy reveals loss of the prominent endotube and disordered but still intact microvilli. Semiquantitative fluorescence microscopy revealed a significant decrease of F actin, suggesting a general role of IFO-1 in cytoskeletal organization. Furthermore, downregulation of the cytoskeletal organizer ERM-1 and the adherens junction component DLG-1, each of which leads to F-actin reduction on its own, induces a novel synthetic phenotype in ifo-1 mutants resulting in disruption of the lumen. We conclude that IFO-1 is a multipurpose linker between different cytoskeletal components of the C. elegans intestinal terminal web and contributes to proper epithelial tube formation. PMID- 22510990 TI - AKT-dependent phosphorylation of Niban regulates nucleophosmin- and MDM2-mediated p53 stability and cell apoptosis. AB - Although Niban is highly expressed in human cancer cells, the cellular functions of Niban remain largely unknown. We demonstrate here that ultraviolet irradiation induces phosphorylation of Niban at S602 by AKT, which increases the association of Niban with nucleophosmin and disassociation of nucleophosmin from the MDM2 complex. This leads to the promotion of MDM2-p53 interaction and subsequent p53 degradation, thereby providing an antiapoptotic effect. Conversely, depletion of or deficiency in Niban expression promotes stabilization of p53 with increased cell apoptosis. Our findings illustrate a pivotal role for AKT-mediated phosphorylation of Niban in protecting cells from genotoxic stress-induced cell apoptosis. PMID- 22510991 TI - Mechanical strengthening of fiberoptic microneedles using an elastomeric support. AB - BACKGROUND AND OBJECTIVES: Microneedles made from silica fiberoptics permit transmission and collection of light, which is an important functional advantage over metal or silicon microneedles. This added functionality may enhance or even enable new percutaneous light-based clinical diagnostic and therapeutic procedures. Micron-diameter fiberoptic microneedles, created from solid fibers capable of light emission and detection, are designed to penetrate several millimeters into tissue while minimizing tissue invasion and disruption. The mechanical strength (critical buckling force) of high aspect ratio (length to diameter) microneedles is a potential problem, which has motivated our invention of an elastomeric support device. In this study, we have tested our hypothesis that embedding the microneedles in an elastomeric support medium may increase microneedle critical buckling force. MATERIALS AND METHODS: The critical buckling force of silica microneedles with 55, 70, and 110 um diameters and 3 mm lengths were measured with and without a surrounding elastomeric support (PDMS, polydimethylsiloxane). These experimental results were compared to theoretical calculations generated by the Rayleigh-Ritz buckling model. The insertion force required to penetrate ex vivo porcine skin was measured for microneedles with 55 and 70 um diameters. RESULTS: Use of the PDMS support increased critical buckling force for microneedles of 55, 70, and 110 um diameters by an average of 610%, 290%, and 33%, respectively. Theoretical calculations by the Rayleigh-Ritz model consistently overestimated the experimentally determined strengthening, but correlated highly with the greater enhancement offered to thinner microneedles. Aided by mechanical strengthening, microneedles 55 um in diameter were able to repeatedly penetrate. CONCLUSIONS: The critical buckling force of microneedles can be increased substantially to allow extremely high-aspect ratio microneedles, 55-110 um in diameter and 3 mm in length, to penetrate ex vivo porcine skin. By this strengthening method, the safety and reliability of microneedles in potential clinical applications can be considerably enhanced. PMID- 22510992 TI - Impact of 4.0% chlorhexidine cord cleansing on the bacteriologic profile of the newborn umbilical stump in rural Sylhet District, Bangladesh: a community-based, cluster-randomized trial. AB - BACKGROUND: Randomized trials from South Asia indicate umbilical cord chlorhexidine cleansing reduces mortality and omphalitis. No community-based data are available on bacteriological profile of the cord, early neonatal colonization dynamics, or impact of cord cleansing on colonizing organisms. Such data could clarify the design of scaled chlorhexidine interventions. METHODS: Umbilical swabs were collected at home (days 1, 3, 6) after birth from infants participating in a trial of 3 cord-care regimens (no chlorhexidine, single cleansing, multiple cleansing) in Sylhet, Bangladesh. Overall and organism specific positivity rates were estimated by cord-care regimen and by day of collection. RESULTS: Between September 2008 and October 2009, 1923 infants contributed 5234 umbilical swabs. Positivity rate was high (4057 of 5234, 77.5%) and varied substantially across groups. Immediate (day 1) reductions in cord colonization were observed in single- (prevalence rate ratio = 0.75, 95% confidence interval: 0.70-0.81) and multiple- (prevalence rate ratio = 0.71, 95% confidence interval: 0.66-0.77) cleansing groups. Reductions persisted and increased in magnitude through day 6 only if babies received multiple applications. On days 1, 3, and 6, respectively, multiple cleansing consistently reduced invasive organisms such as Escherichia coli (49%, 64%, and 42% lower), Klebsiella pneumoniae (46%, 53%, and 33% lower), and Staphylococcus aureus (34%, 84%, and 85% lower). CONCLUSIONS: Cord cleansing with 4.0% chlorhexidine immediately after birth reduces overall and organism-specific colonization of the stump. Reductions are greater and sustained longer with daily cleansing through the first week of life, suggesting that programs promoting chlorhexidine cleansing should favor multiple over single applications. PMID- 22510993 TI - Six-week-old with fever and fussiness. PMID- 22510994 TI - Respiratory syncytial virus in Indonesian children. PMID- 22510996 TI - White blood cell counts in neonatal early-onset sepsis. PMID- 22510998 TI - Cardiobacterium hominis is a rare cause of neonatal sepsis. PMID- 22510999 TI - Primary group A streptococcal peritonitis in a previously healthy child. PMID- 22511000 TI - Gonococcal septic shock associated with eculizumab treatment. PMID- 22511003 TI - Laparoscopic distal pancreatectomy is associated with significantly less overall morbidity compared to the open technique: a systematic review and meta-analysis. AB - OBJECTIVE: To compare laparoscopic distal pancreatectomy (LDP) versus open distal pancreatectomy (ODP) by using meta-analytical techniques. BACKGROUND: LDP is increasingly performed as an alternative approach for distal pancreatectomy in selected patients. Multiple studies have tried to assess the safety and efficacy of LDP compared with ODP. METHODS: A systematic review of the literature was performed to identify studies comparing LDP and ODP. Intraoperative outcomes, postoperative recovery, oncologic safety, and postoperative complications were evaluated. Meta-analysis was performed using a random-effects model. RESULTS: Eighteen studies matched the selection criteria, including 1814 patients (43% laparoscopic, 57% open). LDP had lower blood loss by 355 mL (P < 0.001) and hospital length of stay by 4.0 days (P < 0.001). Overall complications were significantly lower in the laparoscopic group (33.9% vs 44.2%; odds ratio [OR] = 0.73, 95% confidence interval [CI] 0.57-0.95), as was surgical site infection (2.9% vs 8.1%; OR = 0.45, 95% CI 0.24-0.82). There was no difference in operative time, margin positivity, incidence of postoperative pancreatic fistula, and mortality. CONCLUSIONS: LDP has lower blood loss and reduced length of hospital stay. There was a lower risk of overall postoperative complications and wound infection, without a substantial increase in the operative time. Although a thorough evaluation of oncological outcomes was not possible, the rate of margin positivity was comparable to the open technique. The improved complication profile of LDP, taken together with the lack of compromise of margin status, suggests that this technique is a reasonable approach in selected cancer patients. PMID- 22511004 TI - The potential energy surface of isomerising disilyne. AB - A (semi-)global, analytical potential energy surface is reported for the ground electronic state of the isomerising disilyne molecule, Si2H2. The surface reproduces well ab initio energies calculated at the CCSD(T) level with a cc pV(Q+d)Z basis set for over 50 000 symmetrically unique molecular geometries. Of these ab initio points, 33 000 were used in a least-squares fit to determine the parameters of the analytical surface and the remainder to provide an independent test/validation set. The fitted surface includes: the four known isomeric forms of disilyne, dibridged, monobridged, disilavinylidene and trans-bent; the three most important transition states and four other critical points. The surface reproduces accurately existing experimental spectroscopic data for the dibridged and monobridged isomers and predictions are made for the disilavinylidene and trans-bent forms. The surface has the correct symmetry properties with respect to permutation of like atoms and is suitable for detailed dynamics studies of the isomerising Si2H2 system. Also reported is a systematic investigation of the critical points using the CCSD(T) and MRCI methods and basis sets up to 6-zeta quality: the effects of core-correlation, augmentation with diffuse functions and tight-d functions have been studied. The basis sets include the correlation consistent core-valence, cc-pCV(n+d)Z, basis sets recently developed by Yockel and Wilson [Theor. Chem. Acc., 2008, 120, 119]. Very good agreement is obtained between the theoretical and experimental equilibrium geometries, rotational constants and three available vibration frequencies for the dibridged isomer and for the rotational constants of the monobridged isomer. Multireference character, as measured by the T1 diagnostic, is found to vary significantly across the 12 critical points investigated. PMID- 22511005 TI - Towards enhancing light harvesting-subphthalocyanines as electron acceptors. AB - One carbon atom is too many. Two subphthalocyanine-extended TTF electron donor acceptor conjugates were synthesized and characterized. Their photophysical properties prompt the remarkable impact that one extra carbon between the two constitutents exerts on photoinduced processes, that is, charge recombination dynamics in the normal versus inverted region. PMID- 22511006 TI - Individual patient data subgroup meta-analysis of surgery for spontaneous supratentorial intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: By 2010 there had been 14 published trials of surgery for intracerebral hemorrhage reported in systematic reviews or to the authors, but the role and timing of operative intervention remain controversial and the practice continues to be haphazard. This study attempted to obtain individual patient data from each of the 13 studies published since 1985 to better define groups of patients that might benefit from surgery. METHODS: Authors of identified published articles were approached by mail, e-mail, and at conferences and invited to take part in the study. Data were obtained from 8 studies (2186 cases). Individual patient data included patient's age, Glasgow Coma Score at presentation, volume and site of hematoma, presence of intraventricular hemorrhage, method of evacuation, time to randomization, and outcome. RESULTS: Meta-analysis indicated that there was improved outcome with surgery if randomization was [corrected] undertaken within 8 hours of ictus (P=0.003), or the volume of the hematoma was 20 to 50 mL (P=0.004), or the Glasgow Coma Score was between 9 and 12 (P=0.0009), or the patient was aged between 50 and 69 years (P=0.01). In addition, there was some evidence that more superficial hematomas with no intraventricular hemorrhage might also benefit (P=0.09). CONCLUSIONS: There is evidence that surgery is of benefit if undertaken early before the patient deteriorates. This work identifies areas for further research. Ongoing studies in subgroups of patients such as the Surgical Trial in Lobar Intracerebral Hemorrhage (STICH II) will confirm whether these interpretations can be replicated. PMID- 22511007 TI - The role of norepinephrine and estradiol in the pathogenesis of cardiac wall motion abnormality associated with subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: The majority of patients with ventricular wall motion abnormality (WMA) associated with subarachnoid hemorrhage (SAH) are postmenopausal women. In addition to elevated catecholamine, the role of estrogen in the pathogenesis of WMA has recently been implicated. The objective of this study is to clarify the interrelation among catecholamine, estrogen, and WMA in patients with SAH. METHODS: A retrospective analysis was performed on the medical records of 77 patients with SAH (23 men, 54 women) whose plasma levels of epinephrine, norepinephrine, and estradiol had been measured and echocardiograms had been obtained within 48 hours of SAH onset. RESULTS: Twenty-four patients (31%) were found to sustain WMA on admission. Multivariate regression analysis revealed that decreased estradiol (P=0.018; OR, 0.902) and elevated norepinephrine levels (P=0.027; OR, 1.002) were associated with WMA. After quadrichotomization of 77 patients based on sex/WMA, plasma norepinephrine levels were markedly elevated in men with WMA, whereas estradiol levels were markedly decreased in women with WMA. Plasma norepinephrine and estradiol levels were not correlated. Fifty-four female patients with SAH were further quadrichotomized based on norepinephrine/estradiol levels with a threshold value of 1375 pg/mL for norepinephrine and 11 pg/mL for estradiol. The incidence of WMA in the high norepinephrine/low-estradiol group was significantly higher than the low norepinephrine/high-estradiol group. CONCLUSIONS: To our knowledge, this is the first study to evaluate the interrelation among catecholamine, estrogen, and SAH induced WMA. Lack of estradiol in postmenopausal women may predispose them to develop WMA after poor-grade SAH. However, the precise role of multiple sex hormones in SAH-induced WMA should be evaluated in future prospective studies. PMID- 22511008 TI - Hematopoietic progenitor cells and restenosis after carotid endarterectomy. AB - BACKGROUND AND PURPOSE: Hematopoietic progenitor cells (HPCs) may attenuate the response to vascular injury by maintaining endothelial integrity and function. Our aim was to determine whether circulating HPC number and function correlate with restenosis after carotid endarterectomy. METHODS: HPC number (CD34(+)/CD133(+) cells), early colony-forming units, migratory capacity, and senescence were analyzed in blood collected preoperatively, 1 day, and 6 weeks postoperatively. Mobilizing cytokine levels were also measured. Stenosis was assessed by duplex scanning. RESULTS: HPC numbers (P<0.001) and early colony forming unit count (P=0.001) fell rapidly 24 hours postoperatively. Restenosis at 6 months correlated negatively with the magnitude of postoperative falls in HPC numbers (R=-0.38, P=0.013) and early colony-forming unit counts (R=-0.42, P=0.008). The migratory capacity of preoperative HPCs correlated negatively with restenosis (R=-0.48, P=0.007). Preoperative SDF1 levels correlated with falls in HPC number (R=0.42, P=0.044) and early colony-forming unit counts (R=0.56, P=0.004). CONCLUSIONS: HPC function appears to be linked to the development of carotid artery restenosis after endarterectomy. These data support the concept that HPCs have a role in regulating remodeling of the injured arterial wall. PMID- 22511010 TI - Carotid artery anatomy and geometry as risk factors for carotid atherosclerotic disease. AB - BACKGROUND AND PURPOSE: Traditional vascular risk factors do not completely explain the asymmetry, racial, and sex differences in carotid artery disease. Carotid anatomy and geometry may play a role in the pathogenesis of internal carotid artery (ICA) stenosis, but their effects are unknown. We hypothesized that carotid artery anatomy and geometry would be independently associated with ICA stenosis. METHOD: This is a retrospective study of patients with CT angiography at Monash Medical Centre, 2006 to 2007. Carotid arteries were segmented using semiautomated methods to estimate measures of carotid anatomy and geometry. Measurements of carotid artery geometry were performed according to the recent article by Thomas and colleagues. ICA stenosis was dichotomized as <30% or >= 30% stenosis. Cluster logistic regression was used to examine the associations of anatomy and geometry with stenosis accounting for the paired arteries within subjects, adjusting for age, sex, and vascular risk factors. RESULTS: Mean age of the sample (n=178) was 68.4 years (SD, 14 years). The following were independently associated with ICA stenosis: ICA radius at the bifurcation (OR, 0.20; 95% CI, 0.14-0.29), ICA angle (OR, 1.05 per degree increment; 95% CI, 1.04 1.07), age (OR, 1.05 per year increment; 95% CI, 1.03-1.07), male sex (OR, 1.72; 95% CI, 1.08-2.8), and ever-smoker (OR, 1.85; 95% CI, 1.15-2.96). CONCLUSIONS: Carotid anatomy and geometry may enhance the risk of stenosis independent of traditional vascular risk factors and may be of help in very early identification of patients at high risk of developing carotid artery atherosclerosis for aggressive intervention. PMID- 22511009 TI - Asiatic acid attenuates infarct volume, mitochondrial dysfunction, and matrix metalloproteinase-9 induction after focal cerebral ischemia. AB - BACKGROUND AND PURPOSE: Asiatic acid (AA) has been shown to attenuate cerebral infarction in a mouse model of focal ischemia and shows promise as a neuroprotective stroke therapy. To facilitate translation of these findings to clinical studies, we determined pharmacokinetics, a dose-response relationship, the therapeutic time window, and efficacy using multiple stroke models. We also explored potential mechanisms of action. METHODS: Escalating doses of intravenous AA were administered and serum concentrations were measured at multiple time points for the pharmacokinetic studies. Subsequently, a dose-response relationship was determined followed by administration at different intervals after the onset of ischemia to establish a therapeutic time window for neuroprotection. Outcome measurements included both histological and behavioral. Mitochondrial function and matrix metalloproteinase activity in controls and treated rats were also determined. RESULTS: The pharmacokinetic studies showed that AA (75 mg/kg) has a half-life of 2.0 hours. AA significantly decreased infarct volume and improved neurological outcome even when administration was at time points up to 12 hours after the onset of ischemia. Infarct volume was also significantly decreased in female rats and spontaneously hypertensive rats. AA attenuated mitochondrial dysfunction and reduced matrix metalloproteinase-9 induction. CONCLUSIONS: Our study shows AA is effective against multiple models of focal ischemia, has a long therapeutic time window, and is also effective in females and hypertensive animals. AA may mediate neuroprotection by protecting mitochondria and inhibiting matrix metalloproteinase-9 induction and activation. Taken together these data suggest that AA is an excellent candidate for development as a stroke therapy. PMID- 22511011 TI - What causes hematoma enlargement in lobar intracerebral hemorrhage?: novel insights from a genetic study. PMID- 22511012 TI - There is still hope for surgery for spontaneous supratentorial intracerebral hemorrhage. PMID- 22511013 TI - Human fetal testis xenografts are resistant to phthalate-induced endocrine disruption. AB - BACKGROUND: In utero exposure to endocrine-disrupting chemicals may contribute to testicular dysgenesis syndrome (TDS), a proposed constellation of increasingly common male reproductive tract abnormalities (including hypospadias, cryptorchidism, hypospermatogenesis, and testicular cancer). Male rats exposed in utero to certain phthalate plasticizers exhibit multinucleated germ cell (MNG) induction and suppressed steroidogenic gene expression and testosterone production in the fetal testis, causing TDS-consistent effects of hypospadias and cryptorchidism. Mice exposed to phthalates in utero exhibit MNG induction only. This disparity in response demonstrates a species-specific sensitivity to phthalate-induced suppression of fetal Leydig cell steroidogenesis. Importantly, ex vivo phthalate exposure of the fetal testis does not recapitulate the species specific endocrine disruption, demonstrating the need for a new bioassay to assess the human response to phthalates. OBJECTIVES: In this study, we aimed to develop and validate a rat and mouse testis xenograft bioassay of phthalate exposure and examine the human fetal testis response. METHODS: Fetal rat, mouse, and human testes were xenografted into immunodeficient rodent hosts, and hosts were gavaged with a range of phthalate doses over multiple days. Xenografts were harvested and assessed for histopathology and steroidogenic end points. RESULTS: Consistent with the in utero response, phthalate exposure induced MNG formation in rat and mouse xenografts, but only rats exhibited suppressed steroidogenesis. Across a range of doses, human fetal testis xenografts exhibited MNG induction but were resistant to suppression of steroidogenic gene expression. CONCLUSIONS: Phthalate exposure of grafted human fetal testis altered fetal germ cells but did not reduce expression of genes that regulate fetal testosterone biosynthesis. PMID- 22511014 TI - Grid Binary LOgistic REgression (GLORE): building shared models without sharing data. AB - OBJECTIVE: The classification of complex or rare patterns in clinical and genomic data requires the availability of a large, labeled patient set. While methods that operate on large, centralized data sources have been extensively used, little attention has been paid to understanding whether models such as binary logistic regression (LR) can be developed in a distributed manner, allowing researchers to share models without necessarily sharing patient data. MATERIAL AND METHODS: Instead of bringing data to a central repository for computation, we bring computation to the data. The Grid Binary LOgistic REgression (GLORE) model integrates decomposable partial elements or non-privacy sensitive prediction values to obtain model coefficients, the variance-covariance matrix, the goodness of-fit test statistic, and the area under the receiver operating characteristic (ROC) curve. RESULTS: We conducted experiments on both simulated and clinically relevant data, and compared the computational costs of GLORE with those of a traditional LR model estimated using the combined data. We showed that our results are the same as those of LR to a 10(-15) precision. In addition, GLORE is computationally efficient. LIMITATION: In GLORE, the calculation of coefficient gradients must be synchronized at different sites, which involves some effort to ensure the integrity of communication. Ensuring that the predictors have the same format and meaning across the data sets is necessary. CONCLUSION: The results suggest that GLORE performs as well as LR and allows data to remain protected at their original sites. PMID- 22511015 TI - Harmonized patient-reported data elements in the electronic health record: supporting meaningful use by primary care action on health behaviors and key psychosocial factors. AB - BACKGROUND: Electronic health records (EHR) have the potential to improve patient care through efficient access to complete patient health information. This potential may not be reached because many of the most important determinants of health outcome are rarely included. Successful health promotion and disease prevention requires patient-reported data reflecting health behaviors and psychosocial issues. Furthermore, there is a need to harmonize this information across different EHR systems. METHODS: To fill this gap a three-phased process was used to conceptualize, identify and recommend patient-reported data elements on health behaviors and psychosocial factors for the EHR. Expert panels (n=13) identified candidate measures (phase 1) that were reviewed and rated by a wide range of health professionals (n=93) using the grid-enabled measures wiki social media platform (phase 2). Recommendations were finalized through a town hall meeting with key stakeholders including patients, providers, researchers, policy makers, and representatives from healthcare settings (phase 3). RESULTS: Nine key elements from three areas emerged as the initial critical patient-reported elements to incorporate systematically into EHR--health behaviors (eg, exercise), psychosocial issues (eg, distress), and patient-centered factors (eg, demographics). Recommendations were also made regarding the frequency of collection ranging from a single assessment (eg, demographic characteristics), to annual assessment (eg, health behaviors), or more frequent (eg, patient goals). CONCLUSIONS: There was strong stakeholder support for this initiative reflecting the perceived value of incorporating patient-reported elements into EHR. The next steps will include testing the feasibility of incorporating these elements into the EHR across diverse primary care settings. PMID- 22511016 TI - Quality evaluation of value sets from cancer study common data elements using the UMLS semantic groups. AB - OBJECTIVE: The objective of this study is to develop an approach to evaluate the quality of terminological annotations on the value set (ie, enumerated value domain) components of the common data elements (CDEs) in the context of clinical research using both unified medical language system (UMLS) semantic types and groups. MATERIALS AND METHODS: The CDEs of the National Cancer Institute (NCI) Cancer Data Standards Repository, the NCI Thesaurus (NCIt) concepts and the UMLS semantic network were integrated using a semantic web-based framework for a SPARQL-enabled evaluation. First, the set of CDE-permissible values with corresponding meanings in external controlled terminologies were isolated. The corresponding value meanings were then evaluated against their NCI- or UMLS generated semantic network mapping to determine whether all of the meanings fell within the same semantic group. RESULTS: Of the enumerated CDEs in the Cancer Data Standards Repository, 3093 (26.2%) had elements drawn from more than one UMLS semantic group. A random sample (n=100) of this set of elements indicated that 17% of them were likely to have been misclassified. DISCUSSION: The use of existing semantic web tools can support a high-throughput mechanism for evaluating the quality of large CDE collections. This study demonstrates that the involvement of multiple semantic groups in an enumerated value domain of a CDE is an effective anchor to trigger an auditing point for quality evaluation activities. CONCLUSION: This approach produces a useful quality assurance mechanism for a clinical study CDE repository. PMID- 22511017 TI - Genetic testing behavior and reporting patterns in electronic medical records for physicians trained in a primary care specialty or subspecialty. AB - OBJECTIVE: To characterize important patterns of genetic testing behavior and reporting in modern electronic medical records (EMRs) at the institutional level. MATERIALS AND METHODS: Retrospective observational study using EMR data of all 10,715 patients who received genetic testing by physicians trained in a primary care specialty or subspecialty at an academic medical center between January 1, 2008 and December 31, 2010. RESULTS: Patients had a mean+/-SD age of 38.3+/-15.8 years (median 36.1, IQR 30.0-43.8). The proportion of female subjects in the study population was larger than in the general patient population (77.2% vs 55.0%, p<0.001) and they were younger than the male subjects in the study (36.5+/ 13.2 vs 44.6+/-21.2 years, p<0.001). Approximately 1.1% of all patients received genetic testing. There were 942 physicians who ordered a total of 15,320 genetic tests. By volume, commonly tested genes involved mutations for cystic fibrosis (36.7%), prothrombin (13.7%), Tay-Sachs disease (6.7%), hereditary hemochromatosis (4.4%), and chronic myelogenous leukemia (4.1%). EMRs stored reports as free text with categorical descriptions of mutations and an average length of 269.4+/-153.2 words (median 242, IQR 146-401). CONCLUSIONS: In this study, genetic tests were often ordered by a diverse group of physicians for women of childbearing age being evaluated for diseases that may affect potential offspring. EMRs currently serve primarily as a storage warehouse for textual reports that could potentially be transformed into meaningful structured data for next-generation clinical decision support. Further studies are needed to address the design, development, and implementation of EMRs capable of managing the critical genetic health information challenges of the future. PMID- 22511019 TI - [Is there a role for risk-scoring methods in ruptured abdominal aortic aneurysm (rAAA)?]. AB - BACKGROUND: Rupture of an abdominal aortic aneurysm (rAAA) is associated with a high mortality both before and after admission to hospital. In spite of the use of expensive intensive medical therapeutic interventions 30 - 50 % of the operated patients still die. The ASA score is one of the most used scores world wide. Use of the Glasgow aneurysm score (GAS) and the Hardman index (HI) is frequently reported in the literature to predict survival after surgical management of rAAA. With regard to the comorbidity factor severity score (CSS) no evaluated data on the mortality in cases of rAAA are available. On the basis of our own patient collective we intended to assess to what extent the risk score could give an answer to the question of therapeutic options. METHODS: In a retrospective study (7/1998 - 8/2007), 94 patients (m : f = 78 : 16) were assessed after operative management of rAAA. The validity of preoperative risk assessments on the basis of the ASA score, the CSS, the GAS and the HI with regard to intra- or postoperative death in the initial hospitalisation period was examined. Sensitivity and specificity of the score systems were determined by receiver operating characteristics (ROC) analyses. RESULTS: The age of the patients was 72.3 +/- 9.5 years (mean +/- SD). Thirty-five (37.2 %) patients died in the immediate postoperative period. The areas under the receiver operating characteristics curves for ASA, GAS, HI and CSS were 0.598, 0.787, 0.742 and 0.614, respectively. CONCLUSIONS: This study revealed clear differences in the prognostic predictions of the various scores. In accord with the literature, no score gave a 100 % positive result with regard to mortality. Thus, an individual decision or, respectively, a therapeutic option cannot be reached with the help of the investigated scores. Further parameters need to be evaluated in order to make decisions about postoperative therapy. PMID- 22511018 TI - Protecting count queries in study design. AB - OBJECTIVE: Today's clinical research institutions provide tools for researchers to query their data warehouses for counts of patients. To protect patient privacy, counts are perturbed before reporting; this compromises their utility for increased privacy. The goal of this study is to extend current query answer systems to guarantee a quantifiable level of privacy and allow users to tailor perturbations to maximize the usefulness according to their needs. METHODS: A perturbation mechanism was designed in which users are given options with respect to scale and direction of the perturbation. The mechanism translates the true count, user preferences, and a privacy level within administrator-specified bounds into a probability distribution from which the perturbed count is drawn. RESULTS: Users can significantly impact the scale and direction of the count perturbation and can receive more accurate final cohort estimates. Strong and semantically meaningful differential privacy is guaranteed, providing for a unified privacy accounting system that can support role-based trust levels. This study provides an open source web-enabled tool to investigate visually and numerically the interaction between system parameters, including required privacy level and user preference settings. CONCLUSIONS: Quantifying privacy allows system administrators to provide users with a privacy budget and to monitor its expenditure, enabling users to control the inevitable loss of utility. While current measures of privacy are conservative, this system can take advantage of future advances in privacy measurement. The system provides new ways of trading off privacy and utility that are not provided in current study design systems. PMID- 22511020 TI - [Extrahepatic cholangiocarcinoma: current state of palliation therapy]. AB - INTRODUCTION: Decompression of bile ducts is the priority objective in the non curative stage of hilar cholangiocarcinoma. Only this will prevent or slow down infectious complications and secondary biliary cirrhosis thereby sustaining the quality of life. KEY STATEMENTS: At present, photodynamic therapy combined with insertion of an endoprosthesis seems to be best documented and most appropriate therapy. METHODS: Data from a selective literature search combined with our clinical experience were evaluated. CONCLUSIONS: Therapeutic measures should match the dissemination and stage of the tumor: in locally advanced or progressing disease (stage III) a local ablating therapy, in systemically progressing disease (stage IV) systemic chemotherapy should be utilised. PMID- 22511021 TI - [The halberstadt physician Dr. Walter Krienitz--one of the first to describe bacteria of the stomach]. PMID- 22511022 TI - [Leg swelling following inguinal and ilioinguinal dissection of melanoma metastases]. AB - BACKGROUND: With respect to survival and local disease control, the adequate extent of lymph node dissection for melanoma metastasis to the groin is controversial. Since the methods for accurate quantification of leg oedemas are not well standardised, it remains also unclear whether the iliac part of a radical ilioinguinal lymph node dissection contributes to postoperative lymphoedema. PATIENTS AND METHODS: Using a questionnaire and clinical examinations, we prospectively studied 65 persons for the presence of leg swellings (11 with inguinal lymph node dissection (sCLND), 23 with ilioinguinal dissection (rCLND), and 31 without nodal surgery and without signs of venous insufficiency). Exact volumetry of the legs was performed using the Image 3 D method. RESULTS: The mean interval between the lymphadenectomy and the examination for swellings was 24 +/- 30 months. Compared with sCLND, the amount of postoperative drainage fluid was significantly higher after rCLND (1960 +/- 1390 mL versus (vs.) 898 +/- 578 mL). Patients with rCLND perceived more frequently leg swellings (83 % vs. 55 %, p = 0.09), however, also 23 % of the control persons perceived leg swellings. Clinical signs of swelling were found slightly more frequently in the rCLND group (52 % vs. 45 %). After rCLND, the gain in volume of the ipsilateral thigh was significantly higher than after sCLND (7.01 +/- 4.83 % vs. 1.29 +/- 6.12 %, p = 0.01). Patients with rCLND more frequently needed manual lymph drainage (70 % vs. 45 %). In the control persons, the volumes of the right (mostly dominant) and the left legs did not differ significantly. CONCLUSIONS: Our results suggest that the iliac part of an ilioinguinal lymph node dissection significantly contributes to lymphoedema. Because of the multitude of reasons for swellings of the lower leg, volumetry of the thigh seems to be most adequate for quantifying the amount of postoperative lymphoedema. PMID- 22511023 TI - Comparison of pneumatic dissection and forceps dissection in Descemet membrane endothelial keratoplasty: histological and ultrastructural findings. AB - PURPOSE: To compare air and forceps dissection of Descemet membrane (DM) in regard to endothelial cell loss, apoptosis, and ultrastructural findings for transplantation in Descemet membrane endothelial keratoplasty. METHODS: DM of 32 corneoscleral rims were separated using forceps dissection (group A) and air dissection (group B) and had been organ cultured for 1 week. The endothelial cell density (ECD) was evaluated before and immediately after DM dissection and during 1 additional week of organ culture. The presence of any residual stroma, thickness of the DM, thickness of banded and nonbanded layers, and smoothness of the lamella were analyzed. Apoptosis was evaluated by TUNEL (terminal dUTP nick end-labeling) staining. RESULTS: In group A, 15 of 16 usable DM were available, and in group B 14 of 16 usable DM were available. The duration of preparation was 19.7 minutes in group A and 8.8 minutes in group B. The mean ECD was 2050 +/- 167 cells per square millimeter in group A and declined to 1846 +/- 153 cells per square millimeter after 1 week of organ culture. The mean ECD in group B was 2038 +/- 212 cells per square millimeter and declined to 1863 +/- 211 cells per square millimeter. No evidence of adherent rests of corneal stroma in any specimens in either group was observed, demonstrating a stroma free separation with no differences in the smoothness of the lamellae. The rate of apoptosis positive cells was 0.37% in group A and 0.40% in group B. CONCLUSIONS: Both separation methods seem to be equal in regard to the quality of the obtained DM. Finally, it depends on the preference of the surgeon which dissection method to use. PMID- 22511024 TI - Clinical treatment of dry eye using 0.03% tacrolimus eye drops. AB - PURPOSE: To report the clinical outcome of the treatment of dry eyes using 0.03% tacrolimus eye drops (olive oil + tacrolimus 0.03%) (Ophthalmos, Sao Paulo, Brazil). METHODS: Sixteen eyes of 8 patients with Sjogren syndrome dry eyes (age, 51.13 +/- 9.45 years) were enrolled in this study (prospective noncontrolled interventional case series). Patients were instructed to use topical 0.03% tacrolimus eye drops twice a day (every 12 hours) in the lower conjunctival sac. Schirmer I test, break-up time, corneal fluorescein, and rose bengal staining score were performed in all patients 1 day before, and 14, 28, and 90 days after treatment with 0.03% tacrolimus eye drops. RESULTS: The average fluorescein staining and rose bengal staining scores improved statistically significantly after 14 days of treatment and improved even more after 28 and 90 days. The average Schirmer I test did not improve statistically significantly after 28 days of treatment, although we did observe a significant improvement after 90 days of treatment with 0.03% tacrolimus eye drops. The average break-up time did not improve statistically after 14 days of treatment, although we observed a significant improvement after 28 and 90 days of treatment with 0.03% tacrolimus eye drops. CONCLUSIONS: Topical 0.03% tacrolimus eye drops successfully improved tear stability and ocular surface status in patients with dry eyes. PMID- 22511025 TI - In vivo laser scanning confocal microscopy of the cornea in patients with silicone oil tamponade after vitreoretinal surgery. AB - PURPOSE: To evaluate the morphological changes in the cornea by in vivo laser scanning confocal microscopy (LSCM) in a large case series with silicone oil endotamponade after vitreoretinal surgery and to explore the value of LSCM in the early detection of silicone keratopathy (SK). METHODS: Ninety-nine patients (99 eyes) with silicone oil endotamponade after vitreoretinal surgery were included in the current study. Slit-lamp examination and measurement of intraocular pressure (IOP) were performed first. Then the central corneas of the subjects' eyes were examined by in vivo LSCM. The analysis of images of each corneal layer was performed and the endothelial cellular density (ECD), endothelial cellular area (ECA), coefficient of variation of cell size (CoV), and percentage of hexagonal cells (PHC) were measured. Moreover, the total size of stromal deposits was measured, and the correlation between the size of deposits and the parameters of endothelial cells was analyzed. RESULTS: Clinically recognizable abnormalities involving the cornea were identified in only 12 eyes (12.1%) under slit-lamp biomicroscopy, whereas in vivo LSCM revealed morphological abnormalities in 40 eyes (40.4%). The manifestations of endothelial lesions varied from decreased cellular density, increased polymegathism and pleomorphism to hyperreflective silicone oil membrane or droplets adhering to the endothelium. Moreover, hyperreflective deposits with various shapes could be identified in both posterior and anterior stroma, along with the infiltration of Langerhans cells beneath the epithelium. The average ECD and PHC of eyes with corneal abnormalities were significantly lower than those of normal corneas, whereas the average ECA and CoV were significantly larger (all Ps < 0.001). The patients with corneal abnormalities were significantly older than those others (P = 0.003). The rate of pseudophakic and aphakic eyes having corneal abnormalities was significantly higher than that of phakic eyes (P = 0.045). Interestingly, the total size of stromal deposits had a significant negative correlation with ECD and PHC but a significant positive correlation with ECA and CoV (all Ps < 0.001). Further correlation analysis performed in groups divided according to the lens status showed similar results and even stronger correlations in aphakic and pseudophakic eyes, whereas no statistically significant correlations were found in phakic eyes. CONCLUSIONS: In vivo LSCM was a useful tool in the early detection of corneal abnormalities caused by silicone oil injection, including varying corneal endothelium lesions and stromal abnormalities. Pseudophakic or aphakic eyes, as well as those of older patients, should receive more attention because they are more inclined to develop silicone keratopathy. PMID- 22511026 TI - Descemet membrane detachment among siblings: role of anatomic and familial predisposition. AB - PURPOSE: To describe 2 siblings with Descemet membrane detachment (DMD) after intraocular surgery and discuss the potential role of anatomic and familial predisposition. METHOD: Case reports. RESULTS: A 64-year-old woman had bilateral DMDs after trabeculectomy in her right eye and during combined cataract extraction and trabeculectomy in her left eye. Both were successfully treated with intracameral sulfur hexafluoride gas injections. Her older sister also developed DMD in her left eye that was noted after uncomplicated cataract surgery. Slit-lamp examination of her unoperated eye revealed irregular Descemet membrane with thickening and a wavy configuration, suggesting an intrinsic corneal abnormality. No endothelial guttae or polymorphous changes were noted. Intracameral sulfur hexafluoride gas injection was attempted to reattach the Descemet membrane but was unsuccessful. The patient then underwent Descemet stripping endothelial keratoplasty with excellent postoperative results. CONCLUSIONS: Predisposition to DMD among relatives may be linked to hereditary morphological abnormalities present in their corneas. PMID- 22511027 TI - Application of in vivo laser scanning confocal microscopy for evaluation of ocular surface diseases: lessons learned from pterygium, meibomian gland disease, and chemical burns. PMID- 22511028 TI - Comment on "Application of in vivo laser scanning confocal microscopy for evaluation of ocular surface diseases: lessons learned from pterygium, meibomian gland disease, and chemical burns". PMID- 22511029 TI - Histopathology and spectral domain OCT findings of pneumatic-assisted dissection in DALK. AB - PURPOSE: To correlate big-bubble deep anterior lamellar keratoplasty findings in donor corneas with anterior segment optical coherence tomography (OCT) and histology. METHODS: This research was conducted entirely at the University of Texas Southwestern Medical Center in Dallas, Texas. We performed deep intrastromal air injections in donor corneas on artificial chambers. Surgical patterns (big bubble, intrastromal emphysema, and perforation) were assessed by spectral domain OCT with a handheld probe and histology. RESULTS: Surgical patterns were evaluated by histology using a novel embedding technique. A classic big bubble may be a Descemet membrane (DM) detachment with a few attached stromal fibrils. There were no large intra-DM separations as previously reported. The emphysematous surgical patterns result from intrastromal emphysema, which can be accompanied by microdetachments of DM. We saw indirect OCT signs of big bubble, but scatter from intrastromal emphysema limits deeper imaging. CONCLUSIONS: Surgical patterns of big bubble and intrastromal emphysema correlate with characteristic histology findings. Marked scatter on OCT by intrastromal emphysema limits visualization of deeper corneal structures, but the presence of a big bubble may be inferred. PMID- 22511030 TI - Sutured clear corneal incision: wound apposition and permeability to bacterial sized particles. AB - PURPOSE: To determine the effects of single radial or horizontal suture placement in 2-step clear corneal incision (CCI) wound apposition and permeability to particles of India ink. METHODS: Five fresh human globes were included. Two 25 gauge needles connected to a saline solution bag and to a digital manometer were inserted through the limbus, 120 degrees apart from each other. Four 2-step CCIs (2.75 mm wide and 3 mm length) were constructed in each cornea. Incisions were divided into 3 groups: single radial suture (SRS), single horizontal suture (SHS), and unsutured group. Optical coherence tomography (OCT) was performed before and after suture placement. With a preset 10 mm Hg intraocular pressure (IOP), India ink was applied to the incision site and a standardized sudden IOP fluctuation was induced. OCT and superficial images were recorded before and after suture placement. India ink inflow and internal and external CCI gapping were outlined and measured by planimeter. RESULTS: The area and linear distance of India ink inflow after pressure challenge in all study groups were higher when compared with pre-pressure measurements; however, this increase was significant in the SRS and SHS groups (P < 0.05). Additionally, SRS placement significantly increased inner wound gapping (P = 0.018), and SHS significantly widened outer wound gape (P = 0.02). CONCLUSIONS: Well-constructed unsutured 2-step CCI seems to be more efficient at preventing bacterial-sized particles inflow during sudden changes in IOP, and it seems to offer better wound apposition as assessed by OCT. PMID- 22511031 TI - Monitoring the hydration of DNA self-assembled monolayers using an extensional nanomechanical resonator. AB - We have fabricated an ultrasensitive nanomechanical resonator based on the extensional vibration mode to weigh the adsorbed water on self-assembled monolayers of DNA as a function of the relative humidity. The water adsorption isotherms provide the number of adsorbed water molecules per nucleotide for monolayers of single stranded (ss) DNA and after hybridization with the complementary DNA strand. Our results differ from previous data obtained with bulk samples, showing the genuine behavior of these self-assembled monolayers. The hybridization cannot be inferred from the water adsorption isotherms due to the low hybridization efficiency of these highly packed monolayers. Strikingly, we efficiently detect the hybridization by measuring the thermal desorption of water at constant relativity humidity. This finding adds a new nanomechanical tool for developing a label-free nucleic acid sensor based on the interaction between water and self-assembled monolayers of nucleic acids. PMID- 22511032 TI - Commentary: psychological and behavioral challenges for families of children with eosinophilic gastrointestinal disorders. PMID- 22511033 TI - Evaluating treatment participation in an internet-based behavioral intervention for pediatric chronic pain. AB - OBJECTIVE: Little is known about how participation in internet-based behavioral interventions influences outcomes in youth with health conditions. This study describes participation in an online behavioral pain management intervention for families of adolescents with chronic pain. METHODS: 26 adolescent-parent dyads were randomized to the intervention arm of a controlled trial evaluating a cognitive-behavioral pain intervention. Participation was measured by the number of logins, messages, completion of interactive fields, and behavioral assignments. Associations between content of messages from participants and treatment outcomes were evaluated. RESULTS: Most participants (92.3%) logged in and completed assignments. Over half of participants initiated messages to the online coach. A greater number of messages sent by adolescents containing rapport or treatment content predicted positive treatment outcomes. CONCLUSIONS: Most families actively participated in the intervention. Interaction with an online coach may increase the benefit of this Internet behavioral pain management treatment program for adolescents. PMID- 22511034 TI - Transcriptomes of mouse olfactory epithelium reveal sexual differences in odorant detection. AB - To sense numerous odorants and chemicals, animals have evolved a large number of olfactory receptor genes (Olfrs) in their genome. In particular, the house mouse has ~1,100 genes in the Olfr gene family. This makes the mouse a good model organism to study Olfr genes and olfaction-related genes. To date, whether male and female mice possess the same ability in detecting environmental odorants is still unknown. Using the next generation sequencing technology (paired-end mRNA seq), we detected 1,088 expressed Olfr genes in both male and female olfactory epithelium. We found that not only Olfr genes but also odorant-binding protein (Obp) genes have evolved rapidly in the mouse lineage. Interestingly, Olfr genes tend to express at a higher level in males than in females, whereas the Obp genes clustered on the X chromosome show the opposite trend. These observations may imply a more efficient odorant-transporting system in females, whereas a more active Olfr gene expressing system in males. In addition, we detected the expression of two genes encoding major urinary proteins, which have been proposed to bind and transport pheromones or act as pheromones in mouse urine. This observation suggests a role of main olfactory system (MOS) in pheromone detection, contrary to the view that only accessory olfactory system (AOS) is involved in pheromone detection. This study suggests the sexual differences in detecting environmental odorants in MOS and demonstrates that mRNA-seq provides a powerful tool for detecting genes with low expression levels and with high sequence similarities. PMID- 22511035 TI - Characterization of squamate olfactory receptor genes and their transcripts by the high-throughput sequencing approach. AB - The olfactory receptor (OR) genes represent the largest multigene family in the genome of terrestrial vertebrates. Here, the high-throughput next-generation sequencing (NGS) approach was applied to characterization of OR gene repertoires in the green anole lizard Anolis carolinensis and the Japanese four-lined ratsnake Elaphe quadrivirgata. Tagged polymerase chain reaction (PCR) products amplified from either genomic DNA or cDNA of the two species were used for parallel pyrosequencing, assembling, and screening for errors in PCR and pyrosequencing. Starting from the lizard genomic DNA, we accurately identified 56 of 136 OR genes that were identified from its draft genome sequence. These recovered genes were broadly distributed in the phylogenetic tree of vertebrate OR genes without severe biases toward particular OR families. Ninety-six OR genes were identified from the ratsnake genomic DNA, implying that the snake has more OR gene loci than the anole lizard in response to an increased need for the acuity of olfaction. This view is supported by the estimated number of OR genes in the Burmese python's draft genome (~280), although squamates may generally have fewer OR genes than terrestrial mammals and amphibians. The OR gene repertoire of the python seems unique in that many class I OR genes are retained. The NGS approach also allowed us to identify candidates of highly expressed and silent OR gene copies in the lizard's olfactory epithelium. The approach will facilitate efficient and parallel characterization of considerable unbiased proportions of multigene family members and their transcripts from nonmodel organisms. PMID- 22511036 TI - Single treatment of non-melanoma skin cancers using a pulsed-dye laser with stacked pulses. AB - BACKGROUND AND OBJECTIVE: Non-melanoma skin cancers are the most common cause of cancer worldwide. Within this grouping, the most common skin cancer is basal cell carcinoma (BCC) followed by squamous cell carcinoma (SCC). Recent evidence has shown that BCCs can be cleared by a pulsed-dye laser after multiple treatments using a single pass setting. Given the necessity for multiple treatments in the prior studies, we sought to determine whether tumor clearance could instead be achieved using a single treatment of the pulsed-dye laser in a stacked pulse setting. STUDY DESIGN/MATERIALS AND METHODS: Twenty patients with 23 biopsy proven BCCs and SCCIS that measured 0.4-3 cm in size and located on the trunk and extremities were recruited for this study. The lesions were randomized into three study arms: a control group (no treatment), first treatment group (S1), and second treatment group (S2). The S1 group was treated using a 595 nM pulsed-dye laser (PDL) at pulse energy of 15 J/cm(2), 3-millisecond pulse length, with no dynamic cooling, using a 7-mm spot size with 10% overlap of pulses and two passes. The S2 group was treated using the same 595 nM PDL at 7.5 J/cm(2), 3 millisecond pulse length, with no dynamic cooling, using a 10-mm spot size with 10% overlap of pulses and double stacked pulses. All the treated lesions were treated with a 4 mm margin of clinically normal skin. The lesions were subsequently surgically excised and examined by histopathology. RESULTS: There was no significant difference in the dimensions of the tumors between the three study arms, with a mean area of 94 mm(2) [SEM +/- 15.2] for the control group, 88 mm(2) [SEM +/- 12.1] for the S1 treatment group, and 105 mm(2) [SEM +/- 23.6] for the S2 treatment group. In the control group, there were two out seven lesions with no residual tumors, representing a background tumor clearance rate of approximately 28%. The S1 treatment group had two out of eight lesions with no residual lesion representing a clearance rate of 25%, similar to the background clearance rate. The S2 treatment group had a clearance rate of five out seven lesions, representing a clearance rate of 71%. The two lesions with residual tumors were noted to be beyond the central treatment zone by histopathology and if excluded, results in a clearance rate of 100%. By the Fisher's exact test with a Bonferroni correction, there is a trend towards significance between the S2 treatment group and the control group with a P-value of 0.028. CONCLUSIONS: The results of our pilot study suggest that BCCs and SCCIS can be cleared in a single treatment using a pulsed-laser in a stacked pulse setting. However, given the small sample size of this pilot study, further larger scale studies will be needed to determine statistical significance and long-term recurrence rate and to further validate these findings. PMID- 22511037 TI - Rapid micropatterning of cell lines and human pluripotent stem cells on elastomeric membranes. AB - Tissue function during development and in regenerative medicine completely relies on correct cell organization and patterning at micro and macro scales. We describe a rapid method for patterning mammalian cells including human embryonic stem cells (HESCs) and induced pluripotent stem cells (iPSCs) on elastomeric membranes such that micron-scale control of cell position can be achieved over centimeter-length scales. Our method employs surface engineering of hydrophobic polydimethylsiloxane (PDMS) membranes by plasma polymerization of allylamine. Deposition of plasma polymerized allylamine (ppAAm) using our methods may be spatially restricted using a micro-stencil leaving faithful hydrophilic ppAAm patterns. We employed airbrushing to create aerosols which deposit extracellular matrix (ECM) proteins (such as fibronectin and MatrigelTM) onto the same patterned ppAAm rich regions. Cell patterns were created with a variety of well characterized cell lines (e.g., NIH-3T3, C2C12, HL1, BJ6, HESC line HUES7, and HiPSC line IPS2). Individual and multiple cell line patterning were also achieved. Patterning remains faithful for several days and cells are viable and proliferate. To demonstrate the utility of our technique we have patterned cells in a variety of configurations. The ability to rapidly pattern cells at high resolution over macro scales should aid future tissue engineering efforts for regenerative medicine applications and in creating in vitro stem cell niches. PMID- 22511038 TI - Depressive symptoms among older people: a 15-year follow-up. AB - BACKGROUND AND AIMS: Depressive symptoms are common symptoms impairing the quality of life of older people. This population-based birth year cohort study investigated the prevalence of depressive symptoms and factors associated with them among home-dwelling older people. STUDY DESIGN: A prospective, population based 15-year follow-up study of the age cohort of 70-year-olds living in the city of Turku, Finland. METHODS: The data were collected in 1991 by a postal questionnaire that was sent to all residents of Turku, Finland, born in 1920 (n=1530). Follow-ups using the same procedure were conducted in 2001 and 2006. All examinations included an identical study protocol; the participants' self reported health status/habits and depressive symptoms were investigated via a questionnaire. Afterwards, thorough clinical examinations including the Zung depression scale were conducted by a nurse and physician/geriatrician. RESULTS: The mean of the Zung depression scale total score was 34 (SD 7.7) at the age of 70 and a significant increase was found in both re-examinations. At the age of 80 the mean of the Zung score was 35.8 (SD 7.5) while it was 37.6 (SD 8.9) at the age of 85 years. A similar increasing trend was found in the proportion of persons classified into the high Zung score group (>=45 points) indicating more depressive symptoms over the 15 year follow-up. Univariate and multivariate analyses showed that mostly functional and social factors were associated with subjectively reported depressive symptoms, while few associations were evidenced between depressive symptoms and medical conditions or poor health. CONCLUSIONS: Our findings revealed an increase in prevalence of depressive symptoms throughout the course of the investigation. Our findings suggest that even in the absence of a diagnosis of major depression, depressive symptoms assume importance in the evaluation of the health status and need for health care services among older people. PMID- 22511041 TI - Infectious disease trends among immunocompromised hosts. AB - With our rapidly ageing population and advancing treatments for patients with haematological, oncologic and rheumatological diseases, there are increasing numbers of immunocompromised patients presenting to primary care and general hospitals with opportunistic infections. This review considers the trends of these infections across four representative subgroups: fungal infections following haematopoietic stem cell transplant; viral infections post solid organ transplant; mycobacterial infections during treatment with targeted biological agents; and bacterial infections as a cause of fever in neutropenia. We also consider the impact of host, pathogens, environments and treatments on the epidemiology and outcomes of these infections. PMID- 22511042 TI - Antiviral treatment for cirrhosis due to hepatitis C: a review. AB - Chronic hepatitis C infection is an important cause of cirrhosis and hepatocellular carcinoma (HCC). Antiviral therapy (AVT) for patients with cirrhosis due to hepatitis C may retard the progression of cirrhosis and prevent both the development of HCC as well as the recurrence of hepatitis C following liver transplantation. This review highlights the issues associated with AVT for patients with compensated and decompensated cirrhosis due to hepatitis C virus. PMID- 22511043 TI - TB control in Singapore: where do we go from here? AB - The total number of new tuberculosis (TB) cases notified in Singapore among citizens, permanent residents and foreigners rose by 46% from 2004 to 2010. During this period, the proportion of foreigners increased from 29% to 47% of the total case burden. In 2008, the TB incidence rate among Singapore citizens and permanent residents increased for the first time in ten years, despite the on going efforts of the Singapore TB Elimination Programme. Additional measures and resources are clearly needed to curb this rising trend. Pivotal to this is to address TB among foreigners. The political will to battle TB in Singapore must result in action to remove barriers to diagnosis, to enable all TB patients to undergo treatment under directly observed therapy (DOT), and to ensure that all healthcare providers who manage TB patients are responsible and accountable to the public health system. PMID- 22511044 TI - The imminent threat of multidrug-resistant tuberculosis in Singapore. AB - The global emergence of multidrugresistant (MDR) tuberculosis (TB) and extensively drug-resistant (XDR)-TB threatens to derail the efforts of TB control programmes worldwide. From 2000 to 2010, 161 pulmonary MDR-TB cases (including six XDR-TB cases) were reported in Singapore, and of these, 80% occurred among the foreign-born, with an increasing trend seen after 2004. Among new pulmonary TB cases, the highest incidence of MDR-TB occurred among patients from Myanmar (8%), followed by Vietnam (4.4%) and China (2.3%), while among those previously treated, the highest incidence was found in patients from Vietnam (50%), followed by Indonesia (33%) and Bangladesh (33%). Although the proportion of Singapore born pulmonary TB cases with MDR-TB has remained comparatively low (0.2% and 1.3% in new and previously treated cases, respectively), there is no room for complacency. Top priority must be accorded toward the proper treatment of drug susceptible TB cases under strict programme conditions so as to prevent the development of MDR-TB in the first place. PMID- 22511045 TI - Polyarthritis in four patients with chikungunya arthritis. AB - The incidence of chikungunya infection in Singapore has been on the rise since the first reported case in 2006. Acute polyarthritis, a common manifestation among affected patients, may precede fever and present with debilitating arthritis to rheumatologists, orthopaedists, internists and primary care physicians. The diagnosis of chikungunya infection requires careful history taking and a high index of suspicion, with supporting evidence from the reverse transcription-polymerase chain reaction or the chikungunya IgM serology test. Treatment of chikungunya arthritis usually involves non-steroidal anti inflammatory drugs. Rarely, polyarthritis in chikungunya may persist even after resolution of the acute infection, necessitating treatment with disease-modifying anti-rheumatic drugs. In this article, we present the different manifestations of chikungunya arthritis in our local setting and review the literature. PMID- 22511046 TI - Clinical audit of the microbiology of otorrhoea referred to a tertiary hospital in Singapore. AB - INTRODUCTION: Otorrhoea is a common complaint in Ear, Nose and Throat clinics. This study aimed to establish the pathogens involved in cases of otorrhoea in Singapore, their sensitivity patterns and the effectiveness of empirical management. METHODS: A retrospective chart review was conducted on 91 patients with otorrhoea who had undergone swab cultures between July 2010 and February 2011. RESULTS: Of the 91 cases, 53% were diagnosed empirically as bacterial otitis externa and 25% as otomycosis. Aerobic bacteria accounted for 35.8% of the microorganisms cultured, while 34.7% were fungi and 29.5% were anaerobic bacteria. Pseudomonas (P.) aeruginosa and Staphylococcus (S.) aureus made up 31.6% and 21.0% of the microorganisms, respectively. 20% of S. aureus grown was methicillin-resistant. Aspergillus was the most common fungus and 19% of cultures were polymicrobial. 38% of patients had their treatment changed on the basis of culture results, as no improvement was observed on follow-up. P. aeruginosa was sensitive to ciprofloxacin and gentamicin in 81.8% and 76.0% of patients, respectively, while S. aureus was sensitive to cloxacillin in 93.8% and clindamycin in 87.5% of patients. CONCLUSION: The common microorganisms involved in otorrhoea in Singapore are P. aeruginosa, Aspergillus and S. aureus. Resistant strains of Pseudomonas spp. are now present. Methicillin-resistant S. aureus is increasingly prevalent and highly sensitive to vancomycin. Aminoglycoside and fluoroquinolone-containing eardrops are suitable first-line topical antimicrobials. Cloxacillin may be started should a concomitant oral antimicrobial be warranted empirically or for S. aureus infections. Otomycosis should be considered in patients who show no improvement with antibiotics. PMID- 22511047 TI - Outbreak of acute norovirus gastroenteritis in a military facility in Singapore: a public health perspective. AB - INTRODUCTION: Norovirus gastrointestinal disease (GID) outbreaks occur frequently in closed settings, with high attack rates. On October 16, 2008, a norovirus GID outbreak occurred at a Singapore military camp. This study describes the epidemiological investigations conducted to determine the cause of outbreak and the efficacy of the public health measures implemented. METHODS: Epidemiologic investigations included a case-control study of exposure to different food items and an environmental exposure survey. Stool samplings of patients and food handlers for common pathogens, and microbiologic testing of food and water samples were performed. Inspection of dining facilities and health screening of all food-handlers were also conducted. RESULTS: A total of 156 GID cases were reported on October 15-31, 2008. 24 (15.4%) personnel were positive for norovirus. The predominant symptoms were diarrhoea (76.3%) and abdominal pain (69.2%). There was no clinical correlation between any food item and the affected personnel. Testing of food and water samples, dining facility inspections and health screening of food handlers showed satisfactory results. The environmental exposure survey indicated possible transmission due to environmental contamination by vomitus in common areas. Comprehensive environmental decontamination was performed with hypochlorite solution, and personal hygiene measures were enforced. The outbreak lasted 17 days, with a decline in cases post intervention. CONCLUSION: Timely notification and prompt response can curtail disease transmission. Swift implementation of public health measures, such as emphasis on personal hygiene, isolation of affected cases and comprehensive disinfection of the environment, effectively stopped norovirus transmission and may be adapted for future GID outbreaks. PMID- 22511048 TI - External ventricular drain infections: successful implementation of strategies to reduce infection rate. AB - INTRODUCTION: External ventricular drain (EVD) infections can cause serious complications. We performed an audit of EVD infections within our neurosurgical unit. Through this study, we aimed to reduce the incidence of external ventricular drain-related infection, including ventriculities in neurosurgical patients. METHODS: We conducted an audit of the EVD infections in our institution observed over a one-and-a-half year period. This was conducted in three phases. A baseline EVD infection rate was determined for Phase I, from January to June 2007. We introduced the following measures to reduce EVD infection rate in Phase II, from July to December 2007: (1) For Neurosurgery doctors: performing proper surgical techniques to minimise intra-operative infections; educating junior doctors on proper CSF sampling from the EVD; and minimising the number of days the EVD is maintained in situ; (2) For Neurosurgery nurse clinicians: developing Standard Operating Procedures on nursing management of EVDs; conducting EVD care workshops for nurses working in neurosurgical wards; and competency skill checks on the management of EVDs for nurses working in the neurosurgical wards. Silver coated EVDs were introduced in Phase III of the study from January to June 2008. RESULTS: The EVD infection rate decreased from a baseline of 6.1% to 3.8% in Phase II; a further reduction from 3.8% to 0% was achieved during Phase III. CONCLUSION: Good teamwork among doctors and nurses is essential for reducing EVD infection rate. We managed to reduce EVD infections substantially and would continue to strive to remain infection-free in the future. PMID- 22511049 TI - Epidemiology and risk factors of intensive care unit-acquired infections: a prospective multicentre cohort study in a middle-income country. AB - INTRODUCTION: This study aimed to determine the incidence and risk factors of infections among patients admitted to intensive care units (ICUs) in tertiary care hospitals in Turkey. METHODS: Adult patients who were admitted to the ICUs of five tertiary care hospitals for over 48 hours between June and December 2007 were monitored daily. Potential risk factors such as age, gender, comorbidities, diagnosis at admission, severity of disease (Acute Physiology and Chronic Health Evaluation II scores), exposure to antibiotics, history of invasive procedures and significant medical interventions were evaluated. A multivariate analysis of these risk factors was carried out using Cox regression. RESULTS: A total of 313 patients with a median ICU stay of 12 days were selected for the study. 236 infectious episodes (33.8/1,000 ICU-days) were diagnosed among 134 patients (42.8/100 patients) in this group. Multivariate analysis revealed that exposure to a cephalosporin antibiotic (hazard ratio [95% confidence interval] 1.55 [1.10 2.19]) was an independent risk factor, whereas having a tracheostomy cannula (0.53 [0.36-0.81]) or nasogastric tube (0.48 [0.33-0.70]) was protective. Patients admitted to the ICUs from surgical wards were significantly more exposed to cephalosporins. CONCLUSION: ICU-associated infections, which are quite high in Turkey, are largely due to inadequate infrastructure and facilities and understaffing. Abuse of antibiotics, particularly in patients who have undergone surgery, and prolonged ICU stays are significant risk factors for such infections. PMID- 22511050 TI - Epidemiological features and laboratory results of bacterial and fungal keratitis: a five-year study at a rural tertiary-care hospital in western Maharashtra, India. AB - INTRODUCTION: This study was conducted to determine the epidemiological pattern and risk factors associated with corneal ulcers in rural areas of western Maharashtra, India, and to identify the bacterial and fungal agents responsible for causing keratitis. METHODS: A total of 852 patients with corneal ulceration were included in the study. Sociodemographic data and information pertaining to risk factors were collected. Corneal scrapings obtained from these patients were processed for bacterial and fungal agents using standard techniques. RESULTS: Out of the 852 patients studied, 537 (63.02%) were culture positive. A majority of the culture-positive patients were farmers (52.32%), and ocular trauma was the most common predisposing factor (60.15%). Among these patients, fungal isolates (57.91%) were more frequent than bacterial isolates (42.08%). The most common fungal isolate was Fusarium spp. (35.04%) followed by Aspergillus spp. (18.00%). Streptococcus pneumoniae was the predominant bacterial isolates (32.74%) followed by Staphylococcus spp. (17.25%). CONCLUSION: Corneal trauma from plant parts or organic matter was found to be the most common risk factor associated with corneal ulceration in the rural areas of western Maharashtra. Epidemiology and aetiology of microbial keratitis vary from region to region, and therefore, careful history taking and proper identification of aetiological agents are necessary for the institution of appropriate therapy. PMID- 22511051 TI - Profile of antibiotic consumption, sensitivity and resistance in an urban area of Andhra Pradesh, India. AB - INTRODUCTION: Antibiotics are an important category of drugs in which indiscriminate use can affect the susceptibility patterns among infectious organisms, resulting in antibiotic resistance. METHODS: Data on antibiotic usage and susceptibility patterns were collected from public and private health centres in Vijayawada, Andhra Pradesh, India, through the use of questionnaires. The data collected were then coded, tabulated, computed and evaluated using statistical analysis. RESULTS: The consumption profile of the different categories of drugs used in public and private hospitals was as follows: nutrition and metabolism products 19.0%; gastrointestinal disorder-related drugs 18.5%; antibiotics 16.8%; anti-pyretics and anti-analgesics 20.6%. These drugs were found to be in high demand. Among the antibiotics, aminoglycosides (amikacin), quinolones (ofloxacin, ciprofloxacin), tetracyclines (doxycycline), penicillin (ampicillin) and sulphonamides (co-trimoxazole) were the most commonly prescribed drugs for antibiotic therapy. 46% of the culture laboratory reports were positive with the following organism profile: Escherichia coli (36%), Klebsiella pneumoniae (16%), Staphylococcus aureus (29%), Enterococcus faecalis (9%) and Pseudomonas aeruginosa (10%). In terms of the sensitivity profile of antibacterials, amikacin (66.9%) was the only antibiotic showing sensitivity patterns, while the majority of antibiotics, such as cotrimoxazole, nalidixic acid, amoxicillin, gentamycin and norfloxacin, had acquired a resistance rate of 55.1%-80.6%. CONCLUSION: The results of this study suggest that indiscriminate prescription and consumption of new broad-spectrum antibiotics against sensitive organisms results in the development of antimicrobial resistance. Therefore, there is an urgent need to curb the excessive use of antibiotics in local hospitals in order to control the trend of increasing antimicrobial resistance to antibiotics. PMID- 22511052 TI - Doxycycline-based quadruple regimen versus routine quadruple regimen for rescue eradication of Helicobacter pylori: an open-label control study in Chinese patients. AB - INTRODUCTION: This study aimed to compare the efficacy and safety of quadruple therapy containing doxycycline and routine quadruple therapy for Helicobacter (H.) pylori rescue eradication in patients who had failed the one-week triple therapy. METHODS: Patients who failed the first-line eradication therapy were allocated into two groups. Group A patients (n = 43) were administered esomeprazole 20 mg, bismuth potassium citrate 220 mg, amoxicillin 1 g and doxycycline 100 mg, all bid for ten days, while Group B patients (n = 42) were administered esomeprazole 20 mg bid, bismuth potassium citrate 220 mg bid, metronidazole 400 mg bid and tetracycline 750 mg q.6h, for ten days. The results of H. pylori eradication were assessed with 13C urea breath test four weeks after the therapy, and the side effects were recorded. RESULTS: A total of 85 patients (average age 46.9 years) were enrolled in the study. Successful eradication rate for H. pylori was 72.5% in Group A and 64.1% in Group B, with no significant difference between the two groups. 11.6% (5/43) of patients from group A and 31.0% (13/42) from group B reported at least one adverse event. The adverse events of all 18 patients disappeared after the therapy ceased. CONCLUSION: Quadruple therapy containing doxycycline is as effective as routine quadruple therapy for H. pylori rescue eradication. The regimen is well tolerated by most patients and causes fewer adverse events than routine quadruple therapy. Hence, it may be recommended as a suitable alternative H. pylori rescue regimen in China. PMID- 22511053 TI - Emergency ultrasonography in patients with clinically suspected soft tissue infection of the legs. AB - INTRODUCTION: We aimed to retrospectively review the ultrasonography (US) findings of patients with clinically suspected soft tissue infection of the legs and to determine whether there is a correlation between US diagnosis and further clinical management. METHODS: We reviewed the US findings of consecutive patients with clinically suspected soft tissue infection of the legs who were referred for emergency US during a consecutive two-year period. The indications for US were recorded and the findings evaluated. The effect of the US findings on further clinical management (medication alone versus medication with surgical intervention [SI]) was reviewed. RESULTS: A total of 51 legs from 38 patients were enrolled in the study. The most common indication for US was to rule out necrotising fasciitis (35.3%). The most frequent US diagnosis was isolated cellulitis (21.6%). Both groups of patients (with and without abscess) were treated with medication with or without SI. There was no statistically significant correlation between the presence or absence of abscess and further clinical management (p = 0.216), between the size (length and thickness) of the abscess and the type of SI (p = 0.687 and 0.243, respectively) CONCLUSION: In our study, the most frequent US diagnosis was isolated cellulitis, and we found no significant correlation between US findings and clinical management (medication or SI). Our results should encourage sonologists to evaluate in detail patients with clinically suspected soft tissue infection of the legs and to provide information regarding each layer of tissue studied. PMID- 22511054 TI - Clinics in diagnostic imaging (139). Displaced medial meniscus bucket-handle tear. AB - A 58-year-old man presented with knee pain and swelling, following a previous injury. A displaced bucket-handle tear of the medial meniscus was diagnosed on magnetic resonance (MR) imaging and subsequently confirmed by arthroscopy. MR imaging is accurate in diagnosing bucket-handle tears. The different MR imaging signs of bucket-handle tears include the double posterior cruciate ligament sign, displaced fragment in intercondylar notch sign, absent bow-tie sign, anterior flipped meniscus sign and coronal truncation sign. Specificity is increased when a combination of the different imaging signs is present. Understanding the meniscal anatomy and potential mimics of the bucket-handle tear is important in order to ensure an accurate diagnosis and appropriate management. PMID- 22511055 TI - Alpha-foetoprotein: an inaccurate test for surveillance of post-treatment recurrence of hepatocellular carcinoma. PMID- 22511057 TI - Comment on: Markers of genital tuberculosis in infertility. PMID- 22511059 TI - Fine needle aspiration cytology in carotid body tumours. PMID- 22511061 TI - The sandwich technique for vacuum-assisted wound dressing application in the urogenital region: a safe, time-sparing and reliable method. PMID- 22511064 TI - First detection of chikungunya infection and transmission in Brunei Darussalam. AB - This report describes the chikungunya cases and local transmission detected in Brunei Darussalam for the first time, despite the country being situated in a region that has experienced a multitude of outbreaks over the years. A combined strategy of active case detection, patient isolation and vector control measures was deployed in an attempt to avert further transmission. The findings have important public health implications for international surveillance and control strategies for this re-emerging disease. PMID- 22511065 TI - Oesophageal ulcers secondary to doxycycline and herpes simplex infection in an immunocompetent patient. AB - Oesophageal ulcerations are generally rare occurrences that are most commonly associated with gastro-oesophageal reflux disorder. Other causes include medications and infections in immunocompromised patients. Among the medications used in daily practice, doxycycline is most commonly implicated. Multiple aetiologies are generally uncommon. We report a case of mid-oesophageal ulcerations secondary to doxycycline and herpes simplex virus infection in an immunocompetent patient. PMID- 22511066 TI - Leiomyomatosis peritonealis disseminata presenting as omental torsion. AB - Leiomyomatosis peritonealis disseminata is usually asymptomatic or mimics widespread malignancy; acute presentation is rare. We describe a patient with right iliac fossa and lower abdominal pain. Two masses were detected via computed tomography, but at surgery, one of these implanted leiomyomas had undergone acute omental torsion. This case illustrates a rare complication of omental leiomyoma torsion clinically mimicking acute appendicitis. PMID- 22511067 TI - Bilateral first and second arch anomalies: a rare presentation. AB - Branchial sinuses are one of the most common congenital anomalies present. They are usually unilateral; bilateral cases are present but are rare. The presentation of bilateral branchial sinus anomalies along with bilateral first arch anomalies is very rare. Here, we present a case of bilateral first arch anomalies co-existing with bilateral second arch anomalies in a patient with no related family history and no associated syndrome. PMID- 22511068 TI - A rare case of localised AA-type amyloidosis of the ureter with spheroids of amyloid. AB - We present a case of localised AA-type amyloidosis of the ureter with spheroids of amyloid. Localised AA-type amyloidosis of the urogenital tract is uncommon and extremely rare as a cause of ureteric obstruction, with only two such cases described in the literature to date. Most previously described cases at this site are related to primary AL-type amyloidosis. Another interesting finding in this case is the presence of spheroids of amyloid, which to the best of our knowledge, has not been previously reported at this site, and is also unusual at other sites. PMID- 22511069 TI - Ganglion cyst of the posterior cruciate ligament in a child. AB - Ganglion cysts are more commonly associated with the anterior cruciate ligament than the posterior cruciate ligament (PCL). A literature review showed that all reported cases of ganglion cysts to date involved adults. We report a rare case of ganglion cyst in the PCL of a four-year-old boy, and discuss its aetiology, clinical presentation, imaging features and management. Ganglion cysts of the PCL may be confused with meniscal cysts arising from tears of the posterior horn of the medial meniscus on magnetic resonance (MR) imaging. Hence, the posterior horn of the medial meniscus has to be carefully evaluated to rule out a tear. MR imaging is the method of choice to confirm diagnosis, and arthroscopic resection is a safe treatment modality even in children. PMID- 22511070 TI - An unusual case of adult onset progressive heterotopic ossification suggesting a variant form of fibrodysplasia ossificans progressiva. AB - Progressive heterotopic ossification (HO) is a rare disease of genetic inheritance. Fibrodysplasia ossificans progressiva (FOP) is an identified debilitating subcategory in which anomalous ossification usually begins in childhood. Congenital big toe anomalies and specific patterns of progression of ossification confirm the classic disease. Adult onset disease is extremely rare. The mechanism of disease progression is still unclear, and there is no consensus on the treatment modalities. We report a 47-year-old man with adult-onset progressive HO around the bilateral pelvic and shoulder girdles and thoracolumbar spine, which suggested a variant form of FOP. Although surgical excision is considered counterproductive in FOP, our patient showed improvement in his shoulder movement following surgery. Other management strategies, including surgery around the hips, indomethacin prophylaxis, irradiation and bisphosphonate therapy, did not improve his range of movement or disease progression. PMID- 22511071 TI - Temporal approach for small-gauge pars plana vitrectomy combined with anterior segment surgery. AB - PURPOSE: To describe our preliminary experience with temporal small-gauge pars plana vitrectomy (PPV) techniques used to treat anterior and posterior segment pathology. METHODS: A retrospective consecutive case review of patients who underwent temporal PPV was performed. Patients underwent combined temporal small gauge PPV and anterior segment intervention. Pre- and postoperative visual acuity, intraocular pressure, surgical indications, intraoperative techniques, postoperative course, and a survey to determine how the change in position affected surgery were examined. RESULTS: Temporal PPV was performed on 23 eyes with various posterior segment indications and anterior segment pathologies including cataract, pupillary membrane, endophthalmitis, superior filtering blebs, and anterior vitreous membranes. In 20 eyes, 23-gauge instruments were used, and in 3 eyes, 25-gauge instruments were used. Mean postoperative follow-up duration was 7.6 +/- 5.0 months (range, 3-22 months). Surgical objectives were achieved in all cases, and no complications occurred in any study eye. Preoperative logarithm of the minimum angle of resolution mean visual acuity was 1.89 +/- 0.76 and improved significantly on postoperative Week 1 (1.45 +/- 0.81, P = 0.0003), Month 1 (1.13 +/- 0.86, P = 0.0001), and at final follow-up (0.88 +/ 0.79, P = 0.0001). There was no significant difference in preoperative and postoperative intraocular pressures. Surgeon surveys indicated significant advantages with a temporal approach for each anterior segment indication, no significant differences in performing the basic surgical steps of PPV, and relative ease of adopting this technique. CONCLUSION: Performing PPV from the temporal position seems to be advantageous in cases combining posterior and anterior segment surgery such as cataract extraction, pupillary membrane dissection, preservation of superior conjunctival blebs, and trimanual vitrectomy. PMID- 22511072 TI - Quantification of PKC family genes in sporadic breast cancer by qRT-PCR: evidence that PKCiota/lambda overexpression is an independent prognostic factor. AB - Drugs targeting protein kinase C (PKC) show promising therapeutic activity. However, little is known about the expression patterns of the 11 PKC genes in human tumors, and the clinical significance of most PKC genes is unknown. We used qRT-PCR assays to quantify mRNA levels of the 11 PKC genes in 458 breast tumors from patients with known clinical/pathological status and long-term outcome. The proportion of tumors in which the expression of the different genes was altered varied widely, from 9.6% for PKN2 to 40.2% for PKCiota/lambda. In breast tumors, overexpression was the main alteration observed for PKCiota/lambda (33.4%), PKCdelta (29.5%) and PKCzeta (9.6%), whereas underexpression was the main alteration observed for PKCalpha (27.3%), PKCepsilon (11.6%), PKCeta (8.7%) and PKN2 (8.1%). Both overexpression and underexpression were observed for PKCbeta (underexpression 15.5%, overexpression 13.8%), PKCtheta (underexpression 14.8%, overexpression 10.0%) and PKN1 (underexpression 6.6%, overexpression 7.4%). Several links were found between different PKC genes; and also between the expression patterns of PKC genes and several classical pathological and clinical parameters. PKCiota/lambda alone was found to have prognostic significance (p = 0.043), whereas PKCalpha showed a trend towards an influence on relapse-free survival (p = 0.052). PKCiota/lambda retained its prognostic significance in Cox multivariate regression analysis (p = 0.031). These results reveal very complex expression patterns of PKC genes in breast tumors, and suggest that their expression should be considered together when evaluating anti-tumoral drugs. PKCiota/lambda seems to be the most promising therapeutic target in breast cancer. PMID- 22511073 TI - Functionalization of graphene by electrophilic alkylation of reduced graphite. AB - The reaction of Na/K-reduced graphite with hexyliodide represents a new, versatile and mild approach to synthesize alkylated graphene derivatives, which were characterized by a combination of Raman spectroscopy, TEM and TGA/MS analysis. PMID- 22511074 TI - In the name of the migrant father--analysis of surname origins identifies genetic admixture events undetectable from genealogical records. AB - Patrilineal heritable surnames are widely used to select autochthonous participants for studies on small-scale population genetic patterns owing to the unique link between the surname and a genetic marker, the Y-chromosome (Y-chr). Today, the question arises as to whether the surname origin will be informative on top of in-depth genealogical pedigrees. Admixture events that happened in the period after giving heritable surnames but before the start of genealogical records may be informative about the additional value of the surname origin. In this context, an interesting historical event is the demic migration from French speaking regions in Northern France to the depopulated and Dutch-speaking region Flanders at the end of the sixteenth century. Y-chr subhaplogroups of individuals with a French/Roman surname that could be associated with this migration event were compared with those of a group with autochthonous Flemish surnames. Although these groups could not be differentiated based on in-depth genealogical data, they were significantly genetically different from each other. Moreover, the observed genetic divergence was related to the differences in the distributions of main Y-subhaplogroups between contemporary populations from Northern France and Flanders. Therefore, these results indicate that the surname origin can be an important feature on top of in-depth genealogical results to select autochthonous participants for a regional population genetic study based on Y-chromosomes. PMID- 22511076 TI - [When the spinal cord is damaged]. PMID- 22511077 TI - [Does hospital mergers improve efficiency?]. PMID- 22511078 TI - [Can the immune system target cancer?]. PMID- 22511081 TI - Vaccination against pandemic influenza 2009. PMID- 22511083 TI - [Global control for good health]. PMID- 22511085 TI - [Psychoses in children and adolescents]. PMID- 22511086 TI - [Emergency tasks of nursing homes in small communities]. PMID- 22511087 TI - [Thiazides - when do we give up?]. PMID- 22511088 TI - Safety culture in the air ambulance services. PMID- 22511089 TI - Home monitoring of intraocular pressure. PMID- 22511090 TI - [The referral - monologue or dialogue?]. PMID- 22511091 TI - [Exotic imported disease and scourge of the poor]. PMID- 22511092 TI - Merging of three hospitals into one university hospital. AB - BACKGROUND: The merging of hospitals into health enterprises ensued from the Norwegian hospital reform of 2002. A complex restructuring process lasting from 2007 to 2009 resulted in the merger of three hospitals into the University Hospital of North Norway. MATERIAL AND METHOD: Clinical activities were reorganised into fewer and larger units (divisions) and changed from in-patient to day treatment. Leadership was established across geographic units, and a programme for improving patient care pathways was launched. The experience gained is described by means of activity data from January 2006 to April 2011. RESULTS: The number of patient contacts in the somatic sector was temporarily reduced by 7 % in 2009. The mean waiting period increased from 80 days in 2006 to 108 days in 2010, but fell to 85 days in 2011. In psychiatry and specialised cross disciplinary addiction therapy, the number of patient contacts increased, and waits were unchanged or shortened. National quality indicators showed unchanged or improved results. The number of scientific publications increased by 62 %. Productivity (DRG points per employee-month) increased from 0.73 to 0.79. The annual financial outcome was improved by NOK 537 million (12 % of the 2006 budget). 81 % of the employees were satisfied with their jobs after the restructuring. INTERPRETATION: We maintained activity and the quality of patient treatment at a high level through the change period, and the hospital's financial position has improved. The methods used do not allow conclusions on possible causal relationships between the change process and the results achieved in core activities. PMID- 22511093 TI - Post-lumbar puncture headache. AB - BACKGROUND: Headache is a complication of lumbar puncture that has been known for more than a hundred years. The aim of this paper is to provide an overview of the incidence and symptoms of, the risk factors for and the treatment of this type of headache. METHOD: The article is based on a literature search in PubMed for studies on headache after lumbar puncture followed by discretionary selection of publications. RESULTS: Post-dural puncture headache (PDPH) is characterised by the occurrence of a headache with a significant orthostatic component within 5 days of a lumbar puncture. The incidence depends on a number of factors. Younger women with a previous history of headaches appear to be at highest risk. The incidence can be significantly reduced by using a thin lumbar puncture needle with an atraumatic tip. The condition is self-limiting and harmless, but leads to significant morbidity. Caffeine alleviates the symptoms and reduces the course of the illness. When bed rest and caffeine prove ineffective, an epidural blood patch works well for the majority, but there is no consensus on when such treatment should be offered. INTERPRETATION: Headache frequently occurs after lumbar puncture. There is substantial evidence for recommending the use of a thin, atraumatic needle to reduce the incidence. For practical reasons, a needle thinner than 22 G is not suitable for diagnostic lumbar puncture. PMID- 22511094 TI - [A seriously ill patient who does not wake up after mechanical ventilation]. PMID- 22511095 TI - [A man in his fifties with syncope and hypotension]. AB - A man in his fifties was admitted to our hospital because of syncope and hypotension. In the emergency room he reported abdominal pain, but focused assessment with sonography for trauma (FAST) was negative. His systolic blood pressure varied between 60 and 90 mmHg and an arterial blood gas revealed lactic acidosis with normal haemoglobin, which still might indicate acute bleeding. An ECG did not indicate myocardial infarction. In the absence of an obvious bleeding focus, the patient was urgently transported to a CT lab nearby, to identify possible bleeding and rule out other causes of circulatory shock, such as cardiac tamponade. Before radiologic scanning was initiated, the patient lost consciousness and displayed pulseless electrical activity. Resuscitation was initiated and pericardiocentesis was resultless. On vital indication and clinical suspicion of cardiac tamponade, an emergency median sternotomy was performed and a haematoma was evacuated from the pericardial space. The patient was stabilised and immediately taken to the operation theatre where a ruptured ascending aortic aneurysm was identified. The operation was successful, but following serious hypoperfusion, the patient suffered acute kidney failure requiring dialysis for several months, gram-negative septicaemia caused by a central venous catheter, cerebral infarction leading to hemiparesis and impaired vision, ventilator-associated pneumonia/acute lung injury and acalculous cholecystitis. This case report describes the findings on admission, the diagnostic process including surgical resuscitation and a complicated course of multi-organ failure. After almost 5 months, the patient was discharged from our hospital to another institution for further rehabilitation. He now has minimal sequelae and lives at home. Our take-home message is that seriously ill patients require fast, resolute and broad examination; they may need immediate surgical treatment including emergency intervention; and a good clinical outcome may be achieved in spite of serious complications. PMID- 22511097 TI - Traumatic spinal cord injuries--incidence, mechanisms and course. AB - BACKGROUND: The primary purpose of this article is to provide an overview of demography, neurological level of injury, extent of lesion, incidence, prevalence, injury mechanisms as well as lethality and causes of death associated with traumatic spinal cord injuries. MATERIAL AND METHOD: A literature search was carried out in PubMed, with the search words "traumatic spinal cord injury"/"traumatic spinal cord injuries" together with "epidemiology", and "spinal cord injury"/"spinal cord injuries" together with "epidemiology". RESULTS: The reported annual incidence of traumatic spinal cord injuries varies from 2.3 per million in a study from Canada to 83 per million in Alaska. The prevalence is given as ranging from 236 per million in India to 1800 per million in the USA. The average age at the time of injury varies from 26.8 years in Turkey to 55.5 years in the USA. The ratio of men to women varies from 0.9 in Taiwan to 12.0 in Nigeria. The most frequent cause of injury is traffic accidents, followed by falls, violence and sports/leisure activity incidents. Patients with traumatic spinal cord injuries have a higher lethality than the normal population. The most frequent causes of death today are airway problems, heart disease and suicide. INTERPRETATION: There are large geographical differences in reported incidence, prevalence and lethality. This is attributable to differences in definition, inclusion, classification and patient identification procedures in the various studies, together with geographical and cultural differences and differences in prehospital and hospital treatment. PMID- 22511098 TI - [Pressure ulcers after spinal cord injury]. AB - BACKGROUND: Pressure ulcers are a serious and frequently occurring complication in patients with a traumatic spinal cord injury. The purpose of the article is to consider the causes of pressure ulcers and how to prevent them. METHOD: The article is based on a non-systematic search in the PubMed database and own clinical experience. RESULTS: 30-40 % of patients with spinal cord injuries develop pressure ulcers during the acute and rehabilitation phases, most frequently over bony prominences such as the sacrum, tuber ischii, heel, malleolus and trochanter. Risk factors are reduced activity/immobility, lack of sensibility, moisture due to urinary or faecal incontinence, muscular atrophy, prolonged time since injury, depression, smoking and poor nutrition. The most important preventive measures are pressure relief, regular change of position and frequent observation of the skin over bony prominences. INTERPRETATION: In most cases, patients with traumatic spinal cord injuries can be prevented from developing pressure ulcers. Prevention saves patients from long-term hospitalisation and the healthcare system from high costs. PMID- 22511100 TI - Punishment, treatment and fair retribution. PMID- 22511101 TI - [Rule of unaccountability--ripe for revision?]. PMID- 22511102 TI - [How history affects delusions]. PMID- 22511103 TI - [Can you be cured from schizophrenia?]. PMID- 22511104 TI - [Schizophrenia and violence--can one predict violent behavior?]. PMID- 22511105 TI - [Paranoid schizophrenia, paranoid psychoses and personality disorders]. PMID- 22511106 TI - [The physician as expert witness--the role and history]. PMID- 22511107 TI - [Assisted reproduction--biology and ethics]. PMID- 22511109 TI - [Klamydia or chlamydia, uretritt or urethritt?]. PMID- 22511112 TI - Use of the chromogenic factor X assay in patients transitioning from argatroban to warfarin therapy. AB - STUDY OBJECTIVE: To assess the correlation between the chromogenic factor X assay and the international normalized ratio (INR) in patients transitioning from argatroban to warfarin therapy. DESIGN: Retrospective medical record review. SETTING: Academic medical center and community-based teaching hospital. PATIENTS: One hundred thirty-nine patients who had chromogenic factor X levels measured during the transition from argatroban to warfarin therapy between January 1, 2006, and July 31, 2010. MEASUREMENTS AND MAIN RESULTS: The correlation between chromogenic factor X levels and INRs during the transition period was assessed by calculating the sensitivity, specificity, positive predictive value, and negative predictive value for chromogenic factor X levels that were less than or equal to 45% in predicting a therapeutic INR (2.0-3.5). Patients received an average of 4.4 doses of warfarin before argatroban was discontinued. In 60 patients (43.2%), chromogenic factor X levels were subtherapeutic at the time of argatroban discontinuation. Chromogenic factor X levels could predict a therapeutic INR with a sensitivity of 63.2%, a specificity of 80%, a positive predictive value of 93.5, and a negative predictive value of 32.3. In patients who received 5 or more days of warfarin overlap with argatroban, the sensitivity of chromogenic factor X levels to predict an INR greater than 2.0 was 78.2%, with a specificity of 77.8%, a positive predictive value of 95.6, and a negative predictive value of 36.8. The correlation of chromogenic factor X levels and a therapeutic INR was 18.1%; however, this poor correlation may have been due to increases in the INR values of the patients who received less than 5 days of warfarin overlap with argatroban. During the transition period, nine patients developed thrombi and eight patients experienced clinically significant bleeding. CONCLUSION: Measuring chromogenic factor X levels is recommended before transitioning patients from argatroban to warfarin therapy. Patients should receive at least 5 days of overlap with warfarin and have a chromogenic factor X level of 45% or less before discontinuing argatroban. PMID- 22511113 TI - Progress in fluoroalkylation of organic compounds via sulfinatodehalogenation initiation system. AB - The sulfinatodehalogenation reaction represents one of the most important methodologies to incorporate fluorine into organic molecules. Using inexpensive sulfur-containing reactants such as Na(2)S(2)O(4) under mild conditions, per- and polyfluoroalkyl halides (R(F)X, X = Br, I, CCl(3)) can be transformed smoothly into the corresponding sulfinate salts. This method is also used for the perfluoroalkylation of alkenes, dienes, alkynes and aromatics. Notably, after 1998, the sulfinatodehalogenation of perfluoroalkyl chlorides (R(F)Cl) has been realized by using dimethylsulfoxide (DMSO) as a solvent instead of CH(3)CN/H(2)O in the Na(2)S(2)O(4)/NaHCO(3) initiation system. Perfluoroalkyl chlorides, ethyl chlorofluoroacetates and chlorodifluoroacetates, and even nonfluorinated compounds, such as ethyl chloro- or dichloroacetates and chloroform, were either converted into the corresponding sulfinate salts or alkylated alkenes, alkynes and aromatics (including porphyrins). The sulfinatodehalogenation reaction has remarkable advantages. With the increasing demands to utilize the unique properties of fluorine and fluorinated functional groups in medicinal, agricultural and material sciences, we believe that there will continue to be useful developments in sulfinatodehalogenation chemistry and it will be applied more widely in the future. PMID- 22511114 TI - [Management of advanced prostate cancer in elderly patients]. AB - With the increase of the senior demographic, an increase in cancer including prostate cancer has been seen. The challenge is to offer personalized cancer care because of population specificity. The only way is to share two experiences: the oncologist's experience who knows prostate cancer, prognosis and adverses effects of treatments and geriatrician's experience who consider old patients in their entirety thanks to comprehensive geriatric assessment (CGA). This article provides data about treatments of prostate cancer and geriatric evaluation to demonstrate the importance to work together for a "tailored" care. PMID- 22511115 TI - High-throughput, multiplexed analysis of 3-nitrotyrosine in individual proteins. AB - Reactive nitrogen species (RNS) and reactive oxygen species (ROS) are derived as a result of inflammation and oxidative stress and can result in protein modifications. As such, these protein modifications are used as biomarkers for inflammation and oxidative stress. In addition, modifications in single-tissue associated proteins released into blood can provide insight into the tissue localization of the inflammation or oxidative stress. We have developed an enzyme linked immunosorbent assay antibody microarray platform to analyze the levels of 3-nitrotyrosine in specific proteins in a variety of biological samples, including human plasma and sputum. Selective-capture antibodies are used to immunoprecipitate individual proteins from samples onto isolated spots on the microarray chips. Then, a monoclonal antibody for 3-nitrotyrosine is used to detect the amount of 3-nitrotyrosine on each spot. Our studies suggest that this approach can be used to detect trace amounts of 3-nitrotyrosine in human plasma and sputum. In this paper, we describe our antibody microarray protocol for detecting 3-nitrotyrosine in specific proteins. PMID- 22511116 TI - Developmental immunotoxicity (DIT): assays for evaluating effects of exogenous agents on development of the immune system. AB - Developmental immunotoxicity (DIT) occurs when exposure to environmental risk factors prior to adulthood, including chemical, biological, physical, or physiological factors, alters immune system development. DIT may elicit suppression, hyperactivation, or misregulation of immune responses and may present clinically as decreased resistance to pathogens, allergic and autoimmune diseases, and inflammatory diseases. Immunotoxicity testing guidelines established by the Environmental Protection Agency for adult animals (OPPTS 8703.7800) require functional tests and immunophenotyping that are suitable for detecting immunomodulation, especially immunosuppression. However, evaluating immune function in offspring that are not fully immunocompetent yields results that are challenging to interpret. Therefore, this unit will describe an optimum exposure scenario, reference two assays (immunophenotyping and histopathology) appropriate for detecting immunomodulation in weaning-age offspring, and reference four assays (immunophenotyping, histopathology, T cell-dependent antibody responses, and delayed-type hypersensitivity) appropriate for detecting immunomodulation in immunocompetent offspring. The protocol also will reference other assays (natural killer cell and cytotoxic T lymphocyte) with potential utility for assessing DIT. PMID- 22511117 TI - The local lymph node assay (LLNA). AB - The murine local lymph node assay (LLNA) is a widely accepted method for assessing the skin sensitization potential of chemicals. Compared with other in vivo methods in guinea pig, the LLNA offers important advantages with respect to animal welfare, including a requirement for reduced animal numbers as well as reduced pain and trauma. In addition to hazard identification, the LLNA is used for determining the relative skin sensitizing potency of contact allergens as a pivotal contribution to the risk assessment process. The LLNA is the only in vivo method that has been subjected to a formal validation process. The original LLNA protocol is based on measurement of the proliferative activity of draining lymph node cells (LNC), as determined by incorporation of radiolabeled thymidine. Several variants to the original LLNA have been developed to eliminate the use of radioactive materials. One such alternative is considered here: the LLNA:BrdU ELISA method, which uses 5-bromo-2-deoxyuridine (BrdU) in place of radiolabeled thymidine to measure LNC proliferation in draining nodes. PMID- 22511118 TI - CYP1B1 detection. AB - This unit describes procedures for measuring CYP1B1 gene expression by reverse transcription real-time PCR (qRT-PCR), CYP1B1 protein levels by western blotting, and CYP1B1 enzyme activity through conversion of 7-ethoxyresorufin substrate. To achieve specific measurement of CYP1B1 activity in the presence of CYP1A1 and CYP1A2, CYP1B1 inhibition and a subtractive approach have been adopted. 2,4,3',5' Tetramethoxystilbene (TMS) is a potent and selective competitive inhibitor of CYP1B1 with an IC50 of 3 nM for EROD and ~90 nM for E2 4-hydroxylation. Binding studies with purified CYP1B1 suggests that TMS interferes in the proximity of the heme region of CYP1B1 with high affinity. Compared to other potent inhibitors such as alpha-naphthoflavone, which is a known CYP1 family inhibitor with no selectivity between CYP1B1 and CYP1A2, TMS is ~50- and 520-fold selective for inhibition of CYP1B1 when compared to CYP1A1 and CYP1A2, respectively. Thus, TMS can serve as a helpful chemical scalpel for dissecting CYP1B1 activity from the overall activity of CYP1 family members against ethoxyresorufin. PMID- 22511119 TI - Sex-specific differences in the concentration of tubular parameters in the amniotic fluid of second trimester fetuses. AB - OBJECTIVE: Renal dysplasia and obstructive uropathy are more common in males and are associated with an increased tubular loss of electrolytes. We aimed to compare the midtrimester concentration of tubular parameters in the prenatal period between healthy male and female fetuses. METHODS: Amniotic fluid was collected at 16 weeks of gestation at the time of genetic amniocentesis. The concentration of sodium, chloride, potassium, calcium, phosphate, magnesium, alpha1-microglobulin, creatinine and urea was determined in the amniotic fluid of 92 male and 108 female fetuses. RESULTS: The concentration of sodium, chloride and calcium was not significantly higher in male than in female fetuses. In contrast, the concentration of potassium (p=0.01), phosphate (p=0.04), magnesium (p=0.04) and alpha1-microglobulin (p=0.04) was significantly increased in the amniotic fluid of male fetuses. The concentration of electrolytes correlated to the concentration of creatinine, urea and alpha1-microglobulin. CONCLUSION: The concentration of specific tubular parameters in the amniotic fluid was higher in male compared with female fetuses. Whether this might point to sex-specific differences in tubular function in second trimester fetuses or reflect glomerular filtration or other interfering factors remains speculative. PMID- 22511121 TI - Testing of the effect of missing data estimation and distribution in morphometric multivariate data analyses. AB - Missing data are an unavoidable problem in biological data sets and the performance of missing data deletion and estimation techniques in morphometric data sets is poorly understood. Here, a novel method is used to measure the introduced error of multiple techniques on a representative sample. A large sample of extant crocodilian skulls was measured and analyzed with principal component analysis (PCA). Twenty-three different proportions of missing data were introduced into the data set, estimated, analyzed, and compared with the original result using Procrustes superimposition. Previous work investigating the effects of missing data input missing values randomly, a non-biological phenomenon. Here, missing data were introduced into the data set using three methodologies: purely at random, as a function of the Euclidean distance between respective measurements (simulating anatomical regions), and as a function of the portion of the sample occupied by each taxon (simulating unequal missing data in rare taxa). Gower's distance was found to be the best performing non-estimation method, and Bayesian PCA the best performing estimation method. Specimens of the taxa with small sample sizes and those most morphologically disparate had the highest estimation error. Distribution of missing data had a significant effect on the estimation error for almost all methods and proportions. Taxonomically biased missing data tended to show similar trends to random, but with higher error rates. Anatomically biased missing data showed a much greater deviation from random than the taxonomic bias, and with magnitudes dependent on the estimation method. PMID- 22511120 TI - Fluorescent silica particles for monitoring oxygen levels in three-dimensional heterogeneous cellular structures. AB - Bacterial biofilms are a major obstacle challenging the development of more effective therapies to treat implant infections. Oxygen availability to bacterial cells has been implicated in biofilm formation and planktonic cell detachment; however, there are insufficient tools available to measure oxygen concentrations within complex three-dimensional structures with ~ 1 um resolution. Such measurements may complement measures of biofilm structure and cell activity to provide a more comprehensive understanding of biofilm biology. Thus, we developed oxygen-sensing microparticles specifically designed to characterize oxygen transport through the volume of bacterial biofilms. The Stober method was used to synthesize monodisperse silica microparticles of approximately the same size as a bacterium (~ 1 um). Two fluorophores, oxygen-sensitive Ru(Ph(2) phen(3))Cl(2), and the reference fluorophore Nile blue chloride were immobilized on the surface of the particles. We demonstrate application of the microparticles toward measuring the oxygen concentration profiles within a live Staphylococcus aureus biofilm. PMID- 22511122 TI - A disposable picolitre bioreactor for cultivation and investigation of industrially relevant bacteria on the single cell level. AB - In the continuously growing field of industrial biotechnology the scale-up from lab to industrial scale is still a major hurdle to develop competitive bioprocesses. During scale-up the productivity of single cells might be affected by bioreactor inhomogeneity and population heterogeneity. Currently, these complex interactions are difficult to investigate. In this report, design, fabrication and operation of a disposable picolitre cultivation system is described, in which environmental conditions can be well controlled on a short time scale and bacterial microcolony growth experiments can be observed by time lapse microscopy. Three exemplary investigations will be discussed emphasizing the applicability and versatility of the device. Growth and analysis of industrially relevant bacteria with single cell resolution (in particular Escherichia coli and Corynebacterium glutamicum) starting from one single mother cell to densely packed cultures is demonstrated. Applying the picolitre bioreactor, 1.5-fold increased growth rates of C. glutamicum wild type cells were observed compared to typical 1 litre lab-scale batch cultivation. Moreover, the device was used to analyse and quantify the morphological changes of an industrially relevant l-lysine producer C. glutamicum after artificially inducing starvation conditions. Instead of a one week lab-scale experiment, only 1 h was sufficient to reveal the same information. Furthermore, time lapse microscopy during 24 h picolitre cultivation of an arginine producing strain containing a genetically encoded fluorescence sensor disclosed time dependent single cell productivity and growth, which was not possible with conventional methods. PMID- 22511123 TI - Knowledge and attitudes about Alzheimer's disease in the lay public: influence of caregiving experience and other socio-demographic factors in an Italian sample. AB - BACKGROUND AND AIMS: Despite increasing attention on the knowledge of dementia among patients and family members, little is known about the general public's level of understanding about dementia. The aim of this study was to assess the influence of the caregiving experience, sex and age on the knowledge of AD. METHODS: Eleven hundred and eleven individuals were enrolled. They fulfilled a questionnaire made of 25 questions. The questionnaires were submitted in the waiting rooms of several departments of the Hospital "Spedali Civili di Brescia". The questionnaires assessed several issues, including the general knowledge about Alzheimer's disease, the management and ethical problems. The present study is focused on the analysis of 9 of the 25 questions included in the questionnaire, highlighting aspects about knowledge of symptoms, risk factors, therapies and services. RESULTS: The percentage of correct responses was significantly greater among the caregivers. The group of old respondents gave similar answers, independently of their caregiving status. Women, caregivers or not, are the more knowledgeable group. CONCLUSION: The entire population needs accurate information, but education programs should be specifically tailored for the different sections of the population because they may start with different levels of knowledge. PMID- 22511124 TI - Notalgia paraesthetica: a descriptive two-cohort study of 65 patients from Brazil and Germany. AB - Notalgia paraesthetica is a neuropathic pruritus on the back. The aim of this retrospective study was to examine patient characteristics in a consecutive cohort from Brazil and Germany. A total of 65 patients (49 women, 16 men; age range 25-80 years, mean 56.2 +/- 12.7 years; median 57.0 years) were investigated in order to determine the spinal or peripheral origin of notalgia paraesthetica. Protein gene product 9.5-positive intraepidermal nerve fibers were significantly reduced in the pruritic compared with the non-lesional area (p < 0.05). In 32.3% of patients, radiological examinations showed a stenosis and in 47.7% a degeneration. A correlation between the radiological findings and the exact dermatomal localization of notalgia paraesthetica was found in 15.7% of the involved areas. The significant reduction in intraepidermal nerve fiber density suggests that damage to the peripheral nerves is a more important aetiological factor than spinal changes in notalgia paraesthetica. PMID- 22511126 TI - Relationship between neighborhood poverty rate and bloodstream infections in the critically ill. AB - BACKGROUND: Poverty is associated with increased risk of chronic illness, but its contribution to bloodstream infections is not well-defined. METHODS: We performed a multicenter observational study of 14,657 patients, aged 18 yrs or older, who received critical care and had blood cultures drawn between 1997 and 2007 in two hospitals in Boston, Massachusetts. Data sources included 1990 U.S. Census and hospital administrative data. Census tracts were used as the geographic units of analysis. The exposure of interest was neighborhood poverty rate categorized as <5%, 5%-10%, 10%-20%, 20%-40%, and >40%. Neighborhood poverty rate is the percentage of residents with income below the federal poverty line. The primary end point was bloodstream infection occurring 48 hrs before critical care initiation to 48 hrs after. Associations between neighborhood poverty rate and bloodstream infection were estimated by logistic regression models. Adjusted odds ratios were estimated by multivariable logistic regression models. RESULTS: Two thousand four-hundred thirty-five patients had bloodstream infections. Neighborhood poverty rate was a strong predictor of risk of bloodstream infection, with a significant risk gradient across neighborhood poverty rate quintiles. After multivariable analysis, neighborhood poverty rate in the highest quintiles (20%-40% and >40%) were associated with a 26% and 49% increase in bloodstream infection risk, respectively, relative to patients with neighborhood poverty rate of <5%. CONCLUSIONS: Within the limitations of our study design, increased neighborhood poverty rate, a proxy for decreased socioeconomic status, appears to be associated with risk of bloodstream infection among patients who receive critical care. PMID- 22511127 TI - Active surveillance cultures of methicillin-resistant Staphylococcus aureus as a tool to predict methicillin-resistant S. aureus ventilator-associated pneumonia. AB - OBJECTIVE: Ventilator-associated pneumonia is one of the most common infections in the intensive care unit and methicillin-resistant Staphylococcus aureus has emerged as a common cause of ventilator-associated pneumonia. We sought to study the performance characteristics of once weekly active surveillance culture of methicillin-resistant S. aureus colonization in predicting the development of methicillin-resistant S. aureus ventilator-associated pneumonia. DESIGN: Prospective observational study. SETTING: Eighty-nine-bed surgical and medical intensive care units in a university-affiliated urban teaching hospital and level I trauma and burn center. PATIENTS: All patients>=16 yrs old admitted to the intensive care unit on mechanical ventilation>=48 hrs who met diagnostic criteria for ventilator-associated pneumonia by quantitative lower respiratory tract cultures obtained through bronchoscopic alveolar lavage or brush specimen between January 2008 and October 2010 were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Nine hundred twenty-four episodes of suspected ventilator associated pneumonia were evaluated, and 388 patients with bronchoalveolar lavage confirmed ventilator-associated pneumonia were included. Surveillance cultures were taken from the nares, oropharynx or trachea, and any open wound routinely on admission to the intensive care unit, every 7 days afterward, and at intensive care unit discharge. Of the 388 patients, 37 (9.5%) had methicillin-resistant S. aureus ventilator-associated pneumonia and 54 (13.9%) had methicillin-resistant S. aureus colonization documented by active surveillance culture before the development of ventilator-associated pneumonia. The sensitivity and specificity of prior methicillin-resistant S. aureus colonization as a predictor for methicillin-resistant S. aureus ventilator-associated pneumonia are 70.3% (95% confidence interval [CI] 52.8-83.6) and 92.0% (95% CI 88.5-94.5), respectively. The positive and negative predictive values are 48.1% (95% CI 34.5- 62.0) and 96.7% (95% CI 94.0-98.3). CONCLUSIONS: In our study, prior methicillin-resistant S. aureus colonization as ascertained by once-weekly active surveillance culture yielded high specificity and negative predictive value, suggesting that negative active surveillance culture can accurately exclude methicillin-resistant S. aureus as an etiology in most patients with ventilator-associated pneumonia and may decrease the need for empirical methicillin-resistant S. aureus coverage in patients with suspected ventilator-associated pneumonia. PMID- 22511128 TI - Effectiveness of stepwise interventions targeted to decrease central catheter associated bloodstream infections. AB - OBJECTIVE: Determine the impact of three stepwise interventions on the rate of central catheter-associated bloodstream infections. DESIGN: Quasi-experimental study. SETTING: Three surgical intensive care units (general surgery, trauma, and neurosurgery) at a 1500-bed county teaching hospital in the Miami metro area. PATIENTS: All consecutive central catheter-associated bloodstream infection cases as determined by the Infection Control Department. INTERVENTIONS: Three interventions aimed at catheter maintenance were implemented at different times in the units: chlorhexidine "scrub-the-hub," chlorhexidine daily baths, and daily nursing rounds aimed at assuring compliance with an intensive care unit goal oriented checklist. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the monthly intensive care unit rate of central catheter-associated bloodstream infections (infections per 1000 central catheter days). Over 33 months of follow up (July 2008 to March 2011), we found decreased rates in each of the three intensive care units evaluated during the interventions, especially after implementation of chlorhexidine daily baths. Rates in unit A decreased from a rate of 8.6 to 0.5, unit B from 6.9 to 1.6, and unit C from 7.8 to 0.6. Secondary bloodstream infection rates remained unchanged throughout the observation period in units A and B; however, unit C had a decrease in its rates over time. CONCLUSIONS: We report the progressive reduction of central catheter-associated bloodstream infection rates after the stepwise implementation of chlorhexidine "scrub-the-hub" and daily baths in surgical intensive care units, suggesting effectiveness of these interventions. PMID- 22511129 TI - Surviving sepsis: a time for "don't just do something, stand there" philosophy? PMID- 22511130 TI - Sepsis-associated changes of the arachidonic acid metabolism and their diagnostic potential in septic patients. AB - OBJECTIVES: Sepsis-associated changes of the arachidonic acid metabolism and the utility of arachidonic acid metabolites for the diagnosis of sepsis have been poorly investigated so far. Therefore, the primary objective of our study was to screen for differentially regulated arachidonic acid metabolites in septic patients using a lipopolysaccharide whole-blood model and to investigate their diagnostic potential. DESIGN: Prospective, observational, single-center, clinical study. SETTING: Intensive care unit at University Hospital Leipzig. PATIENTS: Thirty-five patients (first cohort 25 patients, second cohort 10 patients) meeting the criteria for severe sepsis or septic shock were enrolled. Eighteen healthy volunteers (first cohort 15 subjects, second cohort 3 subjects) were enrolled as controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Arachidonic acid and its metabolites were investigated in supernatants of nonactivated (baseline) and lipopolysaccharide-activated heparinized whole blood of healthy subjects (n=15) and septic patients (n=25) by solid phase extraction and subsequent liquid chromatography-tandem mass spectrometry. Arachidonic acid, arachidonic acid analogues, and the cyclooxygenase-associated metabolites prostaglandin E2, 11-hydroxyeicosatetraenoic acid, and thromboxane B2 were identified as differentiating metabolites between septic patients and healthy subjects. Some of these compounds, including arachidonic acid, its analogues, and the cyclooxygenase metabolites prostaglandin E2 and thromboxane B2 differed at baseline. The inducibility of arachidonic acid and the cyclooxygenase metabolites 11-hydroxyeicosatetraenoic and prostaglandin E2 were reduced by 80% to 90% in septic patients. The degree of the inducibility was associated with severity of sepsis and clinical outcome. A reduced inducibility of COX-2 but preserved inducibility of mPGES-1 on gene expression level were confirmed in an independent cohort of septic patients (n=10) by quantitative reverse-transcription polymerase chain reaction compared to healthy controls (n=3). CONCLUSIONS: Arachidonic acid metabolism is markedly affected in patients with sepsis. Our data suggest that the analysis of arachidonic acid metabolites in an in vitro whole blood activation model may be a promising approach for risk estimation in septic patients that has to be further evaluated in subsequent large-scale clinical studies. PMID- 22511132 TI - The relationship between organizational culture and family satisfaction in critical care. AB - OBJECTIVES: Family satisfaction with critical care is influenced by a variety of factors. We investigated the relationship between measures of organizational and safety culture, and family satisfaction in critical care. We further explored differences in this relationship depending on intensive care unit survival status and length of intensive care unit stay of the patient. DESIGN: Cross-sectional surveys. SETTING: Twenty-three tertiary and community intensive care units within three provinces in Canada. SUBJECTS: One thousand two-hundred eighty-five respondents from 2374 intensive care unit clinical staff, and 880 respondents from 1381 family members of intensive care unit patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Intensive care unit staff completed the Organization and Management of Intensive Care Units survey and the Hospital Survey on Patient Safety Culture. Family members completed the Family Satisfaction in the Intensive Care Unit 24, a validated survey of family satisfaction. A priori, we analyzed adjusted relationships between each domain score from the culture surveys and either satisfaction with care or satisfaction with decision-making for each of four subgroups of family members according to patient descriptors: intensive care unit survivors who had length of intensive care unit stay <14 days or >14 days, and intensive care unit nonsurvivors who had length of stay <14 days or >=14 days. We found strong positive relationships between most domains of organizational and safety culture, and satisfaction with care or decision-making for family members of intensive care unit nonsurvivors who spent at least 14 days in the intensive care unit. For the other three groups, there were only a few weak relationships between domains of organizational and safety culture and family satisfaction. CONCLUSIONS: Our findings suggest that the effect of organizational culture on care delivery is most easily detectable by family members of the most seriously ill patients who interact frequently with intensive care unit staff, who are intensive care unit nonsurvivors, and who spend a longer time in the intensive care unit. Positive relationships between measures of organizational and safety culture and family satisfaction suggest that by improving organizational culture, we may also improve family satisfaction. PMID- 22511133 TI - Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy: a multicentre pharmacokinetic study. AB - OBJECTIVES: In critically ill patients receiving continuous renal replacement therapy, we aimed to assess the variability of antibiotic trough concentrations, the influence of effluent flow rates on such concentrations, and the incidence of suboptimal antibiotic dosage. DESIGN: Prospective, observational, multicenter, pharmacokinetic study. SETTING: Four tertiary intensive care units within the multicenter RENAL randomized controlled trial of continuous renal replacement therapy intensity. PATIENTS: Twenty-four critically ill adult patients with acute kidney injury receiving ciprofloxacin, meropenem, piperacillin/tazobactam, or vancomycin during continuous renal replacement therapy. INTERVENTIONS: We obtained trough blood samples and measured antibiotic concentrations. MEASUREMENTS AND MAIN RESULTS: We obtained data from 40 dosing intervals and observed wide variability in trough concentrations (6.7-fold for meropenem, 3.8 fold for piperacillin, 10.5-fold for tazobactam, 1.9-fold for vancomycin, and 3.9 fold for ciprofloxacin). The median (interquartile range) trough concentrations (mg/L) for meropenem was 12.1 (7.8-18.4), 105.0 (74.4-204.0)/3.8 (3.4-21.8) for piperacillin/tazobactam, 12.0 (9.8-16.0) for vancomycin, and 3.7 (3.0-5.6) for ciprofloxacin. Overall, 15% of dosing intervals did not meet predetermined minimum therapeutic target concentrations, 40% did not achieve the higher target concentration, and, during 10% of dosing intervals, antibiotic concentrations were excessive. No difference, however, was found between patients on the basis of the intensity of continuous renal replacement therapy; this effect may have been obscured by differences in dosing regimens, time off the filter, or altered pharmacokinetics. CONCLUSIONS: There is significant variability in antibiotic trough concentrations in critically ill patients receiving continuous renal replacement therapy, which did not only appear to be influenced by effluent flow rate. Here, empirical dosing of antibiotics failed to achieve the target trough antibiotic concentration during 25% of the dosing intervals. PMID- 22511134 TI - Trends in the incidence of noncardiogenic acute respiratory failure: the role of race. AB - OBJECTIVE: We sought to examine trends in the race-specific incidence of acute respiratory failure in the United States. DESIGN: Retrospective cohort study. SETTING: We used the National Hospital Discharge Survey database (1992-2007), an annual survey of approximately 500 hospitals weighted to provide national hospitalization estimates. PATIENTS: All incident cases of noncardiogenic acute respiratory failure hospitalized in the United States. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified noncardiogenic acute respiratory failure by the presence of International Classification of Diseases, Ninth Revision, codes for respiratory failure or pulmonary edema (518.4, 518.5, 518.81, and 518.82) and mechanical ventilation (96.7*), excluding congestive heart failure. Incidence rates were calculated using yearly census estimates standardized to the age and sex distribution of the 2000 census population. Annual cases of noncardiogenic acute respiratory failure increased from 86,755 in 1992 to 323,474 in 2007. Noncardiogenic acute respiratory failure among black Americans increased from 56.4 (95% confidence interval 39.7-73.1) to 143.8 (95% confidence interval 123.8-163.8) cases per 100,000 in 1992 and 2007, respectively. Among white Americans, the incidence of noncardiogenic acute respiratory failure increased from 31.2 (95% confidence interval 26.2-36.5) to 94.0 (95% confidence interval 86.7-101.2) cases per 100,000 in 1992 and 2007, respectively. The average annual incidence of noncardiogenic acute respiratory failure over the entire study period was 95.1 (95% confidence interval 93.9-96.4) cases per 100,000 for black Americans compared to 66.5 (95% confidence interval 65.8-67.2) cases per 100,000 for white Americans (rate ratio 1.43, 95% confidence interval 1.42-1.44). Overall in-hospital mortality was greater for other-race Americans, but only among patients with two or more organ failures (57% [95% confidence interval 56%-59%] for other race, 51% [95% confidence interval 50% 52%] for white, 50% [95% confidence interval 49%-51%] for black). CONCLUSIONS: The incidence of noncardiogenic acute respiratory failure in the United States increased between 1992 and 2007. Black and other-race Americans are at greater risk of developing noncardiogenic acute respiratory failure compared to white Americans. PMID- 22511135 TI - Right ventricular function during high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome. AB - OBJECTIVE: To evaluate the effect of mean airway pressure under high-frequency oscillatory ventilation on right ventricular function. DESIGN: Prospective randomized study. SETTING: Intensive care unit of a tertiary care hospital. PATIENTS: Sixteen consecutive patients within the first 48 hrs of mainly pulmonary acute respiratory distress syndrome. INTERVENTIONS: After a 6-hr-period of protective conventional mechanical ventilation, patients were submitted to three 1-hr periods of high-frequency oscillatory ventilation (+5, +10, +15) in a randomized order, with a mean airway pressure level determined by adding 5, 10, or 15 cm H2O to the mean airway pressure recorded during conventional mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Mean airway pressure was 18+/-3 cm H2O during conventional mechanical ventilation and was increased until 33+/-3 cm H2O at high-frequency oscillatory ventilation+15. Right ventricular function was assessed using transesophageal echocardiography. During conventional mechanical ventilation, nine patients presented a right ventricular dysfunction (right ventricular end-diastolic area/left ventricular end-diastolic area ratio>0.6) of whom four patients had a right ventricular failure (right ventricular end diastolic area/left ventricular end-diastolic area ratio>0.9). High-frequency oscillatory ventilation+10 and +15 further worsened right ventricular function, resulting in about a 40% increase in right ventricular end-diastolic area/left ventricular end-diastolic area ratio and a 30% increase in end-diastolic eccentricity index when compared with conventional mechanical ventilation or high frequency oscillatory ventilation+5 periods. At high-frequency oscillatory ventilation+15, 15 patients had right ventricular dysfunction and nine had right ventricular failure. High-frequency oscillatory ventilation did not improve oxygenation whatever the mean airway pressure level. A significant redistribution of tidal variation to the posterior parts of the lung was observed on electrical impedance tomography measurements when increasing mean airway pressure. However, this redistribution was not observed in patients who presented a worsening of right ventricular function (right ventricular end-diastolic area/left ventricular end-diastolic area increase>40%) at high-frequency oscillatory ventilation+15. CONCLUSIONS: In patients with mainly pulmonary acute respiratory distress syndrome, using high mean airway pressure under high-frequency oscillatory ventilation can worsen right ventricular function when compared with protective conventional mechanical ventilation, notably in patients in whom high-frequency oscillatory ventilation produced less alveolar recruitment of the posterior parts of the lungs. This study highlights the interest of monitoring right ventricular function during high-frequency oscillatory ventilation. PMID- 22511131 TI - Critical illness from 2009 pandemic influenza A virus and bacterial coinfection in the United States. AB - OBJECTIVES: The contribution of bacterial coinfection to critical illness associated with 2009 influenza A virus infection remains uncertain. The objective of this study was to determine whether bacterial coinfection increased the morbidity and mortality of 2009 influenza A. DESIGN: Retrospective and prospective cohort study. SETTING: Thirty-five adult U.S. intensive care units over the course of 1 yr. PATIENTS: Six hundred eighty-three critically ill adults with confirmed or probable 2009 influenza A. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A confirmed or probable case was defined as a positive 2009 influenza A test result or positive test for influenza A that was otherwise not subtyped. Bacterial coinfection was defined as documented bacteremia or any presumed bacterial pneumonia with or without positive respiratory tract culture within 72 hrs of intensive care unit admission. The mean age was 45+/-16 yrs, mean body mass index was 32.5+/-11.1 kg/m, and mean Acute Physiology and Chronic Health Examination II score was 21+/-9, with 76% having at least one comorbidity. Of 207 (30.3%) patients with bacterial coinfection on intensive care unit admission, 154 had positive cultures with Staphylococcus aureus (n=57) and Streptococcus pneumoniae (n=19), the most commonly identified pathogens. Bacterial coinfected patients were more likely to present with shock (21% vs. 10%; p=.0001), require mechanical ventilation at the time of intensive care unit admission (63% vs. 52%; p=.005), and have longer duration of intensive care unit care (median, 7 vs. 6 days; p=.05). Hospital mortality was 23%; 31% in bacterial coinfected patients and 21% in patients without coinfection (p=.002). Immunosuppression (relative risk 1.57; 95% confidence interval 1.20 -2.06; p=.0009) and Staphylococcus aureus at admission (relative risk 2.82; 95% confidence interval 1.76-4.51; p<.0001) were independently associated with increased mortality. CONCLUSIONS: Among intensive care unit patients with 2009 influenza A, bacterial coinfection diagnosed within 72 hrs of admission, especially with Staphylococcus aureus, was associated with significantly higher morbidity and mortality. PMID- 22511137 TI - Guidelines for intensive care unit design. AB - OBJECTIVE: To develop a guideline to help guide healthcare professionals participate effectively in the design, construction, and occupancy of a new or renovated intensive care unit. PARTICIPANTS: A group of multidisciplinary professionals, designers, and architects with expertise in critical care, under the direction of the American College of Critical Care Medicine, met over several years, reviewed the available literature, and collated their expert opinions on recommendations for the optimal design of an intensive care unit. SCOPE: The design of a new or renovated intensive care unit is frequently a once- or twice in-a-lifetime occurrence for most critical care professionals. Healthcare architects have experience in this process that most healthcare professionals do not. While there are regulatory documents, such as the Guidelines for the Design and Construction of Health Care Facilities, these represent minimal guidelines. The intent was to develop recommendations for a more optimal approach for a healing environment. DATA SOURCES AND SYNTHESIS: Relevant literature was accessed and reviewed, and expert opinion was sought from the committee members and outside experts. Evidence-based architecture is just in its beginning, which made the grading of literature difficult, and so it was not attempted. The previous designs of the winners of the American Institute of Architects, American Association of Critical Care Nurses, and Society of Critical Care Medicine Intensive Care Unit Design Award were used as a reference. Collaboratively and meeting repeatedly, both in person and by teleconference, the task force met to construct these recommendations. CONCLUSIONS: Recommendations for the design of intensive care units, expanding on regulatory guidelines and providing the best possible healing environment, and an efficient and cost-effective workplace. PMID- 22511136 TI - Predictors and correlates of dissatisfaction with intensive care. AB - OBJECTIVE: Dissatisfaction is an important threat to high-quality care. The aim of this study was to identify factors independently associated with dissatisfaction with critical care. DESIGN: Prospectively collected observational cohort study. SETTING: Nine intensive care units at a tertiary care university hospital in the United States. PARTICIPANTS: Four hundred forty-nine family members of adult intensive care unit patients who completed the Family Satisfaction with Care in the Intensive Care Unit instrument. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Four family-and patient-related factors ascertainable at intensive care unit admission independently predicted low overall satisfaction: living in the same city as the hospital, disagreement within the family regarding care, having a cardiac comorbidity but being hospitalized in a noncardiac-care intensive care unit, and living in a different household than the patient. When three or more risk factors were present, 63% (95% confidence interval 48%-78%) of families were dissatisfied. Among factors ascertained at the end of the intensive care unit stay, dissatisfaction with six items was independently associated with overall dissatisfaction: 1) perceived competence of nurses (odds ratio for dissatisfaction=5.9, 95% confidence interval 2.3-15.2); 2) concern and caring by intensive care unit staff (odds ratio 5.0, 95% confidence interval 1.9-12.6); 3) completeness of information (odds ratio 4.4, 95% confidence interval 2.4-8.1); 4) dissatisfaction with the decision making process (odds ratio 3.0, 95% confidence interval 1.6- 5.6); 5) atmosphere of the intensive care unit (odds ratio 2.6, 95% confidence interval 1.4-4.8); and 6) atmosphere of the waiting room (odds ratio 2.7, 95% confidence interval 1.2 6.0). CONCLUSION: Specific factors ascertainable at intensive care unit admission identify families at high risk of dissatisfaction with care. Other discrete aspects of the patient/family experience that develop during the intensive care unit stay are also strongly associated with dissatisfaction with the critical care experience. These results may provide insight into the design of future evidence-based strategies to improve satisfaction with the intensive care unit experience. PMID- 22511138 TI - Prediction of outcome after moderate and severe traumatic brain injury: external validation of the International Mission on Prognosis and Analysis of Clinical Trials (IMPACT) and Corticoid Randomisation After Significant Head injury (CRASH) prognostic models. AB - OBJECTIVE: The International Mission on Prognosis and Analysis of Clinical Trials and Corticoid Randomisation After Significant Head injury prognostic models predict outcome after traumatic brain injury but have not been compared in large datasets. The objective of this is study is to validate externally and compare the International Mission on Prognosis and Analysis of Clinical Trials and Corticoid Randomisation after Significant Head injury prognostic models for prediction of outcome after moderate or severe traumatic brain injury. DESIGN: External validation study. PATIENTS: We considered five new datasets with a total of 9,036 patients, comprising three randomized trials and two observational series, containing prospectively collected individual traumatic brain injury patient data. MEASUREMENTS AND MAIN RESULTS: Outcomes were mortality and unfavorable outcome, based on the Glasgow Outcome Score at 6 months after injury. To assess performance, we studied the discrimination of the models (by area under the receiver operating characteristic curves), and calibration (by comparison of the mean observed to predicted outcomes and calibration slopes). The highest discrimination was found in the Trauma Audit and Research Network trauma registry (area under the receiver operating characteristic curves between 0.83 and 0.87), and the lowest discrimination in the Pharmos trial (area under the receiver operating characteristic curves between 0.65 and 0.71). Although differences in predictor effects between development and validation populations were found (calibration slopes varying between 0.58 and 1.53), the differences in discrimination were largely explained by differences in case mix in the validation studies. Calibration was good, the fraction of observed outcomes generally agreed well with the mean predicted outcome. No meaningful differences were noted in performance between the International Mission on Prognosis and Analysis of Clinical Trials and Corticoid Randomisation After Significant Head injury models. More complex models discriminated slightly better than simpler variants. CONCLUSIONS: Since both the International Mission on Prognosis and Analysis of Clinical Trials and the Corticoid Randomisation After Significant Head injury prognostic models show good generalizability to more recent data, they are valid instruments to quantify prognosis in traumatic brain injury. PMID- 22511140 TI - Meta-analysis of subclavian insertion and nontunneled central venous catheter associated infection risk reduction in critically ill adults. AB - OBJECTIVE: Catheter-associated infections are common, costly, and potentially lethal. The impact of catheter insertion site on infection risk remains controversial. We aimed to establish whether nontunneled central venous catheters inserted in the subclavian vein are associated with lower risk of catheter associated infection compared to femoral or internal jugular vein insertion. DATA SOURCES: We searched MEDLINE (2000-2011), EMBASE (2000-2011), and Cochrane Library plus meta-analyses, gray literature, reference lists, and articles recommended by experts. STUDY SELECTION AND EXTRACTION: We selected peer reviewed, randomized, or prospective cohort studies with systematic catheter culture using semiquantitative or quantitative catheter culture techniques and data available for catheter-associated infection by insertion site. Two reviewers independently performed study selection, assessed study quality, and extraction. Discrepancies were resolved by discussion and consensus. Outcomes were mean catheter duration and catheter-associated infection expressed as incidence density per 1000 catheter days. DATA SYNTHESIS: Ten studies (3250 subclavian, 3053 internal jugular, and 1554 femoral vein) met the inclusion criteria, one of which was randomized (136 subclavian vein and 134 femoral vein). Subclavian vein catheters were left in place significantly longer than alternative catheters (mean difference: 2 days, 95% confidence interval [0.9-3.1], I=92%, p<.001). The subclavian vein site was associated with fewer catheter-associated infections (1.3 compared to 2.7 per 1000 catheter days for alternative sites, incidence density ratio 0.50; 95% confidence interval [0.33- 0.74], I=0%, p<.001). The same was true when comparisons were stratified by alternative sites (subclavian vein vs. internal jugular vein, incidence density ratio 0.46; 95% confidence interval [0.30-0.70], I=0%; subclavian vein vs. femoral vein, incidence density ratio 0.27; 95% confidence interval [0.15-0.48], I=31%). CONCLUSION: Shortcomings in study design, including channeling, confounding bias, and study heterogeneity, may limit the interpretation of our preliminary study results. Our analysis suggests that the subclavian site may be associated with a lower risk of catheter associated infection. However, a large, randomized, controlled trial comparing each catheter site complication is warranted before the subclavian site can be unequivocally recommended as a first choice for central venous catheter insertion. PMID- 22511142 TI - De-escalation: in drug we trust. PMID- 22511141 TI - A systematic review and meta-analysis of clinical trials of thyroid hormone administration to brain dead potential organ donors. AB - OBJECTIVES: To review all published clinical studies of thyroid hormone administration to brain-dead potential organ donors. METHODS: A search of PubMed using multiple search terms retrieved 401 publications including 35 original reports describing administration of thyroid hormone to brain-dead potential organ donors. Detailed review of the 35 original reports led to identification of two additional publications not retrieved in the original search. The 37 original publications reported findings from 16 separate case series or retrospective audits and seven randomized controlled trials, four of which were placebo controlled. Meta-analysis was restricted to the four placebo-controlled randomized controlled trials. RESULTS: Whereas all case series and retrospective audits reported a beneficial effect of thyroid hormone administration, all seven randomized controlled trials reported no benefit of thyroid hormone administration either alone or in combination with other hormonal therapies. In four placebo-controlled trials including 209 donors, administration of thyroid hormone (n=108) compared with placebo (n=101) had no significant effect on donor cardiac index (pooled mean difference, 0.15 L/min/m2; 95% confidence interval 0.18 to 0.48). The major limitation of the case series and retrospective audits was the lack of consideration of uncontrolled variables that confound interpretation of the results. A limitation of the randomized controlled trials was that the proportion of donors who were hemodynamically unstable or marginal in other ways was too small to exclude a benefit of thyroid hormone in this subgroup. CONCLUSIONS: The findings of this systematic review do not support a role for routine administration of thyroid hormone in the brain-dead potential organ donor. Existing recommendations regarding the use of thyroid hormone in marginal donors are based on low-level evidence. PMID- 22511143 TI - How can we improve the results of cardiopulmonary resuscitation in out-of hospital cardiac arrest in children? Dispatcher-assisted cardiopulmonary resuscitation is a link in the chain of survival. PMID- 22511139 TI - Genetics and genomics in pediatric septic shock. AB - OBJECTIVES: Pediatric septic shock continues to be an important public health problem. Several investigative groups have applied genetic and genomic approaches as a means of identifying novel pathways and therapeutic targets, discovery of sepsis-related biomarkers, and identification of septic shock subclasses. This review will highlight studies in pediatric sepsis with a focus on gene association studies and genome-wide expression profiling. DATA SOURCES: A summary of published literature involving gene association and expression profiling studies specifically involving pediatric sepsis and septic shock. SUMMARY: Several polymorphisms of genes broadly involved in inflammation, immunity, and coagulation have been linked with susceptibility to sepsis, or outcome of sepsis in children. Many of these studies involve meningococcemia, and the strongest association involves a functional polymorphism of the plasminogen activator inhibitor-1 promoter region and meningococcal sepsis. Expression profiling studies in pediatric septic shock have identified zinc supplementation and inhibition of matrix metalloproteinase-8 activity as potential, novel therapeutic approaches in sepsis. Studies focused on discovery of sepsis-related biomarkers have identified interleukin-8 as a robust outcome biomarker in pediatric septic shock. Additional studies have demonstrated the feasibility and clinical relevance of gene expression-based subclassification of pediatric septic shock. CONCLUSIONS: Pediatric sepsis and septic shock are increasingly being studied by genetic and genomic approaches and the accumulating data hold the promise of enhancing our future approach to this ongoing clinical problem. PMID- 22511144 TI - Population health issue in critical care: expanding our focus beyond the intensive care unit. PMID- 22511145 TI - Active surveillance cultures to predict ventilator-associated pneumonia resulting from methicillin-resistant Staphylococcus aureus: is there a role beyond search and destroy? PMID- 22511146 TI - Alteration of microcirculation in sepsis: a reality but how to go further? PMID- 22511147 TI - Obesity in critical illness: what weight or why weight? PMID- 22511148 TI - Deconstructing infection control bundles and the role of buy-in. PMID- 22511149 TI - Statins and acute lung injury: Holy Grail or the next to fail? PMID- 22511150 TI - Science, sceptics, sepsis, and simplicity. PMID- 22511151 TI - Contribution of bacterial coinfection to severe influenza infection. PMID- 22511152 TI - Autoresuscitation and determining circulatory-respiratory death in clinical practice for organ donation. PMID- 22511153 TI - Predicting outcome in patients with acute liver failure: what works best? PMID- 22511154 TI - The vulnerable family. PMID- 22511155 TI - Do not get in RAGE in cardiogenic shock: it is detrimental! PMID- 22511156 TI - Antibiotic dosing and concentration variability during continuous renal replacement therapy: is status quo good enough? PMID- 22511157 TI - Caring to communicate revisited. PMID- 22511158 TI - Race and respiratory failure: we need to learn more. PMID- 22511159 TI - Time for a formal assessment, treatment, and referral structure for families of intensive care unit patients. PMID- 22511160 TI - Customer satisfaction: coming to an intensive care unit near you! PMID- 22511161 TI - Pregnancy joins the hit list. PMID- 22511162 TI - To breathe or not to breathe? PMID- 22511163 TI - Design is how it works (Steven Jobs). PMID- 22511164 TI - Novel insights into the pathophysiology and treatment of intraventricular hemorrhage. PMID- 22511165 TI - Outcome prediction after moderate and severe traumatic brain injury: why two models if we could do with one? PMID- 22511166 TI - Location, location, location--is it everything? PMID- 22511167 TI - Through the looking glass: Alice in meta-analysis. PMID- 22511168 TI - Pulse pressure variation: does lung compliance really matter? PMID- 22511170 TI - Nonuse of RIFLE classification urine output criteria: biases for acute kidney injury biomarkers performance assessment? PMID- 22511172 TI - Low-dose antioxidant is sufficient to regulate pulmonary redox equilibration. PMID- 22511174 TI - Prevention of cardiac arrests in hospitalized patients. PMID- 22511173 TI - Low-dose antioxidant is sufficient to regulate pulmonary redox equilibration. PMID- 22511176 TI - Cascade signal amplification strategy for the detection of cancer cells by rolling circle amplification and nanoparticles tagging. AB - A cascade signal amplification strategy was proposed for detection of cancer cells at ultralow concentration by combining the rolling circle amplification (RCA) technique with oligonucleotide functionalized nanoparticles (NPs), and anodic stripping voltammetric detection. This flexible biosensing system exhibited high sensitivity and specificity with the detection limits of 10 Ramos cells mL(-1). PMID- 22511177 TI - Types, levels and patterns of low-copy DNA sequence divergence, and phylogenetic implications, for Gossypium genome types. AB - To explore types, levels and patterns of genetic divergence among diploid Gossypium (cotton) genomes, 780 cDNA, genomic DNA and simple sequence repeat (SSR) loci were re-sequenced in Gossypium herbaceum (A1 genome), G. arboreum (A2), G. raimondii (D5), G. trilobum (D8), G. sturtianum (C1) and an outgroup, Gossypioides kirkii. Divergence among these genomes ranged from 7.32 polymorphic base pairs per 100 between G. kirkii and G. herbaceum (A1) to only 1.44 between G. herbaceum (A1) and G. arboreum (A2). SSR loci are least conserved with 12.71 polymorphic base pairs and 3.77 polymorphic sites per 100 base pairs, whereas expressed sequence tags are most conserved with 3.96 polymorphic base pairs and 2.06 sites. SSR loci also exhibit the highest percentage of 'extended polymorphisms' (spanning multiple consecutive nucleotides). The A genome lineage was particularly rapidly evolving, with the D genome also showing accelerated evolution relative to the C genome. Unexpected asymmetry in mutation rates was found, with much more transition than transversion mutation in the D genome after its divergence from a common ancestor shared with the A genome. This large quantity of orthologous DNA sequence strongly supports a phylogeny in which A-C divergence is more recent than A-D divergence, a subject that is of much importance in view of A-D polyploid formation being key to the evolution of the most productive and finest-quality cottons. Loci that are monomorphic within A or D genome types, but polymorphic between genome types, may be of practical importance for identifying locus-specific DNA markers in tetraploid cottons including leading cultivars. PMID- 22511178 TI - Body size and risk of differentiated thyroid carcinomas: findings from the EPIC study. AB - Results from case-control and prospective studies suggest a moderate positive association between obesity and height and differentiated thyroid carcinoma (TC). Little is known on the relationship between other measures of adiposity and differentiated TC risk. Here, we present the results of a study on body size and risk of differentiated TC based on a large European prospective study (EPIC). During follow-up, 508 incident cases of differentiated TC were identified in women, and 58 in men. 78% of cases were papillary TC. Cox proportional hazard models were used to estimate hazard ratios (HRs). In women, differentiated TC risk was significantly associated with body mass index (BMI, kg/m(2)) (HR highest vs lowest quintile = 1.41, 95% CI: 1.03-1.94); height (HR = 1.61; 95% CI: 1.18 2.20); HR highest vs lowest tertile waist (HR = 1.34, 95% CI: 1.00-1.79) and waist-to-hip ratio (HR = 1.42, 95% CI: 1.05-1.91). The association with BMI was somewhat stronger in women below age 50. Corresponding associations for papillary TC were similar to those for all differentiated TC. In men the only body size factors significantly associated with differentiated TC were height (non linear), and leg length (HR highest vs. lowest tertile = 3.03, 95% CI: 1.30-7.07). Our study lends further support to the presence of a moderate positive association between differentiated TC risk and overweight and obesity in women. The risk increase among taller individuals of both sexes suggests that some genetic characteristics or early environmental exposures may also be implicated in the etiology of differentiated TC. PMID- 22511179 TI - On the peroxyl scavenging activity of hydroxycinnamic acid derivatives: mechanisms, kinetics, and importance of the acid-base equilibrium. AB - The peroxyl radical scavenging activity of four hydroxycinnamic acid derivatives (HCAD) has been studied in non-polar and aqueous solutions, using the density functional theory. The studied HCAD are: ferulic acid (4-hydroxy-3 methoxycinnamic acid), p-coumaric acid (trans-4-hydroxycinnamic acid), caffeic acid (3,4-dihydroxycinnamic acid), and dihydrocaffeic acid (3-(3,4 dihydroxyphenyl)-2-propionic acid). It was found that the polarity of the environment plays an important role in the relative efficiency of these compounds as peroxyl scavengers. It was also found that in aqueous solution the pH is a key factor for the overall reactivity of HCAD towards peroxyl radicals, for their relative antioxidant capacity, and for the relative importance of the different mechanisms of reaction. The H transfer from the phenolic OH has been identified as the main mechanism of reaction in non-polar media and in aqueous solution at acid pHs. On the other hand, the single electron transfer mechanism from the phenoxide anion is proposed to be the one contributing the most to the overall peroxyl scavenging activity of HCAD in aqueous solution at physiological pH (7.4). This process is also predicted to be a key factor in the reactivity of these compounds towards a large variety of free radicals. PMID- 22511180 TI - Comparison of prescription drug costs in the United States and the United Kingdom, part 2: proton pump inhibitors. AB - STUDY OBJECTIVE: To compare the annual cost of proton pump inhibitors (PPIs) in the United States and in the United Kingdom. DESIGN: Matched-cohort cost analysis. DATA SOURCES: U.K. General Practice Research Database (GPRD) and MarketScan Commercial Claims and Encounter Database, a large, U.S. self-insured medical claims database. STUDY POPULATION: We initially identified more than 1 million people in the GPRD who were younger than 65 years of age and who were prescribed at least one prescription drug in 2005. Each of these people was then matched by year of birth and sex to one person in the U.S. database. From the matched pool, we estimated that 280,000 people were aged 55-64 years from each country. Of these, an estimated 27,230 (9.7%) in the U.S. were prescribed a PPI compared with 22,560 (8.1%) in the U.K. After excluding patients who did not receive the PPI continuously or who switched PPIs during the year, there remained 11,292 people in the U.S. and 9923 in the U.K. who were prescribed a single PPI preparation continuously during 2005 (annual PPI users). MEASUREMENTS AND MAIN RESULTS: Annual drug costs were determined by random sampling. The estimated annual cost/patient in the U.S. ranged from $901 for generic omeprazole to $1485 for lansoprazole. In the U.K., the annual costs were similar, approximately $400 for each PPI, irrespective of whether the agents were available in generic formulation. The total estimated annual cost of PPIs for 2005 in this study group was $14 million in the U.S. compared with $4.1 million in the U.K. CONCLUSION: The cost of continuous use of PPIs covered by private insurance companies in the U.S. in 2005 was more than 3 times the cost covered by the U.K. government. This result is consistent with the findings of an earlier study on relative costs of statins between the countries. PMID- 22511181 TI - Debriefing olympics-a workshop concept to stimulate the adaptation of debriefings to learning contexts. AB - Debriefing is important in simulation-based education but rarely studied empirically. In this article, I describe an experience-based workshop concept that was tested with approximately 80 participants during the Annual Meeting of the Society in Europe for Simulation Applied to Medicine (SESAM), June 2 to 4, 2011, in Granada, Spain. On a metalevel, the goal of the workshop was to raise the awareness of debriefing as an important part of simulation-based learning and to increase the awareness about different styles of debriefing-possibly stimulating further investigations of debriefings. PMID- 22511182 TI - Validation of a performance assessment scale for simulated intraosseous access. AB - We propose an intraosseous (IO) procedure scale for evaluating the insertion process during simulation. A 12-item scale for assessing the performance of IO insertion into the proximal tibia reproduces all the steps of a manual procedure. The performance of 31 emergency physicians was evaluated with this scale on a mannequin simulating a decompensated shock in a 6-month-old infant.Our IO procedure scale was reliable, with a very high interobserver reproducibility. The application of this scale to procedures yielded higher scores for successful than for unsuccessful procedures (P < 10), a 93.5% success rate, and a mean placement time of 2 minutes 23 seconds. Although designed for a manual insertion of an IO needle during simulation, this scale may be also suitable for use in clinical settings. PMID- 22511183 TI - Rapid computation of intermolecular interactions in molecular and ionic clusters: self-consistent polarization plus symmetry-adapted perturbation theory. AB - A method that we have recently introduced for rapid computation of intermolecular interaction energies is reformulated and subjected to further tests. The method employs monomer-based self-consistent field calculations with an electrostatic embedding designed to capture many-body polarization (the "XPol" procedure), augmented by pairwise symmetry-adapted perturbation theory (SAPT) to capture dispersion and exchange interactions along with any remaining induction effects. A rigorous derivation of the XPol+SAPT methodology is presented here, which demonstrates that the method is systematically improvable, and moreover introduces some additional intermolecular interactions as compared to the more heuristic derivation that was presented previously. Applications to various non covalent complexes and clusters are presented, including geometry optimizations and one-dimensional potential energy scans. The performance of the XPol+SAPT methodology in its present form (based on second-order intermolecular perturbation theory and neglecting intramolecular electron correlation) is qualitatively acceptable across a wide variety of systems-and quantitatively quite good in certain cases-but the quality of the results is rather sensitive to the choice of one-particle basis set. Basis sets that work well for dispersion bound systems offer less-than-optimal performance for clusters dominated by induction and electrostatic interactions, and vice versa. A compromise basis set is identified that affords good results for both induction and dispersion interactions, although this favorable performance ultimately relies on error cancellation, as in traditional low-order SAPT. Suggestions for future improvements to the methodology are discussed. PMID- 22511185 TI - alpha-Hydroxy ketones as useful templates in asymmetric reactions. AB - Approaching the Nature's efficiency in controlling both reactivity and stereoselectivity of organic reactions by means of a catalyst species remains a formidable challenge for chemists to face. Despite impressive advances in the design of novel catalysts and activation modes, current catalytic and asymmetric methodologies rarely meet desirable standards of robustness, substrate scope, and selectivity altogether. One trick to improve catalyst behaviour is to identify adequate substrate template-catalyst combinations so that optimum performance of the reaction system could be achieved. During the last couple of years alpha hydroxy ketones, and most particularly alpha'-hydroxy enones, have emerged as useful templates with applications in a number of metal-catalyzed as well as organocatalyzed C-C and C-X bond-forming stereoselective reactions. The first review of these accomplishments is presented here along with a brief historical introduction. PMID- 22511184 TI - Chondroitin sulfate and dynamic loading alter chondrogenesis of human MSCs in PEG hydrogels. AB - While biochemical and biomechanical cues are known to play important roles in directing stem cell differentiation, there remains little known regarding how these inextricably linked biological cues impact the differentiation fate of human marrow stromal cells (hMSCs). This study investigates the chondrogenic differentiation potential of hMSCs when encapsulated in a three dimensional (3D) hydrogel and exposed to a biochemical cue, chondroitin sulfate (ChS), a biomechanical cue, dynamic loading, and their combination. hMSCs were encapsulated in bioinert poly(ethylene glycol) (PEG) hydrogels only, PEG hydrogels modified with covalently incorporated methacrylated ChS and cultured under free swelling conditions or subjected to delayed intermittent dynamic loading for 2 weeks. The 3D hydrogel environment led to the expression of chondrogenic genes (SOX9) and proteins (aggrecan and collagen II), but also upregulated hypertrophic genes (RUNX2 and Col X mRNA) and proteins (collagen X), while the application of loading generally led to a downregulation in chondrogenic proteins (collagen II). The presence of ChS led to elevated levels of aggrecan, but also collagen I, protein expression and when combined with dynamic loading downregulated, but did not suppress, hypertrophic genes (Col X and RUNX2) and collagen I protein expression. Taken together, this study demonstrates that while the 3D environment induces early terminal differentiation during chondrogenesis of hMSCs, the incorporation of ChS into PEG hydrogels may slow the terminal differentiation process down the hypertrophic lineage particularly when dynamic loading is applied. PMID- 22511186 TI - Molecular dynamics study of a one component soft-core system: thermodynamic properties in the crystalline state. AB - In the present work, molecular dynamics (MD) simulations have been performed to study thermal properties of crystals in a one component soft-core system. The system was examined along the phase-diagram using the compressibility factor, P[combining tilde](T*) =PV/NkBT plotted against the reduced density rho* (or reduced temperature, T*). The specific heat, CV, of the system is presented as the function of P[combining tilde](rho*) and also as the function of the reduced potential energy, U*. These CV values are expressed using coefficients of the expansion around the harmonic term. We also derived the expression for entropy using these coefficients. The contribution of an anharmonic term in the specific heat and entropy was clarified by this. These results are compared with those obtained from the fluctuation of kinetic energy. Several quantities related to the distribution of time dependent reduced temperature and dynamical compressibility factor (PV/NkBT)t are also examined and three T* regions of thermal behaviors are characterized. In the diagram, the glass transition by cooling or compression can be treated on the same basis. Results of the present work will be helpful for a better understanding of the changes in the specific heat during the glass transition in the future works. PMID- 22511187 TI - [Criteria and endpoints in advanced prostate cancer]. AB - In castrate-refractory prostate cancers, main efficacy endpoints are progression free survival for phase-II trials and overall survival for phase-III trials. However, various progression criteria have been used, and overall survival may become more difficult to impact due to the recent approval of more effective drugs. PSA is useful in clinical practice, provided it is interpreted with caution, but cannot be used as a surrogate endpoint in clinical trials. Finally, circulating tumor cells represent a promising area of development. PMID- 22511189 TI - Joint attention in toddlerhood predicts internalizing problems at early school age. AB - The authors examined the longitudinal relation between joint attention and socioemotional functioning in a low-risk, typically developing sample of children when the children were toddlers and again during the early school-age years. Fifty-eight mothers and their children were observed in the home or laboratory engaging in 1 unstructured and 4 semistructured tasks designed to assess joint attention episodes when the children were toddlers. Approximately 4 years later, the mother-child dyads were contacted again and mothers completed the Child Behavior Checklist as a measure of their children's socioemotional outcome at the early school years. The authors found that lower frequencies of joint attention episodes at toddlerhood predicted higher internalizing behaviors at early school age. Preliminary findings are discussed in terms of their theoretical implications for work on early mother-child interactions and children's typical and atypical sociemotional development. PMID- 22511190 TI - Facial bruising as a precursor to abusive head trauma. PMID- 22511191 TI - Attitudes and decision making about neonatal male circumcision in a Hispanic population in New York City. AB - OBJECTIVE: To understand attitudes and decision making regarding neonatal male circumcision. METHODS: Parents (n = 150) with a son 3 years old were interviewed regarding demographics, communication with a medical provider, attitudes, and process by which the neonatal circumcision decision was made. RESULTS: Thirty three percent of sons were circumcised. In univariate analyses, choosing male circumcision was associated with parents being interviewed in English, the father being circumcised, positive attitudes, being informed of the advantages of circumcision, making a decision before birth, and being offered a choice. In the final model, parents who came from a culture and family that believed in circumcision and who believed that it was not too risky were more likely to circumcise their sons. CONCLUSIONS: Decisions regarding circumcision appear to be influenced by values, risk perceptions, and medical providers. Future research should address ways of ensuring that families have the opportunity to make an informed decision. PMID- 22511192 TI - Fever, lethargy, and leg weakness in a 9-month-old boy. PMID- 22511193 TI - The use and tolerability of Crotalidae Polyvalent Immune FAB (Ovine) in pediatric envenomations. AB - There are limited data on the use of Crotalidae Polyvalent Immune FAB-Ovine (CroFab) in the management of crotalid envenomations in children. Thus, the primary objective of this retrospective chart review was to evaluate the safety and tolerability of CroFab in a pediatric population. Over an 8-year time period at this institution, there were 204 admissions for snakebite of which 82 received CroFab. Children who received CroFab were more often associated with bites to the hands and fingers and tended to have more significant envenomations as indicated by longer hospital stays, greater tissue injury, and a tendency to require surgery more often. Six (7.3%) of the 82 patients who received CroFab experienced an adverse drug reaction. Reactions consisted of allergic symptoms that were mild, responded to minimal interventions, and did not limit the subsequent use of CroFab. It is concluded that CroFab use is typically well tolerated in pediatric patients. PMID- 22511194 TI - Clonidine utilization trends for Medicaid children. AB - OBJECTIVE: To characterize clonidine utilization trends among children. DESIGN/METHODS: Serial cross-sectional analysis of Michigan Medicaid claims data for children aged 6 to 18 years. The authors identified children with >=1 clonidine prescription; the authors examined their ICD-9 diagnoses categorized as simple and complex attention deficit hyperactivity disorder (ADHD), non-ADHD mental health disorder, hypertension, or others. Also identified were child demographics and prescribing physician specialty. RESULTS: From 2003 to 2008, the proportion of children receiving clonidine prescription nearly doubled in all demographics. Across years, the majority of clonidine prescription was for simple and complex ADHD and other mental health disorders. Leading prescribers were psychiatrists followed by general pediatricians and adult primary care physicians. CONCLUSIONS: Clonidine was used extensively to treat simple and complex ADHD in children although FDA approval for this indication did not occur until 2010. Further study is warranted to better understand clinical outcomes and costs associated with clonidine use for the treatment of children with ADHD. PMID- 22511195 TI - Increased incidence of perforated appendicitis in children with obesity. AB - Based on their clinical impression, the authors hypothesized that children with obesity may more commonly present with perforated appendicitis. Therefore, the authors reviewed their experience from 2008 to 2010 to determine whether obesity affected the clinical presentation of appendicitis. Variables studied were height, weight, use of diagnostic imaging, and clinical findings of appendicitis at presentation. Outcomes assessed were length of stay and complication rate. The study identified 319 patients with appendicitis. Children with obesity were more likely (P = .026) to present with perforation (28/62, 45%) than nonobese patients (78/257, 30%). Neither length of stay nor complication rate was affected by the presence of obesity. The data suggest that children with obesity are more likely to present with perforated appendicitis. This finding suggests that the diagnosis of appendicitis may be more difficult in obese patients or their presentation may be delayed. Practitioners should have heightened awareness in children with obesity and symptoms of abdominal pain. PMID- 22511196 TI - The limping child: when to suspect spinal disorders? PMID- 22511197 TI - Identifying social risk via a clinical social history embedded in the electronic health record. AB - Although the link between social determinants and health outcomes is well established, the social history remains poorly integrated into clinical care processes. This study's purpose was to determine social risk documentation rates among newborns using a new electronic template. A retrospective review of 639 well-infant visits was performed. The authors determined documentation rates for a standardized social history embedded in the clinic electronic health record. Social history completion rates and prevalence of risks were identified. More than 80% of clinicians documented asking at least 1 of 7 questions (mean = 4.5, SD = 2.9). The most commonly asked question was about "making ends meet," and the least common was about personal safety (79% vs 57%, P < .01). Nearly 30% of caregivers reported at least 1 risk, 11% at least 2 risks. An electronic health record-embedded social history led to documented screening in more than 80% of visits, identifying 30% as having at least 1 social risk. PMID- 22511198 TI - Missing documentation of weight and height at preventive visits for children. AB - Despite the importance of measuring weight and height at well-child visits, there are limited data on frequency of anthropometric documentation. The authors aimed to identify characteristics associated with missing weight and height documentation at preventive visits for children. Among preventive visits for children from birth to 18 years old, recorded in the National Ambulatory Medical Care and National Hospital Ambulatory Medical Care Surveys for 2005-2009, the authors found that 20.8% had missing weight and/or height (n = 19,033) documentation. Compared with infants younger than 2 years, school-age children (odds ratio [OR] = 1.30; 95% confidence interval [CI] = 1.03-1.64), and adolescents (OR = 1.61; 95% CI = 1.26-2.04) were more likely to lack documentation. Missing documentation was also more likely for visits with nonphysicians (OR = 4.53; 95% CI = 3.17-6.48) and nonpediatricians (OR = 2.63; 95% CI = 2.02-3.41) compared with pediatricians. Efforts to improve weight and height surveillance should be directed to clinics in which midlevel providers and nonpediatric physicians are caring for school-age children and adolescents. PMID- 22511199 TI - Sternoclavicular joint arthritis as the initial presentation of Crohn's disease in an adolescent. PMID- 22511200 TI - Parainfluenza virus type 3 outbreak in a neonatal nursery. PMID- 22511201 TI - Revisiting the isobole and related quantitative methods for assessing drug synergism. AB - The isobole is well established and commonly used in the quantitative study of agonist drug combinations. This article reviews the isobole, its derivation from the concept of dose equivalence, and its usefulness in providing the predicted effect of an agonist drug combination, a topic not discussed in pharmacology textbooks. This review addresses that topic and also shows that an alternate method, called "Bliss independence," is inconsistent with the isobolar approach and also has a less clear conceptual basis. In its simplest application the isobole is the familiar linear plot in cartesian coordinates with intercepts representing the individual drug potencies. It is also shown that the isobole can be nonlinear, a fact recognized by its founder (Loewe) but neglected or rejected by virtually all other users. Whether its shape is linear or nonlinear the isobole is equally useful in detecting synergism and antagonism for drug combinations, and its theoretical basis leads to calculations of the expected effect of a drug combination. Numerous applications of isoboles in preclinical testing have shown that synergism or antagonism is not only a property of the two agonist drugs; the dose ratio is also important, a fact of potential importance to the design and testing of drug combinations in clinical trials. PMID- 22511202 TI - Effects of ritobegron (KUC-7483), a novel selective beta3-adrenoceptor agonist, on bladder function in cynomolgus monkey. AB - We evaluated the pharmacological profile of ritobegron [KUC-7483; (-)-ethyl 2-[4 (2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)-2,5 dimethylphenyloxy]acetate monohydrochloride] and its effects on the bladder in cynomolgus monkeys by in vitro and in vivo experiments. In vitro, ritobegron decreased the resting tension of the isolated bladder in a concentration dependent manner (EC(50) 8.2 +/- 2.3 * 10(-7) M; maximal relaxation 88.7 +/- 3.7%). The beta(3)-adrenoceptor (AR) antagonist 3-(2-allylphenoxy)-1-[(1S) 1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol hydrochloride (SR58894A) produced a rightward shift of this concentration-response curve without altering the maximal response (pK(B) value 6.56 +/- 0.35). In isolated atria, ritobegron increased the atrial rate only at high concentrations (EC(50) 6.5 +/- 1.2 * 10( 5) M). Ritobegron had no effect on tracheal contraction at concentrations from 10(-9) to 10(-4) M, and even at the highest concentration tested, 10(-3) M, the maximal relaxation it induced was only 26.7 +/- 8.1%. Tests of the selectivity of ritobegron for the bladder gave values of 79.3- and 1200-fold higher versus atria and trachea, respectively. In the in vivo study ritobegron significantly decreased intravesical pressure (ED(50) 1.44 mg/kg) without affecting either mean blood pressure or heart rate. In conclusion, ritobegron displayed potent and selective beta(3)-AR agonistic activity and relaxed the monkey isolated bladder, and in vivo it decreased intravesical pressure without affecting cardiovascular parameters. These results suggest that ritobegron may be a promising potential agent for the treatment of overactive bladder. PMID- 22511203 TI - Carnosol and carnosic acids from Salvia officinalis inhibit microsomal prostaglandin E2 synthase-1. AB - Prostaglandin E(2) (PGE(2)), the most relevant eicosanoid promoting inflammation and tumorigenesis, is formed by cyclooxygenases (COXs) and PGE(2) synthases from free arachidonic acid. Preparations of the leaves of Salvia officinalis are commonly used in folk medicine as an effective antiseptic and anti-inflammatory remedy and possess anticancer activity. Here, we demonstrate that a standard ethyl acetate extract of S. officinalis efficiently suppresses the formation of PGE(2) in a cell-free assay by direct interference with microsomal PGE(2) synthase (mPGES)-1. Bioactivity-guided fractionation of the extract yielded closely related fractions that potently suppressed mPGES-1 with IC(50) values between 1.9 and 3.5 MUg/ml. Component analysis of these fractions revealed the diterpenes carnosol and carnosic acid as potential bioactive principles inhibiting mPGES-1 activity with IC(50) values of 5.0 MUM. Using a human whole blood assay as a robust cell-based model, carnosic acid, but not carnosol, blocked PGE(2) generation upon stimulation with lipopolysaccharide (IC(50) = 9.3 MUM). Carnosic acid neither inhibited the concomitant biosynthesis of other prostanoids [6-keto PGF(1alpha), 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid, and thromboxane B(2)] in human whole blood nor affected the activities of COX-1/2 in a cell-free assay. Together, S. officinalis extracts and its ingredients carnosol and carnosic acid inhibit PGE(2) formation by selectively targeting mPGES-1. We conclude that the inhibitory effect of carnosic acid on PGE(2) formation, observed in the physiologically relevant whole-blood model, may critically contribute to the anti-inflammatory and anticarcinogenic properties of S. officinalis. PMID- 22511204 TI - Recycling between cortisol and cortisone in human splanchnic, subcutaneous adipose, and skeletal muscle tissues in vivo. AB - 11beta-Hydroxysteroid dehydrogenase type 1 (11betaHSD1) is a therapeutic target in metabolic syndrome because it catalyses reductase regeneration of cortisol from cortisone in adipose and liver. 11betaHSD1 can also catalyze the reverse dehydrogenase reaction in vitro (e.g., if cofactor is limited). We used stable isotope tracers to test the hypothesis that both 11betaHSD1-reductase and dehydrogenase activities occur in human metabolic tissues in vivo. 1,2-[(2)H](2) Cortisone (d2-cortisone) was validated as a tracer for 11beta-dehydrogenase activity and its inhibition by licorice. d2-Cortisone and 9,11,12,12-[(2)H](4) cortisol (d4-cortisol) (to measure 11beta-reductase activity) were coinfused and venous samples obtained from skeletal muscle, subcutaneous adipose (n = 6), and liver (n = 4). Steroids were measured by liquid chromatography-tandem mass spectrometry and arteriovenous differences adjusted for blood flow. Data are means +/- SEM. 11beta-Reductase and -dehydrogenase activities were detected in muscle (cortisol release 19.7 +/- 4.1 pmol/100 mL/min, d3-cortisol 5.9 +/- 1.8 pmol/100 mL/min, and cortisone 15.2 +/- 5.8 pmol/100 mL/min) and splanchnic (cortisol 64.0 +/- 11.4 nmol/min, d3-cortisol 12.9 +/- 2.1 nmol/min, and cortisone 19.5 +/- 2.8 nmol/min) circulations. In adipose, dehydrogenase was more readily detected than reductase (cortisone release 38.7 +/- 5.8 pmol/100 g/min). Active recycling between cortisol and cortisone in metabolic tissues in vivo may facilitate dynamic control of intracellular cortisol but makes consequences of dysregulation of 11betaHSD1 transcription in obesity and diabetes unpredictable. Disappointing efficacy of 11betaHSD1 inhibitors in phase II studies could be explained by lack of selectivity for 11beta-reductase. PMID- 22511205 TI - Metabolic signatures of insulin resistance in 7,098 young adults. AB - Metabolite associations with insulin resistance were studied in 7,098 young Finns (age 31 +/- 3 years; 52% women) to elucidate underlying metabolic pathways. Insulin resistance was assessed by the homeostasis model (HOMA-IR) and circulating metabolites quantified by high-throughput nuclear magnetic resonance spectroscopy in two population-based cohorts. Associations were analyzed using regression models adjusted for age, waist, and standard lipids. Branched-chain and aromatic amino acids, gluconeogenesis intermediates, ketone bodies, and fatty acid composition and saturation were associated with HOMA-IR (P < 0.0005 for 20 metabolite measures). Leu, Ile, Val, and Tyr displayed sex- and obesity-dependent interactions, with associations being significant for women only if they were abdominally obese. Origins of fasting metabolite levels were studied with dietary and physical activity data. Here, protein energy intake was associated with Val, Phe, Tyr, and Gln but not insulin resistance index. We further tested if 12 genetic variants regulating the metabolites also contributed to insulin resistance. The genetic determinants of metabolite levels were not associated with HOMA-IR, with the exception of a variant in GCKR associated with 12 metabolites, including amino acids (P < 0.0005). Nonetheless, metabolic signatures extending beyond obesity and lipid abnormalities reflected the degree of insulin resistance evidenced in young, normoglycemic adults with sex-specific fingerprints. PMID- 22511206 TI - Connexin-36 gap junctions regulate in vivo first- and second-phase insulin secretion dynamics and glucose tolerance in the conscious mouse. AB - Insulin is secreted from the islets of Langerhans in coordinated pulses. These pulses are thought to lead to plasma insulin oscillations, which are putatively more effective in lowering blood glucose than continuous levels of insulin. Gap junction coupling of beta-cells by connexin-36 coordinates intracellular free calcium oscillations and pulsatile insulin release in isolated islets, however a role in vivo has not been shown. We test whether loss of gap-junction coupling disrupts plasma insulin oscillations and whether this impacts glucose tolerance. We characterized the connexin-36 knockout (Cx36(-/-)) mouse phenotype and performed hyperglycemic clamps with rapid sampling of insulin in Cx36(-/-) and control mice. Our results show that Cx36(-/-) mice are glucose intolerant, despite normal plasma insulin levels and insulin sensitivity. However, Cx36(-/-) mice exhibit reduced insulin pulse amplitudes and a reduction in first-phase insulin secretion. These changes are similarly found in isolated Cx36(-/-) islets. We conclude that Cx36 gap junctions regulate the in vivo dynamics of insulin secretion, which in turn is important for glucose homeostasis. Coordinated pulsatility of individual islets enhances the first-phase elevation and second-phase pulses of insulin. Because these dynamics are disrupted in the early stages of type 2 diabetes, dysregulation of gap-junction coupling could be an important factor in the development of this disease. PMID- 22511208 TI - The management of overactive bladder syndrome. PMID- 22511207 TI - Serum apolipoproteins are associated with systemic and retinal microvascular function in people with diabetes. AB - Serum apolipoprotein (apo)AI and -B have been shown to be associated with diabetic retinopathy, but the underlying mechanisms are unclear. We investigated whether apoAI and apoB levels are associated with measures of systemic and retinal microvascular function in patients with diabetes. We recruited 224 diabetic patients (85 type 1 and 139 type 2) and assessed serum lipids and lipoproteins from fasting blood, skin responses to sodium nitroprusside (endothelium independent) and acetylcholine (ACh) (endothelium dependent) iontophoresis, flicker-light-induced retinal vasodilatation, and retinal vascular tortuosity. After adjustment for age and sex, every SD increase in apoAI level was associated with ACh-induced skin perfusion (mean change 1.27%; P < 0.001 for apoAI) and flicker-light retinal arteriolar vasodilatation (0.33%; P = 0.003) and was associated inversely with arteriolar tortuosity (-2.83 * 10(-5); P = 0.044). Each SD increase in apoB was associated with arteriolar tortuosity only (1.75 * 10(-5); P = 0.050). These associations, except for apoB, remained in multivariate models. Serum apoAI was associated with increased vasomotor responsiveness to ACh and flickering light and inversely related to retinal vessel tortuosity--a characteristic that has both structural and functional dimensions. These findings provide additional insights into the potential mechanisms of apos in the pathogenesis of diabetic retinopathy and other diabetic microvascular complications. PMID- 22511209 TI - Exempting dissenting patients from pay for performance schemes: retrospective analysis of exception reporting in the UK Quality and Outcomes Framework. AB - OBJECTIVE: To examine the reasons why practices exempt patients from the UK Quality and Outcomes Framework pay for performance scheme (exception reporting) and to identify the characteristics of general practices associated with informed dissent. DESIGN: Retrospective analysis. SETTING: Data for 2008-9 extracted from the clinical computing systems of general practices in England. PARTICIPANTS: 8229 English family practices. MAIN OUTCOME MEASURES: Rates of exception reporting for 37 clinical quality indicators, associations of patient and general practice factors with exception rates, and financial gain for practices relating to their use of exception reporting. RESULTS: The median rate of exception reporting was 2.7% (interquartile range 1.9-3.9%) overall and 0.44% (0.14-1.1%) for informed dissent, but variation in rates was wide between practices and across indicators. Common reasons for exception reporting were logistical (40.6% of exceptions), clinical contraindication (18.7%), and patient informed dissent (30.1%). Higher rates of informed dissent were associated with: higher numbers of registered patients, higher levels of local area deprivation, and failure of the practice to secure maximum remuneration in the previous year. Exception reporting increased the cost of the scheme by L30,844,500 (?36,877,700; $49,053,200) (L0.58 per patient), with two indicators accounting for a quarter of this additional cost. CONCLUSIONS: The provision to exception report enables practices to exempt dissenting patients without being financially penalised. Relatively few patients were excluded for informed dissent, however, suggesting that the incentivised activities were broadly acceptable to patients. PMID- 22511210 TI - A new scramble for Africa: how rich world donors are damaging healthcare. PMID- 22511211 TI - Bad medicine: health promotion. PMID- 22511212 TI - Maternal obesity and diabetes are linked to children's autism and similar disorders. PMID- 22511213 TI - US tops salty fast food league table. PMID- 22511214 TI - Lung cancer teams pair up to review care processes and improve outcomes. PMID- 22511215 TI - Medical colleges and faculties unite to tackle obesity after "failure" of current strategies. PMID- 22511216 TI - Salinity acclimation modulates copper toxicity in the sheepshead minnow, Cyprinodon variegatus. AB - The sheepshead minnow (Cyprinodon variegatus) is able to withstand a wide range of salinities. Salinity acclimation involves physiological and biochemical changes, which may influence how organisms respond to a stressor. The present study investigated effects of salinity acclimation on subsequent Cu toxicity. In experiment 1, fish were acclimated to a hyposmotic, isosmotic, or hyperosmotic salinity for 14 d and then exposed at these salinities to 16.6 uM Cu(2+) for 12 h. Survival differed during this Cu challenge; fish acclimated to 2.5 ppt salinity were much more sensitive to Cu than those acclimated to 10.5 or 18.5 ppt seawater. In experiment 2, fish were exposed to 14.6 uM Cu(2+) for 6 h after the 14-d salinity acclimation. Whole-body Cu, whole-body Na, liver lipid peroxidation (LPO), liver catalase activity, and liver glucose levels were determined before and after Cu exposure. Prior to Cu exposure, the acclimation groups differed only for liver glucose levels, which were higher in the 2.5 ppt acclimated fish than in the others. These same 2.5 ppt acclimated fish were markedly affected by Cu, having increased whole-body Cu and liver LPO and decreased whole-body Na levels. Copper exposure had generally insignificant effects for the 10.5 ppt and the 18.5 ppt acclimated fish. This study showed that even in euryhaline fish, salinity acclimation can have a drastic effect on Cu toxicity. PMID- 22511217 TI - Ring-opening polymerization of epsilon-caprolactone by lithium piperazinyl aminephenolate complexes: synthesis, characterization and kinetic studies. AB - A series of lithium complexes were prepared from 2(N-piperazinyl-N'-methyl)-2 methylene-4-R'-6-R-phenols ([ONN](RR')) and characterized through elemental analysis, (1)H and (13)C{(1)H} NMR spectroscopy, and X-ray crystallography. Treatment of the ligands with n-butyllithium afforded {Li[ONN](RR')}(3) [R = Me, R' = (t)Bu, (1); R = R' = (t)Bu (2); R = R' = (t)Am, (3), (t)Am = C(CH(3))(2)CH(2)CH(3)], with trimetallic structures in the solid-state as shown by single-crystal X-ray diffraction. The reactivity of these complexes in the ring-opening polymerization of epsilon-caprolactone (epsilon-CL), as well as the influences of monomer concentration, monomer/Li molar ratio, polymerization temperature and time, was studied. Rates of polymerization were first order with respect to both monomer and lithium concentrations, and activation energies for the reactions were determined. MALDI-TOF MS analysis revealed that transesterification had occurred during the polymerization. PMID- 22511218 TI - Butyrate production enhancement by Clostridium tyrobutyricum using electron mediators and a cathodic electron donor. AB - Electron mediators and electron supply through a cathode were examined to enhance the reducing power for butyrate production by an acidogenic clostridium strain, Clostridium tyrobutyricum BAS 7. Among the tested electron mediators, methyl viologen (MV)-amended cultures showed an increase of butyrate productivity (1.3 times), final concentration (1.4 times), and yield (1.3 times). The electron flow altered by MV addition from the ferredoxin pool to the NADH pool was shown by one electron model, implying that more available NADH increased butyrate production. In the cathode compartment poised at -400 mV versus the Ag/AgCl electrode, the neutral red (NR)-amended cultures of Clostridium tyrobutyricum BAS 7 increased butyrate concentration (from 5 to 8.8 g/L) and yield (from 0.33 up to 0.44 g/g) with no acetate production at all. Given that electrically reduced NR (NR(red) , yellow) by the cathode was re-oxidized (NR(ox) , red) in the cells on the basis of color change, electron flow from NR(red) to NAD(+) (i.e., NADH generation) induced an increase in butyrate production. This is the first report to show the increase of butyric acid production by electrically driven acidogenesis. These results show that the electron flow altered NADH formation by electron mediators and by the cathodic electron donor, increasing the yield and selectivity of reduced end-products like butyrate. PMID- 22511219 TI - Prenatal diagnosis of atrial restriction in hypoplastic left heart syndrome is associated with decreased 2-year survival. AB - OBJECTIVE: To compare the course of hypoplastic left heart syndrome (HLHS) patients diagnosed prenatally with any degree of atrial restriction with those without evidence of atrial restriction. DESIGN: Retrospective, cohort. METHODS: Prenatally diagnosed HLHS patients from August 1999 to January 2009 were categorized as nonrestrictive versus restrictive, defined by left atrial hypertension on pulmonary venous Doppler and/or an intact interatrial septum. RESULTS: Of 73 total fetal patients identified, 49 were live-born. Survival at 2 years was 29/35 [83% confidence interval (CI): 59.5%-88.9%] for the nonrestrictive group and 6/14 (43% CI: 17.7%-6.0%) for the restrictive group (p<0.0001). Of those who underwent stage 1 palliation (35 with nonrestrictive and 10 with restrictive atrial septa), both groups had a similar incidence of preoperative acidosis and need for ventilation and inotropic support. Postoperatively, there was no difference between groups in ventilator days, length of stay, or survival to discharge. There was decreased survival at 2 years in the restrictive group, 60% (CI: 26.2%-87.8%) versus 83% (CI: 66.4%-93.4%) in the nonrestrictive group. Furthermore, a disproportionate number of interstage deaths was evident in the restrictive group. CONCLUSIONS: Prenatal presence of any degree of atrial septal restriction in the setting of HLHS confers a significant survival disadvantage, with increases in both early and late mortality. PMID- 22511220 TI - Simulation-based training and learning curves in laparoscopic Roux-en-Y gastric bypass. AB - BACKGROUND: Ex vivo simulation-based technical skills training has been shown to improve operating room performance and shorten learning curves for basic laparoscopic procedures. The application of such training for laparoscopic Roux en-Y gastric bypass (LRYGBP) has not been reviewed. METHODS: Relevant studies were identified by one author from a search of MEDLINE and Embase databases from 1 January 1994 to 30 November 2010. Studies examining the learning curves and ex vivo training methods for LRYGBP were included; all other types of bariatric operations were excluded. A manual search of the references was also performed to identify additional potentially relevant papers. RESULTS: Twelve studies (5 prospective and 7 retrospective case series) were selected for review. The learning curve for LRYGBP was reported to be 50-100 procedures. Bench-top laparoscopic jejunojejunostomy, anaesthetized animals and Thiel human cadavers made up the bulk of the reported models for ex vivo training. Most studies were of relatively poor quality. An evidence-based ex vivo training curriculum for LRYGBP is currently lacking. CONCLUSION: Better quality studies are needed to define the learning curve for LRYGBP. Future studies should focus on the design and validation of training models, and a comprehensive curriculum for training and assessment of cognitive, technical and non-technical components of competency for laparoscopic bariatric surgery. PMID- 22511221 TI - A turn-on fluorescent probe based on hydroxylamine oxidation for detecting ferric ion selectively in living cells. AB - We have described a turn on fluorescent probe BOD-NHOH based on hydroxylamine oxidation for detecting intracellular ferric ions. The probe comprises a signal transducer of BODIPY dye and a Fe(3+)-response modulator of hydroxylamine. It is readily employed for assessing intracellular ferric ion levels, and confocal imaging is achieved successfully. PMID- 22511222 TI - Comparison of tetraphenylmethane and tetraphenylsilane as core structures of high triplet-energy hole- and electron-transport materials. PMID- 22511223 TI - Heterolytic activation of hydrogen using frustrated Lewis pairs containing tris(2,2',2''-perfluorobiphenyl)borane. AB - The extremely sterically hindered borane tris(2,2',2''-perfluorobiphenyl)borane (PBB) has been structurally characterised. In combination with bulky nitrogen bases, it forms the 'frustrated Lewis pairs' (FLPs) PBB/2,2,6,6 tetramethylpiperidine (TMP) (1), PBB/1,4-diazobicyclo[2.2.2]-octane (DABCO) (2) and PBB/2,6-lutidine (lut) (3). These novel, unquenched acid-base pairs have been shown to effect facile room temperature heterolytic cleavage of dihydrogen to form the ammonium borate salts [2,2,6,6-Me(4)C(5)H(6)NH(2)][HB(C(12)F(9))(3)] (4) and [N(C(2)H(4))(3)NH][HB(C(12)F(9))(3)] (5), and lutidinium borate [2,6 Me(2)C(5)H(3)NH][HB(C(12)F(9))(3)] (6). Although these reactions are equilibria, the reverse reaction and release of hydrogen gas was not apparent at temperatures up to 120 degrees C. The relative Lewis acidity of PBB has been determined using the Gutmann-Beckett method. PMID- 22511224 TI - Thoughts and facts about antibiotics: where we are now and where we are heading. AB - The declining trends in microbial metabolite and natural products research and the refocusing of this research area are discussed. Renewing natural products research requires inexhaustible natural resources, as well as new genetic techniques and microbial sources, including endophytic microbes. The numbers of known bioactive metabolites are summarized according to their microbiological origin, biological activities and chemical structures. Synthetic and natural product-based libraries are also compared. Importantly, the wide range of microbial metabolite bioactivities, future trends and the importance of prioritizing natural products over synthetic compounds are emphasized. PMID- 22511225 TI - Proteasome inhibitors mechanism; source for design of newer therapeutic agents. AB - The proteasome was first identified as a high MW protease complex that gets resolved into a series of low MW protein species upon denaturation. As the dominant protease dedicated to protein turnover, the proteasome shapes the cellular protein repertoire. Our knowledge of proteasome regulation and activity has improved considerably over the past decade. Novel inhibitors, in particular, have helped to advance our understanding of proteasome biology. They range from small peptide-based structures that can be modified to vary target specificity to large macromolecular inhibitors that include proteins. Although these reagents have an important role in establishing our current knowledge of the proteasome's catalytic mechanism, many questions remain. The future lies in designing compounds that can function as drugs to target processes involved in disease progression. Our focus in this chapter is to highlight the use of various classes of inhibitors to probe the mechanism of the proteasome and to identify its physiological significance in the cell, so that the mechanism of inhibition of proteasome will work as a definite source for design of protocols for newer therapeutic agents for the treatment of inflammation and in cancer therapy. PMID- 22511226 TI - Isolation of actinomycetes from the root of the plant, Ophiopogon japonicus, and proposal of two new species, Actinoallomurus liliacearum sp. nov. and Actinoallomurus vinaceus sp. nov. AB - Actinomycete strains K10-0485(T) and K10-0528(T) were isolated from the roots of Ophiopogon japonicus collected in Yokohama, Kanagawa Prefecture, Japan. The 16S ribosomal RNA (rRNA) gene sequences, morphological characteristics and chemotaxonomic data indicated that these strains belonged to the genus Actinoallomurus. Strain K10-0485(T) showed high similarity of the 16S rRNA gene sequence with A. luridus TT02-15(T) (99.1%), but the DNA-DNA hybridization relatedness values between strain K10-0485(T) and A. luridus TT02-15(T) were below 70%. Three species showed similarities of 16S rRNA gene sequences with K10 0528(T), namely A. spadix JCM 3146(T) (98.0%), A. purpureus TTN02-30(T) (98.0%) and A. luridus TT02-15(T) (97.9%), but all similarity values of the 16S rRNA gene sequences were lower than the boundary value (98.7%) for distinguishing as different species. Based on phylogenetic analyses, DNA-DNA hybridization relatedness and physiological characteristics, the two isolated strains should be classified as two new species in the genus Actinoallomurus, and we propose the names Actinoallomurus liliacearum sp. nov. and Actinoallomurus vinaceus sp. nov. The type strain of Actinoallomurus liliacearum is K10-0485(T) (=JCM 17938(T), BCC 49424(T), NBRC 108672(T)) and that of Actinoallomurus vinaceus is K10-0528(T) (=JCM 17939(T), BCC 49425(T), NBRC 108763(T)). PMID- 22511227 TI - Evaluation, synthesis and characterization of tacrolimus impurities. AB - Tacrolimus is an immunosuppressant macrolactam of fermentative origin. By means of HPLC, LC-MS and NMR analyses, coupled with the reference standard synthesis, the main impurities of tacrolimus bulk drug samples were identified and their chemical-physical properties reported. Known ascomycin and tautomers I and II were detected. The correct relative retention time HPLC value of 39,40-dihydro tacrolimus was established. The not described 23,24-anhydro derivative was detected and completely characterized. A full characterization of ascomycin and 39,40-dihydro tacrolimus was also reported. PMID- 22511228 TI - A new series of the SMTP plasminogen modulators with a phenylamine-based side chain. AB - SMTPs are a family of small-molecule plasminogen modulators that enhance plasminogen activation. SMTP-7, one of the most potent congeners, is effective in treating thrombotic cerebral infarction. The SMTP molecule consists of a tricyclic gamma-lactam moiety, a geranylmethyl group, and an N-linked side chain. The presence of both an aromatic group and a negatively ionizable group in the N linked side chain is crucial for activity. Investigations of the congeners with a phenylglycine-based side chain suggest that a phenolic hydroxy group affects potency. In this study, we isolate and characterize a series of novel SMTP congeners with a phenylamine-based N-linked side chain. Of the 11 congeners isolated, SMTP-19 (with a 4-phenylcarboxylic acid moiety), SMTP-22 (with a 3 hydroxyphenyl-4-carboxylic acid moiety) and SMTP-25 (with a 2-hydroxyphenyl-3 carboxylic acid moiety) are as potent as SMTP-7 in plasminogen-modulating activity. Their isomers with a carboxylic acid group and/or a phenolic hydroxy group at different positions have <40% of the activity of these congeners. Both SMTP-22 and SMTP-25 have >1.7 times more oxygen radical absorbance capacity as compared with SMTP-7. PMID- 22511229 TI - Part 2: Quantitative proton T2 and sodium magnetic resonance imaging to assess intervertebral disc degeneration in a rabbit model. AB - STUDY DESIGN: Comparison of sodium concentration ([Na]) and proton T2 relaxation time between normal and degenerated discs in a rabbit model. OBJECTIVE: The purpose of this article was to evaluate quantitative [Na] and T2 characteristics of discs associated with degenerative changes. SUMMARY OF BACKGROUND DATA: Intervertebral disc degeneration is a common chronic condition that may lead to back pain, limited activity, and disability. Noninvasive imaging method to detect early intervertebral disc degeneration is vital to follow disease progression and guide clinical treatment and management. METHODS: Dual-tuned magnetic resonance imaging of rabbit discs was performed using 3T. Thirteen rabbits were included in the study; 6 control rabbits (24 normal discs) and 7 rabbits with annular puncture-induced disc degeneration (9 degenerated discs, 19 intact internal control discs). Dual-tuned magnetic resonance imaging of discs was performed at baseline and 12-week poststab. [Na] and T2 were measured and compared among 3 groups of discs. RESULTS: The mean [Na] were 274.8 +/- 40.2 mM for the normal discs, 247.2 +/- 27.7 mM for the internal-control discs, and 190.6 +/- 19.1 mM for the degenerated discs. The corresponding T2 for 3 groups were 97.1 +/- 12.1 ms, 93.7 +/- 11.9 ms, and 79.0 +/- 9.1 ms, respectively. The [Na] is highly correlated with the T2 in the degenerated discs (r = 0.90, P < 0.01). The mean percent decreases from the normal to degenerated discs were in 30.6% in [Na] and 18.6% in T2, whereas those from the internal-control to degenerated discs were 22.9% in [Na] and 15.6% in T2. CONCLUSION: Although both [Na] and T2 changes in discs were associated with the disc-punctured rabbits, greater change in [Na] is observed at 12-week poststab compared with T2 change. Because T2 and [Na] reflect different disc properties, performing both imaging under same condition will be helpful in the evaluation of disc degeneration. PMID- 22511230 TI - A method for assessing axial vertebral rotation based on differential rod curvature on the lateral radiograph. AB - STUDY DESIGN: Bench-top and retrospective radiographical analyses to determine apical vertebral rotation based on differential rod curvature on the postoperative lateral radiograph. OBJECTIVE: To develop a clinically relevant methodology for measuring apical vertebral rotation on postoperative lateral radiographs in patients with adolescent idiopathic scoliosis, based on the distance between the spinal rods. SUMMARY OF BACKGROUND DATA: Traditional methods of analyzing vertebral rotation on plain radiographs are limited in the postoperative spine with segmental instrumentation. A previous methodology based on pedicle screw tip to rod distances on the posteroanterior radiograph is effective but limited by surgical technique and patient positioning relative to the x-ray beam. METHODS: The trigonometric relationship between the inter-rod distances on lateral radiographs was defined and validated on a biomechanical model, with apical rotation varying from 0 degrees to 20 degrees . The ability to correct for malposition on the lateral radiograph was tested on 11 postoperative radiographs and correlated against corresponding postoperative computed tomographic scans. RESULTS: The bench-top model had a strong correlation between actual apical rotation and calculated rotation for the full range of image rotations (intraclass correlation coefficient, 0.99). For the 11 clinical cases, comparisons of apical rotation measured on computed tomographic scans were highly correlated to the proposed lateral radiograph calculations (r = 0.84). CONCLUSION: A technique for measuring apical vertebral rotation based on the inter-rod distance on the lateral and posteroanterior radiographs was developed and validated. This technique is resilient to rotation of the patient within the x-ray machine and can complement measurement of rotation on postoperative posteroanterior radiographs. PMID- 22511231 TI - Natural course and prognostic factors in patients with mild cervical spondylotic myelopathy with increased signal intensity on T2-weighted magnetic resonance imaging. AB - STUDY DESIGN: A retrospective comparative study. OBJECTIVE: To investigate natural course and prognostic factors in patients with mild forms of cervical spondylotic myelopathy (CSM), focusing on intramedullary increased signal intensity (ISI) on T2-weighted magnetic resonance imaging. SUMMARY OF BACKGROUND DATA: Long-term natural course of mild forms of CSM, especially with ISI on magnetic resonance imaging, remains uncertain. METHODS: Patients with CSM who visited our institution between 1992 and 2004 and did not undergo surgery at first visit were retrospectively reviewed. The inclusion criteria were as follows: (1) motor function Japanese Orthopedic Association scores of 3 or more in both upper and lower extremities and (2) cervical spinal cord compression with ISI on T2-weighted magnetic resonance imaging. There were 45 patients, with a mean follow-up period of 78 months (range, 24-208). We investigated long-term natural history by setting the timing of conversion to surgery due to neurological deterioration as an end point. We further compared prognostic parameters between patients who converted to surgery and those who continued to be followed up nonsurgically. RESULTS: Sixteen patients gradually deteriorated and underwent decompression surgery, whereas 27 patients did not. Apart from these, 2 patients with acute spinal cord injury after minor trauma underwent surgery. Kaplan-Meier survival analysis revealed that 82% or 56% of patients did not require surgery 5 or 10 years after the initial treatment, respectively. As for prognostic factors, Cox proportional hazard analysis revealed that total cervical range of motion (hazard ratio: 3.25), segmental kyphosis in the maximum compression segment (hazard ratio: 4.51), and local slip (hazard ratio: 4.67) were statistically significant. CONCLUSION: Fifty-six percent of patients with clinically mild CSM with ISI had not deteriorated or undergone surgery at 10 years. Large range of motion, segmental kyphosis, and instability at the narrowest canal were considered to be adverse prognostic factors. PMID- 22511232 TI - Skeletal muscle and bone marrow derived stromal cells: a comparison of tenocyte differentiation capabilities. AB - This study investigated the comparative ability of bone marrow and skeletal muscle derived stromal cells (BMSCs and SMSCs) to express a tenocyte phenotype, and whether this expression could be augmented by growth and differentiation factor-5 (GDF-5). Tissue harvest was performed on the hind limbs of seven dogs. Stromal cells were isolated via serial expansion in culture. After four passages, tenogenesis was induced using either ascorbic acid alone or in conjunction with GDF-5. CD44, tenomodulin, collagen I, and collagen III expression levels were compared for each culture condition at 7 and 14 days following induction. Immunohistochemistry (IHC) was performed to evaluate cell morphology and production of tenomodulin and collagen I. SMSCs and BMSCs were successfully isolated in culture. Following tenocytic induction, SMSCs demonstrated an increased mean relative expression of tenomodulin, collagen I, and collagen III at 14 days. BMSCs only showed increased mean relative expression of collagen I, and collagen III at 14 days. IHC revealed positive staining for tenomodulin and collagen I at 14 days for both cell types. The morphology of skeletal muscle derived stromal cells at 14 days had an organized appearance in contrast to the haphazard arrangement of the bone marrow derived cells. GDF-5 did not affect gene expression, cell staining, or cell morphology significantly. Stromal cells from either bone marrow or skeletal muscle can be induced to increase expression of matrix genes; however, based on expression of tenomodulin and cell culture morphology SMSCs may be a more ideal candidate for tenocytic differentiation. PMID- 22511233 TI - Malabaricone C inhibits PDGF-induced proliferation and migration of aortic smooth muscle cells through induction of heme oxygenase-1. AB - Malabaricone C (Mal-C), isolated from nutmeg, is known to exert a variety of pharmacological activities. However, the effect of Mal-C on vascular smooth muscle cells (VSMCs) is unknown. This study examined the effect of Mal-C on proliferation and migration of primary rat aortic smooth muscle cells (RASMCs) as well as its underlying mechanisms. Treatment of RASMCs with Mal-C induced both protein and mRNA expression of heme oxygenase-1 (HO-1) in a dose- and time dependent manner. Mal-C-mediated HO-1 induction was inhibited by treatment with actinomycin D or by cycloheximide. SB203580 (a p38 inhibitor), SP600125 (a JNK inhibitor), U0126 (a MEK inhibitor), and N-acetylcysteine (NAC, an antioxidant) did not suppress Mal-C-induced HO-1 expression. In contrast, LY294002 (a PI3K inhibitor) blocked Mal-C-induced HO-1 expression. Moreover, RASMCs treated with Mal-C exhibited activation of AKT in a dose- and time-dependent manner. Treatment of RASMCs with Mal-C increased nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2), which is a key regulator of HO-1 expression, and this translocation was also inhibited by LY294002. Consistent with the notion that HO 1 has protective effects against VSMCs, Mal-C remarkably inhibited platelet derived growth factor (PDGF)-induced proliferation and migration of RASMCs. However, inhibition of HO-1 significantly attenuated the inhibitory effects of Mal-C on PDGF-induced proliferation and migration of RASMCs. Taken together, these findings suggest that Mal-C could suppress PDGF-induced proliferation and migration of RASMCs through Nrf2 activation and subsequent HO-1 induction via the PI3K/AKT pathway, and may be a potential HO-1 inducer for preventing or treating vascular diseases. PMID- 22511234 TI - Novel therapy for therapy-resistant mantle cell lymphoma: multipronged approach with targeting of hedgehog signaling. AB - Mantle cell lymphoma (MCL) is one of the most aggressive B-cell lymphomas with a median patient survival of only 5-7 years. The failure of existing therapies is mainly due to disease relapse when therapy-resistant tumor cells remain after chemotherapy. Therefore, development and testing of novel therapeutic strategies to target these therapy-resistant MCL are needed. Here, we developed an in vivo model of therapy-resistant MCL by transplanting a patient-derived MCL cell line (Granta 519) into NOD/SCID mice followed by treatment with combination chemotherapy. Cytomorphologic, immunophenotypic, in vitro and in vivo growth analyses of these therapy-resistant MCL cells confirm their MCL origin and resistance to chemotherapy. Moreover, quantitative real-time PCR revealed the upregulation of GLI transcription factors, which are mediators of the hedgehog signaling pathway, in these therapy-resistant MCL cells. Therefore, we developed an effective therapeutic strategy for resistant MCL by treating the NOD/SCID mice bearing Granta 519 MCL with CHOP chemotherapy to reduce tumor burden combined with GLI-antisense oligonucleotides or bortezomib, a proteosome inhibitor, to target therapy-resistant MCL cells that remained after chemotherapy. This regimen was followed by treatment with MCL-specific cytotoxic T lymphocytes to eliminate all detectable leftover minimal residual disease. Mice treated with this strategy showed a significantly increased survival and decreased tumor burden compared to the mice in all other groups. Such therapeutic strategies that combine chemotherapy with targeted therapy followed by tumor-specific immunotherapy are effective and have excellent potential for clinical application to provide long term, disease-free survival in MCL patients. PMID- 22511235 TI - A comment on rapid progression of hidradenitis suppurativa in the lower leg of a patient with psoriasis vulgaris. PMID- 22511237 TI - Lymph node art. PMID- 22511236 TI - Chip-based protein-protein interaction studied by atomic force microscopy. AB - In this article, a technique for accurate direct measurement of protein-to protein interactions before and after the introduction of a drug candidate is developed using atomic force microscopy (AFM). The method is applied to known immunosuppressant drug candidate Echinacea purpurea derived cynarin. T-cell/CD28 is on-chip immobilized and B-cell/CD80 is immobilized on an AFM tip. The difference in unbinding force between these two proteins before and after the introduction of cynarin is measured. The method is described in detail including determination of the loading rates, maximum probability of bindings, and average unbinding forces. At an AFM loading rate of 1.44 * 10(4) pN/s, binding events were largely reduced from 61 +/- 5% to 47 +/- 6% after cynarin introduction. Similarly, maximum probability of bindings reduced from 70% to 35% with a blocking effect of about 35% for a fixed contact time of 0.5 s or greater. Furthermore, average unbinding forces were reduced from 61.4 to 38.9 pN with a blocking effect of ~ 37% as compared with ~ 9% by SPR. AFM, which can provide accurate quantitative measures, is shown to be a good method for drug screening. The method could be applied to a wider variety of drug candidates with advances in bio-chip technology and a more comprehensive AFM database of protein-to protein interactions. PMID- 22511238 TI - Engineering a large protein by combined rational and random approaches: stabilizing the Clostridium thermocellum cellobiose phosphorylase. AB - The Clostridium thermocellum cellobiose phosphorylase (CtCBP) is a large protein consisting of 812 amino acids and has great potential in the production of sugar phosphates, novel glycosides, and biofuels. It is relatively stable at 50 degrees C, but is rapidly inactivated at 70 degrees C. To stabilize CtCBP at elevated temperatures, two protein-engineering approaches were applied, i.e. site directed mutagenesis based on structure-guided homology analysis and random mutagenesis at various mutation rates. The former chose substitutions by comparison of the protein sequences of CBP homologs, utilized structural information to identify key amino acid residues responsible for enhanced stability, and then created a few variants accurately. The latter constructed large libraries of random mutants at different mutagenesis frequencies. A novel combinational selection/screening strategy was employed to quickly isolate thermostability-enhanced and active variants. Several stability-enhanced mutants were obtained by both methods. Manually combining the stabilizing mutations identified from both rational and random approaches led to the best mutant (CM3) with the halftime of inactivation at 70 degrees C extended from 8.3 to 24.6 min. The temperature optimum of CM3 was increased from 60 to 80 degrees C. These results suggested that a combination of rational design and random mutagenesis could have a solid basis for engineering large proteins. PMID- 22511239 TI - Hematological malignancies and pregnancy: treat or no treat during first trimester. AB - Treatment of hematological malignancies (HM) during pregnancy remain unsolved, although the use of chemotherapy during second and third trimester has been accepted because of the low rate of toxicities, the use of cytotoxic drugs during first trimester is generally forbidden. Most of the concerns are related to congenital abnormalities and development, but long-term follow-up of these children are not available. From 1975 to 2008, we diagnosed and treated 15,750 cases of HM, and 143 female patients were pregnant during this time that were treated with combined chemotherapy. In our study, we present the long-term follow up (the median follow-up was 22.4 years with a range of 3.8-32.0 years) of 54 newborns, whose mothers received chemotherapy during the first trimester of pregnancy with an intent-to-cure HM. Physical and neurological development were carefully assessed, and cardiac and chromosomal studies were performed until the age of 20 years to evaluate late toxicities. The obstetrical development of pregnancy was normal, chemotherapy was used at doses and schedules used in normal patients. Low-weight birth was the most frequent finding. No congenital abnormalities were detected. Physical, psychological and neurological developments were normal. Education and academic degree were according to the economical and social factors. Cardiac function and chromosomal examination were normal. No neoplasm or acute leukemia has been observed in these children. Forty three mothers are alive and disease-free and can be considered cured. The use of cytotoxic drugs during the first trimester to treat HM seems to be beneficial to both the mother and fetus, and chemotherapy during the first trimester can be considered if the cure of the patient is the goal. PMID- 22511240 TI - Macrophage immunomodulatory activity of a purified polysaccharide isolated from Ganoderma atrum. AB - The objective of this study was to evaluate the immunomodulatory effects of the purified Ganoderma atrum polysaccharide (PSG-1) on murine macrophage cell line RAW264.7. Phagocytotic assay by fluorescein isothiocyanate-dextran internalization showed that PSG-1 stimulated the phagocytosis of macrophages. G. atrum polysaccharide increased the production of NO, and the level of mRNA expression of inducible nitric oxide synthase in a dose-response manner. G. atrum polysaccharide also dose-dependently induced the release of TNF-alpha and interleukin-1beta. Generation of reactive oxygen species was promoted by PSG-1, as determined by flow cytometry. Moreover, PSG-1 induced nuclear factor-kappaB activation by elevation of p65 nuclear translocation, suggesting that PSG-1 probably stimulated macrophage activities by activating the nuclear factor-kappaB pathway. PMID- 22511242 TI - Parallel acquisition of awareness and differential delay eyeblink conditioning. AB - There is considerable debate about whether differential delay eyeblink conditioning can be acquired without awareness of the stimulus contingencies. Previous investigations of the relationship between differential-delay eyeblink conditioning and awareness of the stimulus contingencies have assessed awareness after the conditioning session was finished using a post-experimental questionnaire. In two experiments, the point at which contingency awareness developed during the conditioning session was estimated from a button-press measure of expectancy of the unconditioned stimulus (US). In both experiments, knowledge of the stimulus contingencies and acquisition of differential delay eyeblink conditioning developed approximately in parallel. In Experiment 1 it was shown that predicting the US facilitated eyeblink conditioning compared with predicting the eyeblink response. In Experiment 2, a masking task was used that slowed down the emergence of awareness, and it was shown that differential conditioning only occurred in participants who were able to predict the US. The current findings challenge the hypothesis that differential delay eyeblink conditioning is entirely mediated by a functionally and neurally distinct nondeclarative learning system. PMID- 22511241 TI - Differential regulation of glutamic acid decarboxylase gene expression after extinction of a recent memory vs. intermediate memory. AB - Extinction reduces fear to stimuli that were once associated with an aversive event by no longer coupling the stimulus with the aversive event. Extinction learning is supported by a network comprising the amygdala, hippocampus, and prefrontal cortex. Previous studies implicate a critical role of GABA in extinction learning, specifically the GAD65 isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD). However, a detailed analysis of changes in gene expression of GAD in the subregions comprising the extinction network has not been undertaken. Here, we report changes in gene expression of the GAD65 and GAD67 isoforms of GAD, as measured by relative quantitative real-time RT-PCR, in subregions of the amygdala, hippocampus, and prefrontal cortex 24-26 h after extinction of a recent (1-d) or intermediate (14-d) fear memory. Our results show that extinction of a recent memory induces a down-regulation of Gad65 gene expression in the hippocampus (CA1, dentate gyrus) and an up-regulation of Gad67 gene expression in the infralimbic cortex. Extinguishing an intermediate memory increased Gad65 gene expression in the central amygdala. These results indicate a differential regulation of Gad gene expression after extinction of a recent memory vs. intermediate memory. PMID- 22511243 TI - Maxillary dental arch biometry: assessment with fetal MR imaging. AB - OBJECTIVE: To define normal growth of the fetal maxillary dental arch using magnetic resonance imaging. METHOD: Four hundred twenty-four consecutive fetuses (18 to 37 weeks) with a morphologically normal anatomy or only minor malformations, not affecting bone growth and face anatomy were included. On axial T2-weighted images the dental arch length and width were measured. The measurements were correlated with gestational age and the biparietal diameter (BPD) of the fetal head using correlation and regression analysis. RESULTS: A linear growth relationship was observed between the dental arch length and gestational age (r = 0.86; p = < 0.0001; y = -1.85 + 0.75 * gestational age) and the dental arch width and gestational age (r = 0.92; p = < 0.0001; y = -2.19 + 1.05 * gestational age). A significant correlation was found between the dental arch length and the BPD (r = 0.903; p = < 0.0001) and the dental arch width and the BPD (r = 0.927; p = < 0.0001). The interobserver variability showed good agreement for the dental arch length (intraclass coefficient 0.981; r = 0.963) and width (intraclass coefficient 0.987; r = 0.974), respectively. CONCLUSION: We present a nomogram for the in utero assessment of the fetal dental arch. These data may help in the early detection of abnormal dental arch development. PMID- 22511245 TI - Ric-8: different cellular roles for a heterotrimeric G-protein GEF. AB - Signaling via heterotrimeric G-proteins is evoked by agonist-mediated stimulation of seven transmembrane spanning receptors (GPCRs). During the last decade it has become apparent that Galpha subunits can be activated by receptor-independent mechanisms. Ric-8 belongs to a highly conserved protein family that regulates heterotrimeric G-protein function, acting as a non-canonical guanine nucleotide exchange factors (GEF) over a subset of Galpha subunits. In this review we discuss the roles of Ric-8 in the regulation of diverse cell functions, emphasizing the contribution of its multiple domain protein structure in these diverse functions. PMID- 22511246 TI - Assembly of novel organic-decorated quaternary TM-Hg-Sb-Q compounds (TM = Mn, Fe, Co; Q = S, Se) by the combination of three types of metal coordination geometries. AB - Four organic-decorated quaternary TM-Hg-Sb-Q compounds, namely, [Mn(phen)](2)HgSb(2)S(6) (phen = 1,10-phenanthroline) (1) and isomorphic [TM(tren)]HgSb(2)Se(5) (TM = Mn (2), Fe (3), Co (4); tren = tris(2 aminoethyl)amine) have been solvothermally prepared, and structurally characterized by single crystal X-ray diffraction analyses. 1 and 2 (3, 4) feature distinct one-dimensional neutral infinite ribbon-like structures constructed by the combination of Sb(3+), Hg(2+) and TM(2+), the latter two of which adopt different coordination modes. In compound 1, organic-decorated {[Mn(phen)](2)Sb(2)S(6)} clusters assembled by {MnS(4)N(2)} octhedra and {SbS(3)} pyramids are bridged by the {HgS(2)} groups in a linear fashion. Differently, the {SbSe(3)} pyramids, {HgSe(4)} tetrahedra and {TMSeN(4)} trigonal-bipyramids in 2 (3, 4) are combined to form novel {[TM(tren)](2)Hg(2)Sb(4)Se(12)} clusters, which are interconnected to form {[TM(tren)]HgSb(2)Se(5)}(n) ribbons. The results of optical diffuse-reflectance measurements and band structure calculations based on DFT methods indicate that 1 and 2 (3, 4) are indirect and direct semiconductors, respectively. Photocatalytic experiments have shown the ability of 2 in photodegradation of Rhodamine B (RhB). PMID- 22511244 TI - Impaired osteoblastogenesis in a murine model of dominant osteogenesis imperfecta: a new target for osteogenesis imperfecta pharmacological therapy. AB - The molecular basis underlying the clinical phenotype in bone diseases is customarily associated with abnormal extracellular matrix structure and/or properties. More recently, cellular malfunction has been identified as a concomitant causative factor and increased attention has focused on stem cells differentiation. Classic osteogenesis imperfecta (OI) is a prototype for heritable bone dysplasias: it has dominant genetic transmission and is caused by mutations in the genes coding for collagen I, the most abundant protein in bone. Using the Brtl mouse, a well-characterized knockin model for moderately severe dominant OI, we demonstrated an impairment in the differentiation of bone marrow progenitor cells toward osteoblasts. In mutant mesenchymal stem cells (MSCs), the expression of early (Runx2 and Sp7) and late (Col1a1 and Ibsp) osteoblastic markers was significantly reduced with respect to wild type (WT). Conversely, mutant MSCs generated more colony-forming unit-adipocytes compared to WT, with more adipocytes per colony, and increased number and size of triglyceride drops per cell. Autophagy upregulation was also demonstrated in mutant adult MSCs differentiating toward osteogenic lineage as consequence of endoplasmic reticulum stress due to mutant collagen retention. Treatment of the Brtl mice with the proteasome inhibitor Bortezomib ameliorated both osteoblast differentiation in vitro and bone properties in vivo as demonstrated by colony-forming unit osteoblasts assay and peripheral quantitative computed tomography analysis on long bones, respectively. This is the first report of impaired MSC differentiation to osteoblasts in OI, and it identifies a new potential target for the pharmacological treatment of the disorder. PMID- 22511248 TI - Insight into the reaction mechanisms of (MeC5H4)3U with isoelectronic heteroallenes CS2, COS, PhN3, and PhNCO by DFT studies: a unique pathway that involves bimetallic complexes. AB - The mechanisms of the reduction of four isoelectronic heteroallenes (CS(2), COS, PhN(3), and PhNCO) by trivalent uranium complex (MeC(5)H(4))(3)U were determined by using DFT methods. The experimental formation of either the bimetallic CS(2) and the PhNCO uranium(IV) adducts or the bimetallic sulfide complex (COS) and the monometallic uranium(V) phenylimide complex (PhN(3)) were rationalized. The formation of the products was explained by a unique reaction mechanism with a uranium(IV)-bridged heteroallene intermediate. PMID- 22511247 TI - Comparison of liver transplantation outcomes from adult split liver and circulatory death donors. AB - BACKGROUND: Adult whole-organ donation after circulatory death (DCD) and 'split' extended right lobe donation after brain death (ERL-DBD) liver transplants are considered marginal, but direct comparison of outcomes has rarely been performed. Such a comparison may rationalize the use of DCD livers, which varies widely between UK centres. METHODS: Outcomes for adult ERL-DBD livers and 'controlled' DCD liver transplantations performed at the Cambridge Transplant Centre between January 2004 and December 2010 were compared retrospectively. RESULTS: None of the 32 patients in the DCD cohort suffered early graft failure, compared with five of 17 in the ERL-DBD cohort. Reasons for graft failure were hepatic artery thrombosis (3), progressive cholestasis (1) and small-for-size syndrome (1). Early allograft dysfunction occurred in a further five patients in each group. In the DCD group, ischaemic cholangiopathy developed in six patients, resulting in graft failure within the first year in two; the others remained stable. The incidence of biliary anastomotic complications was similar in both groups. Kaplan Meier survival analysis confirmed superior graft survival in the DCD liver group (93 per cent at 3 years versus 71 per cent in the ERL-DBD cohort; P = 0.047), comparable to that of contemporaneous whole DBD liver transplants (93 per cent at 3 years). Patient survival was similar in all groups. CONCLUSION: Graft outcomes of DCD liver transplants were better than those of ERL-DBD liver transplants. Redefining DCD liver criteria and refining donor-recipient selection for ERL-DBD transplants should be further explored. PMID- 22511249 TI - Biomimetic detection of aminoglycosidic antibiotics using polydiacetylene phospholipids supramolecules. AB - We rationally designed highly sensitive and selective polydiacetylene (PDA) phospholipids liposomes for the facile detection of aminoglycosidic antibiotics. The detecting mechanism mimics the cellular membrane interactions between neomycin and phosphatidylinositol-4,5-bisphosphate (PIP(2)) phospholipids. The developed PDA-PIP(2) sensory system showed a detection limit of 61 ppb for neomycin and was very specific to aminoglycosidic antibodies only. PMID- 22511250 TI - Dual-responsive boronate crosslinked micelles for targeted drug delivery. PMID- 22511251 TI - Age and abdominal wall strength: assessing the aging abdominal wall after autologous breast reconstruction. AB - Autologous breast reconstruction is safe in advanced age, yet no study has examined its effects on the aging abdomen. We, therefore, studied 145 women who participated in a prospective study of abdominal strength following abdominal free flap breast reconstruction, comparing preoperative and late follow-up scores in patients >=60 years old (11 unilateral, 13 bilateral) compared with patients <60 (58 unilateral, 63 bilateral). Simple in-office tests were utilized to test abdominal strength. No differences were noted in unilateral absolute scores at either time point, however, a decrease in upper abdominal strength was noted in the younger cohort over time (P = 0.01). Bilateral analyses revealed absolute score decreases in upper abdominal strength for both cohorts but no major differences between the two. We conclude that autologous breast reconstruction with abdominal tissue in older patients result in little to no difference in abdominal function as compared with younger patients. PMID- 22511252 TI - Phase behavior of CO2 in room-temperature ionic liquid 1-ethyl-3-ethylimidazolium acetate. AB - Carbon dioxide solubility (vapor-liquid equilibria: VLE) in an ionic liquid, 1 ethyl-3-ethylimidazolium acetate ([eeim][Ac]) was measured using a gravimetric microbalance at four isotherms (about 283, 298, 323, and 348 K) up to about 2 MPa. An equation-of-state (EOS) model was used to analyze the VLE data and has predicted vapor-liquid-liquid equilibria (VLLE: or liquid-liquid separations) in CO(2)-rich solutions. The VLLE prediction was confirmed experimentally using a volumetric method and likely the liquid-liquid equilibria will intersect with the solid-liquid equilibria such that no lower critical solution temperature can exist and the binary system may be classified as Type III phase behavior. Carbon dioxide solubility in the ionic-liquid-rich solution show extremely unusual behavior. CO(2) dissolves in the ionic liquid at large concentrations (up to about 20 mole % of CO(2)) with almost no vapor pressure above the mixtures. This result is similar to our previous findings with 1-butyl-3-methylimidazolium acetate ([bmim][Ac]) and 1-ethyl-3-methylimidazolium acetate ([emim][Ac]). In all three cases the CO(2) forms a molecular complex (or chemical reaction) with the ionic liquid. (13)C NMR spectroscopy has identified the structure for CO(2) absorbed in [eeim][Ac] to be [eeim]-2-carboxylate. Addition of water to the carboxylate leads to the dissolution of CO(2). The thermodynamic excess properties (enthalpy, entropy, and Gibbs energy) for all three systems have been calculated using the EOS and support the complex formation of the type AB(2) (where A is CO(2) and B is ionic liquid). Isothermal differential scanning calorimetry has verified the heat of reaction calculations and found for CO(2) absorbing in [emim][Ac], [eeim][Ac] and [bmim][Ac] to be about -38 kJ mol(-1). Additional experiments have examined the effect of water on the density, viscosity and CO(2) solubility in [eeim][Ac] and the CO(2) solubility in mixtures of [eeim][Ac] with other acetate salts. PMID- 22511253 TI - Novel renewable ionic liquids as highly effective solvents for pretreatment of rice straw biomass by selective removal of lignin. AB - Cholinium amino acids ionic liquids ([Ch][AA] ILs), a novel type of bio-ILs that can easily be prepared from renewable biomaterials, were investigated for pretreatment of rice straw by selective extraction of lignin from this abundant lignocellulosic biomass material. Of the eight ILs examined, most were demonstrated to be excellent pretreatment solvents. Upon pretreatment using these ILs, the initial saccharification rates of rice straw residues were substantially improved as well as the extent to which polysaccharides could be digested (>90% for cellulose and >60% for xylan). Enzymatic hydrolysis of pretreated rice straw by Trichoderma reesei cellulase/xylanase furnished glucose and xylose with the yields in excess of 80% and 30%, respectively. Detailed spectroscopic characterization showed that the enhancement of polysaccharides degestibility derived mainly from delignification rather than changes in cellulose crystallinity. The yields of fermentable reducing sugars were significantly improved after individual optimization of pretreatment temperature and duration. With [Ch][Lys] as the solvent, the sugar yields of 84.0% for glucose and 42.1% for xylose were achieved after pretreatment at 90 degrees C for 5 h. The IL [Ch][Lys] showed excellent reusability across five successive batches in pretreatment of rice straw. These bio-ILs performed as well as or better than previously investigated non-renewable ILs, and thus present a new and environmentally friendly way to pretreat lignocellulose for production of fermentable sugars and total utilization of the biomass. PMID- 22511254 TI - Susceptibility variants for obesity and colorectal cancer risk: the multiethnic cohort and PAGE studies. AB - Obesity is a leading contributor to colorectal cancer risk. We investigated whether the risk variants identified in genome-wide association studies of body mass index (BMI) and waist size are associated with colorectal cancer risk, independently of the effect of obesity phenotype due to a shared etiology. Twenty four single nucleotide polymorphisms (SNPs) in 15 loci (BDNF, FAIM2, FTO, GNPDA2, KCTD15, LYPLAL1, MC4R, MSRA, MTCH2, NEGR1, NRXN3, SEC16B, SH2B1, TFAP2B and TMEM18) were genotyped in a case-control study of 2,033 colorectal cancer cases and 9,640 controls nested within the multiethnic cohort study, as part of the population architecture using genomics and epidemiology consortium. Risk alleles for two obesity SNPs were associated with colorectal cancer risk--KCTD15 rs29941 [odds ratio (OR) for C allele = 0.90, 95% confidence interval (CI) 0.83-0.98; p = 0.01] and MC4R rs17782313 (OR for C allele = 1.12, 95% CI 1.02-1.22; p = 0.02). These associations were independent of the effect of BMI. However, none of the results remained significant after adjustment for multiple comparisons. No heterogeneity was observed across race/ethnic groups. Our findings suggest that the obesity risk variants are not likely to affect the risk of colorectal cancer substantially. PMID- 22511255 TI - Chronic administration of daidzein, a soybean isoflavone, improves endothelial dysfunction and attenuates oxidative stress in streptozotocin-induced diabetic rats. AB - The effect of chronic daidzein, a soybean isoflavone, on aortic reactivity of streptozotocin-diabetic rats was studied. Male diabetic rats received daidzein for 7 weeks a week after diabetes induction. Contractile responses to KCl and phenylephrine (PE) and relaxation response to acetylcholine (ACh) were obtained from aortic rings. Maximum contractile response of endothelium-intact rings to PE was significantly lower in daidzein-treated diabetic rats relative to untreated diabetic rats, and endothelium removal abolished this difference. Endothelium dependent relaxation to ACh was significantly higher in daidzein-treated diabetic rats as compared with diabetic rats and pretreatment of rings with nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester and/or indomethacin attenuated it. Two-month diabetes also resulted in an elevation of malondialdehyde (MDA) and decreased superoxide dismutase (SOD) activity, and daidzein treatment significantly reversed the increased MDA content and reduced activity of SOD. Therefore, chronic treatment of diabetic rats with daidzein could prevent some abnormal changes in vascular reactivity in diabetic rats through nitric oxide and prostaglandin-related pathways, and via attenuation of oxidative stress in aortic tissue and endothelium integrity seems essential for this effect. PMID- 22511256 TI - Serum levels of receptors for advanced glycation end products in normal-weight and obese children born small and large for gestational age. AB - OBJECTIVE: To assess potential alterations in soluble and endogenous secretory receptors for advanced glycation end products (sRAGE and esRAGE) in normal-weight (NW) and obese (Ob) children born small (SGA) and large (LGA) compared with appropriate for gestational age (AGA) subjects and to explore if birth weight (BW), insulin resistance (IR), and obesity represent independent risk factors. RESEARCH DESIGN AND METHODS: We categorized 130 prepubertal children into six groups according to BW and obesity and evaluated sRAGE, esRAGE, and homeostasis model assessment of IR. RESULTS: sRAGE and esRAGE were lower in Ob SGA and LGA children than Ob AGA subjects (all P < 0.05), and in NW SGA and LGA children than NW AGA subjects (all P < 0.05). Interestingly, BW and IR were significantly and independently related to RAGE. CONCLUSIONS: sRAGE and esRAGE are decreased in SGA and LGA children, and BW and IR seem to play an important role in the reduction of RAGE. PMID- 22511257 TI - The impact of treatment noncompliance on mortality in people with type 2 diabetes. AB - OBJECTIVE: To assess the association of compliance with treatment (medication and clinic appointments) and all-cause mortality in people with insulin-treated type 2 diabetes. RESEARCH DESIGN AND METHODS: Data were extracted from U.K. general practice records and included patients (N = 15,984) who had diagnostic codes indicative of type 2 diabetes or who had received a prescription for an oral antidiabetic agent and were treated with insulin. Records in the 30 months before the index date were inspected for clinical codes (recorded at consultation) indicating medication noncompliance or medical appointment nonattendance. Noncompliance was defined as missing more than one scheduled visit or having at least one provider code for not taking medications as prescribed. Relative survival postindex date was compared by determining progression to all-cause mortality using Cox proportional hazards models. RESULTS: Those identified as clinic nonattenders were more likely to be smokers, younger, have higher HbA(1c), and have more prior primary care contacts and greater morbidity (P < 0.001). Those identified as medication noncompliers were more likely to be women (P = 0.001), smokers (P = 0.014), and have higher HbA(1c), more prior primary care contacts, and greater morbidity (all P < 0.001). After adjustment for confounding factors, medication noncompliance (hazard ratio 1.579 [95% CI 1.167-2.135]), clinic nonattendance of one or two missed appointments (1.163 [1.042-1.299]), and clinic nonattendance of greater than two missed appointments (1.605 [1.356 1.900]) were independent risk factors for all-cause mortality. CONCLUSIONS: Medication noncompliance and clinic nonattendance, assessed during routine care by primary care physicians or their staff, were independently associated with increased all-cause mortality in patients with type 2 diabetes receiving insulin. PMID- 22511258 TI - Fasting insulin level is positively associated with incidence of hypertension among American young adults: a 20-year follow-up study. AB - OBJECTIVE: Although hyperinsulinemia, a surrogate of insulin resistance, may play a role in the pathogenesis of hypertension (HTN), the longitudinal association between fasting insulin level and HTN development is still controversial. We examined the relation between fasting insulin and incidence of HTN in a large prospective cohort. RESEARCH DESIGN AND METHODS: A prospective cohort of 3,413 Americans, aged 18-30 years, without HTN in 1985 (baseline) were enrolled. Six follow-ups were conducted in 1987, 1990, 1992, 1995, 2000, and 2005. Fasting insulin and glucose levels were assessed by a radioimmunoassay and hexokinase method, respectively. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs of incident HTN (defined as the initiation of antihypertensive medication, systolic blood pressure >=140 mmHg, or diastolic blood pressure >=90 mmHg). RESULTS: During the 20-year follow-up, 796 incident cases were identified. After adjustment for potential confounders, participants in the highest quartile of insulin levels had a significantly higher incidence of HTN (HR 1.85 [95% CI 1.42-2.40]; P(trend) < 0.001) compared with those in the lowest quartile. The positive association persisted in each sex/ethnicity/weight status subgroup. A similar dose-response relation was observed when insulin-to glucose ratio or homeostatic model assessment of insulin resistance was used as exposure. CONCLUSIONS: Fasting serum insulin levels or hyperinsulinemia in young adulthood was positively associated with incidence of HTN later in life for both men and women, African Americans and Caucasians, and those with normal weight and overweight. Our findings suggested that fasting insulin ascertainment may help clinicians identify those at high risk of HTN. PMID- 22511259 TI - Defining insulin resistance from hyperinsulinemic-euglycemic clamps. AB - OBJECTIVE: This study was designed to determine a cutoff point for identifying insulin resistance from hyperinsulinemic-euglycemic clamp studies performed at 120 mU/m(2).min in a white population and to generate equations from routinely measured clinic and blood variables for predicting clamp-derived glucose disposal rate (GDR), i.e., insulin sensitivity. RESEARCH DESIGN AND METHODS: We assembled data from hyperinsulinemic-euglycemic clamps (120 mU/m(2).min insulin dose) performed at the Pennington Biomedical Research Center between 2001 and 2011. Subjects were divided into subjects with diabetes (n = 51) and subjects without diabetes (n = 116) by self-report and/or fasting glucose >=126 mg/dL. RESULTS: We found that 75% of individuals with a GDR <5.6 mg/kg fat-free mass (FFM) + 17.7.min were truly insulin resistant. Cutoff values for GDRs normalized for body weight, body surface area, or FFM were 4.9 mg/kg.min, 212.2 mg/m(2).min, and 7.3 mg/kgFFM.min, respectively. Next, we used classification tree models to predict GDR from routinely measured clinical and biochemical variables. We found that individual insulin resistance could be estimated with good sensitivity (89%) and specificity (67%) from the homeostasis model assessment of insulin resistance (HOMA-IR) >5.9 or 2.8< HOMA-IR <5.9 with HDL <51 mg/dL. CONCLUSIONS: We developed a cutoff for defining insulin resistance from hyperinsulinemic-euglycemic clamps. Moreover, we now provide classification trees for predicting insulin resistance from routinely measured clinical and biochemical markers. These findings extend the clamp from a research tool to providing a clinically meaningful message for participants in research studies, potentially providing greater opportunity for earlier recognition of insulin resistance. PMID- 22511261 TI - The effect of fetal congenital heart disease on in utero urine production rate. AB - OBJECTIVES: To evaluate the influence of congenital heart disease (CHD) or congestive heart failure (CHF) on fetal urine production rate (UPR) and to establish normal reference intervals. METHODS: A cross-sectional study was performed on normal fetuses (n = 314) and on fetuses with CHD (n = 49). CHD cases were divided into groups on the basis of heart function as defined by Huhta score: with CHF (n = 11) and without CHF (n = 38). Fetal bladder volume was measured by two-dimensional as well as three-dimensional ultrasound with the Virtual Organ Computer-aided Analysis technique. RESULTS: In normal fetuses, UPR increased with gestational age from a mean value of 4.5 mL/h at 21 weeks to 66.5 mL/h at 40 weeks. There were no significant differences in UPR between CHD cases without CHF and controls (P = 0.581). However, fetuses with CHF had decreased UPR values (Controls vs. CHF, P = 0.007) compared with the controls. The interobserver and intraobserver variability for assessment of UPR was better using three-dimensional rather than two-dimensional US. CONCLUSIONS: Fetal UPR can be reproducibly measured by the Virtual Organ Computer-aided Analysis technique. It appears that heart function, rather than CHD, affects fetal UPR. Fetal UPR may therefore be an additional indicator of CHF. PMID- 22511263 TI - Hepatic artery embolization for neuroendocrine tumors: postprocedural management and complications. AB - BACKGROUND: There is scant evidence to guide the management of patients after hepatic artery embolization (HAE). We examined length of stay (LOS), laboratory patterns, medication usage, morbidity, and mortality of patients hospitalized after HAE for metastatic neuroendocrine tumors. METHODS: Data were abstracted retrospectively from electronic medical records on LOS, liver function tests (LFTs), i.v. antibiotics, analgesia, peak temperature, bacteremia, hepatic abscess formation, carcinoid crisis, and metastatic burden on cross-sectional imaging. RESULTS: In 2005-2009, 72 patients underwent 174 HAEs for carcinoid and islet cell tumors. The median LOS was 4 days (range, 1-8 days). There was no correlation between peak LFTs and tumor burden. Declines in LFTs were not uniform before hospital discharge; 25%, 37%, 30%, 53%, and 67% of patients were discharged before their respective aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total and direct bilirubin levels began to decline, with no readmissions for acute hepatic failure. The median i.v. analgesia dose was 60 mg oral morphine equivalents (range, 3-1,961 mg). Pre-HAE i.v. antibiotics were administered in 99% of cases; post-HAE fever occurred in 37% of patients, with no documented bacteremia. One patient developed a hepatic abscess after HAE. There were two carcinoid crises. The single in-hospital death was associated with air in the portal veins. CONCLUSIONS: The duration and intensity of in-hospital care following HAE should be managed on an individual basis. A downward trend in LFTs is not required before discharge. Modest use of i.v. analgesia suggests that many patients could exclusively receive oral analgesics. Given the rarity of serious complications, hospital stays could be shortened, thereby reducing costs and nosocomial risks. PMID- 22511264 TI - Call it cancer: letting the histopathology determine the diagnosis. PMID- 22511266 TI - Letter to the editor regarding "A prospective, controlled study of the botanical compound mixture LCS101 for chemotherapy-induced hematological complications in breast cancer" by Yaal-Hahoshen et al. (The Oncologist 2011;16:1197-1202). PMID- 22511265 TI - Quality of life and its associated factors in patients with hepatocellular carcinoma receiving one course of transarterial chemoembolization treatment: a longitudinal study. AB - OBJECTIVE: To (a) explore changes in physical and psychological distress and quality of life (QOL) and (b) identify the significant pre- and postdischarge factors related to changes in physical and mental domains of QOL over a period of 2 months in patients with hepatocellular carcinoma receiving one course of transarterial chemoembolization (TACE) treatment. METHODS: A longitudinal prospective design was used, with participants recruited from a teaching hospital in Northern Taiwan. Data were collected three times: within 3 days prior to discharge (T0) and at the fourth (T1) and eighth (T2) weeks after discharge. A set of structured questionnaires was used to assess participants' QOL, symptom distress, anxiety, and depression. Changes in QOL and associated factors were examined using generalized estimating equations. RESULTS: Eighty-nine patients were included in this study. Fatigue was reported to be the most distressful symptom after treatment. Overall QOL improved monthly after discharge. Change in physical QOL 2 months after TACE treatment was associated with age, diagnosis status, level of symptom distress, and depression after discharge. Change in mental QOL was significantly associated with gender, diagnosis status, and anxiety and depression after discharge. CONCLUSIONS: Health care providers should pay special attention to patients of older age, those who are male, and those who have higher levels of depression and anxiety after discharge. Designing personalized education programs before discharge for patients with newly diagnosed cancer versus those who have recurrent disease is suggested to help patients maintain a better QOL after discharge. PMID- 22511260 TI - High concentrations of AGE-LDL and oxidized LDL in circulating immune complexes are associated with progression of retinopathy in type 1 diabetes. AB - OBJECTIVE: To determine whether immunocomplexes (ICs) containing advanced glycation end product (AGE)-LDL (AGE-LDL) and oxidized LDL (oxLDL) contribute to the development of retinopathy over a 16-year period in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: Levels of AGE-LDL and oxLDL in ICs were measured in 517 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Retinopathy was assessed by stereoscopic fundus photography. Cox proportional hazards models were used to assess the effect of AGE-LDL-ICs and oxLDL-ICs on retinopathy progression. RESULTS: In unadjusted models, higher baseline levels of AGE-LDL-ICs and oxLDL-ICs significantly predicted progression of diabetic retinopathy outcomes. After adjustment by study-design variables (treatment group, retinopathy cohort, duration of type 1 diabetes, and baseline albumin excretion rate [AER], hemoglobin A(1c) (HbA(1c)), and Early Treatment Diabetic Retinopathy Study [ETDRS] score), one SD increase in IC levels was associated with 47% (hazard ratio [HR] 1.47 [95% CI 1.19-1.81]; AGE-LDL-IC) and 45% (1.45 [1.17-1.80]; oxLDL-IC) increased risk of developing proliferative diabetic retinopathy (PDR) and 37% (1.37 [1.12-1.66]; to both ICs) increased risk of progressing to severe nonproliferative retinopathy. Analyses were stratified by retinopathy cohort because results differed between primary and secondary cohorts. For AGE-LDL-ICs, HR for progression to PDR was 2.38 (95% CI 1.30-4.34) in the primary cohort and attenuated in the secondary cohort (1.29 [1.03-1.62]). Similar results were observed for oxLDL-ICs. CONCLUSIONS: Increased levels of AGE LDL and oxLDL in ICs are associated with increased risk for progression to advanced retinopathy in patients with type 1 diabetes, indicating that the antibody response to modified LDL plays a significant role in retinopathy progression. PMID- 22511267 TI - MicroRNAs regulate p21(Waf1/Cip1) protein expression and the DNA damage response in human embryonic stem cells. AB - Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this article, we provide evidence that expression of p21 protein is directly regulated by the microRNA (miRNA) pathway under standard culture conditions and after DNA damage. The DDR in hESCs leads to upregulation of tens of miRNAs, including hESC-specific miRNAs such as those of the miR-302 family, miR-371-372 family, or C19MC miRNA cluster. Most importantly, we show that the hESC-enriched miRNA family miR-302 (miR-302a, miR-302b, miR-302c, and miR-302d) directly contributes to regulation of p21 expression in hESCs and, thus, demonstrate a novel function for miR-302s in hESCS. The described mechanism elucidates the role of miRNAs in regulation of important molecular pathway governing the G1/S transition checkpoint before as well as after DNA damage. PMID- 22511268 TI - Proteolysis of beta-galactosidase following SigmaB activation in Bacillus subtilis. AB - In Bacillus subtilis the sigma(B) mediated general stress response provides protection against various environmental and energy related stress conditions. To better understand the general stress response, we need to explore the mechanism by which the components interact. Here, we performed experiments in B. subtilis wild type and mutant strains to test and validate a mathematical model of the dynamics of sigma(B) activity. In the mutant strain BSA115, sigma(B) transcription is inducible by the addition of IPTG and negative control of sigma(B) activity by the anti-sigma factor RsbW is absent. In contrast to our expectations of a continuous beta-galactosidase activity from a ctc::lacZ fusion, we observed a transient activity in the mutant. To explain this experimental finding, we constructed mathematical models reflecting different hypotheses regarding the regulation of sigma(B) and beta-galactosidase dynamics. Only the model assuming instability of either ctc::lacZ mRNA or beta-galactosidase protein is able to reproduce the experiments in silico. Subsequent Northern blot experiments revealed stable high-level ctc::lacZ mRNA concentrations after the induction of the sigma(B) response. Therefore, we conclude that protein instability following sigma(B) activation is the most likely explanation for the experimental observations. Our results thus support the idea that B. subtilis increases the cytoplasmic proteolytic degradation to adapt the proteome in face of environmental challenges following activation of the general stress response. The findings also have practical implications for the analysis of stress response dynamics using lacZ reporter gene fusions, a frequently used strategy for the sigma(B) response. PMID- 22511269 TI - Revascularization of unprotected left main coronary artery disease: strategy selection and systematic risk assessment. AB - Refinement of interventional techniques, adjunctive pharmacological therapy, and the introduction of drug eluting stents have fostered new interest for the percutaneous treatment of unprotected left main coronary artery (ULMCA) stenosis. Several observational registries, some randomized controlled trials and several meta-analyses have consistently shown no difference in mortality and myocardial infarction between percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery in patients with ULMCA stenosis, but a higher rate of target vessel revascularization in patients treated with PCI. As a consequence, PCI of ULMCA stenosis has been upgraded to class IIa or IIb indication in the current European or American College of Cardiology/American Heart Association practice guidelines. Although these results are promising, they do not still represent enough evidence for extending PCI of ULMCA stenosis to current clinical practice. The EXCEL trial will address the value of PCI in relation to CABG for the treatment of ULMCA stenosis in more than 2000 patients. A major breakthrough of the SYNTAX trial has been the demonstration of an interaction between the coronary complexity and the revascularization strategy, suggesting that optimal risk stratification is a key element when deciding the best strategy of revascularization in this high-risk group of patients. Multidisciplinary team approach remains essential to provide a balanced information to the patient and to offer the beast treatment option. PMID- 22511270 TI - Bronsted acid catalyzed cycloisomerizations of 5,2-enyne-1-ones: highly regioselective synthesis of 2,3-dihydro-4H-pyran-4-ones. PMID- 22511271 TI - Antithrombotic and profibrinolytic activities of eckol and dieckol. AB - In order to develop new anticoagulant agents, two single compounds (eckol and dieckol) were isolated from Eisenia bicyclis and examined their anticoagulant activities by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT) as well as cell-based thrombin and activated factor X (FXa) generation activities. And the effects of eckol and dieckol on the expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were tested in tumor necrosis factor-alpha (TNF-alpha) activated human umbilical vein endothelial cells (HUVECs). Data showed that eckol and dieckol prolonged aPTT and PT significantly and inhibited thrombin and FXa activities. They also inhibited the generation of thrombin or FXa in HUVECs. In accordance with these anticoagulant activities, eckol or dieckol showed anticoagulant effect in vivo. Furthermore, eckol and dieckol inhibited TNF-alpha induced PAI-1 production and the ratio between PAI-1 and t-PA was found to be significantly decreased by eckol and dieckol. Surprisingly, these anticoagulant and profibrinolytic effects of dieckol were better than those of eckol indicating that hydroxyl group in eckol positively regulated anticoagulant function of eckol. Therefore, these results suggest that eckol or dieckol possesses antithrombotic activities and provides a possibility to develop as an agent for the anticoagulation. PMID- 22511272 TI - Mitogen-activated protein kinase p38 regulates Krox-20 to direct Schwann cell differentiation and peripheral myelination. AB - We previously reported that addition of extracellular matrix (ECM) extracts to rat Schwann cell-dorsal root ganglion neuron (DRGN) co-cultures activated mitogen activated protein kinase (MAPK) p38, whereas inhibition blocked myelination. Here, we used p38 pharmacological inhibitors and gene silencing to assess their effects on downstream kinases and key transcription factors. We show that p38alpha regulates expression of the master transcription factor, Krox-20, required for the onset of myelination in Schwann cell-DRGNs, as assessed by immunocytochemistry and qRT-PCR. p38 activity is also required for the expression of the cell cycle inhibitor p27(kip1) , associated with Schwann cell differentiation. Three potential effectors of p38 were explored: MAPK-activated protein kinase-2 (MK2), mitogen and stress-activated protein kinase-1 (MSK-1), and the transcription factor cAMP response element-binding protein (CREB). Inhibition of MK2 with CMPD1 or gene knockdown with siRNAs reduced numbers of Krox-20-positive Schwann cells and expression of myelin proteins MBP and MAG. ECM activated CREB and increased Krox-20 expression, whereas CREB1 gene silencing reduced Krox-20. Furthermore, two nonselective inhibitors of MSK-1 (H89 and R0 318820) decreased ECM-induced CREB phosphorylation and, similar to anti-MSK-1 siRNAs, reduced Krox-20-positive cells. In addition, p38 modulated the expression of two transcription factors involved in the regulation of Krox-20 [suppressed cAMP-inducible protein (SCIP) and Sox10], but not Sox2, an antagonist of Krox-20. Collectively, our results show that p38 primarily directs Schwann cell differentiation and peripheral myelination by regulating Krox-20 expression through its downstream effectors, MK2 and MSK-1/CREB, and transcription factors SCIP and Sox10. PMID- 22511273 TI - Severe hemolysis associated with use of the Impella LP 2.5 mechanical assist device. AB - The Impella LP 2.5 is a percutaneously implantable axial flow device designed to offer circulatory support for patients in cardiogenic shock during percutaneous coronary interventions (PCI). While most axial flow devices are associated with hemolysis, clinically relevant hemolysis with this device has not been reported. We report a case of a 66-year-old woman with hemodynamic collapse during an elective PCI who was successfully resuscitated with an Impella device. She developed marked biochemical evidence of intravascular hemolysis. This necessitated device removal which resulted in prompt resolution of the hemolysis. We advise routine measurement of biochemical markers of hemolysis and serial hemoglobin values during Impella device support to allow timely detection and treatment of this important complication. PMID- 22511274 TI - Development and preliminary validation of a measure of social inclusion for use in people with mental health problems: the SInQUE. AB - BACKGROUND: Social exclusion can be both a cause and a consequence of mental health problems. Socially inclusive practice by mental health professionals can mitigate against the stigmatizing and excluding effects of severe mental illness. AIM: To develop and test the validity of a measure of social inclusion for individuals with severe mental illness - the Social Inclusion Questionnaire User Experience (SInQUE). METHOD: The domains of the SInQUE were chosen to reflect the domains of social inclusion identified in the Poverty and Social Exclusion Survey. Patients with severe mental illness were recruited from rehabilitation, general and forensic psychiatric services and were asked to complete the questionnaire in an individual interview with a researcher. RESULTS: Sixty six patients with schizophrenia and schizoaffective disorder completed the SInQUE, alongside measures of psychiatric symptoms, needs and quality of life, to assess its acceptability, and concurrent and construct (convergent and discriminant) validity. The SInQUE took 45 minutes to complete and was found to have good concurrent and discriminant validity. Convergent validity was established for two domains: social integration and productivity. CONCLUSION: Preliminary findings suggest that the SInQUE may be a useful tool for assessing and monitoring social inclusion in individuals with severe mental illness. It has construct and concurrent validity with measures of unmet need and quality of life in this group. Further testing of the reliability of the SInQUE on a larger population is indicated. PMID- 22511275 TI - Quality characteristics of low-fat chicken nuggets: effect of common salt replacement and added bottle gourd (Lagenaria siceraria L.). AB - BACKGROUND: There is growing demand for the meat products having healthier characteristics. In an endeavour to develop low-salt, low-fat and high-fibre chicken nuggets an investigation was carried out to observe the effects of partial replacement (40%) of sodium chloride in pre-standardised low-fat chicken nuggets (Control, 20 g kg-1 NaCl) with a salt substitute blend as well as incorporation of bottle gourd (Lagenaria siceraria L.) in the resulting low-salt, low-fat products at three different levels, i.e. 50, 75 and 100 g kg-1 (Treatments, 12 g kg-1 NaCl) on the various quality attributes. RESULTS: Sodium chloride replacement decreased (P < 0.01) emulsion and product pH, cooking yield, moisture, ash, yellowness, hue value and textural properties. pH values, moisture and dietary fibre increased (P < 0.01) while cooking yield, % protein, textural properties and total cholesterol were decreased with the incorporation of bottle gourd in low-salt, low-fat nuggets. Sensory attributes of the product were not affected with salt replacement; however, inclusion of bottle gourd at higher levels decreased (P < 0.05) flavour and texture scores. CONCLUSION: The results suggest that low-salt, low-fat and high-fibre chicken nuggets can be developed with the use of a salt substitute blend and bottle gourd without affecting their acceptability. PMID- 22511277 TI - [2.2]Paracyclophane derived bisphosphines for the activation of hydrogen by FLPs: application in domino hydrosilylation/hydrogenation of enones. AB - The heterolytic splitting of hydrogen by two types of [2.2]paracyclophane derived bisphosphines (1, 2a and 2b) in combination with tris(pentafluorophenyl)borane (3) at room temperature is described. The corresponding frustrated Lewis pairs (FLPs) exhibit different behavior in the activation of hydrogen. This results from diverse steric and electronic properties of the bisphosphines. The reactivity of the frustrated Lewis pairs was exploited in the first diastereoselective domino hydrosilylation/hydrogenation reaction catalyzed by FLPs. PMID- 22511276 TI - Hormone receptor status influences the locoregional benefit of trastuzumab in patients with nonmetastatic breast cancer. AB - BACKGROUND: Previous studies have shown that hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status influence the outcome of locoregional treatments. However, the interrelationship of these factors with trastuzumab is unclear. In this study, the role of HR and HER2 status on the locoregional benefit of trastuzumab treatment was investigated in patients with nonmetastatic breast cancer. METHODS: Locoregional outcomes of 5683 women treated at The University of Texas MD Anderson Cancer Center from 2000 to 2008 for invasive breast cancer were analyzed using Kaplan-Meier and Cox regression methods to compare 6 subgroups: HR-positive (HR+)/HER2-negative (HER2-), HR-/HER2 (triple-negative), HR+/HER2+ with or without trastuzumab, and HR-/HER2+ with or without trastuzumab. RESULTS: Overall, locoregional recurrence (LRR) was 5% at 5 years among patients with HER2+ disease. Patients with HR+/HER2+ disease treated with trastuzumab had half the rate of LRR as patients who did not receive trastuzumab, whereas patients with HR-/HER2+ disease had similar rates of LRR regardless of trastuzumab treatment. On Cox regression analysis comparing LRR risk to the cohort with HR+/HER2- disease, only the HR+/HER2+ cohort treated with trastuzumab had similar LRR risk (hazard ratio = 1.24, 95% confidence interval = 0.56-2.73, P = .591). All other subgroups, including the HR+/HER2+ cohort who did not receive trastuzumab, had significantly worse outcomes. LRR risk was highest among patients with triple-negative disease (hazard ratio = 4.73, 95% confidence interval = 3.42-6.54, P < .001). CONCLUSIONS: Among patients with HR+/HER2+ disease, treatment with trastuzumab reduces LRR risk to the more favorable outcome of patients with HR+/HER2- disease. In contrast, the increased LRR risk among patients with HR-/HER2+ disease remains despite treatment with trastuzumab. Additional locoregional strategies are needed in this subgroup of patients. PMID- 22511278 TI - [Dietary supplements--evaluation of patient inquiries at a drug information service]. AB - BACKGROUND: Dietary supplements are a product group of foods, which are meant to supplement the general nutrition with micronutrients and other substances. They are widely used in Germany. We evaluated the frequency of their use and of information requirements concerning dietary supplements in patients who contacted the independent drug information service at TU Dresden. PATIENTS AND METHODS: All inquiries from 2008 to 2010 were evaluated regarding information requirement about dietary supplements, the kind of products used and characteristics of patients using supplements. Sociodemographic characteristics, kind and number of drugs and dietary supplements as well as underlying diseases were recorded from the inquiring patients. RESULTS: 23.3 % of persons looking for advice used dietary supplements. The most frequently used product groups included vitamins and minerals (52.5 %) as well as plant extracts (14.0 %). Information requirements were especially high for plant extracts and for products containing glucosamine/chondroitin and lutein/zeaxanthin. Users of dietary supplements were exposed to a higher number of different products than non-users. CONCLUSIONS: Information requirements were primarily detected for products without clearly proven benefits or for supplements which are advertised to relieve certain diseases or symptoms although the product characteristics do not support such utilization. The frequency of use of dietary supplements among patients which already receive multiple medications substantiates the necessity to include dietary supplements in assessments of drug interactions and to scrutinize indications for supplement use. PMID- 22511279 TI - [48-year-old patient with angina pectoris and skin lesions. Xanthomas]. PMID- 22511280 TI - [African tick bite fever--rickettsiosis after holiday in South Africa]. AB - HISTORY AND CLINICAL FINDINGS: A 61-year-old female patient presented with multiple tick bites. Some of them turned into skin ulcera. The patient acquired the tick bites during a stay in South Africa for several weeks. EXAMINATIONS AND DIAGNOSIS: According to the history and typical skin manifestations, a tick borne infection (rickettsiosis) was diagnosed and serologically confirmed. TREATMENT AND CLINICAL COURSE: The empiric treatment with doxycycline resulted in a fast regression of the skin ulcera. CONCLUSION: Rickettsial infections can be diagnosed in the presence of typical skin manifestations (eschar andor centripedal exanthema) and after an appropriate history of travel. In such cases, empiric treatment with tetracyclines can be performed. PMID- 22511281 TI - [Emerging viral diseases in Europe]. AB - Emergence of viral agents in Europe is influenced by various factors. Climatic changes influencing possible vectors, insufficient vaccination, and travel of man and goods are among the most important reasons to explain these changes. Fever and arthralgia are the leading symptoms in infection with Dengue, Sindbis, or Chikungunya virus. In contrast, tick-born encephalitis (TBE), Toscana, or West Nile virus infections mainly lead to meningo-encephalitis. In Europe, hemorrhagic fever is caused by Crimean Congo and Hanta virus. Protective vaccines are available for emerging viral agents like TBE, influenza and measles. PMID- 22511282 TI - Hierarchical micro/nano porous silicon Li-ion battery anodes. AB - A wet-chemical etching method is reported for the scale-up preparation of carbon coated hierarchical micro/nano porous silicon powders as a Li-ion battery anode, which shows no capacity fading at 1500 mA h g(-1) in 50 charge/discharge cycles. PMID- 22511283 TI - Collapse of homeotropic liquid-crystal alignment by increased molecular packing on comb-like polymer surfaces. AB - We report an unusual alignment behavior of liquid crystals (LCs) on well-ordered comb-like poly(oxyethylene) surfaces. The homeotropic LC alignments that are observed on as-coated surfaces of the polymers are transformed to the random planar type after annealing treatment, even though the molecular structure of the polymer surface becomes more ordered and the surface energy decreases. Studies of the surface properties, such as molecular structure, morphology, and wettability, reveal that such an unexpected alteration of the LC alignment originates from the density of the alkyl side chains being enhanced by localized packing. PMID- 22511284 TI - Association of time since last birth, age at first birth and parity with breast cancer survival among parous women: a register-based study from Norway. AB - Reproductive factors that have a well-documented effect on breast cancer risk may also influence the prognosis of the disease, but previous studies on breast cancer survival have yielded conflicting results. We combined information from two population-based registries and obtained information on 16,970 parous women with invasive breast cancer. Cox regression analysis was used to assess breast cancer survival in relation to age at diagnosis, age at first birth, time since last birth and parity. We stratified the analyses by age at diagnosis (<50 and >= 50 years) as an approximation for menopausal age. In women diagnosed before 50 years of age, breast cancer survival was reduced with younger age at diagnosis (p for trend <0.001), whereas in women diagnosed at 50 years or later, survival was reduced with older age at diagnosis (p for trend 0.011). For breast cancer diagnosed before 50 years, survival was poorer in women with four or more births compared to women with one or two births (hazard ratio 1.3, 95% confidence interval 1.1-1.6). A short time since last birth was associated with reduced survival (p for trend 0.05), but adjustment for stage and grade attenuated the association. Among women diagnosed at 50 years or later, we found no association with survival for any of the reproductive factors. In summary, reproductive factors were associated with survival from breast cancer diagnosed before but not after age 50 years. Young women had a particularly poor prognosis throughout the study period. PMID- 22511285 TI - Probing the charge build-up and dissipation on thin PMMA film surfaces at the molecular level by XPS. PMID- 22511286 TI - Prevention of hydrogen peroxide-induced red blood cells lysis by Ilex paraguariensis aqueous extract: participation of phenolic and xanthine compounds. AB - The fresh leaves and stems of Ilex paraguariensis (Aquifoliaceae) are employed to prepare the commercial product used in North-eastern Argentina, Southern Brazil and Eastern Paraguay named yerba mate. The presence of polyphenols and xanthines, which present antioxidant activity, has been described in I. paraguariensis. In living organism, reactive oxygen species can cause tissue damage affecting erythrocyte membranes leading to hemolysis. The aim of this work was to evaluate the protective effect of an aqueous extract of I. paraguariensis (green leaves) on the hemolysis of red blood cells induced by hydrogen peroxide and to correlate this activity with the enzymatic activity related to hydrogen peroxide metabolism. The antioxidant activity of chlorogenic acid and caffeine was also analysed to evaluate their contribution to the activity of the crude extract. The extract as well as the isolated compounds protected red blood cells from hemolysis. This effect was related to a catalase-like activity. This study could contribute to the knowledge of the antioxidant activity of I. paraguariensis in view of the great quantities of yerba mate consumed by the population. PMID- 22511287 TI - Determination and validation of duloxetine hydrochloride in capsules by HPLC with pre-column derivatization and fluorescence detection. AB - A high-performance liquid chromatographic (HPLC) method is described for the determination of duloxetine hydrochloride in capsules. The method was based on pre-column derivatization with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole using the fluorimetric detection technique. Duloxetine hydrochloride was analyzed by HPLC using an Inertsil C18 column (5 MUm, 150 * 4.6 mm) and mobile phase consisted of methanol and water (65:35, v/v). The fluorescence detector was adjusted at excitation and emission wavelengths of 461 and 521 nm, respectively. The linearity of the method was in the range of 10-600 ng/mL. Limits of detection and quantification were 0.51 and 1.53 ng/mL, respectively. The proposed method was successfully applied for determination of duloxetine hydrochloride in its pharmaceutical preparation. The results were in good agreement with those obtained using a reference method. PMID- 22511288 TI - Matrix influences on the determination of common ions by using ion chromatography part 1--determination of inorganic anions. AB - Ion chromatography is the most popular instrumental analytical method used for the determination of anions and cations in water and wastewater. Isocratic ion chromatography with suppressed conductivity detection is frequently used in laboratories carrying out routine analyses of inorganic anions. The paper presents the results of the research into the influence of selected inorganic anions dominant in environmental samples (Cl(-), NO(3)(-), SO(4)(2-)) on the possibility of simultaneous determination of F(-), Cl(-), NO(2)(-), NO(3)(-), PO(4)(3-) and SO(4)(2-) with the application of this most popular ion chromatography type in standard separation conditions. Four Dionex and four Metrohm anion-exchange columns were tested in standard separation conditions recommended by their manufacturers with both standard solutions and environmental samples with complex matrix. PMID- 22511289 TI - Searching for an operational definition of frailty: a Delphi method based consensus statement: the frailty operative definition-consensus conference project. AB - BACKGROUND: There is no consensus regarding the definition of frailty for clinical uses. METHODS: A modified Delphi process was used to attempt to achieve consensus definition. Experts were selected from different fields and organized into five Focus Groups. A questionnaire was developed and sent to experts in the area of frailty. Responses and comments were analyzed using a pre-established strategy. Statements with an agreement more than or equal to 80% were accepted. RESULTS: Overall, 44% of the statements regarding the concept of frailty and 18% of the statements regarding diagnostic criteria were accepted. There was consensus on the value of screening for frailty and about the identification of six domains of frailty for inclusion in a clinical definition, but no agreement was reached concerning a specific set of clinical/laboratory biomarkers useful for diagnosis. CONCLUSIONS: There is agreement on the usefulness of defining frailty in clinical settings as well as on its main dimensions. However, additional research is needed before an operative definition of frailty can be established. PMID- 22511290 TI - Does aging impair the capacity to use stored visuospatial information or online visual control to guide reach-to-grasp reactions evoked by unpredictable balance perturbation? AB - BACKGROUND: Rapid reach-to-grasp reactions are a prevalent response to sudden loss of balance and play an important role in preventing falls. A previous study indicated that young adults are able to guide functionally effective grasping reactions using visuospatial information (VSI) stored in working memory. The present study addressed whether healthy older adults are also able to use "stored" VSI in this manner or are more dependent on "online" visual control. METHODS: Liquid-crystal goggles were used to force reliance on either stored or online VSI while reaching to grasp a small handhold in response to unpredictable platform perturbations. A motor-driven device varied the handhold location unpredictably for each trial. Twelve healthy older adults (65-79 years) were compared with 12 young adults (19-29 years) tested in a previous study. RESULTS: Reach-to-grasp reactions were slower and more variable in older adults, regardless of the nature of the available VSI. When forced to rely on stored VSI, both age groups showed a reduction in reach accuracy; however, a tendency to undershoot the handhold was exacerbated in the older adults. Forced reliance on online VSI led to similar delays in both age groups; however, the older adults were more likely to reach with the "wrong" limb (contralateral to the handhold) and/or raise both arms initially (possibly to "buy" more time for final limb selection). CONCLUSION: Situations that force the central nervous system to rely on either stored or online VSI tend to exacerbate age-related reductions in speed and accuracy of reach-to-grasp balance-recovery reactions. Further work is needed to determine if this increases risk of falling in daily life. PMID- 22511291 TI - Predictive models for transient protein expression in tobacco (Nicotiana tabacum L.) can optimize process time, yield, and downstream costs. AB - The transient expression of recombinant biopharmaceutical proteins in plants can suffer inter-batch variation, which is considered a major drawback under the strict regulatory demands imposed by current good manufacturing practice (cGMP). However, we have achieved transient expression of the monoclonal antibody 2G12 and the fluorescent marker protein DsRed in tobacco leaves with ~ 15% intra-batch coefficients of variation, which is within the range reported for transgenic plants. We developed models for the transient expression of both proteins that predicted quantitative expression levels based on five parameters: The OD(600 nm) of Agrobacterium tumefaciens (from 0.13 to 2.00), post-inoculation incubation temperature (15-30 degrees C), plant age (harvest at 40 or 47 days after seeding), leaf age, and position within the leaf. The expression models were combined with a model of plant biomass distribution and extraction, generating a yield model for each target protein that could predict the amount of protein in specific leaf parts, individual leaves, groups of leaves, and whole plants. When the yield model was combined with a cost function for the production process, we were able to perform calculations to optimize process time, yield, or downstream costs. We illustrate this procedure by transferring the cost function from a production process using transgenic plants to a hypothetical process for the transient expression of 2G12. Our models allow the economic evaluation of new plant-based production processes and provide greater insight into the parameters that affect transient protein expression in plants. PMID- 22511292 TI - Dried blood spot on-card derivatization: an alternative form of sample handling to overcome the instability of thiorphan in biological matrix. AB - Thiorphan, the active metabolite of racecadotril, can undergo oxidation in biological matrices such as blood and plasma. In bioanalysis, a general approach for the stabilization of such a molecule is to derivatize the thiol group to a more stable thioether, often requiring complex handling procedures at the clinical site. In this research, the concept of dried blood spot (DBS) on-card derivatization was evaluated to stabilize thiorphan. DBS cards were in-house pre treated with 2-bromo-3'-methoxyacetophenone and left to dry prior to blood spotting. Thiorphan was shown to be effectively derivatized to thiorphan methoxyacetophenone once applied on the in-house pre-treated cards. Thiorphan methoxyacetophenone was extracted by soaking a 6 mm DBS punch in methanol containing the internal standard (thiorphan-methoxyacetophenone-D5). Chromatographic separation was achieved on a Waters XBridge C18 column with a gradient elution of 5 mM NH4HCO3 and methanol in 2.5 min and detection by ESI(+)/MS/MS. A linear (weighted 1/x2) relationship was obtained over a concentration range of 5.00-600.00 ng/mL. The assay met regulatory guidelines acceptance criteria for sensitivity, selectivity, precision and accuracy, matrix effect, recovery, dilution integrity and multiple stability evaluations. The DBS on-card derivatization has shown to be an easy and reliable alternative form of sample collection for the quantification of thiorphan. PMID- 22511294 TI - Imaging techniques for elements and element species in plant science. AB - Revealing the uptake, transport, localization and speciation of both essential and toxic elements in plants is important for understanding plant homeostasis and metabolism, subsequently, providing information for food and nutrient studies, agriculture activities, as well as environmental research. In the last decade, emerging techniques for elemental imaging and speciation analysis allowed us to obtain increasing knowledge of elemental distribution and availabilities in plants. Chemical imaging techniques include mass spectrometric methods such as secondary ionization mass spectrometry (SIMS), laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and synchrotron-based techniques such as X ray fluorescence spectroscopy (SRXRF), and so forth. On the other hand, X-ray absorption spectroscopy (XAS) based on synchrotron radiation is capable of in situ investigation of local atomic structure around the central element of interest. This technique can also be operated in tandem with SRXRF to image each element species of interest within plant tissue. In this review, the principles and state-of-the-art of these techniques regarding sample preparation, advantages and limitations, and improvement of sensitivity and spatial resolution are discussed. New results with respect to elemental distribution and speciation in plants revealed by these techniques are presented. PMID- 22511293 TI - Paternally inherited gsalpha mutation impairs adipogenesis and potentiates a lean phenotype in vivo. AB - Paternally inherited inactivating mutations of the GNAS gene have been associated with a rare and disabling genetic disorder, progressive osseous heteroplasia, in which heterotopic ossification occurs within extraskeletal soft tissues, such as skin, subcutaneous fat, and skeletal muscle. This ectopic bone formation is hypothesized to be caused by dysregulated mesenchymal progenitor cell differentiation that affects a bipotential osteogenic-adipogenic lineage cell fate switch. Interestingly, patients with paternally inherited inactivating mutations of GNAS are uniformly lean. Using a mouse model of Gsalpha-specific exon 1 disruption, we examined whether heterozygous inactivation of Gnas affects adipogenic differentiation of mesenchymal precursor cells from subcutaneous adipose tissues (fat pad). We found that paternally inherited Gsalpha inactivation (Gsalpha(+/p-) ) impairs adipogenic differentiation of adipose derived stromal cells (ASCs). The Gsalpha(+/p-) mutation in ASCs also decreased expression of the adipogenic factors CCAAT-enhancer-binding protein (C/EBP)beta, C/EBPalpha, peroxisome proliferator-activated receptor gamma, and adipocyte protein 2. Impaired adipocyte differentiation was rescued by an adenylyl cyclase activator, forskolin, and provided evidence that Gsalpha-cAMP signals are necessary in early stages of this process. Supporting a role for Gnas in adipogenesis in vivo, fat tissue weight and expression of adipogenic genes from multiple types of adipose tissues from Gsalpha(+/p-) mice were significantly decreased. Interestingly, the inhibition of adipogenesis by paternally inherited Gsalpha mutation also enhances expression of the osteogenic factors, msh homeobox 2, runt-related transcription factor 2, and osteocalcin. These data support the hypothesis that Gsalpha plays a critical role in regulating the balance between fat and bone determination in soft tissues, a finding that has important implications for a wide variety of disorders of osteogenesis and adipogenesis. PMID- 22511295 TI - Predictors of an optimal clinical outcome with alcohol septal ablation for obstructive hypertrophic cardiomyopathy. AB - BACKGROUND: Alcohol septal ablation has emerged as a therapy for patients with obstructive hypertrophic cardiomyopathy (HCM). However, there are limited data on the predictors of success with the procedure. METHODS: We examined patient characteristics and cardiac morphology as well as procedural data on 166 HCM patients (mean age, 63 years; 43% men), who underwent ablation at Mayo Clinic. Patients were contacted to determine vital status and symptoms to assess the primary endpoint of survival free of death and severe symptoms (New York Heart Association, class III or IV dyspnea). RESULTS: The strongest patient characteristics that predicted clinical success were older age, less severe left ventricular outflow tract gradient, lesser ventricular septal hypertrophy, and a smaller left anterior descending (LAD) diameter. Mitral valve geometry or ventricular septal morphology did not predict outcome. Patients with >=3 characteristics (age >=65 years, gradient <100 mmHg, septal hypertrophy <=18 mm, LAD diameter <4.0 mm) had superior 4-year survival free of death and severe symptoms (90.4%) in comparison to those with two characteristics (81.6%) and <=1 characteristic (57.5%). Case volume with >50 patients was an independent predictor of survival free of severe symptoms. The volume of alcohol injected, number of arteries injected, or size of septal perforator artery were not predictive of clinical success. CONCLUSIONS: Greater case volume and selection for key patient and anatomic characteristics are associated with superior outcomes with alcohol septal ablation. PMID- 22511296 TI - TGF-beta signaling through SMAD2/3 induces the quiescent microglial phenotype within the CNS environment. AB - Microglia are myeloid-derived cells that colonize the central nervous system (CNS) at early stages of development and constitute up to 20% of the glial populations throughout life. While extensive progress has been recently made in identifying the cellular origin of microglia, the mechanism whereby the cells acquire the unique ramified and quiescent phenotype within the CNS milieu remains unknown. Here, we show that upon co-culturing of either CD117(+) /Lin(-) hematopoietic progenitors or CD11c(+) bone marrow derived cells with organotypic hippocampal slices or primary glia, the cells acquire a ramified morphology concomitant with reduced levels of CD86, MHCII, and CD11c and up-regulation of the microglial cell-surface proteins CX(3) CR1 and Iba-1. We further demonstrate that the transforming growth factor beta (TGF-beta) signaling pathway via SMAD2/3 phosphorylation is essential for both primary microglia and myeloid-derived cells in order to acquire their quiescent phenotype. Our study suggests that the abundant expression of TGF-beta within the CNS during development and various inflammatory processes plays a key role in promoting the quiescent phenotype of microglia and may thus serve as a target for therapeutic strategies aimed at modulating the function of microglia in neurodegenerative diseases such as Alzheimer's and prion. PMID- 22511297 TI - Diagnosing cystic fibrosis: what are we sweating about? PMID- 22511299 TI - Randomized study comparing everolimus- and sirolimus-eluting stents in patients with bifurcation lesions treated by provisional side-branch stenting. AB - OBJECTIVES: To compare the efficacy of sirolimus- and everolimus-eluting stents in patients with bifurcation lesions treated with provisional side-branch stenting. BACKGROUND: The efficacy of everolimus-eluting stents in bifurcation lesions has been poorly tested. METHODS: Patients with all types of Medina bifurcation lesions were randomly assigned to treatment with either a sirolimus- (n = 145) or everolimus-eluting stent (n = 148). We included patients with main vessel diameter over 2.5 mm and side branches over 2.25 mm. Patients with diffuse side-branch stenosis were excluded. RESULTS: There were no significant differences between patients from the sirolimus and everolimus groups in terms of age, risk factors, clinical status, location of the bifurcation lesions or angiographic variables. Immediate results and in-hospital outcome were also similar in both groups of patients. In-hospital death occurred in two patients, one from each group. Target lesion revascularization was required in nine patients: four patients (2.7%) from the sirolimus group and five patients (3.4%) from the everolimus group. Late cardiac mortality occurred in two patients from the sirolimus group and in one patient from the everolimus group. Major cardiac event rates at 1 year were similar in both groups: nine patients (6.2%) in the sirolimus group and nine patients (6.1%) from the everolimus group (p: ns). CONCLUSIONS: In patients with bifurcation lesions, no significant differences in clinical outcome at 1-year follow-up were observed between sirolimus- and everolimus-eluting stent groups. PMID- 22511301 TI - Is spending on proton beam therapy for cancer going too far, too fast? PMID- 22511300 TI - Widening access to UK medical education for under-represented socioeconomic groups: modelling the impact of the UKCAT in the 2009 cohort. AB - OBJECTIVE: To determine whether the use of the UK clinical aptitude test (UKCAT) in the medical schools admissions process reduces the relative disadvantage encountered by certain sociodemographic groups. DESIGN: Prospective cohort study. SETTING: Applicants to 22 UK medical schools in 2009 that were members of the consortium of institutions utilising the UKCAT as a component of their admissions process. PARTICIPANTS: 8459 applicants (24,844 applications) to UKCAT consortium member medical schools where data were available on advanced qualifications and socioeconomic background. MAIN OUTCOME MEASURES: The probability of an application resulting in an offer of a place on a medicine course according to seven educational and sociodemographic variables depending on how the UKCAT was used by the medical school (in borderline cases, as a factor in admissions, or as a threshold). RESULTS: On univariate analysis all educational and sociodemographic variables were significantly associated with the relative odds of an application being successful. The multilevel multiple logistic regression models, however, varied between medical schools according to the way that the UKCAT was used. For example, a candidate from a non-professional background was much less likely to receive a conditional offer of a place compared with an applicant from a higher social class when applying to an institution using the test only in borderline cases (odds ratio 0.51, 95% confidence interval 0.45 to 0.60). No such effect was observed for such candidates applying to medical schools using the threshold approach (1.27, 0.84 to 1.91). These differences were generally reflected in the interactions observed when the analysis was repeated, pooling the data. Notably, candidates from several under-represented groups applying to medical schools that used a threshold approach to the UKCAT were less disadvantaged than those applying to the other institutions in the consortium. These effects were partially reflected in significant differences in the absolute proportion of such candidates finally taking up places in the different types of medical schools; stronger use of the test score (as a factor or threshold) was associated with a significantly increased odds of entrants being male (1.74, 1.25 to 2.41) and from a low socioeconomic background (3.57, 1.03 to 12.39). There was a non-significant trend towards entrants being from a state (non-grammar) school (1.60, 0.97 to 2.62) where a stronger use of the test was employed. Use of the test only in borderline cases was associated with increased odds of entrants having relatively low academic attainment (5.19, 2.02 to 13.33) and English as a second language (2.15, 1.03 to 4.48). CONCLUSIONS: The use of the UKCAT may lead to more equitable provision of offers to those applying to medical school from under-represented sociodemographic groups. This may translate into higher numbers of some, but not all, relatively disadvantaged students entering the UK medical profession. PMID- 22511303 TI - Opium, opioids, and an increased risk of death. PMID- 22511304 TI - Drinking nation: have we had enough? PMID- 22511302 TI - Opium use and mortality in Golestan Cohort Study: prospective cohort study of 50,000 adults in Iran. AB - OBJECTIVES: To investigate the association between opium use and subsequent risk of death. DESIGN: Prospective cohort study. SETTING: The Golestan Cohort Study in north-eastern Iran collected detailed validated data on opium use and other exposures at baseline. Participants were enrolled between January 2004 and June 2008 and were followed to May 2011, with a follow-up success rate of over 99%. PARTICIPANTS: 50,045 participants aged 40-75 at baseline. MAIN OUTCOMES: Mortality, all cause and major subcategories. RESULTS: 17% (n = 8487) of the participants reported opium use, with a mean duration of 12.7 years. During the follow-up period 2145 deaths were reported. The adjusted hazard ratio for all cause mortality associated with ever use of opium was 1.86 (95% confidence interval 1.68 to 2.06). Opium consumption was significantly associated with increased risks of deaths from several causes including circulatory diseases (hazard ratio 1.81) and cancer (1.61). The strongest associations were seen with deaths from asthma, tuberculosis, and chronic obstructive pulmonary disease (11.0, 6.22, and 5.44, respectively). After exclusion of people who self prescribed opium after the onset of major chronic illnesses, the associations remained strong with a dose-response relation. CONCLUSION: Opium users have an increased risk of death from multiple causes compared with non-users. Increased risks were also seen in people who used low amounts of opium for a long period and those who had no major illness before use. PMID- 22511305 TI - Records study finds no clear clinical benefit from proton therapy for prostate cancer. PMID- 22511306 TI - Ruthenium-amido complexes: synthesis, structure, and catalytic activity in olefin metathesis. PMID- 22511307 TI - Junctophilin 2 knockdown interfere with mitochondrium status in ESC-CMs and cardiogenesis of ES cells. AB - In the present study, we explored the possible links between Junctophilin 2 (Jp2) and the mitochondrium-sarcoplasmic reticulum (SR) interaction in embryonic stem cell-derived cardiomyocytes (ESC-CMs), as well as the role of Jp2 in cardiogenesis of ES cells. We found that Ca(2+) transient was abnormal and mitochondria were de-energized within siJp2 ESC-CMs. The essential juxtaposition structure of mitochondrium with SR was destroyed accompanied by selectively downregulation of Pgc-1alpha, Nrf-1, and Mfn-2. Impaired co-localization of the JP2 and sarcomeres (alpha-Actinin or Troponin-T) appeared in embryoid bodies (EBs) after Jp2 knockdown. Calsequestrin2 and ryanodine receptor 2 within SR were expressed as early as the initiation of differentiation, while triadin and caveolin3 within t-tubules (TTs) did not appear until the terminal, indicating that JP2 probably did not contribute to anchoring the SR to TTs at the early cardiogenesis stage as usual. In addition, Jp2 knockdown selectively decreased gene transcription toward cardiogenesis (Brachyury, Isl1, and Nkx2.5), subsequently weaken EB beating activity by 60%. Taken together, reducing JP2 expression in ESC-CMs resulted in impaired mitochondrial status due to either abnormal cellular Ca(2+) homeostasis or disturbing of juxtaposition. A sensitive time window of JP2 necessary in cardiac differentiation was found at early stage via an extra non-TTs/SR anchor-dependent role. PMID- 22511308 TI - Combined hypermethylation of APC and GSTP1 as a molecular marker for prostate cancer: quantitative pyrosequencing analysis. AB - A total of 149 human prostate tissues obtained from our institute were assessed: 52 specimens of benign prostate hyperplasia (BPH) and 97 specimens of prostate cancer (PCa). The methylation status of the genes of Adenomatous polyposis coli (APC) and glutathione-S-transferase-P1 (GSTP1) was analyzed by quantitative pyrosequencing. A methylation score (M score) was calculated to capture the combined methylation level of both genes. The methylation level of each single gene and that of both genes combined was significantly higher in PCa specimens than in BPH (each p < 0.001). The value of APC methylation, GSTP1 methylation, and M score for predicting PCa was measured by the area under the receiver operating characteristic (ROC) curve and reached 0.954, 0.942, and 0.983, respectively. The sensitivity and specificity of the M score in discriminating between PCa and BPH reached 92.8% and 100.0%, respectively. The M score was positively associated with the serum prostate-specific antigen (PSA) level (p trend < 0.001). Our study demonstrates that the quantitative measurement of two methylation markers might drastically improve the ability to discriminate PCa from BPH. PMID- 22511309 TI - Enantioselective synthesis of alpha-alkylidene-gamma-butyrolactones: intramolecular Rauhut-Currier reaction promoted by acid/base organocatalysts. PMID- 22511310 TI - Characterization of Epstein-Barr virus (EBV) BZLF1 gene promoter variants and comparison of cellular gene expression profiles in Japanese patients with infectious mononucleosis, chronic active EBV infection, and EBV-associated hemophagocytic lymphohistiocytosis. AB - Epstein-Barr virus (EBV) genotypes can be distinguished based on gene sequence differences in EBV nuclear antigens 2, 3A, 3B, and 3C, and the BZLF1 promoter zone (Zp). EBV subtypes and BZLF1 Zp variants were examined in Japanese patients with infectious mononucleosis, chronic active EBV infection, and EBV-associated hemophagocytic lymphohistiocytosis. The results of EBV typing showed that samples of infectious mononucleosis, chronic active EBV infection, and EBV-associated hemophagocytic lymphohistiocytosis all belonged to EBV type 1. However, sequencing analysis of BZLF1 Zp found three polymorphic Zp variants in the same samples. The Zp-P prototype and the Zp-V3 variant were both detected in infectious mononucleosis and chronic active EBV infection. Furthermore, a novel variant previously identified in Chinese children with infectious mononucleosis, Zp-V1, was also found in 3 of 18 samples of infectious mononucleosis, where it coexisted with the Zp-P prototype. This is the first evidence that the EBV variant distribution in Japanese patients resembles that found in other Asian patients. The expression levels of 29 chronic active EBV infection-associated cellular genes were also compared in the three EBV-related disorders, using quantitative real-time reverse transcription polymerase chain reaction analysis. Two upregulated genes, RIPK2 and CDH9, were identified as common specific markers for chronic active EBV infection in both in vitro and in vivo studies. RIPK2 activates apoptosis and autophagy, and could be responsible for the pathogenesis of chronic active EBV infection. PMID- 22511311 TI - Paclitaxel versus sirolimus eluting stents in diabetic patients: does stent type and/or stent diameter matter?: long-term clinical outcome of 2,429-patient multicenter registry. AB - BACKGROUND: Drug-eluting stents (DES) are more effective in reducing restenosis than bare-metal stents. Less certain is the relative performance of the two widely used DES-sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES)-in diabetic patients undergoing percutaneous coronary intervention (PCI). OBJECTIVES: We studied the long-term effectiveness and safety of SES versus PES in diabetic patients, overall and grouped by the size of the stent placed in the native-stented vessel. METHODS: Data were obtained from an observational, multicenter registry of 2,429 consecutive patients with DM who underwent PCI between August 2003 and August 2009 with SES (n = 1,370) or PES (n = 1,059). Data were analyzed separately for patients with small stents (<3.0 mm, n = 1,274) vs. only large (>=3.0 mm, n = 1,155). RESULTS: At Cox-adjusted analysis of the overall cohort, there was no significant difference between SES and PES with regard to death/myocardial infarction (D/MI) (P = 0.6) or target lesion revascularization (TLR) (P = 0.3) either in "small-stent" (D/MI, P = 0.8; TLR, P = 0.2) or "large stent" group (D/MI, P = 0.8; TLR, P = 0.4) throughout 1 to 5 year follow-up. These results were confirmed by sensitivity, propensity-score matched analysis (717 matched pairs) that failed to find differences in the safety and efficacy between SES and PES. CONCLUSIONS: In this large observational study, PES and SES were equally safe and efficacious in diabetic patients undergoing PCI in clinical practice, regardless of the stent size. PMID- 22511312 TI - Magic pairs and structural transitions in binary metallic clusters. AB - Structures and binding energies for bimetallic clusters consisting of a large variety of atomic species are obtained for all atomic sizes N<=40 and all concentrations, using an interatomic potential derived within a quasi-classical description. It is found that increasing the difference between the two types of atoms leads to a gradual disappearance of the well-known homo-atomic geometric magic numbers and the appearance of magic pairs corresponding to the number of atoms of each atomic species in binary nanostructures with higher stability. This change is accompanied by structural transitions and ground-state<->isomer inversions, induced by changes in composition or concentration. There is a clear tendency towards phase separation, the core-shell radial segregation being predominant (energetically favored) in this model. PMID- 22511313 TI - Early phase clinical trials in pediatric hematology and oncology. AB - Pediatric oncology is an unrivaled success story in the recent history of medicine. This success is mostly based on a persistent refinement of evidence based therapeutic concepts. With that regard physicians and their staff are highly experience in the conduct of prospective evidence based trials and are therefore competent partners for the pharmaceutical industry. In times of personalized medicine the individual target population is diminishing and the borders of indications are not more disease based. A situation that requires new concepts from the industry. Therefore children with cancer could benefit early from the current developments as well as the pharmaceutical industry could benefit from the legislative incentives through highly recruiting and well conducted prospective trials. Pivotal is a functional platform of communication in order to maintain a close dialogue between academia and pharmaceutical companies. PMID- 22511314 TI - The flexion withdrawal reflex reveals an increasing threshold during the first year of life and is influenced by the infant's state of consciousness. AB - BACKGROUND: The idea that preterm and term infants are capable of experiencing pain is now widely accepted. However, there is still insufficient knowledge how pain perception develops throughout infancy. A promising approach to quantify the level of spinal excitability in infants is to measure cutaneous sensitivity by the flexion withdrawal reflex (WR). In our study we wanted to test how the threshold of the WR develops in healthy infants during the first year of life. Furthermore, we aimed to analyse the impact of the state of consciousness on the reflex threshold. PATIENTS AND METHOD: In 44 healthy infants we tested the threshold of the WR with calibrated von-Frey-Filaments at the age of 3 days as well as with 4, 12, 26 and 52 weeks. To analyse the influence of the state of consciousness on the reflex threshold, we documented at 12, 26 and 52 weeks whether the infants were quietly awake or lightly asleep during testing. RESULTS: The median threshold of the WR increased during the first year of life from 1.2 g up to 4.6 g at the age of 1 year. At 12, 26 and 52 weeks we found significantly lower thresholds in sleeping infants compared to infants being awake (p=0.004, p<0.001 and p=0.086, respectively). CONCLUSION: The threshold of the flexion withdrawal reflex increases during infancy, probably reflecting neuronal maturation processes in the first year of life. Besides postnatal age, the threshold of the WR also depends on the state of consciousness. Therefore, future studies about the WR should consider postnatal age as well as the state of consciousness. PMID- 22511315 TI - Production of a mouse line with a conditional Crim1 mutant allele. AB - Crim1 is a developmentally expressed, transmembrane protein essential for normal embryonic development. We generated mice engineered to contain a Crim1 conditional null allele by flanking exons three and four of Crim1 with unidirectional LoxP sites. After crossing Crim1+/FLOX mice with a CMV-Cre line, a Crim1+/Deltaflox colony was established after germline transmission of the deleted allele. We then analyzed genomic DNA, mRNA transcripts, and protein expression from Crim1Deltaflox/Deltaflox null mice to confirm the nature of the genomic lesion. Crim1Deltaflox/Deltaflox mice displayed phenotypes similar to those previously described for a Crim1 gene-trap mutant, Crim1KST264/KST264, including perinatal lethality, digit syndactyly, eye, and kidney abnormalities, with varying penetrance and severity. The production of a conditional mutant allele represents a valuable resource for the study of the tissue-specific roles for Crim1, and for understanding the pleimorphic phenotypes associated with Crim1 mutation. PMID- 22511316 TI - Chamomile confers protection against hydrogen peroxide-induced toxicity through activation of Nrf2-mediated defense response. AB - Oxidative stress plays an important role in the development of various human diseases. Aqueous chamomile extract is used as herbal medicine, in the form of tea, demonstrated to possess antiinflammatory and antioxidant properties. We demonstrate the cytoprotective effects of chamomile on hydrogen peroxide (H2O2) induced cellular damage in macrophage RAW 264.7 cells. Pretreatment of cells with chamomile markedly attenuated H2O2-induced cell viability loss in a dose dependent manner. The mechanisms by which chamomile-protected macrophages from oxidative stress was through the induction of several antioxidant enzymes including NAD(P)H:quinone oxidoreductase, superoxide dismutase, and catalase and increase nuclear accumulation of the transcription factor Nrf2 and its binding to antioxidant response elements. Furthermore, chamomile dose-dependently reduced H2O2-mediated increase in the intracellular levels of reactive oxygen species. Our results, for the first time, demonstrate that chamomile has protective effects against oxidative stress and might be beneficial to provide defense against cellular damage. PMID- 22511317 TI - Neural invasion induces cachexia via astrocytic activation of neural route in pancreatic cancer. AB - Pancreatic cancer is characterized by a high frequency of cachexia, pain and neural invasion (N-inv). Neural damage is occurred by N-inv and modulates pain and muscle atrophy via the activation of astrocyte in the connected spine. The activated astrocyte by N-inv, thus, may affect cachexia in pancreatic cancer. Clinical studies in patients and autopsy cases with pancreatic cancer have revealed that N-inv is related to cachexia and astrocytic activation. We established a novel murine model of cancer cachexia using N-inv of human pancreatic cancer cells. Mice with N-inv showed a loss of body weight, skeletal muscle and fat mass without appetite loss, which are compatible with an animal model of cancer cachexia. Activation of astrocytes in the spinal cord connected with N-inv was observed in our model. Experimental cachexia was suppressed by disrupting neural routes or inhibiting the activation of astrocytes. These data provide the first evidence that N-inv induces cachexia via astrocytic activation of neural route in pancreatic cancer. PMID- 22511318 TI - Inflow occlusion on beating heart. PMID- 22511319 TI - Direct Toll-like receptor-mediated stimulation of hematopoietic stem and progenitor cells occurs in vivo and promotes differentiation toward macrophages. AB - As Toll-like receptors (TLRs) are expressed by hematopoietic stem and progenitor cells (HSPCs), they may play a role in hematopoiesis in response to pathogens during infection. We show here that TLR2, TLR4, and TLR9 agonists (tripalmitoyl-S glyceryl-L-Cys-Ser-(Lys)4 [Pam3CSK4], lipopolysaccharide [LPS], and CpG oligodeoxynucleotide [ODN]) induce the in vitro differentiation of purified murine lineage negative cells (Lin(-) ) as well as HSPCs (identified as Lin(-) c Kit(+) Sca-1(+) IL-7Ralpha(-) [LKS] cells) toward macrophages (Mph), through a myeloid differentiation factor 88 (MyD88)-dependent pathway. In order to investigate the possible direct interaction of soluble microorganism-associated molecular patterns and TLRs on HSPCs in vivo, we designed a new experimental approach: purified Lin(-) and LKS cells from bone marrow of B6Ly5.1 mice (CD45.1 alloantigen) were transplanted into TLR2(-/-) , TLR4(-/-) , or MyD88(-/-) mice (CD45.2 alloantigen), which were then injected with soluble TLR ligands (Pam3CSK4, LPS, or ODN, respectively). As recipient mouse cells do not recognize the TLR ligands injected, interference by soluble mediators secreted by recipient cells is negligible. Transplanted cells were detected in the spleen and bone marrow of recipient mice, and in response to soluble TLR ligands, cells differentiated preferentially to Mph. These results show, for the first time, that HSPCs may be directly stimulated by TLR agonists in vivo, and that the engagement of these receptors induces differentiation toward Mph. Therefore, HSPCs may sense pathogen or pathogen-derived products directly during infection, inducing a rapid generation of cells of the innate immune system. PMID- 22511320 TI - Percutaneous isolated pharmaco-mechanical thrombolysis-thrombectomy system for the management of acute arterial limb ischemia: 30-day results from a single center experience. AB - OBJECTIVE: To study the efficacy of isolated pharmaco-mechanical thrombolysis thrombectomy (IPMT) by Trellis device (Covidien, Mansfield, MA) in managing acute limb ischemic (ALI). BACKGROUND: ALI is both life and limb threatening disease with a reported 9-15% mortality and 15-25% limb loss in the first month after presentation. Pitfalls of current endovascular techniques include major bleeding, distal embolism, and prolonged thrombolytic infusion. IPMT isolates the thrombus between two balloons and utilizes wire oscillation to increase the thombus-lytic exposure surface area followed by aspiration. It decreases systemic lytic exposure, procedure time, and distal embolism. METHODS: Technical aspects, success, and bleeding complications in 24 consecutive patients with ALI treated with IPMT between October 2009 and September 2010 were analyzed. In-hospital and 30-day mortality, amputation rates and treatment success rates were determined. RESULTS: 24 patients constituted 32 arteries; 18 (56.25%) were suprainguinal including 3 grafts (9.4%) and 14 (43.75%) were infrainguinal native arteries. Substantial or complete response was seen in >90% vessels with 87.5% patients revealing TIMI three flow while none demonstrated TIMI 2 or 3 pretreatment. Only three patients required adjunctive post-IPMT thrombolysis. In-hospital and 30-day all cause mortality was 4.16%. One patient died in-hospital and no patient underwent amputation. CONCLUSION: Besides being the largest series of ALI patients treated with IPMT, this is the first and largest series including 14 native infrainguinal arteries. These results suggest IPMT to be a promising and safer therapeutic option in ALI, likely due to its site-specific nature and limited thrombolysis exposure time. PMID- 22511321 TI - The prognostic difference of monoallelic versus biallelic deletion of 13q in chronic lymphocytic leukemia. PMID- 22511323 TI - High-throughput transfection of interfering RNA into a 3D cell-culture chip. AB - A method for high-throughput retroviral transfection of genes and interfering RNA into 3D cell-culture microarrays is described. 3D cultures more closely mimic the in vivo cellular milieu, thus providing cellular responses to genetic manipulation more similar to the in vivo situation than 2D cultures. This technique is applied to transfect several "toxic" short-hairpin RNAs (shRNAs) into 3D cell cultures. It is demonstrated that the toxicity is similar to that obtained by conventional (non-high-throughput) retroviral transfection of cells grown in similar 3D culture microarrays. PMID- 22511322 TI - Preexcisional artery reconstruction: a new strategy in multiple hepatic artery reconstruction for reducing ischemic injury of the liver. AB - Multiple reconstructions of the hepatic arteries (HA) after cancer resection presents a surgical challenge, not only because it is technically demanding, but also because attention must be paid to potential ischemic injury to the liver caused by the prolonged ischemia. We present a novel "preexcisional artery reconstruction" method for minimizing ischemic injury of the liver. A 65-year-old woman presented with cholangiocarcinoma invading the HA. Pancreatoduodenectomy, resection, and multiple reconstruction of the HA were performed. First, the left hepatic artery (LHA) was reconstructed prior to the tumor resection. During this procedure, blood supply was maintained to most of the liver via the right hepatic artery (RHA). Then, resection of the tumor en bloc with the HA was performed, followed by reconstruction of the RHA. During this procedure, blood supply was maintained via the already-reconstructed LHA, thereby limiting the ischemic area. Use of this method allowed the ischemia time and region to be divided and minimized, thereby leading to a reduced risk of ischemia-related complications. We believe that this method may be one of the useful approaches in multiple HA reconstruction. PMID- 22511324 TI - Contrast-enhanced ultrasound diagnosis of splenic artery steal syndrome after orthotopic liver transplantation. AB - The aim of this study was to investigate the use of contrast-enhanced ultrasound (CEUS) for the detection of splenic artery steal syndrome (SASS) after orthotopic liver transplantation (OLT). Two hundred forty-seven patients underwent OLT. Blood tests and color Doppler flow imaging (CDFI) were performed at various time points after the operation. CEUS and celiac angiography were used for patients suspected of having SASS. If the diagnosis of SASS was confirmed, splenic artery embolization was performed to enhance hepatic artery flow. CEUS and angiography were performed for the assessment of postinterventional clinical outcomes. Three of the 247 patients died postoperatively, and 8 patients were suspected of having SASS because of elevated liver enzyme levels and slim or undetectable hepatic artery blood signals by CDFI at various points after the operation. In these 8 patients, CEUS showed a delayed and weak contrast-enhanced blood signal in the hepatic artery associated with a rapid and intense enhancement of the portal vein blood. No narrowing of the hyperintense signal was observed in the hepatic artery by CEUS. The 8 diagnoses of SASS were proven by celiac angiography, which showed delayed perfusion of the hepatic artery and rapid filling of the splenic artery. Immediately after the interventional procedure, CEUS demonstrated a significantly enlarged hyperintense blood signal in the hepatic artery. In conclusion, approximately 3.27% of SASS cases occur after OLT. SASS can be identified as a sluggish and weak hyperintense blood signal in the hepatic artery without the narrowing and interruption of the hypointense signal in CEUS imaging. CEUS is an effective imaging modality for the detection of SASS after OLT. PMID- 22511325 TI - Walking, paddling, waddling: 3D kinematics anatidae locomotion (Callonetta leucophrys). AB - Walking and paddling motions were studied in a semiaquatic bird, the ringed teal (Callonetta leucophrys), to investigate the motions associated with movements in two environments with radically divergent physical properties. A three dimensional (3D) kinematic reconstruction based on nonsynchronous biplanar cineradiographic data was used to quantify the 3D trajectories of the body and hind limb segments. Our study revealed that two subsystems interact to provide propulsion in water and on land. During paddling, the trunk, the femur, and the tibiotarsus are in a stable position and play the role of the hull. The femur and tibiotarsus are positioned laterally and parasagittaly and the intertarsal joint is fixed and positioned caudally allowing large amplitude movements of the "paddle" (tarsometatarsus and palmate foot). During walking, the center of mass is held above the medially oriented foot, providing stability during the single support phase. During stance, the foot is medially oriented because of the lateral and parasagittal positions of the tibiotarsus and tarsometatarsus during both walking and paddling. This position of the foot during walking imposes trunk translation and results in the typical waddling motion of Anatidae. This study provides new insights into how waddling motion relates to semiaquatic birds' ability to move in both terrestrial and aquatic environments. PMID- 22511326 TI - Improvement of surfactin production in Bacillus subtilis using synthetic wastewater by overexpression of specific extracellular signaling peptides, comX and phrC. AB - Surfactin is a biological surfactant with numerous potential applications. In this study, Bacillus subtilis was engineered to improve surfactin production by the activation of two competence-stimulating pheromones, ComX and competence and sporulation factor (CSF) to stimulate the transcription of srfA operon. Both signaling factors, encoded by comX and phrC, were successfully overexpressed and subsequently increased surfactin production. Surfactin produced by engineered strains showed functional groups similar to the commercially available surfactin analyzed via Fourier transform infrared spectroscopy (FTIR). Surfactin production in the B. subtilis (pHT43-comXphrC) strain was 6.4-fold greater than in the wild strain, with approximately 135.1 mg/L surfactin produced after 48 h cultivation. To reduce the production costs of surfactin, synthetic wastewater was used, from which the B. subtilis (pHT43-comXphrC) strain produced approximately 140.2 mg/L surfactin. The results obtained demonstrated the production of surfactin from synthetic wastewater, which is beneficial in lowering the overall production costs. PMID- 22511327 TI - Risk factors for pressure ulcer development in critically Ill patients: a conceptual model to guide research. AB - This paper presents a proposed conceptual model to guide research on pressure ulcer risk in critically ill patients, who are at high risk for pressure ulcer development. However, no conceptual model exists that guides risk assessment in this population. Results from a review of prospective studies were evaluated for design quality and level of statistical reporting. Multivariate findings from studies having high or medium design quality by the National Institute of Health and Clinical Excellence standards were conceptually grouped. The conceptual groupings were integrated into Braden and Bergstrom's (Braden and Bergstrom [1987] Rehabilitation Nursing, 12, 8-12, 16) conceptual model, retaining their original constructs and augmenting their concept of intrinsic factors for tissue tolerance. The model could enhance consistency in research on pressure ulcer risk factors. PMID- 22511328 TI - Neurocognitive function and schizophrenia-proneness in individuals dependent on ketamine, on high potency cannabis ('skunk') or on cocaine. AB - BACKGROUND: Ketamine, psychostimulants and cannabis have all been associated with psychotic phenomena but no study has directly compared users of these drugs. AIMS: The aim of this study was to assess schizophrenia proneness and neurocognitive function in individuals dependent upon ketamine, cannabis and cocaine. METHOD: 130 volunteers - 29 'skunk' users, 22 cocaine users, 21 ketamine users, along with 28 'recreational' poly-drug users and 30 drug-naive controls - were assessed on the Schizophrenia Proneness Instrument, Adult version (SPI-A). They were specifically asked to rate symptoms when not under the acute influence of a psychoactive drug. RESULTS: Ketamine and skunk users manifested the greatest attentional and cognitive disturbances. The symptom profile of the dependent ketamine users was very similar to that of prodromal individuals who transitioned to psychosis. CONCLUSIONS: Given the recent rapid rise in use of high potency cannabis and of ketamine, these findings are important and clinicians should be careful to rule out the effects of persistent drug use, especially in users of ketamine or skunk, when assessing an individual's risk of psychosis. A longitudinal study is needed to differentiate which basic symptoms persist following abstention from ketamine and skunk. PMID- 22511329 TI - Rapid fabrication of polylactide stereocomplex using layer-by-layer deposition by inkjet printing. PMID- 22511330 TI - Guiding crystallization around bends and sharp corners. AB - Control over the molecular orientation in organic thin films is demonstrated with precise in-plane spatial resolution over large areas. By exploiting the differential crystallization rates on substrates with different surface energies, the radial symmetry of spherulitic growth can be disrupted by preferentially selecting the molecular orientations that promote growth along the paths of the underlying patterns. PMID- 22511331 TI - Use of a green (bio) solvent--limonene--as extractant and immiscible diluent for large volume injection in the RPLC-tandem MS assay of statins and related metabolites in human plasma. AB - Limonene, considered a green solvent, was successfully used to extract simvastatin, lovastatin, and their hydroxy-acid metabolites from human plasma samples. The extraction process was followed by the direct injection of a large volume aliquot (100 MUL) from the limonene layer into a Zorbax SB-C(18) Rapid Resolution chromatographic column (50 mm length * 4.6 mm i.d. * 1.8 um d.p.), operated under gradient elution reversed-phase separation mechanism. Tandem mass spectrometry operated under the multiple reaction monitoring mode was used for detection, providing low quantitation limits in the 0.25-0.5 ng/mL concentration interval. This method was validated and used for quantitation of simvastatin and its hydroxy acid metabolite in incurred plasma samples obtained from two volunteers participating in a bioequivalence study, using lovastatin and its hydroxy analog as internal standards. The results were statistically compared with those produced by means of an alternative RPLC-tandem MS using protein precipitation with acetonitrile. The quality attributes of the two methods are comparatively discussed. The agreement between the quality characteristics of the two methods and the experimental results obtained on real samples may be considered as a consistent basis for the simultaneous use of limonene as extraction medium and injection diluent for hydrophobic compounds in bioanalytical approaches. PMID- 22511332 TI - Quantum-chemical validation of the local assumption of chemomechanics for a unimolecular reaction. PMID- 22511333 TI - Directed supramolecular surface assembly of SNAP-tag fusion proteins. AB - Supramolecular assembly of proteins on surfaces and vesicles was investigated by site-selective incorporation of a supramolecular guest element on proteins. Fluorescent proteins were site-selectively labeled with bisadamantane by SNAP-tag technology. The assembly of the bisadamantane functionalized SNAP-fusion proteins on cyclodextrin-coated surfaces yielded stable monolayers. The binding of the fusion proteins is specific and occurs with an affinity in the order of 10(6) M( 1) as determined by surface plasmon resonance. Reversible micropatterns of the fusion proteins on micropatterned cyclodextrin surfaces were visualized by using fluorescence microscopy. Furthermore, the guest-functionalized proteins could be assembled out of solution specifically onto the surface of cyclodextrin vesicles. The SNAP-tag labeling of proteins thus allows for assembly of modified proteins through a host-guest interaction on different surfaces. This provides a new strategy in fabricating protein patterns on surfaces and takes advantage of the high labeling efficiency of the SNAP-tag with designed supramolecular elements. PMID- 22511334 TI - YeiR: a metal-binding GTPase from Escherichia coli involved in metal homeostasis. AB - A comparative genomic analysis predicted that many members of the under characterized COG0523 subfamily of putative P-loop GTPases function in metal metabolism. In this work we focused on the uncharacterized Escherichia coli protein YeiR by studying both the physiology of a yeiR mutant and the in vitro biochemical properties of YeiR expressed as a fusion with the maltose-binding protein (YeiR-MBP). Our results demonstrate that deletion of yeiR increases the sensitivity of E. coli to EDTA or cadmium, and this phenotype is linked to zinc depletion. In vitro, the tagged protein binds several Zn(2+) ions with nanomolar affinity and oligomerizes in the presence of metal. The GTPase activity of YeiR is similar to that measured for other members of the group, but GTP hydrolysis is enhanced by Zn(2+) binding. These results support the predicted connection between the COG0523 P-loop GTPases and roles in metal homeostasis. PMID- 22511335 TI - IL-17 mediates estrogen-deficient osteoporosis in an Act1-dependent manner. AB - Estrogen-deficient osteoporosis may be an inflammatory disorder and we therefore asked if IL-17 participates in its pathogenesis. Deletion of the principal IL-17 receptor (IL-17RA) protects mice from ovariectomy (OVX)-induced bone loss. Further supporting a central role of IL-17 in its pathogenesis, OVX-induced osteoporosis is prevented by a blocking antibody targeting the cytokine. IL-17 promotes osteoclastogenesis by stimulating RANK ligand (RANKL) expression by osteoblastic cells, mediated by the IL-17RA SEFIR/TILL domain. Estrogen deprivation, however does not enhance IL-17RA mRNA expression by osteoblasts or in bone, but augments that of Act1, an IL-17RA-interacting protein and signaling mediator. Similar to IL-17RA(-/-) mice, those lacking Act1 are protected from OVX induced bone loss. Also mirroring IL-17RA-deficiency, absence of Act1 in osteoblasts, but not osteoclasts, impairs osteoclastogenesis via dampened RANKL expression. Transduction of WT Act1 into Act1(-/-) osteoblasts substantially rescues their osteoclastogenic capacity. The same construct, however, lacking its E3 ligase U-box or its SEFIR domain, which interacts with its counterpart in IL 17RA, fails to do so. Estrogen deprivation, therefore, promotes RANKL expression and bone resorption in association with upregulation of the IL-17 effector, Act1, supporting the concept that post-menopausal osteoporosis is a disorder of innate immunity. PMID- 22511336 TI - Anti-hyperglycemic effect of fermented ginseng in type 2 diabetes mellitus mouse model. AB - Ginseng has shown an efficacy in preventing and managing various health conditions. This study aimed to evaluate the effect of the fermented ginseng extract (FGE) in type 2 diabetes mellitus murine model. FGE was provided to male C57BL/ksJ-db/db mice for 8 weeks at 0.1% (w/w) dose in contrast to water for the control group. Potential anti-diabetic mechanisms were investigated with blood glucose, serum insulin, serum adiponectin, hemoglobin A1c (HbA1c), glucose tolerance, insulin secretion assay, quantitative real-time polymerase chain reaction, and hematoxylin-eosin staining. Compared with the control group, the FGE group had lower levels of blood glucose after 6 and 9 h fasting, HbA1c, and the area under the curve in an oral glucose tolerance test and higher levels of adiponectin and serum insulin (p < 0.05). The FGE group had higher levels of peroxisome proliferator-activated receptor gamma 2 and glucose transporter protein 2 mRNAs, a lower level of tumor necrosis factor-alpha (TNF-alpha) (p < 0.05), and less lymphocytes in pancreas than the control group had. The FGE exerted anti-diabetic effects in type 2 diabetic mice. PMID- 22511337 TI - Dimensional paradigm of the long-term course of unipolar major depressive disorder. PMID- 22511338 TI - Fabrication of a carbon-nanotube-based field-effect transistor by microcontact printing. AB - The fabrication of a field-effect transistor with both channel material and source and drain electrodes made from carbon nanotubes (CNTs) through patterned deposition of CNT films by microcontact printing is described. Surfactant dispersed single-walled CNTs are first separated into semiconducting and metallic fractions by gel filtration. The semiconducting and metallic CNTs are then sequentially transferred by dendrimer-coated polydimethylsiloxane stamps onto dendrimer-coated silicon wafers following a printing protocol optimized for this purpose. The resulting CNT micropatterns are visualized by atomic force microscopy. Semiconducting as well as metallic CNTs preserve their characteristic electronic properties within the transferred films. A device composed of a rather thick (ca. 5 nm) and densely patterned film of metallic CNTs cross-printed on top of a thinner (ca. 1.5 nm) and less dense film of semiconducting CNTs shows the typical properties of a field-effect transistor with the metallic CNT stripes as electrodes, the semiconductive CNT stripes as channel material, and the silicon substrate as gate electrode. PMID- 22511339 TI - Aerobic swimming performance of juvenile largemouth bronze gudgeon (Coreius guichenoti) in the Yangtze River. AB - Largemouth bronze gudgeon (Coreius guichenoti), a fish species once abundant in the Yangtze River, has been rapidly declining in recent years. One important factor, among many, is the interruption of the free-flowing rivers by dams. To obtain data that can be applied to the design of an effective fishway for C. guichenoti and other species in the fish community, a laboratory study of juvenile C. guichenoti's swimming ability and energetics was conducted in a flume type respirometer equipped with a high-speed video camera system to record swimming behavior. The critical swimming speed (Ucrit ), standard metabolic rate (SMR), and maximum metabolic rate (MO2,max ) were determined during steady swimming at four water temperatures (10, 15, 20, and 25 degrees C). A power function accurately describes the relationship between oxygen consumption rate (MO2 ) and swimming speed (U) at the four temperatures. The Ucrit , SMR, MO2,max , and metabolic scope increased with increasing temperature. The relationship between cost of transport (COT) and U was characteristically inverse bell-shaped, with minimum COT at Uopt = 4.5-5.0 body lengths per second (bl sec(-1)). This investigation provides data on the swimming ability of C. guichenoti that will add to the basic science required for fishway design. PMID- 22511340 TI - Composite vascularized fibular epiphyseo-osteo-periosteal transfer for hip reconstruction after proximal femoral tumoral resection in a 4-year-old child. AB - Literature on the reconstruction of the proximal femur in skeletally immature patients with the use of an epiphyseal transplant is scarce and with variable results depending on the indication. We report successful outcomes using a modified vascularized fibular epiphyseal transplant in a 4-year-old boy with an oncologic lesion. We discuss the advantages of supplementing the standard graft with a vascularized fibular periosteal tissue. The vascularized fibular epiphyseal transplant (VFET) is an effective option in the reconstruction of the epiphysis in skeletally immature patients, owing to the advantage of restoring both the joint function and the growth potential in a single surgical operation. Multiple reported cases demonstrate the effectiveness of this complex technique in upper extremity reconstruction. However, literature is scarce regarding its use for the reconstruction of the proximal femur and hip joint. Through this article, we report the use of a VFET in the reconstruction of a proximal femur in a 4-year-old boy after an intra-articular wide excision of an epithelioid hemangioendotelioma. We also discuss the advantages of designing the flap as a composite vascularized epiphyseo-osteo-periosteal flap. PMID- 22511341 TI - An alternative angiographic view to unmask the hidden patent ductus arteriosus during device closure. AB - Transcatheter closure of patent ductus arteriosus (PDA) with various devices has been evaluated worldwide and in selected cases can be performed successfully, thus avoiding the morbidity associated with surgical closure. Traditionally, left lateral projection is adopted for angiographic visualization of the PDA. However, rarely due to anatomical variations of the ductus, it may be difficult to properly visualize and deploy device in above-said traditional view. In such cases, right anterior oblique projection may be used for proper visualization. PMID- 22511342 TI - Strangers and friends: residents' social careers in assisted living. AB - OBJECTIVES: This study examines coresident relationships in assisted living (AL) and identifies factors influencing relationships. METHODS: We draw on qualitative data collected from 2008 to 2009 from three AL communities varying in size, location, and resident characteristics. Data collection methods included participant observation, and informal and formal, in-depth interviews with residents, administrators, and AL staff. Data analysis was guided by principles of grounded theory method, an iterative approach that seeks to discover core categories, processes, and patterns and link these together to construct theory. RESULTS: The dynamic, evolutionary nature of relationships and the individual patterns that comprise residents' overall experiences with coresidents are captured by our core category, "negotiating social careers in AL." Across facilities, relationships ranged from stranger to friend. Neighboring was a common way of relating and often involved social support, but was not universal. We offer a conceptual model explaining the multilevel factors influencing residents' relationships and social careers. DISCUSSION: Our explanatory framework reveals the dynamic and variable nature of coresident relationships and raises additional questions about social career variability, trajectories, and transitions. We discuss implications for practice including the need for useable spaces, thoughtful activity programming, and the promotion of neighboring through staff and family involvement. PMID- 22511343 TI - Combinatorial treatment of mammospheres with trastuzumab and salinomycin efficiently targets HER2-positive cancer cells and cancer stem cells. AB - A major obstacle in the successful treatment of cancer is the occurrence of chemoresistance. Cancer cells surviving chemotherapy and giving rise to a recurrence of the tumor are termed cancer stem cells and can be identified by elevated levels of certain stem cell markers. Eradication of this cell population is a priority objective in cancer therapy. Here, we report elevated levels of stem cell markers in MCF-7 mammospheres. Likewise, an upregulation of HER2 and its differential expression within individual cells of mammospheres was observed. Sorting for HER2(high) and HER2(low) cells revealed an upregulation of stem cell markers NANOG, OCT4 and SOX2 in the HER2(low) cell fraction. Accordingly, HER2(low) cells also showed reduced proliferation, ductal-like outgrowths and an increased number of colonies in matrigel. Xenografts from subcutaneously injected HER2(low) sorted cells exihibited earlier onset but slower growth of tumors and an increase in stem cell markers compared to tumors developed from the HER2(high) fraction. Treatment of mammospheres with salinomycin reduced the expression of SOX2 indicating a selective targeting of cancer stem cells. Trastuzumab however, did not reduce the expression of SOX2 in mammospheres. Furthermore, a combinatorial treatment of mammospheres with trastuzumab and salinomycin was superior to single treatment with each drug. Thus, targeting HER2 expressing tumors with anti-HER2 therapies will not necessarily eliminate cancer stem cells and may lead to a more aggressive cancer cell phenotype. Our study demonstrates efficient killing of both HER2 positive cells and cancer stem cells, hence opening a possibility for a new combinatorial treatment strategy. PMID- 22511344 TI - Phase 1/2 trial of single-session stereotactic body radiotherapy for previously unirradiated spinal metastases. AB - BACKGROUND: In this phase 1/2 study, the authors tested the hypothesis that single-fraction stereotactic body radiotherapy (SBRT) for previously unirradiated spinal metastases is a safe, feasible, and efficacious treatment approach. METHODS: All patients were evaluated by a multidisciplinary team. Spinal magnetic resonance imaging studies were obtained before treatment and at regular intervals to define both target volume and response to treatment. SBRT was delivered to a peripheral dose of 16 to 24 grays in a single fraction while limiting the dose to the spinal cord. Higher doses were used for renal cell histology. The National Cancer Institute Common Toxicity Criteria 2.0 and McCormick neurologic function score were used as toxicity assessment tools. RESULTS: In total, 61 patients who had 63 tumors of the noncervical spine were enrolled and received SBRT between 2005 and 2010 on a prospective, phase 1/2 trial at The University of Texas M. D. Anderson Cancer Center. The mean follow-up was 20 months. The actuarial 18-month imaging local control rate for all patients was 88%, the actuarial 18-month overall survival rate for all patients was 64%, and the median survival for all patients was 30 months. No significant differences in outcomes were noted with respect to tumor histology or SBRT dose. Two patients experienced radiation adverse events (grade 3 or higher). The actuarial rate of 18-month freedom from neurologic deterioration from any cause was 82%. CONCLUSIONS: Data from this phase 1/2 trial supported an expanded indication for SBRT as first-line treatment of spinal metastases in selected patients. The authors concluded that additional studies that can prospectively identify predictive factors for spinal cord toxicity after SBRT are warranted to minimize the incidence of this serious yet rare complication. PMID- 22511345 TI - Subcutaneous hepatitis B immune globulin after liver transplantation. PMID- 22511346 TI - Interaction of lapatinib with cytochrome P450 3A5. AB - Lapatinib, an oral tyrosine kinase inhibitor used for breast cancer, has been reported to cause idiosyncratic hepatotoxicity. Recently, it has been found that lapatinib forms a metabolite-inhibitor complex (MIC) with CYP3A4 via the formation of an alkylnitroso intermediate. Because CYP3A5 is highly polymorphic compared with CYP3A4 and also oxidizes lapatinib, we investigated the interactions of lapatinib with CYP3A5. Lapatinib inactivated CYP3A5 in a time-, concentration-, and NADPH-dependent manner using testosterone as a probe substrate with K(I) and k(inact) values of 0.0376 mM and 0.0226 min(-1), respectively. However, similar results were not obtained when midazolam was used as the probe substrate, suggesting that inactivation of CYP3A5 by lapatinib is site-specific. Poor recovery of CYP3A5 activity postdialysis and the lack of a Soret peak confirmed that lapatinib does not form a MIC with CYP3A5. The reduced CO difference spectrum further suggested that a large fraction of the reactive metabolite of lapatinib is covalently adducted to the apoprotein of CYP3A5. GSH trapping of a reactive metabolite of lapatinib formed by CYP3A5 confirmed the formation of a quinoneimine-GSH adduct derived from the O-dealkylated metabolite of lapatinib. In silico docking studies supported the preferential formation of an O-dealkylated metabolite of lapatinib by CYP3A5 compared with an N hydroxylation reaction that is predominantly catalyzed by CYP3A4. In conclusion, lapatinib appears to be a mechanism-based inactivator of CYP3A5 via adduction of a quinoneimine metabolite. PMID- 22511347 TI - Effect of multiple cysteine substitutions on the functionality of human multidrug resistance protein 1 expressed in human embryonic kidney 293 cells: identification of residues essential for function. AB - Multidrug resistance protein 1 (MRP1) is a broad-specificity membrane transporter belonging to the C branch of the ATP binding cassette (ABC) superfamily. MRP1 confers resistance to various chemotherapeutic drugs and transports a wide range of conjugated organic anions. Several ABCC proteins, including MRP1, are unusual among ABC transporters in having a third membrane-spanning domain (MSD), MSD0, at their N termini. MRP1 lacking this additional MSD (DeltaMRP1) is able to traffic to the plasma membrane of mammalian cells and to transport a number of well characterized substrates. A cysteineless (cysless) DeltaMRP1 has been expressed in yeast and reported to be functional. However, we found that trafficking of such a construct in human cells was severely compromised, and, even when expressed in insect Sf21 cells, the protein had extremely low transport activity. Therefore, we have systematically examined the effects of substituting cysteines in the four domains of DeltaMRP1, initially with alanine. These studies allowed us to identify five cysteines that cannot be replaced with alanine without inactivating the protein. Substitution of two of these residues with alternative amino acids has allowed us to produce an almost cysless form of DeltaMRP1 that traffics to the plasma membrane and transports leukotriene C(4), 17beta-estradiol 17-beta-D-glucuronide, and estrone-3-sulfate with kinetic characteristics similar to those of the wild-type protein. The distribution of the remaining Cys residues is such that the protein will provide a useful template for a variety of cysteine based mutagenesis studies. PMID- 22511348 TI - Probabilistic orthology analysis of the ATP-binding cassette transporters: implications for the development of multiple drug resistance phenotype. AB - Drug transporters are rapidly becoming recognized as central to determining a chemical's fate within the body. This action is a double-edged sword, protecting the body from toxicants, but also potentially leading to reduced clinical efficacy of drugs through multiple drug resistance phenotype. To examine the interrelationship of this superfamily, we have constructed phylogenetic trees over an extended evolutionary distance representing each of the seven subfamilies. In addition, using protein sequences from species important in the design and evaluation of novel chemicals, namely human, macaque, rat, mouse, and dog, we have undertaken probabilistic orthology analysis to examine speciation probabilities within this phylogeny. These data allow us to accurately predict orthologous sequences across these species, an important confirmatory step with implications for cross-species extrapolation of data during drug safety testing. Finally, we present the first complete phylogeny for subfamilies within humans constructed using the entire coding sequences, at both the DNA and protein levels. We demonstrate for the first time that genes associated with the multiple drug resistance phenotype cluster separately from other genes within the same subfamily, suggestive of a conserved, fundamental, difference in these proteins. Such work may help guide future studies on the mechanisms underlying multiple drug resistance as well as the development of novel therapeutic approaches to mitigate against its development. PMID- 22511349 TI - The NorR regulon is critical for Vibrio cholerae resistance to nitric oxide and sustained colonization of the intestines. AB - Vibrio cholerae, the cause of an often fatal infectious diarrhea, remains a large global public health threat. Little is known about the challenges V. cholerae encounters during colonization of the intestines, which genes are important for overcoming these challenges, and how these genes are regulated. In this study, we examined the V. cholerae response to nitric oxide (NO), an antibacterial molecule derived during infection from various sources, including host inducible NO synthase (iNOS). We demonstrate that the regulatory protein NorR regulates the expression of NO detoxification genes hmpA and nnrS, and that all three are critical for resisting low levels of NO stress under microaerobic conditions in vitro. We also show that prxA, a gene previously thought to be important for NO detoxification, plays no role in NO resistance under microaerobic conditions and is upregulated by H(2)O(2), not NO. Furthermore, in an adult mouse model of prolonged colonization, hmpA and norR were important for the resistance of both iNOS- and non-iNOS-derived stresses. Our data demonstrate that NO detoxification systems play a critical role in the survival of V. cholerae under microaerobic conditions resembling those of an infectious setting and during colonization of the intestines over time periods similar to that of an actual V. cholerae infection. IMPORTANCE: Little is known about what environmental stresses Vibrio cholerae, the etiologic agent of cholera, encounters during infection, and even less is known about how V. cholerae senses and counters these stresses. Most prior studies of V. cholerae infection relied on the 24-h infant mouse model, which does not allow the analysis of survival over time periods comparable to that of an actual V. cholerae infection. In this study, we used a sustained mouse colonization model to identify nitric oxide resistance as a function critical for the survival of V. cholerae in the intestines and further identified the genes responsible for sensing and detoxifying this stress. PMID- 22511350 TI - Sharing of prey: coinfection of a bacterium by a virus and a prokaryotic predator. AB - Rarely, if ever, has a single bacterial cell been confirmed to simultaneously host two fundamentally different predators. Two such predators are viruses and the predatory prokaryotes known as Bdellovibrio and like organisms. Viruses or bacteriophage are particles requiring prey cells in an active metabolic state to complete their life cycle. The Bdellovibrio and like organisms, unlike viruses, are bacteria that can efficiently infect and grow in prey which are in stationary phase. In this study, electron microscopic examination revealed an unprecedented coinfection by the two agents of Vibrio vulnificus, introducing a new bacterial predation paradigm. Rather than the viruses and Bdellovibrio and like organisms competing for a single prey cell, both can survive in the same cell and successfully reproduce themselves. This is an especially valuable mechanism when the prey is in short supply, and the survival of the predators may be at stake. IMPORTANCE: This article describes the coinfection of a prokaryotic prey or host cell by both a bacteriophage (phage) and the predatory bacterium of the group Bdellovibrio and like organisms (BALOs). Such coinfection has not been previously reported and therefore introduces a new paradigm for predation of bacteria. This finding invites new studies on the interactions of BALOs, phage, and prey in predation. Predation is an important mechanism in nature for helping to keep bacterial populations in check and also plays a major role in the cycling of nutrients through the microbial loop. How dual infection by phage and BALOs imposes on these and other functions of predation is fertile ground for future studies and serves as a keystone reference on bacterial predation and mortality. PMID- 22511352 TI - Human origin for livestock-associated methicillin-resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of human morbidity and mortality worldwide. The emergence in the last decade of a livestock-associated MRSA (LA-MRSA) clone which also has the capacity to cause zoonotic infections in humans has raised important questions regarding its origin and its potential to cause human epidemics. An important study by L. B. Price et al. [mBio 3(1):e00305-11, 2012] provides evidence for a human ancestral origin for LA-MRSA, raising concerns about agricultural practices that may have contributed to its emergence and expansion. The study highlights the potential for comparative whole-genome sequencing of closely related strains to provide valuable insights into the evolutionary history of bacterial pathogens. PMID- 22511351 TI - Engineering a hyperthermophilic archaeon for temperature-dependent product formation. AB - Microorganisms growing near the boiling point have enormous biotechnological potential but only recently have molecular engineering tools become available for them. We have engineered the hyperthermophilic archaeon Pyrococcus furiosus, which grows optimally at 100 degrees C, to switch its end products of fermentation in a temperature-controlled fashion without the need for chemical inducers. The recombinant strain (LAC) expresses a gene (ldh) encoding lactate dehydrogenase from the moderately thermophilic Caldicellulosiruptor bescii (optimal growth temperature [T(opt)] of 78 degrees C) controlled by a "cold shock" promoter that is upregulated when cells are transferred from 98 degrees C to 72 degrees C. At 98 degrees C, the LAC strain fermented sugar to produce acetate and hydrogen as end products, and lactate was not detected. When the LAC strain was grown at 72 degrees C, up to 3 mM lactate was produced instead. Expression of a gene from a moderately thermophilic bacterium in a hyperthermophilic archaeon at temperatures at which the hyperthermophile has low metabolic activity provides a new perspective to engineering microorganisms for bioproduct and biofuel formation. IMPORTANCE: Extremely thermostable enzymes from microorganisms that grow near or above the boiling point of water are already used in biotechnology. However, the use of hyperthermophilic microorganisms themselves for biotechnological applications has been limited by the lack of their genetic accessibility. Recently, a genetic system for Pyrococcus furiosus, which grows optimally near 100 degrees C, was developed in our laboratory. In this study, we present the first heterologous protein expression system for a microorganism that grows optimally at 100 degrees C, a first step towards the potential expression of genes involved in biomass degradation or biofuel production in hyperthermophiles. Moreover, we developed the first system for specific gene induction in P. furiosus. As the cold shock promoter for protein expression used in this study is activated at suboptimal growth temperatures of P. furiosus, it is a powerful genetic tool for protein expression with minimal interference of the host's metabolism and without the need for chemical inducers. PMID- 22511353 TI - (IscS-IscU)2 complex structures provide insights into Fe2S2 biogenesis and transfer. PMID- 22511354 TI - Reliability and validity of the 4-item perceived stress scale among pregnant women: results from the OTIS antidepressants study. AB - We aimed to estimate the reliability of the 4-item Perceived Stress Scale (PSS) and its validity in predicting maternal depression and quality of life (QoL). Data regarding stress, depression and QoL were collected during pregnancy among a sub-sample from the Organization of Teratology Information Specialists Antidepressants in Pregnancy Cohort. The 4-item PSS demonstrated acceptable internal consistency (Cronbach's alpha coefficient = .79), alternate forms stability reliability with the 10-item PSS (Pearson correlation coefficient r = .63; p < .001), convergent validity with the Edinburgh Postnatal Depression Scale (r = .67; p < .001), and concurrent validity with the mental health component of the Short-Form-12 (r = -.62; p < .001) as a measure of QoL. The 4-item PSS is a valid and useful tool for assessing maternal stress during pregnancy. PMID- 22511355 TI - Will IL28B polymorphism remain relevant in the era of direct-acting antiviral agents for hepatitis C virus? PMID- 22511356 TI - Unraveling the mechanism of the photodeprotection reaction of 8-bromo- and 8 chloro-7-hydroxyquinoline caged acetates. AB - Photoremovable protecting groups (PPGs) when conjugated to biological effectors forming "caged compounds" are a powerful means to regulate the action of physiologically active messengers in vivo through 1-photon excitation (1PE) and 2 photon excitation (2PE). Understanding the photodeprotection mechanism is important for their physiological use. We compared the quantum efficiencies and product outcomes in different solvent and pH conditions for the photolysis reactions of (8-chloro-7-hydroxyquinolin-2-yl)methyl acetate (CHQ-OAc) and (8 bromo-7-hydroxyquinolin-2-yl)methyl acetate (BHQ-OAc), representatives of the quinoline class of phototriggers for biological use, and conducted nanosecond time-resolved spectroscopic studies using transient emission (ns-EM), transient absorption (ns-TA), transient resonance Raman (ns-TR(2)), and time-resolved resonance Raman (ns-TR(3)) spectroscopies. The results indicate differences in the photochemical mechanisms and product outcomes, and reveal that the triplet excited state is most likely on the pathway to the product and that dehalogenation competes with release of acetate from BHQ-OAc, but not CHQ-OAc. A high fluorescence quantum yield and a more efficient excited-state proton transfer (ESPT) in CHQ-OAc compared to BHQ-OAc explain the lower quantum efficiency of CHQ-OAc relative to BHQ-OAc. PMID- 22511357 TI - Carbon nanofibers prepared via electrospinning. AB - Carbon nanofibers prepared via electrospinning and following carbonization are summarized by focusing on the structure and properties in relation to their applications, after a brief review of electrospinning of some polymers. Carbon precursors, pore structure control, improvement in electrical conductivity,and metal loading into carbon nanofibers via electrospinning are discussed from the viewpoint of structure and texture control of carbon. PMID- 22511358 TI - Functional heterogeneity of mesenchymal stem cells: implications for cell therapy. AB - The term mesenchymal stem cell (MSCs) was adopted in the 1990s to describe a population of bone-marrow-derived cells that demonstrated the capacity for tri lineage differentiation at a clonal level. Research conducted during the ensuing decades has demonstrated that MSCs fulfill many functions in addition to connective tissue progenitors including contributing to the HSC niche and regulating the function of immune effector cells of both the innate and adaptive immune system. Despite these advances, fundamental aspects of MSC biology remain indeterminate. For example, the embryonic origin of MSCs and their niche in vivo remains a highly debated topic. More importantly, the mechanisms that regulate self-renewal and lineage specification have also been largely unexplored. The later is significant in that MSC population's exhibit considerable donor-to-donor and intra-population heterogeneity but knowledge regarding how different functional attributes of MSCs are specified at the population level is unknown. This poses significant obstacles in research and in efforts to develop clinical manufacturing protocols that reproducibly generate functionally equivalent MSC populations. Herein, I discuss data demonstrating that MSC populations are intrinsically heterogeneous, elaborate on the molecular basis for this heterogeneity, and discuss how heterogeneity impacts clinical manufacturing and the therapeutic potency of MSCs. PMID- 22511359 TI - Rare and unusual glycosylation of peptides and proteins. AB - Glycosylation represents the most complex co- and post-translational modification of proteins. In addition to N- and O-glycans, almost all combinations, including the nature of the carbohydrate moiety and the amino-acid involved, but also the type of the chemical linkage, can be isolated from natural glycoconjugates. This diversity correlates with the importance and the variety of the biological processes (and consequently the diseases) glycosides are involved in. This review focuses on rare and unusual glycosylation of peptides and proteins. PMID- 22511360 TI - The RDoC project: a new paradigm for investigating the pathophysiology of anxiety. PMID- 22511361 TI - The R-DoC initiative: science and practice. AB - A research focus upon dimensions of observable behaviors and neurobiological indices, as outlined in the R-DoC initiative, is likely to enhance our understanding of psychopathology in a number of ways that are outlined in this article. Specific examples include a greater understanding of the mechanisms underlying comorbidity and complexity of symptom manifestation, individual differences in symptom expression, and developmental changes in symptom expression. Furthermore, the R-DoC approach may have treatment implications, including treatment efficacy, and identification of treatment moderators and treatment mediators. PMID- 22511364 TI - Establishing the neurobiologic basis of treatment in children and adolescents with generalized anxiety disorder. AB - Generalized anxiety disorder (GAD) is associated with significant morbidity in children and adolescents, yet only recently have the neuropharmacology and neurophysiology of this condition been studied in youth. Accumulating data suggest structural and functional abnormalities within the brain's fear networks in youth with GAD. Additionally, seven studies examined the efficacy of medications that modulate this system and, in some cases, the direct effects of these medications on structures within these networks (e.g. amygdala, ventrolateral prefrontal cortex [VLPFC]). In this review, we summarize the extant functional, functional connectivity, and structural neuroimaging data in children and adolescents with GAD. In addition, data concerning selective serotonin reuptake inhibitors (SSRIs), selective serotonin norepinephrine reuptake inhibitors (SSNRIs), atypical anxiolytics, benzodiazepines, and psychotherapy are reviewed in the context of the neurophysiology of pediatric GAD. The existing data suggest abnormal activity within the amygdala, VLPFC, and anterior cingulate cortex, as well as the possibility of impaired connectivity among these brain regions. In addition to numerous cognitive behavioral therapy (CBT) trials, five randomized, controlled psychopharmacologic trials primarily in youth with GAD suggest that SSRIs and SSNRIs are effective for this condition. These findings also raise the possibility that functional activity within the amygdala and VLPFC may be altered following successful treatment. PMID- 22511362 TI - The anxiety spectrum and the reflex physiology of defense: from circumscribed fear to broad distress. AB - Guided by the diagnostic nosology, anxiety patients are expected to show defensive hyperarousal during affective challenge, irrespective of the principal phenotype. In the current study, patients representing the whole spectrum of anxiety disorders (i.e., specific phobia, social phobia, panic disorder with or without agoraphobia, obsessive-compulsive disorder, generalized anxiety disorder (GAD), posttraumatic stress disorder(PTSD)), and healthy community control participants, completed an imagery-based fear elicitation paradigm paralleling conventional intervention techniques. Participants imagined threatening and neutral narratives as physiological responses were recorded. Clear evidence emerged for exaggerated reactivity to clinically relevant imagery--most pronounced in startle reflex responding. However, defensive propensity varied across principal anxiety disorders. Disorders characterized by focal fear and impairment (e.g., specific phobia) showed robust fear potentiation. Conversely, for disorders of long-enduring, pervasive apprehension and avoidance with broad anxiety and depression comorbidity (e.g., PTSD secondary to cumulative trauma, GAD), startle responses were paradoxically diminished to all aversive contents. Patients whose expressed symptom profiles were intermediate between focal fearfulness and broad anxious-misery in both severity and chronicity exhibited a still heightened but more generalized physiological propensity to respond defensively. Importantly, this defensive physiological gradient--the inverse of self-reported distress--was evident not only between but also within disorders. These results highlight that fear circuitry could be dysregulated in chronic, pervasive anxiety, and preliminary functional neuroimaging findings suggest that deficient amygdala recruitment could underlie attenuated reflex responding. In summary, adaptive defensive engagement during imagery may be compromised by long term dysphoria and stress-a phenomenon with implications for prognosis and treatment planning. PMID- 22511365 TI - Comprehensive review of factors implicated in the heterogeneity of response in depression. AB - BACKGROUND: Heterogeneity in overall response and outcomes to pharmacological treatment has been reported in several depression studies but with few sources that integrate these results. The goal of this study was to review the literature and attempt to identify nongenetic factors potentially predictive of overall response to depression treatments. METHODS: A comprehensive review of the literature from the last 10 years was performed using three key databases (PubMed, EMBASE, and Cochrane). All relevant studies that met the inclusion criteria were selected and scored for their levels of evidence using the NICE scoring method. A subjective assessment of the strength of evidence for each factor was performed using predefined criteria. RESULTS: Our broad search yielded 76 articles relevant to treatment heterogeneity. Sociodemographic factors, disease characteristics, and comorbidities were the most heavily researched areas. Some of the factors associated with more favorable overall response include being married, other social support, and low levels of baseline depressive symptoms. Evidence relating to baseline disease severity as a factor predictive of antidepressant response was particularly convincing among the factors reviewed. The presence of comorbid anxiety and pain contributed to worse antidepressant treatment outcomes. CONCLUSIONS: Several factors either predictive of or associated with overall response to antidepressant treatment have been identified. Inclusion of factors predictive of response in the design of future trials may help tailor treatments to depression patients presenting to the average clinical practice, resulting in improved outcomes. PMID- 22511363 TI - Elevated tph2 mRNA expression in a rat model of chronic anxiety. AB - BACKGROUND: Allelic variations in TPH2, the gene encoding tryptophan hydroxylase 2, the rate-limiting enzyme for brain serotonin (5-HT) biosynthesis, may be genetic predictors of panic disorder and panic responses to panicogenic challenges in healthy volunteers. To test the hypothesis that tph2 mRNA is altered in chronic anxiety states, we measured tph2 expression in an established rat model of panic disorder. METHODS: We implanted 16 adult, male rats with bilateral guide cannulae and then primed them with daily injections of the corticotropin-releasing factor (CRF) receptor agonist, urocortin 1 (UCN1, 6 fmoles/100 nl per side, n = 8) or vehicle (n = 8) into the basolateral amygdaloid complex (BL) for 5 consecutive days. Anxiety-like behavior was assessed, 24 hr prior to and 48 hr following priming, in the social interaction (SI) test. A third group (n = 7) served as undisturbed home cage controls. All rats were killed 3 days after the last intra-BL injection to analyze tph2 and slc6a4 (gene encoding the serotonin transporter, SERT) mRNA expression in the dorsal raphe nucleus (DR), the main source of serotonergic projections to anxiety-related brain regions, using in situ hybridization histochemistry. RESULTS: UCN1 priming increased anxiety-related behavior in the SI test compared to vehicle-injected controls and elevated tph2, but not slc6a4, mRNA expression in DR subregions, including the ventrolateral DR/ventrolateral periaqueductal gray (DRVL/VLPAG), a subregion previously implicated in control of panic-related physiologic responses. Tph2 mRNA expression in the DRVL/VLPAG was correlated with increased anxiety-related behavior. CONCLUSION: Our data support the hypothesis that chronic anxiety states are associated with dysregulated tph2 expression. PMID- 22511366 TI - Living donation for the very ill patient with type I hepatorenal syndrome: are we ready? PMID- 22511367 TI - Small-tip fast recovery imaging using non-slice-selective tailored tip-up pulses and radiofrequency-spoiling. AB - Small-tip fast recovery (STFR) imaging is a new steady-state imaging sequence that is a potential alternative to balanced steady-state free precession. Under ideal imaging conditions, STFR may provide comparable signal-to-noise ratio and image contrast as balanced steady-state free precession, but without signal variations due to resonance offset. STFR relies on a tailored "tip-up," or "fast recovery," radiofrequency pulse to align the spins with the longitudinal axis after each data readout segment. The design of the tip-up pulse is based on the acquisition of a separate off-resonance (B0) map. Unfortunately, the design of fast (a few ms) slice- or slab-selective radiofrequency pulses that accurately tailor the excitation pattern to the local B0 inhomogeneity over the entire imaging volume remains a challenging and unsolved problem. We introduce a novel implementation of STFR imaging based on "non-slice-selective" tip-up pulses, which simplifies the radiofrequency pulse design problem significantly. Out-of slice magnetization pathways are suppressed using radiofrequency-spoiling. Brain images obtained with this technique show excellent gray/white matter contrast, and point to the possibility of rapid steady-state T(2)/T(1) -weighted imaging with intrinsic suppression of cerebrospinal fluid, through-plane vessel signal, and off-resonance artifacts. In the future, we expect STFR imaging to benefit significantly from parallel excitation hardware and high-order gradient shim systems. PMID- 22511369 TI - Complete interventional heart repair of multiple concomitant cardiac pathologies in a staged approach. AB - OBJECTIVES AND BACKGROUND: The evidence of multiple percutaneous cardiac procedures in patients with numerous concomitant cardiac pathologies is limited. METHODS AND RESULTS: We report on the case of a 90-year-old male patient presenting with advanced heart failure because of degenerative aortic valve stenosis and degenerative mitral valve regurgitation. Moreover, significant coronary artery disease and intolerance of anticoagulation in atrial fibrillation were present. The patient was rejected from surgery because of age and frailty and underwent a staged interventional procedure with percutaneous coronary intervention, followed by transfemoral aortic valve implantation with Edwards Sapien XT, percutaneous mitral valve repair with MitraClip, and left atrial appendage closure with Amplatzer Cardiac Plug. The last procedure was complicated by pericardial tamponade necessitating pericardial drainage. Eight weeks later, the patient reported on the absence of dyspnea in activities of daily living and a significant gain in quality of live. CONCLUSIONS: The case demonstrates feasibility of a staged interventional approach in a select high-risk patient. PMID- 22511368 TI - Ex vivo expansion of haematopoietic stem/progenitor cells from human umbilical cord blood on acellular scaffolds prepared from MS-5 stromal cell line. AB - Lineage-specific expansion of haematopoietic stem/progenitor cells (HSPCs) from human umbilical cord blood (UCB) is desirable because of their several applications in translational medicine, e.g. treatment of cancer, bone marrow failure and immunodeficiencies. The current methods for HSPC expansion use either cellular feeder layers and/or soluble growth factors and selected matrix components coated on different surfaces. The use of cell-free extracellular matrices from bone marrow cells for this purpose has not previously been reported. We have prepared insoluble, cell-free matrices from a murine bone marrow stromal cell line (MS-5) grown under four different conditions, i.e. in presence or absence of osteogenic medium, each incubated under 5% and 20% O2 tensions. These acellular matrices were used as biological scaffolds for the lineage-specific expansion of magnetically sorted CD34+ cells and the results were evaluated by flow cytometry and colony-forming assays. We could get up to 80 fold expansion of some HSPCs on one of the matrices and our results indicated that oxygen tension played a significant role in determining the expansion capacity of the matrices. A comparative proteomic analysis of the matrices indicated differential expression of proteins, such as aldehyde dehydrogenase and gelsolin, which have previously been identified as playing a role in HSPC maintenance and expansion. Our approach may be of value in identifying factors relevant to tissue engineering-based ex vivo HSPC expansion, and it may also provide insights into the constitution of the niche in which these cells reside in the bone marrow. PMID- 22511370 TI - Metastatic basal cell carcinoma in the era of hedgehog signaling pathway inhibitors. AB - BACKGROUND: Inhibition of the hedgehog signaling pathway (HHSP) for the treatment of locally advanced basal cell carcinoma (BCC) and metastatic BCC (mBCC) has produced promising results. Typically, mBCC is not taken into consideration during the workup of a patient with multifocal metastatic disease who has a history of BCC. The objective of the current review, in which the authors evaluated the time from the first BCC diagnosis to metastasis, location of disease, and radiographic features, was to contribute to the general knowledge and awareness among providers, patients, and support groups about mBCC and to provide an outlook for the future of treatments for mBCC. A literature review on mBCC and a review of records from patients with mBCC who presented to Virginia G. Piper Cancer Center Clinical Trials (an oncology clinical trials center) were conducted. The clinical and radiographic findings of 22 patients with mBCC who were evaluated at that center from the initiation of smoothened (SMO) antagonist trials were analyzed along with a review of BCC epidemiology and pathogenesis, the HHSP, and current and future treatments for this rare presentation of the most common malignancy. The results indicated that, in the last 5 years, there has been a plethora of new agents targeting SMO, a key component of the HHSP that, for the majority of patients with mBCC, may be a good match for targeting tumor genetic vulnerability. Like with other targeted therapy for uncommon malignancies, such as chronic myelogenous leukemia and gastrointestinal stromal tumors, the authors anticipate that there will be clinical development of next generation HHSP inhibitors to combat mBCCs that are nonresponsive to or progress on current SMO antagonists. PMID- 22511371 TI - Left-to-right shunt reduction with intra-aortic balloon pump in postmyocardial infarction ventricular septal defect. AB - This case aims to describe the hemodynamic effects of intra-aortic balloon pump (IABP) in patients with ventricular septal defect (VSD) complicating myocardial infarction (MI). A 79-year-old man with no previous cardiovascular history presented to the emergency department with subacute inferior myocardial infarction associated with mild signs of systemic hypoperfusion. A transthoracic echocardiography revealed a large akinesia of the left ventricular inferior wall with preserved global left ventricular ejection fraction, as well as a large VSD in the midinferior portion of the interventricular septum. Coronary angiography showed an occlusion of the mid portion of a dominant circumflex coronary artery. The invasive hemodynamic evaluation showed a sizable left-to-right shunt (Q(p)/Q(s) = 3.1). Activation of the IABP led to an immediate reduction of the shunt (Q(p)/Q(s) = 2.4 = 22% reduction), an increase in systemic cardiac output (from 2.1 L/min to 2.4 L/min = +12%) and a decrease in the systemic vascular resistances (from 2240 to 1920 dyne-sec/cm(5) = 15% reduction). In patients with post-MI VSD, placement of IABP leads to an immediate reduction in left-to-right shunt and as a consequence to an increase in systemic cardiac output, which may allow hemodynamic stabilization of the patient prior to surgical VSD closure. PMID- 22511372 TI - Adjuvant properties of mesoporous silica particles tune the development of effector T cells. AB - Alum is the most frequently used adjuvant today, primarily inducing Th2 responses. However, Th1-type responses are often desirable within immune therapy, and therefore the development of new adjuvants is greatly needed. Mesoporous silica particles with a highly ordered pore structure have properties that make them very interesting for future controlled drug delivery systems, such as controllable particle and pore size; they also have the ability to induce minor immune modulatory effects, as previously demonstrated on human-monocyte-derived dendritic cells (MDDCs). In this study, mesoporous silica particles are shown to be efficiently engulfed by MDDCs within 2 h, probably by phagocytic uptake, as seen by confocal microscopy and transmission electron microscopy. A co-culture protocol is developed to evaluate the capability of MDDCs to stimulate the development of naive CD4(+) T cells in different directions. The method, involving ELISpot as a readout system, demonstrates that MDDCs, after exposure to mesoporous silica particles (AMS-6 and SBA-15), are capable of tuning autologous naive T cells into different effector cells. Depending on the size and functionalization of the particles added to the cells, different cytokine patterns are detected. This suggests that mesoporous silica particles can be used as delivery vehicles with tunable adjuvant properties, which may be of importance for several medical applications, such as immune therapy and vaccination. PMID- 22511373 TI - Carotid stent guidelines: How the Society for Vascular Surgery (SVS) "had its cake and ate it too". PMID- 22511374 TI - Raising the bar by lowering our threshold. PMID- 22511375 TI - A range of options: an alternative to "my way or the highway" interpretation of guidelines. PMID- 22511376 TI - Objective versus subjective guidance of (bioabsorbable) stent implantation: the saga continues. PMID- 22511377 TI - Saphenous vein graft interventions: drug-eluting stents are better and safe but not good enough. PMID- 22511378 TI - Management of SVG disease: are we missing the point (and an opportunity)? PMID- 22511379 TI - NAC and CIN prevention: mounting evidence of inefficacy. PMID- 22511380 TI - Vascular occlusion and vascular closure devices: definitely associated, but still no idea how often or why. PMID- 22511381 TI - Upstream glycoprotein IIb/IIIa inhibitors for STEMI: use on-time or not at all? PMID- 22511382 TI - Left main coronary stenosis and acute myocardial infarction: stent or surgery? An evolving perspective. PMID- 22511383 TI - Influence of DNA repair gene polymorphisms on prognosis in inoperable non-small cell lung cancer patients treated with radiotherapy and platinum-based chemotherapy. AB - Polymorphisms in DNA repair genes may modulate not only an individual DNA repair capacity, DNA damage levels and cancer risk but also clinical outcome after DNA damage-inducing anticancer therapy. In this study, we analyzed the association between the XPA -4G>A, XPD Asp312Asn, hOGG1 Ser326Cys, XRCC1 Arg399Gln, XRCC2 4234G>C, XRCC3 -4541A>G and Thr241Met polymorphisms and prognosis in 250 inoperable non-small cell lung cancer (NSCLC) patients treated with radiotherapy and platinum-based chemotherapy. In univariate model, the XPA-4A and XRCC1 399Gln alleles alone and in combination influenced survival only in stage III group. In multivariate analysis, the XPA-4 GA/AA was associated with poor survival (HR 1.55, p = 0.011 overall and HR 1.72, p = 0.008 in stage III). In chemoradiotherapy group, the XPA-4A carriers were at increased risk of death and progression (HR 1.73, p = 0.013 and HR 1.65, p = 0.016, respectively), especially in stage III (p = 0.008). Moreover, individuals with >= 2 XPA/XRCC1 adverse alleles showed a higher risk of death (HR 1.46, p = 0.036 overall; HR 1.85, p = 0.004 in stage III and HR 1.71, p = 0.022 in chemoradiotherapy group) and progression (HR 1.75, p = 0.011 overall and HR 1.93, p = 0.005 in stage III). The XPA-4 GA/AA genotype individually and together with the XRCC1 399Gln was an independent unfavorable prognostic factor in our study. Thus, our findings indicate a prognostic potential of the XPA-4G>A in unresected NSCLC treated with radiotherapy and chemoradiotherapy. The results require validation in an independent population. PMID- 22511384 TI - Structural and spectroscopic characterization of a monomeric side-on manganese(IV) peroxo complex. PMID- 22511385 TI - Environmental toxicology and chemistry in Latin America. PMID- 22511386 TI - The herbicide atrazine, algae, and snail populations. PMID- 22511388 TI - Clinical utility of interleukin-28B testing in patients with genotype 1. PMID- 22511389 TI - Cancer treatment in US costs more than in Europe but has better outcomes, study says. PMID- 22511390 TI - People with chronic disease should be encouraged to manage their care. PMID- 22511391 TI - Young US doctors are satisfied with the present but pessimistic about the future. PMID- 22511392 TI - India pledges free drugs for all citizens through public hospitals. PMID- 22511393 TI - Lack of warnings over flu may have led to more deaths in year after pandemic, say experts. PMID- 22511394 TI - High-efficiency inverted polymer solar cells with transparent and work-function tunable MoO(3)-Al composite film as cathode buffer layer. AB - High-efficiency inverted polymer solar cells based on PCDTBT:PC(70)BM blend with the MoO(3)-Al composite film as the cathode buffer layer and the MoO(3)/Al as the anode have been demonstrated. A V(OC) of 0.88 V, a J(SC) of 10.88 mA cm(-2), a FF of 70.7% and a PCE of 6.77% are achieved. The MoO(3)-Al composite films are highly transparent with adjustable work functions which can be fine tuned based on the Al content in the composite, thus allowing us to optimize the interfacial property at cathode buffer layer/BHJ interfaces to reduce recombination loss and to improve the photovoltaic performance. This new approach has simplified the device fabrication and will render economizing in large scale applications. PMID- 22511395 TI - Preparation of carbohydrate arrays by using Diels-Alder reactions with inverse electron demand. AB - Carbohydrate microarrays are an emerging tool for the high-throughput screening of carbohydrate-protein interactions that represent the basis of many biologically and medicinally relevant processes. The crucial step in the preparation of carbohydrate arrays is the attachment of carbohydrate probes to the surface. We examined the Diels-Alder reaction with inverse-electron-demand (DARinv) as an irreversible, chemoselective ligation reaction for that purpose. After having shown the efficiency of the DARinv in solution, we prepared a series of carbohydrate-dienophile conjugates that were printed onto tetrazine-modified glass slides. Binding experiments with fluorescently labeled lectins proved successful and homogeneous immobilization was achieved by the DARinv. For immobilization of nonfunctionalized reducing oligosaccharides we developed a bifunctional chemoselective linker that enabled the attachment of a dienophile tag to the oligosaccharides through oxime ligation. The conjugates obtained were successfully immobilized on glass slides. The presented strategies for the immobilization of both synthetic carbohydrate derivatives and unprotected reducing oligosaccharides facilitate the preparation of high-quality carbohydrate microarrays by means of the chemoselective DARinv. This concept can be readily adapted for the preparation of other biomolecule arrays. PMID- 22511396 TI - On B1 inhomogeneity correction of in vivo human brain glutamate chemical exchange saturation transfer contrast at 7T. AB - The effects of radio frequency field (B(1)) inhomogeneity on measured in vivo human brain glutamate chemical exchange saturation transfer contrast maps are normally confounded with contributions from chemical exchange saturation transfer, direct saturation and magnetization transfer effects. Consequently, the chemical exchange saturation transfer effect variation with B(1) follows a complicated function and depends on the tissue types as well. In this work, we developed and tested a novel approach for B(1) inhomogeneity correction based on acquiring calibration data at a coarsely sampled B(1) values in conjunction with the measured B(1) maps. With this approach, different calibration curves are derived for gray matter and white matter instead of a simple linear scaling based on local B(1) values. Potential extensions of this approach to study chemical exchange saturation transfer contrast from other metabolites and tissue types are discussed. PMID- 22511397 TI - Enhancing angiogenesis alleviates hypoxia and improves engraftment of enteric cells in polycaprolactone scaffolds. AB - We examined whether expediting angiogenesis in porous polycaprolactone (PCL) scaffolds could reduce hypoxia and consequently improve the survival of transplanted enteric cells. To accelerate angiogenesis, we delivered vascular endothelial growth factor (VEGF) using PCL scaffolds with surface crosslinked heparin. The fabrication and characterization of scaffolds has been reported in our previous study. Enteric cells, isolated from intestinal tissue of neonatal mice and expanded in vitro for 10 days, exhibited high expression levels for contractile protein alpha-smooth muscle actin and desmin. The cultured enteric cells were seeded in scaffolds and were implanted subcutaneously in immunodeficient mice for 7 and 14 days. At day 7, the heparin-modified PCL scaffolds with VEGF exhibited significantly increased angiogenesis and engraftment of enteric cells, with a simultaneous reduction in hypoxia. At day 14, the blood vessels grew across the entire thickness of the scaffold and resulted in a significantly diminished hypoxic environment; however, the transplanted cell density did not increase further. In conclusion, the enhancement of angiogenesis reduced cellular hypoxia and improved the engraftment of enteric cells. PMID- 22511398 TI - Ursolic acid inhibits acid sphingomyelinase in intestinal cells. AB - Ursolic acid (UA) has antiinflammatory and anticancer effects on mammalian cells. Increase in acid sphingomyelinase (SMase) is associated with several inflammatory diseases including inflammatory bowel diseases. The enzyme has become a target for drug discovery. The present study examined the roles of UA on acid SMase in intestinal cells. We found that UA specifically inhibited acid SMase activity in both human colon cancer Caco-2 cells and rat nontransformed IEC-6 intestinal cells in a dose-dependent manner, with 50% inhibition occurred at 30 MUM for Caco 2 cells and less than 20 MUM for IEC-6 cells. In comparison with some chemicals known to inhibit acid SMase, UA appeared most effective. The decreased acid SMase activity was not associated with significant accumulation of cellular sphingomyelin but significant increase in phosphatidylcholine, the donor of choline for sphingomyelin synthesis. Western blot analysis showed a decreased enzyme levels in the cells after UA stimulation, but real time quantitative polymerase chain reaction (qPCR) failed to show a parallel reduction of acid SMase mRNA after UA stimulation. Finally, UA had no direct effect on acid SMase activity in cell-free extracts. In conclusion, UA has inhibitory effects on acid SMase synthesis and the effect occurs presumably at posttranslational levels. PMID- 22511399 TI - Effects of an uncertainty management intervention on uncertainty, anxiety, depression, and quality of life of chronic obstructive pulmonary disease outpatients. AB - In this controlled, randomized study we explored the effects of an uncertainty management intervention on uncertainty, anxiety, depression, and quality of life (QOL) of chronic obstructive pulmonary disease (COPD) outpatients in China. Ninety-six COPD outpatients completed the study (n = 49 in the intervention group; n = 47 in the control group). Over the 10-month study duration, the intervention group received a cognitive behavioral intervention. Compared with the control group, the intervention group showed significant improvement in uncertainty, coping strategy, anxiety, depression, and the mental health domains of QOL after the intervention, providing the first evidence that uncertainty management can improve the emotional status and QOL of COPD outpatients. PMID- 22511400 TI - Assessment on pollution of Ochratoxin A in grain in China and its apoptosis effect on vitro-cultured human tubular kidney cells. AB - Ochratoxin A (OTA) is nephrotoxic, immunosuppressive, and teratogenic in many species and is a possible human carcinogen. In this study, we investigated the OTA pollution situations of grains in northern China and the signaling pathway that mediated OTA-induced apoptosis in human tubular kidney cells (HKCs). Samples of grains collected from three representative areas were determined by using high performance liquid chromatography fluorescence method. The effects of OTA on cell apoptosis, caspase-3, Bax, and Bcl-2 expression, and phosphorylation of c-Jun NH(2) terminal kinase (JNK) were detected in cultured HKCs via flow cytometry (FCM), Hoechst 33258 staining, and Western blot. It showed that OTA pollution of edible grains was very common in north China. OTA could affect caspase-3, Bax, and Bcl-2 expression and increased cell apoptosis in cultured HKCs. The JNK signalling pathway might play an important role during these cellular events. PMID- 22511401 TI - Remifentanil impairs sperm motility reversibly in vitro. AB - The study is to observe the effects of remifentanil on human sperm motility in vitro. After spermatozoa were washed and resuspended in Ham's F-10 medium, the washed human sperm suspensions were treated in vitro with different concentrations of remifentanil for 30 min. Sperm motility was assessed by computer-assisted sperm analysis at 5, 10, 15, and 30 min. Remifentanil significantly decreased (a + b) grade spermatozoa, between 5 and 10 min at the concentrations ranging from 0.1 to 100 MUg L(-1) in a dose-dependent manner and effects no significant difference at 15 and 30 min as compared with control groups. The results suggest that there is indication that this drug has short term effect on sperm motility. PMID- 22511402 TI - Significant reduction in systolic blood pressure following renal artery stenting in patients with uncontrolled hypertension: results from the HERCULES trial. AB - BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) causes hypertension (HTN) and threatens renal function (RF). The HERCULES Trial is a prospective, multicenter trial of renal stenting in patients with uncontrolled HTN and ARAS evaluating the safety and effectiveness of the RX Herculink Elite Renal Stent System (Abbott Vascular, Santa Clara, CA). METHODS: A total of 202 patients (241 total lesions; 78 bilateral lesions) were enrolled between August 2007 and October 2009. The primary endpoint was 9-month binary restenosis determined by duplex ultrasound and/or angiography. Secondary endpoints included changes in blood pressure, antihypertensive medications, and RF between baseline and 9 months. Brain natriuretic peptide (BNP) was measured at baseline, 24 hr and 30 days postprocedure. RESULTS: Mean systolic blood pressure (SBP) at baseline was 162 mm Hg. Nearly 70% of patients were receiving three or more antihypertensive medications (mean 3.4 medications per patient). Baseline serum creatinine was 1.2 +/- 0.4 and 61.5% of subjects had estimated glomerular filtration <60. The restenosis rate was 10.5% at 9 months. The study device, procedure, and clinical success rates were 96.0, 99.2, and 98.0%, respectively. Freedom from major adverse events was 94.8%. At 9 months, the mean SBP significantly decreased (mean 145, paired t test P < 0.0001) after stenting with no change in medications. There was no correlation between SBP reduction and baseline BNP or BNP reduction. CONCLUSIONS: HERCULES demonstrates clinically and statistically significant SBP reduction in patients with uncontrolled HTN, low in-stent restenosis, and complication rates. This study highlights that when appropriate patients are selected for renal artery stenting, impressive reductions in blood pressure may be anticipated. Although the magnitude of absolute reduction in SBP was related to baseline SBP, elevated baseline BNP levels were not predictive of reduction in SBP. Further studies for predictors of clinical response following percutaneous renal revascularization are needed. PMID- 22511403 TI - Choice of stent and outcomes after treatment of drug-eluting stent restenosis in highly complex lesions. AB - OBJECTIVES: Our aim was to compare the outcomes of a same versus different drug eluting stent (DES) implantation strategy for the treatment of DES instent restenosis (ISR). BACKGROUND: The absence of clear data renders the treatment of DES ISR one of the most challenging situations in interventional cardiology. METHODS: We identified all cases of DES ISR treated with a second DES between January 2004 and January 2009. The lesions were divided into those treated with the same DES as the initial one that restenosed and those treated with a different DES. The main end-point was repeat target lesion revascularization (TLR). RESULTS: We included 116 patients with a total of 132 lesions. The patient population was highly complex: 55.5% with diabetes, 56% with type-C lesions, 15.9% with lesions previously stented with BMS and 18.2% with fluoroscopic evidence of stent fracture. A same and different stent strategy was conducted in 41 lesions (31%) and 91 lesions (69%), respectively. Overall TLR was 31.1% and occurred in 46.3% of patients treated with the same stent and 24.4% of those with a different stent (P = 0.012). Multivariable analysis found same stent strategy (OR 2.84, 95%CI 1.23-6.57;P = 0.014) and occurrence of stent fracture (OR 4.03, 95%CI 1.33-12.01;P = 0.012) to be the only independent predictors of TLR after a median follow-up of 20.4 [12.1-30.2] months. CONCLUSIONS: In highly complex lesions, DES implantation for DES ISR is linked to a high need of future revascularization. An association between implanting a DES type other than the original and lower rate of TLR is suggested. PMID- 22511404 TI - Usability of ringed polytetrafluoroethylene grafts for middle hepatic vein reconstruction during living donor liver transplantation. AB - Large vein allografts are suitable for middle hepatic vein (MHV) reconstruction, but their supply is often limited. Although polytetrafluoroethylene (PTFE) grafts are unlimitedly available, their long-term patency is relatively poor. We intended to enhance the clinical usability of PTFE grafts for MHV reconstruction during living donor liver transplantation (LDLT). Two sequential studies were performed. First, PTFE grafts were implanted as inferior vena cava replacements into dogs. Second, in a 1-year prospective clinical trial of 262 adults undergoing LDLT with a modified right lobe, MHV reconstruction with PTFE grafts was compared with other types of reconstruction, and the outcomes were evaluated. In the animal study, PTFE grafts induced strong inflammatory reactions and luminal thrombus formation, but the endothelial lining was well developed. In the clinical study, the reconstruction techniques were revised to make a composite PTFE graft with an artery patch on the basis of the results of the animal study. MHVs were reconstructed with cryopreserved iliac veins (n = 122), iliac arteries (n = 43), aortas (n = 13), and PTFE (n = 84), and these reconstructions yielded 6 month patency rates of 75.3%, 35.2%, 92.3%, and 76.6%, respectively. The overall 6-month patency rates for the iliac vein and PTFE grafts were similar (P = 0.92), but the 6-month patency rates with vein segment 5 were 51.0% and 34.7%, respectively (P = 0.001). The overall graft and patient survival rates did not differ among these 4 groups. In conclusion, ringed PTFE grafts combined with small vessel patches showed high patency rates comparable to those of iliac vein grafts; thus, they can be used for MHV reconstruction when other sizable vessel allografts are not available. PMID- 22511405 TI - Clinical significance of gastritis cystica profunda and its association with Epstein-Barr virus in gastric cancer. AB - BACKGROUND: Gastritis cystica profunda (GCP) is a relatively rare disorder characterized by hyperplastic and cystic down growth of gastric glands into the submucosa. In the current study, the authors attempted to clarify the clinical and pathologic features of GCP in patients with gastric cancer. METHODS: The records of 10,728 patients with gastric cancer who underwent gastric cancer surgery were reviewed. The clinicopathologic features of patients who had GCP (n = 161) were compared with the features of patients without GCP (n = 10,567). In situ hybridization to determine Epstein-Barr virus (EBV) positivity was performed in cancer tissues from patients with (n = 119) and without (n = 503) GCP. RESULTS: GCP was associated significantly with older age, male gender, proximal tumor location, differentiated histology and Lauren intestinal type compared with non-GCP. GCP also was present more frequently in remnant and multiple gastric cancers. Patients who had GCP presented with earlier tumor stages in terms of depth of invasion and lymph node metastasis, and they had less lymphatic and perineural invasion than patients without GCP; however, the presence of GCP was not an independent prognostic factor. The EBV-positive rate was significantly higher in the GCP group (31.1%) than in the non-GCP group (5.8%). CONCLUSIONS: Patients with gastric cancer who had GCP had clinicopathologic features that differed from the features observed in patients without GCP. GCP was associated significantly with EBV-positive gastric cancers, and its possible role as a premalignant lesion needs to be clarified. PMID- 22511407 TI - High-damping carbon nanotube hinged micromirrors. AB - New developments in digital mirror devices (DMDs) require suspension hinges with a good damping and high temperature stability. Carbon nanotubes (CNTs) offer these unique properties. Herein it is shown how CNT hinges can be integrated in micromirrors. The image illustrates a micromirror with a CNT suspension, and a typical overdamped stepresponse (Q-factor < 0.5). PMID- 22511408 TI - Protective role of dietary N-acetylcysteine on the oxidative stress induced by cylindrospermopsin in tilapia (Oreochromis niloticus). AB - Cylindrospermopsin (CYN) is a toxin produced by various cyanobacteria species. Fish can be exposed to this cyanotoxin in their natural environments and in aquaculture ponds, and toxic effects can be derived. The present study investigated the effects of dietary N-acetylcysteine (NAC) on the oxidative stress induced by pure CYN and CYN from lyophilized cells of Aphanizomenon ovalisporum in tilapia (Oreochromis niloticus). Fish were pretreated with 0, 22, and 45 mg NAC/fish/d for a week, and on day seven, they received a single dose of 200 ug/kg CYN and were killed after 24 h. Oxidative biomarkers evaluated included lipid peroxidation, protein oxidation, glutathione (GSH)/oxidized glutathione (GSSG) ratio, activity of the enzyme gamma-glutamylcysteine synthetase, and activity and gene expression of glutathione-S-transferase and glutathione peroxidase. Results showed that CYN induced oxidative stress as evidenced by the increase of lipid peroxidation and protein oxidation, the decrease in GSH/GSSG, and the alteration of the enzymatic activities assayed. Moreover, exposure to cyanobacterial cells containing CYN induced higher toxic effects in comparison to pure CYN. N-acetylcysteine supplementation was effective at reducing the toxicity induced by CYN, particularly at the highest dose employed, with a recovery of some of the biomarkers assayed to basal levels. Therefore, NAC can be considered a useful chemoprotectant that reduces hepatic and renal oxidative stress in the prophylaxis and treatment of CYN-related intoxication in fish. PMID- 22511409 TI - Most accurate definition of a high femoral artery puncture: aiming to better predict retroperitoneal hematoma in percutaneous coronary intervention. AB - BACKGROUND: Retroperitoneal hematoma (RPH) increases morbidity and mortality in percutaneous coronary intervention (PCI). High femoral arteriotomy is an independent predictor of RPH, but the optimal angiographic criterion for defining a high puncture is unknown. METHODS: We retrospectively identified 557 consecutive PCI cases with femoral angiograms. Arteriotomy sites were categorized as high based on three angiographic criteria: at or above the proximal third of the femoral head (criterion A), at or above the most inferior border of the inferior epigastric artery (criterion B), and at or above the origin of the inferior epigastric artery (criterion C). Cases of RPH were then identified. RESULTS: Of the 557 PCI patients, 26 had a high femoral arteriotomy by criterion A, 17 by criterion B, and 6 by criterion C. Among these patients with a high arteriotomy, RPH occurred in four with criterion A, in three with criterion B, and in one with criterion C. Of the three criteria, criterion A most strongly correlated with RPH (odds ratio [OR] 96, 95% confidence interval [CI] 10.3-898.4; p < 0.0001) compared with criterion B (OR 58, 95% CI 8.9 to 372.6; p < 0.0001) or C (OR 27, 95% CI 2.6 to 290.1; p = 0.053). All criteria had high specificity (A, 96%; B, 97%; C, 99%), but the sensitivity was higher with criterion A (80%) than criterion B (60%) or C (20%), and statistically, the use of criterion A led to the most accurate risk-stratification for RPH (A, kappa = 0.79; B, kappa = 0.59; C, kappa = 0.19). CONCLUSIONS: Among the three common definitions of high arteriotomy, femoral artery puncture at or above the proximal third of the femoral head is the landmark that most accurately risk stratifies PCI patients for development of RPH. PMID- 22511410 TI - Location, location, location: Prostate biopsies and MRIs. PMID- 22511412 TI - Canadian Consensus Conference: The FDA decision on the use of 5ARIs. PMID- 22511414 TI - Opportunity lost and found: Any easy way to improve outcomes for prostate cancer patients in the postoperative setting? PMID- 22511413 TI - The need for, and utilization of prostate-bed radiotherapy after radical prostatectomy for patients with prostate cancer in British Columbia. AB - INTRODUCTION: Three randomized trials have demonstrated that post-radical prostatectomy (RP) radiotherapy decreases biochemical relapse for those with adverse pathology. Our purpose was to describe the incidence of pathologic risk factors for recurrence in a contemporary series of patients treated with RP and to describe the use of post-RP radiotherapy. METHODS: All incident prostate cancers diagnosed between January 2005 and December 2007 were identified from the tumour registry. Cases were then linked to radiotherapy records which included dose and modality (external beam radiotherapy and brachytherapy). The pathology reports in the tumour registry were reviewed for pathologic stage, grade and margin status. RESULTS: We identified 9223 patients with prostate cancer. Overall, 36.3% of patients treated with RP had positive margins, and may have benefited from adjuvant radiotherapy. After RP, 332 (15%) patients had radiotherapy to the prostate bed; of these, only 25 (1.1%) received truly adjuvant radiotherapy (delivered within 6 months with a prostate-specific antigen of <0.2 ng/mL). Of the 2181 patients treated with RP, 270 (12%) were seen by a radiation oncologist within 6 months of RP. Of the 1015 patients (47%) with adverse RP pathology (positive margins, extracapsular extension or seminal vesicle invasion), 230 (23%) were seen by a radiation oncologist within 6 months of RP. CONCLUSION: Not all patients with adverse prostatectomy pathology were seen by a radiation oncologist post-prostatectomy, and very few received adjuvant radiotherapy despite almost half of them having risk factors for relapse. PMID- 22511415 TI - Effect of needle size on cancer detection, pain, bleeding and infection in TRUS guided prostate biopsies: A prospective trial. AB - INTRODUCTION: Transrectal ultrasound (TRUS)-guided prostate biopsies using 18G calibre needles are widely used; most often 12-core tissue samples of the peripheral zone are obtained. Although the diagnostic yield of prostate biopsies is fair, there is still a potential for false negative results, which necessitates repeat biopsies. In an effort to improve the accuracy of prostate biopsies, different sampling schemes have been developed. One strategy has been to increase the number of core biopsies performed on each patient. Another strategy has been to improve the reliability of prostate biopsies using larger calibre needles, thereby increasing the amount of tissue obtained for each core biopsy. METHODS: After approval by our institutional review board, we prospectively compared two biopsy needle sizes (18G vs. 16G) in relation to prostate cancer diagnosis, pain, bleeding and infection rates on 105 patients. Each patient underwent 6 TRUS-guided prostate biopsies with the standard 18G needle and 6 other biopsies with the experimental 16G needle. To evaluate possible complications related to the use of a larger 16G needle in the experimental group, we compared pain, bleeding and infection rates with a control group of 100 patients who underwent 12 biopsies with a single 18G needle (18G group). Pain, bleeding assessment and infection events were evaluated using patient questionnaires and telephone interviews. RESULTS: TRUS-guided prostate biopsies using 16G calibre needles did not increase cancer detection or non malignant pathology rate, including prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferatio (ASAP). Pain, bleeding and infectious complications were similar in both groups. Infection was defined as temperature above 38 degrees C occurring within 48 hours after the procedure. We identified 4 patients with post-biopsy fever in the experimental (16/18G) group and 4 other patients in the (18G) control group. The post-biopsy infection rate is higher than reported just a few years ago and indicates that quinolone resistant Escherichia coli seems to be more prevalent in our urban setting than previously suspected. Limitations to our study include small group numbers. CONCLUSION: Larger 16G needles appear to be safe for TRUS-guided prostate biopsies. Further study in a larger, multi-institutional, prospective, randomized manner with 16G needles is warranted to assess the theoretical benefit of larger core biopsies in prostate cancer detection. PMID- 22511416 TI - Scientific publications in urology and nephrology journals from China: A 10-year analysis. AB - BACKGROUND: The scientific research in urology and nephrology of China has developed significantly. The present study was designed to analyze the outputs of publications in urology and nephrology journals from three regions of China: mainland, Taiwan and Hong Kong. METHODS: The numbers of articles, impact factors, citation reports and other indexes within this category between 2000 and 2009 were extracted for quantity and quality comparisons from PubMed and the ISI (Institute for Scientific Information-currently called the Thomson Reuters Web of Knowledge) database. RESULTS: There were 3100 articles from the mainland (36.5%), Taiwan (46.8%) and Hong Kong (16.7%), and the increasing trend in each region was significant (p < 0.001). The accumulated impact factor and total citation of Taiwan exceeded the other two regions, while the average impact factor and citation of Hong Kong was highest. There were differences between the three regions on the most popular journals. INTERPRETATION: Although the quantity of articles in urology and nephrology from the mainland has exceeded Taiwan and Hong Kong since 2008, there is a considerable gap in the quality of articles between the mainland and the other two regions. PMID- 22511417 TI - Consolidative high-dose chemotherapy after conventional-dose chemotherapy as first salvage treatment for male patients with metastatic germ cell tumours. AB - INTRODUCTION: Some men with metastatic germ cell tumours that have progressed after response to initial cisplatin-based combination chemotherapy are cured with conventional dose first salvage chemotherapy (CDCT)--however, many are not. High dose chemotherapy with autologous stem cell rescue (HDCT) may be of value in these patients. Prognosis has recently been better defined by International Prognostic Factor Study Group (IPFSG) prognostic factors. HDCT after response to CDCT has been offered at our institution over the past two decades. We retrospectively assessed the validity of the IPFSG prognostic factors in our patients and evaluated the value of HDCT. METHODS: We identified eligible men with metastatic germ cell tumour progressed after at least 3 cycles of cisplatin based chemotherapy and treated with cisplatin-based CDCT alone or with carboplatin-based HDCT. We also collected their clinical data. Patients were classified into risk groups using IPFSG factors, and progression-free and overall survival factors were analyzed and compared in patients treated with CDCT alone and with HDCT. RESULTS: We identified 38 eligible first salvage patients who had received a median of 4 cycles (range, 1 to 7 cycles) of CDCT. Twenty patients received CDCT alone and 18 patients received CDCT plus HDCT. The overall median progression- free survival was 24.6 months (95%CI, 7.3 to 28.7 months) and overall median overall survival was 34.6 months (95%CI, 17.2 to 51.3 months). Distribution by IPFSG category and 2-year progression- free survival and 3-year overall survival rates within each risk category were very similar to the IPFSG results. There were two toxic deaths with CDCT and none with HDCT. Overall, patients treated with CDCT plus HDCT had improved progression- free survival and overall survival. CONCLUSIONS: The IPFSG prognostic risk factors appeared valid in our patient population. The safety of HDCT with etoposide and carboplatin was confirmed. HDCT was associated with improved progression- free survival and overall survival outcomes, consistent with observations of the IPFSG group. Ideally, the value of optimal HDCT should be determined in comparison to optimal CDCT as first salvage therapy in men with metastatic germ cell tumour with a randomized trial. PMID- 22511418 TI - Salvage chemotherapy for metastatic germ cell tumours: The known unknowns. PMID- 22511419 TI - Is high-dose chemotherapy superior to conventional chemotherapy as first salvage treatment for patients with metastatic germ cell tumors? PMID- 22511420 TI - Pre-treatment risk stratification of prostate cancer patients: A critical review. AB - INTRODUCTION: The use of accepted prostate cancer risk stratification groups based on prostate-specific antigen, T stage and Gleason score assists in therapeutic treatment decision-making, clinical trial design and outcome reporting. The utility of integrating novel prognostic factors into an updated risk stratification schema is an area of current debate. The purpose of this work is to critically review the available literature on novel pre-treatment prognostic factors and alternative prostate cancer risk stratification schema to assess the feasibility and need for changes to existing risk stratification systems. METHODS: A systematic literature search was conducted to identify original research publications and review articles on prognostic factors and risk stratification in prostate cancer. Search terms included risk stratification, risk assessment, prostate cancer or neoplasms, and prognostic factors. Abstracted information was assessed to draw conclusions regarding the potential utility of changes to existing risk stratification schema. RESULTS: The critical review identified three specific clinically relevant potential changes to the most commonly used three-group risk stratification system: (1) the creation of a very low risk category; (2) the splitting of intermediate-risk into a low- and high intermediate risk groups; and (3) the clarification of the interface between intermediate- and high-risk disease. Novel pathological factors regarding high grade cancer, subtypes of Gleason score 7 and percentage biopsy cores positive were also identified as potentially important risk-stratification factors. CONCLUSIONS: Multiple studies of prognostic factors have been performed to create currently utilized prostate cancer risk stratification systems. We propose potential changes to existing systems. PMID- 22511421 TI - Partial nephrectomy for T1b renal cell carcinoma: A safe and superior treatment option. PMID- 22511422 TI - Partial nephrectomy is not the proven standard for Stage T1b renal cell carcinoma. PMID- 22511424 TI - A rare testicular solid mass in children: Juvenile granulosa cell tumour of testis. AB - Juvenile granulosa cell tumour (JGCT) of the testis is a benign neoplasm rarely seen in children. It usually presents as a unilateral scrotal mass and can be associated with genital ambiguity and chromosomal anomalies. Radical orchiectomy is the treatment of choice. We present an infant with a JGCT of the testis and we review the typical findings of the disease. PMID- 22511425 TI - "U-method" TVT-Secur slings: Are they obstructive? AB - INTRODUCTION: The TVT-Secur, a single incision sling, was introduced in 2006. It is implanted using either the "hammock" or the "U-method" technique. With the latter, the sling is tightened to create a "pillowing effect" on the urethra until a negative stress test is obtained. Short-term results seem promising. However, no study has ever reported on the voiding pattern 12 months after its implantation. Our objective was to assess whether the "U-method" technique creates an obstructive voiding pattern on pressure-flow study (PFS) 12 months after the surgery. METHODS: In this retrospective study, we reviewed the charts of 33 women who underwent the "U-method" TVT-Secur. Patients were evaluated before and 12 months postoperatively with regard to different urodynamic studies (UDS). The incontinence status was also assessed 12 months after surgery. RESULTS: At 12 months after the operation, 12.5% (4/32) of the patients reported an improvement of their stress urinary incontinence, while 78.1% (25/32) reported being cured from it. The objective cure rate was 63% (19/30). One patient had a suspected bladder outlet obstruction (BOO) based on PFS. Maximal flow rate (Q(max)) was significantly lower 12 months after surgery (26.0 mL/s [range: 19.0 36.5] vs. 21.5 mL/s [range: 16.0-32.3]). However, median voided volume was lower on the postoperative uroflowmetry (446 mL [range: 348-605] vs. 320 mL [range: 243 502]). Furthermore, none of the patients complained of voiding symptoms after surgery. CONCLUSIONS: Although one patient had findings compatible with BOO, none complained of voiding symptoms. TVT-Secur may result in a lower Q(max). However, this finding may be due to a lower voiding volume on the postoperative UDS. PMID- 22511427 TI - A simple technique to insert urodynamic catheter in difficult cases. PMID- 22511426 TI - Scientific winds blowing towards Asia. PMID- 22511428 TI - Recurrent nephrogenic adenoma in bladder diverticulum: Case report and literature review. AB - Nephrogenic adenoma is an uncommon benign lesion of the urinary tract induced by chronic irritation of the vesical mucosa, due to infection, trauma, surgery, calculi, foreign bodies and chemical agents. A 68-year-old male was admitted to our linic for a periodical cystoscopic evaluation as part of a follow-up initiated due to a past transitional cell carcinoma. The scheduled cystoscopy revealed, within a bladder diverticulum, an unexpected and completely asymptomatic nephrogenic adenoma that we removed by transurethral resection. We followed up the patient at 24 months, then later we made the diagnosis of nephrogenic adenoma. During this time, the patient experienced three relapses within the same diverticulum, always involving a nephrogenic adenoma we persistently treated by transurethral resections. As the nephrogenic adenoma is considered a benign lesion without any direct evidence of a possible evolution to an overt cancer, we successful attempted a half-yearly cystoscopic follow-up to control the growth of a highly recurrent benign entity, interposing between controls a periodical imaging. This paper represents the second report of a nephrogenic adenoma within a bladder diverticulum, but the first case of a nephrogenic adenoma highly recurrent within the same diverticulum and managed conservatively by regular transurethral resection scheduled over the time. PMID- 22511429 TI - Robotic uretero-ureterostomy of the retrocaval ureter without excision of the retrocaval segment. AB - Robotic reconstruction of the retrocaval ureter is gaining momentum as the method of choice for surgically treating this rare condition. Maintaining the retrocaval ureteric segment further facilitates the procedure. We report a case of a 23-year old man who underwent intraperitoneal robotic resection anastomosis and repositioning of the retrocaval ureter. We also discuss the advantages of this technique. PMID- 22511430 TI - Micropapillary carcinoma of the bladder presented with spontaneous intraperitoneal bladder rupture. AB - Spontaneous bladder perforation is a rare presenting feature of bladder malignancy. We describe an unusual case of a patient, admitted to emergency, with diffuse abdominal pain due to spontaneous bladder rupture in association with a micropapillary carcinoma. A diagnosis of an intraperitoneal bladder perforation was made during an emergency operation. Aspects of etiology, clinical presentation, diagnosis and management are described. Although cases of spontaneous carcinomatous bladder rupture are associated with high morbidity and mortality, prompt identification and treatment can lead to favourable outcomes. PMID- 22511431 TI - The combination therapy of prednisolone and tacrolimus for severe painful bladder syndrome/interstitial cystitis. AB - A 47-year-old woman visited our hospital with complaints of frequent urination and intensive pelvic pain. Painful bladder syndrome/interstitial cystitis (PBS/IC) was suspected based on her symptoms. Hydrodistention was performed, and crack and petechial hemorrhage were found, and she was treated with tricyclic antidepressants and antihistamine. However, these treatments were ineffective. An allergy or autoimmune reaction was suspected as the pathogenesis due to eosinophilia and elevation of serum IgE levels. The patient was then treated with immunosuppressive agents. Although her symptoms were not sufficiently improved by single-agent therapy with prednisolone or tacrolimus, they were completely improved by their combined administration. This is the first case to report the effectiveness of combination therapy consisting of prednisolone and tacrolimus to treat PBS/IC. PMID- 22511432 TI - Large minimally symptomatic iatrogenic urinoma presenting three years after abdominal aortic aneurysm repair. AB - We describe a case of a large, minimally symptomatic, urinoma presenting 3 years after emergent repair of a ruptured abdominal aortic aneurysm. We discuss the symptoms and signs, as well as the imaging, treatment and prevention options, for this rare complication. Because of the high mortality associated with delayed diagnosis of ureteral injury, a high index of suspicion should be maintained in patients who had surgery adjacent to the ureters. PMID- 22511433 TI - Occult infiltrating bi-ventricular papillary renal cell carcinoma metastasis found during coronary artery bypass graft surgery. AB - Metastatic papillary renal cell carcinoma (RCC) to the heart has never been reported. We report the case of a 73-year-old patient with papillary RCC metastatic to the left and right ventricles, found during a triple vessel coronary artery bypass graft surgery. PMID- 22511434 TI - Recurrent transitional cell carcinoma of the bladder: A mixed nested variant case report and literature review. AB - Nested variant of urothelial cell carcinoma (NVUC) is a rare histological entity, with about 80 reported cases. It has a deceptively benign appearance with an aspect characterized by confluent small nest or urothelial's cell tubules. This tumour often resembles inverted papilloma, von Brunn's nests (VBNs), cystitis cystica, nephrogenic metaplasia and sometimes usual transitional cell cancer. It is very important to be able to distinguish between benign lesions and nested variant bladder cancer because, in spite of its bland morphology, there is evidence that it behaves aggressively. PMID- 22511435 TI - Pelvic congenital arteriovenous malformation diagnosed by transrectal ultrasonography: A case report. AB - Arteriovenous malformations (AVMs) of the pelvis are relatively rare and difficult to treat because of multiple and extensive feeding vessels. We report the case of a 69-year-old male with pelvic congenital AVM that was detected during tests for dysuria. He visited our hospital complaining of voiding difficulty. Digital rectal examination revealed a pulsating mass that was palpable on the right side of the prostate. Transrectal ultrasonography showed multiple hypoechoic lesions adjacent to the prostate and colour Doppler ultrasonography revealed the flow regions corresponded to the hypoechoic lesions. Computed tomography demonstrated large-to-small tubular vessels adjacent to the prostate, while pelvic angiography showed many small feeder arteries extending mainly from the right internal iliac artery. He was diagnosed as having pelvic congenital AVM. Uroflowmetry revealed slight voiding difficulty without residual urine. The patient decided against treatment and requested we monitor his clinical course. PMID- 22511436 TI - Renal cell carcinoma with secondary hemophagocytic syndrome: A case report. AB - A patient with a suspected malignancy and pancytopenia warrants much consideration. Most clinicians would consider bone marrow infiltrative process, heralding a grave prognosis. However, rare occurrence of hemophagocytic lymphohistiocytosis is another diagnostic possibility we should keep in mind. The treatment choices and overall prognosis may differ from patients without hemophagocytosis. We present a case of incidentally found advanced renal cell carcinoma (RCC) concurrent with hemophagocytosis process in the bone marrow. We also discuss the importance of this finding. PMID- 22511437 TI - Genitourinary malignancy presenting as an ocular metastasis: A case report and review of the literature. AB - Metastases to the eye or orbit as the initial presentation of genitourinary malignancy are unusual and can be a diagnostic challenge. We report an 81-year old man who presented with pain and proptosis in an eye that had been blind for 50 years. Radiologic investigations identified a mass involving the left globe and orbit. Histology of the enucleation specimen was consistent with a metastatic poorly differentiated carcinoma suggestive of a prostate primary. With the constellation of obstructive urinary symptoms, an abnormal digital rectal examination, elevated prostate-specific antigen and a positive bone scan, androgen deprivation therapy was initiated for metastatic prostate cancer. After an initial response to treatment, the patient's disease progressed in a manner atypical for prostate cancer. After describing our case, we review the literature on ocular and orbital metastases and their relation to genitourinary malignancies. PMID- 22511438 TI - A rare case of recurrent urinary obstruction and acute renal failure from cystitis cystica et glandularis. AB - We report a rare case of recurrent florid cystitis cystica et glandularis (CCEG), common type, causing obstruction of the left ureterovesicle junction (UVJ) leading to renal colic and hydronephrosis. A 43-year-old man was admitted with renal colic, left UVJ obstruction, left hydronephrosis and azotemia. Cystoscopy showed a >4-cm bladder lesion compressing the left UVJ. Transurethral resection of the bladder tumour (TURBT) was performed and pathology revealed the lesion as CCEG. Two months later, the CCEG recurred and caused left UVJ obstruction a second time, requiring TURBT. PMID- 22511439 TI - Chilaiditi syndrome in a patient with urological problems: Incidental diagnosis on computed tomography. AB - A rare syndrome, Chilaiditi's syndrome is interposition of the colon only or with the small intestine in hepatodiaphragmatic area. It may be asymptomatic, but it may also present with symptoms, such as abdominal pain, nausea, vomiting, constipation and respiratory distress. We present a patient who was admitted with urological problems; he was incidentally diagnosed with Chilaiditi's syndrome. PMID- 22511440 TI - Adenocarcinoma following urinary diversion. AB - The use of bowel segments in urinary diversions has been associated with an increased risk of neoplasia. This report describes three cases of intestinal adenocarcinoma following urinary diversion. In the first case, a 73-year-old woman developed moderately-differentiated colonic adenocarcinoma in her Indiana pouch 10.5 years after cystectomy. The second case involved a 77-year-old man with well-differentiated adenocarcinoma in his Indiana pouch 9 years after radical cystoprostatectomy and en bloc urethrectomy. The third case involved a 38 year-old man with moderately-differentiated adenocarcinoma arising in his ileal conduit 33 years after the creation of the conduit. These cases highlight the diagnostic signs of adenocarcinoma arising in urinary diversions and emphasize the importance of lifelong surveillance in these patients. PMID- 22511441 TI - Urothelial carcinoma involving the distal penis. AB - Urothelial carcinoma (UC) rarely metastasizes to the penis and skin. We report the case of a 73-year-old man with UC metastases to the corpus spongiosum and dermis of the distal penis. We also review the clinicopathologic characteristics and management options for UC metastasizing to the penis. The patient presented with priapism and edema of the genital region. This follows a 5-year history of urothelial carcinoma in situ that progressed to invasive cancer despite intravesical immunotherapy. Seventeen months prior to presentation, the patient underwent a radical cystectomy with adjuvant chemotherapy. The cystectomy specimen demonstrated a pT4a N2 M0 G3 UC and margins were positive for carcinoma in situ. Follow-up had been negative for recurrence until his presentation with priapism. Incisional biopsy of the glans revealed UC and radical penectomy was performed with negative margins. The penile specimen demonstrated extensive involvement of the corpus spongiosum by UC with lymphovascular invasion and subepidermal involvement. Three months after penectomy, the patient presented with inguinal nodal recurrence. Palliative radiotherapy was administered and the patient passed away eight months after surgery. PMID- 22511442 TI - Stimulation of a non-functioning pituitary macroadenoma after administration of goserelin acetate for locally advanced prostate cancer causing a sustained elevation in PSA and testosterone. AB - Long-acting luteinizing hormone-releasing hormone (LHRH) agonists, such as goserelin, have been used for locally advanced and metastatic prostate cancer for many years and are the main forms of androgen deprivation therapy (ADT). Acting on pituitary LHRH receptors, they initially stimulate a transient rise in serum follicle-stimulating hormone (FSH) and LH. Long-term administration of an LHRH analogue will eventually lead to down regulation of LHRH receptors, thus suppressing FSH and LH secretion. This in turn suppresses testosterone production hence achieving and maintaining androgen deprivation. This case highlights the potential anomaly of a sustained elevated serum testosterone in the context of newly diagnosed locally advanced prostate cancer with a co-existing pituitary macroadenoma after administration of LHRH analogues. Alternative methods of androgen deprivation must be considered in such patients. PMID- 22511443 TI - Renal leiomyoma: Case report and literature review. AB - Renal leiomyomas are rare benign tumours of the kidney originating from muscle cells. They are usually found by an autopsy, whether the patient is asymptomatic or has symptoms (i.e., abdominal/flank pain, hematuria, palpable mass). Today the widespread use of ultrasonography and computed tomography has increased the detection of clinically asymptomatic renal leiomyomas. The differential diagnosis between leiomyomas and other malignant lesions (above all renal cell carcinoma or leiomyosarcoma) is still possible by histological examination. Radiological examinations are not sufficient for the differential diagnosis. Renal leiomyomas have no aggressive behaviour and they usually do not metastasize. The prognosis, after surgery, is excellent without recurrence. We report a case of leiomyoma in a 31-year-old man who presented hematuria and flank pain. We also review the literature and provide a summary of clinical, radiological and histological features of renal leiomyomas. PMID- 22511444 TI - Surgeon-controlled robotic partial nephrectomy for a rare renal epithelioid angiomyolipoma using near-infrared fluorescence imaging using indocyanine green dye: A case report and literature review. AB - Renal epithelioid angiomyolipoma (E-AML) is a rare variant of angiomyolipoma (AML). It is a mesenchymal tumour believed to originate from the perivascular epithelioid cell (PEC). Unlike conventional AML which are benign, E-AML has a rare aggressive behaviour. Conventional AML is typically triphasic containing adipose tissue, smooth muscle and dystrophic vessels in variable proportions, while E-AML are generally composed of plump spindled and polygonal-shaped "epithelioid cells" showing clear or eosinophilic cytoplasm and occasional pleomorphic multinucleated giant cells. E-AML can be misdiagnosed as renal cell carcinoma (RCC) when these "epithelioid cells" show clearing. Only a small number of cases of E-AML have been reported with the standard treatment being radical or partial nephrectomy. We report the first case report of a surgeon-controlled robotic partial nephrectomy using a near-infrared fluorescence imaging using indocyanine green dye on a 25-year-old woman with a T1B (6.6 cm) right renal mass. The final pathology revealed the diagnosis of E-AML. There was no recurrence and metastases after the 6-month follow-up. PMID- 22511445 TI - Multiple muscle abscesses in a uremic patient. PMID- 22511446 TI - A case report of collecting duct carcinoma of the kidney coexistent with giant adrenal myelolipoma. AB - Collecting duct carcinoma (CDC) of the kidney coexistent with giant adrenal myelolipoma is rare. We report a case of 70-year-old female who presented with a history of gross hematuria and back pain. On investigation, she had a mass in the left kidney and left adrenal gland, respectively. The patient underwent left radical nephrectomy with left adrenalectomy. Pathological findings revealed a renal CDC with partial aquamous metaplasia, in addition to an adrenal myelolipoma. Interleukin-2 was administered for 3 months after operation. Neither signs of recurrence nor metastasis has developed after a 4-year follow-up. PMID- 22511447 TI - Small molecular nanowire arrays assisted by superhydrophobic pillar-structured surfaces with high adhesion. AB - Elaborately programmed fluorescent calcein nanowire arrays can be prepared with the aid of superhydrophobic pillar-structured surfaces with high adhesion. Each nanowire can be precisely positioned by well designed tip-structured micropillars, indicating an advance in the methodologies of controlling small molecular 1D organic nanostructures. The as-prepared fluorescent nanowire arrays can serve as a ferrous salt sensing device. PMID- 22511448 TI - Introduction to the genetics and biology of interleukin-28B. PMID- 22511449 TI - Catalytic epoxidations with peroxides: molybdenum trioxide species as the origin of allylic byproducts. AB - Molybdenum(VI)peroxide species, formed in the reaction of Mo(VI) complexes with peroxides, are able to epoxidize >C=C< double bonds heterolytically. In this study, theoretical and experimental evidence is provided for a kinetically competing reaction reaction of such molybdenum(VI)peroxide species with additional peroxide reagent, leading to molybdenum(VI)trioxide species, which easily decompose into radicals. Under epoxidation conditions, those radicals will reduce the selectivity, due to the formation of allylic byproducts. The involved reaction pathways are characterized by DFT calculations, providing kinetic parameters that are in good agreement with the experimental observations. PMID- 22511453 TI - eComment. Re: Accuracy of two scoring systems for risk stratification in thoracic surgery. PMID- 22511450 TI - Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. AB - The objectives of this study were to characterize gastrointestinal dysfunction (GID) in autism spectrum disorder (ASD), to examine parental reports of GID relative to evaluations by pediatric gastroenterologists, and to explore factors associated with GID in ASD. One hundred twenty-one children were recruited into three groups: co-occurring ASD and GID, ASD without GID, and GID without ASD. A pediatric gastroenterologist evaluated both GID groups. Parents in all three groups completed questionnaires about their child's behavior and GI symptoms, and a dietary journal. Functional constipation was the most common type of GID in children with ASD (85.0%). Parental report of any GID was highly concordant with a clinical diagnosis of any GID (92.1%). Presence of GID in children with ASD was not associated with distinct dietary habits or medication status. Odds of constipation were associated with younger age, increased social impairment, and lack of expressive language (adjusted odds ratio in nonverbal children: 11.98, 95% confidence interval 2.54-56.57). This study validates parental concerns for GID in children with ASD, as parents were sensitive to the existence, although not necessarily the nature, of GID. The strong association between constipation and language impairment highlights the need for vigilance by health-care providers to detect and treat GID in children with ASD. Medications and diet, commonly thought to contribute to GID in ASD, were not associated with GID status. These findings are consistent with a hypothesis that GID in ASD represents pleiotropic expression of genetic risk factors. PMID- 22511454 TI - eComment. Predictive factors for hospital mortality in redo mitral valve patients. PMID- 22511455 TI - eComment. Gastrointestinal complications in cardiac surgery. PMID- 22511456 TI - eComment. The evidence for stress ulcer prophylaxis in patients undergoing cardiac surgery. PMID- 22511457 TI - eComment. Using selective myocardial perfusion for interrupted aortic arch surgery. PMID- 22511458 TI - Quantitative proteomics profiling of murine mammary gland cells unravels impact of annexin-1 on DNA damage response, cell adhesion, and migration. AB - Annexin 1 (ANXA1), the first characterized member of the annexin superfamily, is known to bind or annex to cellular membranes in a calcium-dependent manner. Besides mediating inflammation, ANXA1 has also been reported to be involved in important physiopathological implications including cell proliferation, differentiation, apoptosis, cancer, and metastasis. However, with controversies in ANXA1 expression in breast carcinomas, its role in breast cancer initiation and progression remains unclear. To elucidate how ANXA1 plays a role in breast cancer initiation, we performed stable isotope labeling of amino acids in cell culture analysis on normal mammary gland epithelial cells from ANXA1-heterozygous (ANXA1(+/-)) and ANXA1-null (ANXA1(-/-)) mice. Among over 4000 quantified proteins, we observed 214 up-regulated and 169 down-regulated with ANXA1(-/-). Bioinformatics analysis of the down-regulated proteins revealed that ANXA1 is potentially implicated in DNA damage response, whereas the analysis of up regulated proteins showed the possible roles of ANXA1 in cell adhesion and migration pathways. These observations were supported by relevant functional assays. The assays for DNA damage response demonstrated an accumulation of more DNA damage with slower recovery on heat stress and an impaired oxidative damage response in ANXA1(-/-) cells in comparison with ANXA1(+/-) cells. Overexpressing Yes-associated protein 1 or Yap1, the most down-regulated protein in DNA damage response pathway cluster, rescued the proliferative response in ANXA1(-/-) cells exposed to oxidative damage. Both migration and wound healing assays showed that ANXA1(+/-) cells possess higher motility with better wound closure capability than ANXA1(-/-) cells. Knocking down of beta-parvin, the protein with the highest fold change in the cell adhesion protein cluster, indicated an increased cell migration in ANXA1(-/-) cells. Altogether our quantitative proteomics study on ANXA1 suggests that ANXA1 plays a protective role in DNA damage and modulates cell adhesion and motility, indicating its potential role in cancer initiation as well as progression in breast carcinoma. PMID- 22511460 TI - Embolization of radiopaque tip component of clip delivery system of MitraClip device: a rare complication with successful percutaneous retrieval. AB - This case report describes a rare complication that occurred during the performance of a MitraClip procedure. Following deployment of the clip, the portion of the device that attaches the clip to the clip delivery system (CDS), referred to as the radiopaque tip, embolized to the left atrium during removal of the CDS through the guide catheter. The percutaneous strategy that was used to successfully retrieve the radiopaque tip is described and discussed. PMID- 22511459 TI - Mass spectrometry: reconnaissance at the Frontiers of biology. PMID- 22511461 TI - Measuring patient-provider trust in a primary care population: refinement of the health care relationship trust scale. AB - Accurately measuring trust between patients and health care providers is important because low patient-provider trust can lead to poor treatment adherence and negative health outcomes. To measure patient-provider trust, we developed the Health Care Relationship (HCR) Trust scale. Findings from our initial use of the scale suggested the need to examine the scale's psychometric performance in a larger sample of adults with various chronic health conditions. We therefore examined the psychometric properties of the HCR Trust Scale in a random sample of adult primary care patients. Thirteen of the original 15 items fit the data best; a single-factor structure explained 67% of the variance in patient-provider trust. The Cronbach's alpha for the 13-item HCR Trust Scale-Revised was .96. PMID- 22511462 TI - Small-for-size syndrome after living donor liver transplantation: successful treatment with a transjugular intrahepatic portosystemic shunt. AB - Small-for-size syndrome (SFSS) is a serious complication after living donor liver transplantation (LDLT) that can disrupt liver regeneration and result in hepatic dysfunction. Until now, the treatment options for SFSS after LDLT have been very limited. Here we describe a patient with SFSS after LDLT who was successfully treated with a transjugular intrahepatic portosystemic shunt (TIPS). A 56-year old man who had undergone adult-to-adult LDLT because of decompensated liver cirrhosis started displaying signs of acute jaundice and ascites within 72 hours of the operation. The patient was diagnosed with SFSS, and because he had already undergone splenectomy before the transplant, partial splenic embolization was not feasible. Consequently, the TIPS procedure was chosen in an attempt to reduce portal hyperperfusion. After the procedure, the patient's symptoms were gradually ameliorated and were eventually resolved. In conclusion, when partial splenic embolization is not feasible, TIPS placement may be a feasible option for the treatment of SFSS after LDLT. PMID- 22511463 TI - 3-T proton magnetic spectroscopy in unmedicated first episode psychosis: a focus on creatine. AB - Different lines of evidence suggest an abnormal cerebral energy metabolism as being critical to the pathophysiology of schizophrenia. However, it is unknown as to whether levels of creatine (Cr) would be involved in these anomalies. The study involved 33 unmedicated first episode psychosis patients and 41 healthy controls. Proton magnetic resonance spectroscopy ((1) H-MRS) was performed at 3 T using a long TE (TE/TM/TR of 240/27/3000 ms) such that within the total phosphocreatine (PCr) plus Cr signal (tCr(240)), mainly Cr was detectable. The target region was an 18 cm(3) prefrontal volume. A negative association was found between age of patients and tCr(240) levels referenced to internal water, with 20% of the variance in tCr(240) accounted for by Age. A secondary finding revealed 16% reduction of tCr(240) levels in patients, solely when comparing participants older than the median age of patients. No association existed between tCr(240) levels and clinical variables. These findings support previous data reporting abnormalities in brain creatine kinase isoenzymes involved with the maintenance of energy pools in schizophrenia. The implications of using a long TE are discussed in terms of the relative proportions of Cr and PCr within the tCr(240) signal, and of potential group differences in T(2) times. PMID- 22511464 TI - Imaging a spiral dissection of the superficial femoral artery in high resolution with optical coherence tomography-seeing is believing. AB - Optical coherence tomography (OCT) offers an alternative to intravascular ultrasound (IVUS) for endovascular imaging. Clinical and research applications for OCT have emerged in percutaneous coronary intervention (PCI), however, OCT has not found similar utility in peripheral arterial interventions. Early generation time-domain OCT systems required arterial occlusion to create the blood free environment needed for image acquisition and could not reliably scan vessel diameters encountered in the peripheral circulation. However, the frequency-domain OCT (FD-OCT) system currently FDA approved for use in the United States does not require arterial occlusion to generate images and permits a greater scan diameter allowing for exploratory use in peripheral arteries. To our knowledge, this is the first report using non-occlusive OCT imaging to serve as an adjunct to endovascular intervention for femoropopliteal disease. We illustrate the feasibility of acquiring high resolution images of a spiral dissection of the superficial femoral artery following balloon angioplasty that was not adequately visualized by angiography. PMID- 22511465 TI - Antihyperlipidemic components of Cassia auriculata aerial parts: identification through in vitro studies. AB - Cassia auriculata (Caesalpiniaceae) is a common Asian beverage and medicinal plant widely used in tradition medicine for diabetes, hyperlipidemia and various other disease conditions. Previous studies on crude extracts of C. auriculata have documented the scientific basis for some of its traditional medicinal uses. The present study investigates the antilipase activity of the ethanol extract of the aerial parts along with the previously isolated compounds (kaempferol-3-O rutinoside, rutin, kaempferol, quercetin and luteolin). The crude extract displayed inhibitory activity against pancreatic lipase with IC50 of 6.0 +/- 1.0 ug/mL. The most active antilipase compound was kaempferol-3-O-rutinoside with IC50 value (2.9 +/- 0.50 MUM) only about twice weaker than the standard antilipase drug, orlistat (IC50 = 1.45 +/- 0.26 MUM). Luteolin, quercetin and rutin were found to be weak pancreatic lipase inhibitors (IC50 over 100 MUM), whereas kaempferol showed no activity up to 250 MUM. The antihyperlipidemic effect of C. auriculata could be attributed to direct lipase inhibitory effect of the plant constituents. PMID- 22511466 TI - Paper-based blood typing device that reports patient's blood type "in writing". PMID- 22511467 TI - Cancer prognostics by direct detection of p53-antibodies on gold surfaces by impedance measurements. AB - The identification and measurement of biomarkers is critical to a broad range of methods that diagnose and monitor many diseases. Serum auto-antibodies are rapidly becoming interesting targets because of their biological and medical relevance. This paper describes a highly sensitive, label-free approach for the detection of p53-antibodies, a prognostic indicator in ovarian cancer as well as a biomarker in the early stages of other cancers. This approach uses impedance measurements on gold microelectrodes to measure antibody concentrations at the picomolar level in undiluted serum samples. The biosensor shows high selectivity as a result of the optimization of the epitopes responsible for the detection of p53-antibodies and was validated by several techniques including microcontact printing, self-assembled-monolayer desorption ionization (SAMDI) mass spectrometry, and adhesion pull-off force by atomic force microscopy (AFM). This transduction method will lead to fast and accurate diagnostic tools for the early detection of cancer and other diseases. PMID- 22511468 TI - Mechanisms regulating bioavailability of phenanthrene sorbed on a peat soil origin humic substance. AB - The organic matter-mineral complex plays an important role in regulating the fate of hydrophobic organic compounds (HOCs) in the environment. In the present study, the authors investigated the microbial bioavailability of phenanthrene (PHE) sorbed on the original and demineralized humic acids (HAs) and humin (HM) that were sequentially extracted from a peat soil. Demineralization treatment dramatically decreased the 720-h mineralized percentage of HM-sorbed PHE from 42.5 +/- 2.6% to 3.4 +/- 1.3%, whereas the influence of this treatment on the biodegradability of HA-associated PHE was much lower. Degradation kinetics of HA- and HM-sorbed PHE showed that its initial degradation rate was negatively correlated with the aromatic carbon content of humic substances (p<0.05). This was attributed to the strong interactions between PHE and the aromatic components of humic substances, which hampered its release and subsequent biodegradation. The 720-h mineralized percentage of PHE was inversely correlated with the estimated thickness of the organic matter layer at the surfaces of HAs and HMs. Therefore, in a relatively long term, diffusion of PHE within the organic matter layer could be an important factor that may limit the bioavailability of PHE to bacteria. Results of the present study highlight the molecular-scaled mechanisms governing bioavailability of PHE sorbed on humic substances. PMID- 22511469 TI - Conversion of methanol to hydrocarbons: how zeolite cavity and pore size controls product selectivity. AB - Liquid hydrocarbon fuels play an essential part in the global energy chain, owing to their high energy density and easy transportability. Olefins play a similar role in the production of consumer goods. In a post-oil society, fuel and olefin production will rely on alternative carbon sources, such as biomass, coal, natural gas, and CO(2). The methanol-to-hydrocarbons (MTH) process is a key step in such routes, and can be tuned into production of gasoline-rich (methanol to gasoline; MTG) or olefin-rich (methanol to olefins; MTO) product mixtures by proper choice of catalyst and reaction conditions. This Review presents several commercial MTH projects that have recently been realized, and also fundamental research into the synthesis of microporous materials for the targeted variation of selectivity and lifetime of the catalysts. PMID- 22511471 TI - Highly enantioselective epoxidation catalyzed by cinchona thioureas: synthesis of functionalized terminal epoxides bearing a quaternary stereogenic center. AB - A brilliant debut! Cinchona thioureas have been reported for the first time as catalysts in the area of asymmetric oxidations. They efficiently promote an unprecedented highly enantioselective epoxidation of deactivated 1,1 disubstituted alkenes to terminal epoxides containing a quaternary stereogenic center (see scheme). PMID- 22511470 TI - A "modified crossover technique" for vascular access management in high-risk patients undergoing transfemoral transcatheter aortic valve implantation. AB - OBJECTIVES: To describe results from our "modified crossover technique" for vascular access management during transcatheter aortic valve implantation (TAVI). BACKGROUND: Vascular access management remains a major cause of complications following TAVI due to the large bore sheaths required. METHODS: All suitable patients undergoing TAVI in our center, between June and August 2011, underwent our "modified crossover technique," which enables the passage of a balloon through left radial access and inflation in the proximal iliac to allow percutaneous closure in a clean field. RESULTS: In total, 15 patients were included: the logistic EuroSCORE was 19.7 +/- 12.1% and STS score 5.7 +/- 5.6%. The mean therapeutic femoral access site diameter was 8.1 +/- 1.0 mm. Ten (66.7%) patients received Edwards SAPIENTM XT (two using the new E-sheath) and five (33.3%) patients a Medtronic CoreValve ReValving System(r) device. The "modified crossover technique" was used successfully in all patients. There were three vascular complications occurring at the therapeutic access site: one rupture of the external iliac artery, one Prostar failure, and one pseudoaneurysm of the right common femoral artery. All complications were successfully treated percutaneously with covered stent implantation via access from the contralateral femoral artery. In view of the balloon inflation from the left radial artery, the complications could be treated in a clean field with minimal blood loss. CONCLUSIONS: Our "modified crossover technique" using the left radial artery as the diagnostic site for balloon inflation appears a helpful adjunct in managing TAVI vascular access sites. PMID- 22511472 TI - Nursing care--the art of healing. PMID- 22511473 TI - Nasopharyngeal disease in cats: 1. Diagnostic investigation. AB - PRACTICAL RELEVANCE: Nasal discharge, sneezing and upper respiratory noise are frequent presenting signs in feline practice. CLINICAL CHALLENGES: The small nasal cavity of the cat can make visualisation of lesions challenging. In addition, investigations may identify only secondary complications of a disease process, rather than the initial aetiological agent. GLOBAL IMPORTANCE: Nasopharyngeal disease is a worldwide problem. However, fungal disease shows regional variations in prevalence. AUDIENCE: This review, aimed at general practitioners as well as those undertaking more specialist investigations in feline respiratory disease, aims to provide practical guidance on the approach necessary to obtain a diagnosis in cats with nasopharyngeal disease. It should also help to explain why a specific diagnosis may not always be possible. EQUIPMENT: While access to endoscopy and computed tomography is advantageous, extensive information can be gained from equipment readily available in all practices. EVIDENCE BASE: The information presented in this article is based on peer-reviewed publications and the clinical experience of the authors. PMID- 22511474 TI - Nasopharyngeal disease in cats: 2. Specific conditions and their management. AB - PRACTICAL RELEVANCE: Nasopharyngeal disease is a common presenting problem in feline medicine. CLINICAL CHALLENGES: The management of feline nasopharyngeal disease can be challenging at a number of levels. In many cases, a specific diagnosis may remain elusive. Some conditions may not be curable so owners need to understand the requirement for long-term management. In addition, treatment may be compromised by poor patient compliance. AUDIENCE: This review, which is directed at any clinicians involved in the management of cats with nasopharyngeal disease, discusses acute rhinitis (cat 'flu) and a variety of conditions causing chronic rhinosinusitis/chronic nasopharyngeal disease. The intention is to assist treatment decision making by reviewing the most appropriate therapies from the options available for these patients. EVIDENCE BASE: The information presented in this article is based on peer-reviewed publications and the clinical experience of the authors. PMID- 22511475 TI - From problem to success: feline weight loss programs that work. AB - PRACTICAL RELEVANCE: Obesity is the most common unhealthy nutritional condition that is recognized in cats. Documented associated health risks include diabetes mellitus, lameness, non-allergic skin disease, feline lower urinary tract disease and idiopathic hepatic lipidosis. CLINICAL CHALLENGES: Simply recommending a diet designed for weight loss fails, in most cases, to result in successful weight loss in the obese or overweight cat. A more in-depth approach that centers on communication and commitment, alongside a program of feeding a predetermined amount of a specific diet plus exercise and enrichment of the cat's life, offers a chance for a healthy result. PATIENT GROUP: It has been reported in some developed countries that as much as 40-50% of the feline population may be overweight or obese, with middle-aged cats, male cats, mixed-breed cats and neutered cats being at greatest risk. AUDIENCE: This review of what is currently known about the health risks, predisposing factors and treatment of excessive weight gain in cats is aimed at all veterinary health professionals. EVIDENCE BASE: The information reported in the review is drawn from the current scientific literature as well as from the clinical experience of the authors. PMID- 22511476 TI - AAFP and ISFM feline-friendly nursing care guidelines. AB - NURSING CARE: The term nursing care means different things to different people. The authors of these AAFP and ISFM Feline-Friendly Nursing Care Guidelines define nursing care as any interaction between the cat and the veterinary team (veterinarian, technician or nurse, receptionist or other support staff) in the clinic, or between the cat and its owner at home, that promotes wellness or recovery from illness or injury and addresses the patient's physical and emotional wellbeing. Nursing care also helps the sick or convalescing cat engage in activities that it would be unable to perform without help. GUIDELINES RATIONALE: The purpose of the Guidelines is to help all members of the veterinary team understand the basic concepts of nursing care, both in the clinic and at home. This includes methods for keeping the patient warm, comfortable, well nourished, clean and groomed. The Guidelines provide numerous practical tips gleaned from the authors' many years of clinical experience and encourage veterinary team members to look at feline nursing care in ways they previously may not have considered. OVERARCHING GOAL: The primary goal of feline-friendly nursing care is to make the cat feel safe and secure throughout its medical experience. PMID- 22511477 TI - Suspected acquired hypocobalaminaemic encephalopathy in a cat: resolution of encephalopathic signs and MRI lesions subsequent to cobalamin supplementation. AB - PRESENTING SIGNS AND INITIAL INVESTIGATIONS: An 8-year-old female spayed British shorthair cat was presented with a history of waxing and waning neurological signs. Neuroanatomical localisation was consistent with a diffuse forebrain disease. Blood ammonia concentration was increased. Abdominal ultrasonography and a bile acid stimulation test were normal. Magnetic resonance imaging (MRI) revealed hyperintense, bilaterally symmetrical, diffuse lesions on T2-weighted sequences, predominantly, but not exclusively, affecting the grey matter. Serum cobalamin (vitamin B12) concentration was low. Hypocobalaminaemia resulting in a urea cycle abnormality was considered a likely cause of the hyperammonaemia. TREATMENT: Daily cobalamin injections resulted in a rapid clinical improvement. Eight weeks into treatment neurological examination was unremarkable and there was complete resolution of the MRI lesions. CLINICAL IMPORTANCE: This is the first reported case of acquired feline hypocobalaminaemia resulting in an encephalopathy. Additionally, this case is unique in describing reversible brain MRI abnormalities in a cobalamin-deficient companion animal. PMID- 22511480 TI - Two immunogenic passenger dendritic cell subsets in the rat liver have distinct trafficking patterns and radiosensitivities. AB - The aim of this study was to investigate the trafficking patterns, radiation sensitivities, and functions of conventional dendritic cell (DC) subsets in the rat liver in an allotransplantation setting. We examined DCs in the liver, hepatic lymph, and graft tissues and recipient secondary lymphoid organs after liver transplantation from rats treated or untreated by sublethal irradiation. We identified two distinct immunogenic DC subsets. One was a previously reported population that underwent blood-borne migration to the recipient's secondary lymphoid organs, inducing systemic CD8(+) T-cell responses; these DCs are a radiosensitive class II major histocompatibility complex (MHCII)(+) CD103(+) CD172a(+) CD11b(-) CD86(+) subset. Another was a relatively radioresistant MHCII(+) CD103(+) CD172a(+) CD11b(+) CD86(+) subset that steadily appeared in the hepatic lymph. After transplantation, the second subset migrated to the parathymic lymph nodes (LNs), regional peritoneal cavity nodes, or persisted in the graft. Irradiation completely eliminated the migration and immunogenicity of the first subset, but only partly suppressed the migration of the second subset and the CD8(+) T-cell response in the parathymic LNs. The grafts were acutely rejected, and intragraft CD8(+) T-cell and FoxP3(+) regulatory T-cell responses were unchanged. The radioresistant second subset up-regulated CD25 and had high allostimulating activity in the mixed leukocyte reaction, suggesting that this subset induced CD8(+) T-cell responses in the parathymic LNs and in the graft by the direct allorecognition pathway, leading to the rejection. CONCLUSION: Conventional rat liver DCs contain at least two distinct immunogenic passenger subsets: a radiosensitive blood-borne migrant and a relatively radioresistant lymph-borne migrant. LNs draining the peritoneal cavity should be recognized as a major site of the intrahost T-cell response by the lymph-borne migrant. This study provides key insights into liver graft rejection and highlights the clinical implications of immunogenic DC subsets. PMID- 22511481 TI - Role of L-type calcium channels in altered microvascular responses to propofol in hypertension. AB - BACKGROUND: Propofol acts as an L-type calcium channel (LTCC) antagonist to decrease peripheral resistance and initiate hypotension. This study investigated LTCC sensitivity/expression in hypertension and the role of LTCCs in exaggerated hypotension to propofol in this situation. METHODS: Age-matched 12- to 15-week old normotensive rats [male Wistar Kyoto (WKY)] and spontaneously hypertensive rats (SHR) were used. Propofol (10 mg kg(-1), 10-50 mg kg(-1) h(-1) i.v.) was administered and the mesenteric microcirculation (<70 um) observed with fluorescent in vivo microscopy using fluorescein isothiocyanate-conjugated bovine serum albumin (100 mg kg(-1) i.v.). Western blotting was used to measure tissue expression of the alpha(1C) LTCC subtype. Pressure myography was used to assess isolated mesenteric arterioles (<350 um) in response to BAYK8644 (0.1 nM-1 uM), a specific LTCC channel agonist. RESULTS: Propofol dilated isolated arterioles {336.6 uM [mean (sd) change 16.2 (5.8)%]}. However, constriction to BAYK8644 was reduced at this concentration of propofol [EC(50)=8.3 (0.1) log mol(-1)] compared with controls [7.4 (0.1) log mol(-1), P<0.05], suggesting that propofol inhibited LTCCs. The sensitivity of LTCCs increased during hypertension, as in vivo there was a greater increase in mean arterial pressure (MAP) to BAYK8644 [10 ug kg(-1), WKY: 59.5 (9.3)%; SHR: 97.7 (6.3)%, P<0.05] with exaggerated constriction of arterioles [10 ug kg(-1), WKY: 9.1 (2.5)%; SHR: 19.1 (2.6)%, P<0.05]. Propofol also decreased MAP in SHR over time (P<0.05), but remained unchanged in WKY. Using western blotting, expression of alpha(1C) was greater in SHR compared with WKY (P<0.05). CONCLUSIONS: Propofol acts via LTCC channels, with increased channel expression and sensitivity in genetically hypertensive rats. We suggest that increased sensitivity and expression of LTCCs may be a mechanism for exaggerated hypertension during propofol anaesthesia. PMID- 22511482 TI - Effects of pregabalin on the activity of glutamate transporter type 3. AB - BACKGROUND: Pregabalin, (S)-3-aminomethyl-5-methyl hexanoic acid, is a ligand for the alpha2delta subunit (a component of voltage-gated calcium channels) and has analgesic and anticonvulsant properties. Glutamate uptake by glutamate transporters may be a mechanism for these properties. We investigated the effects of pregabalin on the activity of the neuronal glutamate transporter type 3 (EAAT3). METHODS: EAAT3 was expressed in Xenopus laevis oocytes. Two-electrode voltage clamping was used to record membrane currents before, during, and after applying l-glutamate (30 MUM) in the presence or absence of pregabalin. Currents were also measured in oocytes pretreated with a protein kinase C (PKC) activator (phorbol-12-myristate-13-acetate, PMA), PKC inhibitors (chelerythrine or staurosporine), or a phosphatidylinositol-3-kinase (PI3K) inhibitor wortmannin. RESULTS: The exposure of the oocytes injected with EAAT3 mRNA to serial concentrations of pregabalin (0.06-60 MUM) significantly increased their responses to 30 MUM l-glutamate. A kinetic study showed that pregabalin significantly increased V(max) without changing K(m). Treatment of oocytes with PMA, pregabalin, or pregabalin plus PMA significantly increased transporter currents vs controls, but treatment with PMA plus pregabalin did not increase the responses further vs PMA or pregabalin alone. In addition, pretreatment of oocytes with two PKC inhibitors (chelerythrine or staurosporine), or inhibitor wortmannin, significantly reduced basal and pregabalin-enhanced EAAT3 activity. CONCLUSIONS: Pregabalin increased EAAT3 activity and PKC and PI3K were involved. This may explain the analgesic effect of pregabalin in neuropathic pain. PMID- 22511484 TI - Simple and low-cost high-performance liquid chromatographic method for determination of D- and L-amino acids. AB - In this article, a simple and low-cost method for the analysis of amino acid enantiomers by using high-performance liquid chromatography (HPLC) is described. In this method, the amino acids are modified to diastereomers in order to be separated into enantiomers on a usual C(18) reversed-phase column. Methanol instead of acetonitrile is used as an elution solvent; the results of HPLC with methanol elution are comparable with those of HPLC with acetonitrile elution. Sub nanomolar sensitivity is attained by measuring the absorbance at 340 nm in analysis of 15 amino-acid enantiomers. PMID- 22511483 TI - Long-term followup for rheumatoid arthritis patients in a multicenter outcomes study of silicone metacarpophalangeal joint arthroplasty. AB - OBJECTIVE: Rheumatoid arthritis (RA) often results in deformities at the metacarpophalangeal (MCP) joints. Patients with severe deformities can be treated by silicone metacarpophalangeal joint arthroplasty (SMPA). The objective of the study is to prospectively compare long-term outcomes for an SMPA surgical and a nonsurgical cohort of RA patients. METHODS: A total of 67 surgical and 95 nonsurgical patients with severe subluxation and/or ulnar drift of the fingers at the MCP joints were recruited from 2004-2008 in this multicenter prospective cohort study. Patients could elect to undergo SMPA or not. Outcomes included the Michigan Hand Outcomes Questionnaire (MHQ), Arthritis Impact Measurement Scales 2 (AIMS2), grip/pinch strength, Jebsen-Taylor Test, ulnar deviation, extensor lag, and arc of motion measurements at the MCP joints. RESULTS: There was no significant difference in the mean age, race, education, and income at baseline between the 2 groups. Surgical subjects had worse MHQ function and functional measurements at baseline. At 3 years, the mean overall MHQ score and the MHQ function, activities of daily living, aesthetics, and satisfaction scores showed significant improvement in the surgical group compared to the nonsurgical group. Ulnar deviation, extensor lag, and arc of motion in the MCP and proximal interphalangeal joints also improved significantly in the surgical group. No improvement was seen in the mean AIMS2 scores and grip/pinch strength. Complications were minimal with a fracture rate of 9.5%. CONCLUSION: RA patients with poor baseline functioning showed long-term improvement in hand function and appearance following treatment with SMPA compared to nonsurgical controls. PMID- 22511485 TI - Simultaneous determination of sulfonamides, penicillins and coccidiostats in pork by high-performance liquid chromatography-tandem mass spectrometry. AB - Veterinary drugs are widely and legally used to treat and prevent disease in livestock. However, drugs are also used illegally as growth-promoting agents. To protect the health of consumers, maximum residue limits (MRL) in food of animal origin have been established and are listed in Regulation 37/2010. According to this regulation, more than 300 drugs need to be controlled regularly in laboratories for residues of veterinary drugs. A cost-effective analytical method is very important and explains why the development of multi-residual methods is becoming popular in laboratories. The aim of this work is to describe a simple, rapid and economical high-performance liquid chromatography-tandem mass spectrometry method for the simultaneous identification and quantification of 21 veterinary drugs in pork muscle samples. The sample clean-up procedure is performed with acidified dichloromethane and does not require solid phase extraction. The method is applicable to nine sulfonamides and seven coccidiostats identified within 36 min. Calculated relevant validation parameters such as recoveries (from 72.to 126 %), intra-precision and intermediate precision (relative standard deviation below 40 %) and decision limits (below 7 ug Kg(-1)) were within acceptable range and in compliance with the requirements of Commission Decision 2002/657/EC. PMID- 22511486 TI - Stability-indicating RP-LC method for the determination of vildagliptin and mass spectrometry detection for a main degradation product. AB - A simple, precise and stability-indicating reversed-phase liquid chromatography method was developed and validated for the determination of vildagliptin (VLG) in pharmaceutical dosage form. The chromatographic separation was obtained within 6 min and was linear in the range of 20-80 ug/mL (r(2) = 0.9999). Limit of detection and limit of quantitation were 0.63 and 2.82 ug/mL, respectively. The method was validated in accordance with International Conference on Harmonization acceptance criteria for specificity, linearity, precision, accuracy, robustness and system suitability. Stress studies were carried out and no interference of the degradation products was observed. The excipients did not interfere in the determination of VLG. Furthermore, the main degradation product obtained from the stress studies (thermal, oxidative and alkaline hydrolysis) was evaluated for mass spectrometry and its molecular structure was predicted. The proposed method was successfully applied for the quantitative analysis of VLG in tablet dosage form, which will help to improve quality control and contribute to stability studies of pharmaceutical tablets containing this drug. PMID- 22511487 TI - Simple and fast quantification of nitisone (NTBC) using liquid chromatography tandem mass spectrometry method in plasma of tyrosinemia type 1 patients. AB - Tyrosinemia type 1, which is caused by a deficiency in fumarylacetoacetate hydrolase, is successfully treatable with nitisone (NTBC), an inhibitor of 4 hydroxyphenyl pyruvate dioxygenase. The recommended average dose of NTBC is 1 mg/kg per day. A rapid liquid chromatography (LC) coupled with negative electrospray ionization tandem mass spectrometry method was developed and validated for the quantification of NTBC in heparinized human plasma. The plasma samples were prepared by precipitation in acetonitrile. NTBC and the internal standard (IS) were chromatographed on a BEH C18 column. Gradient elution was done with a mixture of 10 mM ammonium acetate and methanol. The analyte was analyzed by LC-tandem mass spectrometry with only 2 min run time. Selected reaction monitoring modes for detection of NTBC and the IS were achieved by using m/z 328 > 281 and 234 > 190, respectively. The LC retention times for NTBC and IS were 0.99 and 0.93 min, respectively. The method was linear in the concentration range of 0.75-150 uM with r >= 0.998. Thus, this method is suitable for follow-up of patients treated with NTBC, because the current therapeutical concentrations range from 20 to 120 uM. PMID- 22511488 TI - Sensitive, rapid and easy analysis of three catecholamine metabolites in human urine and serum by liquid chromatography tandem mass spectrometry. AB - A sensitive and easy analytical method for catecholamine metabolites including 4 hydroxy-3-methoxyphenylglycol sulfate (HMPG sulfate), vanillylmandelic acid (VMA) and homovanillic acid (HVA) determination was developed based on liquid chromatography-tandem mass spectrometry in a negative multiple reaction monitoring mode. The analytes were rapidly separated on a reversed-phase Waters Xbridge C18 column (150 * 2.1 mm i.d.) with the mobile phase of 15% (v/v) acetonitrile containing 2 mM ammonium formate and 85% (v/v) formic acid solution (0.05%, v/v). Mass spectrometric conditions, such as characteristic fragmentations and quantification ion transitions, both with chromatographic conditions including separation column type and mobile phase composition, were systematically investigated to get optimal sensitivity and specificity. The limits of detection were in the range of 0.03-0.7 ng/mL for the targets. Recovery rates of spiked urine samples with three different concentration levels (low, middle and high) were above 86% with precisions less than 5.7%. For serum analysis, acetonitrile chosen both as protein precipitation reagent and extraction solvent facilitates to reduce matrix effects. Recovery rates of spiked serum sample were in the range of 90.6% to 111.1% for three targets. The intra day and inter-day precisions were satisfactory less than 8.7%. This proposed method was successfully applied to determine HMPG sulfate, HVA and VMA present in human urine and serum. PMID- 22511489 TI - Enantioselective multicomponent synthesis of fused 6-5 bicyclic 2-butenolides by a cascade heterobicyclisation process. AB - The successive coupling of an alkoxy(aryl/heteroaryl)carbene complex of chromium with either a ketone or an imide lithium enolate and then a 3-substituted (H, TMS, PhCH(2), PhCH(2)CH(2), Me) propargylic organomagnesium reagent has afforded novel hydroxy-substituted bicyclic [4.3.0]-gamma-alkylidene-2-butenolides with three modular points that has allowed the efficient introduction of molecular complexity, including a homopropargylic alcohol core. The selective formation of these five- or six-component heterobicyclisation products is the result of the regioselective integration of the Grignard reagent as a propargyl fragment followed by a cascade CO/alkyne/CO insertion, ketene trapping and elimination sequence. By using lithium enolates of chiral N-acetyl-2-oxazolidinones and the corresponding propargylic organocerium reagents, both enantiomers of these bicyclic heterocycles were efficiently prepared with very high enantiomeric purity. Architecturally, these fused bicyclic butenolides are characterised by a highly unsaturated and oxygenated core and they exhibit strong blue fluorescence in solution. PMID- 22511490 TI - Generation and administration of HA-1-specific T-cell lines for the treatment of patients with relapsed leukemia after allogeneic stem cell transplantation: a pilot study. AB - Since HA-1-specific T cells have been shown to make a significant contribution to the clinical responses in patients with relapsed leukemia, we investigated the feasibility of adoptive transfer of in vitro induced HA-1-specific CD8 positive T cells to patients with relapsed leukemia after allogeneic stem cell transplantation. The in vitro generation of clinical grade HA-1-specific T-cell lines from HA-1 negative donors was seen to be feasible and 3 patients were treated with HA-1-specific T-cell lines. No toxicity after infusion was observed. Although in one patient, during a period of stable disease, HA-1-specific T cells could be detected in the peripheral blood and bone marrow, these patients had no clear clinical response. PMID- 22511491 TI - Using an age-dependent D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded. AB - BACKGROUND: D-dimer testing to rule out deep vein thrombosis is less useful in older patients because of a lower specificity. An age-adjusted D-dimer cut-off value increased the proportion of older patients (>50 years) in whom pulmonary embolism could be excluded. We retrospectively validated the efficacy of this cut off combined with clinical probability for the exclusion of deep vein thrombosis. DESIGN AND METHODS: Five management study cohorts of 2818 consecutive outpatients with suspected deep vein thrombosis were used. Patients with non-high or unlikely probability of deep vein thrombosis were included in the analysis; four different D-dimer tests were used. The proportion of patients with a normal D-dimer test and the failure rates were calculated using the conventional (500 MUg/L) and the age-adjusted D-dimer cut-off (patient's age x 10 MUg/L in patients >50 years). RESULTS: In 1672 patients with non-high probability, deep vein thrombosis could be excluded in 850 (51%) patients with the age-adjusted cut-off value versus 707 (42%) patients with the conventional cut-off value. The failure rates were 7 (0.8; 95% confidence interval 0.3-1.7%) for the age-adjusted cut-off value and 5 (0.7%, 0.2-1.6%) for the conventional cut-off value. The absolute increase in patients in whom deep vein thrombosis could be ruled out using the age-adjusted cut-off value was largest in patients >70 years: 19% among patients with non-high probability. CONCLUSIONS: The age-adjusted cut-off of the D-dimer combined with clinical probability greatly increases the proportion of older patients in whom deep vein thrombosis can be safely excluded. PMID- 22511492 TI - Myelodysplasia-associated immunophenotypic alterations of bone marrow cells in myeloma: are they present at diagnosis or are they induced by lenalidomide? AB - Increased risk of acute myeloid leukemia/myelodysplastic syndromes following treatment has been reported in multiple myeloma, but whether dysplastic features are already present at diagnosis remains to be investigated. Using multiparameter flow cytometry, we analyzed the distribution and phenotype of bone marrow hematopoietic cells from 47 multiple myeloma patients (15 symptomatic and 32 high risk smoldering). From the 32 smoldering myeloma patients, 18 were studied at baseline and 22 after nine cycles of lenalidomide/dexamethasone treatment following the QUIREDEX trial (including 8 from baseline). Phenotypic alterations of bone marrow cells of 7 (47%) symptomatic and 6 (33%) smoldering myeloma patients were detected at baseline; there was no difference in the frequency and extent of phenotypic alterations between symptomatic versus smoldering cases. Likewise, no difference was seen between smoldering myeloma patients studied at baseline versus after lenalidomide/dexamethasone treatment. Our results suggest that phenotypic alterations of bone marrow hematopoietic cells are often present in newly diagnosed symptomatic and smoldering multiple myeloma patients. QUIREDEX trial (NCT00480363). PMID- 22511493 TI - Thrombosis is associated with inferior survival in multiple myeloma. AB - Patients with multiple myeloma are at an increased risk of venous thromboembolism and arterial thrombosis. We assessed the impact of venous and arterial thrombosis on survival in a population-based study of 9,399 multiple myeloma patients diagnosed in Sweden from 1987 to 2005. We found multiple myeloma patients with venous thromboembolism to have a higher mortality at 1-, 5-, and 10-years of follow up compared with those without, with hazard ratios of 2.9 (95% confidence interval (CI) 2.4-3.5), 1.6 (95% CI: 1.5-1.8), and 1.6 (95% CI: 1.4-1.7), respectively. There was an increase in risk of death among multiple myeloma patients with arterial thrombosis, with hazard ratios of 3.4 (95% CI: 3.0-3.8), 2.2 (95% CI: 2.0-2.3), and 2.1 (95% CI: 1.9-2.1), respectively. In landmark analyses at six months, early arterial but not venous thromboembolism was associated with a higher risk of death. Thus, in contrast to prior smaller studies, we found the development of thrombosis to be associated with significantly poorer survival. The prevention of thrombosis in multiple myeloma is an important goal in the management of these patients. PMID- 22511494 TI - Molecular analyses of 15,542 patients with suspected BCR-ABL1-negative myeloproliferative disorders allow to develop a stepwise diagnostic workflow. AB - We investigated 15,542 patients with suspected BCR-ABL1- negative myeloproliferative or myelodysplastic/myeloproliferative neoplasm (including 359 chronic myelomonocytic leukemia) by a molecular marker set. JAK2V617F was detected in the suspected categories as follows: polycythemia vera 88.3%, primary myelofibrosis 53.8%, essential thrombocythemia 50.2%, and not further classifiable myeloproliferative neoplasms 38.0%. JAK2 exon 12 mutations were detected in 40.0% JAK2V617F-negative suspected polycythemia vera, MPLW515 mutations in 13.2%JAK2V617F-negative primary myelofibrosis and 7.1% JAK2V617F negative essential thrombocythemia. TET2 mutations were distributed across all entities but were most frequent in suspected chronic myelomonocytic leukemia (77.8%). CBL mutations were identified in suspected chronic myelomonocytic leukemia (13.9%), primary myelofibrosis (8.0%), and not further classifiable myeloproliferative neoplasm (7.0%). This leads to a stepwise workflow for suspected myeloproliferative neoplasms starting with JAK2V617F and investigating JAK2V617F-negative patients for JAK2 exon 12 or MPL mutations, respectively. In cases in which a myeloproliferative neoplasm cannot be established, analysis for TET2, CBL and EZH2 mutations may be indicated. PMID- 22511495 TI - High-dose imatinib induction followed by standard-dose maintenance in pre-treated chronic phase chronic myeloid leukemia patients--final analysis of a randomized, multicenter, phase III trial. AB - BACKGROUND: Previous data suggest that the response of chronic myeloid leukemia cells to imatinib is dose-dependent. The potential benefit of initial dose intensification of imatinib in pre-treated patients with chronic phase chronic myeloid leukemia remains unknown. DESIGN AND METHODS: Two hundred and twenty seven pre-treated patients with chronic myeloid leukemia in chronic phase were randomly assigned to continuous treatment with a standard dose of imatinib (400 mg/day; n=113) or to 6 months of high-dose induction with imatinib (800 mg/day) followed by a standard dose of imatinib as maintenance therapy (n=114). RESULTS: The rates of major and complete cytogenetic responses were significantly higher in the high-dose arm than in the standard-dose arm at both 3 and 6 months (major cytogenetic responses: 36.8% versus 21.2%, P=0.01 and 50.0% versus 34.5%, P=0.018; complete cytogenetic responses: 22.8% versus 6.2%, P<0.001 and 40.4% versus 16.8%, P<0.001) on the basis of an intention-to-treat analysis. At 12 months, the difference between treatment arms remained statistically significant for complete cytogenetic responses (40.4% versus 24.8%, P=0.012) but not for major cytogenetic responses (49.1% versus 44.2%, P=0.462). The rate of major molecular responses was also significantly better at 3 and 6 months in the high dose arm (month 3: 14.9% versus 3.5%, P=0.003; month 6: 32.5% versus 8.8%, P<0.001). Overall and progression-free survival rates were comparable between arms, but event-free survival was significantly worse in the high-dose arm (P=0.014). CONCLUSIONS: Standard-dose imatinib remains the standard of care for pre-treated patients with chronic phase chronic myeloid leukemia (Clinicaltrials.gov identifier: NCT00327262). PMID- 22511496 TI - Recent advances in acute myeloid leukemia stem cell biology. AB - The existence of cancer stem cells has long been postulated, but was proven less than 20 years ago following the demonstration that only a small sub-fraction of leukemic cells from acute myeloid leukemia patients were able to propagate the disease in xenografts. These cells were termed leukemic stem cells since they exist at the apex of a loose hierarchy, possess extensive self-renewal and the ability to undergo limited differentiation into leukemic blasts. Acute myeloid leukemia is a heterogeneous condition at both the phenotypic and molecular level with a variety of distinct genetic alterations giving rise to the disease. Recent studies have highlighted that this heterogeneity extends to the leukemic stem cell, with this dynamic compartment evolving to overcome various selection pressures imposed upon it during disease progression. The result is a complex situation in which multiple pools of leukemic stem cells may exist within individual patients which differ both phenotypically and molecularly. Since leukemic stem cells are thought to be resistant to current chemotherapeutic regimens and mediate disease relapse, their study also has potentially profound clinical implications. Numerous studies have generated important recent advances in the field, including the identification of novel leukemic stem cell-specific cell surface antigens and gene expression signatures. These tools will no doubt prove invaluable for the rational design of targeted therapies in the future. PMID- 22511497 TI - High curability via intensive reinduction chemotherapy and stem cell transplantation in young adults with relapsed acute lymphoblastic leukemia in Sweden 2003-2007. AB - BACKGROUND: A minority of patients with adult acute lymphoblastic leukemia who relapse are rescued. The aim of this population-based study was to assess the results of reinduction treatment and allogeneic stem cell transplantation in patients in second complete remission. DESIGN AND METHODS: Between 2003-2007, 76 adults (<66 years) with relapsed acute lymphoblastic leukemia (Burkitt's leukemia excluded) were prospectively reported to The Swedish Adult Acute Leukemia Registry and later evaluated. RESULTS: Reinduction with: (i) mitoxantrone, etoposide, and cytarabine (MEA); (ii) fludarabine, cytarabine, pegylated asparaginase plus granulocyte colony-stimulating factor (FLAG-Asp); and (iii) cytarabine, betamethasone, cyclophosphamide, daunorubicin, and vincristine (ABCDV) resulted in complete remission in 6/9 (67%), 10/16 (63%) and 9/21 (43%) of the patients, respectively. Allogeneic stem cell transplantation was performed during second complete remission in 29 patients. Multivariate analysis regarding overall survival after relapse revealed that age over 35 years at diagnosis and relapse within 18 months were negative prognostic factors. Overall survival rates at 3 and 5 years were 22% (95% CI: 13-32) and 15% (95% CI: 7-24). Of 19 patients less than 35 years at diagnosis who underwent allogeneic stem cell transplantation in second remission, ten (53%) are still alive at a median of 5.5 years (range, 4.2-8.3) after relapse, whereas all patients over 35 years old at diagnosis have died. CONCLUSIONS: Allogeneic stem cell transplantation remains the treatment of choice for young adults with relapsed acute lymphoblastic leukemia. Both (i) mitoxantrone, etoposide, and cytarabine and (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor seem effective as reinduction treatments and should be further evaluated. New salvage strategies are needed, especially for patients over 35 years old at diagnosis. PMID- 22511499 TI - Lost in translation? IL28B's discovery and the journey back to the patient. PMID- 22511498 TI - Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response. AB - BACKGROUND: Treatment of follicular lymphoma with rituximab is currently recommended at a dose of 375 mg/m(2). We aimed to provide a rationale for optimal dosing and scheduling of this anti-CD20 antibody based on pharmacokinetics. DESIGN AND METHODS: Clinical efficacy of immunochemotherapy with rituximab, fludarabine and mitoxantrone followed by 2-monthly rituximab maintenance was evaluated in 29 patients with previously untreated follicular lymphoma in a prospective phase II trial (AGMT-NHL9). Pharmacokinetic analysis was assessed in 17 patients. RESULTS: Induction treatment resulted in high clinical response rates (complete remission 66%; ORR 100%). Significantly higher complete remission rates were observed in female patients (86 vs. 47%; Odds Ratio 6.8, 95% CI: 1.12; 41.82; P=0.05). Rituximab pharmacokinetic analysis showed a high variability ranging over almost 1 order of magnitude at maintenance cycle 1 (area under the curve 1,540-12,025 g/L*days). Median area under the curve was lower in men (81%) and in patients with initial bone marrow infiltration (76%). Higher rituximab serum concentrations before next therapy (C(trough)) were associated with female sex (P=0.04) as well as with absence of initial bone marrow infiltration (P=0.001). C(trough) correlated with remission quality (complete vs. partial remission; P=0.005) and progression-free survival (P=0.03). A decline in rituximab C(trough) below 25,000 ng/mL was observed 9.5 to 62 months before clinical relapse (P=0.008). CONCLUSIONS: The results of this pilot trial suggest that more differentiated dosing schedules based on gender and bone marrow infiltration should be explored for rituximab therapy for lymphoma. This study was registered in ClinicalTrials.gov (Identifier: NCT01560117). PMID- 22511500 TI - High-resolution slice-selective Fourier velocity encoding in congenital heart disease using spiral SENSE with velocity unwrap. AB - Quantification of peak velocity is important in the assessment of stenotic flow jets in patients with congenital heart disease. Phase-contrast magnetic resonance underestimates peak velocities. Hence, clinically Doppler ultrasound is used as the reference standard for assessing stenoses. It is possible to accurately measure peak velocity in MR using Fourier velocity encoding (FVE). In this study, a fast, high-resolution slice-selective FVE sequence was developed with the use of spiral trajectories, parallel imaging, and partial Fourier in the velocity dimension and a novel velocity-unwrap technique. The resulting sequence was acquired within a short breath-hold (more than 15 heartbeats) making this FVE technique clinically achievable. Peak velocities were compared from Doppler ultrasound, phase-contrast magnetic resonance, and FVE. Experiments were carried out in vitro and in vivo in 25 patients with congenital heart disease with stenoses. It was shown that in vitro and in vivo phase-contrast magnetic resonance tended to underestimate peak velocity when compared with Doppler ultrasound, whereas FVE agreed well with Doppler ultrasound. PMID- 22511502 TI - In-hospital and one year outcomes with drug-eluting versus bare metal stents in large native coronary arteries: a report from the Evaluation of Drug-Eluting Stents and Ischemic Events registry. AB - OBJECTIVES: We sought to compare the clinical outcomes after percutaneous coronary revascularization of large coronary arteries using drug-eluting (DES) or bare-metal (BMS) stents. BACKGROUND: In de novo native coronary lesions with reference diameters of 2.5-3.5 mm, DES reduce target lesion revascularization (TLR) with no increase in death or myocardial infarction (MI). The relative efficacy of DES in larger coronary artery lesions is less certain. METHODS: From the prospective Evaluation of Drug-Eluting Stents and Ischemic Events registry, we identified patients undergoing stenting of de novo lesions in native coronary arteries 3.5-5.0 mm in diameter (n = 1,485). In-hospital and 1-year clinical outcomes were compared for BMS (n = 282) and DES (n = 1,203) patients, using propensity stratification to adjust for differences in potential confounding factors. RESULTS: Most patient characteristics were similar for the two groups, but BMS patients were more likely to have been treated in the setting of ST elevation MI, whereas DES patients had more bifurcation lesions, smaller vessels, and longer total stent lengths. In risk-adjusted analyses, the composite endpoint of 1-year death, MI or TLR was similar for BMS and DES (standardized rate: 11.9% vs. 8.5%, P = 0.10). DES was associated with a 62% reduction in the risk of TLR, although the absolute difference in event rates was small (standardized rates 4.6% vs. 1.8%, P = 0.016). CONCLUSIONS: Among relatively unselected patients undergoing PCI of large native coronary arteries, use of DES was associated with a modest reduction in rates of TLR, with a neutral effect on other ischemic endpoints. PMID- 22511503 TI - A redox-switchable Au8-cluster sensor. AB - The proof of concept of a simple sensing platform based on the fluorescence of a gold cluster consisting of eight atoms, which is easily manipulated by reduction and oxidation of a specific molecule in the absence of chemical linkers, is demonstrated. Without using any coupling reagents to arrange the distance of the donor-acceptor pair, the fluorescence of the Au(8) -cluster is immediately switched off in the presence of 2-pyridinethiol (2-PyT) quencher. Through an upward-curving Stern-Volmer plot, the system shows complex fluorescence quenching with a combination of static and dynamic quenching processes. To analyze the static quenching constant (V) by a "sphere of action" model, the collisional encounter between the Au(8) -cluster and 2-PyT presents a quenching radius (r) ~5.8 nm, which is larger than the sum of the radii of the Au(8) -cluster and 2 PyT. This implies that fluorescence quenching can occur even though the Au(8) cluster and 2-PyT are not very close to each other. The quenching pathway may be derived from a photoinduced electron-transfer process of the encounter pair between the Au(8) -cluster (as an electron donor) and 2-PyT (as an electron acceptor) to allow efficient fluorescence quenching in the absence of coupling reagents. Interestingly, the fluorescence is restored by oxidation of 2-PyT to form the corresponding disulfide compound and then quenched again after the reduction of the disulfide. This redox-switchable fluorescent Au(8) -cluster platform is a novel discovery, and its utility as a promising sensor for detecting H(2) O(2) -generating enzymatic transformations is demonstrated. PMID- 22511504 TI - Direct volume rendering methods for cell structures. AB - The study of the complicated architecture of cell space structures is an important problem in biology and medical research. Optical cuts of cells produced by confocal microscopes enable two-dimensional (2D) and three-dimensional (3D) reconstructions of observed cells. This paper discuses new possibilities for direct volume rendering of these data. We often encounter 16 or more bit images in confocal microscopy of cells. Most of the information contained in these images is unsubstantial for the human vision. Therefore, it is necessary to use mathematical algorithms for visualization of such images. Present software tools as OpenGL or DirectX run quickly in graphic station with special graphic cards, run very unsatisfactory on PC without these cards and outputs are usually poor for real data. These tools are black boxes for a common user and make it impossible to correct and improve them. With the method proposed, more parameters of the environment can be set, making it possible to apply 3D filters to set the output image sharpness in relation to the noise. The quality of the output is incomparable to the earlier described methods and is worth increasing the computing time. We would like to offer mathematical methods of 3D scalar data visualization describing new algorithms that run on standard PCs very well. PMID- 22511505 TI - How many lithium ions can be inserted onto fused C6 aromatic ring systems? PMID- 22511506 TI - Region 8q24 is a susceptibility locus for nonsyndromic oral clefting in Brazil. AB - BACKGROUND: Nonsyndromic cleft lip with or without cleft palate is a relatively common craniofacial defect with multifactorial inheritance. The association of the rs987525 single nucleotide variant, located in a gene desert at 8q24.21 region, has been consistently replicated in European populations. We performed a structured association approach combined with transcriptional analysis of the MYC gene to dissect the role of rs987525 in oral clefting susceptibility in the ethnically admixed Brazilian population. METHODS: We performed the association study conditioned on the individual ancestry proportions in a sample of 563 patients and 336 controls, and in an independent sample of 221 patients and 261 controls. The correlation between rs987525 genotypes and MYC transcriptional levels in orbicularis oris muscle mesenchymal stem cells was also investigated in 42 patients and 4 controls. RESULTS: We found a significant association in the larger sample (p = 0.0016; OR = 1.80 [95% confidence interval {CI}, 1.21-2.69], for heterozygous genotype, and 2.71 [95% CI, 1.47-4.96] for homozygous genotype). We did not find a significant correlation between rs987525 genotypes and MYC transcriptional levels (p = 0.14; r = -0.22, Spearman Correlation). CONCLUSIONS: We present a positive association of rs987525 in the Brazilian population for the first time, and it is likely that the European contribution to our population is driving this association. We also cannot discard a role of rs987515 in MYC regulation, because this locus behaves as an expression quantitative locus of MYC in another tissue. PMID- 22511507 TI - Effect of tubular inhomogeneities on feedback-mediated dynamics of a model of a thick ascending limb. AB - One of the key mechanisms that mediate renal autoregulation is the tubuloglomerular feedback (TGF) system, which is a negative feedback loop in the kidney that balances glomerular filtration with tubular reabsorptive capacity. Tubular fluid flow, NaCl concentration and other related variables are known to exhibit TGF-mediated oscillations. In this study, we used a mathematical model of the thick ascending limb (TAL) of a short loop of Henle of the rat kidney to study the effects of (i) spatially inhomogeneous TAL NaCl active transport rate, (ii) spatially inhomogeneous tubular radius and (iii) compliance of the tubular walls on TGF-mediated dynamics. A bifurcation analysis of the TGF model equations was performed by deriving a characteristic equation and finding its roots. Results of the bifurcation analysis were validated via numerical simulations of the full model equations. Model results suggest that a higher TAL NaCl active transport rate or a smaller TAL radius near the loop bend gives rise to stable oscillatory solutions at sufficiently high TGF gain values, even with zero TGF delay. In addition, when the TAL walls are assumed to be compliant, the TGF system exhibits a heightened tendency to oscillate, a result that is consistent with predictions of a previous modelling study. PMID- 22511508 TI - Socioeconomic burden of total joint arthroplasty for symptomatic hip and knee osteoarthritis in the Italian population: a 5-year analysis based on hospitalization records. AB - OBJECTIVE: To assess the burden of total joint arthroplasties (TJAs) performed for symptomatic hip and knee osteoarthritis (OA) in the Italian population. METHODS: We analyzed national hospitalizations and diagnosis-related group databases to compute incidence, annual percent change (APC), direct costs, and working days lost between 2001 and 2005 following TJA due to OA. RESULTS: In 2005, we recorded a total of 41,816 (APC +5.4; 95% confidence interval [95% CI] 5.1-5.8) and 44,051 (APC +13.4; 95% CI 13.1-13.8) hip and knee arthroplasties, respectively. Women represented the majority of patients undergoing TJA procedures (female:male ratio 1.7:1 for hip arthroplasties and 2.9:1 for knee arthroplasties). When analyzing the data by age groups, most of the patients were in the age groups 65-74 years and >=75 years, although the highest increases were observed in those ages <65 years. Revisions accounted for 6,387 (APC +4.9; 95% CI 4.0-5.7) and 2,295 (APC +17.4; 95% CI 15.7-19.2) procedures for the hip and knee, respectively. Loss of working days in patients ages <65 years was estimated between 805,000 and 1 million days. Hospital costs increased from 741 million to 1 billion euros over the 5-year period (from 412 to 538 million euros for hip arthroplasties and from 329 to 517 million euros for knee arthroplasties). Rehabilitation costs increased from 228 to 322 million euros. Postoperative complications were estimated between 3.1 and 4.4 million euros. The average costs per patient were 16,835 and 15,358 euros for hip and knee arthroplasties, respectively. CONCLUSION: The socioeconomic burden of TJAs performed for symptomatic OA in Italy is remarkable and calls for the adoption of proper preventive measures. PMID- 22511509 TI - Successful high-risk percutaneous coronary intervention with the use of minimal extracorporeal circulation system. AB - Minimal extracorporeal circulation (MECC) represents a contemporary system which integrates several advances in cardiopulmonary bypass technology in a single circuit. We challenged the efficacy of the MECC system to support the circulation in elective high-risk percutaneous coronary intervention (PCI). A 78-year-old patient with complex coronary disease who would have been otherwise rejected for interventional therapy underwent PCI with rotablation on MECC support. The MECC system provided hemodynamic support at a flow of 1.8 L min(-1) m(-2) while perfusion pressure was kept at a minimum of 70 mm Hg. This allowed for successful angioplasty of the left main stem and a chronically occluded right coronary artery, which otherwise produced significant hemodynamic compromise. This case illustrates that mechanical circulatory support with the MECC system could provide a stable environment and a "safety net" for carrying out complex percutaneous coronary intervention in high-risk patients. PMID- 22511511 TI - Reproducibility and factors influencing the assessment of the SYNTAX score in the left main Xience study. AB - BACKGROUND: As assessment of SYNTAX score is made by visual estimate of coronary angiography, discrepancies between evaluations by different observers and the impact of observer experience have not yet been evaluated. METHODS: Using the data of 166 patients with unprotected left main lesions treated with the second generation everolimus-eluting stent, we sought to analyze SYNTAX score assessment provided by one junior and two independent senior observers and to assess the impact of the quality of angiographies on the reproducibility of SYNTAX score determination. Intra-observer variability was assessed by a senior observer by analyzing 50 sets of angiograms after an interval of at least 6 weeks. RESULTS: The weighted kappa value for the inter-observer reproducibility of SYNTAX score classified as tertiles, according to SYNTAX trial, was 0.71 and the intra observer weighted kappa value was 0.79. When compared with junior's measurements, SYNTAX score assessed by senior investigators was 0.46 and 0.50. Changes in SYNTAX score classification were arbitrarily responsible for changes in weighted kappa values. Angiograms showing the higher rates of discrepancies between observers were of lower quality, when compared with random angiograms. SYNTAX score was closely correlated to 1-year incidence of major adverse cerebro- and cardiovascular events for both junior and senior readers. CONCLUSIONS: SYNTAX score was slightly underestimated by junior reader, when compared with experienced operators. Inter- and intra-observer reproducibility of experienced operators was very acceptable. SYNTAX score evaluation was clearly related to the quality of angiograms. SYNTAX score was correlated to 1-year incidence of major cardiac and cerebrovascular events (MACCE) in all readers. PMID- 22511513 TI - Small biparietal diameter in fetuses with spina bifida on 11-13-week and mid gestation ultrasound. AB - OBJECTIVES: To assess whether, at 11-13-week and mid-trimester ultrasound examinations, the biparietal diameter (BPD) in fetuses with open spina bifida is smaller than the reference range. METHODS: In a multicenter retrospective analysis of data from 23 fetuses with open spina bifida diagnosed at 16-24 weeks, BPD at diagnosis was compared with that measured at 11-13 weeks, before diagnosis. Z-scores were calculated for comparison of BPD deviations from the reference range within the groups at 11-13 weeks and 16-24 weeks, and between these two time intervals. RESULTS: BPD Z-scores at 11-13 weeks and 16-24 weeks were significantly lower (P < 0.0001) in fetuses with open spina bifida when compared to the reference range, with mean values of - 1.29 and - 2.14, respectively, corresponding to the 10(th) and 1.5(th) centiles, respectively. At 11-13 weeks only six of the 23 (26%) fetuses with open spina bifida had BPD below the 5(th) centile, in comparison to 16 (69%) at mid-gestation. This was confirmed by paired t-test comparing the first-trimester with the second-trimester BPD measurements, which showed significantly slower growth of the BPD in fetuses with spina bifida. CONCLUSION: In fetuses with open spina bifida, BPD is smaller not only in the second trimester, as previously reported, but also in the first trimester. This is most likely due to loss of cerebrospinal fluid. We suggest that a BPD value < 10(th) centile in an otherwise normally grown fetus at 11-13 weeks' gestation should be considered as a potential subtle early marker for open spina bifida. PMID- 22511512 TI - Incidence of definite stent thrombosis or in-stent restenosis after drug-eluting stent implantation for treatment of coronary in-stent restenosis: from Western Denmark Heart Registry. AB - BACKGROUND: There are limited data on the optimal management of in-stent restenosis after percutaneous coronary intervention (PCI) with bare metal stent (BMS) or drug-eluting stent (DES) implantations. We assessed the clinical presentation, the incidence, and prognosis of definite stent thrombosis or restenosis after DES implantation for treatment of restenosis. METHODS: From January 2002 to June 2005, all consecutive patients with restenosis < 12 months after index PCI with DES or BMS implantation, were identified in the population based Western Denmark Heart Registry. Patients were followed until 24 months after their first restenosis. RESULTS: A total of 589 lesions were treated for clinically driven restenosis with target lesion revascularization (TLR) within 12 months after the index PCI. Among those, 302 lesions were treated with DES (BMS restenosis n = 244 and DES-restenosis n = 58). Admission were due to stable angina pectoris (n = 249 (82.4%)), unstable angina pectoris (n = 34 (11.3%)), or non-ST segment elevation myocardial infarction (n = 19 (6.3%)). The clinical indication was not different between patients with BMS restenosis compared to DES restenosis. In the BMS restenosis group, older age, longer lesion, longer stent length, and a higher number of stents used was observed compared to the DES restenosis group. After a first restenosis, clinically driven re-TLR was seen in 26 (8.6%) patients within the following 24 months, stent thrombosis (median duration 155 days, interquartile range (IQR) 9-627 days) was seen in 3 lesions (1.0%), and secondary restenosis (median duration 168 days, IQR 88-266 days) was seen in 23 (7.6%) [DES restenosis group 6.9% vs. BMS restenosis group 7.8%, P = 0.818] lesions. CONCLUSION: The clinical presentation did not differ between BMS or DES and most patients present with stable angina pectoris. Risk of stent thrombosis or restenosis was not increased in patients with DES restenosis compared to patients with BMS restenosis treated with DES. PMID- 22511514 TI - Mechanistic origin of antagonist effects of usual anionic bases (OH-, CO3(2-)) as modulated by their countercations (Na+, Cs+, K+) in palladium-catalyzed Suzuki Miyaura reactions. AB - The mechanism of the reaction of trans-ArPdBrL(2) (Ar=p-Z-C(6)H(4), Z=CN, H; L=PPh(3)) with Ar'B(OH)(2) (Ar'=p-Z'-C(6)H(4), Z'=H, CN, MeO), which is a key step in the Suzuki-Miyaura process, has been established in N,N-dimethylformamide (DMF) with two bases, acetate (nBu(4)NOAc) or carbonate (Cs(2)CO(3)) and compared with that of hydroxide (nBu(4)NOH), reported in our previous work. As anionic bases are inevitably introduced with a countercation M(+) (e.g., M(+)OH(-)), the role of cations in the transmetalation/reductive elimination has been first investigated. Cations M(+) (Na(+), Cs(+), K(+)) are not innocent since they induce an unexpected decelerating effect in the transmetalation via their complexation to the OH ligand in the reactive ArPd(OH)L(2), partly inhibiting its transmetalation with Ar'B(OH)(2). A decreasing reactivity order is observed when M(+) is associated with OH(-): nBu(4)N(+) > K(+) > Cs(+) > Na(+). Acetates lead to the formation of trans-ArPd(OAc)L(2), which does not undergo transmetalation with Ar'B(OH)(2). This explains why acetates are not used as bases in Suzuki Miyaura reactions that involve Ar'B(OH)(2). Carbonates (Cs(2)CO(3)) give rise to slower reactions than those performed from nBu(4)NOH at the same concentration, even if the reactions are accelerated in the presence of water due to the generation of OH(-). The mechanism of the reaction with carbonates is then similar to that established for nBu(4)NOH, involving ArPd(OH)L(2) in the transmetalation with Ar'B(OH)(2). Due to the low concentration of OH(-) generated from CO(3)(2-) in water, both transmetalation and reductive elimination result slower than those performed from nBu(4)NOH at equal concentrations as Cs(2)CO(3). Therefore, the overall reactivity is finely tuned by the concentration of the common base OH(-) and the ratio [OH(-)]/[Ar'B(OH)(2)]. Hence, the anionic base (pure OH(-) or OH(-) generated from CO(3)(2-)) associated with its countercation (Na(+), Cs(+), K(+)) plays four antagonist kinetic roles: acceleration of the transmetalation by formation of the reactive ArPd(OH)L(2), acceleration of the reductive elimination, deceleration of the transmetalation by formation of unreactive Ar'B(OH)(3)(-) and by complexation of ArPd(OH)L(2) by M(+). PMID- 22511516 TI - Derivation of a brief measure of agitation and aggression in Alzheimer's disease. AB - OBJECTIVE: Neuropsychiatric symptoms, including agitation and aggression (A/A), are highly prevalent in Alzheimer's disease (AD) and are associated with increased disability, functional impairment, caregiver distress, and institutionalization. Previous psychometric work suggests that individual items of agitation, irritability, disinhibition, and aberrant motor behavior from the Neuropsychiatric Inventory (NPI) may be a valid measure of A/A in AD. We provide additional confirmation of this subscale, as well as preliminary validation of it as a measure of A/A (the NPI-4-A/A). METHODS: The sample included 641 individuals identified from the South Carolina Alzheimer's Disease Registry and assessed to be at a nursing home level of care. Demographic and medical data were extracted from the Registry, and phone interviews were conducted with caregivers to collect additional information not included in the Registry. The primary statistical analysis was confirmatory factor analysis of the NPI-12 factor structure. RESULTS: The standardized root mean residual and root mean square error of approximation (90% CI) values of 0.060 and 0.043 (0.030, 0.057), respectively suggest adequate model fit of the data, whereas the Tucker-Lewis index estimate of 0.779 is below the criteria for adequate model fit. All but two normalized residuals (NR) suggested adequate model fit of the data (|NR| < 2.58). NPI-4-A/A scores were higher in patients residing in nursing homes and were correlated with caregiver burden. CONCLUSIONS: The NPI-4-A/A is proposed as a measure of A/A in AD. The utility and validity of this measure should be explored further. Improved measurement and focus on subgroups of neuropsychiatric symptoms should be integrated into interventions for AD. PMID- 22511517 TI - Exploiting boron-zinc transmetallation for the arylation of benzyl halides: what are the reactive species? PMID- 22511515 TI - Electronic structure analysis of the oxygen-activation mechanism by Fe(II)- and alpha-ketoglutarate (alphaKG)-dependent dioxygenases. AB - alpha-Ketoglutarate (alphaKG)-dependent nonheme iron enzymes utilize a high-spin (HS) ferrous center to couple the activation of oxygen to the decarboxylation of the cosubstrate alphaKG to yield succinate and CO(2), and to generate a high valent ferryl species that then acts as an oxidant to functionalize the target C H bond. Herein a detailed analysis of the electronic-structure changes that occur in the oxygen activation by this enzyme was performed. The rate-limiting step, which is identical on the septet and quintet surfaces, is the nucleophilic attack of the distal O atom of the O(2) adduct on the carbonyl group in alphaKG through a bicyclic transition state ((5, 7) TS1). Due to the different electronic structures in (5, 7) TS1, the decay of (7)TS1 leads to a ferric oxyl species, which undergoes a rapid intersystem crossing to form the ferryl intermediate. By contrast, a HS ferrous center ligated by a peroxosuccinate is obtained on the quintet surface following (5)TS1. Thus, additional two single-electron transfer steps are required to afford the same Fe(IV)-oxo species. However, the triplet reaction channel is catalytically irrelevant. The biological role of alphaKG played in the oxygen-activation reaction is dual. The alphaKG LUMO (C=O pi*) serves as an electron acceptor for the nucleophilic attack of the superoxide monoanion. On the other hand, the alphaKG HOMO (C1-C2 sigma) provides the second and third electrons for the further reduction of the superoxide. In addition to density functional theory, high-level ab initio calculations have been used to calculate the accurate energies of the critical points on the alternative potential-energy surfaces. Overall, the results delivered by the ab initio calculations are largely parallel to those obtained with the B3LYP density functional, thus lending credence to our conclusions. PMID- 22511518 TI - Clinimetric properties of observer-assessed impairment tests used to evaluate hip and groin impairments: a systematic review. AB - OBJECTIVE: To recommend the most suitable observer-assessed impairment tests in people with hip and/or groin pathologies by conducting a systematic review of the clinimetric properties of these tests. METHODS: Electronic searches were performed in the Cochrane, PubMed, CINAHL, Embase, SPORTDiscus, and PsycINFO databases up to August 2011. Two reviewers independently rated the measurement properties of clinical tests of impairments, defined by the International Classification of Functioning, Disability and Health as problems in body structure or body function, using the Consensus-Based Standards for the Selection of Health Status Measurement Instruments (COSMIN). "Best evidence synthesis" was made using COSMIN outcomes and the quality of findings was assessed using a purpose criteria system. RESULTS: Fifteen of 2,588 publications were eligible for inclusion. Impairments evaluated were range of motion (ROM; 9 studies), muscle strength (6 studies), tenderness (3 studies), leg length discrepancy (2 studies), balance (2 studies), and muscle length (2 studies) in people with hip osteoarthritis (OA), hip fractures, and mixed hip/groin pathologies. Measurement properties evaluated included reliability, measurement error, construct validity, and criterion validity. Responsiveness and interpretability were not assessed. Intrarater reliability of ROM tests (intraclass correlation coefficient [ICC] 0.82-0.97) and strength tests (ICC 0.84-0.98) for hip OA and of strength tests (ICC 0.66-0.86) and balance tests (ICC 0.73-0.94) for hip fractures was demonstrated. CONCLUSION: This systematic review highlighted a paucity of literature evaluating the clinimetric properties of impairment tests for people with hip and/or groin pathology. A large number of inconclusive findings were found and as such, many clinical impairment tests should be used with caution in people with hip and/or groin pathologies until further clinimetric evidence becomes available. PMID- 22511519 TI - Pharmacologic treatment of hyperthyroidism during pregnancy. AB - Clinical hyperthyroidism has been associated with an increased risk of maternal, fetal, and neonatal complications. The available antithyroid drugs are methimazole/carbimazole and propylthiouracil. Several case reports and some epidemiologic studies suggest that methimazole/carbimazole exposure during the first trimester of pregnancy is associated with an increased risk of congenital malformations, including ectodermal anomalies, choanal atresia, esophageal atresia, and omphalocele. However, the absolute risk appears to be very small, and it remains unclear whether the association is driven by the maternal disease, the medication, or the combination of both factors. Propylthiouracil exposure has not been associated with an increased risk of congenital malformations and is the recommended drug during the first trimester of pregnancy. Since propylthiouracil induced hepatotoxicity has been reported in approximately 0.1% of exposed adults and the number of case-reports of severe liver injury is increasing, treatment with low dose methimazole during the second and third trimesters should be considered. Until now, there has been no evidence that children prenatally exposed to methimazole/carbimazole or propylthiouracil have an increased risk of neurodevelopmental delay. PMID- 22511521 TI - Solution-phase structures of gallium-containing pyrogallol[4]arene scaffolds. PMID- 22511522 TI - Chiral pinwheel clusters lacking local point chirality. AB - The supramolecular pinwheel cluster is a unique chiral structure with evident handedness. Previous studies reveal that the chiral pinwheels are composed of chiral or achiral molecules with polar groups, which result in strong intermolecular interactions such as hydrogen-bonding or dipole interactions. Herein, it is shown that the simple linear aromatic molecule, pentacene, can be self-assembled into large chiral pinwheel clusters on the semimetal Bi(111) surface, due to enhanced intermolecular interactions. The pentacene pinwheels reveal two levels of organizational chirality: the chiral hexamers resulting from asymmetric shifting along the long molecular axis, and chiral arrangement of six hexamers with a rotor motif. Furthermore, a new relation between the local point chirality and organizational chirality is identified from the pinwheels: the former is not essential for the latter in 2D pinwheel clusters of the pentacene molecule. PMID- 22511523 TI - Molecular diversity of methanogens in fecal samples from captive Sumatran orangutans (Pongo abelii). AB - Methane emissions have been previously detected from orangutans, but characterization of the diversity of methanogens in this species has yet to be completed. This preliminary study identified methanogen producing microorganims, also called methanogens, present in the feces from a colony of captive Sumatran orangutans at the Perth Zoo. All animals were housed in the same enclosure and were fed primarily a frugivorous diet. Methanogens were detected using a 16S rRNA gene clone library. A total of 207 clones were examined, revealing 37 different methanogen 16S rRNA sequences, or phylotypes. Of these, 31 phylotypes represented by 170 clones had 96.4-100% sequence identity to Methanosphaera stadtmanae, four phylotypes (32 clones) had 95.1-100% sequence identity to Methanobrevibacter smithii, while two phylotypes (five clones) had 95.9-97.7% sequence identity to Methanobacterium beijingense. Overall, five possible new species were identified from the clone library. This represents the first report of Msp. stadtmanae, a methanol utilizer, as the most predominant methanogen in the gastrointestinal tract of animals. This is likely due to the increased availability of methanol from the highly frugivorous diet of the orangutans. Further studies are warranted to properly assess the effects of frugivorous diets on the methanogen population. PMID- 22511524 TI - Renal evaluation of Aotus azarai infulatus by ultrasonography and serum chemistry profile. AB - This study aimed to characterize anatomical and biochemical properties of owl monkey kidneys in order to provide normal reference values. Sixty-nine Aotus azarai infulatus (45 males and 24 females) were divided into four different age groups (AG1: 3 months-1 year; AG2: 2-3 years; AG3: 4-6 years; and AG4: over 7 years old). The monkeys were evaluated with a serum chemistry profile, focusing on serum creatinine (SCr) and blood urea nitrogen (BUN) and with ultrasound. Mean body mass differed among the age groups. This significance was attributed to AG1 body mass being significantly lower than in AG2 and that in both AG2 and AG3 being significantly lower than in the two older age groups (AG3 and AG4). SCr and BUN concentrations differed significantly between the sexes and SCr level correlated positively with age. In contrast, renal measurements did not differ between males and females. Left and right renal volumes did not differ significantly within age groups, or among AG2, AG3, and AG4. Renal volumes in AG1, however, while not differing from those in AG2, did differ significantly from those in AG3 and AG4. In conclusion, this study provides ultrasonographic reference values for the morphology the kidneys in A. a. infulatus. Evidence is also provided that SCr and BUN levels in owl monkeys are influenced by the sex and age of the individual, factors that should be considered when interpreting test results. PMID- 22511525 TI - Percutaneous therapeutic approaches to closure of cardiac pseudoaneurysms. AB - Cardiac and aortic pseudoaneurysms are rare complications following myocardial infarction or cardiac surgery. They are characterized by a contained cardiac or aortic rupture within surrounding tissue and have a high mortality rate if left untreated. Percutaneous treatment of cardiac pseudoaneurysms might be a feasible treatment option in patients who are at high risk of reoperative surgery. There is limited literature on the outcomes and the approaches to percutaneous treatment of these pseudoaneurysms. We review nine cases of cardiac and aortic pseudoaneurysms and percutaneous techniques for closure. Pseudoaneurysms were categorized anatomically as left ventricular posterior (posterobasal or posterolateral), left ventricular outflow tract, left ventricular apical, and ascending aortic pseudoaneurysms. Two patients with posterior pseudoaneurysms (one posterobasal treated with an Amplatzer Septal Occluder device, and one wide mouthed posterolateral pseudoaneurysm which was not closed, are described. We further describe two left ventricular outflow tract pseudoaneurysms treated successfully with percutaneous coil embolization, one left ventricular apical pseudoaneurysm treated with coils, and three ascending aortic pseudoaneurysms treated with a septal occluder device or vascular plug. We review the technical approaches, device selection strategies, outcomes, and complications with these percutaneous treatment options. The size of the pseudoaneurysm dimensions of its neck and relative anatomy, particularly to the coronaries and valves, are critical issues to be addressed before percutaneous treatment of these pseudoaneurysms. PMID- 22511526 TI - Treatment of type-A aortic dissection using endoprosthesis occurring after coronary artery bypass surgery. AB - Type-A aortic dissection is a rare and often fatal complication following coronary artery bypass surgery (CABG). Corrective surgery seldom improves patient outcome. This report reviews and discusses endoprosthetic correction of type-A aortic dissection. A case of a transluminal correction of acute type-A aortic dissection one year after CABG in a 66-year-old male with a history of ischemic and severely compromised left ventricular function is presented. A prosthesis originally designed for the abdominal aorta was successfully used. Regular follow up was performed and nearly 3 years post prosthesis implantation the patient is stable in New York Heart Association class II. To the authors' knowledge there are no other literature reports of endoprosthetic correction of a type-A aortic dissection in the context of CABG with saphenous grafts. PMID- 22511527 TI - Effects of C60 on the Salmonella typhimurium TA100 transcriptome expression: Insights into C60 -mediated growth inhibition and mutagenicity. AB - Rapid advances are being made in the creation and use of nanomaterials, but little is known about the impact these materials might have on key microbial functions if introduced into the environment. Previous studies have generated conflicting results with respect to the impact of fullerenes on microbial activity. In the present study, Salmonella typhimurium TA100 was selected as a model microbial system with which to investigate further the impact of C(60) aggregates on microbial growth, mutagenicity, and global transcript expression. Aggregates of C(60) predominantly less than 100 nm significantly impacted Salmonella growth at concentrations of >= 0.5 mg/L. In addition, C(60) aggregates also displayed mutagenic potential at concentrations >= 0.1 mg/L. Transcript expression analysis of S. typhimurium TA100 exposed to C(60) for 24 h indicated that 271 transcripts had significant differential expression relative to controls with twofold or more change. Of particular interest was the increased expression of transcripts coding for proteins involved in energy metabolism, amino acid biosynthesis, transcription, and DNA metabolism, and the decreased expression of transcripts coding for proteins involved in protein fate, transport, and binding and bacterial secretion systems. Collectively, these data indicate that C(60) interacts with the outer membrane of S. typhimurium TA100, resulting in delayed growth and mutagenicity, most likely by interfering with key transport functions and inducing a stress response, respectively. PMID- 22511528 TI - An amine-catalyzed enantioselective [3+2] cycloaddition of azomethine ylides and alpha,beta-unsaturated aldehydes: applications and mechanistic implications. AB - The catalytic enantioselective [3+2] cycloaddition between azomethine ylides and alpha,beta-unsaturated aldehydes catalyzed by alpha,alpha-diphenylprolinol has been studied in detail. In particular, the reaction has been extended to the use of 2-alkenylidene aminomalonates generated in situ as azomethine ylide precursors. These reactions lead to the formation of pyrrolidines containing a 5 alkenyl side chain with potential for chemical manipulation. Moreover, a detailed and concise computational study has been carried out to understand the exact nature of the mechanism of this reaction and especially the consequences derived from the incorporation of the chiral secondary amine catalyst on the reaction pathway. PMID- 22511529 TI - Evaluating the cost-effectiveness of prenatal surgery for myelomeningocele: a decision analysis. AB - OBJECTIVE: To determine whether prenatal myelomeningocele repair is a cost effective strategy compared to postnatal repair. METHODS: Decision-analysis modeling was used to calculate the cumulative costs, effects and incremental cost effectiveness ratio of prenatal myelomeningocele repair compared with postnatal repair in singleton gestations with a normal karyotype that were identified with myelomeningocele between T1 and S1. The model accounted for costs and quality adjusted life years (QALYs) in three populations: (1) myelomeningocele patients; (2) mothers carrying myelomeningocele patients; and (3) possible future siblings of these patients. Sensitivity analysis was performed using one-way, two-way and Monte Carlo simulations. RESULTS: Prenatal myelomeningocele repair saves $ 2 066 778 per 100 cases repaired. Additionally, prenatal surgery results in 98 QALYs gained per 100 repairs with 42 fewer neonates requiring shunts and 21 fewer neonates requiring long-term medical care per 100 repairs. However, these benefits are coupled to 26 additional cases of uterine rupture or dehiscence and one additional case of neurologic deficits in future offspring per 100 repairs. Results were robust in sensitivity analysis. CONCLUSION: Prenatal myelomeningocele repair is cost effective and frequently cost saving compared with postnatal myelomeningocele repair despite the increased likelihood of maternal and future pregnancy complications associated with prenatal surgery. PMID- 22511530 TI - Transcatheter therapy for aortic coarctation with severe systemic hypertension during pregnancy. AB - Aortic coarctation is an unusual cause of hypertension during pregnancy and its management is not clarified. We report transcatheter balloon dilatation and stenting for native aortic coarctation in a 22-year-old pregnant woman with severe and uncontrolled systemic hypertension. Arterial blood pressure could be successfully controlled with medical treatment during the rest of the pregnancy and the patient underwent uneventful delivery. No adverse events or recoarctation was observed during 24 months clinical follow-up. In conclusion, native aortic coarctation can be successfully treated during pregnancy with transcatheter therapy. More experience is needed to confirm the safety and efficacy of such management. PMID- 22511531 TI - Silver triflate catalyzed tandem heterocyclization/alkynylation of 1-((2 tosylamino)aryl)but-2-yne-1,4-diols to 2-alkynyl indoles. AB - Don't cross me! 2-Alkynyl indoles were prepared efficiently by the AgOTf catalyzed tandem heterocyclization/alkynylation of 1-(2-tosylamino)aryl)but-2-yne 1,4-diols under mild conditions (see scheme). The attractiveness of this approach lies in the fact that both the indole ring and alkyne side chain of the N heterocycle are sequentially formed from low cost, readily available, and ecologically benign starting materials. It also provides the first route to this synthetically valuable class of compounds that is not based on a cross-coupling strategy. PMID- 22511532 TI - Percutaneous atrial appendage occlusion for stroke prevention in patients with atrial fibrillation: a systematic review. AB - This review aims to evaluate systematically the safety and efficacy of percutaneous left atrial appendage occlusion (PLAAO) in stroke prevention for patients with atrial fibrillation (AF). A systematic review of peer-reviewed journals on PLAAO before June 2011 was performed on three electronic databases. Fourteen studies were identified for evaluation. Overall, implantation was successful in 93% of all cases. Periprocedural mortality and stroke rates were 1.1% and 0.6%, respectively. The incidences of pericardial effusion/cardiac tamponade and device embolisation were 4% and 0.7%, respectively. At the time of the latest follow-up (up to 40 months), the overall incidence of stroke among all studies was 1.4% per annum. Existing evidence suggests that PLAAO is a relatively safe treatment for patients with AF. However, there is a need for further evaluation of its efficacy in the form of large and well-designed randomised controlled trials. PMID- 22511533 TI - It is usually the cigarettes that do it. PMID- 22511534 TI - The effects of a freeze-thaw cycle and pre-analytical storage temperature on the stability of insulin-like growth factor-I and pro-collagen type III N-terminal propeptide concentrations: Implications for the detection of growth hormone misuse in athletes. AB - A method based on two serum biomarkers - insulin-like growth factor-I (IGF-I) and pro-collagen type III N-terminal propeptide (P-III-NP) - has been devised to detect growth hormone (GH) misuse. The aims of this study were to determine the stability of IGF-I and P-III-NP concentrations in serum stored at -20 degrees C and to establish the effects of one freeze-thaw cycle. Blood was collected from 20 healthy volunteers. Serum aliquots were analyzed after storage for one day at 4 degrees C and one day, one week, five weeks, and three months at -20 degrees C. IGF-I and P-III-NP results were combined to calculate a GH-2000 discriminant function score for each volunteer. Inter-assay precision was determined by analysing one quality control sample at each time-point. A single freeze-thaw cycle, storage of serum at 4 degrees C for one day and at -20 degrees C for up to three months had no significant effect on IGF-I or P-III-NP concentration. Intra sample variability for IGF-I was 6.8% (Immunotech assay) and 12.9% (DSL assay). Intra-sample variability for P-III-NP was 10.9% (Cisbio assay) and 13.7% (Orion assay). When IGF-I and P-III-NP results were combined, intra-sample variability of the GH-2000 score expressed as a standard deviation varied between 0.31 and 0.50 depending on the assay combination used. Variability in IGF-I and P--III-NP results of stored samples is largely determined by the characteristics of the assays. A single freeze-thaw cycle, storage of serum at 4 degrees C for one day or at -20 degrees C for up to 3 months does not result in a significant change in GH-2000 score. PMID- 22511535 TI - A systematic review to calculate background miscarriage rates using life table analysis. AB - The objectives of the current study were to calculate: (1) the expected rates of miscarriage by gestational week; (2) the cumulative risk of miscarriage; and (3) the remaining risk of miscarriage for gestational weeks five through 20, through a systematic review of the literature. We searched MEDLINE for articles published in English through the end of 2009. References of articles were also searched. Four studies were identified to have the three necessary pieces of information for the proposed calculations: (1) gestational age at study entry, (2) pregnancy outcome; and (3) the gestational age at which the pregnancy outcome occurred. Data were extracted from each study and Life Table Analysis Methods were conducted. Weekly miscarriage rates varied in the early gestational weeks with the highest rate documented at >20 miscarriages per 1000 women-weeks at each week of gestation prior to week 13. By week 14, the rate for all studies became relatively comparable and fell below 10 miscarriages per 1000 woman-weeks at risk and fell even lower through week 20. The cumulative risk of miscarriage for weeks 5 through 20 of gestation ranged from 11 miscarriages per 100 women to 22 miscarriages per 100 women (11-22%). Based on data from comparable study populations, a range of background miscarriage rates by week of gestation for weeks 5 through 20, the cumulative risk of miscarriage, and the remaining risk of miscarriage are presented. Wider variation of miscarriage rates and risks occurred early in gestation (<14 weeks). PMID- 22511537 TI - Enantioselective beta-arylation of ketones enabled by lithiation/borylation/1,4 addition sequence under flow conditions. PMID- 22511536 TI - Association of dietary magnesium intake with radiographic knee osteoarthritis: results from a population-based study. AB - OBJECTIVE: To examine the cross-sectional association between dietary magnesium intake and radiographic knee osteoarthritis (OA) among African American and white men and women. METHODS: The presence of radiographic knee OA was examined among participants from the Johnston County Osteoarthritis Project and was defined as a Kellgren/Lawrence grade of at least 2 in at least 1 knee. The Block Food Frequency Questionnaire was used to assess magnesium intake. Effect modifiers were explored by testing interactions of magnesium intake and selected factors based on previous studies. The multivariable logistic regression model with standard energy adjustment method was used to estimate the relationship between magnesium intake and radiographic knee OA. RESULTS: The prevalence of knee OA was 36.27% among the 2,112 participants. The relationship between magnesium intake and radiographic knee OA was found to be modified by race (P for interaction = 0.03). An inverse threshold association was observed among whites. Compared to participants in the lowest quintile, the relative odds of radiographic knee OA were cut by one-half for participants in the second quintile of magnesium intake (odds ratio 0.52, 95% confidence interval 0.34-0.79); further magnesium intake did not provide further benefits (P for trend = 0.51). A statistically significant association was not observed among African Americans. CONCLUSION: A modest inverse threshold association was found between dietary magnesium intake and knee OA in whites, but not in African Americans. Further studies are needed to confirm these results and to elucidate the possible mechanisms of action for the racial modification. PMID- 22511539 TI - Rhodium(I)-catalyzed domino asymmetric ring opening/enantioselective isomerization of oxabicyclic alkenes with water. PMID- 22511538 TI - Impact of differential right-to-left shunting on systemic perfusion in pulmonary arterial hypertension. AB - OBJECTIVES: This study aimed at identifying the ideal right-to-left shunt fraction to improve cardiac output (CO) and systemic perfusion in pulmonary arterial hypertension (PHT). BACKGROUND: Atrial septostomy (AS) has been a high risk therapeutic option for symptomatic drug-refractory patients with PHT. Results have been unpredictable due to limited knowledge of the optimal shunt quantity. METHODS: In nine dogs, an 8-mm shunt-prosthesis was inserted between the superior vena cava (SVC) and the left atrium. With pulmonary artery (PA) banding, mean (+/- SEM) systolic right ventricular pressure increased from 37 +/- 1 mm Hg at baseline to 44 +/- 1 mm Hg (moderate PHT, P = 0.005) and 50 +/- 2 mm Hg (severe PHT, P < 0.001). Shunt-flow was adjusted by total (forcing all flow through the shunt) or partial occlusion of the SVC and partial or total clamping of the shunt. Caval-, shunt-, and aortic-flow were measured by ultrasonic flow probes. Blood gases were drawn from the aortic root and PA. RESULTS: At severe PHT, a shunt-flow of 11 +/- 1% of CO (253 +/- 90 mL/min) increased CO significantly by 25% (1.8 +/- 0.1 to 2.4 +/- 0.2 L/min, P = 0.005) causing an increase of systemic oxygen delivery index (DO2 I) by 23% (309 +/- 23 to 399 +/- 32 mL/min/m(2), P = 0.035). Arterial O2 -saturation did not change significantly until a shunt-flow of 18 +/- 2% was exceeded, causing a drop from 96 +/- 1% to 84 +/- 4% (P = 0.013). At moderate PHT, CO or DO2 I did not improve significantly at any shunt-flow. CONCLUSIONS: In severe PHT, a shunt-flow of 11% of CO represented the ideal shunt-fraction. Augmentation of CO compensated for declined O2 saturation due to right-to-left shunting and improved DO2 I. In moderate PHT, AS is less promising. PMID- 22511540 TI - Alignment control of polythiophene chains with mesostructured silica nanofibers having different pore orientations. AB - Alignment control of polythiophene chains with mesostructured silica nanofibers through an organic-inorganic co-assembly approach is realized. Cationic ammonium surfactants with a polymerizable thiophene end group are synthesized and subsequently used as structure-directing agents to grow silica nanofibers with two different pore architectures. In situ polymerization produces mesostructured polythiophene-silica nanofibers with the polymer chains aligned along the pore channels. PMID- 22511541 TI - Percutaneous retrograde left ventricular assist support for interventions in patients with aortic stenosis and left ventricular dysfunction. AB - OBJECTIVES: To evaluate feasibility and technical outcomes in patients with aortic stenosis (AS) who have undergone high-risk procedures with continuous flow left ventricular (LV) assist, with the Impella 2.5 system (Abiomed, Danvers, MA). BACKGROUND: In preparation for transcatheter aortic valve implantation, an increasing number of high-risk patients with severe AS and left ventricular dysfunction are currently considered for percutaneous coronary interventions (PCI) and balloon aortic valvuloplasty (BAV). Hemodynamic support may be required in some patients. METHODS: We reviewed procedural and clinical findings and 30 day outcomes in patients with symptomatic AS who underwent high-risk percutaneous procedures supported by the Impella 2.5 system. All patients carried a high-risk of operative mortality. Impella was used during PCI, BAV, and for hemodynamic support during emergencies. RESULTS: Over a 14-month period, 21 patients with AS underwent insertion of Impella prior to high-risk PCI (n = 3), BAV with subsequent PCI (n = 8), BAV alone (n = 7), or during cardiac arrest immediately following BAV (n = 3). The mean Society of Thoracic Surgeons (STS) predicted mortality risk was 14% (range 7.3-24.7%). Impella was inserted successfully in all patients attempted. Retrograde advancement of two catheters across the aortic valve (for concomitant BAV in 15 patients) was technically feasible. Retrograde continuous flow LV assist produced a reduction in LV end-diastolic pressure and an increase in arterial pressure. Periprocedural complications occurred in 19% (n = 4) patients, with no periprocedural deaths. Mortality at 30 days was 14.2%. CONCLUSION: Our data suggests that continuous flow LV assist with Impella 2.5 can be used in high-risk patients with severe AS who require periprocedural hemodynamic support. PMID- 22511542 TI - Quantifying homo- and heteromolecular hydrogen bonds as a guide for adduct formation. AB - An investigation into the predictability of molecular adduct formation is presented by using the approach of hydrogen bond propensity. Along with the predictions, crystallisation reactions (1a-1j) were carried out between the anti malarial drug pyrimethamine (1) and the acids oxalic (a), malonic (b), acetylenedicarboxylic (c), adipic (d), pimelic (e), suberic (f), azelaic acids (g), as well as hexachlorobenzene (h), 1,4-diiodobenzene (i), and 1,4 diiodotetrafluorobenzene (j); seven (1a to 1g) of these successfully formed salts. Five of these seven salts were found to be either hydrated or solvated. Hydrogen bond propensity calculations predict that hydrogen bonds between 1 and acids a-g are more likely to form rather than the H bonds involved in self association, providing a rationale for the observation of the seven new salts. In contrast, propensity of hydrogen bonds between 1 and h-j is much smaller as compared to other bonds predicted for self-association/solvate formation, in agreement with the observed unsuccessful reactions. PMID- 22511544 TI - {W48} ring opening: Fe16-containing, Ln4-stabilized 49-tungsto-8-phosphateopen wheel [Fe16O2(OH)23(H2O)9(P8W49O189)Ln4(H2O)20]11-. AB - Wheely: For the first time and very unexpectedly, a rupture of the very stable {P(8)W(48)} wheel was observed in aqueous solution at pH 4 and 80 degrees C in the presence of Fe(III), Eu(III)/Gd(III), and H(2)O(2). This inorganic ring opening is unprecedented in polyoxometalate chemistry. PMID- 22511545 TI - Greater radiation savings at higher body mass indexes with dual axis rotational coronary angiography. PMID- 22511543 TI - Muscarinic type 3 receptor induces cytoprotective signaling in salivary gland cells through epidermal growth factor receptor transactivation. AB - Muscarinic type 3 receptor (M3R) plays a pivotal role in the induction of glandular fluid secretions. Although M3R is often the target of autoantibodies in Sjogren's syndrome (SjS), chemical agonists for M3R are clinically used to stimulate saliva secretion in patients with SjS. Aside from its activity in promoting glandular fluid secretion, however, it is unclear whether activation of M3R is related to other biological events in SjS. This study aimed to investigate the cytoprotective effect of chemical agonist-mediated M3R activation on apoptosis induced in human salivary gland (HSG) cells. Carbachol (CCh), a muscarinic receptor-specific agonist, abrogated tumor necrosis factor alpha/interferon gamma-induced apoptosis through pathways involving caspase 3/7, but its cytoprotective effect was decreased by a M3R antagonist, a mitogen activated protein kinase kinase/extracellular signal-regulated kinase (ERK) inhibitor, a phosphatidylinositol 3-kinase/Akt inhibitor, or an epidermal growth factor receptor (EGFR) inhibitor. Ligation of M3R with CCh transactivated EGFR and phosphorylated ERK and Akt, the downstream targets of EGFR. Inhibition of intracellular calcium release or protein kinase C delta, both of which are involved in the cell signaling of M3R-mediated fluid secretion, did not affect CCh-induced ERK or Akt phosphorylation. CCh stimulated Src phosphorylation and binding to EGFR. A Src inhibitor attenuated the CCh/M3R-induced cytoprotective effect and EGFR transactivation cascades. Overall, these results indicated that CCh/M3R induced transactivation of EGFR through Src activation leading to ERK and Akt phosphorylation, which in turn suppressed caspase 3/7-mediated apoptotic signals in HSG cells. This study, for the first time, proposes that CCh-mediated M3R activation can promote not only fluid secretion but also survival of salivary gland cells in the inflammatory context of SjS. PMID- 22511546 TI - Diminished left ventricular function is associated with poor mid-term outcomes in neonates after balloon aortic valvuloplasty. AB - OBJECTIVES: We studied outcomes of neonatal aortic valvuloplasty to determine the risk factors for poor outcomes. BACKGROUND: Balloon aortic valvuloplasty (BAV) is the primary therapy for neonates with severe aortic stenosis (AS). Limited data are available on the mid-term and long-term outcomes in this population, and reported risk factors for poor outcomes vary among studies. METHODS: We reviewed all cases of BAV in neonates in our institution between 1998 and 2009. We reviewed patient characteristics, preintervention echocardiographic, and procedural details. We tracked repeat BAV, aortic valve replacement (AVR), and death/transplant. Kaplan-Meier and Cox regression analyses were performed. Changes in dimensions of left heart structures post-BAV were also studied. RESULTS: Forty-eight neonates were included-of these, 30 (62%) had critical AS. There was one procedural death. The remaining 47 neonates were followed for 4.8 +/- 4.4 years. Repeat BAV was performed in 19 (40%) neonates; AVR was performed in 9 (19%), and death/transplant occurred in 4 (8%) neonates. Multivariate analysis revealed that lower LV shortening fraction pre-BAV, higher pre-BAV and final valve gradient, and need for inotropes were associated with poor long-term outcomes. LV diastolic and systolic dimensions normalized over time, and left heart structures improved in size early and late after BAV. CONCLUSIONS: Neonatal BAV is associated with low mortality. Lower LV shortening fraction pre-BAV is associated with risk of future interventions, while repeat valvuloplasty is safe and effective for recurrent AS. There is significant improvement in dimensions of the LV and aortic valve annulus following BAV. PMID- 22511547 TI - Effects of chronic copper exposure on development and survival in the southern leopard frog (Lithobates [Rana] sphenocephalus). AB - Exposure to environmental contaminants contributes to the global decline of amphibian populations. The impacts of organic contaminants on amphibians are well documented. However, substantially less is known concerning the potential effects of metals on amphibian populations. Copper (Cu) is an essential element, but it can be toxic at concentrations only slightly higher than the normal physiological range. The present study examines the effects of chronic Cu exposure on embryos and larvae of southern leopard frogs, Lithobates (Rana) sphenocephalus. Groups of eggs from multiple clutches were collected from two wetlands and exposed to a range of Cu concentrations (0-150 ug/L) until they reached the free-swimming stage, and then individual larvae were reared to metamorphosis. Higher Cu concentrations significantly reduced embryo survival to the free-swimming stage but did not further reduce survival to metamorphosis. Larval period was affected by Cu treatment, but the clutch from which larvae originated (i.e., parentage) explained a higher proportion of the variation. Embryo survival to hatching varied significantly among clutches, ranging from 42.9 to 79.2%. Measurable levels of Cu were found in larvae with body burdens up to 595 ug Cu/g dry mass in the 100 ug/L treatment, and larval Cu body burdens were higher than in metamorphs. The present study also demonstrated that higher initial egg density ameliorated embryo mortality at higher Cu levels and should be accounted for in future studies. PMID- 22511548 TI - Graphene-oxide-based immunosensing through fluorescence quenching by peroxidase catalyzed polymerization. AB - A graphene oxide (GO)-based immunosensor is developed for the detection of interleukin-5 (IL-5), a key cytokine associated with asthma pathology and eosinophilia. The immunosensing platform utilizes the innate fluorescence of GO, not demanding biomolecules labeled with fluorescent dyes. The GO-based immunoassay exhibits high specificity for IL-5 among other cytokines and is not affected by nonspecific proteins in human serum. PMID- 22511549 TI - International scientific cooperation is key for the Chinese Academy of Sciences. PMID- 22511550 TI - Stilbenoids from Gnetum macrostachyum attenuate human platelet aggregation and adhesion. AB - Platelets play a critical role in pathogenesis of cardiovascular disorders and strokes. The inhibition of platelet function is beneficial for the treatment and prevention of these diseases. The phytochemical investigation of stilbenoids from Gnetum macrostachyum Hook. f. led to the isolation of trans-resveratrol (1), isorhapotigenin (2), gnetol (3), bisisorhapontigenin B (4), gnetin C (5), parvifolol A (6), latifolol (7) and gnetuhainin C (8). The isolated stilbenoids were evaluated for in vitro antiplatelet activities via agonist-induced platelet aggregation and static platelet-collagen adhesion assays using washed human platelets. Compounds 1, 2 and 3 were active in the inhibition of arachidonic acid (AA)-induced platelet aggregation. Compound 2 and its dimer, compound 4, were the most active stilbenoids in thrombin-induced platelet aggregation. Moreover, compounds 4, 5 and 6, tended to be more potent than monomeric and trimeric stilbenoids in a human platelet-collagen adhesion assay under static conditions. This is the first report of the antiplatelet activity of stilbenoids isolated from G. macrostachyum. PMID- 22511552 TI - Imbalanced mortality evidence for tigecycline: 2011, the year of the meta analysis. PMID- 22511551 TI - Bacteremic disseminated tuberculosis in sub-saharan Africa: a prospective cohort study. AB - BACKGROUND: Disseminated tuberculosis is a major health problem in countries where generalized human immunodeficiency virus (HIV) infection epidemics coincide with high tuberculosis incidence rates; data are limited on patient outcomes beyond the inpatient period. METHODS: We enrolled consecutive eligible febrile inpatients in Moshi, Tanzania, from 10 March 2006 through 28 August 2010; those with Mycobacterium tuberculosis bacteremia were followed up monthly for 12 months. Survival, predictors of bacteremic disseminated tuberculosis, and predictors of death were assessed. Antiretroviral therapy (ART) and tuberculosis treatment were provided. RESULTS: A total of 508 participants were enrolled; 29 (5.7%) had M. tuberculosis isolated by blood culture. The median age of all study participants was 37.4 years (range, 13.6-104.8 years). Cough lasting >1 month (odds ratio [OR], 13.5; P< .001), fever lasting >1 month (OR, 7.8; P = .001), weight loss of >10% (OR, 10.0; P = .001), lymphadenopathy (OR 6.8; P = .002), HIV infection (OR, undefined; P < .001), and lower CD4 cell count and total lymphocyte count were associated with bacteremic disseminated tuberculosis. Fifty percent of participants with M. tuberculosis bacteremia died within 36 days of enrollment. Lower CD4 cell count (OR, 0.88; P = .049) and lower total lymphocyte count (OR, 0.76; P = .050) were associated with death. Magnitude of mycobacteremia tended to be higher among those with lower CD4 cell counts, but did not predict death. CONCLUSIONS: In the era of free ART and access to tuberculosis treatment, almost one half of patients with M. tuberculosis bacteremia may die within a month of hospitalization. Simple clinical assessments can help to identify those with the condition. Advanced immunosuppression predicts death. Efforts should focus on early diagnosis and treatment of HIV infection, tuberculosis, and disseminated disease. PMID- 22511554 TI - From low to very high birefringence in bis(2-pyridylimino)isoindolines: synthesis and structure-property analysis. AB - A series of new substituted 1,3-bis(2-pyridylimino)isoindolines--1,3-bis(2 pyridylimino)-5,6-bis(2,6-diisopropylphenoxy)isoindoline (2b), 1,3-bis(2 pyridylimino)-5,6-bis(4-tert-butylphenyl)isoindoline (2c), and 1,3-bis(2 pyridylimino)-5-tert-butylisoindoline (2d)--were synthesized and structurally characterized by single-crystal X-ray diffraction. The birefringence (Deltan) of the crystals of unsubstituted 1,3-bis(2-pyridylimino)isoindoline (2a), 2b, 2c, and 2d were measured and found to vary greatly, with Deltan values of 0.0654(3), 0.0629(17), 0.588(10), 0.701(12), respectively. A structure-property relationship for the birefringence values of 2a-2d was outlined and indicated that the anisotropy of the polarizability of the molecules plays a crucial role in the birefringence of the crystals. The greatest birefringence values are achieved when the molecules are oriented in a face-to-face configuration intermolecularly, and along the crystallographic face being measured. PMID- 22511553 TI - Macrolide-based regimens and mortality in hospitalized patients with community acquired pneumonia: a systematic review and meta-analysis. AB - BACKGROUND: Macrolides are used to treat pneumonia despite increasing antimicrobial resistance. However, the immunomodulatory properties of macrolides may have a favorable effect on pneumonia outcomes. Therefore, we systematically reviewed all studies of macrolide use and mortality among patients hospitalized with community-acquired pneumonia (CAP). METHODS: All randomized control trials (RCTs) and observational studies comparing macrolides to other treatment regimens in adults hospitalized with CAP were identified through electronic databases and gray literature searches. Primary analysis examined any macrolide use and mortality; secondary analysis compared Infectious Diseases Society of America/American Thoracic Society guideline-concordant macrolide/beta-lactam combinations vs respiratory fluoroquinolones. Random effects models were used to generate pooled risk ratios (RRs) and evaluate heterogeneity (I(2)). RESULTS: We included 23 studies and 137,574 patients. Overall, macrolide use was associated with a statistically significant mortality reduction compared with nonmacrolide use (3.7% [1738 of 47,071] vs 6.5% [5861 of 90,503]; RR, 0.78; 95% confidence interval [CI], .64-.95; P = .01; I(2)= 85%). There was no survival advantage and heterogeneity was reduced when analyses were restricted to RCTs (4.6% [22 of 479] vs 4.1% [25 of 613]; RR, 1.13; 95% CI, .65-1.98; P = .66; I(2)= 0%) or to patients treated with guideline-concordant antibiotics (macrolide/beta-lactam, 5.3% [297 of 5574] vs respiratory fluoroquinolones, 5.8% [408 of 7050]; RR, 1.17; 95% CI, .91-1.50; P = .22; I(2)= 43%). CONCLUSIONS: In hospitalized patients with CAP, macrolide-based regimens were associated with a significant 22% reduction in mortality compared with nonmacrolides; however, this benefit did not extend to patients studied in RCTs or patients that received guideline-concordant antibiotics. Our findings suggest guideline concordance is more important than choice of antibiotic when treating CAP. PMID- 22511555 TI - Over-the-wire-technique device implantation. AB - INTRODUCTION: Transcatheter closure of cardiac defects is a mainstay of treatment in congenital and structural heart disease. Occasionally, the devices used are useful in nonstandard or difficult positions but device embolization and malposition can be complicating factors necessitating percutaneous retrieval or emergency surgery. We describe a new "over-the-wire" technique that allows guided safe deployment and easy retrievability if required. METHODS: We describe 5 cases in which Amplatzer devices were delivered over a wire in challenging anatomy in high-risk patients. These cases included baffle leak in complex congenital heart disease, paravalvular leak, a large patent ductus arteriosus, and complex ventricular septal defects. In each case, the device was punctured close to the release mechanism and a guidewire fed through it, the device and guidewire then being loaded into the appropriate delivery system. The procedure is described in each case, illustrating the use of the technique. CONCLUSION: We describe a novel over-the-wire technique that is useful in deployment of Amplatzer devices in difficult and challenging anatomy, allowing careful controlled delivery and easy retrieval. This will help minimize procedural patient risk in complex cases. PMID- 22511556 TI - Effect of lesion length on functional significance of intermediate long coronary lesions. AB - OBJECTIVE: To assess the relationship between lesion length and other angiographic parameters on the functional significance of long coronary lesions with moderate stenosis. BACKGROUND: Coronary revascularization is usually based on angiographic percent stenosis. Coronary stenosis length is not usually considered in daily clinical practice for revascularization decision-making. The relevance of lesion length might be greater in longer lesions with intermediate stenosis. METHODS: All coronary lesions >20 mm and of 40-70% percent stenosis assessed by intracoronary pressure wire between 2007 and 2009 were included. Interventionists performing digital quantification of lesion stenosis were blinded to the result of fractional flow reserve (FFR). Correlations between angiographic data and FFR were analyzed. RESULTS: One hundred and six lesions from 103 patients were included. Reference diameter: 2.9 +/- 0.56 mm; maximal stenosis: 49.0 +/- 8.7%; minimal luminal diameter (MinimalLD): 1.48 +/- 0.4 mm; mean luminal diameter (MeanLD): 2.3 +/- 0.5 mm; mean lesion length: 28.7 +/- 10.6 mm. Lesions with FFR <0.75 accounted for 33% (n = 35). Weak correlations were obtained between FFR and MinimalLD (r = 0.36; P < 0.0005), MeanLD (r = 0.24; P = 0.014), maximal stenosis (r = 0.31; P = 0.001), and mean stenosis (r = 0.018; P = 0.85); strong correlations were observed between FFR and lesion length (r = 0.63; P < 0.0005), lesion length/MinimalLD (r = 0.67; P < 0.0005), and lesion length/MeanLD (0.72; P < 0.0005). The predictive values of lesion length, lesion length/MinimalLD, and lesion length/MeanLD for FFR <0.75 were 0.86, 0.91, and 0.92, respectively. CONCLUSIONS: In long lesions (>20 mm) with moderate angiographic stenosis, lesion length might be the strongest determinant of functional repercussion. Lesion length should be considered when judging the benefit of revascularization or perform functional functional measures that overcome the limitations of simple stenosis quantification. PMID- 22511557 TI - Long-term effects on vascular healing of bare metal stents delivered via paclitaxel-coated balloons in the porcine model of restenosis. AB - BACKGROUND: Clinical trials have consistently demonstrated benefits of paclitaxel coated balloons (PCB) in particular clinical situations such as in-stent restenosis and peripheral vascular interventions. However, the long-term vascular effects of bare metal stents (BMS) delivered via PCB (PCB+BMS) are still unknown. The aim of this study was to assess the long-term effects of PCB+BMS on vascular healing and neointimal formation (NF). METHODS: A total of 208 stents: 56 BMS crimped on PCB, 50 BMS crimped on uncoated balloons (UCB+BMS), 52 Taxus and 50 Cypher stents were implanted in normal coronary arteries of 104 pigs using 1.2:1.0 stent-to-artery ratio. Follow-up occurred at 3, 7, 28, 90, and 180 days. Vascular effects were assessed based on angiographic and histological analysis. Endothelialization was evaluated using an anti von-Willebrand Factor stain. RESULTS: At 28 days, delivery of a BMS using a PCB led to a significant reduction in NF compared to the UCB+BMS and the Taxus stent (P < 0.01). Between 28 and 180 days, the progression of NF tended to be lower in the PCB+BMS compared to all DES groups. At 90 days, the PCB+BMS (2.56 +/- 0.43) and the Taxus stents (2.60 +/- 0.59) had a trend toward higher inflammatory scores compared to the UCB+BMS group (1.85 +/- 1.13, P = 0.09). By 180 days, inflammation and NF had completely normalized between the groups. Expression of peristrut vWF was comparable among all tested groups at 28 days. CONCLUSION: The long-term pattern of vascular healing occurring following PCB+BMS deployment appears to be comparable to what has been reported with DES technologies. PMID- 22511558 TI - Risk of malignancy in children with juvenile idiopathic arthritis not treated with biologic agents. AB - OBJECTIVE: To estimate the relative risk of incident cancer diagnosis among patients with juvenile idiopathic arthritis (JIA) compared to patients without JIA. METHODS: A cohort of biologics-naive patients diagnosed with JIA between 1998 and 2007 and a matched cohort of comparators without JIA were assembled from the PharMetrics Patient-Centric Database. The primary outcome was any incident malignancy, excluding nonmelanoma skin cancer and carcinoma in situ. Claims profiles of patients with any cancer-related diagnosis codes were reviewed to determine outcomes. Incidence rates and 95% confidence intervals (95% CIs) of cancer were calculated and compared between cohorts using Cox proportional hazards regression. Standardized incidence ratios (SIRs) for each cohort compared to the general population were calculated using reference rates from the US Surveillance, Epidemiology, and End-Results (SEER) program. RESULTS: The JIA and non-JIA cohorts included 3,605 and 37,689 patients, respectively, with a mean age of 11 years. The incidence rates of cancer were 67.0 (95% CI 1.3-132.5) cases/100,000 person-years (PY) for JIA and 23.2 (95% CI 12.2-34.2) cases/100,000 PY for non-JIA. The risk of cancer associated with biologics-naive JIA was elevated (hazard ratio 2.8, 95% CI 0.9-8.3). The JIA cohort had a significantly elevated SIR of 4.0 (95% CI 2.6-6.0); the non-JIA cohort SIR was not significantly above SEER rates (SIR 1.4, 95% CI 0.6-2.6). CONCLUSION: We found a nearly 3-fold increased risk of cancer in biologics-naive JIA patients, which approached significance despite the small number of outcomes. This finding suggests an elevated underlying risk of cancer in this disease population. PMID- 22511559 TI - Clinically oriented three-step strategy for assessment of adnexal pathology. AB - OBJECTIVE: To determine the diagnostic performance of ultrasound-based simple rules, risk of malignancy index (RMI), two logistic regression models (LR1 and LR2) and real-time subjective assessment by experienced ultrasound examiners following the exclusion of masses likely to be judged as easy and 'instant' to diagnose by an ultrasound examiner, and to develop a new strategy for the assessment of adnexal pathology based on this. METHODS: 3511 patients with at least one persistent adnexal mass preoperatively underwent transvaginal ultrasonography to assess tumor morphology and vascularity. They were included in two consecutive prospective studies by the International Ovarian Tumor Analysis (IOTA) group: Phase 1 (1999-2005), development of the simple rules and logistic regression models LR1 and LR2, and Phase 2, a validation study (2005-2007). RESULTS: Almost half of the cases (43%) were identified as 'instant' to diagnose on the basis of descriptors applied to the database. To assess diagnostic performance in the more difficult 'non-instant' masses, we used only Phase 2 data (n = 1036). The sensitivity of LR2 was 88%, of RMI it was 41% and of subjective assessment it was 87%. The specificity of LR2 was 67%, of RMI it was 90% and of subjective assessment it was 86%. The simple rules yielded a conclusive result in almost 2/3 of the masses, where they resulted in sensitivity and specificity similar to those of real-time subjective assessment by experienced ultrasound examiners: sensitivity 89 vs 89% (P = 0.76), specificity 91 vs 91% (P = 0.65). When a three-step strategy was applied with easy 'instant' diagnoses as Step 1, simple rules where conclusive as Step 2 and subjective assessment by an experienced ultrasound examiner in the remaining masses as Step 3, we obtained a sensitivity of 92% and specificity of 92% compared with sensitivity 90% (P = 0.03) and specificity 93% (P = 0.44) when using real-time subjective assessment by experts in all tumors. CONCLUSION: A diagnostic strategy using simple descriptors and ultrasound rules when applied to the variables contained in the IOTA database obtains results that are at least as good as those obtained by subjective assessment of a mass by an expert. PMID- 22511560 TI - Comparisons of clinical outcomes for thrombectomy devices with different mechanisms in hemodialysis arteriovenous fistulas. AB - OBJECTIVES: To compare clinical outcomes between mechanical thrombectomy devices with hydrodynamic mechanism and rotational mechanism. BACKGROUND: A number of advantages and concerns have been raised for different mechanical devices but the comparisons of clinical outcomes are absent, especially for the treatment of autogenous hemodialysis arteriovenous (AV) fistulas. METHODS: The authors retrospectively reviewed 275 percutaneous thrombectomy procedures in AV fistulas. Procedures included were thrombectomy using devices with hydrodynamic mechanism, the AngioJet rheolytic catheter (AngioJet) (n = 134) or devices with rotational mechanism, the Arrow-Trerotola percutaneous thrombectomy device (PTD) (n = 141). Measured outcomes included clinical success, complications and patency rates. RESULTS: Clinical success was achieved in 76% (102 of 134) of the AngioJet procedures and in 91% (128 of 141) of the PTD procedures (P = 0.002). The procedure time for the PTD method was significantly shorter than that of the AngioJet method (52 vs. 88 min, P < 0.001). Complications occurred in 14% of the AngioJet procedures and 11% of the PTD procedures. The post-intervention primary patency rates at 6 months were 45% for the AngioJet group and 43% for the PTD group (P = 0.70). The postintervention secondary patency rates at 1 year were 74% for the AngioJet group and 87% for the PTD group (P = 0.01). CONCLUSIONS: For the salvage of thrombosed AV fistulas, a device using rotational mechanism is more time-saving with a higher immediate success rate and secondary patency rate. However, the long-term patency results were not different. PMID- 22511561 TI - Factors controlling the diffusion of ions in ionic liquids. AB - The development of ionic liquids with low viscosity and high ionic conductivity is important for many applications of ionic liquids, such as their use as electrolytes for electronic devices. The transport properties depend on the motion of ions in ionic liquids. The viscosity becomes low and the ionic conductivity becomes high as the diffusion of ions becomes fast. Therefore the elucidation of the factors controlling the diffusion of ions is needed for developing new ionic liquids. In this Minireview we discuss the factors controlling the diffusion of ions in ionic liquids (size of ion; shape of ion; magnitude of interaction between cation and anion; conformational flexibility; molecular mass of ion; mixture of solute; and the effects of nanostructures in ionic liquids). We emphasize the importance of the use of computational methods (molecular dynamic simulations and quantum mechanical calculations) combined with experimental measurements for elucidating the factors controlling the diffusion of ions in ionic liquids. PMID- 22511562 TI - Familial Pelizaeus-Merzbacher disease caused by a 320.6-kb Xq22.2 duplication and the pathological findings of a male fetus. AB - BACKGROUND: Pelizaeus-Merzbacher disease (PMD) is a recessive, X-linked leukoencephalopathy attributed to impaired myelination during central nervous system development, caused by defects in the proteolipid protein 1 (PLP1) gene. PMD presents clinical variability, ranging from the severe connatal form to the classic form. CASES: We report the clinical and molecular findings of two affected males, three carrier females, and an aborted male fetus with familial PMD. The two male probands presented with severe PMD phenotype and intellectual disability. High-resolution oligonucleotide-based array comparative genomic hybridization (aCGH) identified an Xq22.2 duplication of 320.6 kb (102641391 102961998, hg18), including the PLP1 gene and surrounding chromosomal region. Postmortem examination of the aborted fetus at 25 weeks' gestation showed focal subcortical white matter degeneration, focal gliosis, and cerebellar atrophy. CONCLUSIONS: Genotype-phenotype correlation is provided. In the connatal form of PMD, leukodystrophy and cerebellar atrophy can occur antenatally and be established at 25 weeks' gestation. The observation of degenerative brain lesions occurring before the onset of subcortical myelination suggests that the PLP1 gene has a more complex role in human brain development, exceeding its structural function in myelin formation. PMID- 22511564 TI - Topical antiinflammatory activity of essential oil of Lippia sidoides cham: possible mechanism of action. AB - This work reports the chemical composition of the essential oil of Lippia sidoides (EOLS) and evaluation of the topical effect of EOLS and thymol against different irritant agents in vivo. The essential oil was obtained by hydrodistillation, and gas chromatography/mass spectrometry analysis identified the main constituents: thymol (84.9%) and p-cymene (5.33%). The antiinflammatory activity was evaluated using the mouse models of acute ear inflammation induced by croton oil, arachidonic acid, phenol or histamine, and chronic inflammation induced by croton oil. The topical application of EOLS or thymol at a dose of 2 mg/ear significantly reduced (p < 0.001) ear edema induced with arachidonic acid by 45.1% and 47.4% and reduced ear edema induced with phenol by 33.2% (p < 0.05) and 54.7% (p < 0.01) in acute ear edema. However, a proinflammatory effect of EOLS and thymol was evidenced when it was applied for more than 1 day. There were no statistical differences in antiedematogenic activity between EOLS and thymol. In conclusion, the results indicate that thymol is the constituent responsible for the topical antiinflammatory activity of EOLS. Thus, these findings could justify the popular use of L. sidoides by alternative medicine, but chronic use has an inflammatory effect. PMID- 22511563 TI - Associations between aggressive behaviour scores and cardiovascular risk factors in childhood. AB - OBJECTIVE: To examine the influence of aggressive behaviour scores on cardiovascular disease (CVD) risk factors throughout childhood. METHODS: This study utilized cross-sectional and longitudinal data from the Western Australian Pregnancy Cohort (Raine) Study (n = 2900). Aggressive behaviour scores were derived from the Child Behavior Checklist/4-18(CBCL), Youth Self-Report/11-18 (YSR) and Teacher Report Form/6-18 (TRF). CVD risk factors included body mass index (BMI), blood pressure, fasting lipids and homeostasis model of insulin resistance (HOMA-IR). RESULTS: Girls with higher aggressive behaviour scores had higher BMI from 10 years of age (P <= 0.001), higher BMI trajectories throughout childhood (P = 0.0003) and at 14 years higher HOMA-IR (P = 0.008). At the 14-year survey, this equated to a difference of 1.7 kg/m2 in the predicted BMI between the extreme CBCL scores in girls (top 5% (CBCL >= 17) vs. CBCL score = 0). Boys with higher aggressive behaviour scores had higher BMI at 5 years (P = 0.002), lower diastolic pressure at 14 years (P = 0.002) and lower systolic blood pressure trajectories throughout childhood (P = 0.016). CONCLUSION: Aggressive behaviour influences BMI from early childhood in girls but not boys. If this association is causal, childhood offers the opportunity for early behavioural intervention for obesity prevention. PMID- 22511565 TI - Interplay between cationic and neutral species in the rhodium-catalyzed hydroaminomethylation reaction. AB - The reactivity of [Rh(CO)(2){(R,R)-Ph-BPE}]BF(4) (2) toward amine, CO and/or H(2) was examined by high-pressure NMR and IR spectroscopy. The two cationic pentacoordinated species [Rh(CO)(3) {(R,R)-Ph-BPE}]BF(4) (4) and [Rh(CO)(2)(NHC(5)H(10)){(R,R)-Ph-BPE}]BF(4) (8) were identified. The transformation of 2 into the neutral complex [RhH(CO)(2){(R,R)-Ph-BPE}] (3) under hydroaminomethylation conditions (CO/H(2), amine) was investigated. The full mechanisms related to the formation of 3, 4 and 8 starting from 2 are supported by DFT calculations. In particular, the pathway from 2 to 3 revealed the deprotonation by the amine of the dihydride species [Rh(H)(2)(CO)(2){(R,R)-Ph BPE}]BF(4) (6), resulting from the oxidative addition of H(2) on 2. PMID- 22511566 TI - Structural study at the gas-liquid interface of 1-alkyl-3-methylimidazolium alkylsulfates using surface potential measurements. AB - Sum frequency generation, surface potential, and surface tension measurements have been combined on the pure ionic-liquid-gas interface for 1-alkyl-3 methylimidazolium alkylsulfate ionic liquids. The results show that surface potential of the ionic liquid generally increases as the alkyl chain on the cation or anion increases in length. This is due to the increased ordering of the surface dipole, mostly coming from the terminal methyl group of the alkyl chain. Both sum frequency generation spectroscopy and surface potential measurements suggest that the charged components, that is, the aromatic ring and the sulfate, occupy nearly the same plane at the surface for all ionic liquids studied herein. PMID- 22511567 TI - Angiographically confirmed stent thrombosis in contemporary practice: insights from intravascular ultrasound. AB - OBJECTIVE: We hypothesized that patients presenting with stent thrombosis (ST) have a high prevalence of stent underexpansion and malapposition when assessed by intravascular ultrasound (IVUS). BACKGROUND: IVUS can provide mechanistic insight into mechanical factors, including stent underexpansion, malapposition, and fracture that may predispose to ST. METHODS: All consecutive cases of angiographically confirmed ST from a multicenter registry (from 2005 to 2010) were reviewed. All IVUS images were reviewed off-line for the presence of stent underexpansion, malapposition, and fracture. Kaplan-Meier analysis was used to determine whether use of IVUS at the time of ST was associated with long-term mortality and major adverse cardiovascular events. RESULTS: IVUS was performed in 32 of 173 subjects with ST (18%). Stent underexpansion was present in 82% of cases and in all cases of early ST, with a mean stent expansion of 0.7 +/- 0.23 by MUSIC criteria. Stent malapposition was most frequently observed in very late ST (40%). In-hospital mortality was similar between subjects who had IVUS performed at the time of ST when compared with the non-IVUS group (3.2% vs. 4.3%, P = 0.8). Subjects who had IVUS performed at the time of ST had lower rates of mortality (HR 0.4, 95% CI 0.1-1.6, P =0.2) and major adverse cardiovascular events (HR 0.5, 95% CI 0.2-1.4, P =0.2) at follow-up, but these values were not statistically significant. CONCLUSIONS: There is a high prevalence of stent underexpansion in early ST, while the prevalence of malapposition is higher in very late ST. Use of IVUS during treatment for ST may identify mechanisms underlying the development of ST. PMID- 22511568 TI - Malignant pleural mesothelioma in a child with ataxia-telangiectasia. AB - Ataxia-telangiectasia (AT) is a hereditary disorder characterized by progressive neurological dysfunction, oculocutaneous telangiectasia, immunodeficiency, cancer susceptibility, and radiation sensitivity. Pleural neoplasms are extremely rare in the pediatric population, even in patients with AT. We describe the case of a 16-year-old male with AT who developed a malignant pleural mesothelioma (MPM). Benign or infectious lung and pleural diseases are common in those with AT. Hence, delayed diagnosis of respiratory neoplasms can occur in these patients. This report highlights the need of heightened vigilance in patients with AT with recurrent or persistent pleuropulmonary disease. To our knowledge, no other cases of MPM in children with AT have been reported. PMID- 22511569 TI - Novel use of the Mguard mesh-covered stent to treat coronary arterial perforations. AB - Covered stents seem to be an effective tool to seal severe perforations that have persisted despite prolonged balloon inflation. However, the high profile and low flexibility of previous covered stents compromise the deliverability of these devices, particularly in emergency situations. The Mguard stent (InspireMD, Tel Aviv, Israel) is a novel mesh-covered stent that has been designed to prevent distal embolization in thrombotic lesions. We herein report two cases that describe a new potential use of the Mguard stent for sealing perforations in coronary circulation. PMID- 22511570 TI - Randomized prospective study of a work place ergonomic intervention for individuals with rheumatoid arthritis and osteoarthritis. AB - OBJECTIVE: To conduct a longitudinal randomized controlled trial comparing a work place ergonomic intervention versus a control (i.e., provision of written educational materials) for persons with rheumatoid arthritis (RA) or osteoarthritis (OA) regarding employment, physical, and symptom outcomes. METHODS: Eighty-nine participants (mean age 50.54 years, 87% women, 38% with RA, 62% with OA) were randomized into the intervention or control group. Seventy-five participants completed baseline, 12-month, and 24-month evaluations. Outcome measures included Arthritis Impact Measurement Scales 2 (AIMS2) physical, symptom (i.e., pain), and role scores (i.e., impact of arthritis on employment); Job Satisfaction Survey (JSS); and Brief Symptom Inventory Global Severity Index. The study design was a 2-factor (treatment and time) with repeated measures on 1 factor (time) design used with baseline as a covariate for 12- and 24-month data. RESULTS: Between-group analyses indicated differences at 24 months for the AIMS2 role score (P < 0.03), with the intervention group reporting less arthritis related impact on their work. Within-group analyses indicated significant improvements for the intervention group in AIMS2 change scores for physical functioning and symptom variables at 12 months (P < 0.04 and P < 0.01, respectively) and 24 months (P < 0.01 and P < 0.01, respectively). Job satisfaction (JSS) decreased at 12 months for both the intervention (P < 0.01) and control groups (P < 0.01), and at 24 months for the control group (P < 0.01). CONCLUSION: An ergonomic work place intervention (versus a control) is associated with decreased arthritis-related work difficulties over 2 years for individuals with OA and RA, as well as improvements in physical functioning and pain. PMID- 22511571 TI - Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"? AB - Melatonin (N-acetyl-5-methoxytryptamine) is a multifunctional signaling molecule that has a variety of important functions. Numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. Clinical trials have shown that melatonin is efficient in preventing cell damage under acute (sepsis, asphyxia in newborns) and chronic states (metabolic and neurodegenerative diseases, cancer, inflammation, aging). The beneficial effects of melatonin can be explained by its properties as a potent antioxidant and antioxidant enzyme inducer, a regulator of apoptosis and a stimulator of immune functions. These effects support the use of melatonin in viral infections, which are often associated with inflammatory injury and increases in oxidative stress. In fact, melatonin has been used recently to treat several viral infections, which are summarized in this review. The role of melatonin in infections is also discussed herein. PMID- 22511572 TI - Paclitaxel-coated balloon with bare-metal stenting in patients with chronic total occlusions in native coronary arteries. AB - OBJECTIVES: We sought to evaluate the efficacy and safety of paclitaxel-coated balloon plus bare-metal stenting (BMS) in chronic total occlusions (CTOs). BACKGROUND: Drug-eluting stent implantation after recanalization of CTOs is limited by the occurrence of restenosis and risk for late stent thromboses. METHODS: In this prospective, bicenter trial we treated 48 patients after successful chronic total occlusion (CTO) recanalization in a native coronary artery with paclitaxel-coated balloon plus BMS. Patients were matched according to stent length, reference diameter, and diabetes mellitus with 48 patients treated with Taxus stent implantation. Dual antiplatelet therapy was prescribed for 6 months. Angiographic (clinical) follow-up was obtained after 6 (12) months. Primary endpoint was in-stent late lumen loss. RESULTS: There was no difference in patient baseline characteristics or procedural results. Stent length was 59.7 +/- 32.4 mm (16-151 mm) for paclitaxel-coated balloon plus BMS versus 56.2 +/- 25.9 mm (16-132 mm) for Taxus stent. Late loss was statistically not different within the stent with 0.64 +/- 0.69 mm versus 0.43 +/- 0.64 mm (difference 0.20 mm, 95% confidence interval -0.07 to 0.47, P = 0.14) and at the occlusion site with 0.33 +/- 0.69 mm versus 0.26 +/- 0.70 mm, respectively. Restenosis rate was 27.7% compared with 20.8% (P = 0.44) and the combined clinical endpoint (cardiac death, myocardial infarction attributed to the target vessel, target lesion revascularization) was 14.6% versus 18.8% (P = 0.58), respectively. CONCLUSIONS: In conclusion, for patients with complex CTOs in native coronary arteries the use of paclitaxel-coated balloon after bare-metal stenting was associated with similar clinical results and a nonsignificantly higher in-stent late loss compared with a matched population with paclitaxel-eluting stent implantation. PMID- 22511573 TI - Flexible nanogenerators based on graphene oxide films for acoustic energy harvesting. PMID- 22511574 TI - Utilization of antidepressants in Taiwan: a nationwide population-based survey from 2000 to 2009. AB - OBJECTIVE: This study examined trends in antidepressant utilization in Taiwan between 2000 and 2009. METHODS: We collected data from the National Health Insurance Research Database of all incident antidepressant use. We described the incidence, prevalence, and therapeutic indications of antidepressant use. We tested the trends by using logistic regression analyses with adjustment for age and sex. RESULTS: Overall, the prevalence of antidepressant use per 1000 persons increased from 32.1 in 2000 to 46.3 in 2009; however, the incidence per 1000 persons declined from 20.8 in 2000 to 16.5 in 2009. For antidepressant classes, the prescriptions of selective serotonin reuptake inhibitors and other new agents increased during the study periods; however, the use of tricyclic antidepressants, trazodone, and monoamine oxidase inhibitors declined. For therapeutic indications, we found increasing trends of antidepressant use for sleep and adjustment disorders; however, the rates of antidepressant use for mood disorder, anxiety disorders, and non-psychiatric conditions decreased. CONCLUSIONS: Regarding the new use of antidepressants in Taiwan between 2000 and 2009, we found that the decreased incidence of antidepressant use might be attributed mainly to the decreased use of tricyclic antidepressants and monoamine oxidase inhibitors. Decreased use among middle-aged and older persons and fewer antidepressant prescriptions for non-psychiatric conditions were also noted. PMID- 22511576 TI - Surface modification of nanodiamond under Bingel-Hirsch conditions. AB - The Bingel-Hirsch reaction consists in the reaction of a bromomalonate with electron-poor pi bonds, for example, of carbon materials, yielding cyclopropane derivatives. The reactive nucleophile is generated in situ from the respective malonate using CBr(4) and a base. The resulting cyclopropane moiety links the carbon material's surface atoms covalently with the functional side groups of the malonate. So far, the reaction was limited to fullerenes and carbon nanotubes. Herein, we report on the first application of this reaction type for the surface modification of diamond nanoparticles. The surface of thermally annealed nanodiamond consists of fullerene-like sp(2) carbon atoms which exhibit a similar reactivity as those in the all-sp(2) carbon nanomaterials. It was found that the reaction proceeds smoothly and enables the grafting of a large variety of functional groups to the surface of nanodiamond. The generated nucleophiles are also able to react with carbonyl species on the diamond. This reaction pathway enables the grafting of malonates even on oxidized nanodiamond without prior thermal annealing. PMID- 22511575 TI - Contemporary use of adjunctive thrombectomy during primary percutaneous coronary intervention for ST-elevation myocardial infarction in the United States. AB - OBJECTIVES: We sought to examine the contemporary use of thrombectomy during primary percutaneous coronary intervention (PCI) in the United States. BACKGROUND: Adjunctive thrombectomy during primary PCI for patients with ST segment elevation myocardial infarction (STEMI) has demonstrated mixed results. While earlier studies showed either unfavorable or neutral effects with rheolytic thrombectomy, recent clinical trials have shown benefits with manual or rheolytic thrombectomy when compared to PCI alone. METHODS: We analyzed data from 122,449 patients undergoing primary PCI for STEMI from 1,181 centers reported to the CathPCI Registry(r) between July 2009 and December 2010. We used logistic regression analysis to examine factors associated with the use of manual and rheolytic thrombectomy. RESULTS: Thrombectomy was performed in 23,195 patients (18.9%): 22,404 (18.3%) had manual thrombectomy and 791 (0.6%) had rheolytic thrombectomy. The use of manual thrombectomy increased over time (P < 0.05). The use of rheolytic thrombectomy did not change. There was significant variation in the use of thrombectomy across hospitals. The strongest predictors of manual versus no thrombectomy included TIMI 0/1 flow (odds ratio 1.69), younger age (OR 0.90 per 10 year increase), saphenous vein graft (OR 2.22), glycoprotein IIb/IIIa inhibitor (OR 1.34), single-vessel disease (OR 1.13), and year of admission (OR 1.20 per year; all P < 0.001). The strongest predictor of manual versus rheolytic thrombectomy was year of admission (OR 1.23, P < 0.001). CONCLUSIONS: Our data show that thrombectomy is performed infrequently in the US during primary PCI for STEMI. There is significant variation in the use of thrombectomy across US hospitals. PMID- 22511577 TI - Clinical safety, pharmacokinetics, and efficacy of ambrisentan therapy in children with pulmonary arterial hypertension. AB - Recent trials in adult PAH revealed the efficacy of ambrisentan. However, in children with PAH, the clinical safety and pharmacokinetics of ambrisentan has not been well studied. Our aim was to investigate the clinical safety, pharmacokinetics, tolerability, and efficacy of endothelin receptor antagonist therapy with ambrisentan in children with pulmonary arterial hypertension (PAH). This retrospective cohort study provides clinical data from pediatric patients with PAH receiving ambrisentan as add-on therapy or transition from bosentan. Safety included evaluation of adverse events including aminotransferase abnormalities. The clinical impact was evaluated by improvement from baseline in clinical variables. A total of 38 pediatric patients with PAH received ambrisentan. Fifteen of 38 patients were switched from bosentan to ambrisentan. The remaining 23 children were treated with ambrisentan as an add-on therapy due to disease progression. In both transition and add-on cases, mean pulmonary artery pressure significantly improved (transition; 55 +/- 18 vs. 45 +/- 20 mmHg, n = 13, P = 0.04, add-on; 52 +/- 17 vs. 45 +/- 19 mmHg, n = 13, P = 0.03) during the follow-up. World Health Organization functional class improved in 31% of patients, but one patient required an atrial septostomy due to disease progression during the follow-up period (median, range; 20, 4-44 months). Five patients (13%) discontinued ambrisentan due to severe headache, lack of clinical efficacy, or near syncope. Ten patients (26%) had side effects associated with ambrisentan treatment, including nasal congestion, headache, and flushing. However, no patients had aminotransferase abnormalities and there were no deaths after initiation of ambrisentan during follow-up. Pharmacokinetics were evaluated in sixteen children treated with ambrisentan from 2.5 mg to 10.0 mg; the mean peak plasma concentration was 738 +/- 452 ng/ml, mean time to peak plasma concentration was 3.2 +/- 2.1 hours, and mean area under the curve plasma concentration was 6657 +/- 4246 ng.hour/ml. In conclusion, initial experience with ambrisentan in children suggests that treatment is safe with similar pharmacokinetics to those in adults and may improve PAH in some children. PMID- 22511578 TI - Postmenopausal hormone therapy is associated with a reduced risk of colorectal cancer lacking CDKN1A expression. AB - Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell-cycle regulators. However, epidemiologic studies evaluating hormone therapy use and colorectal cancer risk by the status of cell cycle regulators are lacking. In this study, we used data from the prospective Nurses' Health Study to evaluate whether the association between hormone therapy use and colorectal cancer risk differs by the molecular pathologic status of microsatellite instability (MSI) and expression of cell-cycle-related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between hormone therapy use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105,520 postmenopausal women. We found a difference between hormone therapy use and colorectal cancer risk according to CDKN1A expression (P(heterogeneity) = 0.01). Current hormone therapy use was associated with a reduced risk for CDKN1A-nonexpressed [multivariate relative risk (RR), 0.61; 95% confidence interval (CI), 0.46-0.82] but not for CDKN1A-expressed (RR, 1.32; 95% CI, 0.76-2.31) tumors. The lower risk for CDKN1A-nonexpressed but not for CDKN1A-expressed cancers was also present among current users of estrogen alone therapy. We found no significant difference in the relations between hormone therapy use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular pathological epidemiology findings suggest a preventive effect of hormone therapy against colorectal carcinogenesis that depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A. PMID- 22511579 TI - LIGHT delivery to tumors by mesenchymal stem cells mobilizes an effective antitumor immune response. AB - Bone marrow-derived mesenchymal stem cells (MSC) have been shown to home into tumor tissues, where they promote tumor growth and suppress immune rejection. In this study, we tested whether MSCs engineered to express the immune stimulating factor LIGHT, a member of the TNF superfamily, could induce tumor regression. Using in vitro and in vivo migration assays, we found that LIGHT-expressing MSCs (MSC-L) displayed a strong tropism for tumor tissues. MSC-L treatment activated the LIGHT-signaling pathway, effectively organizing a potent antitumor immune response that stimulated an influx of T cells and inhibited tumor growth in vivo. CD4 T cells were found to play a role in the induction phase of the immune response, and CD8 T cells were shown to be essential for the effector phase. Together, our findings indicate that MSCs can effectively home into and deliver immune stimulating molecules to tumor tissues, thereby reversing the immune suppressive environment, promoting antitumor immunity, and inhibiting tumor growth. PMID- 22511580 TI - MEK1/2 inhibition elicits regression of autochthonous lung tumors induced by KRASG12D or BRAFV600E. AB - Genetically engineered mouse (GEM) models of lung tumorigenesis allow careful evaluation of lung tumor initiation, progression, and response to therapy. Using GEM models of oncogene-induced lung cancer, we show the striking similarity of the earliest stages of tumorigenesis induced by KRAS(G12D) or BRAF(V600E). Cre mediated expression of KRAS(G12D) or BRAF(V600E) in the lung epithelium of adult mice initially elicited benign lung tumors comprising cuboidal epithelial cells expressing markers of alveolar pneumocytes. Strikingly, in a head-to-head comparison, oncogenic BRAF(V600E) elicited many more such benign tumors and did so more rapidly than KRAS(G12D). However, despite differences in the efficiency of benign tumor induction, only mice with lung epithelium expression of KRAS(G12D) developed malignant non-small cell lung adenocarcinomas. Pharmacologic inhibition of mitogen-activated protein (MAP)-extracellular signal-regulated kinase (ERK) kinase (MEK)1/2 combined with in vivo imaging showed that initiation and maintenance of both BRAF(V600E)- or KRAS(G12D)-induced lung tumors was dependent on MEK->ERK signaling. Although the tumors dramatically regressed in response to MEK1/2 inhibition, they regrew following cessation of drug treatment. Together, our findings show that RAF->MEK->ERK signaling is both necessary and sufficient for KRAS(G12D)-induced benign lung tumorigenesis in GEM models. The data also emphasize the ability of KRAS(G12D) to promote malignant lung cancer progression compared with oncogenic BRAF(V600E). PMID- 22511582 TI - Role of exercise for knee pain: what do older adults in the community think? AB - OBJECTIVE: Older adults with knee pain report low levels of exercise and physical activity. One explanation for this might be that they believe exercise is unhelpful or even harmful for knee pain. We therefore explored the attitudes and beliefs of older adults in the community about the role of exercise for knee pain using mixed methods. METHODS: A survey was mailed to 2,234 older adults registered with 1 general practice within the UK. The survey included 23 attitude statements derived from published exercise recommendations. Semistructured interviews were completed in a purposeful sample of questionnaire responders (n = 22) and were recorded and analyzed thematically. RESULTS: The questionnaire response rate was 59% (n = 1,276), and 611 respondents reported knee pain in the past 12 months. There was considerable uncertainty about the benefits of exercise; <50% largely or totally agreed on any attitude statement relating to the benefit of exercise for knee pain. The interviews revealed that attitudes and beliefs about exercise for knee pain are linked to the individuals' perceptions about their knee problems, and that many different barriers and facilitators to exercise and physical activity exist. These barriers and facilitators could be grouped as those relating to the person, the knee problem itself, and social or environmental factors. Barriers and facilitators varied between different individuals and over time. CONCLUSION: The overall uncertainty within the community about the role of exercise for knee pain highlights the challenges faced by those living with knee pain in completing physical activity, and for health care professionals prescribing exercise for this patient group. PMID- 22511581 TI - Adipokines linking obesity with colorectal cancer risk in postmenopausal women. AB - Mechanistic associations between obesity and colorectal cancer remain unclear. In this study, we investigated whether adipokines are risk factors for colorectal cancer and whether they may mediate its association with obesity. In a case cohort study nested within the Women's Health Initiative cohort of postmenopausal women, baseline plasma samples from 457 colorectal cancer cases and 841 subcohort subjects were assayed for seven adipokines-adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, hepatocyte growth factor, interleukin-6 (IL-6), and TNF-alpha. Serum insulin and estradiol values measured previously were also available for data analysis. After adjusting for age, race, smoking, colonoscopy history, and estrogen level, a low level of anti-inflammatory adiponectin and high levels of proinflammatory leptin, PAI-1, and IL-6 were associated with increased colorectal cancer risk, though only leptin remained significant after further adjustment for insulin [HRs comparing extreme quartiles (HR(Q4-Q1)), 1.84; 95% CI, 1.17-2.90]. Mediation analyses showed that leptin and insulin partially explained the association between waist circumference and colorectal cancer and attenuated it by 25% and 37%, respectively, with insulin being a significant mediator (P = 0.041). Our findings support the conclusion that adipokines involved in inflammation are associated with colorectal cancer risk, but that their effects may be mediated mostly by insulin, with leptin exerting an independent effect. Hyperinsulinemia and hyperleptinemia may therefore partially explain the adiposity association with colorectal cancer in postmenopausal women. PMID- 22511583 TI - Hirschsprung's disease in the North of England: prevalence, associated anomalies, and survival. AB - INTRODUCTION: Hirschsprung's disease is the commonest congenital gut motility disorder, characterized by the absence of the enteric ganglion cells along the distal gut, which causes intestinal obstruction. Few publications report its epidemiology and temporal trends. METHODS: Cases of Hirschsprung's disease delivered during 1990 to 2008 in the North of England reported to the Northern Congenital Abnormality Survey (NorCAS) formed this population-based case series. RESULTS: Of 612,916 live births, 105 cases were reported to NorCAS. After excluding one diabetic and four multiple pregnancies, the live birth prevalence was 1.63 (95% confidence interval [CI], 1.33-1.98) per 10,000 live births. There was a significant temporal increase in the prevalence of Hirschsprung's disease (p = 0.020), from 1.26 (95% CI, 0.80-1.89) in 1990 to 1994 to 2.29 (95% CI, 1.53 3.29) in 2005 to 2008. The ratio of male to female cases was 2:1. Ten (10.0%) cases occurred with Down syndrome, one with Smith-Lemli-Opitz Syndrome, and six (6.0%) with associated structural anomalies. The remaining 83 (83.0%) cases were isolated. All cases were live born, but nine (9.0%) died in the first year of life. Hirschsprung's disease was not prenatally suspected in any case. Half the cases were diagnosed within 5 days postpartum, but time of diagnosis ranged from birth to 5 years of age. CONCLUSION: This study confirmed a male predominance and an association with Down syndrome, but also found a temporal increase in Hirschsprung's disease prevalence. No cases were suspected prenatally, but half were diagnosed within 5 days of life. PMID- 22511584 TI - Left ventricular end-diastolic pressure as an independent predictor of outcome during balloon aortic valvuloplasty. AB - OBJECTIVES: In this study, we examined the predictive value of the left ventricular end-diastolic pressure (LVEDP) in patients undergoing balloon aortic valvuloplasty (BAV). BACKGROUND: The LVEDP is a useful indicator of hemodynamic status in patients with severe aortic stenosis. In BAV, decompensated heart failure is associated with worse outcomes. METHODS: We identified all consecutive patients with severe symptomatic aortic stenosis who underwent retrograde BAV at the Massachusetts General Hospital from 2004 to 2008. Patients were stratified and compared according to their baseline LVEDP into <=15 mm Hg, 16-20 mm Hg, 21 25 mm Hg, and >=26 mm Hg. Procedural and in-hospital outcomes and adverse events were compared. Multivariate logistic regression was used for the adjusted analysis. RESULTS: A total of 111 patients with a mean age of 83+/-11 years underwent BAV. Of these, the LVEDP was <=15 mm Hg in 29 (26%), 16-20 mm Hg in 41 (37%), 21-25 mm Hg in 16 (14%), and >=26 mm Hg in 25 (23%) patients. Baseline characteristics were similar among the four groups. Noticeably, patients with high LVEDP levels had significantly higher rates of the combined endpoint of in hospital death, myocardial infarction (MI), cardiopulmonary arrest, and tamponade was P = 0.02. Periprocedural MI was more common among those with higher LVEDP (16% vs. 2.3%; P = 0.04). Multivariate analysis revealed LVEDP (OR 1.08, for each mm Hg increase in pressure, 95 % CI 1.02-1.14), small LV chamber size, and New York Heart Association class as independent predictors of adverse outcomes. CONCLUSIONS: The LVEDP is an important independent predictor of poor in-hospital outcome during BAV. In these patients, the immediate hemodynamic status may be more important than the baseline left ventricular systolic function. Hemodynamic optimization before or during BAV should be considered and may be beneficial. PMID- 22511585 TI - Kelvin probe force microscopy study of a Pt/TiO2 catalyst model placed in an atmospheric pressure of N2 environment. AB - A catalyst model comprising platinum nanoparticles deposited on a TiO(2)(110) wafer was prepared in a vacuum, transferred in air, and characterized with a Kelvin probe force microscope placed in a N(2) environment. The topography and local work function of individual nanoparticles were observed with single nanometer resolution in the N(2) environment of one atmosphere pressure. Some nanoparticle presented positive shifts of work function relative to that of the TiO(2) surface, while the others showed negative shifts. This finding suggests heterogeneous properties of the nanoparticles exposed to air and then N(2). The ability of the advanced microscope was demonstrated in observing the work function of metal nanoparticles on a metal oxide support even in the presence of vapor environments. PMID- 22511586 TI - Metal-catalyzed one-pot synthesis of tetrazines directly from aliphatic nitriles and hydrazine. PMID- 22511587 TI - Embolic protection device utilization during stenting of native coronary artery lesions with large lipid core plaques as detected by near-infrared spectroscopy. AB - BACKGROUND: Stenting of large lipid core plaques (LCPs), as assessed by near infrared spectroscopy (NIRS), has been associated with periprocedural myocardial infarction (MI), possibly due to distal embolization. METHODS: An embolic protection device (EPD) was inserted before stenting in nine native coronary arteries with large LCP, as assessed by NIRS. Embolized material was assessed by histopathology. RESULTS: Mean age was 64 +/- 7 years and all patients were men. The target lesion was located in the right (67%) or left anterior descending (33%) coronary artery. A filter was utilized in eight patients (89%) and proximal embolic protection in one (11%). In one patient two filters were required because the originally placed filter became obstructed with debris after initial stent placement. The mean percent angiographic stenosis prestenting and poststenting was 87% +/- 9% and 2% +/- 4%, respectively and final TIMI 3 flow was achieved in all patients. Embolized material was retrieved in eight of nine patients (89%) and consisted mainly of platelet and fibrin thrombi. The mean target segment lipid core burden index decreased from 395 +/- 114 before stenting to 152 +/- 106 after stenting (P < 0.001) and the lesion angular extent decreased from 312 degrees +/- 70 degrees to 240 degrees +/- 90 degrees (P = 0.07). Postprocedural MI occurred in two of nine patients (22%), in one of whom two filters were required. CONCLUSION: Use of EPDs frequently resulted in embolized material retrieval after stenting of native coronary artery lesions with large LCPs. These findings support further study of EPDs as a means to prevent poststenting MI. PMID- 22511588 TI - Association of arterial events with the coexistence of metabolic syndrome and primary antiphospholipid syndrome. AB - OBJECTIVE: Metabolic syndrome (MetS) is highly prevalent in rheumatic diseases and is recognized as a new independent cardiovascular risk factor. This study was undertaken to determine the clinical significance of MetS in patients with primary antiphospholipid syndrome (APS). METHODS: Seventy-one primary APS patients and 73 age- and sex-matched healthy controls were included. Serum samples were tested for lipid profile, Lp(a), glucose, insulin, thyroid stimulating hormone, free T4, erythrocyte sedimentation rate, C-reactive protein level, and uric acid. MetS was defined by the International Diabetes Federation criteria, and insulin resistance was established using the homeostasis model assessment index. RESULTS: The prevalence of MetS was 33.8%, and further comparison between primary APS patients with and without MetS revealed that the former had a higher frequency of arterial events (79.2% versus 42.6%; P = 0.003), angina (29.2% versus 2.1%; P = 0.002), and positive lupus anticoagulant antibody (95.8% versus 76.6%; P = 0.049). In addition, primary APS patients with MetS, as expected, had a higher prevalence of cardiovascular risk factors. On multivariate analysis, only MetS was independently associated with arterial events in primary APS. CONCLUSION: Coexistence of primary APS and MetS seems to identify a subgroup of patients with higher risk of arterial events, suggesting that MetS may aggravate existing endothelial abnormalities of primary APS. PMID- 22511589 TI - Primary osteoporosis without features of OI in children and adolescents: clinical and genetic characteristics. AB - Our aim was to characterize clinical findings and familial associations, and to examine candidate genes for disease-causing mutations in a cohort of children suffering from primary osteoporosis without features of osteogenesis imperfecta. Patients with osteoporosis and their nuclear families were studied. Medical history was reviewed. Calcium homeostasis parameters were measured and spinal radiographs obtained. BMD was determined by DXA for patients, parents and siblings. LRP5, LRP6, and PTHLH genes were sequenced. Twenty-seven patients (14 males) from 24 families were recruited. Median age at presentation was 10.1 years (range 3.3-15.6 years). One-third of the children had at least one parent with a BMD below the expected range for age. LRP5, LRP6, and PTHLH showed no causative mutations. Four polymorphisms in LRP5 were overrepresented in patients; the minor allele frequency of Q89R, V667M, N740N, and A1330V was significantly higher than in controls. Age of onset, clinical severity, and inheritance patterns are variable in children with primary osteoporosis. Several patients had evidence suggestive of familial transmission. The underlying genetic factors remain to be elucidated. PMID- 22511590 TI - Clinical outcomes after bare-metal stenting in diabetic patients with lesions carrying a low risk of restenosis. AB - OBJECTIVE: To evaluate the clinical results of diabetic patients undergoing percutaneous coronary intervention (PCI) for coronary artery lesions carrying a low risk of restenosis treated with a bare-metal stent (BMS). BACKGROUND: There is a discrepancy between current international guidelines on the use of BMS in diabetics with low risk of restenosis coronary artery lesions. METHODS AND RESULTS: Registry data from diabetic patients who underwent non-urgent PCI in a high-volume tertiary referral hospital in the Netherlands was used. The main outcomes were target lesion revascularization (TLR) and the composite of cardiac death, myocardial infarction, and target vessel revascularization at 1-year of follow-up. A total of 1,951 patients were included, of which 1,596 non-diabetics (non-DM), 231 non-insulin requiring diabetics (NIRDM), and 124 insulin requiring diabetics (IRDM).TLR rates in non-DM versus NIRDM were similar (6.3% vs. 5.6%; P = 0.68), whereas TLR in IRDM was higher (6.3% vs. 11.3%; P = 0.03). The composite of cardiovascular clinical outcomes was not significantly different in non-DM versus NIRDM (9.5% vs. 13.4%; P = 0.07), though in IRDM the incidence was higher (9.5% vs. 17.7%; P < 0.01). CONCLUSION: No differences were observed in TLR or composite clinical endpoint at 1-year between non-DM and NIRDM after BMS placement in coronary artery lesions carrying a low risk of restenosis. The presence of IRDM was associated with higher TLR rates when treated with BMS. These results imply that BMS placement may be considered in patients with NIRDM but further work is required to define treatment strategies and, more importantly, improve the outcomes in diabetics. PMID- 22511591 TI - Aerobic amide bond formation with N-hydroxysuccinimide. AB - Breathe easy: Molecular oxygen is one of the most abundant, atom-efficient, and economical oxidants. An aerobic oxidative amide formation from aldehydes and amines is reported. The method uses a catalytic amount of Co(OAc)(2) and N hydroxysuccinimide as reaction promoters. It is applicable to chiral substrates without loss of their optical purity. PMID- 22511592 TI - Relationship between the intensity of heparin anticoagulation and clinical outcomes in patients receiving glycoprotein IIb/IIIa inhibitors during primary percutaneous coronary intervention in acute myocardial infarction. AB - OBJECTIVES: We sought to determine the impact of the activated clotting time (ACT) in patients with ST elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) with unfractionated heparin (UFH) and a glycoprotein IIb/IIIa inhibitor (GPI). BACKGROUND: UFH+GPI is commonly used during primary PCI for STEMI. UFH anticoagulation is titrated with ACT. METHODS: Patients randomized to UFH+GPI in HORIZONS-AMI who underwent primary PCI are included (N = 1,624). Initial UFH bolus was 60 IU kg(-1) (target ACT: 200-250 sec). Patients were divided into three tertiles of peak ACT (cutoffs 240 and 298 sec). The 30-day rates of major and minor bleeding, major adverse cardiovascular events (MACE), and net adverse clinical events (NACE; MACE or major bleeding) were determined. RESULTS: Mortality at 30 days occurred in 2.2, 3.3, and 3.5% of patients in the low to high ACT tertiles, respectively (P(trend) = 0.22). Nor was the peak ACT significantly related to major bleeding, MACE or NACE. However, minor bleeding was increased in the highest ACT tertile (14.7% vs. 14.2% vs. 19.4%, P(trend) = 0.04). By multivariable analysis peak ACT was not significantly related to major bleeding, mortality, MACE, and NACE but was a significant independent predictor of minor bleeding (odds ratio = 1.027 [1.013, 1.042], P < 0.001, for each 10 sec increase in ACT). CONCLUSIONS: In patients undergoing primary PCI for STEMI treated with UFH+GPI, the peak procedural ACT achieved does not have a substantial effect on major bleeding, mortality, or MACE, although lower peak ACT is associated with less minor bleeding. PMID- 22511595 TI - Hnf1b and Pax2 cooperate to control different pathways in kidney and ureter morphogenesis. AB - The transcription factors HNF1B and Pax2, co-expressed in the Wolffian duct and ureteric bud epithelia, play essential roles during the early steps of mouse kidney development. In humans, heterozygous mutations in these genes display a number of common kidney phenotypes, including hypoplasia and multicystic hypoplastic kidneys. Moreover, a high prevalence of mutations either in HNF1B or PAX2 has been observed in children with renal hypodysplasia. To gain a better understanding of Hnf1b and Pax2 interactions in vivo, we generated compound heterozygous mice for Hnf1b and Pax2 null alleles. We show here that compound heterozygous mutants display phenotypes similar to severe congenital anomalies of the kidney and the urinary tract (CAKUT), including strong hypoplasia of the kidneys, caudal ectopic aborted ureter buds, duplex kidneys, megaureters and hydronephrosis. At a molecular level, compound mutants show a delay in nephron segment and medullar interstitial differentiation, increased apoptosis and a transient decrease in Lim1 and Wnt4 expression. We also observe a perturbation of smooth muscle differentiation around the ureter associated with a local down regulation in transcript levels of Bmp4 and Tbx18, two key regulators involved in ureter smooth muscle formation, thus explaining, at least in part, megaureters. These results together uncover a novel role of Hnf1b as a modifier of the Pax2 haplo-insufficient phenotype and show that these two transcription factors operate in common pathways governing both kidney morphogenesis and ureter differentiation. This mouse model should provide new insights into the pathogenic mechanisms of human CAKUT, the most frequent developmental defect identified in newborns. PMID- 22511596 TI - Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory. AB - People with Down syndrome (DS) exhibit abnormal brain structure. Alterations affecting neurotransmission and signalling pathways that govern brain function are also evident. A large number of genes are simultaneously expressed at abnormal levels in DS; therefore, it is a challenge to determine which gene(s) contribute to specific abnormalities, and then identify the key molecular pathways involved. We generated RCAN1-TG mice to study the consequences of RCAN1 over-expression and investigate the contribution of RCAN1 to the brain phenotype of DS. RCAN1-TG mice exhibit structural brain abnormalities in those areas affected in DS. The volume and number of neurons within the hippocampus is reduced and this correlates with a defect in adult neurogenesis. The density of dendritic spines on RCAN1-TG hippocampal pyramidal neurons is also reduced. Deficits in hippocampal-dependent learning and short- and long-term memory are accompanied by a failure to maintain long-term potentiation (LTP) in hippocampal slices. In response to LTP induction, we observed diminished calcium transients and decreased phosphorylation of CaMKII and ERK1/2-proteins that are essential for the maintenance of LTP and formation of memory. Our data strongly suggest that RCAN1 plays an important role in normal brain development and function and its up-regulation likely contributes to the neural deficits associated with DS. PMID- 22511594 TI - Trisomy for synaptojanin1 in Down syndrome is functionally linked to the enlargement of early endosomes. AB - Enlarged early endosomes have been observed in neurons and fibroblasts in Down syndrome (DS). These endosome abnormalities have been implicated in the early development of Alzheimer's disease (AD) pathology in these subjects. Here, we show the presence of enlarged endosomes in blood mononuclear cells and lymphoblastoid cell lines (LCLs) from individuals with DS using immunofluorescence and confocal microscopy. Genotype-phenotype correlations in LCLs carrying partial trisomies 21 revealed that triplication of a 2.56 Mb locus in 21q22.11 is associated with the endosomal abnormalities. This locus contains the gene encoding the phosphoinositide phosphatase synaptojanin 1 (SYNJ1), a key regulator of the signalling phospholipid phosphatidylinositol-4,5-biphosphate that has been shown to regulate clathrin-mediated endocytosis. We found that SYNJ1 transcripts are increased in LCLs from individuals with DS and that overexpression of SYNJ1 in a neuroblastoma cell line as well as in transgenic mice leads to enlarged endosomes. Moreover, the proportion of enlarged endosomes in fibroblasts from an individual with DS was reduced after silencing SYNJ1 expression with RNA interference. In LCLs carrying amyloid precursor protein (APP) microduplications causing autosomal dominant early-onset AD, enlarged endosomes were absent, suggesting that APP overexpression alone is not involved in the modification of early endosomes in this cell type. These findings provide new insights into the contribution of SYNJ1 overexpression to the endosomal changes observed in DS and suggest an attractive new target for rescuing endocytic dysfunction and lipid metabolism in DS and in AD. PMID- 22511597 TI - Cisplatin nephrotoxicity involves mitochondrial injury with impaired tubular mitochondrial enzyme activity. AB - Cisplatin is a widely used antineoplastic agent. However, its major limitation is dose-dependent nephrotoxicity whose precise mechanism is poorly understood. Recent studies have suggested that mitochondrial dysfunction in tubular epithelium contributes to cisplatin-induced nephrotoxicity. Here the authors extend those findings by describing the role of an important electron transport chain enzyme, cytochrome c oxidase (COX). Immunohistochemistry for COX 1 protein demonstrated that, in response to cisplatin, expression was mostly maintained in focally damaged tubular epithelium. In contrast, COX enzyme activity in proximal tubules (by light microscopy) was decreased. Ultrastructural analysis of the cortex and outer stripe of the outer medulla showed decreased mitochondrial mass, disruption of cristae, and extensive mitochondrial swelling in proximal tubular epithelium. Functional electron microscopy showed that COX enzyme activity was decreased in the remaining mitochondria in the proximal tubules but maintained in distal tubules. In summary, cisplatin-induced nephrotoxicity is associated with structural and functional damage to the mitochondria. More broadly, using functional electron microscopy to measure mitochondrial enzyme activity may generate mechanistic insights across a spectrum of renal disorders. PMID- 22511600 TI - An image analysis method for the precise selection and quantitation of fluorescently labeled cellular constituents: application to the measurement of human muscle cells in culture. AB - The accurate measurement of the morphological characteristics of cells with nonuniform conformations presents difficulties. We report here a straightforward method using immunofluorescent staining and the commercially available imaging program Adobe Photoshop, which allows objective and precise information to be gathered on irregularly shaped cells. We have applied this measurement technique to the analysis of human muscle cells and their immunologically marked intracellular constituents, as these cells are prone to adopting a highly branched phenotype in culture. Use of this method can be used to overcome many of the long-standing limitations of conventional approaches for quantifying muscle cell size in vitro. In addition, wider applications of Photoshop as a quantitative and semiquantitative tool in immunocytochemistry are explored. PMID- 22511598 TI - Enhanced immunoreactivity of TIMP-2 in the stromal compartment of tumor as a marker of favorable prognosis in ovarian cancer patients. AB - Degradation of the extracellular matrix and basement membrane is a critical step in tumor progression. Matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP 2) act in a coordinated manner to form an integrated system involved in ovarian cancer (OC) progression. In this study, the authors describe the expression of TIMP-2 detected by immunohistochemistry in 6 OC cell lines and in 43 malignant epithelial ovarian tumors (in tumor and stromal compartments) in sections originating from primary laparotomies. No significant correlations between overall and progression-free survival and TIMP-2 expression in tumor compartment were observed. The analysis demonstrated a significant association between enhanced stromal expression of TIMP-2 and better clinical response to cisplatin- and paclitaxel-based chemotherapy. Increased expression of TIMP-2 in the stromal compartment and simultaneous overexpression in both stromal and tumor compartments strongly correlated with increased survival. No significant correlations were found in vitro between resistance to cisplatin, paclitaxel, or topotecan and the expression of TIMP-2 in the OC cell lines, suggesting stromal influences on tumor chemoresistance in the physiological environment. This study supports the concept of TIMP-2 expression in the stromal compartment of OC as a promising marker of prognosis and response to cisplatin- and paclitaxel-based chemotherapy in OC patients. PMID- 22511599 TI - Overexpression of sigma1 receptor and its positive associations with pathologic TNM classification in esophageal squamous cell carcinoma. AB - Sigma1 receptor (sigma1R), a significant protein, has been found to be frequently upregulated in human tumor cells and tissues. It has been demonstrated that sigma1R is involved in proliferation and adhesion of cancer cells. However, the significance of sigma1R expression in esophageal squamous cell carcinoma (ESCC) remains unclear. In this article, by a series of methods, the authors examined the expression of sigma1R protein in ESCC cell lines and tissues. Flow cytometry indicated intense staining of sigma1R in ESCC cells. Immunocytochemistry staining demonstrated that sigma1R was mainly distributed in cytoplasm and nucleus in ESCC cell lines. Western blotting was performed to characterize the relative expression of sigma1R in different ESCC cell lines. Moreover, different levels of sigma1R were presented from normal epithelium to carcinoma by immunohistochemistry analysis, which demonstrated that sigma1R was highly expressed in tumors. Association analysis showed significant correlations between total sigma1R protein levels and pathologic TNM (pTNM) classification of tumors (r=0.216, p=0.011). Furthermore, the sigma1R in the nucleus was significantly correlated with pTNM classification and lymph node metastasis (r=0.263, p=0.002, and r=0.269, p=0.002, respectively). These data indicated that sigma1R may serve as a potential predictive factor for pTNM classification and tumor development in ESCC. PMID- 22511601 TI - Clinical implication of elevated human cervical cancer oncogene-1 expression in esophageal squamous cell carcinoma. AB - The human cervical cancer oncogene 1 (HCCR-1), a novel human oncoprotein, has been shown to be upregulated in various human tumors and plays a critical role in tumorigenesis and tumor progression. Here, the authors investigated HCCR-1 level in esophageal squamous cell carcinoma (ESCC) tissues and assessed the correlation between HCCR-1 level and prognosis of the patients with ESCC. HCCR-1 levels were investigated by immunohistochemistry, in situ hybridization, real-time quantitative RT-PCR and Western blotting methods; Kaplan-Meier curve was used to evaluate the prognostic value of HCCR-1 level in patients with ESCC using log rank test. HCCR-1 displayed high levels in ESCC tissues compared to squamous dysplasia tissues and normal esophageal epithelial tissues. No significant correlation was observed between the levels of HCCR-1 mRNA and protein and gender and age (all p>0.05) but obviously related to histological grade, clinical stage, and lymph node metastasis (all p<0.001). Moreover, the survival rate of the patients with low HCCR-1 levels was higher than that of the patients with high HCCR-1 levels (both p<0.05). These data demonstrate that HCCR-1 may be used as a novel predictor for the prognosis of the patients with ESCC. PMID- 22511602 TI - Altered expression of key players in vitamin D metabolism and signaling in malignant and benign thyroid tumors. AB - 1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, mediates antitumor effects in various cancers. The expression of key players in vitamin D signaling in thyroid tumors was investigated. Vitamin D receptor (VDR) and CYP27B1 and CYP24A1 (respectively activating and catabolizing vitamin D) expression was studied (RT-PCR, immunohistochemistry) in normal thyroid, follicular adenoma (FA), differentiated thyroid cancer (DTC) consisting of the papillary (PTC) and follicular (FTC) subtype, and anaplastic thyroid cancer (ATC). VDR, CYP27B1, and CYP24A1 expression was increased in FA and DTC compared with normal thyroid. However, in PTC with lymph node metastasis, VDR and CYP24A1 were decreased compared with non-metastasized PTC. In ATC, VDR expression was often lost, whereas CYP27B1/CYP24A1 expression was comparable to DTC. Moreover, ATC with high Ki67 expression (>30%) or distant metastases at diagnosis was characterized by more negative VDR/CYP24A1/CYP27B1 staining. In conclusion, increased expression of key players involved in local 1,25(OH)(2)D(3) signaling was demonstrated in benign and differentiated malignant thyroid tumors, but a decrease was observed for local nodal and especially distant metastasis, suggesting a local antitumor response of 1,25(OH)(2)D(3) in early cancer stages. These findings advocate further studies with 1,25(OH)(2)D(3) and analogs in persistent and recurrent iodine-refractory DTC. PMID- 22511604 TI - The roles of acyl-CoA: diacylglycerol acyltransferase 2 genes in the biosynthesis of triacylglycerols by the green algae Chlamydomonas reinhardtii. PMID- 22511603 TI - A new multicolor fluorescence in situ hybridization probe set directed against human heterochromatin: HCM-FISH. AB - A new multicolor fluorescence in situ hybridization (mFISH) probe set is presented, and its possible applications are highlighted in 25 clinical cases. The so-called heterochromatin-M-FISH (HCM-FISH) probe set enables a one-step characterization of the large heterochromatic regions within the human genome. HCM-FISH closes a gap in the now available mFISH probe sets, as those do not normally cover the acrocentric short arms; the large pericentric regions of chromosomes 1, 9, and 16; as well as the band Yq12. Still, these regions can be involved in different kinds of chromosomal rearrangements such as translocations, insertions, inversions, amplifications, and marker chromosome formations. Here, examples are given for all these kinds of chromosomal aberrations, detected as constitutional rearrangements in clinical cases. Application perspectives of the probe set in tumors as well as in evolutionary cytogenetic studies are given. PMID- 22511605 TI - DICER-LIKE3 activity in Physcomitrella patens DICER-LIKE4 mutants causes severe developmental dysfunction and sterility. AB - Trans-acting small interfering RNAs (ta-siRNAs) are plant-specific siRNAs released from TAS precursor transcripts after microRNA-dependent cleavage, conversion into double-stranded RNA, and Dicer-dependent phased processing. Like microRNAs (miRNAs), ta-siRNAs direct site-specific cleavage of target RNAs at sites of extensive complementarity. Here, we show that the DICER-LIKE 4 protein of Physcomitrella patens (PpDCL4) is essential for the biogenesis of 21 nucleotide (nt) ta-siRNAs. In DeltaPpDCL4 mutants, off-sized 23 and 24-nt ta siRNAs accumulated as the result of PpDCL3 activity. DeltaPpDCL4 mutants display severe abnormalities throughout Physcomitrella development, including sterility, that were fully reversed in DeltaPpDCL3/DeltaPpDCL4 double-mutant plants. Therefore, PpDCL3 activity, not loss of PpDCL4 function per se, is the cause of the DeltaPpDCL4 phenotypes. Additionally, we describe several new Physcomitrella trans-acting siRNA loci, three of which belong to a new family, TAS6. TAS6 loci are typified by sliced miR156 and miR529 target sites and are in close proximity to PpTAS3 loci. PMID- 22511606 TI - Structural and functional studies of the mitochondrial cysteine desulfurase from Arabidopsis thaliana. AB - AtNfs1 is the Arabidopsis thaliana mitochondrial homolog of the bacterial cysteine desulfurases NifS and IscS, having an essential role in cellular Fe-S cluster assembly. Homology modeling of AtNfs1m predicts a high global similarity with E. coli IscS showing a full conservation of residues involved in the catalytic site, whereas the chloroplastic AtNfs2 is more similar to the Synechocystis sp. SufS. Pull-down assays showed that the recombinant mature form, AtNfs1m, specifically binds to Arabidopsis frataxin (AtFH). A hysteretic behavior, with a lag phase of several minutes, was observed and hysteretic parameters were affected by pre-incubation with AtFH. Moreover, AtFH modulates AtNfs1m kinetics, increasing V(max) and decreasing the S(0.5) value for cysteine. Results suggest that AtFH plays an important role in the early steps of Fe-S cluster formation by regulating AtNfs1 activity in plant mitochondria. PMID- 22511607 TI - Mitochondrial sulfide detoxification requires a functional isoform O acetylserine(thiol)lyase C in Arabidopsis thaliana. AB - In non-cyanogenic species, the main source of cyanide derives from ethylene and camalexin biosyntheses. In mitochondria, cyanide is a potent inhibitor of the cytochrome c oxidase and is metabolized by the beta-cyanoalanine synthase CYS-C1, catalyzing the conversion of cysteine and cyanide to hydrogen sulfide and beta cyanoalanine. The hydrogen sulfide released also inhibits the cytochrome c oxidase and needs to be detoxified by the O-acetylserine(thiol)lyase mitochondrial isoform, OAS-C, which catalyzes the incorporation of sulfide to O acetylserine to produce cysteine, thus generating a cyclic pathway in the mitochondria. The loss of functional OAS-C isoforms causes phenotypic characteristics very similar to the loss of the CYS-C1 enzyme, showing defects in root hair formation. Genetic complementation with the OAS-C gene rescues the impairment of root hair elongation, restoring the wild-type phenotype. The mitochondria compromise their capacity to properly detoxify cyanide and the resulting sulfide because the latter cannot re-assimilate into cysteine in the oas-c null mutant. Consequently, we observe an accumulation of sulfide and cyanide and of the alternative oxidase, which is unable to prevent the production of reactive oxygen species probably due to the accumulation of both toxic molecules. Our results allow us to suggest that the significance of OAS-C is related to its role in the proper sulfide and cyanide detoxification in mitochondria. PMID- 22511608 TI - Design and synthesis of new biprivileged molecular scaffolds: indolo-fused benzodiazepinyl/quinoxalinyl benzimidazoles. AB - The present article describes the design and synthesis of new biprivileged molecular scaffolds with diverse structural features. Commercially available, simple heterocyclic building blocks such as 4-fluoro-3-nitrobenzoic acid, 2 chloro-3-nitrobenzoic acid, and indoline were utilized for the synthesis of the novel heterocycles. Pictet-Spengler-type condensation was used as a key step to construct tetracyclic indolo-benzodiazepines and indolo-quinoxalines linked with substituted benzimidazoles. Analysis of single crystals of representative compounds showed that these molecular skeletons have the potential to present various substituents with distinct three-dimensional orientations. PMID- 22511609 TI - Incident knee osteoarthritis-related outcomes and slower walking speed: comment on the article by Purser et al. PMID- 22511610 TI - Asymmetric hybrid silica nanomotors for capture and cargo transport: towards a novel motion-based DNA sensor. AB - An innovative self-propelled nanodevice able to perform motion, cargo transport, and target recognition is presented. The system is based on a mesoporous motor particle, which is asymmetrically functionalized by the attachment of single stranded DNA onto one of its faces, while catalase is immobilized on the other face. This enzyme allows catalytic decomposition of hydrogen peroxide to oxygen and water, giving rise to the driving force for the motion of the whole system. Moreover the motor particles are able to capture and transport cargo particles functionalized with a noncomplementary single-stranded DNA molecule, only if a specific oligonucleotide sequence is present in the media. Functionalization with characteristic oligonucleotide sequences in the system implies a potential for further developments for lab-on-chip devices with applications in biomedical applications. PMID- 22511611 TI - Use of dual-energy x-ray absorptiometry (DXA) scans in HIV-infected patients. AB - Multiple studies have demonstrated increased rates of osteopenia and osteoporosis in HIV-infected patients but there have been no published studies on current screening practices. We conducted a retrospective chart review of 2924 patients attending an urban HIV clinic. Thirty patients (1%) had dual-energy x-ray absorptiometry (DXA) scans. Patients undergoing DXA scans were more likely to be older, women, and have nondetectable HIV viral load and CD4 count >=200. The most frequently cited indications for screening were perimenopausal or postmenopausal status and HIV infection. Of the patients screened, 96% had osteopenia or osteoporosis with a median T-score of -1.9 and a median of 3.8 osteoporosis risk factors in addition to HIV. Of the 20 practitioners in the clinic, only 7 had patients with screening DXA scans. DXA scans are underutilized in the HIV population given the high rate of osteopenia and osteoporosis detected in this study. PMID- 22511612 TI - Phosphine-catalyzed domino reaction for the synthesis of conjugated 2,3 dihydrofurans from allenoates and Nazarov reagents. AB - A new domino reaction for Nazarov reagents: An efficient approach was developed for the construction of highly functionalized conjugated 2,3-dihydrofuran skeletons. Nazarov reagents were used for the first time in a phosphine-catalyzed domino reaction and successfully used to construct five-membered ring compounds using alcohol as the solvent. DFT calculations indicate that alcohol is essential for the catalysis of the [1,2]-proton transfer. PMID- 22511613 TI - Acrosomal biogenesis in human globozoospermia: immunocytochemical, ultrastructural and proteomic studies. AB - BACKGROUND: Acrosome biogenesis is a key event in sperm differentiation that depends on the proper interaction between the Golgi complex and the nuclear envelope of early spermatids. We studied the development, structure and biochemical characteristics of human acrosomes in germ cells and spermatozoa from testicular biopsies and semen samples of fertile men and patients with acrosomeless spermatozoa (globozoospermia). A set of proteins collectively known as the perinuclear theca (PT), which has been related to acrosomal development in many mammalian species, were also investigated. METHODS: We evaluated spermatozoa from five males with globozoospermia and six fertile men, and immature germ cells from testicular biopsies of one globozoospermic patient and three men with obstructive azoospermia. Samples were assessed by transmission electron microscopy, immunofluorescence microscopy, ultrastructural immunocytochemistry and proteomic analysis by western blot. RESULTS: In normal spermiogenesis, the development of the acrosome depends on the correct formation of Golgi-derived proacrosomal vesicles and simultaneous modifications in the nuclear envelope. PT proteins are consistently found in proacrosomic vesicles, localize underneath the acrosome and expand over the nuclear surface along acrosome biogenesis. In fertile men, the PT is composed of six proteins, similar to those previously described for other mammals (16, 22, 29, 34, 50 and 68 kDa). In globozoospermia, abnormal proacrosomal vesicles and paranuclear multivesicular and multilamellar structures were observed that resulted in acrosomes insufficiently developed or detached from the nuclear envelope. PT proteins, dissociated from the acrosomes, were ectopically localized in the cytoplasm. Proteomic analysis showed a significant decrease in all six PT proteins. CONCLUSIONS: The alterations observed during early acrosome biogenesis in globozoospermia are due to anomalous development of Golgi-derived proacrosomic vesicles, failure of PT proteins to properly associate with the nuclear surface and significant deficiencies in specific PT components that are necessary for proper acrosome formation, implantation and expansion over the spermatid nucleus. PMID- 22511614 TI - Direct use of the comet assay to study cell cycle distribution and its application to study cell cycle-dependent DNA damage formation. AB - The comet assay or single cell gel electrophoresis has proven to be a versatile and sensitive method of measuring the induction and repair of DNA damage in individual cells. However, one of the drawbacks of the assay is the bias caused by changes in the ability of cells to repair DNA damage in different cell cycle phases. Whereas the bias seems less important when G0 peripheral blood lymphocytes are studied, it might cause problems when proliferating cells are investigated. In this paper, we validate the assumption that the total comet fluorescence intensity corresponds to the position of the cell in the cell cycle and can be used to assign single cells to specific cell cycle phases. To validate the approach, we used a very homogenous blood mononuclear CD34(+) cell population in G0 phase (unstimulated) or stimulated to enter the cell cycle. An analysis of the cell cycle distribution revealed that the 15 comet intensity classes and the 100 comets usually analyzed in a typical comet experiment are sufficient to obtain a reliable cell cycle distribution comparable with the results obtained by the flow cytometry for the same cell population. The effect of the cell cycle position on the results obtained by the comet assay for proliferating and non proliferating cell populations irradiated with 3 Gy of X-radiation is also discussed. PMID- 22511616 TI - Highly luminescent CdTe/CdS/ZnO core/shell/shell quantum dots fabricated using an aqueous strategy. AB - To create core/shell/shell quantum dots (QDs) with high stability against a harmful chemical environment, CdTe/CdS QDs were coated with a ZnO shell in an aqueous solution. An interfaced CdS layer sandwiched between a CdTe core and ZnO shell provided relaxation of the strain at the core/shell interface since lattice parameters of CdS are intermediate between those of CdTe and ZnO. The photoluminescence (PL) peak wavelength of the core/shell/shell QDs was shifted from 569 to 615 nm by adjusting the size of CdTe cores and thickness of CdS and ZnO shells, along with the highest PL quantum yield of the core/shell/shell QDs reaching 80%, which implies promising applications in the field of biomedical labeling. Due to the decrease of surface defects, it was observed that PL lifetimes significantly increased at room temperature as follows: 29.6 34.2, and 47.5 ns for CdTe (537 nm), CdTe/CdS (555 nm) and CdTe/CdS/ZnO (581 nm) QDs, respectively. PMID- 22511615 TI - Umbilical cord blood levels of maternal antibodies reactive with p200 and full length Ro 52 in the assessment of risk for cardiac manifestations of neonatal lupus. AB - OBJECTIVE: Maternal anti-Ro autoantibodies are associated with cardiac manifestations of neonatal lupus (cardiac NL), yet only 2% of women with this reactivity have an affected child. Identification of a more specific marker would channel intense monitoring to fetuses at greater risk. This study aimed to determine whether autoantibodies against Ro 52 amino acids 200-239 (p200) confer added risk over autoantibodies to full-length Ro 52, Ro 60, or La. METHODS: Anti Ro-exposed pregnancies resulting in cardiac NL or no cardiac manifestations were identified from the Research Registry for Neonatal Lupus and the PR Interval and Dexamethasone Evaluation study. Umbilical cord (n = 123) and maternal (n = 115) samples were evaluated by enzyme-linked immunosorbent assay. RESULTS: The frequencies of p200, Ro 52, Ro 60, and La autoantibodies were not significantly different between affected and unaffected children. However, neonatal anti-Ro 52 and Ro 60 titers were highest in cardiac NL and their unaffected siblings compared to unaffected neonates without a cardiac NL sibling. Although both maternal anti-Ro 52 and p200 autoantibodies were less than 50% specific for cardiac NL, anti-p200 was the least likely of the Ro autoantibodies to be false positive in mothers who have never had an affected child. Titers of anti-Ro 52 and p200 did not differ during a cardiac NL or unaffected pregnancy from the same mother. CONCLUSION: Maternal reactivity to p200 does not confer an added risk to fetal conduction defects over full-length Ro 52 or Ro 60 autoantibodies. Mothers who may never be at risk for having an affected child have lower anti-Ro 60 titers and may require less stringent echocardiographic monitoring compared to women with high-titer autoantibodies. PMID- 22511617 TI - Antegrade percutaneous valve implantation for mitral ring dysfunction, a challenging case. AB - The operative risk for reoperation of degenerated bioprosthetic valves or failing mitral-valve annuloplasty is higher compared with the risks for first isolated native valve repair or replacement (Astor et al., Eur Heart J 2008;29:2382-2387). In the presence of comorbidities, these risks increase exponentially. The recent introduction of transcatheter valve implantation opened new perspectives for the treatment of patients at very high surgical risk. We report a percutaneous mitral valve (MV) implantation using a transatrial approach within a MV ring using the Edwars Sapien XT valve. PMID- 22511618 TI - Structural changes and relaxations monitored by luminescence. AB - Luminescence data have often been used to study imperfections and to characterize lattice distortions because the signals are sensitive to changes of structure and composition. Previous studies have included intentionally added probe ions such as rare earth ions to sense distortions in local crystal fields caused by modified structural environments. An under-exploited extension of this approach was to use luminescence to monitor crystalline phase changes. A current overview of this new and powerful technique shows that continuous scanning of the sample temperatures immediately offered at least three types of signatures for phase transitions. Because of high sensitivity, luminescence signals were equally responsive to structural changes from inclusions and nanoparticles. These coupled to the host material via long-range interactions and modified the host signals. Two frequently observed examples that are normally overlooked are from nanoparticle inclusions of water and CO2. Examples also indicated that phase transitions were detected in more diverse materials such as superconductors and fullerenes. Finally, luminescence studies have shown that in some crystalline examples, high dose ion implantation of surface layers could induce relaxations and/or structural changes of the entire underlying bulk material. This was an unexpected result and therefore such a possibility has not previously been explored. However, the implications for ion implication are significant and could be far more general than the examples mentioned here. PMID- 22511619 TI - Chronic renal artery dissection with aneurysm formation treated by stent implantation with coil embolization with detailed intravascular ultrasound evaluation. AB - Treatment options for chronic renal artery dissection, which is a rare cause of renal artery stenosis and renovascular hypertension, such as medical management, percutaneous intervention, and open surgical repair remain controversial. We describe a 55-year-old man with a chronic dissecting aneurysm of a renal artery complicated with renovascular hypertension that was initially diagnosed by computed tomography angiography, evaluated by intravascular ultrasound, and treated by stent implantation with coil embolization.(c) 2012 Wiley Periodicals, Inc. PMID- 22511620 TI - A new fluorescent chemosensor for Hg2+ in aqueous solution. AB - We prepared an aminothiourea-derived Schiff base (DA) as a fluorescent chemosensor for Hg(2+) ions. Addition of 1 equiv of Hg(2+) ions to the aqueous solution of DA gave rise to an obvious fluorescence enhancement and the subsequent addition of more Hg(2+) induced gradual fluorescence quenching. Other competing ions, including Pb(2+), Cd(2+), Cr(3+), Zn(2+), Fe(2+), Co(3+), Ni(2+), Ca(2+), Mg(2+), K(+) and Na(+) , did not induce any distinct fluorescence changes, indicating that DA can selectively detect Hg(2+) ions in aqueous solution. PMID- 22511621 TI - Interactions between m-phenylenediamine and bovine serum albumin measured by spectroscopy. AB - This study explored interactions between m-phenylenediamine (MPD) and bovine serum albumin (BSA) by spectrophotometry. The Stern-Volmer equation and UV-vis spectra examination at different temperatures and pH were used to explore different quenching mechanisms. Under simulated physiological conditions, the binding distance between MPD and BSA was 5.18 nm with a ratio of 1:1. The quenching effect of MPD on BSA intrinsic fluorescence depended strongly on pH, and maximum quenching was observed at alkaline pH. Moreover, the thermodynamic parameters of the MPD-BSA system showed that the predominant acting force between MPD and BSA was a hydrophobic force. The impact of MPD on the conformation of BSA and the effects of co-ions on binding interactions were also examined. PMID- 22511622 TI - Time-resolved autofluorescence imaging of human donor retina tissue from donors with significant extramacular drusen. AB - PURPOSE: Time and spectrally resolved measurements of autofluorescence have the potential to monitor metabolism at the cellular level. Fluorophores that emit with the same fluorescence intensity can be discriminated from each other by decay time of fluorescence intensity after pulsed excitation. We performed time resolved autofluorescence measurements on fundus samples from a donor with significant extramacular drusen. METHODS: Tissue sections from two human donors were prepared and imaged with a laser scanning microscope. The sample was excited with a titanium-sapphire laser, which was tuned to 860 nm, and frequency doubled by a BBO crystal to 430 nm. The repetition rate was 76 MHz and the pulse width was 170 femtoseconds (fs). The time-resolved autofluorescence was recorded simultaneously in 16 spectral channels (445-605 nm) and bi-exponentially fitted. RESULTS: RPE can be discriminated clearly from Bruch's membrane, drusen, and choroidal connective tissue by fluorescence lifetime. In RPE, bright fluorescence of lipofuscin could be detected with a maximum at 510 nm and extending beyond 600 nm. The lifetime was 385 ps. Different types of drusen were found. Most of them did not contain lipofuscin and exhibited a weak fluorescence, with a maximum at 470 nm. The lifetime was 1785 picoseconds (ps). Also, brightly emitting lesions, presumably representing basal laminar deposits, with fluorescence lifetimes longer than those recorded in RPE could be detected. CONCLUSIONS: The demonstrated differentiation of fluorescent structures by their fluorescence decay time is important for interpretation of in vivo measurements by the new fluorescence lifetime imaging (FLIM) ophthalmoscopy on healthy subjects as well as on patients. PMID- 22511623 TI - Characterization by Belmonte's gas esthesiometer of mechanical, chemical, and thermal corneal sensitivity thresholds in a normal population. AB - PURPOSE: We used a prototype gas esthesiometer to measure corneal threshold sensitivity values for mechanical, chemical, and thermal stimuli. We also evaluated the reproducibility of the esthesiometer measurements, the influence of previous corneal symptoms, and the safety of this technique. METHODS: Forty healthy subjects participated in the study. Mechanical, chemical, and thermal (hot and cold) thresholds were determined at the center of the cornea using a prototype Belmonte's gas esthesiometer. To determine reproducibility of the results, the sensitivity thresholds were measured for each eye on 2 days. Corneal fluorescein staining and bulbar hyperemia after completion of the tests were analyzed. RESULTS: There were no differences for any sensitivity threshold between eyes or between the first and second esthesiometries. The reproducibilities of mechanical and hot thresholds were higher than for chemical and cold thresholds. Men had significantly higher chemical intensity thresholds than did women (men: 23.50 +/- 5.10; women: 10.20 +/- 2.16, P = 0.021). There were no alterations of the ocular surface after completion of the measurements. CONCLUSIONS: Mechanical, chemical, and thermal corneal sensitivity thresholds in the central cornea have been established in healthy men and women of different age groups. The use of the Belmonte gas esthesiometer is safe and reproducible, with the highest reproducibility in determining mechanical and hot thresholds. PMID- 22511624 TI - ERK1/2 signaling pathway in the release of VEGF from Muller cells in diabetes. AB - PURPOSE: Diabetic retinopathy (DR) is one of the most serious complications of diabetes and has become a major blinding eye disease, but its treatment remains unsatisfactory. The ERK1/2 signaling pathway has been shown to participate in regulating secretion of VEGF in DR from our previous studies. The role of VEGF in the development of DR provides a target for treatment. Our present research focuses on Muller cells, a major source of VEGF secretion, to investigate the role of ERK1/2 signaling pathway on regulation of VEGF release in diabetes. METHODS: Immunofluorescence was used to observe the ERK1/2 phosphorylation activity on early diabetic rat retinal Muller cells. Muller cells were stimulated by high glucose in vitro. Western blot and immunohistochemistry were used to determine ERK1/2 signaling pathway expression and phosphorylation. AP-1 DNA binding activity status was monitored by electrophoretic mobility shift assay (EMSA). ELISA and PCR monitored VEGF secretion. Inhibition of ERK1/2 phosphorylation with U0126 was observed for changes in VEGF secretion. RESULTS: Phos-ERK1/2 was expressed on Muller cells early in diabetes. In vitro high glucose stimulation of Muller cells increased VEGF secretion with a peak at 24 hours. An ERK1/2 specific inhibitor, U0126, stopped the phosphorylation of ERK1/2, lowered AP-1 DNA binding activity, and reduced Muller cells secretion of VEGF under high glucose conditions. CONCLUSIONS: ERK1/2 signaling pathway has some role in regulating Muller cells secretion of VEGF in DR. Targeting the ERK1/2 signaling pathway in Muller cells through intervention of the upstream signaling pathway or nuclear transcription factors of VEGF secretion could be a type of anti-VEGF treatment for DR. PMID- 22511626 TI - Divalent cations in tears, and their influence on tear film stability in humans and rabbits. AB - PURPOSE: Reduced tear film stability is reported to contribute to dry eye. Rabbits are known to have a more stable tear film than humans. Thus, we sought to examine the tears of rabbits and humans for metal cations, and to test how they influence tear film stability. METHODS: Tears were collected from 10 healthy humans and 6 rabbits. Tear osmolality was measured by vapor pressure osmometer, and metals analyzed using inductively coupled plasma (ICP) mass spectrometry or ICP atomic emission spectroscopy. The influence of divalent cations on tears was analyzed by measuring surface tension using the Langmuir trough in vitro, using different concentrations of cations in the subphase, and grading the tear break up in rabbits in vivo after instillation of chelating agents. RESULTS: Rabbit tears had a higher osmolality compared to humans. Major metals did not differ between species; however, rabbits had higher levels of Mg(2+) (1.13 vs. 0.39 mM) and Ca(2+) (0.75 vs. 0.36 mM). In rabbit tears in vitro, diminishing divalent cations resulted in a decrease in the maximum surface pressure from 37 to 30 mN/m. In vivo, an increase in the amount of tear film that was broken-up was found. In contrast, when changing divalent cation concentrations in human tears, the maximum surface pressure remained at 26 mN/m. CONCLUSIONS: The normal osmolality of rabbit tears is significantly higher than that in humans. While divalent cations had little influence on human tears, they appear to have an important role in maintaining tear film stability in rabbits. PMID- 22511627 TI - Visualizing hydrophobic domains in silicone hydrogel lenses with Sudan IV. AB - PURPOSE: A lipophilic dye is used to investigate the degree to which the surface and bulk hydrophobic domains of the lenses can be imaged and to identify specific changes in the availability of those domains after in vitro wear and cleaning conditions. The effect of a multipurpose solution (MPS), OPTI-FREE RepleniSH, on lens hydrophobic domains was also investigated. METHODS: Hydrophobic domains were determined using a saturated solution of Sudan IV. Staining periods of 30 minutes and 16 hours were used to determine surface versus bulk hydrophobic domains. Four types of silicone hydrogel lens materials were tested. The degree of staining was visually documented by photography and quantitatively determined by extraction and analysis of the total amount of dye adsorbed. RESULTS: Specific differences in staining were found for all control lenses. Exposure to in vitro wear conditions significantly decreased the staining response for all lens types as compared with unworn lenses (P = 0.001). However, the trend of staining remained the same: balafilcon A > galyfilcon A > senofilcon A > lotrafilcon B. MPS decreased the extent of staining; the degree of its effect varied with lens type. CONCLUSIONS: Hydrophobic staining with Sudan IV visualized domains on and within silicone hydrogel lenses. Differences in staining response after exposure to wear and cleaning conditions indicate the potential for protein and lipid deposition on the different lens types and the ability of MPS to affect that deposition. Hydrophobic staining may be useful for determining differences in surface modification and lipophilicity of silicone hydrogel lenses. PMID- 22511625 TI - PTX3 controls activation of matrix metalloproteinase 1 and apoptosis in conjunctivochalasis fibroblasts. AB - PURPOSE: Conjunctivochalasis (CCh) is an age-related inflammatory ocular surface disease manifesting redundant, loose conjunctiva folds. The pathogenic role of Pentraxin 3 (PTX3) in controlling upregulation of matrix metalloproteinase 1 (MMP 1) and MMP-3 in CCh remains undefined. METHODS: Cytolocation of PTX3 and apoptosis were compared by immunostaining and terminal deoxyribonucleotidyl transferase-mediated FITC-linked dUTP nick-end DNA labeling (TUNEL) assay between normal and CCh specimens containing the conjunctiva and the Tenon. Second to third cultures of normal and CCh fibroblasts were treated with or without Aprotinin, Batimastat, or N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid (NNGH), followed by transfection with or without PTX3 siRNA, and TNF-alpha or IL-1beta. Cell lysates and culture media were collected to assess apoptosis measured by the Cell Death Detection ELISA and expression of PTX3, MMP-1, and MMP 3 transcripts and proteins by quantitative RT-PCR and Western blot, respectively. RESULTS: PTX3 immunostaining was negative in normal specimens, but strongly positive in the subconjunctival stroma of CCh specimens. More apoptotic cells were found in CCh samples than in normal specimens. Expression of PTX3 transcripts and protein was not constitutive in resting normal fibroblasts but was in resting CCh fibroblasts and was upregulated by IL-1beta in both cell lysates and culture media of both fibroblasts. PTX3 siRNA further upregulated MMP 1 and MMP-3 transcripts in resting normal fibroblasts, but synergistically with IL-1beta upregulated the expression of MMP-1 and MMP-3 transcripts only in CCh fibroblasts, with activation of MMP-1 more so than MMP-3. PTX3 siRNA knockdown also promoted cell death characterized by apoptosis and necrosis, and such cell death could be rescued by inhibitors against serine proteinase, MMP1, or MMP3. CONCLUSIONS: Perturbation of PTX3 expression might partake in apoptosis and pathogenesis of CCh by upregulating expression of MMP-1 and MMP-3, and activation of MMP-1 and MMP-3. PMID- 22511628 TI - Do patients with glaucoma have difficulty recognizing faces? AB - PURPOSE: To compare face recognition performance of glaucomatous patients with age-similar visually healthy people. METHODS: Percentage of correctly identified faces in the Cambridge Face Memory Test was assessed in glaucomatous patients (n = 54; mean age = 69) with a range of visual field (VF) defects and visually healthy controls (n = 41; mean age = 67). All participants underwent cognitive and visual assessment (binocular visual acuity [BVA], contrast sensitivity [CS], and Humphrey VFs, both 10-2 and 24-2) and had BVA of at least 0.18 logMAR. Patients were classified as having "early," "moderate," or "advanced" VF defects using the Hodapp, Parrish and Anderson Method: Patients were also stratified by better-eye 10-2 mean deviation (MD) being better or worse than the 1% normative value. RESULTS: There were no significant differences in age (P = 0.25) or cognitive ability (P = 0.31) between groups; however, differences in BVA and CS were statistically significant (P < 0.05). Patients with advanced VF defects identified fewer faces on average (+/-SD) (66% +/- 15%) than those with early (75% +/- 11%) and moderate (75% +/- 13%) defects and controls (75% +/- 11%); P < 0.05. Patients with a best-eye 10-2 MD P < 1% identified fewer faces (67% +/- 13%) than those with 10-2 MD P > 1% (77% +/- 11%) and controls P < 0.01 (75% +/- 11%). Multiple regression analysis revealed CS was important for face recognition. CONCLUSIONS: When compared with age-similar people with healthy vision, glaucomatous patients with advanced bilateral 24-2 VF loss, significant 10-2 VF loss, or poor CS are more likely to experience problems with face recognition. PMID- 22511629 TI - Spontaneous episodic decreased tear secretion in rats is related to opioidergic signaling pathways. AB - PURPOSE: To elucidate the factors in tear production, this study examined the role of endogenous opioids and opioid receptors in spontaneous episodic reduced tear volume. METHODS: A model of spontaneous episodic decreases in the quantity of tears was characterized in otherwise normal Sprague-Dawley rats using Schirmer's test. A single eye drop of 10(-5) M naltrexone (NTX), 10(-5) M [Met(5)]-enkephalin, or sterile vehicle was administered to one eye. Tear secretion, corneal sensitivity, and corneal morphology were examined in both eyes. RESULTS: At any given time period, otherwise normal rats were found to have Schirmer test scores with a bimodal distribution (6.5 mm or less, or 7.0 mm or greater). Decreased tear production was detected in male and female rats aged 4 to 24 weeks at least once per animal. The episodes of reduced tear volume ranged from 1 to 7 days. No changes in corneal sensitivity or corneal morphology were observed in any rat. One drop of NTX given to rats with a decrease in tear volume raised levels of tears to scores of 7.0 mm or greater within 1 hour, and increased tear production persisted for at least 48 hours. NTX had no effect on rats with Schirmer scores of 7.0 mm or higher. Topical application of [Met(5)] enkephalin depressed tear secretion from baseline scores of 9.8 +/- 0.6 mm to as low as 4.5 +/- 0.7 mm. CONCLUSIONS: Normal rats experience fluctuations in tear production that can be modulated by opioidergic signaling pathways. PMID- 22511630 TI - A connective tissue growth factor signaling receptor in corneal fibroblasts. AB - PURPOSE: To biochemically characterize the receptor for connective tissue growth factor (CTGF) of human corneal fibroblasts (HCF). METHODS: Radiolabeled recombinant human CTGF was used to determine the specificity and time course of binding to low-passage cultures of HCF. The affinity and number of receptors present were calculated by Scatchard and best-fit analyses. In vitro immunoprecipitation assays with radiolabeled CTGF and soluble mannose 6 phosphate/insulin-like growth factor 2 receptor (M6P/IGF-2-R) alone, or with CTGF related growth factors were conducted. Additionally, (125)I-CTGF-binding and CTGF stimulated proliferation were measured in cultures of M6P/IGF-2-R knockout fibroblasts. RESULTS: Binding of (125)I-CTGF to fibroblast cultures was significantly displaced by CTGF, but not by related growth factors. Scatchard plot analysis indicated the presence of both a high-affinity, low-abundance binding site, and a low-affinity, high-abundance binding site; whereas, the best fit analysis suggests a single high-affinity, low-abundance binding site. A 280 kDa complex containing cross-linked (125)I-CTGF was immunoprecipitated by antibodies to CTGF or M6P/IGF-2-R. M6P/IGF-2-R knockout cells have a reduced proliferative response to TGF-beta, and don't proliferate at all in response to CTGF. CONCLUSIONS: CTGF binds to the M6P/IGF-2-R with high affinity, and the M6P/IGF-2-R is required for CTGF-stimulated proliferation in fibroblasts. These observations suggest that the M6P/IGF-2-R may be a new antifibrotic target. PMID- 22511631 TI - The maintenance of lymphatic vessels in the cornea is dependent on the presence of macrophages. AB - PURPOSE: It has been shown previously that the presence in the cornea of antigen presenting cells (APC), such as macrophages (MPS) and lymphangiogenesis, is a risk for corneal transplantation. We sought to determine whether the existence of lymphatic vessels in the non-inflamed cornea is associated with the presence of MPS. METHODS: Flat mounts were prepared from corneas of untreated C57BL/6, CD11b( /-), F4/80(-/-), and BALB/c mice, and after suture placement or corneal transplantation, observed by immunofluorescence for the presence of lymphatic vessels using LYVE-1 as a marker of lymphatic endothelium. Innate immune cells were detected in normal mouse corneas using CD11b, F4/80, CD40, as well as MHC class II. Digital images of the flat mounts were taken using a spot image analysis system, and the area covered by lymphatic vessels was measured using NIH Image software. RESULTS: The number of spontaneous lymphatic vessels in C57BL/6 corneas was significantly greater than in BALB/c corneas (P = 0.03). There were more CD11b(+) (P < 0.01) and CD40(+), MHC-class II (+) cells in the C57BL/6 corneas than in BALB/c mouse corneas. MPS depletion via clodronate liposome in C57BL/6 mice led to fewer spontaneous lymphatic vessels and reduced inflammation induced lymphangiogenesis relative to control mice. Mice deficient in CD11b or F4/80 had fewer spontaneous lymphatic vessels and less lymphangiogenesis than control C57BL/6 mice. CONCLUSIONS: C57BL/6 mouse corneas have more endogenous CD11b(+) cells and lymphatic vessels. The endogenous lymphatic vessels, along with pro-inflammatory MPS, account for the high risk of corneal graft rejection in C57BL/6 mice. CD11b(+) and F4/80(+) MPS appear to have an important role in of the formation of new lymphatic vessels. PMID- 22511632 TI - KLEIP deficiency in mice causes progressive corneal neovascular dystrophy. AB - PURPOSE: The BTB-kelch protein KLEIP/KLHL20 is an actin binding protein that regulates cell-cell contact formation and cell migration. The aim of our study was to characterize KLEIP's function in ocular health and disease in mice. METHODS: KLEIP(-/-) mice were generated, and corneas were examined histologically and stained for keratin-1, loricrin, keratin-12, keratin-14, CD31, LYVE-1, F4/80, E-cadherin, and Ki67. Corneal abrasions were performed after eyelid opening. RESULTS: Corneas of KLEIP(+/+) and KLEIP(-/-) mice were indistinguishable at birth. After eyelid opening corneal epithelial hyperplasia started to manifest in KLEIP(-/-) mice, showing a progressive epithelial metaplasia leading to total corneal opacity. In KLEIP(-/-) mice the initial stratified squamous corneal epithelium was altered to an epidermal histo-architecture showing several superficial keratinized cells, cell infiltrations into the stroma, and several apoptotic cells. Skin markers keratin 1 and loricrin were positive, and surface disease was accompanied by deep stromal vascularization. Expression analysis for E-cadherin in KLEIP(-/-) corneas showed acellular areas in the squamous epithelium, indicating a progressive fragile corneal integrity. Removal of the virgin epithelium accelerated strongly development of the epithelial and stromal alterations, identifying mechanical injuries as the major trigger for corneal dystrophy formation and scarification in KLEIP(-/-) mice. CONCLUSIONS: The data identify KLEIP as an important molecule regulating corneal epithelial integrity. PMID- 22511633 TI - Optical quality of emmetropic and myopic eyes in the periphery measured with high angular resolution. AB - PURPOSE: On average, myopic eyes present a relative hyperopia in the peripheral retina. This has been associated with the possibility that by modifying the peripheral refraction, the progression of central myopia could be controlled. The authors explored how refractive errors and optical aberrations interact in the formation of the retinal image in the periphery, in eyes with different central refractions. METHODS: The authors used a fast and high-angular resolution scanning wavefront sensor to measure the optical image quality of the eye in the horizontal meridian (+/- 40 degrees ) in 202 eyes of 101 subjects, 54 males and 47 females with an average age (std) of 27.5 (+/- 7.2) years and an average foveal refraction (std) of -0.8 (+/- 1.3 D) of which 64 were non-myopes (refraction +/- std: 0.01 +/- 0.46 D) and 37 myopes (-2.12 +/- 1.08 D). They evaluated the relationship between peripheral optical properties and central refraction using different metrics. RESULTS: The authors observed a significant tendency to a relative hyperopia in the periphery of the myopic eyes. The relative peripheral refraction (RPR) was significantly different between the emmetropic and myopic eyes from 15 degrees -40 degrees temporal retina and from 20 degrees -40 degrees nasal retina. The mean RPR metric correlated with the central refraction of the subject (r = -0.552 / -0.560 [OD / OS]). The image quality presented only minor differences between the various refractive groups at angles of 30 degrees -40 degrees when the central refraction was corrected. CONCLUSIONS: Peripheral overall blur is mostly influenced by the interaction of defocus and oblique astigmatism, and at larger eccentricities is similar for the different refractive groups. This could argue against the hypothesis that a relative peripheral hyperopia could drive eyes toward myopia. PMID- 22511635 TI - The prevalence of glaucoma in adult rural Chinese populations of the Bai nationality in Dali: the Yunnan Minority Eye Study. AB - PURPOSE: We evaluated the prevalence of glaucoma in adults of the Bai Nationality populations in rural China. METHODS: A population-based survey of Chinese Bai Nationality aged >=50 years from randomly selected block groups in southwestern China was conducted. Eligible persons were invited to local examination sites for a complete ophthalmic examination. Glaucoma was diagnosed using the International Society of Geographical and Epidemiological Ophthalmology Classification scheme. RESULTS: In the study, 2133 subjects (77.8% participation rate) were examined, with a crude prevalence of all glaucoma of 2.2% (95% confidence interval [CI] 1.6%-2.9%). Primary open angle glaucoma (POAG) was found in 1.0% of cases (95% CI 0.6%-1.6%) and primary angle-closure glaucoma (PACG) in 0.9% (95% CI 0.6%-1.4%). The prevalence of all glaucoma was significantly higher in older people and women. Mean intraocular pressure (IOP) was 16.17 +/- 3.74 mm Hg (97.5th and 99.5th percentiles, 24 mm Hg and 30 mm Hg, respectively). The mean vertical cup to-disc ratio (VCDR) was 0.43 +/- 0.17 (97.5th and 99.5th percentiles 0.7 and 0.8, respectively). Unilateral blindness was found in 80% of PACG, compared to only 36.3% of POAG cases. CONCLUSIONS: Prevalence of POAG is similar to PACG in the ethnic Bai population living in rural southwestern China. PACG has a worse visual impairment and prognosis compared to POAG. PMID- 22511634 TI - Chromosome 3 status in uveal melanoma: a comparison of fluorescence in situ hybridization and single-nucleotide polymorphism array. AB - PURPOSE: To compare fluorescence in situ hybridization (FISH) using a centromeric probe for chromosome 3 (CEP3) and 3p26 locus-specific probe with single nucleotide polymorphism array (SNP-A) analysis in the detection of high-risk uveal melanoma. METHODS: Fifty cases of uveal melanoma (28 males, 22 females) treated by enucleation between 2004 and 2010 were analyzed. Fresh tissue was used for FISH and SNP-A analysis. FISH was performed using a CEP3 and a 3p26 locus specific probe. Tumor size, location, and clinical outcome were recorded during the 7-year study period (median follow-up: 35.5 months; mean: 38.5 months). The sensitivity, specificity, positive predictive value, and negative predictive value were calculated. RESULTS: Monosomy 3 was detected by FISH-CEP3 in 27 tumors (54%), FISH-3p26 deletion was found in 30 (60%), and SNP-A analysis identified 31 (62%) of the tumors with monosomy 3. Due to technical failures, FISH and SNP-A were noninterpretable in one case (2%) and two cases (4%), respectively. In both cases of SNP-A failure, tumors were positive for FISH 3p26 deletion and in a single case of FISH failure, monosomy 3 was found using SNP-A. No statistically significant differences were observed in any of the sensitivity or specificity measures. CONCLUSIONS: For prediction of survival at 36 months, FISH CEP3, FISH 3p26, and SNP-A were comparable. A combination of prognostication techniques should be used in an unlikely event of technical failure (2%-4%). PMID- 22511636 TI - Clinical experience with daptomycin for the treatment of patients with knee and hip periprosthetic joint infections. AB - OBJECTIVES: To investigate the clinical efficacy and safety of daptomycin in the treatment of hip and knee periprosthetic joint infections (PJIs). METHODS: We completed a retrospective review of all patients in our institution (n=20) who were treated with daptomycin for hip or knee PJI, over the 36 month period from January 2008 until December 2010. RESULTS: Infection types included eight cases with acute infections, nine cases of chronic infection and three cases of positive intraoperative cultures. Methicillin-resistant coagulase-negative Staphylococcus was the most frequent microorganism found in surgical cultures (40%). Our patients, on average, received daptomycin as salvage therapy at a dose of 6.6 mg/kg/day for 44.9 days. The overall success rate was 78.6% after a median follow-up period of 20 months. In the subgroup of patients with acute PJIs, treatment with daptomycin, debridement and implant retention was successful in all cases. We found two cases of severe side effects (one case of acute renal failure due to massive rhabdomyolysis and one of eosinophilic pneumonia) and two cases of asymptomatic transient creatine phosphokinase (CPK) level elevation. CONCLUSIONS: The combination of high daptomycin doses with an adequate surgical approach could be a viable alternative in cases of difficult-to-treat Gram positive PJIs. Due to the risk of potentially serious adverse events, serum CPK level should be closely monitored. PMID- 22511637 TI - Curcumin enhances non-opsonic phagocytosis of Plasmodium falciparum through up regulation of CD36 surface expression on monocytes/macrophages. AB - OBJECTIVES: Curcumin is a natural plant product with antimalarial activity and immunomodulatory properties. In this study we aimed to investigate its effects on CD36 expression and CD36-mediated Plasmodium falciparum phagocytosis as well as the role played by reactive oxygen species (ROS) and the peroxisome proliferator activated receptor gamma retinoid X receptor (PPARgamma-RXR) in these processes. METHODS: In vitro antimalarial activity was evaluated by the [3H]hypoxanthine assay. ROS production and surface CD36 in human monocyte/macrophages were measured by flow cytometry. PPARgamma and CD36 mRNA expression was determined by the QuantiGene Plex(r) assay and RT-qPCR. Nuclear PPARgamma activation was analysed by a DNA-binding ELISA while nuclear erythroid-related factor 2 (Nrf2) expression was analysed by western blotting. P. falciparum phagocytosis was assessed by light microscopy. RESULTS: Curcumin's antimalarial activity was confirmed and did not differ between drug-susceptible and -resistant P. falciparum strains. Curcumin increased monocyte ROS production and expression of PPARgamma and CD36 at the mRNA and protein levels. Although PPARgamma activation was blocked by the PPARgamma antagonist GW9662, CD36 expression and CD36-mediated P. falciparum phagocytosis were only inhibited by N-acetylcysteine (NAC), suggesting a PPARgamma-independent CD36 expression pathway. We then identified seven putative Nrf2 antioxidant response elements on the CD36 gene promoter and showed that NAC inhibited curcumin-induced Nrf2 protein expression. CONCLUSIONS: CD36 expression and CD36-mediated P. falciparum phagocytosis by curcumin are dependent on ROS production and probably involve the Nrf2 pathway. The dual immunomodulatory and antimalarial mechanisms of curcumin action may mean that curcumin has potential as an adjuvant treatment limiting the risk of recrudescence following standard antimalarial therapy. PMID- 22511638 TI - Complete sequencing of an IncH plasmid carrying the blaNDM-1, blaCTX-M-15 and qnrB1 genes. AB - OBJECTIVES: To characterize plasmid pNDM-MAR recovered from a Klebsiella pneumoniae isolate of sequence type (ST) 15 from Morocco, carrying the genes encoding the metallo-beta-lactamase NDM-1, the extended-spectrum beta-lactamase (ESBL) CTX-M-15 and the qnrB1 quinolone resistance determinant. METHODS: The plasmid DNA sequence was obtained by using the 454-Genome Sequencer FLX procedure on a library constructed from total plasmid DNA obtained from an Escherichia coli J53 transconjugant. Contig assembly and predicted gaps were confirmed and filled by PCR-based gap closure. RESULTS: Plasmid pNDM-MAR was 267 242 bp long and encoded 177 predicted proteins. It harboured novel replicons and transfer loci, defining a novel plasmid type within the IncH plasmid family. The bla(NDM-1) gene was flanked by genetic elements that are distinct from those observed in other bla(NDM-1)-positive plasmids, including the groES and groEL chaperonin genes. This plasmid harboured the ESBL gene bla(CTX-M-15) together with the quinolone resistance gene qnrB1. In addition, it harboured genes encoding resistance to tellurite, mercury, chloramphenicol and aminoglycosides. Interestingly, pNDM-MAR did not carry any 16S rRNA methylase gene, in contrast to other bla(NDM-1) positive plasmids. CONCLUSIONS: This study underlines the diversity of genetic vehicles involved in the spread of the bla(NDM-1) gene. Plasmid pNDM-MAR differed significantly from all known bla(NDM-1)-bearing plasmids. Comparative analysis of the pNDM-MAR sequence identified a novel type of IncH plasmid. PMID- 22511641 TI - Self-monitoring of oral anticoagulation reduces thromboembolic events and does not increase risk of bleeding in selected patients and settings. PMID- 22511642 TI - Low-molecular-weight heparin prophylaxis does not affect mortality in acutely ill medical patients at low risk for venous thromboembolism. PMID- 22511639 TI - Is histone acetylation the most important physiological function for CBP and p300? AB - Protein lysine acetyltransferases (HATs or PATs) acetylate histones and other proteins, and are principally modeled as transcriptional coactivators. CREB binding protein (CBP, CREBBP) and its paralog p300 (EP300) constitute the KAT3 family of HATs in mammals, which has mostly unique sequence identity compared to other HAT families. Although studies in yeast show that many histone mutations cause modest or specific phenotypes, similar studies are impractical in mammals and it remains uncertain if histone acetylation is the primary physiological function for CBP/p300. Nonetheless, CBP and p300 mutations in humans and mice show that these coactivators have important roles in development, physiology, and disease, possibly because CBP and p300 act as network "hubs" with more than 400 described protein interaction partners. Analysis of CBP and p300 mutant mouse fibroblasts reveals CBP/p300 are together chiefly responsible for the global acetylation of histone H3 residues K18 and K27, and contribute to other locus specific histone acetylation events. CBP/p300 can also be important for transcription, but the recruitment of CBP/p300 and their associated histone acetylation marks do not absolutely correlate with a requirement for gene activation. Rather, it appears that target gene context (e.g. DNA sequence) influences the extent to which CBP and p300 are necessary for transcription. PMID- 22511643 TI - The legacy effect: 4.5 years of a chlorthalidone-based antihypertensive regimen reduces cardiovascular mortality and prolongs cardiovascular disease-free survival at 22 years for older patients with isolated systolic hypertension. PMID- 22511644 TI - Acute conjunctivitis in primary care: antibiotics and placebo associated with small increase in the proportion cured by 7 days compared with no treatment. PMID- 22511645 TI - Children with minor blunt head trauma, a Glasgow Coma Scale score of 14 or 15 and a normal CT scan are at very low risk of traumatic findings on subsequent neuroimaging or of requiring neurosurgical intervention. PMID- 22511646 TI - Of 3700 children thought to have non-cardiac chest pain at initial paediatric cardiology clinic evaluation, none suffered cardiac death over a median of 4 years follow-up. PMID- 22511647 TI - Multicondition collaborative care intervention for people with coronary heart disease and/or diabetes, depression and poor control of hypertension, blood sugar or hypercholesterolemia improves disability and quality of life compared with usual care. PMID- 22511648 TI - Catheter-directed thrombolysis prevents post-thrombotic syndrome in patients with acute deep vein thrombosis in the upper half of the thigh. PMID- 22511649 TI - Normal weight is associated with significant reductions in cardiovascular risk for adults, even in those who were overweight or obese as children. PMID- 22511650 TI - Primary care interventions for obesity: behavioural support, whether delivered remotely or in person, facilitates greater weight loss over 2 years than self directed weight loss. PMID- 22511651 TI - Breastfeeding is important for cognitive development in term and preterm infants. PMID- 22511653 TI - Smoking, F2RL3 methylation, and prognosis in stable coronary heart disease. AB - AIMS: In a recent genome-wide study, cytosine bases in the F2RL3 gene, which codes for a protein relevant for cardiovascular physiology, were discovered to be hypomethylated in smokers. We aimed to determine the clinical importance of methylation at the F2RL3 locus. METHODS AND RESULTS: In the KAROLA prospective cohort study, 1206 participants of inpatient cardiovascular rehabilitation programmes after experiencing an acute coronary syndrome, myocardial infarction, or coronary intervention were recruited in two clinics in Germany. Active follow up was conducted over 8 years. Methylation at loci in F2RL3 was characterized by Sequenom matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Associations of methylation and smoking with secondary cardiovascular events, and cause-specific and all-cause mortality were examined by multiple Cox's regression estimating confounder-controlled hazard ratios. A total of 49 non-fatal myocardial infarctions, 41 non-fatal strokes, 64 cardiovascular deaths, and 50 deaths due to other causes were observed. In Cox's models controlling for established prognostic factors, F2RL3 methylation was strongly associated with mortality. Adjusted hazard ratios (95% confidence intervals) for death from cardiovascular, non-cardiovascular, or any cause were 2.32 (0.97-5.58), 5.16 (1.81-14.7), and 3.19 (1.64-6.21) in subjects in the lowest quartile of methylation in comparison to the highest quartile. In contrast, no association was seen with the combined secondary event outcome. The strong association of smoking with all outcomes was markedly attenuated when F2RL3 was included in the regression models. CONCLUSION: The results seem to indicate methylation in F2RL3 to be a potential mediator of the detrimental impact of smoking and to be strongly related to mortality among patients with stable coronary heart disease. Multidisciplinary research efforts are needed to unravel prognostic, preventive, and therapeutic potentials of these pronounced associations. PMID- 22511655 TI - The place of nutrition in critical care of the chest. PMID- 22511654 TI - Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients. AB - AIMS: Renin-angiotensin-aldosterone system (RAAS) inhibitors are well established for the reduction in cardiovascular morbidity, but their impact on all-cause mortality in hypertensive patients is uncertain. Our objective was to analyse the effects of RAAS inhibitors as a class of drugs, as well as of angiotensin converting enzyme (ACE) inhibitors and AT1 receptor blockers (ARBs) separately, on all-cause mortality. METHODS AND RESULTS: We performed a pooled analysis of 20 cardiovascular morbidity-mortality trials. In each trial at least two-thirds of the patients had to be diagnosed with hypertension, according to the trial specific definition, and randomized to treatment with an RAAS inhibitor or control treatment. The cohort included 158 998 patients (71 401 RAAS inhibitor; 87 597 control). The incidence of all-cause death was 20.9 and 23.3 per 1000 patient-years in patients randomized to RAAS inhibition and controls, respectively. Overall, RAAS inhibition was associated with a 5% reduction in all cause mortality (HR: 0.95, 95% CI: 0.91-1.00, P= 0.032), and a 7% reduction in cardiovascular mortality (HR: 0.93, 95% CI: 0.88-0.99, P= 0.018). The observed treatment effect resulted entirely from the class of ACE inhibitors, which were associated with a significant 10% reduction in all-cause mortality (HR: 0.90, 95% CI: 0.84-0.97, P= 0.004), whereas no mortality reduction could be demonstrated with ARB treatment (HR: 0.99, 95% CI: 0.94-1.04, P= 0.683). This difference in treatment effect between ACE inhibitors and ARBs on all-cause mortality was statistically significant (P-value for heterogeneity 0.036). CONCLUSION: In patients with hypertension, treatment with an ACE inhibitor results in a significant further reduction in all-cause mortality. Because of the high prevalence of hypertension, the widespread use of ACE inhibitors may result in an important gain in lives saved. PMID- 22511656 TI - Maternal mid-upper arm circumference is associated with birth weight among HIV infected Malawians. AB - The authors examined the relationship of maternal anthropometry to fetal growth and birth weight among 1005 human immunodeficiency virus (HIV)-infected women in Lilongwe, Malawi, who consented to enrollment in the Breastfeeding, Antiretrovirals, and Nutrition Study (www.thebanstudy.org). Anthropometric assessments of mid-upper arm circumference (MUAC), arm muscle area (AMA), and arm fat area (AFA) were collected at the baseline visit between 12 and 30 weeks' gestation and in up to 4 follow-up prenatal visits. In longitudinal analysis, fundal height increased monotonically at an estimated rate of 0.92 cm/wk and was positively and negatively associated with AMA and AFA, respectively. These latter relationships varied over weeks of follow-up. Baseline MUAC, AMA, and AFA were positively associated with birth weight (MUAC: 31.84 g/cm(2), 95% confidence interval [CI], 22.18-41.49 [P < .01]; AMA: 6.88 g/cm(2), 95% CI, 2.51-11.26 [P < .01]; AFA: 6.97 g/cm(2), 95% CI, 3.53-10.41 [P < .01]). In addition, MUAC and AMA were both associated with decreased odds for low birth weight (LBW; <2500 g) (MUAC: odds ratio [OR] = 0.85, 95% CI, 0.77-0.94 [P < .01]; AMA: OR = 0.95, 95% CI, 0.91-0.99 [P < .05]). These findings support the use of MUAC as an efficient, cost-effective screening tool for LBW in HIV-infected women, as in HIV-uninfected women. PMID- 22511657 TI - Autonomic modulation: an emerging paradigm for the treatment of cardiovascular diseases. PMID- 22511658 TI - Fibroblasts, focal triggers, and persistent atrial fibrillation: is there a connection? PMID- 22511659 TI - Commotio cordis: ventricular fibrillation triggered by chest impact-induced abnormalities in repolarization. PMID- 22511660 TI - Microbiology and pathogenesis of cardiovascular implantable electronic device infections. PMID- 22511661 TI - Arrhythmogenic implications of fibroblast-myocyte interactions. PMID- 22511662 TI - Three-dimensional delayed-enhanced cardiac MRI reconstructions to guide ventricular tachycardia ablations and assess ablation lesions. PMID- 22511663 TI - Deglutition-induced atrial tachycardia: direct visualization by intracardiac echocardiography. PMID- 22511664 TI - Bipolar ablation of ventricular tachycardia in a patient after atrial switch operation for dextro-transposition of the great arteries. PMID- 22511665 TI - Catheter ablation of atrial fibrillation in transposition of the great arteries treated with mustard atrial baffle. PMID- 22511666 TI - Premature beats and unexpected heart block: an unusual mechanism confirmed by ablation. PMID- 22511667 TI - Right coronary artery fistula as a result of delayed right atrial perforation by a passive fixation lead. PMID- 22511669 TI - Letter by Casado-Arroyo et al regarding article, "Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization". PMID- 22511671 TI - US can draw insight from other nations' experiences with evidence-based medicine. PMID- 22511672 TI - A push for comparative effectiveness: US initiatives aim to empower patients, physicians. Interview by Bridget M. Kuehn. PMID- 22511673 TI - Studies may not provide clear view of antipsychotics. PMID- 22511678 TI - Cardiovascular events after bariatric surgery. PMID- 22511679 TI - Potassium levels after acute myocardial infarction. PMID- 22511680 TI - Potassium levels after acute myocardial infarction. PMID- 22511681 TI - Use of administrative data to estimate the incidence of statin-related rhabdomyolysis. PMID- 22511682 TI - The Patient-Centered Outcomes Research Institute (PCORI) national priorities for research and initial research agenda. PMID- 22511683 TI - Risk models and patient-centered evidence: should physicians expect one right answer? PMID- 22511684 TI - Continuous patient engagement in comparative effectiveness research. PMID- 22511685 TI - Addressing low-risk comparative effectiveness research in proposed changes to US federal regulations governing research. PMID- 22511686 TI - A piece of my mind. Ask me if I cleaned my hands. PMID- 22511687 TI - Carboplatin and paclitaxel with vs without bevacizumab in older patients with advanced non-small cell lung cancer. AB - CONTEXT: A previous randomized trial demonstrated that adding bevacizumab to carboplatin and paclitaxel improved survival in advanced non-small cell lung cancer (NSCLC). However, longer survival was not observed in the subgroup of patients aged 65 years or older. OBJECTIVE: To examine whether adding bevacizumab to carboplatin and paclitaxel chemotherapy is associated with improved survival in older patients with NSCLC. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 4168 Medicare beneficiaries aged 65 years or older with stage IIIB or stage IV non-squamous cell NSCLC diagnosed in 2002-2007 in a Surveillance, Epidemiology, and End Results (SEER) region. Patients were categorized into 3 cohorts based on diagnosis year and type of initial chemotherapy administered within 4 months of diagnosis: (1) diagnosis in 2006 2007 and bevacizumab-carboplatin-paclitaxel therapy; (2) diagnosis in 2006-2007 and carboplatin-paclitaxel therapy; or (3) diagnosis in 2002-2005 and carboplatin paclitaxel therapy. The associations between carboplatin-paclitaxel with vs without bevacizumab and overall survival were compared using Cox proportional hazards models and propensity score analyses including information about patient characteristics recorded in SEER-Medicare. MAIN OUTCOME MEASURE: Overall survival measured from the first date of chemotherapy treatment until death or the censoring date of December 31, 2009. RESULTS: The median survival estimates were 9.7 (interquartile range [IQR], 4.4-18.6) months for bevacizumab-carboplatin paclitaxel, 8.9 (IQR, 3.5-19.3) months for carboplatin-paclitaxel in 2006-2007, and 8.0 (IQR, 3.7-17.2) months for carboplatin-paclitaxel in 2002-2005. One-year survival probabilities were 39.6% (95% CI, 34.6%-45.4%) for bevacizumab carboplatin-paclitaxel vs 40.1% (95% CI, 37.4%-43.0%) for carboplatin-paclitaxel in 2006-2007 and 35.6% (95% CI, 33.8%-37.5%) for carboplatin-paclitaxel in 2002 2005. Neither multivariable nor propensity score-adjusted Cox models demonstrated a survival advantage for bevacizumab-carboplatin-paclitaxel compared with carboplatin-paclitaxel cohorts. In propensity score-stratified models, the hazard ratio for overall survival for bevacizumab-carboplatin-paclitaxel compared with carboplatin-paclitaxel in 2006-2007 was 1.01 (95% CI, 0.89-1.16; P = .85) and compared with carboplatin-paclitaxel in 2002-2005 was 0.93 (95% CI, 0.83-1.06; P = .28). The propensity score-weighted model and propensity score-matching model similarly failed to demonstrate a statistically significant superiority for bevacizumab-carboplatin-paclitaxel. Subgroup and sensitivity analyses for key variables did not change these findings. CONCLUSION: Adding bevacizumab to carboplatin and paclitaxel chemotherapy was not associated with better survival among Medicare patients with advanced NSCLC. PMID- 22511688 TI - Association between helicopter vs ground emergency medical services and survival for adults with major trauma. AB - CONTEXT: Helicopter emergency medical services and their possible effect on outcomes for traumatically injured patients remain a subject of debate. Because helicopter services are a limited and expensive resource, a methodologically rigorous investigation of its effectiveness compared with ground emergency medical services is warranted. OBJECTIVE: To assess the association between the use of helicopter vs ground services and survival among adults with serious traumatic injuries. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study involving 223,475 patients older than 15 years, having an injury severity score higher than 15, and sustaining blunt or penetrating trauma that required transport to US level I or II trauma centers and whose data were recorded in the 2007-2009 versions of the American College of Surgeons National Trauma Data Bank. INTERVENTIONS: Transport by helicopter or ground emergency services to level I or level II trauma centers. MAIN OUTCOME MEASURES: Survival to hospital discharge and discharge disposition. RESULTS: A total of 61,909 patients were transported by helicopter and 161,566 patients were transported by ground. Overall, 7813 patients (12.6%) transported by helicopter died compared with 17,775 patients (11%) transported by ground services. Before propensity score matching, patients transported by helicopter to level I and level II trauma centers had higher Injury Severity Scores. In the propensity score-matched multivariable regression model, for patients transported to level I trauma centers, helicopter transport was associated with an improved odds of survival compared with ground transport (odds ratio [OR], 1.16; 95% CI, 1.14-1.17; P < .001; absolute risk reduction [ARR], 1.5%). For patients transported to level II trauma centers, helicopter transport was associated with an improved odds of survival (OR, 1.15; 95% CI, 1.13-1.17; P < .001; ARR, 1.4%). A greater proportion (18.2%) of those transported to level I trauma centers by helicopter were discharged to rehabilitation compared with 12.7% transported by ground services (P < .001), and 9.3% transported by helicopter were discharged to intermediate facilities compared with 6.5% by ground services (P < .001). Fewer patients transported by helicopter left level II trauma centers against medical advice (0.5% vs 1.0%, P < .001). CONCLUSION: Among patients with major trauma admitted to level I or level II trauma centers, transport by helicopter compared with ground services was associated with improved survival to hospital discharge after controlling for multiple known confounders. PMID- 22511689 TI - Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. AB - CONTEXT: There has been rapid adoption of newer radiation treatments such as intensity-modulated radiation therapy (IMRT) and proton therapy despite greater cost and limited demonstrated benefit compared with previous technologies. OBJECTIVE: To determine the comparative morbidity and disease control of IMRT, proton therapy, and conformal radiation therapy for primary prostate cancer treatment. DESIGN, SETTING, AND PATIENTS: Population-based study using Surveillance, Epidemiology, and End Results-Medicare-linked data from 2000 through 2009 for patients with nonmetastatic prostate cancer. MAIN OUTCOME MEASURES: Rates of gastrointestinal and urinary morbidity, erectile dysfunction, hip fractures, and additional cancer therapy. RESULTS: Use of IMRT vs conformal radiation therapy increased from 0.15% in 2000 to 95.9% in 2008. In propensity score-adjusted analyses (N = 12,976), men who received IMRT vs conformal radiation therapy were less likely to receive a diagnosis of gastrointestinal morbidities (absolute risk, 13.4 vs 14.7 per 100 person-years; relative risk [RR], 0.91; 95% CI, 0.86-0.96) and hip fractures (absolute risk, 0.8 vs 1.0 per 100 person-years; RR, 0.78; 95% CI, 0.65-0.93) but more likely to receive a diagnosis of erectile dysfunction (absolute risk, 5.9 vs 5.3 per 100 person years; RR, 1.12; 95% CI, 1.03-1.20). Intensity-modulated radiation therapy patients were less likely to receive additional cancer therapy (absolute risk, 2.5 vs 3.1 per 100 person-years; RR, 0.81; 95% CI, 0.73-0.89). In a propensity score-matched comparison between IMRT and proton therapy (n = 1368), IMRT patients had a lower rate of gastrointestinal morbidity (absolute risk, 12.2 vs 17.8 per 100 person-years; RR, 0.66; 95% CI, 0.55-0.79). There were no significant differences in rates of other morbidities or additional therapies between IMRT and proton therapy. CONCLUSIONS: Among patients with nonmetastatic prostate cancer, the use of IMRT compared with conformal radiation therapy was associated with less gastrointestinal morbidity and fewer hip fractures but more erectile dysfunction; IMRT compared with proton therapy was associated with less gastrointestinal morbidity. PMID- 22511690 TI - Comparison of long-term survival after open vs endovascular repair of intact abdominal aortic aneurysm among Medicare beneficiaries. AB - CONTEXT: Endovascular repair of abdominal aortic aneurysm (AAA) compared with open repair increases perioperative survival, but it is not known if it increases long-term survival. OBJECTIVE: To compare long-term outcomes after open vs endovascular repair of AAA. DESIGN, SETTING, AND PATIENTS: Retrospective analysis of patients 65 years or older in the Medicare Standard Analytic File, 2003-2007, who underwent isolated repair of intact AAA. Cause of death was determined from the National Death Index. MAIN OUTCOME MEASURES: The primary outcome was all cause mortality. Secondary outcomes were AAA-related mortality, hospital length of stay, 1-year readmission, repeat AAA repair, incisional hernia repair, and lower extremity amputation. RESULTS: Of 4529 included patients, 703 were classified as having undergone open repair and 3826 as having undergone endovascular repair. Mean and median follow-up times were 2.6 (SD, 1.5) and 2.5 (interquartile range, 2.4) years, respectively. In unadjusted analysis, both all cause mortality (173 vs 752; 89 vs 76/1000 person-years, P = .04) and AAA specific mortality (22 vs 28; 11.3 vs 2.8/1000 person-years, P < .001) were higher after open vs endovascular repair. After adjusting for emergency admission, age, calendar year, sex, race, and comorbidities, there was a higher risk of both all-cause mortality (hazard ratio [HR], 1.24 [95% CI, 1.05-1.47]; P = .01) and AAA-related mortality (HR, 4.37 [95% CI, 2.51-7.66]; P < .001) after open vs endovascular repair. The adjusted hospital length of stay was, on average, 6.5 days (95% CI, 6.0-7.0 days, P < .001) longer after open repair (mean, 10.4 days), compared with endovascular repair (mean, 3.6 days). Incidence of incisional hernia repair was higher after open AAA repair (19 vs 23; 12 vs 3 per 1000 person-years; adjusted HR, 4.45 [95% CI, 2.37-8.34, P < .001]), whereas the incidence of 1-year readmission (188 vs 1070; 274 vs 376/1000 person-years; adjusted HR, 0.96 [95% CI, 0.85-1.09, P = .52]), repeat AAA repair (15 vs 93; 9.7 vs 12.3/1000 person-years; adjusted HR, 0.80 [95% CI, 0.46-1.38, P = .42]), and lower extremity amputation (3 vs 25; 1.9 vs 3.3/1000 person-years; adjusted HR, 0.55 [95% CI, 0.16-1.86, P = .34]) did not differ by repair type. CONCLUSION: Among older patients with isolated intact AAA, use of open repair compared with endovascular repair was associated with increased risk of all-cause mortality and AAA-related mortality. PMID- 22511692 TI - Methodological standards and patient-centeredness in comparative effectiveness research: the PCORI perspective. AB - Rigorous methodological standards help to ensure that medical research produces information that is valid and generalizable, and are essential in patient centered outcomes research (PCOR). Patient-centeredness refers to the extent to which the preferences, decision-making needs, and characteristics of patients are addressed, and is the key characteristic differentiating PCOR from comparative effectiveness research. The Patient Protection and Affordable Care Act signed into law in 2010 created the Patient-Centered Outcomes Research Institute (PCORI), which includes an independent, federally appointed Methodology Committee. The Methodology Committee is charged to develop methodological standards for PCOR. The 4 general areas identified by the committee in which standards will be developed are (1) prioritizing research questions, (2) using appropriate study designs and analyses, (3) incorporating patient perspectives throughout the research continuum, and (4) fostering efficient dissemination and implementation of results. A Congressionally mandated PCORI methodology report (to be issued in its first iteration in May 2012) will begin to provide standards in each of these areas, and will inform future PCORI funding announcements and review criteria. The work of the Methodology Committee is intended to enable generation of information that is relevant and trustworthy for patients, and to enable decisions that improve patient-centered outcomes. PMID- 22511691 TI - Long-term survival following partial vs radical nephrectomy among older patients with early-stage kidney cancer. AB - CONTEXT: Although partial nephrectomy is the preferred treatment for many patients with early-stage kidney cancer, recent clinical trial data, which demonstrate better survival for patients treated with radical nephrectomy, have generated new uncertainty regarding the comparative effectiveness of these treatment options. OBJECTIVE: To compare long-term survival after partial vs radical nephrectomy among a population-based patient cohort whose treatment reflects contemporary surgical practice. DESIGN, SETTING, AND PATIENTS: We performed a retrospective cohort study of Medicare beneficiaries with clinical stage T1a kidney cancer treated with partial or radical nephrectomy from 1992 through 2007. Using an instrumental variable approach to account for measured and unmeasured differences between treatment groups, we fit a 2-stage residual inclusion model to estimate the treatment effect of partial nephrectomy on long term survival. MAIN OUTCOME MEASURES: Overall and kidney cancer-specific survival. RESULTS: Among 7138 Medicare beneficiaries with early-stage kidney cancer, we identified 1925 patients (27.0%) treated with partial nephrectomy and 5213 patients (73.0%) treated with radical nephrectomy. During a median follow-up of 62 months, 487 (25.3%) and 2164 (41.5%) patients died following partial or radical nephrectomy, respectively. Kidney cancer was the cause of death for 37 patients (1.9%) treated with partial nephrectomy, and 222 patients (4.3%) treated with radical nephrectomy. Patients treated with partial nephrectomy had a significantly lower risk of death (hazard ratio [HR], 0.54; 95% CI, 0.34-0.85). This corresponded with a predicted survival increase with partial nephrectomy of 5.6 (95% CI, 1.9-9.3), 11.8 (95% CI, 3.9-19.7), and 15.5 (95% CI, 5.0-26.0) percentage points at 2, 5, and 8 years posttreatment (P < .001). No difference was noted in kidney cancer-specific survival (HR, 0.82; 95% CI, 0.19-3.49). CONCLUSION: Among Medicare beneficiaries with early-stage kidney cancer who were candidates for either surgery, treatment with partial rather than radical nephrectomy was associated with improved survival. PMID- 22511694 TI - Comparative effectiveness research: relative successes. PMID- 22511693 TI - Is it time for medicine-based evidence? PMID- 22511695 TI - JAMA patient page. Snakebite. PMID- 22511696 TI - Evaluating the relationship between carisoprodol concentrations and meprobamate formation and inter-subject and intra-subject variability in urinary excretion data of pain patients. AB - Using urinary carisoprodol data from pain patients, our objectives were to determine the relationship between carisoprodol concentration and its conversion to meprobamate, and quantify the intra-subject and inter-subject variability in carisoprodol metabolism. Liquid chromatography-tandem mass spectrometry was used to quantitate carisoprodol and meprobamate concentrations in urine specimens. The log creatinine-corrected carisoprodol versus log creatinine-corrected meprobamate showed a marginal positive relationship (R(2) = 0.395), with a 29.1-fold variance between subjects at the mean carisoprodol concentration. The geometric mean carisoprodol and meprobamate urine concentrations were 0.519 +/- 3.38 mg and 28.2 +/- 2.34 mg analyte per gram creatinine, respectively. The log metabolic ratio (MR) versus log creatinine-corrected carisoprodol displayed a marginal positive correlation. A subpopulation of outliers with higher carisoprodol and lower meprobamate levels were considered poor metabolizers and represented 0.483% (n = 21) of the study population. Using a curve-fit mathematical model, we estimated 0.318% (n = 10) to be ultra-rapid metabolizers. The inter-subject population geometric standard deviation (SD) of the MR was 3.64. The intra-subject geometric median and mean SD of the MR were 1.60 (interquartile range: 1.28, 2.07) and 1.72 +/- 1.60, respectively. Inter-subject variability was 2.27 times greater than the median intra-subject variability. With a better understanding of urine carisoprodol and meprobamate concentrations and variability, urine drug testing provides a useful monitoring reference for clinicians. PMID- 22511697 TI - Observations on the urine metabolic ratio of oxymorphone to oxycodone in pain patients. AB - The object of this study was to evaluate the metabolism of oxycodone to oxymorphone in a pain patient population using a quantitative liquid chromatography-tandem mass spectrometry analysis of 32,656 urine specimens obtained from pain patients between March 2008 and Feb 2010. The observed excretion was modeled using logarithmic transformation and approximated a Gaussian distribution. Oxycodone excretion into urine had a geometric mean of 1.93 mg/g of creatinine and oxymorphone had a value of 0.41 mg/g of creatinine. Increasing concentrations of oxycodone correlated with a smaller proportion of oxymorphone excretion suggesting saturation of oxycodone metabolism. Urine samples containing oxycodone without oxymorphone allowed an estimation of the proportion of poor metabolizers (2.4 +/- 2.1%) in the population. A similar analysis of samples containing oxymorphone without oxycodone gave an estimate of the proportion of ultra-rapid metabolizers (1.8 +/- 1.1%) in the population. Samples with concentrations of oxycodone above 10 mg/g of creatinine showed a sub population of subjects with metabolic ratios roughly 100-fold less than the linear predictive model in this study. This study describes typical ranges for oxycodone and oxymorphone in urine, and showed that it is possible to identify fast or slow metabolizers who may be at risk for adverse events. PMID- 22511698 TI - Evaluating the relationship of methadone concentrations and EDDP formation in chronic pain patients. AB - Methadone is used to treat moderate to severe pain in patients not responsive to non-narcotic analgesics and for maintenance treatment of opioid addiction. Methadone is primarily metabolized by N-demethylation to an inactive metabolite 2 ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP) by CYP3A4 and CYP2B6. Establishing expected concentrations for metabolism of methadone to EDDP using urine excretion data may be useful for monitoring "medications" and toxicity. Urine specimens from chronic pain patients were collected during routine clinic visits. Methadone and EDDP were quantified by liquid chromatography-tandem mass spectrometry. Approximately 8,000 subjects who reported taking methadone had creatinine concentrations >=20 mg/dL, and excreted concentrations of methadone and EDDP above >=100 ng/mL were selected. The median methadone urine concentration was 3.03 mg/g cr. Ninety-five percent of the population had concentrations between 0.175 and 20.9 mg/g cr. EDDP was, on average, twice the methadone concentration. The wide variance in relationship of methadone to its metabolite was not concentration-dependent. Variability between subjects was larger than variability within subjects. As the urinary pH increased, the proportion of excreted EDDP increased, implying a preferred excretion of EDDP. PMID- 22511699 TI - Observations on the metabolism of morphine to hydromorphone in pain patients. AB - Morphine is one of several opioids used to treat chronic pain. Because of its high abuse potential, urine drug tests can confirm "consistency with prescribed medications." Hydromorphone is a recently described minor metabolite of morphine, but few data exist on the characteristics of this metabolic pathway or the relationship of morphine and hydromorphone between and within subjects. Part I of this retrospective study shows that formation of hydromorphone from morphine is concentration-dependent and possibly saturated at high concentrations of morphine. In addition, the percentage of ultra-rapid metabolizers and poor metabolizers can be determined using the lower asymptote of a sigmoidal mathematical fit and are estimated to be 0.63 and 4.0%, respectively. Expected limits of morphine and hydromorphone (as a result of morphine metabolism) concentrations in the urine were established. Part II of this study used the metabolic ratio (hydromorphone-morphine) to determine the inter-patient and intra patient variability in morphine metabolism to hydromorphone. Metabolic ratio values varied over a large range; 25-fold and 7-fold, respectively. The expected limits established in this study can assist in assessing the cause for possible variances in metabolism, such as drug interactions. The wide variability between and within subjects may explain unpredictable, adverse effects. PMID- 22511700 TI - Relationship between the concentration of hydrocodone and its conversion to hydromorphone in chronic pain patients using urinary excretion data. AB - Hydrocodone in combination with acetaminophen is commonly used to control moderate pain and is metabolized by cytochrome P4502D6 to form the active metabolite, hydromorphone. The purpose of this study was to determine the metabolic relationship and variability between hydrocodone and its conversion to hydromorphone using urinary excretion data from chronic pain patients. Liquid chromatography-tandem mass spectrometry was used to quantitate hydrocodone and hydromorphone concentrations in urine specimens. The first visits of 25,200 subjects who took hydrocodone and not hydromorphone and had measurable concentrations were included in this study. The geometric mean (95% confidence index) of hydrocodone and hydromorphone urine concentrations were 1.39 (1.37 1.41) mg per gram of creatinine and 0.224 (0.221-0.227) mg per gram of creatinine, respectively. The log of creatinine-corrected hydromorphone versus the log of creatinine-corrected hydrocodone showed a positive relationship (R(2) = 0.20), with 60-fold variability between subjects. The plot of the log of the metabolic ratio ([hydromorphone] divided by [hydrocodone]) versus the log of creatinine-corrected hydrocodone had a coefficient of determination of R(2) = 0.42, with 125-fold variability between subjects. Ultra-rapid metabolizers represented 0.6% of the population, whereas 4% were poor metabolizers. Within subject variability for the excretion of hydrocodone in urine was 23-fold, whereas between-subject variability was 134-fold. Hydrocodone and hydromorphone urine concentrations showed great variability within and between subjects. PMID- 22511701 TI - Accuracy investigation of phthalate metabolite standards. AB - Phthalates are ubiquitous compounds whose metabolites are usually determined in urine for biomonitoring studies. Following suspect and unexplained results from our laboratory in an external quality-assessment scheme, we investigated the accuracy of all phthalate metabolite standards in our possession by comparing them with those of several suppliers. Our findings suggest that commercial phthalate metabolite certified solutions are not always accurate and that lot-to lot discrepancies significantly affect the accuracy of the results obtained with several of these standards. These observations indicate that the reliability of the results obtained from different lots of standards is not equal, which reduces the possibility of intra-laboratory and inter-laboratory comparisons of results. However, agreements of accuracy have been observed for a majority of neat standards obtained from different suppliers, which indicates that a solution to this issue is available. Data accuracy of phthalate metabolites should be of concern for laboratories performing phthalate metabolite analysis because of the standards used. The results of our investigation are presented from the perspective that laboratories performing phthalate metabolite analysis can obtain accurate and comparable results in the future. Our findings will contribute to improving the quality of future phthalate metabolite analyses and will affect the interpretation of past results. PMID- 22511702 TI - Headache bread--a case of high codeine containing variety of poppy seed. PMID- 22511703 TI - LSD screening in urine performed by CEDIA(r) LSD assay: positive interference with sertraline. PMID- 22511704 TI - Is THC-COOH a useful determinant for passive inhalation in oral fluid THC testing? PMID- 22511706 TI - Paraoxonase 1 Q192R variant and clopidogrel efficacy: fact or fiction? PMID- 22511708 TI - Enabling computational proteomics by public and local data management systems. PMID- 22511707 TI - Targeting proteases in cardiovascular diseases by mass spectrometry-based proteomics. PMID- 22511709 TI - Exome sequencing to identify novel genes in hypertension. PMID- 22511710 TI - Hemophilia B gene therapy in humans shows promise. PMID- 22511711 TI - Letter by Singh et al regarding article, "Apolipoprotein isoform e4 does not increase coronary heart disease risk in carriers of low-density lipoprotein receptor mutations". PMID- 22511714 TI - The inexorable resistance of inertia determines the initial regime of drop coalescence. AB - Drop coalescence is central to diverse processes involving dispersions of drops in industrial, engineering, and scientific realms. During coalescence, two drops first touch and then merge as the liquid neck connecting them grows from initially microscopic scales to a size comparable to the drop diameters. The curvature of the interface is infinite at the point where the drops first make contact, and the flows that ensue as the two drops coalesce are intimately coupled to this singularity in the dynamics. Conventionally, this process has been thought to have just two dynamical regimes: a viscous and an inertial regime with a cross-over region between them. We use experiments and simulations to reveal that a third regime, one that describes the initial dynamics of coalescence for all drop viscosities, has been missed. An argument based on force balance allows the construction of a new coalescence phase diagram. PMID- 22511715 TI - Octahydriodo diborane (B2H8) and its protonated cations containing five-, six-, and seven-coordinate boron atoms. AB - Structures of octahydriodo diborane (B(2)H(8)) 1 and its protonated 3, diprotonated 5, triprotonated 6, and tetraprotonated 7 ions were found to be calculationally viable minima at the MP2/cc-pVTZ level of theory. Each structure contains two-electron three-center (2e-3c) bonds. The protonation of 1 to form 3 was found to be strongly exothermic by 176.0 kcal/mol. Subsequent protonation of 3 to form 5 was also found to be exothermic by 28.4 kcal/mol. Further protonation of 5 to form 6 was, however, computed to be endothermic by 122.0 kcal/mol whereas protonation of 6 to form 7 was again highly endothermic by 238.8 kcal/mol. Deprotonation barriers of the ions were also computed. PMID- 22511716 TI - Tissue deformation spatially modulates VEGF signaling and angiogenesis. AB - Physical forces play a major role in the organization of developing tissues. During vascular development, physical forces originating from a fluid phase or from cells pulling on their environment can alter cellular signaling and the behavior of cells. Here, we observe how tissue deformation spatially modulates angiogenic signals and angiogenesis. Using soft lithographic templates, we assemble three-dimensional, geometric tissues. The tissues contract autonomously, change shape stereotypically and form patterns of vascular structures in regions of high deformations. We show that this emergence correlates with the formation of a long-range gradient of Vascular Endothelial Growth Factor (VEGF) in interstitial cells, the local overexpression of the corresponding receptor VEGF receptor 2 (VEGFR-2) and local differences in endothelial cells proliferation. We suggest that tissue contractility and deformation can induce the formation of gradients of angiogenic microenvironments which could contribute to the long range patterning of the vascular system. PMID- 22511717 TI - Climate change and the selective signature of the Late Ordovician mass extinction. AB - Selectivity patterns provide insights into the causes of ancient extinction events. The Late Ordovician mass extinction was related to Gondwanan glaciation; however, it is still unclear whether elevated extinction rates were attributable to record failure, habitat loss, or climatic cooling. We examined Middle Ordovician-Early Silurian North American fossil occurrences within a spatiotemporally explicit stratigraphic framework that allowed us to quantify rock record effects on a per-taxon basis and assay the interplay of macrostratigraphic and macroecological variables in determining extinction risk. Genera that had large proportions of their observed geographic ranges affected by stratigraphic truncation or environmental shifts at the end of the Katian stage were particularly hard hit. The duration of the subsequent sampling gaps had little effect on extinction risk, suggesting that this extinction pulse cannot be entirely attributed to rock record failure; rather, it was caused, in part, by habitat loss. Extinction risk at this time was also strongly influenced by the maximum paleolatitude at which a genus had previously been sampled, a macroecological trait linked to thermal tolerance. A model trained on the relationship between 16 explanatory variables and extinction patterns during the early Katian interval substantially underestimates the extinction of exclusively tropical taxa during the late Katian interval. These results indicate that glacioeustatic sea-level fall and tropical ocean cooling played important roles in the first pulse of the Late Ordovician mass extinction in Laurentia. PMID- 22511718 TI - Toll-like receptor 4-activated B cells out-compete Toll-like receptor 9-activated B cells to establish peripheral immunological tolerance. AB - B-cell-induced peripheral T-cell tolerance is characterized by suppression of T cell proliferation and T-cell-dependent antibody production. However, the cellular interactions that underlie tolerance induction have not been identified. Using two-photon microscopy of lymph nodes we show that tolerogenic LPS-activated membrane-bound ovalbumin (mOVA) B cells (LPS B cells) establish long-lived, highly motile conjugate pairs with responding antigen-specific OTII T cells but not with antigen-irrelevant T cells. Treatment with anti-CTLA-4 disrupts persistent B-cell-T-cell (B-T) contacts and suppresses antigen-specific tolerance. Nontolerogenic CpG-activated mOVA B cells (CpG B cells) also form prolonged, motile conjugates with responding OTII T cells when transferred separately. However, when both tolerogenic and nontolerogenic B-cell populations are present, LPS B cells suppress long-lived CpG B-OTII T-cell interactions and exhibit tolerogenic dominance. Contact of LPS B cells with previously established B-T pairs resulted in partner-swapping events in which LPS B cells preferentially migrate toward and disrupt nontolerogenic CpG mOVA B-cell-OTII T-cell pairs. Our results demonstrate that establishment of peripheral T-cell tolerance involves physical engagement of B cells with the responding T-cell population, acting in a directed and competitive manner to alter the functional outcome of B-T interactions. PMID- 22511719 TI - Test of a motor theory of long-term auditory memory. AB - Monkeys can easily form lasting central representations of visual and tactile stimuli, yet they seem unable to do the same with sounds. Humans, by contrast, are highly proficient in auditory long-term memory (LTM). These mnemonic differences within and between species raise the question of whether the human ability is supported in some way by speech and language, e.g., through subvocal reproduction of speech sounds and by covert verbal labeling of environmental stimuli. If so, the explanation could be that storing rapidly fluctuating acoustic signals requires assistance from the motor system, which is uniquely organized to chain-link rapid sequences. To test this hypothesis, we compared the ability of normal participants to recognize lists of stimuli that can be easily reproduced, labeled, or both (pseudowords, nonverbal sounds, and words, respectively) versus their ability to recognize a list of stimuli that can be reproduced or labeled only with great difficulty (reversed words, i.e., words played backward). Recognition scores after 5-min delays filled with articulatory suppression tasks were relatively high (75-80% correct) for all sound types except reversed words; the latter yielded scores that were not far above chance (58% correct), even though these stimuli were discriminated nearly perfectly when presented as reversed-word pairs at short intrapair intervals. The combined results provide preliminary support for the hypothesis that participation of the oromotor system may be essential for laying down the memory of speech sounds and, indeed, that speech and auditory memory may be so critically dependent on each other that they had to coevolve. PMID- 22511721 TI - Cross-cultural experiments are more useful when explanans and explanandum are separated. PMID- 22511720 TI - Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis. AB - Although melanomas with mutant v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) can now be effectively targeted, there is no molecular target for most melanomas expressing wild-type BRAF. Here, we show that the activation of Pleckstrin homology domain-interacting protein (PHIP), promotes melanoma metastasis, can be used to classify a subset of primary melanomas, and is a prognostic biomarker for melanoma. Systemic, plasmid-based shRNA targeting of Phip inhibited the metastatic progression of melanoma, whereas stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged the survival of tumor-bearing mice. The human PHIP gene resides on 6q14.1, and although 6q loss has been observed in melanoma, the PHIP locus was preserved in melanoma cell lines and patient samples, and its overexpression was an independent adverse predictor of survival in melanoma patients. In addition, a high proportion of PHIP-overexpressing melanomas harbored increased PHIP copy number. PHIP-overexpressing melanomas include tumors with wild-type BRAF, neuroblastoma RAS viral (v-ras) oncogene homolog, and phosphatase and tensin homolog, demonstrating PHIP activation in triple-negative melanoma. These results describe previously unreported roles for PHIP in predicting and promoting melanoma metastasis, and in the molecular classification of melanoma. PMID- 22511723 TI - Juvenile hominoid cranium from the late Miocene of southern China and hominoid diversity in Asia. AB - The fossil ape Lufengpithecus is known from a number of late Miocene sites in Yunnan Province in southern China. Along with other fossil apes from South and Southeast Asia, it is widely considered to be a relative of the extant orangutan, Pongo pygmaeus. It is best represented at the type site of Shihuiba (Lufeng) by several partial to nearly complete but badly crushed adult crania. There is, however, an additional, minimally distorted cranium of a young juvenile from a nearly contemporaneous site in the Yuanmou Basin, which affords the opportunity to better assess the relationships between Lufengpithecus and Pongo. Comparison with similarly aged juvenile skulls of extant great apes reveals no features suggesting clear affinities to orangutans, and instead reveals a morphological pattern largely consistent with a stem member of the hominid (great ape and human) clade. The existence at this time of other hominids in South Asia (Sivapithecus) and Southeast Asia (Khoratpithecus) with clear craniofacial affinities to Pongo suggests both more diversity among Asian Late Miocene apes and more complex patterns of dispersal than previously supposed. Major differences in the associated mammal faunas from the southern China sites and those from South and Southeast Asia are consistent with these findings and suggest more than one dispersal route of apes into East Asia earlier in the Miocene. PMID- 22511724 TI - Weak evidence for sardine collapse. PMID- 22511722 TI - Dynamic migration of gammadelta intraepithelial lymphocytes requires occludin. AB - gammadelta intraepithelial lymphocytes (IELs) are located beneath or between adjacent intestinal epithelial cells and are thought to contribute to homeostasis and disease pathogenesis. Using in vivo microscopy to image jejunal mucosa of GFP gammadelta T-cell transgenic mice, we discovered that gammadelta IELs migrate actively within the intraepithelial compartment and into the lamina propria. As a result, each gammadelta IEL contacts multiple epithelial cells. Occludin is concentrated at sites of gammadelta IEL/epithelial interaction, where it forms a ring surrounding the gammadelta IEL. In vitro analyses showed that occludin is expressed by epithelial and gammadelta T cells and that occludin derived from both cell types contributes to these rings and to gammadelta IEL migration within epithelial monolayers. In vivo TNF administration, which results in epithelial occludin endocytosis, reduces gammadelta IEL migration. Further in vivo analyses demonstrated that occludin KO gammadelta T cells are defective in both initial accumulation and migration within the intraepithelial compartment. These data challenge the paradigm that gammadelta IELs are stationary in the intestinal epithelium and demonstrate that gammadelta IELs migrate dynamically to make extensive contacts with epithelial cells. The identification of occludin as an essential factor in gammadelta IEL migration provides insight into the molecular regulation of gammadelta IEL/epithelial interactions. PMID- 22511725 TI - Associations of anger, anxiety, and depressive symptoms with carotid arterial wall thickness: the multi-ethnic study of atherosclerosis. AB - OBJECTIVE: Carotid arterial wall thickness, measured as intima-media thickness (IMT), is an early subclinical indicator of cardiovascular disease. Few studies have investigated the association of psychological factors with IMT across multiple ethnic groups and by sex. METHODS: We included 6561 men and women (2541 whites, 1790 African Americans, 1436 Hispanics, and 794 Chinese) aged 45 to 84 years who took part in the first examination of the Multi-Ethnic Study of Atherosclerosis. Associations of trait anger, trait anxiety, and depressive symptoms with mean values of common carotid artery (CCA) and internal carotid artery (ICA) IMTs were investigated using multivariable regression and logistic models. RESULTS: In age-, sex-, and race/ethnicity-adjusted analyses, the trait anger score was positively associated with CCA and ICA IMTs (mean differences per 1-standard deviation increment of trait anger score were 0.014 [95% confidence interval {CI} = 0.003-0.025, p = .01] and 0.054 [95% CI = 0.017-0.090, p = .004] for CCA and ICA IMTs, respectively). Anger was also associated with the presence of carotid plaque (age-, sex-, and race/ethnicity-adjusted odds ratio per 1 standard deviation increase in trait anger = 1.27 [95% CI = 1.06-1.52]). The associations of the anger score with thicker IMT were attenuated after adjustment for covariates but remained statistically significant. Associations were stronger in men than in women and in whites than in other race/ethnic groups, but heterogeneity was only marginally statistically significant by race/ethnicity. There was no association of depressive symptoms or trait anxiety with IMT. CONCLUSIONS: Only one of the three measures examined was associated with IMT, and the patterns seemed to be heterogeneous across race/ethnic groups. PMID- 22511726 TI - Combat-exposed war veterans at risk for suicide show hyperactivation of prefrontal cortex and anterior cingulate during error processing. AB - OBJECTIVE: Suicide is a significant public health problem. Suicidal ideation (SI) increases the risk for completed suicide. However, the brain basis of SI is unknown. The objective of this study was to examine the neural correlates of self monitoring in individuals at risk for suicide. We hypothesized that combat veterans with a history of SI relative to those without such a history would show altered activation in the anterior cingulate cortex and related circuitry during self-monitoring. METHODS: Two groups of combat-exposed war veterans (13 men with and 13 men without history of SI) were studied. Both the SI and non-SI participants had two or more of the following: a) current major depressive disorder, b) current posttraumatic stress disorder, and c) history of mild traumatic brain injury, and each subject performed a validated stop task during functional magnetic resonance imaging. Error-related activation was compared between the SI and non-SI groups. RESULTS: The SI group demonstrated more error related activation of the anterior cingulate (8256 mm(3), t = 2.51) and prefrontal cortex (i.e., clusters >2048 mm(3), voxelwise p < .05). The SI and non SI participants showed similar behavioral task performance (i.e., mean error rate, F values < 0.63, p values > .43; and mean reaction times, F = 0.27, p = .61). CONCLUSIONS: These findings suggest neural correlates of altered self monitoring in individuals with a history of SI and may further suggest that functional magnetic resonance imaging could be used to identify individuals at risk for suicide before they engage in suicidal behavior. PMID- 22511727 TI - Somatic depression predicts mortality in chronic heart failure: can this be explained by covarying symptoms of fatigue? AB - OBJECTIVE: Somatic symptoms of depression predict mortality in chronic heart failure (CHF), but symptoms of fatigue that are common to both conditions may confound this association. We therefore examined the contribution of fatigue to the association between somatic depression and increased risk of mortality in patients with CHF. METHODS: At baseline, 380 consecutive patients with CHF were assessed for symptoms of depression, exertion fatigue, and general fatigue. Demographic and clinical data were obtained from the patients' medical records or the treating cardiologist. The primary end point was mortality after a median follow-up of 2.3 years (range = 0.15-4.76 years). RESULTS: At follow-up, 63 patients (16.6%) had died. Exertion fatigue (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 1.01-1.06, p = .003), not general fatigue, was associated with an increased risk of mortality in CHF. Multivariate Cox regression analysis revealed that somatic symptoms of depression (HR = 1.41, 95% CI = 1.05-1.88, p = .02) were independently associated with increased mortality risk and that this association could not be explained by exertion fatigue (HR = 1.02, 95% CI = 0.97-1.05, p = .31). CONCLUSIONS: The adverse effect of somatic depression on prognosis in CHF was not confounded by exertion fatigue. Behavioral interventions should focus not only on fatigue but also on other somatic manifestations of depression in patients with CHF. PMID- 22511728 TI - Distinctive biological correlates of positive psychological well-being in older men and women. AB - OBJECTIVE: Positive psychological well-being is associated with reduced risk of chronic illnesses. Biological risk factors may contribute to these effects, although sex differences may be present. Two aspects of well-being can be distinguished: affective well-being (happiness and pleasure) and eudaemonia (sense of autonomy and purposeful engagement with life). We evaluated relationships between both affective and eudaemonic well-being and biological measures in a large sample of older people. METHODS: This cross-sectional study analyzed the English Longitudinal Study of Ageing, a nationally representative cohort aged 50 years or older. In this study, 7795 participants completed positive well-being and depressive symptom measures. Waist circumference, dehydroepiandosterone sulfate, C-reactive protein, fibrinogen, high-density lipoprotein cholesterol, plasma triglycerides, and peak expiratory flow were assessed. RESULTS: In men, affective well-being was associated with smaller waist circumference (B = -0.206, p < .001) and greater levels of dehydroepiandosterone sulfate (B = 0.072, p = .003). Affective well-being in women was related to lower concentrations of inflammatory markers (C-reactive protein and fibrinogen, B = 0.242 and -0.024, respectively, p < .001) and greater high-density lipoprotein cholesterol (B = 0.011, p = .017). Both men and women showed associations between well-being and lower levels of plasma triglycerides (B = -0.032, p < .001) and better lung function (B = 3.594, p < .001). Associations were independent of age, marital status, socioeconomic circumstances, body mass, smoking, limiting long standing illnesses, health indicators, and depressive symptoms. Similar results were obtained for eudaemonic well-being. CONCLUSIONS: Positive psychological well being has biological correlates that may be health protective, with distinctive patterns for men and women. PMID- 22511730 TI - Introducing analysis of means to medical statistics. AB - Statistical hypothesis testing involving the comparison of three or more means and/or proportions is a frequent undertaking in medical statistics. For comparison of means, analysis of variance is a common choice and for comparison of proportions, chi(2) tests are common. However, both these approaches have important limitations which include the need for post hoc testing to identify the unusual group(s) without an integral graphical device to present the final results. These limitations are elegantly overcome by the analysis of means, which is widely used in industrial statistics, and illustrated here using means and proportions. PMID- 22511729 TI - Structural brain abnormalities in adolescent anorexia nervosa before and after weight recovery and associated hormonal changes. AB - OBJECTIVE: The neurobiological mechanisms of structural brain abnormalities in patients with anorexia nervosa (AN) remain poorly understood. In particular, little is known about the changes in and the recovery of gray matter (GM) volumes after weight gain and the relation to hormonal normalization in adolescent patients with AN. METHODS: Nineteen female patients aged 12 to 17 years were assessed using magnetic resonance imaging at the time of admission to the hospital (T1) and after weight recovery (T2). Patients were compared with typically developing girls matched for age and intelligence quotient. Structural brain images were analyzed using a voxel-based morphometric approach. Circulating levels of cortisol and gonadotropins were assessed in blood samples. RESULTS: Compared with controls, patients with AN showed reduced GM in several brain regions along the cortical midline, reaching from the occipital cortex to the medial frontal areas. These GM reductions were mostly reversible at T1. Patients showed a GM increase from T1 to T2 along the cortical midline and in the occipital, temporal, parietal, and frontal lobes. GM increases at T2 correlated inversely with cortisol levels at T1 and positively with weight gain at T2. The strongest associations between regional GM increase and weight gain were found in the cerebellum. In addition, increases in GM volumes at T2 in the thalamus, hippocampus, and amygdala were associated with increases in follicle-stimulating hormone. CONCLUSIONS: Our data suggest that brain alterations in adolescents with acute AN are mostly reversible at T1 and that GM recovery in specific brain regions is associated with weight and hormonal normalization. PMID- 22511731 TI - An analysis of workers' tritium concentration in urine samples as a function of time after intake at Korean pressurised heavy water reactors. AB - In general, internal exposure from tritium at pressurised heavy water reactors (PHWRs) accounts for ~20-40 % of the total radiation dose. Tritium usually reaches the equilibrium concentration after a few hours inside the body and is then excreted from the body with an effective half-life in the order of 10 d. In this study, tritium metabolism was reviewed using its excretion rate in urine samples of workers at Korean PHWRs. The tritium concentration in workers' urine samples was also measured as a function of time after intake. On the basis of the monitoring results, changes in the tritium concentration inside the body were then analysed. PMID- 22511732 TI - Assessment of leakage doses around the treatment heads of different linear accelerators. AB - Out-of-field doses to untargeted organs may have long-term detrimental health effects for patients treated with radiotherapy. It has been observed that equivalent treatments delivered to patients with different accelerators may result in significant differences in the out-of-field dose. In this work, the points of leakage dose are identified about the gantry of several treatment units. The origin of the observed higher doses is investigated. LiF:Mg,Cu,P thermoluminescent dosimetry has been employed to quantify the dose at a several points around the linac head of various linear accelerators (linacs): a Varian 600C, Varian 21-iX, Siemens Primus and Elekta Synergy-II. Comparisons are also made between different energy modes, collimator rotations and field sizes. Significant differences in leaked photon doses were identified when comparing the various linac models. The isocentric-waveguide 600C generally exhibits the lowest leakage directed towards the patient. The Siemens and Elekta models generally produce a greater leakage than the Varian models. The leakage 'hotspots' are evident on the gantry section housing the waveguide on the 21-iX. For all machines, there are significant differences in the x and y directions. Larger field sizes result in a greater leakage at the interface plate. There is a greater leakage around the waveguide when operating in a low-energy mode, but a greater leakage for the high-energy mode at the linac face. Of the vendors investigated, the Varian 600C showed the lowest average leakage dose. The Varian 21-iX showed double the dose of the 600C. The Elekta Synergy-II had on average four times the dose leakage than the 600C, and the Siemens Primus showed an average of five times that of the 600C. All vendors show strong differences in the x and y directions. The results offer the potential for patient-positioning strategies, linac choice and shielding strategies to reduce the leakage dose to patients. PMID- 22511733 TI - The impact of huts on physiological stress: a refinement in post-transport housing of male guineapigs (Cavia porcellus). AB - The ideal animal model would contribute no confounding variables in experimental science. Variables affect experimental design resulting in increased animal use or repeated studies. We demonstrated a simple refinement which may reduce the number of animals used experimentally while simultaneously improving animal welfare. The objective of this study was to determine if the presence of a hut was an impact on physiological stress levels, as determined by faecal cortisol concentration, during a routine four-day acclimatization period of newly received male Hartley-Outbred guineapigs. We hypothesized that those animals provided with huts would have decreased physiological stress compared with animals not provided with huts. We examined this effect within both paired and single-housed animals. A between-subjects one-way analysis of variance revealed that pair-housed animals with a hut had significantly lower faecal cortisol concentration than pair-housed animals without a hut and the presence and absence of a hut had no significant impact on faecal cortisol concentration in single-housed animals. These findings show that presence of a hut is beneficial in reducing physiological stress when pair housing male guineapigs and does not appear to have an impact when single housing male guineapigs. In addition, we have shown that faecal cortisol, and therefore physiological stress, is still increasing on study day 4 suggesting a longer acclimatization period is necessary. A simple refinement in housing environment and acclimatization time can both reduce the number of animals used experimentally and improve animal welfare. PMID- 22511734 TI - Evaluating methods of mouse euthanasia on the oocyte quality: cervical dislocation versus isoflurane inhalation. AB - Cervical dislocation is a commonly used method of mouse euthanasia. Euthanasia by isoflurane inhalation is an alternative method which allows the sacrifice of several mice at the same time with an anaesthesia, in the aim to decrease pain and animal distress. The objective of our study was to assess the impact of these two methods of euthanasia on the quality of mouse oocytes. By administering gonadotropins, we induced a superovulation in CD1 female mice. Mice were randomly assigned to euthanasia with cervical dislocation and isoflurane inhalation. Oviducts were collected and excised to retrieve metaphase II oocytes. After microscopic examination, oocytes were classified into three groups: intact, fragmented/cleaved and atretic. Intact metaphase II oocytes were employed for biomedical research. A total of 1442 oocytes in the cervical dislocation group were compared with 1230 oocytes in the isoflurane group. In the cervical dislocation group, 93.1% of the oocytes were intact, versus 65.8% in the isoflurane group (P <= 0.001). In light of these results, we conclude that cervical dislocation is the best method of mouse euthanasia for obtaining intact oocytes for biomedical research. PMID- 22511735 TI - Lessons learned from recent randomized clinical trials for intermittent claudication. PMID- 22511736 TI - The prequel: defining prognostically important criteria in the periprocedural PCI troponin saga. PMID- 22511737 TI - On the edge: targeting Toll-like receptor 2 in ischemia/reperfusion injury. PMID- 22511739 TI - Edge effect from drug-eluting stents as assessed with serial intravascular ultrasound: a systematic review. PMID- 22511740 TI - Coronary pressure-derived fractional flow reserve measurements: recommendations for standardization, recording, and reporting as a core laboratory technique. Proposals for integration in clinical trials. PMID- 22511738 TI - Cardiovascular devices and platelet interactions: understanding the role of injury, flow, and cellular responses. PMID- 22511741 TI - Transient increase in pressure gradients after termination of dual antiplatelet therapy in a patient after transfemoral aortic valve implantation. PMID- 22511742 TI - "Frozen" leaflet: a dreadful complication of transcatheter aortic valve implantation. PMID- 22511743 TI - Branch pulmonary artery jailing with a bare metal stent to anchor a transcatheter pulmonary valve in patients with patched large right ventricular outflow tract. PMID- 22511744 TI - Delayed perforation of coronary artery after percutaneous coronary intervention of left main bifurcation lesion using two stents. PMID- 22511747 TI - Testosterone supplementation in heart failure: a meta-analysis. AB - BACKGROUND: Low testosterone is an independent predictor of reduced exercise capacity and poor clinical outcomes in patients with heart failure (HF). We sought to determine whether testosterone therapy improves exercise capacity in patients with stable chronic HF. METHODS AND RESULTS: We searched Medline, Embase, Web of Science, and Cochrane Central Register of Controlled Trials (1980 2010). Eligible studies included randomized controlled trials (RCTs) reporting the effects of testosterone on exercise capacity in patients with HF. Reviewers determined the methodological quality of studies and collected descriptive, quality, and outcome data. Four trials (n=198; men, 84%; mean age, 67 years) were identified that reported the 6-minute walk test (2 RCTs), incremental shuttle walk test (2 RCTs), or peak oxygen consumption (2 RCTs) to assess exercise capacity after up to 52 weeks of treatment. Testosterone therapy was associated with a significant improvement in exercise capacity compared with placebo. The mean increase in the 6-minute walk test, incremental shuttle walk test, and peak oxygen consumption between the testosterone and placebo groups was 54.0 m (95% CI, 43.0-65.0 m), 46.7 m (95% CI, 12.6-80.9 m), and 2.70 mL/kg per min (95% CI, 2.68-2.72 mL/kg per min), respectively. Testosterone therapy was associated with a significant increase in exercise capacity as measured by units of pooled SDs (net effect, 0.52 SD; 95% CI, 0.10-0.94 SD). No significant adverse cardiovascular events were noted. CONCLUSIONS: Given the unmet clinical needs, testosterone appears to be a promising therapy to improve functional capacity in patients with HF. Adequately powered RCTs are required to assess the benefits of testosterone in this high-risk population with regard to quality of life, clinical events, and safety. PMID- 22511746 TI - Beneficiaries with cardiovascular disease and thePart D coverage gap. AB - BACKGROUND: Medicare Part D improved access to cardiovascular medications. Increased cardiovascular drug use and resulting health improvements could be derailed when beneficiaries enter the coverage gap and must pay 100% of drug costs. The coverage gap remains the subject of Congressional debate; evidence regarding its impact on cardiovascular drug use and health outcomes is needed. METHODS AND RESULTS: We followed 122 255 Medicare beneficiaries with cardiovascular conditions with linked prescription and medical claims who reached the coverage gap spending threshold in 2006 or 2007. Beneficiaries entered the study on reaching the threshold and were followed until an event, the catastrophic coverage spending threshold, or year's end. We matched 3980 beneficiaries who reached the threshold and received no financial assistance (exposed) to 3980 with financial assistance during the gap period (unexposed), using propensity score and high-dimensional propensity score approaches. We compared rates of cardiovascular drug discontinuation, drug switching, and death or hospitalization for acute coronary syndrome (ACS) plus revascularization, congestive heart failure, or atrial fibrillation. In propensity score-matched analyses, exposed beneficiaries were more likely to discontinue (hazard ratio, 1.57; 95% confidence interval, 1.39 to 1.79; risk difference,13.76; 95% confidence interval, 10.99 to 16.54 drugs/100 person-years) but no more or less likely to switch cardiovascular drugs. There were no significant differences in rates of death (propensity score-matched hazard ratio,1.23; 95% confidence interval, 0.89 to 1.71) or other outcomes. CONCLUSIONS: Part D beneficiaries with cardiovascular conditions with no financial assistance during the coverage gap were at increased risk for cardiovascular drug discontinuation; however, the impact of this difference on health outcomes is not clear. PMID- 22511748 TI - Rare, nonsynonymous variant in the smooth muscle-specific isoform of myosin heavy chain, MYH11, R247C, alters force generation in the aorta and phenotype of smooth muscle cells. AB - RATIONALE: Mutations in myosin heavy chain (MYH11) cause autosomal dominant inheritance of thoracic aortic aneurysms and dissections. At the same time, rare, nonsynonymous variants in MYH11 that are predicted to disrupt protein function but do not cause inherited aortic disease are common in the general population and the vascular disease risk associated with these variants is unknown. OBJECTIVE: To determine the consequences of the recurrent MYH11 rare variant, R247C, through functional studies in vitro and analysis of a knock-in mouse model with this specific variant, including assessment of aortic contraction, response to vascular injury, and phenotype of primary aortic smooth muscle cells (SMCs). METHODS AND RESULTS: The steady state ATPase activity (actin-activated) and the rates of phosphate and ADP release were lower for the R247C mutant myosin than for the wild-type, as was the rate of actin filament sliding in an in vitro motility assay. Myh11(R247C/R247C) mice exhibited normal growth, reproduction, and aortic histology but decreased aortic contraction. In response to vascular injury, Myh11(R247C/R247C) mice showed significantly increased neointimal formation due to increased SMC proliferation when compared with the wild-type mice. Primary aortic SMCs explanted from the Myh11(R247C/R247C) mice were dedifferentiated compared with wild-type SMCs based on increased proliferation and reduced expression of SMC contractile proteins. The mutant SMCs also displayed altered focal adhesions and decreased Rho activation, associated with decreased nuclear localization of myocardin-related transcription factor-A. Exposure of the Myh11(R247C/R247C) SMCs to a Rho activator rescued the dedifferentiated phenotype of the SMCs. CONCLUSIONS: These results indicate that a rare variant in MYH11, R247C, alters myosin contractile function and SMC phenotype, leading to increased proliferation in vitro and in response to vascular injury. PMID- 22511749 TI - Role of RyR2 phosphorylation at S2814 during heart failure progression. AB - RATIONALE: Increased activity of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is thought to promote heart failure (HF) progression. However, the importance of CaMKII phosphorylation of ryanodine receptors (RyR2) in HF development and associated diastolic sarcoplasmic reticulum Ca(2+) leak is unclear. OBJECTIVE: Determine the role of CaMKII phosphorylation of RyR2 in patients and mice with nonischemic and ischemic forms of HF. METHODS AND RESULTS: Phosphorylation of the primary CaMKII site S2814 on RyR2 was increased in patients with nonischemic, but not with ischemic, HF. Knock-in mice with an inactivated S2814 phosphorylation site were relatively protected from HF development after transverse aortic constriction compared with wild-type littermates. After transverse aortic constriction, S2814A mice did not exhibit pulmonary congestion and had reduced levels of atrial natriuretic factor. Cardiomyocytes from S2814A mice exhibited significantly lower sarcoplasmic reticulum Ca(2+) leak and improved sarcoplasmic reticulum Ca(2+) loading compared with wild-type mice after transverse aortic constriction. Interestingly, these protective effects on cardiac contractility were not observed in S2814A mice after experimental myocardial infarction. CONCLUSIONS: Our results suggest that increased CaMKII phosphorylation of RyR2 plays a role in the development of pathological sarcoplasmic reticulum Ca(2+) leak and HF development in nonischemic forms of HF such as transverse aortic constriction in mice. PMID- 22511750 TI - Formin mDia1 mediates vascular remodeling via integration of oxidative and signal transduction pathways. AB - RATIONALE: The mammalian diaphanous-related formin (mDia1), governs microtubule and microfilament dynamics while functioning as an effector for Rho small GTP binding proteins during key cellular processes such as adhesion, cytokinesis, cell polarity, and morphogenesis. The cytoplasmic domain of the receptor for advanced glycation endproducts binds to the formin homology 1 domain of mDia1; mDia1 is required for receptor for advanced glycation endproducts ligand-induced cellular migration in transformed cells. OBJECTIVE: Because a key mechanism in vascular remodeling is the induction of smooth muscle cell migration, we tested the role of mDia1 in this process. METHODS AND RESULTS: We report that endothelial denudation injury to the murine femoral artery significantly upregulates mDia1 mRNA transcripts and protein in the injured vessel, particularly in vascular smooth muscle cells within the expanding neointima. Loss of mDia1 expression significantly reduces pathological neointimal expansion consequent to injury. In primary murine aortic smooth muscle cells, mDia1 is required for receptor for advanced glycation endproducts ligand-induced membrane translocation of c-Src, which leads to Rac1 activation, redox phosphorylation of AKT/glycogen synthase kinase 3beta, and consequent smooth muscle cell migration. CONCLUSIONS: We conclude that mDia1 integrates oxidative and signal transduction pathways triggered, at least in part, by receptor for advanced glycation endproducts ligands, thereby regulating pathological neointimal expansion. PMID- 22511751 TI - Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension. AB - RATIONALE: Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by pulmonary vascular obstruction caused, in part, by pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Mitochondrial fragmentation and normoxic activation of hypoxia-inducible factor-1alpha (HIF-1alpha) have been observed in PAH PASMCs; however, their relationship and relevance to the development of PAH are unknown. Dynamin-related protein-1 (DRP1) is a GTPase that, when activated by kinases that phosphorylate serine 616, causes mitochondrial fission. It is, however, unknown whether mitochondrial fission is a prerequisite for proliferation. OBJECTIVE: We hypothesize that DRP1 activation is responsible for increased mitochondrial fission in PAH PASMCs and that DRP1 inhibition may slow proliferation and have therapeutic potential. METHODS AND RESULTS: Experiments were conducted using human control and PAH lungs (n=5) and PASMCs in culture. Parallel experiments were performed in rat lung sections and PASMCs and in rodent PAH models induced by the HIF-1alpha activator, cobalt, chronic hypoxia, and monocrotaline. HIF-1alpha activation in human PAH leads to mitochondrial fission by cyclin B1/CDK1-dependent phosphorylation of DRP1 at serine 616. In normal PASMCs, HIF-1alpha activation by CoCl(2) or desferrioxamine causes DRP1-mediated fission. HIF-1alpha inhibition reduces DRP1 activation, prevents fission, and reduces PASMC proliferation. Both the DRP1 inhibitor Mdivi 1 and siDRP1 prevent mitotic fission and arrest PAH PASMCs at the G2/M interphase. Mdivi-1 is antiproliferative in human PAH PASMCs and in rodent models. Mdivi-1 improves exercise capacity, right ventricular function, and hemodynamics in experimental PAH. CONCLUSIONS: DRP-1-mediated mitotic fission is a cell-cycle checkpoint that can be therapeutically targeted in hyperproliferative disorders such as PAH. PMID- 22511753 TI - Specific beta-containing integrins exert differential control on proliferation and two-dimensional collective cell migration in mammary epithelial cells. AB - Understanding how cell cycle is regulated in normal mammary epithelia is essential for deciphering defects of breast cancer and therefore for developing new therapies. Signals provided by both the extracellular matrix and growth factors are essential for epithelial cell proliferation. However, the mechanisms by which adhesion controls cell cycle in normal epithelia are poorly established. In this study, we describe the consequences of removing the beta1-integrin gene from primary cultures of mammary epithelial cells in situ, using CreER. Upon beta1-integrin gene deletion, the cells were unable to progress efficiently through S-phase, but were still able to undergo collective two-dimensional migration. These responses are explained by the presence of beta3-integrin in beta1-integrin-null cells, indicating that integrins containing different beta subunits exert differential control on mammary epithelial proliferation and migration. beta1-Integrin deletion did not inhibit growth factor signaling to Erk or prevent the recruitment of core adhesome components to focal adhesions. Instead the S-phase arrest resulted from defective Rac activation and Erk translocation to the nucleus. Rac inhibition prevented Erk translocation and blocked proliferation. Activated Rac1 rescued the proliferation defect in beta1 integrin-depleted cells, indicating that this GTPase is essential in propagating proliferative beta1-integrin signals. These results show that beta1-integrins promote cell cycle in mammary epithelial cells, whereas beta3-integrins are involved in migration. PMID- 22511752 TI - Association of fetuin-a with incident diabetes mellitus in community-living older adults: the cardiovascular health study. AB - BACKGROUND: The liver-secreted protein fetuin-A induces peripheral insulin resistance in vitro. In a pilot study, we observed that higher fetuin-A levels were associated with diabetes mellitus in older persons. However, this finding has not been confirmed in large cohorts. We sought to confirm the association of fetuin-A with incident diabetes mellitus in older persons and to determine whether the association differs by age, sex, and race and among persons with cardiovascular disease (CVD). METHODS AND RESULTS: Among 3710 community-living individuals >= 65 years of age without diabetes mellitus at baseline, fetuin-A was measured in serum collected in 1992 to 1993. Participants were followed up for 10.6 years (median) for incident diabetes mellitus. Cox regression models evaluated the association of fetuin-A with incident diabetes mellitus. Interaction terms evaluated heterogeneity by age, sex, race, and CVD. Mean age was 75 years; 60 were female; 15 were black; and 16 had CVD. Mean fetuin-A concentrations were 0.47 +/- 0.10 g/L. During follow-up, 305 incident diabetes cases occurred. Each 0.10-g/L (SD)-greater fetuin-A was associated with 19 higher risk of diabetes mellitus (hazard ratio, 1.19; 95 confidence interval, 1.06-1.33) after adjustment for demographics, lifestyle factors, albumin, kidney function, and CVD. Further adjustment for potential mediators (body mass index, waist circumference, hypertension, lipids, and C-reactive protein) moderately attenuated the association (hazard ratio, 1.13; 95 confidence interval, 1.00 1.28). Results were similar by sex, race, and CVD status but were stronger in persons <75 years old (P for interaction=0.01). CONCLUSIONS: Higher fetuin-A is associated with incident diabetes mellitus in older persons regardless of sex, race, or prevalent CVD status. The association may be attenuated in those >= 75 years of age. PMID- 22511754 TI - Signal-dependent slow leukocyte rolling does not require cytoskeletal anchorage of P-selectin glycoprotein ligand-1 (PSGL-1) or integrin alphaLbeta2. AB - In inflamed venules, neutrophils roll on P- or E-selectin, engage P-selectin glycoprotein ligand-1 (PSGL-1), and signal extension of integrin alpha(L)beta(2) in a low affinity state to slow rolling on intercellular adhesion molecule-1 (ICAM-1). Cytoskeleton-dependent receptor clustering often triggers signaling, and it has been hypothesized that the cytoplasmic domain links PSGL-1 to the cytoskeleton. Chemokines cause rolling neutrophils to fully activate alpha(L)beta(2), leading to arrest on ICAM-1. Cytoskeletal anchorage of alpha(L)beta(2) has been linked to chemokine-triggered extension and force regulated conversion to the high affinity state. We asked whether PSGL-1 must interact with the cytoskeleton to initiate signaling and whether alpha(L)beta(2) must interact with the cytoskeleton to extend. Fluorescence recovery after photobleaching of transfected cells documented cytoskeletal restraint of PSGL-1. The lateral mobility of PSGL-1 similarly increased by depolymerizing actin filaments with latrunculin B or by mutating the cytoplasmic tail to impair binding to the cytoskeleton. Converting dimeric PSGL-1 to a monomer by replacing its transmembrane domain did not alter its mobility. By transducing retroviruses expressing WT or mutant PSGL-1 into bone marrow-derived macrophages from PSGL-1 deficient mice, we show that PSGL-1 required neither dimerization nor cytoskeletal anchorage to signal beta(2) integrin-dependent slow rolling on P selectin and ICAM-1. Depolymerizing actin filaments or decreasing actomyosin tension in neutrophils did not impair PSGL-1- or chemokine-mediated integrin extension. Unlike chemokines, PSGL-1 did not signal cytoskeleton-dependent swing out of the beta(2)-hybrid domain associated with the high affinity state. The cytoskeletal independence of PSGL-1-initiated, alpha(L)beta(2)-mediated slow rolling differs markedly from the cytoskeletal dependence of chemokine-initiated, alpha(L)beta(2)-mediated arrest. PMID- 22511755 TI - Urokinase-type plasminogen activator receptor (uPAR)-mediated regulation of WNT/beta-catenin signaling is enhanced in irradiated medulloblastoma cells. AB - Urokinase plasminogen activator receptor (uPAR) is known to promote invasion, migration, and metastasis in cancer cells. In this report, we showed that ionizing radiation (IR)-induced uPAR has a role in WNT-beta-catenin signaling and mediates induction of cancer stem cell (CSC)-like properties in medulloblastoma cell lines UW228 and D283. We observed that IR induced the expression of uPAR and CSC markers, such as Musashi-1 and CD44, and activated WNT-7a-beta-catenin signaling molecules. Overexpression of uPAR alone or with IR treatment led to increased WNT-7a-beta-catenin-TCF/LEF-mediated transactivation, thereby promoting cancer stemness. In contrast, treatment with shRNA specific for uPAR (pU) suppressed WNT-7a-beta-catenin-TCF/LEF-mediated transactivation both in vitro and in vivo. Quercetin, a potent WNT/beta-catenin inhibitor, suppressed uPAR and uPAR mediated WNT/beta-catenin activation, and furthermore, addition of recombinant human WNT-7a protein induced uPAR, indicating the existence of a mutual regulatory relationship between uPAR and WNT/beta-catenin signaling. We showed that uPAR was physically associated with the WNT effector molecule beta-catenin on the membrane, cytoplasm, and nucleus of IR-treated cells and CSC. Most interestingly, we demonstrated for the first time that localization of uPAR in the nucleus was associated with transcription factors (TF) and their specific response elements. We observed from uPAR-ChIP, TF protein, and protein/DNA array analyses that uPAR associates with activating enhancer-binding protein 2alpha (AP2a) and mediates beta-catenin gene transcription. Moreover, association of uPAR with the beta-catenin.TCF/LEF complex and various other TF involved during embryonic development and cancer indicates that uPAR is a potent activator of stemness, and targeting of uPAR in combination with radiation has significant therapeutic implications. PMID- 22511756 TI - PTTG1 oncogene promotes tumor malignancy via epithelial to mesenchymal transition and expansion of cancer stem cell population. AB - The prognosis of breast cancer patients is related to the degree of metastasis. However, the mechanisms by which epithelial tumor cells escape from the primary tumor and colonize at a distant site are not entirely understood. Here, we analyzed expression levels of pituitary tumor-transforming gene-1 (PTTG1), a relatively uncharacterized oncoprotein, in patient-derived breast cancer tissues with corresponding normal breast tissues. We found that PTTG1 is highly expressed in breast cancer patients, compared with normal tissues. Also, PTTG1 expression levels were correlated with the degree of malignancy in breast cancer cell lines; the more migratory and invasive cancer cell lines MDA-MB-231 and BT549 displayed the higher expression levels of PTTG1 than the less migratory and invasive MCF7 and SK-BR3 and normal MCF10A cell lines. By modulating PTTG1 expression levels, we found that PTTG1 enhances the migratory and invasive properties of breast cancer cells by inducing epithelial to mesenchymal transition, as evidenced by altered morphology and epithelial/mesenchymal cell marker expression patterns and up-regulation of the transcription factor Snail. Notably, down-regulation of PTTG1 also suppressed cancer stem cell population in BT549 cells by decreasing self-renewing ability and tumorigenic capacity, accompanying decreasing CD44(high) CD24(low) cells and Sox2 expression. Up-regulation of PTTG1 had the opposite effects, increasing sphere-forming ability and Sox2 expression. Importantly, PTTG1-mediated malignant tumor properties were due, at least in part, to activation of AKT, known to be a key regulator of both EMT and stemness in cancer cells. Collectively, these results suggest that PTTG1 may represent a new therapeutic target for malignant breast cancer. PMID- 22511757 TI - Inhibition of lipid signaling enzyme diacylglycerol kinase epsilon attenuates mutant huntingtin toxicity. AB - Huntington disease (HD) is a dominantly inherited neurodegenerative disease caused by a polyglutamine expansion in the protein huntingtin (Htt). Striatal and cortical neuronal loss are prominent features of this disease. No disease modifying treatments have been discovered for HD. To identify new therapeutic targets in HD, we screened a kinase inhibitor library for molecules that block mutant Htt cellular toxicity in a mouse HD striatal cell model, Hdh(111Q/111Q) cells. We found that diacylglycerol kinase (DGK) inhibitor II (R59949) decreased caspase-3/7 activity after serum withdrawal in striatal Hdh(111Q/111Q) cells. In addition, R59949 decreased the accumulation of a 513-amino acid N-terminal Htt fragment processed by caspase-3 and blocked alterations in lipid metabolism during serum withdrawal. To identify the diacylglycerol kinase mediating this effect, we knocked down all four DGK isoforms expressed in the brain (beta, gamma, epsilon, and zeta) using siRNA. Only the knockdown of the family member, DGKepsilon, blocked striatal Hdh(111Q/111Q)-mediated toxicity. We also investigated the significance of these findings in vivo. First, we found that reduced function of the Drosophila DGKepsilon homolog significantly improves Htt induced motor dysfunction in a fly model of HD. In addition, we find that the levels of DGKepsilon are increased in the striatum of R6/2 HD transgenic mice when compared with littermate controls. Together, these findings indicate that increased levels of kinase DGKepsilon contribute to HD pathogenesis and suggest that reducing its levels or activity is a potential therapy for HD. PMID- 22511758 TI - Crystal structure of novel dye-linked L-proline dehydrogenase from hyperthermophilic archaeon Aeropyrum pernix. AB - Two types of dye-linked L-proline dehydrogenase (PDH1, alpha4beta4-type hetero octamer, and PDH2, alphabetagammadelta-type heterotetramer) have been identified so far in hyperthermophilic archaea. Here, we report the crystal structure of a third type of L-proline dehydrogenase, found in the aerobic hyperthermophilic archaeon Aeropyrum pernix, whose structure (homodimer) is much simpler than those of previously studied L-proline dehydrogenases. The structure was determined at a resolution of 1.92 A. The asymmetric unit contained one subunit, and a crystallographic 2-fold axis generated the functional dimer. The overall fold of the subunit showed similarity to that of the PDH1 beta-subunit, which is responsible for catalyzing L-proline dehydrogenation. However, the situation at the subunit-subunit interface of the A. pernix enzyme was totally different from that in PDH1. The presence of additional surface elements in the A. pernix enzyme contributes to a unique dimer association. Moreover, the C-terminal Leu(428), which is provided by a tail extending from the FAD-binding domain, shielded the active site, and an L-proline molecule was entrapped within the active site cavity. The K(m) value of a Leu(428) deletion mutant for L-proline was about 800 times larger than the K(m) value of the wild-type enzyme, although the k(cat) values did not differ much between the two enzymes. This suggests the C-terminal Leu(428) is not directly involved in catalysis, but it is essential for maintaining a high affinity for the substrate. This is the first description of an LPDH structure with L-proline bound, and it provides new insight into the substrate binding of LPDH. PMID- 22511759 TI - Ras guanine nucleotide-releasing protein-4 (RasGRP4) involvement in experimental arthritis and colitis. AB - RasGRP4 (Ras guanine nucleotide-releasing protein-4) is an intracellular, calcium regulated guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor expressed in mast cells (MCs) and their progenitors. To study the function of this signaling protein in inflammatory disorders, a homologous recombination approach was used to create a RasGRP4-null C57BL/6 mouse line. The resulting transgenic animals had normal numbers of MCs in their tissues that histochemically and morphologically resembled those in WT C57BL/6 mice. MCs could also be generated from RasGRP4-null mice by culturing their bone marrow cells in IL-3-enriched conditioned medium. Despite these data, the levels of the transcripts that encode the proinflammatory cytokines IL-1beta and TNF-alpha were reduced in phorbol 12-myristate 13-acetate-treated MCs developed from RasGRP4 null mice. Although inflammation was not diminished in a Dermatophagoides farinae dependent model of allergic airway disease, dextran sodium sulfate-induced colitis was significantly reduced in RasGRP4-null mice relative to similarly treated WT mice. Furthermore, experimental arthritis could not be induced in RasGRP4-null mice that had received K/BxN mouse serum. The latter findings raise the possibility that the pharmacologic inactivation of this intracellular signaling protein might be an effective treatment for arthritis or inflammatory bowel disease. PMID- 22511760 TI - Discovery of critical residues for viral entry and inhibition through structural Insight of HIV-1 fusion inhibitor CP621-652. AB - The core structure of HIV-1 gp41 is a stable six-helix bundle (6-HB) folded by its trimeric N- and C-terminal heptad repeats (NHR and CHR). We previously identified that the (621)QIWNNMT(627) motif located at the upstream region of gp41 CHR plays critical roles for the stabilization of the 6-HB core and peptide CP621-652 containing this motif is a potent HIV-1 fusion inhibitor, however, the molecular determinants underlying the stability and anti-HIV activity remained elusive. In this study, we determined the high-resolution crystal structure of CP621-652 complexed by T21. We find that the (621)QIWNNMT(627) motif does not maintain the alpha-helical conformation. Instead, residues Met(626) and Thr(627) form a unique hook-like structure (denoted as M-T hook), in which Thr(627) redirects the peptide chain to position Met(626) above the left side of the hydrophobic pocket on the NHR trimer. The side chain of Met(626) caps the hydrophobic pocket, stabilizing the interaction between the pocket and the pocket binding domain. Our mutagenesis studies demonstrate that mutations of the M-T hook residues could completely abolish HIV-1 Env-mediated cell fusion and virus entry, and significantly destabilize the interaction of NHR and CHR peptides and reduce the anti-HIV activity of CP621-652. Our results identify an unusual structural feature that stabilizes the six-helix bundle, providing novel insights into the mechanisms of HIV-1 fusion and inhibition. PMID- 22511761 TI - Molecular basis for T cell response induced by altered peptide ligand of type II collagen. AB - Mounting evidence from animal models has demonstrated that alterations in peptide MHC interactions with the T cell receptor (TCR) can lead to dramatically different T cell outcomes. We have developed an altered peptide ligand of type II collagen, referred to as A9, which differentially regulates TCR signaling in murine T cells leading to suppression of arthritis in the experimental model of collagen-induced arthritis. This study delineates the T cell signaling pathway used by T cells stimulated by the A9.I-A(q) complex. We have found that T cells activated by A9 bypass the requirement for Zap-70 and CD3-zeta and signal via FcRgamma and Syk. Using collagen-specific T cell hybridomas engineered to overexpress either Syk, Zap-70, TCR-FcRgamma, or CD3-zeta, we demonstrate that A9.I-A(q) preferentially activates FcRgamma/Syk but not CD3-zeta/Zap-70. Moreover, a genetic absence of Syk or FcRgamma significantly reduces the altered peptide ligand induction of the nuclear factor GATA3. By dissecting the molecular mechanism of A9-induced T cell signaling we have defined a new alternate pathway that is dependent upon FcRgamma and Syk to secrete immunoregulatory cytokines. Given the interest in using Syk inhibitors to treat patients with rheumatoid arthritis, understanding this pathway may be critical for the proper application of this therapy. PMID- 22511762 TI - Ataxin-1 poly(Q)-induced proteotoxic stress and apoptosis are attenuated in neural cells by docosahexaenoic acid-derived neuroprotectin D1. AB - Neurodegenerative diseases share two common features: enhanced oxidative stress and cellular inability to scavenge structurally damaged abnormal proteins. Pathogenesis of polyglutamine (poly(Q)) diseases involves increased protein misfolding, along with ubiquitin and chaperon protein-containing nuclear aggregates. In spinocerebellar ataxia, the brain and retina undergo degeneration. Neuroprotectin D1 (NPD1) is made on-demand in the nervous system and retinal pigment epithelial (RPE) cells in response to oxidative stress, which activates prosurvival signaling via regulation of gene expression and other processes. We hypothesized that protein misfolding-induced proteotoxic stress triggers NPD1 synthesis. We used ARPE-19 cells as a cellular model to assess stress due to ataxin-1 82Q protein expression and determine whether NPD1 prevents apoptosis. Ectopic ataxin-1 expression induced RPE cell apoptosis, which was abrogated by 100 nm docosahexaenoic acid, 10 ng/ml pigment epithelium-derived factor, or NPD1. Similarly, NPD1 was protective in neurons and primary human RPE cells. Furthermore, when ataxin-1 82Q was expressed in 15-lipoxygenase-1-deficient cells, apoptosis was greatly enhanced, and only NPD1 (50 nm) rescued cells from death. NPD1 reduced misfolded ataxin-1-induced accumulation of proapoptotic Bax in the cytoplasm, suggesting that NPD1 acts by preventing proapoptotic signaling pathways from occurring. Finally, NPD1 signaling interfered with ataxin-1/capicua repression of gene expression and decreased phosphorylated ataxin-1 in an Akt independent manner, suggesting that NPD1 signaling modulates formation or stabilization of ataxin-1 complexes. These data suggest that 1) NPD1 synthesis is an early response induced by proteotoxic stress due to abnormally folded ataxin 1, and 2) NPD1 promotes cell survival through modulating stabilization of ataxin 1 functional complexes and pro-/antiapoptotic and inflammatory pathways. PMID- 22511763 TI - TATA-binding protein (TBP)-like protein is required for p53-dependent transcriptional activation of upstream promoter of p21Waf1/Cip1 gene. AB - TATA-binding protein-like protein (TLP) is involved in development, checkpoint, and apoptosis through potentiation of gene expression. TLP-overexpressing human cells, especially p53-containing cells, exhibited a decreased growth rate and increased proportion of G(1) phase cells. TLP stimulated expression of several growth-related genes including p21 (p21(Waf1/Cip1)). TLP-mediated activation of the p21 upstream promoter in cells was shown by a promoter-luciferase reporter assay. The p53-binding sequence located in the p21 upstream promoter and p53 itself are required for TLP-mediated transcriptional activation. TLP and p53 bound to each other and synergistically enhanced activity of the upstream promoter. TLP specifically activated transcription from the endogenous upstream promoter, and p53 was required for this activation. Etoposide treatment also resulted in activation of the upstream promoter as well as nuclear accumulation of TLP and p53. Moreover, the upstream promoter was associated with endogenous p53 and TLP, and the p53 recruitment was enhanced by TLP. The results of the present study suggest that TLP mediates p53-governed transcriptional activation of the p21 upstream promoter. PMID- 22511764 TI - FoxO1 inhibits sterol regulatory element-binding protein-1c (SREBP-1c) gene expression via transcription factors Sp1 and SREBP-1c. AB - Induction of lipogenesis in response to insulin is critically dependent on the transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c). FoxO1, a forkhead box class-O transcription factor, is an important mediator of insulin action, but its role in the regulation of lipid metabolism has not been clearly defined. We examined the effects of FoxO1 on srebp1 gene expression in vivo and in vitro. In vivo studies showed that constitutively active (CA) FoxO1 (CA-FoxO1) reduced basal expression of SREBP-1c mRNA in liver by ~60% and blunted induction of SREBP-1c in response to feeding. In liver-specific FoxO knock-out mice, SREBP-1c expression was increased ~2-fold. Similarly, in primary hepatocytes, CA-FoxO1 suppressed SREBP1-c expression and inhibited basal and insulin-induced SREBP-1c promoter activity. SREBP-1c gene expression is induced by the liver X receptor (LXR), but CA-FoxO1 did not block the activation of SREBP 1c by the LXR agonist TO9. Insulin stimulates SREBP-1c transcription through Sp1 and via "feed forward" regulation by newly synthesized SREBP-1c. CA-FoxO1 inhibited SREBP-1c by reducing the transactivational capacity of both Sp1 and SREBP-1c. In addition, chromatin immunoprecipitation assays indicate that FoxO1 can associate with the proximal promoter region of the srebp1 gene and disrupt the assembly of key components of the transcriptional complex of the SREBP-1c promoter. We conclude that FoxO1 inhibits SREBP-1c transcription via combined actions on multiple transcription factors and that this effect is exerted at least in part through reduced transcriptional activity of Sp1 and SREBP-1c and disrupted assembly of the transcriptional initiation complex on the SREBP-1c promoter. PMID- 22511765 TI - Vacuolar H+-ATPase (V-ATPase) promotes vacuolar membrane permeabilization and nonapoptotic death in stressed yeast. AB - Stress in the endoplasmic reticulum caused by tunicamycin, dithiothreitol, and azole-class antifungal drugs can induce nonapoptotic cell death in yeasts that can be blocked by the action of calcineurin (Cn), a Ca(2+)-dependent serine/threonine protein phosphatase. To identify additional factors that regulate nonapoptotic cell death in yeast, a collection of gene knock-out mutants was screened for mutants exhibiting altered survival rates. The screen revealed an endocytic protein (Ede1) that can function upstream of Ca(2+)/calmodulin dependent protein kinase 2 (Cmk2) to suppress cell death in parallel to Cn. The screen also revealed the vacuolar H(+)-ATPase (V-ATPase), which acidifies the lysosome-like vacuole. The V-ATPase performed its death-promoting functions very soon after imposition of the stress and was not required for later stages of the cell death program. Cn did not inhibit V-ATPase activities but did block vacuole membrane permeabilization (VMP), which occurred at late stages of the cell death program. All of the other nondying mutants identified in the screens blocked steps before VMP. These findings suggest that VMP is the lethal event in dying yeast cells and that fungi may employ a mechanism of cell death similar to the necrosis-like cell death of degenerating neurons. PMID- 22511766 TI - The Epac-Rap1 signaling pathway controls cAMP-mediated exocytosis of Weibel Palade bodies in endothelial cells. AB - Endothelial cells contain specialized storage organelles called Weibel-Palade bodies (WPBs) that release their content into the vascular lumen in response to specific agonists that raise intracellular Ca(2+) or cAMP. We have previously shown that cAMP-mediated WPB release is dependent on protein kinase A (PKA) and involves activation of the small GTPase RalA. Here, we have investigated a possible role for another PKA-independent cAMP-mediated signaling pathway in the regulation of WPB exocytosis, namely the guanine nucleotide exchange factor Epac1 and its substrate, the small GTPase Rap1. Epinephrine stimulation of endothelial cells leads to Rap1 activation in a PKA-independent fashion. siRNA-mediated knockdown of Epac1 abolished epinephrine-induced activation of Rap1 and resulted in decreased epinephrine-induced WPB exocytosis. Down-regulation of Rap1 expression and prevention of Rap1 activation through overexpression of Rap1GAP effectively reduced epinephrine- but not thrombin-induced WPB exocytosis. Taken together, these data uncover a new Epac-Rap1-dependent pathway by which endothelial cells can regulate WPB exocytosis in response to agonists that signal through cAMP. PMID- 22511767 TI - Lysophosphatidylcholine acyltransferase 3 knockdown-mediated liver lysophosphatidylcholine accumulation promotes very low density lipoprotein production by enhancing microsomal triglyceride transfer protein expression. AB - After de novo biosynthesis phospholipids undergo extensive remodeling by the Lands' cycle. Enzymes involved in phospholipid biosynthesis have been studied extensively but not those involved in reacylation of lysophosphopholipids. One key enzyme in the Lands' cycle is fatty acyl-CoA:lysophosphatidylcholine acyltransferase (LPCAT), which utilizes lysophosphatidylcholine (LysoPC) and fatty acyl-CoA to produce various phosphatidylcholine (PC) species. Four isoforms of LPCAT have been identified. In this study we found that LPCAT3 is the major hepatic isoform, and its knockdown significantly reduces hepatic LPCAT activity. Moreover, we report that hepatic LPCAT3 knockdown increases certain species of LysoPCs and decreases certain species of PC. A surprising observation was that LPCAT3 knockdown significantly reduces hepatic triglycerides. Despite this, these mice had higher plasma triglyceride and apoB levels. Lipoprotein production studies indicated that reductions in LPCAT3 enhanced assembly and secretion of triglyceride-rich apoB-containing lipoproteins. Furthermore, these mice had higher microsomal triglyceride transfer protein (MTP) mRNA and protein levels. Mechanistic studies in hepatoma cells revealed that LysoPC enhances secretion of apoB but not apoA-I in a concentration-dependent manner. Moreover, LysoPC increased MTP mRNA, protein, and activity. In short, these results indicate that hepatic LPCAT3 modulates VLDL production by regulating LysoPC levels and MTP expression. PMID- 22511768 TI - Two in-and-out modulation strategies for endoplasmic reticulum stress-linked gene expression of pro-apoptotic macrophage-inhibitory cytokine 1. AB - Excessive and persistent insults during endoplasmic reticulum (ER) stress lead to apoptotic cell death that is implicated in a range of chronic inflammatory diseases and cancers. Macrophage inhibitory cytokine 1 (MIC-1), a member of the transforming growth factor-beta superfamily, is diversely linked to the pathogenesis of cancer. To investigate the precise molecular mechanisms of MIC-1 gene regulation, ER stress and its related signals were studied in human colon cancer cells. Functionally, MIC-1 played pivotal roles in ER stress-linked apoptotic death, which was also influenced by C/EBP homologous protein, a well known apoptotic mediator of ER stress. ER stress enhanced MIC-1 mRNA stability instead of transcriptional activation, and there were two mechanistic translocations critical for mRNA stabilization. First, C/EBP homologous protein triggered protein kinase C-linked cytosolic translocation of the HuR/ELAVL1 (Elav like RNA-binding protein 1) RNA-binding protein, which bound to and stabilized MIC-1 transcript. As the second critical in-and-out regulation, ER stress activated ERK1/2 signals contributed to enhanced stabilization of MIC-1 transcript by controlling the extended holding of the nucleated mRNA in the stress granules fusing with the mRNA-decaying processing body. We propose that these two sequential in-and-out modulations can account for stabilized transcription and subsequent translation of pro-apoptotic MIC-1 gene in human cancer cells under ER stress. PMID- 22511769 TI - Membrane-microdomain localization of amyloid beta-precursor protein (APP) C terminal fragments is regulated by phosphorylation of the cytoplasmic Thr668 residue. AB - Amyloid beta-precursor protein (APP) is primarily cleaved by alpha- or beta secretase to generate membrane-bound, C-terminal fragments (CTFs). In turn, CTFs are potentially subject to a second, intramembrane cleavage by gamma-secretase, which is active in a lipid raft-like membrane microdomain. Mature APP (N- and O glycosylated APP), the actual substrate of these secretases, is phosphorylated at the cytoplasmic residue Thr(668) and this phosphorylation changes the overall conformation of the cytoplasmic domain of APP. We found that phosphorylated and nonphosphorylated CTFs exist equally in mouse brain and are kinetically equivalent as substrates for gamma-secretase, in vitro. However, in vivo, the level of the phosphorylated APP intracellular domain peptide (pAICD) generated by gamma-cleavage of CTFs was very low when compared with the level of nonphosphorylated AICD (nAICD). Phosphorylated CTFs (pCTFs), rather than nonphosphorylated CTFs (nCTFs), were preferentially located outside of detergent resistant, lipid raft-like membrane microdomains. The APP cytoplasmic domain peptide (APP(648-695)) with Thr(P)(668) did not associate with liposomes composed of membrane lipids from mouse brain to which the nonphosphorylated peptide preferentially bound. In addition, APP lacking the C-terminal 8 amino acids (APP DeltaC8), which are essential for membrane association, decreased Abeta generation in N2a cells. These observations suggest that the pCTFs and CTFDeltaC8 are relatively movable within the membrane, whereas the nCTFs are susceptible to being anchored into the membrane, an interaction made available as a consequence of not being phosphorylated. By this mechanism, nCTFs can be preferentially captured and cleaved by gamma-secretase. Preservation of the phosphorylated state of APP-CTFs may be a potential treatment to lower the generation of Abeta in Alzheimer disease. PMID- 22511770 TI - Integrity of helix 2-helix 3 domain of the PrP protein is not mandatory for prion replication. AB - The process of prion conversion is not yet well understood at the molecular level. The regions critical for the conformational change of PrP remain mostly debated and the extent of sequence change acceptable for prion conversion is poorly documented. To achieve progress on these issues, we applied a reverse genetic approach using the Rov cell system. This allowed us to test the susceptibility of a number of insertion mutants to conversion into prion in the absence of wild-type PrP molecules. We were able to propagate several prions with 8 to 16 extra amino acids, including a polyglycine stretch and His or FLAG tags, inserted in the middle of the protease-resistant fragment. These results demonstrate the possibility to increase the length of the loop between helices H2 and H3 up to 4-fold, without preventing prion replication. They also indicate that this loop probably remains unstructured in PrP(Sc). We also showed that bona fide prions can be produced following insertion of octapeptides in the two C terminal turns of H2. These insertions do not interfere with the overall fold of the H2-H3 domain indicating that the highly conserved sequence of the terminal part of H2 is not critical for the conversion. Altogether these data showed that the amplitude of modifications acceptable for prion conversion in the core of the globular domain of PrP is much greater than one might have assumed. These observations should help to refine structural models of PrP(Sc) and elucidate the conformational changes underlying prions generation. PMID- 22511771 TI - Differential dorso-ventral distributions of Kv4.2 and HCN proteins confer distinct integrative properties to hippocampal CA1 pyramidal cell distal dendrites. AB - The dorsal and ventral regions of the hippocampus perform different functions. Whether the integrative properties of hippocampal cells reflect this heterogeneity is unknown. We focused on dendrites where most synaptic input integration takes place. We report enhanced backpropagation and theta resonance and decreased summation of synaptic inputs in ventral versus dorsal CA1 pyramidal cell distal dendrites. Transcriptional Kv4.2 down-regulation and post transcriptional hyperpolarization-activated cyclic AMP-gated channel (HCN1/2) up regulation may underlie these differences, respectively. Our results reveal differential dendritic integrative properties along the dorso-ventral axis, reflecting diverse computational needs. PMID- 22511772 TI - Structural basis for modulation of gating property of G protein-gated inwardly rectifying potassium ion channel (GIRK) by i/o-family G protein alpha subunit (Galphai/o). AB - G protein-gated inwardly rectifying potassium channel (GIRK) plays a crucial role in regulating heart rate and neuronal excitability. The gating of GIRK is regulated by the association and dissociation of G protein betagamma subunits (Gbetagamma), which are released from pertussis toxin-sensitive G protein alpha subunit (Galpha(i/o)) upon GPCR activation in vivo. Several lines of evidence indicate that Galpha(i/o) also interacts directly with GIRK, playing functional roles in the signaling efficiency and the modulation of the channel activity. However, the underlying mechanism for GIRK regulation by Galpha(i/o) remains to be elucidated. Here, we performed NMR analyses of the interaction between the cytoplasmic region of GIRK1 and Galpha(i3) in the GTP-bound state. The NMR spectral changes of Galpha upon the addition of GIRK as well as the transferred cross-saturation (TCS) results indicated their direct binding mode, where the K(d) value was estimated as ~1 mm. The TCS experiments identified the direct binding sites on Galpha and GIRK as the alpha2/alpha3 helices on the GTPase domain of Galpha and the alphaA helix of GIRK. In addition, the TCS and paramagnetic relaxation enhancement results suggested that the helical domain of Galpha transiently interacts with the alphaA helix of GIRK. Based on these results, we built a docking model of Galpha and GIRK, suggesting the molecular basis for efficient GIRK deactivation by Galpha(i/o). PMID- 22511773 TI - Structural and kinetic insights reveal that the amino acid pair Gln-228/Asn-254 modulates the transfructosylating specificity of Schwanniomyces occidentalis beta fructofuranosidase, an enzyme that produces prebiotics. AB - Schwanniomyces occidentalis beta-fructofuranosidase (Ffase) is a GH32 dimeric enzyme that releases fructose from the nonreducing end of various oligosaccharides and essential storage fructans such as inulin. It also catalyzes the transfer of a fructosyl unit to an acceptor producing 6-kestose and 1 kestose, prebiotics that stimulate the growth of bacteria beneficial for human health. We report here the crystal structure of inactivated Ffase complexed with fructosylnystose and inulin, which shows the intricate net of interactions keeping the substrate tightly bound at the active site. Up to five subsites were observed, the sugar unit located at subsite +3 being recognized by interaction with the beta-sandwich domain of the adjacent subunit within the dimer. This explains the high activity observed against long substrates, giving the first experimental evidence of the direct role of a GH32 beta-sandwich domain in substrate binding. Crucial residues were mutated and their hydrolase/transferase (H/T) activities were fully characterized, showing the involvement of the Gln 228/Asn-254 pair in modulating the H/T ratio and the type beta(2-1)/beta(2-6) linkage formation. We generated Ffase mutants with new transferase activity; among them, Q228V gives almost specifically 6-kestose, whereas N254T produces a broader spectrum product including also neokestose. A model for the mechanism of the Ffase transfructosylation reaction is proposed. The results contribute to an understanding of the molecular basis regulating specificity among GH-J clan members, which represent an interesting target for rational design of enzymes, showing redesigned activities to produce tailor-made fructooligosaccharides. PMID- 22511774 TI - BLOC-2, AP-3, and AP-1 proteins function in concert with Rab38 and Rab32 proteins to mediate protein trafficking to lysosome-related organelles. AB - Lysosome-related organelles (LROs) are synthesized in specialized cell types where they largely coexist with conventional lysosomes. Most of the known cellular transport machinery involved in biogenesis are ubiquitously expressed and shared between lysosomes and LROs. Examples of common components are the adaptor protein complex-3 (AP-3) and biogenesis of lysosome-related organelle complex (BLOC)-2. These protein complexes control sorting and transport of newly synthesized integral membrane proteins from early endosomes to both lysosomes and LROs such as the melanosome. However, it is unknown what factors cooperate with the ubiquitous transport machinery to mediate transport to LROs in specialized cells. Focusing on the melanosome, we show that the ubiquitous machinery interacts with cell type-specific Rab proteins, Rab38 and Rab32, to facilitate transport to the maturing organelle. BLOC-2, AP-3, and AP-1 coimmunoprecipitated with Rab38 and Rab32 from MNT-1 melanocytic cell extracts. BLOC-2, AP-3, AP-1, and clathrin partially colocalized with Rab38 and Rab32 by confocal immunofluorescence microscopy in MNT-1 cells. Rab38- and Rab32-deficient MNT-1 cells displayed abnormal trafficking and steady state levels of known cargoes of the BLOC-2, AP-3, and AP-1 pathways, the melanin-synthesizing enzymes tyrosinase and tyrosinase-related protein-1. These observations support the idea that Rab38 and Rab32 are the specific factors that direct the ubiquitous machinery to mediate transport from early endosomes to maturing LROs. Additionally, analysis of tyrosinase-related protein-2 and total melanin production indicates that Rab32 has unique functions that cannot be carried out by Rab38 in melanosome biogenesis. PMID- 22511775 TI - HAMP domain signal relay mechanism in a sensory rhodopsin-transducer complex. AB - The phototaxis receptor complex composed of sensory rhodopsin II (SRII) and the transducer subunit HtrII mediates photorepellent responses in haloarchaea. Light activated SRII transmits a signal through two HAMP switch domains (HAMP1 and HAMP2) in HtrII that bridge the photoreceptive membrane domain of the complex and the cytoplasmic output kinase-modulating domain. HAMP domains, widespread signal relay modules in prokaryotic sensors, consist of four-helix bundles composed of two helices, AS1 and AS2, from each of two dimerized transducer subunits. To examine their molecular motion during signal transmission, we incorporated SRII HtrII dimeric complexes in nanodiscs to allow unrestricted probe access to the cytoplasmic side HAMP domains. Spin-spin dipolar coupling measurements confirmed that in the nanodiscs, SRII photoactivation induces helix movement in the HtrII membrane domain diagnostic of transducer activation. Labeling kinetics of a fluorescein probe in monocysteine-substituted HAMP1 mutants revealed a light induced shift of AS2 against AS1 by one-half alpha-helix turn with minimal other changes. An opposite shift of AS2 against AS1 in HAMP2 at the corresponding positions supports the proposal from x-ray crystal structures by Airola et al. (Airola, M. V., Watts, K. J., Bilwes, A. M., and Crane, B. R. (2010) Structure 18, 436-448) that poly-HAMP chains undergo alternating opposite interconversions to relay the signal. Moreover, we found that haloarchaeal cells expressing a HAMP2-deleted SRII-HtrII exhibit attractant phototaxis, opposite from the repellent phototaxis mediated by the wild-type di-HAMP SRII-HtrII complex. The opposite conformational changes and corresponding opposite output signals of HAMP1 and HAMP2 imply a signal transmission mechanism entailing small shifts in helical register between AS1 and AS2 alternately in opposite directions in adjacent HAMPs. PMID- 22511776 TI - Monospecific inhibitors show that both mannan-binding lectin-associated serine protease-1 (MASP-1) and -2 Are essential for lectin pathway activation and reveal structural plasticity of MASP-2. AB - The lectin pathway is an antibody-independent activation route of the complement system. It provides immediate defense against pathogens and altered self-cells, but it also causes severe tissue damage after stroke, heart attack, and other ischemia reperfusion injuries. The pathway is triggered by target binding of pattern recognition molecules leading to the activation of zymogen mannan-binding lectin-associated serine proteases (MASPs). MASP-2 is considered as the autonomous pathway-activator, while MASP-1 is considered as an auxiliary component. We evolved a pair of monospecific MASP inhibitors. In accordance with the key role of MASP-2, the MASP-2 inhibitor completely blocks the lectin pathway activation. Importantly, the MASP-1 inhibitor does the same, demonstrating that MASP-1 is not an auxiliary but an essential pathway component. We report the first Michaelis-like complex structures of MASP-1 and MASP-2 formed with substrate-like inhibitors. The 1.28 A resolution MASP-2 structure reveals significant plasticity of the protease, suggesting that either an induced fit or a conformational selection mechanism should contribute to the extreme specificity of the enzyme. PMID- 22511777 TI - Inhibitory tract traps the epithelial Na+ channel in a low activity conformation. AB - Proteolysis plays an important role in the maturation and activation of epithelial Na(+) channels (ENaCs). Non-cleaved channels are inactive at high extracellular Na(+) concentrations and fully cleaved channels are constitutively active. Cleavage of the alpha and gamma subunits at multiple sites activates the channel through the release of imbedded inhibitory tracts. Peptides derived from these released tracts are also inhibitory, likely through binding at the inhibitory tract sites. We recently reported a model of the alpha subunit. We have now cross-linked Cys derivatives of the inhibitory peptide to the channel, using our model to predict sites at a domain interface of the alpha subunit that is in proximity to the N terminus of the peptide. Furthermore, peptide inhibition was mimicked in the absence of peptide by cross-linking the channel across the domain interface. Our results suggest a dynamic domain interface that can be exploited by inhibitory peptides and provides a mechanism for peptide inhibition and proteolytic activation. PMID- 22511778 TI - DiGeorge syndrome critical region 8 (DGCR8) protein-mediated microRNA biogenesis is essential for vascular smooth muscle cell development in mice. AB - DiGeorge Critical Region 8 (DGCR8) is a double-stranded RNA-binding protein that interacts with Drosha and facilitates microRNA (miRNA) maturation. However, the role of DGCR8 in vascular smooth muscle cells (VSMCs) is not well understood. To investigate whether DGCR8 contributes to miRNA maturation in VSMCs, we generated DGCR8 conditional knockout (cKO) mice by crossing VSMC-specific Cre mice (SM22 Cre) with DGCR8(loxp/loxp) mice. We found that loss of DGCR8 in VSMCs resulted in extensive liver hemorrhage and embryonic mortality between embryonic days (E) 12.5 and E13.5. DGCR8 cKO embryos displayed dilated blood vessels and disarrayed vascular architecture. Blood vessels were absent in the yolk sac of DGCR8 KOs after E12.5. Disruption of DGCR8 in VSMCs reduced VSMC proliferation and promoted apoptosis in vitro and in vivo. In DGCR8 cKO embryos and knockout VSMCs, differentiation marker genes, including alphaSMA, SM22, and CNN1, were significantly down-regulated, and the survival pathways of ERK1/2 mitogen activated protein kinase and the phosphatidylinositol 3-kinase/AKT were attenuated. Knockout of DGCR8 in VSMCs has led to down-regulation of the miR 17/92 and miR-143/145 clusters. We further demonstrated that the miR-17/92 cluster promotes VSMC proliferation and enhances VSMC marker gene expression, which may contribute to the defects of DGCR8 cKO mutants. Our results indicate that the DGCR8 gene is required for vascular development through the regulation of VSMC proliferation, apoptosis, and differentiation. PMID- 22511779 TI - p27kip1 protein levels reflect a nexus of oncogenic signaling during cell transformation. AB - SV40 small t-antigen (ST) collaborates with SV40 large T-antigen (LT) and activated rasv12 to promote transformation in a variety of immortalized human cells. A number of oncogenes or the disruption of the general serine-threonine phosphatase protein phosphatase 2A (PP2A) can replace ST in this paradigm. However, the relationship between these oncogenes and PP2A activity is not clear. To address this, we queried the connectivity of these molecules in silico. We found that p27 was connected to each of those oncogenes that could substitute for ST. We further determined that p27 loss can substitute for the expression of ST during transformation of both rodent and human cells. Conversely, knock-in cells expressing the degradation-resistant S10A and T187A mutants of p27 were resistant to the transforming activities of ST. This suggests that p27 is an important target of the tumor-suppressive effects of PP2A and likely an important target of the multitude of cellular oncoproteins that emulate the transforming function of ST. PMID- 22511780 TI - Engineered troponin C constructs correct disease-related cardiac myofilament calcium sensitivity. AB - Aberrant myofilament Ca(2+) sensitivity is commonly observed with multiple cardiac diseases, especially familial cardiomyopathies. Although the etiology of the cardiomyopathies remains unclear, improving cardiac muscle Ca(2+) sensitivity through either pharmacological or genetic approaches shows promise of alleviating the disease-related symptoms. Due to its central role as the Ca(2+) sensor for cardiac muscle contraction, troponin C (TnC) stands out as an obvious and versatile target to reset disease-associated myofilament Ca(2+) sensitivity back to normal. To test the hypothesis that aberrant myofilament Ca(2+) sensitivity and its related function can be corrected through rationally engineered TnC constructs, three thin filament protein modifications representing different proteins (troponin I or troponin T), modifications (missense mutation, deletion, or truncation), and disease subtypes (familial or acquired) were studied. A fluorescent TnC was utilized to measure Ca(2+) binding to TnC in the physiologically relevant biochemical model system of reconstituted thin filaments. Consistent with the pathophysiology, the restrictive cardiomyopathy mutation, troponin I R192H, and ischemia-induced truncation of troponin I (residues 1-192) increased the Ca(2+) sensitivity of TnC on the thin filament, whereas the dilated cardiomyopathy mutation, troponin T DeltaK210, decreased the Ca(2+) sensitivity of TnC on the thin filament. Rationally engineered TnC constructs corrected the abnormal Ca(2+) sensitivities of the thin filament, reconstituted actomyosin ATPase activity, and force generation in skinned trabeculae. Thus, the present study provides a novel and versatile therapeutic strategy to restore diseased cardiac muscle Ca(2+) sensitivity. PMID- 22511781 TI - Loss of mitofusin 2 promotes endoplasmic reticulum stress. AB - The outer mitochondrial membrane GTPase mitofusin 2 (Mfn2) is known to regulate endoplasmic reticulum (ER) shape in addition to its mitochondrial fusion effects. However, its role in ER stress is unknown. We report here that induction of ER stress with either thapsigargin or tunicamycin in mouse embryonic fibroblasts leads to up-regulation of Mfn2 mRNA and protein levels with no change in the expression of the mitochondrial shaping factors Mfn1, Opa1, Drp1, and Fis1. Genetic deletion of Mfn2 but not Mfn1 in mouse embryonic fibroblasts or cardiac myocytes in mice led to an increase in the expression of the ER chaperone proteins. Genetic ablation of Mfn2 in mouse embryonic fibroblasts amplified ER stress and exacerbated ER stress-induced apoptosis. Deletion of Mfn2 delayed translational recovery through prolonged eIF2alpha phosphorylation associated with decreased GADD34 and p58(IPK) expression and elevated C/EBP homologous protein induction at late time points. These changes in the unfolded protein response were coupled to increased cell death reflected by augmented caspase 3/7 activity, lactate dehydrogenase release from cells, and an increase in propidium iodide-positive nuclei in response to thapsigargin or tunicamycin treatment. In contrast, genetic deletion of Mfn1 did not affect ER stress-mediated increase in ER chaperone synthesis or eIF2alpha phosphorylation. Additionally, ER stress induced C/EBP homologous protein, GADD34, and p58(IPK) induction and cell death were not affected by loss of Mfn1. We conclude that Mfn2 but not Mfn1 is an ER stress-inducible protein that is required for the proper temporal sequence of the ER stress response. PMID- 22511783 TI - S-palmitoylation and ubiquitination differentially regulate interferon-induced transmembrane protein 3 (IFITM3)-mediated resistance to influenza virus. AB - The interferon (IFN)-induced transmembrane protein 3 (IFITM3) is a cellular restriction factor that inhibits infection by influenza virus and many other pathogenic viruses. IFITM3 prevents endocytosed virus particles from accessing the host cytoplasm although little is known regarding its regulatory mechanisms. Here we demonstrate that IFITM3 localization to and antiviral remodeling of endolysosomes is differentially regulated by S-palmitoylation and lysine ubiquitination. Although S-palmitoylation enhances IFITM3 membrane affinity and antiviral activity, ubiquitination decreases localization with endolysosomes and decreases antiviral activity. Interestingly, autophagy reportedly induced by IFITM3 expression is also negatively regulated by ubiquitination. However, the canonical ATG5-dependent autophagy pathway is not required for IFITM3 activity, indicating that virus trafficking from endolysosomes to autophagosomes is not a prerequisite for influenza virus restriction. Our characterization of IFITM3 ubiquitination sites also challenges the dual-pass membrane topology predicted for this protein family. We thus evaluated topology by N-linked glycosylation site insertion and protein lipidation mapping in conjunction with cellular fractionation and fluorescence imaging. Based on these studies, we propose that IFITM3 is predominantly an intramembrane protein where both the N and C termini face the cytoplasm. In sum, by characterizing S-palmitoylation and ubiquitination of IFITM3, we have gained a better understanding of the trafficking, activity, and intramembrane topology of this important IFN-induced effector protein. PMID- 22511782 TI - Defining the contribution of AMP-activated protein kinase (AMPK) and protein kinase C (PKC) in regulation of glucose uptake by metformin in skeletal muscle cells. AB - The importance of AMP-activated protein kinase (AMPK) and protein kinase C (PKC) as effectors of metformin (Met) action on glucose uptake (GU) in skeletal muscle cells was investigated. GU in L6 myotubes was stimulated 2-fold following 16 h of Met treatment and acutely enhanced by insulin in an additive fashion. Insulin stimulated GU was sensitive to PI3K inhibition, whereas that induced by Met was not. Met and its related biguanide, phenformin, stimulated AMPK activation/phosphorylation to a level comparable with that induced by the AMPK activator, 5-amino-1-beta-d-ribofuranosyl-imidazole-4-carboxamide (AICAR). However, the increase in GU elicited by AICAR was significantly lower than that induced by either biguanide. Expression of a constitutively active AMPK mimicked the effects of AICAR on GU, whereas a dominant interfering AMPK or shRNA silencing of AMPK prevented AICAR-stimulated GU and Met-induced AMPK signaling but only repressed biguanide-stimulated GU by ~20%. Consistent with this, analysis of GU in muscle cells from alpha1(-/-)/alpha2(-/-) AMPK-deficient mice revealed a significant retention of Met-stimulated GU, being reduced by ~35% compared with that of wild type cells. Atypical PKCs (aPKCs) have been implicated in Met-stimulated GU, and in line with this, Met and phenformin induced activation/phosphorylation of aPKC in L6 myotubes. However, although cellular depletion of aPKC (>90%) led to loss in biguanide-induced aPKC phosphorylation, it had no effect on Met-stimulated GU, whereas inhibitors targeting novel/conventional PKCs caused a significant reduction in biguanide-induced GU. Our findings indicate that although Met activates AMPK, a significant component of Met-stimulated GU in muscle cells is mediated via an AMPK-independent mechanism that involves novel/conventional PKCs. PMID- 22511784 TI - Human adipose tissue macrophages display activation of cancer-related pathways. AB - Obesity is associated with a significantly increased risk for cancer suggesting that adipose tissue dysfunctions might play a crucial role therein. Macrophages play important roles in adipose tissue as well as in cancers. Here, we studied whether human adipose tissue macrophages (ATM) modulate cancer cell function. Therefore, ATM were isolated and compared with monocyte-derived macrophages (MDM) from the same obese patients. ATM, but not MDM, were found to secrete factors inducing inflammation and lipid accumulation in human T47D and HT-29 cancer cells. Gene expression profile comparison of ATM and MDM revealed overexpression of functional clusters, such as cytokine-cytokine receptor interaction (especially CXC-chemokine) signaling as well as cancer-related pathways, in ATM. Comparison with gene expression profiles of human tumor-associated macrophages showed that ATM, but not MDM resemble tumor-associated macrophages. Indirect co culture experiments demonstrated that factors secreted by preadipocytes, but not mature adipocytes, confer an ATM-like phenotype to MDM. Finally, the concentrations of ATM-secreted factors related to cancer are elevated in serum of obese subjects. In conclusion, ATM may thus modulate the cancer cell phenotype. PMID- 22511785 TI - Surfactant protein D (Sp-D) binds to membrane-proximal domain (D3) of signal regulatory protein alpha (SIRPalpha), a site distant from binding domain of CD47, while also binding to analogous region on signal regulatory protein beta (SIRPbeta). AB - Signal regulatory protein alpha (SIRPalpha), a highly glycosylated type-1 transmembrane protein, is composed of three immunoglobulin-like extracellular loops as well as a cytoplasmic tail containing three classical tyrosine-based inhibitory motifs. Previous reports indicate that SIRPalpha binds to humoral pattern recognition molecules in the collectin family, namely surfactant proteins D and A (Sp-D and Sp-A, respectively), which are heavily expressed in the lung and constitute one of the first lines of innate immune defense against pathogens. However, little is known about molecular details of the structural interaction of Sp-D with SIRPs. In the present work, we examined the molecular basis of Sp-D binding to SIRPalpha using domain-deleted mutant proteins. We report that Sp-D binds to the membrane-proximal Ig domain (D3) of SIRPalpha in a calcium- and carbohydrate-dependent manner. Mutation of predicted N-glycosylation sites on SIRPalpha indicates that Sp-D binding is dependent on interactions with specific N-glycosylated residues on the membrane-proximal D3 domain of SIRPalpha. Given the remarkable sequence similarity of SIRPalpha to SIRPbeta and the lack of known ligands for the latter, we examined Sp-D binding to SIRPbeta. Here, we report specific binding of Sp-D to the membrane-proximal D3 domain of SIRPbeta. Further studies confirmed that Sp-D binds to SIRPalpha expressed on human neutrophils and differentiated neutrophil-like cells. Because the other known ligand of SIRPalpha, CD47, binds to the membrane-distal domain D1, these findings indicate that multiple, distinct, functional ligand binding sites are present on SIRPalpha that may afford differential regulation of receptor function. PMID- 22511786 TI - Essential role for IKKbeta in production of type 1 interferons by plasmacytoid dendritic cells. AB - Plasmacytoid dendritic cells (pDCs) are characterized by their ability to produce high levels of type 1 interferons in response to ligands that activate TLR7 and TLR9, but the signaling pathways required for IFN production are incompletely understood. Here we exploit the human pDC cell line Gen2.2 and improved pharmacological inhibitors of protein kinases to address this issue. We demonstrate that ligands that activate TLR7 and TLR9 require the TAK1-IKKbeta signaling pathway to induce the production of IFNbeta via a pathway that is independent of the degradation of IkappaBalpha. We also show that IKKbeta activity, as well as the subsequent IFNbeta-stimulated activation of the JAK STAT1/2 signaling pathway, are essential for the production of IFNalpha by TLR9 ligands. We further show that TLR7 ligands CL097 and R848 fail to produce significant amounts of IFNalpha because the activation of IKKbeta is not sustained for a sufficient length of time. The TLR7/9-stimulated production of type 1 IFNs is inhibited by much lower concentrations of IKKbeta inhibitors than those needed to suppress the production of NFkappaB-dependent proinflammatory cytokines, such as IL-6, suggesting that drugs that inhibit IKKbeta may have a potential for the treatment of forms of lupus that are driven by self-RNA and self-DNA-induced activation of TLR7 and TLR9, respectively. PMID- 22511787 TI - Regulation of protein kinase C-related protein kinase 2 (PRK2) by an intermolecular PRK2-PRK2 interaction mediated by Its N-terminal domain. AB - Protein kinase C-related protein kinases (PRKs) are effectors of the Rho family of small GTPases and play a role in the development of diseases such as prostate cancer and hepatitis C. Here we examined the mechanism underlying the regulation of PRK2 by its N-terminal region. We show that the N-terminal region of PRK2 prevents the interaction with its upstream kinase, the 3-phosphoinositide dependent kinase 1 (PDK1), which phosphorylates the activation loop of PRK2. We confirm that the N-terminal region directly inhibits the kinase activity of PRK2. However, in contrast to previous models, our data indicate that this inhibition is mediated in trans through an intermolecular PRK2-PRK2 interaction. Our results also suggest that amino acids 487-501, located in the linker region between the N terminal domains and the catalytic domain, contribute to the PRK2-PRK2 dimer formation. This dimerization is further supported by other N-terminal domains. Additionally, we provide evidence that the region C-terminal to the catalytic domain intramolecularly activates PRK2. Finally, we discovered that the catalytic domain mediates a cross-talk between the inhibitory N-terminal region and the activating C-terminal region. The results presented here describe a novel mechanism of regulation among AGC kinases and offer new insights into potential approaches to pharmacologically regulate PRK2. PMID- 22511788 TI - Dimerization of plant defensin NaD1 enhances its antifungal activity. AB - The plant defensin, NaD1, from the flowers of Nicotiana alata, is a member of a family of cationic peptides that displays growth inhibitory activity against several filamentous fungi, including Fusarium oxysporum. The antifungal activity of NaD1 has been attributed to its ability to permeabilize membranes; however, the molecular basis of this function remains poorly defined. In this study, we have solved the structure of NaD1 from two crystal forms to high resolution (1.4 and 1.58 A, respectively), both of which contain NaD1 in a dimeric configuration. Using protein cross-linking experiments as well as small angle x-ray scattering analysis and analytical ultracentrifugation, we show that NaD1 forms dimers in solution. The structural studies identified Lys(4) as critical in formation of the NaD1 dimer. This was confirmed by site-directed mutagenesis of Lys(4) that resulted in substantially reduced dimer formation. Significantly, the reduced ability of the Lys(4) mutant to dimerize correlated with diminished antifungal activity. These data demonstrate the importance of dimerization in NaD1 function and have implications for the use of defensins in agribiotechnology applications such as enhancing plant crop protection against fungal pathogens. PMID- 22511789 TI - Dynamic, ligand-dependent conformational change triggers reaction of ribose-1,5 bisphosphate isomerase from Thermococcus kodakarensis KOD1. AB - Ribose-1,5-bisphosphate isomerase (R15Pi) is a novel enzyme recently identified as a member of an AMP metabolic pathway in archaea. The enzyme converts d-ribose 1,5-bisphosphate into ribulose 1,5-bisphosphate, providing the substrate for archaeal ribulose-1,5-bisphosphate carboxylase/oxygenases. We here report the crystal structures of R15Pi from Thermococcus kodakarensis KOD1 (Tk-R15Pi) with and without its substrate or product. Tk-R15Pi is a hexameric enzyme formed by the trimerization of dimer units. Biochemical analyses show that Tk-R15Pi only accepts the alpha-anomer of d-ribose 1,5-bisphosphate and that Cys(133) and Asp(202) residues are essential for ribulose 1,5-bisphosphate production. Comparison of the determined structures reveals that the unliganded and product binding structures are in an open form, whereas the substrate-binding structure adopts a closed form, indicating domain movement upon substrate binding. The conformational change to the closed form optimizes active site configuration and also isolates the active site from the solvent, which may allow deprotonation of Cys(133) and protonation of Asp(202) to occur. The structural features of the substrate-binding form and biochemical evidence lead us to propose that the isomerase reaction proceeds via a cis-phosphoenolate intermediate. PMID- 22511790 TI - Inactivation of Pink1 gene in vivo sensitizes dopamine-producing neurons to 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and can be rescued by autosomal recessive Parkinson disease genes, Parkin or DJ-1. AB - Mutations in the mitochondrial PTEN-induced kinase 1 (Pink1) gene have been linked to Parkinson disease (PD). Recent reports including our own indicated that ectopic Pink1 expression is protective against toxic insult in vitro, suggesting a potential role for endogenous Pink1 in mediating survival. However, the role of endogenous Pink1 in survival, particularly in vivo, is unclear. To address this critical question, we examined whether down-regulation of Pink1 affects dopaminergic neuron loss following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the adult mouse. Two model systems were utilized: virally delivered shRNA-mediated knockdown of Pink1 and germ line-deficient mice. In both instances, loss of Pink1 generated significant sensitivity to damage induced by systemic MPTP treatment. This sensitivity was associated with greater loss of dopaminergic neurons in the Substantia Nigra pars compacta and terminal dopamine fiber density in the striatum region. Importantly, we also show that viral mediated expression of two other recessive PD-linked familial genes, DJ-1 and Parkin, can protect dopaminergic neurons even in the absence of Pink1. This evidence not only provides strong evidence for the role of endogenous Pink1 in neuronal survival, but also supports a role of DJ-1 and Parkin acting parallel or downstream of endogenous Pink1 to mediate survival in a mammalian in vivo context. PMID- 22511791 TI - Enforced presentation of an extrahelical guanine to the lesion recognition pocket of human 8-oxoguanine glycosylase, hOGG1. AB - A poorly understood aspect of DNA repair proteins is their ability to identify exceedingly rare sites of damage embedded in a large excess of nearly identical undamaged DNA, while catalyzing repair only at the damaged sites. Progress toward understanding this problem has been made by comparing the structures and biochemical behavior of these enzymes when they are presented with either a target lesion or a corresponding undamaged nucleobase. Trapping and analyzing such DNA-protein complexes is particularly difficult in the case of base extrusion DNA repair proteins because of the complexity of the repair reaction, which involves extrusion of the target base from DNA followed by its insertion into the active site where glycosidic bond cleavage is catalyzed. Here we report the structure of a human 8-oxoguanine (oxoG) DNA glycosylase, hOGG1, in which a normal guanine from DNA has been forcibly inserted into the enzyme active site. Although the interactions of the nucleobase with the active site are only subtly different for G versus oxoG, hOGG1 fails to catalyze excision of the normal nucleobase. This study demonstrates that even if hOGG1 mistakenly inserts a normal base into its active site, the enzyme can still reject it on the basis of catalytic incompatibility. PMID- 22511792 TI - Essential functions of C terminus of Drosophila Topoisomerase IIIalpha in double holliday junction dissolution. AB - Topoisomerase IIIalpha (Top3alpha) is an essential component of the double Holliday junction (dHJ) dissolvasome complex in metazoans, along with Blm and Rmi1/2. This important anti-recombinogenic function cannot be performed by Top3beta, the other type IA topoisomerase present in metazoans. The two share a catalytic core but diverge in their tail regions. To understand this difference in function, we investigated the role of the unique C terminus of Top3alpha. The Drosophila C terminus contains an insert region not conserved among metazoans. This insert contributes an independent interaction with Blm, which may account for the absence of Rmi1 in Drosophila. Mutant Top3alpha lacking this insert maintains the ability to perform dHJ dissolution but only partially rescues a top3alpha null fly line, indicating an in vivo role for the insert. Truncation of the C terminus has a minimal effect on the type IA relaxation activity of Top3alpha; however, dHJ dissolution is greatly reduced. The Top3alpha C terminus was found to strongly interact with both Blm and DNA, which are critical to the dissolution reaction; these interactions are greatly reduced in the truncated enzyme. The truncation mutant also cannot rescue the viability of top3alpha null flies, indicating an essential in vivo role. Our data therefore suggest that the Top3alpha C terminus has an important role in dHJ dissolution (by providing an interaction interface for Blm and DNA) and an essential function in vivo. PMID- 22511793 TI - Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), a major risk factor for frontotemporal lobar degeneration. AB - TMEM106B was identified as a major risk factor in a genome-wide association study for frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 pathology. The most significant association of TMEM106B single nucleotide polymorphisms with risk of FTLD-TDP was observed in patients with progranulin (GRN) mutations. Subsequent studies suggested an inverse correlation between TMEM106B expression and GRN levels in patient serum. However, in this study, this was not confirmed as we failed to detect a significant alteration of GRN levels upon knockdown or exogenous expression of TMEM106B in heterologous cells. To provide a basis for understanding TMEM106B function in health and disease, we investigated the membrane orientation and subcellular localization of this completely uncharacterized protein. By differential membrane extraction and sequential mutagenesis of potential N-glycosylation sites, we identified TMEM106B as a type 2 integral membrane protein with a highly glycosylated luminal domain. Glycosylation is partially required for the transport of TMEM106B beyond the endoplasmic reticulum to late cellular compartments. Endogenous as well as overexpressed TMEM106B localizes to late endosomes and lysosomes. Interestingly, the inhibition of vacuolar H(+)-ATPases significantly increased the levels of TMEM106B, a finding that may provide an unexpected biochemical link to GRN, because this protein is also strongly increased under the same conditions. Our findings provide a biochemical and cell biological basis for the understanding of the pathological role of TMEM106B in FTLD, an incurable neurodegenerative disorder. PMID- 22511794 TI - Secretory capacity of the parathyroid glands after total thyroidectomy in normocalcemic subjects. AB - CONTEXT: Hypocalcemia, transient or permanent, represents a common complication after total thyroidectomy, but data on the secretory capacity of the parathyroid glands in thyroidectomized patients without clinical or biochemical hypocalcemia are limited. STUDY DESIGN: To address this issue, we studied the parathyroid response to acute hypocalcemia induced by iv infusion of sodium bicarbonate in normocalcemic patients submitted to total thyroidectomy at the early postoperative period and 3 months later. PATIENTS AND METHODS: Sixty patients who underwent total thyroidectomy for benign thyroid disease and did not develop clinical or biochemical hypocalcemia and hypoparathyroidism postoperatively and 50 healthy volunteers were included in the study. Patients (at 48 h and 3 months after surgery) and controls (after overnight fast) were subjected to a sodium bicarbonate infusion test. RESULTS: In healthy volunteers plasma intact PTH increased significantly at 3 min after infusion (4.42 +/- 0.15 ng/ml vs. 11.22 +/ 0.5 ng/ml, P < 0.001) and gradually returned to baseline values. In the thyroidectomized patients, mean PTH levels were also increased after sodium bicarbonate infusion but to a significantly lesser degree compared with healthy controls (1.77 mean fold increase vs. 2.57 mean fold increase, respectively, P < 0.001). Using as criterion the lowest fold increase of plasma PTH levels at 3 min after infusion observed in healthy volunteers, 38% of the thyroidectomized patients at 48 h after surgery and 6.6% of the patients at 3 months after surgery demonstrated a diminished PTH response to acute hypocalcemia induced by sodium bicarbonate infusion. CONCLUSION: In thyroidectomized patients, normal postoperative calcium and PTH values do not exclude a reduced secretory response of the parathyroids to hypocalcemic stimuli. PMID- 22511795 TI - Risk of hypothyroidism following hemithyroidectomy: systematic review and meta analysis of prognostic studies. AB - CONTEXT: The reported risk of hypothyroidism after hemithyroidectomy shows considerable heterogeneity in literature. OBJECTIVE: The aim of this systematic review and meta-analysis was to determine the overall risk of hypothyroidism, both clinical and subclinical, after hemithyroidectomy. Furthermore, we aimed to identify risk factors for postoperative hypothyroidism. DATA SOURCES: A systematic literature search was performed using several databases, including PubMed. STUDY SELECTION: Original articles in which an incidence or prevalence of hypothyroidism after primary hemithyroidectomy could be extracted were included. DATA EXTRACTION: Study identification and data extraction were performed independently by two reviewers. In case of disagreement, a third reviewer was consulted. DATA SYNTHESIS: A total of 32 studies were included in this meta analysis. Meta-analysis was performed using logistic regression with random effect at study level. The overall risk of hypothyroidism after hemithyroidectomy was 22% (95% confidence interval, 19-27). A clear distinction between clinical (supranormal TSH levels and subnormal thyroid hormone levels) and subclinical (supranormal TSH levels and thyroid hormone levels within the normal range) hypothyroidism was provided in four studies. These studies reported on an estimated risk of 12% for subclinical hypothyroidism and 4% for clinical hypothyroidism. Positive anti-thyroid peroxidase status is a relevant preoperative indicator of hypothyroidism after surgery. Effect estimates did not differ substantially between studies with lower risk of bias and studies with higher risk of bias. CONCLUSIONS: This meta-analysis showed that approximately one in five patients will develop hypothyroidism after hemithyroidectomy, with clinical hypothyroidism in one of 25 operated patients. PMID- 22511796 TI - Runx2 mRNA expression in the tissue, serum, and circulating non-hematopoietic cells of patients with thyroid cancer. AB - CONTEXT: Runx2, a master gene of osteogenic differentiation, is also expressed in nonosseous cancer cells. Microcalcifications are characteristic of papillary thyroid carcinoma and represent a useful find for diagnosis. However, the molecular expression of osteogenic differentiation transcription factor Runx2 has been poorly investigated in this tumor. OBJECTIVE: The aim of this study was to investigate Runx2 mRNA expression in normal and pathological thyroid tissue, serum, and circulating non-hematopoietic cells. SETTING: The study was performed in the Endocrine Unit of Internal Medicine of "Azienda Ospedaliera Universitaria Integrata of Verona" (Verona, Italy). PATIENTS: We enrolled 12 patients with a papillary thyroid carcinoma (PTC), who had undergone total thyroidectomy performed by the same surgeon. The results, obtained by real-time RT-PCR, were compared with biological samples obtained from 13 sex- and age-matched normal donors. RESULTS: Our data demonstrated that Runx2 mRNA is overexpressed (7.81 fold expression) in pathological thyroid tissue than in normal tissue (P < 0.05). Runx2 mRNA overexpression was also observed in serum and circulating non hematopoietic cells of PTC patients with respect to normal donors (5.91-fold expression, P < 0.001; 3.82-fold expression, P < 0.05, respectively). We also observed that patients with microcalcifications expressed significantly higher levels of Runx2 mRNA in serum with respect to patients without microcalcifications (P < 0.05). CONCLUSION: This study can open up new research perspectives in the diagnosis and follow-up of PTC, even if further and larger cohort studies will be necessary to validate the Runx2 expression as biomarkers in thyroid cancer. PMID- 22511797 TI - Effect of body mass index and physical exercise on risk of knee and hip osteoarthritis: longitudinal data from the Norwegian HUNT Study. AB - BACKGROUND: Mechanical joint stress imposed by high body mass index (BMI) is associated with increased risk of knee and hip osteoarthritis. This prospective study investigated the independent and joint association of BMI and physical exercise on risk of knee and hip osteoarthritis. METHODS: The study includes 15,191 women and 14,766 men in the Norwegian HUNT Study without pain or physical impairment at baseline. Occurrence of self-reported physician-diagnosed osteoarthritis was assessed at 11 years of follow-up. RESULTS: BMI was positively related to risk of knee osteoarthritis (P(trend)<0.001), with an RR of 4.37 (95% CI 3.01 to 6.33) in women and 2.78 (95% CI 1.59 to 4.84) in men, comparing obese and normal weight persons. No clear association was observed for hip osteoarthritis. Obesity increased the risk of severe activity-limiting osteoarthritis, with an RR of 2.30 (95% CI 1.68 to 3.15) and 2.50 (95% CI 1.56 to 4.03) in women and men, respectively. Physical exercise did not modify the above associations (P(interaction)>0.34). Exercise intensity was not associated with risk of osteoarthritis in any BMI category; that is, obese persons reporting high intensity exercise had an RR of 1.28 (95% CI 0.59 to 2.79) for severe osteoarthritis compared with inactive persons. CONCLUSION: High BMI increases the risk of knee osteoarthritis and severe osteoarthritis. Physical exercise does not increase the risk of osteoarthritis at any level of BMI, suggesting that exercise could be encouraged also among individuals with excessive body mass, without concern for an increased risk of osteoarthritis. PMID- 22511798 TI - Increasing safety by implementing optimized structures of team communication and the mandatory use of checklists. PMID- 22511799 TI - Re: use of surveillance criteria reduces interstage mortality after the Norwood operation for hypoplastic left heart syndrome. PMID- 22511800 TI - Save the brain: a new option! PMID- 22511801 TI - Differentially expressed genes and proteins upon drought acclimation in tolerant and sensitive genotypes of Coffea canephora. AB - The aim of this study was to investigate the molecular mechanisms underlying drought acclimation in coffee plants by the identification of candidate genes (CGs) using different approaches. The first approach used the data generated during the Brazilian Coffee expressed sequence tag (EST) project to select 13 CGs by an in silico analysis (electronic northern). The second approach was based on screening macroarrays spotted with plasmid DNA (coffee ESTs) with separate hybridizations using leaf cDNA probes from drought-tolerant and susceptible clones of Coffea canephora var. Conilon, grown under different water regimes. This allowed the isolation of seven additional CGs. The third approach used two dimensional gel electrophoresis to identify proteins displaying differential accumulation in leaves of drought-tolerant and susceptible clones of C. canephora. Six of them were characterized by MALDI-TOF-MS/MS (matrix-assisted laser desorption-time of flight-tandem mass spectrometry) and the corresponding proteins were identified. Finally, additional CGs were selected from the literature, and quantitative real-time polymerase chain reaction (qPCR) was performed to analyse the expression of all identified CGs. Altogether, >40 genes presenting differential gene expression during drought acclimation were identified, some of them showing different expression profiles between drought tolerant and susceptible clones. Based on the obtained results, it can be concluded that factors involved a complex network of responses probably involving the abscisic signalling pathway and nitric oxide are major molecular determinants that might explain the better efficiency in controlling stomata closure and transpiration displayed by drought-tolerant clones of C. canephora. PMID- 22511802 TI - Developmental silencing of the AtTERT gene is associated with increased H3K27me3 loading and maintenance of its euchromatic environment. AB - Telomerase, an enzyme responsible for the maintenance of linear chromosome ends, is precisely regulated during plant development. In animals, involvement of the epigenetic state of the telomerase reverse transcriptase (TERT) gene in the complex regulation of telomerase activity has been reported. To reveal whether epigenetic mechanisms participate in the regulation of plant telomerase, the relationship between telomerase activity in tissues of Arabidopsis thaliana and DNA methylation and histone modifications in the A. thaliana TERT (AtTERT) upstream region was studied. As expected, a gradual decrease of telomerase activity during leaf maturation was observed. A different pattern with a more progressive loss of telomerase activity and AtTERT transcription during leaf development was revealed in MET1 gene-knockout mutants. Analysis of DNA methylation in the AtTERT upstream region showed low levels of methylated cytosines without notable differences between telomerase-positive and telomerase negative wild-type tissues. Surprisingly, a high level of CG methylation was found in the AtTERT coding region, although this type of methylation is a characteristic attribute of constitutively expressed genes. Analysis of chromatin modifications in the AtTERT upstream region and in exon 5 showed increased loading of the H3K27me3 mark in the telomerase-negative mature leaf compared to telomerase-positive seedlings, whereas H3K4me3, H3K9Ac, and H3K9me2 were approximately at the same level. Consistently, the chromatin structure of the AtTERT gene was maintained. These results are discussed in the context of the general involvement of epigenetic mechanisms in the regulation of gene expression and with respect to similar studies performed in animal models. PMID- 22511803 TI - Graft-union development: a delicate process that involves cell-cell communication between scion and stock for local auxin accumulation. AB - Grafting is an ancient cloning method that has been used widely for thousands of years in agricultural practices. Graft-union development is also an intricate process that involves substantial changes such as organ regeneration and genetic material exchange. However, the molecular mechanisms for graft-union development are still largely unknown. Here, a micrografting method that has been used widely in Arabidopsis was improved to adapt it a smooth procedure to facilitate sample analysis and to allow it to easily be applied to various dicotyledonous plants. The developmental stage of the graft union was characterized based on this method. Histological analysis suggested that the transport activities of vasculature were recovered at 3 days after grafting (dag) and that auxin modulated the vascular reconnection at 2 dag. Microarray data revealed a signal exchange process between cells of the scion and stock at 1 dag, which re established the communication network in the graft union. This process was concomitant with the clearing of cell debris, and both processes were initiated by a wound-induced programme. The results demonstrate the feasibility and potential power of investigating various plant developmental processes by this method, and represent a primary and significant step in interpretation of the molecular mechanisms underlying graft-union development. PMID- 22511804 TI - Enhanced expression of Rhizobium etli cbb3 oxidase improves drought tolerance of common bean symbiotic nitrogen fixation. AB - To investigate the involvement of Rhizobium etli cbb(3) oxidase in the response of Phaseolus vulgaris to drought, common bean plants were inoculated with the R. etli strain, CFNX713, overexpressing this oxidase in bacteroids (cbb(3)(+)) and subjected to drought conditions. The negative effect of drought on plant and nodule dryweight, nitrogen content, and nodule functionality was more pronounced in plants inoculated with the wild-type (WT) strain than in those inoculated with the cbb(3)(+) strain. Regardless of the plant treatment, bacteroids produced by the cbb(3)(+) strain showed higher respiratory capacity than those produced by the WT strain. Inoculation of plants with the cbb(3)(+) strain alleviated the negative effect of a moderate drought on the respiratory capacity of bacteroids and the energy charge of the nodules. Expression of the FixP and FixO components of the cbb(3) oxidase was higher in bacteroids of the cbb(3)(+) strain than in those of the WT strain under all experimental conditions. The decline in sucrose synthase activity and the decrease in dicarboxylic acids provoked by moderate drought stress were more pronounced in nodules from plants inoculated with the WT strain than in those inoculated with the cbb(3)(+) strain. Taken together, these results suggest that inoculation of plants with a R. etli strain having enhanced expression of cbb(3) oxidase in bacteroids reduces the sensitivity of P. vulgaris R. etli symbiosis to drought and can modulate carbon metabolism in nodules. PMID- 22511805 TI - Thermotolerant cyclamen with reduced acrolein and methyl vinyl ketone. AB - Reduced levels of trienoic fatty acids (TAs) in chloroplast membranes induce thermotolerance in several plant species, but the underlying mechanisms remain unclear. TA peroxidation in plant cell membranes generates cytotoxic, TA-derived compounds containing alpha,beta-unsaturated carbonyl groups. The relationship between low TA levels and the amounts of cytotoxic TA-derived compounds was examined using thermotolerant transgenic cyclamen (Cyclamen persicum Mill.) with low TA contents. Changes in the levels of the cytotoxic TA-derived acrolein (ACR), methyl vinyl ketone (MVK), (E)-2-hexenal, 4-hydroxy-2-nonenal, and malondialdehyde were analysed in the leaf tissues of wild-type (WT) and thermotolerant transgenic cyclamen under heat stress. Levels of ACR and MVK in the WT increased in parallel with the occurrence of heat-induced tissue damage, whereas no such changes were observed in the thermotolerant transgenic lines. Furthermore, exogenous ACR and MVK infiltrated into leaves to concentrations similar to those observed in heat-stressed WT leaves caused similar disease symptoms. These results suggest that thermotolerance in transgenic cyclamen depends on reduced production rates of ACR and MVK under heat stress, due to the low level of TAs in these plants. PMID- 22511806 TI - Association mapping in forest trees and fruit crops. AB - Association mapping (AM), also known as linkage disequilibrium (LD) mapping, is a viable approach to overcome limitations of pedigree-based quantitative trait loci (QTL) mapping. In AM, genotypic and phenotypic correlations are investigated in unrelated individuals. Unlike QTL mapping, AM takes advantage of both LD and historical recombination present within the gene pool of an organism, thus utilizing a broader reference population. In plants, AM has been used in model species with available genomic resources. Pursuing AM in tree species requires both genotyping and phenotyping of large populations with unique architectures. Recently, genome sequences and genomic resources for forest and fruit crops have become available. Due to abundance of single nucleotide polymorphisms (SNPs) within a genome, along with availability of high-throughput resequencing methods, SNPs can be effectively used for genotyping trees. In addition to DNA polymorphisms, copy number variations (CNVs) in the form of deletions, duplications, and insertions also play major roles in control of expression of phenotypic traits. Thus, CNVs could provide yet another valuable resource, beyond those of microsatellite and SNP variations, for pursuing genomic studies. As genome-wide SNP data are generated from high-throughput sequencing efforts, these could be readily reanalysed to identify CNVs, and subsequently used for AM studies. However, forest and fruit crops possess unique architectural and biological features that ought to be taken into consideration when collecting genotyping and phenotyping data, as these will also dictate which AM strategies should be pursued. These unique features as well as their impact on undertaking AM studies are outlined and discussed. PMID- 22511807 TI - Survival benefit of post-mastectomy radiotherapy in breast carcinoma patients with T1-2 tumor and 1-3 axillary lymph node(s) metastasis. AB - OBJECTIVE: To investigate the role of post-mastectomy radiotherapy in breast carcinoma patients with a tumor size of 5 cm or smaller (T1-2) and 1-3 axillary lymph node(s) metastasis (N1). METHODS: We retrospectively reviewed the file records of 575 patients receiving radiotherapy (452 patients) and not receiving radiotherapy (123 patients). RESULTS: In the whole series, locoregional recurrence-free survival was significantly better in patients receiving radiotherapy compared with patients not receiving radiotherapy (P<0.001); in the multivariate Cox analysis, radiotherapy had an independent prognostic value (P<0.001). In patients with a tumor size of 2 cm or less (T1), locoregional recurrence-free survival was significantly better in patients receiving radiotherapy compared with those not receiving radiotherapy (P=0.016). In the patient subgroup with a T1 tumor and a lymph node ratio (the ratio of the number of metastatic lymph nodes to the number of removed lymph nodes) of 0.25 or less, there was no significant difference between the patients receiving and not receiving radiotherapy in terms of locoregional recurrence-free survival (P=0.071). In patients with a tumor size of 2.1-5 cm (T2), locoregional recurrence-free survival was significantly better for patients who received radiotherapy compared with those who did not (P=0.001). In patients with a T2 tumor and a lymph node ratio of <=0.08, there was no significant difference in locoregional recurrence-free survival between the patients receiving and not receiving radiotherapy (P=0.645). CONCLUSIONS: Post-mastectomy radiotherapy is beneficial in reducing the locoregional recurrence risk in T1N1 breast carcinoma patients with a lymph node ratio of >0.25 and in T2N1 breast carcinoma patients with a lymph node ratio of >0.08. In patients with a lymph node ratio equal to or less than these ratios, post-mastectomy radiotherapy could be omitted to avoid radiotherapy-related risks. PMID- 22511808 TI - Increased prevalence of subclinical cardiac valve fibrosis in patients with prolactinomas on long-term bromocriptine and cabergoline treatment. AB - BACKGROUND: In contrast to cabergoline, evidence-based information about a possible profibrotic effect of bromocriptine in prolactinoma patients is extremely limited. OBJECTIVE: To assess the prevalence of valvular lesions among patients on long-term bromocriptine or cabergoline therapy. DESIGN: Case-control study. METHODS: A transthoracic echocardiographic evaluation was performed in 334 subjects divided into four groups: 103 cabergoline treated, 55 bromocriptine treated, 74 naive patients, and 102 controls. RESULTS: Clinically relevant valve regurgitations were equally prevalent in all investigated groups whereas subclinical valve fibrosis was significantly more frequent in both bromocriptine- and cabergoline-treated patients (40 vs 43.6 vs 21.6 vs 23.5%; P=0.004). The odds ratio (OR) for developing valvular fibrosis was 2.27 (95% CI 1.17-4.41; P=0.016) for cabergoline and 2.66 (95% CI 1.22-5.78; P=0.014) for bromocriptine groups compared with subjects not exposed to dopamine agonists (DAs). A significantly higher pulmonary arterial pressure corresponding to the longer treatment duration was observed among patients taking bromocriptine compared with cabergoline treated subjects. CONCLUSIONS: Long-term treatment with cabergoline and bromocriptine seems not to be associated with an increased risk of clinically significant valve disease but possible subclinical lesions should be expected. An echocardiographic examination is recommended at the beginning and periodically during therapy with DAs acting as full or partial agonists of 5-hydroxytrytamine 2B receptors (cabergoline and bromocriptine). Bromocriptine seems not to be a safe alternative for patients receiving cabergoline treatment who have preexisting or diagnosed abnormalities suggesting valvular, interstitial myocardial, or pulmonary fibrosis. Further studies are needed to investigate the possible impact of DA treatment on pulmonary arterial pressure. PMID- 22511809 TI - Association of variants in HLA-DQA1-DQB1, PTPN22, INS, and CTLA4 with GAD autoantibodies and insulin secretion in nondiabetic adults of the Botnia Prospective Study. AB - OBJECTIVE: Previously, we observed an association between family history of type 1 diabetes and development of non-insulin-dependent diabetes. The aims of this study were to assess whether type 1 diabetes susceptibility gene variants explain this association and investigate the effect of the variants on insulin secretion and presence of glutamic acid decarboxylase autoantibodies (GADA) in nondiabetic adults. DESIGN AND METHODS: Polymorphisms in INS (rs689), PTPN22 (rs2476601), CTLA4 (rs3087243), and the HLA-DQA1-DQB1 regions (rs2187668 and rs7454108 tagging HLA-DQ2.5 and HLA-DQ8 respectively) were genotyped in the Botnia Prospective Study (n=2764), in which initially nondiabetic participants were followed for a mean of 8.1 years. RESULTS: The variants did not explain the association between family history of type 1 diabetes and development of non-insulin-dependent diabetes. In these nondiabetic adults, HLA-DQ AND PTPN22 risk genotypes were associated with GADA (HLA-DQ2.5/HLA-DQ8 or HLA-DQ8: OR (95% CI): 1.7 (1.3-2.3), P=0.0004; PTPN22 CT/TT: OR: 1.6 (1.2-2.2), P=0.003; P values were adjusted for sex, age, BMI, and follow-up time). A higher genetic risk score was associated with lower insulin secretion (insulinogenic index: 13.27 (16.27) vs 12.69 (15.27) vs 10.98 (13.06), P=0.02) and better insulin sensitivity index (risk score of 0-1 vs 2-3 vs 4-6: 142 (111) vs 144 (118) vs 157 (127), P=0.01) at baseline and a poorer capacity to compensate for the increased insulin demand after follow-up. CONCLUSIONS: In nondiabetic adults, HLA-DQ2.5/HLA-DQ8 and PTPN22 CT/TT genotypes were associated with GADA. PMID- 22511810 TI - Prosthesis/annulus discongruence assessed by three-dimensional transoesophageal echocardiography: a predictor of significant paravalvular aortic regurgitation after transcatheter aortic valve implantation. AB - AIMS: Paravalvular aortic regurgitation (AR) is common after transcatheter aortic valve implantation (TAVI). This study aimed to assess the prosthesis/aortic annulus discongruence by three-dimensional (3D) transoesophageal (TOE) planimetry of aortic annulus and its impact on the occurrence of significant AR after TAVI. METHODS AND RESULTS: We included 33 patients who underwent TAVI with a balloon expandable device for severe aortic stenosis. To appraise the prosthesis/annulus discongruence, we defined a 'mismatch index' expressed as: annulus area - prosthesis area. The aortic annulus area was planimetered with 3D TOE, and approximated by circular area formula (pi r(2)) using annulus diameter obtained by two-dimensional (2D) TOE. After TAVI, 13 patients (39.3%) developed significant AR (>=2/4). The occurrence of significant AR was associated to the 3D planimetered annulus area (P = 0.04), and the 'mismatch index' obtained through 3D planimetered annulus area (P = 0.03), but not to 'mismatch index' derived of 2D annulus diameter. In multivariate analysis, 'mismatch index' for 3D planimetered annulus area was the only independent predictor of significant AR (odds ratio: 10.614; 95% CI: 1.044-17.21; P = 0.04). The area under the receiver operating characteristic curve for the 'mismatch index' by the 3D planimetered annulus area was 0.76 (95% CI: 0.54-0.92), whereas for 'mismatch index' obtained by the 2D circular area was 0.36 (95% CI: 0.17-0.55). Using the 3D planimetered annulus area as the reference parameter to decide the prosthetic size, the choice would have been different in 21 patients (63%). CONCLUSION: Three-dimensional TOE planimetry of aortic annulus improves the assessment of prosthesis/annulus discongruence and predicts the appearance of significant AR after TAVI. PMID- 22511811 TI - Left circumflex to superior vena cava coronary artery fistula. PMID- 22511812 TI - Measuring coronary artery calcification using positron emission tomography computed tomography attenuation correction images. AB - AIMS: Cardiac computed tomography (CT) measured coronary artery calcium (CAC-CT) is a well-validated and accurate tool for estimating atherosclerotic burden and prognosis. Computed tomography attenuation correction (ACCT) obtained during cardiac positron emission tomography (PET) has been used to visually estimate CAC; however, quantification using a non-gated ACCT images has not been described. We sought to understand the relationship between CAC measured using cardiac computed tomography (CT) and CAC using ACCT images obtained during cardiac PET perfusion imaging. METHODS AND RESULTS: Patients with both CAC-CT and cardiac PET within 6 months of each other were identified. CAC-CT images were scored using the Agatston scoring method, while ACCT images were scored using different attenuation thresholds for calcium. CAC-CT and ACCT scores were compared. Between August 2007 and October 2010, 91 patients were included in the analysis. Interobserver reliability was excellent at all thresholds of detection tested. Pearson correlation was strongest between CAC-CT and ACCT at 50 HU threshold of detection (ACCT(50)). Implementing CAC categories (0, 1-100, 101 400, >400), there was a high degree of agreement between observers as well as between CAC-CT and ACCT(50). Correlation was best for lower CAC scores; however, as CAC-CT increased, ACCT(50) underestimated CAC. CONCLUSION: Quantifying CAC using ACCT images appears to be feasible and accurate. In a single cardiac PET examination, information regarding perfusion, LV function, flow quantification, and CAC can be obtained without additional radiation. PMID- 22511813 TI - ? AB - We study existence, uniqueness, and distributional aspects of generalized solutions to the Cauchy problem for first-order symmetric (or Hermitian) hyperbolic systems of partial differential equations with Colombeau generalized functions as coefficients and data. The proofs of solvability are based on refined energy estimates on lens-shaped regions with spacelike boundaries. We obtain several variants and also partial extensions of previous results in Oberguggenberger (1989), Lafon and Oberguggenberger (1991), and Hormann (2004) [26,23,16] and provide aspects accompanying related recent work in Oberguggenberger (2009), Garetto and Oberguggenberger (2011) [28,10,9]. PMID- 22511815 TI - The WHO research agenda for influenza: two years later. PMID- 22511816 TI - Influenza at the beginning of the 21st century. PMID- 22511818 TI - The influenza enigma. PMID- 22511819 TI - Spreading the word about seasonal influenza. PMID- 22511820 TI - Tackling influenza in Ghana. Interview by Ben Jones. PMID- 22511821 TI - The population-based burden of influenza-associated hospitalization in rural western Kenya, 2007-2009. AB - OBJECTIVE: To estimate the burden and age-specific rates of influenza-associated hospitalization in rural western Kenya. METHODS: All 3924 patients with respiratory illness (defined as acute cough, difficulty in breathing or pleuritic chest pain) who were hospitalized between June 2007 and May 2009 in any inpatient health facility in the Kenyan district of Bondo were enrolled. Nasopharyngeal and oropharyngeal swabs were collected and tested for influenza viruses using real time reverse transcriptase polymerase chain reaction (RT-PCR). In the calculation of annual rates, adjustments were made for enrolled patients who did not have swabs tested for influenza virus. FINDINGS: Of the 2079 patients with tested swabs, infection with influenza virus was confirmed in 204 (10%); 176, 27 and 1 were found to be RT-PCR-positive for influenza A virus only, influenza B virus only, and both influenza A and B viruses, respectively. Among those tested for influenza virus, 6.8% of the children aged < 5 years and 14.0% of the patients aged >= 5 years were found positive. The case-fatality rate among admitted patients with PCR-confirmed infection with influenza virus was 2.0%. The annual rate of hospitalization (per 100,000 population) was 699.8 among patients with respiratory illness and 56.2 among patients with influenza (with 143.7, 18.8, 55.2, 65.1 and 57.3 hospitalized patients with influenza virus per 100,000 people aged < 5, 5-19, 20-34, 35-49 and >= 50 years, respectively). CONCLUSION: In a rural district of western Kenya, the rate of influenza-associated hospitalization was highest among children aged less than 5 years. PMID- 22511822 TI - Likely effectiveness of pharmaceutical and non-pharmaceutical interventions for mitigating influenza virus transmission in Mongolia. AB - OBJECTIVE: To assess the likely benefit of the interventions under consideration for use in Mongolia during future influenza pandemics. METHODS: A stochastic, compartmental patch model of susceptibility, exposure, infection and recovery was constructed to capture the key effects of several interventions--travel restrictions, school closure, generalized social distancing, quarantining of close contacts, treatment of cases with antivirals and prophylaxis of contacts- on the dynamics of influenza epidemics. The likely benefit and optimal timing and duration of each of these interventions were assessed using Latin-hypercube sampling techniques, averaging across many possible transmission and social mixing parameters. FINDINGS: Timely interventions could substantially alter the time-course and reduce the severity of pandemic influenza in Mongolia. In a moderate pandemic scenario, early social distancing measures decreased the mean attack rate from around 10% to 7-8%. Similarly, in a severe pandemic scenario such measures cut the mean attack rate from approximately 23% to 21%. In both moderate and severe pandemic scenarios, a suite of non-pharmaceutical interventions proved as effective as the targeted use of antivirals. Targeted antiviral campaigns generally appeared more effective in severe pandemic scenarios than in moderate pandemic scenarios. CONCLUSION: A mathematical model of pandemic influenza transmission in Mongolia indicated that, to be successful, interventions to prevent transmission must be triggered when the first cases are detected in border regions. If social distancing measures are introduced at this stage and implemented over several weeks, they may have a notable mitigating impact. In low-income regions such as Mongolia, social distancing may be more effective than the large-scale use of antivirals. PMID- 22511823 TI - Influenza-associated mortality in 2009 in four sentinel sites in Bangladesh. AB - OBJECTIVE: To estimate influenza-associated mortality in Bangladesh in 2009. METHODS: In four hospitals in Bangladesh, respiratory samples were collected twice a month throughout 2009 from inpatients aged < 5 years with severe pneumonia and from older inpatients with severe acute respiratory infection. The samples were tested for influenza virus ribonucleic acid (RNA) using polymerase chain reaction. The deaths in 2009 in five randomly selected unions (the smallest administrative units in Bangladesh) in each hospital's catchment area were then investigated using formal records and informal group discussions. The deaths of those who had reportedly died within 14 days of suddenly developing fever with cough and/or a sore throat were assumed to be influenza-associated. The rate of such deaths in 2009 in each of the catchment areas was then estimated from the number of apparently influenza-associated deaths in the sampled unions, the proportion of the sampled inpatients in the local hospital who tested positive for influenza virus RNA, and the estimated number of residents of the sampled unions. FINDINGS: Of the 2500 people known to have died in 2009 in all 20 study unions, 346 (14%) reportedly had fever with cough and/or sore throat within 14 days of their deaths. The estimated mean annual influenza-associated mortality in these unions was 11 per 100,000 population: 1.5, 4.0 and 125 deaths per 100,000 among those aged < 5, 5-59 and > 59 years, respectively. CONCLUSION: The highest burden of influenza-associated mortality in Bangladesh in 2009 was among the elderly. PMID- 22511824 TI - Influenza-associated mortality in temperate and subtropical Chinese cities, 2003 2008. AB - OBJECTIVE: To estimate influenza-associated mortality in urban China. METHODS: Influenza-associated excess mortality for the period 2003-2008 was estimated in three cities in temperate northern China and five cities in the subtropical south of the country. The estimates were derived from models based on negative binomial regressions, vital statistics and the results of weekly influenza virus surveillance. FINDINGS: Annual influenza-associated excess mortality, for all causes, was 18.0 (range: 10.9-32.7) deaths per 100,000 population in the northern cities and 11.3 (range: 7.3-17.8) deaths per 100,000 in the southern cities. Excess mortality for respiratory and circulatory disease was 12.4 (range: 7.4 22.2) and 8.8 (range: 5.5-13.6) deaths per 100,000 people in the northern and southern cities, respectively. Most (86%) deaths occurred among people aged >= 65 years. Influenza-associated excess mortality was higher in B-virus-dominant seasons than in seasons when A(H3N2) or A(H1N1) predominated, and more than half of all influenza-associated mortality was associated with influenza B virus. CONCLUSION: Between 2003 and 2008, seasonal influenza, particularly that caused by the influenza B virus, was associated with substantial mortality in three cities in the temperate north of China and five cities in the subtropical south of the country. PMID- 22511825 TI - Integrating pneumonia prevention and treatment interventions with immunization services in resource-poor countries. AB - Pneumonia is a leading cause of morbidity and mortality worldwide. Effective vaccine and non-vaccine interventions to prevent and control pneumonia are urgently needed to reduce the global burden of the disease. This paper explores practical strategies and policies for integrating interventions to prevent and treat pneumonia with routine immunization services, and it investigates the challenges involved in such integration. The primary pneumonia prevention and treatment strategies that are implemented during routine childhood immunization visits are vaccination of children against the disease, caretaker education and referral of children to medical services when necessary. PMID- 22511826 TI - Application of a healthy food markets guide to two Indonesian markets to reduce transmission of "avian flu". AB - PROBLEM: The World Health Organization (WHO) developed a guideline with 10 control measures to reduce transmission of A(H5N1) avian influenza virus in markets in low-resource settings. The practical aspects of guide implementation have never been described. APPROACH: WHO's guideline was implemented in two Indonesian markets in the city of Makassar to try to reduce transmission of the A(H5N1) virus. The guideline was operationalized using a participatory approach to introduce a combination of infrastructural and behavioural changes. LOCAL SETTING: Avian influenza is endemic in birds in Makassar. Two of the city's 22 dilapidated, poorly-run bird markets were chosen for the study. Before the intervention, neither market was following any of WHO's 10 recommended control measures except for batch processing. RELEVANT CHANGES: Market stakeholders' knowledge about the avian influenza A(H5N1) virus improved after the interventions. WHO guideline recommendations for visual inspection, cleaning and poultry-holding practices, as well as infrastructural requirements for zoning and for water supply and utilities, began to conform to the WHO guideline. Low maintenance solutions such as installation of wastewater treatment systems and economic incentives such as composting were well received and appropriate for the low-resource setting. LESSONS LEARNT: Combining infrastructural changes with behaviour change interventions was critical to guideline implementation. Despite initial resistance to behaviour change, the participatory approach involving monthly consultations and educational sessions facilitated the adoption of safe food-handling practices and sanitation. Market authorities assumed important leadership roles during the interventions and this helped shift attitudes towards regulation and market maintenance needs. This shift may enhance the sustainability of the interventions. PMID- 22511827 TI - Improving influenza surveillance in sub-Saharan Africa. AB - PROBLEM: Little is known about the burden of influenza in sub-Saharan Africa. Routine influenza surveillance is key to getting a better understanding of the impact of acute respiratory infections on sub-Saharan African populations. APPROACH: A project known as Strengthening Influenza Sentinel Surveillance in Africa (SISA) was launched in Angola, Cameroon, Ghana, Nigeria, Rwanda, Senegal, Sierra Leone and Zambia to help improve influenza sentinel surveillance, including both epidemiological and virological data collection, and to develop routine national, regional and international reporting mechanisms. These countries received technical support through remote supervision and onsite visits. Consultants worked closely with health ministries, the World Health Organization, national influenza laboratories and other stakeholders involved in influenza surveillance. LOCAL SETTING: Influenza surveillance systems in the target countries were in different stages of development when SISA was launched. Senegal, for instance, had conducted virological surveillance for years, whereas Sierra Leone had no surveillance activity at all. RELEVANT CHANGES: Working documents such as national surveillance protocols and procedures were developed or updated and training for sentinel site staff and data managers was organized. LESSONS LEARNT: Targeted support to countries can help them strengthen national influenza surveillance, but long-term sustainability can only be achieved with external funding and strong national government leadership. PMID- 22511828 TI - Epidemic and intervention modelling--a scientific rationale for policy decisions? Lessons from the 2009 influenza pandemic. AB - PROBLEM: Outbreak analysis and mathematical modelling are crucial for planning public health responses to infectious disease outbreaks, epidemics and pandemics. This paper describes the data analysis and mathematical modelling undertaken during and following the 2009 influenza pandemic, especially to inform public health planning and decision-making. APPROACH: Soon after A(H1N1)pdm09 emerged in North America in 2009, the World Health Organization convened an informal mathematical modelling network of public health and academic experts and modelling groups. This network and other modelling groups worked with policy makers to characterize the dynamics and impact of the pandemic and assess the effectiveness of interventions in different settings. SETTING: The 2009 A(H1N1) influenza pandemic. RELEVANT CHANGES: Modellers provided a quantitative framework for analysing surveillance data and for understanding the dynamics of the epidemic and the impact of interventions. However, what most often informed policy decisions on a day-to-day basis was arguably not sophisticated simulation modelling, but rather, real-time statistical analyses based on mechanistic transmission models relying on available epidemiologic and virologic data. LESSONS LEARNT: A key lesson was that modelling cannot substitute for data; it can only make use of available data and highlight what additional data might best inform policy. Data gaps in 2009, especially from low-resource countries, made it difficult to evaluate severity, the effects of seasonal variation on transmission and the effectiveness of non-pharmaceutical interventions. Better communication between modellers and public health practitioners is needed to manage expectations, facilitate data sharing and interpretation and reduce inconsistency in results. PMID- 22511829 TI - Developing pandemic preparedness in Europe in the 21st century: experience, evolution and next steps. AB - PROBLEM: Improving pandemic planning and preparedness is a challenge in Europe, a diverse region whose regional bodies (the Regional Office for Europe of the World Health Organization [WHO], the European Commission and the European Centre for Disease Prevention and Control) have overlapping roles and responsibilities. APPROACH: European pandemic preparedness indicators were used to develop an assessment tool and procedure based on the 2005 global WHO checklist for pandemic preparedness. These were then applied to Member States of WHO's European Region, initially as part of structured national assessments conducted during short visits by external teams. LOCAL SETTING: Countries in WHO's European Region. RELEVANT CHANGES: From 2005 to 2008, 43 countries underwent a pandemic preparedness assessment that included a short external assessment visit by an expert team. These short visits developed into a longer self-assessment procedure involving an external team but "owned" by the countries, which identified gaps and developed plans for improving preparedness. The assessment tool and procedure became more sophisticated as national and local pandemic preparedness became more complex. The 2009 pandemic revealed new gaps in planning, surveillance communications and immunization. LESSONS LEARNT: Structured national self assessments with support from external teams allow individual countries to identify gaps in their pandemic preparedness plans and enable regional bodies to assess the regional and global resources that such plans require. The 2009 pandemic revealed additional problems with surveillance, pandemic severity estimates, the flexibility of the response, vaccination, involvement of health care workers and communication. European national plans are being upgraded and global leadership is required to ensure that these plans are uniformly applied across the region. PMID- 22511830 TI - Population-based active surveillance cohort studies for influenza: lessons from Peru. PMID- 22511831 TI - Clinical profile and visual outcomes after treatment in patients with dysthyroid optic neuropathy. AB - PURPOSE: To report the clinical data and visual outcomes after treatment of patients with dysthyroid optic neuropathy (DON). METHODS: We retrospectively reviewed the medical records and orbital images of 40 patients (65 eyes) with DON and analyzed the visual outcomes after treatment with intravenous steroids pulse therapy, radiotherapy and orbital decompression. RESULTS: The study included 21 men and 19 women, with 10 (25%) being diabetic patients. Visual field test results revealed defects in 88.7% of DON eyes; afferent pupillary defects in 63.2%; reduced color vision in 78.5%; and abnormal visual evoked potentials in 84%. Orbital imaging showed moderate to severe apical crowding in 95% of the orbits and intracranial fat prolapse in 24.2%. Median best corrected visual acuity improved from 0.4 to 1.0 after one year of treatment (p < 0.001). We noted more improvement in vision with the use of decompressive surgery than with non surgical methods (p < 0.05). Recurrences occurred in 7 patients who had not received orbital radiotherapy. CONCLUSIONS: Visual field defects and apical crowding seen on orbital imaging were the most sensitive indicators for the detection of DON. Treatment with intravenous steroids pulse therapy, radiotherapy and orbital decompression effectively improved visual outcomes in cases of DON. PMID- 22511832 TI - Causes of visual impairment among patients referred to a visual rehabilitation clinic in Iran. AB - PURPOSE: Epidemiologic evaluation and investigating the causes of visual impairment in any society is a matter of concern and has a direct effect on the country's health care planning. In this study we describe causes of low vision and blindness in Iranian patients referred to rehabilitation clinics for taking vision aids. METHODS: In this cross-sectional study, visual acuity was classified based on best-corrected visual acuity in the better eye according to the World Health Organization definition (blindness, visual acuity [VA] < 20 / 400; severe visual impairment, VA < 20 / 200-20 / 400; mild to moderate visual impairment, VA < 20 / 60-20 / 200). The causes of blindness and low vision were determined using the 10th version of International Classification of Diseases based on the main cause in both eyes. To describe data, we used mean +/- SD and frequency. RESULTS: The study included 432 patients, 65% male, with a mean age of 43.6 +/- 25.5 years (range, 3 to 92 years). Mild to moderate visual impairment, severe visual impairment and blindness were present in 122 (28.8%), 196 (46.4%) and 105 (24.8%) of the patients, respectively. The main causes of visual impairment were retinal and choroidal diseases (74.5%), optic nerve and optic tract diseases (9.8%), vitreous and globe disorders (5.3%), congenital cataract (3.1%), and glaucoma (2.6%). The distribution pattern of the causes was similar in all age subgroups. CONCLUSIONS: Diseases of the retina and choroid are the main cause of visual impairment among patients referred to an academic visual rehabilitation clinic in Iran. PMID- 22511833 TI - Circulating total glutathione in normal tension glaucoma patients: comparison with normal control subjects. AB - PURPOSE: Oxidative stress plays a critical role in the pathogenesis of glaucoma. Glutathione is a major antioxidant molecule present in intracellular or extracellular space. Herein, we aimed to examine circulating glutathione level in normal tension glaucoma (NTG), which comprises the largest proportion of glaucoma disease in the Korean population. METHODS: Nineteen NTG patients (NTG group) and 30 age- and gender-matched normal control subjects (control group) were included. Antecubital venous puncture was performed between 8 and 10 o'clock in the morning to obtain a 4 mL venous blood sample. Total glutathione level was measured by the spectrophotometric method at 412 nm. Correlation of total glutathione level with mean deviation and pattern standard deviation from the Humphrey visual field test was analyzed in the NTG group. RESULTS: Total glutathione level in circulating blood was 524.02 +/- 231.09 nmol and 586.06 +/- 156.08 nmol in the NTG group and the control group, respectively. The difference between these values was not statistically significant (p = 0.121, F = 2.212). Age had no significant effect on circulating total glutathione level in either the NTG group (p = 0.171, r = 0.328) or the control group (p = 0.380, r = -0.166). In the NTG group, circulating total glutathione level had no significant relationship with mean deviation (p = 0.226, F = 1.636) and pattern standard deviation (p = 0.200, F = 1.766) after correcting for age and gender. CONCLUSIONS: In NTG patients, circulating total glutathione levels were not different compared to those of normal subjects. PMID- 22511834 TI - Pars plana Ahmed implantation combined with 23-gauge vitrectomy for refractory neovascular glaucoma in diabetic retinopathy. AB - PURPOSE: To evaluate the efficacy and safety of a pars plana Ahmed valve implantation combined with 23-gauge sutureless vitrectomy in the treatment of patients with medically uncontrolled neovascular glaucoma (NVG) in proliferative diabetic retinopathy (PDR). METHODS: The authors retrospectively reviewed the records of 11 consecutive patients with refractory NVG in PDR who underwent a 23 gauge sutureless vitrectomy combined with pars plana placement of an Ahmed valve implant. Control of intraocular pressure (IOP), pre- and postoperative best corrected visual acuity and the development of intra- and postoperative complications were evaluated during the follow-up. RESULTS: The mean follow-up was 12.2 months (range, 8 to 25 months). Mean preoperative IOP was 35.9 +/- 6.3 mmHg and mean postoperative IOP at the last visit was 13.3 +/- 3.2 mmHg. Control of IOP (8 to 18 mmHg) was achieved in all patients, but 91% (10 of 11 patients) needed antiglaucoma medication (mean number of medications, 1.2 +/- 0.6). Postoperative visual acuity improved in 11 eyes, and the logarithmically to the minimum angle of resolution mean visual acuity in these eyes improved from 1.67 +/- 0.61 to 0.96 +/- 0.67. The complications that occurred were transient hypotony in one case, transitory hypertension in two cases, and postoperative vitreous hemorrhage which spontaneously cleared in two cases. CONCLUSIONS: We suggest the combination of 23-gauge pars plana vitrectomy and Ahmed valve implantation is safe and effective in PDR patients with refractory NVG. PMID- 22511835 TI - Anterior chamber configuration changes after cataract surgery in eyes with glaucoma. AB - PURPOSE: To evaluate changes in anterior chamber depth (ACD) and angle width induced by phacoemulsification and intraocular lens (IOL) implantation in eyes with glaucoma, using anterior segment optical coherence tomography (AS-OCT). METHODS: Eleven eyes of 11 patients with angle-closure glaucoma (ACG) and 12 eyes of 12 patients with open-angle glaucoma (OAG) underwent phacoemulsification and IOL implantation. Using AS-OCT, ACD and angle parameters were measured before and 2 days after surgery. Change in intraocular pressure (IOP) and number of ocular hypotensive drugs were evaluated. RESULTS: After surgery, central ACD and angle parameters increased significantly in eyes with glaucoma (p < 0.05). Prior to surgery, mean central ACD in the ACG group was approximately 1.0 mm smaller than that in the OAG group (p < 0.001). Post surgery, mean ACD of the ACG group was still significantly smaller than that of the OAG group. No significant differences were found in angle parameters between the ACG and OAG groups. In the ACG group, postoperative IOP at the final visit was significantly lower than preoperative IOP (p = 0.018) and there was no significant change in the number of ocular hypotensive medications used, although clinically, patients required fewer medications. In the OAG group, the IOP and number of ocular hypotensive drugs were almost unchanged after surgery. CONCLUSIONS: The ACD and angle width in eyes with glaucoma increased significantly after phacoemulsification and IOL implantation. Postoperative ACD significantly differed between the ACG and OAG groups, whereas angle parameters did not differ. PMID- 22511836 TI - The effect of various factors on variability of retinal nerve fiber layer thickness measurements using optical coherence tomography. AB - PURPOSE: To evaluate the effects of various factors on the variability of retinal nerve fiber layer (RNFL) thickness measurements using the Stratus optical coherence tomography (OCT) in normal and glaucomatous eyes. METHODS: Four hundred seventy-four subjects (103 normal eyes and 371 glaucomatous eyes) were scanned to determine the RNFL thickness measurements using the Stratus OCT. Measurements were obtained twice during the same day. The standard deviation (SD) was used to compare the variability in RNFL thickness measurements of the normal subjects to that of the glaucomatous patients. Multivariate regression analysis was used to evaluate which covariates were independent predictors of SD in overall mean RNFL thickness. RESULTS: The mean SD of all RNFL thickness measurements was larger in the glaucoma group except in one sector. In the multivariate regression analysis, the average signal strength (SS) and the relative SS change (difference in SS between initial and repeat scans, divided by initial SS) were independent predictors of the SD in the RNFL thickness measurements (partial R(2) = 0.018, 0.013; p = 0.016, 0.040, respectively). CONCLUSIONS: Glaucomatous eyes tend to be more variable than normal eyes in RNFL thickness measurement using the Straus OCT. The average SS and the relative SS changes appear to correlate with the variability in RNFL thickness measurement. Therefore, the results of the RNFL analysis should not be interpreted independently of these factors. PMID- 22511837 TI - Clinical characteristics of optic neuritis in Koreans greater than 50 years of age. AB - PURPOSE: To report clinical characteristics of optic neuritis (ON) in Koreans >50 years of age. METHODS: A retrospective chart review was performed on patients with ON between January 2000 and December 2009. We obtained the best-corrected visual acuity (BCVA), Goldmann perimetry, relative afferent pupillary defect (RAPD), and color function tests as well as brain magnetic resonance imaging (MRI) findings in patients who were in the acute stage of the disorder. RESULTS: Nine eyes in eight patients were included. The mean age of patients at presentation was 60.5 years (range, 53 to 71 years). Six patients were female, and two were male. There was one patient with bilateral ON. The mean BCVA at presentation was 20 / 400 (no light perception-20 / 70). Eight eyes (89%) complained of pain with eye movement. Six eyes (66%) had disc edema. Central scotoma was the most common field defect. All eyes had color abnormalities. Five eyes in four patients showed abnormalities of the involved optic nerves on MRI. The patients were followed for a mean of 11.3 months (range, 2 to 34 months). All of the patients recovered to a BCVA of 20 / 40 or better within 2 months. On the last follow-up, the mean BCVA was 20 / 20 (20 / 40 to 20 / 16). Four eyes showed remnant central scotoma. One eye had remnant RAPD, and two eyes had mild color abnormalities. CONCLUSIONS: Although ON is uncommon in elderly patients, it can develop in patients >50 years of age, and clinical features of optic neuritis in elderly patients are similar to those of younger patients. PMID- 22511838 TI - Orbital Doppler evaluation of blood flow velocities in optic neuritis. AB - PURPOSE: To evaluate orbital blood flow velocities and optic nerve diameter with Doppler and gray-scale sonography in patients with acute unilateral optic neuritis (ON). METHODS: Orbital Doppler and gray-scale sonography was performed in 46 eyes of 23 patients aged 19- to 47-years with acute unilateral ON. ON was diagnosed by an ophthalmologist on the basis of clinical presentation, presence of decreased visual acuity and assessment of visual evoked potentials. The peak systolic velocity (PSV) and end-diastolic velocity (EDV), as well as the resistance index (RI) and pulsatile index (PI) of the ophthalmic artery (OA), central retinal artery (CRA), posterior ciliary arteries (PCAs) and optic nerve diameter were measured in both eyes. We compared results from affected and unaffected eyes using the paired t-test. The area under the receiver operating characteristic (ROC) curves was used to assess the diagnosis of ON based on measured blood flow parameters of the OA, CRA and PCAs and optic nerve diameter. RESULTS: The mean (standard deviation) optic nerve diameter in eyes with ON was 4.1 (0.8) mm, which was significantly larger than the 3.0 (0.4) mm diameter measured in unaffected control eyes (p < 0.001). There were no differences in average PSV, EDV, RI, or PI of the OA and CRA between affected and unaffected eyes (p > 0.05). The mean RI in the PCAs was slightly lower in the eyes with ON than in the contralateral eyes (0.60 vs. 0.64, p < 0.05). The area under the ROC curves indicated that optic nerve diameter was the best parameter for the diagnosis of ON. CONCLUSIONS: Optic nerve diameter was related to ON, but orbital blood flow parameters were not. PMID- 22511840 TI - A case of central retinal artery occlusion after chiropractic manipulation of the neck. AB - Here we report a case of central retinal artery occlusion after chiropractic manipulation on the neck. A 49-year old man presented at the hospital because of sudden visual loss in his right eye after chiropractic neck manipulation. He had received chiropractic manipulation of the neck by a chiropractor eight days prior. When he first visited us, his best corrected visual acuity in his right eye was hand motion. A full ophthalmic examination was performed. There was cherry-red spot in the macula in his right eye. We performed a fluorescein angiogram and cervical color Doppler. The arterio-venous transit time in the fluorescein angiogram was delayed, and we detected stenosis of the right internal carotid artery with diffuse atherosclerotic plaques in the right common carotid artery. We prescribed ginko biloba extract (Tanamin). Three years after his first visit, the best corrected visual acuity of his right eye was 20 / 200. PMID- 22511839 TI - Effect of advanced glycation end products on oxidative stress and senescence of trabecular meshwork cells. AB - PURPOSE: To investigate the effect of advanced glycation end products (AGE) on oxidative stress and cellular senescence in cultured human trabecular meshwork cells (HTMC). METHODS: Primarily cultured HTMC were exposed to 0, 10, 50, 100, 200 ug/mL of glycated bovine serum albumin (G-BSA) for 5 days. Also co-exposed were L-arginine, sepiapterin, and antioxidant N-acetylcysteine (NAC). Cellular survival and production of nitric oxide (NO), superoxide, and reactive oxygen species were assessed by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide assay, Griess assay, cytochrome c assay, and dichlorofluorescin diacetate assay, respectively. Senescence-associated beta-galactosidase staining was performed to quantify the degree of cellular senescence. RESULTS: G-BSA decreased cellular survival, NO production, and increased superoxide production significantly in a dose-dependent manner. The effects of G-BSA were abolished with co-exposure of L-arginine, sepiapterin, and NAC. G-BSA enhanced cellular senescence accompanied by increased production of reactive oxygen species. G-BSA induced cellular senescence was suppressed by application of L-arginine, sepiapterin, and NAC. CONCLUSIONS: AGE enhances cellular senescence of HTMC accompanied with increased oxidative stress. AGE-induced oxidative stress and cellular senescence could be delayed by application of anti-oxidants. PMID- 22511841 TI - A developmental mechanism of spontaneous reattachment in rhegmatogenous retinal detachment. AB - This retrospective observational case series on eyes from three patients was done to elucidate the developmental mechanism of spontaneous reattachment of rhegmatogenous retinal detachment (SRRRD). The study eyes of each patients showed evidence of retinal break and diffuse retinal pigmentary change. Ultrasound biomicroscopic examination revealed vitreous fibers attached to the area around the retinal break. Posterior vitreous attachment was confirmed in each eye. A thin fibrovascular membrane incompletely sealing the retinal break was noted in one case. We suggest that the vitreous attachment around the retinal break and the sealing of the break with adjacent vitreous fibers seem to be involved in the developmental mechanism of SRRRD. PMID- 22511842 TI - Intravitreal bevacizumab for treatment of refractory central serous choroidoretinopathy. AB - In a clinical case series, 5 patients with not-resolved central serous choroidoretinopathy (CSC) lasting more than 1 year received one intravitreal bevacizumab injection (IVB, 1.25 mg) injection. All patients underwent a through ophthalmic examination 1 day, 1 week, and 1, 2, and 6 months after the injection. Best corrected visual acuity (BCVA) and central macular thickness were compared before and after treatment by optical coherence tomography. Mean BCVA was improved significantly (p = 0.020) from 0.60 +/- 0.25 to 0.50 +/- 0.18 and 0.29 +/- 0.19 logarithm of minimum angle of resolution at 6 and 18 weeks, respectively. Central macular thickness was also decreased significantly (p = 0.010) from 370 +/- 65 to 208 +/- 23 um at 4 months. No recurrence was occurred during follow-up. IVB injection may have beneficial effect in the treatment of refractory CSC. PMID- 22511843 TI - Morphological and functional correlates in Goldmann-Favre syndrome: a case series. AB - The purpose of this study is to describe the correlation of findings between results from spectral domain optical coherence tomography (SD-OCT) and microperimetry in a case series regarding patients with Goldmann-Favre syndrome. Goldmann-Favre syndrome is a rare autosomal recessive hereditary vitreo-retinal degeneration that impacts the functionality of vision in subjects. Three men with this condition were assessed and subjected to microperimetry and SD-OCT. Two of the men were brothers. This study finds that the retinoschisis and macular cystoid changes noted in the SD-OCT matched the scotomas revealed by the microperimetry. The findings of each of the individual cases are reported herein. PMID- 22511844 TI - Pegylated interferon-associated severe retinopathy in a patient with chronic hepatitis. AB - This paper reports a case of pegylated interferon-associated retinopathy in a patient with chronic hepatitis C. A 32-year-old female with chronic hepatitis C undergoing pegylated interferon and ribavirin combination therapy complained of visual blurring. Features of interferon-associated retinopathy, including ocular complications such as cotton wool spots, retinal hemorrhages, macular edema, and branch retinal vein occlusion, were found in the fundus of both of her eyes. Pegylated interferon combination therapy was stopped, and the retinopathy of the patient was treated with intravitreal bevacizumab injections and panretinal photocoagulations. This case shows that pharmacokinetically improved pegylated interferon has ocular complications for patients with chronic hepatitis C. Accordingly, patients undergoing pegylated interferon treatment for hepatitis C need regular eye examinations for protection of their vision. PMID- 22511845 TI - Spontaneous resolution of intravitreal steroid-induced bilateral cytomegalovirus retinitis. AB - A 73-year-old woman underwent vitrectomy and intravitreal triamcinolone acetonide (IVTA) of the right eye and cataract surgery with IVTA of the left eye, for bilateral diabetic macular edema. The patient presented with visual loss in both eyes three-months postoperatively. The fundoscopic examination revealed white yellow, necrotic peripheral lesions in the superotemporal quadrant of both eyes. Although bilateral acute retinal necrosis was suspected, azotemia resulting from diabetic nephropathy limited the use of acyclovir. Antiviral treatment was not started. A sample of the aqueous humor for polymerase chain reaction (PCR) analysis was obtained. One week later, the PCR results indicated the presence of cytomegalovirus (CMV). Since the retinal lesions did not progress and did not threaten the macula, the patient was followed without treatment for CMV. The retinal lesions progressively regressed and completely resolved in both eyes by six months of follow-up. Patients with IVTA-induced CMV retinitis may not require systemic treatment with ganciclovir. PMID- 22511846 TI - Comparison of aqueous humor cytokine and chemokine levels in diabetic patients with and without retinopathy. AB - PURPOSE: To compare the aqueous humor levels of proinflammatory and angiogenic factors of diabetic patients with and without retinopathy. METHODS: Aqueous humor was collected at the start of cataract surgery from diabetic subjects and non diabetic controls. The presence and severity of diabetic retinopathy were graded with fundus examination. Levels of 22 different inflammatory and angiogenic cytokines and chemokines were compared. RESULTS: Aqueous humor samples from 47 diabetic patients (20 without retinopathy, 27 with retinopathy) and 24 non diabetic controls were included. Interleukin (IL)-2, IL-10, IL-12, interferon alpha (IFN-alpha), and tumor necrosis factor (TNF)-alpha were measurable in significantly fewer diabetic samples, and where measurable, were at lower levels than in non-diabetic controls. IL-6 was measurable in significantly more diabetic samples, and the median levels were significantly higher in the eyes with retinopathy than the eyes without retinopathy and the non-diabetic eyes. The vascular endothelial growth factor (VEGF) level was significantly higher in the diabetic eyes with and without retinopathy compared to the non-diabetic controls. The IL-6 level positively correlated with the monocyte chemotactic protein-1 (CCL2) and interleukin-8 (CXCL8) levels and negatively with the TNF-alpha level. The VEGF level negatively correlated with the IL-12 and TNF-alpha levels. CONCLUSIONS: The aqueous humor cytokine profile of diabetic patients without retinopathy was similar to that of patients with diabetic retinopathy. These cytokines may be useful biomarkers for early detection and prognosis of diabetic retinopathy. Compared to diabetic patients without retinopathy, only the IL-6 and VEGF levels were significantly higher in diabetic patients with retinopathy. PMID- 22511847 TI - High-mobility group box 1 protein is implicated in advanced glycation end products-induced vascular endothelial growth factor A production in the rat retinal ganglion cell line RGC-5. AB - PURPOSE: High-mobility group box 1 protein (HMGB1) has been reported to be a potent proangiogenic factor induced by inflammatory stress. In this study, we explore the role of HMGB1 in advanced glycation end products (AGEs)-induced vascular endothelial growth factor A (VEGF-A) production in rat retinal ganglion cell line 5 (RGC-5) cells. METHODS: The VEGF-A protein and mRNA levels in conditioned medium of RGC-5 cells incubated with AGE-modified BSA (AGE-BSA) were examined with real-time PCR and enzyme-linked immunosorbent assay (ELISA), and BSA-treated cells were used as controls. The expression of HMGB1, c-Jun N terminal kinase (JNK), extracellular-signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (p38 MAPK) was assessed with immunofluorescence and western blot analysis. Reactive oxidative species (ROS) were detected with flow cytometry measurements of peroxide-dependent oxidation of 2'-7' dichlorofluorescein-diacetate (DCFH-DA). N-Acetyl-L-cysteine (NAC), glycyrrhizin (GZ), and SP600125 were used to block ROS, HMGB1, and JNK, respectively. RESULTS: Compared with the BSA controls, the RGC-5 cells incubated with AGE-BSA showed a dose- and time-dependent increase in VEGF-A mRNA and VEGF-A protein secretion in the supernatant, with the highest levels achieved at 24 h. AGE-BSA stimulated a significant release of HMGB1 in the supernatant and a significant increase of intracellular ROS production at 3 h. NAC blocked HMGB1 production in a dose dependent manner. Blocking with GZ, NAC, and JNK significantly suppressed AGE induced VEGF-A production. CONCLUSIONS: HMGB1 is implicated in the production of VEGF-A in retinal ganglion cell line-5 (RGC-5). Blocking HMGB1, ROS, or the JNK pathway may attenuate VEGF-A production, suggesting HMGB1 and related signaling molecules play a role in diabetic retinopathy. PMID- 22511848 TI - Inhibition of VEGF expression and corneal neovascularization by shRNA targeting HIF-1alpha in a mouse model of closed eye contact lens wear. AB - PURPOSE: Inappropriate contact lens (CL) use and care often lead to corneal neovascularization (corneal NV). We used mouse eyes which wore CL as the animal model to assess the reason for corneal NV with CL wear. The similar and overlapping activity of vascular endothelial growth factor (VEGF) and the potent angiogenic hypoxia-inducible factor 1alpha (HIF-1alpha) called for a study of the temporal relationship in the expression of these two autocoids. We determined the time dependent expression of HIF-1alpha and correlated it to that of VEGF expression in the mouse model of closed eye with CL wear. METHODS: Mouse eyes were fitted with CL followed by a silk suture tarsorrhaphy. The anterior surface was analyzed at 4, 7, and 10 days after tarsorrhaphy by slit lamp and corneal NV. HIF-1alpha and VEGF levels were measured by reverse transcription PCR, western blotting and immunofluorescence with specific primers and antibodies. We used shRNA targeting HIF-1alpha to substantiate the link between HIF-1alpha, VEGF expression, and angiogenesis in the CL wear model. RESULTS: Corneal NV scores increased in a time dependent manner in the model of closed eye CL induced hypoxic injury. Corneal epithelial HIF-1alpha and VEGF expression increased in a time dependent manner. The prolonged hypoxic state brought by closed eye CL wear induced a time dependent neovascular response which was significantly attenuated by HIF-1alpha specific shRNA but not by nonspecific shRNA. Both HIF-1alpha and VEGF levels were reduced significantly in corneal homogenates from eyes treated with the HIF-1alpha specific shRNA. CONCLUSIONS: The present study documented the increased expression of HIF-1alpha in the corneal epithelium during CL wear. It also demonstrated the presence of VEGF in the corneal epithelium and its increased expression in this model. Altogether, the results of this study raised the possibility of interaction between HIF-1alpha and VEGF, in mediating the neovascularization response induced by the prolonged hypoxic state brought about by closed eye CL wear. The results strongly implicated corneal HIF-1alpha as a component of the inflammatory and neovascular cascade initiated by hypoxic and further suggested that HIF-1alpha was a proximal regulator of VEGF expression in this model. PMID- 22511849 TI - Inhibition of connective tissue growth factor by small interfering ribonucleic acid prevents increase in extracellular matrix molecules in a rodent model of diabetic retinopathy. AB - PURPOSE: Connective tissue growth factor (CTGF) is a profibrotic factor that induces extracellular matrix (ECM) production and angiogenesis, two processes involved in diabetic retinopathy (DR). In this study, we examined whether insulin therapy or a CTGF-specific small interfering RNA (siRNA) administered to diabetic rats decreased the levels of CTGF and of selected putative downstream genes in the retina. METHODS: Rats with streptozotocin-induced diabetes were used. Animals received either no treatment for 12 weeks or were administered constant insulin therapy. MRNA and protein levels of CTGF and select ECM genes were determined using real-time PCR and western blotting of the retina. Localization of CTGF in the retina was visualized using immunohistochemistry. A group of diabetic rats received intravitreal injection of CTGF siRNA, and the retinas were examined three days later. RESULTS: CTGF mRNA and protein significantly increased in the retinas of diabetic rats. Immunohistochemistry indicated that retinal Muller cells of diabetic rats expressed CTGF. Hyperglycemia upregulated mRNA levels of fibronectin, laminin beta1, collagen IValpha3, and vascular endothelial growth factor (VEGF), and this increase was prevented by insulin therapy. Treatment of diabetic rats with CTGF siRNA decreased laminin beta1, collagen IValpha3 mRNA, and CTGF mRNA and protein but did not affect fibronectin or vascular endothelial growth factor mRNA levels. CONCLUSIONS: These results indicate that CTGF and ECM genes can be regulated using insulin. Importantly, these results also suggest that CTGF regulates changes in ECM molecules in DR. PMID- 22511850 TI - Ocular pathogenesis and immune reaction after intravitreal dispase injection in mice. AB - PURPOSE: The purpose of the current study was to examine the ocular pathogenesis and immune reaction in mice after intravitreal dispase injection. METHODS: Three microliters of dispase at a concentration of 0.2 U/MUl were injected into the vitreal cavities of 4-6-week-old mice. Hematoxylin and eosin staining, immunofluorescence analysis, and electroretinograms of the eyes were then performed to assess ocular changes, and enzyme-linked immunospot assays and intracellular staining of single-cell suspensions of the spleens were used to detect immune changes during an 8 week observation period. RESULTS: Neutrophils were the main inflammatory infiltrating cells appearing at the anterior chamber. No cluster of differentiation (CD)3+ labeled T cells, F4/80+ labeled macrophages, or CD56+ labeled natural killer cells were found in the vitreal cavities or retinas in dispase-injected mice within 5 days after injection. Proliferative vitreoretinopathy (PVR)-like signs first appeared at 2 weeks, gradually increased thereafter, and reached peak values at 8 weeks. There was a statistically significant difference in b-wave amplitudes between the PVR and saline-control eyes. Enzyme-linked immunospot assays and intracellular staining showed that specific CD4+ and CD8+ labeled T cells were not involved in dispase-injected mice. CONCLUSIONS: Our data show that neutrophils in the anterior chamber and PVR like signs in the retinas were found, and that specific immune reactions were not involved after intravitreal dispase injection in mice. PMID- 22511851 TI - Representations for phonotactic learning in infancy. AB - Infants rapidly learn novel phonotactic constraints from brief listening experience. Four experiments explored the nature of the representations underlying this learning. 16.5- and 10.5-month-old infants heard training syllables in which particular consonants were restricted to particular syllable positions (first-order constraints) or to syllable positions depending on the identity of the adjacent vowel (second-order constraints). Later, in a headturn listening-preference task, infants were presented with new syllables that either followed the experimental constraints or violated them. Infants at both ages learned first- and second-order constraints on consonant position (Experiments 1 and 2) but found second-order constraints more difficult to learn (Experiment 2). Infants also spontaneously generalized first-order constraints to syllables containing a new, transfer vowel; they did so whether the transfer vowel was similar to the familiarization vowels (Experiment 3), or dissimilar from them (Experiment 4). These findings suggest that infants recruit representations of individuated segments during phonological learning. Furthermore, like adults, they represent phonological sequences in a flexible manner that allows them to detect patterns at multiple levels of phonological analysis. PMID- 22511852 TI - Evolution of the multi-domain structures of virulence genes in the human malaria parasite, Plasmodium falciparum. AB - The var gene family of Plasmodium falciparum encodes the immunodominant variant surface antigens PfEMP1. These highly polymorphic proteins are important virulence factors that mediate cytoadhesion to a variety of host tissues, causing sequestration of parasitized red blood cells in vital organs, including the brain or placenta. Acquisition of variant-specific antibodies correlates with protection against severe malarial infections; however, understanding the relationship between gene expression and infection outcome is complicated by the modular genetic architectures of var genes that encode varying numbers of antigenic domains with differential binding specificities. By analyzing the domain architectures of fully sequenced var gene repertoires we reveal a significant, non-random association between the number of domains comprising a var gene and their sequence conservation. As such, var genes can be grouped into those that are short and diverse and genes that are long and conserved, suggesting gene length as an important characteristic in the classification of var genes. We then use an evolutionary framework to demonstrate how the same evolutionary forces acting on the level of an individual gene may have also shaped the parasite's gene repertoire. The observed associations between sequence conservation, gene architecture and repertoire structure can thus be explained by a trade-off between optimizing within-host fitness and minimizing between-host immune selection pressure. Our results demonstrate how simple evolutionary mechanisms can explain var gene structuring on multiple levels and have important implications for understanding the multifaceted epidemiology of P. falciparum malaria. PMID- 22511853 TI - A new perceptual bias reveals suboptimal population decoding of sensory responses. AB - Several studies have reported optimal population decoding of sensory responses in two-alternative visual discrimination tasks. Such decoding involves integrating noisy neural responses into a more reliable representation of the likelihood that the stimuli under consideration evoked the observed responses. Importantly, an ideal observer must be able to evaluate likelihood with high precision and only consider the likelihood of the two relevant stimuli involved in the discrimination task. We report a new perceptual bias suggesting that observers read out the likelihood representation with remarkably low precision when discriminating grating spatial frequencies. Using spectrally filtered noise, we induced an asymmetry in the likelihood function of spatial frequency. This manipulation mainly affects the likelihood of spatial frequencies that are irrelevant to the task at hand. Nevertheless, we find a significant shift in perceived grating frequency, indicating that observers evaluate likelihoods of a broad range of irrelevant frequencies and discard prior knowledge of stimulus alternatives when performing two-alternative discrimination. PMID- 22511854 TI - Quantifying type-specific reproduction numbers for nosocomial pathogens: evidence for heightened transmission of an Asian sequence type 239 MRSA clone. AB - An important determinant of a pathogen's success is the rate at which it is transmitted from infected to susceptible hosts. Although there are anecdotal reports that methicillin-resistant Staphylococcus aureus (MRSA) clones vary in their transmissibility in hospital settings, attempts to quantify such variation are lacking for common subtypes, as are methods for addressing this question using routinely-collected MRSA screening data in endemic settings. Here we present a method to quantify the time-varying transmissibility of different subtypes of common bacterial nosocomial pathogens using routine surveillance data. The method adapts approaches for estimating reproduction numbers based on the probabilistic reconstruction of epidemic trees, but uses relative hazards rather than serial intervals to assign probabilities to different sources for observed transmission events. The method is applied to data collected as part of a retrospective observational study of a concurrent MRSA outbreak in the United Kingdom with dominant endemic MRSA clones (ST22 and ST36) and an Asian ST239 MRSA strain (ST239-TW) in two linked adult intensive care units, and compared with an approach based on a fully parametric transmission model. The results provide support for the hypothesis that the clones responded differently to an infection control measure based on the use of topical antiseptics, which was more effective at reducing transmission of endemic clones. They also suggest that in one of the two ICUs patients colonized or infected with the ST239-TW MRSA clone had consistently higher risks of transmitting MRSA to patients free of MRSA. These findings represent some of the first quantitative evidence of enhanced transmissibility of a pandemic MRSA lineage, and highlight the potential value of tailoring hospital infection control measures to specific pathogen subtypes. PMID- 22511855 TI - Warm body temperature facilitates energy efficient cortical action potentials. AB - The energy efficiency of neural signal transmission is important not only as a limiting factor in brain architecture, but it also influences the interpretation of functional brain imaging signals. Action potential generation in mammalian, versus invertebrate, axons is remarkably energy efficient. Here we demonstrate that this increase in energy efficiency is due largely to a warmer body temperature. Increases in temperature result in an exponential increase in energy efficiency for single action potentials by increasing the rate of Na(+) channel inactivation, resulting in a marked reduction in overlap of the inward Na(+), and outward K(+), currents and a shortening of action potential duration. This increase in single spike efficiency is, however, counterbalanced by a temperature dependent decrease in the amplitude and duration of the spike afterhyperpolarization, resulting in a nonlinear increase in the spike firing rate, particularly at temperatures above approximately 35 degrees C. Interestingly, the total energy cost, as measured by the multiplication of total Na(+) entry per spike and average firing rate in response to a constant input, reaches a global minimum between 37-42 degrees C. Our results indicate that increases in temperature result in an unexpected increase in energy efficiency, especially near normal body temperature, thus allowing the brain to utilize an energy efficient neural code. PMID- 22511856 TI - Power-law inter-spike interval distributions infer a conditional maximization of entropy in cortical neurons. AB - The brain is considered to use a relatively small amount of energy for its efficient information processing. Under a severe restriction on the energy consumption, the maximization of mutual information (MMI), which is adequate for designing artificial processing machines, may not suit for the brain. The MMI attempts to send information as accurate as possible and this usually requires a sufficient energy supply for establishing clearly discretized communication bands. Here, we derive an alternative hypothesis for neural code from the neuronal activities recorded juxtacellularly in the sensorimotor cortex of behaving rats. Our hypothesis states that in vivo cortical neurons maximize the entropy of neuronal firing under two constraints, one limiting the energy consumption (as assumed previously) and one restricting the uncertainty in output spike sequences at given firing rate. Thus, the conditional maximization of firing-rate entropy (CMFE) solves a tradeoff between the energy cost and noise in neuronal response. In short, the CMFE sends a rich variety of information through broader communication bands (i.e., widely distributed firing rates) at the cost of accuracy. We demonstrate that the CMFE is reflected in the long-tailed, typically power law, distributions of inter-spike intervals obtained for the majority of recorded neurons. In other words, the power-law tails are more consistent with the CMFE rather than the MMI. Thus, we propose the mathematical principle by which cortical neurons may represent information about synaptic input into their output spike trains. PMID- 22511857 TI - Optimization of muscle activity for task-level goals predicts complex changes in limb forces across biomechanical contexts. AB - Optimality principles have been proposed as a general framework for understanding motor control in animals and humans largely based on their ability to predict general features movement in idealized motor tasks. However, generalizing these concepts past proof-of-principle to understand the neuromechanical transformation from task-level control to detailed execution-level muscle activity and forces during behaviorally-relevant motor tasks has proved difficult. In an unrestrained balance task in cats, we demonstrate that achieving task-level constraints center of mass forces and moments while minimizing control effort predicts detailed patterns of muscle activity and ground reaction forces in an anatomically realistic musculoskeletal model. Whereas optimization is typically used to resolve redundancy at a single level of the motor hierarchy, we simultaneously resolved redundancy across both muscles and limbs and directly compared predictions to experimental measures across multiple perturbation directions that elicit different intra- and interlimb coordination patterns. Further, although some candidate task-level variables and cost functions generated indistinguishable predictions in a single biomechanical context, we identified a common optimization framework that could predict up to 48 experimental conditions per animal (n = 3) across both perturbation directions and different biomechanical contexts created by altering animals' postural configuration. Predictions were further improved by imposing experimentally-derived muscle synergy constraints, suggesting additional task variables or costs that may be relevant to the neural control of balance. These results suggested that reduced dimension neural control mechanisms such as muscle synergies can achieve similar kinetics to the optimal solution, but with increased control effort (~2*) compared to individual muscle control. Our results are consistent with the idea that hierarchical, task-level neural control mechanisms previously associated with voluntary tasks may also be used in automatic brainstem-mediated pathways for balance. PMID- 22511858 TI - Differences in cell division rates drive the evolution of terminal differentiation in microbes. AB - Multicellular differentiated organisms are composed of cells that begin by developing from a single pluripotent germ cell. In many organisms, a proportion of cells differentiate into specialized somatic cells. Whether these cells lose their pluripotency or are able to reverse their differentiated state has important consequences. Reversibly differentiated cells can potentially regenerate parts of an organism and allow reproduction through fragmentation. In many organisms, however, somatic differentiation is terminal, thereby restricting the developmental paths to reproduction. The reason why terminal differentiation is a common developmental strategy remains unexplored. To understand the conditions that affect the evolution of terminal versus reversible differentiation, we developed a computational model inspired by differentiating cyanobacteria. We simulated the evolution of a population of two cell types nitrogen fixing or photosynthetic- that exchange resources. The traits that control differentiation rates between cell types are allowed to evolve in the model. Although the topology of cell interactions and differentiation costs play a role in the evolution of terminal and reversible differentiation, the most important factor is the difference in division rates between cell types. Faster dividing cells always evolve to become the germ line. Our results explain why most multicellular differentiated cyanobacteria have terminally differentiated cells, while some have reversibly differentiated cells. We further observed that symbioses involving two cooperating lineages can evolve under conditions where aggregate size, connectivity, and differentiation costs are high. This may explain why plants engage in symbiotic interactions with diazotrophic bacteria. PMID- 22511859 TI - The impact of imitation on vaccination behavior in social contact networks. AB - Previous game-theoretic studies of vaccination behavior typically have often assumed that populations are homogeneously mixed and that individuals are fully rational. In reality, there is heterogeneity in the number of contacts per individual, and individuals tend to imitate others who appear to have adopted successful strategies. Here, we use network-based mathematical models to study the effects of both imitation behavior and contact heterogeneity on vaccination coverage and disease dynamics. We integrate contact network epidemiological models with a framework for decision-making, within which individuals make their decisions either based purely on payoff maximization or by imitating the vaccination behavior of a social contact. Simulations suggest that when the cost of vaccination is high imitation behavior may decrease vaccination coverage. However, when the cost of vaccination is small relative to that of infection, imitation behavior increases vaccination coverage, but, surprisingly, also increases the magnitude of epidemics through the clustering of non-vaccinators within the network. Thus, imitation behavior may impede the eradication of infectious diseases. Calculations that ignore behavioral clustering caused by imitation may significantly underestimate the levels of vaccination coverage required to attain herd immunity. PMID- 22511860 TI - Optimizing provider recruitment for influenza surveillance networks. AB - The increasingly complex and rapid transmission dynamics of many infectious diseases necessitates the use of new, more advanced methods for surveillance, early detection, and decision-making. Here, we demonstrate that a new method for optimizing surveillance networks can improve the quality of epidemiological information produced by typical provider-based networks. Using past surveillance and Internet search data, it determines the precise locations where providers should be enrolled. When applied to redesigning the provider-based, influenza like-illness surveillance network (ILINet) for the state of Texas, the method identifies networks that are expected to significantly outperform the existing network with far fewer providers. This optimized network avoids informational redundancies and is thereby more effective than networks designed by conventional methods and a recently published algorithm based on maximizing population coverage. We show further that Google Flu Trends data, when incorporated into a network as a virtual provider, can enhance but not replace traditional surveillance methods. PMID- 22511861 TI - Impact of adaptation currents on synchronization of coupled exponential integrate and-fire neurons. AB - The ability of spiking neurons to synchronize their activity in a network depends on the response behavior of these neurons as quantified by the phase response curve (PRC) and on coupling properties. The PRC characterizes the effects of transient inputs on spike timing and can be measured experimentally. Here we use the adaptive exponential integrate-and-fire (aEIF) neuron model to determine how subthreshold and spike-triggered slow adaptation currents shape the PRC. Based on that, we predict how synchrony and phase locked states of coupled neurons change in presence of synaptic delays and unequal coupling strengths. We find that increased subthreshold adaptation currents cause a transition of the PRC from only phase advances to phase advances and delays in response to excitatory perturbations. Increased spike-triggered adaptation currents on the other hand predominantly skew the PRC to the right. Both adaptation induced changes of the PRC are modulated by spike frequency, being more prominent at lower frequencies. Applying phase reduction theory, we show that subthreshold adaptation stabilizes synchrony for pairs of coupled excitatory neurons, while spike-triggered adaptation causes locking with a small phase difference, as long as synaptic heterogeneities are negligible. For inhibitory pairs synchrony is stable and robust against conduction delays, and adaptation can mediate bistability of in phase and anti-phase locking. We further demonstrate that stable synchrony and bistable in/anti-phase locking of pairs carry over to synchronization and clustering of larger networks. The effects of adaptation in aEIF neurons on PRCs and network dynamics qualitatively reflect those of biophysical adaptation currents in detailed Hodgkin-Huxley-based neurons, which underscores the utility of the aEIF model for investigating the dynamical behavior of networks. Our results suggest neuronal spike frequency adaptation as a mechanism synchronizing low frequency oscillations in local excitatory networks, but indicate that inhibition rather than excitation generates coherent rhythms at higher frequencies. PMID- 22511862 TI - Establishment and validation of computational model for MT1-MMP dependent ECM degradation and intervention strategies. AB - MT1-MMP is a potent invasion-promoting membrane protease employed by aggressive cancer cells. MT1-MMP localizes preferentially at membrane protrusions called invadopodia where it plays a central role in degradation of the surrounding extracellular matrix (ECM). Previous reports suggested a role for a continuous supply of MT1-MMP in ECM degradation. However, the turnover rate of MT1-MMP and the extent to which the turnover contributes to the ECM degradation at invadopodia have not been clarified. To approach this problem, we first performed FRAP (Fluorescence Recovery after Photobleaching) experiments with fluorescence tagged MT1-MMP focusing on a single invadopodium and found very rapid recovery in FRAP signals, approximated by double-exponential plots with time constants of 26 s and 259 s. The recovery depended primarily on vesicle transport, but negligibly on lateral diffusion. Next we constructed a computational model employing the observed kinetics of the FRAP experiments. The simulations successfully reproduced our FRAP experiments. Next we inhibited the vesicle transport both experimentally, and in simulation. Addition of drugs inhibiting vesicle transport blocked ECM degradation experimentally, and the simulation showed no appreciable ECM degradation under conditions inhibiting vesicle transport. In addition, the degree of the reduction in ECM degradation depended on the degree of the reduction in the MT1-MMP turnover. Thus, our experiments and simulations have established the role of the rapid turnover of MT1-MMP in ECM degradation at invadopodia. Furthermore, our simulations suggested synergetic contributions of proteolytic activity and the MT1-MMP turnover to ECM degradation because there was a nonlinear and marked reduction in ECM degradation if both factors were reduced simultaneously. Thus our computational model provides a new in silico tool to design and evaluate intervention strategies in cancer cell invasion. PMID- 22511864 TI - The role of cofactors in prion propagation and infectivity. PMID- 22511863 TI - Mapping the environmental fitness landscape of a synthetic gene circuit. AB - Gene expression actualizes the organismal phenotypes encoded within the genome in an environment-dependent manner. Among all encoded phenotypes, cell population growth rate (fitness) is perhaps the most important, since it determines how well adapted a genotype is in various environments. Traditional biological measurement techniques have revealed the connection between the environment and fitness based on the gene expression mean. Yet, recently it became clear that cells with identical genomes exposed to the same environment can differ dramatically from the population average in their gene expression and division rate (individual fitness). For cell populations with bimodal gene expression, this difference is particularly pronounced, and may involve stochastic transitions between two cellular states that form distinct sub-populations. Currently it remains unclear how a cell population's growth rate and its subpopulation fractions emerge from the molecular-level kinetics of gene networks and the division rates of single cells. To address this question we developed and quantitatively characterized an inducible, bistable synthetic gene circuit controlling the expression of a bifunctional antibiotic resistance gene in Saccharomyces cerevisiae. Following fitness and fluorescence measurements in two distinct environments (inducer alone and antibiotic alone), we applied a computational approach to predict cell population fitness and subpopulation fractions in the combination of these environments based on stochastic cellular movement in gene expression space and fitness space. We found that knowing the fitness and nongenetic (cellular) memory associated with specific gene expression states were necessary for predicting the overall fitness of cell populations in combined environments. We validated these predictions experimentally and identified environmental conditions that defined a "sweet spot" of drug resistance. These findings may provide a roadmap for connecting the molecular-level kinetics of gene networks to cell population fitness in well-defined environments, and may have important implications for phenotypic variability of drug resistance in natural settings. PMID- 22511865 TI - The problem of auto-correlation in parasitology. AB - Explaining the contribution of host and pathogen factors in driving infection dynamics is a major ambition in parasitology. There is increasing recognition that analyses based on single summary measures of an infection (e.g., peak parasitaemia) do not adequately capture infection dynamics and so, the appropriate use of statistical techniques to analyse dynamics is necessary to understand infections and, ultimately, control parasites. However, the complexities of within-host environments mean that tracking and analysing pathogen dynamics within infections and among hosts poses considerable statistical challenges. Simple statistical models make assumptions that will rarely be satisfied in data collected on host and parasite parameters. In particular, model residuals (unexplained variance in the data) should not be correlated in time or space. Here we demonstrate how failure to account for such correlations can result in incorrect biological inference from statistical analysis. We then show how mixed effects models can be used as a powerful tool to analyse such repeated measures data in the hope that this will encourage better statistical practices in parasitology. PMID- 22511866 TI - Structural basis for type VI secretion effector recognition by a cognate immunity protein. AB - The type VI secretion system (T6SS) has emerged as an important mediator of interbacterial interactions. A T6SS from Pseudomonas aeruginosa targets at least three effector proteins, type VI secretion exported 1-3 (Tse1-3), to recipient Gram-negative cells. The Tse2 protein is a cytoplasmic effector that acts as a potent inhibitor of target cell proliferation, thus providing a pronounced fitness advantage for P. aeruginosa donor cells. P. aeruginosa utilizes a dedicated immunity protein, type VI secretion immunity 2 (Tsi2), to protect against endogenous and intercellularly-transferred Tse2. Here we show that Tse2 delivered by the T6SS efficiently induces quiescence, not death, within recipient cells. We demonstrate that despite direct interaction of Tsi2 and Tse2 in the cytoplasm, Tsi2 is dispensable for targeting the toxin to the secretory apparatus. To gain insights into the molecular basis of Tse2 immunity, we solved the 1.00 A X-ray crystal structure of Tsi2. The structure shows that Tsi2 assembles as a dimer that does not resemble previously characterized immunity or antitoxin proteins. A genetic screen for Tsi2 mutants deficient in Tse2 interaction revealed an acidic patch distal to the Tsi2 homodimer interface that mediates toxin interaction and immunity. Consistent with this finding, we observed that destabilization of the Tsi2 dimer does not impact Tse2 interaction. The molecular insights into Tsi2 structure and function garnered from this study shed light on the mechanisms of T6 effector secretion, and indicate that the Tse2 Tsi2 effector-immunity pair has features distinguishing it from previously characterized toxin-immunity and toxin-antitoxin systems. PMID- 22511867 TI - Necrotrophism is a quorum-sensing-regulated lifestyle in Bacillus thuringiensis. AB - How pathogenic bacteria infect and kill their host is currently widely investigated. In comparison, the fate of pathogens after the death of their host receives less attention. We studied Bacillus thuringiensis (Bt) infection of an insect host, and show that NprR, a quorum sensor, is active after death of the insect and allows Bt to survive in the cadavers as vegetative cells. Transcriptomic analysis revealed that NprR regulates at least 41 genes, including many encoding degradative enzymes or proteins involved in the synthesis of a nonribosomal peptide named kurstakin. These degradative enzymes are essential in vitro to degrade several substrates and are specifically expressed after host death suggesting that Bt has an active necrotrophic lifestyle in the cadaver. We show that kurstakin is essential for Bt survival during necrotrophic development. It is required for swarming mobility and biofilm formation, presumably through a pore forming activity. A nprR deficient mutant does not develop necrotrophically and does not sporulate efficiently in the cadaver. We report that necrotrophism is a highly regulated mechanism essential for the Bt infectious cycle, contributing to spore spreading. PMID- 22511868 TI - Treatment with IL-7 prevents the decline of circulating CD4+ T cells during the acute phase of SIV infection in rhesus macaques. AB - Although treatment with interleukin-7 (IL-7) was shown to transiently expand the naive and memory T-cell pools in patients with chronic HIV-1 infection receiving antiretroviral therapy (ART), it is uncertain whether a full immunologic reconstitution can be achieved. Moreover, the effects of IL-7 have never been evaluated during acute HIV-1 (or SIV) infection, a critical phase of the disease in which the most dramatic depletion of CD4(+) T cells is believed to occur. In the present study, recombinant, fully glycosylated simian IL-7 (50 ug/kg, s.c., once weekly for 7 weeks) was administered to 6 rhesus macaques throughout the acute phase of infection with a pathogenic SIV strain (mac251); 6 animals were infected at the same time and served as untreated controls. Treatment with IL-7 did not cause clinically detectable side effects and, despite the absence of concomitant ART, did not induce significant increases in the levels of SIV replication except at the earliest time point tested (day 4 post-infection). Strikingly, animals treated with IL-7 were protected from the dramatic decline of circulating naive and memory CD4(+) T cells that occurred in untreated animals. Treatment with IL-7 induced only transient T-cell proliferation, but it was associated with sustained increase in the expression of the anti-apoptotic protein Bcl-2 on both CD4(+) and CD8(+) T cells, persistent expansion of all circulating CD8(+) T-cell subsets, and development of earlier and stronger SIV Tat-specific T-cell responses. However, the beneficial effects of IL-7 were not sustained after treatment interruption. These data demonstrate that IL-7 administration is effective in protecting the CD4(+) T-cell pool during the acute phase of SIV infection in macaques, providing a rationale for the clinical evaluation of this cytokine in patients with acute HIV-1 infection. PMID- 22511869 TI - Interaction of the trans-frame potyvirus protein P3N-PIPO with host protein PCaP1 facilitates potyvirus movement. AB - A small open reading frame (ORF), pipo, overlaps with the P3 coding region of the potyviral polyprotein ORF. Previous evidence suggested a requirement for pipo for efficient viral cell-to-cell movement. Here, we provide immunoblotting evidence that the protein PIPO is expressed as a trans-frame protein consisting of the amino-terminal half of P3 fused to PIPO (P3N-PIPO). P3N-PIPO of Turnip mosaic virus (TuMV) fused to GFP facilitates its own cell-to-cell movement. Using a yeast two-hybrid screen, co-immunoprecipitation assays, and bimolecular fluorescence complementation (BiFC) assays, we found that P3N-PIPO interacts with host protein PCaP1, a cation-binding protein that attaches to the plasma membrane via myristoylation. BiFC revealed that it is the PIPO domain of P3N-PIPO that binds PCaP1 and that myristoylation of PCaP1 is unnecessary for interaction with P3N-PIPO. In PCaP1 knockout mutants (pcap1) of Arabidopsis, accumulation of TuMV harboring a GFP gene (TuMV-GFP) was drastically reduced relative to the virus level in wild-type plants, only small localized spots of GFP were visible, and the plants showed few symptoms. In contrast, TuMV-GFP infection in wild-type Arabidopsis yielded large green fluorescent patches, and caused severe stunting. However, viral RNA accumulated to high level in protoplasts from pcap1 plants indicating that PCaP1 is not required for TuMV RNA synthesis. In contrast to TuMV, the tobamovirus Oilseed rape mosaic virus did not require PCaP1 to infect Arabidopsis plants. We conclude that potyviral P3N-PIPO interacts specifically with the host plasma membrane protein PCaP1 to participate in cell-to-cell movement. We speculate that PCaP1 links a complex of viral proteins and genomic RNA to the plasma membrane by binding P3N-PIPO, enabling localization to the plasmodesmata and cell-to-cell movement. The PCaP1 knockout may contribute to a new strategy for recessive resistance to potyviruses. PMID- 22511870 TI - TLR4 and NKT cell synergy in immunotherapy against visceral leishmaniasis. AB - NKT cells play an important role in autoimmune diseases, tumor surveillance, and infectious diseases, providing in most cases protection against infection. NKT cells are reactive to CD1d presented glycolipid antigens. They can modulate immune responses by promoting the secretion of type 1, type 2, or immune regulatory cytokines. Pathogen-derived signals to dendritic cells mediated via Toll like Receptors (TLR) can be modulated by activated invariant Natural Killer T (iNKT) cells. The terminal beta-(1-4)-galactose residues of glycans can modulate host responsiveness in a T helper type-1 direction via IFN-gamma and TLRs. We have attempted to develop a defined immunotherapeutic, based on the cooperative action of a TLR ligand and iNKT cell using a mouse model of visceral leishmaniasis. We evaluated the anti-Leishmania immune responses and the protective efficacy of the beta-(1-4)-galactose terminal NKT cell ligand glycosphingophospholipid (GSPL) antigen of L. donovani parasites. Our results suggest that TLR4 can function as an upstream sensor for GSPL and provoke intracellular inflammatory signaling necessary for parasite killing. Treatment with GSPL was able to induce a strong effective T cell response that contributed to effective control of acute parasite burden and led to undetectable parasite persistence in the infected animals. These studies for the first time demonstrate the interactions between a TLR ligand and iNKT cell activation in visceral leishmaniasis immunotherapeutic. PMID- 22511871 TI - Intraspecies variation in the emergence of hyperinfectious bacterial strains in nature. AB - Salmonella is a principal health concern because of its endemic prevalence in food and water supplies, the rise in incidence of multi-drug resistant strains, and the emergence of new strains associated with increased disease severity. Insights into pathogen emergence have come from animal-passage studies wherein virulence is often increased during infection. However, these studies did not address the prospect that a select subset of strains undergo a pronounced increase in virulence during the infective process- a prospect that has significant implications for human and animal health. Our findings indicate that the capacity to become hypervirulent (100-fold decreased LD(50)) was much more evident in certain S. enterica strains than others. Hyperinfectious salmonellae were among the most virulent of this species; restricted to certain serotypes; and more capable of killing vaccinated animals. Such strains exhibited rapid (and rapidly reversible) switching to a less-virulent state accompanied by more competitive growth ex vivo that may contribute to maintenance in nature. The hypervirulent phenotype was associated with increased microbial pathogenicity (colonization; cytotoxin production; cytocidal activity), coupled with an altered innate immune cytokine response within infected cells (IFN-beta; IL-1beta; IL-6; IL-10). Gene expression analysis revealed that hyperinfectious strains display altered transcription of genes within the PhoP/PhoQ, PhoR/PhoB and ArgR regulons, conferring changes in the expression of classical virulence functions (e.g., SPI 1; SPI-2 effectors) and those involved in cellular physiology/metabolism (nutrient/acid stress). As hyperinfectious strains pose a potential risk to human and animal health, efforts toward mitigation of these potential food-borne contaminants may avert negative public health impacts and industry-associated losses. PMID- 22511872 TI - The transcription factor AmrZ utilizes multiple DNA binding modes to recognize activator and repressor sequences of Pseudomonas aeruginosa virulence genes. AB - AmrZ, a member of the Ribbon-Helix-Helix family of DNA binding proteins, functions as both a transcriptional activator and repressor of multiple genes encoding Pseudomonas aeruginosa virulence factors. The expression of these virulence factors leads to chronic and sustained infections associated with worsening prognosis. In this study, we present the X-ray crystal structure of AmrZ in complex with DNA containing the repressor site, amrZ1. Binding of AmrZ to this site leads to auto-repression. AmrZ binds this DNA sequence as a dimer-of dimers, and makes specific base contacts to two half sites, separated by a five base pair linker region. Analysis of the linker region shows a narrowing of the minor groove, causing significant distortions. AmrZ binding assays utilizing sequences containing variations in this linker region reveals that secondary structure of the DNA, conferred by the sequence of this region, is an important determinant in binding affinity. The results from these experiments allow for the creation of a model where both intrinsic structure of the DNA and specific nucleotide recognition are absolutely necessary for binding of the protein. We also examined AmrZ binding to the algD promoter, which results in activation of the alginate exopolysaccharide biosynthetic operon, and found the protein utilizes different interactions with this site. Finally, we tested the in vivo effects of this differential binding by switching the AmrZ binding site at algD, where it acts as an activator, for a repressor binding sequence and show that differences in binding alone do not affect transcriptional regulation. PMID- 22511873 TI - In vivo suppression of HIV by antigen specific T cells derived from engineered hematopoietic stem cells. AB - The HIV-specific cytotoxic T lymphocyte (CTL) response is a critical component in controlling viral replication in vivo, but ultimately fails in its ability to eradicate the virus. Our intent in these studies is to develop ways to enhance and restore the HIV-specific CTL response to allow long-term viral suppression or viral clearance. In our approach, we sought to genetically manipulate human hematopoietic stem cells (HSCs) such that they differentiate into mature CTL that will kill HIV infected cells. To perform this, we molecularly cloned an HIV specific T cell receptor (TCR) from CD8+ T cells that specifically targets an epitope of the HIV-1 Gag protein. This TCR was then used to genetically transduce HSCs. These HSCs were then introduced into a humanized mouse containing human fetal liver, fetal thymus, and hematopoietic progenitor cells, and were allowed to differentiate into mature human CD8+ CTL. We found human, HIV-specific CTL in multiple tissues in the mouse. Thus, genetic modification of human HSCs with a cloned TCR allows proper differentiation of the cells to occur in vivo, and these cells migrate to multiple anatomic sites, mimicking what is seen in humans. To determine if the presence of the transgenic, HIV-specific TCR has an effect on suppressing HIV replication, we infected with HIV-1 mice expressing the transgenic HIV-specific TCR and, separately, mice expressing a non-specific control TCR. We observed significant suppression of HIV replication in multiple organs in the mice expressing the HIV-specific TCR as compared to control, indicating that the presence of genetically modified HIV-specific CTL can form a functional antiviral response in vivo. These results strongly suggest that stem cell based gene therapy may be a feasible approach in the treatment of chronic viral infections and provide a foundation towards the development of this type of strategy. PMID- 22511874 TI - Neutralization serotyping of BK polyomavirus infection in kidney transplant recipients. AB - BK polyomavirus (BKV or BKPyV) associated nephropathy affects up to 10% of kidney transplant recipients (KTRs). BKV isolates are categorized into four genotypes. It is currently unclear whether the four genotypes are also serotypes. To address this issue, we developed high-throughput serological assays based on antibody mediated neutralization of BKV genotype I and IV reporter vectors (pseudoviruses). Neutralization-based testing of sera from mice immunized with BKV-I or BKV-IV virus-like particles (VLPs) or sera from naturally infected human subjects revealed that BKV-I specific serum antibodies are poorly neutralizing against BKV-IV and vice versa. The fact that BKV-I and BKV-IV are distinct serotypes was less evident in traditional VLP-based ELISAs. BKV-I and BKV-IV neutralization assays were used to examine BKV type-specific neutralizing antibody responses in KTRs at various time points after transplantation. At study entry, sera from 5% and 49% of KTRs showed no detectable neutralizing activity for BKV-I or BKV-IV neutralization, respectively. By one year after transplantation, all KTRs were neutralization seropositive for BKV-I, and 43% of the initially BKV-IV seronegative subjects showed evidence of acute seroconversion for BKV-IV neutralization. The results suggest a model in which BKV-IV-specific seroconversion reflects a de novo BKV-IV infection in KTRs who initially lack protective antibody responses capable of neutralizing genotype IV BKVs. If this model is correct, it suggests that pre-vaccinating prospective KTRs with a multivalent VLP-based vaccine against all BKV serotypes, or administration of BKV-neutralizing antibodies, might offer protection against graft loss or dysfunction due to BKV associated nephropathy. PMID- 22511875 TI - Human monoclonal antibodies to a novel cluster of conformational epitopes on HCV E2 with resistance to neutralization escape in a genotype 2a isolate. AB - The majority of broadly neutralizing antibodies to hepatitis C virus (HCV) are against conformational epitopes on the E2 glycoprotein. Many of them recognize overlapping epitopes in a cluster, designated as antigenic domain B, that contains residues G530 and D535. To gain information on other regions that will be relevant for vaccine design, we employed yeast surface display of antibodies that bound to genotype 1a H77C E2 mutant proteins containing a substitution either at Y632A (to avoid selecting non-neutralizing antibodies) or D535A. A panel of nine human monoclonal antibodies (HMAbs) was isolated and designated as HC-84-related antibodies. Each HMAb neutralized cell culture infectious HCV (HCVcc) with genotypes 1-6 envelope proteins with varying profiles, and each inhibited E2 binding to the viral receptor CD81. Five of these antibodies neutralized representative genotypes 1-6 HCVcc. Epitope mapping identified a cluster of overlapping epitopes that included nine contact residues in two E2 regions encompassing aa418-446 and aa611-616. Effect on virus entry was measured using H77C HCV retroviral pseudoparticles, HCVpp, bearing an alanine substitution at each of the contact residues. Seven of ten mutant HCVpp showed over 90% reduction compared to wild-type HCVpp and two others showed approximately 80% reduction. Interestingly, four of these antibodies bound to a linear E2 synthetic peptide encompassing aa434-446. This region on E2 has been proposed to elicit non neutralizing antibodies in humans that interfere with neutralizing antibodies directed at an adjacent E2 region from aa410-425. The isolation of four HC-84 HMAbs binding to the peptide, aa434-446, proves that some antibodies to this region are to highly conserved epitopes mediating broad virus neutralization. Indeed, when HCVcc were passaged in the presence of each of these antibodies, virus escape was not observed. Thus, the cluster of HC-84 epitopes, designated as antigenic domain D, is relevant for vaccine design for this highly diverse virus. PMID- 22511876 TI - An unbiased assessment of the role of imprinted genes in an intergenerational model of developmental programming. AB - Environmental factors during early life are critical for the later metabolic health of the individual and of future progeny. In our obesogenic environment, it is of great socioeconomic importance to investigate the mechanisms that contribute to the risk of metabolic ill health. Imprinted genes, a class of functionally mono-allelic genes critical for early growth and metabolic axis development, have been proposed to be uniquely susceptible to environmental change. Furthermore, it has also been suggested that perturbation of the epigenetic reprogramming of imprinting control regions (ICRs) may play a role in phenotypic heritability following early life insults. Alternatively, the presence of multiple layers of epigenetic regulation may in fact protect imprinted genes from such perturbation. Unbiased investigation of these alternative hypotheses requires assessment of imprinted gene expression in the context of the response of the whole transcriptome to environmental assault. We therefore analyse the role of imprinted genes in multiple tissues in two affected generations of an established murine model of the developmental origins of health and disease using microarrays and quantitative RT-PCR. We demonstrate that, despite the functional mono-allelicism of imprinted genes and their unique mechanisms of epigenetic dosage control, imprinted genes as a class are neither more susceptible nor protected from expression perturbation induced by maternal undernutrition in either the F1 or the F2 generation compared to other genes. Nor do we find any evidence that the epigenetic reprogramming of ICRs in the germline is susceptible to nutritional restriction. However, we propose that those imprinted genes that are affected may play important roles in the foetal response to undernutrition and potentially its long-term sequelae. We suggest that recently described instances of dosage regulation by relaxation of imprinting are rare and likely to be highly regulated. PMID- 22511877 TI - Type 2 diabetes risk alleles demonstrate extreme directional differentiation among human populations, compared to other diseases. AB - Many disease-susceptible SNPs exhibit significant disparity in ancestral and derived allele frequencies across worldwide populations. While previous studies have examined population differentiation of alleles at specific SNPs, global ethnic patterns of ensembles of disease risk alleles across human diseases are unexamined. To examine these patterns, we manually curated ethnic disease association data from 5,065 papers on human genetic studies representing 1,495 diseases, recording the precise risk alleles and their measured population frequencies and estimated effect sizes. We systematically compared the population frequencies of cross-ethnic risk alleles for each disease across 1,397 individuals from 11 HapMap populations, 1,064 individuals from 53 HGDP populations, and 49 individuals with whole-genome sequences from 10 populations. Type 2 diabetes (T2D) demonstrated extreme directional differentiation of risk allele frequencies across human populations, compared with null distributions of European-frequency matched control genomic alleles and risk alleles for other diseases. Most T2D risk alleles share a consistent pattern of decreasing frequencies along human migration into East Asia. Furthermore, we show that these patterns contribute to disparities in predicted genetic risk across 1,397 HapMap individuals, T2D genetic risk being consistently higher for individuals in the African populations and lower in the Asian populations, irrespective of the ethnicity considered in the initial discovery of risk alleles. We observed a similar pattern in the distribution of T2D Genetic Risk Scores, which are associated with an increased risk of developing diabetes in the Diabetes Prevention Program cohort, for the same individuals. This disparity may be attributable to the promotion of energy storage and usage appropriate to environments and inconsistent energy intake. Our results indicate that the differential frequencies of T2D risk alleles may contribute to the observed disparity in T2D incidence rates across ethnic populations. PMID- 22511878 TI - Cell contact-dependent outer membrane exchange in myxobacteria: genetic determinants and mechanism. AB - Biofilms are dense microbial communities. Although widely distributed and medically important, how biofilm cells interact with one another is poorly understood. Recently, we described a novel process whereby myxobacterial biofilm cells exchange their outer membrane (OM) lipoproteins. For the first time we report here the identification of two host proteins, TraAB, required for transfer. These proteins are predicted to localize in the cell envelope; and TraA encodes a distant PA14 lectin-like domain, a cysteine-rich tandem repeat region, and a putative C-terminal protein sorting tag named MYXO-CTERM, while TraB encodes an OmpA-like domain. Importantly, TraAB are required in donors and recipients, suggesting bidirectional transfer. By use of a lipophilic fluorescent dye, we also discovered that OM lipids are exchanged. Similar to lipoproteins, dye transfer requires TraAB function, gliding motility and a structured biofilm. Importantly, OM exchange was found to regulate swarming and development behaviors, suggesting a new role in cell-cell communication. A working model proposes TraA is a cell surface receptor that mediates cell-cell adhesion for OM fusion, in which lipoproteins/lipids are transferred by lateral diffusion. We further hypothesize that cell contact-dependent exchange helps myxobacteria to coordinate their social behaviors. PMID- 22511880 TI - Whole-exome sequencing and homozygosity analysis implicate depolarization regulated neuronal genes in autism. AB - Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders. PMID- 22511879 TI - Dissection of Pol II trigger loop function and Pol II activity-dependent control of start site selection in vivo. AB - Structural and biochemical studies have revealed the importance of a conserved, mobile domain of RNA Polymerase II (Pol II), the Trigger Loop (TL), in substrate selection and catalysis. The relative contributions of different residues within the TL to Pol II function and how Pol II activity defects correlate with gene expression alteration in vivo are unknown. Using Saccharomyces cerevisiae Pol II as a model, we uncover complex genetic relationships between mutated TL residues by combinatorial analysis of multiply substituted TL variants. We show that in vitro biochemical activity is highly predictive of in vivo transcription phenotypes, suggesting direct relationships between phenotypes and Pol II activity. Interestingly, while multiple TL residues function together to promote proper transcription, individual residues can be separated into distinct functional classes likely relevant to the TL mechanism. In vivo, Pol II activity defects disrupt regulation of the GTP-sensitive IMD2 gene, explaining sensitivities to GTP-production inhibitors, but contrasting with commonly cited models for this sensitivity in the literature. Our data provide support for an existing model whereby Pol II transcriptional activity provides a proxy for direct sensing of NTP levels in vivo leading to IMD2 activation. Finally, we connect Pol II activity to transcription start site selection in vivo, implicating the Pol II active site and transcription itself as a driver for start site scanning, contravening current models for this process. PMID- 22511881 TI - Hypoxia disruption of vertebrate CNS pathfinding through ephrinB2 Is rescued by magnesium. AB - The mechanisms of hypoxic injury to the developing human brain are poorly understood, despite being a major cause of chronic neurodevelopmental impairments. Recent work in the invertebrate Caenorhabditis elegans has shown that hypoxia causes discrete axon pathfinding errors in certain interneurons and motorneurons. However, it is unknown whether developmental hypoxia would have similar effects in a vertebrate nervous system. We have found that developmental hypoxic injury disrupts pathfinding of forebrain neurons in zebrafish (Danio rerio), leading to errors in which commissural axons fail to cross the midline. The pathfinding defects result from activation of the hypoxia-inducible transcription factor (hif1) pathway and are mimicked by chemical inducers of the hif1 pathway or by expression of constitutively active hif1alpha. Further, we found that blocking transcriptional activation by hif1alpha helped prevent the guidance defects. We identified ephrinB2a as a target of hif1 pathway activation, showed that knock-down of ephrinB2a rescued the guidance errors, and showed that the receptor ephA4a is expressed in a pattern complementary to the misrouting axons. By targeting a constitutively active form of ephrinB2a to specific neurons, we found that ephrinB2a mediates the pathfinding errors via a reverse signaling mechanism. Finally, magnesium sulfate, used to improve neurodevelopmental outcomes in preterm births, protects against pathfinding errors by preventing upregulation of ephrinB2a. These results demonstrate that evolutionarily conserved genetic pathways regulate connectivity changes in the CNS in response to hypoxia, and they support a potential neuroprotective role for magnesium. PMID- 22511882 TI - Population structure of Hispanics in the United States: the multi-ethnic study of atherosclerosis. AB - Using ~60,000 SNPs selected for minimal linkage disequilibrium, we perform population structure analysis of 1,374 unrelated Hispanic individuals from the Multi-Ethnic Study of Atherosclerosis (MESA), with self-identification corresponding to Central America (n = 93), Cuba (n = 50), the Dominican Republic (n = 203), Mexico (n = 708), Puerto Rico (n = 192), and South America (n = 111). By projection of principal components (PCs) of ancestry to samples from the HapMap phase III and the Human Genome Diversity Panel (HGDP), we show the first two PCs quantify the Caucasian, African, and Native American origins, while the third and fourth PCs bring out an axis that aligns with known South-to-North geographic location of HGDP Native American samples and further separates MESA Mexican versus Central/South American samples along the same axis. Using k-means clustering computed from the first four PCs, we define four subgroups of the MESA Hispanic cohort that show close agreement with self-identification, labeling the clusters as primarily Dominican/Cuban, Mexican, Central/South American, and Puerto Rican. To demonstrate our recommendations for genetic analysis in the MESA Hispanic cohort, we present pooled and stratified association analysis of triglycerides for selected SNPs in the LPL and TRIB1 gene regions, previously reported in GWAS of triglycerides in Caucasians but as yet unconfirmed in Hispanic populations. We report statistically significant evidence for genetic association in both genes, and we further demonstrate the importance of considering population substructure and genetic heterogeneity in genetic association studies performed in the United States Hispanic population. PMID- 22511883 TI - Mu insertions are repaired by the double-strand break repair pathway of Escherichia coli. AB - Mu is both a transposable element and a temperate bacteriophage. During lytic growth, it amplifies its genome by replicative transposition. During infection, it integrates into the Escherichia coli chromosome through a mechanism not requiring extensive DNA replication. In the latter pathway, the transposition intermediate is repaired by transposase-mediated resecting of the 5' flaps attached to the ends of the incoming Mu genome, followed by filling the remaining 5 bp gaps at each end of the Mu insertion. It is widely assumed that the gaps are repaired by a gap-filling host polymerase. Using the E. coli Keio Collection to screen for mutants defective in recovery of stable Mu insertions, we show in this study that the gaps are repaired by the machinery responsible for the repair of double-strand breaks in E. coli-the replication restart proteins PriA-DnaT and homologous recombination proteins RecABC. We discuss alternate models for recombinational repair of the Mu gaps. PMID- 22511884 TI - Modifier genes and the plasticity of genetic networks in mice. AB - Modifier genes are an integral part of the genetic landscape in both humans and experimental organisms, but have been less well explored in mammals than other systems. A growing number of modifier genes in mouse models of disease nonetheless illustrate the potential for novel findings, while new technical advances promise many more to come. Modifier genes in mouse models include induced mutations and spontaneous or wild-derived variations captured in inbred strains. Identification of modifiers among wild-derived variants in particular should detect disease modifiers that have been shaped by selection and might therefore be compatible with high fitness and function. Here we review selected examples and argue that modifier genes derived from natural variation may provide a bias for nodes in genetic networks that have greater intrinsic plasticity and whose therapeutic manipulation may therefore be more resilient to side effects than conventional targets. PMID- 22511885 TI - Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships. AB - Mammalian nuclear receptors broadly influence metabolic fitness and serve as popular targets for developing drugs to treat cardiovascular disease, obesity, and diabetes. However, the molecular mechanisms and regulatory pathways that govern lipid metabolism remain poorly understood. We previously found that the Caenorhabditis elegans nuclear hormone receptor NHR-49 regulates multiple genes in the fatty acid beta-oxidation and desaturation pathways. Here, we identify additional NHR-49 targets that include sphingolipid processing and lipid remodeling genes. We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors. Gene expression profiles suggest that NHR-49 partners with NHR-66 to regulate sphingolipid and lipid remodeling genes and with NHR-80 to regulate genes involved in fatty acid desaturation. In addition, although we did not detect a direct physical interaction between NHR-49 and NHR-13, we demonstrate that NHR-13 also regulates genes involved in the desaturase pathway. Consistent with this, gene knockouts of these receptors display a host of phenotypes that reflect their gene expression profile. Our data suggest that NHR-80 and NHR-13's modulation of NHR-49 regulated fatty acid desaturase genes contribute to the shortened lifespan phenotype of nhr-49 deletion mutant animals. In addition, we observed that nhr-49 animals had significantly altered mitochondrial morphology and function, and that distinct aspects of this phenotype can be ascribed to defects in NHR-66- and NHR 80-mediated activities. Identification of NHR-49's binding partners facilitates a fine-scale dissection of its myriad regulatory roles in C. elegans. Our findings also provide further insights into the functions of the mammalian lipid-sensing nuclear receptors HNF4alpha and PPARalpha. PMID- 22511886 TI - Transcriptional regulation of rod photoreceptor homeostasis revealed by in vivo NRL targetome analysis. AB - A stringent control of homeostasis is critical for functional maintenance and survival of neurons. In the mammalian retina, the basic motif leucine zipper transcription factor NRL determines rod versus cone photoreceptor cell fate and activates the expression of many rod-specific genes. Here, we report an integrated analysis of NRL-centered gene regulatory network by coupling chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) data from Illumina and ABI platforms with global expression profiling and in vivo knockdown studies. We identified approximately 300 direct NRL target genes. Of these, 22 NRL targets are associated with human retinal dystrophies, whereas 95 mapped to regions of as yet uncloned retinal disease loci. In silico analysis of NRL ChIP Seq peak sequences revealed an enrichment of distinct sets of transcription factor binding sites. Specifically, we discovered that genes involved in photoreceptor function include binding sites for both NRL and homeodomain protein CRX. Evaluation of 26 ChIP-Seq regions validated their enhancer functions in reporter assays. In vivo knockdown of 16 NRL target genes resulted in death or abnormal morphology of rod photoreceptors, suggesting their importance in maintaining retinal function. We also identified histone demethylase Kdm5b as a novel secondary node in NRL transcriptional hierarchy. Exon array analysis of flow-sorted photoreceptors in which Kdm5b was knocked down by shRNA indicated its role in regulating rod-expressed genes. Our studies identify candidate genes for retinal dystrophies, define cis-regulatory module(s) for photoreceptor-expressed genes and provide a framework for decoding transcriptional regulatory networks that dictate rod homeostasis. PMID- 22511887 TI - Context-dependent dual role of SKI8 homologs in mRNA synthesis and turnover. AB - Eukaryotic mRNA transcription and turnover is controlled by an enzymatic machinery that includes RNA polymerase II and the 3' to 5' exosome. The activity of these protein complexes is modulated by additional factors, such as the nuclear RNA polymerase II-associated factor 1 (Paf1c) and the cytoplasmic Superkiller (SKI) complex, respectively. Their components are conserved across uni- as well as multi-cellular organisms, including yeast, Arabidopsis, and humans. Among them, SKI8 displays multiple facets on top of its cytoplasmic role in the SKI complex. For instance, nuclear yeast ScSKI8 has an additional function in meiotic recombination, whereas nuclear human hSKI8 (unlike ScSKI8) associates with Paf1c. The Arabidopsis SKI8 homolog VERNALIZATION INDEPENDENT 3 (VIP3) has been found in Paf1c as well; however, whether it also has a role in the SKI complex remains obscure so far. We found that transgenic VIP3-GFP, which complements a novel vip3 mutant allele, localizes to both nucleus and cytoplasm. Consistently, biochemical analyses suggest that VIP3-GFP associates with the SKI complex. A role of VIP3 in the turnover of nuclear encoded mRNAs is supported by random-primed RNA sequencing of wild-type and vip3 seedlings, which indicates mRNA stabilization in vip3. Another SKI subunit homolog mutant, ski2, displays a dwarf phenotype similar to vip3. However, unlike vip3, it displays neither early flowering nor flower development phenotypes, suggesting that the latter reflect VIP3's role in Paf1c. Surprisingly then, transgenic ScSKI8 rescued all aspects of the vip3 phenotype, suggesting that the dual role of SKI8 depends on species specific cellular context. PMID- 22511888 TI - Mutations in MITF and PAX3 cause "splashed white" and other white spotting phenotypes in horses. AB - During fetal development neural-crest-derived melanoblasts migrate across the entire body surface and differentiate into melanocytes, the pigment-producing cells. Alterations in this precisely regulated process can lead to white spotting patterns. White spotting patterns in horses are a complex trait with a large phenotypic variance ranging from minimal white markings up to completely white horses. The "splashed white" pattern is primarily characterized by an extremely large blaze, often accompanied by extended white markings at the distal limbs and blue eyes. Some, but not all, splashed white horses are deaf. We analyzed a Quarter Horse family segregating for the splashed white coat color. Genome-wide linkage analysis in 31 horses gave a positive LOD score of 1.6 in a region on chromosome 6 containing the PAX3 gene. However, the linkage data were not in agreement with a monogenic inheritance of a single fully penetrant mutation. We sequenced the PAX3 gene and identified a missense mutation in some, but not all, splashed white Quarter Horses. Genome-wide association analysis indicated a potential second signal near MITF. We therefore sequenced the MITF gene and found a 10 bp insertion in the melanocyte-specific promoter. The MITF promoter variant was present in some splashed white Quarter Horses from the studied family, but also in splashed white horses from other horse breeds. Finally, we identified two additional non-synonymous mutations in the MITF gene in unrelated horses with white spotting phenotypes. Thus, several independent mutations in MITF and PAX3 together with known variants in the EDNRB and KIT genes explain a large proportion of horses with the more extreme white spotting phenotypes. PMID- 22511889 TI - Runs of homozygosity implicate autozygosity as a schizophrenia risk factor. AB - Autozygosity occurs when two chromosomal segments that are identical from a common ancestor are inherited from each parent. This occurs at high rates in the offspring of mates who are closely related (inbreeding), but also occurs at lower levels among the offspring of distantly related mates. Here, we use runs of homozygosity in genome-wide SNP data to estimate the proportion of the autosome that exists in autozygous tracts in 9,388 cases with schizophrenia and 12,456 controls. We estimate that the odds of schizophrenia increase by ~17% for every 1% increase in genome-wide autozygosity. This association is not due to one or a few regions, but results from many autozygous segments spread throughout the genome, and is consistent with a role for multiple recessive or partially recessive alleles in the etiology of schizophrenia. Such a bias towards recessivity suggests that alleles that increase the risk of schizophrenia have been selected against over evolutionary time. PMID- 22511892 TI - Loss-of-Function CNKSR2 Mutation Is a Likely Cause of Non-Syndromic X-Linked Intellectual Disability. AB - In a non-dysmorphic 5-year-old boy with developmental delay, well-controlled epilepsy, and microcephaly, a 234-kb deletion of Xp22.12 was detected by copy number analysis. The maternally inherited deletion removed the initial 15 of the 21 exons of the connector enhancer of KSR-2 gene called CNKSR2 or CNK2. Our finding suggests that loss of CNKSR2 is a novel cause of non-syndromic X-linked mental retardation, an assumption supported by high gene expression in the brain, localization to the post-synaptic density, and a role in RAS/MAPK-dependent signal transduction. PMID- 22511890 TI - Deep sequencing of plant and animal DNA contained within traditional Chinese medicines reveals legality issues and health safety concerns. AB - Traditional Chinese medicine (TCM) has been practiced for thousands of years, but only within the last few decades has its use become more widespread outside of Asia. Concerns continue to be raised about the efficacy, legality, and safety of many popular complementary alternative medicines, including TCMs. Ingredients of some TCMs are known to include derivatives of endangered, trade-restricted species of plants and animals, and therefore contravene the Convention on International Trade in Endangered Species (CITES) legislation. Chromatographic studies have detected the presence of heavy metals and plant toxins within some TCMs, and there are numerous cases of adverse reactions. It is in the interests of both biodiversity conservation and public safety that techniques are developed to screen medicinals like TCMs. Targeting both the p-loop region of the plastid trnL gene and the mitochondrial 16S ribosomal RNA gene, over 49,000 amplicon sequence reads were generated from 15 TCM samples presented in the form of powders, tablets, capsules, bile flakes, and herbal teas. Here we show that second-generation, high-throughput sequencing (HTS) of DNA represents an effective means to genetically audit organic ingredients within complex TCMs. Comparison of DNA sequence data to reference databases revealed the presence of 68 different plant families and included genera, such as Ephedra and Asarum, that are potentially toxic. Similarly, animal families were identified that include genera that are classified as vulnerable, endangered, or critically endangered, including Asiatic black bear (Ursus thibetanus) and Saiga antelope (Saiga tatarica). Bovidae, Cervidae, and Bufonidae DNA were also detected in many of the TCM samples and were rarely declared on the product packaging. This study demonstrates that deep sequencing via HTS is an efficient and cost-effective way to audit highly processed TCM products and will assist in monitoring their legality and safety especially when plant reference databases become better established. PMID- 22511891 TI - Zinc status and its association with the health of adolescents: a review of studies in India. AB - BACKGROUND: Zinc is important in adolescence because of its role in growth and sexual maturation. Adolescents from developing countries such as India may be at high risk of zinc deficiency because of unwholesome food habits and poor bioavailability of zinc from plant-based diets. OBJECTIVE: (1) to study zinc status and its association with profile of other micronutrients, (2) to construct a simple tool in the form of Adolescent Micronutrient Quality Index (AMQI) to assess quality of diets of the girls and (3) to examine the effect of zinc supplement on health of adolescent girls. METHODS: Girls (10-16 years) from two secondary schools of Pune, Maharashtra state, in Western India were enrolled in a cross-sectional study (n = 630). Data were collected on dietary intake, cognitive performance, taste acuity, haemoglobin, erythrocyte zinc and plasma levels of zinc, vitamin C, beta-carotene and retinol. AMQI was developed using age-sex specific Indian dietary guidelines and healthy foods and habits described in the recent US dietary guidelines. Zinc-rich recipes were developed considering habitual diets of the girls and vegetarian sources of zinc. An intervention trial (n = 180) was conducted to assess the effect of zinc-rich dietary supplements and ayurvedic zinc (Jasad) supplementation. RESULTS: Prevalence of micronutrient deficiencies was high in these girls. Poor cognitive performance was seen in half of the girls, and salt taste perception was affected in 45%. AMQI was correlated with nutrient intakes and blood micronutrient levels (p < 0.01), indicating the potential of AMQI to measure micronutrient quality of diets of adolescent girls. Results of the intervention trial indicated that supplementation of zinc-rich recipes vis-a-vis ayurvedic Jasad zinc has the potential to improve plasma zinc status, cognitive performance and taste acuity in adolescent girls. CONCLUSIONS: Review of the studies on Indian adolescent girls demonstrates the necessity of adopting zinc and micronutrient-rich diets for positive health building in adolescents. PMID- 22511893 TI - Searching for Copy Number Changes in Nonsyndromic X-Linked Intellectual Disability. AB - Intellectual disability (ID) has a prevalence of 2-3% with 0.3% of the population being severely retarded. Etiology is heterogeneous, owing to numerous genetic and environmental factors. Underlying etiology remains undetermined in 75-80% of mildly disabled patients and 20-50% of those severely disabled. Twelve percent of all ID is thought to be X-linked (XLID). This study covers copy number analysis of some of the known XLID genes, using multiplex ligation-dependent probe amplification (MLPA) in 100 nonsyndromic patients. One of the patients was found to have duplication in all exons of MECP2 gene, and another had duplication in the fifth exon of TM4SF2/TSPAN7 gene. Affymetrix(r) 6.0 whole-genome SNP microarray confirmed the duplication in MECP2 and showed duplication of exons 2-7 in TM4SF2/TSPAN7, respectively. MECP2 duplication has recently been recognized as a syndromic cause of XLID in males, whereas duplications in TM4SF2/TSPAN7 are yet to be determined as a cause of XLID. Being an efficient, rapid, easy-to-perform, easy-to-interpret, and cost-effective method of copy number analysis of specific DNA sequences, MLPA presents wide clinical utility and may be included in diagnostic workup of ID, particularly when microarrays are unavailable as a first line approach. PMID- 22511894 TI - Recurrent Transmission of a 17q12 Microdeletion and a Variable Clinical Spectrum. AB - The relatively rare proximal microdeletion of 17q12 (including deletion of the HNF1B gene) is associated with the renal cysts and diabetes syndrome. Recent reports have suggested that there may also be an association between this microdeletion and learning difficulties/autism. This case report describes one of only a few reported families segregating the 17q12 microdeletion, but which highlights the nonpenetrance and variable expressivity of multiple features of this condition. PMID- 22511895 TI - Novel Tandem Duplication in Exon 1 of the SNURF/SNRPN Gene in a Child with Transient Excessive Eating Behaviour and Weight Gain. AB - A deletion in 15q11.2 involving the SNURF/SNRPN gene is the typical finding in patients with Prader-Willi syndrome. Apart from translocations disrupting this gene, no other mutation types have been described so far. We report a patient in whom a small duplication in exon 1 of the SNURF/SNRPN gene was diagnosed which is predicted to interrupt only SNURF expression. The patient was investigated due to overgrowth, increased appetite and developmental delay in childhood. This duplication was inherited from her father who carries the duplication on his paternal chromosome 15 and also had transient excessive eating behaviour as an adolescent. RNA studies showed that the duplication introduces a premature stop codon in SNURF. PMID- 22511896 TI - Differences in Copy Number Variation between Discordant Monozygotic Twins as a Model for Exploring Chromosomal Mosaicism in Congenital Heart Defects. AB - Studies addressing the role of somatic copy number variation (CNV) in the genesis of congenital heart defects (CHDs) are scarce, as cardiac tissue is difficult to obtain, especially in non-affected individuals. We explored the occurrence of copy number differences in monozygotic (MZ) twins discordant for the presence of a CHD, as an illustrative model for chromosomal mosaicism in CHDs. Array comparative genomic hybridization was performed on peripheral blood-derived DNA obtained from 6 discordant MZ twin pairs and on sex-matched reference samples. To identify CNV differences between both twin members as well as potential CNVs in both twins contributing to the phenotype, DNA from each twin was hybridized against its co-twin, and against a normal control. Three copy number differences in 1 out of 6 MZ twin pairs were detected, confirming the occurrence of somatic CNV events in MZ twins. Further investigation by copy number and (epi)genome sequencing analyses in MZ twins, discordant for the presence of CHDs, is required to improve our knowledge on how postzygotic genetic, environmental and stochastic factors can affect human heart development. PMID- 22511897 TI - Unique Combination of 22q11 and 14qter Microdeletion Syndromes Detected Using Oligonucleotide Array-CGH. AB - We report an infant with a unique combination of 22q11 deletion syndrome and 14q terminal deletion syndrome. The proband had clinical symptoms compatible with diagnosis of 22q11 deletion syndrome: microcephaly, micrognathia, high-arched palate, hypertelorism, short palpebral fissures, square nasal root, prominent tubular nose, hypoplastic nasal alae, bulbous nasal tip, dysplastic low-set ears, short philtrum, and heart defect, but no cell-mediated immunodeficiency typical for the syndrome. G-banding and fluorescence in situ hybridization analyses revealed a karyotype 45,XY,der(14)t(14;22)(q32.3;q11.2),-22.ish del(14)(q32.33)(D14S1420-),del(22)(q11.2q11.2)(N25-). Subsequent analyses disclosed a translocation between chromosomes 14 and 22 in the proband's mother with a deleted 14q telomere. Using comparative genome hybridization on oligonucleotide-based microarray (array-CGH), the deletion at 22q11.21 in the size of ~4.25 Mb was revealed in the proband as well as the deletion of the telomeric area at 14q32.33qter (~3.24 Mb) in the proband and his mother. However, both the proband and his mother showed mild symptoms (microcephaly, thin lips, carp-shaped mouth) typical for patients with the described terminal 14q deletion syndrome. PMID- 22511899 TI - Recent trends in the treatment of chronic hepatitis C. AB - Pegylated interferon and ribavirin combination therapy is accepted as the standard antiviral treatment for chronic hepatitis C regardless of HCV genotype. This combination therapy achieves higher response rates than previous therapy, but, nevertheless, a large proportion of patients suffer from treatment failure or adverse events. Recent clinical studies of viral kinetics during antiviral treatment have led to the introduction of response-guided therapy, the concept of 'customized therapy depending on viral response', which focuses on modulation of the treatment period depending on the viral response to create a sustained viral response without unnecessary medication and costs. New upcoming direct-acting antivirals (DAAs) maximize response rate, and triple therapy including DAAs along with pegylated interferon and ribavirin combination therapy could soon be the standard therapy. In this article, we reviewed the factors affecting treatment, response guided treatment, retreatment after failure of standard treatment, management of adverse events during treatment, and new treatment options. PMID- 22511900 TI - The effect of alanine aminotransferase dynamics on predicting sustained virological response in chronic hepatitis C virus infection. PMID- 22511898 TI - Revision and update on clinical practice guideline for liver cirrhosis. PMID- 22511901 TI - Efficacy and safety of metronomic chemotherapy for patients with advanced primary hepatocellular carcinoma with major portal vein tumor thrombosis. AB - BACKGROUND/AIMS: Low-dose metronomic chemotherapy involves the frequent administration of comparatively low doses of cytotoxic agents with no extended breaks, and it may be as efficient as and less toxic than the conventional maximum tolerated dose therapy. This study evaluated the feasibility and therapeutic efficacy of metronomic chemotherapy in patients with advanced hepatocellular carcinoma (HCC) with major portal vein thrombosis (PVT). METHODS: Thirty consecutive HCC patients with major PVT with or without extrahepatic metastasis were prospectively allocated to metronomic chemotherapy consisting of epirubicin being infused through the correct hepatic artery at a dose of 30 mg/body surface area (BSA) every 4 weeks, and cisplatin (15 mg/BSA) and 5 fluorouracil (50 mg/BSA) every week for 3 weeks, with intervening 1 week breaks. The treatment response was assessed using response evaluation criteria in solid tumors (RECIST). RESULTS: In total, 116 cycles of metronomic chemotherapy were administered to the 30 patients, with a median of 3 cycles given to individual patients (range, 1-15 cycles). Six patients (20.0%) achieved a partial response and six patients (20.0%) had stable disease. The median time to disease progression and overall survival were 63 days (range, 26-631 days) and 162 days (95% confidence interval; range, 62-262 days), respectively. Overall survival was significantly associated with baseline alpha-fetoprotein level (P=0.001) and tumor response (P=0.005). The baseline alpha-fetoprotein level was significantly associated with the disease control rate (P=0.007). Adverse events were tolerable and managed successfully with conservative treatment. CONCLUSIONS: Metronomic chemotherapy may be a safe and useful palliative treatment in HCC patients with major PVT. PMID- 22511902 TI - Rapid normalization of alanine aminotransferase predicts viral response during combined peginterferon and ribavirin treatment in chronic hepatitis C patients. AB - BACKGROUND/AIMS: The treatment for chronic hepatitis C (CHC) is removal of the virus in order to prevent progression to liver cirrhosis and hepatocellular carcinoma (HCC). Few data have been presented regarding the clinical significance of changes in the alanine aminotransferase (ALT) level in this context. We analyzed the patterns of changes in ALT level and investigated the relationship between the rapid normalization of ALT and sustained virologic response (SVR) after combined treatment with peginterferon and ribavirin. METHODS: CHC patients (n=370) were classified into four groups according to the initial ALT level and subsequent changes: (1) initially abnormal ALT level and sustained abnormal ALT level during treatment, (2) initially abnormal ALT level but achievement of ALT normalization, (3) initially normal ALT level and variable ALT abnormality during treatment, and (4) initially normal ALT level and sustained normalization of ALT level during treatment. We subdivided groups 1 and 2 into those with patterns of decreased and normalization of ALT, with or without rapid normalization. We checked the end-treatment response (ETR) and SVR rates in each group and the factors associated with SVR, including patterns of changes in ALT level. RESULTS: A total of 168 patients completed the therapy (age=54.34+/-10.64 years [mean+/ SD], 95 males [56.5%], genotype 1:82 [48.8%]). SVR was achieved in 115 (68.45%) of the completely treated patients. The SVR rate was significantly lower in group 1 than in group 2 (37.8 vs. 81.6%, P<0.001), and significantly higher in the rapid normalization group than in the group without rapid normalization (78.5% vs. 41.2%, P<0.001). Multiple logistic regression analysis revealed that age (odds ratio [OR]=0.94, 95% confidence interval [CI]=0.91-0.98, P=0.005), viral genotype (OR=2.76, 95% CI=1.20-6.38, P=0.017), and initial hepatitis C virus RNA titer (OR=0.28, 95% CI=0.10-0.75, P=0.012) were identified as independent significant predictive factors for SVR. CONCLUSIONS: The SVR rate is significantly associated with normalization, and especially rapid normalization of ALT. Rapid normalization of ALT by 4 weeks after treatment might be a useful response factor that is readily available in clinical practice, and especially for genotype 1 patients. PMID- 22511903 TI - Analysis of prognostic factors and 5-year survival rate in patients with hepatocellular carcinoma: a single-center experience. AB - BACKGROUND/AIMS: Hepatocellular carcinoma (HCC), which is the third most common cancer in Korea, has a very poor prognosis. However, only a few studies have performed a comprehensive survival-related analysis in all patients who were consecutively diagnosed and treated over a given period of time. The aim of this study was to determine the 5-year survival rate and its prognostic factors among HCC patients. METHODS: In total, 257 patients who were consecutively diagnosed with HCC between January 2000 and December 2003 were followed until death or until December 2008. We analyzed their survival outcomes according to their clinical characteristics, tumor staging, and treatment modalities, and determined the independent prognostic factors affecting survival. RESULTS: The patients were aged 59+/-10 years (mean+/-SD). During the follow-up period, 223 patients (86.8%) died and the overall median survival was 10.8 months; the 1-, 3-, and 5-year survival rates were 44.4%, 21.0%, and 12.1%, respectively. The outcomes in patients with tumor node metastasis (TNM) stage I or II and Child-Pugh class A or B were significantly better with surgical resection than with other treatment modalities (P<0.01). Patients who underwent supplementary transcatheter arterial chemoembolization as a second-line treatment after surgical resection had better outcomes than those who underwent surgical resection alone (P=0.02). Initial symptoms, Child-Pugh class, serum alpha-fetoprotein, tumor size, portal vein thrombosis, and TNM stage were found to be independent prognostic factors for survival among HCC patients. CONCLUSIONS: This retrospective cohort study elucidated survival outcomes and prognostic factors affecting survival in HCC patients at a single center. PMID- 22511904 TI - Optimal time for repeating the IgM anti-hepatitis A virus antibody test in acute hepatitis A patients with a negative initial test. AB - BACKGROUND/AIMS: The nonspecific clinical presentation of acute hepatitis A (AHA) mandates the detection of anti-hepatitis A virus IgM antibodies (IgM anti-HAV) in the serum for obtaining a definitive diagnosis. However, IgM anti-HAV might not be present during the early phase of the disease. The aim of this study was to determine the optimal time for repeating the IgM anti-HAV test (HAV test) in AHA patients with a negative initial test. METHODS: In total, 261 patients hospitalized with AHA were enrolled for this retrospective study. AHA was diagnosed when the test for IgM anti-HAV was positive and the serum alanine aminotransferase (ALT) level was >=400 IU/L. Repeat HAV test was conducted after 1-2 weeks if the initial HAV test was negative but AHA was still clinically suspected. RESULTS: The results of the initial HAV test were negative in 28 (10.7%) patients. The intervals from symptom onset to the initial-HAV-test day and from the peak-ALT day to the initial-HAV-test day were significantly shorter in the negative-initial-HAV-test group, but on multivariate analysis only the latter was significantly associated with negative results for the initial HAV test (beta=-0.978; odds ratio [95% confidence interval]=0.376 [0.189-0.747]; P=0.005). The HAV test was positive in all patients when it was performed at least 2 days after the peak-ALT day. CONCLUSIONS: The results of HAV tests were significantly associated with the interval from the peak-ALT day to the HAV-test day. The optimal time for repeating the HAV test in clinically suspicious AHA patients with a negative initial HAV test appears to be at least 2 days after the peak-ALT day. PMID- 22511905 TI - Co-expression patterns of Notch1, Snail, and p53 in grade III hepatocellular carcinoma with postoperative recurrence: a preliminary study. AB - BACKGROUND/AIMS: We aimed to determine the association between the co-expression patterns of Notch1, Snail, and p53 proteins (NSP) and the postoperative prognosis of hepatocellular carcinoma (HCC). METHODS: The immunoblot data for molecular expression (147 HCC/corresponding non-HCC tissues and 15 dysplastic nodules) and the sequencing data for p53 mutations (110 HCCs) were obtained from our previous study. Data analyses were restricted to cases with HCC differentiation grade III (n=47), due to its high p53 mutation rate. RESULTS: Nineteen of the 47 patients (40.4%) -comprising 12 in the liver and 7 in distant organs-had relapsed at 1-2 years after surgery. There was no relationship between p53 mutation and postoperative recurrence in the grade III HCCs. Seven (87.5%) of the eight relapsed cases with Notch1, Snail, and p53 (wild) co-expression experienced recurrence only within the liver, and all tumors were smaller than 5 cm in diameter. Extrahepatic relapse occurred mostly in HCC patients with tumors larger than 5 cm in diameter, without any deviation in the NSP pattern. CONCLUSIONS: The results of this preliminary study suggest that the co-expression of Notch1, Snail, and p53 (wild) is not inferior to the patterns with p53 mutation as an indicator of postoperative recurrence of grade III HCC. PMID- 22511906 TI - High efficacy of adefovir and entecavir combination therapy in patients with nucleoside-refractory hepatitis B. AB - BACKGROUND/AIMS: Newly developed and potent antiviral agents suffer from the problem of drug resistance. Multidrug resistance is a major impediment in the treatment of patients with chronic hepatitis B (CHB). In line with American Association for the Study of Liver Diseases guidelines, adefovir dipivoxil (ADV) add-on therapy is recommended in the case of lamivudine resistance, while tenofovir disoproxil fumarate (TDF) is recommended for ADV or entecavir (ETV) resistance. TDF is currently not available in Korea. ADV+ETV combination therapy may be a viable alternative to TDF in patients with either ADV or ETV resistance. However, the efficacy of ADV+ETV combination therapy in patients with CHB and multidrug resistance is unclear. This study investigated the efficacy of ADV+ETV combination therapy in patients with multidrug resistance. METHODS: Twenty-five patients were enrolled and were administered ADV+ETV combination therapy for at least 6 months. Blood was drawn at baseline and at 3, 6, 9, and 12 months after commencing treatment, and the following blood parameters were analyzed: alanine transaminase, hepatitis B e-antigen (HBeAg), anti-hepatitis B e-antigen, and hepatitis B virus (HBV) DNA levels. The initial virological response (IVR) was defined as an HBV DNA level of <4 log(10) copies/mL after 6 months of combination therapy. RESULTS: The IVR rate was 76%. The proportion of patients with a high viral load (>=5.0 log) dropped from 76% at baseline to only 5% after 6 months of treatment. The biochemical response rate during the first 6 months was 71%. HBeAg was lost in 2 patients (10%). CONCLUSIONS: ADV+ETV combination therapy induced a good IVR in CHB patients who were refractory to more than 2 antiviral agents. This regimen may be a good alternative to TDF in Korea, where that drug is not available. PMID- 22511907 TI - Drug rash with eosinophilia and systemic symptoms syndrome following cholestatic hepatitis A: a case report. AB - Hepatitis A virus (HAV) infections occur predominantly in children, and are usually self-limiting. However, 75-95% of the infections in adults are symptomatic (mostly with jaundice), with the illness symptoms usually persisting for a few weeks. Atypical manifestations include relapsing hepatitis, prolonged cholestasis, and complications involving renal injury. Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a severe, drug-induced hypersensitivity reaction characterized by skin rash, fever, lymph-node enlargement, and internal organ involvement. We describe a 22-year-old male who presented with acute kidney injury and was diagnosed with prolonged cholestatic hepatitis A. The patient also developed DRESS syndrome due to antibiotic and/or antiviral treatment. To our knowledge, this is the first report of histopathologically confirmed DRESS syndrome due to antibiotic and/or antiviral treatment following HAV infection with cholestatic features and renal injury. PMID- 22511908 TI - A case of isolated metastatic hepatocellular carcinoma arising from the pelvic bone. AB - Reports of metastatic hepatocellular carcinoma (HCC) without a primary liver tumor are rare. Here we present a case of isolated HCC that had metastasized to the pelvic bone without a primary focus. A 73-year-old man presented with severe back and right-leg pain. Radiological examinations, including computed tomography (CT) and magnetic resonance imaging (MRI), revealed a huge mass on the pelvic bone (13*10 cm). He underwent an incisional biopsy, and the results of the subsequent histological examination were consistent with metastatic hepatocellular carcinoma. The tumor cells were positive for cytokeratin (AE1/AE3), hepatocyte paraffin 1, and glypican-3, and negative for CD56, chromogranin A, and synaptophysin on immunohistochemical staining. Examination of the liver by CT, MRI, positron-emission tomography scan, and angiography produced no evidence of a primary tumor. Radiotherapy and transarterial chemoembolization were performed on the pelvic bone, followed by systemic chemotherapy. These combination treatments resulted in tumor regression with necrotic changes. However, multiple lung metastases developed 1 year after the treatment, and the patient was treated with additional systemic chemotherapy. PMID- 22511909 TI - A case of emphysematous hepatitis with spontaneous pneumoperitoneum in a patient with hilar cholangiocarcinoma. AB - An 80-year-old woman with hilar cholangiocarcinoma was hospitalized due to sudden onset abdominal pain. Computed tomography revealed hepatic necrosis accompanied with emphysematous change in the superior segment of the right liver (S7/S8), implying spontaneous rupture, based on the presence of perihepatic free air. Although urgent percutaneous drainage was performed, neither pus nor fluids were drained. These findings suggest emphysematous hepatitis with a hepatic mass. Despite the application of intensive care, the patient's condition deteriorated rapidly, and she died 3 days after admission to hospital. Liver gas has been reported in some clinical diseases (e.g., liver abscess) to be caused by gas forming organisms; however, emphysematous hepatitis simulating emphysematous pyelonephritis is very rare. The case reported here was of fatal emphysematous hepatitis in a patient with hilar cholangiocarcinoma. PMID- 22511910 TI - Ciliated hepatic foregut cyst. PMID- 22511911 TI - MR imaging of hepatic lymphangioma. PMID- 22511912 TI - Body iron, serum ferritin, and nonalcoholic fatty liver disease. PMID- 22511913 TI - Neural population representation hypothesis of visual flow and its illusory after effect in the brain: psychophysics, neurophysiology and computational approaches. AB - The neural representation of motion aftereffects induced by various visual flows (translational, rotational, motion-in-depth, and translational transparent flows) was studied under the hypothesis that the imbalances in discharge activities would occur in favor in the direction opposite to the adapting stimulation in the monkey MST cells (cells in the medial superior temporal area) which can discriminate the mode (i.e., translational, rotational, or motion-in-depth) of the given flow. In single-unit recording experiments conducted on anaesthetized monkeys, we found that the rate of spontaneous discharge and the sensitivity to a test stimulus moving in the preferred direction decreased after receiving an adapting stimulation moving in the preferred direction, whereas they increased after receiving an adapting stimulation moving in the null direction. To consistently explain the bidirectional perception of a transparent visual flow and its unidirectional motion aftereffect by the same hypothesis, we need to assume the existence of two subtypes of MST D cells which show directionally selective responses to a translational flow: component cells and integration cells. Our physiological investigation revealed that the MST D cells could be divided into two types: one responded to a transparent flow by two peaks at the instances when the direction of one of the component flow matched the preferred direction of the cell, and the other responded by a single peak at the instance when the direction of the integrated motion matched the preferred direction. In psychophysical experiments on human subjects, we found evidence for the existence of component and integration representations in the human brain. To explain the different motion perceptions, i.e., two transparent flows during presentation of the flows and a single flow in the opposite direction to the integrated flows after stopping the flow stimuli, we suggest that the pattern-discrimination system can select the motion representation that is consistent with the perception of the pattern from two motion representations. We discuss the computational aspects related to the integration of component motion fields. PMID- 22511914 TI - Traveling EEG slow oscillation along the dorsal attention network initiates spontaneous perceptual switching. AB - An ambiguous figure such as the Necker cube causes spontaneous perceptual switching (SPS). The mechanism of SPS in multistable perception has not yet been determined. Although early psychological studies suggested that SPS may be caused by fatigue or satiation of orientation, the neural mechanism of SPS is still unknown. Functional magnetic resonance imaging (fMRI) has shown that the dorsal attention network (DAN), which mainly controls voluntary attention, is involved in bistable perception of the Necker cube. To determine whether neural dynamics along the DAN cause SPS, we performed simultaneous electroencephalography (EEG) and fMRI during an SPS task with the Necker cube, with every SPS reported by pressing a button. This EEG-fMRI integrated analysis showed that (a) 3-4 Hz spectral EEG power modulation at fronto-central, parietal, and centro-parietal electrode sites sequentially appeared from 750 to 350 ms prior to the button press; and (b) activations correlating with the EEG modulation traveled along the DAN from the frontal to the parietal regions. These findings suggest that slow oscillation initiates SPS through global dynamics along the attentional system such as the DAN. PMID- 22511915 TI - Validation of reference genes for the relative quantification of gene expression in human epicardial adipose tissue. AB - BACKGROUND: Relative quantification is a commonly used method for assessing gene expression, however its accuracy and reliability is dependent upon the choice of an optimal endogenous control gene, and such choice cannot be made a priori. There is limited information available on suitable reference genes to be used for studies involving human epicardial adipose tissue. The objective of the current study was to evaluate and identify optimal reference genes for use in the relative quantification of gene expression in human epicardial fat depots of lean, overweight and obese subjects. METHODOLOGY/PRINCIPAL FINDINGS: Some of the commonly used reference genes including 18S, ACTB, RPL27, HPRT, CYCA, GAPDH, RPLPO, POLR2A and B2M were quantified using real-time PCR analysis. The expression stability of these genes was evaluated using Genorm, Normfinder and Bestkeeper algorithms. In addition, the effect of sample size on the validation process was studied by randomly categorizing subjects in two cohorts of n = 2 and n = 33. CONCLUSIONS/SIGNIFICANCE: CYCA, GAPDH and RPL27 were identified as the most stable genes common to all three algorithms and both sample sizes. Their use as reference gene pairs might contribute to the enhanced robustness of relative quantification in the studies involving the human epicardial adipose tissue. PMID- 22511916 TI - Safety and adherence to intermittent pre-exposure prophylaxis (PrEP) for HIV-1 in African men who have sex with men and female sex workers. AB - BACKGROUND: Little is known about safety of and adherence to intermittent HIV PrEP regimens, which may be more feasible than daily dosing in some settings. We present safety and adherence data from the first trial of an intermittent PrEP regimen among Kenyan men who have sex with men (MSM) and female sex workers (FSW). METHODS/PRINCIPAL FINDINGS: MSM and FSW were randomized to daily oral FTC/TDF or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral FTC/TDF or placebo in a 2:1:2:1 ratio; volunteers were followed monthly for 4 months. Adherence was assessed with the medication event monitoring system (MEMS). Sexual activity data were collected via daily text message (SMS) queries and timeline followback interviews with a one-month recall period. Sixty-seven men and 5 women were randomized into the study. Safety was similar among all groups. Median MEMS adherence rates were 83% [IQR: 63-92] for daily dosing and 55% [IQR:28-78] for fixed intermittent dosing (p = 0.003), while adherence to any post-coital doses was 26% [IQR:14-50]. SMS response rates were low, which may have impaired measurement of post-coital dosing adherence. Acceptability of PrEP was high, regardless of dosing regimen. CONCLUSIONS/SIGNIFICANCE: Adherence to intermittent dosing regimens, fixed doses, and in particular coitally-dependent doses, may be more difficult than adherence to daily dosing. However, intermittent dosing may still be appropriate for PrEP if intracellular drug levels, which correlate with prevention of HIV acquisition, can be attained with less than daily dosing and if barriers to adherence can be addressed. Additional drug level data, qualitative data on adherence barriers, and better methods to measure sexual activity are necessary to determine whether adherence to post-coital PrEP could be comparable to more standard regimens. TRIAL REGISTRATION: ClinicalTrials.gov NCT00971230. PMID- 22511917 TI - Anti-stress effects of carnosine on restraint-evoked immunocompromise in mice through spleen lymphocyte number maintenance. AB - Carnosine (beta-alanyl-L-histidine), a naturally occurring dipeptide, has been characterized as a putative neurotransmitter and serves as a reservoir for brain histamine, which could act on histaminergic neurons system to relieve stress induced damages. However, understanding of the role of carnosine in stress-evoked immunocompromise is limited. In this study, results showed that when mice were subjected to restraint stress, spleen index and the number of spleen lymphocytes including Natural Killer (NK) cells were obviously decreased. Results also demonstrated that restraint stress decreased the cytotoxic activity of NK cells per spleen (LU(10)/spleen) while the activity of a single NK cell (LU(10)/10(6) cells) was not changed. However, oral administration of carnosine (150 and 300 mg/kg) increased spleen index and number of spleen lymphocytes (including NK cells), and elevated the cytotoxic activity of NK cells per spleen in restraint stressed mice. These results indicated that carnosine ameliorated stress-evoked immunocompromise through spleen lymphocyte number maintenance. Carnosine was further found to reduce stress-induced elevation of plasma corticosterone level. On the other hand, results showed that carnosine and RU486 (a glucocorticoids receptor antagonist) treatment prevented the reduction in mitochondrion membrane potential and the release of mitochondrial cytochrome c into cytoplasm, increased Bcl-2/Bax mRNA ratio, as well as decreased terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL)-positive cells in spleen lymphocytes of stressed mice. The results above suggested that the maintenance of spleen lymphocyte number by carnosine was related with the inhibition of lymphocytes apoptosis caused by glucocorticoids overflow. The stimulation of lymphocyte proliferation by carnosine also contributed to the maintenance of spleen lymphocyte number in stressed mice. In view of the elevated histamine level, the anti-stress effects of carnosine on restraint-evoked immunocompromise might be via carnosine-histamine metabolic pathway. Taken together, carnosine maintained spleen lymphocyte number by inhibiting lymphocyte apoptosis and stimulating lymphocyte proliferation, thus prevented immunocompromise in restraint-stressed mice. PMID- 22511918 TI - The co-morbidity burden of children and young adults with autism spectrum disorders. AB - OBJECTIVES: Use electronic health records Autism Spectrum Disorder (ASD) to assess the comorbidity burden of ASD in children and young adults. STUDY DESIGN: A retrospective prevalence study was performed using a distributed query system across three general hospitals and one pediatric hospital. Over 14,000 individuals under age 35 with ASD were characterized by their co-morbidities and conversely, the prevalence of ASD within these comorbidities was measured. The comorbidity prevalence of the younger (Age<18 years) and older (Age 18-34 years) individuals with ASD was compared. RESULTS: 19.44% of ASD patients had epilepsy as compared to 2.19% in the overall hospital population (95% confidence interval for difference in percentages 13.58-14.69%), 2.43% of ASD with schizophrenia vs. 0.24% in the hospital population (95% CI 1.89-2.39%), inflammatory bowel disease (IBD) 0.83% vs. 0.54% (95% CI 0.13-0.43%), bowel disorders (without IBD) 11.74% vs. 4.5% (95% CI 5.72-6.68%), CNS/cranial anomalies 12.45% vs. 1.19% (95% CI 9.41 10.38%), diabetes mellitus type I (DM1) 0.79% vs. 0.34% (95% CI 0.3-0.6%), muscular dystrophy 0.47% vs 0.05% (95% CI 0.26-0.49%), sleep disorders 1.12% vs. 0.14% (95% CI 0.79-1.14%). Autoimmune disorders (excluding DM1 and IBD) were not significantly different at 0.67% vs. 0.68% (95% CI -0.14-0.13%). Three of the studied comorbidities increased significantly when comparing ages 0-17 vs 18-34 with p<0.001: Schizophrenia (1.43% vs. 8.76%), diabetes mellitus type I (0.67% vs. 2.08%), IBD (0.68% vs. 1.99%) whereas sleeping disorders, bowel disorders (without IBD) and epilepsy did not change significantly. CONCLUSIONS: The comorbidities of ASD encompass disease states that are significantly overrepresented in ASD with respect to even the patient populations of tertiary health centers. This burden of comorbidities goes well beyond those routinely managed in developmental medicine centers and requires broad multidisciplinary management that payors and providers will have to plan for. PMID- 22511919 TI - Xer recombinase and genome integrity in Helicobacter pylori, a pathogen without topoisomerase IV. AB - In the model organism E. coli, recombination mediated by the related XerC and XerD recombinases complexed with the FtsK translocase at specialized dif sites, resolves dimeric chromosomes into free monomers to allow efficient chromosome segregation at cell division. Computational genome analysis of Helicobacter pylori, a slow growing gastric pathogen, identified just one chromosomal xer gene (xerH) and its cognate dif site (difH). Here we show that recombination between directly repeated difH sites requires XerH, FtsK but not XerT, the TnPZ transposon associated recombinase. xerH inactivation was not lethal, but resulted in increased DNA per cell, suggesting defective chromosome segregation. The xerH mutant also failed to colonize mice, and was more susceptible to UV and ciprofloxacin, which induce DNA breakage, and thereby recombination and chromosome dimer formation. xerH inactivation and overexpression each led to a DNA segregation defect, suggesting a role for Xer recombination in regulation of replication. In addition to chromosome dimer resolution and based on the absence of genes for topoisomerase IV (parC, parE) in H. pylori, we speculate that XerH may contribute to chromosome decatenation, although possible involvement of H. pylori's DNA gyrase and topoisomerase III homologue are also considered. Further analyses of this system should contribute to general understanding of and possibly therapy development for H. pylori, which causes peptic ulcers and gastric cancer; for the closely related, diarrheagenic Campylobacter species; and for unrelated slow growing pathogens that lack topoisomerase IV, such as Mycobacterium tuberculosis. PMID- 22511920 TI - Phylogeny and diversification patterns among vesicomyid bivalves. AB - Vesicomyid bivalves are among the most abundant and diverse symbiotic taxa in chemosynthetic-based ecosystems: more than 100 different vesicomyid species have been described so far. In the present study, we investigated the phylogenetic positioning of recently described vesicomyid species from the Gulf of Guinea and their western Atlantic and Pacific counterparts using mitochondrial DNA sequence data. The maximum-likelihood (ML) tree provided limited support for the recent taxonomic revision of vesicomyids based on morphological criteria; nevertheless, most of the newly sequenced specimens did not cluster with their morphological conspecifics. Moreover, the observed lack of geographic clustering suggests the occurrence of independent radiations followed by worldwide dispersal. Ancestral character state reconstruction showed a significant correlation between the characters "depth" and "habitat" and the reconstructed ML phylogeny suggesting possible recurrent events of 'stepwise speciation' from shallow to deep waters in different ocean basins. This is consistent with genus or species bathymetric segregation observed from recent taxonomic studies. Altogether, our results highlight the need for ongoing re-evaluation of the morphological characters used to identify vesicomyid bivalves. PMID- 22511921 TI - Text mining for literature review and knowledge discovery in cancer risk assessment and research. AB - Research in biomedical text mining is starting to produce technology which can make information in biomedical literature more accessible for bio-scientists. One of the current challenges is to integrate and refine this technology to support real-life scientific tasks in biomedicine, and to evaluate its usefulness in the context of such tasks. We describe CRAB - a fully integrated text mining tool designed to support chemical health risk assessment. This task is complex and time-consuming, requiring a thorough review of existing scientific data on a particular chemical. Covering human, animal, cellular and other mechanistic data from various fields of biomedicine, this is highly varied and therefore difficult to harvest from literature databases via manual means. Our tool automates the process by extracting relevant scientific data in published literature and classifying it according to multiple qualitative dimensions. Developed in close collaboration with risk assessors, the tool allows navigating the classified dataset in various ways and sharing the data with other users. We present a direct and user-based evaluation which shows that the technology integrated in the tool is highly accurate, and report a number of case studies which demonstrate how the tool can be used to support scientific discovery in cancer risk assessment and research. Our work demonstrates the usefulness of a text mining pipeline in facilitating complex research tasks in biomedicine. We discuss further development and application of our technology to other types of chemical risk assessment in the future. PMID- 22511922 TI - Longitudinal analysis of the temporal evolution of Acinetobacter baumannii strains in Ohio, USA, by using rapid automated typing methods. AB - Genotyping methods are essential to understand the transmission dynamics of Acinetobacter baumannii. We examined the representative genotypes of A. baumannii at different time periods in select locations in Ohio, using two rapid automated typing methods: PCR coupled with electrospray ionization mass spectrometry (PCR/ESI-MS), a form of multi-locus sequence typing (MLST), and repetitive sequence-based-PCR (rep-PCR). Our analysis included 122 isolates from 4 referral hospital systems, in 2 urban areas of Ohio. These isolates were associated with outbreaks at 3 different time periods (1996, 2000 and 2005-2007). Type assignments of PCR/ESI-MS and rep-PCR were compared to each other and to worldwide (WW) clone types. The discriminatory power of each method was determined using the Simpson's index of diversity (DI). We observed that PCR/ESI MS sequence type (ST) 14, corresponding to WW clone 3, predominated in 1996, whereas ST 12 and 14 co-existed in the intermediate period (2000) and ST 10 and 12, belonging to WW clone 2, predominated more recently in 2007. The shift from WW clone 3 to WW clone 2 was accompanied by an increase in carbapenem resistance. The DI was approximately 0.74 for PCR/ESI-MS, 0.88 for rep-PCR and 0.90 for the combination of both typing methods. We conclude that combining rapid automated typing methods such as PCR/ESI-MS and rep-PCR serves to optimally characterize the regional molecular epidemiology of A. baumannii. Our data also sheds light on the changing sequence types in an 11 year period in Northeast Ohio. PMID- 22511923 TI - A model of cancer stem cells derived from mouse induced pluripotent stem cells. AB - Cancer stem cells (CSCs) are capable of continuous proliferation and self-renewal and are proposed to play significant roles in oncogenesis, tumor growth, metastasis and cancer recurrence. CSCs are considered derived from normal stem cells affected by the tumor microenvironment although the mechanism of development is not clear yet. In 2007, Yamanaka's group succeeded in generating Nanog mouse induced pluripotent stem (miPS) cells, in which green fluorescent protein (GFP) has been inserted into the 5'-untranslated region of the Nanog gene. Usually, iPS cells, just like embryonic stem cells, are considered to be induced into progenitor cells, which differentiate into various normal phenotypes depending on the normal niche. We hypothesized that CSCs could be derived from Nanog miPS cells in the conditioned culture medium of cancer cell lines, which is a mimic of carcinoma microenvironment. As a result, the Nanog miPS cells treated with the conditioned medium of mouse Lewis lung carcinoma acquired characteristics of CSCs, in that they formed spheroids expressing GFP in suspension culture, and had a high tumorigenicity in Balb/c nude mice exhibiting angiogenesis in vivo. In addition, these iPS-derived CSCs had a capacity of self renewal and expressed the marker genes, Nanog, Rex1, Eras, Esg1 and Cripto, associated with stem cell properties and an undifferentiated state. Thus we concluded that a model of CSCs was originally developed from miPS cells and proposed the conditioned culture medium of cancer cell lines might perform as niche for producing CSCs. The model of CSCs and the procedure of their establishment will help study the genetic alterations and the secreted factors in the tumor microenvironment which convert miPS cells to CSCs. Furthermore, the identification of potentially bona fide markers of CSCs, which will help the development of novel anti-cancer therapies, might be possible though the CSC model. PMID- 22511925 TI - Multiple local and recent founder effects of TGM1 in Spanish families. AB - BACKGROUND: Mutations in the TGM1 gene encoding transglutaminase 1 are a major cause of autosomal recessive congenital ichthyosis. In the Galician (NW Spain) population, three mutations, c.2278C>T, c.1223_1227delACAC and c.984+1G>A, were observed at high frequency, representing ~46%, ~21% and ~13% of all TGM1 gene mutations, respectively. Moreover, these mutations were reported only once outside of Galicia, pointing to the existence of historical episodes of local severe genetic drift in this region. METHODOLOGY/PRINCIPAL FINDINGS: In order to determine whether these mutations were inherited from a common ancestor in the Galician population, and to estimate the number of generations since their initial appearance, we carried out a haplotype-based analysis by way of genotyping 21 SNPs within and flanking the TGM1 gene and 10 flanking polymorphic microsatellite markers spanning a region of 12 Mb. Two linkage disequilibrium based methods were used to estimate the time to the most recent common ancestor (TMRCA), while a Bayesian-based procedure was used to estimate the age of the two mutations. Haplotype reconstruction from unphased genotypes of all members of the affected pedigrees indicated that all carriers for each of the two mutations harbored the same haplotypes, indicating common ancestry. CONCLUSIONS/SIGNIFICANCE: In good agreement with the documentation record and the census, both mutations arose between 2,800-2,900 years ago (y.a.), but their TMRCA was in the range 600-1,290 y.a., pointing to the existence of historical bottlenecks in the region followed by population growth. This demographic scenario finds further support on a Bayesian Coalescent Analysis based on TGM1 haplotypes that allowed estimating the occurrence of a dramatic reduction of effective population size around 900-4,500 y.a. (95% highest posterior density) followed by exponential growth. PMID- 22511924 TI - Genetic dissection of acute ethanol responsive gene networks in prefrontal cortex: functional and mechanistic implications. AB - BACKGROUND: Individual differences in initial sensitivity to ethanol are strongly related to the heritable risk of alcoholism in humans. To elucidate key molecular networks that modulate ethanol sensitivity we performed the first systems genetics analysis of ethanol-responsive gene expression in brain regions of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens, and ventral midbrain) across a highly diverse family of 27 isogenic mouse strains (BXD panel) before and after treatment with ethanol. RESULTS: Acute ethanol altered the expression of ~2,750 genes in one or more regions and 400 transcripts were jointly modulated in all three. Ethanol-responsive gene networks were extracted with a powerful graph theoretical method that efficiently summarized ethanol's effects. These networks correlated with acute behavioral responses to ethanol and other drugs of abuse. As predicted, networks were heavily populated by genes controlling synaptic transmission and neuroplasticity. Several of the most densely interconnected network hubs, including Kcnma1 and Gsk3beta, are known to influence behavioral or physiological responses to ethanol, validating our overall approach. Other major hub genes like Grm3, Pten and Nrg3 represent novel targets of ethanol effects. Networks were under strong genetic control by variants that we mapped to a small number of chromosomal loci. Using a novel combination of genetic, bioinformatic and network-based approaches, we identified high priority cis-regulatory candidate genes, including Scn1b, Gria1, Sncb and Nell2. CONCLUSIONS: The ethanol-responsive gene networks identified here represent a previously uncharacterized intermediate phenotype between DNA variation and ethanol sensitivity in mice. Networks involved in synaptic transmission were strongly regulated by ethanol and could contribute to behavioral plasticity seen with chronic ethanol. Our novel finding that hub genes and a small number of loci exert major influence over the ethanol response of gene networks could have important implications for future studies regarding the mechanisms and treatment of alcohol use disorders. PMID- 22511926 TI - Immunohistochemical detection of MYC-driven diffuse large B-cell lymphomas. AB - Diffuse large B cell lymphoma (DLBCL) is a clinically and genetically heterogeneous disease. A small subset of DLBCLs has translocations involving the MYC locus and an additional group has a molecular signature resembling Burkitt lymphoma (mBL). Presently, identification of such cases by morphology is unreliable and relies on cytogenetic or complex molecular methods such as gene transcriptional profiling. Herein, we describe an immunohistochemical (IHC) method for identifying DLBCLs with increased MYC protein expression. We tested 77 cases of DLBCL and identified 15 cases with high MYC protein expression (nuclear staining in >50% of tumor cells). All MYC translocation positive cases had increased MYC protein expression by this IHC assay. In addition, gene set enrichment analysis (GSEA) of the DLBCL transcriptional profiles revealed that tumors with increased MYC protein expression (regardless of underlying MYC translocation status) had coordinate upregulation of MYC target genes, providing molecular confirmation of the IHC results. We then generated a molecular classifier derived from the MYC IHC results in our cases and employed it to successfully classify mBLs from two previously reported independent case series, providing additional confirmation that the MYC IHC results identify clinically important subsets of DLBCLs. Lastly, we found that DLBCLs with high MYC protein expression had inferior overall survival when treated with R-CHOP. In conclusion, the IHC method described herein can be used to readily identify the biologically and clinically distinct cases of MYC-driven DLBCL, which represent a clinically significant subset of DLBCL cases due to their inferior overall survival. PMID- 22511927 TI - Beta-catenin phosphorylated at threonine 120 antagonizes generation of active beta-catenin by spatial localization in trans-Golgi network. AB - The stability and subcellular localization of beta-catenin, a protein that plays a major role in cell adhesion and proliferation, is tightly regulated by multiple signaling pathways. While aberrant activation of beta-catenin signaling has been implicated in cancers, the biochemical identity of transcriptionally active beta catenin (ABC), commonly known as unphosphorylated serine 37 (S37) and threonine 41 (T41) beta-catenin, remains elusive. Our current study demonstrates that ABC transcriptional activity is influenced by phosphorylation of T120 by Protein Kinase D1 (PKD1). Whereas the nuclear beta-catenin from PKD1-low prostate cancer cell line C4-2 is unphosphorylated S37/T41/T120 with high transcription activity, the nuclear beta-catenin from PKD1-overexpressing C4-2 cells is highly phosphorylated at T120, S37 and T41 with low transcription activity, implying that accumulation of nuclear beta-catenin alone cannot be simply used as a read out for Wnt activation. In human normal prostate tissue, the phosphorylated T120 beta-catenin is mainly localized to the trans-Golgi network (TGN, 22/30, 73%), and this pattern is significantly altered in prostate cancer (14/197, 7.1%), which is consistent with known down regulation of PKD1 in prostate cancer. These in vitro and in vivo data unveil a previously unrecognized post-translational modification of ABC through T120 phosphorylation by PKD1, which alters subcellular localization and transcriptional activity of beta-catenin. Our results support the view that beta-catenin signaling activity is regulated by spatial compartmentation and post-translational modifications and protein level of beta-catenin alone is insufficient to count signaling activity. PMID- 22511928 TI - Analysis method and experimental conditions affect computed circadian phase from melatonin data. AB - Accurate determination of circadian phase is necessary for research and clinical purposes because of the influence of the master circadian pacemaker on multiple physiologic functions. Melatonin is presently the most accurate marker of the activity of the human circadian pacemaker. Current methods of analyzing the plasma melatonin rhythm can be grouped into three categories: curve-fitting, threshold-based and physiologically-based linear differential equations. To determine which method provides the most accurate assessment of circadian phase, we compared the ability to fit the data and the variability of phase estimates for seventeen different markers of melatonin phase derived from these methodological categories. We used data from three experimental conditions under which circadian rhythms - and therefore calculated melatonin phase - were expected to remain constant or progress uniformly. Melatonin profiles from older subjects and subjects with lower melatonin amplitude were less likely to be fit by all analysis methods. When circadian drift over multiple study days was algebraically removed, there were no significant differences between analysis methods of melatonin onsets (P = 0.57), but there were significant differences between those of melatonin offsets (P<0.0001). For a subset of phase assessment methods, we also examined the effects of data loss on variability of phase estimates by systematically removing data in 2-hour segments. Data loss near onset of melatonin secretion differentially affected phase estimates from the methods, with some methods incorrectly assigning phases too early while other methods assigning phases too late; missing data at other times did not affect analyses of the melatonin profile. We conclude that melatonin data set characteristics, including amplitude and completeness of data collection, differentially affect the results depending on the melatonin analysis method used. PMID- 22511930 TI - Global assessment of extinction risk to populations of Sockeye salmon Oncorhynchus nerka. AB - BACKGROUND: Concern about the decline of wild salmon has attracted the attention of the International Union for the Conservation of Nature (IUCN). The IUCN applies quantitative criteria to assess risk of extinction and publishes its results on the Red List of Threatened Species. However, the focus is on the species level and thus may fail to show the risk to populations. The IUCN has adapted their criteria to apply to populations but there exist few examples of this type of assessment. We assessed the status of sockeye salmon Oncorhynchus nerka as a model for application of the IUCN population-level assessments and to provide the first global assessment of the status of an anadromous Pacific salmon. METHODS/PRINCIPAL FINDINGS: We found from demographic data that the sockeye salmon species is not presently at risk of extinction. We identified 98 independent populations with varying levels of risk within the species' range. Of these, 5 (5%) are already extinct. We analyzed the risk for 62 out of 93 extant populations (67%) and found that 17 of these (27%) are at risk of extinction. The greatest number and concentration of extinct and threatened populations is in the southern part of the North American range, primarily due to overfishing, freshwater habitat loss, dams, hatcheries, and changing ocean conditions. CONCLUSIONS/SIGNIFICANCE: Although sockeye salmon are not at risk at the species level, about one-third of the populations that we analyzed are at risk or already extinct. Without an understanding of risk to biodiversity at the level of populations, the biodiversity loss in salmon would be greatly underrepresented on the Red List. We urge government, conservation organizations, scientists and the public to recognize this limitation of the Red List. We also urge recognition that about one-third of sockeye salmon global population diversity is at risk of extinction or already extinct. PMID- 22511929 TI - A genome-wide survey of switchgrass genome structure and organization. AB - The perennial grass, switchgrass (Panicum virgatum L.), is a promising bioenergy crop and the target of whole genome sequencing. We constructed two bacterial artificial chromosome (BAC) libraries from the AP13 clone of switchgrass to gain insight into the genome structure and organization, initiate functional and comparative genomic studies, and assist with genome assembly. Together representing 16 haploid genome equivalents of switchgrass, each library comprises 101,376 clones with average insert sizes of 144 (HindIII-generated) and 110 kb (BstYI-generated). A total of 330,297 high quality BAC-end sequences (BES) were generated, accounting for 263.2 Mbp (16.4%) of the switchgrass genome. Analysis of the BES identified 279,099 known repetitive elements, >50,000 SSRs, and 2,528 novel repeat elements, named switchgrass repetitive elements (SREs). Comparative mapping of 47 full-length BAC sequences and 330K BES revealed high levels of synteny with the grass genomes sorghum, rice, maize, and Brachypodium. Our data indicate that the sorghum genome has retained larger microsyntenous regions with switchgrass besides high gene order conservation with rice. The resources generated in this effort will be useful for a broad range of applications. PMID- 22511931 TI - BRCA1-IRIS overexpression promotes formation of aggressive breast cancers. AB - INTRODUCTION: Women with HER2(+) or triple negative/basal-like (TN/BL) breast cancers succumb to their cancer rapidly due, in part to acquired Herceptin resistance and lack of TN/BL-targeted therapies. BRCA1-IRIS is a recently discovered, 1399 residue, BRCA1 locus alternative product, which while sharing 1365 residues with the full-length product of this tumor suppressor gene, BRCA1/p220, it has oncoprotein-like properties. Here, we examine whether BRCA1 IRIS is a valuable treatment target for HER2(+) and/or TN/BL tumors. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemical staining of large cohort of human breast tumor samples using new monoclonal anti-BRCA1-IRIS antibody, followed by correlation of BRCA1-IRIS expression with that of AKT1, AKT2, p-AKT, survivin and BRCA1/p220, tumor status and age at diagnosis. Generation of subcutaneous tumors in SCID mice using human mammary epithelial (HME) cells overexpressing TERT/LT/BRCA1-IRIS, followed by comparing AKT, survivin, and BRCA1/p220 expression, tumor status and aggressiveness in these tumors to that in tumors developed using TERT/LT/Ras(V12)-overexpressing HME cells. Induction of primary and invasive rat mammary tumors using the carcinogen N-methyl-N nitrosourea (NMU), followed by analysis of rat BRCA1-IRIS and ERalpha mRNA levels in these tumors. High BRCA1-IRIS expression was detected in the majority of human breast tumors analyzed, which was positively correlated with that of AKT1-, AKT2 , p-AKT-, survivin, but negatively with BRCA1/p220 expression. BRCA1-IRIS positivity induced high-grade, early onset and metastatic HER2(+) or TN/BL tumors. TERT/LT/BRCA1-IRIS overexpressing HME cells formed invasive subcutaneous tumors that express high AKT1, AKT2, p-AKT and vimentin, but no CK19, p63 or BRCA1/p220. NMU-induced primary and invasive rat breast cancers expressed high levels of rat BRCA1-IRIS mRNA but low levels of rat ERalpha mRNA. CONCLUSION/SIGNIFICANCE: BRCA1-IRIS overexpression triggers aggressive breast tumor formation, especially in patients with HER2(+) or TN/BL subtypes. We propose that BRCA1-IRIS inhibition may be pursued as a novel therapeutic option to treat these aggressive breast tumor subtypes. PMID- 22511932 TI - Diagnosis of pancreatic ductal adenocarcinoma and chronic pancreatitis by measurement of microRNA abundance in blood and tissue. AB - A solid process for diagnosis could have a substantial impact on the successful treatment of pancreatic cancer, for which currently mortality is nearly identical to incidence. Variations in the abundance of all microRNA molecules from peripheral blood cells and pancreas tissues were analyzed on microarrays and in part validated by real-time PCR assays. In total, 245 samples from two clinical centers were studied that were obtained from patients with pancreatic ductal adenocarcinoma or chronic pancreatitis and from healthy donors. Utilizing the minimally invasive blood test, receiver operating characteristic (ROC) curves and the corresponding area under the curve (AUC) analysis demonstrated very high sensitivity and specificity of a distinction between healthy people and patients with either cancer or chronic pancreatitis; respective AUC values of 0.973 and 0.950 were obtained. Confirmative and partly even more discriminative diagnosis could be performed on tissue samples with AUC values of 1.0 and 0.937, respectively. In addition, discrimination between cancer and chronic pancreatitis was achieved (AUC = 0.875). Also, several miRNAs were identified that exhibited abundance variations in both tissue and blood samples. The results could have an immediate diagnostic value for the evaluation of tumor reoccurrence in patients, who have undergone curative surgical resection, and for people with a familial risk of pancreatic cancer. PMID- 22511933 TI - Causality in the association between P300 and alpha event-related desynchronization. AB - Recent findings indicated that both P300 and alpha event-related desynchronization (alpha-ERD) were associated, and similarly involved in cognitive brain functioning, e.g., attention allocation and memory updating. However, an explicit causal influence between the neural generators of P300 and alpha-ERD has not yet been investigated. In the present study, using an oddball task paradigm, we assessed the task effect (target vs. non-target) on P300 and alpha-ERD elicited by stimuli of four sensory modalities, i.e., audition, vision, somatosensory, and pain, estimated their respective neural generators, and investigated the information flow among their neural generators using time varying effective connectivity in the target condition. Across sensory modalities, the scalp topographies of P300 and alpha-ERD were similar and respectively maximal at parietal and occipital regions in the target condition. Source analysis revealed that P300 and alpha-ERD were mainly generated from posterior cingulate cortex and occipital lobe respectively. As revealed by time varying effective connectivity, the cortical information was consistently flowed from alpha-ERD sources to P300 sources in the target condition for all four sensory modalities. All these findings showed that P300 in the target condition is modulated by the changes of alpha-ERD, which would be useful to explore neural mechanism of cognitive information processing in the human brain. PMID- 22511934 TI - CD8 T-cell induction against vascular endothelial growth factor receptor 2 by Salmonella for vaccination purposes against a murine melanoma. AB - The Salmonella type III secretion system (T3SS) efficiently translocates heterologous proteins into the cytosol of eukaryotic cells. This leads to an antigen-specific CD8 T-cell induction in mice orally immunized with recombinant Salmonella. Recently, we have used Salmonella's T3SS as a prophylactic and therapeutic intervention against a murine fibrosarcoma. In this study, we constructed a recombinant Salmonella strain translocating the immunogenic H-2D(b) specific CD8 T-cell epitope VILTNPISM (KDR2) from the murine vascular endothelial growth factor receptor 2 (VEGFR2). VEGFR2 is a member of the tyrosine protein kinase family and is upregulated on proliferating endothelial cells of the tumor vasculature. After single orogastric vaccination, we detected significant numbers of KDR2-tetramer-positive CD8 T cells in the spleens of immunized mice. The efficacy of these cytotoxic T cells was evaluated in a prophylactic setting to protect mice from challenges with B16F10 melanoma cells in a flank tumor model, and to reduce dissemination of spontaneous pulmonary melanoma metastases. Vaccinated mice revealed a reduction of angiogenesis by 62% in the solid tumor and consequently a significant decrease of tumor growth as compared to non immunized mice. Moreover, in the lung metastasis model, immunization with recombinant Salmonella resulted in a reduction of the metastatic melanoma burden by approximately 60%. PMID- 22511935 TI - Most networks in Wagner's model are cycling. AB - In this paper we study a model of gene networks introduced by Andreas Wagner in the 1990s that has been used extensively to study the evolution of mutational robustness. We investigate a range of model features and parameters and evaluate the extent to which they influence the probability that a random gene network will produce a fixed point steady state expression pattern. There are many different types of models used in the literature, (discrete/continuous, sparse/dense, small/large network) and we attempt to put some order into this diversity, motivated by the fact that many properties are qualitatively the same in all the models. Our main result is that random networks in all models give rise to cyclic behavior more often than fixed points. And although periodic orbits seem to dominate network dynamics, they are usually considered unstable and not allowed to survive in previous evolutionary studies. Defining stability as the probability of fixed points, we show that the stability distribution of these networks is highly robust to changes in its parameters. We also find sparser networks to be more stable, which may help to explain why they seem to be favored by evolution. We have unified several disconnected previous studies of this class of models under the framework of stability, in a way that had not been systematically explored before. PMID- 22511936 TI - Junctional adhesion molecule 2 mediates the interaction between hatched blastocyst and luminal epithelium: induction by progesterone and LIF. AB - BACKGROUND: Junctional adhesion molecule 2 (Jam2) is a member of the JAM superfamily. JAMs are localized at intercellular contacts and participated in the assembly and maintenance of junctions, and control of cell permeability. Because Jam2 is highly expressed in the luminal epithelium on day 4 of pregnancy, this study was to determine whether Jam2 plays a role in uterine receptivity and blastocyst attachment in mouse uterus. METHODOLOGY/PRINCIPAL FINDINGS: Jam2 is highly expressed in the uterine luminal epithelium on days 3 and 4 of pregnancy. Progesterone induces Jam2 expression in ovariectomized mice, which is blocked by progesterone antagonist RU486. Jam2 expression on day 4 of pregnancy is also inhibited by RU486 treatment. Leukemia inhibitory factor (LIF) up-regulates Jam2 protein in isolated luminal epithelium from day 4 uterus, which is blocked by S3I 201, a cell-permeable inhibitor for Stat3 phosphorylation. Under adhesion assay, recombinant Jam2 protein increases the rate of blastocyst adhesion. Both soluble recombinant Jam2 and Jam3 can reverse this process. CONCLUSION: Jam2 is highly expressed in the luminal epithelium of receptive uterus and up-regulated by progesterone and LIF via tyrosine phosphorylation of Stat3. Jam2 may play a role in the interaction between hatched blastocyst and receptive uterus. PMID- 22511937 TI - Hepatitis C viral evolution in genotype 1 treatment-naive and treatment experienced patients receiving telaprevir-based therapy in clinical trials. AB - BACKGROUND: In patients with genotype 1 chronic hepatitis C infection, telaprevir (TVR) in combination with peginterferon and ribavirin (PR) significantly increased sustained virologic response (SVR) rates compared with PR alone. However, genotypic changes could be observed in TVR-treated patients who did not achieve an SVR. METHODS: Population sequence analysis of the NS3*4A region was performed in patients who did not achieve SVR with TVR-based treatment. RESULTS: Resistant variants were observed after treatment with a telaprevir-based regimen in 12% of treatment-naive patients (ADVANCE; T12PR arm), 6% of prior relapsers, 24% of prior partial responders, and 51% of prior null responder patients (REALIZE, T12PR48 arms). NS3 protease variants V36M, R155K, and V36M+R155K emerged frequently in patients with genotype 1a and V36A, T54A, and A156S/T in patients with genotype 1b. Lower-level resistance to telaprevir was conferred by V36A/M, T54A/S, R155K/T, and A156S variants; and higher-level resistance to telaprevir was conferred by A156T and V36M+R155K variants. Virologic failure during telaprevir treatment was more common in patients with genotype 1a and in prior PR nonresponder patients and was associated with higher-level telaprevir resistant variants. Relapse was usually associated with wild-type or lower-level resistant variants. After treatment, viral populations were wild-type with a median time of 10 months for genotype 1a and 3 weeks for genotype 1b patients. CONCLUSIONS: A consistent, subtype-dependent resistance profile was observed in patients who did not achieve an SVR with telaprevir-based treatment. The primary role of TVR is to inhibit wild-type virus and variants with lower-levels of resistance to telaprevir. The complementary role of PR is to clear any remaining telaprevir-resistant variants, especially higher-level telaprevir-resistant variants. Resistant variants are detectable in most patients who fail to achieve SVR, but their levels decline over time after treatment. PMID- 22511938 TI - Equilibrium of global amphibian species distributions with climate. AB - A common assumption in bioclimatic envelope modeling is that species distributions are in equilibrium with contemporary climate. A number of studies have measured departures from equilibrium in species distributions in particular regions, but such investigations were never carried out for a complete lineage across its entire distribution. We measure departures of equilibrium with contemporary climate for the distributions of the world amphibian species. Specifically, we fitted bioclimatic envelopes for 5544 species using three presence-only models. We then measured the proportion of the modeled envelope that is currently occupied by the species, as a metric of equilibrium of species distributions with climate. The assumption was that the greater the difference between modeled bioclimatic envelope and the occupied distribution, the greater the likelihood that species distribution would not be at equilibrium with contemporary climate. On average, amphibians occupied 30% to 57% of their potential distributions. Although patterns differed across regions, there were no significant differences among lineages. Species in the Neotropic, Afrotropics, Indo-Malay, and Palaearctic occupied a smaller proportion of their potential distributions than species in the Nearctic, Madagascar, and Australasia. We acknowledge that our models underestimate non equilibrium, and discuss potential reasons for the observed patterns. From a modeling perspective our results support the view that at global scale bioclimatic envelope models might perform similarly across lineages but differently across regions. PMID- 22511940 TI - The sex determination gene shows no founder effect in the giant honey bee, Apis dorsata. AB - BACKGROUND: All honey bee species (Apis spp) share the same sex determination mechanism using the complementary sex determination (csd) gene. Only individuals heterogeneous at the csd allele develop into females, and the homozygous develop into diploid males, which do not survive. The honeybees are therefore under selection pressure to generate new csd alleles. Previous studies have shown that the csd gene is under balancing selection. We hypothesize that due to the long separation from the mainland of Hainan Island, China, that the giant honey bees (Apis dorsata) should show a founder effect for the csd gene, with many different alleles clustered together, and these would be absent on the mainland. METHODOLOGY/PRINCIPAL FINDINGS: We sampled A. dorsata workers from both Hainan and Guangxi Provinces and then cloned and sequenced region 3 of the csd gene and constructed phylogenetic trees. We failed to find any clustering of the csd alleles according to their geographical origin, i.e. the Hainan and Guangxi samples did not form separate clades. Further analysis by including previously published csd sequences also failed to show any clade-forming in both the Philippines and Malaysia. CONCLUSIONS/SIGNIFICANCE: Results from this study and those from previous studies did not support the expectations of a founder effect. We conclude that because of the extremely high mating frequency of A. dorsata queens, a founder effect does not apply in this species. PMID- 22511939 TI - An equine herpesvirus type 1 (EHV-1) expressing VP2 and VP5 of serotype 8 bluetongue virus (BTV-8) induces protection in a murine infection model. AB - Bluetongue virus (BTV) can infect most species of domestic and wild ruminants causing substantial morbidity and mortality and, consequently, high economic losses. In 2006, an epizootic of BTV serotype 8 (BTV-8) started in northern Europe that caused significant disease in cattle and sheep before comprehensive vaccination was introduced two years later. Here, we evaluate the potential of equine herpesvirus type 1 (EHV-1), an alphaherpesvirus, as a novel vectored DIVA (differentiating infected from vaccinated animals) vaccine expressing VP2 of BTV 8 alone or in combination with VP5. The EHV-1 recombinant viruses stably expressed the transgenes and grew with kinetics that were identical to those of parental virus in vitro. After immunization of mice, a BTV-8-specific neutralizing antibody response was elicited. In a challenge experiment using a lethal dose of BTV-8, 100% of interferon-receptor-deficient (IFNAR(-/-)) mice vaccinated with the recombinant EHV-1 carrying both VP2 and VP5, but not VP2 alone, survived. VP7 was not included in the vectored vaccines and was successfully used as a DIVA marker. In summary, we show that EHV-1 expressing BTV 8 VP2 and VP5 is capable of eliciting a protective immune response that is distinguishable from that after infection and as such may be an alternative for BTV vaccination strategies in which DIVA compatibility is of importance. PMID- 22511941 TI - Expression of NADPH oxidase (NOX) 5 in rabbit corneal stromal cells. AB - PURPOSE: To determine whether NOX 5 is expressed in rabbit corneal stromal cells (RCSC). NADPH oxidases (NOXes) are enzymes that preferentially use NADPH as a substrate and generate superoxide. Several isoforms of NOXes function as multi protein complexes while NOX5 and DUOXs do not require the accessory proteins for their activity and possess calcium binding EF hands. METHODS: Human NOX5 primers were used to amplify the rabbit NOX5 by RT-PCR. Amplified product was sequenced to confirm its identity. The protein encoded by the NOX5 was identified by western blot analysis. NOX5 siRNA was used to reduce transcript, protein, and calcium stimulated activity. In silico analyses were performed to establish the putative structure, functions, and evolution of rabbit NOX5. RESULTS: NOX activity was measured in RCSC with NADPH rather than NADH as a substrate. RT-PCR with NOX5 primers amplified 288 bp product using RCSC cDNA, which, when sequenced, confirmed its identity to human NOX5 mRNA. This sequence was used to predict the rabbit (Oryctolagus cuniculus) NOX5 gene. NOX5 siRNA reduced amounts of NOX5 mRNA in RCSC and reduced ionomycin stimulated superoxide production. A protein of about 65 to 70 kDa encoded by the NOX5 was detected by western blot analysis. In silico analysis predicted a putative rabbit NOX5 protein containing 801 amino acids. Motif searches predicted the presence of at least 3 putative EF hands in N-terminus and a NOX domain in C terminal region. CONCLUSIONS: The data document that the NOX5 gene was expressed in cells of lagomorphs unlike rodents, making the rabbit an interesting model to study NOX5 functions. The activity of the rabbit NOX5 was calcium stimulated, a trait of NOX5 in general. NOX5 may also prove to be a useful genetic marker for studying the taxonomic position of lagomorphs and the Glires classification. PMID- 22511942 TI - Efficacy of short-term high-dose statin in preventing contrast-induced nephropathy: a meta-analysis of seven randomized controlled trials. AB - BACKGROUND: A few studies focused on statin therapy as specific prophylactic measures of contrast-induced nephropathy have been published with conflicting results. In this meta-analysis of randomized controlled trials, we aimed to assess the effectiveness of short-term high-dose statin treatment for the prevention of CIN and clinical outcomes and re-evaluate of the potential benefits of statin therapy. METHODS: We searched PubMed, OVID, EMBASE, Web of science and the Cochrane Central Register of Controlled Trials databases for randomized controlled trials comparing short-term high-dose statin treatment versus low-dose statin treatment or placebo for preventing CIN. Our outcome measures were the risk of CIN within 2-5 days after contrast administration and need for dialysis. RESULTS: Seven randomized controlled trials with a total of 1,399 patients were identified and analyzed. The overall results based on fixed-effect model showed that the use of short-term high-dose statin treatment was associated with a significant reduction in risk of CIN (RR =0.51, 95% CI 0.34-0.76, p =0.001; I(2) = 0%). The incidence of acute renal failure requiring dialysis was not significant different after the use of statin (RR = 0.33, 95% CI 0.05-2.10, p = 0.24; I(2) = 0%). The use of statin was not associated with a significant decrease in the plasma C-reactive protein level (SMD -0.64, 95% CI: -1.57 to 0.29, P = 0.18, I(2) = 97%). CONCLUSIONS: Although this meta-analysis supports the use of statin to reduce the incidence of CIN, it must be considered in the context of variable patient demographics. Only a limited recommendation can be made in favour of the use of statin based on current data. Considering the limitations of included studies, a large, well designed trial that incorporates the evaluation of clinically relevant outcomes in participants with different underlying risks of CIN is required to more adequately assess the role for statin in CIN prevention. PMID- 22511943 TI - Genome-wide DNA methylation scan in major depressive disorder. AB - While genome-wide association studies are ongoing to identify sequence variation influencing susceptibility to major depressive disorder (MDD), epigenetic marks, such as DNA methylation, which can be influenced by environment, might also play a role. Here we present the first genome-wide DNA methylation (DNAm) scan in MDD. We compared 39 postmortem frontal cortex MDD samples to 26 controls. DNA was hybridized to our Comprehensive High-throughput Arrays for Relative Methylation (CHARM) platform, covering 3.5 million CpGs. CHARM identified 224 candidate regions with DNAm differences >10%. These regions are highly enriched for neuronal growth and development genes. Ten of 17 regions for which validation was attempted showed true DNAm differences; the greatest were in PRIMA1, with 12-15% increased DNAm in MDD (p = 0.0002-0.0003), and a concomitant decrease in gene expression. These results must be considered pilot data, however, as we could only test replication in a small number of additional brain samples (n = 16), which showed no significant difference in PRIMA1. Because PRIMA1 anchors acetylcholinesterase in neuronal membranes, decreased expression could result in decreased enzyme function and increased cholinergic transmission, consistent with a role in MDD. We observed decreased immunoreactivity for acetylcholinesterase in MDD brain with increased PRIMA1 DNAm, non-significant at p = 0.08.While we cannot draw firm conclusions about PRIMA1 DNAm in MDD, the involvement of neuronal development genes across the set showing differential methylation suggests a role for epigenetics in the illness. Further studies using limbic system brain regions might shed additional light on this role. PMID- 22511944 TI - A biomechanical analysis of ventral furrow formation in the Drosophila melanogaster embryo. AB - The article provides a biomechanical analysis of ventral furrow formation in the Drosophila melanogaster embryo. Ventral furrow formation is the first large-scale morphogenetic movement in the fly embryo. It involves deformation of a uniform cellular monolayer formed following cellularisation, and has therefore long been used as a simple system in which to explore the role of mechanics in force generation. Here we use a quantitative framework to carry out a systematic perturbation analysis to determine the role of each of the active forces observed. The analysis confirms that ventral furrow invagination arises from a combination of apical constriction and apical-basal shortening forces in the mesoderm, together with a combination of ectodermal forces. We show that the mesodermal forces are crucial for invagination: the loss of apical constriction leads to a loss of the furrow, while the mesodermal radial shortening forces are the primary cause of the internalisation of the future mesoderm as the furrow rises. Ectodermal forces play a minor but significant role in furrow formation: without ectodermal forces the furrow is slower to form, does not close properly and has an aberrant morphology. Nevertheless, despite changes in the active mesodermal and ectodermal forces lead to changes in the timing and extent of furrow, invagination is eventually achieved in most cases, implying that the system is robust to perturbation and therefore over-determined. PMID- 22511945 TI - Interspecific hybridization increased in congeneric flatfishes after the Prestige oil spill. AB - Marine species with relatively low migratory capacity are threatened by habitat alterations derived from human activities. In November 2002 the tanker Prestige sank off the Spanish northwest coast releasing 70,000 tons of fuel and damaging biota in the area. Despite efforts to clean the damaged areas, fuel remnants have affected marine species over the last nine years. This study is focused on two flatfish, Lepidorhombus boscii (four-spotted megrim) and L. whiffiagonis (megrim), whose spawning areas are located at the edge of the continental platform. We have analyzed megrim samples from North Spanish and French waters obtained before and after the oil spill. Genotypes at the nuclear marker 5S rDNA indicate a significant increase in interspecific hybridization after the Prestige accident, likely due to forced spawning overlap. The mitochondrial D-Loop region was employed for determining the direction of hybrid crosses, which were most frequently L. boscii female x L. whiffiagonis male. Reduced ability of L. boscii females to select conspecific mates would explain such asymmetric hybridization. To our knowledge this is the first time that increased hybridization between fish species can be associated to an oil spill. These results illustrate the potential long-term effect of petrol wastes on wild fish species. PMID- 22511946 TI - Kokumi substances, enhancers of basic tastes, induce responses in calcium-sensing receptor expressing taste cells. AB - Recently, we reported that calcium-sensing receptor (CaSR) is a receptor for kokumi substances, which enhance the intensities of salty, sweet and umami tastes. Furthermore, we found that several gamma-glutamyl peptides, which are CaSR agonists, are kokumi substances. In this study, we elucidated the receptor cells for kokumi substances, and their physiological properties. For this purpose, we used Calcium Green-1 loaded mouse taste cells in lingual tissue slices and confocal microscopy. Kokumi substances, applied focally around taste pores, induced an increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)) in a subset of taste cells. These responses were inhibited by pretreatment with the CaSR inhibitor, NPS2143. However, the kokumi substance induced responses did not require extracellular Ca(2+). CaSR-expressing taste cells are a different subset of cells from the T1R3-expressing umami or sweet taste receptor cells. These observations indicate that CaSR-expressing taste cells are the primary detectors of kokumi substances, and that they are an independent population from the influenced basic taste receptor cells, at least in the case of sweet and umami. PMID- 22511947 TI - A directed RNAi screen based on larval growth arrest reveals new modifiers of C. elegans insulin signaling. AB - Genes regulating Caenorhabditis elegans insulin/IGF signaling (IIS) have largely been identified on the basis of their involvement in dauer development or longevity. A third IIS phenotype is the first larval stage (L1) diapause, which is also influenced by asna-1, a regulator of DAF-28/insulin secretion. We reasoned that new regulators of IIS strength might be identified in screens based on the L1 diapause and the asna-1 phenotype. Eighty- six genes were selected for analysis by virtue of their predicted interaction with ASNA-1 and screened for asna-1-like larval arrest. ykt-6, mrps-2, mrps-10 and mrpl-43 were identified as genes which, when inactivated, caused larval arrest without any associated feeding defects. Several tests indicated that IIS strength was weaker and that insulin secretion was defective in these animals. This study highlights the role of the Golgi network and the mitochondria in insulin secretion and provides a new list of genes that modulate IIS in C. elegans. PMID- 22511949 TI - Treatment of hepatitis C as prevention: a modeling case study in Vietnam. AB - BACKGROUND: Treatment of hepatitis C (HCV) is very effective, achieving a cure in 50-90% of patients. Besides its own good for individuals, this most likely translates in reduced transmission, but this phenomenon has yet to be fully explored. METHODS AND FINDINGS: In this mathematical modeling study done in the context of Vietnam, we estimated the public health benefit that HCV therapy for injecting drug users (IDUs) may achieve. Treatment coverage of 25, 50 and 75% of chronically HCV-infected IDUs (4 years into infection) is predicted to reduce the chronic HCV viremia prevalence respectively by 21, 37 and 50%, 11 years after full scale up to the intended coverage. At a constant 50% coverage level, earlier treatment, 3, 2, and 1 year into infection is predicted to reduce the chronic HCV viremia prevalence by 46, 60 and 85%. In these later 3 scenarios, for every 100 treatment courses provided, a total of respectively 50, 61 and 94 new infections could be averted. These benefits were projected in the context of current low coverage of methadone maintenance therapy and needles/syringes exchange programs, and these services expansion showed complementary preventive benefits to HCV therapy. The program treatment commitment associated with the various scenarios is deemed reasonable. Our model projections are robust under adjustment for uncertainty in the model parameter values. CONCLUSIONS: In this case study in Vietnam, we project that treatment of HCV for injecting drug users will have a preventative herd effect in addition to curing patients in need for therapy, achieving a substantial reduction in HCV transmission and prevalence. PMID- 22511948 TI - MicroRNA dysregulation in the spinal cord following traumatic injury. AB - Spinal cord injury (SCI) triggers a multitude of pathophysiological events that are tightly regulated by the expression levels of specific genes. Recent studies suggest that changes in gene expression following neural injury can result from the dysregulation of microRNAs, short non-coding RNA molecules that repress the translation of target mRNA. To understand the mechanisms underlying gene alterations following SCI, we analyzed the microRNA expression patterns at different time points following rat spinal cord injury.The microarray data reveal the induction of a specific microRNA expression pattern following moderate contusive SCI that is characterized by a marked increase in the number of down regulated microRNAs, especially at 7 days after injury. MicroRNA downregulation is paralleled by mRNA upregulation, strongly suggesting that microRNAs regulate transcriptional changes following injury. Bioinformatic analyses indicate that changes in microRNA expression affect key processes in SCI physiopathology, including inflammation and apoptosis. MicroRNA expression changes appear to be influenced by an invasion of immune cells at the injury area and, more importantly, by changes in microRNA expression specific to spinal cord cells. Comparisons with previous data suggest that although microRNA expression patterns in the spinal cord are broadly similar among vertebrates, the results of studies assessing SCI are much less congruent and may depend on injury severity. The results of the present study demonstrate that moderate spinal cord injury induces an extended microRNA downregulation paralleled by an increase in mRNA expression that affects key processes in the pathophysiology of this injury. PMID- 22511952 TI - Seed mucilage improves seedling emergence of a sand desert shrub. AB - The success of seedling establishment of desert plants is determined by seedling emergence response to an unpredictable precipitation regime. Sand burial is a crucial and frequent environmental stress that impacts seedling establishment on sand dunes. However, little is known about the ecological role of seed mucilage in seedling emergence in arid sandy environments. We hypothesized that seed mucilage enhances seedling emergence in a low precipitation regime and under conditions of sand burial. In a greenhouse experiment, two types of Artemisia sphaerocephala achenes (intact and demucilaged) were exposed to different combinations of burial depth (0, 5, 10, 20, 40 and 60 mm) and irrigation regimes (low, medium and high, which simulated the precipitation amount and frequency in May, June and July in the natural habitat, respectively). Seedling emergence increased with increasing irrigation. It was highest at 5 mm sand burial depth and ceased at burial depths greater than 20 mm in all irrigation regimes. Mucilage significantly enhanced seedling emergence at 0, 5 and 10 mm burial depths in low irrigation, at 0 and 5 mm burial depths in medium irrigation and at 0 and 10 mm burial depths in high irrigation. Seed mucilage also reduced seedling mortality at the shallow sand burial depths. Moreover, mucilage significantly affected seedling emergence time and quiescence and dormancy percentages. Our findings suggest that seed mucilage plays an ecologically important role in successful seedling establishment of A. sphaerocephala by improving seedling emergence and reducing seedling mortality in stressful habitats of the sandy desert environment. PMID- 22511951 TI - Subgroup economic analysis for glioblastoma in a health resource-limited setting. AB - BACKGROUND: The aim of this research was to evaluate the economic outcomes of radiotherapy (RT), temozolomide (TMZ) and nitrosourea (NT) strategies for glioblastoma patients with different prognostic factors. METHODOLOGY/PRINCIPAL FINDINGS: A Markov model was developed to track monthly patient transitions. Transition probabilities and utilities were derived primarily from published reports. Costs were estimated from the perspective of the Chinese healthcare system. The survival data with different prognostic factors were simulated using Weibull survival models. Costs over a 5-year period and quality-adjusted life years (QALYs) were estimated. Probabilistic sensitivity and one-way analyses were performed. The baseline analysis in the overall cohort showed that the TMZ strategy increased the cost and QALY relative to the RT strategy by $25,328.4 and 0.29, respectively; and the TMZ strategy increased the cost and QALY relative to the NT strategy by $23,906.5 and 0.25, respectively. Therefore, the incremental cost effectiveness ratio (ICER) per additional QALY of the TMZ strategy, relative to the RT strategy and the NT strategy, amounts to $87,940.6 and $94,968.3, respectively. Subgroups with more favorable prognostic factors achieved more health benefits with improved ICERs. Probabilistic sensitivity analyses confirmed that the TMZ strategy was not cost-effective. In general, the results were most sensitive to the cost of TMZ, which indicates that better outcomes could be achieved by decreasing the cost of TMZ. CONCLUSIONS/SIGNIFICANCE: In health resource-limited settings, TMZ is not a cost-effective option for glioblastoma patients. Selecting patients with more favorable prognostic factors increases the likelihood of cost-effectiveness. PMID- 22511950 TI - Focused examination of the intestinal lamina propria yields greater molecular insight into mechanisms underlying SIV induced immune dysfunction. AB - BACKGROUND: The Gastrointestinal (GI) tract is critical to AIDS pathogenesis as it is the primary site for viral transmission and a major site of viral replication and CD4(+) T cell destruction. Consequently GI disease, a major complication of HIV/SIV infection can facilitate translocation of lumenal bacterial products causing localized/systemic immune activation leading to AIDS progression. METHODOLOGY/PRINCIPAL FINDINGS: To better understand the molecular mechanisms underlying GI disease we analyzed global gene expression profiles sequentially in the intestine of the same animals prior to and at 21 and 90d post SIV infection (PI). More importantly we maximized information gathering by examining distinct mucosal components (intraepithelial lymphocytes, lamina propria leukocytes [LPL], epithelium and fibrovascular stroma) separately. The use of sequential intestinal resections combined with focused examination of distinct mucosal compartments represents novel approaches not previously attempted. Here we report data pertaining to the LPL. A significant increase (+/ 1.7-fold) in immune defense/inflammation, cell adhesion/migration, cell signaling, transcription and cell division/differentiation genes were observed at 21 and 90d PI. Genes associated with the JAK-STAT pathway (IL21, IL12R, STAT5A, IL10, SOCS1) and T-cell activation (NFATc1, CDK6, Gelsolin, Moesin) were notably upregulated at 21d PI. Markedly downregulated genes at 21d PI included IL17D/IL27 and IL28B/IFNgamma3 (anti-HIV/viral), activation induced cytidine deaminase (B cell function) and approximately 57 genes regulating oxidative phosphorylation, a critical metabolic shift associated with T-cell activation. The 90d transcriptome revealed further augmentation of inflammation (CXCL11, chitinase-1, JNK3), immune activation (CD38, semaphorin7A, CD109), B-cell dysfunction (CD70), intestinal microbial translocation (Lipopolysaccharide binding protein) and mitochondrial antiviral signaling (NLRX1) genes. Reduced expression of CD28, CD4, CD86, CD93, NFATc1 (T-cells), TLR8, IL8, CCL18, DECTIN1 (macrophages), HLA-DOA and GPR183 (B cells) at 90d PI suggests further deterioration of overall immune function. CONCLUSIONS/SIGNIFICANCE: The reported transcriptional signatures provide significant new details on the molecular pathology of HIV/SIV induced GI disease and provide new opportunity for future investigation. PMID- 22511953 TI - Phylogeography of the endangered Otago skink, Oligosoma otagense: population structure, hybridisation and genetic diversity in captive populations. AB - Climatic cooling and substantial tectonic activity since the late Miocene have had a pronounced influence on the evolutionary history of the fauna of New Zealand's South Island. However, many species have recently experienced dramatic range reductions due to habitat fragmentation and the introduction of mammalian predators and competitors. These anthropogenic impacts have been particularly severe in the tussock grasslands of the Otago region. The Otago skink (Oligosoma otagense), endemic to the region, is one of the most critically endangered vertebrates in New Zealand. We use mitochondrial DNA sequence data to investigate the evolutionary history of the Otago skink, examine its population genetic structure, and assess the level of genetic diversity in the individuals in the captive breeding program. Our data indicate that the Otago skink diverged from its closest relatives in the Miocene, consistent with the commencement of tectonic uplift of the Southern Alps. However, there is evidence for past introgression with the scree skink (O. waimatense) in the northern Otago-southern Canterbury region. The remnant populations in eastern Otago and western Otago are estimated to have diverged in the mid-Pliocene, with no haplotypes shared between these two regions. This divergence accounts for 95% of the genetic diversity in the species. Within both regions there is strong genetic structure among populations, although shared haplotypes are generally evident between adjacent localities. Although substantial genetic diversity is present in the captive population, all individuals originate from the eastern region and the majority had haplotypes that were not evident in the intensively managed populations at Macraes Flat. Our data indicate that eastern and western populations should continue to be regarded as separate management units. Knowledge of the genetic diversity of the breeding stock will act to inform the captive management of the Otago skink and contribute to a key recovery action for the species. PMID- 22511955 TI - Delayed toxicity associated with soluble anthrax toxin receptor decoy-Ig fusion protein treatment. AB - Soluble receptor decoy inhibitors, including receptor-immunogloubulin (Ig) fusion proteins, have shown promise as candidate anthrax toxin therapeutics. These agents act by binding to the receptor-interaction site on the protective antigen (PA) toxin subunit, thereby blocking toxin binding to cell surface receptors. Here we have made the surprising observation that co-administration of receptor decoy-Ig fusion proteins significantly delayed, but did not protect, rats challenged with anthrax lethal toxin. The delayed toxicity was associated with the in vivo assembly of a long-lived complex comprised of anthrax lethal toxin and the receptor decoy-Ig inhibitor. Intoxication in this system presumably results from the slow dissociation of the toxin complex from the inhibitor following their prolonged circulation. We conclude that while receptor decoy-Ig proteins represent promising candidates for the early treatment of B. anthracis infection, they may not be suitable for therapeutic use at later stages when fatal levels of toxin have already accumulated in the bloodstream. PMID- 22511954 TI - The role of SDF-1-CXCR4/CXCR7 axis in the therapeutic effects of hypoxia preconditioned mesenchymal stem cells for renal ischemia/reperfusion injury. AB - In vitro hypoxic preconditioning (HP) of mesenchymal stem cells (MSCs) could ameliorate their viability and tissue repair capabilities after transplantation into the injured tissue through yet undefined mechanisms. There is also experimental evidence that HP enhances the expression of both stromal-derived factor-1 (SDF-1) receptors, CXCR4 and CXCR7, which are involved in migration and survival of MSCs in vitro, but little is known about their role in the in vivo therapeutic effectiveness of MSCs in renal ischemia/reperfusion (I/R) injury. Here, we evaluated the role of SDF-1-CXCR4/CXCR7 pathway in regulating chemotaxis, viability and paracrine actions of HP-MSCs in vitro and in vivo. Compared with normoxic preconditioning (NP), HP not only improved MSC chemotaxis and viability but also stimulated secretion of proangiogenic and mitogenic factors. Importantly, both CXCR4 and CXCR7 were required for the production of paracrine factors by HP-MSCs though the former was only responsible for chemotaxis while the latter was for viability. SDF-1alpha expression was upregulated in postischemic kidneys. After 24 h systemical administration following I/R, HP-MSCs but not NP-MSCs were selectively recruited to ischemic kidneys and this improved recruitment was abolished by neutralization of CXCR4, but not CXCR7. Furthermore, the increased recruitment of HP-MSCs was associated with enhanced functional recovery, accelerated mitogenic response, and reduced apoptotic cell death. In addition, neutralization of either CXCR4 or CXCR7 impaired the improved therapeutic potential of HP-MSCs. These results advance our knowledge about SDF-1-CXCR4/CXCR7 axis as an attractive target pathway for improving the beneficial effects of MSC-based therapies for renal I/R. PMID- 22511956 TI - Non-agonistic bivalent antibodies that promote c-MET degradation and inhibit tumor growth and others specific for tumor related c-MET. AB - The c-MET receptor has a function in many human cancers and is a proven therapeutic target. Generating antagonistic or therapeutic monoclonal antibodies (mAbs) targeting c-MET has been difficult because bivalent, intact anti-Met antibodies frequently display agonistic activity, necessitating the use of monovalent antibody fragments for therapy. By using a novel strategy that included immunizing with cells expressing c-MET, we obtained a range of mAbs. These c-MET mAbs were tested for binding specificity and anti-tumor activity using a range of cell-based techniques and in silico modeling. The LMH 80 antibody bound an epitope, contained in the small cysteine-rich domain of c-MET (amino acids 519-561), that was preferentially exposed on the c-MET precursor. Since the c-MET precursor is only expressed on the surface of cancer cells and not normal cells, this antibody is potentially tumor specific. An interesting subset of our antibodies displayed profound activities on c-MET internalization and degradation. LMH 87, an antibody binding the loop connecting strands 3d and 4a of the 7-bladed beta-propeller domain of c-MET, displayed no intrinsic agonistic activity but promoted receptor internalization and degradation. LMH 87 inhibited HGF/SF-induced migration of SK-OV-3 ovarian carcinoma cells, the proliferation of A549 lung cancer cells and the growth of human U87MG glioma cells in a mouse xenograft model. These results indicate that c-MET antibodies targeting epitopes controlling receptor internalization and degradation provide new ways of controlling c-MET expression and activity and may enable the therapeutic targeting of c-MET by intact, bivalent antibodies. PMID- 22511957 TI - Analyses of the large subunit histidine-rich motif expose an alternative proton transfer pathway in [NiFe] hydrogenases. AB - A highly conserved histidine-rich region with unknown function was recognized in the large subunit of [NiFe] hydrogenases. The HxHxxHxxHxH sequence occurs in most membrane-bound hydrogenases, but only two of these histidines are present in the cytoplasmic ones. Site-directed mutagenesis of the His-rich region of the T. roseopersicina membrane-attached Hyn hydrogenase disclosed that the enzyme activity was significantly affected only by the replacement of the His104 residue. Computational analysis of the hydrogen bond network in the large subunits indicated that the second histidine of this motif might be a component of a proton transfer pathway including Arg487, Asp103, His104 and Glu436. Substitutions of the conserved amino acids of the presumed transfer route impaired the activity of the Hyn hydrogenase. Western hybridization was applied to demonstrate that the cellular level of the mutant hydrogenases was similar to that of the wild type. Mostly based on theoretical modeling, few proton transfer pathways have already been suggested for [NiFe] hydrogenases. Our results propose an alternative route for proton transfer between the [NiFe] active center and the surface of the protein. A novel feature of this model is that this proton pathway is located on the opposite side of the large subunit relative to the position of the small subunit. This is the first study presenting a systematic analysis of an in silico predicted proton translocation pathway in [NiFe] hydrogenases by site directed mutagenesis. PMID- 22511958 TI - Immunoregulatory mechanisms underlying prevention of colitis-associated colorectal cancer by probiotic bacteria. AB - BACKGROUND: Inflammatory bowel disease (IBD) increases the risk of colorectal cancer. Probiotic bacteria produce immunoregulatory metabolites in vitro such as conjugated linoleic acid (CLA), a polyunsaturated fatty acid with potent anti carcinogenic effects. This study aimed to investigate the cellular and molecular mechanisms underlying the efficacy of probiotic bacteria in mouse models of cancer. METHODOLOGY/PRINCIPAL FINDINGS: The immune modulatory mechanisms of VSL#3 probiotic bacteria and CLA were investigated in mouse models of inflammation driven colorectal cancer. Colonic specimens were collected for histopathology, gene expression and flow cytometry analyses. Immune cell subsets in the mesenteric lymph nodes (MLN), spleen and colonic lamina propria lymphocytes (LPL) were phenotypically and functionally characterized. Mice treated with CLA or VSL#3 recovered faster from the acute inflammatory phase of disease and had lower disease severity in the chronic, tumor-bearing phase of disease. Adenoma and adenocarcinoma formation was also diminished by both treatments. VSL#3 increased the mRNA expression of TNF-alpha, angiostatin and PPAR gamma whereas CLA decreased COX-2 levels. Moreover, VSL#3-treated mice had increased IL-17 expression in MLN CD4+ T cells and accumulation of Treg LPL and memory CD4+ T cells. CONCLUSIONS/SIGNIFICANCE: Both CLA and VSL#3 suppressed colon carcinogenesis, although VSL#3 showed greater anti-carcinogenic and anti inflammatory activities than CLA. Mechanistically, CLA modulated expression of COX-2 levels in the colonic mucosa, whereas VSL#3 targeted regulatory mucosal CD4+ T cell responses. PMID- 22511959 TI - A mid-cretaceous origin of sociality in xylocopine bees with only two origins of true worker castes indicates severe barriers to eusociality. AB - The origin of sterile worker castes, resulting in eusociality, represents one of the major evolutionary transitions in the history of life. Understanding how eusociality has evolved is therefore an important issue for understanding life on earth. Here we show that in the large bee subfamily Xylocopinae, a simple form of sociality was present in the ancestral lineage and there have been at least four reversions to purely solitary nesting. The ancestral form of sociality did not involve morphological worker castes and maximum colony sizes were very small. True worker castes, entailing a life-time commitment to non-reproductive roles, have evolved only twice, and only one of these resulted in discrete queen-worker morphologies. Our results indicate extremely high barriers to the evolution of eusociality. Its origins are likely to have required very unusual life-history and ecological circumstances, rather than the amount of time that selection can operate on more simple forms of sociality. PMID- 22511960 TI - Anthropomorphic measurements that include central fat distribution are more closely related with key risk factors than BMI in CKD stage 3. AB - BACKGROUND: Body Mass Index (BMI) as a marker of obesity is an established risk factor for chronic kidney disease (CKD) and cardiovascular disease (CVD). However, BMI can overestimate obesity. Anthropomorphic measurements that include central fat deposition are emerging as a more important risk factor. We studied BMI, waist circumference (WC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR) and conicity index (CI) in a cohort of patients with CKD stage 3 and compared the associations with other known risk factors for CKD progression and CVD. METHODS: 1740 patients with CKD stage 3 were recruited from primary care for the Renal Risk in Derby study. Each participant underwent clinical assessment, including anthropomorphic measurements and pulse wave velocity (PWV), as well as urine and serum biochemistry tests. RESULTS: The mean age of the cohort was 72.9+/-9 years with 60% females. The mean eGFR was 52.5+/-10.4 ml/min/1.73 m(2) and 16.9% of the cohort had diabetes. With the cohort divided into normal and increased risk of morbidity and mortality using each anthropomorphic measurement, those measurements that included increased central fat distribution were significantly associated with more risk factors for CKD progression and CVD than increased BMI. Univariable analysis demonstrated central fat distribution was correlated with more risk factors than BMI. Subgroup analyses using recognised BMI cut-offs to define obesity and quartiles of WHR and CI demonstrated that increasing central fat distribution was significantly associated with more CKD and CVD risk factors than increasing BMI. CONCLUSION: Anthropomorphic measurements that include a measure of central fat deposition are related to more key risk factors in CKD stage 3 patients than BMI. Central fat deposition may be of greater importance as a risk factor in CKD than BMI and reliance on BMI alone may therefore underestimate the associated risk. PMID- 22511961 TI - Nkx3.2 promotes primary chondrogenic differentiation by upregulating Col2a1 transcription. AB - BACKGROUND: The Nkx3.2 transcription factor promotes chondrogenesis by forming a positive regulatory loop with a crucial chondrogenic transcription factor, Sox9. Previous studies have indicated that factors other than Sox9 may promote chondrogenesis directly, but these factors have not been identified. Here, we test the hypothesis that Nkx3.2 promotes chondrogenesis directly by Sox9 independent mechanisms and indirectly by previously characterized Sox9-dependent mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: C3H10T1/2 pluripotent mesenchymal cells were cultured with bone morphogenetic protein 2 (BMP2) to induce endochondral ossification. Overexpression of wild-type Nkx3.2 (WT-Nkx3.2) upregulated glycosaminoglycan (GAG) production and expression of type II collagen alpha1 (Col2a1) mRNA, and these effects were evident before WT-Nkx3.2-mediated upregulation of Sox9. RNAi-mediated inhibition of Nkx3.2 abolished GAG production and expression of Col2a1 mRNA. Dual luciferase reporter assays revealed that WT Nkx3.2 upregulated Col2a1 enhancer activity in a dose-dependent manner in C3H10T1/2 cells and also in N1511 chondrocytes. In addition, WT-Nkx3.2 partially restored downregulation of GAG production, Col2 protein expression, and Col2a1 mRNA expression induced by Sox9 RNAi. ChIP assays revealed that Nkx3.2 bound to the Col2a1 enhancer element. CONCLUSIONS/SIGNIFICANCE: Nkx3.2 promoted primary chondrogenesis by two mechanisms: Direct and Sox9-independent upregulation of Col2a1 transcription and upregulation of Sox9 mRNA expression under positive feedback system. PMID- 22511962 TI - Excitability and synaptic alterations in the cerebellum of APP/PS1 mice. AB - In Alzheimer's disease (AD), the severity of cognitive symptoms is better correlated with the levels of soluble amyloid-beta (Abeta) rather than with the deposition of fibrillar Abeta in amyloid plaques. In APP/PS1 mice, a murine model of AD, at 8 months of age the cerebellum is devoid of fibrillar Abeta, but dosage of soluble Abeta(1-42), the form which is more prone to aggregation, showed higher levels in this structure than in the forebrain. Aim of this study was to investigate the alterations of intrinsic membrane properties and of synaptic inputs in Purkinje cells (PCs) of the cerebellum, where only soluble Abeta is present. PCs were recorded by whole-cell patch-clamp in cerebellar slices from wild-type and APP/PS1 mice. In APP/PS1 PCs, evoked action potential discharge showed enhanced frequency adaptation and larger afterhyperpolarizations, indicating a reduction of the intrinsic membrane excitability. In the miniature GABAergic postsynaptic currents, the largest events were absent in APP/PS1 mice and the interspike intervals distribution was shifted to the left, but the mean amplitude and frequency were normal. The ryanodine-sensitive multivescicular release was not altered and the postsynaptic responsiveness to a GABA(A) agonist was intact. Climbing fiber postsynaptic currents were normal but their short-term plasticity was reduced in a time window of 100-800 ms. Parallel fiber postsynaptic currents and their short-term plasticity were normal. These results indicate that, in the cerebellar cortex, chronically elevated levels of soluble Abeta(1-42) are associated with alterations of the intrinsic excitability of PCs and with alterations of the release of GABA from interneurons and of glutamate from climbing fibers, while the release of glutamate from parallel fibers and all postsynaptic mechanisms are preserved. Thus, soluble Abeta(1-42) causes, in PCs, multiple functional alterations, including an impairment of intrinsic membrane properties and synapse-specific deficits, with differential consequences even in different subtypes of glutamatergic synapses. PMID- 22511963 TI - MicroRNA159 can act as a switch or tuning microRNA independently of its abundance in Arabidopsis. AB - The efficacy of gene silencing by plant microRNAs (miRNAs) is generally assumed to be predominantly determined by their abundance. In Arabidopsis the highly abundant miRNA, miR159, acts as a molecular "switch" in vegetative tissues completely silencing the expression of two GAMYB-like genes, MYB33 and MYB65. Here, we show that miR159 has a diminished silencing efficacy in the seed. Using reporter gene constructs, we determined that MIR159 and MYB33 are co-transcribed in the aleurone and embryo of germinating seeds. However in contrast to vegetative tissues, MYB33 is not completely silenced. Instead, miR159 appears to shape the spatio-temporal expression pattern of MYB33 during seed germination. Transcript profiling in a time course during seed germination in wild-type and a mir159 mutant in which miR159 is almost absent, revealed that transcript levels of the GAMYB-like genes were similar between these two genotypes during germination, but much higher in the mir159 mutant once germination had completed. This attenuation in the silencing of the GAMYB-like genes was not explained by a decrease in mature miR159 levels, which remained constant at all time points during seed germination. We propose that miR159 acts as a tuner of GAMYB-like levels in Arabidopsis germinating seeds and that the activity of this miRNA is attenuated in the seed compared to vegetative tissues. This implies that the efficacy of miRNA-mediated silencing is not solely determined by miRNA abundance and target transcript levels, but is being determined through additional mechanisms. PMID- 22511964 TI - Characterization of an IncFII plasmid encoding NDM-1 from Escherichia coli ST131. AB - BACKGROUND: The current spread of the gene encoding the metallo-beta-lactamase NDM-1 in Enterobacteriaceae is linked to a variety of surrounding genetic structures and plasmid scaffolds. METHODOLOGY: The whole sequence of plasmid pGUE NDM carrying the bla(NDM-1) gene was determined by high-density pyrosequencing and a genomic comparative analysis with other bla(NDM-1)-negative IncFII was performed. PRINCIPAL FINDINGS: Plasmid pGUE-NDM replicating in Escherichia coli confers resistance to many antibiotic molecules including beta-lactams, aminoglycosides, trimethoprim, and sulfonamides. It is 87,022 bp in-size and carries the two beta-lactamase genes bla(NDM-1) and bla(OXA-1), together with three aminoglycoside resistance genes aacA4, aadA2, and aacC2. Comparative analysis of the multidrug resistance locus contained a module encompassing the bla(NDM-1) gene that is actually conserved among different structures identified in other enterobacterial isolates. This module was constituted by the bla(NDM-1) gene, a fragment of insertion sequence ISAba125 and a bleomycin resistance encoding gene. SIGNIFICANCE: This is the first characterized bla(NDM-1)-carrying IncFII-type plasmid. Such association between the bla(NDM-1) gene and an IncFII type plasmid backbone is extremely worrisome considering that this plasmid type is known to spread efficiently, as examplified with the worldwide dissemination of bla(CTX-M-15)-borne IncFII plasmids. PMID- 22511965 TI - The genealogic tree of mycobacteria reveals a long-standing sympatric life into free-living protozoa. AB - Free-living protozoa allow horizontal gene transfer with and between the microorganisms that they host. They host mycobacteria for which the sources of transferred genes remain unknown. Using BLASTp, we searched within the genomes of 15 mycobacteria for homologous genes with 34 amoeba-resistant bacteria and the free-living protozoa Dictyostelium discoideum. Subsequent phylogenetic analysis of these sequences revealed that eight mycobacterial open-reading frames (ORFs) were probably acquired via horizontal transfer from beta- and gamma Proteobacteria and from Firmicutes, but the transfer histories could not be reliably established in details. One further ORF encoding a pyridine nucleotide disulfide oxidoreductase (pyr-redox) placed non-tuberculous mycobacteria in a clade with Legionella spp., Francisella spp., Coxiella burnetii, the ciliate Tetrahymena thermophila and D. discoideum with a high reliability. Co-culturing Mycobacterium avium and Legionella pneumophila with the amoeba Acanthamoeba polyphaga demonstrated that these two bacteria could live together in amoebae for five days, indicating the biological relevance of intra-amoebal transfer of the pyr-redox gene. In conclusion, the results of this study support the hypothesis that protists can serve as a source and a place for gene transfer in mycobacteria. PMID- 22511966 TI - SIRT2 ablation has no effect on tubulin acetylation in brain, cholesterol biosynthesis or the progression of Huntington's disease phenotypes in vivo. AB - Huntington's disease (HD) is a devastating neurodegenerative disorder for which there are no disease-modifying treatments. The molecular pathogenesis of HD is complex and many mechanisms and cellular processes have been proposed as potential sites of therapeutic intervention. However, prior to embarking on drug development initiatives, it is essential that therapeutic targets can be validated in mammalian models of HD. Previous studies in invertebrate and cell culture HD models have suggested that inhibition of SIRT2 could have beneficial consequences on disease progression. SIRT2 is a NAD(+)-dependent deacetylase that has been proposed to deacetylate alpha-tubulin, histone H4 K16 and to regulate cholesterol biogenesis - a pathway which is dysregulated in HD patients and HD mouse models. We have utilized mice in which SIRT2 has been reduced or ablated to further explore the function of SIRT2 and to assess whether SIRT2 loss has a beneficial impact on disease progression in the R6/2 mouse model of HD. Surprisingly we found that reduction or loss of SIRT2 had no effect on the acetylation of alpha-tubulin or H4K16 or on cholesterol biosynthesis in the brains of wild type mice. Equally, genetic reduction or ablation of SIRT2 had no effect on HD progression as assessed by a battery of physiological and behavioural tests. Furthermore, we observed no change in aggregate load or levels of soluble mutant huntingtin transprotein. Intriguingly, neither the constitutive genetic loss nor acute pharmacological inhibition of SIRT2 affected the expression of cholesterol biosynthesis enzymes in the context of HD. Therefore, we conclude that SIRT2 inhibition does not modify disease progression in the R6/2 mouse model of HD and SIRT2 inhibition should not be prioritised as a therapeutic option for HD. PMID- 22511967 TI - Potential role of aromatase over estrogen receptor gene polymorphisms in migraine susceptibility: a case control study from North India. AB - BACKGROUND: The present study was undertaken to find out the role of estrogen pathway related gene polymorphisms in susceptibility to migraine in Northern Indian population. Aromatase, CYP19A1 (rs10046 and rs4646); estrogen receptors, ESR1 (rs2234693, rs1801132, rs2228480 and rs9340799) and ESR2 (rs1271572 and rs1256049) polymorphisms were selected for the present study. METHODOLOGY/PRINCIPAL FINDINGS: The patients were recruited in two cohorts - primary (207) and replicative (127) along with 200 healthy controls and genotyped for various polymorphisms. Logistic regression analysis was applied for statistical analyses. The results were validated in the replicative cohort and pooled by meta analysis using Fisher's and Mantel-Haenszel test. Furthermore, Benjamini - Hochberg false discovery rate test was used to correct for multiple comparisons. CYP19A1 rs10046 and CYP19A1 rs4646 polymorphisms were found to confer risk and protective effect, respectively. Out of four ESR1 polymorphisms, only rs2234693 variant allele was significantly associated in migraine with aura. No significant associations were observed for ESR2 polymorphisms. Significant haplotypes were identified for CYP19A1 and ESR1 polymorphisms. Gene- gene interactions of genotypes as well as haplotypes were observed for CYP19A1- ESR1 showing both risk and protective combinations. CONCLUSION: We strongly suggest CYP19A1 polymorphisms to be the major contributing factors in migraine susceptibility instead of genetic variants of estrogen receptors. PMID- 22511968 TI - Twenty-two years of warming, fertilisation and shading of subarctic heath shrubs promote secondary growth and plasticity but not primary growth. AB - Most manipulation experiments simulating global change in tundra were short-term or did not measure plant growth directly. Here, we assessed the growth of three shrubs (Cassiope tetragona, Empetrum hermaphroditum and Betula nana) at a subarctic heath in Abisko (Northern Sweden) after 22 years of warming (passive greenhouses), fertilisation (nutrients addition) and shading (hessian fabric), and compare this to observations from the first decade of treatment. We assessed the growth rate of current-year leaves and apical stem (primary growth) and cambial growth (secondary growth), and integrated growth rates with morphological measurements and species coverage. Primary- and total growth of Cassiope and Empetrum were unaffected by manipulations, whereas growth was substantially reduced under fertilisation and shading (but not warming) for Betula. Overall, shrub height and length tended to increase under fertilisation and warming, whereas branching increased mostly in shaded Cassiope. Morphological changes were coupled to increased secondary growth under fertilisation. The species coverage showed a remarkable increase in graminoids in fertilised plots. Shrub response to fertilisation was positive in the short-term but changed over time, likely because of an increased competition with graminoids. More erected postures and large, canopies (requiring enhanced secondary growth for stem reinforcement) likely compensated for the increased light competition in Empetrum and Cassiope but did not avoid growth reduction in the shade intolerant Betula. The impact of warming and shading on shrub growth was more conservative. The lack of growth enhancement under warming suggests the absence of long-term acclimation for processes limiting biomass production. The lack of negative effects of shading on Cassiope was linked to morphological changes increasing the photosynthetic surface. Overall, tundra shrubs showed developmental plasticity over the longer term. However, such plasticity was associated clearly with growth rate trends only in fertilised plots. PMID- 22511969 TI - Transcriptional analysis of distant signaling induced by insect elicitors and mechanical wounding in Zea mays. AB - When plants are under insect herbivore attack defensive measures are activated not only locally, but also in distant and systemic tissues. While insect elicitors (IE) abundant in the oral secretions of the attacking herbivore are essential in the regulation of induced defenses, little is known about their effects on systemic defense signaling in maize (Zea mays). The goal of this study was therefore to identify genetic markers that can be used to further characterize local and systemic signaling events induced by IE or mechanical wounding (MW). We selected genes for this study based on their putative involvement in signaling (allene oxide synthase), regulation of gene expression (transcription factor MYC7), and in direct defenses (ribosome inactivating protein) and analyzed their expression in different sections of the treated leaf as well as in systemic parts of the same plant. We found the most significant transcript accumulation of the selected genes after treatment with insect elicitors in those parts with increased JA levels. Additionally, treatment with IE did also induce the accumulation of MYC7 transcripts in basal parts of the treated leaf and systemically. MW, in contrast, did induce RIP and AOS only locally, but not MYC7. This local suppression of MYC7 was further studied by adding glutathione (GSH) as an electron donor to MW plants to quench putative alpha, beta-unsaturated carbonyls, which build up to significant levels around the damage site. Indeed, GSH-treated MW plants accumulated MYC7 at the damage site and also produced more volatiles, suggesting a putative redox-regulatory element being involved in the suppression of MYC7. The results presented herein provide evidence for the specific induction of distant signaling events triggered by IE, most likely through electric signaling. Additionally, a putative role for MW-induced alpha, beta-unsaturated carbonyls in the transcriptional regulation of defense genes was discovered. PMID- 22511970 TI - Effects of hepatocyte CD14 upregulation during cholestasis on endotoxin sensitivity. AB - Cholestasis is frequently related to endotoxemia and inflammatory response. Our previous investigation revealed a significant increase in plasma endotoxin and CD14 levels during biliary atresia. We therefore propose that lipopolysacharides (LPS) may stimulate CD14 production in liver cells and promote the removal of endotoxins. The aims of this study are to test the hypothesis that CD14 is upregulated by LPS and investigate the pathophysiological role of CD14 production during cholestasis. Using Western blotting, qRT-PCR, and promoter activity assay, we demonstrated that LPS was associated with a significant increase in CD14 and MD2 protein and mRNA expression and CD14 promoter activity in C9 rat hepatocytes but not in the HSC-T6 hepatic stellate cell line in vitro. To correlate CD14 expression and endotoxin sensitivity, in vivo biliary LPS administration was performed on rats two weeks after they were subjected to bile duct ligation (BDL) or a sham operation. CD14 expression and endotoxin levels were found to significantly increase after LPS administration in BDL rats. These returned to basal levels after 24 h. In contrast, although endotoxin levels were increased in sham-operated rats given LPS, no increase in CD14 expression was observed. However, mortality within 24 h was more frequent in the BDL animals than in the sham-operated group. In conclusion, cholestasis and LPS stimulation were here found to upregulate hepatic CD14 expression, which may have led to increased endotoxin sensitivity and host proinflammatory reactions, causing organ failure and death in BDL rats. PMID- 22511971 TI - A caprine herpesvirus 1 vaccine adjuvanted with MF59TM protects against vaginal infection and interferes with the establishment of latency in goats. AB - The immunogenicity and the efficacy of a beta-propiolactone-inactivated caprine herpesvirus 1 (CpHV-1) vaccine adjuvanted with MF59TM were tested in goats. Following two subcutaneous immunizations, goats developed high titers of CpHV-1 specific serum and vaginal IgG and high serum virus neutralization (VN) titers. Peripheral blood mononuclear cells (PBMC) stimulated in vitro with inactivated CpHV-1 produced high levels of soluble IFN-gamma and exhibited high frequencies of IFN-gamma producing cells while soluble IL-4 was undetectable. On the other hand, control goats receiving the inactivated CpHV-1 vaccine without adjuvant produced only low serum antibody responses. A vaginal challenge with virulent CpHV-1 was performed in all vaccinated goats and in naive goats to assess the efficacy of the two vaccines. Vaginal disease was not detected in goats vaccinated with inactivated CpHV-1 plus MF59TM and these animals had undetectable levels of infectious challenge virus in their vaginal washes. Goats vaccinated with inactivated CpHV-1 in the absence of adjuvant exhibited a less severe disease when compared to naive goats but shed titers of challenge virus that were similar to those of naive goats. Detection and quantitation of latent CpHV-1 DNA in sacral ganglia in challenged goats revealed that the inactivated CpHV-1 plus MF59TM vaccine was able to significantly reduce the latent viral load when compared either to the naive goats or to the goats vaccinated with inactivated CpHV-1 in the absence of adjuvant. Thus, a vaccine composed of inactivated CpHV-1 plus MF59TM as adjuvant was strongly immunogenic and induced effective immunity against vaginal CpHV-1 infection in goats. PMID- 22511972 TI - Recipients affect prosocial and altruistic choices in jackdaws, Corvus monedula. AB - Other-regarding preferences are a critical feature of human cooperation but to what extent non-human animals exhibit these preferences is a matter of intense discussion. We tested whether jackdaws show prosocial behaviour (providing benefits to others at no cost to themselves) and altruism (providing benefits to others while incurring costs) with both sibling and non-sibling recipients. In the prosocial condition, a box was baited on both the actor's and the recipient's side (1/1 option), whereas another box provided food only for the actor (1/0 option). In the altruistic condition, the boxes contained food for either the actor (1/0 option) or the recipient (0/1 option). The proportion of selfish (1/0 option) and cooperative (1/1 and 0/1 option, respectively) actors' choices was significantly affected by the recipients' behaviour. If recipients approached the boxes first and positioned themselves next to the box baited on their side, trying to access the food reward (recipient-first trials), actors were significantly more cooperative than when the actors approached the boxes first and made their choice prior to the recipients' arrival (actor-first trials). Further, in recipient-first trials actors were more cooperative towards recipients of the opposite sex, an effect that was even more pronounced in the altruistic condition. Hence, at no cost to the actors, all recipients could significantly influence the actors' behaviour, whereas at high costs this could be achieved even more so by recipients of different sex. Local/stimulus enhancement is discussed as the most likely cognitive mechanism to account for these effects. PMID- 22511974 TI - Label-free phenotypic profiling identified D-luciferin as a GPR35 agonist. AB - Fluorescent and luminescent probes are essential to both in vitro molecular assays and in vivo imaging techniques, and have been extensively used to measure biological function. However, little is known about the biological activity, thus potential interferences with the assay results, of these probe molecules. Here we show that D-luciferin, one of the most widely used bioluminescence substrates, is a partial agonist for G protein-coupled receptor-35 (GPR35). Label-free phenotypic profiling using dynamic mass redistribution (DMR) assays showed that D luciferin led to a DMR signal in native HT-29 cells, whose characteristics are similar to those induced by known GPR35 agonists including zaprinast and pamoic acid. DMR assays further showed that D-luciferin is a partial agonist competitive to several known GPR35 agonists and antagonists. D-luciferin was found to cause the phosphorylation of ERK that was suppressed by known GPR35 antagonists, and also result in beta-arrestin translocation signal but with low efficacy. These results not only suggest that D-luciferin is a partial agonist of GPR35, but also will evoke careful interpretation of biological data obtained using molecular and in vivo imaging assays when these probe molecules are used. PMID- 22511973 TI - Mechanisms underlying the confined diffusion of cholera toxin B-subunit in intact cell membranes. AB - Multivalent glycolipid binding toxins such as cholera toxin have the capacity to cluster glycolipids, a process thought to be important for their functional uptake into cells. In contrast to the highly dynamic properties of lipid probes and many lipid-anchored proteins, the B-subunit of cholera toxin (CTxB) diffuses extremely slowly when bound to its glycolipid receptor GM(1) in the plasma membrane of living cells. In the current study, we used confocal FRAP to examine the origins of this slow diffusion of the CTxB/GM(1) complex at the cell surface, relative to the behavior of a representative GPI-anchored protein, transmembrane protein, and fluorescent lipid analog. We show that the diffusion of CTxB is impeded by actin- and ATP-dependent processes, but is unaffected by caveolae. At physiological temperature, the diffusion of several cell surface markers is unchanged in the presence of CTxB, suggesting that binding of CTxB to membranes does not alter the organization of the plasma membrane in a way that influences the diffusion of other molecules. Furthermore, diffusion of the B-subunit of another glycolipid-binding toxin, Shiga toxin, is significantly faster than that of CTxB, indicating that the confined diffusion of CTxB is not a simple function of its ability to cluster glycolipids. By identifying underlying mechanisms that control CTxB dynamics at the cell surface, these findings help to delineate the fundamental properties of toxin-receptor complexes in intact cell membranes. PMID- 22511975 TI - The chemokine CXCL12 is essential for the clearance of the filaria Litomosoides sigmodontis in resistant mice. AB - Litomosoides sigmodontis is a cause of filarial infection in rodents. Once infective larvae overcome the skin barrier, they enter the lymphatic system and then settle in the pleural cavity, causing soft tissue infection. The outcome of infection depends on the parasite's modulatory ability and also on the immune response of the infected host, which is influenced by its genetic background. The goal of this study was to determine whether host factors such as the chemokine axis CXCL12/CXCR4, which notably participates in the control of immune surveillance, can influence the outcome of the infection. We therefore set up comparative analyses of subcutaneous infection by L. sigmodontis in two inbred mouse strains with different outcomes: one susceptible strain (BALB/c) and one resistant strain (C57BL/6). We showed that rapid parasite clearance was associated with a L. sigmodontis-specific CXCL12-dependent cell response in C57BL/6 mice. CXCL12 was produced mainly by pleural mesothelial cells during infection. Conversely, the delayed parasite clearance in BALB/c mice was neither associated with an increase in CXCL12 levels nor with cell influx into the pleural cavity. Remarkably, interfering with the CXCL12/CXCR4 axis in both strains of mice delayed filarial development, as evidenced by the postponement of the fourth molting process. Furthermore, the in vitro growth of stage 4 filariae was favored by the addition of low amounts of CXCL12. The CXCL12/CXCR4 axis thus appears to have a dual effect on the L. sigmodontis life cycle: by acting as a host-cell restriction factor for infection, and as a growth factor for worms. PMID- 22511976 TI - Body fatness and markers of thyroid function among U.S. men and women. AB - BACKGROUND: We evaluated the association of central versus overall adiposity on levels of thyroid stimulating hormone (TSH), free triiodothyronine (fT(3)), and free thyroxine (fT(4)) among euthyroid subjects taken from a cross-sectional, representative sample of the adult non-institutionalized U.S. population. METHODS: The National Health and Nutrition Examination Survey 2007-2008 included 1,623 men and 1,491 women who were 20 years and older, with no history of thyroid or liver disease, kidney failure, diabetes, or thyroid function-altering prescription medication use (based on self-report), and having TSH, fT(3), and fT(4) levels between 0.5-4.49 mIU/L, 2.5-3.9 pg/mL, and 0.6-1.6 ng/dL, respectively. Associations between body mass index (BMI) and waist circumference (measures of overall and central adiposity, respectively) and TSH, fT(3), and fT(4) levels were estimated using multivariable linear regression models stratified by sex and adjusted for age, race, smoking status, and alcohol intake. RESULTS: An increase in serum TSH levels was observed for every 1-quartile increase in BMI in euthyroid men (3.8% [95% CI 0.8%, 6.8%]) and euthyroid women (4.0% [95% CI 1.6%, 6.5%]). Similar, albeit slightly weaker, associations were observed with waist circumference. We also found increases in fT(3) levels with every 1-quartile increase in BMI (1.0% in men and 1.3% in women) and waist circumference (1.2% in men and 1.2% in women). No associations were observed with fT(4.) CONCLUSIONS: Our results provide support that BMI and waist circumference are positively associated with levels of serum TSH and f T(3) but not fT(4) among euthyroid adults. Longitudinal studies are needed to define the temporality of these associations and their potential health implications. PMID- 22511977 TI - Molecular mechanism underlying the interaction of typical Sac10b family proteins with DNA. AB - The Sac10b protein family is regarded as a family of DNA-binding proteins that is highly conserved and widely distributed within the archaea. Sac10b family members are typically small basic dimeric proteins that bind to DNA with cooperativity and no sequence specificity and are capable of constraining DNA negative supercoils, protecting DNA from Dnase I digestion, and do not compact DNA obviously. However, a detailed understanding of the structural basis of the interaction of Sac10b family proteins with DNA is still lacking. Here, we determined the crystal structure of Mth10b, an atypical member of the Sac10b family from Methanobacterium thermoautotrophicum DeltaH, at 2.2 A. Unlike typical Sac10b family proteins, Mth10b is an acidic protein and binds to neither DNA nor RNA. The overall structure of Mth10b displays high similarity to its homologs, but three pairs of conserved positively charged residues located at the presumed DNA-binding surface are substituted by non-charged residues in Mth10b. Through amino acids interchanges, the DNA-binding ability of Mth10b was restored successfully, whereas the DNA-binding ability of Sso10b, a typical Sac10b family member, was weakened greatly. Based on these results, we propose a model describing the molecular mechanism underlying the interactions of typical Sac10b family proteins with DNA that explains all the characteristics of the interactions between typical Sac10b family members and DNA. PMID- 22511978 TI - Transcranial direct current stimulation augments perceptual sensitivity and 24 hour retention in a complex threat detection task. AB - We have previously shown that transcranial direct current stimulation (tDCS) improved performance of a complex visual perceptual learning task (Clark et al. 2012). However, it is not known whether tDCS can enhance perceptual sensitivity independently of non-specific, arousal-linked changes in response bias, nor whether any such sensitivity benefit can be retained over time. We examined the influence of stimulation of the right inferior frontal cortex using tDCS on perceptual learning and retention in 37 healthy participants, using signal detection theory to distinguish effects on perceptual sensitivity (d') from response bias (beta). Anodal stimulation with 2 mA increased d', compared to a 0.1 mA sham stimulation control, with no effect on beta. On completion of training, participants in the active stimulation group had more than double the perceptual sensitivity of the control group. Furthermore, the performance enhancement was maintained for 24 hours. The results show that tDCS augments both skill acquisition and retention in a complex detection task and that the benefits are rooted in an improvement in sensitivity (d'), rather than changes in response bias (beta). Stimulation-driven acceleration of learning and its retention over 24 hours may result from increased activation of prefrontal cortical regions that provide top-down attentional control signals to object recognition areas. PMID- 22511979 TI - Role of microRNAs in controlling gene expression in different segments of the human epididymis. AB - BACKGROUND: The molecular mechanisms implicated in regionalized gene expression in the human epididymis have not yet been fully elucidated. Interestingly, more than 200 microRNAs (miRNAs) have been identified in the human epididymis and could be involved in the regulation of mRNA stability and post-transcriptional expression in this organ. METHODS: Using a miRNA microarray approach, we investigated the correlation between miRNA signatures and gene expression profiles found in three distinct regions (caput, corpus and cauda) of human epididymides from 3 donors. In silico prediction of transcript miRNA targets was performed using TargetScan and Miranda software's. FHCE1 immortalized epididymal cell lines were cotransfected with mimic microRNAs and plasmid constructs containing the 3'UTR of predicted target genes downstream of the luciferase gene. RESULTS: We identified 35 miRNAs differentially expressed in the distinct segments of the epididymis (fold change >=2, P-value <= 0.01). Among these miRNAs, miR-890, miR-892a, miR-892b, miR-891a, miR-891b belonging to the same epididymis-enriched cluster located on the X chromosome, are significantly more expressed in the corpus and cauda regions than in the caput. Interestingly, a strong negative correlation (r = -0,89, P-value <= 0.001) was found between the pattern of expression of miR-892b and its potential mRNA target Esrrg (Estrogen Related Receptor Gamma) and with miR-145 and Cldn10 mRNA (r = -0,92, P-value <= 0.001). We confirmed that miR-145 and miR-892b inhibit the expression of the luciferase reporter via Cldn10 and Esrrg 3' UTRs, respectively. CONCLUSION: Our study shows that the expression of miRNAs is segmented along the human epididymis and correlates with the pattern of target gene expression in different regions. Therefore, epididymal miRNAs may be in control of the maintenance of gene expression profile in the epididymis, which dictates segment-specific secretion of proteins and establishes physiological compartments that directly or indirectly affect sperm maturation and fertility. PMID- 22511980 TI - Highly variable chloroplast markers for evaluating plant phylogeny at low taxonomic levels and for DNA barcoding. AB - BACKGROUND: At present, plant molecular systematics and DNA barcoding techniques rely heavily on the use of chloroplast gene sequences. Because of the relatively low evolutionary rates of chloroplast genes, there are very few choices suitable for molecular studies on angiosperms at low taxonomic levels, and for DNA barcoding of species. METHODOLOGY/PRINCIPAL FINDINGS: We scanned the entire chloroplast genomes of 12 genera to search for highly variable regions. The sequence data of 9 genera were from GenBank and 3 genera were of our own. We identified nearly 5% of the most variable loci from all variable loci in the chloroplast genomes of each genus, and then selected 23 loci that were present in at least three genera. The 23 loci included 4 coding regions, 2 introns, and 17 intergenic spacers. Of the 23 loci, the most variable (in order from highest variability to lowest) were intergenic regions ycf1-a, trnK, rpl32-trnL, and trnH psbA, followed by trnS(UGA)-trnG(UCC), petA-psbJ, rps16-trnQ, ndhC-trnV, ycf1-b, ndhF, rpoB-trnC, psbE-petL, and rbcL-accD. Three loci, trnS(UGA)-trnG(UCC), trnT psbD, and trnW-psaJ, showed very high nucleotide diversity per site (pi values) across three genera. Other loci may have strong potential for resolving phylogenetic and species identification problems at the species level. The loci accD-psaI, rbcL-accD, rpl32-trnL, rps16-trnQ, and ycf1 are absent from some genera. To amplify and sequence the highly variable loci identified in this study, we designed primers from their conserved flanking regions. We tested the applicability of the primers to amplify target sequences in eight species representing basal angiosperms, monocots, eudicots, rosids, and asterids, and confirmed that the primers amplified the desired sequences of these species. SIGNIFICANCE/CONCLUSIONS: Chloroplast genome sequences contain regions that are highly variable. Such regions are the first consideration when screening the suitable loci to resolve closely related species or genera in phylogenetic analyses, and for DNA barcoding. PMID- 22511981 TI - Structural and functional diversity of acidic scorpion potassium channel toxins. AB - BACKGROUND: Although the basic scorpion K(+) channel toxins (KTxs) are well-known pharmacological tools and potential drug candidates, characterization the acidic KTxs still has the great significance for their potential selectivity towards different K(+) channel subtypes. Unfortunately, research on the acidic KTxs has been ignored for several years and progressed slowly. PRINCIPAL FINDINGS: Here, we describe the identification of nine new acidic KTxs by cDNA cloning and bioinformatic analyses. Seven of these toxins belong to three new alpha-KTx subfamilies (alpha-KTx28, alpha-KTx29, and alpha-KTx30), and two are new members of the known kappa-KTx2 subfamily. ImKTx104 containing three disulfide bridges, the first member of the alpha-KTx28 subfamily, has a low sequence homology with other known KTxs, and its NMR structure suggests ImKTx104 adopts a modified cystine-stabilized alpha-helix-loop-beta-sheet (CS-alpha/beta) fold motif that has no apparent alpha-helixs and beta-sheets, but still stabilized by three disulfide bridges. These newly described acidic KTxs exhibit differential pharmacological effects on potassium channels. Acidic scorpion toxin ImKTx104 was the first peptide inhibitor found to affect KCNQ1 channel, which is insensitive to the basic KTxs and is strongly associated with human cardiac abnormalities. ImKTx104 selectively inhibited KCNQ1 channel with a K(d) of 11.69 uM, but was less effective against the basic KTxs-sensitive potassium channels. In addition to the ImKTx104 toxin, HeTx204 peptide, containing a cystine-stabilized alpha helix-loop-helix (CS-alpha/alpha) fold scaffold motif, blocked both Kv1.3 and KCNQ1 channels. StKTx23 toxin, with a cystine-stabilized alpha-helix-loop-beta sheet (CS-alpha/beta) fold motif, could inhibit Kv1.3 channel, but not the KCNQ1 channel. CONCLUSIONS/SIGNIFICANCE: These findings characterize the structural and functional diversity of acidic KTxs, and could accelerate the development and clinical use of acidic KTxs as pharmacological tools and potential drugs. PMID- 22511982 TI - Transgenic Cry1Ab rice does not impact ecological fitness and predation of a generalist spider. AB - BACKGROUND: The commercial release of rice genetically engineered to express a Cry1Ab protein from Bacillus thuringiensis (Bt) for control of Lepidoptera in China is a subject of debate. One major point of the debate has focused on the ecological safety of Bt rice on nontarget organisms, especially predators and parasitoids that help control populations of insect pests. METHODOLOGY/PRINCIPAL FINDINGS: A tritrophic bioassay was conducted to evaluate the potential impact of Cry1Ab-expressing rice on fitness parameters of a predaceous ground spider (Pardosa pseudoannulata (Bosenberg et Strand)) that had fed on Bt rice-fed brown planthopper (Nilaparvata lugens (Stal)) nymphs. Survival, development time and fecundity of this spider were not different when they were fed with Bt rice-fed or non-Bt rice-fed prey. Furthermore, ELISA and PCR gut assays, as well as a functional response trial, indicated that predation by P. pseudoannulata was not significantly different in Bt rice or non-Bt rice fields. CONCLUSIONS/SIGNIFICANCE: The transgenic Cry1Ab rice lines tested in this study had no adverse effects on the survival, developmental time and fecundity of P. pseudoannulata in the laboratory or on predation under field conditions. This suggests that this important predator would not be harmed if transgenic Cry1Ab rice were commercialized. PMID- 22511983 TI - A new generation of T7 RNA polymerase-independent inducible expression plasmids for Trypanosoma brucei. AB - Expression of transgenes is central to forward and reverse genetic analysis in Trypanosoma brucei. The inducible expression of transgenes in trypanosomes is based on the tetracycline repressor binding to a tetracycline operator to prevent transcription in the absence of tetracycline. The same inducible system is used to produce double-stranded RNA for RNAi knockdown of target genes. This study describes a new plasmid pSPR2.1 that drives consistent high-level expression of tetracycline repressor in procyclic form trypanosomes. A complementary expression plasmid, p3227, was constructed. The major difference between this and current plasmids is the separation of the inducible transgene and selectable marker promoters by the plasmid backbone. The plasmid p3227 was able to support inducible expression in cell lines containing pSPR2.1 as well as the established Lister 427 29-13 cell line. p3666, a derivative of p3227, was made for inducible expression of stem loop RNAi constructs and was effective for knockdown of DRBD3, which had proved problematic using existing RNAi plasmids with head-to-head promoters. The plasmid system was also able to support inducible transgene expression and DRBD3 RNAi knockdown in bloodstream form cells expressing tetracycline repressor from an integrated copy of the plasmid pHD1313. PMID- 22511984 TI - The mitochondrial genome of the lycophyte Huperzia squarrosa: the most archaic form in vascular plants. AB - Mitochondrial genomes have maintained some bacterial features despite their residence within eukaryotic cells for approximately two billion years. One of these features is the frequent presence of polycistronic operons. In land plants, however, it has been shown that all sequenced vascular plant chondromes lack large polycistronic operons while bryophyte chondromes have many of them. In this study, we provide the completely sequenced mitochondrial genome of a lycophyte, from Huperzia squarrosa, which is a member of the sister group to all other vascular plants. The genome, at a size of 413,530 base pairs, contains 66 genes and 32 group II introns. In addition, it has 69 pseudogene fragments for 24 of the 40 protein- and rRNA-coding genes. It represents the most archaic form of mitochondrial genomes of all vascular plants. In particular, it has one large conserved gene cluster containing up to 10 ribosomal protein genes, which likely represents a polycistronic operon but has been disrupted and greatly reduced in the chondromes of other vascular plants. It also has the least rearranged gene order in comparison to the chondromes of other vascular plants. The genome is ancestral in vascular plants in several other aspects: the gene content resembling those of charophytes and most bryophytes, all introns being cis spliced, a low level of RNA editing, and lack of foreign DNA of chloroplast or nuclear origin. PMID- 22511985 TI - Intracellular Streptococcus pyogenes in human macrophages display an altered gene expression profile. AB - Streptococcus pyogenes is an important human pathogen, which has recently gained recognition as an intracellular microorganism during the course of severe invasive infections such as necrotizing fasciitis. Although the surface anchored M protein has been identified as a pivotal factor affecting phagosomal maturation and S. pyogenes survival within macrophages, the overall transcriptional profile required for the pathogen to adapt and persist intracellularly is as of yet unknown. To address this, the gene expression profile of S. pyogenes within human macrophages was determined and compared to that of extracellular bacteria using customized microarrays and real-time qRT-PCR. In order to model the early phase of infection involving adaptation to the intracellular compartment, samples were collected 2h post-infection. Microarray analysis revealed that the expression of 145 streptococcal genes was significantly altered in the intracellular environment. The majority of differentially regulated genes were associated with metabolic and energy-dependent processes. Key up-regulated genes in early phase intracellular bacteria were ihk and irr, encoding a two-component gene regulatory system (TCS). Comparison of gene expression of selected genes at 2h and 6h post infection revealed a dramatic shift in response regulators over time with a down regulation of ihk/irr genes concurring with an up-regulation of the covR/S TCS. In re-infection assays, intracellular bacteria from the 6h time point exhibited significantly greater survival within macrophages than did bacteria collected at the 2h time point. An isogenic S. pyogenes mutant deficient in ihk/irr displayed significantly reduced bacterial counts when compared to wild-type bacteria following infection of macrophages. The findings illustrate how gene expression of S. pyogenes during the intracellular life cycle is fine-tuned by temporal expression of specific two-component systems. PMID- 22511986 TI - Impaired adaptive response to mechanical overloading in dystrophic skeletal muscle. AB - Dystrophin contributes to force transmission and has a protein-scaffolding role for a variety of signaling complexes in skeletal muscle. In the present study, we tested the hypothesis that the muscle adaptive response following mechanical overloading (ML) would be decreased in MDX dystrophic muscle lacking dystrophin. We found that the gains in muscle maximal force production and fatigue resistance in response to ML were both reduced in MDX mice as compared to healthy mice. MDX muscle also exhibited decreased cellular and molecular muscle remodeling (hypertrophy and promotion of slower/oxidative fiber type) in response to ML, and altered intracellular signalings involved in muscle growth and maintenance (mTOR, myostatin, follistatin, AMPKalpha1, REDD1, atrogin-1, Bnip3). Moreover, dystrophin rescue via exon skipping restored the adaptive response to ML. Therefore our results demonstrate that the adaptive response in response to ML is impaired in dystrophic MDX muscle, most likely because of the dystrophin crucial role. PMID- 22511987 TI - Supernumerary formation of olfactory glomeruli induced by chronic odorant exposure: a constructivist expression of neural plasticity. AB - It is accepted that sensory experience instructs the remodelling of neuronal circuits during postnatal development, after their specification has occurred. The story is less clear with regard to the role of experience during the initial formation of neuronal circuits, whether prenatal or postnatal, since this process is now supposed to be primarily influenced by genetic determinants and spontaneous neuronal firing. Here we evaluated this last issue by examining the effect that postnatal chronic exposure to cognate odorants has on the formation of I7 and M72 glomeruli, iterated olfactory circuits that are formed before and after birth, respectively. We took advantage of double knock-in mice whose I7 and M72 primary afferents express green fluorescent protein and beta-galactosidase, correspondingly. Our results revealed that postnatal odorant chronic exposure led to the formation of permanent supernumerary I7 and M72 glomeruli in a dose and time dependent manner. Glomeruli in exposed mice were formed within the same regions of olfactory bulb and occupy small space volumes compared to the corresponding single circuits in non-exposed mice. We suggest that local reorganization of the primary afferents could participate in the process of formation of supernumerary glomeruli. Overall, our results support that sensory experience indeed instructs the permanent formation of specific glomeruli in the mouse olfactory bulb by means of constructivist processes. PMID- 22511988 TI - A genome-wide association study identifies UGT1A1 as a regulator of serum cell free DNA in young adults: The Cardiovascular Risk in Young Finns Study. AB - INTRODUCTION: Circulating cell-free DNA (cf-DNA) is a useful indicator of cell death, and it can also be used to predict outcomes in various clinical disorders. Several innate immune mechanisms are known to be involved in eliminating DNA and chromatin-related material as part of the inhibition of potentially harmful autoimmune responses. However, the exact molecular mechanism underlying the clearance of circulating cf-DNA is currently unclear. METHODS: To examine the mechanisms controlling serum levels of cf-DNA, we carried out a genome-wide association analysis (GWA) in a cohort of young adults (aged 24-39 years; n = 1841; 1018 women and 823 men) participating in the Cardiovascular Risk in Young Finns Study. Genotyping was performed with a custom-built Illumina Human 670 k BeadChip. The Quant-iT(TM) high sensitivity DNA assay was used to measure cf-DNA directly from serum. RESULTS: The results revealed that 110 single nucleotide polymorphisms (SNPs) were associated with serum cf-DNA with genome-wide significance (p<5*10(-8)). All of these significant SNPs were localised to chromosome 2q37, near the UDP-glucuronosyltransferase 1 (UGT1) family locus, and the most significant SNPs localised within the UGT1 polypeptide A1 (UGT1A1) gene region. CONCLUSION: The UGT1A1 enzyme catalyses the detoxification of several drugs and the turnover of many xenobiotic and endogenous compounds by glucuronidating its substrates. These data indicate that UGT1A1-associated processes are also involved in the regulation of serum cf-DNA concentrations. PMID- 22511989 TI - Miiuy croaker hepcidin gene and comparative analyses reveal evidence for positive selection. AB - Hepcidin antimicrobial peptide (HAMP) is a small cysteine-rich peptide and a key molecule of the innate immune system against bacterial infections. Molecular cloning and genomic characterization of HAMP gene in the miiuy croaker (Miichthys miiuy) were reported in this study. The miiuy croaker HAMP was predicted to encode a prepropeptide of 99 amino acids, a tentative RX(K/R)R cleavage motif and eight characteristic cysteine residues were also identified. The gene organization is also similar to corresponding genes in mammals and fish consisting of three exons and two introns. Sequence polymorphism analysis showed that only two different sequences were identified and encoded two proteins in six individuals. As reported for most other species, the expression level was highest in liver and an up-regulation of transcription was seen in spleen, intestine and kidney examined at 24 h after injection of pathogenic bacteria, Vibrio anguillarum, the expression pattern implied that miiuy croaker HAMP is an important component of the first line defense against invading pathogens. In addition, we report on the underlying mechanism that maintains sequences diversity among fish and mammalian species, respectively. A series of site-model tests implemented in the CODEML program revealed that moderate positive Darwinian selection is likely to cause the molecular evolution in the fish HAMP2 genes and it also showed that the fish HAMP1 genes and HAMP2 genes under different selection pressures. PMID- 22511990 TI - Downregulation of miR-31, miR-155, and miR-564 in chronic myeloid leukemia cells. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) are short non-coding regulatory RNAs that control gene expression and play an important role in cancer development and progression. However, little is known about the role of miRNAs in chronic myeloid leukemia (CML). Our objective is to decipher a miRNA expression signature associated with CML and to determine potential target genes and signaling pathways affected by these signature miRNAs. RESULTS: Using miRNA microarrays and miRNA real-time PCR we characterized the miRNAs expression profile of CML cell lines and patients in reference to non-CML cell lines and healthy blood. Of all miRNAs tested, miR-31, miR-155, and miR-564 were down-regulated in CML cells. Down-regulation of these miRNAs was dependent on BCR-ABL activity. We next analyzed predicted targets and affected pathways of the deregulated miRNAs. As expected, in K562 cells, the expression of several of these targets was inverted to that of the miRNA putatively regulating them. Reassuringly, the analysis identified CML as the main disease associated with these miRNAs. MAPK, ErbB, mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF) were the main molecular pathways related with these expression patterns. Utilizing Venn diagrams we found appreciable overlap between the CML-related miRNAs and the signaling pathways-related miRNAs. CONCLUSIONS: The miRNAs identified in this study might offer a pivotal role in CML. Nevertheless, while these data point to a central disease, the precise molecular pathway/s targeted by these miRNAs is variable implying a high level of complexity of miRNA target selection and regulation. These deregulated miRNAs highlight new candidate gene targets allowing for a better understanding of the molecular mechanism underlying the development of CML, and propose possible new avenues for therapeutic treatment. PMID- 22511992 TI - A novel osteogenesis technique: The expansible guided bone regeneration. AB - Guided bone regeneration is a unique osteogenesis technique that requires a barrier membrane under periosteum to create space for bone regeneration. However, creating sizeable spaces is clinically not commonly feasible. A titanium plate and a thin silicone membrane were surgically layered on each calvaria of eight rabbits. Then, the periphery of the silicone membrane was fixed by a plastic ring to the underlying bone using titanium micro screws. After 1 week, a 5-mm-length titanium screw was used to elevate the titanium plate, which in turn elevated the silicone membrane together with overlying soft tissue in a rate of 1 mm/day for 5 days to create a secluded space. Animals were killed at 2 months (n = 4, group 1) and 4 months (n = 4, group 2) after the elevation. Histological and microradiographical analyses demonstrated creation of an amount of de novo bone formation (68.2 +/- 22 mm(3) in group 1 and 70.3 +/- 14 mm(3) in group 2) in the sizeable created spaces (207.1 +/- 31 mm(3) in group 1 and 202 +/- 21 mm(3) in group 2) without exposure of the device. This novel osteogenesis technique, "expansible guided bone regeneration," created a substantial in vivo incubator without applying growth factors or osteoprogenitor cells. Creating a growing space over the secluded surface allowed the development of normal biological healing process occurring on the bone surface into a regenerative process, generating bone outside the genetically determined skeletal bone. This technique is a new tissue engineering approach stimulating endogenous tissue repair without applying cells or factors exogenously. PMID- 22511991 TI - Polymeric additives to enhance the functional properties of calcium phosphate cements. AB - The vast majority of materials used in bone tissue engineering and regenerative medicine are based on calcium phosphates due to their similarity with the mineral phase of natural bone. Among them, calcium phosphate cements, which are composed of a powder and a liquid that are mixed to obtain a moldable paste, are widely used. These calcium phosphate cement pastes can be injected using minimally invasive surgery and adapt to the shape of the defect, resulting in an entangled network of calcium phosphate crystals. Adding an organic phase to the calcium phosphate cement formulation is a very powerful strategy to enhance some of the properties of these materials. Adding some water-soluble biocompatible polymers in the calcium phosphate cement liquid or powder phase improves physicochemical and mechanical properties, such as injectability, cohesion, and toughness. Moreover, adding specific polymers can enhance the biological response and the resorption rate of the material. The goal of this study is to overview the most relevant advances in this field, focusing on the different types of polymers that have been used to enhance specific calcium phosphate cement properties. PMID- 22511993 TI - Safety of recombinant human platelet-derived growth factor-BB in Augment((r)) Bone Graft. AB - This article discusses nonclinical and clinical data regarding the safety of recombinant human platelet-derived growth factor-BB as a component of the Augment((r)) Bone Graft (Augment). Augment is a bone graft substitute intended to be used as an alternative to autologous bone graft in the fusion of hindfoot and ankle joints. Nonclinical studies included assessment of the pharmacokinetic profile of intravenously administered recombinant human platelet-derived growth factor-BB in rat and dog, effects of intravenous administration of recombinant human platelet-derived growth factor-BB in a reproductive and development toxicity study in rats, and chronic toxicity and carcinogenicity of Augment in a 12-month implantation model. These studies showed that systemic exposure was brief and clearance was rapid. No signs of toxicity, carcinogenicity, or tumor promotion were observed even with doses far exceeding the maximum clinical dose. Results of clinical trials (605 participants) and commercial use of recombinant human platelet-derived growth factor-BB containing products indicate that these products are not associated with increased incidence of adverse events or cancer. The safety data presented provide evidence that recombinant human platelet derived growth factor-BB is a safe therapeutic when used in combination products as a single administration during surgical procedures for bone repair and fusion. There is no evidence associating use of recombinant human platelet-derived growth factor-BB in Augment with chronic toxicity, carcinogenicity, or tumor promotion. PMID- 22511994 TI - Osteogenic stimulatory conditions enhance growth and maturation of endothelial cell microvascular networks in culture with mesenchymal stem cells. AB - To optimize culture conditions for in vitro prevascularization of tissue engineered bone constructs, the development of organotypic blood vessels under osteogenic stimulatory conditions (OM) was investigated. Coculture of endothelial cells and mesenchymal stem cells was used to assess proangiogenic effects of mesenchymal stem cells on endothelial cells. Four different culture conditions were evaluated for their effect on development of microvascular endothelial cell networks. Mineralization, deposition of extracellular matrix, and perivascular gene expression were studied in OM. After 3 days, endothelial cells established elongated capillary-like networks, and upregulated expression of vascular markers was seen. After 15 days, all parameters evaluated were significantly increased for cultures in OM. Mature networks developed in OM presented lumens enveloped by basement membrane-like collagen IV, with obvious mineralization and upregulated perivascular gene expression from mesenchymal stem cells. Our results suggest osteogenic stimulatory conditions to be appropriate for in vitro development of vascularized bone implants for tissue engineering. PMID- 22511995 TI - A short review: Recent advances in electrospinning for bone tissue regeneration. AB - Nanofibrous structures developed by electrospinning technology provide attractive extracellular matrix conditions for the anchorage, migration, and differentiation of tissue cells, including those responsible for the regeneration of hard tissues. Together with the ease of set up and cost-effectiveness, the possibility to produce nanofibers with a wide range of compositions and morphologies is the merit of electrospinning. Significant efforts have exploited the development of bone regenerative nanofibers, which includes tailoring of composite/hybrid compositions that are bone mimicking and the surface functionalization such as mineralization. Moreover, by utilizing bioactive molecules such as adhesive proteins, growth factors, and chemical drugs, in concert with the nanofibrous matrices, it is possible to provide artificial materials with improved cellular responses and therapeutic efficacy. These studies have mainly focused on the regulation of stem cell behaviors for use in regenerative medicine and tissue engineering. While there are some challenges in achieving controllable delivery of bioactive molecules and complex-shaped three-dimensional scaffolds for tissue engineering, the electrospun nanofibrous matrices can still have a beneficial impact in the area of hard-tissue regeneration. PMID- 22511996 TI - A high-throughput behavioral paradigm for Drosophila olfaction - The Flywalk. AB - How can odor-guided behavior of numerous individual Drosophila be assessed automatically with high temporal resolution? For this purpose we introduce the automatic integrated tracking and odor-delivery system Flywalk. In fifteen aligned small wind tunnels individual flies are exposed to repeated odor pulses, well defined in concentration and timing. The flies' positions are visually tracked, which allows quantification of the odor-evoked walking behavior with high temporal resolution of up to 100 ms. As a demonstration of Flywalk we show that the flies' behavior is odorant-specific; attractive odors elicit directed upwind movements, while repellent odors evoke decreased activity, followed by downwind movements. These changes in behavior differ between sexes. Furthermore our findings show that flies can evaluate the sex of a conspecific and males can determine a female's mating status based on olfactory cues. Consequently, Flywalk allows automatic screening of individual flies for their olfactory preference and sensitivity. PMID- 22511997 TI - Indiscriminable sounds determine the direction of visual motion. AB - On cross-modal interactions, top-down controls such as attention and explicit identification of cross-modal inputs were assumed to play crucial roles for the optimization. Here we show the establishment of cross-modal associations without such top-down controls. The onsets of two circles producing apparent motion perception were accompanied by indiscriminable sounds consisting of six identical and one unique sound frequencies. After adaptation to the visual apparent motion with the sounds, the sounds acquired a driving effect for illusory visual apparent motion perception. Moreover, the pure tones with each unique frequency of the sounds acquired the same effect after the adaptation, indicating that the difference in the indiscriminable sounds was implicitly coded. We further confrimed that the aftereffect didnot transfer between eyes. These results suggest that the brain establishes new neural representations between sound frequency and visual motion without clear identification of the specific relationship between cross-modal stimuli in early perceptual processing stages. PMID- 22511998 TI - Calcineurin Controls Voltage-Dependent-Inactivation (VDI) of the Normal and Timothy Cardiac Channels. AB - Ca(2+)-entry in the heart is tightly controlled by Cav1.2 inactivation, which involves Ca(2+)-dependent inactivation (CDI) and voltage-dependent inactivation (VDI) components. Timothy syndrome, a subtype-form of congenital long-QT syndrome, results from a nearly complete elimination of VDI by the G406R mutation in the alpha(1)1.2 subunit of Cav1.2. Here, we show that a single (A1929P) or a double mutation (H1926A-H1927A) within the CaN-binding site at the human C terminal tail of alpha(1)1.2, accelerate the inactivation rate and enhances VDI of both wt and Timothy channels. These results identify the CaN-binding site as the long-sought VDI-regulatory motif of the cardiac channel. The substantial increase in VDI and the accelerated inactivation caused by the selective inhibitors of CaN, cyclosporine A and FK-506, which act at the same CaN-binding site, further support this conclusion. A reversal of enhanced-sympathetic tone by VDI-enhancing CaN inhibitors could be beneficial for improving Timothy syndrome complications such as long-QT and autism. PMID- 22511999 TI - If players are sparse social dilemmas are too: Importance of percolation for evolution of cooperation. AB - Spatial reciprocity is a well known tour de force of cooperation promotion. A thorough understanding of the effects of different population densities is therefore crucial. Here we study the evolution of cooperation in social dilemmas on different interaction graphs with a certain fraction of vacant nodes. We find that sparsity may favor the resolution of social dilemmas, especially if the population density is close to the percolation threshold of the underlying graph. Regardless of the type of the governing social dilemma as well as particularities of the interaction graph, we show that under pairwise imitation the percolation threshold is a universal indicator of how dense the occupancy ought to be for cooperation to be optimally promoted. We also demonstrate that myopic updating, due to the lack of efficient spread of information via imitation, renders the reported mechanism dysfunctional, which in turn further strengthens its foundations. PMID- 22512000 TI - HD mouse models reveal clear deficits in learning to perform a simple instrumental response. AB - Mouse models of Huntington's disease (HD) were trained to acquire one of two simple instrumental responses (a lever press or a nosepoke) to obtain food reinforcement. Animals from several HD strains revealed apparently progressive deficits in this task, being significantly less able than littermate controls to perform the required responses, at ages where motor function is only mildly affected. These data could provide a simple way to measure learning deficits in these mouse models, likely related to the characteristic pattern of neural damage observed in HD mouse models. PMID- 22512001 TI - UK guidelines on the management of iron deficiency in pregnancy. AB - Iron deficiency is the most common deficiency state in the world, affecting more than 2 billion people globally. Although it is particularly prevalent in less developed countries, it remains a significant problem in the developed world, even where other forms of malnutrition have already been almost eliminated. Effective management is needed to prevent adverse maternal and pregnancy outcomes, including the need for red cell transfusion. The objective of this guideline is to provide healthcare professionals with clear and simple recommendations for the diagnosis, treatment and prevention of iron deficiency in pregnancy and the postpartum period. This is the first such guideline in the UK and may be applicable to other developed countries. Public health measures, such as helminth control and iron fortification of foods, which can be important to developing countries, are not considered here. The guidance may not be appropriate to all patients and individual patient circumstances may dictate an alternative approach. PMID- 22512002 TI - [Year in memory of Dr. Istvan Bugyi]. PMID- 22512003 TI - A deeper look at mitochondrial dynamics in Parkinson's disease. PMID- 22512004 TI - New experimental approach for modeling Parkinson's disease. PMID- 22512005 TI - Multiple ways for a-synuclein degradation. PMID- 22512006 TI - Health insurance moderates the association between immigrant length of stay and health status. AB - Previous studies reported that immigrants' health worsens with acculturation to US lifestyle; however, role of health insurance has not been investigated. We used crosssectional National Immigrant Survey (n = 6,381) to examine the potential moderating effect of health insurance on the association between time in the US and self reported changes in health (comparing health status before and after immigration)and current health status. Separate logistic regression models were fit to assess these associations among insured and uninsured immigrants, adjusting for covariates. Among uninsured immigrants there was a stronger negative association between length of stay and health, compared to immigrants with health insurance. Insured immigrants were almost two times more likely than uninsured immigrants to have received preventive screenings, such as a Pap smear or prostate exam. This suggests that health insurance may somewhat attenuate this association, and is an important resource for US immigrants. PMID- 22512007 TI - Transportation to clinic: findings from a pilot clinic-based survey of low-income suburbanites. AB - Health care policymakers have cited transportation barriers as key obstacles to providing health care to low-income suburbanites, particularly because suburbs have become home to a growing number of recent immigrants who are less likely to own cars than their neighbors. In a suburb of New York City, we conducted a pilot survey of low income, largely immigrant clients in four public clinics, to find out how much transportation difficulties limit their access to primary care. Clients were receptive to the opportunity to participate in the survey (response rate = 94%). Nearly one-quarter reported having transportation problems that had caused them to miss or reschedule a clinic appointment in the past. Difficulties included limited and unreliable local bus service, and a tenuous connection to a car. Our pilot work suggests that this population is willing to participate in a survey on this topic. Further, since even among those attending clinic there was significant evidence of past transportation problems, it suggests that a population based survey would yield information about substantial transportation barriers to health care. PMID- 22512009 TI - Conflict of interest guidelines for clinical guidelines. PMID- 22512008 TI - Patient characteristics and behaviours associated with self-harm and attempted suicide in acute psychiatric wards. AB - AIMS AND OBJECTIVES: The study examined events before and after incidents of self harm and attempted suicide and the characteristics of patients who engage in these behaviours. BACKGROUND: Psychiatric inpatient populations have an elevated risk of self-harm and suicide, but relatively little is known about the circumstances of these events during an admission. DESIGN: Retrospective case note analysis. METHOD: Data were collected on conflict (aggression, rule breaking, etc.) and containment (coerced medication, restraint, etc.) during the first two weeks of admission for a sample of 522 acute psychiatric inpatients. RESULTS: One in 10 patients self-harmed, and 4% attempted suicide. Aggression, attempting to leave the ward without permission and medication refusal were frequent precursors to incidents. Pro re nata medication and de-escalation were the most frequent interventions to follow an incident. Self-harm and attempted suicides during the current admission were significantly associated with younger age and a history of self-harm. CONCLUSIONS: A minority of the sample were involved in these behaviours, but incidents occurred soon after admission and sometimes repeatedly during the course of a day. Assessment of risk should be completed as early as possible. RELEVANCE TO CLINICAL PRACTICE: At-risk patients should be monitored for signs of withdrawal from ward activity, wanting to leave the ward without permission or non-compliance with medication to enable early intervention. PMID- 22512010 TI - Abstracts of the Annual Meeting of the Society of Academic and Research Surgery. January 4-5, 2012. Nottingham, United Kingdom. PMID- 22512011 TI - Early behaviour relationships & prognostic indicators. Abstracts of the 3rd UK Paediatric Neuropsychology Symposium. April 23-27, 2012. London, United Kingdom. PMID- 22512012 TI - Abstracts of the 16th Annual Meeting of French Society of Pharmacology and Therapeutics, the 79th Annual Meeting of Society of Physiology, the 33th Pharmacovigilance Meeting, the 13th APNET Seminar and the 10th CHU CIC Meeting. April 4-6, 2012. Dijon, France. PMID- 22512014 TI - Abstracts of the 2012 Canadian Conference on Medical Education (CCME). April 14 18, 2012. Banff, Alberta, Canada. PMID- 22512013 TI - A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. PMID- 22512015 TI - P-values in baseline tables of randomised controlled trials are inappropriate but still common in high impact journals. PMID- 22512016 TI - [A typical cause the scapula alata on the basis of the scapula exostosis]. PMID- 22512017 TI - Phase II study of 2-chlorodeoxyadenosine plus idarubicin for children with acute myeloid leukaemia in first relapse: a paediatric oncology group study. AB - Relapse remains the leading cause of death in patients with acute myeloid leukaemia (AML). Relatively few new chemotherapy agents have been proven to be effective in this population. We report on a Phase 2 clinical trial using the novel combination of 2-chlorodeoxyadenosine (2-CDA) (8 mg/m2 per d x 5 d) plus idarubicin (Ida) (10 mg/m2 per d x 3 d). The study involved 109 paediatric patients with AML at first relapse, of whom 104 were available for analysis. The overall response rate was 51% (complete response [CR] + partial response) with a CR rate of 46%. 2-year event-free survival (EFS) and overall survival (OS) were 20% and 26%. The only significant variable in determining response, EFS and OS was duration of initial remission, with patients who had an initial remission >1 year having much worse outcomes overall (response rate 74% vs. 25%, EFS 8% vs. 37% and OS of 16% vs. 39%, P < 0.01 for all). There was an acceptable toxicity profile with one neurological event and no cardiac events observed. The most common grade 3-4 toxicities observed were neutropenia (59%) and thrombocytopenia (68%). This study demonstrated that the novel combination of 2-CDA/Ida was effective and should be considered for incorporation in front line therapy for children with AML. PMID- 22512018 TI - Women who have experienced intimate partner violence. Editor's introduction. PMID- 22512019 TI - Facilitating play through communication: significance of teeth exposure in the gorilla play face. AB - Primate facial expressions (FEs) likely play an important role in primate society: through facial signals, individuals can potentially send and receive information and may benefit from coordinating their behavior accordingly. Many primates use a relaxed open mouth (ROM) facial display or "play face" (PF) during play behavior, where the mouth is open but teeth are covered. In addition to this conventional PF, however, Western Lowland gorillas (Gorilla gorilla gorilla) also use a full PF where the upper teeth are exposed. As the teeth are similarly exposed in the bared-teeth expression (which is a signal of appeasement, submission and/or affiliation), the full PF may be a blend of the PF and bared teeth face, and have a different signal function to the PF alone. Focal animal sampling of captive Western Lowland gorillas (N=10) showed that the full PF was more often observed in intense rather than gentle play, and intense play bouts that featured the full PF were longer than those that featured only the PF. Both expressions were associated with an increase in affinitive behavior between sender and receiver postplay, but only the full PF was associated with an increase higher than that of play alone. Overall, the findings suggest that the full PF has an additional role in coordinating and maintaining play, possibly though reducing uncertainty in the receiver and confirming that play is only play. PMID- 22512020 TI - The available time window for embryo transfer in the rhesus monkey (Macaca mulatta). AB - Much effort has been focused on improving assisted reproductive technology procedures in humans and nonhuman primates (NHPs). However, the pregnancy rate after embryo transfer (ET) has not been satisfactory, indicating that some barriers still need to be overcome in this important procedure. One of the key factors is embryo-uterine synchronicity, which is little known in NHPs. The objective of this study was to investigate the available ET time window in rhesus monkey (Macaca mulatta). Eighty-two adult female rhesus monkeys were superovulated with recombinant human FSH. Ovarian phases were identified according to estrogen (E2) and progesterone (P4) levels as well as ovarian examination by ultrasonography and laparoscopy. A total of 259 embryos were transferred by the laparoscopic approach into the oviducts of 63 adult female monkeys. Ovarian phases were divided into late follicular and early luteal phases. Similar pregnancy rates (30-36.4%) were obtained from recipients receiving ET either in their late follicular or early luteal phases, regardless of embryo developmental stages. This study indicates that the available time window for ET in rhesus monkeys is from the late follicular to early luteal phases. PMID- 22512022 TI - [Regulatory mechanism underlying pathogen biofilm formation and potential drug targets]. AB - Bacterial communities usually develop biofilms abound in nature niche. The development of biofilm is a highly dynamic and complex process coordinated by multiple mechanisms, of which two-component system and quorum sensing are two well-defined systems. Biofilm is involved in the virulence of many pathogens. Therefore, targeting the key factors involved in the biofilm formation represents a novel and promising avenue for developing better antibiotics. PMID- 22512021 TI - Reproductive efficiency of captive Chinese- and Indian-origin rhesus macaque (Macaca mulatta) females. AB - Reproductive and survival records (n=2,913) from 313 Chinese-origin and 365 Indian-derived rhesus macaques at the Tulane National Primate Research Center (TNPRC) spanning three generations were studied. Least-squares analysis of variance procedures were used to compare reproductive and infant survival traits while proportional hazards regression procedures were used to study female age at death, number of infants born per female, and time from last birth to death. Chinese females were older at first parturition than Indian females because they were older when placed with males, but the two subspecies had similar first postpartum birth interval (1st PPBI) and lifetime postpartum birth interval (LPPBI). Females that gave birth to stillborn infants had shorter first postpartum birth intervals (1st PPBI) than females giving birth to live infants. Postpartum birth intervals decreased in females from age 3 to 12 but then increased again with advancing age. Chinese infants had a greater survival rate than Indian infants at 30 days, 6 months, and 1 year of age. Five hundred and forty-three females (80.01%) had uncensored, or true records for age at death, number of infants born per female, and time from the birth until death whereas 135 females (19.91%) had censored records for these traits. Low- and high uncensored observations for age at death were 3 and 26 years for Chinese, and 3 and 23 years for Indian females. Uncensored number of infants born per female ranged from 1 to 15 for Chinese females and 1 to 18 for Indian females. Each of these traits was significantly influenced by the origin*generation interaction in the proportional hazards regression analyses, indicating that probabilities associated with age at death, number of infants born per female, and time from last birth to death for Chinese and Indian females did not rank the same across generations. PMID- 22512023 TI - [Modification of natural products for drug discovery]. AB - Pharmacological activity and druggability are two essential factors for drug innovation. The pharmacological activity is definitely indispensable, and the druggability is destined by physico-chemical, biochemical, pharmacokinetic and safety properties of drugs. As secondary metabolites of animals, plants, microbes and marine organisms, natural products play key roles in their physiological homeostasis, self-defense, and propagation. Natural products are a rich source of therapeutic drugs. As compared to synthetic molecules, natural products are unusually featured by structural diversity and complexity more stereogenic centers and fewer nitrogen or halogen atoms. Naturally active substances usually are good lead compounds, but unlikely meet the demands for druggability. Therefore, it is necessary to modify and optimize these structural phenotypes. Structural modification of natural products is intent to (1) realize total synthesis ready for industrialization, (2) protect environment and resources, (3) perform chemical manipulation according to the molecular size and complexity of natural products, (4) acquire novel structures through structure-activity relationship analysis, pharmacophore definition, and scaffold hopping, and (5) eliminate unnecessary chiral centers while retain the bioactive configuration and conformation. The strategy for structural modification is to increase potency and selectivity, improve physico-chemical, biochemical and pharmacokinetic properties, eliminate or reduce side effects, and attain intellectual properties. This review elucidates the essence of natural products-based drug discovery with some successful examples. PMID- 22512024 TI - [Mass spectrometry technology and its application in analysis of biological samples]. AB - With the excellent merits of wide analytical range, high sensitivity, small sample size, fast analysis speed, good repeatability, simple operation, low mobile phase consumption, as well as its capability of simultaneous isolation and identification, etc, mass spectrometry techniques have become widely used in the area of environmental science, energy chemical industry, biological medicine, and so on. This article reviews the application of mass spectrometry technology in biological sample analysis in the latest three years with the focus on the new applications in pharmacokinetics and bioequivalence, toxicokinetics, pharmacokinetic-pharmacodynamic, population pharmacokinetics, identification and fragmentation pathways of drugs and their metabolites and metabonomics to provide references for further study of biological sample analysis. PMID- 22512025 TI - [Application research of hot-melt extrusion in preparation of solid dispersion]. AB - Hot-melt extrusion (HME) is mainly used to enhance the dissolution rate and bioavailability of poorly water soluble drugs. It has many advantages, such as simple process, continuous operation, high efficiency, on-line monitoring and so on. HME provides an innovative approach, which has been concerned by pharmaceutical workers, for preparation of solid dispersion abroad. This article reviews recent advances on preparation of solid dispersion by HME in preparation processing, carrier materials and quality evaluation in order to further promote and apply HME in preparation of solid dispersion. PMID- 22512026 TI - [High-throughput screening for hamster chymase 2 inhibitors]. AB - To screen potential hamster chymase 2 inhibitors, a high-throughput screening (HTS) model was established. Recombinant hamster chymase 2 with active form was cloned and expressed in E. coli. The HTS model with total volume of 50 microL in 384-well microplate was based on fluorescence analysis and was proved sensitive as well as specific (Z' = 0.84). A total of 40 080 samples (including 28 060 compounds and 12 020 natural products) were screened, and 613 samples with inhibition greater than 90% were selected for further rescreening. Finally, compounds J16647 and J16648 were identified with high inhibitory activity on chymase 2, and whose IC50 values were 0.823 and 0.690 micromol x L(-1), respectively. PMID- 22512027 TI - [Effect of osthol on apoptosis and bone resorption of osteoclasts cultured in vitro]. AB - This study is to investigate the effect of osthol on osteoclasts' activity, bone resorption as well as apoptosis in vitro, and explore the mechanism of osthol in preventing osteoporosis. Osteoclasts were separated from long-limb bones of new born rabbits, cultured in 24-well plate with glass slices and bone slices, and treated by 1 x 10(-5) mol x L(-1) osthol. Osteoclasts were identified by observing live cells with phase contrast microscope, HE staining, TRAP staining and toluidine blue staining of bone resorption pits. The numbers of bone resorption pits were counted as well as the surface area of bone resorption on bone slice. Osteoclasts were stained with acridine orange to detect the cell apoptosis. The ratio of apoptotic osteoclasts was observed under fluorescence microscope. The gene expression of RANKL, OPG, TRAP and p-JNK1/2 protein expression were examined using real time PCR and Western blotting, respectively. Comparing with the control group without osthol, the rates of apoptotic osteoclasts increased obviously and the number and area of bone resorption pits decreased evidently with 1 x 10(-5) mol x L(-1) osthol. There is significant difference between control group and experiment group treated by 1 x 10(-5) mol x L(-1) osthol. Therefore, the osthol through RANK+RANKL/TRAF6/Mkk/JNK signal pathway inhibits the osteoclasts activity, enhances osteoclasts apoptotic and inhibits the bone resorption. PMID- 22512028 TI - [Effect of carvedilol on T-type calcium current in myocytes of non-infarcted area of the rabbit healed myocardial infarction]. AB - This article reports the investigation of the effect of carvedilol (Car) on T type calcium current (I(Ca,T)) of noninfarcted ventricular myocytes in rabbit models of healed myocardial infarction (HMI). Rabbits with left anterior descending artery ligation were prepared and allowed to recover for 8 weeks, as HMI group. Animals undergoing an identical surgical procedure without coronary ligation were served as the sham-operated group (sham group). Whole cell voltage clamp techniques were used to measure and compare currents in cells from the different groups. Noting that I(Ca,T) density in HMI cells increased markedly to 2.36 +/- 0.12 pA/pF (at -30 mV) compared with cells of sham, where little I(Ca,T) (-0.35 +/- 0.02 pA/pF) was observed. Meanwhile, further analysis revealed a significant hyperpolarizing shift of steady-state activation curve of I(Ca,T) in HMI cells, where the time constants of deactivation were prolonged and the time of recovery from inactivation was shortened. Finally, the amplitude of I(Ca,T) was increased. Carvedilol (1 micromol x L(-1)) was found to decrease the amplitude of I(Ca,T) to -1.38 +/- 0.07 pA/pF through inhibiting process of I(Ca,T) activation. Furthermore, carvedilol delayed recovery from inactivation of I(Ca,T) and shortened the time constants of deactivation in HMI cells. This study suggested that the application of carvedilol in HMI cells contributes to the dynamic changes in I(Ca,T) and may account for reduction of incidence of arrhythmia after myocardial infarction. PMID- 22512029 TI - [Effect of high altitude hypoxia on the activity and protein expression of CYP2C9 and CYP2C19]. AB - This study is to investigate the effect of high altitude hypoxia on the activity and protein expression of CYP2C9 and CYP2C19. Rats from plain (P) and rats with acute middle altitude hypoxia (AMH), chronic middle altitude hypoxia (CMH), acute high altitude hypoxia (AHH) and chronic high altitude hypoxia (CHH) were administered orally phenytoin sodium (PHT) and omeprazole (OMZ) to evaluate the activity of CYP2C9 and CYP2C19, separately. The serum concentrations of PHT and metabolite 4'-hydroxyphenytoin (HPPH) at 12 h after treatment and the serum concentrations of OMZ and metabolite 5-hydroxy omeprazole (5-OHOMZ) at 3 h after treatment were determined by RP-HPLC. The activity of CYP2C9 and CYP2C19 was evaluated by the ratio of HPPH to PHT and the ratio of 5-OHOMZ to OMZ, respectively. The protein expressions of CYP2C9 and CYP2C19 were determined by ELISA method. The activities of CYP2C9 (HPPH/PHT) in P, AMH, CMH, AHH and CHH were 0.67 +/- 0.31, 0.75 +/- 0.29, 0.76 +/- 0.23, 0.79 +/- 0.31 and 0.75 +/- 0.18, respectively, and the activities of CYP2C19 (5-OHOMZ/OMZ) in P, AMH, CMH, AHH and CHH were 0.17 +/- 0.06, 0.20 +/- 0.10, 0.11 +/- 0.05, 0.37 +/- 0.13 and 0.19 +/- 0.05, respectively. The protein expressions of CYP2C9 in P, AMH, CMH, AHH and CHH were 4.20 +/- 1.27, 3.95 +/- 0.81, 3.93 +/- 1.11, 4.32 +/- 1.03 and 4.12 +/- 0.86 ng x g(-1), respectively, and the protein expressions of CYP2C19 in P, AMH, CMH, AHH and CHH were 3.91 +/- 1.82, 3.63 +/- 2.07, 2.55 +/- 0.85, 4.78 +/- 2.37 and 3.51 +/- 1.03 ng x g(-1), respectively. The activities and protein expressions of CYP2C9 in AMH, CMH, AHH and CHH were not significantly different with those of P. The protein expressions of CYP2C19 in AMH, CMH, AHH and CHH were not significantly different with those of P, but the activity of CYP2C19 in AHH was significantly higher than that of P. This study found significant changes in the activity of CYP2C19 under the special environment of acute high altitude hypoxia. PMID- 22512030 TI - [Design, synthesis and activities of 4-(2-acetoxybenzoylamino) butyramide derivatives]. AB - To explore new agents of gamma-aminobutyric acid (GABA) derivatives with more potent antiepileptic activity, a series of 4-(2-acetoxybenzoylamino) butyramide derivatives were designed and synthesized. All of the novel compounds (5a-51) were synthesized from GABA as starting material, and their structures were confirmed with IR, 1H NMR, EI-MS and elemental analysis. Preliminary pharmacological test in vitro showed that all target compounds displayed strong antiepileptic activities and were worth for further study. The structure-activity relationship of 4-(2-acetoxybenzoylamino) butyramide derivatives was also discussed preliminarily. PMID- 22512031 TI - [Synthesis and structure-activity relationship of N-(2-arylethyl) isoquinoline derivatives as anti-cancer agents]. AB - A series of novel N-(2-arylethyl) isoquinoline derivatives were designed, synthesized and evaluated for their anti-cancer activities. Among these analogs, compound 9a exhibited the potential anti-cancer activities on HepG2 and HCT116 cells with IC50 values of 2.52 and 1.99 microg x mL(-1), respectively. Cell cycle was blocked at S phase of HepG2 cells treated with 9a by flow cytometry detection. Our results provided a basis for the development of a new series of anti-cancer candidates. PMID- 22512032 TI - [Coumarins of Anemone raddeana Regel and their biological activity]. AB - To study the coumarins of Anemone raddeana Regel, the compounds were separated by silica gel column chromatography and HPLC. Their structures were identified by their physicochemical property and spectral analysis. Two new compounds were isolated and identified as 4, 7-dimethoxyl-5-methyl-6-hydroxy coumarin (1) and 4, 7-dimethoxyl-5-formyl-6-hydroxycoumarin (2). The bioassays indicated that compounds 1 and 2 could significantly inhibit the proliferation of cancer cell, and showed the agonist effect on the transactivity of retinoic acid receptor alpha (RARalpha). In addition, the two compounds had inhibitory effect against human leukocyte elastase (HLE). PMID- 22512033 TI - [In vivo comparison of estradiol metabolism in liver microsomes of human, Beagle dog and rat]. AB - The inter-species differences of estradiol metabolism were investigated in human, Beagle dog and rat liver microsomes by comparing enzyme kinetics of parent drug and the formation of its major metabolites. The incubation systems of estradiol with liver microsomes of the three species were optimized in terms of estradiol concentration, microsomal protein content and incubation time. The concentrations of estradiol and its metabolites were measured by LC-MS/MS method. The t1/2, CLint, CLh, Km and Vmax of estradiol incubated with male human liver microsomes were 40.02 +/- 8.32 min, 41.39 +/- 6.57 mL x min(-1) x kg(-1), 13.81 +/- 12.36 mL x min(-1) x kg(-1), 26.8 +/- 6.99 micromol x L(-1) and 0.75 +/- 0.92 micromol x L(-1) x min(-1), respectively. The corresponding parameters of female human were 44.71 +/- 10.21 min, 29.85 +/- 8.97 mL x min(-1) x kg(-1), 0.01 +/- 0.68 mL x min(-1) x kg(-1), 44.2 +/- 7.73 micromol x L(-1) and 1.27 +/- 4.41 micromol x L( 1) x min(-1), that of male dog were 21 +/- 7.33 min, 165.53 +/- 29.33 mL x min( 1) xkg(-1), 26.01 +/- 8.39 mL x min(-1) x kg(-1), 19.5 +/- 7.34 micromol x L(-1) and 1.6 +/- 0.65 micromol x L(-1) x min(-1), that of female dog were 25.5 +/- 5.32 min, 135.11 +/- 42.34 mL x min(-1) x kg(-1), 0.24 +/- 3.18 mL x min(-1) x kg(-1), 8.33 +/- 6.32 micromol x L(-1) and 0.51 +/- 2.15 micromol x L(-1) x min( 1), that of male rat were 5.11 +/- 3.84 min, 485.63 +/- 36.52 mL x min(-1) x kg( 1), 49.57 +/- 15.29 mL x min(-1) x kg(-1), 62 +/- 13.74 micromol x L(-1) and 19.16 +/- 9.67 micromol x L(-1) x min(-1), and that of female rat were 7.0 +/- 3.69 min, 354.82 +/- 33.33 mL x min(-1) x kg(-1), 8.04 +/- 3.23 mL x min(-1) x kg(-1), 35.38 +/- 7.65 micromol x L(-1) and 8.39 +/- 4.91 micromol x L(-1) min( 1), respectively. There were nine metabolites detected from all the three species, but the relative amounts of the metabolites generated were different in three species. The results indicted that the major phase I metabolic pathway of estradiol was similar in the liver microsomes from all the three species. However, the inter-species differences were found in the view of relative amounts of the metabolites as well as the metabolic characteristics of estradiol in liver microsomal incubation. PMID- 22512034 TI - [Measurement of the amino acid sequence for the fusion protein FP3 with LC MS/MS]. AB - The amino acid sequence of the fusion protein FP3 was measured by two types of LC MS/MS and its primary structure was confirmed. After reduction and alkylation, the protein was digested with trypsin and glycosyl groups in glycopeptide were removed by PNGase F. The mixed peptides were separated by LC, then Q-TOF and Ion trap tandem mass spectrometry were used to measure b, y fragment ions of each peptide to analyze the amino acid sequence of fusion protein FP3. Seventy-six percent of full amino acid sequence of the fusion protein FP3 was measured by LC ESI-Q-TOF with the remaining 24% completed by LC-ESI-Trap. As LC-MS and tandem mass spectrometry are rapid, sensitive, accurate to measure the protein amino acid sequence, they are important approach to structure analysis and identification of recombinant protein. PMID- 22512035 TI - [Analysis and evaluation of the impurity of felodipine and its tablets]. AB - The paper reports the systematic study on felodipine and its impurities in tablets, to improve its quality standards for the control of the related substances. HPLC-DAD, UPLC-MS, IR and NMR methods were used for the isolation of felodipine and its impurities in tablets, their identification and the zebrafish animal model was used for the analysis of the toxic impurities. In felodipine material and its tablets, three impurities are isolated and identified. They are impurity 1 [dimethyl 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydropyridine 3, 5-dicarboxylate], impurity 2 [ethyl methyl 4-(2, 3-dichlorophenyl)-2, 6 dimethylpyridine-3, 5-dicarboxylate] and impurity 3 [diethyl 4-(2, 3 dichlorophenyl)-2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylate], separately. The result of zebrafish animal model analysis showed that the teratogenic effects of four compounds were: impurity 3 > or = felodipine > impurity 1 > impurity 2, lethal effects were as follows: impurity 2 = impurity 3 > felodipine > or = impurity 1. This study confirmed the toxicity of three impurities in felodipine. According to the results, the paper suggested the amendments to the standard of the medicine and provided the support to the control of impurities in the manufacturing process. PMID- 22512036 TI - [Transport of limonin in rat intestine in situ and Caco-2 cells in vitro]. AB - Limonin existed in citrus fruits has been shown to have anti-bacterial, anti viral, anti-feedant, anti-nociceptive, anti-inflammatory activities and anti carcinogenic activities. But the clinical use is limited by its low bioavailability. The aim of this study is to observe the absorption and secretion transport mechanisms of limonin in intestine which can pave the way for the further study and clinical use. The transport characteristics and mechanisms of limonin in rat were studied by in situ intestine perfusion and in vitro Caco-2 cells method. The intestinal absorption of limonin was probably via a facilitated diffusion pathway which was poor and without segment-selection. Verapamil and ketoconazole improved the absorption remarkably according to the result of in vitro Caco-2 cells study; however, probenecid had no significant effect on the absorption. The P-gp efflux and CYP3A4 metabolism were involved in the poor intestinal absorption and low bioavailability of limonin. The exploration of the intestinal absorption mechanism is crucial to the design of dosage form and clinical use of limonin. PMID- 22512037 TI - [Intestinal absorption of berberine alone and in combinations by rats single pass intestinal perfusion in situ]. AB - The aim of the study is to investigate the effects of concentration, intestinal segments, pH, inhibitors of proteins (P-gp), Na(+)-dependent glucose transporter (SGLT1) on the intestinal absorption of berberine, and to compare intestinal absorption of berberine in combinations. With phenol red as the indicator, in situ single pass intestinal perfusion (SPIP) model was used and intestinal absorption of pure berberine at concentrations of 36.70, 46.17 and 92.33 microg x mL(-1), simulated system of HLJDT (mixture of berberine, baicalin and geniposide), HLJDT with the concentration of berberine 92.33 microg x mL(-1) in perfusion solution of different intestinal segments (duodenum, jejunum, ileum, and colon) were determined by HPLC in combination with diode array detection (DAD). The results indicated that Ka values ofberberine at different concentrations had little significant difference among that obtained after perfusing via duodenum, jejunum, ileum and colon indicating that the absorption of berberine was mainly the passive diffusion. It was also suggested that SGLT1 and P-gp might exert some effects on the absorption of berberine. Ka and Peff values of berberine in a mixture of pure compounds and HLJDT for different intestine segments of rat showed an increasing tendency and was significantly different (P < 0.05) indicating that berberine in a mixture of pure compounds and HLJDT was assimilated better in small intestine. These results indicate that the intestinal absorption of berberine may be affected by compatibility of compounds. Additionally, berberine has wide absorption window and better absorption in colon. PMID- 22512038 TI - [Improving the dissolution rate of poorly water-soluble resveratrol by the ordered mesoporous silica]. AB - The aim of this study is to synthesize the ordered mesoporous silica (OMS) as drug carrier to improve release property of insoluble drug and investigate the dissolution profile of insoluble drug from the porous carrier. The OMS was obtained by using cetyltrimethyl ammonium bromide as the template and resveratrol was selected as the model drug. The resveratrol-loaded OMS (Res-OMS) were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), N2 adsorption-desorption, X-ray diffraction (XRD) and FT-IR spectroscopy. In vitro drug release behavior was also investigated. It was found that the synthesized OMS showed a large surface area, a narrow pore size distribution and an important mesoporosity associated to hexagonally organized channels. Compared with physical mixture and crystalline powder, resveratrol was in amorphous or molecular form after loading into OMS. The release rate ofresveratrol from drug-loaded OMS was significantly increased suggesting the great potential application of OMS for the formulation of poorly soluble drugs. PMID- 22512039 TI - [The preparation of paeonol transdermal delivery systems based on the microemulsion-based gels and its pharmacokinetics characters]. AB - Investigation of the pharmacokinetics of paeonol microemulsion, microemulsion based gels and marketed paeonol ointments by the skin-blood synchronous microdialysis coupled with LC/MS is reported in this study. The microdialysis systems were established by linear probes and concentric circles probes. In vivo recovery of paeonol in skin is (69.7 +/- 4.8) % and in blood is (51.6 +/- 7.2)%. The paeonol microemulsion, microemulsion-based gels and marketed paeonol ointments were administered to rats. PBS (pH 7.4) served as perfused solution. The perfusion rate was 5 microL x mL(-1) and the microdialysis samples were collected every 20 min intervals. The paeonol concentration in perfused solution was determined by LC/MS. The results showed that paeonol microemulsion and microemulsion-based gels significantly raised the drug concentrations in skin more than that of paeonol ointments. The paeonol microemulsion-based gels has similar bioavailability as the paeonol ointments in blood, but its blood drug concentrations were steadier. The paeonol microemulsion-based gels may be developed into a new preparation for dermis eczema. The skin-blood synchronous microdialysis technique proved to be a new method for the pharmacokinetics study of transdermal delivery systems. PMID- 22512040 TI - [Mechanism of genuineness of liquorice Glycyrrhiza uralensis based on CNVs of HMGR, SQS1 and beta-AS gene]. AB - This study is to reveal the correlation between CNVs of HMGR, SQS1, beta-AS gene and genuineness of liquorice. Real-time PCR was used to detect the copy number of HMGR, SQS1, beta-AS gene of liquorice. According to the results, the range of the copy number variation of HMGR gene was between 1 and 3, the copy number of SQS1 gene was 1 or 2, and the copy number of beta-AS gene was only 1. On the basis of the copy number of HMGR, SQS1 and beta-AS gene, there were five groups, type A (2 + 1 + 1), type B (1 + 1 + 1), type C (3 + 2 + 1), type D (2 + 2 + 1) and type E (3 + 1 + 1). There were two types, type A and type B, in Hangjinqi of Inner Mongolia, and the ratio of A to B was 1:1.3. There were also two types, type A and type B, in Chifeng of Inner Mongolia, and the ratio of A to B was 3:1. There were four types, type A, type B, type C and type D, in Yanchi of Ningxia province, and the ratio of A to B was 1:5.1. There were three types, type A, type B and type E, in Minqin of Gansu province, and the ratio of A to B was 2:1. So CNVs mainly existed in the liquorice from Ningxia and Gansu provinces. While the genetic background of liquorice from Hangjinqi of Inner Mongolia was stabilized. The results of the experiment proved that the correlation between CNVs and origins was one of the reasons of genuineness of liquorice. PMID- 22512041 TI - [Effect of ferulic acid on learning and memory impairments of vascular dementia rats and its mechanism of action]. AB - This study is to investigate the effect of ferulic acid on learning and memory impairments of vascular dementia (VD) rats and its mechanism of action. VD rats model was replicated by permanent bilateral common carotid artery occlusion (2VO). The learning and memory capability of VD rats was evaluated by Morris water maze. The activity of acetylcholinesterase (AChE) and superoxide dismutase (SOD) and the content of glutamic acid (Glu) and malondialdehyde (MDA) in hippocampus of VD rats' brain were determined, separately. The results showed that ferulic acid could alleviate learning and memory deficits of VD rats significantly. Ferulic acid was found to inhibit the activity of AChE and increased the activity of SOD in rat hippocampus. In addition, ferulic acid could also decrease the content of Glu and MDA in rat hippocampus. These results suggested that ferulic acid could alleviate VD rats' learning and memory deficits, which might be due to antioxidation, the improvement of cholinergic system in brain, or the inhibitory of nerve injury by excitatory amino acids. PMID- 22512042 TI - Spatial variations in US poverty: beyond metropolitan and non-metropolitan. AB - Because poverty in rural and urban areas of the US often has different causes, correlates and solutions, effective anti-poverty policies depend on a thorough understanding of the ruralness or urbanness of specific places. This paper compares several widely used classification schemes and the varying magnitudes of poverty that they reveal in the US. The commonly used 'metropolitan/non metropolitan' distinction obscures important socioeconomic differences among metropolitan areas, making our understanding of the geography of poverty imprecise. Given the number and concentration of poor people living in mixed rural and rural counties in metropolitan regions, researchers and policy-makers need to pay more nuanced attention to the opportunities and constraints such individuals face. A cross-classification of the Office of Management and Budget's metro system with a nuanced RUDC scheme is the most effective for revealing the geographical complexities of poverty within metropolitan areas. PMID- 22512043 TI - Representation, labour markets and immigrant and minority ethnic workers networking, new forms of representation and politics in the multi-ethnic city. PMID- 22512047 TI - The proliferation of brands: the case of food in Belgium, 1890-1940. PMID- 22512048 TI - A census-based count of the Civil War dead. PMID- 22512049 TI - Dismantling the asylum and charting new pathways into the community: mental health care in twentieth century Canada. PMID- 22512050 TI - [First initiatives for social integration of the mentally ill in one phase of pre deinstitutionalization. The example of Saint-Jean-de-Dieu, 1910-1950]. AB - This article on the first initiatives of social integration of the mentally ill, using the example of the Hopital St-Jean-de-Dieu, explores the implementation of a period of deinstitutionalization in the early decades of the 20th century. Our study is situated in the recent historiography that offers a rereading of the period just prior to the Quiet Revolution in Quebec. We intend to contribute by demonstrating that the policies, strategies and practices of the Sisters of Providence and the psychiatrists of St-Jean-de-Dieu developed a system of deinstitutionalization that reintegrated patients into their family as early as the 1910s, half a century before the first wave of deinstitutionalization of the 1960s was orchestrated by the authors of the Bedard report. PMID- 22512051 TI - Deinstitutionalization reconsidered: geographic and demographic changes in mental health care in British Columbia and Alberta, 1950-1980. AB - Using demographics on admission to, and discharge from, mental hospitals in Alberta and British Columbia, this paper analyzes the social process commonly framed as deinstitutionalization between 1950 and 1980. A focus on the two most western Canadian provinces permits an exploration of these changes in these regional contexts. Pressured by new funding arrangements, a shift towards community care, and growing criticism of the alleged oppressive nature of large institutions, the three main mental hospitals scaled down as of the 1950s. This trend did not mean, however, that the overall number of hospitalized patients decreased during this time period. The total number of hospitalizations, particularly short-term admissions, actually expanded, while trans institutionalization also occurred. This case study mirrors larger trends of postwar mental health care, illustrating the social, political, and cultural challenges experienced in the reconstruction of institutional care. PMID- 22512052 TI - Effect of GnRHa on apoptosis and release of VEGF in endometrial cell cultures from patients with adenomyosis. AB - AIM: To investigate the effect of Gonadotropin-realeasing hormone agonist (GnRHa) on apoptosis and the release of vascular endothelial growth factor (VEGF) in the in vitro eutopic endometrial cell of adenomyosis. METHODS: Biopsy specimens of eutopic endometrium obtained from 32 women with adenomyosis and 20 normal womenwere studied. Cells were cultured with GnRHa for 24 h, 48 h and 72 h in the concentration of 10-7 mol/L and 105 mol/L. Apoptotic ratio was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and flow cytometry before and after using GnRHa. VEGF concentrations in culture supernatant were detected by commercial enzyme-linked immunosorbent assay (ELISA). RESULTS: (1)Cells in two groups showed cell shrinkage, floating, nucleus concentration, nuclear fragmentation and typical apoptotic bodies. (2) The apoptotic ratio of cultured AM endometrial cell without GnRHa was lower than that in control group and the apoptotic ratio increased with the prolongation of time in two groups(P<0.01). (3)After GnRHa addition, each group showed higher apoptotic ratio and a trend towards higher apoptotic ratio linked to advanced concentration. Furthermore, apoptotic ratio in study group was significantly higher than that in control group at the same time point and same concentration ( P < 0. 01 ). ( 4 ) The concentrations of VEGF in the eutopic endometrial cells of adenomyosis were significantly higher than those in the normal endometrimn. The concentrations of VEGF in the both groups were downregulated by GnRHa in a dose dependent manner. CONCLUSION: (1) The abnormality of apoptotic ratio of AM endometrial cells may be associated with the AM pathogenesis. GnRHa nmy increase the apoptotic ratio of cultured AM endometrial cells by autocrine or paracrine. (2) VEGF may play an impotant role in the pathogenesis of adenomyosim. GnRHa can directly suppress the survival and growth of ectopic endometrial by decreasing the release of VEGF which was related to the adenomyosis angiogenesis. PMID- 22512053 TI - [The image of dentistry. Part 2: The ideal dentist]. AB - Our second part of the publication entitled "The image of Dentistry" discusses the properties that correspond to the ideal image of dentistry or even the ideal scientist such as the management of the dental practice, the dentist-patient relationship and the appropriate handling of the patient's emotions such as anxiety or pain. The quality of treatment and the friendly, honest and compassionate attitude of the dentist can immediately affect the image of dentistry. Therefore, the dental professional must try to keep the balance between practice profit, staffing and patient well-being in order to fulfill both social and public health responsibilities. PMID- 22512054 TI - Continuing professional education. Foreword. PMID- 22512055 TI - Canine-assisted therapy in military medicine. Perspectives: commander's introduction. PMID- 22512056 TI - [Psychotherapy for refugee children]. PMID- 22512057 TI - [The animal police and the emergency number 144...Starting point for national legislation to help animals in need]. PMID- 22512058 TI - [The bullet is through the cow]. PMID- 22512059 TI - [A practice succeeds or fails with good leadership]. PMID- 22512060 TI - [150 years KNMVD: education packet for primary schools]. PMID- 22512061 TI - [Now also a cheaper basic version of Development of Young Veterinarians]. PMID- 22512062 TI - [Surveillance]. PMID- 22512063 TI - Poultry meat as a source of human campylobacteriosis. AB - Campylobacteriosis is a prevalent diarrhoeal illness in humans, and poultry meat is considered the most important source of foodborne infection with Campylobacter spp. In this review, the disease burden of campylobacteriosis, the most important risk factors for Campylobacter colonization in broilers, and potential interventions to reduce poultry-related human exposure to Campylobacter spp. are discussed. PMID- 22512064 TI - [Methicillin resistant Staphylococcus pseudointermedius: recent insights for small animal practices]. PMID- 22512065 TI - [What a practicing veterinarian should know about the Eyach virus]. PMID- 22512066 TI - [What a practicing veterinarian should know about the "louping ill" virus]. PMID- 22512067 TI - [Back disorders in dogs and humans show many similarities]. PMID- 22512068 TI - [NVWA promotes good employment principles: "We offer veterinarians work that matters"]. PMID- 22512069 TI - [Vaccine promotion foundation D10 supports farmers in Malawi]. PMID- 22512070 TI - [Passion for parrots]. PMID- 22512071 TI - [Quickscan helps customize prizes]. PMID- 22512072 TI - [Instructions from a veterinarian]. PMID- 22512073 TI - [Predictive value of bacteriological analysis of bulk milk]. PMID- 22512074 TI - [Carl Konig: practitioner, researcher, professor and writer]. PMID- 22512075 TI - [Don't keep left]. PMID- 22512076 TI - [Reporting blood samples]. PMID- 22512077 TI - Metabonomics for discovering biomarkers of hepatotoxicity and nephrotoxicity. AB - Metabonomics has played increasingly important roles in pharmaceutical research and development. Safety assessment of drugs is a key stage in drug development and one which represents a significant attritional hurdle. However, characterization of the molecular mechanisms of drug toxicity still remains an enormous challenge. Recent advancements in 'omics' sciences, and in particular metabonomics, has enabled some elucidation or insights into toxicological sequelae. Metabonomics is a global metabolic profiling framework which utilizes high resolution analytics together with chemometric statistical tools to derive an integrated picture of both endogenous and xenobiotic metabolism. Hepatotoxicity and nephrotoxicity are major reasons that drugs are withdrawn post market, and hence it is of major concern to both the Food and Drug Administration and pharmaceutical companies. There is a strong need to develop reliable biomarkers that can accurately predict toxicity in the drug discovery and development process and are translatable to the clinic. A deeper understanding of global perturbations in biochemical pathways and useful biomarkers could provide valuable insights about mechanisms of toxicity. This review summarizes some current progress in the application of metabonomic in understanding drug-induced hepatotoxicity and nephrotoxicity, with an emphasis on identifying early toxicity biomarkers. PMID- 22512078 TI - Screening and identification of various components in Thalictrum fortunei using a combination of liquid chromatography/time-of-flight tandem mass spectrometry. AB - An approach for screening and identification of various components in a traditional Chinese medicine (TCM), using a combination of LC/TOF-MS technique was described in this paper. The chemical profile of Thalictrum fortunei, well known in TCM, was studied using the established method. The possibilities of screening and identifying non-target components inside TCM with modern data acquisition methods of acceleration time of flight mass spectrometers, such as data-dependent MS to MS/MS switching were investigated. As a result, 27 components were identified. This study was aimed to screen and identify the main components of T. fortunei using LC/TOF-MS, expecting to provide a rapid, sensitive, economical and systematical method for the identification and further quality evaluation of TCM preparation. PMID- 22512079 TI - Simultaneous determination of four alkaloids in Solanum lyratum Thunb by UPLC MS/MS method. AB - Four alkaloids, strychnine, soladulcidine, solamargine and (3-O-beta-D glucopyranosyl-(1 --> 2)beta-D-glucopyranosyl-(1 --> 4)-beta-D-galactopyranoside (25xi)-solanidan-3beta,23beta-diol)(abbreviation, glycoalkaloid A) were isolated from Solanum lyratum Thunb. The structures were elucidated by NMR and measuring physicochemical properties. Then a novel and rapid method using an ultra performance liquid chromatography coupled with mass spectrometry was developed and validated for the simultaneous determination of these compounds. An acquit UPLC BEH C18 column (2.1 mm x 50 mm, 1.7 microm) was used. Acetonitrile and 0.1% formic acid were adopted as mobile phase. Detection was performed on a Waters Micromass Quattro Premier tandem quadrupole mass spectrometer in the positive ion mode using an electrospray source. The multiple reaction monitoring (MRM) mode was used to detect the target compounds. The established method showed a good linearity (R2 > 0.999 0) over the investigated concentration ranges, good inter day and intra-day precisions (less than 2%) and good recoveries (from 99.8% to 100.1%) for all four target compounds. Compared to previous methods employing conventional high performance liquid chromatography (HPLC) separation, the ultra high-pressure liquid chromatography-tandem mass spectrometry achieved preferable chromatographic parameters and significantly increased sample throughput. PMID- 22512080 TI - Comparison of two in vitro methods to evaluate the water resistance of sunscreens. AB - For a long time, the water resistance of sunscreens has been determined in vivo, according to Colipa's (Comite de Liaison des Industries de la Parfumerie) procedure. This method is not so ethical as healthy volunteers are irradiated, and can be replaced by an in vitro method which is easy and quick to perform. The objective of this work was to correlate the experimental device proposed by Choquenet et al. and the dissolutest (Sotax AT6). This equipment is used in the pharmaceutical industry to control the tablets. The experimental conditions have been fixed to correlate the results obtained with both methods. The stirring speed for the dissolutest was fixed at 75 rpm, which is the speed value recommended by the European Pharmacopeia to study the dissolution over time of tablets. PMID- 22512081 TI - Pharmacokinetics of beta-asarone in rabbit blood, hippocampus, cortex, brain stem, thalamus and cerebellum. AB - beta-Asarone has significant pharmacological effects on the central nervous system. As a potential therapeutic agent to manage brain diseases, analysis of the pharmacokinetics of beta-asarone in brain is necessary. We used cardio perfusion method to exclude the beta-asarone in the brain blood. The brain was divided into five regions: hippocampus, cortex, brain stem, thalamus and cerebellum, and pharmacokinetic differences were investigated. We found that concentration-time profile of beta-asarone in blood, hippocampus, cortex, brain stem and cerebellum could be adequately described by a first-order equation, consistent with a linear two-compartmental model, but a first-order equation with a linear one-compartmental model in thalamus. The half lives of beta-asarone in blood, hippocampus, cortex, brain stem, thalamus and cerebellum were 1.3801, 1.300, 1.937, 7.142, 2.832 and 8.149 h, respectively. Gender differences do not significantly influence plasma pharmacokinetics of beta-asarone. PMID- 22512082 TI - Effects of curcumin on the pharmacokinetics of tamoxifen and its active metabolite, 4-hydroxytamoxifen, in rats: possible role of CYP3A4 and P glycoprotein inhibition by curcumin. AB - The effects of curcumin, a natural anti-cancer compound, on the bioavailability and pharmacokinetics of tamoxifen and its metabolite, 4-hydroxytamoxifen, were investigated in rats. Tamoxifen and curcumin interact with cytochrom P450 (CYP) enzymes and P-glycoprotein, and the increase in the use of health supplements may result in curcumin being taken concomitantly with tamoxifen as a combination therapy to treat or prevent cancer. A single dose of tamoxifen was administered orally (9 mg x kg(-1)) with or without curcumin (0.5, 2.5 and 10 mg x kg(-1)) and intravenously (2mg x kg(-1)) with or without curcumin (2.5 and 10 mg x kg(-1)) to rats. The effects of curcumin on P-glycoprotein (P-gp) and CYP3A4 activity were also evaluated. Curcumin inhibited CYP3A4 activity with 50% inhibition concentration (IC50) values of 2.7 microM. In addition, curcumin significantly (P < 0.01 at 10 microM) enhanced the cellular accumulation of rhodamine-123 in MCF 7/ADR cells overexpressing P-gp in a concentration-dependent manner. This result suggested that curcumin significantly inhibited P-gp activity. Compared to the oral control group (given tamoxifen alone), the area under the plasma concentration-time curve (AUC(0-infinity)) and the peak plasma concentration (C(max)) of tamoxifen were significantly (P < 0.05 for 2.5 mg x kg(-1); P < 0.01 for 10 mg x kg(-1)) increased by 33.1-64.0% and 38.9-70.6%, respectively, by curcumin. Consequently, the absolute bioavailability of tamoxifen in the presence of curcumin (2.5 and 10 mg x kg(-1)) was 27.2-33.5%, which was significantly enhanced (P < 0.05 for 2.5 mg x kg(-1); P < 0.01 for 10 mg x kg(-1)) compared to that in the oral control group (20.4%). Moreover, the relative bioavailability of tamoxifen was 1.12- to 1.64-fold greater than that in the control group. Furthermore, concurrent use of curcumin significantly decreased (P < 0.05 for 10 mg x kg(-1)) the metabolite-parent AUC ratio (MR), implying that curcumin may inhibit the CYP-mediated metabolism of tamoxifen to its active metabolite, 4 hydroxytamoxifen. The enhanced bioavailability of tamoxifen by curcumin may be mainly due to inhibition of the CYP3A4-mediated metabolism of tamoxifen in the small intestine and/or in the liver and to inhibition of the P-gp efflux transporter in the small intestine rather than to reduction of renal elimination of tamoxifen, suggesting that curcumin may reduce the first-pass metabolism of tamoxifen in the small intestine and/or in the liver by inhibition of P-gp or CYP3A4 subfamily. PMID- 22512083 TI - Influence of cosolvents, ionic strength and the method of sample preparation on the solubilization of curcumin by Pluronics and HP-gamma-cyclodextrin. Studies of curcumin and curcuminoids, XLIV. AB - Curcumin was solubilized by Pluronics and the concentration of dissolved curcumin seemed to be related to the number of propylene oxide units in the Pluronic polymer. All Pluronics showed a maximum solubilizing capacity at a certain curcumin: Pluronic molar ratio and exceeding this molar ratio resulted in precipitation of curcumin when following the samples for 356 hours. PEG 400 could to a certain extent stabilize the supersaturated samples, while ethanol physically destabilized the samples. Ionic strength did not influence the solubilization of curcumin by the Pluronics. Supersaturation and precipitation inhibition caused a higher concentration of curcumin in samples prepared by SEM compared to samples prepared by SFM (i.e. the thermodynamic solubility). PMID- 22512084 TI - Investigation of a fenofibrate-hydroxypropyl-beta-cyclodextrin system prepared by a co-grinding method. AB - Considering the poor water solubility and the low oral bioavailability in humans, the complex formation of fenofibrate (FNB) with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) in aqueous solution was studied. The effect of temperature on the complexation was examined and thermodynamic parameters of the complexation process such as Gibbs free energy change (deltaG), enthalpy change (deltaH) and entropy (deltaS) change were also determined. Meanwhile, the solid dispersion of FNB with HP-beta-CD was prepared and characterized by X-ray diffractometry and Fourier IR spectroscopy. The experimental results indicated that a 1:1 molar ratio complex of FNB with HP-beta-CD could form in aqueous solution and the complexation was exothermic and enthalpy-driven process. The FNB-HP-beta-CD solid dispersion presented a remarkable improvement in the solubility and dissolution rate of the drug. This might be attributed to the amorphous state, the enhanced wettability and as well as the complex formation of the drug with HP-beta-CD in aqueous solution. PMID- 22512085 TI - Mathematical modeling of drug release profiles for modified hydrophobic HPMC based gels. AB - Hydroxypropyl methylcellulose (HPMC) is now available in modified hydrophobic forms (Sangelose). In this paper, the effect of viscosity grade and HPMC concentration on in vitro release kinetics of a topically applied drug were studied using gel formulations of a nonsteroidal anti-inflammatory drug (NSAID), diclofenac potassium (DP), with different viscosity grades of the polymer (60L, 60 M, 90 M for hydrophobic HPMC and 50 cPs for conventional hydrophilic HPMC) in different proportions. It was found that hydrophobic HPMC-based gels having a higher viscosity and lower polymer concentration release a notably higher amount of drug compared with hydrophilic HPMC-based gels containing a higher concentration of polymer but with lower viscosity. For gels, the suitability of different common empirical (zero-order, first-order, and Higuchi), and semi empirical (Ritger-Peppas and Peppas-Sahlin) models, and some new statistical (logistic, log-logistic, Weibull, Gumbel, and generalized extreme value distribution) models to describe the drug release profile were tested through non linear least-square curve fitting. A general purpose mathematical analysis tool MATLAB was used. Further, instead of the widely used transformed linear fit method, direct fitting was used in the paper to avoid any form of truncation and transformation errors. The results revealed that the log-logistic distribution, amongst all the models investigated, was the best fit for hydrophobic formulations. For hydrophilic ones, the semi-empirical models and Weibull distribution worked best, although log-logistic also showed a close fit. The shape parameter for the log-logistic and Weibull distribution conveys vital information about the rate of release and helps improve understanding of drug release profiles. PMID- 22512086 TI - Preparation and in vitro evaluation of an ilomastat microemulsion gel by a self microemulsifying system. AB - The purpose of this study was to construct a microemulsion gel formulation by a self-microemulsifying system for transdermal topical delivery of ilomastat. The optimum formulations were screened by penetration evaluation in vitro. Ilomastat microemulsion gel was prepared by drawing a ternary phase diagram and Pluronic F127 was added as gel matrix for the formulation. The optimal formulations had wide microemulsion existent field and good self-microemulsifying efficiency. The droplet size was within 100 nm. Statistical comparison of the permeation throughout 24 h showed that the two microemulsion gel preparations of ilomastat provided higher permeation than that of the normal gel which had only a low cumulative amount of ilomastat (6.03 microg x cm(-2)) 24 h after application. Cumulative amount of ilomastat from microemulsion gels A and B was 2.2 times and 1.8 times that of the normal gel at 24 h respectively. These results indicate that the microemulsion gel may be a promising vehicle for topical delivery of ilomastat. PMID- 22512087 TI - Characterization and pharmacokinetics of coenzyme Q10 nanoparticles prepared by a rapid expansion of supercritical solution process. AB - Coenzyme Q10 (CoQ10) has been found to be effective in cardiovascular diseases and neurodegenerative diseases. However, the extremely poor solubility of CoQ10 in water is hampering its bioavailability as a therapeutic agent. To overcome solubility problem, we micronized the CoQ10 powder to the nanometer level by the supercritical solution (RESS) process, which does not employ any toxic organic solvent. The obtained CoQ10 nanoparticles were 147.9 +/- 27.3nm in diameter and their physicochemical properties were characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS), liquid chromatography-mass spectrometry (LC-MS), X-ray diffractometry (XRD) and differential scanning calorimetry (DSC) analyzes. Moreover, the pharmacokinetics of the CoQ10 nanoparticles, in comparison with the unprocessed CoQ10 powder, were investigated in rats. From the results of physicochemical and pharmacokinetic studies, the CoQ10 nanoparticles had high solubility in water and possessed less crystalline structure, which can enhance the bioavailability of CoQ10, and provide a water soluble solid dosage form of CoQ10. PMID- 22512088 TI - Carboxymethylcellulose sodium improves the pharmacodynamics of 1-deoxynojirimycin by changing its absorption characteristics and pharmacokinetics in rats. AB - 1-Deoxynojirimycin (DNJ) has excellent inhibitory activity against alpha glucosidase and can therefore decrease the postprandial blood glucose level in humans. However, a major limitation of DNJ is its fast absorption rate compared with other alpha-glucosidase inhibitors. In this study, we investigated the effect of adjuvants on the pharmacokinetics of DNJ, and found that carboxymethylcellulose sodium (CMCNa) can remarkably improve the activity of DNJ on glucose levels. When DNJ was used in combination with CMCNa, its absorption was suppressed and delayed by CMCNa. CMCNa can also change the pharmacokinetics of DNJ in rats. Pharmacodynamics were further studied using the oral glucose tolerance test, and the results confirmed that CMCNa can enhance DNJ's modulation of glucose level. All the results indicate that carboxymethylcellulose sodium can improve the pharmacodynamics of 1-deoxynojirimycin by changing the absorption characteristics and pharmacokinetics of DNJ in rats. PMID- 22512089 TI - Self-assembled human serum albumin-coated complexes for gene delivery with improved transfection. AB - The efficiency and safety of gene delivery vectors were important factors for gene therapy. To enhance gene transfection efficiency and to incorporate biocompatible components to the polyamidoamine (PAMAM) dendrimer mediated gene delivery systems, human serum albumin (HSA) was introduced to dendriplexes of PAMAM dendrimer and DNA via electrostatic interactions to form self-assembled PAMAM/DNA/HSA complexes (HSA-dendriplexes). The self-assembled complexes were characterized by gel retardation assay and particle size and zeta potential analysis. Meanwhile, the toxicity of HSA-dendriplexes was evaluated by the MTT assay and haemolysis test, which indicated that the complexes exhibited decreased cytotoxicity with the incorporation of HSA. As compared to dendriplexes, the ternary HSA-dendriplexes increased the enhanced green fluorescent protein gene (EGFP) expression in vitro by 1.7-fold. In addition, HSA-dendriplexes showed a significantly higher luciferase gene expression than dendriplexes or naked DNA in the liver, kidney, lungs and spleen of mice. Our results demonstrated that HSA dendriplexes increases PAMAM mediated gene transfection efficiency and decreases the cytotoxicity and haemolysis, which made the ternary complexes a promising targeting gene delivery system. PMID- 22512090 TI - The function of calcineurin and ERK1/2 signal in the antihypertrophic effects of kappa-opioid receptor stimulation on myocardial hypertrophy induced by isoprenaline. AB - The aim of the present study, performed in an in vitro model of cardiac hypertrophy, was to examine the possible function of calcineurin and ERK1/2 in the inhibitory effects of kappa-opioid receptor stimulation on Ca2+ transients and myocardial hypertrophy induced by beta1-adrenoceptor stimulation. We determined the effects of trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzeneacetamid methanesulfonate salt (U50,488H), a selective kappa opioid receptor agonist, on the enhancement of spontaneous Ca2+ transients and the induction of hypertrophy by isoprenaline, a beta-adrenoceptor agonist, in cultured neonatal ventricular myocytes. Total protein content, [3H]leucine incorporation and cell size were used as indices of hypertrophy; calcineurin activity and phospho-ERK1/2 level were determined by immunoblotting. Isoprenaline (10 micromol x L(-1)) increased all the three indices of hypertrophy, Ca2+ transients, calcineurin activity and the level of phospho-ERK1/2. The effects of isoprenaline were abolished by 1 micromol x L(-1) U50,488H in the absence but not in the presence of nor-binaltorphimine, a kappa-opioid receptor antagonist. The inhibitory effects of U50,488H were reproduced by cyclosporine-A, an inhibitor of calcineurin, U0126, the inhibitor of ERK1/2 and verapamil, a L-type Ca2+ channel antagonist. In addition, suppression of calcineurin activity by cyclosporine-A was associated with modest suppression of ERK1/2 phosphorylation. Meanwhile, suppression of ERK1/2 phosphorylation by U0126 was associated with modest suppression of calcineurin activity. In conclusion, the inhibitory effects of kappa-opioid receptor stimulation involved calcineurin and ERK1/2, and the two signaling pathways showed interaction in the mechanism of antihypertrophic effects afforded by kappa-opioid receptor stimulation. PMID- 22512091 TI - The proteasome inhibitor bortezomib reverses P-glycoprotein-mediated leukemia multi-drug resistance through the NF-kappaB pathway. AB - Multi-drug resistance (MDR) is one of the obstacles for leukemia therapy, the major cause is an overexpression of P-glycoprotein (P-gp) leading to increased drug efflux. We investigated the reversion of multi-drug resistance and the possible mechanism by which the proteasome inhibitor bortezomib affects the expression of the multi-drug resistance gene mdrl in the K562/DNR cell line. The drug resistance of the cells and the cellular toxicity of bortezomib were confirmed by MTT. Intracellular drug concentrations and cell apoptosis were detected by flow cytometry. The expression of mdrl mRNA was examined by fluorescence quantitative PCR. The expression levels of nuclear factor-kappa B (NF-kappaB), inhibitor of NF-kappaB (IkappaB) and P-gp were detected by western blotting, and NF-kappaB activity was detected by ELISA. DNR-induced apoptosis increased in a dose-dependent manner after adding bortezomib. Bortezomib decreased IkappaB degradation, decreased NF-kappaB and NF-kappaB p65 activity, reduced P-gp/mdr1 mRNA expression, and increased the intracellular DNR concentration in K562/DNR cells in vitro. The bortezomib reversed leukemic multi drug resistance in a dose-dependent manner as the result of decreasing IkappaB degradation, thus preventing the translocation of NF-kappaB into the nucleus and leading the down-regulation of mdr1 and a reduction in P-gp expression. Therefore, the intracellular drug concentration increased, and then apoptosis was induced. PMID- 22512092 TI - Research biopsies in phase I studies: views and perspectives of participants and investigators. PMID- 22512093 TI - Exempting all minimal-risk research from IRB review: pruning or poisoning the regulatory tree? PMID- 22512094 TI - Protecting people who decline to participate in research: an example from a prison setting. PMID- 22512095 TI - Misunderstanding, continued. PMID- 22512096 TI - [Ethics in medical training]. PMID- 22512097 TI - [Medium-term results of arthroscopic repair of relapsing anteroinferior glenohumeral instability]. AB - OBJECTIVES: Arthroscopic repair of Bankart lesion has become the treatment of choice of anterior shoulder instability. Our objective is to analyze the medium term results of arthroscopic Bankart repair. MATERIAL AND METHODS: Between January 1999 and November 2007, 86 shoulders of 85 patients with diagnosis of relapsing shoulder dislocation were treated arthroscopically. After a mean 62 month follow-up (minimum 24 months) the results obtained were retrospectively assessed according the Rowe and Constant functional scales. A statistical analysis was done of the relation between functional results and age, sex, the side operated, capsulorrhaphy, rehabilitation and postoperative immobilization in our series. Moreover, the validity of MRI for diagnosing Bankart lesion was assessed. RESULTS: Eighty-five percent of patients had good or excellent results according to the Rowe scale. The mean Constant scale score was 90.6. There dislocation rate in our series was 9%. The statistical analysis showed that female sex and immobilization time were related with worse results according to the Constant scale. CONCLUSIONS: In our hands, arthroscopic Bankart repair provides results similar to those in other published series. MRI is a useful diagnostic test in our setting, albeit its important implications for the diagnosis of Bankart lesion. Female sex and prolonged immobilization were related with worse functional results. PMID- 22512098 TI - [Long-term analysis of minimally invasive surgery in knee arthroplasty]. AB - BACKGROUND: Knee arthroplasty is the treatment of choice for gonarthrosis. The development of minimally invasive surgery (MIS) requires assessing results based on the classical approaches and this is the purpose of our study. METHODS: Randomized, prospective study comparing two groups; one underwent MIS (45 patients) and the second one a classical approach (51 patients); both groups were comparable. The following variables were assessed in the immediate postoperative period and at 4 and 8 years: blood loss, pain according to the VAS, flexion and extension and quality of life measured with the SF-36. RESULTS: In the immediate postoperative period we observed statistically significant differences (p < 0.05) in favor of the MIS approach in pain, hospital stay and blood loss. However, this was not observed at 4 and 8 years concerning pain, quality of life and range of motion. We observed an improvement in the functional scale and quality of life compared with the preoperative status, without any differences when both groups were compared. CONCLUSIONS: The MIS technique results in a better immediate postoperative period, but no differences were seen in the choice of the approach 4 and 8 years after surgery. PMID- 22512099 TI - [Minimally invasive surgical treatment of acromioclavicular dislocations]. AB - INTRODUCTION: Treatment of grade III Rockwood acromioclavicular lesions continues to be controversial. A new surgical technique for reduction using minimally invasive surgery provides good results. The purpose of this paper is to present the short and medium-term results of a series of patients with grade III acromioclavicular dislocations who underwent surgery. METHODS: Prospective assessment of a series of 14 patients with acromioclavicular dislocation who underwent surgery from May 2009 to June 2010 consisting of open reduction and synthesis with coracoclavicular fixation with a double anchor. Radiologic, functional and personal satisfaction parameters were assessed. RESULTS: Statistically significant radiologic results were obtained, which reflect a correct reduction. An "excellent" mean score was obtained in the functional assessment using the Imatani test. Patients reported subjective satisfaction during the interviews at the outpatient visits. CONCLUSIONS: There are only a few papers reporting postoperative results with this surgical technique. Without a control group it is not possible to make a comparison with orthopedic treatment, so comparisons were made with published series using classical techniques. The surgical technique provides similar results; it is simple, inexpensive and has not shown to have any postoperative complications during a mean follow-up of 13.7 months. Surgical treatment of grade III acromioclavicular lesions using this surgical technique has provided appropriate results in this group of patients. PMID- 22512100 TI - [Morphometric analysis of cervical pedicles in a Mexican population]. AB - BACKGROUND: Knowledge of the morphometric anatomy of cervical pedicles is essential for the safe and accurate placement of pedicle screws during instrumentation of the cervical spine. Screw placement in the lumbar and thoracic vertebrae is considered as a safe practice, unlike the cervical vertebrae due to the risks involved. There are few reports on this technique. The little available information comes from populations different from the Mexican population. Knowing the measurements of each cervical vertebra will provide proper screw orientation and selection at the time of screw placement. METHODS: Prospective, cross sectional, descriptive study in subjects who presented at the outpatient and emergency services. Patient's in whom a CAT scan of the cervical spine was ordered as part of the work-up protocol, from April 1st 2010 to October 31st 2010, were included. A morphometric anatomic study was undertaken using the CAT software. In a saggital view: a) Saggital angle, b) Saggital diameter. In an axial view: a) Work distance, b) Cross-sectional angle and c) Cross-sectional diameter. RESULTS: The following measurements were obtained for each segment from C2 to C7: mean, standard deviation, range and minimal and maximal values. CONCLUSIONS AND CLINICAL RELEVANCE: Appropriate preoperative planning prior to cervical transpedicular instrumentation is essential to achieve greater accuracy during screw placement. The information obtained allows performing the procedure. As a result of this, a report based on out center's experience may be disseminated thus sharing our technique with the medical community. PMID- 22512101 TI - [Trapeziometacarpal arthrodesis. Overall functional hand assessment]. AB - Trapeziometacarpal arthrosis is a degenerative condition described by Fostier in 1937. Osteoarthrosis of the trapeziometacarpal joint is a common condition among postmenopausal women; mean age of individuals affected by this disease is 64 years. The male:female ratio is 1:10; 33% of patients have a bilateral component. This study was conducted at Lomas Verdes Traumatology and Orthopedics UMAE hospital, hand surgery module, between March and December 2006. Descriptive, cross-sectional, retrospective study including a total of 18 patients, 12 females (66.6%) and 6 males (33.3%). Mean age is 49.3 years. Patients were clinically and radiographically diagnosed and classified by stages according to the Eaton classification. Surgery was performed more frequently in right hands, which were a total of 10 (55.6%), than left hands, which were 8 (44.4%). Surgery of the dominant hand was performed in 8 patients, 7 of them right handed, and one left handed. Arthrodesis with nails was performed in 12 patients (66.7%) and with a 2.0 condylar plate in 6 (33.3%). Mean operative time was 52.8 minutes. Eleven patients were found to have primary arthrosis, and 7 had posttraumatic arthrosis: 2 due to untreated Benett fractures, one due to a healed trapezius fracture and 4 patients had recurrent dislocation. As regards their occupation, 12 were employees, 5 were housewives and one was unemployed. The concomitant conditions found included: 9 without disease, 7 with hypertension, 7 diabetes mellitus, and one had rheumatoid arthritis. Two patients were reoperated (11.1%) due to pseudoarthrosis. In one of them a new arthrodesis was performed 18 months later, which failed and 8 months later triscaphoid arthrodesis was performed with a 10 week healing time. Trapeziometacarpal arthrodesis is a procedure involving a certain difficulty due to the anatomic conformation of the joint, which results in the various complications that have already been described. It provides pain relief; it is a good option for people who need to resume a type of work requiring the use of force; a longer follow-up is required to determine the course of these patients. PMID- 22512102 TI - [Enchondroma of the distal phalanx]. AB - Enchondroma is the most frequent benign tumor in hand bones. It occasionally occurs in the distal phalanx of the fingers; it is usually an asymptomatic lesion, but pain may occur when it is associated with a fracture. The most recommended treatment is lesion curettage and application of a bone graft, besides fixation as needed. Five cases with location in the distal phalanx are reported, as well as treatment results from January 1978 to May 2010. Of the 5 patients, 4 were females and one was male. The most frequently affected digit was the middle finger followed by the little finger. The most frequent symptom at the time of diagnosis was pain. Lesion curettage was performed in all cases, with the use of an autologous distal radius bone graft in 4 and coralline graft in one. Mean follow-up was 193 months (2-384 months). No complications or relapses were reported. PMID- 22512103 TI - [Platelet-rich plasma for managing calcaneus tendon tendinopathy and plantar fasciitis]. AB - INTRODUCTION: Non-surgical treatment of Achilles tendinopathies ad plantar fasciitis has shown good results in up to 90% of cases. However, the remaining 10% of patients with these conditions represent a true challenge for the orthopedic surgeon. New technologies for the development of orthobiologic materials make it possible to use platelet-rich plasma (PRP) as an alternative to treat cases that have been refractory to prior treatment and that have a chronicity exceeding 12 months. MATERIAL AND METHODS: Prospective, analytical study. Patients with diagnosis of Achilles tendinopathy, plantar fasciitis or both, with a course of more than 12 months, previously treated with non-surgical alternatives, without any clinical improvement. The AOFAS hindfoot scale was used, together with the Visual Analog Scale (VAS) for pain, and photographic documentation at 2, 4, 8 and 12 months after infiltration. A treatment program that included immobilization, NSAIDs, eccentric exercises for the Achilles calcaneal-plantar system and strengthening of the sural triceps was established. The statistical analysis included measurements of the central trend and scatter with the SPSS 15. RESULTS: A sample consisting of 10 patients (12 feet) that met the diagnostic and inclusion criteria was obtained. Mean age at the time of presentation was 43 years (range 23-56), with females being predominant (70%) and 50% laterality for the right and left feet. The initial AOFAS score was 39 (range 28-68) and the VAS score was 9 (range 7-10). By week 16 the AOFAS score had increased to 97 (range 88-99) and the VAS score was 2 (range 1-4). All patients resumed independent gait. CONCLUSION: The use of PRP in patients with Achilles tendinopathy and plantar fasciitis is an effective and safe alternative for the management of patients with a poor response to conventional non-surgical treatment. Other non-surgical modalities are recommended besides PRP for the treatment of these patients to achieve appropriate results. PMID- 22512104 TI - [Proximal focal femoral deficiency complicated by a proximal femur fracture]. AB - Proximal focal femoral deficiency (PFFD) is a rare skeletal condition characterized by development failure of the subtrochanteric region of the femoral axis, with several degrees of shortening of the proximal region. There are no case reports of patients with this condition associated with a subtrochanteric fracture. We therefore describe herein the case of a newborn patient with clinical and radiographic diagnosis of proximal focal femoral deficiency complicated by a proximal femur fracture, and managed conservatively with pelvipodalic immobilization, which led to bone healing. The patient will continue to be managed in the long-term to assess and treat the sequelae of PFFD according to the growth stage he is in. PMID- 22512105 TI - [Pelvic chondroblastoma in an adolescent. New treatment approach]. AB - Surgical management of tumors located in the spine and the pelvis involves greater difficulty. Moreover, these tumors are usually very large and vascularized. Preoperative embolization of the internal iliac artery is a relatively safe procedure that may reduce the risk of bleeding and local recurrence in the case of benign tumors. Chondroblastoma is a tumor that is rarely located in the pelvis; its more frequent location is the triradiate cartilage. We describe a case of a chondroblastoma with a relapsing aneurysmal cystic component in the acetabulum of an adolescent patient. Treatment consisted of embolization of the internal iliac artery, fluid hyperthermia, hydrogen peroxide and bone marrow application. The patient was found to be asymptomatic at the 5-year postoperative follow-up. The technetium (99mTc) sestamibi scan was negative for tumor activity and found no lung metastases. PMID- 22512106 TI - [Description of an arthroscopic and percutaneous technique to repair posterolateral corner knee lesions]. AB - Posterolateral corner knee lesions are infrequent and very disabling. They usually occur with other ligament lesions, so historically different techniques have been used to reconstruct this kind of lesions. Most of them involve open surgery, with the Clancy procedure as one of the most popular ones. After thorough preoperative planning taking into account the patient's activities, we propose a new arthroscopic and percutaneous technique based on Clancy's procedure, using a calcaneal tendon or quadriceps allograft. PMID- 22512107 TI - [Do metal-on-metal prosthesis should be under surveillance?]. PMID- 22512108 TI - [Rotator cuff tear: correlation between ultrasound and arthroscopic findings]. AB - OBJECTIVE: To analyze the preoperative shoulder ultrasound (US) findings in patients with a diagnosis of rotator cuff (RC) tear and correlate them with the arthroscopic findings. METHODS: Retrospective analysis of a consecutive series of patients with a diagnosis of RC pathology in whom US was performed and who underwent surgery (shoulder arthroscopy). The US/arthroscopic findings were correlated with Fisher's and chi2 tests. RESULTS: The total number of patients was 53. We identified US/arthroscopic correlation in 22/34 cases for the total tears (64.7%) and in 7/19 cases for the partial tears (36.8%) (p = 0.048). Overall correlation (total and partial tears) was seen in 29/53 patients (54.7%). Of the 24 patients without correlation, 11 (45.8%) had ultrasound reports of tendinitis; 75% of the cases in this group had findings of partial supraspinous tear during arthroscopy (p = 0.006). CONCLUSION: US shows an appropriate correlation with the diagnosis of RC total tear confirmed with arthroscopy, and the correlation is significantly lower for partial tears. In cases of an ultrasound-diagnosed lesion, such as tendinitis, most cases showed a partial tear during arthroscopy. PMID- 22512109 TI - [Management of intertrochanteric fractures with lazcano hemiarthroplasty in elderly patients]. AB - OBJECTIVE: To determine if elderly osteopenic patients sustaining an intertrochanteric fracture recover sooner when treated with Lazcano hemiarthroplasty compared with those treated with internal fixation, and whether they can return to their prefracture physical activity level. METHODS: A case control study was conducted at 1o de Octubre ISSSTE Hospital. Patients over age 70 with intertrochanteric hip fracture and advanced osteopenia were enrolled. The cases were treated with Lazcano hemiarthroplasty and the controls (20 patients) with standard internal fixation (angled plate, DHS system, gamma nail). The comorbid conditions and the prefracture activity level were assessed in both groups. The relation between comorbid conditions and complications was studied and the postoperative activity level of both groups was compared. RESULTS: Thirty patients with these characteristics were included. Ten were cases and 20 were controls. No relation was found between the comorbid conditions and the patients' ability to resume gait postoperatively. Patients treated with hemiarthroplasty walk sooner than those treated with standard internal fixation and have a lower complication rate. CONCLUSIONS: The Lazcano hemiarthroplasty is an excellent choice in the treatment of intertrochanteric fractures in osteopenic patients. Long-term studies with more patients are required to assess the presence of complications. PMID- 22512110 TI - [Risk factors affecting fusion in the treatment of lumbar spine instability]. AB - BACKGROUND: Risk factors are the endogenous or exogenous factors that may be controlled and they are responsible for disease. The objective of this paper is to describe the risk factors affecting vertebral fusion in patients with lumbar spine instability seen at our hospital and to see how they relate to nutritional factors. MATERIAL AND METHODS: Patients undergoing vertebral fusion due to several diagnoses were analyzed. Different parameters were captured to determine the interaction among them and assess the factors affecting vertebral fusion healing. They were compared with patients with pseudoarthrosis to determine its risk factors. Patients were divided into two groups: the control group, who underwent fusion, and the cases, who had pseudoarthrosis. RESULTS: A total of 59 patients were examined; 15 (25.4%) were cases (pseudoarthrosis) and 44 (74.6%) were controls (fusion). The demographic distribution was 27 (45.8%) females and 32 (54.2%) males; mean age was 51 +/- 12 years, with a minimum age of 20 and a maximum of 85. The diagnostic-based distribution was as follows: 29 (49.1%) spondylolistheses, 21 (35.6%) fractures, 5 (8.5%) herniated discs, 3 (5.1%) infections, and one (1.7%) tumor. Mean body weight was 75.9 kg, height was 160 cm, BMI 24.5, Hb 15.2, Hct 35.9, and Alb 3.5. Various risk factors were analyzed including the following: age over 60 years, which showed a 49% higher chance of pseudoarthrosis compared with the control group, with a 95% CI, 0.12-2.27; body weight over 90 kg, which showed an 82% higher chance of pseudoarthrosis compared with the fusion group, with a 95% CI, 0.03-0.43; BMI, which showed a 25% higher chance of pseudoarthrosis, with a 95% CI, 0.18-3.18; hypoalbuminemia < 3.4 mg/100 ml, which showed a 78% higher chance of pseudoarthrosis, with a 95% CI, 0.06 0.75. CONCLUSIONS: This study found that pseudoarthrosis is caused by risk factors linked to the nutritional profile, i.e., obesity, and hypoalbuminemia; its chance of occurring is 1.5 greater than in individuals with normal values. For this reason it is important to assess these values and correct them early on during the preoperative period with supportive measures allowing for an appropriate metabolic control and the consequent optimum result, i.e., fusion. PMID- 22512111 TI - [Functional assessment of the different types of anterior cruciate ligament plasty used at the Xoco General Hospital Arthroscopy Service]. AB - INTRODUCTION: Currently, anterior cruciate ligament lesions have an increased frequency; their management is predominantly surgical; there are several functional assessment systems. MATERIAL AND METHODS: We used the IKDC (International Knee Documentation Committee) functional assessment in patients who underwent anterior cruciate ligament reconstruction at the Xoco Hospital Arthroscopy Service. RESULTS: A total of 73 patients underwent functional assessment; 43 underwent bone-tendon-bone (BTB) repair with patellar tendon graft and 30 underwent repair with pes anserinus tendon graft (T4). In the former group 39 patients had favorable results and 4 unfavorable results; in the latter group 27 patients had favorable results and 3 unfavorable results. DISCUSSION: The results found do not differ significantly between both groups, something that is in agreement with the reviewed literature. The study should be continued with a larger sample size to eliminate variables and obtain more reliable results. PMID- 22512112 TI - [Comparison of patellar dislocation recurrence in patients ages 9 to 16 years treated surgically with the green technique versus an arthroscopic approach]. AB - OBJECTIVE: To report the patellar dislocation recurrence in patients ages 9 to 16 years treated surgically with the Green technique or an arthroscopic approach. MATERIAL AND METHODS: A prospective, longitudinal study was conducted with patients ages 9 to 16 years who presented at the pediatric orthopedics and arthroscopy service at IMSS "Lomas Verdes" UMAE Orthopedics and Traumatology Hospital with a diagnosis of patellar dislocation from January 1st 2003 to December 31st 2006. The patellar dislocation recurrences were recorded. RESULTS: Twenty patients and 24 knees were included; 13 females and 7 males; mean age was 14.3 years +/- 1.75. The dislocations prior to surgical treatment occurred at a mean of 5.5 +/- 2.57 dislocation events, with a range of 2 to 10 events. As regards the side involved, 40% had involvement of the left side, 40% of the right side, with 8 patients each, and 20% were bilateral dislocations. No significant differences were found in the clinical course of the patients treated with the Green technique compared with the arthroscopic surgery group (p = 0.371). CONCLUSIONS: The number of dislocation recurrences after the surgical procedure was not related with the age, gender, number of prior dislocations or surgical technique. No significant difference was found between both groups. PMID- 22512113 TI - [Treatment of pediatric humeral supracondylar fractures with a lateral external fixator. A case report]. AB - We present the case of a child with a Gartland III humeral supracondylar fracture treated with a lateral external fixator and 1.6 mm Kirschner nails. The edema and postoperative pain subsided and the patient had early mobility, thus avoiding the use of cast immobilization. The patient was discharged with elbow mobility and no complications. Follow-up was conducted at weeks 1, 3, 6, 8, 12 and 16 with favorable results. The outcome was early mobility and the resulting shorter rehabilitation period, as well as better management of the skin and soft tissues, decreased muscle hypotrophy and appropriate healing. PMID- 22512114 TI - [Bilateral avascular necrosis after resurfacing hip arthroplasty. A case report]. AB - Resurfacing hip arthroplasty is an alternative to conventional arthroplasty and it is indicated in young and active patients. Good results and the prevention of complications stem from a meticulous surgical technique and proper patient selection. We present herein the case of a 43 year-old patient who, after undergoing bilateral hip replacement with resurfacing prostheses, sustained a non simultaneous fracture of both femoral necks due to avascular necrosis. He was treated by placing a metaphyseal anchoring stem. Postoperative X-rays showed proper implant placement without femoral notching, with a discrete 7 degrees valgus alignment of the femoral component. Both passive and active mobility was painful. X-rays showed cervical fracture of the right femur. The femoral head was attached to the implant, with no metallosis nor loosening of the femoral or acetabular components, but the bone had a fragmented and friable appearance that histopathologically was defined as avascular necrosis. Femoral neck fracture is the main complication after resurfacing hip arthroplasty. The effect of other factors like bone necrosis due to cement is unknown. PMID- 22512115 TI - [Thrombosis of the superficial femoral vein due to psoas bursitis secondary to particle disease in total hip arthroplasty]. AB - The case of a male 76 year-old patient with a history of total hip replacement surgery is presented herein. The patient had tumors in the iliac fossa with swelling of the thigh and pain upon hip flexion and extension. The complementary ultrasound and computed tomography show a large lobed cystic tumor in the left iliac fossa, 7 cm in diameter, close to the prosthesis. The diagnosis was psoas bursitis secondary to the release of polyethylene particles that caused compression and thrombosis of the superficial femoral vein. Cyst formation caused by polyethylene disease after total hip arthroplasty is infrequent. PMID- 22512116 TI - [Open talar enucleation with talar loss: a case report]. AB - Talar enucleation is a very infrequent injury; the reported cases have a traumatic etiology. These injuries are important because they occur in individuals in productive ages and result in irreversible complications and sequelae, such as talarthrosis, osteomyelitis and avascular necrosis. This is why we report herein the case of a 33 year-old patient with posttraumatic open enucleation of the left talus, with bone loss at the site of trauma. He was treated with cadaver bone graft plus subtalar arthrodesis using a retrograde endomedullary nail. We present the patient's one-year course and follow-up. PMID- 22512117 TI - [Management of early onset scoliosis]. AB - Infantile idiopathic scoliosis (IIS) represents one of the most severe forms of scoliosis. At the time of skeletal maturity the untreated progressive curves are usually over 100 degrees and have an important rotational component. That is why the natural course of IIS is thought to occur until the time that patients are treated, around 10 years of age. A close follow-up is recommended in these cases and, if necessary, starting active treatment in cases of progression. Patients who started treatment at an earlier age had better results than those who started at around 2 years of age. The overall risk of complications of IIS during the treatment period using a construct with rods is 58%. This percent decreases if implant placement is delayed as much as possible until the time of the initial surgery, at around 6 years of age, besides using a double rod instead of a single rod (10 vs 27%) and limiting the number of lengthening procedures (each subsequent lengthening results in a 24% increase in the risk of complications). The complications rate is moderate, but manageable. At present the use of a double rod with scheduled serial lengthenings seems to offer better results than the use of a single rod, due to its better capacity to control the spine. Early onset scoliosis should be distinguished from other types of scoliosis. There are relevant doubts concerning the etiology and treatment, which should be addressed specifically. PMID- 22512119 TI - [Humanism and bioethics]. PMID- 22512118 TI - [William Heberden (1710-1801)]. PMID- 22512120 TI - [Growing pains. Simplified treatment regimen]. AB - OBJECTIVES: The purpose of this study is to show that a simplified stretching exercise regimen for the pelvic limbs, together with analgesics and physical therapy, may improve growing pains during an 8-week period. The Evans and Scutter diagnostic criteria modified by Peterson were used. MATERIAL AND METHODS: Prospective, longitudinal study of the clinical trial type, conducted from November 2002 to December 2008. The following tests were requested from patients: CBC, rheumatoid factor, antistreptolysins and a pharyngeal smear. A simplified regimen consisting of three stretching exercises for the adductors, the knee extensors and the hamstrings, plus analgesics and physical therapy was used. Both parents and patients were instructed on the regimen. The treatment was performed by parents at home. ANALYSIS: The sampling was non-randomized; patients were selected based on the diagnosis. The statistical analysis included the central tendency measurements and scatter plots, the Z-test for comparison of means, and the linear correlation. RESULTS: The correlation between treatment and pain relief resulted in an r = 0.97, the correlation between pain and the study variables resulted in the following: sports practice r = 0.82, obesity r = 0.86. The Z-test corroborates the improvement in the clinical picture with the treatment provided, with p = 0.0001. CONCLUSION: The simplified treatment regimen was effective to improve growing pains in the patients in the study. The high risk factors were: age, male gender and practicing sports. PMID- 22512121 TI - [Anterolateral approach for minimally invasive hip surgery]. AB - INTRODUCTION: The approach for total hip arthroplasty (THA) using a mini-incision has been used progressively to decrease morbidity, achieve prompt patient recovery without an increased risk and shorten the hospital stay. However, the advantages and probable complications of these approaches are not clear. The objective of this paper is to compare the preliminary perioperative results of two groups of patients undergoing THA, one using the standard approach and the second one with a mini-incision. MATERIAL AND METHODS: 170 patients underwent surgery; they were divided into two groups. In group I (GI) patients an anterolateral mini-incision was performed, and in group II (GII) patients a standard Watson-Jones incision was used. Mean incision length was 8 cm in GI and 20 cm in GII. RESULTS: No statistically significant differences were found between both groups in the clinical and radiographic results and in the complications; however, a significant difference was found in the need for transfusions, wound size and hospital stay. CONCLUSIONS: This study showed that primary THA with a mini-incision was a safe procedure that reduced the operative time without increasing the complications. PMID- 22512122 TI - [Complications of oncologic hemipelvectomy]. AB - INTRODUCTION: The treatment of bone pelvic tumors is associated with high compli cation rates. The surgeon usually has to decide between external and internal hemipelvectomy. OBJECTIVE: To describe the frequency of infectious and wound related complications in a group of patients undergoing hemipelvectomy for different types of musculoskeletal tumors. MATERIAL AND METHODS: This is an observational, descriptive, retrospective study with a single measurement. We observed the complications that occurred in eight patients treated with different modalities of hemipelvectomy without reconstruction. Infectious and wound-related complications were described as follows: a) no complications, b) seroma, c) hematoma, d) mild infectious process, e) moderate infectious process, f) severe infectious process, and g) flap necrosis. Internal hemipelvectomies were classified usin Enneking and Dunham's criteria. RESULTS: Eight patients were assessed. Five patients underwent external hemipelvectomy and three internal hemipelvectomy. Two patients had no complications (25%), three had seromas (37.5%), one patient wa treated for a mild infectious process (12.5%) and two for severe infectious processes (25%). 75% of the patients had complications. No cases of flap necrosis were observed. DISCUSSION: The surgeon decides which the best procedure in each case is. Different types of complications of hemipelvectomy have been reported; the most common ones are infectious processes and flap necrosis, and our results are similar to those reported by other authors. CONCLUSIONS: Pelvic bone tumors are usually large masses that hinder the achievement of tumor-free surgical margins. There is a high likelihood of postoperative wound complications. PMID- 22512123 TI - [Clinical-imaging-arthroscopic correlation in the diagnosis of meniscal lesions]. AB - OBJECTIVE: To assess the relation between location and intensity of pain in the articular interline as reported by the patient and proven objectively with the physical exam, and the type and location of the meniscal lesion found in the knee imaging study and arthroscopy. METHOD: Prospective, observational, longitudinal study including 34 consecutive patients with a clinical and arthroscopic diagnosis of symptomatic meniscal tears. Pain location was reported, an MRI was taken and finally all patients were assessed with knee arthroscopy. RESULTS: We found an excellent correlation between the clinical manifestation of pain and the arthroscopic findings (p < 0.001), as well as between the clinical findings and the MRI (p < 0.001). CONCLUSION: Correlating the clinical expression of meniscal pathology with the anatomical lesion could be useful at the time of deciding to perform surgery, as the clinical identification of certain types of meniscal tears could potentially determine what the best time to perform surgery is. Our study shows that there is no significant relation neither between the magnitude of pain and the laterality of the lesion, nor between the magnitude of pain and the type of lesion diagnosed arthroscopically. This shows that patients cannot be selected considering the anatomy of the lesion based only on the physical exam. PMID- 22512124 TI - [Glomus tumor of the hand]. AB - BACKGROUND: Glomus type of tumors are benign tumors of the hand phalanges. Their most frequent location is the nail bed. The diagnosis requires a certain index of suspicion and is usually a clinical one. The recommended approach is surgery. MATERIAL AND METHODS: The clinical files of patients with glomus of the hand were reviewed from June 1978 to May 2010, analyzing the characteristics of their management. RESULTS: Twelve patients with a glomus type of tumor were found; 4 females and 8 males, ages 31-55 years. The distal phalanx and the little finger were the most frequent sites. The diagnosis was mostly clinical and treatment in all cases was surgical. Mean follow-up was 8 years. CONCLUSIONS: The glomus type of tumor is a lesion often involving the distal phalanx, with unique clinical and pathologic characteristics that the orthopedic surgeon should know to determine management. PMID- 22512125 TI - [Evaluation of the uncemented Mayo femoral stem. The first 10 years]. AB - OBJECTIVE: To show the results of the study on the Mayo femoral stem during its first ten years of use in Mexico. MATERIAL: Forty-two bone sparing Mayo femoral stems were studied; they were placed in 39 patients from July 2000 to March 2009, ages 24-71 years (mean 51.6 years), with a mean follow-up of 61 months. METHODS: The clinical results of 42 arthroplasties performed by 3 surgeons were assessed using the Merle D'Aubigne scale; a radiologic assessment was made and the findings and complications were described. RESULTS: No stem-related complications were found in this study. There was one case of revision due to recurrent dislocation, secondary to poor placement of the acetabulum. No cases of clinical or radiologic loosening were reported. CONCLUSIONS: Conservative hip arthroplasty with the Mayo stem has proven to be an excellent medium- and long-term option for femoral hip replacement, with expectations that it may exceed the durability of other types of implants without harming the femoral diaphysis. This may facilitate eventual stem revision and give us the opportunity of using a standard primary implant. PMID- 22512126 TI - [Treatment of an old Achilles tendon rupture with allografts. Report of case series]. AB - Rupture of Achilles tendon occurs at 2-6 cm from its attachment in the calcaneus; its frequency is estimated at 7-18 cases per 100,000 population in the United States and it occurs more frequently in males. The diagnosis is made clinically and with ultrasound or magnetic resonance imaging and treatment may be divided into acute or late. We present herein the use of allograft to treat patients with ruptures more than six weeks old; several techniques were used depending on the rupture site and the available allograft. Ten plasties were performed in ten patients with ruptures that occurred a mean of 8 months back; early rehabilitation was instituted and weight bearing was allowed at 4 weeks with a brace, which was removed at 12 weeks; patients could run at 12 weeks. Four wound dehiscence complications were reported, which resolved with second intention healing without the need for any other surgery, with good results and patient satisfaction. PMID- 22512127 TI - [Comparison of the postoperative intraarticular use of RV023 and hyaluronate G F20 in knee arthroscopy. Experience at Hospital Espanol de Mexico]. AB - For the past two decades arthroscopic surgery has revolutionized the treatment of acute traumatic knee injuries with patients returning sooner to activities of daily living. However, there are factors that delay this goal, such as postoperative intraarticular bleeding, and the swelling and pain that restrain immediate articular mobility. This paper analyzes such factors and their pathophysiologic processes. This led us to formulating a preparation for intraarticular use called RV023. The report of an original, prospective, longitudinal trial is presented herein, assessing the functional results of preparation RV023 in a 60-patient sample selected based on the following inclusion criteria: knee pain lasting 2 years and unresponsive to NSAID treatment, an MRI showing an Outerbridge grade I chondral injury without evidence of ligament or meniscal injury or fracture, and having undergone arthroscopic knee surgery. A significant difference was found in the articular function of subjects treated with the preparation as compared with those in whom it was not used. The articular function recovery curves of individuals treated with the preparation were virtually symmetrical to the curves for healthy controls. On the other hand, no allergic reactions, unwanted or side effects were reported. We therefore conclude that the safety and the benefits seen with preparation RV023 in experimental models are enough to support its use in humans. PMID- 22512128 TI - [Total hip arthroplasty in Klippel-Trenaunay syndrome. Case report and literature review]. AB - INTRODUCTION: Klippel-Tranaunay syndrome is a rare congenital condition characterized by skin angiomas with arteriovenous malformations and hypertrophy of the soft and bone tissues of one extremity. The clinical case presented herein involved total hip replacement due to arthrosis secondary to avascular necrosis of the femoral head, which resulted in the hypervascularity that occurs with this syndrome. A 37 year-old female was diagnosed with grade IV hip arthrosis and Klippel-Trenaunay syndrome. Laboratory and imaging tests were performed to determine the local conditions for the surgical approach to the hip. The preoperative MR angiography identified the arteriovenous malformation tract to determine the limits of the approach. DISCUSSION: The arteriovenous malformations that occur in this syndrome turn the approach into a challenging one due to the potential bleeding, thus extreme prophylactic and technical measures must be applied. There are very few reports in the literature on this treatment. PMID- 22512129 TI - [Aneurysmal bone cyst of the lumbar spine. Medico-surgical experience. A case report]. AB - The aneurysmal bone cyst (ABC) of the lumbar spine is an infrequent entity, of undefined nature and aggressive behavior; there are only a few reports in Mexico, so we present the case of a patient with radicular and lumbar pain that progressed to pelvic limb paresthesia. Lesions in the vertebral body of L1 were located with imaging studies and confirmed with biopsy; treatment with corticosteroids was started and later resection of the lesion was performed together with stabilization of the spine using first a posterior approach and at a second stage an anterior approach. Corticosteroid therapy led to remission of tumor progression, so only vacuolated areas and destruction of the posterior wall were found, leading to instability and radiculopathy. This type of lesions usually appears in long bones and less often in the spine, but it is even rarer in the lumbar spine. The prognosis of ABC is usually good, with the exception of the rare cases of extremely disseminated cysts located in the spine. It is therefore important to consider this before deciding what the best approach is for each patient, as well as the appropriate medico-surgical measures. PMID- 22512130 TI - [The skid of bariatric surgery: when the amount of risk exceeds the quality]. PMID- 22512131 TI - [Cardio-metabolic profile is influenced by modest modifications of body weight]. AB - Cardio-metabolic profile is influenced by modest modifications of body weight An increased body mass index (BMI) is associated with the metabolic syndrome (MS) and parameters composing it. There is a quasi linear relationship between BMI and number of MS components: an increase in BMI is associated with increasing number of cardio-metabolic alterations. This relationship exists not only in subjects with established obesity but also in those who are overweight or even have normal body weight. It has been also shown that a modest weight gain is associated with an increase in the number of MS components which, in turn, could contribute to the development of atherosclerosis. On the other hand, a modest weight loss is associated with decrease of MS components number and improvement of the cardio metabolic profile. PMID- 22512132 TI - [When the obese patient can't lose any weight or keeps putting some on]. AB - The traditional obesity treatments have proven to be ineffective in the long term. The presence of eating disorders frequently explains this phenomena. Eating educational and behavioral aspects must be addressed in a practical way so that patients could gradually become aware of their behavior towards food as well as internal sensations associated with hunger, satiety, craving and pleasure. Finally, the link between emotions and compulsive eating behaviors during and between meals is an essential aspect that the general practitioner can help the patient to understand. A specialized psychological treatment can then be considered when the patient shows sufficient motivation and consciousness. PMID- 22512133 TI - [Are severe dieting procedures still prescribed?]. AB - Very restrictive weight-loss diets are still recommended by a number of physicians although their negative impact has been widely documented. Considering the complexity of obesity as a chronic disease, general practitioners' role in the assessment and follow-up of obese patients is crucial. In particular, they should set realistic guidelines-based goals, in coordination with the health care network. Our pilot study in one region of Switzerland showed a lack of coherence between guidelines and clinical management of obesity. Improved coordination and education of all health care professionals in this field could increase therapeutic efficacy and solve some of the ethical issues raised by inadequate prescriptions. PMID- 22512134 TI - [Light food and beverages: what to think about?]. AB - Light food and beverages are increasing on the market for many years, first for economic reasons and, more and more for aesthetisme, however without aimed a defined population. The interest of these products is not evident, reason why it is difficult to get a clear and objective opinion without being influenced by marketing messages. Under what circumstances can they be a solution? Can we advise them? Do they have an influence in the loss or weight control? This article offers some thoughts and suggestions on the use of these specific products. PMID- 22512135 TI - [The dilemma between the functional deficits of obese people and recommended physical activity: what part can dance therapy play?]. AB - Obese people may have trouble with walking and may present reduced postural control. Medical doctors or therapists should guide the patient to restart doing physical activities that are gentle and progressive. Exercise should take into account walking difficulties. Thus, the first challenge is to help obese individuals start exercising without risk, or excessive strain on the joints. The second stage should encourage individuals to persevere in the chosen activity. Enjoyment is a key factor for attaining these objectives. Dance therapy, with its psychological and physiological impact, could help individuals take on the challenge. PMID- 22512136 TI - [Psychological preparation for gastric bypass surgery]. AB - Bariatric surgery is one of the treatment of choice for morbidly obese patients. However some of them regain weight post-surgery. Psychological factors involved in weight regain have not been clearly identified yet. The Geneva University Hospitals offer patients a psychological preparation for gastric bypass. In order to evaluate this preparation, 22 patients completed questionnaires assessing depressive symptoms (BDI-II), anxiety symptoms (HAD), and the presence of eating disorders (EDI-2) before and after psychological treatment. The results showed a significant improvement of the following EDI-2 subscales: drive for thinness, bulimia, interpersonal distrust, asceticism and interoceptive awareness. These results highlight the importance of a psychological preparation before surgery. PMID- 22512137 TI - [Multispectral bioimpedance and sarcopenia in the elderly]. AB - The definition of sarcopenia includes both a loss of muscle strength and a decline in functional quality in addition to the loss of muscle protein mass. Multispectral bioimpendance allows bedside assessment of muscle mass. Using this new tool, we performed a pilot study to look for a possible correlation between muscle mass and various tests of muscle strength (grip strength, key-pitch, tip pinch) and with functional tests (walk speed on 10 meters and Tinetti test). Our study demonstrates a good correlation between muscle mass determined by spectroscopic bioimpendance and muscle strength assessment, but no correlation with functional tests. PMID- 22512138 TI - [Letter to a young ambitious colleague]. PMID- 22512139 TI - [Atopic dermatitis=immunosuppressants?]. PMID- 22512140 TI - [When the warming comes, we will die even in winter]. PMID- 22512141 TI - [Contagion of horror]. PMID- 22512142 TI - [Drugs: time to bless the tetrachloride fly swatter]. PMID- 22512143 TI - [Praise of the unfinished]. PMID- 22512144 TI - [Hereditary epidermolysis bullosa: clinical and ultrastructural analysis of 21 cases]. AB - Hereditary epidermolysis bullosa (HEB) constitute a genodermatosis group with variable clinical severity. The aim of the study was to confront the diagnosis established by electron microscopy (EM), with the clinical presentation and evolution, genetic analysis and immunofluorescence, and to observe if there was concordance. Biopsies diagnosed as HEB in the last 15 years, were retrieved from the database of the C.H.U. Saint-Pierre EM lab. Each corresponding medical file was reviewed and the following data were recorded: date of birth, sex, age, age at biopsy, ultrastructural characteristics, degree of certainty regarding the EM diagnosis, family history, clinical lesions and their evolution as well as other diagnostic tests performed. 21 patients, aged 1 day to 26 year old were included. A HEB simplex was diagnosed in 10 cases, a junctional EBH in 5 cases and a dystrophic HEB in 6 cases. Immunofluorescence was requested in 4 cases. 7 patients benefited from a genetic analysis. Physical examination revealed hyperpigmented spots in 1 case. A patient with dystrophic HEB had a family history of symptoms restricted to the nails. 4 patients died. In conclusion, the accurate clinical diagnosis of the HEB sub-type is difficult because of the symptomatology heterogeneity. EM remains the gold standard for diagnosis even if immunofluorescence and genetic analysis should be more systematically considered. PMID- 22512145 TI - [Mastocytosis: revisited with new cytogenetic data]. AB - Mastocytosis is a heterogenous disorder due to abnormal proliferation and infiltration of mast cells in different tissues, primarily the skin and the bone marrow. Cutaneous mastocytosis is often benign and regresses spontaneously. Systemic mastocytosis is a chronic disease in which some types are indolent but other types such as mast cell leukemia are very aggressive. Pathogenesis of systemic mastocytosis involves a somatic mutation of the gene coding for the c kit receptor, the most frequent mutation being D816V. Diagnostic criteria have been established by the WHO using histopathological, molecular and biochemical parameters. Treatment of systemic mastocytosis remains a challenge for the clinician due to variability and complexity of the disease. There is, in addition, a lack of a standard and efficient treatment. New targeted therapies with tyrosine kinase inhibitors directed against the c-kit receptor are currently being studied, with the purpose to act specifically on the " primum movens "of the disease. The current review provides an overview of pathogenesis, clinical presentation, diagnosis and classification of cutaneous and systemic mastocytosis. We also discuss the prognosis and the different treatments currently available according to the sub-type of mastocytosis. PMID- 22512146 TI - [Violence in schools, adolescents suffering]. AB - The schoolbullying is a neologism which designates " a long-term violence, physical or psychological, perpetrated by one or more attackers (bully) against a victim (bullied) in a relationship of domination "(C. Blaya). This term is primarily used to describe repeated harassment behavior in schools. This phenomenon concerns one child out of seven in schools. Difficult to detect, it can have more or less serious psychological impacts (medium or long-term effects), such as dropout or anxious school refusal, loss of self esteem, major depressive disorder, suicide, eating disorders and leakage to substance abuse or alcohol. Its therapeutic follow-up is multidisciplinary and difficult. The aim of this paper is to draw the attention of health professionals to these new phenomena of violence in order to detect them as early as possible and thus provide optimal care. PMID- 22512147 TI - [Risk assessment of developing aggressive behavior]. AB - The article concerns the problem of patients with aggressive behaviour and the most common methods for estimating the potential risk of appearance of such behaviour. The problem mentioned above is related in particular to psychiatric facilities, but it is also present in medical facilities of general type. The importance of this problem is underlined by epidemiological data. The article includes a description of two widely used instruments, namely the HCR 20 (The Historical Clinical and Risk Management Scale 20) and the PCL-R (The Hare Psychopathy Checklist-Revised) but also the actuarial instruments the VRAG (The Violence Risk Assessment Guide) and the SORAG (The Sex Offender Risk Assessment Guide). The article also presents an instrument for the dynamic assessment, the START (The Short-Term Assessment of Risk and Treatability). The usefulness and limitations of these instruments are developed. Some personality disorders may predispose an individual to commit acts of aggression or violence. This topic is also developed in the text. The article focuses on the rationale for the usefulness of regular training of risk assessment for staff, which increases security and helps to plan the care correctly. PMID- 22512148 TI - [Sexuality of our seniors: happy end or new beginning?]. AB - Comparing surveys from successive periods demonstrates that elderly people now enjoy a better and more varied sexual life than previous generations. The proportion of older people who remain sexually active has significantly increased, and the practices of masturbation or oral sex have spread considerably. The generation effect has an incidence upon sexual behaviour: older people's repertoire of sexual practices differs from that of younger people, in the sense that it focuses less on sexual intercourse and oral sex. Women and men, beyond the common trends towards sexuality characterised by a more open repertoire of sexual practices, differ in terms of sexual interest and subjective sexual wellbeing. The cessation of sexual activity by individuals who had previously been sexually active is often the result of a cascade of reactions, such as the occurrence of a sexual dysfunction in one or both partners, anticipation of failure, increased anxiety, lack of adaptation of sexuality and/or avoidance behaviour. PMID- 22512149 TI - [Pneumatosis cystoides intestinalis during palliative chemotherapy for colorectal cancer]. AB - Pneumatosis cystoides intestinalis is a rare disease characterized by the presence of gas into the colonic wall. Symptoms are non specific and, most of the time, the diagnosis is done by an abdominal CT scan. We report a case of pneumatosis cystoides intestinalis which occurred in a patient with a colorectal cancer in palliative stage. This patient was treated by 5 fluorouracil (5FU), folinic acid and oxaliplatin chemotherapy, after a first lign of chemotherapy with 5FU, irinotecan and cetuximab. The association of chemotherapy is most likely probable. PMID- 22512150 TI - [Comment on: Thyroid nodules, benign or malignant]. PMID- 22512151 TI - [Forced delivery instead of postmortem cesarean section]. AB - The Lex Regia stipulated that no pregnant women shall be buried unless the child has been removed from her womb. The post mortem caesarean delivery was upheld till 1861 by the majority of obstetricians but nevertheless, anterior to the XIXth century, in 1729, Delamotte practiced delivery in the agonising patient in the absence of labour in view to bypass the cesarean section in hope of better child survival. This article describes the beginning of forced ante mortem delivery upon post mortem cesarean section, which contributed to a decrease in child mortality. PMID- 22512152 TI - [A new face for the man of Spy]. PMID- 22512153 TI - [A primary study of 8-14 microm band emittance]. AB - According to the previous experimental results, the band emittance of two materials were computed for 8-14 mm bandwidth in infrared measuring. The band emittance of several materials was surveyed by a simple experiment. The experiment and reckoning show that there is some kind of functional relation between band emittance and temperature. If the object measured is non-gray, and emissivity is regarded as a constant, acute measurement error will be generated for band pass radiation thermometer and thermal imaging system. The band emittance is nearly linear with the temperature for nonmetal and metal in vacuum by primary analysis. The fitted function equation can be used as the modification of band pass radiation thermometer and thermal imaging system, and the band emittance not only simplifies the calculation, but also improves the accuracy of measurement. PMID- 22512154 TI - [Experimental investigation on plasma assistant combustion actuator in argon/air]. AB - In order to obtain the characteristics of argon/air plasma assistant combustion actuators, experiments of three different actuators with normal, paratactic and meshy electrode configurations were respectively performed in argon/air mixture firstly, the results showed that the shape of electrode has little influence on the discharge characteristics. Then normal electrode was applied to study spectrum and discharge characteristics under the condition of 100% air and 10% argon/90% air. The comparison showed that, though in mixture the law of discharge characteristic was the same as that of pure air, discharge current and emission spectrum were strengthened, and initial discharge voltage reduced from 27 to 24 kV. PMID- 22512155 TI - [Photoemission characteristic of transmission-mode extended blue GaAs photocathodes]. AB - Based on the theoretical models of computing the photocathode optical performance, quantum yield and integral sensitivity, the photoemission characteristics of the domestic and ITT's transmission-mode extended blue GaAs photocathodes, namely the cathode optical properties and performance parameters, were respectively investigated. The compared results show that the integral sensitivity of the domestic transmission-mode extended blue photocathode has achieved 2,100 microA x lm(-1), still falling behind the ITT's integral sensitivity of 2,750 MUA x m(-1). The reasons for the difference in quantum yield curves are that, on one hand, the thickness of GaAlAs window-layer and the Al mole fraction play a critical role in the short-wavelength response, especially in the extended blue region. On the other hand, the cathode performance parameters such as electron diffusion length and back interface recombination velocity work on the long-wavelength and short-wavelength response. All these factors are subject to the backwardness of basic industrial manufacturing level. PMID- 22512156 TI - [Resonance wavelength effects on sensitivity of resonant grating waveguide biosensor]. AB - Resonant grating waveguide (RGW) biosensor has been widely investigated in recent years. The system has several advantages such as minimizing, label-free, high throughput, real time monitoring and so on. The sensitivity of RGW biosensor was theoretically analyzed for different resonance wavelength. Sensitivity to the refractive index and thickness of the sample was analyzed using rigorous coupled wave analysis method. Results indicate that the sensitivity to refractive index is constant for a certain resonance wavelength as the thickness of sample does not change. The sensitivity to refractive index is enhanced with the increase of resonance wavelength. RGW with 1 250 nm resonance wavelength is approximately 4 times as sensitive as RGW with 830 nm resonance wavelength. The sensitivity to thickness drastically decreased at first, and then achieved zero for a certain resonance wavelength as the refractive index of sample is invariable. It was showed that it is limited to test sample thickness for every RGW. RGW with 1 250 nm resonance wavelength is approximately 2 times the measure range as RGW with 830 nm resonance wavelength. The sensitivity to thickness is enhanced with the increase of resonance wavelength. RGW with 1 250 nm resonance wavelength is approximately 3 times as sensitive as RGW with 830 nm resonance wavelength. The above results reveal that the sensitivity to both sample refractive index and sample thickness is enhanced with the increase of resonance wavelength. And the capability of testing sample thickness improves with longer resonance wavelength. The results provided the theory basis for resonance wavelength choice of RGW biosensor. PMID- 22512157 TI - [Study on spectral line profile of different types of filaments in dielectric barrier discharge]. AB - The variations of width and shifts of Ar I (2P2 --> 1S(5)) spectral line emitted from two types of filaments, whose diameters and states are different, in argon/air dielectric barrier discharge with the change in air content were researched for the first time. In order to measure the wavelength shift, Ar I (2P2 --> 1S(5)) spectral line emitted from argon discharge at pressure of 10 Pa was used as a reference line. Regular arrangements of static wide filaments (static big dots) and moving thin filaments (reciprocating moving small dots whose traces are lines) were obtained in discharge at atmospheric pressure when the air content was in the range of 0.4%-4%. The variations of width and shifts of Ar I (2P2 --> 1S(5)) spectral line emitted from the big and small dots with the change in air content were measured respectively. It was found that they all increase with the increasing in air content. The width and shift of small dot are bigger than those of the big dot at any air content. The difference between the former and the latter decreases with the increase in air content firstly and remains basically unchanged after the air content reaches up to 1%. PMID- 22512158 TI - [White light upconversion luminescence and its mechanism of Yb3+/Ho3+/Tm3+ co doped tellurite glass]. AB - Yb3+ /Ho3+, Yb3+ /Tm3+ and Yb3+ /Ho3+ /Tm3+ co-doped tellurite glasses were prepared by melt-quenching method. Under the excitation of 980 nm laser, Yb3+ /Ho3+/Tm3+ co-doped glass sample shows strong blue, green and red emissions, corresponding to the transitions 1G4 --> 3H6 of Tm3+, 5F4 (5S2) --> 5 I8 of Ho3+, as well as 5F5 -->5 I8 of Ho3+ and 1G4 --> 3F4 of Tm3+ ions, respectively. It was found that the integrated emission intensity ratio of the red to green in Yb3+/Ho3+ /Tm3+ co-doped sample (3.95) is greater than that in Yb3+/Ho3+ co-doped sample (1.69) due to the cross-relaxation between Ho3+ and Tm3+ ions : 3H4 (Tm3+) + 5 I6 (Ho3+) -->3F4 (Tm3+) + 5F5 (Ho3+), and 3F4 (Tm3+ ) + 5 I8 (Ho3+) --> 3H6 (Tm3+) +5 I7 (Ho3+). When the pump power density is 8.2 W x cm(-2), the calculated color coordinates of Yb3+ /Ho3+ /Tm3+ co-doped sample are x = 0.345, y = 0.338, which is very close to the equal energy white light (x = 0.333, y = 0.333). PMID- 22512159 TI - [The linearity analysis of ultrahigh temperature FTIR spectral emissivity measurement system]. AB - To study thermal radiation properties of special materials at high temperature in aerospace fields, the ultrahigh temperature spectral emissivity measurement system with Fourier spectrometer has been established. The linearity of system is the guarantee of emissivity measurement precision. Through measuring spectral radiation signals of a blackbody source at different temperatures, the function relations between spectral signal values and blackbody spectral radiation luminance of every spectrum points were calculated with the method of multi temperature and multi-spectrum linear fitting. The spectral radiation signals of blackbody were measured between 1 000 degrees C and 2 000 degrees C in the spectral region from 3 to 20 microm. The linear relations between spectral signal and theory line at wavelength of 4 microm were calculated and introduced. The spectral response is well good between 4 and 18 microm, the spectral linearity are less than 1% except CO2 strong absorption spectrum regions. The results show that when the errors of measured spectrum radiation and linear fitting theory lines are certain, the higher the temperature, the smaller the spectral errors on emissivity. The linearity analysis of spectrum response is good at eliminating errors caused by individual temperature' disturbance to the spectra. PMID- 22512160 TI - [Study on the effect of high hydrostatic pressure treatment on the secondary structure of mushroom polyphenoloxidase by SRCD and FTIR]. AB - The secondary structure of the mushroom polyphenoloxidase treated by the high hydrostatic pressure (HHP) was analyzed by the synchrotron radiation circular dichroism (SRCD) and Fourier transform infrared spectroscopy (FTIR). The alpha helix content of mushroom PPO was decreased after HHP treatment, which indicated that the secondary structure of PPO was changed. There was a discrepancy of the result of the secondary structure content between untreated or HHP-treated mushroom PPO analyzed by SRCD and FTIR spectra, and this discrepancy may be due to the different determination temperature, the concentration of the PPO solution and the spectra analysis method etc. The fluorescence spectra showed that the fluorescence intensity of the mushroom PPO was decreased after HHP treatment, and a red shift was observed after HHP treatment, which indicated that the tertiary structure of the enzyme molecule has been modified. PMID- 22512161 TI - [FTIR and XPS analysis of characteristics of synthesized zeolite and removal mechanisms for Cr(III)]. AB - Zeolite products were synthesized from fly ash using one-stage method, and the characteristics of zeolite were analyzed with approaches of XRD, SEM and zeta potential, the removal mechanism for Cr(III) was further investigated by FTIR and XPS. From the pH value of 8 to 12, the negative zeta potential of NaP1 zeolite products decreased from -8.72 to -24.46 mV. The pseudo-second-order kinetics equation and Langmuir isotherm fit better the reaction, the maximum adsorption capacity was 33.557 0 mg x g(-1). Functional groups of -OH and Si-O were important for Cr(III) removal shown from FTIR spectra. The Cr(2p3/2) peak was found at the binding energy of 576.45 eV, indicating the effectiveness of reaction. The binding energy of Si-Si and Si-O increased by 0.25 eV and 0.60 eV, respectively, coordination effect might work between functional groups and Cr(III), and O(1s) binding energy decreased after the adsorption process. The removal for Cr(III) on zeolite was the comprehensive results of physical and chemical adsorption effects. PMID- 22512162 TI - [Evaluation of nutrient release profiles from polymer coated fertilizers using Fourier transform mid-infrared photoacoustic spectroscopy]. AB - The acrylate-like materials were used to develop the polymer coated controlled release fertilizer, the nutrients release profiles were determined, meanwhile the Fourier transform mid-infrared photoacoustic spectra of the coatings were recorded and characterized; GRNN model was used to predict the nutrients release profiles using the principal components of the mid-infrared photoacoustic spectra as input. Results showed that the GRNN model could fast and effectively predict the nutrient release profiles, and the predicted calibration coefficients were more than 0.93; on the whole, the prediction errors (RMSE) were influenced by the profiling depth of the spectra, the average prediction error was 10.28%, and the spectra from the surface depth resulted in a lowest prediction error with 7.14%. Therefore, coupled with GRNN modeling, Fourier transform mid-infrared photoacoustic spectroscopy can be used as an alternative new technique in the fast and accurate prediction of nutrient release from polymer coated fertilizer. PMID- 22512163 TI - [Determination of cationic degree in PDA with near infrared reflectance spectroscopy]. AB - Cationic degree has been investigated as an important factor in polyacrylamide materials. Diallyl dimethyl ammonium chloride and acrylamide (PDA) was grafted by free radical polymerisation of acrylamide monomer (AM) onto the cationic monomer dimethyl diallyl ammonium chloride (DMDAAC). In the present study, near infrared reflectance spectroscopy (NIRS) was used as a rapid and accurate method to determine the cationic degree in the PDA. In this experiment, the near infrared spectra of 37 PDA samples that were self-prepared in the laboratory from 900.00 to 1 700.00 were collected. The characteristic peaks and the entire spectrum segment as the input layer neurons in radical basis function (RBF) were investigated for establishing the mathematical conversion NIRS calibration mode. For reduction of the NIR spectrum noise, the wavelet analysis was used as pretreatment process. The measured value was determined by using precipitation titration and a comparison between the simulated value and measured value was made. It was found that the external validation determination coefficient was more than 0.9, and the simulation value is in good agreement with the measured value. The statistics analysis showed that there was no significant difference between simulated value and measured value. Therefore, the calibration model (RBF neural network) established in this paper exhibited a remarkable feasibility for predicting the cationic degree of PDA based on the near infrared spectroscopy. PMID- 22512164 TI - [Anomalous absorption and a qualified far infrared spectrum]. AB - The ideal 100% line could not be obtained when the content of water vapor in the spectrometer is constant but high during the whole procedure of a far-infrared spectrum collection. This result indicates that anomalous absorption phenomenon takes place in high relative humidity atmosphere. In the present paper, the influences of the relative humidity of ambient air and spectral resolution on anomalous absorption were studied. It was found that both decreasing the water vapor content in the spectrometer and adopting low spectral resolution are effective methods to avoid anomalous absorption. Furthermore, the water vapor bands can be eliminated by "dry air and wet air titration" in the fluctuant humidity. This provides us a quick and economic method to obtain a qualified far infrared spectrum conveniently. It should be noticed that the working condition for "dry air and wet air titration" is low relative humidity to prevent water vapor abnormal absorption. PMID- 22512165 TI - [Research on calibration methods of ground-based thermal-infrared radiometer CE312]. AB - The accuracy of the calibration coefficients of the ground-based thermal-infrared radiometer CE312 is one of the most important factors affecting the calibration of the thermal-infrared remote sensors. The theory of two calibration methods which calculate the bandpass radiance and spectral radiance respectively is introduced. The calibration of the CE312-1b is conducted with the blackbody in the laboratory, the accuracy and influence factors of the results are conducted by the MODIS data combined with in situ measurements data at Qinghai Lake in Aug 2010. The results show that calibration coefficients of thermal-infrared field radiometer CE312 calculated by the bandpass radiance method has better performance in the accuracy and applicability than the spectral radiance method. PMID- 22512166 TI - [Prediction of soil organic carbon in different soil fractions of black soils in Northeast China using near-infrared reflectance spectroscopy]. AB - The soil organic carbon (SOC) associated with different soil fractions varies in the composition and dynamics. The present work is aimed to evaluate the potential of near infrared spectroscopy (NIRS) to predict SOC content in different soil fractions of black soils. SOC contents of 136 black soil samples in China were analyzed and the NIR spectra were collected using a VECTOR/22 (Fourier transform infrared spectroscopy). Partial least squares (PLS) regression with cross validation was used to develop calibrations between reference data and NIRS spectra (n = 100) which were validated using an independent set of samples (n = 36). Predictions for water-sieved aggregate associated organic carbon were generally good with R2 (coefficient of determination) ranging from 0.69 to 0.82 and the RPD (residual prediction deviation) from 1.2 to 1.8. NIRS well predicted the SOC in < 53 microm mineral fraction (R2 = 0.97, RPD = 5.4), but the prediction for SOC in 250-2 000 microm or in 53-250 microm particulate matter fractions was poor. However, the prediction for the SOC in 53-2 000 microm fraction was good (R2 = 0.79, RPD = 2.2). In addition, NIRS very well predicted the SOC in fine particle fraction (< 20 microm) (R2 = 0.93, RPD = 3.8). Accordingly, NIRS showed a good potential to predict SOC in some soil fractions and could reduce tedious laboratory analysis. PMID- 22512167 TI - [Qualitative and quantitative detection of minced pork quality by near infrared reflectance spectroscopy]. AB - The present study is concerning qualitative and quantitative detection of minced pork quality based on FT-near infrared (FT-NIR) spectroscopy and achieving the rapid approach to detecting the minced pork quality. Firstly, FT-NIR spectroscopy combined with partial least squares (PLS) and least squares-support vector machine (LS-SVM) was used for minced pork quality prediction including discrimination of the different muscle type of pig and quantitative detection of the fat, protein and moisture content of pork. The result indicated that 100% recognition ratio for calibration and 96% recognition ratio for validation were achieved by PLSDA for 4 different muscle types of pig. These two methods for chemical composition detection both have good performances in predicting fat and moisture content, the correlation coefficient for calibration and validation was all more than 0.9, but the models for protein content prediction were of less well performances, the correlation coefficients for calibration and validation, RMSEC, RMSEP and RMSECV respectively were 0.722, 0.593, 1.595, 1.550 and 1.888, respectively. The LS-SVM method is more accurate in predicting each quality index than the PLSR method. The result shows that the prediction models for fat and moisture content based on LS-SVM have a better performance with high precision, good stability and adaptability and can be used to predict the fat and moisture content of minced pork rapidly, and provide a fast approach to discrimination of the different muscle type of pig. PMID- 22512168 TI - [FTIR detection of unregulated emissions from a diesel engine with biodiesel fuel]. AB - Biodiesel, as one of the most promising alternative fuels, has received more attention because of limited fossil fuels. A comparison of biodiesel and petroleum diesel fuel is discussed as regards engine unregulated exhaust emissions. A diesel fuel, a pure biodiesel fuel, and fuel with 20% V/V biodiesel blend ratio were tested without engine modification The present study examines six typical unregulated emissions by Fourier transform infrared spectroscopy (FTIR) method: formaldehyde (HCHO), acetaldehyde (C2 H4 O), acetone (C3 H6 O), toluene (C7 H8), sulfur dioxide (SO2), and carbon dioxide (CO2). The results show addition of biodiesel fuel increases the formaldehyde emission, and B20 fuel has little change, but the formaldehyde emission of pure biodiesel shows a clear trend of addition. Compared with the pure diesel fuel, the acetaldehyde of B20 fuel has a distinct decrease, and the acetaldehyde emission of pure biodiesel is lower than that of the pure diesel fuel at low and middle engine loads, but higher at high engine load. The acetone emission is very low, and increases for B20 and pure biodiesel fuels as compared to diesel fuel. Compared with the diesel fuel, the toluene and sulfur dioxide values of the engine show a distinct decrease with biodiesel blend ratio increasing. It is clear that the biodiesel could reduce aromatic compounds and emissions of diesel engines. The carbon dioxide emission of pure biodiesel has a little lower value than diesel, showing that the biodiesel benefits control of greenhouse gas. PMID- 22512169 TI - [Calibration methods of infrared spectra for geographical origins determination of Radix Zanthoxyli]. AB - The instrument and the experimental environment influence the infrared spectra, which may limited the identification of the samples by a prediction model. Based on the Fourier transform infrared spectroscopy (FTIR) technology, the authors performed different infrared spectral calibration methods for Radix Zanthoxyli geographical origins determination, the SIMCA was used to establish an identification models, and the model was used to distinguish samples from four different regions of Guangxi. According to the result of prediction, the authors could obtain the most suitable calibration method for the identification model. The results showed that, respectively, by the multiple scattering correction and standard normal variation, their PCA data distribution and the distance between models is ideal, suggesting that we can eliminate the interference from the environmental and human factors by these two correction methods, and also separate each samples of different habitats. The test using the method to measure the geographical origins of Radix Zanthoxyli proved that the recognition rate and rejection rate are both at or near 100%. Visible, and both the multiplicative scatter correction and the standard normal variation are all the ideal calibration methods for Radix Zanthoxyli infrared spectral geographical origins determination. PMID- 22512170 TI - [Analysis of transgenic and non-transgenic rice leaves using visible/near infrared spectroscopy]. AB - Visible/near-infrared (Vis/NIR) spectroscopy was investigated for the fast discrimination of rice leaves with different genes and the determination of chlorophyll content. Least squares-support vector machines (LS-SVM) was employed to discriminate transgenic rice leaves from non-transgenic ones. The classification accuracy of calibration samples reached to 100%. Successive projections algorithm (SPA) was proposed to select effective wavelengths. SPA-LS SVM discrimination model was performed, and the result indicated that an 87.27% recognition ratio was achieved using only 0.3% of total variables. The optimal performance of each quantification model was achieved after orthogonal signal correction (OSA). Performances treated by SPA were better than that of full spectrum PLS, which indicated that SPA is a powerful way for effective wavelength selection. The best performance of quantification was obtained by SPA-LS-SVM model; with correlation coefficient (R) and root mean square error of prediction (RMSEP) being 0.902 2 and 1.312 1, respectively. Excellent classification and prediction precision were achieved. The overall results indicated that the new proposed SPA-LS-SVM is a powerful method for varieties recognition and SPAD prediction. This study supplied a new and alternative approach to the further application of Vis/NIR spectroscopy in on-field classification and monitoring. PMID- 22512171 TI - [Study of density functional theory for surface-enhanced Raman spectra of furfural]. AB - In the present paper, DFT method at the B3LYP/6-31+G* * (C, H, O)/LANL2DZ(Ag) level was used to optimize molecular configurations of furfural. Based on the optimized structure, the normal Raman spectrum (NRS) of FUR and the surface enhanced Raman spectrum (SERS) of FUR adsorbed on Ag, Ag2 and Ag4 were all calculated, which were compared with the experimental values. The calculation results indicated that a good conformity was found between the computed and the experimental results. The results of furfural adsorbed on Ag4 were more approximate to the ever reported experimental date than those of furfural adsorbed on Ag and Ag2. At the end, detailed analysis of the Raman spectrum and more comprehensive assignments of the vibration mode for furfural were studied by the software of GaussView. The data of the SERS by comparing with the one of NRS show that furfural molecule and Ag atoms interact with each other. And we suppose that the molecular plane with the ring of adsorbed furfural molecule is vertically orientated to the silver surface. The work in this paper offers a theory evidence for detection and trace analysis of drinks containing furfural. PMID- 22512172 TI - [In situ experimental study of phase transition of calcite by Raman spectroscopy at high temperature and high pressure]. AB - The phase transitions of calcite at high temperature and high pressure were investigated by using hydrothermal diamond anvil cell combined with Raman spectroscopy. The result showed that the Raman peak of 155 cm(-1) disappeared, the peak of 1 087 cm(-1) splited into 1083 and 1 090 cm(-1) peaks and the peak of 282 cm(-1) abruptly reduced to 231 cm(-1) at ambient temperature when the system pressure increased to 1 666 and 2 127 MPa respectively, which proved that calcite transformed to calcite-II and calcite-III. In the heating process at the initial pressure of 2 761 MPa and below 171 degrees C, there was no change in Raman characteristic peaks of calcite-III. As the temperature increased to 171 degrees C, the color of calcite crystal became opaque completely and the symmetric stretching vibration peak of 1 087 cm(-1), in-plane bending vibration peak of 713 cm(-1) and lattice vibration peaks of 155 and 282 cm(-1) began to mutate, showing that the calcite-III transformed to a new phase of calcium carbonate at the moment. When the temperature dropped to room temperature, this new phase remained stable all along. It also indicated that the process of phase transformation from calcite to the new phase of calcium carbonate was irreversible. The equation of phase transition between calcite-III and new phase of calcium carbonate can be determined by P(MPa) = 9.09T x (degrees C) +1 880. The slopes of the Raman peak (v1 087) of symmetrical stretching vibration depending on pressure and temperature are dv/dP = 5.1 (cm(-1) x GPa(-1)) and dv/dT = -0.055 3(cm(-1) x degrees C(-1)), respectively. PMID- 22512173 TI - [Raman spectroscopic study on the influence of ultraviolet-A radiation on collagen I]. AB - Raman spectroscopy was used to study the influence of ultraviolet-A(UV-A) radiation on collagen I. The Raman spectra of collagen I and that after 90 min UV A radiation were reported. The results proved that irradiation with 90 min UV-A caused the change in the structures of collagen I. Intramolecular hydrogen bonds were broken, and the hydrogen bonding system was changed. The intensity of helix was decreased, while the intensity of the disordered conformation in proteins such as random coil was increased. Otherwise, the UV-A radiation influenced the hydroxylation of proline and the content of hydroxyproline was reduced. The changes caused by UV-A radiation could damage the triple helical structure of collagen I. It would lead to a series of changes, such as the destruction of collagen fibers during the photoaging of skin. PMID- 22512174 TI - [Fabrication of silver ordered nanoarrays SERS-active substrates and their applications in bladder cancer cells detection]. AB - Highly ordered silver nanopore and nanocap arrays, which were used as surface enhanced Raman scattering active (SERS-active) substrates, were fabricated by electron-beam evaporating silver on the surface of porous layer and barrier layer of porous anodic alumina (PAA) membranes, respectively. The SERS characteristics of the SERS-active substrates were tested with bladder cancer cells as molecular probe. The results indicated that both the SERS-active substrates displayed a strong SERS enhancement effect. The silver nanocap ordered arrays SERS-active substrate displayed not only higher SERS and fluorescence quenching effect, but also no interferential spectrum related with oxalate impurity remaining in PAA membranes, and therefore can result in the high quality Raman spectroscopy of bladder cancer cells. PMID- 22512175 TI - [Surface enhanced Raman spectroscopy (SERS) of saliva for the diagnosis of lung cancer]. AB - Surface enhanced Raman spectroscopy (SERS) has shown the advantage of detecting low concentration biofluids presently. Saliva SERS of 21 lung cancer patients and 22 normal people were measured and differentiated in the present paper. Intensities of most peaks of lung cancer patients are weaker than that of normal people, while some stronger but with a small change rate. Those peaks were assigned to proteins and nucleic acids which indicate a corresponding decrease of those substances in saliva. Principal component analysis (PCA) and linear discriminant analysis (LDA) were used to deduce and discriminate the two groups of data, resulting in accuracy, sensitivity, and specificity being 84%, 94%, and 81%, respectively. PMID- 22512176 TI - [Detection and analysis of several kinds of oils with Raman spectrum]. AB - Applying Raman spectrometry to detect several kinds of oils such as petrol, diesel oil, naphtha and KHF (aviation fuel hydro treating), the authors can explore the regular laws existing among these oils. The authors detected 150 cases of oils using Raman spectrometer developed by ourselves with 785 nm excitation wavelength miniature portable, and dealed with these spectra paragraphs of the oils on level and SNV (normalization method) methods. The spectrograms of four categories of oils including petrol, diesel oil, naphtha and KHF and also the additives of them have different characteristics and rules. According to the alkenes peak's location and intensity we can distinguish petrol and naphtha, and then screen out some unqualified petrol. Raman spectrometry is very simple and has advantages that it needs a small amount of oil samples, at the same time, it also has no damage to test samples. The spectra-paragraphs show that different kinds of samples have different character on location and intensity of Raman peak. The Raman spectrometry method has great potential on establishing a rapid oil screening detection and identification method. PMID- 22512177 TI - [Vibrational spectra of Hetian nephrite from Xinjiang]. AB - In previous studies, EMPA, PIXE and others were employed to study the chemical compositions of nephrite separately without a systematical measurement. In the present study, XRF, XRD, IR and LR were used together to examine chemical and spectra characteristics of white, green and black nephrite from Hetian, Xinjiang. XRD results indicate that all nephrite samples consist of tremolite. Then IR spectra of nephrite samples suggest that the M-OH stretching vibration bands show that the M1 and M3 sites are not only occupied by Mg2+ and Fe2+, but also by Fe3+, which is consistent with the chemical compositions of these samples. This information might be useful to understanding the variety of nephrite. Their Raman spectra are almost the same, while some differences exist because of different content of FeO/Fe2O3. PMID- 22512178 TI - [Research on optical fiber SPR humidity sensor and resonance spectrum characteristic]. AB - A new type of humidity sensor based on optical fiber SPR sensor probe was introduced and manufactured. Firstly the sensitivity of optical fiber SPR sensor probe to environment humidity was studied. On this basis, coating with thin PVA film of different thickness and with capacity of adsorbing water molecule on the surface of optical fiber SPR sensor probe, for the purpose of monitoring relative humidity was proposed. The research shows that the SPR sensor probe coated with double layers of thin PVA film gets better detection result, and humidity measurement sensitivity is 1.59%/%RH, being improved notably compared with SPR optical fiber probe. The SPR sensor coated with single layer of thin PVA film has relative humidity measuring sensitivity of 2.411 nm/%RH related to resonance wavelength in high humidity area. In addition, the new type of optical fiber humidity-sensitive probe with PVA film losing efficiency can be reusable after special treatment. PMID- 22512179 TI - [Study on Ca2+ transmembrane behaviors of magnetic-treated S. aureus with Fura 2/AM fluorescence probe and LCSM]. AB - The purpose of the present paper is to study Ca2+ transmembrane behaviors of the S. aureus treated with high intensity pulsed magnetic field. For this purpose, the method of Fura-2/AM fluorescence probe was investigated to determine the change in intracellular Ca2+ concentration in S. aureus, fluorescence intensities of S. aureus cells treated by pulsed magnetic field under different pulse number were determined, and the change in intracellular Ca2+ concentration was observed by laser confocal scanning microscope (LCSM). Research results showed that Fura 2/AM can load in S. aureus successfuuly, and can be used to determine the change in intracellular free Ca2+ concentration. After being treated with high intensity pulsed magnetic field, intra cellular free Ca2+ concentration of S. aureus went up significantly, and the regulation of Ca2+ increase was close consistent with the decrease in living bacterium number, and relatedness reached to -0.989 15; the number and fluorescence intensity of intracellular lightspot increased significantly, meaning that large amount of exocellular calcium ions across cell membrane enter into inside of cells. So, it was judged that the change in microbial membrane permeability and increase in intracellular free Ca2+ concentration are important reasones why high intensity pulsed magnetic field has sterilization effect. PMID- 22512180 TI - [Thermoluminescence characteristics of Lu2SiO5 : Ce phosphors]. AB - To investigate the origin of the thermoluminescence at high temperature, Lu2SiO5 : Ce0.006 (LSO : Ce) phosphors were prepared by sol-gel chemistry in air and graphite respectively. The patterns of X-ray diffraction, excitation and emission spectra and thermoluminescence curves of these samples were analyzed. In comparison with the phosphors prepared in the air, the luminescence intensity was improved and the thermoluminescence peak at 598 K was restrained for the sample prepared in graphite. It was found that the thermoluminescence peak at 598 K was relevant to Ce4+. In order to achieve more evidences, LSO : Ce0.006, K(x) (x = 0.01-0.08) phosphors were prepared. The structures and spectra of K(+) -codoped samples were also studied. By codoping with K+ ions, the luminescence intensity of LSO : Ce phosphor could be enhanced distinctly, but the crystallinity was not improved. The results of the K(+) -codoped LSO: Ce exhibited that K(+) -codoping could improve the concentration of oxygen vacancy and restrain the peak at 598 K. When K+ ion occupied the position of Lu3+, more oxygen vacancies could be created and Ce4+ turned into Ce3+ simultaneously due to the balance of electric charge, which was consistent with the result of the thermoluminescence. So it can also come to the conclusion that the thermoluminescence peak at 598 K was relevant to Ce4+. The reason for K+ ions enhancing the intensity of LSO : Ce can be attributed to the improvement of concentration ratio for Ce3+/Ce4+. PMID- 22512181 TI - [Fluorescence fingerprint properties of refinery wastewater]. AB - Fluorescence organic matters contain the information about total amount and components of organic substances and could be treated as a novel water quality parameter to make up the ambiguity of COD and BOD about the pollutant composition. Refinery wastewater is a type of nonbiodegradable industrial wastewater containing a large number of toxic pollutants. The investigation on the excitation-emission matrixes of the wastewater from a large-scale refinery plant indicated that the matrix was unique for each sample; the fluorescence was intensive and was derived from the overlaps of fluorescence related to peaks at around lambda(ex)/lambda(em) = 270/300 nm, 220/300 nm and 230/350 nm. The intensity of 270/300 nm was the highest and that of 220/300 nm was the secondly highest. The location and intensities of peaks varied within small ranges. The fluorescence of the refinery wastewater contains information about products and raw materials. Phenol significantly contributed to the fluorescence intensity of 270/300 nm and 220/300 nm, and other compounds with one benzene ring such as dichlorobenzene and benzene contributed to the two peaks too. The fluorescence of 230/350 nm would be closely related to alkane and benzene. The location and intensity of peaks would be used to diagnose if the performance of the manufacturing processes and influent of treatment plant is proper. PMID- 22512182 TI - [Study on the characteristics of three-dimensional fluorescence excitation emission spectra of methanol and ethanol]. AB - For the purpose of revealing the spectra characteristics of methyl and ethanol, and establishing a method for distinguishing each other, the fluorescence features of methyl and ethanol were studied by three-dimensional fluorescence excitation-emission matrix spectra. The results obtained showed that there were two peaks in the three-dimensional fluorescence excitation-emission matrix spectra of methyl, and the intensities of the two peaks were positively related to the concentration of methyl when it was less than 15%. On the other hand, a whole fluorescence peak was only observed in the three-dimensional fluorescence excitation-emission matrix spectra of ethanol, and the intensity of the peak was positively correlated to the content of ethanol when it was less than 50%. There was a higher fluorescence efficiency for the methanol as compared to the ethanol. When the methyl was used for organic solvents to study the fluorescent nature of the organic matter, the fluorescence emitted by the methyl should be deduced. The locations of the fluorescence peaks of the methyl and ethanol were different. The peaks of the methyl were located at 225/350 nm and 250/375 nm, while the peak of the ethanol was characterized by 240/310 nm. Therefore, the fluorescence peak locations of the two alcohols could be applied to discriminate each other. PMID- 22512183 TI - [Application of polarization fluorescence to the study on the effects of oxidative stress on wheat chloroplast]. AB - In the present paper wheat flag leaves were collected during the tasseling period, and then 1 mmol x L(-1) hydrogen peroxide was added to induce oxidative stress on leaves. In comparison, the detached leaves were also kept under drought or darkness condition for 24 h for the same purpose. Following the preparation of chloroplasts, polarization fluorescence spectroscopic method was utilized to measure fluorescence emission spectra and fluorescence excitation spectra of chloroplasts in the case of VV, VH, HV and HH, where V and H is representative of vertical polarization and horizontal polarization, respectively. Gaussian deconvolution was done on emission spectra, and the fitting data revealed that no matter whether Chla or Chlb molecules were excited upon excitation at 436 nm or 475 nm, the ratio of fluorescence peak area at 684 nm and 720 nm, i. e. A684/ A720, tends to increase slightly after oxidative stress. In addition, some useful information was available from polarization excitation spectra, where it was observed that the treatment of oxidative stress gave rise to higher ratio of excitation peak intensity between 436 nm and 475 nm (E436/E475), indicating that Chla made more contribution to PSII fluorescence emission than Chlb did. Simultaneously, the ratio of 475 nm and 600 nm (E475/E600), representing the energy transfer efficiency from Car to Chlb, was also found to be higher after the detached leaves were treated. In addition, both fluorescence polarization and viscosity were calculated in this paper, and the data showed that oxidative stress should be responsible for higher fluorescence polarization at 680 nm and higher viscosity in microenviroment. The above-mentioned phenomenon is consistent with the lipid peroxidation of unsaturated fatty acids. It also provides a simple and feasible method to study oxidative stress. PMID- 22512184 TI - [In-flight absolute radiometric calibration of UAV hyperspectral camera and its validation analysis]. AB - With the data in Urad Front Banner, Inner Mongolia on November 14th, 2010, hyper spectral camera on UAV was calibrated adopting reflectance-based method. During the in-flight absolute radiometric calibration, 6 hyper-spectral radiometric gray scale targets were arranged in the validation field. These targets' reflectances are 4.5%, 20%, 30%, 40%, 50% and 60% separately. To validate the calibration result, four extra hyper-spectral targets with sharp-edge spectrum were arranged to simulate the reflection and absorption peaks in natural objectives. With these peaks, the apparent radiance calculated by radiation transfer model and that calculated through calibration coefficients are much different. The result shows that in the first 15 bands (blue bands), errors are somewhat huge due to the noises of equipment. In the rest bands with quite even spectrum, the errors are small, most of which are less than 10%. For those bands with sharp changes in spectral curves, the errors are quite considerable, varying from 10% to 25%. PMID- 22512185 TI - [The prediction of barley grain protein content based on hyperspectral data]. AB - The prediction of crop grain protein by hyperspectral data has the nondestructive and quick advantages. At present, there are only a few reports about the prediction of barley grain protein by remote sensing. The present research focuses on the malt barley of Northeast China. Firstly, we analyzed the sensitive band area, compared many vegetation indexes related with the plant nitrogen. According to the mechanism of nitrogen transfer, the authors built the prediction model based on the hyperspectral vegetation indexes. Finally, we validated the results. It can meet the standard. The outcome shows that (1) the sensitive band region of barley plant nitrogen is 550-590 nm and 670-710 nm. (2) GRVI was significantly correlated with plant nitrogen. The relationship between GRVI and barley plant nitrogen had a coefficient of determination of R2 = 0.665 1. The results indicated that the prediction of barley grain protein by hyperspectral data is feasible. This research will be a strong scientific support for barley purchase. PMID- 22512186 TI - [Effects of leaf hair on leaf reflectance and hyperspectral vegetation indices]. AB - Many hyperspectral vegetation indices have been used to estimate the biochemical contents such as pigment content, nondestructively. These reflectance indices are influenced by leaf hair, and the existence of the leaf hair affects the performance of the indices on the estimation of the biochemical contents. The present research studied the possible effects of the leaf hair on the reflectance of the same leaf before and after removal of leaf hair. The authors found that dehairing had decreased the reflectance between wavelength 400 and 1 000 nm, and the decrease depends on the wavelength. The changes of 39 hyperspectral indices before and after the hair removal were compared. The results revealed that some indices that only use visible wavebands or the near infrared wavebands such as CTR1: R695/R420, D740/D720, WBI: R900/R970, R860/(R550 x R708) and REP (Red-edge position) were not affected much by the dehairing process and are thought relatively robust to estimate the biochemical contents. PMID- 22512187 TI - [Research on the spectral characteristics of grassland in arid regions based on hyperspectral image]. AB - The grassland spectrum was got from Hyperion images of Shiyang River Basin using PPI, after FLAASH atmosphere correction, to understand the spectral characteristics quantitatively. The results show that red edge moves left, slope reduced, blue and yellow edge feature is abated, reflectance is higher in visible bands, and lower near-infrared bands when grassland is at decline stage relative to the spectrum characteristics of grassland at well growth. The red edge, green peaks, absorption valley location of blue and red light keep consistent for different coverage grassland, and spectrum absorption characteristics (band depth, width, area, symmetry) in visual bands change regularly as coverage increases, so it can be a basis for extraction or judgment of vegetation coverage. PMID- 22512188 TI - [Study on the reflected and hyperspectral mixed-pixel character of aquatic plants and water]. AB - A study on the reflected and hyperspectral mixed-pixel of aquatic plants and water was given by using a orthogonal experimental design with three factors and two levels. The results of F test suggest that for the single factors, the band and the area ratio of mixed-pixel on the reflected and hyperspectral mixed-pixel of the reflection effects are particularly significant, however, the detector angle had no significant effect under these experimental conditions; For the interaction, the band and the area ratio of mixed-pixel, the detector and the area ratio of mixed-pixel, the effects of these two interactions on the reflected and hyperspectral mixed-pixel are also particularly significant, This study did quantitative analysis of the factors affecting the reflected and hyperspectral mixed-pixel character and their interaction, and provided a new method for the indepth study of mixed-pixel. PMID- 22512189 TI - [Spectral reflectance response of plant leaf to simulated UVB stress]. AB - In the present study, we evaluate the relative content of chlorophyll and spectral reflectance variations in the visible light under different intensity of UVB (L-UVB, CK and UVB) of three typical evergreen broadleaf plants in China subtropical area. In different simulated UVB condition, the experiment shows that different tree species have different UVB sensitivity, and chlorophyll content varies greatly with species, and the chlorophyll relative content with the filter UVB w as significantly higher than with enhanced UVB. In the spectral reflectance of the visible part, it is generally higher with enhanced UVB's treatment than with L-UVB treatment; and any treatments present adaptation, species under different stress. After roles of the different UVB intensity, for each tree species the visible part of the spectral reflectance shows difference between green and red mainly. The study results show that the subtropical evergreen broad leaved species has a strong sensitivity to the UVB, and UVB response of different tree species varies greatly. PMID- 22512190 TI - [Reduction of hyperspectral dimensions and construction of discriminating models for identifying wetland plant species]. AB - The present paper researched and analyzed the hyperspectral data of wetland plant species often occurred in Beijing. The methods of Mahalanobis Distance (MD) and principal component analysis (PCA) were mainly applied to reduce the dimensions of hyperspectral data and to analyze and extract the features of spectra. The authors use the extracted spectra to build identification models for identifying the wetland species. The authors then compared and evaluated the precisions of models and finally obtained the best discriminating model. The results showed that (1) the dimensions of hyperspectral data can be efficiently reduced by both MD and PCA methods. (2) The discriminating models established using the parameters extracted from the resulting spectra of MD and PCA could identify the wetland plants with high precisions of more than 90%. As a result, the conversion and usage of the hyperspectral data can help better understand and well extract the spectra of different wetland plants. Furthermore, the constructed discriminating models for wetland species could also be used in the future to guide us in mapping and monitoring of wetland ecosystem by applying the remote sensing data. PMID- 22512191 TI - [Estimating total nitrogen content in wetland vegetation based on measured reflectance spectra]. AB - More and more urban wetlands have been supplied with reclaimed water. And monitoring the growth condition of large-area wetland vegetation is playing a very important role in wetland restoration and reconstruction. Recently, remote sensing technology has become an important tool for vegetation growth monitoring. The South Wetland in the Olympic Park, a typical wetland using reused water, was selected as the research area. The leaf reflectance spectra and were acquired for the main wetland plants reed (Phragmites australis) and cattail (Typha angustifolia) with an ASD FieldSpec 3 spectrometer (350 2 500 nm). The total nitrogen (TN) content of leaf samples was determined by Kjeldahl method subsequently. The research established univariate models involving simple ratio spectral index (SR) model and normalized difference spectral index (ND) model, as well as multivariate models including stepwise multiple linear regression (SMLR) model and partial least squares regression (PLSR) model. Moreover, the accuracy of all the models was tested through cross-validated coefficient of determination (R2(CV)) and cross-validated root mean square error (RMSE(CV)). The results showed that (1) comparing different types of wetland plants, the accuracy of all established prediction models using Phragmites australis reflectance spectra was higher than that using Typha angustifolia reflectance spectra. (2) compared with univariate techniques, multivariate regressions improved the estimation of TN concentration in leaves. (3) among the various investigated models, the accuracy of PLSR model was the highest (R2(CV) = 0.80, RMSE(CV) = 0.24). PLSR provided the most useful explorative tool for unraveling the relationship between spectral reflectance and TN consistence of leaves. The result would not only provide a scientific basis for remote sensing retrieval of biochemical variables of wetland vegetation, but also provide a strong scientific basis for the monitoring and management of urban wetlands using recycled water. PMID- 22512192 TI - [Decomposition and analysis of the natural source SLF spectrum using curvelet transform method]. AB - Because natural source super low frequency (SLF) electromagnetic detection equipment receives wideband multi-source signal, how to decompose the signal to filter out the interference signal was a key factor for the application of natural source SLF electromagnetic detection technology. In the present article, the detection equipment developed by Peking University was used to survey the coal bed methane data in the Qinshui basin, Shanxi province, and the curvelet transform method was employed to decompose those data. The analysis results indicated that the high-frequency information coming from the decomposition is the interference signals mainly generated by lightning in the atmospheric and directly received by the detection equipment, while the low frequency signal mainly contains the target information. So the reconstructed curve based on the low-frequency information was more favorable for the interpretation of the target, compared with the original spectrum curve. But the curvelet transform method could not remove the artificial frequency signal. PMID- 22512193 TI - [Study on the measurement of ambient ammonia in urban area based on open-path DOAS technique]. AB - As a key role in the acid-deposition and the generation of secondary particle matter (PM), measurement of the concentration of atmospheric ammonia in urban area has been attracting the scientists' interests nowadays. After studying the special absorption features of ammonia in short UV wavelength range, detailed concernful issues were put forward in the present paper. The decision of using xenon lamp as the light source was made after the evaluation of measurement of light spectroscopy. Retrieval wavelength band for NH3 was fixed from 204 to 214 nm and optimal method of deducting other interferential gases was also shown. A home-made open-path DOAS (OP-DOAS) system was set up for the measurement of the concentration of atmospheric NH3. The detection limit of such system was calculated with the typical noise level as low as 0.33 microg x m(-3) with the optical path 228 m. Through field experiment in Guangzhou city, such a system can be competent for the online and high time-resolution monitoring of the concentration of atmospheric ammonia. With a significant diurnal variation, the atmospheric ammonia changed from 0.83 to 3.11 microg x m(-3) with the mean value 1.59 microg x m(-3). The representative character of the diurnal variation is that the concentration of NH3 peaks during night while drops to bottom in the daytime. After the error analysis procedure, typical measurement accuracy of such OP-DOAS system was within 10%. PMID- 22512194 TI - [Application and progress of the nondestructive spectral technology used in polychrome ceramic relics analysis]. AB - The polychrome ceramic relics own abundant information which play an important role in studying ancient Chinese history, culture, economy, science and technology. Because the polychrome ceramic relics analysis couldn't be satisfied by common analytical methods, various kinds of nondestructive spectral technology have been introduced in this area gradually. This paper presented the theory, feature and limitation of the nondestructive spectral technology such as Laser Raman microscopic spectrum, laser induced breakdown spectra, and EDXRF from three parts: pigment analysis, ceramic analysis and relic information identification. Finally, the future development trends were discussed. PMID- 22512195 TI - [Equalization of whole-band signal's SNR in the blood components noninvasive measurement]. AB - To fully extend the category of blood components that can be noninvasively measured by dynamic spectrum (DS) method and to increase its measuring precision, an overall consideration of light source, tissue absorption and sensor's sensitivity was made. Compensating the light source and adding the telecentric lens not only expand the spectral effective detecting range, but also balance the signal-to-noise ratio (SNR) of the photoelectric pulse in the whole band equalization. The integral SNR of DS signal was increased and the measurement bandwidth was expanded. The effectiveness of this method was validated by the quality evaluation criterion of DS data: the effective detecting range of visible DS was widened from 600-1 000 nm to 500-1 135 nm; the effective detecting range of near-infrared DS was widened from 900-1 100 nm to 900-1 700 nm. The results show that the design can create the condition for detection of new blood components noninvasively, and enhance the prediction accuracy of the blood components, for which noninvasive measuring using DS method has been achieved. PMID- 22512196 TI - [Component analysis of complex mixed solution based on multidimensional diffuse reflectance spectroscopy]. AB - In the present paper, the authors proposed a method for component analysis of complex mixed solutions based on multidimensional diffuse reflectance spectroscopy by analyzing the information carried by spectrum signals from various optical properties of various components of the analyte. The experiment instrument was designed with supercontinuum laser source, the motorized precision translation stage and the spectrometer. The Intralipid-20% was taken as an analyte, and was diluted over a range of 1%-20% in distilled water. The diffuse reflectance spectrum signal was measured at 24 points within the distance of 1.5 13 mm (at an interval of 0.5 mm) above the incidence point. The partial least squares algorithm model was used to perform a modeling and forecasting analysis for the spectral analysis data collected from single-point and multi-point. The results showed that the most accurate calibration model was created by the spectral data acquired from the nearest 1-13 points above the incident point; the most accurate prediction model was created by the spectral signal acquired from the nearest 1-7 points above the incident point. It was proved that multidimensional diffuse reflectance spectroscopy can improve the spectral signal to noise ratio. Compared with the traditional spectrum technology using a single optical property such as absorbance or reflectance, this method increased the impact of scattering characteristics of the analyte. So the use of a variety of optical properties of the analytes can make an improvement of the accuracy of the modeling and forecasting, and also provide a basis for component analysis of the complex mixed solution based on multidimensional diffuse reflectance spectroscopy. PMID- 22512197 TI - [Preparation by template method and spectral characterization of alpha-MoO3 nanorods and nanometer rectangular pieces]. AB - alpha-MoO3 was paid special attention to nano scale with its layered crystal structure and potential applications in material chemistry fields. In the present paper, (NH4)6 Mo7O24 x 4H2O and hexadecyl trimethyl ammonium bromide (CTAB) were proposed as molybdenum precursor and template agent, respectively, and the precursor was prepared by statistic ion exchange with strong acidic ion exchange resin (R-H). The precursor can be transformed into alpha-MoO3 nanorods and nanometer rectangular small pieces via calcining precursor at 600 degrees C for different times. The phasestate, structure and morphology of samples were identified by FTIR, XRD, TEM and SEM. The alpha-MoO3 nanorods with the length of about 1-1.6 microm, the diameter of about 0. 10-0. 20 microm and the ratio of length to diameter of 8, and the nanometer rectangular small pieces with the length of about 0. 14-0. 18 microm, the width of about 60-80 nm and the thickness of 28-32 nm, were obtained after 600 degrees C sintering for 4 and 8 h. This preparation procedure is simple, without the need for artificially adjusting the pH, redundantly washing can be avoided, the resin can be regenerated and NH4 Cl was recycled without environmental pollution. PMID- 22512198 TI - [UV spectroscopy coupled with partial least squares to determine the enantiomeric composition in chiral drugs]. AB - In the present study, sucrose was used as a chiral selector to detect the molar fraction of R-metalaxyl and S-ibuprofen due to the UV spectral difference caused by the interaction of the R- and S-isomer with sucrose. The quantitative model of the molar fraction of R-metalaxyl was established by partial least squares (PLS) regression and the robustness of the models was evaluated by 6 independent validation samples. The determination coefficient R2 and the standard error of calibration set (SEC) was 99.98% and 0.003 respectively. The correlation coefficient of estimated value and specified value, the standard error and the relative standard deviation (RSD) of the independent validation samples was 0.999 8, 0.000 4 and 0.054% respectively. The quantitative models of the molar fraction of S-ibuprofen were established by PLS and the robustness of models was evaluated. The determination coefficient R2 and the standard error of calibration set (SEC) was 99.82% and 0.007 respectively. The correlation coefficient of estimated value and specified value of the independent validation samples was 0.998 1. The standard error of prediction (SEP) was 0.002 and the relative standard deviation (RSD) was 0.2%. The result demonstrates that sucrose is an ideal chiral selector for building a stable regression model to determine the enantiomeric composition. PMID- 22512199 TI - [Column chromatography purification and analysis of biodiesel by transesterification]. AB - In the present paper, crude biodiesel prepared with sorbifolia oil as raw material by transesterification was purified by column chromatography, then the composition of biodiesel was analyzed by gas chromatography, FTIR, GC-MS and 1H NMR. Column chromatography can separate the crude biodiesel into two fractions: petroleum ether eluted fraction (A1) and methanol eluted fraction (A2). Petroleum ether eluted fraction was mainly biodiesel fraction, which was produced from sorbifolia oil by transesterification, including methyl linoleate, methyl cis-9 octadecenoate and so on; methanol eluted fraction was mainly glycerol fraction, which came from the side reaction of transesterification. The results show that the purity of refined biodiesel increased from 77.51% to 93.872, and the product recovery rate reached up to 91.04% after the purification by column chromatography. The results obtained by FTIR and 1H NMR further showed that the column chromatography can effectively improve the purity of biodiesel. This paper provides a basis for industrialization of purification of biodiesel. PMID- 22512200 TI - [Data mining approach to cataclysmic variables candidates based on random forest algorithm]. AB - An automatic and efficient method for cataclysmic variables candidates is presented in the present paper. The identified CVs were selected as templates. A model was constructed by random forest algorithm with templates and random selected spectra. Wavelength ranking was described by the model and the classifier was constructed afterwards. Most of the non-candidates were excluded by the method. Template matching strategy was used to identify the final candidates which were analyzed to complement the templates as feedback. 16 new CVs candidates were found in the experiment that shows that our approach to finding special celestial bodies can be feasible in LAMOST. PMID- 22512201 TI - [Enrichment of trace iron with activated carbon in Bi-based superconductor powder and determination by inductively coupled plasma atomic emission spectroscopy]. AB - A new method for determination of trace iron in superconductor powder by ICP-AES was proposed. The instrument parameters were optimized, and the matrix effects as well as the method of eliminating interferences were also studied systemically. The results showed that matrix interference was serious when the amount of matrix increased, and the repeatability was poor, so it was necessary that separation and preconcentration were used to improve the accuracy and precision. In the experiment, complex was formed with Fe and phenanthroline after the matrix elements Bi and Cu were masked by triethanolamine in an appropriate acidity condition. Then the complex was quantitatively adsorbed by activated carbon, and desorbed by 1 : 1 HNO3. The enrichment conditions were investigated in detail. Under the optimal condition, an artificial sample was analysed, and the result was identical with reference values, with the RSD and detection limit being 2.42% and 0.033 microg x g(-1), respectively. The method was applied for the determination of trace iron in Bi-based superconductor powder samples with satisfactory results, in which the recoveries experiment was performed with the recovery coefficient falling in the range of 95.6% to 98.0%. PMID- 22512202 TI - [Spectroscopic characterization of dissolubility and surface properties of chalcopyrite in aqueous solution]. AB - The dissolubility and surface properties of chalcopyrite were studied in different mechanical stirring time and different pH value solution under argon and oxygen atmosphere by ICP-MS, AFM and XPS analysis. Besides, the XRD tern and crystal structure of chalcopyrite and its dissolution model in aqueous solution were established. The laboratory results indicate that the relationship between copper and iron concentrations in solution and time in pure water can be derived as the equation c = ks(a)t+b. The lower pH value makes it easier for chalcopyrite to dissolve, and that the surface oxidation is slow has minor effect on the dissolubility. In pure water, the dissolution of chalcopyrite has little influence on the effective specific surface area, and the dissolution is controlled by surface chemical reaction under acidic conditions. After long time dissolution, the surface of the chalcopyrite assumes copper-rich state relative to iron and the surface roughness and lattice imperfections increase. PMID- 22512203 TI - [Determination and analysis of trace elements in Lycium barbarum L. from different regions of Qinghai province]. AB - For comparison of the quality of Lycium barbarum L., the authors determined 11 trace elements in the fruits of Lycium barbarum L. from 12 different regions of Qinghai province by ICP-MS and ICP-AES. Meanwhile, 7 trace elements essential for human body were selected to the object of principal component analysis by SPSS statistic software. Three principal component equations were obtained, and the regression equation related to principal component was also set up. The research is very important to quality analysis and to obtaining high quality Lycium barbarum L. , and provided science basis for the development and utilization of Lycium barbarum L. in Qinghai province. PMID- 22512204 TI - [Determination of mineral elements in Bupleurum based on ICP-AES]. AB - ICP-AES technique was used to determine the mineral elements in Bupleurum at different habitat. The results show that: (1) In Bupleurum, the content and accumulation of K was the highest among 5 macroelements, the content and accumulation of Fe was the highest among 5 microelements. (2) In Bupleurum, the content of Ca, Mg, P, Na and Cu was high in habitat of Beijing, the content can respectively reach to 6.40, 3.84, 3.45, 4.97 mg x g(-1), and 25.20 microg x g( 1); while the content of K, Ca, Mg, P, Zn, Mn and Cu was low in habitat of Wanrong,and the content was only 12.43, 4.57, 1.92, 1.79 mg x g(-1) and 50.04, 32.21, 15.43 microg x g respectively. (3) In Bupleurum, the content of P : K, Zn : Fe, Cu and Mn was significantly different at different habitat, while Mg and Ca showed little difference. CONCLUSION: In Bupleurum, the content, accumulation and proportion of mineral elements were difference at different habitat. PMID- 22512205 TI - [Determination of total selenium in water by hydride generation atomic fluorescence spectrometry]. AB - In order to establish a rapid and accurate hydride generation-atomic fluorescence spectrometry method for the determination of selenium content in water samples, the influence factors on Se nitrolysis in the water such as nitrolysis temperature and the amount of hydrochloric acid were studied. The authors determined a simple and practical test method that is to add 3 mL hydrochloric acid at 3 degrees C. We measured the precision and accuracy of the method by the standard liquid of 3, 6 and 10 micro x L(-1), and the test results were 2.96, 5.43 and 9.66 mg x L(-1). The recovery varied from 90.50% to 98.67%. Meanwhile we tested 29 water samples by different methods. The error of standard sample was 8.95%-25.46% by hydride generation-atomic fluoresence spectrometry in the GB/T 5750. 6-2006, and the error of standard sample was 1.33%-3.40% by new method. Compared with the national standards of GB/T 5750.6-2006, the method has the advantages of operating simplicity and and easy control, and it is also reliable and economical. PMID- 22512206 TI - [Analysis of Cd pollution & spatial variability characteristics of typical agricultural soils in suburbs of Urumqi City, Xinjiang]. AB - Cd content in agricultural soils from 4 townships in north suburb and 2 townships in south suburb of Urumqi City was determined with graphite furnace (GF-990) atomic absorption spectrometry, and the spatial variability of Cd content there was analyzed with geo-statistics method. The result indicates that Cd content from the sampling points in north suburb exceeds the stipulated standard and falls into medium or strong spatial variability with nugget value > 75%, which explains a weak self-correlation among those variable spaces under mainly the impact of random factors of external pollution such as local fertilization level, irrigation and cultivation etc. Cd content from the sampling points in north suburb does not exceed the stipulated standard but approaches to the critical warning value with nugget value at 50.2%, which falls into medium self correlation among those variable spaces. Spatial variability characteristics of Cd distribution in suburban agricultural soils of Urumqi City, Xinjiang were studied in this paper for providing scientific basic data to source analysis and control of Cd pollution in the far mLands there. PMID- 22512207 TI - [Determination of trace lead and cadmium in transgenic rice by crosslinked carboxymethyl konjac glucomannan microcolumn preconcentration combined with graphite furnace atomic absorption spectrometry]. AB - A novel method was developed for the determination of trace lead and cadmium in transgenic brown rice based on separation and preconcentration with a micro column packed with crosslinked carboxymethyl konjac glucomannan (CCMKGM) prior to its determination by graphite furnace atomic absorption spectrometry. Variables affecting the separation and preconcentration of lead and cadmium, such as the acidity of the aqueous solution, sample flow rate and volume, and eluent concentration and volume, were optimized. Under optimized condition, detection limits of the method for the determination of trace lead and cadmium in transgenic brown rice were 0.11 and 0.002 microg x L(-1), respectively. The obtained results of lead and cadmium in the certified reference material (GBW10010, GBS1-1) were in good agreement with the certified values. The recoveries were in the range of 90%-103% and 93%-105% for detection of Pb and Cd in transgenic brown rice and the wild-type brown rice samples respectively. This study could provide technical support for determination of trace Pb and Cd in transgenic rice. PMID- 22512208 TI - [Analysis of atractylodes macrocephala koidz of spaceflight breeding with XRF and PXRD]. AB - The contents of various elements in the fourth generation atractylodes macrocephala koidz cultivated by spaceflight breeding were analyzed and compared with those of the ground group on the whole jointly by XRF and PXRD. The results showed that the element Na and Ti could not be detected in the space group, and the levels of K and Mn were enhanced by 1.16 and 1.15 times as these elements were measured in ground group, but other elements' contents declined to different degrees, and the most notable elements are Si and P, decreasing by 82.1% and 71.2% accordingly; there is some whewellite in the ground group, whereas much less is found in the space group. The ground group contains inulin, however none in the space group. Spaceflight breeding can harvest significantly mutated specific Chinese herbal medicines varieties. The combination of two testing techniques has a positive role in space breeding applied in cultivation of medicinal plants. PMID- 22512209 TI - [A review of Dyson optical system in the measure of infrared imaging spectrum]. AB - It is difficult for the traditional infrared imaging spectrometers to satisfy the requirement of high signal to noise ratio (SNR) and small size simultaneously. The new infrared remote sensing imaging spectrometers based on Dyson concentric optical configuration have the advantages of high aperture, high SNR, simpleness small volume and low weight. The Dyson imaging spectrometers can achieve high SNR, which is difficult for the traditional imaging spectrometers for infrared imaging spectrum. The present review introduces the beginning, the development and the present research of the Dyson imaging spectrometers, especially illustrates the principle of Dyson concentric spectrometer, difficulty during its manufacture and the application in the high-performance infrared remote sensing imaging spectrometers, providing a reference for the high-performance research of infrared remote sensing imaging spectrometers. PMID- 22512210 TI - [Design of a dual-channel Mach-Zehnder lateral shearing interferometer for the large aperture static imaging spectrometer]. AB - Large aperture static imaging spectrometry (LASIS) is a kind of joint temporally and spatially modulated Fourier transform imaging spectrometry. In such instruments, lateral shearing interferometer is a key element, the most frequently used type of which is the Sagnac interferometer. In this configuration, one half of the light entering the interferometer backtracks and causes a great decrease in energy efficiency. The present paper proposes a modified Mach-Zehnder lateral shearing interferometer structure to tackle this problem. With the ability to produce the same lateral shear, it features the advantage of dual channel output. We present a ray tracing procedure to induce the general expression of the lateral shear as well as analyze the contributions of error sources to the shear accuracy. The results serve as a new idea for the design of large aperture static imaging spectrometers and can be used to instruct the design and optimization of this kind of imaging spectrometer. PMID- 22512211 TI - [Comparison of NO2 slant columns between two ground-based MAX-DOAS]. AB - The study of comparison of NO2 SCD between two ground-based multi axis DOAS is introduced. The slant columns of NO2 from JAMASTEC are compared with those of AIOFM during the period from November to 31 December 2009. It says that the more signal to noise ratio is obtained by using the adjusted integral time rather than fixed settings; Two instrument show good accordance in the lower viewing angles, with the correlation coefficient of 0.995, but it becomes bad with higher viewing angles. The low deviation between the two instruments was achieved during the period from 9am to 17pm, the results in the 20 degree direction show best agreement with a deviation of 12%, but in other period the deviation becomes larger. The results in the visible range are better than those in the UV range, the residual in the fit decreases by more than 60%, and the results in the visible range show good agreements with those of AIOFM in the UV range during the whole day. PMID- 22512212 TI - [Optimization of broad-band flat-field holographic concave grating without astigmatism]. AB - The desirable imaging locations of the flat-field holographic concave gratings should be in a plane. And the object can be imaged perfectly by the grating when the tangential focal curve and sagittal focal curve both superpose the intersection of the image plane and dispersion plane. But actually, the defocus can not be eliminated over the entire wavelength range, while the astigmatism vanishes when the grating parameters satisfy some conditions. An optimization method for broad-band flat-field holographic concave gratings with absolute astigmatism correction was proposed. The ray tracing software ZEMAX was used for investigating the imaging properties of the grating. And we made a comparison between spectral performance of gratings designed by this new method and that by conventional method, respectively. The results indicated that the spectral performance of gratings designed by using the absolute astigmatism correction method can be as good as gratings designed with the conventional method. And the focusing performance in the sagittal direction is much better, so that the S/N ratio can be greatly improved. PMID- 22512213 TI - [A mobile sensor for remote detection of natural gas leakage]. AB - The detection of natural gas pipeline leak becomes a significant issue for body security, environmental protection and security of state property. However, the leak detection is difficult, because of the pipeline's covering many areas, operating conditions and complicated environment. A mobile sensor for remote detection of natural gas leakage based on scanning wavelength differential absorption spectroscopy (SWDAS) is introduced. The improved soft threshold wavelet denoising was proposed by analyzing the characteristics of reflection spectrum. And the results showed that the signal to noise ratio (SNR) was increased three times. When light intensity is 530 nA, the minimum remote sensitivity will be 80 ppm x m. A widely used SWDAS can make quantitative remote sensing of natural gas leak and locate the leak source precisely in a faster, safer and more intelligent way. PMID- 22512214 TI - Ward-rounds: role in clinical teaching and learning in contemporary medicine. PMID- 22512215 TI - Association of the KCNJ11 variant E23K with type 2 diabetes in Indo-Trinidadians. AB - OBJECTIVE: To examine the effect of genetic variation in KCNJ11 on the risk of Type 2 diabetes mellitus in Trinidadians. METHODS: The coding and bordering intron-exon regions of the KCNJ11 gene were sequenced in 168 diabetic and 61 non diabetic subjects who historically were thought to be of South Asian Indian ancestry as well as 66 diabetic and 59 non-diabetic subjects of African ancestry. Allele and haplotype frequency differences were calculated between cases and controls and linkage equilibrium was assessed across the KCNJ11 region. RESULTS: We identified novel missense mutations in both subject groups including A94P and R369C in a diabetic Indo-Trinidadian subject, S113G in a non-diabetic Indo Trinidadian subject, and S118L in a diabetic Afro-Trinidadian subject. It is unknown if these mutations are pathogenic as other family members were not available for study. Additionally, the common variant E23K was associated with Type 2 diabetes in the Indo-Trinidadian group (OR = 1.797 [1.148-2.814], p = 0.0098). CONCLUSIONS: Rare variants in KCNJ11 are segregating in the Indo- and Afro-Trinidadian populations and further studies are needed to determine their contribution, if any, to the overall prevalence of diabetes in these groups. Common variants such as E23K may increase the risk in the Indo-Trinidadian population. PMID- 22512216 TI - Cassia alata leaf extract induces cytotoxicity in A549 lung cancer cells via a mechanism that is caspase 8 dependent. AB - OBJECTIVE: To evaluate the cytotoxic effect of a hexane extract of Cassia alata leaves in A549 lung cancer cells. METHOD: Parental A549 lung cancer cells were exposed to various concentrations (100-180 microg/ml) of Cassia alata leaf extract for 24 hours. Following treatment, the cells were evaluated using the 3 (4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay to determine the cytotoxic effect of the extract. Caspase 8, 3 and 9 negative A549 cells were also prepared using lentiviral based shRNA knockdown of the caspase 8, 3 and 9 genes, respectively. The cytotoxic effect of Cassia alata leaf extract was then evaluated in these knockdown cells using the MTT assay. Chemical analysis was performed on the extract using high performance liquid chromatography (HPLC). RESULTS: Cassia alata extract was cytotoxic in parental and caspase-9 negative, but not caspase 3 and 8 negative A549 cells. The IC50 values were 143 microg/ml and 145 microg/ml in parental and caspase 9 negative A549 cells respectively. The flavanoid kaempferol was identified as a constituent of Cassia alata leaf extract. CONCLUSIONS: Cassia alata produces cytotoxicity in A549 cancer cells that is mediated by caspase 8 activation. This effect may be attributable to kaempferol. PMID- 22512217 TI - Anti-inflammatory activities of Cassia alata leaf extract in complete Freund's adjuvant arthritis in rats. AB - OBJECTIVE: To investigate the anti-inflammatory effects of a hexane extract of Cassia alata leaves in complete Freund's adjuvant (CFA) arthritis in rats. METHOD: A hexane extract of Cassia alata leaves was administered by oral gavage to CFA arthritic rats (500 mg/kg, n = 6). Controls received corn oil (2 ml, n = 6). The CFA arthritic model was induced by the injection of 0.5 ml (CFA) into the synovial cavity of the right knee joint of the hind leg of rats. The ability of the plant extract to reduce swelling as a sign of arthritic inflammation was assessed by obtaining the circumference of the knee joint before and for twenty eight days post arthritis induction. Reduction of leukocyte infiltration into the blood and synovial cavity of the arthritic rats were assessed using automated counting and Wrights method. Protection against cartilage erosion was also assessed histologically. RESULTS: Cassia alata extract significantly (p = 0.0032) reduced knee circumference (swelling) in the CFA arthritic rats. Total and differential leukocyte counts in both blood and synovial fluid from Cassia alata treated animals were significantly (p < or = 0.05) lower than in control animals. Protective effects against cartilage degradation on the femoral head of the knee joint were observed in Cassia alata treated animals, as normal cartilage structure and chondrocyte arrangement were maintained. CONCLUSIONS: The results suggest that Cassia alata exhibits anti-inflammatory activities that should be further examined and potentially exploited for anti-arthritic therapies. PMID- 22512218 TI - The anatomical basis of the medial sural artery perforator flaps. AB - OBJECTIVES: To study the perforators of the medial sural artery and the possible size of their flap. METHODS: The external iliac arteries often adult preserved cadavers (males and females) were injected with a mixture of red latex and lead oxide. The skin was reflected and the medial sural artery and its perforators were identified. The diameters and origins of perforators were measured from the central popliteal crease. RESULTS: The medial sural artery originated from the popliteal artery in 70% and had its external diameter at a mean of 3 +/- 0.02 mm and was accompanied by two venae comitantes. The number of its perforators was at a mean of two perforators. Length of the pedicle of the medial sural artery perforator flap was at a mean of 18 +/- 0.03 cm. The largest of the perforator had an average external diameter of 0.9 mm. The perforators ramified the skin with branches of the artery accompanying the posterior cutaneous nerve and the perforating branches of the peroneal and the posterior tibial arteries. The possible size of the medial sural perforators flap was at an average 8.2 cm x 13.3 cm. CONCLUSION: The medial sural artery perforator flap has at least one or two perforators with an average size of 8.2 cm x 13.3 cm. Elevation of the flap will not affect the vascularity of the gastrocnemius muscle. PMID- 22512219 TI - Long-term effects of chronic Achilles tendon rupture treatment, using reconstruction with peroneus brevis transfer, on sports activities. AB - OBJECTIVE: This study reports long-term effects of chronic Achilles tendon rupture treatment, using reconstruction with peroneus brevis transfer (PBT), on sports activities based on an approximate 10-year follow-up study. METHODS: Twenty patients (6 women and 14 men; mean age, 43 +/- 12.85 years at the time of operation) underwent chronic Achilles tendon repair with an average follow-up of 164.05 +/- 5.07 months. Seven were involved in competitive sports, 10 participated in recreational activities and three were not involved in any sporting activities. All patients were Asians. Results were assessed using Cybex strength testing and the American Othopaedic Foot and Ankle Society (AOFAS) Score, the muscle manual test (MMT), sports activities and comprehensive satisfaction assessment. RESULTS: Cybex strength testing resulted in an average gain of 87.05 +/- 14.83% in dorsiflexion strength (range 65-110%) and 98.05 +/- 9.02% in plantar flexion strength (range 85%-120%). The AOFAS score average was 86.9 +/- 7.27. There were no postoperative re-ruptures, no recurrences and no wound complications. Plantar flexion strength and the AOFAS score were negatively correlated with the age at the time of operation (r = -0.566, r = -0.669, respectively). Seventeen patients (85%) were level five of MMT in eversion strength. Following treatment, six patients (30%) returned to competitive sports, while 10 (50%) who, prior to the injury and surgery, were involved in recreational activities, returned to similar activities. The relatively younger group tended to continue sport activities as competitive athletes (p < 0.05). Significant differences were observed in age at the operation between non satisfaction group and excellent group (p < 0.05). The under 40-year age group tended to show a poor value. CONCLUSION: Recreational athletes and non-athletes could return to their sports activities satisfactorily, while young competitive athletes found difficulties in certain actions, especially related to eversion. PMID- 22512220 TI - Open abdominal aortic aneurysm repair in the era of endovascular repair. AB - OBJECTIVES: The development of minimally invasive techniques for abdominal aortic aneurysm (AAA) repair and the establishment of specialized centres have resulted in improved patient outcomes. This study examines open AAA repair at a non specialized centre where advanced techniques are not practised. METHODS: We conducted a retrospective analysis on a cohort of 83 patients presenting for AAA repair to a non-specialized hospital, the University Hospital of the West Indies (UHWI). The end points assessed included operative (30-day) mortality, postoperative complications, duration of operation, blood loss, intensive care unit (ICU) stay and overall hospital stay. RESULTS: The overall operative mortality was 9.4% (23% for ruptured aneurysms and 5% for unruptured aneurysms). Mean operating time, blood loss, ICU stay and hospital stay were 326 +/- 98 minutes, 2420 +/- 1397 mls, 3 +/- 5 days and 9 +/- 5 days, respectively with no significant differences noted between ruptured and unruptured aneurysms. Mean aneurysm diameter was 6.13 +/- 1.59 cm. CONCLUSION: Mortality rates for open aneurysm repair at the UHWI are consistent with findings in the current literature. Open AAA repair remains a safe treatment option in this environment. Continued improvements need to be made with respect to minimizing blood loss and operation duration, particularly in repairs of unruptured aneurysms. PMID- 22512221 TI - Operative hysteroscopy in a Jamaican cohort. AB - OBJECTIVE: The objective of this study is to determine the indications, success, and complications of operative hysteroscopy performed at The University of the West Indies (UWI). METHODS: A five-year retrospective cohort study was done of women undergoing operative hysteroscopy at the Hugh Wynter Fertility Management Unit (HWFMU) of the University of the West Indies from January 1, 2001 to December 31, 2005. The demographics of the patients, indications, complications of the procedure and postoperative follow-up were assessed. Patient's post procedural quality of life was assessed by a questionnaire. RESULTS: During this period, 92 operative hysteroscopies were performed on 87 patients, with repeat procedures being performed in three patients. The mean age of patients undergoing operative hysteroscopy was 36.65 years with a range of 23 to 50 years. The main indications for operative hysteroscopy at the HWFMU were submucosal fibroids (50%), intrauterine synechiae (26%) and removal of an intrauterine contraceptive device (11%). There were four procedure-related complications, all of which occurred during myomectomy and required hospitalization. CONCLUSION: Operative hysteroscopy is a safe and highly effective therapy for carefully selected women. As a consequence of technological advancements, an increasing number of gynaecological conditions, traditionally treated by laparotomy, can now be treated safely and effectively using outpatient operative hysteroscopy. PMID- 22512222 TI - Left ventricular posterior wall thickness is an independent risk factor for paroxysmal atrial fibrillation. AB - BACKGROUND: Atrial fibrillation is the most common significant cardiac arrhythmia in clinical practice, but its risk factors remain to be clarified. We have hypothesized that left ventricular posterior wall thickness is an independent risk factor for paroxysmal atrial fibrillation (PAF). METHODS: A total of 166 consecutive patients with paroxysmal atrial fibrillation were included in this study. Another 166 healthy check-up people, strictly age and sex-matched, were enrolled as controls in the same period. Univariable analysis and multivariable conditional logistic stepwise regression analysis were conducted. Receiver operating characteristic (ROC) curve analysis was performed on those significant indices obtained from the multivariable logistic regression analysis. RESULTS: The multivariable stepwise analysis identified left ventricular posterior wall thickness, left atrial diameter tricuspid insufficiency and residence (countryside) as independent predictors for paroxysmal atrial fibrillation. Receiver operating characteristic curve analysis demonstrated the cutoff values of those risk factors aforementioned. CONCLUSIONS: In this strictly age and sex matched population-based sample, left ventricular posterior wall thickness, left atrial diameter, tricuspid insufficiency and residence were predictive risks for paroxysmal atrial fibrillation. This study offers novel information therapeutically beyond that provided by traditional clinical atrial fibrillation risk factors. PMID- 22512223 TI - Clinical utility of transoesophageal echocardiography in low resource environments: the Jamaican experience. AB - OBJECTIVE: To provide the first detailed review of the indications and clinical utility of transoesophageal echocardiogram (TEE) in the Caribbean. DESIGN AND METHODS: Data for patients who had TEE performed at the Heart Institute of the Caribbean over a three-year period were abstracted and reviewed. Information gathered included demographic data, indications for the procedure, findings and clinical recommendations. The effect of age and sex on these variables was assessed using the Chi-square or Fishers Exact tests. Significance was set at a p < or = 0.05. RESULTS: Of the 116 procedures performed between 2005 and 2008, medical records were reviewed for 107 (50 male, 57 female) patients. The patients ranged in age from 15-86 years with a mean age of 45.4 +/- 18.5 years. With the exception of four patients, all attempted TEE were completed. The most common indications for the procedure were valvular heart disease (41.1%), strokes (17.8%), shunts (10.3%) and infective endocarditis (11.2%). Less common indications included arrhythmias, cardiac masses, aortic dissection and shortness of breath. Transoesophageal echocardiogram altered the treatment course in about 30% of all patients including 66.6% of patients referred for suspected infective endocarditis. Furthermore, TEE resulted in recommendation for surgery in 43% of patients referred for evaluation of severity of valvular disease. Minor complications occurred in two persons. No severe complications or deaths occurred as a result of the procedure. CONCLUSIONS: Transoesophageal echocardiogram has been most commonly performed to evaluate valvular heart disease in Jamaica without any major complications resulting from the procedure. It provides additional information that supplements transthoracic echocardiography in a wide range of clinical conditions. Measures should be put in place to make TEE more widely available and accessible in Jamaica. PMID- 22512224 TI - Correlation of brain natriuretic peptide and microalbuminuria in patients with heart failure. AB - OBJECTIVE: To evaluate the changes of plasma levels of N-terminal pro-brain natriuretic pepide (NT-proBNP) and microalbuminuria (MAU) in patients with heart failure and the correlation between them. METHODS: Ninety-one patients with heart failure were divided into different groups according to different stages of heart failure. Plasma levels of NT-proBNP were measured by microsome enzyme immunoassay (MEIA). Plasma levels of MAU were determined by immune scattering turbidimetry (ICTM). Simultaneously, left ventricular ejection fraction (LVEF) and left ventricular end diastolic diameter (LVEDD) were measured by Doppler echocardiography for all patients. The correlation of NT-proBNP and MAU was evaluated at different stages of heart failure. RESULTS: The plasma levels of NT proBNP and MAU increased with the severity of heart failure. There was a high correlation between NT-proBNP and MAU (r = 0.885, p < 0.001). CONCLUSION: Both NT proBNP and MAU levels were closely associated with the severity of heart failure. PMID- 22512225 TI - Seroprevalence of Helicobacter pylori infection in adults in the Bahamas. AB - OBJECTIVES: A number of studies have evaluated Helicobacter pylori (H. pylori) infection in the Caribbean. However to date there is no available epidemiological data on its occurrence in the Bahamas. Therefore, we determined the seroprevalence of H. pylori in a healthy adult population in Nassau, Bahamas. METHODS: A prevalence study was conducted using volunteer blood donors to the blood bank at Princess Margaret Hospital, the only public hospital in Nassau, Bahamas. Sera collected were screened using enzyme linked immunosorbent assay (ELISA) for antibodies to H. pylori. RESULTS: Two hundred and four persons were screened for H. pylori in this study Prevalence of H. pylori in the study population was 58%. CONCLUSION: Helicobacter pylori infection is a common chronic infection in Nassau, Bahamas. Published seroprevalence rates for this infection in other Caribbean territories range from 55% to 70%. PMID- 22512226 TI - The hypothesis of an effective strategy for resistance of hepatocellular carcinoma to therapy-autophagy. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant tumours and its five-year survival rate remains low. Autophagy is a catabolic process conserved among all eukaryotes ranging from yeast to mammals. Recently, many studies show that tumour cells can utilize autophagy as a cellular defence mechanism when facing metabolic stress. Thus, we hypothesize that autophagy may play an important role in the resistance of hepatocellular carcinomas to therapy. Although the exact role of autophagy on tumour cells is still complex and further studies are needed to prove the impact of autophagy on HCC, it suggests that autophagy may be a new therapeutic target for the resistance to therapy of HCC. PMID- 22512227 TI - Post Ross procedure aortic right sinus of Valsalva fistula to right ventricle. AB - Post Ross procedure complications have been limited predominantly to neoaortic valvular dilatation (10-30%) and insufficiency, right ventricular prosthetic deterioration or right ventricular pulmonary artery conduit obstruction. Arrhythmia has been documented to occur in a third of these patients. This is the first time that neoaortic right sinus of valsalva dissection and rupture to the right ventricle with a fistulous communication has occurred and been described, as far as the author is aware. PMID- 22512228 TI - Persistent hypokalaemia in a Jamaican hypertensive patient. AB - We report the case of a 48-year old man with uncontrolled hypertension and persistent hypokalaemia from an aldosterone producing adrenal adenoma treated by laparoscopic adrenalectomy. Clinicians' identification of primary hyperaldosteronism is critical as the correct treatment results in improved blood pressure control and reduced risk of complications. PMID- 22512229 TI - Ileocolorectal intussusception due to caecal hamartoma. AB - Although 75% of intussusceptions occur within the first two years of life, they can also develop in teenage years. This is a case report of a 13-year old boy with an ileocolorectal intussusception from a large caecal hamartoma (10 x 6 x 2 cm3) adjacent to the ileocaecal valve. Partial resection of the ascending colon and terminal ileum was performed, and the pathology of the resected mass revealed a hamartoma. Ileocolorectal intussusception secondary to hamartoma represents a particularly rare event in the paediatric population. With early surgical intervention, this patient's outcome was uneventful. PMID- 22512230 TI - Multiple myeloma associated with light-chain amyloidosis manifesting as gastric retention: a case report and review of the literature. AB - We report a case of multiple myeloma associated with light-chain amyloidosis in a 62-year old woman. The patient came to hospital with the main complaint of epigastric pain and gastroscopy showed gastric retention. The patient had been diagnosed with multiple myeloma associated with light-chain amyloidosis after biopsy of the gastric mucosa and bone marrow aspirate. A review of the literature was also performed. PMID- 22512231 TI - Recurrent parotitis as a first manifestation in a child with primary Sjogren's syndrome. AB - Recurrent parotitis is an acute, severe inflammation of one or both parotid glands, the major salivary glands in young children. We report the case of a seven-year old boy with Primary Sjogrens syndrome (PSS) who presented with 15 episodes of painful recurrent bilateral swellings of the parotid glands over a four-year period. PMID- 22512232 TI - Systemic lupus erythematosus and Neisseria gonorrhoea. A case of the arthritis dermatitis syndrome. PMID- 22512233 TI - Massive pleural effusion due to metastasis of prostate cancer. AB - We describe the case of a 72-year old male with pleural effusion associated with prostate cancer. There was a previous history of tobacco smoking (pack/year: 47) and of total prostatectomy followed by external beam radiation therapy seven years previously for prostate cancer. Furthermore, he was submitted to orchiectomy plus non-steroidal anti-androgen blockage, in addition to docetaxel based chemotherapy and prednisone. After the beginning of chemotherapy, a progressive elevation in prostate specific antigen (PSA) levels was observed. On admission, he presented with fever, weight loss, and respiratory symptoms due to a massive right pleural effusion. Fluid samples obtained by needle aspiration showed haemorrhagic exudates without malignant cells. Pleural metastasis were detected by thorax imaging studies, and biopsy samples revealed prostate adenocarcinoma as the origin of his pleural effusion. Pleural fluid was drained and talc pleurodesis was performed. This report aims to describe the occurrence of massive pleural effusion due to metastasis of prostate cancer and emphasizes the role of pleural biopsy with immunohistochemical studies to characterize this diagnosis. PMID- 22512234 TI - Additional efforts to prevent malignant neoplasms in Japan with a focus on the statistics. PMID- 22512235 TI - MuSK antibody positive myasthenia gravis in a 38-year old West Indian female. PMID- 22512236 TI - Mechanisms of propylene glycol and triacetin pyrolysis. AB - Propylene glycol and triacetin are chemical compounds, commonly used as food additives. Though the usage of the pure chemicals is not considered harmful when used as dietary supplements, little is known about the nature of their thermal degradation products and the impact they may have on human health. For these reasons, in this manuscript we investigate the thermal decomposition mechanisms of both neutral propylene glycol and triacetin in the gas phase by a novel simulation framework. This is based on a free energy sampling methodology followed by an accurate energy refinement. Structures, Gibbs free energy barriers, and rate constants at 800 K were computed for the different steps involved in the two pyrolytic processes. The thermal decomposition mechanisms found theoretically for propylene glycol and triacetin were validated by a qualitative experimental investigation using gas-phase chromatography-mass spectroscopy, with excellent agreement. The results provide a validation of the novel simulation framework and shed light on the potential hazard to the health that propylene glycol and triacetin may have when exposed to high temperatures. PMID- 22512237 TI - Narrowband ultraviolet B treatment for psoriasis increases serum vitamin A levels. PMID- 22512238 TI - The Gordian knot of interim 18-fluorodeoxyglucose positron emission tomography for Hodgkin lymphoma: a meta-analysis and commentary on published studies. AB - We assessed the diagnostic performance of interim 18-fluorodeoxyglucose positron emission tomography (FDG-PET) with regard to the final outcome of adult patients with newly diagnosed Hodgkin lymphoma (HL). The predefined outcome was treatment failure at the end of follow-up. Bivariate meta-analysis of diagnostic data was used to calculate combined (pooled) estimates. Demographics, quality data and study characteristics were used as potential moderators of outcome in subgroup analysis and meta-regression. A total of 14 studies (16 arms stratified by staging or therapy, 1328 evaluable patients) were deemed eligible for final analysis, after excluding intention-to-treat studies (i.e. those where treatment decision was based on interim PET). The combined effect (95% confidence interval) for sensitivity was 0.67 (0.57-0.76) and specificity 0.89 (0.84-0.93). The corresponding likelihood ratios (LRs) were 6.2 (3.9-10.0) for LR + and 0.37 (0.27 0.50) for LR -, with moderate heterogeneity (I(2) =67%). The estimated negative predictive value was 0.93 (0.85-1.00). The diagnostic performance was influenced by most covariates tested, including age, duration of follow-up, criteria used and time of interim PET. Interim PET retains a high specificity for final outcome, but the sensitivity is low. The use of a PET + study as a surrogate marker is hampered by inconsistent interpretation criteria and study populations. However, the high negative predictive value may permit treatment stratification based on a negative outcome. PMID- 22512239 TI - Evaluation of the correlation between self-report and electronic monitoring of adherence to hypertension therapy. AB - Blood pressure (BP) control remains sub-optimal all over the world. Medication adherence is an important determinant of BP control. None of the available methods for measuring medication adherence is currently regarded as a universal consensus gold standard. In this study, we evaluated the correlation between self report (Morisky's Medication Adherence Self-assessment Scale) and electronic (eCap) methods of medication adherence assessment. The self-report measure was administered at study entry while electronic compliance data was collected prospectively. Almost all (97.4%) of enrolled patients completed the study. Medication adherence scores ranged from 0 to 100% (69.33, +/- 27.57) and 6.6-100% (66.92 +/- 22.59) for Morisky's scale and eCap, respectively (Wilcoxon rank sum test, p = 0.253). Modal class interval for adherence scores were 61-80% (n = 28, 37.3%) and 81-100% (n = 23, 30.7%) for the eCap and Morisky's scale respectively. Overall, a weak correlation was found between the two methods (r = 0.056). The weak correlation was also maintained in subgroup analysis defined by attainment of BP control (r = 0.109 vs 0.0009), age (range r = -0.53 to 0.067), sex (0.009 to 0.151), level of education (-0.217 to 0.276), and Mini Mental State Examination score (-0.107 to 0.258). Our findings suggest that these methods are not equivalent in the evaluation of medication adherence. PMID- 22512240 TI - Evaluative conditioning without directly experienced pairings of the conditioned and the unconditioned stimuli. AB - Evaluative conditioning (EC) is the valence change of a stimulus (conditioned stimulus, CS) that is due to the previous pairing with another stimulus (unconditioned stimulus, US). We investigated whether EC can occur also when the CS-US pairings are not experienced directly by the participant but are implied by other events that the participant encounters. In two experiments, positive USs were presented in some trials and negative USs in other trials. Afterwards, participants were given information from which it was possible to conclude that CSs were covertly present during these trials. Finally, the valence of these CSs was registered using both implicit (Implicit Association Test, affective priming) and explicit measures (valence ratings). In line with the assumption that EC effects can be based on CS-US pairings that are not directly experienced, the valence of the CSs changed in the direction of the US with which they were covertly paired. This effect was observed both on explicit and on implicit measures. We argue that several aspects of our results are in line with propositional models of EC and fit less well with association formation models. PMID- 22512241 TI - ApoE and TDP-43 neuropathology in two siblings with familial FTLD-motor neuron disease. AB - Frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) is characterized by neuronal cytoplasmic inclusions containing TDP-43. Apolipoprotein E4 (apoE4), derived from the apoE epsilon4 allele, enhances brain atrophy in FTLD through unknown mechanisms. Here, we studied two siblings with C9ORF72-linked familial FTLD-MND, an apoE epsilon4 homozygote and an apoE epsilon3 homozygote. The apoE epsilon4 homozygote had more cognitive-behavioral symptoms, fronto-insulo-temporal atrophy, and apoE fragments and aggregates in the anterior cingulate cortex. ApoE formed complexes with TDP-43 that were more abundant in the apoE epsilon4 homozygote. Although differences seen in a sibling pair could arise due to chance, these findings raise the possibility that apoE4 exacerbates brain pathology in FTLD through formation of neurotoxic apoE fragments and interactions with TDP-43. PMID- 22512242 TI - Somatostatin-immunoreactive senile plaque-like structures in the frontal cortex and nucleus accumbens of aged tree shrews and Japanese macaques. AB - BACKGROUND: Previously, we demonstrated decreased expression of somatostatin mRNA in aged macaque brain, particularly in the prefrontal cortex. To investigate whether or not this age-dependent decrease in mRNA is related to morphological changes, we analyzed somatostatin cells in the cerebra of aged Japanese macaques and compared them with those in rats and tree shrews, the latter of which are closely related to primates. METHODS: Brains of aged macaques, tree shrews, and rats were investigated by immunohistochemistry with special emphasis on somatostatin. RESULTS: We observed degenerating somatostatin-immunoreactive cells in the cortices of aged macaques and tree shrews. Somatostatin-immunoreactive senile plaque-like structures were found in areas 6 and 8 and in the nucleus accumbens of macaques, as well as in the nucleus accumbens and the cortex of aged tree shrews, where amyloid accumulations were observed. CONCLUSIONS: Somatostatin degenerations may be related to amyloid accumulations and may play roles in impairments of cognitive functions during aging. PMID- 22512243 TI - Bengt Westermark and our current understanding of tumor pathogenesis. PMID- 22512244 TI - Autocrine PDGF stimulation in malignancies. AB - Platelet-derived growth factor (PDGF) isoforms are important mitogens for different types of mesenchymal cells, which have important functions during the embryonal development and in the adult during wound healing and tissue homeostasis. In tumors, PDGF isoforms are often over-expressed and contribute to the growth of both normal and malignant cells. This review focuses on tumors expressing PDGF isoforms together with their tyrosine kinase receptors, thus resulting in autocrine stimulation of growth and survival. Patients with such tumors could benefit from treatment with inhibitors of either PDGF or PDGF receptors. PMID- 22512245 TI - Neural stem cells: brain building blocks and beyond. AB - Neural stem cells are the origins of neurons and glia and generate all the differentiated neural cells of the mammalian central nervous system via the formation of intermediate precursors. Although less frequent, neural stem cells persevere in the postnatal brain where they generate neurons and glia. Adult neurogenesis occurs throughout life in a few limited brain regions. Regulation of neural stem cell number during central nervous system development and in adult life is associated with rigorous control. Failure in this regulation may lead to e.g. brain malformation, impaired learning and memory, or tumor development. Signaling pathways that are perturbed in glioma are the same that are important for neural stem cell self-renewal, differentiation, survival, and migration. The heterogeneity of human gliomas has impeded efficient treatment, but detailed molecular characterization together with novel stem cell-like glioma cell models that reflect the original tumor gives opportunities for research into new therapies. The observation that neural stem cells can be isolated and expanded in vitro has opened new avenues for medical research, with the hope that they could be used to compensate the loss of cells that features in several severe neurological diseases. Multipotent neural stem cells can be isolated from the embryonic and adult brain and maintained in culture in a defined medium. In addition, neural stem cells can be derived from embryonic stem cells and induced pluripotent stem cells by in vitro differentiation, thus adding to available models to study stem cells in health and disease. PMID- 22512246 TI - Multidisciplinary treatment of patients with rectal cancer: Development during the past decades and plans for the future. AB - In rectal cancer treatment, both the local primary and the regional and systemic tumour cell deposits must be taken care of in order to improve survival. The three main treatments, surgery, radiotherapy, and chemotherapy, each with their own advantages and limitations, must then be combined to improve results. Several large randomized trials have shown that combinations of the modalities have markedly reduced the loco-regional recurrences, but have not yet had any major influence on overall survival. The best integration of the weakest modality, to date the drugs (conventional cytotoxics and biologicals), is not known. A new generation of trials exploring the best sequence of treatments is required. Furthermore, treatment of rectal cancer is administered to populations of individuals, based upon clinical factors and imaging, and can presently not be further individualized. There is an urgent need to develop response predictors. PMID- 22512247 TI - Glioblastoma--a moving target. AB - The slow development of effective treatment of glioblastoma is contrasted by the rapidly advancing research on the molecular mechanisms underlying the disease. Amplification and overexpression of receptor tyrosine kinases, particularly EGFR and PDGFRA, are complemented by mutations in the PI3K, RB1, and p53 signaling pathways. In addition to finding effective means to target these pathways, we may take advantage of the recent understanding of the hierarchical structure of tumor cell populations, where the progressive expansion of the tumor relies on a minor subpopulation of glioma stem cells, or glioma-initiating cells. Finding ways to reprogram these cells and block their self-renewal is one of the most important topics for future research. PMID- 22512248 TI - Structural changes in bacteriorhodopsin caused by two-photon-induced photobleaching. AB - Bacteriorhodopsin (BR) is the key protein of the halobacterial photosynthetic system. BR assembles into two-dimensional crystalline patches, the so-called purple membranes (PM), and acts as a light-driven proton pump converting light energy into the chemical energy of a proton gradient over the cell membrane. The two-photon absorption (TPA) of BR is so far not fully understood. Astonishingly high TPA cross sections have been reported, but the molecular mechanisms have not been elucidated. In this work, we address structural changes in BR and PM upon TPA, investigating its TPA photochemistry by spectroscopy, small-angle X-ray scattering, as well as electron and atomic force microscopy. We observe that TPA of BR leads to formation of an UV-absorbing N-retinyl-bacterioopsin state, which is accompanied by the loss of crystalline order in PM. FTIR and CD spectroscopy confirm that BR trimers as well as the secondary structure of the BR molecules are preserved. We demonstrate that excitation by TPA results in the photochemical reduction of the retinal Schiff base, which in turn causes a permanent asymmetric shape change of BR, similar to the one transiently observed during the photocycle related opening and closing of the cytoplasmic proton half channel. This shape change causes PM sheets to merely roll up toward the extracellular side and causes the loss of crystallinity of PM. We present a model for the TPA photoresponse of BR, which also explains the irreversibility of the process in terms of a photochemical reduction of the Schiff base. PMID- 22512249 TI - Enantioselective synthesis of the C1-C6 and C7-C23 fragments of the proposed structure of iriomoteolide 1a. AB - Synthesis of the C1-C6 and C7-C23 fragments of the proposed structure of iriomoteolide 1a has been accomplished. Key steps include a cross metathesis to form the C15-C16 E olefin and a chelation controlled Grignard addition to form the tertiary alcohol at C14. Notably, 7 of the 9 stereocenters of the proposed structure have been set using various aldol reactions employing metallo enolates of thiazolidinethiones. PMID- 22512250 TI - Six patients with pyoderma gangrenosum successfully treated with infliximab. PMID- 22512251 TI - Potential association of single nucleotide polymorphisms in pigmentation genes with the development of basal cell carcinoma. AB - The risk of developing skin cancers is dependent on a combination of environmental factors and personal genetic predispositions. Basal cell carcinoma (BCC) has been associated with single nucleotide polymorphisms in several pigmentation genes; however, there is still controversy concerning the mechanism by which these variants may increase the risk of BCC. The pathway may lead to pigmentation alone, but evidence for their independent influence is growing. Using a single base extension protocol, candidate polymorphisms within 11 known pigment-related genes were studied for their association with BCC in a population sample consisting of 164 patients and 707 controls. The significance of variation within the MC1R gene was confirmed and, in addition, position rs12203592 within the IRF4 gene was shown to be associated with BCC. These associations remained significant after adjustment for skin color. Gene-gene interactions were found to influence susceptibility to BCC. Among interacting genes are the two above mentioned loci with main effect on BCC risk and additionally KITLG, TYRP1, ASIP and TYR. The obtained results indicate that polymorphism at MC1R and IRF4 constitute pigmentation-independent risk factor in the development of BCC. Moreover, susceptibility to BCC may be influenced by epistatic effects between pigmentation genes. PMID- 22512252 TI - Thinking of Co2+-staining explant tissue or cultured cells? How to make it reliable and specific. AB - Ca(2+) and/or Zn(2+) entry into neurons and glial cells is often a key step driving the processes of neurodevelopment and disease. As a result, a major pre occupation of many neuroscientists has been in tracking down when and where nervous tissues express ion channels with appreciable divalent ion permeability. The cobalt (Co(2+))-staining technique is one of the few techniques that allow a snapshot of the entire neuronal circuit, and selectively labels cells expressing divalent-permeable ion channels with a brown-black precipitate. Despite this, its use has been remarkably limited in the past decade. Reluctance to employ this approach has largely been related to an earlier concern with obtaining a reliable and reproducible means of visualizing transported Co(2+). Here we show that recent advances have resolved these issues, opening this straightforward and valuable technique to a much larger neuroscience audience. PMID- 22512253 TI - Neuroblast survival depends on mature vascular network formation after mouse stroke: role of endothelial and smooth muscle progenitor cell co-administration. AB - Pro-angiogenic cell-based therapies constitute an interesting and attractive approach to enhancing post-stroke neurogenesis and decreasing neurological deficit. However, most new stroke-induced neurons die during the first few weeks after ischemia, thus impairing total recovery. Although the neovascularization process involves different cell types and various growth factors, most cell therapy protocols are based on the biological effects of single-cell-type populations or on the administration of heterogeneous populations of progenitors, namely human cord blood-derived CD34(+) cells, with scarce vascular progenitor cells. Tight cooperation between endothelial cells and smooth muscle cells/pericytes is critical for the development of functional neovessels. We hypothesized that neuroblast survival in stroke brain depends on mature vascular network formation. In this study, we injected a combination of endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs), isolated from human umbilical cord blood, into a murine model of permanent focal ischemia induced by middle cerebral artery occlusion. The co-administration of SMPCs and EPCs induced enhanced angiogenesis and vascular remodeling in the peri-infarct and infarct areas, where vessels exhibited a more mature phenotype. This activation of vessel growth resulted in the maintenance of neurogenesis and neuroblast migration to the peri-ischemic cortex. Our data suggest that a mature vascular network is essential for neuroblast survival after cerebral ischemia, and that co-administration of EPCs and SMPCs may constitute a novel therapeutic strategy for improving the treatment of stroke. PMID- 22512255 TI - Pharmacological mechanisms underlying switching from the large-scale depolarization wave to segregated activity in the mouse central nervous system. AB - During the early development of the nervous system, synchronized activity is observed in a variety of structures, and is considered to play a fundamental role in neural development. One of the most striking examples of such activity is the depolarization wave reported in chick and rat embryos. In the accompanying paper (Momose-Sato et al., 2012), we have demonstrated that a depolarization wave is also present in the mouse embryo by showing large-scale optical waves, which spread remarkably over the central nervous system, including the spinal cord, hindbrain, cerebellum, midbrain, and forebrain. In the present study, we examined the pharmacological nature of the mouse depolarization wave and its developmental changes. We show here that two types of switching in pharmacological characteristics occur during development. One is that the depolarization wave is strongly dependent on nicotinic acetylcholine receptors during the early developmental stage [embryonic day (E)11-12], but is dominated by glutamate at the later stage (E13 onwards). The second is that gamma-aminobutyric acid (GABA), which acts as an excitatory mediator of the depolarization wave during the early phase, becomes an inhibitory modulator by E14. These changes seemed to occur earlier in the hindbrain than in the spinal cord. Furthermore, we show that the second switch causes the loss of synchronization over the network, resulting in the disappearance of the depolarization wave and segregation of the activity into discrete regions of the medulla and spinal cord. We suggest that pharmacological switching is a possible mechanism underlying replacement of the primordial correlated network by a mature neuronal circuit. PMID- 22512254 TI - Prostaglandin E2 is an endogenous modulator of cerebellar development and complex behavior during a sensitive postnatal period. AB - Prostaglandins are lipid-derived molecules that mediate the generation of fever in the central nervous system. In addition to their proinflammatory role, prostaglandins also impact neuronal development and synaptic plasticity, sometimes in a sex-specific manner. The cerebellum has a high expression of prostaglandin receptors during development, but the role that these molecules play during normal cerebellar maturation is unknown. We demonstrate here that disrupting prostaglandin synthesis with cyclo-oxygenase inhibitors during a time sensitive window in early postnatal life alters cerebellar Purkinje cell development in rats, resulting in initially increased dendritic growth in both sexes. We show that this results in later cerebellar atrophy in males only, resulting in a sex-specific loss of cerebellar volume. Further, although performance in motor tasks is spared, social interaction and the sensory threshold are altered in males developmentally exposed to cyclo-oxygenase inhibitors. This work demonstrates a previously unknown role for prostaglandins in cerebellar development and emphasizes the role that the cerebellum plays outside motor tasks, in cognitive and sensory domains that may help to explain its connection to complex neurodevelopmental disorders such as autism. PMID- 22512256 TI - Topography of descending projections from anterior insular and medial prefrontal regions to the lateral habenula of the epithalamus in the rat. AB - The epithalamic lateral nucleus of the habenula (LHb) plays a key role in regulating firing of dopamine and serotonin neurons in the midbrain and is thereby involved in various cognitive and affective behaviors. It is not yet clear, however, from where the LHb receives cognitive and affective information relevant to its regulation of the midbrain monoaminergic systems. The prefrontal cortex would be among the ideal sources. Here, using anterograde and retrograde tracer injections in the rat brain, we characterized the topography of the corticohabenular projections. Following injections of cholera toxin subunit B into the LHb, retrogradely labeled neurons were produced in the anterior insular, cingulate, prelimbic and infralimbic cortices. Consistent with this retrograde tracing, injections of biotinylated dextran amine (BDA) into these cortical regions labeled robust terminals in the LHb. Our quantification of the BDA impregnated varicosities revealed that projections from the anterior insula terminated mainly in the intersection regions of the lateral and ventral two thirds of the LHb, while projections from the cingulate cortex terminated mainly in the lateral two-thirds of the LHb. By comparison, BDA-labeled terminals originating from the medial prefrontal regions were contained mainly in the medial plus ventral one-third of LHb. Based on these data, we hypothesize that LHb provides a link for conveying cognitive and affective information from prefrontal and insular regions to the midbrain monoaminergic centers. PMID- 22512257 TI - Experience-dependent regulation of functional maps and synaptic protein expression in the cat visual cortex. AB - Although the basis of our knowledge of experience-dependent plasticity comes from studies on carnivores and primates, studies examining the physiological and molecular mechanisms that underlie development and plasticity have increasingly employed mice. We have used several common rearing paradigms, such as dark rearing and monocular deprivation (MD), to examine the timing of the physiological and molecular changes to altered experience in the cat primary visual cortex. Dark-rearing from birth or for 1 week starting at 4 weeks of age produced a similar reduction in the amplitude of responses measured through intrinsic signal imaging and a reduction in orientation selectivity. One week of visual experience following dark-rearing until 4 weeks of age yielded normal responses in both amplitude and orientation selectivity. The depression of deprived-eye responses was similar in magnitude after 2 and 7 days of MD. In contrast, non-deprived-eye responses almost doubled in magnitude after 7 days compared with 2 days of MD. These changes in the functional properties of primary visual cortex neurons were mirrored by specific changes in synaptic protein expression. Changes in proteins such as the NR2A and NR2B subunits of the N methyl-D-aspartate receptor, postsynaptic density protein 95, alpha-CA(2+) /calmodulin-dependent protein kinase II (alphaCaMKII), and GABA(A) alpha1a indicated that the levels of sensory activity regulated mechanisms associated with both excitatory (NR2A and NR2B) and inhibitory (GABA(A) alpha1a) transmission so as to maintain response homeostasis. Additionally, we found that MD regulated the AMPA receptor glutamate (GluR1) subunit as well as signalling molecules (alphaCaMKII and synaptic Ras GTPase activating protein, SynGAP) downstream of N-methyl-D-aspartate receptors. Proteins in a common signalling pathway appeared to have similar developmental expression profiles that were broadly similar between cats and rodents. PMID- 22512258 TI - Morphological patterns of the collateral sulcus in the human brain. AB - The collateral sulcal complex is an important landmark on the medial surface of the temporal lobe. Anteriorly, it delineates the limbic regions of the parahippocampal gyrus from the visual-processing areas of the fusiform gyrus. Posteriorly, it continues into the occipital lobe, bearing no relationship to the memory-related limbic regions. Given the considerable extent of the sulcus and functional heterogeneity of the surrounding cortex, an investigation of the morphology of this sulcus was carried out to examine whether it is continuous or a series of sulcal parts, i.e. independent sulci classified together under the name collateral sulcus. We investigated the collateral sulcal complex using magnetic resonance images taking into account the three-dimensional nature of the brain. Our examination demonstrated three separate sulcal segments: (i) an anterior segment, the rhinal sulcus, delineating the uncus from the adjacent temporal neocortex, (ii) a middle segment, the collateral sulcus proper, forming the lateral border of the posterior parahippocampal cortex, and (iii) a caudal segment, the occipital extent of the collateral sulcus, within the occipital lobe. Three relationships exist between the rhinal sulcus and collateral sulcus proper, only one being clearly identifiable from the surface. Posteriorly, the collateral sulcus proper and the occipital collateral sulcus, although appearing continuous on the brain surface, can be separated in the depth of the sulcus in all cases. These results provide quantification of the location and variability within standard stereotaxic space for the three collateral sulcus segments that could be used to aid accurate identification of functional activation peaks derived from neuroimaging studies. PMID- 22512260 TI - Social experience affects neuronal responses to male calls in adult female zebra finches. AB - Plasticity studies have consistently shown that behavioural relevance can change the neural representation of sounds in the auditory system, but what occurs in the context of natural acoustic communication where significance could be acquired through social interaction remains to be explored. The zebra finch, a highly social songbird species that forms lifelong pair bonds and uses a vocalization, the distance call, to identify its mate, offers an opportunity to address this issue. Here, we recorded spiking activity in females while presenting distance calls that differed in their degree of familiarity: calls produced by the mate, by a familiar male, or by an unfamiliar male. We focused on the caudomedial nidopallium (NCM), a secondary auditory forebrain region. Both the mate's call and the familiar call evoked responses that differed in magnitude from responses to the unfamiliar call. This distinction between responses was seen both in single unit recordings from anesthetized females and in multiunit recordings from awake freely moving females. In contrast, control females that had not heard them previously displayed responses of similar magnitudes to all three calls. In addition, more cells showed highly selective responses in mated than in control females, suggesting that experience-dependent plasticity in call evoked responses resulted in enhanced discrimination of auditory stimuli. Our results as a whole demonstrate major changes in the representation of natural vocalizations in the NCM within the context of individual recognition. The functional properties of NCM neurons may thus change continuously to adapt to the social environment. PMID- 22512259 TI - Different stressors produce excitation or inhibition of mesolimbic dopamine neuron activity: response alteration by stress pre-exposure. AB - Stressors can exert a wide variety of responses, ranging from adaptive responses to pathological changes; moreover, recent studies suggest that mild stressors can attenuate the response of a system to major stressful events. We have previously shown that 2-week exposure to cold, a comparatively mild inescapable stressor, induced a pronounced reduction in ventral tegmental area (VTA) dopamine (DA) neuron activity, whereas restraint stress increases DA neuron activity. However, it is not known if these stressors differentially impact the VTA in a region specific manner, if they differentially impact behavioral responses, or whether the effects of such different stressors are additive or antagonistic with regard to their impact on DA neuron firing. To address these questions, single-unit extracellular recordings were performed in anesthetized control rats and rats exposed to chronic cold, and tested after delivery of a 2-h restraint session. Chronic cold stress strongly attenuated the number of DA neurons firing in the VTA, and this effect occurred primarily in the medial and central VTA regions that preferentially project to reward-related ventral striatal regions. Chronic cold exposure also prevented the pronounced increase in DA neuron population activity without affecting the behavioral sensitization to amphetamine produced by restraint stress. Taken together, these data show that a prolonged inescapable mild stressor can induce plastic changes that attenuate the DA system response to acute stress. PMID- 22512261 TI - Serotonin2C receptors in the nucleus accumbens are involved in enhanced alcohol drinking behavior. AB - Dopamine and serotonin (5-HT) in the nucleus accumbens (ACC) and ventral tegmental area of the mesoaccumbens reward pathways have been implicated in the mechanisms underlying development of alcohol dependence. We used a C57BL/6J mouse model with increased voluntary alcohol-drinking behavior by exposing the mice to alcohol vapor for 20 consecutive days. In the alcohol-exposed mice, the expression of 5-HT(2C) receptor mRNA increased in the ACC, caudate nucleus and putamen, dorsal raphe nucleus (DRN), hippocampus and lateral hypothalamus, while the protein level of 5-HT(2C) receptor significantly increased in the ACC. The expression of 5-HT(7) receptor mRNA increased in the ACC and DRN. Contents of 5 HT decreased in the ACC shell (ACC(S) ) and DRN of the alcohol-exposed mice. The basal extracellular releases of dopamine (DA) and 5-HT in the ACC(S) increased more in the alcohol-exposed mice than in alcohol-naive mice. The magnitude of the alcohol-induced ACC(S) DA and 5-HT release in the alcohol-exposed mice was increased compared with the control mice. Intraperitoneal (i.p.) administration or local injection into ACC(S) of the 5-HT(2C) receptor antagonist, SB-242084, suppressed voluntary alcohol-drinking behavior in the alcohol-exposed mice. But the i.p. administration of the 5-HT(7) receptor antagonist, SB-258719, did not have significant effects on alcohol-drinking behavior in the alcohol-exposed mice. The effects of the 5-HT(2C) receptor antagonist were not observed in the air-exposed control mice. These results suggest that adaptations of the 5-HT system, especially the upregulation of 5-HT(2C) receptors in the ACC(S) , are involved in the development of enhanced voluntary alcohol-drinking behavior. PMID- 22512262 TI - Small-molecule inhibitors of the HIF pathway and synthetic lethal interactions. AB - INTRODUCTION: Activation of the hypoxia response pathway is a feature of many tumours and is one of the key mechanisms associated with tumour growth, chemoresistance and radioresistance. The major component of the hypoxia response pathway is the heterodimeric transcription factor, hypoxia-inducible factor (HIF), which is upregulated in many human cancers. Therefore, HIF is an attractive therapeutic target and several strategies have been developed to target it. AREAS COVERED: Approaches used in targeting the hypoxia response pathway are discussed. Reviewed are agents that target upstream, directly and downstream of HIF, as well as some of the challenges in HIF-targeted therapy. EXPERT OPINION: Many of the therapeutic agents that are in clinical use inhibit downstream HIF target genes, but ideally a molecule specific to HIF will have a more potent effect in inhibiting multiple HIF pathways. However, many anti-HIF molecules have multiple targets, which may increase non-specific cytotoxicity. In addition, many anti-HIF agents cannot discriminate between the different isoforms of HIF-alpha. So, it is important to assess whether targeting both HIF-1alpha and HIF-2alpha or each subunit selectively will provide better therapeutic effects. PMID- 22512263 TI - Continuous glucose monitoring during breastfeeding in women with recent gestational diabetes mellitus. AB - AIMS: This study monitored blood glucose profiles in normotolerant breastfeeding women, with and without previous gestational diabetes, in real life in order to identify normal blood glucose fluctuations during breastfeeding. SUBJECTS AND METHODS: Two groups were studied: (1) 18 women with recent gestational diabetes mellitus but normotolerant postpartum (pGDM-N group) and (2) 15 women normotolerant both during pregnancy and postpartum (pN-N group). All participants underwent continuous glucose monitoring during which they recorded their main daily activities and three standardized events: "suckling," "meal," and "meal and suckling." Other than these three events, these women were essentially on an "ad lib" diet. Data were expressed as median and SD values. Student's t test and Fisher's test were used to compare mean, variances, and percentages. Differences were significant with P<0.05. Clustering analysis was used to determine the normal range of glucose values. RESULTS: The two groups were matched for age, follow-up duration, and monitoring measurements but not for body mass index. Blood glucose levels and variances were higher in the pGDM-N group, particularly during daytime and the three standardized events, and were not related to body mass index. Suckling had no direct effect on glucose profile during both the non fed and the fed state. Blood glucose levels that best represent the normal breastfeeding population were between 50 and 126 mg/dL (from 2.8 to 7.0 mmol/L). CONCLUSIONS: Three months after delivery, normotolerant women with recent gestational diabetes had higher daily blood glucose levels than women who were always normotolerant, with no direct effect of suckling. The blood glucose profiles of healthy subjects could be representative of the normal range of the population during breastfeeding. PMID- 22512264 TI - Vildagliptin added to metformin on beta-cell function after a euglycemic hyperinsulinemic and hyperglycemic clamp in type 2 diabetes patients. AB - BACKGROUND: This study evaluated the effect of vildagliptin + metformin on glycemic control and beta-cell function in type 2 diabetes patients. SUBJECTS AND METHODS: One hundred seventy-one type 2 diabetes patients, naive to antidiabetes therapy and with poor glycemic control, were instructed to take metformin for 8+/ 2 months up to a mean dosage of 2,500+/-500 mg/day; then they were randomly assigned to add vildaglipin 50 mg twice a day or placebo for 12 months. We evaluated at 3, 6, 9, and 12 months: body mass index, glycemic control, fasting plasma insulin, homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment beta-cell function index (HOMA-beta), fasting plasma proinsulin, proinsulin/fasting plasma insulin ratio, C-peptide, glucagon, adiponectin, and high-sensitivity C-reactive protein. Before and at 12 months after the addition of vildagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation, to assess insulin sensitivity and insulin secretion. RESULTS: After 12 months of treatment, vildagliptin + metformin gave a better decrease of body weight, glycemic control, HOMA-IR, and glucagon and a better increase of HOMA-beta compared with placebo + metformin. Regarding the measures of beta-cell function, treatment-induced changes in M-value, first- and second-phase C-peptide response to glucose, and C-peptide response to arginine were significantly higher in the vildagliptin + metformin group compared with the placebo + metformin group. CONCLUSION: The addition of vildagliptin to metformin gave a better improvement of glycemic control, insulin resistance, and beta-cell function compared with metformin alone. PMID- 22512265 TI - The effect of sitagliptin versus glibenclamide on arterial stiffness, blood pressure, lipids, and inflammation in type 2 diabetes mellitus patients. AB - AIM: This study evaluated the effect of sitagliptin versus glibenclamide on arterial stiffness, blood pressure, lipid profile, oxidative stress, and high sensitivity C-reactive protein (hsCRP) in type 2 diabetes mellitus patients. SUBJECTS AND METHODS: Forty diabetes patients, inadequately controlled on metformin, were randomly assigned to either sitagliptin (100 mg/day) or glibenclamide (5 mg/day) for 3 months. Following a 1-month washout period, a crossover switch from glibenclamide to sitagliptin and vice versa was performed for an additional 3 months. Arterial stiffness, 24-h ambulatory blood pressure monitoring, lipids, hsCRP, glycated hemoglobin, fasting glucose, STAT-8 isoprostane (a measure of oxidative stress), body mass index (BMI), and waist circumference were measured at baseline and at 3 months with each of the study drugs. RESULTS: Thirty-four patients completed the study. Glibenclamide had a better glucose-lowering effect than sitagliptin, but this was associated with more hypoglycemic events. BMI increased following glibenclamide treatment, whereas sitagliptin proved weight-neutral. Mean BMI gain was +0.5+/-1.0 kg/m(2) for glibenclamide versus -0.01+/-0.9 kg/m(2) for sitagliptin (P<0.001). Triglyceride levels significantly dropped following sitagliptin, although they remained unaltered after glibenclamide treatment. Mean triglyceride decrease was 18.4+/-45 mg/mL after sitagliptin but -0.2+/-57 mg/dL following glibenclamide treatment (P=0.018). There was no change in low-density lipoprotein, high-density lipoprotein, arterial stiffness, blood pressure monitoring, hsCRP, or STAT-8 isoprostane with each of the study drugs. CONCLUSIONS: Sitagliptin, but not glibenclamide, demonstrated a significant beneficial effect on BMI and triglyceride levels. However, arterial stiffness, blood pressure, oxidative stress, and inflammatory status were not significantly affected by adding sitagliptin or glibenclamide to metformin-treated type 2 diabetes patients. PMID- 22512266 TI - Influence of time point of calibration on accuracy of continuous glucose monitoring in individuals with type 1 diabetes. AB - BACKGROUND AND AIMS: Data on the influence of calibration on accuracy of continuous glucose monitoring (CGM) are scarce. The aim of the present study was to investigate whether the time point of calibration has an influence on sensor accuracy and whether this effect differs according to glycemic level. SUBJECTS AND METHODS: Two CGM sensors were inserted simultaneously in the abdomen on either side of 20 individuals with type 1 diabetes. One sensor was calibrated predominantly using preprandial glucose (calibration(PRE)). The other sensor was calibrated predominantly using postprandial glucose (calibration(POST)). At minimum three additional glucose values per day were obtained for analysis of accuracy. Sensor readings were divided into four categories according to the glycemic range of the reference values (low, <=4 mmol/L; euglycemic, 4.1-7 mmol/L; hyperglycemic I, 7.1-14 mmol/L; and hyperglycemic II, >14 mmol/L). RESULTS: The overall mean+/-SEM absolute relative difference (MARD) between capillary reference values and sensor readings was 18.3+/-0.8% for calibration(PRE) and 21.9+/-1.2% for calibration(POST) (P<0.001). MARD according to glycemic range was 47.4+/-6.5% (low), 17.4+/-1.3% (euglycemic), 15.0+/-0.8% (hyperglycemic I), and 17.7+/-1.9% (hyperglycemic II) for calibration(PRE) and 67.5+/-9.5% (low), 24.2+/-1.8% (euglycemic), 15.5+/-0.9% (hyperglycemic I), and 15.3+/-1.9% (hyperglycemic II) for calibration(POST). In the low and euglycemic ranges MARD was significantly lower in calibration(PRE) compared with calibration(POST) (P=0.007 and P<0.001, respectively). CONCLUSIONS: Sensor calibration predominantly based on preprandial glucose resulted in a significantly higher overall sensor accuracy compared with a predominantly postprandial calibration. The difference was most pronounced in the hypo- and euglycemic reference range, whereas both calibration patterns were comparable in the hyperglycemic range. PMID- 22512267 TI - Isothermal microcalorimetry: a novel method for real-time determination of antifungal susceptibility of Aspergillus species. AB - We evaluated microcalorimetry for real-time susceptibility testing of Aspergillus spp. based on growth-related heat production. The minimal heat inhibitory concentration (MHIC) for A. fumigatus ATCC 204305 was 1 mg/L for amphotericin B, 0.25 mg/L for voriconazole, 0.06 mg/L for posaconazole, 0.125 mg/L for caspofungin and 0.03 mg/L for anidulafungin. Agreement within two 2-fold dilutions between MHIC (determined by microcalorimetry) and MIC or MEC (determined by CLSI M38A) was 90% for amphotericin B, 100% for voriconazole, 90% for posaconazole and 70% for caspofungin. This proof-of-concept study demonstrated the potential of isothermal microcalorimetry for growth evaluation of Aspergillus spp. and real-time antifungal susceptibility testing. PMID- 22512269 TI - Population transcriptomics of cactus host shifts in Drosophila mojavensis. AB - In the presence of environmental change, natural selection can shape the transcriptome. Under a scenario of environmental change, genotypes that are better able to modulate gene expression to maximize fitness will tend to be favoured. Therefore, it is important to examine gene expression at the population level to distinguish random or neutral gene expression variation from the pattern produced by natural selection. This study investigates the natural variation in transcriptional response to a cactus host shift utilizing the mainland Sonora population of Drosophila mojavensis. Drosophila mojavensis is a cactophilic species composed of four cactus host populations endemic to the deserts of North America. Overall, the change in cactus host was associated with a significant reduction in larval viability as well as the differential expression of 21% of the genome (3109 genes). Among the genes identified were a set of genes previously known to be involved in xenobiotic metabolism, as well as genes involved in cellular energy production, oxidoreductase/carbohydrate metabolism, structural components and mRNA binding. Interestingly, of the 3109 genes whose expression was affected by host use, there was a significant overrepresentation of genes that lacked an orthologous call to the D. melanogaster genome, suggesting the possibility of an accelerated rate of evolution in these genes. Of the genes with a significant cactus effect, the majority, 2264 genes, did not exhibit a significant cactus-by-line interaction. This population-level approach facilitated the identification of genes involved in past cactus host shifts. PMID- 22512268 TI - Effects of early- and late-gestational maternal stress and synthetic glucocorticoid on development of the fetal hypothalamus-pituitary-adrenal axis in sheep. AB - Prenatal maternal stress (PMS) programs dysregulation of the hypothalamus pituitary-adrenal axis (HPAA) in postnatal life, though time periods vulnerable to PMS, are still unclear. We evaluated in pregnant sheep the effect of PMS during early gestation [30-100 days of gestation (dGA); term is 150 dGA] or late gestation (100-120 dGA) on development of fetal HPAA function. We compared the effects of endogenous cortisol with synthetic glucocorticoid (GC) exposure, as used clinically to enhance fetal lung maturation. Pregnant sheep were exposed to repeated isolation stress twice per week for 3 h in a separate box with no visual, tactile, or auditory contact with their flock-mates either during early (n = 7) or late (n = 7) gestation. Additional groups received two courses of betamethasone (BM; n = 7; 2 * 110 MUg kg(- 1) body weight, 24 h apart) during late gestation (106/107 and 112/113 dGA, n = 7) or acted as controls (n = 7). Fetal cortisol responses to hypotensive challenge, a physiological fetal stressor, were measured at 112 and 129 dGA, i.e. before and during maturation of the HPAA. Hypotension was induced by fetal infusion of sodium nitroprusside, a potent vasodilator. At 112 dGA, neither PMS nor BM altered fetal cortisol responses. PMS, during early or late gestation, and BM treatment increased fetal cortisol responses at 129 dGA with the greatest increase achieved in stressed early pregnant sheep. Thus, development of the HPAA is vulnerable to inappropriate levels of GCs during long periods of fetal life, whereas early gestation is most vulnerable to PMS. PMID- 22512270 TI - Expression of the T-cell regulatory marker FOXP3 in primary cutaneous large B cell lymphoma tumour cells. AB - BACKGROUND: Primary cutaneous B-cell lymphomas (PCBCL) are subdivided into the aggressive form, primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT) and two subtypes of indolent behaviour (primary cutaneous follicle centre lymphoma and primary cutaneous marginal zone B-cell lymphoma). The difference in clinical behaviour can be explained by the tumour cell itself, or the lymphoma microenvironment including the antitumour immune response. OBJECTIVES: To investigate the presence of regulatory T cells (Treg), CD4+CD25+FOXP3+, in the microenvironment of PCBCL in correlation with clinical outcome. METHODS: Tumour specimens of 55 consecutive cases of PCBCL were blinded and analysed for FOXP3, CD4 and CD25 expression by immunohistochemistry. Confocal images were taken with a Leica SP5. Statistical analyses were performed to determine significance. The test was considered significant when P<0.05. RESULTS: The CD4 and FOXP3 expression as well as the CD4/FOXP3 ratio were significantly increased in PCBCL of indolent behaviour in contrast to PCLBCL, LT (P=0.0002 for CD4, P<0.0001 for FOXP3 and P=0.0345 for FOXP3/CD4 ratio). CD25 expression did not differ in the three groups (P=0.9414). Within the group of patients with PCLBCL, LT we identified a subgroup with FOXP3+ tumour cells as demonstrated by CD20/FOXP3 double stainings. Patients with FOXP3+ PCLBCL, LT tumour cells showed a better prognosis on Kaplan-Meier analysis. CONCLUSION: High numbers of Treg in the lymphoma microenvironment correlate with a better prognosis in PCBCL. In PCLBCL, LT the presence of FOXP3+ tumour cells is beneficial for prognosis suggesting that FOXP3 expression of PCLBCL, LT tumour cells might serve as a tumour suppressor. PMID- 22512271 TI - Pharmacogenetics: a reality or misplaced optimism? AB - The paper aims to review current evidence that supports the application of genetic information in the management and use of psychotropic medication. Although the importance of an individual's genetic makeup in the metabolism of drugs has been known for at least 50 years, it is only recently that such information is finding clinical application. A literature review of recent studies suggest that there are clear variations in the way people respond to psychotropic medication. These variations can be seen across racial and ethnic lines, and are genetically determined. The hope is that, in future we will be able to use genetic information to predict which patient will benefit from which drug and at what dose. In other fields of health care such as anticoagulant therapy, the application of pharmacogenetics is now established in routine clinical care. Several psychiatric pharmacogenetic tests are currently available, including tests for the determination of metabolic status, risk of agranulocytosis and metabolic syndrome, and selection of beneficial medications. Since nurses are the centrepiece of mental health care, these advances are likely to alter significantly future mental health nurse education and practice. PMID- 22512272 TI - Distribution of a dechlorinating community in relation to the distance from a trichloroethene dense nonaqueous phase liquid in a model aquifer. AB - The toxicity of trichloroethene (TCE) likely restricts microbial activity in close vicinity of a TCE dense nonaqueous phase liquid (DNAPL). This study examined the distribution of a dechlorinating community in relation to the distance from a TCE DNAPL using a diffusion-cell set-up. Subcultures of the KB 1(TM) culture dechlorinating TCE to cis-dichloroethene and grown with either formate or lactate as electron donor were used to inoculate the diffusion-cells. 16S rRNA gene clone library analysis showed that both inocula consisted of dechlorinating bacteria similar to Geobacter lovleyi SZ and fermentative microorganisms related to Clostridium and Clostridiales. qPCR and RFLP analyses of pore water and sand samples showed a stratified microbial community composition in the diffusion-cells. Geobacter dominated where TCE was present, that is, in the lower 3 cm of the 5.5-cm-thick sand layer. Even at 0.5 cm distance from the DNAPL layer, Geobacter densities were two orders of magnitude higher than at inoculation, despite the expected TCE toxicity. In the upper 2.5 cm of the sand layer, where TCE was depleted, apparently fermenting populations prevailed, corresponding to Clostridium in some diffusion-cells. This analysis demonstrates that the microbial community composition in a source zone is related to the distance from the DNAPL. PMID- 22512273 TI - Circulating microRNAs as potential biomarkers for smoking-related interstitial fibrosis. AB - Numerous efforts have been made to indentify reliable and predictive biomarkers to detect the early signs of smoking-induced lung disease. Using 6-month cigarette smoking in mice, we have established smoking-related interstitial fibrosis (SRIF). Microarray analyses and cytokine/chemokine biomarker measurements were made to select circulating microRNAs (miRNAs) biomarkers. We have demonstrated that specific miRNAs species (miR-125b-5p, miR-128, miR-30e, and miR-20b) were significantly changed, both in the lung tissue and in plasma, and exhibited mainstream (MS) exposure duration-dependent pathological changes in the lung. These findings suggested a potential use of specific circulating miRNAs as sensitive and informative biomarkers for smoking-induced lung disease. PMID- 22512274 TI - Chemometric analysis of voltammetric data on metal ion binding by selenocystine. AB - The behavior of selenocystine (SeCyst) alone or in the presence of various metal ions (Bi(3+), Cd(2+), Co(2+), Cu(2+), Cr(3+), Ni(2+), Pb(2+), and Zn(2+)) was studied using differential pulse voltammetry (DPV) over a wide pH range. Voltammetric data matrices were analyzed using chemometric tools recently developed for nonlinear data: pHfit and Gaussian Peak Adjustment (GPA). Under the experimental conditions tested, no evidence was found for the formation of metal complexes with Bi(3+), Cu(2+), Cr(3+), and Pb(2+). In contrast, SeCyst formed electroinactive complexes with Co(2+) and Ni(2+) and kinetically inert but electroactive complexes with Cd(2+) and Zn(2+). Titrations with Cd(2+), Co(2+), Ni(2+), and Zn(2+) produced data that were reasonably consistent with the formation of stable 1:1 M(SeCyst) complexes. PMID- 22512275 TI - Letter to the editor: A potential mechanism for the pathogenesis of psoriasis vulgaris. PMID- 22512276 TI - Probing structure-nanoaggregation relations of polyaromatic surfactants: a molecular dynamics simulation and dynamic light scattering study. AB - Four synthetic perylene bisimide-based polyaromatic (PA) surfactants with a structural or functional group difference in their attached hydrophilic/hydrophobic substituent side chains were used to probe structure nanoaggregation relations in organic media by molecular dynamics simulations and dynamic light scattering. The results from the simulated radial distribution functions and light scattering experiments indicate that variation in the structure of side chains and polarity of functional groups leads to significant variations in molecular association, dynamics of molecular nanoaggregation and structure of nanoaggregates. The aggregates of PA surfactant molecules grow to much larger sizes in heptane than in toluene. The aromatic solvent is shown to hinder molecular association by weakening pi-pi stacking, demonstrating the control of molecular aggregation by tuning solvent properties. In aliphatic solvent, the aggregates formed from PA surfactants of aliphatic alkyl groups and phenylalanine derivatives as a side chain usually have a higher solvent accessible surface area to accessible volume ratio (SASA:AV) than that of tryptophan derivatives in their side chains. PA surfactants with an aliphatic functional group in both side chains does not form polyaromatic pi-pi stacking (T stacking) due to its strong steric hindrance in both solvents. Depending on the nature of the side chains attached, various stacking distributions, aggregation sizes, and SASA:AV ratios were obtained. In PA surfactant nanoaggregates, all of the solvent molecules were found to be excluded from the interstices of the stacked polyaromatic cores, regardless of whether the solvent molecules are aliphatic or aromatic. Although the change in the structure of side chain substituent in polyaromatic surfactants has a negligible impact on their self diffusivity, it can strongly influence their intermolecular interactions, leading to different aggregate diffusion coefficients. PMID- 22512277 TI - Aberrant epigenetic modifications in peripheral blood mononuclear cells from patients with pemphigus vulgaris. AB - BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune blistering disorder with a complex aetiology involving genetic and environmental factors, most of which remain unknown. It has become increasingly evident that aberrant epigenetic modifications are associated with the occurrence and development of autoimmune skin disorders. However, it is not known whether epigenetic modifications play a role in the development of PV. OBJECTIVES: To analyse DNA methylation and histone modification patterns in peripheral blood mononuclear cells (PBMCs) of patients with PV. METHODS: PBMC samples were isolated from 24 patients with PV and 20 healthy controls. Skin lesion biopsies and control skin specimens were obtained from 25 patients with PV and 15 healthy controls. Global DNA methylcytosine levels, as well as histone acetylation and methylation levels, were measured by enzyme-linked immunosorbent assay. mRNA expression levels were determined using real-time reverse transcription-polymerase chain reaction. RESULTS: Genomic DNA methylation in PBMCs of patients with PV was increased relative to controls. DNMT1 expression levels were significantly higher in PV PBMCs than in controls. MBD3 expression was repressed in PV PBMCs compared with healthy controls. Global histone H3/H4 acetylation and H3K4/H3K27 methylation levels were significantly decreased in patient PBMCs compared with healthy controls. These changes were accompanied by increased HDAC1, HDAC2 and SUV39H2 and decreased SUV39H1 and EZH2 in PV PBMCs. CONCLUSIONS: Aberrant DNA methylation and histone modifications occur in PBMCs of patients with PV, possibly due to the deregulation of epigenetic modifier genes. These changes may contribute to the pathological immune responses in PV. PMID- 22512278 TI - Role of vasoactive intestinal peptide in seasonal encoding by the suprachiasmatic nucleus clock. AB - The neuropeptide vasoactive intestinal peptide (VIP) is critical for the proper functioning of the neural circuit that generates circadian rhythms. Mice lacking VIP show profound deficits in the ability to generate many behavioral and physiological rhythms. To explore how the loss of VIP impacts on the intact circadian system, we carried out in vivo multiunit neural activity (MUA) recordings from the suprachiasmatic nucleus of freely moving VIP knockout (KO) mice. The MUA rhythms were largely unaltered in the VIP KO mice, with no significant differences being seen in the amplitude or phase of the rhythms in light-dark conditions. Robust differences between the genotypes were revealed when the mice were transferred from light-dark to constant darkness conditions. In addition, the ability of the VIP KO mice to encode changes in photoperiod was examined. Strikingly, the behavioral and physiological rhythms of VIP KO mice showed no adaptation to short or long photoperiods. The data indicate that the intact circadian system can compensate for some of the consequences of the loss of VIP, whereas this peptide is indispensable for endogenous encoding of seasonal information. PMID- 22512279 TI - Are preventive and generative causal reasoning symmetrical? Extinction and competition. AB - We tested whether preventive and generative reasoning processes are symmetrical by keeping the training and testing of preventive (inhibitory) and generative (excitatory) causal cues as similar as possible. In Experiment 1, we extinguished excitors and inhibitors in a blocking design, in which each extinguished cause was presented in compound with a novel cause, with the same outcome occurring following the compound and following the novel cause alone. With this novel extinction procedure, the inhibitory cues seemed more likely to lose their properties than the excitatory cues. In Experiment 2, we investigated blocking of excitatory and inhibitory causes and found similar blocking effects. Taken together, these results suggest that acquisition of excitation and inhibition is similar, but that inhibition is more liable to extinguish with our extinction procedure. In addition, we used a variable outcome, and this enabled us to test the predictions of an inferential reasoning account about what happens when the outcome level is at its minimum or maximum (De Houwer, Beckers, & Glautier, 2002). We discuss the predictions of this inferential account, Rescorla and Wagner's (1972) model, and a connectionist model-the auto-associator. PMID- 22512281 TI - First steps in designing a videophone for people with dementia: identification of users' potentials and the requirements of communication technology. AB - PURPOSE: To identify, based on the literature, people with dementia's potentials to manage an easy-to-use videophone, and to develop a videophone requirement specification for people with dementia. METHOD: The study is based on the Inclusive Design method, utilising the first two of four phases. Content analyses of literature reviews were used to identify users' potentials for managing a videophone and to gather recommendations regarding communication technology design for the target group. Existing videophones in Sweden were examined regarding potential fit to users with dementia. FINDINGS: This led to detailed identification of cognitive, physical and psychosocial challenges that people with dementia will probably have when using an ordinary telephone or videophone. A requirement specification for videophone design to fit users with dementia was formulated, with the seven principles of Universal Design as a framework. CONCLUSIONS: The requirement specification presented here is aimed at designing a videophone but might also facilitate design of other products for people with dementia, particularly in the field of communication technology. Based on this, further work will focus on developing a design concept and a prototype to be empirically tested by people with dementia and their significant others, i.e. the final two design process phases. PMID- 22512282 TI - Reflectance confocal microscopy: an effective tool for monitoring ultraviolet B phototherapy in psoriasis. AB - BACKGROUND: In vivo reflectance confocal microscopy (RCM) is a novel, noninvasive imaging technique which enables imaging of skin at a cellular resolution comparable to conventional microscopy. OBJECTIVES: We performed a pilot study to evaluate RCM as a noninvasive tool for monitoring ultraviolet (UV) B phototherapy in psoriasis. METHODS: In six patients with psoriasis, lesional and nonlesional skin was selected for RCM imaging using a standardized protocol. Well-known histological features of psoriasis were visualized: parakeratosis, acanthosis, agranulosis, papillomatosis, presence of epidermal inflammatory cells, increased number of papillary capillaries and increased capillary blood flow. RCM imaging was performed before the first irradiation with UVB phototherapy, after nine irradiations, at clearance and 12 weeks after clearance. In four patients, 4-mm punch biopsies were obtained and stained with haematoxylin-eosin. Additionally, immunohistochemical staining was performed with monoclonal antibodies specific for CD31, CD3, filaggrin, K16, Ki67 and CD1a for correlation to RCM images. RESULTS: There was a high correlation between clinical, RCM and histological features. Normalization of RCM and histological features corresponded highly to clinical improvement of psoriasis. CONCLUSIONS: This study is the first to establish the use of RCM as an effective tool for noninvasive monitoring of UVB phototherapy in patients with psoriasis. Potentially, RCM could be used in many other skin diseases for monitoring therapeutic response on a cellular level in a clinical or research setting. PMID- 22512280 TI - The herpes simplex virus type 1 latency-associated transcript inhibits phenotypic and functional maturation of dendritic cells. AB - We recently found that the herpes simplex virus-1 (HSV-1) latency-associated transcript (LAT) results in exhaustion of virus-specific CD8+ T cells in latently infected trigeminal ganglia (TG). In this study we sought to determine if this impairment may involve LAT directly and/or indirectly interfering with DC maturation. We found that a small number of HSV-1 antigen-positive DCs are present in the TG of latently-infected CD11c/eYFP mice; however, this does not imply that these DCs are acutely or latently infected. Some CD8+ T cells are adjacent to DCs, suggesting possible interactions. It has previously been shown that wild-type HSV-1 interferes with DC maturation. Here we show for the first time that this is associated with LAT expression, since compared to LAT- virus: (1) LAT+ virus interfered with expression of MHC class I and the co-stimulatory molecules CD80 and CD86 on the surface of DCs; (2) LAT+ virus impaired DC production of the proinflammatory cytokines IL-6, IL-12, and TNF-alpha; and (3) DCs infected in vitro with LAT+ virus had significantly reduced the ability to stimulate HSV-specific CD8+ T cells. While a similar number of DCs was found in LAT+ and LAT- latently-infected TG of CD11c/eYFP transgenic mice, more HSV-1 Ag positive DCs and more exhausted CD8 T cells were seen with LAT+ virus. Consistent with these findings, HSV-specific cytotoxic CD8+ T cells in the TG of mice latently-infected with LAT+ virus produced less IFN-gamma and TNF-alpha than those from TG of LAT--infected mice. Together, these results suggest a novel immune-evasion mechanism whereby the HSV-1 LAT increases the number of HSV-1 Ag positive DCs in latently-infected TG, and interferes with DC phenotypic and functional maturation. The effect of LAT on TG-resident DCs may contribute to the reduced function of HSV-specific CD8+ T cells in the TG of mice latently infected with LAT+ virus. PMID- 22512283 TI - Atypical erosive pustular dermatosis of the scalp with eosinophilia and erythroderma. PMID- 22512284 TI - 14-3-3 zeta as novel molecular target for cancer therapy. AB - INTRODUCTION: 14-3-3zeta acts as a central hub in signaling networks, which promotes cell proliferation, adhesion and survival and inhibits apoptosis in multiple cancers. Development of inhibitors or agents that interfere with 14-3 3zeta-dependent signaling networks are likely to serve as novel molecular agents for targeted cancer therapy. AREAS COVERED: The role of 14-3-3zeta in cancer and its potential as a novel molecular target for therapy. The involvement of 14-3 3zeta in chemoresistance in multiple cancers provides a rationale for developing novel molecular therapies targeting this protein for more effective cancer management. The keywords used to conduct the literature search for this paper were '14-3-3/14-3-3zeta and cancer', '14-3-3 structure', '14-3-3 inhibitors', '14 3-3 cancer prognosis', '14-3-3 and cancer therapy', 'role/ functions of 14-3-3'. EXPERT OPINION: 14-3-3zeta is a central cellular hub protein regulating multiple signaling pathways involved in cancer development, progression and therapeutic resistance. Thus, 14-3-3zeta may serve as a novel molecular target for cancer therapy. New approaches including synthetic and/or natural inhibitors that interfere with 14-3-3zeta-client interactions need to be developed for effective cancer therapy. PMID- 22512285 TI - Transparent, conducting ATO thin films by epoxide-initiated sol-gel chemistry: a highly versatile route to mixed-metal oxide films. AB - A robust synthesis approach to transparent conducting oxide (TCO) materials using epoxide assisted sol-gel chemistry is reported. The new route utilizes simple tin and antimony chloride precursors in aqueous solution, thus eliminating the need for organometallic precursors. Propylene oxide acts as a proton scavenger and drives metal hydroxide formation and subsequent polycondensation reactions. Thin films of antimony-doped tin oxide (ATO) were prepared by dip-coating of mixed metal oxide sols. After annealing at 600 degrees C in air, structural, electrical and optical properties of undoped and Sb-doped tin oxide films were characterized. Single layer films with 5 mol % Sb doping exhibited an optical transparency which was virtually identical to that of the plain glass substrate and an electrical resistivity of 2.8 * 10(-2) Omega cm. SEM and AFM analysis confirmed the presence of surface defects and cracks which increased with increasing Sb dopant concentration. Multiple depositions of identical ATO films showed a roughly 1 order of magnitude decrease in the film resistivity after the third layer, with typical values below 5 * 10(-3) Omega cm. This suggests that a second and third deposition fill up residual cracks and defects in the first layer and thus brings out the full performance of the ATO material. The epoxide assisted sol chemistry is a promising technique for the preparation of mixed oxide thin film materials. Its superiority over conventional alkoxide and metal salt-based methods is explained in the context of a general description of the reaction mechanism. PMID- 22512286 TI - The association between skin blood flow and edema on epidermal thickness in the diabetic foot. AB - BACKGROUND: Skin blood flow plays an important role in maintaining the health of the skin. The development of interstitial edema may impede oxygen diffusion to the skin. The aim of this study was to evaluate the association of skin blood flow and edema and epidermal thickness in the feet of people with and without diabetic neuropathy compared with a healthy control group. SUBJECTS AND METHODS: Eighty-seven subjects (19 people with diabetic neuropathy and foot ulceration, 35 people with diabetes but without neuropathy, and 33 healthy controls without diabetes) participated in the study. High-frequency ultrasonography was used to measure the epidermal thickness and edema in papillary skin at the big toe as reflected by the thickness of the subepidermal low echogenic band (SLEB). The capillary nutritive blood flow was measured by the use of video capillaroscopy, and skin blood flux was monitored by laser Doppler flowmetry. RESULTS: There was a 7.2% increase in epidermal thickness in those with diabetes but without neuropathy and a 16.5% decrease in people with diabetic neuropathy and foot ulceration compared with the healthy controls (all P<0.05). The SLEB thickness increased in all subjects with diabetes to a greater degree in those with neuropathy and ulceration than in those without (64.7% vs. 11.8%, P<0.001). Skin blood flux was shown to be higher in the diabetes groups than in the controls (all P<0.05), but no significant differences were found in the resting nutritive capillary blood flow (P>0.05). A significant negative correlation (P=0.002, r= 0.366) was demonstrated between the SLEB and epidermal thickness at the pulp of the big toe, whereas no significant correlation was demonstrated between skin blood flow and epidermal thickness (all P>0.05). CONCLUSIONS: An increase in subepidermal edema was demonstrated in people with diabetic neuropathy and ulceration, which may partly contribute to reduced epidermal thickness at the pulp of the big toe. This may subsequently lead to the breaking down of skin in the diabetic foot. PMID- 22512287 TI - Impact of a telemedicine system with automated reminders on outcomes in women with gestational diabetes mellitus. AB - BACKGROUND: Health information technology has been proven to be a successful tool for the management of patients with multiple medical conditions. The purpose of this study was to examine the impact of an enhanced telemedicine system on glucose control and pregnancy outcomes in women with gestational diabetes mellitus (GDM). SUBJECTS AND METHODS: We used an Internet-based telemedicine system to also allow interactive voice response phone communication between patients and providers and to provide automated reminders to transmit data. Women with GDM were randomized to either the telemedicine group (n=40) or the control group (n=40) and asked to monitor their blood glucose levels four times a day. Women in the intervention group transmitted those values via the telemedicine system, whereas women in the control group maintained paper logbooks, which were reviewed at prenatal visits. Primary outcomes were infant birth weight and maternal glucose control. Data collection included blood glucose records, transmission rates for the intervention group, and chart review. RESULTS: There were no significant differences between the two groups (telemedicine vs. controls) in regard to maternal blood glucose values or infant birth weight. However, adding telephone access and reminders increased transmission rates of data in the intervention group compared with the intervention group in our previous study (35.6+/-32.3 sets of data vs.17.4+/-16.9 sets of data; P<0.01). CONCLUSIONS: Our enhanced telemedicine monitoring system increased system utilization and contact between women with GDM and their healthcare providers but did not impact upon pregnancy outcomes. PMID- 22512289 TI - Determination of crossed language dominance: dissociation of language lateralization within the temporoparietal cortex. AB - 'Crossed language dominance' is a rare form of language lateralization, characterized by a dissociation of anterior and posterior language regions. We present the case of a healthy subject whose language lateralization pattern, as assessed by functional magnetic resonance imaging, is reliably characterized as crossed language dominance based on a word generation task, but typical left lateralized when a semantic decision task is applied. A single language task is therefore not sufficient to characterize language lateralization, at least not for subjects with rare forms of language dominance. In the pre-surgical diagnostic of language lateralization, several language tasks tapping into different aspects of language functions should be applied. PMID- 22512288 TI - Real-time continuous glucose monitoring in an intensive care unit: better accuracy in patients with septic shock. AB - OBJECTIVE: This study assessed the accuracy of real-time continuous glucose monitoring system (RTCGMS) devices in an intensive care unit (ICU) to determine whether the septic status of the patient has any influence on the accuracy of the RTCGMS. SUBJECTS AND METHODS: In total, 41 patients on insulin therapy were included. Patients were monitored for 72 h using RTCGMS. Arterial blood glucose (ABG) samples were obtained following the protocol established in the ICU. The results were evaluated using paired values (excluding those used for calibration) with the performance assessed using numerical accuracy. Nonparametric tests were used to determine statistically significant differences in accuracy. RESULTS: In total, 956 ABG/RTCGMS pairs were analyzed. The overall median relative absolute difference (RAD) was 13.5%, and the International Organization for Standardization (ISO) criteria were 68.1%. The median RADs reported for patients with septic shock, with sepsis, and without sepsis were 11.2%, 14.3%, and 16.3%, respectively (P<0.05). Measurements meeting the ISO criteria were 74.5%, 65.6%, and 63.7% for patients with septic shock, with sepsis, and without sepsis, respectively (P<0.05). CONCLUSIONS: The results showed that the septic status of patients influenced the accuracy of the RTCGMS in the ICU. Accuracy was significantly better in patients with septic shock in comparison with the other patient cohorts. PMID- 22512290 TI - Synthesis of polysubstituted isoquinolines through cross-coupling reactions with alpha-alkoxytosylhydrazones. AB - A Pd-catalyzed cross-coupling reaction of alpha-alkoxytosylhydrazones with sulfonates derived from salicyl aldehydes gives rise to protected 1,5-dicarbonyl compounds. Treatment with ammonium hydroxide readily transforms these alkenes into isoquinolines with diverse substitution patterns at positions 3 and 4. In a similar way, the employment of o-cyanononaflates in the coupling reaction, followed by treatment with an organometallic, provides isoquinolines that incorporate substitution also at position 1. The combination of both approaches represents a versatile method for the preparation of isoquinolines substituted at any position of the heterocyclic ring. PMID- 22512291 TI - Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A. AB - OBI-1 is a recombinant B-domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti-FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI-1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI-1 in a double-blind fashion. FVIII levels were assayed using both a one-stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti-porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C(max) appeared higher for OBI-1 (OSCA: 176.00 U dL(-1), standard deviation +/- 88.00; chromogenic: 151.00 +/- 31.51 U dL(-1)) than Hyate:C (OSCA: 82.3 +/- 19.22 U dL(-1); chromogenic: 52.67 +/- 13.8 U dL(-1)). Mean AUC also appeared higher for OBI-1 (OSCA: 2082.87 +/- 1323.43 U h(-1) dL(-1) ; chromogenic: 1817.28 +/- 625.14 U h(-1) dL(-1)) than Hyate:C (OSCA: 1177.8 +/- 469.49 U h(-1) dL(-1); chromogenic: 707.61 +/- 420.05 U h(-1) dL(-1)). Two infusion-related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI-1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti-porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study. PMID- 22512293 TI - Marriage and family therapists working with couples who have children with autism. AB - Current research about families and couples who have children with autism is discussed using the Double ABCX model as a guide. A case study is presented along with recommendations for therapists who work with couples who have children with autism. Marriage and family therapists are encouraged to use the Double ABCX model as both an assessment tool as well as for intervention. More research and effective therapists in this area are needed in order to keep up with the rising rates of families that include children diagnosed with autism. PMID- 22512294 TI - Men's psychological functioning in the context of women's breast cancer. AB - Previous research indicates that men are affected when their female partners have breast cancer. However, little is known about what predicts men's psychological well-being in this context. The current investigation involved couples in which the woman had early stage breast cancer and explored the degree to which men's positive and negative well-being was related to women's well-being, women's physical symptoms, relationship functioning, and relationship duration. The findings indicate that all of these factors play a role and interact in predicting men's well-being. In particular, when women have a high level of physical symptoms, the typical associations between men's well-being with women's well-being and relationship adjustment no longer persist. Implications for working with couples addressing health problems are provided. PMID- 22512295 TI - Outness and relationship satisfaction in same-gender couples. AB - Self-disclosure of sexual orientation, or outness, is a fundamental feature of gay, lesbian, and bisexual (GLB) experience, yet little is known about how outness impacts same-gender relationship satisfaction. Through a qualitative analysis of interviews with 15 same-gender couples, the complexities of navigating a stigmatized identity in a homonegative society emerged, including (a) characteristics of outness, (b) the influence of coupling on an individual's outness, and (c) the impact of outness on same-gender relationship satisfaction. Findings suggest that for GLB persons, outness is a developmental skill, an expression of identity and values, as well as a resilience strategy for managing discrimination and gay-related stress that influences, though does not singularly determine, relationship satisfaction. Implications for clinical practice and future research suggestions are presented. PMID- 22512296 TI - Natural disasters: an assessment of family resiliency following Hurricane Katrina. AB - This study explored the role of family characteristics in the coping process of a family after having experienced Hurricane Katrina to gain an understanding of the relationship between family resiliency, hope, family hardiness, and spirituality for survivors of this natural disaster. It was hypothesized that families who demonstrate higher levels of hope, family hardiness, and spirituality would be more likely to effectively cope after the storm. Further, great resource loss was hypothesized to diminish a family's ability to cope. Four hundred fifty-two participants completed the survey. Results indicate a relationship between hope, family hardiness and spirituality, and the criterion variable, family coping. The importance of these findings in terms of exploring family resiliency following a natural disaster is discussed. PMID- 22512297 TI - A Mexico City-based immersion education program: training mental health clinicians for practice with Latino communities. AB - This article describes the philosophical foundations and educational methods of a Spanish language and cultural immersion program based in Mexico City, Mexico. The program is designed to assist U.S. graduate students in marriage and family therapy and clinical psychology programs to improve clinical service delivery with Latino clients. Utilizing critical pedagogy, the program works with future clinicians to develop multicultural and international competencies; acquire increased Spanish language skills; engage in self-of-the-therapist work; and expand their understanding of the historical and cultural influences shaping the mental healthcare needs of Latin American clients. A report of the themes from postimmersion surveys is provided and the implications for training are discussed. PMID- 22512298 TI - Transformative learning through international immersion: building multicultural competence in family therapy and counseling. AB - This study explores the experiences of graduate students who completed one of two international courses facilitated by family therapy faculty in a U.S. master's level counseling psychology department. Participants reported that international courses were personally and professionally transformative. Spending time in a foreign country gave them opportunities to learn from cultural differences, ultimately increasing the social and global awareness required for multicultural sensitivity. Experiential learning, reflection, and dialogue resulted in raised critical consciousness among participants. In this article, we discuss the transformational learning processes embedded in international courses and the potential benefits of these experiences on the development of multicultural sensitivity in family therapists and counselors in training. PMID- 22512299 TI - Making a difference in making miracles: common roadblocks to miracle question effectiveness. AB - This article describes a clinical investigation of student-therapists' use of the miracle question (MQ). Data used for this project came from transcribed role-play videotapes by six student-therapists. Transcripts were coded, and findings highlight challenges that prevent beginning therapists from effectively using the MQ. The primary themes that emerged were problems related to introducing, framing, and following up on the MQ. Practical recommendations are offered for improving therapist training in effective use of the MQ. PMID- 22512301 TI - Problematic within-family alliances in conjoint family therapy: a close look at five cases. AB - We intensively analyzed five sessions in which the within-family alliance was manifestly problematic and family members reported discrepant perceptions of the family's sense of purpose about working together in therapy. Triangulation of observer ratings with (a) session content, (b) participants' post-session perceptions, (c) therapists' alliance-related interventions, and (d) clients' pretreatment target complaints and problem descriptions suggested three essential, interrelated aspects of the within-family alliance: family members (a) agreeing on the problem(s) and goals for treatment, (b) feeling connected in coping with their concerns ("a felt unity"), and (c) seeing conjoint therapy as valuable. Within-family disagreements on any of these aspects seemed to account for the observed in-session struggles. The analysis also suggested several missed opportunities for strengthening the within-family alliance. PMID- 22512300 TI - Marriage and family therapy faculty members' balance of work and personal life. AB - A sense of imbalance is common among both professors and therapists, though few studies have been published examining the work and personal life balance of those who work in both professions simultaneously. Using in-depth telephone interviews, this study examined the work and personal life balance of 16 marriage and family therapy (MFT) faculty members. Results showed that six were satisfied with their balance, six were dissatisfied, and four were "middle of the road." Men, older participants, and those who were in their career longer were more likely to report feeling satisfied with their balance. Internal indicators of their balance included family and workplace messages, health indicators, feelings of contentment, and congruence with personal values. Child and relationship status, tenure status, and gender issues also impacted their sense of balance. Specific balance enhancers and reducers were highlighted, and participants discussed coping strategies and recommendations for other MFT faculty members. Clinical, training, and career implications are discussed. PMID- 22512302 TI - Innate immunity and the evolution of resistance to an emerging infectious disease in a wild bird. AB - Innate immunity is expected to play a primary role in conferring resistance to novel infectious diseases, but few studies have attempted to examine its role in the evolution of resistance to emerging pathogens in wild vertebrate populations. Here, we used experimental infections and cDNA microarrays to examine whether changes in the innate and/or acquired immune responses likely accompanied the emergence of resistance in house finches (Carpodacus mexicanus) in the eastern United States subject to a recent outbreak of conjunctivitis-causing bacterium (Mycoplasma gallisepticum-MG). Three days following experimental infection with MG, we observed differences in the splenic transcriptional responses between house finches from eastern U.S. populations, with a 12-year history of MG exposure, versus western U.S. populations, with no history of exposure to MG. In particular, western birds down-regulated gene expression, while eastern finches showed no expression change relative to controls. Studies involving poultry have shown that MG can manipulate host immunity, and our observations suggest that pathogen manipulation occurred only in finches from the western populations, outside the range of MG. Fourteen days after infection, eastern finches, but not western finches, up-regulated genes associated with acquired immunity (cell mediated immunity) relative to controls. These observations suggest population differences in the temporal course of the response to infection with MG and imply that innate immune processes were targets of selection in response to MG in the eastern U.S. population. PMID- 22512303 TI - Inhibition of [FeFe]-hydrogenases by formaldehyde and wider mechanistic implications for biohydrogen activation. AB - Formaldehyde-a rapid and reversible inhibitor of hydrogen evolution by [FeFe] hydrogenases-binds with a strong potential dependence that is almost complementary to that of CO. Whereas exogenous CO binds tightly to the oxidized state known as H(ox) but very weakly to a state two electrons more reduced, formaldehyde interacts most strongly with the latter. Formaldehyde thus intercepts increasingly reduced states of the catalytic cycle, and density functional theory calculations support the proposal that it reacts with the H cluster directly, most likely targeting an otherwise elusive and highly reactive Fe-hydrido (Fe-H) intermediate. PMID- 22512304 TI - GVVPT2 multireference perturbation theory description of diatomic scandium, chromium, and manganese. AB - With relatively simple model spaces derived from valence bond models, a straightforward zero-order Hamiltonian, and the use of moderate-sized Dunning type correlation consistent basis sets (cc-pVTZ, aug-cc-pVTZ, and cc-pVQZ), the second order generalized Van Vleck perturbation theory (GVVPT2) method is shown to produce potential energy curves (PECs) and spectroscopic constants close to experimental results for both ground and low-lying excited electronic states of Sc(2), Cr(2) and Mn(2). In spite of multiple quasidegeneracies (particularly for the cases of Sc(2) and Mn(2)), the GVVPT2 PECs are smooth with no discontinuities. Since these molecules have been identified as ones that widely used perturbative methods are inadequate for describing well, due to intruder state problems, unless shift parameters are introduced that can obfuscate the physics, this study suggests that the conclusion about the inadequacy of multireference perturbation theory be re-evaluated. The ground state of Sc(2) is predicted to be X(5)?(u)(-), and its spectroscopic constants are close to the ones at the MRCISD level. Near equilibrium geometries, the 1(3)?(u)(-) electronic state of Sc(2) is found to be less stable than the quintet ground state by 0.23 eV. The Cr(2) PEC has several features of the Rydberg-Klein-Rees (RKR) experimental curve (e.g., the pronounced shelf at elongated bond lengths), although the predicted bond length is slightly long (R(e) = 1.80 A with cc-pVQZ compared to the experimental value of 1.68 A). The X(1)?(g)(+) ground state of Mn(2) is predicted to be a van der Waals molecule with a long bond length, R(e), of 3.83 A using a cc-pVQZ basis set (experimental value = 3.40 A) and a binding energy, D(e), of only 0.05 eV (experimental value = 0.1 eV). We obtained R(e) = 3.40 A and D(e) = 0.09 eV at the complete basis set (CBS) limit for ground state Mn(2). Low lying excited state curves have also been characterized for all three cases (Cr(2), Mn(2), and Sc(2)) and show similar mathematical robustness as the ground states. These results suggest that the GVVPT2 multireference perturbation theory method is more broadly applicable than previously documented. PMID- 22512305 TI - Contributions of far-field hydrodynamic interactions to the kinetics of electrostatically driven molecular association. AB - We simulated the diffusional encounters in periodic systems of model isotropic and anisotropic molecules using Brownian dynamics. We considered the electrostatic, excluded volume, and far-field hydrodynamic forces between diffusing molecules. Our goal was to estimate to what extent the hydrodynamic interactions influence the association kinetics when the associating partners are oppositely charged and their direct electrostatic interactions are screened by small mobile ions of dissolved salt. Overall, including hydrodynamic interactions decreases the association rate constants. The relative magnitude of this decrease does not depend on the ionic strength for the association of isotropic charged objects. This also holds true for nonspecific association (i.e., without restrictions regarding the relative orientation of binding partners in an encounter complex) of anisotropic objects. However, such dependence is visible for orientation-specific association of anisotropic objects. Moreover, we observe that some orientations of anisotropic molecules are hydrodynamically favorable during their mutual approach, and that such molecules can be hydrodynamically steered toward a particular relative orientation. This hydrodynamic orientational steering is impeded in case of strong electrostatic interactions or steric hindrance. PMID- 22512306 TI - High-dose melphalan with bortezomib as conditioning regimen for autologous stem cell transplant in patients with newly diagnosed multiple myeloma who exhibited at least very good partial response to bortezomib-based induction therapy. PMID- 22512307 TI - Altered profile of basket cell afferent synapses in hyper-excitable dentate gyrus revealed by optogenetic and two-pathway stimulations. AB - Cholecystokinin (CCK-) positive basket cells form a distinct class of inhibitory GABAergic interneurons, proposed to act as fine-tuning devices of hippocampal gamma-frequency (30-90 Hz) oscillations, which can convert into higher frequency seizure activity. Therefore, CCK-basket cells may play an important role in regulation of hyper-excitability and seizures in the hippocampus. In normal conditions, the endogenous excitability regulator neuropeptide Y (NPY) has been shown to modulate afferent inputs onto dentate gyrus CCK-basket cells, providing a possible novel mechanism for excitability control in the hippocampus. Using GAD65-GFP mice for CCK-basket cell identification, and whole-cell patch-clamp recordings, we explored whether the effect of NPY on afferent synapses to CCK basket cells is modified in the hyper-excitable dentate gyrus. To induce a hyper excitable state, recurrent seizures were evoked by electrical stimulation of the hippocampus using the well-characterized rapid kindling protocol. The frequency of spontaneous and miniature excitatory and inhibitory post-synaptic currents recorded in CCK-basket cells was decreased by NPY. The excitatory post-synaptic currents evoked in CCK-basket cells by optogenetic activation of principal neurons were also decreased in amplitude. Interestingly, we observed an increased proportion of spontaneous inhibitory post-synaptic currents with slower rise times, indicating that NPY may inhibit gamma aminobutyric acid release preferentially in peri-somatic synapses. These findings indicate that increased levels and release of NPY observed after seizures can modulate afferent inputs to CCK-basket cells, and therefore alter their impact on the oscillatory network activity and excitability in the hippocampus. PMID- 22512308 TI - Cross-domain interference costs during concurrent verbal and spatial serial memory tasks are asymmetric. AB - Some evidence suggests that memory for serial order is domain-general. Evidence also points to asymmetries in interference between verbal and visual-spatial tasks. We confirm that concurrently remembering verbal and spatial serial lists provokes substantial interference compared with remembering a single list, but we further investigate the impact of this interference throughout the serial position curve, where asymmetries are indeed apparent. A concurrent verbal order memory task affects spatial memory performance throughout the serial positions of the list, but performing a spatial order task affects memory for the verbal serial list only for early list items; in the verbal task only, the final items are unaffected by a concurrent task. Adding suffixes eliminates this asymmetry, resulting in impairment throughout the list for both tasks. These results suggest that domain-general working memory resources may be supplemented with resources specific to the verbal domain, but perhaps not with equivalent spatial resources. PMID- 22512309 TI - Effects of Malassezia yeasts on serum Th1 and Th2 cytokines in patients with guttate psoriasis. AB - BACKGROUND: Systemic and focal infections caused by microorganisms have been known to induce or exacerbate psoriasis. Although the role of yeast species of the genus Malassezia in the pathogenesis of psoriasis is not fully understood, it is thought that these lipophilic yeasts may represent a triggering factor in the exacerbation of psoriatic lesions. OBJECTIVES: This study investigated the effects of Malassezia yeasts on serum Th1 and Th2 cytokines in patients with guttate psoriasis (GP) in order to define their role in the pathogenesis of psoriasis. METHODS: Fifty patients with GP and 29 clinically healthy individuals were included in the study. All samples consisted of scales and scrapings taken from the scalps, trunks, and upper limbs of both psoriasis patients and healthy subjects. Psoriasis patients and healthy subjects were grouped according to their positivity or negativity for Malassezia yeasts as ascertained by direct microscopy and/or culture. An enzyme-linked immunosorbent assay (ELISA) was used to measure serum levels of Th1 and Th2 cytokines in these groups. RESULTS: No significant differences in positivity for Malassezia yeasts were found between psoriatic skin and healthy skin in samples taken from different body sites. Serum interleukin-13 (IL-13) levels were significantly lower in the psoriasis group compared with the control group (P = 0.04). Levels of other cytokines did not differ significantly between the psoriasis and control groups. Mean levels of Th2 cytokines (IL-4, IL-10, IL-13), but not of Th1 cytokines (IL-2 and IFN-gamma), were significantly lower in psoriasis patients positive for Malassezia yeasts compared with those negative for Malassezia yeasts and control subjects (P = 0.04, P < 0.001 and P = 0.01, respectively). CONCLUSIONS: The isolation of Malassezia yeasts from GP lesions does not necessarily mean that these species are pathogenic, but their downregulating effects on anti-inflammatory Th2 cytokines may contribute to the occurrence of GP. PMID- 22512310 TI - Simple and specific detection of Bordetella holmesii by using a loop-mediated isothermal amplification assay. AB - A loop-mediated isothermal amplification (LAMP) assay for simple detection of Bordetella holmesii was developed. This assay discriminates between B. holmesii and other Bordetella species and successfully detect B. holmesii DNA in nasopharyngeal swab samples from subjects with suspected pertussis. The LAMP assay results were in complete agreement with the results of previously published real-time PCR assay, indicating that the former is a powerful tool for the accurate diagnosis and surveillance of B. holmesii. PMID- 22512311 TI - Vaccination with CpG-adjuvanted avian influenza virosomes promotes antiviral immune responses and reduces virus shedding in chickens. AB - The use of virosomes as a vaccine platform has proven successful against several viruses. Here we examined the protective efficacy of a virosome-based vaccine consisting of avian influenza virus (AIV) A/Duck/Czech/56/H4N6 in chickens against a homologous AIV challenge. Virosomes adjuvanted with CpG-ODN or recombinant chicken interferon (IFN)-gamma significantly reduced virus shedding after virus challenge. Furthermore, immunization with virosomes adjuvanted with CpG-ODN increased hemagglutination inhibition (HI) and virus-specific neutralizing serum antibodies, as well as virus-specific serum IgG and mucosal IgA responses. We also found a significant increase in the expression of type I and II interferon genes in the protected birds following virus challenge. In summary, this study demonstrated the ability of virosomes adjuvanted with CpG-ODN to reduce AIV shedding, and elicit virus-specific protective antibody responses in vaccinated birds. PMID- 22512312 TI - (13Z)- and (9Z)-lycopene isomers are major intermediates in the oxidative degradation of lycopene by cigarette smoke and Sin-1. AB - The breakdown of lycopene in the presence of reactive oxygen and reactive nitrogen species has been studied in order to identify key in vitro intermediates. These compounds may in turn be produced as metabolites in the body and may have significant physiological properties, such as increased antioxidant capacity. We have studied the in vitro degradation of lycopene in solvent, in plasma and in low density lipoprotein, when challenged with freshly generated gaseous cigarette smoke or free radicals generated in situ by S morpholinosydonimine at 37 degrees C. The emphasis has been to establish the major intermediates and to compare the data with previous studies using different reactants. We have found that (13Z)-lycopene is the major intermediate in both cigarette smoke and S-morpholinosydonimine reactions (representing >=60% of the converted (all-E)-lycopene at ~50% depletion). Additionally, (9Z)-lycopene and various (all-E) and (Z)-lycopene epoxides were predominant. Notably, (5Z) lycopene appeared to be the most stable form of lycopene under the stated conditions. Previous theoretical studies of isomer thermodynamics and rotational energy barriers for carbon double bonds fully support the pattern of isomer production and stability. In contrast to beta-carotene studies, nitro-derivatives of lycopene could not be detected. In conclusion, (Z)-lycopene production and (5Z)-lycopene stability may help explain elevated (Z)-lycopene in plasma over (Z) lycopene content in lycopene-containing foods in the diet. PMID- 22512313 TI - Disability rights in the context of HIV and AIDS: a critical review of nineteen Eastern and Southern Africa (ESA) countries. AB - PURPOSE: Many Eastern and Southern African (ESA) states are obliged to review and amend their legal frameworks with regards to disability since signing and ratifying the UN Convention on the Rights of Persons with Disabilities (CRPD). The HIV epidemic is one of the main health concerns in the region and is becoming increasingly associated with causing disabilities. In addition, people with disabilities are particularly at risk of exposure to HIV. Despite this, HIV programming has not yet included the interrelationship of disability and HIV. The principles within the CRPD may create much-needed international pressure and so provide a platform for the integration and inclusion of disability into HIV policies and programs. METHOD: This paper is based on a review of the legal framework in relation to HIV and disability in 19 ESA countries. It identifies 12 key articles of the Convention, which are particularly relevant to the interrelationship of HIV and disability. The paper assesses how these are integrated in the region's disability or HIV legal frameworks and identifies the main gaps within these legal systems. RESULTS: While many country's constitutions, disability and HIV laws protect certain key rights, such as the rights to equality and nondiscrimination, employment and health, there are clear gaps in the legal responses to disability and HIV. In particular, legal frameworks fail to provide adequately for accessibility, mobility and access to justice and protection from violence for people with disabilities. This results in limited protection for people with disabilities from HIV exposure and access to services to address HIV-related health and welfare needs. CONCLUSIONS: The paper identifies the gaps and makes recommendations for implementing steps toward the integration of disability into HIV-related laws, policies and programs. PMID- 22512314 TI - Elevated temperature anodized Nb2O5: a photoanode material with exceptionally large photoconversion efficiencies. AB - Here, we demonstrate that niobium pentoxide (Nb(2)O(5)) is an ideal candidate for increasing the efficiencies of dye-sensitized solar cells (DSSCs). The key lies in developing a Nb(2)O(5) crisscross nanoporous network, using our unique elevated temperature anodization process. For the same thicknesses of ~4 MUm, the DSSC based on the Nb(2)O(5) layer has a significantly higher efficiency (~4.1%) when compared to that which incorporates a titanium dioxide nanotubular layer (~2.7%). This is the highest efficiency among all of the reported photoanodes for such a thickness when utilizing back-side illumination. We ascribe this to a combination of reduced electron scattering, greater surface area, wider band gap, and higher conduction band edge, as well as longer effective electron lifetimes. PMID- 22512315 TI - Development and introduction of recombinant factor VIII--a clinician's experience. PMID- 22512316 TI - Guest editorial: reforming home care in ageing societies. PMID- 22512317 TI - Quality reforms in Danish home care - balancing between standardisation and individualisation. AB - Despite relatively generous coverage of the over-65 population, Danish home help services receive regular criticism in the media and public opinion polls. Perhaps as a consequence, reforms of Danish home care policy for senior citizens have placed a strong emphasis on quality since the 1990s. This reform strategy represents a shift from the welfare state modernisation programme of the 1980s, which built mainly on economic strategies of cost-efficiency and New Public Management principles, including contract management and performance management. Recent reforms have instead attempted to increase the overall quality of care by increasing the transparency at the political, administrative and user levels. However, reforms have revolved around the conflicting principles of standardisation and the individualisation of care provision. This approach has succeeded in increasing the political and administrative control over home help at the expense of the control by users, care workers and case managers. PMID- 22512320 TI - Evaluation of sample preparation methods for MALDI-TOF MS identification of highly dangerous bacteria. AB - AIMS: To propose a universal workflow of sample preparation method for the identification of highly pathogenic bacteria by MALDI-TOF MS. METHODS AND RESULTS: Fifteen bacterial species, including highly virulent Gram-positive (Bacillus anthracis and Clostridium botulinum) and Gram-negative bacteria (Brucella melitensis, Burkholderia mallei, Francisella tularensis, Shigella dysenteriae, Vibrio cholerae, Yersinia pestis and Legionella pneumophila), were employed in the comparative study of four sample preparation methods compatible with MALDI-TOF MS. The yield of bacterial proteins was determined by spectrophotometry, and the quality of the mass spectra, recorded in linear mode in the range of 2000-20,000 Da, was evaluated with respect to the information content (number of signals) and quality (S/N ratio). CONCLUSIONS: Based on the values of protein concentration and spectral quality, the method using combination of ethanol treatment followed by extraction with formic acid and acetonitrile was the most efficient sample preparation method for the identification of highly pathogenic bacteria using MALDI-TOF MS. SIGNIFICANCE AND IMPACT OF THE STUDY: The method using ethanol/formic acid generally shows the highest extraction efficacy and the spectral quality with no detrimental effect caused by storage. Thus, this can be considered as a universal sample preparation method for the identification of highly virulent micro-organisms by MALDI-TOF mass spectrometry. PMID- 22512321 TI - Semipinacol rearrangement of cis-fused beta-lactam diols into keto-bridged bicyclic lactams. AB - The 6-azabicyclo[3.2.1]octane ring system, prevalent in a range of biologically active molecules, is prepared through a novel semipinacol rearrangement utilizing a cyclic phosphorane or sulfite intermediate. The rearrangement proceeds with exclusive N-acyl group migration of a beta-lactam ring and results in carbonyl functionality at the 7- and bridging 8-position of the bicycle. Precursor ring fused beta-lactam diols are prepared through a sequence of 4-exo trig carbamoyl radical cyclization, regioselective dithiocarbamate group elimination, and dihydroxylation. PMID- 22512322 TI - Spatial attention can transfer to the contralateral hemisphere in neonatal stroke patients: a case report following hemispherectomy. AB - Patients suffer hemispatial neglect after stroke. However, whether the function of spatial attention is reorganized to the contralateral brain remains poorly understood. Here we present a case report of neonatal stroke to demonstrate the reorganization of spatial attention in the contralateral hemisphere using a series of tests including star cancellation task, line bisection test, the bells test, letter cancellation test, and drawing tests. The patient underwent right hemispherectomy for treatment of refractory epilepsy and did not have hemispatial neglect after surgery, supporting transfer of function prior to the operation. After analyzing the literature in this field, we proposed that the function of spatial attention may transfer to the contralateral side in childhood. Thus, this study sheds new light on the preserved function of spatial attention in neonatal stroke patients even when hemispherectomy is performed. PMID- 22512323 TI - DFT models of molecular species in carbonate molten salts. AB - Raman spectra of high temperature carbonate melts are correlated with carbonate species modeled at 923 K using B3LYP/(6-311+G(2d,p)) density functional calculations. Species that are theoretically stable at 923 K include O(2-), O(2)( ), O(2)(2-), CO(3)(2-), C(2)O(6)(2-), CO(4)(-), CO(4)(2-), CO(4)(4-), CO(5)(2-), KCO(4)(-), LiCO(4)(-), KO(2)(-), LiO(2)(-), NaO(2)(-), KO(2), LiO(2), NaO(2), KCO(3)(-), LiCO(3)(-), and NaCO(3)(-). Triangular, linear, and bent forms are theoretically possible for KO(2)(-) and NaO(2)(-). Triangular and linear forms may exist for LiO(2)(-). Linear and triangular versions are theoretically possible for LiO(2)(-) and KO(2). A triangular version of NaO(2) may exist. The correlation between measured and theoretical Raman spectra indicate that monovalent cations are to be included in several of the species that produce Raman spectra. PMID- 22512324 TI - Interpreting conjoined noun phrases and conjoined clauses: collective versus distributive preferences. AB - Two experiments are reported that show that introducing event participants in a conjoined noun phrase (NP) favours a single event (collective) interpretation, while introducing them in separate clauses favours a separate events (distributive) interpretation. In Experiment 1, acceptability judgements were speeded when the bias of a predicate toward separate events versus a single event matched the presumed bias of how the subjects' referents were introduced (as conjoined noun phrases or in conjoined clauses). In Experiment 2, reading of a phrase containing an anaphor following conjoined noun phrases was facilitated when the anaphor was they, relative to when it was neither/each of them; the opposite pattern was found when the anaphor followed conjoined clauses. We argue that comprehension was facilitated when the form of an anaphor was appropriate for how its antecedents were introduced. These results address the very general problem of how we individuate entities and events when presented with a complex situation and show that different linguistic forms can guide how we construe a situation. The results also indicate that there is no general penalty for introducing the entities or events separately-in distinct clauses as "split" antecedents. PMID- 22512325 TI - Applicability of the Polish Vocal Tract Discomfort (VTD) scale in the diagnostics of occupational dysphonia. AB - Occupational dysphonia is mainly of hyperfunctional origin, expressed by complaints experienced in the vocal tract. The aim of the paper was to evaluate the applicability of the Polish Vocal Tract Discomfort (VTD) scale in the diagnostics of occupational dysphonia. Patients with occupational dysphonia (n = 218) and controls (n = 140) were subjected to the VTD scale, VHI evaluation, and maximum phonation time (MPT) measurement. The patients also underwent videostroboscopy. The comparison of the frequency and severity of VTD symptoms showed that the results of the study group were significantly higher (P = 0.000). The VTD scale is characterized by high values of Cronbach's alpha. This study results indicate that the VTD scale can be a valuable tool, useful in the diagnostics of occupational dysphonia. PMID- 22512326 TI - Neuroanatomical distribution of the orphan GPR50 receptor in adult sheep and rodent brains. AB - GPR50, formerly known as melatonin-related receptor, is one of three subtypes of the melatonin receptor subfamily, together with the MT(1) and MT(2) receptors. By contrast to these two high-affinity receptor subtypes and despite its high identity with the melatonin receptor family, GPR50 does not bind melatonin or any other known ligand. Specific and reliable immunological tools are therefore needed to be able to elucidate the physiological functions of this orphan receptor that are still largely unknown. We have generated and validated a new specific GPR50 antibody against the ovine GPR50 and used it to analyse the neuroanatomical distribution of the GPR50 in sheep, rat and mouse whole brain. We demonstrated that GPR50-positive cells are widely distributed in various regions, including the hypothalamus and the pars tuberalis of the pituitary, in all the three species studied. GPR50 expressing cells are abundant in the dorsomedial nucleus of the hypothalamus, the periventricular nucleus and the median eminence. In rodents, immunohistochemical studies revealed a broader distribution pattern for the GPR50 protein. GPR50 immunoreactivity is found in the medial preoptic area (MPA), the lateral septum, the lateral hypothalamic area, the bed nucleus of the stria terminalis, the vascular organ of the laminae terminalis and several regions of the amygdala, including the medial nuclei of amygdala. Additionally, in the rat brain, GPR50 protein was localised in the CA1 pyramidal cell layer of the dorsal hippocampus. In mice, moderate to high numbers of GPR50-positive cells were also found in the subfornical organ. Taken together, these results provide an enlarged distribution of GPR50 protein, give further insight into the organisation of the melatoninergic system, and may lay the framework for future studies on the role of the GPR50 in the brain. PMID- 22512328 TI - Standard states and thermochemical kinetics in heterogeneous atmospheric chemistry. AB - The significance of the (often implicit) choice of standard state in the analysis and interpretation of heterogeneous chemical processes is not well acknowledged. This paper attempts to illuminate how the specific choice of standard state influences the numerical values of the parameters obtained from such analysis. Examples are drawn from air-solution and air-surface equilibria. PMID- 22512327 TI - DNA electrochemistry with tethered methylene blue. AB - Methylene blue (MB'), covalently attached to DNA through a flexible C(12) alkyl linker, provides a sensitive redox reporter in DNA electrochemistry measurements. Tethered, intercalated MB' is reduced through DNA-mediated charge transport; the incorporation of a single base mismatch at position 3, 10, or 14 of a 17-mer causes an attenuation of the signal to 62 +/- 3% of the well-matched DNA, irrespective of position in the duplex. The redox signal intensity for MB'-DNA is found to be least 3-fold larger than that of Nile blue (NB)-DNA, indicating that MB' is even more strongly coupled to the pi-stack. The signal attenuation due to an intervening mismatch does, however, depend on DNA film density and the backfilling agent used to passivate the surface. These results highlight two mechanisms for reduction of MB' on the DNA-modified electrode: reduction mediated by the DNA base pair stack and direct surface reduction of MB' at the electrode. These two mechanisms are distinguished by their rates of electron transfer that differ by 20-fold. The extent of direct reduction at the surface can be controlled by assembly and buffer conditions. PMID- 22512329 TI - Bone marrow derived cells and reactive oxygen species in hypertrophy of contralateral kidney of transient unilateral renal ischemia-induced mouse. AB - Renal mass reduction, such as unilateral nephrectomy induces a compensatory hypertrophy of remaining renal mass in response to overload induced by reduction of functional renal parenchyma. In our recent study, we observed that the recovery of ischemic injured kidney following transient unilateral renal ischemia took longer time than that following transient bilateral renal ischemia, indicating that non-damaged kidney may affect the damaged kidney and vice versa. Here, we investigated whether transient and partial renal parenchymal injury by transient unilateral renal ischemia (UI) results in the hypertrophy of its contralateral kidney (CLK) and reactive oxygen species is associated with the hypertrophy. Thirty minutes of UI resulted in gradual increase in CLK weight over time. UI increased superoxide formation, but not lipid peroxidation in the CLK. After UI, a significant increase in the number of NADPH oxidase 2 (Nox2) expressing cells and the level of Nox2 expression in the CLK was observed. In parallel with the increases in Nox2-expressing cells in CLKs, infiltration of bone marrow-derived cells (BMDC) increased in CLK. Treatments with Mn(III) Tetrakis(1-methyl-4-pyridyl) porphyrin (MnTMPyP, a superoxide dismutase (SOD) mimetic) and apocynin (a putative NADPH oxidase inhibitor) inhibited UI-induced hypertrophy of CLK along with reduction in Nox2-positive cell, BMDC, amount of Nox2 expression and superoxide formation. In conclusion, transient and partial renal mass reduction by UI resulted in the hypertrophy of CLK through increased ROS formation by infiltrated cells into the interstitium of CLK. PMID- 22512330 TI - Cardiovascular risk factors in subjects with psoriasis: a cross-sectional general population study. AB - BACKGROUND: Epidemiological data have established an association between cardiovascular disease and psoriasis. Only one general population study has so far compared prevalences of cardiovascular risk factors among subjects with psoriasis and control subjects. We aimed to determine the prevalence of cardiovascular risk factors in subjects with and without psoriasis in the general population. METHODS: During 2006-2008, a cross-sectional study was performed in the general population in Copenhagen, Denmark. A total of 3471 subjects participated in a general health examination that included assessment of current smoking status, weight, height, waist and hip circumferences, systolic and diastolic blood pressures, resting heart rate, and plasma lipids, hemoglobin A1c, fasting glucose, and insulin levels. RESULTS: Physician-diagnosed psoriasis was reported by 238 (7.1%) of 3374 participants. There were no differences between subjects with and without psoriasis with regard to traditional cardiovascular risk factors. CONCLUSIONS: Our results contrast with the hitherto-reported increased prevalence of metabolic syndrome in subjects with psoriasis in the general U.S. population. However, our results agree with those of other previous studies in which the association between mild psoriasis and cardiovascular risk factors is often non-significant. Further controlled research is needed to describe the prevalence of cardiovascular risk factors in subjects with mainly mild to moderate psoriasis in the general population. PMID- 22512331 TI - Response to Hrudey et al. letter in reference to Timoney critique of Royal Society of Canada report. PMID- 22512332 TI - Nutritional status assessment in complete denture wearers. AB - BACKGROUND AND OBJECTIVES: The relationship between oral health and the nutritional status in the elderly is complex and controversial. It has been suggested that poor oral health and a decreased ability to chew have a profound influence on food selection, diet and thereby the nutritional status of the individual. This study aimed to evaluate the effect of edentulousness and prosthetic treatment on the nutritional status of the individual. METHODS: A total of 94 patients were selected for the study, which was conducted over a period of 16 months. The nutritional status was assessed using the Mini Nutritional Assessment Form (MNA) before the complete denture treatment and after an interval of 6 months and 9 months following the treatment. The individual scores obtained for each question and the total scores at the baseline study were compared with those obtained after 6 and 9 months. Proportions were compared using chi-squared test of significance. RESULTS: The results showed statistically significant differences in the total MNA scores between the baseline study and after 6 and 9 months. The edentulous patients without complete dentures had significantly lower MNA scores. CONCLUSION: Prosthetic rehabilitation of the edentulous patients with complete dentures, along with the dietary counselling, improved the nutritional status of these patients. PMID- 22512333 TI - Brain connectivity in disorders of consciousness. AB - The last 10 years witnessed a considerable increase in our knowledge of brain function in survivors to severe brain injuries with disorders of consciousness (DOC). At the same time, a growing interest developed for the use of functional neuroimaging as a new diagnostic tool in these patients. In this context, particular attention has been devoted to connectivity studies-as these, more than measures of brain metabolism, may be more appropriate to capture the dynamics of large populations of neurons. Here, we will review the pros and cons of various connectivity methods as potential diagnostic tools in brain-damaged patients with DOC. We will also discuss the relevance of the study of the level versus the contents of consciousness in this context. PMID- 22512334 TI - "But I know what works"--patients' experience of spinal cord injury neuropathic pain management. AB - PURPOSE: To explore and obtain increased knowledge about (i) strategies and treatments used by individuals with neuropathic pain following spinal cord injury (SCI) for handling long-term pain, and (ii) their experience, needs and expectations of SCI neuropathic pain management. METHODS: Qualitative methods with an emergent research design were used. Eighteen informants who suffered from long-term SCI neuropathic pain participated. Data were collected with diaries and thematized research interviews. Content analysis and constant comparison according to grounded theory were used for the analyses. RESULTS: A model with four categories emerged: "Pain is my main problem" explained the impact of pain in the informants' everyday life; "Drugs--the health care solution" described the informants' experience of pain management; "The gap in my meeting with health care" described the discrepancy between what the informants wanted and what health care could offer. "But...this works for me" described treatments and strategies, which the informants found helpful for pain control and pain relief. CONCLUSION: Neuropathic pain, one of the major problems following SCI, is difficult to treat successfully. To improve treatment outcome, health care needs to listen to, respond to and respect the patient's knowledge, experience and wishes. Future research needs to address treatments that patients find effective. PMID- 22512335 TI - Approximate entropy normalized measures for analyzing social neurobiological systems. AB - When considering time series data of variables describing agent interactions in social neurobiological systems, measures of regularity can provide a global understanding of such system behaviors. Approximate entropy (ApEn) was introduced as a nonlinear measure to assess the complexity of a system behavior by quantifying the regularity of the generated time series. However, ApEn is not reliable when assessing and comparing the regularity of data series with short or inconsistent lengths, which often occur in studies of social neurobiological systems, particularly in dyadic human movement systems. Here, the authors present two normalized, nonmodified measures of regularity derived from the original ApEn, which are less dependent on time series length. The validity of the suggested measures was tested in well-established series (random and sine) prior to their empirical application, describing the dyadic behavior of athletes in team games. The authors consider one of the ApEn normalized measures to generate the 95th percentile envelopes that can be used to test whether a particular social neurobiological system is highly complex (i.e., generates highly unpredictable time series). Results demonstrated that suggested measures may be considered as valid instruments for measuring and comparing complexity in systems that produce time series with inconsistent lengths. PMID- 22512336 TI - Remote doping and Schottky barrier formation in strongly quantum confined single PbSe nanowire field-effect transistors. AB - We report studies of charge injection and transport in ambipolar, predominantly n type, and unipolar p-type single, strongly quantum confined PbSe nanowire (NW) field effect transistors (FETs). The PbSe NW FETs operate as Schottky barrier FETs in which the Fermi level is pinned near midgap, consistent with the low ionicity of PbSe, and is nearly invariant with semiconductor doping. Electron and hole mobilities increase monotonically with decreasing temperature, dominated at high temperature by electron-phonon scattering with no evidence of scattering at low temperatures. Transport in NWs is consistent with their single crystalline nature. Surface oxygen used to dope the NWs acts remotely, providing a promising route to dope nanostructures. PMID- 22512338 TI - Nectins localize Willin to cell-cell junctions. AB - Willin is a FERM-domain protein, which is related to the Drosophila Expanded, a protein known to be a component of the Hippo signaling pathway. We recently showed that Willin localizes at the apical junctional complex (AJC) in epithelial cells together with Par3 and regulates the contractility of the circumferential actomyosin cables by recruiting aPKC to the AJC. However, it remains unresolved how Willin becomes associated with the AJC. Here, we report that Willin binds to nectins, Ig-family proteins, which also localize at the AJC via their homophilic or heterophilic interactions, and this binding participates in the junctional recruitment of Willin. In addition, we report that the positioning of nectins at the AJC is dependent on their binding to afadin. Thus, our results suggest that the nectin-afadin interaction plays a role in the correct localization of Willin. PMID- 22512337 TI - A novel and conserved protein AHO-3 is required for thermotactic plasticity associated with feeding states in Caenorhabditis elegans. AB - Although a large proportion of molecules expressed in the nervous system are conserved from invertebrate to vertebrate, functional properties of such molecules are less characterized. Here, we show that highly conserved hydrolase AHO-3 acts as a novel regulator of starvation-induced thermotactic plasticity in Caenorhabditis elegans. As wild-type animals, aho-3 mutants migrated to the cultivation temperature on a linear thermal gradient after cultivation at a particular temperature with food. Whereas wild-type animals cultivated under food deprived condition showed dispersed distribution on the gradient, aho-3 mutants exhibited tendency to migrate toward higher temperature. Such an abnormal behavior was completely rescued by the expression of human homologue of AHO-3, indicating that the molecular function of AHO-3 is highly conserved between nematode and human. The behavioral regulation by AHO-3 requires the N-terminal cysteine cluster, which ensures the proper subcellular localization of AHO-3 to sensory endings. Double-mutant analysis suggested that AHO-3 acts in the same pathway with ODR-3, a heterotrimeric G protein alpha subunit. Our results unveiled a novel neural protein in C. elegans, confirming its conserved role in behavioral regulation. PMID- 22512339 TI - Phase-dependent generation and transmission of time information by the KaiABC circadian clock oscillator through SasA-KaiC interaction in cyanobacteria. AB - Circadian clocks allow organisms to predict environmental changes of the day/night cycle. In the cyanobacterial circadian clock machinery, the phosphorylation level and ATPase activity of the clock protein KaiC oscillate with a period of approximately 24 h. The time information is transmitted from KaiC to the histidine kinase SasA through the SasA autophosphorylation-enhancing activity of KaiC, ultimately resulting in genome-wide transcription cycles. Here, we showed that SasA derived from the thermophilic cyanobacterium Thermosynechococcus elongatus BP-1 has the domain structure of an orthodox histidine kinase and that its C-terminal domain, which contains a phosphorylation site at His160, is responsible for the autophosphorylation activity and the temperature- and phosphorylation state-dependent trimerization / hexamerization activity of SasA. SasA and KaiC associate through their N-terminal domains with an affinity that depends on their phosphorylation states. Furthermore, the SasA autophosphorylation-enhancing activity of KaiC requires the C-terminal ATPase catalytic site and depends on its phosphorylation state. We show that the phosphotransfer activity of SasA is essential for the generation of normal circadian gene expression in cyanobacterial cells. Numerical simulations suggest that circadian time information (free phosphorylated SasA) is released mainly by unphosphorylated KaiC during the late subjective night. PMID- 22512340 TI - Organotrifluoroborate hydrolysis: boronic acid release mechanism and an acid-base paradox in cross-coupling. AB - The hydrolysis of potassium organotrifluoroborate (RBF(3)K) reagents to the corresponding boronic acids (RB(OH)(2)) has been studied in the context of their application in Suzuki-Miyaura coupling. The "slow release" strategy in such SM couplings is only viable if there is an appropriate gearing of the hydrolysis rate of the RBF(3)K reagent with the rate of catalytic turnover. In such cases, the boronic acid RB(OH)(2) does not substantially accumulate, thereby minimizing side reactions such as oxidative homocoupling and protodeboronation. The study reveals that the hydrolysis rates (THF, H(2)O, Cs(2)CO(3), 55 degrees C) depend on a number of variables, resulting in complex solvolytic profiles with some RBF(3)K reagents. For example, those based on p-F-phenyl, naphthyl, furyl, and benzyl moieties are found to require acid catalysis for efficient hydrolysis. This acid-base paradox assures their slow hydrolysis under basic Suzuki-Miyaura coupling conditions. However, partial phase-splitting of the THF/H(2)O induced by the Cs(2)CO(3), resulting in a lower pH in the bulk medium, causes the reaction vessel shape, material, size, and stirring rate to have a profound impact on the hydrolysis profile. In contrast, reagents bearing, for example, isopropyl, beta styryl, and anisyl moieties undergo efficient "direct" hydrolysis, resulting in fast release of the boronic acid while reagents bearing, for example, alkynyl or nitrophenyl moieties, hydrolyze extremely slowly. Analysis of B-F bond lengths (DFT) in the intermediate difluoroborane, or the Swain-Lupton resonance parameter (R) of the R group in RBF(3)K, allows an a priori evaluation of whether an RBF(3)K reagent will likely engender "fast", "slow", or "very slow" hydrolysis. An exception to this correlation was found with vinyl-BF(3)K, this reagent being sufficiently hydrophilic to partition substantially into the predominantly aqueous minor biphase, where it is rapidly hydrolyzed. PMID- 22512341 TI - Bilateral endogenous endophthalmitis associated with methicillin sensitive Staphylococcus aureus (MSSA) related tenosynovitis: case report. AB - Endogenous endophthalmitis is a rare, devastating intraocular infection associated with poor outcome often from late diagnosis. We present a case report of acute onset bilateral endogenous endophthalmitis caused by Methicillin Sensitive Staphylococcus Aureus causing tenosynovitis of carpometacarpal joint in a 64 year old man with Type II Diabetes Mellitus. To the best of our knowledge, this is the first case report of endogenous endophthalmitis following tenosynovitis. This case also highlights the fact that prompt diagnosis and treatment is the key for good outcome. PMID- 22512342 TI - Re-infused lymphocyte dose does not influence disease control following upfront autologous stem cell transplantation for multiple myeloma. PMID- 22512343 TI - Eye gaze cannot be ignored (but neither can arrows). AB - Recent studies have tried to shed light on the automaticity of attentional shifts triggered by gaze and arrows with mixed results. In the present research, we aimed at testing a strong definition of resistance to suppression for orienting of attention elicited by these two cues. In five experiments, participants were informed with 100% certainty about the future location of a target they had to react to by presentation of either a direction word at the beginning of each trial or instructions at the beginning of each block. Gaze and arrows were presented before the target as uninformative distractors irrelevant for the task. The results showed similar patterns for gaze and arrows-namely, an interference effect when the distractors were incongruent with the upcoming target location. This suggests that the orienting of attention mediated by gaze and arrows can be considered as strongly automatic. PMID- 22512344 TI - Segmental motions of poly(ethylene glycol) chains adsorbed on Laponite platelets in clay-based hydrogels: a NMR investigation. AB - The segmental dynamics of poly(ethylene glycol) (PEG) chains adsorbed on the clay platelets within nanocomposite PEG/Laponite hydrogels was investigated over the tens of microseconds time scale, using combined solution and solid-state NMR approaches. In a first step, the time evolution of the molecular mobility displayed by the PEG chains following the addition to a Laponite aqueous dispersion was monitored during the aggregation of the clay disks and the hydrogel formation, by means of (1)H solution-state NMR. Part of the PEG repeat units were found to get strongly constrained during the gelation process. Comparisons between this time evolution of the PEG local dynamics in the PEG/Laponite/water systems and the increase of the macroscopic storage shear modulus, mainly governed by the assembling of the Laponite disks, indicate that the slowing down of the segmental motions arises from adsorbed PEG repeat units or chain portions strongly constrained between aggregated clay layers. In a second step, after completion of the gelation process, the molecular motions of the adsorbed PEG chains were probed by (1)H solid-state NMR spectroscopy. (1)H double-quantum experiments indicate that the adsorbed PEG repeat units, though reported to be frozen over a few tens of nanoseconds, still display significant reorientational motions over the tens of microseconds time scale. Using a comparison with a model system of amorphized PEG chains, the characteristic frequency of these segmental motions was found to range between 78.0 kHz and 100.7 MHz at 300 K. Interestingly, at this temperature, the level of reorientational motions detected for these adsorbed PEG chain portions was found to be as restricted as the one of bulk amorphous PEG chains, cooled at a slightly lower temperature (about 290 K). PMID- 22512345 TI - Preparation and characterization of aryl or heteroaryl(3-indolyl)methylium o benzenedisulfonimides. AB - An initial study has been accomplished into the synthetic feasibility of the preparation of diarylcarbenium salt via the direct coupling of aryl (or heteroaryl) aldehydes and arenes (or heteroaryl analogues) in the presence of a strong organic Bronsted acid. A number of stabilized aryl or heteroaryl(3 indolyl)carbenium ions, never previously prepared in the solid state, have been isolated in excellent yields as highly stable o-benzenedisulfonimide salts and have been fully characterized. Their purity has been proven by spectroscopic methods and chemical reduction with NaBH(4). An X-ray crystal structure analysis has been performed on one of the products: an azafulvenium species was shown to be the exclusive structure in the solid state. PMID- 22512346 TI - Synthesis, release ability and bioactivity evaluation of chitin beads incorporated with curcumin for drug delivery applications. AB - Spherical curcumin-incorporated chitin porous beads, with porosity exceeding 98%, were successfully fabricated by combining a coagulation method with freeze drying. Tween 20 was used to enhance the solubility of curcumin in the chitin beads during the incorporation step. The internal pores and the outer non-porous shell structure of the chitin beads determined the curcumin-releasing behaviour: the internal porous structure could dramatically increase the uptake of the releasing medium, while the non-porous outer skin layer dominated the slow releasing behaviour of curcumin. In addition, the amount of Tween 20 also played an important role in the release characteristic of curcumin from the chitin matrix. Bioactivity evaluation of the obtained chitin beads was conducted by immersion in a simulated body fluid (SBF). It could be postulated the entrapment of curcumin into the cores of Tween 20 micelles encapsulated in the chitin shell could be a promising candidate for drug delivery devices. PMID- 22512347 TI - Direct characterization of hydrophobic hydration during cold and pressure denaturation. AB - Cold and pressure denaturation are believed to have their molecular origin in hydrophobic interactions between nonpolar groups and water. However, the direct characterization of the temperature- and pressure-dependent variations of those interactions with atomistic simulations remains challenging. We investigated the role of solvent in the cold and pressure denaturation of a model hydrophobic 32 mer polymer by performing extensive coarse-grained molecular dynamics simulations including explicit solvation. Our simulations showed that the water-excluded folded state of this polymer is marginally stable and can be unfolded by heating or cooling, as well as by applying pressure, similar to globular proteins. We further detected essential population of a hairpin-like configuration prior to the collapse, which is consistently accompanied by a vapor bubble at the elbow of the kink. Increasing pressure suppresses formation of this vapor bubble by reducing water fluctuations in the hydration shell of the polymer, thus promoting unfolding. Further analysis revealed a slight reduction of water tetrahedrality in the polymer hydration shell compared to the bulk. Cold denaturation is driven by an enhanced tetrahedral ordering of hydration shell water than bulk water. At elevated pressures, the strikingly reduced fluctuations combined with the increase in interstitial water molecules in the polymer hydration shell contribute to weakening of hydrophobic interactions, thereby promoting pressure unfolding. These findings provide critical molecular insights into the changes in hydrophobic hydration during cold and pressure unfolding of a hydrophobic polymer, which is strongly related to the cold and pressure denaturation of globular proteins. PMID- 22512348 TI - tDCS-induced analgesia and electrical fields in pain-related neural networks in chronic migraine. AB - OBJECTIVE: We investigated in a sham-controlled trial the analgesic effects of a 4-week treatment of transcranial direct current stimulation (tDCS) over the primary motor cortex in chronic migraine. In addition, using a high-resolution tDCS computational model, we analyzed the current flow (electric field) through brain regions associated with pain perception and modulation. METHODS: Thirteen patients with chronic migraine were randomized to receive 10 sessions of active or sham tDCS for 20 minutes with 2 mA over 4 weeks. Data were collected during baseline, treatment and follow-up. For the tDCS computational analysis, we adapted a high-resolution individualized model incorporating accurate segmentation of cortical and subcortical structures of interest. RESULTS: There was a significant interaction term (time vs group) for the main outcome (pain intensity) and for the length of migraine episodes (ANOVA, P < .05 for both analyses). Post-hoc analysis showed a significant improvement in the follow-up period for the active tDCS group only. Our computational modeling studies predicted electric current flow in multiple cortical and subcortical regions associated with migraine pathophysiology. Significant electric fields were generated, not only in targeted cortical regions but also in the insula, cingulate cortex, thalamus, and brainstem regions. CONCLUSIONS: Our findings give preliminary evidence that patients with chronic migraine have a positive, but delayed, response to anodal tDCS of the primary motor cortex. These effects may be related to electrical currents induced in pain-related cortical and subcortical regions. PMID- 22512349 TI - Pyridine is an organocatalyst for the reductive ozonolysis of alkenes. AB - Whereas the cleavage of alkenes by ozone typically generates peroxide intermediates that must be decomposed in an accompanying step, ozonolysis in the presence of pyridine directly generates ketones or aldehydes through a process that neither consumes pyridine nor generates any detectable peroxides. The reaction is hypothesized to involve nucleophile-promoted fragmentation of carbonyl oxides via formation of zwitterionic peroxyacetals. PMID- 22512350 TI - SNO spectral counting (SNOSC), a label-free proteomic method for quantification of changes in levels of protein S-nitrosation. AB - S-Nitrosation plays an important role in regulation of protein function and signal transduction. Discovering S-nitrosated targets is a prerequisite for further functional study. However, current proteomic methods used to quantify S nitrosation are limited in their applicability to certain types of samples, or by the need for special reagents and complex procedures to obtain the results. Here we devised a label-free proteomic method for quantification of changes in the level of protein S-nitrosation on the basis of a spectral counting strategy, called S-nitrosothiol (SNO) spectral counting (SNOSC). With this method, samples can be from any source (cells, tissues); there is no need for labelling reagents or procedures, and the results yield quantitative information. Moreover, as it is based on the irreversible biotinylation procedure (IBP) for S-nitrosation protein enrichment, false positive targets caused by the interference of intermolecular disulphide bonds are ruled out. Using SNOSC we studied S-nitrosation in the cell line RAW264.7 induced exogenously with S-nitrosoglutathione (GSNO), or induced endogenously by lipopolysaccharides/interferon-gamma (LPS/IFN-gamma). We detected a significant increase in S-nitrosation of 50 proteins after exogenous induction and 17 proteins after endogenous induction. We thus demonstrate that SNOSC is a widely applicable proteomic method for fast screening of SNO proteins. PMID- 22512351 TI - Clinal variation in the non-acclimated and cold-acclimated freezing tolerance of Arabidopsis thaliana accessions. AB - Arabidopsis thaliana is a geographically widely spread species consisting of local accessions differing both genetically and phenotypically. These differences may constitute environmental adaptations and a latitudinal cline in freezing tolerance has been shown previously. Many plants, including Arabidopsis, exhibit increased freezing tolerance after cold exposure (cold acclimation). Here we present evidence for geographical clines (both latitudinal and longitudinal) in acclimated (ACC) and non-acclimated (NA) freezing tolerance, estimated from electrolyte leakage measurements on 54 accessions. Leaf Pro contents were not correlated with freezing tolerance, while sugar contents (Glc, Fru, Suc, Raf) were in the ACC, but not the NA state. Expression levels of 14 cold-induced genes were investigated before and after 2 weeks of cold acclimation by quantitative RT PCR. Expression of the CBF1, 2 and 3 genes was not correlated with freezing tolerance. The expression of some CBF-regulated (COR) genes, however, was correlated specifically with ACC freezing tolerance. A tight correlation between CBF and COR gene expression was only observed under non-acclimating conditions, where CBF and COR expression were also correlated with the expression of PRR5, a component of the circadian clock. Collectively, this study sheds new light on the molecular determinants of plant-freezing tolerance and cold acclimation and their geographical dependence. PMID- 22512352 TI - Novel coordination frameworks incorporating the 4,4'-bipyrazolyl ditopic ligand. AB - The reaction of the rigid spacer 4,4'-bipyrazole (H(2)BPZ) with late transition metals, either following conventional routes or under solvothermal conditions, afforded the coordination polymers [M(BPZ)].Solv (M = Zn, 1; Co, 2; Cd, 3; Hg, 4; Cu, 5; Ni, 6; Pd, 7; Solv = DMF, 3; MeCN, 5 and 6; H(2)O, 7), [Cu(H(2)BPZ)(2)(NO(3))(2)] (8), and [Cd(H(2)BPZ)(CH(3)COO)(2)] (9). State-of-the art laboratory powder diffraction methods allowed to disclose the isomorphous character of 1 and 2, as well as of 5 and 6, which feature 3D porous networks containing 1D channels of square and rhombic shape, respectively. 3, crystallizing in the relatively rare P6(1)22 space group, consists of homochiral helices of octahedral Cd(II) ions, packing in bundles mutually linked by "radial", nonplanar BPZ ligands. Finally, the dense species 8 and 9 contain parallel 2D layers of square and rectangular meshes, respectively. Thermogravimetric analyses witnessed the relevant thermal robustness of all the [M(BPZ)] materials [except the mercury(II) derivative], which are stable in air at least up to 300 degrees C, with the zinc(II) derivative decomposing only around 450 degrees C. Variable-temperature powder diffraction experiments highlighted the permanent porosity of 1-3, 5, and 6, retained along consecutive temperature cycles in all cases but 3. When probed with N(2) at 77 K, 1-3 and 5-7 showed Brunauer-Emmett-Teller and Langmuir specific surface areas in the ranges 314(2)-993(11) and 509(16)-1105(1) m(2)/g, respectively. PMID- 22512353 TI - Reducing maternal mortality: better monitoring, indicators and benchmarks needed to improve emergency obstetric care. Research summary for policymakers. AB - Several limitations of emergency obstetric care (EmOC) indicators and benchmarks are analysed in this short paper, which synthesises recent research on this topic. A comparison between Sri Lanka and Zambia is used to highlight the inconsistencies and shortcomings in current methods of monitoring EmOC. Recommendations are made to improve the usefulness and accuracy of EmOC indicators and benchmarks in the future. PMID- 22512354 TI - Relationships between higher-level functional capacity and dental health behaviors in community-dwelling older adults. AB - OBJECTIVE: The aim of the present study was to elucidate relationships between higher-level functional capacity and dental health behaviours in community dwelling older adults. BACKGROUND: In ageing society, it is necessary to promote oral health in the elderly, because good oral health is a significant contributing factor to good general health. Higher-level functional capacity has been considered a crucial factor for successful independent living in the elderly. We hypothesised that functional capacity is a significant indicator of dental health behaviours. METHODS: Three hundred and thirty-eight adults aged 65 years or older were enrolled in this study. Higher-level functional capacity was evaluated using the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-index). Univariate and multivariate models were constructed with dental health behaviours, such as regular visits to a dentist, brushing frequency and use of extra cleaning devices, as the dependent variable, and the total TMIG index score and its subcategory scores as the principal independent variable. RESULTS: Univariate logistic regression analysis demonstrated a significant correlation between low TMIG-index and 'intellectual activity' subcategory scores to lack of regular visits to a dentist and not using extra cleaning devices. Using a multivariate model, significant relationships remained after adjusting for a number of variables including demographics, medical status, lifestyle and number of remaining teeth. CONCLUSION: Intellectual activity of higher-level functional capacity may be an accurate indicator of dental health behaviours in community-dwelling older adults. Intellectual activity should be taken into consideration to effectively promote oral health behaviours and oral hygiene in elderly persons living independently. PMID- 22512355 TI - Enhanced motor learning in older adults is accompanied by increased bilateral frontal and fronto-parietal connectivity. AB - We recently demonstrated that older adults can benefit as much as younger adults from learning skills in an interleaved manner. Here we investigate whether optimized learning through interleaved practice (IP) is associated with changes in inter-regional brain connectivity and whether younger and older adults differ in such brain-behavior correlations. Younger and older adults practiced a set of three 4-element motor sequences in a repetitive or in an interleaved order for 2 consecutive days. Retention of the practiced sequences was evaluated 3 days after practice with functional images acquired simultaneously. A within-subject design was used so that subjects practiced sequences in the other condition (repetitive or interleaved) 2-4 weeks later. Using the psychophysiological interaction (PPI) analysis approach, we found that IP led to higher functional connectivity between the right and left dorsal lateral prefrontal cortex (DLPFC) and between the dorsal premotor cortex (PMd) and inferior parietal lobule (IPL) in older adults. Moreover, increased connectivity between these regions was significantly associated with the learning benefits of IP. In contrast, in younger adults, enhanced learning as a result of IP was associated with increased connectivity between DLPFC and the supplementary motor area (SMA) and the inferior frontal gyrus. These data suggest that though younger and older gain similar behavioral benefits from interleaved training, aging may alter the operation of brain networks underlying such optimized learning. PMID- 22512356 TI - Electromechanical actuator with controllable motion, fast response rate, and high frequency resonance based on graphene and polydiacetylene. AB - Although widely investigated, novel electromechanical actuators with high overall actuation performance are still in urgent need for various practical and scientific applications, such as robots, prosthetic devices, sensor switches, and sonar projectors. In this work, combining the properties of unique environmental perturbations-actuated deformational isomerization of polydiacetylene (PDA) and the outstanding intrinsic features of graphene together for the first time, we design and fabricate an electromechanical bimorph actuator composed of a layer of PDA crystal and a layer of flexible graphene paper through a simple yet versatile solution approach. Under low applied direct current (dc), the graphene-PDA bimorph actuator with strong mechanical strength can generate large actuation motion (curvature is about 0.37 cm(-1) under a current density of 0.74 A/mm(2)) and produce high actuation stress (more than 160 MPa/g under an applied dc of only 0.29 A/mm(2)). When applying alternating current (ac), this actuator can display reversible swing behavior with long cycle life under high frequencies even up to 200 Hz; significantly, while the frequency and the value of applied ac and the state of the actuators reach an appropriate value, the graphene-PDA actuator can produce a strong resonance and the swing amplitude will jump to a peak value. Moreover, this stable graphene-PDA actuator also demonstrates rapidly and partially reversible electrochromatic phenomenon when applying an ac. Two mechanisms-the dominant one, electric-induced deformation, and a secondary one, thermal-induced expansion of PDA-are proposed to contribute to these interesting actuation performances of the graphene-PDA actuators. On the basis of these results, a mini-robot with controllable direction of motion based on the graphene PDA actuator is designed to illustrate the great potential of our discoveries for practical use. Combining the unique actuation mechanism and many outstanding properties of graphene and PDA, this novel kind of graphene-PDA actuator exhibits compelling advantages to traditional electromechanical actuation technology and may provide a new avenue for actuation applications. PMID- 22512357 TI - Chiroptical dissymmetries in fluorescence excitation from single molecules of (M 2) helicene dimers. AB - We report on the single-molecule chiroptical properties of "right"-handed bridged triaryl amine helicene dimers, MH2. Using an experimental setup to precisely define the circular excitation polarization at the sample plane, we investigated the circular dichroic response in luminescence from individual molecules in which induced ellipticity from microscope optics is minimized. Our results comparing circular anisotropies in fluorescence excitation from MH2 and perylene diimide (PDI), an achiral, centrosymmetric chromophore, demonstrate a significant reduction in the breadth of the distribution of circular dissymmetry parameters obtained from modulation of the circularly polarized excitation source (457 nm). For PDI, we observe a symmetric distribution of circular anisotropy parameters centered about zero, with a fwhm of 0.25. For MH2, we observe an asymmetric distribution peaked at g = -0.09, with a slightly larger width as the corresponding PDI distribution. These results indicate that the large dissymmetry parameters (|g| > 0.5) in fluorescence excitation described in our original report (Hassey, R.; et al. Chirality 2008, 20, 1039-1046 and Hassey, R.; et al. Science 2006, 314, 1437-1439) were indeed affected by (at the time, unknown) linear polarization artifacts. However, the present results on MH2 provide compelling evidence for single-molecule circular dissymmetries much larger than solution or thin-film ensemble values, defined primarily by the enhanced rotatory strength (relative to the monomer), and restricted orientation at the sample surface. PMID- 22512358 TI - Nitric oxide is responsible for oxidative skin injury and modulation of cell proliferation after 24 hours of UVB exposures. AB - Nitric oxide (NO) is produced by various mammalian cells and plays a variety of regulatory roles in normal physiology and in pathological processes. This article provides evidence regarding the participation of NO in UVB-induced skin lesions and in the modulation of skin cell proliferation following UVB skin irradiation. Hairless mice were subjected to UVB irradiation for 3 hours and the skin evaluated immediately, 6 and 24 hours postirradiation. The skin lipid peroxidation, and NO levels evaluated by chemiluminescence and inducible nitric oxide synthase (iNOS) and nitrotyrosine immunolabelling increased significantly 24 hours after irradiation and decreased under the treatment with aminoguanidine (AG). On the other hand, cell proliferation markers, PCNA and VEGF showed a strong labelling index when AG was used. The data indicate that NO mediates, at least in part, the lipid peroxidation and protein nitration and also promotes the down regulation of factors involved in cell proliferation. This work shows that the NO plays an important role in the oxidative stress damage and on modulation of cell proliferation pathways in UVB irradiated skin. PMID- 22512359 TI - Two novel heterometallic chains featuring Mn(II) and Na(I) ions in trigonal prismatic geometries alternately linked to octahedral Mn(IV) ions: synthesis, structures, and magnetic behavior. AB - Two new one-dimensional heterometallic complexes, [Mn(3)Na(L)(4)(CH(3)CO(2))(MeOH)(2)](ClO(4))(2).3H(2)O (1), [Mn(3)Na(L)(4)(CH(3)CH(2)CO(2))(MeOH)(2)](ClO(4))(2).2MeOH.H(2)O (2) [LH(2) = 2 methyl-2-(2-pyridyl)propane-1,3-diol], have been synthesized and characterized by X-ray crystallography. Both complexes feature Mn(II) and Na(I) ions in trigonal prismatic geometries that are linked to octahedral Mn(IV) ions by alkoxy bridges. Variable-temperature direct- and alternating-current magnetic susceptibility data indicated a spin ground state of S = 11/2 for both complexes. Density functional theory calculations performed on 1 supported this conclusion. PMID- 22512360 TI - Adult polycystic kidney disease: who needs hospital follow-up? AB - Clinical data from 120 adult patients with genetically undifferentiated polycystic kidney disease who had been followed up for more than 3 months (range 3-172) were reviewed in order to try to identify clinical indicators that might predict deterioration in renal function. They were split into two groups dependent on whether annualized fall in estimated glomerular filtration rate (DeltaeGFR mL/min/1.73 m(2) /year) was statistically significant or not. Only 26 patients (22%) had a statistically significantly decreasing DeltaeGFR with a median decrease of -2.6 mL/min/1.73 m(2) /year (range -6.2 to -0.7). There was no difference in initial age, gender, or racial distributions between the groups or in initial eGFR. Follow-up was longer (median 86, range 23-172 months vs. 46, range 3-161 months; P = 0.002) and initial blood pressure values tended to be lower (with mean systolic values of 128 vs. 148 mm Hg; P = 0.02) in the group with statistically significant fall in DeltaeGFR, but this trend failed to achieve an a priori level of statistical significance. However, the proportion of patients with initial systolic blood pressure <= 144 developing a statistically significant fall in DeltaeGFR was 0.26 (95% confidence interval = 0.13 to 0.45). No differences were found in initial hemoglobin or cholesterol concentrations. Overall, the annualized rate of decrease in eGFR tended to be greater in those with the higher initial eGFR (P = 0.04), but correlation was poor (rho(2) = 0.04) and failed to achieve an a priori level of statistical significance. No statistically significant correlation was found between DeltaeGFR and any other variable. Only those patients with polycystic kidney disease with a statistically significant annualized decrease in eGFR may need to be referred for hospital follow-up in the renal clinic. This simple selection would reduce referrals by 78%. PMID- 22512361 TI - Wrist activity monitor counts are correlated with dynamic but not static assessments of arm elevation exposure made with a triaxial accelerometer. AB - There is evidence in the literature of a link between workplace arm elevation exposure and atraumatic shoulder injuries. However, there are several methods that can be used to assess this exposure. The goal of the present study was to compare the outcomes of an activity monitor attached to the wrist and a triaxial accelerometer mounted on the humerus. Twenty-one workers wore both sensors over the course of a full workday. While the activity monitor data was not significantly correlated with any static humeral parameters, it was strongly correlated with all dynamic parameters. The use of a simple, commercially available activity monitor might offer an inexpensive alternative for the assessment of a large number of subjects over multiple workdays to determine the relationship between dynamic motion and occupation shoulder injuries in the future. PRACTITIONER SUMMARY: Arm overuse has been linked to occupation-related shoulder injuries. An activity monitor attached to the wrist and a triaxial accelerometer mounted on the humerus were compared in a field trial. The results demonstrate that, under certain conditions, a commercially available activity monitor might be a useful tool for exposure assessment. PMID- 22512362 TI - Cellular microfabrication: observing intercellular interactions using lithographically-defined DNA capture sequences. AB - Previous reports have shown that synthetic DNA strands can be attached to the plasma membrane of living cells to equip them with artificial adhesion "receptors" that bind to complementary strands extending from material surfaces. This approach is compatible with a wide range of cell types, offers excellent capture efficiency, and can potentially be used to create complex multicellular arrangements through the use of multiple capture sequences. In this work, we apply an aluminum "lift off" lithography method to allow the efficient generation of complex patterns comprising different DNA sequences. The resulting surfaces are then demonstrated to be able to capture up to three distinct types of living cells in specific locations. The utility of this approach is demonstrated through the observation of patterned cells as they communicate by diffusion-based paracrine signaling. It is anticipated that the ability of this technique to create virtually any type of 2D heterogeneous cell pattern should prove highly useful for the examination of key questions in cell signaling, including stem cell differentiation and cancer metastasis. PMID- 22512363 TI - Methadone and buprenorphine for the management of opioid dependence in pregnancy. AB - This article provides an overview and discussion of the collective maternal, fetal and neonatal outcome research on women maintained on methadone or buprenorphine during pregnancy. Its focus is on an assessment of the comparative effectiveness of methadone and buprenorphine pharmacotherapy, with particular attention given to recent findings from the literature. Recommendations for clinical practice are outlined, and directions for future research are presented. Findings from comparative studies of methadone and buprenorphine underscore the efficacy of both medications in preventing relapse to illicit opioid use in the treatment of opioid-dependent pregnant patients, as well as the simplicity of induction onto methadone and patient retention while receiving such therapy. Fetal monitoring suggests that buprenorphine results in less fetal cardiac and movement suppression than does methadone. The clinical implications of these findings need future exploration. For the neonate, evidence from studies using a wide range of designs, including retrospective chart reviews, prospective observational studies, and randomized clinical trials, show consistent results, with prenatal exposure to buprenorphine resulting in less severe neonatal abstinence syndrome relative to methadone. Any medication given to pregnant women should be prescribed only after considering the risk : benefit ratio for the maternal-fetal dyad. Medication choices for each opioid-dependent patient during pregnancy need to be made on a patient-by-patient basis, taking into consideration the patient's opioid dependence history, previous and current treatment experiences, medical circumstances and treatment preferences. Moreover, for a full remission of opioid addiction to be sustainable, both post-partum and across the lifespan, treatment providers must not rely solely on medication to treat their patients but should also utilize women-specific comprehensive treatment models that address the underlying multifaceted complexities of their patient's lives. PMID- 22512364 TI - Drug therapy of hypercholesterolaemia in children and adolescents. AB - Cardiovascular disease (CVD) remains the leading cause of death and morbidity in the world. The origins of atherosclerosis and subsequent CVD begin in childhood. In order to prevent CVD, children and adolescents at high risk for premature atherosclerosis should be identified and treated as early as possible. Hypercholesterolaemia is a major risk factor for atherosclerosis. Childhood hypercholesterolaemia can be either primary, due to hereditary disorders such as familial hypercholesterolaemia (FH) and familial combined hyperlipidaemia (FCHL), or secondary due to obesity, diabetes mellitus or nephrotic syndrome. Current guidelines suggest screening for hypercholesterolaemia between the ages of 2 and 10 years. Treatment strategies include lifestyle interventions involving dietary changes and increased physical activity. If these interventions are insufficient in lowering serum low-density lipoprotein cholesterol (LDL-C) levels, pharmacological therapy should be considered from the age of 8 years. Currently, statins are the preferred initial pharmacological therapy and have proven to be both efficient and well tolerated. However, long-term data on safety, and regular monitoring of those patients treated with statins, are still required, because in children with primary hypercholesterolaemia, treatment should be continued for life. PMID- 22512368 TI - Up north and down south: implicit associations between topography and cardinal direction. AB - Route planners show a reliable tendency to select south- relative to north-going routes between two horizontally (east/west) aligned landmarks, suggesting the application of a north-is-up heuristic (Brunye, Mahoney, Gardony, & Taylor, 2010). The source of this north-is-up bias remains unknown, and there is no strong evidence to suggest that it is due to explicit strategy use. In four experiments, we attempt to further elucidate the source of this effect by testing whether it can be attributed to implicit associations between cardinal direction (north/south) and topography (mountainous/level terrain). Experiments 1 and 2 used an adapted Implicit Association Test and demonstrate automatically activated judgements that associate north with mountainous and south with relatively level terrain. Experiment 3 rules out the possibility that this effect is due to the local topography of New England by replicating in participants from the topographically dissimilar Midwestern United States. Finally, Experiment 4 tests the relative contribution of implicit versus explicit associations between cardinal direction and topography in predicting route-planning asymmetries; we show that implicit associations are a stronger predictor of southern route biases than explicit processes. Overall, results demonstrate that the conceptualization of space can be driven by physically unfounded implicit associations between cardinal directions and topographical features, and these associations are at least partially responsible for southern route preferences. PMID- 22512366 TI - Etravirine: a review of its use in the management of treatment-experienced patients with HIV-1 infection. AB - Etravirine (Intelence(r)) is an orally administered next-generation non nucleoside reverse transcriptase inhibitor (NNRTI). It is approved for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and are harbouring HIV-1 strains resistant to other antiretroviral (ARV) agents. In the US, etravirine must be used in combination with other ARV agents; in the EU, it must be used in combination with other ARV agents that include a boosted HIV-1 protease inhibitor. Etravirine shows good activity in vitro against most wild-type strains of HIV-1, as well as against several strains resistant to available NNRTIs. Furthermore, etravirine appears to present a higher barrier than first-generation NNRTIs against the development of drug resistance. Whereas the presence of a single mutation is sufficient to affect the virological response to efavirenz or nevirapine, the resistance profile of etravirine is more complex and a prediction of virological response may be calculated using a weighted genotypic score. Importantly, the most prevalent NNRTI-associated mutation, K103N, alone does not affect the etravirine response. In two identically designed randomized clinical trials, the addition of etravirine to an optimized background therapy (OBT) regimen improved virological responses to a greater extent than placebo plus OBT following 24 weeks' treatment in highly treatment-experienced adult patients with HIV-1 infection who had evidence of viral replication (HIV-1 RNA levels of >5000 copies/mL at baseline). Furthermore, pre-planned pooled analyses of the trials at 48 and 96 weeks showed that etravirine plus OBT provided durable virological suppression. Consistently higher virological response rates were observed for recipients of etravirine plus OBT than placebo plus OBT in a pre-specified subgroup analysis of baseline viral loads, CD4+ cell counts, HIV-1 subtype or the composition of background ARV therapy. Greater improvements from baseline in immunological outcomes were also observed for recipients of etravirine plus OBT compared with those receiving placebo plus OBT over the 96-week treatment period of the trials. When used as part of an OBT regimen in trials of up to 96 weeks duration, etravirine was well tolerated with an overall tolerabilty profile similar to that of placebo. The only treatment-emergent adverse event that occurred with a higher frequency for recipients of etravirine compared with placebo plus OBT was rash. In highly treatment-experienced patients with HIV-1 infection and evidence of viral replication, the addition of etravirine to an OBT regimen provides an effective and well tolerated treatment that leads to improvements in both virological and immunological outcomes. PMID- 22512370 TI - Systematic reviews of optometric interventions. PMID- 22512371 TI - An introduction to systematic reviews and meta-analyses in health care. AB - Important issues in medical research are often examined in a number of studies, sometimes using different study designs. Data from such studies are often reviewed to provide a consensus in support or arguing against a particular hypothesis, such as the use of a new therapy/treatment or public health policy. However, it is important to recognise that while reviews can provide a rapid synthesis of the findings on a given issue, they may not represent a panacea of evidence. Evidence they provide is heavily dependent on the quality of studies that contribute to that review. Reviews of studies of good quality will provide stronger evidence for the research question under investigation, compared to reviews of studies with weaker methodology. Reviewers who 'cherry pick' studies to be included may bias findings towards a preconceived hypothesis. Hence, it is important when reviewing evidence that all studies on a given topic are identified and included where possible, i.e. the review is systematic, reproducible and representative of the totality of evidence; a so called 'systematic review'. This article aims to familiarise those in the ophthalmic sector with methods/guidelines used to improve the quality of studies and systematic reviews. It will also outline how numerical data obtained from a systematic review can be combined using statistical methods called 'meta analysis'. By combining numerical estimates from different studies we can be more precise about the estimate for an effect or outcome of interest. PMID- 22512365 TI - Probiotics in the management of inflammatory bowel disease: a systematic review of intervention studies in adult patients. AB - INTRODUCTION: Mounting evidence suggests an important role for the intestinal microbiota in the chronic mucosal inflammation that occurs in inflammatory bowel disease (IBD), and novel molecular approaches have further identified a dysbiosis in these patients. Several mechanisms of action of probiotic products that may interfere with possible aetiological factors in IBD have been postulated. OBJECTIVE: Our objective was to discuss the rationale for probiotics in IBD and to systematically review clinical intervention studies with probiotics in the management of IBD in adults. METHODS: A systematic search was performed in PubMed up to 1 October 2011, using defined keywords. Only full-text papers in the English language addressing clinical outcomes in adult patients were included. The 41 eligible studies were categorized on disease type (ulcerative colitis [UC] with/without an ileo-anal pouch and Crohn's disease [CD]) and disease activity. Pooled odds ratios were only calculated per probiotic for a specific patient group when more than one randomized controlled trial was available. RESULTS: Well designed randomized controlled trials supporting the application of probiotics in the management of IBD are still limited. Meta-analyses could only be performed for a limited number of studies revealing overall risk ratios of 2.70 (95% CI 0.47, 15.33) for inducing remission in active UC with Bifido-fermented milk versus placebo or no additive treatment (n = 2); 1.88 (95% CI 0.96, 3.67) for inducing remission in active UC with VSL#3 versus placebo (n = 2); 1.08 (95% CI 0.86, 1.37) for preventing relapses in inactive UC with Escherichia coli Nissle 1917 versus standard treatment (n = 3); 0.17 (95% CI 0.09, 0.33) for preventing relapses in inactive UC/ileo-anal pouch anastomosis (IPAA) patients with VSL#3 versus placebo; 1.21 (95% CI 0.57, 2.57) for preventing endoscopic recurrences in inactive CD with Lactobacillus rhamnosus GG versus placebo (n = 2); and 0.93 (95% CI 0.63, 1.38) for preventing endoscopic recurrences in inactive CD with Lactobacillus johnsonii versus placebo (n = 2). CONCLUSION: Further well designed studies based on intention-to-treat analyses by several independent research groups are still warranted to support the promising results for E. coli Nissle in inactive UC and the multispecies product VSL#3 in active UC and inactive pouch patients. So far, no evidence is available to support the use of probiotics in CD. Future studies should focus on specific disease subtypes and disease location. Further insight into the aetiology of IBD and the mechanisms of probiotic strains will aid in selecting probiotic strains for specific disease entities and disease locations. PMID- 22512372 TI - Optical quality for keratoconic eyes with conventional RGP lens and simulated, customised contact lens corrections: a comparison. AB - PURPOSE: To compare monochromatic aberrations of keratoconic eyes when uncorrected, corrected with spherically-powered RGP (rigid gas-permeable) contact lenses and corrected using simulations of customised soft contact lenses for different magnitudes of rotation (up to 15 degrees ) and translation (up to 1mm) from their ideal position. METHODS: The ocular aberrations of examples of mild, moderate and severe keratoconic eyes were measured when uncorrected and when wearing their habitual RGP lenses. Residual aberrations and point-spread functions of each eye were simulated using an ideal, customised soft contact lens (designed to neutralise higher-order aberrations, HOA) were calculated as a function of the angle of rotation of the lens from its ideal orientation, and its horizontal and vertical translation. RESULTS: In agreement with the results of other authors, the RGP lenses markedly reduced both lower-order aberrations and HOA for all three patients. When compared with the RGP lens corrections, the customised lens simulations only provided optical improvements if their movements were constrained within limits which appear to be difficult to achieve with current technologies. CONCLUSIONS: At the present time, customised contact lens corrections appear likely to offer, at best, only minor optical improvements over RGP lenses for patients with keratoconus. If made in soft materials, however, these lenses may be preferred by patients in term of comfort. PMID- 22512374 TI - Accuracy of intraocular lens power calculation using partial coherence interferometry in patients with high myopia. AB - PURPOSE: Ultrasound-A-scan-biometry intraocular lens power calculation for cataract surgery sometimes shows lack of accuracy in patients with high myopia. The purpose of this retrospective study was to assess the accuracy of lens power calculation with optical biometry using the Zeiss IOLMaster across a large range of myopia levels. METHODS: We included 37 consecutive, myopic eyes with an axial length >26.5mm (31 patients, 62+/-13years old, average preoperative refraction of -14.46+/-6.61D, range -3.5 to -32.0D which underwent phacoemulsification and implantation of an intraocular lens following biometry using the IOLMaster. For lens power calculation, the Haigis formula was used in all cases. For comparison, refraction was back-calculated using the SRK/T and Holladay I formulae. RESULTS: The preoperative mean axial length was 29.37+/-2.44 mm with a range of 26.50 35.52mm. Thirty eyes (81.1%) showed a postoperative spherical equivalent which differed 1.00D or less from the predicted value, in 20 cases (54.1%) the postoperative refractive error was within+/-0.50D. The mean absolute error (MAE) was 0.70+/-0.59D (Holladay I, 0.85+/-0.68; SRK/T, 1.01+/-0.61D). CONCLUSIONS: Optical biometry for intraocular lens power calculation seems to deliver reliable results for cataract surgery in patients with high myopia, although our data describe an increasing lack of accuracy beyond an axial length of 30mm. The Haigis formula provided the best predictability of postoperative refractive outcome for myopic eyes in general. PMID- 22512373 TI - Retinal measurements using time domain OCT imaging before and after myopic Lasik. AB - PURPOSE: To compare retinal measurements obtained by time domain optical coherence tomography (OCT) devices before and after myopic laser in situ keratomileusis (Lasik) and to assess the interaction of Lasik and retinal structures as measured by time domain OCT. METHODS: Fifty-three patients randomly selected participated in the study. Only the right eye of each subject was included in the study. Comprehensive ophthalmic examinations including refraction examination, slit lamp examination, dilated fundus examination, corneal topography, corneal thickness, intraocular pressure, and retinal Stratus OCT scans were acquired for each patient before myopic Lasik and 3months after surgery. RESULTS: Total macular volume (TMV) changed significantly between preoperative and postoperative measurements (p=0.003). No statistical differences were found between preoperative and postoperative disc area, rim area, cup/disk vert. ratio, or average foveal thickness (p>0.05). The variation in TMV correlated significantly with the change in spherical refraction equivalent, maximal corneal curvature, minimal corneal curvature, and corneal ablation depth. CONCLUSIONS: Most retinal OCT measurements undergo no obvious changes after myopic Lasik. The increased TMV measurements we measured after Lasik seem to be correlated with the alteration in corneal shape. The exact mechanism for this change is not clear, while we examined several possibilities including subclinical macular oedema, magnification changes, errors in OCT analysis and IOP, none of these seem to be a likely cause. PMID- 22512375 TI - Ethnicity and paediatric optic discs. PMID- 22512377 TI - Dopamine stimulates propagation of Toxoplasma gondii tachyzoites in human fibroblast and primary neonatal rat astrocyte cell cultures. AB - Toxoplasma gondii is an obligate intracellular parasite often found in the brain of humans. Research has shown a correlation between prevalence of antibody titers to T. gondii and psychological illness in humans. Recent studies indicate that individuals seropositive for T. gondii antibodies are more likely to develop psychotic disorders including schizophrenia, which is associated with changes in the dopamine neurotransmitter system. Dopamine in the brain may play a role in proliferation, chemoattraction, infection efficiency, or stage conversion of T. gondii . Because tachyzoites are the first developmental stage to reach the brain, the present study was conducted to determine the effects of dopamine on their development in vitro. In human fibroblast host cells, dopamine was added at either 100 nM or 250 nM to cell culture media, and the numbers of tachyzoites produced at 48 hr were determined and compared to vehicle-treated controls. An increase of tachyzoite numbers and increased destruction in cell monolayer were observed at both concentrations of dopamine. Dopamine used at 250 nM caused a significant (P < 0.05) increase in tachyzoites counts compared to controls. Dopamine antagonists (10 MUM) did not significantly alter dopamine-stimulated tachyzoite production in human fibroblasts. In primary neonatal rat astrocyte cell cultures, dopamine (200 MUM) significantly (P < 0.05) increased numbers of intracellular tachyzoites after 24 hr. The role that this increase plays in tachyzoite production under the stimulus of dopamine in the modulation of neural infection in humans awaits further studies. PMID- 22512378 TI - Expanding provider-initiated HIV testing at STI clinics in China. AB - Despite expanding sexually transmitted epidemics in South China, the majority of patients presenting to sexually transmitted infection (STI) clinics are not routinely screened for HIV infection. Identifying barriers to offering HIV testing among STI care providers is an important public health priority. The aim of this study was to investigate the frequency of offering HIV testing among STI care providers in South China and reported physician barriers to offering HIV testing. More detailed operational data regarding HIV test offer frequency and barriers to testing may enhance routine HIV testing at STI clinics. A sample of 62 STI care providers within the Pearl River Delta Region of South China completed a survey including socio-demographic and training background information (including sex, age, medical education, year of terminal medical degree, and HIV-specific training), reasons for not offering HIV testing routinely, and physical examination and sexual history taking practices. Frequency of offering HIV testing was calculated based on reports from research assistants and operational data. STI care providers offered HIV testing to 3011/10,592 (28.4%) of their patients. There was substantial variability across providers in the frequency of offering testing, ranging from 3 to 100%. None of the identified physician factors were associated with offering HIV testing 100% of the time in the multivariate model. The most commonly physician reported barriers to HIV testing included: (1) low perceived prevalence of disease and (2) not recommended by current guidelines. Forty-seven providers (76%) reported asking about same sex behaviors rarely or never. Further research on HIV screening practices of STI care providers may help scale up HIV provider initiated testing and counseling programs. PMID- 22512380 TI - Trichoderma harzianum enhances antioxidant defense of tomato seedlings and resistance to water deficit. AB - Some plant-symbiotic strains of the genus Trichoderma colonize roots and induce profound changes in plant gene expression that lead to enhanced growth, especially under biotic and abiotic stresses. In this study, we tested the hypothesis that one of the protective mechanisms enhanced by T. harzianum T22 colonization is the antioxidant defense mechanism. Having established that strain T22 modulates the expression of the genes encoding antioxidant enzymes, the status of antioxidant defense of tomato seedlings in response to colonization by T22 and water deficit was investigated. Total ascorbate or glutathione levels were not affected by either stimuli, but under water deficit, antioxidant pools became more oxidized (lower ratios of reduced to oxidized forms), whereas colonized plants maintained redox state as high as or higher than unstressed and untreated plants. The enhanced redox state of colonized plants could be explained by their higher activity of ascorbate and glutathione-recycling enzymes, higher activity of superoxide dismutase, catalase, and ascorbate peroxidase, in both root and shoot throughout the experiment. Similar enzymes were induced in uncolonized plants in response to water-deficit stress but to a lower extent when compared with colonized plants. This orchestrated enhancement in activity of reactive oxygen species (ROS)-scavenging pathways in colonized plants in response to stress supports the hypothesis that enhanced resistance of colonized plants to water deficit is at least partly due to higher capacity to scavenge ROS and recycle oxidized ascorbate and glutathione, a mechanism that is expected to enhance tolerance to abiotic and biotic stresses. PMID- 22512379 TI - Ethylene signaling pathway and MAPK cascades are required for AAL toxin-induced programmed cell death. AB - Programmed cell death (PCD), known as hypersensitive response cell death, has an important role in plant defense response. The signaling pathway of PCD remains unknown. We employed AAL toxin and Nicotiana umbratica to analysis plant PCD. AAL toxin is a pathogenicity factor of the necrotrophic pathogen Alternaria alternata f. sp. lycopersici. N. umbratica is sensitive to AAL toxin, susceptible to pathogens, and effective in Tobacco rattle virus-based virus-induced gene silencing (VIGS). VIGS analyses indicated that AAL toxin-triggered cell death (ACD) is dependent upon the mitogen-activated protein (MAP) kinase kinase MEK2, which is upstream of both salicylic acid-induced protein kinase (SIPK) and wound induced protein kinase (WIPK) responsible for ethylene (ET) synthesis. ET treatment of MEK2-silenced N. umbratica re-established ACD. In SIPK- and WIPK silenced N. umbratica, ACD was compromised and ET accumulation was not observed. However, in contrast to the case of MEK2-silenced plants, ET treatment did not induce cell death in SIPK- and WIPK-silenced plants. This work showed that ET dependent pathway and MAP kinase cascades are required in ACD. Our results suggested that MEK2-SIPK/WIPK cascades have roles in ET biosynthesis; however, SIPK and WIPK have other roles in ET signaling or another pathway leading to cell death by AAL toxin. PMID- 22512381 TI - Dual regulatory roles of the extended N terminus for activation of the tomato MI 1.2 resistance protein. AB - Plant resistance (R) proteins mediate race-specific immunity and initiate host defenses that are often accompanied by a localized cell-death response. Most R proteins belong to the nucleotide binding-leucine-rich repeat (NB-LRR) protein family, as they carry a central NB-ARC domain fused to an LRR domain. The coiled coil (CC) domain at the N terminus of some solanaceous NB-LRR proteins is extended with a solanaceae domain (SD). Tomato Mi-1.2, which confers resistance against nematodes, white flies, psyllids, and aphids, encodes a typical SD-CNL protein. Here, we analyzed the role of the extended N terminus for Mi-1.2 activation. Removal of the first part of the N terminus (Nt1) induced Mi-1.2 mediated cell death that could be suppressed by overexpression of the second half of the N-terminal region. Yet, autoactivating NB-ARC-LRR mutants require in trans coexpression of the N-terminal region to induce cell death, indicating that the N terminus functions both as a negative and as a positive regulator. Based on secondary structure predictions, we could link both activities to three distinct subdomains, a typical CC domain and two novel, structurally-conserved helical subdomains called SD1 and SD2. A negative regulatory function could be assigned to the SD1, whereas SD2 and the CC together function as positive regulators of Mi 1.2-mediated cell death. PMID- 22512382 TI - The P25 pathogenicity factor of Beet necrotic yellow vein virus targets the sugar beet 26S proteasome involved in the induction of a hypersensitive resistance response via interaction with an F-box protein. AB - P25, a Beet necrotic yellow vein virus (BNYVV) pathogenicity factor, interacts with a sugar beet protein with high homology to Arabidopsis thaliana kelch repeat containing F-box family proteins (FBK) of unknown function in yeast. FBK are members of the Skp1-Cullin-F-box (SCF) complex that mediate protein degradation. Here, we confirm this sugar beet FBK-P25 interaction in vivo and in vitro and provide evidence for in planta interaction and similar subcellular distribution in Nicotiana tabacum leaf cells. P25 even interacts with an FBK from A. thaliana, a BNYVV nonhost. FBK functional classification was possible by demonstrating the interaction with A. thaliana orthologs of Skp1-like (ASK) genes, a member of the SCF E3 ligase. By means of a yeast two-hybrid bridging assay, a direct effect of P25 on SCF-complex formation involving ASK1 protein was demonstrated. FBK transient Agrobacterium tumefaciens-mediated expression in N. benthamiana leaves induced a hypersensitive response. The full-length F-box protein consists of one F-box domain followed by two kelch repeats, which alone were unable to interact with P25 in yeast and did not lead to cell-death induction. The results support the idea that P25 is involved in virus pathogenicity in sugar beet and suggest suppression of resistance response. PMID- 22512383 TI - Group modified constraint-induced movement therapy (mCIMT) in a clinical setting. AB - PURPOSE: We evaluated the effectiveness of a modified constraint-induced movement therapy (mCIMT) program delivered in a group format. METHODS: Thirteen subacute or chronic stroke and two subacute brain injured participants attended a group mCIMT program for 3.5 h daily for 10 treatment days. The groups consisted of three participants supervised by two staff. Motor recovery, functional arm use, and participation were evaluated by an independent assessor at five time points (baseline, immediately preprogram, immediately postprogram, 1 and 3-month postprogram). RESULTS: Participants achieved statistical and clinically significant improvements in motor recovery (Wolf Motor Function Test), functional use (Motor Activity Log) and participation (Canadian Occupational Performance Measure). These improvements were maintained over a 3-month follow-up period. CONCLUSION: Group delivery of mCIMT produces meaningful results and is a potentially effective way of extending availability of this program without placing overwhelming demands on health care resources. PMID- 22512384 TI - Assessment of CSF flow dynamics using PC-MRI in spontaneous intracranial hypotension. AB - AIM: Spontaneous intracranial hypotension (SIH) is caused by spontaneous cerebrospinal fluid (CSF) leaks and is known to cause orthostatic headaches. Phase-contrast magnetic resonance imaging (PC-MRI) is a non-invasive technique that can be used to quantify variation in CSF flow. The aim of this study was to assess CSF flow dynamics using PC-MRI in SIH. MATERIALS AND METHODS: Twenty-five patients with a definitive diagnosis of SIH and 25 healthy subjects were evaluated with PC-MRI. Magnetic resonance (MR) images were acquired using a 1.5-T unit with an 8-channel head coil. Differences between SIH patients and control subjects were assessed statistically using Wilcoxon's rank sum test, Spearman's rho test, or Pearson's chi-square test, as appropriate. RESULTS: CSF flow volumes toward the third ventricle, CSF flow volumes toward the fourth ventricle, the absolute stroke volume, the peak systolic velocity, and the peak diastolic velocity in SIH patients were significantly smaller than those in control subjects (P < .0001). On the other hand, the net CSF flow volume (P = .9227) and the net CSF flow direction (P = .2472) for SIH patients and control subjects were not significantly different. CONCLUSIONS: The results obtained by CSF flow analysis were directly related to values of CSF opening pressure, determined by lumbar puncture, and clinical findings, such as headache scores. Thus, CSF flow analysis with PC-MRI, which has a short performance time and is non-invasive, may contribute to assessment of SIH patients. PMID- 22512385 TI - Drugs in pediatric intensive care. PMID- 22512386 TI - Off-label drug use in paediatrics: a world-wide problem. AB - Since more than 35 years, the international medical scientific community tries to solve the problem of the off-label use of paediatric drugs. The aim is simple, but ambitious: to supply children and adolescents with effective drugs, as safe as possible, with known and well-documented side effects, and with accurate and up-to-date information on dosage and administration form. However, despite the significant efforts of paediatricians, researchers and international health politics, a number of severe obstacles for the optimal supply of children and adolescents with safe drugs remain. The detailed analysis of the problem shows not only a still remaining lack of medical knowledge, but also persistent weaknesses in the ethical, legal, medical, pharmacological, and political practices that surround the phenomenon of off-label use in paediatrics. The article gives an overview about the remaining difficulties in the field of paediatric off-label medication with special consideration to ethical and regulatory questions. PMID- 22512387 TI - Antibiotic use in children - off-label use. AB - Systemic antibiotics are the group of drugs most commonly used in children. Off label antibiotic use in children is still common in the community and in hospitals, mostly because of young age, dosage, or frequency of drug application. There is an important incentive gap that hinders paediatric drug development resulting from a series of factors, such as small market size, a predominance of off-patent use, no incentives for generic drug manufacturers, and a greater complexity of drug development. The latter is due to varying capacities of drug absorption and metabolism during growth and maturation and the need for oral formulations in neonates and infants. High ethical barriers, combined with concerns of parents about drug safety, further complicate the conduct of clinical studies in children. While many off-patent antibiotics today are labelled for use in children, newer substances such as fluoroquinolones, azithromycin, linezolid, or daptomycin are not. This is of concern in the light of emerging multidrug resistant pathogens. PMID- 22512388 TI - Plasma substitutes therapy in pediatrics. AB - Hypovolemia is the most common cause of circulatory failure in children and may lead to critical tissue perfusion and eventually multiple-organ failure. Administration of fluids to maintain or restore intravascular volume represents a common intervention after hemorrhagic shock occurring during surgical procedures or in patients with trauma. Notwithstanding, there is uncertainty whether the type of fluid may significantly influence the outcome, especially in pediatrics. Both human albumin and crystalloids are usually administered: the advantages of crystalloids include low cost, lack of effect on coagulation, no risk of anaphylactic reaction or transmission of infectious agents. However, large amount of crystalloid infusion has been correlated with pulmonary oedema, bilateral pleural effusions, intestinal intussusception, excessive bowel edema, impairing closure of surgical wounds and peripheral edema. Moreover, intravascular volume expansion obtained by crystalloids is known to be significantly shorter and less efficacious than colloids. Among synthetic colloids, gelatins have been used for many years in children, also in early infancy, to treat intravascular fluid deficits. Hydroxyethylstarch (HES) preparations have been introduced recently, becoming very popular for vascular loading both in adults and children. However, the number of pediatric studies aimed at evaluating HES efficacy and tolerance is limited. Given the ongoing controversies on the use of colloids in childhood, this review will focus on the pharmacodynamics of synthetic and non synthetic colloids for the treatment of critical blood loss in pediatrics. PMID- 22512389 TI - Inotropic and vasoactive drugs in pediatric ICU. AB - Circulatory failure recognition and treatment represents an important issue in critically ill infants and children. Early diagnosis and prompt institution of adequate treatment may be life-saving for pediatric patients with cardiocirculatory instability in the setting of intensive care. However, the hemodynamic status of the critically ill child is poorly reflected by baseline vital parameters or laboratory blood tests. A reliable tool for diagnosis and monitoring of evolution of both heart performance and vascular status is strictly needed. Advanced hemodynamic monitoring consists - among others - of measuring cardiac output, predicting fluid responsiveness and calculating systemic oxygen delivery. Identification and quantifying of pulmonary edema has also been recently appreciated in pediatric critical care. In the last decade, the number of vasoactive drugs has increased, together with a better understanding of clinical application of both different monitoring devices and treatment strategies. PMID- 22512390 TI - Pharmacological therapies for pediatric and neonatal ALI/ARDS: an evidence-based review. AB - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life threating conditions still lacking a definite therapy and carrying a high mortality and morbidity, especially in children and infants. Albeit respiratory assistance and supportive therapies are crucial for ALI/ARDS, many drugs have been proposed to treat such syndromes through various mechanisms of action. On the whole the pharmacological therapy might play an important role in such a complex clinical situation but few evidence based data are available in pediatric and neonatal critical care. This review will focus on drugs directly available on the bedside, that is, medicines already administered in the practice or investigated in at least one clinical study. We will value the differences due to patient's age and the various causes of the syndrome, that may affect the response to the pharmacological therapy. A special attention will be given to the drugs directly deliverable into the lungs, as this strategy allows a total availability to the lung tissue. The experimental background behind each drug will be discussed and then clinical data in neonates and infants will be presented, if available. Data coming from adult critical care and thought to be somehow pertinent for the pediatric setting will otherwise be reviewed. Quality and evidence for or against each therapy will be evaluated according to the Scottish Intercollegiate Guidelines Network statement and practical reminders for clinicians will accordingly be provided. PMID- 22512391 TI - Drugs in pediatric ischemic stroke. AB - Traditionally, drug therapy for pediatric ischemic stroke has been extrapolated from adult guidelines and studies. This approach is not optimal due to important differences between adult and pediatric stroke (e.g. etiologies, maturation changes in hemostasis). Research in pediatric stroke is increasing, and pediatric specific management guidelines have recently become available. This manuscript summarizes available drug therapy recommendations for pediatric ischemic stroke. Both acute management and secondary stroke prevention are discussed, including antiplatelet, anticoagulant, and thrombolytic drugs. When relevant, recommendations from adult ischemic stroke guidelines and data from pediatric stroke studies are incorporated. PMID- 22512392 TI - Neuroprotection and hypothermia in infants and children. AB - Brain injury is the leading cause of death in pediatric ICU. Current evidence supports the use of therapeutic hypothermia (TH) in unconscious patients after out-of-hospital cardiac arrest when the initial heart rhythm was ventricular fibrillation. TH has been proved to be also beneficial in term neonates after hypoxic-ischemic encephalopathy (HIE) and in children with traumatic brain injury (TBI). Recent reports have also investigated TH for the treatment of superrefractory status epilepticus. The clinical application of TH is based on the possibility to inhibit or lessen a myriad of destructive processes (including excitotoxicty, neuroinflammation, apoptosis, free radical production, seizure activity, blood- brain barrier disruption, blood vessel leakage) that take place in the injured tissue following ischemia-reperfusion. TH may also represent a useful tool when conventional therapy fails to achieve an effective control of elevated intracranial pressure. This review is aimed to provide an update of the available literature concerning this intriguing topic. PMID- 22512393 TI - Sedation and analgesia in pediatric intensive care. AB - Almost all children in the pediatric intensive care (PICU) need analgesia and/or sedation. Analgesics drugs are used to control pain from surgical incisions, drainages, vascular access or endotracheal suctioning. Sedatives are used to facilitate the delivery of nursing care, to facilitate mechanical ventilation, prevent self-extubation and to minimize patient discomfort. A therapeutic plan for analgesia and sedation should be established for each patient and regularly reviewed. The most often used sedation agents in PICU patients are Morphine or Fentanyl alone or in combination with Midazolam. Several other drugs should be helpful to manage PICU patients therefore techniques like regional anesthesia and patient controlled analgesia to decrease the use of intravenous analgesia and sedation and to reduce the incidence of withdrawal syndrome. The therapeutic plan for analgesia and sedation should be established for each patient and regularly reviewed. Doses of sedative agents should be titrated to produce the desired level of sedation. The level of sedation should be regularly assessed and documented using few validated sedation assessment tool. However, behavioral evaluation tools based on patient responsiveness, cannot be used during the administration of neuromuscular blocking agents. Under this conditions it could be difficult to interpret the degree of sedation. EEG derived Monitoring devices may represents an useful tools of assessing the level of sedation, but there is insufficient evidence to support the routine use of the BIS monitor in PICU. PMID- 22512395 TI - Local anesthetis and adjuvants in pediatric regional anesthesia. AB - The pediatric loco-regional techniques are considered very safe and effective, first of all because they target the therapy directly to the site of surgery, decreasing the risks of intravenous analgesia. The quality of local anesthesia is influenced by structural and biophysical characteristics of local anesthetics drug, dose, site of injection, mixture of local anesthetics and possible addition of a vasoconstrictor or an adjuvant to prolong the analgesic effect. In children, unlike adults, small nerve diameters and short distance between Ranvier nodes permit to use large volumes and low concentrations of local anesthetics. The clinical practice has shown that in pediatric population, effective analgesia is obtained by 1% mepivacaine, 1% lidocaine and 0.25% bupivacaine or better 0.2% ropivacaine, 0.2-0.25% levobupivacaine. In addition, levobupivacaine and ropivacaine have a better profile in terms of safety in comparison to bupivacaine and are the local anesthetics of choice for the daily clinical practice also in children as in adults. Among the adjuvant, clonidine and ketamine showed the best pharmacokinetic and pharmacodynamic profiles of effective and safety, improving and prolonging the action of associated local anesthetics. Therefore, the use of enantiomers, in association with adjuvants as clonidine or ketamine, using the multimodal approach of integrated anesthesia, makes the clinical practice effective and safe in the pediatric operating rooms. This review focuses on the overview of local anesthetics and adjuvants used today in locoregional pediatric anesthesia, with an emphasis on the advantages and disadvantages of each drug. PMID- 22512396 TI - Ultrasound guided central vascular access in neonates, infants and children. AB - Ultrasound guided central venous cannulation is rapidly becoming the standard technique for achieving a central line in neonates, infants and children. Older techniques such as surgical cutdown and 'blind' percutaneous venipuncture have many disadvantages: they are time consuming, vein consuming and/or associated with dangerous immediate or late complications. On the other hand, ultrasound has only advantages, giving the operator the possibility of (a) choosing the most appropriate and safest venous access on the basis of ultrasound assessment, (b) performing a 100% safe insertion, (c) ruling out malpositions or pleuro-pulmonary damages, during and after the procedure. Ultrasound guided central venous cannulation has been described in many clinical studies of the last decade, each one showing the higher efficacy and safety of ultrasound guidance in children when compared to the traditional landmark method. Ultrasound can be used for puncturing many different deep veins of the arm, neck, groin and thorax. The vein can be visualized either in short axis or in long axis, while the puncture can be performed 'in-plane' (when the needle trajectory is included in the plane of the ultrasound probe) or 'out-of-plane' (when the needle trajectory is not in that plane). Though, the best clinical results of ultrasound guidance can be achieved particularly in neonates and infants - only if the operator has been properly trained in this technique through an appropriate curriculum that should include theory lessons, simulation practice and a tutored learning curve. PMID- 22512394 TI - General anesthetics in pediatric anesthesia: influences on the developing brain. AB - Millions of newborn and infants receive anesthetic, sedative and analgesic drugs for surgery and painful procedures on a daily basis. However, recent laboratory reports clearly demonstrate that anesthetic and sedative drugs induced both neuroapoptosis and neurocognitive deficits in laboratory models. This issue is of paramount interest to pediatric anesthesiologists and intensivists because it questions the safety of anesthetics used for fetal and neonatal anesthesia. Most clinically utilized anesthetic drugs have been found to induce neuronal cell death in the developing brain and to potentially cause long-term neurological impairment. Conversely, painful stimuli without analgesia and anesthesia have been implicated in triggering neuro-apoptosis in juvenile mammalian models. Published retrospective reviews demonstrate temporary neurological sequelae after prolonged anesthetic exposure in young children and larger studies identify long term neurodevelopmental impairment after neonatal surgery and anesthesia. This paper examines the evidence for the effects of commonly used anesthetics on neuronal structure and neurocognitive function in laboratory models and reviews the relevant clinical human epidemiologic data. PMID- 22512397 TI - A new chronotype of Schistosoma mansoni: adaptive significance. AB - OBJECTIVES: To optimise host-to-host transmission, digenean trematodes (parasites) synchronize their cercarial emission patterns with the aquatic activities of their vertebrate hosts. Schistosoma mansoni has a strictly diurnal shedding pattern involving two circadian chronotypes: an early shedding pattern with a mean peak occurring at 11:00 h and a late pattern with a mean peak occurring at 16:00 h. We analysed the cercarial emergence pattern of three schistosome populations from Oman where S. mansoni is resurgent. METHODS: For each schistosome population, the cercarial emergence pattern was assessed hourly over several days. Because we identified a new chronotype hitherto unknown in S. mansoni, we undertook taxonomic characterisation based on egg morphology and mitochondrial DNA sequence (COX1). RESULTS: Taxonomic characterisation revealed that the three schistosome populations belong to the species S. mansoni. Hence, this is the first report of this species exhibiting a nocturnal chronotype, with the mean peak occurring at 20:00 h. We interpreted the new chronotype as being the result of a lateral transfer of S. mansoni from humans to Rattus rattus. CONCLUSION: The cercarial emergence pattern of S. mansoni from Oman is circadian, exhibiting either a diurnal or a nocturnal phenotype. PMID- 22512398 TI - Electronic structure, spin-states, and spin-crossover reaction of heme-related Fe porphyrins: a theoretical perspective. AB - The electronic structures, spin-states, and geometrical parameters of tetra-, penta-, and hexa-coordinated iron-porphyrins are investigated applying density functional theory (DFT) based calculations, utilizing the plane-wave pseudopotential as well as localized basis set approaches. The splitting of the spin multiplet energies are investigated applying various functionals including recently developed hybrid meta-GGA (M06 family) functionals. Almost all of the hybrid functionals accurately reproduce the experimental ground state spins of the investigated Fe-porphyrins. However, the energetic ordering of the spin states and the energies between them are still an issue. The widely used B3LYP provides consistent results for all chosen systems. The GGA+U functionals are found to be equally competent. After assessing the performance of various functionals in spin-state calculations, the potential energy surfaces of the oxygen binding process by heme is investigated. This reveals a "double spin crossover" feature for the lowest energy reaction path that is consistent with previous CASPT2 calculations but predicting a lowest energy singlet state. The calculations have hence captured the spin-crossover as well as spin-flip processes. These are driven by the intra-atomic orbital polarization on the central metal atom due to the atomic and orbitals rearrangements. The nature of the chemical bonding and a molecular orbital analysis are also performed for the geometrically simple but electronic structurally complicated system tetra coordinated planar Fe porphyrin in comparison to the penta-coordinated systems. This analysis explains the observed paradoxical appearance of certain peaks in the local density of states (DOS). PMID- 22512399 TI - Graphene photonics, plasmonics, and broadband optoelectronic devices. AB - Graphene has been hailed as a wonderful material in electronics, and recently, it is the rising star in photonics, as well. The wonderful optical properties of graphene afford multiple functions of signal emitting, transmitting, modulating, and detection to be realized in one material. In this paper, the latest progress in graphene photonics, plasmonics, and broadband optoelectronic devices is reviewed. Particular emphasis is placed on the ability to integrate graphene photonics onto the silicon platform to afford broadband operation in light routing and amplification, which involves components like polarizer, modulator, and photodetector. Other functions like saturable absorber and optical limiter are also reviewed. PMID- 22512400 TI - Coordination-network-based ionic plastic crystal for anhydrous proton conductivity. AB - An ionic coordination network consisting of protonated imidazole and anionic one dimensional chains of Zn(2+) phosphate was synthesized. The compound possesses highly mobile ions in the crystal lattice and behaves as an ionic plastic crystal. The dynamic behavior provides a proton conductivity of 2.6 * 10(-4) S cm(-1) at 130 degrees C without humidity. PMID- 22512401 TI - Preparation of chitosan-coated polyethylene packaging films by DBD plasma treatment. AB - Polyethylene (PE) packaging films were coated with chitosan in order to introduce the antibacterial activity to the films. To augment the interaction between the two polymers, we modified the surfaces of the PE films by dielectric barrier discharge (DBD) plasma before chitosan coating. After that the plasma-treated PE films were immersed in chitosan acetate solutions with different concentrations of chitosan. The optimum plasma treatment time was 10 s as determined from contact angle measurement. Effect of the plasma treatment on the surface roughness of the PE films was investigated by atomic force microscope (AFM) while the occurrence of polar functional groups was observed by X-ray photoelectron spectroscope (XPS) and Fourier transformed infrared spectroscope (FTIR). It was found that the surface roughness as well as the occurrence of oxygen-containing functional groups (i.e., C?O, C-O, and -OH) of the plasma-treated PE films increased from those of the untreated one, indicating that the DBD plasma enhanced hydrophilicity of the PE films. The amounts of chitosan coated on the PE films were determined after washing the coated films in water for several number of washing cycles prior to detection of the chitosan content by the Kjaldahl method. The amounts of chitosan coated on the PE films were constant after washing for three times and the chitosan-coated PE films exhibited appreciable antibacterial activity against Escherichia coli and Staphylococcus aureus. Hence, the obtained chitosan-coated PE films could be a promising candidate for antibacterial food packaging. PMID- 22512402 TI - Terbium(III), europium(III), and mixed terbium(III)-europium(III) mucicate frameworks: hydrophilicity and stoichiometry-dependent color tunability. AB - Two 3D porous terbium(III) mucicate frameworks, {[Tb(2)(Mu(2 ))(3)(H(2)O)(2)].4H(2)O}(n) (1) and {[Tb(Mu(2-))(Ox(2-))(0.5)(H(2)O)].H(2)O}(n) (2), have been synthesized under hydrothermal conditions by changing the pH of the reaction medium. Isostructural europium(III) and seven mixed terbium(III) europium(III) mucicates were synthesized by doping different percentages of Eu(III) under similar reaction conditions and unveiling different emission colors ranging from green to red under the same wavelength. Both dehydrated Tb(III) metal-organic frameworks exhibit selective H(2)O vapor sorption over other solvent molecules (MeOH, MeCN, and EtOH) of less polarity and bigger size and have been correlated to the highly hydrophilic pore surfaces decorated with -OH groups and O atoms from the carboxyl groups of mucicate. PMID- 22512403 TI - Pioglitazone in acromegaly - an open-label, prospective study. AB - OBJECTIVE: Preclinical studies demonstrate that thiazolidinediones (TZDs) decrease growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels, suggesting that they might be effective treatments for acromegaly. This study investigated the effect of pioglitazone on biochemical indices of disease activity in acromegaly. DESIGN AND PARTICIPANTS: This was a 4-month open-label prospective study in 16 patients with active acromegaly who were attending public hospital endocrinology clinics. METHODS: The intervention was pioglitazone 45 mg/day. The primary outcome was change in serum IGF-1; the secondary outcome was change in area under the curve of glucose-suppressed GH. RESULTS: Serum IGF-1 did not change during treatment with pioglitazone (P = 0.95). After 4 months, the mean (95% CI) change from baseline was -1 MUg/l (-51, 49). GH levels following oral glucose loading were unchanged during pioglitazone therapy. After 4 months, the mean (95% CI) change from baseline in area under curve for glucose-suppressed GH was 31 MUg/l (-75, 138, P = 0.54). CONCLUSIONS: Short-term treatment with conventional doses of pioglitazone did not improve biochemical measures of disease activity in acromegaly. PMID- 22512404 TI - How to cannulate? A survey of the Scandinavian Association for Digestive Endoscopy (SADE) in 141 endoscopists. AB - Cannulation of the papilla vateri represents an enigmatic first step in endoscopic retrograde cholangiopancreaticography (ERCP). In light of falling numbers of (diagnostic) ERCP and novel techniques, e.g. short-wire system, we were interested in the approach novice and experienced endoscopist are taking; especially, what makes a papilla difficult to cannulate and how to approach this. We devised a structured online questionnaire, sent to all endoscopists registered with SADE, the Scandinavian Association for Digestive Endoscopy. A total of 141 responded. Of those, 49 were experienced ERCP-endoscopists (>900 ERCPs). The first choice of cannulation is with a sphincterotome and a preinserted wire. Both less experienced and more experienced endoscopists agreed on the criteria to describe a papilla difficult to cannulate and both would choose the needle-knife sphincterotomy (NKS) to get access to the bile duct. The less experienced used more "upward" NKS, whereas the more experienced also used the "downward" NKS technique. This survey provides us with a database allowing now for a more differentiated view on cannulation techniques, success, and outcome in terms of pancreatitis. PMID- 22512405 TI - A new species of Megalobatrachonema (Nematoda: Kathlaniidae) in Fojia bumui (Squamata: Scincidae) from Papua New Guinea. AB - Megalobatrachonema papuaensis n. sp. (Ascaridida: Kathlaniidae) from the small intestine of Fojia bumui (Squamata: Scincidae) collected in Papua New Guinea is described and illustrated. Megalobatrachonema papuaensis represents the first species from the Australian realm and the third species assigned to the genus. It is distinguished from other species of Megalobatrachonema by the distribution pattern of caudal papillae (8 precloacal, 10 postcloacal, and 1 median), length of spicules (201-226 um), and absence of a pseudosucker. PMID- 22512406 TI - Effect of different root canal obturating materials on push-out bond strength of a fiber dowel. AB - PURPOSE: During dowel space preparation, the instrumentation forms a thick smear layer along with sealer-occluded dentinal tubules. The purpose of this study was to evaluate the effect of different obturating materials on push-out bond strength of a fiber dowel. MATERIALS AND METHODS: Fifty human uniradicular teeth were decoronated and prepared using the step-back technique. The specimens were divided into five groups on the basis of obturating materials: group I received no obturation; group II (ZOE) gutta-percha and zinc oxide eugenol sealer; group III (ZOAH) gutta-percha and AH plus sealer; group IV (GF) GuttaFlow; and group V (RE) with Resilon Epiphany system. Dowel spaces were made with manufacturer's provided drills, and a fiber dowel was luted. Horizontal slices were obtained from the middle third, and push-out bond strength (S) was evaluated. Statistical analysis was carried out using one-way ANOVA and post hoc Tukey's test. RESULTS: The push-out bond strength values in the control group, ZOE, ZOAH, GF, and RE were 9.303 +/- 0.565 MPa, 8.859 +/- 0.539 MPa, 8.356 +/- 0.618 MPa, 9.635 +/- 0.435 MPa, and 8.572 +/- 0.256 MPa, respectively. There was no statistically significant difference between the S values of all the groups (p > 0.05). CONCLUSION: There was no effect of different tested obturating materials on the push-out bond strength of fiber dowels; however, further studies should be conducted. PMID- 22512407 TI - Fabrication of patterned nanofibrous mats using direct-write electrospinning. AB - Due to the numerous advantages of nanofibers, there is a strong demand in various fields for nanofibrous structures fabricated by electrospinning. However, the process is currently beset by troublesome limitations with respect to geometric and morphological control of electrospun nanofibrous mats. This study presents a direct-write electrospinning process and apparatus with improved focusing and scanning functionalities for the fabrication of various patterned thick mats and nanofibrous patterns with high geometric fidelity, supported by a number of experimental results. Consequently, various patterned nanofibrous mats were fabricated using the developed method. Additionally, the fabricated mat was successfully used for cell patterning as a bioengineering application. The proposed method is expected to significantly improve the properties and functionalities of nanofibrous mats in a variety of applications. PMID- 22512408 TI - Physiological performance of a detergent decellularized heart valve implanted for 15 months in Vietnamese pigs: surgical procedure, follow-up, and explant inspection. AB - This study features the longest experimental follow-up for decellularized heart valves implanted in an animal model. Porcine aortic heart valves were decellularized according to a disclosed standardized method in which TRITON X-100 and sodium cholate (TRICOL) are used in succession, followed by a further treatment with the endonuclease Benzonase to completely remove the nucleic acid remnants. Experimental animals (n = 17), represented by Vietnamese pigs (VPs), received a decellularized aortic allograft as a substitute for the replacement of their right ventricular outflow tract. The surgical implantation of the TRICOL treated aortic valve conduit was successful in 11 VPs, while perioperative or postoperative complications occurred in the remaining six animals. In the sham operated group (n = 4), the native pulmonary root was excised and immediately reimplanted orthotopically in the same animal. Echocardiography demonstrated a satisfactory hemodynamic performance of the TRICOL-treated valves during follow up as well as the absence of relevant leaflet alterations concerning thickness and motility or valve insufficiency. At explantation, macroscopic inspection of tissue-engineered heart valve conduits did not evidence calcifications and showed a decreased wall thickness, comparable to that of the reimplanted native pulmonary roots. Noteworthy, extended functional performance, recovery of DNA content, and active extracellular matrix precursor incorporation are apparently compatible with the properties of a living self-supporting substitute. PMID- 22512409 TI - Phonological, visual, and semantic coding strategies and children's short-term picture memory span. AB - Three experiments addressed controversies in the previous literature on the development of phonological and other forms of short-term memory coding in children, using assessments of picture memory span that ruled out potentially confounding effects of verbal input and output. Picture materials were varied in terms of phonological similarity, visual similarity, semantic similarity, and word length. Older children (6/8-year-olds), but not younger children (4/5-year olds), demonstrated robust and consistent phonological similarity and word length effects, indicating that they were using phonological coding strategies. This confirmed findings initially reported by Conrad (1971), but subsequently questioned by other authors. However, in contrast to some previous research, little evidence was found for a distinct visual coding stage at 4 years, casting doubt on assumptions that this is a developmental stage that consistently precedes phonological coding. There was some evidence for a dual visual and phonological coding stage prior to exclusive use of phonological coding at around 5-6 years. Evidence for semantic similarity effects was limited, suggesting that semantic coding is not a key method by which young children recall lists of pictures. PMID- 22512410 TI - Daily stressors in patients with acute whiplash associated disorders. AB - PURPOSE: Stressors in acute whiplash associated disorders (WAD), as reported on a daily basis, have hitherto been neglected in research. The primary aim of this study was to describe the most stressful daily situation or event reported by individuals with acute WAD within a month of a whiplash trauma. Another aim was to describe the meaning and significance of these daily stressors, i.e. primary appraisal. METHOD: A descriptive design with a content analysis approach was used. 260 WAD-daily coping assessments (WAD-DCA) generated during 1 week by 51 participants with acute WAD were included in the study. Stressors were analysed using qualitative content analysis. RESULTS: The reported stressors generated 13 categories covering a wide range of stressful situations in daily life related to (i) work, (ii) physical symptoms, (iii) feelings and cognitions, (iv) family and home responsibilities and (v) recreation. The majority of the stressors were appraised as "expected" as well as "disabling". Most threatening stressors were related to work, driving and feelings/cognitions. CONCLUSIONS: The wide variety of stressors indicates that it is not only pain itself that influences daily life in acute WAD. Early identification of individual and situation-specific stressors gives new data regarding what bothers individuals suffering from WAD after a collision and may be helpful in understanding the coping process in relation to specific stressors and stressor appraisals. PMID- 22512411 TI - Habituation to pain in "medication overuse headache": a CO2 laser-evoked potential study. AB - OBJECTIVE: Our aim was to investigate CO(2) laser-evoked potential (LEP) habituation to experimental pain in a group of patients affected by medication overuse headache, with a history of episodic migraine becoming chronic, before and after treatment, consisting in acute medication withdrawal and a preventive treatment cycle. BACKGROUND: One of the main features of LEPs in migraineurs is a lower habituation to repetitive noxious stimuli during the interictal phase. METHODS: LEPs were recorded to stimulation of both the right hand and the right perioral region in 14 patients and in 14 healthy subjects. The habituation of both the N1 and the vertex N2/P2 components was assessed by measuring the LEP amplitude changes across 3 consecutive repetitions of 30 trials each. RESULTS: In the 8 patients who had clinically improved after treatment, the N2/P2 amplitude habituation was significantly higher after treatment than before treatment following both hand (F = 43.2, P < .0001) and face stimulation (F = 6.9, P = .01). In these patients, the N2/P2 amplitude habituation after treatment was not different from that obtained in healthy controls (P = .18 and P = .73 for hand and face stimulation, respectively). On the contrary, in the patients who did not improve, the N2/P2 amplitude still showed reduced habituation after both hand (F = 3.1, P = .08) and face (F = 0.7, P = .4) stimulation. CONCLUSION: The deficient habituation of the vertex N2/P2 complex was partly restored after successful treatment of medication-overuse headache, reflecting a modification in pain processing pathways. PMID- 22512413 TI - Life events and change in leisure time physical activity: a systematic review. AB - The global epidemic of chronic non-communicable diseases is closely related to changes in lifestyle, including decreasing leisure time physical activity (PA). Physical inactivity is a major public health challenge. To respond to that challenge, it is essential to know which personal and environmental factors affect PA behaviour. Certain life events may be one contributing factor, by creating emotional distress and disrupting a person's daily routine. The aim was to examine the literature concerning the effects of life events on changes in PA. A systematic literature search was performed on studies that assessed at least one major change in life circumstances and a change in PA. To be included, studies had to assess PA at two timepoints at least (before and after the event). Diseases as life events were excluded from this review. Thirty-four articles met the inclusion criteria. The studies examined the following life-change events: transition to university; change in employment status; marital transitions and changes in relationships; pregnancy/having a child; experiencing harassment at work, violence or disaster; and moving into an institution. The studies reviewed showed statistically significant changes in leisure PA associated with certain life events. In men and women, transition to university, having a child, remarriage and mass urban disaster decreased PA levels, while retirement increased PA. In young women, beginning work, changing work conditions, changing from being single to cohabiting, getting married, pregnancy, divorce/separation and reduced income decreased PA. In contrast, starting a new personal relationship, returning to study and harassment at work increased PA. In middle aged women, changing work conditions, reduced income, personal achievement and death of a spouse/partner increased PA, while experiencing violence and a family member being arrested or jailed decreased PA. In older women, moving into an institution and interpersonal loss decreased PA, while longer-term widowhood increased PA. In addition, experiencing multiple simultaneous life events decreased PA in men and women. Major life events have a strong effect on leisure PA behaviour. Consequently, people experiencing life events could be an important target group for PA promotion. More research is needed to examine the short- and long-term effects of different life events on PA, gender differences in the effects of life events and the specific determinants of PA change during life events. PMID- 22512412 TI - Skin manifestations of athletes competing in the summer olympics: what a sports medicine physician should know. AB - Olympic athletes are vulnerable to traumatic, environmental and infectious skin manifestations. Although dermatological complaints are frequent among Olympians, there is a scarcity of literature that reviews sports-related dermatoses among Olympic athletes. A comprehensive review of PREMEDLINE and MEDLINE searches of all available literature through to January 2011 was conducted, focusing on sports-related dermatological presentations as well as the key words 'Olympic athletes' and 'skin diseases'. Common skin conditions can be harmful and even prohibitive for competition. Common aetiologies of dermatological conditions related to sports include: skin infections with dermatophytes such as tinea pedis and tinea corporis, bacteria such as pitted keratolysis, and folliculitis and viruses such as herpes gladiatorum. Frictional dermatoses occur commonly and include athlete's nodules, jogger's itch, frictional blisters, callosities and talon noir. Trauma can cause haematomas such as auricular haematomas. Due to long training hours in the sun, many endurance athletes experience high levels of UV radiation and a higher risk for both melanoma and non-melanoma skin cancer. Pre existing dermatoses can also be aggravated with practice and competition; in particular, atopic eczema and physical urticarias. Infrequent dermatoses are susceptible to misdiagnosis, delay in treatment and needless biopsies. This review highlights the diagnosis and management of sports-related dermatoses by the following general categories of Olympic sport: endurance, resistance, team sport, and performing arts. PMID- 22512414 TI - Thyroid abscess with esophageal perforation in papillary thyroid cancer. PMID- 22512415 TI - Relative levels of the inflammatory cytokine TNFalpha and the soluble CD40 ligand profile in serum correlate with the thyrotoxic activity of Graves' disease. AB - BACKGROUND: Interactions between CD40 and its ligand (CD40L) have important roles in T-cell-dependent activation of B cells, which may be related to the thyrotoxic activity of Graves' disease (GD). Soluble forms of CD40 ligand (sCD40L) are released from activated T cells and platelets, and several types of inflammatory cytokines are increased in patients with hyperthyroid GD. The aim of this study was to assess sCD40L and other cytokines as clinical indicators of disease activity or as possible markers of remission in GD. METHODS: Serum levels of sCD40L, interleukin 18 (IL-18), tumor necrosis factor-alpha (TNFalpha), and TNFalpha receptors 1 and 2 (TNFR1 and TNFR2) were investigated in patients with active GD (GD-A), intractable GD (GD-IT), inactive GD (GD-IA), GD in remission (GD-R), and Hashimoto's thyroiditis (HT), and in control subjects (CON). RESULTS: Serum concentrations of sCD40L were higher in the GD-A and GD-IT groups than in the HT and CON groups. Similarly, serum concentrations of IL-18, which induces Th1 cytokines, such as interferon-gamma, were higher in the GD-A and GD-IT groups than in all other groups. Serum levels of TNFR1 and TNFR2 were also significantly higher in the GD-A than in all other groups. The mean serum concentration of TNFalpha was higher in the GD-R compared with the GD-A and GD-IT groups, although the difference was not significant. Serum sCD40L concentrations in the GD-R group were lower than in the GD-A and GD-IT groups. Finally, the ratio of serum TNFalpha to sCD40L was higher in the GD-R group than in the GD-A and GD-IT groups. This is the first report that serum sCD40L is increased in active GD, and that the serum TNFalpha:sCD40L ratio is a marker for remission in GD. CONCLUSIONS: Our results suggest that not only thyrotoxicosis, but also the activity of the immunoreaction presenting as anti-thyrotropin receptor antibodies (TRAb) titer in GD, affects inflammatory cytokine serum profiles. Serum profiles of cytokines vary in patients with GD depending on disease activity. An elevated serum TNFalpha:sCD40L ratio indicates declining disease activity and reflects a shift from Th2 to Th1 dominance, suggesting that suppression of sCD40L or increased production of TNFalpha is required to initiate or maintain remission of GD. PMID- 22512416 TI - Positive feelings of caregiving among Latino Alzheimer's family caregivers: understanding the role of spirituality. AB - This study used structural equation modeling to examine the effects of spirituality on positive aspects of caregiving (PAC) among a sample of American Latino family members caring for a relative with Alzheimer's disease (AD). Participants consisted of 209 Latino caregivers (CGs) drawn from baseline data from the Resources for Enhancing Alzheimer's Caregivers Health II study. The findings indicate that spirituality is positively related to PAC and may partially mediate the effect of subjective stress on PAC. AD CGs typically provide better care when they perceive the caregiving experience to be satisfying and rewarding. Toward this end, gerontological practitioners should adopt a proactive stance to ensure Latino AD CGs can operationalize their spiritual strengths. PMID- 22512417 TI - Verbal learning and memory and their associations with brain morphology and illness course in schizophrenia spectrum psychoses. AB - The California Verbal Learning Test and structural brain imaging were administered to 57 subjects with schizophrenia spectrum disorders and 94 controls in a general population sample. Cases had lower semantic cluster scores. Poorer verbal memory strategies were associated with longer duration of illness and heavier use of antipsychotic medication. After controlling for duration of illness, sex, and total gray matter, poorer verbal memory was associated with lower gray matter volume in the cingulate cortex, juxtapositional lobule, right superior temporal gyrus, and precuneus. After controlling for use of antipsychotic medication, there was an association between higher serial clustering and smaller anterior cingulate gyrus and larger intracalcarine cortex. PMID- 22512419 TI - Purpose, insight, and the review of literature. PMID- 22512418 TI - pH optimum of the photosystem II H2O oxidation reaction: effects of PsbO, the manganese-stabilizing protein, Cl- retention, and deprotonation of a component required for O2 evolution activity. AB - Hydroxide ion inhibits Photosystem II (PSII) activity by extracting Cl(-) from its binding site in the O(2)-evolving complex (OEC) under continuous illumination [Critchley, C., et al. (1982) Biochim. Biophys. Acta 682, 436]. The experiments reported here examine whether two subunits of PsbO, the manganese-stabilizing protein, bound to eukaryotic PSII play a role in protecting the OEC against OH(-) inhibition. The data show that the PSII binding properties of PsbO affect the pH optimum for O(2) evolution activity as well as the Cl(-) affinity of the OEC that decreases with an increasing pH. These results suggest that PsbO functions as a barrier against inhibition of the OEC by OH(-). Through facilitation of efficient retention of Cl(-) in PSII [Popelkova, H., et al. (2008) Biochemistry 47, 12593], PsbO influences the ability of Cl(-) to resist OH(-)-induced release from its site in the OEC. Preventing inhibition by OH(-) allows for normal (short) lifetimes of the S(2) and S(3) states in darkness [Roose, J. L., et al. (2011) Biochemistry 50, 5988] and for maximal steady-state activity by PSII. The data presented here indicate that activation of H(2)O oxidation occurs with a pK(a) of ~6.5, which could be a function of deprotonation of one or more amino acid residues that reside near the OEC active site on the D1 and CP43 intrinsic subunits of the PSII reaction center. PMID- 22512420 TI - Does household structure affect adolescent smoking? AB - OBJECTIVES: To examine household structure when studying determinants of youth smoking, as the configuration of a family is an important factor in the etiology of adolescent problem behaviors. DESIGN AND SAMPLE: The study sample (n = 13,001) included respondents aged 12-19 years who were either living in two-parent households, single-parent households, or no-parent households, and with valid response to the smoking status questions from the Canadian Community Health Survey. MEASURES: Multivariate logistic regression was used to test the presence and strength of the association between household structure and the likelihood of smoking while controlling for age, sex, household education, and exposure to secondhand smoking. RESULTS: The odds of youth smoking in the single-parent household was 1.78 times greater than the odds of youth smoking in two-parent households. Similarly, the odds of youth smoking in no-parent households was 1.47 times greater than the odds of youth smoking in two-parent households. CONCLUSIONS: The results indicate that there is an association between household structure and smoking among adolescents in Canada. Findings might be helpful for decision makers to recognize the context within which adolescents initiate and sustain smoking when developing strategies for the prevention and cessation of smoking among youth. PMID- 22512421 TI - Potential health effects related to pesticide use on athletic fields. AB - OBJECTIVES: Children come in contact with athletic fields on a daily basis. How these fields are maintained may have an impact on children's potential exposure to pesticides and associated health effects. DESIGN AND SAMPLE: This is a cross sectional, descriptive study that utilized a survey to assess playing field maintenance practices regarding the use of pesticides. Athletic fields (N = 101) in Maryland were stratified by population density and randomly selected. MEASURES: A survey was administered to field managers (n = 33) to assess maintenance practices, including the use of pesticides. Analysis included descriptive statistics and generalized estimating equations. RESULTS: Managers of 66 fields (65.3%) reported applying pesticides, mainly herbicides (57.4%). Managers of urban and suburban fields were less likely to apply pesticides than managers of rural fields. Combined cultivation practice was also a significant predictor of increased pesticide use. CONCLUSIONS: The use of pesticides on athletic fields presents many possible health hazards. Results indicate that there is a significant risk of exposure to pesticide for children engaged in sports activities. Given that children are also often concurrently exposed to pesticides as food residues and from home pest management, we need to examine opportunities to reduce their exposures. Both policy and practice questions are raised. PMID- 22512422 TI - Physical activity status in adults with depression in the National Health and Nutrition Examination Survey, 2005-2006. AB - OBJECTIVE: To examine physical activity levels among adults with depression. METHODS: Cross-sectional descriptive study with the National Health and Nutritional Examination Survey, 2005-2006. SAMPLE: Four thousand and fifty-eight men and women aged 20 years and older. MEASURES: Self-reported Patient Health Questionnaire [PHQ-9] for depression, accelerometer for amounts of physical activity, demographic information, and self-reported health status were weighted to represent population estimates. Bivariate analysis and multivariate logistic regression were applied to data. RESULTS: Overall prevalence of depression was 13.9% and 5.6% in mild and moderate to severe levels, respectively. Adults in depression groups spent significantly less time in both light and moderate physical activity than nondepression groups. There were no differences in sedentary and vigorous physical activity among groups. After controlling for socio-demographic factors, those at greater risk for depression were middle-aged women with self-reported poor health status with less moderate physical activity. CONCLUSIONS: Although depressed adults were less active than nondepressed adults, their physical activity levels were close to the recommended guidelines. Public education regarding efficacy of physical activity and encouragement of appropriate activity levels could contribute to prevention and treatment of depression. PMID- 22512423 TI - Evaluation of a public health nurse visiting program for pregnant and parenting teens. AB - A visiting nurse agency created the Pregnant and Parenting Team Program, an innovative program for serving pregnant and parenting teen mothers to promote family and child health and family self-sufficiency. Public health nurses (PHNs) provide home visits that offer social, emotional, educational, and health care support to pregnant and parenting teen mothers 19 years of age and younger and their children. Foundational program pillars include: (1) a trusting relationship between teen mothers and a PHN through home visits; (2) outreach and coordination with schools, hospital, clinics, and human service agencies; (3) a comprehensive and intensive maternal mental health curriculum; and (4) community support and caring through provision of essential items needed for success in parenting. Measures of program effectiveness included identification of pregnant and parenting adolescent mothers, birth outcomes, active enrollment in school, delay of repeat pregnancy, maternal-infant bonding and attachment, use of community resources, and infant growth and development. Participants in the program were more likely to be enrolled in school and had better birth outcomes in comparison with nonparticipants. Outcome data collected from January 1, 2008 to July 23, 2010 demonstrated progress toward stated goals. PMID- 22512424 TI - Qualitative exploration of the acceptability of a mobile phone and pedometer based physical activity program in a diverse sample of sedentary women. AB - OBJECTIVES: The objectives of this paper were to explore the acceptability of components of a mobile phone/pedometer-based physical activity program and to understand motivators and barriers to increase physical activity in a diverse sample of sedentary women. DESIGN AND SAMPLE: Face-to-face semi-structured interviews were conducted following a 3-week pilot mobile phone/pedometer-based physical activity intervention. Forty-one sedentary women participated in the study. MEASURES: Subjects were interviewed using a semi-structured interview guide. A qualitative description method was used to thematically analyze the interviews. Two investigators reviewed the transcripts independently and identified codes based on the main concerns in the interview questions. RESULTS: Three themes emerged from qualitative data shedding light on the perceived acceptability and usefulness of a mobile phone/pedometer-based intervention: (1) Monitor me: mobile phone/pedometer as self-monitoring tools, (2) Motivate me: cycle of feedback in goal setting and usefulness/uselessness of daily random messages, (3) Mobilize me: engaging and adapting physical activity to fit one's own lifestyle. CONCLUSION: Mobile phone and pedometer-based physical activity programs might be helpful in keeping sedentary women engaged and motivated to increase their physical activity. A randomized controlled trial of this intervention is warranted. PMID- 22512425 TI - The decisional balance sheet to promote healthy behavior among ethnically diverse older adults. AB - OBJECTIVE: The rising health care costs and increasing older adult population in the United States make preventive medicine for this age group especially crucial. Regular physical activity and fruit and vegetable consumption may prevent or delay the onset of many chronic conditions that are common among older adults. The decisional balance sheet is a promotional tool targeting the perceived pros and cons of behavior adoption. The current study tested the efficiency and effectiveness of a single-day decisional balance sheet program, targeting increased physical activity and fruit and vegetable intake among older adults. DESIGN AND SAMPLE: Participating adults (N = 21, age = 72.2) who represented a diverse population in Hawaii (Japanese = 5, Filipino = 4, Caucasian = 4, Native American = 1, Native Hawaiian = 1, Hispanic = 1, and Others = 5) were recruited from housing communities and randomized to a decisional balance sheet program adapted for physical activity or fruit and vegetable consumption. MEASURES: Physical activity was assessed using the International Physical Activity Questionnaire (IPAQ) short form, and daily fruit and vegetable intake with the National Health and Nutrition Examination Survey single item instrument. Baseline and follow-up data were collected. RESULTS: Both programs were implemented efficiently, and participants in both groups improved their daily physical activity. The decisional balance sheet for fruit and vegetable consumption appeared less effective. CONCLUSIONS: Specific suggestions for similar programs are reported. PMID- 22512426 TI - A transformative decision-making process for mammography screening among rural, low-income women. AB - OBJECTIVE: The study objective was to expand theoretical knowledge of the mammography-screening decision-making process. The purpose of this article was to report the decision-making process of participants who moved from nonscreening to screening. DESIGN AND SAMPLE: Grounded theory methodology was used. Seventeen rural, low-income women aged 46-64 years were recruited. MEASURES: In-depth, face to-face interviews were conducted. Semi-structured questions focused on decision making, readiness for change, and health care experiences. RESULTS: Two phases of decision making were identified. Phase I, A Dormant Period of Nonscreening Behavior, is an inactive screening period characterized by (a) knowledge deficits, (b) unengaged cognition, and (c) misleading perceptions. Phase II, A Transformative Learning Process Resulting in Screening Behavior, is characterized by (a) aroused affective responses, (b) awakened cognitive responses, (c) new knowledge construction, and (d) changed perceptual responses. A catalytic event provides the stimulus to move from Phase I to Phase II. Transformative learning emerged as the central conceptual category underlying the decision to obtain screening. Transformative learning includes a triggering event that facilitates questioning previously held assumptions about mammography. CONCLUSION: Participants demonstrated a transformative process resulting in movement from nonscreening to screening. Further study is needed regarding nursing interventions that serve as catalysts for transformation and subsequent screening. PMID- 22512427 TI - Smoke-free policy and alcohol use among undergraduate college students. AB - OBJECTIVES: The purpose of this study was to assess attitudes and behaviors related to smoke-free policy among undergraduate student alcohol drinkers on a campus in a community with smoke-free bars. DESIGN AND SAMPLE: This was a secondary data analysis of a study in which participants completed mailed surveys assessing demographic characteristics, attitudes and behaviors related to alcohol and tobacco use and smoke-free policy (n = 337). Opinion and behavior items were summarized descriptively; associations were examined using Kruskal Wallis tests and chi-square tests of association. Logistic regression tested for predictors of importance of smoke-free policy. RESULTS: Respondents were predominantly female and Caucasian; mean age 20.3 years. One fourth were current smokers. Seventy-nine percent said the community smoke-free law had no effect on frequency of visiting bars. Eighty-seven percent said smoke-free policy in campus buildings was "somewhat" or "very important." Predictors of perceived importance of smoke-free policy included gender and smoking status. CONCLUSIONS: Most smokers in this sample did not experience a change in their motivation to quit smoking or in number of cigarettes smoked daily. Implementation of a community smoke-free law did not reduce the likelihood of visiting bars. Women and nonsmokers were more likely to rate smoke-free campus policy as very important. PMID- 22512428 TI - Ethical issues in practice: a survey of public health nurses in Japan. AB - OBJECTIVES: The purposes of this study were to identify specific components and frequencies of ethical issues that public health nurses (PHNs) encountered in their practice, relationships between ethical issues and demographic data, and ethics education and workplace environment. DESIGN AND SAMPLE: Cross-sectional survey for PHNs at local governmental agencies in Japan. Usable data were 3,409. MEASURES: Public health nurses completed the frequency of ethical issues, experience of ethics education, workplace environment, and demographics. RESULTS: Item and exploratory factor analysis for the frequency of encountering ethical issues revealed: (1) discrepancy of intention between client and his/her family on treatment or care; (2) differences in views between PHNs and their organization's administrators regarding providing services; and (3) discrepancy of caretaking views between PHNs and various professionals. All factors were related to work experience and one factor was specifically related to the type of local government employing PHNs. Only 11.1% of PHNs received ethics education via continuing education programs. PHNs reported that programmed continuing education systems were not sufficiently available. CONCLUSIONS: Systematic continuing ethics education programs for PHNs need developing, tailored to the specific characteristics associated with PHNs' ethical concerns, such as nurses' working experience and the type of employing local government. PMID- 22512430 TI - The many sided opportunity of field nursing. 1916. PMID- 22512429 TI - Clinical indicators of the nursing diagnosis of "imbalanced nutrition: more than body requirements" in pregnant women. AB - OBJECTIVES: To verify the accuracy measures of certain clinical indicators for the diagnosis of "Imbalanced Nutrition: More than Body Requirements" in pregnant women. DESIGN AND SAMPLE: A cross-sectional, descriptive, and exploratory study. In total, 146 pregnant women treated in the public health unit in northeast Brazil. MEASURES: Data were collected through structured interviews and by measuring the body mass index and the thickness of the triceps skin fold. The sensitivity, specificity, and predictive value of these clinical indicators were also analyzed. RESULTS: The clinical indicators of patients with this diagnosis were sedentary lifestyle (97.1%); eating in response to internal suggestions (86.98%); obesity/overweight; and triceps skin fold (>25 mm) (99.3%). Eating in response to external suggestions was the most specific clinical indicator (70.1%). There was a statistically significant association between eating in response to internal suggestions besides hunger (p = .022), overweight/obesity (p < .001) ,and triceps skin fold >25 mm (p = .014). CONCLUSION: The clinical indicator with the highest sensitivity value (86.96%) for the diagnosis of imbalanced nutrition: greater than body requirements was eating in response to internal suggestions besides hunger. Indicators with the higher specificity value for this nursing diagnosis were obesity/overweight (98.73%) and triceps skin fold >25 mm (98.59%). PMID- 22512432 TI - Crystal structure and physical properties of the new one-dimensional metal Ba2Cu(7-x)Te6. AB - The telluride Ba(2)Cu(7-x)Te(6) was synthesized from the elements in stoichiometric ratios, heated to 1073 K, followed by slow cooling to 873 K over 120 h. Ba(2)Cu(7-x)Te(6) crystallizes in space group P2(1)/m with lattice dimensions of a = 6.8591(7) A, b = 12.1439(12) A, c = 9.0198(9) A, beta = 110.7509(14) degrees , V = 702.58(12) A(3), and Z = 2. The structure is comprised of Cu atoms forming a six-membered ring and triangles, interconnected to an infinite ribbon of Cu atoms. The ribbons are connected to each other via Cu-Te bonds to yield a three-dimensional structure, wherein each Cu atom is tetrahedrally coordinated by four Te atoms. A special feature of this telluride is the occurrence of a quasi-linear Te atom chain, which causes one-dimensional metallic properties, in accordance with electronic structure calculations and property measurements. PMID- 22512431 TI - Acyclic cucurbit[n]uril molecular containers selectively solubilize single-walled carbon nanotubes in water. AB - Making single-walled carbon nanotubes (SWNTs) soluble in water is a challenging first step to use their remarkable electronic and optical properties in a variety of applications. We report that acyclic cucurbit[n]uril molecular containers 1 and 2 selectively solubilize small-diameter and low chiral angle SWNTs. The selectivity is tunable by increasing the concentration of the molecular containers or by adjusting the ionic strength of the solution. Even at a concentration 1000 times lower than typically required for surfactants, the molecular containers render SWNTs soluble in water. Molecular mechanics simulations suggest that these C-shaped acyclic molecules complex the SWNTs such that a large portion of nanotube sidewalls are exposed to the external environment. These "naked" nanotubes fluoresce upon patching the exposed surface with sodium dodecylbenzene sulfonate. PMID- 22512433 TI - Street-level workers' criteria for identifying indigents to be exempted from user fees in Burkina Faso. AB - OBJECTIVES: Universal healthcare coverage cannot be achieved in Africa as long as the indigent, the poorest, are unable to access healthcare systems. This study was carried out in Burkina Faso to obtain street-level workers' perspectives on what criteria should be used to select indigents to be exempted from user fees. METHODS: Two group consensus techniques were used (Delphi and Concept Mapping). The participants were nurses (CM; n = 24), midwives (CM; n = 23) from a rural district and Social Action agents (CM; n = 31) and healthcare workers (Delphi n = 23) in training at two national schools. RESULTS: Altogether, 446 criteria were proposed. The nurses put forward criteria related to being ill without support and being a victim of society. The midwives focused more on the disabled poor and those who were ill and unsupported. The healthcare workers in training mentioned disabled persons and the elderly with no family support. The Social Action agents spoke about vulnerability related to illness or disability and the fact of being excluded or being a disaster victim. CONCLUSIONS: These criteria proposed by street-level workers add to other studies conducted in Burkina Faso and should help the State to improve indigents' access to care. PMID- 22512434 TI - Highly conductive poly(methyl methacrylate) (PMMA)-reduced graphene oxide composite prepared by self-assembly of PMMA latex and graphene oxide through electrostatic interaction. AB - We report a simple, environmentally friendly approach for preparing highly conductive poly(methyl methacrylate)-reduced graphene oxide (PMMA-RGO) composites by self-assembly of positively charged PMMA latex particles and negatively charged graphene oxide sheets through electrostatic interactions, followed by hydrazine reduction. The PMMA latex was prepared by surfactant-free emulsion polymerization using a cationic free radical initiator, which created the positive charges on the surface of the PMMA particle. By mixing PMMA latex with a graphene oxide dispersion, positively charged PMMA particles easily assembled with negatively charged graphene oxide sheets through electrostatic interaction. The obtained PMMA-RGO exhibited excellent electrical properties with a percolation threshold as low as 0.16 vol % and an electrical conductivity of 64 S/m at only 2.7 vol %. Moreover, the thermomechanical properties of PMMA-RGO were also significantly improved. The storage modulus of PMMA-RGO increased by about 30% at 4.0 wt % RGO at room temperature while the glass transition temperature of PMMA-RGO increased 15 degrees C at only 0.5 wt % RGO. PMID- 22512435 TI - Effects of testosterone therapy on sleep and breathing in obese men with severe obstructive sleep apnoea: a randomized placebo-controlled trial. AB - STUDY OBJECTIVES: High doses of short-term testosterone have been shown to acutely worsen sleep-disordered breathing in men with obstructive sleep apnoea (OSA). The effects of lower, near-conventional doses of testosterone in obese men with OSA may differ over the longer term but have not been systematically studied. We assessed sleep and breathing effects of near-conventional testosterone treatment as an adjunct to weight loss in obese men with severe OSA. DESIGN: An 18-week randomized, double-blind, placebo-controlled, parallel group trial in 67 men. INTERVENTIONS: All subjects were placed on a hypocaloric diet and then received intramuscular injections of 1000 mg testosterone undecanoate or placebo at 0, 6 and 12 weeks. MEASUREMENTS AND RESULTS: Sleep and breathing were measured by nocturnal polysomnography at 0, 7 and 18 weeks. Testosterone, compared to placebo, worsened the oxygen desaturation index (ODI) by 10.3 events/h (95%CI, 0.8-19.8 events/h; P = 0.03) and nocturnal hypoxaemia (sleep time with oxygen saturation <90%, SpO(2) T90%) by 6.1% (95%CI, 1.5-10.6; P = 0.01) at 7 weeks. Testosterone therapy did not alter ODI (4.5, -5.4 to 14.4 events/h; P = 0.36) or SpO(2) T90% at 18 weeks (2.9, -1.9-7.7%; P = 0.23) compared to placebo. The testosterone treatment effects on ODI and SpO(2) T90% were not influenced by baseline testosterone concentrations (testosterone by treatment interactions, all P > 0.35). Blood testosterone concentrations did not correlate with ODI or SpO(2) T90% (all P > 0.19). CONCLUSIONS: Testosterone therapy in obese men with severe OSA mildly worsens sleep-disordered breathing in a time-limited manner, irrespective of initial testosterone concentrations. This time-dependency was not related to testosterone concentrations. TRIAL REGISTRATION: www.anzctr.org.au Identifier: ACTRN1260-6000404527. PMID- 22512436 TI - Transient elastography in patients with celiac disease: a noninvasive method to detect liver involvement associated with celiac disease. AB - BACKGROUND: Liver involvement in celiac disease (CD) is clinically relevant and could require specific treatment in addition to gluten-free diet (GFD). Transient elastography (TE), a noninvasive tool for assessing liver stiffness (LS), has widely been reported as an accurate surrogate marker of liver fibrosis. AIMS: To prospectively identify celiac patients with liver involvement by TE and to assess the effect of GFD. MATERIAL AND METHODS: Ninety-five histologically confirmed CD patients (24 newly diagnosed) were consecutively evaluated by TE and compared with 146 patients with chronic hepatitis C (HCV) and 54 healthy subjects. RESULTS: LS ranged between 2.8 and 6.7 kPa (median 4.9) in healthy subjects, defining 6.9 kPa as the upper reference limit (2 SD above the mean levels). TE was above 6.9 kPa in 10 (10.5%) CD patients. Median TE values resulted significantly higher in CD patients with hypertransaminasemia than those without [6.1 vs. 4.2 kPa (p < 0.01)]. Among the 24 newly diagnosed patients with CD, median TE values declined from 4.4 to 4 kPa, after 6 months of GFD, resulting below 6.9 kPa in 100% of the patients. CONCLUSIONS: A subset of CD patients with hypertransaminasemia showed liver involvement by TE. Accordingly, based on its accuracy in predicting liver fibrosis, TE could be used to identify those CD patients suitable for liver biopsy. PMID- 22512437 TI - In vitro evaluation of shear bond strength and mode of failure of the interface between an indirect composite bonded to fiber-reinforced composite substructures. AB - PURPOSE: Failures of fixed partial dentures (FPDs) fabricated with fiber reinforced composites (FRCs) have been attributed to veneering fractures. The aim of the present study was to investigate the shear bond strength and mode of failure between an indirect composite and FRC substructures. MATERIAL AND METHODS: SR Adoro indirect composite was bonded to the following substructures: (a) flat surface made of unidirectional glass fibers (group A), (b) retentive sticks made of unidirectional glass fibers (group B), (c) flat surface made of fiber net (group C), (d) retentive sticks made of fiber net (group D), (e) nickel chromium dental alloy (control, group E). For every group, 13 specimens were fabricated. All specimens were hydrothermocycled (5000 cycles, 5 degrees C/30 sec, and 55 degrees C/30 sec). A bond test was performed in a testing machine at a 0.5 mm/min crosshead speed according to ISO 10477. The failure mode was determined by examination of the fractured surfaces under an optical microscope. Selected specimens were examined with scanning electron microscope and with energy dispersive spectroscopy for compositional determination. The morphology (flat-sticks) and the type (unidirectional-net) of fibers on the bond strength were estimated. RESULTS: The mean shear bond strength was significantly different between groups E and A (p= 0.044), and groups A and B (p= 0.010). All FRC specimens showed cohesive failure. Group E showed predominantly adhesive failure. The bond strength was higher when sticks or fiber nets were used. CONCLUSIONS: Fiber nets and retentive sticks increase the shear bond strength between FRCs and indirect composite. CLINICAL IMPLICATIONS: In FPDs, the morphology and type of FRC substructures might influence the shear bond strength between the FRC substructure and the indirect veneering composite. With the proper design of these substructures, the number of veneering fractures may be decreased. PMID- 22512438 TI - Seroprevalence of Toxoplasma gondii infection in chickens in Jinzhou, northeastern China. AB - There is a lack of epidemiological data on Toxoplasma gondii infection in chickens in China. In the present study, serum samples from 160 free-range chickens and 450 caged chickens collected from Jinzhou, northeastern China were examined for T. gondii antibodies using a modified agglutination test (MAT). Antibodies to T. gondii were found in 30 of 160 free-range chickens (18.8%) and in 25 of 450 caged chickens (5.6%), with a significantly higher prevalence in free-range chickens (P < 0.01). In caged chickens, 8 of 100 breeders (8.0%), 15 of 190 layers (7.9%), and 2 of 160 broilers (1.3%) were positive, with the highest prevalence in breeders and layers (P < 0.05). No significant difference was found in comparing free-range chickens and caged chickens from different regions. The results of the present study indicated that infection with T. gondii in chickens, particularly in free-range chickens, is common in Jinzhou and that the meat from the poultry may be an important source for human infection by T. gondii . PMID- 22512439 TI - Tailor-made solutions and multidirectional approach in the combat of degenerative pathologies. PMID- 22512440 TI - Modified polysaccharides as versatile materials in controlled delivery of antidegenerative agents. AB - The mechanisms and factors causing or influencing degenerative diseases require tailor-made solutions. Natural polysaccharides are among the most versatile building units of the novel drug delivery systems. Their properties can be easily tailored to specific needs because they depend not only on the first-order structure, but also on the molecular weight, the type of end-groups and the conformation of the chain. The review presents the current state-of-art in the field of modifications of natural polysaccharides aiming at improving the delivery of anti-degenerative agents. Derivatization includes introducing of ionic or hydrophobic groups in order to adjust polarity or to obtain amphiphilic material, as well as degradable bonds, spacers and targeting moieties. The influence of the modification on the properties of the carrier, such as its size, surface charge, encapsulation efficiency, drug release profile, and stability in vivo, is discussed. Application of the polysaccharide derivatives to enhance the mucoadhesion and to actively target the drug to its site of action is also shown for a variety of carriers: nano and microparticulate systems, coated liposomes, hollow particles and polymer-drug conjugates. PMID- 22512441 TI - Advances in hydrogels applied to degenerative diseases. AB - Hydrogels are currently applied in the treatment of numerous degenerative diseases because of their three dimensional (3D) nature, high water content and wide range of polymers that can be used for their fabrication. Hydrogels have been investigated and commercialized, for example, as soft contact lens-based ophthalmic drug delivery systems. These novel devices improved the bioavailability of ophthalmic drugs and their residence time. Hydrogels are also being investigated to facilitate and augment targeted delivery of chemotherapeutic agents. This approach minimizes significantly the side effects associated with conventional administration of anti-cancer therapeutics. The application of hydrogels as 3D scaffold has recently gained momentum because they can mimic key features of the extracellular matrix. For this reason, hydrogels are representing a viable alternative to traditional tumor xenograft in cancer biology studies. This review highlights recent advances in the development of hydrogels that are applied in degenerative diseases such as ocular, cancer, spine and cartilage degenerative pathologies. PMID- 22512442 TI - Stem cells as a novel tool for drug screening and treatment of degenerative diseases. AB - Degenerative diseases similarly as acute tissue injuries lead to massive cell loss and may cause organ failure of vital organs (e.g., heart, central nervous system). Therefore, they belong to a group of disorders that may significantly benefit from stem cells (SCs)-based therapies. Several stem and progenitor cell populations have already been described as valuable tools for developing therapeutic strategies in regenerative medicine. In particular, pluripotent stem cells (PSCs), including adult-tissue-derived PSCs, neonatal-tissue-derived SCs, embryonic stem cells (ESCs), and recently described induced pluripotent stem cells (iPSCs), are the focus of particular attention because of their capacity to differentiate into all the cell lineages. Although PSCs are predominantly envisioned to be applied for organ regeneration, they may be also successfully employed in drug screening and disease modeling. In particular, adult PSCs and iPSCs derived from patient tissues may not only be a source of cells for autologous therapies but also for individual customized in vitro drug testing and studies on the molecular mechanisms of disease. In this review, we will focus on the potential applications of SCs, especially PSCs i) in regenerative medicine therapies, ii) in studying mechanisms of disease, as well as iii) in drug screening and toxicology tests that are crucial in new drug development. In particular, we will discuss the application of SCs in developing new therapeutic approaches to treat degenerative diseases of the neural system and heart. The advantage of adult PSCs in all the above-mentioned settings is that they can be directly harvested from patient tissues and used not only as a safe non immunogenic source of cells for therapy but also as tools for personalized drug screening and pharmacological therapies. PMID- 22512443 TI - Can PET imaging facilitate optimization of cancer therapies? AB - Positron emission tomography (PET) has become an indispensable tool in the study of cancer biology, as well as in the clinical management of patients with cancer. Quantitative measurements of tracer accumulation enable researchers to detect tumor changes much earlier than by conventional imaging modalities. 18F-FDG has been widely utilized for staging and restaging of cancer, evaluation of response to the treatment, and assessment of prognosis; however, recently target-specific PET tracers have raised even more attention. This overview discusses the current status of PET imaging in optimization of cancer therapies in preclinical and clinical studies. PMID- 22512444 TI - Bioresorbable and nonresorbable polymers for bone tissue engineering. AB - In recent years, bone tissue engineering has emerged as one of the main research areas in the field of regenerative biomedicine. Frequency and relevance age related diseases, such as healing and regeneration of bone tissues, are rising due to increasing life expectancy. Even though bone tissue has excellent self regeneration ability, when bone defects exceed a critical size, impaired bone formation can occur and surgical intervention becomes mandatory. Bone tissue engineering represents an alternative approach to conventional bone transplants. The main aim of tissue engineering is to repair, regenerate or reconstruct damaged or degenerative tissue. This review presents an overview on the main materials, techniques and strategies in the field of bone tissue engineering. Whilst presenting some reviews recently published that deepen on each of the sections of the paper, this review article aims to present some of the most relevant advances, both in terms of new materials and strategies, currently being developed for bone repair and regeneration. PMID- 22512445 TI - Heparin--a key drug in the treatment of the circulatory degenerative diseases: controlling its action with polymers. AB - The properties of heparin, a key anticoagulant, are reviewed. The important issues in heparinotherapy, i.e., reaching quick anticoagulant effect, maintaining therapeutic level of anticoagulation, heparin inhibition and non-invasive heparin formulations have been reviewed and discussed, with the focus on the role of polymeric substances in the proposed solutions. PMID- 22512446 TI - Nanostructural hybrid sensitizers for photodynamic therapy. AB - Photodynamic therapy (PDT) is a clinically approved method for treatment of cancer, microbial infections, and some other diseases. PDT has proved effective in the treatment of malignancies of various organs, including lung, bladder, gastrointestinal tract, and skin, and in the therapy of bacterial infection of skin wounds and carious lesions. It employs a combination of light and a drug (photosensitizer, PS) to induce phototoxicity against cancerous cells or bacteria. The efficiency of currently used PSs is limited due to their hydrophobic nature, which causes aggregation of the PS in aqueous media and low tumor selectivity (a low value of the tumor-to-normal tissue ratio). The purpose of this review is to present some aspects of the current state of knowledge on nanostructural carriers for the PS delivery. In this paper we reviewed studies on the development of nanostructural materials for PDT, especially those based on the polymeric and liposomal formulation of PS. We focused mainly on the nanostructural PSs obtained by the covalent attachment of hydrophilic polymer chain to the low-molecular-weight PS, the incorporation of PS into polymeric nanostructures such as micelles, and the solubilization of PS in liposome carriers. PMID- 22512447 TI - Polymeric nanocarriers and nanoreactors: a survey of possible therapeutic applications. AB - There is, today, great need for new systems and strategies for therapeutic applications that will lead to improvements in patient conditions and prognoses, especially in complex diseases such as neurodegenerative diseases and cancer. Recently, polymer nanocarriers have been developed to protect and transport active compounds to pathological sites more efficiently than free compounds in terms of stability, amount required, localization and efficacy. There are two strategies to deliver active compounds: conventional drug delivery systems based on transport and release of active compounds in biological compartments and nanoreactors that transport active compounds and permit them to act in situ, behaving like rudimentary artificial organelles. Here, we present both strategies with their advantages and limitations, and indicate how they can contribute to therapeutic improvement. We focus on presenting the design and development of polymer nanocarriers and nanoreactors as an essential stage of conceiving therapeutic approaches. The properties of the polymer carrier and its behavior under biological conditions dramatically influence the efficacy of the active compound, and thus of the treatment scheme. The key contributions that nanocarriers and nanoreactors could make include protecting active compounds from degradation in biological compartments other than those desired, and concentrating such compounds within their assemblage to allow for multiple deliveries in one single polymer assembly. To efficiently cope with the challenges of complex pathological conditions it is necessary to go one step beyond conventional drug delivery systems by designing and developing nanocarriers that mimic organelles, by combining various active molecules in a single carrier, and even by combining therapeutic agents along with agents for detection, as in a theragnostic approach. PMID- 22512448 TI - Implantable (bio)polymer coated titanium scaffolds: a review. AB - In the current review we aim to give an overview of the state of the art of the research on (bio)polymer functionalised titanium implants for bone tissue engineering applications. After a short introduction on bone tissue engineering and the requirements the applied materials have to meet, an extensive discussion on titanium in bone tissue engineering will be given. Starting with a short description of both the titanium bulk and surface properties, the requirement for surface modified titanium will be highlighted. The discussion will encompass inorganic and organic chemical modifications and a combination thereof with a focus on the organic modifications. Within the latter type of modification, physical adsorption, physical incorporation and covalent immobilisation will be compared. In the final part of the review an overview will be given of the fabrication and characterisation of three-dimensional titanium scaffolds. PMID- 22512449 TI - Glutamate and GABA in the medial amygdala induce selective central sympathetic/parasympathetic cardiovascular responses. AB - Glutamate and gamma-aminobutyric acid (GABA) participate in central cardiovascular control, and are found in the rat posterodorsal medial amygdala (MePD), an area of the forebrain that modulates emotional/social behaviors. Here we tested whether these neurotransmitters in the MePD could change the basal activity, chemoreflex, and baroreflex cardiovascular responses in awake rats. Power spectral analysis and symbolic analysis were used to evaluate these responses. Microinjections of saline, glutamate (2 ug), or GABA (61 ng or 100 ug; n = 5-7 rats per group) did not affect basal parameters or chemoreflex responses. However, baroreflex responses showed marked changes. Glutamate increased power spectral and symbolic sympathetic indexes related to both cardiac and vascular modulations (P < 0.05). In turn, the displacement of the baroreflex half-maximal heart rate (HR) response was associated with a GABA (61 ng) mediated decrease in the upper plateau (P < 0.05). Administration of GABA (61 ng, but not 100 ug) also increased HR variability (P < 0.05), in association with parasympathetic activation. These data add novel evidence that the MePD can promote selective responses in the central regulation of the cardiovascular system, i.e., glutamate in the MePD evoked activation of a central sympathetic reflex adjustment, whereas GABA activated a central parasympathetic one. PMID- 22512450 TI - Phenolic compounds and saponins in quinoa samples (Chenopodium quinoa Willd.) grown under different saline and nonsaline irrigation regimens. AB - Quinoa is a pseudocereal from South America that has received increased interest around the world because it is a good source of different nutrients and rich in antioxidant compounds. Thus, this study has focused on the effects of different agronomic variables, such as irrigation and salinity, on the phenolic and saponin profiles of quinoa. It was observed that irrigation with 25% of full water restitution, with and without the addition of salt, was associated with increases in free phenolic compounds of 23.16 and 26.27%, respectively. In contrast, bound phenolic compounds were not affected by environmental stresses. Saponins decreased if samples were exposed to drought and saline regimens. In situations of severe water deficit, the saponins content decreased 45%, and 50% when a salt stress was added. The results suggest that irrigation and salinity may regulate the production of bioactive compounds in quinoa, influencing its nutritional and industrial values. PMID- 22512452 TI - Is Medicaid constitutional? PMID- 22512453 TI - Making the best of hospital pay for performance. PMID- 22512451 TI - Identification of the key residues determining the product specificity of isomerohydrolase. AB - The efficient recycling of the chromophore of visual pigments, 11-cis-retinal, through the retinoid visual cycle is an essential process for maintaining normal vision. RPE65 is the isomerohydrolase in retinal pigment epithelium and generates predominantly 11-cis-retinol (11cROL) and a minor amount of 13-cis-retinol (13cROL), from all-trans-retinyl ester (atRE). We recently identified and characterized novel homologues of RPE65, RPE65c, and 13-cis-isomerohydrolase (13cIMH), which are expressed in the zebrafish inner retina and brain, respectively. Although these two homologues have 97% identical amino acid sequences, they exhibit distinct product specificities. Under the same assay conditions, RPE65c generated predominantly 11cROL, similar to RPE65, while 13cIMH generated exclusively 13cROL from atRE substrate. To study the impacts of the key residues determining the isomerization product specificity of RPE65, we replaced candidate residues by site-directed mutagenesis in RPE65c and 13cIMH. Point mutations at residues Tyr58, Phe103, and Leu133 in RPE65c resulted in significantly altered isomerization product specificities. In particular, our results showed that residue 58 is a primary determinant of isomerization specificity, because the Y58N mutation in RPE65c and its reciprocal N58Y mutation in 13cIMH completely reversed the respective enzyme isomerization product specificities. These findings will contribute to the elucidation of molecular mechanisms underlying the isomerization reaction catalyzed by RPE65. PMID- 22512454 TI - The origin and evolution of the ectodermal placodes. AB - Many of the features that distinguish the vertebrates from other chordates are found in the head. Prominent amongst these differences are the paired sense organs and associated cranial ganglia. Significantly, these structures are derived developmentally from the ectodermal placodes. It has therefore been proposed that the emergence of the ectodermal placodes was concomitant with and central to the evolution of the vertebrates. More recent studies, however, indicate forerunners of the ectodermal placodes can be readily identified outside the vertebrates, particularly in urochordates. Thus the evolutionary history of the ectodermal placodes is deeper and more complex than was previously appreciated with the full repertoire of vertebrate ectodermal placodes, and their derivatives, being assembled over a protracted period rather than arising collectively with the vertebrates. PMID- 22512456 TI - Exocyclic carbons adjacent to the N6 of adenine are targets for oxidation by the Escherichia coli adaptive response protein AlkB. AB - The DNA and RNA repair protein AlkB removes alkyl groups from nucleic acids by a unique iron- and alpha-ketoglutarate-dependent oxidation strategy. When alkylated adenines are used as AlkB targets, earlier work suggests that the initial target of oxidation can be the alkyl carbon adjacent to N1. Such may be the case with ethano-adenine (EA), a DNA adduct formed by an important anticancer drug, BCNU, whereby an initial oxidation would occur at the carbon adjacent to N1. In a previous study, several intermediates were observed suggesting a pathway involving adduct restructuring to a form that would not hinder replication, which would match biological data showing that AlkB almost completely reverses EA toxicity in vivo. The present study uses more sensitive spectroscopic methodology to reveal the complete conversion of EA to adenine; the nature of observed additional putative intermediates indicates that AlkB conducts a second oxidation event in order to release the two-carbon unit completely. The second oxidation event occurs at the exocyclic carbon adjacent to the N(6) atom of adenine. The observation of oxidation of a carbon at N(6) in EA prompted us to evaluate N(6) methyladenine (m6A), an important epigenetic signal for DNA replication and many other cellular processes, as an AlkB substrate in DNA. Here we show that m6A is indeed a substrate for AlkB and that it is converted to adenine via its 6 hydroxymethyl derivative. The observation that AlkB can demethylate m6A in vitro suggests a role for AlkB in regulation of important cellular functions in vivo. PMID- 22512457 TI - Surfactant-assisted synthesis and characterization of stable silver bromide nanoparticles in aqueous media. AB - Colloidal dispersions of silver bromide (AgBr) in aqueous surfactant medium have been prepared using a surfactant-assisted synthesis approach with hexadecyltrimethylammonium bromide (CTAB). The surfactant acts both as source of bromide ion as well as the stabilizing agent. Upon progressive addition of silver nitrate to aqueous CTAB solution, stable AgBr dispersions were obtained. Formation of surfactant cation (CTA(+)) stabilized AgBr was confirmed by way of XRD, FTIR and NMR studies. Thermal behavior of the isolated nanoparticles was investigated by differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA), where the occurrence of phase transition in the surfactant stabilized nanoparticles was observed. Kinetics of the particle growth was investigated by dynamic light scattering measurements, which predicted the formation of surfactant bilayered structures associated with the nanoparticles of AgBr. Band gap of the nanoparticles was determined by suitably analyzing the UV visible spectral data, which concluded that the particles behaved like insulators. Morphology of the particles, studied by TEM measurements, was found to be spherical. Finally, enthalpy of formation of surfactant-stabilized AgBr, determined calorimetrically, was found to be dependent on the concentration of the precursors. PMID- 22512458 TI - Retaining older experienced nurses in the Northern Territory of Australia: a qualitative study exploring opportunities for post-retirement contributions. AB - INTRODUCTION: Many countries are facing an ageing of the nursing workforce and increasing workforce shortages. This trend is due to members of the 'baby boomer' generation leaving the workforce for retirement and a declining pool of younger people entering the nursing profession. New approaches to engaging older nurses in the workforce are becoming common in nursing globally but have yet to be adapted to remote contexts such as the Northern Territory (NT) of Australia. This article reports findings from a qualitative study of 15 participants who explored perceived opportunities for and barriers to implementing flexible strategies to engage older nurses in the NT workforce after they resign from full-time work. METHODS: The study used a descriptive qualitative design. Data were collected using semi-structured interviews with NT nurses approaching retirement (six nurses aged 50 years and over) and their managers (n=9). Clinicians were employed in practice settings that included hospitals, community health and 'Top End' (north of and including the town of Katherine), as well as Central Australian remote area communities. One participant who was employed as primary health centre manager in a remote community also held a clinical role. Managers were employed in both senior and line management positions in community and remote health as well as NT hospitals. RESULTS: Three major themes emerged from the data. First, interview participants identified potential for flexible post retirement engagement of older nurses and a range of concrete engagement opportunities 'on and off the floor' were identified. Second, the main barriers to post-retirement engagement were an existing focus on the recruitment of younger Australian and overseas-trained nurses, and the remoteness of nursing practice settings from the residential locations of retired nurses. Third, existing informal system of post-retirement working arrangements, characterized by ad hoc agreements between individual nurses and managers, is poorly suited to scaling up. CONCLUSION: A knowledge and change-management approach is required to change employers' views of the value of older nurses. Better engagement of those nurses may assist the NT Department of Health address the severe nursing workforce shortages and prevent the loss of significant remote area nursing knowledge. PMID- 22512459 TI - Standard tensorial analysis of local ordering in proteins from residual dipolar couplings. AB - Residual dipolar couplings (RDCs) in proteins arise from independent external medium-related and internal protein-related ordering of the spin-bearing probe. Griesinger et al. developed a method for treating RDCs in proteins. The global ordering is given in the standard manner by a rank 2 tensor specified in a known molecular frame, MF. The local ordering is described by the spherical harmonic ensemble averages, , m = 0, +/-1, +/-2, also given in MF. From these quantities, a method we call mf-RDC derives the squared generalized order parameter (S(rdc)(2)), the amplitude (direction) of the anisotropic disorder, eta (Phi'), and an approximation, (N-H)(eff), to the average probe orientation, i.e., to the local director. (N-H)(eff) is determined through a frame transformation where is maximized. Phi' is associated with a subsequent frame transformation where is maximized. The mf-RDC method was applied previously to N-H and C-C(methyl) sites in ubiquitin. In this study, we convert the respective 's into a Saupe tensor, which is diagonalized. This is the standard procedure. It yields the eigenvalues, S(xx), S(yy), and S(zz), and the Principal Axis System (PAS) of the rank 2 local ordering tensor, S(l). S(rdc)(2), eta, and Phi' can be recast as S(xx), S(yy), and S(zz). The mf RDC frame transformations are not the same as the conventional Wigner rotation. The standard tensorial analysis provides new information. The contribution of local ordering rhombicity to S(rdc)(2) is evaluated. For the alpha-helix of ubiquitin, the main local ordering axis is assigned as C(i-1)(alpha) - C(i)(alpha); for the methyl sites, it is associated with the C-C(methyl) axis, as in mf-RDC. Ordering strength correlates with methyl type. The strength (rhombicity) of S(l) associated with picosecond-nanosecond local motions is reduced moderately (substantially) by nanosecond-millisecond local motions. A scheme for analyzing experimental RDCs based on the standard tensorial perspective, which allows for arbitrary orientation of the local director in the protein and of the PAS of S(l) in the probe, is formulated. PMID- 22512460 TI - Influence of the cation size on the framework structures and space group centricities in AMo2O5(SeO3)2 (A = Sr, Pb, and Ba). AB - Two new quaternary mixed-metal selenites, SrMo(2)O(5)(SeO(3))(2) and PbMo(2)O(5)(SeO(3))(2), have been synthesized as crystals and pure polycrystalline phases by standard solid-state reactions using SrMoO(4), PbO, MoO(3), and SeO(2) as reagents. The crystal structures of the reported materials have been determined by single-crystal X-ray diffraction. SrMo(2)O(5)(SeO(3))(2) and PbMo(2)O(5)(SeO(3))(2) are isostructural and crystallized in the triclinic centrosymmetric space group P1 (No. 2). The reported materials exhibit chain structures consisting of MoO(6) octahedra and asymmetric SeO(3) polyhedra. Complete characterizations including IR spectroscopy and thermal analyses for the compounds are also presented, as are dipole moment calculations. In addition, the powder second-harmonic-generating (SHG) properties of noncentrosymmetric polar BaMo(2)O(5)(SeO(3))(2) have been measured using 1064 nm radiation. Through powder SHG measurement, we are able to determine that BaMo(2)O(5)(SeO(3))(2) has a SHG efficiency of approximately 80 times that of alpha-SiO(2). Additional SHG measurements reveal that the material is phase-matchable (type 1). A detailed cation size effect on the symmetry and framework structure is discussed. PMID- 22512461 TI - Control of periodontal infections: a randomized controlled trial I. The primary outcome attachment gain and pocket depth reduction at treated sites. AB - OBJECTIVE: To compare the treatment outcome of scaling and root planing (SRP) in combination with systemic antibiotics, local antibiotic therapy and/or periodontal surgery. MATERIAL AND METHODS: One hundred and eighty-seven patients were assigned to eight groups treated by SRP plus none, one, two or three adjunctive treatments and monitored for 24 months in a randomized controlled clinical trial using a 2 * 2 * 2 factorial design. Systemic amoxicillin + metronidazole (SMA), local tetracycline delivery (LTC) and periodontal surgery (SURG) were evaluated as adjuncts. Changes in clinical attachment level (CAL) and probing pocket depth (PPD) were statistically evaluated by ancova of main effects. RESULTS: Effects of adjunctive therapy to SRP were minimal at 3 months. Between 3 and 6 months PPD reduction occurred particularly in patients receiving periodontal surgery. After 6 months, both CAL gain and PPD reduction reached a plateau that was maintained at 24 months in all groups. The 24-month CAL gain was improved by SMA (0.50 mm) while PPD was reduced by SMA (0.51 mm) and SURG (0.36 mm). Smoking reduced CAL gain and PPD reduction. CONCLUSION: Patients receiving adjunctive therapies generally exhibited improved CAL gain and/or PPD reduction when compared with the outcome of SRP alone. Only additive, not synergistic effects of the various adjunctive therapies were observed. PMID- 22512462 TI - Prosthodontic rehabilitation for total glossectomy with a magnetic detachable mandibular tongue prosthesis: a clinical report. AB - Total glossectomy can result in significant functional impairments in mastication, swallowing, and speech. In addition to these functional problems, severe psychological problems may follow complete loss of the tongue. Placement of a mandibular tongue prosthesis obturates this large defect, increases the patient's ability to produce intelligible sounds, and assists with a return to a normal diet. Prosthetic rehabilitation can also improve the user's appearance and psychosocial adjustment. This clinical report describes a magnetically attached two-piece tongue prosthesis used to treat a patient who underwent total glossectomy. PMID- 22512463 TI - Substrate-independent method for growing and modulating the density of polymer brushes from surfaces by ATRP. AB - We describe a method for grafting PEG-based polymer chains of variable surface density using a substrate independent approach, allowing grafting from virtually any material substrate. The approach relies upon initial coupling of a macroinitiator to plasma polymer treated surfaces. The macroinitiator is a novel random terpolymer containing ATRP initiator residues, strongly negatively charged groups, and carboxylic acid moieties that facilitate covalent surface anchoring. Surface-initiated ATRP (SI-ATRP) using polyethylene glycol methyl ether methacrylate (PEGMA) at different concentrations led to grafted surfaces of controlled thickness in either the "brush" or "mushroom" morphology, which was controlled by the abundance of initiator residues in the macroinitiator. Grafted polymer layer structure was investigated via direct interaction force measurements using colloid probe atomic force microscopy (AFM). Equilibrium, hydrated graft layer thicknesses inferred from the highly repulsive AFM force data suggest that the polymer brush graft layer contained polymer chains which were fully stretched. Since the degree of stretching resulted in layer thicknesses approaching the polymer contour length, the polymer brushes studied must be very close to maximum graft density. Grafted layers where the polymer molecules were in the mushroom regime resulted in much thinner layers but the chains had greater chain entropic freedom as indicated by strongly attractive bridging interactions between tethered chains and the silica colloid probe. Use of this experimental methodology would be suitable for preparing grafted polymer layers of a preferred density free from substrate-specific linking chemistries. PMID- 22512465 TI - Prolidase function in proline metabolism and its medical and biotechnological applications. AB - Prolidase is a multifunctional enzyme that possesses the unique ability to degrade imidodipeptides in which a proline or hydroxyproline residue is located at the C-terminal end. Prolidases have been isolated from archaea and bacteria, where they are thought to participate in proline recycling. In mammalian species, prolidases are found in the cytoplasm and function primarily to liberate proline in the final stage of protein catabolism, particularly during the biosynthesis and degradation of collagen. Collagen comprises nearly one-third of the total protein in the body, and it is essential in maintaining tissue structure and integrity. Prolidase deficiency (PD), a rare autosomal recessive disorder in which mutations in the PEPD gene affect prolidase functionality, tends to have serious and sometimes life-threatening clinical symptoms. Recombinant prolidases have many applications and have been investigated not only as a possible treatment for PD, but also as a part of anti-cancer strategies, a component of biodecontamination cocktails and in the dairy industry. This review will serve to discuss the many in vivo functions of procaryotic and eucaryotic prolidases, as well as the most recent advances in therapeutic and biotechnological application of prolidases. PMID- 22512464 TI - Modelling intravascular delivery from drug-eluting stents with biodurable coating: investigation of anisotropic vascular drug diffusivity and arterial drug distribution. AB - In-stent restenosis occurs in coronary arteries after implantation of drug eluting stents with non-uniform restenosis thickness distribution in the artery cross section. Knowledge of the spatio-temporal drug uptake in the arterial wall is useful for investigating restenosis growth but may often be very expensive/difficult to acquire experimentally. In this study, local delivery of a hydrophobic drug from a drug-eluting stent implanted in a coronary artery is mathematically modelled to investigate the drug release and spatio-temporal drug distribution in the arterial wall. The model integrates drug diffusion in the coating and drug diffusion with reversible binding in the arterial wall. The model is solved by the finite volume method for both high and low drug loadings relative to its solubility in the stent coating with varied isotropic-anisotropic vascular drug diffusivities. Drug release profiles in the coating are observed to depend not only on the coating drug diffusivity but also on the properties of the surrounding arterial wall. Time dependencies of the spatially averaged free- and bound-drug levels in the arterial wall on the coating and vascular drug diffusivities are discussed. Anisotropic vascular drug diffusivities result in slightly different average drug levels in the arterial wall but with very different spatial distributions. Higher circumferential vascular diffusivity results in more uniform drug loading in the upper layers and is potentially beneficial in reducing in-stent restenosis. An analytical expression is derived which can be used to determine regions in the arterial with higher free-drug concentration than bound-drug concentration. PMID- 22512466 TI - No indication of strict host associations in a widespread mycoparasite: grapevine powdery mildew (Erysiphe necator) is attacked by phylogenetically distant Ampelomyces strains in the field. AB - Pycnidial fungi belonging to the genus Ampelomyces are common intracellular mycoparasites of powdery mildews worldwide. Some strains have already been developed as commercial biocontrol agents (BCAs) of Erysiphe necator and other powdery mildew species infecting important crops. One of the basic, and still debated, questions concerning the tritrophic relationships between host plants, powdery mildew fungi, and Ampelomyces mycoparasites is whether Ampelomyces strains isolated from certain species of the Erysiphales are narrowly specialized to their original mycohosts or are generalist mycoparasites of many powdery mildew fungi. This is also important for the use of Ampelomyces strains as BCAs. To understand this relationship, the nuclear ribosomal DNA internal transcribed spacer (ITS) and partial actin gene (act1) sequences of 55 Ampelomyces strains from E. necator were analyzed together with those of 47 strains isolated from other powdery mildew species. These phylogenetic analyses distinguished five major clades and strains from E. necator that were present in all but one clade. This work was supplemented with the selection of nine inter-simple sequence repeat (ISSR) markers for strain-specific identification of Ampelomyces mycoparasites to monitor the environmental fate of strains applied as BCAs. The genetic distances among strains calculated based on ISSR patterns have also highlighted the genetic diversity of Ampelomyces mycoparasites naturally occurring in grapevine powdery mildew. Overall, this work showed that Ampelomyces strains isolated from E. necator are genetically diverse and there is no indication of strict mycohost associations in these strains. However, these results cannot rule out a certain degree of quantitative association between at least some of the Ampelomyces lineages identified in this work and their original mycohosts. PMID- 22512467 TI - Mohs micrographic surgery in primary care: knowledge of the technique and perceptions of Mohs surgeons among general practitioners in one U.K. region. PMID- 22512468 TI - Selective thyromimetics using receptor and tissue selectivity approaches: prospects for dyslipidemia. PMID- 22512469 TI - Asynchrony in discrete bimanual aiming: evidence for visual strategies of coordination. AB - The bimanual coupling literature supposes an inherent drive for synchrony between the upper limbs when making discrete bimanual movements. The level of synchrony is argued to be task dependent, reliant on the visual demands of the two targets, and the result of a complex pattern of hand and eye movements (Bingham, Hughes, & Mon-Williams, 2008 ; Riek, Tresilian, Mon-Williams, Coppard, & Carson, 2003). However, recent work by Bruyn and Mason (2009) suggests that temporal coordination is not solely influenced by visual saccades. In this experimental series, a total of 8 participants performed congruent movements to targets either near or far from the midline. Targets far from the midline, requiring a visual saccade, resulted in greater terminal asynchrony. Initial and terminal asynchrony were not consistent, but linked to the task demands at that stage of the movement. If the asynchrony evident at the end of a bimanual movement is due to a complex pattern of hand and eye movements then the removal of visual feedback should result in an increase in synchrony. Sixteen participants then completed congruent and incongruent bimanual aiming movements to near and/or far targets. Movements were made with or without visual feedback of hands and targets. Analyses revealed that movements made without visual feedback showed increased synchrony between the limbs, yet movements to incongruent targets still showed greater asynchrony. We suggest that visual constraints are not the sole cause of asynchrony in discrete bimanual movements. PMID- 22512470 TI - A randomized control trial of interventions in school-aged children with auditory processing disorders. AB - OBJECTIVE: The primary purpose of the study was to compare intervention approaches for children with auditory processing disorder (APD): bottom-up training including activities focused on auditory perception, discrimination, and phonological awareness, and top-down training including a range of language activities. Another purpose was to determine the benefits of personal FM systems. DESIGN: The study is a randomized control trial where participants were allocated to groups receiving one of the two interventions, with and without personal FM, or to the no intervention group. The six-week intervention included weekly one hour sessions with a therapist in the clinic, plus 1-2 hours per week of parent directed homework. STUDY SAMPLE: 55 children (7 to 13 years) with APD participated in the study. Intervention outcomes included reading, language, and auditory processing. RESULTS: Positive outcomes were observed for both training approaches and personal FM systems on several measures. Pre-intervention nonverbal IQ, age, and severity of APD did not influence outcomes. Performance of control group participants did not change when retested after the intervention period. CONCLUSIONS: Both intervention approaches were beneficial and there were additional benefits with the use of personal FM. Positive results were not limited to the areas specifically targeted by the interventions. PMID- 22512471 TI - Absorption of aminoethyl cysteine ketimine decarboxylated dimer in mice: effect on plasma antioxidant potential. AB - Aminoethylcysteine ketimine decarboxylated dimer (AECK-DD) is a natural compound with antioxidant properties of a new family of sulfur-containing amino acids. It has been detected in human urine and plasma, in mammalian cerebellum, and in dietary vegetables. In this study, we first demonstrate the absorption of AECK-DD in mice from AECK-DD-supplemented diet, using both liquid chromatography with electrochemical detection and gas chromatography coupled with mass spectrometry. AECK-DD circulates in the plasma of supplemented mice at a micromolar concentration and is incorporated in liver tissue. The absorption of AECK-DD is dose dependent. The dehydrogenation product of AECK-DD was also identified in plasma and liver of mice fed the AECK-DD-supplemented diet. A significant increase in plasma antioxidant potential was measured in mice fed AECK-DD supplemented diet with respect to mice fed the control diet. These results demonstrate for the first time the absorption of AECK-DD from diet and the physiological relevance of this compound through its antioxidant action in vivo. PMID- 22512474 TI - Development of the hypothalamus and pituitary in platypus (Ornithorhynchus anatinus) and short-beaked echidna (Tachyglossus aculeatus). AB - The living monotremes (platypus and echidnas) are distinguished by the development of their young in a leathery-shelled egg, a low and variable body temperature and a primitive teat-less mammary gland. Their young are hatched in an immature state and must deal with the external environment, with all its challenges of hypothermia and stress, as well as sourcing nutrients from the maternal mammary gland. The Hill and Hubrecht embryological collections have been used to follow the structural development of the monotreme hypothalamus and its connections with the pituitary gland both in the period leading up to hatching and during the lactational phase of development, and to relate this structural maturation to behavioural development. In the incubation phase, development of the hypothalamus proceeds from closure of the anterior neuropore to formation of the lateral hypothalamic zone and putative medial forebrain bundle. Some medial zone hypothalamic nuclei are emerging at the time of hatching, but these are poorly differentiated and periventricular zone nuclei do not appear until the first week of post-hatching life. Differentiation of the pituitary is also incomplete at hatching, epithelial cords do not develop in the pars anterior until the first week, and the hypothalamo-neurohypophyseal tract does not appear until the second week of post-hatching life. In many respects, the structure of the hypothalamus and pituitary of the newly hatched monotreme is similar to that seen in newborn marsupials, suggesting that both groups rely solely on lateral hypothalamic zone nuclei for whatever homeostatic mechanisms they are capable of at birth/hatching. PMID- 22512472 TI - The loss of an electrostatic contact unique to AMPA receptor ligand binding domain 2 slows channel activation. AB - Ligand-gated ion channels undergo conformational changes that transfer the energy of agonist binding to channel opening. Within ionotropic glutamate receptor (iGluR) subunits, this process is initiated in their bilobate ligand binding domain (LBD) where agonist binding to lobe 1 favors closure of lobe 2 around the agonist and allows formation of interlobe hydrogen bonds. AMPA receptors (GluAs) differ from other iGluRs because glutamate binding causes an aspartate-serine peptide bond in a flexible part of lobe 2 to rotate 180 degrees (flipped conformation), allowing these residues to form cross-cleft H-bonds with tyrosine and glycine in lobe 1. This aspartate also contacts the side chain of a lysine residue in the hydrophobic core of lobe 2 by a salt bridge. We investigated how the peptide flip and electrostatic contact (D655-K660) in GluA3 contribute to receptor function by examining pharmacological and structural properties with an antagonist (CNQX), a partial agonist (kainate), and two full agonists (glutamate and quisqualate) in the wildtype and two mutant receptors. Alanine substitution decreased the agonist potency of GluA3(i)-D655A and GluA3(i)-K660A receptor channels expressed in HEK293 cells and differentially affected agonist binding affinity for isolated LBDs without changing CNQX affinity. Correlations observed in the crystal structures of the mutant LBDs included the loss of the D655-K660 electrostatic contact, agonist-dependent differences in lobe 1 and lobe 2 closure, and unflipped D(A)655-S656 bonds. Glutamate-stimulated activation was slower for both mutants, suggesting that efficient energy transfer of agonist binding within the LBD of AMPA receptors requires an intact tether between the flexible peptide flip domain and the rigid hydrophobic core of lobe 2. PMID- 22512475 TI - Plateau Rayleigh instability simulation. AB - The well-known phenomena of Plateau-Rayleigh instability has been simulated using computational fluid dynamics (CFD). The breakup of a liquid film into an array of droplets on a cylindrical element was simulated using a volume-of-fluid (VOF) solver and compared to experimental observations and existing theory. It is demonstrated that the VOF method can correctly predict the breakup of thins films into an array of either axisymmetric droplets or clam-shell droplets, depending on the surface energy. The existence of unrealistically large films is precluded. Droplet spacing was found to show reasonable agreement with theory. Droplet motion and displacement under fluid flow was also examined and compared to that in previous studies. It was found that the presence of air flow around the droplet does not influence the stable film thickness; however, it reduces the time required for droplet formation. Novel relationships for droplet displacement were derived from the results. PMID- 22512476 TI - Recent developments in buccal and sublingual delivery systems. AB - INTRODUCTION: There have been several advances in the delivery of drugs through the buccal mucosa over the last 5 years, which have resulted in a number of new buccal delivery products appearing on the market. AREAS COVERED: This review discusses the most recent developments in the area of buccal and sublingual drug delivery, with a focus on marketed drugs. Likely future directions are also considered and reported. EXPERT OPINION: The future potential of buccal and sublingual delivery systems looks favorable. It is envisaged that in the future, buccal and sublingual delivery technologies will provide a platform for the successful delivery of vaccines and antigens. It is also foreseen that physical means of enhancing drug uptake (e.g., sonophoresis, iontophoresis and electroporation) will be commercialized for buccal delivery, thereby expanding the current drug candidate list for this area. The formulation of delivery systems for photosensitizers in photodynamic therapy is a potential emerging area, while buccal and sublingual delivery, in general, is attractive for the development of intellectual property. PMID- 22512477 TI - Exchange coupling mediated by N-H...Cl hydrogen bonds: experimental and theoretical study of the frustrated magnetic system in bis(o phenylenediamine)nickel(II) chloride. AB - The title compound crystallizes in the monoclinic P2(1)/c space group with a = 11.2470(3) A, b = 5.9034(2) A, c = 12.0886(3) A, beta = 115.143(1) degrees , and V = 726.58(4) A(3) and consists of discrete monomeric NiCl(2)(o phenylendiamine)(2) molecules. Each o-phen ligand coordinates in a bidentate mode with the chloride ions occupying trans positions in the resulting tetragonally distorted octahedral coordination sphere. Two discrete sets of N-H...Cl hydrogen bonds link the octahedral molecules into a two-dimensional network, with type 1 interactions linking adjacent monomers along the c axis and type 2 interactions linking monomers along the diagonals in the bc plane. Analysis of the magnetic data reveals the existence of weak antiferromagnetic coupling within the layers via these hydrogen bonds, in addition to the presence of zero field splitting, with the best fit obtained for a 1d antiferromagnetic model with g = 2.0917(7), J/k = -2.11(4) K [J = -1.47(3) cm(-1)], and D = 1.05(3) cm(-1) [beta = D/|J| = 0.72(6)] for the model with D > 0 and g = 2.0911(6), J/k = -2.26(1) K [J = 1.57(1) cm(-1)], and D = -0.86(1) cm(-1) [beta = D/|J| = 0.55(6)] for the model with D < 0. Theoretical calculations of the exchange coupling confirm the experimental results, yielding values of J(1) = -1.39 cm(-1) for the type 1 hydrogen bonds and J(2)/k = -0.56 cm(-1) for the type 2 hydrogen bonds. PMID- 22512479 TI - Editorial: bone and immune system cross-talk. PMID- 22512478 TI - A review of animal and human studies for management of benign prostatic hyperplasia with natural products: perspective of new pharmacological agents. AB - OBJECTIVE: In this paper, we reviewed plants being effective in treatment of BPH for the purpose of finding new sources of pharmaceutical agents. METHODS: All pertinent literature databases were searched. The search keywords were plant, herb, herbal therapy, phytotherapy, benign prostatic hyperplasia, BPH, and prostate. All of the human, animal and in vitro studies were evaluated. RESULTS: According to the studies, some of the substantial effective constituents of the plants in treatment of BPH are oenothein B, icaritin, xanthohumol, diarylheptanoid, 2,6,4'-trihydroxy-4-methoxybenzophenone, emodin, fatty acids, atraric acid, n-butylbenzene-sulfonamide, curbicin, theaflavin-3,30-digallate, penta-O-galloyl-b-D-glucose, lycopene, sinalbin, beta-sitosterol, secoisolariciresinol diglucoside, genistein, apigenin, baicalein, and daidzein. Besides, Serenoa repens, Pygeum africanum, Curcubita pepo, and Urtica dioica as the most prevalent plants used to treat BPH. S. repens in human studies showed equivalent effectiveness to tamsulosin and in combination to U. dioica revealed equal effects to finastride with less side effects. CONCLUSION: There are numerous plants that have beneficial influence on BPH although the mechanisms of action in some plants are not well understood yet. Active ingredients of some of these plants are known and can be used as lead components for development of new effective and safe drugs. PMID- 22512480 TI - The evolving roles of the medical journal. PMID- 22512482 TI - Albendazole therapy and enteric parasites in United States-bound refugees. AB - BACKGROUND: Beginning on May 1, 1999, the Centers for Disease Control and Prevention (CDC) recommended presumptive treatment of refugees for intestinal parasites with a single dose of albendazole (600 mg), administered overseas before departure for the United States. METHODS: We conducted a retrospective cohort study involving 26,956 African and Southeast Asian refugees who were screened by means of microscopical examination of stool specimens for intestinal parasites on resettlement in Minnesota between 1993 and 2007. Adjusted prevalence ratios for intestinal nematodes, schistosoma species, giardia, and entamoeba were calculated among refugees who migrated before versus those who migrated after the CDC recommendation of presumptive predeparture albendazole treatment. RESULTS: Among 4370 untreated refugees, 20.8% had at least one stool nematode, most commonly hookworm (in 9.2%). Among 22,586 albendazole-treated refugees, only 4.7% had one or more nematodes, most commonly trichuris (in 3.9%). After adjustment for sex, age, and region, albendazole-treated refugees were less likely than untreated refugees to have any nematodes (prevalence ratio, 0.19), ascaris (prevalence ratio, 0.06), hookworm (prevalence ratio, 0.07), or trichuris (prevalence ratio, 0.27) but were not less likely to have giardia or entamoeba. Schistosoma ova were identified exclusively among African refugees and were less prevalent among those treated with albendazole (prevalence ratio, 0.60). After implementation of the albendazole protocol, the most common pathogens among 17,011 African refugees were giardia (in 5.7%), trichuris (in 5.0%), and schistosoma (in 1.8%); among 5575 Southeast Asian refugees, only giardia remained highly prevalent (present in 17.2%). No serious adverse events associated with albendazole use were reported. CONCLUSIONS: Presumptive albendazole therapy administered overseas before departure for the United States was associated with a decrease in the prevalence of intestinal nematodes among newly arrived African and Southeast Asian refugees. PMID- 22512481 TI - Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. AB - BACKGROUND: Radiotherapy is an alternative to cystectomy in patients with muscle invasive bladder cancer. In other disease sites, synchronous chemoradiotherapy has been associated with increased local control and improved survival, as compared with radiotherapy alone. METHODS: In this multicenter, phase 3 trial, we randomly assigned 360 patients with muscle-invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. The regimen consisted of fluorouracil (500 mg per square meter of body-surface area per day) during fractions 1 to 5 and 16 to 20 of radiotherapy and mitomycin C (12 mg per square meter) on day 1. Patients were also randomly assigned to undergo either whole bladder radiotherapy or modified-volume radiotherapy (in which the volume of bladder receiving full-dose radiotherapy was reduced) in a partial 2-by-2 factorial design (results not reported here). The primary end point was survival free of locoregional disease. Secondary end points included overall survival and toxic effects. RESULTS: At 2 years, rates of locoregional disease-free survival were 67% (95% confidence interval [CI], 59 to 74) in the chemoradiotherapy group and 54% (95% CI, 46 to 62) in the radiotherapy group. With a median follow-up of 69.9 months, the hazard ratio in the chemoradiotherapy group was 0.68 (95% CI, 0.48 to 0.96; P=0.03). Five-year rates of overall survival were 48% (95% CI, 40 to 55) in the chemoradiotherapy group and 35% (95% CI, 28 to 43) in the radiotherapy group (hazard ratio, 0.82; 95% CI, 0.63 to 1.09; P=0.16). Grade 3 or 4 adverse events were slightly more common in the chemoradiotherapy group than in the radiotherapy group during treatment (36.0% vs. 27.5%, P=0.07) but not during follow-up (8.3% vs. 15.7%, P=0.07). CONCLUSIONS: Synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, with no significant increase in adverse events. (Funded by Cancer Research U.K.; BC2001 Current Controlled Trials number, ISRCTN68324339.). PMID- 22512484 TI - Alopecia areata. PMID- 22512483 TI - Integrin alpha3 mutations with kidney, lung, and skin disease. AB - Integrin alpha(3) is a transmembrane integrin receptor subunit that mediates signals between the cells and their microenvironment. We identified three patients with homozygous mutations in the integrin alpha(3) gene that were associated with disrupted basement-membrane structures and compromised barrier functions in kidney, lung, and skin. The patients had a multiorgan disorder that included congenital nephrotic syndrome, interstitial lung disease, and epidermolysis bullosa. The renal and respiratory features predominated, and the lung involvement accounted for the lethal course of the disease. Although skin fragility was mild, it provided clues to the diagnosis. PMID- 22512485 TI - Images in clinical medicine. Metastatic inguinal lymphadenopathy. PMID- 22512486 TI - Case records of the Massachusetts General Hospital. Case 12-2012. A 10-month-old girl with vomiting and episodes of unresponsiveness. PMID- 22512487 TI - Old drugs, new purpose--bladder cancer turning a corner. PMID- 22512488 TI - A muscular twist on the fate of fat. PMID- 22512490 TI - Bone-density testing interval and transition to osteoporosis. PMID- 22512491 TI - Bone-density testing interval and transition to osteoporosis. PMID- 22512492 TI - Bone-density testing interval and transition to osteoporosis. PMID- 22512494 TI - Iron overload in human disease. PMID- 22512495 TI - Iron overload in human disease. PMID- 22512496 TI - Iron overload in human disease. PMID- 22512498 TI - Interpreting the coronary-artery calcium score. PMID- 22512499 TI - Pulmonary fibrosis, bone marrow failure, and telomerase mutation. PMID- 22512500 TI - Images in clinical medicine. Unilateral dermatoheliosis. PMID- 22512501 TI - Pressure-induced transport of DNA confined in narrow capillary channels. AB - Pressure-induced transport of double-stranded DNA (dsDNA) from 10 base pairs (bp) to 1.9 mega base pairs (Mbp) confined in a 750-nm-radius capillary was studied using a hydrodynamic chromatographic technique and four distinct length regions (rod-like, free-coiled, constant mobility, and transition regions) were observed. The transport behavior varied closely with region changes. The rod-like region consisted of DNA shorter than the persistence length (~150 bp) of dsDNA, and these molecules behaved like polymer rods. Free-coiled region consisted of DNA from ~150 bp to ~2 kilo base pairs (kbp), and the effective hydrodynamic radius R(HD) of these DNA scaled to L(0.5) (L is the DNA length in kbp), a characteristic property of freely coiled polymers. Constant mobility region consisted of DNA longer than ~100 kbp, and these DNA had a constant hydrodynamic mobility and could not be resolved. Transition region existed between free-coiled and constant mobility regions. The transport mechanism of DNA in this region was complicated, and a general empirical equation was established to relate the mobility with DNA length. Understanding of the fundamental principles of DNA transport in narrow capillary channels will be of great interest in the development of "lab-on-chip" technologies and nongel DNA separations. PMID- 22512502 TI - The impact of self-confidence on the compromise effect. AB - This research reports an investigation into whether the personality aspect of self-confidence affects the compromise effect. We hypothesize that highly self confident people have greater certainty in making decisions and are more attracted to risk-taking, which makes them less likely to choose the safe or middle option in a large choice set. The three studies involved are conducted using between- and within-subjects experimental designs. Various product categories are used to generalize the findings. Study 1 looks at purchasing decisions and utilizes three scales of self-confidence, risk preference, and uncertainty; it demonstrates that consumers with high self-confidence are less likely to choose a compromise option due to high certainty in their decision making. Study 2 discovers that people with low self-confidence are more likely to choose the middle option in a risky condition than in a nonrisky condition. Study 3 decomposes self-confidence into general and specific self-confidence, and reveals that people with low general self-confidence and low specific self confidence are more likely to choose the middle option. PMID- 22512503 TI - Expression and effects of glial cell line-derived neurotrophic factor on periodontal ligament cells. AB - AIM: To investigate Glial cell line-derived neurotrophic factor (GDNF) expression in normal and wounded rat periodontal ligament (PDL) and the effects of GDNF on human PDL cells (HPDLCs) migration and extracellular matrix expression in HPDLCs. MATERIAL AND METHODS: The expression of GDNF and GDNF receptors was examined by immunocyto/histochemical analyses. Gene expression in HPDLCs treated with GDNF, interleukin-1 beta (IL-1beta), or tumour necrosis factor-alpha (TNF-alpha) was quantified by quantitative RT-PCR (qRT-PCR). In addition, we examined the migratory effect of GDNF on HPDLCs. RESULTS: GDNF was expressed in normal rat PDL and cultured HPDLCs. HPDLCs also expressed GDNF receptors. In wounded rat PDL, GDNF expression was up-regulated. QRT-PCR analysis revealed that IL-1beta and TNF alpha significantly increased the expression of GDNF in HPDLCs. Furthermore, GDNF induced migration of HPDLCs, which was blocked by pre-treatment with the peptide including Arg-Gly-Asp (RGD) sequence, or neutralizing antibodies against integrin alphaVbeta3 or GDNF. Also, GDNF up-regulated expression of bone sialoprotein (BSP) and fibronectin in HPDLCs. CONCLUSIONS: GDNF expression is increased in rat wounded PDL tissue and HPDLCs treated with pro-inflammatory cytokines. GDNF enhances the expression of BSP and fibronectin, and migration in an RGD-dependent manner via the integrin alphaVbeta3. These findings suggest that GDNF may contribute to wound healing in PDL tissue. PMID- 22512504 TI - Platelet-associated angiogenesis regulating factors: a pharmacological perspective. AB - Platelets, in addition to maintaining hemostasis, also stimulate angiogenesis by generating and releasing, upon activation, factors that promote the growth of new blood vessels. To date, at least 20 angiogenesis-regulating factors have been identified in platelets, including both promoters and inhibitors. Platelet derived angiogenesis regulators promote angiogenesis during wound healing, tumor growth, and in response to ischemia. Within platelets, angiogenesis regulators are primarily stored in alpha-granules, but are also found in the cytosol or derived from membrane lipids. Their release can be inhibited pharmacologically by anti-platelet agents, which consequently suppress platelet-stimulated angiogenesis. Several years ago, our research group discovered that platelets generate the angiogenesis inhibitor angiostatin independent of the activation state of platelets, and that platelet-derived angiostatin serves to limit the angiogenesis-stimulating effects of platelets. In this review, we summarize the current knowledge of platelet-associated angiogenesis regulators, how they impact angiogenesis, and how they are controlled pharmacologically. PMID- 22512505 TI - Butyl pocket formation in the vitamin D receptor strongly affects the agonistic or antagonistic behavior of ligands. AB - Previously, we reported that 22S-butyl-25,26,27-trinor-1alpha,24-dihydroxyvitamin D(3)2 represents a new class of antagonist for the vitamin D receptor (VDR). The crystal structure of the ligand-binding domain (LBD) of VDR complexed with 2 showed the formation of a butyl pocket to accommodate the 22-butyl group and insufficient interactions between ligand 2 and the C-terminus of VDR. Here, we designed and synthesized new analogues 5a-c and evaluated their biological activities to probe whether agonistic activity is recovered when the analogue restores interactions with the C-terminus of VDR. Analogues 5a-c exhibited full agonistic activity in transactivation. Interestingly, 5c, which bears a 24 diethyl group, completely recovered agonistic activity, although 3c and 4c act as an antagonist and a weak agonist, respectively. The crystal structures of VDR-LBD complexed with 3a, 4a, 5a, and 5c were solved, and the results confirmed that butyl pocket formation in VDR strongly affects the agonistic or antagonistic behaviors of ligands. PMID- 22512507 TI - Development of a finite element/multi-body model of a newborn infant for restraint analysis and design. AB - A finite element/multi-body model of a newborn infant has been developed by researchers at the University of Windsor. The geometry of this model is derived from a Nita newborn hospital training mannequin. It consists of 17 parts: eight upper and lower limb segments, the torso, head, and a seven-segment neck with seven translational and eight rotational joints. Anthropometry is consistent with hospital growth charts, measurements requested from health professionals and data from the open literature. The biomechanical properties of the model (i.e. joint stiffnesses) are implementations of data identified in the open literature. The model has been validated with respect to studies of the biomechanics of shaken baby syndrome, infant falls and the Q0 anthropomorphic testing device. A significant conclusion of this study is that the kinetics of the Q0 neck is not biofidelic. This model is currently used in an analysis of airway patency for infants in modern automotive child restraints. PMID- 22512506 TI - Omega-3 essential fatty acid status is improved during nutritional rehabilitation of adolescent girls with eating disorders and weight loss. AB - AIM: Essential fatty acid status is altered in eating disorders with weight loss, and deficiencies in polyunsaturated omega-3 essential fatty acids have been implicated in the development of depression and other psychopathologies. Presently, recovery of essential fatty status during the treatment of adolescent girls with eating disorders has been investigated. METHODS: Fatty acids were analysed in erythrocyte membranes of 24 adolescents girls with eating disorders of short duration, and on the average >10 kg weight loss at presentation. Blood samples were obtained at presentation and following weight recovery on standard diet without supplementation with essential fatty acids. RESULTS: Alterations of essential fatty status observed at presentation largely normalized during treatment. Omega-3 status improved following weight gain. CONCLUSION: Adequate nutrition, normalization of eating behaviours, weight gain and the consequent return to normalization of metabolism and endocrine function are sufficient to ensure normalization of essential fatty acid status. Supplementation with omega-3 polyunsaturated fatty acids does not appear warranted. PMID- 22512508 TI - CD11c decrease in mouse thymic dendritic cells after vanadium inhalation. AB - Vanadium (V) is a transition metal found in air adsorbed onto suspended particles. As a result, urban populations are often exposed to this element as a constituent of particulate matter (PM). One aspect of the myriad toxicities that might arise from these exposures is altered immune responses. Previous reports from the laboratory reported modifications in splenic architecture - with germinal center hyperplasia and a suppressed humoral immune response - in mice that had been exposed to vanadium agents via inhalation. This paper reports a decrease in the presence of the CD11c surface marker on mouse thymic dendritic cells (DC) as a result of host exposure to vanadium (here, in the form of vanadium pentoxide; V(2)O(5)) over a period of 4 weeks. All results were obtained using immunohistochemistry and flow cytometry. It is surmised that this decrease might induce a dysfunction, including possible negative selection of T-cells, which could increase the presence of autoreactive clones in the exposed host. Such an outcome could, in turn, increase the risk for development of autoimmune reactions in different organs specifically, and of autoimmune diseases in general in these V-exposed hosts. PMID- 22512509 TI - Comparison of narrowband ultraviolet B exposure and oral vitamin D substitution on serum 25-hydroxyvitamin D concentration. AB - BACKGROUND: A short course of narrowband ultraviolet B (NB-UVB) exposures increases the serum 25-hydroxyvitamin D [25(OH)D] concentration in patients with psoriasis and healthy subjects. OBJECTIVES: To compare the effects of NB-UVB and oral vitamin D substitution in healthy subjects in winter. METHODS: Healthy adult hospital employees and medical students were screened for serum 25(OH)D concentration. Those with 25(OH)D below 75 nmol L(-1) were randomly given either 12 NB-UVB exposures or 20 MUg of oral cholecalciferol daily for 4 weeks. The NB UVB exposures were given with a Waldmann UV 7001 cabin and the mean cumulative dose was 48.4 standard erythema doses. Serum 25(OH)D was measured before and after the treatments by radioimmunoassay. RESULTS: The baseline serum 25(OH)D concentrations were 52.9 +/- 10.4 (mean +/- SD) in the 33 NB-UVB-treated and 53.5 +/- 12.7 nmol L(-1) in the 30 oral cholecalciferol-treated subjects. The mean increase in serum 25(OH)D was 41.0 nmol L(-1) [95% confidence interval (CI) 34.8 47.2; P < 0.001] in the NB-UVB group and 20.2 nmol L(-1) (95% CI 14.6-26.0; P < 0.001) in the cholecalciferol group. The difference between the two treatments was significant at 2 weeks (P = 0.033) and at 4 weeks (P < 0.001). One month after the treatments the 25(OH)D concentrations had increased further. CONCLUSIONS: The present study shows that 12 NB-UVB exposures given during 4 weeks increase serum 25(OH)D concentration significantly more than 20 MUg of oral cholecalciferol daily. A short NB-UVB course is an effective way to improve vitamin D balance in winter and the response is still evident 2 months after the course. PMID- 22512510 TI - The Social Communication Intervention Project: a randomized controlled trial of the effectiveness of speech and language therapy for school-age children who have pragmatic and social communication problems with or without autism spectrum disorder. AB - BACKGROUND: Children who show disproportionate difficulty with the pragmatic as compared with the structural aspects of language are described as having pragmatic language impairment (PLI) or social communication disorder (SCD). Some children who have PLI also show mild social impairments associated with high functioning autism or autism spectrum disorder (ASD). There is little robust evidence of effectiveness of speech-language interventions which target the language, pragmatic or social communication needs of these children. AIMS: To evaluate the effectiveness of an intensive manualized social communication intervention (SCIP) for children who have PLI with or without features of ASD. METHODS & PROCEDURES: In a single-blind RCT design, 88 children with pragmatic and social communication needs aged 5;11-10;8, recruited from UK speech and language therapy services, were randomly assigned in a 2:1 ratio to SCIP or to treatment-as-usual. Children in the SCIP condition received up to 20 sessions of direct intervention from a specialist research speech and language therapist working with supervised assistants. All therapy content and methodology was derived from an intervention manual. A primary outcome measure of structural language and secondary outcome measures of narrative, parent-reported pragmatic functioning and social communication, blind-rated perceptions of conversational competence and teacher-reported ratings of classroom learning skills were taken pre-intervention, immediately post-intervention and at 6-month follow-up. Analysis was by intention to treat. OUTCOMES & RESULTS: No significant treatment effect was found for the primary outcome measure of structural language ability or for a measure of narrative ability. Significant treatment effects were found for blind-rated perceptions of conversational competence, for parent-reported measures of pragmatic functioning and social communication, and for teacher reported ratings of classroom learning skills. CONCLUSIONS & IMPLICATIONS: There is some evidence of an intervention effect on blind and parent/teacher-reported communication outcomes, but not standardized language assessment outcomes, for 6 11-year-old children who have pragmatic and social communication needs. These findings are discussed in the context of the increasingly central role of service user outcomes in providing evidence for an intervention. The substantial overlap between the presence of PLI and ASD (75%) across the whole cohort suggests that the intervention may also be applicable to some verbally able children with ASD who have pragmatic communication needs. PMID- 22512511 TI - Implementation of a manualized communication intervention for school-aged children with pragmatic and social communication needs in a randomized controlled trial: the Social Communication Intervention Project. AB - BACKGROUND: Speech-language interventions are often complex in nature, involving multiple observations, variable outcomes and individualization in treatment delivery. The accepted procedure associated with randomized controlled trials (RCT) of such complex interventions is to develop and implement a manual of intervention in order that reliable treatment delivery can be achieved. AIMS: To present the rationale, structure and content of an intensive manualized intervention as implemented within an RCT for children with complex pragmatic and social communication needs; to investigate factors associated with implementation in a mainstream school environment; and to determine treatment fidelity. METHODS & PROCEDURES: The manualized SCIP intervention, including procedures for developing individualized treatment plans, was developed and then implemented within an RCT with 57 school-aged children with complex pragmatic communication needs (CwPLI). The paper describes the delivery protocol, staffing requirements, and content and structure of the intervention. A mapping procedure for individualization of intervention and the implemented components of intervention are presented. The findings from a school-therapy alliance checklist for recording factors affecting implementation in a school context are also reported. Treatment fidelity was carried out using measures of delivered versus planned treatment content and quality of therapy. OUTCOMES & RESULTS: The manual was effective at detailing intervention procedures and allowing for development of individualized treatment plans whilst maintaining satisfactory treatment fidelity. Treatment planning and delivery required continuous specialist speech and language therapist input with assistants needing substantive training and supervision. Key components of intervention for CwPLI were therapies aimed at improving conversation skills, narrative construction, comprehension monitoring, understanding of social cues and metapragmatic awareness. The school-therapy alliance checklist indicated high rates of therapist-education staff and therapist-parent liaison. Parents were nearly always involved in treatment planning though only half-attended therapy sessions. Learning support provision in schools for participating children was highly variable. CONCLUSIONS & IMPLICATIONS: Predetermining theoretical background, structure, and content in a treatment manual contributed towards the quality and reliability of intervention within the context of an RCT. The implementation of SCIP intervention in a broader clinical context is discussed with reference to staff expertise, the therapeutic process and the essential ingredients of social communication intervention. PMID- 22512512 TI - Non-word repetition in adolescents with specific language impairment (SLI). AB - BACKGROUND: Non-word repetition (NWR) difficulties are common, but not universal, among children with specific language impairment (SLI). However, older children and adolescents with SLI have rarely been studied. Studies disagree on the relationship between NWR difficulties and difficulties with other areas of language and literacy. There is also no consensus about the underlying reason for the difficulties (some) children with SLI have with NWR. Some scholars argue that difficulties with phonological short-term memory or storage cause NWR and other language difficulties, whereas others argue that difficulties with NWR may be due more to difficulties with phonological representations. AIMS: To investigate NWR abilities and their relationship to other language and literacy abilities in a group of older children with SLI and typically developing controls. To investigate the relative effects of increasing phonological complexity and the number of syllables on the ability of the participants to repeat non-words. METHODS & PROCEDURES: An NWR test (The Test of Phonological Structure; TOPhS), which systematically varies phonological complexity, was administered to 15 participants with SLI (aged 11-15 years), 30 language and 15 age controls. Standardized language and literacy tests and a specific test of verb agreement and tense marking (Verb Agreement and Tense Test; VATT) were also administered. OUTCOMES & RESULTS: The participants with SLI showed a bimodal distribution: half achieved age-appropriate NWR, while half scored significantly below language and age controls (d > 7). The two groups of participants with SLI (high versus low scorers) only differed in NWR (d > 5) and agreement (d > 3) and tense marking (d > 2.5), not on the standardized language and literacy measures administered. NWR was also highly correlated with verb agreement (r= 0.97) and tense marking (r= 0.89) among participants with SLI, but not among controls (r= 0.16 and 0.30 respectively). Phonological complexity was related to NWR accuracy, particularly among participants with SLI. The number of syllables had no independent effect on NWR performance for any group. CONCLUSIONS & IMPLICATIONS: Some children with SLI (who have good NWR) have language difficulties unrelated to any of the factors underlying NWR. Others have a (probably additional) deficit which affects NWR and also leads to greater difficulties with verb agreement and tense marking. The results indicate that difficulties with this particular NWR test are more likely to be due to a deficit with phonology per se, rather than with phonological short term memory or storage. PMID- 22512513 TI - Language and disadvantage: a comparison of the language abilities of adolescents from two different socioeconomic areas. AB - BACKGROUND: It is recognized that children from areas associated with socioeconomic disadvantage are at an increased risk of delayed language development. However, so far research has focused mainly on young children and there has been little investigation into language development in adolescence. AIMS: To investigate the language abilities of adolescents from two different socioeconomic areas. The paper aims to determine if a higher proportion of adolescents from an area of socioeconomic disadvantage have low language scores when compared with adolescents from a relatively advantaged area. METHODS & PROCEDURES: Six standardized language assessments were used to measure expressive and receptive language skills across vocabulary, syntax and narrative in two cohorts of 13 and 14 year olds: one cohort attending a school in an area of socioeconomic disadvantage (103 participants) and the other cohort attending a school in an area of relative socioeconomic advantage (48 participants). OUTCOMES & RESULTS: The cohort from the area of disadvantage performed significantly lower than the assessments' normative mean on all measures of language ability. There were significant differences between the two cohorts on four of the six language measures. More adolescents from the school in the area of socioeconomic disadvantage had standardized assessment scores that suggest hitherto undetected language difficulties. CONCLUSIONS & IMPLICATIONS: Results suggest that socioeconomic background is associated with language ability in adolescence as measured by standardized tests. In particular, adolescents from an area of socioeconomic disadvantage were at risk of low vocabulary scores. The advantages and disadvantages of using standardized language assessments are discussed and the implications for clinical and educational practice and for school level policies are highlighted. PMID- 22512514 TI - Dynamic Assessment of Sentence Structure (DASS): design and evaluation of a novel procedure for the assessment of syntax in children with language impairments. AB - BACKGROUND: Sentence construction and syntactic organization are known to be poor in children with specific language impairments (SLI), but little is known about the way in which children with SLI approach language tasks, and static standardized tests contribute little to the differentiation of skills within the population of children with language impairments (LI). Information about the nature and intensity of prompts that facilitate sentence construction for a particular child may be useful in planning effective intervention. AIMS: This paper describes the development of a dynamic assessment (DA) task which requires implicit knowledge of syntactic structure. The aim was to formulate a valid and reliable procedure for the DA of sentence formulation that could yield useful information for planning intervention for children with LI. METHODS & PROCEDURES: The Dynamic Assessment of Sentence Structure (DASS) was employed on 24 children aged 8-10 years, with identified language impairments, who were tested four times, at 4 monthly intervals. OUTCOMES & RESULTS: A range of scores was elicited with no limiting ceiling or floor effects, and the test showed high internal reliability of alpha= 0.833. Inter-rater reliability was high. Concurrent validity was demonstrated by significant correlation with scores obtained on the CELF-3(UK) and predictive validity of the measure was also found to exceed that of the standardized test measure. Information about the ability of the children to use strategies and less directive prompts, and to transfer learning between items was elicited, and the information was thought to be useful by speech and language therapists involved in their management. CONCLUSIONS & IMPLICATIONS: The application of DA principles to the assessment of children previously diagnosed with LI, for the purposes of finding out more information about their potential to benefit from language intervention, was found to be effective. The tool developed was shown to be valid and reliable, and it has potentially important applications for the planning of individual intervention programmes and service delivery. PMID- 22512515 TI - A prospective, randomized comparative study of patient perceptions and preferences of two types of indwelling voice prostheses. AB - BACKGROUND: Technical and device life issues are frequently the focus of post laryngectomy rehabilitation studies examining indwelling voice prostheses. Patient perceptions and preferences are considered less often. AIMS: To determine patient perceptions of two indwelling voice prostheses across parameters relating to device use and maintenance and to determine what factors contribute to patient preferences. METHODS & PROCEDURES: In a randomized, cross-over study, 31 laryngectomy patients completed a 3-week trial of both the new indwelling Provox Vega and a comparator device, the Blom-Singer Classic Indwelling. Patient perceptions of the insertion process, cleaning and care, and voicing were explored after each trial. At the end, overall preference and factors influencing device preference were examined. OUTCOME & RESULTS: At the conclusion of the crossover trial, a significantly higher proportion of patients felt voice effort, overall voicing, bloating, and ease and effectiveness of cleaning were superior for the Provox Vega. No preference was noted for insertion processes. Overall device preference was influenced by improved voicing followed by cleaning and care. CONCLUSIONS & IMPLICATIONS: Patients do not perceive all indwelling devices as equal and should have the opportunity to trial different devices to find the best device for their needs. PMID- 22512516 TI - Effects of social cognitive demand on Theory of Mind in conversations of adults with traumatic brain injury. AB - BACKGROUND: A requisite skill for successful conversation is the ability to adjust one's language according to contextual factors. AIMS: This study examined one aspect of language use in context-the use of mental-state terms, i.e. words that communicate thoughts, beliefs or feelings-in conversations between adult males with and without traumatic brain injury (TBI) and familiar partners. METHODS & PROCEDURES: Participants were five males in the chronic stage of recovery following severe TBI and five male peers matched for age, conversing with friends. Conversational context was manipulated using conversation starters that were designed to induce differing levels of self-disclosure or intimacy, with the expectation that mental-state term use would increase when participants talked about more intimate topics. OUTCOMES & RESULTS: Participants in both groups used more mental-state terms in more intimate conversations; however, adults with TBI did not increase their mental-state term use to the same extent as matched peers. Adults with TBI also used a significantly different pattern of mental-state term types across intimacy levels as compared with peers. CONCLUSIONS & IMPLICATIONS: These quantitative and qualitative differences may contribute to social conversation problems of adults with TBI. PMID- 22512517 TI - Preparation, clinical support, and confidence of speech-language therapists managing clients with a tracheostomy in the UK. AB - BACKGROUND: Literature regarding the education, training, clinical support and confidence of speech-language therapists (SLTs) working with patients with a tracheostomy is limited; however, it suggests that many clinicians have reduced clinical confidence when managing this complex population, many face role and team challenges practising in this area, and most are seeking more opportunities for professional development and training. AIMS: To investigate the education, training, clinical support and confidence of SLTs in the UK who manage patients with a tracheostomy in order to identify current challenges and inform the future clinical training needs of this professional group. METHODS & PROCEDURES: Via an online survey, the clinical training, clinical support and confidence of SLTs with more than one year of clinical experience was examined. A total of 106 SLTs from the UK completed the survey. Within the questionnaire, clinicians were also asked to identify if their workplace had a tracheostomy competency training programme (CTP) to allow further exploration of the preparation, clinical support and confidence of respondents with (43% of respondents) and without (32% of respondents) a CTP. OUTCOMES & RESULTS: Most SLTs (71%) were confident managing patients with a tracheostomy. The majority were accessing professional development and receiving expert support, though many identified specific areas where more support and training was needed. Less than half the group felt up to date with the current evidence. Only 35% of clinicians felt they worked in an optimal team for tracheostomy management, and poor recognition of the role of the SLT in managing dysphagia in patients with a tracheostomy was an issue for many clinicians, particularly on more general care wards. SLTs in workplaces with a CTP were found to have received significantly more expert support, on-the-job training, access to evidence-based practice and were significantly more confident in managing ventilator-assisted patients. CONCLUSIONS & IMPLICATIONS: SLTs are eager to access further professional development and training; however, such training needs to target specific areas of need. The significant difference in the preparation, support and confidence of SLTs with CTPs in their workplace highlights potential benefits that can be achieved through workplace training and support. PMID- 22512518 TI - The Levels of Speech Usage rating scale: comparison of client self-ratings with speech pathologist ratings. AB - BACKGROUND: The term 'speech usage' refers to what people want or need to do with their speech to fulfil the communication demands in their life roles. Speech language pathologists (SLPs) need to know about clients' speech usage to plan appropriate interventions to meet their life participation goals. The Levels of Speech Usage is a categorical scale intended for client self-report of speech usage, but SLPs may want the option to use it as a proxy-report tool. The relationship between self-report and clinician ratings should be examined before the instrument is used in a proxy format. AIMS: The primary purpose of this study was to compare client self-ratings with SLP ratings on the Levels of Speech Usage scale. The secondary purpose was to determine if the SLP ratings differed depending on whether or not the SLPs knew about the clients' medical condition. METHODS & PROCEDURES: Self-ratings of adults with communication disorders on the Levels of Speech Usage scale were available from prior research. Vignettes about these individuals were created from existing data. Two sets of vignettes were created. One set contained information about demographic information, living situation, occupational status and hobbies or social activities. The second set was identical to the first with the addition of information about the clients' medical conditions and communication disorders. Various communication disorders were represented including dysarthria, voice disorders, laryngectomy, and mild cognitive and language disorders. Sixty SLPs were randomly divided into two groups with each group rating one set of vignettes. The task was completed online. While this does not replicate typical in-person clinical interactions, it was a feasible method for this study. For data analysis, the client self-ratings were considered fixed points and the percentage of SLP ratings in agreement with the self-ratings was calculated. OUTCOMES & RESULTS: The percentage of SLP ratings in exact agreement with client self-ratings was 44.9%. Agreement was lowest for the less-demanding speech usage categories and highest for the most demanding usage category. There was no significant difference between the two groups of SLPs based on knowledge of medical condition. CONCLUSIONS & IMPLICATIONS: SLPs often need to document the speech usage levels of clients. This study suggests the potential for SLPs to misjudge how clients see their own speech demands. Further research is needed to determine if similar results would be found in actual clinical interactions. Until then, SLPs should seek the input of their clients when using this instrument. PMID- 22512520 TI - Regarding 'McCurtin, A. and Roddam, H., 2012, Evidence-based practice: SLTs under siege or opportunity for growth? The use and nature of research evidence in the profession. PMID- 22512521 TI - Be prepared now for when disaster strikes: how can psychiatric nurses help? PMID- 22512522 TI - Barriers and facilitators to implementation of the institute of medicine recommendations on preventing mental, emotional, and behavioral disorders among young people. AB - PROBLEM: The purpose of this study was to gain an understanding of the barriers and facilitators to implementation of the five overarching recommendations of the Institute of Medicine report and to consider the implications for nursing. METHODS: Data were collected through use of a semi-structured interview of purposive sample of 22 key informants regarding the barriers and facilitators to implementation of the report's five major recommendations. FINDINGS: The major barriers were competing priorities, lack of infrastructure for implementation, lack of public education regarding mental health and the effectiveness of prevention, stigma, and a paucity of facilitating factors. The facilitators were leadership, flexible resources, linkage to healthcare reform or other legislation, coordination across agencies and governmental levels, and additional research. CONCLUSIONS: The discussion focuses on ways of promoting facilitating factors and consideration of nursing's potential contributions in the areas of education, practice, and research. PMID- 22512523 TI - Personality traits as predictors of adherence in adolescents with type I diabetes. AB - TOPIC: Diabetes is a serious, chronic illness with long-term implications for health and lifestyle. Significant differences in health outcome may be achieved as a result of the degree of adherence to recommended diabetes management regimens. Adherence is a particularly challenging issue with adolescents with diabetes. PURPOSE: The present study examined the association between primary personality traits and adolescent adherence to prescribed diabetes management regimens. SOURCES: A measure of the five-factor model of personality was administered to a sample of adolescents with insulin-dependent diabetes mellitus. Five self-reported indicators of adherence were assessed: blood glucose monitoring, insulin administration, diet, exercise, and most recent glycosylated hemoglobin (HbA1c) level. CONCLUSIONS: Results revealed a pattern of significant correlations between the Conscientiousness and Neuroticism personality domains and one or more self-reported adherence behaviors. In addition, correlations were also found between one facet of Extraversion and one facet of Agreeableness. These suggestive results, if replicated in larger studies, provide useful information to clinicians as they design and monitor individualized diabetes management regimens for adolescents. PMID- 22512524 TI - A comparative assessment of early adult life status of graduates of the North Carolina adolescent parenting program. AB - PROBLEM: What is the comparative impact of a second pregnancy prevention program for teen mothers on those who graduate from the program compared with a sample of young mothers of similar age and social circumstances who did not participate in the program? METHODS: Fifteen program graduates and 20 nonprogram cohorts were surveyed regarding a range of life domains. FINDINGS: Data indicated that program graduates were on a more positive life course: greater primary responsibility for housing and utilities, greater higher education enrollment, more job stability, and greater focus on career goals. CONCLUSION: The differences demonstrate the value of programs designed to assist teen mothers through the challenges of parenting and their own adolescent development. Teen mothers who received these resources became more capable, happier, and confident, which in turn will make them better parents and more empowered to pursue their own personal development. PMID- 22512525 TI - Investigation of autism comorbidities and associations in a school-based community sample. AB - PROBLEM: Individuals with autism spectrum disorders (ASDs) have at least as many comorbidities as individuals with typical development may show, but sometimes with different presentations. METHODS: The study used a school-based health survey related to children diagnosed with ASD in Tehran to determine the possibility of comorbid conditions. Ninety-one children and adolescents with ASD between the ages of 6 and 14 years were included in the study, all from five schools of different districts of the city, using stratified random sampling. All of the subjects had received a clinical diagnosis of ASD (autism, Asperger, and pervasive developmental disorder-not otherwise specified) by a child neurologist or psychiatrist. All of the schools had registered the subjects and were restricted to those with high-functioning forms of ASD, and none were identified with co-occurring mental retardation. FINDINGS: Results indicated that 72.5% had at least one comorbid condition. There was a trend of higher severity in autism symptoms in subjects with comorbidity. Results showed that attention deficit/hyperactivity disorder and epileptic disorders were the leading comorbidity in respective categories. CONCLUSION: Autistic individuals should be monitored regarding their comorbid profiles, with an emphasis on female subjects and those with more severe symptoms. Clinically, the current study has implications for school healthcare providers, including nurses, in addition to researchers and practitioners working with children diagnosed with ASDs. PMID- 22512526 TI - Y.O.O. Rock Columbia County: development of a volunteer reference guide for families, children, and youth. AB - TOPIC: Y.O.O. Rock Columbia County Youth Outreach Opportunities for Families Children, and Youth (Waibel-Duncan & Gillam, 2009) represents our nonurban county's first organized effort to systematically identify and promote awareness of volunteer and outreach opportunities for families, children, and youth. PURPOSE: In addition to describing Y.O.O. Rock's development, this article summarizes feedback from parents, professionals, and paraprofessionals and outlines their recommendations for the second edition of the guide. SOURCE: Issue briefs from the Corporation for National & Community Service (2005, 2006, 2008) suggest the need for reference guides like Y.O.O. Rock insofar as they document limited volunteer and outreach opportunities for young children as well as the family's role in engaging children in service to others. CONCLUSION: This article will inform others who seek to increase families', children's, and youth's awareness of volunteer activities and outreach opportunities in their communities. PMID- 22512528 TI - Latest on child welfare systems and continued call for White House conference on children. PMID- 22512527 TI - Pregnancy intentions, long-acting contraceptive use, and rapid subsequent pregnancies among adolescent and adult first-time mothers. AB - PROBLEM: Greater understanding is needed related to qualitatively assess pregnancy intentions and rapid subsequent pregnancies among adolescent and adult mothers. METHODS: Four-site prospective study of 227 adolescent and adult mothers. Data were analyzed to understand the relationship between pregnancy intentions, adolescent status, and use of long-acting contraceptives and rapid subsequent pregnancy. FINDINGS: The findings from this study provide evidence of the importance of goal-oriented pregnancy intentions, long-acting contraceptive use, and older age in delaying a second pregnancy. CONCLUSION: Findings reveal the need for clinician awareness of the qualitative pregnancy intentions of young women and potential desired use of long-acting contraceptives. PMID- 22512529 TI - How can we reclaim the "voice" of child and adolescent psychiatric-mental health nurses? PMID- 22512531 TI - Cordycepin stimulated steroidogenesis in MA-10 mouse Leydig tumor cells through the protein kinase C Pathway. AB - Cordycepin (3'-deoxyadenosine) is an adenosine analogue isolated from Cordyceps sinensis , which is a Chinese herbal medicine known to have many benefits, including adjustment of the physical condition, an anticancer effect, and enhancement of sexual performance. It was previously demonstrated that cordycepin could simultaneously activate steroidogenesis and apoptosis in MA-10 mouse Leydig tumor cells. However, the mechanism remains elusive. Thus, aim of the present study was to investigate the steroidogenic and apoptotic mechanism of cordycepin in MA-10 cells. MA-10 cells were treated with cordycepin at various dosages and time courses plus different protein kinase inhibitors. Steroid production, protein expression, and cell viability were then determined. Results illustrated that cordycepin stimulated MA-10 cell steroidogenesis in dose- and time-dependent relationships. However, cordycepin could not induce steroidogenic acute regulatory (StAR) protein expression. However, cordycepin did activate the phospholipase C/protein kinase C (PLC/PKC), but not PKA and PI3K, pathway to induce MA-10 cell steroidogenesis. Moreover, cordycepin could stimulate the phosphorylation of PKC, extracellular signal-regulated kinase 1/2 (ERK1/2), and c Jun N-terminal kinase (c-JNK), but not p38, in MA-10 cells. In addition, cordycepin could activate the PKC pathway to induce MA-10 cell death, and this death effect was not caused by cordycepin-stimulated progesterone from MA-10 cells. In conclusion, cordycepin stimulated intracellular PLC/PKC and MAPK signal transduction pathways to induce steroidogenesis and cell death in MA-10 mouse Leydig tumor cells. PMID- 22512532 TI - The factor structure of ADHD in a general population of primary school children. AB - OBJECTIVE: To examine whether a bifactor model with a general ADHD factor and domain specific factors of inattention, hyperactivity and impulsivity was supported in a large general population sample of children. We also explored the utility of forming subscales based on the domain-specific factors. METHODS: Child mental health questionnaires were completed by both teachers and parents of all children in grades 2-4 in Bergen, Norway. Confirmatory factor analysis was performed on the ADHD items of a modified version of the Swanson, Nolan and Pelham Questionnaire-IV (SNAP-IV) for 6,237 children. RESULTS: The bifactor model showed very good model fit with a strong general ADHD factor and specific factors for impulsivity and inattention. The subfactors, especially hyperactivity, generated from the SNAP-IV ADHD items conveyed little unique variance in the model. CONCLUSIONS: The findings in this general population sample with a strong general ADHD factor in the bifactor model supports the view on ADHD as a unitary concept with specific domain factors for inattention and impulsivity, but not for hyperactivity. The bifactor model questions the utility of constructing ADHD subscales by the use of a simple sum score when using the SNAP-IV. PMID- 22512533 TI - Investigation of the hydration of nonfouling material poly(sulfobetaine methacrylate) by low-field nuclear magnetic resonance. AB - The strong surface hydration layer of nonfouling materials plays a key role in their resistance to nonspecific protein adsorption. Poly(sulfobetaine methacrylate) (polySBMA) is an effective material that can resist nonspecific protein adsorption and cell adhesion. About eight water molecules are tightly bound with one sulfobetaine (SB) unit, and additional water molecules over 8:1 ratio mainly swell the polySBMA matrix, which is obtained through the measurement of T(2) relaxation time by low-field nuclear magnetic resonance (LF-NMR). This result was also supported by the endothermic behavior of water/polySBMA mixtures measured by differential scanning calorimetry (DSC). Furthermore, by comparing both results of polySBMA and poly(ethylene glycol) (PEG), it is found that (1) the hydrated water molecules on the SB unit are more tightly bound than on the ethylene glycol (EG) unit before saturation, and (2) the additional water molecules after forming the hydration layer in polySBMA solutions show higher freedom than those in PEG. These results might illustrate the reason for higher resistance of zwitterionic materials to nonspecific protein adsorptions compared to that of PEGs. PMID- 22512534 TI - Measured and calculated oxidation potentials of 1-X-12-Y-CB11Me10- anions. AB - Cyclic voltammetry of 31 icosahedral carborane anions 1-X-12-Y-CB(11)Me(10)(-) at a Pt electrode in liquid SO(2) revealed a completely reversible one-electron oxidation even at low scan rates, except for the anions with Y = I, which are oxidized irreversibly up to a scan rate of 5.0 V/s, and the anion with X = COOH and Y = H, whose oxidation is irreversible at scan rates below 1.0 V/s. Relative reversible oxidation potentials agree well with RI-B3LYP/TZVPP,COSMO and significantly less well with RI-BP86/TZVPP,COSMO or RI-HF/TZVPP,COSMO calculated adiabatic electron detachment energies. Correlations with HOMO energies of the anions are nearly as good, even though the oxidized forms are subject to considerable Jahn-Teller distortion. Except for the anion with X = F and Y = Me, the oxidation potentials vary linearly with substituent sigma(p) Hammett constants. The slopes (reaction constants) are ~0.31 and ~0.55 V for positions 1 and 12, respectively. PMID- 22512535 TI - Recent trends in oral transmucosal drug delivery systems: an emphasis on the soft palatal route. AB - INTRODUCTION: The oral mucosa is an appropriate route for drug delivery systems, as it evades first-pass metabolism, enhances drug bioavailability and provides the means for rapid drug transport to the systematic circulation. This delivery system offers a more comfortable and convenient delivery route compared with the intravenous route. Although numerous drugs have been evaluated for oral mucosal delivery, few of them are available commercially. This is due to limitations such as the high costs associated with developing such drug delivery systems. AREAS COVERED: The present review covers recent developments and applications of oral transmucosal drug delivery systems. More specifically, the review focuses on the suitability of the oral soft palatal site as a new route for drug delivery systems. EXPERT OPINION: The novelistic oral soft palatal platform is a promising mucoadhesive site for delivering active pharmaceuticals, both systemically and locally, and it can also serve as a smart route for the targeting of drugs to the brain. PMID- 22512536 TI - Supramolecularly engineered perylene bisimide assemblies exhibiting thermal transition from columnar to multilamellar structures. AB - Perylene 3,4:9,10-tetracarboxylic acid bisimide (PBI) was functionalized with ditopic cyanuric acid to organize it into complex columnar architectures through the formation of hydrogen-bonded supermacrocycles (rosette) by complexing with ditopic melamines possessing solubilizing alkoxyphenyl substituents. The aggregation study in solution using UV-vis and NMR spectroscopies showed the formation of extended aggregates through hydrogen-bonding and pi-pi stacking interactions. The cylindrical fibrillar nanostructures were visualized by microscopic techniques (AFM, TEM), and the formation of lyotropic mesophase was confirmed by polarized optical microscopy and SEM. X-ray diffraction study revealed that a well-defined hexagonal columnar (Col(h)) structure was formed by solution-casting of fibrillar assemblies. All of these results are consistent with the formation of hydrogen-bonded PBI rosettes that spontaneously organize into the Col(h) structure. Upon heating the Col(h) structure in the bulk state, a structural transition to a highly ordered lamellar (Lam) structure was observed by variable-temperature X-ray diffraction, differential scanning calorimetry, and AFM studies. IR study showed that the rearrangement of the hydrogen-bonding motifs occurs during the structural transition. These results suggest that such a striking structural transition is aided by the reorganization in the lowest level of self-organization, i.e., the rearrangement of hydrogen-bonded motifs from rosette to linear tape. A remarkable increase in the transient photoconductivity was observed by the flash-photolysis time-resolved microwave conductivity (FP TRMC) measurements upon converting the Col(h) structure to the Lam structure. Transient absorption spectroscopy revealed that electron transfer from electron donating alkoxyphenyl groups of melamine components to electron-deficient PBI moieties takes place, resulting in a higher probability of charge carrier generation in the Lam structure compared to the Col(h) structure. PMID- 22512537 TI - The BASES Expert Statement on use of music in exercise. AB - The use of music during exercise has become ubiquitous over the past two decades and is now supported by a burgeoning body of research detailing its effects and the contingencies surrounding its use. The purpose of this statement is to present a synopsis of the body of knowledge, with selected references, and to provide practical recommendations for exercise practitioners regarding music selection. Following the identification of methodological shortcomings in early studies, researchers have been guided by new conceptual frameworks, and have produced more consistent findings as a consequence. The use of music has been found to yield ergogenic effects in the exercise domain while also promoting psychological (e.g. enhanced affect) and psychophysical (reduced ratings of perceived exertion) benefits. There is a paucity of research examining the longitudinal effects of music on key outcome variables such as exercise adherence. PMID- 22512538 TI - The heat shock response in FAP: the role of the extracellular chaperone clusterin. AB - Extracellular chaperones, such as clusterin, have been proposed to contribute to extracellular protein homeostasis. In Alzheimer's disease (AD), clusterin was suggested to be involved in fibrillogenesis and extracellular misfolded protein clearance. Here, we study the relevance of clusterin in familial amyloidotic polyneuropathy (FAP). Analysis of clusterin levels by ELISA showed decreased levels in asymptomatic and in FAP patients, which could be regarded as a consequence of clusterin mobilization to tissues. Incubation of a neuroblastoma cell line with transthyretin (TTR) oligomers resulted in secretion of clusterin into the media and binding to oligomeric species, not observed in parallel experiments with soluble TTR. Overall, our results allow us to postulate a putative protective role of clusterin in FAP, namely in the modulation of TTR aggregate formation. Future experiments are required to clarify the role of clusterin in FAP. PMID- 22512539 TI - Venlafaxine enhances the effect of bupropion on extracellular dopamine in rat frontal cortex. AB - Venlafaxine is recognised as an effective treatment for depression and is known to inhibit the reuptake of serotonin (5-HT) and noradrenaline (NA). Another antidepressant, bupropion, acts to inhibit dopamine (DA) and NA reuptake and is commonly co-administered with other antidepressants to improve the efficacy of the antidepressant effect. The present study was designed to investigate the acute effect of combining the 2 drugs on extracellular levels of 5-HT, DA, and NA in rat frontal cortex using brain microdialysis, with the drugs being administered by intraperitoneal injection (i.p). Bupropion (10 mg/kg body mass, i.p.) alone had no effect on extracellular 5-HT levels, whereas venlafaxine (10 mg/kg, i.p.) alone significantly elevated extracellular 5-HT over basal values. As expected, bupropion alone elevated extracellular dopamine above basal values at 40 min post-drug administration, and this effect lasted for a further 2 h. Venlafaxine alone did not statistically elevate extracellular dopamine. The co administration of venlafaxine with bupropion resulted in a dramatic increase in extracellular dopamine, and this effect was significantly greater than that seen with bupropion alone. In the frontal cortex, NA was elevated by bupropion alone and venlafaxine alone, relative to the control animals. The combination of bupropion and venlafaxine resulted in a marked elevation of NA. PMID- 22512540 TI - Protein aggregation: kinetics versus thermodynamics. AB - In this study, we address the questions of how important is the kinetics in protein aggregation, and what are the intrinsic properties of proteins that cause this behavior. On the basis of our recent quantitative calculation of the equilibrium phase diagram of natively folded alpha-helical and beta-sheet forming peptides, we perform molecular dynamics simulations to demonstrate how the aggregation mechanism and end product depend on the temperature, concentration, and starting point in the phase diagram. The results obtained show that there are severe differences between the thermodynamically predicted and the kinetically obtained aggregate structures. The observed differences help to rationalize the suggestion that monomeric proteins in their native functional structure can be metastable with respect to the amyloid state, and that the native fold is a special property that protects them from aggregation. PMID- 22512541 TI - Gluten ataxia: an important treatable etiology of sporadic ataxia. AB - BACKGROUND: Gluten ataxia is a known cause of sporadic ataxia. CASE: We report the case of a patient with imbalance and no abdominal symptoms diagnosed with gluten ataxia. Her neurological symptoms responded to gluten-free diet. CONCLUSION: Gluten ataxia should be considered in all patients with sporadic ataxia with or without abdominal symptoms, as early diagnosis and treatment may result in neurological improvement. PMID- 22512542 TI - What does being initiated severely into a group do? The role of rewards. AB - Undergoing an admission process (an initiation) can induce exaggerated feelings about a group, but there is little research about the role of rewards. This study replicated Aronson and Mills' (1959) experiment. Seventy participants underwent either a severe initiation or a mild initiation. After the initiation, about half the sample received an extrinsic reward for merely completing the task. The remaining half did not receive an extrinsic reward. This was to vary the amount of dissonance. Initiation severity and reward condition had significant, noncrossing interactions. A reward led to higher group identity than no reward, supporting Levine and Moreland's (1994) group socialization model. A severe initiation did not lead to more group identity than a mild initiation; therefore, Aronson and Mills' findings were not replicated. Interestingly, a mild initiation followed by a reward led to more group identity than a severe initiation followed by a reward. Another unexpected finding was that the extrinsic reward made no difference to group identity if the initiation was severe. Effects on ratings of the discussion were nonsignificant. Future research needs to establish how new group members ponder the severity of the admission process during the cost benefit calculation preceding their identification with a group. PMID- 22512543 TI - Tacrine-ferulic acid-nitric oxide (NO) donor trihybrids as potent, multifunctional acetyl- and butyrylcholinesterase inhibitors. AB - In search of multifunctional cholinesterase inhibitors as potential anti Alzheimer drug candidates, tacrine-ferulic acid-NO donor trihybrids were synthesized and tested for their cholinesterase inhibitory activities, release of nitric oxide, vasodilator properties, cognition improving potency, and hepatotoxicity. All of the novel target compounds show higher in vitro cholinesterase inhibitory activity than tacrine. Three selected compounds (3a, 3f, and 3k) produce moderate vasorelaxation in vitro, which correlates with the release of nitric oxide. Compared to its non-nitrate dihybrid analogue (3u), the trihybrid 3f exhibits better performance in improving the scopolamine-induced cognition impairment (mice) and, furthermore, less hepatotoxicity than tacrine. PMID- 22512544 TI - IPCRG: International Primary Care Respiratory Group. IPCRG working locally, collaborating globally. PMID- 22512545 TI - Significant delay in the introduction of systemic treatment of moderate to severe psoriasis: a prospective multicentre observational study in outpatients from hospital dermatology departments in France. AB - BACKGROUND: There is a low rate of systemic treatment usage in moderate to severe psoriasis. OBJECTIVES: The primary objective of the present study was to assess the time period between lack of control of moderate to severe psoriasis with topical treatment or phototherapy as perceived by patients and the medical decision to introduce a systemic treatment. METHODS: This was a prospective multicentre study, which included patients with moderate to severe psoriasis. A standardized questionnaire was completed by physicians and patients at the time the decision was taken to introduce a systemic treatment. The primary outcome was the duration of uncontrolled psoriasis, as estimated by the patient, prior to the introduction of systemic treatment. Factors associated with a delay in systemic treatment defined as > 2 years of uncontrolled psoriasis were assessed. The agreement between patients and physicians on the duration of uncontrolled psoriasis was estimated. RESULTS: The study included 142 patients. The mean age was 48 years, the mean Psoriasis Area and Severity index (PASI) was 18.5 and the mean Dermatology Life Quality Index (DLQI) was 12. The median duration of uncontrolled psoriasis estimated by patients and physicians was 3 years and 2 years, respectively. Factors associated with a delay in the introduction of systemic treatment as assessed by patients were fewer than three physician visits since psoriasis was uncontrolled [odds ratio (OR) 3.05; 95% confidence interval (CI) 1.29-7.21], Hospital Anxiety and Depression (HAD) scale < 10 (OR 2.83; 95% CI 1.19-6.71), continuous psoriasis evolution (OR 2.67; 95% CI 1.12-6.42), low consumption of topical treatment (OR 2.35; 95% CI 1.03-5.34). CONCLUSIONS: There is a significant delay in the introduction of systemic treatment in moderate to severe psoriasis. Patients with low level anxiety and limited use of healthcare resources appear to be at higher risk of experiencing long delays. PMID- 22512546 TI - Can the individual calibration be modified when laser fluorescence method is used for caries detection? AB - BACKGROUND: Individual calibration (IC) for caries detection methods based on fluorescence is time-consuming, especially for paediatric dentists, if the calibration has to be performed tooth-by-tooth. However, it is not clear how this calibration actually interfere in laser fluorescence (LF) readings. AIM: This in vivo study was to verify the influence of different modes of IC on laser fluorescence (LF) readings. DESIGN: Ninety six occlusal and 95 buccal surfaces of 1st permanent molars were examined using LF device after IC performed on control (no IC), the examined teeth, a permanent incisor, a 1st primary molar or a 2nd primary molar. All modes of IC were performed in the same child. Wilcoxon test and Bland-Altman analysis were used to compare the readings. Intraclass correlation coefficients (ICC) were calculated. RESULTS: Laser fluorescence readings without prior calibration were higher than readings performed after any mode of IC and resulted in different values of ICC. After other IC modes, the LF readings were statistically similar. CONCLUSION: The absence of IC influences LF readings and LF reproducibility, but different IC methods can be considered in clinical practice. PMID- 22512547 TI - Prevalence of Toscana virus antibodies in residents of Croatia. AB - To assess the prevalence of Toscana virus (TOSV) infection among healthy residents of Croatia we tested sera from 2016 persons, for IgG antibodies to TOSV, by an enzyme immunoassay. A total of 755 (37.5%) persons had IgG antibodies to TOSV: 53.9%, 33.6% and 6.1% among residents of the islands, coastal area and mainland of Croatia, respectively. Risk factors significantly associated with seropositivity to TOSV were: living on islands (OR, 11.10; 95% CI, 6.02-20.50; p <0.001) or in coastal areas (OR, 6.96; 95% CI, 3.81-12.71; p <0.001) and increase of age (OR, 1.03; 95% CI, 1.02-1.03; p <0.001). PMID- 22512548 TI - On chemical structures with potent antiepileptic/anticonvulsant profile. AB - Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures. There has been a considerable interest in the development of many antiepileptic and anticonvulsant agents for controlling epilepsy with fewer side effects and improvement of quality of life. Since the terms antiepileptics /anticonvulsants are used interchangeably, this article reviews their classification according to the chemical structure into: hydantoins, oxazolidinediones, succinimides, barbiturates, amides, benzodiazepines, valproic acid and its derivatives, GABA-analogues, cycloalkanes, semicarbazones, gamma butyrolactones (GBLs), imidaquinazolines and pyrrolidine derivatives as well as miscellaneous compounds. In addition, the review discusses the different mechanisms of action of antiepileptic and anticonvulsant agents. PMID- 22512549 TI - Chemistry and biology of fascaplysin, a potent marine-derived CDK-4 inhibitor. AB - Marine natural products offer an abundant source of pharmacologically active agents with great diversity and complexity, and the potential to produce valuable therapeutic entities. Indole alkaloids is one of the important class of marine derived secondary metabolites, with wide occurrence amongst variety of marine sources such as sponges, tunicates, algae, worms and microorganisms and have been extensively studied for their biological activities. Among this chemical family, a sponge-derived bis-indole alkaloid fascaplysin (1) exhibited broad range of bioactivities including antibacterial, antifungal, antiviral, anti-HIV-1-RTase, p56 tyrosine kinase inhibition, antimalarial, anti-angiogenic, antiproliferative activity against numerous cancer cell lines, specific inhibition of cyclin dependent kinase-4 (IC(50) 350 nM) and action as a DNA intercalator. In the present review, the chemical diversity of natural as well as synthetic analogues of fascaplysin has been reviewed with a detailed account on synthetic reports and pharmacological studies. Our analysis of the structure-activity relationships of this family of compounds highlights the existence of various potential leads for the development of novel anticancer agents. PMID- 22512550 TI - Meridianins: marine-derived potent kinase inhibitors. AB - Marine invertebrates are a rich source of novel, bioactive secondary metabolites and have attracted a great deal of attention from scientists in the fields of chemistry, pharmacology, ecology, and molecular biology. This profilic natural source has produced several antitumor secondary metabolites and amongst these, indole alkaloids are of wide occurrence. Meridianins A-G (1-7) are indole alkaloids isolated from tunicate Aplidium meridianum and are known to inhibit variety of protein kinases associated with cancer and neurodegenerative diseases. These compounds also exhibited promising antiproliferative activity in several cancer cell lines. Amongst natural meridianins, meridianin E (5) showed potent and selective inhibition of CDK-1 and CDK-5. Several synthetic meridianin analogs exhibited potent and selective inhibition of glycogen synthase-3 (GSK-3) and dual specificity tyrosine-phosphorylation regulated kinase 1A (Dyrk-1A) which are known to be implicated in progression of Alzheimer's disease. The present review provides the critical account of isolation, medicinal chemistry and pharmacology of meridianins. Our analysis of the structure-activity relationships of this family of compounds highlights the existence of various potential leads for the development of novel anticancer and anti-Alzheimer's agents. PMID- 22512551 TI - Cyclin-dependent kinase inhibition by flavoalkaloids. AB - Chromone alkaloids and flavoalkaloids are an important group of natural products possessing promising medicinal properties. A chromone alkaloid rohitukine is a major bioactive chemical constituent of plant Dysoxylum binectariferum (Meliaceae) Hook. which is phylogenetically related to the Ayurvedic plant, D. malabaricum Bedd. used for treatment of rheumatoid arthritis. This chromone alkaloid led to discovery of two synthetic flavoalkaloids: flavopiridol (Sanofi) and P-276-00 (Piramal) which have reached to advanced stages of clinical development for cancer treatment. Flavopiridol (Alvocidib; L868275; HMR-1275; NSC 649890 of Sanofi-Aventis + NCI) is approved as an orphan drug for treatment of chronic lymphocytic leukemia and is currently undergoing phase II studies as monotherapy and also as in combination regimes with traditional chemotherapy agents. P-276-00 (12) is currently in phase II clinical studies for advanced refractory neoplasms and multiple myeloma. Extensive amount of medicinal chemistry efforts have been reported on these flavoalkaloids. Flavopiridol demonstrated potent and specific in vitro inhibition of variety of cyclindependent kinases with clear block in cell cycle progression at the G1/S and G2/M phases. Preclinical studies demonstrated the capacity of flavopiridol to induce programmed cell death, promote differentiation, inhibit angiogenic processes and modulate transcriptional events. The co-crystallised structure of deschloro-flavopiridol with CDK-2 is available and key interactions in the ATP binding site have been reported. Flavopiridol has also been studied for the treatment of arthritis and atherosclerotic plaque formation. The present review comprises discovery, medicinal chemistry, pharmacology and preclinical/clinical development of flavoalkaloids as CDK inhibitors. PMID- 22512553 TI - Recent progress on synthesis and activities of allosamidin and its analogues. AB - The pseudotrisaccharide allosamidin 1 is a potent family-18 chitinase inhibitor, and it demonstrates biological activities against insects and fungi. Recent development for the synthesis and activities of compound 1 and its analogues was reviewed. Huang et al. described the solid-phase synthesis of allosamidin 1 and its analogues, which were obtained by iterative glycosylation reactions, catalytic hydrogenation, acetylation, and deacetylation, respectively. It indicated that di-N-acetyl-beta-chitobiosyl allosamizoline was strongly against insect chitinase from Bombyx mori. Withers and his coworkers have synthesized chitobiose and chitotriose thiazolines, which exhibit chitinase inhibition activity. PMID- 22512552 TI - Melatonin synthetic analogs as nitric oxide synthase inhibitors. AB - Nitric oxide (NO), which is produced by oxidation of L-arginine to L-citrulline in a process catalyzed by different isoforms of nitric oxide synthase (NOS), exhibits diverse roles in several physiological processes, including neurotransmission, blood pressure regulation and immunological defense mechanisms. On the other hand, an overproduction of NO is related with several disorders as Alzheimer's disease, Huntington's disease and the amyotrophic lateral sclerosis. Taking melatonin as a model, our research group has designed and synthesized several families of compounds that act as NOS inhibitors, and their effects on the excitability of N-methyl-D-aspartate (NMDA)-dependent neurons in rat striatum, and on the activity on both nNOS and iNOS were evaluated. Structural comparison between the three most representative families of compounds (kynurenines, kynurenamines and 4,5-dihydro-1H-pyrazole derivatives) allows the establishment of structure-activity relationships for the inhibition of nNOS, and a pharmacophore model that fulfills all of the observed SARs were developed. This model could serve as a template for the design of other potential nNOS inhibitors. The last family of compounds, pyrrole derivatives, shows moderate in vitro NOS inhibition, but some of these compounds show good iNOS/nNOS selectivity. Two of these compounds, 5-(2-aminophenyl)-1H-pyrrole-2-carboxylic acid methylamide and cyclopentylamide, have been tested as regulators of the in vivo nNOS and iNOS activity. Both compounds prevented the increment of the inducible NOS activity in both cytosol (iNOS) and mitochondria (i-mtNOS) observed in a MPTP model of Parkinson's disease. PMID- 22512554 TI - Nanostructures as promising tools for delivery of antimicrobial peptides. AB - Antimicrobial peptides have been extensively investigated for their potential applications as therapeutics and food biopreservatives. The antimicrobial activity may be impaired by the susceptibility for proteolytic degradation and undesirable interactions of the antimicrobial peptide in the biological environment. Development of nanostructures for entrapment and delivery of antimicrobial peptides may represent an alternative to the direct application of these substances. Lipid nanovesicles have been developed for encapsulation of antimicrobial peptides. Phosphatidylcholine is often employed in liposome manufacture, which is mostly achieved by the thin-film hydration method. Nanofibers may allow different physical modes of drug loading, including direct adsorption on the nanofiber surface or the assembly of drug-loaded nanoparticles. Self-assembled peptides reveal attractive features as nanostructures for applications in drug delivery and promising as antimicrobial agent for treatment of brain infections. Magnetic nanoparticles and nanotubules are also potential structures for entrapment of antimicrobial peptides. Nanoparticles can be also chemically modified with specific cell surface ligands to enhance cell adhesion and site specific delivery. This article reviews the most important nanostructures as promising tools for peptide delivery systems. PMID- 22512556 TI - Metals and Metal derivatives in Medicine. AB - Several chemical elements are required by living organisms in addition to the four elements carbon, hydrogen, nitrogen and oxygen usually present in common organic molecules. Many metals (e.g. sodium, potassium, magnesium, calcium, iron, zinc, copper, manganese, chromium, molybdenum and selenium) are known to be required for normal biological functions in humans. Disorders of metal homeostasis and of metal bioavailability, or toxicity caused by metal excess, are responsible for a large number of human diseases. Metals are also extensively used in medicine as therapeutic and/or diagnostic agents. In the past 5000 years, metals such as arsenic, gold and iron have been used to treat a variety of human diseases. Nowadays, an ever-increasing number of metal-based drugs is available. These contain a broad spectrum of metals, many of which are not among those essential for humans, able to target proteins and/or DNA. This mini-review describes metal-containing compounds targeting DNA or proteins currently in use, or designed to be used, as therapeutics against cancer, arthritis, parasitic and other diseases, with a special focus on the available information, often provided by X-ray studies, about their mechanism of action at a molecular level. In addition, an overview of metal complexes used for diagnosing diseases is presented. PMID- 22512555 TI - The cyclodextrin sugammadex and anaphylaxis to rocuronium: is rocuronium still potentially allergenic in the inclusion complex form? AB - Rocuronium, a non-depolarizing neuromuscular blocking drug has a rapid onset of action, a comparatively low potency and, with a more favourable side effects profile than succinylcholine, it has become a popular alternative to that drug for rapid sequence inductions in anaesthesia. The rocuronium-binding cyclodextrin derivative sugammadex, prepared by per-6 substitution of the primary hydroxyls of gamma-cyclodextrin with thiol ether-linked propionic acid side chains to extend the hydrophobic cavity to accommodate rocuronium, is used to reverse neuromuscular blockade by encapsulating the drug as an inclusion complex and removing it from the neuromuscular junction to the plasma. It has recently been suggested that sugammadex might also be of value in the management of rocuronium induced anaphylaxis and this has been potentially supported by recent case reports. However, before sugammadex can be recommended for this purpose, it is important to establish whether or not the allergenic substituted ammonium groups at each end of the rocuronium molecule in the inclusion complex are masked within the cavity or left exposed for interaction with rocuronium-reactive IgE antibodies in the sera of rocuronium-allergic patients. Detailed experimental strategies and experimental protocols to investigate the allergenic potential of the sugammadex-rocuronium inclusion complex are presented and a possible explanation of the apparently rapid and successful reversal of anaphylaxis by administration of sugammadex is advanced and discussed. PMID- 22512557 TI - Inhibitors of serine proteinases from blood coagulation cascade - view on current developments. AB - The importance of Factor Xa and thrombin in thrombosis and haemostasis is widely appreciated in the last years. This understanding logically leads to the concept of Factor Xa and thrombin inhibition as viable and attractive target for the antithrombotic therapy. The following review collects and summarizes information on numerous anticoagulant peptides, proteins, chemical compounds and low molecular weight fragment analogues of natural peptides isolated from hematophagous. Unfortunately, not much data from clinical trials of direct Factor Xa and thrombin inhibitors is available in the present moment. The current information reveals that Factor Xa and thrombin inhibition is a promising approach for prevention and treatment of hemostatic impairments. The synthesis of a low molecular weight synthetic peptide mimetics could be a key point in the fight against many diseases related to haemostatic disorders. PMID- 22512558 TI - Doxorubicin vs. ladirubicin: methods for improving osteosarcoma treatment. AB - Osteosarcoma is the most common primary bone tumor in children and adolescents, with a 5-year disease free survival rate of 70%. Current chemotherapy regimens comprise a group of chemotherapeutic agents in which doxorubicin is included. However, tumor resistance to anthracyclines and cardiotoxicity are limiting factors for its usage. Liposomal formulations of doxorubicin improve its anti cancer effects but are still insufficient. The research in this area has lead to the production of anthracyclines analogues, such as ladirubicin, the leading compound of alkylcyclines. This new anticancer agent has shown promising results in vivo and in vitro, being effective against osteosarcoma cell lines, including those with a multidrug resistant phenotype. In phase I clinical trials, this molecule caused mild side effects and did not induce significant cardiotoxicity at doses ranging from 1 to 16 mg/m(2), resulting in a peak plasma concentration (C(max)) ranging from 0.5 to 1.5 MUM. The recommended doses for phase II studies were 12 and 14 mg/m(2) in heavily and minimally pretreated/non-pretreated patients, respectively. Phase II clinical trials in ovary, breast, colorectal cancer, NSCLC and malignant melanoma are underway. Given the improved molecular targeting efficacy of these new compounds, ongoing approaches have sought to improve drug delivery systems, to improve treatment efficacy while reducing systemic toxicity. The combination of these two approaches may be a good start for the discovery of new treatment for osteosarcoma. PMID- 22512559 TI - The impact of the induction of multidrug resistance transporters in therapies by used drugs: recent studies. AB - Multidrug resistance (MDR) against groups of therapeutic drugs emerged to a central problem in the treatment of various diseases, i.e. cancer and infectious diseases like HIV or malaria. ABC transporters namely P-glycoprotein (P-gp) and various multidrug resistance associated proteins (MRPs) mainly contribute to the MDR phenomenon in cancer treatment and HIV therapy. Their cellular expression in respective cells like cancer cells lowers the intracellular drug concentrations and thus reasons the cellular resistance. The induction of such efflux pumps occurs during the therapy with drugs which will be affected by the MDR phenomenon as a consequence of the induction. In this review studies which report such drugs caused inductions will be viewed. The review will cover the literature of recent years and attract attention to this important question in drug resistance. Finally, the discussion will suggest possible strategies to overcome the problem, i. e. by using non-inducing drugs. PMID- 22512560 TI - 1,3,4-oxadiazole: a biologically active scaffold. AB - There has been considerable interest in the development of novel compounds with anticonvulsant, antidepressant, analgesic, anti-inflammatory, antiallergic, antipsychotic, antimicrobial, antimycobecterial, antitumour, antiviral and antitubercular activities. 1,3,4-oxadiazoles constitute an important class of compounds for new drug development. Therefore, many researchers have synthesized these compounds as target structures and evaluated their biological activities. These observations led to the development of new 1,3,4-oxadiazole derivatives. This review article describes the various biological activities associated with 1,3,4-oxadiazole ring system and is useful in guiding the researchers across the world working on this moiety and consequently have been instrumental in the advancement of 1,3,4-oxadiazole chemistry. PMID- 22512561 TI - SHP-2 regulates growth factor dependent vascular signalling and function. AB - Cellular responses to the environment are mediated by intracellular signalling pathways monitoring several essential cellular processes, such as proliferation, migration, differentiation and survival. Cellular dysfunction is caused by dysregulation of intracelleular signalling pathways and may ultimately result in pathophysiological conditions. The non- transmembrane protein tyrosine phosphatase SHP-2 has been shown to be important for the control of cellular behaviour. It influences the activity of several growth factor and cytokine dependent signalling pathways by association with growth factor receptors, cell surface adhesion molecules and adaptor molecules such as Gab-1, Grb2 and IRS-1. Upon FGF-2, EGF and insulin stimulation SHP-2 regulates MAPK pathway activation. In addition, SHP-2 is involved in the regulation of cell survival by influencing the PI3-K/Akt pathway upon EGF, IGF and PDGF stimulation. Due to these properties, SHP-2 function has recently gained more interest in vascular processes, such as in the differentiation of cardiac progenitor cells and angiogenic events. Indeed, SHP-2 was shown to positively regulate endothelial cell motility and angiogenesis in vitro and in vivo as well as controlling intracellular pH of endothelial and vascular smooth muscle cells. On the other hand, SHP-2 was also demonstrated to be responsible for down regulation of VEGF receptor 2 activation upon dopamin and collagen stimulation. Finally, mutations in the Ptpn11 gene (encoding SHP-2) underlie the developmental disorders Noonan syndrome and Leopard syndrome characterized by congenital heart disease and hematologic abnormalities. Different mutations in this gene also result in myeloid and lymphoid malignancies. This article summarizes the role of SHP-2 in signalling pathways relevant for vascular biology and associated disorders. PMID- 22512562 TI - Functionalized mesoporous silica particles for application in drug delivery system. AB - In these years, ordered mesoporous silica materials have shown promising applications in drug delivery system as drug carriers. These carriers with stable mesoporous structure, large surface area, good biocompatibility and tailored size of mesopores exhibit significant property of higher drug loading. However, silica based mesoporous materials cannot control the release of the loaded drug without modifications. In this paper, we review the recent research work discussing functionalization of mesoporous materials by various components and methods for application in drug delivery systems. All the examples show that these functionalized mesoporous silica-based systems have great potential for a variety of drug delivery applications, specifically in the fields of the drug targeted and controlled delivery systems. PMID- 22512563 TI - From fungus to pharmaceuticals--the chemistry of statins. AB - It has long been recognised that high circulating levels of cholesterol are associated with the development of cardiovascular disease. With the discovery of the cholesterol biosynthetic pathway in 1950, it was soon realised that blockade of key conversions in this pathway may provide useful therapeutic targets for the management of hypercholesterolaemia. In the 1970s the first useful inhibitors of cholesterol biosynthesis were isolated, and paved the way for what would become a multimillion dollar pharmaceutical industry. Modern-day statins are incredibly effective hypolipidaemic agents, interrupting cholesterol biosynthesis at the rate-limiting step through a competitive inhibition mechanism. These compounds' structures interact with key amino acid residues through a variety of defined bonding interactions, and by understanding how these interactions form, better, and safer, hypolipidaemic agents were found. This review describes the historical development of statins and brings us up-to-date with current structure-activity relationships between statins and their target enzyme. PMID- 22512564 TI - Prediction of cytochrome 450 mediated drug-drug interactions by three-dimensional cultured hepatocytes. AB - Cytochrome P450 (CYP) inhibition and induction are the key mechanisms in drug drug interactions which should be avoided in clinic for the uncertain influence on the efficacy and safety of drug co-administration. The CYPmediated drug-drug interactions urgently need to be predicted by in vitro models before animal and clinical trials, while the primary hepatocytes may represent the most appropriate experimental system by now. However, traditional twodimensional (2D) culture of hepatocyte monolayer, regardless of the good facilitation and repeatability, rapidly loses its CYP-inducibility during short-term culture due to the deviated microenvironments from in vivo. Also, 2D culture did not reproduce the CYP inhibition mediated hepatotoxicity in drug co-administration. Recently, three dimensional (3D) cultured hepatocytes have been recognized as the promising models for predicting in vivo drug-drug interactions. The 3D cultures such as sandwich and gel entrapped hepatocytes showed the comparable response to CYP inhibitors and inducers as in vivo and well reflected the inhibitor/inducer mediated hepatotoxicity. In this regard, this review, for the first time, compares the effect of 2D and 3D hepatocyte cultures on reflecting CYP-mediated drug-drug interactions in vivo. And the advantage of 3D cultured hepatocytes on predicting in vivo CYP-induction/inhibition will be particularly discussed. PMID- 22512565 TI - NK-1 receptor antagonists: a new generation of anticancer drugs. AB - After binding to the neurokinin-1 (NK-1) receptor, substance P (SP) induces tumor cell proliferation, angiogenesis, and the migration of tumor cells for invasion and metastasis. After binding to NK-1 receptors, NK-1 receptor antagonists inhibit tumor cell proliferation, angiogenesis and the migration of tumor cells. These antagonists are broad-spectrum antitumor drugs. In addition, in the host they display beneficial effects: anxiolytic, antiemetic, neuroprotector, nephroprotector, hepatoprotector, antiinflammatory and analgesic. In combination therapy with classic cytostatics, NK-1 receptor antagonists have synergic effects and minimize the side-effects of these classic drugs. Thus, NK-1 receptor antagonists could offer a new and promising generation of anticancer drugs. PMID- 22512566 TI - Antioxidants countermeasures against sulfur mustard. AB - Sulfur mustard (SM) is a vesicant chemical warfare agent that persists as a serious menace from the viewpoint of acute and chronic toxicity, simple synthesis and no effective treatment currently being available. The two most deleterious basic molecular mechanisms in SM poisoning are: inflammation and over-activation of poly(ADP-ribose) polymerase and the resulting DNA alkylation. Oxidative stress is the common consequence of these pathway activations. In the present review, the significance of oxidative stress in SM poisoning is discussed along with research on antioxidant therapy as a suitable antidote. The temporal dynamics of the redox imbalance, the antioxidant depletion and impact this has on tissues are described as the pathologies induced by SM. Special attention is paid to ameliorating the damage using low molecular weight antioxidants. Melatonin, epigallocatechin gallate and flavone derivatives, in particular, have been studied in recent experiments. The suitability of these antioxidants for therapy purposes is considered in a separate chapter. The review concludes with a view to the future and the studies needed on antioxidant therapy as a countermeasure to SM poisoning. PMID- 22512567 TI - Small diverse antioxidant functionalities for oxidative stress disease drug discovery. AB - There is an up-surge of interest in antioxidants because of their potential use in mitigating a wide array of oxidative stress mediated diseases. In the course of our literature search for diverse functional groups, with utility in the design of potential drugs for preventing oxidative stress related cell injury, we have collected a small literature library of core structures or moieties possessing antioxidant activities. These functional groups can be re-configured into robust antioxidants drug molecules, in their own right, or incorporated into drug structures where the antioxidant capability is required. The lack of single papers presenting a collection of diverse small molecule antioxidant moieties as potential design leads prompted us to write this short review of twenty five such functionalities. PMID- 22512568 TI - Angiogenesis as a therapeutic target in breast cancer. AB - Current evidence indicates that angiogenesis plays an important role in the pathogenesis of several malignancies, including breast cancer. Bevacizumab is a monoclonal antibody that targets the vascular endothelial growth factor (VEGF). Recent clinical data have demonstrated that the addition of bevacizumab to first line chemotherapy improves the progression-free survival of patients with advanced breast cancer. This review presents an update on the role of bevacizumab, as well as other anti-angiogenic agents in the management of patients with breast carcinoma. PMID- 22512569 TI - Perspectives on the development of novel potentially active quinolones against tuberculosis and cancer. AB - Quinolones and its derivatives comprise an important group of heterocyclic compounds that exhibit a wide range of pharmacological properties such as antibacterial, antitumor, antiviral, anti-ischemic, antiparasitic and anxiolytic. Persistent efforts have been made over the years to develop novel congeners with superior biological activities and minimal potential for undesirable side effects. The present review aims to highlight some recent discoveries on the development of novel quinolone-based compounds with potential antitubercular and anticancer activity. PMID- 22512570 TI - Development for anticancer therapy: small-molecule inhibitors targeting protein kinase B. AB - Protein kinase B (PKB, also known as Akt) plays a critical role in the multiple cellular processes including glucose metabolism, cell growth, survival, apoptosis, transcription, and cell migration. Unregulated activation of protein kinase B is common in a significant fraction of human cancer, making enzyme an exciting new target for cancer therapy. A series of inhibitors with different mechanisms have been found, which is bound to be a positive impact on drug screening and cancer treatment. However, the development of inhibitors targeting PKB has been hampered by lacking of PKB-specific and isoform-specific inhibitors. This article describes the structure and functions of PKB as well as the recent advances in the development and biological evaluation of PKB's inhibitors. It was focused on the developments of selective small-molecule inhibitors with a well defined, direct molecular interaction with protein kinase B, expecting to give information to design new inhibitors with high selectivity, bioavailability, and potency. PMID- 22512571 TI - The vigilance promoting drug modafinil modulates serotonin transmission in the rat prefrontal cortex and dorsal raphe nucleus. Possible relevance for its postulated antidepressant activity. AB - Modafinil, (RS)-2-(diphenylmethylsulfinyl)acetamide derivative (Modiodal, Provigil), is a vigilance-promoting agent which reduces sleep episodes by improving wakefulness. It is approved by the USA FDA for narcolepsy, shiftwork sleep disorder and obstructive sleep apnoea with residual excessive sleepiness despite optimal use of continuous positive airway pressure. Unlike classical psychostimulants such as amphetamine and amphetamine-like compounds, the awaking effect of modafinil is not associated with a disturbance of nighttime sleep, tolerance, and sensitization. Its precise mechanism of action is still unclear. In animal studies, modafinil and its analogues have been shown to modify dopaminergic, noradrenergic, glutamatergic, GABAergic, serotoninergic, orexinergic, and histaminergic pathways. Besides the approved use in sleep disorders, modafinil has been investigated for the treatment of fatigue, impaired cognition and some symptoms in a number of other disorders. In particular, clinical studies seem to indicate that the drug could be particularly successful in the treatment of depression and its use in major depressive and bipolar disorders, has been suggested. However, the molecular mechanisms underlying this possible effect are still unknown. The present review firstly summarizes the structure-activity relationship studies and the mechanism of action of modafinil and its related compounds. Then, it focuses on data demonstrating that modafinil interacts with serotonin neuronal activity in rat frontal cortex and dorsal raphe nucleus, two brain areas linked together and involved in depression. Preclinical and clinical evidence of a positive interaction between modafinil and classical antidepressant drugs, is also summarized. PMID- 22512572 TI - Role of polymorphisms in factor V (FV Leiden), prothrombin, plasminogen activator inhibitor type-1 (PAI-1), methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthase (CBS) genes as risk factors for thrombophilias. AB - Thrombophilias are defined as a predisposition to thrombosis due to hematological changes which induce blood hypercoagulability; they can be inherited or acquired. They are individually characterized by a large phenotypic variability, even when they occur within the same family. Hereditary thrombophilias are, in most cases, due to changes related to physiological coagulation inhibitors or mutations in the genes of coagulation factors. High levels of plasma homocysteine may also be responsible for vaso-occlusive episodes and may have acquired (nutritional deficiencies of folate and vitamins B6 and B12) and/or genetic causes (mutations in the genes responsible for expression of enzymes involved in the intracellular metabolism of homocysteine). Considering that: (1) thromboses are events of multigenic and multifactorial etiopathology; (2) the presence of mutations in several genes significantly increases the risk of their occurrence; (3) the vascular territory (venous and/or arterial) affected involves different pathophysiological mechanisms and treatments, knowledge of genetic variants that may contribute to the risk and variability of the phenotypic manifestations of these diseases is extremely important. This understanding may provide support for a more individualized and therefore more effective treatment for thrombophilia carriers. Thus, this mini-review aims to address a comprehensive summary of thrombophilias and thrombosis, and discuss the role of polymorphisms in Factor V (FV Leiden), Prothrombin, Plasminogen activator inhibitor type-1 (PAI-1), Methylenetetrahydrofolate reductase (MTHFR) and Cystathionine beta-synthase (CBS) genes as risk factors for thrombophilias. PMID- 22512573 TI - Structure-activity relationships of biphalin analogs and their biological evaluation on opioid receptors. AB - Biphalin (Tyr-D-Ala-Gly-Phe-NH-NH < -Phe < -Gly < -D-Ala < -Tyr) is an opioid octapeptide with a dimeric structure based on two identical pharmacophore portions, derived from enkephalins, joined "tail to tail" by a hydrazide bridge. This particular structure enhances the antinociceptive activity of the native enkephalins with an unknown mechanism, probably based on a cooperative binding and improved enzymatic stability. Biphalin has excellent binding affinity for MU and delta receptors and it is a highly potent analgesic, as potent as or more than ethorphine. A definitive explanation of the extraordinary in vivo potency shown by this compound, which has pronounced efficacy in pain modulation, is still not available; it has been suggested, however, that the high agonist activity may be related to its binding mode at both MU and delta opioid receptors. Biphalin has significantly higher potency than other analgesics with novel biological profiles; in particular, most recent data show that biphalin is unlikely to produce dependency in chronic use. In the past 20 years, there have been many attempts to modify its structure to obtain products unaffected by the action of enkephalinases, to enhance its antinociceptive activity and to modify the BBB penetration. In addition, structure-activity relationship studies (SAR) were performed in order to understand the elements responsible for biphalin's high activity. The aim of the studies reported in this review was to clarify: i) the role of the hydrazide bridge, ii) the role of residues in position 4, 4' and 3, 3', iii) the consequences of molecular simplifications (truncation, delection), iv) the consequences of cyclization through a disulfide bridge, v) conjugation with PEG and fluorescet residues, and vi) radiolabeling on Tyr. PMID- 22512574 TI - Studies on alpha-glucosidase inhibitors development: magic molecules for the treatment of carbohydrate mediated diseases. AB - alpha-Glucosidase (EC 3.2.1.20) enzyme belongs to the glycosidase family enzymes, cleave the glycosidic bond of the oligosaccharides that liberate glucose and its inhibition retards the carbohydrate digestion. In the present review, we have discussed the structural features of different alpha-glucosidase inhibitors (small molecules) responsible for the inhibitory activities. The reported computational studies including, QSAR, pharmacophore modelling, homology models, docking (with analogs enzymes), etc revealed that the topological, electronic and hydrophobicity properties determine the interactions of those molecules. The aromatic substituents connected with flexible bonds in the molecules have significant effect on the interactions, which may due to the presence of aromatic amino acid residues in the active site. The reported homology modelled and other analogs enzymes (enzymes of other species) also confirmed the existence of aromatic residue (amino acids) especially, histidine, phenylalanine and tyrosine in their active site along with the polar (glutamic and aspartic acids) residues. Multiple sequence alignments of the alpha-glucosidase enzymes (from different species) described that the abovementioned amino acid residues are present in the active site of all the studied enzymes. Recently, Celgosivir (MIGENIX Inc) is an oral prodrug of the natural product castanospermine used for the treatment of HCV infection by inhibiting alpha-glucosidase I. BMN-701 is an alpha-glucosidase inhibitors in the phase I pipeline (BioMarine) for the treatment of Pompe diseases. CKD-711 and CKD-711a are aminooligosaccharide alpha-glucosidase inhibitors and the in vitro study of CKD-711 showed similar effects to acarbose on porcine intestinal maltase and sucrase (IC50s of 2.5 and 0.5 MUg/ml). This review also concluded that many alpha-glucosidases inhibitors obtained from natural products are used for the treatment of various carbohydrate mediated diseases. The structural analysis of these synthetic and natural derivatives guide for the development of novel semisynthetic/synthetic alpha-glucosidase inhibitors with free of toxicities. PMID- 22512575 TI - Pharmacophore development and SAR studies of imidazoline receptor ligands. AB - Relationship between biological responses and binding affinities at I(1)/I(2)/I(3) imidazoline receptors of compounds with imidazoline, pyrroline or oxazoline moieties was studied by 2D-QSAR, 3D-QSAR and quantitative pharmacophore development approaches. Since the I(1) imidazoline receptor is involved in central inhibition of sympathicus that produce hypotensive effect, the I(2) receptor is allosteric modulator of monoamine oxidase B (MAO-B) and the I(3) receptor regulates insulin secretion from pancreatic beta-cells, design and synthesis of selective I(1)/I(2)/I(3) imidazoline ligands are very important for the development of new effective therapeutic agents. New agonists and antagonists with high selectivity for I(1)/I(2)/I(3) imidazoline receptor classes have been recently synthesized and examined. The present review will highlight the main chemical diversity and pharmacophore features of selective I(1)/I(2)/I(3) imidazoline receptor ligands. PMID- 22512576 TI - Effects of synthetic peptides on the inflammatory response and their therapeutic potential. AB - Recently, interest in small peptide molecules as potential drug candidates has revived. In this review, two series of synthetic peptides and their selective effects on the inflammatory response have been described, focusing on the intracellular pathways involved and on their therapeutic potential. A series of F(D)LF(D)LF analogs has been synthesized, including either N- t-Boc or different N-ureido substituents. The free acid derivatives as they are good candidates as antiinflammatory drugs are able to antagonize the multiple neutrophil functions evoked by N-formyl-L-methionyl-L-leucyl-Lphenylalanine (fMLF), i.e. chemotaxis, superoxide anion production and lysozyme release. Their methyl-ester derivatives are ineffective. The second series of peptides derives from the endogenous protein kinase C (PKC) inhibitor PKI55, a 55-amino acid protein, whose synthesis is induced by PKC activation, so that a feedback loop of inhibition is established. In vitro experiments showed that PKI55 inhibits recombinant PKC isoforms alpha, beta1, beta2, gamma, delta, zeta, ; to identify the minimal amino acid sequence of PKI55 protein maintaining the inhibitory effects on PKC, peptides derived from both C- and N-terminal sequences have been synthesized. The N-terminal peptides 5 (MLYKLHDVCRQLWFSC), 8 (CRQLWFSC) and 9 (CRQLW), that in human neutrophils retain the inhibitory activity on PKC, decrease the chemotaxis, and, in mice, display anti-inflammatory and analgesic action, after both central and peripheral administration of very low doses. Furthermore, the peptide 5 shows neuroprotective activity in a model of cerebral ischemia in vitro, favouring the recovery of synaptic function. These findings suggest interesting possible therapeutic applications for these peptides. PMID- 22512577 TI - Recent updates on biological activities of oxadiazoles. AB - Among the plethora of heterocyclic nucleus discovered, the oxadiazoles have also been explored extensively. The oxadiazole structure has been demonstrated to bear important biological activities such as anti-cancer, antiinflammatory, anti tuberculosis, anti-malarial and anti-schistosomiasis etc. The presence of oxadiazole motifs in diverse types of compounds proves its importance in the field of medicinal chemistry. This review is complementary to earlier reviews and covers recent updates of various pharmacological aspects of oxadiazoles. To help the reader better know the context for these approaches, a summary of various aspects of background of related topic is presented. PMID- 22512578 TI - Antioxidant and antimicrobial activities of cinnamic acid derivatives. AB - Cinnamic acid is an organic acid occurring naturally in plants that has low toxicity and a broad spectrum of biological activities. In the search for novel pharmacologically active compounds, cinnamic acid derivatives are important and promising compounds with high potential for development into drugs. Many cinnamic acid derivatives, especially those with the phenolic hydroxyl group, are well known antioxidants and are supposed to have several health benefits due to their strong free radical scavenging properties. It is also well known that cinnamic acid has antimicrobial activity. Cinnamic acid derivatives, both isolated from plant material and synthesized, have been reported to have antibacterial, antiviral and antifungal properties. Acids, esters, amides, hydrazides and related derivatives of cinnamic acid with such activities are here reviewed. PMID- 22512579 TI - Perspectives on developing small molecule inhibitors targeting HIV-1 integrase. AB - HIV-1 integrase (IN) is a crucial enzyme in the life cycle of HIV-1 and also a validated target for developing anti-HIV inhibitors. Recent progress in drug design has significantly accelerated the development of anti-AIDS IN inhibitors. A large amount of novel inhibitors that interact specifically with IN were developed along with the expanding and application of methods to drug design. This article reviewed the anti-HIV IN inhibitors discovered by the rational drug design approaches in the recent 5-year. PMID- 22512580 TI - Hypoxia-inducible factor-1alpha: molecular-targeted therapy for hepatocellular carcinoma. AB - Hypoxia-inducible factor (HIF)-1alpha is over-expressed in hepatocellular carcinoma (HCC) and degraded by ubiquitin-proteasome pathways under normoxic conditions. Hepatocyte hypoxia enhances proliferation, angiogenesis, metastasis, chemoresistance, and radioresistance of HCC. The importance role of HIF-1alpha expression in HCC may improve the prognostic and therapeutic technique. This article reviews the HIF-1alpha expression and its gene during the rat HCC development, the level of HIF-1alpha expression in HCC patients, and the effect of silencing HIF-1alpha gene by miRNA on inhibition of HepG2 cell proliferation. PMID- 22512581 TI - Long term ketamine and ketamine plus alcohol toxicity - what can we learn from animal models? AB - This review addressed the adverse effects of the frequently-used recreational drug, ketamine through using mice and monkey models. Our laboratory has documented initially that ketamine can induce the formation of hyperphosphorlated tau (hypertau), which is a hallmark of Alzheimer's disease (AD), in the cerebral cortex of both mice and monkeys as well as apoptosis in neurons in these species. Besides the cerebral cortex, other centers in the central nervous system (CNS) and peripheral nervous system (PNS) are also influenced by ketamine. Cerebellum was found to be down-regulated in both mice and humans after long-term of ketamine administration and it was caused by the apoptosis of Purkinje cells. Deleterious effects in other organs reported in long-term ketamine users include of kidney dysfunction leading to proteinuria, fibrosis of the urinary bladder and reduction in size of the urinary bladder leading to frequent urination, increase of liver fibrosis and cardiac problems such as premature ventricular beats. Moreover, ketamine is usually co-administrated with other chemicals such as caffeine or alcohol. It has been reported increased harmful effects when ketamine was used in combination with the above substances. Mechanisms of damages of ketamine might be due to 1) up-regulation of NMDA receptors leading to overestimation of glutamatergic system or 2) the metabolite of ketamine which was a hydroquinone exerted toxicity. PMID- 22512582 TI - Novel serine protease dipeptidyl peptidase IV inhibitor: alogliptin. AB - Alogliptin (codenamed SYR-322) is a recently approved anti-diabetic drug in Japan, which has been under clinical development phase III in USA and Europe. Alogliptin has been developed by Takeda under the brand name "Nesina". Alogliptin is a highly selective ( > 10,000-time selectivity, potent, reversible and durable serine protease dipeptidyl peptidase IV enzyme is compared to DPP-8 and DPP-9) inhibitor, which has been developed as an alternative second-line to metformin in place of a sulphonylurea. Alogliptin has been observed to increase and prolong the action of incretin hormone by inhibiting the DPP-IV enzyme activity. Alogliptin has been observed to well absorb and show low plasma protein binding, which displays slow-binding properties to DPP-IV enzyme. The X-ray crystallography studies have been revealed that Alogliptin binds to DPP-IV active site by non-covalently and provides sustained reduction of plasma DPP-IV activity as well as lowering of blood glucose, in drug-naive patients with T2DM and inadequate glycemic control, once daily oral dosing regimen with varying levels of doses ranging from 25-800 mg. Alogliptin is approved as monotherapy and in combination with alpha-glucosidase & thiazolidinediones. The 26 week clinical study of Alogliptin revealed that Alogliptin doesn't increase the weight and well tolerated. In the present review, we have tried to cover biology of DPP-IV, molecular chemistry, chemical characterization, crystal polymorphic information, interaction studies, commercial synthesis, current patent status, adverse effects and clinical status of Alogliptin giving emphasis on the medicinal chemistry aspect. PMID- 22512583 TI - Sydnones: a brief review. AB - Sydnones are mesoionic heterocyclic aromatic compounds. They have been widely studied for some important biological activities like antiviral, antitumor, antimicrobial, anti-inflammatory, anticancer, analgesic, anthelmintic and antihypertensive activities. The aim of the present article is to review the available information on sydnones and the derivatives of sydnones and also a look at the future perspectives. PMID- 22512584 TI - Marine natural products and other derivatives as potent indoleamine 2,3 dioxygenase inhibitors. AB - Cancer cells are able to elaborate enzymatic mechanisms allowing tumors to resist or escape imune rejection. Among the enzymes involved, indoleamine 2,3 dioxygenase (IDO), an intracellular enzyme that initiates the first and rate limiting step of tryptophan breakdown along the kynurenine pathway, has emerged as a promising molecular target for the development of new immunotherapeutic anticancer agents. This review summarizes the synthesis and IDO activities of the different classes of marine and other inhibitors reported so far. PMID- 22512585 TI - Antioxidative activities of medicinal plants from TCM. AB - As a natural antioxidant resource, traditional Chinese medicine (TCM) has been paid much more attentions than before. The studies on its antioxidative activity have also increased dramatically in recent years. Abundant studies on TCM show that some TCM can increase body's activity of antioxidant enzymes, enhance body's ability of scavenging free radicals and decrease the generation of lipid peroxide (LPO) and malondialdehyde (MDA) in the body etc. The action mechanism of TCM is closely related to its active constituents, including polysaccharides, quinines, flavonoids, saponins, alkaloids, terpenes, phenolic acids compounds and tannins etc. Through referring to related reports on TCM, in the last 20 years, this paper reviews literatures involved in antioxidation research on TCM. Antioxidative mechanism, functional property and application prospect of some active constituents with antioxidation in TCM are discussed. PMID- 22512586 TI - Rational development of neuraminidase inhibitor as novel anti-flu drug. AB - The highly pathogenic influenza virus has caused many human fatalities and poses an increasing pandemic threat. Neuraminidase inhibitors such as oseltamivir and zanamivir have been widely used in the treatment and have gained remarkable success. Although, they are effective in prevention of influenza; the concern for drug resistance still remains a question. Recently, the availability of crystal structures of the enzyme gave a new trend to the structure based drug designing of neuraminidase inhibitors. The article reviews a detailed understanding of the structural features within neuraminidase enzyme which turnouts to be crucial for future drug development. In depth analysis for the newly proposed spots within the 150 and 430-loop regions in N1 makes it distinguishable among the subtypes. Further we have discussed the various computational studies carried out in optimizing the designing of neuraminidase inhibitors thereby providing new clues to modify the currently available drugs. PMID- 22512587 TI - A review on the development in the field of NIDDM based thiazolidinedione PPARgamma agonists. AB - Peroxisome Proliferator Activated Receptors gamma (PPARgamma) are a class of ligand activated transcription factors with a prominent role in the regulation of metabolic processes. The present work aims towards examining the functional and structural features that facilitate the binding of small molecules based on Thiazolidinedione pharmacophore to PPARs. The intent of this article is to review all the reported thiazolidinediones and associated groups of PPARgamma ligands. PMID- 22512588 TI - Antioxidant hybrid compounds: a promising therapeutic intervention in oxidative stress induced diseases. AB - Reactive oxygen species/nitrogen species (ROS/RNS) are major causative agents of oxidative stress related diseases such as neurodegenerative, cancer, cardiovascular, and inflammation via intracellular signal transduction pathways. Synthetic modification of antioxidants and development of hybrid compounds by conjugation or integration of two or more moiety opened a new era in development of antioxidant based therapeutics. In this review, our attention is focused on structural, chemical and biochemical feature of free radicals, description of mechanistic modulation in signaling pathways by antioxidants and establishment of relationship between structural and biological accepts of antioxidant hybrid systems (1,2-dithiolone, alpha,beta-unsaturated carbonyl, cinnamate based hybrids and miscellaneous hybrids). PMID- 22512589 TI - A Review for Mini-Review in Medicinal Chemistry. AB - Cantharidin, as a natural toxin, can inhibit multifarious tumor cell lines, especially to hepatocellular carcinoma cells. It is a strong inhibitor of protein phos- phatases type 1 (PP1) and 2A (PP2A). Because of the cytotoxicity, the clinical application is limited. While the analogues, such as norcantharidin(NCTD), cantha- rimide and heterocyclic substituted cantharidin reveal more powerful antitumor activity and less cytotoxicity. PMID- 22512590 TI - Chitin synthase inhibitors as antifungal agents. AB - Increased risk of fungal diseases in immunocompromised patients, emerging fungal pathogens, limited repertoire of antifungal drugs and resistance development against the drugs demands for development of new and effective antifungal agents. With greater knowledge of fungal metabolism efforts are being made to inhibit specific enzymes involved in different biochemical pathways for the development of antifungal drugs. Chitin synthase is one such promising target as it is absent in plants and mammals. Nikkomycin Z, a chitin synthase inhibitor is under clinical development. Chitin synthesis in fungi, chitin synthase as a target for antifungal agent development, different chitin synthase inhibitors isolated from natural sources, randomly synthesized and modified from nikkomycin and polyoxin are discussed in this review. PMID- 22512591 TI - Biological Activities and Corresponding Sar Analysis of Andrographolide and its Derivatives. AB - In recent years pharmaceutical chemists have synthesized large numbers of andrographolide derivatives, which bear important biological activities such as anti-inflammatory, antibacterial, antivirus, antitumor, antidiabetic, and antifeedant. Consequently, the corresponding SAR presents more and more pronounced. This paper aimed to review all the available literature on this field, which highlighted the significant achievements on the structural modification and SAR of andrographolide and its derivatives. PMID- 22512592 TI - Perspectives on the development of antioxidant antiepileptogenic agents. AB - Epilepsy is a chronic disorder of abnormal electrical activity in the brain characterized by recurrent unprovoked seizures. Currently used pharmaceutical agents do not treat the underlying disease process, and a significant proportion of epileptic patients are refractory to current therapies. Therefore there is a strong need for additional therapeutic agents, especially those that address the underlying disease process of epileptogenesis. The redox potential of cells is maintained by an appropriate balance between pro- and anti-oxidative molecules; oxidative stress and increases in toxic reactive oxygen species occur when this balance shifts towards oxidation. Neural tissues are especially sensitive to oxygen levels, and oxidative stress is thought to be involved in epileptogenesis. Increases in reactive oxygen species occur in response to sustained neuronal electrical activity and seizures. Therefore antioxidants have been suggested as therapeutic design strategies for the treatment and modulation of epilepsy. This minireview focuses on several key antioxidants and agents involved in defending against oxidative stress that may be targets for new antiepileptogenic drug design, including directacting antioxidants, Nrf2-activating agents, and prolyl-4 hydroxylase inhibitors. A description of the necessary physicochemical properties and a summary of animal models that are thought to be useful for developing antiepileptogenic agents are presented. PMID- 22512595 TI - Aerosolized antibiotics: the past, present and future, with a special emphasis on inhaled colistin. PMID- 22512596 TI - Industrial perspective of gastroretentive drug delivery systems: physicochemical, biopharmaceutical, technological and regulatory consideration. AB - INTRODUCTION: Gastroretentive drug delivery systems (GRDDS) can overcome drawbacks associated with oral drug delivery, by defeating natural physiological principles. Various gastroretentive technologies have been developed in the past, but few of them achieved success on the market. AREAS COVERED: This review is focused on the key concepts required to make a high-quality drug product available in a timely and economical manner. EXPERT OPINION: Pharmacotherapy of various disease states can be amended by drug repurposing through GRDDS. Assessment of the effect of the fed and fasted condition on product performance should be necessary during initial development phases. Dual working technology would be a possible way to overcome drawbacks associated with different GRDDS. Before development of a drug product, the principles of scale up and process validation must be considered to improve the quality and market availability of GRDDS. Knowledge of all regulatory aspects will help to deliver a product to the market within a reasonable timeframe and in a cost-effective manner. PMID- 22512597 TI - Exploring oral nanoemulsions for bioavailability enhancement of poorly water soluble drugs. AB - INTRODUCTION: More than 40% of new chemical entities discovered are poorly water soluble and suffer from low oral bioavailability. In recent years, nanoemulsions are receiving increasing attention as a tool of delivering these low-bioavailable moieties in an efficient manner. AREAS COVERED: This review gives a brief description about how oral nanoemulsions act as a tool to improve the bioavailability of poorly water-soluble drugs. The recurrent confusion found in the literature regarding the theory behind the formation of nanoemulsions is clarified, along with the difference between nanoemulsion and lyotropic 'microemulsion' phase. This paper gives a clear-cut idea about all possible methods for the preparation of nanoemulsions and the advantages and disadvantages of each method are described. A description of the stability problems of nanoemulsions and their prevention methods is also provided, in addition to a comprehensive update on the patents and research works done in the arena of oral nanoemulsions. EXPERT OPINION: Low-energy emulsification techniques can also produce stable nanoemulsions. It is guaranteed that oral nanoemulsions can act as a potential tool for the delivery of poorly water-soluble therapeutic moieties in a very efficient manner. PMID- 22512598 TI - Formation and dissociation processes of gas-phase detergent micelles. AB - Growing interest in micelles to protect membrane complexes during the transition from solution to gas phase prompts a better understanding of their properties. We have used ion mobility mass spectrometry to separate and assign detergent clusters formed from the n-trimethylammonium bromide series of detergents. We show that cluster size is independent of detergent concentration in solution, increases with charge state, but surprisingly decreases with alkyl chain length. This relationship contradicts the thermodynamics of micelle formation in solution. However, the liquid drop model, which considers both the surface energy and charge, correlates extremely well with the experimental cluster size. To explore further the properties of gas-phase micelles, we have performed collision induced dissociation on them during tandem mass spectrometry. We observed both sequential asymmetric charge separation and neutral evaporation from the precursor ion cluster. Interestingly, however, we also found markedly different dissociation pathways for the longer alkyl chain detergents, with significantly fewer intermediate ions formed than for those with a shorter alkyl chain. These experiments provide an essential foundation for understanding the process of the gas-phase analysis of membrane protein complexes. Moreover they imply valuable mechanistic details of the protection afforded to protein complexes by detergent clusters during gas-phase activation processes. PMID- 22512599 TI - First web-based database on total phenolics and oxygen radical absorbance capacity (ORAC) of fruits produced and consumed within the south Andes region of South America. AB - This paper reports the first database on antioxidants contained in fruits produced and consumed within the south Andes region of South America. The database ( www.portalantioxidantes.com ) contains over 500 total phenolics (TP) and ORAC values for more than 120 species/varieties of fruits. All analyses were conducted by a single ISO/IEC 17025-certified laboratory. The characterization comprised native berries such as maqui ( Aristotelia chilensis ), murtilla ( Ugni molinae ), and calafate ( Barberis microphylla ), which largely outscored all other studied fruits. Major differences in TP and ORAC were observed as a function of the fruit variety in berries, avocado, cherries, and apples. In fruits such as pears, apples, apricots, and peaches, a significant part of the TP and ORAC was accounted for by the antioxidants present in the peel. These data should be useful to estimate the fruit-based intake of TP and, through the ORAC data, their antioxidant-related contribution to the diet of south Andes populations. PMID- 22512601 TI - Obstructive sleep apnoea - a marker of increased cardiovascular risk. PMID- 22512600 TI - Grape seed and skin extract mitigates garlic-induced oxidative stress in rat liver. AB - Garlic is a commonly used spice in folk medicine that can exert adverse health effects when given at a high dose. Grape seed and skin extract (GSSE) exhibits a variety of beneficial effects even at a high dose. In the present study we evaluated the toxicity of high-dose garlic treatment on liver and the protective effect of GSSE. Rats were intraperitoneally administered either with garlic extract (5 g.(kg body weight)(-1)) or GSSE (500 mg.(kg body weight)(-1)) or a combination of garlic and GSSE at the same doses daily for 1 month. Plasma and hepatic levels of cholesterol, triacylglycerol, and transaminases and liver antioxidant status were evaluated. Data showed that a high garlic dose induced liver toxicity and a pro-oxidative status characterized by increased malondialdehyde and decreased antioxidant enzyme activities as catalase, peroxidase, and superoxide dismutase. Garlic increased intracellular H(2)O(2) but decreased free iron and Ca(2+). GSSE alone or in co-treatment with garlic had the reverse effect and counteracted almost all garlic-induced deleterious impacts to near control levels. In conclusion, a high garlic dose induced a pro-oxidative state characterized by the Fenton reaction between H(2)O(2) and free iron, inducing Ca(2+) depletion, while GSSE exerted antioxidant properties and Ca(2+) repletion. PMID- 22512602 TI - Do the current atrial fibrillation guidelines for stroke prevention need to be changed with the availability of new data on the new oral anticoagulants? PMID- 22512603 TI - Up to the test? Routine HIV testing in everyday clinical practice. PMID- 22512604 TI - Predicting survival following non-invasive ventilation for hypercapnic exacerbations of chronic obstructive pulmonary disease. AB - INTRODUCTION: Non-invasive ventilation (NIV) has revolutionised the management of hypercapnic exacerbations of chronic obstructive pulmonary disease (COPD). We wished to evaluate factors related to its overall success in the 'real-life' setting. METHODS: A retrospective analysis of patients receiving NIV for a hypercapnic exacerbation of COPD was performed. Demographics, laboratory data, blood gases and outcomes (hospital discharge or in-patient death) were extracted and subsequently analysed to identify factors relating to its overall success or failure. RESULTS: Over 6 years, 240 patients (mean age 70 years), received NIV with mean pH and pCO(2) prior to NIV 7.24 and 10.4kPa respectively; of these, 167 survived to hospital discharge with a median age (70 vs. 74; p = 0.02) lower than non-survivors. Absolute values of pH and pCO(2) (higher and lower respectively) prior to NIV and at 1 h were both associated with successful hospital discharge. An improvement (p = 0.02) in pH within an hour of receiving NIV - but not pCO(2) was associated with surviving to hospital discharge. Of all laboratory data assessed, only baseline urea was significantly (p = 0.021) associated with a successful outcome. CONCLUSION: Younger patients with a lower urea, higher pH and lower pCO(2) at baseline and who demonstrate an improvement in pH within 1 h, are more likely to have a successful outcome when given NIV for a hypercapnic exacerbation of COPD on an unselected basis. Prospective studies evaluating many other parameters are now required to help identify patients in whom NIV is likely to be successful. PMID- 22512605 TI - Endobronchial ultrasound-guided transbronchial needle aspiration in routine care plenty of benign results and follow-up tests. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a widespread technique for tissue sampling from hilar and mediastinal lymph nodes (LN). The diagnostic yield of this method is reported to be very high even outside clinical trials. We aimed to assess the diagnostic accuracy of EBUS-TBNA after its implementation at a University hospital. METHODS: We analysed the first 100 consecutive patients who underwent an EBUS-TBNA procedure at our institution with respect to indication and cytological results. Sensitivity and negative predictive value (NPV) were calculated on the basis of histological confirmation or follow-up. RESULTS: From 03/2007 to 03/2008, EBUS TBNA of 218 LNs was performed on the basis of chest computed tomography. The primary indication for EBUS-TBNA was lymphadenopathy of unknown cause with (44%) or without (37%) pulmonary nodule(s). Only 19% of patients had known cancer and underwent the procedure for (re-)staging. In 73% of patients a non-diagnostic cytology was reported. A diagnosis could be established in only 27% by EBUS-TBNA including four patients with sarcoidosis. Sensitivity and NPV were low with 61.4% and 76.7%, respectively. Diagnostic yield increased over time and was better in cancer patients than in patients with incidental lymphadenopathy. CONCLUSION: Although EBUS-TBNA is reported to have a very high diagnostic yield in selected patients, the predominant finding in routine care, depending on the patient population, can be a non-diagnostic cytology result with the need for surgical procedures or follow-up studies. This should be considered in the approach to patients with mediastinal or hilar lymphadenopathy. PMID- 22512606 TI - Sitagliptin add-on to low dosage sulphonylureas: efficacy and safety of combination therapy on glycaemic control and insulin secretion capacity in type 2 diabetes. AB - AIMS: To assess the efficacy and safety of combination therapy with sitagliptin and low dosage sulphonylureas on glycaemic control and insulin secretion capacity in Japanese type 2 diabetes. METHODS: Eighty-two subjects were sequentially recruited for the 52-week, prospective, single arm study. Sitagliptin was added on to sulphonylureas (glimepride or gliclazide) with or without metformin. The primary endpoint was a change in A1C. The secondary endpoints were changes in BMI, insulin secretion capacity, blood pressure and urinary albumin excretion, unresponsive rate, and hypoglycaemia. Insulin secretion capacity was evaluated by glucagon loading test. RESULTS: Change in A1C was -0.80% (95% CI -0.90 to -0.68) (p < 0.001). Change in BMI, systemic and diastolic blood pressure, and urinary albumin excretion were -0.38 kg/m(2) (95% CI -0.72 to -0.04) (p < 0.05), -6.7/ 3.6 mmHg (95% CI -10.0 to -3.4/-4.8 to -2.4) (p < 0.001), and -43.2 mg/gCr (95% CI -65.7 to -20.8) (p < 0.001) respectively. Mild hypoglycaemia was observed in three cases. The unresponsive rate was 6.1%. Glucagon loading test showed that 0 min and 6-min CPR at baseline and 52-week were not significantly changed: 0-min CPR, 1.58 +/- 0.58-1.71 +/- 0.73 ng/ml; 6-min CPR, 3.48 +/- 1.47-3.58 +/- 1.21 ng/ml. Insulin secretion capacity, CPI and SUIT index at baseline did not predict the efficacy of the combination therapy. The final dosages of glimepiride and gliclazide were 1.44 +/- 0.90 mg and 34.5 +/- 15.3 mg respectively. The dosage of sitagliptin was increased from 50 mg to 69.0 +/- 24.5 mg in 52-week. CONCLUSIONS: The combination therapy with sitagliptin and low dosage sulphonylureas was safe and effective for glycaemic control. Glucagon loading test indicated that 1 year administration of sitagliptin and sulphonylureas preserved insulin secretion capacity. PMID- 22512608 TI - Symptom-based diagnosis of urinary tract infection in women: are we over prescribing antibiotics? AB - BACKGROUND: Current clinical guidelines for the management of symptoms suggesting urinary tract infection recommend empiric antibiotic therapy. OBJECTIVE: To determine the diagnostic accuracy of urinary tract symptoms for early identification of urinary tract infection (UTI) in sexually active women when culture results are not available. METHOD: This was a cross-sectional observational study conducted in a tertiary care hospital between July 2009 and May 2011. Subjects comprised 312 women >= 18 year of age who reported to the physician with symptoms suggestive of UTI. A predesigned questionnaire was filled and urine was analysed by microscopic examination and culture. Diagnostic values were calculated against gold standard urine culture results (> 10(2) CFU/ml) and 95% CIs and likelihood ratios are reported. RESULTS: A total of 312 women were enrolled, as culture was contaminated in 36 only 276 women were included in final analysis. Prevalence of UTI was 46.01% amongst symptomatic women. Urgency (p = 0.001), burning sensation during micturition (p = 0.035), dysuria (p = 0.004), frequency of sexual intercourse > 5 per month (p = 0.010) and pyuria (p = 0.000) were significantly associated with culture positivity. Absence of pyuria emerged as best predictor for ruling out UTI even if the woman had symptoms (sensitivity 93.70%, NPV 91.84%, AUC 77.07%, LR- 0.1). The combination of urgency, burning during micturition and pyuria was the best predictor of UTI in our study (sensitivity 85.83%, PPV 71.71%, AUC 78.48%, LR+ 2.97) CONCLUSION: Symptoms alone have low accuracy when assessed against the reference standard for diagnosing UTI. Empiric treatment of UTI based on symptoms may expose large number of patients to unnecessary antibiotics. Wet mount microscopy for presence of pyuria as a 'near patient test' before starting antibiotics seems a rational approach for management of UTI in symptomatic women. PMID- 22512607 TI - Diagnostic accuracy of exercise stress testing for coronary artery disease: a systematic review and meta-analysis of prospective studies. AB - BACKGROUND: Exercise stress testing offers a non-invasive, less expensive way of risk stratification prior to coronary angiography, and a negative stress test may actually avoid angiography. However, previous meta-analyses have not included all exercise test modalities, or patients without known Coronary artery disease (CAD). METHODS AND RESULTS: We systematically reviewed the literature to determine the diagnostic accuracy of exercise stress testing for CAD on angiography. MEDLINE (January 1966 to November 2009), MEDION (1966 to July 2009), CENTRAL (1966 to July 2009) and EMBASE (1980-2009) databases were searched for English language articles on diagnostic accuracy of exercise stress testing. We included prospective studies comparing exercise stress testing with a reference standard of coronary angiography in patients without known CAD. From 6,055 records, we included 34 studies with 3,352 participants. Overall, we found published studies regarding five different exercise testing modalities: treadmill ECG, treadmill echo, bicycle ECG, bicycle echo and myocardial perfusion imaging. The prevalence of CAD ranged from 12% to 83%. Positive and negative likelihood ratios of stress testing increased in low prevalence settings. Treadmill echo testing (LR+ = 7.94) performed better than treadmill ECG testing (LR+ = 3.57) for ruling in CAD and ruling out CAD (echo LR- = 0.19 vs. ECG LR- = 0.38). Bicycle echo testing (LR+ = 11.34) performed better than treadmill echo testing (LR+ = 7.94), which outperformed both treadmill ECG and bicycle ECG. A positive exercise test is more helpful in younger patients (LR+ = 4.74) than in older patients (LR+ = 2.8). CONCLUSIONS: The diagnostic accuracy of exercise testing varies, depending upon the age, gender and clinical characteristics of the patient, prevalence of CAD and modality of test used. Exercise testing, whether by echocardiography or ECG, is more useful at excluding CAD than confirming it. Clinicians have concentrated on individualising the treatment of CAD, but there is great scope for individualising the diagnosis of CAD using exercise testing. PMID- 22512609 TI - Effect of the disclosure of MS diagnosis on anxiety, mood and quality of life of patients: a prospective study. AB - BACKGROUND: In the light of the new diagnostic criteria for multiple sclerosis (MS) and currently available early treatment, this study aimed to explore whether, and to what extent, disclosure of the diagnosis of MS or clinically isolated syndrome (CIS) affects patients' anxiety, mood and quality of life (QoL). METHODS: Eligible participants were all patients referred for the first time to the Neurological Unit who had manifested symptoms suggestive of MS for no more than 6 months. All patients were evaluated for (i) QoL (SEIQoL and MS QoL54), (ii) Anxiety (STAI) and Depression (CMDI) on study inclusion (T0), 30 days after diagnosis disclosure (T30), and after 1 (T1y) and 2 (T2y) years' follow-up. RESULTS: Two hundred and twenty-nine patients were enrolled; 93 of these were unaware of their diagnosis. Patients who already knew their diagnosis (100 with CIS and 22 with MS) were excluded from the main analyses and used to perform control analyses. At the end of the screening, an MS diagnosis was disclosed to 18 of the 93 patients, whereas a CIS diagnosis was disclosed to 62 patients (12 patients received a diagnosis other than MS or CIS). Thirty days after diagnosis disclosure, irrespective of the diagnosis disclosed, both QoL and Anxiety and Depression were significantly rated as better compared to the start of screening, (p(s) < 0.03), and this improvement remained stable over the two annual follow-ups. However, as suggested by a significant 'Time' * 'Diagnosis' interaction with regard to both QoL and Anxiety and Depression (p(s) < 0.02), the effect of the disclosure in the short term differed depending on CIS or MS diagnosis. Specifically, on MSQoL, which is a health-related QoL scale, we found a statically significant improvement, immediately after the diagnosis disclosure, in both the MS and CIS groups (p(s) < 0.01). Differently, on SEIQoL, which is a non health-related QoL measure, and on the anxiety scale, we observed a statistically significant improvement only in the group which received a MS diagnosis (p(s) < 0.03). CONCLUSIONS: This first prospective study provides objective data showing that early disclosure of MS diagnosis improves both the patient's QoL and psychological well-being. In addition, the results seem to suggest that CIS disclosure does not lead to the same favourable effects. PMID- 22512610 TI - Switching to open access publishing is challenging. PMID- 22512611 TI - Trying to treat diabetes in Greek crisis. PMID- 22512612 TI - Developing the libraries and health partnership. PMID- 22512613 TI - The 'action-research' philosophy: from bedside to bench, to bedside again. PMID- 22512614 TI - Age and gender differences in depression across adolescence: real or 'bias'? AB - BACKGROUND: Since developmental psychologists are interested in explaining age and gender differences in depression across adolescence, it is important to investigate to what extent these observed differences can be attributed to measurement bias. Measurement bias may arise when the phenomenology of depression varies with age or gender, i.e., when younger versus older adolescents or girls versus boys differ in the way depression is experienced or expressed. METHODS: The Children's Depression Inventory (CDI) was administered to a large school population (N = 4048) aged 8-17 years. A 4-factor model was selected by means of factor analyses for ordered categorical measures. For each of the four factor scales measurement invariance with respect to gender and age (late childhood, early and middle adolescence) was tested using item response theory analyses. Subsequently, to examine which items contributed to measurement bias, all items were studied for differential item functioning (DIF). Finally, it was investigated how developmental patterns changed if measurement biases were accounted for. RESULTS: For each of the factors Self-Deprecation, Dysphoria, School Problems, and Social Problems measurement bias with respect to both gender and age was found and many items showed DIF. Developmental patterns changed profoundly when measurement bias was taken into account. The CDI seemed to particularly overestimate depression in late childhood, and underestimate depression in middle adolescent boys. CONCLUSIONS: For scientific as well as clinical use of the CDI, measurement bias with respect to gender and age should be accounted for. PMID- 22512615 TI - Fast tandem ring-opening/ring-closing metathesis polymerization from a monomer containing cyclohexene and terminal alkyne. AB - We report extremely fast tandem ring-opening/ring-closing metathesis polymerization of a monomer containing two rather unreactive functional groups: cyclohexene and a terminal alkyne. When a third-generation Grubbs catalyst was used at low temperature, this tandem polymerization produced polymers with controlled molecular weights and narrow polydispersity indices. To explain this extremely fast polymerization, its reaction mechanism was studied. This new type of controlled polymerization allowed for the preparation of block copolymers using other conventional living metathesis polymerizations. The diene on the backbone of the polymer was postfunctionalized by sequential Diels-Alder and aza Diels-Alder reactions, which led to selective functionalization depending on the stereochemistry of the diene. PMID- 22512616 TI - The possible selves of international students and their cross-cultural adjustment in Canada. AB - We assessed 93 international students' reports of their expected and feared possible selves in terms of their thematic content and configuration, and examined the relations between possible selves and cultural adjustment in Canada. The results showed that international students mostly envisioned possible selves in career, education, intrapersonal, and interpersonal domains, and reported more balanced configurations than matched configurations of possible selves. Balanced possible selves in the educational domain were associated with better psychological well-being, but balanced selves in the intrapersonal domains were linked with more frequent sociocultural difficulties. The findings suggest that the content of international students' possible selves reflects not only their academic-focused and career-inspired sojourn, but also their intercultural experiences with various ethnic groups in the Canadian multicultural society. As well, they speak to the motivational significance of possible selves, particularly the balanced possible selves, for supporting international students' motivation to pursue an international education and for facilitating a successful cross-cultural sojourn. PMID- 22512617 TI - Mixed-method pre-cooling reduces physiological demand without improving performance of medium-fast bowling in the heat. AB - This study examined physiological and performance effects of pre-cooling on medium-fast bowling in the heat. Ten, medium-fast bowlers completed two randomised trials involving either cooling (mixed-methods) or control (no cooling) interventions before a 6-over bowling spell in 31.9+/-2.1 degrees C and 63.5+/-9.3% relative humidity. Measures included bowling performance (ball speed, accuracy and run-up speeds), physical characteristics (global positioning system monitoring and counter-movement jump height), physiological (heart rate, core temperature, skin temperature and sweat loss), biochemical (serum concentrations of damage, stress and inflammation) and perceptual variables (perceived exertion and thermal sensation). Mean ball speed (114.5+/-7.1 vs. 114.1+/-7.2 km . h(-1); P = 0.63; d = 0.09), accuracy (43.1+/-10.6 vs. 44.2+/-12.5 AU; P = 0.76; d = 0.14) and total run-up speed (19.1+/-4.1 vs. 19.3+/-3.8 km . h(-1); P = 0.66; d = 0.06) did not differ between pre-cooling and control respectively; however 20-m sprint speed between overs was 5.9+/-7.3% greater at Over 4 after pre-cooling (P = 0.03; d = 0.75). Pre-cooling reduced skin temperature after the intervention period (P = 0.006; d = 2.28), core temperature and pre-over heart rates throughout (P = 0.01-0.04; d = 0.96-1.74) and sweat loss by 0.4+/-0.3 kg (P = 0.01; d = 0.34). Mean rating of perceived exertion and thermal sensation were lower during pre-cooling trials (P = 0.004-0.03; d = 0.77-3.13). Despite no observed improvement in bowling performance, pre-cooling maintained between-over sprint speeds and blunted physiological and perceptual demands to ease the thermoregulatory demands of medium-fast bowling in hot conditions. PMID- 22512618 TI - Discovery of a novel pyrrole derivative 1-[5-(2-fluorophenyl)-1-(pyridin-3 ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate (TAK-438) as a potassium competitive acid blocker (P-CAB). AB - In our pursuit of developing a novel and potent potassium-competitive acid blocker (P-CAB), we synthesized pyrrole derivatives focusing on compounds with low log D and high ligand-lipophilicity efficiency (LLE) values. Among the compounds synthesized, the compound 13e exhibited potent H(+),K(+)-ATPase inhibitory activity and potent gastric acid secretion inhibitory action in vivo. Its maximum efficacy was more potent and its duration of action was much longer than those of proton pump inhibitors (PPIs). Therefore, compound 13e (1-[5-(2 fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate, TAK-438) was selected as a drug candidate for the treatment of gastroesophageal reflux disease (GERD), peptic ulcer, and other acid-related diseases. PMID- 22512620 TI - Size- and coating-dependent uptake of polymer-coated gold nanoparticles in primary human dermal microvascular endothelial cells. AB - A library-orientated approach is used to gain understanding of the interactions of well-defined nanoparticles with primary human endothelial cells, which are a key component of the vasculature. Fifteen sequentially modified gold nanoparticles (AuNPs) based on three different core sizes (18, 35, 65 nm) and five polymeric coatings were prepared. The synthetic methodology ensured homogeneity across each series of particles to allow sequential investigation of the chemical features on cellular interactions. The toxicity of these nanoparticles, their uptake behavior in primary human dermal microvascular endothelial cells (HDMECs), and quantification of uptake were all investigated. The results of our studies indicated that high concentrations of gold nanoparticles (250 MUg/mL) were nontoxic and that the number of internalized nanoparticles was related to nanoparticle size and surface chemistry. In summary, the positive-charged ethanediamine-coated AuNPs were internalized to a greater extent than the negative- or neutral-charged AuNPs. Moreover, differences in the amounts of internalized AuNPs could be shown for the three neutral-charged AuNPs, whereas the uptake of hydroxypropylamine-coated particles was preferred compared with glucosamine-coated or PEGylated AuNPs. Hydroxypropylamine-coated AuNPs were found to be the most efficient neutral-charged particles in overcoming the endothelial cell barrier and entering the cell. PMID- 22512622 TI - Investigation into the morphology of the third metacarpal bone in the horse. AB - AIMS: To describe key morphological attributes of the third metacarpal bone (Mc3) of horses and to determine whether or not the symmetry of the Mc3 varied significantly between limbs of the same horse. METHODS: Ten pairs of metacarpi were collected from slaughter facilities. The age and breed of the horses were recorded. Fixed points and axes that could be easily reproduced between bones were identified on high-quality photographic images of each bone. Using image analysis, three angles were measured. Angle gamma measured the rotation around the long axis of the diaphysis of Mc3, angle delta the angle between the dorsal long axis of the cannon bone and the surface of the condyle of Mc3, and angle theta the angle between the surface of the condyle and the long axis of the sagittal ridge of the condyle of Mc3. These angles represent some of the characteristic morphologic relationships within the equine Mc3. RESULTS: The coefficient of variation for angles gamma, delta and theta and were 1.2%, 0.2% and 0.5%, respectively. Angle gamma was larger in the left compared with the right limb (p=0.041). Angles delta and theta were larger in the right compared with the left limb (p=0.001 and p=0.003, respectively). There was a single outlier in a left limb for angle gamma. When this was excluded from the analysis, angle gamma in the left limb was still larger than in the right limb. Angle delta was consistently greater than 90 degrees in 19/20 metacarpi. CONCLUSIONS: There were significant morphological differences in the Mc3 between the left and right limbs of the 10 horses examined. These findings provide some reliable reference data for future investigation. Further work is required to document these differences in a larger population of horses and to determine whether the morphology of the Mc3 is influenced by age or other factors such as use of the animal. PMID- 22512621 TI - Familial amyloidotic polyneuropathy type IV--gelsolin amyloidosis. AB - Familial amyloidotic polyneuropathy type IV, or Gelsolin amyloidosis (GA), is a rare condition caused by G654A or G654T mutation in gelsolin gene at 9q32-34. Gelsolin seems essential in many processes, including inflammation, cell motility, neural recovery, apoptosis and even carcinogenesis. So far reported from many European countries, USA, Japan, Iran and Brazil, GA is probably still underdiagnosed. The typical diagnostic triad includes corneal lattice dystrophy, progressive bilateral facial paralysis and cutis laxa. Patients present with progressive cranial and peripheral neuropathy, eye symptoms, usually mild proteinuria, and cardiac conductive disturbances with age. Central nervous system symptoms are rare. Gelsolin amyloid collection in tissues is widespread. To date, treatment is symptomatic. Regular check-ups with ophthalmologist are recommended. Plastic surgery relieves the functional symptoms caused by facial paralysis and loose, hanging facial skin. PMID- 22512623 TI - Usefulness of antimicrobial susceptibility in the eradication of Helicobacter pylori. AB - The rate of eradication of Helicobacter pylori with standard triple therapy using omeprazole, amoxicillin and clarithromycin (OAC) is unacceptable in populations with high rates of clarithromycin resistance (15-20%). The aim of this study was to compare the efficacy of 10-day OAC therapy as the first-line treatment in patients diagnosed by culture with antimicrobial susceptibility or diagnosed by a (13) C-labelled urea breath test (UBT) without antimicrobial susceptibility in an area where the clarithromycin resistance rate was 15-20%. This was a retrospective cohort study of 266 patients, recruited consecutively throughout 2008. A total of 247 H. pylori-infected patients received antibiotic therapy (221 received the 10-day OAC therapy and 26 received other regimens) of which 134 patients were diagnosed by culture of gastric samples followed by antimicrobial susceptibility testing and 113 were diagnosed by UBT. In all patients, the eradication of H. pylori was checked by UBT. The cost of eradication by 10-day OAC treatment was assessed in each patient. The success rate of 10-day OAC therapy in patients diagnosed by culture and by UBT was 88% (103/117) and 49% (51/104), respectively (p <0.0005). The treatment was also more cost-effective in the former of these two groups (?571 versus ?666). To perform culture and antimicrobial susceptibility of the H. pylori isolates was a more successful and cost effective strategy than empirical 10-day OAC treatment in populations with high rates of resistance to clarithromycin. PMID- 22512624 TI - T-cell therapy for cancer. PMID- 22512625 TI - Belatacept and Tregs: friends or foes? PMID- 22512626 TI - Distinct roles of dendritic and B cells in the activation of naive CD4+ T cells. PMID- 22512628 TI - Research highlights: highlights from the latest articles in immunotherapy. PMID- 22512627 TI - News & views in ... Immunotherapy. PMID- 22512629 TI - Chasing cancer with chimeric antigen receptor therapy. AB - Many attempts to use genetically modified T cells to halt tumor progression have been met with disappointment and significant challenges in the successful application within human patients. Porter et al., however, describe the use of genetically modified lymphocytes bearing a chimeric antigen receptor that bypasses many of the common limitations of adoptive lymphocyte therapy. Through incorporation of a costimulatory domain within the chimeric antigen receptor, the investigators engineered lymphocytes with significantly higher tumor rejection activity and demonstrated significant expansion and prolonged survival after in vivo transfer to a single patient who showed a complete regression of refractory chronic lymphoid leukemia. This recent success in using genetically modified T cells to kill chronic lymphoid leukemia tumor cells is an encouraging advancement in the development of specific and targeted immune-based therapies against cancer. PMID- 22512630 TI - JAK2 inhibition in murine systemic lupus erythematosus. AB - Systemic lupus erythematosus is a systemic autoimmune disease characterized by the presence of myriad autoantibodies, some with pathogenic potential, and diverse clinical manifestations. Involvement of the kidney is a major cause of morbidity and mortality in human lupus patients and in murine models of the disease. It is hoped that more specific inhibition of crucial disease pathways would improve patient response rates, while reducing the considerable rates of drug-related side effects associated with current therapy. IL-6 has a pivotal regulatory role in the development and maturation of long-lived plasma cells, one of the key cell types driving the lupus disease phenotype as the source for the majority of lupus-related autoreactive antibodies. In this study, Lu et al. target the IL-6 signal transduction pathway using a specific JAK2 inhibitor of the JAK-STAT pathway, CEP-33779. In murine lupus models, they show significant improvement in nephritis, and prolonged survival, in mice treated with CEP-33779. The study presents the promise of a novel pathway for therapeutic intervention in systemic lupus erythematosus using a medication administered orally. PMID- 22512632 TI - Therapeutic effects of inhaled inactivated Mycobacterium phlei in adult patients with moderate persistent asthma. AB - BCG and other mycobacterial infections suppress airway hyper-responsiveness and inflammation in asthma models; however, its efficacy in human populations remains controversial. We use inactivated Mycobacterium phlei by way of atomizing inhalation to investigate whether it would protect against asthma in adult patients. Patients with newly diagnosed, uncontrolled, moderate persistent bronchial asthma were randomly divided into two groups. The patients in group A were treated with a solution of inhaled inactivated-M. phlei. Group B were treated with salmeterol xinafoate and fluticasone propionate powder. The Spirometry and Bronchial Provocation Test and Asthma Control Test were carried out; the peak expiratory flow and forced expiratory volume in 1 s-PD20 of the patients in the two groups increased significantly. However, overall, there was no significant difference between the two groups. Asthma Control Test scores of the patients in the two groups were significantly increased. We concluded that inhaled inactivated M. phlei, to a certain extent, improves asthma symptoms, reduces the need for rescue medication and reduces acute exacerbation of asthma. It plays the same role as inhaled Seretide treatment in reducing airway hyper responsiveness. PMID- 22512631 TI - Serial assessment of lymphocytes and apoptosis in the prostate during coordinated intraprostatic dendritic cell injection and radiotherapy. AB - Local radiotherapy plus intratumoral syngeneic dendritic cell injection can mediate apoptosis/cell death and immunological tumor eradication in murine models. A novel method of coordinated intraprostatic, autologous dendritic cell injection together with radiation therapy was prospectively evaluated in five HLA A2(+) subjects with high-risk, localized prostate cancer, using androgen suppression, 45 Gy external beam radiation therapy in 25 fractions over 5 weeks, dendritic cell injections after fractions 5, 15 and 25 and then interstitial radioactive seed placement. Serial prostate biopsies before and during treatment showed increased apoptotic cells and parenchymal distribution of CD8(+) cells. CD8(+) T-cell responses to test peptides were assessed using an enzyme-linked immunosorbent spot IFN-gamma production assay, demonstrating some prostate cancer specific protein-derived peptides associated with increased titer. In conclusion, the technique was feasible and well-tolerated and specific immune responses were observable. Future trials could further test the utility of this approach and improve on temporal coordination of intratumoral dendritic cell introduction with particular timelines of therapy-induced apoptosis. PMID- 22512633 TI - Regulatory cells in allergen-specific immunotherapy. AB - Allergen-specific immunotherapy (SIT) is currently the best available curative treatment in allergies and has been used for the treatment of patients for the past 100 years. The formation of a Th2 cell predominant inflammation in addition to production of allergen-specific IgE, the attraction of proinflammatory cells and the degranulation of effector cells, such as mast cells, are essential mechanisms in allergy development. Tregs aim to diminish these effects by IL-10- and TGF-beta-mediated anti-inflammatory reactions and therefore are one of the main targets in SIT. The induction of allergen tolerance is the key to successful SIT. With a special focus on Tregs, this review aims to clarify what is currently known about allergy development and the mode of action in allergen-SIT, which helps to develop further therapeutic strategies in the fight against allergic diseases. PMID- 22512634 TI - Potential avenues for immunotherapy of colitis-associated neoplasia. AB - In patients with inflammatory bowel disease, chronic intestinal inflammation severely increases the risk for cancer development. In fact, various aspects of inflammation such as oxidative stress, cyclooxygenases and proinflammatory cytokines have been shown to support many aspects of cancer growth. During recent years, various experimental studies have increased our understanding of the molecular mechanisms leading to colitis-associated cancer. In particular, cytokines such as TNF-alpha or IL-6, which are involved in the pathogenesis of inflammation and cancer development, could be promising targets for the molecular prevention of colitis-associated cancer. PMID- 22512635 TI - Immunotherapeutic approaches to improve graft-versus-tumor effect and reduce graft-versus-host disease. AB - The therapeutic efficacy of allogeneic stem cell transplantation is mainly based on the alloreactive immune response of the graft against the host. However, the graft-versus-host process can be viewed as a double-edged sword since it is responsible for both the beneficial graft-versus-tumor effect and the deleterious graft-versus-host disease. During the last two decades, intensive research has been focused on the development of novel immunotherapeutic methods aimed to dissociate graft-versus-host disease from graft-versus-tumor effect. A brief description of these efforts is discussed in this review. PMID- 22512637 TI - IL-13 receptor-directed cancer vaccines and immunotherapy. AB - Many immunotherapy approaches including therapeutic cancer vaccines targeting specific tumor-associated antigens are at various stages of development. Although the significance of overexpression of (IL-13Ralpha2) in cancer is being actively investigated, we have reported that IL-13Ralpha2 is a novel tumor-associated antigen. The IL-13Ralpha2-directed cancer vaccine is one of the most promising approaches to tumor immunotherapy, because of the selective expression of IL 13Ralpha2 in various solid tumor types but not in normal tissues. In this article, we will summarize its present status and potential strategies to improve IL-13Ralpha2-directed cancer vaccines for an optimal therapy of cancer. PMID- 22512636 TI - Particle-mediated delivery of cytokines for immunotherapy. AB - The ability of cytokines to direct the immune response to vaccination, infection and tumors has motivated their use in therapy to augment or shape immunity. To avoid toxic side effects associated with systemic cytokine administration, several approaches have been developed using particle-encapsulated cytokines to deliver this cargo to specific cell types and tissues. Initial work used cytokine loaded particles to deliver proinflammatory cytokines to phagocytes to enhance antimicrobial and antitumor responses. These particles have also been used to create a cytokine depot at a local site to supplement prophylactic or antitumor vaccines or injected directly into solid tumors to activate immune cells to eliminate established tumors. Finally, recent advances have revealed that paracrine delivery of cytokines directly to T cells has the potential to enhance T-cell mediated therapies. The studies reviewed here highlight the progress in the last 30 years that has established the potential of particle-mediated cytokine immunotherapy. PMID- 22512639 TI - Differentiation of Vitis vinifera L. and hybrid red grapes by matrix-assisted laser desorption/ionization mass spectrometry analysis of berry skin anthocyanins. AB - Among the methods that have been developed for anthocyanin characterization, matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) offers several analytical advantages in terms of speed, minimal sample handling, specificity, and reliability, without requiring any previous chromatographic separation. This study used MALDI-TOF MS to profile the anthocyanins from the berry skins of 23 red grape varieties clustered as (i) authentic Vitis vinifera grapes, (ii) American hybrid cultivars, and (iii) Casavecchia cultivars, previously characterized as functional crosses of V. vinifera with nondefined hybrid grapevines. Anthocyanin profiling demonstrated evidence of several varietal traits that enabled the differentiation of authentic V. vinifera from hybrid cultivars on a molecular basis. In particular, acyl 3,5-O diglucoside anthocyanins were established as easily monitored molecular markers of the hybrid varieties. It was also demonstrated that MALDI-post source decay MS is a powerful tool to differentiate isobaric 3,5-O-diglucosides and their derivatives, which prevail in hybrid cultivars, from acylated 3-O-glucoside anthocyanins. PMID- 22512640 TI - Association of gas cooking with children's respiratory health: results from GINIplus and LISAplus birth cohort studies. AB - Previous studies have found inconsistent results on the association between asthma in children and gas cooking emissions. We aimed to assess the effects of the long-term exposure to gas cooking on the onset of asthma and respiratory symptoms, focusing on wheezing, in children from two German birth cohorts: LISAplus and GINIplus. A total of 5078 children were followed until the age of 10 years. Asthma, wheezing, gas cooking, and exposure to other indoor factors were assessed through parental reported questionnaires administered periodically. Logistic and multinomial regressions adjusting for potential confounders were performed. The prevalence of asthma and persistent wheezing was higher among children exposed to gas cooking but the results were not statistically significant. Exposure to gas cooking was positively associated (P-value < 0.05) with exposure to other indoor factors (dampness, environmental tobacco smoke, and pets). Our results did not show a statistically significant association between the exposure to gas cooking and children's respiratory health. PRACTICAL IMPLICATIONS: These analyses are consistent with the assumption of no effect of the exposure to low doses of nitrogen dioxide. The strong positive associations found between gas cooking and other indoor factors highlight the importance of considering other indoor factors when assessing health effects of gas cooking. Low-dose exposure to indoor nitrogen dioxide through gas cooking might not contribute to increase the risk of asthma and respiratory symptoms in children. PMID- 22512638 TI - Gene silencing activity of siRNA molecules containing phosphorodithioate substitutions. AB - Chemically synthesized small interfering RNAs (siRNAs) have been widely used to identify gene function and hold great potential in providing a new class of therapeutics. Chemical modifications are desired for therapeutic applications to improve siRNA efficacy. Appropriately protected ribonucleoside-3'-yl S-[beta (benzoylmercapto)ethyl]pyrrolidino-thiophosphoramidite monomers were prepared for the synthesis of siRNA containing phosphorodithioate (PS2) substitutions in which the two non-bridging oxygen atoms are replaced by sulfur atoms. A series of siRNAs containing PS2 substitutions have been strategically designed, synthesized, and evaluated for their gene silencing activities. These PS2-siRNA duplexes exhibit an A-form helical structure similar to unmodified siRNA. The effect of PS2 substitutions on gene silencing activity is position-dependent, with certain PS2-siRNAs showing activity significantly higher than that of unmodified siRNA. The relative gene silencing activities of siRNAs containing either PS2 or phosphoromonothioate (PS) linkages at identical positions are variable and depend on the sites of modification. 5'-Phosphorylation of PS2 siRNAs has little or no effect on gene silencing activity. Incorporation of PS2 substitutions into siRNA duplexes increases their serum stability. These results offer preliminary evidence of the potential value of PS2-modified siRNAs. PMID- 22512641 TI - CGRP receptor antagonists: an expanding drug class for acute migraine? AB - INTRODUCTION: Migraine afflicts approximately 11% of the population worldwide producing substantial disability, resulting in loss of productivity both at home and at the workplace. Calcitonin gene-related peptide (CGRP) is closely involved in the cascade of molecular events leading to migraine painful crisis. AREAS COVERED: Acute treatment of migraine is actually based on the use of triptans, class drug which presents a clear limitation due to its cardiovascular side effects. Gepants, a CGRP antagonist class, might offer a new non-vasoconstrictive approach in the acute treatment of migraine. Four chemically unrelated CGRP receptor (CGRP-R) antagonists (olcegepant, telcagepant, MK-3207 and BI 44370 TA) have displayed efficacy in the treatment of migraine. EXPERT OPINION: When compared with triptans, gepants class showed a similar efficacy, moreover corresponding to the best published results for oral triptans. CGRP antagonists are in different phases of their development, and the treatment of migraine could be based on the use of gepants, as class of acute medications. However, CGRP-R antagonists clinical trials seem to be discouraging for their forthcoming use in clinical practice. New CGRP-R antagonists, such as BMS-927711 and BI 44370 TA, are in the pipeline and their developments will outline the future of this drug class. PMID- 22512642 TI - Paediatric-onset psoriasis is associated with ERAP1 and IL23R loci, LCE3C_LCE3B deletion and HLA-C*06. AB - BACKGROUND: Recent genome-wide association studies have identified several genetic risk factors for psoriasis, but data on their association with age at onset are lacking. OBJECTIVES: To compare the association between known risk alleles and psoriasis in well-defined cohorts with paediatric- and adult-onset psoriasis. METHODS: Based on previous studies we selected seven genes and loci associated with psoriasis. Patients with paediatric-onset (< 18 years) and adult onset psoriasis (>= 18 years) and controls were genotyped. Genotype frequencies were compared between controls (n = 450) and all cases (n = 217), and between controls and cases stratified for confirmed age at onset (paediatric onset n = 80, adult onset n = 85). RESULTS: Paediatric-onset psoriasis showed a significant association with single nucleotide polymorphisms in the ERAP1 (P = 0.042) and IL23R loci (P = 0.042), LCE3C_LCE3B-del (P = 0.003) and HLA-C*06 (P = 1.72 * 10( 19)) when compared with the control group. A significant association of these four genes was also demonstrated when all psoriasis cases were compared with controls. In adult-onset psoriasis a significant association was found for HLA C*06 (P = 5.11 * 10(-6)) and for LCE3C_LCE3B-del (P = 0.042). No associations were found for the IFIH1, IL12B and TRAF3IP2 loci. CONCLUSIONS: Notwithstanding the small cohort sizes, we demonstrated an association with established and recently discovered genetic risk factors in paediatric-onset psoriasis including genes involved in epidermal barrier function and adaptive immunity. Our data suggest that heritable factors may play a more important role in paediatric-onset psoriasis than in adult-onset psoriasis. PMID- 22512643 TI - Giving or giving back: new psychosocial insights from sperm donors in France. AB - Despite the growing importance of the international scientific literature concerning donor insemination, studies of French samples are rare. We recently had the opportunity to conduct a nationwide study on psychosocial issues related to semen donation in France. In this article, we present the main results of an analysis of the narratives of 33 sperm donors. We examine the meaning they attribute to this experience, their motivations, the social ramifications of their action, and their perspective on the principles of sperm donation in France. We highlight our results by comparing them to those derived from other recent international studies in different legislative contexts. Finally, we suggest a hypothesis regarding donor motivations based on recent literature in social sciences regarding the fundamental role of gift and reciprocity. These issues, particularly the anonymity of gamete donation, are currently at the heart of a national debate related to the expected revision of the French bioethics law. PMID- 22512644 TI - Modulating the reactivity of functionalized N,S-ketene acetal in MCR: selective synthesis of tetrahydropyridines and thiochromeno[2,3-b]pyridines via DABCO catalyzed tandem annulation. AB - An efficient and straightforward three-component synthetic protocol was developed to synthesize 1,2,3,4-tetrahydropyridine derivatives or thiochromeno[2,3 b]pyridine derivatives from beta-aroylthioacetanilides or beta-(2 haloaroyl)thioacetanilides, aldehydes, and aroyl acetonitriles via DABCO catalyzed tandem [3 + 2 + 1] annulation and S(N)Ar reaction. This synthetic approach has the prominent features of high chemo-, stereo- (or enantio-), and unusual regioselectivity. In the domino processes, at least seven reactive sites were involved, and up to three covalent bonds and one functionalized pyridine ring were generated. This facile and efficient reaction is a quite general for the preparation of tetrahydropyridine derivatives or thiochromeno[2,3-b]pyridine derivatives. PMID- 22512646 TI - Purification and characterization of a lectin of the Swartzieae Legume Taxa. AB - This work aimed at describing the first biochemical and structural data of a lectin belonging to Swartzieae, a primitive Legume Taxa. A lactose-binding seed lectin (SLL) was purified by affinity chromatography of crude saline extracts of Swartzia laevicarpa on immobilized lactose. The SLL agglutinated rabbit erythrocytes but not rat or human (A, B, O) erythrocytes. Lectin activity was retained after heating at 100 ?C for 15 min and was best inhibited by Nacetylgalactosamine, lactose and galactose. The lectin exhibited a single electrophoretic pattern that corresponded to a molecular mass of 29,000 Da, which was confirmed by MS analysis. In addition, the lectin reacted positively with Schiff's reagent. The unique N-terminal amino acid sequence (39 residues) and the internal peptide sequence were determined by Edman degradation and MS/MS, respectively. The sequencing revealed complete homology of the SLL with legume lectins belonging to primitive groups (Dalbergieae and Sophoreae). The SLL (at 1 mg/ml) did not exhibit antifungal activity against various phytopathogens or cytotoxicity (at 100 MUg/ml) towards different cancer cell lines. PMID- 22512645 TI - Expression in Pichia Pastoris and biological activity of Avian beta-defensin 6 and its mutant peptide without cysteines. AB - Avian beta-defensin 6 (AvBD-6) is an antimicrobial peptide that plays significant roles in the innate immunity of chickens. To explore the effects of disulfide bonds on antimicrobial activity of AvBD-6, two peptides with or without Cys residues were designed and expressed in Pichia Pastoris. The peptide AvBD-6-B was obtained by removing six Cys residues of AvBD-6. According to the codon bias of Pichia Pastoris, the genes of AvBD-6 and AvBD-6-B were synthesized. The Bgl II linearized recombinant plasmids pGAPHalphaM-AvBD-6 and pGAPHalphaM-AvBD-6-B were transformed into Pichia Pastoris GS115 by electroporation. The recombinant AvBD-6 and AvBD-6-B were expressed in YPD for 48 h, 72 h and 96 h at 30 ?C Tricine-SDS PAGE analysis demonstrated that both AvBD-6 and AvBD-6-B were expressed in Pichia Pastoris. The concentration of recombinant AvBD-6 and AvBD-6-B reached 114.9 mg/l and 93.8 mg/l, respectively. The expression products exhibited antimicrobial activity against Gram-positive and Gram-negative bacteria. Antimicrobial activity of AvBD-6-B suggests that the removal of six Cys residues had no significant effect on the antimicrobial activity of avian beta-defensins. Neither peptide showed hemolytic activity. This study could serve as an impetus for the production of this antimicrobial peptide as a replacement for antibiotics in animal feed. PMID- 22512647 TI - A Method for isolation of DNA-binding proteins based on solubility of DNA-protein complexes. AB - The study of DNA-binding proteins is crucial in understanding gene regulatory networks. We developed a new method for the enrichment of DNA-binding proteins based on the variability of DNA-protein complexes' solubility in different ionic strength solutions. 0.14M sodium chloride was determined as the most efficient extraction concentration to precipitate DNA-binding proteins. SDS-PAGE analysis revealed that some high-abundance proteins were removed effectively and at the same time DNA-binding proteins were isolated in this simple process. Twenty kinds of proteins were identified in the acquired sample by 1-D gel-LC-MS/MS. Furthermore, computerized analysis of MS data showed that quite a number of unmatched peptides have the classic structure of leucine zipper or zinc finger, which were symbolic elements of transcription factors. These results suggested that this new method can acquire DNA-binding proteins effectively and allow improvement in the isolation of high-quality DNA-binding proteins. PMID- 22512649 TI - Hydropathic self-organized criticality: a magic wand for protein physics. AB - Self-organized criticality (SOC) is a popular concept that has been the subject of more than 3000 articles in the last 25 years. The characteristic signature of SOC is the appearance of self-similarity (power-law scaling) in observable properties. A characteristic observable protein property that describes protein water interactions is the water-accessible (hydropathic) interfacial area of compacted globular protein networks. Here we show that hydropathic power-law (size- or length-scale-dependent) exponents derived from SOC enable theory to connect standard Web-based (BLAST) short-range amino acid (aa) sequence similarities to long-range aa sequence hydropathic roughening form factors that hierarchically describe evolutionary trends in water - membrane protein interactions. Our method utilizes hydropathic aa exponents that define a non Euclidean metric realistically rooted in the atomic coordinates of 5526 protein segments. These hydropathic aa exponents thereby encapsulate universal (but previously only implicit) non-Euclidean long-range differential geometrical features of the Protein Data Bank. These hydropathic aa exponents easily organize small mutated aa sequence differences between human and proximate species proteins. For rhodopsin, the most studied transmembrane signaling protein associated with night vision, analysis shows that this approach separates Euclidean short- and non-Euclidean long-range aa sequence properties, and shows that they correlate with 96% success for humans, monkeys, cats, mice and rabbits. Proper application of SOC using hydropathic aa exponents promises unprecedented simplifications of exponentially complex protein sequence-structure-function problems, both conceptual and practical. PMID- 22512648 TI - L-arginine mediated renaturation enhances yield of human, alpha6 Type IV collagen non-collagenous domain from bacterial inclusion bodies. AB - The anti-angiogenic, carboxy terminal non-collagenous domain (NC1) derived from human Collagen type IV alpha 6 chain, [alpha6(IV)NC1] or hexastatin, was earlier obtained using different recombinant methods of expression in bacterial systems. However, the effect of L-arginine mediated renaturation in enhancing the relative yields of this protein from bacterial inclusion bodies has not been evaluated. In the present study, direct stirring and on-column renaturation methods using L arginine and different size exclusion chromatography matrices were applied for enhancing the solubility in purifying the recombinant alpha6(IV)NC1 from bacterial inclusion bodies. This methodology enabled purification of higher quantities of soluble protein from inclusion bodies, which inhibited endothelial cell proliferation, migration and tube formation. Thus, the scope for L-arginine mediated renaturation in obtaining higher yields of soluble, biologically active NC1 domain from bacterial inclusion bodies was evaluated. PMID- 22512650 TI - Proteome-wide inference of human endophilin 1-binding peptides. AB - Human endophilin 1 (hEndo1) is a multifunctional protein that was found to bind a wide spectrum of prolinerich endocytic proteins through its Src homology 3 (SH3) domain. In order to elucidate the unknown biological functions of hEndo1, it is essential to find out the cytoplasmic components that hEndo1 recognizes and binds. However, it is too time-consuming and expensive to synthesize all peptide candidates found in the human proteome and to perform hEndo1 SH3-peptide affinity assay to identify the hEndo1-binding partners. In the present work, we describe a structure/ sequence-hybrid approach to perform proteome-wide inference of human hEndo1-binding peptides using the information gained from both the primary sequence of affinity-known peptides and the interaction profile involved in hEndo1 SH3-peptide complex three-dimensional structures. Modeling results show that (i) different residue positions contribute distinctly to peptide affinity and specificity; P-1, P2 and P4 are most important, P1 and P3 are also effective, and P-3, P-2, P0, P5 and P6 are relatively insignificant, (ii) the consensus core PXXP motif is necessary but not sufficient for determining high affinity of peptides, and some other positions must be also essential in the hEndo1 SH3 peptide binding, and (iii) the alternating arrangement of polar and nonpolar amino acids along peptide sequence is critical for the high specificity of peptide recognition by hEndo1 SH3 domain. In addition, we also find that the residue type at a specific position of hEndo1-binding peptides is not stringently invariable; amino acids that possess similar polarity could replace each other without substantial influence on peptide affinity. In this way, hEndo1 presents a broad specificity in the peptide ligands that it binds. PMID- 22512651 TI - Characterization of the interaction between endostatin short peptide and VEGF receptor 3. AB - Corneal angiogenesis and lymphangiogenesis are induced by vascular endothelial growth factors (VEGFs) signaling through its receptors VEGFR-1, -2, and -3. Endostatin is a peptide antagonist of these receptors that causes inhibition of bFGF-induced corneal angiogenesis and lymphangiogenesis. Here we show that binding of VEGF-C and endostatin to recombinant VEGFR-3 is competitive. Alignments of the primary amino acid sequences of VEGF-C and the C-terminal endostatin peptide (mEP: LEQKAASCHNSYIVLCIENSFMTSFSK) identified two conserved cysteine residues separated by seven amino acids. Peptides of VEGF-C and mEP containing these conserved residues bound to VEGFR-3. However, substitution of alanine for either of the cysteines in the mEP peptide perturbed the secondary structure, and this mutated peptide was unable to bind to VEGFR-3. Analysis by surface plasmon resonance demonstrated that the binding of the mEP peptide for recombinant VEGFR-3 had a Ka of 1.41 x 107 M-1 s-1, Kd of 0.6718 s-1, and a KD of 4.78 x 10-8 M. Characterization of the mechanism of endostatin binding to VEGFR-3 may lead to the development of novel therapies for lymphangiogenesis-related disorders, such as transplant rejection, lymphedema, and cancer metastasis. PMID- 22512652 TI - Functional analysis of hybrid peptide CAMA-Syn: expression in mammalian cells and antimicrobial potential. AB - CAMA-syn, a hybrid composed of N-terminal alpha-helical segment of Cecropin A(amino acid 1-8) and Magainin 2 (amino acid 1-12), is a novel small peptide with the potent antibacterial and synergistic activity without cytotoxicity. In order to test the antibacterial function of CAMA-syn produced in mammalian cells, several vectors containing the synthesized CAMA-syn DNA fragment were constructed and transfected into recipient cells. The results showed that CAMAsyn fusion to green fluorescent protein (GFP) or to hemagglutinin epitope (HA) tag was expressed in both bovine embryo fibroblasts (BEF) and mouse macrophage RAW264.7 cells. The antibacterial assays of CAMA-syn were conducted against both Gram positive and negative bacteria, including S. abortusovis, P. anatis, S. hyicus and S. suis. The results of colony-forming efficiency and cell growth curves proved that the in vitro expressed CAMA-syn could have the antibacterial activity, demonstrating that macrophage specific expression of antimicrobial peptide CAMA-syn could inhibit the growth of bacteria. PMID- 22512653 TI - Purification of pectin methylesterase from Lycopersicon esculentum and its application. AB - Pectin methylesterase (PME) (3.1.1.11) is the pectin degrading enzyme which catalyses the hydrolysis of pectin methylester group, resulting in de esterification. PME is widely distributed in plants, fungi, yeast and bacteria. In the present study, PME was extracted from tomato by using 8.8% NaCl (4 degrees C). The crude enzyme precipitated with 60% ammonium sulphate resulted in 1.02 fold purification of the enzyme. The purification was done by ion exchange chromatography using DEAE-Cellulose column. This resulted in 1.82 fold purification of the enzyme. The molecular weight of purified enzyme was determined by SDS-PAGE which was found to be 34.0 kDa. During characterization of the purified enzyme, the maximum activity was found at temperature 50 degrees C, pH 6.5, reaction time 45 min. Citrus pectin was the best substrate for maximum enzyme activity. The enzyme did not require any metal ion to express its activity, enzyme was found to be very stable at 4 degrees C and at 50 degrees C the enzyme was stable upto 2 h as it retained 70% of its activity. The K(m) and V(max) values of the enzyme were found to be 0.115 mg/ml and 1.03 MUmol/ml/min. PME enhanced the pectin degradation process in apple juice clarification in combination with polygalacturonase and increased %T(650) from 1.7% to 5.6%. PMID- 22512654 TI - Crystal structure of a flavin-dependent thymidylate synthase from Helicobacter pylori strain 26695. AB - ThyX, a flavin-dependent thymidylate synthase that is involved in the synthesis of dTMP from dUMP, is a promising target for the development of novel antibacterial drugs that aimed at blocking the biosynthesis of dTMP, one of the building blocks of DNA. This enzyme has been recently identified in some dsDNA viruses and pathogenic bacteria, including the gastric pathogen Helicobacter pylori. It shares neither sequence nor structural homology with the classical ThyA in humans and other organisms. Further more, ThyX and ThyA are the only source of dTMP in these organisms and other pathways cannot substitute for their function. Thus, ThyX-specific inhibitors could be effective antibacterial reagents while having no impact on human cells. Here we report the crystal structure of ThyX from Helicobacter pylori strain 26695 in complex with co-factor FAD and substrate dUMP at 2.5 A resolution, which consists of a 1.5 tetramer of ThyX with a total of 1248 residues, six FAD and six dUMP molecules in an asymmetric unit. The structure revealed the key residues that are involved in co factor FAD and substrate dUMP binding, site-directed mutagenesis were performed to analysis the importance of these residues on ThyX activity by genetic complementation and FAD binding assay. PMID- 22512655 TI - Inactivation kinetics of beta-N-acetyl-D-glucosaminidase from green crab (Scylla serrata) by guanidinium chloride. AB - beta-N-acetyl-D-glucosaminidase (NAGase) is a major member in chitinolytic enzymes system, which plays an important role in the hatching and molting processes of marine organism. The effects of guanidinium chloride (GuHCl) on the activity of NAGase from green crab (Scylla serrata) were investigated in this study. In results, GuHCl causes reversible inactivation of the enzyme at below 0.8 M concentrations, and the IC50 is estimated to be 0.15 M. The relationship between the enzyme activity and conformation was charaterized by monitoring the change of protein fluorescence spectra. With increasing GuHCl concentration, the fluorescence intensity of the enzyme distinctly decreases , and the maximal emission peaks appear red-shifted (from 338 nm to 343 nm). The enzyme inactivation precedes conformational changes, indicating that the enzyme active site is more flexible than the whole enzyme molecule. The result of the kinetics of inactivation shows that the value of k(+0) is larger than that of k(+0)'. It suggests that the substrate could protect the enzyme to a certain extent during guanidine denaturation. Our results provide important new insights in marine organism culture, especially in crustacean growth. PMID- 22512656 TI - Design, synthesis, and activity evaluation of a new 5-fluorouracil prodrug containing an Asn-Gly-Arg(NO2)COOCH3 tripeptide. AB - Aminopeptidase N (APN/CD13) of the M1 family is a broad specificity enzyme that is intimately involved in tumor angiogenesis and metastasis. Asparagine-glycine arginine (NGR) is a tumor-homing tripeptide, which can selectively combine with APN/CD13 that is overexpressed on the surface of some tumor cells. Various anti tumor drugs can be conjugated to NGR to improve selectivity, efficacy, and to decrease drug toxicity. In this study, a tripeptide NGR(NO2) was synthesized and conjugated with 5-fluorouracil. The anti-tumor activities of this new prodrug were evaluated in vivo. More significant anti-tumor effects were observed over the parent 5-fluorouracil. PMID- 22512657 TI - Surface tension-induced gel fracture. Part 1. Fracture of agar gels. AB - This work involves an experimental investigation of the spreading of liquids on gel layers in the presence of surfactants. Of primary interest is the instability that accompanies the cracking of gels through the deposition and subsequent spreading of a drop of surfactant solution on their surfaces. This instability manifests itself via the shaping of crack-like spreading "arms", in formations that resemble starbursts. The main aim of this study is to elucidate the complex interactions between spreading surfactants and underlying gels and to achieve a fundamental understanding of the mechanism behind the observed phenomenon of the cracking pattern formation. By spreading SDS and Silwet L-77 surfactant solutions on the surfaces of agar gels, the different ways that system parameters such as the surfactant chemistry and concentration and the gel strength can affect the morphology and dynamics of the starburst patterns are explored. The crack propagation dynamics is fitted to a power law by measuring the temporal evolution of the length of the spreading arms that form each one of the observed patterns. The values of the exponent of the power law are within the predicted limits for Marangoni-driven spreading on thick layers. Therefore, Marangoni stresses, induced by surface tension gradients between the spreading surfactant and the underlying gel layer, are identified to be the main driving force behind these phenomena, whereas gravitational forces were also found to play an important role. A mechanism that involves the "unzipping" of the gel in a manner perpendicular to the direction of the largest surface tension gradient is proposed. This mechanism highlights the important role of the width of the arms in the process; it is demonstrated that a cracking pattern is formed only within the experimental conditions that allow S/Deltaw to be greater than G', where S is the spreading coefficient, Deltaw is the change in the width of the crack, and G' is the storage modulus of the substrate. PMID- 22512658 TI - If patient-reported outcome measures are considered key health-care quality indicators, who is excluded from participation? AB - Patient-reported outcome measures have received increasing attention with regard to ensuring quality improvement across the health service. However, there is a risk that people with disabilities and low literacy are systematically excluded from the development of these measures as well as their application in clinical practice. This editorial highlights some of these risks and the potential consequences of exclusion for these groups. PMID- 22512659 TI - Met expectations and the wellbeing of diaspora immigrants: a longitudinal study. AB - Previous research has pointed to the importance of expectations for the adaptation of immigrants. However, most studies have been methodologically retrospective with only limited possibilities to show the optimal relationship between migrants' expectations and actual acculturation experiences for their wellbeing and other aspects of psychological adaptation. Moreover, previous research has been conducted mostly among sojourners and students. This longitudinal study focused on the relationship between premigration expectations and postmigration experiences of diaspora immigrants from Russia to Finland (N = 153). We examined how the fulfillment of premigration expectations in social (i.e., family relations, friendships, and free time) and economic (i.e., occupational position, working conditions, and economic and career situation) domains affects immigrants' wellbeing (i.e., satisfaction with life and general mood) after migration. Three alternative models of expectation confirmation (i.e., disconfirmation model, ideal point model, and the importance of experiences only) derived from previous organizational psychological research were tested with polynomial regression and response surface analysis. In the economic domain, immigrants' expectations, experiences, and their interrelationship did not affect wellbeing in the postmigration stage. However, in the social domain, the more expectations were exceeded by actual experiences, the better were life satisfaction and the general mood of immigrants. The results underline the importance of social relationships and the context-dependent nature of immigrants' wellbeing. Interventions in the preacculturation stage should create positive but realistic expectations for diaspora immigrants and other groups of voluntary (re)migrants. Furthermore, policies concerning the postmigration stage should facilitate the fulfillment of these expectations and support the social adaptation of immigrants. PMID- 22512661 TI - Changes in mitochondrial proteome of renal tubular cells induced by calcium oxalate monohydrate crystal adhesion and internalization are related to mitochondrial dysfunction. AB - Calcium oxalate monohydrate (COM) crystals, the major crystalline compound in kidney stones, have been suggested to induce oxidative stress by overproduction of reactive oxygen species (ROS) and renal tubular cell injury. Our present study aimed to examine changes in mitochondrial proteome in distal renal tubular cells induced by COM crystals (100 MUg of crystals/mL of culture medium). Adhesion and internalization of COM crystals by MDCK cells were examined by fluorescent and laser-scanning confocal microscopy. Moreover, the internalized COM crystals were quantified by flow cytometry. Thereafter, mitochondria were isolated from controlled and COM-treated cells, and mitochondrial proteins were subjected to 2 DE-based comparative proteomic analysis, which revealed 15 differentially expressed proteins. These significantly altered proteins were identified by Q-TOF MS and MS/MS analyses, including those involved in several biological processes, e.g., cellular structure, carbohydrate metabolism, and energy metabolism. 2-D Western blot analysis confirmed the increase of ezrin and decrease of beta-actin. Global protein network analysis was then performed to obtain additional functional significance of the identified proteins and to guide for subsequent functional analysis. The results implicated that the altered proteins were involved in energy production and might contribute to mitochondrial dysfunction. The loss of ROS regulation by mitochondria was finally confirmed by OxyBlot assay, which demonstrated markedly increased levels of the oxidatively modified mitochondrial proteins in the COM-treated cells in a dose-dependent manner. Our data may lead to a better understanding of molecular mechanisms of mitochondrial dysfunction underlying the overt oxidative stress induced by COM crystals in kidney stone disease. PMID- 22512660 TI - Suppressing surface reconstruction of superhydrophobic PDMS using a superhydrophilic zwitterionic polymer. AB - Poly(dimethyl siloxane) (PDMS) is extensively used for biomedical applications due to its low cost, ease of fabrication, high durability and flexibility, oxygen permeability, and self-healing properties. PDMS, however, has some significant drawbacks. PDMS endures unacceptably high levels of nonspecific protein fouling when used with biological samples due to its superhydrophobic characteristics. Unfortunately, conventional surface modification methods do not work for PDMS due to its low glass transition temperature. This phenomenon has been well-known for years as "hydrophobic regeneration". For the same reason, it is also very difficult to bring functionalities onto PDMS surfaces. Herein, we demonstrate how a superhydrophilic zwitterionic material, poly(carboxybetaine methacrylate) (pCBMA), can provide a highly stable coating with long-term stabilty due to the sharp contrast in hydrophobicity between pCBMA and PDMS. This material is able to suppress nonspecific protein adsorption in complex media and functionalize desired biomolecules needed in applications, such as diagnostics, without sacrificing its nonfouling characteristics. PMID- 22512662 TI - A new triterpenoid from the rhizomes of Nelumbo nucifera. AB - A new triterpenoid, 2alpha,24-diacetoxy-3beta-hydroxyolean-12-en-28-oic acid (1), was characterised from the rhizomes of Nelumbo nucifera Gaertn by spectroscopic and chemical methods along with four known compounds, hyptatic acid-A (2alpha,3beta,24-trihydroxyolean-12-en-28-oic acid) (2), maslinic acid (2alpha,3beta-dihydroxyoleane-12-ene-28-oic acid), betulin and lupeol. PMID- 22512663 TI - Population-based burden of bloodstream infections in Finland. AB - Bloodstream infections (BSI) are a major cause of mortality, morbidity and medical cost, but few population-based studies have concomitantly evaluated BSI incidence and mortality. Data on BSI episodes reported to national, population based surveillance by all clinical microbiology laboratories in Finland during 2004-07 were linked to vital statistics. Age-, sex and microbe-specific incidence and mortality rates were calculated. During 2004-07, 33 473 BSI episodes were identified; BSI incidence increased from 147 to 168 per 100 000 population (average annual increase, 4.4%; p <0.001). Rates were highest among persons >=65 years and <1 year, and higher among male patients than female patients (166 versus 152 per 100 000). The most common aetiologies were Escherichia coli (27%) and Staphylococcus aureus (13%). Among male patients, 52% of BSI were caused by gram-positive bacteria compared with 42% among female patients (p <0.001). The overall 30-day case-fatality was 13%. Of the deaths, 32% occurred within 2 days, 70% were among people aged 65 years or more and 33% were caused by E. coli or S. aureus infections. The BSI mortality rate increased from 19 to 22 per 100 000 (average annual increase: 4.0%, p 0.01). Among people aged 25 years or more, the mortality rate was 1.4-fold higher in men than women (34 versus 25 per 100 000 population). Overall excess annual mortality from BSI in the population was 18 per 100 000. The substantial BSI burden among the elderly and among adult men highlights the need for developing and implementing effective interventions, particularly for BSI caused by E. coli and S. aureus. One-third of BSI deaths occurred early, emphasizing the importance of early identification and treatment. PMID- 22512664 TI - The effects of Syzygium aromaticum-derived oleanolic acid on kidney function of male Sprague-Dawley rats and on kidney and liver cell lines. AB - Studies indicate that Syzygium spp-derived oleanolic acid (OA) enhances renal function of streptozotocin (STZ)-induced diabetic rats as evidenced by its reversal of the previously reported inability of the kidney to excrete Na(+) in these animals. We postulated that OA influences Na(+) excretion in the proximal tubule, the site where two-thirds of filtered NaCl is reabsorbed through a process mediated by transport proteins. Therefore, the study investigated the effects of OA on proximal tubular Na(+) handling in male Sprague-Dawley rats using renal lithium clearance (C(Li)). Renal C(Li) has been used widely in animal and clinical studies to assess proximal tubular function. Sub-chronic doses of OA were administered to rats twice every third day for 5 weeks. Rats treated with deionized water served as control animals. Cytotoxicity of OA on kidney and liver cell lines was assessed by the MTT and comet assays. OA increased Na(+) excretion of conscious male Sprague-Dawley rats from week 3 to week 5. By the end of the 5 week experimental period, OA treatment significantly reduced (p < 0.05) plasma creatinine concentration of STZ-induced diabetic rats with a concomitant elevation in glomerular filtration rate (GFR). Acute OA infusion was also associated with increases in fractional excretion of sodium (FE(Na)) and lithium (FE(Li)) in anesthetized rats in the absence of significant changes in GFR. The MTT assay studies demonstrated that OA increased the metabolic activity of kidney and liver cell lines. Taken together with previous observations, this study implicates the proximal tubule in OA-evoked increases in urinary Na(+) output. PMID- 22512665 TI - Ontogeny of mammalian metabolizing enzymes in humans and animals used in toxicological studies. AB - It is well recognized that expression of enzymes varies during development and growth. However, an in-depth review of this acquired knowledge is needed to translate the understanding of enzyme expression and activity into the prediction of change in effects (e.g. kinetics and toxicity) of xenobiotics with age. Age related changes in metabolic capacity are critical for understanding and predicting the potential differences resulting from exposure. Such information may be especially useful in the evaluation of the risk of exposure to very low (ug/kg/day or ng/kg/day) levels of environmental chemicals. This review is to better understand the ontogeny of metabolizing enzymes in converting chemicals to either less-toxic metabolite(s) or more toxic products (e.g. reactive intermediate[s]) during stages before birth and during early development (neonate/infant/child). In this review, we evaluated the ontogeny of major "phase I" and "phase II" metabolizing enzymes in humans and commonly used experimental animals (e.g. mouse, rat, and others) in order to fill the information gap. PMID- 22512666 TI - Total allowable concentrations of monomeric inorganic aluminum and hydrated aluminum silicates in drinking water. AB - Maximum contaminant levels are used to control potential health hazards posed by chemicals in drinking water, but no primary national or international limits for aluminum (Al) have been adopted. Given the differences in toxicological profiles, the present evaluation derives total allowable concentrations for certain water soluble inorganic Al compounds (including chloride, hydroxide, oxide, phosphate and sulfate) and for the hydrated Al silicates (including attapulgite, bentonite/montmorillonite, illite, kaolinite) in drinking water. The chemistry, toxicology and clinical experience with Al materials are extensive and depend upon the particular physical and chemical form. In general, the water solubility of the monomeric Al materials depends on pH and their water solubility and gastrointestinal bioavailability are much greater than that of the hydrated Al silicates. Other than Al-containing antacids and buffered aspirin, food is the primary source of Al exposure for most healthy people. Systemic uptake of Al after ingestion of the monomeric salts is somewhat greater from drinking water (0.28%) than from food (0.1%). Once absorbed, Al accumulates in bone, brain, liver and kidney, with bone as the major site for Al deposition in humans. Oral Al hydroxide is used routinely to bind phosphate salts in the gut to control hyperphosphatemia in people with compromised renal function. Signs of chronic Al toxicity in the musculoskeletal system include a vitamin D-resistant osteomalacia (deranged membranous bone formation characterized by accumulation of the osteoid matrix and reduced mineralization, reduced numbers of osteoblasts and osteoclasts, decreased lamellar and osteoid bands with elevated Al concentrations) presenting as bone pain and proximal myopathy. Aluminum-induced bone disease can progress to stress fractures of the ribs, femur, vertebrae, humerus and metatarsals. Serum Al >=100 ug/L has a 75-88% positive predictive value for Al bone disease. Chronic Al toxicity is also manifest in the hematopoietic system as an erythropoietin-resistant microcytic hypochromic anemia. Signs of Al toxicity in the central nervous system (speech difficulty to total mutism to facial grimacing to multifacial seizures and dyspraxia) are related to Al accumulation in the brain and these symptoms can progress to frank encephalopathy. There are four groups of people at elevated risk of systemic Al intoxication after repeated ingestion of monomeric Al salts: the preterm infant, the infant with congenital uremia and children and adults with kidney disease. There is a dose-dependent increase in serum and urinary Al in people with compromised renal function, and restoration of renal function permits normal handling of systemically absorbed Al and resolution of Al bone disease. Clinical experience with 960 mg/day of Al(OH)(3) (~5 mg Al/kg-day) given by mouth over 3 months to men and women with compromised renal function found subclinical reductions in hemoglobin, hematocrit and serum ferritin. Following adult males and females with reduced kidney function found that ingestion of Al(OH)(3) at 2.85 g/day (~40 mg/kg-day Al) over 7 years increased bone Al, but failed to elicit significant bone toxicity. There was one report of DNA damage in cultured lymphocytes after high AlCl(3) exposure, but there is no evidence that ingestion of common inorganic Al compounds presents an increased carcinogenic risk or increases the risk for adverse reproductive or developmental outcomes. A number of studies of Al exposure in relation to memory in rodents have been published, but the results are inconsistent. At present, there is no evidence to substantiate the hypothesis that the pathogenesis of Alzheimer's Disease is caused by Al found in food and drinking water at the levels consumed by people living in North America and Western Europe. Attapulgite (palygorskite) has been used for decades at oral doses (recommended not to exceed two consecutive days) of 2,100 mg/day in children of 3-6 years, 4,200 mg/day in children of 6-12 years, and 9,000 mg/day in adults. Chronic ingestion of insoluble hydrated Al silicates (in kg) can result in disturbances in iron and potassium status, primarily as a result of clay binding to intestinal contents and enhanced fecal iron and zinc elimination. Sufficiently high doses of ingested Al silicates (>=50 g/day) over prolonged periods of time can elicit a deficiency anemia that can be corrected with oral Fe supplements. There is essentially no systemic Al uptake after ingestion of the hydrated Al silicates. Rats fed up to 20,000 ppm Ca montmorillonite (equivalent to 1,860 ppm total Al as the hydrated Al silicate) for 28 weeks failed to develop any adverse signs. The results of dietary Phase I and II clinical trials conducted in healthy adult volunteers over 14 days and 90 days with montmorillonite found no adverse effects after feeding up to 40 mg/kg day as Al. Since the Al associated with ingestion of hydrated Al silicates is not absorbed into the systemic circulation, the hydrated Al silicates seldom cause medical problems unless the daily doses consumed are substantially greater than those used clinically or as dietary supplements. A no-observable-adverse-effect level (NOAEL) of 13 mg/kg-day as total Al can be identified based on histologic osteomalacia seen in adult hemodialysis patients given Al hydroxide for up to 7 years as a phosphate binder. Following U.S. EPA methods for calculation of an oral reference dose (RfD), an intraspecies uncertainty factor of 10x was applied to that value results in a chronic oral reference dose (RfD) of 1.3 mg Al/kg-day; assuming a 70-kg adult consumes 2 L of drinking water per day and adjusting for a default 20% relative source contribution that value corresponds to a drinking water maximum concentration of 9 mg/L measured as total Al. A chronic NOAEL for montmorillonite as representative of the hydrated Al silicates was identified from the highest dietary concentration (20,000 ppm) fed in a 28-week bioassay with male and female Sprague-Dawley rats. Since young rats consume standard laboratory chow at ~23 g/day, this concentration corresponds to 56 mg Al/kg-day. Application of 3x interspecies uncertainty factor and a 3x factor to account for study duration results in a chronic oral RfD of 6 mg Al/kg-day. Of note, this RfD is 5-10 fold less than oral doses of Al silicates consumed by people who practice clay geophagy and it corresponds to a maximum drinking water concentration of 40 mg Al/L. To utilize the values derived here, the risk manager must recognize the particular product (e.g., alum) or source (e.g., groundwater, river water, clay or cement pipe) of the Al found in tap water, apply the appropriate analytical methods (atomic absorption, energy dispersive X-ray diffraction, infrared spectral analysis and/or scanning transmission electron microscopy) and compare the results to the most relevant standard. The drinking water concentrations derived here are greater than the U.S. EPA secondary maximum contaminant level (MCL) for total Al of 0.05-0.2 mg/L [40 CFR 143.3]. As such, domestic use of water with these concentrations is likely self-limiting given that its cloudy appearance will be greater than the maximum permitted (0.5-5.0 nephalometric turbidity units; 40 CFR Parts 141 and 142). Therefore, the organoleptic properties of Al materials in water determine public acceptance of potable water as contrast to any potential health hazard at the concentrations ordinarily present in municipal drinking water. PMID- 22512667 TI - Assaying embryotoxicity in the test tube: current limitations of the embryonic stem cell test (EST) challenging its applicability domain. AB - Testing for embryotoxicity in vitro is an attractive alternative to animal experimentation. The embryonic stem cell test (EST) is such a method, and it has been formally validated by the European Centre for the Validation of Alternative Methods. A number of recent studies have underscored the potential of this method. However, the EST performed well below the 78% accuracy expected from the validation study using a new set of chemicals and pharmaceutical compounds, and also of toxicity criteria, tested to enlarge the database of the validated EST as part of the Work Package III of the ReProTect Project funded within the 6th Framework Programme of the European Union. To assess the performance and applicability domain of the EST we present a detailed review of the substances and their effects in the EST being nitrofen, ochratoxin A, D-penicillamine, methylazoxymethanol, lovastatin, papaverine, warfarin, beta-aminopropionitrile, dinoseb, furosemide, doxylamine, pravastatin, and metoclopramide. By delineation of the molecular mechanisms of the substances we identify six categories of reasons for misclassifications. Some of these limitations might also affect other in vitro methods assessing embryotoxicity. Substances that fall into these categories need to be included in future validation sets and in validation guidelines for embryotoxicity testing. Most importantly, we suggest conceivable improvements and additions to the EST which will resolve most of the limitations. PMID- 22512668 TI - Radiative and nonradiative properties of single plasmonic nanoparticles and their assemblies. AB - A surface plasmon is the coherent oscillation of the conduction band electrons. When a metal nanoparticle is excited to produce surface plasmons, incident light is both scattered and absorbed, giving rise to brilliant colors. One available technique for measuring these processes, ensemble extinction spectroscopy, only measures the sum of scattering and absorption. Although the spectral responses of these processes are closely related, their relative efficiencies can differ significantly as a function of nanoparticle size and shape. For some applications, researchers may need techniques that can quantitatively measure absorption or scattering alone. Through advances in single particle spectroscopy, researchers can overcome this problem, separately determining the radiative (elastic and inelastic scattering) and nonradiative (absorption) properties of surface plasmons. Furthermore, because we can use the same sample preparation for both single particle spectroscopy measurements and electron microscopy, this technique provides detailed structural information and a direct correlation between optical properties and nanostructure morphology. In this Account, we present our quantitative investigations of both radiative (scattering and one photon luminescence) and nonradiative (absorption) properties of the same individual plasmonic nanostructures employing different single particle spectroscopy techniques. In particular, we have used a combined setup to study the same structure with dark-field scattering spectroscopy, photothermal heterodyne imaging, confocal luminescence microscopy, and scanning electron microscopy. While Mie theory thoroughly describes the overall size dependence of scattering and absorption for nanospheres, our real samples deviate significantly from the predicted trend: their particle shape is not perfectly spherical, especially when supported on a substrate. Because of the high excitation rate in laser based single particle measurements, we can efficiently detect one-photon luminescence despite a low quantum yield. For gold nanoparticles, the luminescence spectrum follows the scattering response, and therefore we assigned it to the emission of a plasmon. Due to strong near-field interactions the plasmonic response of closely spaced nanoparticles deviates significantly from that of the constituent nanoparticles. This response arises from coupled surface plasmon modes that combine those of the individual nanoparticles. Our correlated structural and optical imaging strategy is especially powerful for understanding these collective modes and their dependence on the assembly geometry. PMID- 22512670 TI - The reassurance questionnaire: comparison of the latent structure in university, community, and medical samples. AB - The Reassurance Questionnaire (RQ; Speckens, Spinhoven, Van Hemert, & Bolk, ( 2000 ) is a self-report measure designed to assess the extent to which patients feel reassured by their attending physicians. While the original RQ was validated in Dutch, the invariance of the factor structure has not been examined in the English version of the RQ. In the current study, the English RQ was completed by university (n = 459), community (n = 244), and medical samples (n = 281). Unlike the original one-factor solution found for the Dutch RQ, a two-factor solution for the English RQ was found for all three samples. The two factors were labeled: (1) Doubt in Physician, and (2) Persistent Health Anxiety. Item loadings were invariant across the community and medical samples. Implications of the findings along with directions for future research are discussed. PMID- 22512669 TI - Synthesis and photodynamic effect of new highly photostable decacationically armed [60]- and [70]fullerene decaiodide monoadducts to target pathogenic bacteria and cancer cells. AB - Novel water-soluble decacationically armed C(60) and C(70) decaiodide monoadducts, C(60)- and C(70)[>M(C(3)N(6)(+)C(3))(2)], were synthesized, characterized, and applied as photosensitizers and potential nano-PDT agents against pathogenic bacteria and cancer cells. A high number of cationic charges per fullerene cage and H-bonding moieties were designed for rapid binding to the anionic residues displayed on the outer parts of bacterial cell walls. In the presence of a high number of electron-donating iodide anions as parts of quaternary ammonium salts in the arm region, we found that C(70)[>M(C(3)N(6)(+)C(3))(2)] produced more HO(*) than C(60)[>M(C(3)N(6)(+)C(3))(2)], in addition to (1)O(2). This finding offers an explanation of the preferential killing of Gram-positive and Gram-negative bacteria by C(60)[>M(C(3)N(6)(+)C(3))(2)] and C(70)[>M(C(3)N(6)(+)C(3))(2)], respectively. The hypothesis is that (1)O(2) can diffuse more easily into porous cell walls of Gram-positive bacteria to reach sensitive sites, while the less permeable Gram-negative bacterial cell wall needs the more reactive HO(*) to cause real damage. PMID- 22512671 TI - The needs of parents with children suffering from lethal epidermolysis bullosa. AB - BACKGROUND: Some subtypes of the heterogeneous genetic blistering disease epidermolysis bullosa (EB) lead to lethality in childhood. The severity and extent of blistering leaves these patients living in excruciating pain and distress their entire lives. Parents of these patients experience some specific problems, such as the unfamiliarity of EB amongst healthcare professionals and the suffering and loss of their child. OBJECTIVE: To identify the needs of parents who have lost their child to lethal EB. METHODS: A qualitative study was performed, comprising semistructured, in-depth interviews with 16 parents. The transcripts were analysed and common themes were identified. RESULTS: Parents indicated that they have the need (i) for a fast and correct referral to a specialized EB clinic, (ii) to be informed as honestly as possible about the diagnosis and lethal prognosis, (iii) to have a structured network of caregivers in the palliative care, (iv) to be involved in the care and the medical decisions involving their child, (v) to be informed about the end of life and to discuss euthanasia, (vi) for guidance and to have remembrances of their child, and (vii) for genetic counselling. CONCLUSIONS: Our job as healthcare professionals is to provide the best care not only for children suffering from lethal EB, but also for their parents. In this study, parents have provided us with some guidelines to care for them. However, it is important to keep in mind that every parent is different, and that the guidance should be tailored to their individual needs. PMID- 22512672 TI - Crystal structures of human sulfotransferases: insights into the mechanisms of action and substrate selectivity. AB - INTRODUCTION: Cytosolic sulfotransferases (SULTs) are the enzymes that catalyze the sulfonation reaction, an important metabolic pathway for numerous endogenous and exogenous compounds. Human SULTs exhibit complex patterns of broad, differential and overlapping substrate selectivity. Moreover, these enzymes often display substrate inhibition kinetics (i.e., inhibition of the enzyme activity at high substrate concentrations). AREAS COVERED: At present, the crystal structures for 12 human SULTs (i.e., SULT1A1, 1A2, 1A3, 1B1, 1C1, 1C2, 1C3, 1E1, 2A1, 2B1a, 2B1b and 4A1) are available, many of which are in complex with a substrate. This review describes the similarities and differences in these structures (particularly the active-site structures) of SULT enzymes. The authors also discuss the structural basis for understanding the catalytic mechanism, the substrate inhibition mechanisms, the cofactor (3'-phosphoadenosine 5' phosphosulfate or PAPS) binding and the substrate recognition. EXPERT OPINION: Correlations of the structural features (including conformational flexibility) in the active sites with the substrate profiles of several SULTs have been well established. One is encouraged to closely integrate in silico approaches with the structural knowledge of the active sites for development of a rationalized and accurate tool that is able to predict metabolism of SULTs toward chemicals and drug candidates. PMID- 22512674 TI - Synthesis of isocoumarin derivatives via the copper-catalyzed tandem sequential cyclization of 2-halo-N-phenyl benzamides and acyclic 1,3-diketones. AB - A facile and rapid synthesis of isocoumarin derivatives using a copper-catalyzed tandem C-C/C-O coupling strategy from readily available substrates is described. The reactions of a wide range of 2-iodo-N-phenyl benzamides and acyclic diketones as starting materials were investigated. PMID- 22512673 TI - Intensive care unit nurses' perceptions of patient participation in the acute phase of chronic obstructive pulmonary disease exacerbation: an interview study. AB - AIM: To report a study conducted to explore intensive care unit nurses' perceptions of patient participation in the acute phase of chronic obstructive pulmonary disease exacerbation. BACKGROUND: An acute exacerbation is a life threatening situation, which patients often consider to be extremely frightening. Healthcare personnel exercise considerable power in this situation, which challenges general professional notions of patient participation. DESIGN: Critical discourse analysis. METHODS: In the autumn of 2009, three focus group interviews with experienced intensive care nurses were conducted at two hospitals in western Norway. Two groups had six participants each, and one group had five (N = 17). The transcribed interviews were analysed by means of critical discourse analysis. FINDINGS: The intensive care nurses said that an exacerbation is often an extreme situation in which healthcare personnel are exercising a high degree of control and power over patients. Patient participation during exacerbation often takes the form of non-involvement. The participating nurses attached great importance to taking a sensitive approach when meeting patients. The nurses experienced challenging ethical dilemmas. CONCLUSION: This study shows that patient participation should not be understood in universal terms, but rather in relation to a specific setting and the interactions that occur in this setting. Healthcare personnel must develop skill, understanding, and competence to meet these challenging ethical dilemmas. A collaborative inter-professional approach between physicians and nurses is needed to meet the patients' demand for involvement. PMID- 22512675 TI - Evidence-based recommendations on topical treatment and phototherapy of psoriasis: systematic review and expert opinion of a panel of dermatologists. AB - BACKGROUND: Although topical treatments and phototherapy are available for more than 40 years, there is a paucity of evidence-based recommendations regarding their use. OBJECTIVES: The aim of this work was to develop evidence-based recommendations on topical treatments and phototherapy in psoriasis for daily clinical use. METHODS: A scientific committee selected clinically relevant questions on efficacy and safety of topical agents and phototherapy in psoriasis. This selection was made using the Delphi method. A systematic literature search was performed in Medline, Embase and the Cochrane Library. The articles selected for analysis were reviewed and the level of evidence was appraised according to the Oxford Levels of Evidence. An Expert consensus meeting took place in June 2011, including 42 dermatologists. Recommendations for use of topical treatments and phototherapy were made during interactive workshops where the evidence was presented and discussed. Agreement among participants was assessed on a 10-point scale. The participants systematically assessed the impact of the recommendations on clinical practice. RESULTS: A total of 3555 references were identified, among which 312 articles were included in the systematic reviews. Three recommendations were issued on phototherapy including both PUVA and narrow-band UVB. The recommendations related to administration schedule, clearance rate and risk of side-effects. The mean agreement between participants was good varying from 8.5 to 9.5. Six recommendations were issued on topical treatments focusing on administration schedule, clearance rate, risk of side-effects, cost-effectiveness and measures to improve treatment adherence. The mean agreement between participants varied from 7.3 to 9.9. CONCLUSIONS: These recommendations for the use of topical agents and phototherapy in psoriasis are evidence-based and supported by a panel of dermatologists. The next step will be to disseminate these recommendations and assess the opinion of physicians who were not involved in generating the recommendations. PMID- 22512676 TI - Efficacy of psoralen UV-A therapy vs. narrowband UV-B therapy in chronic plaque psoriasis: a systematic literature review. AB - BACKGROUND: Oral 8-methoxypsoralen-UV-A (PUVA) and Narrowband UV-B (NB-UVB or UVB TL-01) are well established treatments for chronic plaque psoriasis but there is limited evidence regarding their respective efficacy. OBJECTIVES: To prepare for evidence-based recommendations concerning the practical use of oral 8 methoxypsoralen-UV-A and Narrowband UV-B in psoriasis, a systematic review to assess respective response rates, remission duration and predictive factors of efficacy was performed. METHODS: A systematic search was carried out in PubMed, Cochrane and Embase databases, using the key words 'Psoriasis', 'UVB therapy', 'UVA therapy' for the period from 1980 to December 2010. RESULTS: The initial literature search identified 773 articles. The final selection included 29 randomized controlled trials: 18 were about the efficacy of PUVA, eight about the efficacy of NB-UVB and three directly compared PUVA vs. NB-UVB. The response rate defined by 75% or more improvement in PASI was 80% with PUVA vs. 70% with NB-UVB. The meta-analysis of the three comparative studies found a higher probability of remission at 6 months with PUVA than with NB-UVB [OR = 2.73 (95% CI 1.19-6.27), P = 0.02]. The choice of initial dose, according to skin type, the minimal erythemal dose or minimal phototoxic dose, incremental regimen and periodicity of the sessions did not appear to be predictive factors of efficacy for PUVA or NB UVB. Despite methodological limitations in trials, the number of sessions needed for psoriasis clearance appeared to be lower with PUVA than with NB-UVB (approx. 17 vs. 25, respectively). CONCLUSION: PUVA and NB-UVB are both effective therapies in treatment of psoriasis. Our results suggest that compared with NB UVB, PUVA tends to clear psoriasis more reliably, with fewer sessions, and provides with longer lasting clearance. However, the long-term safety of PUVA, especially its cutaneous carcinogenic risk, and the easier administration procedure often lead dermatologists to prefer NB-UVB as first line phototherapy treatment in plaque type psoriasis. PMID- 22512677 TI - Carcinogenic risks of psoralen UV-A therapy and narrowband UV-B therapy in chronic plaque psoriasis: a systematic literature review. AB - BACKGROUND: Oral 8-methoxypsoralen-UV-A (PUVA) and narrowband UV-B (NB-UVB or UVB TL-01) are effective and widely used treatments for chronic plaque psoriasis. Although the role of PUVA therapy in skin carcinogenesis in humans with psoriasis has been clearly demonstrated, there is still controversy regarding the risk of skin cancer with NB-UVB. Furthermore, there is no clear evidence about the maximum cumulative number of sessions not to be exceeded in a lifetime. OBJECTIVES: To assess the respective cutaneous carcinogenic risks of PUVA or NB UVB in psoriasis; to estimate the respective dose-relationship between skin cancers and PUVA or NB-UVB; to estimate a maximum number of sessions for PUVA or NB-UVB not to be exceeded in a lifetime. METHODS: A systematic literature search was carried out in Medline, Embase and Cochrane Library databases from1980 to December 2010 in English and French, with the keywords 'Psoriasis' AND 'UVB therapy' AND 'UVA therapy' AND 'cancer' AND 'skin' OR 'neoplasm' OR 'cutaneous carcinoma' OR 'melanoma'. RESULTS: Of 243 identified references, 49 published studies were included. Most of them (45/49) concerned PUVA therapy, with 41 assessing the risk of non-melanoma skin cancers (NMSC) following PUVA. All publications referring to the US prospective PUVA follow-up study revealed an increased risk of NMSC with the following characteristics: risk most pronounced for squamous cell carcinomas developing even with low exposures and increasing linearly with the number of sessions, tumors occurring also on non-exposed skin including invasive penile tumors, risk persisting after cessation of treatment. An increased risk of basal cell carcinomas was observed in patients receiving more than hundred PUVA sessions. The four prospective European studies selected in our review and most of the pre-1990 European and US retrospective studies failed to find a link between exposure to PUVA and skin cancer. Only the most recent cohorts, including three large long-term retrospective European studies comparing records with their respective national cancer registries reported on an independent increased risk of NMSC with PUVA, The risk was lower as compared to the US prospective PUVA follow-up study. Six studies assessed the risk of melanoma following PUVA therapy: two of the three US publications coming from the same PUVA prospective follow-up study revealed an increased risk with more than doubled incidence of both invasive and in situ melanoma among patients exposed to at least 200 PUVA treatments compared with patients exposed to lower doses, whereas the three retrospectives European studies, comparing the incidence of melanoma in PUVA users with national cancer registers, did not find any increased risk of melanoma. No increased risk of skin cancer was evidenced in the four studies specifically assessing the potential carcinogenic risk of NB-UVB. CONCLUSION: There is an increased risk of skin cancer following PUVA, shown by both US and European studies. The greater risk measured by the US studies may be at least partly explained by high UVA dose exposure and the lighter phototypes of the treated patients. The lack of prospective studies in psoriasis patients treated with NB-UVB constitutes a barrier to the robust assessment of carcinogenic risk of this phototherapy technique. PMID- 22512678 TI - Ocular damage in patients with psoriasis treated by psoralen UV-A therapy or narrow band UVB therapy: a systematic literature review. PMID- 22512679 TI - Topical corticosteroids in plaque psoriasis: a systematic review of efficacy and treatment modalities. AB - INTRODUCTION: Topical steroids are used for more than 50 years to treat mild-to moderate plaque psoriasis. The purpose of this systematic review was to evaluate the efficacy but also the optimal modalities of administration of topical corticosteroids in psoriasis i.e. influence of steroid potency on clinical response, putative impact of topical formulation, occlusion procedure, rate of application to control the initial response and the potential interest of a maintenance treatment to prolong psoriasis clearance. MATERIAL AND METHODS: A systematic search was performed between 1980 and January 2011 in Medline, Embase and Cochrane databases (English and French language, adults), using the keywords 'psoriasis'/exp/mj AND 'corticosteroid'/exp/mj. To analyse response across studies, three levels of response were categorized depending on the data available in studies: percentage of patients who achieved more than 50%, 75% or 90% improvement of initial psoriasis severity. RESULTS: From an initial selection of 1269 references, 1166 references were excluded on reading the title or the abstract and 32 on reading the article and 71 were finally retained and analysed. Fifty randomized controlled trials (RCT) assessing topical steroids in the initial treatment of mild-to-severe psoriasis body plaque psoriasis were retained: 40 were parallel-group studies and 10 were within-patient studies. Treatment duration was mostly 4 weeks. Sample size varied from 30 to 1 603 patients. Outcome measures to assess efficacy were highly variable. A total of 30 90% patients across parallel group studies experienced more than 50% of initial mild-to-severe psoriasis improvement while from 7% to 85% experienced more than 75% improvement and from 5% to 85% experienced at least 90% of improvement. The success rate in the within-patient studies varied from 10% to 70%. Eighteen RCT were performed in scalp psoriasis: 16 were parallel-group and two were within patient studies, with a treatment follow-up time from 2 weeks to 6 months, enrolling 42-1417 patients. A total from 40% to 75% patients across studies experienced more than 75% of initial scalp psoriasis improvement and from 43% to 90% experienced more than 90% initial psoriasis improvement. Only three RCT studies evaluated topical steroids as a maintenance treatment for body psoriasis and one for scalp lesions. Despite heterogeneity in treatment schedule, topical steroid intermittent maintenance treatment was shown to prolong remission. The literature analysis did not provide with high evidence-based quality data on the role of formulation, topical steroid potency, number of applications per day to obtain the highest rate of success excepting occlusion dressing which provided with additional benefit. CONCLUSION: The clinical development of topical steroids in psoriasis did not follow state of the art modern methodology. Treatment success appears to be highly variable across studies. Maintenance intermittent treatment appears to be useful to prolong remission. Recommendations concerning topical steroids treatment modalities in plaque psoriasis should be mostly based on expert opinion. PMID- 22512680 TI - Topical corticosteroids in plaque psoriasis: a systematic review of risk of adrenal axis suppression and skin atrophy. AB - BACKGROUND: Topical steroids have been used for more than 50 years in mild-to moderate plaque psoriasis and carry a theoretical risk of adverse events. OBJECTIVES: The aim of this systematic literature review was to evaluate the risk of hypothalamo-pituitary-adrenal (HPA) axis suppression and the risk of skin atrophy with topical steroids in the treatment of plaque psoriasis. METHODS: A systematic search between 1980 and January 2011 in Medline, Embase and Cochrane databases (English, French language, adults), using the keywords 'psoriasis'/exp/mj AND 'corticosteroid'/exp/mj, RESULTS: Altogether 1269 references were found. Of these 1124 articles were excluded by reading the abstract and 123 by reading the article. A total of 22 randomized trials were selected. Effects on HPA axis: Thirteen studies, with a sample size varying from 7 to 341 patients, were selected. The effect on HPA axis was evaluated by the morning cortisol level (11 studies), the 24 h urine steroid levels (five studies) and/or by the Synacthen test (three studies). Reduction of morning cortisol was observed in 0-25% of patients in 10 short-term studies (two in scalp psoriasis, eight in body psoriasis) and in 48% of patients in the remaining short-term study (body psoriasis). Only four of these studies with three on body psoriasis evaluated the effect of long-term treatment defined as 6-month treatment duration or longer and did not identify HPA axis suppression by cortisol level measurement. The Synacthen test, considered as the gold standard to assess HPA axis, was always normal. There was no evidence of clinically significant HPA axis suppression due to absorption of topical steroids even when treating the scalp or in patients with extensive disease. Risk of skin atrophy: Thirteen studies with topical steroid evaluating treatment durations from 4 weeks to 1 year were analysed. The frequency of skin atrophy assessed clinically, varied from 0% to 5% of patients. CONCLUSIONS: The literature analysis on topical steroids in psoriasis is reassuring although the quality of safety studies is limited with a majority of short-term studies. Although short-term biological effects of topical steroids on the HPA axis were observed in several clinical studies, they were not associated with clinical signs. Adequately designed long-term studies would be necessary to better determine the risk of skin atrophy using modern methods of evaluation such as dermoscopy and echography. PMID- 22512681 TI - Topical vitamin D analogues alone or in association with topical steroids for psoriasis: a systematic review. AB - OBJECTIVE: The objective of this systematic review was to prepare for evidence based recommendations on the use of vitamin D analogues, and their combination with topical steroids in psoriasis. METHODS: Literature systematic review performed in May 2011. The Cochrane, PubMed and Embase databases were systematically searched with different combinations: including Psoriasis AND calcipotriol expanded to all vitamin D analogues. To assess efficacy across studies, we used two predefined criteria to account for the numerous endpoints found in the literature, 'Treatment success' corresponding to 90% improvement in severity and 'Satisfactory response' corresponding to 75% improvement. We conducted a meta-analysis comparing the efficacy of vitamin D analogues plus topical steroids (VDS) vs. vitamin D analogues alone (VD). To determine the relative cost-efficacy of the topical drugs available on the market, cost/efficacy ratios were calculated for each product according to the approved therapeutic regimen. RESULTS: 51 articles were selected. The application duration varied between three to 52 weeks across studies. VD as monotherapy had a satisfactory response rate between 22% to 96% and a treatment success rate ranging from 4% to 40%. VDS had a satisfactory response rate between 35% to 86% and a treatment success rate ranging from 27% to 53%. A meta-analysis found a probability of success twice higher with VDS than with VD in adult plaque psoriasis. The cost/efficacy ratio was evaluated as 1.2-1.8 times higher for VDS than for VD. CONCLUSION: VDS is twice more effective than VD and displays a better cost per success. Additional studies are needed to clarify maintenance treatment, impact on quality of life, treatment of non-plaque psoriasis. It will be important to harmonize outcome measures in future studies with topical agents in psoriasis to better appraise their efficacy. PMID- 22512682 TI - Adherence to topical treatment in psoriasis: a systematic literature review. AB - BACKGROUND: Treatment adherence has been recognized as an important issue in the management of chronic diseases such as psoriasis. OBJECTIVE: The aim of this work was to analyse data about topical treatment adherence in psoriasis. METHODS: Systematic literature review (62 references) between 1980 and 2011 (database: PubMed, Embase and Cochrane; Mesh keywords: Patient Compliance [Mesh] OR Medication Adherence [Mesh] AND Psoriasis [Mesh]; limits: date of publication >1980, humans subjects, written in French or English, aged >= 19 years). Two parameters were evaluated: (i) the ratio of number of product applications performed vs. number of applications expected according to physician recommendations, (ii) the ratio of amount of product used vs. amount of product prescribed. RESULTS: A total of 22 studies were selected. Nine studies reported on the frequency of topical treatment application in a real world setting. Five studies showed a frequency of applications varying between 50% and 60% of those expected. Because of the high variability in medication adherence assessment methods, the data could not be combined. Twelve articles reported on the frequency of topical treatment application in randomized controlled trials with adherence varying between 55% and 100%. Concerning the amount of product use, four studies showed patients applied between 35% and 72% of the recommended dose during a treatment period of 14 days to 8 weeks. The most frequently mentioned reasons for non-adherence to topical treatment were low efficacy, time consumption and poor cosmetic characteristics of topical agents. Patients experiencing adherence issues were significant younger, were men, had younger age at onset of psoriasis and had a higher self-assessed severity. To improve adherence, the following strategies were suggested: to give patients information about psoriasis, to recognize social impact, to give written instructions for use such as a care plan, to explain side effects of topical therapies, to choose treatment and its cosmetic properties in agreement with the patient. CONCLUSIONS: Literature data about topical treatment adherence are heterogeneous and scarce. They confirm the limited topical treatment adherence in psoriasis in real life, much lower than what is reported in randomized controlled trials. Therapeutic education and clear instructions on the use of topical agents are necessary to improve adherence. Studies are needed to identify predictors of limited adherence and to identify interventions improving adherence to topical medications in psoriasis. PMID- 22512683 TI - Topical treatment and phototherapy in psoriasis: systematic review and expert opinion of a panel of dermatologists. PMID- 22512685 TI - Different molecular bases underlie the mitochondrial respiratory activity in the homoeothermic spadices of Symplocarpus renifolius and the transiently thermogenic appendices of Arum maculatum. AB - Symplocarpus renifolius and Arum maculatum are known to produce significant heat during the course of their floral development, but they use different regulatory mechanisms, i.e. homoeothermic compared with transient thermogenesis. To further clarify the molecular basis of species-specific thermogenesis in plants, in the present study we have analysed the native structures and expression patterns of the mitochondrial respiratory components in S. renifolius and A. maculatum. Our comparative analysis using Blue native PAGE combined with nano LC (liquid chromatography)-MS/MS (tandem MS) has revealed that the constituents of the respiratory complexes in both plants were basically similar, but that several mitochondrial components appeared to be differently expressed in their thermogenic organs. Namely, complex II in S. renifolius was detected as a 340 kDa product, suggesting an oligomeric or supramolecular structure in vivo. Moreover, the expression of an external NAD(P)H dehydrogenase was found to be higher in A. maculatum than in S. renifolius, whereas an internal NAD(P)H dehydrogenase was expressed at a similar level in both species. Alternative oxidase was detected as smear-like signals that were elongated on the first dimension with a peak at around 200 kDa in both species. The significance and implication of these data are discussed in terms of thermoregulation in plants. PMID- 22512686 TI - Dying with motor neurone disease, what can we learn from family caregivers? AB - BACKGROUND: Increasingly, people with neurodegenerative illness are cared for at home until close to death. Yet, discussing the reality of dying remains a social taboo. OBJECTIVE: To examine the ways, family caregivers of people living with motor neurone disease (MND) experienced the dying of their relative and to identify how health practitioners can better prepare families for end-of-life care. DESIGN: Secondary analysis was undertaken on data sets generated from two longitudinal qualitative studies employing similar data collection and analysis methods. Combining data sets increased participant numbers in a low incidence disease group. SETTING AND PARTICIPANTS: Primary studies were undertaken with family caregivers in England and Australia. Interview and observational data were collected mostly in home. Participants who discussed dying and death formed the sample for secondary analysis. RESULTS: Combined data revealed four major themes: planning for end of life, unexpected dying, dignity in the dying body and positive end to MND. Despite short survival predictions, discussions among family members about dying were often sporadic and linked to loss of hope. Effective planning for death assisted caregivers to manage the final degenerative processes of dying. When plans were not effectively communicated or enacted, capacity to preserve personhood was reduced. DISCUSSION AND CONCLUSION: Returning death and dying to social discourse will raise the level of community awareness and normalize conversations about end-of-life care. Strategies for on-going, effective communication that facilitates advance care planning among patients, their families and practitioners are essential to improve dying and death for people with MND and their family caregivers. PMID- 22512687 TI - Repetition priming within and between languages in verb generation: evidence for shared verb concepts. AB - Although translation equivalents for concrete nouns are known to have shared core conceptual representations in bilingual memory (Francis, 1999), the status of translation-equivalent verbs has not been systematically tested. Three repetition priming experiments using a verb generation task were used to determine whether verbs have shared representations across languages and to identify the processes facilitated in repeated verb generation. In Experiment 1 fluent Spanish-English bilingual speakers exhibited repetition priming both within and between languages, but between-language priming was weaker. In Experiment 2 performance of non-bilingual English and Spanish speakers was equivalent to that of bilingual speakers responding in their dominant language. Experiment 3 used manipulations meant to isolate noun comprehension, verb concept selection, and verb production. The between-language priming in Experiments 1 and 3 indicates that verb concepts are shared across languages and that verb concept selection exhibits facilitation. Experiment 3 showed that the greater within-language priming was due primarily to facilitation of verb production processes. PMID- 22512688 TI - Hydrogel biopolymer created from the self-assembly of a designed protein containing a four-helix bundle forming motif. AB - A protein hydrogel system based on the assembly of a four-helix bundle motif was proposed and synthesized by genetic engineering methods. This new polypeptide, named GBH1, consists of identical amphipathic helices of 22 residues in length oriented in opposite fashion to one another at each end of a polypeptide with a total length of 227 amino acids. The middle portion of the polypeptide (residues 79-147) is an unstructured random coil. The region between the amphipathic and unstructured segment is an alpha-helical stretch (23-78 and 148-204) not possessing a sequence compatible with a coiled-coil conformation, but rather possesses regions that have overwinding of the helix. The thermal unfolding of GBH1 shows more than one inflection point (T(m1) = 30.5 degrees C, T(m2) = 64.6 degrees C), indicative of a partially unfolded intermediate and, thus, multiple interactions in the folded state. A qualitative assessment of hydrogel formation with varying pH showed that acidic conditions did not support the gel state, indirectly indicating that the proposed four-helix bundle is the major cross linking structure and not a leucine zipper motif. Scanning electron microscopy reveals a network of interacting protein molecules forming a spongelike matrix with numerous pores that would be occupied with water molecules. PMID- 22512689 TI - Adult-onset Still's disease with dermatomyositis-like eruption. PMID- 22512690 TI - Isolated prospective confabulation in Wernicke-Korsakoff syndrome: a case for reality filtering. AB - A 57-year-old man suffered severe amnesia and disorientation, accompanied by content-specific confabulation, due to an alcoholic Wernicke-Korsakoff syndrome. For months, he was deeply concerned about a single obligation that he thought he had to respond to, but which he had already assumed 20 years previously. This monothematic, prospective confabulation was associated with failures of reality filtering as previously documented in behaviorally spontaneous confabulation and disorientation: the patient failed to suppress the interference of currently irrelevant memories and to abandon anticipations that were no longer valid (impaired extinction capacity). Magnetic resonance imaging showed damage to the mamillary bodies and the dorsomedial thalamic nucleus. Positron emission tomography (FDG-PET) showed extended orbitofrontal hypometabolism. We suggest that isolated prospective confabulation shares the core feature (acts and thoughts based on currently irrelevant memory), mechanism (failure of reality filtering), and anatomical basis (orbitofrontal dysfunction) with behaviorally spontaneous confabulations. PMID- 22512691 TI - Reduced circulating miR-15b is correlated with phosphate metabolism in patients with end-stage renal disease on maintenance hemodialysis. AB - BACKGROUND: Disorders of mineral metabolism can facilitate the progression of vascular calcification and are closely associated with adverse outcomes in end stage renal disease (ESRD). miR-15b has been implicated in the epigenetic regulation of key metabolism, stress response, and osteoblast differentiation. METHODS AND RESULTS: In this study, we detected miR-15b in the plasma of 30 patients with ESRD and 20 healthy controls using real-time quantitative RT-PCR (RT-qPCR). Compared with healthy controls, the circulating levels of miR-15b were significantly reduced in patients with ESRD. However, there is no significant difference in circulating miR-15b levels when comparing prehemodialysis and posthemodialysis in patients with ESRD. In addition, to further estimate the potential roles of aberrantly expressed candidate miR-15b in the pathogenesis of ESRD, we utilized a bioinformatics exploratory analysis and identified gene ontology "biological process" classifications which revealed that dysregulated circulating miR-15b might be involved in phosphate metabolism. Furthermore, circulating miR-15b positively correlated with both estimated glomerular filtration rate (r = 0.502, p = 0.003) and hemoglobin levels (r = 0.432, p = 0.017) and inversely correlated with phosphate level (r = -0.516, p = 0.004). CONCLUSION: The findings indicated that the dysregulated miR-15b might contribute to the progression of ESRD by modulating genes that might be involved in the phosphate metabolism, which might have the potential of being used as a biomarker for monitoring disease. PMID- 22512692 TI - On the time course of exogenous cueing effects in bilinguals: higher proficiency in a second language is associated with more rapid endogenous disengagement. AB - Previous investigations have demonstrated a bilingual advantage on various aspects of executive control. It remains unclear how the language proficiency of bilinguals might relate to the mechanisms involved in attentional disengagement. In the present investigation, we tested the hypothesis that high bilingual proficiency would lead to a more rapid endogenous disengagement of attention from task-irrelevant peripheral cues. We predicted that more rapid attentional disengagement would result in an earlier appearance of inhibition of return (IOR). In this study Hindi-English bilinguals who differed in their L2 (English) proficiency participated in a target detection task. Visual targets were preceded by uninformative peripheral cues at various stimulus onset asynchronies (SOAs) allowing for us to visualize the time course of cue-related facilitation and inhibition. High-proficient Hindi-English bilinguals showed an earlier appearance of IOR than did low-proficient bilinguals, suggesting increased efficiency in disengagement of attention from task-irrelevant inputs. Furthermore, consistent with the "global" advantage that characterizes bilinguals in many tasks, the high proficient group outperformed low-proficient bilinguals in overall reaction time. PMID- 22512693 TI - Aquaculture and stress management: a review of probiotic intervention. AB - To meet the ever-increasing demand for animal protein, aquaculture continuously requires new techniques to increase the production yield. However, with every step towards intensification of aquaculture practices, there is an increase in stress level on the animal as well as on the environment. Feeding practices in aqua farming usually plays an important role, and the addition of various additives to a balanced feed formula to achieve better growth is a common practice among the fish and shrimp culturists. Probiotics, also known as 'bio friendly agents', such as LAB (Lactobacillus), yeasts and Bacillus sp., can be introduced into the culture environment to control and compete with pathogenic bacteria as well as to promote the growth of the cultured organisms. In addition, probiotics are non-pathogenic and non-toxic micro-organisms, having no undesirable side effects when administered to aquatic organisms. Probiotics are also known to play an important role in developing innate immunity among the fishes, and hence help them to fight against any pathogenic bacterias as well as against environmental stressors. The present review is a brief but informative compilation of the different essential and desirable traits of probiotics, their mode of action and their useful effects on fishes. The review also highlights the role of probiotics in helping the fishes to combat against the different physical, chemical and biological stress. PMID- 22512694 TI - Surface tension-induced gel fracture. Part 2. Fracture of gelatin gels. AB - The spreading of surfactants on gel layers has been found to be accompanied by an intriguing instability which involves the formation of crack-like patterns on the surface of the gel. In an attempt to extend the findings on the spreading on agar gels presented in part 1 of this series, this paper examines the case of surfactant spreading on gelatin, which is a characteristic example of a protein based gel. Aqueous solutions of Silwet L-77 of varying concentrations were spread on thick gelatin layers of varying concentrations. The resulting pattern formation was found to have many similarities to the corresponding phenomenon on agar. In terms of spreading dynamics, the values of the spreading exponent, n, of the power law L(t) ~ kt(n), which describes the temporal evolution of the cracks, are similar to those of the agar case, within the predicted limits for surface tension gradient-induced spreading on thick films, highlighting the dominant presence of Marangoni stresses. However, the values of the spreading coefficient, k, are much smaller compared to those measured during the spreading on agar. Further observations are linked with the rheological properties of gelatin, which are also measured in detail. PMID- 22512695 TI - Tacrolimus in confluent and reticulated papillomatosis of Gougerot Carteaud. PMID- 22512696 TI - Potent aminocyclitol glucocerebrosidase inhibitors are subnanomolar pharmacological chaperones for treating gaucher disease. AB - Amino-myo-inositol derivatives have been found to be potent inhibitors of glucocerebrosidase (GCase), the beta-glucosidase enzyme deficient in Gaucher disease (GD). When tested using lymphoblasts derived from patients with GD homozygous for N370S or L444P mutations, the compounds enhanced GCase activity at very low concentrations. The most potent inhibitor, (1R,2S,3R,4S,5S,6R)-5 (nonylamino)-6-(nonyloxy)cyclohexane-1,2,3,4-tetraol had a K(i) of 1 nM using isolated enzyme and an IC(50) of 4.3 nM when assayed in human fibroblast cell culture. This aminocyclitol produced maximum increases of GCase activities of 90% in N370S lymphoblasts at 1 nM and 40% in L444P at 0.01 nM following a three-day incubation. In addition to inhibitory potency, this compound has the permeability, subcellular distribution, and cell metabolism characteristics that are important for use as a pharmacological chaperone. It is a remarkable finding that picomolar concentrations of aminocyclitols are sufficient to enhance activity in the L444P variant, which produces a severe neuronopathic form of GD without clinical treatment. PMID- 22512697 TI - Long-term follow-up of patients with Herlitz-type junctional epidermolysis bullosa. AB - BACKGROUND: Junctional epidermolysis bullosa, type Herlitz (JEB-H) is a rare, autosomal recessive disease caused by absence of the epidermal basement membrane adhesion protein laminin-332. It is characterized by extensive and devastating blistering of the skin and mucous membranes, leading to death in early childhood. OBJECTIVES: To present the results of the long-term follow-up of a cohort of patients with JEB-H, and to provide guidelines for prognosis, treatment and care. METHODS: All patients with JEB-H included in the Dutch Epidermolysis Bullosa (EB) Registry between 1988 and 2011 were followed longitudinally by our EB team. Diagnosis was established using immunofluorescence antigen mapping, electron microscopy and DNA analysis. RESULTS: In total, we included 22 patients with JEB H over a 23-year period. Their average age at death was 5.8 months (range 0.5 32.6 months). The causes of death were, in order of frequency: failure to thrive, respiratory failure, pneumonia, dehydration, anaemia, sepsis and euthanasia. The pattern of initial weight gain was a predictor of lifespan in these patients. Invasive treatments to extend life did not promote survival in our patients. CONCLUSIONS: It is important to diagnose JEB-H as soon as possible after birth so that the management can be shifted from life-saving to comfort care. The palliative end-of-life care can take place in hospital, but is also safe in the home setting. Suffering in patients with JEB-H can become so unbearable that in some patients who do not respond to adequate analgesic and sedative treatment, newborn euthanasia, performed according to the Groningen protocol, is legally permitted in the Netherlands. PMID- 22512698 TI - Olive leaf extract as a hypoglycemic agent in both human diabetic subjects and in rats. AB - Olive tree (Olea europaea L.) leaves have been widely used in traditional remedies in European and Mediterranean countries as extracts, herbal teas, and powder. They contain several potentially bioactive compounds that may have hypoglycemic properties. To examine the efficacy of 500 mg oral olive leaf extract taken once daily in tablet form versus matching placebo in improving glucose homeostasis in adults with type 2 diabetes (T2DM). In this controlled clinical trial, 79 adults with T2DM were randomized to treatment with 500 mg olive leaf extract tablet taken orally once daily or matching placebo. The study duration was 14 weeks. Measures of glucose homeostasis including Hba1c and plasma insulin were measured and compared by treatment assignment. In a series of animal models, normal, streptozotocin (STZ) diabetic, and sand rats were used in the inverted sac model to determine the mechanism through which olive leaf extract affected starch digestion and absorption. In the randomized clinical trial, the subjects treated with olive leaf extract exhibited significantly lower HbA1c and fasting plasma insulin levels; however, postprandial plasma insulin levels did not differ significantly by treatment group. In the animal models, normal and STZ diabetic rats exhibited significantly reduced starch digestion and absorption after treatment with olive leaf extract compared with intestine without olive leaf treatment. Reduced digestion and absorption was observed in both the mucosal and serosal sides of the intestine. Though reduced, the decline in starch digestion and absorption did not reach statistical significance in the sand rats. Olive leaf extract is associated with improved glucose homeostasis in humans. Animal models indicate that this may be facilitated through the reduction of starch digestion and absorption. Olive leaf extract may represent an effective adjunct therapy that normalizes glucose homeostasis in individuals with diabetes. PMID- 22512699 TI - Diagnostic performance of P wave duration in the identification of left atrial enlargement in dogs. AB - OBJECTIVES: To determine sensitivity and specificity of P wave duration in the identification of left atrial enlargement in dogs. METHODS: Electrocardiograms from normal dogs and dogs with various cardiovascular diseases were evaluated. Inclusion criteria were the availability of an electrocardiogram showing a stable isoelectric line, easily recognizable P waves and good quality two-dimensional echocardiographic estimate of left atrial dimensions using the left atrial to aortic root ratio. Using a metal caliper system, P wave duration was measured to the nearest 10 milliseconds for six consecutive heart beats; data were then averaged for each dog. The accuracy of P wave duration in predicting left atrial enlargement was determined using a receiver operating characteristic analysis. RESULTS: One hundred and fifty-six dogs were included in the study. Average P wave durations of 20, 30, 40 and 50 milliseconds yielded sensitivities of 100, 85, 68 and 40% and specificities of 0, 16, 64 and 93%, respectively, for the diagnosis of Left Atrial Enlargement by echocardiography. The estimated area under curve of the receiver operating characteristic curve was 0.70 (95% confidence interval: 0.60 to 0.80). CLINICAL SIGNIFICANCE: The diagnostic performance of P wave duration for identification of left atrial enlargement in dogs presents considerable limitations. PMID- 22512700 TI - Increased body satisfaction after exposure to thin ideal children's television in young girls showing thin ideal internalisation. AB - This study tested the direct effect of watching thin ideal children's television on body satisfaction in preadolescent girls (6-8 years old). A within-subject design was used in which girls (N = 51) were tested three times. They watched television clips in random order containing either (1) thin ideal animated characters or (2) animated characters with no thin ideal features or (3) 'real' human actors with no thin ideal features. After watching, their state body satisfaction was measured. Girls with higher levels of thin ideal internalisation showed higher body satisfaction after exposure to the thin ideal characters than after exposure to animated or real characters featuring no thin ideal features. No differences on body satisfaction between the exposure conditions were found in girls with lower levels of thin ideal internalisation. The results might suggest that young girls who internalised the thin ideal are inspired by thin ideal characters in children's media. PMID- 22512701 TI - The crystal structure of human alpha(1)-microglobulin reveals a potential haem binding site. AB - We describe the 2.3 A (1 A=0.1 nm) X-ray structure of alpha1m (alpha1 microglobulin), an abundant protein in human blood plasma, which reveals the beta barrel fold typical for lipocalins with a deep pocket lined by four loops at its open rim. Loop #1 harbours the residue Cys34 which is responsible for covalent cross-linking with plasma IgA. A single disulfide bond between Cys72 and Cys169 connects the C-terminal segment to the beta-barrel, as in many other lipocalins. The exposed imidazole side chains of His122 and His123 in loop #4 give rise to a double Ni2+-binding site together with a crystallographic neighbour. The closest structural relatives of alpha1m are the complement protein component C8gamma, the L-prostaglandin D synthase and lipocalin 15, three other structurally characterized members of the lipocalin family in humans that have only distant sequence similarity. In contrast with these, alpha1m is initially expressed as a bifunctional fusion protein with the protease inhibitor bikunin. Neither the electron density nor ESI-MS (electrospray ionization MS) provide evidence for a chromophore bound to the recombinant alpha1m, also known as 'yellow/brown lipocalin'. However, the three side chains of Lys92, Lys118 and Lys130 that were reported to be involved in covalent chromophore binding appear to be freely accessible to ligands accommodated in the hydrophobic pocket. A structural feature similar to the well-known Cys-Pro haem-binding motif indicates the presence of a haem-binding site within the loop region of alpha1m, which explains previous biochemical findings and supports a physiological role in haem scavenging, as well as redox-mediated detoxification. PMID- 22512702 TI - Livestock-associated Staphylococcus aureus. AB - Staphylococcus aureus has long been associated with livestock. Livestock can be carriers of S. aureus, but can also become infected. The best-known infection is bovine mastitis. The discovery of methicillin-resistant S. aureus belonging to sequence type (ST)398 boosted interest in livestock-associated S. aureus. ST398 is pandemic. Whole genome sequencing and other genetic analyses have shown that livestock-associated strains are distinct from human-derived strains. However, there is also an exchange of strains between the reservoirs. Livestock-associated and human-associated strains share virulence factors, but have also distinct virulence factors that appear to be important in host adaptation. Exchange of genes encoding these virulence factors between strains may expand the host range and thereby threaten public health. Vaccination of animals may be a solution to this problem, but new avenues for vaccination need to be explored, because no vaccine is currently available. PMID- 22512703 TI - Expression of MMP-2, TIMP-2, TGF-beta1, and decorin in Dupuytren's contracture. AB - To investigate the mechanisms underlying matrix deposition in Dupuytren's disease, the expression of gelatinase A (MMP-2), the tissue inhibitor of metalloproteinase-2 (TIMP-2), transforming growth factor beta 1 (TGF-beta1), decorin (DCN), and periostin was studied. The level of relative MMP-2 activation was investigated using zymography. The mRNA expression of MMP-2, TIMP-2, TGF beta1, and DCN was detected using reverse transcription polymerase chain reaction (RT-PCR), while the presence of protein was detected using immunohistochemical (IHC) and Western blot techniques. The level of MMP-2 activation was significantly elevated in tissues with Dupuytren's contracture. RT-PCR demonstrated significantly higher expression of MMP-2, TIMP-2, TGF-beta1, and DCN mRNA in the pathological tissues; and the IHC and immunoblotting studies revealed elevated expression of TGF-beta1, DCN, and periostin. The balance between MMP-2 and TIMP-2 was disrupted in patients with Dupuytren's disease. TGF-beta1, DCN, and periostin are involved in extracellular matrix (ECM) homeostasis in Dupuytren's contracture. PMID- 22512705 TI - Predicting and detecting adverse drug reactions in old age: challenges and opportunities. AB - Increased, often inappropriate, drug exposure, pharmacokinetic and pharmacodynamic changes, reduced homeostatic reserve and frailty increase the risk of adverse drug reactions (ADRs) in the older population, thereby imposing a significant public health burden. Predicting and diagnosing ADRs in old age presents significant challenges for the clinician, even when specific risk scoring systems are available. The picture is further compounded by the potential adverse impact of several drugs on more 'global' health indicators, for example, physical function and independence, and the fragmentation of care (e.g., increased number of treating doctors and care transitions) experienced by older patients during their clinical journey. The current knowledge of drug safety in old age is also curtailed by the lack of efficacy and safety data from pre marketing studies. Moreover, little consideration is given to individual patients' experiences and reporting of specific ADRs, particularly in the presence of cognitive impairment. Pending additional data on these issues, the close review and monitoring of individual patients' drug prescribing, clinical status and biochemical parameters remain essential to predict and detect ADRs in old age. Recently developed strategies, for example, medication reconciliation and trigger tool methodology, have the potential for ADRs risk mitigation in this population. However, more information is required on their efficacy and applicability in different healthcare settings. PMID- 22512706 TI - Perifosine , an oral, anti-cancer agent and inhibitor of the Akt pathway: mechanistic actions, pharmacodynamics, pharmacokinetics, and clinical activity. AB - INTRODUCTION: Perifosine is a novel targeted oral Akt inhibitor currently in Phase III clinical development for treatment of colorectal cancer (CRC, in combination with capecitabine) and multiple myeloma (MM, in combination with bortezomib and dexamethasone). AREAS COVERED: The mechanism, preclinical testing, and clinical activity of perifosine in CRC and MM are discussed, with supportive pharmacokinetic information presented. Appropriate literature searches were carried out for background and discussion purposes. EXPERT OPINION: In preclinical models, perifosine has been shown to target phosphatidylinositol 3 kinase-Akt signaling. In CRC cell lines, preclinical studies indicate that perifosine may enhance the cytotoxic effects of fluorouracil, likely primarily through the nuclear transcription factor-kappa B pathway. A placebo-controlled Phase II randomized trial of capecitabine +/- perifosine in previously treated patients with metastatic CRC showed the combination to be superior. In MM, Phase I/II clinical trials have established the optimal dosing schedule for perifosine and bortezomib in combination, and demonstrated that perifosine can sensitize to, or overcome resistance to, bortezomib, associated with prolonged responses and a favorable side effect profile. Ultimately, the favorable tolerability of perifosine will allow for its testing in combination with multiple targeted therapies to improve PFS and OS, which represent an important unmet need in these populations. PMID- 22512708 TI - Involvement of melanocortin-1 receptor in the hyperpigmentation of human skin autografts. AB - Hyperpigmentation frequently occurs in human skin autografts resulting in an unsatisfactory appearance. This study aimed to elucidate the role of melanocortin 1 receptor in the hyperpigmentation process of skin autografts by analyzing the expression of melanocortin-1 receptor. The data were correlated with the amount of melanin in autografted human skin and normal skin determined in a previous study. Immunohistochemistry, western blotting and quantitative real-time polymerase chain reaction were carried out to detect the expression and distribution of melanocortin-1 receptor in skin autografts including full thickness skin autografts, split-thickness skin autografts and normal full thickness skin. Fontana-Masson stain was used to detect melanin in all types of skin specimens. The expression level of melanocortin-1 receptor in autografted skin was much higher than that in control normal skin, and thinner split thickness skin autografts had higher levels of expression of melanocortin-1 receptor than thicker grafts. The amount of melanin in skin autografts was significantly increased compared with normal skin. The expression of melanocortin 1 receptor correlated well with the amount of melanin in the epidermis of skin autografts. These results indicate that melanogenesis is dramatically enhanced in skin autografts by the melanocortin-1 receptor, and suggest that overexpression of melanocortin-1 receptor may play an important role in the hyperpigmented process of skin autografts. This study provides a novel mechanism for hyperpigmentation in skin autografts. PMID- 22512707 TI - Biodiversity of Mimosa pudica rhizobial symbionts (Cupriavidus taiwanensis, Rhizobium mesoamericanum) in New Caledonia and their adaptation to heavy metal rich soils. AB - Rhizobia are soil bacteria able to develop a nitrogen-fixing symbiosis with legumes. They are taxonomically spread among the alpha and beta subclasses of the Proteobacteria. Mimosa pudica, a tropical invasive weed, has been found to have an affinity for beta-rhizobia, including species within the Burkholderia and Cupriavidus genera. In this study, we describe the diversity of M. pudica symbionts in the island of New Caledonia, which is characterized by soils with high heavy metal content, especially of Ni. By using a plant-trapping approach on four soils, we isolated 96 strains, the great majority of which belonged to the species Cupriavidus taiwanensis (16S rRNA and recA gene phylogenies). A few Rhizobium strains in the newly described species Rhizobium mesoamericanum were also isolated. The housekeeping and nod gene phylogenies supported the hypothesis of the arrival of the C. taiwanensis and R. mesoamericanum strains together with their host at the time of the introduction of M. pudica in New Caledonia (NC) for its use as a fodder. The C. taiwanensis strains exhibited various tolerances to Ni, Zn and Cr, suggesting their adaptation to the specific environments in NC. Specific metal tolerance marker genes were found in the genomes of these symbionts, and their origin was investigated by phylogenetic analyses. PMID- 22512710 TI - How does encoding context affect memory in younger and older adults? AB - How does encoding context affect memory? Participants studied visually presented words viewed concurrently with a rich (intact face) or weak (scrambled face) image as context and subsequently made "Remember", "Know", or "New" judgements to words presented alone. In Experiment 1a, younger, but not older, adults showed higher recollection accuracy to words from rich- than from weak-context encoding trials. The age-related deficit in recollection occurred, in Experiment 1b, even when encoding and retrieval time was doubled in older adults, suggesting that insufficient processing time cannot account for this age-related deficit. In Experiment 1c, dividing attention in young, during encoding, reduced overall memory, though the recollection boost from rich encoding contexts remained, suggesting that reduced attention resources cannot explain this age-related deficit. Experiment 2 showed that an own-age bias, to face images as context, could not explain the age-related differences either. Results suggest that age deficits in recollection stem from a lack of spontaneous binding, or elaboration, of context to target information during encoding. PMID- 22512709 TI - Parents' views on how health professionals should work with them now to get the best for their child in the future. AB - BACKGROUND: Pregnancy and the first years of life are important times for future child well-being. Early identification of families and children who might be likely to experience poorer outcomes could enable health professionals and parents to work together to promote each child's well-being. Little is known about the acceptability and feasibility of such an approach to parents. OBJECTIVE: To investigate parents' views about how health professionals should identify and work with families who may benefit from additional input to maximize their children's future health and well-being. DESIGN: A qualitative study using focus groups. SETTING AND PARTICIPANTS: Eleven focus groups were conducted with a total of 54 parents; 42 mothers and 12 fathers living in the north of England. RESULTS: Parents welcomed the idea of preventive services. They strongly believed that everyone should have access to services to enhance child well-being whilst recognizing that some families need additional support. Making judgements about who should receive additional services based on specific criteria evoked powerful emotions because of the implication of failure. Parents projected a belief in themselves as 'good parents' even in adverse circumstances. CONCLUSIONS: Targeted additional preventive services can be acceptable and welcome if health professionals introduce them sensitively, in the context of an existing relationship, providing parents are active participants. PMID- 22512711 TI - Photoproduct channels from BrCD2CD2OH at 193 nm and the HDO + vinyl products from the CD2CD2OH radical intermediate. AB - We present the results of our product branching studies of the OH + C(2)D(4) reaction, beginning at the CD(2)CD(2)OH radical intermediate of the reaction, which is generated by the photodissociation of the precursor molecule BrCD(2)CD(2)OH at 193 nm. Using a crossed laser-molecular beam scattering apparatus with tunable photoionization detection, and a velocity map imaging apparatus with VUV photoionization, we detect the products of the major primary photodissociation channel (Br and CD(2)CD(2)OH), and of the secondary dissociation of vibrationally excited CD(2)CD(2)OH radicals (OH, C(2)D(4)/CD(2)O, C(2)D(3), CD(2)H, and CD(2)CDOH). We also characterize two additional photodissociation channels, which generate HBr + CD(2)CD(2)O and DBr + CD(2)CDOH, and measure the branching ratio between the C-Br bond fission, HBr elimination, and DBr elimination primary photodissociation channels as 0.99:0.0064:0.0046. The velocity distribution of the signal at m/e = 30 upon 10.5 eV photoionization allows us to identify the signal from the vinyl (C(2)D(3)) product, assigned to a frustrated dissociation toward OH + ethene followed by D-atom abstraction. The relative amount of vinyl and Br atom signal shows the quantum yield of this HDO + C(2)D(3) product channel is reduced by a factor of 0.77 +/- 0.33 from that measured for the undeuterated system. However, because the vibrational energy distribution of the deuterated radicals is lower than that of the undeuterated radicals, the observed reduction in the water + vinyl product quantum yield likely reflects the smaller fraction of radicals that dissociate in the deuterated system, not the effect of quantum tunneling. We compare these results to predictions from statistical transition state theory and prior classical trajectory calculations on the OH + ethene potential energy surface that evidenced a roaming channel to produce water + vinyl products and consider how the branching to the water + vinyl channel might be sensitive to the angular momentum of the beta-hydroxyethyl radicals. PMID- 22512712 TI - A case of color-taste synesthesia. AB - This is a report on a case of color-taste synesthesia exhibited by an artist painter. This case is unique in that it is not common for color to appear as an inducer or taste as a concurrent. A comprehensive description of this particular case of synesthesia is provided first. The application and results of consistency, psychophysical, and Stroop tests are presented later. Finally, the difficulties encountered with the application of such tests are discussed. PMID- 22512713 TI - Enhancement of the nanofibrillation of wood cellulose through sequential periodate-chlorite oxidation. AB - Sequential regioselective periodate-chlorite oxidation was employed as a new and efficient pretreatment to enhance the nanofibrillation of hardwood cellulose pulp through homogenization. The oxidized celluloses with carboxyl contents ranging from 0.38 to 1.75 mmol/g could nanofibrillate to highly viscous and transparent gels with yields of 100-85% without clogging the homogenizer (one to four passes). On the basis of field-emission scanning electron microscopy images, the nanofibrils obtained were of typical widths of approximately 25 +/- 6 nm. All of the nanofibrillar samples maintained their cellulose I crystalline structure according to wide-angle X-ray diffraction results, and the crystallinity index was approximately 40% for all samples. PMID- 22512714 TI - Readability of consumer health information on the internet: a comparison of U.S. government-funded and commercially funded websites. AB - The Internet has become an extremely prevalent means of communicating health information to consumers. Guidelines for selecting reliable health information websites give preference to U.S. government sites over commercially funded sites. However, these websites are not useful to consumers unless they are able to read and understand them. The authors' objective was to compare the readability of Internet health information intended for consumers found on U.S. government funded websites versus that found on commercially funded websites. Consumer health websites were identified through a systematic Internet search. Webpages for 10 common health topics were extracted from each website. Readability of webpages was determined by 3 validated measures: Flesch Reading Ease, Flesch Kincaid Reading Level, and SMOG Formula. Mean readability of government-funded and commercially funded websites was compared using the Mann-Whitney U test. Commercially funded websites were significantly more difficult to read as measured by Flesch Reading Ease (49.7 vs. 55.6 for government-funded sites, p = .002) and Flesch-Kincaid Reading Level (10.1 vs. 9.3, p = .012). There was no significant difference according to SMOG Formula (12.8 vs. 13.2, p = .150). The overall readability of Internet health information intended for consumers was poor. Efforts should be made to ensure that health information communicated via the Internet is easy for consumers to read and understand. PMID- 22512715 TI - A Bayesian analysis of gene flow from crops to their wild relatives: cultivated (Lactuca sativa L.) and prickly lettuce (L. serriola L.) and the recent expansion of L. serriola in Europe. AB - Interspecific gene flow can lead to the formation of hybrid populations that have a competitive advantage over the parental populations, even for hybrids from a cross between crops and wild relatives. Wild prickly lettuce (Lactuca serriola) has recently expanded in Europe and hybridization with the related crop species (cultivated lettuce, L. sativa) has been hypothesized as one of the mechanisms behind this expansion. In a basically selfing species, such as lettuce, assessing hybridization in natural populations may not be straightforward. Therefore, we analysed a uniquely large data set of plants genotyped with SSR (simple sequence repeat) markers with two programs for Bayesian population genetic analysis, STRUCTURE and NewHybrids. The data set comprised 7738 plants, including a complete genebank collection, which provided a wide coverage of cultivated germplasm and a fair coverage of wild accessions, and a set of wild populations recently sampled across Europe. STRUCTURE analysis inferred the occurrence of hybrids at a level of 7% across Europe. NewHybrids indicated these hybrids to be advanced selfed generations of a hybridization event or of one backcross after such an event, which is according to expectations for a basically selfing species. These advanced selfed generations could not be detected effectively with crop-specific alleles. In the northern part of Europe, where the expansion of L. serriola took place, the fewest putative hybrids were found. Therefore, we conclude that other mechanisms than crop/wild gene flow, such as an increase in disturbed habitats and/or climate warming, are more likely explanations for this expansion. PMID- 22512717 TI - Probing the bioactivity-relevant chemical space of robust reactions and common molecular building blocks. AB - In the search for new bioactive compounds, there is a trend toward increasingly complex compound libraries aiming to target the demanding targets of the future. In contrast, medicinal chemistry and traditional library design rely mainly on a small set of highly established and robust reactions. Here, we probe a set of 58 such reactions for their ability to sample the chemical space of known bioactive molecules, and the potential to create new scaffolds. Combined with ~26,000 common available building blocks, the reactions retrieve around 9% of a scaffold diverse set of compounds active on human target proteins covering all major pharmaceutical target classes. Almost 80% of generated scaffolds from virtual one step synthesis products are not present in a large set of known bioactive molecules for human targets, indicating potential for new discoveries. The results suggest that established synthesis resources are well suited to cover the known bioactivity-relevant chemical space and that there are plenty of unexplored regions accessible by these reactions, possibly providing valuable "low-hanging fruit" for hit discovery. PMID- 22512716 TI - Netrin-1-mediated axon guidance in mouse embryonic stem cells overexpressing neurogenin-1. AB - Stem cell therapy holds great promise for treating neurodegenerative disease, but major barriers to effective therapeutic strategies remain. A complete understanding of the derived phenotype is required for predicting cell response once introduced into the host tissue. We sought to identify major axonal guidance cues present in neurons derived from the transient overexpression of neurogenin-1 (Neurog1) in mouse embryonic stem cells (ESCs). Neurog1 upregulated the netrin-1 axon guidance receptors DCC (deleted in colorectal cancer) and neogenin (NEO1). Quantitative polymerase chain reaction results showed a 2-fold increase in NEO1 mRNA and a 36-fold increase in DCC mRNA in Neurog1-induced compared with control ESCs. Immunohistochemistry indicated that DCC was primarily expressed on cells positive for the neuronal marker TUJ1. DCC was preferentially localized to the cell soma and growth-cones of induced neurons. In contrast, NEO1 expression showed less specificity, labeling both TUJ1-positive and TUJ1-negative cells as well as uninduced control cells. Axonal outgrowth was directed preferentially toward aggregates of HEK293 cells secreting a recombinant active fragment of netrin-1. These data indicate that DCC and NEO1 are downstream products of Neurog1 and may guide the integration of Neurog1-induced ESCs with target cells secreting netrin-1. Differential expression profiles for netrin receptors could indicate different roles for this guidance cue on neuronal and non-neuronal cells. PMID- 22512718 TI - Plumbagin induces apoptosis in Her2-overexpressing breast cancer cells through the mitochondrial-mediated pathway. AB - Breast cancer is the leading cause of death-related cancers in women. Approximately 30% of breast cancers overexpress the Her2 oncogene, which is associated with a poor prognosis and increased resistance to chemotherapy. Plumbagin (1), a constituent of species in the plant genera Drosera and Plumbago, displays antineoplastic activity toward various cancers. The present study was aimed at determining the anticancer potential of 1 toward Her2-overexpressing breast cancer cells and defining the mode of cell death induced in these cells. The results showed that 1 exhibited high antiproliferative activity toward the Her2-overexpressing cell lines SKBR3 and BT474. The antiproliferative activity of 1 was associated with apoptosis-mediated cell death, as revealed by caspase activation and an increase in the sub-G1 fraction of the cell cycle. Compound 1 increased the levels of the proapoptotic Bcl-2 family of proteins and decreased the level of the antiapoptotic Bcl-2 protein in SKBR3 and BT474 cells. Thus, these findings indicate that 1 induces apoptosis in Her2-overexpressing breast cancers through the mitochondrial-mediated pathway and suggest its potential for further investigation for the treatment of Her2-overexpressing breast cancer. PMID- 22512719 TI - BAFF levels are increased in lesional skin and sera in patients with cutaneous T cell lymphoma. AB - BACKGROUND: B-cell-activating factor belonging to the tumour necrosis factor family (BAFF) is known for its role in the survival and maturation of B cells. It has been recently suggested that BAFF also plays important roles in T-cell activation in T-cell mediated diseases such as psoriasis. OBJECTIVES: To investigate the role of BAFF in cutaneous T-cell lymphoma (CTCL). METHODS: BAFF messenger RNA (mRNA) expression in skin samples (24 CTCL cases and seven healthy controls) and in skin-derived fibroblasts (five CTCL cases and five healthy controls) was examined by quantitative reverse transcription-polymerase chain reaction. We also performed immunohistochemical staining for BAFF and its receptors. Serum BAFF levels were measured in patients with CTCL (n=46), atopic dermatitis (n=36) or psoriasis (n=27) and 27 healthy controls by enzyme-linked immunosorbent assay. RESULTS: Lesional skin of CTCL contained higher levels of BAFF mRNA than normal skin and the expression levels correlated with disease activity. BAFF mRNA expression levels were elevated in fibroblasts from CTCL skin. Tumour cells in the lesional skin of CTCL expressed BAFF and its receptors, while fibroblasts expressed only BAFF. Serum BAFF levels of CTCL patients were significantly higher than those of healthy controls and correlated with types of skin lesions and clinical stages. They also significantly correlated with serum soluble interleukin-2 receptor and lactate dehydrogenase levels. CONCLUSIONS: BAFF expression in CTCL skin and serum BAFF levels are significantly increased and correlate with the severity of CTCL. These results suggest that BAFF may have important roles in the development of CTCL. PMID- 22512720 TI - Successful treatment of annular elastolytic giant cell granuloma with hydroxychloroquine. PMID- 22512721 TI - Secondary ions mass spectrometric signal enhancement of peptides on enlarged-gold nanoparticle surfaces. AB - A high surface coverage of gold nanoparticles (AuNPs) is a prerequisite for enhancing the peptide signal intensity in time-of-flight secondary ion mass spectrometry (TOF-SIMS). Here, we demonstrate the TOF-SIMS signal amplification of peptides on a surface by enlarging surface-confined AuNPs using the NH(2)OH/Au(3+) seeding method. Because of the increased surface area and spherical structure of the Au, the SIMS intensity of the peptides became significantly enhanced on the enlarged-AuNPs surface, especially at high concentrations of peptide solution (>10 MUM), compared to that of the bare gold surface or submonolyer of AuNPs. We are confident that this will be a useful method for diagnosis and bioassay with high sensitivity in a label-free manner. PMID- 22512722 TI - Carriage of methicillin-resistant Staphylococcus aureus on admission to European rehabilitation centres--a prospective study. AB - This study aimed to determine the prevalence of and risk factors for methicillin resistant Staphylococcus aureus (MRSA) carriage among patients newly admitted to rehabilitation centres. It is a prospective study examining MRSA carriage on admission to seven rehabilitation wards in four countries. Risk factors for MRSA carriage were analysed using univariate and multivariate analyses. A total of 1204 patients were studied. Among them, 105 (8.7%) had a positive admission MRSA screening result. The MRSA carriers were more likely to be male, to have had a recent stay in another long-term-care facility or >2 weeks acute-care hospital stay, history of colonization with MRSA, reduced level of consciousness, peripheral vascular disease and pressure sores. In multivariable logistic regression male gender (odds ratio (OR) 2.2, 95% confidence interval (CI) 1.4 3.6, p 0.001), history of MRSA positivity (OR 6.8, 95% CI 3.8-12.3, p <0.001), peripheral vascular disease (OR 2.5, 95% CI 1.2-5, p 0.013), recent stay in another long-term-care facility (OR 2.1, 95% CI 1.3-3.5, p 0.004), or long (>2 weeks) acute-care hospital stay (OR 1.9, 95% CI 1.2-3, p 0.004), remained significant risk factors for MRSA carriage. MRSA carriage is common on admission to rehabilitation centres but less so, than previously described in long-term care facilities. Male gender, history of MRSA positivity, previous hospitalization and peripheral vascular disease may predict MRSA carriage, and may serve as indicators for using pre-emptive infection control measures. PMID- 22512723 TI - A new depsidone of Lobaria pulmonaria with acetylcholinesterase inhibition activity. AB - The phytochemical investigation conducted on a foliose lichen, Lobaria pulmonaria(L.) Hoffm. (Lobariaceae), led to the isolation of a new depsidone in the form of its diacetate derivative which showed a moderate acetylcholinesterase inhibition activity (1 ug) in vitro. This is the first record of identified depsidone structure in searching for these inhibitors. PMID- 22512724 TI - Inhibitory effect of Terminalia chebula Retz. fruit extracts on digestive enzyme related to diabetes and oxidative stress. AB - Terminalia chebula fruit extracts were prepared sequentially with hexane, ethyl acetate, methanol and methanol-water (70:30) and tested for their alpha glucosidase inhibitory and antioxidant potential. The study resulted in the formulation of an extract with high alpha-glucosidase inhibitory potential (IC(50) 0.19 +/- 0.03 ug mL(-1)) enriched with hydrolysable tannins. Also, each of the extract was chemically characterized by reversed-phase high-performance liquid chromatography on the basis of their marker compounds chebulagic acid, chebulinic acid and corilagin in order to give explanation to the significant activity shown by the extracts. The antioxidant potential of the highly active extract was evaluated in the cellular level also using superoxide dismutase, glutathione S-transferase and induced oxidative stress assays. The results indicated the possibility of using the extract as a nutraceutical health supplement in the management of type 2 diabetes. PMID- 22512725 TI - Famotidine inhibits glycogen synthase kinase-3beta: an investigation by docking simulation and experimental validation. AB - Famotidine was investigated as an inhibitor of glycogen synthase kinase-3beta (GSK-3beta) in an attempt to explain the molecular mechanism of its hypoglycemic side effects. The investigation included simulated docking experiments, in vitro enzyme inhibition assay, glycogen sparing studies using animal models and single dose oral glucose tolerance test (OGTT). Docking studies showed how famotidine is optimally fit within the binding pocket of GSK-3beta via numerous attractive interactions with some specific amino acids. Experimentally, famotidine could inhibit GSK-3beta (IC50 = 1.44 MUM) and increased significantly liver glycogen spares in fasting animal models. Moreover, a single oral dose of famotidine was shown to decrease the glycemic response curve after 75 g OGTT. PMID- 22512726 TI - The effect of some antineoplastic agents on glutathione S-transferase from human erythrocytes. AB - Glutathione S-transferase was purified from human erythrocytes and effects of some antineoplastic agents were investigated on the enzyme activity. The purification procedure was composed of Glutathione-Agarose affinity chromatography after preparation of erythrocytes hemolysate. Using this procedure, the enzyme, having the specific activity of 16.00 EU/mg proteins, was purified 1143-fold with a yield of 80%. The purified enzyme showed a single band on the SDS-PAGE. The effects of paclitaxel, cyclophosphamide, and gemcitabine, are antineoplastic agents, were examined on the in vitro enzyme activity of glutathione S-transferase and were determined to be inhibitors for the enzyme. IC50 values were 0.23 mM for paclitaxel, 5.57 mm for cyclophosphamide, and 6.35 mM for gemcitabine. These constants were 0.182 +/- 0.028 mM and 0.162 +/- 0.062 mM for paclitaxel, 6.97 +/- 0.49 mM and 10.50 +/- 5.43 mM for cyclophosphamide, and 6.71 mM and 7.93 mM for gemcitabine, with GSH and CDNB substrates, respectively. Inhibition types of all inhibitors were noncompetitive. PMID- 22512727 TI - Synthesis and carbonic anhydrase inhibitory properties of novel coumarin derivatives. AB - A newly series of water-soluble 1-alkyl-3-(4-methyl-7, 8-dihydroxy-2H-chromen-2 one) benzimidazolium chloride salts (3a-j) were synthesized and their inhibitory effects on the activity of purified human carbonic anhydrase (hCA) I and II were evaluated. hCA I and II from human erythrocytes were purified by a simple one step procedure by using Sepharose 4B-L-tyrosine-sulphanilamide affinity column. The result showed that all the synthesized compounds were inhibited the CA isoenzymes activity. Among them, 3g and 3j were found to be most active (IC(50) = 22.09 uM and 20.33 uM) for hCA I and hCA II, respectively. PMID- 22512728 TI - Association of MBL2 polymorphism with asthma after bronchiolitis in infancy. AB - BACKGROUND: Mannose-binding lectin (MBL) is a component of innate immunity and has been linked with the pathogenesis of asthma. The aim of the present study was to evaluate the association of MBL genotypes with preschool asthma and allergy in children with bronchiolitis in early infancy. METHODS: In all, 205 infants were hospitalized for bronchiolitis at <6 months of age. Asthma and allergy were studied from a total of 166 children at 6.4 years (mean). A total of 141 (85%) frozen whole blood samples were available for MBL genotyping and MBL2 gene mutations were determined on pyrosequencing for detection of three single nucleotide polymorphisms. RESULTS: Ninety-five children (67.4%) had the wild-type MBL genotype A/A and 46 had A/O or O/O genotypes. Asthma was present in 16 children (11.3%) at 5-7 years of age. Nine children (19.6%) with non-AA genotype had asthma (vs 7.4% of those with genotype AA, P= 0.03). The result remained significant after adjustment for age, gender and atopy. There were no significant associations between MBL genotypes and asthma at any age before the study. Atopic dermatitis, allergic rhinitis or paternal and/or maternal asthma had no significant associations with MBL genotypes. CONCLUSIONS: The variant non-A/A MBL genotype is associated with asthma after bronchiolitis in infancy, but not earlier than at 5-7 years of age. PMID- 22512729 TI - Late onset of multiple myeloma in a patient with immunoglobulin A pemphigus. PMID- 22512730 TI - Predominance of Flavobacterium, Pseudomonas, and Polaromonas within the prokaryotic community of freshwater shallow lakes in the northern Victoria Land, East Antarctica. AB - A polyphasic approach that included PCR-dependent and PCR-independent molecular techniques was applied to analyze the prokaryotic community in surface waters of shallow Antarctic lakes. The in situ abundance of different bacterial groups was determined by the fluorescence in situ hybridization, whereas bacterial diversity was investigated by 16S rRNA gene sequencing of bacterial clones and isolates. The different approaches allowed the identification of the significant microbial components of the lake bacterioplanktonic communities, indicating a predominance of Flavobacterium, Pseudomonas, and Polaromonas (up to about 56% of total sequences). These genera also appear to be important in freshwater systems elsewhere in the world. Interestingly, closest blast matches to our sequences were predominantly from polar lakes and ponds, in addition to streams and glaciers, suggesting a bipolar distribution of freshwater lake bacterioplankton. Bacteria that are more traditionally associated with the marine environment were also detected, thus indicating an external input by atmospheric deposition and/or seabird excreta. Finally, a slightly different microbial community occurred in the lake at Inexpressible Island that was characterized by low N : P ratio and very high conductivity value, reinforcing the idea that physicochemical and trophic status may affect the structure and composition of the bacterioplankton assemblages in Antarctic lakes. PMID- 22512731 TI - Global patterns of the dynamics of soil carbon and nitrogen stocks following afforestation: a meta-analysis. AB - * Afforestation has been proposed as an effective method of carbon (C) sequestration; however, the magnitude and direction of soil carbon accumulation following afforestation and its regulation by soil nitrogen (N) dynamics are still not well understood. * We synthesized the results from 292 sites and carried out a meta-analysis to evaluate the dynamics of soil C and N stocks following afforestation. * Changes in soil C and N stocks were significantly correlated and had a similar temporal pattern. Significant C and N stock increases were found 30 and 50 yr after afforestation, respectively. Before these time points, C and N stocks were either depleted or unchanged. Carbon stock increased following afforestation on cropland and pasture, and in tropical, subtropical and boreal zones. The soil N stock increased in the subtropical zone. The soil C stock increased after afforestation with hardwoods such as Eucalyptus, but did not change after afforestation with softwoods such as pine. Soil N stocks increased and decreased, respectively, after afforestation with hardwoods (excluding Eucalyptus) and pine. * These results indicate that soil C and N stocks both increase with time after afforestation, and that C sequestration through afforestation depends on prior land use, climate and the tree species planted. PMID- 22512732 TI - Design and characterization of enteric-coated controlled release mucoadhesive microcapsules of Rabeprazole sodium. AB - The objectives of present work was to design and characterize the rabeprazole sodium loaded microcapsules prepared by solvent evaporation technique using ethyl cellulose (EC) based various mucoadhesive polymer, followed by a triple coating with Eudragit L100. The Box-behnken design (BBD) was applied for optimization of formulations containing EC, HPMCK100M and Eudragit L100 as factors for selected responses like entrapment efficiency, mucoadhesive property and drug release in 24 h. The prepared microcapsules were characterized for particle size, drug content, swelling index, mucoadhesive strength, and in vivo antiulcer activity. FT-IR studies revealed that there was no drug-polymer interaction. SEM studies revealed that microcapsules were non-aggregated, spherical shape and smooth appearance. In vitro drug release data from microcapsules was fitted to different kinetic models to explain release profiles. The correlation coefficient value (r(2)) indicated that the drug release followed Higuchi model. Analysis of variance (ANOVA) showed significant difference in the release of drug from all formulations at p < 0.05 level. Accelerated stability study of optimized formulation (F4) upto 6 months showed there was no change in drug content and release characteristics during storage. In vivo antiulcer activity showed that the optimized microcapsules were able to protect rat stomach against ulcer formation vis-a-vis aqueous solution of the drug showed only negligible and minimum effect. PMID- 22512733 TI - Emotional nouns affect attachment decisions in sentence completion tasks. AB - We report three sentence completion experiments in which we manipulate the emotional dimension of the nouns in a complex noun phrase (NP) that precedes a relative clause (RC), as in the classic ambiguity in Someone shot the servant of the actress who was on the balcony. The aim was to see whether nouns such as orgy or genocide affect the well-established preference of Spanish to adjoin the relative clause high in the tree (to servant instead of actress in the example above). We manipulated the valence and arousal of the lexical entities residing in the NP. Our results indicate that (a) the inclusion of either pleasant or unpleasant words induces changes in the usual NP1 preference found in Spanish; (b) the effects of high-arousal words are especially clear, in that they pull RC adjunction towards the NP where they are located, be it the NP1 or the NP2; and (c) in the context of sentence production, these kinds of words seem intense enough to promote changes in (and even reverse) a solid syntactic bias. We discuss these findings in the light of existing theories of syntactic ambiguity resolution. PMID- 22512734 TI - Citizens' participation in the Italian health-care system: the experience of the Mixed Advisory Committees. AB - BACKGROUND: In 1994, the region of Emilia-Romagna recognized the importance of citizens' participation in the regional health-care system and recommended the institution of Mixed Advisory Committees in the health districts and hospitals with the objective of monitoring and assessing health-care quality from the users' perspective. DESIGN: This paper reports findings from a qualitatively based evaluation involving direct observations of the committees and 39 semi structured interviews: 20 with representatives of patients and users' associations and 19 with health professionals and managers involved in the activities of the committees. RESULTS: The Mixed Advisory Committees introduced for the first time in the Italian health system an ongoing deliberative approach that gave patients and users' representatives the opportunity to be involved in health service governance. The committees enabled the creation of a method of collective participation that overcame the reductive individualistic 'approach' to health-care participation. MAC participants evaluated the committees positively for their mixed composition, which integrated different cultures, experiences and professional profiles with the potential to contribute to solving health-care problems, in a consultative role. Although patients and users' representatives were able to exert some form of influence, their expectations were greater than the results obtained. The study illuminated some weak points of public consultation, such as a decline in participation by citizen representatives and a weak influence on decision making. DISCUSSION AND CONCLUSIONS: MACs developed a mechanism of participation that provides health care users' representatives with the opportunity to contribute to the identification and analysis of critical points of the health-care system. A strength of the MACs is their level of institutionalization within the health system in the region of Emilia-Romagna. However, they contain a problem of representativeness, lacking a formal system of determining a representative composition from among patients and users' associations. The case study also illustrates that participation without the cooperation of the health service, and financial and organizational support, will result in a decline in citizen participation, given the resources required of these volunteer citizens in return for limited results. PMID- 22512735 TI - Divergent natural selection with gene flow along major environmental gradients in Amazonia: insights from genome scans, population genetics and phylogeography of the characin fish Triportheus albus. AB - The unparalleled diversity of tropical ecosystems like the Amazon Basin has been traditionally explained using spatial models within the context of climatic and geological history. Yet, it is adaptive genetic diversity that defines how species evolve and interact within an ecosystem. Here, we combine genome scans, population genetics and sequence-based phylogeographic analyses to examine spatial and ecological arrangements of selected and neutrally evolving regions of the genome of an Amazonian fish, Triportheus albus. Using a sampling design encompassing five major Amazonian rivers, three hydrochemical settings, 352 nuclear markers and two mitochondrial DNA genes, we assess the influence of environmental gradients as biodiversity drivers in Amazonia. We identify strong divergent natural selection with gene flow and isolation by environment across craton (black and clear colour)- and Andean (white colour)-derived water types. Furthermore, we find that heightened selection and population genetic structure present at the interface of these water types appears more powerful in generating diversity than the spatial arrangement of river systems and vicariant biogeographic history. The results from our study challenge assumptions about the origin and distribution of adaptive and neutral genetic diversity in tropical ecosystems. In addition, they have important implications for measures of biodiversity and evolutionary potential in one of the world's most diverse and iconic ecosystems. PMID- 22512737 TI - NADINE: new approaches to detecting breast cancer by sequential MUm-wavelength imaging with the aid of novel frequency analysis techniques. AB - The study focuses on 12 breasts of six breast cancer patients sequential um wavelength imaging, taken by two different 3-5 MUm wavelength area indium antimony (InSb) photovoltaic cameras. The aim of the study was to compare the functionality of area and pixel-based frequency analyses. Comparisons between these frequency analysis methods were made according to their relevancy to mammographic findings. Another objective of the study was to find reliable imaging conditions by specifying the border conditions for the patient stabilizing imaging bed and managing the imaging situation. According to the results, the match of pixel based frequency analysis to the mammography findings is better than using area frequency analysis. The results also indicate that when the optical axis of the camera in relation to the surface of the breast to be imaged grows to more than 40 degrees , the emissivity changes dramatically and at that point reliable results will not be obtained. Consequently the analysis of the imagined breast requires more images to be fused into one analysis image to cover the whole breast. PMID- 22512736 TI - Cellular aspects of the distinct M protein and SfbI anchoring pathways in Streptococcus pyogenes. AB - Wall-anchored surface proteins are critical for the in vivo survival of Streptococcus pyogenes. Cues in the signal sequence direct the membrane translocation of surface proteins: M protein to the septum, and SfbI to the poles. Both proteins are subsequently anchored to the wall by the membrane bound enzyme sortase A. However, the cellular features of these pathways are not fully understood. Here we show that M protein and SfbI are anchored simultaneously throughout the cell cycle. M protein is rapidly anchored at the septum, and in part of the cell cycle, is anchored simultaneously at the mother and daughter septa. Conversely, SfbI accumulates gradually on peripheral peptidoglycan, resulting in a polar distribution. Sortase is not required for translocation of M protein or SfbI at their respective locations. Methicillin-induced unbalanced peptidoglycan synthesis diminishes surface M protein but not SfbI. Furthermore, overexpression of the division regulator DivIVA also diminishes surface M protein but increases SfbI. These results demonstrate a close connection between the regulation of cell division and protein anchoring. Better understanding of the spatial regulation of surface anchoring may lead to the identification of novel targets for the development of anti-infective agents, given the importance of surface molecules for pathogenesis. PMID- 22512738 TI - Isoprenylated flavonoid and adipogenesis-promoting constituents of Dodonaea viscosa. AB - Ten new isoprenylated flavonol derivatives, dodoviscins A-J (1-10), and seven known compounds (11-17) were isolated from the aerial parts of Dodonaea viscosa. Compounds 1, 2, 4, 5, 7-9, 5,7,4'-trihydroxy-3',5'-bis(3-methyl-2-buten-1-yl)-3 methoxyflavone (11), 5,7,4'-trihydroxy-3',5'-bis(3-methyl-2-buten-1-yl)-3,6 dimethoxyflavone (12), 5,7,4'-trihydroxy-3'-(4-hydroxy-3-methylbutyl)-5'-(3 methyl-2-buten-1-yl)-3,6-dimethyoxyflavone (13), sakuranetin (14), and blumeatin (15) promoted adipocyte differentiation as characterized by increased triglyceride levels in 3T3L1 cells. Compounds 1, 13, and 15 also enhanced the accumulation of lipid droplets and induced upregulation of the expression of the adipocyte-specific genes aP2 and GLUT4. PMID- 22512739 TI - High incidence of Campylobacter concisus in gastroenteritis in North Jutland, Denmark: a population-based study. AB - The incidence of non-thermophilic Campylobacter species was assessed in an unselected population-based study in a mixed urban and rural community in North Jutland, Denmark. In a 2-year study period, 11,314 faecal samples from 8302 patients with gastroenteritis were cultured with supplement of the filter method. We recovered a high incidence of Campylobacter concisus (annual incidence 35/100,000 inhabitants), almost as high as the common Campylobacter jejuni/coli. In contrast, there was a very low incidence of other non-thermophilic Campylobacter species, such as Campylobacter upsaliensis. Campylobacter concisus was, unlike C. jejuni/coli, found more frequently among small children (<1 year) and the elderly (>= 65 years). Around 10% of the patients with C. consisus had co infections dominated by Clostridium difficile and Salmonella enterica, whereas co infections occurred in about 5% of C. jejuni/coli patients. We observed a seasonal variation in C. jejuni/coli with a peak incidence in late summer months and autumn, whereas there was an almost constant monthly prevalence of C. concisus. Among patients participating in a questionnaire sub-study, there was a higher degree of close contacts with animals, especially dogs, as well as a higher travel exposure among C. jejuni/coli patients compared with C. concisus patients. We did not culture any C. concisus in stool samples from a small cohort of healthy individuals. Future studies have to focus on the clinical follow-up and the long-term risk of inflammatory bowel diseases in C. concisus-positive patients. We conclude that there is a high incidence of C. concisus in Denmark. PMID- 22512740 TI - Rapid wound healing of scalp wounds devoid of periosteum with milling of the outer table and split-thickness skin grafting. AB - BACKGROUND: Excision of large scalp tumours may result in exposed bone devoid of periosteum. The resultant surgical defects may be too large to close by either primary closure or local cutaneous flap. The denuded bone usually precludes the immediate placement of a skin graft. OBJECTIVES: To describe our experience with milling the outer cortical table of the skull in order to promote granulation and hasten wound healing. METHODS: In 11 patients, we expanded existing techniques of exposing diploic veins in the cancellous bone by completely milling the exposed outer table of the scalp bone with a rose head burr driven by a pneumatic power drill. After induction of punctate bleeding a split-skin graft was placed in the same session and secured with a tie-over foam dressing. Dressing was removed 7 days after surgery. All patients received perioperative antibiotics. Informed consent was obtained prior to the procedure. RESULTS: In all 11 patients a healing of the split-thickness skin graft was observed within 1 week. CONCLUSIONS: The combination of extensive exposure of cancellous bone and an immediate split-thickness skin graft reduces convalescence time from multiple weeks to 7 days. This is beneficial in older patients sparing them from frequent visits to the doctor. Furthermore, early closure may reduce the risk of infection. PMID- 22512741 TI - Psychiatric polypharmacy: a clinical approach based on etiology and differential diagnosis. AB - Polypharmacy is common clinical practice in the United States for many psychiatric conditions and for many reasons. In this article we encourage clinicians to use the familiar practice of differential diagnosis to systematically identify etiological factors contributing to polypharmacy. We offer a clinical approach based on (1) reviewing the four main factors responsible for polypharmacy (the disease, the patient, the physician, and society) and (2) answering two questions about optimizing medication regimens (What can I do without explicit permission from the patient or others? What can I do with permission from them?). We contend that all physicians share a professional responsibility for prescribing medications judiciously because unnecessary prescribing exposes patients to unwarranted risks and squanders valuable and scarce resources. Psychiatrists can ask themselves a Kantian question: would my way of prescribing lead to good, socially acceptable outcomes if followed by all physicians treating similar patients? PMID- 22512742 TI - "Sexting" among U.S. adolescents: psychological and legal perspectives. AB - This article will discuss the phenomenon of "sexting" (i.e., the exchange of sexually explicit images between adolescents via cell phone) in the United States, with a particular focus on clinical and legal implications. Although sexting is frequently discussed in the popular press, there is virtually no scientific literature available on this topic. In contrast, the legal literature has discussed sexting more comprehensively due to the implications of child pornography statutes for the social response to involved youth. This article will consider sexting from a clinical and legal perspective, and recommend ways to understand and address this practice clinically with adolescent patients. PMID- 22512743 TI - Intensive short-term dynamic psychotherapy: a systematic review and meta-analysis of outcome research. AB - Habib Davanloo has spent his career developing and teaching methods to accelerate dynamic psychotherapy, including his technique of intensive short-term dynamic psychotherapy (ISTDP). Over the past 20 years, outcome studies using this treatment have been conducted and published. We performed a systematic review of the literature to obtain studies presenting ISTDP outcome data. We found 21 studies (10 controlled, and 11 uncontrolled) reporting the effects of ISTDP in patients with mood, anxiety, personality, and somatic disorders. Using the random effects model, we performed meta-analyses including 13 of these studies and found pre- to post-treatment effect sizes (Cohen's d) ranging from 0.84 (interpersonal problems) to 1.51 (depression). Post-treatment to follow-up effect sizes suggested that these gains were maintained at follow-up. Based on post-treatment effect sizes, ISTDP was significantly more efficacious than control conditions (d = 1.18; general psychopathology measures). Study quality was highly variable, and there was significant heterogeneity in some analyses. Eight studies using various measures suggested ISTDP was cost-effective. Within limitations of study methodologies, this evidence supports the application of ISTDP across a broad range of populations. Further rigorous and targeted research into this method is warranted. PMID- 22512744 TI - "Something is better than nothing": psychotherapy with an older woman. PMID- 22512745 TI - Major health-care providers and the 10 leading reasons for adolescent ambulatory visits. AB - BACKGROUND: Epidemiological research underpins the importance of effective health care strategies for adolescents. This descriptive study compares the 10 most common diseases among Taiwanese adolescents for 2000 and 2009. METHODS: Data for a total of 69,594 visits in 2000 and 65,802 visits in 2009 by adolescents aged between 10 and 20 years were collected from the National Health Insurance Research Database. A maximum of three outpatient diagnostic codes (International Classification of Disease, ninth revision) could be listed for every visit. The data categories were: principal diagnosis, patient age, and physician specialty. RESULTS: The middle adolescent age group utilized the least amount of medical services. Respiratory (46.2% in 2000, 40.5% in 2009) and digestive (16.5% in 2000 and 16.9% in 2009) tracts were the leading two diagnostic categories for adolescent ambulatory visits. Teeth (6.8%, 6.1%) and eye (4.0%, 3.1%) problems were also among the top 10 diseases. Family practitioners, ear-nose-throat specialists, and traditional Chinese medicine physicians were the major health care providers for Taiwanese adolescents, especially in the middle and late groups. Although noted as the first option for consultation in the early group, the role of pediatricians with regard to adolescent health care declined in importance with age. CONCLUSIONS: Nearly 99% of the population in Taiwan is covered under the national health insurance system. The different disease patterns and major health-care providers between Taiwan and other countries are compared. PMID- 22512746 TI - Informed choice in bowel cancer screening: a qualitative study to explore how adults with lower education use decision aids. AB - BACKGROUND: Offering informed choice in screening is increasingly advocated, but little is known about how evidence-based information about the benefits and harms of screening influences understanding and participation in screening. OBJECTIVE: We aimed to explore how a bowel cancer screening decision aid influenced decision making and screening behaviour among adults with lower education and literacy. METHODS: Twenty-one men and women aged 55-64 years with lower education levels were interviewed about using a decision aid to make their screening decision. Participants were purposively selected to include those who had and had not made an informed choice. RESULTS: Understanding the purpose of the decision aid was an important factor in whether participants made an informed choice about screening. Participants varied in how they understood and integrated quantitative risk information about the benefits and harms of screening into their decision making; some read it carefully and used it to justify their screening decision, whereas others dismissed it because they were sceptical of it or lacked confidence in their own numeracy ability. Participants' prior knowledge and beliefs about screening influenced how they made sense of the information. DISCUSSION AND CONCLUSIONS: Participants valued information that offered them a choice in a non directive way, but were concerned that it would deter people from screening. Healthcare providers need to be aware that people respond to screening information in diverse ways involving a range of literacy skills and cognitive processes. PMID- 22512747 TI - Choice of therapeutic strategies in the context of HIV infection: key role of patient-reported outcomes. PMID- 22512748 TI - Coadministration of probiotics with antibiotics: why, when and for how long? PMID- 22512749 TI - Could CCR5 be a potential target against infections? PMID- 22512751 TI - Emerging fungal infections. AB - Trends in Medical Mycology is one of the most attractive international meetings completely dedicated to clinical and fundamental research in the field of medical mycology. It is organized by the European Confederation of Medical Mycology and the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer. Approximately 1500 participants, mainly microbiologists, clinicians and basic researchers, from more than 40 countries exchanged the most important advances in mycology from basic science to clinical research. A quick focus on some relevant clinical presentations is presented here. PMID- 22512752 TI - Norovirus diagnostics: options, applications and interpretations. AB - Noroviruses are a frequent cause of both acute gastroenteritis and outbreaks of gastroenteritis. Infection is usually self-limiting although it has been associated with mortality in children in the developing world and in vulnerable groups such as immunodeficient or immunosuppressed and elderly patients elsewhere. Diagnostic tests may be useful in preventing or limiting the spread and duration of outbreaks, and are needed to define norovirus-associated morbidity and mortality. However, the interpretation of test results should take account of the limitations of the different tests currently available. Therefore, the clinical, immunological and molecular tests available for norovirus detection have been reviewed. Early recognition of cases (clinical diagnoses) together with confirmation by sensitive and specific laboratory tests may contribute to reducing the spread of norovirus within hospitals. Syndromic testing that includes multiple or multiplex assays for the detection of viral, bacterial and parasitic pathogens with the inclusion of control groups are likely to better define norovirus-associated morbidity and mortality in low- and middle-income countries. PMID- 22512754 TI - Benchmarking antimicrobial drug use in hospitals. AB - Measuring and monitoring antibiotic use in hospitals is believed to be an important component of the strategies available to antimicrobial stewardship programs to address acquired antimicrobial resistance. Recent efforts to organize large numbers of hospitals into networks allow for interhospital comparisons of a variety of healthcare processes and outcomes, a process often called 'benchmarking'. For comparisons of antimicrobial use to be valid, usage figures must be risk-adjusted to account for differences in patient mix and hospital characteristics. The purpose of this review is to describe recent methods to benchmark antimicrobial drug use and to critically assess the potential advantages and the remaining challenges. While many methodological challenges remain, and the clinical outcomes resulting from benchmarking programs have yet to be determined, recent developments suggest that benchmarking antimicrobial drug use will become an important component of antimicrobial stewardship program activities. PMID- 22512753 TI - Immune responses to cholera in children. AB - Cholera is a severe acute dehydrating diarrheal disease caused by Vibrio cholerae O1 or O139 infection, and is associated with significant mortality and morbidity globally. Although young children bear a high burden of the disease, currently available oral vaccines give a lower efficacy and shorter duration of protection in this group than in adults. According to the studies of natural infection, young children achieve comparable systemic anti-V. cholerae antigen-specific antibody, gut-homing antibody-secreting cell and memory B-cell responses as adults. Studies on innate and cell-mediated immune responses are lacking in children, and may offer important insights into differences in vaccine efficacy. The impact of host factors such as malnutrition, genetics and coinfection with other pathogens also remains to be fully defined. PMID- 22512756 TI - Cutaneous adverse drug reactions to anti-tuberculosis drugs: state of the art and into the future. AB - First- and second-line anti-tuberculosis drugs are associated with a diverse presentation of cutaneous adverse drug reactions (CADR), ranging from mild to life threatening. An individual drug can cause multiple types of CADR, and a specific type of CADR can be due to any anti-tuberculosis drug, which can make the management of tuberculosis (TB) following CADR challenging. The higher incidence of TB and CADR in HIV-infected persons makes TB-associated CADR a burgeoning problem for clinicians, particularly in high HIV-prevalence settings. This review discusses the pathogenesis, epidemiology, clinical presentation, diagnosis and management of TB-associated CADR. Clinical controversies including its impact on treatment outcomes, challenges in restarting optimal anti tuberculosis therapy and the timing of highly active antiretroviral therapy initiation in those with HIV coinfection are also discussed. Finally, gaps in the current knowledge of TB-associated CADR have been identified and a research agenda has been proposed. PMID- 22512755 TI - Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. AB - Plazomicin (formerly ACHN-490) is a next-generation aminoglycoside that was synthetically derived from sisomicin by appending a hydroxy-aminobutyric acid substituent at position 1 and a hydroxyethyl substituent at position 6'. Plazomicin inhibits bacterial protein synthesis and exhibits dose-dependent bactericidal activity. Plazomicin demonstrates activity against both Gram negative and Gram-positive bacterial pathogens, including isolates harboring any of the clinically relevant aminoglycoside-modifying enzymes. However, like older parenteral aminoglycosides, plazomicin is not active against bacterial isolates expressing ribosomal methyltransferases conferring aminoglycoside resistance. Plazomicin has been reported to demonstrate in vitro synergistic activity when combined with daptomycin or ceftobiprole versus methicillin-resistant Staphylococcus aureus, heteroresistant vancomycin-intermediate S. aureus, vancomycin-intermediate S. aureus, and vancomycin-resistant S. aureus and against Pseudomonas aeruginosa when combined with cefepime, doripenem, imipenem or piperacillin-tazobactam. After intravenous administration of plazomicin to humans at a dose of 15 mg/ kg, the maximum concentraration was 113 MUg/ml, the area under the curve(0-24) was 239 h.MUg/ml, the half-life was 4.0 h and the steady state volume of distribution was 0.24 L/kg. Results from a Phase II randomized, double-blind study in patients with complicated urinary tract infection and acute pyelonephritis including cases with concurrent bacteremia comparing plazomicin 15 mg/kg intravenously once daily for 5 days with levofloxacin 750 mg intravenously. for 5 days are anticipated in 2012. Human studies to date have not reported nephrotoxicity or ototoxicity, and lack of ototoxicity has been reported in the guinea pig model. Given reported increases in bacterial resistance to current antimicrobial agents and the lack of availability of new agents with novel mechanisms, plazomicin may become a welcomed addition to the antibacterial armamentarium pending positive results from large-scale clinical trials and other required clinical studies. PMID- 22512757 TI - Recent perspectives in the diagnosis and evidence-based treatment of Mycoplasma genitalium. AB - Mycoplasma genitalium is a globally important sexually transmitted pathogen. Men infected with M. genitalium frequently present with dysuria, while women may present with or without urogenital symptoms. In some populations, M. genitalium is significantly associated with HIV-1 infection, and is also an etiological agent in pelvic inflammatory disease. However, there is insufficient evidence to establish a causative role of the organism in obstetric complications, including tubal factor infertility. Although several nucleic acid amplification tests offer rapid, sensitive methods for detecting M. genitalium, there is no standardized assay. Available evidence supports treatment of M. genitalium infections with an extended regimen of azithromycin and resistant strains respond to moxifloxacin. Accumulating evidence indicates growing fluoroquinolone resistance, including against moxifloxacin, emphasizing the need for new therapeutic strategies to treat M. genitalium infections. PMID- 22512758 TI - Appropriate use of echocardiography in managing Staphylococcus aureus bacteremia. AB - Staphylococcus aureus bacteremia (SAB) is increasing, both in the community and in healthcare settings. Accurate and timely diagnosis of underlying infective endocarditis (IE) is critical for optimal management of SAB cases as it has significant management and prognostic implications. Reported prevalence of IE in patients with SAB varies depending on the study population, and ranges from 10 to 30%. As clinical presentation of IE can be nonspecific, echocardiography is usually recommended in SAB cases to 'rule out' IE. Due to its poor sensitivity (<50%), especially for diagnosing prosthetic valve IE, transthoracic echocardiography is considered inadequate in this setting and clinicians have to rely on transesophageal echocardiography (TEE) to confirm or exclude endocarditis in SAB cases. Although some experts recommend TEE in all patients presenting with SAB, it is believed that the use of TEE could be guided by individual patient risk factors, mode of acquisition of SAB and clinical presentation. In this article, published data regarding the use of TEE in the SAB population are reviewed and a simplified algorithm to guide use of TEE in SAB cases is proposed. PMID- 22512759 TI - Identification and treatment of infected total hip arthroplasty. AB - Periprosthetic joint infection (PJI) in the hip following prosthetic joint placement is a devastating outcome of an otherwise often successful surgical treatment (total-hip arthroplasty). Management of PJI is dependent upon accurate diagnosis and successful treatment, both of which are challenging. Recently, great strides have been made in improving the diagnosis of PJI, which has no 'gold standard' diagnostic tool. Proper diagnosis is essential as untreated or undetected PJI can quickly lead to biofilm formation on the implant surface depending upon the infecting organism. Upon complete biofilm formation, successful treatment requires prosthetic resection with immediate or delayed reimplantation. Even with the most aggressive surgical treatment, PJI eradication currently has a success rate of approximately 80%. Unfortunately, technologies to improve the local delivery of antibiotics are not expected to be available in the near future. PMID- 22512761 TI - Statins in dermatology: is nonmelanoma skin cancer the dark side of the moon? PMID- 22512763 TI - A pragmatic trial in the Rio de Janeiro subway to capture smokers for a quitline: methodological challenges and opportunities. AB - According to the World Health Organization, smoking is an important cause of death worldwide. To encourage smoking cessation, persuasive messages can be used to raise smokers' risk perception. This article discusses challenges and solutions in designing a study to evaluate the effect of two different communication strategies ("gains from quitting" vs. "losses from continuing smoking") in encouraging calls to a quitline. The authors conducted an intervention study in two subway stations for 4 weeks, considering only 1 strategy per station. Large posters containing non-age-specific images and texts, on the basis of the theme"shortness of breath," were displayed on central dividing columns on the boarding platforms. Call rates from the selected stations, and respective rate ratios, overall and per study week, were calculated. Passengers who were smokers, exposed to the positive-content message, called on average 1.7 times more often than did those exposed to the negative content message (p = .01). Moreover, call rate ratios did not decline over the 4 weeks of the study (p = .40). The effectiveness findings suggest that antismoking campaigns could use positive-content messages in order to recruit a larger smoker population. The proposed methodology can also be used to evaluate effectiveness of messages for "capturing" individuals with other health problems (e.g., alcohol abuse), thereby increasing its potential impact. PMID- 22512762 TI - asb11 is a regulator of embryonic and adult regenerative myogenesis. AB - The specific molecular determinants that govern progenitor expansion and final compartment size in the myogenic lineage, either during gestation or during regenerative myogenesis, remain largely obscure. Recently, we retrieved d-asb11 from a zebrafish screen designed to identify gene products that are downregulated during embryogenesis upon terminal differentiation and identified it as a potential regulator of compartment size in the ectodermal lineage. A role in mesodermal derivatives remained, however, unexplored. Here we report pan vertebrate expression of Asb11 in muscle compartments, where it highly specifically localizes to the Pax7(+) muscle satellite cell compartment. Forced expression of d-asb11 impaired terminal differentiation and caused enhanced proliferation in the myogenic progenitor compartment both in in vivo and in vitro model systems. Conversely, introduction of a germline hypomorphic mutation in the zebrafish d-asb11 gene produced premature differentiation of the muscle progenitors and delayed regenerative responses in adult injured muscle. Thus, the expression of d-asb11 is necessary for muscle progenitor expansion, whereas its downregulation marks the onset of terminal differentiation. Hence, we provide evidence that d-asb11 is a principal regulator of embryonic as well as adult regenerative myogenesis. PMID- 22512764 TI - There, their, and they're; its and it's; principle and principal; lead and led: common "typos" that confuse us all. PMID- 22512765 TI - Caring theory and practice--entering a simultaneous concept analysis. AB - PROBLEM: To better understand the approach of caring in nursing and the role of theory in practice, we wanted to consolidate the caring theory of Watson with the empirical findings from the three studies performed to reveal nurses' caring intentions and their lived experience of reflecting caring theory in practice. METHOD: Through a simultaneous concept analysis of nine concepts, caring science theory was consolidated with the findings of the three empirical studies to reveal the dynamics of caring theory and caring practice. FINDINGS AND CONCLUSION: These nine concepts were found to be interrelated with the advanced concept of mediating care, which emphasizes that mediating care calls for an authenticity of being and ability--an ability to be present to self and others in the dynamism of openness and frames of thought. PMID- 22512766 TI - From documentation to the problem: controlling postoperative pain. AB - PROBLEM: Adequate pain control continues to be an enigma in the face of the Joint Commission (TJC) well-intended pain management standards. Notable in the pain standards is the mandate to make pain the fifth vital sign to increase pain visibility and awareness. METHOD: The following databases were searched: EBSCOHost, CINHAL, PubMed Central, Medline, and government/societies sites for guidelines on pain control. Various search terms used included pain, post operative pain, pain control, pain as the 5th vital sign, pain documentation, pain assessment, Joint Commission Pain Standard, PRN effectiveness, and pay-for performance. FINDINGS: Accredited facilities are mandated to have plans to assess for pain and evaluate pain management effectiveness. These mandates have necessitated a flurry of initiatives and programs by hospitals and healthcare facilities focusing on documentation processes to meet TJC compliance. Notable programs include Pain as the 5th Vital Sign and PRN (as needed) effectiveness documentation. Many facilities have programs to assess and document pain but lack programs that effectively control patient's pain. CONCLUSION: This article is a call for facilities to refocus on pain control. A need to evaluate current programs by facilities is evident. Studies show that Pain as the 5(th) Vital Sign and PRN effectiveness documentation are not effective and invariably have not met the goals of TJC pain standard--adequate and effective pain control. PMID- 22512767 TI - Concept analysis: awareness of discrimination based on genetic information. AB - PROBLEM: All nurses have the responsibility to deliver nondiscriminatory genetic health care. Patients perceive discriminatory nursing practices when they are being treated differently and unfairly. Nurses are expected to integrate genetic information about their patients into their clinical decision making. Thus, it is both timely and imperative that nurses have an operational definition of the concept "awareness of discrimination based on genetic information." METHOD: An operational definition of the concept was derived and Wilson's method of concept analysis was utilized to show how the operational definition may be applied in three different case models. FINDINGS: Awareness of discrimination based on genetic information can be operationally defined as "to know differences against people or distinguish between people based on the ancestral, heritable, communicated facts or knowledge". CONCLUSION: This concept analysis of words and terms used in genetic health care may serve as a framework for further genetic/genomics healthcare concepts under exploration. PMID- 22512768 TI - Prevention and management of "do not return" notices: a quality improvement process for supplemental staffing nursing agencies. AB - This article describes a quality improvement process for "do not return" (DNR) notices for healthcare supplemental staffing agencies and healthcare facilities that use them. It is imperative that supplemental staffing agencies partner with healthcare facilities in assuring the quality of supplemental staff. Although supplemental staffing agencies attempt to ensure quality staffing, supplemental staff are sometimes subjectively evaluated by healthcare facilities as "DNR." The objective of this article is to describe a quality improvement process to prevent and manage "DNR" within healthcare organizations. We developed a curriculum and accompanying evaluation tool by adapting Rampersad's problem-solving discipline approach: (a) definition of area(s) for improvement; (b) identification of all possible causes; (c) development of an action plan; (d) implementation of the action plan; (e) evaluation for program improvement; and (f) standardization of the process. Face and content validity of the evaluation tool was ascertained by input from a panel of experienced supplemental staff and nursing faculty. This curriculum and its evaluation tool will have practical implications for supplemental staffing agencies and healthcare facilities in reducing "DNR" rates and in meeting certification/accreditation requirements. Further work is needed to translate this process into future research. PMID- 22512769 TI - An exploratory study about meaningful work in acute care nursing. AB - OBJECTIVE: To develop deeper understandings about nurses' perceptions of meaningful work and the contextual factors that impact finding meaning in work. BACKGROUND: Much has been written about nurses' job satisfaction and the impact on quality of health care. However, scant qualitative evidence exists regarding nurses' perceptions of meaningful work and how factors in the work environment influence their perceptions. The literature reveals links among work satisfaction, retention, quality of care, and meaningfulness in work. METHODS: Using a narrative design, researchers interviewed 13 public health nurses and 13 acute care nurses. Categorical-content analysis with Atlas.ti data management software was conducted separately for each group of nurses. This article reports results for acute care nurses. RESULTS: Twenty-four stories of meaningful moments were analyzed and categorized. Three primary themes of meaningful work emerged: connections, contributions, and recognition. Participants described learning focused environment, teamwork, constructive management, and time with patients as facilitators of meaningfulness and task-focused environment, stressful relationships, and divisive management as barriers. Meaningful nursing roles were advocate, catalyst and guide, and caring presence. CONCLUSIONS: Nurse administrators are the key to improving quality of care by nurturing opportunities for nurses to find meaning and satisfaction in their work. Study findings provide nurse leaders with new avenues for improving work environments and job satisfaction to potentially enhance healthcare outcomes. PMID- 22512770 TI - Heterosexism and health care: a concept analysis. AB - BACKGROUND: The concept of heterosexism is used in a variety of ways in healthcare literature. The lack of consensus of the term makes identifying when and how it impacts the health care of lesbian, gay, and bisexual people difficult. A lack of clarity of the concept could also hinder effectiveness of education, awareness, and research tool development efforts. PURPOSE: The purpose of this concept analysis is to offer a synthesized definition of the term heterosexism, including its relation to and distinction from related concepts like homophobia and heteronormativity. METHODS: The authors use Walker and Avant's eight-step concept analysis method: select a concept, determine the aim of analysis, identify all uses of the concept, determine defining attributes, construct a model case, construct additional cases, identify antecedents and consequences, and define empirical referents. CONCLUSION: The results of the analysis reveal focus areas for future research, tool development, and suggestions for improvements in nursing clinical practice. PMID- 22512771 TI - Elders adapting to a chronic diagnosis within a nursing refuge. AB - PROBLEM: The increasing numbers of people seeking care for chronic disease has placed unparalleled demands on nurses who journey with them as they grasp the meaning of their altered health status. The complexity of the newly diagnosed chronic disease can be overwhelming. Newly diagnosed elder patients need a refuge in which to explore the uncertainties and challenges in managing a chronic illness. Reactions to a new diagnosis are uniquely shaped by the elder person's culture, age, life circumstances, and previous coping strategies. Six dichotomous response pairs are posed: relief versus devastation, courage versus cowardice, disease obsession versus disease aversion, rational thinking versus intuition, reawakening versus stuck, and self-reliance versus dependence. Nurses can create a sanctuary for elderly patients with protected space, presence, partnership, past to future orientation, and perspective on life. Nurses who embrace this mission may find themselves returning to the reasons they sought a nursing career, to support and strengthen elderly people in the most vulnerable moments of their lives. PMID- 22512772 TI - From primary progressive aphasia to corticobasal syndrome: two clinical and rCBF functional reports. AB - We describe two cases, both presenting with a 2-year history of isolated language disorders, one compatible with logopenic variant and the other with non-fluent variant of primary progressive aphasia (PPA). Afterwards, each developed a corticobasal syndrome (CBS) with alien limb phenomenon and a multi-domain cognitive impairment. Regional cerebral perfusion (rCBF) study using 99mTc-ECD single photon emission computed tomography (SPECT) revealed hypoperfusion patterns consistent with these aphasia types and with the presence of limb apraxia. We report two cases of PPA variants associated with CBS and we suggest that SPECT rCBF correlates can be useful in making a differential diagnosis within the PPA spectrum. PMID- 22512773 TI - Matching cavities in g protein-coupled receptors to infer ligand-binding sites. AB - To understand the activity and cross reactivity of ligands and G protein-coupled receptors, we take stock of relevant existing receptor mutation, sequence, and structural data to develop a statistically robust and transparent scoring system. Our method evaluates the viability of binding of any ligand for any GPCR sequence of amino acids. This enabled us to explore the binding repertoire of both receptors and ligands, relying solely on correlations between carefully identified receptor features and without requiring any chemical information about ligands. This study suggests that sequence similarity at specific binding pockets can predict relative affinity of ligands; enabling recovery of over 80% of known ligands for a withheld receptor and almost 80% of known receptors for a ligand. The method enables qualitative prediction of ligand binding for all nonredundant human G protein-coupled receptors. PMID- 22512774 TI - What is driving people's dissatisfaction with their own health care in 17 Latin American countries? AB - BACKGROUND: A number of expert reports have pointed to serious problems with health care in many Latin American countries and argued the need to reform and improve health-care systems. In addition, the Ministers of Health of the Americas have stated that health systems should be accountable to citizens. OBJECTIVE: This paper examines, in each of 17 Latin American countries, public dissatisfaction with the health care to which people have access, the proportion of people reporting problems with access to and the cost of health care and the factors that are most important in driving public dissatisfaction. METHODS: Data are drawn from a 2007 Latinobarometro survey of 19 212 adults interviewed face-to face in 17 Latin American countries. RESULTS: The proportion of people expressing dissatisfaction with their health care varies a great deal by country, as do the proportions reporting problems with access to and the cost of health care. Problems with access to care seem to matter most in trying to explain public dissatisfaction with their health care. More traditional measures of health outcomes and resources seem to matter less as drivers of dissatisfaction. CONCLUSIONS: For governments trying to improve their citizens' satisfaction with the health care they receive, the highest priority would be improving people's basic access to health-care services. Also, it appears that democratic governments are seen as being more responsive to the public's needs in health care. PMID- 22512775 TI - HLA-G 14bp del/ins genetic variation: association with susceptibility to human immunodeficiency virus-1 vertical transmission but not with human immunodeficiency virus-1 infection through horizontal transmission. PMID- 22512778 TI - The scaffolding and signalling functions of a localization factor impact polar development. AB - In the differentiating alphaproteobacterium Caulobacter crescentus, organelle synthesis at cell poles is critical to forming different progeny after cell division. Co-ordination of polar organelle synthesis, including pili and holdfast, and flagellum ejection, is mediated in part by the scaffolding protein PodJ. At the time of cell division, PodJ undergoes regulated processing to a short form that persists at the flagellar pole of swarmer cells. This study analyses how PodJ's role in structural and signalling protein localization impacts organelle synthesis. A PodJ mutant with an internal deletion exhibits reduced sensitivity to pili-tropic phage PhiCbK, resulting from reduced pilA gene expression, which can be linked to altered signalling protein localization. The phage sensitivity defect of a DeltapodJ mutant can be partially suppressed by ectopic pilA expression. Induction of PodJ processing, by manipulation of podJ itself or controlled perP expression, resulted in decreased pilus biogenesis and, when coupled with a podJ mutation that reduced pilA expression, led to complete loss of phage sensitivity. As a whole, the results show that PodJ's scaffolding role for structural and signalling proteins both contribute to flagellar pole organelle development. PMID- 22512779 TI - Decreased plasma concentrations of apolipoprotein M in sepsis and systemic inflammatory response syndromes. AB - INTRODUCTION: Apolipoprotein M (apoM) is present in 5% of high-density lipoprotein (HDL) particles in plasma. It is a carrier of sphingosine-1-phosphate (S1P), which is important for vascular barrier protection. The aim was to determine the plasma concentrations of apoM during sepsis and systemic inflammatory response syndrome (SIRS) and correlate them to levels of apolipoprotein A-I (apoA1), apolipoprotein B (apoB), HDL-, and low-density lipoprotein (LDL)-cholesterol. METHODS: Plasma samples from patients with (1), severe sepsis with shock (n = 26); (2), severe sepsis without shock (n = 44); (3), sepsis (n = 100); (4), infections without SIRS (n = 43); and (5) SIRS without infection (n = 20) were analyzed. The concentrations of apoM, apoA1, and apoB were measured with enzyme-linked immunosorbent assays (ELISAs). Total, HDL-, and LDL-cholesterol concentrations were measured with a commercial HDL/LDL cholesterol test. RESULTS: ApoM concentrations correlated negatively to acute phase markers. Thus, apoM behaved as a negative acute-phase protein. Decreased values were observed in all patient groups (P < 0.0001), with the most drastic decreases observed in the severely sick patients. ApoM levels correlated strongly to those of apoA1, apoB, HDL, and LDL cholesterol. The HDL and LDL cholesterol levels were low in all patient groups, as compared with controls (P < 0.0001), in particular, HDL cholesterol. ApoA1 and apoB concentrations were low only in the more severely affected patients. CONCLUSIONS: During sepsis and SIRS, the plasma concentrations of apoM decrease dramatically, the degree of decrease reflecting the severity of the disease. As a carrier for barrier-protective S1P in HDL, the decrease in apoM could contribute to the increased vascular leakage observed in sepsis and SIRS. PMID- 22512780 TI - Policy assessment and policy development for physical activity promotion: results of an exploratory intervention study in 15 European nations. AB - BACKGROUND: Purpose of the study was to test a theoretical model to assess and develop policies for the promotion of physical activity among older people as part of an international intervention study. METHODS: 248 semi-standardized interviews with policy-makers were conducted in 15 European nations. The questionnaire assessed policy-makers' perceptions of organizational goals, resources, obligations, as well as organizational, political and public opportunities in the area of physical activity promotion among older people. In order to develop policies, workshops with policy-makers were conducted. Workshop outputs and outcomes were assessed for four nations nine months after the workshops. RESULTS: Policy assessment: Results of the policy assessment were diverse across nations and policy sectors. For example, organizational goals regarding actions for physical activity promotion were perceived as being most favorably by the sports sector. Organizational obligations for the development of such policies were perceived as being most favorably by the health sector. Policy development: The workshops resulted in different outputs: a national intersectoral action plan (United Kingdom), a national alliance (Sweden), an integrated policy (the Netherlands), and a continuing dialogue (Germany). CONCLUSIONS: Theory-driven policy assessment and policy-maker workshops might be an important means of scientific engagement in policy development for health promotion. PMID- 22512783 TI - Interleukin-4 genetic variants correlate with its transcript and protein levels in patients with vitiligo. AB - BACKGROUND: Vitiligo is an acquired pigmentary disorder resulting from loss of melanocytes. Interleukin (IL)-4 has been shown to stimulate B-cell proliferation, to regulate immunoglobulin class switching (IgG1 and IgE) and to promote T-cell development. Polymorphisms in the IL4 gene are known to increase its expression, thereby implicating its role in vitiligo susceptibility. OBJECTIVES: To explore intron 3 VNTR (IVS3) and -590 C/T (rs2243250) promoter polymorphisms in the IL4 gene and to correlate them with the IL4 transcript, serum IL-4 and IgE levels to achieve genotype-phenotype correlation in patients with vitiligo from Gujarat. A replication study was done in a North Indian population. METHODS: The case control study was performed to investigate these polymorphisms in 505 patients and 744 controls in Gujarat, and 596 patients and 397 controls in North India by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism analysis. IL4 transcript levels were monitored by real-time PCR. Serum IL-4 and IgE levels were measured by enzyme-linked immunosorbent assay and electrochemiluminescence immunoassay, respectively. RESULTS: The genotype frequencies differed significantly between patients with generalized vitiligo and controls for both the polymorphisms in both populations. Allele frequencies significantly differed between patients with generalized vitiligo and controls for both the polymorphisms in the population from Gujarat. Interestingly, genotype and allele frequencies for -590 C/T single nucleotide polymorphism were significantly different between patients with localized vitiligo and controls in both the populations. The study revealed significantly increased IL4 mRNA, serum IL-4 and IgE levels in patients from Gujarat. Age of onset analysis of disease in patients suggested that the TTR2R2, TTR1R2 and CTR2R2 haplotypes had a profound effect in the early onset of the disease. CONCLUSIONS: Our results suggest that these polymorphisms of the IL4 gene may be genetic risk factors for susceptibility towards vitiligo and the upregulation of the IL4 transcript, protein and IgE levels in individuals with susceptible haplotypes reveal the crucial role of IL-4 in the pathogenesis of vitiligo. PMID- 22512781 TI - Neuroprotection by the histone deacetylase inhibitor trichostatin A in a model of lipopolysaccharide-sensitised neonatal hypoxic-ischaemic brain injury. AB - BACKGROUND: Perinatal brain injury is complex and often associated with both inflammation and hypoxia-ischaemia (HI). In adult inflammatory brain injury models, therapies to increase acetylation are efficacious in reducing inflammation and cerebral injury. Our aim in the present study was to examine the neuropathological and functional effects of the histone deacetylase inhibitor (HDACi) trichostatin A (TSA) in a model of neonatal lipopolysaccharide (LPS) sensitised HI. We hypothesised that, by decreasing inflammation, TSA would improve injury and behavioural outcome. Furthermore, TSA's effects on oligodendrocyte development, which is acetylation-dependent, were investigated. METHODS: On postnatal day 8 (P8), male and female mice were exposed to LPS together with or without TSA. On P9 (14 hours after LPS), mice were exposed to HI (50 minutes at 10% O2). Neuropathology was assessed at 24 hours, 5 days and 27 days post-LPS/HI via immunohistochemistry and/or Western blot analysis for markers of grey matter (microtubule-associated protein 2), white matter (myelin basic protein) and cell death (activated caspase-3). Effects of TSA on LPS or LPS/HI-induced inflammation (cytokines and microglia number) were assessed by Luminex assay and immunohistochemistry. Expression of acetylation-dependent oligodendrocyte maturational corepressors was assessed with quantitative PCR 6 hours after LPS and at 24 hours and 27 days post-LPS/HI. Animal behaviour was monitored with the open-field and trace fear-conditioning paradigms at 25 days post-LPS/HI to identify functional implications of changes in neuropathology associated with TSA treatment. RESULTS: TSA induced increased Ac-H4 in females only after LPS exposure. Also only in females, TSA reduced grey matter and white matter injury at 5 days post-LPS/HI. Treatment altered animal behaviour in the open field and improved learning in the fear-conditioning test in females compared with LPS/HI-only females at 25 days post-HI. None of the inflammatory mechanisms assessed that are known to mediate neuroprotection by HDACi in adults correlated with improved outcome in TSA-treated neonatal females. Oligodendrocyte maturation was not different between the LPS-only and LPS + TSA-treated mice before or after exposure to HI. CONCLUSIONS: Hyperacetylation with TSA is neuroprotective in the female neonatal mouse following LPS/HI and correlates with improved learning long-term. TSA appears to exert neuroprotection via mechanisms unique to the neonate. Deciphering the effects of age, sex and inflammatory sensitisation in the cerebral response to HDACi is key to furthering the potential of hyperacetylation as a viable neuroprotectant. TSA did not impair oligodendrocyte maturation, which increases the possible clinical relevance of this strategy. PMID- 22512782 TI - Atypical DNA methylation of genes encoding cysteine-rich peptides in Arabidopsis thaliana. AB - BACKGROUND: In plants, transposons and non-protein-coding repeats are epigenetically silenced by CG and non-CG methylation. This pattern of methylation is mediated in part by small RNAs and two specialized RNA polymerases, termed Pol IV and Pol V, in a process called RNA-directed DNA methylation. By contrast, many protein-coding genes transcribed by Pol II contain in their gene bodies exclusively CG methylation that is independent of small RNAs and Pol IV/Pol V activities. It is unclear how the different methylation machineries distinguish between transposons and genes. Here we report on a group of atypical genes that display in their coding region a transposon-like methylation pattern, which is associated with gene silencing in sporophytic tissues. RESULTS: We performed a methylation-sensitive amplification polymorphism analysis to search for targets of RNA-directed DNA methylation in Arabidopsis thaliana and identified several members of a gene family encoding cysteine-rich peptides (CRPs). In leaves, the CRP genes are silent and their coding regions contain dense, transposon-like methylation in CG, CHG and CHH contexts, which depends partly on the Pol IV/Pol V pathway and small RNAs. Methylation in the coding region is reduced, however, in the synergid cells of the female gametophyte, where the CRP genes are specifically expressed. Further demonstrating that expressed CRP genes lack gene body methylation, a CRP4-GFP fusion gene under the control of the constitutive 35 S promoter remains unmethylated in leaves and is transcribed to produce a translatable mRNA. By contrast, a CRP4-GFP fusion gene under the control of a CRP4 promoter fragment acquires CG and non-CG methylation in the CRP coding region in leaves similar to the silent endogenous CRP4 gene. CONCLUSIONS: Unlike CG methylation in gene bodies, which does not dramatically affect Pol II transcription, combined CG and non-CG methylation in CRP coding regions is likely to contribute to gene silencing in leaves because loss of this methylation in synergid cells is associated with CRP gene expression. We discuss this unusual methylation pattern and its alteration in synergid cells as well as the possible retrogene origin and evolutionary significance of CRP genes that are methylated like transposons. PMID- 22512784 TI - Design and evaluation of self-emulsifying drug delivery systems of Rhizoma corydalis decumbentis extracts. AB - To improve the dissolution and oral absorption of Rhizoma corydalis decumbentis extracts (RCDE), a famous traditional Chinese herbal medicine which contains poorly water-soluble active components, self-emulsifying drug-delivery systems (SEDDS) were designed and evaluated in vitro and in vivo for the first time. Six formulations were prepared, and pseudoternary phase diagrams were constructed to identify the efficient self-emulsication region through the modified visual test. The optimized formulation consisted of 45% Solutol, 40% ethyl oleate, and 15% Transcutol P. The mean droplet size distribution of the optimized SEDDS was less than 100 nm. The release of the active components (protopine and tetrahydropalmatine) in RCDE from SEDDS hard gelatin capsules showed a faster rate in comparison with the commercial tablets. After oral administration of RCDE SEDDS capsules or the commercial tablets to fasted rats, the relative bioavailability of SEDDS capsules for protopine and tetrahydropalmatine was 209.7% and 133.2% compared with commercial tablets, respectively. Our study indicated that SEDDS has the potential to improve the bioavailability of traditional Chinese medicines, in which many active components are hydrophobic, such as RCDE. PMID- 22512785 TI - Forecasting changes in population genetic structure of alpine plants in response to global warming. AB - Species range shifts in response to climate and land use change are commonly forecasted with species distribution models based on species occurrence or abundance data. Although appealing, these models ignore the genetic structure of species, and the fact that different populations might respond in different ways because of adaptation to their environment. Here, we introduced ancestry distribution models, that is, statistical models of the spatial distribution of ancestry proportions, for forecasting intra-specific changes based on genetic admixture instead of species occurrence data. Using multi-locus genotypes and extensive geographic coverage of distribution data across the European Alps, we applied this approach to 20 alpine plant species considering a global increase in temperature from 0.25 to 4 degrees C. We forecasted the magnitudes of displacement of contact zones between plant populations potentially adapted to warmer environments and other populations. While a global trend of movement in a north-east direction was predicted, the magnitude of displacement was species specific. For a temperature increase of 2 degrees C, contact zones were predicted to move by 92 km on average (minimum of 5 km, maximum of 212 km) and by 188 km for an increase of 4 degrees C (minimum of 11 km, maximum of 393 km). Intra-specific turnover-measuring the extent of change in global population genetic structure-was generally found to be moderate for 2 degrees C of temperature warming. For 4 degrees C of warming, however, the models indicated substantial intra-specific turnover for ten species. These results illustrate that, in spite of unavoidable simplifications, ancestry distribution models open new perspectives to forecast population genetic changes within species and complement more traditional distribution-based approaches. PMID- 22512786 TI - Esophageal impedance baselines in infants before and after placebo and proton pump inhibitor therapy. AB - BACKGROUND: Esophageal impedance monitoring records changes in conductivity. During esophageal rest, impedance baseline values may represent mucosal integrity. The aim of this study was to assess the influence of acid suppression on impedance baselines in a placebo-controlled setting. METHODS: Impedance recordings from 40 infants (0-6 months) enrolled in randomized placebo-controlled trials of proton pump inhibitor (PPI) were retrospectively analyzed. Infants underwent 24 h pH-impedance monitoring prior to and after 2 weeks of double blind therapy with placebo or a PPI. Typical clinical signs of gastro-esophageal reflux (GER) were recorded and I-GERQ-R questionnaire was completed. KEY RESULTS: Median (IQR) impedance baseline increased on PPI treatment (from 1217 (826-1514) to 1903 (1560-2194) Omega, P < 0.001) but not with placebo (from 1445 (1033-1791) to 1650 (1292-1983) Omega, P = 0.13). Baselines before treatment inversely correlate with the number of GER, acid GER, weakly acid GER, acid exposure, and symptoms. The change in baseline on treatment inversely correlates with acid exposure and acid GER. Patients with initial low baselines have no improved symptomatic response to treatment. CONCLUSIONS & INFERENCES: Impedance baselines are influenced by GER and increase significantly more with PPI therapy than with placebo. Clinical impact of this observation remains undefined as targeting therapy at infants with low baselines does not improve symptomatic response to treatment. PMID- 22512787 TI - Dealing with emotions when the ability to cry is hampered: emotion processing and regulation in patients with primary Sjogren's syndrome. AB - OBJECTIVES: The hampered ability to cry in patients with Sjogren's syndrome may affect their ways of dealing with emotions. The aim of this study was to examine differences in emotion processing and regulation between people with and without Sjogren's syndrome and correlations of emotion processing and regulation with mental well-being. METHODS: In 300 patients with primary Sjogren's syndrome and 100 demographically matched control participants (mean age 56.8 years, 93% female), emotion processing (affect intensity and alexithymia, i.e. difficulty identifying and describing feelings), emotion regulation (cognitive reappraisal, suppression and expression of emotions), and mental well-being were assessed. RESULTS: Criteria for clinical alexithymia applied to 22% of the patients and 12% of the control participants; patients had significantly more difficulty identifying feelings than control participants. No other significant differences in emotion processing and emotion regulation were found. In patients, the emotion processing styles affect intensity and alexithymia (0.32=grade 2 RILT. Among the clinical factors, only adjuvant chemotherapy was significantly correlated with RILT (p=0.039). For lung dosimetric factors, V(20) through V(40) were all significantly higher in the RILT group than in the non-RILT group. In the lobectomy group, the incidence of RILT was 27.3% in patients who received adjuvant chemotherapy and whose V(20) was greater than 20%. It was 9.7% in lobectomy patients with one of the risk factors, and 0.0% in those with no risk factors (p=0.032). CONCLUSIONS: The lung toxicity of PORT was found to be acceptably low. Adjuvant chemotherapy and lung dosimetric factors of V(20) V(40) were significantly correlated with RILT risk in NSCLC patients. PMID- 22512814 TI - Muckle-Wells syndrome and male hypofertility: a case series. AB - OBJECTIVES: Muckle-Wells syndrome (MWS) is a rare autoinflammatory disorder associated with NLRP3 gene mutations, which cause excessive caspase-1 activation and processing of interleukin (IL)-1beta and IL-18. Here we investigated whether MWS disease may be associated with impaired fertility in male patients. METHODS: Medical records of all male MWS patients with NLRP3 mutations followed in our tertiary center for inherited autoinflammatory diseases were reviewed retrospectively for data indicating fertility problems. RESULTS: Six of 9 patients were unable to have children despite regular sexual activity during at least 2 years; 3 succeeded in having children through in vitro fertilization. Infertility was the main reason for divorce in 1 patient. Spermiogram analyses were available in 8 of the 9 patients. Oligozoospermia was observed in 5 patients and azoospermia in 3 patients. In 2 patients, treatment with IL-1-targeting drugs for 6 and 12 months, respectively, had a moderate or no effect on spermatozoa counts. In 2 patients testosterone levels were low and testosterone treatment significantly increased spermatozoa counts in 1 of them. CONCLUSIONS: MWS may be associated with subfertility and infertility in male patients. Consequently, sexual health and fertility should be assessed systematically in adolescent and adult male patients. Additional studies are required to establish the frequency of subfertility in male MWS patients, to understand when subfertility occurs in the disease natural history, and, finally, to investigate whether early management with IL-1-targeting drugs, or testosterone treatment or early sperm cryo-conservation may help to allow procreation. PMID- 22512815 TI - The use of Canakinumab, a novel IL-1beta long-acting inhibitor, in refractory adult-onset Still's disease. AB - OBJECTIVES: We describe the successful treatment of adult-onset Still's disease (AOSD) with canakinumab, a novel anti-interleukin (IL)-1beta, long-acting, monoclonal antibody, on patients refractory to anakinra and rilonacept. In many cases the expected positive therapeutic effect of short-acting IL-1 inhibitors is transient or completely absent, leading to our hypothesis that their short half life may be associated with incomplete IL-1 blockade, given the cyclic nature of the disease. METHODS: We report 2 cases of AOSD resistant to short-acting IL-1 blockade, which were subsequently treated with canakinumab. A retrospective chart review was conducted of patients diagnosed with AOSD in our regional referral center. RESULTS: Response to treatment was assessed by its effect on the systemic symptoms (resolution of fever and rash), polyarthritis (using the disease activity score 28--C-reactive protein score), and the levels of serum ferritin. Canakinumab demonstrated sustained efficacy in both patients as evidenced by clinical and laboratory parameters with minimal adverse reactions. CONCLUSIONS: This is the first documented report of successful use of canakinumab, a novel IL 1beta inhibitor, in AOSD patients refractory to traditional disease-modifying antirheumatic drugs and short- to moderate-acting IL-1 blockade. Prospective comparative studies are needed to validate canakinumab's efficacy and safety. PMID- 22512816 TI - Has the clinical spectrum of gout changed over the last decades? AB - OBJECTIVES: To evaluate if the clinical spectrum of gout has changed over the last decades, a cohort of 107 patients was studied in relation to the date of disease onset and of presentation to our Institution. METHODS: The structured questionnaires of 107 consecutive patients with gout seen between 1989 and 2009 were retrospectively reviewed. Patients were divided into two subgroups according to the year of the first acute arthritis attack: (a) patients with gout onset dating back to 1967-2001, and (b) patients with gout of later (2002-2009) onset. The patients were also subdivided according to the date of their first admission to our Institution: 1989-2006 and 2007-2009 admissions. RESULTS: The male to female ratio changed from 11.3 in the patients who had the first attack before 2002 to 2.4 in the second onset group (p=0.02). A family history of gout was slightly more frequent in the second subgroup (22.7% vs. 6.4%, p=0.05). The mean number of acute attacks was higher in patients seen before 2002 (p=0.01). Synovial fluid was examined more frequently in the subgroup visited for the first time after 2006 (p=0.001). CONCLUSIONS: Our data indicating that the patients' sex ratio has changed over time, with women more frequently affected, could be of importance to clinicians who often believe that gout is a disease affecting males only. The increased utilisation of synovial fluid analysis suggests a closer attention to the disease in recent years. Clinicians should be aware that gout is increasingly affecting women. PMID- 22512817 TI - Antiaromaticity proved by the anisotropic effect in 1H NMR spectra. AB - The spatial magnetic properties (through-space NMR shieldings, or TSNMRSs) of the antiaromatic 9-oxaanthracene anion 12(-) and of the corresponding 9-dimeric dianion 11(2-) have been calculated by the gauge-invariant atomic orbitals (GIAO) perturbation method employing the nucleus independent chemical shift (NICS) concept and visualized as iso-chemical-shielding surfaces (ICSSs) of various size and direction. The TSNMRS values, thus obtained, can be employed to indicate antiaromaticity by paratropic ring currents of the anionic compounds of 11(2-) and 12(-) studied and other neutral and ionic antiaromatic molecules from previous studies because anisotropic effects of functional groups in (1)H NMR spectra have quantitatively proven to be the molecular response property of theoretical spatial nucleus independent chemical shieldings (NICS). PMID- 22512818 TI - Assessing patients' involvement in decision making during the nutritional consultation with a dietitian. AB - BACKGROUND: Shared decision making (SDM) represents an interesting approach to optimize the impact of dietary treatment, but there is no evidence that SDM is commonly integrated into diet-related health care. OBJECTIVE: To assess the extent to which dietitians involve patients in decisions about dietary treatment. METHODS: We audiotaped dietitians conducting nutritional consultations with their patients, and we transcribed the tapes verbatim. Three trained raters independently evaluated the content of the nutritional consultations using a coding frame based on the 12 items of the French-language version of the OPTION scale, a validated and reliable third-observer instrument designed to assess patients' involvement by examining specific health professionals' behaviours. Coding was facilitated by the qualitative research software NVivo 8. We assessed internal consistency with Cronbach's alpha and inter-rater reliability with the intraclass correlation coefficient (ICC). RESULTS: Of the 40 dietitians eligible to participate in the study, 19 took part. We recruited one patient per participating dietitian. The overall mean OPTION score was 29 +/- 8% [range, 0% (no patient involvement in the decision] to 100% [high patient involvement)]. The mean duration of consultations was 50 +/- 26 min. The OPTION score was positively correlated with the duration of the consultation (r = 0.65, P < 0.01). Internal consistency and inter-rater reliability were both good (Cronbach's alpha = 0.72; ICC = 0.65). CONCLUSION: This study is the first to use a framework based on the OPTION scale to report on dietitians' involvement of patients in decisions about patients' dietary treatment. The results suggest that involvement is suboptimal. Interventions to increase patients' involvement in diet-related decision making are indicated. PMID- 22512820 TI - Early immune dynamics following infection with Salmonella enterica serovars Enteritidis, Infantis, Pullorum and Gallinarum: cytokine and chemokine gene expression profile and cellular changes of chicken cecal tonsils. AB - Salmonella enterica subspecies enterica infection remains a serious problem in a wide range of animals and in man. Poultry-derived food is the main source of human infection with the non-host-adapted serovars while fowl typhoid and pullorum disease are important diseases of poultry. We have assessed cecal colonization and immune responses of newly hatched and older chickens to Salmonella serotypes Enteritidis, Infantis, Gallinarum and Pullorum. S. Enteritidis and S. Infantis colonized the ceca more efficiently than S. Gallinarum and S. Pullorum. Salmonella infection was also associated with increased staining for B-lymphocytes and macrophages in the cecal tonsils of infected birds. S. Enteritidis infection in newly hatched birds stimulated the expression of CXCLi1 and CXCLi2 chemokines in the cecal tonsils, while S. Gallinarum up-regulated the expression of LITAF. In older chickens, S. Enteritidis infection resulted in a significantly higher expression of CXCLi2, iNOS, LITAF and IL-10 while S. Pullorum appeared to down-regulate CXCLi1 expression in the cecal tonsils. Data from spleens showed either no expression or down-regulation of the tested genes. PMID- 22512819 TI - Improved immune responses against avian influenza virus following oral vaccination of chickens with HA DNA vaccine using attenuated Salmonella typhimurium as carrier. AB - This study evaluates the immune responses of single avian influenza virus (AIV) HA DNA vaccine immunization using attenuated Salmonella enterica sv. Typhimurium as an oral vaccine carrier and intramuscular (IM) DNA injection. One-day-old specific-pathogen-free (SPF) chicks immunized once by oral gavage with 10(9) Salmonella colony-forming units containing plasmid expression vector encoding the HA gene of A/Ck/Malaysia/5858/04 (H5N1) (pcDNA3.1.H5) did not show any clinical manifestations. Serum hemagglutination inhibition (HI) titer samples collected from the IM immunized chickens were low compared to those immunized with S. typhimurium.pcDNA3.1.H5. The highest average antibody titers were detected on day 35 post immunization for both IM and S. typhimurium.pcDNA3.1.H5 immunized groups, at 4.0+/-2.8 and 51.2+/-7.5, respectively. S. typhimurium.pcDNA3.1.H5 also elicited both CD4(+) and CD8(+) T cells from peripheral blood mononuclear cells (PBMCs) of immunized chickens as early as day 14 after immunization, at 20.5+/ 2.0 and 22.9+/-1.9%, respectively. Meanwhile, the CD4(+) and CD8(+) T cells in chickens vaccinated intramuscularly were low at 5.9+/-0.9 and 8.5+/-1.3%, respectively. Immunization of chickens with S. typhimurium.pcDNA3.1.H5 enhanced IL-1beta, IL-12beta, IL-15 and IL-18 expressions in spleen although no significant differences were recorded in chickens vaccinated via IM and orally with S. typhimurium and S. typhimurium.pcDNA3.1. Hence, single oral administrations of the attenuated S. typhimurium containing pcDNA3.1.H5 showed antibody, T cell and Th1-like cytokine responses against AIV in chickens. Whether the T cell response induced by vaccination is virus-specific and whether vaccination protects against AIV infection requires further study. PMID- 22512821 TI - Purified fish oil eliminating linoleic and alpha linolenic acid meets essential fatty acid requirements in rats. AB - This study examined whether purified fish oil (PFO) supplemented to an essential fatty acid deficient (EFAD) diet meets EFA needs in rats. The EFAD diet contained 10% hydrogenated coconut oil (HCO). A similar diet contained 7% HCO and 3% PFO which also provided 2.84% arachidonic acid (AA), 52.50% eicosapentaenoic acid (EPA) and 35.73% docosahexaenoic acid (DHA) but no linoleic acid (LA) or alpha linolenic acid (ALA). A 10% soybean oil control diet provided ample LA and ALA. After 4 weeks of feeding, blood glucose, plasma triglyceride and phospholipid fatty acid profiles, C-reactive protein (CRP), TNF and IL-6 were determined after saline or LPS injection. EFAD developed with the HCO diet with triene:tetraene ratios in plasma phospholipids >.20, which remained <.02 with the control and HCO+PFO diets. Mead acid levels significantly increased by a factor of 10 with the HCO diet compared to the AIN and HCO+PFO diets and were significantly lowest with the HCO+PFO diet. 18:1 n9 levels were significantly higher in plasma phospholipids and triglycerides with the HCO diet. CRP levels were significantly highest with the control diet and significantly lowest with the HCO diet. LPS significantly increased 18:1 n9 and cytokines, and decreased AA and plasma glucose in all diets and significantly increased plasma triglycerides and decreased plasma glucose in controls. Providing AA, EPA and DHA in EFAD prevents EFAD over the short-term as reflected in Mead acid production, triene:tetraene ratio, and de novo lipogenesis and may reduce the inflammatory response to LPS. PMID- 22512823 TI - Estrogen mediation of hormone responses to exercise. AB - The roles of estrogens extend from the regulation of reproduction to other functions involved in control of metabolism, fluid balance, as well as gastrointestinal, lung, and brain function, with a strong effect on other hormones that subsequently alter the physiology of multiple tissues. As such, alteration of endogenous estrogens across the menstrual cycle, or from oral contraception and estrogen replacement therapy, can affect these tissues. Due to the important effects that estrogens have on different tissues, there are many investigations concerning the effects of a human estrogenic environment on endocrine responses to exercise. The following review will describe the consequences of varying estrogen levels on pituitary, adrenal, gonadal, and endocrine function, followed by discussion of the outcomes of different estrogen levels on endocrine tissues in response to exercise, problems encountered for interpretation of findings, and recommended direction for future research. PMID- 22512822 TI - Determinants of ApoB, ApoA1, and the ApoB/ApoA1 ratio in healthy schoolgirls, prospectively studied from mean ages 10 to 19 years: the Cincinnati National Growth and Health Study. AB - The objectives were to prospectively assess determinants of apolipoproteins B (ApoB), A1 (ApoA1), and the ApoB/ApoA1 ratio in 797 healthy black and white schoolgirls from mean ages 10 to 19. There was prospective 9-year follow-up, with measures of ApoB at mean ages 10, 12, 14, 16 and 19, ApoA1 at mean ages 12, 14, 16, and 19, and assessment of annual reports of delayed menstrual cyclicity (>=42 days) from ages 14 to 19. Studies of 402 black and 395 white healthy schoolgirls were done in public and private schools, in urban and suburban Cincinnati. Black girls had lower ApoB, higher ApoA1, and lower ApoB/ApoA1. SHBG at age 14 in white and black girls was inversely correlated with the ApoB/ApoA1. At age 19, >=3 annual reports of menstrual delay >=42 days and metabolic syndrome were associated with higher ApoB and a higher ApoB/ApoA1 ratio. From ages 14 to 19, BMI and TG were independently positively associated with ApoB. Menstrual cyclicity >=42 days, metabolic syndrome, BMI, and TG were independently positively associated with ApoB/ApoA1 ratios, while black race was negatively associated. The atherogenic ApoB/ApoA1 ratio from ages 14 to 19 is lower in black girls, and positively associated with hyperandrogenism, menstrual cyclicity >=42 days, BMI, TG, and the metabolic syndrome, facilitating an adolescent approach to primary prevention of cardiovascular disease. PMID- 22512824 TI - Casein protein results in higher prandial and exercise induced whole body protein anabolism than whey protein in chronic obstructive pulmonary disease. AB - Exercise is known to improve physical functioning and health status in Chronic Obstructive Pulmonary Disease (COPD). Recently, disturbances in protein turnover and amino acid kinetics have been observed after exercise in COPD. The objective was to investigate which dairy protein is able to positively influence the protein metabolic response to exercise in COPD. 8 COPD patients and 8 healthy subjects performed a cycle test on two days while ingesting casein or whey protein. Whole body protein breakdown (WbPB), synthesis (WbPS), splanchnic amino acid extraction (SPE), and NetWbPS (=WbPS-WbPB) were measured using stable isotope methodology during 20 min of exercise (at 50% peak work load of COPD group). The controls performed a second exercise test at the same relative workload. Exercise was followed by 1 h of recovery. In the healthy group, WbPS, SPE, and NetPS were higher during casein than during whey feeding (P<.01). WbPS and NetPS were higher during exercise, independent of exercise intensity (P<.01). NetPS was higher during casein feeding in COPD due to lower WbPB (P<.05). Higher SPE was found during exercise during casein and whey feeding in COPD (P<.05). Lactate levels during exercise were higher in COPD (P<.05) independent of the protein. Post-exercise, lower NetPS values were found independent of protein type in both groups. Casein resulted in more protein anabolism than whey protein which was maintained during and following exercise in COPD. Optimizing protein intake might be of importance for muscle maintenance during daily physical activities in COPD. PMID- 22512825 TI - Rosette-forming glioneuronal tumour: imaging features, histopathological correlation and a comprehensive review of literature. AB - BACKGROUND: Rosette-forming glioneuronal tumour (RGNT) is a rare and novel brain tumour. We present a case of rosette forming glioneuronal tumour of the fourth ventricle and highlight the imaging and histological features of this tumour entity. We also performed a comprehensive review of the imaging features, treatments and outcomes of all past cases and make recommendations on diagnosis and management. METHOD: We conducted a PUBMED search using the words 'rosette forming glioneuronal tumour', and identified 48 cases of rosette forming glioneuronal tumour. We reviewed the location, imaging features of this rare tumour entity as well as the treatment and follow-up. We also present a case of a 42-year-old man with an incidental finding of a solid-cystic midline mass in the posterior fossa at the level of fourth ventricle with morphological features and immunohistochemical characteristic of a RGNT (WHO Grade I). FINDINGS: RGNT is commonly found in association with the fourth ventricle often with local extension; however, it is known to occur at sites outside of its usual location. RGNT can demonstrate solid, cystic or mixed features on MRI and frequently shows focal contrast enhancement. It is often associated with an element of hydrocephalus. Gross or subtotal tumour resection was the most common treatment of choice. Due to the intimate relationship of these tumours to key neural structures in the cerebellum, variable degrees of postoperative neurological deficits were reported in half of the patients. Among the reported cases, no evidence of recurrence following gross or subtotal resection of tumour was seen in the majority of patients. However, owing to lack of lengthy follow-up, we recommend routine imaging follow-up. CONCLUSION: Knowledge of this tumour is of importance as they are relatively slow growing and exhibit benign histological characteristics, thus depending on its location maybe amenable to gross total resection. PMID- 22512826 TI - Antibiotic prophylaxis in diagnostic hysteroscopy: is it necessary or not? AB - OBJECTIVE: Surgical site infection remains the most common complication of surgery. Up to 5% of patients undergoing operative procedures will develop an infection leading to a prolonged hospital stay with increased cost. On the other hand the indiscriminate use of antibiotics has been associated with the development of antibiotic-resistant bacteria. The aim of this study was to examine the effect of antibiotic prophylaxis in cases of diagnostic hysteroscopy. STUDY DESIGN: This was an eight-year randomized controlled clinical trial. The study group consisted of 364 women who underwent diagnostic hysteroscopy because of menometrorrhagia, post-menopausal vaginal bleeding, ultrasound findings of increased thickness of the endometrium, or as a routine examination prior to a first in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. RESULTS: Of the 364 women who underwent diagnostic hysteroscopy during this eight-year study period, 176 received antibiotic prophylaxis whereas 188 did not. There were no significant differences in the prevalence of postoperative infections observed between women who received antibiotic prophylaxis (0.57%) and those who underwent the procedure without prophylaxis (0.53%). CONCLUSION: Given the very low risk of infection after diagnostic hysteroscopy and lack of evidence of efficacy, routine antibiotic prophylaxis is not recommended. PMID- 22512827 TI - Does 45,X/46,XX mosaicism with 6-28% of aneuploidy affect the outcomes of IVF or ICSI? AB - OBJECTIVE: Several studies have shown an increased frequency of chromosomal aberrations in female partners of couples examined prior to intracytoplasmic sperm injection (ICSI). A retrospective cohort study was performed to determine whether 45,X/46,XX mosaicism affects the outcomes of in vitro fertilization (IVF) or ICSI. STUDY DESIGN: Forty-six women with a 45,X/46,XX karyotype with 6-28% of aneuploidy were compared with 59 control women (46,XX), matched for age, from the female population who underwent IVF or ICSI between 1 January 1996 and 31 December 2006 at the Reproductive Medicine Unit at Brest University Hospital. The outcomes of 254 treatment cycles were compared according to patient karyotype. RESULTS: No difference was found in the number of retrieved oocytes (8.9 +/- 5.5 vs 8.5 +/- 4.7; p=0.56) or the number of mature oocytes (7.4 +/- 4.7 vs 6.9 +/- 4.2; p=0.49) between the 45,X/46,XX group and the 46,XX group, respectively. Fertilization rates did not differ between the groups for either IVF or ICSI. In addition, no difference was found in the pregnancy rate by cycle (17.4% vs 18.7%, respectively; p=0.87). The percentage of first-trimester miscarriages was similar in both groups (13.6% vs 12.5%, respectively; p=0.51). CONCLUSION: 45,X/46,XX mosaicism with 6-28% of aneuploidy has no adverse effect on the outcomes of IVF or ICSI among women referred to assisted reproductive technologies. PMID- 22512828 TI - Use of laparoscopy in unexplained infertility. AB - OBJECTIVE: The use of laparoscopy in unexplained infertility work-up is still a subject of debate, although laparoscopy remains the gold standard for diagnosis and treatment of several pelvic pathologies. The objective of this study was to assess the rates and types of pelvic pathologies observed during diagnostic laparoscopy, and the pregnancy rate in couples with unexplained infertility following laparoscopy. STUDY DESIGN: Prospective study, from November 2003 to October 2009, including 114 infertile, spontaneously ovulating women with normal clinical examination, ovarian reserve assessment, pelvic ultrasound scan and patent tubes on hysterosalpingography. Semen analyses were normal according to the World Health Organization criteria. After three cycles of ovulation induction with or without intra-uterine insemination and no pregnancy, women were referred for diagnostic laparoscopy. RESULTS: Laparoscopy revealed pelvic pathology in 95 patients. Endometriosis, pelvic adhesions and tubal disease were observed and treated in 72, 46 and 24 patients, respectively. Following laparoscopy, bilateral and unilateral tubal patencies were observed in 107 and five patients, respectively. Pregnancy was observed in 77 out of 102 patients who tried to conceive after surgery, 35 of whom conceived using their own tubes. CONCLUSION: Diagnostic laparoscopy should be strongly considered in unexplained infertility work-up, and tubal efficiency should not be underestimated. PMID- 22512829 TI - Polycystic ovary syndrome: double click and right check. What do patients learn from the Internet about PCOS? AB - OBJECTIVE: To identify the websites most visited by patients regarding polycystic ovary syndrome (PCOS), and to evaluate the quality of information provided by these websites. STUDY DESIGN: We sought data regarding the popularity of sites providing information about PCOS regardless of the way the visitors reached the site. We then scrutinized the top sites for predefined quality check points to evaluate the quality of information provided, including Health on Net Foundation (HON) accreditation. Finally, we searched for the expansion of these sites in social networks (Facebook and Twitter). RESULTS: Of the top 15 sites, 8 were HONcode certified. The mean performance of content presence for all sites was 7.33 (min=4, max=10, SD=1.633). There was a moderate correlation of higher performance score with HON accreditation (R: 0.535, p<0.05). Several sites have expanded in social media. None of the high-score sites has a page dedicated to PCOS. CONCLUSIONS: There exists a lack of HON accreditation in many sites and a wide variability in the quality of the information provided. In some cases, key elements of content, necessary for complete appreciation of PCOS, are missing. Official and high authority healthcare organisms should introduce themselves in the social media world. PMID- 22512831 TI - Availability of services in Ontario hospices and hospitals providing inpatient palliative care. AB - PURPOSE: Most Canadians die in inpatient settings. Our aim was to determine the availability of medical services, programs, and care for common palliative procedures, in hospices, palliative care units (PCUs), and hospital medical wards (MWs) providing inpatient palliative care in Ontario, Canada. METHODS: We identified facilities providing inpatient palliative care using the Ontario Hospital Association (OHA) and Hospice Association of Ontario (HAO) websites. An electronic survey was sent to the person responsible for palliative care at each facility. We compared services available among the three types of units, using Fisher's exact and Kruskal-Wallis tests. RESULTS: Of 128 surveys sent, 102 (80%) were completed and returned, from 58 MWs, 31 PCUs, and 13 hospices. MWs were the most common location of palliative care overall, particularly in rural areas. PCUs were most likely to provide care for common procedures (e.g., tracheostomy, nephrostomy; p<0.01); methadone for pain management (p<0.0001); and palliative radiation (p<0.01). MWs were most likely to offer intravenous chemotherapy and antibiotics (p<0.01). Transfusions were available in most PCUs and MWs, but only in one hospice (p<0.0001). Hospices were most likely to provide complementary therapies. Lack of financial support and human resources were the most frequent perceived barriers to providing quality palliative care. CONCLUSIONS: There is considerable variability of available services depending on the setting where inpatient palliative care is provided. Further financial support and resources are required to ensure consistent high quality of care in both urban and rural areas. PMID- 22512830 TI - Reliability of an interactive computer program for advance care planning. AB - Despite widespread efforts to promote advance directives (ADs), completion rates remain low. Making Your Wishes Known: Planning Your Medical Future (MYWK) is an interactive computer program that guides individuals through the process of advance care planning, explaining health conditions and interventions that commonly involve life or death decisions, helps them articulate their values/goals, and translates users' preferences into a detailed AD document. The purpose of this study was to demonstrate that (in the absence of major life changes) the AD generated by MYWK reliably reflects an individual's values/preferences. English speakers >=30 years old completed MYWK twice, 4 to 6 weeks apart. Reliability indices were assessed for three AD components: General Wishes; Specific Wishes for treatment; and Quality-of-Life values (QoL). Twenty four participants completed the study. Both the Specific Wishes and QoL scales had high internal consistency in both time periods (Knuder Richardson formula 20 [KR-20]=0.83-0.95, and 0.86-0.89). Test-retest reliability was perfect for General Wishes (kappa=1), high for QoL (Pearson's correlation coefficient=0.83), but lower for Specific Wishes (Pearson's correlation coefficient=0.57). MYWK generates an AD where General Wishes and QoL (but not Specific Wishes) statements remain consistent over time. PMID- 22512832 TI - An adult case of waxy keratosis. PMID- 22512833 TI - Pedometer determined physical activity tracks in African American adults: the Jackson Heart Study. AB - BACKGROUND: This study investigated the number of pedometer assessment occasions required to establish habitual physical activity in African American adults. METHODS: African American adults (mean age 59.9 +/- 0.60 years; 59 % female) enrolled in the Diet and Physical Activity Substudy of the Jackson Heart Study wore Yamax pedometers during 3-day monitoring periods, assessed on two to three distinct occasions, each separated by approximately one month. The stability of pedometer measured PA was described as differences in mean steps/day across time, as intraclass correlation coefficients (ICC) by sex, age, and body mass index (BMI) category, and as percent of participants changing steps/day quartiles across time. RESULTS: Valid data were obtained for 270 participants on either two or three different assessment occasions. Mean steps/day were not significantly different across assessment occasions (p values > 0.456). The overall ICCs for steps/day assessed on either two or three occasions were 0.57 and 0.76, respectively. In addition, 85 % (two assessment occasions) and 76 % (three assessment occasions) of all participants remained in the same steps/day quartile or changed one quartile over time. CONCLUSION: The current study shows that an overall mean steps/day estimate based on a 3-day monitoring period did not differ significantly over 4 - 6 months. The findings were robust to differences in sex, age, and BMI categories. A single 3-day monitoring period is sufficient to capture habitual physical activity in African American adults. PMID- 22512834 TI - Risk factors for acute organ failure in intensive care unit patients who receive respiratory support in the absence of non-respiratory organ failure: an international prospective cohort study. AB - INTRODUCTION: Many supposed low-risk intensive care unit (ICU) admissions develop acute organ failure (AOF). Identifying patients at high risk of developing AOF and targeting them with preventative strategies may be effective. Our study question was: in a population of ICU patients receiving positive pressure respiratory support (invasive or non-invasive) in the absence of non-respiratory AOF, what is the 14-day incidence of, risk factors for and time to acute organ failure? METHODS: In an international prospective cohort study, patients receiving positive pressure respiratory support (invasive or non-invasive) in the absence of non-respiratory AOF were enrolled and followed for 14 days. The primary outcome measure was the incidence of any AOF (defined as SOFA 3 to 4) during follow-up. RESULTS: A total of 123 of 766 screened patients (16.1%) were enrolled. Data are reported for 121 patients. In total, 45 out of 121 patients (37.2%) developed AOF. Mortality rates were higher in those with AOF: 17.8% versus 4.0% OR 5.11, P = 0.019) for ICU mortality; and 28.9% versus 11.8% (OR 2.80, P = 0.019) for hospital mortality. Median ICU length of stay was also longer in those with AOF (11 versus 3.0 days; P < 0.0001). Hypoxemic respiratory failure (P = 0.001) and cardiovascular dysfunction (that is, SOFA 1 to 2; P = 0.03) were associated with AOF. The median time to first AOF was two days. CONCLUSIONS: Patients receiving positive (invasive or non-invasive) pressure respiratory support in the absence of non-respiratory AOF are commonly admitted to ICU; AOF is frequent in these patients. Organ failure developed within a short period after admission. Hypoxemic respiratory failure and cardiovascular dysfunction were strongly associated with AOF. PMID- 22512835 TI - An optimal search filter for retrieving systematic reviews and meta-analyses. AB - BACKGROUND: Health-evidence.ca is an online registry of systematic reviews evaluating the effectiveness of public health interventions. Extensive searching of bibliographic databases is required to keep the registry up to date. However, search filters have been developed to assist in searching the extensive amount of published literature indexed. Search filters can be designed to find literature related to a certain subject (i.e. content-specific filter) or particular study designs (i.e. methodological filter). The objective of this paper is to describe the development and validation of the health-evidence.ca Systematic Review search filter and to compare its performance to other available systematic review filters. METHODS: This analysis of search filters was conducted in MEDLINE, EMBASE, and CINAHL. The performance of thirty-one search filters in total was assessed. A validation data set of 219 articles indexed between January 2004 and December 2005 was used to evaluate performance on sensitivity, specificity, precision and the number needed to read for each filter. RESULTS: Nineteen of 31 search filters were effective in retrieving a high level of relevant articles (sensitivity scores greater than 85%). The majority achieved a high degree of sensitivity at the expense of precision and yielded large result sets. The main advantage of the health-evidence.ca Systematic Review search filter in comparison to the other filters was that it maintained the same level of sensitivity while reducing the number of articles that needed to be screened. CONCLUSIONS: The health-evidence.ca Systematic Review search filter is a useful tool for identifying published systematic reviews, with further screening to identify those evaluating the effectiveness of public health interventions. The filter that narrows the focus saves considerable time and resources during updates of this online resource, without sacrificing sensitivity. PMID- 22512836 TI - Identification of potential target genes of cardioprotection against ischemia reperfusion injury by express sequence tags analysis in rat hearts. AB - BACKGROUND: Ischemic preconditioning (IPC) is a powerful mechanism for limiting myocardial infarction during or after ischemia-reperfusion (IR) injury. However, effective target genes and proteins for IPC are unknown. We characterized global changes in gene expression in the heart during IR, and identified effective target genes for IPC. METHODS: Hearts were isolated from Sprague-Dawley rats under control, IR, and IPC conditions. We generated expressed-sequence-tags (ESTs) for each group and investigated their functions and the major biological processes in which they are involved using the eukaryotic clusters of orthologous groups (KOG) database and bioinformatics analysis tools. RESULTS: IR modified the expression of 126 genes. Of these, 62 were upregulated, 64 were downregulated, and 77 were found to be effective target genes for IPC. In KOG analysis, most of the genes whose expression was modified were involved in energy production and conversion and the cytoskeleton. A gene-to-gene interaction map revealed that IR modified the expression of genes in four major functional modules: electron transport chain/oxidative phosphorylation; tricarboxylic acid cycle/glucose metabolism/amino acid metabolism; cellular structure and contraction; and gene transcription, translation, and protein folding. At the individual gene level, the genes encoding mitochondrial cytochrome c oxidase subunits 2 and 3 were downregulated, and those encoding the major cytoskeleton components tropomyosin, myosin light chain, myomesin 2, and myosin regulatory light chain 2, as well as the gene encoding the iron-storage protein ferritin, were upregulated, and thus were identified as potential target genes. Real time PCR evaluated expression patterns of three mitochondrial IPC effective genes. Two-dimensional electrophoresis proteomic analyses revealed altered expression of 14 target proteins. The expression patterns of six proteins matched the corresponding EST expression patterns. CONCLUSION: The global profiling of cardiac ischemia-related genes provides the possible mechanisms of IR and IPC and ways of treating IR injury. PMID- 22512837 TI - The analysis of 168 randomised controlled trials to test data integrity. PMID- 22512838 TI - Effects of regularly consuming dietary fibre rich soluble cocoa products on bowel habits in healthy subjects: a free-living, two-stage, randomized, crossover, single-blind intervention. AB - BACKGROUND: Dietary fibre is both preventive and therapeutic for bowel functional diseases. Soluble cocoa products are good sources of dietary fibre that may be supplemented with this dietary component. This study assessed the effects of regularly consuming two soluble cocoa products (A and B) with different non starch polysaccharides levels (NSP, 15.1 and 22.0% w/w, respectively) on bowel habits using subjective intestinal function and symptom questionnaires, a daily diary and a faecal marker in healthy individuals. METHODS: A free-living, two stage, randomized, crossover, single-blind intervention was carried out in 44 healthy men and women, between 18-55 y old, who had not taken dietary supplements,laxatives, or antibiotics six months before the start of the study. In the four-week-long intervention stages, separated by a three-week-wash-out stage, two servings of A and B, that provided 2.26 vs. 6.60 g/day of NSP respectively, were taken. In each stage, volunteers' diet was recorded using a 72 h food intake report. RESULTS: Regularly consuming cocoa A and B increased fibre intake, although only cocoa B significantly increased fibre intake (p < 0.001) with respect to the non-cocoa stage. No changes in body weight were observed in either of the 4 week interventions. With cocoa product B, the number of daily bowel movements increased (p = 0.002), the frequency of having a bowel movement once a day increased (p = 0.009), the time to have a bowel movement was lower (p = 0.016) as well as the feeling of constipation (p = 0.046) without inducing adverse gastrointestinal symptoms, only flatulence increased (p = 0.019). CONCLUSIONS: Regular consumption of the cocoa products increases dietary fibre intake to recommended levels and product B improves bowel habits. The use of both objective and subjective assessments to evaluate the effects of food on bowel habits is recommended. PMID- 22512839 TI - Femtosecond (FS) laser vision correction procedure for moderate to high myopia: a prospective study of ReLEx((r)) flex and comparison with a retrospective study of FS-laser in situ keratomileusis. AB - PURPOSE: To present our initial clinical experience with ReLEx((r)) flex (ReLEx) for moderate to high myopia. We compare efficacy, safety and corneal higher-order aberrations after ReLEx with femtosecond laser in situ keratomileusis (FS-LASIK). METHODS: Prospective study of ReLEx compared with a retrospective study of FS LASIK. ReLEx is a new keratorefractive procedure, where a stromal lenticule is cut by a femtosecond laser and manually extracted. Forty patients were treated with ReLEx on both eyes. A comparable group of 41 FS-LASIK patients were retrospectively identified. Visual acuity, spherical equivalent (SE) and corneal tomography were measured before and 3 months after surgery. RESULTS: Preoperative SE averaged -7.50 +/- 1.16 D (ReLEx) and -7.32 +/- 1.09 D (FS-LASIK). For all eyes, mean corrected distance visual acuity remained unchanged in both groups. For eyes with emmetropia as target refraction, 41% of ReLEx and 61% of FS-LASIK eyes had an uncorrected distance visual acuity of logMAR <= 0.10 at day 1 after surgery, increasing to, respectively, 88% and 69% at 3 months. Mean SE was -0.06 +/- 0.35 D 3 months after ReLEx and -0.53 +/- 0.60 D after FS-LASIK. The proportion of eyes within +/-1.00 D after 3 months was 100% (ReLEx) and 85% (FS LASIK). For a 6.0-mm pupil, corneal spherical aberrations increased significantly less in ReLEx than FS-LASIK eyes. CONCLUSIONS: ReLEx is an all-in-one femtosecond laser refractive procedure, and in this study, results were comparable to FS LASIK. Refractive predictability and corneal aberrations at 3 months seemed better than or equal to FS-LASIK, whereas visual recovery after ReLEx was slower. PMID- 22512840 TI - Pre- vs. post-pubertal onset of vitiligo: multivariate analysis indicates atopic diathesis association in pre-pubertal onset vitiligo. AB - BACKGROUND: Limited epidemiological data exist that compare clinical features of pre- and post-pubertal nonsegmental vitiligo. OBJECTIVES: To compare factors associated with pre- and post-pubertal onset vitiligo. PATIENTS AND METHODS: A prospective observational study was conducted of patients with vitiligo attending the clinic between 1 January 2006 and 1 July 2011. The Vitiligo European Task Force questionnaire was completed for each patient and thyroid function and antithyroid antibodies were screened. Other forms of vitiligo (segmental, focal, mucosal, not classifiable) were excluded. RESULTS: A total of 679 patients were included; 422 had post-pubertal and 257 pre-pubertal onset of vitiligo. Vitiligo universalis was seen only in post-pubertal onset. In univariate analysis, there was no significant statistical difference for sex, Koebner phenomenon or disease activity between both groups; thyroid disease or presence of thyroid antibodies was more frequent in post-pubertal onset [odds ratio (OR) 0.31, P < 0.003] whereas atopic dermatitis was more often associated with or preceding pre pubertal onset (OR 2.42, P = 0.006). In multivariate analysis, halo naevi, family history of vitiligo, premature hair greying, atopic dermatitis and previous episode of spontaneous repigmentation were independently associated with pre pubertal onset. In contrast, stress as onset factor, personal history of thyroid disease and acrofacial type were associated with post-pubertal onset. CONCLUSIONS: Pre-pubertal onset vitiligo is strongly associated with personal and family history of atopy, suggesting that the predisposing immune background in vitiligo is not limited to autoimmunity, as also noted in alopecia areata. This study also suggests reconsidering the epidemiological data on sex ratio in vitiligo. PMID- 22512841 TI - Alerting and orienting of attention without visual awareness. AB - Two types of the attentional network, alerting and orienting, help organisms respond to environmental events for survival in the temporal and spatial dimensions, respectively. Here, we applied chromatic flicker beyond the critical fusion frequency to address whether awareness was necessary for activation of the two attentional networks. We found that high-frequency chromatic flicker, despite its failure to reach awareness, produced the alerting and orienting effects, supporting the dissociation between attention and awareness. Furthermore, as the flicker frequency increased, the orienting effect attenuated whereas the alerting effect remained unchanged. According to the systematic decline in temporal frequency sensitivity across the visual hierarchy, this finding suggests that unconscious alerting might be associated with activity in earlier visual areas than unconscious orienting. Since high-frequency flicker has been demonstrated to only activate early visual cortex, we suppose that neural activation in early visual areas might be sufficient to activate the two attentional networks. PMID- 22512842 TI - Autoimmune disease-associated CD226 gene variants are not involved in giant cell arteritis susceptibility in the Spanish population. AB - OBJECTIVES: CD226 genetic variants have been associated with a number of autoimmune diseases. The aim of this study was to investigate the potential implication of the CD226 loci in the susceptibility to and main clinical manifestations of giant cell arteritis (GCA). METHODS: A Spanish Caucasian cohort of 455 patients diagnosed with biopsy-proven GCA and 1414 healthy controls were included in the study. Three CD226 polymorphisms, rs727088, rs34794968 and rs763361, were genotyped using the TaqMan(r) allelic discrimination technology. PLINK software was used for the statistical analyses. RESULTS: No significant association between the CD226 polymorphisms and susceptibility to GCA was found (rs727088: p=0.92, OR=1.01, CI 95% 0.86-1.18; rs34794968: p=0.61, OR=1.04, CI 95% 0.89-1.22; rs763361: p=0.88, OR=0.99, CI 95% 0.84-1.16). Similarly, when patients were stratified according to the specific clinical features of GCA such as polymyalgia rheumatica, visual ischaemic manifestations or irreversible occlusive disease, no association was observed either between the case subgroups and the control set or between GCA patients with and without the specific features of the disease. Furthermore, the haplotype analysis revealed no significant association with the clinical manifestations of the disease. CONCLUSIONS: Our results show that the three CD226 polymorphisms analysed do not play a relevant role in the susceptibility to GCA and clinical manifestations of this vasculitis. PMID- 22512843 TI - Gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (INFORM; C-TONG 0804): a multicentre, double-blind randomised phase 3 trial. AB - BACKGROUND: Maintenance treatment of patients with advanced non-small-cell lung cancer (NSCLC) without disease progression after first-line chemotherapy is a subject of ongoing research. The aim of the randomised, double-blind, placebo controlled, INFORM study was to investigate the efficacy, safety, and tolerability of the EGFR-tyrosine-kinase inhibitor gefitinib in the maintenance setting. METHODS: Patients were aged 18 years or older, were of east Asian ethnic origin, had a life expectancy of more than 12 weeks, histologically or cytologically confirmed stage IIIb or IV NSCLC, a WHO performance status of 0-2, and had completed four cycles of first-line platinum-based doublet chemotherapy without disease progression or unacceptable toxic effects. Between Sept 28, 2008 and Aug 11, 2009, 296 patients were randomly assigned 1:1 to receive either gefitinib (250 mg per day orally) or placebo (orally) within 3-6 weeks after chemotherapy until progression or unacceptable toxic effects. Randomisation was done via an interactive web response system with computer-generated randomisation codes. Our primary endpoint was progression-free survival assessed in the intention-to-treat population. This completed study is registered with Clinicaltrials.gov, number NCT00770588. FINDINGS: Progression-free survival was significantly longer with gefitinib (n=148) than with placebo (148) (median progression-free survival 4.8 months [95% CI 3.2-8.5] vs 2.6 months [1.6-2.8]; hazard ratio [HR] 0.42, 95% CI 0.33-0.55; p<0.0001). Adverse events occurred more frequently with gefitinib than with placebo; the most common adverse events of any grade were rash (73 [50%] of 147 in the gefitinib group vs 14 [9%] of 148 in the placebo group), diarrhoea (37 [25%] vs 13 [9%]), and alanine aminotransferase increase (31 [21%] vs 12 [8%]). The most commonly reported grade 3 or 4 adverse event was alanine aminotransferase increase (3 [2%] of 147 in the gefitinib group, none of 148 in the placebo group). Ten of 147 (7%) patients given gefitinib and five of 148 (3%) patients given placebo had serious adverse events. Three deaths were thought to be related to treatment with gefitinib: one from interstitial lung disease; one from lung infection; and one from pneumonia. INTERPRETATION: Maintenance treatment with gefitinib significantly prolonged progression-free survival compared with placebo in patients from east Asia with advanced NSCLC who achieved disease control after first-line chemotherapy. Clinicians should consider these data when making decisions about maintenance treatment in such patients. FUNDING: AstraZeneca. PMID- 22512845 TI - Prostate cancer treatment unblinded. PMID- 22512844 TI - Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study. AB - BACKGROUND: Radical whole-gland therapy can lead to significant genitourinary and rectal side-effects for men with localised prostate cancer. We report on whether selective focal ablation of unifocal and multifocal cancer lesions can reduce this treatment burden. METHODS: Men aged 45-80 years were eligible for this prospective development study if they had low-risk to high-risk localised prostate cancer (prostate specific antigen [PSA] <=15 ng/mL, Gleason score <=4 + 3, stage <=T2), with no previous androgen deprivation or treatment for prostate cancer, and who could safely undergo multiparametric MRI and have a general anaesthetic. Patients received focal therapy using high-intensity focused ultrasound, delivered to all known cancer lesions, with a margin of normal tissue, identified on multiparametric MRI, template prostate-mapping biopsies, or both. Primary endpoints were adverse events (serious and otherwise) and urinary symptoms and erectile function assessed using patient questionnaires. Analyses were done on a per-protocol basis. This study is registered with ClinicalTrials.gov, number NCT00561314. FINDINGS: 42 men were recruited between June 27, 2007, and June 30, 2010; one man died from an unrelated cause (pneumonia) 3 months after treatment and was excluded from analyses. After treatment, one man was admitted to hospital for acute urinary retention, and another had stricture interventions requiring hospital admission. Nine men (22%, 95% CI 11-38) had self-resolving, mild to moderate, intermittent dysuria (median duration 5.0 days [IQR 2.5-18.5]). Urinary debris occurred in 14 men (34%, 95% CI 20-51), with a median duration of 14.5 days (IQR 6.0-16.5). Urinary tract infection was noted in seven men (17%, 95% CI 7-32). Median overall International Index of Erectile Function-15 (IIEF-15) scores were similar at baseline and at 12 months (p=0.060), as were median IIEF-15 scores for intercourse satisfaction (p=0.454), sexual desire (p=0.644), and overall satisfaction (p=0.257). Significant deteriorations between baseline and 12 months were noted for IIEF-15 erectile (p=0.042) and orgasmic function (p=0.003). Of 35 men with good baseline function, 31 (89%, 95% CI 73-97) had erections sufficient for penetration 12 months after focal therapy. Median UCLA Expanded Prostate Cancer Index Composite (EPIC) urinary incontinence scores were similar at baseline as and 12 months (p=0.045). There was an improvement in lower urinary tract symptoms, assessed by International Prostate Symptom Score (IPSS), between baseline and 12 months (p=0.026), but the IPSS-quality of life score showed no difference between baseline and 12 months (p=0.655). All 38 men with no baseline urinary incontinence were leak-free and pad-free by 9 months. All 40 men pad-free at baseline were pad-free by 3 months and maintained pad-free continence at 12 months. No significant difference was reported in median Trial Outcomes Index scores between baseline and 12 months (p=0.113) but significant improvement was shown in median Functional Assessment of Cancer Therapy (FACT)-Prostate (p=0.045) and median FACT-General scores (p=0.041). No histological evidence of cancer was identified in 30 of 39 men biopsied at 6 months (77%, 95% CI 61-89); 36 (92%, 79 98) were free of clinically significant cancer. After retreatment in four men, 39 of 41 (95%, 95% CI 83-99) had no evidence of disease on multiparametric MRI at 12 months. INTERPRETATION: Focal therapy of individual prostate cancer lesions, whether multifocal or unifocal, leads to a low rate of genitourinary side-effects and an encouraging rate of early absence of clinically significant prostate cancer. FUNDING: Medical Research Council (UK), Pelican Cancer Foundation, and St Peters Trust. PMID- 22512846 TI - Is benefit of maintenance therapy for NSCLC best defined by progression-free survival? PMID- 22512847 TI - Accelerometry-based gait analysis, an additional objective approach to screen subjects at risk for falling. AB - This study investigated whether the Tinetti scale, as a subjective measure for fall risk, is associated with objectively measured gait characteristics. It is studied whether gait parameters are different for groups that are stratified for fall risk using the Tinetti scale. Moreover, the discriminative power of gait parameters to classify elderly according to the Tinetti scale is investigated. Gait of 50 elderly with a Tinneti>24 and 50 elderly with a Tinetti<=24 was analyzed using acceleration-based gait analysis. Validated algorithms were used to derive spatio-temporal gait parameters, harmonic ratio, inter-stride amplitude variability and root mean square (RMS) from the accelerometer data. Clear differences in gait were found between the groups. All gait parameters correlated with the Tinetti scale (r-range: 0.20-0.73). Only walking speed, step length and RMS showed moderate to strong correlations and high discriminative power to classify elderly according to the Tinetti scale. It is concluded that subtle gait changes that have previously been related to fall risk are not captured by the subjective assessment. It is therefore worthwhile to include objective gait assessment in fall risk screening. PMID- 22512848 TI - How an acute mastering of balance on a seesaw can improve the relationship between "static" and "dynamic" upright postural control. AB - Postural control ability has been widely evaluated using undisturbed upright stance protocols. However, standing on a seesaw may offer additional insights due to changes in the available sensory information and the amplification of the motor command resulting from the translational and rotational movement of the device. These two tasks share close biomechanical and neurophysiological principles. To highlight their possible linkage, 32 young healthy adults participated in this study, which consisted of testing postural performance while standing on a firm surface or on a seesaw producing rolling or pitching movements. The results showed increased CP displacements along the seesaw's pitching or rolling axis and also along the perpendicular axis. However, comparing the two tasks can be difficult because of discrepancies in the ability to rapidly master the new constraints brought about by the seesaw. To highlight the role played by adaptation, 15 subjects of the whole sample participated in a complementary protocol consisting of a 20-min training session aimed at improving the mastery of the seesaw producing pitch motions. The relationship between the amplitudes of the CP displacements between "static" and "dynamic" tasks was investigated. Interestingly, whereas no statistically significant linear correlation was found before training, several significant correlations were found after pitch training for AP displacements. By emphasizing the key role played by short-term adaptation in standing performance, these results are likely to have potential implications regarding the conception of standardized tests aimed at evaluating postural ability in healthy or disabled subjects. PMID- 22512849 TI - Infrared probing of 4-azidoproline conformations modulated by azido configurations. AB - 4-Azidoproline (Azp) can tune the stability of the polyproline II (P(II)) conformation in collagen. The azido group in the 4R and 4S configurations stabilizes and destabilizes the P(II) conformation, respectively. To obtain insights into the dependence of the conformational stability on the azido configuration, we carried out Fourier transform (FT) IR experiments with four 4 azidoproline derivatives, Ac-(4R/S)-Azp-(NH/O)Me. We found that the amide I and azido IR spectra are different depending on the azido configuration and C terminal structure. The origin of such spectral differences between 4R and 4S configurations and between C-terminal methylamide and ester ends was elucidated by quantum chemistry calculations in combination with (1)H NMR and time- and frequency-resolved IR pump-probe spectroscopy. We found that the azido configurations and C-terminal structures affect intramolecular interactions, which are responsible for the ensuing conformational and thereby IR spectral differences. Consequently, 4-azidoproline conformations modulated by azido configurations can be probed by IR spectroscopy. These findings suggest that 4 azidoproline can be both a structure-control and -probing element, which enables the infrared tracking of proline roles in protein structure, function, and dynamics. PMID- 22512850 TI - Unexplained neonatal jaundice as an early diagnostic sign of urinary tract infection. AB - BACKGROUND: Hyperbilirubinemia is one of the presenting signs of bacterial infection in newborns, and the association of neonatal jaundice with urinary tract infection (UTI) has been particularly emphasized. The aim of this study was to determine the prevalence of UTI in asymptomatic jaundiced neonates younger than 4 weeks old. METHODS: We prospectively evaluated 120 asymptomatic jaundiced and 122 healthy neonates without jaundice younger than 4 weeks old for UTI. Patients with UTI, defined as >10,000 colony-forming units of a single pathogen per milliliter urine obtained by bladder catheterization, were evaluated for sepsis. RESULTS: Of 120 asymptomatic jaundiced neonates with a mean age of 7 +/- 4 days, 15 (12.5%) had a UTI. Of 122 healthy neonates, positive urine cultures from a urine bag were found in eight cases; however on reevaluation, urine cultures from bladder catheterization were negative. The most common pathogen isolated from the UTI cases was Klebsiella pneumoniae. Also, unconjugated hyperbilirubinemia was detected in all jaundiced patients with UTI. CONCLUSION: UTI was found in 12.5% of the asymptomatic jaundiced neonates with the onset of unconjugated hyperbilirubinemia in the first week of life. Therefore, we suggest that urine culture should be considered as a part of the diagnostic evaluation of jaundiced neonates older than 3 days with an unexplained etiology. PMID- 22512851 TI - Emerging clinico-epidemiological trends in melioidosis: analysis of 95 cases from western coastal India. AB - OBJECTIVES: To study the clinico-epidemiological trends in melioidosis, an emerging disease in the western coastal region of India. METHODS: Data of 95 patients with melioidosis in the western coastal region of India were retrospectively analyzed with respect to monthly rainfall, risk factors, clinical presentations, and outcome. RESULTS: A strong linear correlation was seen between average monthly rainfall and the occurrence of cases (p=0.002). Mortality was seen only in patients with bacteremia (p<0.001). Nine (40.9%) patients with septic shock died (p<0.001). Age >= 40 years and diabetes mellitus were seen in 75.8% of cases, each. Pneumonia was the most common clinical presentation (32.6%), followed by musculoskeletal disease (20%), melioidotic lymphadenopathy (7.4%), and dental abscess (6.3%). Only 36.8% of patients had exposure to wet soil/surface water. CONCLUSIONS: Melioidosis is quite prevalent in the western coastal region of India, and is strongly associated with rainfall, age, and diabetes mellitus. Higher proportions of musculoskeletal, dental, and lymph node melioidosis were seen in this region as compared to endemic areas. Bacteremic melioidosis has a poorer prognosis than non-bacteremic melioidosis. The presence of septic shock is a strong predictor of mortality. Percutaneous inoculation may not be the main portal of entry for Burkholderia pseudomallei in this region. PMID- 22512852 TI - Comparison of the epidemiology, risk factors, outcome and degree of organ failures of patients with candidemia acquired before or during ICU treatment. AB - INTRODUCTION: The aim of this study was to compare the epidemiology, risk factors, severity and outcome of two types of ICU-treated candidemias: namely, ICU-acquired candidemia (acquired after 48-hour ICU stay) (ICUAC group), and those needing ICU treatment for candidemia acquired before ICU admission or during the first 48-hour ICU stay (non-ICUAC group). METHODS: A retrospective cohort study was conducted between 2000 and 2009 in a mixed tertiary ICU among patients with blood-culture-confirmed candidemia. RESULTS: The study involved 82 patients (53 men). The ICUAC group consisted of 38 patients (46.3%) and the non- ICUA group included 44 patients (53.6). The ICUAC group had undergone previous surgery more often and had ICU stays that were 3.7 times longer than the non ICUAC group, whose members more often had co-morbidities (95.6% versus 73.7%, P = 0.001). The ICUAC group had significantly more frequent organ failures with cardiovascular, renal, central nervous and coagulation systems than the non-ICUAC group. ICU, hospital and one-year mortality rates did not differ between the groups (23%, 36.8% and 65.8%, respectively, in the ICUAC group and 26%, 44.4% and 64.4%, respectively, in the non-ICUAC group). Among patients with APACHE II scores greater than 25, the ICUAC group had lower one-year mortality (65.0% versus 87.5%). Among patients with APACHE II scores of 25 or less, the ICUAC group had higher mortality (66.7% versus 50.0). Candida albicans was most common cause of candidemia in both groups (76.3% and 68.9%, respectively). CONCLUSIONS: More than half of the ICU-treated candidemias were acquired prior to admission to the ICU. Patients with ICU- and non-ICU-acquired candidemias had different risk factors and different needs for ICU resources. Hospital mortality was similar in both groups; however, the groups had different mortality rates when the severity of disease and underlying diseases were taken into account. PMID- 22512853 TI - Racial/ethnic and age differences in women's awareness of heart disease. AB - BACKGROUND: The purpose of this study was to examine differences in awareness of heart disease among women according to race/ethnicity by age group, adjusted for confounders. METHODS: American Heart Association (AHA) National Surveys conducted in 2006 (n=1005) and 2009 (n=1142) were pooled using common variables (n=2147) and reweighted to reflect the 2010 United States Census. Surveys comprised standardized, interviewer-assisted demographic and awareness questions. Associations between racial/ethnic group and heart disease awareness stratified by age were assessed by weighted chi-square statistics; logistic regression was used for multivariable adjustment. RESULTS: Black and Hispanic women were 66% less likely than white women to be aware that heart disease is the leading cause of death in women (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.23-0.50) after multivariable adjustment for significant confounders. The percent aware among white women was 65%; awareness did not differ between black and Hispanic women (37% vs. 38%). Other significant multivariable predictors included =55 years). Awareness of heart attack signs, such as shortness of breath (34%), nausea (15%), and fatigue (7%), was low among all women. CONCLUSIONS: Racial/ethnic minority status and age<55 years were significant risk factors for lower heart disease awareness among women, suggesting these groups should be targeted for educational programs. Awareness of heart attack signs was low among all subgroups of women. PMID- 22512856 TI - Is advice incompatible with autonomous informed choice? Women's perceptions of advice in the context of antenatal screening: a qualitative study. AB - BACKGROUND: Patient autonomy in antenatal screening is a high priority for policy developers in many countries. OBJECTIVE: This paper presents women's understandings of how health professionals should facilitate informed screening choices with an emphasis on their understandings of autonomy and advice. DESIGN, SETTING AND PARTICIPANTS: The study was carried out in 2009 in the UK, using a qualitative approach. Ninety-eight participants of African, British White, Caribbean, Chinese and Pakistani origin had semi-structured interviews, which were analysed using framework analysis. RESULTS: Four themes were identified during the analysis: 'Meanings of advice in antenatal screening: the advice continuum', 'Recognition of the role of health professionals in decision making', 'Understandings of advice in the context of autonomous decision making' and 'Reasons given for wanting advice'. Women said they valued advice from health professionals to make decisions about antenatal screening, but their understandings of 'advice' ranged from information giving only to direction about screening choices. CONCLUSION: Many women wanted health professionals to support the process of making informed choices by engaging in discussion and did not see advice as incompatible with making autonomous choices. However, some women wanted direction about whether to have a screening test or not, something which policy and guidelines explicitly prohibit. This may cause an ethical dilemma for health professionals who are required to both support women's preference for care and adhere to a policy of non-directiveness. Further clarification is needed on how health professionals should support the process of making informed choices when women ask for clear direction on screening choices. PMID- 22512857 TI - High prevalence of antibiotic resistance in commensal Escherichia coli among children in rural Vietnam. AB - BACKGROUND: Commensal bacteria represent an important reservoir of antibiotic resistance genes. Few community-based studies of antibiotic resistance in commensal bacteria have been conducted in Southeast Asia. We investigated the prevalence of resistance in commensal Escherichia coli in preschool children in rural Vietnam, and factors associated with carriage of resistant bacteria. METHODS: We tested isolates of E. coli from faecal samples of 818 children aged 6 60 months living in FilaBavi, a demographic surveillance site near Hanoi. Daily antibiotic use data was collected for participating children for three weeks prior to sampling and analysed with socioeconomic and demographic characteristics extracted from FilaBavi's re-census survey 2007. Descriptive statistics were generated, and a logistic regression model was used to identify contributions of the examined factors. RESULTS: High prevalences of resistance were found to tetracycline (74%), co-trimoxazole (68%), ampicillin (65%), chloramphenicol (40%), and nalidixic acid (27%). Two isolates were resistant to ciprofloxacin. Sixty percent of isolates were resistant to three or more antibiotics. Recent sulphonamide use was associated with co-trimoxazole resistance [OR 3.2, 95% CI 1.8-5.7], and beta-lactam use with ampicillin resistance [OR 1.8, 95% CI 1.3 2.4]. Isolates from children aged 6-23 months were more likely to be resistant to ampicillin [OR 1.8, 95% CI 1.3-2.4] and co-trimoxazole [OR 1.5, 95% CI 1.1-2.0]. Associations were identified between geographical areas and tetracycline and ampicillin resistance. CONCLUSIONS: We present high prevalence of carriage of commensal E. coli resistant to commonly used antibiotics. The identified associations with recent antibiotic use, age, and geographical location might contribute to our understanding of carriage of antibiotic resistant commensal bacteria. PMID- 22512858 TI - SPR sensing of bisphenol A using molecularly imprinted nanoparticles immobilized on slab optical waveguide with consecutive parallel Au and Ag deposition bands coexistent with bisphenol A-immobilized Au nanoparticles. AB - A slab-type optical waveguide (s_OWG)-based microfluidic SPR measurement system for bisphenol A was developed. This s_OWG possesses consecutive parallel gold and silver deposition bands in the line of plasmon flow, allowing two individual SPR signals to be independently obtained as a result of the difference in resonant reflection spectra of these metals. As a molecular recognition element, molecularly imprinted polymer nanoparticles (MIP-Np) were employed and immobilized on the surface of each of the gold and silver deposition bands. The resonant reflection spectra were measured on the MIP-Np-immobilized consecutive parallel gold and silver deposition bands coexistent with BPA-AuNp. The Ag-based SPR spectra showed a red shift (0.7 nm) when free BPA (0.1 mM) was passed over the BPA-AuNp/immobilized MIP-Np complexes formed on the s_OWG, unlike the case for the Au deposition band, while a large excess of BPA induced a blue shift due to the competitive desorption of BPA-AuNp from the immobilized MIP-Np on the s_OWG. By using the proposed detection system, binding events of other small molecules could be monitored in conjunction with the use of MIP-Np and labeled AuNp. PMID- 22512860 TI - Surface-plasmon-induced modification on the spontaneous emission spectrum via subwavelength-confined anisotropic Purcell factor. AB - The mechanism of using the anisotropic Purcell factor to control the spontaneous emission linewidths in a four-level atom is theoretically demonstrated; if the polarization angle bisector of the two dipole moments lies along the axis of large/small Purcell factor, destructive/constructive interference narrows/widens the fluorescence center spectral lines. Large anisotropy of the Purcell factor, confined in the subwavelength optical mode volume, leads to rapid spectral line narrowing of atom approaching a metallic nanowire, nanoscale line width pulsing following periodically varying decay rates near a periodic metallic nanostructure, and dramatic modification on the spontaneous emission spectrum near a custom-designed resonant plasmon nanostructure. The combined system opens a good perspective for applications in ultracompact active quantum devices. PMID- 22512861 TI - Mediators of weight loss in the 'Healthy Dads, Healthy Kids' pilot study for overweight fathers. AB - BACKGROUND: A poor understanding of the specific lifestyle behaviors that result in weight loss has hindered the development of effective interventions. The aim of this paper was to identify potential behavioral mediators of weight loss in the Healthy Dads, Healthy Kids (HDHK) intervention for overweight fathers. FINDINGS: The three-month intervention was evaluated in a randomized controlled trial and conducted in Newcastle, New South Wales, Australia. Baseline, three month (immediate post-intervention) and six month assessments were conducted. Recruitment and follow-up occurred between October 2008 and May 2009. The study sample included 53 overweight/obese men [mean ( SD) age=40.6( 97.1) years; body mass index (BMI)=33.2 (3.9) kgm-2] and their primary school-aged children [n=71, 54% boys; age=8.2 (2.0) years] who were randomized to HDHK program or a wait-list control group. Physical activity (PA) was assessed using pedometers and dietary behaviors were measured using a validated food frequency questionnaire. The intervention resulted in significant weight loss (5.131.27 kg, P<0.0001) and increased PA among fathers (2769750 steps/day, P<0.001) and their children (1486521 steps/day, P<0.01). Fathers PA mediated weight loss in the intervention (AB=2.31, 95% CI=4.63 to 0.67) and was responsible for 47% of the intervention effect. Changes in dietary behaviors were not statistically significant. CONCLUSIONS: PA was an important mediator of weight loss in the HDHK intervention. Encouraging overweight fathers to be more active with their children appears to be a promising strategy for obesity treatment in men. PMID- 22512859 TI - Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cdelta. AB - This study examined the role of protein kinase C (PKC) isozymes in methamphetamine (MA)-induced dopaminergic toxicity. Multiple-dose administration of MA did not significantly alter PKCalpha, PKCbetaI, PKCbetaII, or PKCzeta expression in the striatum, but did significantly increase PKCdelta expression. Go6976 (a co-inhibitor of PKCalpha and -beta), hispidin (PKCbeta inhibitor), and PKCzeta pseudosubstrate inhibitor (PKCzeta inhibitor) did not significantly alter MA-induced behavioral impairments. However, rottlerin (PKCdelta inhibitor) significantly attenuated behavioral impairments in a dose-dependent manner. In addition, MA-induced behavioral impairments were not apparent in PKCdelta knockout (-/-) mice. MA-induced oxidative stress (i.e., lipid peroxidation and protein oxidation) was significantly attenuated in rottlerin-treated mice and was not apparent in PKCdelta (-/-) mice. Consistent with this, MA-induced apoptosis (i.e., terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive apoptotic cells) was significantly attenuated in rottlerin-treated mice. Furthermore, MA-induced increases in the dopamine (DA) turnover rate and decreases in tyrosine hydroxylase (TH) activity and the expression of TH, dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) were not significantly observed in rottlerin-treated or PKCdelta (-/-) mice. Our results suggest that PKCdelta gene expression is a key mediator of oxidative stress and dopaminergic damage induced by MA. Thus, inhibition of PKCdelta may be a useful target for protection against MA-induced neurotoxicity. PMID- 22512862 TI - CcpA forms complexes with CodY and RpoA in Bacillus subtilis. AB - The Bacillus subtilis catabolite control protein A (CcpA) is a global transcriptional regulator that is controlled by interactions with the phosphoproteins histidine-containing protein (HPr)Ser46P and the catabolite responsive HPr (Crh)Ser46P and with low molecular weight effectors, depending on the availability of preferred carbon sources such as glucose. Distinct point mutations in CcpA abolish the regulation of some but not all target genes, suggesting additional interactions of CcpA. Therefore, in vivo crosslinking and MS were applied to identify CcpA complexes active in repression and activation. To compensate for an excess of promoters only repressed by CcpA, this experiment was accomplished with cells using multiple copies of the activated ackA promoter. Among the identified proteins HPr, RNA polymerase subunits and the global regulator transcriptional pleiotropic repressor (CodY) were observed. Bacterial two-hybrid assays combining each RNA polymerase subunit with CcpA localized CcpA binding at the alpha-subunit of the RNA polymerase (RpoA). In vivo crosslinking combined with immunoblot analyses revealed CcpA-RpoA complexes in cultures with or without glucose, whereas CcpA-HPr and CcpA-CodY complexes occurred only or predominantly in cultures with glucose. Surface plasmon resonance analyses confirmed the binding of CcpA to the N-terminal domain (alphaNTD) and C-terminal domain (alphaCTD) of RpoA, as well as to CodY. Furthermore, interactions of CodY with the alphaNTD and the alphaCTD were detected by surface plasmon resonance. The K(D) values of complexes of CcpA or CodY with the alphaNTD or the alphaCTD are in the range 5-8 MUm. CcpA and CodY form a loose complex with a K(D) of 60 MUm. These data were combined to propose a model for a transcription initiation complex at the ackA promoter. PMID- 22512865 TI - Penetration of Prulifloxacin in human aqueous humour following oral administration. PMID- 22512866 TI - Aquagenic (pseudo) keratoderma: a clinical series with new pathological insights. AB - BACKGROUND: Aquagenic keratoderma is an uncommon condition that occurs after brief water exposure. An association with cystic fibrosis has been suggested. Histopathology is considered to be nonspecific. OBJECTIVES: To describe the microscopic findings in seven of 12 new patients and compare the histopathological results of the lesions which appeared on the palmar skin after immersion into water with normal skin. PATIENTS AND METHODS: Nine female and three male patients (mean age 27 years) were collected prospectively and evaluated for common demographic, clinical and histopathological features. RESULTS: Lesions were located on only the palms in seven patients; the soles were involved in two patients; and one patient had involvement of the dorsal aspect of the hands. One patient had a similar family history. None of the patients reported associated conditions. Genetic studies revealed heterozygosis for mutation in the cystic fibrosis gene in two patients. The most specific histopathological findings were: orthohyperkeratosis with increased thickness and abnormal staining of the stratum corneum; dilated acrosyringia and dermal eccrine ducts with hyperplasia of eccrine glands, clear cell change and vacuolation; increased capillaries around and adjacent to the eccrine glands. A skin biopsy taken after restoration of normal skin with drying revealed a normal stratum corneum with a physiological uniform stain and normal thickness without further evidence of dilation of acrosyringia or dermal eccrine ducts. Incipient dilation of the secretory and ductal structures was also observed in a transitional area between the involved and the clinically normal skin of the palms. CONCLUSIONS: Aquagenic keratoderma may be associated with a heterozygous mutation in the cystic fibrosis gene. Although the diagnosis is a clinical one, histopathology is useful and may reveal some characteristic diagnostic clues. Aquagenic pseudokeratoderma seems to be a more appropriate term to name it. PMID- 22512864 TI - Cyclin K goes with Cdk12 and Cdk13. AB - The cyclin-dependent kinases (Cdks) regulate many cellular processes, including the cell cycle, neuronal development, transcription, and posttranscriptional processing. To perform their functions, Cdks bind to specific cyclin subunits to form a functional and active cyclin/Cdk complex. This review is focused on Cyclin K, which was originally considered an alternative subunit of Cdk9, and on its newly identified partners, Cdk12 and Cdk13. We briefly summarize research devoted to each of these proteins. We also discuss the proteins' functions in the regulation of gene expression via the phosphorylation of serine 2 in the C terminal domain of RNA polymerase II, contributions to the maintenance of genome stability, and roles in the onset of human disease and embryo development. PMID- 22512867 TI - Ultrasonography in gout: a case-control study. AB - OBJECTIVES: To determine the sensitivity and specificity of ultrasonography for gout, and to investigate the relationship with severity of gout. METHODS: In this case-control study, we prospectively enrolled 53 patients with crystal-proven gout and 50 controls. Ultrasonography was performed on 10 joints for each patient (metatarsophalangeal [MTP] joints 1-2, knees, metacarpophalangeal [MCP] joints 2 3) to determine the prevalence of the double contour (DC) sign and tophi in each site. RESULTS: We assessed 530 joints in gouty patients and 500 in controls. Gouty patients had a mean disease duration 9.2+/-10.7 years and a mean of 14.7+/ 19.8 acute attacks. Clinical exam revealed tophi in 44% of patients. Mean urate level was 656.7+/-145.3 MUM. Inter-reader agreement between the 2 sonographers was excellent for both DC sign and tophi. The frequency of the DC sign in MTPs, knees and MCPs for gouty patients and controls was 67% vs. 2%, 57% vs. 0%, and 21% vs. 0%, respectively (all p<0.001), whereas that of tophi, only found in gouty patients, was 74%, 42% and 22%, respectively (p<0.001). The sensitivity of the DC sign was 67% for MTPs, 57% for knees and 21% for MCPs, and specificity was high (all >98%). The sensitivity of tophi was 74%, 42% and 22%, respectively, and specificity 100% for all sites. For MTPs, the DC sign, but not tophi, was significantly associated with uricemia (p<0.05) and disease duration (p=0.01). CONCLUSIONS: Ultrasonography has good sensitivity and specificity to diagnose gout. Sensitivity depends on disease duration, joint site and severity of the disease. PMID- 22512869 TI - Effects of workshop trainings on evidence-based practice knowledge and attitudes among youth community mental health providers. AB - Enhancing the public health impact of evidence-based practices (EBPs) in usual care settings is a key priority of the National Institute of Mental Health. Longitudinal data from community mental health providers (N = 268) participating in a series of state-sponsored workshops in modular approaches to EBPs for youth are presented. EBP workshop attendance for youth anxiety resulted in increased knowledge for EBPs for anxiety (and not other conditions) and EBP workshop attendance for youth disruptive behaviors resulted in increased knowledge for EBPs for disruptive behaviors (and not other conditions). Providers' tendencies toward incorrectly classifying non-EBP therapies as evidence-based increased over time, suggesting that providers over-generalize the EBP label as a result of attending these types of workshops. Regarding EBP attitudes, most measures of attitudes improved when providers attended a workshop. Additionally, an overly inclusive view of what constitutes an EBP at intake was related to significant decreases in openness to trying EBPs over time, whereas more positive attitudes at intake was related to achieving a more refined view of what constitutes an EBP over the course of attending trainings. Study limitations and implications for implementation of EBPs in usual care settings are discussed. PMID- 22512868 TI - Regulation of transcriptome, translation, and proteome in response to environmental stress in fission yeast. AB - BACKGROUND: Gene expression is controlled globally and at multiple levels in response to environmental stress, but the relationships among these dynamic regulatory changes are not clear. Here we analyzed global regulation during different stress conditions in fission yeast, Schizosaccharomyces pombe, combining dynamic genome-wide data on mRNA, translation, and protein profiles. RESULTS: We observed a strong overall concordance between changes in mRNAs and co directional changes in translation, for both induced and repressed genes, in response to three conditions: oxidative stress, heat shock, and DNA damage. However, approximately 200 genes each under oxidative and heat stress conditions showed discordant regulation with respect to mRNA and translation profiles, with genes and patterns of regulation being stress-specific. For oxidative stress, we also measured dynamic profiles for 2,147 proteins, comprising 43% of the proteome. The mRNAs induced during oxidative stress strongly correlated with increased protein expression, while repressed mRNAs did not relate to the corresponding protein profiles. Overall changes in relative protein expression correlated better with changes in mRNA expression than with changes in translational efficiency. CONCLUSIONS: These data highlight a global coordination and fine-tuning of gene regulation during stress that mostly acts in the same direction at the levels of transcription and translation. In the oxidative stress condition analyzed, transcription dominates translation to control protein abundance. The concordant regulation of transcription and translation leads to the expected adjustment in protein expression only for up-regulated mRNAs. These patterns of control might reflect the need to balance protein production for stress survival given a limited translational capacity. PMID- 22512871 TI - Impact of defoliation intensities on plant biomass, nutrient uptake and arbuscular mycorrhizal symbiosis in Lotus tenuis growing in a saline-sodic soil. AB - The impact of different defoliation intensities on the ability of Lotus tenuis plants to regrowth, mobilise nutrients and to associate with native AM fungi and Rhizobium in a saline-sodic soil was investigated. After 70 days, plants were subjected to 0, 25, 50, 75 and 100% defoliation and shoot regrowth was assessed at the end of subsequent 35 days. Compared to non-defoliated plants, low or moderate defoliation up to 75% did not affect shoot regrowth. However, 100% treatment affected shoot regrowth and the clipped plants were not able to compensate the growth attained by non-defoliated plants. Root growth was more affected by defoliation than shoot growth. P and N concentrations in shoots and roots increased with increasing defoliation while Na(+) concentration in shoots of non-defoliated and moderately defoliated plants was similar. Non-defoliated and moderately defoliated plants prevented increases of Na(+) concentration in shoots through both reducing Na(+) uptake and Na(+) transport to shoots by accumulating Na(+) in roots. At high defoliation, the salinity tolerance mechanism is altered and Na(+) concentration in shoots was higher than in roots. Reduction in the photosynthetic capacity induced by defoliation neither changed the root length colonised by AM fungi nor arbuscular colonisation but decreased the vesicular colonisation. Spore density did not change, but hyphal density and Rhizobium nodules increased with defoliation. The strategy of the AM symbiont consists in investing most of the C resources to preferentially retain arbuscular colonisation as well as inoculum density in the soil. PMID- 22512870 TI - Smoking and behavioral health of women. AB - BACKGROUND: Using data from a study of reliability and validity of a screening tool for co-occurring substance abuse and mental health problems, our objective was to compare behavioral health issues of female smokers and nonsmokers and explore correlates of smoking. METHODS: Using a convenience sample (n=1021), we recruited participants to complete an online survey conducted in substance abuse treatment, primary care, mental health services, senior, and public settings. The survey included demographic questions, smoking status, the co-occurring disorders screening tool, the Global Appraisal of Individual Needs-Short Screener (GAIN-SS) and the Postraumatic Stress Disorder Checklist (PCL)-Civilian. RESULTS: One third of participants self-identified as smokers, and African American, American Indian, and bisexual women reported the highest rates of smoking. Seventy-two percent of women reported at least one mental health problem in the past year; 29% had a past year substance abuse problem, and 26% reported a past year co occurring disorder of both. Smokers had significantly higher rates of posttraumatic stress disorder (PTSD), past year depression and anxiety, suicidality, past year substance abuse, and co-occurring disorders. Smokers also had significantly higher rates of lifetime intimate partner violence (IPV) and childhood abuse. CONCLUSIONS: Smoking in women was associated with significantly higher rates of mental health and substance abuse problems. Substance abuse, being in a treatment setting, IPV, African American and mixed ethnicity, Medicaid insurance status, reduced income, and no home ownership were identified as predictors of smoking. Screening and evaluation of smoking status, mental health, substance use disorders, and the presence and impact of violence are essential for women's health. PMID- 22512872 TI - Truncation of class IV chitinases from Arabidopsis by secreted fungal proteases. AB - Plant class IV chitinases have a small amino-terminal chitin-binding domain and a larger chitinase domain, and are involved in plant defence against fungal infection. Our previous work on the chitinases ChitA and ChitB from the model monocotyledon Zea mays showed that the chitin-binding domain is removed by secreted fungal proteases called fungalysins. In this article, we extend this work to dicotyledons. The effects of fungalysin-like proteases on four class IV chitinases from the model dicotyledon Arabidopsis thaliana were analysed. Four Arabidopsis chitinases were heterologously expressed in Pichia pastoris, purified and shown to have chitinase activity against a chitohexaose (dp6) substrate. The incubation of these four chitinases with Fv-cmp, a fungalysin protease secreted by Fusarium verticillioides, resulted in the truncation of AtchitIV3 and AtchitIV5. Moreover, incubation with secreted proteins from Alternaria brassicae, a pathogen of A. thaliana and brassica crops, also led to a similar truncation of AtchitIV3 and AtchitIV4. Our finding that class IV chitinases from both dicotyledons (A. thaliana) and monocotyledons (Z. mays) are truncated by proteases secreted by specialized pathogens of each plant suggests that this may be a general mechanism of plant-fungal pathogenicity. PMID- 22512873 TI - Seroprevalence of avian influenza A (H5N1) virus among poultry workers in Jiangsu Province, China: an observational study. AB - BACKGROUND: Since 2003 to 06 Jan 2012, the number of laboratory confirmed human cases of infection with avian influenza in China was 41 and 27 were fatal. However, the official estimate of the H5N1 case-fatality rate has been described by some as an over estimation since there may be numerous undetected asymptomatic/mild cases of H5N1 infection. This study was conducted to better understand the real infection rate and evaluate the potential risk factors for the zoonotic spread of H5N1 viruses to humans. METHODS: A seroepidemiological survey was conducted in poultry workers, a group expected to have the highest level of exposure to H5N1-infected birds, from 3 counties with habitat lakes of wildfowl in Jiangsu province, China. Serum specimens were collected from 306 participants for H5N1 serological test. All participants were interviewed to collect information about poultry exposures. RESULTS: The overall seropositive rate was 2.61% for H5N1 antibodies. The poultry number was found associated with a 2.39-fold significantly increased subclinical infection risk after adjusted with age and gender. CONCLUSIONS: Avian-to -human transmission of avian H5N1 virus remained low. Workers associated with raising larger poultry flocks have a higher risk on seroconversion. PMID- 22512874 TI - Classification bias in commercial business lists for retail food stores in the U.S. AB - BACKGROUND: Aspects of the food environment such as the availability of different types of food stores have recently emerged as key modifiable factors that may contribute to the increased prevalence of obesity. Given that many of these studies have derived their results based on secondary datasets and the relationship of food stores with individual weight outcomes has been reported to vary by store type, it is important to understand the extent to which often-used secondary data correctly classify food stores. We evaluated the classification bias of food stores in Dun & Bradstreet (D&B) and InfoUSA commercial business lists. METHODS: We performed a full census in 274 randomly selected census tracts in the Chicago metropolitan area and collected detailed store attributes inside stores for classification. Store attributes were compared by classification match status and store type. Systematic classification bias by census tract characteristics was assessed in multivariate regression. RESULTS: D&B had a higher classification match rate than InfoUSA for supermarkets and grocery stores, while InfoUSA was higher for convenience stores. Both lists were more likely to correctly classify large supermarkets, grocery stores, and convenience stores with more cash registers and different types of service counters (supermarkets and grocery stores only). The likelihood of a correct classification match for supermarkets and grocery stores did not vary systemically by tract characteristics whereas convenience stores were more likely to be misclassified in predominately Black tracts. CONCLUSION: Researches can rely on classification of food stores in commercial datasets for supermarkets and grocery stores whereas classifications for convenience and specialty food stores are subject to some systematic bias by neighborhood racial/ethnic composition. PMID- 22512875 TI - The relation between sunscreen layer thickness and vitamin D production after ultraviolet B exposure: a randomized clinical trial. AB - BACKGROUND: Sunscreens absorb ultraviolet B (UVB) and it is a major concern that sunscreen use may lead to vitamin D deficiency. OBJECTIVES: To investigate the relation between the amount of sunscreen applied and the vitamin D serum level in humans after UVB exposure under controlled conditions. METHODS: Thirty-seven healthy volunteers with fair skin types were randomized to receive an inorganic sunscreen with sun protection factor (SPF) 8 of 0 mg cm(-2) , 0.5 mg cm(-2) , 1 mg cm(-2) , 1.5 mg cm(-2) , or 2 mg cm(-2) thickness on the upper body, approximately 25% of the body area. Participants were irradiated with a fixed UVB dose of 3 standard erythema doses 20 min after sunscreen application. This procedure was repeated four times with a 2- to 3-day interval. Blood samples were drawn before the first irradiation and 3 days after the last to determine the serum vitamin D level expressed as 25-hydroxyvitamin D(3) [25(OH)D]. RESULTS: The vitamin D serum level increased in an exponential manner with decreasing thickness of sunscreen layer in response to UVB exposure. For all thicknesses of sunscreen, the level of 25(OH)D increased significantly after irradiation (P<0.05), except for the group treated with 2 mg cm(-2) , in which the increase in 25(OH)D was not statistically significant (P=0.16). CONCLUSIONS: Vitamin D production increases exponentially when thinner sunscreen layers than recommended are applied (<2 mg cm(-2) ). When the amount of sunscreen and SPF advised by the World Health Organization are used, vitamin D production may be abolished. Re evaluation of sun-protection strategies could be warranted. PMID- 22512876 TI - Simple synthesis of beta-trifluoromethylstyrenes using (E)-trimethyl-(3,3,3 trifluoroprop-1-enyl)silane. AB - (E)-trimethyl-(3,3,3-trifluoroprop-1-enyl)silane (1) was synthesized as a reagent for use in Hiyama cross-coupling reactions for the production of beta trifluoromethylstyrene derivatives. Cross-coupling of 1 with electronically diverse aryl iodides was achieved by treatment with CsF in the presence of catalytic amounts of palladium to afford the desired products in moderate to good yields. PMID- 22512878 TI - [Intravenous glutamine and early nasojejunal nutrition in severe acute pancreatitis -- a prospective randomized clinical study]. AB - INTRODUCTION: Severe acute pancreatitis (SAP) is still one of the great challenges in gastro-intestinal surgery. According to recent studies, intravenously administered glutamine with total parenteral nutrition may be beneficial in the prevention of infectious complications and may reduce mortality rate. However, it has not been investigated yet, whether i.v. glutamine is able to achieve the same effect with early enteral nutrition as well. OBJECTIVES: The objective of our prospective randomized double-blind study was to explore the effects of intravenously administered glutamine with early nasojejunal nutrition in severe acute pancreatitis. PATIENTS AND METHODS: Forty-five patients with severe acute pancreatitis (with a Glasgow score at least 3 and/or a CRP level above 150 mg/ml on admission) were randomized into two groups. Group Glutamine (n = 24) was given 0.5 g/kg/die glutamine intravenously, while the control group (n = 21) received normal amino acid solution in the same quantity for 7 days. Nasojejunal nutrition was introduced 48 hours after admission in case of all patients, and their management was the same in every other aspect, too. The primary end-points of the study were the rate of pancreas-specific infectious complications and organ failure, and the secondary end-points were the necessity for radiological and surgical interventions, length of hospital stay and mortality rate. RESULTS: In group Glutamine, infected acute peripancreatic fluid collections (APFC) were detected in 4 patients, 2 patients had post-necrotic pancreatic/peripancreatic fluid collections (PNPFC), 2 patients had infected pseudocysts and 2 patients had walled-off pancreatic necrosis (WOPN). Ten patients were cured by ultrasound assisted puncture or drainage successfully. No surgical intervention was necessary. In the control group, 4 patients had infected APFC, 2 patients had infected PNPFC, infected pseudocysts and infected WOPN were diagnosed in 3 cases. Radiological intervention was effective in 9 cases, but 3 patients needed surgery. Three patients died of multi-organ failure, thus the mortality rate of the control group was 14%, while the mortality rate of the Glutamine group was zero. The mean hospital stay of the Glutamine group was 10.6 days, which is significantly shorter than the mean hospital stay of the control group, which was 15.9 days (p = 0.00104). DISCUSSION: The results of the Glutamine group are better in every end-points, however, statistically significant difference was detected in one parameter only, the length of hospital stay. PMID- 22512879 TI - [Our efforts to decrease surgical complications following pancreatic resections]. AB - INTRODUCTION: The most frequent surgical complications following pancreatic resections are pancreatic fistula and delayed gastric emptying. The aim of the authors was to analyse these complications in their own practice. MATERIAL AND METHODS: Clinical data of 287 patients were reviewed, who were radically operated on for malignant pancreatic or periampullary tumours during 14 years period. The most common neoplasm was pancreatic adenocarcinoma, located in the head of the pancreas. Pylorus-preserving pancreatoduodenectomy was most frequently performed. In the early period pancreatogastrostomy and double-layer pancreatojejunostomy were preferred during the reconstruction, as well as retrocolic duodeno-, and gastrojejunostomy, respectively. Later the authors turned to the single-layer implantation pancreatojejunostomy and to the antecolic reconstruction, the latter was completed with Braun anastomosis. RESULTS: In the postoperative course complications occurred in 39%, reoperation was done in 5.6%, and the early mortality rate was 3.8%. The rate of pancreatic fistula decreased to 5.9% following single-layer pancreatojejunostomy, and the difference was significant compared to the 17.6% rate after pancreatogastrostomy. Due to the antecolic reconstruction the frequency of delayed gastric emptying has reduced from 10.2% to 2.1%, which is a statistically significant difference. CONCLUSIONS: As a result of changes in the surgical techniques during the 14 years period, the frequency of pancreatic fistula and delayed gastic emptying has dramatically decreased, which underlines the need of continuous progress in surgical methods. PMID- 22512880 TI - [Hepatic encephalopathy and liver transplantation]. AB - About 6500-7000 people/year die in Hungary due to liver cirrhosis which is often complicated with hepatic encephalopathy (HE). While conventional interpretation is that hepatic encephalopathy is a consequence of high blood ammonia level, recent data indicate that the degree of encephalopathy is related to systemic inflammatory response during decompensation. In this review the authors overview and analyze the latest treatment modalities of hepatic encephalopathy based on most recent findings. They found that frequently used evidence based treatment which apply metronidazole, neomycine or disaccharides was only partially effective in clinical studies. Use of rifaximine only is supported by grade I evidence, however it is quite a costly drug. The authors could not identify a generally accepted guideline for the treatment of HE with a systematic literature review, although it has significant effect on survival after liver transplantation. Therefore, the authors urge to develop a consensus guideline for the treatment of HE. PMID- 22512881 TI - [Double DIEP flaps for unilateral breast reconstruction]. AB - DIEP flap is a reliable option for autologous breast reconstruction after mastectomy. Previously performed lower median laparotomy can cause some difficulties in cases when more volume is needed than the DIEP flap harvested from one side can provide. We performed breast reconstruction using double hemi DIEP flaps in three of the cases discussed. All patients recovered without complications and had a good aesthetic outcome. This method offers a safe opportunity and broadens the spectrum of breast reconstruction. PMID- 22512882 TI - [Women as surgeons]. PMID- 22512883 TI - [Comment on the original publication by Dezso Toth et al., "Prospective comparative study of sentinel lymph node mapping -- submucous versus subserous method"]. PMID- 22512886 TI - Fertility preservation in women with vasculitis: experiences from the FertiPROTEKT network. AB - OBJECTIVES: Fertility preservation is not only important for malignant diseases but should also be offered to patients with autoimmune diseases (AID) like vasculitides, prior to cyclophosphamide therapy. No recommendations are available for patients with AID. METHODS: Analysis from the Fertiprotekt registry of all female patients with age <40 and the diagnosis of a vasculitis. The number of counselled patients, their diagnosis and age, the number of children before the start of therapy as well as the fertility preservation treatment chosen were evaluated. RESULTS: From January 2007 to November 2011, 47 patients with the diagnosis AID were counselled at 17 of the 69 Fertiprotekt centres. 80.9% decided for at least one of the offered preservation methods. Ovarian cryopreservation was performed in 6 patients, 36 patients opted for GnRH-analogue treatment. Two patients decided for a stimulation therapy for cryopreservation of oocytes. CONCLUSIONS: Regarding the experiences from the registry and the literature gonadotropin releasing hormone analogues are evaluated best and recommended to most of the patients with AID. Cryoconservation of ovarian tissue is a promising option. Stimulation for oocyte cryopreservation can be offered to patients with vasculitis. A combination of the methods might have the biggest preservative effect. PMID- 22512887 TI - The six most essential questions in psychiatric diagnosis: a pluralogue part 2: Issues of conservatism and pragmatism in psychiatric diagnosis. AB - In face of the multiple controversies surrounding the DSM process in general and the development of DSM-5 in particular, we have organized a discussion around what we consider six essential questions in further work on the DSM. The six questions involve: 1) the nature of a mental disorder; 2) the definition of mental disorder; 3) the issue of whether, in the current state of psychiatric science, DSM-5 should assume a cautious, conservative posture or an assertive, transformative posture; 4) the role of pragmatic considerations in the construction of DSM-5; 5) the issue of utility of the DSM--whether DSM-III and IV have been designed more for clinicians or researchers, and how this conflict should be dealt with in the new manual; and 6) the possibility and advisability, given all the problems with DSM-III and IV, of designing a different diagnostic system. Part I of this article took up the first two questions. Part II will take up the second two questions. Question 3 deals with the question as to whether DSM V should assume a conservative or assertive posture in making changes from DSM IV. That question in turn breaks down into discussion of diagnoses that depend on, and aim toward, empirical, scientific validation, and diagnoses that are more value-laden and less amenable to scientific validation. Question 4 takes up the role of pragmatic consideration in a psychiatric nosology, whether the purely empirical considerations need to be tempered by considerations of practical consequence. As in Part 1 of this article, the general introduction, as well as the introductions and conclusions for the specific questions, are written by James Phillips, and the responses to commentaries are written by Allen Frances. PMID- 22512888 TI - Lower incidence and severity of tomato virus in elevated CO(2) is accompanied by modulated plant induced defence in tomato. AB - Elevation in atmospheric CO(2) concentration broadly affects plant phenology and physiology, and these effects may alter the performance of plant viruses. The effects of elevated CO(2) on the susceptibility of tomato plants to Tomato yellow leaf curl virus (TYLCV) were examined for two successive years in open top chambers (OTC) in the field. We experimentally tested the hypothesis that elevated CO(2) would reduce the incidence and severity of TYLCV on tomato by altering plant defence strategies. Our results showed that elevated CO(2) decreased TYLCV disease incidence (by 14.6% in 2009 and 11.8% in 2010) and decreased disease severity (by 20.0% in 2009 and 10.4% in 2010). Elevated CO(2) also decreased the level of TYLCV coat protein in tomato leaves. Regardless of virus infection, elevated CO(2) increased plant height and aboveground biomass. Additionally, elevated CO(2) increased the leaf C:N ratio of tomato, but decreased soluble protein content in leaves. Notably, elevated CO(2) increased the salicylic acid (SA) level in uninfected and infected plants. In contrast, elevated CO(2) reduced jasmonic acid (JA) in uninfected plants while it increased JA and abscisic acid (ABA) in virus-infected plants. Furthermore, combined exogenous SA and JA application enhanced resistance to TYLCV more than application of either SA or JA alone. Our results suggest that the modulated antagonistic relationship between SA and JA under elevated CO(2) makes a great contribution to increased tomato resistance to TYLCV, and the predicted increases in tomato productivity may be enhanced by reduced plant virus susceptibility under projected rising CO(2) conditions. PMID- 22512889 TI - Traditional Chinese medicine for pressure ulcer: a meta-analysis. AB - To assess the effect of Traditional Chinese Medicine (TCM) [Chinese herbal medicine ointment (CHMO), acupuncture and moxibustion] on pressure ulcer. In this study, we searched MEDLINE, EMBASE, CENTER, CBM, CNKI, WAN FANG and VIP for articles published from database inception up to 4 April 2011. We included randomised controlled trials (RCTs), which compared the effects of TCM with other interventions. We assessed the methodological quality of these trials using Cochrane risk of bias criteria. Ten of 565 potentially relevant trails that enrolled a total of 893 patients met our inclusion criteria. All the included RCTs only used CHMO intervention, because acupuncture and moxibustion trials failed to meet the inclusive criteria. A meta-analysis showed beneficial effects of CHMO for pressure ulcer compared with other treatments on the total effective rate [risk ratio (RR): 1.28; 95% confidence interval (CI): 1.20-1.36; P = 0.53; I(2) = 0%), curative ratio (RR: 2.02; 95% CI: 1.73-2.35; P = 0.11; I(2) = 37%) and inefficiency rate (RR: 0.16; 95% CI: 0.02-0.80; P = 0.84; I(2) = 0%). However, the funnel plot indicated that there was publication bias in this study. The evidence that CHMO is effective for pressure ulcer is encouraging, but due to several caveats, not conclusive. Therefore, more rigorous studies seem warranted. PMID- 22512890 TI - Programmed cell death in C. elegans, mammals and plants. AB - Programmed cell death (PCD) is the regulated removal of cells within an organism and plays a fundamental role in growth and development in nearly all eukaryotes. In animals, the model organism Caenorhabditis elegans (C. elegans) has aided in elucidating many of the pathways involved in the cell death process. Various analogous PCD processes can also be found within mammalian PCD systems, including vertebrate limb development. Plants and animals also appear to share hallmarks of PCD, both on the cellular and molecular level. Cellular events visualized during plant PCD resemble those seen in animals including: nuclear condensation, DNA fragmentation, cytoplasmic condensation, and plasma membrane shrinkage. Recently the molecular mechanisms involved in plant PCD have begun to be elucidated. Although few regulatory proteins have been identified as conserved across all eukaryotes, molecular features such as the participation of caspase-like proteases, Bcl-2-like family members and mitochondrial proteins appear to be conserved between plant and animal systems. Transgenic expression of mammalian and C. elegans pro- and anti-apoptotic genes in plants has been observed to dramatically influence the regulatory pathways of plant PCD. Although these genes often show little to no sequence similarity they can frequently act as functional substitutes for one another, thus suggesting that action may be more important than sequence resemblance. Here we present a summary of these findings, focusing on the similarities, between mammals, C. elegans, and plants. An emphasis will be placed on the mitochondria and its role in the cell death pathway within each organism. Through the comparison of these systems on both a cellular and molecular level we can begin to better understand PCD in plant systems, and perhaps shed light on the pathways, which are controlling the process. This manuscript adds to the field of PCD in plant systems by profiling apoptotic factors, to scale on a protein level, and also by filling in gaps detailing plant apoptotic factors not yet amalgamated within the literature. PMID- 22512891 TI - Competitive DNA transfection formulation via electroporation for human adipose stem cells and mesenchymal stem cells. AB - BACKGROUND: Adipose stem cells have a strong potential for use in cell-based therapy, but the current nucleofection technique, which relies on unknown buffers, prevents their use. RESULTS: We developed an optimal nucleofection formulation for human adipose stem cells by using a three-step method that we had developed previously. This method was designed to determine the optimal formulation for nucleofection that was capable of meeting or surpassing the established commercial buffer (Amaxa), in particular for murine adipose stem cells. By using this same buffer, we determined that the same formulation yields optimal transfection efficiency in human mesenchymal stem cells. CONCLUSIONS: Our findings suggest that transfection efficiency in human stem cells can be boosted with proper formulation. PMID- 22512892 TI - Hierarchical cluster analysis of labour market regulations and population health: a taxonomy of low- and middle-income countries. AB - BACKGROUND: An important contribution of the social determinants of health perspective has been to inquire about non-medical determinants of population health. Among these, labour market regulations are of vital significance. In this study, we investigate the labour market regulations among low- and middle-income countries (LMICs) and propose a labour market taxonomy to further understand population health in a global context. METHODS: Using Gross National Product per capita, we classify 113 countries into either low-income (n = 71) or middle income (n = 42) strata. Principal component analysis of three standardized indicators of labour market inequality and poverty is used to construct 2 factor scores. Factor score reliability is evaluated with Cronbach's alpha. Using these scores, we conduct a hierarchical cluster analysis to produce a labour market taxonomy, conduct zero-order correlations, and create box plots to test their associations with adult mortality, healthy life expectancy, infant mortality, maternal mortality, neonatal mortality, under-5 mortality, and years of life lost to communicable and non-communicable diseases. Labour market and health data are retrieved from the International Labour Organization's Key Indicators of Labour Markets and World Health Organization's Statistical Information System. RESULTS: Six labour market clusters emerged: Residual (n = 16), Emerging (n = 16), Informal (n = 10), Post-Communist (n = 18), Less Successful Informal (n = 22), and Insecure (n = 31). Primary findings indicate: (i) labour market poverty and population health is correlated in both LMICs; (ii) association between labour market inequality and health indicators is significant only in low-income countries; (iii) Emerging (e.g., East Asian and Eastern European countries) and Insecure (e.g., sub-Saharan African nations) clusters are the most advantaged and disadvantaged, respectively, with the remaining clusters experiencing levels of population health consistent with their labour market characteristics. CONCLUSIONS: The labour market regulations of LMICs appear to be important social determinant of population health. This study demonstrates the heuristic value of understanding the labour markets of LMICs and their health effects using exploratory taxonomy approaches. PMID- 22512893 TI - Primary domestication and early uses of the emblematic olive tree: palaeobotanical, historical and molecular evidence from the Middle East. AB - Our knowledge of the origins of olive tree domestication in the Middle East and on the processes governing its extension and persistence in different vegetation types from prehistory through antiquity to modern times derives from diverse sources, spanning the biological sciences to the humanities. Nonetheless, it lacks a robust overview that may lead to floating interpretations. This is especially true in the Middle East, considered as the cradle of agriculture, and where the evolutionary history of this emblematic tree is intertwined with that of civilizations. Olive fruit, oil and wood have been, since Prehistoric times, characteristic products of the lands bordering the Mediterranean Sea. In the domestic economy of these countries, the olive tree gradually became a traditional tree crop since the first oil extraction, through the emergence of regional commerce that accompanied the rise and fall of early Near-Middle Eastern urbanism, until the development of modern trade, with an oil production estimated at circa 3000000 tons per year. The rising importance of the olive tree in human life has turned the tree into an endless source of fascination in the Aegean and Eastern Mediterranean, a symbol and a sacred tree, widely cited in the Bibles, the Koran, and in ancient literature. Here we argue that advances in radiocarbon chronology, palaeobotany, genetics, and archaeology-history have profoundly refined the history of olive trees in the Middle East. This review shows that the heartland of primary olive domestication must be enlarged to the Levant and not only focus on the Jordan Valley. The domestication of the olive tree is a long and ongoing process, linked to the early production of oil and the development of the olive trade. We also suggest that the olive tree became a particular icon, a sacred tree, during the Biblical period in the Levant. PMID- 22512894 TI - Retigabine as adjunctive therapy in adults with partial-onset seizures: integrated analysis of three pivotal controlled trials. AB - We assessed the efficacy and tolerability of retigabine (RTG; international non proprietary name)/ezogabine (EZG; US adopted name) as adjunctive therapy in adults with partial-onset seizures in an integrated analysis of three trials. Studies 205, 301 (NCT00232596), and 302 (NCT00235755) were randomized, double blind, placebo-controlled studies in adults having >=4 partial-onset seizures per 28 days and receiving 1-3 antiepileptic drugs with/without vagus nerve stimulator. Patients underwent titration to RTG/EZG 600, 900, or 1200 mg/day or to placebo followed by 8 or 12 weeks maintenance. For efficacy analyses, placebo was compared with RTG/EZG 600 and 900 mg/day in Studies 205 and 302, and RTG/EZG 1200 mg/day in Studies 205 and 301. Responder rates (>=50% reduction in baseline seizure frequency) were 35% and 45% for RTG/EZG 600 and 900 mg/day, respectively (placebo=21%; p<0.001), and 50% for RTG/EZG 1200 mg/day (placebo=24%, p<0.001). Reductions in 28-day total partial-seizure frequency (medians: placebo=14%; 600 mg/day=26%, p=0.003; 900 mg/day=37%, p<0.001; placebo=15%; 1200 mg/day=39%, p<0.001) were significantly greater with all RTG/EZG doses vs. placebo from baseline to the double-blind phase, and similarly during the maintenance phase. The most commonly reported (>10%) treatment-emergent adverse events were dizziness, somnolence, headache, and fatigue. RTG/EZG demonstrated efficacy and was generally tolerated as adjunctive therapy in adults with partial-onset seizures in this integrated analysis. PMID- 22512895 TI - A comparison of quality of life in adolescents with epilepsy or asthma using the Short-Form Health Survey (SF-36). AB - PURPOSE: To compare the quality of life (QOL) in adolescents with epilepsy or asthma. METHODS: Eighty-five epileptic adolescents, 81 adolescents with asthma and 71 normal controls were recruited from the Affiliated Children's Hospital of FuDan University from June, 2007 to December, 2007. These adolescents received the Medical Outcomes Study 36-Item Short-Form Health Survey (MOS F-36) in order to evaluate QOL. RESULTS: Although the onset age for adolescents with asthma was younger (P=0.032), there were no significant differences in clinical characteristics between adolescents with epilepsy and asthma. The results of MOS SF-36 demonstrated the following: (1) For the adolescents with epilepsy, the total QOL score and sub-scores for 8 items were significantly different between epilepsy patients and healthy controls, and the total QOL score and sub-scores for 4 items were significantly different between controlled and uncontrolled epilepsy groups; (2) for the adolescents with asthma, the total QOL score and sub scores for 4 items were significantly different between asthma patients and healthy controls, and the total QOL score and sub-scores for 4 items were significantly different between controlled and uncontrolled asthma groups; (3) the QOL of adolescents with epilepsy was poorer than that of the adolescents with asthma regardless of the remission stage and disease stage; (4) the emotional and mental health of adolescents with epilepsy was inferior to that of adolescents with asthma. CONCLUSIONS: The QOL of adolescents with chronic paroxysmal diseases including epilepsy and asthma deserves close attention and should be included as a key parameter when evaluating disease status. PMID- 22512896 TI - Polymorphisms in the Annexin A5 gene influence circulating Annexin A5 levels in healthy controls. PMID- 22512897 TI - Evaluation of recurrent venous thromboembolism in patients with Factor V Leiden mutation in heterozygous form. AB - INTRODUCTION: To evaluate the risk for recurrence after first venous thromboembolism (VTE) among patients with or without Factor V Leiden (FVL) mutation. MATERIALS AND METHODS: A prospective population based study of 1465 consecutive unselected VTE patients was performed at Skane University Hospital 1998-2008. The VTE was objectively verified and the patients answered questionnaire and left blood samples for evaluation. RESULTS: Out of 1465 patients (721[49%] men and 744[51%] women) thrombophilia data were available for 1267, and FVL mutation was found in heterozygous form in 339 (27). The homozygous form and prothrombin mutation (PTM) were much less common. Patients were followed during 4.8 +/- 2.3 years (total 6133 patient years) and recurrence after first VTE (evaluated in 1108 patients) occurred in 131 (12%, 95%CI 10-14%), where of 49(37%) had heterozygous FVL mutation and 57(44%) were without thrombophilia. The remaining 25(19%) patients had either PTM, FVL in homozygous form, compound PTM/FVL or unknown thrombophilia status. Having FVL mutation in heterozygous form significantly increased the risk for VTE recurrence (odds ratio 2.4 (95 %CI 1.6 3.6; p<0.01). In a Kaplan-Meier analysis the FVL group also differed significantly (p<0.01) from the other patients concerning time to recurrence (almost 25% vs. 10% after 8 years). CONCLUSIONS: FVL mutation in heterozygous form is common among VTE patients and significantly increases the risk for VTE recurrence. PMID- 22512898 TI - Differences in the in vitro and in vivo pharmacokinetic profiles of once-daily modified-release methylphenidate formulations in Canada: examination of current bioequivalence criteria. AB - BACKGROUND: Current Canadian bioequivalence criteria rely on rate and extent of drug exposure, that is, C(max) and AUC. In the case of complex modified-release formulations, these criteria may not address pharmacokinetic differences with potential therapeutic and tolerability implications. OBJECTIVE: This study was performed to characterize in vitro dissolution and in vivo pharmacokinetic profiles of three modified-release formulations of methylphenidate (MPH) marketed in Canada, two of which meet the criteria for assuming bioequivalence as defined by Health Canada: MPH extended-release (ER-C) and osmotic controlled-release oral delivery-system (OROS-MPH). METHODS: In vitro dissolution tests were performed using 54-mg OROS-MPH, 54-mg MPH ER-C, and 20-mg MPH sustained-release (SR) tablets. In vivo pharmacokinetics of single oral doses of 54 mg OROS-MPH, 54 mg MPH ER-C, and 60 mg MPH-SR were evaluated in an open-label, randomized, crossover study in healthy subjects. Plasma samples were collected up to 24 hours after administration of the drug. RESULTS: In vitro dose-corrected release profiles of MPH ER-C and MPH-SR tablets were similar (<10% difference), whereas OROS-MPH exhibited a profile distinct from that of the other formulations. Twenty-four subjects completed the pharmacokinetic study and were included in the analyses. Analysis of C(max) and AUC of MPH showed that OROS-MPH and MPH ER-C met the criteria for assumed bioequivalence according to Health Canada guidelines. However, partial AUCs exhibited significant differences between the two formulations, which were supported by ratios of MPH concentrations over time. Comparison of MPH ER-C with MPH-SR (dose corrected) also satisfied bioequivalence criteria. CONCLUSIONS: The pharmacokinetic data suggest that in vitro and in vivo profiles of OROS-MPH and MPH ER-C are distinct. However, using traditional criteria for bioequivalence, MPH ER-C would be assumed bioequivalent to both OROS MPH and MPH-SR. Inclusion of partial AUCs as additional criteria could aid in ensuring therapeutic equivalence. ClinicalTrials.gov identifier: NCT01118702. PMID- 22512899 TI - Utility of interferon-gamma release assay results to monitor anti-tubercular treatment in adults and children. AB - BACKGROUND: Interferon-gamma release assays (IGRAs), including the commercially available T-SPOT.TB, QuantiFERON-TB Gold (QFT-G), and QuantiFERON-TB Gold In-Tube (QTF-G-IT), enable detection of circulating T lymphocytes responsive to specific Mycobacterium tuberculosis antigens. Studies of the potential role of serial IGRAs for assessment of response to anti-tubercular therapy are accumulating. OBJECTIVE: The objective of this systematic review was to evaluate the potential clinical utility of serial IGRAs in anti-tubercular therapy. METHODS: We conducted a literature search of the Cochrane Library and MEDLINE by PubMed, from database inception through October 1, 2011, for serial IGRA results in anti tubercular therapy, in adults and children, using commercial stardardized assays. All types of articles in the English language were included. Meta-analysis was performed to estimate the pooled percentage of reversion from a positive to a negative IGRA value at 3- to 6-month follow-up. RESULTS: According to inclusion and exclusion criteria, three T-SPOT.TB-based (n = 319 patients), three QFT-G based (n = 75 patients), and seven QFT-G-IT-based (n = 558 patients) longitudinal studies were included. The percentage of patients with reversion from a positive to a negative IGRA value ranged from 5.71% to 13.93% for T-SPOT.TB, 5.26% to 71.05% for QFT-G, and 14.28% to 41.89% for QFT-G-IT assays. Meta-analysis estimation of reversion was feasible only for the QFT-G-IT assay, at 30.54% (95% CI, 22.89-38.75). In two pediatric studies, which were QFT-G-IT based (n = 122 children), the reported reversion rates were 14.28% and 20.33%, respectively. CONCLUSIONS: Because IGRAs require time and cost resources, and reversion from positive to negative IGRA values occurs in a minority of treated patients, monitoring IGRA changes over time seems to have only speculative value in adults. Data in children are poor, but are in line with results reported in adults. PMID- 22512901 TI - Therapeutics, imaging and toxicity of nanomaterials in the central nervous system. AB - Treatment and diagnosis of neurodegenerative diseases and other CNS disorders are nowadays considered some of the most challenging tasks in modern medicine. The development of effective strategies for the prevention, diagnosis and treatment of CNS pathologies require better understanding of neurological disorders that is still lacking. The use of nanomaterials is thought to contribute to our further understanding of the CNS and the development of novel therapeutic and diagnostic modalities for neurological interventions. Even though the application of nanoparticles in neuroscience is still embryonic, this article attempts to illustrate the use of different types of nanomaterials and the way in which they have been used in various CNS applications in an attempt to limit or reverse neuropathological processes. PMID- 22512903 TI - Re: Meelan Bul, Xiaoye Zhu, Antti Rannikko, et al. Radical prostatectomy for low risk prostate cancer following initial active surveillance: results from a prospective observational study. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2012.02.002. PMID- 22512900 TI - Lack of thrombospondin-2 reduces fibrosis and increases vascularity around cardiac cell grafts. AB - BACKGROUND: Fibrosis around cardiac cell injections represents an obstacle to graft integration in cell-based cardiac repair. Thrombospondin-2 (TSP-2) is a pro fibrotic, anti-angiogenic matricellular protein and an attractive target for therapeutic knockdown to improve cardiac graft integration and survival. METHODS: We used a TSP-2 knockout (KO) mouse in conjunction with a fetal murine cardiomyocyte grafting model to evaluate the effects of a lack of TSP-2 on fibrosis, vascular density, and graft size in the heart. RESULTS: Two weeks after grafting in the uninjured heart, fibrosis area was reduced 4.5-fold in TSP-2 KO mice, and the thickness of the peri-graft scar capsule was reduced sevenfold compared to wild-type (WT). Endothelial cell density in the peri-graft region increased 2.5-fold in the absence of TSP-2, and cardiomyocyte graft size increased by 46% in TSP-2 KO hearts. CONCLUSIONS: TSP-2 is a key regulator of fibrosis and angiogenesis following cell grafting in the heart, and its absence promotes better graft integration, vascularization, and survival. SUMMARY: Fibrosis around cardiac cell injections impairs graft integration in cell-based cardiac repair. TSP-2 is a pro-fibrotic, anti-angiogenic matricellular protein. Using a TSP-2-knockout mouse model and cardiac cell transplantation, we found significantly reduced fibrosis and increased endothelial cell density in the peri graft region. Thus, TSP-2 is an attractive target for therapeutic knockdown to improve cardiac graft integration and survival. PMID- 22512904 TI - Direct and selective benzylic oxidation of alkylarenes via C-H abstraction using alkali metal bromides. AB - A direct benzylic oxidation of alkylarenes via C-H bond abstraction was developed using alkali metal bromides and oxidants under mild conditions. This reaction proceeded with excellent selectivity by thermal oxidation or photooxidation to provide a broad range of carbonyl compounds containing electron-deficient aryl carbonyl compounds in high yields. PMID- 22512905 TI - Pharmacological evaluation of a novel cyclic phosphatidic acid derivative 3-S cyclic phosphatidic acid (3-S-cPA). AB - Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator possessing cyclic phosphate ring, which is necessary for its specific biological activities. To stabilize cyclic phosphate ring of cPA, we synthesized a series of cPA derivatives. We have shown that racemic 3-S-cPA, with a phosphate oxygen atom replaced with a sulfur atom at the sn-3, was a more effective autotaxin (ATX) inhibitor than cPA. In this study, we showed that racemic 3-S-cPA also had potent biological activities such as inhibition of cancer cell migration, suppression of the nociceptive reflex, and attenuation of ischemia-induced delayed neuronal cell death in the hippocampal CA1. Moreover, we synthesized both enantiomers of palmitoleoyl derivative of 3-S-cPA, and found that the chirality of 3-S-cPA is not involved in ATX inhibition. Based on these findings, racemic 3-S-cPA is suggested as an effective therapeutic compound like cPA. PMID- 22512906 TI - Synthesis, biological evaluation, and molecular docking studies of 2,6-dinitro-4 (trifluoromethyl)phenoxysalicylaldoxime derivatives as novel antitubulin agents. AB - A series of 2,6-dinitro-4-(trifluoromethyl)phenoxysalicylaldoxime derivatives (1h 20h) have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and tubulin polymerization inhibitors. Among all the compounds, 2h showed the most potent activity in vitro, which inhibited the growth of MCF-7, Hep-G2 and A549 cell lines with IC(50) values of 0.70 +/- 0.05, 0.68 +/- 0.02 and 0.86 +/- 0.05 MUM, respectively. Compound 2h also exhibited significant tubulin polymerization inhibitory activity (IC(50)=3.06 +/- 0.05 MUM). The result of flow cytometry (FCM) demonstrated that compound 2h induced cell apoptosis. Docking simulation was performed to insert compound 2h into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. Based on the preliminary results, compound 2h with potent inhibitory activity in tumor growth may be a potential anticancer agent. PMID- 22512907 TI - Discovery of potent and orally bioavailable 17beta-hydroxysteroid dehydrogenase type 3 inhibitors. AB - We have previously reported the discovery of a new class of potent inhibitors of 17beta-hydroxysteroid dehydrogenase type 3 (17beta-HSD3) derived from benzylidene oxazolidinedione and thiazolidinedione scaffolds. In this study, these analogs were designed, synthesized, and evaluated in a human cell-based assay. The detailed structure-activity relationship (SAR) surrounding this pharmacophore were developed, and consequently a number of compounds from this series demonstrated single-digit nanomolar 17beta-HDS3 inhibitory activity in vitro. Subsequent optimization work in pursuit of the improvement of oral bioavailability demonstrated in vivo proof-of-concept by prodrug strategy based on phosphate esters for these 17beta-HSD3 inhibitors. When a phosphate ester 16 was administered orally at a high dose of 100mg/kg, 16 showed approximately two times more potent testosterone (T)-lowering effect against a positive control in the luteinizing hormone-releasing hormone (LH-RH)-induced T production assay. The T-lowering effect continued at ca 10% level of control over 4h after administration. The nonsteroidal molecules based on this series have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer. PMID- 22512908 TI - Synthesis, sigma1, sigma2-receptors binding affinity and antiproliferative action of new C1-substituted adamantanes. AB - The synthesis of N-{4-[a-(1-adamantyl)benzyl]phenyl}piperazines 2a-e is described. The in vitro antiproliferative activity of most compounds against main cancer cell lines is significant. The sigma(1), sigma(2)-receptors and sodium channels binding affinity of compounds 2 were investigated. One of the most active analogs, 2a, had an interesting in vivo anticancer profile against the BxPC-3 and Mia-Paca-2 pancreas cancer cell lines with caspase-3 activation, which was associated with an anagelsic activity against the neuropathic pain. PMID- 22512909 TI - Investigating the activity of quinine analogues versus chloroquine resistant Plasmodium falciparum. AB - Plasmodium falciparum, the deadliest malarial parasite species, has developed resistance against nearly all man-made antimalarial drugs within the past century. However, quinine (QN), the first antimalarial drug, remains efficacious worldwide. Some chloroquine resistant (CQR) P. falciparum strains or isolates show mild cross resistance to QN, but many do not. Further optimization of QN may provide a well-tolerated therapy with improved activity versus CQR malaria. Thus, using the Heck reaction, we have pursued a structure-activity relationship study, including vinyl group modifications of QN. Certain derivatives show good antiplasmodial activity in QN-resistant and QN-sensitive strains, with lower IC(50) values relative to QN. PMID- 22512910 TI - Orf-induced pemphigoid with antilaminin-332 antibodies. PMID- 22512911 TI - [The pro-social nature of blood donation]. AB - "L'etablissement francais du sang" faces chronic shortages of blood to meet the growing needs of the health system. This article aims at clarifying the pro social nature of blood donation. An analysis of the literature allows us to characterize the act as being altruist. The prospective of this focus is to test the labeling paradigm, which is to return to the experiment that makes a preparatory behaviour, information enabling someone to perceive themselves as generous versus stingy or helpful versus not helpful. Being true to nature as reasons and motivations that conduct to the act of giving blood, seems to be essential for fundamental and experimental approach. PMID- 22512912 TI - [Knowledge and attitudes of medical personnel in blood transfusion in Bamako, Mali]. AB - PURPOSE OF THE STUDY: We undertook a study to determine the level of knowledge and practice of medical staff personnel on transfusion medicine in Mali at Bamako and Kati. PATIENTS AND METHODS: The study was conducted from January to April 2010 in the three main teaching hospitals of Bamako and Kati and in the six referral health centers of the district of Bamako. Medical staff knowledge and practice were assessed using a questionnaire. The study population consisted of specialized practitioners (15%), general practitioners (21.4%), nurses (41.6%), and midwives (22%). RESULTS: Overall, 70.9% of the staff did not receive any training in blood transfusion since their graduation. The general knowledge about blood transfusion was insufficient in 53.9% of staff and excellent in 46.1%. Only 42.9% of medical staff has a good basic knowledge of blood products, their indications, and related accidents. CONCLUSION: Our study showed weaknesses in the transfusion system in Bamako, with insufficient knowledge of the medical staff in blood transfusion and little experience. PMID- 22512913 TI - FCGR3B allele frequencies in Tunisians of sub-Saharan origin. AB - PURPOSE OF THE STUDY: The importance of human neutrophil antigens (HNA) in immunogenetics and their involvement in hematologic diseases have accelerated the elucidation of their molecular basis and their allele frequencies distribution has been described in many populations over the world. In this study, our aim was to evaluate the frequency of FCGR3B alleles encoding HNA-1a, 1b and 1c among Tunisians of sub-Saharan origin and to compare them to Tunisian blood donors and to a group from sub-Saharan Africa. PATIENTS AND METHODS: We typed the DNA of 106 individuals (62 Tunisians of sub-Saharan origin, 33 Tunisian blood donors and 11 from sub-Saharan Africa) for the three FCGR3B alleles by polymerase chain reaction using sequence specific primer (PCR-SSP). RESULTS: FCGR3B*1, FCGR3B*2 and FCGR3B*3 allele frequencies were respectively 0.347, 0.573 and 0.080 among Tunisians of sub-Saharan origin, 0.379, 0.591 and 0.030 among Tunisian blood donors and 0.318, 0.546 and 0.136 among the group from sub-Saharan Africa. CONCLUSION: These allele frequencies were similar to those previously reported in other black and white populations. The frequencies found in the two Tunisian groups confirm the intermixing origin from Europe, sub-Africa and Asia of the Tunisian population. Our results provide a database for future studies of the HNA system and associated diseases in Tunisia. PMID- 22512915 TI - Comparative analysis of different commercial ELISA systems for the detection of anti-neutrophil cytoplasm antibodies in ANCA-associated vasculitides. AB - OBJECTIVES: To assess the diagnostic performance of 11 commercial PR3- and MPO ANCA ELISA systems (direct, capture and high sensitive [hs] ELISA). METHODS: Sera from 90 patients with AAV (GPA, MPA and CSS) and 20 disease controls (SLE; RA) and healthy individuals were tested for the presence of ANCA by IFT and by different ELISAs for the presence of PR3-and MPO-ANCA, respectively. Furthermore, the binding capacity of the IUIS-CDC reference sera for PR3-/MPO-ANCA in different commercial assays was analysed. RESULTS: Commercial ELISA kits for PR3 ANCA differed moderately in their sensitivity (from 45% to 62.5%). The highest sensitivity for PR3-ANCA was obtained with hs ELISA (kit A) and capture ELISA (kit N). Testing for MPO-ANCA the highest sensitivity (85%) was obtained with direct ELISA (kit D and I). Specificity was high in all kits. Only three PR3-ANCA commercial kits and three MPO-ANCA kits produced binding at the expected value for the IUIS-CDC reference sera (100 U/ml). In all of the kits, serial dilutions of the reference sera did not yield linearity. CONCLUSIONS: Second (capture) and third (high sensitivity) generation PR3-ANCA ELISA kits are superior to conventional ELISAs. Direct and capture MPO-ANCA ELISAs showed a good overall performance in all kits. Most of the kits have not been standardised to allow their results to be compared. PMID- 22512914 TI - Dynamic adaptation process to implement an evidence-based child maltreatment intervention. AB - BACKGROUND: Adaptations are often made to evidence-based practices (EBPs) by systems, organizations, and/or service providers in the implementation process. The degree to which core elements of an EBP can be maintained while allowing for local adaptation is unclear. In addition, adaptations may also be needed at the system, policy, or organizational levels to facilitate EBP implementation and sustainment. This paper describes a study of the feasibility and acceptability of an implementation approach, the Dynamic Adaptation Process (DAP), designed to allow for EBP adaptation and system and organizational adaptations in a planned and considered, rather than ad hoc, way. The DAP involves identifying core elements and adaptable characteristics of an EBP, then supporting implementation with specific training on allowable adaptations to the model, fidelity monitoring and support, and identifying the need for and solutions to system and organizational adaptations. In addition, this study addresses a secondary concern, that of improving EBP model fidelity assessment and feedback in real world settings. METHODS: This project examines the feasibility, acceptability, and utility of the DAP; tests the degree to which fidelity can be maintained using the DAP compared to implementation as usual (IAU); and examines the feasibility of using automated phone or internet-enabled, computer-based technology to assess intervention fidelity and client satisfaction. The study design incorporates mixed methods in order to describe processes and factors associated with variations in both how the DAP itself is implemented and how the DAP impacts fidelity, drift, and adaptation. The DAP model is to be examined by assigning six regions in California (USA) to either the DAP (n=3) or IAU (n=3) to implement an EBP to prevent child neglect. DISCUSSION: The DAP represents a data informed, collaborative, multiple stakeholder approach to maintain intervention fidelity during the implementation of EBPs in the field by providing support for intervention, system, and organizational adaptation and intervention fidelity to meet local needs. This study is designed to address the real-world implications of EBP implementation in public sector service systems and is relevant for national, state, and local service systems and organizations. PMID- 22512916 TI - Hydrodynamically mediated macrophyte silica dynamics. AB - In most aquatic ecosystems, hydrodynamic conditions are a key abiotic factor determining species distributions and abundance of aquatic plants. Resisting stress and keeping an upright position often relies on investment in tissue reinforcement, which is costly to produce. Silica could provide a more economical alternative. Two laboratory experiments were conducted to measure the response of two submerged species, Egeria densa Planch. and Limnophila heterophylla (Roxb.) Benth., to dissolved silicic acid availability and exposure to hydrodynamic stress. The results were verified with a third species in a field study (Nuphar lutea (L.) Smith). Biogenic silica (BSi) concentration in both stems and leaves increases with increasing dissolved silica availability but also with the presence of hydrodynamic stress. We suggest that the inclusion of extra silica enables the plant to alternatively invest its energy in the production of lignin and cellulose. Although we found no significant effects of hydrodynamic stress on cellulose or lignin concentrations either in the laboratory or in the field, BSi was negatively correlated with cellulose concentration and positively correlated with lignin concentration in samples collected in the field study. This implies that the plant might perform with equal energy efficiency in both standing and running water environments. This could provide submerged species with a tool to respond to abiotic factors, to adapt to new ecological conditions and hence potentially colonise new environments. PMID- 22512918 TI - Professional organisation profile: a faculty of expedition and wilderness medicine for Australasia. AB - A profile of the recent genesis of the Sub-Faculty of Expedition Medicine into a Faculty of Expedition and Wilderness Medicine of The Australasian College of Tropical Medicine is presented. Information is given on aims, structure, professional grades of membership, and the various activities of the Faculty, including publications and scientific meetings. PMID- 22512917 TI - Beta-hydroxy-beta-methyl-butyrate blunts negative age-related changes in body composition, functionality and myofiber dimensions in rats. AB - PURPOSE: To determine the effects of 16 wk. of beta-hydroxy-beta-methylbutyrate (HMB) administration on age-related changes in functionality and diffusion tensor imaging (DTI) determined myofiber dimensions. METHODS: Twelve young (44 wk.), 6 middle-aged (60 wk.), 10 old (86 wk.), and 5 very old (102 wk.) male Fisher-344 rat's body composition and grip strength were assessed at baseline. Following, 6 young, 6 middle-aged, 5 old and 5 very old rats were sacrificed for baseline myofiber dimensions and gene transcript factor expression in the soleus (SOL) and gastrocnemius (GAS). The remaining 6 young and 5 old rats were given HMB for 16 wk. and then sacrificed. RESULTS: Fat mass increased in the middle-aged control condition (+49%) but not the middle-aged HMB condition. In addition, fat mass declined (-56%) in the old HMB condition but not the old control condition. Normalized strength declined and maintained respectively in the control and HMB conditions from 44 to 60 wk. and increased (+23%) (p < 0.05) from 86 to 102 wk. in only the HMB condition. Declines occurred in myofiber size in all muscles from 44 to 102 wk. in the control condition(-10 to -15%), but not HMB condition. Atrogin-1 mRNA expression in the SOL and GAS muscles was greater in the 102-wk control condition than all other conditions: SOL (+45%) and GAS (+100%). This elevation was blunted by HMB in the 102 wk. old SOL. There was a condition effect in the SOL for myogenin, which significantly increased (+40%) only in the 102-wk. HMB group relative to the 44-wk. group. CONCLUSIONS: HMB may blunt age-related losses of strength and myofiber dimensions, possibly through attenuating the rise in protein breakdown. PMID- 22512919 TI - Mapping African ethical review committee activity onto capacity needs: the MARC initiative and HRWeb's interactive database of RECs in Africa. AB - Health research initiatives worldwide are growing in scope and complexity, particularly as they move into the developing world. Expanding health research activity in low- and middle-income countries has resulted in a commensurate rise in the need for sound ethical review structures and functions in the form of Research Ethics Committees (RECs). Yet these seem to be lagging behind as a result of the enormous challenges facing these countries, including poor resource availability and lack of capacity. There is thus an urgent need for ongoing capacity and resource development in these regions in general, and in Africa in particular. Similarly, there is a need for research and initiatives that can identify existing capacity and funding and indicate the areas where this needs to be developed. This discussion paper argues that the Mapping African Research Ethics Capacity (MARC) project is a timely initiative aimed at identifying existing capacity. MARC provides a platform and tool on the Council on Health Research for Development's (COHRED) Health Research website (HRWeb), which can be used by RECs and key stakeholders in health research in Africa to identify capacity, constraints and development needs. MARC intends to provide the first comprehensive interactive database of RECs in Africa, which will allow for the identification of key relationships and analyses of capacity. The potential of MARC lies in the mapping of current ethical review activity onto capacity needs. This paper serves as a starting point by providing a descriptive illustration of the current state of RECs in Africa. PMID- 22512920 TI - Expression of NMDA receptor subunit 1 in the rat retina. AB - N-methyl-D-aspartate receptors (NMDARs) belong to the ionotropic glutamate receptors, which play key roles in neuronal communication in the retina. NMDA receptors are tetrameric protein complexes usually comprising two obligatory NMDA receptor 1 (NR1) subunits and modulatory NMDA receptor 2/3 (NR2/3) subunits. Although the expression patterns of different NMDA receptor subunits have been extensively studied, in this study we focused on NR1 protein expression in the rat retina by immunofluorescence double labeling. We show that NR1 labeling is diffusely distributed in the outer plexiform layer (OPL) and throughout the whole inner plexiform layer (IPL). The NR1-immunoreactivity (IR) was displayed in a variety of cells in the inner nuclear layer (INL) and the ganglion cell layer (GCL). Interestingly, NR1 was expressed in both rod and cone bipolar cells identified by specific bipolar cell markers Chx10, protein kinase C (PKC) and recoverin. All the amacrine cells that we studied, including cholinergic, dopaminergic, GABAergic and glycinergic amacrine cells, were NR1-IR positive. In the ganglion cell layer, NR1-IR was expressed in all cells that were positive for the ganglion cell marker Brn3a. Our study suggests that the NR1 subunit is expressed more widely than was previously appreciated. PMID- 22512921 TI - Generation of disease-specific induced pluripotent stem cells from patients with different karyotypes of Down syndrome. AB - INTRODUCTION: Down syndrome (DS), a major cause of mental retardation, is caused by trisomy of some or all of human chromosome 21 and includes three basic karyotypes: trisomy 21, translocation, and mosaicism. The derivation of DS specific induced pluripotent stem cells (iPSCs) provides us novel DS models that can be used to determine the DS mechanism and to devise therapeutic approaches for DS patients. METHODS: In the present study, fibroblasts from patients with DS of various karyotypes were reprogrammed into iPSCs via the overexpression of four factors: OCT4, SOX2, KLF4, and c-MYC, by using lentiviral vectors. The abilities of the iPSC-DS in the self-renewal and pluripotency in vitro and in vivo were then examined. RESULTS: The iPSC-DS showed characteristics similar to those of human embryonic stem cells, particularly the morphology, surface marker (SSEA4, TRA-1-60, and TRA-1-81) expression, pluripotent-specific transcription-factor expression levels, and methylation status of the OCT4 promoter. The pluripotency of iPSC-DS was also tested in vitro and in vivo. Embryoid bodies were formed and showed the expression of differentiated markers for three germ layers. Furthermore, iPSC-DS formed classic teratomas when injected into nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice. CONCLUSIONS: iPSCs were generated from patients with DS. The iPSCs derived from different types of DS may be used in DS modeling, patient-care optimization, drug discovery, and eventually, autologous cell-replacement therapies. PMID- 22512922 TI - Emphysema distribution and annual changes in pulmonary function in male patients with chronic obstructive pulmonary disease. AB - BACKGROUND: The progression of chronic obstructive pulmonary disease (COPD) considerably varies among patients. Those with emphysema identified by quantitative computed tomography (CT) are associated with the rapid progression assessed by forced expiratory volume in one second (FEV1). However, whether the rate of the decline in lung function is independently affected by the regional distribution or the severity of emphysema in the whole lung is unclear. METHODS: We followed up 131 male patients with COPD for a median of 3.7 years. We measured wall area percent (WA%) in right apical segmental bronchus, total lung volume, percent low attenuation volume (LAV%), and the standard deviation (SD) of LAV% values from CT images of 10 isovolumetric partitions (SD-LAV) as an index of cranial-caudal emphysema heterogeneity. Annual changes in FEV1 were then determined using a random coefficient model and relative contribution of baseline clinical parameters, pulmonary function, and CT indexes including LAV%, SD-LAV, and WA% to annual changes in FEV1 were examined. RESULTS: The mean (SD) annual change in FEV1 was -44.4 (10.8) mL. Multivariate random coefficient model showed that higher baseline FEV1, higher LAV%, current smoking, and lower SD-LAV independently contributed to an excessive decline in FEV1, whereas ratio of residual volume to total lung capacity, ratio of diffusing capacity to alveolar ventilation, and WA% did not, after adjusting for age, height, weight, and ratio of CT-measured total lung volume to physiologically-measured total lung capacity. CONCLUSIONS: A more homogeneous distribution of emphysema contributed to an accelerated decline in FEV1 independently of baseline pulmonary function, whole lung emphysema severity, and smoking status. In addition to whole-lung analysis of emphysema, CT assessment of the cranial-caudal distribution of emphysema might be useful for predicting rapid, progressive disease and for developing a targeted strategy with which to prevent disease progression. PMID- 22512923 TI - Assessment of the face validity of two pain scales in Kenya: a validation study using cognitive interviewing. AB - BACKGROUND: Patients in sub-Saharan Africa commonly experience pain, which often is un-assessed and undertreated. One hindrance to routine pain assessment in these settings is the lack of a single-item pain rating scale validated for the particular context. The goal of this study was to examine the face validity and cultural acceptability of two single-item pain scales, the Numerical Rating Scale (NRS) and the Faces Pain Scale-Revised (FPS-R), in a population of patients on the medical, surgical, and pediatric wards of Moi Teaching and Referral Hospital in Kenya. METHODS: Swahili versions of the NRS and FPS-R were developed by standard translation and back-translation. Cognitive interviews were performed with 15 patients at Moi Teaching and Referral Hospital in Eldoret, Kenya. Interview transcripts were analyzed on a question-by-question basis to identify major themes revealed through the cognitive interviewing process and to uncover any significant problems participants encountered with understanding and using the pain scales. RESULTS: Cognitive interview analysis demonstrated that participants had good comprehension of both the NRS and the FPS-R and showed rational decision-making processes in choosing their responses. Participants felt that both scales were easy to use. The FPS-R was preferred almost unanimously to the NRS. CONCLUSIONS: The face validity and acceptability of the Swahili versions of the NRS and FPS-R has been demonstrated for use in Kenyan patients. The broader application of these scales should be evaluated and may benefit patients who currently suffer from pain. PMID- 22512924 TI - A lifetime of violence: results from an exploratory survey of Mexican women with HIV. AB - Despite recognition that traditional Mexican gender norms can contribute to the twin epidemics of violence against women and HIV, there is an absence of published literature on experiences of violence among Mexican women with HIV. We conducted a cross-sectional survey with 77 HIV-infected women from 21 of Mexico's 32 states to describe experiences of violence before and after HIV-diagnosis. We measured lifetime physical, sexual, and psychological violence; physical violence from a male partner in the previous 12 months; and physical and psychological violence related to disclosing an HIV diagnosis. Respondents reported ever experiencing physical violence (37.3%) and sexual violence (29.2%). Disclosure of HIV status resulted in physical violence for 7.2% and psychological violence for 26.5% of the respondents. This study underlines the need to identify and address past and current gender-based violence during pre- and post-HIV test counseling and as a systematic and integral part of HIV care. PMID- 22512925 TI - Reducing HIV in Michigan African American young adult women. AB - African American (AA) women are at disproportionate risk for contracting HIV, which has reached epidemic proportions, especially in women of color. Reducing the risk of exposure to HIV in AA women is a priority for health care providers. Despite the many studies conducted on HIV in the AA community, factors that influence sexual risk taking, such as non-condom use by AA women, have yet to be understood. The purpose of this study was to investigate how AA women define HIV risky behavior. Quantitative and qualitative data were collected from a convenience sample of AA women (N = 33) from three metropolitan regions within Michigan. The results offer important insight into how AA women define HIV risky behavior as well as highlight behaviors that are amenable to intervention. PMID- 22512926 TI - Creating a paper-based personal health record for HIV-infected persons. AB - A personal health record (PHR) contains information that a client believes is important to his/her health status; it can be either paper or Internet-based. The purposes of this action research were to determine the length of time an expert HIV nurse clinician needed to create a comprehensive PHR and to determine how hard it was for the patient to understand different components of a PHR. The average respondent (N = 9) was older, female, completed high school, African American, diagnosed with AIDS, and taking HIV medications for 11 years. The HIV nurse expert spent an average of 79 minutes preparing the PHR. Clients had the greatest difficulty understanding laboratory tests, medications, medical history, and immunizations. PHRs are evolving through the consumer-empowerment movement, technology, and a growing awareness of the consequences of medical errors. Nurses need to assist clients to create and use the PHR as an important tool in self care management. PMID- 22512929 TI - Concise total synthesis of (-)-mersicarpine. AB - A concise total synthesis of (-)-mersicarpine from a known cyclohexanone was accomplished. The azepinoindole core was constructed by a DIBAL-H-mediated reductive ring-expansion reaction of oxime. PMID- 22512930 TI - Anterior cingulate morphology in people at genetic high-risk of schizophrenia. AB - BACKGROUND: Morphological abnormalities of the anterior cingulate (AC) occur in patients with schizophrenia and in symptomatic high-risk individuals, and may be predictive of subsequent psychosis. We investigated AC sulcal morphology in the Edinburgh High Risk Study cohort to see if such abnormalities are evident and predict psychosis in patients' relatives. We also investigated the association of the cingulate sulcus (CS) and paracingulate sulcus (PCS) variants with intelligence quotient (IQ). PATIENTS AND METHODS: We compared cingulate and paracingulate sulcal anatomy, using reliable standardised measurements, blind to group membership, in those at high genetic risk (n=146), first episode patients (n=34) and healthy controls (n=36); and compared high-risk subjects who did (n=17) or did not develop schizophrenia. RESULTS: Interruptions of the cingulate sulcus were more common in high-risk individuals and in those with schizophrenia, in both hemispheres, compared to controls. When separated by gender, these results were only present in males in the left hemisphere and only in females in the right hemisphere. A well-formed paracingulate sulcus was less common in high risk participants and patients with schizophrenia, compared to controls; but this association was only present in males. These morphological variants of the paracingulate sulcus and the continuous cingulate sulcus were also associated with the higher IQ in male high-risk individuals. CONCLUSIONS: An interrupted cingulate sulcus pattern in both males and females and paracingulate morphology in males are associated with increased genetic risk of schizophrenia. Associations between cingulate and paracingulate morphology and premorbid IQ scores provide evidence that intellectual ability could be related to particular cytoarchitectural brain regions. Given that these sulci develop in early fetal life, such findings presumably reflect early neurodevelopmental abnormalities of genetic origin, although environmental effects and interactions cannot be ruled out. PMID- 22512931 TI - Clinical correlates of cannabis use among adolescent psychiatric inpatients. AB - OBJECTIVES: This study sought to determine the clinical correlates of adolescents with cannabis use and no additional drug use (CU) compared to adolescents with no drug use (NDU) among a group of adolescent psychiatric inpatients in Israel. METHODS: Two hundred and thirty-six patients consecutively admitted to an adolescent inpatient unit at a university-affiliated mental health center in Israel during a 3-year period were screened. Individuals with polydrug use were excluded from the study. RESULTS: Prevalence of cannabis use was 13%. In the CU group, 39% were diagnosed with attention deficit and disruptive behavior disorders compared with 16% in the NDU group. Antipsychotics were the most common medications prescribed in both groups. Mood stabilizers were more frequently prescribed to CU than to NDU patients (39% vs 16%, respectively). A higher prevalence of alcohol abuse and criminal behaviors was found among CU compared to NDU patients (61% and 39% vs 6% and 4%, respectively). CONCLUSIONS: The high prevalence of disruptive behaviors and frequent treatment with antipsychotics and mood stabilizers in the CU group may be related to the strong association between externalizing behavior and cannabis use and the non-specific pharmacological treatment of disruptive behaviors. Formal screening for cannabis use should be considered in psychiatric facilities. Specifically, adolescents with disruptive behaviors could benefit from early interventions, before and after cannabis initiation. PMID- 22512927 TI - Immobilized antibiotics to prevent orthopaedic implant infections. AB - Many surgical procedures require the placement of an inert or tissue-derived implant deep within the body cavity. While the majority of these implants do not become colonized by bacteria, a small percentage develops a biofilm layer that harbors invasive microorganisms. In orthopaedic surgery, unresolved periprosthetic infections can lead to implant loosening, arthrodeses, amputations and sometimes death. The focus of this review is to describe development of an implant in which an antibiotic tethered to the metal surface is used to prevent bacterial colonization and biofilm formation. Building on well-established chemical syntheses, studies show that antibiotics can be linked to titanium through a self-assembled monolayer of siloxy amines. The stable metal-antibiotic construct resists bacterial colonization and biofilm formation while remaining amenable to osteoblastic cell adhesion and maturation. In an animal model, the antibiotic modified implant resists challenges by bacteria that are commonly present in periprosthetic infections. While the long-term efficacy and stability is still to be established, ongoing studies support the view that this novel type of bioactive surface has a real potential to mitigate or prevent the devastating consequences of orthopaedic infection. PMID- 22512933 TI - Neurocognitive correlates of the trail making test for older children in patients with traumatic brain injury. AB - Studies have found that processing speed and working memory influence performance on the Trail Making Test (TMT), though little research is available in this regard for the TMT for Children (TMT-C), particularly in clinical populations. The purpose of the present study was to examine cognitive mechanisms that are thought to underline performance on the TMT-C in a sample of children who sustained traumatic brain injury. Sixty-one children and adolescents with moderate to severe brain injuries completed the TMT-C and performed a battery of neuropsychological tests. Regression analysis was used to analyze the relationship between cognitive constructs and TMT-C performance. Results indicated that processing speed predicted Trails A performance while backwards span tasks predicted Trails B performance. These findings corroborate with previous studies and provide evidence of the mechanisms that underlie TMT-C performance in brain injured children. PMID- 22512928 TI - Studies of bone morphogenetic protein-based surgical repair. AB - Over the past several decades, recombinant human bone morphogenetic proteins (rhBMPs) have been the most extensively studied and widely used osteoinductive agents for clinical bone repair. Since rhBMP-2 and rhBMP-7 were cleared by the U.S. Food and Drug Administration for certain clinical uses, millions of patients worldwide have been treated with rhBMPs for various musculoskeletal disorders. Current clinical applications include treatment of long bone fracture non-unions, spinal surgeries, and oral maxillofacial surgeries. Considering the growing number of recent publications related to clincal research of rhBMPs, there exists enormous promise for these proteins to be used in bone regenerative medicine. The authors take this opportunity to review the rhBMP literature paying specific attention to the current applications of rhBMPs in bone repair and spine surgery. The prospective future of rhBMPs delivered in combination with tissue engineered scaffolds is also reviewed. PMID- 22512934 TI - Variability in Wechsler Adult Intelligence Scale-IV subtest performance across age. AB - Normal Wechsler Adult Intelligence Scale (WAIS)-IV performance relative to average normative scores alone can be an oversimplification as this fails to recognize disparate subtest heterogeneity that occurs with increasing age. The purpose of the present study is to characterize the patterns of raw score change and associated variability on WAIS-IV subtests across age groupings. Raw WAIS-IV subtest means and standard deviations for each age group were tabulated from the WAIS-IV normative manual along with the coefficient of variation (CV), a measure of score dispersion calculated by dividing the standard deviation by the mean and multiplying by 100. The CV further informs the magnitude of variability represented by each standard deviation. Raw mean scores predictably decreased across age groups. Increased variability was noted in Perceptual Reasoning and Processing Speed Index subtests, as Block Design, Matrix Reasoning, Picture Completion, Symbol Search, and Coding had CV percentage increases ranging from 56% to 98%. In contrast, Working Memory and Verbal Comprehension subtests were more homogeneous with Digit Span, Comprehension, Information, and Similarities percentage of the mean increases ranging from 32% to 43%. Little change in the CV was noted on Cancellation, Arithmetic, Letter/Number Sequencing, Figure Weights, Visual Puzzles, and Vocabulary subtests (<14%). A thorough understanding of age related subtest variability will help to identify test limitations as well as further our understanding of cognitive domains which remain relatively steady versus those which steadily decline. PMID- 22512935 TI - Position paper: Management of men complaining of a small penis despite an actually normal size. AB - INTRODUCTION: With the worldwide increase in penile augmentation procedures and claims of devices designed to elongate the penis, it becomes crucial to study the scientific basis of such procedures or devices, as well as the management of a complaint of a small penis in men with a normal penile size. AIM: The aim of this work is to study the scientific basis of opting to penile augmentation procedures and to develop guidelines based on the best available evidence for the management of men complaining of a small penis despite an actually normal size. METHODS: We reviewed the literature and evaluated the evidence about what the normal penile size is, what patients complaining of a small penis usually suffer from, benefits vs. complications of surgery, penile stretching or traction devices, and outcome with patient education and counseling. Repeated presentation and detailed discussions within the Standard Committee of the International Society for Sexual Medicine were performed. MAIN OUTCOME MEASURE: Recommendations are based on the evaluation of evidence-based medical literature, widespread standards committee discussion, public presentation, and debate. RESULTS: We propose a practical approach for evaluating and counseling patients complaining of a small-sized penis. CONCLUSIONS: Based on the current status of science, penile lengthening procedure surgery is still considered experimental and should only be limited to special circumstances within research or university institutions with supervising ethics committees. PMID- 22512932 TI - Measurement of apolipoprotein E and amyloid beta clearance rates in the mouse brain using bolus stable isotope labeling. AB - BACKGROUND: Abnormal proteostasis due to alterations in protein turnover has been postulated to play a central role in several neurodegenerative diseases. Therefore, the development of techniques to quantify protein turnover in the brain is critical for understanding the pathogenic mechanisms of these diseases. We have developed a bolus stable isotope-labeling kinetics (SILK) technique coupled with multiple reaction monitoring mass spectrometry to measure the clearance of proteins in the mouse brain. RESULTS: Cohorts of mice were pulse labeled with 13C6-leucine and the brains were isolated after pre-determined time points. The extent of label incorporation was measured over time using mass spectrometry to measure the ratio of labeled to unlabeled apolipoprotein E (apoE) and amyloid beta (Abeta). The fractional clearance rate (FCR) was then calculated by analyzing the time course of disappearance for the labeled protein species. To validate the technique, apoE clearance was measured in mice that overexpress the low-density lipoprotein receptor (LDLR). The FCR in these mice was 2.7-fold faster than wild-type mice. To demonstrate the potential of this technique for understanding the pathogenesis of neurodegenerative disease, we applied our SILK technique to determine the effect of ATP binding cassette A1 (ABCA1) on both apoE and Abeta clearance. ABCA1 had previously been shown to regulate both the amount of apoE in the brain, along with the extent of Abeta deposition, and represents a potential molecular target for lowering brain amyloid levels in Alzheimer's disease patients. The FCR of apoE was increased by 1.9- and 1.5-fold in mice that either lacked or overexpressed ABCA1, respectively. However, ABCA1 had no effect on the FCR of Abeta, suggesting that ABCA1 does not regulate Abeta metabolism in the brain. CONCLUSIONS: Our SILK strategy represents a straightforward, cost effective, and efficient method to measure the clearance of proteins in the mouse brain. We expect that this technique will be applicable to the study of protein dynamics in the pathogenesis of several neurodegenerative diseases, and could aid in the evaluation of novel therapeutic agents. PMID- 22512936 TI - Manipulation of domain wall dynamics in amorphous microwires through the magnetoelastic anisotropy. AB - We studied the effect of magnetoelastic anisotropy on domain wall (DW) dynamics and remagnetization process of magnetically bistable Fe-Co-rich microwires with metallic nucleus diameters (from 1.4 to 22 MUm). We manipulated the magnetoelastic anisotropy applying the tensile stresses and changing the magnetostriction constant and strength of the internal stresses. Microwires of the same composition of metallic nucleus but with different geometries exhibit different magnetic field dependence of DW velocity with different slopes. Application of stresses resulted in decrease of the DW velocity, v, and DW mobility, S. Quite fast DW propagation (v until 2,500 m/s at H about 30 A/m) has been observed in low magnetostrictive magnetically bistable Co56Fe8Ni10Si10B16 microwires. Consequently, we observed certain correlation between the magnetoelastic energy and DW dynamics in microwires: decreasing the magnetoelastic energy, Kme, DW velocity increases. PMID- 22512938 TI - Geometrical analysis of the V-Y advancement flap applied to a keystone flap. AB - BACKGROUND: The V-Y advancement flap and, more recently, the keystone flap are commonly used to cover skin defects. Both flaps allow for primary closure after advancement by substituting the initial defect for a narrower defect distributed over a greater length. The first objective of this study was to develop a geometrical analysis of the V-Y advancement flap. The second objective was to explain the benefit of using the keystone flap compared to a single V-Y advancement flap. MATERIAL AND METHOD: A geometrical analysis is proposed using a two-dimensional analysis in which the flaps are assumed to have a rigid-body behaviour. First, in the case of the V-Y advancement flap, a trigonometric relationship is defined between the distance of closure before and after advancement, thus implying the value of the flap's apex angle. Second, by considering the keystone flap as the association of three V-Y advancement flaps, the trigonometric relationship is applied to the keystone flap. RESULTS: In the case of the V-Y advancement flap, the optimal apex angles are between 20 degrees and 60 degrees . At less than 20 degrees , the length of the flap increases in an exaggerated manner. At greater than 60 degrees , the distance of closure, particularly at the apex of the flap where a corner stitch is performed, is greater than the distance of closure of the initial defect. In the case of the keystone flap, the width of the final defect around the flap is clearly smaller and more regular compared to the final defect around a single V-Y advancement flap. CONCLUSION: The geometrical analysis of the V-Y advancement flap in our description illustrates the major benefit of the keystone flap over a single V-Y advancement flap. PMID- 22512937 TI - Estimated medication costs of primary TNFalpha antagonist failure in patients with rheumatoid arthritis. PMID- 22512939 TI - Effects of hyperbaric oxygen therapy on rapid tissue expansion in rabbits. AB - BACKGROUND: Tissue expansion has been widely used to provide additional soft tissue for clinical reconstruction. Rapid expansion requires a much shorter clinical period than conventional expansion; however, less natural skin growth occurs resulting in a larger stretch-back ratio and insufficient extra soft tissue for clinical use. In this study, hyperbaric oxygen therapy (HBOT) was used in the inflation phase of rapid expansion to increase natural skin growth. METHODS: Twelve rabbits were divided into two groups. Each group received rapid expander inflation every day. One group received HBOT and the other did not. Blood flow in the expanded skin of each rabbit was assayed in the 10-day inflation phase. After the inflation phase, a rectangular expanded flap of each rabbit was harvested. The instant stretch-back ratio, tension, weight and histological characteristics of the flaps were evaluated. RESULTS: (1) After the second inflation day, the mean blood flow of the HBOT group became significantly higher than that of the control with each day (P < 0.05). At the last day, the blood flow of the HBOT group increased to 131 +/- 17 pu, while the control group decreased to 35 +/- 5 pu. (2) The mean instant stretch-back ratio of the HBOT group under no-tension conditions was 29 +/- 4%, which was significantly less than that of the control group, 46 +/- 3% (P < 0.01). (3) The mean flap tension of the HBOT group was 15.3000 +/- 1.47648 g and 12.9833 +/- 0.73598 g in the transverse and longitudinal axis, respectively, both significantly smaller than that of the control group (33.9167 +/- 4.78390 g and 26.5000 +/- 2.45031 g, respectively) (P < 0.01). (4) Mean per unit flap weight of the HBOT group was 0.221 +/- 0.005 g cm(-2), significantly heavier (P < 0.01) than that of the control group (0.143 +/- 0.010 g cm(-2)). (5) Histologically, the epidermal layer and thickness of the expanded skin of the HBOT group were much thicker than those of the control group, and more vessels were visible in the subcutaneous tissue. CONCLUSIONS: The use of HBOT in the inflation phase of rapid expansion can effectively promote blood flow in the expanded skin, increase its natural skin growth and reduce the instant stretch-back ratio and tension of expanded skin. PMID- 22512940 TI - A new device expanding operability of fingertip replantation: subzone 1 fingertip replantation assisted by non-enhanced angiography in a 2-year-old boy. AB - Fingertip replantation in young children is difficult, especially in cases with amputation at subzone 1. Replantation is preferred whenever possible, but the identification of vessels of operative size can be very challenging. Non-enhanced angiography (NEA; Genial Viewer; Genial Light, Shizuoka, Japan) emits infrared light with the wavelength of 850 nm, which is exclusively absorbed by haemoglobin. The light penetrates the bones and other soft tissues, effectively visualising vessels containing blood, and the image is shown in real time on the screen of a laptop computer. We present a case in which preoperative NEA visualised vessels in the amputated fingertip, allowing a successful replantation in a 2-year-old boy. By taking the guesswork out of vessel localisation, NEA can be useful in expanding operability of replantation surgery in fingertip amputations. PMID- 22512941 TI - Is the term "obstetrical brachial plexus palsy" obsolete? An international survey to assess consensus among peripheral nerve surgeons. AB - BACKGROUND: Brachial plexus injury diagnosed following delivery often causes lifelong disability and frequently results in litigation. While there is no universally accepted name for this condition, the term 'obstetrical brachial plexus palsy' (OBPP) is commonly used worldwide. The difficulty with the term 'OBPP' lies with the use of the word 'obstetrical', which some have construed to imply obstetrical malpractice even if none occurred. Many regions, especially in the United States, are suffering increasing obstetrician shortages, sometimes as a result of unsustainable liability insurance premiums. We wanted to determine whether surgeons felt that an alternative to the term 'OBPP' was more appropriate. METHODS: We surveyed peripheral nerve surgeons worldwide to determine the appropriateness of the term 'OBPP' and alternative terms. RESULTS: The majority of US-based surgeons (94%) preferred alternative terms, such as 'neonatal brachial plexus palsy'. However, only 53% of surgeons from other regions preferred alternative terms. This difference was statistically significant (p < 0.0002). CONCLUSIONS: More precise and descriptive alternatives to the term 'OBPP' are available and acceptable to many surgeons. An alternative to 'OBPP' may improve communication between practitioners, families and the legal system, especially in the United States. Our peripheral nerve organisations may be able to provide further leadership on this matter. PMID- 22512942 TI - Morphometric partitioning of the respiratory surface area and diffusion capacity of the gills and swim bladder in juvenile Amazonian air-breathing fish, Arapaima gigas. AB - The gills and the respiratory swim bladders of juvenile specimens (mean body mass 100g) of the basal teleost Arapaima gigas (Cuvier 1829) were evaluated using stereological methods in vertical sections. The surface areas, harmonic mean barrier thicknesses and morphometric diffusing capacities for oxygen and carbon dioxide were estimated. The average respiratory surface area of the swim bladder (2173 cm2 kg-1) exceeded that of the gills (780 cm2 kg-1) by a factor of 2.79. Due to the extremely thin air-blood barrier in the swim bladder (harmonic mean 0.22 MUm) and the much thicker water-blood barrier of the gills (9.61 MUm), the morphometric diffusing capacity for oxygen and carbon dioxide was 88 times greater in the swim bladder than in the gills. These data clearly indicate the importance of the swim bladder, even in juvenile A. gigas that still engage in aquatic respiration. Because of the much greater diffusion constant of CO2 than O2 in water, the gills also remain important for CO2 release. PMID- 22512943 TI - An approach to the determination of winter chill requirements for different Ribes cultivars. AB - Winter chilling is critical for flowering and fruiting of many temperate fruits, with evidence that blackcurrant (Ribes nigrum L.) cropping has been adversely affected by warm winters. Accurate models of chill accumulation in blackcurrant are required so that breeding strategies can be formulated for the generation of new cultivars with resilience to future climates. Existing models for chill accumulation have largely been derived from statistical correlation; here we report the derivation of improved models for blackcurrant using controlled environment treatments. Hardwood cuttings from a diverse set of cultivars were exposed to constant or varying chilling temperatures and the effects on bud break after transfer to a warm, permissive environment evaluated. The impact of different combinations of temperature and chilling periods were described in terms of their overall 'Effectiveness' (E). Clear genotypic differences were found, with excessive chilling often inhibiting bud break. There was a significant interaction between observed chilling response and the period of low temperature exposure. A number of chilling models to explain observed interactions between chilling temperature and time of exposure on bud break were compared; the most effective involved an optimal response to increasing chill accumulation. The effects of varying temperatures during chilling on bud break were complex, with warm temperature breaks substantially inhibiting bud development and cooler temperature breaks tending to enhance bud burst. The relevance of these models to generic studies of endodormancy is discussed, together with their potential application to the development of phenotyping screens for future breeding using diverse blackcurrant germplasm. PMID- 22512944 TI - Sex estimation in a modern American osteological sample using a discriminant function analysis from the calcaneus. AB - Reliable methods for sex estimation during the development of a biological profile are important to the forensic community in instances when the common skeletal elements used to assess sex are absent or damaged. Sex estimation from the calcaneus has potentially significant importance for the forensic community. Specifically, measurements of the calcaneus provide an additional reliable method for sex estimation via discriminant function analysis based on a North American forensic population. Research on a modern American sample was chosen in order to develop up-to-date population specific discriminant functions for sex estimation. The current study addresses this matter, building upon previous research and introduces a new measurement, posterior circumference that promises to advance the accuracy of use of this single, highly resistant bone in future instances of sex determination from partial skeletal remains. Data were collected from The William Bass Skeletal Collection, housed at The University of Tennessee. Sample size includes 320 adult individuals born between the years 1900 and 1985. The sample was comprised of 136 females and 184 males. Skeletons used for measurements were confined to those with fused diaphyses showing no signs of pathology or damage that may have altered measurements, and that also had accompanying records that included information on ancestry, age, and sex. Measurements collected and analyzed include maximum length, load-arm length, load arm width, and posterior circumference. The sample was used to compute a discriminant function, based on all four variables, and was performed in SAS 9.1.3. The discriminant function obtained an overall cross-validated classification rate of 86.69%. Females were classified correctly in 88.64% of the cases and males were correctly classified in 84.75% of the cases. Due to the increasing heterogeneity of current populations further discussion on this topic will include the importance that the re-evaluation of past studies has on modern forensic populations. Due to secular and micro evolutionary changes among populations, the near future must include additional methods being updated, and new methods being examined, both which should cover a wide population spectrum. PMID- 22512945 TI - Chitooligosaccharide elicits acute inflammatory cytokine response through AP-1 pathway in human intestinal epithelial-like (Caco-2) cells. AB - Chitooligosaccharides (COSs) are bioactive carbohydrate derivatives that have numerous health benefits, including stimulation of the immune system. The objectives of this study were to evaluate the effect of chitooligosaccharide (COS) on expression of a specific panel of cytokine genes involved in inflammation and to delineate the signal transduction pathway underlying the COS mediated inflammatory response. Human intestinal epithelial-like (Caco-2) cells were treated with COS (5000-10,000Da) and expression of a panel of eighty-four cytokine genes was analyzed by quantitative real-time PCR. COS induced up regulation of a total of 11 genes including CCL20 and IL8 and concurrent down regulation of 10 genes including pro-inflammatory mediators CCL15, CCL25 and IL1B. To further establish the signal transduction pathway of COS mediated response in Caco-2 cells, two major inflammatory signal transduction pathways (NF kappaB and AP-1) were investigated. COS had inhibitory effect (P<0.01) on TNF alpha induced NF-kappaB binding activity while stimulatory effect (P<0.001) on AP 1 binding activity. COS also inhibited the expression of RELA (P<0.01) and IKBKB (P<0.01) genes of NF-kappaB pathway while stimulate the expression of JUN (P<0.05) gene of AP-1 pathway. In conclusion, COS elicits an acute inflammatory cytokine response in Caco-2 cells and hence it has the potential to stimulate the immune system in the gut epithelium. PMID- 22512946 TI - [Port-site metastasis after retroperitoneal lymphadenectomy for endometrial adenocarcinoma]. AB - Port-site metastasis is a rare but serious complication of laparoscopic surgery. The etiologies are poorly identified and multiple. We report the case of port site metastasis after laparoscopic retroperitoneal lymphadenectomy for endometrial adenocarcinoma. In the literature, three cases of port-site metastasis after laparoscopic retroperitoneal lymphadenectomy are reported: two cases concerning cervical cancer and one case concerning a kidney cancer. To our knowledge, this is the only case about port site metastasis after laparoscopic retroperitoneal lymphadenectomy for endometrial adenocarcinoma. PMID- 22512947 TI - Acute bilateral medial medullary infarct with hypoplastic vertebral artery. PMID- 22512948 TI - Transient Tournay's pupillary phenomenon in a patient with a vertebrobasilar TIA. PMID- 22512950 TI - 2D array of cold-electron nanobolometers with double polarised cross-dipole antennas. AB - A novel concept of the two-dimensional (2D) array of cold-electron nanobolometers (CEB) with double polarised cross-dipole antennas is proposed for ultrasensitive multimode measurements. This concept provides a unique opportunity to simultaneously measure both components of an RF signal and to avoid complicated combinations of two schemes for each polarisation. The optimal concept of the CEB includes a superconductor-insulator-normal tunnel junction and an SN Andreev contact, which provides better performance. This concept allows for better matching with the junction gate field-effect transistor (JFET) readout, suppresses charging noise related to the Coulomb blockade due to the small area of tunnel junctions and decreases the volume of a normal absorber for further improvement of the noise performance. The reliability of a 2D array is considerably increased due to the parallel and series connections of many CEBs.Estimations of the CEB noise with JFET readout give an opportunity to realise a noise equivalent power (NEP) that is less than photon noise, specifically, NEP = 4 10-19 W/Hz1/2 at 7 THz for an optical power load of 0.02 fW. PMID- 22512949 TI - Adjunctive naturopathic care for type 2 diabetes: patient-reported and clinical outcomes after one year. AB - BACKGROUND: Several small, uncontrolled studies have found improvements in self care behaviors and reductions in clinical risk in persons with type 2 diabetes who received care from licensed naturopathic physicians. To extend these findings and determine the feasibility and promise of a randomized clinical trial, we conducted a prospective study to measure the effects of adjunctive naturopathic care (ANC) in primary care patients with inadequately controlled type 2 diabetes. METHODS: Forty patients with type 2 diabetes were invited from a large integrated health care system to receive up to eight ANC visits for up to one year. Participants were required to have hemoglobin A1c (HbA1c) values between 7.5-9.5 % and at least one additional cardiovascular risk factor (i.e., hypertension, hyperlipidemia or overweight). Standardized instruments were administered by telephone to collect outcome data on self-care, self-efficacy, diabetes problem areas, perceived stress, motivation, and mood. Changes from baseline scores were calculated at 6- and 12-months after entry into the study. Six and 12-month changes in clinical risk factors (i.e., HbA1c, lipid and blood pressure) were calculated for the ANC cohort, and compared to changes in a cohort of 329 eligible, non-participating patients constructed using electronic medical records data. Between-cohort comparisons were adjusted for age, gender, baseline HbA1c, and diabetes medications. Six months was pre-specified as the primary endpoint for outcome assessment. RESULTS: Participants made 3.9 ANC visits on average during the year, 78 % of which occurred within six months of entry into the study. At 6-months, significant improvements were found in most patient-reported measures, including glucose testing (P = 0.001), diet (P = 0.001), physical activity (P = 0.02), mood (P = 0.001), self-efficacy (P = 0.0001) and motivation to change lifestyle (P = 0.003). Improvements in glucose testing, mood, self efficacy and motivation to change lifestyle persisted at 12-months (all P < 0.005). For clinical outcomes, mean HbA1c decreased by -0.90 % (P = 0.02) in the ANC cohort at 6-months, a -0.51 % mean difference compared to usual care (P = 0.07). Reductions at 12-months were not statistically significant (-0.34 % in the ANC cohort, P = 0.14; -0.37 % difference compared to the usual care cohort, P = 0.12). CONCLUSIONS: Improvements were noted in self-monitoring of glucose, diet, self-efficacy, motivation and mood following initiation of ANC for patients with inadequately controlled type 2 diabetes. Study participants also experienced reductions in blood glucose that exceeded those for similar patients who did not receive ANC. Randomized clinical trials will be necessary to determine if ANC was responsible for these benefits. PMID- 22512951 TI - Altered slow wave activity in major depressive disorder with hypersomnia: a high density EEG pilot study. AB - Hypersomnolence in major depressive disorder (MDD) plays an important role in the natural history of the disorder, but the basis of hypersomnia in MDD is poorly understood. Slow wave activity (SWA) has been associated with sleep homeostasis, as well as sleep restoration and maintenance, and may be altered in MDD. Therefore, we conducted a post-hoc study that utilized high density electroencephalography (hdEEG) to test the hypothesis that MDD subjects with hypersomnia (HYS+) would have decreased SWA relative to age- and sex-matched MDD subjects without hypersomnia (HYS-) and healthy controls (n=7 for each group). After correction for multiple comparisons using statistical non-parametric mapping, HYS+ subjects demonstrated significantly reduced parieto-occipital all night SWA relative to HYS- subjects. Our results suggest hypersomnolence may be associated with topographic reductions in SWA in MDD. Further research using an adequately powered prospective design is indicated to confirm these findings. PMID- 22512953 TI - Microbicides in obstetrics and gynaecology. Preface. PMID- 22512952 TI - Structural abnormalities in language circuits in genetic high-risk subjects and schizophrenia patients. AB - Schizophrenia is a severe psychiatric disorder with a strong genetic predisposition. Structural and functional brain deficits throughout the cerebral cortex, particularly in the language-processing associated brain regions, are consistently reported. Recently, increasing evidence from magnetic resonance imaging (MRI) studies suggests that healthy relatives of schizophrenia patients also show structural brain abnormalities in cortical gray matter (GM) volume and thickness, suggesting that this may be associated with an unexpressed genetic liability for the disorder. Unfortunately, the findings are not consistent, which may be caused by different age ranges of the cohorts studied. In the present study, we examined the voxel-based whole brain cortical thickness, area, GM volume densities, and regional cortical thickness-related laterality indices in 14 bilateral regions of interest (ROIs) from known language-processing circuits in 20 schizophrenia patients, 21 young non-psychotic subjects with heightened genetic risk for schizophrenia at the peak ages for development of the disorder, and 48 matched controls. The results showed widespread significant reductions in cortical thickness, cortical GM volume density, and scattered decreases in cortical surface area in the schizophrenia patients compared with those in the high-risk subjects and normal controls. Moreover, the genetic high-risk subjects showed significantly increased regional cortical thickness in 7 of the 14 ROIs in the language-processing pathway when compared with controls. They also had increased GM volume density in scattered regions associated with language processing when compared with the normal controls. Laterality analyses showed that the spatial distribution of abnormal cortical thickness in the schizophrenia patients, as well as in the high-risk subjects, contributes to a decrease of the normal left-greater-than-right anatomical asymmetry in the inferior orbital frontal area, and a increased left-greater-than-right pattern in the inferior parietal and occipital regions. Together with the existing findings in the literature, the results of the present study suggest that developmental disruption of the anatomical differentiation of the hemispheres provides a basis for understanding the language impairment and symptoms of psychosis, and that these may arise because of abnormal left-right hemispherical communications that interrupt the normal flow of information processing. The early structural deficits in language-processing circuits may precede the appearance of psychotic symptoms and may be an indicator of an increased risk of developing schizophrenia. PMID- 22512954 TI - Evolution or revolution: changes in the approach to urologic care. PMID- 22512955 TI - Legends in urology. PMID- 22512956 TI - Legends in urology--in memoriam. PMID- 22512957 TI - Post-vasectomy pain syndrome: clinical features and treatment options. AB - INTRODUCTION: Post-vasectomy pain syndrome (PVPS), defined as chronic epididymal pain that is continuous or recurrent in the absence of proven epididymal or testicular infection, has become more common as the number of vasectomies performed rises. With more than four million vasectomies performed annually, the prevention and treatment of this condition becomes more important. Multiple theories have been proposed as a potential etiology of this condition, and along with this have come multiple modalities of treatment. With the uncertainty surrounding the etiology of this syndrome, the aims of treatment are varied and are described and analyzed in this review. MATERIALS AND METHODS: A literature review was conducted to ascertain the various theories explaining the source of the discomfort in this syndrome, along with several treatment modalities, both medical and surgical. CONCLUSIONS: Options for the management of PVPS are rapidly expanding. Among the existing surgical options that include spermatic cord denervation and vasovasostomies, testosterone has emerged as a potential medical therapy with some promising results. Our review of the literature reveals the etiology of PVPS is still uncertain, as multiple theories still prevail. However, progress has been made in the development of additional medical therapies that could provide some relief for patients who are unwilling to accept the risks of surgery. Nevertheless, the importance of counseling patients of the risks of PVPS with vasectomy cannot be overstated. Through review of the pathophysiology of this condition and treatment options including conservative approaches, topical therapies, denervation of the spermatic cord, and surgical approaches, a comprehensive therapeutic approach can be offered to affected patients. PMID- 22512958 TI - Patient costs associated with external beam radiotherapy treatment for localized prostate cancer: the benefits of hypofractionated over conventionally fractionated radiotherapy. AB - INTRODUCTION: To estimate the out-of-pocket costs for patients undergoing external beam radiotherapy (EBRT) for prostate cancer and calculate the patient related savings of being treated with a 5-fraction versus a standard 39-fraction approach. MATERIALS AND METHODS: Seventy patients accrued to the pHART3 (n = 84) study were analyzed for out-of-pocket patient costs as a result of undergoing treatment. All costs are in Canadian dollars. Using the postal code of the patient's residence, the distance between the hospital and patient home was found using Google Maps. The Canada Revenue Agency automobile allowance rate was then applied to determine the cost per kilometer driven. RESULTS: The average cost of travel from the hospital and pHART3 patient's residence was $246 per person after five trips. In a standard fractionation regimen, pHART3 patients would have incurred an average cost of $1921 after 39 visits. The patients receiving hypofractionated radiotherapy would have paid an average of $38 in parking while those receiving conventional treatment would have paid $293. The difference in out-of-pocket costs for the patients receiving a standard versus hypofractionated treatment was $1930. CONCLUSIONS: Medium term prospective data shows that hypofractionated radiotherapy is an effective treatment method for localized prostate cancer. Compared to standard EBRT, hypofractionated radiotherapy requires significantly fewer visits. Due to the long distance patients may have to travel to the cancer center and the expense of parking, the short course treatment saves each patient an average of $1900. A randomized study of standard versus hypofractionated accelerated radiotherapy should be conducted to confirm a favorable efficacy and tolerability profile of the shorter fractionation scheme. PMID- 22512959 TI - Trends and attitudes in surgical management of benign prostatic hyperplasia. AB - INTRODUCTION: Surgical management of benign prostatic hyperplasia (BPH) has changed over the past 15 years with newer techniques emerging such as laser therapy that can be used with anticoagulation, an increasing issue with modern patients. We sought to evaluate current trends in procedure utilization based on age, location, type of practice, and experience. We also hoped to determine what factors influence surgeons' decisions to choose or reject particular surgical techniques. METHODS AND MATERIALS: A 90-item on-line survey was sent via electronic mail to the American Urological Association (AUA), Veterans Administration, Society for Government Service Urologists, and Endourological Society. Data concerning utilization of 12 BPH surgical techniques were analyzed and compared to the surgeons' demographics using categorical data analysis and logistic regression. RESULTS: Of approximately 5500 urologists contacted, 600 urologists replied with 570 currently performing BPH surgery. The two procedures that continue to be utilized by urologists are open prostatectomy (OP) at 78% and monopolar transurethral resection of prostate (TURP) at 73%. When stratified by urologist age and year of residency completion, there were no differences in procedure utilization. There were no differences in types of procedures utilized between AUA sections except in the Northeastern AUA section which utilized less monopolar TURP and the New York section which utilized less photoselective vaporization (PVP). Higher volume surgeons were more likely to perform holmium laser enucleation of the prostate (HoLEP), diode laser vaporization of the prostate, holmium laser ablation of the prostate (HoLAP), and thulium laser ablation. There were no trends for low volume surgeons. There were no differences in types of procedures performed in full time academic versus non academic settings except for robotic prostatectomy and button TURP which were utilized more often in academic settings. Urologists were more likely to accept a technique that produces good clinical outcomes, is safe in practice, and minimally invasive. Urologists reject procedures most frequently due to preference for another technique or lack of training/equipment. Interestingly, reimbursement/cost issues were never reported as primary reasons for acceptance/rejection of any approach. CONCLUSIONS: Change in technology has led urologists to change their approach to surgical treatment of BPH. OP and monopolar TURP are still the procedures utilized by most urologists, however, laser therapy is emerging as a commonly used technique. As more high-risk patients are treated, laser therapies may become a more popularized technique. Further larger scale studies evaluating surgeon attitudes might clarify how changing technology influences practice patterns. PMID- 22512960 TI - Editorial comment re: Trends and attitudes in surgical management of benign prostatic hyperplasia - pages 6170-6175. PMID- 22512961 TI - Penile Kaposis sarcoma in the state of California. AB - INTRODUCTION: Penile Kaposi's sarcoma (PKS) is a rare and poorly characterized disease. Kaposi's sarcoma is common in HIV disease and is an AIDS-defining illness. This study aimed to review epidemiologic characteristics and changes in the incidence of PKS using a total population-based database. MATERIALS AND METHODS: Data from the California Cancer Registry (CCR) were reviewed for the years 1988-2004, identifying all cases of penile cancer. Tumors were classified by histology and stage. Annual age-adjusted incidence and actuarial survival rates were calculated for the overall population and subdivided histology. RESULTS: From 1988-2004, 2870 cases of penile cancer were identified. Squamous cell carcinoma accounted for 87% of all penile cancer (n = 2507), and PKS was the second most common, accounting for 4.6% (n = 132). Patients diagnosed with PKS demonstrated a significantly lower mean age (years) than the overall cohort (43.7 versus 62.6, p < .0001). The incidence of PKS peaked in 1992 with a subsequent dramatic decline, the same year as incident AIDS cases. The percentage of all penile cancer comprised by PKS dropped from 7.4% in the 1988-1995 cohort to 1.7% in the 1995-2004 cohort (p < 0.0001). Patients diagnosed with PKS demonstrated a significantly lower 5 (32.8% versus 76.6%, p < .0001) and 10 year (29.5% versus 69.6%, p < .0001) relative overall survival than those with squamous cell carcinoma. CONCLUSION: PKS is the second most frequent malignancy of the penis, occurring at a younger age and portending a worse prognosis than other forms of penile cancer. The proportion of PKS tumors has declined in recent years, reflecting improvements in HIV treatment that occurred during the study period. PMID- 22512962 TI - Editorial comment re: Penile Kaposis sarcoma in the state of California. PMID- 22512963 TI - Association of bladder sensation measures and bladder diary in patients with urinary incontinence. AB - INTRODUCTION: Investigation suggests the involvement of afferent actions in the pathophysiology of urinary incontinence. Current diagnostic modalities do not allow for the accurate identification of sensory dysfunction. We previously reported urodynamic derivatives that may be useful in assessing bladder sensation. We sought to further investigate these derivatives by assessing for a relationship with 3-day bladder diary. MATERIALS AND METHODS: Subset analysis was performed in patients without stress urinary incontinence (SUI) attempting to isolate patients with urgency symptoms. RESULTS: No association was demonstrated between bladder diary parameters and urodynamic derivatives (r coefficient range (-0.06 to 0.08)(p > 0.05)). However, subset analysis demonstrated an association between detrusor overactivity (DO) and bladder urgency velocity (BUV), with a lower BUV identified in patients without DO. Subset analysis of patients with isolated urgency/urge incontinence identified weak associations between voiding frequency and FSR (r = 0.39) and between daily incontinence episodes and BUV (r = 0.35). However, these associations failed to demonstrate statistical significance. CONCLUSIONS: No statistical association was seen between bladder diary and urodynamic derivatives. This is not unexpected, given that bladder diary parameters may reflect numerous pathologies including not only sensory dysfunction but also SUI and DO. However, weak associations were identified in patients without SUI and, further, a statistical relationship between DO and BUV was seen. Additional research is needed to assess the utility of FSR/BUV in characterizing sensory dysfunction, especially in patients without concurrent pathology (e.g. SUI, DO). PMID- 22512964 TI - Ureteral stricture formation in laparoscopically procured living donor kidney transplantation. AB - INTRODUCTION: To identify the incidence of and risk factors for ureteral stricture formation in laparoscopically procured living donor kidney transplantation (LLDKT). MATERIALS AND METHODS: An IRB approved retrospective review of our institution's living donor database was performed. Patients were divided into two cohorts, those with ureteral strictures requiring procedural intervention and those without evidence of ureteral strictures. Analysis was limited to those patients with at least 1 year of follow up. RESULTS: Of the 584 LLDKT's performed at our institution since June 1999, 510 had at least 1 year of follow up. Four hundred and ninety-six patients had no evidence of stricture disease (97.2%) while 14 (2.8%) developed clinically significant ureteral strictures. The incidence of delayed graft function was higher in the stricture group (21% versus 3%, p < 0.0001) while the intraoperative placement of a ureteral stent was associated with decreased incidence of ureteral strictures (21% of the stricture group received stents compared to 58% in the no stricture group, p = 0.006). In multivariable logistic regression models, delayed graft function was strongly associated with the development of clinically significant ureteral stricture disease (OR 19.3; 95% CI 3.59, 104.2; p = 0.001) while the placement of intraoperative ureteral stents was protective against ureteral stricture formation (OR 0.09; 95% CI: 0.02, 0.49; p = 0.005). CONCLUSION: Delayed graft function and nonuse of ureteral stents are associated with the development of ureteral strictures following LLDKT. PMID- 22512965 TI - Integrating robotic partial nephrectomy to an existing robotic surgery program. AB - INTRODUCTION: As more centers develop robotic proficiency, progressing to a successful robot-assisted partial nephrectomy (RAPN) program depends on a number of factors. We describe our technique, results, and analysis of program setup for RAPN. MATERIALS AND METHODS: Between 2005 and 2011, 92 RAPNs were performed following maturation of a robotic prostatectomy program. Operating rooms and supply rooms were outfitted for efficient robotic throughput. Tilepro and intraoperative ultrasound were used for all cases. Training and experiential learning for surgeons, anesthesia and nursing staff was a high priority. An onsite robotic technician helped troubleshoot, prepare the room and staff prior to starting surgery, and provide assistance with different robotic models. RESULTS: Average operative time decreased over time from 235 min to 199 min (p = .03). Warm ischemia time decreased from 26 minutes to 23 minutes (p = .02) despite an increased complexity of tumors and operations on multiple tumors. Median estimated blood loss was 150 mL. Average length of hospital stay was 3 days (range 1-9). Average size of lesions was 2.7 cm (range 0.7-8.6). Final pathology demonstrated 71 (77%) malignant lesions and 21 (23%) benign lesions. CONCLUSIONS: The addition of a robot-assisted partial nephrectomy program to an institutional robotic program can be coordinated with several key steps. Outcomes from an operational, oncologic, and renal functional standpoint are acceptable. Despite increased complexity of tumors and treatment of multiple lesions, operative and warm ischemia times showed a decrease over time. An organizational model that involves the surgeons, anesthesia, nursing staff, and possibly a robotic technical specialist helps to overcome the learning curve. PMID- 22512966 TI - Large teratoma at aortic bifurcation: an unusual metastasis of testicular cancer. AB - A 29-year-old man presented with a right testicular mass. Serum tumor markers were within normal limits. When compared to a previous computed tomography (CT) scan, a new 4 cm presacral mass was present. He underwent radical right inguinal orchiectomy that demonstrated a mature teratoma and seminomatous components. The patient received four cycles of chemotherapy. Over the course of chemotherapy, the mass grew in size and therefore he underwent retroperitoneal lymph node dissection. Pathology confirmed it to be a teratoma with negative retroperitoneal lymph nodes. The unusual presentation of an isolated metastasis to the presacral region raises the question of altered lymphatic drainage. PMID- 22512967 TI - Transperitoneal laparoscopic radical nephrectomy after multiple previous abdominal surgeries and intraperitoneal hyperthermic chemotherapy: a case report. AB - Laparoscopic indications are still growing due to the acquisition and development of new skills and expertise in the laparoscopic field. We report the first case of a successful transperitoneal right radical nephrectomy after intraperitoneal hyperthermic chemotherapy in a 56-year-old female who previously underwent multiple abdominal surgeries for appendicular adenocarcinoma with pseudomyxoma peritonei. In patients with multiples previous abdominal surgeries and intraperitoneal chemotherapy, transperitoneal laparoscopic surgeries are feasible in experienced hands. However, patient safety is paramount and conversion to open surgery should always be considered in case of complications. PMID- 22512968 TI - Distal urethral reconstruction with AlloDerm: a case report and review of the literature. AB - Reconstruction of large urethral defects is a complex problem for which no standardized surgical guidelines exist due to the lack of clinical trials demonstrating definitively the superiority of one technique over another. AlloDerm has been used in other surgical specialties with success, however, its utility in urologic surgery and, more specifically, for urethral reconstruction has been limited. In this case report, we demonstrate its application in a single-staged closure of a significant anterior urethral defect following distal penile necrosis secondary to an extruded penile prosthesis in a diabetic patient. PMID- 22512969 TI - Initial North American experience with the use of the Olympus Button Electrode for vaporization of bladder tumors. AB - The current treatment standard of care for patients who present de novo or with a recurrent bladder tumor is transurethral resection of the bladder tumor (TURBT) using monopolar or bipolar electrocautery in the form of a 90-degree loop electrode, which has been used since its introduction in 1952. This intervention, accomplished transurethrally, is both diagnostic and potentially therapeutic for patients with bladder cancer, especially for low grade, non muscle-invasive bladder tumors. Although usually safe and sufficient, this technique can create technical challenges, especially in the dynamically changing spherical space of the bladder. Bipolar energy has been available for many years and has been readily adopted for the endoscopic treatment of benign prostatic enlargement. A further refinement on bipolar energy has been the recent introduction of the Olympus Button Electrode (Olympus, Southborough, MA, USA). Coupling bipolar energy into the Olympus Button Electrode not only harnesses the benefits of less thermal spread but also obviates many of the geometric challenges associated with loop electrodes during resection of either large or inauspiciously placed bladder tumors. In this article, we detail our initial experience vaporizing bladder tumors with the Olympus Button Electrode. Although still very early in our experience, we have been able to completely vaporize very large tumors as well as tumors located in difficult parts of the bladder to access with minimal blood loss and no bladder perforations. Furthermore, our ability to obtain adequate grade and stage information has not been compromised by using this vaporization technique. PMID- 22512970 TI - UroLift system for relief of prostate obstruction under local anesthesia. AB - Many men with benign prostatic hyperplasia (BPH) forego therapy because they are dissatisfied with current treatment options. While surgical resection and ablation using many different forms of energy remain the reference standard for BPH treatment, many men seek a less invasive technique that will improve symptoms but not risk the complications associated with tissue removal. The Prostatic Urethral Lift opens the prostatic urethra with UroLift (NeoTract Inc., Pleasanton, CA, USA) permanent implants that are delivered under cystoscopic visualization. The implants literally "hold open" the lateral prostatic lobes creating a passage through the obstructed prostatic urethra. Voiding and symptoms are significantly improved without the morbidity or possible complications following prostate resection. The entire procedure can be readily performed using local anesthesia. As with all new implant procedures, the technique has evolved with experience. The objective of this article is to describe the most current technique for the delivery of the UroLift implant in order to achieve maximal impact on symptom relief. PMID- 22512972 TI - Blue light cystoscopy for detection and treatment of non-muscle invasive bladder cancer. AB - In patients with non-muscle invasive bladder cancer, fluorescence cystoscopy can improve the detection and ablation of bladder tumors. In this paper we describe the technique and practical aspects of hexaminolevulinate (HAL) fluorescence cystoscopy, also known as "blue light cystoscopy". PMID- 22512971 TI - Photoselective vaporization of the prostate in office and outpatient settings. AB - The 980 nm/1470 nm diode laser represents the latest in laser technology for photovaporization of the prostate. Surgeons have already used this device in both inpatient and outpatient (office and ASC) setting to produce transurethral resection of the prostate (TURP) like lesions-albeit with fewer complications than traditional methods. The objective of this article is to report the techniques we used to demonstrate its efficacy and safety of the Evolve Dual (biolitec Inc., East Longmeadow, MA, USA) system in an outpatient surgery type setting. PMID- 22512973 TI - Open clinical uro-oncology trials in Canada. PMID- 22512974 TI - Evaluation of metabolite changes in visual cortex in diabetic retinopathy by MR spectroscopy. AB - PURPOSE: To evaluate metabolite changes in the visual cortex of diabetic patients with nonproliferative or proliferative diabetic retinopathy by Magnetic Resonance Spectroscopy (MRS). MATERIALS AND METHODS: 15 normal subjects (group 1), 15 patients with diabetes who did not have diabetic retinopathy (group 2), 15 patients with nonproliferative diabetic retinopathy (NPDR) (group 3), and 15 patients with proliferative diabetic retinopathy (PDR) (group 4) were included in the study. Furthermore, diabetic patients were divided into two groups according to HbA1c levels (Group A: 20 patients, HbA1c <8%; Group B: 20 patients, HbA1c >8%). In all cases' left visual cortex, amounts of N-acetyl-aspartate (NAA), choline (Cho), and creatine (Cr) were measured by MRS. NAA/Cr, Cho/Cr, and NAA/Cho ratios were calculated. Furthermore, all cases' complete blood count (CBC) and biochemical parameters were evaluated. RESULTS: There was no statistically significant difference for NAA/Cr, Cho/Cr, and NAA/Cho ratios between groups 1, 2, 3, and 4 (P>0.05). However there was a statistically significant difference for NAA/Cr and NAA/Cho ratios between groups A and B (P<0.05). There was no statistically significant difference for Cho/Cr ratio between groups A and B (P>0.05). CONCLUSION: Although NAA/Cr and NAA/Cho ratios decrease in the visual cortex while diabetic retinopathy progresses, these decreases are not statistically significant. While HbA1c levels increase, the NAA concentration decreases in the visual cortex which indicates neuronal loss. The metabolite changes in the visual cortex are associated with acute events rather than chronic. PMID- 22512975 TI - Simple function tests for autonomic neuropathy have a higher predictive value on all-cause mortality in diabetes compared to 24-h heart rate variability. AB - AIM: To compare the long-term predictive power of heart rate variability (HRV) based on 24 h ECG recordings with a battery of simple autonomic function tests with regard to all-cause mortality in diabetic individuals. METHODS: 240 diabetic persons were randomly selected from the diabetic population. A 24-h ECG was obtained and analysed on the Pathfinder 700. In the RR Tools Program time domain and frequency domain parameters were computed. Five function tests were conducted: Valsalva ratio, heart rate response to standing (30:15 ratio), expiration/inspiration ratio (E/I ratio), orthostatic blood pressure response (Ortho BP), and increase in diastolic blood pressure during sustained handgrip. RESULTS: 178 patients agreed to participate and 136 patients who completed all 5 function tests and had an acceptable ECG recording were included in the analyses. 64 individuals (47%) died during the 151/2 year follow-up. Using Cox proportional hazard analyses correcting for age and gender we found that among the HRV parameters only the power in the low frequency band (LF) had an independent predictive value on all-cause mortality (p=0.0002). Multivariate analysis of the five function tests showed that Valsalva (p=0.002), 30:15 ratio (p=0.037), and handgrip (p=0.037) were independent predictors of death. When finally the independent predictors among the function tests and the HRV parameters were assessed in the same model, no significant value could be shown for LF power (p=0.44). CONCLUSION: The study indicates that simple autonomic function tests are superior to HRV based on 24-h ECG recordings in predicting all-cause mortality in the diabetic population. PMID- 22512976 TI - Alkyl hydroperoxide reductase: a candidate Helicobacter pylori vaccine. AB - Helicobacter pylori (H. pylori) is the most important etiological agent of chronic active gastritis, peptic ulcer disease and gastric cancer. The aim of this study was to evaluate the efficacy of alkyl hydroperoxide reductase (AhpC) and mannosylated AhpC (mAhpC) as candidate vaccines in the C57BL/6J mouse model of H. pylori infection. Recombinant AhpC was cloned, over-expressed and purified in an unmodified form and was also engineered to incorporate N and C-terminal mannose residues when expressed in the yeast Pichia pastoris. Mice were immunized systemically and mucosally with AhpC and systemically with mAhpC prior to challenge with H. pylori. Serum IgG responses to AhpC were determined and quantitative culture was used to determine the efficacy of vaccination strategies. Systemic prophylactic immunization with AhpC/alum and mAhpC/alum conferred protection against infection in 55% and 77.3% of mice, respectively. Mucosal immunization with AhpC/cholera toxin did not protect against infection and elicited low levels of serum IgG in comparison with systemic immunization. These data support the use of AhpC as a potential vaccine candidate against H. pylori infection. PMID- 22512977 TI - The prevalence and identity of Chlamydia-specific IgE in children with asthma and other chronic respiratory symptoms. AB - BACKGROUND: Recent studies have confirmed the presence of viable Chlamydia in the bronchoalveolar lavage (BAL) fluid of pediatric patients with airway hyperresponsiveness. While specific IgG and IgM responses to C. pneumoniae are well described, the response and potential contribution of Ag-specific IgE are not known. The current study sought to determine if infection with Chlamydia triggers the production of pathogen-specific IgE in children with chronic respiratory diseases which might contribute to inflammation and pathology. METHODS: We obtained BAL fluid and serum from pediatric respiratory disease patients who were generally unresponsive to corticosteroid treatment as well as sera from age-matched control patients who saw their doctor for wellness checkups. Chlamydia-specific IgE was isolated from BAL and serum samples and their specificity determined by Western blot techniques. The presence of Chlamydia was confirmed by species-specific PCR and BAL culture assays. RESULTS: Chlamydial DNA was detected in the BAL fluid of 134/197 (68%) patients. Total IgE increased with age until 15 years old and then decreased. Chlamydia-specific IgE was detected in the serum and/or BAL of 107/197 (54%) patients suffering from chronic respiratory disease, but in none of the 35 healthy control sera (p < 0.0001). Of the 74 BAL culture-positive patients, 68 (91.9%, p = 0.0001) tested positive for Chlamydia-specific IgE. Asthmatic patients had significantly higher IgE levels compared to non-asthmatics (p = 0.0001). Patients who were positive for Chlamydia DNA or culture had significantly higher levels of serum IgE compared to negative patients (p = 0.0071 and p = 0.0001 respectively). Only 6 chlamydial antigens induced Chlamydia-specific IgE and patients with C. pneumoniae-specific IgE had significantly greater levels of total IgE compared to C. pneumoniae-specific IgE negative ones (p = 0.0001). CONCLUSIONS: IgE antibodies play a central role in allergic inflammation; therefore production of Chlamydia-specific IgE may prove significant in the exacerbation of chronic, allergic airway diseases, thus highlighting a direct role for Chlamydia in asthma pathogenesis. PMID- 22512978 TI - Calibration of semiconductor detectors in the 200-8500 keV range at VNIIM. AB - At the ionising radiation department of the D.I. Mendeleyev Institute for Metrology, a semiconductor detector was calibrated in the energy range 200-8500 keV using (n,2gamma) and (n,gamma) reactions. Separate cylindrical targets (77 mm diameter and 10mm height) were made from mercuric sulphate, sodium chloride and metallic titanium. A (252)Cf spontaneous fission neutron source, placed in 150 mm diameter polyethylene ball, was used to generate thermal neutrons. The optimal target dimensions were determined taking into account the thermal neutron cross sections and gamma-radiation attenuations in the target materials. The influence of the background radiation induced by neutrons from the walls, floors and ceilings was also taken into account. The shapes of the efficiency curves for point and volume sources in the 200-8500 keV range have been investigated. The experimental results are in good agreement with Monte-Carlo calculations. The emission rate of the 6.13 MeV photons from a (238)Pu-(13)C source was determined with an expanded uncertainty, U(c), of 10% (k=2). PMID- 22512979 TI - Molecular pathways: old drugs define new pathways: non-histone acetylation at the crossroads of the DNA damage response and autophagy. AB - Histone deacetylases (HDAC) modulate acetylation and the function of histone and non-histone proteins. HDAC inhibitors have been developed to block the aberrant action of HDACs in cancer, and several are in clinical use (vorinostat, romidepsin, and valproic acid). Detailed understanding of their action is lacking, however, and their clinical activity is limited in most cases. Recently, HDACs have been involved in the control of the DNA damage response (DDR) at several levels and in directly regulating the acetylation of a number of DDR proteins (including CtIP and Exo1). Mechanistically, acetylation leads to the degradation of double-strand break repair enzymes through autophagy, providing a novel, direct link between DDR and autophagy. These observations, obtained in yeast cells, should now be translated to mammalian model systems and cancer cells to reveal whether this acetylation link is maintained in mammals, and if and how it is deregulated in cancer. In addition to HDACs, DDR and autophagy have been addressed pharmacologically, suggesting that the acetylation link, if involved in cancer, can be exploited for the design of new anticancer treatments. PMID- 22512980 TI - Decreased selenium-binding protein 1 enhances glutathione peroxidase 1 activity and downregulates HIF-1alpha to promote hepatocellular carcinoma invasiveness. AB - PURPOSE: We aimed to characterize the role of selenium-binding protein 1 (SBP1) in hepatocellular carcinoma (HCC) invasiveness and underlying clinical significance. EXPERIMENTAL DESIGN: SBP1 expression was measured in stepwise metastatic HCC cell lines by Western blotting. The role of SBP1 in HCC was investigated using siRNA. Immunofluorescence analyses were used to detect the interaction between SBP1 and glutathione peroxidase 1 (GPX1). Nineteen fresh tumor tissues and 323 paraffin-embedded samples were used to validate in vitro findings and to detect the prognostic significance of SBP1, respectively. RESULTS: Inhibition of SBP1 effectively increased cell motility, promoted cell proliferation, and inhibited apoptosis only under oxidative stress; it also greatly enhanced GPX1 activity without altering GPX1 expression and downregulated hypoxia-inducible factor-1alpha (HIF-1alpha) expression. SBP1 and GPX1 formed nuclear bodies and colocalized under oxidative stress. In freshly isolated clinical HCC tissues, decreased SBP1 was linked with increased GPX1 activity and correlated with vascular invasion. Tumor tissue microarrays indicated that SBP1 was an independent risk factor for overall survival and disease recurrence; patients with lower SBP1 expression experienced shorter overall survival periods and higher rates of disease recurrence (P < 0.001). Further analyses indicated that the predictive power of SBP1 was more significant for patients beyond the Milan criteria than patients within the Milan criteria. CONCLUSIONS: Decreased expression of SBP1 could promote tumor invasiveness by increasing GPX1 activity and diminishing HIF-1alpha expression in HCC; SBP1 could be a novel biomarker for predicting prognosis and guiding personalized therapeutic strategies, especially in patients with advanced HCC. PMID- 22512981 TI - Hidden in the crowd: primordial germ cells and somatic stem cells in the mesodermal posterior growth zone of the polychaete Platynereis dumerillii are two distinct cell populations. AB - BACKGROUND: In the polychaete Platynereis, the primordial germ cells (PGCs) emerge from the vasa, piwi, and PL10 expressing mesodermal posterior growth zone (MPGZ) at the end of larval development, suggesting a post-embryonic formation from stem cells. METHODS: In order to verify this hypothesis, embryos and larvae were pulse labeled with the proliferation marker 5-ethynyl-2'-deoxyuridine (EdU) at different stages of development. Subsequently, the PGCs were visualized in 7 day-old young worms using antibodies against the Vasa protein. RESULTS: Surprisingly, the primordial germ cells of Platynereis incorporate EdU only shortly before gastrulation (6-8 hours post fertilization (hpf)), which coincides with the emergence of four small blastomeres from the mesoblast lineage. We conclude that these so-called 'secondary mesoblast cells' constitute the definitive PGCs in Platynereis. In contrast, the cells of the MPGZ incorporate EdU only from the pre-trochophore stage onward (14 hpf). CONCLUSION: While PGCs and the cells of the MPGZ in Platynereis are indistinguishable in morphology and both express the germline markers vasa, nanos, and piwi, a distinct cluster of PGCs is detectable anterior of the MPGZ following EdU pulse-labeling. Indeed the PGCs form independently from the stem cells of the MPGZ prior to gastrulation. Our data suggest an early PGC formation in the polychaete by preformation rather than by epigenesis. PMID- 22512982 TI - [Interest of Geriatric Nutritional Risk Index for mortality prediction in hemodialysis patients: preliminary study]. AB - INTRODUCTION: Geriatric Nutritional Risk Index (GNRI) is a simple and quantitative method (based on three objective measurements: weight, height, albumin) for screening patients at risk for malnutrition. However no data are available regarding its relation with mortality in Caucasian hemodialysis patients. We tested the predictive value of GNRI on mortality in a hemodialysis population followed up prospectively for 18 months. METHODS: A total of 46 stable prevalent (mean age: 76 +/- 11 years, range: 42-95) hemodialysis patients from one center were included in the study. GNRI with other nutritional parameters were evaluated for all patients. RESULTS: Sixteen patients (35%) died during the 18 months of follow-up. Multiple logistic model showed that GNRI and Charlson co morbidity score were significant predictors of mortality. Age and gender were not significant. CONCLUSION: Our preliminary study carried out on a series of prevalent hemodialysis patients suggests that GNRI is predictor of mortality. To recommend the use of this index for the screening of hemodialysis patients with malnutrition at risk of mortality, our results should be confirmed by a large cohort study. PMID- 22512983 TI - Pathologic epithelial and anterior corneal nerve morphology in early-stage congenital aniridic keratopathy. AB - OBJECTIVE: To document the clinical and morphologic corneal findings in the early stages of congenital aniridic keratopathy in Swedish families. DESIGN: Prospective, observational, comparative case series. PARTICIPANTS: A total of 16 eyes of 16 subjects with congenital aniridic keratopathy and a clear central cornea, and 6 eyes from 6 healthy controls (unaffected relatives). Nine of the 16 eyes with aniridia came from 5 families with a documented familial history of aniridia. METHODS: Detailed ophthalmic examinations included best spectacle corrected visual acuity (BSCVA), tear film production, tear break-up time (BUT), corneal touch sensitivity, intraocular pressure measurement, ultrasound pachymetry, slit-lamp biomicroscopy, and laser scanning in vivo confocal microscopy (IVCM). MAIN OUTCOME MEASURES: Confirmed stage of aniridic keratopathy, clinical parameters of cornea and tear film (visual acuity, sensitivity, corneal thickness, tear production, and BUT), and the morphologic status of corneal epithelium, sub-basal nerves, and limbal palisades of Vogt. RESULTS: In early-stage aniridic keratopathy, BSCVA and tear BUT were reduced relative to controls (P < 0.001 for both), and corneal thickness was increased (P=0.01). Inflammatory dendritic cells were present in the central epithelium in aniridia, with significantly increased density relative to controls (P = 0.001). Discrete focal opacities in the basal epithelial region were present in 5 of 11 aniridia cases with an otherwise clear cornea. Opacities were associated with dendritic cells and harbored structures presumed to be goblet cells. Sub-basal nerves were extremely dense in 3 aniridia cases, and a prominent whorl pattern of nerves and epithelial cells was observed in 1 case. Normal limbal palisade morphology was absent in aniridia but present in controls. CONCLUSIONS: Early stage aniridic keratopathy is characterized by the development of focal opacities in the basal epithelium, altered sub-basal nerves, infiltration of the central epithelium by dendritic cells, tear film instability, and increased corneal thickness and degradation of limbal palisade architecture. These findings may help to elucidate the pathogenesis of aniridic keratopathy. PMID- 22512984 TI - Photographic assessment of baseline fundus morphologic features in the Comparison of Age-Related Macular Degeneration Treatments Trials. AB - OBJECTIVE: To describe the methods used for assessment of baseline fundus characteristics from color photography and fluorescein angiography (FA) in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and to describe the relationship between these characteristics and visual acuity. DESIGN: Randomized, masked, multicenter trial. PARTICIPANTS: This investigation included 1185 participants of the CATT study. METHODS: Baseline stereoscopic color fundus photographs and FAs of participants in the CATT study were assessed at a central fundus photograph reading center by masked readers. Replicate assessments of random samples of photographs were performed to assess intragrader and intergrader agreements. The association of the lesion characteristics with baseline visual acuity was assessed using analyses of variance and correlation coefficients. MAIN OUTCOME MEASURES: Intragrader and intergrader reproducibility, visual acuity, and lesion characteristics. RESULTS: Intragrader and intergrader reproducibility showed agreements ranging from 75% to 100% and weighted kappa values ranging from 0.48 to 1.0 for qualitative determinations. The intraclass correlation coefficients were 0.96 to 0.97 for quantitative measurements of choroidal neovascularization (CNV) area and total area of CNV lesion. The mean visual acuity varied by the type of pathologic features in the foveal center: 64.5 letters (standard error, 0.7 letters) for fluid only, 59.0 letters (standard error, 0.5 letters) for CNV, and 58.7 letters (standard error, 1.3 letters) for hemorrhage (P<0.001). Fibrotic or atrophic scar present in the lesion, but not under the center of the fovea, also was associated with a markedly reduced visual acuity of 48.4 letters (standard error, 2.2 letters; P<0.0001). Although total area of CNV lesion was correlated weakly with visual acuity when all participants were assessed (Spearman correlation coefficient, rho = -0.16; P<0.001), the correlation was stronger within patients with predominantly classic lesions (rho = -0.42; P<0.001). CONCLUSIONS: These results show that the methodology used for grading CATT fundus images has good reproducibility. As expected, larger total CNV lesion area and pathologic findings such as hemorrhage, fibrosis, and atrophy at baseline are associated with decreased visual acuity. PMID- 22512985 TI - Keratoplasty for corneal endothelial disease, 2001-2009. AB - PURPOSE: To determine the rates of keratoplasty for corneal endothelial disease (CED) from 2001 to 2009 in a large managed care network in the United States, factors that affect which patients undergo this procedure and surgical outcomes. DESIGN: A retrospective review of data from a longitudinal cohort study. PARTICIPANTS: Beneficiaries with CED aged >= 40 years who were receiving eye care during 2001 to 2009. METHODS: Rates of keratoplasty for CED were determined at 6 month intervals from January 2001 to December 2009. The mean number of postoperative visits and rates of severe adverse events in the year after keratoplasty surgery were monitored over the course of the decade. Univariable and multivariable logistic regression were performed to identify sociodemographic and other factors associated with undergoing keratoplasty for CED. MAIN OUTCOME MEASURES: Odds of undergoing keratoplasty with 95% confidence intervals, changes in the number of postoperative visits, and rates of adverse events in the year after keratoplasty. RESULTS: Of the 38 648 enrollees who met the inclusion criteria, 2187 underwent >= 1 keratoplasty surgeries from January 2001 to December 2009. After adjustment for confounding factors, individuals with CED had 47% increased odds of undergoing keratoplasty during 2007-2009 relative to 2001 2006. The mean number of postoperative visits to eyecare providers in the year after keratoplasty declined from 12.6 in 2001-2006 to 10.5 in 2007-2008. There was no difference in the proportion of enrollees who developed adverse events after keratoplasty over time. CONCLUSIONS: In this analysis of claims data, from 2001 to 2009, a period during which there was an increase in the rate of endothelial keratoplasty, we observed a trend of greater rates of keratoplasty in patients with CED and fewer visits for postoperative care in the later years of the decade compared with the earlier years, along with no change in rates of severe adverse events. PMID- 22512986 TI - International results with the Boston type I keratoprosthesis. AB - PURPOSE: To determine the indications and outcomes of Boston type 1 keratoprosthesis (Massachusetts Eye and Ear Infirmary, Boston, MA) surgery performed outside of North America and to compare them with those obtained in the United States by the surgeon who trained the international surgeons. DESIGN: Retrospective review of consecutive clinical case series. PARTICIPANTS: One hundred ninety-four patients (223 keratoprosthesis procedures performed in 205 eyes) who received Boston type 1 keratoprosthesis at 11 ophthalmology centers in Armenia, India, Indonesia, Nepal, Philippines, Russia, and Saudi Arabia between May 1, 2006, and July 1, 2011 (international series), and at the Jules Stein Eye Institute between May 1, 2004, and July 1, 2011 (University of California, Los Angeles [UCLA] series). METHODS: Data were collected for each procedure regarding the preoperative characteristics of each eye, the surgical procedure(s) performed, and the postoperative outcomes. Statistical analysis was performed to identify significant differences between the international and UCLA series in terms of retention and complications. MAIN OUTCOME MEASURES: Interval visual acuities, keratoprosthesis retention, and significant postoperative complications. RESULTS: In the international series, 113 Boston type I keratoprostheses were implanted in 107 eyes of 100 patients. The most common indication for surgery was corneal graft failure (n = 50; 44%) followed by chemical injury (n = 30; 27%). Although only 2% of eyes had a preoperative corrected distance visual acuity (CDVA) of 20/20 to 20/200, 70%, 68%, and 59% of eyes had a postoperative CDVA of 20/20 to 20/200 at 6 months, 1 year, and 2 years after surgery, respectively. Ninety-one of the 113 keratoprostheses implanted (80.5%) were retained at a mean follow-up of 14.2 months, for a retention failure rate of 22 per 134.6 eye-years (0.163/eye-year). The most common postoperative complications were retroprosthetic membrane formation (27%) and sterile corneal necrosis (18%). The only postoperative complication that was more common in the international series than in the UCLA series was infectious endophthalmitis, which developed in 9% of eyes. CONCLUSIONS: Boston keratoprosthesis is a viable means of managing repeat graft failure and ocular chemical injury outside of North America, with similar visual acuity outcomes, retention rates, and incidence rates of postoperative complications to those obtained by North American surgeons. PMID- 22512988 TI - Extended follow-up after stopping mepolizumab in relapsing/refractory Churg Strauss syndrome. AB - OBJECTIVES: To report on the extended follow-up of relapsing/refractory CSS patients treated with mepolizumab with respect to relapse rates. METHODS: The follow-up consisted of regular clinic visits of patients who received nine infusions of mepolizumab (750mg IV) and switched to methotrexate 0.3mg/kg for maintenance of remission. Glucocorticoids were maintained as low as possible. Disease activity was measured using the Birmingham Vasculitis Activity Score (BVAS). Disease states as remission or relapse were defined according to the EULAR/EUVAS recommendations. The serum eosinophil cationic protein (ECP) was measured regularly and concentrations were correlated with BVAS. RESULTS: The follow-up of the study population under standard methotrexate maintenance therapy was extended to a median of 22 months. Three of nine patients were still in remission at the end of follow-up. During this time five major relapses in three and seven minor relapses in five out of the total nine patients were recognised. ECP levels were found to correlate stronger with the BVAS (r=0.38; p<0.0001) than other measures such as eosinophil counts. CONCLUSIONS: After induction of remission with mepolizumab the majority of patients suffered relapses when switched to methotrexate maintenance therapy. These data suggest that patients with CSS may require long term treatment with mepolizumab. Future trials in CSS should use other doses or dosing intervals for patients in remission. ECP is a promising marker of disease activity in CSS. PMID- 22512989 TI - False-negative FAST examination: associations with injury characteristics and patient outcomes. AB - STUDY OBJECTIVE: Focused assessment with sonography in trauma (FAST) is widely used for evaluating patients with blunt abdominal trauma; however, it sometimes produces false-negative results. Presenting characteristics in the emergency department may help identify patients at risk for false-negative FAST result or help the physician predict injuries in patients with a negative FAST result who are unstable or deteriorate during observation. Alternatively, false-negative FAST may have no clinical significance. The objectives of this study are to estimate associations between false-negative FAST results and patient characteristics, specific abdominal organ injuries, and patient outcomes. METHODS: This was a retrospective cohort study including consecutive patients who presented to an urban Level I trauma center between July 2005 and December 2008 with blunt abdominal trauma, a documented FAST, and pathologic free fluid as determined by computed tomography, diagnostic peritoneal lavage, laparotomy, or autopsy. Physicians blinded to the study purpose used standardized abstraction methods to confirm FAST results and the presence of pathologic free fluid. Multivariable modeling was used to assess associations between potential predictors of a false-negative FAST result and false-negative FAST result and adverse outcomes. RESULTS: During the study period, 332 patients met inclusion criteria. Median age was 32 years (interquartile range 23 to 45 years), 67% were male patients, the median Injury Severity Score was 27 (interquartile range 17 to 41), and 162 (49%) had a false-negative FAST result. Head injury was positively associated with false-negative FAST result (odds ratio [OR] 4.9; 95% confidence interval [CI] 1.5 to 15.7), whereas severe abdominal injury was negatively associated (OR 0.3; 95% CI 0.1 to 0.5). Injuries to the spleen (OR 0.4; 95% CI 0.24 to 0.66), liver (OR 0.36; 95% CI 0.21 to 0.61), and abdominal vasculature (OR 0.17; 95% CI 0.07 to 0.38) were also negatively associated with false negative FAST result. False-negative FAST result was not associated with mortality (OR 0.89; 95% CI 0.42 to 1.9), prolonged ICU length of stay (relative risk 0.88; 95% CI 0.69 to 1.12), or total hospital length of stay (relative risk 0.92; 95% CI 0.76 to 1.12). However, patients with false-negative FAST results were substantially less likely to require therapeutic laparotomy (OR 0.31; 95% CI 0.19 to 0.52). CONCLUSION: Patients with severe head injuries and minor abdominal injuries were more likely to have a false-negative than true-positive FAST result. On the other hand, patients with spleen, liver, or abdominal vascular injuries are less likely to have false-negative FAST examination results. Adverse outcomes were not associated with false-negative FAST examination results, and in fact patients with false-negative FAST result were less likely to have a therapeutic laparotomy. Further studies are needed to assess the strength of these findings. PMID- 22512990 TI - Peripheral nerve abnormalities in pediatric patients with spinal muscular atrophy. AB - We examined the specific nerve conduction deficits distinguishing spinal muscular atrophy (SMA) subtypes I and II. Five SMA I patients (age, 0.2-1.1 years) and 10 SMA II patients (age, 1.0-2.8 years) were examined. Patients were compared to age matched controls for motor and sensory conduction velocity (MCV and SCV) changes, compound muscle and sensory nerve action potential amplitudes (CMAP and SNAP), and F-wave occurrence (FO). Slower MCVs were found in three of five SMA I patients; all five exhibited markedly decreased CMAP amplitudes. Tibial nerve CMAP amplitudes significantly reduced in SMA II patients (p<0.01). Slower SCVs and decreased SNAP amplitudes were observed in three of five SMA I patients but not in SMA II patients. Although FOs were reduced in both extremities of SMA I patients, the reduction was prominent in the tibial nerve of SMA II patients (p=0.031). Loss of motor units may be widespread in the early stage of SMA I, while specific to the legs in young SMA II patients. SMA I showed sensory nerve degeneration, especially of large myelinated fibers. SMA II showed no sensory nerve abnormalities. PMID- 22512987 TI - Fundus autofluorescence in polypoidal choroidal vasculopathy. AB - PURPOSE: To investigate and compare the characteristics of fundus autofluorescence (FAF) in polypoidal choroidal vasculopathy (PCV) with those in typical neovascular age-related macular degeneration (AMD). DESIGN: Retrospective, observational, consecutive case series. PARTICIPANTS: Ninety-two patients with PCV (92 affected eyes and 86 unaffected fellow eyes) and 31 patients with typical neovascular occult AMD with no classic choroidal neovascularization (31 affected eyes and 24 unaffected fellow eyes). METHODS: All study eyes underwent FAF photography with a fundus camera-based system. The incidence and distribution of hypoautofluorescence, that is, the manifestation of retinal pigment epithelium (RPE) damages, were evaluated. MAIN OUTCOME MEASURES: The characteristic FAF findings in PCV. RESULTS: In the affected eyes with PCV, the sites of the neovascular lesions showed 2 distinct FAF patterns: (1) the confluent hypoautofluorescence at the polypoidal lesions and (2) the granular hypoautofluorescence at the branching choroidal vascular networks. The confluent hypoautofluorescence, most of which was surrounded by a hyperautofluorescent ring, was seen in 74 eyes (80.4%) with PCV but was seen in no eyes with typical neovascular AMD (P < 0.001). The granular hypoautofluorescence was seen in 91 eyes (98.9%) with PCV and 27 eyes (87.1%) with typical neovascular AMD (P = 0.014). In addition, the eyes with PCV more frequently showed hypoautofluorescence outside the macular area than those with typical neovascular AMD (P = 0.021). In the unaffected fellow eyes, the hypoautofluorescence was more frequently observed in patients with PCV than in those with typical neovascular AMD, inside the macular area and in the entire FAF image (P = 0.012, P = 0.003, respectively). CONCLUSIONS: In eyes with PCV, the polypoidal lesions and the branching choroidal vascular networks appeared to affect the RPE and induce peculiar FAF findings. When compared with the patients with typical neovascular AMD, widespread RPE damage was more frequently observed in the patients with PCV, both in the affected eyes and in the unaffected fellow eyes. PMID- 22512991 TI - Community health nursing in China: status, challenges, and development strategies. AB - The article describes the origins and current state of development of community health nursing (CHN) in China, as well as several factors that have shaped its development. CHN began in China in 1997, and the quantity of services has increased greatly in recent years. However, most community nurses report that they merely duplicate the jobs of hospital nurses. Thus, CHN has not developed to its full potential, and the main causes can be attributed to inadequate management and a lack of personnel, funding, and public confidence. Although the Chinese government has implemented several policies to promote its development, Chinese CHN is still in its infancy and many difficulties must be overcome before it can meet the demands of social development. PMID- 22512992 TI - Hydrogen peroxide is involved in nitric oxide-induced cell death in maize leaves. AB - Recent evidence indicates that nitric oxide (NO) plays an important role in plant hypersensitive cell death. Here, we report that NO treatment led to rapid cell death and induced hydrogen peroxide (H(2)O(2)) accumulation in maize leaves. We also show that NO induced the expression of Zmrboh genes. Pharmacological study suggests that NO-induced cell death is in part mediated via H(2)O(2). In addition, semi-quantitative RT-PCR revealed that NO induced expression of the systemic acquired resistance (SAR) genes, ZmPR1 and ZmPR5. PMID- 22512993 TI - Estrogens in men: clinical implications for sexual function and the treatment of testosterone deficiency. AB - INTRODUCTION: The role of estrogens in male sexual function and the pathogenesis of testosterone deficiency remain controversial and poorly understood. AIMS: To review the distribution of estrogens in normal and testosterone deficient men, their potential role in sexual function, and the clinical implications of elevated estrogens during testosterone therapy. METHODS: A comprehensive, broad based literature review was conducted on the role of estrogens in male sexual function and testosterone deficiency. RESULTS: Estrogens elicit a variety of physiological responses in men and may contribute to modulation of sexual function. In the absence of testosterone deficiency, elevations in estrogens do not appear to be harmful and estrogens may help maintain some, but not all, sexual function in castrated men. While the therapeutic use of estrogens at pharmacologic doses has been used to suppress serum testosterone, naturally occurring elevations of estrogens do not appear to be a cause of low testosterone. During testosterone replacement, estrogens may rise and occasionally reach elevated levels. There is a lack of evidence that treatment of elevated estrogen levels during testosterone replacement has benefit in terms of male sexuality. CONCLUSION: Further research on the importance of estrogens in male sexual function is needed. Current evidence does not support a role of naturally occurring estrogen elevations in testosterone deficiency or the treatment of elevated estrogens during testosterone therapy. PMID- 22512995 TI - Influence of population and radius of cavity bubbles on size of sodium chloride crystals in ultrasound ablation. AB - Crystal size distribution as a function of power in ultrasound ablation is simulated by using a theoretical method based on population and radius of bubbles. In this method, population and radius of bubbles are related to ultrasound power and Debye temperature of crystals. The best power for production of crystals with uniform size is obtained from the theory. In addition, it is shown that the population of bubbles effects the radius of the productions and the radius of bubbles influences the population of products. Results from the theory are supported by experimental results. PMID- 22512994 TI - Threat or boost? Social comparison affects older people's performance differently depending on task domain. AB - OBJECTIVES: In this research, we investigate whether social comparison with younger people can result in either a stereotype-based threat or boost in older people's performance. METHODS: Study 1 used nationally representative data to establish domains of performance in which older people are either stereotypically disadvantaged or advantaged relative to younger people. Study 2 was an experiment to test how a potentially threatening versus control versus enhancing comparison with younger people would affect performance in negatively and positively stereotyped task domains. RESULTS: As predicted, compared with the control condition, stereotype threat caused performance decrements in both task domains. This effect was partially mediated by anxiety. Moreover, the enhancing social comparison boosted performance, but only on a crossword task, a task on which older people's abilities are favorably stereotyped. DISCUSSION: The research demonstrates that a threatening comparison can result in underperformance by older people both in negatively and positively self-stereotyped task domains. It also demonstrates that social comparison with younger people can enhance older people's performance in a positively stereotyped task domain. The implications for creating circumstances likely to enable older people to achieve their full potential are discussed. PMID- 22512996 TI - Extraction optimization for antioxidant phenolic compounds in red grape jam using ultrasound with a response surface methodology. AB - Optimization of the extraction methodology for antioxidant phenolic compounds in red grape jam was performed with an ultrasound-assisted system. The antioxidant phenolic compounds were extracted and analyzed by determining the total phenolic content (Folin Ciocalteu), as well as by employing free radical DPPH() and the beta-carotene/linoleic acid system. To optimize the parameters of solvent concentration, time and extraction temperature, the experiments were carried out using the central composite rotatable design (CCRD) method. Using response surface methodology (RSM), the best combinations achieved were with 60% ethanol and water for 20min at 50 degrees C. The optimized parameters for this method were compared to an extraction method that has been commonly noted in the literature, which used to be the standard method, and the results were expressed in the milligram equivalent of quercetin per gram of jam (mg E.Q/g Jam). With the new method, the antioxidant potential measured by DPPH(i) was 70% higher than that obtained with the standard extraction method, and the antioxidant potential measured using the beta-carotene/linoleic acid system was 65% higher. In addition, a significant decrease in the total analysis time was achieved (from 10h to 30min), when compared to the standard method. PMID- 22512998 TI - Mutagenicity assessment of aerosols in emissions from wood combustion in Portugal. AB - Polycyclic aromatic hydrocarbon (PAH) extracts of fine particles (PM(2.5)) collected from combustion of seven wood species and briquettes were tested for mutagenic activities using Ames test with Salmonella typhimurium TA98 and TA100. The woods were Pinus pinaster (maritime pine), Eucalyptus globulus (eucalypt), Quercus suber (cork oak), Acacia longifolia (golden wattle), Quercus faginea (Portuguese oak), Olea europea (olive), and Quercus ilex rotundifolia (Holm oak). Burning experiments were done using woodstove and fireplace, hot start and cold start conditions. A mutagenic response was recorded for all species except golden wattle, maritime pine, and briquettes. The mutagenic extracts were not correlated with high emission factors of carcinogenic PAHs. These extracts were obtained both from two burning appliances and start-up conditions. However, fireplace seemed to favour the occurrence of mutagenic emissions. The negative result recorded for golden wattle was interesting, in an ecological point of view, since after confirmation, this invasive species, can be recommended for domestic use. PMID- 22512999 TI - Estimating safe concentrations of trace metals from inter-continental field data on river macroinvertebrates. AB - We derived safe concentrations (SCs) of copper, zinc, cadmium, and manganese using river macroinvertebrate surveys at over 400 individual sites on three continents represented by the UK, USA, and Japan. We related a standardized measure of EPT (Ephemeroptera, Plecoptera, and Trichoptera) taxon richness to dissolved metal concentrations and identified SCs as the thresholds at which effects became apparent. Estimated SCs (and 95% confidence interval, MUg/L) for copper, zinc, cadmium, and manganese were 6.6 (1.2-14.2), 34 (11-307), 0.11 (0.06 0.49), and 7.1 (1.4-20.5), respectively. These values for copper, zinc, and cadmium overlapped closely with laboratory-derived SCs available from water quality criteria/standards in the USA/UK and also predicted no effect concentrations from European Union risk assessments. Such laboratory-derived SCs for manganese are unavailable. These results not only add considerable confidence to the application of existing metal standards, but illustrate also how standard values might be widely transportable geographically. PMID- 22512997 TI - Socioeconomic disparities in lung cancer treatment and outcomes persist within a single academic medical center. AB - BACKGROUND: Socioeconomic disparities in treatment and outcomes of non-small-cell lung cancer (NSCLC) are well established. To explore whether these differences are secondary to individual or institutional characteristics, we examined treatment selection and outcome in a diverse population treated at a single medical center. PATIENTS AND METHODS: We performed a retrospective analysis of consecutive patients diagnosed with NSCLC stages I-III from 2000 to 2005 at the University of Texas Southwestern Medical Center. Treatment selection was dichotomized as 'standard' (surgery for stage I-II; surgery and/or radiation therapy for stage III) or 'other.' Associations between patient characteristics (including socioeconomic status) and treatment selection were examined using logistic regression; associations between characteristics and overall survival were examined using Cox regression models and Kaplan-Meier survival analysis. RESULTS: A total of 450 patients were included. Twenty-eight percent of patients had private insurance, 43% had Medicare, and 29% had an indigent care plan. The likelihood of receiving 'standard' therapy was significantly associated with insurance type (indigent plan versus private insurance odds ratio [OR] 0.13, 95% confidence interval [CI] 0.04, 0.43 for stage I-II; OR 0.38, 95% CI 0.14, 1.00 for stage III). For patients with stage I-II NSCLC, survival was associated with age, sex, insurance type (indigent plan versus private insurance hazard ratio for death 1.98; 95% CI 1.16, 3.37), stage, and treatment selection. In stage III NSCLC, survival was associated with treatment selection. CONCLUSION: Within a single academic medical center, socioeconomically disadvantaged patients with stage I-III NSCLC are less likely to receive 'standard' therapy. Socioeconomically disadvantaged patients with stage I-II NSCLC have inferior survival independent of therapy. PMID- 22513000 TI - Impact of atmospheric deposition of As, Cd and Pb on their concentration in carrot and celeriac. AB - Root crops, carrot and celeriac, were exposed to atmospheric deposition in a polluted versus reference area. An effect was observed on the As, Cd and Pb concentrations of the leaves and the storage organs. The concentrations in the whole storage organs correlated well with atmospheric deposition, which shows that they even could be used for biomonitoring. Nevertheless, leaves remain much more appropriate. The results revealed also a significant increase of the As and Cd concentration in the consumable part of the storage organs as a function of their atmospheric deposition. As such the experiments allowed deriving regression equations, useful for modeling the atmospheric impact of trace elements on the edible parts of root crops. For Pb, however, there was hardly any significant impact on the inner parts of the storage organs and as such the transfer of Pb in the food chain through root crops can be considered to be negligible. PMID- 22513001 TI - Caddisflies as biomonitors identifying thresholds of toxic metal bioavailability that affect the stream benthos. AB - It has been proposed that bioaccumulated concentrations of toxic metals in tolerant biomonitors be used as indicators of metal bioavailability that could be calibrated against the ecological response to metals of sensitive biotic assemblages. Our hypothesis was that metal concentrations in caddisfly larvae Hydropsyche siltalai and Plectrocnemia conspersa, as tolerant biomonitors, indicate metal bioavailability in contaminated streams, and can be calibrated against metal-specific ecological responses of mayflies. Bioaccumulated concentrations of Cu, As, Zn and Pb in H. siltalai from SW English streams were related to the mayfly assemblage. Mayflies were always sparse where bioavailabilities were high and were abundant and diverse where bioavailabilities of all metals were low, a pattern particularly evident when the combined abundance of heptageniid and ephemerellid mayflies was the response variable. The results offer promise that bioaccumulated concentrations of metals in tolerant biomonitors can be used to diagnose ecological impacts on stream benthos from metal stressors. PMID- 22513002 TI - Malformations of cortical development and epilepsy in adult patients. AB - OBJECTIVE: To describe clinical features of epilepsy secondary to Malformation of Cortical Development (MCD) in a series of adult patients. MATERIALS AND METHODS: We searched our database for all cases with confirmed epilepsy and MCD and included in the study only those with complete data. Mean age, sex, age at seizure onset (ASO), seizure types, abnormal neurological exam (ANE), mental retardation, family history, gestational or perinatal insults (G-PI), interictal EEG and response to treatment were analyzed. Cases were classified into the 3 main groups (G) according to the Barkovich classification (BC) and then compared: (G1) "malformations due to abnormal cell proliferation", (G2) "malformations due to abnormal migration" and (G3) "malformations due to abnormal cortical organization". RESULTS: We identified 152 (5.06%) patients with MCD from a total of 3000 with epilepsy. In total, 138 patients with complete medical data were included in this study. The mean age of patients was 36.2 years, 52.2% were female, the mean ASO was 12.3 years, 5.1% of cases had a positive family history and 21% had G-PI. An ANE was observed in 21% and mental retardation in 31.9%. Most of the patients (84.8%) had refractory epilepsy. The distribution of cases according to the BC was: 51.4% in G1, 28.9% in G2 and 19.6% in G3. Comparing the 3 groups, we found that an ANE was statistically more frequent in G3 and was present in 70.4% of cases. CONCLUSION: Our series of adult patients with epilepsy and MCD suggests that MCD are identified as commonly in a developing country as in previous "first world" series. Neurological deficits were more common in the subgroup of patients with polymicrogyria and schizencephaly (BC Group 3). PMID- 22513003 TI - Direct synthesis of graphene-chitosan composite and its application as an enzymeless methyl parathion sensor. AB - This paper proposed a direct electrodeposition approach to synthesis of graphene chitosan (GR-CS) composite onto glassy carbon electrode (GCE) under controlled potential. This direct electrodeposition approach for the construction of GR based hybrid was environmentally friendly, which would not involve the chemical reduction of graphene oxide (GO) and therefore result in no further contamination. The whole procedure was simply and cost only several minutes. Moreover, Combining the advantages of GR (large surface-to-volume ratio and high conductivity) and CS (good biocompatibility and adsorption), the GR-CS composite could be highly efficient to capture OPs and used as solid phase extraction (SPE). The GR-CS/GCE was used to detect organophosphate pesticides (OPs), using methyl parathion (MP) as a model analyte. The significantly redox response of MP on the GR-CS/GCE was proved. The linear range was wide from 4.0 ng mL(-1) to 400 ng mL(-1), and a low detection limit of 0.8 ng mL(-1) for MP was achieved. Moreover, the proposed sensor exhibited high reproducibility, long-time storage stability and satisfactory anti-interference ability. The proposed GR-CS/GCE opens new opportunity for green, fast, simple, and sensitive analysis of OP compounds. PMID- 22513005 TI - A composition and size controllable approach for Au-Ag alloy nanoparticles. AB - A capillary micro-reaction was established for the synthesis of Au-Ag alloy nanoparticles (NPs) with a flexible and controllable composition and grain size by tuning the synthesis temperature, the residence time, or the mole ratio of Au3+:Ag+. By extending the residence time from 5 to 900 s, enhancing the temperature from 120 degrees C to 160 degrees C, or decreasing the mole ratio of Au3+:Ag+ from 1:1 to 1:20, the composition of samples was changed continuously from Au-rich to Ag-rich. The particles became large with the increase of the residence time; however, synthesis temperatures showed less effect on the particle size change. The particle size of the Au-Ag alloy NPs with various composition could be kept by adjusting the mole ratio of Au3+:Ag+. TEM observation displayed that the as-obtained NPs were sphere-like with the smallest average size of 4.0 nm, which is half of those obtained by the traditional flask method. PMID- 22513006 TI - Evidence for local dendritic cell activation in pulmonary sarcoidosis. AB - BACKGROUND: Sarcoidosis is a granulomatous disease characterized by a seemingly exaggerated immune response against a difficult to discern antigen. Dendritic cells (DCs) are pivotal antigen presenting cells thought to play an important role in the pathogenesis. Paradoxically, decreased DC immune reactivity was reported in blood samples from pulmonary sarcoidosis patients. However, functional data on lung DCs in sarcoidosis are lacking. We hypothesized that at the site of disease DCs are mature, immunocompetent and involved in granuloma formation. METHODS: We analyzed myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in broncho-alveolar lavage (BAL) and blood from newly diagnosed, untreated pulmonary sarcoidosis patients and healthy controls using 9-color flowcytometry. DCs, isolated from BAL using flowcytometric sorting (mDCs) or cultured from monocytes (mo-DCs), were functionally assessed in a mixed leukocyte reaction with naive allogeneic CD4+ T cells. Using Immunohistochemistry, location and activation status of CD11c+DCs was assessed in mucosal airway biopsies. RESULTS: mDCs in BAL, but not in blood, from sarcoidosis patients were increased in number when compared with mDCs from healthy controls. mDCs purified from BAL of sarcoidosis patients induced T cell proliferation and differentiation and did not show diminished immune reactivity. Mo-DCs from patients induced increased TNFalpha release in co-cultures with naive allogeneic CD4+ T cells. Finally, immunohistochemical analyses revealed increased numbers of mature CD86+ DCs in granuloma-containing airway mucosal biopsies from sarcoidosis patients. CONCLUSION: Taken together, these finding implicate increased local DC activation in granuloma formation or maintenance in pulmonary sarcoidosis. PMID- 22513007 TI - Angiogenic efficacy of Heparin on chick chorioallantoic membrane. AB - Heparin is an anticoagulant agent known to have diverse effects on angiogenesis with some reports suggesting that it can induce angiogenesis while a few have indicated of its inhibitory property. Cancer patients treated for venous thromboembolism with low molecular heparin had a better survival than the unfractionated heparin (UFH). Heparin is known to interact with various angiogenic growth factors based on its sulfation modifications within the glycosaminoglycan chains. Therefore it is important to study the mechanism of action of heparin of different molecular weight to understand its angiogenic property. In this concern, we examined the angiogenic response of higher molecular weight Heparin (15 kDa) of different concentrations using late CAM assay. Growth of blood vessels in terms of their length and size was measured and thickness of the CAM was calculated morphometrically. The observed increase in the thickness of the CAM is suggestive of the formation of capillary like structures at the treated region. Analysis of the diffusion pattern showed internalized action of heparin that could affect gene expression leading to proliferation of endothelial cells. Angiogenesis refers to formation of new blood vessels from the existing ones and occurrence of new blood vessels at the treated area strongly confirms that heparin of 15 kDa molecular weight has the ability to induce angiogenesis on CAM vascular bed in a dose dependent manner. The results demonstrate the affinity of heparin to induce angiogenesis and provide a novel mechanism by which heparin could be used in therapeutics such as in wound healing process. PMID- 22513008 TI - Chemical constituents and free radical scavenging activity of corn pollen collected from Apis mellifera hives compared to floral corn pollen at Nan, Thailand. AB - BACKGROUND: Bee pollen is composed of floral pollen mixed with nectar and bee secretion that is collected by foraging honey (Apis sp.) and stingless bees. It is rich in nutrients, such as sugars, proteins, lipids, vitamins and flavonoids, and has been ascribed antiproliferative, anti-allergenic, anti-angiogenic and free radical scavenging activities. This research aimed at a preliminary investigation of the chemical constituents and free radical scavenging activity in A. mellifera bee pollen. METHODS: Bee pollen was directly collected from A. mellifera colonies in Nan province, Thailand, in June, 2010, whilst floral corn (Zea mays L.) pollen was collected from the nearby corn fields. The pollen was then sequentially extracted with methanol, dichloromethane (DCM) and hexane, and each crude extract was tested for free radical scavenging activity using the DPPH assay, evaluating the percentage scavenging activity and the effective concentration at 50% (EC50). The most active crude fraction from the bee pollen was then further enriched for bioactive components by silica gel 60 quick and adsorption or Sephadex LH-20 size exclusion chromatography. The purity of all fractions in each step was observed by thin layer chromatography and the bioactivity assessed by the DPPH assay. The chemical structures of the most active fractions were analyzed by nuclear magnetic resonance. RESULTS: The crude DCM extract of both the bee corn pollen and floral corn pollen provided the highest active free radical scavenging activity of the three solvent extracts, but it was significantly (over 28-fold) higher in the bee corn pollen (EC(50) = 7.42 +/- 0.12 MUg/ml), than the floral corn pollen (EC(50) = 212 +/- 13.6% MUg/ml). After fractionation to homogeneity, the phenolic hydroquinone and the flavone 7-O-R-apigenin were found as the minor and major bioactive compounds, respectively. Bee corn pollen contained a reasonably diverse array of nutritional components, including biotin (56.7 MUg/100 g), invert sugar (19.9 g/100 g), vitamin A and beta carotene (1.53 mg/100 g). CONCLUSIONS: Bee pollen derived from corn (Z. mays), a non-toxic or edible plant, provided a better free radical scavenging activity than floral corn pollen. PMID- 22513009 TI - Antifungal saponins from bulbs of garlic, Allium sativum L. var. Voghiera. AB - A bioassay-guided phytochemical analysis of the polar extract from the bulbs of garlic, Allium sativum L., var. Voghiera, typical of Voghiera, Ferrara (Italy), allowed the isolation of ten furostanol saponins; voghieroside A1/A2 and voghieroside B1/B2, based on the rare agapanthagenin aglycone; voghieroside C1/C2, based on agigenin aglycone; and voghieroside D1/D2 and E1/E2, based on gitogenin aglycone. In addition, we found two known spirostanol saponins, agigenin 3-O-trisaccharide and gitogenin 3-O-tetrasaccharide. The chemical structures of the isolated compounds were established through a combination of extensive nuclear magnetic resonance, mass spectrometry and chemical analyses. High concentrations of two eugenol diglycosides were also found for the first time in Allium spp. The isolated compounds were evaluated for their antimicrobial activity towards two fungal species, the air-borne pathogen Botrytis cinerea and the antagonistic fungus Trichoderma harzianum. PMID- 22513010 TI - Analysis of commercial proanthocyanidins. Part 2: An electrospray mass spectrometry investigation into the chemical composition of sulfited quebracho (Schinopsis lorentzii and Schinopsis balansae) heartwood extract. AB - Proanthocyanidins (PACs) are natural plant-derived polymers used in leather tanning, wood adhesives, water purification, and mud additives for oil drilling. Quebracho (Schinopsis lorentzii and Schinopsis balansae) heartwood and mimosa (Acacia mearnsii) bark extracts are the major industrial sources of PACs. These commercial extracts are often sulfited via treatment with sodium hydrogen sulfite to reduce their viscosity and increase their solubility in water. An ESI-MS investigation into the molecular composition of sulfited (cold-water-soluble) quebracho heartwood extract indicates that sulfitation of the PACs occurs via S(N)2 attack of a sulfite ion at both C-2 and C-4 of the constituent flavan-3-ol monomer extender units. Attack at C-2 leads to the opening of the pyran ring. This releases an additional electron-donating phenolic hydroxy group on the A ring and renders the extract more nucleophilic and suitable for the manufacturing of adhesives. Attack at C-4 leads to interflavanyl bond fission and decrease of the PAC oligomer chain length. The introduction of sulfonic acid moieties at C-2 or C-4 increases the polarity and water solubility of the hot water soluble (unsulfited) extract and transforms it into a cold-water-soluble extract. PMID- 22513011 TI - E3-independent ubiquitination of AtMAPR/MSBP1. AB - AtMAPR5/MSBP1 and its homologs can be ubiquitinated in the absence of E3 ligase in in vitro ubiquitination assays. Ubiquitinated AtMAPR3, AtMAPR5/MSBP1, and AtMAPR2 were identified using LC-MS/MS. Analysis of trypsin-released signature peptides showed that this E3-independent ubiquitination of AtMAPR3, AtMAPR5/MSBP1, and AtMAPR2 was dominated by mono-ubiquitination at multiple sites. Unlike AtUBC8-type E2s, AtUBC36 was not able to transfer ubiquitin to AtMAPR2. The truncated mutants AtMAPR2Delta1-10, AtMAPR2Delta1-30, and AtMAPR2_1 73 could also be ubiquitinated. The presence of a ubiquitin-binding domain (UBD) allows proteins to be ubiquitinated independently of E3 ligases. However, AtMAPRs do not contain any known UBD. In vitro ubiquitination of AtMAPR2 observed in this study will be further studied in biochemical and physiological aspects. PMID- 22513012 TI - Controlled clinical trial of a self-management program for people with mental illness in an adult mental health service - the Optimal Health Program (OHP). AB - OBJECTIVE: The objective of this study was to evaluate the effect and cost effectiveness of a self-management intervention, delivered as part of routine care in an adult mental health service. METHOD: In a community mental health setting, routine care was compared with routine care plus a nine-session intervention (the Optimal Health Program) using a non-randomised controlled design. Adult (18-65 years) consumers of mental health services in the Australian Capital Territory were eligible for participation. RESULTS: The Optimal Health Program was associated with significant improvements in health and social functioning as measured by the Health of the Nation Outcome Scale (average change relative to control: -3.17; 95% CI -4.49 to -1.84; P<0.001). In addition, there was a reduction in hospital admissions in the treatment group (percentage of time in hospital reduced from 3.20 to 0.82; P=0.07). This translated into a net cost saving of over AU$6000 per participant per year (uncertainty range AU$744 to AU$12656). CONCLUSIONS: This study shows promising results for incorporating a self-management program into routine care to improve the health and social functioning of mental health consumers in a cost-effective manner. PMID- 22513013 TI - Standardising practices improves clinical diabetic foot management: the Queensland Diabetic Foot Innovation Project, 2006-09. AB - OBJECTIVE: The aim of this paper is to report the clinical practice changes resulting from strategies to standardise diabetic foot clinical management in three diverse ambulatory service sites in Queensland, Australia. METHODS: Multifaceted strategies were implemented in 2008, including: multidisciplinary teams, clinical pathways, clinical training, clinical indicators, and telehealth support. Prior to the intervention, none of the aforementioned strategies were used, except one site had a basic multidisciplinary team. A retrospective audit of consecutive patient records from July 2006 to June 2007 determined baseline clinical activity (n=101). A clinical pathway teleform was implemented as a clinical activity analyser in 2008 (n=327) and followed up in 2009 (n=406). Pre- and post-implementation data were analysed using Chi-square tests with a significance level set at P<0.05. RESULTS: There was an improvement in surveillance of the high risk population of 34% in 2008 and 19% in 2009, and treating according to risk of 15% in 2009 (P<0.05). The documentation of all best practice clinical activities performed improved 13-66% (P<0.03). CONCLUSION: These findings support the use of multifaceted strategies to standardise practice and improve diabetic foot complications management in diverse ambulatory services. PMID- 22513004 TI - The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. AB - Neutrophil gelatinase associated lipocalin (NGAL), also known as oncogene 24p3, uterocalin, siderocalin or lipocalin 2, is a 24kDa secreted glycoprotein originally purified from a culture of mouse kidney cells infected with simian virus 40 (SV-40). Subsequent investigations have revealed that it is a member of the lipocalin family of proteins that transport small, hydrophobic ligands. Since then, NGAL expression has been reported in several normal tissues where it serves to provide protection against bacterial infection and modulate oxidative stress. Its expression is also dysregulated in several benign and malignant diseases. Its small size, secreted nature and relative stability have led to it being investigated as a diagnostic and prognostic biomarker in numerous diseases including inflammation and cancer. Functional studies, conducted primarily on lipocalin 2 (Lcn2), the mouse homologue of human NGAL have revealed that Lcn2 has a strong affinity for iron complexed to both bacterial siderophores (iron-binding proteins) and certain human proteins like norepinephrine. By sequestering iron laden siderophores, Lcn2 deprives bacteria of a vital nutrient and thus inhibits their growth (bacteriostatic effect). In malignant cells, its proposed functions range from inhibiting apoptosis (in thyroid cancer cells), invasion and angiogenesis (in pancreatic cancer) to increasing proliferation and metastasis (in breast and colon cancer). Ectopic expression of Lcn2 also promotes BCR-ABL induced chronic myelogenous leukemia in murine models. By transporting iron into and out of the cell, NGAL also regulates iron responsive genes. Further, it stabilizes the proteolytic enzyme matrix metalloprotease-9 (MMP-9) by forming a complex with it, and thereby prevents its autodegradation. The factors regulating NGAL expression are numerous and range from pro-inflammatory cytokines like interleukins, tumor necrosis factor-alpha and interferons to vitamins like retinoic acid. The purpose of this review article is to examine the expression, structure, regulation and biological role of NGAL and critically assess its potential as a novel diagnostic and prognostic marker in both benign and malignant human diseases. PMID- 22513015 TI - How nurse practitioners implement their roles. AB - OBJECTIVE: This is a report of a qualitative health research study examining how nurse practitioners construct and implement their roles. METHODS: In-depth interviews and a focus group discussion were conducted to obtain narrative data from nurse practitioners from a variety of clinical backgrounds. Data were analysed utilising the principles of grounded theory. Subjects. Seven nurse practitioners participated in face-to-face interviews and six participated in a focus group discussion. RESULTS: The central process of 'developing legitimacy and credibility' is achieved through the processes of: 'developing Clinical Practice Guidelines', 'collaborating with the multidisciplinary team', 'communicating', and 'transitioning to practice'. CONCLUSION: Policy makers and those responsible for operationalising nurse practitioner roles need to support the central process of developing legitimacy and credibility vital for successful implementation. First, this involves enabling a supportive and informed process of Clinical Practice Guideline development. Second, key inter-disciplinary relationships need to be identified to facilitate collaboration and sources of mentorship for nurse practitioners. Finally, an identified period of transition will facilitate identification, development and implementation of the above processes. PMID- 22513014 TI - An organised approach to the podiatric care of people with diabetes in regional Australia. AB - OBJECTIVE: To ensure an efficient publicly funded podiatric service for people with diabetes in regional Victoria, a Podiatry Diabetes Model (PDM) of care was developed. The aim of this study was to determine if people with diabetes attended the most appropriate podiatric service as depicted by the model. METHODS: A 3-month prospective clinical audit of the PDM was undertaken. Primary variables of interest were the podiatric service where the patients were seen and the patients' risk of future foot morbidity. Chi-square analyses for each service category were undertaken to compare the expected number of patients seen according to foot-health risk as predicted by the model, with what was observed. RESULTS: Five hundred and seventy-six people with diabetes were seen in the 3 month period. There was no statistically significant difference between the proportion of patients seen by each podiatric service according to risk status, with what was expected (community: chi(2)=3.3, P=0.4; subacute: chi(2)=8.0, P=0.05; acute: chi(2)=6.6, P=0.09). CONCLUSIONS: The Podiatry Diabetes Model is a sound podiatric model of care and is an example of cross-organisational collaboration that could be implemented in other areas of Australia. PMID- 22513016 TI - Universal for whom? Evaluating an urban Aboriginal population's access to a mainstream universal health home visiting program. AB - OBJECTIVE: To investigate access to a Universal Health Home Visit program for families of Aboriginal and non-Aboriginal infants and the effect of a one-off home visit on subsequent health service utilisation. METHODS: A case-control study was undertaken drawing 175 Aboriginal infants from an Aboriginal birth cohort study and 352 matched non-Aboriginal infants. A structured file audit extracted data from child and family health nurse records. Receipt of home visit and effect on ongoing use of child and family nurses services was compared for Aboriginal and non-Aboriginal infants. RESULTS: Of the 527 infants, 279 (53.0%) were visited at home within 2 weeks. This is below NSW Health benchmarks. Significantly fewer Aboriginal infants (42.9%) compared to non-Aboriginal infants (58.0%) received a home visit within 2 weeks (P<0.01). Receipt of a single home visit did not affect future service use or the number of child health checks infants received. CONCLUSION: This study highlights the challenges of ensuring equitable access to a universal post-natal home visiting program. Assessing ways in which universal services are delivered to ensure equity of access may help to re-evaluate target expectations, reduce demand on nursing staff, improve targeting of vulnerable infants and help in further developing and implementing effective health policy. PMID- 22513018 TI - Effective change management in a regional Sub-acute Ambulatory Care Services setting. AB - Government policies and community expectations in Australia continually lead to calls for healthcare change. These changes are often met with resistance from clinicians and managers. Making change happen requires consideration of the way policies, culture, context, shared vision and leadership can drive or impede change. This reflective case study critically investigates one change process; the evolution of a Sub-acute Ambulatory Care Services (SACS) program in an Australian regional hospital over a 3-year period. The new Community Rehabilitation Services (CRS) program evolved from a merger of Centre and Home Based Rehabilitation (CBR and HBR). Hospital amalgamations, closures and privatisation, and the Department of Health policy relating to SACS, ambulatory care and rehabilitation were some of the key elements explored in this paper. PMID- 22513017 TI - Influence of living arrangements on health services utilisation in Australia. AB - BACKGROUND: The number of people living alone is increasing markedly. Others live as couples only, couples with child(ren) and single adult with child(ren). Health service utilisation could differ for people in different living arrangements as a result of varying levels of risk factors, health status, access to informal care and decision-making for accessing care. OBJECTIVE: To identify the association between living arrangements and health service use. METHODS: The Australian Bureau of Statistics' National Health Survey 2001 data for people 18-65 years old were analysed for household composition and service use. RESULTS: People in various household types differ in terms of their overall use of health services and their use of services by general practitioners. Sex, rurality, socioeconomic status and status of heart condition significantly influenced the use of health services. CONCLUSION: There are implications for health services provision and planning within the context of rapid changes in living arrangements. Additional research is required to explore the reasons to such differences, level of access to informal care, healthcare decision-making processes and consequences of under- or over-utilisation of services. PMID- 22513019 TI - Engaging medical staff in clinical governance: introducing new technologies and clinical practice into public hospitals. AB - INTRODUCTION: To enhance patient care, medical staff at major tertiary teaching hospitals are encouraged to innovate through introducing new technologies and clinical practices. However, such introduction must be safe, efficient, effective and appropriate for patients and the organisation, and actively lead by engage medical staff. METHOD: This study outlines the development, implementation and evaluation of a framework for introducing new technologies and clinical practice to a major tertiary health service. Evaluation includes survey of medical Heads of Units (HOUs) for framework's effectiveness, and comparison of level of medical staff engagement against a best-practice model. RESULTS: Over 2-year period: 19 applications, 7 approved. Successful external funding of $1.993 million achieved. Survey of HOUs in June 2009: response rate 59% (25 of 42 HOUs), with 11 of 25 respondents utilised the committee. Of those 14 of 25 who had not utilised the committee, low awareness of the committee's existence (2 respondents). Most elements of the best-practice model for engaging medical staff were achieved. Recommendations include improvements to committee process and raising profile with medical staff. DISCUSSION: This study demonstrates an effective and successful clinical governance process for introducing new technologies and clinical practice into a major tertiary teaching hospital, supported by moderate levels of medical staff engagement. PMID- 22513020 TI - Adaptive decision-making: how Australian healthcare managers decide. AB - Despite many calls for the utilisation of research evidence in health policy making, it is not widely practised, and little is known about how decision-makers in healthcare organisations actually make decisions. We recruited a purposive sample of Australian healthcare decision-makers to complete a web-based survey. We then took a sub-sample from willing respondents for individual interviews. All interviews were audio-recorded, transcribed verbatim and coded thematically. We found that resource allocation decision-making varied greatly across the Australian healthcare system. Decision-making was highly dependent on the operational context in time, place and purpose, and that research evidence was rarely exploited to its full potential. Decision-making involved a multifaceted interplay of elements in situation of inquiry. All decisions were made by networks or collectives of people; and no instance of individual decision-making was reported. This varied, social and contextual nature of decision-making points to a complexity that is not reflected in systematic evidence-based reviews or evidence-based models for decision-making, and we did not discover an appropriate model to reflect this complexity in the health- related literature. We developed a model of 'adaptive decision-making' that has potential to guide robust decision making in complex situations, and could have some value as an explanatory or theoretical model for teaching and practice. PMID- 22513021 TI - Opportunistic evidence: evidence-based policy in the setting of the Australian Government's chlamydia screening pilot. AB - OBJECTIVE: Chlamydia prevention and control form a significant part of the Australian Government's sexual health policy. This paper examines the evidence for policy development and in particular the role of systematic reviews in evidence-based policy. METHODS: The author undertook a review of the literature on evidence-based policy. The major theories for evidence-based policy were then linked to the Australian Government's main chlamydia policy. RESULTS: A systematic review on chlamydia screening has been influential in policy development, but like all systematic reviews its validity must be assessed. It has been suggested that methodological appropriateness and the question being asked are perhaps more important than study design per se. Partnerships between researchers and policymakers are important but it should be noted that experts have their own particular biases. Policymaking can also be determined by political ideologies. CONCLUSIONS AND IMPLICATIONS: The publication of a systematic review has provided a good summative evaluation of chlamydia screening that has been built upon through partnerships with researchers. The resulting chlamydia screening pilot will provide further evidence for future policy; however, a variety of sources are required to develop robust policy directions. PMID- 22513022 TI - The Victorian experience of transitional registration for Chinese Medicine practitioners and its implications for national registration. AB - BACKGROUND: Statutory registration of Chinese Medicine (CM) practitioners was introduced in Victoria in 2000. The application assessment process for those who were granted registration during the transitional period (2002-04) was resource intensive, as little was known about their age, education, practice and language proficiency. This study offers insights that may be useful for the planning of national registration to commence in 2012. METHODS: Data were extracted from registration application forms submitted to the Chinese Medicine Registration Board of Victoria (CMRB) between 2002 and 2004, using pre-defined data collection forms. RESULTS: In 2006, 639 'grandparented' Victorian CM practitioners had been registered, with a median age of 44 years old (range 23-86). There was a higher proportion of younger female, English-speaking, acupuncturists v. a higher proportion of older male, non-English-speaking, Chinese herbalists. There were few CM practitioners in rural areas, particularly herbalists. More than one-third of practitioners had obtained qualifications overseas and almost half of these practitioners provided no evidence of past study in professional issues and medical ethics. CONCLUSIONS: Ageing, diversity in qualifications and training, English proficiency, and level of study in professional issues and medical ethics represent major challenges for the implementation of CM national registration in 2012. PMID- 22513023 TI - Do Indigenous Australians age prematurely? The implications of life expectancy and health conditions of older Indigenous people for health and aged care policy. AB - OBJECTIVE: To assess whether Indigenous Australians age prematurely compared with other Australians, as implied by Australian Government aged care policy, which uses age 50 years and over for population-based planning for Indigenous people compared with 70 years for non-indigenous people. METHODS: Cross-sectional analysis of aged care assessment, hospital and health survey data comparing Indigenous and non-indigenous age-specific prevalence of health conditions. Analysis of life tables for Indigenous and non-indigenous populations comparing life expectancy at different ages. RESULTS: At age 63 for women and age 65 for men, Indigenous people had the same life expectancy as non-indigenous people at age 70. There is no consistent pattern of a 20-year lead in age-specific prevalence of age-associated conditions for Indigenous compared with other Australians. There is high prevalence from middle-age onwards of some conditions, particularly diabetes (type unspecified), but there is little or no lead for others. CONCLUSION: The idea that Indigenous people age prematurely is not well supported by this study of a series of discrete conditions. The current focus and type of services provided by the aged care sector may not be the best way to respond to the excessive burden of chronic disease and disability of middle-aged Indigenous people. PMID- 22513024 TI - Managing projected midwifery workforce deficits through collaborative partnerships. AB - To address workforce shortages, the Australian Government funded additional nursing and midwifery places in 2009 pre-registration courses. An existing deficit in midwifery clinical placements, combined with the need to secure additional clinical placements, contributed to a serious shortfall. In response, a unique collaboration between Midwifery Academics of Victoria (MIDAC), rural and metropolitan maternity managers (RMM and MMM) groups and Department of Health (DOH) Victoria was generated, in order to overcome difficulties experienced by maternity services in meeting the increased need. This group identified the large number of different clinical assessment tools required to be being completed by midwives supervising students as problematic. It was agreed that the development of a Common Assessment Tool (CAT) for use in clinical assessment across all pre registration midwifery courses in Victoria had the potential to reduce workload associated with student assessments and, in doing so, release additional placements within each service. The CAT was developed in 2009 and implemented in 2010. The unique collaboration involved in the development of the CAT is a blueprint for future projects. The collaboration on this project provided a range of benefits and challenges, as well as unique opportunities for further collaborations involving industry, government, regulators and the tertiary sector. PMID- 22513025 TI - Bringing them home: a Gippsland mental health workforce recruitment strategy. AB - This paper reports on preliminary findings of a novel program piloted in 2010 to address rural mental health workforce shortages. The program involved exposing allied health and nursing students from rural backgrounds studying in Melbourne to mental health service employment opportunities in Gippsland. A longitudinal study is underway to evaluate the effect and outcomes of the program and includes surveying participants' interest in rural mental health work through an online questionnaire immediately prior to and following the program; and surveying career decisions at 6 months and yearly intervals. Paired sample t-tests were used to analyse participants' level of interest in rural work (pre-event 4.67 (1.50); post-event 5.93 (0.96); P=0.001), career in a rural setting (pre-event 4.67 (1.63); post-event 5.67 (1.23); P=0.006), mental health work (pre-event 4.73 (1.39); post-event 6.07 (0.80); P<0.000) and rural mental health career (pre event 4.73 (1.33); post-event 5.80 (1.21); P=0.002). These findings indicate a significant increase from pre- to post-event and are supported by strong effect sizes suggesting that the program had a significant effect on participant interest in rural mental health work. Longer-term evaluation will determine whether the program influences participant career decisions and thereby addressing mental health workforce shortages in Gippsland. PMID- 22513026 TI - Stabilising the aged care workforce: an analysis of worker retention and intention. AB - Concerns about the capacity of the aged care industry to attract and retain a workforce with the skills required to deliver high quality care are widespread, but poor conceptualisation of the problem can result in strategies to address turnover being poorly targeted. A census of residential and community aged care services conducted by the National Institute of Labour Studies (NILS) in 2007 provided a comprehensive empirical account of the workforce, and estimated turnover on the basis of retention: that is, the proportion of the workforce who had been in their job for 1 year or less. This paper adds the dimension of intention: that is, workers' expectations as to whether in 1 year's time, they would still be working in the same aged care service. The dual driver model that takes both retention and intention into account was applied in further analysis of the 2007 NILS data. Investigation of relationships between workforce instability and 13 variables covering worker attributes, organisational attributes and structural attributes of the industry demonstrated the usefulness of the dual driver model for reconceptualising and analysing stability and, in turn, refining strategies to address turnover. PMID- 22513027 TI - Effective clinical supervision for regional allied health professionals - the supervisee's perspective. AB - AIM: Clinical supervision (CS) for health professionals supports quality clinical practice. This study explored current CS effectiveness for allied health professionals (AHPs) at a regional health service from a supervisee perspective and identified improvements. METHOD: The Manchester Clinical Supervision Scale (MCSS) was completed by 30 supervisees to determine their perceptions of CS effectiveness. RESULTS: Supervision sessions typically occurred monthly (56.7%) and were one-to-one (86.2%). The mean total MCSS score was 142.83 (s.d. 15.73), greater than the reported threshold score of 136 for effective CS. The mean subscale scores of 'trust/rapport' and 'improved care/skills' were high, in contrast to the mean subscale scores for 'finding time' and 'personal issues', which were significantly lower than the other subscales (P<0.001). Low scores for 'finding time' and 'personal issues' subscales may be associated with emotional exhaustion and depersonalisation. CONCLUSIONS: In this first study evaluating CS for AHPs using the MCSS, CS was reported as being valued and important. However, there is a need for improvement in addressing personal issues that affect work performance and for finding time for CS. As effective CS is an important component of clinical governance by supporting safe and effective healthcare provision, it is vital that CS processes are improved. PMID- 22513028 TI - Uptake and implementation of Advance Care Planning in Australia: findings of key informant interviews. AB - OBJECTIVE: Advance Care Planning (ACP) has an important role in enhancing patient autonomy and guiding end-of-life care. However, there is low uptake of ACP and evidence that advance care plans are often not implemented. We explored these issues in interviews with expert clinicians and representatives of key stakeholder organisations with interest in end-of-life care. METHOD: Qualitative descriptive study of semi-structured telephone interviews with 23 participants. RESULTS: Participants thought that the low uptake of ACP in Australia is a result of inadequate awareness, societal reluctance to discuss end-of-life issues, and lack of health professionals' involvement in ACP. Problems in implementation of advance care plans were thought to be a result of problems in accessing ACP documents; interpreting written documents; making binding decisions for future unpredictable situations; and paternalistic attitudes of health professionals and families. Participants had different perspectives on how advance care plans should be implemented, with some believing in strict implementation, whereas others believed in a more flexible approach. IMPLICATIONS: Low uptake and poor implementation of advance care plans may be addressed by (1) increasing community awareness; (2) encouraging health professional involvement; and (3) system-wide implementation of multi-faceted interventions. A patient-centred approach to ACP is required to resolve the differences in views on how advance care plans should be implemented. PMID- 22513029 TI - Diabetes-related major lower limb amputation in Far North Queensland, 1998-2008. AB - OBJECTIVE: To report on the accuracy of reports of diabetes-related major amputations, rates per 100000 people and trends over the 10-year period from 1998 99 to 2007-08 in Far North Queensland. METHODS: Three data sources were cross checked. Poisson regression was used to calculate the percentage change in trends in diabetes amputation hospitalisations over the period. RESULTS; There was a discrepancy of 6 (3.7%) in 161 cases over 10 years. The number of diabetes related hospitalisations for major lower limb amputation did not show a significant trend during this period, with an annual percentage change of -0.32%, P=0.915. CONCLUSION: Amputation data in Far North Queensland were accurate. There was a modest reduction in the hospitalisation rate for major lower limb amputation over the 10-year period, demonstrating the need for improvements in the organisation of care. PMID- 22513030 TI - Judging a patient's decision to seek emergency healthcare: clues for managing increasing patient demand. AB - OBJECTIVE: In recent years, the concept of an 'inappropriate' emergency department or ambulance user has arisen. This discussion paper explores definition and measurement of inappropriate emergency healthcare utilisation, and the effect on demand. METHOD: A comprehensive literature review of published articles was conducted. RESULTS: Exploration of the definitions of 'inappropriate' emergency healthcare utilisation identified two patient cohorts; emergency healthcare utilisation by those who are not experiencing a health emergency, and those who do not seek emergency healthcare who should. Several position papers from Australian and international sources emphasised the patient's right to access emergency healthcare when they feel the need, and the responsibility of emergency healthcare workers to provide treatment to all patients. Differences between medical classifications of urgency based on physiological measures are contrasted with patient-based determination of urgency, which is defined by psychosocial factors. CONCLUSIONS: This literature review raises questions about patients' understanding of the role of emergency healthcare services in an emergency. This has implications for determining the patient's point of access to the health system in an acute health event, and offers an opportunity to selectively educate patients and carers to change help seeking behaviours to suit the health system resources and moderate patient demand. PMID- 22513031 TI - Palliative care case conferencing involving general practice: an argument for a facilitated standard process. AB - OBJECTIVE: To discuss the results of a qualitative analysis of the group dynamics of General Practitioner (GP)-led case conferences for palliative care patients, where the GP becomes the care coordinator. Two outcomes are sought: (1) raise the understanding of this type of case conferencing for palliative care patients; and (2) recommend improvements to this process that will positively affect its efficacy. METHODS: Original data is the qualitative component of quantitative and qualitative study of 17 GP-led case conferences for palliative care patients. Data were analysed using Carney's Ladder of Analytical Abstraction. RESULTS: Analysis produced four persistent themes: ambiguity of purpose; ambiguity of role; lack of information; and involvement of multiple interconnected and dynamic groups. These themes are a natural result of the case conferencing process that occurred during the study. CONCLUSION: Case conferences were inherently uncertain and complex. Complexity results from the range of people and groups interacting with the patient before the case conference who do not attend the conference. Uncertainty results from a lack of direction, leadership and agreed outcomes against which the conference can be structured and measured. A standard process facilitated by someone other than the GP and containing necessary information would offer a better chance of optimising this process. PMID- 22513032 TI - Scaffoldless tissue engineering of stem cell derived cavernous tissue for treatment of erectile function. AB - INTRODUCTION: As one-third of erectile dysfunction (ED) patients do not respond to phosphodiesterase-5 inhibitors, there is great demand for new therapeutic options. Adipose tissue-derived stem cells (ADSCs) represent an ideal source for new ED treatment. AIM: To test if ADSCs can be differentiated into smooth muscle cells (SMCs) and endothelial cells (ECs), if these differentiated cells can be used to engineer cavernous tissue, and if this engineered tissue will remain for long time after implantation and integrate into corporal tissue. METHOD: Rat ADSCs were isolated and differentiated into SMC and ECs. The differentiated cells were labeled with 5-ethynyl-2-deoxyuridine (EdU) and used to construct cavernous tissue. This engineered tissue was implanted in penises of normal rats. The rats were sacrificed after 1 and 2 months; penis and bone marrow were collected to assess cell survival and inclusion in the penile tissues. MAIN OUTCOME MEASURES: The phenotype conversion was checked using morphology, immunocytochemistry (immunohistochemistry [IHC]), and Western blot for SMC and EC markers. The cavernous tissue formation was assessed using rat EC antibody (RECA), calponin, and collagen. The implanted cell survival and incorporation into penis were evaluated with hematoxylin and eosin, Masson's trichrome, and IHC (RECA, calponin, and EdU). RESULTS: The phenotype conversion was confirmed with positive staining for SMC and EC markers and Western blot. The formed tissue exhibited architecture comparable to penile cavernous tissue with SMC and ECs and extracellular matrix formation. The implanted cells survived in significant numbers in the penis after 1 and 2 months. They showed proof of SMC and EC differentiation and incorporation into penile tissue. CONCLUSIONS: The results showed the ability of ADSCs to differentiate into SMC and ECs and form cavernous tissue. The implanted tissue can survive and integrate into the penile tissues. The cavernous tissue made of ADSCs forms new technology for improvement of in vivo stem cell survival and ED treatment. PMID- 22513033 TI - Primary neuroendocrine breast carcinoma. PMID- 22513034 TI - Clinical outcomes of nonoperative management in emphysematous urinary tract infections. AB - OBJECTIVE: To investigate the clinical outcomes of nonoperative management of emphysematous urinary tract infections (EUTIs). METHODS: We retrospectively reviewed 28 consecutive cases of EUTI over a 5-year period, all of which were treated with urinary drainage and medical management without surgical intervention. EUTIs were classified as either emphysematous pyelonephritis (EP) or emphysematous cystitis (EC). Clinical, diagnostic, and therapeutic data were analyzed. RESULTS: Of the 28 patients evaluated, 13 had EP and 15 had EC, all of which were diagnosed by computed tomography. Of EP patients, the mean age was 54 years with a median serum creatinine (sCr) of 1.8 mg/dL (estimated glomerular filtration rate [eGFR] 38 mL/min/1.73 m(2)). Obstructive uropathy was present in 69%, and 100% received antibiotics and percutaneous drainage without mortality. Median follow-up was 10 months without any subsequent nephrectomy and median sCr decreased to 1.1 mg/dL (P = .04) and eGFR increased to 63.5 mL/min/1.73 m(2) (P = .06). Of EC patients, the mean age was 60 years with a median sCr of 1.3 mg/dL (eGFR 55 mL/min/1.73 m(2)). All were managed with antibiotics and catheter drainage with a single mortality (7%). Median follow-up was 2 months and median sCr decreased to 1.2 mg/dL (P = .83) and eGFR increased to 46 mL/min/1.73 m(2) (P = .68). The most common causative pathogen was Escherichia coli for both EP (54%) and EC (53%). CONCLUSION: Early detection, medical management, and urinary drainage of EUTI can result in a favorable prognosis. This strategy results in low levels of mortality without the need for surgical intervention and can preserve renal function. PMID- 22513035 TI - A novel DNA/peptide combined vaccine induces PSCA-specific cytotoxic T-lymphocyte responses and suppresses tumor growth in experimental prostate cancer. AB - OBJECTIVE: To develop a completely novel DNA peptide-combined vaccine and determine whether it can efficiently improve tumor-specific cytotoxic T lymphocyte (CTL) responses and inhibit tumor progression in experimental prostate cancer models. METHODS: The DNA/peptide combined vaccine was prepared by the self assembly of a cationic peptide ([K]18P9) containing 18 lysines and a CTL epitope peptide, prostate stem cell antigen (PSCA (14-22)) (HLA-A2 restricted) with a recombinant plasmid encoding human full-length PSCA gene (pcDNA3.1(+)-PSCA) through electrostatic interactions. The formation of a DNA/peptide complex was examined by DNA retardation assay, DNase I protection assay, and transmission electron microscopy. The efficacy of vaccination using this complex was demonstrated in terms of the PSCA-specific CTL activity and antitumor immunity to PSCA(+) tumors in a murine model. RESULTS: This form of DNA/peptide complex could efficiently transfer the plasmid encoding full-length PSCA gene into mammalian cells and induced potent CTLs cytotoxicity against a human prostate carcinoma cell line established from the left supraclavicular lymph node metastasis from a 50-year-old man with prostate carcinoma in 1977. Expressing PSCA compared with pcDNA3.1(+)-PSCA, [K]18P9 peptide, or pcDNA3.1(+). Moreover, the vaccination of mice with this complex induced a potent antitumor immunity to prostate carcinomas in a xenograft tumor model in nude mice. CONCLUSION: This study suggests that a specific antitumor immune response can be induced by this DNA/peptide combined vaccine, which represents a new strategy for use in the immunotherapy of prostate cancer. PMID- 22513037 TI - Construction and validation of the Dynamic Parkinson Gait Scale (DYPAGS). AB - The dynamic evaluation of Parkinson's disease (PD)-related episodic gait disturbances in routine is challenging. Therefore, the aim of our study was to assess the reliability/validity of the Dynamic Parkinson Gait Scale (DYPAGS) composed of eight relevant items for the objective quantification of PD gait features: walking forwards/backwards/with dual-task, turning to both sides, imaginary obstacle avoidance with both legs and passing through narrow spaces. The scale was validated on thirty-five patients with mild to severe parkinsonism in their habitual "on-state". A shorter 6 item-version was designed on the basis of a principal component analysis. No significant floor/ceiling effect was detected. The internal consistency was excellent. The levels of interrater agreement, precision and minimal detectable change were adequate. The criterion related validity was demonstrated by strong correlations with the DYPAGS scores and those at the gait subscales of the Tinetti Mobility Test and MDS-UPDRS. The construct validity was assessed by moderate-strong correlations with the Freezing of Gait Questionnaire, mobility index of the PD Questionnaire (PDQ-39), disease duration and levodopa equivalent daily doses. Statistical analyses using the coefficient of determination showed that both DYPGAS versions were superior to the other instruments to identify patients with gait disturbances with poorer response to dopaminergic treatment. Full and short DYPAGS are reliable instruments for the quantification of "on" PD-related episodic gait disturbances. The full version is sensitive to detect subtle disturbances in mild parkinsonism. The shorter one is easily administered and reliably quantifies gait disturbances in moderate to severe parkinsonism. We recommend their use for research and clinical practice. PMID- 22513038 TI - The impact of analytical sensitivity on screening algorithms for syphilis. PMID- 22513040 TI - Exposure to 2.45 GHz electromagnetic fields elicits an HSP-related stress response in rat hippocampus. AB - The issue of possible neurobiological effects of the electromagnetic field (EMF) exposure is highly controversial. To determine whether electromagnetic field exposure could act as an environmental stimulus capable of producing stress responses, we employed the hippocampus, a sensitive target of electromagnetic radiation, to assess the changes in its stress-related gene and protein expression after EMF exposure. Adult male Sprague-Dawley rats with body restrained were exposed to a 2.45 GHz EMF at a specific absorption rate (SAR) of 6 W/kg or sham conditions. cDNA microarray was performed to examine the changes of gene expression involved in the biological effects of electromagnetic radiation. Of 2048 candidate genes, 23 upregulated and 18 downregulated genes were identified. Of these differential expression genes, two heat shock proteins (HSP), HSP27 and HSP70, are notable because expression levels of both proteins are increased in the rat hippocampus. Result from immunocytochemistry revealed that EMF caused intensive staining for HSP27 and HSP70 in the hippocampus, especially in the pyramidal neurons of cornu ammonis 3 (CA3) and granular cells of dentate gyrus (DG). The gene and protein expression profiles of HSP27 and HSP70 were further confirmed by reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Our data provide direct evidence that exposure to electromagnetic fields elicits a stress response in the rat hippocampus. PMID- 22513039 TI - Surface tension of Nanofluid-type fuels containing suspended nanomaterials. AB - The surface tension of ethanol and n-decane based nanofluid fuels containing suspended aluminum (Al), aluminum oxide (Al2O3), and boron (B) nanoparticles as well as dispersible multi-wall carbon nanotubes (MWCNTs) were measured using the pendant drop method by solving the Young-Laplace equation. The effects of nanoparticle concentration, size and the presence of a dispersing agent (surfactant) on surface tension were determined. The results show that surface tension increases both with particle concentration (above a critical concentration) and particle size for all cases. This is because the Van der Waals force between particles at the liquid/gas interface increases surface free energy and thus increases surface tension. At low particle concentrations, however, addition of particles has little influence on surface tension because of the large distance between particles. An exception is when a surfactant was used or when (MWCNTs) was involved. For such cases, the surface tension decreases compared to the pure base fluid. The hypothesis is the polymer groups attached to (MWCNTs) and the surfactant layer between a particle and the surround fluid increases the electrostatic force between particles and thus reduce surface energy and surface tension. PMID- 22513036 TI - Human milk oligosaccharides: every baby needs a sugar mama. AB - Human milk oligosaccharides (HMOs) are a family of structurally diverse unconjugated glycans that are highly abundant in and unique to human milk. Originally, HMOs were discovered as a prebiotic "bifidus factor" that serves as a metabolic substrate for desired bacteria and shapes an intestinal microbiota composition with health benefits for the breast-fed neonate. Today, HMOs are known to be more than just "food for bugs". An accumulating body of evidence suggests that HMOs are antiadhesive antimicrobials that serve as soluble decoy receptors, prevent pathogen attachment to infant mucosal surfaces and lower the risk for viral, bacterial and protozoan parasite infections. In addition, HMOs may modulate epithelial and immune cell responses, reduce excessive mucosal leukocyte infiltration and activation, lower the risk for necrotizing enterocolitis and provide the infant with sialic acid as a potentially essential nutrient for brain development and cognition. Most data, however, stem from in vitro, ex vivo or animal studies and occasionally from association studies in mother-infant cohorts. Powered, randomized and controlled intervention studies will be needed to confirm relevance for human neonates. The first part of this review introduces the pioneers in HMO research, outlines HMO structural diversity and describes what is known about HMO biosynthesis in the mother's mammary gland and their metabolism in the breast-fed infant. The second part highlights the postulated beneficial effects of HMO for the breast-fed neonate, compares HMOs with oligosaccharides in the milk of other mammals and in infant formula and summarizes the current roadblocks and future opportunities for HMO research. PMID- 22513041 TI - Impaired plasmalogens in patients with schizophrenia. AB - Plasmalogens are a subclass of glycerophospholipids and ubiquitous constituents of cellular membranes and serum lipoproteins. Several neurological disorders show decreased level of plasmogens. An earlier study found differences in plasma phospholipids between unmedicated patients with schizophrenia and matched healthy control subjects. We here report a comparison of plasma plasmalogen levels across 20 drug-naive patients experiencing first psychotic episodes, 20 recently unmedicated patients experiencing psychotic relapses after failing to comply with prescribed medications, and 17 matched healthy control subjects. Multiple plasma phosphatidylcholine and phosphatidylethanolamine plasmalogen levels were significantly lower in first episode patients and patients with recurrent disease compared to healthy controls. Reduced plasmalogen levels appear to be a trait evident at the onset of psychotic illness and after multiple psychotic relapses. It is implied that reductions in plasmalogen levels are not related to antipsychotic treatment but due to the illness itself. Reduced plasmalogen levels suggest impairments in membrane structure and function in patients with schizophrenia that might happen early in development. This may serve as a clue to the neurobiology of schizophrenia and should be studied as a potential biomarker for individuals at risk for schizophrenia. PMID- 22513042 TI - Sustained attention in bipolar I disorder patients with familial psychosis and their first-degree relatives. AB - Sustained attention (SA) was examined in patients with familial, psychotic Bipolar Disorder (BD) (n=43), their non-bipolar, non-psychotic relatives (n=44) and controls (n=47). Patients were impaired compared to relatives, but the latter did not differ from controls. Having a relative with familial, psychotic BD does not confer risk for SA deficits. PMID- 22513043 TI - The role of ethnic identity in symptoms of anxiety and depression in African Americans. AB - Ethnic identity has been identified as a factor contributing to resilience and coping in African Americans. Ethnic identity includes positive feelings of ethnic affirmation and belonging, appreciation for one's ethnic identity, and increased ethnic behaviors. This study examines the role of ethnic identity in symptoms of anxiety and depression. Participants were an adult student and community sample (N=572), administered the Beck Anxiety Inventory (BAI), Center for Epidemiologic Studies of Depression Scale (CES-D), State Trait Anxiety Inventory-state portion (STAI-S), and Multigroup Ethnic Identity Measure (MEIM). Compared to European Americans, African Americans reported significantly greater depression and more negative state anxiety, as well as higher levels of ethnic identity. For African Americans, higher ethnic identity was correlated to reduced anxiety and depression, whereas this was not true for European Americans. Findings support the proposition that a strong, positive ethnic identity may serve a protective role among African Americans by moderating the relationship between discriminatory experiences and psychological well-being. An Afrocentric perspective may also contribute to reduced anxiety due to a greater emphasis on a present versus future-oriented worldview. Clinical implications and directions for future research are discussed. PMID- 22513044 TI - Spatio-temporal variability of tastes and odors of drinking water within a distribution system. AB - The threshold of human perception in the detection of tastes and odors (T&O) relating to compounds in drinking water is variable. For example, chlorine can be detected at the ppm level and geosmin can be perceived at the ppt level. In this paper, sensory tests (using a human panel), physicochemical analyses (total and free residual chlorine, temperature, metals, geosmin, and 2-methylisoborneol (2MIB)) and microbiological analyses (algae, Actinomycetes and heterotrophic plate count) were performed for water samples collected during a seventeen-month period at ten different locations of a municipal distribution network of Quebec City (Canada). The results showed that different flavors(1) assessed by a panel and aggregated into global flavor intensity (GFI) vary considerably spatially and seasonally. Multiple regression analysis showed that the factors best explaining the variability of GFI are (in order) the season, the location, the concentration of total residual chlorine and the presence of cyanobacteria. Results also demonstrate that chlorine has a masking effect on other T&O. PMID- 22513046 TI - Mechanistic theory and modelling of complex food-web dynamics in Lake Constance. AB - Mechanistic understanding of consumer-resource dynamics is critical to predicting the effects of global change on ecosystem structure, function and services. Such understanding is severely limited by mechanistic models' inability to reproduce the dynamics of multiple populations interacting in the field. We surpass this limitation here by extending general consumer-resource network theory to the complex dynamics of a specific ecosystem comprised by the seasonal biomass and production patterns in a pelagic food web of a large, well-studied lake. We parameterised our allometric trophic network model of 24 guilds and 107 feeding relationships using the lake's food web structure, initial spring biomasses and body-masses. Adding activity respiration, the detrital loop, minimal abiotic forcing, prey resistance and several empirically observed rates substantially increased the model's fit to the observed seasonal dynamics and the size abundance distribution. This process illuminates a promising approach towards improving food-web theory and dynamic models of specific habitats. PMID- 22513045 TI - Clinical utility of diagnostic guidelines and putative biomarkers in lymphangioleiomyomatosis. AB - BACKGROUND: Lymphangioleiomyomatosis is a rare disease occurring almost exclusively in women. Diagnosis often requires surgical biopsy and the clinical course varies between patients with no predictors of progression. We evaluated recent diagnostic guidelines, clinical features and serum biomarkers as diagnostic and prognostic tools. METHODS: Serum vascular endothelial growth factor-D (VEGF-D), angiotensin converting enzyme (ACE), matrix metalloproteinases (MMP) -2 and -9, clinical phenotype, thoracic and abdominal computerised tomography, lung function and quality of life were examined in a cohort of 58 patients. 32 healthy female controls had serum biomarkers measured. RESULTS: Serum VEGF-D, ACE and total MMP-2 levels were elevated in patients. VEGF-D was the strongest discriminator between patients and controls (median = 1174 vs. 332 pg/ml p < 0.0001 with an area under the receiver operating characteristic curve of 0.967, 95% CI 0.93-1.01). Application of European Respiratory Society criteria allowed a definite diagnosis without biopsy in 69%. Adding VEGF-D measurement to ERS criteria further reduced the need for biopsy by 10%. VEGF-D was associated with lymphatic involvement (p = 0.017) but not the presence of angiomyolipomas. CONCLUSIONS: Combining ERS criteria and serum VEGF-D reduces the need for lung biopsy in LAM. VEGF-D was associated with lymphatic disease but not lung function. PMID- 22513047 TI - Empty nose syndrome. AB - Empty nose syndrome (ENS) is a clinical entity without consensual definition; it is a rare complication of nose or sinus surgery, and of inferior turbinectomy in particular. Physiopathology remains unclear, but probably involves disorder caused by excessive nasal permeability affecting neurosensitive receptors and inhaled air humidification and conditioning functions. Neuropsychological involvement is suspected. Symptomatology is variable and changeable, the most common sign being paradoxical nasal obstruction. Diagnosis is founded on: (1) a range of symptoms that need to be precisely collated; (2) broad post-surgical nasal permeability. Management is problematic, deploying the full range of simple nasal cavity hygiene and humidification techniques, with surgery reserved for the most severe cases; whatever the technique, surgery aims at partial filling of the nasal airway. Prevention is the most important strategy, and seeks (1) to check, before any surgery is envisaged, the reality of nasal dyspermeability resistant to medical treatment; and (2) to prefer the most conservative surgical techniques. PMID- 22513048 TI - A protective effect of 5-HT3 antagonist against vestibular deficit? Metoclopramide versus ondansetron at the early stage of vestibular neuritis: a pilot study. AB - OBJECTIVES: Ondansetron is an antiemetic 5-HT3 receptor antagonist with proven efficacy in central balance disorder. A pilot study investigated impact on acute unilateral vestibular neuritis. PATIENTS AND METHODS: A randomized clinical trial included 20 vestibular neuritis patients. Subjects received methylprednisolone valacyclovir, associated to 5 days' metoclopramide (30 mg/d; group M, n=10) or ondansetron (8 mg/d; group O, n=10). Assessment was based on early and 1 month videonystagmography, duration of hospital stay and time to first independent walking. Blinded intention-to-treat analysis used univariate (Student test) and multivariate (linear logistic regression) analysis. RESULTS: Early caloric vestibular deficit was significantly lower in group O than group M (56.53% versus 84.38%; P=0.03). Vestibular preponderance did not differ between groups (8.2 degrees /s in O versus 10.34 degrees /s in M). At 1 month, trends were observed for vestibular deficit (43% in O versus 63.4% in M; P=0.07) and preponderance (1.67 degrees /s in O versus 1.74 degrees /s in M; P=0.4). Hospital stay and time to first independent walking were significantly shorter in O (2.88 versus 4.5 days (P=0.03); and 1.25 versus 2.25 days (P=0.001), respectively). CONCLUSION: Early treatment with ondansetron associated to corticosteroids and antiviral treatment reduced vestibular deficit in acute-phase vestibular neuritis as compared to reference histamine H1 receptor antagonists. The treatment did not affect central compensation. Benefit includes improved tolerance of vertigo syndrome and reduced hospital stay. These results should be confirmed on a larger series, particularly to determine the mechanism of action of 5-HT3 antagonists on vestibular function. PMID- 22513049 TI - Dento-osseous anomalies associated to familial adenomatous polyposis mimicking florid cemento-osseous dysplasia. AB - Familial adenomatous polyposis (FAP) is a colorectal cancer syndrome characterized by the development of multiple polyps of the colon and rectum with high risk of malignant transformation. The extraintestinal manifestations such as dento-osseous changes are associated with FAP. This is a case report of a 36-year old female patient who was referred for dental treatment with the initial diagnosis of florid cemento-osseous dysplasia (FCOD). However, the association of the imaging dento-osseous findings with the medical history confirmed the diagnosis of FAP. The paper illustrates the clinical characteristics and imaging findings associated with FAP, and also discusses misdiagnosis based exclusively on imaging features. PMID- 22513050 TI - Bovine hydroxyapatite (Bio-Oss((r))) induces osteocalcin, RANK-L and osteoprotegerin expression in sinus lift of rabbits. AB - PURPOSE: The aim of this study was to analyze and compare the expression of osteocalcin, RANK-L, osteoprotegerin, in sinus lift procedures using bovine hydroxyapatite (HA). MATERIAL AND METHODS: Twenty four male rabbits underwent bilateral sinus lift procedures were distributed into two groups, according to the sinus filling material: Group 1) autogenous bone graft; and Group 2) bovine HA. All groups were sacrificed after 14 and 30 days, for microscopic and immunohistochemistry analysis. RESULTS: At 14 days after surgery, discrete osteogenesis was observed in the highly vascularized granulation tissue surrounding HA particles, as well as woven bone deposition on the biomaterial surface. Following 30 days, well organized bone trabeculas were seen surrounding the HA granules presenting areas of osteogenic activity. Morphometric findings did not show remarkable differences between groups. Bovine HA induced similar osteocalcin, RANK-L, osteoprotegerin immunoexpressivity when compared to autogenous bone graft group for both periods evaluated in this setting. CONCLUSION: Taken together, these data are consistent with the notion that HA has a similar biological behavior to autogenous bone graft in sinus lift of rabbits. PMID- 22513051 TI - Alteration of cardiac progenitor cell potency in GRMD dogs. AB - Among the animal models of Duchenne muscular dystrophy (DMD), the Golden Retriever muscular dystrophy (GRMD) dog is considered the best model in terms of size and pathological onset of the disease. As in human patients presenting with DMD or Becker muscular dystrophies (BMD), the GRMD is related to a spontaneous X linked mutation of dystrophin and is characterized by myocardial lesions. In this respect, GRMD is a useful model to explore cardiac pathogenesis and for the development of therapeutic protocols. To investigate whether cardiac progenitor cells (CPCs) isolated from healthy and GRMD dogs may differentiate into myocardial cell types and to test the feasibility of cell therapy for cardiomyopathies in a preclinical model of DMD, CPCs were isolated from cardiac biopsies of healthy and GRMD dogs. Gene profile analysis revealed an active cardiac transcription network in both healthy and GRMD CPCs. However, GRMD CPCs showed impaired self-renewal and cardiac differentiation. Population doubling and telomerase analyses highlighted earlier senescence and proliferation impairment in progenitors isolated from GRMD cardiac biopsies. Immunofluorescence analysis revealed that only wt CPCs showed efficient although not terminal cardiac differentiation, consistent with the upregulation of cardiac-specific proteins and microRNAs. Thus, the pathological condition adversely influences the cardiomyogenic differentiation potential of cardiac progenitors. Using PiggyBac transposon technology we marked CPCs for nuclear dsRed expression, providing a stable nonviral gene marking method for in vivo tracing of CPCs. Xenotransplantation experiments in neonatal immunodeficient mice revealed a valuable contribution of CPCs to cardiomyogenesis with homing differences between wt and dystrophic progenitors. These results suggest that cardiac degeneration in dystrophinopathies may account for the progressive exhaustion of local cardiac progenitors and shed light on cardiac stemness in physiological and pathological conditions. Furthermore, we provide essential information that canine CPCs may be used to alleviate cardiac involvement in a large preclinical model of DMD. PMID- 22513052 TI - IL-1, quo vadis? PMID- 22513053 TI - Estimation of lipoprotein profile in patients with type II diabetes and its relevance to remnant lipoprotein cholesterol levels. AB - BACKGROUND: Remnant lipoprotein (RLP), associated with atherosclerosis progression, is often elevated in diabetes mellitus. The RLP level is estimated by immune-separation method and agarose-gel electrophoresis (AGE). METHODS: The patients were grouped into three groups according to tertile of RLP-cholesterol (RLP-C) levels. The lipoprotein profiles of type II diabetic patients (T2DM) (n=194) were measured by an anion-exchange liquid chromatography (AEX-HPLC) and an AGE with lipid-staining or cholesterol-staining. RESULTS: IDL- and VLDL cholesterol by the AEX-HPLC, and VLDL-levels by the AGE with lipid-staining and with cholesterol-staining were significantly different in the three groups. In all the subjects, IDL-cholesterol (r=0.531) and VLDL-cholesterol (r=0.880) by the AEX-HPLC method were strongly correlated with RLP-C, but only VLDL levels were correlated with RLP-C in AGE, respectively. CONCLUSION: These results suggest that the AEX-HPLC, which can provide cholesterol levels of not only VLDL but also IDL, is helpful for estimation of lipid profiles in T2DM with high RLP-C. PMID- 22513054 TI - Associations between cellular growth factors and ischemic and hemorrhagic strokes. PMID- 22513055 TI - Antidepressant effects of fibroblast growth factor-2 in behavioral and cellular models of depression. AB - BACKGROUND: Basic and clinical studies report that the expression of fibroblast growth factor-2 (FGF-2) is decreased in the prefrontal cortex (PFC) of depressed subjects or rodents exposed to stress and increased following antidepressant treatment. Here, we aim to determine if 1) FGF-2/fibroblast growth factor receptor (FGFR) signaling is sufficient and required for mediating an antidepressant response behaviorally and cellularly; and 2) if the antidepressant actions of FGF-2 are mediated specifically by the PFC. METHODS: The role of FGF-2 signaling in behavioral models of depression and anxiety was tested using chronic unpredictable stress (CUS)/sucrose consumption test (SCT), forced swim test (FST), and novelty suppressed feeding test (NSFT). We also assessed the number of bromodeoxyuridine labeled dividing glial cells in the PFC as a cellular index relevant to depression (i.e., decreased by stress and increased by antidepressant treatment). RESULTS: Chronic FGF-2 infusions (intracerebroventricular) blocked the deficit in SCT caused by CUS. Moreover, the response to antidepressant treatment in the CUS/SCT and FST was abolished upon administration of an inhibitor of FGFR activity, SU5402. These results are consistent with the regulation of proliferating cells in the PFC, a portion of which are of oligodendrocyte lineage. Lastly, subchronic infusions of FGF-2 into the PFC but not into the dorsal striatum produced antidepressant-like and anxiolytic-like effects on FST and NSFT respectively. CONCLUSIONS: These findings demonstrate that FGF-2/FGFR signaling is sufficient and necessary for the behavioral, as well as gliogenic, actions of antidepressants and highlight the PFC as a brain region sensitive to the antidepressant actions of FGF-2. PMID- 22513057 TI - Profiling characteristics of men who use phosphodiesterase type 5 inhibitors based on obtaining patterns: data from the nationwide Japanese population. AB - INTRODUCTION: Worldwide, certain subsets of men bypass healthcare provider (HCP) interactions and obtain phosphodiesterase type 5 inhibitors (PDE5i) from uncontrolled sources. AIM: To stratify men who are PDE5i users based on their obtaining patterns and investigate the characteristics that differentiate these groups. METHODS: A Web-based observational study conducted between March and June 2009 in Japan. MAIN OUTCOME MEASURES: We stratified the reported obtaining patterns into three categories: men who had a prescription for PDE5is from HCP, those who obtained PDE5is from friends, and those who purchased PDE5is via the Internet. Logistic regressions were conducted to determine independent predictors for each obtaining patterns. Erection function was evaluated by erection hardness score (EHS). RESULTS: Of 7,710 total recruited subjects, 1,144 men (14.8%) reported PDE5i use within the past year. Among 1,144 men, 625 men (54.6%) were prescribed PDE5i from HCP, whereas 267 men (23.4%) obtained PDE5i from friends and 252 men (22.0%) purchased PDE5i via the Internet. In a multivariable regression analyses, men being prescribed PDE5i from HCP were more likely to live in a northern area of Japan (OR 0.98), have a lower rate of smoking (OR 0.77), and have an awareness of ED (OR 3.04). In contrast, men who obtained PDE5i from friends were more likely to live in a southern area (OR 1.02), to have higher rate of alcohol intake and smoking (OR 1.20, OR 1.45), and lower awareness of ED (OR 0.39). Men purchasing PDE5i via the Internet were more likely to consider themselves to be in worse health (OR 0.85) and to have lower awareness of ED (OR 0.62). CONCLUSIONS: Our results could help to identify men who may bypass HCP interactions. These findings could aid in the targeting of public service announcements designed to encourage men to avoid obtaining uncontrolled PDE5i and consult with HCPs to protect their health. PMID- 22513056 TI - Autoantibodies to transcription intermediary factor TIF1beta associated with dermatomyositis. AB - INTRODUCTION: Myositis specific autoantibodies are associated with unique clinical subsets and are useful biomarkers in polymyositis/dermatomyositis (PM/DM). A 120 kD protein recognized by certain patients with DM was identified and clinical features of patients with this specificity were characterized. METHODS: The 120 kD protein recognized by a prototype serum was purified and identified by mass spectrometry and immunological methods. Autoantibody to this 120 kD protein was screened in sera from 2,356 patients with various diagnoses from four countries, including 254 PM/DM, by immunoprecipitation of 35S methionine labeled K562 cell extracts. Clinical information of patients with this specificity was collected. RESULTS: The 120 kD protein, which exactly comigrated with PL-12, was identified as transcription intermediary factor TIF1beta (TRIM28) by mass spectrometry and validated by immunoassays. By immunofluorescence, anti TIF1beta positivity showed a fine-speckled nuclear staining pattern. Four cases of anti-TIF1beta were identified; all are women, one each in a Japanese, African American, Caucasian, and Mexican individual. Three had a diagnosis of DM and one case was classified as having an undifferentiated connective tissue disease with an elevated CPK but without significant muscle symptoms. This individual also had a history of colon cancer, cervical squamous metaplasia and fibroid tumors of the uterus. Myopathy was mild in all cases and resolved without treatment in one case. The anti-TIF1beta specificity was not found in other conditions. CONCLUSIONS: Anti-TIF1beta is a new DM autoantibody associated with a mild form of myopathy. Whether it has an association with malignancy, as in the case of anti-TIF1gamma, or other unique features will need to be evaluated in future studies. PMID- 22513058 TI - Is necrolytic migratory erythema due to glucagonoma a misnomer? A more apt name might be mucosal and intertriginous erosive dermatitis. AB - BACKGROUND: In dermatology, many conditions are given names that ultimately prove to be a misnomer (eg, mycosis fungoides, pyogenic granuloma). For most misnomers, continued use of the inappropriate word(s) rarely results in a delay in diagnosis and/or treatment. An argument can be made that the term necrolytic migratory erythema (NME) due to glucagonoma results in a delay in diagnosis, often with fatal consequences. OBJECTIVE: We reviewed the literature of the past 30 years concerning the dermatologic and histologic findings of NME in association with glucagonoma. The most striking feature evident in nearly all reported cases is the presence of mucosal lesions and annular, eroded, eczematous patches and plaques of intertriginous areas. CONCLUSION: We propose the renaming of the eruption associated with glucagonoma to one that emphasizes its unique localization to the mucosa and intertriginous areas: mucosal and intertriginous erosive dermatitis. It is hoped that this will lead to a more timely recognition of the condition and a possible improvement in prognosis. PMID- 22513059 TI - 40-year trends in skin cancer in British Columbia, Canada, 1973 to 2003. AB - BACKGROUND: Skin cancer is common in North America. Incidence rate trends are potentially important in the assessment of the effects of measures to increase sun awareness in the population as well as measures to reduce sun damage. OBJECTIVE: To determine the incidence of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and cutaneous malignant melanoma (CMM) in a geographically defined Canadian population over a 40-year period. METHODS: Data were obtained from the BC Cancer Registry for the calendar years 1973, 1983, 1993, and 2003. RESULTS: Age-standardized incidence rates increased significantly from 1973 to 2003 for BCC, SCC, and CMM. LIMITATIONS: The ethnic makeup of British Columbia has changed over time, and a novel method of accounting for the effect of this on skin cancer rates is presented. CONCLUSION: The incidence rate for skin cancers continued to rise in British Columbia, but there appears to have been a decline in the incidence of CMM and BCC in the youngest cohorts. PMID- 22513060 TI - Physician survey regarding patient nonattendance at follow-up appointments at a university-affiliated medical dermatology clinic. AB - BACKGROUND: Patient nonattendance is a frequent occurrence in dermatology clinics, and our responsibility regarding the follow-up of these patients remains nebulous. OBJECTIVE: This study sought to evaluate the beliefs and practices of physicians at a university-affiliated medical dermatology clinic regarding patient nonattendance at follow-up appointments and to provide an algorithm to deal appropriately with absentee patients based on various Canadian medical association guidelines. METHODS: A questionnaire was distributed to the 17 dermatologists practicing at the Centre Hospitalier de l'Universite de Montreal medical dermatology clinic. We contacted provincial and national medical associations regarding directives for patient follow-up. RESULTS: There is a lack of consensus among dermatologists at the Centre Hospitalier de l'Universite de Montreal regarding responsibility toward patients who miss their follow-up appointments. However, the majority of survey respondents consider that patient follow-up must be adjusted on a case-by-case basis and that diagnoses at risk for high morbidity and mortality require particular attention, which is in line with various Canadian medical association guidelines. CONCLUSION: Dermatologists should have a structured approach to dealing with patients who miss their follow up appointments to ensure the appropriate care of all patients. PMID- 22513061 TI - Use of pioglitazone in patients with lichen planopilaris. AB - BACKGROUND: Recent basic science research has revealed a decreased tissue expression of peroxisome proliferator-activated receptor (PPAR) gamma in lichen planopilaris (LPP). Therefore, thiazolidinediones, being PPARgamma agonists, could be used to treat LPP. METHODS: We followed 24 patients with LPP who were treated with oral pioglitazone hydrochloride. Improvement in LPP was defined as a decrease in or disappearance of symptoms and perifollicular erythema in the context of halted spread of old patches. RESULTS: Twenty of 24 patients were females. The average age was 52.5 years, and ages ranged from 22 to 70 years. Five of 24 patients have achieved remission; improvement was noted in half of the patients; there was no change in 3 patients; and 4 patients discontinued treatment due to side effects. Side effects were mild and included left calf pain, lightheadedness and nausea, dizziness, and hives. CONCLUSION: Use of thiazolidinediones might be a new promising venue of LPP treatment. PMID- 22513062 TI - Local infiltrative anesthetic effect of tramadol compared to lidocaine for excision of cutaneous lesions: pilot randomized, double-blind clinical study. AB - BACKGROUND: In this double-blind, randomized study, the efficacy of tramadol, an atypical opioid, was tested versus lidocaine in excision of cutaneous lesions of the face. METHODS: Eighty-eight patients were randomly assigned to receive either 2 mg/kg tramadol 2% plus adrenaline 1:200,000 (group T, n = 46) or 3 mg/kg lidocaine 2% plus adrenaline 1:200,000 (group L, n = 42) for excision of cutaneous lesions. Pain at the injection site, 2 and 20 minutes postinjection and 3, 6, and 12 hours postoperatively, was monitored on a 0 to 10 numerical rating scale (NRS). Irritation at the injection point and the duration of postoperative analgesia were also recorded. RESULTS: There were no significant differences in demographic data, topography, size of the lesions removed, and operative time between the two groups. A tendency toward lower injection NRS pain scores was observed in group L compared to group T (p = .064). No statistically significant differences between the two groups were found at 2 and 20 minutes postinjection (p = .741 and p = .142, respectively); however, pain scores were significantly higher in group L at 3, 6, and 12 hours postoperatively (all p < .001). Erythema at the injection site was observed in nine group T and two group L patients (p = .076). No postoperative analgesics were required in the tramadol group of patients, whereas acetaminophen with or without codeine was administered in all but five lidocaine group patients during the first 12 hours. CONCLUSION: Tramadol may be used as a reliable local anesthetic agent, providing longer postoperative analgesia compared to lidocaine; however, it bears a higher incidence of irritation at the injection site. PMID- 22513063 TI - Practice trends in the treatment of actinic keratosis in the United States: 0.5% fluorouracil and combination cryotherapy plus fluorouracil are underused despite evidence of benefit. AB - BACKGROUND: Topical fluorouracil and cryotherapy are among the most commonly used treatments for actinic keratosis. Evidence shows that 0.5% fluorouracil has similar efficacy and is better tolerated than 5% fluorouracil. Evidence also shows that combination therapy with cryosurgery and fluorouracil is beneficial. OBJECTIVE: To examine fluorouracil and cryotherapy use in the treatment of actinic keratosis. METHODS: The National Ambulatory Medical Care Survey database was queried for visits for actinic keratosis. Visits were analyzed for patient demographics, provider specialty, and treatment regimens. Fluorouracil and cryotherapy use was analyzed over time. RESULTS: Cryotherapy was the most commonly used treatment for actinic keratosis. Fluorouracil products were prescribed to 1.1 million patients (6.6%) between 2001 and 2008; of these, dermatologists prescribed 0.5% fluorouracil in 51.8% of cases and 5% fluorouracil in 38.9% of cases. Combination fluorouracil and cryotherapy was used for only 1.1% of actinic keratosis visits between 1993 and 2008 and was never used by nondermatologists. CONCLUSIONS: Despite evidence suggesting comparable efficacy, greater tolerability, and lower cost of 0.5% fluorouracil relative to 5% fluorouracil, 5% fluorouracil is used by dermatologists almost as often as 0.5% fluorouracil. Among nondermatologists, 5% fluorouracil is used exclusively. Combination therapy of fluorouracil and cryotherapy is underused despite evidence of its benefit. PMID- 22513064 TI - Propranolol in the treatment of problematic infantile hemangioma: review of 35 consecutive patients from a vascular anomalies clinic. AB - BACKGROUND: Propranolol, a nonselective beta-blocker, has been reported as efficient for controlling the growth of complicated infantile hemangiomas (IHs). No uniformly accepted protocol exists regarding the administration of oral propranolol for IH. OBJECTIVE: We sought to share our experience using propranolol for problematic IH and to evaluate the efficacy of this treatment modality. METHODS: A retrospective chart review analysis was performed for 35 consecutive children treated with propranolol as an oral solution on an outpatient basis in our dermatology/vascular anomalies clinic. A protocol was established with the help of our pediatric cardiologists, including pretreatment electrocardiography and echocardiography. Medical photographs taken after 2 months of treatment were rated by two independent evaluators. RESULTS: We treated 31 girls and 4 boys with a median age of 3.5 months. Rapid improvement was reported in the first days of treatment in 34 patients. Mean improvement after 2 months was 61.5%. No serious adverse effects were reported. CONCLUSION: Propranolol was effective in controlling the proliferative phase of problematic IH. It was well tolerated in our study. Outpatient treatment is possible if parents follow strict guidelines. Propranolol should be a first-line treatment for problematic IH in carefully selected patients. PMID- 22513065 TI - High prevalence of psoriatic arthritis in a cohort of patients with psoriasis seen in a dermatology practice. AB - BACKGROUND/OBJECTIVES: The prevalence of psoriatic arthritis (PsA) is expected to range from 5 to 40% in individuals with psoriasis. The objective of this study was to quantify the prevalence of PsA in psoriasis patients seen in a dermatology practice and to define their characteristics using the validated Psoriatic Arthritis Screening Questionnaire (PASQ). METHODS: Patients with definite plaque psoriasis (as determined by a dermatologist) completed the self-administered PASQ tool, and patients with a score >= 7 or >= 9 were assessed by a rheumatologist to ascertain the diagnosis of PsA according to the CASPAR (Classification Criteria for Psoriatic Arthritis) criteria. RESULTS: Using a PASQ cutoff of 7, the estimated prevalence (95% CI) of PsA was 40.9% (29.0-52.8%), whereas a prevalence (95% CI) of 36.4% (24.8-48.0%) was estimated when a PASQ cutoff of 9 was used. CONCLUSION: Our estimated prevalence of PsA in psoriasis patients from a population of patients drawn from a dermatology practice is greater than most previous estimates. This finding illustrates the importance of screening for PsA in psoriasis patients as this comorbidity may affect the course of treatment and, if left untreated, may have a profound effect on the disability and quality of life of a large number of psoriasis patients. PMID- 22513066 TI - Sweet syndrome and pemphigus vulgaris. AB - BACKGROUND: Pemphigus vulgaris is an autoimmune blistering disease of the skin and mucous membranes. Sweet syndrome is an uncommon reactive neutrophilic dermatosis. OBJECTIVE: This case report describes the rare presentation of a 58 year-old female patient with newly diagnosed pemphigus vulgaris who later presented with erythematous plaques and leukocytosis highly suggestive of Sweet syndrome. METHODS: Review of the literature using the PubMed and Medline databases. RESULTS: The clinical presentation of new-onset Sweet syndrome in a patient with pemphigus has been reported in the literature only on one other occasion. CONCLUSION: The observation of an association between Sweet syndrome and autoimmune diseases, such as pemphigus vulgaris, may ultimately lead to better understanding of the pathophysiology of this disease. PMID- 22513067 TI - A suspected squamous cell carcinoma in a renal transplant recipient revealing a rare cutaneous phaeohyphomycosis by Alternaria infectoria. AB - BACKGROUND: Squamous cell carcinoma of the skin is the most common neoplasm after organ transplantation. In addition, fungal infections are increasingly described in immunocompromised patients, such as kidney recipients. METHOD AND RESULTS: We report a case of a 64-year-old woman with a renal transplant presenting with 6 month-old skin lesions. In other centers, she had undergone previous biopsies, the results of which were suggestive of squamous cell carcinoma and aspecific inflammation. Therefore, she came to our center for surgical excision. Only our clinical experience and a detailed clinical history allowed us to doubt previous diagnoses and perform further examinations. Our investigation revealed an extremely rare fungus infection: phaeohyphomycosis by Alternaria infectoria. It was successfully treated with oral terbinafine until a complete regression of the lesions was achieved. At a 16-month follow-up visit, no recurrence of the skin lesion was observed. CONCLUSION: Despite a difficult diagnosis and rare occurrence, physicians and surgeons should be aware of infection with this emerging fungus in immunocompromised patients. PMID- 22513068 TI - KIT gene mutations and patterns of protein expression in mucosal and acral melanoma. AB - BACKGROUND: Recently characterized KIT (CD117) gene mutations have revealed new pathways involved in melanoma pathogenesis. In particular, certain subtypes harbor mutations similar to those observed in gastrointestinal stromal tumors, which are sensitive to treatment with tyrosine kinase inhibitors. OBJECTIVE: The purpose of this study was to characterize KIT gene mutations and patterns of protein expression in mucosal and acral melanoma. METHODS: Formalin-fixed, paraffin-embedded tissues were retrieved from our archives. Histologic assessment included routine hematoxylin-eosin stains and immunohistochemical staining for KIT. Genomic DNA was used for polymerase chain reaction-based amplification of exons 11 and 13. RESULTS: We identified 59 acral and mucosal melanoma cases, of which 78% showed variable levels of KIT expression. Sequencing of exons 11 and 13 was completed on all cases, and 4 (6.8%) mutant cases were isolated. CONCLUSION: We successfully optimized conditions for the detection of KIT mutations and showed that 8.6% of mucosal and 4.2% of acral melanoma cases at our institution harbor KIT mutations; all mutant cases showed strong, diffuse KIT protein expression. Our case series represents the first Canadian study to characterize KIT gene mutations and patterns of protein expression in acral and mucosal melanoma. PMID- 22513069 TI - Hypomelanotic nail melanoma in a patient with Gorlin Syndrome. PMID- 22513071 TI - The vitamin D grey areas in pediatric primary care. Very low serum 25 hydroxyvitamin D levels in asymptomatic children living in northeastern Italy. AB - The principal questions about the vitamin D topic are far to be resolved: in which children 25-hydroxyvitamin D blood testing is appropriate and how much cholecalciferol should be given in the absence of the test? Analyzing vitamin D status in a group of children cared by a "family pediatrician" in northeastern Italy we noted a high incidence of deficiency in asymptomatic preschool children without risk factors. As routine vitamin D testing is not recommended in the average risk population the supplementation with cholecalciferol represents a "grey area" mostly in pediatric primary care. PMID- 22513072 TI - [Solution to case 43. Intraductal papillary mucinous tumour of the pancreas]. PMID- 22513073 TI - Duplicated odontoid process and atlas clefts associated to Klippel-Feil syndrome. PMID- 22513074 TI - The effect of temporal sampling on quantitative pharmacokinetic and three-time point analysis of breast DCE-MRI. AB - The effects of temporal sampling on the previously published three-time-point (3TP) method are compared with those of a Tofts-Kety model using an arterial input function from the alternating minimization with model (AMM) method. Computer simulations are done to estimate the expected error in both the 3TP and Tofts-Kety models as a function of the temporal sampling rate of the data. The error in the 3TP model parameters remained essentially constant with respect to temporal sampling. The Tofts-Kety model showed a linear increase in parameter error with respect to temporal sampling. Both analysis methods were also applied to 87 clinically acquired breast scans. These scans were downsampled in time by a factor of 2 and 4, and the methods were reapplied. The spatial resolution was held constant throughout this study. At temporal resolutions less than 19.4 s, the Tofts-Kety model outperformed the 3TP model using receiver operating characteristic curve analysis (area under the ROC curve [AUC] of 0.94 compared to 0.91). As the temporal sampling rate decreased, the 3TP model outperformed the Tofts-Kety model (AUC of 0.89 versus 0.85). When the temporal sampling rate of the data was less than 20 s, the Tofts-Kety model with the AMM method had lower parameter error than the 3TP method. PMID- 22513075 TI - Enhanced choline metabolism in a rodent rhabdomyosarcoma model: correlation between RT-PCR and translational 3 T H-MRS. AB - PURPOSE: To investigate which transmembrane choline transporters and intracellular choline kinases play a prominent role at gene expression level in the rise of the total choline (tCho) peak at proton MR spectra in a rodent rhabdomyosarcoma model. MATERIALS AND METHODS: Twenty-two rats bearing grafted bilateral syngenic rhabdomyosarcoma were examined on a clinical 3 T MR system. Total choline concentration was measured from proton MR spectra using cubic centimeter volumes of interest (VOIs) located contiguously along the greater axis of the tumour. After euthanasia, cubic centimetre tissue specimens corresponding to Proton magnetic resonance spectroscopy (H-MRS) VOIs were frozen in liquid nitrogen. Out of 89 H-MRS voxels, only 39 with a corresponding tissue specimen suitable for biochemical processing were included in the analysis. RNA was extracted from all the 39 samples and reverse-transcribed into cDNA. Choline kinase alpha and beta gene expression as well as genes of the transmembrane transporters OCT1, OCT2, OCT3, CTL1, CTL3, CTL4 and CHT1 were studied using reverse transcriptase polymerase chain reaction. The expression level of each gene (DeltaCt), was normalized referred to that of the RPL19 gene. The Spearman rank correlation coefficient was used to analyse variables. RESULTS: There was no overexpression of genes coding for kinases; however, significant correlation was observed between kinase alpha sub-type and the tCho peak (P=.002; r=0.51). OCT1 was the most overexpressed transporter gene. Less overexpressed CTL1 gene was significantly correlated with the tCho peak (P=.02; r=0.38). CONCLUSION: Choline transporters seem to play a predominant role in the increase in total choline concentration at the gene expression level in our model. PMID- 22513076 TI - Myocyte enhancer factor-2 and cardiac muscle gene expression during hibernation in thirteen-lined ground squirrels. AB - Many small mammals turn to hibernation to survive the winter, cycling through bouts of prolonged torpor where metabolic rate and body temperature fall to low levels. Remarkably, hypertrophy is promoted in cardiac muscle to support the stronger contractions needed in the cold. We proposed that altered expression of mRNA/protein levels of myocyte enhancer factor-2 (MEF2A, MEF2C) transcription factors and downstream targets (e.g., desmin, glucose transporter 4, and myomesin 1) would aid cardiac muscle of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) in meeting challenges associated with hibernation. Gene and protein responses were compared over six conditions: control (euthermic animals in a 5 degrees C cold room), entrance into torpor, short and long torpors, arousal and interbout. Mef2a relative transcript levels were significantly elevated from controls contributing to increases in MEF2A protein levels throughout the torpor-arousal bout. In addition, levels of phosphorylated, activated MEF2A (Thr312) correlated with increases in MEF2A-DNA binding. MEF2C transcript/protein levels were significantly elevated over controls at selected sampling points whereas phosphorylated/activated MEF2C (Ser387) levels rose during torpor and DNA binding was most prominent during entrance into torpor. Some gene targets of MEF2 action were also upregulated. Desmin transcript levels remained constant whereas enhanced protein expression occurred during entrance into torpor. Glut4 transcript levels were enhanced in arousal and protein expression was elevated over all five sampling points during torpor/arousal. Myomesin 1 transcript levels increased between early torpor and early arousal and protein levels increased during entrance and deep torpor. These data provide insights into the changes in gene/protein in expression that help to prepare cardiac muscle for hibernation. PMID- 22513077 TI - Monoubiquitination-dependent chromatin loading of FancD2 in silkworms, a species lacking the FA core complex. AB - The Fanconi anemia (FA) pathway is required for activation and operation of the DNA interstrand cross-link (ICL) repair pathway, although the precise mechanism of the FA pathway remains largely unknown. A critical step in the FA pathway is the monoubiquitination of FANCD2 catalyzed by a FA core complex. This modification appears to allow FANCD2 to coordinate ICL repair with other DNA repair proteins on chromatin. Silkworm, Bombyx mori, lacks apparent homologues of the FA core complex. However, BmFancD2 and BmFancI, the putative substrates of the complex, and BmFancL, the putative catalytic E3 ubiquitin ligase, are conserved. Here, we report that the silkworm FancD2 is monoubiquitinated depending on FancI and FancL, and stabilized on chromatin, following MMC treatment. A substitution of BmFancD2 at lysine 519 to arginine abolishes the monoubiquitination, but not the interaction between the FancD2 and FancI. In addition, we demonstrated that depletion of BmFancD2, BmFancI or BmFancL had effects on cell proliferation in the presence of MMC. These results suggest that the FA pathway in B. mori works in the same manner as that in vertebrates. PMID- 22513078 TI - Early intervention and assessment of speech and language development in young children with cochlear implants. AB - OBJECTIVE: Age is one of the most important determinants of the benefit achieved in the cochlear implantation of pre-lingually deafened children. Earlier age at implantation increases the exposure of children with a hearing impairment to auditory stimuli. Earlier auditory stimulation enables children to better understand spoken language and to use spoken language themselves. Furthermore, there appears to be critical period under 2 years of age during which access to spoken language is essential in order for language development to proceed appropriately. The present study aimed to assess the impact of cochlear implantation under 2 years of age on subsequent speech and language development. METHODS: 28 children implanted with a cochlear implant prior to 2 years of age were included in this study and the effects of age at implantation were determined using a reception of grammar test, active vocabulary test and speech development test. Demographic features were described using descriptive statistics and data were compared to the normative values (T-values) of their hearing peers by t-test or Mann-Whitney U-test. RESULTS: The present data indicates that overall children with a hearing impairment implanted at less than 2 years of age perform as well as or better than their hearing peers in speech and grammar development. Word Comprehension was significantly greater in children with a cochlear implant compared to their normative peers (p=0.003), whereas Phonological Working Memory for Nonsense Words was poorer (p=0.031). An effect of age on grammatical and speech development could be found for younger implanted children (<12 months), who reached higher scores than children implanted after 12 months of age. CONCLUSIONS: The data suggests that early hearing loss intervention via cochlear implantation in children benefits the speech and language development of children. A potential sensitive period exists for implantation before 12 months of age. These outcomes support the recent trend toward early cochlear implantation in pre-lingually deaf children. PMID- 22513079 TI - Clinical features and management of aspiration of plastic pen caps. AB - OBJECTIVE: To describe the clinical features of pen cap aspiration and removal techniques. STUDY DESIGN: We retrospectively reviewed all children with a history of inhaling a pen cap who were referred to the ENT department, at Beijing Children's Hospital, between Jan 2006 and Dec 2010. Methods Clinical data was recorded, including patients' common information, physical examination, radiologic data and final outcome. RESULTS: Data from 44 children, with a median age of 8.7 years of age (35 months to 12 years) and a male-female ratio of 7.8:1 were analyzed. The time between inhalation and diagnosis with extraction of the foreign body ranged from several hours to 6 years, but 75% (33/44) were seen within one week. 89% (39/44) had pen caps removed by rigid bronchoscopy under general anesthesia. Reverse grasping forceps were used in 62% of the cases and ordinary forceps in 38% of the cases (24/15, p<0.05). In 2 cases, the pen caps were coughed up. In 2 cases the FB was removed via a tracheotomy and in 1 case by thoracotomy. CONCLUSIONS: Pen caps are an unusual foreign body in the airway, occurring frequently in school age children. Rigid bronchoscopy under general anesthesia with reverse grasping forceps was the most favorable method for extraction of pen caps, but open surgical approaches should be available. PMID- 22513080 TI - Bacteriology of the paranasal sinuses in pediatric cystic fibrosis patients. AB - OBJECTIVES: To review the characteristic microbiology of the paranasal sinuses in patients with cystic fibrosis who undergo endoscopic sinus surgery. To examine the subtypes of organisms cultured from the maxillary sinuses and determine their sensitivity to antibiotic therapy. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care children's hospital. METHODS: Sinus cultures were obtained from 51 patients with cystic fibrosis during endoscopic sinus procedures between 2000 and 2004 at a tertiary care children's hospital. A retrospective chart review was undertaken to obtain culture and sensitivity data of the sinus contents. RESULTS: The most common bacteria isolated was Staphylococcus aureus (71%), followed by Pseudomonas aeruginosa (PSA) (27%), Haemophilus influenzae (21%), Staphylococcus non-aureus (16%) and Streptococcus viridans (12%). Streptococcus pneumoniae and Moraxella catarrhalis were rarely isolated (2% and 0% respectively). Twenty-nine percent of the patients with cultures positive for PSA were of the mucoid variant. Only one patient had culture positive Escherichia coli. Antibiotic resistance among the more common organisms cultured from the sinus samples is also listed. CONCLUSION: Staph. aureus is the most common isolate in the sinuses of this pediatric CF population followed by P. aeruginosa and H. influenzae. Although many isolates are pansensitive, some isolates are panresistant. PMID- 22513081 TI - A trial of adding Lactobacillus johnsonii EM1 to levocetirizine for treatment of perennial allergic rhinitis in children aged 7-12 years. AB - BACKGROUND: Supplementary consumption of probiotics may temporarily alter the intestinal microflora of infants and children, thereby preventing and treating allergic disorders. OBJECTIVE: To compare the clinical efficacy of levocetirizine with that of levocetirizine plus Lactobacillus johnsonii EM1 (Lj EM1) for treating perennial allergic rhinitis (PAR) in children. METHODS: Sixty-three children aged 7-12 years fulfilled the entry criteria for the study and had moderate to severe PAR of at least 1 year's duration. The treatment followed a randomized, open-label crossover design: all subjects were randomized to 2 crossover treatment regimens of levocetirizine with Lj EM1 (group 1) or levocetirizine alone (group 2) for 12 weeks; subsequently, treatments were reversed for a further 12 weeks. The effects of the 2 regimens were compared using the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) and the total symptom score (TSS) from diary cards. The parameters evaluated were nasal peak expiratory flow rate (nPEFR), FVC, FEV1, serum immunoglobulin E (IgE), mite-specific IgE, eosinophilic cationic protein (ECP), resistin, blood eosinophils, eosinophil percentage in nasal smears, IL-4, IL-10, interferon-gamma (IFN-gamma), and transforming growth factor-beta (TGF-beta). RESULTS: After the first 12 weeks of treatment, TSS in both groups had improved progressively compared with that in the run-in period. Both groups had improved TSS at weeks 4, 8, and 12 (P<0.05), and group 1 was more efficacious than group 2 at week 4 (P=0.014), week 8 (P=0.011), and week 12 (P<0.009). During the second 12-week period, group 2 showed continual and progressive improvement, while group 1 did not. The PRQLQ scores were significantly decreased in both groups (P<0.05), but there was no statistically significant difference between the 2 groups (P=0.446). The eosinophil percentage in nasal smears decreased in both groups compared with that in the run-in period, and significant differences were detected in groups 2 and 1at 16 and 24 weeks of treatment, respectively (P<0.05). Both groups showed significant improvement in nPEFR at weeks 4, 8, 12, 16, and 24 (P<0.01), and the treatment for group 1 appeared to be more efficacious than that for group 2 at weeks 12, 16, and 20 (P<0.05). FVC and FEV1 were improved in both groups at weeks 8 through 24 (P<0.05), but there was no significant difference between the 2 groups. In cytokine measurements, IFN-gamma and IL-10 increased significantly and IL-4 decreased significantly in both groups, while elevation of TGF-beta was seen only in group 1 at 12 weeks (P<0.001). However, the difference in TGF-beta disappeared after 24 weeks treatment. There was no difference in serum resistin levels. No serious adverse events were recorded in either treatment group. CONCLUSION: The 24-week, 2-phase, crossover treatment program showed that levocetirizine plus Lj EM1 was more effective for PAR than levocetirizine and that this difference persisted for at least 3 months after discontinuation of Lj EM1. PMID- 22513082 TI - Tooth discoloration induced by endodontic materials: a literature review. AB - It is common knowledge that materials used in endodontics may cause discoloration and thus impair the aesthetic outcome of the treated tooth. The purpose of this review is to summarise the existing knowledge on the discoloration potential of materials used for endodontic procedures. A comprehensive literature search covering the period from 1966 to 2011 was conducted on Pubmed and the Cochrane Library using different keyword combinations including 'tooth', 'colour', 'discoloration', 'staining', 'endodontic''root canal''sealer', 'dressing', 'medicament', 'obturation', 'filling', 'treatment', 'portland cement', 'MTA' and 'antibiotic paste'. Any relevant work published in the English language in peer reviewed journals and presenting pertinent information related to the purpose of this overview was considered for inclusion. In addition, bibliographies of all relevant papers and previous review articles were hand searched and the reference lists from endodontic textbooks were also reviewed. Articles were excluded if an English abstract was unavailable, if only single clinical reports or conference reports were included, or if the topic was unrelated to the subject. Ten in-vitro studies, one randomized controlled trial and one multicenter randomized controlled trial met the inclusion criteria. There were not any recently used endodontic materials that would not induce at least measurable colour changes. For a wide range of materials currently available on the market there is only scarce or no evidence available on their staining ability. Endodontic therapy should not focus solely on biological and functional aspects, but take aesthetic considerations into account as well. To reduce the risk of material-induced tooth discoloration all materials should be applied carefully in areas of aesthetic concern. The need for further research in this field and for the development of non-staining endodontic materials is evident. PMID- 22513084 TI - The effects of increased expression of DLK1 gene on the pathogenesis of myelodysplastic syndromes. AB - To study the potential role of Delta-like-1 (DLK1) in myelodysplastic syndromes (MDS), we carried out a series of experiments and found that DLK1 mRNA levels are dysregulated in patients with MDS or acute myelogenous leukemia (AML), and its overexpression leads to dysfunction of 32D and 3T3 cells. We conclude that DLK1 dysfunction may contribute to abnormal hematopoiesis of MDS and may be 1 of the antioncogenes. Delta-like-1 (DLK1) is frequently expressed at elevated levels in CD34(+) cells from patients with MDS. To investigate its role in the pathogenesis of MDS, we tested bone marrow samples from a panel of patients with MDS, AML, or myeloproliferative neoplasms, with real-time polymerase chain reaction (PCR). We show here that DLK1 mRNA levels are higher in MDS patients and lower in AML patients than in healthy individuals. Myeloid progenitor 32D cells overexpressing DLK1 display increased apoptosis, reduced differentiation, and decreased cell number expansion, which is also accompanied by changes in cell cycle progression. Immortalized fibroblastic 3T3 cells can grow into tumors in nude mice but the size of tumors are smaller from those overexpressing DLK1. These observations suggest that DLK1 dysfunction may contribute to the ineffective hematopoiesis of MDS. PMID- 22513083 TI - Bacteria in sputum of stable severe asthma and increased airway wall thickness. AB - BACKGROUND: Patients with chronic asthma have thicker intrapulmonary airways measured on high resolution computed tomography (HRCT). We determined whether the presence of lower airway bacteria was associated with increased airway wall thickness. METHODS: In 56 patients with stable severe asthma, sputum specimens obtained either spontaneously or after induction with hypertonic saline were cultured for bacteria and thoracic HRCT scans obtained. Wall thickness (WT) and area (WA) expressed as a ratio of airway diameter (D) and total area, respectively, were measured at five levels. RESULTS: Positive bacterial cultures were obtained in 29 patients, with H. influenzae, P. aeruginosa and S. aureus being the commonest strains. Logistic regression analysis showed that this was associated with the duration of asthma and the exacerbations during the past year. In airways > 2 mm, there was no significant difference in WA (67.5 +/- 5.4 vs 66.4 +/- 5.4) and WT/D (21.6 +/- 2.7 vs 21.3 +/- 2.4) between the culture negative versus positive groups. Similarly, in airways (<= 2 mm), there were no significant differences in these parameters. The ratio of ?wall area to Pi was negatively correlated with FEV1% predicted (p < 0.05). CONCLUSIONS: Bacterial colonization of the lower airways is common in patients with chronic severe asthma and is linked to the duration of asthma and having had exacerbations in the past year, but not with an increase in airway wall thickness. PMID- 22513085 TI - Safety and efficacy of influenza vaccination in a prospective longitudinal study of 31 children with juvenile idiopathic arthritis. AB - OBJECTIVES: Influenza vaccination in children with rheumatic diseases is often recommended, but not frequently performed. Our aim was to assess the safety and efficacy of annual influenza vaccination in a longitudinal follow-up study of an unselected group of children with juvenile idiopathic arthritis (JIA). METHODS: Thirty-one children with stable JIA (10 boys, 21 girls, mean age 11.0 years) receiving various therapies and 14 children in a control group (10 boys, 4 girls, mean age 11.9 years) were vaccinated with the annual influenza vaccine Begrivac(r) 2008/2009. The children in both groups were followed for adverse events and infections 6 months after vaccination. Autoantibodies production and antibody titers against three vaccine viruses were determined in serial samples taken before, 1 and 6 months after vaccination. RESULTS: Eleven (35%) children with JIA and 5 (36%) children in the control group reported short-term adverse events. A JIA flare was observed one month after vaccination in 4 (13%) patients, and in the following five months in 7 (23%) patients. The response to vaccination after one month was significant in the control and study groups as a whole, but not in a subgroup of 4 children receiving anti-TNF-alpha therapy. After six months, no significant differences in the protective titers against vaccine viruses among the patient and control groups were observed. Changes in the mean values of autoantibodies after vaccination were found only for IgG aCL in the JIA group. CONCLUSIONS: No long-term adverse events were reported after influenza vaccination in JIA and control group. Thirty-five percent of children with JIA experienced flare of the disease after vaccination. Protective antibodies against at least 2 vaccine viruses 6 months after vaccination were detected in all patients. PMID- 22513086 TI - A hierarchy of computationally derived surgical and patient influences on metal on metal press-fit acetabular cup failure. AB - The impact of anatomical variation and surgical error on excessive wear and loosening of the acetabular component of large diameter metal-on-metal hip arthroplasties was measured using a multi-factorial analysis through 112 different simulations. Each surgical scenario was subject to eight different daily loading activities using finite element analysis. Excessive wear appears to be predominantly dependent on cup orientation, with inclination error having a higher influence than version error, according to the study findings. Acetabular cup loosening, as inferred from initial implant stability, appears to depend predominantly on factors concerning the area of cup-bone contact, specifically the level of cup seating achieved and the individual patient's anatomy. The extent of press fit obtained at time of surgery did not appear to influence either mechanism of failure in this study. PMID- 22513087 TI - Multiple repeat elements within the FAM21 tail link the WASH actin regulatory complex to the retromer. AB - Wiskott-Aldrich syndrome protein (WASPs) control actin dynamics in cellular processes, including cell motility, receptor-mediated endocytosis, bacterial invasion, and vesicular trafficking. We demonstrated that WASH, a recently identified WASP family protein, colocalizes on endosomal subdomains with the cargo-selective complex (CSC) of the retromer, where it regulates retrograde sorting from endosomes in an actin-dependent manner. However, the mechanism of WASH recruitment to these retromer-enriched endosomal subdomains is unclear. Here we show that a component of the WASH regulatory complex (SHRC), FAM21, which contains 21 copies of a novel L-F-[D/E](3-10)-L-F motif, directly interacts with the retromer CSC protein VPS35. Endosomal localization of FAM21 is VPS35 dependent and relies on multivalency of FAM21 repeat elements. Using a combination of pull-down assays and isothermal calorimetry, we demonstrate that individual repeats can bind CSC, and binding affinity varies among different FAM21 repeats. A high-affinity repeat can be converted into a low-affinity one by mutation of a hydrophobic residue within the motif. These in vitro data mirror the localization of FAM21 to retromer-coated vesicles in cells. We propose that multivalency enables FAM21 to sense the density of retromer on membranes, allowing coordination of SHRC recruitment, and consequent actin polymerization, with retromer sorting domain organization/maturation. PMID- 22513088 TI - Regulation of Wnt signaling by the tumor suppressor adenomatous polyposis coli does not require the ability to enter the nucleus or a particular cytoplasmic localization. AB - Wnt signaling plays key roles in development and disease. The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling. Its best-characterized role is as part of the destruction complex, targeting the Wnt effector beta-catenin (betacat) for phosphorylation and ultimate destruction, but several studies suggested APC also may act in the nucleus at promoters of Wnt-responsive genes or to shuttle betacat out for destruction. Even in its role in the destruction complex, APC's mechanism of action remains mysterious. We have suggested APC positions the destruction complex at the appropriate subcellular location, facilitating betacat destruction. In this study, we directly tested APC's proposed roles in the nucleus or in precisely localizing the destruction complex by generating a series of APC2 variants to which we added tags relocalizing otherwise wild-type APC to different cytoplasmic locations. We tested these for function in human colon cancer cells and Drosophila embryos. Strikingly, all rescue Wnt regulation and down-regulate Wnt target genes in colon cancer cells, and most restore Wnt regulation in Drosophila embryos null for both fly APCs. These data suggest that APC2 does not have to shuttle into the nucleus or localize to a particular subcellular location to regulate Wnt signaling. PMID- 22513089 TI - Conformational epitopes at cadherin calcium-binding sites and p120-catenin phosphorylation regulate cell adhesion. AB - We investigated changes in cadherin structure at the cell surface that regulate its adhesive activity. Colo 205 cells are nonadhesive cells with a full but inactive complement of E-cadherin-catenin complexes at the cell surface, but they can be triggered to adhere and form monolayers. We were able to distinguish the inactive and active states of E-cadherin at the cell surface by using a special set of monoclonal antibodies (mAbs). Another set of mAbs binds E-cadherin and strongly activates adhesion. In other epithelial cell types these activating mAbs inhibit growth factor-induced down-regulation of adhesion and epithelial morphogenesis, indicating that these phenomena are also controlled by E-cadherin activity at the cell surface. Both types of mAbs recognize conformational epitopes at different interfaces between extracellular cadherin repeat domains (ECs), especially near calcium-binding sites. Activation also induces p120 catenin dephosphorylation, as well as changes in the cadherin cytoplasmic domain. Moreover, phospho-site mutations indicate that dephosphorylation of specific Ser/Thr residues in the N-terminal domain of p120-catenin mediate adhesion activation. Thus physiological regulation of the adhesive state of E-cadherin involves physical and/or conformational changes in the EC interface regions of the ectodomain at the cell surface that are mediated by catenin-associated changes across the membrane. PMID- 22513090 TI - An essential role for the DNA breakage-repair protein Ku80 in programmed DNA rearrangements in Tetrahymena thermophila. AB - Programmed DNA rearrangements are important processes present in many organisms. In the ciliated protozoan Tetrahymena thermophila, DNA rearrangements occur during the sexual conjugation process and lead to the deletion of thousands of specific DNA segments and fragmentation of the chromosomes. In this study, we found that the Ku80 homologue, a conserved component of the nonhomologous end joining process of DNA repair, was essential for these two processes. During conjugation, TKU80 was highly expressed and localized to the new macronucleus, where DNA rearrangements occur. Homokaryon TKU80-knockout mutants are unable to complete conjugation and produce progeny and are arrested at the two micronuclei/two-macronuclei stage. Analysis of their DNA revealed failure to complete DNA deletion. However, the DNA-cutting step appeared to have occurred, as evidenced by the presence of circularized excised DNA. Moreover, chromosome breakage or de novo telomere addition was affected. The mutant appears to accumulate free DNA ends detectable by terminal deoxynucleotidyl transferase dUTP nick end labeling assays that led to the degradation of most DNA in the developing macronucleus. These findings suggest that Tku80p may serve an end protective role after DNA cleavage has occurred. Unexpectedly, the large heterochromatin structures that normally associate with DNA rearrangements failed to form without TKU80. Together the results suggest multiple roles for Tku80p and indicate that a Ku-dependent DNA-repair pathway is involved in programmed DNA rearrangements in Tetrahymena. PMID- 22513091 TI - The inner-mitochondrial distribution of Oxa1 depends on the growth conditions and on the availability of substrates. AB - The Oxa1 protein is a well-conserved integral protein of the inner membrane of mitochondria. It mediates the insertion of both mitochondrial- and nuclear encoded proteins from the matrix into the inner membrane. We investigated the distribution of budding yeast Oxa1 between the two subdomains of the contiguous inner membrane--the cristae membrane (CM) and the inner boundary membrane (IBM)- under different physiological conditions. We found that under fermentable growth conditions, Oxa1 is enriched in the IBM, whereas under nonfermentable (respiratory) growth conditions, it is predominantly localized in the CM. The enrichment of Oxa1 in the CM requires mitochondrial translation; similarly, deletion of the ribosome-binding domain of Oxa1 prevents an enrichment of Oxa1 in the CM. The predominant localization in the IBM under fermentable growth conditions is prevented by inhibiting mitochondrial protein import. Furthermore, overexpression of the nuclear-encoded Oxa1 substrate Mdl1 shifts the distribution of Oxa1 toward the IBM. Apparently, the availability of nuclear- and mitochondrial-encoded substrates influences the inner-membrane distribution of Oxa1. Our findings show that the distribution of Oxa1 within the inner membrane is dynamic and adapts to different physiological needs. PMID- 22513093 TI - Reversal of iC3b-inhibited dendritic cell differentiation via inhibition of the extracellular signal-regulated mitogen-activated protein kinase promotes CD4(+) T cell proliferation. AB - OBJECTIVES: To investigate the roles of ERK1/2 and p38 MAPK cascades in the differentiation of iC3b-combined CD14(+) monocyte into CD1a(+) MDDC, and to study how these cells influence CD4(+) T cell proliferation. METHODS: CD14(+) monocyte was co-cultured with iC3b with or without inhibitors specific for ERK1/2 or p38 MAPK pathways for 2days, then the expressions of CD14, CD1a, phophso-ERK1/2, phophso-p38, IL-10 and IL-12 p70 were detected, and CD4(+) T cell proliferation was measured via (3)H-TdR as well. RESULTS: Maturation of CD1a(+) DC was inhibited by iC3b along with downregulated expressions of CD1a, phophso-p38 and IL-12p70 and upregulated expressions of phophso-ERK1/2 and IL-10, and the CD4(+) T cell proliferation was restrained accordingly. When pretreated with inhibitor specific for ERK1/2 pathway, the inhibited maturation of imDC was reversed prominently with a higher level expression of CD1a and IL-12p70, whereas expressions of phophso-ERK1/2 and IL-10 were lowered, and accordingly the CD4(+) T cell proliferation restored significantly. CONCLUSIONS: iC3b inhibited the differentiation of CD14(+) monocytes into CD1a(+) MDDCs via ERK1/2 pathway, and restoration of CD1a(+) MDDCs maturation occurred with the treatment of inhibitors specific for ERK1/2 pathway. Meanwhile, treatment of the inhibitor for the ERK1/2 cascade reversed the inhibited CD4(+) T cell proliferation, implying a potential possibility for clinical intervention. PMID- 22513092 TI - [Microbiological characterisation of Listeria monocytogenes isolates from human cases in Andalusia]. AB - OBJECTIVE: The aim of this study was to perform a retrospective study by genotyping 154 isolates from human listeriosis cases occurred in the region of Andalusia (southern Spain) in the period 2005-2009. MATERIAL AND METHODS: Serotyping was performed for 1 and 4 somatic antigens using commercial Listeria antisera, and by multiplex-PCR serogrouping according to the method described by Doumith et al. (2004). The antimicrobial susceptibility was performed by Epsilon test and interpreted by CLSI criteria. PFGE was performed according to the PulseNet protocol with the ApaI enzyme. The similarity of PFGE profiles was evaluated using the Bionumerics software. The multiplex PCR protocol described by Chen and Knabel (2007) was used for the identification of isolates belonging to L. monocytogenes ECI, ECII, and ECIII epidemic clones. RESULTS: The 154 isolates were grouped into four serotypes: 4b [94 (61%)] strains, 1/2b [30 (19%)] strains, 1/2a [27 (18%)] strains, and 1/2c [3 (2%)] strains, with 100% of susceptibility to ampicillin and cotrimoxazole. A further sixty-two ApaI distinct pulsotypes were recognized. Thirty-seven isolates (24%) showed unique ApaI pulsotypes, and the remaining 117 strains (76%) were assigned to 25 ApaI clusters (60% in clusters of more than two isolates). The EC markers were found in 62 (40.3%) of the L. monocytogenes isolates tested. The ECI marker was present in 43 (46.2%) 4b serotype isolates, ECII in 10 (10.7%) 4b serotype isolates, and ECIII in 9 (33,3%) 1/2a serotype isolates. DISCUSSION: A large proportion of the human listeriosis cases under investigation could be grouped into molecular subtype clusters, and our cases could be related to international food-borne outbreaks. PMID- 22513094 TI - Application of photoremovable protecting group for controlled release of plant growth regulators by sunlight. AB - We report a novel technique for controlled release of plant growth regulators (PGRs) by sunlight using photoremovable protecting group (PRPG) as a delivery device. In the present work, carboxyl-containing PGRs of the auxin group [indoleacetic acid (IAA) and naphthoxyacetic acid (NOAA)] were chemically caged using PRPGs of coumarin derivatives. Photophysical studies showed that caged PGRs exhibited good fluorescence properties. Irradiation of caged PGRs by sunlight in both aqueous ethanol and soil media resulted in controlled release of PGRs. The results of the bioactivity experiments indicated that caged PGRs showed better enhancement in the root and shoot length growth of Cicer arietinum compared to PGRs after 10days of sunlight exposure. Our results indicated that use of PRPG as a delivery device for controlled release of PGRs by sunlight in soil holds great interest for field application since it can overcome the rapid loss of PGRs in environmental conditions. PMID- 22513095 TI - Study on the interaction of glycyrrhizin and glycyrrhetinic acid with RNA. AB - Glycyrrhizin is a well known pharmacologically bioactive natural glycoside. Glycyrrhizin (GL) has been widely used as a therapeutic agent for chronic active liver diseases. Glycyrrhetinic acid is an aglycone and an active metabolite of glycyrrhizin. This study is the first attempt to locate the binding sites of glycyrrhizin and glycyrrhetinic acid to RNA. The effect of the ligand complexation on RNA aggregation was investigated in aqueous solution at physiological conditions, using constant RNA concentration (6.25 mM) and various ligand/polynucleotide (phosphate) ratios of 1/280, 1/240, 1/120, 1/80, 1/40, 1/20, 1/10, 1/5, 1/2 and 1/1. Fourier transform infrared (FTIR) and UV-Visible spectroscopic methods as well as molecular modeling were used to determine the ligand binding modes, the binding constants, and the stability of ligands-RNA complexes in aqueous solution. Spectroscopic evidence showed that glycyrrhizin and glycyrrhetinic acid bind RNA via G-C and A-U base pairs as well as the backbone phosphate group with overall binding constants of K(GL-RNA)=3.03*10(3)M( 1), K(GA-RNA)=2.71*10(3)M(-1). The affinity of ligands-RNA binding is in the order of glycyrrhizin>glycyrrhetinic acid. RNA remains in the A-family structure, while biopolymer aggregation occurred at high triterpenoid concentrations. PMID- 22513096 TI - Study of DNA-emodin interaction by FTIR and UV-vis spectroscopy. AB - Emodin, a plant- and fungus-derived anthraquinone, exerts genotoxic and antioxidative effects and shows promise in antitumor and antibacterial therapies. The aim of this study was to examine the molecular interactions of emodin with DNA in aqueous solution at physiological pH using spectroscopic methods. Fourier Transform Infrared (FTIR) Spectroscopy and UV absorption spectra were used to determine the structural features, the binding mode and the association constants. Our UV-spectroscopic results indicate that emodin interacts with DNA by intercalation and by external binding. FTIR results suggest that emodin interaction occurs preferably via adenine and thymine base pairs and also weakly with the phosphate backbone of the DNA double helix. The binding constant for emodin-DNA complex formation is estimated to be K=5.59*10(3)M(-1). No significant changes of DNA conformation were observed upon emodin-DNA complexation. PMID- 22513097 TI - New insights into Escherichia coli metabolism: carbon scavenging, acetate metabolism and carbon recycling responses during growth on glycerol. AB - BACKGROUND: Glycerol has enhanced its biotechnological importance since it is a byproduct of biodiesel synthesis. A study of Escherichia coli physiology during growth on glycerol was performed combining transcriptional-proteomic analysis as well as kinetic and stoichiometric evaluations in the strain JM101 and certain derivatives with important inactivated genes. RESULTS: Transcriptional and proteomic analysis of metabolic central genes of strain JM101 growing on glycerol, revealed important changes not only in the synthesis of MglB, LamB and MalE proteins, but also in the overexpression of carbon scavenging genes: lamB, malE, mglB, mglC, galP and glk and some members of the RpoS regulon (pfkA, pfkB, fbaA, fbaB, pgi, poxB, acs, actP and acnA). Inactivation of rpoS had an important effect on stoichiometric parameters and growth adaptation on glycerol. The observed overexpression of poxB, pta, acs genes, glyoxylate shunt genes (aceA, aceB, glcB and glcC) and actP, suggested a possible carbon flux deviation into the PoxB, Acs and glyoxylate shunt. In this scenario acetate synthesized from pyruvate with PoxB was apparently reutilized via Acs and the glyoxylate shunt enzymes. In agreement, no acetate was detected when growing on glycerol, this strain was also capable of glycerol and acetate coutilization when growing in mineral media and derivatives carrying inactivated poxB or pckA genes, accumulated acetate. Tryptophanase A (TnaA) was synthesized at high levels and indole was produced by this enzyme, in strain JM101 growing on glycerol. Additionally, in the isogenic derivative with the inactivated tnaA gene, no indole was detected and acetate and lactate were accumulated. A high efficiency aromatic compounds production capability was detected in JM101 carrying pJLBaroG(fbr)tktA, when growing on glycerol, as compared to glucose. CONCLUSIONS: The overexpression of several carbon scavenging, acetate metabolism genes and the absence of acetate accumulation occurred in JM101 cultures growing on glycerol. To explain these results it is proposed that in addition to the glycolytic metabolism, a gluconeogenic carbon recycling process that involves acetate is occurring simultaneously in this strain when growing on glycerol. Carbon flux from glycerol can be efficiently redirected in JM101 strain into the aromatic pathway using appropriate tools. PMID- 22513098 TI - Antagonist-mediated down-regulation of Toll-like receptors increases the prevalence of human papillomavirus infection in systemic lupus erythematosus. AB - INTRODUCTION: Prevalence of an abnormal Papanicolaou smear was significantly increased in lupus patients in cross-sectional studies, associated with a higher prevalence of high-risk human papillomavirus (HPV) infection. The nucleic acid specific Toll-like receptors (TLRs) locate at the endolysosomal compartments and trigger the induction of cytokines for the innate immune response. This study evaluated whether abnormal host innate immune response in lupus patients may enhance HPV persistence. METHODS: Protein levels of TLRs 3, 7, 8 and 9 in cervical epithelial cells of lupus patients and controls with or without HPV infection were assessed using flow cytometry. Characteristics associated with the differential expression of TLRs in systemic lupus erythematosus (SLE) were elucidated. The effect and interferon-stimulated genes (ISGs) (ISG15 and Mx-1) gene expressions were then measured in oncogenic HeLa (HPV18), CaSki (HPV) and C33A (HPV negative) cell lines using flow cytometry and quantitative real-time PCR. Ex vivo productions of cytokines and interferon-gamma (IFN-gamma) upon TLR ligands stimulations were subsequently measured using cytometric bead array and ELISA. RESULTS: For subjects with HPV infection, levels of TLR3 and TLR7 were significantly lower in lupus patients compared with controls. Significantly decreased TLRs 7, 8 and 9 levels were observed in HPV-negative SLE compared to healthy controls. For SLE with and without HPV infection, TLR7 and 9 levels were significantly lower in infected SLE than those in HPV-negative patients. Independent explanatory variables associated with down-regulation of TLR7 level included HPV infection and a higher cumulative dose of prednisolone; while a higher cumulative dose of hydroxychloroquine and HPV infection were associated with down-regulation of TLR9 level. In cervical cell lines, TLRs 3, 7, 8, 9 protein levels and antiviral ISG15 and Mx-1 gene expressions were inhibited in two oncogenic HPV types. Functional data showed that the induction of pro inflammatory cytokines by TLR ligands (R837, ssRNA and ODN2395) was greatly impaired in CaSki and HeLa than C33A cells. CONCLUSIONS: In conclusion, prednisolone and TLR antagonist (hydroxychloroquine) may down-regulate protein levels of TLR7 and TLR9 in lupus patients, thereby decreasing the innate immune response against HPV infection. Upon infection, HPV further down-regulate TLR7 and 9 levels for viral persistence. Furthermore, reduction of nucleic acid sensing TLRs 7, 8 and 9 in carcinogenic HPVs ensures that the expression of inducible pro-inflammatory cytokines is minimized to prevent the expression of antiviral ISGs (ISG15 and Mx-1) on a biologically relevant antiviral response. PMID- 22513102 TI - Methodological optimization of tinnitus assessment using prepulse inhibition of the acoustic startle reflex. AB - Recently prepulse inhibition of the acoustic startle reflex (ASR) became a popular technique for tinnitus assessment in laboratory animals. This method confers a significant advantage over the previously used time-consuming behavioral approaches utilizing basic mechanisms of conditioning. Although this technique has been successfully used to assess tinnitus in different laboratory animals, many of the finer details of this methodology have not been described enough to be replicated, but are critical for tinnitus assessment. Here we provide detail description of key procedures and methodological issues that provide guidance for newcomers with the process of learning to correctly apply gap detection techniques for tinnitus assessment in laboratory animals. The major categories of these issues include: refinement of hardware for best performance, optimization of stimulus parameters, behavioral considerations, and identification of optimal strategies for data analysis. This article is part of a Special Issue entitled: Tinnitus Neuroscience. PMID- 22513101 TI - Fragile X Protein is required for inhibition of insulin signaling and regulates glial-dependent neuroblast reactivation in the developing brain. AB - Fragile X syndrome (FXS) is the most common form of inherited mental disability and known cause of autism. It is caused by loss of function for the RNA binding protein FMRP, which has been demonstrated to regulate several aspects of RNA metabolism including transport, stability and translation at synapses. Recently, FMRP has been implicated in neural stem cell proliferation and differentiation both in cultured neurospheres as well as in vivo mouse and fly models of FXS. We have previously shown that FMRP deficient Drosophila neuroblasts upregulate Cyclin E, prematurely exit quiescence, and overproliferate to generate on average 16% more neurons. Here we further investigate FMRP's role during early development using the Drosophila larval brain as a model. Using tissue specific RNAi we find that FMRP is required sequentially, first in neuroblasts and then in glia, to regulate exit from quiescence as measured by Cyclin E expression in the brain. Furthermore, we tested the hypothesis that FMRP controls brain development by regulating the insulin signaling pathway, which has been recently shown to regulate neuroblast exit from quiescence. Our data indicate that phosphoAkt, a readout of insulin signaling, is upregulated in dFmr1 brains at the time when FMRP is required in glia for neuroblast reactivation. In addition, dFmr1 interacts genetically with dFoxO, a transcriptional regulator of insulin signaling. Our results provide the first evidence that FMRP is required in vivo, in glia for neuroblast reactivation and suggest that it may do so by regulating the output of the insulin signaling pathway. This article is part of a Special Issue entitled: RNA-Binding Proteins. PMID- 22513100 TI - Understanding tinnitus: the dorsal cochlear nucleus, organization and plasticity. AB - Tinnitus, the perception of a phantom sound, is a common consequence of damage to the auditory periphery. A major goal of tinnitus research is to find the loci of the neural changes that underlie the disorder. Crucial to this endeavor has been the development of an animal behavioral model of tinnitus, so that neural changes can be correlated with behavioral evidence of tinnitus. Three major lines of evidence implicate the dorsal cochlear nucleus (DCN) in tinnitus. First, elevated spontaneous activity in the DCN is correlated with peripheral damage and tinnitus. Second, there are somatosensory inputs to the DCN that can modulate spontaneous activity and might mediate the somatic-auditory interactions seen in tinnitus patients. Third, we have found a subpopulation of DCN neurons in the adult rat that express doublecortin, a plasticity-related protein. The expression of this protein may reflect a role of these neurons in the neural reorganization causing tinnitus. However, there is a problem in extending the findings in the rodent DCN to humans. Classic studies state that the structure of the primate DCN is quite different from that of rodents, with primates lacking granule cells, the recipients of somatosensory input. To address the possibility of major species differences in DCN organization, we compared Nissl-stained sections of the DCN in five different species. In contrast to earlier reports, our data suggest that the organization of the primate DCN is not dramatically different from that of the rodents, and validate the use of animal data in the study of tinnitus. This article is part of a Special Issue entitled: Tinnitus Neuroscience. PMID- 22513103 TI - Longitudinal in-vivo diffusion tensor imaging for assessing brain developmental changes in BALB/cJ mice, a model of reduced sociability relevant to autism. AB - Diffusion tensor imaging (DTI) is highly sensitive in detecting brain structure and connectivity phenotypes in autism spectrum disorders (ASD). Since one of the core symptoms of ASD is reduced sociability (reduced tendency to seek social interaction), we hypothesized that DTI will be sensitive in detecting neural phenotypes that correlate with decreased sociability in mouse models. Relative to C57BL/6J (B6) mice, juvenile BALB/cJ mice show reduced sociability. We performed social approach test in a three-chambered apparatus and in-vivo longitudinal DTI at post-natal days 30, 50 and 70 days-of-age in BALB/cJ (n=32) and B6 (n=15) mice to assess the correlation between DTI and sociability and to evaluate differences in DTI parameters between these two strains. Fractional anisotropy (FA) and mean diffusivity (MD) values from in-vivo DTI data were analyzed from white matter (corpus callosum, internal and external capsule) and gray matter (cerebral cortex, frontal motor cortex, hippocampus, thalamus and amygdaloid) regions based on their relevance to ASD. A moderate but significant (p<0.05) negative correlation between sociability and FA in hippocampus and frontal motor cortex was noted for BALB/cJ mice at 30 days-of-age. Significant differences in FA and MD values between BALB/cJ and B6 mice were observed in most white and gray matter areas at all three time points. Significant differences in developmental trajectories of FA and MD values from thalamus and frontal motor cortex were also observed between BALB/cJ and B6, indicating relative under-connectivity in BALB/cJ mice. These results indicate that DTI may be used as an in-vivo, non invasive imaging method to assess developmental trajectories of brain connectivity in mouse models of neurodevelopmental and behavioral disorders. PMID- 22513104 TI - A phantom study to assess accuracy of needle identification in real-time planning of ultrasound-guided high-dose-rate prostate implants. AB - PURPOSE: High-dose-rate brachytherapy of the prostate is commonly performed using transrectal ultrasound (US) guidance, with CT imaging used for needle reconstruction and treatment planning. Transrectal ultrasound images can, however, be used for the entire process, allowing treatment without changes in the patient position. This study assesses needle reconstruction accuracy using US images. METHODS AND MATERIALS: Prostate phantoms were implanted with 10-18 needles. Three-dimensional US images were acquired, and needles were reconstructed using specialized software. A CT scan was also obtained. The image sets were registered and needle reconstruction errors were assessed. A dose plan was obtained using the US images and the dwell times were transferred to the CT reconstruction to obtain the true "delivered dose," which was evaluated using standard dosimetric parameters. RESULTS: Two sources of error were identified. First, reconstruction based on the bright echoes in the US images introduces a systematic error because these echoes correspond to the proximal wall of the needle, and not the center of the needle channel. If left uncorrected, this shift can lead to an underestimate of urethral doses. Second, incorrect needle tip identification can occur in the cranial-caudal direction. Errors up to 5.8mm were observed. A measurement of needle lengths protruding beyond the template can be used to compensate for this. CONCLUSIONS: Factors limiting the accuracy of US based needle reconstruction have been identified. Once recognized, these errors can be corrected for, resulting in accurate implant geometry. This facilitates a treatment technique combining excellent anatomic definition, minimal prostate motion, and accurate dose planning and delivery. PMID- 22513105 TI - Defining a magnetic resonance scan sequence for permanent seed prostate brachytherapy postimplant assessment. AB - PURPOSE: We describe a magnetic resonance (MR) scan sequence for prostate brachytherapy postimplant assessment. METHODS AND MATERIALS: One brachytherapy team at the British Columbia Cancer Agency has incorporated MR-CT fusion into their permanent seed prostate brachytherapy quality assurance procedure. Several attempts were required to ensure that the diagnostic MR scanner at the adjoining general hospital performed the desired sequence, providing many examples of suboptimal scans and underlining the pitfalls for a center trying to incorporate the use of MR scanning into their brachytherapy program. RESULTS: The recommended sequence (Fast Spin Echo T2-weighted, repetition time [TR]/echo time [TE] 4500/90, echo train length [ETL] 10, 20*20 field of view [FOV], 80 bandwidth [BW]) is associated with superior edge detection when compared with those images in which a typical diagnostic sequence was used. The use of a low bandwidth sequence does not compromise edge detection or seed identification when compared with a higher bandwidth. CONCLUSIONS: We have defined a magnetic resonance imaging sequence, which appears to optimize both prostate delineation and identification of seeds, lending itself to straightforward fusion with CT images and allowing for less uncertainty in permanent seed prostate brachytherapy quality assurance. PMID- 22513107 TI - Plants as alternative hosts for Salmonella. AB - Recent findings show that many human pathogenic bacteria can use multiple host organisms. For example, Salmonella Typhimurium can use plants as alternative hosts to humans and other animals. These bacteria are able to adhere to plant surfaces and actively infect the interior of plants. Similarly to the infection of animal cells, S. Typhimurium suppresses plant defense responses by a type III secretion mechanism, indicating that these bacteria possess a dedicated multi kingdom infection strategy, raising the question of host specificity. In addition, evidence is accumulating that the interaction of Salmonella with plants is an active process with different levels of specificity, because different Salmonella serovars show variations in pathogenicity, and different plant species reveal various levels of resistance towards these bacteria. PMID- 22513106 TI - High-dose-rate interstitial computed tomography-based brachytherapy for the treatment of cervical cancer: early results. AB - PURPOSE: There is limited published data on high-dose-rate interstitial brachytherapy (HDRBT) for cervical cancer resulting in no consensus on a fractionation schedule. This study reports our experience of CT-based HDRBT for treating locally advanced cervical cancer. METHODS AND MATERIALS: Forty-seven patients diagnosed with Stage IIB-IVA cervical cancer not suitable for intracavitary brachytherapy were treated with HDRBT from March 2005 to November 2010. All patients received external beam radiation therapy with a median dose of 45Gy and all had one interstitial implantation followed by 3.75-5Gy*5 fractions in a twice daily (BID) schedule. Total doses for clinical target volume and organs at risk, including rectum, bladder, and sigmoid, were summated and normalized to a biologically equivalent dose of 2Gy per fraction. At 3 months posttherapy, early response was assessed with clinical examination and positron emission tomography (PET/CT) imaging. RESULTS: Median clinical target volume D(90) (dose delivered to 90% of the clinical target volume) was 76.3 (59.0-86.9) Gy and the 2cc dose to the bladder, rectum, and sigmoid colon organs were 70.2 (55.9-77.7), 65.8 (54.9-80.6), and 56.5 (45.0-71.2) Gy, respectively. Posttreatment, 12 patients had evidence of persistent disease on PET/CT. Eleven of the 35 patients who had complete response developed recurrences. Two patients developed late Radiation Therapy Oncology Group >=3 rectal toxicities. Two-year actuarial local control, disease-free survival, overall survival, and Grade >=3 toxicities were 61%, 43%, 59%, and 10%, respectively. CONCLUSION: Our approach of a single implantation procedure followed by five fractions of HDRBT was well tolerated with early results demonstrating a moderate response and local control rate with acceptable toxicities. PMID- 22513108 TI - Plant Proteus: brown algal morphological plasticity and underlying developmental mechanisms. AB - Brown algae are multicellular photosynthetic marine organisms, ubiquitous on rocky intertidal shores at cold and temperate latitudes. Nevertheless, little is known about many aspects of their biology, particularly their development. Given their phylogenetic distance (1.6 billion years) from other plant organisms (land plants, and green and red algae), brown algae harbor a high, as-yet undiscovered diversity of biological mechanisms governing their development. They also show great morphological plasticity, responding to specific environmental constraints, such as sea currents, reduced light availability, grazer attacks, desiccation and UV exposure. Here, we show that brown algal morphogenesis is rather simple and flexible, and review recent genomic data on the cellular and molecular mechanisms known to date that can possibly account for this developmental strategy. PMID- 22513110 TI - Utility of apparent diffusion coefficient ratios in distinguishing common pediatric cerebellar tumors. AB - RATIONALE AND OBJECTIVES: The aim of this study was to identify clinically useful tumor/normal brain apparent diffusion coefficient (ADC) ratios for distinguishing common pediatric cerebellar tumors. MATERIALS AND METHODS: Review of medical records revealed 79 patients with cerebellar tumors who underwent preoperative magnetic resonance imaging, including diffusion-weighted imaging sequences, and surgery. There were 31 pilocytic astrocytomas, 27 medulloblastomas, 14 ependymomas, and seven atypical teratoid/rhabdoid tumors. ADC values were measured by placing regions of interest on the solid tumor and normal brain parenchyma by two reviewers. Tumor/normal brain ADC ratios were calculated. RESULTS: Mean ADC values of the pilocytic astrocytomas were greater than those of ependymomas, whose mean ADC values were greater than those of medulloblastomas and atypical teratoid/rhabdoid tumors. Using a tumor/normal brain ADC ratio threshold of 1.70 to distinguish pilocytic astrocytomas from ependymomas, sensitivity of 92% and specificity of 79% were achieved. A tumor/normal brain ADC ratio threshold of 1.20 enabled the sorting of ependymomas from medulloblastomas with sensitivity of 93% and specificity of 88%. CONCLUSIONS: Tumor/normal brain ADC ratios allow the distinguishing of common pediatric cerebellar tumors. PMID- 22513109 TI - Sugar transporters in plants and in their interactions with fungi. AB - Sucrose and monosaccharide transporters mediate long distance transport of sugar from source to sink organs and constitute key components for carbon partitioning at the whole plant level and in interactions with fungi. Even if numerous families of plant sugar transporters are defined; efflux capacities, subcellular localization and association to membrane rafts have only been recently reported. On the fungal side, the investigation of sugar transport mechanisms in mutualistic and pathogenic interactions is now emerging. Here, we review the essential role of sugar transporters for distribution of carbohydrates inside plant cells, as well as for plant-fungal interaction functioning. Altogether these data highlight the need for a better comprehension of the mechanisms underlying sugar exchanges between fungi and their host plants. PMID- 22513111 TI - Nutritional deficiencies and parasitic disease: lessons and advancements from rodent models. AB - The dissection of the molecular interactions between nutrition and immunity to nematodes is of strategic importance to predict the risk of infection, define disease predisposition and develop sustainable measures for parasite control in ruminants. Despite the evidence on the effects of nutrition on the manifestations of immunity to gastrointestinal parasites at phenotypic level, the lack of progress on the characterisation of the molecular interactions is directly related to the current lack of appropriate tools for such advancements, including fully sequenced and annotated genomes and immunological tools for small ruminants. To overcome such constraints and achieve rapid progress in exploring the molecular interactions between nutrition and immunity to nematodes, it is proposed here that we capitalise more on the advancements in small mammal models. In this paper, first the literature deriving from growing animals is reviewed, where most evidence originates from primary infection models. The focus is then shifted on peri-parturient animals; the immunomodulatory effects of nutrition are investigated during re-infection. Finally, an approach is suggested on how advancements made in the rodent models, can be utilised in order to expand our understanding in sheep and provide specific examples on how this should work to address sustainable parasite control in ruminants. PMID- 22513112 TI - Pyrethroid tolerance in the chewing louse Bovicola (Werneckiella) ocellatus. AB - Equine pediculosis is a significant health and welfare issue, particularly in elderly and chronically debilitated animals. Currently infestation is controlled predominantly using topically applied pyrethroid insecticides, allowing limited scope for the rotation of drugs and increasing the risk of selection for resistance. Here the insecticidal efficacies of two pyrethroid-based products against the louse Bovicola (Werneckiella) ocellatus collected from donkeys were examined in vitro. The products were cypermethrin (DeosectTM, Pfizer Ltd., 5% (w/v) cypermethrin, cutaneous spray) and permethrin (SwitchTM, VetPlus Ltd., 4% (w/v) permethrin, pour-on). The pyrethroid efficacy was contrasted with that of the organophosphate diazinon, since the louse populations examined were unlikely to have had prior exposure to this compound. The efficacy of diluted pure permethrin, the excipient, butyl dioxitol and the synergist piperonyl butoxide in the presence of the pyrethroids, were also considered. At the concentrations recommended for animal application, neither 4% (w/v) permethrin, nor 0.1% (w/v) cypermethrin had any significant effect on the mortality of B. ocellatus and neither induced significantly more mortality than an acetone-only control. In contrast, 0.04% diazinon caused 70% mortality within 4h and 100% mortality after 24h exposure. The addition of a potential pyrethroid synergist, piperonyl butoxide, in combination with cypermethrin and permethrin, resulted in no significant increase in mortality. It is concluded that the population of lice tested display a high level of pyrethroid tolerance which is likely to reflect the development of resistance. Twenty-four hours after routine treatment of 10 donkeys with a pour-on permethrin product (SwitchTM, VetPlus Ltd., 4% (w/v) permethrin, pour-on) hair tufts taken from their flanks were not significantly insecticidal compared with hair from the midline application site, implying a low level of insecticide distribution. Such a distribution pattern is likely to create an insecticide concentration gradient over the body and further facilitate selection for resistance. PMID- 22513114 TI - Polyploidization increases meiotic recombination frequency in Arabidopsis: a close look at statistical modeling and data analysis. AB - This paper is a response to Pecinka A, Fang W, Rehmsmeier M, Levy AA, Mittelsten Scheid, O: Polyploidization increases meiotic recombination frequency in Arabidopsis. BMC Biology 2011, 9:24.See research article at http://www.biomedcentral.com/1741-7007/9/24. PMID- 22513113 TI - Bivalent histone modifications in early embryogenesis. AB - Histone modifications influence the interactions of transcriptional regulators with chromatin. Studies in embryos and embryonic stem (ES) cells have uncovered histone modification patterns that are diagnostic for different cell types and developmental stages. For example, bivalent domains consisting of regions of H3 lysine 27 trimethylation (H3K27me3) and H3 lysine 4 trimethylation (H3K4me3) mark lineage control genes in ES cells and zebrafish blastomeres. Such bivalent domains have garnered attention because the H3K27me3 mark might help repress lineage-regulatory genes during pluripotency while the H3K4me3 mark could poise genes for activation upon differentiation. Despite the prominence of the bivalent domain concept, studies in other model organisms have questioned its universal nature, and the function of bivalent domains has remained unclear. Histone marks are also associated with developmental regulatory genes in sperm. These observations have raised the possibility that specific histone modification patterns might persist from parent to offspring, but it is unclear whether histone marks are inherited or formed de novo. Here, we review the potential roles of H3K4me3 and H3K27me3 marks in embryos and ES cells and discuss how histone marks might be established, maintained and resolved during embryonic development. PMID- 22513115 TI - NEMO differentially regulates TCR and TNF-alpha induced NF-kappaB pathways and has an inhibitory role in TCR-induced NF-kappaB activation. AB - NF-kappaB essential modulator (NEMO), the regulatory subunit of the IkappaB kinase (IKK) complex, is an essential adaptor both for inflammation stimuli and TCR-induced NF-kappaB activation. However, the exact mechanism of its function has not been fully understood. Here, we report that knockdown of NEMO by RNA interference in Jurkat E6.1 cells enhanced TCR-induced NF-kappaB report gene activity and IL-2 production by promotion of IkappaBalpha degradation and p65 nuclear translocation, whereas inhibited TNF-alpha and LPS-induced IkappaBalpha degradation without influencing the phosphorylation of MAPKs. In human primary T and Jurkat E6.1 cells, both CD3/CD28 and PMA/Ionomycin induced NF-kappaB activation showed a para-curve correlation with the dosage of small interfering RNA targeting NEMO (siNEMO): the NF-kappaB report gene activity was increased along with ascending doses of transfected siNEMO and reached the highest activity when knockdown about 70% of NEMO, then turned to decline and gradually be blocked once almost thoroughly knockdown of NEMO. Meanwhile, TNF-alpha induced NF-kappaB was always inhibited no matter how much NEMO was knockdown. Subcellular fractionation results suggested that upon CD3/CD28 costimulation, NEMO and IKKbeta may not cotranslocate to cytoskeleton fraction as a conventional NEMO/IKK complex with a static stoichiometric ratio, instead the ratio of NEMO: IKKbeta continuously shift from high to low. Depletion of NEMO accelerated TCR-induced cytoskeleton translocation of IKKbeta. Altogether, this study suggests that NEMO may function as a rheostat exerting a negative action on TCR-induced NF-kappaB activation and differentially regulates TNF-alpha and TCR-induced NF-kappaB pathways. PMID- 22513116 TI - Development and validation of a useful HPLC-UV method for quantification of total and phosphorylated-ribavirin in blood and erythrocytes of HCV+ patients. AB - Ribavirin-induced hemolytic anemia is the main cause of discontinuation of the combination therapy with alpha-interferon-2b and ribavirin for the treatment of hepatitis C virus (HCV) infection. The determination of intracellular ribavirin levels in blood, including the levels of its phosphorylated metabolites, might be useful for predicting ribavirin-induced anemia, which could be caused by the accumulation of these molecules within the erythrocytes. In this work, we simplified and validated a previously developed assay method, to make it suitable for routine monitoring of cellular ribavirin. Whole blood diluted with a five fold volume of ice-cold distilled underwent a process of acid phosphatase digestion to convert phosphorylated ribavirin metabolites to free ribavirin. The resulting mixture, spiked with an internal standard, was treated with a protein precipitation protocol in acetonitrile, followed by reverse-phase high performance liquid chromatography analysis. The calibration curve for ribavirin levels in whole blood was linear at concentrations from 625 to 320,000 ng/mL (r(2)=0.998). Accuracy, intra-day and inter-day precision for ribavirin and phosphorylated-ribavirin quality controls were all below 9.0%. We tested this method by monitoring blood ribavirin concentrations in 13 HCV+ patients, receiving alpha interferon-plus ribavirin combination therapy. PMID- 22513117 TI - Chemical profile and seasonal variation of phenolic acid content in bastard balm (Melittis melissophyllum L., Lamiaceae). AB - Melittis melissophyllum L. is an old medicinal plant. Nowadays it is only used in the folk medicine but formerly it has been applied in the official medicine as a natural product described in French Pharmacopoeia. M. melissophyllum herbs used in our studies were collected from two localities in Poland in May and September. Methanolic plant extracts were purified by means of solid-phase extraction and then analysed by HPLC-DAD for their phenolic acid profile. Eleven compounds were identified in all plant samples and quantitatively analysed as: protocatechuic, chlorogenic, p-hydroxybenzoic, vanillic, caffeic, syringic, p-coumaric, ferulic, sinapic, o-coumaric and cinnamic acid. Plant materials contained free and bound phenolic acids. The main compounds were: p-hydroxybenzoic acid (30.21-54.16 mg/100 g dw and 37.04-56.75 mg/100 g dw, free and bound, respectively) and p coumaric acid (40.48-80.55 mg/100 g dw and 28.09-40.85 mg/100 g dw, free and bound, respectively). The highest amounts of the investigated compounds were found in all samples collected in September, e.g. p-hydroxybenzoic acid (September 51.72-54.16 mg/100 g dw vs. May 30.21-34.07 mg/100 g dw), p-coumaric acid (September 77.14-80.55 mg/100 g dw vs. May 40.48-43.2 5mg/100 g dw). Multivariate statistical and data mining techniques, such as cluster analysis (CA) and principal component analysis (PCA), were used to characterize the sample populations according to the geographical localities, vegetation period and compound form (free or bound). To the best of our knowledge we report for the first time the results of quantitative analysis of M. melissophyllum phenolic acids and seasonal variation of their content. Plant herbs are usually collected at flowering for plant derived medical preparations. Our results show that it is not always the optimal time for the highest contents of active compounds. PMID- 22513118 TI - Quantification of particle-induced inflammatory stress response: a novel approach for toxicity testing of earth materials. AB - BACKGROUND: Reactive oxygen species (ROS) are vital regulators of many cellular functions in the body. The intracellular ROS concentration is highly regulated by a balance between pro-oxidants and anti-oxidants. A chronic excess of pro oxidants leads to elevated ROS concentrations and inflammation, possibly initiating or enhancing disease onset. Mineral-induced generation of ROS, the role of minerals in upregulating cellular ROS, and their role in the development of several occupational diseases are now widely recognized. However, there is no standard protocol to determine changes in ROS production in cells after exposure to mineral dust or earth materials in general. In this study, a new method for determining the degree of cellular toxicity (i.e., cytotoxicity) of particles is described that will help bridge the gap in knowledge. RESULTS: By measuring the production of ROS and the viability of cells, an inflammatory stress response (ISR) indicator is defined. This approach normalizes the ROS upregulation with respect to the number of viable cells at the time of measurement. We conducted experiments on a series of minerals and soils that represent materials that are inert (i.e., glass beads, anatase, and a soil with low trace element content), moderately reactive (i.e., soil with high trace element content), and highly reactive (i.e., pyrite). Inert materials generated the lowest ISR, averaging 350% compared to the control. Acid washed pyrite produced the highest ISR (1,100 fold higher than the control). The measurements conducted as a function of time showed a complex response. Most materials showed an increase in ISR with particle loading. CONCLUSIONS: The amount of cellularly generated ROS and cell viability combined provide a better understanding of particle-induced oxidative stress. The results indicate that some earth materials may solicit an initial burst of ROS, followed by a second phase in which cell viability decreases and ROS production increases, leading to a high ISR value. Hence, measurements conducted over a range of particle loading combined with multiple data measurements up to 24 hours can provide new insights in the possible effect of exposure to earth materials on human health. PMID- 22513119 TI - Effect of a grocery store intervention on sales of nutritious foods to youth and their families. AB - Grocery stores represent a unique opportunity to initiate nutrition interventions. The aim of this study was to develop and evaluate a 12-week, child focused intervention at one grocery store. An observational uninterrupted time series design was implemented from May to September 2009. The Healthy Kids campaign consisted of a point-of-purchase kiosk featuring fruits, vegetables, and healthy snacks as well as a sampling pod comprised of food items from the kiosk. Data collection included changes in sales for featured products; observations of customers at the kiosk/intervention; and brief questionnaires for customers who engaged with the kiosk. Descriptive statistics were computed for questionnaire responses and observational data. Correlational analyses were conducted to identify potential predictors of engagement. Sales data were analyzed using analysis of variance. Results showed an overall increase in the proportion of sales of the featured items to total store sales during the intervention period (P<0.05). Individual items that increased sales during the intervention period included whole-wheat bagels, bananas, radishes, honey, sunflower seeds, baked tortilla chips, and almond butter (P<0.05). Almost two thirds (61.7%) of the patrons interviewed noticed the Healthy Kids kiosk, with about one quarter (28.7%) indicating that they purchased at least one item. Fifty-eight percent reported that the kiosk encouraged them to buy healthier foods. PMID- 22513120 TI - Nationwide population-based epidemiologic study of rheumatoid arthritis in Taiwan. AB - OBJECTIVES: Epidemiological studies of rheumatoid arthritis in Asia are rare. The aim of this research was to study the epidemiology and associated medical expenses of rheumatoid arthritis in Taiwan. METHODS: Cases of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria, were retrieved from the National Health Insurance Research Database with corresponding International Classification of Diseases, Ninth Revision code (ICD-9) 714.0 from January 2000 to December 2007, and limited to those 16 years and older. Age- and sex-specific incidences were estimated by dividing the incidence number by population data obtained from the Department of Statistics, Ministry of the Interior. RESULTS: There were a total of 40,995 cases. The average age-adjusted annual incidence rate was 15.8 per 100,000. The adjusted incidence rates were very stable at 20.9-25.2/100,000/year and 7.0-8.2/100,000/year for females and males, respectively, during the study period. The adjusted average incidence ratio of females/males was 3.1. The age-specific incidence peaked in the 60-64 and 70-74 year age groups for females and males, respectively. The adjusted prevalence rate increased steadily during the study period from 57.7/100,000 in 2000 to 99.6/100,000 in 2007. The average total yearly expense per patient increased from 1,155 United States Dollars (USD) in 2000 to 1,821 USD in 2007. Sicca syndrome (ICD-9 code 710.2) was the most common co-existing ICD-9 code. CONCLUSIONS: This is the first incidence study based on the 1987 American College of Rheumatology criteria in Asia. The prevalence rate based on these criteria was lower than in previous Asia studies. The medical expenses increased continuously. PMID- 22513121 TI - 5-acetyl-2-arylbenzimidazoles as antiviral agents. Part 4. AB - Within a project aimed at discovering new Flaviviridae inhibitors, new variously substituted 2-phenylbenzimidazoles were synthesized and evaluated in cell-based assays for cytotoxicity and antiviral activity against viruses representatives of the three genera of the Flaviviridae family, i.e.: Pestivirus (BVDV), Flavivirus (YFV) and Hepacivirus (HCV). Title compounds were also tested against RNA viruses representative of other single-stranded, positive-sense (ssRNA(+)) negative-sense (RNA(-)), or double-stranded (dsRNA) genomes, as well as against representatives of two DNA virus families. Nine compounds showed activity against BVDV (EC(50) = 0.8-8.0 MUM), compound 31 being the most potent (EC(50) = 0.80 MUM) and selective (SI = CC(50)/EC(50) = >100). When tested in an HCV replicon assay, compound 31 resulted again the most potent, displaying an EC(50) value of 1.11 MUM and an SI of 100. Besides inhibiting BVDV, two compounds (35 and 38) showed a moderate activity also against YFV (EC(50) = 13 MUM). Interestingly, 35 was moderately active also against RSV (EC(50) = 25 MUM). PMID- 22513122 TI - 12-N-Methylated 5,6-dihydrobenzo[c]acridine derivatives: a new class of highly selective ligands for c-myc G-quadruplex DNA. AB - 12-N-Methylated and non-methylated 5,6-dihydrobenzo[c]acridine derivatives were designed and synthesized as new series of c-myc G-quadruplex binding ligands. Their interactions with c-myc G-quadruplex were evaluated using fluorescence resonance energy transfer (FRET) melting assay, circular dichroism (CD) spectroscopy, surface plasmon resonance (SPR), polymerase chain reaction (PCR) stop assay, and molecular modeling. Compared with the non-methylated derivatives, 12-N-methylated derivatives had stronger binding affinity and stabilizing ability to c-myc G-quadruplex structure, and could more effectively stack on the G quartet surface. All these derivatives had high selectivity for c-myc G quadruplex DNA over duplex DNA. The reverse transcription (RT) PCR assay showed that compound 21c could down-regulate transcription of c-myc gene in Ramos cell line containing NHE III(1) element, but had no effect in CA46 cell line with NHE III(1) element removed. PMID- 22513123 TI - Can slide positivity rates predict malaria transmission? AB - BACKGROUND: Malaria is a significant threat to population health in the border areas of Yunnan Province, China. How to accurately measure malaria transmission is an important issue. This study aimed to examine the role of slide positivity rates (SPR) in malaria transmission in Mengla County, Yunnan Province, China. METHODS: Data on annual malaria cases, SPR and socio-economic factors for the period of 1993 to 2008 were obtained from the Center for Disease Control and Prevention (CDC) and the Bureau of Statistics, Mengla, China. Multiple linear regression models were conducted to evaluate the relationship between socio ecologic factors and malaria incidence. RESULTS: The results show that SPR was significantly positively associated with the malaria incidence rates. The SPR (beta = 1.244, p = 0.000) alone and combination (SPR, beta = 1.326, p < 0.001) with other predictors can explain about 85% and 95% of variation in malaria transmission, respectively. Every 1% increase in SPR corresponded to an increase of 1.76/100,000 in malaria incidence rates. CONCLUSION: SPR is a strong predictor of malaria transmission, and can be used to improve the planning and implementation of malaria elimination programmes in Mengla and other similar locations. SPR might also be a useful indicator of malaria early warning systems in China. PMID- 22513124 TI - Morphological features of the inflammatory response in molluscs. AB - Over the last few years, there has been a large increase in studying the biology and pathology of molluscs, predominantly in addressing the molecular patterns involved in their immune-mediated and inflammatory responses. Conversely, the literature-based diagnostic criteria concerning the morphology of the above phenomena still involves pathogenetic confusion and conflicting terminology. A comparison of bibliographic resources, such as the Abridged Glossary of Terms Used in Invertebrate Pathology and the National Status manual for molluscan histopathological examination and analysis from the NOAA, have revealed variability in the definitions of superimposable lesions, emphasising the need for further efforts in establishing standard terminology and methodologies in this field of study. This review suggests some possible solutions for overcoming the use of parallel terminologies in diagnosing inflammation in molluscs and also highlights conflicting features requiring further discussion. PMID- 22513125 TI - Presumptive primary central nervous system T cell lymphoma in a deer (Capreolus capreolus). AB - This report describes the morphological and immunohistochemical findings in an approximately 7-year old wild European roe deer (Capreolus capreolus) with an infiltrative primary central nervous system T cell lymphoma. The roebuck had lost its timidity and was shot by a hunter. It was submitted for necropsy to exclude rabies. Gross examination revealed besides a verminous pneumonia no abnormal findings. Histologically, there was a highly cellular, not well demarcated, unencapsulated, and infiltrative neoplasm within basal parts of the brain. Tumour cells were round, up to 15 MUm in diameter and loosely arranged in sheets with a multifocally predominant perivascular infiltration. Immunohistochemically, tumour cells were positive for CD3 antigen. Whilst secondary lymphomas of the central nervous system emerge by metastatic seeding of tumour cells, primary lymphomas originate within the neuroparenchyma. This is the first report of a primary central nervous system lymphoma in an European roe deer. PMID- 22513126 TI - Hepatocyte apoptosis in dairy cows with fatty infiltration of the liver. AB - The objective of the present study was to analyse the apoptotic process of liver cells in dairy cows with fatty infiltration of the liver using indicators of DNA damage and immunohistochemistry. For this purpose, sixteen dairy cows with fatty liver were examined. On clinical examination, the physical condition of the animals was fair in nine and poor in seven cows. The most dominant clinical signs were reduced ruminal motility, inappetance and/or anorexia and recumbency. Postmortem examination, in seven cases, revealed enlarged liver (18-33 kg), icteric carcasses and distended gallbladder. Laboratory results included neutrophilia, hypochloraemia, decreased concentrations of total bilirubin and increased concentrations of beta-hydroxy butyric acid, non-esterified fatty acids and insulin. The activities of aspartate aminotransferase, gamma-glutamyl transpeptidase, creatine kinase and lactate dehydrogenase were high. Histopathological examination of hepatic specimen showed lipid drops in cytosol with indistinct cellular membranes. In control hepatic cells, the DNA was tightly compressed and maintained the circular disposition of the normal nucleus. However, in the diseased cows, the damaged DNA migrated from the core toward the anode, forming a tail of a comet. Compared to controls, numerous ssDNA and caspase-3-positive cells were detected in the liver. To the authors' knowledge, this is the first study to document accelerated apoptosis of hepatocytes in dairy cows with fatty infiltration of the liver. PMID- 22513127 TI - Low prevalence of honeybee viruses in Spain during 2006 and 2007. AB - RNA viruses that affect honeybees have been involved in colony losses reported around the world. The aim of the present work was to evaluate the prevalence and distribution of honeybee viruses during 2006-2007 in Spanish professional apiaries, and their association with colony losses. Four hundred and fifty-six samples from apiaries located in different geographic regions of Spain were analyzed. Thirty-seven percent of the samples had viral presence. Most (80%) had one virus and 20% two different viruses. All the analyzed viruses, Deformed Wing Virus (DWV), Israeli Acute Paralysis Virus (IAPV), Black Queen Cell Virus (BQCV), Sacbrood Virus (SBV) and Kashmir Bee Virus (KBV) were detected, but detection rates were lower than expected. According to these results and considering the high prevalence of other honeybee pathogens in Spain, the role of viruses in colony losses in Spain may be discussed. PMID- 22513128 TI - Prevalence, risk factors, and biochemical markers in dogs with ultrasound diagnosed biliary sludge. AB - Regarded as an incidental finding, biliary sludge is often diagnosed in dogs on abdominal ultrasound. The aims of the present study were to assess the risk factors, biochemical markers and ultrasonographic findings and to estimate the prevalence and influence of different breeds, sexes, and ages on biliary sludge in dogs. Results demonstrate that the prevalence of biliary sludge is high, especially in senior dogs. The biochemical markers did not have a significant correlation with biliary sludge, and the type of diet was not considered to be the major risk factor. Hepatomegaly was frequently observed on the ultrasound scan of affected animals and of dogs on different systemic drugs and with cardiopathies, which have been referred to as risk groups for the development of inspissated bile. PMID- 22513129 TI - Text mining for the biocuration workflow. AB - Molecular biology has become heavily dependent on biological knowledge encoded in expert curated biological databases. As the volume of biological literature increases, biocurators need help in keeping up with the literature; (semi-) automated aids for biocuration would seem to be an ideal application for natural language processing and text mining. However, to date, there have been few documented successes for improving biocuration throughput using text mining. Our initial investigations took place for the workshop on 'Text Mining for the BioCuration Workflow' at the third International Biocuration Conference (Berlin, 2009). We interviewed biocurators to obtain workflows from eight biological databases. This initial study revealed high-level commonalities, including (i) selection of documents for curation; (ii) indexing of documents with biologically relevant entities (e.g. genes); and (iii) detailed curation of specific relations (e.g. interactions); however, the detailed workflows also showed many variabilities. Following the workshop, we conducted a survey of biocurators. The survey identified biocurator priorities, including the handling of full text indexed with biological entities and support for the identification and prioritization of documents for curation. It also indicated that two-thirds of the biocuration teams had experimented with text mining and almost half were using text mining at that time. Analysis of our interviews and survey provide a set of requirements for the integration of text mining into the biocuration workflow. These can guide the identification of common needs across curated databases and encourage joint experimentation involving biocurators, text mining developers and the larger biomedical research community. PMID- 22513130 TI - Visualisation of J-type counter-current chromatography: a route to understand hydrodynamic phase distribution and retention. AB - This paper has addressed decade sought-after questions on phase bilateral distribution and stationary phase retention in any J-type high-speed counter current chromatographic (CCC) centrifuge. Using a 2-D spiral column operated on such a CCC device and an aqueous two-phase system, this work systematically observed the phase interaction during transitional period and at dynamic equilibration under stroboscopic illumination. The experimental results thus obtained were used to examine the effects of the liquid-solid friction force, tangential centrifugal force, and physical properties of the two-phase system on hydrodynamic phase behaviour. We identified that (a) density difference between lower and upper phases is the critical factor to cause unusual phase bilateral distribution in the 2-D spiral column and (b) interfacial tension (manifested primarily as phase settling time) of any two-phase system is the critical factor in explaining inability to retain stationary phase in 3-D helical column and, for certain flow modes, in the 2-D spiral column. This work thus has extended or modified the well-established rule-of-thumb for operating J-type CCC devices and our conclusions can accommodate virtually all the anomalies concerning both hydrophobic and hydrophilic phase systems. To this end, this work has not only documented valuable experimental evidences for directly observing phase behaviour in a CCC column, but also finally resolved fundamentally vital issues on bilateral phase distribution orientation and stationary phase retention in 2-D spiral and 3-D helical CCC columns. Revised recommendations to end users of this technology could thus be derived out of the essence of the present work presumably following further experimental validation and a consensus in the CCC R&D and manufacturing circle. PMID- 22513131 TI - Impact of the limitations of state-of-the-art micro-fabrication processes on the performance of pillar array columns for liquid chromatography. AB - We report on the practical limitations of the current state-of-the-art in micro fabrication technology to produce the small pillar sizes that are needed to obtain high efficiency pillar array columns. For this purpose, nine channels with a different pillar diameter, ranging from 5 to 0.5 MUm were fabricated using state-of the-art deep-UV lithography and deep reactive ion etching (DRIE) etching technology. The obtained results strongly deviated from the theoretically expected trend, wherein the minimal plate height (H(min)) would reduce linearly with the pillar diameter. The minimal plate height decreases from 1.7 to 1.2 MUm when going from 4.80 to 3.81 MUm diameter pillars, but as the dimensions are further reduced, the minimal plate heights rise again to values around 2 MUm. The smallest pillar diameter even produced the worst minimal plate height (4 MUm). An in-depth scanning electron microscopy (SEM) inspection of the different channels clearly reveals that these findings can be attributed to the micro-fabrication limitations that are inevitably encountered when exploring the limits of deep-UV lithography and DRIE etching processes. When the target dimensions of the design approach the etching resolution limits, the band broadening increases in a strongly non-linear way with the decreased pillar dimensions. This highly non linear relationship can be understood from first principles: when the machining error is of the order of 100-200 nm and when the target design size for the inter pillar distance is of the order of 250 nm, this inevitably leads to pores that will range in size between 50 and 450 nm that we want to highlight with our paper highly non-linear relationship. This highly non-linear relationship can be understood from first principles: when the machining error is of the order of 100 200 nm and when the target design size for the inter-pillar distance is of the order of 250 nm, this inevitably leads to pores that will range in size between 50 and 450 nm. PMID- 22513132 TI - Interaction between smoking and functional polymorphism in the TGFB1 gene is associated with ischaemic heart disease and myocardial infarction in patients with rheumatoid arthritis: a cross-sectional study. AB - INTRODUCTION: Transforming growth factor-beta1 (TGF-beta1) is a pleiotropic cytokine that plays important roles in immunity and inflammation. Some studies have suggested that polymorphism in the TGFB1 gene is associated with heart disease in the general population. The purpose of the present study was to determine whether common single-nucleotide polymorphisms (SNP) in the TGFB1 gene are associated with ischaemic heart disease (IHD) and/or myocardial infarction (MI) in patients with rheumatoid arthritis (RA), and to investigate the influence of smoking on any association. METHODS: PCR-based assays were used to determine the genotypes of TGFB1 SNPs including TGFB1-509 C/T (rs1800469, in the promoter region), +868 T/C (rs1800470, in exon 1) and +913 G/C (rs1800471, in exon 1) in 414 subjects with established RA. Genotyping for the +868 SNP was also carried out on a second study population of RA patients (n = 259) with early disease. Serum levels of TGF-beta1 were measured using a commercial ELISA kit. Smoking history and IHD/MI status were obtained on each patient. Associations with IHD/MI were assessed using contingency tables and logistic regression analyses. RESULTS: The heterozygous genotype of TGFB+868 was associated with an increased risk of IHD (OR 2.14, 95% CI 1.30 - 3.55) and MI (OR 2.42, 95% CI 1.30-4.50), compared to the homozygous genotypes combined. Smoking was an independent risk for IHD and MI, and evidence of interaction between smoking and TGFB+868 was found. Multivariate analyses indicated that the strongest associations with IHD and MI were due to the combined effect of the TGFB1+868 TC genotype and smoking (OR 2.75, 95% CI 1.59-4.75; and OR 2.58 95% CI 1.33-4.99, respectively), independent of other cardiovascular risk factors. The association of the +868 TC genotype and evidence of +868 TC-smoking interaction with IHD were replicated in a second population of RA patients with early disease. Serum TGF-beta1 levels were not associated with TGFB1 genetic variations, smoking or IHD/MI status. CONCLUSIONS: Interaction between smoking and polymorphism in the TGFB1 gene may influence the risk of IHD and MI in patients with RA. PMID- 22513133 TI - Amish children living in northern Indiana have a very low prevalence of allergic sensitization. PMID- 22513134 TI - Synthesis and evaluation of D-gluconamides as green mineral scales. AB - A series of 13 D-gluconamides were synthesized in moderate to good yields and evaluated as green scale inhibitors. The crystal structures of two compounds were determined by X-ray crystallography. The compounds 6c and 6d showed a reasonable inhibition of BaSO(4) precipitation from aqueous solution (47% and 51%, respectively) that indicated the potential for these derivatives of delta gluconolactone. PMID- 22513135 TI - I(2)-mediated carbamate annulation: scope and application in the synthesis of azasugars. AB - The I(2)-mediated carbamate annulation provides an efficient and highly stereoselective route for the synthesis of a variety of pyrrolidines and piperidines, both in the presence and absence of protecting groups. Evidence for the formation of an iodoamine intermediate during the annulation is provided and, for the first time, we explore possible mechanisms of the annulation. The high cis-selectivity of the carbamate annulation is also compared to other N halocyclisations and aminomercurations and some general conclusions about the diastereoselectivity of these types of reactions are made. PMID- 22513136 TI - MRI to X-ray mammography registration using a volume-preserving affine transformation. AB - X-ray mammography is routinely used in national screening programmes and as a clinical diagnostic tool. Magnetic Resonance Imaging (MRI) is commonly used as a complementary modality, providing functional information about the breast and a 3D image that can overcome ambiguities caused by the superimposition of fibro glandular structures associated with X-ray imaging. Relating findings between these modalities is a challenging task however, due to the different imaging processes involved and the large deformation that the breast undergoes. In this work we present a registration method to determine spatial correspondence between pairs of MR and X-ray images of the breast, that is targeted for clinical use. We propose a generic registration framework which incorporates a volume-preserving affine transformation model and validate its performance using routinely acquired clinical data. Experiments on simulated mammograms from 8 volunteers produced a mean registration error of 3.8+/-1.6mm for a mean of 12 manually identified landmarks per volume. When validated using 57 lesions identified on routine clinical CC and MLO mammograms (n=113 registration tasks) from 49 subjects the median registration error was 13.1mm. When applied to the registration of an MR image to CC and MLO mammograms of a patient with a localisation clip, the mean error was 8.9mm. The results indicate that an intensity based registration algorithm, using a relatively simple transformation model, can provide radiologists with a clinically useful tool for breast cancer diagnosis. PMID- 22513138 TI - Characterization of the first alginolytic operons in a marine bacterium: from their emergence in marine Flavobacteriia to their independent transfers to marine Proteobacteria and human gut Bacteroides. AB - Alginate constitutes a significant part of seaweed biomass and thus a crucial nutrient for numerous marine heterotrophic bacteria. However, the mechanisms for alginate assimilation remain largely unknown in marine microorganisms. We show here that the genome of the marine flavobacterium Zobellia galactanivorans contains seven putative alginate lyase genes, five of them localized within two clusters comprising additional carbohydrate-related genes. The transcription of these genes and the alginolytic activity were strongly induced when Z. galactanivorans used alginate as sole carbon source. These clusters were shown to be transcribed as polycistronic mRNAs and thus to constitute operons. Several candidate enzymes were successfully overexpressed in Escherichia coli, purified and their activity tested. Particularly, AlyA1, AlyA4, AlyA5 and AlyA7 are confirmed as active alginate lyases. Zg2622 and Zg2614 are a dehydrogenase and a kinase, respectively, further converting the terminal unsaturated monosaccharides released by alginate lyases into 2-keto-3-deoxy-6-phosphogluconate. In-depth phylogenomic analyses reveal that such alginolytic operons originated from an ancestral marine flavobacterium and were independently transferred to marine proteobacteria and Japanese gut Bacteroides. These bacteria thus gained the capacity to assimilate the main polysaccharide of brown algae, an adaptive advantage in coastal environments but also in the gut microbiota of specific human population. PMID- 22513137 TI - The follicle-stimulating hormone receptor: a novel target in genitourinary malignancies. AB - Follicle-stimulating hormone (FSH) is a central hormone in mammalian reproductive biology. The FSH receptor (FSHR), which was previously believed to be expressed primarily in the ovary and testis, was recently found to be expressed in the tumor blood vessels of many solid tumor types, including prostate adenocarcinoma, urothelial carcinoma, and renal cell carcinoma. While the biologic significance of FSHR in tumor blood vessels has yet to be elucidated, FSHR may contribute to neoangiogenesis. FSHR has been reported to be expressed by prostate cancer cells and, thus, targeting FSHR in prostate cancer may be of particular utility. In this report, we discuss the finding of FSHR in tumor blood vessels and review the literature concerning FSHR in genitourinary malignancy. We also discuss the features that make FSHR an appealing target for therapeutic and imaging purposes and the potential utility of FSHR as a prognostic and/or predictive biomarker in genitourinary cancers. PMID- 22513139 TI - Patient education programs for childhood atopic dermatitis: who is interested? AB - BACKGROUND: Atopic dermatitis (AD) is a skin disease which causes psychological distress to patients and their families. Patient education programs for childhood AD have positive effects on the severity of the skin disease as well as on psychological variables. So far it has not been determined whether particular patient characteristics lead to being interested in patient education programs. The aim of this cross-sectional study was to identify exploratory predictors of being interested in patient education programs in parents of children with atopic dermatitis. PATIENTS AND METHODS: A severity index (SCORAD) as well as questionnaire data were collected from 73 parents of children with AD to measure satisfaction with medical care, quality of life, coping strategies, and the subjective benefit of former treatments as possible predictors. RESULTS: A regression analysis revealed that besides dissatisfaction with medical care, low social support and high active problem-solving behavior were significant predictors of interest in patient education programs (R(2) = 0.244). CONCLUSIONS: Our study gives a preliminary indication that participation in a patient education program for childhood AD should be offered to parents without sufficient social support, but who would like to gather more information on coping with AD. This could also enhance satisfaction with the medical care provided. PMID- 22513141 TI - Answer to Wang and Luo, "Polyploidization increases meiotic recombination frequency in Arabidopsis: a close look at statistical modelling and data analysis". PMID- 22513140 TI - Increased glial glutamate transporter EAAT2 expression reduces epileptogenic processes following pilocarpine-induced status epilepticus. AB - Several lines of evidence indicate that glutamate plays a crucial role in the initiation of seizures and their propagation; abnormal glutamate release causes synchronous firing of large populations of neurons, leading to seizures. In the present study, we investigated whether enhanced glutamate uptake by increased glial glutamate transporter EAAT2, the major glutamate transporter, could prevent seizure activity and reduce epileptogenic processes. EAAT2 transgenic mice, which have a 1.5-2 fold increase in EAAT2 protein levels as compared to their non transgenic counterparts, were tested in a pilocarpine-induced status epilepticus (SE) model. Several striking phenomena were observed in EAAT2 transgenic mice compared with their non-transgenic littermates. First, the post-SE mortality rate and chronic seizure frequency were significantly decreased. Second, neuronal degeneration in hippocampal subfields after SE were significantly reduced. Third, the SE-induced neurogenesis and mossy fiber sprouting were significantly decreased. The severity of cell loss in epileptic mice was positively correlated with that of mossy fiber sprouting and chronic seizure frequency. Our results suggest that increased EAAT2 expression can protect mice against SE-induced death, neuropathological changes, and chronic seizure development. This study suggests that enhancing EAAT2 protein expression is a potential therapeutic approach. PMID- 22513142 TI - Age-related inducibility of carboxylesterases by the antiepileptic agent phenobarbital and implications in drug metabolism and lipid accumulation. AB - Carboxylesterases (CES) constitute a class of hydrolytic enzymes that play critical roles in drug metabolism and lipid mobilization. Previous studies with a large number of human liver samples have suggested that the inducibility of carboxylesterases is inversely related with age. To directly test this possibility, neonatal (10 days of age) and adult mice were treated with the antiepileptic agent phenobarbital. The expression and hydrolytic activity were determined on six major carboxylesterases including ces1d, the ortholog of human CES1. Without exception, all carboxylesterases tested were induced to a greater extent in neonatal than adult mice. The induction was detected at mRNA, protein and catalytic levels. Ces1d was greatly induced and found to rapidly hydrolyze the antiplatelet agent clopidogrel and support the accumulation of neutral lipids. Phenobarbital represents a large number of therapeutic agents that induce drug metabolizing enzymes and transporters in a species-conserved manner. The higher inducibility of carboxylesterases in the developmental age likely represents a general phenomenon cross species including human. Consequently, individuals in the developmental age may experience greater drug-drug interactions. The greater induction of ces1d also provides a molecular explanation to the clinical observation that children on antiepileptic drugs increase plasma lipids. PMID- 22513144 TI - Adult-onset Still's disease in a patient with cystic fibrosis and its successful treatment with anakinra. PMID- 22513143 TI - Role of human CYP3A4 in the biotransformation of sorafenib to its major oxidized metabolites. AB - The tyrosine kinase inhibitor drug sorafenib is used in the treatment of liver and renal cancers but adverse effects may necessitate dose interruption and under dosage may lead to therapeutic failure. Sorafenib also undergoes cytochrome P450 (CYP)-dependent biotransformation to the N-oxide and other metabolites. However, although CYPs are major determinants of efficacy and toxicity the roles of these enzymes in the formation of multiple sorafenib metabolites are unclear. In the present study CYP-mediated pathways of sorafenib oxidation in human liver were evaluated. cDNA-expressed CYP3A4 was the major catalyst in the formation of the principal N-oxide and N-hydroxymethyl metabolites of sorafenib, as well as the minor N-desmethyl metabolite. In contrast, CYP3A5 exhibited only ~5% of the activity of CYP3A4 and eleven other CYPs and three flavin-containing monooxygenases were inactive. In human hepatic microsomes metabolite formation was correlated with CYP3A4-mediated midazolam 1'-hydroxylation, but not with other CYP-specific substrate oxidations. In accord with these findings the CYP3A4 inhibitor ketoconazole selectively inhibited microsomal sorafenib oxidation pathways. From computational modeling studies atoms in the structure of sorafenib that undergo biotransformation were within ~5.4 A of the CYP3A4 heme. Important hydrogen bonding interactions between sorafenib and amino acids Ser-119 and Glu 374 in the active center of CYP3A4 were identified. These findings indicate that sorafenib is oxidized selectively by human CYP3A4. This information could be adapted in individualized approaches to optimize sorafenib safety and efficacy in cancer patients. PMID- 22513146 TI - Optimal use of non-biologic therapy in the treatment of rheumatoid arthritis. AB - With the evolution of therapies for RA, new treatment strategies and goals of therapy have evolved. Recent European League Against Rheumatism (EULAR) guidelines on the treatment of RA proposed three phases of therapy: phase I comprising first-line synthetic DMARD with or without glucocorticoid; phase II comprising second-line synthetic DMARD with or without glucocorticoid, or combination synthetic DMARD therapy, or (if prognostic factors are poor) first line biologic DMARD; and phase III comprising alternative biologic DMARDs. In all phases, the key principle is tight control: striving to achieve a predefined goal of remission or low disease activity (treat to target) with frequent dose and medication adjustments tailored to the individual patient, preferably within the window of opportunity during early RA. In all phases, MTX is recognized as an anchor drug; it is characterized by proven efficacy in combination DMARD strategies, relatively low cost, relatively rapid onset of action, proven beneficial impact on radiological progression and mortality and a wide dose range that facilitates dose adjustments. Prednisone and its active metabolite, prednisolone, have similar characteristics, making them ideal anchor drugs too. The EULAR guidelines reserve a place for MTX and glucocorticoids in all phases of treatment. The second CAMERA (Computer Assisted Management in Early Rheumatoid Arthritis) study in early RA has demonstrated that including prednisone from the start in an MTX-based tight control strategy aimed at remission improves disease activity variables, time to remission, functional disability and radiological joint damage compared with the same strategy without prednisone. In conclusion, both MTX and prednisone play key roles in modern RA treatment strategies. PMID- 22513145 TI - The assessment of biologic treatment in patients with rheumatoid arthritis using FDG-PET/CT. AB - OBJECTIVES: To evaluate whether there is a correlation between the differences in joint uptake of 2-[18F]-fluoro-2-deoxy-d-glucose ((18)F-FDG) and the improvement of clinical findings in RA patients undergoing anti-TNF therapies. METHODS: Twenty-two patients who received anti-TNF therapies, including infliximab for 16 patients and etanercept for 6 patients, were assessed. PET with (18)F-FDG studies and clinical assessments were performed at baseline and 6 months after the initiation of therapy. The maximal standardized uptake value (SUV(max)) was used as a representative value for the assessment of the FDG uptake in the bilateral shoulder, elbow, wrist, hip, knee and ankle joints. Spearman's rank correlation test was applied to assess the correlation between the SUV and the clinical parameters. RESULTS: The DeltaSUV (12 joints), the difference in the SUV(max) of the affected 12 joints before and after treatment, was positively correlated with the DeltaDAS28 (r = 0.609, P = 0.003), DeltaDAS28-CRP (r = 0.656, P = 0.001) and Deltatender joint count (TJC) (r = 0.609, P = 0.003). There were also significantly positive correlations between DeltaSUV (8 joints); the difference in the SUV(max) of the bilateral shoulder, elbow, wrist and knee joints before and after treatment and the DeltaDAS28 (r = 0.642, P = 0.001), DeltaDAS28-CRP (r = 0.712, P < 0.001) and DeltaTJC (r = 0.608, P = 0.003), respectively. CONCLUSION: The FDG uptake observed in the inflamed RA joints may reflect disease activity. The FDG-PET response was correlated with the clinical response to the biologic treatment of RA. PMID- 22513147 TI - CD4+CD25+ regulatory T cells from MRL/lpr mice were functionally more active in vitro but did not prevent spontaneous as well as adriamycin-induced nephropathy in vivo. AB - OBJECTIVE: The frequency and function of Tregs are important in the pathogenesis of SLE. Nonetheless, the function of Tregs is still controversial in SLE patients and lupus mouse models. In the present study, we investigated the suppressive function of Tregs from MRL/lpr mice in vitro and in vivo by using an alternative quantitative assay. METHODS: We assessed the suppressive function of CD4(+)CD25(+) Tregs, the proliferative activity of CD4(+)CD25(-) effector T cells (Teffs) and the feeder activity of CD11c(+) dendritic cells (DCs), isolated from the spleens of MRL/lpr mice and wild-type (WT) MRL/+ mice, by carboxyfluorescein diacetate succinimidyl ester dilution assay stimulated with two distinct types of signals, weak and strong. In order to assess the protective function of Tregs from an immune-mediated disease in vivo, we induced renal damage by injecting adriamycin (ADN) into the mice. RESULTS: The in vitro assay showed enhanced suppressive activity of Tregs and feeder activity of DCs, but far less proliferative activity of Teffs from MRL/lpr mice, compared with those from the WT mice. The in vivo study showed more severe ADN-induced nephropathy in MRL/lpr mice than in the WT mice, while mild interstitial nephritis had already begun spontaneously by 16 weeks in MRL/lpr mice. CONCLUSION: It was suggested that Tregs from MRL/lpr mice were functionally competent and intrinsically more active in vitro, but they were not capable of preventing the ADN-induced as well as the spontaneously developing nephropathy in vivo. PMID- 22513148 TI - First update of the current evidence for the management of ankylosing spondylitis with non-pharmacological treatment and non-biologic drugs: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis. AB - OBJECTIVE: To perform a systematic literature review as a basis for the update of the Assessment in SpondyloArthritis International Society and European League Against Reumatism (ASAS/EULAR) recommendations for the management of AS with non pharmacological interventions and non-biologic drugs. METHODS: The search was performed in PubMed, EMBASE, PEDro and Cochrane between 1 January 2005 and 1 December 2009, and in abstracts of EULAR and ACR meetings (2007-09). Effect sizes for outcomes on pain, disease activity, spinal mobility and physical function and level of evidence were presented. RESULTS: Of 2383 papers, 35 with complete data were included. Physical therapy exercises in various modalities have positive effects on BASFI, BASDAI, pain and mobility function. Various NSAIDs including coxibs improve BASDAI, disease activity and BASFI. No effect of SSZ and MTX on any variable was found. Surgical interventions of the spine and the hip can give excellent results by restoring function. CONCLUSION: This concise summary of current evidence for non-pharmacological interventions and non-biologic drugs formed the basis for the update of the ASAS/EULAR recommendations for the management of AS. PMID- 22513149 TI - Sweet syndrome revealing microscopic polyangiitis. PMID- 22513150 TI - Tocilizumab for treating refractory haemolytic anaemia in a patient with systemic lupus erythematosus. PMID- 22513151 TI - Childrens' and parents' beliefs about childhood onset scleroderma are influenced by child age and physical function impairment. PMID- 22513152 TI - The link between HLA-B27 and SpA--new ideas on an old problem. AB - The strong association of the HLA-B27 with AS was first discovered independently by groups in London and California in 1972 and has recently been confirmed beyond reasonable doubt by fine mapping in the latest and most sophisticated genome-wide association study (GWAS) published this July. Yet, despite nearly four decades of extensive research, the exact role that HLA-B27 plays in pathogenesis remains unknown. However, we believe that recent developments in three fields have allowed us to view this conundrum in a new light and to propose coherent theories of disease pathogenesis. These areas are as follows: (i) GWASs, (ii) studies of B27 biology and (iii) lessons from biologic therapies. In this review we will discuss these recent advances before discussing the current models of AS pathogenesis under investigation. PMID- 22513153 TI - Radiological cervical spine involvement in young adults with polyarticular juvenile idiopathic arthritis. AB - OBJECTIVES: Radiological cervical spine involvement in JIA has already been assessed with a large range of prevalence (5-80%), but most studies were performed a long time ago, in symptomatic JIA and without differentiating subsets of JIA. We set out to describe structural cervical spine involvement in young adults with polyarticular JIA (pJIA) regardless of the cervical symptoms and to compare lesions with those observed in adult RA. METHODS: All consecutive pJIAs followed in a transition programme were included. Standard radiographs of the cervical spine, hands, feet and hip were analysed by two independent radiologists blinded to the diagnosis. An RA control group (<55 years), matched for sex and disease duration, was recruited. RESULTS: Fifty-seven pJIA and 58 RA patients were included. Radiographs showed cervical lesions in 65% of pJIA and 67% of RA patients. In total, 51% of pJIA with radiographic abnormalities had no clinical symptoms. In pJIA, the most frequent structural lesions were anterior atlantoaxial subluxation (33%), erosion of the odontoid process (19%), C1-C2 arthritis (17%) and apophyseal joint arthritis (16%). Cervical lesions in pJIA were similar to those in RA except for ankylosis and hypotrophia (P < 0.05). The presence of cervical lesions correlated with a more severe disease. CONCLUSION: Structural cervical spine involvement is common in pJIA persisting into adulthood, frequently asymptomatic and associated with a more severe disease. We suggest that radiographic assessment of the cervical spine should be done systematically at onset of the disease and regularly during its course regardless of clinical symptoms. PMID- 22513154 TI - Using e-learning to enhance nursing students' pain management education. AB - CONTEXT: Absence of standardised pain curricula has led to wide diversity in the understanding and awareness of pain by healthcare students. Indeed pain management is frequently under-prioritised in nursing education, providing potential to negatively impact upon patient care. Yet the recent addition of Pain to the UK National Health Service's Essence of Care Benchmarks has highlighted the need to address this issue, and in response pain educators have called for the development of high quality, globally accessible e-learning resources in pain management. OBJECTIVES: This study will determine the effectiveness of an e learning intervention on pain management developed for nursing students. METHODS: Two variants of an e-learning resource on pain management were developed, each containing the same core content but one with a section focusing on pain assessment and the other on pharmacological management. Nursing students (n=42) were randomly assigned to trial one resource, after which they undertook a questionnaire adapted (to ensure alignment with the content of the e-learning resources) from Ferrell and McCaffrey's Nurses Knowledge and Attitudes Towards Pain Survey. Scores were analysed for each resource and year of study, and compared with scores from a standard non-intervention group completing the questionnaire only (n=164). RESULTS: Scores averaged 19.2% higher for students undertaking the e-learning resources (p<0.005). Specifically, undertaking the assessment resource improved assessment knowledge more, whilst assignment to the treatment resource particularly enhanced pharmacological knowledge (p<0.005). Correlation was found between year of study and pain knowledge. CONCLUSION: Results support the effectiveness of the resources independent of voluntary response bias. Conclusions recommend that introducing e-learning has substantial benefit to enhance pain education in nursing. PMID- 22513155 TI - Assessment of goals in problem-based learning. AB - Assessing the learning goals set by faculty is an important part of problem-based learning (PBL). Students also develop individual and group goals during module tutorials. They choose learning activities and create a framework for their self directed study in order to achieve these goals. This investigation analyzes perceptions of the depth of understanding that students acquire. The effects of setting learning goals by faculty and by students themselves are examined, and we explore differences within groups and within the different years in the program. Nursing students responded to a questionnaire indicating how well they thought they had understood new material, according to both the goals preset by the faculty and those developed by the students themselves. A five-point Likert scale was used for this. The findings indicate no significant difference between tutors' and students' evaluations of student level of understanding within the different years of the program. Students and tutors in all three years indicated that they achieved adequate or good understanding of learning goals. (Students: First year: 91.6%, second year: 76.5%, third year: 90.1%; Tutors: First year: 76.8%, second year: 65.7%, third year: 89.1%) These findings are useful for evaluation of PBL outcomes for curriculum committees. Based on these research results, our faculty curriculum committee has decided to give the students a list of faculty generated learning goals at the end of every curriculum module. The students then compare these with their own self-directed goals in feedback sessions with faculty members. These feedback sessions have been very popular with students. PMID- 22513156 TI - A theoretically informed education program designed specifically for acute surgical nurses. AB - AIM: The aim of the research was to evaluate the effectiveness of implementing the Respiratory Skills Update (ReSKU) education program using integrated teaching and learning strategies, in the context of organisational utility, on improving surgical nurses' practice in the area of respiratory assessment. BACKGROUND: Technological advances and changes in healthcare delivery have necessitated that nurse educators adopt innovative teaching and learning strategies to better prepare acute care nurses for their increasingly complex roles. This 2007 study used a robust overarching theoretical framework to develop and evaluate an educational model using the ReSKU program as a basis for the content. METHODS: The study was conducted in a 400 bed regional referral public hospital, in Australia. The research was guided by the work of Forneris (2004) to operationalise a critical thinking process incorporating the complexities of the clinical context. The theoretical framework used multi-modal, interactive educational strategies that were learner-centred and participatory. These strategies aimed to engage the clinician in dynamic thinking processes in clinical practice situations guided by coaches and educators. CONCLUSION: The construct of critical thinking in practice combined with clinical reasoning and purposeful and collective reflection is a powerful educational strategy to enhance competency and capability in clinicians. PMID- 22513157 TI - Reclaiming craftsmanship in nursing. PMID- 22513159 TI - Investigations into the landfill behaviour of pretreated wastes. AB - Mechanical-biological treatment of municipal solid waste has become popular throughout the UK and other parts of Europe to enable compliance with the Landfill Directive. Pretreatment will have a major influence on the degradation and settlement characteristics of the waste in landfills owing to the changes in the composition and properties of the wastes. This paper presents and compares the results of long term landfill behaviour of the UK and German MBT wastes pretreated to different standards. The gas generating potential, leachate quality and settlement characteristics are highlighted. The results reveal that it is possible to achieve stabilisation of MBT waste within a year and the biogas yield and leachate strength of German MBT waste was significantly reduced compared with the UK MBT waste. The settlement resulting from mechanical creep is more significant than the biodegradation induced settlement in both cases. PMID- 22513163 TI - Thiazolidinediones and PPARgamma agonists: time for a reassessment. AB - Thiazolidinediones (TZDs) are anti-diabetic drugs that act as insulin sensitizers and are used in the management of type 2 diabetes mellitus. TZDs, which are ligands for the transcription factor peroxisome proliferator-activated receptor PPARgamma, have a wide spectrum of action, including modulation of glucose and lipid homeostasis, inflammation, atherosclerosis, bone remodeling and cell proliferation. Randomized clinical trials have demonstrated the efficacy and durability of the anti-hyperglycemic action of TZDs, and have suggested that the TZD pioglitazone also exerts cardioprotective action. However, the clinical use of TZDs is limited by the occurrence of several adverse events, including body weight gain, congestive heart failure, bone fractures and possibly bladder cancer. Therefore, there is an unmet need for the development of new safer PPARgamma-modulating drugs. PMID- 22513164 TI - Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome: is PTPN22 involved? PMID- 22513165 TI - Changes in stigma and discrimination of onchocerciasis in Africa. AB - Forms of onchocerciasis-related stigmatisation, following over 10 years of implementation of community directed treatment with ivermectin (CDTI), were documented through a survey conducted between September and November 2009 to look at perceived changes in stigma over the past 7-10 years. We documented people's perceptions towards stigma before and after the introduction of CDTI from 1600 structured interviews with households selected from the community treatment registers; in-depth interviews with 57 community leaders, community directed distributors and health personnel; 33 focus group discussions with male and female community members in different age groups (18-24, 25-54 and >=55 years) and 13 case studies. People with onchocercal skin disease (OSD) with rough skin, swellings and rashes were the most stigmatised. People still fear sexual intimacy with infected persons. In the past, people with OSD were considered unclean and stigmatised because of fear of OSD transmission and embarrassment. People who had lived in the community less than 5 years tended to stigmatise OSD patients more than those people who had lived in the community for longer than 5 years. The youth stigmatised the most. Although stigmatisation persists, avoidance of people with OSD decreased from 32.7% to 4.3%. It is notable that treatment availability has improved relationships between healthy people and those with OSD symptoms in endemic communities and this can be attributed to CDTI. Health education should be emphasised in the communities during distribution. PMID- 22513162 TI - Artemisinin-based combination therapy does not measurably reduce human infectiousness to vectors in a setting of intense malaria transmission. AB - BACKGROUND: Artemisinin-based combination therapy (ACT) for treating malaria has activity against immature gametocytes. In theory, this property may complement the effect of terminating otherwise lengthy malaria infections and reducing the parasite reservoir in the human population that can infect vector mosquitoes. However, this has never been verified at a population level in a setting with intense transmission, where chronically infectious asymptomatic carriers are common and cured patients are rapidly and repeatedly re-infected. METHODS: From 2001 to 2004, malaria vector densities were monitored using light traps in three Tanzanian districts. Mosquitoes were dissected to determine parous and oocyst rates. Plasmodium falciparum sporozoite rates were determined by ELISA. Sulphadoxine-pyrimethamine (SP) monotherapy was used for treatment of uncomplicated malaria in the contiguous districts of Kilombero and Ulanga throughout this period. In Rufiji district, the standard drug was changed to artesunate co-administered with SP (AS + SP) in March 2003. The effects of this change in case management on malaria parasite infection in the vectors were analysed. RESULTS: Plasmodium falciparum entomological inoculation rates exceeded 300 infective bites per person per year at both sites over the whole period. The introduction of AS + SP in Rufiji was associated with increased oocyst prevalence (OR [95%CI] = 3.9 [2.9-5.3], p < 0.001), but had no consistent effect on sporozoite prevalence (OR [95%CI] = 0.9 [0.7-1.2], p = 0.5). The estimated infectiousness of the human population in Rufiji was very low prior to the change in drug policy. Emergence rates and parous rates of the vectors varied substantially throughout the study period, which affected estimates of infectiousness. The latter consequently cannot be explained by the change in drug policy. CONCLUSIONS: In high perennial transmission settings, only a small proportion of infections in humans are symptomatic or treated, so case management with ACT may have little impact on overall infectiousness of the human population. Variations in infection levels in vectors largely depend on the age distribution of the mosquito population. Benefits of ACT in suppressing transmission are more likely to be evident where transmission is already low or effective vector control is widely implemented. PMID- 22513166 TI - Surface properties, aggregation behavior and micellization thermodynamics of a class of gemini surfactants with ethyl ammonium headgroups. AB - Cationic gemini surfactant homologues alkanediyl-alpha,omega bis(dodecyldiethylammonium bromide), [C(12)H(25)(CH(3)CH(2))(2)N(CH(2))(S)N(CH(2)CH(3))(2)C(12)H(25)]Br(2) (where S=2, 4, 6, 8, 10, 12, 16, 20), referred to as C(12)C(S)C(12)(Et) were synthesized systematically. This paper focused on various properties of the above gemini surfactants in order to give a full understanding of this series of surfactants. The following points are covered: (1) surface properties, which include (i) effect of the spacer carbon number on the general properties and (ii) the effect of added NaBr on the general surface properties; (2) aggregation behavior in bulk solution, including (i) morphologies of above gemini surfactants classed as having short spacers, middle-length spacers and long spacers and (ii) superior vesicle stability against high NaBr concentration for the long spacer gemini surfactants; (3) thermodynamic properties during micellization and the effect of spacer carbon number on them; and (4) perspectives for the further use and application of these compounds. PMID- 22513167 TI - Adsorption of roxarsone from aqueous solution by multi-walled carbon nanotubes. AB - Roxarsone, an organoarsenic compound serving as a common feeding additive in poultry industry, brings about potential risk of the toxic inorganic arsenate contamination in ambient environment. Current understanding in the dynamics of roxarsone removal and the determining environmental processes remains unclear, thus restricts the progress in roxarsone-contaminated wastewater treatment. In this study, the adsorption of roxarsone on multi-walled carbon nanotubes (MWCNTs) was investigated. The adsorption of roxarsone on MWCNTs decreased dramatically with increasing pH from 2.0 to 11.7 and decreased significantly with increasing ionic strength from 0 to 1.0 mol/L KCl. It was found that the sorption isotherms of roxarsone on MWCNTs were nonlinear, which can be well described according to the Freundlich and Polanyi-Manes models. Thermodynamic analysis indicates that the adsorption of roxarsone on MWCNTs is an exothermic and spontaneous process. Sorption site energy analysis reveals a distribution of sorption energy and the heterogeneous adsorption sites of roxarsone on MWCNTs. The dynamic adsorption with column shows the potential of the practical application for the roxarsone contaminated wastewater treatment by MWCNTs. The FTIR analysis indicates that EDA interaction and electrostatic repulsion might be the dominant mechanisms for the adsorption of roxarsone on MWCNTs. PMID- 22513168 TI - In situ synthesis, characterization, and catalytic performance of tungstophosphoric acid encapsulated into the framework of mesoporous silica pillared clay. AB - Mesoporous silica pillared clay (SPC) incorporated with tungstophosphoric acid (HPW) has been synthesized via in situ introducing P and W source in the acidic suspension of the clay interlayer template during the formation of the silica pillared clay. The samples were characterized by XRD, XRF, FT-IR, TG-DTA, N(2) adsorption-desorption, and SEM techniques. The results showed that the HPW formed by in situ method has been effectively introduced into the framework of mesoporous silica pillared clay and its Keggin structure remained perfectly after formation of the materials. In addition, samples with similar HPW loadings were also prepared by impregnation method using SPC as the support. HPW in the incorporated samples was better dispersed into the silica pillared clay than in the impregnated samples. The results of catalytic tests indicated that the encapsulated materials demonstrated better catalytic performance than the impregnated samples in oxidative desulfurization (ODS) of dibenzothiophene (DBT). PMID- 22513169 TI - Effect of poly(ethylene oxide)-silane graft molecular weight on the colloidal properties of iron oxide nanoparticles for biomedical applications. AB - The size, charge, and stability of colloidal suspensions of magnetic nanoparticles with narrow size distribution and grafted with poly(ethylene glycol)-silane of different molecular weights were studied in water, biological buffers, and cell culture media. X-ray photoelectron spectroscopy provided information on the chemical nature of the nanoparticle surface, indicating the particle surfaces consisted of a mixture of amine groups and grafted polymer. The results indicate that the exposure of the amine groups on the surface decreased as the molecular weight of the polymer increased. The hydrodynamic diameters correlated with PEG graft molecular weight and were in agreement with a distributed density model for the thickness of a polymer shell end-grafted to a particle core. This indicates that the particles obtained consist of single iron oxide cores coated with a polymer brush. Particle surface charge and hydrodynamic diameter were measured as a function of pH, ionic strength, and in biological buffers and cell culture media. DLVO theory was used to analyze the particle stability considering electrostatic, magnetic, steric, and van der Waals interactions. Experimental results and colloidal stability theory indicated that stability changes from electrostatically mediated for a graft molecular weight of 750 g/mol to sterically mediated at molecular weights of 1000 g/mol and above. These results indicate that a graft molecular weight above 1000 g/mol is needed to produce particles that are stable in a wide range of pH and ionic strength, and in cell culture media. PMID- 22513170 TI - Novel zinc(II) and copper(II) complexes of a Mannich base derived from lawsone: Synthesis, single crystal X-ray analysis, ab initio density functional theory calculations and vibrational analysis. AB - Zinc(II) and copper(II) complexes of a tridentate Mannich base L1 derived from 2 hydroxy-1,4-naphthoquinone, pyridinecarboxyaldehyde and 2-aminomethylpyridine, [ZnL1Cl(2)].H(2)O 1 and [CuL1Cl(2)].2H(2)O 2, have been synthesized and fully characterized. The structure of complex 1 has been elucidated by a single crystal X-ray diffraction study: the zinc atom is pentacoordinate and the coordination geometry is a distorted square base pyramid, with a geometric structural parameter tau equal to 0.149. Vibrational spectroscopy and ab initio DFT calculations of both compounds have confirmed that the two complexes exhibit similar structures. Full assignment of the vibrational spectra was also supported by careful analysis of the distorted geometries generated by the normal modes. PMID- 22513171 TI - Synthesis and characterization of new chromium, molybdenum and tungsten complexes of 2-[2-(methylaminoethyl)] pyridine. AB - A green chemistry route of synthesis using direct sunlight irradiation for the reactions of [M(CO)(6)] M=Cr, Mo or W with 2-[2-(methylaminoethyl)] pyridine (maepy) in THF. The reactions resulted in the formation of the oxo complex [Cr(2)(O)(4)(maepy)(2)] (1) and the tetracarbonyl complexes [Mo(CO)(4)(maepy)] (2) and [W(CO)(4)(maepy)] (3). The prepared complexes were characterized by elemental analysis, IR, NMR, mass spectrometry and magnetic measurement. The complexes (1-3) were further investigated by thermogravimetric technique (TG). The biological activity of maepy and complexes as antibacterial and antifungal reagents have been investigated. PMID- 22513172 TI - Angina bullosa haemorrhagica. PMID- 22513173 TI - Explaining brain size variation: from social to cultural brain. AB - Although the social brain hypothesis has found near-universal acceptance as the best explanation for the evolution of extensive variation in brain size among mammals, it faces two problems. First, it cannot account for grade shifts, where species or complete lineages have a very different brain size than expected based on their social organization. Second, it cannot account for the observation that species with high socio-cognitive abilities also excel in general cognition. These problems may be related. For birds and mammals, we propose to integrate the social brain hypothesis into a broader framework we call cultural intelligence, which stresses the importance of the high costs of brain tissue, general behavioral flexibility and the role of social learning in acquiring cognitive skills. PMID- 22513174 TI - Bone morphogenetic protein-2-induced Wnt/beta-catenin signaling pathway activation through enhanced low-density-lipoprotein receptor-related protein 5 catabolic activity contributes to hypertrophy in osteoarthritic chondrocytes. AB - INTRODUCTION: Events normally taking place in the terminal chondrocyte differentiation in the growth plate are also observed during osteoarthritis (OA) development, suggesting that molecules, such as Wnts and bone morphogenetic proteins (BMPs) regulating chondrocyte activity in the growth plate, may play a key role in osteoarthritis pathogenesis. The aim of the study was to investigate the possible cross-talk between BMP-2 and Wnt/beta-catenin pathways in OA progression. METHODS: Low-density-lipoprotein receptor-related protein 5 (LRP-5) and 6, BMP-2, -4, and -7, bone morphogenetic protein receptor-IA and IB (BMPR-IA and BMPR-IA), lymphoid enhancer factor-1 (LEF-1), and transcription factor 4 (TCF 4) expression levels were investigated in normal and osteoarthritic chondrocytes. LRP-5, beta-catenin (phospho and active form), matrix metalloproteinases (MMPs) 7, 9, 13, 14, ADAMTS-4, 5, as well as collagen X (COL10A1) expression levels were evaluated after LRP-5 silencing in BMP-2-treated chondrocytes. The investigation of Smad1/5/8 binding to LRP-5 promoter was assessed with chromatin immunoprecipitation (ChIP). Furthermore, we evaluated the effect of experimental activation of the Wnt/beta-catenin pathway with LiCl and LEF-1 silencing, in LiCl treated chondrocytes, on matrix metalloproteinases (MMPs) 7, 9, 13, 14, ADAMTS-4, 5, and collagen X (COL10A1) expression, as well as possible interactions between LEF-1 and MMPs and COL10A1 promoters by using a ChIP assay. RESULTS: LRP-5, BMP 2, BMP-4, BMPR-IA, and LEF-1 mRNA and protein expression levels were found to be significantly upregulated in osteoarthritic chondrocytes compared with normal. We showed that treatment of cultured chondrocytes with BMP-2 resulted in increased beta-catenin nuclear translocation and LRP-5 expression and that the BMP-2 induced LRP-5 upregulation is mediated through Smad1/5/8 binding on LRP-5 promoter. LRP-5 silencing reduced nuclear beta-catenin protein levels, MMPs and collagen X expression, whereas increased phospho-beta-catenin protein levels in BMP-2-treated chondrocyte. Furthermore, we demonstrated that activation of the Wnt/beta-catenin signaling pathway by LiCl and LEF-1 downregulation by using siRNA regulates MMP-9, 13, 14, ADAMTS-5, and COL10A1 expression, evidenced by the observed strong binding of LEF-1 to MMP-9, 13, 14, ADAMTS-5 and COL10A promoters. CONCLUSIONS: Our findings suggest, for the first time to our knowledge, that BMP 2-induced Wnt/beta-catenin signaling activation through LRP-5 may contribute to chondrocyte hypertrophy and cartilage degradation in osteoarthritis. PMID- 22513175 TI - Anti-M(3) peptide IgG from Sjogren's syndrome triggers apoptosis in A253 cells. AB - Primary Sjogren's syndrome (pSS) is an autoimmune disease that targets salivary and lachrymal glands, characterized by anti-cholinergic autoantibodies directed against the M(3) muscarinic acetylcholine receptor (mAChR). The aim of this work was to evaluate if cholinergic autoantibodies contained in IgG purified from Sjogren sera could trigger apoptosis of A253 cell line. We also determined if caspase-3 and matrix metalloproteinase-3 (MMP-3) are involved in the induction of A253 cell death. Our results demonstrated that anti-cholinergic autoantibodies stimulate apoptosis and inositol phosphate (InsP) accumulation accompanied by caspase-3 activation and MMP-3 production. All of these effects were blunted by atropine and J104794, indicating that M(3) mAChRs are impacted by the anti cholinergic autoantibodies. The intracellular pathway leading to autoantibody induced biological effects involves phospholipase C (PLC), calcium/calmodulin (CaM) and extracellular calcium as demonstrated by treatment with U-73122, W-7, verapamil, BAPTA and BAPTA-AM, all of which blocked the effects of the anti cholinergic autoantibodies. In conclusion, anti-cholinergic autoantibodies in IgG purified from pSS patient's sera mediates apoptosis of the A253 cell line in an InsP, caspase-3 and MMP-3 dependent manner. PMID- 22513176 TI - Modeling of angiotensin II-angiotensin-(1-7) counterbalance in disease progression in spontaneously hypertensive rats treated with/without perindopril. AB - Angiotensin II (Ang II) and angiotensin-(1-7) (Ang-(1-7)) are biologically active effectors in the renin-angiotensin system (RAS) and have been demonstrated to have potential function in predicting cardiovascular diseases. We developed mechanism-based mathematical models to characterize the up/down-regulation of Ang II/Ang-(1-7), and the effects of perindopril on hypertension progression in spontaneously hypertensive rats (SHR). SHR were randomly assigned to the control group (n=6) and treatment group (n=6). Rats in the treatment group received oral perindopril (5mgkg(-1)day(-1)). Systolic blood pressure (SBP) was measured by the tail-cuff method. Serum Ang II and Ang-(1-7) concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Three linked turnover models were developed to describe Ang II, Ang-(1-7) and SBP profiles. All parameters were estimated using nonlinear mixed-effects modeling. The results showed that Ang II, Ang-(1-7) and SBP gradually increased in the control group. These counterbalance mechanisms were reflected in the models with two feedback cycles. It was assumed that the Ang-(1-7) production rate constant (K(in_Ang17)) was stimulated by Ang II, and the Ang II output rate constant (K(out_Ang2)) reflecting Ang II degradation was stimulated by Ang-(1-7). The decrease in Ang II and increase in Ang-(1-7) were observed in rats treated with perindopril. The models described the counterbalance relationship of Ang II and Ang-(1-7) well, and provided insights into ACE inhibition using perindopril. The models could be extended to incorporate other biomarkers and the effects of various ACE inhibitors (ACEIs). PMID- 22513177 TI - Response to Wang and Luo. AB - This article is a response to Wang and Luo.See correspondence article http://www.biomedcentral.com/1741-7007/10/30 and the original research article http://www.biomedcentral.com/1741-7007/9/24. PMID- 22513178 TI - [Change: Today or tomorrow]. PMID- 22513179 TI - [Tracheal tube obstruction mimicking a bronchospasm]. PMID- 22513180 TI - A scoring system (DISTAL) for predicting failure of snuffbox arteriovenous fistulas. AB - OBJECTIVES: A first fistula failing will lead to serious morbidity in a proportion of patients. Snuffbox fistulas have the advantage of proximal vessel preservation, and although several factors have been associated with failure, the relative importance of these factors combined and their clinical applicability is unknown. The aim of this study was to determine the relative importance of risk factors for snuffbox fistula failure and create a simple scoring system to aid fistula placement decision making. METHODS: 218 consecutive patients were examined using Cox regression analysis to determine risk factors for failure. Primary patency was used as the endpoint. RESULTS: Diabetes, IHD, Stroke, Two snuffbox procedures, Age > 70 and Less than 2.0 mm vein (DISTAL, maximum score 6) were significant predictors of primary patency failure. There was a clear decrease in primary patency with increasing DISTAL score (log rank chi(2) = 30.3, DF = 5, P < 0.001). Performing snuffbox procedures on patients with a score <= 3 would give a 23% reduction in the number of failures within two months for a 12% reduction in the number of patients offered snuffbox procedures. CONCLUSION: The DISTAL scoring system could give large improvements in primary patency for the snuffbox fistula if the results can be validated in other datasets. PMID- 22513182 TI - Prognostic usefulness of clinical and subclinical peripheral arterial disease in men with stable coronary heart disease. AB - The prognostic value of symptomatic peripheral arterial disease (PAD) in patients with coronary heart disease (CHD) is well documented, but few reports differentiating between symptomatic and asymptomatic forms of PAD are available. We investigated the respective prognostic effect of clinical and subclinical PAD on long-term all-cause mortality in patients with stable CHD. We analyzed 710 patients with stable CHD referred for hospitalization for CHD evaluation and management. As a part of the study, they completed questionnaires on medical history, underwent a standardized clinical examination, including ankle-brachial index (ABI) measurement, and provided a fasting blood sample. Three groups of patients were individualized: no PAD (no history of PAD and ABI >0.9 but <=1.4); subclinical PAD (no history of PAD but abnormal ABI [i.e., <=0.9 or >1.4); and clinical PAD (history of claudication, peripheral arterial surgery, or amputation due to PAD). Clinical and subclinical PAD was present in 83 (11.7%) and 181 (25.5%) patients, respectively. After a median follow-up of 7.2 years, 130 patients died. On multivariate analysis adjusted for age, hypertension, diabetes, dyslipidemia, smoking, left ventricular ejection fraction, CHD duration, heart rate, history of stroke or transient ischemic attack, and coronary revascularization, previous clinical PAD (hazard ratio 2.11, 95% confidence interval 1.28 to 3.47) and subclinical PAD (hazard ratio 1.65, 95% confidence interval 1.11 to 2.44) were significantly associated with increased all-cause mortality. In conclusion, our study has demonstrated that the detection of subclinical PAD by ABI in patients with stable CHD provides additional information for long-term mortality risk evaluation. PMID- 22513183 TI - Dihydroquercetin: More than just an impurity? AB - Dihydroquercetin (taxifolin) is a potent flavonoid found in onions, French maritime bark, milk thistle, tamarind seeds and commercially available semi synthetic monoHER marketed as Venoruton. This review focuses on the therapeutic promise of dihydroquercetin in major disease states such as cancer, cardiovascular disease and liver disease by reviewing the proposed mechanism(s) of action, including the activation of the antioxidant response element (ARE) and detoxifying phase II enzymes, inhibition of cytochrome P(450) and fatty acid synthase in carcinogenesis. TNF-alpha and NF-KB dependent transcription in hepatitis C infections, the scavenging effect of myeloperoxidase (MPO) derived reactive nitrogen species and subsequent effects on cholesterol biosynthesis as well as the effects on apob/apoA-I, HMG-CoA reductase and apoptosis are reviewed. The stereochemistry and pro-oxidant effect of dihydroquercetin are also considered. Although the majority of research on dihydroquercetin to date has focused on the identification of molecular targets in vitro, this review will bring together evidence of the potency and mode of action of dihydroquercetin and will propose a role for the therapeutic potential of flavonoid antioxidants. PMID- 22513181 TI - Managing delirium in the acute care setting: a pilot focus group study. AB - BACKGROUND: Delirium frequently occurs in hospitalised older adults leading to poor outcomes and frequent adverse events. Proper recognition and management of delirium by acute care nurses can minimise the effects of negative sequelae associated with delirium. AIM: This pilot study used focus group methodology to: (i) describe acute care nurse's experience and knowledge regarding assessment and management of delirium in hospitalised older adults; (ii) illustrate potential facilitators and barriers to non-drug management of delirium; and (iii) to explicate the use of non-drug interventions by acute care nurses to manage delirium in hospitalised older adults. DESIGN: Qualitative, pilot study. METHODS: A total of 16 nurse participants, working on medical, surgical and orthopaedic units from one acute care hospital participated in two focus groups. RESULTS: Main themes included the following: confusion is normal; our duty is to protect; and finding a balance. Nurses were able to identify non-pharmacological interventions for delirium and facilitators and barriers to using these in clinical practice. CONCLUSIONS: Findings from this pilot study illustrate the need for regular assessment of cognitive status in hospitalised older adults and nursing staff education regarding the use of non-pharmacological management of delirium. Based on their experience, nurses have a wealth of ideas for managing delirium. Areas for future research and policy are also highlighted. IMPLICATIONS FOR PRACTICE: More research is needed on how to improve delirium management by acute care nurses to increase the efficacy and use of non-pharmacological interventions in the management of delirium in hospitalised older adults. To translate these findings into practice, nursing care needs to be guided by evidence-based guidelines to implement non-pharmacological strategies in the acute care setting. PMID- 22513184 TI - Comparison between dual-energy X-ray absorptiometry and skinfolds thickness in assessing body fat in anorexia nervosa before and after weight restoration. AB - BACKGROUND & AIMS: The aim of the study was to evaluate the correspondence between body fat mass composition (percentage) measured with dual-energy X-ray absorptiometry (DXA) and estimated by means of skinfold thicknesses (ST) measurement in patients with anorexia nervosa (AN), before and after weight gain. METHODS: Percentage body fat (%BF) was measured with DXA and estimated by ST measurements using Siri, Brozek, and Heyward equations in 27 adult patients with AN before and after weight gain (pre- and post-treatment) achieved with inpatient treatment and in 42 healthy age-matched controls. RESULTS: Due to Lohman criteria and Bland Altman plot there is no correspondence between the %BF measured with DXA and the %BF estimated by predictive equations based on ST measurements in patients with AN before and after weight gain, with the exception of Brozek equation which showed a mild agreement in pre-treatment AN. However, a correspondence was observed between the two procedures in healthy controls. CONCLUSIONS: Our data supporting the use of ST measurements do not appear to be an alternative to DXA in estimating body fat percentage, before and after weight gain in patients with AN. PMID- 22513185 TI - Effect of single or dual blockade of renin-angiotensin system in acute myocardial infarction patients according to renal function. PMID- 22513186 TI - The off-hours paradigm in primary PCI can be overcome by a uniform regional treatment protocol. PMID- 22513187 TI - Meeting the needs of new graduates in the emergency department: a qualitative study evaluating a new graduate internship program. AB - BACKGROUND: The purpose of this study was to explore the experiences of new graduate emergency nurses participating in a structured internship program. In order to meet the needs of new graduate nurses in emergency departments, these departments have developed a variety of orientation programs, some more successful than others. One type of program involves a combination of didactic content and hands-on clinical experience. This study examines the experiences of new graduate nurses in an internship program at a 200-bed community hospital. METHODS: A qualitative design was used. Interviews with 8 of 9 nurses who participated in the new graduate internship program between 2006 and 2007 were conducted. Content analysis was used to analyze the data. RESULTS: Three themes were identified from the experiences and expectations reported in the interviews: (1) the acquisition of new knowledge and skills in a specialty area, (2) becoming more proficient, and (3) assistance with role transition. The significant role and importance of the unit-base clinical nurse specialist (CNS) and the nurse preceptors were also identified. CONCLUSIONS: The findings of this study suggest that a structured internship program is helpful to new graduate nurses when orienting to a critical care area such as the emergency department. Furthermore, the combination of didactic and clinical content, and the roles of the preceptor and unit-base CNS appear to be key factors in the successful transition from new graduate to emergency nurse. PMID- 22513188 TI - An integrative review: triage protocols and the effect on ED length of stay. AB - The purpose of this integrative review is to identify the effectiveness of using triage protocols to decrease ED length of stay. The review method described by Ganong was used to guide the review process. Data sources included CINAHL (Cumulative Index to Nursing and Allied Health Literature), Medline, the Cochrane Library, Mosby's Nursing Consult, and the National Guideline Clearinghouse. In addition, reference lists of all articles were reviewed, 3 authors of previous articles were contacted for more current or updated work, and a hand search of the Journal of Emergency Nursing was conducted. The search generated 56 articles, 8 of which met inclusion criteria. Data were interpreted and evaluated by use of a data summary sheet. Key conclusions drawn from the appraisals included that a decrease in length of stay was related to protocol use and nurses were able to initiate diagnostic testing and treatments appropriately. These conclusions apply to acuity levels 3 and 4, which require either little or no testing or require testing to facilitate a disposition decision. The implications for nursing are that appraisals of evidence lead to better practice decisions, protocols can provide greater nursing autonomy and satisfaction, and protocols are able to increase the facilitation of patient care in the emergency department. PMID- 22513189 TI - Improving the ED experience with service excellence focused on teamwork and accountability. PMID- 22513190 TI - Synthesis of multiple Pseudomonas aeruginosa biofilm matrix exopolysaccharides is post-transcriptionally regulated. AB - Exopolysaccharide is a critical biofilm matrix component, yet little is known about how the synthesis of multiple exopolysaccharides is regulated. Pseudomonas aeruginosa can produce several biofilm matrix exopolysaccharides that include alginate, Psl and Pel. Here we demonstrated that AlgC, a key enzyme that provides sugar precursors for the synthesis of alginate and lipopolysaccharides (LPS) is also required for both Psl and Pel production. We showed that forced-synthesis of Psl in alginate-producing mucoid bacteria reduced alginate production but this was not due to transcription of the alginate biosynthesis-operon. Likewise, when either alginate or Psl were overproduced, levels of B-band LPS decreased. Induction of Pel resulted in a reduction of Psl levels. Because the effects of reduced exopolysaccharide synthesis when another is overproduced didn't appear to be regulated at the transcriptional level, this suggests that the biosynthesis pathways of Psl, Pel, alginate, and LPS compete for common sugar precursors. As AlgC is the only enzyme that provides precursors for each of these exopolysaccharides, we propose that AlgC is a key checkpoint enzyme that coordinates the total amount of exopolysaccharide biosynthesis by controlling sugar precursor pool. Our data also provide a plausible strategy that P.aeruginosa utilizes to modulate its biofilm matrix exopolysaccharides. PMID- 22513191 TI - Insulin-like growth factor-1 cytokines cross-talk in type 1 diabetes mellitus: relationship to microvascular complications and bone mineral density. AB - OBJECTIVE: This study was designed to investigate the association between inflammatory cytokines (IL-8, IL-6) and IGF-1 levels in relation to metabolic control, microvascular complications and bone mineral density (BMD) in a cohort of Egyptian adolescents with T1DM. RESEARCH DESIGN AND METHODS: Sixty patients with T1DM (mean age was 14.67+/-1.53 years, mean disease duration was 6.87+/-1.25 years) and 40 controls participated in the study. Thirty-six patients (60%) had poor glycemic control (HbA1C measurements >=8%) while the rest (n=24%, 40%) had good glycemic control (HbA1C measurements <8%). Serum IL-6, IL-8, and IGF-1 levels were measured. Whole body DXA scan were assessed. Total body and lumbar spine (L2-L4) bone mineral content (BMC, g) and bone area (BA, cm(2)) were measured by DXA scan, bone mineral density (BMD, g/cm(2)) was calculated by BMC/BA. RESULTS: Patients with T1DM had higher IL-6 and IL-8 levels with lower IGF-1 than healthy controls (P<0.001). Within the T1DM patients those with poor glycemic control had higher IL-6 and IL-8 as well as lower IGF-1 and total BMD than those with good glycemic control (P<0.001 for all). IL-6 and IL-8 were negatively correlated with IGF-1 (P=0.005 and 0.021, respectively). The peripheral neuropathy rate was also greater in T1DM patients with poor glycemic control (P=0.02). Presence of nephropathy or retinopathy was not different (P=0.69 and 0.50, respectively). CONCLUSION: High IL-6, IL-8 with low IGF-1 levels are found in adolescents with T1DM. It seems that poor glycemic control exacerbates inflammatory cytokines, increases peripheral neuropathy, and decreases bone mineral density. PMID- 22513192 TI - Comparison of molecular tests for the diagnosis of malaria in Honduras. AB - BACKGROUND: Honduras is a tropical country with more than 70% of its population living at risk of being infected with either Plasmodium vivax or Plasmodium falciparum. Laboratory diagnosis is a very important factor for adequate treatment and management of malaria. In Honduras, malaria is diagnosed by both, microscopy and rapid diagnostic tests and to date, no molecular methods have been implemented for routine diagnosis. However, since mixed infections, and asymptomatic and low-parasitaemic cases are difficult to detect by light microscopy alone, identifying appropriate molecular tools for diagnostic applications in Honduras deserves further study. The present study investigated the utility of different molecular tests for the diagnosis of malaria in Honduras. METHODS: A total of 138 blood samples collected as part of a clinical trial to assess the efficacy of chloroquine were used: 69 microscopically confirmed P. falciparum positive samples obtained on the day of enrollment and 69 follow-up samples obtained 28 days after chloroquine treatment and shown to be malaria negative by microscopy. Sensitivity and specificity of microscopy was compared to an 18 s ribosomal RNA gene-based nested PCR, two single-PCR reactions designed to detect Plasmodium falciparum infections, one single-PCR to detect Plasmodium vivax infections, and one multiplex one-step PCR reaction to detect both parasite species. RESULTS: Of the 69 microscopically positive P. falciparum samples, 68 were confirmed to be P. falciparum-positive by two of the molecular tests used. The one sample not detected as P. falciparum by any of the molecular tests was shown to be P. vivax-positive by a reference molecular test indicating a misdiagnosis by microscopy. The reference molecular test detected five cases of P. vivax/P. falciparum mixed infections, which were not recognized by microscopy as mixed infections. Only two of these mixed infections were recognized by a multiplex test while a P. vivax-specific polymerase chain reaction (PCR) detected three of them. In addition, one of the day 28 samples, previously determined to be malaria negative by microscopy, was shown to be P. vivax-positive by three of the molecular tests specific for this parasite. CONCLUSIONS: Molecular tests are valuable tools for the confirmation of Plasmodium species and in detecting mixed infections in malaria endemic regions. PMID- 22513193 TI - The physics of geriatric pharmacotherapy: overcoming therapeutic inertia and momentum. PMID- 22513195 TI - Low-dose aspirin and cancer mortality: a meta-analysis of randomized trials. AB - OBJECTIVE: Low-dose aspirin is a common strategy for preventing cardiovascular disease and associated mortality. A recent individual patient data meta-analysis of 8 trials of low- and high-dose aspirin, with long-term follow-up, found important reductions in cancer mortality. We aimed to determine whether cancer mortality also is reduced by low-dose aspirin in the shorter term. METHODS: We conducted a comprehensive search of 10 electronic databases up to December 2011. We conducted a meta-analysis using data from all randomized clinical trials evaluating low-dose (75-325 mg) daily aspirin. We extracted data on non cardiovascular disease mortality and cancer mortality. We pooled studies using a random-effects model and conducted a meta-regression. We supplemented this with a cumulative meta-analysis and trial sequential monitoring analysis. RESULTS: Twenty-three randomized studies reported on nonvascular death. There were 944 nonvascular deaths of 41,398 (2.28%) patients receiving low-dose aspirin and 1074 nonvascular deaths of 41,470 (2.58%) patients not receiving aspirin therapy. The relative risk of nonvascular death was 0.88 (95% confidence interval [CI], 0.81 0.96, I(2) = 0%). Eleven trials included data evaluating cancer mortality involving 16,066 patients. There were 162 of 7998 (2.02%) and 210 of 8068 (2.60%) cancer deaths among low-dose aspirin users versus non-aspirin users, respectively, reported over an average follow-up of 2.8 years. The relative risk of cancer mortality was 0.77 (95% CI, 0.63-0.95, I(2) = 0%). Studies demonstrated a significant treatment effect after approximately 4 years of follow-up. The optimal information size analysis showed that a sufficient number of patients had been randomized to provide convincing evidence of a preventive role of low-dose aspirin in nonvascular deaths. CONCLUSION: Nonvascular deaths, including cancer deaths, are reduced with low-dose aspirin. PMID- 22513194 TI - Increased risk of mortality and readmission among patients discharged against medical advice. AB - BACKGROUND: Approximately 500,000 patients are discharged from US hospitals against medical advice annually, but the associated risks are unknown. METHODS: We examined 148,810 discharges from an urban, academic health system between July 1, 2002 and June 30, 2008. Of these, 3544 (2.4%) were discharged against medical advice, and 80,536 (54.1%) were discharged home. We excluded inpatient deaths, transfers to other hospitals or nursing facilities or discharges with home care. Using adjusted and propensity score-matched analyses, we compared 30-day mortality, 30-day readmission, and length of stay between discharges against medical advice and planned discharges. RESULTS: Discharge against medical advice was associated with higher mortality than planned discharge, after adjustment (odds ratio [OR](adj) 2.05; 95% confidence interval [CI], 1.48-2.86), and in propensity-matched analysis (OR(matched) 2.46; 95% CI, 1.29-4.68). Discharge against medical advice also was associated with higher 30-day readmission after adjustment (OR(adj) 1.84; 95% CI, 1.69-2.01), and in propensity-matched analysis (OR(matched) 1.65; 95% CI, 1.46-1.87). Finally, discharges against medical advice had shorter lengths of stay than matched planned discharges (3.37 vs 4.16 days, P <.001). CONCLUSIONS: Discharge against medical advice is associated with increased risk for mortality and readmission. In addition, discharges against medical advice have shorter lengths of stay than matched planned discharges, suggesting that the increased risks associated with discharge against medical advice are attributable to premature discharge. PMID- 22513196 TI - Fish consumption and colorectal cancer risk in humans: a systematic review and meta-analysis. AB - BACKGROUND: Fish consumption may protect against colorectal cancer, but results from observational studies are inconsistent; therefore, a systematic review with a meta-analysis was conducted. METHODS: Relevant studies were identified by a search of MEDLINE and EMBASE databases to May 2011, with no restrictions. Reference lists from retrieved articles also were reviewed. Studies that reported odds ratio (OR) or relative risk estimates with 95% confidence intervals (CIs) for the association between the consumption of fish and the risk of colorectal, colon, or rectal cancer were included. Two authors independently extracted data and assessed study quality. The risk estimate (hazard ratio, relative risk, or OR) of the highest and lowest reported categories of fish intake were extracted from each study and analyzed using a random-effects model. RESULTS: Twenty-two prospective cohort and 19 case-control studies on fish consumption and colorectal cancer risk met the inclusion criteria and were included in the meta-analysis. Our analysis found that fish consumption decreased the risk of colorectal cancer by 12% (summary OR, 0.88; 95% CI, 0.80-0.95). The pooled ORs of colorectal cancer for the highest versus lowest fish consumption in case-control studies and cohort studies were 0.83 (95% CI, 0.72-0.95) and 0.93 (95% CI, 0.86-1.01), respectively. There was heterogeneity among case-control studies (P<.001) but not among cohort studies. A significant inverse association was found between fish intake and rectal cancer (summary OR, 0.79; 95% CI, 0.65-0.97), and there was a modest trend seen between fish consumption and colon cancer (summary OR, 0.96; 95% CI, 0.81 1.14). This study had no publication bias. CONCLUSION: Our findings from this meta-analysis suggest that fish consumption is inversely associated with colorectal cancer. PMID- 22513197 TI - Motivation to change and treatment attendance as predictors of alcohol-use outcomes among project-based Housing First residents. AB - Collins et al. (2012) indicated that time spent in a project-based Housing First (HF) intervention was associated with improved two-year alcohol-use trajectories among chronically homeless individuals with alcohol problems. To explore potential correlates of these findings, we tested the relative prediction of alcohol-use outcomes by motivation to change (MTC) and substance abuse treatment attendance. Participants (N=95) were chronically homeless individuals with alcohol problems receiving a project-based HF intervention in the context of a larger nonrandomized controlled trial (Larimer et al., 2009). Participants were interviewed regularly over the two-year follow-up. Treatment attendance and MTC were measured using items from the Addiction Severity Index and the SOCRATES, respectively. Alcohol-use outcomes included alcohol quantity, problems and dependence. Generalized estimating equation modeling indicated that MTC variables and not treatment attendance consistently predicted alcohol-use outcomes over the two-year follow-up. Findings suggest that the importance of motivation to change may outweigh treatment attendance in supporting alcohol behavior change in this population. PMID- 22513198 TI - Crystal structure of the Rna14-Rna15 complex. AB - A large protein machinery is required for 3'-end processing of mRNA precursors in eukaryotes. Cleavage factor IA (CF IA), a complex in the 3'-end processing machinery in yeast, contains four subunits, Rna14, Rna15, Clp1, and Pcf11. Rna14 has a HAT (half a TPR) domain at the N terminus and a region at the C terminus that mediates interactions with Rna15. Rna15 contains a RNA recognition module (RRM) at the N terminus, followed by a hinge region. These two proteins are homologs of CstF-77 and CstF-64 in the cleavage stimulation factor (CstF) of the mammalian 3'-end processing machinery. We report the first crystal structure of Rna14 in complex with the hinge region of Rna15, and the structures of the HAT domain of Rna14 alone in two different crystal forms. The complex of the C terminal region of Rna14 with the hinge region of Rna15 does not have strong interactions with the HAT domain of Rna14, and this complex is likely to function independently of the HAT domain. Like CstF-77, the HAT domain of Rna14 is also a tightly associated dimer with a highly elongated shape. However, there are large variations in the organization of this dimer among the Rna14 structures, and there are also significant structural differences to CstF-77. These observations suggest that the HAT domain and especially its dimer may have some inherent conformational variability. PMID- 22513199 TI - Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome) with E250K mutation in CD2BP1 gene treated with the tumor necrosis factor inhibitor adalimumab. PMID- 22513201 TI - Factors influencing the production of hydrogen by the purple non-sulphur phototrophic bacterium Rhodopseudomonas acidophila KU001. AB - Rhodopseudomonas acidophila KU001 was isolated from leather industry effluents and the effect of different cultural conditions on hydrogen production was studied. Anaerobic light induced more hydrogen production than anaerobic dark conditions. Growing cells produced more amounts of hydrogen between 96 and 144 h of incubation. Resting and growing cells preferred a pH of 6.0 +/- 0.24 for hydrogen production. Succinate was the most preferred carbon source for the production of hydrogen while citrate was a poor source of carbon. Acetate and malate were also good carbon sources for hydrogen production under anaerobic light. Among the nitrogen sources, R. acidophila preferred ammonium chloride followed by urea for production of hydrogen. L-tyrosine was the least preferred nitrogen source by both growing and resting cells. PMID- 22513202 TI - Concentrations of alpha- and gamma-tocopherols in human breast milk during the first months of lactation and in infant formulas. AB - The aim of this study was to determine the concentrations of alpha- and gamma tocopherols in human breast milk samples from different periods of lactation and to compare them with tocopherol content in commercially available formulas for infants at corresponding ages. The study included 93 breast milk samples obtained on the 2nd (colostrum, n = 17), 14th (n = 30), 30th (n = 27) and 90th day of lactation (n = 19), along with 90 samples of commercially available initial and follow-on infant formulas. Concentrations of tocopherols were determined using normal-phase high-performance liquid chromatography. Depending on the stage of lactation, human breast milk contained 2.07-9.99 mg L-1 of alpha-tocopherol and 0.22-0.60 mg L-1 of gamma-tocopherol. Breast milk concentrations of alpha tocopherol decreased with the time of lactation, while significant differences in gamma-tocopherol concentration were observed only between the 14th and 30th day of lactation. There was no significant correlation between the dietary intake of vitamin E and its estimated breast milk concentration, also in women who declared vitamin supplementation. Compared with colostrum, infant formulas were characterised by significantly lower concentrations of alpha-tocopherol and vitamin E. This finding indicates the need of additional vitamin E supplementation of bottle-fed infants during the initial 2-3 days of life. PMID- 22513203 TI - A vaccine based on biodegradable microspheres induces protective immunity against scuticociliatosis without producing side effects in turbot. AB - The histiophagous scuticociliate parasite Philasterides dicentrarchi is an emergent pathogen in aquaculture and causes significant economic losses on turbot (Scophthalmus maximus) farms. In this study, the surface antigens (Ag) of the parasite were encapsulated and covalently linked to a polymeric microparticle formulation composed of two biodegradable polymers (chitosan and Gantrez). The antigenicity of the formulation and the protection provided were compared in mice and turbot. This formulation induced a higher antibody (Ab) response in mice at doses of 5mg of microspheres (MS) conjugated with approximately 230 MUg of Ag (MS Ag(c)). However, Ab levels were significantly lower than in mice vaccinated with the same concentration of Ag in complete Freund's adjuvant (FCA). In turbot, the MS-Ag(c) formulation induced a higher level of Abs than that induced by the same vaccine emulsified in FCA. The challenge experiments performed with P. dicentrarchi and vaccinated turbot also showed a clear correlation between Ab levels and survival levels. Growth was significantly affected in fish vaccinated with FCA, but not in fish vaccinated with MS. The high adjuvant capacity of MS, together with its biodegradability and low toxicity to fish, makes this new vaccine an economical, effective and safe alternative to oil-based adjuvants for the immunoprophylaxis of scuticociliatosis in turbot. PMID- 22513204 TI - [Inflammatory polyarthralgia reveling acute hepatitis E]. PMID- 22513205 TI - [Sarcoidosis: the involvement of anterior pituitary hormones is poorly recognized]. AB - OBJECTIVE: Hypothalamic-pituitary locations of sarcoidosis are rare. Achieving more systematic hormonal testing could increase the screening of such patients. The objective of this study was to evaluate the impact on the detection of hypothalamic-pituitary sarcoidosis in patients hospitalized for this condition in a lung disease sensibilized department. METHODS: In hormonology department, we collected and analyzed hormonal testing, from the list of patients hospitalized for pulmonary sarcoidosis in 2007-2008. Diabetes insipidus was defined clinically. The case of patients with multiple hormone deficiencies was analyzed for the diagnosis of hypothalamic-pituitary damage. RESULTS: In a cohort of 486 patients, 158 (33%) had a hormonal abnormality. Forty-six of 158 patients (~30%) had at least one pituitary deficiency or hyperprolactinemia: 31 adrenal insufficiency (isolated for 21), 20 gonadotrop deficiency, 14 hyperprolactinemia, 3 thyreotrop deficiency and a growth hormone deficiency. Among eight patients with association of hyperprolactinemia and hypogonadism, four have a probable diagnosis of hypothalamic-pituitary sarcoidosis, including 3 new cases. DISCUSSION: Despite a selection bias (hospital patients, more severe forms), prevalence of hormonal abnormalities was higher than expected. CONCLUSION: In the condition of this study, hypothalamic-pituitary affected 2.5% of patients with sarcoidosis in pneumologic department (4/158). Hormonal abnormalities were present in one third of hospitalized patients. The most prevalent deficiency found was corticotrope deficiency, secondary to corticosteroid therapy. PMID- 22513206 TI - A transcriptome map of perennial ryegrass (Lolium perenne L.). AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) are increasingly becoming the DNA marker system of choice due to their prevalence in the genome and their ability to be used in highly multiplexed genotyping assays. Although needed in high numbers for genome-wide marker profiles and genomics-assisted breeding, a surprisingly low number of validated SNPs are currently available for perennial ryegrass. RESULTS: A perennial ryegrass unigene set representing 9,399 genes was used as a reference for the assembly of 802,156 high quality reads generated by 454 transcriptome sequencing and for in silico SNP discovery. Out of more than 15,433 SNPs in 1,778 unigenes fulfilling highly stringent assembly and detection parameters, a total of 768 SNP markers were selected for GoldenGate genotyping in 184 individuals of the perennial ryegrass mapping population VrnA, a population being previously evaluated for important agronomic traits. A total of 592 (77%) of the SNPs tested were successfully called with a cluster separation above 0.9. Of these, 509 (86%) genic SNP markers segregated in the VrnA mapping population, out of which 495 were assigned to map positions. The genetic linkage map presented here comprises a total of 838 DNA markers (767 gene-derived markers) and spans 750 centi Mogan (cM) with an average marker interval distance of less than 0.9 cM. Moreover, it locates 732 expressed genes involved in a broad range of molecular functions of different biological processes in the perennial ryegrass genome. CONCLUSIONS: Here, we present an efficient approach of using next generation sequencing (NGS) data for SNP discovery, and the successful design of a 768-plex Illumina GoldenGate genotyping assay in a complex genome. The ryegrass SNPs along with the corresponding transcribed sequences represent a milestone in the establishment of genetic and genomics resources available for this species and constitute a further step towards molecular breeding strategies. Moreover, the high density genetic linkage map predominantly based on gene associated DNA markers provides an important tool for the assignment of candidate genes to quantitative trait loci (QTL), functional genomics and the integration of genetic and physical maps in perennial ryegrass, one of the most important temperate grassland species. PMID- 22513207 TI - Oral dysplasia and squamous cell carcinoma: correlation between increased expression of CD21, Epstein-Barr virus and CK19. AB - OBJECTIVES: Epstein-Barr virus is an orally transmitted human gammaherpesvirus that infects B lymphocytes and epithelial cells. Although most primary infections are asymptomatic, long term carriage of the virus can be associated with either lymphoid or epithelial malignancies. The association of EBV with oral squamous cell carcinomas is sporadic and it is uncertain if the virus is involved in initiation of the tumor or, possibly, in its progression. Complement receptor type 2, CR2 or CD21, is a receptor for the major attachment protein of EBV, which significantly enhances epithelial cell infection, but its expression on normal tissues is restricted to tonsil and adenoid epithelium. As cells become dysplastic they are reported to express higher levels of CK19. We sought to evaluate whether CD21 and CK19 expression change as oral epithelial cells outside Waldeyer's ring become dysplastic. MATERIALS AND METHODS: Epithelial cells were isolated by laser capture microdissection and levels of CD21, CK19 and EBV RNA were measured by quantitative reverse transcriptase PCR. RESULTS: We report that expression of CD21 increases in frequency and intensity as oral epithelial cells become more dysplastic and that expression correlates with an increase in infection by EBV. Tumors or dysplastic lesions that carry EBV also generally express higher levels of CK19 than those that do not. CONCLUSION: The findings suggest that dysplasia may make cells more susceptible to infection by EBV and that infection by the virus may alter the phenotype of the infected cell in a manner which could affect prognosis. PMID- 22513208 TI - Phase II study of gefitinib adaptive dose escalation to skin toxicity in recurrent or metastatic squamous cell carcinoma of the head and neck. AB - BACKGROUND: Gefitinib has activity in patients with advanced squamous cell carcinoma of the head and neck (SCCHN) and skin toxicity has been postulated to be a predictor of response and improved outcome. METHODS: This open-label, multi institution, phase II study evaluated the activity of gefitinib at individually escalated doses up to 750 mg to achieve the skin toxicity grade >=2. RESULTS: Forty four patients were enrolled. Only twenty-three (52%) experienced skin rash grade >=2. Of 44 patients, partial responses were noted in 3 (7%), stable disease in 8 (18%) and progressive disease in 33 patients. Median progression-free survival was 1.9 months (95% CI 1.6-2.2) and median overall survival was 5.1 months (95% CI 2.4-7.8). Grade of skin rash was not associated with response rate (p=0.169) nor tumor control rate (p=0.284); however, higher gefitinib trough levels were associated with disease control. Of the 11 tissue samples analyzed for EGFR gene copy by FISH, 7 were EGFR FISH positive, but this was not associated with improved tumor control or survival. CONCLUSIONS: Gefitinib has clinical activity as monotherapy in SCCHN. Dose escalation of gefitinib is feasible and may increase skin toxicity, but our data do not support increased activity. PMID- 22513209 TI - Oral microbial carriage in oral squamous cell carcinoma patients at the time of diagnosis and during radiotherapy - a comparative study. AB - OBJECTIVES: Tobacco chewing habit, presence of squamous cell carcinoma in oral cavity and radiotherapy causes alterations in healthy oral microflora. Abnormal flora developed due to radiotherapy in oral squamous cell carcinoma (OSCC) patients can exacerbate mucositis and can cause systemic infections. The role of oral microorganisms in carcinogenesis is gaining interest recently. Abnormal flora in development of second tumor in the field of first tumor is to be established. The study fundamentally tries to evaluate the shift that occurs during the radiotherapy in OSCC patients. METHODS: Microbial analysis of saliva samples from OSCC patients undergoing radiotherapy, tobacco chewers and controls was undertaken. The microorganisms were grouped into categories as total aerobes, total anaerobes, candida, coliforms and gram negative anaerobic bacteria. RESULTS: The frequency of isolation of total aerobes, total anaerobes, coliforms and gram negative anaerobic bacteria was significantly high in OSCC patients compared to healthy controls whereas candida was isolated most frequently during radiation period. The tobacco chewers showed significant increase in colony forming units of total aerobes and coliforms. All the microbial groups were high in OSCC and radiotherapy patients. While OSCC patients showed significant increase in total anaerobes and gram negative anaerobes, candida was increased in radiotherapy patients only. CONCLUSION: Habits promote coliforms. Tumor supports efficiently anaerobes and candida. The latter is supported more by radiation. The study stresses the importance on administration of appropriate antimicrobial therapy right at the time of diagnosis of the lesion. PMID- 22513211 TI - Influence of experimental periodontitis on cholinergic stimulation of K+ release in rat parotid glands. AB - In a rat model of experimental periodontitis it was investigated whether the presence of the inflammatory disease induced changes in carbachol-induced fluid secretion in parotid glands, by monitoring potassium release. The potency of carbachol, to induce K+ release, was higher in parotid glands from rats with experimental periodontitis. The antagonist with higher affinity for M3 muscarinic acetyl-choline receptor subtype, 4-DAMP (selectivity: M1=M3), was more potent in inhibiting K+ release in periodontitis rats while the antagonist with a muscarinic M1-receptor-selective profile (selectivity: M1>M3), pirenzepine, was more potent in control rats. Competition binding assays showed that both, M1 and M3 muscarinic acetyl-choline receptor subtypes are expressed in membranes of parotid glands. The K(i) of 4-DAMP was decreased in parotid glands from rats with experimental periodontitis while the Ki of pirenzepine was increased. The effect of periodontitis was reverted by the inhibition of the cyclooxygenase activity through indomethacin treatment (100 mg/k ip, 4 days). It was concluded that periodontitis could induce changes in muscarinic acetyl-choline receptor subtypes expression with a preferential increase of M3 subtype, resulting in increased K+ released in response to carbachol and in a greater potency of 4-DAMP. These findings agree with the fact that a decrease of fluid secretion is not a condition of patients with periodontal disease. PMID- 22513210 TI - Preschool-age children and adults flexibly shift their preferences for auditory versus visual modalities but do not exhibit auditory dominance. AB - The goal of this study was to evaluate the claim that young children display preferences for auditory stimuli over visual stimuli. This study was motivated by concerns that the visual stimuli employed in prior studies were considerably more complex and less distinctive than the competing auditory stimuli, resulting in an illusory preference for auditory cues. Across three experiments, preschool-age children and adults were trained to use paired audio-visual cues to predict the location of a target. At test, the cues were switched so that auditory cues indicated one location and visual cues indicated the opposite location. In contrast to prior studies, preschool-age children did not exhibit auditory dominance. Instead, children and adults flexibly shifted their preferences as a function of the degree of contrast within each modality, with high contrast leading to greater use. PMID- 22513212 TI - Risk of end-stage renal disease associated with gout: a nationwide population study. AB - INTRODUCTION: We explored the risk of end-stage renal disease (ESRD) among gout patients in a representative cohort in Taiwan. METHODS: The primary database used was the Taiwan National Health Insurance Research Database. Subjects older than 20 years without ESRD, coronary heart disease, or stroke were included in the study. The case definition of gout in the present study was gout diagnosis and medical treatment for gout. An ESRD case was defined by the presence of chronic renal failure necessitating long-term renal replacement therapy. Multivariate Cox proportional hazards models were used to evaluate the risk of ESRD among gout patients. RESULTS: The analysis included data of 656,108 patients who were followed up for a mean of 8.0 years. Among them, 19,963 (3.0%) patients had gout. At the end of 2008, 2,377 individuals (gout, n = 276; non-gout, n = 2,101) had ESRD, and 861 individuals (gout, n = 77, 27.9%; non-gout, n = 521, 24.8%) died due to ESRD. The rates of incidence of ESRD were 1.73 and 0.41 cases per 1,000 patient-years in the gout and non-gout groups. After adjustment for age, sex, and history of diabetes mellitus and/or hypertension, gout was associated with a hazard ratio (HR) of 1.57 for ESRD (95% confidence interval [CI], 1.38-1.79; P < 0.001). In patients with ESRD, the adjusted HR for death in patients with gout was 0.95 (0.74-1.23, P = 0.71), which was similar to the HR obtained in patients without gout. CONCLUSIONS: Gout is associated with an increased hazard for development of ESRD. PMID- 22513213 TI - Involved field radiation for Hodgkin's lymphoma: the actual dose to breasts in close proximity. AB - To decrease the risk of late toxicities in Hodgkin's lymphoma (HL) patients treated with radiation therapy (RT) (HL), involved field radiation therapy (IFRT) has largely replaced the extended fields. To determine the out-of-field dose delivered from a typical IFRT to surrounding critical structures, we measured the dose at various points in an anthropomorphic phantom. The phantom is divided into 1-inch-thick slices with the ability to insert TLDs at 3-cm intervals grid spacing. Two treatment fields were designed, and a total of 45 TLDs were placed (equally spaced) at the margin of the each of the 2 radiation fields. After performing a computed tomography simulation, 2 treatment plans targeting the mediastinum, a typical treatment field in patients with early stage HL, were generated. A total dose of 3060 cGy was delivered to the gross tumor volume for each field consecutively. The highest measured dose detected at 1 cm from the field edge in the planning target volume was 496 cGy, equivalent to 16% of the isocentric dose. The dose dropped significantly with increasing distance from the field edge. It ranged from 1.1-3.9% of the isocentric dose at a distance of 3.2-4 cm to <1.6% at a distance of >6 cm. Although the computer treatment planning system (CTPS) frequently underestimated the dose delivered, the difference in dose between measured and generated by CTPS was <2.5% in 90 positions measured. The collateral dose of radiation to breasts from IFRT is minimal. The out-of field dose, although mildly underestimated by CTPS, becomes insignificant at >3 cm from the field edge of the radiation field. PMID- 22513215 TI - The IAEA handbook on radionuclide transfer to wildlife. AB - An IAEA handbook presenting transfer parameter values for wildlife has recently been produced. Concentration ratios (CRwo-media) between the whole organism (fresh weight) and either soil (dry weight) or water were collated for a range of wildlife groups (classified taxonomically and by feeding strategy) in terrestrial, freshwater, marine and brackish generic ecosystems. The data have been compiled in an on line database, which will continue to be updated in the future providing the basis for subsequent revision of the Wildlife TRS values. An overview of the compilation and analysis, and discussion of the extent and limitations of the data is presented. Example comparisons of the CRwo-media values are given for polonium across all wildlife groups and ecosystems and for molluscs for all radionuclides. The CRwo-media values have also been compared with those currently used in the ERICA Tool which represented the most complete published database for wildlife transfer values prior to this work. The use of CRwo-media values is a pragmatic approach to predicting radionuclide activity concentrations in wildlife and is similar to that used for screening assessments for the human food chain. The CRwo-media values are most suitable for a screening application where there are several conservative assumptions built into the models which will, to varying extents, compensate for the variable data quality and quantity, and associated uncertainty. PMID- 22513214 TI - The proteasome inhibitor MG132 potentiates TRAIL receptor agonist-induced apoptosis by stabilizing tBid and Bik in human head and neck squamous cell carcinoma cells. AB - Head and neck squamous cell carcinoma (HNSCC) is often resistant to conventional chemotherapy and thus requires novel treatment regimens. Here, we investigated the effects of the proteasome inhibitor MG132 in combination with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or agonistic TRAIL receptor 1 (DR4)-specific monoclonal antibody, AY4, on sensitization of TRAIL- and AY4 resistant human HNSCC cell lines. Combination treatment of HNSCC cells synergistically induced apoptotic cell death accompanied by caspase-8, caspase-9, and caspase-3 activation and Bid cleavage into truncated Bid (tBid). Generation and accumulation of tBid through the cooperative action of MG132 with TRAIL or AY4 and Bik accumulation through MG132-mediated proteasome inhibition are critical to the synergistic apoptosis. In HNSCC cells, Bak was constrained by Mcl 1 and Bcl-X(L), but not by Bcl-2. Conversely, Bax did not interact with Mcl-1, Bcl-X(L), or Bcl-2. Importantly, tBid plays a major role in Bax activation, and Bik indirectly activates Bak by displacing it from Mcl-1 and Bcl-X(L), pointing to the synergistic mechanism of the combination treatment. In addition, knockdown of both Mcl-1 and Bcl-X(L) significantly sensitized HNSCC cells to TRAIL and AY4 as a single agent, suggesting that Bak constraint by Mcl-1 and Bcl-X(L) is an important resistance mechanism of TRAIL receptor-mediated apoptotic cell death. Our results provide a novel molecular mechanism for the potent synergy between MG132 proteasome inhibitor and TRAIL receptor agonists in HNSCC cells, suggesting that the combination of these agents may offer a new therapeutic strategy for HNSCC treatment. PMID- 22513216 TI - Po-210 and Pb-210 in water and fish from Taboshar uranium mining Pit Lake, Tajikistan. AB - Polonium-210 in water and (210)Pb and (210)Po in different fish organs from 3 different fish species in Taboshar Pit Lake (n = 13), located in the uranium mining area in Tajikistan, and in Kairakkum Reservoir (reference lake, n = 3), have been determined as part of a Joint project between Norway, Kazakhstan, Kyrgyzstan and Tajikistan. The average activity concentration of (210)Pb and (210)Po in liver, muscle and bone of Carassius auratus was higher than the concentration in similar tissues of C. carpio and Sander lucioperca from the reference site. The accumulation of (210)Po was higher than for (210)Pb, and the accumulation of (210)Po was highest in the liver of C. auratus (3673 +/- 434 Bq kg(-1) ww). Although the average activity concentration of (210)Pb in liver and bones of C. auratus from Pit Lake were fairly similar, a huge variation in the liver activity concentrations (25-327 Bq kg(-1) ww) was found. The results confirm direct uptake of unsupported (210)Po into the liver, and that the distributions of (210)Po and (210)Pb in fish organs were different. The BCF (L/kg) for (210)Po in bone, liver and muscle clearly demonstrates high accumulation of (210)Po in C. auratus, especially in the liver. The average BCFs of liver, bone and muscle were >1.4 * 10(5), >2.5 * 10(4) and >1.4 * 10(4), respectively. All fish in the Pit Lake were found to be in the same trophic level, however, a linear correlation between log (210)Po in liver and delta(15)N could indicate biomagnification of (210)Po in liver of C. auratus. In regards to the recommended Annual Limit of Intake (ALI) for (210)Po, the concentration of (210)Po in muscle tissues of C. auratus is alarming, as there is a high probability for the local population at risk to exceed the recommended ALI through consumption of fish from Taboshar Pit Lake. PMID- 22513220 TI - Proteomic analysis of porcine alveolar macrophages infected with porcine circovirus type 2. AB - Post-weaning multi-systemic wasting syndrome (PMWS), which is primarily caused by porcine circovirus type 2 (PCV2), is an emerging swine immunosuppressive disease. To characterize the interaction between target immune cells and PCV2, the differential proteomes of porcine alveolar macrophages, with and without PCV2 infection, were analyzed at different time points with two-dimensional gel electrophoresis (2-DE) followed by MALDI-TOF/TOF identification. Mass spectrometry identified 21 altered host-encoded protein spots (9 up-regulated and 12 down-regulated protein spots), which included cytoskeleton proteins, macromolecular biosynthesis-associated proteins, stress response proteins, signal transduction proteins, energy metabolism, and ubiquitin proteasome pathway associated proteins. The majority of the changes occurred 48h after PCV2 infection. Moreover, 9 corresponding genes of the differentially expressed proteins were quantified by real time RT-PCR to examine the transcriptional profiles. Western blot analysis further confirmed the differential expression of proteins, including SFN, PSME1, PRP19, HSPB1, TUBA|B, CK-19 and ACTB, in the proteomic profiles. Subcellular distribution analysis of the cytoskeletal proteins and PCV2 clearly demonstrated interactions between PCV2 and the differential protein beta-tubulin. Thus, this work effectively provides useful and dynamic protein-related information to further understand the underlying pathogenesis of PCV2 infection. PMID- 22513221 TI - Special issue "Genome regulation". PMID- 22513218 TI - Developmental dyslexia. AB - Dyslexia is a neurodevelopmental disorder that is characterised by slow and inaccurate word recognition. Dyslexia has been reported in every culture studied, and mounting evidence draws attention to cross-linguistic similarity in its neurobiological and neurocognitive bases. Much progress has been made across research specialties spanning the behavioural, neuropsychological, neurobiological, and causal levels of analysis in the past 5 years. From a neuropsychological perspective, the phonological theory remains the most compelling, although phonological problems also interact with other cognitive risk factors. Work confirms that, neurobiologically, dyslexia is characterised by dysfunction of the normal left hemisphere language network and also implicates abnormal white matter development. Studies accounting for reading experience demonstrate that many recorded neural differences show causes rather than effects of dyslexia. Six predisposing candidate genes have been identified, and evidence shows gene by environment interaction. PMID- 22513219 TI - Recent advances in sialic acid-focused glycomics. AB - Recent emergences of glycobiology, glycotechnology and glycomics have been clarifying enormous roles of carbohydrates in biological recognition systems. For example, cell surface carbohydrates existing as glycoconjugates (glycolipids, glycoproteins and proteoglycans) play crucial roles in cell-cell communication, cell proliferation and differentiation, tumor metastasis, inflammatory response or viral infection. In particular, sialic acids (SAs) existing as terminal residues in carbohydrate chains on cell surface are involved in signal recognition and adhesion to ligands, antibodies, enzymes and microbes. In addition, plasma free SAs and sialoglycans have shown great potential for disease biomarker discovery. Therefore, the development of efficient analytical methods for structural and functional studies of SAs and sialylglycans are very important and highly demanded. The problems of SAs and sialylglycans analysis are vanishingly small sample amount, complicated and unstable structures, and complex mixtures. Nevertheless, in the past decade, mass spectrometry in combination with chemical derivatization and modern separation methodologies has become a powerful and versatile technique for structural analysis of SAs and sialylglycans. This review summarizes these recent advances in glycomic studies on SAs and sialylglycans. Specially, derivatization and capturing of SAs and sialylglycans combined with mass spectrometry analysis are highlighted. PMID- 22513222 TI - Prevention of thrombosis relapse in antiphospholipid syndrome patients refractory to conventional therapy using intravenous immunoglobulin. AB - OBJECTIVES: To investigate the long-term effects of megadoses of intravenous immunoglobulin (IVIG) in a small cohort of patients with relapsing primary APS resistant to conventional treatments. METHODS: Five primary APS patients, 4 women, mean age 45.1 years (range 31-76 years), were considered eligible for IVIG therapy due to relapsing thrombotic events (4 recurrent venous thromboses, 2 ischaemic cerebral strokes, 2 pulmonary thromboembolisms, 1 thrombotic event on the vena cava filter), despite conventional therapy with anticoagulants. All patients had anti-nuclear antibodies at low-medium titre without other signs or symptoms of systemic lupus erythematosus. IVIG was combined with hydroxychloroquine and, in patients with cerebral strokes, acetylsalicylic acid. Three consecutive daily infusions of IVIG were administered intravenously at a dose of 0.4 g/kg/day every month for 3 months, followed by a single monthly infusion for 9 months. RESULTS: No further thromboses occurred in the 5 treated patients (mean follow-up 89.2 months, range 61-114). Visual analogue score (VAS 0 10) improved (mean 3.5, range 3.0-5.0, before, and 7.35, range 9.9-6.0, p= 0.05) after IVIG treatment. CONCLUSIONS: In a long-term (>5 years) open study in a small cohort of high risk primary APS patients, IVIG was found to be effective in preventing recurrent thrombosis. Full understanding of the mechanisms and efficacy, as well as the optimal doses of IVIG in APS patients with recurrent thrombosis, will require appropriately designed clinical studies. Presently, IVIG use is restricted by costs and limited availability. PMID- 22513223 TI - If you can't comply with dialysis, how do you expect me to trust you with transplantation? Australian nephrologists' views on indigenous Australians' 'non compliance' and their suitability for kidney transplantation. AB - INTRODUCTION: Indigenous Australians suffer markedly higher rates of end-stage kidney disease (ESKD) but are less likely than their non-Indigenous counterparts to receive a transplant. This difference is not fully explained by measurable clinical differences. Previous work suggests that Indigenous Australian patients may be regarded by treating specialists as 'non-compliers', which may negatively impact on referral for a transplant. However, this decision-making is not well understood. The objectives of this study were to investigate: whether Indigenous patients are commonly characterised as 'non-compliers'; how estimations of patient compliance factor into Australian nephrologists' decision-making about transplant referral; and whether this may pose a particular barrier for Indigenous patients accessing transplants. METHODS: Nineteen nephrologists, from eight renal units treating the majority of Indigenous Australian renal patients, were interviewed in 2005-06 as part of a larger study. Thematic analysis was undertaken to investigate how compliance factors in specialists' decision-making, and its implications for Indigenous patients' likelihood of obtaining transplants. RESULTS: Specialists commonly identified Indigenous patients as both non-compliers and high-risk transplant candidates. Definition and assessment of 'compliance' was neither formal nor systematic. There was uncertainty about the value of compliance status in predicting post-transplant outcomes and the issue of organ scarcity permeated participants' responses. Overall, there was marked variation in how specialists weighed perceptions of compliance and risk in their decision-making. CONCLUSION: Reliance on notions of patient 'compliance' in decision-making for transplant referral is likely to result in continuing disadvantage for Indigenous Australian ESKD patients. In the absence of robust evidence on predictors of post-transplant outcomes, referral decision-making processes require attention and debate. PMID- 22513225 TI - [Development of a virtual tool for monitoring quality of care in acute myocardial infarction via the Internet]. AB - BACKGROUND: Measurement of quality indicators contributes to monitoring the performance of initial treatment of ST-elevated myocardial infarction (STEMI). OBJECTIVE: To develop a virtual tool to calculate performance indicators of initial treatment of STEMI online via the internet. METHODS: We identified critical elements of the therapeutic process and formulated indicators in a retrospective pilot study, and developed a virtual tool for prospective data collection on initial treatment of STEMI. Rio de Janeiro hospitals with emergency care units were selected and invited to participate in the project. Online reports were developed to be accessed at www.qualiiam.icict.fiocruz.br/indicadores.php and analyzed. RESULTS: Five hospitals agreed to participate in the project and monitored treatment of different numbers of patients with a diagnosis of STEMI (A = 7, B = 14, C = 16, D = 44 and E = 43). Aspirin was administered in 94.6% of cases, angiotensin converting enzyme inhibitors or angiotensin receptor blockers in 76.1% and beta blockers in 82.5%; 68.4% of patients with no contraindication received fibrinolysis. In no case was door-to-needle time less than 30 min, and mean time was 122 min. All patients admitted to hospitals with catheterization facilities underwent primary angioplasty; mean door-to-balloon time in these patients was 161 min; in only 28% was it less than 90 min. CONCLUSION: The system can be used as a tool to monitor the performance of initial treatment of patients with STEMI. Analysis of these indicators in the future may help to evaluate the contribution of online reporting to the development of better treatment practices. PMID- 22513224 TI - Inhibition of P2X7 receptor ameliorates transient global cerebral ischemia/reperfusion injury via modulating inflammatory responses in the rat hippocampus. AB - BACKGROUND: Neuroinflammation plays an important role in cerebral ischemia/reperfusion (I/R) injury. The P2X7 receptor (P2X7R) has been reported to be involved in the inflammatory response of many central nervous system diseases. However, the role of P2X7Rs in transient global cerebral I/R injury remains unclear. The purpose of this study is to determine the effects of inhibiting the P2X7R in a rat model of transient global cerebral I/R injury, and then to explore the association between the P2X7R and neuroinflammation after transient global cerebral I/R injury. METHODS: Immediately after infusion with the P2X7R antagonists Brilliant blue G (BBG), adenosine 5'-triphosphate-2',3'-dialdehyde (OxATP) or A-438079, 20 minutes of transient global cerebral I/R was induced using the four-vessel occlusion (4-VO) method in rats. Survival rate was calculated, neuronal death in the hippocampal CA1 region was observed using H & E staining, and DNA cleavage was observed by deoxynucleotidyl transferase-mediated UTP nick end labeling TUNEL). In addition, behavioral deficits were measured using the Morris water maze, and RT-PCR and immunohistochemical staining were performed to measure the expression of IL-1beta, TNF-alpha and IL-6, and to identify activated microglia and astrocytes. RESULTS: The P2X7R antagonists protected against transient global cerebral I/R injury in a dosage-dependent manner. A high dosage of BBG (10 MUg) and A-0438079 (3 MUg), and a low dosage of OxATP (1 MUg) significantly increased survival rates, reduced I/R-induced learning memory deficit, and reduced I/R-induced neuronal death, DNA cleavage, and glial activation and inflammatory cytokine overexpression in the hippocampus. CONCLUSIONS: Our study indicates that inhibiting P2X7Rs protects against transient global cerebral I/R injury by reducing the I/R-induced inflammatory response, which suggests inhibition of P2X7Rs may be a promising therapeutic strategy for clinical treatment of transient global cerebral I/R injury. PMID- 22513226 TI - Resistance and resilience of microbial communities--temporal and spatial insurance against perturbations. AB - Bacteria play fundamental roles for many ecosystem processes; however, little empirical evidence is available on how environmental perturbations affect their composition and function. We investigated how spatial and temporal refuges affect the resistance and resilience of a freshwater bacterioplankton community upon a salinity pulse perturbation in continuous cultures. Attachment to a surface avoided the flushing out of cells and enabled re-colonization of the liquid phase after the perturbation, hence serving as a temporal refuge. A spatial refuge was established by introduction of bacteria from an undisturbed reservoir upstream of the continuous culture vessel, acting analogous to a regional species pool in a metacommunity. The salinity pulse affected bacterial community composition and the rates of respiration and the pattern of potential substrate utilization as well as the correlation between composition and function. Compared with the no refuge treatment, the temporal refuge shortened return to pre-perturbation conditions, indicating enhanced community resilience. Composition and function were less disturbed in the treatment providing a spatial refuge, suggesting higher resistance. Our results highlight that spatial and temporal dynamics in general and refuges in particular need to be considered for conceptual progress in how microbial metacommunities are shaped by perturbations. PMID- 22513228 TI - Adrenal function in adult long-term survivors of nephroblastoma and neuroblastoma. AB - BACKGROUND: Adrenal insufficiency, or relative insufficiency, might partly explain increased mortality rates in nephroblastoma and neuroblastoma survivors after unilateral adrenalectomy. OBJECTIVE: To assess adrenal function and its metabolic effects in survivors after adrenalectomy. METHODS: In this cross sectional study, 67 adult long-term survivors of nephroblastoma, 36 survivors of neuroblastoma and 49 control subjects participated. Adrenal function was assessed by a 1MUg short Synacthen-test. Levels of cortisol, adrenocorticotrophic hormone (ACTH), low (LDL-C) and high-density lipoprotein-cholesterol (HDL-C), triglycerides, apolipoprotein-B, glucose and insulin were assessed in blood samples taken at baseline. In addition, cortisol levels were assessed after 30 (t=30) and 60 min. Homoeostatic Model Assessment (HOMA) was calculated. RESULTS: Adrenal insufficiency was not present in survivors. Interestingly, baseline serum cortisol levels were higher in survivors after unilateral adrenalectomy (mean 503 nmol/l) (N=46) than in survivors with both adrenals intact (mean 393 nmol/l, P=0.002) (N=52), and than in controls (mean 399 nmol/l, P=0.013) (N=49). After correcting for age, sex and use of oral oestrogens, unilateral adrenalectomy was independently associated with elevated baseline cortisol and ACTH levels. Baseline cortisol levels were positively associated with triglycerides (P<0.001), LDL-C (P=0.004), apolipoprotein-B (P<0.001) and HOMA (P=0.008). CONCLUSIONS: No adrenal insufficiency was observed in survivors of nephroblastoma and neuroblastoma. Survivors treated with unilateral adrenalectomy had relatively high basal cortisol and ACTH levels, indicating a higher central setpoint of the hypothalamic-pituitary-adrenal axis. This higher setpoint was associated with lipid concentrations and insulin resistance and can therefore influence the cardiovascular risk profile in long-term survivors of nephroblastoma and neuroblastoma. PMID- 22513227 TI - Glycerol as a substrate for aerobic succinate production in minimal medium with Corynebacterium glutamicum. AB - Corynebacterium glutamicum, an established microbial cell factory for the biotechnological production of amino acids, was recently genetically engineered for aerobic succinate production from glucose in minimal medium. In this work, the corresponding strains were transformed with plasmid pVWEx1-glpFKD coding for glycerol utilization genes from Escherichia coli. This plasmid had previously been shown to allow growth of C. glutamicum with glycerol as sole carbon source. The resulting strains were tested in minimal medium for aerobic succinate production from glycerol, which is a by-product in biodiesel synthesis. The best strain BL-1/pVWEx1-glpFKD formed 79 mM (9.3 g l(-1)) succinate from 375 mM glycerol, representing 42% of the maximal theoretical yield under aerobic conditions. A specific succinate production rate of 1.55 mmol g(-1) (cdw) h(-1) and a volumetric productivity of 3.59 mM h(-1) were obtained, the latter value representing the highest one currently described in literature. The results demonstrate that metabolically engineered strains of C. glutamicum are well suited for aerobic succinate production from glycerol. PMID- 22513229 TI - Mammographic changes resulting from benign breast surgery impair breast cancer detection at screening mammography. AB - PURPOSE: To study possible explanations for lower screening performance after previous benign breast surgery. PATIENTS AND METHODS: We included a consecutive series of 351,009 screening examinations in 85,274 women, obtained between January 1, 1997 and January 1, 2009. The examinations of women with screen detected cancers (SDC) or interval cancers (IC), diagnosed after previous benign breast surgery, were reviewed by two screening radiologists. They determined the presence and degree of post surgical changes, classified breast density and determined whether mammographic interpretation was hampered by tissue characteristics. They also assessed whether the cancer had already been visible at a previous screen. RESULTS: Screening sensitivity was lower in women with prior benign breast surgery than without (63.5% (115/181) versus 73.5% (1643/2236), p=0.004). A total of 115 SDCs and 66 ICs were diagnosed in breasts after previous benign breast surgery. Post surgical mammographic alterations in the breast segment where cancer was diagnosed were more distinct in ICs than in SDCs (p=0.001). Women with post surgical mammographic changes at the location of the breast cancer had an increased interval cancer risk (OR=2.12, 95% confidence interval (CI)=1.05-4.26). Limited mammographic interpretation due to tissue characteristics was mentioned, only in three SDCs and one IC. The proportions of SDCs and ICS that were already visible at a previous screen were comparable for women with and without prior surgery (SDC: 47.5% versus 43.8%, p=0.3, IC: 50.0% versus 48.4%, p=0.8). CONCLUSION: Previous benign breast surgery decreases screening sensitivity and this is likely due to postoperative mammographic changes. PMID- 22513230 TI - Neoadjuvant therapy for breast cancer has no benefits on overall survival or on the mastectomy rate in routine clinical practice. A population-based study with a median follow-up of 11 years using propensity score matching. AB - BACKGROUND: Even though neoadjuvant chemotherapy has shown no benefits on overall survival (OS), it is being widely used in the treatment of breast cancer. This is based on the assumption that it may diminish the mastectomy rate and therefore be clinically relevant for patients. Our objective was to assess the impact of neoadjuvant chemotherapy on OS and on the rate of mastectomy in patients with non metastatic primary operable breast carcinoma in routine practice. METHODS: The Cote d'Or district breast cancer registry was used to analyse the OS and mastectomy rate in patients with invasive primary operable unilateral breast cancer diagnosed between 1982 and 2006. We performed Cox proportional hazard ratio (HR) analyses for OS and multivariate logistic regression for the mastectomy rate for the overall population. Different matching methods based on the propensity score were used as sensitivity analyses to ensure that corrections for selection bias were adequate. RESULTS: We analysed 1578 patients, among whom 174 had received neoadjuvant chemotherapy. Median follow-up was 11.1 years. There was no difference between the two treatment groups for OS (HR=1.08 (95% confidence interval (CI): 0.77-1.51 for neoadjuvant chemotherapy)). The mastectomy rate was higher among patients treated with neoadjuvant chemotherapy (odds ratio 1.54 (95%CI: 1.03-2.31)). Sensitivity analyses confirmed these results: for OS, there was no difference between the two populations precisely matched using propensity scores (HR 1.08; 95%CI: 0.671-1.65). CONCLUSION: Despite long term follow-up, neoadjuvant chemotherapy provided no benefit for either OS or the mastectomy rate in our population. PMID- 22513231 TI - Intra- and inter-group coordination patterns reveal collective behaviors of football players near the scoring zone. AB - This study examined emergent coordination processes in collective patterns of behavior in 3 vs 3 sub-phases of the team sport of association football near the scoring zone. We identified coordination tendencies for the centroid (i.e., team center) and surface area (i.e., occupied space) of each sub-group of performers (n=20 plays). We also compared these kinematic variables at three key moments of play using mixed-model ANOVAs. The centroids demonstrated a strong symmetric relation that described the coordinated attacking/defending actions of performers in this sub-phase of play. Conversely, analysis of the surface area of each team did not reveal a clear coordination pattern between sub-groups. But the difference in the occupied area between the attacking and defending sub-groups significantly increased over time. Findings emphasized that major changes in sub group behaviors occurred just before an assisted pass was made (i.e., leading to a loss of stability in the 3 vs 3 sub-phases). PMID- 22513232 TI - Trunk-arm coordination in reaching for moving targets in people with Parkinson's disease: comparison between virtual and physical reality. AB - We used a trunk-assisted prehension task to examine the effect of task (reaching for stationary vs. moving targets) and environmental constraints (virtual reality [VR] vs. physical reality) on the temporal control of trunk and arm motions in people with Parkinson's disease (PD). Twenty-four participants with PD and 24 age matched controls reached for and grasped a ball that was either stationary or moving along a ramp 120% of arm length away. In a similar VR task, participants reached for a virtual ball that was either stationary or moving. Movement speed was measured as trunk and arm movement times (MTs); trunk-arm coordination was measured as onset interval and offset interval between trunk and arm motions, as well as a summarized index-desynchrony score. In both VR and physical reality, the PD group had longer trunk and arm MTs than the control group when reaching for stationary balls (p<.001). When reaching for moving balls in VR and physical reality, however, the PD group had lower trunk and arm MTs, onset intervals, and desynchrony scores (p<.001). For the PD group, VR induced shorter trunk MTs, shorter offset intervals, and lower desynchrony scores than did physical reality when reaching for moving balls (p<.001). These findings suggest that using real moving targets in trunk-assisted prehension tasks improves the speed and synchronization of trunk and arm motions in people with PD, and that using virtual moving targets may induce a movement termination strategy different from that used in physical reality. PMID- 22513233 TI - Re-evaluation of the significance of penicillin binding protein 3 in the susceptibility of Listeria monocytogenes to beta-lactam antibiotics. AB - BACKGROUND: Penicillin binding protein 3 (PBP3) of L. monocytogenes has long been thought of as the primary lethal target for beta-lactam antibiotics due to the excellent correlation between the MICs of different beta-lactams and their affinity for this protein. The gene encoding PBP3 has not yet been directly identified in this gram-positive bacterium, but based on in silico analysis, this protein is likely to be encoded by lmo1438. However, studies examining the effects of mutations in genes encoding known and putative L. monocytogenes PBPs have demonstrated that inactivation of lmo1438 does not affect sensitivity to beta-lactams. RESULTS: In this study, overexpression of lmo1438 was achieved using an inducible (nisin-controlled) expression system. This permitted the direct demonstration that lmo1438 encodes PBP3. PBP3 overexpression was accompanied by slightly elevated PBP4 expression. The recombinant strain overexpressing PBP3 displayed significant growth retardation and greatly reduced cell length in the stationary phase of growth in culture. In antibiotic susceptibility assays, the strain overexpressing PBP3 displayed increased sensitivity to subinhibitory concentrations of several beta-lactams and decreased survival in the presence of a lethal dose of penicillin G. However, the MIC values of the tested beta-lactams for this recombinant strain were unchanged compared to the parent strain. CONCLUSIONS: The present study allows a reevaluation of the importance of PBP3 in the susceptibility of L. monocytogenes to beta-lactams. It is clear that PBP3 is not the primary lethal target for beta lactams, since neither the absence nor an excess of this protein affect the susceptibility of L. monocytogenes to these antibiotics. The elevated level of PBP4 expression observed in the recombinant strain overexpressing PBP3 demonstrates that the composition of the L. monocytogenes cell wall is subject to tight regulation. The observed changes in the morphology of stationary phase cells in response to PBP3 overexpression suggests the involvement of this protein in cell division during this phase of growth. PMID- 22513234 TI - Serial remote ischemic preconditioning and rhythmic isometric exercise training: a hypothesis. PMID- 22513235 TI - Pancreatic stellate cells promotes the perineural invasion in pancreatic cancer. AB - Perineural invasion is a prominent characteristic of pancreatic cancer. Pancreatic cancer has an extremely high incidence of perineural invasion which has been associated with poor survival. Early studies mostly focus on the interaction between cancer cells and nerves. Recently, the effect of pancreatic stellate cells in progression of pancreatic cancer has been paid more attention. Both in vitro studies and in vivo ones revealed that pancreatic stellate cells can enhance the proliferation, migration and invasion of pancreatic cancer cells. Pancreatic stellate cells can also regulate the expression and effect of molecules involved in perineural invasion. In addition, pancreatic stellate cells seems to associated with the generation of neuronal plasticity in pancreatic cancer. Herein the hypothesis that pancreatic stellate cells play a potential role in promote the perineural invasion in pancreatic cancer through three mechanisms. One is that pancreatic stellate cells enhance the proliferation, migration and invasion directly through releasing a variety of stimuli and providing a suitable microenvironment. Pancreatic stellate cells also regulate the expression and effects of molecules involved in perineural invasion such as nerve growth factor. Another is that pancreatic stellate cells induce neuronal plasticity, which makes nerves more vulnerable to be invaded. We can conclude that pancreatic stellate cells play a central role in regulating the perineural invasion process by producing different effects on cancer cells and nerve. To inhibit the activity of pancreatic stellate cells or block the interaction between pancreatic stellate cells and cancer cells or nerve tissue might reduce the perineural invasion in pancreatic cancer. PMID- 22513236 TI - The potential role of quorum-sensing peptides in oncology. AB - Cancer is a leading cause of death worldwide, with a limited cure rate and late diagnosis for certain types of cancer (e.g. pancreatic cancer). As this disease presents an enormous challenge for scientists, new paradigms in oncology are needed to defeat this serious disease. Currently, several peptide drugs are investigated for their preventive, diagnostic and therapeutic properties in oncology, with already 15 peptide drugs marketed for cancer therapy. However, we suggest that quorum-sensing peptide agonists and antagonists can be used in oncology as well, resulting in a larger potential peptide space. This hypothesis is based on (1) the recent evidence of prokaryote-eukaryote signalling by the use of quorum-sensing signalling molecules, (2) the apoptotic phenomenon seen in bacteria, (3) the clear similarities between the bacterial quorum-sensing mechanisms and the metastatic process tumor cells initiate, (4) the multiple receptor targeting and (5) the possibility of pharmacologic manipulation of peptides, resulting in increased receptor targeting. Up till now, however, the use of quorum-sensing signalling peptides in oncology has not yet been investigated, despite the urgent need for new insights in oncology and the promising perspectives. PMID- 22513237 TI - Erythrocyte sedimentation rate - possible role in determining the existence of the low grade inflammation in Irritable Bowel Syndrome patients. AB - Irritable Bowel Syndrome (IBS), the most prevalent functional gastrointestinal disorder, is best described by the presence of recurrent symptoms of abdominal pain, diarrhea and/or constipation. It has been thought that IBS is stress related disorder with no known structural abnormalities, e.g. infectious, biochemical or metabolic causes. But, recent evidence suggests that inflammation within the gastrointestinal tract may be of great importance in the pathogenesis of IBS. Our question is could the conventional and widely available general biological markers of inflammation such as erythrocyte sedimentation rate (ESR) be indicator of microscopic inflammatory process in some IBS patients? We hypothesize that mild inflammation in IBS patients could be detected by meaning of a sensitive but cheap and ubiquitous test - ESR. Furthermore we assume that ESR would be related with the disease severity index and decreased general and disease-specific health-related quality of life (HRQoL). A pilot study has been conducted with 86 outpatients (65% female) with IBS, average age 47.76 (SD=13.68). The preliminary results were partly in favor of our hypothesis. They showed that IBS patients with higher ESR expressed lower disease-specific HRQoL (e.g. they expressed more bowel symptoms, social and emotional disturbances related to disease). No significant correlations were found between ESR and the disease severity as well as general HRQoL. PMID- 22513238 TI - Distal ureteral seeding metastasis of collecting duct carcinoma manifesting as deep vein thrombosis. PMID- 22513239 TI - Identification of low-frequency TRAF3IP2 coding variants in psoriatic arthritis patients and functional characterization. AB - INTRODUCTION: In recent genome-wide association studies for psoriatic arthritis (PsA) and psoriasis vulgaris, common coding variants in the TRAF3IP2 gene were identified to contribute to susceptibility to both disease entities. The risk allele of p.Asp10Asn (rs33980500) proved to be most significantly associated and to encode a mutant protein with an almost completely disrupted binding property to TRAF6, supporting its impact as a main disease-causing variant and modulator of IL-17 signaling. METHODS: To identify further variants, exons 2-4 encoding both known TNF-receptor-associated factor (TRAF) binding domains were sequenced in 871 PsA patients. Seven missense variants and one three-base-pair insertion were identified in 0.06% to 1.02% of alleles. Five of these variants were also present in 931 control individuals at comparable frequency. Constructs containing full-length wild-type or mutant TRAF3IP2 were generated and used to analyze functionally all variants for TRAF6-binding in a mammalian two-hybrid assay. RESULTS: None of the newly found alleles, though, encoded proteins with different binding properties to TRAF6, or to the cytoplasmic tail of the IL-17-receptor alpha-chain, suggesting that they do not contribute to susceptibility. CONCLUSIONS: Thus, the TRAF3IP2-variant p.Asp10Asn is the only susceptibility allele with functional impact on TRAF6 binding, at least in the German population. PMID- 22513240 TI - Peripheral temperature drop in response to anticipation and consumption of a signaled palatable reward in laying hens (Gallus domesticus). AB - The present study describes effects of anticipation and consumption of a palatable reward on comb surface temperature. The purpose was to investigate temperature responses as a potential physiological indicator of positive emotional states in laying hens. A rise in body temperature in response to stimuli predictive of or during exposure to unpleasant events has been interpreted as evidence of emotions in mammals and avians. However, this phenomenon has so far only been studied during anticipation of or exposure to negative events; i.e., emotions of a negative valence. Infrared thermography was used to record potential alterations in comb surface temperature to a conditioned cue signaling a reward (mealworms) and during reward delivery. On average, comb temperature dropped 1.5 degrees C (95% CI: +/-1.2 degrees C) after exposure to CS and consumption of reward (p~0.0014) when initial comb temperature was above 30 degrees C. Such temperature drop indicates a peripheral vasoconstriction and has clear resemblances to emotional fever as seen during negative emotional states. Thus, we propose that a drop in peripheral temperature reflects emotional arousal more than emotional valence. Substantial temperature responses due to diet-induced thermogenesis were found, further emphasizing a cautious interpretation of altered comb temperature in studies of animal welfare. PMID- 22513241 TI - Prevalence and characteristics of hip involvement in spondyloarthritis: a single centre observational study of 275 patients. AB - OBJECTIVES: Hip involvement is a classic feature of spondyloarthritis (SpA). The aim of the present paper is to study the prevalence, clinical and radiological features of hip involvement, and the association with criteria for severity, in a cohort of patients with SpA in a tertiary care centre. METHODS: DESIGN: retrospective single centre observational study in 2010 of patients with definite SpA who underwent direct interview by a physician. Hip involvement was defined as hip pain considered related to SpA inflammation and confirmed radiographically. Other data collection: demographic data, SpA characteristics, treatments performed for hip involvement. ANALYSIS: prevalence of hip involvement was analysed according to disease duration (Kaplan-Meyer). Multivariate Cox analysis compared patients with vs. without hip involvement over time. RESULTS: In all, 275 SpA patients were assessed. The median age was 45 (IQR 35-55) years, the median SpA symptom duration 14 (7-25) years, 61% (169) were men, and 79% were HLA B27 positive. Hip involvement was found in 18% (49) SpA patients, with already 13% after 5 years of disease duration and with frequent bilateral involvement (61%). Hip involvement was associated with non-Caucasian origin (p=0.05). Thirty three percent (16/49) needed surgery (23 total joint replacements in all) with good functional results. CONCLUSIONS: Hip involvement is a frequent manifestation in SpA (18%), often bilateral, and associated with non-Caucasian origin. One third of the patients needed total joint replacement. Physicians should be wary of hip pain in SpA patients and implement rapid diagnostic procedures in such cases. PMID- 22513242 TI - Binding of FoxM1 to G2/M gene promoters is dependent upon B-Myb. AB - The promoters of genes which regulate entry into and progress through mitosis are typically induced maximally in G2 by transcription factors that include B-Myb and FoxM1. As FoxM1 gene transcription is a target of B-Myb, we investigated in this study how these transcription factors functionally interact to regulate these G2/M genes. Using a 3T3 cell line containing floxed B-myb alleles (B-myb(F/F)) that could be conditionally deleted by Cre recombinase, we confirmed that B-myb knockout caused both decreased mRNA expression of several G2/M genes, including FoxM1, and delayed entry into mitosis. Although FoxM1 protein expression was actually unaffected by B-myb knockout when quiescent B-myb(F/F) 3T3 cells re entered the cell cycle upon serum-stimulation, chromatin immunoprecipitation revealed that FoxM1 binding to G2/M promoters was substantially reduced. FoxM1 transcriptional activity requires sequential phosphorylation by Cyclin-dependent kinases and Plk1, which are B-Myb target genes, and we found that phosphorylation at Plk1-specific sites was somewhat reduced upon B-myb knockout. Neither this effect nor nuclear accumulation of FoxM1, which was unaffected by B-myb knockout, was sufficient to account for the dependence on B-Myb for FoxM1 promoter binding, however. More significantly, assays using paired Birc5 (survivin) promoter luciferase reporters with either wild-type or mutated Myb binding sites showed that FoxM1 was unable to bind and activate the promoter in the absence of B-Myb binding. Our data suggest that B-Myb is required as a pioneer factor to enable FoxM1 binding to G2/M gene promoters and explains how these transcription factors may collaborate to induce mitosis. PMID- 22513243 TI - Changes in subtidal assemblages in a scenario of warming: proliferations of ephemeral benthic algae in the Canary Islands (eastern Atlantic Ocean). AB - The present work analysed the main changes in subtidal algal assemblages in the last decade in an oceanic archipelago (Canary Islands--eastern Atlantic Ocean). Changes result from increases in cover of ephemeral benthic algae, such as the non-native chlorophyte Pseudotetraspora marina and the native cyanophytes Blennothrix lyngbyacea, Schizothrix calcicola and Schizothrix mexicana. Ephemeral algae overgrow subtidal assemblages which are extensively dominated by Lobophora variegata, but competitively do not exclude other species. Increases in the abundance of species coincided with a warming of about 2 degrees C in surface seawater temperature (SST) linked to the weakening of the Cold Canary Current and the Northwestern African upwelling. Shifts in the distribution and cover of ephemeral species follow the SST gradient from warmer waters in the western islands to colder waters in the eastern ones. While in the warmest western islands, species have spread quickly colonizing all type of substrates in just a few years (2005-2008), the occurrence of ephemerals towards the coldest eastern islands is yet inconspicuous. PMID- 22513244 TI - [Early detection of anthracyclines cardiotoxicity by tissue Doppler echocardiography about 45 cases at Abidjan institute of cardiology]. AB - OBJECTIVE: Evaluate the early anthracyclines cardiotoxicity. METHODS: It is a prospective study made on 10 months of period from October 2008 to July 2009 and on patients who contracted a solid canny tumor hospitalized or followed in their movement and who would receive chemotherapy with an anthracycline molecule. On this effect, we have used tissue Doppler of mitral ring to detect clinic infratoxicity. RESULT: Forty-five patients (43 women and 2 men) who contracted the solid cancers were included in the study. The patients were 48 of age in average +/- 10.12. All our patients did not show any cardiovascular symptoms at the time of the study. Cardiothoracic and electrocardiograms were not significantly modified by the chemotherapy. The cardioecography with the use of tissue Doppler revealed as followed: (a) significant low of the ejection fraction and the pick of systolic myocardia wave (Sa) on four patients (8.8%). These concerned patients were considered as having anthracycline cardio toxicity. The factor causing this cardiotoxicity was the nature of the anthracycline, which was used: the doxorubicin. The quantity accumulated threshold of the doxorubicin that shod (where toxicity appeared was 150 mg/m(2)); (b) a low of Sa pick without that of left ventricular fraction ejection observed on five patients (11.11%). These concerned patients were considered as having potential risks to develop anthracyclines cardiotoxicity; (c) the left ventricular ejection fraction was not a good indicator the check up of the patients under chemotherapy made up with anthracyclines. CONCLUSION: The tissue Doppler not only enables to make diagnostics of early myocardia dysfunctions but it mainly allows to identify people with risks of a cardiotoxicity due to a going on chemotherapy. PMID- 22513245 TI - Place-specific constructs of social capital and their possible associations to health: a Japanese case study. AB - The story of Roseto, Pennsylvania, USA, is one of the most widely cited studies of the putative influence of community social cohesion on population health. However, few contemporary studies of community-based "social capital" on health have addressed "communities" as unique places with unique histories outside of a Western context. In the present study, we focus on a specific region of Japan (which we call the M-region to preserve anonymity). Using survey data and qualitative interviews, we discuss the historical and contextual origins of the high social capital in the M-region that could account for its relatively good health profile. The analysis of survey data suggested that the residents of M region have higher norms of reciprocity and participate more in horizontal organizations (including volunteer group, citizen or consumer group, sports group or club, and hobby group), and it also indicated better health status and behaviors in some outcomes among the residents of M-region. Based on qualitative interviews, the origins of social capital in the M-region appeared to be rooted in the strong sense of solidarity fostered by the fact that many of the residents were recruited into the region by the same local employer (a steel manufacturing company). Our study points to the need to ground studies of community-based "social capital" and health on detailed knowledge of the historical context of specific places. PMID- 22513246 TI - Acceptance of dying: a discourse analysis of palliative care literature. AB - The subject of death denial in the West has been examined extensively in the sociological literature. However, there has not been a similar examination of its "opposite", the acceptance of death. In this study, I use the qualitative method of discourse analysis to examine the use of the term "acceptance" of dying in the palliative care literature from 1970 to 2001. A Medline search was performed by combining the text words "accept or acceptance" with the subject headings "terminal care or palliative care or hospice care", and restricting the search to English language articles in clinical journals discussing acceptance of death in adults. The 40 articles were coded and analysed using a critical discourse analysis method. This paper focuses on the theme of acceptance as integral to palliative care, which had subthemes of acceptance as a goal of care, personal acceptance of healthcare workers, and acceptance as a facilitator of care. For patients and families, death acceptance is a goal that they can be helped to attain; for palliative care staff, acceptance of dying is a personal quality that is a precondition for effective practice. Acceptance not only facilitates the dying process for the patient and family, but also renders care easier. The analysis investigates the intertextuality of these themes with each other and with previous texts. From a Foucauldian perspective, I suggest that the discourse on acceptance of dying represents a productive power, which disciplines patients through apparent psychological and spiritual gratification, and encourages participation in a certain way to die. PMID- 22513247 TI - The disappearing health effects of rapid privatisation: a case of statistical obscurantism? PMID- 22513248 TI - Food insecurity, depression and the modifying role of social support among people living with HIV/AIDS in rural Uganda. AB - Depression is common among people living with HIV/AIDS and contributes to a wide range of worsened HIV-related outcomes, including AIDS-related mortality. Targeting modifiable causes of depression, either through primary or secondary prevention, may reduce suffering as well as improve HIV-related outcomes. Food insecurity is a pervasive source of uncertainty for those living in resource limited settings, and cross-sectional studies have increasingly recognized it as a critical determinant of poor mental health. Using cohort data from 456 men and women living with HIV/AIDS initiating HIV antiretroviral therapy in rural Uganda, we sought to (a) estimate the association between food insecurity and depression symptom severity, (b) assess the extent to which social support may serve as a buffer against the adverse effects of food insecurity, and (c) determine whether the buffering effects are specific to certain types of social support. Quarterly data were collected by structured interviews and blood draws. The primary outcome was depression symptom severity, measured by a modified Hopkins Symptom Checklist for Depression. The primary explanatory variables were food insecurity, measured with the Household Food Insecurity Access Scale, and social support, measured with a modified version of the Functional Social Support Questionnaire. We found that food insecurity was associated with depression symptom severity among women but not men, and that social support buffered the impacts of food insecurity on depression. We also found that instrumental support had a greater buffering influence than emotional social support. Interventions aimed at improving food security and strengthening instrumental social support may have synergistic beneficial effects on both mental health and HIV outcomes among PLWHA in resource limited settings. PMID- 22513250 TI - Perceived annoyance from environmental odors and association with atmospheric ammonia levels in non-urban residential communities: a cross-sectional study. AB - OBJECTIVE: Odor exposure is an environmental stressor that is responsible of many citizens complains about air pollution in non-urban areas. However, information about the exposure-response relation is scarce. One of the main challenges is to identify a measurable compound that can be related with odor annoyance responses. We investigated the association between regional and temporal variation of ammonia (NH3) concentrations in five Danish non-urban regions and environmental odor annoyance as perceived by the local residents. METHODS: A cross-sectional study where NH3 concentration was obtained from the national air quality monitoring program and from emission-dispersion modelling, and odor pollution perception from questionnaires. The exposure-response model was a sigmoid model. Linear regression analyses were used to estimate the model constants after equation transformations. The model was validated using leave-one-out cross validation (LOOCV) statistical method. RESULTS: About 45% of the respondents were annoyed by odor pollution at their residential areas. The perceived odor was characterized by all respondents as animal waste odor. The exposure-annoyance sigmoid model showed that the prevalence of odor annoyance was significantly associated with NH3 concentrations (measured and estimated) at the local air quality monitoring stations (p < 0.01,R2 = 0.99; and p < 0.05,R2 = 0.93; respectively). Prediction errors were below 5.1% and 20% respectively. The seasonal pattern of odor perception was associated with the seasonal variation in NH3 concentrations (p < 0.001, adjusted R2 = 0.68). CONCLUSION: The results suggest that atmospheric NH3 levels at local air quality stations could be used as indicators of prevalence of odor annoyance in non-urban residential communities. PMID- 22513249 TI - Nicotine replacement therapy in the intensive care unit: a systematic review. AB - OBJECTIVE: The objective of this review was to systematically review and evaluate available literature describing the effect of nicotine replacement therapy (NRT) on mortality and other outcomes in nicotine-dependent critically ill patients admitted to the intensive care unit (ICU). DATA SOURCES: A systematic search of the following databases was performed: MEDLINE (1948-August 2011), EMBASE (1980 August 2011), Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts (1970-August 2011), Google, and Google Scholar. STUDY SELECTION: Studies that reported outcomes associated with any form of NRT in any intensive care setting were included. Studies were included regardless of design or number of participants reported. Studies published in languages other than English were excluded. DATA EXTRACTION: Data from each study were extracted using a standardized data extraction tool. Information included the study design, number of patients, classification of ICU, baseline characteristics, outcomes assessed, and overall results. DATA SYNTHESIS: Our search identified 8 studies, of which 7 met the inclusion criteria. These 7 studies were qualitatively reviewed and critically appraised for methodological quality, robustness of results, and internal and external validity. The results of similar studies and populations were compared in order to draw conclusions pertaining to specific intensive care settings. CONCLUSIONS: We conclude that NRT should not be routinely prescribed to patients admitted to intensive care settings. With only equivocal evidence of efficacy and signals suggesting increased toxicity, we believe that its use should be limited to selected patients where the potential benefit clearly outweighs the risk. There is a need for adequately powered randomized controlled trials to confirm the benefits and risks of NRT in the ICU overall but also in its unique subpopulations. PMID- 22513251 TI - Evolution of char structure during steam gasification of the chars produced from rapid pyrolysis of rice husk. AB - The structural evolution of rice husk char particles during steam gasification was studied by ultimate analysis, inductively coupled plasma atomic emission spectroscopy, scanning electronic microscope, N(2) physisorption method and X-ray diffraction. Drastic changes in char structure occurred even when the char conversion was minimal. The C, H and O content decreased by more than 85%, 67% and 91%, respectively. The H/C atomic ratio always increased, while the O/C exhibited a "~" shape. The maximum porosity appeared at char conversion of 48.6%. D(s) and d(ave) showed a good linear relationship. Aliphatic structures and smaller aromatic rings tended to be preferentially consumed to left the char more ordered and enriched with larger aromatic ring systems. The presence of steam favored the volatilization of Na. K, Mg and Ca showed a similar behavior and their concentrations reached maxima at 60.3%. Great loss of O-containing structures caused significant volatilization of K, Mg and Ca. PMID- 22513252 TI - Life-cycle energy production and emissions mitigation by comprehensive biogas digestate utilization. AB - In the context of global energy shortages and climate change, developing biogas plants with links to agricultural system has become an important strategy for cleaner rural energy and renewable agriculture. In this study, a life-cycle energy and environmental assessment was performed for a biogas-digestate utilization system in China. The results suggest that biogas utilization (heating, illumination, and fuel) and comprehensive digestate reuse are of equal importance in the total energy production of the system, and they also play an important role in systemic greenhouse gas mitigation. Improvement can be achieved in both energy production and emissions mitigation when the ratio of the current three biogas utilization pathways is adjusted. Regarding digestate reuse, a tradeoff between energy and environmental performance can be obtained by focusing on the substitution for top-dressing, base fertilizers, and the application to seed soaking. PMID- 22513253 TI - Sub-critical filtration conditions of commercial hollow-fibre membranes in a submerged anaerobic MBR (HF-SAnMBR) system: the effect of gas sparging intensity. AB - A submerged anaerobic MBR demonstration plant with two commercial hollow-fibre ultrafiltration systems (PURON(r), Koch Membrane Systems, PUR-PSH31) was operated using municipal wastewater at high levels of mixed liquor total solids (MLTS) (above 22 g L(-1)). A modified flux-step method was applied to assess the critical flux (J(C)) at different gas sparging intensities. The results showed a linear dependency between J(C) and the specific gas demand per unit of membrane area (SGD(m)). J(C) ranged from 12 to 19 LMH at SGD(m) values of between 0.17 and 0.5 Nm(3) h(-1) m(-2), which are quite low in comparison to aerobic MBR. Long term trials showed that the membranes operated steadily at fluxes close to the estimated J(C), which validates the J(C) obtained by this method. After operating the membrane for almost 2 years at sub-critical levels, no irreversible fouling problems were detected, and therefore, no chemical cleaning was conducted. PMID- 22513254 TI - Partitioning studies of L-glutaminase production by Bacillus cereus MTCC 1305 in different PEG-salt/dextran. AB - Partitioning studies of L-glutaminase production by Bacillus cereus MTCC 1305 was carried out in different PEG-salt/PEG-dextran system. The partitioning value of L glutaminase increased with increasing molecular weight of PEG from 2000-4000 kDa and decreased with higher molecular weight of 6000 kDa. Phase system of PEG 4000 (8.5%)/dextran T500 (9.5%) was selected for the extractive fermentative production of L-glutaminase on the basis maximum partition coefficient (1.31). The production of L-glutaminase was found higher in top phase of ATPS (2.09 U/ml) than control media (1.42 U/ml). Overall production of L-glutaminase (1.83 U/ml) was found lower than top phase (2.09 U/ml) in ATPS system. The growth profile with short lag phase and higher cell concentration was obtained for ATPS. The partition coefficient of L-glutaminase increased with increase of system pH and temperature and optimum production was obtained at pH 7.5 and temperature 30 degrees C in top phase of PEG 4000/dextran T500 system. PMID- 22513255 TI - The use of the fungus Dichomitus squalens for degradation in rotating biological contactor conditions. AB - Biodegradation potential of Dichomitus squalens in biofilm cultures and rotating biological contactor (RBC) was investigated. The fungus formed thick biofilms on inert and lignocellulosic supports and exhibited stable activities of laccase and manganese peroxidase to reach 40-62 and 25-32% decolorization of anthraquinone Remazol Brilliant Blue R and heterocyclic phthalocyanine dyes, respectively. The decolorization ceased when glucose concentration dropped to 1 mmol l(-1). In RBC reactor, respective decolorizations of Remazol Brilliant Blue R and heterocyclic Methylene Blue and Azure B dyes (50 mg l(-1)) attained 99%, 93%, and 59% within 7, 40 and 200 h. The fungus exhibited tolerance to coliform and non-coliform bacteria on rich organic media, the inhibition occurred only on media containing tryptone and NaCl. The degradation efficiency in RBC reactor, capability to decolorize a wide range of dye structures and tolerance to bacterial stress make D. squalens an organism applicable to remediation of textile wastewaters. PMID- 22513256 TI - Characteristics of products from fast pyrolysis of fractions of waste square timber and ordinary plywood using a fluidized bed reactor. AB - Fractions of waste square timber and waste ordinary plywood were pyrolyzed in a pyrolysis plant equipped with a fluidized bed reactor and a dual char separation system. The maximum bio-oil yield of about 65 wt.% was obtained at reaction temperatures of 450-500 degrees C for both feed materials. For quantitative analysis of bio-oil, the relative response factor (RRF) of each component was calculated using an effective carbon number (ECN) that was multiplied by the peak area of each component detected by a GC-FID. The predominant compounds in the bio oils were methyl acetate, acids, hydroxyacetone, furfural, non-aromatic ketones, levoglucosan and phenolic compounds. The WOP-derived bio-oil showed it to have relatively high nitrogen content. Increasing the reaction temperature was shown to have little effect on nitrogen removal. The ash and solid contents of both bio oils were below 0.1 wt.% due to the excellent performance of the char separation system. PMID- 22513258 TI - A quadruple mutant of Arabidopsis reveals a beta-carotene hydroxylation activity for LUT1/CYP97C1 and a regulatory role of xanthophylls on determination of the PSI/PSII ratio. AB - BACKGROUND: Xanthophylls are oxygenated carotenoids playing an essential role as structural components of the photosynthetic apparatus. Xanthophylls contribute to the assembly and stability of light-harvesting complex, to light absorbance and to photoprotection. The first step in xanthophyll biosynthesis from alpha- and beta-carotene is the hydroxylation of epsilon- and beta-rings, performed by both non-heme iron oxygenases (CHY1, CHY2) and P450 cytochromes (LUT1/CYP97C1, LUT5/CYP97A3). The Arabidopsis triple chy1chy2lut5 mutant is almost completely depleted in beta-xanthophylls. RESULTS: Here we report on the quadruple chy1chy2lut2lut5 mutant, additionally carrying the lut2 mutation (affecting lycopene epsilon-cyclase). This genotype lacks lutein and yet it shows a compensatory increase in beta-xanthophylls with respect to chy1chy2lut5 mutant. Mutant plants show an even stronger photosensitivity than chy1chy2lut5, a complete lack of qE, the rapidly reversible component of non-photochemical quenching, and a peculiar organization of the pigment binding complexes into thylakoids. Biochemical analysis reveals that the chy1chy2lut2lut5 mutant is depleted in Lhcb subunits and is specifically affected in Photosystem I function, showing a deficiency in PSI-LHCI supercomplexes. Moreover, by analyzing a series of single, double, triple and quadruple Arabidopsis mutants in xanthophyll biosynthesis, we show a hitherto undescribed correlation between xanthophyll levels and the PSI-PSII ratio. The decrease in the xanthophyll/carotenoid ratio causes a proportional decrease in the LHCII and PSI core levels with respect to PSII. CONCLUSIONS: The physiological and biochemical phenotype of the chy1chy2lut2lut5 mutant shows that (i) LUT1/CYP97C1 protein reveals a major beta carotene hydroxylase activity in vivo when depleted in its preferred substrate alpha-carotene; (ii) xanthophylls are needed for normal level of Photosystem I and LHCII accumulation. PMID- 22513259 TI - Optimization of un-tethered, low voltage, 20-100kHz flexural transducers for biomedical ultrasonics applications. AB - This paper describes optimization of un-tethered, low voltage, 20-100kHz flexural transducers for biomedical ultrasonics applications. The goal of this work was to design a fully wearable, low weight (<100g), battery operated, piezoelectric ultrasound applicator providing maximum output pressure amplitude at the minimum excitation voltage. Such implementation of ultrasound applicators that can operate at the excitation voltages on the order of only 10-25V is needed in view of the emerging evidence that spatial-peak temporal-peak ultrasound intensity (I(SPTP)) on the order of 100mW/cm(2) delivered at frequencies below 100kHz can have beneficial therapeutic effects. The beneficial therapeutic applications include wound management of chronic ulcers and non-invasive transdermal delivery of insulin and liposome encapsulated drugs. The early prototypes of the 20 and 100kHz applicators were optimized using the maximum electrical power transfer theorem, which required a punctilious analysis of the complex impedance of the piezoelectric disks mounted in appropriately shaped metal housings. In the implementation tested, the optimized ultrasound transducer applicators were driven by portable, customized electronics, which controlled the excitation voltage amplitude and facilitated operation in continuous wave (CW) or pulsed mode with adjustable (10-90%) duty cycle. The driver unit was powered by remotely located rechargeable lithium (Li) polymer batteries. This was done to further minimize the weight of the applicator unit making it wearable. With DC voltage of approximately 15V the prototypes were capable of delivering pressure amplitudes of about 55kPa or 100mW/cm(2) (I(SPTP)). This level of acoustic output was chosen as it is considered safe and side effects free, even at prolonged exposure. PMID- 22513260 TI - Fluorescence response of human HER2+ cancer- and MCF-12F normal cells to 200MHz ultrasound microbeam stimulation: a preliminary study of membrane permeability variation. AB - Targeted mechanical cell stimulation has been extensively studied for a better understanding of its effect on cellular mechanotransduction signaling pathways and structures by utilizing a variety of mechanical sources. In this work, an ultrasound-driven single cell stimulation method is thus proposed, and a preliminary study is carried out by comparing the fluorescence intensities representing a change in cell membrane permeability between MDA-MB-435 human HER2+ cancer cells (~40-50MUm in diameter) and MCF-12F normal cells (~50-60MUm) in the presence of ultrasound. A 200MHz single element zinc oxide (ZnO) transducer is employed to generate ultrasound microbeam (UM) whose beamwidth and depth of focus are 9.5 and 60MUm, comparable to typical cell size. The cells in tetramethyl rhodamine methyl ester (TMRM) are interrogated with 200MHz sinusoidal bursts. The number of cycles per burst is 5 and the pulse repetition frequency (PRF) is 1kHz. The temporal variation of fluorescence intensity in each cell is measured as a function of input voltage to the transducer (16, 32, and 47V), and its corresponding fluorescence images are obtained via a confocal microscope. A systematic method for visualizing UM's focus by adding Rhodamine B to the immersion medium is also proposed to enhance the precision in aiming the beam at an individual cell. Both types of cells exhibit a decrease in the intensity upon UM irradiation. In particular, normal cells show more fluorescence reduction (down to 0.7 in normalized intensity) than cancer cells (~0.9) under the same excitation condition of the transducer. With UM being turned off, the normalized intensity level in normal cells is slowly increased to 1.1. The cell images taken before and after UM exposure indicate that the intensity reduction is more pronounced in those cells after exposure. Hence the results show the potential of UM as a non-invasive in vitro stimulation tool for facilitating targeted drug delivery and gene transfection as well as for studying cellular mechanotransduction. PMID- 22513261 TI - Somatomotor mu rhythm amplitude correlates with rigidity during deep brain stimulation in Parkinsonian patients. AB - OBJECTIVE: Parkinsonian patients have abnormal oscillatory activity within the basal ganglia-thalamocortical circuitry. Particularly, excessive beta band oscillations are thought to be associated with akinesia. We studied whether cortical spontaneous activity is modified by deep brain stimulation (DBS) in advanced Parkinson's disease and if the modifications are related to the clinical symptoms. METHODS: We studied the effects of bilateral electrical stimulation of subthalamic nucleus (STN) on cortical spontaneous activity by magnetoencephalography (MEG) in 11 Parkinsonian patients. The artifacts produced by DBS were suppressed by tSSS algorithm. RESULTS: During DBS, UPDRS (Unified Parkinson's Disease Rating Scale) rigidity scores correlated with 6-10 Hz and 12 20 Hz somatomotor source strengths when eyes were open. When DBS was off UPDRS action tremor scores correlated with pericentral 6-10 Hz and 21-30 Hz and occipital alpha source strengths when eyes open. Occipital alpha strength decreased during DBS when eyes closed. The peak frequency of occipital alpha rhythm correlated negatively with total UPDRS motor scores and with rigidity subscores, when eyes closed. CONCLUSION: STN DBS modulates brain oscillations both in alpha and beta bands and these oscillations reflect the clinical condition during DBS. SIGNIFICANCE: MEG combined with an appropriate artifact rejection method enables studies of DBS effects in Parkinson's disease and presumably also in the other emerging DBS indications. PMID- 22513262 TI - The Junior Temperament and Character Inventory: Italian validation of a questionnaire for the measurement of personality from ages 6 to 16 years. AB - The Junior Temperament and Character Inventory (JTCI) has been developed for the assessment of the personality in individuals 6 to 14 years old according to the psychobiological model of Cloninger. The aim of the present study was to evaluate the psychometric properties of an Italian version of JTCI. The sample included 459 subjects ranging in age from 6 to 15.9 years. Starting from the original parent version, an Italian version of JTCI was developed and administered to parents recruited in primary schools of Lazio and Campania. Using statistically appropriate methods for the analysis of dichotomous variables (binary coded), we analyzed the factor structure, the internal consistency, and the test-retest reliability. The architecture of the JTCI was consistent with the original hypothesis of the Cloninger model. Parent reports of each of the JTCI dimensions had good internal consistency and test-retest reliability over 3 months. Regarding the analysis of risk personality traits, significant correlations were found between several JTCI factors and Strengths and Difficulties Questionnaire scales. The JTCI is useful in research and in clinical practice to evaluate the role of temperament and character dimensions in psychopathology. PMID- 22513263 TI - Carbonic anhydrase autoantibodies and sicca symptoms in primary Sjogren's syndrome. PMID- 22513264 TI - Dipole relaxation in erythrocyte membrane: involvement of spectrin skeleton. AB - Polarization of spectrin-actin undermembrane skeleton of red blood cell (RBC) plasma membranes was studied by impedance spectroscopy. Relatedly, dielectric spectra of suspensions that contained RBCs of humans, mammals (bovine, horse, dog, cat) and birds (turkey, pigeon, duck), and human RBC ghost membranes were continuously obtained during heating from 20 to 70 degrees C. Data for the complex admittance and capacitance were used to derive the suspension resistance, R, and capacitance, C, as well as the energy loss as a function of temperature. As in previous studies, two irreversible temperature-induced transitions in the human RBC plasma membrane were detected at 49.5 degrees C and at 60.7 degrees C (at low heating rate). The transition at 49.5 degrees C was evident from the abrupt changes in R, and C and the fall in the energy loss, due to dipole relaxation. For the erythrocytes of indicated species the changes in R and C displayed remarkable and similar frequency profiles within the 0.05-13MHz domain. These changes were subdued after cross-linking of membranes by diamide (0.3 1.3mM) and glutaraldehyde (0.1-0.4%) and at the presence of glycerol (10%). Based on the above results and previous reports, the dielectric changes at 49.5 degrees C were related to dipole relaxation and segmental mobility of spectrin cytoskeleton. The results open the possibility for selective dielectric thermolysis of cell cytoskeleton. PMID- 22513257 TI - Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers. AB - INTRODUCTION: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. METHODS: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers. RESULTS: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBPalpha, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048). CONCLUSIONS: Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele. PMID- 22513265 TI - Voltammetric detection of L-dopa and carbidopa on graphene modified glassy carbon interfaces. AB - The present work reports on the use of graphene nanosheets, deposited on glassy carbon, as electrode materials, and their electrochemical characterization. The graphene nanosheets were obtained by chemical reduction of graphene oxide using hydrazine. The possibility of analyzing L-dopa and carbidopa, two important catecholamines found in pharmaceutical products, separately and simultaneously by differential pulse voltammetry utilizing graphene modified GC interfaces is investigated. Voltammetric peak currents showed a linear response for both catecholamines in the range of 1-16 MUM. The detection limit was about two times lower for L-dopa than carbidopa being 0.8 MUM and 1.8 MUM, respectively with a current sensitivity of (2.15 +/- 0.5) and (0.48 +/- 0.3) MUA MUM(-1). Simultaneous detection of both catecholamines can be achieved on these electrodes. Equivalent amounts of L-dopa and carbidopa have no effect on the detection limit of L-dopa. In addition, the presence of L-dopa with concentrations 4 times higher than carbidopa has no influence on the voltammetric profile. PMID- 22513266 TI - The initial phase for validating the European algorithm for functional assessment prior to lung resection: quantifying compliance with the recommendations in actual clinical practice. AB - OBJECTIVE: To quantify the degree of compliance with the recommendations of the clinical practice guidelines published in 2009 by the ERS and the ESTS regarding the preoperative assessment of risk of lung resection in daily clinical practice at a tertiary hospital. METHOD: A prospective, observational study of real-time data collected from consecutive patients who had been referred for evaluation from September 2009 to December 2010. We recorded the presence or absence of the recommended studies included in the algorithm, their results and, when a test was missing, the reasons why it was not performed. Hospital mortality and cardio respiratory morbidity rates are also presented. RESULTS: 173 patients were evaluated. In 171 cases, lung resection was performed, with a mortality of 1.2% and a cardio-respiratory morbidity of 11.7%. The failure rate of the first level of the algorithm was 4.6% and for the second level (VO(2max) test) it was 26%. The absence of exercise tests was mainly due to hospital structural problems and the patients' inability to perform it. Out of the patients who performed the exercise testing, 31 reached a VO(2max) of 20 ml/kg-min or more and underwent surgery without calculation of FEV(1)ppo and DCLOppo; 35 patients required the calculation to determine their operability and in 2 cases the intervention was not recommended due to functional inoperability of the patient. CONCLUSIONS: The validation process found lack of compliance with the proposed algorithm in 18.5% of the cases basically due to the absence of the exercise tests. The rate of adherence to the algorithm recommendations should be improved before performing any other validation studies. PMID- 22513267 TI - Thrombotic complications and thromboprophylaxis across all three stages of single ventricle heart palliation. AB - OBJECTIVES: To describe the incidence of thrombotic complications across all 3 stages of single ventricle palliation and the association between thromboprophylaxis use and thrombotic risk. STUDY DESIGN: Two separate cross sectional studies were performed that included 195 patients born between 2003 2008 and 162 patients who underwent Fontan after 2000. RESULTS: The incidence of thrombotic complications was 40% and 28% after initial palliation and superior cavopulmonary connection (SCPC), respectively; 5-year freedom from thrombotic complications after Fontan was 79%. Thromboprophylaxis was initiated for 70%, 46%, and 94% of patients after initial palliation, SCPC, and Fontan, respectively. Thromboprophylaxis with enoxaparin (vs no thromboprophylaxis) was associated with a reduction in risk of thrombotic complications after initial palliation (hazard ratio [HR] 0.5, P = .05) and SCPC (HR 0.2, P = .04). Thromboprophylaxis with warfarin was associated with a reduction in thrombotic complications after Fontan (HR 0.27, P = .05 vs acetylsalicylic acid; HR 0.18, P = .02 vs no thromboprophylaxis). Thrombotic complications were associated with increased mortality after initial palliation (HR 5.5, P < .001) and SCPC (HR 12.5, P < .001). Three patients experienced major bleeding complications without permanent sequelae (2 enoxaparin, 1 warfarin). CONCLUSIONS: Given the negative impact of thrombotic complications on survival, the low risk of serious bleeding complications, and the association between thromboprophylaxis and lowered thrombotic complication risk across all 3 palliative stages, routine use of thromboprophylaxis from the initial palliation to the early post-Fontan period in this population may be indicated. PMID- 22513268 TI - A potential new method to estimate tissue cystine content in nephropathic cystinosis. AB - OBJECTIVES: To evaluate intestinal mucosal cystine crystal (CC) load as a way to estimate tissue cystine content in children with cystinosis. STUDY DESIGN: Intestinal mucosal biopsies were obtained endoscopically from children (ages 2-18 years) with cystinosis. Using a special processing technique, CC within histiocytes were easily visible and enumerable in the mucosal tissue. Mean CC counts, calculated from stomach and duodenum combined (CC-GD), were correlated with duration of cysteamine treatment, estimated glomerular filtration rate (eGFR), and mean white blood cells (WBC) cystine levels. RESULTS: Seventeen subjects (6 male) were enrolled in 2 studies from 2001 and 2003. The CC-GD count (mean 12.5 +/- 1.41 crystals/histiocyte) was lower than the colonic crystal count (mean 23.6 +/- 3.38, P = .0031). Nine of 17 subjects underwent repeated endoscopy 2 years later and the trend for CC-GD was to decrease over time (P = .065). Biopsies, however, were never completely depleted of CC. In subjects who were diagnosed before age 18 months, the percent change from baseline of both eGFR and CC-GD were inversely correlated (P = .026). Mean WBC cystine levels were positively correlated with CC-GD (P = .023). CONCLUSIONS: CC are easily visible in the intestinal mucosa. CC-GD counts appear to correlate with eGFR and may help monitor response to treatment. Even when mean WBC cystine levels are low, the mucosal CC are not depleted suggesting that tissue cysteamine levels may not achieve therapeutic efficacy. PMID- 22513269 TI - Growth of preterm and full-term children aged 0-4 years: integrating median growth and variability in growth charts. AB - OBJECTIVES: To assess the distribution of height, weight, and head circumference (HC) in preterm infants for ages 0-4 years, by gestational age (GA) and sex, and to construct growth reference charts for preterm-born children, again by GA and sex, for monitoring growth in clinical practice. STUDY DESIGN: The community based cohort study covered a quarter of The Netherlands. 1690 preterm infants (GA, 25-35(+6) weeks) and a random sample of 634 full-term control infants (GA 38 41(+6)), who were followed from birth to 4 years of age. Height, weight, and HC were regularly assessed during routine well-child visits and data were retrospectively collected. RESULTS: At all ages, the median height and weight of preterm children were lower compared with full-term children. Growth depended on the child's GA. Increase in HC showed an early catch-up and was similar to full term children by the age of 1. Height, weight, and HC were more variable in boys, particularly in the very preterm children. CONCLUSIONS: At 0 to 4 years, the growth of preterm children differed from that of full-term children and depended on their GA. The greater variability of growth in boys suggests that they are more vulnerable to the complications of preterm birth that influence growth. These growth charts are the most precise tools currently available for monitoring growth in preterm children. PMID- 22513270 TI - Cow's milk challenge increases weakly acidic reflux in children with cow's milk allergy and gastroesophageal reflux disease. AB - OBJECTIVE: To assess and compare the pattern of reflux in a selected population of infants with cow's milk (CM) allergy (CMA) and suspected gastroesophageal reflux disease (GERD) while on dietary exclusion and following challenge with CM. STUDY DESIGN: Seventeen children (median age: 14 months) with a proven diagnosis of CMA and suspected GERD underwent 48-hour multichannel intraluminal impedance pH monitoring. For the first 24 hours, the infants were kept on amino acid-based formula, and for the subsequent 24 hours, they were challenged with CM. RESULTS: The total reflux episodes and the number of weakly acidic episodes were higher during CM challenge compared with the amino acid-based formula period [total reflux episodes: 105 (58-127.5) vs 65 (39-87.5), P < .001; weakly acidic episodes: 53 (38.5-60.5) vs 19 (13-26.5), P < .001; median (25th-75th)]. No differences were found for either acid or weakly alkaline episodes (not significant). The number of weakly acidic episodes reaching the proximal, mid, and distal esophagus was higher during CM challenge (P < .001). No differences were found in either acid exposure time or number of long-lasting episodes (not significant). CONCLUSIONS: In children with CMA and suspected GERD, CM exposure increases the number of weakly acidic reflux episodes. CM challenge during 48 hour multichannel intraluminal impedance-pH monitoring identifies a subgroup of patients with allergen-induced reflux, and in selected cases of children with CMA in whom GERD is suspected, its use could be considered as part of diagnostic work up. PMID- 22513271 TI - The influence of age at menarche on cross-sectional geometry of bone in young adulthood. AB - Elucidating the somatic and maturational influences on the biomechanical properties of bone in children is crucial for a proper understanding of bone strength and quality in childhood and later life, and has significant potential for predicting adult fracture and osteoporosis risks. The ability of a long bone to resist bending and torsion is primarily a function of its cross-sectional geometric properties, and is negatively impacted by smaller external bone diameter. In pubescent girls, elevated levels of estrogen impede subperiosteal bone growth and increase endosteal bone deposition, resulting in bones averaging a smaller external and internal diameter relative to boys. In addition, given a well-documented secular trend for an earlier menarche, the age at which the rate of subperiosteal bone deposition decreases may also be younger in more recent cohorts of girls. In this study we examined the relationship between pubertal timing and subsequent bone strength in girls. Specifically, we investigated the effects of age at menarche on bone strength indicators (polar moment of inertia and section modulus) determined from cross-sectional geometry of the second metacarpal (MC2) using data derived from serial hand-wrist radiographs of female participants (N=223) in the Fels Longitudinal Study, with repeated measures of MC2 between the ages of 7 and 35 years. Using multivariate regression models, we evaluated the effects of age at menarche on associations between measures of bone strength in early adulthood and the same measures at a prepubertal age. Results indicate that later age at menarche is associated with stronger adult bone (in torsion and bending) when controlling for prepubertal bone strength (R(2) ranged between 0.54 and 0.70, p<0.001). Since cross-sectional properties of bone in childhood may have long lasting implications, they should be considered along with pubertal timing in assessing risk for future fracture and in clinical recommendations. PMID- 22513273 TI - Regulation of the fate of human mesenchymal stem cells by mechanical and stereo topographical cues provided by silicon nanowires. AB - Extracellular stimuli imposed on stem cells enable efficient initiation of mechanotransductive signaling to regulate stem cell fates; however, how such physical cues conferred by the stereo-topographical matrix govern the fate of stem cells still remains unknown. The purpose of this study is to delineate the effects of stereotopography and its various relevant physical properties on the fate regulation of human mesenchymal stem cells (hMSCs). Stereo-topographical silicon nanowires (SiNWs) that were precisely controlled with respect to their various dimensions and their growth orientation were used in this study. hMSCs cultured on stereo SiNWs of different lengths in the absence of biochemical osteogenic induction cues displayed a spherical and less-elongated morphology and showed an approximately 10% loss of cell viability compared to those grown on two dimensional (2-D) flat Si. Moreover, osteogenic gene expression of COL1A1 and Runx2 in hMSCs cultured on the shortest SiNWs was significantly higher than those grown on the longer SiNWs and 2-D flat Si. hMSCs grown on shorter SiNWs also demonstrated higher expression levels for F-actin, phosphorylated focal adhesion kinase (pFAK), vinculin and alpha 2 integrin. Stereo-topographical cues provided by SiNWs are able to regulate osteogenic differentiation of hMSCs via cytoskeleton remodeling and this is correlated with the differential expression of alpha 2/beta 1 integrin heterodimers and the focal adhesion molecules pFAK and vinculin. The findings in this study provide insights in terms of the design of stereo-topographical structures for use in tissue engineering, bone regeneration and relevant medical applications. PMID- 22513274 TI - Thoracoscopic talc versus tunneled pleural catheters for palliation of malignant pleural effusions. AB - BACKGROUND: A malignant pleural effusion (MPE) is a late complication of malignancy that affects respiratory function and quality of life. A strategy for palliation of the symptoms caused by MPE should permanently control fluid accumulation, preclude any need for reintervention, and limit hospital length of stay (LOS). We compared video-assisted thorascopic (VATS) talc insufflation with placement of a tunneled pleural catheter (TPC) to assess which intervention better met these palliative goals. METHODS: We conducted a retrospective chart review of consecutive MPE at a single institution from 2005 through June 2011. Primary a priori outcomes were reintervention in the ipsilateral hemithorax, postprocedure LOS, and overall LOS. RESULTS: One hundred nine patients with MPE were identified. Fifty-nine patients (54%) had TPC placed, and 50 (46%) were treated with VATS talc. Patients who underwent TPC placement had significantly fewer reinterventions for recurrent ipsilateral effusions than patients treated with VATS talc (TPC 2% [1 of 59], talc 16% [8 of 50], p=0.01). Patients treated with TPC had significantly shorter overall LOS (TPC LOS mean 7 days, mode 1 day; talc mean 8 day, mode 4 days, p=0.006) and postprocedure LOS (TPC post-procedure LOS mean 3 days, mode 0 days; talc mean 6 days, mode 3 days, p<0.001). Type of procedure was not associated with differences in complication rate (TPC 5% [3 of 59], talc 14% [7 of 50], p=0.18), or in-hospital mortality (TPC 3% [2 of 59], talc 8% [4 of 50], p=0.41). CONCLUSIONS: TPC placement was associated with a significantly reduced postprocedure and overall LOS compared with VATS talc. Also, TPC placement was associated with significantly fewer ipsilateral reinterventions. Placement of TPC should be considered for palliation of MPE associated symptoms. PMID- 22513272 TI - Mechanisms of carbon nanotube-induced toxicity: focus on oxidative stress. AB - Nanotechnologies are emerging as highly promising technologies in many sectors in the society. However, the increasing use of engineered nanomaterials also raises concerns about inadvertent exposure to these materials and the potential for adverse effects on human health and the environment. Despite several years of intensive investigations, a common paradigm for the understanding of nanoparticle induced toxicity remains to be firmly established. Here, the so-called oxidative stress paradigm is scrutinized. Does oxidative stress represent a secondary event resulting inevitably from disruption of biochemical processes and the demise of the cell, or a specific, non-random event that plays a role in the induction of cellular damage e.g. apoptosis? The answer to this question will have important ramifications for the development of strategies for mitigation of adverse effects of nanoparticles. Recent examples of global lipidomics studies of nanoparticle induced tissue damage are discussed along with proteomics and transcriptomics approaches to achieve a comprehensive understanding of the complex and interrelated molecular changes in cells and tissues exposed to nanoparticles. We also discuss instances of non-oxidative stress-mediated cellular damage resulting from direct physical interference of nanomaterials with cellular structures. PMID- 22513275 TI - Barrett's esophagus. Practical issues for daily routine diagnosis. AB - Most clinicians and researchers agree that Barrett's esophagus (BE) is a precancerous condition which, however, is not easily defined. Whether goblet cells must be present or not is a matter of debate and definitions vary worldwide. Although the use of the term "columnar metaplasia" tends to circumvent these issues, it can also be subdivided into those with and without goblet cells. There is some evidence that Barrett's esophagus results from a multistep process in which goblet cells are a secondary event. Hence, Barrett's adenocarcinoma has recently been shown to originate from areas lacking goblet cells. The histological diagnosis of neoplasia is often hampered by marked interobserver variation. New endoscopic techniques allow for local resections of neoplasia with curative intent. Pathologists should know which pieces of information gastroenterologists need for management options: surveillance versus therapy such as endoscopic resection with or endoscopic ablation without histological specimen. The most important information for gastroenterologists is whether there is neoplasia or not; if any, they need to know the grade (low grade, high grade, carcinoma) and risk factors (vessel permeation, poor differentiation, resection complete in case of endoscopic resection, depth of infiltration). PMID- 22513276 TI - AGT M235T polymorphism contributes to risk of preeclampsia: evidence from a meta analysis. AB - OBJECTIVE: Preeclampsia a hypertensive disorder of pregnancy that mainly manifests as high blood pressure and proteinuria. Angiotensinogen (AGT) plays important roles in the regulation of blood pressure. The purpose of this study was to investigate the relationship between AGT M235T polymorphism and risk of preeclampsia using a meta-analysis. METHODS: In this meta-analysis, 22 studies were selected by searching PubMed, EMBASE, ISI and CNKI databases up to October 2011. Crude odds ratios with corresponding 95% confidence intervals were used to evaluate the association between the AGT M235T polymorphism and risk of preeclampsia. Subgroup analyses were conducted by ethnicity and parity. RESULTS: The TT genotype of the AGT M235T polymorphism was associated with elevated risk of preeclampsia in the overall analysis. In subgroup analysis according to ethnicity, increased risks were also found in Caucasians. After stratification based on parity, the excess risk was found in multigravida. CONCLUSIONS: These results showed that the TT genotype may play critical roles in the development of preeclampsia. PMID- 22513277 TI - Working against gravity: horizontal honeybee waggle runs have greater angular scatter than vertical waggle runs. AB - The presence of noise in a communication system may be adaptive or may reflect unavoidable constraints. One communication system where these alternatives are debated is the honeybee (Apis mellifera) waggle dance. Successful foragers communicate resource locations to nest-mates by a dance comprising repeated units (waggle runs), which repetitively transmit the same distance and direction vector from the nest. Intra-dance waggle run variation occurs and has been hypothesized as a colony-level adaptation to direct recruits over an area rather than a single location. Alternatively, variation may simply be due to constraints on bees' abilities to orient waggle runs. Here, we ask whether the angle at which the bee dances on vertical comb influences waggle run variation. In particular, we determine whether horizontal dances, where gravity is not aligned with the waggle run orientation, are more variable in their directional component. We analysed 198 dances from foragers visiting natural resources and found support for our prediction. More horizontal dances have greater angular variation than dances performed close to vertical. However, there is no effect of waggle run angle on variation in the duration of waggle runs, which communicates distance. Our results weaken the hypothesis that variation is adaptive and provide novel support for the constraint hypothesis. PMID- 22513278 TI - Biology, not environment, drives major patterns in maximum tetrapod body size through time. AB - Abiotic and biological factors have been hypothesized as controlling maximum body size of tetrapods and other animals through geological time. We analyse the effects of three abiotic factors--oxygen, temperature and land area--on maximum size of Permian-Jurassic archosauromorphs and therapsids, and Cenozoic mammals, using time series generalized least-squares regression models. We also examine maximum size growth curves for the Permian-Jurassic data by comparing fits of Gompertz and logistic models. When serial correlation is removed, we find no robust correlations, indicating that these environmental factors did not consistently control tetrapod maximum size. Gompertz models--i.e. exponentially decreasing rate of size increase at larger sizes--fit maximum size curves far better than logistic models. This suggests that biological limits such as reduced fecundity and niche space availability become increasingly limiting as larger sizes are reached. Environmental factors analysed may still have imposed an upper limit on tetrapod body size, but any environmentally imposed limit did not vary substantially during the intervals examined despite variation in these environmental factors. PMID- 22513279 TI - Ontogenetic niche shifts in dinosaurs influenced size, diversity and extinction in terrestrial vertebrates. AB - Given the physiological limits to egg size, large-bodied non-avian dinosaurs experienced some of the most extreme shifts in size during postnatal ontogeny found in terrestrial vertebrate systems. In contrast, mammals--the other dominant vertebrate group since the Mesozoic--have less complex ontogenies. Here, we develop a model that quantifies the impact of size-specific interspecies competition on abundances of differently sized dinosaurs and mammals, taking into account the extended niche breadth realized during ontogeny among large oviparous species. Our model predicts low diversity at intermediate size classes (between approx. 1 and 1000 kg), consistent with observed diversity distributions of dinosaurs, and of Mesozoic land vertebrates in general. It also provides a mechanism--based on an understanding of different ecological and evolutionary constraints across vertebrate groups--that explains how mammals and birds, but not dinosaurs, were able to persist beyond the Cretaceous-Tertiary (K-T) boundary, and how post-K-T mammals were able to diversify into larger size categories. PMID- 22513281 TI - Niche-based mechanisms operating within extreme habitats: a case study of subterranean amphipod communities. AB - It has been suggested that both niche-based and neutral mechanisms are important for biological communities to evolve and persist. For communities in extreme and isolated environments such as caves, theoretical and empirical considerations (low species turnover, high stress, strong convergence owing to strong directional selection) predict neutral mechanisms and functional equivalence of species. We tested this prediction using subterranean amphipod communities from caves and interstitial groundwater. Contrary to expectations, functional morphological diversity within communities in both habitats turned out to be significantly higher than the null model of randomly assembled communities. This suggests that even the most extreme, energy-poor environments still maintain the potential for diversification via differentiation of niches. PMID- 22513280 TI - Trans-oceanic host dispersal explains high seabird tick diversity on Cape Verde islands. AB - Parasites represent ideal models for unravelling biogeographic patterns and mechanisms of diversification on islands. Both host-mediated dispersal and within island adaptation can shape parasite island assemblages. In this study, we examined patterns of genetic diversity and structure of Ornithodoros seabird ticks within the Cape Verde Archipelago in relation to their global phylogeography. Contrary to expectations, ticks from multiple, geographically distant clades mixed within the archipelago. Trans-oceanic colonization via host movements probably explains high local tick diversity, contrasting with previous research that suggests little large-scale dispersal in these birds. Although host specificity was not obvious at a global scale, host-associated genetic structure was found within Cape Verde colonies, indicating that post-colonization adaptation to specific hosts probably occurs. These results highlight the role of host metapopulation dynamics in the evolutionary ecology and epidemiology of avian parasites and pathogens. PMID- 22513282 TI - Synthesis and anti-norovirus activity of pyranobenzopyrone compounds. AB - During the last decade, noroviruses have gained media attention as the cause of large scale outbreaks of gastroenteritis on cruise ships, dormitories, nursing homes, etc. Although noroviruses do not multiply in food or water, they can cause large outbreaks because approximately 10-100 virions are sufficient to cause illness in a healthy adult. Recently, it was shown that the activity of acyl coenzyme A:cholesterol acyltransferase-1 (ACAT1) enzyme may be important in norovirus infection. In search of anti-noroviral agents based on the inhibition of ACAT1, we synthesized and evaluated the inhibitory activities of a class of pyranobenzopyrone molecules containing amino, pyridine, substituted quinolines, or 7,8-benzoquinoline nucleus. Three of the sixteen evaluated compounds possess ED(50) values in the low micrometer range. 2-Quinolylmethyl derivative 3A and 4 quinolylmethyl derivative 4A showed ED(50) values of 3.4 and 2.4 MUM and TD(50) values of >200 and 96.4 MUM, respectively. The identified active compounds are suitable for further modification for the development of anti-norovirus agents. PMID- 22513283 TI - Substrate specificity of galactokinase from Streptococcus pneumoniae TIGR4 towards galactose, glucose, and their derivatives. AB - Galactokinases (GalKs) have attracted significant research attention for their potential applications in the enzymatic synthesis of unique sugar phosphates. The galactokinase (GalKSpe4) cloned from Streptococcus pneumoniae TIGR4 presents a remarkably broad substrate range including 14 diverse natural and unnatural sugars. TLC and MS studies revealed that GalKSpe4 had relaxed activity towards galactose derivatives with modifications on the C-6, 4- or 2-positions. Additionally, GalKSpe4 can also tolerate glucose while glucose derivatives with modifications on the C-6, 4- or 2-positions were unacceptable. More interestingly, GalKSpe4 can phosphorylate L-mannose in moderate yield (43%), while other L-sugars such as L-Gal cannot be recognized by this enzyme. These results are very significant because there is rarely enzyme reported that can phosphorylate such uncommon substrates as l-mannose. PMID- 22513284 TI - Positive selection on the gene RNASEL: correlation between patterns of evolution and function. AB - RNASEL is a 2-5A-dependent endoribonuclease that is a component of the interferon induced 2-5A system, which plays a crucial role in the antiviral and apoptotic activities of interferons. In humans, many polymorphic sites within the RNASEL gene have been associated with an increased risk of developing prostate cancer. Here, we obtained coding sequences for the RNASEL gene from 11 primates and found evidence that positive selection has operated on the C-terminal endoribonuclease domain and the N-terminal ankyrin repeats domain of the protein, domains that directly interact with virus (i.e., ankyrin repeats are responsible for receiving environmental signals, and the endoribonuclease catalyses the destruction of the pathogenic viral RNA). To extend this finding, we studied variation within this gene in modern human populations by resequencing alleles from 144 individuals representing four separate populations. Interestingly, the frequency of the 541D allele shows a negative association with the incidence rate of prostate cancer in worldwide populations, and haplotypes containing the 541D polymorphisms demonstrate signatures of positive selection. RNASEL variants having the 541D haplotype likely have a greater ability to defend against infections by viruses, thus the loss of this activity may be associated with the development of prostate cancer. We provide evidence that positive selection has operated on the RNASEL gene, and its evolution is correlated with its function in pathogen defense and cancer association. PMID- 22513285 TI - Blood system formation in the urochordate Ciona intestinalis requires the variable receptor vCRL1. AB - Adaptive immune systems are present only in vertebrates. How do all the remaining animals withstand continuous attacks of permanently evolving pathogens? Even in the absence of adaptive immunity, every organism must be able to unambiguously distinguish "self" cells from any imaginable "nonself." Here, we analyzed the function of highly polymorphic gene vCRL1, which is expressed in follicle and blood cells of Ciona intestinalis, pointing to possible recognition roles either during fertilization or in immune reactions. By using segregation analysis, we demonstrate that vCRL1 locus is not involved in the control of self-sterility. Interestingly, genetic knockdown of vCRL1 in all tissues or specifically in hemocytes results in a drastic developmental arrest during metamorphosis exactly when blood system formation in Ciona normally occurs. Our data demonstrate that vCRL1 gene might be essential for the establishment of a functional blood system in Ciona. Presumably, presence of the vCRL1 receptor on the surface of blood cells renders them as self, whereas any cell lacking it is referred to as nonself and will be consequently destroyed. We propose that individual-specific receptor vCRL1 might be utilized to facilitate somatic self/nonself discrimination. PMID- 22513286 TI - Local adaptation in the flowering-time gene network of balsam poplar, Populus balsamifera L. AB - Identifying the signature and targets of local adaptation is an increasingly important goal in empirical population genetics. Using data from 443 balsam poplar Populus balsamifera trees sampled from 31 populations, we tested for evidence of geographically variable selection shaping diversity at 27 homologues of the Arabidopsis flowering-time network. These genes are implicated in the control of seasonal phenology, an important determinant of fitness. Using 335 candidate and 412 reference single nucleotide polymorphisms (SNPs), we tested for evidence of local adaptation by searching for elevated population differentiation using F(ST)-based outlier analyses implemented in BayeScan or a Hierarchical Model in Arelquin and by testing for significant associations between allele frequency and environmental variables using BAYENV. A total of 46 SNPs from 14 candidate genes had signatures of local adaptation-either significantly greater population differentiation or significant covariance with one or more environmental variable relative to reference SNP distributions. Only 11 SNPs from two genes exhibited both elevated population differentiation and covariance with one or more environmental variables. Several genes including the abscisic acid gene ABI1B and the circadian clock genes ELF3 and GI5 harbored a large number of SNPs with signatures of local adaptation-with SNPs in GI5 strongly covarying with both latitude and precipitation and SNPs in ABI1B strongly covarying with temperature. In contrast to several other systems, we find little evidence that photoreceptors, including phytochromes, play an important role in local adaptation. Our results additionally show that detecting local adaptation is sensitive to the analytical approaches used and that model-based significance thresholds should be viewed with caution. PMID- 22513287 TI - Ancient structure in Africa unlikely to explain Neanderthal and non-African genetic similarity. AB - Neanderthals have been shown to share more genetic variants with present-day non Africans than Africans. Recent admixture between Neanderthals and modern humans outside of Africa was proposed as the most parsimonious explanation for this observation. However, the hypothesis of ancient population structure within Africa could not be ruled out as an alternative explanation. We use simulations to test whether the site frequency spectrum, conditioned on a derived Neanderthal and an ancestral Yoruba (African) nucleotide (the doubly conditioned site frequency spectrum [dcfs]), can distinguish between models that assume recent admixture or ancient population structure. We compare the simulations to the dcfs calculated from data taken from populations of European, Chinese, and Japanese descent in the Complete Genomics Diversity Panel. Simulations under a variety of plausible demographic parameters were used to examine the shape of the dcfs for both models. The observed shape of the dcfs cannot be explained by any set of parameter values used in the simulations of the ancient structure model. The dcfs simulations for the recent admixture model provide a good fit to the observed dcfs for non-Africans, thereby supporting the hypothesis that recent admixture with Neanderthals accounts for the greater similarity of Neanderthals to non Africans than Africans. PMID- 22513289 TI - Pancreatic tumor sensitivity to plasma L-asparagine starvation. AB - OBJECTIVES: In this study, our aim was to test whether asparagine synthetase (ASNS) deficiency in pancreatic malignant cells can lead to sensitivity to asparagine starvation. We also investigated, in tumor-bearing mice, the efficacy of L-asparaginase entrapped in red blood cells (RBCs), a safe formulation, to induce asparagine depletion. METHODS: First, ASNS expression was evaluated by immunohistochemistry in sporadic pancreatic ductal adenocarcinoma. Then, 4 pancreatic carcinoma cell lines were examined by Western blot, immunocytochemistry, and cytotoxicity assay to L-asparaginase and in asparagine free or reduced-asparagine media. Finally, mice bearing the most in vitro sensitive cell line received RBC-entrapped L-asparaginase to investigate the anticancer efficacy of serum asparagine depletion in vivo. RESULTS: Approximately 52% of pancreatic adenocarcinomas expressed no or low ASNS. The highest in vitro cytotoxicity to L-asparaginase or to reduced asparagine medium was observed with SW1990 line when ASNS expression was the lowest. In vivo sensitivity was confirmed for this cell line. CONCLUSIONS: Plasma asparagine depletion by RBC entrapped L-asparaginase in selected patients having no low or no ASNS may be a promising therapeutic approach for pancreatic cancer. PMID- 22513290 TI - Meta-analysis: the placebo rate of abdominal pain remission in clinical trials of chronic pancreatitis. AB - OBJECTIVES: Treatment of the pain caused by chronic pancreatitis (CP) is not standardized. Knowledge of the response to placebo in this setting may aid the design of future trials. We aimed at investigating the placebo effect on abdominal pain remission rates in patients with CP. METHODS: MEDLINE, EMBASE, and Scopus were searched, and randomized placebo-controlled trials in CP providing data on abdominal pain remission rates in placebo arms were included. Pooled estimates of the placebo rate were calculated using random-effects logistic regression analysis. Stratum-specific rates for different patients and study level covariates were calculated to account for heterogeneity. RESULTS: Seven randomized controlled trials (202 placebo-treated patients) met the predefined criteria. The pooled estimate of the placebo rate for pain remission was 19.9% (95% confidence interval, 9%-36%). There was a statistically significant heterogeneity among the studies (I(2) = 76%; P < 0.001). A multicenter design, a run-in period of less than 2 weeks, and absence of a washout in crossover trials were all significant sources of heterogeneity associated with higher placebo responses. CONCLUSIONS: This meta-analysis identifies for the first time the efficacy of placebo for pain in CP and variables determining it. These data provide a sound basis for designing future placebo-controlled randomized clinical trials for the treatment of pain in CP. PMID- 22513288 TI - Analysis of terminal duct lobular unit involution in luminal A and basal breast cancers. AB - INTRODUCTION: Involution of terminal duct lobular units (TDLUs), the structures that give rise to most breast cancers, has been associated with reduced breast cancer risk. Data suggest that the etiology and pathogenesis of luminal A and core basal phenotype (CBP) breast cancers differ, but associations with TDLU involution are unknown. Accordingly, we performed a masked microscopic assessment of TDLU involution in benign tissues associated with luminal A and CBP breast cancers diagnosed among women less than age 55 years. METHODS: Cases were participants in a population-based case-control study conducted in Poland. Increased TDLU involution was defined as fewer acini per TDLU or shorter TDLU diameter. Luminal A was defined as estrogen receptor (ER) positive and/or progesterone receptor (PR) positive and human epidermal growth factor receptor 2 (HER2) negative and CBP as negative for ER, PR, and HER2 with expression of basal cytokeratins or epidermal growth factor receptor (EGFR). We performed logistic regression to evaluate associations between TDLU involution and tumor subtypes, adjusted for clinical characteristics and breast cancer risk factors. RESULTS: Among 232 luminal A and 49 CBP cancers associated with evaluable TDLUs, CBP tumors were associated with significantly greater average number of acini per TDLU (odds ratio (OR) = 3.36, 95% confidence interval (CI) = 1.36 to 8.32, P = 0.009) and larger average TDLU diameter (OR = 2.49, 95% CI = 1.08 to 5.74, P = 0.03; comparing highest to lowest group, adjusted for age and study site). CONCLUSIONS: We suggest that TDLU involution is less marked in benign tissues surrounding CBP as compared to luminal A cancers, which may reflect differences in the etiology and pathogenesis of these tumor subtypes. PMID- 22513291 TI - Enhanced antitumor effect of combination therapy with gemcitabine and guggulsterone in pancreatic cancer. AB - OBJECTIVES: Guggulsterone is a dietary plant sterone possessing therapeutic potential against cancers. However, the antitumor effect of this natural compound on pancreatic cancer has not been determined yet. This study was designed to investigate the therapeutic efficacy of guggulsterone in pancreatic cancer. METHODS: In this study, we examined the effect of guggulsterone on cell proliferation and apoptosis in pancreatic cancer cell lines, and then, we investigated the mechanisms responsible for the effect of guggulsterone. Finally, we investigated whether the combination of guggulsterone and gemcitabine had an additional therapeutic effect compared to gemcitabine single regimen in pancreatic cancer cell lines (in vitro) and in a xenograft model using nude mice (in vivo). RESULTS: In vitro, the combination treatment resulted in more growth inhibition and apoptosis through the down-regulation of nuclear factor kappaB activity with suppression of Akt and BcL-2 and through the activation of c-Jun NH(2)-terminal kinase and Bax in pancreatic cancer cell lines. In vivo, the combination therapy augmented tumor growth inhibition through the same mechanisms in tumor tissue. CONCLUSIONS: The combination of guggulsterone to gemcitabine enhanced antitumor efficacy through apoptosis induction by suppressing Akt and nuclear factor kappaB activity and by modulating apoptosis-related protein expression in pancreatic cancer. PMID- 22513292 TI - Clinical burden of illness in patients with neuroendocrine tumors. AB - OBJECTIVE: The objective of this study was to evaluate the incremental risk of morbidities affecting the cardiovascular, hepatic, gastrointestinal, skeletal, and neuropsychiatric systems in patients with neuroendocrine tumors (NETs) compared with a noncancer cohort. METHODS: In a retrospective, matched-control study using US claims databases, noncancer control subjects (n = 3524) were matched 2:1 with patients with newly diagnosed NET (n = 1762) on age, sex, region, hospital data availability, and index year. Rates of select morbidities were compared between patients with NET and control subjects. Incremental risks were analyzed using logistic regressions adjusting for baseline characteristics. RESULTS: In the first 3 years after diagnosis in patients with NET versus matched control subjects without cancer, (1) the adjusted risk of cardiovascular morbidities was higher (odds ratio [OR], 1.26; P = 0.0206); (2) the adjusted risk of hepatic or gastrointestinal morbidities was higher (OR, 1.95, P < 0.0001); (3) the adjusted risk of osteoporosis/osteopenia was higher among those 50 years or younger (OR, 3.24; P = 0.0081); and (4) the adjusted risk of anxiety/depression was higher among those 65 years or younger (OR, 1.48; P = 0.0210). CONCLUSIONS: Patients with NET have greater clinical burden of disease than matched control subjects with respect to conditions affecting the cardiovascular, hepatic, and gastrointestinal systems. Excess clinical burden of disease with respect to anxiety, depression, osteoporosis, and osteopenia was observed in patients with NET in the younger age groups. PMID- 22513293 TI - Plasma Shh levels reduced in pancreatic cancer patients. AB - OBJECTIVES: Normally, sonic hedgehog (Shh) is expressed in the pancreas during fetal development and transiently after tissue injury. Although pancreatic cancers express Shh, it is not known if the protein is secreted into the blood and whether its plasma levels change with pancreatic transformation. The goal of this study was to develop an enzyme-linked immunosorbent assay to detect human Shh in blood and determine its levels in subjects with and without pancreatic cancer. METHODS: A human Shh enzyme-linked immunosorbent assay was developed, and plasma Shh levels were measured in blood samples from healthy subjects and patients with pancreatitis or pancreatic cancer. The biological activity of plasma Shh was tested using NIH-3T3 cells. RESULTS: The mean levels of Shh in human blood were lower in patients with pancreatitis and pancreatic cancer than in healthy subjects. Hematopoietic cells did not express Shh, suggesting that Shh is secreted into the bloodstream. Plasma fractions enriched with Shh did not induce Gli-1 messenger RNA, suggesting that the protein was not biologically active. CONCLUSIONS: Shh is secreted from tissues and organs into the circulation, but its activity is blocked by plasma proteins. Reduced plasma levels were found in pancreatic cancer patients, but alone were not sufficient to predict pancreatic cancer. PMID- 22513294 TI - Circulating microRNAs in serum of human K-ras oncogene transgenic rats with pancreatic ductal adenocarcinomas. AB - OBJECTIVES: Novel biomarkers for pancreatic ductal adenocarcinoma (PDAC) are urgently needed because of its poor prognosis. We have previously established an animal model for human PDAC using transgenic rats in which expression of a human K-ras(G12V) oncogene is regulated by the Cre/lox system. Using this model, we searched for candidate circulating microRNAs (miRNAs) for use as novel clinical diagnostic biomarkers for PDAC. METHODS: Rats bearing PDACs were generated using our model. MicroRNA expression in serum and pancreatic tissues of PDAC and control rats was compared by microarray analysis. Rat serum levels of 28 miRNAs identified by microarray analysis and 4 miRNAs previously reported to be high in plasma of PDAC patients were quantified by real-time quantitative reverse transcription polymerase chain reaction. RESULTS: Quantification by real-time quantitative polymerase chain reaction revealed that miR-155, miR-21, and miR-210 were higher in serum of PDAC rats, similar to plasma of patients with PDAC. In addition, miR-18a, miR-203, miR-30b-5p, miR-31, miR-369-5p, miR-376a, and miR-541 were higher and miR-375 was lower in the serum of PDAC rats. CONCLUSION: We identified 4 previously unreported miRNAs (miRNA-203, miRNA-369-5p, miRNA-376a, and miRNA-375) whose expression is significantly different in PDAC rats compared to control rats. These miRNAs need to be quantitated in humans as potential novel clinical diagnostic biomarkers for PDAC. PMID- 22513295 TI - Nutritional support in chronic obstructive pulmonary disease: a systematic review and meta-analysis. AB - BACKGROUND: The efficacy of nutritional support in the management of malnutrition in chronic obstructive pulmonary disease (COPD) is controversial. Previous meta analyses, based on only cross-sectional analysis at the end of intervention trials, found no evidence of improved outcomes. OBJECTIVE: The objective was to conduct a meta-analysis of randomized controlled trials (RCTs) to clarify the efficacy of nutritional support in improving intake, anthropometric measures, and grip strength in stable COPD. DESIGN: Literature databases were searched to identify RCTs comparing nutritional support with controls in stable COPD. RESULTS: Thirteen RCTs (n = 439) of nutritional support [dietary advice (1 RCT), oral nutritional supplements (ONS; 11 RCTs), and enteral tube feeding (1 RCT)] with a control comparison were identified. An analysis of the changes induced by nutritional support and those obtained only at the end of the intervention showed significantly greater increases in mean total protein and energy intakes with nutritional support of 14.8 g and 236 kcal daily. Meta-analyses also showed greater mean (+/-SE) improvements in favor of nutritional support for body weight (1.94 +/- 0.26 kg, P < 0.001; 11 studies, n = 308) and grip strength (5.3%, P < 0.050; 4 studies, n = 156), which was not shown by ANOVA at the end of the intervention, largely because of bias associated with baseline imbalance between groups. CONCLUSION: This systematic review and meta-analysis showed that nutritional support, mainly in the form of ONS, improves total intake, anthropometric measures, and grip strength in COPD. These results contrast with the results of previous analyses that were based on only cross-sectional measures at the end of intervention trials. PMID- 22513297 TI - Construction of a 3-D anatomical model for teaching temporal lobectomy. AB - Although we live and work in 3 dimensional space, most of the anatomical teaching during medical school is done on 2-D (books, TV and computer screens, etc). 3-D spatial abilities are essential for a surgeon but teaching spatial skills in a non-threatening and safe educational environment is a much more difficult pedagogical task. Currently, initial anatomical knowledge formation or specific surgical anatomy techniques, are taught either in the OR itself, or in cadaveric labs; which means that the trainee has only limited exposure. 3-D computer models incorporated into virtual learning environments may provide an intermediate and key step in a blended learning approach for spatially challenging anatomical knowledge formation. Specific anatomical structures and their spatial orientation can be further clinically contextualized through demonstrations of surgical procedures in the 3-D digital environments. Recordings of digital models enable learner reviews, taking as much time as they want, stopping the demonstration, and/or exploring the model to understand the anatomical relation of each structure. We present here how a temporal lobectomy virtual model has been developed to aid residents and fellows conceptualization of the anatomical relationships between different cerebral structures during that procedure. We suggest in comparison to cadaveric dissection, such virtual models represent a cost effective pedagogical methodology providing excellent support for anatomical learning and surgical technique training. PMID- 22513299 TI - Canine inflammatory bowel disease: does innate immunity fail to discriminate between friend and foe? PMID- 22513298 TI - Capture-related myopathy in marine mammals and exertional rhabdomyolysis in horses: a possible link? PMID- 22513300 TI - An assessment of the impact of rumenocentesis on pain and stress in cattle and the effect of local anaesthesia. AB - Rumenocentesis is commonly used to collect rumen fluid to screen for acidosis. This study was designed to investigate whether rumenocentesis induced pain and stress and, if so, whether local anaesthesia could limit this. Twenty-four dairy cows were assigned to one of three treatments: (1) rumenocentesis with local anaesthesia (AR); (2) rumenocentesis without local anaesthesia (R); and (3) local anaesthesia only (A). Treatments were performed in a restraining cage. The cows were placed in the cage on three consecutive days and anaesthesia and/or rumenocentesis was performed on the second day. Blood samples for cortisol determination and heart rate were recorded from 0.25 h before treatment until 4h after. Behaviour was noted while the cows were caged. Feed intake and milk production were measured the week before treatment, on the day of treatment, and the day after. With all three treatments, cortisol concentrations and heart rate were increased while cows were in the cage. Cortisol, cardiac and behavioural responses were not significantly higher in the R and AR treatments than the A group. Cortisol concentrations and heart rate did not change between days. Feed intake and milk production were unaffected by the treatments. It was concluded that rumenocentesis does not appear more stressful than local anaesthesia or handling. PMID- 22513301 TI - Protection and antibody isotype responses against Fasciola hepatica with specific antibody to pIII-displayed peptide mimotopes of cathepsin L1 in sheep. AB - Fluke burdens, liver fluke size and biomass, fecal eggs counts, serum levels of hepatic enzymes and immune response were assessed in sheep immunized with peptide mimotopes of cathepsin L1 and challenged with Fasciola hepatica metacercariae. Twenty sheep were randomly allocated to four groups of five animals each; groups 1 and 2 were immunized at weeks 0 and 2 with mimotopes YVYRWVEAECVA and FSPAYLRDAALK, respectively; group 3 was immunized with wild-type M13KE phage and the control group received phosphate-buffered saline (PBS). All groups were challenged with 300 metacercariae at week 6 and slaughtered 16 weeks later. Groups 1 and 2 showed a reduction in fluke burden of 51.7% and 35.9%, respectively, when compared to the control group, but only the former was significant at the 5% level. Vaccinated animals showed a significant reduction in fluke length and width, wet weights and egg output. A significant diminution in the total biomass of parasites recovered was also observed in group 1. Levels of anti-phage total IgG increased rapidly within 2 weeks of the first immunization and were always significantly higher in groups 1 and 2 than in the infected control group. The fluke burden in group 1 was significantly correlated with IgG1 and total IgG. The vaccinated sheep with phage clones produced significantly high titres of IgG1 and IgG2 antibodies indicating a mixed Th1/Th2 response. PMID- 22513302 TI - Arthroscopic approaches to the fetlock joint of adult cattle: a cadaver study. AB - The objective of the present study was to describe the arthroscopic anatomy of the bovine fetlock joint using one palmar/plantar and three dorsal joint approaches. A comparative anatomic, ultrasonographic and arthroscopic study using 20 cadaveric feet from 13 non-lame adult dairy cows was performed. Arthroscopy was accomplished using a rigid arthroscope to view the synovial cavities with their synovial villi and parts of the following structures: the distal ends of the metacarpal/metatarsal III/IV bones with their trochleae and sagittal ridges, synovial grooves, the articular surfaces of the proximal sesamoid bones, the proximal aspects of the first phalanges, the lateral and medial collateral ligaments, the suspensory ligament and the interdigital ligaments as parts of the interosseus muscle, the cruciate sesamoidean ligaments, the communication site between the lateral and medial pouch in the palmar/plantar area, and dorsally the septum between the lateral and the medial pouch. The technique allowed a good overall view of most relevant structures in the sound cadaver joint. Further investigations are warranted to evaluate the diagnostic, therapeutic and prognostic applications of these techniques in the treatment of septic arthritis. PMID- 22513303 TI - The degradation products of UV filters in aqueous and chlorinated aqueous solutions. AB - Ultraviolet (UV) filters are vital constituents of sunscreens and other personal care products since they absorb, reflect and/or scatter UV radiation, therefore protecting us from the sun's deleterious UV radiation and its effects. However, they suffer degradation, mainly through exposure towards sunlight and from reactions with disinfectant products such as chlorine. On the basis of their increasing production and use, UV filters and their degradation products have already been detected in the aquatic environment, especially in bathing waters. This paper presents a comprehensive review on the work done so far as to identify and determine the by-products of UV filter photodegradation in aqueous solutions and those subsequent to disinfection-induced degradation in chlorinated aqueous solutions, namely swimming pools. PMID- 22513304 TI - The effect of ankle taping or bracing on proprioception in functional ankle instability: a systematic review and meta-analysis. AB - OBJECTIVES: To determine if wearing an ankle brace or taping the ankle, compared to no brace or tape, improves proprioceptive acuity in people with a history of ankle sprain or functional ankle instability. DESIGN: Systematic review and meta analysis. METHODS: Studies using controlled, cross-over designs whereby participants who had sprained their ankle at least once or had functional ankle instability, underwent some form of proprioceptive sensation testing with and without ankle brace or tape, were included. Proprioceptive acuity was reported for the ankle tape/brace condition and the condition where no tape or brace was worn. Meta-analysis was employed to compare proprioceptive acuity with and without ankle tape/brace. RESULTS: Eight studies were included in the review. Studies measured either sense of movement or sense of joint position. The mean differences in 19 of 32 comparisons were not significant. Of the remaining mean differences, 10 were positive, indicating better proprioceptive acuity in the taped/braced condition and 3 were negative, indicating poorer proprioceptive acuity. Overall, there was no significant effect with ankle tape/brace compared to the no tape/brace condition (mean difference: 0.08 degrees , 95% CI: -0.39 to 0.55). This finding was consistent when the two aspects of proprioception (sense of movement or joint position) were considered separately. CONCLUSIONS: The pooled evidence suggests that using an ankle brace or ankle tape has no effect on proprioceptive acuity in participants with recurrent ankle sprain or who have functional ankle instability. PMID- 22513296 TI - Obesity susceptibility loci and dietary intake in the Look AHEAD Trial. AB - BACKGROUND: Genome-wide association studies (GWAS) have identified consistent associations with obesity. However, the mechanisms remain unclear. OBJECTIVE: The objective was to determine the association between obesity susceptibility loci and dietary intake. DESIGN: The association of GWAS-identified obesity risk alleles (FTO, MC4R, SH2B1, BDNF, INSIG2, TNNI3K, NISCH-STAB1, MTIF3, MAP2K5, QPCTL/GIPR, and PPARG) with dietary intake, measured through food-frequency questionnaires, was investigated in 2075 participants from the Look AHEAD (Action for Health in Diabetes) clinical trial. We adjusted for age, sex, population stratification, and study site. RESULTS: Obesity risk alleles at FTO rs1421085 significantly predicted more eating episodes per day (P = 0.001)-an effect that persisted after adjustment for body weight (P = 0.004). Risk variants within BDNF were significantly associated with more servings from the dairy product and the meat, eggs, nuts, and beans food groups (P <= 0.004). The risk allele at SH2B1 rs4788099 was significantly associated with more servings of dairy products (P = 0.001), whereas the risk allele at TNNI3K rs1514176 was significantly associated with a lower percentage of energy from protein (P = 0.002). CONCLUSION: These findings suggest that obesity risk loci may affect the pattern and content of food consumption among overweight or obese individuals with type 2 diabetes. The Look AHEAD Genetic Ancillary Study was registered at clinicaltrials.gov as NCT01270763 and the Look AHEAD study as NCT00017953. PMID- 22513307 TI - The many sides of off-label prescribing. PMID- 22513305 TI - Three dimensional culture of fresh and vitrified mouse pre-antral follicles in a hyaluronan-based hydrogel: a preliminary investigation of a novel biomaterial for in vitro follicle maturation. AB - BACKGROUND: Folliculogenesis within the ovary requires interaction between somatic cell components and the oocyte. Maintenance of 3-dimensional (3-D) architecture and granulosa-oocyte interaction may be critical for successful in vitro maturation of follicles. Testing of novel biomaterials for the 3-D culture of follicles may ultimately lead to a culture model that can support the longer in vitro culture intervals needed for in vitro maturation of human oocytes from ovarian tissue biopsies. METHODS: A novel tyramine-based hyaluronan (HA) hydrogel was tested for its biocompatibility with ovarian follicles. The HA was prepared at concentrations from 2 to 5 mg/ml. HA hydrogel was also formulated and tested with matrix proteins (ECM). Enzymatically isolated pre-antral follicles from the ovaries of 10-12 day SJL pups were divided amongst control (CT) and HA treatments. The growth of both fresh and vitrified follicles was assessed after encapsulation in the hydrogel. The basal culture medium was MEM alpha supplemented with FSH, LH, ITS and 5% FBS. Maturation was triggered by addition of hCG and EGF after in vitro culture (IVC). Outcome parameters monitored were follicle morphology, survival after IVC, antrum formation, GVBD and MII formation. Differences between treatments were analyzed. RESULTS: HA and ECM-HA encapsulated follicles looked healthy and maintained their 3-D architecture during IVC. In control cultures, the follicles flattened and granulosa:oocyte connections appeared fragile. Estradiol secretion per follicle was significantly higher by Day 12 in ECM-HA compared to HA or CT (4119, 703 and 1080 pg/ml, respectively). HA and ECM-HA cultured follicles had similar survival rates (62% and 54%, respectively), percent GV breakdown (96-97%), MII formation (47-48%) and oocyte diameters at the end of IVC. Control cultures differed significantly in percent GVBD (85%) and MII formation (67%) . Vitrified-warmed follicles encapsulated in HA had an oocyte maturation rate to MII of 54% as compared to 57% in non-embedded follicles. CONCLUSIONS: Initial testing of this new and unique HA based hydrogel was quite promising. The ease of follicle encapsulation in HA, its optical transparency and ability to be molded combined with its support of follicle growth, estradiol secretion and resumption of meiosis make this HA hydrogel particularly attractive as model for 3-D ovarian follicle culture. PMID- 22513311 TI - Using models to predict the future: what to do when the data run out? AB - Although clinical trials often provide "best evidence" comparing the effectiveness of alternative management strategies, such evidence can be limited in duration or in the results reported, causing clinicians and policy analysts to wonder "what if?" Models of the clinical prognosis-often spanning patients' lifetimes (the "long haul")-are perhaps weaker evidence, but can help answer questions about the management of individual patients and place that best evidence into the context of clinical reality. PMID- 22513313 TI - Clopidogrel: a case for indication-specific pharmacogenetics. AB - The CYP2C19*2 loss-of-function allele is associated with reduced generation of active metabolites of clopidogrel. However, meta-analyses have supported or discounted the impact of genotype on adverse cardiovascular outcomes during clopidogrel therapy, depending on studies included in the analysis. Here we review these data and conclude that evidence supports a differential effect of genotype on protection from major adverse cardiovascular outcomes following percutaneous coronary intervention (PCI), but not for other clopidogrel indications. PMID- 22513314 TI - Right ventricular longitudinal peak systolic strain measurements from the subcostal view in patients with suspected pulmonary hypertension: a feasibility study. AB - BACKGROUND: The assessment of right ventricular (RV) function with two dimensional echocardiography can be challenging in patients with pulmonary hypertension, especially in those with chronic pulmonary disease. The aim of the present study was to evaluate the feasibility of measuring RV longitudinal peak systolic strain (LPSS) in the echocardiographic subcostal view in patients with suspected pulmonary hypertension. METHODS: A total of 179 patients evaluated for pulmonary hypertension were included (85 with systemic disorder, 64 with pulmonary disease, and 30 with RV dilatation and dysfunction). Additionally, 30 normal controls were evaluated. The feasibility of RV LPSS speckle-tracking measurements in the apical four-chamber view and in the subcostal view was evaluated. Furthermore, the RV LPSS speckle-tracking measurements performed in these two echocardiographic views were compared. RESULTS: The feasibility of RV LPSS in the subcostal view was 95.3%, 92.2%, 93.3%, and 93.3% in patients with systemic disorder, with pulmonary disease, with RV dilatation and dysfunction, and controls, respectively. In comparison, the feasibility of RV LPSS in the apical four-chamber view was 92.9%, 82.8%, 90%, and 93.3% in each group, respectively. Bland-Altman analysis showed good agreement between measurements in both echocardiographic views (systemic disorder: mean bias, -0.14; pulmonary disease: mean bias, 0.28; RV dilatation and dysfunction: mean bias, 0.3; and normal controls: mean bias, -0.14). CONCLUSIONS: The subcostal view provides a good alternative for RV strain assessment in patients who are evaluated for pulmonary hypertension. This measurement may be a valuable surrogate of RV function in patients with challenging apical windows. PMID- 22513312 TI - The need for translational research on drug-drug interactions. AB - Drug-drug interactions (DDIs) are an important clinical and public health concern. Although DDI screening now occurs during drug development, it is difficult to predict clinical importance based on in vitro experiments. Furthermore, older drugs that were not screened may have interactions that have not yet been identified. In this Commentary, we review the importance of DDIs and argue that a translational research approach is needed to produce clinically actionable information as well as generalizable biological knowledge. PMID- 22513316 TI - Lung cancer screening trials: Denmark and beyond. PMID- 22513315 TI - Growth-associated hyperphosphatemia in young recipients accelerates aortic allograft calcification in a rat model. AB - OBJECTIVES: Cardiovascular allografts in the young have limited durability because of early graft calcification. The objective of this study was to examine the hypothesis that growth-associated hyperphosphatemia in youth accelerates aortic allograft calcification by osteogenic transformation of graft medial smooth muscle cells (SMCs). METHODS: The descending aortas of donor rats were subcutaneously transplanted into recipients. Syngeneic (Lewis-to-Lewis) transplantations between 3-week-old "young" (Y) rats and between 10-week-old "adult" (A) rats were combined with standard (ST, 0.9% phosphate) and low phosphate (LP, 0.2%) diets, resulting in Y-ST, Y-LP, and A-ST groups. Allotransplantations (Brown-Norway-to-Lewis) involving these ages and diets were also made. The grafts and sera were retrieved from recipients after 14 days. Cultured rat aortic SMCs were used to analyze the effects of tumor necrosis factor-alpha (TNF-alpha) and phosphate on SMC calcification. RESULTS: In vivo, serum phosphate levels were higher in Y-ST (11.5 mg/dL) than those in Y-LP (8.9 mg/dL) and A-ST (8.5 mg/dL). Graft medial calcification appeared severe only in Y ST. Allotransplants did not affect these outcomes. Graft medial cells showed phenotypic changes (contractile to synthetic) and osteogenic transformation (alpha-smooth muscle actin to Runx2 and osteocalcin), together with up-regulated proinflammatory TNF-alpha and sodium-phosphate cotransporter, Pit-1, despite ages and diets. In vitro, TNF-alpha induced phenotypic changes and osteogenic transformation of SMCs with Pit-1 up-regulation, but SMC calcification occurred only with high phosphate (4.5 mmol/L). CONCLUSIONS: Growth-associated hyperphosphatemia with inflammatory responses may be essential for accelerating allograft calcification in youth and could be a therapeutic target. PMID- 22513317 TI - Complete revascularization is compromised in off-pump coronary artery bypass grafting. AB - OBJECTIVE: Patients who undergo off-pump coronary artery bypass grafting (OPCAB) commonly receive fewer bypass grafts and are more often incompletely revascularized compared with those receiving conventional coronary artery bypass (CCAB) recipients. Because this can compromise survival, we sought to determine whether patients undergoing OPCAB are incompletely revascularized and whether this affects long-term survival and freedom from cardiac events. METHODS: OPCAB cases (n = 411) performed from January 1, 1997 to June 30, 2003 were considered for inclusion and matching with 874 randomly selected, contemporary CCAB cases. After propensity matching, 308 OPCAB cases and 308 CCAB cases were included in the final analysis. We compared the number of bypass grafts and the completeness of revascularization by coronary territory. Survival and readmission for cardiac causes were monitored for up to 10 years postoperatively, with a median follow-up period of 5.9 years. RESULTS: On average, the patients undergoing OPCAB received significantly fewer distal anastomoses than did those undergoing CCAB (mean +/- standard deviation, 2.6 +/- 0.9 vs 3.0 +/- 1.0, P < .0001). The circumflex territory was the most likely territory to be ungrafted during OPCAB in patients with angiographically significant obstruction (P = .0006). The frequency of complete revascularization was significantly different between the 2 groups (OPCAB, 79.2% vs CCAB, 88.3%; P = .0.002). The OPCAB group had a significantly greater rate of total arterial grafting (OPCAB, 66.6% vs CCAB, 49.7%; P = .0001). No difference was seen in 8-year survival or freedom from cardiac cause hospital readmission between the 2 groups. CONCLUSIONS: Despite receiving fewer distal anastomoses and the decreased frequency of complete revascularization, OPCAB and CCAB techniques produced comparable results. PMID- 22513318 TI - Endoscopic management of gastroesophageal reflux disease: a review. AB - Gastroesophageal reflux disease is the most common esophageal disorder encountered in the United States. Gastroesophageal reflux disease symptoms are associated with a negative quality of life and increased healthcare costs and therefore require an effective management strategy. Although proton pump inhibitors remain the primary treatment of gastroesophageal reflux disease, they do not cure the disorder and can leave patients with persistent symptoms despite treatment. Moreover, patients are still at risk of developing such complications as peptic strictures, Barrett's metaplasia, and esophageal cancer. Although laparoscopic Nissen fundoplication has been the conventional alternative treatment for those patients who develop complications of gastroesophageal reflux disease, have intractable symptoms, or wish to discontinue taking proton pump inhibitors, investigators have persisted in developing a number of endoscopic approaches to the treatment of gastroesophageal reflux disease. The present report reviews the history of endoscopic treatments devised for the management of gastroesophageal reflux disease and explores the published data and outcomes associated with the latest approach-endoscopic fundoplication using the EsophyX2 device. PMID- 22513319 TI - Ultrasonography of MADSAM neuropathy: focal nerve enlargements at sites of existing and resolved conduction blocks. AB - Using the emerging technique of peripheral nerve ultrasonography, multiple focal nerve swellings corresponding to sites of existing conduction blocks have been described in demyelinating polyneuropathies. We report two cases of multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). In the first, multiple focal nerve enlargements were detected by ultrasound at sites of previous conduction blocks, well after complete clinical and electrophysiological resolution. In the second case, existing proximal conduction blocks could be localized by ultrasound. Our cases highlight the importance of nerve ultrasound in identifying conduction blocks and demonstrate that ultrasonographic morphological changes may outlast functional recovery in demyelinating neuropathies. PMID- 22513320 TI - Cardiomyopathy is common in patients with the mitochondrial DNA m.3243A>G mutation and correlates with mutation load. AB - Although neuromuscular clinical features often dominate the clinical presentation of mitochondrial disease due to the m.3243A>G mitochondrial DNA (mtDNA) mutation, many patients develop cardiac failure, which is often overlooked until it reaches an advanced stage. We set out to determine whether cardiac complications are sufficiently common to warrant prospective screening in all mutation carriers. Routine clinical echocardiography and 3 Tesla cardiac MRI were performed on ten m.3243A>G mutation carriers and compared to age and gender matched controls, with contemporaneous quadriceps muscle biopsies to measure respiratory chain activity and mtDNA mutation levels. Despite normal echocardiography, all ten m.3243A>G mutation carriers had evidence of abnormal cardiac function on MRI. The degree of cardiac dysfunction correlated with the percentage level of mutant mtDNA in skeletal muscle. Sub-clinical cardiac dysfunction was a universal finding in this study, adding weight to the importance of screening for cardiac complications in patients with m.3243A>G. The early detection of cardiac dysfunction with MRI opens up opportunities to prevent heart failure in these patients through early intervention. PMID- 22513321 TI - Sex-specific basis of severe placental dysfunction leading to extreme preterm delivery. AB - OBJECTIVES: Since pregnancies with a male fetus have higher perinatal complications attributed to placental dysfunction, including severe pre-eclampsia and intrauterine growth restriction, the objective of our study was to formally evaluate placental pathology for a placental origin of these sex-specific differences. DESIGN: Retrospective study at Mount Sinai Hospital in Toronto, Canada. Identification of 262 singleton pregnancies affected by severe pre eclampsia and/or intrauterine growth restriction who delivered between 22 and 32 weeks' gestation from 2000 to 2010. Detailed placental pathology was reviewed, and data from 140 pregnancies with male fetuses were compared with 122 pregnancies with female fetuses. A comparison group of 40 unaffected pregnancies who delivered in the same gestational range was used to determine baseline rates of placental pathology. MAIN OUTCOME MEASURED: Detailed placental pathology, including placental development/differentiation, velamentous umbilical cord insertion, maternal-fetal interface pathology, villous infarction, hemorrhagic lesions, villous development, and fetal vascular under-perfusion. RESULTS: Impaired placental development and differentiation was equally common amongst males (73/140, 52.1%) and females (69/122, 56.6%). Male placentas exhibited significantly higher rates of chronic deciduitis (17.9% vs. 9.0%; relative risk [RR] 1.98, 95% confidence interval [CI] 1.02-3.86) and velamentous umbilical cord insertion (9.5% vs. 1.7%; RR 5.66, 95% CI 1.30-24.6), and a significantly lower frequency of villous infarction (55.4% vs. 73.7%; RR 0.75, 95% CI 0.62-0.90) than female placentas. No significant differences were noted for other lesions. CONCLUSIONS: Fetal sex exerts a differential effect on the placental pathology that mediates severe pre-eclampsia and/or IUGR. Placental pathology at birth may provide insight into the mechanisms linking adverse in utero events with long term adult disease since, for example, a male tendency to an inflammatory pathology at the maternal-fetal interface may be linked to the excess risk of coronary artery disease. PMID- 22513322 TI - The Else Kroner-Fresenius Immunology Award. PMID- 22513323 TI - Lessons learned from HIV-1 vaccine trials: new priorities and directions. AB - A vaccine against human immunodeficiency virus (HIV) seems to be on the horizon. Correlates of risk of infection for [corrected] the RV144 vaccine trial have been found. There is understanding of what makes HIV envelope-specific antibodies broadly neutralizing and new T cell vaccine approaches can overcome virus variability. PMID- 22513324 TI - For gut's sake: NLRC4 inflammasomes distinguish friend from foe. PMID- 22513325 TI - Thymic signatures of tailored peripheral functions. PMID- 22513326 TI - Restraining IL-17: Del-1 deals the blow. PMID- 22513327 TI - Lipids-YA-Us: peroxisome generation of iNKT ligands. PMID- 22513336 TI - Evidence for the inhibitory effects of silver nanoparticles on the activities of soil exoenzymes. AB - Silver nanoparticles (AgNPs) are well known to have antimicrobial ability, but very little is known about the effect of AgNPs on soil exoenzyme activities, which reflect the potential of a soil to support biochemical processes. This study provides evidence of the inhibitory effects of AgNPs on the activities of soil exoenzymes. Six exoenzymes related to nutrient cycles (urease, acid phosphatase, arylsulfatase, beta-glucosidase) and the overall microbial activity (dehydrogenase, fluorescein diacetate hydrolase) were tested in soils treated with AgNPs (1, 10, 100 and 1000 MUg g(-1)) and silver ion (0.035, 0.175, 0.525, 1 and 1.5 MUg g(-1)). AgNPs were capable of inhibiting the activities of all the exoenzymes tested in this study. Especially, the urease and dehydrogenase activities were significantly related to the presence of AgNPs. The effects of silver ions dissolved from the AgNPs were not significant, indicating the adverse effects caused by AgNPs themselves. This study suggested that AgNPs negatively affect soil exoenzyme activities, with the urease activity especially sensitive to AgNPs. PMID- 22513335 TI - Obesity aggravates the joint inflammation in a collagen-induced arthritis model through deviation to Th17 differentiation. AB - White fat cells secrete adipokines that induce inflammation and obesity has been reported to be characterized by high serum levels of inflammatory cytokines such as IL-6 and TNF-alpha. Rheumatoid arthritis (RA) is a prototype of inflammatory arthritis, but the relationship between RA and obesity is controversial. We made an obese inflammatory arthritis model: obese collagen-induced arthritis (CIA). C57BL/6 mice were fed a 60-kcal high fat diet (HFD) from the age of 4 weeks and they were immunized twice with type II collagen (CII). After immunization, the obese CIA mice showed higher arthritis index scores and histology scores and a more increased incidence of developing arthritis than did the lean CIA mice. After treatment with CII, mixed lymphocyte reaction also showed CII-specific response more intensely in the obese CIA mice than lean CIA. The anti-CII IgG and anti-CII IgG2a levels in the sera of the obese CIA mice were higher than those of the lean CIA mice. The number of Th17 cells was higher and the IL-17 mRNA expression of the splenocytes in the obese CIA mice was higher than that of the lean CIA mice. Obese CIA mice also showed high IL-17 expression on synovium in immunohistochemistry. Although obesity may not play a pathogenic role in initiating arthritis, it could play an important role in amplifying the inflammation of arthritis through the Th1/Th17 response. The obese CIA murine model will be an important tool when we investigate the effect of several therapeutic target molecules to treat RA. PMID- 22513334 TI - Protein tyrosine phosphatases in lymphocyte activation and autoimmunity. AB - Lymphocyte activation must be tightly regulated to ensure sufficient immunity to pathogens and prevent autoimmunity. Protein tyrosine phosphatases (PTPs) serve critical roles in this regulation by controlling the functions of key receptors and intracellular signaling molecules in lymphocytes. In some cases, PTPs inhibit lymphocyte activation, whereas in others they promote it. Here we discuss recent progress in elucidating the roles and mechanisms of action of PTPs in lymphocyte activation. We also review the accumulating evidence that genetic alterations in PTPs are involved in human autoimmunity. PMID- 22513337 TI - Photolysis of flumequine: identification of the major phototransformation products and toxicity measures. AB - Direct photolysis of flumequine (FLU, 20 mg L(-1)) in different types of water (demineralised water (DW) and synthetic seawater (SW)), was conducted in a Suntest CPS+solar simulator to evaluate its persistence and toxicity, and to identify the major phototransformation products (PTPs) generated during photolysis in DW. It was observed that FLU is susceptible to transformation when subjected to direct solar radiation. The composition of the water affects the FLU degradation kinetics, which is slower in SW. Photolytic transformation products generated during direct photolysis were identified by liquid chromatography-time of flight-mass spectrometry (LC-TOF-MS). Fourteen PTPs generated in DW were identified. The transformation of FLU begins with the opening of the heterocyclic ring by oxidation of the double bond. Loss of the fluorine atom and the hydroxylation of the aromatic ring also appear as the majority, especially in the early stages. Comparative acute toxicity evaluation by Vibrio fischeri and Daphnia magna bioassays was performed for the first and last irradiated solutions in both matrices studied. These bioassays demonstrated that in the SW matrix, the most persistent PTPs are highly toxic to D. magna but less so to V. fischeri. PMID- 22513338 TI - DFT M06-2X investigation of alkaline hydrolysis of nitroaromatic compounds. AB - The nitroaromatic compounds 2,4,6-trinitrotoluene (TNT), 2,4-dinitrotoluene (DNT) and 2,4-dinitroanisole (DNAN) are potential environmental contaminants and their transformations under a variety of environmental conditions are consequently of great interest. One possible method to safely degrade these nitrocompounds is alkaline hydrolysis. A mechanism of the initial stages of this reaction was investigated computationally. Simulations of UV-VIS and NMR spectra for this mechanism were also produced. The results obtained were compared to available experimental data on the alkaline hydrolysis of TNT and suggest that the formation of Meisenheimer complexes and an anion of TNT are potential first-step intermediates in the reaction path. As the reaction proceeds, computational results indicate that polynegative complexes dominate the degradation pathway, followed by cycles of carbon chain opening and breaking. A second possible pathway was identified that leads to polymeric products through Janovsky complex formation. Results from this study indicate that the order of increasing resistance to alkaline hydrolysis is TNT, DNT and DNAN. PMID- 22513339 TI - Purification of carbonic anhydrase from bovine erythrocytes and its application in the enzymic capture of carbon dioxide. AB - This work presents a study of industrially applicable techniques to obtain a biologically supported carbon dioxide capture system, based on the extraction of carbonic anhydrase from bovine blood. Carbonic anhydrase is a metalloenzyme which catalyzes the reversible hydration of carbon dioxide. The objective of this study was to establish conditions to obtain carbonic anhydrase from bovine erythrocytes and apply it in the capture of carbon dioxide. To achieve this, two different purification techniques were evaluated: one by extraction with the organic solvents chloroform and ethanol, where different solvent proportions were studied; and the other by ammonium sulfate precipitation, testing percent saturations between 10% and 80%. Carbon dioxide was enzymatically captured by its precipitation as calcium carbonate with the enzyme obtained by both techniques. The enzyme extracted by ethanol and chloroform showed an activity of 2623 U mL( 1), recovery of 98% and purification factor of 104-fold. That precipitated by ammonium sulfate showed an activity of 2162 U mL(-1), recovery of 66% and purification factor of 1.4-fold using 60% ammonium sulfate saturation. The results obtained in the carbon dioxide capture experiments showed that the carbonic anhydrase extracted in this study not only enhanced the hydration of CO(2), but also promoted the formation of CaCO(3). PMID- 22513340 TI - Left parietal alpha enhancement during working memory-intensive sentence processing. AB - Both functional magnetic resonance imaging (fMRI) and event-related brain potential (ERP) studies have shown that verbal working memory plays an important role during sentence processing. There is growing evidence from outside of sentence processing that human alpha oscillations (7-13 Hz) play a critical role in working memory. This study aims to link this to the sentence processing domain. Time-frequency analyses and source localization were performed on electroencephalography (EEG) data that were recorded during the processing of auditorily presented sentences involving either a short or a long distance between an argument (subject or object) and the respective sentence-final verb. We reasoned that oscillatory activity in the alpha band should increase during sentences with longer argument-verb distances, since decreased temporal proximity should result in increased memory demands. When verbal working memory-intensive long-dependency sentences were compared to short-dependency sentences, a sustained oscillatory enhancement at 10 Hz was found during storage prior to the sentence-final verb, turning into a transient power increase in the beta band (13 20 Hz) at the sentence-final verb. The sources of the alpha oscillations were localized to bilaterally occipital and left parietal cortices. Only the source activity in the left parietal cortex was negatively correlated with verbal working memory abilities. These findings indicate that the parsimonious role of alpha oscillations in domain-general working memory can be extended to language, that is, sentence processing. We suggest that the function of left parietal cortex underlying verbal working memory storage during sentence processing is to inhibit the premature release of verbal information that will subsequently be integrated. PMID- 22513342 TI - Enhancing lexical ambiguity resolution by brain polarization of the right posterior superior temporal sulcus. AB - Previous studies have reported a hemispheric asymmetry in processing dominant (e.g., paper) and subordinate (e.g., farmer) associations of ambiguous words (pen). Here we applied sham and anodal Transcranial Direct Current Stimulation (tDCS) over Wernicke's area and its right homologue to test whether we can modulate the selective hemispheric expertise in processing lexical ambiguity. Ambiguous prime words were presented followed by target words that could be associated to the dominant or subordinate meaning of the prime in a semantic relatedness task. Anodal stimulation of the right Wernicke's area significantly decreased response time (RTs) to subordinate but not dominant associations compared to sham stimulation. There was also a complementary trend of faster responses to dominant associations following anodal stimulation of Wernicke's area. The results support brain asymmetry in processing lexical ambiguity and show that tDCS can enhance complex language processing even in a sample of highly literate individuals. PMID- 22513341 TI - Visuospatial deficits and hemispheric perfusion asymmetries in posterior cortical atrophy. AB - We studied visuospatial performance and obtained brain perfusion scintigraphy in 27 patients with posterior cortical atrophy (PCA) and 24 healthy controls, with two aims: (1) to determine inter-hemispheric perfusion imbalances underlying signs of spatial neglect and (2) to establish the functional substrates of patients' performance on distinct visuospatial tasks (line bisection and target cancellation). Between-groups and correlation analyses were performed on a voxel wise basis with Statistical Parametric Mapping, and right-to-left hemispheric perfusion ratios were calculated in anatomical regions of interest. Nineteen patients had pathological spatial biases. Compared with controls, patients with signs of left-sided and right-sided neglect presented prominent hypoperfusion in the right and left parietal cortex, respectively. Importantly, hypoperfusion extended to the ipsilateral prefrontal regions. Correlation analyses between task scores and brain perfusion showed that shifts in line bisection correlated with hypoperfusion in parieto-frontal regions, whereas omissions on target cancellation mainly correlated with hypoperfusion in prefrontal structures. Overall, the results indicate that spatial neglect in PCA is related to inter hemispheric perfusion asymmetries in fronto-parietal networks, with partially different neural correlates for line bisection and target cancellation. PMID- 22513343 TI - High-efficiency pyrene-based blue light emitting diodes: aggregation suppression using a calixarene 3D-scaffold. AB - An efficient blue light emitting diode based on solution processable pyrene-1,3 alt-calix[4]arene is demonstrated, providing a record current efficiency of 10.5 cd A(-1) in a simple non-doped OLED configuration. Complete suppression of pyrene aggregation in the solid state is achieved by controlling chromophore dispersion using the 1,3-alt-calix[4]arene scaffold. PMID- 22513344 TI - Heart failure survival score in patients with Chagas disease: correlation with functional variables. AB - INTRODUCTION AND OBJECTIVES: Chagas disease is a prevalent cause of heart failure in Latin America, and its prognosis is worse than other etiologies. The Heart Failure Survival Score has been used to assess prognosis in patients with heart failure; however, this score has not yet been studied in patients with Chagas cardiopathy. METHODS: The Heart Failure Survival Score was calculated in 55 patients with severe left ventricular systolic dysfunction due to Chagas disease. Correlations were assessed between the Heart Failure Survival Score and variables obtained from, cardiopulmonary exercise tests, quality-of-life measures, and 6 minute walking tests. RESULTS: Patients were distributed among New York Heart Association classes II-IV; 89% were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 62% were taking beta-blockers, 86% were taking diuretics, and 74% were taking aldosterone receptor blockers. The mean Heart Failure Survival Score was 8.75 (0.80). The score correlated well with cardiopulmonary test variables such as peak oxygen uptake (0.662; P<.01), oxygen uptake at the anaerobic threshold (0.644; P<.01), ventilation carbon dioxide efficiency slope (-0.417; P<.01), oxygen pulse (0.375; P<.01), oxygen uptake efficiency slope (0.626; P<.01), 6-minute walking test (0.370; P<.01), left ventricle ejection fraction (0.650; P=.01), and left atrium diameter (-0.377; P<.01). There was also a borderline significant correlation between the Heart Failure Survival Score and quality of life (-0.283; P<.05). CONCLUSIONS: In heart failure patients with Chagas disease, the Heart Failure Survival Score correlated well with the main prognostic functional test variables. PMID- 22513345 TI - Percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG) in the treatment of diabetic patients with multi-vessel coronary disease: a meta-analysis. AB - Diabetes is prevalent in patients with coronary artery disease. In diabetic patients with multi-vessel coronary disease, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) are widely used for revascularization. We aimed to compare the effectiveness and safety of PCI and CABG in these patients. Nine randomized controlled trials were identified in which a total of 1047 diabetic patients were randomly assigned to PCI and 1054 to CABG. Results showed that five-year mortality was significantly higher in diabetic patients after PCI than after CABG (risk difference (RD) of 7%; P<0.001); repeated revascularization was more common after PCI than after CABG (one-year RD of 13%; P<0.001); major adverse cardiac and cerebrovascular events were also more frequent after PCI (one-year RD of 12%; P<0.001); however, the cerebrovascular accident rate was lower in the PCI group than the CABG group (one year RD of -2%; P=0.004). Conclusively, in diabetic patients with multi-vessel coronary disease, CABG was not only more effective than PCI in reducing mortality but also led to fewer repeated revascularizations and fewer major adverse cardiac and cerebrovascular events. Despite these benefits, CABG did put diabetic patients at higher risk for cerebrovascular accident than PCI. PMID- 22513346 TI - Diabetes Australia position statement. A new language for diabetes: improving communications with and about people with diabetes. AB - Diabetes is the fastest growing chronic condition in Australia, affecting 1.7 million Australians, requiring daily self-care, and known to reduce quantity and quality of life. On average, people with diabetes experience greater emotional distress than those without diabetes. One source of distress can be the language used to refer to diabetes, its management and the person with diabetes. The way verbal and written language is used reflects and shapes people's thoughts, beliefs and behaviours. Language has the power to persuade, change or reinforce beliefs and stereotypes - for better or worse. Words do more than reflect people's reality: they create reality and affect how people view the world and their diabetes. Language needs to engage people with diabetes and support their self-care efforts. Importantly, language that de-motivates or induces fear, guilt or distress needs to be avoided and countered. Diabetes Australia believes optimal communication increases the motivation, health and well-being of people with diabetes, and that careless or negative language can be de-motivating, is often inaccurate, and can be harmful. Diabetes Australia developed this position statement to encourage greater awareness of the language surrounding diabetes and provide recommendations for more careful and positive language use. PMID- 22513350 TI - Comparative performance of direct and indirect laryngoscopes for emergency intubation under cervical stabilization. PMID- 22513348 TI - Five novel mutations and two large deletions in a population analysis of the phenylalanine hydroxylase gene. AB - Mutational spectrum of the phenylalanine hydroxylase (PAH) deficiency was investigated in 107 families (90% of the Slovene PKU population). The entire coding region of the PAH gene was analyzed with dHPLC to select the samples where subsequently the automated sequencing analysis was performed. MLPA analysis was performed to identify large deletions, which were later confirmed with long-range PCR. Correlations with patients' phenotypes and genotype-based predictions of BH(4)-responsiveness were assessed. Altogether, disease-causing mutations were identified on 209 alleles (detection rate 97.7%). A spectrum of 36 different disease-causing mutations was identified: 20 missense mutations (80% of the alleles), eight splicing mutations (13% of the alleles), one nonsense mutation (0.5% of the alleles), four small deletions with frame shift (6% of the alleles), one small insertion with frame shift (0.5% of the alleles), and two large deletions (2% of the alleles). The most frequent mutation was p.R408W in exon 12, representing 29% of the alleles, which is in concordance with other neighboring and/or Slavic PKU populations. Other common mutations were: p.R158Q, p.A403V, p.P281L and p.E390G, accounting for 9%, 7%, 7% and 7% of the alleles respectively. Five novel mutations were detected: c.43_44insAG, c.56_59+1delACAGG, p.V45A, p.L62P and p.R157S. Large deletion of exon 5 (EX5del955) was found in three patients and a deletion of exon 3 (EX3del4765) in one patient. A spectrum of 64 different genotypes was found, seven of them accounting for over than a third of all families. Among thirteen families with homozygous mutation (13% of the PKU population), 10 had p.R408W, two had p.R158Q and one had p.E390G. Among 107 families, 58 were classified as classic PKU (54.2%), 28 as mild PKU (25.9%) and 21 as MHP (19.6%). Twenty-six different genotypes (40.6%) were predicted to be BH(4)-responsive, represented by 38 different families (35.5%). PMID- 22513347 TI - Pathogenesis of lumbar spine disease in mucopolysaccharidosis VII. AB - Mucopolysaccharidosis type VII (MPS VII) is characterized by deficient beta glucuronidase (GUSB) activity, which leads to accumulation of chondroitin, heparan and dermatan sulfate glycosaminoglycans (GAGs), and multisystemic disease. MPS VII patients can develop kypho-scoliotic deformity and spinal cord compression due to disease of intervertebral disks, vertebral bodies, and associated tissues. We have previously demonstrated in MPS VII dogs that intervertebral disks degenerate, vertebral bodies have irregular surfaces, and vertebral body epiphyses have reduced calcification, but the pathophysiological mechanisms underlying these changes are unclear. We hypothesized that some of these manifestations could be due to upregulation of destructive proteases, possibly via the binding of GAGs to Toll-like receptor 4 (TLR4), as has been proposed for other tissues in MPS models. In this study, the annulus fibrosus of the intervertebral disk of 6-month-old MPS VII dogs had cathepsin B and K activities that were 117- and 2-fold normal, respectively, which were associated with elevations in mRNA levels for these cathepsins as well as TLR4. The epiphyses of MPS VII dogs had a marked elevation in mRNA for the cartilage associated gene collagen II, consistent with a developmental delay in the conversion of the cartilage to bone in this region. The spine obtained at autopsy from a young man with MPS VII exhibited similar increased cartilage in the vertebral bodies adjacent to the end plates, disorganization of the intervertebral disks, and irregular vertebral end plate morphology. These data suggest that the pathogenesis of destructive changes in the spine in MPS VII may involve upregulation of cathepsins. Inhibition of destructive proteases, such as cathepsins, might reduce spine disease in patients with MPS VII or related disorders. PMID- 22513351 TI - Seizures and status epilepticus in post cardiac arrest syndrome: therapeutic opportunities to improve outcome or basis to withhold life sustaining therapies? PMID- 22513353 TI - Presentation of a cone-beam CT scanning protocol for preprosthetic cranial bone grafting of the atrophic maxilla. AB - The use of autologous calvarian split thickness bone grafts is a well accepted preprosthetic surgical procedure for reconstruction of the severely atrophied maxilla. Although generally accepted as being a superior bone graft regarding long-term stability, the reported risks in the literature may dissuade the surgeon. A modified cone-beam computed tomography (CBCT) scanning protocol (extended field of view starting from 1cm below the occlusal plane up to the limit of the cranial vault, 0.4 voxel) is proposed that allows assessment of both the cranial donor site as the maxillary receptor site and the sinus conditions with a single scan. Issues regarding quality of the data, radiation dose and clinical practicability are discussed. PMID- 22513352 TI - Identifying cancer patients with greater need for information about sexual issues. AB - PURPOSE: The aim of the research was to identify cancer patients who may have a greater need about sexuality-related information. The study explored the association between sexuality-related information need and socio-demographic factors, cancer type, types of cancer treatment, experienced adverse effects on sexuality, and changes experienced in relationships. METHODS AND SAMPLE: This study used a survey design. Questionnaires were distributed and completed by 505 patients, with a diversity of cancer diagnoses, treated at a university hospital in Finland in 2009 and 2010. Information needs were rated using the international and well validated Information Needs Questionnaire (INQ). Sosiodemographic factors, cancer type, treatments, experienced adverse effects on sexuality and changed experienced in relationships were measured by using another questionnaire. KEY RESULTS: Those patients with experiences of functional problems or other adverse effects on sexuality due to cancer or treatment found sexuality related information more important than those with no experiences of adverse effects on sexuality. Patients with experiences of weakened relationships due to cancer had greater information needs than those with experiences of strengthened relationships or no changes in relationships due to cancer. CONCLUSIONS: Cancer patients should be asked whether cancer or treatment has caused problems in their sexuality and possible relationships. Patients who experience problems in their sexuality or relationships should be provided an opportunity to discuss the issues. The whole oncology team have a role to play in patient sexuality guidance. The items on the INQ could be used as a reference tool for exploring patients' information needs. PMID- 22513356 TI - The Alliance for Nursing Informatics Emerging Leaders program: reflections from the 2010-2012 Emerging Leader in nursing informatics. PMID- 22513355 TI - Hydroxyapatite coating for titanium fibre mesh scaffold enhances osteoblast activity and bone tissue formation. AB - This study investigated the bone regeneration properties of titanium fibre mesh as a tissue engineering material. A thin hydroxyapatite (HA) coating on the titanium fibre web was created using the developed molecular precursor method without losing the complex interior structure. HA-coated titanium fibre mesh showed apatite crystal formation in vitro in a human osteoblast culture. Titanium fibre mesh discs with or without a thin HA coating were implanted into rat cranial bone defects, and the animals were killed at 2 and 4 weeks. The in vivo experience revealed that the amount of newly formed bone was significantly higher in the HA-coated titanium fibre mesh than in the non-coated titanium fibre mesh 2 weeks after implantation. These results suggest that thin HA coating enhances osteoblast activity and bone regeneration in the titanium fibre mesh scaffold. Thin HA-coating improved the ability of titanium fibre mesh to act as a bone regeneration scaffold. PMID- 22513358 TI - Involvement of Toll-like receptor 2 in apoptosis of Aggregatibacter actinomycetemcomitans-infected THP-1 cells. AB - BACKGROUND/PURPOSE: Aggregatibacter (Actinobacillus) actinomycetemcomitans is a gram-negative bacterium that has been associated with aggressive periodontitis. A actinomycetemcomitans infection induces apoptosis in the human monocytic cell line THP-1, and p38 mitogen-activated protein kinase (p38) activity and tumor necrosis factor-alpha (TNF-alpha) production are enhanced by A actinomycetemcomitans infection. However, mechanisms governing the recognition of A actinomycetemcomitans by monocytes during apoptosis have not been elucidated. A actinomycetemcomitans cell wall components stimulate Toll-like receptor (TLR)2 and/or TLR4. The authors examined whether TLR2 and/or TLR4 were involved in the apoptosis of A actinomycetemcomitans-infected THP-1 cells. METHODS: A actinomycetemcomitans-infected THP-1 cells were transferred to six-well culture plates and incubated for 0 to 6 hours. In some experiments, THP-1 cells were incubated with anti-TLR2, anti-TLR4, or isotype control antibody (10 MUg/mL) for 30 minutes prior to A actinomycetemcomitans infection. Expression of messenger RNA (mRNA) was examined by reverse transcription-polymerase chain reaction. Intracellular bacteria recovered from A actinomycetemcomitans-infected cells and apoptotic cells were detected by APOPercentage dye (Biocolor Ltd, Northern Ireland, UK) staining. Cellular p38 activity and TNF-alpha production were assessed with enzyme-linked immunosorbent assay. RESULTS: The expression of TLR2 mRNA was increased by A actinomycetemcomitans infection. Phagocytosis and apoptosis in A actinomycetemcomitans-infected THP-1 cells were inhibited by the addition of anti-TLR2 antibody. Also, anti-TLR2 antibody suppressed the activation of p38 and production of TNF-alpha in A actinomycetemcomitans-infected THP-1 cells. CONCLUSION: These results suggest that A actinomycetemcomitans induces increased expression of TLR2, leading to phagocytosis and apoptosis of THP-1 cells via p38 activation and TNF-alpha production. PMID- 22513359 TI - Alcohol, acetaldehyde and breast cancer risk. PMID- 22513360 TI - Cold autoimmune haemolytic anaemia secondary to Epstein Barr virus infection presenting with peripheral gangrene; case report. AB - A sixty year old male presented with dark urine, symptomatic anaemia and peripheral gangrene following cold exposure. Investigations revealed that he had haemolysis and serological evidence of recent Epstein Barr virus infection. Although acrocyanosis is commonly associated with cold agglutinin disease, gangrene is a rare complication. Management of secondary cold agglutinin disease is mainly supportive. PMID- 22513361 TI - Assessment of persistent organochlorine pollutants in sediments from Lake Manzala, Egypt. AB - Organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were determined in surface and core sediment samples collected from Manzala Lake, the largest of the Egyptian coastal lakes. Total concentrations of OCPs and ?7 PCBs (ICES) in sediments ranged from 0.63 to 31.31 ng/g and 0.26 to 31.27 ng/g, respectively. Geographical distribution indicates that levels of contaminants were significantly higher in areas which are mainly influenced by municipal discharge, indicating significant sources of these compounds in urbanised areas. The composition of DDT and its metabolites suggest old input of DDT. The levels of contaminants in Manzala Lake were similar or lower than those observed in comparable areas worldwide. The profiles of ?OCPs and ?PCBs in a core from a site heavily impacted by sewage discharge have highest concentrations in the surface core section indicating recent inputs. Assessment of ecotoxicological risk indicated that sediments in two sites were likely to pose potential biological adverse impact. PMID- 22513362 TI - Pten regulates Aurora-A and cooperates with Fbxw7 in modulating radiation-induced tumor development. AB - The Aurora-A kinase gene is frequently amplified and/or overexpressed in a variety of human cancers, leading to major efforts to develop therapeutic agents targeting this pathway. Here, we show that Aurora-A is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7 in a process that is regulated by GSK3beta. Using a series of truncated Aurora-A proteins and site-directed mutagenesis, we identified distinct FBXW7 and GSK3beta-binding sites in Aurora-A. Mutation of critical residues in either site substantially disrupts degradation of Aurora-A. Furthermore, we show that loss of Pten results in the stabilization of Aurora-A by attenuating FBXW7-dependent degradation of Aurora-A through the AKT/GSK3beta pathway. Moreover, radiation-induced tumor latency is significantly shortened in Fbxw7(+/-)Pten(+/-) mice as compared with either Fbxw7(+/-) or Pten(+/-) mice, indicating that Fbxw7 and Pten appear to cooperate in suppressing tumorigenesis. Our results establish a novel posttranslational regulatory network in which the Pten and Fbxw7 pathways appear to converge on the regulation of Aurora-A level. PMID- 22513363 TI - Heparanase-induced GEF-H1 signaling regulates the cytoskeletal dynamics of brain metastatic breast cancer cells. AB - Heparanase is the only mammalian endoglycosidase which has been widely implicated in cancer because of its capability to degrade heparan sulfate chains of heparan sulfate proteoglycans (HSPG). Specifically, the cell surface HSPG syndecan-1 and 4 (SDC1 and SDC4) are modulators of growth factor action, and SDC4 is implicated in cell adhesion as a key member of focal adhesion complexes. We hypothesized that extracellular heparanase modulates brain metastatic breast cancer (BMBC) cell invasiveness by affecting cytoskeletal dynamics, SDC4 carboxy-terminal associated proteins, and downstream targets. We used two independently derived human BMBC cell systems (MB-231BR and MB-231BR3), which possess distinct cellular morphologies and properties. Highly aggressive spindle-shaped 231BR3 cells changed to a round cell morphology associated with expression of the small GTPase guanine nucleotide exchange factor-H1 (GEF-H1). We showed that GEF-H1 is a new component of the SDC4 signaling complex in BMBC cells. Treatment with heparanase resulted in regulation of the SDC4/protein kinase C alpha axis while maintaining a constitutive GEF-H1 level. Third, GEF-H1 knockdown followed by cell exposure to heparanase caused a significant regulation of activities of Rac1 and RhoA, which are GEF-H1 targets and fundamental effectors in cell plasticity control. Fourth, L-heparanase augmented expression of beta1 integrin in BMBC cells and of vascular cell adhesion molecule 1 (VCAM1; the major beta1 integrin receptor) in human brain microvascular endothelial cells. Finally, using a newly developed blood brain barrier in vitro model, we show that BMBC cell transmigration was significantly reduced in GEF-H1 knockdown cells. These findings implicate heparanase in mechanisms of cytoskeletal dynamics and in the cross-talk between tumor cells and vascular brain endothelium. They are of relevance because they elucidate molecular events in the initial steps leading to BMBC onset and capturing distinct roles of latent and active heparanase in the brain microenvironment. PMID- 22513364 TI - The permeability transition pore as a Ca(2+) release channel: new answers to an old question. AB - Mitochondria possess a sophisticated array of Ca(2+) transport systems reflecting their key role in physiological Ca(2+) homeostasis. With the exception of most yeast strains, energized organelles are endowed with a very fast and efficient mechanism for Ca(2+) uptake, the ruthenium red (RR)-sensitive mitochondrial Ca(2+) uniporter (MCU); and one main mechanism for Ca(2+) release, the RR insensitive 3Na(+)-Ca(2+) antiporter. An additional mechanism for Ca(2+) release is provided by a Na(+) and RR-insensitive release mechanism, the putative 3H(+) Ca(2+) antiporter. A potential kinetic imbalance is present, however, because the V(max) of the MCU is of the order of 1400nmol Ca(2+)mg(-1) proteinmin(-1) while the combined V(max) of the efflux pathways is about 20nmol Ca(2+)mg(-1) proteinmin(-1). This arrangement exposes mitochondria to the hazards of Ca(2+) overload when the rate of Ca(2+) uptake exceeds that of the combined efflux pathways, e.g. for sharp increases of cytosolic [Ca(2+)]. In this short review we discuss the hypothesis that transient opening of the Ca(2+)-dependent permeability transition pore may provide mitocondria with a fast Ca(2+) release channel preventing Ca(2+) overload. We also address the relevance of a mitochondrial Ca(2+) release channel recently discovered in Drosophila melanogaster, which possesses intermediate features between the permeability transition pore of yeast and mammals. PMID- 22513365 TI - Predictors of survival in Chinese patients with lupus nephritis. AB - The current study was to determine the predictors of survival in 491 Chinese patients with lupus nephritis (LN). All patients were evaluated and consecutively followed up from 2003 to 2010. The female: male ratio was 9.5:1, with a median age of 31.1 +/- 12 years. Forty-nine (10.0%) patients were lost to follow-up and 47 (10.3%) patients died. The overall cumulative probability of survival at 5, 10, 15 and 20 years by Kaplan-Meier analysis was 88%, 77%, 53% and 45%, respectively. The log-rank test showed that the probability of survival was significantly decreased in the late-onset patients (>=50 years) (P = 0.036), patients with hypoproteinaemia (<=35 g/l) (P = 0.014), patients with increased creatinine (>=1.5 mg/dl) (P = 0.002) and patients with massive proteinuria (>=3.5 g/24 h) (P = 0.009). However, the probability of survival was significantly higher in patients treated with hydroxychloroquine (HCQ) (P = 0.003) than those not treated with it. Based on a multivariate model, increased creatinine (hazard ratio (HR) = 2.041; P = 0.017) and proteinuria >=3.5 g/24hours (HR=1.716; P = 0.016) were independent risk factors. Glucocorticoid (HR = 0.457; P = 0.01) and HCQ (HR=0.197; P = 0.026) were independent protective factors. Our findings suggest that renal dysfunction and massive proteinuria are independent risk factors for mortality. HCQ could improve the survival of patients with LN. PMID- 22513366 TI - Receptor for advanced glycation end products (RAGE) polymorphisms are associated with systemic lupus erythematosus and disease severity in lupus nephritis. AB - OBJECTIVE: Interaction of advanced glycation end products (AGEs) with their receptors (RAGE) plays an important role in inflammation in auto-immune diseases. Several functional polymorphisms of RAGE have been described. In this study we analysed the role of RAGE polymorphisms in disease susceptibility for systemic lupus erythematosus (SLE). In addition, we investigated whether these polymorphisms in SLE are associated with serum levels of soluble RAGE (sRAGE), renal involvement (lupus nephritis (LN)) and its outcome. METHODS: For this cross sectional study DNA samples of 97 SLE patients, 114 LN patients and 429 healthy controls (HC) were genotyped for four RAGE polymorphisms: -429 T/C, -374 T/A, 2184 A/G and Gly82Ser. Differences in genotype frequencies and allele frequencies were tested between patients and HCs. In SLE patients, sRAGE was measured by enzyme-linked immunosorbent assay (ELISA). In addition, association of genotypes with sRAGE and disease severity in LN was analysed. RESULTS: The C allele of -429 T/C, the T allele of -374 T/A and the G allele of 2184 A/G were significantly more prevalent in SLE and LN compared with HC. In LN, the C allele of RAGE -429 T/C, the A allele of -374 T/A and the G allele of RAGE 2184 A/G polymorphism were significantly associated with more proteinuria and worse renal function during the first two years of treatment. No association of genotype with sRAGE was found. CONCLUSION: RAGE polymorphisms are associated with susceptibility to SLE and LN. In addition, some of these polymorphisms are likely to be associated with disease severity and initial response to treatment in LN. PMID- 22513367 TI - The basis for spinal manipulation: chiropractic perspective of indications and theory. AB - It is reasonable to think that patients responding to spinal manipulation (SM), a mechanically based therapy, would have mechanical derangement of the spine as a critical causal component in the mechanism of their condition. Consequently, SM practitioners routinely assess intervertebral motion, and treat patients on the basis of those assessments. In chiropractic practice, the vertebral subluxation has been the historical raison d'etre for SM. Vertebral subluxation is a biomechanical spine derangement thought to produce clinically significant effects by disturbing neurological function. This paper reviews the putative mechanical features of the subluxation and three theories that form the foundation for much of chiropractic practice. It concludes with discussion of subluxation as an indicator for SM therapy, particularly from the perspective that subluxation may be one contributory cause of ill-health within a "web of causation". PMID- 22513368 TI - Influence of the intensity of a conditioning contraction on the subsequent twitch torque and maximal voluntary concentric torque. AB - This study aimed to clarify the influence of the intensity of a conditioning contraction on subsequent isometric twitch and maximal voluntary concentric torques. Subjects (n=12men) performed voluntary isometric plantar flexion for six seconds as a conditioning contraction, at intensities of 40%, 60%, 80% and 100% of a maximal voluntary isometric contraction (MVIC). Before and immediately after the conditioning contraction, isometric twitch and maximal voluntary concentric (180 degrees /s) plantar flexion torques were determined. Surface electromyograms were recorded from the triceps surae muscles and M-wave amplitudes and root-mean square values of the electromyographic signals (RMS(EMG)) were calculated. The isometric twitch torque increased significantly after conditioning contraction at all intensities (P<0.05), whereas maximal voluntary concentric torque increased significantly only at 80% and 100% MVIC conditions (P<0.05). It is concluded that during a six second conditioning contraction, the effect of the intensity of a conditioning contraction on subsequent torque development is different between an isometric twitch and maximal voluntary concentric contractions, with the latter being less affected. PMID- 22513370 TI - Timing of anaphase-promoting complex activation in mouse oocytes is predicted by microtubule-kinetochore attachment but not by bivalent alignment or tension. AB - Homologous chromosome segregation errors during meiosis I are common and generate aneuploid embryos. Here, we provide a reason for this susceptibility to mis segregation by live cell imaging of mouse oocytes. Our results show that stable kinetochore-microtubule attachments form in mid-prometaphase, 3-4 hours before anaphase. This coincided with the loss of Mad2 from kinetochores and with the start of anaphase-promoting complex/cyclosome (APC/C)-mediated cyclin B1 destruction. Therefore, the spindle assembly checkpoint (SAC) ceased to inhibit the APC/C from mid-prometaphase. This timing did not coincide with bivalent congression in one-third of all oocytes examined. Non-aligned bivalents were weakly positive for Mad2, under less tension than congressed bivalents and, by live-cell imaging, appeared to be in the process of establishing correct bi orientation. The time from when the APC/C became active until anaphase onset was affected by the rate of loss of CDK1 activity, rather than by these non-aligned bivalents, which occasionally persisted until anaphase, resulting in homolog non disjunction. We conclude that, in oocytes, a few erroneous attachments of bivalent kinetochores to microtubules do not generate a sufficient SAC 'wait anaphase' signal to inhibit the APC/C. PMID- 22513371 TI - Stable and dynamic microtubules coordinately determine and maintain Drosophila bristle shape. AB - Within interphase cells, microtubules (MTs) are organized in a cell-specific manner to support cell shape and function. Here, we report that coordination between stable and dynamic MTs determines and maintains the highly elongated bristle cell shape. By following MT-decorating hooks and by tracking EB1 we identified two MT populations within bristles: a stable MT population polarized with their minus ends distal to the cell body, and a dynamic MT population that exhibits mixed polarity. Manipulating MT dynamics by Klp10A downregulation demonstrates that MTs can initiate new shaft extensions and thus possess the ability to determine growth direction. Actin filament bundling subsequently supports the newly formed shaft extensions. Analysis of ik2 mutant bristles, established by elongation defects in the Drosophila ikkepsilon homolog, led to the observation that stable and dynamic MT orientation and polarized organization are important for proper bristle elongation. Thus, we demonstrate for the first time that coordination between stable and dynamic MT sets that are axially organized yet differently polarized drives cell elongation. PMID- 22513369 TI - Sim2 prevents entry into the myogenic program by repressing MyoD transcription during limb embryonic myogenesis. AB - The basic helix-loop-helix transcription factor MyoD is a central actor that triggers the skeletal myogenic program. Cell-autonomous and non-cell-autonomous regulatory pathways must tightly control MyoD expression to ensure correct initiation of the muscle program at different places in the embryo and at different developmental times. In the present study, we have addressed the involvement of Sim2 (single-minded 2) in limb embryonic myogenesis. Sim2 is a bHLH-PAS transcription factor that inhibits transcription by active repression and displays enhanced expression in ventral limb muscle masses during chick and mouse embryonic myogenesis. We have demonstrated that Sim2 is expressed in muscle progenitors that have not entered the myogenic program, in different experimental conditions. MyoD expression is transiently upregulated in limb muscle masses of Sim2(-/-) mice. Conversely, Sim2 gain-of-function experiments in chick and Xenopus embryos showed that Sim2 represses MyoD expression. In addition, we show that Sim2 represses the activity of the mouse MyoD promoter in primary myoblasts and is recruited to the MyoD core enhancer in embryonic mouse limbs. Sim2 expression is non-autonomously and negatively regulated by the dorsalising factor Lmx1b. We propose that Sim2 represses MyoD transcription in limb muscle masses, through Sim2 recruitment to the MyoD core enhancer, in order to prevent premature entry into the myogenic program. This MyoD repression is predominant in ventral limb regions and is likely to contribute to the differential increase of the global mass of ventral muscles versus dorsal muscles. PMID- 22513372 TI - Spindle assembly checkpoint signalling is uncoupled from chromosomal position in mouse oocytes. AB - The spindle assembly checkpoint (SAC) averts aneuploidy by coordinating proper bipolar chromosomal attachment with anaphase-promoting complex/cyclosome (APC/C) mediated securin and cyclin B1 destruction required for anaphase onset. The generation of a Mad2-based signal at kinetochores is central to current models of SAC-based APC/C inhibition. During mitosis, kinetochores of polar-displaced chromosomes, which are at greatest risk of mis-segregating, recruit the highest levels of Mad2, thereby ensuring that SAC activation is proportionate to aneuploidy risk. Paradoxically, although an SAC operates in mammalian oocytes, meiosis I (MI) is notoriously error prone and polar-displaced chromosomes do not prevent anaphase onset. Here we find that Mad2 is not preferentially recruited to the kinetochores of polar chromosomes of wild-type mouse oocytes, in which polar chromosomes are rare, or of oocytes depleted of the kinesin-7 motor CENP-E, in which polar chromosomes are more abundant. Furthermore, in CENP-E-depleted oocytes, although polar chromosomal displacement intensified during MI and the capacity to form stable end-on attachments was severely compromised, all kinetochores nevertheless became devoid of Mad2. Thus, it is possible that the ability of the SAC to robustly discriminate chromosomal position might be compromised by the propensity of oocyte kinetochores to become saturated with unproductive attachments, thereby predisposing to aneuploidy. Our data also reveal novel functions for CENP-E in oocytes: first, CENP-E stabilises BubR1, thereby impacting MI progression; and second, CENP-E mediates bi-orientation by promoting kinetochore reorientation and preventing chromosomal drift towards the poles. PMID- 22513374 TI - The regenerative capacity of the zebrafish heart is dependent on TGFbeta signaling. AB - Mammals respond to a myocardial infarction by irreversible scar formation. By contrast, zebrafish are able to resolve the scar and to regenerate functional cardiac muscle. It is not known how opposing cellular responses of fibrosis and new myocardium formation are spatially and temporally coordinated during heart regeneration in zebrafish. Here, we report that the balance between the reparative and regenerative processes is achieved through Smad3-dependent TGFbeta signaling. The type I receptor alk5b (tgfbr1b) is expressed in both fibrotic and cardiac cells of the injured heart. TGFbeta ligands are locally induced following cryoinjury and activate the signaling pathway both in the infarct area and in cardiomyocytes in the vicinity of the trauma zone. Inhibition of the relevant type I receptors with the specific chemical inhibitor SB431542 qualitatively altered the infarct tissue and completely abolished heart regeneration. We show that transient scar formation is an essential step to maintain robustness of the damaged ventricular wall prior to cardiomyocyte replacement. Taking advantage of the reversible action of the inhibitor, we dissected the multifunctional role of TGFbeta signaling into three crucial processes: collagen-rich scar deposition, Tenascin C-associated tissue remodeling at the infarct-myocardium interface, and cardiomyocyte proliferation. Thus, TGFbeta signaling orchestrates the beneficial interplay between scar-based repair and cardiomyocyte-based regeneration to achieve complete heart regeneration. PMID- 22513373 TI - EYA1 and SIX1 drive the neuronal developmental program in cooperation with the SWI/SNF chromatin-remodeling complex and SOX2 in the mammalian inner ear. AB - Inner ear neurogenesis depends upon the function of the proneural basic helix loop-helix (bHLH) transcription factors NEUROG1 and NEUROD1. However, the transcriptional regulation of these factors is unknown. Here, using loss- and gain-of-function models, we show that EYA1 and SIX1 are crucial otic neuronal determination factors upstream of NEUROG1 and NEUROD1. Overexpression of both Eya1 and Six1 is sufficient to convert non-neuronal epithelial cells within the otocyst and cochlea as well as the 3T3 fibroblast cells into neurons. Strikingly, all the ectopic neurons express not only Neurog1 and Neurod1 but also mature neuronal markers such as neurofilament, indicating that Eya1 and Six1 function upstream of, and in the same pathway as, Neurog1 and Neurod1 to not only induce neuronal fate but also regulate their differentiation. We demonstrate that EYA1 and SIX1 interact directly with the SWI/SNF chromatin-remodeling subunits BRG1 and BAF170 to drive neurogenesis cooperatively in 3T3 cells and cochlear nonsensory epithelial cells, and that SOX2 cooperates with these factors to mediate neuronal differentiation. Importantly, we show that the ATPase BRG1 activity is required for not only EYA1- and SIX1-induced ectopic neurogenesis but also normal neurogenesis in the otocyst. These findings indicate that EYA1 and SIX1 are key transcription factors in initiating the neuronal developmental program, probably by recruiting and interacting with the SWI/SNF chromatin remodeling complex to specifically mediate Neurog1 and Neurod1 transcription. PMID- 22513375 TI - Response to the BMP gradient requires highly combinatorial inputs from multiple patterning systems in the Drosophila embryo. AB - Pattern formation in the developing embryo relies on key regulatory molecules, many of which are distributed in concentration gradients. For example, a gradient of BMP specifies cell fates along the dorsoventral axis in species ranging from flies to mammals. In Drosophila, a gradient of the BMP molecule Dpp gives rise to nested domains of target gene expression in the dorsal region of the embryo; however, the mechanisms underlying the differential response are not well understood, partly owing to an insufficient number of well-studied targets. Here we analyze how the Dpp gradient regulates expression of pannier (pnr), a candidate low-level Dpp target gene. We predicted that the pnr enhancer would contain high-affinity binding sites for the Dpp effector Smad transcription factors, which would be occupied in the presence of low-level Dpp. Unexpectedly, the affinity of Smad sites in the pnr enhancer was similar to those in the Race enhancer, a high-level Dpp target gene, suggesting that the affinity threshold mechanism plays a minimal role in the regulation of pnr. Our results indicate that a mechanism involving a conserved bipartite motif that is predicted to bind a homeodomain factor in addition to Smads and the Brinker repressor, establishes the pnr expression domain. Furthermore, the pnr enhancer has a highly complex structure that integrates cues not only from the dorsoventral axis, but also from the anteroposterior and terminal patterning systems in the blastoderm embryo. PMID- 22513377 TI - Rp58 is essential for the growth and patterning of the cerebellum and for glutamatergic and GABAergic neuron development. AB - Cerebellum development depends on the correct differentiation of progenitors into neurons, a process controlled by a transcriptional program that remains poorly understood. Here we show that neural-specific deletion of the BTB/POZ zinc-finger transcription factor-encoding gene Rp58 (Znf238, Zfp238) causes severe cerebellar hypoplasia and developmental failure of Purkinje neurons, Bergmann glia and granule neurons. Deletion of Rp58 in mouse embryonic Atoh1(+) progenitors leads to strong defects in growth and foliation owing to its crucial role in the differentiation of granule neurons. Analysis of the Rp58 mutant at E14.5 demonstrates that Rp58 is required for the development of both glutamatergic and GABAergic neurons. Rp58 mutants show decreased proliferation of glutamatergic progenitors at E14.5. In addition, Rp58 ablation results in a reduced number of GABAergic Pax2(+) neurons at E16.5 together with defects in the transcriptional program of ventricular zone progenitors. Our results indicate that Rp58 is essential for the growth and organization of the cerebellum and regulates the development of both GABAergic and glutamatergic neurons. PMID- 22513376 TI - The floral homeotic protein APETALA2 recognizes and acts through an AT-rich sequence element. AB - Cell fate specification in development requires transcription factors for proper regulation of gene expression. In Arabidopsis, transcription factors encoded by four classes of homeotic genes, A, B, C and E, act in a combinatorial manner to control proper floral organ identity. The A-class gene APETALA2 (AP2) promotes sepal and petal identities in whorls 1 and 2 and restricts the expression of the C-class gene AGAMOUS (AG) from whorls 1 and 2. However, it is unknown how AP2 performs these functions. Unlike the other highly characterized floral homeotic proteins containing MADS domains, AP2 has two DNA-binding domains referred to as the AP2 domains and its DNA recognition sequence is still unknown. Here, we show that the second AP2 domain in AP2 binds a non-canonical AT-rich target sequence, and, using a GUS reporter system, we demonstrate that the presence of this sequence in the AG second intron is important for the restriction of AG expression in vivo. Furthermore, we show that AP2 binds the AG second intron and directly regulates AG expression through this sequence element. Computational analysis reveals that the binding site is highly conserved in the second intron of AG orthologs throughout Brassicaceae. By uncovering a biologically relevant AT rich target sequence, this work shows that AP2 domains have wide-ranging target specificities and provides a missing link in the mechanisms that underlie flower development. It also sets the foundation for understanding the basis of the broad biological functions of AP2 in Arabidopsis, as well as the divergent biological functions of AP2 orthologs in dicotyledonous plants. PMID- 22513378 TI - Trajectories of criteria of nicotine dependence from adolescence to early adulthood. AB - BACKGROUND: To identify patterns and correlates of developmental trajectories of DSM-IV nicotine dependence criteria from adolescence to early adulthood. METHODS: The analytical sample of lifetime smokers (N=877) is from a longitudinal cohort of 6th-10th graders drawn from an urban school system. Subjects were interviewed 5 times at 6-month intervals and once 4.5 years later. Growth mixture models were estimated to identify trajectories of DSM-IV nicotine dependence criteria over ages 12-23. RESULTS: A four-class solution fitted the data best: No dependence criteria (class 1, 32.0%); early onset/chronic course (class 2, 26.1%); early onset/remission (class 3, 15.4%); late onset (class 4, 26.5%). There appeared to be three critical periods. At ages 12-15, symptoms increased rapidly. As of age 16, the early onset/chronic class stabilized at high levels of symptoms, the early onset/remission class started its symptomatic decline, and the late onset class experienced a sharp increase in symptoms. At age 20, there was a convergence in the prevalence of symptoms experienced at high (classes 2 and 4) and low levels (classes 1 and 3). Extensiveness of smoking and marijuana use were associated with higher baseline levels of nicotine dependence criteria. Anxiety disorders were associated with all three symptomatic trajectories. Parental smoking and nicotine dependence were associated specifically with the early/chronic class, while pleasant initial sensitivity and earlier onset ages of cigarette and marijuana use characterized the two early onset classes (2 and 3). CONCLUSIONS: Trajectories of dependence criteria constitute an advantageous phenotype for research and intervention over static summaries of smoking behaviors. PMID- 22513379 TI - The influence of living along the U.S.-Mexico border on unintentional drug overdose death, New Mexico (USA), 2005-2009. AB - BACKGROUND: The objective of this study was to characterize unintentional drug overdose death patterns among Hispanic ethnicity/sex strata by residence in New Mexico counties that border Mexico and non-border counties. METHODS: We analyzed medical examiner data for all unintentional drug overdose death in New Mexico during 2005-2009. Logistic and Poisson regression was used to examine the relationship of unintentional drug overdose death with border residence and demographics. Risk of overdose death was examined by the interactions of ethnicity, sex and border residence. RESULTS: During 2005-2009, the statewide drug overdose death rate was 17.6 per 100,000 (n=1812). Border decedents were more likely to have died from overdose of prescription opioids other than methadone (Schedule II, Adjusted Odds Ratio (aOR)=1.98; Schedule III/IV, aOR=1.56) but less likely to have died from heroin overdose (aOR=0.35), compared to non-border decedents. In population-based analyses, people living in border counties had lowest rates of overall overdose death and from illicit drugs, particularly heroin and cocaine. Hispanic males (adjusted incidence rate ratio [aRR]=2.41), Hispanic females (aRR=1.77) and non-Hispanic males (aRR=1.37) from non-border counties had higher risk of drug overdose death than their counterparts from border counties. Border residence had no effect on risk of drug overdose death among non-Hispanic females. CONCLUSIONS: Residents in border counties incurred a protective effect for drug overdose death, most pronounced among Hispanics. There is a component of overdose death risk for which border residence is a proxy, likely an array of cultural and healthcare-related factors. PMID- 22513381 TI - The environmental context for the origins of modern human diversity: a synthesis of regional variability in African climate 150,000-30,000 years ago. AB - We synthesize African paleoclimate from 150 to 30 ka (thousand years ago) using 85 diverse datasets at a regional scale, testing for coherence with North Atlantic glacial/interglacial phases and northern and southern hemisphere insolation cycles. Two major determinants of circum-African climate variability over this time period are supported by principal components analysis: North Atlantic sea surface temperature (SST) variations and local insolation maxima. North Atlantic SSTs correlated with the variability found in most circum-African SST records, whereas the variability of the majority of terrestrial temperature and precipitation records is explained by local insolation maxima, particularly at times when solar radiation was intense and highly variable (e.g., 150-75 ka). We demonstrate that climates varied with latitude, such that periods of relatively increased aridity or humidity were asynchronous across the northern, eastern, tropical and southern portions of Africa. Comparisons of the archaeological, fossil, or genetic records with generalized patterns of environmental change based solely on northern hemisphere glacial/interglacial cycles are therefore imprecise. We compare our refined climatic framework to a database of 64 radiometrically-dated paleoanthropological sites to test hypotheses of demographic response to climatic change among African hominin populations during the 150-30 ka interval. We argue that at a continental scale, population and climate changes were asynchronous and likely occurred under different regimes of climate forcing, creating alternating opportunities for migration into adjacent regions. Our results suggest little relation between large scale demographic and climate change in southern Africa during this time span, but strongly support the hypothesis of hominin occupation of the Sahara during discrete humid intervals ~135-115 ka and 105-75 ka. Hominin populations in equatorial and eastern Africa may have been buffered from the extremes of climate change by locally steep altitudinal and rainfall gradients and the complex and variable effects of increased aridity on human habitat suitability in the tropics. Our data are consistent with hominin migrations out of Africa through varying exit points from ~140-80 ka. PMID- 22513382 TI - The relative congruence of cranial and genetic estimates of hominoid taxon relationships: implications for the reconstruction of hominin phylogeny. AB - Previous analyses of extant catarrhine craniodental morphology have often failed to recover their molecular relationships, casting doubt on the accuracy of hominin phylogenies based on anatomical data. However, on the basis of genetic, morphometric and environmental affinity patterns, a growing body of literature has demonstrated that particular aspects of cranial morphology are remarkably reliable proxies for neutral modern human population history. Hence, it is important to test whether these intra-specific patterns can be extrapolated to a broader primate taxon level such that inference rules for understanding the morphological evolution of the extinct hominins may be devised. Here, we use a matrix of molecular distances between 15 hominoid taxa to test the genetic congruence of 14 craniomandibular regions, defined and morphometrically delineated on the basis of previous modern human analyses. This methodology allowed us to test directly whether the cranial regions found to be reliable indicators of population history were also more reliable proxies for hominoid genetic relationships. Cranial regions were defined on the basis of three criteria: developmental-functional units, individual bones, and regions differentially affected by masticatory stress. The results found that all regions tested were significantly and strongly correlated with the molecular matrix. However, the modern human predictions regarding the relative congruence of particular regions did not hold true, as the face was statistically the most reliable indicator of hominoid genetic distances, as opposed to the vault or basicranium. Moreover, when modern humans were removed from the analysis, all cranial regions improved in their genetic congruence, suggesting that it is the inclusion of morphologically-derived humans that has the largest effect on incongruence between morphological and molecular estimates of hominoid relationships. Therefore, it may be necessary to focus on smaller intra-generic taxonomic levels to more fully understand the effects of neutral and selective evolutionary processes in generating morphological diversity patterns. PMID- 22513380 TI - Acute baclofen diminishes resting baseline blood flow to limbic structures: a perfusion fMRI study. AB - BACKGROUND: Preclinical and clinical evidence show that the GABA B agonist, baclofen is a promising treatment for addictive disorders; however, until recently its mechanism of action in the human brain was unknown. In previous work we utilized a laboratory model that included a medication versus placebo regimen to examine baclofen's actions on brain circuitry. Perfusion fMRI [measure of cerebral blood flow (CBF)] data acquired 'at rest' before and on the last day of the 21-day medication regimen showed that baclofen diminished CBF bilaterally in the VS, insula and medial orbitofrontal cortex (mOFC). In the present study, we hypothesized that a single dose of baclofen would have effects similar to repeated dosing. METHODS: To test our hypothesis, in a crossover design, CBF data were acquired using pseudo continuous arterial spin labeled (pCASL) perfusion fMRI. Subjects were either un-medicated or were administered a 20mg dose of baclofen approximately 110 min prior to scanning. RESULTS: Acute baclofen diminished mOFC, amygdala, and ventral anterior insula CBF without causing sedation (family-wise error corrected at p=0.001). CONCLUSIONS: Results demonstrate that similar to repeated dosing, an acute dose of baclofen blunts the 'limbic' substrate that is hyper-responsive to drugs and drug cues. Smokers often manage their craving and can remain abstinent for extended periods after quitting, however the risk of eventual relapse approaches 90%. Given that chronic medication may not be a practical solution to the long-term risk of relapse, acute baclofen may be useful on an 'as-needed' basis to block craving during 'at risk' situations. PMID- 22513383 TI - SigMate: a Matlab-based automated tool for extracellular neuronal signal processing and analysis. AB - Rapid advances in neuronal probe technology for multisite recording of brain activity have posed a significant challenge to neuroscientists for processing and analyzing the recorded signals. To be able to infer meaningful conclusions quickly and accurately from large datasets, automated and sophisticated signal processing and analysis tools are required. This paper presents a Matlab-based novel tool, "SigMate", incorporating standard methods to analyze spikes and EEG signals, and in-house solutions for local field potentials (LFPs) analysis. Available modules at present are - 1. In-house developed algorithms for: data display (2D and 3D), file operations (file splitting, file concatenation, and file column rearranging), baseline correction, slow stimulus artifact removal, noise characterization and signal quality assessment, current source density (CSD) analysis, latency estimation from LFPs and CSDs, determination of cortical layer activation order using LFPs and CSDs, and single LFP clustering; 2. Existing modules: spike detection, sorting and spike train analysis, and EEG signal analysis. SigMate has the flexibility of analyzing multichannel signals as well as signals from multiple recording sources. The in-house developed tools for LFP analysis have been extensively tested with signals recorded using standard extracellular recording electrode, and planar and implantable multi transistor array (MTA) based neural probes. SigMate will be disseminated shortly to the neuroscience community under the open-source GNU-General Public License. PMID- 22513385 TI - Heterologous RNA-silencing suppressors from both plant- and animal-infecting viruses support plum pox virus infection. AB - HCPro, the RNA-silencing suppressor (RSS) of viruses belonging to the genus Potyvirus in the family Potyviridae, is a multifunctional protein presumably involved in all essential steps of the viral infection cycle. Recent studies have shown that plum pox potyvirus (PPV) HCPro can be replaced successfully by cucumber vein yellowing ipomovirus P1b, a sequence-unrelated RSS from a virus of the same family. In order to gain insight into the requirement of a particular RSS to establish a successful potyviral infection, we tested the ability of different heterologous RSSs from both plant- and animal-infecting viruses to substitute for HCPro. Making use of engineered PPV chimeras, we show that PPV HCPro can be replaced functionally by some, but not all, unrelated RSSs, including the NS1 protein of the mammal-infecting influenza A virus. Interestingly, the capacity of a particular RSS to replace HCPro does not correlate strictly with its RNA silencing-suppression strength. Altogether, our results suggest that not all suppression strategies are equally suitable for efficient escape of PPV from the RNA-silencing machinery. The approach followed here, based on using PPV chimeras in which an under-consideration RSS substitutes for HCPro, could further help to study the function of diverse RSSs in a 'highly sensitive' RNA-silencing context, such as that taking place in plant cells during the process of a viral infection. PMID- 22513384 TI - Adhesion molecule CADM1 contributes to gap junctional communication among pancreatic islet alpha-cells and prevents their excessive secretion of glucagon. AB - Cell adhesion molecule-1 (CADM1) is a recently identified adhesion molecule of pancreatic islet alpha-cells that mediates nerve-alpha-cell interactions via trans-homophilic binding and serves anatomical units for the autonomic control of glucagon secretion. CADM1 also mediates attachment between adjacent alpha-cells. Since gap junctional intercellular communication (GJIC) among islet cells is essential for islet hormone secretion, we examined whether CADM1 promotes GJIC among alpha-cells and subsequently participates in glucagon secretion regulation. Dye transfer assays using alphaTC6 mouse alpha-cells, which endogenously express CADM1, supported this possibility; efficient cell-to-cell spread of gap junction permeable dye was detected in clusters of alphaTC6 cells transfected with nonspecific, but not with CADM1-targeting, siRNA. Immunocytochemical analysis of connexin 36, a major component of the gap junction among alphaTC6 cells, revealed that it was localized exclusively to the cell membrane in CADM1-non-targeted alphaTC6 cells, but diffusely to the cytoplasm in CADM1-targeted cells. Next, we incubated CADM1-targeted and non-targeted alphaTC6 cells in a medium containing 1 mM glucose and 200 mM arginine for 30 min to induce glucagon secretion, and found that the targeted cells secreted three times more glucagon than did the non targeted. We conducted similar experiments using pancreatic islets that were freshly isolated from wild-type and CADM1-knockout mice, and expressed glucagon secretion as ratios relative to baseline values. The increase in ratio was larger in CADM1-knockout islets than in wild-type islets. These results suggest that CADM1 may serve as a volume limiter of glucagon secretion by sustaining alpha cell attachment necessary for efficient GJIC. PMID- 22513386 TI - Identification and characterization of two novel genomic RNA segments of fig mosaic virus, RNA5 and RNA6. AB - Fig mosaic virus (FMV), a negative-strand RNA virus, is recognized as a causal agent of fig mosaic disease. We performed RT-PCR for 14 FMV isolates collected from symptomatic fig plants in Japan and Serbia using primers corresponding to the conserved 13 nt stretches found at the termini of FMV genomic segments. The resulting simultaneous amplification of all FMV genomic segments yielded four previously identified segments of FMV and two novel segments. These novel FMV genomic RNA segments were found in each of the 14 FMV isolates analysed. In Northern blot studies, both the sense and antisense strands of these novel RNA molecules accumulated in FMV-infected fig leaves but not in uninfected fig leaves, confirming that they replicate as FMV genomic segments. Sequence analysis showed that the novel RNA segments are similar, in their structural organization and molecular evolutionary patterns, to those of known FMV genomic RNA segments. Our findings thus indicate that these newly discovered RNA segments are previously unidentified FMV genomic segments, which we have designated RNA5 and RNA6. PMID- 22513387 TI - mdv1-miR-M7-5p, located in the newly identified first intron of the latency associated transcript of Marek's disease virus, targets the immediate-early genes ICP4 and ICP27. AB - Marek's disease virus serotype 1 (MDV-1) is an oncogenic alphaherpesvirus causing fatal T-cell lymphoma in chickens. MDV latency is characterized by the production of latency-associated transcripts (LATs), a family of non-protein-coding spliced RNAs. A cluster of four microRNAs (cluster mdv1-miR-M8-M10) was identified, but not formally mapped, at the predicted LAT 5' end. We established a LAT cDNA library from latently MDV-infected cell line MSB-1. We identified 22 highly variable LATs, which were due to the extensive alternative splicing of a total of 14 introns. RACE PCR confirmed the predicted 3' end and allowed identification of the 5' end, 400 nt upstream of the previously predicted LAT end. The LATs share their transcription start site with the microRNA-expressing transcript described previously, localizing the microRNAs to the first LAT intron and identifying the LATs as the primary transcripts of the microRNAs. We identified MDV immediate early (IE) genes ICP4 and ICP27 as putative targets of mdv1-miR-M7-5p, the third microRNA of the cluster mdv1-miR-M8-M10. Endogenously expressed mdv1-miR-M7-5p in MSB-1 cells reduced luciferase activity significantly when microRNA-responsive elements from ICP4 or ICP27 were cloned in the 3' UTR of the firefly luciferase gene. ICP27 protein levels were decreased by 70 % when the mdv1-miR-M7-5p precursor was co-expressed with an ICP27 expression plasmid. Additionally, we showed a negative correlation between the decreased expression of mdv1-miR-M7-5p and an increase in ICP27 expression during virus reactivation. Our results suggest that, by targeting two IE genes, MDV microRNAs produced from LAT transcripts may contribute to establish and/or maintain latency. PMID- 22513388 TI - Insertion of type O-conserved neutralizing epitope into the foot-and-mouth disease virus type Asia1 VP1 G-H loop: effect on viral replication and neutralization phenotype. AB - Previously, we finely mapped the neutralizing epitopes recognized by foot-and mouth disease virus (FMDV) type Asia1-specific mAb 3E11 and FMDV type O-specific mAb 8E8. In this study, we engineered recombinant FMDVs of the serotype Asia1 (rFMDVs) displaying the type O-neutralizing epitope recognized by the mAb 8E8. These epitope-inserted viruses were genetically stable and exhibited growth properties that were similar to those of their parental virus. Importantly, the recombinant virus rFMDV-C showed neutralization sensitivity to both FMDV type Asia1 and type O mAbs, as well as to polyclonal antibodies. These results indicated that this epitope-inserted virus has the potential to induce neutralizing antibodies against both FMDV type Asia1 and type O. Our results demonstrated that the G-H loop of FMDV type Asia1 effectively displays the protective neutralizing epitopes of other FMDV serotypes, making this an attractive approach for the design of novel FMDV vaccines. PMID- 22513389 TI - The small genome segment of Bunyamwera orthobunyavirus harbours a single transcription-termination signal. AB - Transcription termination of the mRNA produced from the small (S) genome segment of Bunyamwera orthobunyavirus (BUNV) has previously been mapped to two cis-acting sequences located within the 5' UTR using a virus-free replication assay. The ability of these sequences to terminate transcription was attributed to the shared pentanucleotide motif 3'-UGUCG-5'. Taking advantage of our plasmid-based rescue system to generate recombinant viruses, we re-evaluated the importance of both pentanucleotide motifs as well as that of two other conserved sequences in transcription termination in vivo. Analysis of the 3' ends of positive-stranded viral RNAs derived from the S segment revealed that only the region around the upstream pentanucleotide motif mediated transcription termination in cells infected with wild-type BUNV, leading to mRNAs that were about 100 nt shorter than antigenome RNA. Furthermore, the downstream motif was not recognized in recombinant viruses in which the upstream signal has been disrupted. Our results suggest that in the context of virus infection transcription termination of the BUNV S genome segment mRNA is exclusively directed by the upstream-termination signal. Interestingly, within this region we identified a motif similar to a transcription-termination sequence used by Rift Valley fever phlebovirus. PMID- 22513390 TI - MBT/Pas mouse: a relevant model for the evaluation of Rift Valley fever vaccines. AB - Currently, there are no worldwide licensed vaccines for Rift Valley fever (RVF) that are both safe and effective. Development and evaluation of vaccines, diagnostics and treatments depend on the availability of appropriate animal models. Animal models are also necessary to understand the basic pathobiology of infection. Here, we report the use of an inbred MBT/Pas mouse model that consistently reproduces RVF disease and serves our purpose for testing the efficacy of vaccine candidates; an attenuated Rift Valley fever virus (RVFV) and a recombinant RVFV-capripoxvirus. We show that this model is relevant for vaccine testing. PMID- 22513391 TI - Long-chain cationic derivatives of PTA (1,3,5-triaza-7-phosphaadamantane) as new components of potential non-viral vectors. AB - The purpose of this study was to investigate the potential of new positively charged solid lipid nanoparticles (SLN) to convey nucleic acids. The cationic character of SLN was obtained by adding as cationic molecules two different long chain cationic phosphines (CP), namely hexadecyl-PTA iodide (CP16) and octadecyl PTA iodide (CP18). The obtained CP-SLN are characterized by a positive charge on the surface and reproducible dimensions around 220 nm. These nanosystems are able to efficiently bind nucleic acid molecules and to protect DNA from the activity of serum nucleases up to 120 min. Lastly, in vitro experiments demonstrated that CP-SLN exhibit a quite pronounced antiproliferative effect on cultured human K562 erythroleukemic cells and a limited effect as transfecting adjuvant. These data, and particularly the ability of CP-SLN to protect DNA from degradation, encourages further studies aimed at proposing these nanosystems as a potential approach to deliver nucleic acid to cells in living organisms. PMID- 22513392 TI - [Alternative biological materials to detect prenatal exposure to drugs of abuse in the third trimester of pregnancy]. AB - INTRODUCTION: Detection of prenatal drug abuse exposure is essential to ensure an appropriate monitoring of affected children. A maternal questionnaire is not an efficient screening tool. The usefulness of maternal hair and meconium as biological materials to assess this exposure has been described in last few years. The aim of this study was to compare both these alternative biological materials for prenatal drug exposure detection in the third trimester of pregnancy, in order to assess its use as a screening tool. PATIENTS AND METHODS: Between January and March 2010, samples of maternal hair and meconium from 107 mother-infant dyads were collected in Can Misses Hospital, Ibiza. The presence of opiates, cocaine, cannabis, and amphetamines, was determined in both materials, using standard chromatographic techniques. RESULTS: Maternal hair analysis showed a 15.9% positivity for drugs of abuse (17 cases): 11 cannabis, 7 cocaine, 1 cannabis and ecstasy, and 1 cannabis and cocaine. Only one mother reported cannabis consumption and another one, cocaine. Of the 7 cocaine positive cases in hair, 6 were confirmed in meconium analysis, while of 11 cannabis positive cases, only 3 were confirmed in meconium. Two different consumer profiles were defined: cocaine consumers and cannabis consumers (with only 2 cases of multiple drug use). The highest level of cocaine ever published was detected (1.582ng/g) in one case. DISCUSSION: This study reveals a high prevalence of drug abuse in this cohort during pregnancy. Improved screening methods may optimize prevention and monitoring of exposed infants. Maternal hair seems to be more sensitive than meconium to detect prenatal exposure to cannabis during the third trimester, so it might become a good screening tool. PMID- 22513393 TI - Phrenic nerve injury after radiofrequency ablation of lung tumors: retrospective evaluation of the incidence and risk factors. AB - PURPOSE: To retrospectively investigate the incidence of and risk factors for phrenic nerve injury after radiofrequency (RF) ablation of lung tumors. MATERIALS AND METHODS: The study included 814 RF ablation procedures of lung tumors. To evaluate the development of phrenic nerve injury, chest radiographs obtained before and after the procedure were examined. Phrenic nerve injury was assumed to have developed if the diaphragmatic level was elevated after the procedure. To identify risk factors for phrenic nerve injury, multiple variables were compared between cases of phrenic nerve injury and randomly selected controls by using univariate analyses. Multivariate analysis was then performed to identify independent risk factors. RESULTS: Evaluation of phrenic nerve injury from chest radiographs was possible after 786 procedures. Evidence of phrenic nerve injury developed after 10 cases (1.3%). Univariate analysis revealed that larger tumor size (>= 20 mm; P = .014), proximity of the phrenic nerve to the tumor (< 10 mm; P < .001), the use of larger electrodes (array diameter or noninsulated tip length >= 3 cm; P = .001), and higher maximum power applied during ablation (>= 100 W; P < .001) were significantly associated with the development of phrenic nerve injury. Multivariate analysis demonstrated that the proximity of the phrenic nerve to the tumor (< 10 mm; P < .001) was a significant independent risk factor. CONCLUSIONS: The incidence of phrenic nerve injury after RF ablation was 1.3%. The proximity of the phrenic nerve to the tumor was an independent risk factor for phrenic nerve injury. PMID- 22513395 TI - Magneto-chiral dichroism of artificial light-harvesting antenna. AB - We have demonstrated the presence of magneto-chiral dichroism (MChD) of chiral J aggregates of zinc chlorins. To the best of our knowledge, this is the first observation of MChD in artificial light-harvesting antennas. PMID- 22513394 TI - Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions. PMID- 22513398 TI - Role of neuropeptide Y in regulating hypothalamus-pituitary-gonad axis in the rats treated with electro-acupuncture. AB - Neuropeptide Y (NPY) is an important regulator of reproductive axis, which mainly plays some roles in regulating secretion of gonadotropin-releasing hormone (GnRH) in hypothalamus. In previous studies, we found that the repeated low frequency electro-acupuncture (EA) down-regulated hypothalamus-pituitary-gonad (HPG) axis of common rats and rabbits during puberty. In this study, we investigated the role of NPY in regulating the reproductive axis of common rats at different developmental stages and rats treated with the repeated EA. Low frequency EA (3 Hz) was performed at acupoints (treatment groups) or non-acupoints (control groups) for 20 min daily for 10 days in Sprague-Dawley (SD) rats at four developmental stages, which were juvenile stage, early puberty stage, later puberty stage and adult stage. NPY expression in the hypothalamus were determined using RT-PCR and real-time quantitative PCR (qPCR) after 10 days-treatments. The results showed that NPY expression in the early pubertal group (EPG) was significantly depressed after repeated EA (P<0.05). Compared with the results of GnRH expression and body weights, the change of NPY expression was similar with the fluctuation of GnRH expression after EA and the increase of body weights of rats was not influenced by the depression of NPY expression after EA during early puberty. The results demonstrated that repeated low frequency EA was an effective method on down-regulating not only the GnRH expression but also the NPY expression in the hypothalamus without reducing body weights of rats during early puberty. PMID- 22513397 TI - Decreased cyclooxygenase inhibition by aspirin in polymorphic variants of human prostaglandin H synthase-1. AB - OBJECTIVES: Aspirin (ASA), a major antiplatelet and cancer-preventing drug, irreversibly blocks the cyclooxygenase (COX) activity of prostaglandin H synthase 1 (PGHS-1). Considerable differences in ASA effectiveness are observed between individuals, and some of this variability may be due to PGHS-1 protein variants. Our overall aim is to determine which, if any, of the known variants in the mature PGHS-1 protein lead to functional alterations in COX catalysis or inhibition by ASA. The present study targeted four PGHS-1 variants: R53H, R108Q, L237M, and V481I. METHODS: Wild-type human PGHS-1 and the four polymorphic variants were expressed as histidine-tagged, homodimeric proteins in insect cells using baculovirus vectors, solubilized with a detergent, and purified by affinity chromatography. The purified proteins were characterized in vitro to evaluate COX and peroxidase (POX) catalytic parameters and the kinetics of COX inhibition by ASA and NS-398. RESULTS: Compared with the wild type, several variants showed a higher COX/POX ratio (up to 1.5-fold, for R108Q), an elevated arachidonate Km (up to 1.9-fold, for R108Q), and/or a lower ASA reactivity (up to 60% less, for R108Q). The decreased ASA reactivity in R108Q reflected both a 70% increase in the Ki for ASA and a 30% decrease in the rate constant for acetyl group transfer to the protein. Computational modeling of the brief ASA pulses experienced by PGHS-1 in circulating platelets during daily ASA dosing predicted that the 60% lower ASA reactivity in R108Q yields a 15-fold increase in surviving COX activity; smaller, approximately two-fold increases in surviving COX activity were predicted for L237M and V481I. NS-398 competitively inhibited COX catalysis of the wild type (Ki=6 umol/l) and inhibited COX inactivation by 1.0 mmol/l ASA in both the wild type (IC50=0.8 umol/l) and R108Q (IC50=2.1 umol/l). CONCLUSION: Of the four PGHS-1 variants examined, R108Q exerts the largest functional effects, with evidence for impaired interactions with a COX substrate and inhibitors. As Arg108 is located on the protein surface and not in the active site, the effects of R108Q suggest a novel, unsuspected mechanism for the modulation of the PGHS-1 active site structure. The lower intrinsic ASA reactivity of R108Q, V481I, and L237M, combined with the rapid hydrolysis of ASA in the blood, suggests that these variants decrease the antiplatelet effectiveness of the drug. These PGHS-1 variants are uncommon but ASA is used widely; hence, a considerable number of individuals could be affected. Further examination of these and other PGHS-1 variants will be needed to determine whether PGHS-1 genotyping can be used to personalize anti-COX therapy. PMID- 22513399 TI - Effect of arginine vasopressin on the behavioral activity in the behavior despair depression rat model. AB - Arginine vasopressin (AVP), a nonapeptide posterior hormone of the pituitary, is mainly synthesized and secreted in the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). Large numbers of studies have reported that AVP plays a role in depression. The present study was to investigate by which level, brain or periphery, AVP affects the behavioral activity in the behavior despair depression rat model. The results showed that (1) either forced swimming or tail suspension significantly increased AVP concentration not only in the brain (PVN, SON, frontal of cortex, hippocampus, amygdala, lumber spinal cord) but also in the periphery (posterior pituitary and serum); (2) intraventricular injection (icv) of AVP decreased the animal immobility time, whereas V1 receptor antagonist d(CH2)5Tyr(Me)AVP (icv) increased the animal immobility time in a dose-dependent manner not only in FST but also in TST, but the V2 receptor antagonist d(CH2)5[D Ile, Ile, Ala-NH9]AVP did not change the animal immobility time in FST or TST; (3) V1, not V2 receptor antagonist could inhibit the animal immobility time decrease induced by AVP (icv); (4) neither AVP nor its receptor antagonist (including V1 and V2 receptor antagonist) influenced the animal immobility time in both FST and TST. The data suggested that AVP in the brain rather than the periphery played a role in the behavior despair depression by V1, not V2 receptors, which behavior despair might have a positive feedback effect on central AVP and blood AVP might have a negative feedback on central AVP in the depressive process. PMID- 22513402 TI - Genomics: Constructing a 'cancerpaedia'. PMID- 22513403 TI - Environment and genotype controls on mercury accumulation in rice (Oryza sativa L.) cultivated along a contamination gradient in Guizhou, China. AB - Accumulation of total Hg (THg) and methylmercury (MeHg) was investigated among 50 indica rice varieties cultivated in 3 sites in Guizhou, China, classified as highly-contaminated, moderately-contaminated, and background sites. Concentrations of soil and pore water (depth: 0-2 cm) THg and MeHg were poor predictors of THg and MeHg concentrations in polished white rice and bran, with significantly higher accumulation in the moderately-contaminated site compared to the other 2 sites (ANOVA, p<0.0001). Results indicated other environmental factors played a critical role in the translocation of Hg species from paddy soil to rice grain. We hypothesized alkaline conditions at the highly-contaminated site (surface water pH 11, other 2 sites pH 7.6-8.0), mitigated the uptake of Hg species by decreasing the solubility of micronutrients needed for plant growth, or by reducing the bioavailability of Hg species. White rice MeHg concentrations were associated with genotype but not inorganic Hg(II) concentrations (IHg=THG MeHg) (MeHg: p<0.001, IHG: p=0.44), while bran MeHg and IHg concentrations were not significantly associated with genotype (p>0.05 for both analyses), indicating there may be genetic markers for the translocation of MeHg from the caryopsis to the endosperm, i.e., from the maternal to the filial tissue. Lastly, calculation of daily MeHg ingestion rates confirmed international guidelines for MeHg exposure were exceeded at the moderately-contaminated site (background: 0.013+/ 0.0052 MUg kg(-1) d(-1), n=46; highly-contaminated: 0.066+/-0.034 MUg kg(-1) d( 1), n=49; moderately-contaminated: 0.42+/-0.13 MUg kg(-1) d(-1), n=49). However, MeHg exposure at this site may be decreased up to 69% by cultivating low Hg accumulating rice varieties. PMID- 22513401 TI - Intra-tumour heterogeneity: a looking glass for cancer? AB - Populations of tumour cells display remarkable variability in almost every discernable phenotypic trait, including clinically important phenotypes such as ability to seed metastases and to survive therapy. This phenotypic diversity results from the integration of both genetic and non-genetic influences. Recent technological advances have improved the molecular understanding of cancers and the identification of targets for therapeutic interventions. However, it has become exceedingly apparent that the utility of profiles based on the analysis of tumours en masse is limited by intra-tumour genetic and epigenetic heterogeneity, as characteristics of the most abundant cell type might not necessarily predict the properties of mixed populations. In this Review, we discuss both genetic and non-genetic causes of phenotypic heterogeneity of tumour cells, with an emphasis on heritable phenotypes that serve as a substrate for clonal selection. We discuss the implications of intra-tumour heterogeneity in diagnostics and the development of therapeutic resistance. PMID- 22513404 TI - Monitored natural attenuation (MNA) of contaminated soils: state of the art in Europe--a critical evaluation. AB - The use of natural attenuation (NA) processes for contaminated site cleanup and remediation has been gaining more attention over the last few years. However, the need for an inventory of the existing information concerning monitored natural attenuation (MNA), including the existing return on experience, has been sounding increasingly louder over recent years as well. This paper will focus on the application of MNA throughout Europe. First, a literature study and a survey were performed in order to collect all available data on both qualitative and quantitative aspects of MNA. Secondly, a questionnaire was created and sent out to experts in the field of regulation and research from six countries, including Finland, Spain, and the UK. Thirdly, further contributions from a SNOWMAN workshop concerning MNA (November 7th, 2011, Paris) were included in this paper. The result is a state of the art concerning MNA for several countries, including the legal framework and existing protocols, a comparison between different countries, and an overview of some existing MNA cases throughout Europe combined with a discussion on relevant aspects related to "return on experience". The results demonstrate that MNA is now considered to be a conventional remediation technique in most countries that were included in this study. Although MNA is currently being applied for the remediation of contaminated sites, some countries still don't recognise it as an official remediation technique (e.g. Finland). This study also confirms and illustrates the differences concerning the MNA approach that exists between different countries, as well as the differences in application levels. However, it is important to note that at the same time a certain level of coherence exists concerning the MNA approach, e.g. with regard to the importance of biodegradation processes. Furthermore, the main outcome of this study emphasises the clear need to systematically collect and share information concerning existing MNA cases. Only then a clear return of experience will be possible. PMID- 22513407 TI - The Molecularly Crowded Cytoplasm of Bacterial Cells: Dividing Cells Contrasted with Viable but Non-culturable (VBNC) Bacterial Cells. AB - In this perspective, we discuss the cytoplasm in actively growing bacterial cells contrasted with viable but nonculturable (VBNC) cells. Actively growing bacterial cells contain a more molecularly crowded and organized cytoplasm, and are capable of completing their cell cycle resulting in cell division. In contrast, nutrient starving bacteria in the physiological VBNC state are struggling to survive, as essential nutrients are not available or limiting. The cytoplasm is not as molecularly crowded as gene expression is minimal (e.g., ribosome, transcript, tRNA and protein numbers are decreased), energy pools are depleted, cells may exhibit leakage, and DNA is not being replicated for cell division. PMID- 22513406 TI - Balancing antiviral potency and host toxicity: identifying a nucleotide inhibitor with an optimal kinetic phenotype for HIV-1 reverse transcriptase. AB - Two novel thymidine analogs, 3'-fluoro-3'-deoxythymidine (FLT) and 2',3' didehydro-3'-deoxy-4'-ethynylthymidine (Ed4T), have been investigated as nucleoside reverse transcriptase inhibitors (NRTIs) for treatment of HIV infection. Ed4T seems very promising in phase II clinical trials, whereas toxicity halted FLT development during this phase. To understand these different molecular mechanisms of toxicity, pre-steady-state kinetic studies were used to examine the interactions of FLT and Ed4T with wild-type (WT) human mitochondrial DNA polymerase gamma (pol gamma), which is often associated with NRTI toxicity, as well as the viral target protein, WT HIV-1 reverse transcriptase (RT). We report that Ed4T-triphosphate (TP) is the first analog to be preferred over native nucleotides by RT but to experience negligible incorporation by WT pol gamma, with an ideal balance between high antiretroviral efficacy and minimal host toxicity. WT pol gamma could discriminate Ed4T-TP from dTTP 12,000-fold better than RT, with only an 8.3-fold difference in discrimination being seen for FLT-TP. A structurally related NRTI, 2',3'-didehydro-2',3'-dideoxythymidine, is the only other analog favored by RT over native nucleotides, but it exhibits only a 13-fold difference (compared with 12,000-fold for Ed4T) in discrimination between the two enzymes. We propose that the 4'-ethynyl group of Ed4T serves as an enzyme selectivity moiety, critical for discernment between RT and WT pol gamma. We also show that the pol gamma mutation R964C, which predisposes patients to mitochondrial toxicity when receiving 2',3'-didehydro-2',3'-dideoxythymidine to treat HIV, produced some loss of discrimination for FLT-TP and Ed4T-TP. These molecular mechanisms of analog incorporation, which are critical for understanding pol gamma-related toxicity, shed light on the unique toxicity profiles observed during clinical trials. PMID- 22513408 TI - Mechanisms of transcriptional precision in animal development. AB - We review recently identified mechanisms of transcriptional control that ensure reliable and reproducible patterns of gene expression in natural populations of developing embryos, despite inherent fluctuations in gene regulatory processes, variations in genetic backgrounds and exposure to diverse environmental conditions. These mechanisms are not responsible for switching genes on and off. Instead, they control the fine-tuning of gene expression and ensure regulatory precision. Several such mechanisms are discussed, including redundant binding sites within transcriptional enhancers, shadow enhancers, and 'poised' enhancers and promoters, as well as the role of 'redundant' gene interactions within regulatory networks. We propose that such regulatory mechanisms provide population fitness and 'fine-tune' the spatial and temporal control of gene expression. PMID- 22513409 TI - Interaction between two sulfate-conjugated uremic toxins, p-cresyl sulfate and indoxyl sulfate, during binding with human serum albumin. AB - Recently, p-cresyl sulfate (PCS) has been identified as a protein-bound uremic toxin. Moreover, the serum-free concentration of PCS, which is associated with its efficacy of hemodialysis, appears to be a good predictor of survival in chronic kidney disease (CKD). We previously found that PCS interacts with indoxyl sulfate (IS), another sulfate-conjugated uremic toxin, during renal excretion via a common transporter. The purpose of this study was to further investigate the interaction between PCS and IS on the binding to human serum albumin (HSA). Here, we used ultrafiltration to show that there is only one high-affinity binding site for PCS, with a binding constant on the order of 10(5) M(-1) (i.e., comparable to that of IS). However, a binding constant of the low-affinity binding site for PCS is 2.5-fold greater than that for IS. Displacement of a fluorescence probe showed that PCS mainly binds to site II, which is the high-affinity site for PCS, on HSA. This finding was further supported by experiments using mutant HSA (R410A/Y411A) that displayed reduced site II ligand binding. A Klotz analysis showed that there could be competitive inhibition between PCS and IS on HSA binding. A similar interaction between PCS and IS on HSA was also observed under the conditions mimicking CKD stage 4 to 5. The present study suggests that competitive interactions between PCS and IS in both HSA binding and the renal excretion process could contribute to fluctuations in their free serum concentrations in patients with CKD. PMID- 22513410 TI - High-temperature ferromagnetism in Co-doped CeO2 synthesized by the coprecipitation technique. AB - The aim of the present study is to check the influence of annealing under vacuum and a mixture of N(2)-H(2) atmosphere on the magnetic properties of polycrystalline Co-doped CeO(2) diluted magnetic oxides (DMOs) with Co concentrations of 5 at% synthesized using the coprecipitation technique. X-Ray diffraction (XRD) patterns and transmission electron microscopy (TEM) showed for all samples the expected CeO(2) cubic fluorite-type structure and that Co ions are uniformly distributed inside the samples. Room-temperature Raman and photoluminescence (PL) spectroscopies indicate an increase in the concentration of oxygen vacancies upon Co doping and further annealing. Field dependent magnetization measurements revealed a paramagnetic behavior for as-prepared Co doped CeO(2), while a ferromagnetic behavior appears when the same samples are annealed under vacuum or N(2)-H(2) atmosphere. Temperature dependent magnetization measurements suggest that the observed ferromagnetism is due to the presence of metallic Co clusters with nanometric size and broad size distribution. These results are supported by electron paramagnetic resonance studies. PMID- 22513413 TI - Gamete interactions in teleost fish: the egg envelope. Basic studies and perspectives as environmental biomonitor. AB - The current knowledge about teleost fish egg envelope is summarized. The paper analyzes the organization and deposition process of the protein composition and genes involved in the synthesis of teleost fish egg envelopes and their role in gamete interaction during fertilization. Pelagic and demersal species that our research group is working with are especially considered. The vertebrate ZP family of proteins, the evolution and relationship among the different genes and their expression are taken into account. We consider fish envelope as a possible biomonitor for ecological contaminants. The biotechnological applications for aquaculture and genomic and post-genomic approaches are auspicious. PMID- 22513411 TI - Effect of sodium channel abundance on Drosophila development, reproductive capacity and aging. AB - The voltage-gated Na (+) channels (VGSC) are complex membrane proteins responsible for generation and propagation of the electrical signals through the brain, the skeletal muscle and the heart. The levels of sodium channels affect behavior and physical activity. This is illustrated by the maleless mutant allele (mle (napts)) in Drosophila, where the decreased levels of voltage-gated Na(+) channels cause temperature-sensitive paralysis. Here, we report that mle (napts) mutant flies exhibit developmental lethality, decreased fecundity and increased neurodegeneration. The negative effect of decreased levels of Na(+) channels on development and ts-paralysis was more pronounced at 18 and 29 degrees C than at 25 degrees C, suggesting particular sensitivity of the mle (napts) flies to temperatures above and below normal environmental conditions. Similarly, longevity of mle (napts) flies was unexpectedly short at 18 and 29 degrees C compared with flies heterozygous for the mle (napts) mutation. Developmental lethality and neurodegeneration of mle (napts) flies was partially rescued by increasing the dosage of para, confirming a vital role of Na(+) channels in development, longevity and neurodegeneration of flies and their adaptation to temperatures. PMID- 22513414 TI - In vitro fertilization of the rock shrimp, Rhynchocinetes typus (Decapoda, Caridea): a review. AB - This review compiles all the research done on gametes and fertilization in the rock shrimp, R. typus, and describes the sequence of events from the first gamete interaction to zygote formation and the first cleavage of the embryo, with light, fluorescence confocal and electron microscopes. Early studies showed that sperm from the vas deferens have a tack-shape with a "needle-like process" or rigid spike (RS) that extends from a semi-spherical body that contains the arms with chromatin and spines. Upon contact with seawater and by action of Na +, the arms and spines extend, producing an inverted umbrella form of the spermatozoa. The first sperm-oocyte interaction occurs between protein receptors type lectins of the sperm RS and oocyte chorion sperm ligands. These ligands contain residues of alpha-Glu, Man (alpha 1-3) Man, alpha and beta-GlcNAc and alpha-GalNA terminal residues. It was found that alpha-Man and GlcNAc residues are the ligands that are directly related to the adhesion process and further penetration of sperm. After this first interaction, the RS enters the oocyte envelope by the action of a trypsin-like enzyme, rhynchocinecine, present in the acicular process. Later, arms and spines penetrate the oocyte cytoplasm, where the chromatin of the arms begin to migrate to the central area of the sperm, condensing in a cup-shaped structure near the connecting piece, which forms the male pronucleus. PMID- 22513415 TI - Cysteine-rich secretory proteins (CRISP) and their role in mammalian fertilization. AB - Epididymal protein CRISPI is a member of the CRISP (Cysteine-RIch Secretory proteins) family and is involved in sperm-egg fusion through its interaction with complementary sites on the egg surface. Results from our laboratory have shown that this binding ability resides in a 12-amino-acid region corresponding to a highly conserved motif of the CRISP family, named Signature 2 (S2). In addition to this, our results revealed that CRISP1 could also be involved in the previous step of sperm binding to the zona pellucida, identifying a novel role for this protein in fertilization. As another approach to elucidate the participation of CRISP1 in fertilization, a mouse line containing a targeted disruption of CRISP1 was generated. Although CRISP1-deficient mice exhibited normal fertility, CRISP1 defficient sperm presented a decreased level of protein tyrosine phosphorylation during capacitation, and an impaired ability to fertilize both zona-intact and zona-free eggs in vitro, confirming the proposed roles for the protein in fertilization. Evidence obtained in our laboratory indicated that testicular CRISP2 would also be involved in sperm-egg fusion. Competition assays between CRISP1 and CRISP2, as well as the comparison of their corresponding S2 regions, suggest that both proteins bind to common complementary sites in the egg. Together, these results suggest a functional cooperation between CRISP1 and CRISP2 to ensure the success of fertilization. PMID- 22513416 TI - Acrosin release and acrosin activity during incubation in capacitating media using fresh and frozen-thawed dog sperm. AB - We evaluated the effect of time and temperature on acrosin release from the acrosomal cap and the activity of this enzyme during in vitro capacitation in fresh and frozen/thawed dog sperm. Sperm-rich fractions of six ejaculates from three dogs were processed as fresh and frozen samples. Each sperm sample was incubated in canine capacitation medium (CCM) for 0, 1, 2 and 3 h at 20 degrees C and at 37 degrees C. After incubation, the samples were assessed by the indirect immunofluorescent staining technique. The probability of having unlabeled sperm (PUS), indicating acrosin loss, was modelled by a binomial distribution using logistic regression. There was a linear relationship between PUS and time at both temperatures (p<0.001); however, a major percentage of unlabeled sperm was observed in frozen/thawed samples soon after incubation, indicating that the release of acrosin was affected by capacitation time, mainly in frozen samples. Temperature influenced acrosin release only in cryopreserved sperm (p<0.05). Acrosin activity was measured by digestion halos on slides coated with gelatin substrate film during each time period; a significant increase in the number of large halos was observed in fresh samples throughout the experiment, whereas frozen/thawed sperm showed a decreased rate of halo diameters during culture. Thus, there appears to differences between fresh and frozen dog sperm in terms of acrosin release and the level of acrosin activity in the course of in vitro capacitation. PMID- 22513417 TI - Protease activity involvement in the passage of mammalian sperm through the zona pellucida. AB - The interaction between acrosome-reacted sperm and zona pellucida proteins is not yet fully understood. Serine protease acrosin and its zymogen proacrosin have been proposed to fulfill this function due to their capacity to bind zona pellucida glycoproteins. However, the molecular mechanism underlying this interaction has been merely speculative. Here we show that fucoidan (a sulfated polysaccharide) and solubilized zona pellucida glycoproteins, but not soybean trypsin inhibitor, are able to detach bound spermatozoa, which suggests that live sperm binds to the zona pellucida in a non-enzymatical way. Interestingly, mild proteolytic digestion with acrosin or trypsin does not modify the structure of the zona pellucida, but rather results in fewer spermatozoa binding to the zona. These results agree with a model where the active site of acrosin digests the zona pellucida and binds through the polysulfate-binding domain through a three dimensional zona structure rather than a single ligand. PMID- 22513418 TI - Modulation of spermatozoon acrosome reaction. AB - Spermatozoon acrosome reaction is an exocytotic event of the utmost importance for the development of mammalian fertilisation. Current evidence shows that the triggering of the acrosome reaction (AR) could be regulated by the action of diverse compounds, namely, metabolites, neurotransmitters and hormones. The aim of the present review is to describe the modulating effects of several compounds that have been classified as inductors or inhibitors of acrosome reaction. Among AR inductors, it is necessary to mention progesterone, angiotensin II, atrial natriuretic peptide, cathecolamines, insulin, leptin, relaxin and other hormones. Regarding the inhibitors, oestradiol and epidermal growth factor are among the substances that retard AR. It is worth mentioning that gamma-aminobutyric acid, a neurotransmitter known to be an inhibitor in the central nervous system, has been shown to induce AR. The multiple hormones located in the fluids of the female reproductive tract are also likely to act as subtle regulators of AR, constituting a fundamental aspect for the development of successful fertilisation. Finally, it is necessary to emphasise that the study of regulation exerted by hormones and other compounds on AR is essential for further understanding of mammalian reproductive biology, especially spermatozoon physiology. PMID- 22513419 TI - Effects of hypoxia on epididymal sperm parameters and protective role of ibuprofen and melatonin. AB - Hypobaric hypoxia is of interest due to an increase of human populations working at high altitude. Testicular damage is related to the physiological response (neoangiogenesis) to increased intrascrotal blood flow as temperature rises. Hypoxia is a stress factor with overproduction of reactive oxygen species (ROS). The effect of hypoxia in mice reproductive parameters is analyzed. Animals were exposed to simulated hypoxia of 4,200 meters above sea level (m.a.s.l.) in a chamber for 33.2 days, both to continuous (HH) or intermittent hypoxia (HI) with an intermittency period of 4 days hypoxia /4 days normoxia (500 m.a.s.l.). The anti-inflammatory drug Ibuprofen was administered to a group of mice to control vasodilation and increased blood flow. Melatonin was administered to another group of mice as a potent ROS scavenger. Animals in both HH and HI exposure were compared to normoxic non-treated controls. There was a hematological response in hypoxia, with an increase in hematocrit and reticulocytosis. There was also increased teratozoospermia. This damage was more pronounced in HH than HI, suggesting that alternating normoxic periods permits compensation for the effects of hypoxia. In both hypoxia systems, the level of lipoperoxidation and the instability of DNA increased. In HH, there was a reduction of teratozoospermia in melatonin-treated mice. Ibuprofen presented a protective effect on the same parameters as melatonin with both HI and HH. The quality of sperm DNA, fragmentation, unpacking and DNA stability diminished. In conclusion, reproductive damage elicited by HH or HI was partially ameliorated by simultaneous treatment with antiflogistic and/or antioxidant agents. PMID- 22513420 TI - Vitamin C and oxidative stress in the seminiferous epithelium. AB - In this article, we focus on the fundamental role of vitamin C transporters for the normal delivery of vitamin C to germ cells in the adluminal compartment of seminiferous tubules. We argue that the redox status within spermatozoa or in semen is partly responsible for the etiology of infertility. In this context, antioxidant defence plays a critical role in male fertility. Vitamin C, a micronutrient required for a wide variety of metabolic functions, has long been associated with male reproduction. Two systems for vitamin C transport have been described in mammals. Facilitative hexose transporters (GLUTs), with 14 known isoforms to date, GLUT1-GLUT14, transport the oxidized form of vitamin C (dehydroascorbic acid) into the cells. Sodium ascorbic acid co-transporters (SVCTs), SVCT1 and SVCT2 transport the reduced form of vitamin C (ascorbic acid). Sertoli cells control germ cell proliferation and differentiation through cell cell communication and form the blood-testis barrier. Because the blood-testis barrier limits direct access of molecules from the plasma into the adluminal compartment of the seminiferous tubule, one important question is the method by which germ cells obtain vitamin C. Some interesting results have thrown light on this matter. Expression of SVCT2 and some isoforms of GLUT transporters in the testis have previously been described. Our group has demonstrated that Sertoli cells express functionally active vitamin C transporters. Kinetic characteristics were described for both transport systems (SVCT and GLUT systems). Sertoli cells are able to transport both forms of vitamin C. These findings are extremely relevant, because Sertoli cells may control the amount of vitamin C in the adluminal compartment, as well as regulating the availability of this metabolite throughout spermatogenesis. PMID- 22513421 TI - Propylthiouracil-induced hypothyroidism delays apoptosis during the first wave of spermatogenesis. AB - Mammalian germ cell apoptosis plays a key role in controlling the correct number of germ cells supported by Sertoli cells during the first wave of spermatogenesis in mammalian puberty. However, little is known about hormonal factors that could influence the rate of germ cell apoptosis during puberty or adulthood. In this work we evaluate germ cell apoptosis under hypothyroidism induced by goitrogen propylthiouracil (PTU) during the first wave of spermatogenesis. Neonatally administered PTU promoted a delay in the differentiation of Sertoli cells as evaluated by the expression of clusterin using immunohistochemistry and RT-PCR. Clusterin had different expression levels in control and PTU-treated animals, but under both conditions the highest levels were found in 35-day-old rats. In addition, clusterin displayed a cytoplasmic localization in control testes, but appeared located in the nucleus in PTU-treated animals. The wave of apoptosis (determined by caspase activity and quantification of apoptotic cells) characteristic of the first round of spermatogenesis was delayed by at least 10 days in these animals. The expression levels of proapoptotic genes like BAX or BAD were different between control and PTU-treated rats; although in both groups the highest level was found at the same age (days). Thus our results indicate that the characteristic pubertal apoptotic wave during rat spermatogenesis is delayed in neonatal hypothyroid rats. PMID- 22513422 TI - The effect of cigarette smoke on fertilization and pre-implantation development: assessment using animal models, clinical data, and stem cells. AB - Numerous studies have repeatedly shown that women who smoke experience problems establishing and maintaining pregnancies, and recent work has further demonstrated that the in utero effects of smoke may not be manifested until months or even years after birth. The purpose of this review is to examine the recent literature dealing with the effects of cigarette smoke on the earliest stages of human prenatal development. Studies in this area have included the use of animal models, patients undergoing in vitro fertilization, and embryonic stem cell models. Events leading to fertilization, such as cumulus expansion, hyperactivation of sperm motility, and oocyte pick-up by the oviduct are all impaired by smoke exposure in animal models. Steps crucial to fertilization such as the acrosome reaction and sperm binding to the zona pellucida are likewise inhibited by cigarette smoke. Preimplantation embryos and stem cells that model embryos show a number of adverse responses to smoke exposure, including poor adhesion to extracellular matrices, diminished survival and proliferation, and increased apoptosis. The current literature demonstrates that the earliest stages of prenatal development are sensitive to smoke exposure and indicates that pregnant women should be advised not to smoke during this time. PMID- 22513423 TI - Extended culture up to the blastocyst stage: a strategy to avoid multiple pregnancies in assisted reproductive technologies. AB - The aim of this study was to review the experience and outcomes of assisted reproduction cycles with embryos grown up to day 5 of development, comparing different parameters according to the ages of the patients. We retrospectively studied 1,874 assisted reproduction cycles where embryo culture was extended up to the fifth or sixth day of development. All IVF and ICSI cycles were included, comparing, according to patient age, the following rates: blastocyst formation, pregnancy, implantation and abortion. As control, we analyzed cycles with donated oocytes from young donors (OD). The number of embryos reaching the blastocyst stage is similar in all groups of patients. Only the OD group was different in terms of blastocyst formation, pregnancy and implantation rates. Patients over 39 years of age had an abortion rate of 59.1 %, which is significantly higher than the other groups. Extended embryo culture up to the blastocyst stage can be implemented in programs of assisted reproduction in order to increase the pregnancy rate. The potential of blastocyst implantation is high, allowing us to transfer fewer embryos and reduce the probability of multiple pregnancies. PMID- 22513424 TI - The beginning of life of a new human being from the scientific biological perspective and its bioethical implications. AB - The issue of when the human life begins is a very important subject since it has a significant impact on the decisions that we have to take in relation to human beings in development, particularly human embryos. In this article we discuss some of the more relevant biological evidence supporting the fact that beginning human life begins unquestionably at fertilization and the bioethical consequences. PMID- 22513425 TI - Electronic coupling for charge transfer in donor-bridge-acceptor systems. Performance of the two-state FCD model. AB - Electronic coupling is a key parameter that determines the rate of electron transfer reactions and electrical conductivity of molecular wires. To examine the performance of a two-state approach based on the orthogonal transformation of adiabatic states to diabatic states, we compare the effective donor-acceptor coupling V(DA) computed with three different approaches in model donor-bridge acceptor (D-B-A) systems. It is found that V(DA) derived with the two-state method accounts properly for both the direct and superexchange interactions. The approach becomes, however, less accurate with the increasing energy difference of the donor and acceptor states. We suggest a simple diagnostic to identify the situation when the estimated coupling might be inaccurate and consider how to improve the performance of the two-state scheme in such a case. PMID- 22513426 TI - Laparoscopy...for all? PMID- 22513427 TI - Laparoscopic colectomy for the treatment of cancer has been widely adopted in the United States. AB - BACKGROUND: Fewer than 10% of patients with colon cancer in the United States are reportedly treated with a laparoscopic colectomy despite the benefits it has over the open approach. This estimate, however, may be artificially low because of inaccurate case identification. OBJECTIVE: The aim of this study was to estimate the proportion of colon resections performed laparoscopically for the treatment of colon cancer and to identify factors associated with its use. DESIGN: This study is a retrospective review of the 2008 to 2009 Nationwide Inpatient Sample. SETTINGS, PATIENTS, INTERVENTIONS: Adult patients with a diagnosis of colon cancer who underwent an elective colectomy were included. MAIN OUTCOME MEASURES: The overall proportion of colon resections performed laparoscopically was calculated. Multivariable regression modeling was used to identify patient and hospital characteristics associated with undergoing a laparoscopic procedure. RESULTS: During the study period, 9075 (weighted = 45,549) patients were identified with 50% treated via the laparoscopic approach. Patients were more likely to undergo a laparoscopic procedure if their median annual income was $63,000+ based on home zip code (adjusted relative risk = 1.08 (1.02-1.16)) and less likely if they were 70+ years of age (adjusted relative risk = 0.93 (0.87 1.00)), female (adjusted relative risk = 0.96 (0.92-0.99)), and had Medicaid (adjusted relative risk =0.84 (0.73-0.97)), or 3+ chronic conditions (adjusted relative risk = 0.84 (0.79-0.89)). Treatment at teaching hospitals (adjusted relative risk =1.10 (1.00-1.20)) and high-volume centers (adjusted relative risk =1.41 (1.22-1.63)) was associated with undergoing a laparoscopic colectomy, whereas treatment at rural hospitals was associated with less frequent use of laparoscopic colectomy (adjusted relative risk = 0.76 (0.64-0.90)). LIMITATIONS: This study is subject to the limitations of using administrative data. CONCLUSIONS: There has been widespread adoption of the laparoscopic approach to colon resection for cancer in the United States. Disparities in access remain, with application of this technique favoring patients with a higher socioeconomic status and those able to be treated at higher-volume, academic, and nonrural centers. PMID- 22513429 TI - High tie versus low tie vascular ligation of the inferior mesenteric artery in colorectal cancer surgery: impact on the gain in colon length and implications on the feasibility of anastomoses. AB - BACKGROUND: There is no demonstrated benefit of high-tie versus low-tie vascular transections in colorectal cancer surgery. OBJECTIVE: The aim of this study was to compare the effects of high-tie and low-tie vascular transections on colonic length after oncological sigmoidectomy, the theoretical feasibility of colorectal anastomosis at the sacral promontory, and straight or J-pouch coloanal anastomosis after rectal cancer surgery with total mesorectal excision. DESIGN: This study is an anatomical study on surgical techniques. SETTINGS: This study was conducted in a surgical anatomy research unit. PATIENTS: Thirty fresh nonembalmed cadavers were randomly assigned to high-tie and low-tie groups (n = 15). INTERVENTIONS: Oncological sigmoidectomy followed by total mesorectal excision was performed. MAIN OUTCOME MEASURES: The distances from the proximal colon limb to the lower edge of the pubis symphysis were recorded after each step of vascular division. RESULTS: The successive mean gains in length in high-tie vs low-tie vascular transections were 2.9+/-1.2 cm vs 3.1 +/- 1.8 cm (p = 0.83) after inferior mesenteric artery division, 8.1 +/- 3.1 cm vs 2.5 +/- 1.2 cm (p = 0.0016) after inferior mesenteric vein division at the lower part of the pancreas, 8.1 +/- 3.8 cm vs 3.3 +/- 1.7 cm (p = 0.0016) after sigmoidectomy. The mean cumulative gain in length was significantly higher in high-tie vs low-tie vascular transections (19.1 +/- 3.8 vs 8.8 +/- 2.9 cm, p = 0.00089). After secondary left colic artery division, the gain in length was similar to that of the high-tie group (17 +/- 3.1 vs 19.1 +/- 3.8 cm) (p = 0.089). Colorectal anastomosis at the promontory and straight and J-pouch coloanal anastomosis feasibility rates were 100% in the high-tie group, 87%, 53%, and 33% in the low tie group, but 100%, 100%, and 87% after secondary left colic artery division. LIMITATIONS: This anatomical study, based on cadavers rather than live patients, does not evaluate colon limb vascularization. CONCLUSIONS: The gain in colonic length is 10 cm greater for high-tie vascular transections. With low-tie vascular transections, high inferior mesenteric vein division produced a small additional gain in length, and secondary left colic artery division produced the same length gain as high-tie vascular transections. PMID- 22513428 TI - Population-based evaluation of adenosquamous carcinoma of the colon and rectum. AB - BACKGROUND: Information about adenosquamous carcinoma of the colon and rectum is scarce because of its extremely low incidence. OBJECTIVE: The aim of this study was to examine the prognostic significance of a histological diagnosis of adenosquamous carcinoma in comparison with adenocarcinoma of the colon and rectum. DESIGN: This study was retrospective in design. SETTING: California Cancer Registry data from 1994 through 2004 with follow-up through 2008 were analyzed. PATIENTS: Patients were included whose cancer of the colon and rectum, excluding the anus with a tumor histology of adenocarcinoma and adenosquamous carcinoma, was surgically treated. MAIN OUTCOME MEASURES: The primary outcomes measured were histology-specific survival analyses (with the use of the Kaplan Meier method), and overall and colorectal-specific mortality (with the use of multivariable Cox proportional hazards regression analyses). RESULTS: A total of 111,263 adenocarcinoma and adenosquamous carcinoma of colon and rectal cancer cases were identified (adenocarcinoma, 99.91%; adenosquamous carcinoma, 0.09%). There was no significant difference in sex, age, race, and socioeconomic status between the 2 groups. The most common location of adenocarcinoma and adenosquamous carcinoma was the right and transverse colon. The adenosquamous carcinoma group was significantly associated with a higher rate of metastasis at the time of operation (adenosquamous carcinoma, 36.56% vs adenocarcinoma, 13.92%) and with poorly differentiated tumor grade (adenosquamous carcinoma, 65.96% vs adenocarcinoma, 19.74%) in comparison with the adenocarcinoma group. The median overall survival time was significantly greater in the adenocarcinoma group (82.4 months) in comparison with the adenosquamous carcinoma group (35.3 months). With the use of multivariable hazard regression analyses, adenosquamous carcinoma histology was independently associated with increased overall mortality (hazard ratio, 1.67) and colorectal-specific mortality (hazard ratio, 1.69) in comparison with adenocarcinoma. CONCLUSIONS: This is one of the largest studies of adenosquamous carcinoma of the colon and rectum to date. This uncommon colorectal cancer subtype was associated with higher overall and colorectal-specific mortality in comparison with adenocarcinoma. Among colorectal cancer cases, adenosquamous carcinoma histology should be considered a poor prognostic feature. PMID- 22513430 TI - The incidence and risk factors of metachronous colorectal cancer: an indication for follow-up. AB - BACKGROUND: Patients with colorectal cancer are at risk for developing metachronous colorectal cancer. The purpose of posttreatment surveillance is to detect and remove premalignant lesions to prevent metachronous colorectal cancer. OBJECTIVE: The aim of this study was to investigate the incidence of and predictive factors for metachronous colorectal cancer in patients with newly diagnosed colorectal cancer. DESIGN AND PATIENTS: The data on all patients with newly diagnosed colorectal cancer between 1995 and 2006 were obtained from the Rotterdam Cancer Registry in The Netherlands and studied for metachronous colorectal cancer. MAIN OUTCOME MEASURES: The annual incidence rate and the standardized incidence ratios were calculated. RESULTS: In total, colorectal cancer was diagnosed in 10,283 patients; there were 39,974 person-years of follow up. The mean annual incidence rate of metachronous colorectal cancer was 314/100,000 person-years at risk during 10 years of follow-up, corresponding with a mean annual incidence of 0.3% and a cumulative incidence of 1.1% at 3 years, 2.0% at 6 years, and 3.1% at 10 years. The incidence of metachronous colorectal cancer after resection of a first colorectal cancer is significantly higher than the incidence of colorectal cancer in an age- and sex-matched general population (standardized incidence ratio 1.3, 95% CI 1.1-1.5). This difference is especially seen during the first 3 years after first colorectal cancer diagnosis (standardized incidence ratio 1.4, 95% CI 1.1-1.8). The presence of synchronous colorectal cancer was the only significant risk factor for developing metachronous colorectal cancer (relative risk 13.9, 95% CI 4.7-41.0). CONCLUSIONS: Despite the availability of colonoscopy, metachronous colorectal cancer is still seen during follow-up in patients with colorectal cancer; the highest risk is during the first 3 years after initial diagnosis. For this reason, a follow-up colonoscopy is useful at a short-term interval after colorectal cancer diagnosis. The presence of synchronous colorectal cancer at the time of first colorectal cancer diagnosis is the only predictive risk factor for developing metachronous colorectal cancer. Tailored surveillance programs may be considered in patients with a diagnosis of synchronous tumors. PMID- 22513432 TI - The management of anastomotic pouch sinus after IPAA. AB - BACKGROUND: Anastomotic sinus is a relatively uncommon complication after an IPAA. Disease course is poorly defined, and management can be challenging. OBJECTIVE: The purpose of this study was to evaluate the frequency, management, and outcome of anastomotic pouch sinus. DESIGN: This research is a retrospective cohort study from a prospectively collected database. SETTING: The investigation took place in a high-volume specialized colorectal surgery department. PATIENTS: Patients with an anastomotic sinus after pouch surgery from 1997 to 2009 were included. MAIN OUTCOMES MEASURES: The primary outcomes measured were sinus healing and pouch failure. RESULTS: Of 2286 patients who underwent an IPAA, 45 (2.0%) patients were identified with an anastomotic pouch sinus. There were 32 (71%) males, and the mean age was 40 (+/-13) years. The pouch sinus was initially managed by observation in 23 (51%) patients, drainage of the sinus in 9 (20%) patients, unroofing of the sinus tract in 8 (18%) patients, sinus closure in 3 (7%) patients, and a diverting ileostomy in 2 (4%) patients. In 28 patients (62%), subsequent treatment was necessary. Sinus healing was achieved in 27 (60%) patients, whereas 15 (33%) eventually developed pouch failure. Of the treatment modalities applied, a strategy with observation as initial treatment was the most successful with a healing rate of 65%. The healing rate was significantly lower in symptomatic patients in comparison with asymptomatic patients (30% vs 84%, p = 0.001). Pouch failure was also higher (45% vs 24%, p = 0.14). No other factors associated with healing rate or pouch failure were identified. LIMITATIONS: This study was limited by its nonrandomized retrospective design. CONCLUSION: Anastomotic pouch sinuses after pouch surgery are associated with a high rate of pouch failure. Symptomatic presentation is a significant predictor for low healing rates and is associated with a high risk of pouch failure. Observation and watchful monitoring is the initial treatment of choice when permitted by the patient's condition. PMID- 22513431 TI - Genetic variation in the transforming growth factor-beta-signaling pathway, lifestyle factors, and risk of colon or rectal cancer. AB - BACKGROUND: The transforming growth factor-beta-signaling pathway has been identified as being involved in colorectal cancer. OBJECTIVE: The aim of this study was to determine how diet and lifestyle factors in combination with genetic variation in the transforming growth factor-beta-signaling pathway alters colorectal cancer risk. DESIGN: We used data from 2 population-based case-control studies. PATIENTS: Participants included patients with colon cancer (n = 1574) and controls (n = 1970) and patients with rectal cancer ( n = 791) and controls (n = 999). MAIN OUTCOME MEASURES: The primary outcomes measured were newly diagnosed cases of colon or rectal cancer. RESULTS: Colon and rectal cancer risk increased with the number of at-risk genotypes within the transforming growth factor-beta-signaling pathway (OR 3.68, 95% CI 2.74,4.94 for colon cancer; OR 3.89, 95% CI 2.66,5.69 for rectal cancer). A high at-risk lifestyle score also resulted in significant increased risk with number of at-risk lifestyle factors (OR 2.99, 95% CI 2.32,3.85 for colon cancer; OR 3.37, 95% CI 2.24,5.07 for rectal cancer). The combination of high-risk genotype and high-risk lifestyle results in the greatest increase in risk (OR 7.89, 95% CI 4.45,13.96 for colon cancer; OR 8.75, 95% CI 3.66,20.89 for rectal cancer). LIMITATIONS: The study results need validation in other large studies of colon and rectal cancer. CONCLUSIONS: In summary, our data suggest that there is increased colon and rectal cancer risk with increasing number of at-risk genotypes and at-risk lifestyle factors. Although the integrity of the pathway can be diminished by a number of high-risk genotypes, this risk can be offset, in part, by maintaining a healthy lifestyle. PMID- 22513433 TI - Increased crypt apoptosis is a feature of autoimmune-associated chronic antibiotic refractory pouchitis. AB - BACKGROUND: Restorative proctocolectomy with IPAA is the surgical treatment of choice in patients with ulcerative colitis who require colectomy. Pouchitis is the most common long-term complication in patients with IPAA. While immune mediated disorders frequently coexist with IBD, they appear to be associated with an increased risk for chronic antibiotic-refractory pouchitis. OBJECTIVE: This study aimed to evaluate histologic features of autoimmune-associated chronic antibiotic-refractory pouchitis in comparison with controls and to assess their possible diagnostic utility. DESIGN: Clinical definition for autoimmune associated chronic pouchitis included 1) chronic antibiotic-refractory pouchitis with response only to corticosteroids, immunomodulators, or biologics; 2) positive serum autoantibodies, including antinuclear antibody, rheumatoid factor, and antimicrosomal antibody; and 3) concurrent immune-mediated disorders. Various histologic features of pouch biopsy specimens were evaluated. SETTING: The investigation was conducted at a tertiary referral center. PATIENTS: From our Pouchitis Registry, all eligible patients with autoimmune-associated pouchitis (n = 17) were included. The control groups included 16 patients with nonautoimmune associated chronic antibiotic-refractory pouchitis, 39 with antibiotic-responsive pouchitis, and 19 patients with normal pouches. Various histologic features of pouch biopsy specimens were evaluated. RESULTS: In comparison with the control groups, the autoimmune-associated pouchitis group showed a significant increase in deep crypt apoptosis (p < 0.001). It also showed more pyloric gland metaplasia in comparison with antibiotic-responsive pouchitis and normal pouches. With the use of apoptosis score which we developed as a diagnostic marker for autoimmune associated chronic antibiotic-refractory pouchitis, we constructed a receiver operating curve and obtained an area-under-curve value of 0.89 (95% CI: 0.79, 0.99). CONCLUSION: Increased deep crypt apoptosis is a distinctive histologic feature of autoimmune-associated chronic antibiotic-refractory pouchitis, and this feature may aid in the diagnosis and differential diagnosis in pouchitis. PMID- 22513434 TI - Influence of risk factors on the safety of ileocolic anastomosis in Crohn's disease surgery. AB - BACKGROUND: Ileocecal resection is the most commonly performed operation in patients with Crohn's disease. Anastomotic-associated complications, with their associated morbidity, are the most feared risks of surgery. OBJECTIVE: This study aimed to assess the influence of a variety of putative risk factors in a homogenous group of patients undergoing first or subsequent surgery for Crohn's disease to quantify the cumulative risk for anastomotic-associated complications. DESIGN AND PATIENTS: All patients undergoing ileocecal or ileocolic resections for Crohn's disease from 2000 to 2010 were studied with the use of a prospective database. Demographics, operative details, possible risk factors, and anastomotic associated complications were recorded. Patients having strictureplasties, multiple resections, or subtotal colonic resections were excluded from analysis. Statistical analysis was by univariate analysis (Mann-Whitney U test) and binary logistic regression. OUTCOMES: An anastomotic-associated complication was defined as a proven anastomotic leak, postoperative fistulation, or intra-abdominal abscess formation. RESULTS: Two hundred seven patients (109 female) with a median age of 35 years (range, 13-75 years) were identified. One hundred seventy-three underwent primary anastomosis, 94 as an emergency procedure. Fifty-three had laparoscopic (5 converted) procedures. Nineteen of 173 anastomotic complication events (11%) were recorded. Steroid usage (OR 2.67, 95% CI 1.0-7.2) and the presence of preoperative abscess formation (OR 3.4, 95% CI 1.2-9.8) were identified as independent predictors of anastomotic-associated complications. In the absence of both steroids and intra-abdominal abscess, the risk of anastomotic complications was 6%, which increased to 14% if either risk factor was present. When both risk factors were present, complication rates reached 40%. CONCLUSION: Steroid usage and preoperative abscess were associated with higher rates of anastomotic complications following ileocolic resection for Cohn's disease. When both risk factors are present, it is best to avoid primary anastomosis. PMID- 22513435 TI - Does preoperative immunosuppression influence unplanned hospital readmission after surgery in patients with Crohn's disease? AB - BACKGROUND: Steroids, immunomodulators, and biologics, often in combination with one another, are frequently used in the treatment of Crohn's disease. Retrospective studies have yielded conflicting results regarding the influence of preoperative immunosuppressive therapy on postoperative complications after surgery in Crohn's disease. Unplanned hospital readmission is considered to be an index of quality surgical care. OBJECTIVE: The aim of this study was to examine the association, if any, between the number of preoperative immunosuppressive therapies and unplanned hospital readmission after surgery in patients with Crohn's disease. DESIGN: Consecutive patients with Crohn's disease requiring abdominal surgery were identified from a prospectively maintained database. Preoperative immunosuppressive therapy within 3 months before surgery was categorized into 3 classes: steroids, immunomodulators, and biologics. MAIN OUTCOME MEASURES: Unplanned readmission occurring within 30 days of hospital discharge was assessed. Trend analysis was performed with the use of the Cochrane Armitage test. RESULTS: The study group included 338 patients. Preoperative medical therapy included steroids (n = 199; 59%), immunomodulators (n = 162; 48%), and biologics (n = 59; 18%). Sixty-three patients (19%) were not treated with any immunosuppressive medications preoperatively, whereas 148 patients (44%), 108 patients (32%), and 19 patients (6%) were treated with 1, 2, or 3 classes of immunosuppressive medications. Twenty-eight patients (8.3%) had an unplanned readmission. The incidence of unplanned readmission was similar among patients treated with steroids (11%), immunomodulators (9%), and biologics (12%). The incidence of unplanned readmission was 3%, 7%, 11%, and 16% in patients treated with 0, 1, 2, or 3 preoperative medication classes (trend analysis p = 0.02). No significant differences were observed between patient groups treated with 0, 1, 2, or 3 preoperative immunosuppressive therapies with respect to patient, disease, or surgical factors. CONCLUSIONS: Unplanned hospital readmission occurs frequently (8.3%) after surgery for Crohn's disease. Combination immunosuppressive therapy before surgery in patients with Crohn's disease appears to be associated with an increased incidence of postoperative unplanned hospital readmission. PMID- 22513436 TI - Risk factors for anastomotic leakage after colectomy. AB - BACKGROUND: Anastomotic leakage is a morbid and potentially fatal complication of colorectal surgery. Determination of pre- and intraoperative risk factors may identify patients requiring increased postoperative surveillance for this major complication. OBJECTIVE: The purpose of this study was to identify risk factors associated with anastomotic leakage after colectomy with primary intra-abdominal anastomosis. DESIGN: The prospective, statewide multicenter Michigan Surgical Quality Collaborative database was analyzed. SETTING: This study was performed at academic and community medical centers in the state of Michigan. PATIENTS: Included were all cases of open and laparoscopic colectomy with primary intra abdominal anastomosis from 2007 through 2010. MAIN OUTCOME MEASURES: Univariate analysis followed by a multivariate logistic regression model was used to determine the influence of patient factors and operative events with respect to the incidence of postoperative anastomotic leakage. RESULTS: Inclusion criteria were met by 4340 cases. Anastomotic leakage occurred in 85 (3.2%) of the 2626 (60.5%) open colectomies, and in 51 (3.0%) of the 1714 (39.5%) laparoscopic procedures, which was not significantly different (p = 0.63). Significant risk factors associated with anastomotic leakage based on the multivariate logistic regression model were fecal contamination with OR 2.51, 95% CI, 1.16 to 5.45, p = 0.02; and intraoperative blood loss of more than 100 mL and 300 mL, with OR 1.62, 95% CI, 1.10 to 2.40, p = 0.02; and OR 2.22, 95% CI, 1.32 to 3.76, p = 0.003. LIMITATIONS: The Michigan Surgical Quality Collaborative colectomy project excluded high-risk rectal resections and low pelvic anastomoses. Information about operative technique and intraoperative events is limited, and anastomotic leakage was determined through chart review. CONCLUSION: Fecal contamination and increased blood loss during colectomy should raise suspicion for potential postoperative anastomotic leakage. PMID- 22513437 TI - A diagnostic accuracy meta-analysis of endoanal ultrasound and MRI for perianal fistula assessment. AB - BACKGROUND: Imaging modalities such as endoanal ultrasound or MRI can be useful preoperative adjuncts before the appropriate surgical intervention for perianal fistulas. OBJECTIVES: We present a systematic review of published literature comparing endoanal ultrasound with MRI for the assessment of idiopathic and Crohn's perianal fistulas. DESIGN: A meta-analysis was performed to obtain pooled values for specificity and sensitivity. SETTINGS: Electronic databases were searched from January 1970 to October 2010 for published studies. PATIENTS AND INTERVENTIONS: Four studies were used in our analysis. There were 241 fistulas in the ultrasound group and 240 in the magnetic resonance group. RESULTS: The combined sensitivity and specificity of magnetic resonance for fistula detection were 0.87 (95% CI: 0.63-0.96) and 0.69 (95% CI: 0.51-0.82). There was a high degree of heterogeneity between studies reporting on MRI sensitivity (df = 3, I = 93%). This compares to a sensitivity and specificity for endoanal ultrasound of 0.87 (95% CI: 0.70-0.95) and 0.43 (95% CI: 0.21-0.69). There was a high degree of heterogeneity between studies reporting on endoanal ultrasound sensitivity (df = 3, I = 92%). CONCLUSIONS: From the available literature, the summarized performance characteristics for MRI and endoanal ultrasound demonstrate comparable sensitivities at detecting perianal fistulas, although the specificity for MRI was higher than that for endoanal ultrasound. Both specificity values are considered to be diagnostically poor, however. The high degree of data heterogeneity and the shortage of applicable studies precludes any firm conclusions being made for clinical practice. Future trials with improved study design (including prospective data collection and consideration of verification bias) may help to further clarify the role of MRI in the assessment and treatment response monitoring of perianal fistulas (particularly in patients with Crohn's disease). PMID- 22513438 TI - Economic cost of fecal incontinence. AB - BACKGROUND: Despite its prevalence and deleterious impact on patients and families, fecal incontinence remains an understudied condition. Few data are available on its economic burden in the United States. OBJECTIVE: The aim of this study was to quantify per patient annual economic costs associated with fecal incontinence. DESIGN: A mail survey of patients with fecal incontinence was conducted in 2010 to collect information on their sociodemographic characteristics, fecal incontinence symptoms, and utilization of medical and nonmedical resources for fecal incontinence. The analysis was conducted from a societal perspective and included both direct and indirect (ie, productivity loss) costs. Unit costs were determined based on standard Medicare reimbursement rates, national average wholesale prices of medications, and estimates from other relevant sources. All cost estimates were reported in 2010 US dollars. SETTINGS: This study was conducted at a single tertiary care institution. PATIENTS: The analysis included 332 adult patients who had fecal incontinence for more than a year with at least monthly leakage of solid, liquid, or mucous stool. MAIN OUTCOME MEASURES: The primary outcome measured was the per patient annual economic costs associated with fecal incontinence. RESULTS: The average annual total cost for fecal incontinence was $4110 per person (median = $1594; interquartile range, $517-$5164). Of these costs, direct medical and nonmedical costs averaged $2353 (median, $1176; interquartile range, $294-$2438) and $209 (median, $75; interquartile range, $17-$262), whereas the indirect cost associated with productivity loss averaged $1549 per patient annually (median, $0; interquartile range, $0-$813). Multivariate regression analyses suggested that greater fecal incontinence symptom severity was significantly associated with higher annual direct costs. LIMITATIONS: This study was based on patient self-reported data, and the sample was derived from a single institution. CONCLUSIONS: Fecal incontinence is associated with substantial economic cost, calling for more attention to the prevention and effective management of this condition. PMID- 22513439 TI - Bowel habits and fecal incontinence in patients with obesity undergoing evaluation for weight loss: the importance of stool consistency. AB - BACKGROUND: Fecal incontinence is highly prevalent in the general population and especially in risk groups. Obesity is also common and is associated with comorbidities that impair general health and interfere with daily activities. Identifying mutable factors for fecal incontinence, such as stool consistency, is of paramount importance to improve quality of life. OBJECTIVE: The aim of this study was to estimate the prevalence of fecal incontinence in patients with obesity undergoing evaluation for weight loss, its relationship with bowel habits, and its impact on quality of life. DESIGN: This investigation is a cross sectional observational study. SETTINGS: This study was conducted in patients with obesity who were undergoing evaluation for weight loss. MAIN OUTCOME MEASURES: Fecal incontinence was defined as loss of flatus or liquid/solid stool occurring at least monthly. Data on comorbidities, BMI, quality of life, bowel habits including stool consistency measured with the Bristol Stool Form Scale, and symptoms of fecal incontinence were collected. RESULTS: Fifty-two patients were included, with a mean BMI of 39.6 kg/m2. Symptoms of fecal incontinence were found in 17 patients (32.7%): flatus in 9 of 17 (52.9%), liquid stool in 6 of 17 (35.2%), and solid stool in 2 of 17 (11.7%). No differences were found between patients with and without fecal incontinence in age, sex, comorbidities, or BMI. Health-related quality of life was lower in patients with fecal incontinence than in those without, but this difference was not significant, with the exception of the dimensions of role-physical (p = 0.03) and social functioning (p = 0.04). Patients with incontinence reported significantly higher percentages of altered bowel habits with nonformed stools (p = 0.004). LIMITATIONS: The cross-sectional design hampered identification of the time at which the impact of obesity occurred. CONCLUSIONS: Fecal incontinence is common in patients with obesity. Stool consistency was significantly different in these patients. This study supports the possibility of improving incontinence during weight loss by modifying stool consistency. PMID- 22513440 TI - Radiofrequency treatment for fecal incontinence: is it effective long-term? AB - OBJECTIVE: The aim of this study was to evaluate the short- and long-term outcome of the radiofrequency treatment for moderate to severe fecal incontinence. DESIGN: This study is a retrospective review of a single-institution experience. PATIENTS: Patients who underwent the radiofrequency procedure were included. MAIN OUTCOME MEASURES: The primary outcomes measured were the complication rate, short and long-term response, and the rate of subsequent intervention for incontinence. RESULTS: Twenty-seven patients underwent 31 radiofrequency procedures (81% women; mean age, 64 years). Median length of symptoms was 3 years. Biofeedback had failed for 52% of patients, and 23% of patients had previous surgical intervention. Thirty-eight percent of patients had a sphincter defect. Minor complications were observed in 19% of the patients. A treatment response was noted in 78% of the patients (mean Cleveland Clinic Florida Fecal Incontinence Score: 16 (baseline) and 10.9 (3 months postoperatively)). However, a sustained long-term response without any additional intervention was noted in 22% of the patients, and 52% of the patients underwent or are awaiting additional intervention for persistent or recurrent incontinence (mean follow-up, 40 months). LIMITATION: This study is limited by its retrospective nature and the limited number of subjects. CONCLUSIONS: The radiofrequency procedure was safe, but a long-term benefit was noted in a minority of patients with moderate to severe fecal incontinence. Additional interventions were required in more than half of the patients. Larger studies are needed to determine the impact of various patient-related factors on the outcome of the radiofrequency treatment to identify the ideal patient for this therapy. PMID- 22513441 TI - A meta-analysis of the effectiveness of the opioid receptor antagonist alvimopan in reducing hospital length of stay and time to GI recovery in patients enrolled in a standardized accelerated recovery program after abdominal surgery. AB - BACKGROUND: Despite accelerated recovery programs and the widespread uptake of laparoscopic surgery, postoperative ileus remains a significant factor affecting length of stay after abdominal surgery. Alvimopan, an opioid-receptor antagonist, may reduce the incidence of postoperative ileus and expedite hospital discharge. OBJECTIVE: The aim of this study was to perform a meta-analysis to determine the role of alvimopan in accelerating GI recovery and hospital discharge after laparoscopic and open abdominal surgery performed within an accelerated recovery program. DATA SOURCES AND STUDY SELECTION: Cochrane (1999-2010), Embase (1980 2010), MEDLINE (1980-2010), and International Pharmaceutical Abstracts (1970 2010) were searched for relevant double-blinded, randomized controlled trials. INTERVENTIONS: Twelve milligrams of alvimopan and placebo were given to patients enrolled in an accelerated recovery program after abdominal surgery. MAIN OUTCOME MEASURES: The primary outcomes measured were the length of stay as defined by the writing of the hospital discharge order and GI-3 and GI-2 GI tract recovery. RESULTS: : Three trials were included that reported on a pooled modified intention-to-treat population of 1388 patients; 685 (49%) patients received alvimopan. On meta-analysis, alvimopan reduced time to the hospital discharge order (HR 1.37 (1.21, 1.62), p < 0.0001), GI-3 recovery (HR 1.42 (1.25, 1.62), p < 0.001), and GI-2 recovery (HR 1.49 (1.32, 1.68), p < 0.0001). LIMITATIONS: The search criteria identified only a small number of trials of alvimopan after abdominal surgery with no randomized trials of alvimopan after laparoscopic surgery. In addition, the use of length of hospital stay as the primary outcome measure may be inappropriate, because it is open to many confounding factors. Finally, adverse events, in particular, adverse cardiovascular events, were not considered. CONCLUSIONS: Alvimopan 12 mg can further reduce time to GI recovery and hospital discharge in patients undergoing abdominal surgery within an accelerated recovery program. Investigation into the effect of alvimopan following laparoscopic surgery and additional cost-benefit analyses are required to further define the role of this intervention. PMID- 22513442 TI - Sacral nerve stimulation for fecal incontinence: at a crossroad and future challenges. PMID- 22513443 TI - Is the placement of the new synthetic anal fistula plug really so ineffective? PMID- 22513449 TI - Changes in pharmaceutical treatment of diabetes and family financial burdens. AB - Recent changes in diabetes treatment guidelines and the introduction of new, more expensive pharmaceuticals appear to increase the financial challenges for nonelderly adults with diabetes. The authors used Medical Expenditure Panel Survey data to examine changes in the prevalence of diabetes and comorbidities, diabetes treatment, financial burdens, and the relationship between high financial burdens and patient characteristics. From 1997-1998 to 2006-2007, the total number of nonelderly adults treated for diabetes nearly doubled, from 5.4 to 10.7 million, and the proportion of diabetes patients using multiple drugs to treat their condition increased significantly. About a fifth of diabetes patients spent 10% or more of their family income on health care, and about one in nine spent 20% or more of their family income on health care. In 2006-2007, diabetes patients who were older, female, in poor health, or lacked insurance were more likely than others to have high burdens. PMID- 22513451 TI - Chemical and electrochemical insertion of Li into the spinel structure of CuCr2Se4: ex situ and in situ observations by X-ray diffraction and scanning electron microscopy. AB - The chemical and electrochemical insertion of lithium into the spinel structure of CuCr(2)Se(4) was studied and the chemical reaction pathway was followed by ex situ X-ray diffraction on samples with different Li contents. The electrochemical reaction was investigated by in situ X-ray diffraction and in situ scanning electron microscopy. In the early steps of chemical intercalation, two phases with a different Li content coexist and Cu is extruded from the host material. After 4 days of Li intercalation, a conversion reaction is observed. The overall Li uptake is 8 Li ions per formula unit. The structural behaviour of the two intercalated phases at the early stages of intercalation is totally different. For one phase a strong expansion of the a-axis is observed while for the other phase it is only slightly affected by Li uptake. A three-step mechanism was found consisting of reduction of Se(-) followed by a Cu-Li exchange and finally a complete reduction of Cr(3+) to the metallic state accompanied by the formation of Li(2)Se. The discharge capacity of the first cycle amounts to 530 mAh g(-1) and drops to about 380 mAh g(-1) in the fifth cycle. In in situ SEM images the occurrence of Cu whiskers that partially grow out of the crystallites can be observed. PMID- 22513450 TI - Dual testing with QF-PCR and karyotype analysis for prenatal diagnosis of chromosomal abnormalities. Evaluation of 13,500 cases with consideration of using QF-PCR as a stand-alone test according to referral indications. AB - OBJECTIVE: Evaluate the results obtained from Quantitative Fluorescent (QF)-PCR and conventional karyotype analysis to determine the advantages and disadvantages of dual testing in prenatal diagnosis. METHODS: From 1 June 2006 to 1 June 2010, dual testing by QF-PCR and karyotype analysis was performed in 13,500 prenatal samples. The rates of concordant results between the two methods were evaluated and the rates of clinically significant chromosomal abnormalities undetected by QF-PCR were assessed. RESULTS: Abnormal karyotype was found in 320 out of 13,500 cases (2.37%, 95% confidence interval (CI) 2.11-2.63%). From these, QF-PCR did not detect the abnormality in 70 cases (0.52%, 95% CI 0.4-0.64%), whereas 34 had a high/unknown risk of adverse outcome (0.25%, 95% CI 0.17-0.33%). By selectively applying dual testing only at cases with ultrasound findings and/or genetic history, 13 cases of high/unknown risk would have been missed (0.1%, 95% CI 0.05 0.15%). CONCLUSION: Selective dual testing is expected to achieve a serious beneficial economical outcome and reduce parental anxiety produced by ambiguous cytogenetic findings. However, the percentage of 0.1% undetected clinically significant abnormalities cannot be ignored. A suggestion would include the offering of a choice to the pregnant women, undergoing prenatal screening, by informing them about different approaches and various complications. PMID- 22513452 TI - CIITA gene variants are associated with rheumatoid arthritis in Scandinavian populations. AB - Expression of the major autoimmune risk loci DRB1 and DQB1 is regulated by the class II MHC (major histocompatibility complex) transactivator (CIITA), making the CIITA gene a strong autoimmune risk locus candidate. A CIITA promoter single nucleotide polymorphism (SNP), rs3087456 (-168 A/G), has indeed been associated with several autoimmune diseases, including rheumatoid arthritis (RA). Recently, an intronic SNP rs8048002 has been suggested as a better susceptibility marker in Addison's disease. Therefore, we tested both SNPs in a panel of autoimmune diseases, consisting of Norwegian patients with RA (n=819), juvenile idiopathic arthritis (JIA; n=524), or type 1 diabetes (T1D; n=1211), and 2149 controls. We also included an independent Swedish RA cohort (n=2503) and controls (n=1416). Both rs3087456 and rs8048002 were significantly associated with RA (combined Norwegian and Swedish patients P(corrected)=0.012 and P(corrected)=0.0016, respectively), but not with JIA or T1D. Meta-analysis of 16 RA cohorts confirmed rs3087456 with only marginal significance (P=0.016). However, results were stronger in the Scandinavian subgroup (4 cohorts, P=3.8 * 10(-4)), indicating a population-dependent effect. A similar pattern was observed in a meta-analysis of rs8048002. Our results support involvement of CIITA in RA, but imply that this is population dependent and that the aetiological variant is yet to be discovered. PMID- 22513453 TI - Sjogren's syndrome pathological neovascularization is regulated by VEGF-A stimulated TACE-dependent crosstalk between VEGFR2 and NF-kappaB. AB - We explore the involvement of tumor necrosis factor alpha (TNF-alpha)-converting enzyme (TACE) in vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR2) (VEGF-A/VEGFR2)-mediated angiogenesis in Sjogren's syndrome (SS), one of the most common autoimmune rheumatic diseases. To test the hypothesis that SS autoantibodies (Abs) regulate VEGF-A/VEGFR2 expression by a TACE-dependent nuclear factor-kappaB (NF-kappaB) activation pathway, their effects on the expression and activation of the VEGF-A/TACE/VEGFR2/NF-kappaB pathway were determined in human salivary gland epithelial cells (SGEC). An enhanced angiogenesis in SS salivary gland biopsies was observed, associated with an increased VEGF-A expression and activation of VEGF-A/VEGFR2 signaling. Human cytokine array analysis of the pro-inflammatory and pro-angiogenic protein response in SGEC treated with SS Abs revealed an overexpression of multiple pro angiogenic factors. TACE RNA knockdown, the use of anti-VEGF-A monoclonal antibody and the inhibition of NF-kappaB activity significantly abrogated the release of pro-angiogenic factors, demonstrating that VEGF-A/TACE/VEGFR2/NF kappaB axis dysfunction may be contributory to pathogenesis and exacerbation of this autoimmune condition. PMID- 22513454 TI - D1 versus D2 lymphadenectomy for gastric cancer. AB - Significant variability exists throughout the world in the extent of lymphadenectomy that is performed for gastric adenocarcinoma. D2 lymphadenectomy is the standard lymphadenectomy performed in high incidence countries such as Japan and South Korea, and less extensive lymphadenectomies are often performed in lower incidence countries such as the Unites States. This article reviews the evidence on the extent of lymphadenectomy that should be performed for gastric adenocarcinoma. PMID- 22513456 TI - Early on-treatment viral load and baseline METAVIR score: improved prediction of sustained virological response in HCV genotype 1 patients. AB - BACKGROUND: On-treatment HCV viral load during early therapy with pegylated interferon (PEG-IFN) and ribavirin is highly predictive of sustained virological response (SVR). We sought to provide further refinement of this prediction through an extensive evaluation of the effect of HCV viral loads at weeks 4, 8 and 12 on SVR, including analysis by liver disease stage grouping. METHODS: A total of 309 patients with genotype 1 chronic HCV and recent liver biopsy enrolled in the CHARIOT study received 180 MUg of PEG-IFN-alpha2a weekly with 1,000/1,200 mg of ribavirin daily. The probability of an SVR was estimated using baseline METAVIR fibrosis stage and HCV viral loads at weeks 4, 8 and 12. RESULTS: HCV RNA was undetectable in 27.5%, 50.3% and 62.6% of patients at weeks 4, 8 and 12, respectively. SVR was 80.0%, 76.8% and 72.4% among patients with undetectable HCV RNA at weeks 4, 8 and 12, respectively. SVR decreased in a progressive fashion with increasing HCV viral loads at each early time point, but was similar for patients with HCV viral load <15 IU/ml, 15-100 IU/ml and 100 1,000 IU/ml. The effect of fibrosis stage on SVR was modest for patients with HCV viral load <1,000 IU/ml at week 4, but more marked for those with week 4 HCV viral load >1,000 IU/ml, and all HCV viral load categories at weeks 8 and 12. CONCLUSIONS: A combination of baseline fibrosis stage and on-treatment HCV viral load at early time points provides improved estimates for treatment response in patients with chronic HCV genotype 1. PMID- 22513458 TI - Catalytic and non-catalytic roles of pendant groups in the decomposition of N@C60: a DFT investigation. AB - The decomposition mechanism of N@C(60) derivatives has been elucidated by DFT calculations, revealing different roles of the pendant groups in the escape course of the incarcerated nitrogen. Whereas the pyrrolidine group facilitates the inversion of the incarcerated nitrogen, the cyclopropane group prohibits this process. PMID- 22513457 TI - Study of polycyclic aromatic hydrocarbons in atmospheric particulate matter of an urban area with iron and steel mills. AB - Polycyclic aromatic hydrocarbons (PAHs) were analyzed from ambient air particulate matter <10 um (PM(10) ) and the total suspended particulate (TSP) phase continuously for a period of six months (May-October 2010) at five sampling sites located in the urban area of Divinopolis (Minas Gerais), southeastern Brazil, near iron and steel mills. The carcinogenic potency of priority PAHs relative to benzo[a]pyrene was estimated for a period of six months. Benzo[a]pyrene equivalents were 7.52 ng/m(3) for the study period. The estimated risk of lifetime lung cancer was 6.5 * 10(-4) . A model based on the diagnostic ratio and principal component analysis was applied for source apportionment. Considering the entire study period, the burning of biomass and fuel oil accounted for about 70% of the PAH profile. An inventory was performed during the monitoring period, with 37 companies representing major industries located in the urban area. The observations were consistent with the distribution of sources and indicated that the iron and steel sector was the largest contributor. PMID- 22513455 TI - Genetics and neurobiology of aggression in Drosophila. AB - Aggressive behavior is widely present throughout the animal kingdom and is crucial to ensure survival and reproduction. Aggressive actions serve to acquire territory, food, or mates and in defense against predators or rivals; while in some species these behaviors are involved in establishing a social hierarchy. Aggression is a complex behavior, influenced by a broad range of genetic and environmental factors. Recent studies in Drosophila provide insight into the genetic basis and control of aggression. The state of the art on aggression in Drosophila and the many opportunities provided by this model organism to unravel the genetic and neurobiological basis of aggression are reviewed. PMID- 22513459 TI - Mechanical properties and composition of mesenteric small arteries of simulated microgravity rats with and without daily -G(x) gravitation. AB - The aim of the present study was to evaluate the active and passive mechanical properties and wall collagen and elastin contents of mesenteric small arteries (MSAs) isolated from rats of 28-day simulated microgravity (SUS), countermeasure [S + D: SUS plus 1 h/d -G(x) to simulate intermittent artificial gravity (IAG)] and control (CON) groups. Three mechanical parameters were calculated: the overall stiffness (beta), circumferential stress (sigma(theta))-strain (epsilon(theta)) relationship and pressure-dependent incremental elastic modulus (E(inc,p)). Vessel wall collagen and elastin percentage were quantified by electron microscopy. The results demonstrate that the active mechanical behavior of MSAs differs noticeably among the three groups: the active stress-strain curve of SUS vessels is very close to the passive curve, whereas the active sigma(theta)-epsilon(theta) curves of CON and S + D vessels are shifted leftward and display a parabolic shape, indicating that for MSAs isolated from S + D, but not those from SUS rats, the pressure-induced myogenic constriction can effectively stiffen the vessel wall as the CON vessels. The passive mechanical behavior of MSAs does not show significant differences among the three groups. However, the percentage of collagen is decreased in the wall of SUS and S + D compared with CON vessels in the following order: SUS < S + D < CON. Thus, the relationship between passive mechanical behavior and compositional changes may be complex and yet depends on factors other than the quantity of collagen and elastin. These findings have provided biomechanical data for the understanding of the mechanism of postflight orthostatic intolerance and its gravity-based countermeasure. PMID- 22513460 TI - [beta-estradiol activates BK(Ca) in mesenteric artery smooth muscle cells of post menopause women]. AB - The aim of the present study was to study the effect of beta-estradiol (beta E(2)) on the large-conductance Ca(2+)-activated potassium (BK(Ca)) channel in mesenteric artery smooth muscle cells (SMCs). The mesenteric arteries were obtained from post-menopause female patients with abdominal surgery, and the SMCs were isolated from the arteries using an enzymatic disassociation. According to the sources, the SMCs were divided into non-hypertension (NH) and essential hypertension (EH) groups. Single channel patch clamp technique was used to investigate the effect of beta-E(2) and ICI 182780 (a specific blocker of estrogen receptor) on BK(Ca) in the SMCs. The results showed the opening of BK(Ca) in the SMCs was voltage and calcium dependent, and could be blocked by IbTX. beta-E(2) (100 MUmol/L) significantly increased open probability (Po) of BK(Ca) in both NH and EH groups. After beta-E(2) treatment, NH group showed higher Po of BK(Ca) compared with EH group. ICI 182780 could inhibit the activating effect of beta-E(2) on BK(Ca) in no matter NH or EH groups. These results suggest beta-E(2) activates BK(Ca) in mesenteric artery SMCs from post menopause women via estrogen receptor, but hypertension may decline the activating effect of beta-E(2) on BK(Ca). PMID- 22513461 TI - [Involvement of HIF-1 in the migration-promoting effects of hydrogen sulfide in vascular endothelial cells under normoxic conditions]. AB - The purpose of this study was to investigate the molecular mechanisms whereby hydrogen sulfide (H2S) exerts the promoting effect on vascular endothelial cells migration. We used wound healing assay to study the effect of NaHS (H2S donor) on the migration ability of rhesus retinal pigment epithelial cell line, RF/6A cells, under normoxic conditions. Real-time PCR was used to measure hypoxia inducible factor 1alpha (HIF-1alpha) mRNA level. Western blot was used to measure the expression of HIF-1alpha protein. The probe 2',7'-dichlorofluorescein diacetate (DCFH-DA) was used to measure intracellular reactive oxygen species (ROS) level. The results showed that NaHS (10-100 MUmol/L) could significantly promote RF/6A cells migration under normoxic conditions, and this effect could be inhibited by 50 umol/L HIF-1 inhibitor, CdCl2. NaHS increased the protein level of HIF-1alpha in a dose- and time-dependent manner, and up-regulated the mRNA level of HIF-1alpha quickly and continuously. Moreover, NaHS could significantly decrease ROS levels in RF/6A cells under normoxic conditions. These results suggest HIF-1 may mediate the promoting effect of H2S on vascular endothelial cells migration under normoxic conditions. ROS, as an upstream regulator of HIF 1alpha, may be involved in the migration-promoting effect of H2S. PMID- 22513462 TI - [Effects of Panax notoginseng saponins on pneumocyte apoptosis and c-Jun N terminal kinase in lung ischemia/reperfusion injury]. AB - The aim of the present study is to investigate the effects of Panax notoginseng saponins (PNS) on pneumocyte apoptosis and apoptosis-related protein, as well as c-Jun N-terminal kinase (JNK) in lung ischemia/reperfusion (I/R) injury. Thirty Wistar rats were randomly divided into control group, I/R group and PNS group. The unilateral lung I/R model was replicated by obstruction of left lung hilus for 30 min and reperfusion for 120 min in vivo. The rats in PNS group were given intraperitoneal injection of PNS at 60 min before ischemia and 10 min before reperfusion. Some lung tissues sampled at the end of the experiment were assayed for wet/dry weight ratio (W/T). The expressions of phosphorylated JNK (p-JNK) and JNK protein were detected by Western blot. The expressions of Bcl-2, Bax and Caspase-3 protein were detected by immunocytochemistry techniques. The pneumocyte apoptotic index (AI) was detected by terminal deoxynuleotidy1 transferase mediated dUTP nick end labeling (TUNEL). The morphological and ultrastructure changes were observed under light microscope and electron microscope, and the injured alveolus rate (IAR) was counted as well. The results showed that compared to control group, I/R group showed increased expressions of p-JNK, Bcl-2, Bax and Caspase-3 protein (all P < 0.01), decreased ratio of Bcl-2/Bax (P < 0.05), and increased values of AI, W/T and IAR (all P < 0.01). Moreover, light microscope and electron microscope showed serious morphological and ultrastructure injury in I/R group. Compared to I/R group, PNS group showed markedly decreased expressions of p-JNK, Bax and Caspase-3 protein (all P < 0.01), increased expression of Bcl-2 protein and ratio of Bcl-2/Bax (both P < 0.01), and lower values of AI, W/T and IAR (all P < 0.01). Meanwhile, light morphological and ultrastructure injury was found to be alleviated in PNS group. These results suggest that PNS can protect lung tissue from I/R injury, and the mechanism may correlate with suppressing JNK signal pathway, up-regulating the ratio of Bcl-2/Bax which results in inhibition of Caspase-3 dependent apoptosis. PMID- 22513463 TI - [Central reactive oxygen species mediate cardiovascular effects of urotensin II in spontaneously hypertensive rats]. AB - Central urotensin II (UII) may participate in the regulation of cardiovascular functions by stimulating sympathy pathway. However, the central mechanism remained unknown. Recent studies have shown that brain reactive oxygen species (ROS) mediate the sympatho-excitatory effects. In the present study, we tested the hypothesis that ROS mediate central cardiovascular effects of UII. Experiments were conducted in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Immunocytochemistry, intracerebroventricular (icv) infusion and lucigenin-enhanced chemiluminescence assay were employed to detect UII receptor expression and ROS level, respectively. The following results were obtained: (1) Expressions of UII receptors of rostral ventrolateral medulla (RVLM) and nucleus tractus solitarii (NTS) were increased in SHR rats compared with WKY rats (P < 0.05). (2) UII (icv) significantly increased mean arterial pressure (MAP) (P < 0.05), and the effect of UII was significantly more pronounced in SHR rats than that in WKY rats (P < 0.05); (3) Tempol (a superoxide dismutase mimic) or Urantide (an antagonist of UII receptor) pretreatments eliminated the pressor effect of UII (P < 0.05) in SHR rats; (4) Brain superoxide level was increased in UII-treated SHR rats compared with that in cerebrospinal fluid (CSF)-treated SHR rats (P < 0.05). These results indicate that ROS mediate central cardiovascular effects of UII in SHR rats and provide evidence for a novel relationship between UII and ROS. PMID- 22513464 TI - [Inhibitory effect of caveolin-1 on endoplasmic reticulum stress-induced apoptosis in macrophages via p38 MAPK pathway]. AB - Endoplasmic reticulum (ER) stress occurs in macrophage-rich areas of advanced atherosclerotic lesions and contributes to macrophage apoptosis and subsequent plaque necrosis. The purpose of the present study was to investigate the effects of caveolin-1 (Cav-1) on ER stress-induced apoptosis in cultured macrophages and the underlying mechanisms. RAW264.7 cells were incubated with thapsigargin (TG) to establish ER stress model. And Cav-1 expression was detected by Western blot. After being pretreated with filipin(III), a caveolae inhibitor, RAW264.7 cells were assayed with flow cytometry and confocal laser scanning microscopy to detect cell apoptosis. Moreover, p38 mitogen-activated protein kinase (MAPK) phosphorylation and C/EBP homologous protein (CHOP) expression were detected with Western blot. The results showed that Cav-1 expression was markedly increased at early stage of TG treatment (P < 0.05) and then decreased with prolonged or high dose TG treatments. The increasing of Cav-1 expression induced by TG in RAW264.7 cells was abolished under inhibition of caveolae by filipin(III) (P < 0.05). The effect of TG on apoptosis of RAW264.7 cells was further augmented after pretreatment with filipin(III) (P < 0.05). Western blotting showed that MAPK phosphorylation induced by TG was inhibited by filipin(III) in RAW264.7 cells (P < 0.05), whereas CHOP remained unchanged (P > 0.05). These results suggest that Cav-1 may play a critical role in suppressing ER stress-induced macrophages apoptosis in vitro, and one of the mechanisms may be correlated with the activation of p38 MAPK prosurvival pathway. PMID- 22513465 TI - [Effects of etomidate on descending activation of motoneurons in neonatal rat spinal cord in vitro]. AB - Descending activation pathways in spinal cord are essential for inducing and modulating autokinesis, but whether the effects of general anesthetic agents on the descending pathways are involved in initiation of skeletal muscle relaxation or not, as well as the underlying mechanisms on excitatory amino acid receptors still remain unclear. In order to explore the mechanisms underlying etomidate's effects on descending activation of spinal cord motoneurons (MNs), the conventional intracellular recording techniques in MNs of spinal cord slices isolated from neonatal rats (7-14 days old) were performed to observe and analyze the actions of etomidate on excitatory postsynaptic potential (EPSP) elicited by electrical stimulation of the ipsilateral ventrolateral funiculus (VLF), which was named VLF-EPSP. Etomidate at 0.3, 3.0 (correspond to clinical concentration) and 30.0 umol/L were in turn perfused to MN with steadily recorded VLF-EPSPs. At low concentration (0.3 umol/L), etomidate increased duration, area under curve and/or half-width of VLF-EPSP and N-methyl-D-aspartate (NMDA) receptor-mediated VLF-EPSP component (all P < 0.05), as well as amplitude, area under curve and half-width of non-NMDA receptor-mediated VLF-EPSP component (all P < 0.05), or decreased amplitude and area under curve of VLF-EPSP, its NMDA receptor component, and non-NMDA receptor component (all P < 0.05). However, at 3.0 and 30.0 umol/L, it was only observed that etomidate exerted inhibitory effects on amplitude and/or duration and/or area under curve of VLF-EPSP (P < 0.05 or P < 0.01) with concentration- and time-dependent properties. Moreover, NMDA receptor mediated VLF-EPSP component was more sensitive to etomidate at >= 3.0 umol/L than non-NMDA receptor-mediated VLF-EPSP component did. As a conclusion, etomidate, at different concentrations, exerts differential effects on VLF-EPSP and glutamate receptors mediating the synaptic transmission of descending activation of MNs in neonatal rat spinal cord in vitro. PMID- 22513466 TI - [Inhibitory effects of propofol on supraoptic nucleus neurons of rat hypothalamus in vitro]. AB - To investigate the effects of novel intravenous general anesthetic propofol on membrane electrophysiological characteristics and action potential (AP) of the supraoptic nucleus (SON) neurons and possible ionic mechanisms, intracellular recordings were conducted in SON neurons from the coronal hypothalamic slice preparation of adult male Sprague Dawley (SD) rats. The results showed that bath application of 0.1 mmol/L propofol induced a significant decline in resting potential (P < 0.01), and higher concentrations of propofol (0.3 and 1.0 mmol/L) decreased time constant and slope resistance of cell membrane (P < 0.01). Under the hyperpolarizing current pulses exceeding 0.5 nA, an anomalous rectification was induced by hyperpolarization-activated cation channel (I(h) channel) in 11 out of 18 tested SON neurons. Bath of propofol reversibly decreased the anomalous rectification. Moreover, 0.1 mmol/L propofol elevated threshold level (P < 0.01) and decreased Max L. slope (P < 0.05) of the spike potential in SON neurons. Interestingly, 0.3 and 1.0 mmol/L propofol nullified APs in 6% (1/18) and 71% (12/17) tested SON neurons, respectively. In the SON neurons where APs were not nullified, propofol (0.3 mmol/L) decreased the amplitude of spike potential (P < 0.05). The higher concentrations of propofol (0.3 and 1.0 mmol/L) decreased firing frequencies evoked by depolarizing current pulses (0.1-0.7 nA), and shifted the current intensity-firing frequency relation curves downward and to the right. These results suggest that propofol decreases the excitability of SON neurons by inhibiting I(h) and sodium channels. PMID- 22513467 TI - [Repeated morphine pretreatment reduces glutamatergic synaptic potentiation in the nucleus accumbens induced by acute morphine exposure]. AB - Repeated exposure to morphine leads to the addiction, which influences its clinical application seriously. The glutamatergic projection from prefrontal cortex (PFC) to the nucleus accumbens (NAc) plays an important role in rewarding effects. It is still unknown whether morphine exposure changes PFC-NAc synaptic transmission. To address this question, in vivo field excitatory postsynaptic potentials (fEPSPs) induced by electric stimulating PFC-NAc projection fibers were recorded to evaluate the effect of acute morphine exposure (10 mg/kg, s.c.) on glutamatergic synaptic transmission in NAc shell of repeated saline/morphine pretreated rats. It was showed that acute morphine exposure enhanced fEPSP amplitude and reduced paired-pulse ratio (PPR) in saline pretreated rats, which could be reversed by following naloxone injection (1 mg/kg, i.p.), an opiate receptor antagonist. However, repeated morphine pretreatment significantly inhibited both the enhancement of fEPSP amplitude and reduction of PPR induced by acute morphine exposure. Those results indicate that the initial morphine exposure enhances PFC-NAc synaptic transmission by pre-synaptic mechanisms, whereas morphine pretreatment occludes this effect. PMID- 22513468 TI - [Functional difference of malate-aspartate shuttle system in liver between plateau zokor (Myospalax baileyi) and plateau pika (Ochotona curzoniae)]. AB - To explore the adaptive mechanisms of plateau zokor (Myospalax baileyi) to the enduring digging activity in the hypoxic environment and of plateau pika (Ochotona curzoniae) to the sprint running activity, the functional differences of malate-aspartate shuttle system (MA) in liver of plateau zokor and plateau pika were studied. The ratio of liver weight to body weight, the parameters of mitochondria in hepatocyte and the contents of lactic acid in serum were measured; the open reading frame of cytoplasmic malate dehydrogenase (MDH1), mitochondrial malate dehydrogenase (MDH2), and the partial sequence of aspartate glutamate carrier (AGC) and oxoglutarate malate carrier (OMC) genes were cloned and sequenced; MDH1, MDH2, AGC and OMC mRNA levels were determined by real-time PCR; the specific activities of MDH1 and MDH2 in liver of plateau zokor and plateau pika were measured using enzymatic methods. The results showed that, (1) the ratio of liver weight to body weight, the number and the specific surface of mitochondria in hepatocyte of plateau zokor were markedly higher than those of plateau pika (P < 0.01 or P < 0.05), but the content of lactic acid in serum of plateau pika was significantly higher than that of plateau zokor (P < 0.01); (2) MDH1 and MDH2 mRNA levels as well as their enzymatic activities in liver of plateau zokor were significantly higher than those of plateau pika (P < 0.01 or 0.05), AGC mRNA level of the zokor was significantly higher than that of the pika (P < 0.01), while no difference was found at OMC mRNA level between them (P > 0.05); (3) mRNA level and enzymatic activity of MDH1 was significantly lower than those of MDH2 in the pika liver (P < 0.01), MDH1 mRNA level of plateau zokor was markedly higher than that of MDH2 (P < 0.01), but the activities had no difference between MDH1 and MDH2 in liver of the zokor (P > 0.05). These results indicate that the plateau zokor obtains ATP in the enduring digging activity by enhancing the function of MA, while plateau pika gets glycogen for their sprint running activity by increasing the process of gluconeogenesis. As a result, plateau pika converts the lactic acid quickly produced in their skeletal muscle by anaerobic glycolysis and reduces dependence on the oxygen. PMID- 22513469 TI - [Diltiazem enhances food intake and gastrointestinal function in rats]. AB - The present study was to investigate the effects of diltiazem, a ghrelin receptor agonist, on food intake and gastrointestinal functions in rats. Rats were intragastrically administered with diltiazem solution (daily 16 mg/kg, 30 mg/kg or 80 mg/kg, 30 d), and the rats with saline as control. To detect the effects of diltiazem on food intake and body weight, the average daily food intake and body weight were recorded, and the serum metabolic hormones of plasma growth hormone (GH) and neuropeptide Y (NPY) were tested by radioimmunoassay. By means of the spectrophotometer and the modified Mett's method, the effects of diltiazem on rat's gastrointestinal function and pepsin activity were tested, respectively. In addition, the gastric juice's acidity of rats was detected by titration and the secretion amount was calculated. The results showed that the food intake and body weight were maximally promoted by diltiazem at the dose of 30 mg/kg daily (30 d). The average daily food intake and body weight were significantly increased, and the serum concentrations of GH and NPY were also remarkably increased in diltiazem-treated groups compared with those in control group. The results also showed that the gastric emptying rate, gastric acid secretion and the activity of pepsin were significantly increased in diltiazem-treated group compared with those in control group. These results suggest that diltiazem induces enhancement of eating, in the same time, it can also stimulate the gastrointestinal function and regulate growth of rat. PMID- 22513470 TI - [Effects of acute hypobaric hypoxia and exhaustive exercise on AMP-activated protein kinase phosphorylation in rat skeletal muscle]. AB - The present study was aimed to explore the changes of phosphorylated AMP activated protein kinase (pAMPK) level in skeletal muscle after exposure to acute hypobaric hypoxia and exhaustive exercise. Thirty-two male Sprague-Dawley (SD) rats were randomly divided into sea level and high altitude groups. The rats in high altitude group were submitted to simulated 5 000 m of high altitude in a hypobaric chamber for 24 h, and sea level group was maintained at normal conditions. All the rats were subjected to exhaustive swimming exercise. The exhaustion time was recorded. Before and after the exercise, blood lactate and glycogen content in skeletal muscle were determined; AMPK and pAMPK levels in skeletal muscle were detected by Western blot. The results showed that the exhaustion time was significantly decreased after exposure to high altitude. At the moment of exhaustion, high altitude group had lower blood lactate concentration and higher surplus glycogen content in gastrocnemius compared with sea level group. Exhaustive exercise significantly increased the pAMPK/AMPK ratio in rat skeletal muscles from both sea level and high altitude groups. However, high altitude group showed lower pAMPK/AMPK ratio after exhaustion compared to sea level group. These results suggest that, after exposure to acute hypobaric hypoxia, the decrement in exercise capacity may not be due to running out of glycogen, accumulation of lactate or disturbance in energy status in skeletal muscle. PMID- 22513471 TI - Puerarin decreases apoptosis of retinal pigment epithelial cells in diabetic rats by reducing peroxynitrite level and iNOS expression. AB - The purpose of this study was to investigate the protective effect of puerarin on retina pigment epithelial (RPE) cells of diabetic rats against apoptosis. One hundred and eight Sprague-Dawley (SD) rats were randomly divided into 3 groups: control group, streptozotocin (STZ) group and puerarin group. STZ and puerarin groups received 3 d of STZ injection (45 mg/kg per day, i.p.). Additionally, puerarin groups were treated with puerarin (140 mg/kg, i.p.) from the 4th day to the end of experiment. The rats from different groups were sacrificed on 20, 40 and 60 d after STZ injection for harvesting RPE cells. Western blot analysis, DNA laddering, RT-PCR and immunohistochemistry were used for determining the expression of nitrotyrosine (NT, the foot print of peroxynitrite), cell apoptosis, iNOS mRNA and Fas/Fas ligand (FasL) signal transduction in RPE cells, respectively. The results showed that control group maintained low apoptosis level and little NT, iNOS mRNA, Fas/FasL protein expressions, as well as normal blood glucose and body weight during 60 d of the experiment. Compared with control group, STZ group showed obvious apoptosis and higher NT, iNOS mRNA, Fas/FasL protein expressions from 20 d after STZ injection. Puerarin relieved apoptosis of RPE cells and decreased NT, iNOS mRNA, Fas/FasL protein expressions in puerarin group 20 or 40 d after STZ injection, compared with STZ group. These results suggest puerarin can decrease RPE cells apoptosis in diabetic rats by reducing peroxynitrite level and iNOS expression, thus being a potential therapeutic agent in controlling of diabetic retinopathy. PMID- 22513472 TI - [Wogonin inhibits IGF-1-stimulated cell growth and estrogen receptor alpha expression in breast adenocarcinoma cell and angiogenesis of chick chorioallantoic membrane]. AB - The aim of the present study was to investigate the involvements of insulin-like growth factor-1 (IGF-1) and estrogen receptor alpha (ERalpha) in the inhibitory effect of wogonin on the breast adenocarcinoma growth. Moreover, the effect of wogonin on the angiogenesis of chick chorioallantoic membrane (CAM) was also investigated. MCF-7 cells (human breast adenocarcinoma cell line) were subjected to several drugs, including IGF-1, wogonin and ER inhibitor ICI182780, alone or in combination. MTT assay was used to detect breast cancer proliferation. Western blot was used to analyze ERalpha and p-Akt expression levels. CAM models prepared from 6-day chicken eggs were employed to evaluate angiogenesis inhibition. The results showed wogonin and ICI182780 both exhibited a potent ability to blunt IGF 1-stimulated MCF-7 cell growth. Either of wogonin and ICI182780 significantly inhibited ERalpha and p-Akt expressions in IGF-1-treated cells. The inhibitory effect of wogonin showed no difference from that of ICI182780 on IGF-1-stimulated expressions of ERalpha and p-Akt. Meanwhile, wogonin at different concentrations showed significant inhibitory effect on CAM angiogenesis. These results suggest the inhibitory effect of wogonin on breast adenocarcinoma growth via inhibiting IGF-1-mediated PI3K-Akt pathway and regulating ERalpha expression. Furthermore, wogonin has a strong anti-angiogenic effect on CAM model. PMID- 22513473 TI - [Involvement of protein kinase C in enhancement of vascular calcium sensitivity by blocking mesenteric lymph return in hemorrhagic shock rats]. AB - The aim of the present study was to investigate whether protein kinase C (PKC) was involved in the effect of mesenteric lymph duct ligation or mesenteric lymph drainage on vascular calcium sensitivity in hemorrhagic shock rats. Male Wistar rats were randomly divided into Sham, Shock (hemorrhagic shock), Shock+Ligation (mesenteric lymph duct ligation plus shock) and Shock+Drainage (mesenteric lymph drainage plus shock) groups. After being in shock (hypotension 40 mmHg) for 3 h, the tissue of superior mesenteric artery (SMA) was taken out for detecting the PKC expression and phospho-PKC (p-PKC) activity, and the vascular rings of SMA were prepared and used to measure the response to gradient calcium concentration for assaying the calcium sensitivity, the parameters of which including tension, maximum tension (E(max)) and negative logarithm of EC(50), called the pD(2). Other vascular rings from Shock+Ligation and Shock+Drainage groups were incubated with PKC regulator PMA or Staurosporine before the measurement of calcium sensitivity. The results showed that, PKC expression, p-PKC activity and calcium sensitivity of SMA in Shock group was significantly lower than that of Sham group, whereas the above-mentioned indexes were significantly elevated in Shock+Ligation and Shock+Drainage groups compared with those in Shock group. PKC agonist PMA enhanced the contractile activity of vascular rings to gradient calcium ions, and increased E(max) of SMA in Shock+Ligation and Shock+Drainage groups. On the contrary, PKC inhibitor Staurosporine significantly decreased the response to gradient calcium ions and E(max) of SMA in Shock+Ligation and Shock+Drainage groups. These results suggest that PKC plays a role in the improvement of vascular calcium sensitivity by blockade of mesenteric lymph return in hemorrhagic shock rats. PMID- 22513474 TI - [Current progress in functions of axon guidance molecule Slit and underlying molecular mechanism]. AB - The axon guidance molecule Slit is a secreted glucoprotein which is conserved during evolution. Slit has been implicated in regulating a variety of life activities, such as axon guidance, neuronal migration, neuronal morphological differentiation, tumor metastasis, angiogenesis and heart morphogenesis. Slit function mainly depends on the binding of its LRR-2 domain to the Ig1 domain of Roundabout (Robo) receptor, meanwhile Slit function is also mediated by a range of signaling molecules, including the heparan sulfate proteoglycans (HSPGs), GTPase-activating proteins (GAPs), tyrosine kinase Abelson, calcium ions, MicroRNA-218 and other axon guidance molecules. Several transcription factors, including Single-minded, Irx and Midline, were shown to regulate slit expression. In addition, multiple Slit isoforms exist as a consequence of alternative spliced transcripts. The research on guidance mechanism of Slit will facilitate the understanding of molecular mechanism underlying neural networks formation in the process of neural development and regeneration. Meanwhile, the studying of Slit guidance mechanism could promote the prevention and treatment of human neurological diseases and cancer metastasis. PMID- 22513475 TI - [S100A8 protein in inflammation]. AB - S100A8, an important member of the S100 protein family, is a low-molecular-weight (10.8 kDa) calcium-binding protein containing conserved EF-hand structural motifs. Previous studies have shown that the biological function of S100A8 protein is associated with a variety of inflammatory diseases, for example asthma. S100A8 protein plays important roles in the regulation of inflammation. It can activate inflammatory cells and cytokines via chemotactic activity for neutrophils, and bind to the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), thus mediating intracellular inflammatory signaling transduction. Additionally, recent studies have reported the anti inflammation activity of S100A8 protein, which indicates that S100A8 may have a more complex function of biological regulation in the different pathophysiological conditions. In this review, we summarized the studies on the functions and molecular mechanisms of S100A8 protein in inflammation, which would propose a novel strategy for the prophylaxis and treatment of asthma and other inflammatory diseases. PMID- 22513476 TI - [Progress in mechanisms underlying melamine toxicity in central nervous system]. AB - In recent years there have been more widely and deeply studies in investigating melamine toxicity. Generally, it is believed that the main target of melamine is the urinary system. However, previous studies revealed that it also had additional biological actions. Obviously, the toxicity mechanisms of melamine have not been fully clarified. It is well known that fetus and infant periods play the most fundamental role in the brain development. And melamine can pass through the placental and blood-brain barrier, and then exerts toxic effects on the central nervous system. This article reviewed the reports about the topic in recent years, for better understanding the dangers of melamine to infants and providing experimental data for further study. PMID- 22513477 TI - A B3LYP-DBLOC empirical correction scheme for ligand removal enthalpies of transition metal complexes: parameterization against experimental and CCSD(T)-F12 heats of formation. AB - Average ligand removal enthalpies of 30 differently coordinated mono-nuclear fourth-row transition metal complexes taken from a database recently considered by Johnson and Becke [Can. J. Chem., 2009, 8, 1369] have been computed in the gas phase using unrestricted pseudo-spectral (LACV3P) and fully analytic (qzvp(-g)) B3LYP including a recently developed empirical dispersion correction. Heats of formation of neutral singlet reactants and neutral, potentially high spin, products have been taken from NIST's Organometallic Thermochemistry Database. Comparison of B3LYP-MM//qzvp(-g) and experimental average ligand removal enthalpies reveals a systematic error in the reported experimental enthalpies for manganese-containing complexes which is verified with high-level, CCSD(T) F12//family of cc-pVTZ, explicitly correlated coupled-cluster methods. Other B3LYP-MM//qzvp(-g) error patterns give rise to a d-block localized orbital correction (DBLOC) scheme containing six transferable parameters that correct the functional's description of metal-ligand bonding, cation-pi, and dispersion interactions as well as metal and/or ligand multi-reference effects. Metal-ligand cation-pi and dispersion interactions have been fit to the monopole/induced dipole, C(4)/R(4), and induced-dipole/induced-dipole, C(6)/R(6), interaction functions, respectively. This DBLOC model has been built upon a previously determined set of metal atom parameters which are necessary to properly describe the free metal atom reaction products. The final DBLOC model brings the mean unsigned error of B3LYP-MM//qzvp(-g) from 3.74 +/- 3.51 kcal/mol to 0.94 +/- 0.68 kcal/mol and corrects the functional's under binding in nearly every case. Several important connections among DBLOC parameters have been made. PMID- 22513478 TI - CASP8 -652 6N del polymorphism and cancer risk: a meta-analysis of 30 case control studies in 50,112 subjects. AB - Disruptions of normal apoptotic pathways, which are mainly mediated by caspases, play an essential role in cancer development. Caspase-8 (CASP8) is encoded by the CASP8 gene and is centrally involved in the apoptosis of T lymphocytes. The association between a six-nucleotide deletion polymorphism (-652 6N del) of the CASP8 gene and the risk of cancer is widely reported; however, study results have been inconsistent and contradictory. To evaluate the association between the CASP8 -652 6N del polymorphism and the risk of cancer and to overcome the limitations of any individual study, a meta-analysis based on a total of 23 700 cases and 26 412 controls from 30 case-control studies was conducted. The results of the overall analysis suggested that the CASP8 -652 6N del polymorphism is associated with decreased risk of cancer for the allele contrast [del versus ins: odd ratio (OR) = 0.86, 95% confidence interval (CI) = 0.80-0.92], the additive genetic model (del/del versus ins/ins: OR = 0.78, 95% CI = 0.69-0.88), the dominant genetic model (del/del+del/ins versus ins/ins: OR = 0.83, 95% CI = 0.78 0.89) and the recessive genetic model (del/del versus ins/ins+del/ins: OR = 0.84, 95% CI = 0.75-0.93). In addition, after stratification for ethnicity and cancer type, significantly reduced risk was found for Asians and Caucasians as well as for individuals in the colorectal cancer group and the 'other cancers' group. Accordingly, there is an association between the CASP8 -652 6N del polymorphism and reduced cancer risk, especially among Asians, Caucasians and those with colorectal cancer. However, further research, such as studies focusing on additional ethnic groups and cancer types, is needed to provide a more exact and comprehensive synthesis conclusion. PMID- 22513479 TI - The ADAM family: Insights into Notch proteolysis. AB - Notch signaling is integral to a large number of developmental and homeostasis events, and either gain or loss of Notch signaling results in a wide range of defects. Notch must be processed by several proteases, including a member of the ADAM (a disintegrin and metalloprotease) family to mediate downstream signaling. Until recently, interactions of Notch with specific ADAMs in different contexts were unclear. ADAM10 is now known to be specifically essential for development and homeostasis of mouse epidermis and cardiovascular structures, and ADAM17 may not be able to fully replace ADAM10 in these contexts. However, Notch from T-cell acute lymphoblastic leukemia (T-ALL) patients can be cleaved by both ADAMs 10 and 17. Studies have revealed that ADAM10 is necessary for Notch processing when Notch is activated by a ligand, while ADAM17 is the major protease for processing Notch that is activated independently of ligand in both flies and mammals. PMID- 22513480 TI - Urinary neutrophil gelatinase-associated lipocalin accurately detects acute allograft rejection among other causes of acute kidney injury in renal allograft recipients. AB - BACKGROUND: Urinary neutrophil gelatinase-associated lipocalin (NGAL) has emerged an early marker protein, predicative of acute kidney injury (AKI) in various clinical settings. Here, we demonstrate urinary NGAL to allow for differential diagnosis of AKI, accurately discriminating acute allograft rejection from other causes of AKI in renal allograft recipients. METHODS: Urinary NGAL was assessed in spot urine of 182 outpatient renal allograft recipients on maintenance immunosuppression. Samples were blinded and NGAL concentrations determined by enzyme-linked immunosorbent assay. Patient data were classed according to standard criteria into stable allograft function or AKI, and according to underlying pathology into acute allograft rejection or AKI of other cause. RESULTS: Of the 182 patients investigated, 44 (24.2%) presented with AKI and 9 (4.9%) were diagnosed with acute allograft rejection. In 138 patients with stable allograft function, median urinary NGAL concentration was 7.8 ng/mL (interquartile range, 3.7-17.4 ng/mL). In acute allograft rejection, urinary NGAL concentration was 339 ng/mL (165-499 ng/mL), and in AKI of other cause was 59.1 ng/mL (33.1-136 ng/mL). With a cut-off at 100 ng/mL, urinary NGAL accurately predicted acute rejection as underlying pathology of AKI in our cohort (area under the curve-receiver operating characteristic 0.98, sensitivity 1.0, specificity 0.93). This concept was confirmed in an independent clinical setting in allograft recipients referred to our hospital with AKI. CONCLUSIONS: Urinary NGAL, at respective cut-off, accurately discriminates acute allograft rejection from other causes of AKI in follow-up after kidney transplantation. As a readily available parameter, urinary NGAL may guide differential diagnosis and initial therapy in allograft recipients with AKI. PMID- 22513481 TI - Meloxicam improves object recognition memory and modulates glial activation after splenectomy in mice. AB - CONTEXT: Surgery-induced neuroinflammation has been implicated in the development of postoperative cognitive dysfunction (POCD). OBJECTIVE: To test the hypothesis that meloxicam, a selective cyclooxygenase (COX)-2 inhibitor, preserves postoperative cognitive function and inhibits surgery-induced neuroinflammation in a mouse model. DESIGN: A mouse model of splenectomy-induced inflammation. METHODS: Sixty Swiss Webster male mice (6-8 week old) were randomised into six groups that underwent splenectomy. Animals in groups 1-4 were tested once on day 1, 5, 9 or 14 to determine the time course of delayed transient cognitive dysfunction associated with splenectomy. Animals in groups 5 and 6 were tested once on day 5 or 9 to determine the ability of the NSAID meloxicam to attenuate cognitive dysfunction. INTERVENTION: Animals in groups 1-4 received one dose 500 MUl intraperitoneal physiological saline 24 h after splenectomy. Animals in groups 5 and 6 received one dose of intraperitoneal meloxicam (60 mg kg in 500 MUl saline) 24 h after splenectomy. MAIN OUTCOME MEASURES: Short-term working memory as determined by Object Recognition Test (ORT) index on days 1, 5, 9 and 14 was the first main outcome. Tomato lectin staining histochemistry of glial cells was assessed on days 1, 5, 9 and 14 as a second main outcome. RESULTS: Compared with day 1 (group 1), the mean ORT indices at day 5 (group 2) and day 9 (group 3) were decreased by 27.5% [95% confidence interval (CI): 0.9 to 54.1%, P = 0.04] and 23.8% (95% CI, 4.3 to 51.9%, P = 0.09), respectively. At day 5 (group 5) and day 9 (group 6), the ORT indices in the meloxicam groups were reduced by 6.6% (95% CI: -11.4 to 24.5%) and 4.3% (95% CI: -25.3 to 34.0). Thus, the administration of meloxicam attenuated the decrease in ORT indices (P = 0.031). Histochemical staining with tomato lectin showed features of microglia activation at day 5 and 9, which was reduced by the administration of meloxicam. CONCLUSION: These findings suggest that COX-2-dependent mechanisms may play a role in the development of POCD. This effect may be dependent on the modulation of glial cell activation. PMID- 22513482 TI - Does insulin and not reduced blood glucose levels decrease postoperative infections? PMID- 22513483 TI - Basophils infiltrate the skin lesions in lepromatous leprosy. PMID- 22513484 TI - Nanoscale periodic modulations on sodium chloride surface revealed by tuning fork atomic force microscopy. AB - The sodium chloride surface is one of the most common platforms for the study of catalysts, thin film growth, and atmospheric aerosols. Here we report a nanoscale periodic modulation pattern on the surface of a cleaved NaCl single crystal, revealed by non-contact atomic force microscopy with a tuning fork sensor. The surface pattern shows two orthogonal domains, extending over the entire cleavage surface. The spatial modulations exhibit a characteristic period of 5.4 nm, along <110> crystallographic directions of the NaCl. The modulations are robust in vacuum, not affected by the tip-induced electric field or gentle annealing (<300 degrees C); however, they are eliminated after exposure to water and an atomically flat surface can be recovered by subsequent thermal annealing after water exposure. A strong electrostatic charging is revealed on the cleavage surface which may facilitate the formation of the observed metastable surface reconstruction. PMID- 22513485 TI - Structural, electronic, optical, and chiroptical properties of small thiolated gold clusters: the case of Au6 and Au8 cores protected with dimer [Au2(SR)3] and trimer [Au3(SR)4)] motifs. AB - We report results of a theoretical study, based on density functional theory (DFT), on the structural, electronic, optical, and chiroptical properties of small thiolated gold clusters, [Au(n)(SR)(m) (n = 12-15, 16-20; m = 9-12, 12 16)]. Some of these clusters correspond to those recently synthesized with the surfactant-free method. To study the cluster physical properties, we consider two cluster families with Au(6) and Au(8) cores, respectively, covered with dimer [Au(2)(SR)(3)] and trimer [Au(3)(SR)(4)] (CH(3) being the R group) motifs or their combinations. Our DFT calculations show, by comparing the relaxed structures of the [Au(6)[Au(2)(SR)(3)](3)](+), [Au(6)[Au(2)(SR)(3)](2)[Au(3)(SR)(4)]](+), [Au(6)[Au(2)(SR)(3)][Au(3)(SR)(4)](2)](+), and [Au(6)[Au(3)(SR)(4)](3)](+) cationic clusters, that there is an increasing distortion in the Au(6) core as each dimer is replaced by a longer trimer motif. For the clusters in the second family, Au(8)[Au(3)(SR)(4)](4), Au(8)[Au(2)(SR)(3)][Au(3)(SR)(4)](3), Au(8)[Au(2)(SR)(3)](2)[Au(3)(SR)(4)](2), Au(8)[Au(2)(SR)(3)](3)[Au(3)(SR)(4)], and Au(8)[Au(2)(SR)(3)](4), a smaller distortion of the Au(8) core is observed as dimer motifs are substituted by trimer ones. An interesting trend emerging from the present calculations shows that as the number of trimer motifs increases in the protecting layer of both Au(6) and Au(8) cores, the average of the interatomic Au(core)-S distances reduces. This shrinkage in the Au(core)-S distances is correlated with an increase of the cluster HOMO-LUMO (H-L) gap. From these results, it is predicted that a larger number of trimer motifs in the cluster protecting layer would induce larger H-L gaps. By analyzing the electronic transitions that characterize the optical absorption and circular dichroism spectra of the clusters under study, it is observed that the molecular orbitals involved are composed of comparable proportions of orbitals corresponding to atoms forming the cluster core and the protecting dimer and trimer motifs. PMID- 22513487 TI - Hydrogel of ketoconazole and PAMAM dendrimers: formulation and antifungal activity. AB - Ketoconazole (KET), an imidazole derivative with well-known antifungal properties, is lipophilic and practically insoluble in water, therefore its clinical use has some practical disadvantages. The aim of the present study was to investigate the influence of PAMAM-NH(2) and PAMAM-OH dendrimers generation 2 and generation 3 on the solubility and antifungal activity of KET and to design and evaluate KET hydrogel with PAMAM dendrimers. It was shown that the surface charge of PAMAM dendrimers strongly affects their influence on the improvement of solubility and antifungal activity of KET. The MIC and MFC values obtained by broth dilution method indicate that PAMAM-NH(2) dendrimers significantly (up to 16-fold) increased the antifungal activity of KET against Candida strains (e.g., in culture Candida albicans 1103059/11 MIC value was 0.008 MUg/mL and 0.064 MUg/mL, and MFC was 2 MUg/mL and 32 MUg/mL for KET in 10 mg/mL solution of PAMAM NH(2) G2 and pure KET, respectively). Antifungal activity of designed KET hydrogel with PAMAM-NH(2) dendrimers measured by the plate diffusion method was definitely higher than pure KET hydrogel and than commercial available product. It was shown that the improvement of solubility and in the consequence the higher KET release from hydrogels seems to be a very significant factor affecting antifungal activity of KET in hydrogels containing PAMAM dendrimers. PMID- 22513486 TI - KCNE2 and the K (+) channel: the tail wagging the dog. AB - KCNE2, originally designated MinK-related peptide 1 (MiRP1), belongs to a five strong family of potassium channel ancillary (beta) subunits that, despite the diminutive size of the family and its members, has loomed large in the field of ion channel physiology. KCNE2 dictates K (+) channel gating, conductance, alpha subunit composition, trafficking and pharmacology, and also modifies functional properties of monovalent cation-nonselective HCN channels. The Kcne2 (-/-) mouse exhibits cardiac arrhythmia and hypertrophy, achlorhydria, gastric neoplasia, hypothyroidism, alopecia, stunted growth and choroid plexus epithelial dysfunction, illustrating the breadth and depth of the influence of KCNE2, mutations which are also associated with human cardiac arrhythmias. Here, the modus operandi and physiological roles of this potent regulator of membrane excitability and ion secretion are reviewed with particular emphasis on the ability of KCNE2 to shape the electrophysiological landscape of both excitable and non-excitable cells. PMID- 22513490 TI - Allergen-induced bone marrow eosinophilopoiesis and airways eosinophilic inflammation in leptin-deficient ob/ob mice. AB - Asthma and obesity are growing epidemics in the world. It is well established that obesity worsens the asthma outcomes. High-fat diet-induced obesity in mice exacerbates the pulmonary eosinophilic inflammation. We have used wild-type (WT) and ob/ob mice to further explore the mechanisms by which obesity aggravates the pulmonary eosinophilic inflammation. The eosinophil (EO) number in bronchoalveolar lavage (BAL) fluid, lung tissue, blood, and bone marrow were evaluated at 24, 48, and 72 h after ovalbumin (OVA) challenge in sensitized mice. The basal EO number (phosphate-buffered saline (PBS)-instilled mice) in lung tissue was about 3.5-fold greater in ob/ob compared with WT mice. OVA challenge in ob/ob mice promoted an EO accumulation into the lung that was accompanied by a lower emigration to airways lumen (BAL fluid) in comparison with WT mice. OVA challenge also markedly elevated the number of mature and immature EO in bone marrow of ob/ob mice at 24 h compared with WT group. Blood EO at 48 h was markedly greater in ob/ob mice. Tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 levels in BAL fluid were significantly higher in ob/ob mice, whereas no changes for IL-5 and eotaxin were found. The IL-6 levels were significantly lower in ob/ob mice. In conclusion, OVA challenge in ob/ob obese mice potentiates eosinophilopoiesis and promotes an accumulation of EO into the lung tissue, delaying their transit to airways lumen. The longer EO remain into the lung tissue is likely to contribute, at least in part, to the asthma worsened by obesity. PMID- 22513491 TI - Bright Start: Description and main outcomes from a group-randomized obesity prevention trial in American Indian children. AB - The aim of the Bright Start study was to develop and test the effectiveness of a school environment intervention, supplemented with family involvement, to reduce excessive weight gain by increasing physical activity and healthy eating practices among kindergarten and first-grade American Indian children. Bright Start was a group-randomized, school-based trial involving 454 children attending 14 schools on the Pine Ridge Reservation in South Dakota. Children were followed from the beginning of their kindergarten year through the end of first grade. Main outcome variables were mean BMI, mean percent body fat, and prevalence of overweight/obese children. The goals of the intervention were to: increase physical activity at school to at least 60 min/day; modify school meals and snacks; and involve families in making behavioral and environmental changes at home. At baseline, 32% of boys and 25% of girls were overweight/obese. Although the intervention was not associated with statistically significant change in mean levels of BMI, BMI-Z, skinfolds or percentage body fat, the intervention was associated with a statistically significant net decrease of 10% in the prevalence of overweight. Intervention children experienced a 13.4% incidence of overweight, whereas the control children experienced a corresponding incidence of 24.8%; a difference of -11.4% (P = 0.033). The intervention significantly reduced parent reported mean child intakes of sugar-sweetened beverages, whole milk, and chocolate milk. Changes in duration of school physical activity were not significant. Because obesity is the most daunting health challenge facing American Indian children today, more intervention research is needed to identify effective approaches. PMID- 22513493 TI - Ski overexpression in skeletal muscle modulates genetic programs that control susceptibility to diet-induced obesity and insulin signaling. AB - Transgenic mice overexpressing chicken Ski (c-Ski) have marked decrease in adipose mass with skeletal muscle hypertrophy. Recent evidence indicates a role for c-Ski in lipogenesis and energy expenditure. In the present study, wild type (WT) and c-Ski mice were challenged on a high-fat (HF) diet to determine whether c-Ski mice were resistant to diet-induced obesity. During the HF feeding WT mice gained significantly more weight than chow-fed animals, while c-Ski mice were partially resistant to the effects of the HF diet on weight. Body composition analysis confirmed the decreased adipose mass in c-Ski mice compared to WT mice. c-Ski mice possess a similar metabolic rate and level of food consumption to WT littermates, despite lower activity levels and on chow diet show mild glucose intolerance relative to WT littermates. On HF diet, glucose tolerance surprisingly remained unchanged in c-Ski mice, while it became worse in WT mice. Skeletal muscle of c-Ski mice exhibit impaired insulin-stimulated Akt phosphorylation and glucose uptake. In concordance, gene expression profiling of skeletal muscle of chow and HF-fed mice indicated that Ski suppresses gene expression associated with insulin signaling and glucose uptake and alters gene pathways involved in myogenesis and adipogenesis. In conclusion, c-Ski mice are partially resistant to diet-induced obesity and display aberrant insulin signaling and glucose homeostasis which is associated with alterations in gene expression that inhibit lipogenesis and insulin signaling. These results suggest Ski plays a major role in skeletal muscle metabolism and adipogenesis and hence influences risk of obesity and diabetes. PMID- 22513492 TI - Effects of sleep restriction on glucose control and insulin secretion during diet induced weight loss. AB - Insufficient sleep is associated with changes in glucose tolerance, insulin secretion, and insulin action. Despite widespread use of weight-loss diets for metabolic risk reduction, the effects of insufficient sleep on glucose regulation in overweight dieters are not known. To examine the consequences of recurrent sleep restriction on 24-h blood glucose control during diet-induced weight loss, 10 overweight and obese adults (3F/7M; mean (s.d.) age 41 (5) years; BMI 27.4 (2.0) kg/m(2)) completed two 14-day treatments with hypocaloric diet and 8.5- or 5.5-h nighttime sleep opportunity in random order 7 (3) months apart. Oral and intravenous glucose tolerance test (IVGTT) data, fasting lipids and free fatty acids (FFA), 24-h blood glucose, insulin, C-peptide, and counter-regulatory hormone measurements were collected after each treatment. Participants had comparable weight loss (1.0 (0.3) BMI units) during each treatment. Bedtime restriction reduced sleep by 131 (30) min/day. Recurrent sleep curtailment decreased 24-h serum insulin concentrations (i.e., enhanced 24-h insulin economy) without changes in oral glucose tolerance and 24-h glucose control. This was accompanied by a decline in fasting blood glucose, increased fasting FFA, which suppressed normally following glucose ingestion, and lower total and low-density lipoprotein cholesterol concentrations. Sleep-loss-related changes in counter regulatory hormone secretion during the IVGTT limited the utility of the test in this study. In conclusion, sleep restriction enhanced 24-h insulin economy without compromising glucose homeostasis in overweight individuals placed on a balanced hypocaloric diet. The changes in fasting blood glucose, insulin, lipid and FFA concentrations in sleep-restricted dieters resembled the pattern of human metabolic adaptation to reduced carbohydrate availability. PMID- 22513494 TI - Sympathetic denervation of one white fat depot changes norepinephrine content and turnover in intact white and brown fat depots. AB - It is well-established that the sympathetic nervous system (SNS) regulates adipocyte metabolism and recently it has been reported that sensory afferents from white fat overlap anatomically with sympathetic efferents to white fat. The studies described here characterize the response of intact fat pads to selective sympathectomy (local 6-hydroxydopamine (6OHDA) injections) of inguinal (ING) or epididymal (EPI) fat in male NIH Swiss mice and provide in vivo evidence for communication between individual white and brown fat depots. The contralateral ING pad, both EPI pads, perirenal (PR), and mesenteric (MES) pads were significantly enlarged 4 weeks after denervating one ING pad, but only intrascapular brown adipose tissue (IBAT) increased when both ING pads were denervated. Denervation of one or both EPI pad had no effect on fat depot weights. In an additional experiment, norepinephrine turnover (NETO) was inhibited in ING, retroperitoneal (RP), MES, and IBAT 2 days after denervation of both EPI or of both ING pads. NE content was reduced to 10-30% of control values in all fat depots. There was no relation between early changes in NETO and fat pad weight 4 weeks after denervation, even though the reduction in NE content of intact fat pads was maintained. These data demonstrate that there is communication among individual fat pads, presumably through central integration of activity of sensory afferent and sympathetic efferent fibers, that changes sympathetic drive to white adipose tissue in a unified manner. In specific situations, removal of sympathetic efferents to one pad induces a compensatory enlargement of other intact depots. PMID- 22513495 TI - Predictors of attendance in a practical clinical trial of two pediatric weight management interventions. AB - The objective of this study was to evaluate demographic and psychosocial predictors of attendance in a family-based behavioral weight management clinical trial. Ninety-three children and adolescents aged 7-17 (Mean age = 11.59, s.d. = 2.6) who were either overweight or obese (Mean BMI percentile = 98.2) and their parents received either a 10-session behavioral treatment or a three-session brief family intervention in the context of a randomized clinical trial (10). Psychosocial and anthropometric measures were obtained before enrollment and at the end of 10 weeks for both treatment groups. Univariate linear regression and hierarchical multiple regression analyses were used to identify predictors of attendance to treatment from an a priori set of hypothesized predictors. Three variables demonstrated significant associations with the dependent variable, percent of treatment sessions attended. Specifically, distance from participant's home to treatment site, lower gross family income, and youth self-report of depressive symptoms were each associated with lower percent attendance (all Ps < 0.05). These results corroborate (i.e., income, depressive symptoms) and expand (i.e., distance from treatment site) previous reports in the literature of potential barriers to effective treatment for pediatric obesity, and suggest the need for research on treatment delivery methods that could increase participation among low-income families (e.g., eHealth, mHealth options). Depressive symptoms could represent an additional barrier to treatment attendance, suggesting that assessment and treatment for these symptoms may be appropriate before commencing weight management treatment. PMID- 22513497 TI - The presence of the mandibular incisive canal: a panoramic radiographic examination. AB - PURPOSE: The mandibular incisive canal (MIC) is the anterior extension of the mandibular canal and its presence is of interest in surgical procedures in the chin region. The aim of this study was to investigate the presence of a MIC in panoramic radiographs (OPGs). METHODS: One thousand forty-five OPGs were randomly chosen from patient population. The data collected included patient characteristics and MIC presence/absence according to the type of the dentition. Measurements (in mm) were performed evaluating the following: (A) minimum and (B) maximum distance from the alveolar ridge; (C) thickness and (D) length of the canal; and (E) distance (in bilateral cases) between the canals. RESULTS: The MIC was found in 2.7% of the patients. CONCLUSIONS: This study demonstrates the frequency of the MIC in OPGs and suggests that this anatomical structure should be considered to prevent injury during surgery. PMID- 22513498 TI - Alveolar bone stress around implants with different abutment angulation: an FE analysis of anterior maxilla. AB - OBJECTIVES: To comparatively assess the masticatory stress distribution in bone around implants placed in the anterior maxilla with three different labial inclinations. MATERIALS AND METHODS: Three-dimensional finite element models were fabricated for three situations in anterior maxilla: (1) a fixture in contact with buccal cortical plate restored by straight abutment, (2) a fixture inclined at 15 degrees, and (3) 20 degrees labially restored with corresponding angled abutment. A palatal bite force of 146 N was applied to a point 3 mm below the incisal edge. Stress distribution around the bone-fixture interface was determined using ANSYS software. RESULTS: The maximum compressive stress, concentrated in the labial crestal cortical bone, was measured to be 62, 108, and 122 MPa for 0-, 15-, and 20-degree labially inclined fixtures, respectively. The maximum tensile stress, concentrated in the palatal crestal cortical bone, was measured to be 60, 108, and 120 MPa for 0-, 15-, and 20-degree labially inclined fixtures, respectively. CONCLUSIONS: While all compressive stress values were under the cortical yield strength of 169 MPa, tensile stress values partially surpassed the yield strength (104 MPa) especially when a 20-degree inclination was followed for fixture placement. PMID- 22513499 TI - A comparative study between early occlusal loading at 1 and 6 weeks in implant retained mandibular overdentures. AB - PURPOSE: A clinical and a radiographic comparison of periimplant hard and soft tissue changes for the possible effects of early occlusal loading at 1 week versus 6 weeks. MATERIALS AND METHODS: Twelve edentulous patients were treated with two unsplinted implant-retained mandibular overdentures. The patients were randomly divided into two groups. In group I, implants were loaded 1 week after surgery, whereas in group II, implants were loaded 6 weeks after surgery. Clinical periimplant parameters and marginal bone height were recorded first day after loading then after 3, 6, 9, and 12 months. RESULTS: Clinical periimplant soft tissues parameters and marginal bone levels showed no statistically significant differences between the two groups during 12 months. CONCLUSION: Early loading after 1 and 6 weeks for two unsplinted implants retaining mandibular overdentures does not compromise periimplant soft tissue health and marginal bone levels. PMID- 22513500 TI - Biological complication in guided bone regeneration with a polylactic acid membrane: a case report. AB - PURPOSE: This case report describes a biologic complication related to polylactic acid membrane in guided bone regeneration (GBR). MATERIALS AND METHODS: A healthy 42-year-old patient complained of persistent discomfort of the maxillary anterior gingiva. Clinical examination and radiographs showed severe periodontal destruction of teeth 7 through 10. Teeth extraction was followed by early implant placement with GBR. RESULTS: Four months later, severe bone resorption was observed upon surgical exposure. A second GBR was performed. Wound healing progressed uneventfully and an implant-supported fixed partial denture was later loaded. CONCLUSION: We presume that this complication was a foreign body reaction to the polylactic acid membrane. Such a reaction can affect soft and hard tissue healing following GBR. Long-term follow-up is needed to determine stability of the results. PMID- 22513501 TI - Biomechanical rationale for six splinted implants in bilateral canine, premolar, and molar regions in an edentulous maxilla. AB - PURPOSE: To determine the influence of number and location of implants loaded on the stress to the bone in an edentulous maxilla using a three-dimensional finite element model (3D FEM). MATERIAL AND METHODS: Computed tomographic data with the bone density of a dry skull were used to construct a 3D FEM. Titanium implants were simulated in the configuration as 14 unsplinted implants (US14), 14 splinted implants (S14), 6 splinted implants (canine, premolar, and molar regions, S6), 4 splinted implants (S4), and 6 anterior implants (incisors and canines, A6). Distributed loads of 200 N were applied on the occlusal table of the superstructures. RESULTS: The S6 model was subjected to a similar amount of stress and deformation to the US14 and the S14. The S4 and A6 models were subjected to approximately three times of stress under the vertical load, and approximately five times of stress under the inclined load, respectively, compared with the S6 model. CONCLUSIONS: The 3D FEM analyses suggest that the six splinted implants configuration has a similar stress and deformation pattern as compared with naturally positioned splinted 14 implants in the edentulous maxilla. PMID- 22513502 TI - Analysis of the therapeutic effect of tadalafil on male ED after transurethral resection of prostate. AB - The objective of this study is to explore the therapeutic effect of Tadalafil on male ED after transurethral resection of prostate (TURP). Using the 5-item version of the International Index of Erectile Function (IIEF-5), ED was assessed in 104 male patients who experienced ED after TURP. These patients were assigned randomly into the therapy group and matched group on the basis of the degree of ED. The patients of the therapy group received Tadalafil, and the patients of matched group received placebo of starch. According to their actual conditions, all patients were informed of the action mechanism and administration of Tadalafil in detail, and advised to use the drug 1 h before sexual activity as recommended. The dose was increased from 10 to 20 mg by week 2 and 4, depending on the effects and adverse reactions. After 8 weeks, ED was re-assessed by IIEF 5. In therapy group, ED was cured in 28 cases, improved in 17 cases, and nonresponsive in 7 cases, with an overall effective rate of 86.5%. In matched group, ED was cured in 6 cases, improved in 7 cases, and non-responsive in 39 cases, with an overall effective rate of 25%. The statistical difference was significant (P<0.05). No significant adverse reaction was observed in any patient. In conclusion, Tadalafil is safe and effective, and can be used as the first-line medication for the clinical treatment of post-TURP ED. PMID- 22513503 TI - Early stages in the degradation of metal-organic frameworks in liquid water from first-principles molecular dynamics. AB - IRMOF-1 structures are known to suffer lattice break-up when exposed to water rich environments, a limiting factor in their everyday use. To shed light on the underlying mechanism of disruption, the role of the metal in the secondary building unit (SBU) has been systematically investigated, and the global behaviour of IRMOF-1-type structures with the three metals Zn, Mg, and Be studied by Born-Oppenheimer Molecular Dynamics in liquid water. Results show that fully hydrated Be based compounds are stable up to 500 K while the equivalent structures with Mg or Zn break down already at 300 K. The reasons behind this instability are in the tendency of the metal atom to form penta- and hexa coordination spheres and in the strength of the M-O bond. These are the key factors that generate unique breaking patterns for Mg and Zn IRMOF-1 analogues, as well as the reason for the high hydrothermal stability of the Be-IRMOF-1. PMID- 22513504 TI - Cutaneous Serratia marcescens infection in an immunocompetent patient after filler injection. PMID- 22513505 TI - Bone remodeling after total hip arthroplasty with a short stemmed metaphyseal loading implant: finite element analysis validated by a prospective DEXA investigation. AB - In total hip arthroplasty (THA), short stemmed cementless implants are used because they are thought to stimulate physiological bone remodeling and reduce stress shielding. We performed a numerical investigation on bone remodeling after implantation of a specific short stemmed implant using finite element analysis (FEA). Overall bone mass loss was 2.8% in the entire femur. Bone mass decrease was mostly found in the proximal part of the calcar and in the greater trochanter due to the vast cross section of the implant, probably leading to stress shielding. In the diaphysis, no change in the apparent bone density was proven. The assumptions made agreed well with bone remodeling data from THA recipients who underwent dual-energy X-ray absorptiometry. However, the clinical investigation revealed a bone mass increase in the minor trochanter region that was less pronounced in the FEA. Further comparisons to other stem designs must be done to verify if the relative advantages of the investigated implant can be accepted. PMID- 22513506 TI - Towards Alzheimer's root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction. Hypothetical role of the adapter protein ECSIT in familial and sporadic Alzheimer's disease pathogenesis. AB - Here we postulate that the adapter protein evolutionarily conserved signalling intermediate in Toll pathway (ECSIT) might act as a molecular sensor in the pathogenesis of Alzheimer's disease (AD). Based on the analysis of our AD associated protein interaction network, ECSIT emerges as an integrating signalling hub that ascertains cell homeostasis by the specific activation of protective molecular mechanisms in response to signals of amyloid-beta or oxidative damage. This converges into a complex cascade of patho-physiological processes. A failure to repair would generate severe mitochondrial damage and ultimately activate pro-apoptotic mechanisms, promoting synaptic dysfunction and neuronal death. Further support for our hypothesis is provided by increasing evidence of mitochondrial dysfunction in the disease etiology. Our model integrates seemingly controversial hypotheses for familial and sporadic forms of AD and envisions ECSIT as a biomarker to guide future therapies to halt or prevent AD. PMID- 22513507 TI - Perioperative considerations in patients with adrenal tumors. AB - In this article the pre-operative, intraoperative, and post-operative management of patients with pheochromocytoma, aldosterone-producing adenoma, cortisol producing tumors, and adrenal cortical carcinoma are reviewed. A detailed plan for pre-operative assessment and medical optimization is discussed. The potential intraoperative and post-operative complications that occur in patients with an adrenal tumor are reviewed with emphasis on recognition, treatment and prevention. Recommendations for anesthetic management, intraoperative and post operative monitoring, blood pressure management, laboratory analysis and medication adjustments are presented. PMID- 22513508 TI - Fabrication of uniform and high resolution copper nanowire using intermediate self-assembled monolayers through direct AFM lithography. AB - Electrochemical AFM lithography was used to directly fabricate copper nanowires. The copper ions were strongly reduced by a negative sample bias at the point where the AFM tip was localized, and copper metal wires were successfully fabricated following the direction of the electrical field of the bias. A TDA?HCl self-assembled monolayer (SAM) was found to play an important role as an intermediate layer for enhancing the capability of high resolution and complete development after the AFM lithographic process. The physical and electrical properties of the wires were analyzed by AFM, EFM, SEM, TEM and I-V measurement. The fabricated copper has promising potential for applications such as masks and interconnectors for nanoelectronic devices. PMID- 22513509 TI - Asystole in ultrabrief pulse electroconvulsive therapy. AB - OBJECTIVES: Ultrabrief (UB) pulse electroconvulsive therapy (ECT) has been gaining popularity in recent years because of its improved cognitive adverse effect profile compared with treatments triggered by brief pulses. When delivered at maximal charge, UB pulses are administered for 8 seconds. Because electrical stimulation triggers a parasympathetic surge and transient asystole, we checked whether UB pulses delivered for 8 seconds were associated with prolonged cardiac pause compared with maximal charge delivered for 4 seconds with brief pulses. METHODS: This is a retrospective study of cardiac pause length of all patients undergoing ECT treatment at The Johns Hopkins Hospital during 1 year. RESULTS: Electrocardiac pause length for patients undergoing ECT with right unilateral placement at maximal charge was not affected by pulse width. However, we did find cardiac pause length to be sensitive to 2- versus 4-second duration stimuli using brief pulses (P < 0.0001). CONCLUSIONS: Notwithstanding the clear limitations of small sample size and retrospective design, we found that right unilateral ECT was not affected by pulse width when maximal charge was delivered. PMID- 22513510 TI - Repetitive transcranial magnetic stimulation in depressed adolescents: experience, knowledge, and attitudes of recipients and their parents. AB - BACKGROUND: Comprehensive assessment of new treatments in psychiatry should include evaluation of their acceptability to patients, and in the case of children and adolescents, this must extend to acceptability for parents. The views of young patients and their parents in relation to repetitive transcranial magnetic stimulation (rTMS) for adolescent depression have not been previously studied. OBJECTIVE: We sought to (1) describe the experience, knowledge, and attitudes regarding rTMS among young people who had been treated with rTMS for depression as adolescents; (2) report the views of their parents; and (3) compare these to opinions about pharmacotherapy among a group who had been treated with fluoxetine for adolescent depression. METHODS: Eight of 9 subjects who had participated in an open-label rTMS study, 13 of their parents, and an age-matched group of 8 subjects who had been treated with fluoxetine for depression as adolescents were assessed using detailed questionnaires. RESULTS: Repetitive TMS recipients and their parents found rTMS largely acceptable in terms of adverse effects and treatment experience, but most considered it ineffective. In contrast, most patients who had been treated with fluoxetine viewed their treatment as effective. CONCLUSIONS: Transcranial magnetic stimulation is relatively well tolerated by depressed adolescents, but it is also perceived as mostly unhelpful by them and their parents. This is at odds with emerging studies suggesting that rTMS can be an effective and safe treatment in this age group, indicating that further research is required to confirm our findings and understand reasons for any disparity. PMID- 22513511 TI - Flumazenil pretreatment in benzodiazepine-free patients: a novel method for managing declining ECT seizure quality. AB - OBJECTIVE: Seizure threshold increases with successive electroconvulsive therapy (ECT) treatments, which can be especially problematic when treating older patients who have higher seizure thresholds at baseline because ECT devices are limited by the amount of charge that can be delivered. CASE REPORTS: We present a case series of 3 older patients who had long ECT courses that were complicated by inability to generate seizures, poor quality seizures, and inadequate clinical response despite established measures to lower seizure threshold including prehydration, hyperventilation, and minimizing methohexital dose using remifentanil. As preclinical studies show electroconvulsive seizure increases diazepam binding, we hypothesized that a contributor to declining seizure quality and inadequate ECT responsiveness in these individuals was enhanced benzodiazepine receptor function, although none of the 3 patients were taking benzodiazepines or any other anticonvulsant medication. Accordingly, we pretreated patients with flumazenil, a competitive inhibitor at the benzodiazepine-binding site, and observed improvement in seizure quality and clinical response. CONCLUSION: Flumazenil pretreatment of elderly ECT patients with declining seizure quality and inadequate clinical response in the setting of repeated treatments may represent a novel strategy for managing such patients. A clinical trial would be required to test this hypothesis. PMID- 22513512 TI - Is the use of electroconvulsive therapy falling because of fewer referrals of patients with severe depression? AB - BACKGROUND: The reasons for the fall in the use of electroconvulsive therapy (ECT) in the United Kingdom have never been systematically assessed. Between 2005 and 2006, the Edinburgh clinic saw the greatest fall ever in the rate of ECT usage between consecutive years. OBJECTIVE: To test the anecdotal hypothesis that this fall resulted from the referral of fewer patients with a diagnosis of severe depression (with or without psychotic symptoms) as per the International Classification of Diseases, 10th Revision. Diagnostic data from 2007 were included to aid comparison. RESULTS: The rates of ECT usage (number of individual patients treated per 10,000 total population) were 1.33, 0.82, and 0.88 in the study years. The numbers of patients with a diagnosis of severe depression of either type were identical in the study years. The fall in the rate of ECT usage resulted mainly from fewer referred patients with a diagnosis of other mood disorders, that is, disorders that did not meet criteria for more specific diagnoses such as depressive episode or bipolar affective disorder. CONCLUSIONS: Just as many severely depressed patients were treated despite the marked fall in the rate of ECT usage. PMID- 22513513 TI - Cognitive impairment in multiple sclerosis. AB - Cognitive impairment occurs in 40-65% of multiple sclerosis (MS) patients, typically involving complex attention, information processing speed, (episodic) memory and executive functions. It is seen in the subclinical radiologically isolated syndrome, clinically isolated syndrome, and all phases of clinical MS. In pediatric-onset MS cognition is frequently impaired and worsens relatively rapidly. Cognitive impairment often affects personal life and vocational status. Depression, anxiety and fatigue aggravate symptoms, whereas cognitive reserve partially protects. Cognitive dysfunction correlates to brain magnetic resonance imaging (MRI) lesion volumes and (regional) atrophy, and degree of and increase in MRI abnormalities predict further worsening. Experimental MRI indicates a crucial role for (focal) cortical lesions and atrophy, abnormal cortical integrity, and early changes in normal appearing brain tissue. Functional MRI suggests compensatory reorganization and adaptation changes in neural activities. Screening tools are the Brief Repeatable Neuropsychological Battery, Symbol Digit Modalities Test and Audio Recorded Cognitive Screen. The Minimal Assessment of Cognitive Function in Multiple Sclerosis (MS) is used for formal neuropsychological evaluation. What constitutes a clinically relevant change and how to optimally monitor cognition are issues to be settled. In relapsing remitting MS timely and adequate disease modifying drug treatment may stabilize or possibly improve cognition. There is no evidence-based symptomatic drug treatment, nor are there optimal non-pharmacological approaches. Leisure activities enhance cognitive reserve. Cognitive rehabilitation in MS patients is still in its infancy. Cognitive behavioral therapy, exercise, and education programs are promising psychosocial interventions to improve coping and lessen cognitive symptoms. PMID- 22513514 TI - Comparison of a 1.5T standard vs. 3T optimized protocols in multiple sclerosis patients. AB - AIM: Use of postcontrast T1-weighted imaging (WI) is an important tool in diagnosing and predicting the course of multiple sclerosis (MS). Application of optimized imaging strategies has the potential to increase detection of magnetic resonance imaging (MRI) disease activity. This study investigated the superiority of the 3T optimized vs. the 1.5T standardized protocols in detecting gadolinium enhancing (GD-E) lesions in patients with MS. METHODS: A standard protocol was defined as a 1.5T scan with a single-dose of Gd and a 5-minute scanning delay after injection. An optimized protocol was defined as a 3T MRI scan, using a triple dose of Gd, 20 min scan delay, and using an off-resonance saturated magnetization transfer pulse to reduce the background signal. Fourteen relapsing remitting MS patients and 3 healthy controls (HC) were scanned with 1.5T standardized and a 3T optimized protocols in random order over 72 hours. RESULTS: There were 47 Gd-E lesions in the MS patients on 3T optimized and 34 on 1.5T standard protocols, a 38.2% increase. There was a significant increase in Gd enhanced lesion volume (LV) detected with the optimized protocol (179.6%, P<0.05), with 94.6% of the mean Gd-enhanced LV detected only on the 3T optimized protocol. No Gd-E lesions were detected in HC on either protocol. CONCLUSION: The 3T optimized protocol is a useful technique for increasing sensitivity of MRI to detect Gd-E lesions. PMID- 22513515 TI - Incidence of hypercalcemia, hypercalciuria and related factors in patients treated with recombinant human parathyroid hormone (1-84). AB - AIM: The aim of this paper was to determine the incidence of hypercalcemia and hypercalciuria (and related factors) in 22 postmenopausal women with osteoporosis treated with PTH (1-84) in daily practice. METHODS: Osteoporosis was defined as history of osteoporotic fracture or a T score less than -3 SD on bone densitometry. Patients were treated with PTH (1-84), 100 mcg/daily, for 12 months. Clinical and laboratory data at baseline and after 6 months of treatment were assessed. RESULTS: The mean age was 71.9 years. The incidence of hypercalcemia and the hypercalciuria were 6 events. Increase in serum calcium levels showed a statistically significant correlation with 24-hour urinary calcium (rho [rho]=0.83, P<0.001), serum alkaline phosphatase (rho=0.76, P=0.001), total proteins (rho=0.77, P=0.005), and beta-CTx (rho=0.82, P=0.002). On the other hand, 24-hour urinary calcium excretion correlated significantly with beta-CTx (rho=0.83, P=0.002), alkaline phosphatase (rho=0.73, P=0.005), total proteins (rho=0.73, P=0.02), and serum phosphate (rho=0.58, P=0.04). When the group of patients with and without hypercalcemia were compared, there were statistically significant differences in increases of beta-CTx and baseline beta CTx values, whereas the group of patients with and without hypercalciuria showed significant differences in serum calcium increases and baseline values of T score at the femoral neck. CONCLUSION: The incidence of hypercalcemia and hypercalciuria after treatment with PTH (1-84) is similar to that expected according to the product's technical specifications. There was a significant correlation between increases of serum calcium, urinary calcium excretion, serum alkaline phosphatase, and beta-CTx after treatment with PTH (1-84). Baseline beta CTx values were significantly lower in patients who developed hypercalcemia than in those with normal serum calcium levels. PMID- 22513516 TI - Efficacy and safety of 10% HES 130/0.4 versus 10% HES 200/0.5 for plasma volume expansion in cardiac surgery patients. AB - AIM: Hydroxyethyl starch (HES) solutions are frequently used for perioperative volume replacement. Whereas older HES specimen tended to accumulate in the plasma and to cause negative effects on hemostasis, more recent products, e.g., HES 130/0.4, are characterised by improved pharmacological properties. The present study was designed to compare the efficacy and safety of 10% HES 130/0.4 and 10% HES 200/0.5. METHODS: In this post-hoc analysis of a prospective, randomised, double-blind, multi-center therapeutic equivalence trial, 76 patients undergoing elective on-pump cardiac surgery received perioperative volume replacement using either 10% HES 130/0.4 (N.=37) or 10% HES 200/0.5 (N.=39) up to a maximum dose of 20 mL kg-1. RESULTS: Equivalent volumes of investigational medication were infused until 24 hours after the first administration (1577 vs. 1540 mL; treatment difference 37 [-150; 223] mL; P<0.0001 for equivalence). Whereas standard laboratory tests of coagulation were comparable between groups, von Willebrand factor activity on the first postoperative morning tended to be higher following treatment with 10% HES 130/0.4 as compared to 10% HES 200/0.5 (P=0.025) with this difference being statistically significant only in the per-protocol analysis (P=0.02). Treatment groups were comparable concerning other safety parameters and the incidence of adverse drug reactions. In particular, renal function was well preserved in both groups. CONCLUSION: Ten percent HES 130/0.4 was equally effective and safe as compared to 10% HES 200/0.5 for volume therapy in patients undergoing cardiovascular surgery. Postoperative coagulation and renal function, as measured by standard laboratory tests, were similar among groups. PMID- 22513517 TI - [From iron accumulation to organ damage]. AB - Iron is an important metal in the complex biochemistry in human beings. However there are primary or secondary diseases that lead to an accumulation of iron in parenchymal organs and induce progressive and serious systemic harm. This review aims to define the fundamental steps of cell biology and physiology of iron and the pathophysiological mechanisms responsible for its accumulation in the parenchyma. In addition, we analyze the main primitive (hemochromatosis) and secondary (inflammation, liver diseases and hematological) diseases, responsible for the damage caused by iron, and we analyze the clinical consequences of iron overload. Furthermore, we pass under review a particular classification of general mechanisms and kinetics of iron overload responsible for its clinical phenotypes, dividing them into systemic, cellular and subcellular overload mechanisms. Finally we describe the main pathologic stages resulting from iron overload, with particular reference to liver damage and progression to hepatocellular carcinoma. PMID- 22513518 TI - Echocardiography might not be able to detect left ventricular hypertrophy in all dialysis patients. PMID- 22513519 TI - Highly dispersed encapsulated AuPd nanoparticles on ordered mesoporous carbons for the direct synthesis of H2O2 from molecular oxygen and hydrogen. AB - AuPd nanoparticles (<3 nm) have been encapsulated on the pores of a nanostructured CMK-3 carbon prepared by a nanocasting procedure. This material has been shown to be an excellent catalyst for the direct synthesis of hydrogen peroxide from molecular hydrogen and oxygen. PMID- 22513520 TI - No association between chronic cerebrospinal venous insufficiency and pediatric onset multiple sclerosis. AB - OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI) was hypothesized to play a causative role in multiple sclerosis (MS). The assessment of pediatric onset MS (POMS) may provide a unique window of opportunity to study hypothesized risk factors in close temporal association with the onset of the disease. METHODS: Internal jugular veins, vertebral veins and intracranial veins were evaluated with extracranial and intracranial ultrasound in 15 POMS and 16 healthy controls. Assessor's blinding was maintained during the study. We considered subjects positive to CCSVI when at least two criteria were fulfilled. RESULTS: CCSVI frequency was comparable between POMS and controls (p > 0.05). Clinical features were not significantly different between CCSVI-positive and CCSVI negative patients. CONCLUSIONS: Our findings add to previous data pointing against a causative role of CCSVI in MS. PMID- 22513521 TI - Oligoclonal band and multiple sclerosis risk in monosymptomatic optic neuritis patients: a retrospective study of 84 patients. PMID- 22513522 TI - 'Obstructive sleep apnea is associated with fatigue in multiple sclerosis' by Kaminska et al. PMID- 22513523 TI - Does state budget pressure matter for uncompensated care spending in hospitals? Findings from Texas and California. AB - OBJECTIVE: This study examined the impact of state budget cuts on uncompensated care at general acute care hospital organizations. This study capitalized on the variations in the states of Texas and California to form a natural experiment testing the joint impact of budget cut status on uncompensated care costs, as well as specific charity care costs and bad debt expenses from indigent patients. METHODOLOGY: Budget cuts in the state of Texas occurred in the year 2004. Information was obtained from the Texas Department of Health and the California Department of Health Services regarding financial characteristics of hospitals and from the American Hospital Directory annual survey regarding organizational characteristics of hospitals. We created three dependent variables: R(UC) (the ratio of total uncompensated care costs to gross patient revenue), R(CC) (the ratio of charity care to total patient revenue) and R(BD) (the ratio of bad debt expenses to gross patient revenue). Using a two-period panel data set and individual hospital fixed effects, we captured hospital uncompensated care spending that could also have influenced budget cut status. Additionally, the impact of the state budget cut status on hospitals' uncompensated care spending, charity care spending and bad debt expenses was also estimated using the similar methodology. POPULATION STUDIED: In this study, we included 416 (in Texas) and 352 (in California) public, not-for-profit (NFP) and for-profit (FP) hospitals that completed the annual survey during the study period 2002-2005. FINDINGS: For the state of Texas, results from the fixed effect model confirmed that the year 2005 was directly related to increased R(UC) and R(CC) . The coefficients of 2005 were significantly and positively associated with R(UC) (0.43, p < 0.05) and R(CC) (0.29, p < 0.05). These results supported the findings that the R(UC) and the R(CC) would be more positively associated with 2005 than any other year, with other things being equal. However, for the state of California, even though the coefficient of 2005 was significant and positively associated with R(CC) (0.31, p < 0.05), the coefficient of uncompensated care spending was not statistically significant for 2005. CONCLUSION: The healthcare industry is characterized by increased regulation, a growing number of uninsured patients, increasingly stringent reimbursement and competitive practices among hospitals and other providers. Federal and state healthcare agencies are restricting the criteria for eligibility for outlier payments and uncompensated care provisions. Tax exempt status of many NFP hospitals is being examined and tied to specific performances, particularly the provision of uncompensated care. This study provides evidence of the impact of budget cut pressure on uncompensated care provided in Texas general acute care hospitals. PMID- 22513524 TI - Opioid modulation of facial itch- and pain-related responses and grooming behavior in rats. AB - Intradermal facial injections of pruritogens or algogens elicit distinct behavioral hindlimb scratch or forelimb wiping responses in rodents. We systematically investigated the parameters and opioid modulation of these evoked behaviors and spontaneous facial grooming in rats. Serotonin (5-HT) elicited hindlimb scratch bouts with few wipes. Scratching was attenuated by the u-opiate antagonist naltrexone but not morphine. In contrast, cheek injection of mustard oil (allyl-isothiocyanate (AITC)) elicited ipsilateral forelimb wipes but little hindlimb scratching. AITC-evoked wiping was significantly attenuated by morphine but not naltrexone. Spontaneous facial grooming by the forepaws was attenuated by naltrexone, whereas morphine did not affect grooming behavior before or after cheek injections of 5-HT or AITC. These data validate that the rodent "cheek" model discriminates between itch- and pain-related behaviors. Naltrexone sensitivity of facial grooming and 5-HT-evoked scratch-ing suggests a common functionality. Forelimb wipes may represent a nocifensive response akin to rubbing an injury to relieve pain. PMID- 22513525 TI - Scaling parallel dielectrophoresis of carbon nanotubes: an enabling geometry. AB - Dielectrophoresis has been used as a technique for the parallel localization and alignment of both semiconducting and metallic carbon nanotubes (CNTs) at junctions between electrodes. A variation of this technique known as floating potential dielectrophoresis (FPD) allows for a self-limiting number of CNTs to be localized at each junction, on a massively parallel scale. However, the smallest FPD geometries to date are restricted to conductive substrates and have a lower limit on floating electrode size. We present a geometry which eliminates this lower limit and enables FPD to be performed on non-conducting substrates. We also discuss experiments clarifying the self-limiting mechanism of CNT localization and how it can be used advantageously as devices are scaled downwards to smaller sizes. PMID- 22513526 TI - Measles - United States, 2011. AB - In 2000, the United States achieved measles elimination (defined as interruption of year-round endemic measles transmission). However, importations of measles into the United States continue to occur, posing risks for measles outbreaks and sustained measles transmission. During 2011, a total of 222 measles cases (incidence rate: 0.7 per 1 million population) and 17 measles outbreaks (defined as three or more cases linked in time or place) were reported to CDC, compared with a median of 60 (range: 37-140) cases and four (range: 2-10) outbreaks reported annually during 2001-2010. This report updates an earlier report on measles in the United States during the first 5 months of 2011. Of the 222 cases, 112 (50%) were associated with 17 outbreaks, and 200 (90%) were associated with importations from other countries, including 52 (26%) cases in U.S. residents returning from abroad and 20 (10%) cases in foreign visitors. Other cases associated with importations included 67 (34%) linked epidemiologically to importations, 39 (20%) with virologic evidence suggesting recent importation, and 22 (11%) linked to cases with virologic evidence of recent importation. Most patients (86%) were unvaccinated or had unknown vaccination status. The increased numbers of outbreaks and measles importations into the United States underscore the ongoing risk for measles among unvaccinated persons and the importance of vaccination against measles. PMID- 22513527 TI - Human papillomavirus-associated cancers - United States, 2004-2008. AB - Oncogenic human papillomavirus (HPV) has a causal role in nearly all cervical cancers and in many vulvar, vaginal, penile, anal, and oropharyngeal cancers. Most HPV infections clear within 1-2 years, but those that persist can progress to precancer or cancer. In the United States, public health prevention of cervical cancer includes both secondary prevention through cervical cancer screening and primary prevention through HPV vaccination. Transmission of HPV also can be reduced through condom use and limiting the number of sexual partners. Two vaccines (bivalent and quadrivalent) are available to protect against HPV types 16 and 18, which are responsible for 70% of cervical cancers. HPV 16 also is the most common HPV type found in the other five cancers often associated with HPV. To assess the incidence of HPV-associated cancers (i.e., cancers at specific anatomic sites and with specific cell types in which HPV DNA frequently is found), CDC analyzed 2004-2008 data from the National Program of Cancer Registries (NPCR) and the Surveillance, Epidemiology, and End Results (SEER) program. During 2004-2008, an average of 33,369 HPV-associated cancers were diagnosed annually (rate: 10.8 per 100,000 population), including 12,080 among males (8.1 per 100,000) and 21,290 among females (13.2). Multiplying the counts for HPV-associated cancers by percentages attributable to HPV, CDC estimated that approximately 26,000 new cancers attributable to HPV occurred each year, including 18,000 among females and 8,000 among males. Population-based cancer registries are important surveillance tools to measure the impact on cancer rates of public health interventions such as vaccination and screening. PMID- 22513528 TI - Pseudomonas aeruginosa respiratory tract infections associated with contaminated ultrasound gel used for transesophageal echocardiography - Michigan, December 2011-January 2012. AB - In late December 2011, the Department of Epidemiology at Beaumont Health System (BHS) in Royal Oak, Michigan, noted an increase in the number of positive respiratory cultures in one surgical intensive-care unit (ICU), prompting further investigation. The increase in positive cultures was attributed entirely to Pseudomonas aeruginosa. Investigation by BHS staff members found that all of these positive cultures were related to use of ultrasound transmission gel from a single manufacturer during transesophageal echocardiography. Seven patients were infected with P. aeruginosa based on National Healthcare Safety Network (NHSN) criteria, and nine were colonized. Cultures from one open and one unopened bottle of the gel grew P. aeruginosa closely related to the outbreak strain based on molecular typing via repetitive extragenic palindromic polymerase chain reaction (rep-PCR). The Oakland County Health Department, the Michigan Department of Community Health, and the Food and Drug Administration (FDA) were notified of the findings. On January 23, all implicated ultrasound gel in multiuse bottles was removed from BHS facilities and replaced with a single-use, sterile ultrasound gel for all potentially invasive procedures. On April 18, FDA issued a Safety Communication* advising health-care professionals and facilities not to use certain lot numbers of the ultrasound transmission gel and further advising that the only ultrasound gel that is sterile is unopened gel in containers labeled as sterile. To date, no further respiratory cultures have been positive for P. aeruginosa. PMID- 22513529 TI - Tracking progress toward global polio eradication, 2010-2011. AB - In January 2012, polio eradication was declared a "programmatic emergency for global public health" by the Executive Board of the World Health Organization (WHO). Since the Global Polio Eradication Initiative (GPEI) began in 1988, progress has been tracked by surveillance of acute flaccid paralysis (AFP) cases and testing of linked stool specimens for polioviruses (PVs) in WHO-accredited Global Polio Laboratory Network (GPLN) laboratories, complemented by sewage testing (environmental surveillance) in selected areas. Monitoring AFP surveillance quality at national and subnational administrative levels using standard performance indicators identifies potential gaps where PV circulation might go undetected; monitoring specimen transport and laboratory reporting timeliness identifies areas where reporting delays could lead to late response, permitting ongoing transmission. This report provides an assessment of 2010-2011 performance indicators for AFP surveillance at national and subnational levels in polio-affected countries and laboratory reporting at the regional level, updated from 2009-2010. Overall, 16 (62%) of 26 countries with circulating wild PV (WPV) met national AFP surveillance indicator targets during both 2010 and 2011. All three countries with reestablished WPV transmission and 16 of 19 countries with WPV outbreaks had substantial proportions (>20%) of their respective populations living in areas with underperforming surveillance during 2010 or 2011. Targets for timely reporting of PV isolation and type characterization results were met in three of six WHO regions in 2010 and five regions in 2011. To achieve polio eradication, efforts are needed to improve AFP surveillance and laboratory performance. PMID- 22513530 TI - Vital signs: Unintentional injury deaths among persons aged 0-19 years - United States, 2000-2009. AB - BACKGROUND: Unintentional injuries are the leading cause of death in the United States for persons aged 1-19 years and the fifth leading cause of death for newborns and infants aged <1 year. This report describes 10-year trends in unintentional injury deaths among persons aged 0-19 years. METHODS: CDC analyzed 2000-2009 mortality data from the National Vital Statistics System by age group, sex, race/ethnicity, injury mechanism, and state. RESULTS: From 2000 to 2009, the overall annual unintentional injury death rate decreased 29%, from 15.5 to 11.0 per 100,000 population, accounting for 9,143 deaths in 2009. The rate decreased among all age groups except newborns and infants aged <1 year; in this age group, rates increased from 23.1 to 27.7 per 100,000 primarily as a result of an increase in reported suffocations. The poisoning death rate among teens aged 15 19 years nearly doubled, from 1.7 to 3.3 per 100,000, in part because of an increase in prescription drug overdoses (e.g., opioid pain relievers). Childhood motor vehicle traffic-related death rates declined 41%; however, these deaths remain the leading cause of unintentional injury death. Among states, unintentional injury death rates varied widely, from 4.0 to 25.1 per 100,000 in 2009. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Although the annual rate is declining, unintentional injury remains the leading cause of death among children and adolescents in the United States, led by motor vehicle traffic related deaths. Death rates from infant suffocation and teen poisoning are increasing. The 2012 National Action Plan for Child Injury Prevention provides actions in surveillance, research, communication, education, health care, and public policy to guide efforts in saving lives by reducing injuries. PMID- 22513531 TI - Notes from the field: Infections with Salmonella I 4,[5],12:i:- linked to exposure to feeder rodents - United States, August 2011-February 2012. AB - CDC is collaborating with 22 state health departments in an ongoing investigation of an outbreak of human Salmonella I 4,[5],12:i:- infections associated with exposure to rodents sold as food for pet reptiles and amphibians (i.e., feeder rodents). This outbreak strain also was implicated in a 2009 outbreak in the United Kingdom and a 2010 outbreak in the United States, both linked to frozen feeder rodents from a single U.S. supplier, resulting in recalls. PMID- 22513533 TI - Marine microalgae attack and feed on metazoans. AB - Free-living microalgae from the dinoflagellate genus Karlodinium are known to form massive blooms in eutrophic coastal waters worldwide and are often associated with fish kills. Natural bloom populations, recently shown to consist of the two mixotrophic and toxic species Karlodinium armiger and Karlodinium veneficum have caused fast paralysis and mortality of finfish and copepods in the laboratory, and have been associated with reduced metazooplankton biomass in situ. Here we show that a strain of K. armiger (K-0688) immobilises the common marine copepod Acartia tonsa in a density-dependent manner and collectively ingests the grazer to promote its own growth rate. In contrast, four strains of K. veneficum did not attack or affect the motility and survival of the copepods. Copepod immobilisation by the K. armiger strain was fast (within 15 min) and caused by attacks of swarming cells, likely through the transfer and action of a highly potent but uncharacterised neurotoxin. The copepods grazed and reproduced on a diet of K. armiger at densities below 1000, cells ml(-1), but above 3500 cells ml(-1) the mixotrophic dinoflagellates immobilised, fed on and killed the copepods. Switching the trophic role of the microalgae from prey to predator of copepods couples population growth to reduced grazing pressure, promoting the persistence of blooms at high densities. K. armiger also fed on three other metazoan organisms offered, suggesting that active predation by mixotrophic dinoflagellates may be directly involved in causing mortalities at several trophic levels in the marine food web. PMID- 22513534 TI - True time delays using conversion/dispersion with flat magnitude response for wideband analog RF signals. AB - We demonstrate optical true time delays using wavelength conversion coupled with chromatic dispersion. The transfer function of the delay system is investigated, and it is shown that 3-dB bandwidth of the system can be increased over 40 GHz by using offset pumps. A flat magnitude response (<1 dB peak-peak, 0.2 dB RMS deviation) is achieved in the 1-30 GHz band. Calculated matched filter output to LFM pulses shows good performance, maintaining a > 30 dB peak-to-sidelobe-ratio. The effect of pump depletion during wavelength conversion is also investigated. PMID- 22513535 TI - Dependences of photoluminescence from P-implanted epitaxial Ge. AB - A systematic investigation has been carried out to study the influence of various annealings and implantations on the photoluminescence (PL) properties of phosphorus (P)-implanted Ge epitaxial films on Si substrate. For un-capped Ge samples, rapid thermal annealing (RTA) at 700 degrees C for 300 seconds yields the strongest PL emission peaked at 1550 nm. The influence of employing various capping layers (i.e., SiO(2), Si(3)N(4), and alpha-Si ) on the PL properties has been investigated. The capping layers are found to effectively decrease the dopant loss, leading to a significant PL enhancement. Si(3)N(4) is found to be the most efficient capping layer to prevent dopant out-diffusion and thus lead to strongest PL. Furthermore, it has been found that capping layers not only enhance the PL intensities but also make PL emission peak red- and blue- shift, depending on the stress type of the capping films. The effect of implantation dose on the PL has been also investigated. PMID- 22513536 TI - Distributed flow sensing using optical hot -wire grid. AB - An optical hot-wire flow sensing grid is presented using a single piece of self heated optical fiber to perform distributed flow measurement. The flow-induced temperature loss profiles along the fiber are interrogated by the in-fiber Rayleigh backscattering, and spatially resolved in millimeter resolution using optical frequency domain reflectometry (OFDR). The flow rate, position, and flow direction are retrieved simultaneously. Both electrical and optical on-fiber heating were demonstrated to suit different flow sensing applications. PMID- 22513537 TI - Redundancy in Cantor diffractals. AB - Cantor diffractals are waves that have encountered a Cantor grating. In this paper, we report an important property of Cantor diffractals, namely that of redundancy. We observe that the Fraunhofer diffraction pattern comprises of several bands, each containing complete information about the fractal aperture. This redundancy allows for a faithful reconstruction of the Cantor grating by an inverse Fourier transformation of an arbitrary band. PMID- 22513538 TI - Analytical calculation of nonreciprocal phase shifts and comparison analysis of enhanced magneto-optical waveguides on SOI platform. AB - Transfer matrices for one-dimensional (1-D) multi-layered magneto-optical (MO) waveguides are formulated to analytically calculate the nonreciprocal phase shifts (NRPS). The Cauchy contour integration (CCI) method is introduced in detail to calculate the two complex roots of the transcendental equation corresponding to backward and forward waves. By virtue of perturbation theory and the variational principle, we also present the general upper limit of NRPSs in 1 D MO waveguides. These analytical results are applied to compare silicon-on insulator (SOI) based MO waveguides. First, a three-layered waveguide system with MO medium is briefly examined and discussed to check the validity and efficiency of the above theory. Then we revisited the reported low-index-gap-enhanced NRPSs in MO waveguides and obtained substantially different results. Finally, the potential of common plasmonic waveguides to enhance the nonreciprocal effect is investigated by studying different waveguides composed of Metal, MO medium and dielectrics. Our study shows that the reasonable NRPSs can be optimized to some extent but not as much as claimed in previous publications. PMID- 22513539 TI - Computation time-saving mirror image suppression method in Fourier-domain optical coherence tomography. AB - The theory and experimental results of a computation time-saving mirror image suppression method in Fourier-domain optical coherence tomography, which utilizes the property of reversed system phase shift between the real and mirror images, for differentiating one from the other are demonstrated. By solving a set of two equations based on a reasonable approximation, the real image signal can be obtained. The theoretical backgrounds and the improved real image quality of the average and iteration procedures in this method are particularly illustrated. Also, the mirror image suppression ratios under various process conditions, including different process iteration numbers and different system phase shifts between two neighboring A-mode scans, are evaluated. Meanwhile, the mirror image suppression results based on our method are compared with those obtained from the widely used BM-scan technique. It is found that when a process procedure of two iterations is used, the mirror image suppression quality based on our method can be higher than that obtained from the BM-scan technique. The computation time of our method is significantly shorter than that of the BM-scan technique. PMID- 22513540 TI - Ultimate resolution for refractometric sensing with whispering gallery mode microcavities. AB - Many proposed microfluidic biosensor designs are based on the measurement of the resonances of an optical microcavity. Fluorescence-based resonators tend to be simpler and more robust than setups that use evanescent coupling from tuneable laser to probe the cavity. In all sensor designs the detection limits depend on the wavelength resolution of the detection system, which is a limitation of fluorescence-based devices. In this work, we explore the ultimate resolution and detection limits of refractometric microcavity sensor structures. Because many periodic modes are collected simultaneously from fluorescent resonators, standard Fourier methods can be best suited for rapid and precise analysis of the resonance shifts. Simple numerical expressions to calculate the ultimate sensor resolution and detection limits were found, and the results compared to experiments in which the resonances of fluorescent-core microcapillaries responded to various sucrose concentrations in water. PMID- 22513541 TI - Experimental compressive phase space tomography. AB - Phase space tomography estimates correlation functions entirely from snapshots in the evolution of the wave function along a time or space variable. In contrast, traditional interferometric methods require measurement of multiple two-point correlations. However, as in every tomographic formulation, undersampling poses a severe limitation. Here we present the first, to our knowledge, experimental demonstration of compressive reconstruction of the classical optical correlation function, i.e. the mutual intensity function. Our compressive algorithm makes explicit use of the physically justifiable assumption of a low-entropy source (or state.) Since the source was directly accessible in our classical experiment, we were able to compare the compressive estimate of the mutual intensity to an independent ground-truth estimate from the van Cittert-Zernike theorem and verify substantial quantitative improvements in the reconstruction. PMID- 22513542 TI - Resonant transmission of self-collimated beams through coupled zigzag-box resonators: slow self-collimated beams in a photonic crystal. AB - The resonant transmission of self-collimated beams through zigzag-box resonators is demonstrated experimentally and numerically. Numerical simulations show that the flat-wavefront and the width of the beam are well maintained after passing through zigzag-box resonators because the up and the down zigzag-sides prevent the beam from spreading out and the wavefront is perfectly reconstructed by the output zigzag-side of the resonator. Measured split resonant frequencies of two- and three-coupled zigzag-box resonators are well agreed with those predicted by a tight binding model to consider optical coupling between the nearest resonators. Slowing down the speed of self-collimated beams is also demonstrated by using a twelve-coupled zigzag-box resonator in simulations. Our work could be useful in implementing devices to manipulate self-collimated beams in time domain. PMID- 22513543 TI - Probing the dynamics of an optically trapped particle by phase sensitive back focal plane interferometry. AB - The dynamics of an optically trapped particle are often determined by measuring intensity shifts of the back-scattered light from the particle using position sensitive detectors. We present a technique which measures the phase of the back scattered light using balanced detection in an external Mach-Zehnder interferometer scheme where we separate out and beat the scattered light from the particle and that from the top surface of our trapping chamber. The technique has improved axial motion resolution over intensity-based detection, and can also be used to measure lateral motion of the trapped particle. In addition, we are able to track the Brownian motion of trapped 1.1 and 3 MUm diameter particles from the phase jitter and show that, similar to intensity-based measurements, phase measurements can also be used to simultaneously determine displacements of the trapped particle as well as the spring constant of the trap. For lateral displacements, we have matched our experimental results with a simulation of the overall phase contour of the back-scattered light by using plane wave decomposition in conjunction with Mie scattering theory. The position resolution is limited by path drifts of the interferometer which we have presently reduced to demonstrate the capability of sub-nm displacement resolution in the axial direction for 1.1 MUm diameter particles by locking the interferometer to a frequency stabilized diode laser. PMID- 22513544 TI - Impact of upconverted scattered light on advanced interferometric gravitational wave detectors. AB - Second generation gravitational wave detectors are being installed in a number of locations globally. These long-baseline, Michelson interferometers increase the sensitivity between 10 and 40 Hz by many orders of magnitude compared with first generation instruments. Control of non-linear noise coupling from scattered light fields is critical to achieve low frequency performance. In this paper we investigate the requirements on the attenuation of scattered light using a novel time-domain analysis and two years of seismic data from the LIGO Livingston Observatory. PMID- 22513545 TI - The effect of propagation in air on the filament spectrum. AB - Filamentation studies traditionally start from letting a beam focus in air. We present filament studies with control over the preparation propagation, in air or vacuum, using an aerodynamic window. The spectral content of the filament strongly depends on its preparation medium. PMID- 22513546 TI - Terahertz field enhancement to the MV/cm regime in a tapered parallel plate waveguide. AB - We investigate field enhancement properties of a tapered parallel plate waveguide for ultrashort terahertz (THz) pulses. We use two independent methods, air biased coherent detection inside the waveguide and free-space electro-optic sampling, respectively, which enables a calibrated, quantitative measurement of the field strength at the output of the waveguide. Field enhancement factors greater than 20 are demonstrated and record-high field strengths of > 1.4 MV/cm are reached. We find an excellent agreement between the two independent methods of field measurement and a numerical 3D full-vectorial time-domain simulations. PMID- 22513547 TI - Comparison of 128-SP-QAM with PM-16-QAM. AB - In this paper we investigate an interesting modulation format for fiber optic communications, set-partitioning 128 polarization-multiplexed 16-QAM (128-SP QAM), which consists of the symbols with even parity from the symbol alphabet of polarization-multiplexed 16-QAM (PM-16-QAM). We compare 128-SP-QAM and PM-16-QAM using numerical simulations in long-haul transmission scenarios at bit rates of 112 Gbit/s and 224 Gbit/s, and at the same symbol rates (14 and 28 Gbaud). The transmission link is made up of standard single-mode fiber with 60, 80 or 100 km amplifier spacing and both single channel and WDM transmission (25- and 50 GHz spaced) is investigated. The results show that 128-SP-QAM achieves more than 40% increase in transmission reach compared to PM-16-QAM at the same data rate for all cases studied for a bit error rate of 10-3. In addition, we find that in single channel transmission there is, as expected, an advantage in terms of transmission distance when using a data rate of 112 Gbit/s as compared to 224 Gbit/s. However, when comparing the two different WDM systems with the same aggregate data rates, the reach is similar due to the smaller impact of nonlinear crosstalk between the WDM channels in the systems with 50 GHz spacing. We also discuss decoding and phase estimation of 128-SP-QAM and implement differential coding, which avoids error bursts due to cycle slips in the phase estimation. Simulations including laser phase noise show that the phase noise tolerance is similar for the two formats, with 0.5 dB OSNR penalty compared to the case with zero phase noise for a laser linewidth to symbol rate ratio of 10-4. PMID- 22513548 TI - Quantum frequency translation by four-wave mixing in a fiber: low-conversion regime. AB - In this paper we consider frequency translation enabled by Bragg scattering, a four-wave mixing process. First we introduce the theoretical background of the Green function formalism and the Schmidt decomposition. Next the Green functions for the low-conversion regime are derived perturbatively in the frequency domain, using the methods developed for three-wave mixing, then transformed to the time domain. These results are also derived and verified using an alternative time domain method, the results of which are more general. For the first time we include the effects of convecting pumps, a more realistic assumption, and show that separability and arbitrary reshaping is possible. This is confirmed numerically for Gaussian pumps as well as higher-order Hermite-Gaussian pumps. PMID- 22513549 TI - A family of Nyquist pulses for coherent optical communications. AB - A new family of Nyquist pulses for coherent optical single carrier systems is introduced and is shown to increase the nonlinearity tolerance of dual polarization (DP)-QPSK and DP-16-QAM systems. Numerical investigations for a single-channel 28 Gbaud DP-16-QAM long-haul system without optical dispersion compensation indicate that the proposed pulse can increase the reach distance by 26% and 19%, for roll-off factors of 1 and 2, respectively. In multi-channel transmissions and for a roll-off factor of 1, a reach distance increase of 20% is reported. Experimental results for DP-QPSK and DP-16-QAM systems at 10 Gbaud confirm the superior nonlinearity tolerance of the proposed pulse. PMID- 22513550 TI - Propagation of partially coherent annular beams with decentered field in turbulence along a slant path. AB - The model of partially coherent annular beams with linear non-uniformity field profile in the x direction is set up. The analytic expressions for the average intensity and the centre of gravity of partially coherent annular beams with decentered field propagating through atmospheric turbulence along a slant path are derived. The propagation equation governing the position of the intensity maximum is also given. It is found that the beam non-uniformity is amended gradually as the propagation distance and the strength of turbulence increase. The centre of beam gravity is independent of both the propagation distance and the turbulence. However, the position of the intensity maximum changes versus the propagation distance and the turbulence, and is farthest away from the propagation z-axis at a certain propagation distance. When the propagation distance is large enough, the position of the intensity maximum reaches an asymptotic value which increases with decreasing the zenith angle and is largest for the free space case. When the propagation distance is large enough, the position of the intensity maximum is not on the propagation z-axis, and is nearer to the propagation z-axis than the centre of beam gravity. On the other hand, changes in the intensity maximum in the far field are also examined in this paper. PMID- 22513551 TI - Flicker minimization in an LCoS Spatial Light Modulator. AB - We present a method for reducing the phase flicker originated by the pulsed modulation of a Liquid Crystal on Silicon (LCoS) Spatial Light Modulator (SLM). It consists in reducing the temperature of the LCoS in a controlled way, in order to increase the viscosity of the liquid crystal. By doing this, we increase the time response of the liquid crystal, and thus reduce the amplitude of phase fluctuations. We evaluate the efficacy of this method quantifying the temporal evolution of phase shift using an experiment that is insensitive to optical polarization fluctuations. Additionally, we determine the effect of the temperature reduction on the effective phase modulation capability of the LCoS. We demonstrate that a reduction of up to 80% of the flicker initial value can be achieved when the LCoS is brought to -8 degrees C. PMID- 22513552 TI - High-speed indoor optical wireless communication system with single channel imaging receiver. AB - In this paper we experimentally investigate a gigabit indoor optical wireless communication system with single channel imaging receiver. It is shown that the use of single channel imaging receiver rejects most of the background light. This single channel imaging receiver is composed of an imaging lens and a small photo sensitive area photodiode attached on a 2-axis actuator. The actuator and photodiode are placed on the focal plane of the lens to search for the focused light spot. The actuator is voice-coil based and it is low cost and commercially available. With this single channel imaging receiver, bit rate as high as 12.5 Gbps has been successfully demonstrated and the maximum error-free (BER<10-9) beam footprint is even larger than 1 m. Compared with our previous experimental results with a single wide field-of-view non-imaging receiver, an improvement in error-free beam footprint of >20% has been achieved. When this system is integrated with our recently proposed optical wireless based indoor localization system, both high speed wireless communication and mobility can be provided to users over the entire room. Furthermore, theoretical analysis has been carried out and the simulation results agree well with the experiments. In addition, since the rough location information of the user is available in our proposed system, instead of searching for the focused light spot over a large area on the focal plane of the lens, only a small possible area needs to be scanned. By further pre-setting a proper comparison threshold when searching for the focused light spot, the time needed for searching can be further reduced. PMID- 22513553 TI - Radiation hardening techniques for Er/Yb doped optical fibers and amplifiers for space application. AB - We investigated the efficiencies of two different approaches to increase the radiation hardness of optical amplifiers through development of improved rare earth (RE) doped optical fibers. We demonstrated the efficiency of codoping with Cerium the core of Erbium/Ytterbium doped optical fibers to improve their radiation tolerance. We compared the gamma-rays induced degradation of two amplifiers with comparable pre-irradiation characteristics (~19 dB gain for an input power of ~10 dBm): first one is made with the standard core composition whereas the second one is Ce codoped. The radiation tolerance of the Ce-codoped fiber based amplifier is strongly enhanced. Its output gain decrease is limited to ~1.5 dB after a dose of ~900 Gy, independently of the pump power used, which authorizes the use of such fiber-based systems for challenging space missions associated with high total doses. We also showed that the responses of the two amplifiers with or without Ce-codoping can be further improved by another technique: the pre-loading of these fibers with hydrogen. In this case, the gain degradation is limited to 0.4 dB for the amplifier designed with the standard composition fiber whereas 0.2 dB are reported for the one made with Ce-codoped fiber after a cumulated dose of ~900 Gy. The mechanisms explaining the positive influences of these two treatments are discussed. PMID- 22513554 TI - THz surface plasmon modes on planar Goubau lines. AB - The dispersion relation and confinement of terahertz surface plasmon modes propagating along planar Goubau lines are studied using guided-wave time domain spectroscopy. We demonstrate the radial nature of the surface plasmon mode known as the Goubau mode and the transverse confinement of the electric field over a few tenths of microns (~l/10). We experimentally and computationally observed a transition of the shape of the THz pulses from unipolar to bipolar as the propagation distance increases, indicating that the Goubau line acts as a high pass filter. The deviation of the dispersion relation curve from a linear law above 600 GHz is discussed. PMID- 22513555 TI - An ethanol vapor detection probe based on a ZnO nanorod coated optical fiber long period grating. AB - A new ethanol vapor detection probe based on an optical fiber long period grating overlaid with a zinc oxide (ZnO) nanorods layer is presented. The ZnO nanorod layer was developed onto the cladding of the fiber using aqueous chemical growth, seeded by a thin layer of metallic Zn. The growth of the ZnO nanorods overlayer onto the long period grating cladding is monitored in real time for investigating its effect on the spectral properties of the device and its subsequent role in the sensing mechanism. Results are presented, on the correlation between the growth time of the ZnO layer and the ethanol vapor detection performance. Reversible spectral changes of the notch extinction ratio of more than 4 dB were recorded for ~50 Torr of ethanol vapor concentration. In addition, photoluminescence emission studies of the ZnO overlayer performed simultaneously with the optical fiber spectral measurements, revealed significant ethanol induced changes in the intensity of the bandgap peak. PMID- 22513556 TI - Strongly interacting photons in asymmetric quantum well via resonant tunneling. AB - We propose an asymmetric quantum well structure to realize strong interaction between two slow optical pulses. The essential idea is the combination of the advantages of inverted-Y type scheme and resonant tunneling. We analytically demonstrate that giant cross-Kerr nonlinearity can be achieved with vanishing absorptions. Owing to resonant tunneling, the contributions of the probe and signal cross-Kerr nonlinearities to total nonlinear phase shift vary from destructive to constrictive, leading to nonlinear phase shift on order of pi at low light level. In this structure, the scheme is inherent symmetric for the probe and signal pulses. Consequently, the condition of group velocity matching can be fulfilled with appropriate initial electron distribution. PMID- 22513557 TI - Multimode dynamics in bidirectional laser cavities by folding space into time delay. AB - Multimode dynamics in bidirectional laser cavities can be accurately described by folding space into time delay. This results in a set of delayed algebraic equations that preserve the dynamics of all cavity modes while drastically reducing number of degrees of freedom. This reduction allows for both linear stability analysis and bifurcation diagram reconstruction, as well as integration times reduced by orders of magnitude. PMID- 22513558 TI - Broadband third harmonic generation in tapered silica fibres. AB - Optical microfibres have recently attracted much attention for nonlinear applications, due to their tight modal confinement. Here, we report broadband third harmonic generation based on the intermodal phase matching technique in silica microfibres of several centimetres. The third harmonic signal is predominantly generated from the taper transition regions (rather than the waist), wherein the range of diameters permits phase matching over a wide bandwidth. Microfibres up to 4.5 cm long were fabricated with waist diameters below 2.5 MUm to allow a lambda = 1.55 MUm pump to phase match with several higher order third harmonic modes; conversion rates up to 3 * 10-4 were recorded when pumped with 4 ns pulses at a peak power of 1.25 kW. Analysis of the third harmonic frequencies generated from the nonlinearly broadened pump components indicate a 5 dB conversion bandwidth of at least 36 nm, with harmonic power detected over a 150 nm range. PMID- 22513559 TI - Integrated in-band optical signal-to-noise ratio monitor implemented on SOI platform. AB - Based on different coherence properties of signal and noise, we measured the in band optical signal-to-noise ratio using an integrated thermally tunable Mach Zehnder optical delay interferometer on SOI platform. The experimental results exhibit errors smaller than 1 dB for signals with bit rate <40 Gbps over an OSNR range of 9~30 dB. The effects of the extinction ratio, noise equivalent bandwidth and arm length difference on the implementation of measurement are analyzed. PMID- 22513560 TI - Chirality in nonlinear-optical response of planar G-shaped nanostructures. AB - Chirality effects in optical second harmonic generation (SHG) are studied in periodic planar arrays of gold G-shaped nanostructures. We show that G-shaped structures of different handedness demonstrate different SHG efficiency for the left and right circular polarizations, as well as the opposite directions of the SHG polarization plane rotation. The observed effects are interpreted as the appearance of chirality in the SHG response which allows clear distinguishing of two enantiomers. PMID- 22513561 TI - Kerr-induced all-optical switching in a GaInP photonic crystal Fabry-Perot resonator. AB - We describe nonlinear properties of a GaInP photonic crystal Fabry-Perot resonator containing integrated reflectors. The device exhibits an extremely large static nonlinearity due to a thermal effect. Dynamical measurements were used to discriminate between the thermal and Kerr contributions to the nonlinearity. The high frequency nonlinear response is strictly due to the Kerr effect and the efficiency is similar to that obtained in self-phase modulation and four wave mixing experiments. The waveguide dispersion and the wavelength dependent integrated reflectors yield a series of transmission peaks with varying widths which determine the maximum speed at which the device can operate. Switching and wavelength conversion experiments with 92ps and 30ps wide pulses were demonstrated using pulse energies of a few pJ. The switching process is Kerr dominated with the fundamental response being essentially instantaneous so that the obtainable switching speed is strictly determined by the resonator structure. PMID- 22513562 TI - A nano-opto-mechanical pressure sensor via ring resonator. AB - This paper reports a nano-opto-mechanical pressure sensor based on nano-scaled ring resonator. The pressure is measured through the output spectrum shift which is induced via mechanical deformation of the ring resonator. The sensitivity as high as 1.47 pm/kPa has been experimentally achieved which agrees with numerical prediction. Due to the strong variation of sensitivity with different ring radius and thickness of the diaphragm, the pressure sensor can be used to form an array structure to detect the pressure distribution in highly accurate measurement with low-cost advantages. The nano-opto-mechanical pressure sensor has potential applications such as shear stress displacement detection, pressure wave detector and pressure mapping etc. PMID- 22513563 TI - Artificial Kerr-type medium using metamaterials. AB - We investigated an artificial Kerr-medium realized by actuated THz metamaterials. Instead of directly applying E-field inside the medium, we use micromechanical systems actuated by voltage to tune the phase shift. We established that the combined system can have a relationship between the phase shift and the voltage similar to a Kerr cell. A metamaterial Kerr-cell is designed to modulate the transmission phase difference by 0.99 degrees /V2 which is much stronger than natural Kerr crystals. It is attributed to the mechanical tunability of metamaterials with high indices in two orthogonal directions. A Lorentzian model is used in explaining the artificial Kerr cell. PMID- 22513564 TI - Time-resolved imaging of near-fields in THz antennas and direct quantitative measurement of field enhancements. AB - We investigate the interaction between terahertz waves and resonant antennas with sub-cycle temporal and lambda/100 spatial resolution. Depositing antennas on a LiNbO3 waveguide enables non-invasive electro-optic imaging, quantitative field characterization, and direct measurement of field enhancement (up to 40-fold). The spectral response is determined over a bandwidth spanning from DC across multiple resonances, and distinct behavior is observed in the near- and far field. The scaling of enhancement and resonant frequency with gap size and antenna length agrees well with simulations. PMID- 22513565 TI - A self-coupling multi-port microcoil resonator. AB - A new type of self-coupling multi-port microcoil resonator using a microfiber coupler is presented. The microresonators, a simple combination of a microfiber coupler and microcoil resonator, were fabricated by coiling a four port microfiber coupler around a low index support rod to induce optical resonance via coupling between adjacent turns. Light propagates along the coil whilst the beating between the supermodes of the coupler is still present, giving an increased extinction ratio and an output spectrum strongly dependent on the microfiber coupler diameter. The multiport microcoil resonator was embedded in a low refractive index polymer to improve its robustness and the polarization dependence was further analyzed. PMID- 22513566 TI - Planar InAs photodiodes fabricated using He ion implantation. AB - We have performed Helium (He) ion implantation on InAs and performed post implant annealing to investigate the effect on the sheet resistance. Using the transmission line model (TLM) we have shown that the sheet resistance of a p+ InAs layer, with a nominal doping concentration of 1x1018 cm-3, can increase by over 5 orders of magnitude upon implantation. We achieved a sheet resistance of 1x105 Omega/Square in an 'as-implanted' sample and with subsequent annealing this can be further increased to 1x107 Omega/Square. By also performing implantation on p-i-n structures we have shown that it is possible to produce planar photodiodes with comparable dark currents and quantum efficiencies to chemically etched reference mesa InAs photodiodes. PMID- 22513567 TI - Fast Brillouin Optical Time Domain Analysis for dynamic sensing. AB - A new technique for the fast implementation of Brillouin Optical Time Domain Analysis (BOTDA) is proposed and demonstrated, carrying the classical BOTDA method to the dynamic sensing domain. By using a digital signal generator which enables fast switching among 100 scanning frequencies, we demonstrate a truly distributed and dynamic measurement of a 100 m long fiber with a sampling rate of ~10 kHz, limited only by the fiber length and the frequency granularity. With 10 averages the standard deviation of the measured strain was ~5 uepsilon. PMID- 22513568 TI - Frequency-selective 3-D integration of nanoplasmonic circuits on a Si platform. AB - Vertical integration of nanoplasmonic circuits through the use of vertically coupled nanoring resonators was examined. The devices are shown to be capable of frequency selective signal transfer between device layers with planar device footprints on the order of 1.00 MUm2. The frequency selectivity of the devices is shown to be tunable through altering the radius of the coupled nanoring resonators. Coupling efficiencies of up to 39% between adjacent device layers are reached for two and three-levels coupling. PMID- 22513569 TI - Self-mixing interference measurement system of a fiber ring laser with ultra narrow linewidth. AB - A novel device for self-mixing interference measurement based on the fiber ring laser with ultra-narrow linewidth was investigated for the first time. In order to achieve requirement of our measurement system, a saturable-absorber which consists of a segment un-pumped erbium-doped fiber and a fiber Bragg grating is employed to provide a fine mode selection and guarantee the ultra-narrow linewidth operation. Results demonstrate that the signal-to-noise ratio of the self-mixing interference signal could be enhanced from 18.01 dB to 38.35 dB by inserting a saturable-absorber in the laser cavity. It is in good agreement with the theoretical analysis and proved potential using in self-mixing interference measurement system for high sensitivity and remote measurement. PMID- 22513570 TI - Broadband optical cloak and illusion created by the low order active sources. AB - In present work, we demonstrate an optical cloak and illusion by appropriate design of a cluster of active sources. As pointed out by Vasquez and coworkers, the merit of such proposal with active controls is to overcome the drawback of narrow operating frequency and intrinsic loss inherent in the cloaking device made of metamaterials. Accordingly, the illusion device designed thuswise has a broadband operating frequency. By use of the rigorous multiple scattering theory, we have performed the simulations. It is shown that the active illusion device can be used as an beam rotator. In particular, we have shown that the active sources can even be reduced to dipole ones, which is expected to enable much easier experimental implementation of the cloaking and illusion effect. PMID- 22513571 TI - Bulk and surface plasmon polariton excitation in RuO2 for low-loss plasmonic applications in NIR. AB - Transition-metal oxides, such as RuO2, offer an exciting alternative to conventional metals for metamaterials and plasmonic applications due to their low optical losses in the visible and near-infrared ranges. In this manuscript we report observation of optically excited surface plasmon polaritons (SPPs) and bulk plasmons in RuO2 thin films grown using DC reactive magnetron sputtering on glass and TiO2 (001) substrates. We show that both plasmon modes can exist simultaneously for the infrared region of the optical spectrum, while only the bulk plasmons are supported at higher optical frequencies. Finally, we demonstrate that the film properties can be tailored to favor excitation of either SPP or bulk plasmons. PMID- 22513572 TI - Linear and nonlinear optical properties of Ag/Au bilayer thin films. AB - The linear and nonlinear optical properties of Ag/Au bilayer metallic thin films with a total thickness of around 20 nm and with different Ag/Au mass-thickness ratios were studied. This study shows that the spectral dispersion of the effective refractive index of bilayer films can be tuned by controlling the mass thickness ratio between Au and Ag. Improvement of the figure-of-merit for potential plasmonic applications and linear optical filters in the visible spectral range are reported and discussed. The nonlinear optical properties of bilayer metal films studied using femtosecond white-light continuum pump-probe experiments are also shown to be tunable with this ratio. The nonlinear change of optical path length is extracted from the pump-probe data and agrees with simulated values derived from a combination of the two-temperature model, describing the ultrafast electron heating dynamics, and a physical model that describes the dielectric permittivity of Au as a function of electron and lattice temperature. PMID- 22513573 TI - Dual-view liquid crystal display fabricated by patterned electrodes. AB - We design a dual-view liquid crystal display (DVLCD) which display two different images in the left and right viewing directions simultaneously. The main-pixel of the DVLCD comprises the right sub-pixels (RSPs) and the left sub-pixels (LSPs). The LCs in the RSPs and the LSPs have the opposite rotation directions, which are controlled by the inclined electric fields provided by the patterned electrodes. Addressing the RSPs and LSPs with the voltages having different polarities effectively decreases the maximum operation voltage of the DVLCD. The proposed DVLCD is free of the complicate multiple-step rubbing and shadow mask treatments, and hence has the advantages of low cost and easy fabrication. PMID- 22513574 TI - High performance mode locking characteristics of single section quantum dash lasers. AB - Mode locking features of single section quantum dash based lasers are investigated. Particular interest is given to the static spectral phase profile determining the shape of the mode locked pulses. The phase profile dependence on cavity length and injection current is experimentally evaluated, demonstrating the possibility of efficiently using the wide spectral bandwidth exhibited by these quantum dash structures for the generation of high peak power sub picosecond pulses with low radio frequency linewidths. PMID- 22513575 TI - Probing photonic Bloch wavefunctions with plasmon-coupled leakage radiation. AB - We demonstrate theoretically and experimentally the direct observation of photonic Bloch wavefunctions in dielectric loaded plasmonic crystals. The ultimate ability to observe the Bloch wavefunctions in the surface emission images depends not on the light diffraction through the holes but on the strength of the in-plane light scattering from the individual lattice features and the presence of the metal layer which allows the light propagating within the crystal to be imaged in the far-field. Experimental results are in excellent agreement with simulated surface emission and back focal plane images of plasmonic crystals. PMID- 22513576 TI - Low-threshold supercontinuum generation in semiconductor nanoribbons by continuous-wave pumping. AB - We report the first observation of supercontinuum (SC) generation in single semiconductor nanoribbons (NRs). By launching a continuous wave (CW) 532-nm pump light along a 200-MUm-length CdS NR for waveguiding excitation, SC generation is realized with a threshold down to sub-milliwatt level, which is ~3 orders lower compared with previous CW-pumped SC generated in glass fibers. The low threshold is benefitted from the favorable material properties and waveguide geometries including high Raman gains, strong light confinement, more optical guided modes and phonon modes. Our work paves the way to low-threshold nanoscale SC sources and may find widespread applications ranging from spectroscopic analysis and biological imaging to material research. PMID- 22513577 TI - Bandwidth broadening of near-infrared emission through nanocrystallization in Bi/Ni co-doped glass. AB - We demonstrated an effective way to broaden the bandwidth of near-infrared (NIR) emission from Bi/Ni codoped 58SiO2-21ZnO-13Al2-O3-5TiO2-3Ga2O3 glass through nanocrystallization. The nanocrystallized glass shows ultra-wide NIR luminescence with a full width at half maximum (FWHM) of 350 nm and long lifetime up to 476 us. The observed broadband NIR emission, attributed to energy transfer suppression between Ni and Bi active centers, was realized by a separation process with Ni2+ ions selectively incorporated into nanocrystals. This bandwidth engineering through nanocrystallization inside glass suggests a promising approach for enhancement of glass functionality and construction of broadband light sources. PMID- 22513578 TI - Error-free transmission of microring-modulated BPSK. AB - We demonstrate the generation of error-free binary-phase-shift-keyed (BPSK) data at 5 Gb/s using a silicon microring modulator. The microring-modulated BPSK signal is propagated at fiber lengths up to 80 km, maintaining error-free performance, while demonstrating resilience to chromatic dispersion. Bit-error rate measurements and eye diagrams show near equivalent performance of a microring-based BPSK modulator as compared to commercial LiNbO3 phase modulators. PMID- 22513579 TI - Role of in-plane polarizability of the tip in scattering near-field microscopy of a plasmonic nanoparticle. AB - We report that a pyramid-shaped scanning probe microscopy tip has non-zero polarizability along the in-plane direction (perpendicular to the tip axis, z) at visible frequency. The in-plane polarizability enables the scattering-type scanning near-field optical microscopy (s-SNOM) to measure the in-plane field component around a plasmon-resonant nanoparticle. Because of the non-zero in plane polarizability, the cross-polarized s-SNOM images may contain contributions from the in-plane field component of an out-of-plane plasmon mode as well as the out-of-plane field component of an in-plane mode. By comparing a scattering model and experimental s-SNOM images, we estimate the polarization anisotropies of pyramid-shaped Si-tips and metal-coated Si-tips. PMID- 22513580 TI - Vanadium dioxide based plasmonic modulators. AB - Actively tunable metal-insulator-metal waveguides that employ vanadium dioxide films as the active medium are analyzed numerically. Vanadium dioxide exhibits strong contrast between the optical properties of its insulating and metallic phases. In particular, the large optical absorption in the metallic phase makes it straightforward to implement broadband attenuation modulators and switches, but this strong loss can also complicate the design of other types of devices. We present a plasmonic waveguide that functions as an index modulator with Deltan > 20% at lambda0 = 1,550 nm (0.80 eV), by using a thin active layer to strike a balance between maximizing index contrast while mitigating attenuation. A second device is configured as a band-stop absorption modulator, taking advantage of symmetry to selectively suppress the TM1 and TM3 modes, with relatively minimal attenuation of the TM0 and TM2 modes. PMID- 22513581 TI - Electrically generated unidirectional surface plasmon source. AB - We experimentally demonstrated an electrically excited surface plasmon source, which was fulfilled in a silver coated light emitting diode (LED) with well designed gratings. With a DC current supply, surface plasmon polariton (SPP) waves were generated directly from the illuminations of the LED via the grating coupler. By adjusting the grating to a tilted one, a unidirectional SPP beam was successfully attained with a high extinction ratio (ER~10) and an improved launching efficiency. Detailed analyses show that this electrically generated unidirectional SPP has a considerable long propagation distance (~14 MUm), allowing for further manipulations in plasmonic integrations and sensors. PMID- 22513582 TI - Dark current reduction of Ge photodetector by GeO2 surface passivation and gas phase doping. AB - We have investigated the dark current of a germanium (Ge) photodetector (PD) with a GeO2 surface passivation layer and a gas-phase-doped n+/p junction. The gas phase-doped PN diodes exhibited a dark current of approximately two orders of magnitude lower than that of the diodes formed by a conventional ion implantation process, indicating that gas-phase doping is suitable for low-damage PN junction formation. The bulk leakage (Jbulk) and surface leakage (Jsurf) components of the dark current were also investigated. We have found that GeO2 surface passivation can effectively suppress the dark current of a Ge PD in conjunction with gas phase doping, and we have obtained extremely low values of Jbulk of 0.032 mA/cm2 and Jsurf of 0.27 MUA/cm. PMID- 22513583 TI - Evaluation of breast tumor margins in vivo with intraoperative photoacoustic imaging. AB - The use of photoacoustic effect is a promising approach for biomedical imaging in living tissues. Photoacoustic tomography (PAT) has been demonstrated to image breast cancer, brain vasculature, arthritis and seizure focus owing to its rich optical contrast and high resolution in a single imaging modality. Here we report a microelectromechanical systems (MEMS)-based intraoperative PAT (iPAT) technique, and demonstrate its ability to accurately map tumors in three dimension and to inspect the completeness of tumor resection during surgery in a tumor-bearing mouse model. The MEMS imaging probe is small and has the potential to be conveniently used to guide surgical resection of tumors in the breast. PMID- 22513584 TI - Microbubble generation using fiber optic tips coated with nanoparticles. AB - We show that fiber optic tips can be used as microbubble generators in liquid media. Using standard single-mode silica fibers incorporating nanoparticles (carbon nanoparticles and metallic powders), bubbles can be generated with low optical powers owing to the enhanced photothermal effects of the coating materials. We provide details about the hydrodynamic effects generated in the vicinity of the fiber tip during the coating process, bubble generation and growth. Flow visualization techniques show that thermal effects lead to bubble formation on the tip of the fibers, and coating optimization is crucial for optimal performance of the probes. PMID- 22513585 TI - Parabolic and hyper-Gaussian similaritons in fiber amplifiers and lasers with gain saturation. AB - We present a new asymptotically exact analytical similariton solution of the generalized nonlinear Schrdinger equation for pulses propagating in fiber amplifiers and lasers with normal dispersion including the effect of gain saturation. Numerical simulations are in excellent agreement with this analytical solution describing self-similar linearly chirped parabolic pulses. We have also found that for small enough values of the dimensionless saturation energy parameter the fiber amplifiers and lasers can generate a new type of linearly chirped self-similar pulses, which we call Hyper-Gaussian similaritons. The analytical Hyper-Gaussian similariton solution of the generalized nonlinear Schrdinger equation is also in a good agreement with numerical simulations. PMID- 22513586 TI - Femtosecond superradiant emission in AlGaInAs quantum-well semiconductor laser structures. AB - Ultrashort superradiant pulse generation from a 1580 nm AlGaInAs multiple quantum well (MQW) semiconductor structure has been experimentally demonstrated for the first time. Superradiance is confirmed by analyzing the evolution of the optical temporal waveforms and spectra. Superradiant trends and regimes are studied as a function of driving condition. An optical pulse train is obtained at 1580 nm wavelength, with pulse durations as short as 390 fs and pulse peak powers of 7.2 W. PMID- 22513587 TI - Reverse chromatic aberration and its numerical optimization in a metamaterial lens. AB - In planar metamaterial lenses, the focal point moves with the frequency. Here it is shown numerically that this movement can be controlled by properly engineering the dimensions of the metamaterial-based phase shifters that constitute the lens. In particular, such lenses can be designed to exhibit unusual chromatic aberration with the focal length increasing, rather than decreasing, with the frequency. It is proposed that such an artificial "reverse" chromatic aberration may optimize the transverse resolution of millimeter wave diagnostics of plasmas and be useful in compensating for the natural "ordinary" chromatic aberration of other components in an optical system. More generally, optimized chromatic aberration will allow for simultaneous focusing of several objects located at different distances and emitting or reflecting at different frequencies. PMID- 22513588 TI - Standardized speckle measurement method matched to human speckle perception in laser projection systems. AB - We present a standardized procedure to measure the amount of speckle in laser based projection systems. The parameters of the measurement procedure are chosen such that the measured speckle contrast values are in correspondence with the subjective speckle perception of a human observer, independent of the particularities of the laser projector's illumination configuration. The resulting measurement configuration consists of a single digital image sensor in combination with a camera lens of which the settings are related to the human eye. In addition, a standardized measurement procedure and speckle pattern analysis method are suggested. Finally, the speckle measurement set-up is applied to a laser projection system and corresponding subjective speckle perception results of a large test public are discussed. PMID- 22513589 TI - Bandwidth tunable THz wave generation in large-area periodically poled lithium niobate. AB - A new scheme of optical rectification (OR) of femtosecond laser pulses in a periodically poled lithium niobate (PPLN) crystal, which generates high energy and bandwidth tunable multicycle THz pulses, is proposed and demonstrated. We show that the number of the oscillation cycles of the THz electric field and therefore bandwidth of generated THz spectrum can easily and smoothly be tuned from a few tens of GHz to a few THz by changing the pump optical spot size on PPLN crystal. The minimal bandwidth is 17 GHz that is smallest ever of reported in scheme of THz generation by OR at room temperature. Similar to the case of Cherenkov-type OR in single-domain LiNbO3, the spectrum of THz generation extends from 0.1 THz to 3 THz when laser beam is focused to a size close to half-period of PPLN structure. The energy spectral density of narrowband THz generation is almost independent of the bandwidth and is typically 220 nJ/THz for ~1 W pump power at 1 kHz repetition rate. PMID- 22513590 TI - Measurement of nonlinear refractive index and ionization rates in air using a wavefront sensor. AB - A wavefront sensor has been used to measure the Kerr nonlinear focal shift of a high intensity ultrashort pulse beam in a focusing beam geometry while accounting for the effects of plasma-defocusing. It is shown that plasma-defocusing plays a major role in the nonlinear focusing dynamics and that measurements of Kerr nonlinearity and ionization are coupled. Furthermore, this coupled effect leads to a novel way that measures the laser ionization rates in air under atmospheric conditions as well as Kerr nonlinearity. The measured nonlinear index n2 compares well with values found in the literature and the measured ionization rates could be successfully benchmarked to the model developed by Perelomov, Popov, and Terentev (PPT model) [Sov. Phys. JETP 50, 1393 (1966)]. PMID- 22513591 TI - Real-time FPGA data collection of pulsed-laser cavity ringdown signals. AB - This paper presents results from a pulsed-laser cavity ring-down spectrometer with novel field programable gate array real-time data collection. We show both theoretically and experimentally that the data extraction can be achieved from a single cavity ringdown event, and that the absorbance can be determined without the need to fit the ringdown time explicitly. This methodology could potentially provide data acquisition rate up to 1 MHz, with the accuracy and precision comparable to nonlinear least squares fitting algorithms. PMID- 22513592 TI - Using an aliasing operator and a single discrete Fourier transform to down-sample the Fresnel transform. AB - In Digital Holography there are applications where computing a few samples of a wavefield is sufficient to retrieve an image of the region of interest. In such cases, the sampling rate achieved by the direct and the spectral methods of the discrete Fresnel transform could be excessive. A few algorithmic methods have been proposed to numerically compute samples of propagated wavefields while allowing down-sampling control. Nevertheless, all of them require the computation of at least two 2D discrete Fourier transforms which increases the computational load. Here, we propose the use of an aliasing operator and a single discrete Fourier transform to achieve an efficient method to down-sample the wavefields obtained by the Fresnel transform. PMID- 22513593 TI - High dynamic range optical projection tomography (HDR-OPT). AB - Traditional optical projection tomography (OPT) acquires a single image at each rotation angle, thereby suffering from limitations in CCD dynamic range; this conventional usage cannot resolve features in samples with highly heterogeneous absorption, such as in small animals with organs of varying size. We present a novel technique, applying multiple-exposure high dynamic range (HDR) imaging to OPT, and demonstrate its ability to resolve fine details in zebrafish embryos, without complicated chemical clearing. We implement the tomographic reconstruction algorithm on the GPU, yielding a performance increase of two orders of magnitude. These features give our method potential application in high throughput, high-resolution in vivo 3D imaging. PMID- 22513594 TI - Control of third harmonic generation by plasma grating generated by two noncollinear IR femtosecond filaments. AB - A plasma grating is formed by two femtosecond filaments, and the influence of probe filament on the plasma grating is shown. By using the plasma grating, the enhancement of the third harmonic (TH) generated from the probe filament is studied, and more than three orders of magnitude enhancement of TH generation is demonstrated as compared with that obtained from a single filament. The dependences of TH generation on the time delay, the spatial period of plasma grating, the relative polarization and the crossing position between the probe beam and the two pump beams are investigated. The spectral broadening of TH generated from the probe filament induced by the interaction between the probe filament and the plasma grating is also studied. PMID- 22513595 TI - Table screen 360-degree three-dimensional display using a small array of high speed projectors. AB - We propose a 360-degree three-dimensional display with a table screen, which consists of a small number of high-speed projectors and a rotating screen. Because each high-speed projector is located outside the rotating axis of the screen, multiple projectors can be aligned. The lens shift technique is used to superimpose multiple images generated by all projectors on the rotating screen. The screen has an off-axis lens function such that the rotation of the screen generates numerous viewing points on a circle. The use of multiple projectors enables an increase in the number of colors, an increase in the number of viewing points, and a reduction in the screen rotation speed. We develop an image synthesis technique for the proposed display system. A color display system employing three high-speed projectors is demonstrated. PMID- 22513596 TI - EEPN and CD study for coherent optical nPSK and nQAM systems with RF pilot based phase noise compensation. AB - A radio frequency (RF) carrier can be used to mitigate the phase noise impact in n-level PSK and QAM systems. The systems performance is influenced by the use of an RF pilot carrier to accomplish phase noise compensation through complex multiplication in combination with discrete filters to compensate for the chromatic dispersion (CD). We perform a detailed study comparing two filters for the CD compensation namely the fixed frequency domain equalizer (FDE) filter and the adaptive least-mean-square (LMS) filter. The study provides important novel physical insight into the equalization enhanced phase noise (EEPN) influence on the system bit-error-rate (BER) versus optical signal-to-noise-ratio (OSNR) performance. Important results of the analysis are that the FDE filter position relative to the RF carrier phase noise compensation module provides a possibility for choosing whether the EEPN from the Tx or the LO laser influences the system quality. The LMS filter works very inefficiently when placed prior to the RF phase noise compensation stage of the Rx whereas it works much more efficiently and gives almost the same performance as the FDE filter when placed after the RF phase noise compensation stage. PMID- 22513597 TI - Harmonic distortion in microwave photonic filters. AB - We present a theoretical and experimental analysis of nonlinear microwave photonic filters. Far from the conventional condition of low modulation index commonly used to neglect high-order terms, we have analyzed the harmonic distortion involved in microwave photonic structures with periodic and non periodic frequency responses. We show that it is possible to design microwave photonic filters with reduced harmonic distortion and high linearity even under large signal operation. PMID- 22513598 TI - Variable multilayer reflection together with long-pass filtering pigment determines the wing coloration of papilionid butterflies of the nireus group. AB - The dorsal wing surfaces of papilionid butterflies of the nireus group are marked by bands of brilliant blue-green-colored cover scales. The thin, cuticular lower lamina of the scales acts as a blue reflector. The thick upper lamina forms a dense two-dimensional cuticular lattice of air cavities with a pigment acting as a long-pass optical filter. Reflectance spectra of small scale areas oscillate, but for large scale areas and the intact wing they are smooth. Theoretical modeling shows that the oscillations vanish for a scale ensemble with varying layer thicknesses and cavity dimensions. The scales combine in a subtle way structural and pigmentary coloration for an optical effect. PMID- 22513599 TI - Coupling of silicon-vacancy centers to a single crystal diamond cavity. AB - Optical coupling of an ensemble of silicon-vacancy (SiV) centers to single crystal diamond microdisk cavities is demonstrated. The cavities are fabricated from a single-crystal diamond membrane generated by ion implantation and electrochemical liftoff followed by homo-epitaxial overgrowth. Whispering gallery modes spectrally overlap with the zero-phonon line (ZPL) of the SiV centers and exhibit quality factors ~ 2200. Lifetime reduction from 1.8 ns to 1.48 ns is observed from SiV centers in the cavity compared to those in the membrane outside the cavity. These results are pivotal in developing diamond integrated photonics networks. PMID- 22513600 TI - Terahertz emission by diffusion of carriers and metal-mask dipole inhibition of radiation. AB - Terahertz (THz) radiation can be generated by ultrafast photo-excitation of carriers in a semiconductor partly masked by a gold surface. A simulation of the effect taking into account the diffusion of carriers and the electric field shows that the total net current is approximately zero and cannot account for the THz radiation. Finite element modelling and analytic calculations indicate that the THz emission arises because the metal inhibits the radiation from part of the dipole population, thus creating an asymmetry and therefore a net current. Experimental investigations confirm the simulations and show that metal-mask dipole inhibition can be used to create THz emitters. PMID- 22513601 TI - Negative radiation pressure and negative effective refractive index via dielectric birefringence. AB - We show that light guided in a planar dielectric slab geometry incorporating a biaxial medium has lossless modes with group and phase velocities in opposite directions. Particles in a vacuum gap inserted into the structure experience negative radiation pressure: the particles are pulled by light rather than pushed by it. This effectively one-dimensional dielectric structure represents a new geometry for achieving negative radiation pressure in a wide range of frequencies with minimal loss. Moreover, this geometry provides a straightforward platform for experimentally resolving the Abrahams-Minkowski dilemma. PMID- 22513602 TI - 11 W narrow linewidth laser source at 780 nm for laser cooling and manipulation of Rubidium. AB - We present a narrow linewidth continuous laser source with over 11 W output power at 780 nm, based on single-pass frequency doubling of an amplified 1560 nm fibre laser with 36% efficiency. This source offers a combination of high power, simplicity, mode quality and stability. Without any active stabilization, the linewidth is measured to be below 10 kHz. The fibre seed is tunable over 60 GHz, which allows access to the D2 transitions in 87Rb and 85Rb, providing a viable high-power source for laser cooling as well as for large-momentum-transfer beamsplitters in atom interferometry. Sources of this type will pave the way for a new generation of high flux, high duty-cycle degenerate quantum gas experiments. PMID- 22513603 TI - Efficient terahertz-wave generation via four-wave mixing in silicon membrane waveguides. AB - Terahertz (THz) wave generation via four-wave mixing (FWM) in silicon membrane waveguides is theoretically investigated with mid-infrared laser pulses. Compared with the conventional parametric amplification or wavelength conversion based on FWM in silicon waveguides, which needs a pump wavelength located in the anomalous group-velocity dispersion (GVD) regime to realize broad phase matching, the pump wavelength located in the normal GVD regime is required to realize collinear phase matching for the THz-wave generation via FWM. The pump wavelength and rib height of the silicon membrane waveguide can be tuned to obtain a broadband phase matching. Moreover, the conversion efficiency of the THz-wave generation is studied with different pump wavelengths and rib heights of the silicon membrane waveguides, and broadband THz-wave can be obtained with high efficiency exceeding 1%. PMID- 22513604 TI - Actively tunable bistable optical Yagi-Uda nanoantenna. AB - We propose and theoretically demonstrate a novel type of optical Yagi-Uda nanoantennas tunable via variation of the free-carrier density of a semiconductor disk placed in a gap of a metallic dipole feeding element. Unlike its narrowband all-metal counterparts, this nanoantenna exhibits a broadband unidirectional emission and demonstrates a bistable response in a preferential direction of the far-field zone, which opens up unique possibilities for ultrafast control of subwavelength light not attainable with dipole or bowtie architectures. PMID- 22513605 TI - Spatiotemporal focusing-based widefield multiphoton microscopy for fast optical sectioning. AB - In this study, a microscope based on spatiotemporal focusing offering widefield multiphoton excitation has been developed to provide fast optical sectioning images. Key features of this microscope are the integrations of a 10 kHz repetition rate ultrafast amplifier featuring high instantaneous peak power (maximum 400 MUJ/pulse at a 90 fs pulse width) and a TE-cooled, ultra-sensitive photon detecting, electron multiplying charge-coupled camera into a spatiotemporal focusing microscope. This configuration can produce multiphoton images with an excitation area larger than 200 * 100 MUm2 at a frame rate greater than 100 Hz (current maximum of 200 Hz). Brownian motions of fluorescent microbeads as small as 0.5 MUm were observed in real-time with a lateral spatial resolution of less than 0.5 MUm and an axial resolution of approximately 3.5 MUm. Furthermore, second harmonic images of chicken tendons demonstrate that the developed widefield multiphoton microscope can provide high resolution z sectioning for bioimaging. PMID- 22513606 TI - Compact and low power operation optical switch using silicon-germanium/silicon hetero-structure waveguide. AB - We proposed a silicon-based optical switch with a carrier-plasma-induced phase shifter which employs a silicon-germanium (SiGe) / silicon (Si) hetero-structure in the waveguide core. A type-I hetero-interface formed by SiGe and Si is expected to confine carriers effectively in the SiGe waveguide core. The fabricated Mach-Zehnder optical switch shows a low switching power of only 1.53 mW with a compact phase shifter length of 250 MUm. The switching time of the optical switch is less than 4.6 ns for the case of a square waveform driving condition, and 1 ns for the case of a pre-emphasis electric driving condition. These results show that our proposed SiGe/Si waveguide structure holds promise for active devices with compact size and low operation power. PMID- 22513607 TI - A dual-spectrometer approach to reflectance measurements under sub-optimal sky conditions. AB - This paper presents a practical method for the development of spectral reflectance libraries under sub-optimal sky conditions. Although there are commercially available spectrometers which simultaneously measure both downwelling and upwelling radiance to mitigate the impact of sub-optimal sky conditions, these spectrometers only record in the visible and near infra-red. There are presently no commercially available spectrometers with this capability that can record the visible through short-wave infra-red. This paper presents a practical method of recording and processing data using coordinated measurements from two full-range spectrometers and discusses potential pitfalls and solutions required to achieve accurate reflectance spectra. Results demonstrate that high quality spectral reflectance libraries can be developed with this approach. PMID- 22513608 TI - Loss mechanisms of surface plasmon polaritons propagating on a smooth polycrystalline Cu surface. AB - We study the propagation properties of surface plasmon polaritons on a Cu surface by means of photoemission electron microscopy. Use of a CMOS process to fabricate the Cu thin film is shown to enable very high propagation distances (up to 65 MUm at 750 nm wavelength), provided that the copper native oxide is removed. A critical review of the optical loss mechanisms is undertaken and shed light on the effect of single grain boundaries in increasing the propagation losses of the plasmon. A microscopic interpretation is provided, relying on groove induced electromagnetic hot spots. PMID- 22513609 TI - Covariant description of transformation optics in nonlinear media. AB - The technique of transformation optics (TO) is an elegant method for the design of electromagnetic media with tailored optical properties. In this paper, we focus on the formal structure of TO theory. By using a complete covariant formalism, we present a general transformation law that holds for arbitrary materials including bianisotropic, magneto-optical, nonlinear and moving media. Due to the principle of general covariance, the formalism is applicable to arbitrary space-time coordinate transformations and automatically accounts for magneto-electric coupling terms. The formalism is demonstrated for the calculation of the second harmonic wave generation in a twisted TO concentrator. PMID- 22513610 TI - Nearly three orders of magnitude enhancement of Goos-Hanchen shift by exciting Bloch surface wave. AB - Goos-Hanchen effect is experimentally studied when the Bloch surface wave is excited in the forbidden band of a one-dimensional photonic band-gap structure. By tuning the refractive index of the cladding covering the truncated photonic crystal structure, either a guided or a surface mode can be excited. In the latter case, strong enhancement of the Goos-Hanchen shift induced by the Bloch surface-wave results in sub-millimeter shifts of the reflected beam position. Such giant Goos-Hanchen shift, ~750 times of the wavelength, could enable many intriguing applications that had been less than feasible to implement before. PMID- 22513612 TI - Characterization of highly-sensitive and fast-responding monitoring module for extended-reach passive optical networks. AB - The extended-reach broadband access network is widely acknowledged as a future proof solution to providing bandwidth-intensive services to an increased number of users spread across a large geographical area. To address fiber failure detection and reliability issues specific to these networks, a simple automatic protection switching and pump laser shutdown scheme that exploits the use of highly-sensitive and fast-responding monitoring modules is proposed and experimentally demonstrated in this work. We also present an analytical model that describes the probability distribution function of the response time, thus allowing the mean response time, jitter, and sensitivity to be evaluated. Our results show a high sensitivity of < -50 dBm can be achieved, thus allowing the module to be applied in topologies with extended reach and/or split ratio beyond that of conventional PONs. PMID- 22513611 TI - Single element spectral splitting solar concentrator for multiple cells CPV system. AB - Shockley Read Hall equation poses a limit to the maximum conversion efficiency of broadband solar radiation attainable by means of a single bandgap converter. A possible approach to overcome such a limit is to convert different parts of the broadband spectrum using different single junction converters. We consider here a different modus operandi where a single low-cost optimized plastic prismatic structure performs simultaneously the tasks of concentrating the solar light and, based on the dispersive behavior of the employed material, spatially splitting it into its spectral component. We discuss its approach, optical simulations, fabrication issues and preliminary experimental results demonstrating its feasibility for cost effective high efficiency Concentrated Photovoltaic Systems (CPV) systems. PMID- 22513613 TI - Single-camera, three-dimensional particle tracking velocimetry. AB - This paper introduces single-camera, three-dimensional particle tracking velocimetry (SC3D-PTV), an image-based, single-camera technique for measuring 3 component, volumetric velocity fields in environments with limited optical access, in particular, optically accessible internal combustion engines. The optical components used for SC3D-PTV are similar to those used for two-camera stereoscopic-uPIV, but are adapted to project two simultaneous images onto a single image sensor. A novel PTV algorithm relying on the similarity of the particle images corresponding to a single, physical particle produces 3 component, volumetric velocity fields, rather than the 3-component, planar results obtained with stereoscopic PIV, and without the reconstruction of an instantaneous 3D particle field. The hardware and software used for SC3D-PTV are described, and experimental results are presented. PMID- 22513614 TI - P-i-n junction quantum dot saturable absorber mirror: electrical control of ultrafast dynamics. AB - We report on nonlinear optical properties of a p-i-n junction quantum dot saturable absorber based on InGaAs/GaAs. Absorption recovery dynamics and nonlinear reflectivity are investigated for different reverse bias and pump power conditions. A decrease in absorption recovery time of nearly two orders of magnitude is demonstrated by applying a voltage between 0 and -20 V. The saturable absorber modulation depth and saturation fluence are found to be independent from the applied reverse bias. PMID- 22513615 TI - 1 W at 785 nm from a frequency-doubled wafer-fused semiconductor disk laser. AB - We demonstrate an optically pumped semiconductor disk laser operating at 1580 nm with 4.6 W of output power, which represents the highest output power reported from this type of laser. 1 W of output power at 785 nm with nearly diffraction limited beam has been achieved from this laser through intracavity frequency doubling, which offers an attractive alternative to Ti:sapphire lasers and laser diodes in a number of applications, e.g., in spectroscopy, atomic cooling and biophotonics. PMID- 22513616 TI - Effects of spherical mode coupling on near-field focusing by clusters of dielectric microspheres. AB - Colloidal particle lens array (CPLA) proved to be an efficient near-field focusing device for laser nanoprocessing of materials. Within CPLA, spherical particles do not act as independent microlenses. Due to the coupling of the spherical modes, the field near the clusters of spherical microparticles cannot be calculated by means of the superposition of Mie solutions for individual spheres. In the paper, the electromagnetic field distributions near laser irradiated clusters of dielectric microspheres with configurations that match the fragments of the close-packed CPLA are studied. It is shown that some practically important mode coupling effects can be understood in terms of an effective immersion medium formed for the spherical particle by its surrounding. PMID- 22513617 TI - Spatial angle dependent lasing from a dye-doped two-dimensional hexagonal photonic crystal made of holographic polymer-dispersed liquid crystals. AB - The observation of spatial angle dependent lasing from a dye-doped two dimensional photonic crystal (2D PC) holographic polymer dispersed liquid crystals made of hexagonal lattice structure is reported. With the increasing output angle of the laser beam in the plane perpendicular to the 2D PC, the lasing wavelength is red-shifted. By analyzing the lasing oscillation trace, we found that the effective lattice constant changes with the output angle, causing the spatial angle dependent lasing. PMID- 22513618 TI - Numerical retrieval of thin aluminium layer properties from SPR experimental data. AB - The inverse problem for Surface Plasmon Resonance measurements [1] on a thin layer of aluminium in the Kretschmann configuration, is solved with a Particle Swarm Optimization method. The optical indexes as well as the geometrical parameters are found for the best fit of the experimental reflection coefficient in s and p polarization, for four samples, under three theoretical hypothesis on materials: the metal layer is pure, melted with its oxyde, or coated with oxyde. The influence of the thickness of the metal layer on its optical properties is then investigated. PMID- 22513619 TI - A new view on the temperature insensitivity of intracavity SHG configuration. AB - Experimental results indicate that there is a distinct difference between the temperature tuning curves obtained with intracavity second harmonic generation (Intra-SHG) and extracavity SHG (Extra-SHG) configuration. By introducing the nonlinear SHG loss with the phase mismatch taken into consideration, the rate equations are established to describe the Intra-SHG laser performance. As for the widely used SHG crystal, KTP and LBO, theoretically calculated variation trends of the temperature insensitivity are in agreement with that obtained experimentally. The corresponding explanations have also been given in this paper. Our results may provide a new view on the temperature insensitivity of Intra-SHG configuration. The method employed in our study can be extended to other nonlinear crystals and intracavity nonlinear frequency conversions. PMID- 22513620 TI - Simultaneous measurement of quality factor and wavelength shift by phase shift microcavity ring down spectroscopy. AB - Optical resonant microcavities with ultra high quality factors are widely used for biosensing. Until now, the primary method of detection has been based upon tracking the resonant wavelength shift as a function of biodetection events. One of the sources of noise in all resonant-wavelength shift measurements is the noise due to intensity fluctuations of the laser source. An alternative approach is to track the change in the quality factor of the optical cavity by using phase shift cavity ring down spectroscopy, a technique which is insensitive to the intensity fluctuations of the laser source. Here, using biotinylated microtoroid resonant cavities, we show simultaneous measurement of the quality factor and the wavelength shift by using phase shift cavity ring down spectroscopy. These measurements were performed for disassociation phase of biotin-streptavidin reaction. We found that the disassociation curves are in good agreement with the previously published results. Hence, we demonstrate not only the application of phase shift cavity ring down spectroscopy to microcavities in the liquid phase but also simultaneous measurement of the quality factor and the wavelength shift for the microcavity biosensors in the application of kinetics measurements. PMID- 22513621 TI - Wavelength scaling of optimal hollow-core fiber compressors in the single-cycle limit. AB - We systematically investigate supercontinuum generation using three-dimensional numerical simulations of nonlinear femtosecond pulse propagation in hollow-core fibers (HCF) at different pump wavelengths ranging from 400 nm to 2 MUm. A general design strategy for HCF compressors is presented, maximizing the spectral broadening while preserving high beam quality for given pump pulse energy, duration and wavelength. We show close fitting of the modeled results with simple analytical formulas, enabling the construction of high-energy pulse compressors at the wavelength range of interest. Based on the presented wavelength scaling study, we propose an orthogonally polarized two-color pumping scheme in a single HCF compressor for the coherent synthesis of the electric fields in the sub-cycle regime with mJ level energies. PMID- 22513622 TI - Enhanced resolution and throughput of Fresnel incoherent correlation holography (FINCH) using dual diffractive lenses on a spatial light modulator (SLM). AB - Fresnel incoherent correlation holography (FINCH) records holograms under incoherent illumination. FINCH was implemented with two focal length diffractive lenses on a spatial light modulator (SLM). Improved image resolution over previous single lens systems and at wider bandwidths was observed. For a given image magnification and light source bandwidth, FINCH with two lenses of close focal lengths yields a better hologram in comparison to a single diffractive lens FINCH. Three techniques of lens multiplexing on the SLM were tested and the best method was randomly and uniformly distributing the two lenses. The improved quality of the hologram results from a reduced optical path difference of the interfering beams and increased efficiency. PMID- 22513623 TI - Optimal spectra of white light-emitting diodes using quantum dot nanophosphors. AB - The relationship and trade-offs between the performance parameters including color rendering index (CRI), luminous efficacy of radiation (LER) and correlated color temperature (CCT) of white LEDs using quantum dot nanophosphors (QD-WLEDs) are investigated for CRI >= 80 and LER >= 300 lm/W at 1500 K <= CCT <= 6500 K. The optimal spectra of QD-WLEDs with CCTs of 2700-6500 K have been obtained with a nonlinear program for maximizing LER under conditions of both CRI and a special CRI of R9 strong red above 90 or 95. Furthermore, high performance QD-WLEDs with LER = 381 lm/W for CRI = R9 = 90 and LER = 371 lm/W for CRI = R9 = 95 at CCT = 3000 K, with LER = 361 lm/W for CRI = R9 = 90 and LER = 352 lm/W for CRI = R9 = 95 at CCT = 4500 K, and with LER = 346 lm/W for CRI = R9 = 90 and LER = 338 lm/W for CRI = R9 = 95 at CCT = 5700 K could be achieved. The LERs of high performance white LEDs using QD nanophosphors increase by 13% to 32% compared with that of white LEDs using traditional phosphors. PMID- 22513624 TI - Frequency up-converted lasing in polymeric composites with two-photon absorbing antenna. AB - Energy-transfer-coupled polymeric composites with donors of two-absorbing dyes and acceptors of polymer gain medium are introduced for up-converted laser applications. The two-photon pumped hybrid polymer lasers show significant performance improvement with nearly 10 times reduction of lasing threshold and over 100 times extension of lifespan. PMID- 22513625 TI - Dynamic multidimensional optical networking based on spatial and spectral processing. AB - The recent introduction of optical OFDM and spatial MIMO techniques has led to considerable increases in spectral efficiency and aggregate throughput for future optical networks. However, these spatial and spectral domains can also be exploited for next-generation elastic optical networking. In this paper, we introduce the first hierarchy for dynamic multidimensional spatial and spectral optical networking and complement it with adaptive coded-modulation to form the basis of a novel elastic networking concept. PMID- 22513627 TI - Comparison of surface integral equation formulations for electromagnetic analysis of plasmonic nanoscatterers. AB - The performance of most widespread surface integral equation (SIE) formulations with the method of moments (MoM) are studied in the context of plasmonic materials. Although not yet widespread in optics, SIE-MoM approaches bring important advantages for the rigorous analysis of penetrable plasmonic bodies. Criteria such as accuracy in near and far field calculations, iterative convergence and reliability are addressed to assess the suitability of these formulations in the field of plasmonics. PMID- 22513628 TI - High-speed photodiodes for InP-based photonic integrated circuits. AB - We demonstrate the feasibility of monolithic integration of evanescently coupled Uni-Traveling Carrier Photodiodes (UTC-PDs) having a bandwidth exceeding 100 GHz with Multimode Interference (MMI) couplers. This platform is suitable for active passive, butt-joint monolithic integration with various Multiple Quantum Well (MQW) devices for narrow linewidth millimeter-wave photomixing sources. The fabricated devices achieved a high 3-dB bandwidth of up to 110 GHz and a generated output power of more than 0 dBm (1 mW) at 120 GHz with a flat frequency response over the microwave F-band (90-140 GHz). PMID- 22513626 TI - Timing jitter from the optical spectrum in semiconductor passively mode locked lasers. AB - An analysis of the passively mode locked regime in semiconductor lasers is presented, leading to an explicit expression relating the timing jitter diffusion constant to the optical linewidths in these devices. Experimental results for single section quantum-dash based lasers validating the theoretical analysis are presented for the first time. Timing jitter of mode locked lasers at rates of up to 130 GHz has been experimentally estimated from the optical spectra without requiring fast photodetection. PMID- 22513629 TI - Frequency-comb-referenced singly-resonant OPO for sub-Doppler spectroscopy. AB - We present a widely-tunable, singly-resonant optical parametric oscillator, emitting more than 1 W between 2.7 and 4.2 MUm, which is phase locked to a self referenced frequency comb. Both pump and signal frequencies are directly phase locked to the frequency comb of a NIR-emitting fs mode-locked fibre laser, linked, in turn, to the caesium primary standard. We estimate for the idler frequency a fractional Allan deviation of ~ 3 * 10-12tau-1/2 between 1 and 200 s. To test the spectroscopic performance of the OPO, we carried out saturation spectroscopy of several transitions belonging to the nu1 rovibrational band of CH3I, resolving their electronic quadrupole hyperfine structure, estimating a linewidth better than 200 kHz FWHM for the idler, and determining the absolute frequency of the hyperfine components with a 50-kHz-uncertainty. PMID- 22513630 TI - T-shape microresonator-based high sensitivity quartz-enhanced photoacoustic spectroscopy sensor. AB - A novel spectrophone sensor prototype consisting of a T-shaped acoustic microresonator (T-mR) in off-beam quartz-enhanced photoacoustic spectroscopy (T mR QEPAS) is introduced for the first time. Its performance was evaluated and optimized through an acoustic model and experimental investigation via detection of water vapor in the atmosphere. The present work shows that the use of T-mR in QEPAS based sensor can improve the detection sensitivity by a factor of up to ~30, compared with that using only a bare QTF. This value is as high as that obtained in a conventional "on-beam" QEPAS, while keeping the advantages of "off beam" QEPAS configuration: it is no longer necessary to couple excitation light beam through the narrow gap between the QTF prongs. In addition, the T-mR is really suitable for mass production with high precision. PMID- 22513632 TI - Real-time quantitative visualization of 3D structural information. AB - We demonstrate a novel approach for the real time visualization and quantification of the 3D spatial frequencies in an image domain. Our approach is based on the spectral encoding of spatial frequency principle and permits the formation of an image as a color map in which spatially separated spectral wavelengths correspond to the dominant 3D spatial frequencies of the object. We demonstrate that our approach can visualize and analyze the dominant axial internal structure for each image point in real time and with nanoscale sensitivity to structural changes. Computer modeling and experimental results of instantaneous color visualization and quantification of 3D structures of a model system and biological samples are presented. PMID- 22513633 TI - Optical transmission of corrugated metal films on a two-dimensional hetero colloidal crystal. AB - The near infrared transmission of corrugated metal films deposited on hetero colloidal crystals is investigated. The transmission response of the quasi-three dimensional (quasi-3D) metal film is modified by controlling the nominal thickness of a dielectric layer pre-deposited on the top surface of the colloidal crystal to form a new hetero-colloidal crystal. An extraordinary optical transmission (EOT) phenomenon could be presented in such metallodielectric (MD) architectures. We have found that the main transmission peak is suppressed as the thickness of the intercalated dielectric layer is increased. We propose that the observed EOT is a result of constructive interference between a localized sphere like plasmon mode and an index-guided eigen mode mainly confined in the colloidal crystal, which is confirmed by our numerical simulations. Based on the MD microstructures, a distinct plasmon sensitivity response difference is achieved, which indicates potential applications for biochemical sensing. PMID- 22513631 TI - In vivo Brillouin optical microscopy of the human eye. AB - We report the first Brillouin measurement of the human eye in vivo. We constructed a Brillouin optical scanner safe for human use by employing continuous-wave laser light at 780 nm at a low power of 0.7 mW. With a single scan along the optic axis of the eye, the axial profile of Brillouin frequency shift was obtained with a pixel acquisition time of 0.4 s and axial resolution of about 60 MUm, showing the depth-dependent biomechanical properties in the cornea and lens. PMID- 22513635 TI - Width-modulation of Si photonic wires for quasi-phase-matching of four-wave mixing: experimental and theoretical demonstration. AB - We experimentally demonstrate quasi-phase-matched (QPM) four-wave-mixing (FWM) in silicon (Si) nanowire waveguides with sinusoidally modulated width. We perform discrete wavelength conversion over 250 nm, and observe 12 dB conversion efficiency (CE) enhancement for targeted wavelengths more than 100 nm away from the edge of the 3-dB conversion bandwidth. The QPM process in Si nanowires is rigorously modeled, with results explaining experimental observations. The model is further used to investigate the dependence of the CE on key device parameters, and to introduce devices that facilitate wavelength conversion between the C-band and mid-IR. Devices based on a superposition of sinusoidal gratings are investigated theoretically, and are shown to provide CE enhancement over the entire C-band. Width-modulation is further shown to be compatible with zero dispersion-wavelength pumping for broadband wavelength conversion. The results indicate that QPM via width-modulation is an effective technique for extending the spectral domain of efficient FWM in Si waveguides. PMID- 22513636 TI - Convergent optical wired and wireless long-reach access network using high spectral-efficient modulation. AB - To provide broadband services in a single and low cost perform, the convergent optical wired and wireless access network is promising. Here, we propose and demonstrate a convergent optical wired and wireless long-reach access networks based on orthogonal wavelength division multiplexing (WDM). Both the baseband signal and the radio-over-fiber (ROF) signal are multiplexed and de-multiplexed in optical domain, hence it is simple and the operation speed is not limited by the electronic bottleneck caused by the digital signal processing (DSP). Error free de-multiplexing and down-conversion can be achieved for all the signals after 60 km (long-reach) fiber transmission. The scalability of the system for higher bit-rate (60 GHz) is also simulated and discussed. PMID- 22513637 TI - Designing coupled-resonator optical waveguides based on high-Q tapered grating defect resonators. AB - We present a systematic design of coupled-resonator optical waveguides (CROWs) based on high-Q tapered grating-defect resonators. The formalism is based on coupled-mode theory where forward and backward waveguide modes are coupled by the grating. Although applied to strong gratings (periodic air holes in single-mode silicon-on-insulator waveguides), coupled-mode theory is shown to be valid, since the spatial Fourier transform of the resonant mode is engineered to minimize the coupling to radiation modes and thus the propagation loss. We demonstrate the numerical characterization of strong gratings, the design of high-Q tapered grating-defect resonators (Q>2 * 106, modal volume = 0.38.(lambda/n)3), and the control of inter-resonator coupling for CROWs. Furthermore, we design Butterworth and Bessel filters by tailoring the numbers of holes between adjacent defects. We show with numerical simulation that Butterworth CROWs are more tolerant against fabrication disorder than CROWs with uniform coupling coefficient. PMID- 22513638 TI - Design proposal for a low loss in-plane active photonic crystal waveguide with vertical electrical carrier injection. AB - We propose an active waveguide design that provides both low propagation losses (< 20 dB/cm) and the capability for electrical pumping of the photonic crystal waveguide with a vertical contacting scheme. A careful estimation of a large number of parameters is required in order to obtain both properties. The proposed device supports single mode operation at the telecom wavelength lambda = 1550 nm and is suitable for the implementation of in-plane active photonic crystal devices, such as semiconductor optical amplifiers and lasers. PMID- 22513639 TI - Short time behavior of fluorescence intensity fluctuations in single molecule polarization sensitive experiments. AB - Recent developments in the field of single molecule orientation imaging have led us to devise a simple framework for analyzing fluorescence intensity fluctuations in single molecule polarization sensitive experiments. Based on the new framework, rotational dynamics of individual molecules are quantified, in this paper, from the short time behavior of the time averaged fluorescence intensity fluctuation trajectories. The suggested model can be applied in single molecule fluorescence fluctuations experiments to extract accurate expectation values of photon counts during very short integration time in which rotational diffusion is likely not to be averaged out. PMID- 22513640 TI - Performance improvement of on-off-keying free-space optical transmission systems by a co-propagating reference continuous wave light. AB - In this paper, we analytically investigate an optical signal detection scheme to mitigate the scintillation effect with the assistance of a co-propagating reference continuous wave (CW) light. Using the correlation coefficient between the intensities of the data light and the reference CW light, we mathematically derive their joint intensity distributions under two widely used atmospheric turbulence channel models, namely log-normal distributed channel model and Gamma Gamma distributed channel model, respectively. We also carry out the Monte-Carlo (MC) simulation and show that theoretical results agree with simulation results well. Our analytical results reveal that when the correlation coefficient is 0.99, the power reductions to achieve BER of 10-3 are 12.3 dB and 20.4 dB under moderate and strong atmospheric turbulence conditions (i.e., Rytov variances of 1.0 and 4.0), respectively. In addition, the feasibility of the scheme applied to wavelength-division-multiplexed (WDM) free-space-optical (FSO) transmission systems is also investigated, where only a single reference CW light could be used to mitigate the scintillation effects on all WDM channels. PMID- 22513641 TI - Evaluation of four-dimensional nonbinary LDPC-coded modulation for next generation long-haul optical transport networks. AB - Leveraging the advanced coherent optical communication technologies, this paper explores the feasibility of using four-dimensional (4D) nonbinary LDPC-coded modulation (4D-NB-LDPC-CM) schemes for long-haul transmission in future optical transport networks. In contrast to our previous works on 4D-NB-LDPC-CM which considered amplified spontaneous emission (ASE) noise as the dominant impairment, this paper undertakes transmission in a more realistic optical fiber transmission environment, taking into account impairments due to dispersion effects, nonlinear phase noise, Kerr nonlinearities, and stimulated Raman scattering in addition to ASE noise. We first reveal the advantages of using 4D modulation formats in LDPC coded modulation instead of conventional two-dimensional (2D) modulation formats used with polarization-division multiplexing (PDM). Then we demonstrate that 4D LDPC-coded modulation schemes with nonbinary LDPC component codes significantly outperform not only their conventional PDM-2D counterparts but also the corresponding 4D bit-interleaved LDPC-coded modulation (4D-BI-LDPC-CM) schemes, which employ binary LDPC codes as component codes. We also show that the transmission reach improvement offered by the 4D-NB-LDPC-CM over 4D-BI-LDPC-CM increases as the underlying constellation size and hence the spectral efficiency of transmission increases. Our results suggest that 4D-NB-LDPC-CM can be an excellent candidate for long-haul transmission in next-generation optical networks. PMID- 22513642 TI - Performance analysis of coherent optical 8-star QAM systems using decision-aided maximum likelihood phase estimation. AB - An approximate bit-error rate (BER) expression of 8-star quadrature amplitude modulation (QAM) in the presence of a phase estimation error is derived. The accuracy of the approximate BER is verified via numerical integration of the conditional BER and the Monte-Carlo (MC) simulations. This approximation allows quick estimation of the BER performance and prediction of laser linewidth tolerance, and also facilitates optimization of the ring ratio. PMID- 22513643 TI - Monolithic integration of a silica AWG and Ge photodiodes on Si photonic platform for one-chip WDM receiver. AB - On the silicon (Si) photonic platform, we monolithically integrated a silica based arrayed-waveguide grating (AWG) and germanium (Ge) photodiodes (PDs) using low-temperature fabrication technology. We confirmed demultiplexing by the AWG, optical-electrical signal conversion by Ge PDs, and high-speed signal detection at all channels. In addition, we mounted a multichannel transimpedance amplifier/limiting amplifier (TIA/LA) circuit on the fabricated AWG-PD device using flip-chip bonding technology. The results show the promising potential of our Si photonic platform as a photonics-electronics convergence. PMID- 22513644 TI - High angular tolerance and reflectivity with narrow bandwidth cavity-resonator integrated guided-mode resonance filter. AB - Guided mode resonance filters (GMRFs) are a promising new generation of reflective narrow band filters, that combine structural simplicity with high efficiency. However their intrinsic poor angular tolerance and huge area limit their use in real life applications. Cavity-resonator-integrated guided-mode resonance filters (CRIGFs) are a new class of reflective narrow band filters. They offer in theory narrow-band high-reflectivity with a much smaller footprint than GMRF. Here we demonstrate that for tightly focused incident beams adapted to the CRIGF size, we can obtain simultaneously high spectral selecitivity, high reflectivity, high angular acceptance with large alignment tolerances. We demonstrate experimentally reflectivity above 74%, angular acceptance greater than +/-4.2 degrees for a narrow-band (1.4 nm wide at 847 nm) CRIGF. PMID- 22513645 TI - Broadband multiple-cascaded integration of electroabsorption modulators and high impedance transmission lines by lowering standing-wave effect. AB - Standing wave effect of applied electrical field on optical modulation in multiple-cascaded integration (CI) electroabsorption modulator (EAM) and high impedance transmission line (HITL) has been investigated in this paper. As modulation frequency is increased to the scale that electrical wavelength is in the order of optical modulator length, multiple electrical reflection and self interference on impedance-mismatch boundaries becomes significant, leading to strong position-dependent field distribution and degrading modulation bandwidth. Sharp bandwidth roll of electrical-optical (EO) conversion by standing wave has been found experimentally in CI structure, consistent with simulation results. By comparing different segment number and length of CI- structure, larger section number of design can overcome such problem to get more flatten bandwidth response. Such simple CI for 300MUm long EAM has been demonstrated with flat EO response of -3dB drop 45GHz and -10dB microwave reflection (up to 65GHz) in 6 segement device, suggesting this scheme design is quite useful for efficient broad band modulation. PMID- 22513646 TI - Arbitrary shape surface Fresnel diffraction. AB - Fresnel diffraction calculation on an arbitrary shape surface is proposed. This method is capable of calculating Fresnel diffraction from a source surface with an arbitrary shape to a planar destination surface. Although such calculation can be readily calculated by the direct integral of a diffraction calculation, the calculation cost is proportional to O(N2) in one dimensional or O(N4) in two dimensional cases, where N is the number of sampling points. However, the calculation cost of the proposed method is O(N log N) in one dimensional or O(N2 log N) in two dimensional cases using non-uniform fast Fourier transform. PMID- 22513647 TI - Atypical femur fractures: refining the clinical picture. PMID- 22513649 TI - Effect of vertebroplasty on pain relief, quality of life, and the incidence of new vertebral fractures: a 12-month randomized follow-up, controlled trial. AB - Uncertainty regarding the benefits of vertebroplasty (VP) for the treatment of acute osteoporotic vertebral fractures has recently arisen. A prospective, controlled, randomized single-center trial (ClinicalTrials.gov registration number NCT00994032) was designed to compare the effects of VP versus conservative treatment on the quality of life and pain in patients with painful osteoporotic vertebral fractures, new fractures and secondary adverse effects were also analyzed during a 12-month follow-up period. A total of 125 patients were randomly assigned to receive conservative treatment or VP. The primary end point was to compare the evolution of the quality of life (Quality of Life Questionnaire of the European Foundation for Osteoporosis [Qualeffo-41] and pain (Visual Analogue Scale [VAS]) during a 12 month follow-up. Secondary outcomes included comparison of analgesic consumption, clinical complications, and radiological vertebral fractures at the same time points. Both arms showed significant improvement in VAS scores at all time points, with greater improvement (p = 0.035) in the VP group at the 2-month follow-up. Significant improvement in Qualeffo total score was seen in the VP group throughout the study, whereas this was not seen in the conservative treatment arm until the 6 month follow-up. VP treatment was associated with a significantly increased incidence of vertebral fractures (odds ratio [OR], 2 . 78; 95% confidence interval [CI], 1.02-7.62, p = 0.0462). VP and conservative treatment are both associated with significant improvement in pain and quality of life in patients with painful osteoporotic vertebral fractures over a 1-year follow-up period. VP achieved faster pain relief with significant improvement in the pain score at the 2-month follow-up but was associated with a higher incidence in vertebral fractures. PMID- 22513648 TI - Genetic evidence that thyroid hormone is indispensable for prepubertal insulin like growth factor-I expression and bone acquisition in mice. AB - Understanding how bone growth is regulated by hormonal and mechanical factors during early growth periods is important for optimizing the attainment of peak bone mass to prevent or postpone the occurrence of fragility fractures later in life. Using genetic mouse models that are deficient in thyroid hormone (TH) (Tshr(-/-) and Duox2(-/-)), growth hormone (GH) (Ghrhr(lit/lit)), or both (Tshr( /-); Ghrhr(lit/lit)), we demonstrate that there is an important period prior to puberty when the effects of GH are surprisingly small and TH plays a critical role in the regulation of skeletal growth. Daily administration of T3/T4 during days 5 to 14, the time when serum levels of T3 increase rapidly in mice, rescued the skeletal deficit in TH-deficient mice but not in mice lacking both TH and GH. However, treatment of double-mutant mice with both GH and T3/T4 rescued the bone density deficit. Increased body fat in the TH-deficient as well as TH/GH double mutant mice was rescued by T3/T4 treatment during days 5 to 14. In vitro studies in osteoblasts revealed that T3 in the presence of TH receptor (TR) alpha1 bound to a TH response element in intron 1 of the IGF-I gene to stimulate transcription. In vivo studies using TRalpha and TRbeta knockout mice revealed evidence for differential regulation of insulin-like growth factor (IGF)-I expression by the two receptors. Furthermore, blockade of IGF-I action partially inhibited the biological effects of TH, thus suggesting that both IGF-I-dependent and IGF-I-independent mechanisms contribute to TH effects on prepubertal bone acquisition. PMID- 22513650 TI - Agminated blue naevi in a patient with EMO syndrome. PMID- 22513651 TI - Naphthazarin has a protective effect on the 1-methyl-4-phenyl-1,2,3,4 tetrahydropyridine-induced Parkinson's disease model. AB - "Neurohormesis" refers to a response to a moderate level of stress that enhances the ability of the nervous systems to resist more severe stress that might be lethal or cause dysfunction or disease. Neurohormetic phytochemicals, such as, resveratrol, sulforaphane, curcumin, and catechins, protect neurons against injury and disease. Naphthoquinones, such as, juglone and plumbagin, induce robust hormetic stress responses. However, the possibility that subtoxic dose of 5,8-dihydroxy-1,4-naphthoquinone (naphthazarin) may protect against brain diseases via the activation of an adaptive stress response pathway in the brain has not been investigated. In this study, we examined the neurohormetic effect of a subtoxic dose of naphthazarin in a Parkinson's disease model. It was found that, under these conditions, naphthazarin enhanced movement ability, prevented loss of dopaminergic neurons, and attenuated neuroinflammation in a 1-methyl-4 phenyl-1,2,3,4-tetrahydropyridine-induced Parkinson's disease model. Furthermore, it was found that the neuroprotective effect of naphthazarin was mediated by the suppression of astroglial activation in response to 1-methyl-4-phenylpyridine treatment. In conclusion, we suggest that naphthazarin, in view of its hormetic effect on neuroprotection, be viewed as a potential treatment for Parkinson's disease and other neurodegenerative diseases associated with neuroinflammation. PMID- 22513652 TI - Surfactant-free CZTS nanoparticles as building blocks for low-cost solar cell absorbers. AB - A process route for the fabrication of solvent-redispersible, surfactant-free Cu2ZnSnS4 (CZTS) nanoparticles has been designed with the objective to have the benefit of a simple sulfide source which advantageously acts as (i) a complexing agent inhibiting crystallite growth, (ii) a surface additive providing redispersion in low ionic strength polar solvents and (iii) a transient ligand easily replaced by an carbon-free surface additive. This multifunctional use of the sulfide source has been achieved through a fine tuning of ((Cu2+)(a)(Zn2+)(b)(Sn4+)(c)(Tu)(d)(OH-)(e))(t+), Tu = thiourea) oligomers, leading after temperature polycondensation and S2- exchange to highly concentrated (c > 100 g l-1), stable, ethanolic CZTS dispersions. The good electronic properties and low-defect concentration of the sintered, crack-free CZTSe films resulting from these building blocks was shown by photoluminescence investigation, making these building blocks interesting for low-cost, high performance CZTSe solar cells. PMID- 22513653 TI - Unweaving the rainbow: a review of the relationship between single-walled carbon nanotube molecular structures and their chemical reactivity. AB - Single-walled carbon nanotubes (SWNTs) are a fundamental family of distinct molecules, each bearing the possibility of different reactivities due to their intrinsically distinct chemical properties. SWNT syntheses generate a heterogeneous mixture of species with varying electronic character, lengths, diameters and helicities, (n,m), as well as other amorphous, graphitic and metal catalyst impurities. In recent years, selective syntheses and post-synthetic separation strategies have advanced, driven by the requirement for pure SWNTs displaying particular features. Covalent surface modifications are widely-used to adapt SWNTs for specific applications with modified solubility, compatibility and specific functionalities. In many cases, such reactions have been found to be selective, illuminating the fundamentally distinct chemistry of each (n,m) species. This differential reactivity has found immediate utility in facilitating the sorting of nanotubes according to specific diameter, electronic properties and, most importantly, helicity. In this tutorial review, we discuss a wide range of selective reactions, the mechanisms that are thought to govern selectivity, and the challenges of separating, characterising and regenerating the modified SWNTs. PMID- 22513656 TI - Effects of worksite health interventions involving reduced work hours and physical exercise on sickness absence costs. AB - OBJECTIVE: To investigate the effects of physical exercise during work hours (PE) and reduced work hours (RWH) on direct and indirect costs associated with sickness absence (SA). METHODS: Sickness absence and related costs at six workplaces, matched and randomized to three conditions (PE, RWH, and referents), were retrieved from company records and/or estimated using salary conversion methods or value-added equations on the basis of interview data. RESULTS: Although SA days decreased in all conditions (PE, 11.4%; RWH, 4.9%; referents, 15.9%), costs were reduced in the PE (22.2%) and RWH (4.9%) conditions but not among referents (10.2% increase). CONCLUSIONS: Worksite health interventions may generate savings in SA costs. Costs may not be linear to changes in SA days. Combing the friction method with indirect cost estimates on the basis of value added productivity may help illuminate both direct and indirect SA costs. PMID- 22513655 TI - What is the role of thiurams in allergy to natural rubber latex products? PMID- 22513657 TI - Increased Micronodule Counts Are More Common in Occupationally Silica Dust Exposed Smokers Than in Control Smokers. AB - OBJECTIVE:: To determine the prevalence of increased micronodule counts in silica dust-exposed smokers. METHODS:: We evaluated 54 male smokers with severe silica dust exposure and 54 male control smokers. Both groups underwent low-dose chest computed tomography and lung function testing. Computed tomographic scans were visually evaluated for solid micronodules (<3 mm). The 95th percentile of micronodule count was calculated for the control smokers. Prevalence of an increased micronodule count was assessed for the dust-exposed subjects. RESULTS:: Solid micronodules were present in most participants of both groups. The 95th percentile of micronodule count in the control group was 13. Increased micronodule counts were significantly more common in the exposed group than in the control group (P = 0.01). CONCLUSIONS:: A substantial number of silica exposed heavy smokers evaluated for silicosis have increased micronodule counts on chest computed tomographic scan. This finding might represent an early stage of silicosis. PMID- 22513658 TI - Multisource surveillance system for work-related burns. AB - OBJECTIVES: The purpose of this study was to develop a multisource surveillance system for work-related burns. METHODS: For 2009, records about work-related burns were obtained from Michigan's 134 hospitals, the Workers' Compensation Agency, the state's sole Poison Control Center, and death certificates. Companies where the most severe burns occurred were referred to the Occupational Safety and Health Administration. RESULTS: There were 1461 work-related burns in 2009. Sixty six percent of the burns were reported in male workers and 85.3% in whites. One third of the individuals sustained burns to the wrist(s) and hand(s). Second degree and thermal burns were the most common. Accommodation and food services and health care and social assistance industries accounted for 50% of all burns. CONCLUSIONS: The Michigan multidata source surveillance system identified three times more burns than the Bureau of Labor Statistics' employer-based system, which reported 450 burns in 2009. PMID- 22513661 TI - 4Pi focusing of spatially modulated radially polarized vortex beams. AB - We propose a method for generating focal beams with special intensity distributions using radially polarized vortex beams in a 4Pi configuration. A spherical dark-hollow beam and hollow beam array can be obtained by vortex beams with topological charge of m=1. A dark channel can be generated using vortex beams with topological charge of m=2. The length of the well-defined hollow beam array and the dark channel is about 30lambda. These interesting beams are useful in optical trapping and manipulation. PMID- 22513660 TI - Role of quaternary ammonium salts as new additives in the enantioselective organocatalytic beta-benzylation of enals. AB - We report herein the efficiency of quaternary ammonium salts as co-catalysts in organocatalytic Michael reactions involving iminium activation of alpha,beta unsaturated aldehydes. The enantioselective formal benzylation of these substrates has been optimized and used to rationalize the role of the ammonium salts in these processes. PMID- 22513659 TI - Randomized clinical trial of glutamine-supplemented versus standard parenteral nutrition in infants with surgical gastrointestinal disease. AB - BACKGROUND: Addition of glutamine to parenteral nutrition in surgical infants remains controversial. The aim of this trial was to determine whether glutamine supplementation of parenteral nutrition in infants requiring surgery would reduce the time to full enteral feeding and/or decrease the incidence of sepsis and septicaemia. METHODS: A prospective double-blind multicentre randomized clinical trial was performed in surgical infants less than 3 months old who required parenteral nutrition. Patients were allocated to treatment or control groups by means of minimization. Infants received either 0.6 g per kg per day alanyl glutamine (treatment group) or isonitrogenous isocaloric parenteral nutrition (control group) until full enteral feeding was achieved. Primary outcomes were time to full enteral feeding and incidence of sepsis. Cox regression analysis was used to compare time to full enteral feeding, and to calculate risk of sepsis/septicaemia. RESULTS: A total of 174 patients were randomized, of whom 164 completed the trial and were analysed (82 in each group). There was no difference in time to full enteral feeding or time to first enteral feeding between groups, and supplementation with glutamine had no effect on the overall incidence of sepsis or septicaemia. However, during total parenteral nutrition (before the first enteral feed), glutamine administration was associated with a significantly decreased risk of developing sepsis (hazard ratio 0.33, 95 per cent confidence interval 0.15 to 0.72; P = 0.005). CONCLUSION: Glutamine supplementation during parenteral nutrition did not reduce the incidence of sepsis in surgical infants with gastrointestinal disease. REGISTRATION NUMBER: ISRCTN83168963 (http://www.controlled-trials.com). PMID- 22513662 TI - Parallel Raman microspectroscopy using programmable multipoint illumination. AB - We present a novel parallel Raman microspectroscopy scheme for simultaneously collecting Raman spectra from multiple points. This scheme is realized by projectinga multiple-point laser illumination pattern using a spatial light modulator (SLM) and wide-field Raman imaging collection. We demonstrate the performance of this scheme using uniform samples, trapped polymer microparticles and fixed polymer microparticles with mixed molecular composition within a 50*50 MUm(2) field of view. This scheme enables the acquisition of Raman spectra from as many as 40 points simultaneously using a single illumination pattern and detector recording frame without scanning. PMID- 22513663 TI - Low bending loss and effectively single-mode all-solid photonic bandgap fiber with an effective area of 650 MUm2. AB - A large-mode-area all-solid photonic bandgap fiber with a seven-cell core and five high-index rod rings is investigated. Numerical simulations show that an effective area of more than 500 MUm(2), a bending loss of less than 0.1 dB/m at a bending radius of 10 cm and effectively single-mode operation can be achieved simultaneously. A core diameter of 44.8 MUm and an effective area of 650 MUm(2) at 1064 nm are achieved in a fabricated fiber. Bending loss at 1064 nm is 0.09 dB/m at a bending radius of 7 cm. Effectively single-mode operation is also realized at a bending radius of 10 cm. PMID- 22513664 TI - Subwavelength imaging enhancement through a three-dimensional plasmon superlens with rough surface. AB - In this Letter we investigate the subwavelength imaging of a three-dimensional plasmon superlens based on the full vector wave simulations of optical wave propagation and transmission. The optical transfer functions are computed. Comparisons are made between the results of lenses with flat and periodic/random rough surfaces. We also study the problem of practical imaging system geometry using laser as an illumination source. Results show that the lens with periodic or random roughness can reduce the field interference effects, and provide improved focus on the transmission field and the Poynting flux. We illustrate that the subwavelength roughness in a plasmon lens can enhance the image resolution over a flat lens for both matched and unmatched permittivity conditions. The enhancement of resolution occurs because the introduced subwavelength roughness can amplify the evanescent wave components and suppress the surface plasmon resonance peaks. PMID- 22513665 TI - Reduced linewidth enhancement factor due to excited state transition of quantum dot lasers. AB - The carrier induced refractive index change and linewidth enhancement factor alpha due to ground-state (GS) and excited-state (ES) transitions have been compared by measuring the optical gain spectra from an InAs/GaAs quantum dot (QD) laser structure. It is shown that the ES transition exhibits a reduced alpha factor compared to the value due to the GS transition. This result can be explained by the alpha-factor due to the ES transition having a smaller increase from the non-resonant carriers in the combined state of the wetting layer and InGaAs strain reducing layer than the alpha-factor increase due to the GS transition, since the relaxation time for carriers from the combined state of the wetting layer and InGaAs strain reducing layer to the ES is shorter than to the GS. The result reported here shows another advantage of using ES QD lasers for optical communication, in addition to their higher modulation speed. PMID- 22513666 TI - Topological charge dependent propagation of optical vortices under quadratic phase transformation. AB - We make optical vortices of different topological charge and diffract them through a quadratic phase mask using the same spatial light modulator. This phase mask shows the diffraction in which the positive diffracted order has different dynamics than the negative diffracted order. The diffraction pattern and its orientation depend on the charge of the vortex as well as its sign. The experimental results are verified with exact analytical results. PMID- 22513667 TI - Double resonance 1-D photonic crystal cavities for single-molecule mid-infrared photothermal spectroscopy: theory and design. AB - We propose and theoretically examine a novel mid-infrared (mid-IR) photothermal spectroscopic sensing technique capable of detecting a single small molecule. Our conceptual design attains such high sensitivity by leveraging dramatically amplified photothermal effects in an optical nanocavity doubly resonant at both mid-IR pump and near-IR probe wavelengths. Unlike conventional mid-IR spectroscopy, the technique eliminates the need for cryogenically cooled mid-IR photodetectors, as optical detection is performed solely at the near-IR probe wavelength. A device design based on nested one-dimensional nanobeam photonic crystal cavities is numerically analyzed to demonstrate the technique's potential for single small gas molecule detection. PMID- 22513668 TI - Spectral-domain optical coherence tomography with a Fresnel spectrometer. AB - We propose a novel spectral-domain optical coherence tomography (SD-OCT) equipped with a Fresnel spectrometer, which utilizes a Fresnel zone plate (FZP) as both dispersion and focusing optics and thus spreads the spectral interferogram evenly in wavenumber domain because of the proportional relation between the focal length of the FZP and the wavenumber. With no need of the conversion calculation from wavelength to wavenumber in conventional SD-OCT, this new design is favorable for fast imaging with high resolution. As only a FZP and CCD are used, the Fresnel spectrometer is simple and compact. It is experimentally shown that its performance is as good as that of numerical interpolation in conventional SD OCT. Imaging of bio-tissue by Fresnel SD-OCT is also demonstrated. PMID- 22513669 TI - Pump-probe imaging of historical pigments used in paintings. AB - A recently developed nonlinear optical pump-probe microscopy technique uses modulation transfer to sensitively extract excited-state dynamics of endogenous biological pigments, such as eumelanin and pheomelanin. In this work, we use this method to image and characterize several inorganic and organic pigments used in historical art. We show substantial differences in the near-IR pump-probe signatures from nominally similar pigments and suggest extensions to art restoration. PMID- 22513670 TI - Frequency locked micro disk resonator for real time and precise monitoring of refractive index. AB - We experimentally demonstrate a frequency modulation locked servo loop, locked to a resonance line of an on-chip microdisk resonator in a silicon nitride platform. By using this approach, we demonstrate real-time monitoring of refractive index variations with a precision approaching 10(-7) RIU, using a moderate Q factor of 10(4). The approach can be applied for intensity independent, dynamic and precise index of refraction monitoring for biosensing applications. PMID- 22513671 TI - Terahertz interferometric synthetic aperture tomography for confocal imaging systems. AB - Terahertz (THz) interferometric synthetic aperture tomography (TISAT) for confocal imaging within extended objects is demonstrated by combining attributes of synthetic aperture radar and optical coherence tomography. Algorithms recently devised for interferometric synthetic aperture microscopy are adapted to account for the diffraction-and defocusing-induced spatially varying THz beam width characteristic of narrow depth of focus, high-resolution confocal imaging. A frequency-swept two-dimensional TISAT confocal imaging instrument rapidly achieves in-focus, diffraction-limited resolution over a depth 12 times larger than the instrument's depth of focus in a manner that may be easily extended to three dimensions and greater depths. PMID- 22513672 TI - Stimulated Raman scattering of lattice translational modes in liquid heavy water. AB - A study was conducted on stimulated Raman scattering (SRS) when laser-induced plasma is formed in heavy water by focusing an intense picosecond pulsed Nd:YAG laser beam with wavelength 532 nm at room temperature. An unexpected 280 cm(-1) low frequency SRS line attributed to the lattice translational modes is observed. This SRS line and the internal-mode SRS lines indicate that the ice VII structure is formed in heavy water under the condition of laser-induced shockwave production. PMID- 22513673 TI - Transmission line model for extraction of transmission characteristics in photonic crystal waveguides with stubs: optical filter design. AB - A simple and efficient transmission line model is proposed here to study how the transmission characteristics of photonic crystal waveguides are tailored by introduction of stubs patterned in the photonic crystal lattice. It is shown that band-pass and band-stop optical filters can be easily designed and optimized when stubs of appropriate length are brought in. Since the lengths of the designed stubs are not necessarily integer multiples of the photonic crystal lattice constant, a geometric shift in a portion of the photonic crystal structure is shown to be essential. The proposed model is verified by using a rigorous numerical method. An excellent agreement is observed between the numerical results and the transmission characteristics as extracted by the proposed model. PMID- 22513674 TI - Color encoding of binary fringes for gamma correction in 3-D profiling. AB - Three-dimensional profiling by sinusoidal fringe projection using PSI-algorithms are distorted by the nonlinear response of digital cameras and commercial video projectors. To solve the problem, we present a fringe generation technique that consists of projecting and acquiring a temporal sequence of strictly binary color patterns, whose (adequately weighted) average leads to sinusoidal fringe patterns with the required number of bits, which allows for a reliable three-dimensional profile using a PSI-algorithm. Validation experiments are presented. PMID- 22513675 TI - Shape-invariant pulses in resonant linear absorbers. AB - We theoretically describe ultrashort self-similar pulses propagating in coherent linear absorbers near optical resonance and propose a method for their experimental realization. PMID- 22513676 TI - Ultralow power continuous-wave frequency conversion in hydrogenated amorphous silicon waveguides. AB - We demonstrate wavelength conversion through nonlinear parametric processes in hydrogenated amorphous silicon (a-Si:H) with maximum conversion efficiency of -13 dB at telecommunication data rates (10 GHz) using only 15 mW of pump peak power. Conversion bandwidths as large as 150 nm (20 THz) are measured in continuous-wave regime at telecommunication wavelengths. The nonlinear refractive index of the material is determined by four-wave mixing (FWM) to be n(2)=7.43*10(-13) cm(2)/W, approximately an order of magnitude larger than that of single crystal silicon. PMID- 22513677 TI - Square-wave pulse with ultra-wide tuning range in a passively mode-locked fiber laser. AB - We report the generation of ultrawide tunable square-wave pulse in an erbium doped mode-locked fiber laser. The pulse width can be tuned in an ultrawide range of more than 1700 ns by simply increasing the pump power. The pulse-width tuning is 5.1 ns/mW. To the best of our knowledge, this is the widest pulse-width tuning range of any square-wave pulse in an all-fiber passively mode-locked fiber laser. Experimental results show that the fiber nonlinearity plays an important role in the tuning range of the output pulse width. The high nonlinearity helps to increase the tuning range of the pulse width. PMID- 22513678 TI - Generating maximum entanglement under asymmetric couplings to surface plasmons. AB - Generating entangled states is a vital ingredient for quantum information engineering. Here, we investigate the entanglement generation between two quantum dots coupled to nanoring surface plasmons with asymmetric coupling strength g(1) and g(2). The dynamics of concurrence C is obtained by solving the corresponding master equation. High entanglement can be generated at appropriate times through the scatterings of the incident field and its scattered field. Furthermore, we find that maximum entanglement can be created when r=g(1)/g(2) is the ratio of odd numbers. Contrary to intuition, relative high entanglement (C?1) can remain even if the ratio r is far off the required values, which is useful in real experiments. PMID- 22513679 TI - Statistical physics inspired energy-efficient coded-modulation for optical communications. AB - Because Shannon's entropy can be obtained by Stirling's approximation of thermodynamics entropy, the statistical physics energy minimization methods are directly applicable to the signal constellation design. We demonstrate that statistical physics inspired energy-efficient (EE) signal constellation designs, in combination with large-girth low-density parity-check (LDPC) codes, significantly outperform conventional LDPC-coded polarization-division multiplexed quadrature amplitude modulation schemes. We also describe an EE signal constellation design algorithm. Finally, we propose the discrete-time implementation of D-dimensional transceiver and corresponding EE polarization division multiplexed system. PMID- 22513680 TI - Remote sub-diffraction imaging with femtosecond laser filaments. AB - Achieving super-resolution has become a scientific imperative for remote imaging of objects and scenes needing increased detail and has motivated the development of various laser-based techniques. We demonstrate a scheme which achieves subdiffraction imaging of remote objects by using femtosecond laser filaments. The use of laser filaments for imaging is destined to have applications in many environments. PMID- 22513681 TI - Quasi-continuous burst-mode laser for high-speed planar imaging. AB - The pulse-burst duration of a compact burst-mode Nd:YAG laser is extended by one order of magnitude compared to previous flashlamp-pumped designs by incorporating a fiber oscillator and diode-pumped solid-state amplifiers. The laser has a linewidth of <2 GHz at 1064.3 nm with 150 mJ per individual pulse at 10 kHz. The performance of the system is evaluated by using the third-harmonic output at 354.8 nm for high-speed planar laser-induced fluorescence of formaldehyde in a lifted methane-air diffusion flame. A total of 100 and 200 sequential images of unsteady fluid-flame interactions are acquired at repetition rates of 10 kHz and 20 kHz, respectively. PMID- 22513682 TI - Multifocal multiphoton endoscope. AB - We report a miniaturized resonant/non-resonant multi-fiber raster scanner that is paired with a gradient-index lens assembly to achieve a compact and flexible multifocal multiphoton endoscope capable of longitudinal parallel image acquisition. Multiphoton images are obtained simultaneously at three axial depths, separated by >=4.8 MUm, by incorporating three axially offset double clad optical fibers into the miniaturized scanner. The fabricated endoscope has an outer diameter of 3 mm, a rigid length of 4 cm, and acquires images at 4 frames/s per focal plane, with lateral and axial resolutions for two-photon imaging of 0.8 and 10 MUm, respectively. PMID- 22513683 TI - Peak intensity measurement of relativistic lasers via nonlinear Thomson scattering. AB - The measurement of peak laser intensities exceeding 10(20) W/cm(2) is in general a very challenging task. We suggest a simple method to accurately measure such high intensities up to about 10(23) W/cm(2), by colliding a beam of ultrarelativistic electrons with the laser pulse. The method exploits the high directionality of the radiation emitted by ultrarelativistic electrons via nonlinear Thomson scattering. Initial electron energies well within the reach of laser wake-field accelerators are required, allowing in principle for an all optical setup. Accuracies of the order of 10% are theoretically envisaged. PMID- 22513684 TI - Single-shot photonic time-intensity integration based on a time-spectrum convolution system. AB - Real-time and single-shot ultra-fast photonic time-intensity integration of arbitrary temporal waveforms is proposed and demonstrated. The intensity integration concept is based on a time-spectrum convolution system, where the use of a multi-wavelength laser with a flat envelope, employed as the incoherent broadband source, enables single-shot operation. The experimental implementation is based on optical intensity modulation of the multi-wavelength laser with the input waveform, followed by linear dispersion. In particular, photonic temporal intensity integration with a processing bandwidth of 36.8 GHz over an integration time window of 1.24 ns is verified by experimentally measuring the integration of an ultra-short microwave pulse and an arbitrary microwave waveform. PMID- 22513685 TI - Current and frequency modulation characteristics for continuous-wave quantum cascade lasers at 9.06 MUm. AB - We report the characteristics of current induced frequency modulation (FM) for two continuous-wave quantum cascade lasers (QCLs) at 9.06 MUm. Both the frequency tuning rate and the phase shift between intensity modulation and FM are measured at different modulation frequencies from 10 Hz to 200 kHz. The frequency tuning rate of the QCLs depends on both the modulation frequency and amplitude. The tested QCL has been used to detect ambient water vapor with wavelength modulation spectroscopy for validation with a numerical model. PMID- 22513687 TI - High-efficiency near-degenerate PPMgLN optical parametric oscillator with a volume Bragg grating. AB - We demonstrate a high-efficiency near-degenerate periodically poled MgO:LiNbO(3) (PPMgLN) optical parametric oscillator (OPO) using a volume Bragg grating (VBG) output coupler (OC) pumped by a multilongitudinal Q-switched Nd:YVO(4) laser at 20 kHz repetition rate. A total parametric power of 4.3 W with a conversion efficiency of 60% is achieved in a double-pass pump configuration. The output power improvement over the case of a single-pass pump is nearly 60%. Both the signal and the idler bandwidths are less than 40 GHz and are confined within 170 GHz bandwidth at 2128.8 nm. Such efficiency is, to our knowledge, the highest ever achieved from a degenerate OPO using a VBG OC. PMID- 22513686 TI - Employment of frame accumulation and shaped function for upgrading low-light level image detection sensitivity. AB - We demonstrate a novel method that employs a frame-accumulation and shaped function technique to improve an image sensor's detection sensitivity using probability statistics. It can obtain the unbiased estimate for the low-light level image signal, thus upgrading the signal-to-noise ratio to a high degree. It was verified by an experiment in a sealed box. By the help of a variable light beam-shaped function saw-tooth signal in front of a camera, the low-light-level shadow image that was invisible to the camera could be revealed clearly from the frame accumulation data. The method can surpass an image sensor's detection limitation. PMID- 22513688 TI - Snapshot imaging Mueller matrix polarimeter using polarization gratings. AB - A snapshot imaging Mueller matrix polarimeter (SIMMP) is theoretically described and empirically demonstrated through simulation. Spatial polarization fringes are localized onto a sample by incorporating polarization gratings (PGs) into a polarization generator module. These fringes modulate the Mueller matrix (MM) components of the sample, which are subsequently isolated with PGs in an analyzer module. The MM components are amplitude modulated onto spatial carrier frequencies which, due to the PGs, maintain high visibility in spectrally broadband illumination. An interference model of the SIMMP is provided, followed by methods of reconstruction and calibration. Lastly, a numerical simulation is used to demonstrate the system's performance in the presence of noise. PMID- 22513689 TI - Polymer optical fiber Bragg grating acting as an intrinsic biochemical concentration sensor. AB - We demonstrate an intrinsic biochemical concentration sensor based on a polymer optical fiber Bragg grating. The water content absorbed by the polymer fiber from a surrounding solution depends on the concentration of the solution because of the osmotic effect. The variation of water content in the fiber causes a change in the fiber dimensions and a variation in refractive index and, therefore, a shift in the Bragg wavelength. Saline solutions with concentration from 0% to 22% were used to demonstrate the sensing principle, resulting in a total wavelength shift of 0.9 nm, allowing high-resolution concentration measurements to be realized. PMID- 22513690 TI - Photonic crystal fiber tip interferometer for refractive index sensing. AB - In this paper we present an interferometer based on photonic crystal fiber (PCF) tip ended with a solid silica-sphere for refractive index sensing. The sensor is fabricated by splicing one end of the holey PCF to a single mode fiber (SMF) and applying arc at the other end to form a solid sphere. The sensor has been experimentally tested for refractive index and temperature sensing by monitoring its wavelength shift. Measurement results show that the sensor has the resolution of the order of 8.7*10(-4) over the refractive index range of 1.33-1.40, and temperature sensitivity of the order of 10 pm/ degrees C in the range of 20-100 degrees C. PMID- 22513691 TI - Diode-pumped mode-locked femtosecond Tm:CLNGG disordered crystal laser. AB - A diode-end-pumped passively mode-locked femtosecond Tm-doped calcium lithium niobium gallium garnet (Tm:CLNGG) disordered crystal laser was demonstrated for the first time to our knowledge. With a 790 nm laser diode pumping, stable CW mode-locking operation was obtained by using a semiconductor saturable absorber mirror. The disordered crystal laser generated mode-locked pulses as short as 479 fs, with an average output power of 288 mW, and repetition rate of 99 MHz in 2 MUm spectral region. PMID- 22513692 TI - Hyperfine Paschen-Back regime realized in Rb nanocell. AB - A simple and efficient scheme based on a one-dimensional nanometric-thin cell filled with Rb and strong permanent ring magnets allows direct observation of the hyperfine Paschen-Back regime on the D(1) line in the 0.5-0.7 T magnetic field. Experimental results are perfectly consistent with the theory. In particular, with sigma(+) laser excitation, the slopes of the B-field dependence of frequency shifts for all 10 individual transitions of (85,87)Rb are the same and equal to 18.6 MHz/mT. Possible applications for magnetometry with submicron spatial resolution and tunable atomic frequency references are discussed. PMID- 22513693 TI - Pattern-effect-free all-optical wavelength conversion using a hydrogenated amorphous silicon waveguide with ultra-fast carrier decay. AB - Ultra-fast carrier decay, recently discovered in a hydrogenated amorphous silicon waveguide, can be exploited for pattern-effect-free all-optical signal processing based on optical Kerr nonlinearity. In this study, we utilized a 10 Gbit/s RZ-OOK data stream as a pump for degenerate four-wave mixing in a low-loss hydrogenated amorphous silicon waveguide. The propagation loss of the waveguide used was 1.0+/ 0.2 dB/cm at 1550 nm. Unlike crystalline silicon waveguides, no noticeable difference was observed in the BER characteristics between the cases of PRBS 2(7) 1 and 2(31)-1. PMID- 22513694 TI - Compressor optimization with compressor-based multiphoton intrapulse interference phase scan (MIIPS). AB - The multiphoton intrapulse interference phase scan (MIIPS) technique is modified to optimize the compressor settings of a chirped pulse amplification (CPA) laser system. Here, we use the compressor itself to perform the phase scan inherent in MIIPS measurement . A frequency-resolved optical gating measurement shows that the pulse duration of the compressor optimized using the modified MIIPS technique is 33.8 fs with a 2.24 rad temporal phase variation above 2% intensity. The measured time-bandwidth product is 0.60, which is close to that of transform limited Gaussian pulse (0.44). PMID- 22513695 TI - Cerebral blood flow imaged with ultrahigh-resolution optical coherence angiography and Doppler tomography. AB - Speckle contrast based optical coherence angiography (OCA) and optical coherence Doppler tomography (ODT) have been applied to image cerebral blood flow previously. However, the contrast mechanisms of these two methods are not fully studied. Here, we present both flow phantom and in vivo animal experiments using ultrahigh-resolution OCA (MUOCA) and ODT (MUODT) to investigate the flow sensitivity differences between these two methods. Our results show that the high sensitivity of MUOCA for visualizing minute vasculature (e.g., slow capillary beds) is due to the enhancement by random Brownian motion of scatterers (e.g., red and white blood cells) within the vessels; whereas, MUODT permits detection of directional flow below the Brownian motion regime (e.g., laser-induced microischemia) and is, therefore, more suitable for brain functional imaging. PMID- 22513696 TI - Optically controlled terahertz beam steering and imaging. AB - We propose a spatial modulator for terahertz waves based on light induced electron plasma in photo-active semiconductors. A two-dimensional array of computer controlled light is used to create free carries in bulk silicon, which results in a spatial modulation of the transmission at terahertz frequencies. This method not only exhibits a remarkable modulation depth over a broad frequency range but also allows for an optically controlled beam steering of terahertz waves by inducing virtual grating structures. In addition, we analyze the possibility of all-optically controlled terahertz imaging. PMID- 22513697 TI - Meta-analysis of the association between the interleukin-1A -889C/T polymorphism and Alzheimer's disease. AB - No clear consensus has been reached on the Interleukin-1A (IL-1A) -889C/T polymorphism and Alzheimer's disease (AD) risk. In this meta-analysis, 27 case control studies were assessed to evaluate the possible association. Overall, positive associations of the IL-1A -889C/T polymorphism with AD risk were found in allele comparison T vs. C (OR = 1.09, 95% CI = 1.01-1.18), recessive model TT vs. CT + CC (OR = 1.21, 95% CI = 1.01-1.45), and homozygote comparison (TT vs. CC; OR = 1.32, 95% CI = 1.04-1.67). In subgroup analysis stratified by ethnicity, significant associations were demonstrated in Caucasians but not in Asians. In subgroup analysis according to the age of onset, the data showed a significant association in patients with late-onset AD in Caucasians but not in early-onset AD. In conclusion, this meta-analysis supports the idea that IL-1A -889C/T polymorphism is capable of causing AD and LOAD susceptibility in Caucasians but not in Asians. PMID- 22513698 TI - Etanercept-induced clinical remission of type II pityriasis rubra pilaris with rheumatoid arthritis. PMID- 22513699 TI - Efficacy of memantine in delaying clinical worsening in Alzheimer's disease (AD): responder analyses of nine clinical trials with patients with moderate to severe AD. AB - OBJECTIVE: Responder analyses are of relevance to evaluate the benefits of a medical treatment. The aim of the current paper is to analyse the response of patients with moderate to severe Alzheimer's disease (AD) to memantine, and clinical relevant response is defined as a delay of clinical worsening. METHODS: Post hoc analyses were performed over the results of nine individual clinical trials including 2506 study patients. Overall, estimates of the odds ratio (OR) and corresponding confidence intervals were based upon a random-effect model for three individual domains (cognition, activities of daily living and clinical global impression). In addition, a combined responder criterion (triple response) includes all three individual domains. RESULTS: Responder analyses have shown that AD patients treated with memantine benefited from a significant delay of clinical worsening compared with placebo-treated patients, and fewer patients faced clinical worsening in the relevant domains cognition (24.6% vs 36.2%, p < 0.001), activities of daily living (56.2% vs 61.6%, p < 0.05) and global impression of change (40.9% vs 49.8, p < 0.001). In addition, response to treatment on the combined domains (triple response) was significantly in favour of memantine compared with placebo, with fewer patients showing clinical worsening (11.0% vs 20.4%, p < 0.001). CONCLUSIONS: Treatment with memantine delays clinical worsening in patients with moderate to severe AD when compared with placebo. This effect was seen in single domains (cognition, functional abilities and clinical global impression) as well as in the combination of these domains. The consistent results prove the beneficial effects of memantine in moderate to severe AD patients. PMID- 22513700 TI - Is delay of clinical worsening a valuable goal in the treatment of Alzheimer's disease? PMID- 22513702 TI - The heart speaks: embracing integrative medicine for heart health. PMID- 22513703 TI - Parenteral nutrition product shortages: the A.S.P.E.N. strategy. AB - Product (drug) shortages have had a significant impact on the healthcare system, particularly on patients and clinicians. This has been especially true with patients requiring parenteral nutrition (PN). The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) has dealt with PN product shortages in the past on behalf of its members and their patients. However, the shortage severity and duration have made dealing with the PN product shortages in 2010-2012 extremely challenging. PMID- 22513704 TI - Anti-microbial locks increase the prevalence of Staphylococcus aureus and antibiotic-resistant Enterobacter: observational retrospective cohort study. AB - BACKGROUND: Anti-microbial lock solutions (AML), in conjunction with systemic antibiotics, may successfully treat tunnelled haemodialysis catheter-related bloodstream infections (CR-BSI). It is unknown whether AML promote anti-microbial resistance. METHODS: This is a retrospective cohort study of all CR-BSI (2003 2006) in our dialysis unit. Controls (n = 265) were treated with systemic vancomycin and gentamicin. In addition to the systemic antibiotics, the study group (n = 662) received AML containing vancomycin and gentamicin during inter dialytic periods. Antibiotic sensitivity/resistance profiles of all organisms were analysed. Changes in the incidence of infection (chi-square test) and resistant organisms (Fisher's exact test) were calculated. RESULTS: The incidence of CR-BSI decreased from 8.50/1000 catheter days (controls) to 3.80 (study group; P < 0.0001), and the incidence of relapses decreased (P = 0.0027). The number needed to treat to prevent subsequent bacteraemia using an AML adjunct is 3 +/- 0.4. The proportion of Gram-positive cultures increased (P < 0.0001), including Staphylococcus aureus (P = 0.03), but the proportion of methicillin-resistant S. aureus (P = 0.87) and vancomycin resistance (P = 0.90) did not. Increased gentamicin resistance (P < 0.0001) and ciprofloxacin resistance (P = 0.04) were observed in Gram-negative cultures. Gentamicin resistance [relative risk (RR) > 15.29; P < 0.0001] and ciprofloxacin resistance (RR = 6; P = 0.007) increased in Enterobacter species, but not Pseudomonas or Escherichia coli species. CONCLUSION: AML decrease CR-BSI incidence, although proportions of S. aureus and anti-microbial-resistant Enterobacter are increased. PMID- 22513705 TI - The effect of metanephros transplantation on blood pressure in anephric rats with induced acute hypotension. AB - BACKGROUND: The kidney is an important organ for maintaining blood pressure. We have previously reported that transplanted metanephroi can reproduce some kidney functions. The aim of the present study was to determine the metabolic function of transplanted metanephroi with particular reference to maintaining blood pressure. METHODS: Male Wistar rats were transplanted with metanephroi (transplanted group, n = 28), following unilateral nephrectomy. For comparison, we performed unilateral nephrectomy without transplantation in 32 rats (non transplanted group, n = 18; haeminephrectomy control group, n = 14). The remaining kidney was removed 2 weeks after the initial operation, while control rats had a sham operation. Hypotension was induced by intravenous infusion of diltiazem hydrochloride or rapid withdrawal of blood. Mean arterial blood pressure (MAP) was invasively monitored and plasma renin activity (PRA) was analysed at multiple time points. Renin expression by metanephroi was evaluated by real-time polymerase chain reaction and immunohistochemistry. RESULTS: Metanephroi in the transplanted group expressed renin messenger RNA. Metanephros transplantation significantly raised PRA and maintained MAP compared with the non transplanted group. No significant differences between the transplanted and control groups were found with respect to PRA or MAP. PRA was positively correlated with metanephroi weight as well as MAP in the transplanted group. CONCLUSION: The present study shows that transplantation of metanephroi produces PRA and contributes to raising MAP in a rat model of acute hypotension. PMID- 22513706 TI - Intermittent high-volume predilution on-line haemofiltration versus standard intermittent haemodialysis in critically ill patients with acute kidney injury: a prospective randomized study. AB - BACKGROUND: The optimal modality of dialysis treatment in critically ill patients with acute kidney injury (AKI) remains unclear. Intermittent high-volume predilution on-line haemofiltration (HF) is not a well-established dialysis modality. The purpose of the study was to compare clinical outcomes between HF and standard intermittent haemodialysis (HD) in this specific population. METHODS: In this prospective, randomized, controlled single-centre clinical study, we compared mortality and recovery of kidney function between HF and HD in critically ill adult patients with AKI. The primary study outcome was 60-day all cause mortality. Secondary study outcomes included 30-day and in-hospital all cause mortality along with recovery of kidney function. Time to kidney function recovery and the number of required dialysis procedures were analyzed in the subgroup of patients with in-hospital recovery of kidney function. RESULTS: Baseline characteristics of the 273 patients in the two study groups were similar. All-cause mortality by Day 60 was 65.0% in the HF group and 65.5% in the HD group (hazard ratio, 0.98; 95% confidence interval, 0.71-1.33; P = 0.87). There were also no significant differences between the two groups in 30-day and in-hospital all-cause mortality or recovery of kidney function. Time to kidney function recovery and the number of required dialysis procedures were similar between the HF and the HD subgroup of patients with in-hospital recovery of kidney function. CONCLUSIONS: Dialysis treatment with intermittent high-volume predilution on-line HF in critically ill patients with AKI did not decrease mortality, improve recovery of kidney function or reduce the need for dialysis support compared to standard intermittent HD. PMID- 22513708 TI - Coulomb blockade behaviors in individual Au nanoparticles as observed through noncontact atomic force spectroscopy at room temperature. AB - Coulomb blockade behaviors in individual Au nanoparticles of 2 nm core diameter in double-barrier structures have been studied by means of noncontact atomic force spectroscopy (NC-AFS) at room temperature. The Au nanoparticles with a 1 decanethiol ligand were chemisorbed by 1,10-decanedithiol molecules of a mixed 1 octanethiol/1,10-decanedithiol self-assembled monolayer coated on a Au(111) surface; these particles were observed through NC-AFS. NC-AFS measurements of the cantilever frequency shift-sample voltage (Deltaf-V(S)) curves were sequentially conducted on three Au nanoparticles under the same experimental conditions; the Deltaf-V(S) curves were found to deviate from the parabolic (Deltaf(N)) curve in the cases where no extra charge existed on the Au core. The experimental Deltaf(CB)(=Deltaf-Deltaf(N)) and Deltaf(CB)/V curves agree well with the theoretical curves obtained using a golden-rule calculation and the same parabolic parameters. All the results, through NC-AFS, suggest Coulomb blockade behaviors in the Au nanoparticles at room temperature. PMID- 22513707 TI - Stable expression of foreign gene in nonessential region of nonstructural protein 2 (nsp2) of porcine reproductive and respiratory syndrome virus: applications for marker vaccine design. AB - The nonstructural protein 2 (nsp2) of porcine reproductive and respiratory syndrome virus (PRRSV) has been shown to be highly heterogeneous and variable among PRRSV strains and some sequences in the middle region of the nsp2 are not essential to viral replication. Recent studies have attempted to insert foreign genes in the nsp2 nonessential regions but the foreign genes were not stably expressed by recombinant viruses in vitro. In the present study, we first constructed an infectious cDNA clone with deletion of 75 nucleotides (25 amino acids) in the nsp2 region (rHuN4-F112-Delta508-532) of the attenuated vaccine virus HuN4-F112 derived from a highly pathogenic PRRSV HuN4 and then inserted a gene fragment encoding a immunodominant B-cell epitope (49 amino acids) of Newcastle disease virus (NDV) nucleoprotein (NP) in-frame into the deletion site. The viable recombinant virus was rescued from the full-length cDNA infectious clone in vitro. The engineered viruses rescued from the cDNA clone indicated that the deletions of 75 nucleotides and insertion of NDV NP gene in the nsp2 region did not affect viral replication; they had similar growth kinetics to its parental virus. The inserting gene could be expressed consistently when the recombinant virus was passaged up to twenty times in cell cultures as determined by immunofluorescence assay (IFA) and genomic sequencing. To investigate the potential application of the NDV NP gene-inserted PRRSV as a marker vaccine, piglets were immunized with the recombinant virus and then challenged with lethal dose of highly pathogenic PRRSV. The immunized piglets produced specific antibodies against both the NDV NP and PRRSV, and lacked antibodies against the deleted 25aa nsp2 epitope. After challenge, all immunized piglets were protected from clinical disease or death, while all piglets in control group died (5/5) by ten days post challenge. The results of the present study indicated that the recombinant PRRSV (rHuN4-F112-Delta508-532) could be used as a potential marker vaccine against PRRS. PMID- 22513709 TI - Electrophilic alkynylation: the dark side of acetylene chemistry. AB - In addition to the well-established nucleophilic alkynylation, the use of electrophilic alkynes can expand tremendously the scope of acetylene transfer reactions. The use of metal catalysis has recently led to a rebirth of this research area. Halogenoalkynes, hypervalent alkynyliodoniums, acetylene sulfones and in situ oxidized terminal acetylenes are the most often used reagents for electrophilic alkynylation. Heteroatoms such as N, O, S and P can be now efficiently alkynylated. For C-C bond formation, electrophilic acetylenes can be coupled with different organometallic reagents. Recently, the first breakthrough in direct C-H and C[double bond, length as m-dash]C bond alkynylation has also been reported. Finally, sulfonyl acetylenes are efficient for alkyne transfer on carbon-centered radicals. PMID- 22513711 TI - Photoelastic determination of polymerization shrinkage stress in low-shrinkage resin composites. AB - Low-shrinkage resin composites are in the focus of research in posterior resin composite restoratives. The aim of the study was to examine the polymerization shrinkage stress of new composites (Venus Diamond/ Heraeus Kulzer; SDR/DENTSPLY) and an experimental low-shrinkage resin composite (Ormocer/VOCO) in comparison to established low-shrinkage resin composites (Filtek Silorane/ 3M ESPE; els/Saremco; Filtek Supreme XT/3M ESPE; Clearfil Majesty Posterior/Kuraray). Cylindrical cavities (? 4 mm) in Araldit-B epoxy resin plates (40*40*4 mm) were pretreated with the Rocatec system to ensure bonding of the resin composites. The resin composite specimens (n = 10) were exposed to light for 60 s with a QTH curing device (Translux energy, Heraeus Kulzer, Germany). The samples were stored dark and dry (23 degrees C). Polymeri-zation shrinkage stress data (MPa) 4 min and 24 h post exposure were calculated based on the diameter of the first-order isochromatic rings, obtained from the Araldit plates. The statistical analysis of the obtained data was carried out with the Wilcoxon test (p = 0.05). After 24 h, the following mean stress values and standard deviations were obtained: Venus Diamond 3.4 +/- 0.27 MPa; SDR 3.3 +/- 0.26 MPa; exp. Ormocer 4.0 +/- 0.18 MPa; Filtek Silorane 2.8 +/- 0.19 MPa; els 2.5 +/- 0.09 MPa; Filtek Supreme XT 6.0 +/ 0.20 MPa; and Clearfil Majesty Posterior 5.6 +/- 0.15 MPa. For all materials, higher polymerization stress values were recorded after 24 h. All differences in the shrinkage data obtained after 24 h were statistically significant (p < 0.05) except Venus Diamond/SDR. Venus Diamond, els and SDR showed shrinkage data closer to that of Filtek Silorane. PMID- 22513710 TI - Comparison of magnetic resonance enterography with endoscopy, histopathology, and laboratory evaluation in pediatric Crohn disease. AB - BACKGROUND AND OBJECTIVE: Children with Crohn disease (CD) often undergo cross sectional imaging during clinical evaluation. Magnetic resonance enterography (MRE) is becoming the preferred radiologic assessment due to the lack of radiation exposure; however, there are few data in children with CD comparing MRE with objective disease measures. The aim of the present study was to compare MRE with endoscopy, histopathology, and laboratory evaluation in children with CD. METHODS: We performed an institutional review board-approved query of our prospective CD MRE database, which includes data in children with CD undergoing MRE since 2008. RESULTS: A total of 147 MRE studies were performed in 119 different children with symptomatic CD. Of those, 53 (39.6%) MRE studies were performed at diagnosis to evaluate small bowel disease burden. A total of 117 (79.6%) MRE studies displayed active and/or chronic disease, whereas 30 (20.4%) MRE studies were normal. When compared with normal MRE studies, active inflammation on MRE was associated with a higher mean C-reactive protein (3.6 vs 1.1, P < 0.001), higher erythrocyte sedimentation rate (36 vs 22, P = 0.0.31), higher platelet value (439 vs 352, P = 0.033), and lower albumin (3.4 vs 3.7, P = 0.049). Comparison between MRE and endoscopy demonstrated excellent agreement when ulcers were present, and moderate agreement with histopathology. CONCLUSIONS: Active inflammation on MRE is associated with higher C-reactive protein, erythrocyte sedimentation rate, platelets, and lower albumin in children with CD. MRE displays excellent agreement with endoscopic disease described by ulcers but poor agreement with mild mucosal disease described by erythema and friability. The present study adds to a growing body of evidence that MRE provides excellent assessment of inflammation and measures disease activity in CD. PMID- 22513712 TI - Enantioselective cyclopropanation of enals by oxidative N-heterocyclic carbene catalysis. AB - Carbene catalysed redox activation of alpha,beta-unsaturated aldehydes is applied for generation of alpha,beta-unsaturated acyl azoliums which undergo cyclopropanation upon reaction with a sulfur ylide and an alcohol to give the corresponding cyclopropanecarboxylic acid esters. With chiral carbenes good to excellent diastereo and enantioselectivities are obtained. PMID- 22513713 TI - Highly efficient single-layer polymer ambipolar light-emitting field-effect transistors. AB - Single-layer polymer light-emitting field-effect transistors (LEFETs) that yield EQEs of >8% and luminance efficiencies >28 cd A(-1) are demonstrated. These values are the highest reported for LEFETs and amongst the highest values for fluorescent OLEDs. Due to the electrostatics of the ambipolar LEFET channel, LEFETs provide an inherent advantage over OLEDs in terms of minimizing exciton polaron quenching. PMID- 22513714 TI - Genetic architecture for susceptibility to gout in the KARE cohort study. AB - This study aimed to identify functional associations of cis-regulatory regions with gout susceptibility using data resulted from a genome-wide association study (GWAS), and to show a genetic architecture for gout with interaction effects among genes within each of the identified functions. The GWAS was conducted with 8314 control subjects and 520 patients with gout in the Korea Association REsource cohort. However, genetic associations with any individual nucleotide variants were not discovered by Bonferroni multiple testing in the GWAS (P>1.42 * 10(-7)). Genomic regions enrichment analysis was employed to identify functional associations of cis-regulatory regions. This analysis revealed several biological processes associated with gout susceptibility, and they were quite different from those with serum uric acid level. Epistasis for susceptibility to gout was estimated using entropy decomposition with selected genes within each biological process identified by the genomic regions enrichment analysis. Some epistases among nucleotide sequence variants for gout susceptibility were found to be larger than their individual effects. This study provided the first evidence that genetic factors for gout susceptibility greatly differed from those for serum uric acid level, which may suggest that research endeavors for identifying genetic factors for gout susceptibility should not be heavily dependent on pathogenesis of uric acid. Interaction effects between genes should be examined to explain a large portion of phenotypic variability for gout susceptibility. PMID- 22513715 TI - Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy. AB - Myotonic dystrophy type 1 (DM1) is an RNA gain-of-function disorder in which abnormally expanded CTG repeats of DMPK sequestrate a splicing trans-factor MBNL1 and upregulate another splicing trans-factor CUGBP1. To identify a diverse array of aberrantly spliced genes, we performed the exon array analysis of DM1 muscles. We analyzed 72 exons by RT-PCR and found that 27 were aberrantly spliced, whereas 45 were not. Among these, 25 were novel and especially splicing aberrations of LDB3 exon 4 and TTN exon 45 were unique to DM1. Retrospective analysis revealed that four parameters efficiently detect aberrantly spliced exons: (i) the signal intensity is high; (ii) the ratio of probe sets with reliable signal intensities (that is, detection above background P-value=0.000) is high within a gene; (iii) the splice index (SI) is high; and (iv) SI is deviated from SIs of the other exons that can be estimated by calculating the deviation value (DV). Application of the four parameters gave rise to a sensitivity of 77.8% and a specificity of 95.6% in our data set. We propose that calculation of DV, which is unique to our analysis, is of particular importance in analyzing the exon array data. PMID- 22513716 TI - Association between dopamine beta hydroxylase rs5320 polymorphism and smoking behaviour in elderly Japanese. AB - The dopaminergic brain pathway is involved in many addictive behaviours, hence represents a good candidate in the study of smoking behaviour and nicotine addiction. Dopamine beta hydroxylase (DBH) is an enzyme that catalyses the conversion of dopamine into noradrenaline. This study, the first of its kind, was done to investigate the role of DBH rs5320 polymorphism in smoking behaviour of elderly Japanese. This was done by collecting blood samples from 2521 subjects with various smoking habits to genotype the DBH rs5320 polymorphism. Participants also had to fill out a questionnaire containing questions regarding their lifestyles. Some of the questions were from the Fagerstrom Test for Nicotine Dependence (FTND) and the Tobacco Dependence Screener (TDS). It was found that male ever-smokers with AA genotype smoked less cigarettes per day than those with GG and AG genotypes. FTND scores were also lowest in male ever-smokers with AA genotype and in female ever-smokers with AG genotype. There was no correlation detected between the TDS scores and any of the genotypes. This study shows that DBH rs5320 polymorphism influences nicotine dependence. PMID- 22513717 TI - Cooperative action of JNK and AKT/mTOR in 1-methyl-4-phenylpyridinium-induced autophagy of neuronal PC12 cells. AB - Parkinson's disease has been widely related to both apoptosis and oxidative stress. Many publications relate the loss of mitochondrial potential to an apoptosis-mediated cell death in different in vivo and in vitro models of this pathology. The present study used the dopaminegic specific neurotoxin 1-methyl-4 phenylpyridinium (MPP(+) ) on neuron-like PC12 cells, which is a well-accepted model of Parkinson's disease. Results showed an early increase in oxidants, which drives the modulation of c-Jun N-terminal kinase (JNK) and AKT/mammalian target of rapamycin (mTOR) pathways, mimicking peroxide treatment. However, the cell death found in neuronal PC12 cells treated with MPP(+) was not a caspase associated apoptosis. Electron microscopic images illustrated autophagic cell death, which was confirmed by a Beclin-1 and ATG expression increase, accumulation of acidic vesicles, and rescue by an autophagy inhibitor. In conclusion, the boost in oxidants from MPP(+) treatment in neuronal PC12 is modulating both survival (AKT/mTOR) and death (JNK) pathways, which are the perpetrators of an autophagic cell death. PMID- 22513719 TI - Haptoglobin baseline value in jennies and the effect of ovariectomy on its serum concentration. AB - The study was conducted to determine the baseline concentration of serum haptoglobin (Hp) in jennies during the breeding and nonbreeding season and to evaluate the effects of ovariectomy on serum Hp concentrations in jennies. Eighteen adult jennies were divided in three groups: nine jennies (OVA) were ovariectomized using laparoscopic surgery, six jennies (LAP) were exploratory examined by laparoscopic surgery, and three jennies were used as a control group. Blood samples were collected from the animals at Day -6, -2, -1, 0, 1, 2, 5, 8, 15, 22, 29 and 36 of surgery. Serum samples were analyzed by an ELISA specifically developed for determining equine Hp. The mean weekly Hp concentration ranged between 149.76 +/- 7.55 and 178.94 +/- 6.67 mg/L. The Hp concentrations of clinically healthy jennies revealed no significant variation among time, and there was no effect of reproductive season on Hp concentrations in jennies. Serum Hp concentration was elevated at the first day after operations in the OVA and LAP group. Five days after the operation, the Hp concentration reached the maximum in the LAP and OVA group (278.84 +/- 34.22 and 359.88 +/- 35.45 mg/L, respectively) and decreased at Day 8 after the operations. On Day 22, 29 and 32 after the operations, the concentration of Hp in LAP and OVA animals was close to its concentration in the control group. In conclusion, Hp is not related to reproductive status of jennies and it can be used as an indicator for cell and tissue damage after surgical operations. PMID- 22513720 TI - Modelling deuterium labelling of lymphocytes with temporal and/or kinetic heterogeneity. AB - To study the kinetics of lymphocytes, models have divided the cell population into subpopulations with different turnover rates. These have been called 'kinetic heterogeneity models' so as to distinguish them from 'temporal heterogeneity models', in which a cell population may have different turnover rates at different times, e.g. when resting versus when activated. We model labelling curves for temporally heterogeneous populations, and predict that they exhibit equal biphasic up- and downslopes. We show when cells divide only once upon activation, these slopes are dominated by the slowest exponent, yielding underestimates of the average turnover rate. When cells undergo more than one division, the labelling curves allow fitting of the two exponential slopes in the temporal heterogeneity model. The same data can also be described with a two compartment kinetic heterogeneity model. In both instances, the average turnover rate is correctly estimated. Because both models assume a different cell biology but describe the data equally well, the parameters of either model have no simple biological interpretation, as each parameter could reflect a combination of parameters of another biological process. Thus, even if there are sufficient data to reliably estimate all exponentials, one can only accurately estimate an average turnover rate. We illustrate these issues by re-fitting labelling data from healthy and HIV-infected individuals. PMID- 22513721 TI - Acute inflammatory response to cobalt chromium orthopaedic wear debris in a rodent air-pouch model. AB - This study used a rodent air-pouch model to assess the acute inflammatory response to cobalt-chromium (CoCr) alloy wear debris from a metal-on-metal hip resurfacing implant that may contribute to joint failure. Air-pouches were injected with either sterile phosphate-buffered saline, 1 MUg lipopolysaccharide (LPS) or 2.5 mg CoCr wear debris. The in situ inflammatory response was monitored 4, 24, 48 and 72 h and 7 days later. A flow cytometric analysis of the inflammatory exudates showed that CoCr wear debris induced a different inflammatory pattern compared with LPS. LPS induced a strong early (4 h) neutrophil influx, with monocyte/macrophage influx peaking at 24 h, whereas CoCr wear debris initiated almost equal numbers of early monocyte/macrophage and neutrophil recruitment. Histological analyses also showed CoCr debris accumulated in the pouch wall and this was accompanied by vast cellular infiltration and fibrosis around the debris throughout the duration of the experiment. Assessment of inflammatory gene transcripts from air-pouch tissue showed that CoCr wear debris increased the expression of cytokines involved in promoting inflammation and fibrosis (IL-1beta, TGF-beta) and chemokines that promote the recruitment of neutrophils and monocytes/macrophages (CXCL2 and CCL2). The data suggest that inflammatory responses to CoCr debris induce a specific acute process in which the recruitment of monocytes/macrophages is key. PMID- 22513722 TI - Competition-colonization trade-off promotes coexistence of low-virulence viral strains. AB - RNA viruses exist as genetically diverse populations displaying a range of virulence degrees. The evolution of virulence in viral populations is, however, poorly understood. On the basis of the experimental observation of an RNA virus clone in cell culture diversifying into two subpopulations of different virulence, we study the dynamics of mutating virus populations with varying virulence. We introduce a competition-colonization trade-off into standard mathematical models of intra-host viral infection. Colonizers are fast-spreading virulent strains, whereas the competitors are less-virulent variants but more successful within co-infected cells. We observe a two-step dynamics of the population. Early in the infection, the population is dominated by colonizers, which later are outcompeted by competitors. Our simulations suggest the existence of steady state in which all virulence classes coexist but are dominated by the most competitive ones. This equilibrium implies collective virulence attenuation in the population, in contrast to previous models predicting evolution of the population towards increased virulence. PMID- 22513723 TI - Prediction of invasion from the early stage of an epidemic. AB - Predictability of undesired events is a question of great interest in many scientific disciplines including seismology, economy and epidemiology. Here, we focus on the predictability of invasion of a broad class of epidemics caused by diseases that lead to permanent immunity of infected hosts after recovery or death. We approach the problem from the perspective of the science of complexity by proposing and testing several strategies for the estimation of important characteristics of epidemics, such as the probability of invasion. Our results suggest that parsimonious approximate methodologies may lead to the most reliable and robust predictions. The proposed methodologies are first applied to analysis of experimentally observed epidemics: invasion of the fungal plant pathogen Rhizoctonia solani in replicated host microcosms. We then consider numerical experiments of the susceptible-infected-removed model to investigate the performance of the proposed methods in further detail. The suggested framework can be used as a valuable tool for quick assessment of epidemic threat at the stage when epidemics only start developing. Moreover, our work amplifies the significance of the small-scale and finite-time microcosm realizations of epidemics revealing their predictive power. PMID- 22513724 TI - Balancing on tightropes and slacklines. AB - Balancing on a tightrope or a slackline is an example of a neuromechanical task where the whole body both drives and responds to the dynamics of the external environment, often on multiple timescales. Motivated by a range of neurophysiological observations, here we formulate a minimal model for this system and use optimal control theory to design a strategy for maintaining an upright position. Our analysis of the open and closed-loop dynamics shows the existence of an optimal rope sag where balancing requires minimal effort, consistent with qualitative observations and suggestive of strategies for optimizing balancing performance while standing and walking. Our consideration of the effects of nonlinearities, potential parameter coupling and delays on the overall performance shows that although these factors change the results quantitatively, the existence of an optimal strategy persists. PMID- 22513726 TI - Monte Carlo study of the potential reduction in out-of-field dose using a patient specific aperture in pencil beam scanning proton therapy. AB - This study is aimed at identifying the potential benefits of using a patient specific aperture in proton beam scanning. For this purpose, an accurate Monte Carlo model of the pencil beam scanning (PBS) proton therapy (PT) treatment head at Massachusetts General Hospital (MGH) was developed based on an existing model of the passive double-scattering (DS) system. The Monte Carlo code specifies the treatment head at MGH with sub-millimeter accuracy. The code was configured based on the results of experimental measurements performed at MGH. This model was then used to compare out-of-field doses in simulated DS treatments and PBS treatments. For the conditions explored, the penumbra in PBS is wider than in DS, leading to higher absorbed doses and equivalent doses adjacent to the primary field edge. For lateral distances greater than 10 cm from the field edge, the doses in PBS appear to be lower than those observed for DS. We found that placing a patient specific aperture at nozzle exit during PBS treatments can potentially reduce doses lateral to the primary radiation field by over an order of magnitude. In conclusion, using a patient-specific aperture has the potential to further improve the normal tissue sparing capabilities of PBS. PMID- 22513725 TI - Real time forecasting of near-future evolution. AB - A metaphor for adaptation that informs much evolutionary thinking today is that of mountain climbing, where horizontal displacement represents change in genotype, and vertical displacement represents change in fitness. If it were known a priori what the 'fitness landscape' looked like, that is, how the myriad possible genotypes mapped onto fitness, then the possible paths up the fitness mountain could each be assigned a probability, thus providing a dynamical theory with long-term predictive power. Such detailed genotype-fitness data, however, are rarely available and are subject to change with each change in the organism or in the environment. Here, we take a very different approach that depends only on fitness or phenotype-fitness data obtained in real time and requires no a priori information about the fitness landscape. Our general statistical model of adaptive evolution builds on classical theory and gives reasonable predictions of fitness and phenotype evolution many generations into the future. PMID- 22513728 TI - The privilege and responsibility of having choices: decision-making for new vaccines in developing countries. PMID- 22513729 TI - Introducing multiple vaccines in low- and lower-middle-income countries: issues, opportunities and challenges. AB - Low- and lower-middle-income countries are faced with a large and increasingly complicated portfolio of vaccines to introduce into their national immunization programmes. Countries must also incorporate their vaccine introduction plans into donor-required assessments and multi-year plans. An international workshop and series of key informant interviews were conducted to explore the interest, opportunities and challenges for the proactive planning of multiple vaccine introduction within a single planning cycle and the underlying processes for planning the introduction of new vaccines. The study found limited experience with this proactive planning process in low-income countries and used the experience of two lower-middle-income countries in simultaneously introducing rotavirus and pneumococcal vaccines to highlight the importance of integrating the planning processes for new vaccine introduction into broader immunization systems planning and financing. The study's findings suggest that this strategy for vaccine introduction may have promise for accelerating the pace of new vaccine introduction. However, we also show that realizing these benefits will require improved logistic and financial planning activities and continued actions to resolve uncertainties in the relationships between donors, technical agencies, and the national immunization programmes. PMID- 22513727 TI - Compensated second-order recoupling: application to third spin assisted recoupling. AB - We consider the effect of phase shifts in the context of second-order recoupling techniques in solid-state NMR. Notably we highlight conditions leading to significant improvements for the Third Spin Assisted Recoupling (TSAR) mechanism and demonstrate the benefits of resulting techniques for detecting long-distance transfer in biomolecular systems. The modified pulse sequences of PAR and PAIN CP, Phase-Shifted Proton Assisted Recoupling (AH-PS-PAR) and Phase-Shifted Proton Assisted Insensitive Nuclei Cross Polarization (ABH-PS-PAIN-CP), still rely on cross terms between heteronuclear dipolar couplings involving assisting protons that mediate zero-quantum polarization transfer between low-gamma nuclei ((13)C (13)C, (15)N-(15)N, (15)N-(13)C polarization transfer). Using Average Hamiltonian Theory we show that phase inversion compensates off-resonance contributions and yields improved polarization transfer as well as substantial broadening of the matching conditions. PS-TSAR greatly improves on the standard TSAR based methods because it alleviates their sensitivity to precise RF settings which significantly enhances robustness of the experiments. We demonstrate these new methods on a 19.6 kDa protein (U-[(15)N, (13)C]-YajG) at high magnetic fields (up to 900 MHz (1)H frequency) and fast sample spinning (up to 65 kHz MAS frequency). PMID- 22513730 TI - Using social network analysis to examine the decision-making process on new vaccine introduction in Nigeria. AB - The decision-making process to introduce new vaccines into national immunization programmes is often complex, involving many stakeholders who provide technical information, mobilize finance, implement programmes and garner political support. Stakeholders may have different levels of interest, knowledge and motivations to introduce new vaccines. Lack of consensus on the priority, public health value or feasibility of adding a new vaccine can delay policy decisions. Efforts to support country-level decision-making have largely focused on establishing global policies and equipping policy makers with the information to support decision making on new vaccine introduction (NVI). Less attention has been given to understanding the interactions of policy actors and how the distribution of influence affects the policy process and decision-making. Social network analysis (SNA) is a social science technique concerned with explaining social phenomena using the structural and relational features of the network of actors involved. This approach can be used to identify how information is exchanged and who is included or excluded from the process. For this SNA of vaccine decision making in Nigeria, we interviewed federal and state-level government officials, officers of bilateral and multilateral partner organizations, and other stakeholders such as health providers and the media. Using data culled from those interviews, we performed an SNA in order to map formal and informal relationships and the distribution of influence among vaccine decision-makers, as well as to explore linkages and pathways to stakeholders who can influence critical decisions in the policy process. Our findings indicate a relatively robust engagement of key stakeholders in Nigeria. We hypothesized that economic stakeholders and implementers would be important to ensure sustainable financing and strengthen programme implementation, but some economic and implementation stakeholders did not appear centrally on the map; this may suggest a need to strengthen the decision-making processes by engaging these stakeholders more centrally and earlier. PMID- 22513731 TI - New vaccine adoption in lower-middle-income countries. AB - OBJECTIVES: Lower-middle-income countries (LMICs) are lagging behind both high income and low-income countries in new vaccine adoption. Our study involved the following objectives: (1) understand the decision-making processes of LMICs on new vaccine adoption, (2) identify the factors influencing LMIC decisions, (3) obtain the views of vaccine manufacturers about LMIC markets for new vaccines, and (4) make recommendations concerning how to speed up and improve decision making, including proposing mechanisms for implementation of the recommendations. METHODS: Collect and analyse qualitative data from participants in decision making in 15 case study countries [12 LMICs and three upper-middle-income countries (UMICs)] and multinational and developing country vaccine manufacturers. FINDINGS: Interviews of actors in decision making indicate that the aspects deemed most important for adoption are: World Health Organization (WHO) recommendations, the existence of local epidemiological data and a set of factors comprising affordability, cost-effectiveness and overall cost of the new vaccine for the programme. National Immunization Technical Advisory Groups (NITAG) have a key role in advising decision-makers, although their resources and capacity vary. Country decision-makers and manufacturers both see advantages in pooled procurement mechanisms for vaccine purchasing. Recommendations for countries and the international community involve assisting with making epidemiological data and vaccine market information accessible to countries, building and reinforcing related analysis capacity, and assisting with purchasing mechanisms and practices such as pooled procurement. PMID- 22513732 TI - New vaccine adoption: qualitative study of national decision-making processes in seven low- and middle-income countries. AB - As more new and improved vaccines become available, decisions on which to adopt into routine programmes become more frequent and complex. This qualitative study aimed to explore processes of national decision-making around new vaccine adoption and to understand the factors affecting these decisions. Ninety-five key informant interviews were conducted in seven low- and middle-income countries: Bangladesh, Cameroon, Ethiopia, Guatemala, Kenya, Mali and South Africa. Framework analysis was used to explore issues both within and between countries. The underlying driver for adoption decisions in GAVI-eligible countries was the desire to seize GAVI windows of opportunity for funding. By contrast, in South Africa and Guatemala, non-GAVI-eligible countries, the decision-making process was more rooted in internal and political dynamics. Decisions to adopt new vaccines are, by nature, political. The main drivers influencing decisions were the availability of funding, political prioritization of vaccination or the vaccine-preventable disease and the burden of disease. Other factors, such as financial sustainability and feasibility of introduction, were not as influential. Although GAVI procedures have established more formality in decision making, they did not always result in consideration of all relevant factors. As familiarity with GAVI procedures increased, questioning by decision-makers about whether a country should apply for funding appeared to have diminished. This is one of the first studies to empirically investigate national processes of new vaccine adoption decision-making using rigorous methods. Our findings show that previous decision-making frameworks (developed to guide or study national decision-making) bore little resemblance to real-life decisions, which were dominated by domestic politics. Understanding the realities of vaccine policy decision-making is critical for developing strategies to encourage improved evidence-informed decision-making about new vaccine adoptions. The potential for international initiatives to encourage evidence-informed decision-making should be realised, not assumed. PMID- 22513734 TI - The role of publics in the introduction of new vaccines. PMID- 22513733 TI - Country planning for health interventions under development: lessons from the malaria vaccine decision-making framework and implications for other new interventions. AB - Traditionally it has taken years or decades for new public health interventions targeting diseases found in developing countries to be accessible to those most in need. One reason for the delay has been insufficient anticipation of the eventual processes and evidence required for decision making by countries. This paper describes research into the anticipated processes and data needed to inform decision making on malaria vaccines, the most advanced of which is still in phase 3 trials. From 2006 to 2008, a series of country consultations in Africa led to the development of a guide to assist countries in preparing their malaria vaccine decision-making frameworks. The guide builds upon the World Health Organization's Vaccine Introduction Guidelines. It identifies the processes and data for decisions, when they would be needed relative to the development timelines of the intervention, and where they will come from. Policy development will be supported by data (e.g. malaria disease burden; roles of other malaria interventions; malaria vaccine impact; economic and financial issues; malaria vaccine efficacy, quality and safety) as will implementation decisions (e.g. programmatic issues and socio-cultural environment). This generic guide can now be applied to any future malaria vaccine. The paper discusses the opportunities and challenges to early planning for country decision-making-from the potential for timely, evidence-informed decisions to the risks of over-promising around an intervention still under development. Careful and well-structured planning by countries is an important way to ensure that new interventions do not remain unused for years or decades after they become available. PMID- 22513735 TI - Use of real-time sensors to characterise human exposures to combustion related pollutants. AB - Concentrations of black carbon and nitrogen dioxide have been collected concurrently using a MicrAeth AE-51 and an Aeroqual GSS NO(2) sensor. Forty five sampling events with a duration spanning between 16 and 22 hours have collected 10,800 5 min data in Birmingham (UK) from July to October 2011. The high temporal resolution database allowed identification of peak exposures and which activities contributed the most to these peaks, such as cooking and commuting. Personal exposure concentrations for non-occupationally exposed subjects ranged between 0.01 and 50 MUg m(-3) for BC with average values of 1.3 +/- 2.2 MUg m(-3) (AM +/- SD). Nitrogen dioxide exposure concentrations were in the range 0.7) and related to a larger flow-increasing forward-running compression wave arising from right ventricular (RV) impulsive contraction. Moreover, while the increased PT flow was confined to systole, the rise in PA flow spanned systole (316 ml/min) and diastole (163 ml/min). This elevated PA diastolic flow was accompanied by a 170% greater discharge from a PT and main PA reservoir filled in systole (P < 0.001), but loss of retrograde blood discharge from a conduit PA reservoir that was evident at baseline. These data suggest that 1) an increase in fetal pulmonary blood flow produced by adenosine infusion is primarily supported by a higher PT blood flow (i.e., RV output); 2) about two-thirds of this increased RV output passes into the pulmonary circulation during systole; and 3) the remainder is transiently stored in a central PT and main PA systolic reservoir, from where it discharges into the lungs in diastole. PMID- 22513747 TI - Meal-contingent intestinal lymph sampling from awake, unrestrained rats. AB - Standard procedures for intestinal lymph collection involve continuous, quantitative drainage of the lymph fluid in anesthetized or restrained animals that are often euthanized within 48 h. We here describe a novel technique for the nonocclusive cannulation of the major intestinal lymph duct in rats that allows for repetitive in vivo sampling of intestinal lymph from unrestrained, awake, and ad libitum-fed animals. The distinctive feature of this novel technique is that a 5- to 7-mm long piece of Vialon tubing (OD/ID: 0.8/0.7 mm) with a small hole in its wall is first implanted into the major intestinal lymph duct for stabilization. The tapered tip (OD: ~0.1 mm) of the catheter is then inserted into the hole of the tubing and fixed in place with a polyamid suture and a drop of tissue glue. In our hands, catheters implanted this way remain patent for up to 6 wk after surgery. In an initial experiment we collected lymph from six adult rats before (0) and 15, 30, 45, 60, 75, 90, 120, and 180 min (120 MUl, each) after the onset of isocaloric (12.5 kcal) low-fat (LF) or high-fat (HF) test meals and measured active glucagon-like peptide-1 (GLP-1). Intestinal lymphatic GLP-1 concentration increased (P < 0.05) from ~4 pmol/l (0 min) to a peak of 33 +/- 6 (means +/- SE) or 22 +/- 4 pmol/l at 15 (HF) or 30 min (LF) after meal onset and gradually returned to baseline levels by 180 min. With this new technique fewer animals are required to generate physiologically relevant data for various aspects of gastrointestinal physiology that involve the lymphatic system. Furthermore, the advantage of this system is that the animal can act as its own control when the effect of different experimental protocols is tested. PMID- 22513746 TI - Activation of NPY receptors suppresses excitatory synaptic transmission in a taste-feeding network in the lower brain stem. AB - Consummatory responses to taste stimuli are modulated by visceral signals processed in the caudal nucleus of the solitary tract (cNST) and ventrolateral medulla. On the basis of decerebrate preparations, this modulation can occur through local brain stem pathways. Among the large number of neuropeptides and neuromodulators implicated in these visceral pathways is neuropeptide Y (NPY), which is oftentimes colocalized in catecholaminergic neurons themselves implicated in glucoprivic-induced feeding and satiety. In addition to the cNST and ventrolateral medulla, noradrenergic and NPY receptors are found in circumscribed regions of the medullary reticular formation rich in preoromotor neurons. To test the hypothesis that NPY may act as a neuromodulator on preoromotor neurons, we recorded the effects of bath application of NPY and specific Y1 and Y2 agonists on currents elicited from electrical stimulation of the rostral (taste) NST in prehypoglossal neurons in a brain stem slice preparation. A high proportion of NST-driven responses were suppressed by NPY, as well as Y1 and Y2 agonists. On the basis of paired pulse ratios and changes in membrane resistance, we concluded that Y1 receptors influence these neurons both presynaptically and postsynaptically and that Y2 receptors have a presynaptic locus. To test the hypothesis that NPY may act in concert with norepinephrine (NE), we examined neurons showing suppressed responses in the presence of a Y2 agonist and demonstrated a greater degree of suppression to a Y2 agonist/NE cocktail. These suppressive effects on preoromotoneurons may reflect a satiety pathway originating from A2 neurons in the caudal brain stem. PMID- 22513749 TI - Outcomes of hospitalization in pregnant women with CNS neoplasms: a population based study. AB - Managing a CNS neoplasm during pregnancy presents complex challenges, and population-based studies are lacking. We designed a retrospective cohort study using the Nationwide Inpatient Sample (NIS) to investigate pregnancy outcomes in women with CNS neoplasms. We constructed a logistic regression model for maternal mortality, preterm labor, intrauterine growth restriction (IUGR), and Caesarean delivery, controlling for age, comorbidities, and demographic characteristics. We identified 379 malignant brain tumors, 437 benign brain tumors, and 44 spine tumors among 19 million pregnancy-related admissions from 1988 through 2009. Malignant brain tumors were associated with maternal mortality (odds ratio [OR], 143), preterm labor (OR, 3.4), and IUGR (OR, 2.9). Benign brain tumors were associated with preterm labor (OR, 2.3). A diagnosis of hyperemesis gravidarum was more common in malignant (OR, 2.2) and benign (OR, 2.8) brain tumors. Compared with the general population, Caesarean delivery was more frequent for malignant (OR, 6.4) and benign (OR, 2.8) brain tumors and spine tumors (OR, 3.9). Admission without delivery was more common for malignant (OR, 8.6) and benign (OR, 4.3) brain tumors and spine tumors (OR, 3.8; P < .05 for all outcomes). Thirty-three percent of all hospitalizations involved neurosurgical procedures, but pregnancy complications were not significantly more likely to occur in surgical patients. In conclusion, malignant brain tumors were associated with adverse pregnancy outcomes, and CNS neoplasms were associated with higher rates of Caesarean delivery. Additional research is needed to improve understanding of obstetric risk in these patients and to assist with treatment, counseling, and monitoring during delivery. PMID- 22513751 TI - Temporal profile of molecular signatures associated with circulating endothelial progenitor cells in human ischemic stroke. AB - Endothelial progenitor cells (EPC) have been associated with good functional outcome in ischemic stroke. From preclinical studies, it has been reported that EPC proliferation is mediated by several molecular markers, including vascular endothelial growth factor (VEGF), stromal cell-derived factor-1alpha (SDF 1alpha), and the activity of matrix metalloproteinase-9 (MMP-9). Therefore, our aim was to study the role of these molecular factors in EPC proliferation in human ischemic stroke. Forty-eight patients with first episode of nonlacunar ischemic stroke were prospectively included in the study within 12 hr of symptom onset. EPC colonies were classified as early-outgrowth colony forming unit endothelial cell (CFU-EC) and quantified at admission, at 24 and 72 hr, at day 7, and at 3 months. At the same time, serum levels of VEGF, SDF-1alpha, and active MMP-9 were measured by ELISA. The primary endpoint was EPC increment during the first week, which was defined as the difference in the number of CFU-EC between day 7 and admission. We found that VEGF (r = 0.782), SDF-1alpha (r = 0.828), and active MMP-9 (r = 0.740) levels at 24 hr from stroke onset showed a strong correlation with EPC increment. Similar results were found for VEGF levels at 72 hr (r = 0.839) and at day 7 (r = 0.602) as well as for active MMP-9 levels at 72 hr (r = 0.442) and at day 7 (r = 0.474). In the multivariate analyses, serum levels of VEGF at 72 hr (B: 0.074, P < 0.0001) and SDF-1alpha at 24 hr (B: 0.049, P = 0.008) were independent factors for EPC increment during the first week of evolution. These findings suggest that VEGF and SDF-1alpha may mediate EPC proliferation in human ischemic stroke. PMID- 22513748 TI - Naturally occurring hypothermia is more advantageous than fever in severe forms of lipopolysaccharide- and Escherichia coli-induced systemic inflammation. AB - The natural switch from fever to hypothermia observed in the most severe cases of systemic inflammation is a phenomenon that continues to puzzle clinicians and scientists. The present study was the first to evaluate in direct experiments how the development of hypothermia vs. fever during severe forms of systemic inflammation impacts the pathophysiology of this malady and mortality rates in rats. Following administration of bacterial lipopolysaccharide (LPS; 5 or 18 mg/kg) or of a clinical Escherichia coli isolate (5 * 10(9) or 1 * 10(10) CFU/kg), hypothermia developed in rats exposed to a mildly cool environment, but not in rats exposed to a warm environment; only fever was revealed in the warm environment. Development of hypothermia instead of fever suppressed endotoxemia in E. coli-infected rats, but not in LPS-injected rats. The infiltration of the lungs by neutrophils was similarly suppressed in E. coli-infected rats of the hypothermic group. These potentially beneficial effects came with costs, as hypothermia increased bacterial burden in the liver. Furthermore, the hypotensive responses to LPS or E. coli were exaggerated in rats of the hypothermic group. This exaggeration, however, occurred independently of changes in inflammatory cytokines and prostaglandins. Despite possible costs, development of hypothermia lessened abdominal organ dysfunction and reduced overall mortality rates in both the E. coli and LPS models. By demonstrating that naturally occurring hypothermia is more advantageous than fever in severe forms of aseptic (LPS-induced) or septic (E. coli-induced) systemic inflammation, this study provides new grounds for the management of this deadly condition. PMID- 22513753 TI - Inflammation, blood pressure and cardiovascular disease: heading east. PMID- 22513752 TI - [Digital workflow with the Lava Chairside Oral Scanner C.O.S. and Lava technique]. AB - This article describes the clinical procedure and functioning of the LAVA C.O.S scanner (3MEspe) in making digital impressions of patients. When used in combination with LAVA technology, fully ceramic tooth replacements can be produced in an entirely digital way. After scanning the prepared abutment teeth, the data is directly transmitted to the dental laboratory to enable the production of the ceramic structures, while, on the other hand, stereo lithography can be used to produce master models. The milled and sintered zirconium oxide caps are covered with system-specific baked ceramics on the model. Initial clinical results have confirmed the functionality of the system. C.O.S-(Chairside Oral Scanning) is a true innovation in reconstructive dental medicine. PMID- 22513754 TI - Hypertension therapy in the older adults-do we know the answers to all the questions? The status after publication of the ACCF/AHA 2011 expert consensus document on hypertension in the elderly. PMID- 22513755 TI - Blood pressure change and antihypertensive treatment in old and very old people: evidence of age, sex and cohort effects. AB - The epidemiology of blood pressure in very old age has not been thoroughly studied. The objective of this study was to study blood pressure changes throughout old age and changes in blood pressure and antihypertensive drug use from 1981 to 2005. The study includes 1133 blood pressure measurements from two studies carried out in Umea, Sweden. The U70 study (1981-1990) included individuals aged 70-88 and the Umea 85+/GERDA study (2000-2005) covered people aged 85, 90 or >=95 years. The impact of age, sex and year of investigation on blood pressure was investigated using linear regression. Mean diastolic blood pressure (DBP) decreased by 0.35 mm Hg (P<0.001) for each year of age. An inverted U-shaped relation was found between age and systolic blood pressure (SBP), with SBP reaching its maximum at 74.5 years. Mean SBP and DBP also decreased over time (SBP by 0.44 mm Hg per year, P<0.001 and DBP by 0.34 mm Hg per year, P<0.001). The proportion of participants on antihypertensive drugs increased from 39.0% in 1981 to 69.4% in 2005. In this study of people aged >=70 years, mean SBP and DBP decreased with higher age and later investigation year. Antihypertensive drug use increased with time, which might partly explain the observed cohort effect. PMID- 22513756 TI - The theory of cyclic voltammetry of electrochemically heterogeneous surfaces: comparison of different models for surface geometry and applications to highly ordered pyrolytic graphite. AB - The cyclic voltammetry at electrodes composed of multiple electroactive materials, where zones of one highly active material are distributed over a substrate of a second, less active material, is investigated by simulation. The two materials are assumed to differ in terms of their electrochemical rate constants towards any given redox couple. For a one-electron oxidation or reduction, the effect on voltammetry of the size and relative surface coverages of the zones as well as the rate constant of the slower zone are considered for systems where it is much slower than the rate constant of the faster zones. The occurrence of split peak cyclic voltammetry where two peaks are observed in the forward sweep, is studied in terms of the diffusional effects present in the system. A number of surface geometries are compared: specifically the more active zones are modelled as long, thin bands, as steps in the surface, as discs, and as rings (similar to a partially blocked electrode). Similar voltammetry for the band, step and ring models is seen but the disc geometry shows significant differences. Finally, the simulation technique is applied to the modelling of highly-ordered pyrolytic graphite (HOPG) surface and experimental conditions under which it may be possible to observe split peak voltammetry are predicted. PMID- 22513757 TI - Prevalence, presentation and prognosis of delirium in older people in the population, at home and in long term care: a review. AB - OBJECTIVE: The aim of this study is to provide an overview of prevalence, symptoms, risk factors and prognosis of delirium in primary care and institutionalized long-term care. DESIGN: The method used in this study is a systematic PubMed search and literature review. RESULTS: The prevalence of delirium in the population among the elderly aged 65+ years is 1-2%. Prevalence rises with age: 10% among a "general" population aged 85+ years. Prevalence rises up to 22% in populations with higher percentages of demented elder. In long-term care, prevalence ranges between 1.4% and 70%, depending on diagnostic criteria and on the prevalence of dementia. There is a significant increase of the risk of delirium with age and cognitive decline in all groups. Concerning prognosis, most studies agree that older people who previously experienced delirium have a higher risk of dementia and a higher mortality rate. Population and long-term care studies show the same tendency. CONCLUSIONS: Delirium in a non-selected population aged 65+ years is uncommon. However, prevalence rises very quickly in selected older groups. Primary care doctors should be aware of a relatively high risk of delirium among the elderly in long-term care, those older than 85 years and those with dementia. PMID- 22513758 TI - DNA-cisplatin interaction studied with single molecule stretching experiments. AB - By performing single molecule stretching experiments with optical tweezers, we have studied the changes in the mechanical properties of DNA-cisplatin complexes as a function of some variables of interest such as the drug diffusion time and concentration in the sample. We propose a model to explain the behavior of the persistence length as a function of the drug concentration, extracting the binding data from pure mechanical measurements. Such analysis has allowed us to show that cisplatin binds cooperatively to the DNA molecule. In addition, DNA compaction by the action of the drug was also observed under our experimental conditions by studying the kinetics of some mechanical properties such as the radius of gyration and the end-to-end distance, e.g. Crisafuli et al., Integr. Biol., 2011, xx, xxxx. PMID- 22513759 TI - Beam range estimation by measuring bremsstrahlung. AB - We describe a new method for estimating the beam range in heavy-ion radiation therapy by measuring the ion beam bremsstrahlung. We experimentally confirm that the secondary electron bremsstrahlung process provides the dominant bremsstrahlung contribution. A Monte Carlo simulation shows that the number of background photons from annihilation gamma rays is about 1% of the bremsstrahlung strength in the low-energy region used in our estimation (63-68 keV). Agreement between the experimental results and the theoretical prediction for the characteristic shape of the bremsstrahlung spectrum validates the effectiveness of our new method in estimating the ion beam range. PMID- 22513760 TI - Co-evaporated bulk heterojunction solar cells with >6.0% efficiency. AB - High power conversion efficiencies of over 6.0% are achieved with a squaraine compound from co-deposited photovoltaic cells with a simple device structure, in which the efficiency is insensitive to blending ratios and thicknesses of photoactive layers. It demonstrates the huge potential of low molecular weight materials in photovoltaic cells via vacuum processes. PMID- 22513761 TI - Wikicountries: enhancing global health awareness without leaving home. PMID- 22513763 TI - Ensuring NLNAC's accountability in the accreditation process. AB - This ongoing column provides information on accreditation for nursing programs of all types by the National League for Nursing Accrediting Commission (NLNAC). Readers may submit questions to me at NLNAC. General questions of interest to a wide audience are addressed here; those with more specific questions or those requiring confidentiality are answered directly. PMID- 22513764 TI - Supporting student success on the NCLEX-RN. AB - Many new nursing leaders assuming deanships, assistant, or interim deanships have limited education, experience, or background to prepare them for the job. To assist new deans and those aspiring to be deans, the authors of this department, 2 deans, offer survival tips based on their personal experiences and insights. They address common issues, challenges, and opportunities that face academic executive teams, such as negotiating an executive contract, obtaining faculty lines, building effective work teams, managing difficult employees, and creating nimble organizational structure to respond to changing consumer, healthcare delivery, and community needs. The authors welcome counterpoint discussions with readers. PMID- 22513766 TI - A framework for improving the quality of multiple-choice assessments. AB - Multiple-choice questions are frequently used in high-stakes nursing assessments. Many nurse educators, however, lack the necessary knowledge and training to develop these tests. The authors discuss test development guidelines to help nurse educators produce valid and reliable multiple-choice assessments. PMID- 22513768 TI - Actors needed: clinical faculty get the call. AB - Simulation activities have been developed for many areas of nursing, but there are minimal nursing simulation activities in the area of mental health nursing. In this article, the authors describe development of mental health simulation activities for junior BSN students using clinical faculty as the standardized patients. Faculty who want to incorporate mental health simulations into their learning experiences can use the lessons learned from this project. PMID- 22513769 TI - Hold that TIGER! A collaborative service-learning academic-practice partnership with rural healthcare facilities. AB - Observing a renewed focus on community engagement as part of our university's strategic plan and the experiential learning partnerships encouraged by the TIGER (Technology and Information Guiding Education Reform) Initiative in health information technology, an academic-practice partnership was initiated between a group of Midwestern rural hospitals and a university's advanced practice nursing students via the graduate online nursing informatics course. Using a service learning approach, the course features an emphasis on the collaborative design and implementation of student- and healthcare provider team-driven projects to support rural hospital staff and administrators in meeting the broad spectrum of challenges they face every day. The author discusses the adaptable course outline of foundational and service-learning course activities, recent service-learning projects and outcomes, and results of a cumulative 2-year course evaluation by internal/external stakeholders. PMID- 22513770 TI - Monitoring student attendance, participation, and performance improvement: an instrument and forms. AB - When students receive consistent and fair feedback about their behavior, program liability decreases. To help students to have a clearer understanding of minimum program standards and the consequences of substandard performance, the author developed attendance and participation monitoring and performance improvement instruments. The author discusses the tools that address absenteeism, tardiness, unprofessional, and unsafe clinical behaviors among students. PMID- 22513772 TI - Teaching the literacy of professionalism: when clinical skills are not enough. AB - Many RNs seeking their BSN degrees do not have well-developed nonclinical professional skills related to scholarship. To address this issue, faculty used the Community of Inquiry Framework to develop an elective, online course to help RN-BSN students explore professional growth through writing, presenting, and portfolio development. The authors discuss the course and its outcomes. PMID- 22513773 TI - Say yes to peer review: a collaborative approach to faculty development. AB - Student evaluations are relied on heavily to provide feedback for teaching improvement and professional growth. However, their use as the primary source of performance feedback may be limiting. To add another dimension to faculty evaluation, a peer-review process for both clinical and didactic teaching was implemented. The authors describe the initiation and development of a peer-review process as a means to ensure comprehensive and multidimensional evaluation. PMID- 22513774 TI - Concept maps and nursing theory: a pedagogical approach. AB - Faculty seek to teach nursing students how to link clinical and theoretical knowledge with the intent of improving patient outcomes. The author discusses an innovative 9-week concept mapping activity as a pedagogical approach to teach nursing theory in a graduate theory course. Weekly concept map building increased student engagement and fostered theoretical thinking. Unexpectedly, this activity also benefited students through group work and its ability to enhance theory practice knowledge. PMID- 22513777 TI - Emergency circulatory support in refractory cardiogenic shock patients in remote institutions: a pilot study (the cardiac-RESCUE program). AB - AIMS: Temporary circulatory support with extracorporeal membrane oxygenation (ECMO) is often the only alternative for supporting patients with refractory cardiogenic shock (RCS). In practice, this strategy is limited to a small minority of patients hospitalized in tertiary-care centres with ECMO programs. The cardiac-RESCUE program was designed to test the feasibility of providing circulatory support distant from specialized ECMO centres, for RCS patients in remote locations. METHODS AND RESULTS: From January 2005 to December 2009, hospitals without ECMO facilities throughout the Greater Paris area were invited to participate. One hundred and four RCS cases were assessed and 87 consecutively eligible patients (mean age 46 +/- 15 years, 41% following cardiac arrest) had ECMO support instituted locally and were enrolled into the program. Local initiation of ECMO support allowed successful transfer to the tertiary-care centre in 75 patients. Of these, 32 patients survived to hospital discharge [overall survival rate 36.8%, 95% confidence interval (CI) 27.4-46.2]. Independent predictors for in-hospital mortality included initiation of ECMO during cardiopulmonary resuscitation [hazard ratio (HR) = 4.81, 95% CI 2.25 10.30, P < 0.001] and oligo-anuria (HR = 2.48, 95% CI 1.29-4.76, P = 0.006). After adjusting for other confounding factors, in-hospital mortality was not statistically different from that of 123 consecutive patients who received ECMO at our institution during the same period (odds ratio 1.48, 95% CI 0.72-3.00, P = 0.29). CONCLUSION: Offering local ECMO support appears feasible in a majority of RCS patients hospitalized in remote hospitals. In this otherwise lethal situation, our pilot experience suggests that over one-third of such patients can survive to hospital discharge. PMID- 22513779 TI - Exons 5-15 of kazrin are dispensable for murine epidermal morphogenesis and homeostasis. AB - Kazrin binds to periplakin and ARVCF catenin, and regulates adhesion and differentiation of cultured human keratinocytes. To explore kazrin function in vivo, we generated a kazrin gene-trap mouse in which only exons 1-4 were expressed, fused to beta-galactosidase. On transient transfection, the protein encoded by exons 1-4 did not enter the nucleus, but did cause keratinocyte shape changes. The mice had no obvious defects in skin development or homeostasis, and periplakin and desmoplakin localization was normal. Expression of the kazrin-beta galactosidase fusion protein faithfully reported endogenous kazrin expression. Kazrin was not expressed in embryonic epidermis and was first detected at postnatal day 1. In adult mice, epidermal kazrin expression was less widespread than in humans and Xenopus, being confined to the bulb of anagen hair follicles, the infundibulum, and parakeratotic tail epidermis. In anagen bulbs, kazrin was expressed by a band of cells with elongated morphology and low desmoplakin levels, suggesting a role in morphogenetic cell movements. We conclude that exons 5-15 of kazrin, encoding the nuclear localization signal and C-terminal domain, are not required for epidermal development and function. The previously reported role of kazrin in regulating cell shape appears to reside within the N-terminal coiled-coil domain encoded by exons 1-4. PMID- 22513778 TI - Galectin-3 predicts response to statin therapy in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). AB - AIMS: To investigate whether plasma galectin-3, a mediator of fibrogenesis, can identify patients with chronic heart failure (HF) for whom statins are effective. METHODS AND RESULTS: Patients with ischaemic systolic HF enrolled in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) were randomly assigned to 10 mg/day of rosuvastatin or placebo. Galectin-3 was measured in plasma. The primary outcome was cardiovascular death, myocardial infarction, or stroke. Of 1492 patients, 411 had a primary event during a median follow-up of 32.8 months. There was an interaction between baseline galectin-3 and rosuvastatin on the primary endpoint (P-value for interaction = 0.036). Among patients with below the median plasma concentrations of galectin-3 (<= 19.0 ng/mL), those assigned to rosuvastatin had a lower primary event rate [hazard ratio (HR) 0.65; 95% confidence interval (CI), 0.46-0.92; P= 0.014], lower total mortality (HR 0.70; 95% CI, 0.50-0.98; P= 0.038), and lower event rate of all cause mortality and HF hospitalizations (HR 0.72; 95% CI, 0.54-0.98; P= 0.017) compared with placebo, but no benefit was observed in patients with higher levels of galectin-3. The combination of concurrently low concentrations of galectin-3 and N-terminal pro-B-type natriuretic peptide (<102.7 pmol/L) identified patients with a large benefit with rosuvastatin (HR 0.33; 95% CI, 0.16-0.67; P= 0.002). CONCLUSION: Patients with systolic HF of ischaemic aetiology who have galectin-3 values <19.0 ng/mL may benefit from rosuvastatin treatment. However, the data from this post hoc analysis should be interpreted with caution since the overall results of the CORONA study did not show a significant effect on the primary endpoint. PMID- 22513780 TI - Systemic isotretinoin therapy normalizes exaggerated TLR-2-mediated innate immune responses in acne patients. AB - Retinoids are used in the treatment of inflammatory skin diseases and malignancies, but studies characterizing the in vivo actions of these drugs in humans are lacking. Isotretinoin is a pro-drug for all-trans retinoic acid, which can induce long-term remissions of acne; however, its complete mechanism of action is unknown. We hypothesized that isotretinoin induces remission of acne by normalizing the innate immune response to the commensal bacterium Propionibacterium acnes. Compared with normal subjects, peripheral blood monocytes from acne patients expressed significantly higher levels of Toll-like receptor 2 (TLR-2) and exhibited significantly greater induction of TLR-2 expression following P. acnes stimulation. Treatment of patients with isotretinoin significantly decreased monocyte TLR-2 expression and subsequent inflammatory cytokine response to P. acnes after 1 week of therapy. This effect was sustained 6 months following cessation of therapy, indicating that TLR-2 modulation may be involved in the durable therapeutic response to isotretinoin. This study demonstrates that isotretinoin exerts immunomodulatory effects in patients and sheds light on a potential mechanism for its long-term effects on acne. The modulation of TLR-2 expression on monocytes has important implications in other inflammatory disorders characterized by TLR-2 dysregulation. PMID- 22513781 TI - Endocannabinoids regulate growth and survival of human eccrine sweat gland derived epithelial cells. AB - The functional existence of the emerging endocannabinoid system (ECS), one of the new neuroendocrine players in cutaneous biology, is recently described in the human skin. In this study, using human eccrine sweat gland-derived immortalized NCL-SG3 model cells and a wide array of cellular and molecular assays, we investigated the effects of prototypic endocannabinoids (anandamide, 2 arachidonoylglycerol) on cellular functions. We show here that both endocannabinoids dose-dependently suppressed proliferation, induced apoptosis, altered expressions of various cytoskeleton proteins (e.g., cytokeratins), and upregulated lipid synthesis. Interestingly, as revealed by specific agonists and antagonists as well as by RNA interference, neither the metabotropic cannabinoid receptors (CB) nor the "ionotropic" CB transient receptor potential ion channels, expressed by these cells, mediated the cellular actions of the endocannabinoids. However, the endocannabinoids selectively activated the mitogen-activated protein kinase signaling pathway. Finally, other elements of the ECS (i.e., enzymes involved in the synthesis and degradation of endocannabinoids) were also identified on NCL-SG3 cells. These results collectively suggest that cannabinoids exert a profound regulatory role in the biology of the appendage. Therefore, from a therapeutic point of view, upregulation of endocannabinoid levels might help to manage certain sweat gland-derived disorders (e.g., tumors) characterized by unwanted growth. PMID- 22513782 TI - A promiscuous survivin-derived T-cell epitope restricted to the HLA-A3 super-type alleles. PMID- 22513783 TI - Interfollicular epidermal homeostasis: a response to Ghadially, '25 years of epidermal stem cell research'. PMID- 22513784 TI - A meta-analysis of gene expression data identifies a molecular signature characteristic for tumor-stage mycosis fungoides. AB - Mycosis fungoides (MF) is the most common type of primary cutaneous T-cell lymphoma (CTCL). To identify a molecular signature characteristic of MF tumor stage, we used a bioinformatic approach involving meta-analysis of publicly available gene expression data sets combined with previously generated gene expression data. Results for a selection of genes were further refined and validated by quantitative PCR and inclusion of additional controls. With this approach, we identified a profile specific for MF tumor stage, consisting of 989 aberrantly expressed genes, the majority of which (718 genes) are statistically significantly more expressed in MF compared with normal skin, inflamed skin, and normal T cells. As expected, the signature contains genes reflecting the highly proliferative characteristic of this T-cell malignancy, including altered expression of cell cycle and kinetochore regulators. We uncovered details of the immunophenotype, suggesting that MF originates from IL-32-producing cells and identified previously unreported therapeutic targets and/or diagnostic markers, for example, GTSF1 and TRIP13. Loss of expression of the NF-kappaB inhibitor, NFKBIZ, may partly explain the enhanced activity of NF-kappaB, which is a hallmark of MF and other CTCLs. PMID- 22513785 TI - NADPH oxidase 1 overexpression enhances invasion via matrix metalloproteinase-2 and epithelial-mesenchymal transition in melanoma cells. AB - NADPH oxidase 1 (Nox1) is a member of the NADPH oxidase family that has not been well characterized in the melanocytic cell lineage. Here we demonstrated that Nox1 and Nox4 were detected in melanocytic lineage, with only Nox1 detected in normal human melanocytes and Nox4 in a subset of metastatic melanoma cell lines. The protein level and enzymatic activity of Nox1 was elevated in all melanoma cells as compared with normal melanocytes. Overexpression of GFP-Nox1 protein in Wm3211 primary melanoma cells increased invasion rate by 4- to 6-fold as measured by Matrigel invasion assay, whereas knocking down or inhibiting Nox1 decreased invasion by approximately 40-60% in Wm3211 and SK-Mel-28 cells. Matrix metalloproteinase-2 (MMP-2) was increased by Nox1 overexpression at the mRNA, protein, and activity levels, and decreased by Nox1 knockdown. MMP-2 promoter activity was also regulated by Nox1 knockdown. In addition, stable clones overexpressing Nox1 exhibited an epithelial-mesenchymal transition (EMT) as examined by cell morphology and EMT markers; knockdown or inhibiting Nox1 led to a reversal of EMT. Supplementing MMP-2 to culture media did not induce EMT, suggesting that EMT induction by Nox1 was not through MMP-2 upregulation. In summary, Nox1 was overexpressed in all melanoma cell lines examined, and enhanced cell invasion by MMP-2 upregulation and EMT induction. PMID- 22513786 TI - Interleukin-1beta interferes with epidermal homeostasis through induction of insulin resistance: implications for psoriasis pathogenesis. AB - Response pathways of the metabolic and the immune system have been evolutionary conserved, resulting in a high degree of integrated regulation. Insulin is a central player in the metabolic system and potentially also in the homeostasis of the skin. Psoriasis is a frequent and often severe autoimmune skin disease, clinically characterized by altered epidermal homeostasis, of which the molecular pathomechanisms are only little understood. In this study, we have examined a potential role for insulin signaling in the pathogenesis of this disease. We show that IL-1beta is present in high quantities in tissue fluid collected via microdialysis from patients with psoriasis; these levels are reduced under successful anti-psoriatic therapy. Our results suggest that IL-1beta contributes to the disease by dual effects. First, it induces insulin resistance through p38MAPK (mitogen-activated protein kinase), which blocks insulin-dependent differentiation of keratinocytes, and at the same time IL-1beta drives proliferation of keratinocytes, both being hallmarks of psoriasis. Taken together, our findings point toward insulin resistance as a contributing mechanism to the development of psoriasis; this not only drives cardiovascular comorbidities, but also its cutaneous phenotype. Key cytokines inducing insulin resistance in keratinocytes and kinases mediating their effects may represent attractive targets for novel anti-psoriatic therapies. PMID- 22513787 TI - Absence of distinguishing senescence traits in human melanocytic nevi. AB - Cellular senescence permanently restricts the replicative capacity of cells in response to various stress signals, including aberrant activation of oncogenes. The presence of predictive senescence markers in human premalignant lesions suggests that senescence may function as a genuine tumor suppressor. These markers are not exclusive to the senescence program, however, and it is possible that their expression in vivo does not discriminate irreversible from reversible forms of proliferative arrest. In this study, we aimed to clarify whether human nevus cells can be distinguished from primary and transformed melanocytes by examining the expression of eight senescence markers, including those previously purported to define nevi as senescent tumors. Specifically, we analyzed effectors of senescence, including p16(INK4a), p53, and DNA damage (gamma-H2AX), as well as predictive markers of senescence including Ki67, PML, senescence-associated beta galactosidase, heterochromatic foci (H3K9Me, 4'-6-diamidino-2-phenylindole), and nuclear size. We found that these commonly accepted senescence markers do not in fact distinguish nevi from precursor/normal and transformed/malignant melanocytes. We conclude that on the basis of current evidence it cannot be reasonably inferred that nevi are permanently growth arrested via senescence. PMID- 22513788 TI - Multifunctional nanoparticle-loaded spherical and wormlike micelles formed by interfacial instabilities. AB - Hybrid spherical and wormlike amphiphilic block copolymer micelles are formed through evaporation-induced interfacial instabilities of emulsion droplets, allowing the incorporation of pre-synthesized hydrophobic inorganic nanoparticles within the micelle cores, as well as co-encapsulation of different nanoparticles. This encapsulation behavior is largely insensitive to particle surface chemistry, shape, and size, thus providing a versatile route to fabricate multifunctional micelles. PMID- 22513789 TI - Quantitative assessment of diffuse optical tomography sensitivity to the cerebral cortex using a whole-head probe. AB - We quantify the variability in diffuse optical tomography (DOT) sensitivity over the cortical surface in eight young adult subjects. We use the 10/5 electroencephalography system as a basis for our whole-head optical high-density probe design. The contrast-to-noise ratio (CNR) is calculated along with the percentage of the cortex that is above a CNR = 0 dB threshold. We also quantify the effect of including vasculature on the forward model and list our assumptions that allow us to estimate light penetration depth in the head. We show that using the 10/5 system for the optical probe design allows for the measurement of 37% of the cortical surface on average, with a mean CNR in the visible region of 5.5 dB. Certain anatomical regions, such as the lateral occipital cortex, had a very high percentage above the CNR threshold, while other regions such as the cingulate cortex were not measurable. Vasculature blocked optical sensitivity over 1% of the cortex. Cortical coverage was positively correlated with intracranial volume and relative cerebrospinal fluid volume, and negatively correlated with relative scalp volume and skull volume. These contributions allow experimenters to understand how anatomical variation in a subject population may impact DOT or functional near-infrared spectroscopy measurements. PMID- 22513790 TI - nBu4NI-catalyzed C3-formylation of indoles with N-methylaniline. AB - nBu(4)NI-catalyzed C3-selective formylation of N-H and N-substituted indoles by using N-methylaniline as a formylating reagent was first successfully demonstrated. PMID- 22513791 TI - [Specifics of histopathological and genetical diagnosis and classification of lymphomas in children and adolescents]. AB - Malignant lymphoma along with leukemias account for nearly half of all malignancies arising in childhood and adolescence. The correct tissue-based histopathological diagnosis of lymphomas results from a close interdisciplinary exchange between pediatric oncologists and hematopathologists. We describe here relevant features of lymphoma subtypes arising in the young age group, Burkitt lymphoma, precursor/lymphoblastic lymphomas, anaplastic large cell lymphoma and diffuse large B-cell lymphoma as well as primary mediastinal B-cell lymphoma and the rare pediatric follicular lymphomas. Special focus is put on specific diagnostic difficulties as well as new insights into biological features of pediatric lymphomas in comparison with their adult counterpart. In addition the relevance of newly defined lymphoma entities of the WHO-classification 2008, e.g. greyzone lymphomas, will be discussed for the young age group. PMID- 22513792 TI - Malignant peritoneal mesothelioma in a 16-year-old girl: presentation of a rare disease. AB - Malignant peritoneal mesothelioma is extremely rarely seen in young patients.A 16 year-old girl presented with appendicitis-like acute abdominal pain. Intra operatively, multiple confluent peritoneal nodules were seen on the entire greater omentum and in the pelvis infiltrating the uterus and both ovaries. Biopsies were obtained and interpreted as serous ovarian carcinoma. Radical surgical resection and hyperthermic intraperitoneal chemotherapy -(HIPEC) with carboplatin was performed and followed by 2 cycles of carboplatin/paclitaxel. Histological reevaluation showed characteristic features of epithelioid peritoneal mesothelioma and ruled out serous ovarian cancer. Therapy was continued with 6 cycles of pemetrexed/cisplatin.3 months after end of chemotherapy vital tumor tissue was found in the recess behind the liver, which could be resected completely. The patient is currently disease-free 17 months after initial diagnosis.Malignant peritoneal mesothelioma in young female patients might be under-recognized and possibly misdiagnosed as ovarian serous carcinoma in some cases. International and interdisciplinary cooperation is necessary in order to provide evidence based guidelines for diagnosis and treatment in the future. PMID- 22513793 TI - Primary lung metastases in pediatric malignant non-Wilms renal tumors: data from SIOP 93-01/GPOH and SIOP 2001/GPOH. AB - Malignant non-Wilms renal tumors (NWRT) are a small but relevant subgroup of renal neoplasms in children. In this study we analyzed corresponding data from the trials SIOP 93-01/GPOH and SIOP 2001/GPOH of the Society of Pediatric Oncology and Hematology.Data of 22 patients with NWRT and primary lung metastases were retrospectively reviewed. Analyses included epidemiology, tumor characteristics, chemotherapy, local treatment, and outcome.The following diagnoses were registered: Malignant Rhabdoid tumor of the kidney (MRTK, n=15), Renal-cell carcinoma (RCC, n=3), Clear-cell sarcoma of the kidney (CCSK, n=3), and primitive neuro ectodermal tumor (PNET, n=1). Median age of patients at diagnosis was 14 months. Overall survival was 36.36% (8/22). Of the 15 children with MRTK 3 survived, 3/3 patients with RCC, 1/3 patients with CCSK, and 1/1 patient with PNET survived. Lung metastases disappeared in 6 patients after initial chemotherapy, 6/8 patients undergoing local treatment of lung metastases (surgery, irradiation, or both) achieved complete remission. Only patients with complete clearance of lung lesions, either through neoadjuvant chemotherapy or subsequent local treatment, survived. Mean Follow up was 31 months (1 137).Survival of patients with stage IV NWRT is dismal. Complete removal of lung metastases seems mandatory for survival. An aggressive diagnostic and therapeutic approach seems justified in affected children. PMID- 22513794 TI - Nephrotic syndrome leading to the diagnosis of classical Hodgkin's lymphoma in a 13-year-old girl. PMID- 22513795 TI - High dose methotrexate treatment in childhood ALL: pilot study on the impact of the MTHFR 677C>T and 1298A>C polymorphisms on MTX-related toxicity. AB - Methotrexate (MTX) is commonly administered in high doses for treatment of childhood acute lymphoblastic leukemia (ALL). The aim of this analysis was to study the influence of 2 common MTHFR polymorphisms (MTHFR 677C>T and 1298 A>C) on MTX toxicity in children with ALL.Retrospective analysis of 129 MTX courses in 34 pediatric patients with ALL.677C>T variants (CT or TT) were found in 19 (14 heterozygous, 5 homozygous) and 1298A>C variants (AC or CC) in 20 (16 heterozygous, 4 homozygous) patients. The MTHFR 677C>T wild type was associated with an increased frequency of grade III and IV leukopenia (60% vs. 31%, p<0.05) compared to the variants. The rate of severe infections (21% vs. 0%, p<0.05) and grade III-IV anemia (26% vs. 5%, p<0.05) was increased in carriers of the MTHFR 677C>T wild type compared to patients with the TT variant. Grade III-IV anemia was more frequent in patients with the MTHFR 1298A>C CC variant compared to the wild type (56% vs. 21%, p<0.05). The differences were not significant in a patient-based analysis.MTX related toxicity might be influenced by the MTHFR 677C>T or the MTHFR 1298A>C polymorphisms. Differences in MTX toxicity are only partially explainable by these 2 polymorphisms. PMID- 22513796 TI - [GATA1-mutation associated leukemia in children with trisomy 21 mosaic]. AB - Mutations of the hematopoietic transcription factor GATA1 (GATA1s) are pathognomonic in newborn with transient leukemia and children with Down syndrome and myeloid leukemia (ML-DS). Both TL and ML-DS can also occur in children with trisomy 21 mosaic.Between 2002 and 2011, 15 newborns and infants were diagnosed with DS mosaic. 9 of them presented with TL and 8 children suffered from ML-DS; 2 of them with a history of TL. In children without stigmata the special morphology and immunophenotype of blasts triggered the screening for GATA1 mutation and trisomy 21 mosaic.All newborns with TL achieved complete remission (CR). Due to clinical symptoms caused by the leukemic blasts, in 3 children low-dose cytarabine was applied. 1 patient died due to cardiac defect. In all patients GATA 1 s was confirmed. 6 children with ML-DS were initially treated according the AML-BFM protocol. After ML-DS was confirmed, therapy was continued with the intensity reduced schedule according to the ML-DS 2006 protocol. All children are still in CR (follow-up 1.8-7 years, median 2.7 yrs). 2 children with unknown trisomy 21 mosaic were diagnosed as acute megakaryoblastic leukemia (AMKL) and treated according the high risk arm of the AML-BFM 2004 including allogeneic stem cell transplantation in one child). GATA1 mutation was identified retrospectively. Both children are alive in CR.GATA1s associated leukemia has to be excluded in all young children with AMKL (<5 years old) to prevent overtreatment. Treatment with reduced intensity seems sufficient in children trisomy 21 mosaic and ML-DS. PMID- 22513797 TI - Homozygous point mutations in platelet glycoprotein ITGA2B gene as cause of Glanzmann thrombasthenia in 2 families. AB - Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by quantitative and/or qualitative defects of the platelet glycoprotein (GP) IIb/IIIa complex. Physiologically, the integrin GPIIb/IIIa binds Von Willebrand factor and fibrinogen on activated platelets. GT is caused by genetic alterations in ITGA2B or ITGB3 (genes encoding GPIIb and GPIIIa).This study describes 2 siblings diagnosed with GT type I associated with homozygous point mutations in ITGA2B. All patients presented with typical bleeding disorder including moderate hematomas, petechiae, and mucocutaneous bleedings.Both siblings showed severely reduced platelet aggregation especially after stimulation with collagen and adenosine diphosphate. Absence of platelet GPIIb/GPIIIa complex was determined using flow cytometry. Molecular genetic analysis revealed 2 distinct homozygous point mutations in exon 18 of ITGA2B. Family 1 was identified with c.1878G>C and family 2 with c.1787T>C substitution. While the c.1787T>C mutation causes a single amino acid substitution p.I565T, the c.1878G>C mutation (p.Q595H) is predicted to induce a mRNA splicing anomaly.These mutations were identified as cause of GT type I in the described patients. Patients with GT should be documented in a prospective register to verify the correlation between the severity of bleeding symptoms and the pathogenic mutation. This can have effects on therapeutic decisions. PMID- 22513798 TI - Choice of synonymous codons associated with protein folding. AB - Bioinformatical studies suggest that additional information provided by nucleic acids is necessary to construct protein three-dimensional structures. We find underlying correlations between the contents of bases. All correlations occur at the third codon position of a gene sequence. Four inverse relationships are observed between u(3) and c(3), between a(3) and g(3), between u(3) and g(3), and between c(3) and a(3); and two positive relationships are apparent between u(3) and a(3), and between c(3) and g(3). Their correlation coefficients reach -0.92, 0.89, -0.83, -0.85, 0.83, and 0.66, respectively, for large proteins with multistate folding kinetics. The interconnection of bases can be ascribed to choice of synonymous codons associated with protein folding in vivo. In this study, the refolding rate constants of large proteins correlate with the contents of the third base, suggesting that there is underlying biochemical rationale of guiding protein folding in choosing synonymous codons. PMID- 22513799 TI - Rapid determination of vitamin B12 concentration with a chemiluminescence lab on a chip. AB - This paper reports a novel method for the rapid determination of vitamin B(12) concentration in a continuous-flow lab-on-a-chip system. This new method is based on luminol-peroxide chemiluminescence (CL) assays for the detection of cobalt(II) ions in vitamin B(12) molecules. The lab-on-a-chip device consisted of two passive micromixers acting as microreactors and a double spiral microchannel network serving as an optical detection region. This system could operate in two modes. In the first mode, samples are acidified and evaluated directly in the microchip. In the second mode, samples are treated externally by acidification prior to detection in the microchip. In the first mode, the linear range obtained was between 1.00 ng ml(-1) to 10 MUg ml(-1), R(2) = 0.996, with a relative standard deviation (RSD) of 1.23 to 2.31% (n = 5) and a limit of detection (lod) of 0.368 pg ml(-1). The minimum sample volume required and the analytical time were 30 MUl and 3.6 s, respectively. In the second mode, the linear range obtained was between 0.10 ng ml(-1) to 10 MUg ml(-1), R(2) = 0.994, with the RSD of 0.90 to 2.32% (n = 6) and a lod of 0.576 pg ml(-1). The minimum sample and the analytical time required were 50 MUl and 6 s, respectively. The lab on a chip working in mode II was successfully used for the determination of vitamin B(12) concentrations in nutritional supplemental tablets and hen egg yolks. PMID- 22513800 TI - Bidirectional influences between parents and children in smoking behavior: a longitudinal full-family model. AB - BACKGROUND: The present study investigated longitudinal associations and bidirectional influences between family members in smoking behavior using a longitudinal full-family design. Family systems provide a powerful social context in which modeling and imitation take place. In current literature, however, bidirectional associations between parents and children in smoking behavior are seldom considered. METHODS: Participants were 426 families, including mothers, fathers, and 2 adolescent children. Associations were assessed over 5 waves with yearly intervals using a cross-lagged model in structural equation modeling. RESULTS: Findings demonstrate that families resemble an interactive system affording smoking contagion across family members. Results suggest that associations between parents and children are bidirectional, that is, parental smoking behavior influences adolescent smoking behavior and adolescent smoking behavior influences parental smoking behavior. There is insufficient evidence to conclude that longitudinal associations between family members are generally bidirectional, as only unidirectional longitudinal associations were found between between siblings and partners. CONCLUSIONS: The present study extends previous research on the intergenerational transmission of smoking behavior by demonstrating bidirectional influences between parents and children in smoking behavior. Moreover, the present study suggests that family members may be susceptible to adjust their smoking behavior across time in response to smoking behavior within the family. PMID- 22513801 TI - Dependence and withdrawal-induced craving predict abstinence in an incentive based model of smoking relapse. AB - INTRODUCTION: Understanding factors that render some individuals more vulnerable to smoking relapse during the early stages of a quit attempt is critical to tailoring treatment efforts. Development of laboratory models of relapse can provide a framework for identifying underlying mechanisms that may contribute to vulnerability. Here, we explored predictors of abstinence in a novel incentive based model of relapse. METHODS: Fifty-six nontreatment seeking daily smokers completed several nicotine dependence measures prior to participating in a 1-week abstinence incentive test. During the abstinence procedure, participants earned monetary reinforcement for each biochemically verified day of abstinence according to a descending schedule of reinforcement. RESULTS: Compliance with the procedure was excellent. All but 3 participants were able to initiate abstinence; nearly 70% lapsed as incentives were reduced. Scores on the Fagerstrom Test for Nicotine Dependence (FTND), number of cigarettes smoked per day, and self reported craving on the first day of abstinence each independently predicted time to lapse. The single item of time to first cigarette in the morning on the FTND significantly predicted time to lapse, even when controlling for other significant predictors just listed. The Nicotine Dependence Syndrome Scale (NDSS) and Wisconsin Inventory of Smoking Dependence Motives did not predict lapse, but the NDSS did predict reinitiation of abstinence among those experiencing an initial lapse. CONCLUSIONS: These findings partially replicate those of previous full-scale clinical trials and support the feasibility and validity of an incentive-based model of relapse. The time-limited and laboratory-based nature of this model has the potential to further investigations of underlying mechanisms contributing to relapse. PMID- 22513802 TI - EBV infection and mismatch repair deficiency mediated by loss of hMLH1 expression contribute independently to the development of multiple synchronous gastric carcinomas. AB - BACKGROUND: To explore the possible association between EBV, microsatellite instability (MSI), and alterations of hMLH1 protein, 282 tumors from 141 patients with multiple synchronous gastric carcinomas (MSGC) were studied. METHODS: In situ hybridization for EBV-encoded small RNA and hMLH1 immunohistochemistry were performed in tissue microarrays. In 19 MSGC cases with altered hMLH1 expression, methylation analyses by MethyLight and MSI tests were performed. RESULTS: Loss of hMLH1 was found in 19 of 141 MSGC patients (13.5%) and 26 of 282 MSGC tumors (9.2%). hMLH1 loss was associated with differentiated histology (P = 0.03). Out of the 38 tumors from 19 hMLH1-negative MSGCs, 12 tumors from six cases (31.6%) showed concurrent methylation of hMLH1 and MSI-high in both multiple tumors. EBV was found in 31 of 141 MSGC patients (21.9%) and 49 of 282 MSGC tumors (17.4%) and was significantly associated with undifferentiated histology and a location within the upper third of the stomach (P < 0.002). EBV was not observed in any of the tumors that had a loss of hMLH1 expression. CONCLUSIONS: Considering that EBV associated GCs show global CpG island methylation, our findings suggest that EBV infection allows the gastric mucosa to escape from aberrant methylation of hMLH1 and induces a malignant pathway independent of MSI. PMID- 22513804 TI - Cutaneous clear cell neoplasms: a histopathological reappraisal. AB - Cutaneous clear cell neoplasms represent a heterogenous group of several primary and metastatic tumors with diverse histogenesis. Tumors with widespread clear cell change can seem strikingly similar under the microscope resulting in diagnostic difficulties. Although most cases are idiopathic, intracytoplasmic accumulation, artifact of tissue processing, and degenerative phenomenon have been cited as possible causes of clear cell change. An awareness of the various entities demonstrating this attribute, judicious use of ancillary techniques, and knowledge of the clinical setting are crucial to the accurate diagnosis. This review details the histological features of clear cell neoplasms of the skin with particular emphasis on the discriminating features. PMID- 22513803 TI - NAIPs: building an innate immune barrier against bacterial pathogens. NAIPs function as sensors that initiate innate immunity by detection of bacterial proteins in the host cell cytosol. AB - The innate immune system of mammals encodes several families of immune detector proteins that monitor the cytosol for signs of pathogen invasion. One important but poorly understood family of cytosolic immunosurveillance proteins is the NLR (nucleotide-binding domain, leucine-rich repeat containing) proteins. Recent work has demonstrated that one subfamily of NLRs, the NAIPs (NLR family, apoptosis inhibitory proteins), are activated by specific interaction with bacterial ligands, such as flagellin. NAIP activation leads to assembly of a large multiprotein complex called the inflammasome, which initiates innate immune responses by activation of the Caspase-1 protease. NAIPs therefore appear to detect pathogen molecules via a simple and direct receptor-ligand mechanism. Interestingly, other NLR family members appear to detect pathogens indirectly, perhaps by responding to host cell "stress" caused by the pathogen. Thus, the NLR family may have evolved surprisingly diverse mechanisms for detecting pathogens. PMID- 22513806 TI - Lipoatrophic panniculitis of the ankles in childhood: differential diagnosis with subcutaneous panniculitis-like T-cell lymphoma. AB - We describe the clinical, histopathologic, immunohistochemical, and molecular findings in an additional case of lipoatrophic panniculitis selectively involving the ankles in a 12-year-old boy. This idiopathic, rarely reported entity is presumed to have an autoimmune pathogenesis. Histological findings are a lipophagic lobular panniculits, that in our case featured focally increased numbers of lymphocytes rimming the adipocytes, and infiltration of vascular walls by mildly atypical lymphoid cells, raising the differential diagnosis of subcutaneous panniculitis-like T-cell lymphoma. PMID- 22513805 TI - False-negative tumor-free margins following mohs surgery for aggressive trichoblastoma. AB - Trichoblastoma (TB) is an infrequent, generally benign neoplasm arising from the germinative hair bulb with induction of mesenchymal stroma and with no adverse outcomes such as relapses, metastasis, or death. We report 2 cases of false negative tumor-free margins after Mohs micrographic surgery (MMS) for aggressive TB. PMID- 22513808 TI - Intralymphatic granulomas in orofacial granulomatosis. PMID- 22513809 TI - Cortical reorganization following neurotization: a diffusion tensor imaging and functional magnetic resonance imaging study. AB - BACKGROUND: Following successful intercostal-musculocutaneous nerve (ICN-MCN) neurotization for brachial plexus injuries (BPIs), patients initially show a synkinetic movement of elbow flexion during inspiration. Later they are able to flex the elbow, independent of respiratory activity. OBJECTIVE: To demonstrate cortical reorganization following ICN-MCN coaptation in BPI through functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). METHODS: Thirty adult patients underwent ICN-MCN coaptation for BPI. The controls were age and sex matched. All patients had Sunderland 3 or 4 degree of injury. Patients underwent fMRI and DTI (pre- and postoperatively) with electromyography of the biceps. Maps of neural activity within the motor cortex were generated in the paralyzed and control arms and center of maximum activity was calculated. Fractional anisotropy and apparent diffusion coefficient were generated from fMRI and DTI over the motor cortex and comparison was made between the paralyzed and control arms. RESULTS: Median deinnervation interval was 6 months. Seventeen patients improved from grade 0 to grade 3 or more. There was no significant difference between the coordinates for maximum activity, when the cortical activity following elbow flexion of the patients who improved was compared with the control arm activity. There was reduction in FA and ADC values in patients who have improved following surgery when compared to controls. Fractional anisotropy and apparent diffusion coefficient values of the postoperative patients revealed no significant difference from the controls or preoperative patients. CONCLUSION: Cortical plasticity following ICN-MCN transfer in BPI does occur. There was no correlation between the degree of improvement either with the transposition of activity on the motor cortex from the chest to the elbow area, or the amount of activity on the motor cortex representing the elbow area. PMID- 22513810 TI - Re: The method of aneurysm treatment does not affect clot clearance after aneurysmal subarachnoid hemorrhage. PMID- 22513816 TI - A zinc porphyrin-based molecular probe for the determination of contamination in commercial acetonitrile. AB - A zinc porphyrin-based receptor containing four triazole groups at the ortho position of each phenyl group (1) was utilized as a useful probe for the determination of contaminants in acetonitrile (MeCN). Through the simple observation of the absorption spectrum of 1 in MeCN, the cyanide contamination concentration could be directly determined. PMID- 22513818 TI - Monodisperse titania microspheres via controlled nanoparticle aggregation. AB - This paper describes the fabrication of highly monodisperse TiO(2) nanoparticle aggregates (NPAs) by controlled aggregation of nanoparticles in a water-in-oil emulsion. Equally sized drops containing a titanium dioxide nanoparticle suspension are produced in a T-channel device. This procedure has a high tuning potential. Increasing the velocity of the titania suspension phase leads to an enlargement of the droplets, while raising the velocity of the oil phase reduces the drop diameter. The technique enables the preparation of monodisperse (<2%) drops between 150 and 400 MUm in diameter. Evaporation of the suspension medium leads to nanoparticle aggregates. There is no significant change in dispersity from emulsion drops to NPAs, if the drying is carried out slowly. PMID- 22513817 TI - Quantifying the anthropogenic fraction of fatty alcohols in a terrestrial environment. AB - Fatty alcohols are naturally produced hydrocarbons present in all living organisms. They are also used in detergent and cosmetic formulations, may be sourced from either petroleum or biological materials, and are typically disposed of down the drain. This study was conducted on the Luray catchment, Virginia, USA, where sales data indicate that approximately 2 kg of fatty alcohols from detergent enter the wastewater every day. Reconstructing fatty alcohols in the influent on the basis of sales data indicated a mix of odd and even chain compounds, with C(12) being dominant. This profile was influenced strongly by liquid laundry detergents (69%). Sediment and soil samples from the catchment were analyzed by gas chromatography-mass spectrometry and by stable isotope ratio mass spectrometry to determine the delta(13)C and delta(2)H signatures. The long chain components in agricultural soils and river sediments were distinguishable clearly from the algal fatty alcohols produced within the river system. The wastewater was a mixture of fecal and detergent sources of fatty alcohols in a ratio of 75:25%. The fatty alcohols in the effluent had different stable isotopic signatures and chain-length profiles from the influent, indicating that these compounds are not the same as those that entered the treatment plant. The total quantity of fatty alcohols leaving the treatment plant through the effluent pipe was low compared with the input. Analysis of the contributions based on the stable isotopes and profiles suggests that of the fatty alcohols present in the river system downstream of the treatment plant, 84% were derived from terrestrial plant production, 15% came from in situ algal synthesis, and 1% were derived from the effluent. PMID- 22513819 TI - What drives the precipitation of long-chain calcium carboxylates (soaps) in aqueous solution? AB - The interaction of sodium octanoate, decanoate or dodecanoate with calcium(ii) in aqueous solutions has been studied using turbidity, conductivity and potentiometric measurements. These show a marked alkyl chain length dependence on the behaviour. At the calcium concentration used (1.0 mM), there is little interaction with the octanoate, the decanoate shows initially formation of a 1:1 complex, followed by precipitation, while the dodecanoate precipitates at low surfactant concentrations. The solid calcium carboxylates were prepared, and show lamellar, bilayer structures with planes of calcium(II) ions coordinated to carboxylate groups through bidentate chelate linkages. Thermogravimetry and elemental analyses indicate the presence of coordinated water with the calcium decanoate but not with longer chain carboxylates. The results of both the solution and solid state studies suggest that precipitation of long-chain carboxylates depends on a balance between hydration effects and hydrophobic (largely van der Waals') interactions. Electrostatic effects make little energetic contribution but play the important structural role of ordering the carboxylate anions before precipitation. Differences are observed in the interactions between calcium(II) and long chain alkylcarboxylates and alkylsulfates, and are interpreted in terms of stronger binding to the metal of the carboxylate group. A general mechanism is proposed for calcium carboxylate precipitation from aqueous solution based on this and previous studies. PMID- 22513820 TI - The intrinsic prostaglandin E2-EP4 system of the renal tubular epithelium limits the development of tubulointerstitial fibrosis in mice. AB - Inflammatory responses in the kidney lead to tubulointerstitial fibrosis, a common feature of chronic kidney diseases. Here we examined the role of prostaglandin E(2) (PGE(2)) in the development of tubulointerstitial fibrosis. In the kidneys of wild-type mice, unilateral ureteral obstruction leads to progressive tubulointerstitial fibrosis with macrophage infiltration and myofibroblast proliferation. This was accompanied by an upregulation of COX-2 and PGE(2) receptor subtype EP(4) mRNAs. In the kidneys of EP(4) gene knockout mice, however, obstruction-induced histological alterations were significantly augmented. In contrast, an EP(4)-specific agonist significantly attenuated these alterations in the kidneys of wild-type mice. The mRNAs for macrophage chemokines and profibrotic growth factors were upregulated in the kidneys of wild-type mice after ureteral obstruction. This was significantly augmented in the kidneys of EP(4)-knockout mice and suppressed by the EP(4) agonist but only in the kidneys of wild-type mice. Notably, COX-2 and MCP-1 proteins, as well as EP(4) mRNA, were localized in renal tubular epithelial cells after ureteral obstruction. In cultured renal fibroblasts, another EP(4)-specific agonist significantly inhibited PDGF-induced proliferation and profibrotic connective tissue growth factor production. Hence, an endogenous PGE(2)-EP(4) system in the tubular epithelium limits the development of tubulointerstitial fibrosis by suppressing inflammatory responses. PMID- 22513822 TI - Online feedback-controlled renal constant infusion clearances in rats. AB - Constant infusion clearance techniques using exogenous renal markers are considered the gold standard for assessing the glomerular filtration rate. Here we describe a constant infusion clearance method in rats allowing the real-time monitoring of steady-state conditions using an automated closed-loop approach based on the transcutaneous measurement of the renal marker FITC-sinistrin. In order to optimize parameters to reach steady-state conditions as fast as possible, a Matlab-based simulation tool was established. Based on this, a real time feedback-regulated approach for constant infusion clearance monitoring was developed. This was validated by determining hourly FITC-sinistrin plasma concentrations and the glomerular filtration rate in healthy and unilaterally nephrectomized rats. The transcutaneously assessed FITC-sinistrin fluorescence signal was found to reflect the plasma concentration. Our method allows the precise determination of the onset of steady-state marker concentration. Moreover, the steady state can be monitored and controlled in real time for several hours. This procedure is simple to perform since no urine samples and only one blood sample are required. Thus, we developed a real-time feedback-based system for optimal regulation and monitoring of a constant infusion clearance technique. PMID- 22513821 TI - The association of genetic variants of type 2 diabetes with kidney function. AB - Type 2 diabetes is highly prevalent and is the major cause of progressive chronic kidney disease in American Indians. Genome-wide association studies identified several loci associated with diabetes but their impact on susceptibility to diabetic complications is unknown. We studied the association of 18 type 2 diabetes genome-wide association single-nucleotide polymorphisms (SNPs) with estimated glomerular filtration rate (eGFR; MDRD equation) and urine albumin-to creatinine ratio in 6958 Strong Heart Study family and cohort participants. Center-specific residuals of eGFR and log urine albumin-to-creatinine ratio, obtained from linear regression models adjusted for age, sex, and body mass index, were regressed onto SNP dosage using variance component models in family data and linear regression in unrelated individuals. Estimates were then combined across centers. Four diabetic loci were associated with eGFR and one locus with urine albumin-to-creatinine ratio. A SNP in the WFS1 gene (rs10010131) was associated with higher eGFR in younger individuals and with increased albuminuria. SNPs in the FTO, KCNJ11, and TCF7L2 genes were associated with lower eGFR, but not albuminuria, and were not significant in prospective analyses. Our findings suggest a shared genetic risk for type 2 diabetes and its kidney complications, and a potential role for WFS1 in early-onset diabetic nephropathy in American Indian populations. PMID- 22513823 TI - Ureteral obstruction promotes proliferation and differentiation of the renal urothelium into a bladder-like phenotype. AB - The renal urothelium, the monolayered epithelium that covers the papilla, is the direct target of increased pressure during obstruction, yet most studies have mainly focused on tubules, fibroblasts, and inflammatory cells. We studied this epithelium in a unilateral ureteral obstruction mouse mode land found that it was disrupted and had broken tight junctions, enlarged intercellular space, with loss of apicaluroplakins, and marginal lumen desquamation. Shortly after obstruction these urothelial cells proliferated, peaking at day 2. By day 14, the renal urothelium was transformed into a multilayered barrier with newly synthesized uroplakins including the de novo induction of uroplakin II. This proliferation was found to be fibroblast growth factor (FGF)dependent. Renal urothelial cells constitutively express the FGF receptor 2, and obstruction activated the receptor by phosphorylation. Treatment with FGF receptor 2-antisense or vitamin A (an inhibitor of the MAP kinase in the FGFR2 pathway) decreased renal urothelial cell proliferation. Among known FGF receptor 2 ligands, only FGF7 was upregulated.Infusion of FGF7 into control mice caused the formation of a multilayered structure at 7 days, resembling the urothelium 14 days following obstruction. Thus, the pressure/stretching of renal monolayered urothelial cells is a very efficient trigger for proliferation, causing the formation of a bladder like multistratified barrier with enhanced apical uroplakin plaques. Presumably, this ensures efficient barrier protection and repair. PMID- 22513824 TI - Endothelial injury in transplant glomerulopathy is correlated with transcription factor T-bet expression. AB - Transplant glomerulopathy is an important cause of late graft loss. Inflammatory lesions including glomerulitis and peritubular capillaritis, suggestive of endothelial injury, are prominent in this condition but the mechanism underlying this inflammation remains unclear. Here we measured the expression of T-bet (a member of the T-box family of transcription factors regulating Th1 lineage commitment) and its relationship with inflammation in 70 patients with transplant glomerulopathy. Within this cohort, 32 patients were diagnosed with transplant glomerulopathy, 23 with interstitial fibrosis/tubular atrophy, and 15 with stable grafts. There was a significant increase in T-bet expression in both glomerular and peritubular capillaries of the transplant glomerulopathy group. This expression was strongly correlated with CD4(+), CD8(+), and CD68(+) cell infiltration within glomerular and peritubular capillaries. The expression of GATA3, a Th2 regulator, was rarely found in the transplant glomerulopathy group. Transplant glomerulopathy was associated with diffuse peritubular capillary dilation without reduced capillary density. Moreover, the degree of capillary dilation was significantly correlated with the number of infiltrating CD68(+) cells. Since endothelial injury is a typical lesion that follows alloantibody reactivity, our results suggest that T-bet is involved in the pathogenesis of this glomerulopathy. PMID- 22513825 TI - Composition and plaque patterns of coronary culprit lesions and clinical characteristics of patients with chronic kidney disease. AB - Coronary artery disease is a serious complication of chronic kidney disease (CKD); however, there is little information about coronary plaque morphology in these patients. Here we identified the characteristics of coronary culprit plaques and their clinical manifestations in 78 patients with CKD divided into four groups based on their estimated glomerular filtration rate. Patients were examined by Virtual Histology-Intravascular Ultrasound, a tomographic imaging method that can visualize atherosclerotic plaques in vivo using radiofrequency analysis of ultrasound backscatter signals. These ultrasound analyses showed an increase in the relative volumes of both dense calcium and necrotic core with decreasing renal function. The necrotic core/dense calcium ratio was significantly higher in patients with acute myocardial infarction compared to those with stable angina pectoris. Furthermore, the necrotic core/dense calcium ratio decreased in advanced CKD. Thus, the plaque composition of coronary culprit lesions changed from necrotic core-rich to extensively calcium-rich plaques as renal function decreased, suggesting that such coronary culprit composition was associated with stability, particularly in advanced CKD. PMID- 22513826 TI - Thinning and shaping solid films into functional and integrative nanomembranes. AB - Conventional solid films on certain substrates play a crucial role in various applications, for example in flat panel displays, silicon technology, and protective coatings. Recently, tremendous attention has been directed toward the thinning and shaping of solids into so-called nanomembranes, offering a unique and fantastic platform for research in nanoscience and nanotechnology. In this Review, a conceptual description of nanomembranes is introduced and a series of examples demonstrate their great potential for future applications. The thinning of nanomembranes indeed offers another strategy to fabricate nanomaterials, which can be integrated onto a chip and exhibit valuable properties (e.g. giant persistent photoconductivity and thermoelectric property). Furthermore, the stretching of nanomembranes enables a macroscale route for tuning the physical properties of the membranes at the nanoscale. The process by which nanomembranes release from a substrate presents several approaches to shaping nanomembranes into three-dimensional architectures, such as rolled-up tubes, wrinkles, and the resulting channels, which can provide fascinating applications in electronics, mechanics, fluidics, and photonics. Nanomembranes as a new type of nanomaterial promise to be an attractive direction for nanoresearch. PMID- 22513827 TI - Breast tumor cell detection at single cell resolution using an electrochemical impedance technique. AB - Gold micro-electrodes with various diameters (25, 50, 75, 100 and 250 MUm) were manufactured using standard micro-fabrication techniques and optimized for counting of MCF-7 cells (breast tumor cells) with single cell resolution. For specific cell capture, anti-EpCAM was immobilized on 11-mercaptoundecanoic acid (11-MUA)-3-mercaptopropionic acid (3-MPA) mixed self-assembled monolayer (SAM) modified gold surface of micro-electrodes. Electrodes were characterized using optical, cyclic voltammetry and electrochemical impedance spectroscopic (EIS) techniques. Cell capture response recorded using EIS suggested that optimum electrode dimensions should be analogous to desired cell size. For MCF-7 cells with an average diameter of 18 +/- 2 MUm, an electrode with 25 MUm diameter was established as the optimum electrode size for precise single cell recognition and enumeration. In EIS investigation, the 25 MUm electrode exhibited an impedance change of ~2.2 * 10(7) Omega in response to a single tumor cell captured on its surface. On the other hand other electrodes (250, 100, 75 and 50 MUm) showed much less response for a single tumor cell. In future, the use of high density arrays of such electrodes with surface modifications will result in miniaturized lab on a chip devices for precise counting of MCF-7 cells with single cell resolution. PMID- 22513828 TI - Bacterial CYP153A monooxygenases for the synthesis of omega-hydroxylated fatty acids. AB - CYP153A from Marinobacter aquaeolei has been identified as a fatty acid omega hydroxylase with a broad substrate range. Two hotspots predicted to influence substrate specificity and selectivity were exchanged. Mutant G307A is 2- to 20 fold more active towards fatty acids than the wild-type. Residue L354 is determinant for the enzyme omega-regioselectivity. PMID- 22513830 TI - Arterial stiffness is associated with carotid atherosclerosis in hypertensive patients (the Campania Salute Network). AB - BACKGROUND: Pulse pressure/stroke volume indexed to height(2.04) (PP/SVi) is a validated measure of arterial stiffness, but its relation to carotid atherosclerosis is unknown. METHODS: Clinical, echocardiographic, and carotid ultrasound data from 6,209 hypertensive patients without prevalent cardiovascular (CV) disease in the Campania Salute Network were analyzed. The population was grouped into tertiles of PP/SVi. From carotid ultrasound, peak and mean intima media thickness (IMT) and presence of carotid plaques in the common and internal carotid arteries were reported. RESULTS: Increasing PP/SVi tertile was associated with a parallel increase in age, blood pressure, total serum cholesterol and the number of antihypertensive drugs used (all P < 0.01). Higher PP/SVi was also associated with greater peak and mean IMT (all P < 0.01), also when adjusting for age, gender, blood pressure, lipid profile, and diabetes mellitus (all P < 0.01). Similarly, compared to the lower PP/SVi tertile, the multiple adjusted prevalence ratio of carotid plaque was 7 (95% confidence interval (CI) 1-13, P < 0.03) in the middle tertile and 21 (95% CI 15-28, P < 0.0001) in the upper tertile, independently of confounders. CONCLUSION: In treated hypertensive patients participating in the Campania Salute Network, higher PP/SVi is associated with carotid atherosclerosis independent of well-known clinical confounders. PMID- 22513831 TI - Increasing the validity and efficiency of blood pressure estimates using ambulatory and clinic measurements and modern missing data methods. AB - BACKGROUND: Ambulatory blood pressure monitoring (ABPM) is considered the gold standard for BP measurement, compared to clinic BP measurements (CBP), which are a less valid predictor of target organ damage and cardiovascular events. However, ABPM is considerably more expensive than CBP, leaving BP researchers with a difficult dilemma: Use the less efficient CBP measure, or bear the cost of the more expensive ABPM. Recent developments in missing data methods, notably the two method measurement (TMM) design, address this problem. With the TMM design, all research participants receive the less expensive CBP measure, but only a random subset receives the more expensive ABPM. The total number of participants must be increased, with additional participants receiving only CBP measurements. Even so, the TMM still reduces costs. METHODS: We applied the TMM approach, which makes use of a "bias correction" structural equation model, to an empirical data set in which data were available for ABPM and CBP, as well as an echocardiographic measure of left ventricular mass (LVM). RESULTS: Based on an estimated fivefold difference in cost for using ABPM compared to CBP, we found that statistical power can be considerably increased, or that BP measurement costs can be considerably reduced, when using this planned missing data design. CONCLUSIONS: These benefits were observed with no loss of predictive validity (i.e., the observed association between BP and LVM). This suggests that the TMM design is a promising technique that in some studies may be able to decrease costs and/or increase one's power to detect effects. PMID- 22513829 TI - A genetic risk variant for myocardial infarction on chromosome 6p24 is associated with impaired central hemodynamic indexes. AB - BACKGROUND: Genome-wide association studies (GWAS) have identified novel variants associated with myocardial infarction (MI) in Caucasians. We hypothesized that those variants whose mechanism of risk is currently unknown, confer risk via pathways mediating arterial wave reflections which is an increasingly recognized risk factor for cardiovascular disease. METHODS: Single-nucleotide polymorphisms (SNPs) at eight MI risk loci were genotyped and correlated with noninvasively determined pulse wave analysis (PWA)-derived central hemodynamic indexes (augmentation index (AIx); augmented pressure (AP); time to reflected wave (TrW) and central systolic blood pressure (SBP) and diastolic BP (DBP)) in two independent Caucasian populations including (i) those free of measured cardiovascular risk factors (n = 133) and (ii) a community-based population (n = 270). RESULTS: Of the eight SNPs examined in the healthy group, the variants at loci 6p24 (AIx and AP both P < 0.001, TrW P = 0.02) and 21q22 (AIx P = 0.002, TrW P = 0.037) were significantly associated with PWA indexes. In the replication group, only the 6p24 variant correlated with these phenotypes (AIx P = 0.005, AP P = 0.049, TrW P = 0.013). In the pooled population (n = 403), no new associations were identified but the association with 6p24 and AIx remained significant even after Bonferroni correction and adjustment for covariates including age, mean arterial pressure, height, gender, glucose, cholesterol, body mass index (BMI), and smoking (AIx (P = 0.03)). Each copy of the risk allele C increased the AIx by 3.5%. CONCLUSIONS: The GWAS discovered MI risk variant at 6p24 in the protein phosphatase 1 regulator gene (PHACTR1) is associated with adverse arterial wave reflection indexes and may mediate MI risk through this pathway. PMID- 22513835 TI - [Case report of a foreign object in the larynx of a child]. PMID- 22513832 TI - Computational analysis predicts the Kaposi's sarcoma-associated herpesvirus tegument protein ORF63 to be alpha helical. AB - The innate immune response provides our first line of defence against infection. Over the course of evolution, pathogens have evolved numerous strategies to either avoid activating or to limit the effectiveness of the innate immune system. The Kaposi's sarcoma-associated herpesvirus (KSHV) contains tegument proteins in the virion that contribute to immune evasion and aid the establishment of viral infection. For example, the KSHV tegument protein ORF63 modulates inflammasome activation to inhibit the innate immune response against the virus. Understanding the likely structure of proteins involved in immune evasion enables potential mechanisms of action to be proposed. To understand more fully how ORF63 modulates the innate immune system we have utilized widely available bioinformatics tools to analyze the primary protein sequence of ORF63 and to predict its secondary and tertiary structure. We found that ORF63 is predicted to be almost entirely alpha-helical and may possess similarity to HEAT repeat containing proteins. Consequently, ORF63 is unlikely to be a viral homolog of the NLR protein family. ORF63 may inhibit the innate immune response by flexibly interacting with its target protein and inhibiting the recruitment of protein co-factors and/or conformational changes required for immune signaling. PMID- 22513836 TI - High performance n-type single crystalline transistors of naphthalene bis(dicarboximide) and their anisotropic transport in crystals. AB - High-performance n-type organic single crystal transistors of a naphthalene diimide are demonstrated. The accomplished transistors exhibit electron mobility as high as 0.7 cm(2) V(-1) s(-1). The anisotropic charge transport in the elongated hexagonal crystals of the naphthalene diimide is also explored. The transport anisotropy along different directions is at least 1.6 (mobility ratio). PMID- 22513838 TI - A powerful example of history's lessons for today. PMID- 22513837 TI - RET fusion genes are associated with chronic myelomonocytic leukemia and enhance monocytic differentiation. AB - Myeloproliferative neoplasms are frequently associated with aberrant constitutive tyrosine kinase (TK) activity resulting from chimaeric fusion genes or point mutations such as BCR-ABL1 or JAK2 V617F. We report here the cloning and functional characterization of two novel fusion genes BCR-RET and FGFR1OP-RET in chronic myelomonocytic leukemia (CMML) cases generated by two balanced translocations t(10;22)(q11;q11) and t(6;10)(q27;q11), respectively. The two RET fusion genes leading to the aberrant activation of RET, are able to transform hematopoietic cells and skew the hematopoietic differentiation program towards the monocytic/macrophage lineage. The RET fusion genes seem to constitutively mimic the same signaling pathway as RAS mutations frequently involved in CMML. One patient was treated with Sorafenib, a specific inhibitor of the RET TK function, and demonstrated cytological and clinical remissions. PMID- 22513839 TI - Exploring the links between macro-level contextual factors and their influence on nursing workforce composition. AB - Research that links macro-level socioeconomic development variables to health care human resources workforce composition is scarce at best. The purpose of this study was to explore the links between nonnursing factors and nursing workforce composition through a secondary, descriptive analysis of year 2000, publicly available national nursing human resources data from Mexico. Building on previous research, the authors conducted multiple robust regression analysis by federal typing of nursing human resources from 31 Mexican states against macro-level socioeconomic development variables. Average education in a state was significantly associated in predicting all types of formally educated nurses in Mexico. Other results suggest that macro-level indicators have a different association with each type of nurse. Context may play a greater role in determining nursing workforce composition than previously thought. Further studies may help to explain differences both within and between countries. PMID- 22513840 TI - Fluid outflow in a large-animal model of posttraumatic syringomyelia. AB - BACKGROUND: Posttraumatic syringomyelia affects approximately 28% of spinal cord injury patients, and current treatments are often ineffective. The pathogenesis of this condition remains poorly understood. Previous reports have focused on pathways and mechanisms of fluid inflow; however, disturbances of fluid outflow mechanisms and pathways may be important in syrinx formation and enlargement. OBJECTIVE: To determine the route of fluid outflow from a syrinx in an animal model of posttraumatic syringomyelia. METHODS: A model of posttraumatic syringomyelia using excitotoxic amino acid and kaolin-induced arachnoiditis was created in 12 Merino wethers. Six weeks after syrinx induction, the cavities were localized and a cerebrospinal fluid tracer, horseradish peroxidase (HRP), was injected into the syrinx under ultrasonic guidance. After 10 minutes, the animals were killed and the spinal cords harvested for microscopy. RESULTS: An extracanalicular syrinx developed in 6 of the 12 sheep. HRP was successfully injected into 5 of the 6 syrinx cavities. HRP reaction product was observed in gray and white matter adjacent to the syrinx in a diffuse pattern. There were moderate amounts of HRP around the central canal and perivascular spaces and minimal amounts in the dorsal subarachnoid space. CONCLUSION: In this model of posttraumatic syringomyelia, fluid outflow occurred in a diffuse manner into the surrounding extracellular space and toward the central canal and perivascular spaces. Fluid outflow may be an important consideration in the pathogenesis of syringomyelia and the development of new therapies. PMID- 22513841 TI - High-definition fiber tractography of the human brain: neuroanatomical validation and neurosurgical applications. AB - BACKGROUND: High-definition fiber tracking (HDFT) is a novel combination of processing, reconstruction, and tractography methods that can track white matter fibers from cortex, through complex fiber crossings, to cortical and subcortical targets with subvoxel resolution. OBJECTIVE: To perform neuroanatomical validation of HDFT and to investigate its neurosurgical applications. METHODS: Six neurologically healthy adults and 36 patients with brain lesions were studied. Diffusion spectrum imaging data were reconstructed with a Generalized Q Ball Imaging approach. Fiber dissection studies were performed in 20 human brains, and selected dissection results were compared with tractography. RESULTS: HDFT provides accurate replication of known neuroanatomical features such as the gyral and sulcal folding patterns, the characteristic shape of the claustrum, the segmentation of the thalamic nuclei, the decussation of the superior cerebellar peduncle, the multiple fiber crossing at the centrum semiovale, the complex angulation of the optic radiations, the terminal arborization of the arcuate tract, and the cortical segmentation of the dorsal Broca area. From a clinical perspective, we show that HDFT provides accurate structural connectivity studies in patients with intracerebral lesions, allowing qualitative and quantitative white matter damage assessment, aiding in understanding lesional patterns of white matter structural injury, and facilitating innovative neurosurgical applications. High-grade gliomas produce significant disruption of fibers, and low-grade gliomas cause fiber displacement. Cavernomas cause both displacement and disruption of fibers. CONCLUSION: Our HDFT approach provides an accurate reconstruction of white matter fiber tracts with unprecedented detail in both the normal and pathological human brain. Further studies to validate the clinical findings are needed. PMID- 22513842 TI - Twiglike middle cerebral arteries. PMID- 22513843 TI - Obesity and brain addiction circuitry: implications for deep brain stimulation. AB - Obesity is a growing health problem worldwide and is responsible for a significant proportion of health expenditures in developed nations. It is also notoriously difficult to treat. Prior attempts at pharmacological or neurological modulation, including deep brain stimulation, have primarily targeted homeostatic mechanisms of weight control centered in the hypothalamus. To date, these attempts have had limited success. Multiple lines of independent data suggest that dysregulated reward circuitry in the brain underlies behaviors leading to obesity. Here, we review the existing data and related neurocircuitry, as well as the scope of obesity and currently available treatments. Finally, we suggest a neuromodulation strategy geared toward regulating these dysfunctional circuits, primarily by alteration of frontolimbic circuits. PMID- 22513844 TI - Reoperative hemispherectomy for intractable epilepsy: a report of 36 patients. AB - BACKGROUND: In patients with medically intractable epilepsy and diffuse unilateral hemispheric disease, functional or disconnective hemispherectomy is a widely accepted and successful treatment option. If recurrent seizures develop after disconnective hemispherectomy, management options become more complex and include conversion to anatomic hemispherectomy. OBJECTIVE: To present the outcomes of all patients undergoing reoperative hemispherectomy in 1 institution by 1 surgeon since 1998. METHODS: The medical records, operative reports, and imaging studies for 36 patients undergoing reoperative hemispherectomy for continuing medically intractable epilepsy from 1998 to 2011 at Cleveland Clinic were reviewed. Patient characteristics, cause of seizure, imaging findings, surgery-related complications, and long-term seizure outcomes were evaluated. RESULTS: Patients presented with a variety of seizure origins, including Rasmussen encephalitis, perinatal infarction, cortical dysplasia, and hemimegalencephaly. Overall, 19% of patients were seizure free after conversion to anatomic hemispherectomy, and 45% reported a decrease in seizure frequency by >= 90%. An additional 36% reported no improvement. Generalized ictal electroencephalography tended to confer a poorer prognosis, as did cortical dysplasia as the underlying diagnosis. CONCLUSION: The possibility that residual epileptogenic tissue in the operated hemisphere remains connected should be considered after failed functional hemispherectomy because our data suggest that improvement in seizure frequency is possible after reoperative hemispherectomy, although the chance of obtaining seizure freedom is relatively low. The decision to proceed with reoperative hemispherectomy should be made after proper discussion with the patient and family and informed consent is given. PMID- 22513845 TI - We use anteroposterior fluoroscopy exclusively during electrode placement to optimize electrode position relative to anatomic midline. PMID- 22513846 TI - Protein phosphatase 1 modulates the inhibitory effect of With-no-Lysine kinase 4 on ROMK channels. AB - With-no-Lysine kinase 4 (WNK4) inhibited ROMK (Kir1.1) channels and the inhibitory effect of WNK4 was abolished by serum-glucocorticoid-induced kinase 1 (SGK1) but restored by c-Src. The aim of the present study is to explore the mechanism by which Src-family tyrosine kinase (SFK) modulates the effect of SGK1 on WNK4 and to test the role of SFK-WNK4-SGK1 interaction in regulating ROMK channels in the kidney. Immunoprecipitation demonstrated that protein phosphatase 1 (PP1) binds to WNK4 at amino acid (aa) residues 695-699 (PP1(#1)) and at aa 1211-1215 (PP1(#2)). WNK4(-PP1#1) and WNK4(-PP1#2), in which the PP1(#1) or PP1(#2) binding site was deleted or mutated, inhibited ROMK channels as potently as WNK4. However, c-Src restored the inhibitory effect of WNK4 but not WNK4( PP1#1) on ROMK channels in the presence of SGK1. Moreover, expression of c-Src inhibited SGK1-induced phosphorylation of WNK4 but not WNK4(-PP1#1) at serine residue 1196 (Ser(1196)). In contrast, coexpression of c-Src restored the inhibitory effect of WNK4(-PP1#2) on ROMK in the presence of SGK1 and diminished SGK1-induced WNK4 phosphorylation at Ser(1196) in cells transfected with WNK4( PP1#2). This suggests the possibility that c-Src regulates the interaction between WNK4 and SGK1 through activating PP1 binding to aa 695-9 thereby decreasing WNK4 phosphorylation and restoring the inhibitory effect of WNK4. This mechanism plays a role in suppressing ROMK channel activity during the volume depletion because inhibition of SFK or serine/threonine phosphatases increases ROMK channel activity in the cortical collecting duct of rats on a low-Na diet. We conclude that regulation of phosphatase activity by SFK plays a role in determining the effect of aldosterone on ROMK channels and on renal K secretion. PMID- 22513847 TI - Adverse effects of alpha-ketoglutarate/malate in a rat model of acute kidney injury. AB - Acute kidney injury (AKI) is the most common kidney disease in hospitalized patients with high mortality. Ischemia and reperfusion (I/R) is one of the major causes of AKI. The combination of alpha-ketoglutarate+malate (alphaKG/MAL) showed the ability to reduce hypoxia-induced damage to isolated proximal tubules. The present study utilizes a rat model of I/R-induced AKI accompanied by intensive biomonitoring to examine whether alphaKG/MAL provides protection in vivo. AKI was induced in male Sprague-Dawley rats by bilateral renal clamping (40 min) followed by reperfusion (240 min). alphaKG/MAL was infused continuously for 60 min before and 45 min after ischemia. Normoxic and I/R control groups received 0.9% NaCl solution. The effect of alphaKG/MAL was evaluated by biomonitoring, blood and plasma parameters, histopathology, and immunohistochemical staining for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), as well as by determination of tissue ATP and nonesterified fatty acid concentrations. Intravenous infusion of alphaKG/MAL at a cumulative dose of 1 mmol/kg each (146 mg/kg alphaKG and 134 mg/kg MAL) did not prevent I/R-induced increases in plasma creatinine, histopathological alterations, or cortical ATP depletion. On the contrary, the most notable adverse affect in animals receiving alphaKG/MAL was the decrease in mean arterial blood pressure, which was also accompanied by a reduction in heart rate. Supplementation with alphaKG/MAL, which is very protective against hypoxia-induced injury in isolated proximal tubules, does not protect against I/R-induced renal injury in vivo, possibly due to cardiovascular depressive effects. PMID- 22513848 TI - Elevated urinary excretion of immunoglobulins in nonproteinuric patients with type 1 diabetes. AB - Increased albuminuria is a hallmark of early diabetic nephropathy, whereas the role of immunoglobulins (Igs), such as IgG (its 1-4 subtypes), IgA, and IgM, different in charge and size, has not been examined in early nephropathy in the past due to lack of a sensitive and reliable method. Our study group consisted of subjects with type 1 diabetes (T1D) and normoalbuminuria (n = 78), microalbuminuria (n = 78), and of 75 healthy subjects (HS). A Luminex-based immunoassay (1,000 time more sensitive than nephelometry-based method) was validated for the urine matrix and used for the measurements of IgG1-4, IgA, and IgM in our study groups. The Luminex-based assay detected Igs in 87% of HS subjects and in 100% of T1D subjects. Recovery of known amounts of Igs added to urine was 92-118%. In the normoalbuminuria group, urinary concentrations of albumin, IgG2, IgA, and IgM were significantly higher than in HS, whereas in the microalbuminuria, further elevation of IgG2, IgG4, and IgA was the most pronounced. In all three groups, fractional excretion of Igs was at least 100 times lower than that of albumin. Fractional excretion of IgG2 was the highest among all Igs. We validated a sensitive method for measuring Igs in urine using Luminex. We found that elevated concentrations of Igs, particularly in IgG2 and IgA, is present in subjects with T1D and no proteinuria. Elevation of those particular Ig subtypes suggests a contribution of novel mechanisms in early diabetic nephropathy, different from charge and size barrier impairment. PMID- 22513849 TI - BuMPy road of delayed graft function. PMID- 22513851 TI - Re: Selective cerebral perfusion using moderate flow in complex cardiac surgery provides sufficient neuroprotection. Are children young adults? PMID- 22513850 TI - RNA-binding protein IGF2BP2/IMP2 is required for laminin-beta2 mRNA translation and is modulated by glucose concentration. AB - Laminin-beta2 (LAMB2) is a critical component of the glomerular basement membrane as content of LAMB2 in part determines glomerular barrier permeability. Previously, we reported that high concentrations of glucose reduce expression of this laminin subunit at the translational level. The present studies were undertaken to further define systems that control Lamb2 translation and the effect of high glucose on those systems. Complementary studies were performed using in vitro differentiation of cultured podocytes and mesangial cells exposed to normal and elevated concentrations of glucose, and tissues from control and diabetic rats. Together, these studies provide evidence for regulation of Lamb2 translation by IMP2, an RNA binding protein that targets Lamb2 mRNA to the actin cytoskeleton. Expression of Imp2 itself is regulated by the transcription factor HMGA2, which in turn is regulated by the microRNA let-7b. Elevated concentrations of glucose increase let-7b, which reduces HMGA2 expression, in turn reducing IMP2 and LAMB2. Correlative changes in kidney tissues from control and streptozotocin induced diabetic rats suggest these control mechanisms are operative in vivo and may contribute to proteinuria in diabetic nephropathy. To our knowledge, this is the first time that translation of Lamb2 mRNA has been linked to the actin cytoskeleton, as well as to specific RNA-binding proteins. These translational control points may provide new targets for therapy in proteinuric disorders such as diabetic nephropathy where LAMB2 levels are reduced. PMID- 22513852 TI - Mitral repair for functional mitral regurgitation in idiopathic dilated cardiomyopathy: a good operation done well may help. PMID- 22513855 TI - Risk and the evolution of human exchange. AB - Compared with other species, exchange among non-kin is a hallmark of human sociality in both the breadth of individuals and total resources involved. One hypothesis is that extensive exchange evolved to buffer the risks associated with hominid dietary specialization on calorie dense, large packages, especially from hunting. 'Lucky' individuals share food with 'unlucky' individuals with the expectation of reciprocity when roles are reversed. Cross-cultural data provide prima facie evidence of pair-wise reciprocity and an almost universal association of high-variance (HV) resources with greater exchange. However, such evidence is not definitive; an alternative hypothesis is that food sharing is really 'tolerated theft', in which individuals possessing more food allow others to steal from them, owing to the threat of violence from hungry individuals. Pair wise correlations may reflect proximity providing greater opportunities for mutual theft of food. We report a laboratory experiment of foraging and food consumption in a virtual world, designed to test the risk-reduction hypothesis by determining whether people form reciprocal relationships in response to variance of resource acquisition, even when there is no external enforcement of any transfer agreements that might emerge. Individuals can forage in a high-mean, HV patch or a low-mean, low-variance (LV) patch. The key feature of the experimental design is that individuals can transfer resources to others. We find that sharing hardly occurs after LV foraging, but among HV foragers sharing increases dramatically over time. The results provide strong support for the hypothesis that people are pre-disposed to evaluate gains from exchange and respond to unsynchronized variance in resource availability through endogenous reciprocal trading relationships. PMID- 22513856 TI - Speciation with gene flow in a heterogeneous virtual world: can physical obstacles accelerate speciation? AB - The origin of species remains one of the most controversial and least understood topics in evolution. While it is being widely accepted that complete cessation of gene-flow between populations owing to long-lasting geographical barriers results in a steady, irreversible increase of divergence and eventually speciation, the extent to which various degrees of habitat heterogeneity influences speciation rates is less well understood. Here, we investigate how small, randomly distributed physical obstacles influence the distribution of populations and species, the level of population connectivity (e.g. gene flow), as well as the mode and tempo of speciation in a virtual ecosystem composed of prey and predator species. We adapted an existing individual-based platform, EcoSim, to allow fine tuning of the gene flow's level between populations by adding various numbers of obstacles in the world. The platform implements a simple food chain consisting of primary producers, herbivores (prey) and predators. It allows complex intra- and inter-specific interactions, based on individual evolving behavioural models, as well as complex predator-prey dynamics and coevolution in spatially homogenous and heterogeneous worlds. We observed a direct and continuous increase in the speed of evolution (e.g. the rate of speciation) with the increasing number of obstacles in the world. The spatial distribution of species was also more compact in the world with obstacles than in the world without obstacles. Our results suggest that environmental heterogeneity and other factors affecting demographic stochasticity can directly influence speciation and extinction rates. PMID- 22513857 TI - The central role of the host cell in symbiotic nitrogen metabolism. AB - Symbiotic nitrogen recycling enables animals to thrive on nitrogen-poor diets and environments. It traditionally refers to the utilization of animal waste nitrogen by symbiotic micro-organisms to synthesize essential amino acids (EAAs), which are translocated back to the animal host. We applied metabolic modelling and complementary metabolite profiling to investigate nitrogen recycling in the symbiosis between the pea aphid and the intracellular bacterium Buchnera, which synthesizes EAAs. The results differ from traditional notions of nitrogen recycling in two important respects. First, aphid waste ammonia is recycled predominantly by the host cell (bacteriocyte) and not Buchnera. Host cell recycling is mediated by shared biosynthetic pathways for four EAAs, in which aphid transaminases incorporate ammonia-derived nitrogen into carbon skeletons synthesized by Buchnera to generate EAAs. Second, the ammonia substrate for nitrogen recycling is derived from bacteriocyte metabolism, such that the symbiosis is not a sink for nitrogenous waste from other aphid organs. Host cell mediated nitrogen recycling may be general among insect symbioses with shared EAA biosynthetic pathways generated by the loss of symbiont genes mediating terminal reactions in EAA synthesis. PMID- 22513858 TI - Effects of diurnally oscillating pCO2 on the calcification and survival of coral recruits. AB - Manipulative studies have demonstrated that ocean acidification (OA) is a threat to coral reefs, yet no experiments have employed diurnal variations in pCO(2) that are ecologically relevant to many shallow reefs. Two experiments were conducted to test the response of coral recruits (less than 6 days old) to diurnally oscillating pCO(2); one exposing recruits for 3 days to ambient (440 uatm), high (663 uatm) and diurnally oscillating pCO(2) on a natural phase (420 596 uatm), and another exposing recruits for 6 days to ambient (456 uatm), high (837 uatm) and diurnally oscillating pCO(2) on either a natural or a reverse phase (448-845 uatm). In experiment I, recruits exposed to natural-phased diurnally oscillating pCO(2) grew 6-19% larger than those in ambient or high pCO(2). In experiment II, recruits in both high and natural-phased diurnally oscillating pCO(2) grew 16 per cent larger than those at ambient pCO(2), and this was accompanied by 13-18% higher survivorship; the stimulatory effect on growth of oscillatory pCO(2) was diminished by administering high pCO(2) during the day (i.e. reverse-phased). These results demonstrate that coral recruits can benefit from ecologically relevant fluctuations in pCO(2) and we hypothesize that the mechanism underlying this response is highly pCO(2)-mediated, night-time storage of dissolved inorganic carbon that fuels daytime calcification. PMID- 22513859 TI - A sex-specific trade-off between mating preferences for genetic compatibility and body size in a cichlid fish with mutual mate choice. AB - Mating preferences for genetic compatibility strictly depend on the interplay of the genotypes of potential partners and are therein fundamentally different from directional preferences for ornamental secondary sexual traits. Thus, the most compatible partner is on average not the one with most pronounced ornaments and vice versa. Hence, mating preferences may often conflict. Here, we present a solution to this problem while investigating the interplay of mating preferences for relatedness (a compatibility criterion) and large body size (an ornamental or quality trait). In previous experiments, both sexes of Pelvicachromis taeniatus, a cichlid fish with mutual mate choice, showed preferences for kin and large partners when these criteria were tested separately. In the present study, test fish were given a conflicting choice between two potential mating partners differing in relatedness as well as in body size in such a way that preferences for both criteria could not simultaneously be satisfied. We show that a sex specific trade-off occurs between mating preferences for body size and relatedness. For females, relatedness gained greater importance than body size, whereas the opposite was true for males. We discuss the potential role of the interplay between mating preferences for relatedness and body size for the evolution of inbreeding preference. PMID- 22513860 TI - Historical pesticide applications coincided with an altered diet of aerially foraging insectivorous chimney swifts. AB - Numerous environmental pressures have precipitated long-term population reductions of many insect species. Population declines in aerially foraging insectivorous birds have also been detected, but the cause remains unknown partly because of a dearth of long-term monitoring data on avian diets. Chimney swifts (Chaetura pelagica) are a model aerial insectivore to fill such information gaps because their roosting behaviour makes them easy to sample in large numbers over long time periods. We report a 48-year-long (1944-1992) dietary record for the chimney swift, determined from a well-preserved deposit of guano and egested insect remains in Ontario (Canada). This unique archive of palaeo-environmental data reflecting past chimney swift diets revealed a steep rise in dichlorodiphenyltrichloroethane (DDT) and metabolites, which were correlated with a decrease in Coleoptera remains and an increase in Hemiptera remains, indicating a significant change in chimney swift prey. We argue that DDT applications decimated Coleoptera populations and dramatically altered insect community structure by the 1960s, triggering nutritional consequences for swifts and other aerial insectivores. PMID- 22513861 TI - Modes and mechanisms of a Daphnia invasion. AB - Whether exotic species invade new habitats successfully depends on (i) a change in the invaded habitat that makes it suitable for the invader and (ii) a genetic change in the invading taxon that enhances its fitness in the new habitat, or both. We dissect the causes of invasions of Swiss lakes, north of the Alps, by Daphnia galeata (a zooplankter typical of eutrophic lakes, e.g. those south of the Alps, which are also warmer) by comparing the fitness performance of eight geographically distributed clones that were fed algal-food typical of oligotrophic versus eutrophic conditions at two temperatures. Daphnia longispina, native to oligotrophic Swiss lakes, served as a reference. Daphnia galeata requires eutrophic food to persist, whereas D. longispina survives and grows on oligotrophic food but does even better on eutrophic food. Invasion by D. galeata is further explained because invading clones from the north perform better on eutrophic food and at cooler temperatures than native clones from the south, suggesting a local response to countergradient selection. Our data support the hypothesis that populations of the invader in northern lakes are dominated by well-adapted genotypes. Our results illustrate how environmental change (i.e. eutrophication) and local adaptation can act together to drive a successful invasion. PMID- 22513862 TI - Syntactic structure and geographical dialects in the songs of male rock hyraxes. AB - Few mammalian species produce vocalizations that are as richly structured as bird songs, and this greatly restricts the capacity for information transfer. Syntactically complex mammalian vocalizations have been previously studied only in primates, cetaceans and bats. We provide evidence of complex syntactic vocalizations in a small social mammal: the rock hyrax (Procavia capensis: Hyracoidea). We adopted three algorithms, commonly used in genetic sequence analysis and information theory, to examine the order of syllables in hyrax calls. Syntactic dialects exist, and the syntax of hyrax calls is significantly different between different regions in Israel. Call syntax difference is positively correlated to geographical distance over short distances. No correlation is found over long distances, which may reflect limited dispersal movement. These findings indicate that rich syntactic structure is more common in the vocalizations of mammalian taxa than previously thought and suggest the possibility of vocal production learning in the hyrax. PMID- 22513863 TI - Impedance measurement technique for high-sensitivity cell detection in microstructures with non-uniform conductivity distribution. AB - Particle detection in microstructures is a key procedure required by modern lab on-a-chip devices. Unfortunately, state of the art approaches to impedance measuring as applied to cell detection do not perform well in regions characterized by non-homogeneous physical parameters due, for example, to the presence of air-liquid interfaces or when the particle-electrode distance is relatively high. This paper presents a robust impedance measurement technique and a circuit for detecting cells flowing in microstructures such as microchannels and microwells. Our solution makes use of an innovative three-electrode measurement scheme with asymmetric polarization in order to increase cell detection ability in microstructures featuring large electrode distances of up to 100 MUm as well as to limit signal loss due to cell position relative to the electrodes. Compared to standard techniques, numerical simulations show that, with the proposed approach, the cell detection sensitivity is increased by more than 40%. In addition, we propose a custom circuit based on division instead of difference between signals, as in standard differential circuits, so as to reduce the baseline signal drift induced by non-homogeneous conductivity. A simplified analytical model shows an increase in the signal-to-noise-ratio comprised in the range 3.9-5.9. Experimental results, carried out using an open-microwell device made with flexible printed circuit board technology, are in agreement with simulations, suggesting a six-fold increase of the signal-to-noise ratio compared to the differential measurement technique. We were thus able to successfully monitor the process of isolating K562 leukemia cells inside open-microwells determining all single-cell events with no false positive detection. PMID- 22513864 TI - Prediction of internal pressure profile of compression bandages using stress relaxation parameters. AB - The efficacy of compression therapy using compression bandages is highly dependent on the level of compression applied and the sustenance of the pressure during the course of treatment. This study attempts to predict the pressure profile generated by compression bandages using constitutive equations describing relaxation behavior of viscoelastic materials. It is observed that this pressure profile is highly correlated with the stress relaxation behavior of the bandage. To model the pressure profile, the stress relaxation behavior of compression bandages was studied and modeled using three mechanical models: the Maxwell model, the standard linear solid model and the two-component Maxwell model with a nonlinear spring. It was observed that the models with more component values explained the experimental relaxation curves better. The parameters used for modelling relaxation behavior were used to describe the pressure profile, which is significantly dependent on the longitudinal stress relaxation behavior of the bandage, using the modified Laplace's law equation. This approach thus helps in evaluating the bandage performance with time during compression therapy as novel wound care management. PMID- 22513865 TI - Acute microcirculatory responses induced by skin-surface vibration stimulation at a frequency near the heart rate. AB - OBJECTIVE: We aimed to elucidate the frequency-specific microcirculatory blood flow (MBF) effect induced by weak vibration stimulation (VS) in healthy human subjects. METHODS: VS was implemented by a rod (connected to a DC motor) hitting a water-filled bag. VS was applied to the left palm at frequencies near to the heart rate (HR) (n=35; Group A) and 50% higher than the HR (n=20; Group B), and laser-Doppler-flowmetry measurements were made on the back of the left hand (Site 1). A control group without applying VS was also used (n=21). RESULTS: The mean MBF (MMBF), pulsatile MBF, and pulse width at Site 1 only increased significantly in Group A, and the coefficient of variance of the MMBF sequence increased significantly at Site 1 in Groups A and B. CONCLUSION: These results illustrate the VS-induced changes in the regulatory activities of arteriolar openings, and improvement of the MBF near the VS application site in Group A. The improvement in MBF depended on whether the VS frequency was near to, or higher than the HR. The present findings may be pertinent to amelioration of disease induced by an abnormal MBF. PMID- 22513866 TI - Fish meal replacement by plant protein substitution and guar gum addition in trout feed. Part II: Effects on faeces stability and rheology. AB - In the explosively growing aquaculture industry, the challenge of sustainability includes a requirement to produce more fish than are consumed by stock. A promising avenue of research is the substitution of the fish meal in feeds with plant protein. However, there are inherent risks in the development of such feeds, and serious consideration should be given not only to nutritional content, but also to the mechanical quality of resulting faecal wastes. The present study uses a plate on plate rheometer running in different flow modes (creep, oscillation) to assess the rheological properties of wastes resulting from different diets.All faeces were shown to be thixotropic in nature, independent of diet composition. Details of dietary composition influence the consistency and the characteristic stresses at which faecal structure changes from a viscoelastic solid into a viscoelastic liquid. Furthermore, in linking active food components with mechanical properties of chyme faeces, rheological studies may be used to understand and counteract some problematic properties. Substituting 100% of fish meal with plant proteins leads to faeces that rapidly disintegrate into very fine solids which threaten the viability of aquacultural operations. Adding just 0.3% of the rapidly hydrating non-starch polysaccharide, guar gum (GG), significantly increased the viscosity and elastic modulus of the faeces. These mechanical improvements increase the size of the resulting particles and the effectiveness with which they can be removed, thereby leading to optimized water quality. GG addition was sufficiently effective to counter the stability and particle size effects of a 50% substitution of fish meal, but could not mitigate those of a 100% substitution, wherein dissolution effects of an unknown emulsifier are suspected. PMID- 22513867 TI - Bladder tissue passive response to monotonic and cyclic loading. AB - The fundamental passive mechanical properties of the bladder need to be known in order to design the most appropriate long-term surgical repair procedures and develop materials for bladder reconstruction. This study has focused on the bladder tissue viscoelastic behavior, providing a comprehensive analysis of the effects of fibers orientation, strain rate and loading history. Whole bladders harvested from one year old fat pigs (160 kg approximate weight) were dissected along the apex-to-base direction and samples were isolated from the lateral region of the wall, as well as along apex-to-base and transverse directions. Uniaxial monotonic (stress relaxation) and cyclic tests at different frequencies have been performed with the Bose Electroforce((r)) 3200. Normalized stress relaxation functions have been interpolated using a second-order exponential series and loading and unloading stress-strain curves have been interpolated with a non-linear elastic model. The passive mechanical behavior of bladder tissue was shown to be heavily influenced by frequency and loading history, both in monotonic and cyclic tests. The anisotropy of the tissue was evident in monotonic and in cyclic tests as well, especially in tests performed on an exercised tissue and at high frequencies. In contrast, transverse and apex-to-base samples demonstrated an analogous relaxation behavior. PMID- 22513868 TI - Time course of flow-induced adaptation of carotid artery biomechanical properties, structure and zero-stress state in the arteriovenous shunt. AB - Numerous studies have provided evidence of diameter adaptation secondary to flow overload, but with ambiguous findings vis a vis other morphological parameters and information on the biomechanical aspects of arterial adaptation is rather incomplete. We examined the time course of large-artery biomechanical adaptation elicited by long-term flow-overload in a porcine shunt model between the carotid artery and ipsilateral jugular vein. Post-shunting, the proximal artery flow was doubled and retained so until euthanasia (up to three months post-operatively), without pressure change. This hemodynamic stimulus induced lumen diameter enlargement, accommodated by elastin fragmentation and connective tissue accumulation, as witnessed by optical and confocal microscopy. Heterogeneous mass growth of the adventitia was observed at the expense of the media, associated with declining residual strains and opening angle at three months. The in vitro elastic properties of shunted arteries determined by inflation/extension testing were also modified, with the thickness-pressure curves shifted to larger thicknesses and the diameter-pressure curves shifted to larger diameters at physiologic pressures, resulting in normalization of intramural and shear stresses within fifteen and thirty days, respectively. We infer that the biomechanical adaptation in moderate flow-overload leads to normalization of intimal shear, without, however, restoring compliance and distensibility at mean in vivo pressure to control levels. PMID- 22513869 TI - Morphogenesis of polyoxometalate cluster-based materials to microtubular network architectures. AB - Pressed pellets of polyoxometalate (POM)-based materials are shown to undergo morphogenesis to produce microtubular network architectures without the need for a large single crystal precursor. The compression of the POM material into a pellet lowers the solubility sufficiently to allow tube initiation and growth from POMs that would otherwise be too soluble in their native crystalline state, thus yielding hollow, highly controllable, tubes of diameter 10-100 MUm. PMID- 22513870 TI - Refinement of protein structure homology models via long, all-atom molecular dynamics simulations. AB - Accurate computational prediction of protein structure represents a longstanding challenge in molecular biology and structure-based drug design. Although homology modeling techniques are widely used to produce low-resolution models, refining these models to high resolution has proven difficult. With long enough simulations and sufficiently accurate force fields, molecular dynamics (MD) simulations should in principle allow such refinement, but efforts to refine homology models using MD have for the most part yielded disappointing results. It has thus far been unclear whether MD-based refinement is limited primarily by accessible simulation timescales, force field accuracy, or both. Here, we examine MD as a technique for homology model refinement using all-atom simulations, each at least 100 MUs long-more than 100 times longer than previous refinement simulations-and a physics-based force field that was recently shown to successfully fold a structurally diverse set of fast-folding proteins. In MD simulations of 24 proteins chosen from the refinement category of recent Critical Assessment of Structure Prediction (CASP) experiments, we find that in most cases, simulations initiated from homology models drift away from the native structure. Comparison with simulations initiated from the native structure suggests that force field accuracy is the primary factor limiting MD-based refinement. This problem can be mitigated to some extent by restricting sampling to the neighborhood of the initial model, leading to structural improvement that, while limited, is roughly comparable to the leading alternative methods. PMID- 22513871 TI - Tumour suppressor Fus1 provides a molecular link between inflammatory response and mitochondrial homeostasis. AB - Fus1, encoded by a 3p21.3 tumour suppressor gene, is down-regulated, mutated or lost in the majority of inflammatory thoracic malignancies. The mitochondrial localization of Fus1 stimulated us to investigate how Fus1 modulates inflammatory response and mitochondrial function in a mouse model of asbestos-induced peritoneal inflammation. Asbestos treatment resulted in a decreased Fus1 expression in wild-type (WT) peritoneal immune cells, suggesting that asbestos exposure may compromise the Fus1-mediated inflammatory response. Untreated Fus1( /-) mice had an ~eight-fold higher proportion of peritoneal granulocytes than Fus1(+/+) mice, pointing at ongoing chronic inflammation. Fus1(-/-) mice exhibited a perturbed inflammatory response to asbestos, reflected in decreased immune organ weight and peritoneal fluid protein concentration, along with an increased proportion of peritoneal macrophages. Fus1(-/-) immune cells showed augmented asbestos-induced activation of key inflammatory, anti-oxidant and genotoxic stress response proteins ERK1/2, NFkappaB, SOD2, gammaH2AX, etc. Moreover, Fus1(-/-) mice demonstrated altered dynamics of pro- and anti inflammatory cytokine expression, such as IFNgamma, TNFalpha, IL-1A, IL-1B and IL 10. 'Late' response cytokine Ccl5 was persistently under-expressed in Fus1(-/-) immune cells at both basal and asbestos-activated states. We observed an asbestos related difference in the size of CD3(+) CD4(-) CD8(-) DN T cell subset that was expanded four-fold in Fus1(-/-) mice. Finally, we demonstrated Fus1-dependent basal and asbestos-induced changes in major mitochondrial parameters (ROS production, mitochondrial potential and UCP2 expression) in Fus1(-/-) immune cells and in Fus1-depleted cancer cells, thus supporting our hypothesis that Fus1 establishes its immune- and tumour-suppressive activities via regulation of mitochondrial homeostasis. PMID- 22513872 TI - Wig-1, a novel regulator of N-Myc mRNA and N-Myc-driven tumor growth. AB - Wig-1 is a transcriptional target of the p53 tumor suppressor and encodes an mRNA stability-regulating protein. We show here that Wig-1 knockdown causes a dramatic inhibition of N-Myc expression and triggers differentiation in neuroblastoma cells carrying amplified N-Myc. Transient Wig-1 knockdown significantly delays development of N-Myc-driven tumors in mice. We also show that N-Myc expression is induced upon moderate p53-activating stress, suggesting a role of the p53-Wig-1-N Myc axis in promoting cell cycle re-entry upon p53-induced cell cycle arrest and DNA repair. Moreover, our findings raise possibilities for the improved treatment of poor prognosis neuroblastomas that carry amplified N-Myc. PMID- 22513873 TI - Resistance to ABT-737 in activated T lymphocytes: molecular mechanisms and reversibility by inhibition of the calcineurin-NFAT pathway. AB - Dynamic regulation of the intrinsic apoptosis pathway controls central and peripheral lymphocyte deletion, and may interfere with the pro-apoptotic potency of B-cell lymphoma 2 inhibitors such as ABT-737. By following a T-cell receptor (TCR) transgenic population of alloantigen-specific T cells, we found that sensitivity to ABT-737 radically changed during the course of allo-specific immune responses. Particularly, activated T cells were fully resistant to ABT-737 during the first days after antigen recognition. This phenomenon was caused by a TCR-calcineurin-nuclear factor of activated T cells-dependent upregulation of A1, and was therefore prevented by cyclosporine A (CsA). As a result, exposure to ABT 737 after alloantigen recognition induced selection of alloreactive T cells in vivo, whereas in combination with low-dose CsA, ABT-737 efficiently depleted alloreactive T cells in murine host-versus-graft and graft-versus-host models. Thus, ABT-737 resistance is not a prerogative of neoplastic cells, but it physiologically occurs in T cells after antigen recognition. Reversibility of this process by calcineurin inhibitors opens new pharmacological opportunities to modulate this process in the context of cancer, autoimmunity and transplantation. PMID- 22513875 TI - Low glucose under hypoxic conditions induces unfolded protein response and produces reactive oxygen species in lens epithelial cells. AB - Aging is enhanced by hypoxia and oxidative stress. As the lens is located in the hypoglycemic environment under hypoxia, aging lens with diabetes might aggravate these stresses. This study was designed to examine whether low glucose under hypoxic conditions induces the unfolded protein response (UPR), and also if the UPR then generates the reactive oxygen species (ROS) in lens epithelial cells (LECs). The UPR was activated within 1 h by culturing the human LECs (HLECs) and rat LECs in <1.5 mM glucose under hypoxic conditions. These conditions also induced the Nrf2-dependent antioxidant-protective UPR, production of ROS, and apoptosis. The rat LECs located in the anterior center region were the least susceptible to the UPR, whereas the proliferating LECs in the germinative zone were the most susceptible. Because the cortical lens fiber cells are differentiated from the LECs after the onset of diabetes, we suggest that these newly formed cortical fibers have lower levels of Nrf2, and are then oxidized resulting in cortical cataracts. Thus, low glucose and oxygen conditions induce the UPR, generation of ROS, and expressed the Nrf2 and Nrf2-dependent antioxidant enzymes at normal levels. But these cells eventually lose reduced glutathione (GSH) and induce apoptosis. The results indicate a new link between hypoglycemia under hypoxia and impairment of HLEC functions. PMID- 22513876 TI - Application of Trichoderma harzianum SQR-T037 bio-organic fertiliser significantly controls Fusarium wilt and affects the microbial communities of continuously cropped soil of cucumber. AB - BACKGROUND: The reduction in diversity of the soil microbial community causes the disorder of continuous cropping. The aim of this study was to determine the effects of applying Trichoderma harzianum SQR-T037 bio-organic fertiliser (BIO) on the microbial community in continuously cropped cucumber soil. Four treatments were set: (1) control, where neither seedling nursery soil (N) nor transplanted soil (T) was amended with BIO; (2) N treatment, where nursery soil was amended with BIO (1% w/w) but transplanted soil was not; (3) N + T treatment, where BIO was added to both nursery soil (1% w/w) and transplanted soil (0.5% w/w); (4) uncropped soil, where soil was left uncropped consistently. RESULTS: A disease index of 72.2% was found for the control treatment, while the N and N + T treatments had disease indices of only 25 and 15% respectively. Analysis of the denaturing gradient gel electrophoresis (DGGE) profiles showed that the bacterial communities of the N and N + T treatments were similar to those of the uncropped soil but distinct from those of the control soil. The fungal communities of the N and N + T treatments differed from those of both the uncropped soil and the control. CONCLUSION: Addition of BIO to both the nursery soil and the transplanted soil can diversify the microbial community in continuously cropped cucumber soil and thus effectively control Fusarium wilt of cucumber plants. PMID- 22513874 TI - LAMTOR1 depletion induces p53-dependent apoptosis via aberrant lysosomal activation. AB - Lysosomal regulation is a poorly understood mechanism that is central to degradation and recycling processes. Here we report that LAMTOR1 (late endosomal/lysosomal adaptor, MAPK and mTOR activator 1) downregulation affects lysosomal activation, through mechanisms that are not solely due to mTORC1 inhibition. LAMTOR1 depletion strongly increases lysosomal structures that display a scattered intracellular positioning. Despite their altered positioning, those dispersed structures remain overall functional: (i) the trafficking and maturation of the lysosomal enzyme cathepsin B is not altered; (ii) the autophagic flux, ending up in the degradation of autophagic substrate inside lysosomes, is stimulated. Consequently, LAMTOR1-depleted cells face an aberrant lysosomal catabolism that produces excessive reactive oxygen species (ROS). ROS accumulation in turn triggers p53-dependent cell cycle arrest and apoptosis. Both mTORC1 activity and the stimulated autophagy are not necessary to this lysosomal cell death pathway. Thus, LAMTOR1 expression affects the tuning of lysosomal activation that can lead to p53-dependent apoptosis through excessive catabolism. PMID- 22513877 TI - How does it become possible to treat delocalized and/or open-shell systems in fragmentation-based linear-scaling electronic structure calculations? The case of the divide-and-conquer method. AB - The authors have developed a fragmentation-based linear-scaling electronic structure calculation strategy named the divide-and-conquer (DC) method, which has been implemented into the Gamess program package. Although there are many sorts of fragmentation-based linear-scaling schemes, most of them require the charge and spin multiplicity of each fragment a priori. Therefore, their applications to delocalized and/or open-shell systems have been limited. However, the DC method is a notable exception because the distribution of electrons in the entire system is automatically determined by the universal Fermi level. In this perspective, the authors have summarized the performance of the linear-scaling self-consistent field (SCF) and post-SCF calculations of delocalized and/or open shell systems based on the DC method. Furthermore, some future prospects of the method have been discussed. PMID- 22513878 TI - Predictors of discharge to acute care after inpatient rehabilitation in severely affected stroke patients. AB - OBJECTIVE: This study aimed to determine the predictors of discharge to acute care after inpatient rehabilitation in severely affected stroke patients. DESIGN: This was a retrospective study using data from the Uniform Data System for Medical Rehabilitation (UDSMR) between 2008 and 2009. The main outcome variable was discharge location, which included discharge to acute care or discharge to the community after inpatient rehabilitation. The study sample included 223 of the most severely affected stroke patients (Case-Mix Group 0110 of Medicare reimbursement classification), of whom 86 were discharged to acute care from after the inpatient medical rehabilitation setting; 137 similarly classified stroke patients were discharged to the community after inpatient medical rehabilitation. The variables examined were Functional Independence Measure ratings, co-morbid medical conditions, and four groups of stroke-related neurologic deficits (hemiparesis, dysphagia, language deficits, and other stroke related neurologic deficits). The groups were devised based on International Classification of Diseases, 9th Revision codes. RESULTS: There were no significant demographic differences between the two groups-those discharged to the acute care hospital and those discharged to the community. There was a difference in admission Functional Independence Measure ratings, whereby patients discharged to acute care were significantly lower (P < 0.05) on admission motor and cognitive function than were patients discharged to the community. When controlling for 19 groups of co-morbid medical conditions and 4 groups of stroke related neurologic deficits, there was no significant difference between patients being discharged to an acute care hospital and those discharged to the community. CONCLUSIONS: In the current study, controlling for impairment (stroke), severity of condition, demographic variables, inpatient rehabilitation admission day of the week and discharge day of the week, prehospitalization living setting, prehospitalization living with (alone, family, other), payer (secondary insurance coverage), onset days, co-morbid medical conditions, and classification of stroke related neurologic deficits, the only variable predictive of discharge to the acute care hospital from an inpatient rehabilitation facility is function at admission, mainly the admission motor Functional Independence Measure rating. If clinicians routinely assess the functional status of patients during the preadmission screening process, it may aid in identifying whether the patient is at an increased risk of being readmitted to the acute care hospital. PMID- 22513879 TI - Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid. AB - OBJECTIVE: This study aimed to find a simple, cost-effective, and time-efficient method for the preparation of platelet-rich plasma (PRP), so the acquired benefits will be readily available for multiple procedures in smaller outpatient clinics and to explore the safety and efficacy of the application of PRP in the treatment of degenerative lesions of articular cartilage of the knee. DESIGN: The study was designed as a prospective, cohort study with a control group. A total of 120 patients with Grade 1, 2, or 3 osteoarthritis according to the Kellgren and Lawrence grading scale were enrolled in the study. One group of patients was treated using three intra-articular applications of PRP, and the second group of patients was given three injections of hyaluronic acid. Outcome measures included the Western Ontario and McMaster Universities Osteoarthritis Index and the 11 point pain intensity Numeric Rating Scale. RESULTS: On average, a 4.5-fold increase in platelet concentration was obtained in the PRP group. No severe adverse events were observed. Statistically significantly better results in the Western Ontario and McMaster Universities Osteoarthritis Index and Numeric Rating Scale scores were recorded in a group of patients who received PRP injections after a 3- and 6-mo follow-up. CONCLUSIONS: Our preliminary findings support the application of autologous PRP as an effective and safe method in the treatment of the initial stages of knee osteoarthritis. Further studies are needed to confirm these results and to investigate the persistence of the beneficial effects observed. PMID- 22513880 TI - A mannitol based phase selective supergelator offers a simple, viable and greener method to combat marine oil spills. AB - Though phase selective organogelators (PSOGs) are thought to be useful for oil spill recovery, all known PSOGs require a water-miscible carrier solvent for their introduction. Providing a simple, cheap, green and practical solution to the problem of oil spills, we report a nontoxic super-PSOG that can be sprayed aerially in a carrier solvent destined to get co-congealed with the oil. PMID- 22513881 TI - alpha-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease. AB - Although alpha-synuclein (alpha-SYN) aggregation is a hallmark of sporadic and familial Parkinson's disease (PD), it is not known how it contributes to early events of PD pathogenesis such as oxidative and inflammatory stress. Here, we addressed this question in a new animal model based on stereotaxic delivery of an adeno-associated viral vector (rAAV) for expression of human alpha-SYN in the ventral midbrain of mice lacking the transcription factor Nrf2 (Nrf2(-/-)). Two months after surgery, Nrf2(-/-) mice exhibited exacerbated degeneration of nigral dopaminergic neurons and increased dystrophic dendrites, reminiscent of Lewy neurites, which correlated with impaired proteasome gene expression and activity. Dopaminergic neuron loss was associated with an increase in neuroinflammation and gliosis that were intensified in Nrf2(-/-) mice. In response to exogenously added alpha-SYN, Nrf2(-/-) microglia failed to activate the expression of two anti inflammatory genes, heme oxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphate quinone oxidorreductase-1 (NQO1). This impaired Nrf2 response correlated with a shift in the microglial activation profile, towards increased production of proinflammatory markers, IL-6, IL-1beta and iNOS and reduced phagocytic capacity of fluorescent beads, and lower messenger RNA levels for TAM receptors Axl and Mer. Postmortem brain tissue samples from patients in early- to middle-stage progression of PD showed increased HO-1 expression in astrocytes and microglia, suggesting an attempt of the diseased brain to compensate these hallmarks of PD through activation of the Nrf2 pathway. This study demonstrates that alpha-SYN and Nrf2 deficiency cooperate on protein aggregation, neuroinflammation and neuronal death and provides a bifactorial animal model to study early-stage PD. PMID- 22513882 TI - Frequency and causes of adrenal crises over lifetime in patients with 21 hydroxylase deficiency. AB - OBJECTIVE: To study adrenal crisis (AC) in patients with congenital adrenal hyperplasia due to classical 21-hydroxylase deficiency (21-OHD). AC was defined as an acute state of health impairment requiring i.v. glucocorticoid administration and hospital admission. DESIGN AND METHODS: In a cross-sectional study with detailed retrospective assessment, AC was studied following two approaches: i) questionnaire based: 122 adult 21-OHD patients (50 men, 72 women, median age 35 years, range 18-69 years) completed a disease-specific questionnaire; and ii) patient chart based: charts of 67 21-OHD patients (32 males, 35 females, median age 31 years, range 20-66 years) were analyzed from diagnosis to last follow-up with regard to frequency and causes of AC since diagnosis. RESULTS: Evaluation of questionnaires revealed 257 ACs in 4456 patient years (py; frequency 5.8 crises/100 py), while patient charts documented 106 ACs in 2181 py (4.9 crises/100 py). The chart-based evaluation showed that gastrointestinal infections (29%) and salt-wasting crisis (18%) were the main causes of AC. In 14%, the cause remained uncertain. There was no difference in the overall frequency of AC in males and females. AC mostly occurred during childhood, with more than 70% of AC in the first 10 years of life and one-third of AC in the first year of life. Still, 20% of cases of AC were observed in adults (>18 years). CONCLUSION: Our data demonstrate a significant risk of AC in patients with 21-OHD over lifetime. Specific age-adapted and repeated crisis prevention training may help to reduce morbidity due to AC in 21-OHD. PMID- 22513883 TI - A comparison of different energy window subtraction methods to correct for scatter and downscatter in I-123 SPECT imaging. AB - OBJECTIVE: One of the main problems in quantification of single photon emission computer tomography imaging is scatter. In iodine-123 (I-123) imaging, both the primary 159 keV photons and photons of higher energies are scattered. In this experimental study, different scatter correction methods, based on energy window subtraction, have been compared with each other. METHODS AND MATERIALS: Iodine 123 single photon emission computed tomography images of a phantom with a known intensity ratio between background and hollow spheres were acquired for three different collimators (low energy high resolution, low energy general purpose, and medium energy general purpose). The hollow spheres were filled with a higher activity concentration than the uniform background activity concentration, resulting in hot spots. Counts were collected in different energy windows, and scatter correction was performed by applying different methods such as effective scatter source estimation, triple and dual energy window (TEW and DEW), double peak window (DPW) and downscatter correction. The intensity ratio between the spheres and the background was used to compare the performance of the different methods. RESULTS: The results revealed that the efficiency of the scatter correction techniques vary depending on the collimator used. For the low energy high resolution collimator, all correction methods except the effective scatter source estimation and the DPW perform well. For the medium energy general purpose collimator, even without scatter correction, the calculated ratio is close to the real ratio. The DEW and DPW methods tend to overestimate the ratio. For the low energy general purpose collimator, only the DEW and the combined DEW and downscatter correction methods perform well. CONCLUSION: The only correction method that provides a ratio that differs by less than 5% from the real ratio for all the collimators is the combined DEW and downscatter correction method. PMID- 22513884 TI - Quantitative imaging of 223Ra-chloride (Alpharadin) for targeted alpha-emitting radionuclide therapy of bone metastases. AB - OBJECTIVE: Ra is an alpha particle emitter that targets areas of increased bone turnover in bone metastases. Alpha particles account for 95% of the 27.8 MeV emitted per decay. Less than 2% of the emissions are from photons. This means that a high absorbed dose will be delivered locally, although the number of photons for imaging will be low. The purpose of this study was to investigate the possibility of quantitative imaging of Ra to enable biodistribution studies. METHODS: A Philips Forte gamma camera, equipped with a medium-energy collimator, was used. Basic imaging parameters were determined from phantom studies, and the accuracy of activity quantification was tested in a phantom study and within a patient study. RESULTS: Imaging parameters were determined for the three most suitable photon peaks from the acquired energy spectrum (82, 154 and 270 keV). Camera sensitivity is constant for circular sources with areas greater than 10 cm. The spatial resolution (full-width at half-maximum) was 1.1 cm for each of the three energy windows. The possibility for quantitative imaging was further investigated for the 82 keV energy window, which showed the highest sensitivity and spatial resolution. A phantom study showed that activity could be quantified to within 10% for a 200 ml volume placed within water containing background activity and to within 50% for a 0.5 ml phantom. Quantification of activity in bone after administrations of 100 kBq/kg of Ra-chloride proved the feasibility of quantitative imaging of patients who have received radionuclide therapy. CONCLUSION: Because of the high-energy deposition of Ra, only a low injected activity is required for therapy, which results in a low count rate for the gamma camera. Nevertheless, this study has demonstrated that it is possible to quantify uptake with a sufficient degree of accuracy to obtain clinically relevant information. PMID- 22513885 TI - The clinical value and histopathological correlation of lacrimal scintigraphy in patients with primary Sjogren's syndrome. AB - PURPOSE: To evaluate the lacrimal gland function in patients with primary Sjogren's syndrome (SS) using lacrimal scintigraphy (LS) and to determine the relationship between clinicopathological stage of primary SS and LS findings. METHODS: Seventy eyes from 35 patients with primary SS and 20 eyes from 10 healthy age-matched and sex-matched individuals who served as the control group were included in this study. The patients with primary SS were divided into two groups - early stage and advanced stage - according to the labial biopsy scores (23 patients in early stage and 12 in advanced stage). LS, the Schirmer-1 test, determination of break-up time (BUT), Rose bengal ocular surface vital staining and assessment of functional parameters including ocular surface disease index (OSDI) scores were performed for all cases. LS was used to evaluate tear clearance. Lacrimal scintigrams were evaluated for the presence and severity of delayed tear clearance. Delay in clearance was also subclassified according to the severity of delay (mild, moderate, severe and very severe). LS findings and ophthalmological test results of patients in early stage of disease were compared with the results of those in advanced stage and with those of normal individuals. RESULT: The Schirmer-1 test and BUT values of patients in advanced stage of primary SS decreased significantly, whereas the Rose bengal and OSDI values increased significantly when compared with the values of patients in early stage of primary SS and with those of normal individuals (P<0.05 and P<0.001, respectively). Tear clearance of patients in advanced-stage disease was delayed significantly, compared with the tear delay in patients in early stage of disease and that of normal individuals (P<0.001). An inverse correlation existed between tear clearance and both the Schirmer-1 test and BUT value in all patients (P<0.001). However, there was a positive correlation between both the Rose bengal ocular surface staining values and OSDI scores and tear clearance in all cases (P<0.001). LS findings and ophthalmologic test results were significantly different between early-stage and advanced-stage primary SS. CONCLUSION: The results indicate that LS, which is correlated closely with ophthalmological test results, may be a useful method for the assessment of the lacrimal gland function in patients with primary SS. LS findings and ophthalmological tests may be used for determining disease severity in primary SS. PMID- 22513886 TI - Differentiation of septic and aseptic loosening by PET with both 11C-PK11195 and 18F-FDG in rat models. AB - PURPOSE: This study aims to determine the value of PET with C-isoquinoline carboxamide (C-PK11195) and F-fluorodeoxyglucose (F-FDG) in assisting the differentiation of aseptic loosening (AL) from septic loosening (SL) in rat models. PROCEDURES: Initially, the histological profiles of SL and AL (cellular infiltration and the number of CD68 macrophage and PBR cells) were compared. Subsequently, we investigated whether C-PK11195 alone and also in combination with F-FDG increases the sensitivity and specificity of PET imaging for distinguishing SL from AL. RESULTS: There were distinguishable features between the histological profiles of the SL and AL rat groups. The number of CD68/PBR cells in AL rats was significantly higher than that seen in SL rats (P<0.05). The uptake of C-PK1195 was higher in AL and lower in SL rats. The uptake of F-FDG was higher in SL and lower in AL rats. CONCLUSION: PET with a C-PK11195 and F-FDG imaging protocol is helpful in the clinical differential diagnosis of AL from SL. PMID- 22513888 TI - [Training and education in ultrasound]. PMID- 22513889 TI - [Doppler ultrasound in obstetrics]. PMID- 22513887 TI - Proteoglycan sequence. AB - Proteoglycans (PGs) are among the most structurally complex biomacromolecules in nature. They are present in all animal cells and frequently exert their critical biological functions through interactions with protein ligands and receptors. PGs are comprised of a core protein to which one or multiple, heterogeneous, and polydisperse glycosaminoglycan (GAG) chains are attached. Proteins, including the protein core of PGs, are now routinely sequenced either directly using proteomics or indirectly using molecular biology through their encoding DNA. The sequencing of the GAG component of PGs poses a considerably more difficult challenge because of the relatively underdeveloped state of glycomics and because the control of their biosynthesis in the endoplasmic reticulum and the Golgi is poorly understood and not believed to be template driven. Recently, the GAG chain of the simplest PG has been suggested to have a defined sequence based on its top-down Fourier transform mass spectral sequencing. This review examines the advances made over the past decade in the sequencing of GAG chains and the challenges the field face in sequencing complex PGs having critical biological functions in developmental biology and pathogenesis. PMID- 22513890 TI - 3D imaging of the fetal face - recommendations from the International 3D Focus Group. PMID- 22513891 TI - Long-term recovery of irradiated prostate cancer increases cancer stem cells. AB - BACKGROUND: Despite improvements in treatment, prostate cancer (PC) remains the second-leading cause of cancer death in men. Radiotherapy is among the first-line treatments for PC, but a significant number of patients relapse. Recent evidence supports the idea that PC is initiated by a subset of cells, termed cancer stem cells (CSCs). CSCs have also been implicated in radioresistance in various malignancies, but their role in PC has not yet been investigated. METHODS: We compared the relative radiosensitivity of isolated CSCs to the total population of their corresponding cell lines, and examined the relative numbers of CSCs in irradiated cell lines following long-term recovery and in recurrent human PC. RESULTS: Here, we show that while irradiation does not immediately favor increased survival of CSCs, irradiated PC cell lines showed an increase in CSC properties with long-term recovery. These data suggest that, although CSCs are initially damaged by radiation, they possess a greater capacity for recovery and regrowth. CONCLUSIONS: The combination of radiotherapy with a CSC-targeted therapeutic strategy may prevent tumor recurrence. PMID- 22513892 TI - Multibrominated hyperbranched polymers: synthesis and further functionalizations by ARGET ATRP or click chemistry. AB - Hyperbranched polymers with multiple alkyl bromide peripheral groups were synthesized by the copolymerization of styrene with ethylene glycol dimethacrylate (2.5, 5.0, 7.5, or 10.0 mol% relative to styrene) in the presence of CBr(4) (10-20-fold excess vs. the radical initiator). The latter compound markedly delayed the gelation and served as the source of terminal bromine atoms via transfer to the propagating radicals. The degree of branching increased with the amount of crosslinker. The alkyl bromide groups were used in further chemical modifications (ATRP at low catalyst concentration or azidation with NaN(3) followed by CuBr-catalyzed click coupling of an alkyne-terminated polymer) that yielded star copolymers with hyperbranched cores. PMID- 22513893 TI - Assessment of hormonal activities and genotoxicity of industrial effluents using in vitro bioassays combined with chemical analysis. AB - Wastewaters from various industries are a main source of the contaminants in aquatic environments. The authors evaluated the hormonal activities (estrogenic/anti-estrogenic activities, androgenic/anti-androgenic activities) and genotoxicity of various effluents from textile and dyeing plants, electronic and electroplate factories, pulp and paper mills, fine chemical factories, and municipal wastewater treatment plants in the Pearl River Delta region by using in vitro bioassays (yeast estrogen screen [YES]; yeast androgen screen [YAS]; and genotoxicity assay [umu/SOS]) combined with chemical analysis. The results demonstrated the presence of estrogenic, anti-estrogenic, and anti-androgenic activity in most industrial effluents, whereas no androgenic activities were detected in all of the effluents. The measured estrogenic activities expressed as estradiol equivalent concentrations (EEQs) ranged from below detection (3 of 26 samples) to 40.7 ng/L, with a mean of 7.33 ng/L in all effluents. A good linear relationship was found between the EEQs measured by YES bioassay and the EEQs calculated from chemical concentrations. These detected estrogenic compounds, such as 4-nonylphenol and estrone, were responsible for the estrogenic activities in the effluents. The genotoxic effects expressed as benzo[a]pyrene equivalent concentrations (BaP EQs) varied between below detection and 88.2 ug/L, with a mean of 8.76 ug/L in all effluents. The target polycyclic aromatic hydrocarbons were minor contributors to the genotoxicity in the effluents, and some nontarget compounds in the effluents were responsible for the measured genotoxicity. In terms of estrogenic activities and genotoxicity, discharge of these effluents could pose high risks to aquatic organisms in the receiving environments. PMID- 22513894 TI - Hedgehog regulates angiogenesis of intersegmental vessels through the VEGF signaling pathway. AB - BACKGROUND: The cellular mechanisms regulating branching and growth of the intersegmental vessels (ISVs) are not well understood. We have carried out studies demonstrating that Hedgehog (Hh) signaling is a major regulator of intersomitic vessel growth. RESULTS: Inhibition of Hh activity by cyclopamine completely blocks formation of intersomitic vessels in the avian embryo. Examination of gene expression patterns in Hh-deficient embryos shows that components of the VEGF and Notch signaling pathways are down-regulated. However, we find no evidence that Notch signaling plays a significant role in regulation of intersomitic vessel growth. Indeed, it appears that Hh modulation of Vascular Endothelial Growth Factor, VEGF, is the primary regulator of growth of intersomitic vessels in the avian embryo. CONCLUSIONS: Inhibition of the VEGF pathway results in absence of ISVs, whereas stimulation of VEGF expression leads to precocious branching of ISVs. These results demonstrate that Hh is an essential modulator of VEGF expression during developmental angiogenesis. PMID- 22513895 TI - Characterization of the homodimerization interface and functional hotspots of the CXCR4 chemokine receptor. AB - The recent crystallographic structures of the human chemokine CXC Receptor 4 (CXCR4) provide experimental evidence of a human G Protein-Coupled Receptor (GPCR) dimer in atomic detail. The CXCR4 homodimers reveal an unexpected dimerization mode involving transmembrane helices TM5 and TM6, which is examined here using all-atom molecular dynamics (MD) simulations in the physiological environment of a lipid bilayer. The bacteriophage T4 lysozyme (T4L), which was fused to the crystallized protein but absent in our simulations, is found to slightly affect the observed relative position of the protomers in the two dimers studied here, and consequently some rearrangements of the dimerization interface are proposed. In addition, the simulations provide further evidence about the role of the two stabilizing single point mutations introduced to crystallize the receptor. Finally, this work analyzes the structural and dynamic role of key residues involved both in ligand binding and in the infection process of HIV. In particular, the different side chain conformations of His113(3.39) are found to influence the dynamics of the surrounding functional hotspot region being evaluated both in the presence and in the absence of the co-crystallized ligand IT1t. The analysis reported here adds valuable knowledge for future structure based drug design (SBDD) efforts on this pharmacological target. PMID- 22513896 TI - The hydrogen bond properties of water from 273 K to 573 K; equations for the prediction of gas-water partition coefficients. AB - An equation due to Plyasunov and Shock for the calculation of gas to water partition coefficients, as log K(w), at high temperature requires knowledge of experimental values of log K, DeltaH the standard enthalpy of hydration at 298 K, DeltaCp the heat capacity of hydration at 298 K and b' that is a constant that refers to the variation of DeltaCp(w) with temperature. Linear free energy relationships based on Abraham descriptors for solutes have been constructed for all of these four input quantities, so that log K(w), DeltaH, DeltaCp and b' can be estimated. Known values of the four input quantities, where available, together with estimated values enabled values of log K(w) from 273 to 573 K to be calculated for 555 solutes. At various fixed temperatures LFERs again based on Abraham descriptors were constructed from the obtained log K(w) values for the 555 solutes. These LFERs can then be used to estimate further values of log K(w) between 273 and 573 K for any solute with already determined descriptors, so that knowledge of experimental values of log K, DeltaH, DeltaCp and b' is no longer necessary. The obtained LFERs show how the solvation properties of water vary with temperature. Both water hydrogen bond acidity and hydrogen bond basicity towards solutes decrease substantially with increase of temperature until at 573 K the hydrogen bond properties of water resemble those for solvents such as nitrobenzene and acetonitrile at 298 K. A characteristic property of water at ambient temperatures is that water will not solvate non-polar solutes, thus leading to large Henry's law constants and small values of K(w). Although this property also decreases with increase of temperature, our results indicate that it still remains to some extent even at 573 K, so that the general solvation properties of water at 573 K do not resemble the solvation properties of organic solvents at 298 K. PMID- 22513897 TI - Fetal electrocardiogram (ECG) for fetal monitoring during labour. AB - BACKGROUND: Hypoxaemia during labour can alter the shape of the fetal electrocardiogram (ECG) waveform, notably the relation of the PR to RR intervals, and elevation or depression of the ST segment. Technical systems have therefore been developed to monitor the fetal ECG during labour as an adjunct to continuous electronic fetal heart rate monitoring with the aim of improving fetal outcome and minimising unnecessary obstetric interference. OBJECTIVES: To compare the effects of analysis of fetal ECG waveforms during labour with alternative methods of fetal monitoring. SEARCH METHODS: The Cochrane Pregnancy and Childbirth Group's Trials Register (28 February 2012). SELECTION CRITERIA: Randomised trials comparing fetal ECG waveform analysis with alternative methods of fetal monitoring during labour. DATA COLLECTION AND ANALYSIS: Trial quality assessment and data extraction were performed by one review author, without blinding. MAIN RESULTS: Six trials (16,295 women) were included: five trials of ST waveform analysis (15,338 women) and one trial of PR interval analysis (957 women). In comparison to continuous electronic fetal heart rate monitoring alone, the use of adjunctive ST waveform analysis made no significant difference to primary outcomes: births by caesarean section (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.91 to 1.08), the number of babies with severe metabolic acidosis at birth (cord arterial pH less than 7.05 and base deficit greater than 12 mmol/L) (RR 0.78, 95% CI 0.44 to 1.37, data from 14,574 babies), or babies with neonatal encephalopathy (RR 0.54, 95% CI 0.24 to 1.25). There were, however, on average fewer fetal scalp samples taken during labour (RR 0.61, 95% CI 0.41 to 0.91) although the findings were heterogeneous; there were fewer operative vaginal deliveries (RR 0.90, 95% CI 0.81 to 0.98) and admissions to special care unit (RR 0.89, 95% CI 0.81 to 0.99); there was no statistically significant difference in the number of babies with low Apgar scores at five minutes or babies requiring neonatal intubation. There was little evidence that monitoring by PR interval analysis conveyed any benefit. AUTHORS' CONCLUSIONS: These findings provide some modest support for the use of fetal ST waveform analysis when a decision has been made to undertake continuous electronic fetal heart rate monitoring during labour. However, the advantages need to be considered along with the disadvantages of needing to use an internal scalp electrode, after membrane rupture, for ECG waveform recordings. PMID- 22513899 TI - Home care by outreach nursing for chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow obstruction, worsening exercise performance and health deterioration. It is associated with significant morbidity, mortality and health system burden. OBJECTIVES: To evaluate the effectiveness of outreach respiratory health care worker programmes for COPD patients in terms of improving lung function, exercise tolerance and health related quality of life (HRQL) of patient and carer, and reducing mortality and medical service utilisation. SEARCH METHODS: The Cochrane Airways Group Specialised Register of Trials was searched (November 2011). Study references were hand-searched for additional studies we contacted study authors to identify other unpublished studies. SELECTION CRITERIA: We included only randomised controlled trials of COPD patients. We included interventions involving an outreach nurse visiting patients in their homes, providing support, education, monitoring health and liaising with physicians. Studies in which the therapeutic intervention under test was physical training were not included. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: We pooled mortality data from eight studies and found a non-significant reduction in mortality at 12 months (OR 0.72, 95% CI 0.45 to, 1.15).We pooled four studies that assessed disease-specific heath-related quality of life (HRQL) and found a statistically significant improvement in HRQL (mean difference -2.61, 95% CI -4.82 to 0.40).Hospitalisations were reported in five studies. Although there was no statistically significant difference in the number of hospitalisations (OR 1.01, 95% CI 0.71 to 1.44), there was significant heterogeneity. Although this heterogeneity appeared to be caused by one outlying study with a statistically significant decrease in hospitalisations in patients receiving home care, whereas the other studies showed a non-significant increase in hospitalisations, we could not draw firm conclusions about why this heterogeneity exists. Data on GP visits and emergency department presentations were available, however no consistent effect in these was observed with the intervention. The intervention also incurred higher health care costs than standard care as reported in a single study.Very few studies provided data on lung function or exercise performance, so there was insufficient evidence to assess impact on these outcomes. AUTHORS' CONCLUSIONS: Outreach nursing programmes for COPD improved disease-specific HRQL. However the effect on hospitalisations was heterogeneous, reducing admissions in one study, but increasing them in others, therefore we could not draw firm conclusions for this outcome. PMID- 22513898 TI - Zuclopenthixol acetate for acute schizophrenia and similar serious mental illnesses. AB - BACKGROUND: Medication used for acute aggression in psychiatry must have rapid onset of effect, low frequency of administration and low levels of adverse effects. Zuclopenthixol acetate is said to have these properties. OBJECTIVES: To estimate the clinical effects of zuclopenthixol acetate for the management of acute aggression or violence thought to be due to serious mental illnesses, in comparison to other drugs used to treat similar conditions. SEARCH METHODS: We searched the Cochrane Schizophrenia's Group Trials Register (July 2011). We supplemented this by citation searching and personal contact with authors and relevant pharmaceutical companies. SELECTION CRITERIA: All randomised clinical trials involving people thought to have serious mental illnesses comparing zuclopenthixol acetate with other drugs. DATA COLLECTION AND ANALYSIS: Two review authors extracted and cross-checked data independently. We calculated fixed effect relative risks (RR) and 95% confidence intervals (CI) for dichotomous data. We analysed by intention-to-treat. We used mean differences (MD) for continuous variables. MAIN RESULTS: We found no data for the primary outcome, tranquillisation. Compared with haloperidol, zuclopenthixol acetate was no more sedating at two hours (n = 40, 1 RCT, RR 0.60, 95% CI 0.27 to 1.34). People given zuclopenthixol acetate were not at reduced risk of being given supplementary antipsychotics (n = 134, 3 RCTs, RR 1.49, 95% CI 0.97 to 2.30) although additional use of benzodiazepines was less (n = 50, 1 RCT, RR 0.03, 95% CI 0.00 to 0.47). People given zuclopenthixol acetate had fewer injections over seven days compared with those allocated to haloperidol IM (n = 70, 1 RCT, RR 0.39, 95% CI 0.18 to 0.84, NNT 4, CI 3 to 14). We found no data on more episodes of aggression or harm to self or others. One trial (n = 148) reported no significant difference in adverse effects for people receiving zuclopenthixol acetate compared with those allocated haloperidol at one, three and six days (RR 0.74, 95% CI 0.43 to 1.27). Compared with haloperidol or clotiapine, people allocated zuclopenthixol did not seem to be at more risk of a range of movement disorders (< 20%). Three studies found no difference in the proportion of people getting blurred vision/dry mouth (n = 192, 2 RCTs, RR at 24 hours 0.90, 95% CI 0.48 to 1.70). Similarly, dizziness was equally infrequent for those allocated zuclopenthixol acetate compared with haloperidol (n = 192, 2 RCTs, RR at 24 hours 1.15, 95% CI 0.46 to 2.88). There was no difference between treatments for leaving the study before completion (n = 522, RR 0.85, 95% CI 0.31 to 2.31). One study reported no difference in adverse effects and outcome scores, when high dose (50-100 mg/injection) zuclopenthixol acetate was compared with low dose (25 50 mg/injection) zuclopenthixol acetate. AUTHORS' CONCLUSIONS: Recommendations on the use of zuclopenthixol acetate for the management of psychiatric emergencies in preference to 'standard' treatment have to be viewed with caution. Most of the small trials present important methodological flaws and findings are poorly reported. This review did not find any suggestion that zuclopenthixol acetate is more or less effective in controlling aggressive acute psychosis, or in preventing adverse effects than intramuscular haloperidol, and neither seemed to have a rapid onset of action. Use of zuclopenthixol acetate may result in less numerous coercive injections and low doses of the drug may be as effective as higher doses. Well-conducted pragmatic randomised controlled trials are needed. PMID- 22513901 TI - Interventions for ingrowing toenails. AB - BACKGROUND: Ingrowing toenails are a common problem in which part of the nail penetrates the skinfold alongside the nail, creating a painful area. Different non-surgical and surgical interventions for ingrowing toenails are available, but there is no consensus about a standard first-choice treatment. OBJECTIVES: To evaluate the effects of non-surgical and surgical interventions in a medical setting for ingrowing toenails, with the aim of relieving symptoms and preventing regrowth of the nail edge or recurrence of the ingrowing toenail. SEARCH METHODS: We updated our searches of the following databases to January 2010: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE, and EMBASE. We also updated our searches of CINAHL, WEB of SCIENCE, ongoing trials databases, and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials of non-surgical and surgical interventions for ingrowing toenails, which are also known by the terms 'unguis incarnatus' and 'onychocryptosis', and those comparing postoperative treatment options. Studies must have had a follow-up period of at least one month. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, assessed methodological quality, and extracted data from selected studies. We analysed outcomes as risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: This is an update of the Cochrane review 'Surgical treatments for ingrowing toenails'. In this update we included 24 studies, with a total of 2826 participants (of which 7 were also included in the previous review). Five studies were on non-surgical interventions, and 19 were on surgical interventions.The risk of bias of each included study was assessed; this is a measure of the methodological quality of several characteristics in these studies. It was found to be unclear for several items, due to incomplete reporting. Participants were not blinded to the treatment they received because of the nature of the interventions, e.g. surgery or wearing a brace on the toe. Outcome assessors were reported to be blinded in only 9 of the 24 studies.None of the included studies addressed our primary outcomes of 'relief of symptoms' or 'regrowth', but 16 did address 'recurrence'. Not all of the included studies addressed all of our secondary outcomes (healing time, postoperative complications - infection and haemorrhage, pain of operation/postoperative pain, participant satisfaction), and two studies did not address any of the secondary outcomes.Surgical interventions were better at preventing recurrence than non-surgical interventions with gutter treatment (or gutter removal), and they were probably better than non-surgical treatments with orthonyxia (brace treatment).In 4 of the 12 studies in which a surgical intervention with chemical ablation (e.g. phenol) was compared with a surgical intervention without chemical ablation, a significant reduction of recurrence was found. The surgical interventions on both sides in these comparisons were not equal, so it is not clear if the reduction was caused by the addition of the chemical ablation.In only one study, a comparison was made of a surgical intervention known as partial nail avulsion with matrix excision compared to the same surgical intervention with phenol. In this study of 117 participants, the surgical intervention with phenol was significantly more effective in preventing recurrence than the surgical intervention alone (14% compared to 41% respectively, RR 0.34, 95% CI 0.17 to 0.69).None of the postoperative interventions described, such as the use of antibiotics or manuka honey; povidone iodine with paraffin; hydrogel with paraffin; or paraffin gauze, showed any significant difference when looking at infection rates, pain, or healing time. AUTHORS' CONCLUSIONS: Surgical interventions are more effective than non-surgical interventions in preventing the recurrence of an ingrowing toenail.In the studies comparing a surgical intervention to a surgical intervention with the application of phenol, the addition of phenol is probably more effective in preventing recurrence and regrowth of the ingrowing toenail. Because there is only one study in which the surgical interventions in both study arms were equal, more studies have to be done to confirm these outcomes.Postoperative interventions do not decrease the risk of postoperative infection, postoperative pain, or healing time. PMID- 22513900 TI - Corticosteroids for treating optic neuritis. AB - BACKGROUND: Optic neuritis is an inflammatory disease of the optic nerve. It occurs more commonly in women than in men. Usually presenting with an abrupt loss of vision, recovery of vision is almost never complete. Closely linked in pathogenesis to multiple sclerosis, it may be the initial manifestation for this condition. In certain patients, no underlying cause can be found. OBJECTIVES: To assess the effects of corticosteroids on visual recovery of patients with acute optic neuritis. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 1), MEDLINE (January 1950 to February 2012), EMBASE (January 1980 to February 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to February 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 21 February 2012. We also searched reference lists of identified trial reports to find additional trials. SELECTION CRITERIA: We included randomized trials that evaluated corticosteroids, in any form, dose or route of administration, in people with acute optic neuritis. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data on methodological quality and outcomes for analysis. MAIN RESULTS: We included six randomized trials which included a total of 750 participants. Two trials evaluated low dose oral corticosteroids while one trial evaluated low dose intravenous corticosteroids across two treatment arms and two trials evaluated a higher dose of intravenous corticosteroids. One three arm trial evaluated low-dose oral corticosteroids and high-dose intravenous corticosteroids against placebo. Trials evaluating oral corticosteroids compared varying doses of corticosteroids with placebo. Hence, we did not conduct a meta analysis of such trials. In a meta-analysis of trials evaluating corticosteroids with total dose greater than 3000 mg administered intravenously, the relative risk of normal visual acuity with intravenous corticosteroids compared with placebo was 1.06 (95% confidence interval (CI) 0.89 to 1.27) at six months and 1.06 (95% CI 0.92 to 1.22) at one year. The risk ratio of normal contrast sensitivity for the same comparison was 1.10 (95% CI 0.92 to 1.32) at six months follow up. We did not conduct a meta-analysis for this outcome at one year follow up since there was substantial statistical heterogeneity. The risk ratio of normal visual field for this comparison was 1.08 (95% CI 0.96 to 1.22) at six months and 1.02 (95% CI 0.86 to 1.20) at one year. Quality of life was assessed and reported in one trial. AUTHORS' CONCLUSIONS: There is no conclusive evidence of benefit in terms of recovery to normal visual acuity, visual field or contrast sensitivity with either intravenous or oral corticosteroids at the doses evaluated in trials included in this review. PMID- 22513902 TI - Shouldice technique versus other open techniques for inguinal hernia repair. AB - BACKGROUND: Inguinal hernia repair is the most frequent operation in general surgery. There are several techniques: the Shouldice technique is sometimes considered the best method but different techniques are used as the "gold standard" for open hernia repair. Outcome measures, such as recurrence rates, complications and length of post operative stay, vary considerably among the various techniques. OBJECTIVES: To evaluate the efficacy and safety of the Shouldice technique compared to other non-laparoscopic techniques for hernia repair. SEARCH METHODS: We searched MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials (CENTRAL), April 2008 and updated the searches September 2011, for relevant randomised controlled trials. SELECTION CRITERIA: Any randomised or quasi-randomised controlled trials (RCT) on the treatment of primary inguinal hernia in adults were considered for inclusion. DATA COLLECTION AND ANALYSIS: All abstracts identified by the search strategies were assessed by two independent researchers to exclude studies that did not meet the inclusion criteria. The full publications of all possibly relevant abstracts were obtained and formally assessed. Missing or updated informations was sought by contacting the authors. MAIN RESULTS: Sixteen trials contributed to this review. A total of 2566 hernias were analysed in the Shouldice group with 1121 mesh and 1608 non mesh techniques. The recurrence rate with Shouldice techniques was higher than mesh techniques (OR 3.80, 95% CI 1.99 to 7.26) but lower than non-mesh techniques (OR 0.62, 95% CI 0.45 to 0.85). There were no significant differences in chronic pain, complications and post-operative stay. Female were nearly 3% of included patients. AUTHORS' CONCLUSIONS: Shouldice herniorrhaphy is the best non-mesh technique in terms of recurrence, though it is more time consuming and needs a slightly longer post-operative hospital stay. The use of mesh is associated with a lower rate of recurrence. The quality of included studies, assessed with jaded scale, were low. Patients have similar characteristic in the treatment and control group but seems more healthy than in general population, this features may affect the dimension of effect in particularly recurrence rate could be higher in general population. Lost to follow-up were similar in the treatment and control group but the reasons were often not reported. The length of follow-up vary broadly among the studies from 1 year to 13.7 year. PMID- 22513903 TI - Bisphosphonates for osteoporosis in people with cystic fibrosis. AB - BACKGROUND: Osteoporosis is a bone mineralisation disorder occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids. OBJECTIVES: To assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group Trials Register of references (identified from electronic database searches and handsearches of journals and abstract books) on 15 February 2012.Additional searches of PubMed were performed on 14 May 2011. SELECTION CRITERIA: Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials and extracted data. Trial investigators were contacted to obtain missing data. MAIN RESULTS: Nine trials were identified and seven (with a total of 237 adult participants) were included.Data were combined (when available) from six included studies in participants without a lung transplant. Data showed that there was no significant reduction in fractures between treatment and control groups at 12 months, odds ratio 0.72 (95% confidence interval 0.13 to 3.80). No fractures were reported in studies with follow-up at 24 months. However, in patients taking bisphosphonates after six months the percentage change in bone mineral density increased at the lumbar spine, mean difference 4.61 (95% confidence interval 3.90 to 5.32) and at the hip or femur, mean difference 3.35 (95% confidence interval 1.63 to 5.07); but did not significantly change at the distal forearm, mean difference -0.49 (95% confidence interval -2.42 to 1.45). In patients taking bisphosphonates, at 12 months the percentage change in bone mineral density increased at the lumbar spine, mean difference 6.10 (95% confidence interval 5.10 to 7.10) and at the hip or femur, mean difference 4.35 (95% confidence interval 2.99 to 5.70). At 24 months, in patients treated with bisphosphonates the percentage change in bone mineral density also increased at the lumbar spine, mean difference 5.49 (95% confidence interval 4.38 to 6.60) and at the hip or femur, mean difference 6.05 (95% confidence interval 3.74 to 8.36). There was clinical heterogeneity between studies and not all studies reported all outcomes. Bone pain was the most common adverse event with intravenous agents. Flu-like symptoms were also increased in those taking bisphosphonates.In participants with a lung transplant (one study), intravenous pamidronate did not change the number of new fractures. At axial sites, bone mineral density increased with treatment compared to controls: percentage change in bone mineral density at lumbar spine, mean difference 6.20 (95% confidence interval 4.28 to 8.12); and femur mean difference 7.90 (95% confidence interval 5.78 to 10.02). AUTHORS' CONCLUSIONS: Oral and intravenous bisphosphonates increase bone mineral density in people with cystic fibrosis. Severe bone pain and flu-like symptoms may occur with intravenous agents. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids ameliorate or prevent these adverse events. Additional trials are also required to further assess gastrointestinal adverse effects associated with oral bisphosphonates. Trials in larger populations are needed to determine effects on fracture rate and survival. PMID- 22513904 TI - Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. AB - BACKGROUND: Most clinical practice guidelines recommend restrictive red cell transfusion practices, with the goal of minimising exposure to allogeneic blood. The purpose of this review is to compare clinical outcomes in patients randomised to restrictive versus liberal transfusion thresholds (triggers). OBJECTIVES: To examine the evidence for the effect of transfusion thresholds on the use of allogeneic and/or autologous red cell transfusion, and the evidence for any effect on clinical outcomes. SEARCH METHODS: We identified trials by searching; The Cochrane Injuries Group Specialised Register (searched 01 Feb 2011), Cochrane Central Register of Controlled Trials 2011, issue 1 (The Cochrane Library), MEDLINE (Ovid) 1948 to January Week 3 2011, EMBASE (Ovid) 1980 to 2011 (Week 04), ISI Web of Science: Science Citation Index Expanded (1970 to Feb 2011), ISI Web of Science: Conference Proceedings Citation Index- Science (1990 to Feb 2011). We checked reference lists of other published reviews and relevant papers to identify any additional trials. SELECTION CRITERIA: Controlled trials in which patients were randomised to an intervention group or to a control group. Trials were included where intervention groups were assigned on the basis of a clear transfusion 'trigger', described as a haemoglobin (Hb) or haematocrit (Hct) level below which a red blood cell (RBC) transfusion was to be administered. DATA COLLECTION AND ANALYSIS: Risk ratios of requiring allogeneic blood transfusion, transfused blood volumes and other clinical outcomes were pooled across trials, using a random effects model. Data extraction and assessment of the risk of bias was performed by two people. MAIN RESULTS: Nineteen trials involving a total of 6264 patients were identified, and were similar enough that the results could be combined. Restrictive transfusion strategies reduced the risk of receiving a RBC transfusion by 39% (RR 0.61, 95% CI 0.52 to 0.72). This equates to an average absolute risk reduction (ARR) of 34% (95% CI 24% to 45%). The volume of RBCs transfused was reduced on average by 1.19 units (95% CI 0.53 to 1.85 units). However, heterogeneity between trials was statistically significant (P<0.00001; I(2)>=93%) for these outcomes. Restrictive transfusion strategies did not appear to impact the rate of adverse events compared to liberal transfusion strategies (i.e. mortality, cardiac events, myocardial infarction, stroke, pneumonia and thromboembolism). Restrictive transfusion strategies were associated with a statistically significant reduction in hospital mortality (RR 0.77, 95% CI 0.62 0.95) but not 30 day mortality (RR 0.85, 95% CI 0.70 to 1.03). The use of restrictive transfusion strategies did not reduce functional recovery, hospital or intensive care length of stay. The majority of patients randomised were included in good quality trials, but some items of methodological quality were unclear. There are no trials in patients with acute coronary syndrome. AUTHORS' CONCLUSIONS: The existing evidence supports the use of restrictive transfusion triggers in most patients including those with pre-existing cardiovascular disease. As there are no trials, the effects of restrictive transfusion triggers in high risk groups such as acute coronary syndrome need to be tested in further large clinical trials. In countries with inadequate screening of donor blood, the data may constitute a stronger basis for avoiding transfusion with allogeneic red cells. PMID- 22513905 TI - Single dose oral aspirin for acute postoperative pain in adults. AB - BACKGROUND: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews on 'Single dose oral aspirin for acute pain'. Aspirin has been known for many years to be an effective analgesic for many different pain conditions. Although its use as an analgesic is now limited in developed countries, it is widely available, inexpensive, and remains commonly used throughout the world. OBJECTIVES: To assess the analgesic efficacy and associated adverse events of single dose oral aspirin in acute postoperative pain. SEARCH METHODS: For the earlier review, we identified randomised trials by searching CENTRAL (The Cochrane Library) (1998, Issue 1), MEDLINE (1966 to March 1998), EMBASE (1980 to January 1998), and the Oxford Pain Relief Database (1950 to 1994). We updated searches of CENTRAL, MEDLINE, and EMBASE to January 2012. SELECTION CRITERIA: Single oral dose, randomised, double-blind, placebo controlled trials of aspirin for relief of established moderate to severe postoperative pain in adults. DATA COLLECTION AND ANALYSIS: We assessed studies for methodological quality and two review authors extracted the data independently. We used summed total pain relief (TOTPAR) over four to six hours to calculate the number of participants achieving at least 50% pain relief. We used these derived results to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over four to six hours. We sought numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, as additional measures of efficacy. We collected information on adverse events and withdrawals. MAIN RESULTS: We included 68 studies in which aspirin was used at doses from 300 mg to 1200 mg, but the vast majority of participants received either 600/650 mg (2409 participants, 64 studies) or 990/1000 mg (380 participants, eight studies). There was only one new study.Studies were overwhelmingly of adequate or good methodological quality. NNTs for at least 50% pain relief over four to six hours were 4.2 (3.9 to 4.8), 3.8 (3.0 to 5.1), and 2.7 (2.0 to 3.8) for 600/650 mg, 900/1000 mg, and 1200 mg respectively, compared with placebo. Type of pain model had no significant impact on the results. Lower doses were not significantly different from placebo. These results do not differ from those of the earlier review.Fewer participants required rescue medication with aspirin than with placebo over four to eight hours postdose, but by 12 hours there was no difference. The number of participants experiencing adverse events was not significantly different from placebo for 600/650 mg aspirin, but for 900/1000 mg the number needed to treat to harm was 7.5 (4.8 to 17). The most commonly reported events were dizziness, drowsiness, gastric irritation, nausea, and vomiting, nearly all of which were of mild to moderate severity. AUTHORS' CONCLUSIONS: Aspirin is an effective analgesic for acute pain of moderate to severe intensity. High doses are more effective, but are associated with increased adverse events, including drowsiness and gastric irritation. The pain relief achieved with aspirin was very similar milligram for milligram to that seen with paracetamol. There was no change to the conclusions in this update. PMID- 22513906 TI - Late (>= 7 days) inhalation corticosteroids to reduce bronchopulmonary dysplasia in preterm infants. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD), defined as oxygen dependence at 36 weeks postmenstrual age (PMA), remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD. Attenuating pulmonary inflammation with postnatal systemic corticosteroids reduces the incidence of BPD in preterm infants but may be associated with an increased risk of adverse neurodevelopmental outcomes. Local administration of corticosteroids via inhalation might be an effective and safe alternative. OBJECTIVES: To determine if administration of inhalation corticosteroids after the first week of life to preterm infants at high risk of developing BPD is effective and safe in reducing the incidence of death and BPD as separate or combined outcomes. SEARCH METHODS: We identified randomised, controlled trials by searching the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), PubMed (from 1966), EMBASE (from 1974), CINAHL (from 1982), references from retrieved trials and handsearches of journals, all assessed to February 2012. SELECTION CRITERIA: Randomised controlled trials comparing inhalation corticosteroids, started >= 7 days postnatal age (PNA) but before 36 weeks PMA, to placebo in ventilated and non-ventilated infants at risk of BPD were included. Trials investigating systemic corticosteroids versus inhalation corticosteroids were excluded. DATA COLLECTION AND ANALYSIS: Data on patient characteristics, trial methodology, and inhalation regimens were collected. The primary outcomes were death or BPD, or both, at 28 days PNA or 36 weeks PMA. Secondary outcomes were short-term respiratory outcomes, such as failure to extubate, total days of mechanical ventilation and oxygen use, and the need for systemic corticosteroids. The original trialists were contacted to verify the validity of extracted data and to provide missing data. All data were analysed using RevMan 5.0.24. When possible, meta-analysis was performed using typical risk ratio (TRR) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes along with their 95% confidence intervals (CI). Ventilated and non-ventilated participants were analysed separately. MAIN RESULTS: Eight trials randomising 232 preterm infants were included in this review. Inhalation corticosteroids did not reduce the separate or combined outcomes of death or BPD. Furthermore, inhalation steroids did not impact short-term respiratory outcomes such as failure to extubate and total duration of mechanical ventilation or oxygen dependency. There was a trend to a reduced use of systemic corticosteroids in favour of inhalation corticosteroids (TRR 0.51; 95% CI 0.26 to 1.00). There was a paucity of data on short-term and long-term adverse effects. These results should be interpreted with caution because the total number of randomised patients is relatively small and most trials differed considerably in patient characteristics, inhalation therapy and outcome definitions. AUTHORS' CONCLUSIONS: Based on the results of the currently available evidence, inhalation corticosteroids initiated at >= 7 days of life for preterm infants at high risk of developing BPD cannot be recommended at this point in time. More and larger randomised, placebo-controlled trials are needed to establish the efficacy and safety of inhalation corticosteroids. PMID- 22513907 TI - Neuraminidase inhibitors for preventing and treating influenza in children (published trials only). AB - BACKGROUND: During epidemics, influenza attack rates in children may exceed 40%. Options for prevention and treatment currently include the neuraminidase inhibitors zanamivir and oseltamivir. Laninamivir octanoate, the prodrug of laninamivir, is currently being developed. OBJECTIVES: To assess the efficacy, safety and tolerability of neuraminidase inhibitors in the treatment and prevention of influenza in children. SEARCH METHODS: For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1) which includes the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to January week 2, 2011) and EMBASE (January 2010 to January 2011). SELECTION CRITERIA: Double-blind, randomised controlled trials (RCTs) comparing neuraminidase inhibitors with placebo or other antiviral drugs in children aged up to and including 12 years. We also included safety and tolerability data from other types of studies. DATA COLLECTION AND ANALYSIS: Four review authors selected studies, assessed study quality and extracted data for the current and previous versions of this review. We analysed data separately for oseltamivir versus placebo, zanamivir versus placebo and laninamivir octanoate versus oseltamivir. MAIN RESULTS: Six treatment trials involving 1906 children with clinical influenza and 450 children with influenza diagnosed on rapid near patient influenza testing were included. Of these 2356 children, 1255 had laboratory-confirmed influenza. Three prophylaxis trials involving 863 children exposed to influenza were also included. In children with laboratory-confirmed influenza oseltamivir reduced median duration of illness by 36 hours (26%, P < 0.001). One trial of oseltamivir in children with asthma who had laboratory confirmed influenza showed only a small reduction in illness duration (10.4 hours, 8%), which was not statistically significant (P = 0.542). Laninamivir octanoate 20 mg reduced symptom duration by 2.8 days (60%, P < 0.001) in children with oseltamivir-resistant influenza A/H1N1. Zanamivir reduced median duration of illness by 1.3 days (24%, P < 0.001). Oseltamivir significantly reduced acute otitis media in children aged one to five years with laboratory-confirmed influenza (risk difference (RD) -0.14, 95% confidence interval (CI) -0.24 to 0.04). Prophylaxis with either zanamivir or oseltamivir was associated with an 8% absolute reduction in developing influenza after the introduction of a case into a household (RD -0.08, 95% CI -0.12 to -0.05, P < 0.001). The adverse event profile of zanamivir was no worse than placebo but vomiting was more commonly associated with oseltamivir (number needed to harm = 17, 95% CI 10 to 34). The adverse event profiles of laninamivir octanoate and oseltamivir were similar. AUTHORS' CONCLUSIONS: Oseltamivir and zanamivir appear to have modest benefit in reducing duration of illness in children with influenza. However, our analysis was limited by small sample sizes and an inability to pool data from different studies. In addition, the inclusion of data from published trials only may have resulted in significant publication bias. Based on published trial data, oseltamivir reduces the incidence of acute otitis media in children aged one to five years but is associated with a significantly increased risk of vomiting. One study demonstrated that laninamivir octanoate was more effective than oseltamivir in shortening duration of illness in children with oseltamivir-resistant influenza A/H1N1. The benefit of oseltamivir and zanamivir in preventing the transmission of influenza in households is modest and based on weak evidence. However, the clinical efficacy of neuraminidase inhibitors in 'at risk' children is still uncertain. Larger high-quality trials are needed with sufficient power to determine the efficacy of neuraminidase inhibitors in preventing serious complications of influenza (such as pneumonia or hospital admission), particularly in 'at risk' groups. PMID- 22513908 TI - Prophylactic drug management for febrile seizures in children. AB - BACKGROUND: Febrile seizures occurring in a child older than one month during an episode of fever affect 2% to 4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs. OBJECTIVES: To evaluate the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011. Issue 3); MEDLINE (1966 to May 2011); EMBASE (1966 to May 2011); Database of Abstracts of Reviews of Effectiveness (DARE) (May 2011). No language restrictions were imposed. We also contacted researchers in the field to identify continuing or unpublished studies. SELECTION CRITERIA: Trials using randomised or quasi randomised patient allocation that compared the use of antiepileptic or antipyretic agents with each other, placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors (RN and MO) independently applied pre-defined criteria to select trials for inclusion and extracted the pre-defined relevant data, recording methods for randomisation, blinding and exclusions. Outcomes assessed were seizure recurrence at 6, 12, 18, 24, 36 months and at age 5 to 6 years in the intervention and non-intervention groups, and adverse medication effects. The presence of publication bias was assessed using funnel plots. MAIN RESULTS: Thirty-six articles describing 26 randomised trials with 2740 randomised participants were included. Thirteen interventions of continuous or intermittent prophylaxis and their control treatments were analysed. Methodological quality was moderate to poor in most studies. We could not do a meta-analysis for eight of the 13 comparisons due to insufficient numbers of trials. No significant benefit for valproate, pyridoxine, intermittent phenobarbitone or ibuprofen versus placebo or no treatment was found; nor for diclofenac versus placebo followed by ibuprofen, acetominophen or placebo; nor for intermittent rectal diazepam versus intermittent valproate, nor phenobarbitone versus intermittent rectal diazepam.There was a significant reduction of recurrent febrile seizures with intermittent oral diazepam versus placebo with a relative risk (RR) of 0.67 (95% confidence interval (CI) 0.48 to 0.94) at 24 months), RR of 0.61 (95% CI 0.15 to 0.89) at 48 months, with no benefit at 6, 12 or 72 months. Phenobarbitone versus placebo or no treatment reduced seizures at 6, 12 and 24 months but not at 18 or 72 month follow up (RR 0.60, 95% CI 0.42 to 0.84 at 6 months; RR 0.59, 95% CI 0.46 to 0.75 at 12 months; and RR 0.65, 95% CI 0.49 to 0.88 at 24 months). Intermittent rectal diazepam versus no treatment or placebo also reduced seizures (RR 0.60, 95% CI 0.41 to 0.86 at 6 months; RR 0.65, 95% CI 0.49 to 0.87 at 12 months; RR 0.2, 95% CI 0.1 to 0.39 at 18 months; RR 0.36, 95% CI 0.18 to 0.71 at 36 months), with no benefit at 24 months. Intermittent clobazam compared to placebo at 6 months resulted in a RR of 0.09 (95% CI 0.02 to 0.30), an effect found against an extremely high (83.3%) recurrence rate in the controls and which is a result that needs replication.The recording of adverse effects was variable. Lower comprehension scores in phenobarbitone treated children were found in two studies. In general, adverse effects were recorded in up to some 30% of children in the phenobarbitone treated group and in up to 36% in benzodiazepine treated groups. Evidence of publication bias was found in the meta analyses of comparisons for phenobarbitone versus placebo (8 studies) at 12 months but not at 6 months (6 studies); and valproate versus placebo (4 studies) at 12 months; with too few studies to identify publication bias for the other comparisons. AUTHORS' CONCLUSIONS: No clinically important benefits for children with febrile seizures were found for intermittent oral diazepam, phenytoin, phenobarbitone, intermittent rectal diazepam, valproate, pyridoxine, intermittent phenobarbitone or intermittent ibuprofen, nor for diclofenac versus placebo followed by ibuprofen, acetominophen or placebo. Adverse effects were reported in up to 30% of children. Apparent benefit for clobazam treatment in one recent trial needs to be replicated to be judged reliable. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management and, most importantly, the benign nature of the phenomenon. PMID- 22513909 TI - Angiotensin receptor blockers for heart failure. AB - BACKGROUND: Chronic heart failure (HF) is a prevalent world-wide. Angiotensin receptor blockers (ARBs) are widely prescribed for chronic HF although their role is controversial. OBJECTIVES: To assess the benefit and harm of ARBs compared with ACE inhibitors (ACEIs) or placebo on mortality, morbidity and withdrawals due to adverse effects in patients with symptomatic HF and left ventricular systolic dysfunction or preserved systolic function. SEARCH METHODS: Clinical trials were identified by searching CENTRAL, HTA, and DARE , (The Cochrane Library 2010 Issue 3), as well as MEDLINE (2002 to July 2010), and EMBASE (2002 to July 2010). Reference lists of retrieved articles and systematic reviews were checked for additional studies not identified by the electronic searches. SELECTION CRITERIA: Double blind randomised controlled trials in men and women of all ages who have symptomatic (NYHA Class II to IV) HF and: 1) left ventricular systolic dysfunction, defined as left ventricular ejection fraction (LVEF) <=40%; or 2) preserved ejection fraction, defined as LVEF >40%. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias and extracted data from included studies. MAIN RESULTS: Twenty two studies evaluated the effects of ARBs in 17,900 patients with a LVEF <=40% (mean 2.2 years). ARBs did not reduce total mortality (RR 0.87 [95% CI 0.76, 1.00]) or total morbidity as measured by total hospitalisations (RR 0.94 [95% CI 0.88, 1.01]) compared with placebo.Total mortality (RR 1.05 [95% CI 0.91, 1.22]), total hospitalisations (RR 1.00 [95% CI 0.92, 1.08]), MI (RR 1.00 [95% CI 0.62, 1.63]), and stroke (RR 1.63 [0.77, 3.44]) did not differ between ARBs and ACEIs but withdrawals due to adverse effects were lower with ARBs (RR 0.63 [95% CI 0.52, 0.76]). Combinations of ARBs plus ACEIs increased the risk of withdrawals due to adverse effects (RR 1.34 [95% CI 1.19, 1.51]) but did not reduce total mortality or total hospital admissions versus ACEI alone.Two placebo-controlled studies evaluated ARBs in 7151 patients with a LVEF >40% (mean 3.7 years). ARBs did not reduce total mortality (RR 1.02 [95% CI 0.93, 1.12]) or total morbidity as measured by total hospitalisations (RR 1.00 [95% CI 0.97, 1.05]) compared with placebo. Withdrawals due to adverse effects were higher with ARBs versus placebo when all patients were pooled irrespective of LVEF (RR 1.06 [95% CI 1.01, 1.12]). AUTHORS' CONCLUSIONS: In patients with symptomatic HF and systolic dysfunction or with preserved ejection fraction, ARBs compared to placebo or ACEIs do not reduce total mortality or morbidity. ARBs are better tolerated than ACEIs but do not appear to be as safe and well tolerated as placebo in terms of withdrawals due to adverse effects. Adding an ARB in combination with an ACEI does not reduce total mortality or total hospital admission but increases withdrawals due to adverse effects compared with ACEI alone. PMID- 22513910 TI - Immunosuppressant and immunomodulatory treatments for multifocal motor neuropathy. AB - BACKGROUND: Multifocal motor neuropathy is characterised by progressive, predominantly distal, asymmetrical limb weakness and usually multiple partial motor nerve conduction blocks. Intravenous immunoglobulin is beneficial but the role of immunosuppressive agents is uncertain. This is an update of a review first published in 2002 and previously updated in 2003, 2005 and 2008. OBJECTIVES: To provide the best available evidence from randomised controlled trials on the role of immunosuppressive agents for the treatment of multifocal motor neuropathy. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (4 October 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 3 in The Cochrane Library), MEDLINE (January 1966 to September 2011), EMBASE (January 1980 to September 2011), and LILACS (January 1982 to September 2011) for trials of multifocal motor neuropathy. SELECTION CRITERIA: We planned to include randomised and quasi randomised controlled trials. We considered prospective and retrospective case series and case reports in the Discussion. DATA COLLECTION AND ANALYSIS: Two review authors searched the titles and abstracts of the articles identified and extracted the data independently. MAIN RESULTS: Only one randomised controlled trial of an immunosuppressive or immunomodulatory agent has been performed in multifocal motor neuropathy. This study randomised 28 participants and showed that mycophenolate mofetil, when used with intravenous immunoglobulin, did not significantly improve strength, function or reduce the need for intravenous immunoglobulin. No serious adverse events were observed. The study was deemed at low risk of bias. We summarised the results of retrospective and prospective case series in the discussion. AUTHORS' CONCLUSIONS: According to moderate quality evidence, mycophenolate mofetil did not produce significant benefit in terms of reducing need for intravenous immunoglobulin or improving muscle strength. Trials of other immunosuppressants should be undertaken. PMID- 22513911 TI - In vitro fertilisation for unexplained subfertility. AB - BACKGROUND: In vitro fertilisation (IVF) is a widely accepted treatment for unexplained infertility (NICE 2004), which affects up to a third of all infertile couples. With estimated live birth rates (LBRs) per cycle varying from 33.1% in women aged under 35 years down to 12.5% in women aged between 40 and 42 years (HFEA 2011), its effectiveness has not been rigorously evaluated in comparison with other treatments. With increasing awareness of the role of expectant management, less-invasive procedures such as intrauterine insemination (IUI), and concerns about multiple pregnancies and costs associated with IVF, it is important to evaluate the effectiveness of IVF against other treatment options in couples with unexplained infertility. OBJECTIVES: To evaluate the effectiveness and safety of IVF compared to expectant management, clomiphene citrate, IUI alone and intrauterine insemination plus controlled ovarian stimulation (IUI+SO). SEARCH METHODS: Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched July 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, first quarter), MEDLINE (1970 to July 2011), EMBASE (1985 to July 2011) and reference lists of articles were searched. Relevant conference proceedings were handsearched. Authors were contacted. SELECTION CRITERIA: Randomised controlled trials (RCTs) were included. LBR per woman was the primary outcome. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and quality of trials. MAIN RESULTS: Six RCTs were included in the final analysis. LBR per woman was significantly higher with IVF (45.8%) than expectant management (3.7%) (odds ratio (OR) 22.00, 95% confidence interval (CI) 2.56 to 189.37, 1 RCT, 51 women). There were no comparative data for clomiphene citrate. There was no evidence of a significant difference in LBR between IVF and IUI alone (OR 1.96, 95% CI 0.88 to 4.36, 1 RCT, 113 women), 40.7% with IVF versus 25.9% with IUI. In studies comparing IVF versus IUI+SO, LBR per woman did not differ significantly between the groups among treatment-naive women (OR 1.09, 95% CI 0.74 to 1.59, 2 RCTs, 234 women) but was significantly higher in a large RCT of women pretreated with IUI + clomiphene citrate (OR 2.66, 95% CI 1.94 to 3.63, 1 RCT, 341 women). These three studies could not be pooled due to high heterogeneity (I(2) = 84%). There was no evidence of a significant difference in multiple pregnancy rate (MPR) or ovarian hyperstimulation syndrome (OHSS) between the two treatments (OR 0.64, 95% CI 0.31 to 1.29, 3 RCTs, 351 women; OR 1.53, 95% CI 0.25 to 9.49, 1 RCT, 118 women, respectively). AUTHORS' CONCLUSIONS: IVF may be more effective than IUI+SO. Due to paucity of data from RCTs the effectiveness of IVF for unexplained infertility relative to expectant management, clomiphene citrate and IUI alone remains unproven. Adverse events and the costs associated with these interventions have not been adequately assessed. PMID- 22513912 TI - Drug therapies for reducing gastric acidity in people with cystic fibrosis. AB - BACKGROUND: Malabsorption of fat and protein contributes to poor nutritional status in people with cystic fibrosis. Impaired pancreatic function may also result in increased gastric acidity, leading in turn to heartburn, peptic ulcers and the impairment of oral pancreatic enzyme replacement therapy. The administration of gastric acid-reducing agents has been used as an adjunct to pancreatic enzyme therapy to improve absorption of fat and gastro-intestinal symptoms in people with cystic fibrosis. It is important to establish the evidence regarding potential benefits of drugs that reduce gastric acidity in people with cystic fibrosis. OBJECTIVES: To assess the effect of drug therapies for reducing gastric acidity for: nutritional status; symptoms associated with increased gastric acidity; fat absorption; lung function; quality of life and survival; and to determine if any adverse effects are associated with their use. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, abstract books and conference proceedings.Most recent search of the Group's Trials Register: 15 February 2012. SELECTION CRITERIA: All randomised and quasi-randomised trials involving agents that reduce gastric acidity compared to placebo or a comparator treatment. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed trial quality and extracted data. MAIN RESULTS: Thirty-eight trials were identified from the searches. Sixteen trials, with 256 participants, were suitable for inclusion. Seven trials were limited to children and three trials enrolled only adults. Meta-analysis was not performed. However, one trial found that drug therapies that reduce gastric acidity improved gastro-intestinal symptoms such as abdominal pain; seven trials reported significant improvement in measures of fat malabsorption; and two trials reported no significant improvement in nutritional status. Only one trial reported measures of respiratory function and one trial reported an adverse effect with prostaglandin E2 analogue misoprostol. No trials have been identified assessing the effectiveness of these agents in improving quality of life, the complications of increased gastric acidity, or survival. AUTHORS' CONCLUSIONS: Trials have shown limited evidence that agents that reduce gastric acidity are associated with improvement in gastro intestinal symptoms and fat absorption. Currently, there is insufficient evidence to indicate whether there is an improvement in nutritional status, lung function, quality of life, or survival. We therefore recommend that large, multicentre, randomised controlled clinical trials are undertaken to evaluate these interventions. PMID- 22513913 TI - Intravenous secretin for autism spectrum disorders (ASD). AB - BACKGROUND: In 1998 secretin, a gastrointestinal hormone, was suggested as an effective treatment for autism spectrum disorders (ASD) based on anecdotal evidence. OBJECTIVES: To assess whether intravenous secretin improves the core features of ASD, other aspects of behaviour or function such as self-injurious behaviour, and the quality of life of affected individuals and their carers. We also assessed whether secretin causes harm. This is an updated version of our review of this topic originally published in 2005. SEARCH METHODS: We searched CENTRAL (2010 Issue 1), MEDLINE (1950 to January 2010) , EMBASE (1980 to 2010 Week 2), PsycINFO (1806 to 2010 Week 2), CINAHL (1938 to January 2010), ERIC (1966 to January 2010), Sociological Abstracts (1952 to January 2010). Sociofile and HealthStar were searched in March 2005 when this review was first published, but were not available for this update. Records were limited to studies published since 1998 as this is when secretin was first proposed as a possible treatment for ASD. We searched reference lists of trials and reviews; we also contacted experts and trialists to find unpublished studies. SELECTION CRITERIA: Randomised controlled trials of intravenous secretin compared to a placebo treatment in children or adults diagnosed with ASD, where at least one standardised outcome measure was reported. DATA COLLECTION AND ANALYSIS: Sixteen studies met the inclusion criteria but for two of these, conducted by Repligen, the only available multisite data were reported in press releases. All outcome data from the other 14 trials were continuous. Where trials used cross-over designs, we conducted analysis on results from the first treatment phase. Where mean change from baseline was reported, we used this in preference to post-treatment scores for meta-analyses or forest plots. Meta-analysis was able to be attempted for only one outcome (Childhood Autism Rating Scale). Insufficient data were available to conduct sensitivity or subgroup analyses to assess the impact of study quality, clinical differences in the intervention or clinically relevant differences between groups, such as age or presence of gastrointestinal symptoms. MAIN RESULTS: Over 900 children were recruited for the secretin trials. Twenty five established standardised outcome measures were reported to assess core features of ASD, communication, behaviour, visuospatial skills, affect and adverse events. One standardised measure of global impression was also used. No more than four studies used any one outcome measure similarly. When duration from the start of the intervention to outcome assessment was known, outcomes were reported at between three and six weeks. Meta-analysis of data was not possible but there is now consistency of findings, with RCTs of the efficacy of secretin in autism not showing improvements for core features of ASD. AUTHORS' CONCLUSIONS: There is no evidence that single or multiple dose intravenous secretin is effective and as such currently it should not be recommended or administered as a treatment for ASD. Further experimental assessment of secretin's effectiveness for ASD can only be justified if there is new high quality and replicated scientific evidence that either finds that secretin has a role in neurotransmission in a way that could benefit all children with ASD or identifies important subgroups of children with ASD who could benefit from secretin because of a proven link between the action of secretin and the known cause of their ASD, or the type of problems they are experiencing. PMID- 22513914 TI - Primary care based clinics for asthma. AB - BACKGROUND: Asthma is defined as the presence of variable airflow obstruction with symptoms (more than one of wheeze, breathlessness, chest tightness, cough). It is becoming increasingly common worldwide and this is especially true in higher income countries. In several of these countries there has been a move towards delivery of asthma care via primary care based asthma clinics. Such clinics deliver proactive asthma care sited within primary care, via regular, dedicated sessions which are usually nurse led and doctor supported. They include organised recall of patients on an asthma register and care usually comprises education, symptom review and guideline-based management. Despite the proliferation of such clinics, especially in countries such as the United Kingdom (UK), there is a paucity of evidence to support their use. This review sets out to look at the evidence for the effectiveness of asthma clinics. OBJECTIVES: To determine the effectiveness of organised asthma care delivered via primary care based asthma clinics. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (last search December 2011) and reviewed reference lists of all primary studies for additional references. SELECTION CRITERIA: We included randomised controlled trials of primary care based asthma clinics with a parallel group design, where clinics took place within dedicated time slots and included face-to-face interaction with doctor or nurse and control groups received usual clinical practice care by a general practitioner. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the trials for inclusion and conducted all data extraction and analysis. All disagreements were resolved by discussion. MAIN RESULTS: A total of three studies involving 466 participants were included. There was no statistically significant difference between the asthma clinic group and the control group for most outcomes (primary outcomes: asthma exacerbations leading to hospitalisation or accident and emergency (A&E) visit, use of reliever and preventer medication, quality of life; secondary outcomes: symptoms, time lost from work and withdrawals from the intervention or usual care). However, the confidence intervals were wide for all outcomes and there was substantial heterogeneity between the studies for both A&E visits and time lost from work. One study (101 patients) looked at nocturnal awakenings due to asthma and found a statistically significant reduction in the number of patients reporting this symptom in the asthma clinic group compared to the usual care group (OR 0.31; 95% CI 0.12 to 0.77). There were no studies looking at the secondary outcome of exacerbations requiring oral steroids. AUTHORS' CONCLUSIONS: There is limited evidence of efficacy for primary care based asthma clinics, and firm conclusions cannot be formed until more good quality trials have been carried out. PMID- 22513915 TI - Face washing promotion for preventing active trachoma. AB - BACKGROUND: Trachoma remains a major cause of avoidable blindness among underprivileged populations in many developing countries. It is estimated that about 146 million people have active trachoma and nearly six million people are blind due to complications associated with repeat infections. OBJECTIVES: The objective of this review was to assess the effects of face washing on the prevalence of active trachoma in endemic communities. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 8), MEDLINE (January 1950 to September 2011), EMBASE (January 1980 to September 2011), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to September 2011), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) and ClinicalTrials.gov (www.clinicaltrials.gov). There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 2 September 2011. We checked the reference list of the included trials to identify further relevant trials. We used the Science Citation Index to search for references that cite the studies that are included in the review. We also contacted investigators and experts in the field to identify additional trials. SELECTION CRITERIA: We included randomized or quasi-randomized controlled trials, comparing face washing with no treatment or face washing combined with antibiotics against antibiotics alone. Participants in the trials were people normally resident in endemic trachoma communities. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. Study authors were contacted for additional information. Two clinically heterogeneous trials are included, therefore a meta-analysis was considered inappropriate. MAIN RESULTS: This review included two trials with data from a total of 2560 participants. Face washing combined with topical tetracycline was compared to topical tetracycline alone in three pairs of villages in one trial. The trial found a statistically significant effect for face washing combined with topical tetracycline in reducing 'severe' active trachoma compared to topical tetracycline alone. No statistically significant difference was observed between the intervention and control villages in reducing ('non-severe') active trachoma. The prevalence of clean faces was higher in the intervention villages than the control villages and this was statistically significant. Another trial compared eye washing to no treatment or to topical tetracycline alone or to a combination of eye washing and tetracycline drops in children with follicular trachoma. The trial found no statistically significant benefit of eye washing alone or in combination with tetracycline eye drops in reducing follicular trachoma amongst children with follicular trachoma. AUTHORS' CONCLUSIONS: There is some evidence that face washing combined with topical tetracycline can be effective in reducing severe trachoma and in increasing the prevalence of clean faces. Current evidence does not however support a beneficial effect of face washing alone or in combination with topical tetracycline in reducing active trachoma. PMID- 22513916 TI - Anticholinergic therapy for acute asthma in children. AB - BACKGROUND: Inhaled anticholinergics as single agent bronchodilators (or in combination with beta(2)-agonists) are one of the several medications available for the treatment of acute asthma in children. OBJECTIVES: To determine the effectiveness of only inhaled anticholinergic drugs (i.e. administered alone), compared to a control in children over the age of two years with acute asthma. SEARCH METHODS: The Cochrane Register of Controlled Trials (CENTRAL), and the Cochrane Airways Group Register of trials were searched by the Cochrane Airways Group. The latest search was performed in April 2011. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) in which inhaled anticholinergics were given as single therapy and compared with placebo or any other drug or drug combinations for children over the age of two years with acute asthma. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, extracted data and assessed trial quality. MAIN RESULTS: Six studies met the inclusion criteria but were limited by small sample sizes, various treatment regimes used and outcomes assessed. The studies were overall of unclear quality. Data could only be pooled for the outcomes of treatment failure and hospitalisation. Other data could not be combined due to divergent outcome measurements. Meta-analysis revealed that children who received anticholinergics alone were significantly more likely to have treatment failure compared to those who received beta(2)-agonists from four trials on 171 children (odds ratio (OR) 2.27; 95% CI 1.08 to 4.75). Also, treatment failure on anticholinergics alone was more likely than when anticholinergics were combined with beta(2)-agonists from four trials on 173 children (OR 2.65; 95% CI 1.2 to 5.88). Data on clinical scores/symptoms that were measured on different scales were conflicting. Individual trials reported that lung function was superior in the combination group when compared with anticholinergic agents used alone. The use of anticholinergics was not found to be associated with significant side effects. AUTHORS' CONCLUSIONS: In children over the age of two years with acute asthma exacerbations, inhaled anticholinergics as single agent bronchodilators were less efficacious than beta(2)-agonists. Inhaled anticholinergics were also less efficacious than inhaled anticholinergics combined with beta(2)-agonists. Inhaled anticholinergic drugs alone are not appropriate for use as a single agent in children with acute asthma exacerbations. PMID- 22513917 TI - Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. AB - BACKGROUND: Brain metastases represent a significant healthcare problem. It is estimated that 20% to 40% of patients with cancer will develop metastatic cancer to the brain during the course of their illness. The burden of brain metastases impacts on quality and length of survival. Presenting symptoms include headache (49%), focal weakness (30%), mental disturbances (32%), gait ataxia (21%), seizures (18%), speech difficulty (12%), visual disturbance (6%), sensory disturbance (6%) and limb ataxia (6%).Brain metastases may spread from any primary site. The most common primary site is the lung, followed by the breast then gastrointestinal sites. Eighty-five per cent of brain metastases are found in the cerebral hemispheres, 10% to 15% in the cerebellum and 1% to 3% in the brainstem. Brain radiotherapy is used to treat cancer participants who have brain metastases from various primary malignancies.This is an update to the original review published in Issue 3, 2006. OBJECTIVES: To assess the effectiveness and adverse effects of whole brain radiotherapy (WBRT) in adult participants with multiple metastases to the brain. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3, 2011), MEDLINE and EMBASE to July 2011. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing WBRT either alone or with other treatments in adults with newly diagnosed multiple metastases to the brain from any primary cancer. Trials of prophylactic WBRT were excluded as well as trials that dealt with surgery or WBRT, or both, for the treatment of single brain metastasis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and abstracted information. Adverse effects information was also collected from the trials. MAIN RESULTS: Nine RCTs involving 1420 participants were added in this updated review. This updated review now includes a total of 39 trials involving 10,835 participants.Eight published reports (nine RCTs) showed no benefit of altered dose-fractionation schedules as compared to the control fractionation (3000 cGy in 10 fractions daily) of WBRT for overall survival. These studies also showed no improvement in symptom control nor neurologic improvement among the different dose-fractionation schemes as compared to 3000 cGy in 10 daily fractions of WBRT. This updated review includes two trials comparing 4000 cGy in 20 fractions given twice daily versus 2000 cGy in 4 or 5 daily fractions. Overall, there was no survival advantage (hazard ratio (HR) 1.18, 95% confidence interval (CI) 0.89 to 1.56, P = 0.25) with the use of 4000 cGy in 20 fractions given twice daily compared to 2000 cGy in 4 or 5 daily fractions.The addition of radiosensitizers in six RCTs did not confer additional benefit to WBRT in either the overall survival times (HR 1.08, 95% CI 0.98 to 1.18, P = 0.11) or brain tumour response rates (HR 0.87, 95% CI 0.60 to 1.26, P = 0.46).Two RCTs found no benefit in overall survival (HR 0.61, 95% CI 0.27 to 1.39, P = 0.24) with the use of WBRT and radiosurgery boost as compared to WBRT alone for selected participants with multiple brain metastases (up to four brain metastases). Overall, there was a statistically significant improvement in local brain control (HR 0.35, 95% CI 0.20 to 0.61, P = 0.0003) favouring the WBRT and radiosurgery boost arm. Only one trial of radiosurgery boost with WBRT reported an improved Karnofsky performance score outcome and improved ability to reduce the dexamethasone dose.In this updated review, a total of three RCTs reported on selected patients (with up to three or four brain metastases) treated with radiosurgery alone versus WBRT and radiosurgery. Based on two trials, there was no difference in overall survival (HR 0.98, 95% CI 0.71 to 1.35, P = 0.88). The addition of WBRT when added to radiosurgery significantly improved locally treated brain metasatases control (HR 2.61, 95% CI 1.68 to 4.06, P < 0.0001) and distant brain control (HR 2.15, 95% CI 1.55 to 2.99, P < 0.00001). On the other hand, one trial concluded that patients treated with WBRT and radiosurgery boost were significantly more likely to show a decline in learning and memory function as compared to those treated with radiosurgery alone.One RCT examined the use of WBRT and prednisone versus prednisone alone and produced inconclusive results. AUTHORS' CONCLUSIONS: None of the RCTs with altered WBRT dose-fractionation schemes as compared to standard (3000 cGy in 10 daily fractions or 2000 cGy in 4 or 5 daily fractions) found a benefit in terms of overall survival, neurologic function, or symptom control.The use of radiosensitizers or chemotherapy in conjunction with WBRT remains experimental.Radiosurgery boost with WBRT may improve local disease control in selected participants as compared to WBRT alone, although survival remains unchanged for participants with multiple brain metastases.This updated review now includes a total of three RCTs examining the use of radiosurgery alone versus WBRT and radiosurgery. The addition of WBRT to radiosurgery improves local and distant brain control but there is no difference in overall survival. Patients treated with radiosurgery alone were found to have better neurocognitive outcomes in one trial as compared to patients treated with WBRT and radiosurgery.The benefit of WBRT as compared to supportive care alone has not been studied in RCTs. It may be that supportive care alone, without WBRT, is appropriate for some participants, particularly those with advanced disease and poor performance status. PMID- 22513918 TI - Adjuvant radiotherapy for stage I endometrial cancer. AB - BACKGROUND: This is an updated version of the original Cochrane review published in Issue 2, 2007. The role of radiotherapy (both pelvic external beam radiotherapy (EBRT) and vaginal intracavity brachytherapy (VBT)) in stage I endometrial cancer following hysterectomy remains controversial. OBJECTIVES: To assess the efficacy of adjuvant radiotherapy following surgery for stage I endometrial cancer. SEARCH METHODS: We searched The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Specialised Register to end 2005 for the original review, and extended the search to January 2012 for the update. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared post-operative adjuvant radiotherapy (either EBRTor VBT, or both) versus no radiotherapy or VBT in women with stage I endometrial cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials and extracted data to a specifically designed data collection form. The primary outcome was overall survival. Secondary outcomes were endometrial cancer-related deaths, locoregional recurrence and distant recurrence. Meta-analyses were performed using Cochrane Review Manager Software 5.1. MAIN RESULTS: We included eight trials. Seven trials (3628 women) compared EBRT with no EBRT (or VBT), and one trial (645 women) compared VBTwith no additional treatment. We considered six of the eight trials to be of a high quality. Time-to-event data were not available for all trials and all outcomes.EBRT (with or without VBT) compared with no EBRT (or VBT alone) for stage I endometrial carcinoma significantly reduced locoregional recurrence (time to-event data: five trials, 2965 women; Hazard Ratio (HR) 0.36, 95% Confidence Interval (CI) 0.25 to 0.52; and dichotomous data: seven trials, 3628 women; Risk Ratio (RR) 0.33, 95% CI 0.23 to 0.47). This reduced risk of locoregional recurrence did not translate into improved overall survival (time-to-event data: five trials, 2,965 women; HR 0.99, 95% CI 0.82 to1.20; and dichotomous data: seven trials, 3628 women; RR 0.98, 95% CI 0.83 to 1.15) or improved endometrial cancer-related survival (time-to-event data: five trials, 2965 women; HR 0.96, 95% CI 0.72 to 1.28; and dichotomous data: seven trials, 3628 women; RR 1.02, 95% CI 0.81 to 1.29) or improved distant recurrence rates (dichotomous data: seven trials, 3628 women; RR 1.04, 95% CI 0.80 to 1.35).EBRT did not improve survival outcomes in either the intermediate-risk or high-risk subgroups, although high risk data were limited, and a benefit of EBRT for high-risk women could not be excluded. One trial (PORTEC-2) compared EBRT with VBT in the high-intermediate risk group and reported that VBT was effective in ensuring vaginal control with a non-significant difference in loco-regional relapse rate compared to EBRT (5.1% versus 2.1%; HR 2.08, 95% CI 0.71 to 6.09; P = 0.17). In the subgroup of low-risk patients (IA/B and grade 1/2), EBRT increased the risk of endometrial carcinoma related deaths (including treatment-related deaths) (two trials, 517 women; RR 2.64, 95% CI 1.05 to 6.66) but there was a lack of data on overall survival. We considered the evidence for the low-risk subgroup to be of a low quality.EBRT was associated with significantly increased severe acute toxicity (two trials, 1328 patients, RR 4.68, 95% CI 1.35 to 16.16), increased severe late toxicity (six trials, 3501 women; RR 2.58, 95% CI 1.61 to 4.11) and significant reductions in quality of life scores and rectal and bladder function more than 10 years after randomisation (one trial, 351 women) compared with no EBRT.One trial of VBT versus no additional treatment in women with low-risk lesions reported a non significant reduction in locoregional recurrence in the VBT group compared with the no additional treatment group (RR 0.39, (95% CI 0.14 to 1.09). There were no significant differences in survival outcomes in this trial. AUTHORS' CONCLUSIONS: EBRT reduces the risk of locoregional recurrence but has no significant impact on cancer-related deaths or overall survival. It is associated with significant morbidity and a reduction in quality of life. There is no demonstrable survival advantage from adjuvant EBRT for high-risk stage I endometrial cancer, however, the meta-analyses of this subgroup were underpowered and also included high intermediate risk women, therefore we cannot exclude a small benefit in the high risk subgroup. EBRT may have an adverse effect on endometrial cancer survival when used to treat uncomplicated low-risk (IA/B grade 1/2) endometrial cancer. For the intermediate to high-intermediate risk group, VBT alone appears to be adequate in ensuring vaginal control compared to EBRT. Further research is needed to guide practice for lesions that are truly high risk. In addition, the definitions of risk should be standardised. PMID- 22513919 TI - Interventions for preventing infection in nephrotic syndrome. AB - BACKGROUND: Infection is one of the most common complications and still remains a significant cause of morbidity and occasionally mortality in patients, especially children with nephrotic syndrome. Many different prophylactic interventions have been used or recommended for reducing the risks of infection in nephrotic syndrome in clinical practice. Whether the existing evidence is scientifically rigorous and which prophylactic intervention can be recommended for routine use based on the current evidence is still unknown. OBJECTIVES: To assess the benefits and harms of any prophylactic intervention for reducing the risk of infection in children and adults with nephrotic syndrome. SEARCH METHODS: We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library), MEDLINE and Pre-MEDLINE (from 1966), EMBASE (from 1980), China Biological Medicine Database (1979 to December 2009), Chinese Science and Technique Journals Database (to December 2009), China National Infrastructure (to December 2009), WangFang database (to December 2009), reference lists of nephrology textbooks, review articles, relevant studies and abstracts from nephrology meetings without language restriction.Date of last search: 6 February 2012 SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any prophylactic interventions (pharmacological or non-pharmacological) for preventing any infection in children and adults with nephrotic syndrome. DATA COLLECTION AND ANALYSIS: Two authors independently assessed and extracted information. Information was collected on methods, participants, interventions and outcomes (appearance of infection, mortality, quality of life and adverse events). Results were expressed as risk ratios (RR) for dichotomous outcomes or as mean differences (MD) for continuous data with 95% confidence intervals (CI). MAIN RESULTS: Twelve studies conducted in China, including 762 children with nephrotic syndrome were identified. No studies were identified in adults. All studies compared one kind of prophylactic pharmacotherapy (intravenous immunoglobulin (IVIG), thymosin, oral transfer factor, mannan peptide tablet, Bacillus Calmette Guerin (BCG) vaccine injection, polyvalent bacterial vaccine (Lantigen B) and two kinds of Chinese medicinal herbs: a compound of Chinese medicinal herbs (TIAOJINING) and Huangqi (astragalus) granules) plus baseline treatment with baseline treatment alone. No RCTs were identified comparing antibiotics, non pharmacological prophylaxis, or pneumococcal vaccination. Four studies showed a significantly beneficial effect of IVIG on preventing nosocomial or unspecified infection in children with nephrotic syndrome (RR 0.47, 95% CI 0.31 to 0.73). Thymosin (RR 0.50, 95% CI 0.26 to 0.97), oral transfer factor (RR 0.51, 95% CI 0.35 to 0.73), BCG vaccine injection (RR 0.68, 95% CI 0.48 to 0.95), Huangqi granules (RR 0.62, 95% CI 0.47 to 0.83) and TIAOJINING (RR 0.59, 95% CI 0.43 to 0.81) were also effective in reducing the risk of infection in children with nephrotic syndrome. However mannan peptide tablet (RR 0.46, 95% CI 0.21 to 1.01) and polyvalent bacterial vaccine (RR 0.24, 95% CI 0.06 to1.00) were not superior to baseline treatment in reducing the risk of infection for nephrotic children. No serious adverse events were reported. AUTHORS' CONCLUSIONS: IVIG, thymosin, oral transfer factor, BCG vaccine, Huangqi granules and TIAOJINING may have positive effects on the prevention of nosocomial or unspecified infection with no obvious serious adverse events in children with nephrotic syndrome. However the methodological quality of all studies was poor, the sample sizes small, and all studies were from China, and thus there is no strong evidence on the effectiveness of these interventions. PMID- 22513920 TI - Hyperbaric oxygen therapy for chronic wounds. AB - BACKGROUND: Chronic wounds are common and present a health problem with significant effect on quality of life. Various pathologies may cause tissue breakdown, including poor blood supply resulting in inadequate oxygenation of the wound bed. Hyperbaric oxygen therapy (HBOT) has been suggested to improve oxygen supply to wounds and therefore improve their healing. OBJECTIVES: To assess the benefits and harms of adjunctive HBOT for treating chronic ulcers of the lower limb. SEARCH METHODS: For this first update we searched the Cochrane Wounds Group Specialised Register (searched 12 January 2012); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4); Ovid MEDLINE (1950 to January Week 1 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, 11 July 2012); Ovid EMBASE (1980 to 2012 Week 01); and EBSCO CINAHL (1982 to 6 January 2012). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effect on chronic wound healing of therapeutic regimens which include HBOT with those that exclude HBOT (with or without sham therapy). DATA COLLECTION AND ANALYSIS: Three review authors independently evaluated the risk of bias of the relevant trials using the Cochrane methodology and extracted the data from the included trials. We resolved any disagreement by discussion. MAIN RESULTS: We included nine trials (471 participants). Eight trials (455 participants) enrolled people with a diabetic foot ulcer: pooled data of three trials with 140 participants showed an increase in the rate of ulcer healing (risk ratio (RR) 5.20, 95% confidence interval (CI) 1.25 to 21.66; P = 0.02) with HBOT at six weeks but this benefit was not evident at longer-term follow-up at one year. There was no statistically significant difference in major amputation rate (pooled data of five trials with 312 participants, RR 0.36, 95% CI 0.11 to 1.18). One trial (16 participants) considered venous ulcers and reported data at six weeks (wound size reduction) and 18 weeks (wound size reduction and number of ulcers healed) and suggested a significant benefit of HBOT in terms of reduction in ulcer area only at six weeks (mean difference (MD) 33.00%, 95% CI 18.97 to 47.03, P < 0.00001). We did not identify any trials that considered arterial and pressure ulcers. AUTHORS' CONCLUSIONS: In people with foot ulcers due to diabetes, HBOT significantly improved the ulcers healed in the short term but not the long term and the trials had various flaws in design and/or reporting that means we are not confident in the results. More trials are needed to properly evaluate HBOT in people with chronic wounds; these trials must be adequately powered and designed to minimise all kinds of bias. PMID- 22513921 TI - Treatment for cramps in amyotrophic lateral sclerosis/motor neuron disease. AB - BACKGROUND: Cramps are painful, involuntary muscle contractions. They commonly affect people with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) at all stages of the disease. To date, the treatment of muscle cramps in ALS has been largely empirical without any evidence from randomised controlled trials. OBJECTIVES: To systematically assess the effect of interventions on muscle cramps as a primary or secondary endpoint or adverse event in people with ALS/MND. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (14 February 2011), the Cochrane Central Register of Controlled Trials (Issue 1, 2011 in The Cochrane Library), MEDLINE (January 1966 to January 2011) and EMBASE (January 1980 to January 2011) and reference lists of articles searched using the terms motor neuron disease, motor neurone disease, motoneuron disease or amyotrophic lateral sclerosis. We contacted authors of trials for further information. SELECTION CRITERIA: We included all randomised and quasi randomised trials of oral medications in people with ALS which assessed cramps as a primary or secondary outcome measure or as an adverse event. We also included trials using subcutaneous or intravenous medications or physical therapy. DATA COLLECTION AND ANALYSIS: All authors applied the selection criteria and assessed study quality independently, and all authors performed independent data extraction. MAIN RESULTS: Twenty studies including 4789 participants were identified. Only one trial, of tetrahydrocannabinol (THC), assessed cramps as the primary endpoint. Thirteen studies assessed cramps as a secondary endpoint. The medications comprised vitamin E, baclofen, riluzole, L-threonine, xaliproden, indinavir, and memantine. Six studies assessed cramps as an adverse event. The medications comprised creatine, gabapentin, dextromethorphan, quinidine, and lithium. In all 20 studies no favourable effect for the treatment of cramps in ALS/MND could be demonstrated, but many studies were underpowered to draw a definite conclusion. A meta-analysis of two small studies showed a statistically nonsignificant result for the amino acid L-threonine for the treatment of cramps in ALS/MND. No study was identified using physical therapy as a therapeutic intervention for cramps. AUTHORS' CONCLUSIONS: There is no evidence to support the use of any intervention for muscle cramps in ALS/MND. More and larger randomised controlled trials evaluating treatments for muscle cramps in ALS/MND are needed. PMID- 22513922 TI - Single dose oral etoricoxib for acute postoperative pain in adults. AB - BACKGROUND: Etoricoxib is a selective cyclo-oxygenase-2 (COX-2) inhibitor licensed for the relief of chronic pain in osteoarthritis and rheumatoid arthritis, and acute pain in some jurisdictions. This class of drugs is believed to be associated with fewer upper gastrointestinal adverse effects than conventional non-steroidal anti-inflammatory drugs (NSAIDs). One additional study in acute postoperative pain has been published since the original review was completed in Issue 2, 2009. OBJECTIVES: To assess the analgesic efficacy and adverse effects of a single oral dose of etoricoxib for moderate to severe postoperative pain. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Database, ClinicalTrials.gov, and reference lists of articles. The date of the most recent search was 3 January 2012. SELECTION CRITERIA: Randomised, double-blind, placebo controlled clinical trials of single dose, oral etoricoxib for acute postoperative pain in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently considered trials for inclusion in the review, assessed quality, and extracted data. We used the area under the pain relief versus time curve to derive the proportion of participants prescribed etoricoxib or placebo with at least 50% pain relief over six hours, using validated equations. We calculated relative risk (RR) and number needed to treat to benefit (NNT). We used information on use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse effects. MAIN RESULTS: One additional study has been added to this updated review, making a total of six included studies with 1214 participants in comparisons of etoricoxib with placebo. All six studies reported on the 120 mg dose (798 participants in a comparison with placebo). At least 50% pain relief was reported by 66% with etoricoxib 120 mg and 12% with placebo (NNT 1.8 (1.7 to 2.0)). For dental studies only the NNT was 1.6 (1.5 to 1.8). Although the new study almost doubled the number of participants in included studies it added only about 25% more data for the 120 mg dose and the result was unchanged. Other doses (60, 90, 180, and 240 mg) were each studied in only one treatment arm and we did not undertake pooled analysis.Significantly fewer participants used rescue medication over 24 hours when taking etoricoxib 120 mg than placebo (NNT to prevent remedication 2.2 (1.9 to 2.8)), and the median time to use of rescue medication was 20 hours for etoricoxib and two hours for placebo. Adverse events were reported at a similar rate to placebo, with no serious events. AUTHORS' CONCLUSIONS: The additional study did not change the results from the first review published in 2009, but does make the result more robust. Single dose oral etoricoxib produces high levels of good quality pain relief after surgery and adverse events did not differ from placebo. The 120 mg dose is as effective as, or better than, other commonly used analgesics. PMID- 22513923 TI - Treatment for mitochondrial disorders. AB - BACKGROUND: Mitochondrial respiratory chain disorders are the most prevalent group of inherited neurometabolic diseases. They present with central and peripheral neurological features usually in association with other organ involvement including the eye, the heart, the liver, and kidneys, diabetes mellitus and sensorineural deafness. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and premature death. Vitamin supplements, pharmacological agents and exercise therapy have been used in isolated cases and small clinical trials, but the efficacy of these interventions is unclear. The first review was carried out in 2003, and identified six clinical trials. This major update was carried out to identify new studies and grade the original studies for potential bias in accordance with revised Cochrane Collaboration guidelines. OBJECTIVES: To determine whether there is objective evidence to support the use of current treatments for mitochondrial disease. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (4 July 2011), CENTRAL (2011, Issue 2, MEDLINE (1966 to July 2011), and EMBASE (January 1980 to July 2011), and contacted experts in the field. SELECTION CRITERIA: We included randomised controlled trials (including cross-over studies). Two of the authors independently selected abstracts for further detailed review. Further review was performed independently by all five authors to decide which trials fit the inclusion criteria and graded risk of bias. Participants included males and females of any age with a confirmed diagnosis of mitochondrial disease based upon muscle histochemistry, respiratory chain complex analysis of tissues or cell lines or DNA studies. Interventions included any pharmacological agent, dietary modification, nutritional supplement, exercise therapy or other treatment. The review authors excluded studies at high risk of bias in any category. The primary outcome measures included an change in muscle strength and/or endurance, or neurological clinical features. Secondary outcome measures included quality of life assessments, biochemical markers of disease and negative outcomes. DATA COLLECTION AND ANALYSIS: Two of the authors (GP and PFC) independently identified studies for further evaluation from all abstracts within the search period. For those studies identified for further review, all five authors then independently assessed which studies met the entry criteria. For the included studies, we extracted details of the number of randomised participants, treatment, study design, study category, allocation concealment and other risk of bias criteria, and participant characteristics. Analysis was based on intention-to-treat data. We planned to use meta-analysis, but this did not prove necessary. MAIN RESULTS: The authors reviewed 1335 abstracts, and from these identified 21 potentially eligible abstracts. Upon detailed review, 12 studies fulfilled the entry criteria. Of these, eight were new studies that had been published since the previous version of this review. Two studies which were included in the previous version of this review were excluded because of potential for bias. The comparability of the included studies is extremely low because of differences in the specific diseases studied, differences in the therapeutic agents used, dosage, study design, and outcomes. The methodological quality of included studies was generally high, although risk of bias was unclear in random sequence generation and allocation concealment for most studies. Otherwise, the risk of bias was low for most studies in the other categories. Serious adverse events were uncommon, except for peripheral nerve toxicity in a long-term trial of dichloroacetate (DCA) in adults.One trial studied high-dose coenzyme Q10 without clinically meaningful improvement (although there were multiple biochemical, physiologic, and neuroimaging outcomes, in 30 participants). Three trials used creatine monohydrate alone, with one reporting evidence of improved measures of muscle strength and post-exercise lactate, but the other two reported no benefit (total of 38 participants). One trial studied the effects of a combination of coenzyme Q10, creatine monohydrate, and lipoic acid and reported a statistically significant improvement in biochemical markers and peak ankle dorsiflexion strength, but overall no clinical improvement in 16 participants. Five trials studied the effects of DCA: three trials in children showed a statistically significant improvement in secondary outcome measures of mitochondrial metabolism (venous lactate in three trials, and magnetic resonance spectroscopy (MRS) in one trial; total of 63 participants). One trial of short-term DCA in adults demonstrated no clinically relevant improvement (improved venous lactate but no change in physiologic, imaging, or questionnaire findings, in eight participants). One longer-term DCA trial in adults was terminated prematurely due to peripheral nerve toxicity without clinical benefit (assessments included the GATE score, venous lactate and MRS, in 30 participants). One trial using dimethylglycine showed no significant effect (measurements of venous lactate and oxygen consumption (VO(2)) in five participants). One trial using a whey-based supplement showed statistically significant improvement in markers of free radical reducing capacity but no clinical benefit (assessments included the Short Form 36 Health Survey (SF-36) questionnaire and UK Medical Research Council (MRC) muscle strength, in 13 participants). AUTHORS' CONCLUSIONS: Despite identifying eight new trials there is currently no clear evidence supporting the use of any intervention in mitochondrial disorders. Further research is needed to establish the role of a wide range of therapeutic approaches. We suggest further research should identify novel agents to be tested in homogeneous study populations with clinically relevant primary endpoints. PMID- 22513924 TI - WITHDRAWN: Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease. AB - BACKGROUND: Randomized trials have demonstrated that adding a drug to a single agent or to a two-agent regimen increased the tumor response rate in patients with advanced non-small cell lung cancer (NSCLC), although its impact on survival remains controversial. OBJECTIVES: To evaluate the clinical benefit of adding a drug to a single-agent or two-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC. SEARCH METHODS: There were no language restrictions. Searches of MEDLINE and EMBASE were performed using the search terms non-small cell lung carcinoma/drug therapy, adenocarcinoma, large-cell carcinoma, squamous-cell carcinoma, lung, neoplasms, clinical trial phase III, and randomized trial. Manual searches were also performed to find conference proceedings published between January 1982 and June 2006. SELECTION CRITERIA: Data from all randomized controlled trials performed between 1980 and 2006 (published between January 1980 and June 2006) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, one-year survival rate, and toxicity rate were calculated using the fixed-effect model. Pooled median ratios (MRs) for median survival also were calculated using the fixed effect model. ORs and MRs lower than unity (< 1.0) indicate a benefit of a doublet regimen compared with a single-agent regimen (or a triplet regimen compared with a doublet regimen). MAIN RESULTS: Sixty-five trials (13601 patients) were eligible. In the trials comparing a doublet regimen with a single agent regimen, a significant increase was observed in tumor response (OR 0.42, 95% confidence interval [CI] 0.37 to 0.47, P < 0.001) and one-year survival (OR 0.80, 95% CI 0.70 to 0.91, P < 0.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI 0.79 to 0.89, P < 0.001). An increase also was observed in the tumor response rate (OR 0.66, 95% CI 0.58 to 0.75, P < 0.001) in favor of the triplet regimen, but not for one-year survival (OR 1.01, 95% CI 0.85 to 1.21, P = 0.88). The median survival ratio was 1.00 (95% CI 0.94 to 1.06, P = 0.97). AUTHORS' CONCLUSIONS: Adding a second drug improved tumor response and survival rate. Adding a third drug had a weaker effect on tumor response and no effect on survival. PMID- 22513925 TI - Total versus subtotal hysterectomy for benign gynaecological conditions. AB - BACKGROUND: Hysterectomy using an abdominal approach removes either the uterus alone (subtotal hysterectomy) or both the uterus and the cervix (total hysterectomy). The latter is more common but the outcomes have not been systematically compared. OBJECTIVES: To compare short term and long term outcomes of subtotal hysterectomy (STH) with total hysterectomy (TH) for benign gynaecological conditions. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials (July 2011), CENTRAL (July 2011), MEDLINE (1966 to July 2011), EMBASE (1980 to July 2011), CINAHL (January 2005 to July 2011), Biological Abstracts (1980 to December 2005), the National Research Register and relevant citation lists. SELECTION CRITERIA: Only randomised controlled trials of women undergoing either total or subtotal hysterectomy for benign gynaecological conditions were included. DATA COLLECTION AND ANALYSIS: Nine trials including 1553 participants were included. Independent selection of trials, assessment for risk of bias and data extraction were undertaken by two review authors and the results compared. MAIN RESULTS: There was no evidence of a difference in the rates of multiple outcomes that assessed urinary, bowel or sexual function between TH and STH, either in the short term (up to two years post-surgery) or long term (nine years post-surgery). Length of operation (difference of 11 min) and amount of blood lost during surgery (difference of 57 ml) were significantly reduced during subtotal hysterectomy when compared with total hysterectomy. These differences are unlikely to constitute a clinical benefit and there was no evidence of a difference in the odds of blood transfusion. Post-operative fever and urinary retention were less likely (fever: OR 0.48, 95% CI 0.3 to 0.8; retention: OR 0.23, 95% CI 0.1 to 0.8) and ongoing cyclical vaginal bleeding up to two years after surgery was more likely (OR 16.0, 95% CI 6.1 to 41.6) after STH compared with TH. There was no evidence of a difference in the rates of other complications, recovery from surgery, alleviation of pre-surgery symptoms or readmission rates between the two types of hysterectomy carried out through the abdominal or laparoscopic route, although trials comparing the laparoscopic route were underpowered to detect some differences. AUTHORS' CONCLUSIONS: This review has not confirmed the perception that subtotal hysterectomy offers improved outcomes for sexual, urinary or bowel function when compared with total abdominal hysterectomy. Women are more likely to experience ongoing cyclical bleeding up to a year after surgery with subtotal hysterectomy compared to total hysterectomy. PMID- 22513926 TI - Hyperbaric oxygenation for tumour sensitisation to radiotherapy. AB - BACKGROUND: Cancer is a common disease and radiotherapy is one well-established treatment for some solid tumours. Hyperbaric oxygenation therapy (HBOT) may improve the ability of radiotherapy to kill hypoxic cancer cells, so the administration of radiotherapy while breathing hyperbaric oxygen may result in a reduction in mortality and recurrence. OBJECTIVES: To assess the benefits and harms of radiotherapy while breathing HBO. SEARCH METHODS: In March 2011 we searched The Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 3), MEDLINE, EMBASE, DORCTHIM and reference lists of articles. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing the outcome of malignant tumours following radiation therapy while breathing HBO versus air. DATA COLLECTION AND ANALYSIS: Three review authors independently evaluated the quality of the relevant trials and extracted the data from the included trials. MAIN RESULTS: Nineteen trials contributed to this review (2286 patients: 1103 allocated to HBOT and 1153 to control). With HBOT, there was a reduction in mortality for head and neck cancers at both one year and five years after therapy (risk ratio (RR) 0.83, P = 0.03, number needed to treat (NNT) = 11; and RR 0.82, P = 0.03, NNT = 5 respectively), as well as improved local tumour control at three months (RR with HBOT 0.58, P = 0.006, NNT = 7). The effect of HBOT varied with different fractionation schemes. Local tumour recurrence was less likely with HBOT at one year (head and neck: RR 0.66, P < 0.0001, NNT = 5), two years (uterine cervix: RR 0.60, P = 0.04, NNT = 5) and five years (head and neck: (RR 0.77, P = 0.01, NNT = 6). Any advantage is achieved at the cost of some adverse effects. There was a significant increase in the rate of both severe radiation tissue injury (RR 2.35, P < 0.0001, (number needed to harm (NNH) = 8) and the chance of seizures during therapy (RR 6.76, P = 0.03, NNH = 22) with HBOT. AUTHORS' CONCLUSIONS: There is some evidence that HBOT improves local tumour control and mortality for cancers of the head and neck, and local tumour recurrence in cancers of the head and neck, and uterine cervix. These benefits may only occur with unusual fractionation schemes. HBOT is associated with significant adverse effects including oxygen toxic seizures and severe tissue radiation injury. The methodological and reporting inadequacies of the studies included demand a cautious interpretation. More research is needed for head and neck cancer, but is probably not justified for bladder cancer. There is little evidence available concerning malignancies at other anatomical sites on which to base a recommendation. PMID- 22513927 TI - Plugs for containing faecal incontinence. AB - BACKGROUND: Faecal incontinence is a distressing disorder with high social stigma. Not all people with faecal incontinence can be cured with conservative or surgical treatment and they may need to rely on containment products, such as anal plugs. OBJECTIVES: To assess the performance of different types of anal plugs for containment of faecal incontinence. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register (searched 29 February 2012). Reference lists of identified trials were searched and plugs manufacturers were contacted for trials. No language or other limitations were imposed. SELECTION CRITERIA: Types of studies: This review was limited to randomised and quasi randomised controlled trials (including crossovers) of anal plug use for the management of faecal incontinence. TYPES OF PARTICIPANTS: Children and adults with faecal incontinence.Types of interventions: Any type of anal plug. Comparison interventions might include no treatment, conservative (physical) treatments, nutritional interventions, surgery, pads and other types or sizes of plugs. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed methodological quality and extracted data from the included trials. Authors of all included trials were contacted for clarification concerning methodological issues. MAIN RESULTS: Four studies with a total of 136 participants were included. Two studies compared the use of plugs versus no plugs, one study compared two sizes of the same brand of plug, and one study compared two brands of plugs. In all included studies there was considerable dropout (in total 48 (35%) dropped out before the end of the study) for varying reasons. Data presented are thus subject to potential bias. 'Pseudo-continence' was, however, achieved by some of those who continued to use plugs, at least in the short-term. In a comparison of two different types of plug, plug loss was less often reported and overall satisfaction was greater during use of polyurethane plugs than polyvinyl-alcohol plugs. AUTHORS' CONCLUSIONS: The available data were limited and incomplete, and not all pre-specified outcomes could be evaluated. Consequently, only tentative conclusions are possible. The available data suggest that anal plugs can be difficult to tolerate. However, if they are tolerated they can be helpful in preventing incontinence. Plugs could then be useful in a selected group of people either as a substitute for other forms of management or as an adjuvant treatment option. Plugs come in different designs and sizes; the review showed that the selection of the type of plug can impact on its performance. PMID- 22513928 TI - Interventions for unilateral and bilateral refractive amblyopia. AB - BACKGROUND: Refractive amblyopia is a common cause of reduced visual acuity in childhood, but optimal treatment is not well defined. This review examined the treatment effect from spectacles and conventional occlusion. OBJECTIVES: Evaluation of the evidence of the effectiveness of spectacles, occlusion or both in the treatment of unilateral and bilateral refractive amblyopia. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 1), MEDLINE (January 1950 to January 2012), EMBASE (January 1980 to January 2012), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to January 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). There were no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 24 January 2012. We manually searched relevant conference proceedings. SELECTION CRITERIA: Randomised controlled trials of treatment for unilateral and bilateral refractive amblyopia by spectacles, with or without occlusion, were eligible. We included studies with participants of any age. DATA COLLECTION AND ANALYSIS: Two authors independently assessed abstracts identified by the searches. We obtained full-text copies and contacted study authors where necessary. Eleven trials were eligible for inclusion. We extracted data from eight. Insufficient data were present for the remaining three trials so data extraction was not possible. We identified no trials as containing participants with bilateral amblyopia. We performed no meta-analysis as there were insufficient trials for each outcome. MAIN RESULTS: For all studies mean acuity (standard deviation (SD)) in the amblyopic eye post-treatment was reported. All included trials reported treatment for unilateral refractive amblyopia.One study randomised participants to spectacles only compared to no treatment, spectacles plus occlusion compared to no treatment and spectacles plus occlusion versus spectacles only. For spectacles only versus no treatment, mean (SD) visual acuity was: spectacles group 0.31 (0.17); no treatment group 0.42 (0.19) and mean difference (MD) between groups was -0.11 (borderline statistical significance: 95% confidence interval (CI) -0.22 to 0.00). For spectacles plus occlusion versus no treatment, mean (SD) visual acuity was: full treatment 0.22 (0.13); no treatment 0.42 (0.19). Mean difference (MD) between the groups -0.20 (statistically significant: 95% CI -0.30 to -0.10). For spectacles plus occlusion versus spectacles only, MD was -0.09 (borderline statistical significance 95% CI 0.18 to 0.00). For two other trials that also looked at this comparison MD was 0.15 (not statistically significant 95% CI -0.32 to 0.02) for one trial and MD 0.01 (not statistically significant 95% CI -0.08 to 0.10) for the second trial.Three trials reviewed occlusion regimes.One trial looked at two hours versus six hours for moderate amblyopia: MD 0.01 (not statistically significant: 95% CI -0.06 to 0.08); a second trial 2003b reviewed six hours versus full-time for severe amblyopia: MD 0.03 (not statistically significant: 95% CI -0.08 to 0.14) and a third trial looked at six hours versus full-time occlusion: MD -0.12 (not statistically significant: 95% CI -0.27 to 0.03). One trial looked at occlusion supplemented with near or distance activities: MD-0.03 (not statistically significant 95% CI -0.09 to 0.03). One trial looked at partial occlusion and glasses versus glasses only: MD -0.01 (not statistically significant: 95% CI -0.05 to 0.03). AUTHORS' CONCLUSIONS: In some cases of unilateral refractive amblyopia it appears that there is a treatment benefit from refractive correction alone. Where amblyopia persists there is evidence that adding occlusion further improves vision. Despite advances in the understanding of the treatment of amblyopia it is currently still not possible to tailor individual treatment plans for amblyopia. The nature of any dose/response effect from occlusion still needs to be clarified. Partial occlusion appears to have the same treatment effect as glasses alone when started simultaneously for the treatment of unilateral refractive amblyopia. Treatment regimes for bilateral and unilateral refractive amblyopia need to be investigated further. PMID- 22513929 TI - Interventions to promote the wearing of hearing protection. AB - BACKGROUND: This is an update of a Cochrane Review first published in The Cochrane Library in Issue 2, 2006 and previously updated in 2009.Noise-induced hearing loss can be prevented by eliminating or lowering noise exposure levels. Where the source of the noise cannot be eliminated, workers have to rely on hearing protection equipment. Several trials have been conducted to study the effectiveness of interventions to influence the wearing of hearing protection. OBJECTIVES: To evaluate the effectiveness of interventions to enhance the wearing of hearing protection among persons regularly exposed to high noise levels. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 8 April 2011. SELECTION CRITERIA: We included studies if they had a randomised design, if they were among noise exposed (> 80 dB(A)) persons, if they included an intervention to promote the wearing of hearing protection (compared to another intervention or no intervention), and if the outcome measured was the amount of use of hearing protection or a proxy measure thereof. DATA COLLECTION AND ANALYSIS: Two authors selected relevant trials, assessed risk of bias and extracted data. MAIN RESULTS: Seven studies, involving 4670 participants, were included.A computer-based intervention lasting 30 minutes, tailored to the risk of an individual worker, was not found to be more effective than a video providing general information among workers, around 80% of whom already used hearing protection.A four-year school-based hearing loss prevention programme found that the intervention group was twice as likely to wear some kind of hearing protection as the control group that received a baseline hearing test and two additional tests at years two and three.We conducted two meta-analyses for the comparisons 'tailored strategy (the use of communication or other types of interventions that are specific to an individual or a group and aim to change behaviour) versus non-tailored strategy' and 'tailored strategy versus a commercial video on the use of hearing protection' to look at mean percentage use of hearing protective devices (HPDs), that showed improvement in the mean use of HPDs for the tailored group. A meta-analysis of the comparison 'mixed interventions' (classroom instruction, distribution of HPDs, mailings, noise level assessments and audiometric testing) versus control (audiometric testing alone) also showed improvement in self reported use of HPDs when shooting firearms.Tailored education showed an improvement in HPD use of 8.3% versus targeted education (6.1%). AUTHORS' CONCLUSIONS: The evidence found in this review shows that some interventions improve the mean use of hearing protection devices compared to non-intervention. Future trials should have standard outcomes and interventions to allow the combining of results in meta-analysis. PMID- 22513930 TI - Recombinant human activated protein C for severe sepsis in neonates. AB - BACKGROUND: Sepsis is a common problem in preterm and term infants. The incidence of neonatal sepsis has declined, but mortality remains high. Recombinant human activated protein C (rhAPC) possess a broad spectrum of activity modulating coagulation and inflammation. In septic adults it may reduce mortality, but no significant benefit has been reported in children with severe sepsis. OBJECTIVES: To determine whether treatment with rhAPC reduces mortality and/or morbidity in neonatal sepsis. SEARCH METHODS: For this update searches were carried out in May 2011 of the Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL, and abstracts of annual meetings of the Pediatric Academic Societies. Doctoral dissertations, theses and the Science Citation Index for articles on activated protein C were searched. No language restriction was applied. SELECTION CRITERIA: Randomized or quasi-randomized trials, assessing the efficacy of rhAPC compared to placebo or no intervention as an adjunct to antibiotic therapy of suspected or confirmed severe sepsis in term and preterm infants less than 28 days old. Eligible trials should report at least one of the following outcomes: mortality during initial hospital stay, neurodevelopmental assessment at two years of age or later, length of hospital stay, duration of ventilation, chronic lung disease, periventricular leukomalacia, intraventricular haemorrhage, necrotizing enterocolitis, bleeding, and any other adverse events. DATA COLLECTION AND ANALYSIS: Review authors were to independently evaluate the articles for inclusion criteria and quality, and abstract information for the outcomes of interest. Differences were to be resolved by consensus. The statistical methods were to include relative risk, risk difference, number needed to treat to benefit or number needed to treat to harm for dichotomous and weighed mean difference for continuous outcomes reported with 95% confidence intervals. A fixed effect model was to be used for meta analysis. Heterogeneity tests, including the I(2) statistic, were to be performed to assess the appropriateness of pooling the data. MAIN RESULTS: No eligible trials were identified. In October 2011 rhAPC (Xigris(r)) was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. Xigris(r) (DrotAA)( rhAPC) should no longer be used in any age category and the product should be returned to the distributor. AUTHORS' CONCLUSIONS: Despite the scientific rationale for its use, there is insufficient data to use rhAPC for the management of severe sepsis in newborn infants. Due to the results among adults with lack of efficacy, an increase in bleeding and resulting withdrawal of rhAPC from the market, neonates should not be treated with rhAPC and further trials should not be conducted. PMID- 22513931 TI - Carbetocin for preventing postpartum haemorrhage. AB - BACKGROUND: Postpartum haemorrhage (PPH) is one of the major contributors to maternal mortality and morbidity worldwide. Active management of the third stage of labour has been proven to be effective in the prevention of PPH. Syntometrine is more effective than oxytocin but is associated with more side effects. Carbetocin, a long-acting oxytocin agonist, appears to be a promising agent for the prevention of PPH. OBJECTIVES: To determine if the use of oxytocin agonist is as effective as conventional uterotonic agents for the prevention of PPH, and assess the best routes of administration and optimal doses of oxytocin agonist. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 March 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1 of 4), MEDLINE (1966 to 1 March 2011) and EMBASE (1974 to 1 March 2011). We checked references of articles and communicated with authors and pharmaceutical industry contacts. SELECTION CRITERIA: Randomised controlled trials which compared oxytocin agonist (carbetocin) with other uterotonic agents or with placebo or no treatment for the prevention of PPH. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, assessed risk of bias and extracted data. MAIN RESULTS: We included 11 studies (2635 women) in the review. Six trials compared carbetocin with oxytocin; four of these were conducted for women undergoing caesarean deliveries, one was for women following vaginal deliveries and one did not state the mode of delivery clearly. The carbetocin was administered as 100 ug intravenous dosage across the trials, while oxytocin was administered intravenously but at varied dosages. Four trials compared intramuscular carbetocin and intramuscular syntometrine for women undergoing vaginal deliveries. Three of the trials were on women with no risk factor for PPH, while one trial was on women with risk factors for PPH. One trial compared the use of intravenous carbetocin with placebo. Use of carbetocin resulted in a statistically significant reduction in the need for therapeutic uterotonics (risk ratio (RR) 0.62; 95% confidence interval (CI) 0.44 to 0.88; four trials, 1173 women) compared to oxytocin for those who underwent caesarean section, but not for vaginal delivery. Compared to oxytocin, carbetocin was associated with a reduced need for uterine massage following both caesarean delivery (RR 0.54; 95% CI 0.37 to 0.79; two trials, 739 women) and vaginal delivery (RR 0.70; 95% CI 0.51 to 0.94; one trial, 160 women). There were no statistically significant differences between carbetocin and oxytocin in terms of risk of any PPH (blood loss greater than 500 ml) or in risk of severe PPH (blood loss greater than 1000 ml). Comparison between carbetocin and syntometrine showed a lower mean blood loss in women who received carbetocin compared to syntometrine (mean difference (MD) -48.84 ml; 95% CI -94.82 to -2.85; four trials, 1030 women). There was no statistically significant difference in terms of the need for therapeutic uterotonic agents, but the risk of adverse effects such as nausea and vomiting were significantly lower in the carbetocin group: nausea (RR 0.24; 95% CI 0.15 to 0.40; four trials, 1030 women); vomiting (RR 0.21; 95% CI 0.11 to 0.39; four trials, 1030 women). The incidence of postpartum hypertension was also significantly lower in women who received carbetocin compared to those who received syntometrine. Cost-effectiveness of carbetocin was investigated by one study published as an abstract, with limited data. AUTHORS' CONCLUSIONS: For women who undergo caesarean section, carbetocin resulted in a statistically significant reduction in the need for therapeutic uterotonics compared to oxytocin, but there is no difference in the incidence of postpartum haemorrhage. Carbetocin is associated with less blood loss compared to syntometrine in the prevention of PPH for women who have vaginal deliveries and is associated with significantly fewer adverse effects. Further research is needed to analyse the cost-effectiveness of carbetocin as a uterotonic agent. PMID- 22513932 TI - Combined DTP-HBV-HIB vaccine versus separately administered DTP-HBV and HIB vaccines for primary prevention of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae B (HIB). AB - BACKGROUND: Advantages to combining childhood vaccines include reducing the number of visits, injections and patient discomfort, increasing compliance and optimising prevention. The World Health Organization (WHO) recommends that routine infant immunisation programmes include a vaccination against Haemophilus influenzae (H. influenzae) type B (HIB) in the combined diphtheria-tetanus pertussis (DTP)-hepatitis B virus (HBV) vaccination. The effectiveness and safety of the combined vaccine should be carefully and systematically assessed to ensure its acceptability by the community. OBJECTIVES: To compare the effectiveness of combined DTP-HBV-HIB vaccines versus combined DTP-HBV and separate HIB vaccinations. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (January 1966 to week 1, November 2011), EMBASE (January 1990 to November 2011) and www.clinicaltrials.gov (up to April 2011). SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing vaccination with any combined DTP-HBV-HIB vaccine, with or without three types of inactivated polio virus (IPV) or concomitant oral polio vaccine (OPV) in any dose, preparation or time schedule, compared with separate vaccines or placebo, administered to infants up to two years old. DATA COLLECTION AND ANALYSIS: Two review authors independently inspected references identified by the searches and evaluated them against the inclusion criteria, extracted data and assessed the methodological quality of included trials. MAIN RESULTS: Data for the primary outcome (prevention of disease) were lacking. We performed a meta-analysis to pool the results of 20 studies with 5874 participants in an immunogenicity analysis and 5232 participants in the reactogenicity analysis. There were no data on clinical outcomes for the primary outcome (prevention of disease) and all studies used immunogenicity and reactogenicity (adverse events). The number of vaccine doses differed significantly between the studies. Heterogeneous interventions, study location, healthcare environment and combining research across disparate geographical locations, may have lead to bias. The risk of bias was unclear across most of the included studies. Comparisons found little heterogeneity. In two immunological responses the combined vaccine achieved lower responses than the separate vaccines for HIB and tetanus. No significant differences in immunogenicity were found for pertussis, diphtheria, polio and hepatitis B. Serious adverse events were comparable with mainly hospitalisation and acute bronchiolitis cases. Minor adverse events such as pain and redness were more common in children given the combined vaccine. Overall, the direction shown by the results is in favour of the DTPw (diptheria-tetanus-whole cell pertussis)-HBV HIB vaccine rather than the DTPa (diptheria-tetanus-acellular pertussis)-HBV-HIB vaccine when compared to the separate vaccines (size of effect: risk ratio (RR) 1.43; 95% confidence interval (CI) 0.98 to 2.10, for 5269 participants). AUTHORS' CONCLUSIONS: We could not conclude that the immune responses elicited by the combined vaccine were different from or equivalent to the separate vaccines. There was significantly less immunological response for HIB and tetanus and more local reactions in the combined injections. However, these differences rely mostly on one study each. Studies did not use an intention-to-treat (ITT) analysis and we were uncertain about the risk of bias in many of the studies. These results are therefore inconclusive. Studies addressing clinical end points whenever possible, using correct methodology and a large enough sample size should be conducted. PMID- 22513933 TI - Instruments for assessing readiness to commence suck feeds in preterm infants: effects on time to establish full oral feeding and duration of hospitalisation. AB - BACKGROUND: One of the most challenging milestones for preterm infants is the acquisition of safe and efficient feeding skills. The majority of healthy full term infants are born with skills to coordinate their suck, swallow and respiration. However, this is not the case for preterm infants who develop these skills gradually as they transition from tube feeding to suck feeds. For preterm infants the ability to engage in oral feeding behaviour is dependent on many factors. The complexity of factors influencing feeding readiness has led some researchers to investigate the use of an individualised assessment of an infant's abilities. A limited number of instruments that aim to indicate an individual infant's readiness to commence either breast or bottle feeding have been developed. OBJECTIVES: To determine the effects of using a feeding readiness instrument when compared to no instrument or another instrument on the outcomes of time to establish full oral feeding and duration of hospitalisation. SEARCH METHODS: We used the standard methods of the Cochrane Neonatal Review Group, including a search of the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 2), MEDLINE via EBSCO (1966 to July 2010), EMBASE (1980 to July 2010), CINAHL via EBSCO (1982 to July 2010), Web of Science via EBSCO (1980 to July 2010) and Health Source (1980 to July 2010). Other sources such as cited references from retrieved articles and databases of clinical trials were also searched. We did not apply any language restriction. We updated this search in March 2012. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing a formal instrument to assess a preterm infant's readiness to commence suck feeds with either no instrument (usual practice) or another feeding readiness instrument. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Neonatal Review Group were used. Two authors independently screened potential studies for inclusion. No studies were found that met our inclusion criteria. MAIN RESULTS: No studies met the inclusion criteria. AUTHORS' CONCLUSIONS: There is currently no evidence to inform clinical practice, with no studies meeting the inclusion criteria for this review. Research is needed in this area to establish an evidence base for the clinical utility of implementing the use of an instrument to assess feeding readiness in the preterm infant population. PMID- 22513934 TI - Household interventions for preventing domestic lead exposure in children. AB - BACKGROUND: Lead poisoning is associated with physical, cognitive and neurobehavioural impairment in children and trials have tested many household interventions to prevent lead exposure. This is an update of the original review by the same authors first published in 2008. OBJECTIVES: To determine the effectiveness of household interventions in preventing or reducing lead exposure in children as measured by reductions in blood lead levels and/or improvements in cognitive development. SEARCH METHODS: We identified trials through electronic searches of CENTRAL (The Cochrane Library, 2010, Issue 2), MEDLINE (1948 to April Week 1 2012), EMBASE (1980 to 2012 Week 2), CINAHL (1937 to 20 Jan 2012), PsycINFO (1887 to Dec week 2 2011), ERIC (1966 to 17 Jan 2012), Sociological Abstracts (1952 to 20 January 2012), Science Citation Index (1970 to 20 Jan 2012), ZETOC (20 Jan 2012), LILACS (20 Jan 2012), Dissertation Abstracts (late 1960s to Jan 2012), ClinicalTrials.gov (20 Jan 2012), Current Controlled Trials (Jan 2012), Australian New Zealand Clinical Trials Registry (Jan 2012) and the National Research Register Archive. We also contacted experts to find unpublished studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of household educational or environmental interventions to prevent lead exposure in children where at least one standardised outcome measure was reported. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed all eligible studies for inclusion, assessed risk of bias and extracted data. We contacted trialists to obtain missing information. MAIN RESULTS: We included 14 studies (involving 2656 children). All studies reported blood lead level outcomes and none reported on cognitive or neurobehavioural outcomes. We put studies into subgroups according to their intervention type. We performed meta-analysis of both continuous and dichotomous data for subgroups where appropriate. Educational interventions were not effective in reducing blood lead levels (continuous: mean difference (MD) 0.02, 95% confidence interval (CI) -0.09 to 0.12, I(2) = 0 (log transformed); dichotomous >= 10ug/dL (>= 0.48 umol/L): relative risk (RR) 1.02, 95% CI 0.79 to 1.30, I(2)=0; dichotomous >= 15ug/dL (>= 0.72 umol/L): RR 0.60, 95% CI 0.33 to 1.09, I(2) = 0). Meta-analysis for the dust control subgroup also found no evidence of effectiveness (continuous: MD -0.15, 95% CI -0.42 to 0.11, I(2) = 0.9 (log transformed); dichotomous >= 10ug/dL (>= 0.48 umol/L): RR 0.93, 95% CI 0.73 to 1.18, I(2) =0; dichotomous >= 15ug/dL (>= 0.72 umol/L): RR 0.86, 95% CI 0.35 to 2.07, I(2) = 0.56). When meta-analysis for the dust control subgroup was adjusted for clustering, no statistical significant benefit was incurred. The studies using soil abatement (removal and replacement) and combination intervention groups were not able to be meta-analysed due to substantial differences between studies. AUTHORS' CONCLUSIONS: Based on current knowledge, household educational or dust control interventions are ineffective in reducing blood lead levels in children as a population health measure. There is currently insufficient evidence to draw conclusions about the effectiveness of soil abatement or combination interventions.Further trials are required to establish the most effective intervention for prevention of lead exposure. Key elements of these trials should include strategies to reduce multiple sources of lead exposure simultaneously using empirical dust clearance levels. It is also necessary for trials to be carried out in developing countries and in differing socioeconomic groups in developed countries. PMID- 22513935 TI - WITHDRAWN: Elemene for the treatment of lung cancer. AB - BACKGROUND: Elemene, isolated from the Chinese medicinal herb Rhizoma Zedoariae and be used to treat patients with lung cancer in China. Until now, the effects have not been systematically reviewed. OBJECTIVES: The purpose of this review was to determine the effectiveness and safety of elemene in the treatment of patients with lung cancer. SEARCH METHODS: We searched according to the strategy suggested by Lung Cancer group: the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, Issue 2); MEDLINE (1966 to June 2006); EMBASE (1974 to June 2006); OVID (1950 to June, 2006); CBMdisc on Chinese Biomedical Literature (Issue 1 2004 Chinese Language) and CNKI (Chinese Knowledge Internet 1994 to June 2006). SELECTION CRITERIA: Only randomised controlled trials (RCTs) that compared elemene with chemotherapy agents, radiotherapy, surgery, physical therapy or other effective Chinese herb therapy, either alone or in combination, had been sought in this review, regardless of language or publication status. DATA COLLECTION AND ANALYSIS: Two authors telephoned the original trial authors of claimed randomised controlled trials and made a decision about trial inclusion and exclusion. MAIN RESULTS: We identified 20 trials which claimed to use random allocation. Sixteen study authors were contacted by telephone and we discovered that they misunderstood the randomisation procedure and the trials were identified as non-RCTs. We were unable to contact the authors of the remaining four studies and these have been allocated to the 'Studies awaiting assessment' section. AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials to confirm or refute the effectiveness of elemene as a treatment for lung cancer. Randomised clinical trials, on elemene for the treatment of lung cancer are needed in order to define the efficacy and acceptability of elemene for lung cancer. PMID- 22513936 TI - Nicotine receptor partial agonists for smoking cessation. AB - BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). OBJECTIVES: The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including cytisine, dianicline and varenicline for smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist') in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, PsycINFO and Web of Science using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialised register was in December 2011. We also searched online clinical trials registers. SELECTION CRITERIA: We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. DATA COLLECTION AND ANALYSIS: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow-up.The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs), using the Mantel-Haenszel fixed-effect model. MAIN RESULTS: Two recent cytisine trials (937 people) found that more participants taking cytisine stopped smoking compared with placebo at longest follow-up, with a pooled RR of 3.98 (95% confidence interval (CI) 2.01 to 7.87). One trial of dianicline (602 people) failed to find evidence that it was effective (RR 1.20, 95% CI 0.82 to 1.75). Fifteen trials compared varenicline with placebo for smoking cessation; three of these also included a bupropion treatment arm. We also found one open-label trial comparing varenicline plus counselling with counselling alone. We found one relapse prevention trial, comparing varenicline with placebo, and two open-label trials comparing varenicline with nicotine replacement therapy (NRT). We also include one trial in which all the participants were given varenicline, but received behavioural support either online or by phone calls, or by both methods. This trial is not included in the analyses, but contributes to the data on safety and tolerability. The included studies covered 12,223 participants, 8100 of whom used varenicline.The pooled RR for continuous or sustained abstinence at six months or longer for varenicline at standard dosage versus placebo was 2.27 (95% CI 2.02 to 2.55; 14 trials, 6166 people, excluding one trial evaluating long term safety). Varenicline at lower or variable doses was also shown to be effective, with an RR of 2.09 (95% CI 1.56 to 2.78; 4 trials, 1272 people). The pooled RR for varenicline versus bupropion at one year was 1.52 (95% CI 1.22 to 1.88; 3 trials, 1622 people). The RR for varenicline versus NRT for point prevalence abstinence at 24 weeks was 1.13 (95% CI 0.94 to 1.35; 2 trials, 778 people). The two trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated during long-term use. The main adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. A meta-analysis of reported serious adverse events occurring during or after active treatment and not necessarily considered attributable to treatment suggests there may be a one-third increase in the chance of severe adverse effects among people using varenicline (RR 1.36; 95% CI 1.04 to 1.79; 17 trials, 7725 people), but this finding needs to be tested further. Post-marketing safety data have raised questions about a possible association between varenicline and depressed mood, agitation, and suicidal behaviour or ideation. The labelling of varenicline was amended in 2008, and the manufacturers produced a Medication Guide. Thus far, surveillance reports and secondary analyses of trial data are inconclusive, but the possibility of a link between varenicline and serious psychiatric or cardiovascular events cannot be ruled out. AUTHORS' CONCLUSIONS: Cytisine increases the chances of quitting, although absolute quit rates were modest in two recent trials. Varenicline at standard dose increased the chances of successful long-term smoking cessation between two- and threefold compared with pharmacologically unassisted quit attempts. Lower dose regimens also conferred benefits for cessation, while reducing the incidence of adverse events. More participants quit successfully with varenicline than with bupropion. Two open-label trials of varenicline versus NRT suggested a modest benefit of varenicline but confidence intervals did not rule out equivalence. Limited evidence suggests that varenicline may have a role to play in relapse prevention. The main adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Possible links with serious adverse events, including serious psychiatric or cardiovascular events, cannot be ruled out.Future trials of cytisine may test extended regimens and more intensive behavioural support. There is a need for further trials of the efficacy of varenicline treatment extended beyond 12 weeks. PMID- 22513937 TI - Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus. AB - BACKGROUND: Many hormonal contraceptives have been associated with changes in carbohydrate metabolism. Alterations may include decreased glucose tolerance and increased insulin resistance, which are risk factors for Type 2 diabetes mellitus and cardiovascular disease. These issues have been raised primarily with contraceptives containing estrogen. OBJECTIVES: To evaluate the effect of hormonal contraceptives on carbohydrate metabolism in healthy women and those at risk for diabetes due to overweight. SEARCH METHODS: In February 2012, we searched the computerized databases MEDLINE, POPLINE, CENTRAL, and LILACS for studies of hormonal contraceptives and carbohydrate metabolism. We also searched for clinical trials in ClinicalTrials.gov and ICTRP. Previous searches also included EMBASE. SELECTION CRITERIA: All randomized controlled trials were considered if they examined carbohydrate metabolism in women without diabetes who used hormonal contraceptives for contraception. Comparisons could be a placebo, a non-hormonal contraceptive, or another hormonal contraceptive that differed in drug, dosage, or regimen. Interventions included at least three cycles. Outcomes included glucose and insulin measures. DATA COLLECTION AND ANALYSIS: We assessed all titles and abstracts identified during the literature searches. The data were extracted and entered into RevMan. We wrote to researchers for missing data. For continuous variables, the mean difference (MD) was computed with 95% confidence interval (CI) using a fixed-effect model. For dichotomous outcomes, the Peto odds ratio with 95% CI was calculated. MAIN RESULTS: We found 31 trials that met the inclusion criteria. Twenty-one trials compared combined oral contraceptives (COCs); others examined different COC regimens, progestin-only pills, injectables, a vaginal ring, and implants. None included a placebo. Of 34 comparisons, eight had any notable difference between the study groups in an outcome.Twelve trials studied desogestrel-containing COCs, and the few differences from levonorgestrel COCs were inconsistent. A meta-analysis of two studies showed the desogestrel group had a higher mean fasting glucose (MD 0.20; 95% CI 0.00 to 0.41). Where data could not be combined, single studies showed lower mean fasting glucose (MD -0.40; 95% CI -0.72 to -0.08) and higher means for two-hour glucose response (MD 1.08; 95% CI 0.45 to 1.71) and insulin area under the curve (AUC) (MD 20.30; 95% CI 4.24 to 36.36).Three trials examined the etonogestrel vaginal ring and one examined an etonogestrel implant. One trial showed the ring group had lower mean AUC insulin than the levonorgestrel-COC group (MD -204.51; 95% CI -389.64 to -19.38).Of eight trials of norethisterone preparations, five compared COCs and three compared injectables. In a COC trial, a norethisterone group had smaller mean change in glucose two-hour response than a levonorgestrel-COC group (MD -0.30; 95% CI -0.54 to -0.06). In an injectable study, a group using depot medroxyprogesterone acetate had higher means than the group using norethisterone enanthate for fasting glucose (MD 10.05; 95% CI 3.16 to 16.94), glucose two-hour response (MD 17.00; 95% CI 5.67 to 28.33), and fasting insulin (MD 3.40; 95% CI 2.07 to 4.73).Among five recent trials, two examined newer COCs with different estrogen types. One showed the group with nomegestrel acetate plus 17beta-estradiol had lower means than the levonorgestrel group for incremental AUC glucose (MD -1.43; 95% CI -2.55 to -0.31) and glycosylated hemoglobin (HbA1c) (MD -0.10; 95% CI -0.18 to -0.02). Two trials compared extended versus conventional (cyclic) regimens. With a dienogest COC, an extended-use group had greater mean change in AUC glucose (MD 82.00; 95% CI 10.72 to 153.28). In a small trial using two levonorgestrel COCs, the lower-dose group showed smaller mean change in fasting glucose (MD -3.00; 95% CI -5.89 to -0.11), but the obese and normal weight women did not differ significantly. AUTHORS' CONCLUSIONS: Current evidence suggests no major differences in carbohydrate metabolism between different hormonal contraceptives in women without diabetes. We cannot make strong statements due to having few studies that compared the same types of contraceptives. Many trials had small numbers of participants and some had large losses. Many of the earlier studies had limited reporting of methods.We still know very little about women at risk for metabolic problems due to being overweight. More than half of the trials had weight restrictions as inclusion criteria. Only one small trial stratified the groups by body mass index (obese versus normal). PMID- 22513938 TI - Trastuzumab containing regimens for early breast cancer. AB - BACKGROUND: Approximately one-fifth of women who develop early breast cancer have HER2-positive tumours, which if untreated, have a worse prognosis than HER2 negative tumours. Trastuzumab is a selective treatment targeting the HER2 pathway. Although the results on efficacy seem to support its use, there are potential cardiac toxicities which need to be considered, especially for women at lower risk of recurrence, or those at increased cardiovascular risk. OBJECTIVES: To assess the evidence on the efficacy and safety of therapy with trastuzumab, overall and in relation to its duration, concurrent or sequential administration with the standard chemotherapy regimen in patients with HER2-positive early breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's (CBCGs) Specialised Trials Register, and used the search strategy developed by the CBCG to search for randomised controlled trials (RCTs) in CENTRAL, MEDLINE, EMBASE, BIOSIS, TOXNET, and the WHO ICTRP search portal (up to February 2010). SELECTION CRITERIA: RCTs comparing the efficacy and safety of trastuzumab alone, or in combination with chemotherapy, or no treatment, or standard chemotherapy alone, in women with HER2-positive early breast cancer including women with locally advanced breast cancer. DATA COLLECTION AND ANALYSIS: We collected data from published and unpublished trials. We used hazard ratios (HRs) for time-to event outcomes and risk ratio (RRs) for binary outcomes. Subgroup analyses included duration (less or greater than six months) and concurrent or sequential trastuzumab administration. MAIN RESULTS: We included eight studies involving 11,991 patients. The combined HRs for overall survival (OS) and disease-free survival (DFS) significantly favoured the trastuzumab-containing regimens (HR 0.66; 95% confidence interval (CI) 0.57 to 0.77, P < 0.00001; and HR 0.60; 95% CI 0.50 to 0.71, P < 0.00001, respectively). Trastuzumab significantly increased the risk of congestive heart failure (CHF: RR 5.11; 90% CI 3.00 to 8.72, P < 0.00001); and left ventricular ejection fraction decline (LVEF: RR 1.83; 90% CI 1.36 to 2.47, P = 0.0008). For haematological toxicities, risks did not differ. The two small trials that administered trastuzumab for less than six months did not differ in efficacy from longer studies, but found fewer cardiac toxicities. Studies with concurrent administration gave similar efficacy and toxicity results to sequential studies. AUTHORS' CONCLUSIONS: Trastuzumab significantly improves OS and DFS in HER2-positive women with early and locally advanced breast cancer, although it also significantly increases the risk of CHF and LVEF decline. The available subgroup analyses are limited by the small number of studies. Studies that administered trastuzumab concurrently or sequentially did not differ significantly in efficacy. Shorter duration of therapy may reduce cardiotoxicity and maintain efficacy, however there is insufficient evidence at present to conclude this due to small numbers of patients in these trials. PMID- 22513939 TI - Drug treatment for spinal muscular atrophy type I. AB - BACKGROUND: Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells of the spinal cord, which leads to progressive muscle weakness. Children with SMA type I will never be able to sit without support and usually die by the age of two years. There are no known efficacious drug treatments that influence the course of the disease. This is an update of a review first published in 2009. OBJECTIVES: To evaluate whether drug treatment is able to slow or arrest the disease progression of SMA type I, and to assess if such therapy can be given safely. Drug treatment for SMA types II and III is the topic of a separate updated Cochrane review. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), CENTRAL (The Cochrane Library 2011, Issue 1), MEDLINE (January 1991 to February 2011), EMBASE (January 1991 to February 2011) and ISI Web of Knowledge (January 1991 to 8 March 2011). We searched the Clinical Trials Registry of the U.S. National Institute of Health (www.ClinicalTrials.gov) (8 March 2011) to identify additional trials that had not yet been published. SELECTION CRITERIA: We sought all randomised or quasi randomised trials that examined the efficacy of drug treatment for SMA type I. Participants had to fulfil the clinical criteria and have a deletion or mutation of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis.The primary outcome measure was time from birth until death or full time ventilation. Secondary outcome measures were development of rolling, sitting or standing within one year after the onset of treatment, and adverse events attributable to treatment during the trial period. DATA COLLECTION AND ANALYSIS: Two authors (RW and AV) independently reviewed and extracted data from all potentially relevant trials. For included studies, pooled relative risks and standardised mean differences were to be calculated to assess treatment efficacy. MAIN RESULTS: One small randomised controlled study comparing riluzole treatment to placebo for 10 SMA type 1 children was identified and included in the original review. No further trials were identified for the update in 2011. Regarding the primary outcome measure, three of seven children treated with riluzole were still alive at the ages of 30, 48 and 64 months, whereas all three children in the placebo group died; but the difference was not statistically significant. Regarding the secondary outcome measures, none of the children in the riluzole or placebo group developed the ability to roll, sit or stand, and no adverse effects were observed. For several reasons the overall quality of the study was low, mainly because the study was too small to detect an effect and because of baseline differences. Follow-up of the 10 included children was complete. AUTHORS' CONCLUSIONS: No drug treatment for SMA type I has been proven to have significant efficacy. PMID- 22513941 TI - Interventions for improving outcomes in patients with multimorbidity in primary care and community settings. AB - BACKGROUND: Many people with chronic disease have more than one chronic condition, which is referred to as multimorbidity. While this is not a new phenomenon, there is greater recognition of its impact and the importance of improving outcomes for individuals affected. Research in the area to date has focused mainly on descriptive epidemiology and impact assessment. There has been limited exploration of the effectiveness of interventions for multimorbidity. OBJECTIVES: To determine the effectiveness of interventions designed to improve outcomes in patients with multimorbidity in primary care and community settings. Multimorbidity was defined as two or more chronic conditions in the same individual. SEARCH METHODS: We searched MEDLINE, EMBASE, CINAHL, CAB Health, AMED, HealthStar, The Cochrane Central Register of Controlled Trials (CENTRAL), the EPOC Register and the Database of Abstracts of Reviews of Effectiveness (DARE), and the EPOC Register in April 2011. SELECTION CRITERIA: We considered randomised controlled trials (RCTs), controlled clinical trials (CCTs), controlled before and after studies (CBAs), and interrupted time series analyses (ITS) reporting on interventions to improve outcomes for people with multimorbidity in primary care and community settings. The outcomes included any validated measure of physical or mental health, psychosocial status including quality of life outcomes, well-being, and measures of disability or functional status. We also included measures of patient and provider behaviour including measures of medication adherence, utilisation of health services, and acceptability of services and costs. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility, extracted data, and assessed study quality. Meta-analysis of results was not possible so we carried out a narrative synthesis of the results from the included studies. MAIN RESULTS: Ten studies examining a range of complex interventions for patients with multimorbidity were identified. All were RCTs and there was low risk of bias. Two of the nine studies focused on specific co-morbidities. The remaining studies focused on multimorbidity, generally in older patients. All studies involved complex interventions with multiple elements. In six of the ten studies, the predominant intervention element was a change to the organisation of care delivery, usually through case management or enhanced multidisciplinary team work. In the remaining four studies, the interventions were predominantly patient oriented. Overall the results were mixed with a trend towards improved prescribing and medication adherence. The results indicate that it is difficult to improve outcomes in this population but that interventions focusing on particular risk factors or functional difficulties in patients with co-morbid conditions or multimorbidity may be more effective. Cost data were limited with no economic analyses included, though the improvements in prescribing and risk factor management in some studies provided potentially significant cost savings. AUTHORS' CONCLUSIONS: This review highlights the paucity of research into interventions to improve outcomes for multimorbidity with the focus to date being on co-morbid conditions or multimorbidity in older patients. The limited results suggest that interventions to date have had mixed effects but have shown a tendency to improve prescribing and medication adherence, particularly if interventions can be targeted at risk factors or specific functional difficulties in people with co-morbid conditions or multimorbidity. There is a need for clear definitions of participants, consideration of appropriate outcomes, and further pragmatic studies based in primary care settings. PMID- 22513940 TI - Drug treatment for spinal muscular atrophy types II and III. AB - BACKGROUND: Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. There are no known efficacious drug treatments that influence the disease course of SMA. This is an update of a review first published in 2009. OBJECTIVES: To evaluate whether drug treatment is able to slow or arrest the disease progression of SMA types II and III and to assess if such therapy can be given safely. Drug treatment for SMA type I is the topic of a separate updated Cochrane review. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1), MEDLINE (January 1991 to February 2011), EMBASE (January 1991 to February 2011) and ISI Web of Knowledge (January 1991 to March 8 2011). We also searched clinicaltrials.gov to identify as yet unpublished trials (8 March 2011). SELECTION CRITERIA: We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a deletion or mutation of the survival motor neuron 1 (SMN1) gene (5q11.2-13.2) that was confirmed by genetic analysis.The primary outcome measure was to be change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were to be change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full time ventilation and adverse events attributable to treatment during the trial period. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed and extracted data from all potentially relevant trials. Pooled relative risks and pooled standardised mean differences were to be calculated to assess treatment efficacy. Risk of bias was systematically analysed. MAIN RESULTS: Six randomised placebo-controlled trials on treatment for SMA types II and III were found and included in the review: the four in the original review and two trials added in this update. The treatments were creatine (55 participants), phenylbutyrate (107 participants), gabapentin (84 participants), thyrotropin releasing hormone (9 participants), hydroxyurea (57 participants), and combination therapy with valproate and acetyl-L-carnitine (61 participants). None of these studies were completely free of bias. All studies had adequate blinding, sequence generation and reports of primary outcomes.None of the included trials showed any statistically significant effects on the outcome measures in participants with SMA types II and III. One participant died due to suffocation in the hydroxyurea trial and one participant died in the creatine trial. No participants in any of the other four trials died or reached the state of full time ventilation. Serious side effects were infrequent. AUTHORS' CONCLUSIONS: There is no proven efficacious drug treatment for SMA types II and III. PMID- 22513942 TI - Zinc supplements for preventing otitis media. AB - BACKGROUND: Otitis media (OM) is inflammation of the middle ear and is usually caused by infection. It affects people of all ages but is particularly common in young children. Around 164 million people worldwide have long-term hearing loss caused by this condition, 90% of them in low-income countries. As zinc supplements prevent pneumonia in disadvantaged children, we wanted to investigate whether zinc supplements could also prevent OM. OBJECTIVES: To evaluate whether zinc supplements prevent OM in adults and children of different ages. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2012, Issue 1) which includes the Cochrane Acute Respiratory Infections Groups' Specialised Register, MEDLINE (1950 to February week 1, 2012) and EMBASE (1974 to February 2012). SELECTION CRITERIA: Randomised, placebo-controlled trials of zinc supplements given at least once a week for at least a month for preventing OM. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility and methodological quality of the included trials and extracted and analysed data. We summarised results using risk ratios (RRs) or rate ratios for dichotomous data and mean differences (MDs) for continuous data. We combined trial results where appropriate. MAIN RESULTS: We identified 12 trials for inclusion, 10 of which contributed outcomes data. There was a total of 6820 participants. In trials of healthy children living in low-income communities, two trials did not demonstrate a significant difference between the zinc supplemented and placebo groups in the numbers of participants experiencing an episode of definite OM during follow-up (3191 participants); another trial showed a significantly lower incidence rate of OM in the zinc group (rate ratio 0.69, 95% confidence interval (CI) 0.61 to 0.79, n = 1621). A small trial of 39 infants undergoing treatment for severe malnutrition suggested a benefit of zinc for the mean number of episodes of OM (mean difference (MD) -1.12 episodes, 95% CI -2.21 to -0.03). Zinc supplements did not seem to cause any serious adverse events but a small minority of children were reported to have vomited shortly after ingestion of the supplements. The trial evidence included is generally of good quality, with a low risk of bias. AUTHORS' CONCLUSIONS: Evidence on whether zinc supplementation can reduce the incidence of OM in healthy children under the age of five years living in low- and middle-income countries is mixed. There is some evidence of benefit in children being treated for marasmus (severe malnutrition) but this is based on one small trial and should therefore be treated with caution. PMID- 22513943 TI - Patellar taping for patellofemoral pain syndrome in adults. AB - BACKGROUND: Patellofemoral pain syndrome refers to the clinical presentation of knee pain related to changes in the patellofemoral joint. Patellofemoral pain syndrome usually has a gradual onset of pain with none of the features associated with other knee diseases or trauma. It is often treated by physiotherapists, who use a variety of techniques including patellar taping. This involves the application of adhesive sports medical tape applied directly to the skin over the patella on the front of the knee. Patients often report an instantaneous improvement in pain and function after the tape is applied, but its longer term effects are uncertain. OBJECTIVES: The objective was to assess the effects, primarily on pain and function, of patellar taping for treating patellofemoral pain syndrome in adults. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, CINAHL, EMBASE, PEDro, SPORTDiscus, AMED, reference lists of articles, trial registers and conference proceedings. All were searched to August 2011. SELECTION CRITERIA: Randomised controlled trials and quasi randomised controlled trials testing the effects of patellar taping on clinically relevant outcomes, pain and function, in adults with patellofemoral pain syndrome. We excluded studies testing only the immediate effects of tape application. DATA COLLECTION AND ANALYSIS: Both review authors independently performed study selection, data extraction and assessment of risk of bias. Trialists were contacted for more information. Data were pooled where possible. MAIN RESULTS: Five small heterogeneous randomised controlled trials, all at high risk of performance bias and most at risk of at least one other type of bias, were included. These involved approximately 200 participants with a diagnosis of patellofemoral pain syndrome. All compared taping versus control (no or placebo taping) and all included one or more co-interventions given to both taping and control group participants; this was prescribed exercise in four trials. The intensity and length of treatment was very varied: for example, length of treatment ranged from one week in one trial to three months in another. A meta analysis of the visual analogue scale (VAS) pain data (scale 0 to 10: worst pain), measured in different ways, from four trials (data from 161 knees), found no statistically or clinically significant difference between taping and non taping in pain at the end of the treatment programmes (mean difference (MD) 0.15; 95% confidence interval (CI) -1.15 to 0.85; random-effects model used given the significant heterogeneity (P < 0.0001)). Data for other outcomes measuring function and activities of daily living were from single trials only and gave contradictory results. AUTHORS' CONCLUSIONS: The currently available evidence from trials reporting clinically relevant outcomes is low quality and insufficient to draw conclusions on the effects of taping, whether used on its own or as part of a treatment programme. Further research involving large, preferably multi-centre, good quality and well reported randomised controlled trials that measure clinically important outcomes and long-term results is warranted. Before this, consensus is required on the diagnosis of patellofemoral pain syndrome, the standardisation of outcome measurement and an acceptable approach for patellar taping. PMID- 22513945 TI - Catheter ablation for paroxysmal and persistent atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia seen in cardiovascular departments. Treatments include medical interventions and catheter ablation. Due to uncertainties in medical therapies for AF, and the need to continue sinus rhythm, ablation has been recently considered as a viable alternative. Many new ablation methods based on pulmonary vein isolation (PVI) have been developed. OBJECTIVES: The primary objective of this review was to assess the beneficial and harmful effects of catheter ablation (CA) in comparison with medical treatment in patients with paroxysmal and persistent AF. The secondary objective was to determine the best regimen of CA. SEARCH METHODS: Searches were run on The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library Issue 3 2009, MEDLINE (1950 to August 2009), EMBASE (1980 to August 2009), the Chinese Biomedical Literature Database (1978 to August 2009) and the CKNI Chinese Paper Database (1994 to 2009) . Several journals published in Chinese were also handsearched. SELECTION CRITERIA: Randomised controlled trials (RCTs) in people with paroxysmal and persistent AF treated by any type of CA method. Two reviewers independently selected the trials for inclusion. DATA COLLECTION AND ANALYSIS: Assessments of risk of bias were performed by two reviewers, and relative risk (RR) and 95% confidence intervals (CI) were used for dichotomous variables. Meta-analysis were performed where appropriate. MAIN RESULTS: A total of 32 RCTs (3,560 patients) were included. RCTs were small in size and of poor quality.CA compared with medical therapies: seven RCTs indicated that CA had a better effect in inhibiting recurrence of AF [RR 0.27; 95% CI 0.18, 0.41)] but there was significant heterogeneity. There was limited evidence to suggest that sinus rhythm was restored during CA (one small trial: RR 0.28, 95% CI 0.20-0.40), and at the end of follow-up (RR 1.87, 95% CI 1.31-2.67; I(2)=83%). There were no differences in mortality (RR, 0.50, 95% CI 0.04 to 5.65), fatal and non-fatal embolic complication (RR 1.01, 95% CI 0.18 to 5.68) or death from thrombo-embolic events (RR 3.04, 95% CI 0.13 to 73.43).Comparisons of different CAs; 25 RCTs compared CA of various kinds. Circumferential pulmonary vein ablation was better than segmental pulmonary vein ablation in improving symptoms of AF (p<=0.01) and in reducing the recurrence of AF (p<0.01). There is limited evidence to suggest which ablation method was the best. AUTHORS' CONCLUSIONS: There is limited evidence to suggest that CA may be a better treatment option compared to medical therapies in the management of persistent AF. This review was also unable to recommend the best CA method. PMID- 22513946 TI - Interventions for restoring patency of occluded central venous catheter lumens. AB - BACKGROUND: Central venous catheters (CVCs) facilitate the administration of intravenous drugs, fluids, blood products and parenteral nutrition to patients with either chronic disease or critical illness. Despite a pivotal role within medical management, a common complication associated with CVC use is occlusion of the CVC lumen(s). CVC occlusion can interrupt and cause serious delays in administration of treatment interventions. OBJECTIVES: The primary objective of this review was to assess the efficacy and safety of different interventions used to restore patency of occluded CVC lumens, in adults and children. SEARCH METHODS: We identified trials by searching the Cochrane Central Register of Clinical Trials (CENTRAL) (The Cochrane Library 2011, Issue 9); OvidSP MEDLINE (1950 to September 2011); OvidSP EMBASE (1980 to September 2011) and NHS Evidence CINAHL (1982 to September 2011). We also searched clinical trial registers, handsearched reference lists, contacted pharmaceutical companies and authors of publications that met the inclusion criteria to identify trials. SELECTION CRITERIA: We selected randomized controlled trials which investigated the efficacy of an intervention (chemical, surgical or drug) used to restore patency to an occluded CVC lumen, in either adults or children. DATA COLLECTION AND ANALYSIS: Three authors independently assessed those studies that met the inclusion criteria for quality and extracted the relevant data using a standardized form. MAIN RESULTS: No studies were found that investigated the efficacy and safety of either chemical or surgical interventions.Seven studies (eight papers) with a total of 632 participants were identified from the search. They investigated different comparisons, strengths of thrombolytic or anticoagulant drug interventions for treating CVC lumen occlusion thought to be caused by a thrombus.There was low quality evidence from a meta-analysis of two studies suggesting that urokinase (various strengths) was more effective than placebo for restoring patency to occluded CVC lumens in adults and children with underlying medical conditions (relative risk (RR) 2.09, 95% confidence interval (CI) 1.47 to 2.95), with a number needed to treat of 4 (95% CI 2 to 8). There was insufficient evidence to draw conclusions on the safety of urokinase.The overall quality of the evidence provided by these studies was low to very low due to one or more domains being assessed as either at 'unclear risk of bias' or 'high risk of bias'. Furthermore, the total number of participants in these studies was small and consequently may lead to spurious results. AUTHORS' CONCLUSIONS: There is inadequate evidence to draw strong conclusions on the efficacy or safety of the drug interventions included in this review. There is some low quality evidence from a meta-analysis of two studies investigating urokinase (various strengths) and some very low evidence from two single studies investigating alteplase 2 mg/2 mL that suggest that these two drug interventions may be effective in treating withdrawal or total occlusion of CVC lumens caused by thrombosis. Further high quality, sufficiently powered research is still required to look at the efficacy and safety of urokinase, alteplase and other chemical, surgical and drug interventions for treating CVC lumen occlusion. Research studies which exclusively include child participants are especially warranted. PMID- 22513944 TI - Regular treatment with formoterol for chronic asthma: serious adverse events. AB - BACKGROUND: Epidemiological evidence has suggested a link between beta(2) agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long acting beta(2)-agonists are safe. OBJECTIVES: The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular formoterol versus placebo or regular short-acting beta(2)-agonists. SEARCH METHODS: We identified trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol. The date of the most recent search was January 2012. SELECTION CRITERIA: We included controlled, parallel design clinical trials on patients of any age and severity of asthma if they randomised patients to treatment with regular formoterol and were of at least 12 weeks' duration. Concomitant use of inhaled corticosteroids was allowed, as long as this was not part of the randomised treatment regimen. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion in the review. One author extracted outcome data and the second author checked them. We sought unpublished data on mortality and serious adverse events. MAIN RESULTS: The review includes 22 studies (8032 participants) comparing regular formoterol to placebo and salbutamol. Non-fatal serious adverse event data could be obtained for all participants from published studies comparing formoterol and placebo but only 80% of those comparing formoterol with salbutamol or terbutaline.Three deaths occurred on regular formoterol and none on placebo; this difference was not statistically significant. It was not possible to assess disease-specific mortality in view of the small number of deaths. Non-fatal serious adverse events were significantly increased when regular formoterol was compared with placebo (Peto odds ratio (OR) 1.57; 95% CI 1.06 to 2.31). One extra serious adverse event occurred over 16 weeks for every 149 people treated with regular formoterol (95% CI 66 to 1407 people). The increase was larger in children than in adults, but the impact of age was not statistically significant. Data submitted to the FDA indicate that the increase in asthma-related serious adverse events remained significant in patients taking regular formoterol who were also on inhaled corticosteroids.No significant increase in fatal or non-fatal serious adverse events was found when regular formoterol was compared with regular salbutamol or terbutaline. AUTHORS' CONCLUSIONS: In comparison with placebo, we have found an increased risk of serious adverse events with regular formoterol, and this does not appear to be abolished in patients taking inhaled corticosteroids. The effect on serious adverse events of regular formoterol in children was greater than the effect in adults, but the difference between age groups was not significant.Data on all-cause serious adverse events should be more fully reported in journal articles, and not combined with all severities of adverse events or limited to those events that are thought by the investigator to be drug-related. PMID- 22513948 TI - Interventions for the management of temporomandibular joint osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis of the temporomandibular joint (TMJ), and can often lead to severe pain in the orofacial region. Management options for TMJ OA include reassurance, occlusal appliances, physical therapy, medication in addition to several surgical modalities. OBJECTIVES: To investigate the effects of different surgical and non-surgical therapeutic options for the management of TMJ OA in adult patients. SEARCH METHODS: We searched the following databases: the Cochrane Oral Health Group Trials Register (to 26 September 2011); CENTRAL (The Cochrane Library 2011, Issue 3); MEDLINE via OVID (1950 to 26 September 2011); EMBASE via OVID (1980 to 26 September 2011); and PEDro (1929 to 26 September 2011). There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any form of non-surgical or surgical therapy for TMJ OA in adults over the age of 18 with clinical and/or radiological diagnosis of TMJ OA according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) guideline or compatible criteria.Primary outcomes considered were pain/tenderness/discomfort in the TMJs or jaw muscles, self assessed range of mandibular movement and TMJ sounds. Secondary outcomes included the measurement of quality of life or patient satisfaction evaluated with a validated questionnaire, morphological changes of the TMJs assessed by imaging, TMJ sounds assessed by auscultation and any adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors screened and extracted information and data from, and independently assessed the risk of bias in the included trials. MAIN RESULTS: Although three RCTs were included in this review, pooling of data in a meta analysis was not possible due to wide clinical diversity between the studies. The reports indicate a not dissimilar degree of effectiveness with intra-articular injections consisting of either sodium hyaluronate or corticosteroid preparations, and an equivalent pain reduction with diclofenac sodium as compared with occlusal splints. Glucosamine appeared to be just as effective as ibuprofen for the management of TMJ OA. AUTHORS' CONCLUSIONS: In view of the paucity of high level evidence for the effectiveness of interventions for the management of TMJ OA, small parallel group RCTs which include participants with a clear diagnosis of TMJ OA should be encouraged and especially studies evaluating some of the possible surgical interventions. PMID- 22513947 TI - Interventions for preventing excessive weight gain during pregnancy. AB - BACKGROUND: Excessive weight gain during pregnancy is associated with multiple maternal and neonatal complications. However, interventions to prevent excessive weight gain during pregnancy have not been adequately evaluated. OBJECTIVES: To evaluate the effectiveness of interventions for preventing excessive weight gain during pregnancy and associated pregnancy complications. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (20 October 2011) and MEDLINE (1966 to 20 October 2011). SELECTION CRITERIA: All randomised controlled trials and quasi-randomised trials of interventions for preventing excessive weight gain during pregnancy. DATA COLLECTION AND ANALYSIS: We assessed for inclusion all potential studies we identified as a result of the search strategy. At least two review authors independently assessed trial quality and extracted data. We resolved discrepancies through discussion. We have presented results using risk ratio (RR) for categorical data and mean difference for continuous data. We analysed data using a fixed-effect model. MAIN RESULTS: We included 28 studies involving 3976 women; 27 of these studies with 3964 women contributed data to the analyses. Interventions focused on a broad range of interventions. However, for most outcomes we could not combine data in a meta analysis, and where we did pool data, no more than two or three studies could be combined for a particular intervention and outcome. Overall, results from this review were mainly not statistically significant, and where there did appear to be differences between intervention and control groups, results were not consistent. For women in general clinic populations one (behavioural counselling versus standard care) of three interventions examined was associated with a reduction in the rate of excessive weight gain (RR 0.72, 95% confidence interval 0.54 to 0.95); for women in high-risk groups no intervention appeared to reduce excess weight gain. There were inconsistent results for mean weight gain (reported in all but one of the included studies). We found a statistically significant effect on mean weight gain for five interventions in the general population and for two interventions in high-risk groups.Most studies did not show statistically significant effects on maternal complications, and none reported significant effects on adverse neonatal outcomes. AUTHORS' CONCLUSIONS: There is not enough evidence to recommend any intervention for preventing excessive weight gain during pregnancy, due to the significant methodological limitations of included studies and the small observed effect sizes. More high quality randomised controlled trials with adequate sample sizes are required to evaluate the effectiveness of potential interventions. PMID- 22513949 TI - Vitamin D supplementation for cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) is a genetic disorder with multiorgan effects. In a subgroup with pancreatic insufficiency malabsorption of the fat soluble vitamins (A, D, E, K) may occur. Vitamin D is involved in calcium homeostasis and bone mineralisation and may have extraskeletal effects. This review examines the evidence for vitamin D supplementation in CF. OBJECTIVES: To assess the effects of vitamin D supplementation on the frequency of vitamin D deficiency, respiratory outcomes and vitamin D toxicity in the CF population. SEARCH METHODS: We searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 15 February 2012. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of vitamin D supplementation compared to placebo in the CF population regardless of exocrine pancreatic function. DATA COLLECTION AND ANALYSIS: Both authors independently assessed the 'risk of bias' of each included trial and extracted outcome data (from published trial information) for assessment of bone mineralization, growth and nutritional status, frequency of vitamin D deficiency, respiratory status, quality of life and adverse events. MAIN RESULTS: Three studies are included, although only data from two were available (41 adults and children with CF). One of these studies compared supplemental 800 international units (IU) vitamin D and placebo for 12 months in 30 osteopenic pancreatic insufficient adults; both groups continued 900 IU vitamin D daily. The other (abstract only) compared supplemental 1g calcium alone, 1600 IU vitamin D alone, 1600 IU vitamin D and 1g calcium and placebo in a double-blind randomised cross-over trial; only 11 children (vitamin D and placebo groups) after six-months supplementation are included; inclusion criteria, pancreatic sufficiency or disease status of participants are not defined. There were no significant differences in primary or secondary outcomes in either study. The studies are not directly comparable due to differences in supplementation, outcome reporting and possibly participant characteristics (eg severity of lung disease, growth and nutrition, pancreatic sufficiency). There were no adverse events in either study. The third study (abstract only) compared daily calcitriol (0.25 or 0.5 micrograms) with placebo in pancreatic insufficient children and young adults, only pre-intervention data were available. AUTHORS' CONCLUSIONS: There is no evidence of benefit or harm in the limited number of small-sized published trials. Adherence to relevant CF guidelines on vitamin D should be considered until further evidence is available. PMID- 22513950 TI - Botulinum toxin for myofascial pain syndromes in adults. AB - BACKGROUND: Myofascial pain syndrome (MPS) is a regional muscular pain syndrome characterised by the presence of trigger points, which are painful points in one or more muscles. The pain can be felt at the site where the trigger point is located or it can be felt away from that place when the muscle is pressed (referred pain). Botulinum toxin is a protein produced by the bacterium Clostridium botulinum and is a potent neurotoxin that eventually inhibits muscle contractions. It is capable of selectively weakening painful muscles and interrupting the pain cycle. OBJECTIVES: To assess the effectiveness and safety of botulinum toxin in treating MPS, excluding MPS in neck and head muscles. SEARCH METHODS: The search strategy was composed of terms for myofascial pain and botulinum toxin. We searched the Cochrane Pain, Palliative and Supportive Care (PaPaS) Review Group's Specialised Register until December 2011, CENTRAL (Cochrane Database of Systematic Reviews 2011, Issue 4), PUBMED (from 1966 to 2011), EMBASE (from 1980 to 2011) and LILACS (from 1982 to 2011). There was no language restriction. SELECTION CRITERIA: We included randomised controlled trials (RCTs) involving botulinum toxin for treating participants with MPS. We excluded studies with MPS of the neck and head from this review, as they have already been assessed in existing systematic reviews. We considered a diagnosis of MPS to be based on the identification of trigger points in the taut band through palpation of sensitive nodules, local twitch response and specific patterns of referred pain associated with each trigger point. DATA COLLECTION AND ANALYSIS: Two review authors independently screened identified studies, extracted data, assessed trial quality and analysed results using the Cochrane PaPaS Review Group criteria. MAIN RESULTS: Four studies with a total of 233 participants, comparing botulinum toxin A (BTXA) with placebo, met the inclusion criteria. In one study with 145 participants, a significant improvement rate of pain intensity scores, as shown by the mean difference (MD) of -0.23 (95% confidence interval (CI) -0.26 to -0.20; P value < 0.00001) and duration of daily pain (MD -1.11; 95% CI -1.37 to -0.85; P value < 0.00001), was demonstrated when comparing BTXA with placebo. The three other studies showed that there was no statistically significant difference between BTXA and placebo in pain intensity. AUTHORS' CONCLUSIONS: There is inconclusive evidence to support the use of botulinum toxin in the treatment of MPS based on data from four studies with a total of 233 participants, which we considered adequate to be included in this review. Meta analyses were not possible due to the heterogeneity between studies. We suggest that in future studies the same methodology to assess pain, a standardised dose of treatment, follow-up of at least four months (to observe the maximum/minimum curve of the drug effect) and appropriate data presentation should be used. More high-quality RCTs of botulinum toxin for treating MPS need to be conducted before firm conclusions on its effectiveness and safety can be drawn. PMID- 22513951 TI - Glucocorticoids for the treatment of anaphylaxis. AB - BACKGROUND: Anaphylaxis is a serious hypersensitivity reaction that is rapid in onset and may result in death. Anaphylaxis guidelines recommend glucocorticoids for the treatment of people experiencing anaphylaxis. OBJECTIVES: We sought to assess the benefits and harms of glucocorticoid treatment during episodes of anaphylaxis. SEARCH METHODS: In our previous version we searched the literature until September 2009. In this version we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (Ovid) (1956 to September 2011), EMBASE (Ovid) (1982 to September 2011), CINAHL (EBSCOhost) (to September 2011). We also searched the UK National Research Register and websites listing ongoing trials, and contacted international experts in anaphylaxis in an attempt to locate unpublished material. SELECTION CRITERIA: We planned to include randomized and quasi-randomized controlled trials comparing glucocorticoids with any control (either placebo, adrenaline (epinephrine), an antihistamine, or any combination of these). DATA COLLECTION AND ANALYSIS: Two authors independently assessed articles for inclusion. MAIN RESULTS: We found no studies that satisfied the inclusion criteria. AUTHORS' CONCLUSIONS: We are, based on this review, unable to make any recommendations for the use of glucocorticoids in the treatment of anaphylaxis. PMID- 22513952 TI - Aromatherapy for treatment of postoperative nausea and vomiting. AB - BACKGROUND: Postoperative nausea and vomiting is a common and unpleasant phenomenon and current therapies are not always effective for all patients. Aromatherapy has been suggested as a possible addition to the available treatment strategies. OBJECTIVES: This review sought to establish what effect the use of aromatherapy has on the severity and duration of established postoperative nausea and vomiting and whether aromatherapy can be used with safety and clinical effectiveness comparable to standard pharmacological treatments. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3); MEDLINE; EMBASE; CINAHL; CAM on PubMed; Meditext; LILACS; and ISI Web of Science as well as grey literature sources and the reference lists of retrieved articles. We conducted database searches up to August 2011. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) and controlled clinical trials (CCTs) where aromatherapy was used to treat postoperative nausea and vomiting. Interventions were all types of aromatherapy. Aromatherapy was defined as the inhalation of the vapours of any substance for the purposes of a therapeutic benefit. Primary outcomes were the severity and duration of postoperative nausea and vomiting. Secondary outcomes were adverse reactions, use of rescue anti-emetics and patient satisfaction with treatment. DATA COLLECTION AND ANALYSIS: Two review authors assessed risk of bias in the included studies and extracted data. As all outcomes analysed were dichotomous, we used a fixed-effect model and calculated relative risk (RR) with associated 95% confidence interval (95% CI). MAIN RESULTS: The nine included studies comprised six RCTs and three CCTs with a total of 402 participants. The mean age and range data for all participants were not reported for all studies. The method of randomization in four of the six included RCTs was explicitly stated and was adequate. Incomplete reporting of data affected the completeness of the analysis. Compared with placebo, isopropyl alcohol vapour inhalation was effective in reducing the proportion of participants requiring rescue anti-emetics (RR 0.30, 95% CI 0.09 to 1.00, P = 0.05). However, compared with standard anti-emetic treatment, isopropyl alcohol was not effective in reducing the proportion of participants requiring rescue anti-emetics (RR 0.66, 95% CI 0.39 to 1.13, P = 0.13) except when the data from a possibly confounded study were included (RR 0.66, 95% CI 0.45 to 0.98, P = 0.04). Where studies reported data on patient satisfaction with aromatherapy, there were no statistically significant differences between the groups (RR 1.12, 95% CI 0.62 to 2.03, P = 0.71). AUTHORS' CONCLUSIONS: Isopropyl alcohol was more effective than saline placebo for reducing postoperative nausea and vomiting but less effective than standard anti emetic drugs. There is currently no reliable evidence for the use of peppermint oil. PMID- 22513953 TI - Antioxidants and other pharmacological treatments for Friedreich ataxia. AB - BACKGROUND: Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis and pes cavus. Heart abnormalities cause premature death in 60% to 80% of people with the disorder. There is no easily defined clinical or biochemical marker and no known treatment. This is the first update of a review published in 2009. OBJECTIVES: To examine the efficacy of antioxidants and other pharmacological treatments for Friedreich ataxia. SEARCH METHODS: We searched The Cochrane Neuromuscular Disease Group Specialized Register (11 July 2011), CENTRAL (2011, Issue 3), MEDLINE (January 1966 to July 2011), EMBASE (January 1980 to July 2011), AMED (January 1985 to July 2011), CINAHL Plus (January 1937 to July 2011), LILACS (January 1982 to July 2011), ORPHANET (1990 to July 2011), TRIP (1998 to July 2011) and PEDRO (October 1999 to July 2011). SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs of drug treatment in people with genetically confirmed Friedreich ataxia. The primary outcome was change in ataxia rating scale as measured by the International Co-operative Ataxia Rating Scale (ICARS) after 12 months. Secondary outcomes included change in left ventricular heart mass as measured by magnetic resonance imaging or echocardiography. We excluded trials of shorter duration than 12 months. DATA COLLECTION AND ANALYSIS: Three authors selected the trials and two authors extracted data. We obtained missing data from the one RCT that met our inclusion criteria. We planned to collect adverse event data from included studies. MAIN RESULTS: More than 10 studies used idebenone in the treatment of Friedreich ataxia but only one small RCT, with 29 participants, using the synthetic antioxidant idebenone 5 mg/kg, fulfilled the selection criteria for this review. Other RCTs were of insufficient duration. We identified no additional RCT when the searches were updated in 2011. In the included study, the primary outcome specified for this review, change in ICARS scale, did not reveal any significant differences with idebenone treatment compared to placebo. The secondary outcome of change in left ventricular heart mass index as measured by magnetic resonance spectroscopy was not assessed. The second secondary outcome, change in left ventricular mass as measured by echocardiography, did improve significantly; there was a 10.7% worsening after 12 months of treatment in the placebo group and a 5.6% improvement in the idebenone group. The mean difference was 16.37% (95% CI 95% 2% to 31%). There were no adverse events. We considered the included study at low risk of bias in five of the seven domains assessed. A larger trial using idebenone published an interm report in May 2010 stating that the study had failed to reach its primary endpoint, which was change in the ICARS scale. AUTHORS' CONCLUSIONS: No RCT using idebenone or any other pharmacological treatment has shown significant benefit on neurological symptoms associated with Friedreich ataxia. Idebenone has shown a positive effect on left ventricular heart mass but the clinical relevance of this change was not assessed in the included study. PMID- 22513954 TI - Interventions for treating acute elbow dislocations in adults. AB - BACKGROUND: Dislocation of the elbow joint is a relatively uncommon injury. OBJECTIVES: To assess the effects of various forms of treatment for acute simple elbow dislocations in adults. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (April 2011), the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2011 Issue 1), MEDLINE (1948 to March Week 5 2011), EMBASE (1980 to 2011 Week 14), PEDro (April 2011), CINAHL (April 2011), various trial registers, various conference proceedings and bibliographies of relevant articles. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of conservative and surgical treatment of dislocations of the elbow in adults. Excluded were trials involving dislocations with associated fractures, except for avulsion fractures. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of risk of bias were independently performed by two review authors. There was no pooling of data. MAIN RESULTS: Two small randomised controlled trials, involving a total of 80 participants with simple elbow dislocations, were included. Both trials were methodologically flawed and potentially biased.One trial, involving 50 participants, compared early mobilisation at three days post reduction versus cast immobilisation. At one year follow-up, the recovery of range of motion appeared better in the early mobilisation group (e.g. participants with incomplete recovery of extension: 1/24 versus 5/26; risk ratio 0.22, 95% confidence interval 0.03 to 1.72). However, the results were not statistically significant. There were no reports of instability or recurrence. One person in each group had residual pain at one year.The other trial, involving 30 participants, compared surgical repair of the torn ligaments versus conservative treatment (cast immobilisation for two weeks). At final follow-up (mean 27.5 months), there were no statistically significant differences between the two groups in the numbers of patients who considered their injured elbow to be inferior to their non-injured elbow (10/14 versus 7/14; RR 1.43, 95% CI 0.77 to 2.66) or in other patient complaints about their elbow such as weakness, pain or weather-related discomfort. There were no reports of instability or recurrence. There were no statistically significant differences between the two groups in range of motion of the elbow (extension, flexion, pronation, and supination) or grip strength at follow-up. No participants had neurological disturbances of the hand but two surgical group participants had recurrent dislocation of the ulnar nerve (no other details provided). One person in each group had radiologically detected myositis ossificans (bone formation within muscles following injury). AUTHORS' CONCLUSIONS: There is insufficient evidence from randomised controlled trials to determine which method of treatment is the most appropriate for simple dislocations of the elbow in adults. Although weak and inconclusive, the available evidence from a trial comparing surgery versus conservative treatment does not suggest that the surgical repair of elbow ligaments for simple elbow dislocation improves long-term function. Future research should focus on questions relating to non-surgical treatment, such as the duration of immobilisation. PMID- 22513955 TI - Fermented milk for hypertension. AB - BACKGROUND: Fermented milk has been suggested to have a blood pressure lowering effect through increased content of proteins and peptides produced during the bacterial fermentation. Hypertension is one of the major risk factors for cardiovascular disease world wide and new blood pressure reducing lifestyle interventions, such as fermented milk, would be of great importance. OBJECTIVES: To investigate whether fermented milk or similar products produced by lactobacilli fermentation of milk proteins has any blood pressure lowering effect in humans when compared to no treatment or placebo. SEARCH METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), English language databases, including MEDLINE (1966-2011), EMBASE (1974-2011), Cochrane Complementary Medicine Trials Register, Allied and Complementary Medicine (AMED) (1985-2011), Food science and technology abstracts (1969-2011). SELECTION CRITERIA: Randomised controlled trials; cross over and parallel studies evaluating the effect on blood pressure of fermented milk in humans with an intervention period of 4 weeks or longer. DATA COLLECTION AND ANALYSIS: Data was extracted individually by two authors, afterwards agreement had to be obtained before imputation in the review. MAIN RESULTS: A modest overall effect of fermented milk on SBP was found (MD 2.45; 95% CI -4.30 to -0.60), no effect was evident on DBP (MD -0.67; 95% CI 1.48, 0.14). AUTHORS' CONCLUSIONS: The review does not support an effect of fermented milk on blood pressure. Despite the positive effect on SBP the authors conclude, for several reasons, that fermented milk has no effect on blood pressure. The effect found was very modest and only on SBP, the included studies were very heterogeneous and several with weak methodology. Finally, sensitivity and subgroup analyses could not reproduce the antihypertensive effect. The results do not give notion to the use of fermented milk as treatment for hypertension or as a lifestyle intervention for pre-hypertension nor would it influence population blood pressure. PMID- 22513956 TI - Daclizumab for relapsing remitting multiple sclerosis. AB - BACKGROUND: The anti-CD25 treatment of daclizumab appears to be effective in patients with relapsing remitting multiple sclerosis (RRMS) as regards clinical and MRI outcomes. Moreover, there are no severe safety concerns arising from clinical testing so far. OBJECTIVES: To assess the efficacy and safety of daclizumab for the clinical progression of patients with relapsing remitting multiple sclerosis. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's Trials Register (February 2012), MEDLINE (January 1966 to February 2012), EMBASE (January 1985 to February 2012). At the same time, we handsearched the references quoted in the identified trials reports (February 2012) from the most important neurological associations and MS Societies. Contacts with researchers participating in trials on daclizumab have been established. SELECTION CRITERIA: All randomized controlled clinical trials (RCTs) evaluating daclizumab, alone or combined with other treatments versus placebo, or any other treatment for patients with RRMS. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed references retrieved for possible inclusion. Disagreements regarding inclusion were resolved by consensus. We contacted study authors for additional information. We collected adverse effects information from the trials. MAIN RESULTS: We identified 470 references from all electronic databases searched excluding duplicate. After screening of titles and abstracts, full papers of 10 studies were obtained and assessed for eligibility. An additional ongoing trial was found. Only one trial (230 participants) evaluating the efficacy of daclizumab versus placebo in interferon beta treated patients was included. It was judged as of high quality study. No significant difference was found in the expanded disability score changes and the annualised relapse rate comparing treated versus placebo groups. No significant difference of common adverse events was found across all the groups at the endpoint. The mean number of new or enlarged gadolinium contrast-enhancing lesions was significantly decreased in the interferon beta and high-dose daclizumab group, compared with that in the interferon beta and placebo group. AUTHORS' CONCLUSIONS: Daclizumab is well tolerated in combination with interferon beta treated multiple sclerosis population. Comparing with placebo, high-dose daclizumab can significantly decreased the number of new or enlarged gadolinium contrast-enhancing lesions. However, the evidence of recommendation is insufficient. More well-designed RCTs or crossover controlled trials are required to evaluate the efficacy and safety of daclizumab. PMID- 22513957 TI - Prophylactic antibiotics to reduce morbidity and mortality in newborn infants with intercostal catheters. AB - BACKGROUND: Intercostal catheters are commonly used for the drainage of intrathoracic collections in newborn infants, including pneumothorax and pleural effusions. Placement of an intercostal drain is a potential risk factor for nosocomial infection due to breach of the cutaneous barrier. Therefore, neonates who require intercostal drainage, especially those in high risk groups for nosocomial infection, may benefit from antibiotic prophylaxis. However, injudicious antibiotic use carries the risk of promoting the emergence of resistant strains of micro-organisms or of altering the pattern of pathogens causing infection. OBJECTIVES: To determine the effect of prophylactic antibiotics compared to selective use of antibiotics on mortality and morbidity (especially septicaemia) in neonates undergoing placement of an intercostal catheter. SEARCH METHODS: The standard search strategy of the Cochrane Neonatal Review Group was used to search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 5), MEDLINE (1948 to June 2011) and CINAHL (1982 to June 2011). SELECTION CRITERIA: Randomised controlled trials or some types of non-randomised (that is, quasi-randomised) controlled trials of adequate quality in which either individual newborn infants or clusters of infants were randomised to receive prophylactic antibiotics versus placebo or no treatment. DATA COLLECTION AND ANALYSIS: We used the standard methods of the Cochrane Neonatal Review Group. MAIN RESULTS: We did not find any randomised controlled trials that met the eligibility criteria. AUTHORS' CONCLUSIONS: There are no data from randomised trials to either support or refute the use of antibiotic prophylaxis for intercostal catheter insertion in neonates. Any randomised controlled trials of antibiotic prophylaxis would need to account for the fact that neonates who require insertion of an intercostal catheter may already be receiving antibiotics for other indications. PMID- 22513958 TI - Pycnogenol(r) (extract of French maritime pine bark) for the treatment of chronic disorders. AB - BACKGROUND: Oxidative stress has been implicated in the development of a number of conditions including cancer, arthritic disorders and cardiovascular disease. Pycnogenol((r)), a herbal dietary supplement derived from French maritime pine bark extract, is standardised to contain 70% procyanidin which is a powerful antioxidant. Pycnogenol((r)) is marketed as a supplement for preventing or treating a wide range of chronic conditions. OBJECTIVES: To assess the efficacy and safety of Pycnogenol((r)) for the treatment of chronic disorders. SEARCH METHODS: We searched CENTRAL (until 18 September 2010), MEDLINE (until 18 September 2010) and EMBASE (until 13 October 2010) as well as three trial registries. We also contacted the manufacturer of Pycnogenol((r)) and hand searched bibliographies of included studies. SELECTION CRITERIA: Randomised controlled trials evaluating the effectiveness of Pycnogenol((r)) in adults or children with any chronic disorder were included. We assessed clinical outcomes directly related to the disorder (stratified as participant- and investigator reported) and all-cause mortality as primary outcomes. We also assessed adverse events and biomarkers of oxidative stress. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, extracted all data and assessed risk of bias. A third author additionally extracted information on outcomes and results. With three exceptions, results for outcomes across studies could not be pooled. MAIN RESULTS: This review includes 15 trials with a total of 791 participants that have evaluated Pycnogenol((r)) for the treatment of seven different chronic disorders. These included asthma (two studies; N = 86), attention deficit hyperactivity disorder (one study; N = 61), chronic venous insufficiency (two studies; N = 60), diabetes mellitus (four studies; N = 201), erectile dysfunction (one study; N = 21), hypertension (two studies; N = 69) and osteoarthritis (three studies; N = 293). Two of the studies were conducted exclusively in children; the others involved adults.Due to small sample size, limited numbers of trials per condition, variation in outcomes evaluated and outcome measures used, as well as the risk of bias in the included studies, no definitive conclusions regarding the efficacy or safety of Pycnogenol((r)) are possible. AUTHORS' CONCLUSIONS: Current evidence is insufficient to support Pycnogenol((r)) use for the treatment of any chronic disorder. Well-designed, adequately powered trials are needed to establish the value of this treatment. PMID- 22513959 TI - Preoperative statin therapy for patients undergoing cardiac surgery. AB - BACKGROUND: Patients referred to cardiac surgery for cardiovascular disease are at significant risk for the development of post-operative major adverse events despite significant advances in surgical techniques and perioperative care. Statins (HMG-CoA reductase inhibitors) have gained a pivotal role in the primary and secondary prevention of coronary artery disease, and are thought to improve perioperative outcomes in patients undergoing cardiac surgery. OBJECTIVES: To determine the effectiveness of a preoperative statin therapy in patients undergoing cardiac surgery. SEARCH METHODS: We searched CENTRAL (Issue 2 of 4, 2010 on The Cochrane Library), MEDLINE (1950 to May, Week 1 2010), EMBASE (1980 to 2010 Week 19), and the metaRegister of Controlled Trials. Additionally, ongoing trials were searched through the National Research Register, the ClinicalTrials.gov registry and grey literature. Conference indices from relevant scientific meetings (2006-2009) were screened online for eligible trials. No language restrictions were applied. SELECTION CRITERIA: All randomized controlled trials comparing any statin treatment before cardiac surgery, for any given duration and dose, to no preoperative statin therapy (standard of care) or placebo. DATA COLLECTION AND ANALYSIS: Two authors evaluated trial quality and extracted data from titles and abstracts identified from the electronic database searches according to pre-defined criteria. Accordingly, full text articles of potentially relevant studies that met the inclusion criteria were retrieved to assess definite eligibility for inclusion. Effect measures are reported as odds ratios (OR) or weighted mean difference (WMD) with 95% confidence intervals (95% CI). MAIN RESULTS: Eleven randomized controlled studies including a total of 984 participants undergoing on- or off-pump cardiac surgical procedures were identified. Pooled analysis showed that statin pre-treatment before surgery reduced the incidence of post-operative atrial fibrillation (AF) (OR 0.40; 95% CI: 0.29 to 0.55; p<0.01), but failed to influence short-term mortality (OR 0.98, 95%-CI: 0.14 to 7.10; p=0.98) or post-operative stroke (OR 0.70, 95%-CI: 0.14 to 3.63; p=0.67). In addition, statin therapy was associated with a shorter length of stay of patients on the intensive care unit (ICU) (WMD: -3.39 hours; 95%-CI: 5.77 to -1.01) and in-hospital (WMD: -0.48 days; 95%-CI: -0.85 to -0.11) where significant heterogeneity was observed. There was no reduction in myocardial infarction (OR 0.52; 95%-CI: 0.2. to 1.30) or renal failure (OR 0.41; 95%-CI: 0.15 to 1.12). These results were unaffected after subgroup analysis. No major or minor perioperative statin side-effects were reported from trials investigating this safety endpoint. AUTHORS' CONCLUSIONS: Preoperative statin therapy reduces the odds of post-operative AF and shortens the stay on the ICU and in the hospital. Statin pretreatment had no influence on perioperative mortality, stroke, myocardial infarction or renal failure. Since analysed studies included mainly patients undergoing myocardial revascularizations the results cannot be extrapolated to patients undergoing other cardiac procedures such as heart valve or aortic surgery. PMID- 22513960 TI - Interventions for congenital talipes equinovarus (clubfoot). AB - BACKGROUND: Congenital talipes equinovarus (CTEV), which is also known as clubfoot, is a common congenital orthopaedic condition. It is characterised by an excessively turned in foot (equinovarus) and high medial longitudinal arch (cavus). If left untreated it can result in long-term disability, deformity and pain. Interventions can be conservative (such as splinting or stretching) or surgical. OBJECTIVES: To evaluate the effectiveness of interventions for CTEV. SEARCH METHODS: We searched CENTRAL (2011, Issue 2), NHSEED (2011, Issue 2), MEDLINE (January 1966 to April 2011), EMBASE (January 1980 to April 2011), CINAHL Plus (January 1937 to April 2011), AMED (1985 to April 2011) and the Physiotherapy Evidence Database (PEDro to April 2011). We checked the references of included studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials evaluating interventions for CTEV. Participants were people of all ages with CTEV of either one or both feet. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias in included trials and extracted the data. We contacted authors of included trials for missing information. We collected adverse event information from trials when it was available. MAIN RESULTS: We identified 13 trials in which there were 507 participants. The use of different outcome measures prevented pooling of data for meta-analysis even when interventions and participants were comparable. All trials displayed bias in four or more areas. One trial reported on the primary outcome of function, though raw data were not available to be analysed. We were able to analyse data on foot alignment (Pirani score), a secondary outcome, from three trials. The Pirani score is scored from zero to six, in which higher is worse. Two of the trials involved participants at initial presentation. One of them reported that the Ponseti technique significantly improved foot alignment compared to the Kite technique. After 10 weeks of serial casting, the average total Pirani score of the Ponseti group was 1.15 (95% confidence interval 0.98 to 1.32) lower than that of the Kite group. The second trial found the Ponseti technique to be superior to a traditional technique, with average total Pirani scores of the Ponseti participants 1.50 lower (95% confidence interval 0.72 to 2.28) after serial casting and Achilles tenotomy. A trial in which the type of presentation was not reported found no difference between an accelerated Ponseti or standard Ponseti treatment. At the end of serial casting, the average total Pirani scores in the standard group were 0.31 lower (95% confidence interval -0.40 to 1.02) than the accelerated group. Adverse events were not compared in the trial. There is a lack of evidence for different plaster casting products or the addition of botulinum toxin A during the Ponseti technique. There is also a lack of evidence for different types of major foot surgery for CTEV, continuous passive motion treatment following major foot surgery, or treatment of relapsed or neglected cases of CTEV. Most trials did not report on adverse events. In trials evaluating serial casting techniques, adverse events included cast slippage (needing replacement), plaster sores (pressure areas) and skin irritation. Adverse events following surgical procedures included infection and the need for skin grafting. AUTHORS' CONCLUSIONS: From the limited evidence available, the Ponseti technique may produce better short-term outcomes compared to the Kite technique. An accelerated Ponseti technique may be as effective as a standard technique. We could draw no conclusions from other included trials because of the limited use of validated outcome measures and lack of available raw data. Future randomised controlled trials should address these issues. PMID- 22513961 TI - Thalidomide for managing cancer cachexia. AB - BACKGROUND: Cancer cachexia is a multidimensional syndrome characterised by wasting, loss of weight, loss of appetite, metabolic alterations, fatigue and reduced performance status. A significant number of patients with advanced cancer develop cachexia before death. There is no identified optimum treatment for cancer cachexia. While the exact mechanism of the action of thalidomide is unclear, it is known to have immunomodulatory and anti-inflammatory properties, which are thought to help reduce the weight loss associated with cachexia. Preliminary studies of thalidomide have demonstrated encouraging results. OBJECTIVES: This review aimed to (1) evaluate the effectiveness of thalidomide, and (2) identify and assess adverse effects from thalidomide for cancer cachexia. SEARCH METHODS: Electronic searches were undertaken in CENTRAL, MEDLINE, EMBASE, Web of Science and CINAHL (from inception to April 2011). Reference lists from reviewed articles, trial registers, relevant conference documents and thalidomide manufacturers identified additional literature. SELECTION CRITERIA: This review included randomised controlled trials (RCTs) and non-RCTs. Participants were adults diagnosed with advanced or incurable cancer and weight loss or a clinical diagnosis of cachexia who were administered thalidomide. DATA COLLECTION AND ANALYSIS: All titles and abstracts retrieved by electronic searching were downloaded to a reference management database. Duplicates were removed and the remaining citations were read by two review authors and checked for eligibility. Studies that were deemed ineligible for inclusion had clear reasons for exclusion documented. Data were extracted independently by two review authors for all eligible studies. While a meta-analysis was planned for this review, this was not possible due to the small number of studies included and high heterogeneity among them. Thus a narrative synthesis of the findings is presented. MAIN RESULTS: The literature search revealed a dearth of large, well conducted trials in this area. This has hindered the review authors' ability to make an informed decision about thalidomide for the management of cancer cachexia. At present, there is insufficient evidence to refute or support the use of thalidomide for the management of cachexia in advanced cancer patients. AUTHORS' CONCLUSIONS: The review authors cannot confirm or refute previous literature on the use of thalidomide for patients with advanced cancer who have cachexia and there is inadequate evidence to recommend it for clinical practice. Additional, well conducted, large RCTs are needed to test thalidomide both singularly and in combination with other treatment modalities to ascertain its true benefit, if any, for this population. Furthermore, one study (out of the three reviewed) highlighted that thalidomide was poorly tolerated and its use needs to be explored further in light of the frailty of this population. PMID- 22513962 TI - Modifications of the Epley (canalith repositioning) manoeuvre for posterior canal benign paroxysmal positional vertigo (BPPV). AB - BACKGROUND: Benign paroxsymal positional vertigo (BPPV) is a syndrome characterised by short-lived episodes of vertigo associated with rapid changes in head position. It is a common cause of vertigo presenting to primary care and specialist otolaryngology (ENT) clinics. BPPV of the posterior canal is a specific type of BPPV for which the Epley (canalith repositioning) manoeuvre is a verified treatment. A range of modifications of the Epley manoeuvre are used in clinical practice, including post-Epley vestibular exercises and post-Epley postural restrictions. OBJECTIVES: To assess whether the various modifications of the Epley manoeuvre for posterior canal BPPV enhance its efficacy in clinical practice. SEARCH METHODS: We searched the Cochrane ENT Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 15 December 2011. SELECTION CRITERIA: Randomised controlled trials of modifications of the Epley manoeuvre versus a standard Epley manoeuvre as a control in adults with posterior canal BPPV diagnosed with a positive Dix Hallpike test. Specific modifications sought were: application of vibration/oscillation to the mastoid region, vestibular rehabilitation exercises, additional steps in the Epley manoeuvre and post-treatment instructions relating to movement restriction. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies from the search results and the third author reviewed and resolved any disagreement. Two authors independently extracted data from the studies using standardised data forms. All authors independently assessed the trials for risk of bias. MAIN RESULTS: The review includes 11 trials involving 855 participants. A total of nine studies used post-Epley postural restrictions as their modification of the Epley manoeuvre. There was no evidence of a difference in the results for post-treatment vertigo intensity or subjective assessment of improvement in individual or pooled data. All nine trials included the conversion of a positive to a negative Dix-Hallpike test as an outcome measure. Pooled data identified a significant difference from the addition of postural restrictions in the frequency of Dix-Hallpike conversion when compared to the Epley manoeuvre alone. In the experimental group 88.7% (220 out of 248) patients versus 78.2% (219 out of 280) in the control group converted from a positive to negative Dix-Hallpike test (risk ratio (RR) 1.13, 95% confidence interval (CI) 1.05 to 1.22, P = 0.002). No serious adverse effects were reported, however three studies reported minor complications such as neck stiffness, horizontal BPPV, dizziness and disequilibrium in some patients.There was no evidence of benefit of mastoid oscillation applied during the Epley manoeuvre, or of additional steps in the Epley manoeuvre. No adverse effects were reported. AUTHORS' CONCLUSIONS: There is evidence supporting a statistically significant effect of post-Epley postural restrictions in comparison to the Epley manoeuvre alone. However, it important to note that this statistically significant effect only highlights a small improvement in treatment efficacy. An Epley manoeuvre alone is effective in just under 80% of patients with typical BPPV. The additional intervention of postural restrictions has a number needed to treat (NNT) of 10. The addition of postural restrictions does not expose the majority of patients to risk of harm, does not pose a major inconvenience, and can be routinely discussed and advised. Specific patients who experience discomfort due to wearing a cervical collar and inconvenience in sleeping upright may be treated with the Epley manoeuvre alone and still expect to be cured in most instances.There is insufficient evidence to support the routine application of mastoid oscillation during the Epley manoeuvre, or additional steps in an 'augmented' Epley manoeuvre. Neither treatment is associated with adverse outcomes. Further studies should employ a rigorous randomisation technique, blinded outcome assessment, a post-treatment Dix-Hallpike test as an outcome measure and longer-term follow-up of patients. PMID- 22513963 TI - Anaesthesia for evacuation of incomplete miscarriage. AB - BACKGROUND: An incomplete miscarriage occurs when all the products of conception are not expelled through the cervix. Curettage or vacuum aspiration have been used to remove retained tissues. The anaesthetic techniques used to facilitate this procedure have not been systematically evaluated in order to determine which provide better outcomes to the patients. OBJECTIVES: To assess the effects of general anaesthesia, sedation or analgesia, regional or paracervical block anaesthetic techniques, or differing regimens of these, for surgical evacuation of incomplete miscarriage. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (23 January 2012), CENTRAL (The Cochrane Library 2012, Issue 1), PubMed (1966 to 23 January 2012), EMBASE (1974 to 23 January 2012), CINAHL (1982 to 23 January 2012), LILACS (1982 to 23 January 2012) and reference lists of retrieved studies. SELECTION CRITERIA: All published and unpublished randomised controlled trials (RCTs) or cluster-RCTs comparing the use of any anaesthetic technique (defined by authors as general anaesthesia, sedation/analgesia, regional or paracervical local block (PCB) procedures) to perform surgical evacuation of an incomplete miscarriage. We excluded quasi randomised trials and studies that were only available as abstracts. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and assessed risk of bias. Data were independently extracted and checked for accuracy. MAIN RESULTS: We included seven trials involving 800 women. The comparisons revealed a very high clinical heterogeneity. As a result of the heterogeneity in the randomisation unit, we did not combine trials but reported the individual trial results in the 'Data and analysis' section and in the text. Half of trials have unclear or high risk of bias in several domains.We did not find any trial reporting data about maternal mortality. In terms of postoperative pain, PCB does not improve the control of postoperative pain when it is compared against sedation/analgesia or versus no anaesthesia/no analgesia. In the comparison of PCB with lidocaine versus PCB with saline solution, significant differences favouring the group with lidocaine were found in one trial (moderate or severe postoperative pain) (risk ratio (RR) 0.32; 95% confidence interval (CI) 0.18 to 0.59).When opioids were used, postoperative nausea and vomiting was more frequent in two trials comparing those versus PCB. In terms of requirement of blood transfusion, two trials showed conflicting results. AUTHORS' CONCLUSIONS: Particular considerations that influence the choice of anaesthesia for this procedure such as availability, effectiveness, safety, side effects, practitioner's choice, costs and woman's preferences of each technique should continue to be used until more evidence supporting the use of one technique or another. PMID- 22513964 TI - Exercise interventions for shoulder dysfunction in patients treated for head and neck cancer. AB - BACKGROUND: Shoulder dysfunction is a common problem in patients treated for head and neck cancer. Both neck dissections and radiotherapy can cause morbidity to the shoulder joint. Exercise interventions have been suggested as a treatment option for this population. OBJECTIVES: To evaluate the effectiveness and safety of exercise interventions for the treatment of shoulder dysfunction caused by the treatment of head and neck cancer. SEARCH METHODS: We searched the Cochrane ENT Group Trials Register; CENTRAL; PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ISRCTN and additional sources for published and unpublished trials. The date of the search was 7 July 2011. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing any type of exercise therapy compared with any other intervention in patients with shoulder dysfunction due to treatment of head and neck cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed risk of bias and extracted data from studies. We contacted study authors for information not provided in the published articles. MAIN RESULTS: Three trials involving 104 people were included. We classified one study as having low risk of bias; the others had some limitations and we classified them as having high risk of bias.Two studies (one with low risk of bias and the other with high risk of bias) applied progressive resistance training (PRT) combined with range of motion exercises and stretching; the comparison group received standard care. Pooled data demonstrated that PRT can improve shoulder pain (mean difference (MD) -6.26; 95% confidence interval (CI) -12.20 to -0.31) and shoulder disability (MD -8.48; 95% CI -15.07 to -1.88), both measured using the Shoulder Pain and Disability Index (SPADI) (range 0 to 100). Similarly, secondary outcomes were also improved: active range of motion for external rotation (MD 14.51 degrees; 95% CI 7.87 to 21.14), passive range of motion for abduction (MD 7.65 degrees; 95% CI 0.64 to 14.66), forward flexion (MD 6.20 degrees; 95% CI 0.69 to 11.71), external rotation (MD 7.17 degrees; 95% CI 2.20 to 12.14) and horizontal abduction (MD 7.34 degrees; 95% CI 2.86 to 11.83). Strength and resistance of scapular muscles was assessed in one study and the results showed a statistically significant benefit of PRT. The studies did not demonstrate a statistically significant difference in quality of life. Only two non-serious adverse events were described in the PRT group compared with none in the standard care group.One study with high risk of bias used a broad spectrum of techniques including free active exercises, stretching and postural care for a period of three months following surgery. This study did not demonstrate a difference between the exercise group and routine postoperative physiotherapy care in shoulder function and quality of life, but serious methodological limitations could explain this. No serious adverse events were reported. AUTHORS' CONCLUSIONS: Limited evidence from two RCTs demonstrated that PRT is more effective than standard physiotherapy treatment for shoulder dysfunction in patients treated for head and neck cancer, improving pain, disability and range of motion of the shoulder joint, but it does not improve quality of life. However, although statistically significant the measured benefits of the intervention may be small. Other exercise regimes were not shown to be effective compared to routine postoperative physiotherapy. Further studies which apply other exercise interventions in head and neck cancer patients in the early postoperative and radiotherapy period are needed, with long term follow-up. PMID- 22513965 TI - Antifibrinolytic therapy to reduce haemoptysis from any cause. AB - BACKGROUND: Haemoptysis is a common pathology around the world, occurring with more frequency in low-income countries. It has different etiologies, many of which have infectious characteristics. Antifibrinolytic agents are commonly used to manage bleeding from different sources, but their usefulness in pulmonology is unclear. OBJECTIVES: To evaluate the effectiveness and safety of antifibrinolytic agents in reducing the volume and duration of haemoptysis in adult and paediatric patients. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effects (DARE) in The Cochrane Library, EMBASE and LILACS for publications that describe randomized controlled trials (RCTs) of antifibrinolytic therapy in patients presenting with haemoptysis. We also performed an independent search in MEDLINE for relevant trials not yet included in CENTRAL or DARE.We conducted electronic and manual searches of relevant national and international journals.We reviewed the reference lists of included studies to locate relevant randomized controlled trials (RCTs). An additional search was carried out to find unpublished RCTs. SELECTION CRITERIA: We included RCTs designed to evaluate the effectiveness and safety of antifibrinolytic agents in reducing haemoptysis in adult and paediatric patients of both genders presenting with haemoptysis of any etiology and severity. The intervention of interest was the administration of antifibrinolytic agents compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: All reviewers independently assessed methodological quality and extracted data tables pre-designed for this review. MAIN RESULTS: We found two randomized controlled trials which met the inclusion criteria: Tscheikuna 2002 (via electronic searches) and Ruiz 1994 (via manual searches). We did not exclude any of the relevant studies we found.Tscheikuna 2002, a double-blind RCT performed in Thailand, evaluated the effectiveness of tranexamic acid (TXA, an antifibrinolytic agent) administered orally in 46 hospital in- and outpatients with haemoptysis of various etiologies. Ruiz 1994, a double-blind RCT performed in Peru, evaluated the effectiveness of intravenous TXA in 24 hospitalised patients presenting with haemoptysis secondary to tuberculosis.Pooled together, results demonstrated a significant reduction in bleeding time between patients receiving TXA and patients receiving placebo with a weighted mean difference (WMD) of -19.47 (95% CI -26.90 to -12.03 hours), but with high heterogeneity (I2 = 52%). TXA did not affect remission of haemoptysis evaluated at seven days after the start of treatment. Adverse effects caused by the drug's mechanism of action were not reported. There was no significant difference in the incidence of mild side effects between active and placebo groups (OR 3.13, 95% CI 0.80 to 12.24). AUTHORS' CONCLUSIONS: There is insufficient evidence to judge whether antifibrinolytics should be used to treat haemoptysis from any cause, though limited evidence suggests they may reduce the duration of bleeding. PMID- 22513967 TI - Manual small incision cataract surgery (MSICS) with posterior chamber intraocular lens versus extracapsular cataract extraction (ECCE) with posterior chamber intraocular lens for age-related cataract. AB - BACKGROUND: Age-related cataract is the opacification of the lens, which occurs as a result of denaturation of lens proteins. Age-related cataract remains the leading cause of blindness globally, except in the most developed countries. A key question is what is the best way of removing the lens, especially in lower income settings. OBJECTIVES: To compare two different techniques of lens removal in cataract surgery: manual small incision surgery (MSICS) and extracapsular cataract extraction (ECCE). SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 1), MEDLINE (January 1950 to February 2012), EMBASE (January 1980 to February 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to February 2012), Web of Science Conference Proceedings Citation Index- Science (CPCI-S), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 14 February 2012. SELECTION CRITERIA: We included randomised controlled trials (RCTs) only. Participants in the trials were people with age-related cataract. We included trials where MSICS with a posterior chamber intraocular lens (IOL) implant was compared to ECCE with a posterior chamber IOL implant. DATA COLLECTION AND ANALYSIS: Data were collected independently by two authors. We aimed to collect data on presenting visual acuity 6/12 or better and best corrected visual acuity of less than 6/60 at three months and one year after surgery. Other outcomes included intraoperative complications, long-term complications (one year or more after surgery), quality of life, and cost effectiveness. There were not enough data available from the included trials to perform a meta-analysis. MAIN RESULTS: Three trials randomly allocating people with age-related cataract to MSICS or ECCE were included in this review (n = 953 participants). Two trials were conducted in India and one in Nepal. Trial methods, such as random allocation and allocation concealment, were not clearly described; in only one trial was an effort made to mask outcome assessors. The three studies reported follow-up six to eight weeks after surgery. In two studies, more participants in the MSICS groups achieved unaided visual acuity of 6/12 or 6/18 or better compared to the ECCE group, but overall not more than 50% of people achieved good functional vision in the two studies. 10/806 (1.2%) of people enrolled in two trials had a poor outcome after surgery (best-corrected vision less than 6/60) with no evidence of difference in risk between the two techniques (risk ratio (RR) 1.58, 95% confidence interval (CI) 0.45 to 5.55). Surgically induced astigmatism was more common with the ECCE procedure than MSICS in the two trials that reported this outcome. In one study there were more intra- and postoperative complications in the MSICS group. One study reported that the costs of the two procedures were similar. AUTHORS' CONCLUSIONS: There are no other studies from other countries other than India and Nepal and there are insufficient data on cost-effectiveness of each procedure. Better evidence is needed before any change may be implemented. Future studies need to have longer term follow-up and be conducted to minimize biases revealed in this review with a larger sample size to allow examination of adverse events. PMID- 22513966 TI - Cognitive behaviour therapy versus other psychosocial treatments for schizophrenia. AB - BACKGROUND: Cognitive behavioural therapy (CBT) is now a recommended treatment for people with schizophrenia. This approach helps to link the person's distress and problem behaviours to underlying patterns of thinking. OBJECTIVES: To review the effects of CBT for people with schizophrenia when compared with other psychological therapies. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (March 2010) which is based on regular searches of CINAHL, EMBASE, MEDLINE and PsycINFO. We inspected all references of the selected articles for further relevant trials, and, where appropriate, contacted authors. SELECTION CRITERIA: All relevant randomised controlled trials (RCTs) of CBT for people with schizophrenia-like illnesses. DATA COLLECTION AND ANALYSIS: Studies were reliably selected and assessed for methodological quality. Two review authors, working independently, extracted data. We analysed dichotomous data on an intention-to-treat basis and continuous data with 65% completion rate are presented. Where possible, for dichotomous outcomes, we estimated a risk ratio (RR) with the 95% confidence interval (CI) along with the number needed to treat/harm. MAIN RESULTS: Thirty papers described 20 trials. Trials were often small and of limited quality. When CBT was compared with other psychosocial therapies, no difference was found for outcomes relevant to adverse effect/events (2 RCTs, n = 202, RR death 0.57 CI 0.12 to 2.60). Relapse was not reduced over any time period (5 RCTs, n = 183, RR long-term 0.91 CI 0.63 to 1.32) nor was rehospitalisation (5 RCTs, n = 294, RR in longer term 0.86 CI 0.62 to 1.21). Various global mental state measures failed to show difference (4 RCTs, n = 244, RR no important change in mental state 0.84 CI 0.64 to 1.09). More specific measures of mental state failed to show differential effects on positive or negative symptoms of schizophrenia but there may be some longer term effect for affective symptoms (2 RCTs, n = 105, mean difference (MD) Beck Depression Inventory (BDI) -6.21 CI -10.81 to -1.61). Few trials report on social functioning or quality of life. Findings do not convincingly favour either of the interventions (2 RCTs, n = 103, MD Social Functioning Scale (SFS) 1.32 CI -4.90 to 7.54; n = 37, MD EuroQOL -1.86 CI -19.20 to 15.48). For the outcome of leaving the study early, we found no significant advantage when CBT was compared with either non-active control therapies (4 RCTs, n = 433, RR 0.88 CI 0.63 to 1.23) or active therapies (6 RCTs, n = 339, RR 0.75 CI 0.40 to 1.43) AUTHORS' CONCLUSIONS: Trial-based evidence suggests no clear and convincing advantage for cognitive behavioural therapy over other - and sometime much less sophisticated - therapies for people with schizophrenia. PMID- 22513968 TI - Intracystic bleomycin for cystic craniopharyngiomas in children. AB - BACKGROUND: Craniopharyngiomas are the commonest benign histological tumours to involve the hypothalamo-pituitary region in childhood. Cystic craniopharyngiomas occur in more than 90% of tumours. The optimal treatment of cystic craniopharyngioma remains controversial. Radical resection is the treatment of choice in patients with favourable tumour localization. When the tumour localization is unfavourable, a gross-total or partial resection followed by radiotherapy is the main treatment option in adults. However, it presents risk of morbidity especially for children. Intracystic bleomycin has been utilized to potentially delay the use of radiotherapy or radical resection to decrease morbidity. OBJECTIVES: To determine the benefits and harms of intracystic bleomycin versus other treatments for cystic craniopharyngiomas in children. SEARCH METHODS: We searched the electronic databases of CENTRAL (The Cochrane Library 2010, Issue 4), MEDLINE/PubMed (from 1966 to Oct 2010), and EMBASE/Ovid (from 1980 to Oct 2010) with pre-specified terms. In addition, we searched reference lists of relevant articles and reviews, conference proceedings and ongoing trial databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) quasi-randomised trials or controlled clinical trials (CCTs) comparing intracystic bleomycin and other treatments for cystic craniopharyngiomas in children (from birth to 18 years). DATA COLLECTION AND ANALYSIS: Two review authors independently performed the data extraction and the 'Risk of bias' assessment. We used risk ratio (RR) for binary data and mean difference (MD) for continuous data. We planned that if one of the treatment groups experienced no events and there was only one study available for the outcome, we would use the Fischer's exact test. MAIN RESULTS: We could not identify any studies in which the only difference between the treatment groups was the use of intracystic bleomycin. We did identify a RCT comparing intracystic bleomycin with intracystic (32)P (n = 7 children). The trial had a high risk of bias. Survival could not be evaluated. There was no evidence of a significant difference in cyst reduction (MD = -0.15, 95% confidence interval (CI) -0.69 to 0.39, P= 0.59), neurological status (Fisher's exact P = 0.429), 3rd nerve paralysis (Fischer's exact P = 1.00), fever (RR = 2.92, 95% CI 0.73 to 11.70, P = 0.13) and total adverse effects (RR = 1.75, 95% CI 0.68 to 4.53, P = 0.25 ) between the treatment groups. There was a significant difference in favour of the (32)P group for the occurrence of headache and vomiting (Fischer's exact P = 0.029 for both outcomes). AUTHORS' CONCLUSIONS: Since no RCTs, quasi-randomised trials or CCTs in which only the use of intracystic bleomycin differed between the treatment groups in the treatment of cystic craniopharyngiomas in children, no definitive conclusions could be made about the effects of intracystic bleomycin in these patients. Only one low-power RCT comparing intracystic bleomycin with intracystic (32)P treatment was available, but no definitive conclusions can be made about the effectiveness of these agents in children with cystic craniopharyngiomas. Based on the currently available evidence, we are not able to give recommendations for the use of intracystic bleomycin in the treatment of cystic craniopharyngiomas in children. High quality RCTs are needed. PMID- 22513969 TI - Long-acting beta(2)-agonist in addition to tiotropium versus either tiotropium or long-acting beta(2)-agonist alone for chronic obstructive pulmonary disease. AB - BACKGROUND: Long-acting bronchodilators comprising long-acting beta(2)-agonists and the anticholinergic agent tiotropium are commonly used for managing persistent symptoms of chronic obstructive pulmonary disease. Combining these treatments, which have different mechanisms of action, may be more effective than the individual components. However, the benefits and risks of combining tiotropium and long-acting beta(2)-agonists for the treatment of chronic obstructive pulmonary (COPD) disease are unclear. OBJECTIVES: To assess the relative effects of treatment with tiotropium in addition to long-acting beta(2) agonist compared to tiotropium or long-acting beta(2)-agonist alone in patients with chronic obstructive pulmonary disease. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials and clinicaltrials.gov up to January 2012. SELECTION CRITERIA: We included parallel group, randomised controlled trials of three months or longer comparing treatment with tiotropium in addition to long-acting beta(2)-agonist against tiotropium or long-acting beta(2)-agonist alone for patients with chronic obstructive pulmonary disease. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and then extracted data on trial quality and the outcome results. We contacted study authors for additional information. We collected information on adverse effects from the trials. MAIN RESULTS: Five trials were included in this review, mostly recruiting participants with moderate or severe chronic obstructive pulmonary disease. All of them compared tiotropium in addition to long-acting beta(2)-agonist to tiotropium alone, but only one trial additionally compared a combination of the two types of bronchodilator with long-acting beta(2)-agonist (formoterol) alone. Two studies used the long-acting beta(2) agonist indacaterol, two used formoterol and one used salmeterol.Compared to tiotropium alone (3263 patients), treatment with tiotropium plus long-acting beta(2)-agonist resulted in a slightly larger improvement in the mean health related quality of life (St George's Respiratory Questionnaire (SGRQ) MD -1.61; 95% CI -2.93 to -0.29). In the control arm, tiotropium alone, the SGRQ improved by falling 4.5 units from baseline and with both treatments the improvement was a fall of 6.1 units from baseline (on average). High withdrawal rates in the trials increased the uncertainty in this result, and the GRADE assessment for this outcome was therefore moderate. There were no significant differences in the other primary outcomes (hospital admission or mortality).The secondary outcome of pre-bronchodilator FEV(1) showed a small mean increase with the addition of long acting beta(2)-agonist (MD 0.07 L; 95% CI 0.05 to 0.09) over the control arm, which showed a change from baseline ranging from 0.03 L to 0.13 L on tiotropium alone. None of the other secondary outcomes (exacerbations, symptom scores, serious adverse events, and withdrawals) showed any statistically significant differences between the groups. There were wide confidence intervals around these outcomes and moderate heterogeneity for both exacerbations and withdrawals.The results from the one trial comparing the combination of tiotropium and long acting beta(2)-agonist to long-acting beta(2)-agonist alone (417 participants) were insufficient to draw firm conclusions for this comparison. AUTHORS' CONCLUSIONS: The results from this review indicate a small mean improvement in health-related quality of life for patients on a combination of tiotropium and long-acting beta(2)-agonist compared to tiotropium alone, but it is not clear how clinically important this mean difference may be. Hospital admission and mortality have not been shown to be altered by adding long-acting beta(2) agonists to tiotropium. There were not enough data to determine the relative efficacy and safety of tiotropium plus long-acting beta(2)-agonist compared to long-acting beta(2)-agonist alone. There were insufficient data to make comparisons between the different long-acting beta(2)-agonists when used in addition to tiotropium. PMID- 22513970 TI - Cervical stitch (cerclage) for preventing preterm birth in singleton pregnancy. AB - BACKGROUND: Cervical cerclage is a well-known surgical procedure carried out during pregnancy. It involves positioning of a suture (stitch) around the neck of the womb (cervix), aiming to give a mechanical support to the cervix and thereby reducing the risk of preterm birth. The effectiveness and safety of this procedure remains controversial. OBJECTIVES: To assess whether the use of cervical stitch in singleton pregnancy at high risk of pregnancy loss based on a woman's history and/or ultrasound finding of 'short cervix' and/or physical exam improves subsequent obstetric care and fetal outcome. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2011) and reference lists of identified studies. SELECTION CRITERIA: We included all randomised trials of cervical suturing in singleton pregnancies carried out when pregnancy was considered to be at sufficiently high risk of pregnancy loss for cerclage to be potentially indicated. We included any study that compared cerclage with either no treatment or any alternative intervention. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion. Two review authors independently assessed risk of bias and extracted data. Data were checked for accuracy. MAIN RESULTS: We included 12 trials (involving 3328 women). When cerclage was compared with no treatment, there was no statistically significant difference in perinatal deaths (8.4% versus 10.7%) (risk ratio (RR) 0.78; 95% confidence interval (CI) 0.61 to 1.00; eight trials, 2391 women) and neonatal morbidity (9.6% versus 10.2%) (RR 0.95; 95% CI 0.63 to 1.43; four trials, 818 women), despite significant reduction in preterm births (average RR 0.80; 95% CI 0.69 to 0.95; nine trials, 2898 women). Cervical cerclage was associated with the higher rate of maternal side effects (vaginal discharge and bleeding, pyrexia) (average RR 2.25; 95% CI 0.89 to 5.69; three trials, 953 women). Caesarean section rates were significantly higher after cervical cerclage (RR 1.19; 95% CI 1.01 to 1.40; 8 trials, 2817 women).There was no evidence of any important differences across all prespecified clinical subgroups (history-indicated, ultrasound-indicated)One study that compared cerclage with weekly intramuscular injections of 17 alpha-hydroxyprogesterone caproate in women with a short cervix detected by transvaginal ultrasound, failed to reveal any obvious differences in obstetric and neonatal outcomes between the two management strategies.Two studies compared the benefits of performing cerclage based on previous history with cerclage, only if the cervix was found to be short on transvaginal ultrasound. There was no significant difference in any of the primary and secondary outcomes. AUTHORS' CONCLUSIONS: Compared with no treatment, cervical cerclage reduces the incidence of preterm birth in women at risk of recurrent preterm birth without statistically significant reduction in perinatal mortality or neonatal morbidity and uncertain long-term impact on the baby. Ceasarean section is more likely in women who had cervical suture inserted during pregnancy.The decision on how best to minimise the risk of recurrent preterm birth in women at risk, either because of poor history of a short or dilated cervix, should be 'personalised', based on the clinical circumstances, the skill and expertise of the clinical team and, most importantly, woman's informed choice. PMID- 22513971 TI - Management of reported decreased fetal movements for improving pregnancy outcomes. AB - BACKGROUND: Clinical observations indicate that mothers commonly perceive a reduction in, or absence of, the baby's movements for some days preceding a baby's death. For this reason, fetal movement monitoring is advised by caregivers and used spontaneously by mothers to assess the baby's well-being. However, it is possible that the harmful effects of interventions may outweigh the benefits of such testing. Evidence of effectiveness of fetal movement screening to improve outcomes is limited, though indirect evidence suggests a potential benefit. A secondary question is whether any specific management response to perceived decreased fetal movements (DFM) improves clinical outcome. OBJECTIVES: To determine, from the best available evidence, the effectiveness of various management strategies for DFM. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (28 February 2012) and bibliographies of included studies. SELECTION CRITERIA: Randomised clinical trials comparing various management strategies for DFM, including delivery, expectant management, cardiotocography (visual and computerised), ultrasound examination including Doppler ultrasound, and fetal arousal tests (cardiotocographic or clinical). DATA COLLECTION AND ANALYSIS: Two assessors evaluated potentially eligible trials for inclusion, and extracted data onto a purpose-designed form. Where DFM was one among a number of inclusion criteria for the trial, we contacted trial authors for information on outcomes specific to the DFM subgroups. MAIN RESULTS: No randomised trials of management of DFM were found. Of 13 randomised trials of management strategies for pregnancies with risk factors for fetal compromise including DFM, data on the DFM subgroups could only be provided by the authors of one trial. The numbers were too small for meaningful analysis (there were 28 cases of DFM). AUTHORS' CONCLUSIONS: There are insufficient data from randomised trials to guide practice regarding the management of DFM. Based on the results of other systematic reviews of management strategies for women whose babies are thought to be at risk of compromise for various reasons, the following strategies show promise and may be prioritised for further research: Doppler ultrasound studies, computerised cardiotocography, and fetal arousal to facilitate cardiotocography.For settings where electronic fetal assessment methods are not available, clinical fetal arousal tests should be investigated. PMID- 22513972 TI - Local anaesthetic nerve block for pain management in labour. AB - BACKGROUND: Local anaesthetic nerve block is an important modality for pain management in labour. Pudendal and paracervical block (PCB) are most commonly performed local anaesthetic nerve blocks which have been used for decades. OBJECTIVES: To establish the efficacy and safety of local anaesthetic nerve blocks for pain relief in labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (28 February 2012). SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing pain management in labour with the use of local anaesthetic nerve blocks. We did not include results from quasi-RCTs. DATA COLLECTION AND ANALYSIS: We designed a form to extract data. For eligible studies, two review authors extracted the data using the agreed form. We resolved discrepancies through discussion or, if required, we consulted a third person. We entered and analysed data using Review Manager software and checked for accuracy. MAIN RESULTS: We found 41 trials for consideration of inclusion into this review. We included only 12 RCTs (1549 participants) of unclear quality. We excluded 29 studies (30 reports). The majority of excluded studies were not relevant to this review, and a few were not randomised.Local anaesthetic nerve block versus placebo or no treatment. We found that more women were satisfied with pain relief after local anaesthetic nerve block (in particular 2% lidocaine PCB) than after placebo (one study, 198 participants, risk ratio (RR) 32.31, 95% confidence interval (CI) 10.60 to 98.54). Local anaesthetic nerve block was associated with more side effects (one study, 200 participants, RR 29.0, 95% CI 1.75 to 479.61).Local anaesthetic nerve block (in particular, PCB) versus opioid Local anaesthetic nerve block (in particular, PCB) in comparison with opioid (in particular, intramuscular pethidine or fentanyl patient-controlled analgesia) was found to be more effective for pain relief (one study, 109 participants, RR 2.52, 95% CI 1.65 to 3.83) and was not associated with an increased rate of assisted vaginal birth (two studies, 129 participants, RR 1.02, 95% CI 0.56 to 1.87) or with an increased caesarean section rate (two studies, 129 participants, RR 0.23, 95% CI 0.03 to 1.87).Local anaesthetic nerve block versus non-opioid agents Satisfaction with pain relief and rate of caesarean sections were found to be the same in women receiving local anaesthetic nerve block and non-opioid agents (one study, 100 participants, RR 1.11, 95% CI 0.67 to 1.84; RR 2.0, 95% CI 0.19 to 21.36, respectively). More women who received non-opioid agent in comparison with women who received local anaesthetic nerve block required additional interventions for pain relief (one study, 100 participants, RR 0.06, 95% CI 0.02 to 0.25).Local anaesthetic nerve block using different anaesthetic agents There was no difference in pain relief satisfaction, assisted vaginal birth, caesarean section, side effects for mother, Apgar score or admission to the neonatal intensive care unit between different anaesthetic agents, e.g. bupivacaine, carbocaine, lidocaine, chloroprocaine. AUTHORS' CONCLUSIONS: Local anaesthetic nerve blocks are more effective than placebo, opioid and non-opioid analgesia for pain management in labour based on RCTs of unclear quality and limited numbers. Side effects are more common after local anaesthetic nerve blocks in comparison with placebo. Different local anaesthetic agents used for pain relief provide similar satisfaction with pain relief. Further high-quality studies are needed to confirm the findings, to assess other outcomes and to compare local anaesthetic nerve blocks with various modalities for pain relief in labour. PMID- 22513973 TI - Helminth therapy (worms) for allergic rhinitis. AB - BACKGROUND: Allergic rhinitis is a disorder of the nasal membranes and surrounding tissues, and a worldwide cause of illness and disability. Helminths are complex tissue-dwelling or lumen-dwelling organisms that inhabit larger organisms and are frequently asymptomatic. Helminths modulate the natural immune responses of their human hosts, and may prevent or cure immune-mediated or allergic diseases (e.g. allergic rhinitis) in the host. Non-randomised studies support this hypothesis. OBJECTIVES: To assess the safety and effectiveness of helminth therapy in people with allergic rhinitis. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 24 June 2011. SELECTION CRITERIA: All randomised controlled trials where the intervention was any helminth species or combination of helminth species, administered to people with allergic rhinitis in any dose, by any route and for any duration of exposure. We accepted both intermittent and persistent allergic rhinitis patients. DATA COLLECTION AND ANALYSIS: We independently extracted data and assessed eligibility and risk of bias using a standardised data collection form. We resolved any disagreement through discussion. We combined dichotomous data using risk ratio (RR) and continuous data using mean difference (MD), presenting both with 95% confidence intervals (CI). MAIN RESULTS: We found five reports of two single-centre, placebo-controlled, double-blinded studies (130 participants). Participants in both studies were a mix of adults with either intermittent or persistent allergic rhinitis. Both studies had a low risk of bias. One study, with 12 weeks' follow-up, used a single percutaneous application of 10 Necator americanus (i.e. human hookworm) larvae. The other study, with 24 weeks' follow up, used three-weekly oral dosing with 2500 Trichuris suis (i.e. pig whipworm) eggs in aqueous suspension. Of 17 outcomes evaluated in this review, eight were positive (i.e. favoured helminths). Participants taking helminths had no reduction in allergic rhinitis symptoms, percentage of well days (i.e. days with minimal symptoms and no use of medication for allergic rhinitis), lung function measures and quality of life scores. Total use of medication for allergic rhinitis (eye drops, nasal sprays, tablets) did not change; however, in the helminth group there was a statistically significant reduction in the percentage of days during the grass pollen season when participants needed to take tablets as rescue medication for their allergic rhinitis symptoms (MD -14.0%, 95% CI 26.6 to -1.40); in a typical 60-day pollen season this 14% reduction translates into 19 days when tablets would be needed in the helminth group versus 27 days when tablets would be needed in the placebo group. Participants taking helminths percutaneously (i.e. as hookworm larvae) had local skin itching and redness in the first few days after administration. Participants taking helminths were more likely to report any gastrointestinal adverse event (RR 1.79, 95% CI 1.31 to 2.45), moderate or severe abdominal pain (RR 7.67, 95% CI 1.87 to 31.57), moderate or severe flatulence (RR 2.01, 95% CI 1.06 to 3.81) and moderate or severe diarrhoea (RR 1.99, 95% CI 1.18 to 3.37). There was no difference between the helminth and placebo groups in the incidence of serious adverse events, and in study withdrawals. AUTHORS' CONCLUSIONS: There is currently insufficient evidence on the efficacy, tolerability and likely costs of helminth therapy to support its use in the routine management of allergic rhinitis. Administered to humans in carefully measured doses, helminths appear to be safe. More preclinical studies should be performed, before larger and extended duration trials of helminths for allergic rhinitis are carried out. Future studies should collect and report comparative data on the costs of helminth therapy versus conventional pharmacotherapy. PMID- 22513975 TI - Sildenafil citrate for erectile dysfunction in patients with multiple sclerosis. AB - BACKGROUND: Erectile dysfunction (ED) is a common sexual disease in male patients with multiple sclerosis (MS). Sildenafil citrate is considered as an effective drug in the treatment of male ED in the general population, but it has not been systematically reviewed in patients with MS. OBJECTIVES: To assess the efficacy and safety of sildenafil citrate for ED in patients with MS. SEARCH METHODS: We searched the Cochrane (November 2011), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4 of 4, 2011), MEDLINE (PubMed) (January 1966 to November 2011), EMBASE (January 1974 to November 2011) and the China Biological Medicine Database (CBM) (1979 to November 2011). We searched trials registers and conference proceedings and contacted pharmaceutical company and authors of included studies for additional data. There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials comparing sildenafil citrate with placebo or no treatment for ED in patients with MS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected articles for inclusion, extracted data and assessed trial quality. Disagreements were resolved by discussion between review authors. Authors of included studies were contacted for additional information. Results were presented as relative risks (RR) or mean differences (MD) with 95% confidence intervals (CI). MAIN RESULTS: Two randomised controlled trials involving a total of 420 patients were identified. Both trials investigated the short-term efficacy and safety of sildenafil citrate for ED in patients with MS. Patients taking sildenafil citrate were more likely to improve their ability to achieve and maintain an erection measured by International Index of Erectile Function and achieve vaginal penetration ( (RR 1.28, 95%CI 0.92 to 1.78) and complete intercourse measured by Sexual Encounter Profile diary (RR RR 1.38, 95%CI 1.00 to 1.90). and receive A global well respond measured by Global Assessment Question (RR 2.72, 95%CI 1.40 to 5.28) was reported. One trial showed sildenafil citrate is effective in quality of life improvement, while the other trial did not find any significant difference between both groups. Both included trials were judged as high risk of attrition bias. Adverse events were also reported: the most common were headache, flushing, rhinitis, visual disturbances and dyspepsia. Two patients suffered serious adverse events: one with coronary artery disease requiring triple bypass surgery and one with a cerebrovascular accident. AUTHORS' CONCLUSIONS: There is limited evidence to support sildenafil citrate as an effective treatment for ED in patients with MS. Future well designed randomised, double blinded, placebo-controlled trials with long-term duration are needed. PMID- 22513977 TI - Improving outcomes in gynaecological cancer: the benefits of subspecialisation. PMID- 22513976 TI - Monoamine oxidase inhibitors (MAOIs) for fibromyalgia syndrome. AB - BACKGROUND: Fibromyalgia (FM) syndrome is a chronic condition of unknown aetiology characterised by musculoskeletal pain that often co-exists with sleep disturbance, cognitive dysfunction and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of FM, drug therapy focuses on pain reduction and improvement of other bothersome symptoms. OBJECTIVES: The objective of this review was to assess the effectiveness and safety of monoamine oxidase inhibitors (MAOIs) in the treatment of FM syndrome. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 10), MEDLINE (1966 to November 2010), EMBASE (1980 to November 2010) and the reference lists of reviewed articles. SELECTION CRITERIA: We selected all randomised, double-blind trials of MAOIs used for the treatment of FM pain in adult participants. DATA COLLECTION AND ANALYSIS: Two authors assessed risk of bias and extracted data independently onto a specially designed pro forma and a third review author cross-checked them. MAIN RESULTS: We included two studies of inconsistent risk of bias with a total of 230 patients diagnosed with FM. We evaluated two MAOIs: pirlindole and moclobemide. Pirlindole showed statistically significant results compared with placebo for several outcomes (pain, tender points and overall assessment by the patient and the physician), whereas moclobemide did not show statistically significant differences between groups. Pooled results of the two studies displayed a modest effect size in pain (mean difference (MD) -1.45 (121 patients; 95% confidence interval (CI) -2.71 to -0.20; number needed to treat (NNT) 2 (95% CI 1 to 12); I(2) = 59%)), implying a minimal clinically important difference (MCID) and a small effect on tender points (standardised mean difference (SMD) -0.36 (121 patients; 95% CI -0.72 to -0.00; I(2) = 31%)). No effect was seen on global assessment by patient. Physical function and sleep disturbance were not measured. The most frequent adverse events were nausea and vomiting, with statistically significant differences between groups (risk ratio (RR) 7.82 (89 patients; 95% CI 1.02 to 59.97; NNT 7 (95% CI 4 to 33)). AUTHORS' CONCLUSIONS: Data suggest that the effectiveness of MAOIs for the treatment of FM symptoms is limited. Although we observed a moderate effect size on pain and a small one on tender points, these results should be taken with caution as they are only based on two studies with a small number of patients and inconsistent risk of bias among them. PMID- 22513974 TI - Negative pressure wound therapy for skin grafts and surgical wounds healing by primary intention. AB - BACKGROUND: Indications for the use of negative pressure wound therapy (NPWT) are broadening with a range of systems on the market, including those designed for use on clean, closed incisions and skin grafts. Reviews have concluded that the evidence for the effectiveness of NPWT remains uncertain. However, this is a rapidly evolving therapy. Consequently, a systematic review of the evidence for the effects of NPWT on postoperative wounds expected to heal by primary intention is required. OBJECTIVES: To assess the effects of NPWT on surgical wounds (primary closure or skin grafting) that are expected to heal by primary intention. SEARCH METHODS: We searched the following electronic databases to identify reports of relevant randomised clinical trials: the Cochrane Wounds Group Specialised Register (searched 11 November 2011); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4); Database of Abstracts of Reviews of Effects (The Cochrane Library 2011, Issue 4); Ovid MEDLINE (2005 to October Week 4 2011); Ovid MEDLINE (In-Process & Other Non Indexed Citations 8 November 2011); Ovid EMBASE (2009 to 2011 Week 44); and EBSCO CINAHL (1982 to 04 November 2011). We conducted a separate search to identify economic evaluations. SELECTION CRITERIA: We included trials if they allocated patients at random and compared NPWT with any other type of wound dressing or compared one type of NPWT with a different type of NPWT. DATA COLLECTION AND ANALYSIS: We assessed trials for their appropriateness for inclusion and for their quality. This was done by three review authors working independently, using pre-determined inclusion and quality criteria. MAIN RESULTS: We included five eligible trials with a total of 280 participants. Two trials involved skin grafts and three acute wounds. Only one of the five trials reported the proportion of wounds completely healed and in this study all wounds healed. All five studies reported adverse events. In the four trials that compared standard dressings with negative pressure wound therapy (NPWT) the adverse event rate was similar between groups (negative pressure 33/86; standard dressing 37/103); risk ratio (RR) 0.97 (95% confidence intervals (CI) 0.33 to 2.89). There was significant heterogeneity for this result, due to the high incidence of fracture blisters in the NPWT group in one trial. One trial (87 participants) compared a commercial negative pressure device VAC(r) system with a negative pressure system developed in the hospital (GSUC). The adverse event rate was lower in the GSUC group (VAC(r) 3/42; GSUC 0/45); the RR was 0.13 (95% CI 0.01 to 2.51). Results indicate uncertainty about the true effect of either method on adverse events. The mean cost to supply equipment for VAC(r) therapy was USD 96.51/day compared to USD 4.22/day for the GSUC therapy (P = 0.01). Labour costs for dressing changes were similar. Pain intensity score was also reported to be lower in the GSUC group when compared with the VAC(r) group (p = 0.02) AUTHORS' CONCLUSIONS: Evidence for the effectiveness of NPWT on complete healing of wounds expected to heal by primary intention remains unclear. Rates of graft loss may be lower when NPWT is used; but evidence to date suggests that hospital-based products are as effective in this area as commercial applications. There are clear cost benefits when non commercial systems are used to create the negative pressure required for wound therapy, with no reduction in clinical outcome. Pain levels are also rated lower when hospital systems are compared with their commercial counterparts. The high incidence of blisters occurring when NPWT is used following orthopaedic surgery suggests that the therapy should be limited until safety in this population is established. Given the cost and widespread use of NPWT, there is an urgent need for suitably powered, high-quality trials to evaluate the effects of the newer NPWT products that are designed for use on clean, closed surgical incisions. Such trials should focus initially on wounds that may be difficult to heal, such as sternal wounds or surgeries for obese patients. PMID- 22513978 TI - Assessing academic researchers. PMID- 22513980 TI - Evaluating the physiological state of maize (Zea mays L.) plants by direct injection electrospray mass spectrometry (DIESI-MS). AB - Climatic change is an increasing challenge for agriculture that is driving the development of suitable crops in order to ensure supply for both human nutrition and animal feed. In this context, it is increasingly important to understand the biochemical responses of cells to environmental cues at the whole system level, an aim that is being brought closer by advances in high throughput, cost efficient plant metabolomics. To support molecular breeding activities, we have assessed the economic, technical and statistical feasibility of using direct mass spectrometry methods to evaluate the physiological state of maize (Zea mays L.) plants grown under different stress conditions. PMID- 22513979 TI - Coordinated expression of galectin-3 and caveolin-1 in thyroid cancer. AB - Galectin-3 (Gal3) is the single most accurate marker for the diagnosis of differentiated thyroid cancer (DTC). Gal3 overrides the tumour suppressor activity of caveolin-1 (Cav1) and functions in concert with Cav1 to promote focal adhesion turnover and tumour cell migration and invasion. To study their coordinated role in progression of a human cancer, we investigated the expression of Gal3 and Cav1 in specimens of human benign thyroid lesions, DTC and anaplastic thyroid cancer (ATC). Gal3 and Cav1 expression is significantly associated with DTC and ATC, but not benign nodules. Essentially all Cav1-positive DTC cancers express Gal3, supporting the synergistic activity of these two proteins in DTC progression. Similarly, coordinated elevated Gal3/Cav1 expression was observed in three DTC-derived cell lines (papillary TCP1 and KTC1 and follicular FTC133) but only one (ACT1) of five ATC-derived cell lines. Using siRNA knockdown, Gal3 and Cav1 were shown to be required for RhoA GTPase activation, stabilization of focal adhesion kinase (FAK; a measure of focal adhesion signalling and turnover) and increased migration of the DTC cell lines studied, but not the ATC cell lines, including ACT1, which expresses elevated levels of Gal3 and Cav1. Co-expression of Gal3 and Cav1 in the T238 anaplastic cell line stabilized FAK-GFP in focal adhesions. Gal3 and Cav1 therefore function synergistically to promote focal adhesion signalling, migration and progression of DTC. PMID- 22513981 TI - Evaluation of MDM2, p16, and p53 staining levels as biomarkers of biochemical recurrence following salvage radiation therapy for recurrent prostate cancer. AB - BACKGROUND AND PURPOSE: The selection of appropriate candidates for salvage radiation therapy (SRT) to address a rising PSA following radical prostatectomy remains challenging. Herein, we provide the first evaluation of the ability of staining levels of the tumor based biomarkers MDM2, p16, and p53 to aid in prediction of biochemical recurrence (BCR) among men undergoing SRT for recurrent prostate cancer. MATERIAL AND METHODS: We identified 152 patients who were treated with SRT between July 1987 and July 2003. Staining levels of MDM2, p16, and p53 in primary tumor samples removed during prostatectomy were detected using monoclonal antibodies and quantified by use of a computer-assisted method. Associations of staining levels with BCR were evaluated using Cox proportional hazards regression models; relative risks (RRs) and 95% confidence intervals (CIs) were estimated. RESULTS: Compared to patients with low staining (<=median) as measured by percentage of cells with nuclear staining, there was no significant difference in risk of BCR for patients with high MDM2 staining (RR: 0.90, 95% CI: 0.57-1.45, P = 0.67), high p16 staining (RR: 0.88, 95% CI: 0.54 1.44, P = 0.62), or high p53 staining (RR: 1.33, 95% CI: 0.84-2.11, P = 0.23) in multivariable analysis. These results were consistent when considering alternate percentile cutpoints and alternate quantifications of biomarker staining. CONCLUSIONS: Our results provide evidence that MDM2, p16, and p53 staining levels are not useful in the prediction of BCR after SRT. As such, these biomarkers are of little clinical use in the selection of appropriate candidates for SRT. PMID- 22513983 TI - Cytogenetic analysis of 531 Chinese women with premature ovarian failure. AB - BACKGROUND: This retrospective cohort study was to determine the frequency and types of chromosomal abnormalities in Han Chinese women with well-documented premature ovarian failure (POF). METHODS: Karyotype analysis and correlation to phenotypes were performed on 531 Chinese patients with proven POF (FSH > 40 mIU/ml) attending four reproductive centers in China. G-banded metaphase chromosomes were prepared and analyzed, with mosaicism excluded by counting up to 100 cells from lymphocytes. RESULTS: Chromosomal abnormalities were present in 64 of 531 (12.1%) POF cases, of which 32 were X-structural aberrations (7 mosaic): 15 del(Xq), 2 del(Xp), 11 isochromosomes [6 i(Xp); 5 i(Xq)], 1 ring chromosome (mosaic), 1 inversion (mosaic), 1 isodicentric chromosome and 1 complex arrangement. Nine non-mosaic X-autosome translocations were detected, all but 1 involving Xq. Aneuploidy without a structurally abnormal X was found in 19 cases: 7 non-mosaic 45,X, 9 45,X mosaicisms and 3 47,XXX (1 mosaic with 46,XX line). Karyotypic abnormalities were more frequent in patients with primary amenorrhea (15/70, 21.4%) than those with secondary amenorrhea (49/461, 10.6%; P = 0.01). 45,X and 45,X/46,XX mosaicism were the complements most frequently associated with primary amenorrhea (46.7%). Two of the three cases with 46,XY or 45,X/46,XY karyotype presented with 'secondary amenorrhea'. One balanced autosomal Robertsonian translocation was also detected. CONCLUSIONS: The overall prevalence of chromosomal abnormalities was 12.1% in this first large scale report of chromosomal aberrations in Chinese women with POF. In one of the largest samples of women with POF reported from any population, the prevalence of X-structural abnormalities, X-autosome translocations and X aneuploidy confirms the essential role X chromosomal abnormalities play in POF. PMID- 22513982 TI - Computer-aided surgery: concepts and applications in vascular surgery. AB - Computer-aided surgery makes use of a variety of technologies and information sources. The challenge over the past 10 years has been to apply these methods to tissues that deform, as do vessels when relatively rigid flexible objects are introduced into them (Lunderquist rigid guide wire, aortic prosthesis, etc) Three stages of computer-aided endovascular surgery are examined: sizing, planning, and intraoperative assistance. The authors' work shows that an approach based on optimized use of the imaging data acquired during the various observation phases (pre- and intraoperative), involving only lightweight computer equipment that is relatively transparent for the user, makes it possible to provide useful (ie, necessary and sufficient) information at the appropriate moment, in order to aid decision making and enhance the security of endovascular procedures. PMID- 22513984 TI - Octanoate and nonaoate oxidation increases 50-80% over the first two days of life in piglet triceps brachii and gracilis muscle strips. AB - An in vitro muscle strip incubation system was developed to measure the rate of catabolism of 1 mmol/L [1-(14)C]octanoate, 1 mmol/L [1-(14)C]nonanoate, 1 mmol/L [9-(14)C]nonanoate, and 10 mmol/L [U-(14)C]glucose by measuring the recovery of (14)CO(2). Muscle strips (13 mm * 1.5 mm, ~50 mg) were isolated from triceps brachii and gracilis muscles of newborn and 2-d-old, small (<950 g) and large (>1450 g) piglets. The position of the (14)C label in the substrate affected the rate and amount of recovery in (14)CO(2). Therefore, comparisons were made between age groups (0 vs. 2 d old) within substrates but limited across substrates to comparisons of [1-(14)C]-labeled fatty acids. The medium-chain fatty acid (MCFA) oxidation rates [pmol/(h . mg)] in muscle strips isolated from piglets from the 2 weight groups (<950 and >1450 g) did not differ (P > 0.99), there was a trend towards a difference between triceps brachii and gracilis muscle (P = 0.09; data not shown), and there were no significant interactions involving pig weight or muscle type; therefore, results were pooled across these factors. During the first 2 d of life, MCFA oxidation [pmol/(h * . mg muscle strip)] increased (P < 0.05) 50-80%, but the glucose oxidation rate did not change (P > 0.82). By d 2, the oxidation rate of nonanoate as represented by the one carbon was 25% greater than for octanoate (P < 0.05). The conversion of [9 (14)C]nonanoate to (14)CO(2) indicated that muscle had the capacity to oxidize the propionyl-CoA produced by beta-oxidation of nonanoate and that odd-chain C-9 MCFA provided anabolic carbon to the citric acid cycle. PMID- 22513985 TI - Restriction of dietary energy intake has a greater impact on bone integrity than does restriction of calcium in exercising female rats. AB - We sought to elucidate the effects of restricting calcium, energy, or food on the skeletal integrity of exercising female rats. Female Sprague-Dawley rats (4 mo old) were randomly assigned to 5 groups (n = 10/group): ad libitum intake of an AIN-93M diet (Research Diets D10012M, Research Diets, Inc.) with no exercise (AL S) or with exercise (AL-EX) or to 1 of 3 exercising restriction groups [40% restriction of calcium only (CAR-EX), energy only (ER-EX), or food (FR-EX)]. All EX rats were treadmill trained 3 d/wk, 45 min/d for 12 wk at ~60% maximal oxygen consumption. After 12 wk, total body bone mineral content (by DXA) and body mass, but not lean mass, were lower in ER-EX (-17%) and FR-EX rats (-13%) compared with the AL-EX group. CAR-EX had few negative effects on bone geometry (by peripheral quantitative computed tomography) or histomorphometry. However, declines in total volumetric bone mineral density at the proximal tibia metaphysic (PTM) were observed in ER-EX (-6%) and FR-EX (-8%) groups; only FR-EX rats exhibited increased osteoclast surface and decreased mineral apposition rate in PTM cancellous bone. Decrements in serum estradiol, uterine weights, or both in these 2 groups implicate altered estrogen status as contributory. Urine pH declined significantly by 12 wk in all restricted groups, but net acid excretion increased only in CAR-EX rats. These findings, when compared with published data on sedentary rats, suggest that treadmill running exercise may mitigate some, but not all, deleterious effects on bone after chronic energy or food restriction but is more protective during calcium restriction. PMID- 22513987 TI - Metabolomic analysis reveals differences in umbilical vein plasma metabolites between normal and growth-restricted fetal pigs during late gestation. AB - Intrauterine growth restriction (IUGR) remains a major problem for both human health and animal production due to its association with high rates of neonatal morbidity and mortality, low efficiency of food utilization, permanent adverse effects on postnatal growth and development, and long-term health and productivity of the offspring. However, the underlying mechanisms for IUGR are largely unknown. In this study, one IUGR fetus and one normal body weight (NBW) fetus were obtained from each of 9 gilts at each of 2 gestational ages (d 90 and 110). Metabolomes of umbilical vein plasma in IUGR and NBW fetuses were determined by MS, while hormones, amino acids, and related metabolites in maternal and fetal plasma were measured using assay kits and chromatographic methods. Metabolites (including glucose, urea, ammonia, amino acids, and lipids) in umbilical vein plasma exhibited a cluster of differences between IUGR and NBW fetuses on d 90 and 110 of gestation. These changes in the IUGR group are associated with disorders of nutrient and energy metabolism as well as endocrine imbalances, which may contribute to the retardation of fetal growth and development. The findings help provide information regarding potential mechanisms responsible for IUGR in swine and also have important implications for the design of effective strategies to prevent, diagnose, and treat IUGR in other mammalian species, including humans. PMID- 22513986 TI - Plasma vitamin E and coenzyme Q10 are not associated with a lower risk of acute myocardial infarction in Singapore Chinese adults. AB - Vitamin E and coenzyme Q10 (CoQ10) have antioxidant effects that may benefit cardiovascular health. Meta-analyses of randomized controlled trials have not shown a protective effect of supplementation with the vitamin E isomer alpha tocopherol on the risk of acute myocardial infarction (AMI), but data on other isomers and CoQ10 are limited. Our objective was to examine the association of the plasma concentrations of vitamin E isomers (alpha-, gamma-, and delta tocopherol and alpha-, gamma-, and delta-tocotrienol) and CoQ10 (ubiquinol and ubiquinone) with the incidence of AMI. We conducted a nested case-control study with 233 cases of incident AMI and 466 matched controls selected from the Singapore Chinese Health Study, aged 45-74 y at the time of recruitment and free of cardiovascular disease at the time of blood collection. We used conditional logistic regression to examine the association between vitamin E and CoQ10 and the risk of AMI adjusted for other risk factors. In the basic model, higher delta tocopherol and ubiquinone concentrations were significantly associated with a higher risk of AMI, whereas there were no significant associations for the other vitamin E and CoQ10 isomers. After adjusting for lifestyle and other risk factors, only the association between delta-tocopherol and AMI risk remained significant [OR = 3.09 (95% CI: 1.53, 6.25) highest vs. lowest quintile; P-trend = 0.028]. We did not observe an inverse association between plasma concentrations of vitamin E isomers or CoQ10 and risk of AMI in Singapore Chinese. In contrast, plasma delta-tocopherol concentrations were associated with a higher risk of AMI. Our findings do not support a role of higher vitamin E or CoQ10 intakes in the prevention of AMI. PMID- 22513988 TI - An updated systematic review and meta-analysis of the efficacy of vitamin D food fortification. AB - Food fortification is a potentially effective public health strategy to increase vitamin D intakes and circulating 25-hydroxyvitamin D [25(OH)D] concentrations. We updated a previous systematic review to evaluate current evidence from randomized controlled intervention studies in community-dwelling adults of the effect of fortified foods on 25(OH)D concentrations. Ovid MEDLINE, PubMed, CINAHL, Embase, and Cochrane Central Register of Controlled Trials were searched for randomized controlled intervention studies with vitamin D-fortified foods in free-living adults and data on circulating 25(OH)D. Two reviewers independently screened 441 papers for eligibility and extracted the relevant data. A meta analysis of the absolute mean change in circulating 25(OH)D concentrations was conducted using a random effects model. Sixteen studies from 15 publications were included, of which 14 showed a significant effect of fortified foods on 25(OH)D concentrations. Heterogeneity was high (P = <0.0001, I(2) = 89%) and was partly explained by dose, latitude (range, 3-60 degrees ), and baseline 25(OH)D (range, 24.0-83.6 nmol/L). When combined in a random effects analysis (n = 1513; 767 treated, 746 controls), a mean individual intake of ~11 MUg/d (440 IU/d) from fortified foods (range, 3-25 MUg/d) increased 25(OH)D by 19.4 nmol/L (95% CI: 13.9, 24.9), corresponding to a 1.2 nmol/L (95% CI: 0.72, 1.68) increase in 25(OH)D for each 1 MUg ingested. Vitamin D food fortification increases circulating 25(OH)D concentrations in community-dwelling adults. Safe and effective food-based strategies could increase 25(OH)D across the population distribution and prevent vitamin D deficiency with potential benefit for public health. PMID- 22513990 TI - Magnesium intake is not related to depression risk in Spanish university graduates. AB - Magnesium is the second most predominant intracellular cation and it is an important cofactor in over 300 enzymatic reactions. It is a calcium antagonist and a voltage-dependent blocker of the N-methyl-D-aspartate channel, which plays a role in the entrance of calcium into the neuron. Other mechanisms also add biological plausibility to neuro-protective properties for magnesium, including an inverse association with major depression. A higher magnesium intake has been related to lower depressive symptoms. However, epidemiological evidence on this issue is scarce. Our aim was to prospectively evaluate the association between dietary magnesium intake and depression incidence in a cohort of 12,939 Spanish university graduates initially free of depression (Seguimiento Universidad de Navarra Cohort Study). Total magnesium intake was assessed with a validated, semiquantitative FFQ and incident depression was ascertained through self-reports of a new clinical diagnosis of depression done by a medical doctor and/or the habitual use of antidepressive drugs. The self-report was validated against the Diagnostic and Statistical Manual of Mental Disorders (4th edition) criteria in a subsample of the cohort. Cox regression models were used to obtain HR of incident depression during follow-up according to baseline quintiles of magnesium intake using the lowest quintile as the reference category. After a median follow-up of 6.3 y, 737 new cases of depression were identified. No association between magnesium intake and depression was found, with multivariate-adjusted HR = 1 (reference), 1.00 (95% CI: 0.78-1.27), 1.00 (0.76-1.31), 0.95 (0.70-1.30), and 1.11 (0.77-1.59) for increasing categories (quintiles 1-5) of total magnesium intake. No dose-response relationship was found (P-trend = 0.59). Results were robust through different sensitivity analyses, including nutrient density or residual models. In conclusion, our findings do not suggest an inverse association between magnesium intake and depressive disorder. PMID- 22513989 TI - Alternative dietary indices both strongly predict risk of chronic disease. AB - The Healthy Eating Index-2005 (HEI-2005) measures adherence to the 2005 Dietary Guidelines for Americans, but the association between the HEI-2005 and risk of chronic disease is not known. The Alternative Healthy Eating Index (AHEI), which is based on foods and nutrients predictive of chronic disease risk, was associated inversely with chronic disease risk previously. We updated the AHEI, including additional dietary factors involved in the development of chronic disease, and assessed the associations between the AHEI-2010 and the HEI-2005 and risk of major chronic disease prospectively among 71,495 women from the Nurses' Health Study and 41,029 men from the Health Professionals Follow-Up Study who were free of chronic disease at baseline. During >=24 y of follow-up, we documented 26,759 and 15,558 incident chronic diseases (cardiovascular disease, diabetes, cancer, or nontrauma death) among women and men, respectively. The RR (95% CI) of chronic disease comparing the highest with the lowest quintile was 0.84 (0.81, 0.87) for the HEI-2005 and 0.81 (0.77, 0.85) for the AHEI-2010. The AHEI-2010 and HEI-2005 were most strongly associated with coronary heart disease (CHD) and diabetes, and for both outcomes the AHEI-2010 was more strongly associated with risk than the HEI-2005 (P-difference = 0.002 and <0.001, respectively). The 2 indices were similarly associated with risk of stroke and cancer. These findings suggest that closer adherence to the 2005 Dietary Guidelines may lower risk of major chronic disease. However, the AHEI-2010, which included additional dietary information, was more strongly associated with chronic disease risk, particularly CHD and diabetes. PMID- 22513991 TI - Decreased metal accumulation in passerines as a result of reduced emissions. AB - Technological advances in industrial processes have resulted in reduced atmospheric emissions from metal industries all over the globe, but the response of the environment is not well known. The authors studied metal (As, Cd, Cu, Ni, Pb, and Se) accumulation in passerine birds (pied flycatcher, Ficedula hypoleuca, and great tit, Parus major) following almost 20 years of reduced metal emissions from the largest nonferrous smelter in Finland. Close to the industry, emission reductions resulted in reduced exposure to several of the elements and, more importantly, reduced accumulation by 58 to 95% in liver tissue. Albeit showing significant tissue reductions, nestlings had elevated concentrations of arsenic, cadmium, lead, and selenium close to the industry. Single-element concentrations were below critical levels associated with subclinical effects, but the mixture of toxic elements indirectly affected health and reproduction. Our study indicates that in environments with moderate duration of industrial activity, impact, and soil pollution, metal accumulation in organisms can decrease relatively rapidly when atmospheric emissions are reduced. PMID- 22513992 TI - Stability of gene rankings from RNAi screens. AB - MOTIVATION: Genome-wide RNA interference (RNAi) experiments are becoming a widely used approach for identifying intracellular molecular pathways of specific functions. However, detecting all relevant genes involved in a biological process is challenging, because typically only few samples per gene knock-down are available and readouts tend to be very noisy. We investigate the reliability of top scoring hit lists obtained from RNAi screens, compare the performance of different ranking methods, and propose a new ranking method to improve the reproducibility of gene selection. RESULTS: The performance of different ranking methods is assessed by the size of the stable sets they produce, i.e. the subsets of genes which are estimated to be re-selected with high probability in independent validation experiments. Using stability selection, we also define a new ranking method, called stability ranking, to improve the stability of any given base ranking method. Ranking methods based on mean, median, t-test and rank sum test, and their stability-augmented counterparts are compared in simulation studies and on three microscopy image RNAi datasets. We find that the rank-sum test offers the most favorable trade-off between ranking stability and accuracy and that stability ranking improves the reproducibility of all and the accuracy of several ranking methods. AVAILABILITY: Stability ranking is freely available as the R/Bioconductor package staRank at http://www.cbg.ethz.ch/software/staRank. PMID- 22513993 TI - INRICH: interval-based enrichment analysis for genome-wide association studies. AB - SUMMARY: Here we present INRICH (INterval enRICHment analysis), a pathway-based genome-wide association analysis tool that tests for enriched association signals of predefined gene-sets across independent genomic intervals. INRICH has wide applicability, fast running time and, most importantly, robustness to potential genomic biases and confounding factors. Such factors, including varying gene size and single-nucleotide polymorphism density, linkage disequilibrium within and between genes and overlapping genes with similar annotations, are often not accounted for by existing gene-set enrichment methods. By using a genomic permutation procedure, we generate experiment-wide empirical significance values, corrected for the total number of sets tested, implicitly taking overlap of sets into account. By simulation we confirm a properly controlled type I error rate and reasonable power of INRICH under diverse parameter settings. As a proof of principle, we describe the application of INRICH on the NHGRI GWAS catalog. AVAILABILITY: A standalone C++ program, user manual and datasets can be freely downloaded from: http://atgu.mgh.harvard.edu/inrich/. PMID- 22513994 TI - TSSi--an R package for transcription start site identification from 5' mRNA tag data. AB - High-throughput sequencing has become an essential experimental approach for the investigation of transcriptional mechanisms. For some applications like ChIP-seq, several approaches for the prediction of peak locations exist. However, these methods are not designed for the identification of transcription start sites (TSSs) because such datasets contain qualitatively different noise. In this application note, the R package TSSi is presented which provides a heuristic framework for the identification of TSSs based on 5' mRNA tag data. Probabilistic assumptions for the distribution of the data, i.e. for the observed positions of the mapped reads, as well as for systematic errors, i.e. for reads which map closely but not exactly to a real TSS, are made and can be adapted by the user. The framework also comprises a regularization procedure which can be applied as a preprocessing step to decrease the noise and thereby reduce the number of false predictions. AVAILABILITY: The R package TSSi is available from the Bioconductor web site: www.bioconductor.org/packages/release/bioc/html/TSSi.html. PMID- 22513995 TI - NanoStringNorm: an extensible R package for the pre-processing of NanoString mRNA and miRNA data. AB - MOTIVATION: The NanoString nCounter Platform is a new and promising technology for measuring nucleic acid abundances. It has several advantages over PCR-based techniques, including avoidance of amplification, direct sequence interrogation and digital detection for absolute quantification. These features minimize aspects of experimental error and hold promise for dealing with challenging experimental conditions such as archival formalin-fixed paraffin-embedded samples. However, systematic inter-sample technical artifacts caused by variability in sample preservation, bio-molecular extraction and platform fluctuations must be removed to ensure robust data. RESULTS: To facilitate this process and to address these issues for NanoString datasets, we have written a pre-processing package called NanoStringNorm in the R statistical language. Key features include an extensible environment for method comparison and new algorithm development, integrated gene and sample diagnostics, and facilitated downstream statistical analysis. The package is open-source, is available through the CRAN package repository, includes unit-tests to ensure numerical accuracy, and provides visual and numeric diagnostics. AVAILABILITY: http://cran.r project.org/web/packages/NanoStringNorm PMID- 22513996 TI - Automated gene-model curation using global discriminative learning. AB - MOTIVATION: Gene-model curation creates consensus gene models by combining multiple sources of protein-coding evidence that may be incomplete or inconsistent. To date, manual curation still produces the highest quality models. However, manual curation is too slow and costly to be completed even for the most important organisms. In recent years, machine-learned ensemble gene predictors have become a viable alternative to manual curation. Current approaches make use of signal and genomic region consistency among sources and some voting scheme to resolve conflicts in the evidence. As a further step in that direction, we have developed eCRAIG (ensemble CRAIG), an automated curation tool that combines multiple sources of evidence using global discriminative training. This allows efficient integration of different types of genomic evidence with complex statistical dependencies to maximize directly annotation accuracy. Our method goes beyond previous work in integrating novel non-linear annotation agreement features, as well as combinations of intrinsic features of the target sequence and extrinsic annotation features. RESULTS: We achieved significant improvements over the best ensemble predictors available for Homo sapiens, Caenorhabditis elegans and Arabidopsis thaliana. In particular, eCRAIG achieved a relative mean improvement of 5.1% over Jigsaw, the best published ensemble predictor in all our experiments. AVAILABILITY: The source code and datasets are both available at http://www.seas.upenn.edu/abernal/ecraig.tgz. PMID- 22513997 TI - Socioeconomic status, stature, and obesity in women: 20-year trends in urban Colombia. AB - OBJECTIVES: Ongoing social and economic changes in developing countries are associated with increases in body size, and most notably increases in the prevalence of obesity. The social patterning of these changes in terms of socioeconomic status (SES) is not well documented. The aim of this study was to assess the changes in stature, body mass index (BMI) and fatness in adult women in urban Cali, Colombia between 1988-1989 and 2007-2008. METHODS: We compared the results of anthropometric surveys completed in 1988-1989 and 2007-2008 of nonpregnant, nonlactating women, 18-44 years of age. Samples in both studies were stratified by SES. We calculated age-standardized prevalence rates to assess time trends in obesity. Body fatness was assessed by skinfold thicknesses. RESULTS: Stature increased in all SES groups and remained positively associated with SES. BMI increased only in the lower SES group, from 24.4 to 25.9 kg/m(2) and remained negatively associated with SES. The age-standardized prevalence of obesity increased from 7.9 to 17.0% in the lower SES group, but only from 4.5 to 8.2% in the middle SES group, and was unchanged in the upper SES group. Body fatness increased in all SES groups, but only in the upper body. CONCLUSION: The increased stature in all SES groups is indicative of general improvements in socioeconomic conditions. The increased prevalence of obesity in the lower SES groups is in keeping with the findings in other middle-income developing countries. PMID- 22513999 TI - Catalytic enantioselective construction of quaternary stereocenters by direct vinylogous Michael addition of deconjugated butenolides to nitroolefins. AB - A direct vinylogous Michael reaction of gamma-substituted deconjugated butenolides with nitroolefins has been developed with the help of a newly identified quinine-derived bifunctional catalyst, allowing the synthesis of densely functionalized products with contiguous quaternary and tertiary stereocenters in excellent yield with perfect diastereoselectivity (>20:1 dr) and high enantioselectivity (up to 99:1 er). PMID- 22513998 TI - Chemical reporters for monitoring RNA synthesis and poly(A) tail dynamics. AB - A versatile "clickable" nucleoside: Metabolic labeling of cells is useful in studying the dynamics of biological molecules. N(6) pA can be utilized by all three mammalian RNA polymerases, as well as poly(A) polymerase. Because of its alkyne modification, RNA labeled with N(6) pA can be visualized and purified by using click chemistry. PMID- 22514000 TI - The core competencies of James Marion Sims, MD. AB - The concept of core competencies in graduate medical education was introduced by the Accreditation Council for Graduate Medical Education of the American Medical Association to semiquantitatively assess the professional performance of students, residents, practitioners, and faculty. Many aspects of the career of J. Marion Sims, MD, are exemplary of those core competencies: MEDICAL KNOWLEDGE: Author of the first American textbook related to gynecology. MEDICAL CARE: Innovator of the Sims' Vaginal Speculum, Sims' Position, Sims' Test, and vesico /rectovaginal fistulorrhaphy; advocated abdominal exploration for penetrating wounds; performed the first cholecystostomy. PROFESSIONALISM: Served as President of the New York Academy of Medicine, the American Medical Association, and the American Gynecologic Society. INTERPERSONAL RELATIONSHIPS/COMMUNICATION: Cared for the indigent, hearthless, indentured, disenfranchised; served as consulting surgeon to the Empress Eugenie (France), the Duchess of Hamilton (Scotland), the Empress of Austria, and other royalty of the aristocratic Houses of Europe; accorded the National Order of the Legion of Honor. PRACTICE-BASED LEARNING: Introduction of silver wire sutures; adoption of the principles of asepsis/antisepsis; adoption of the principles of general anesthesia. SYSTEMS BASED PRACTICE: Established the Woman's Hospital, New York City, New York, the predecessor of the Memorial Sloan-Kettering Center for the Treatment of Cancer and Allied Diseases; organized the Anglo-American Ambulance Corps under the patronage of Napoleon III. What led him to a life of clinical and humanitarian service? First, he was determined to succeed. His formal medical/surgical education was perhaps the best available to North Americans during that era. Second, he was courageous in experimentation and innovation, applying new developments in operative technique, asepsis/antisepsis, and general anesthesia. Third, his curiosity was not burdened by rigid adherence to old doctrines or antiquated theories. Fourth, he broadened his professional experience and knowledge by travels to renowned intellectual centers in Western Europe. Fifth, he was perceived as cautiously optimistic and judiciously positive as he interacted with patients, students, and colleagues. Courage, confidence, creativity, compassion, charisma, character, and controversy marked his career. His legacy is illustrative and exemplary of the core competencies fostered contemporaneously in graduate medical educational programs. PMID- 22514001 TI - Hydrated alizarin complexes: hydrogen bonding and proton transfer. AB - We investigated the hydrogen bonding structures and proton transfer for the hydration complexes of alizarin (Az) produced in a supersonic jet using fluorescence excitation (FE), dispersed laser induced fluorescence (LIF), visible visible hole burning (HB), and fluorescence detected infrared (FDIR) spectroscopy. The FDIR spectrum of bare Az with two O-H groups exhibits two vibrational bands at 3092 and 3579 cm(-1), which, respectively, correspond to the stretching vibration of O1-H1 that forms a strong intramolecular hydrogen bond with the C9=O9 carbonyl group and the stretching vibration of O2-H2 that is weakly hydrogen-bonded to O1-H1. For the 1:1 hydration complex Az(H(2)O)(1), we identified three conformers. In the most stable conformer, the water molecule forms hydrogen bonds with the O1-H1 and O2-H2 groups of Az as a proton donor and proton acceptor, respectively. In the other conformers, the water binds to the C10=O10 group in two nearly isoenergetic configurations. In contrast to the sharp vibronic peaks in the FE spectra of Az and Az(H(2)O)(1), only broad, structureless absorption was observed for Az(H(2)O)(n) (n>= 2), indicating a facile decay process, possibly due to proton transfer in the electronic excited state. The FDIR spectrum with the wavelength of the probe laser fixed at the broad band exhibited a broad vibrational band near the O2-H2 stretching vibration frequency of the most stable conformer of Az(H(2)O)(1). With the help of theoretical calculations, we suggest that the broad vibrational band may represent the occurrence of proton transfer by tunnelling in the electronic ground state of Az(H(2)O)(n) (n>= 2) upon excitation of the O2-H2 vibration. PMID- 22514008 TI - Two different pentalogies in an adult patient: a pentalogy of Cantrell associated with a pentalogy of Fallot. PMID- 22514009 TI - Effect of preload on left atrial function: evaluated by tissue Doppler and strain imaging. AB - AIMS: Both strain and strain rate (SR) measure the regional myocardial deformation and can assess phasic left atrial (LA) function. However, there is still a lack of evidence for their volume independency. In this study, strain and SR determined by tissue Doppler imaging were used to evaluate the effect of preload reduction in end-stage renal disease patients who were undergoing regular haemodialysis (HD). METHODS AND RESULTS: Forty-one subjects who underwent transthoracic echocardiography just before and after HD were enrolled. LA strain was measured during late systole, and LA peak tissue velocity and SR were measured during systole and during early and late diastolic periods. The values of tissue velocity, strain, and SR were obtained in the basal septal, lateral, inferior, and anterior walls of the LA. The mean strain value was 23.89 +/- 7.29% at baseline and decreased to 21.88 +/- 5.85% after HD (P = 0.019). SR during systole (before HD 1.55 +/- 0.40; after HD 1.38 +/- 0.35, P = 0.001) and early diastole (before HD -1.41 +/- 0.54; after HD -1.16 +/- 0.45, P = 0.001) also changed. However, the acute preload change caused by HD did not affect the peak tissue velocity (before HD -6.34 +/- 1.58 cm/s; after HD -6.46 +/- 1.54 cm/s, P = 0.436) and the SR (before HD -1.36 +/- 0.45/s; after HD -1.34 +/- 0.29/s, P = 0.621) measured during late diastole. CONCLUSION: Both tissue velocity and SR during late diastole, representing the contractile function of the LA, are relatively preload-independent parameters and are available for the evaluation of the LA function. PMID- 22514010 TI - A giant right atrial myxoma presenting as acute pulmonary emboli. PMID- 22514007 TI - Epigenetic regulation of cardiac development and function by polycomb group and trithorax group proteins. AB - Heart disease is a leading cause of death and disability in developed countries. Heart disease includes a broad range of diseases that affect the development and/or function of the cardiovascular system. Some of these diseases, such as congenital heart defects, are present at birth. Others develop over time and may be influenced by both genetic and environmental factors. Many of the known heart diseases are associated with abnormal expression of genes. Understanding the factors and mechanisms that regulate gene expression in the heart is essential for the detection, treatment, and prevention of heart diseases. Polycomb Group (PcG) and Trithorax Group (TrxG) proteins are special families of chromatin factors that regulate developmental gene expression in many tissues and organs. Accumulating evidence suggests that these proteins are important regulators of development and function of the heart as well. A better understanding of their roles and functional mechanisms will translate into new opportunities for combating heart disease. PMID- 22514012 TI - Probing riboswitch-ligand interactions using thiamine pyrophosphate analogues. AB - The Escherichia coli thiM riboswitch forms specific contacts with its natural ligand, thiamine pyrophosphate (TPP or thiamine diphosphate), allowing it to generate not only nanomolar binding affinity, but also a high degree of discrimination against similar small molecules. A range of synthetic TPP analogues have been used to probe each of the riboswitch-ligand interactions. The results show that the pyrimidine-sensing helix of thiM is exquisitely tuned to select for TPP by recognising the H-bonding donor and acceptors around its aminopyrimidine ring and also by forming pi-stacking interactions that may be sensitive to the electronics of the ring. The central thiazolium ring of TPP appears to be more important for ligand recognition than previously thought. It may contribute to binding via long-range electrostatic interactions and/or by exerting an electron withdrawing effect on the pyrimidine ring, allowing its presence to be sensed indirectly and thereby allowing discrimination between thiamine (and its phosphate esters) and other aminopyrimidines found in vivo. The pyrophosphate moiety is essential for submicromolar binding affinity, but unexpectedly, it does not appear to be strictly necessary for modulation of gene expression. PMID- 22514011 TI - Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes. AB - The application of paired-end next generation sequencing approaches has made it possible to systematically characterize rearrangements of the cancer genome to base-pair level. Utilizing this approach, we report the first detailed analysis of ovarian cancer rearrangements, comparing high-grade serous and clear cell cancers, and these histotypes with other solid cancers. Somatic rearrangements were systematically characterized in eight high-grade serous and five clear cell ovarian cancer genomes and we report here the identification of > 600 somatic rearrangements. Recurrent rearrangements of the transcriptional regulator gene, TSHZ3, were found in three of eight serous cases. Comparison to breast, pancreatic and prostate cancer genomes revealed that a subset of ovarian cancers share a marked tandem duplication phenotype with triple-negative breast cancers. The tandem duplication phenotype was not linked to BRCA1/2 mutation, suggesting that other common mechanisms or carcinogenic exposures are operative. High-grade serous cancers arising in women with germline BRCA1 or BRCA2 mutation showed a high frequency of small chromosomal deletions. These findings indicate that BRCA1/2 germline mutation may contribute to widespread structural change and that other undefined mechanism(s), which are potentially shared with triple-negative breast cancer, promote tandem chromosomal duplications that sculpt the ovarian cancer genome. PMID- 22514013 TI - Physical strength, fighting ability, and aggressiveness in adolescents. AB - OBJECTIVES: Recent research suggests that evolutionary selection pressures have shaped mental mechanisms to be able to assess one's own and other's physical strength, fighting ability, and aggressiveness. According to the recalibrational theory, anger may be linked to fighting ability and serve as a bargaining mechanism to improve welfare obtained in social conflict. We hypothesized that late adolescent men (but not mid-adolescent men or women) use this mechanism, as it would be particularly adaptive for them to avoid potential costs from direct conflict in male competition. METHODS: The present study investigated the relationship between fighting ability (estimated from handgrip strength [HGS], a measure of upper body strength, and self-reported fighting ability) and aggressiveness (physical and nonphysical) in 288 Spanish adolescents aged 14-18 years. RESULTS: Our results indicated a positive relationship between self perceived fighting ability and HGS in both sexes during adolescence. There was no association between fighting ability and aggressiveness in late adolescent women (17-18 years). For men, there was a positive relationship between fighting ability and physical aggression, but the strength of this relationship decreased with age. Additionally, for men, there was a positive relationship between fighting ability and anger but only in late adolescence, and thus arguing that for adolescent men aggression strategies shift from physical to nonphysical as they age. CONCLUSIONS: With reference to the recalibrational theory of anger, our results suggest that the sex- and age-dependent associations between fighting ability and physical and nonphysical aggression indicate divergent adaptive skills between sexes, which are driven by intrasexual competition. PMID- 22514015 TI - Highly biocompatible, hollow coordination polymer nanoparticles as cisplatin carriers for efficient intracellular drug delivery. AB - Highly biocompatible coordination polymer (Prussian Blue) nanoparticles (LC(50) > 1000 MUg mL(-1)) with a hollow interior and a microporous framework (denoted as HPB) are utilized as an anticancer drug (i.e. cisplatin) capsule for chemotherapy of bladder cancer T24 cells. PMID- 22514014 TI - Exposure to the pesticide linuron affects androgen-dependent gene expression in the three-spined stickleback (Gasterosteus aculeatus). AB - Previous research demonstrated that exposure to exogenous androgens and effluents with androgenic activity can induce spiggin mRNA production in the kidney of the three-spined stickleback (Gasterosteus aculeatus). In the present study, we determine whether a short-term exposure to a known antiandrogenic pesticide, linuron (LN), suppresses spiggin mRNA in male stickleback and in androgenized female stickleback. Primers were designed from previously characterized sequences for each androgen receptor (AR) isoform in stickleback, aralpha and arbeta, to assess whether these receptors are differentially regulated by androgen or antiandrogen exposure. Fish were exposed for 72 h to one of four treatments: control, LN (250 ug/L), 17alpha-methyltestosterone (MT, 500 ng/L), and an LN-MT mixture at those same concentrations. There was no effect of LN on spiggin and arbeta mRNA levels in male kidney, while levels of aralpha were significantly increased twofold. Exposure to LN significantly inhibited MT-induced spiggin RNA production in female kidney with no effect on expression of aralpha and arbeta. The present study is the first to demonstrate the antiandrogenic effect of LN at the transcript level and to examine androgenic/antiandrogenic responsiveness of the two ARs in the stickleback. From the present study, it was determined that measurement of spiggin RNA is a reliable and sensitive screening tool for the detection of both androgenic and antiandrogenic compounds. PMID- 22514016 TI - A high-fat diet enhances proliferation of prostate cancer cells and activates MCP 1/CCR2 signaling. AB - BACKGROUND: Dietary patterns including high-fat diet (HFD) and high-carbohydrate diet (HCD) play an important role in prostate cancer progression. However, which of these diets have the greatest effect on tumor progression and its underlying mechanisms remains unclear. METHODS: We investigated the effects of different diets on prostate cancer cell growth and the relevant circulating factors including serum insulin, growth factors, and inflammatory cytokines using the in vivo and ex vivo model. RESULTS: The tumor growth of prostate cancer LNCaP xenograft was significantly higher in the HFD group than in the HCD and control diet (CD) groups (P = 0.01; HFD vs. HCD, P = 0.025; HFD vs. CD, P = 0.003). The mean level of the serum monocyte chemoattractant protein-1 (MCP-1) in the HFD group was significantly higher than that in the HCD and CD groups (P = 0.024; HFD vs. HCD, P = 0.033; HFD vs. CD, P = 0.001). The mRNA levels of CC chemokine receptor 2 (CCR2), which is an MCP-1 receptor, and the expression of activated Akt were the highest in the HFD group. Furthermore, serum from HFD-fed mice enhanced the proliferation of two PCa cells and CCR2 knockdown inhibited HFD induced proliferation of LNCaP cells. CONCLUSIONS: An HFD enhanced prostate cancer cell growth more strongly than an HCD or CD. MCP-1/CCR2 signaling may be involved in an HFD-induced prostate cancer progression. PMID- 22514017 TI - Azo N=N bond cleavage with a redox-active vanadium compound involving metal ligand cooperativity. PMID- 22514018 TI - Development of tools to study lacto-N-biosidase: an important enzyme involved in the breakdown of human milk oligosaccharides. AB - Milk and sugar? The elucidation of the catalytic mechanism and the development of the first known inhibitor for lacto-N-biosidases, which are important enzymes involved in the breakdown of human milk oligosaccharides, are described. PMID- 22514019 TI - The importance of RF bandwidth for effective tagging in pulsed arterial spin labeling MRI at 9.4T. AB - The movement towards MRI at higher field strengths (>7T) has enhanced the appeal of arterial spin labeling (ASL) for many applications due to improved SNR of the measurements. Greater field strength also introduces increased magnetic susceptibility effects resulting in marked B(0) field inhomogeneity. Although B(0) field perturbations can be minimised by shimming over the imaging volume, marked field inhomogeneity is likely to remain within the labeling region for pulsed ASL (PASL). This study highlights a potential source of error in cerebral blood flow quantification using PASL at high field. We show that labeling efficiency in flow-sensitive alternating inversion recovery (FAIR) displayed marked sensitivity to the RF bandwidth of the inversion pulse in a rat model at 9.4T. The majority of preclinical PASL studies have not reported the bandwidth of the inversion pulse. We show that a high bandwidth pulse of > = 15 kHz was required to robustly overcome the field inhomogeneity in the labeling region at high field strength, which is significantly greater than the inversion bandwidth ~2-3 kHz used in previous studies. Unless SAR levels are at their limit, we suggest the use of a high bandwidth labeling pulse for most PASL studies. PMID- 22514020 TI - Structural and electronic properties of CuSbS2 and CuBiS2: potential absorber materials for thin-film solar cells. AB - As the demand for photovoltaics rapidly increases, there is a pressing need for the identification of new visible light absorbing materials for thin-film solar cells that offer similar performance to the current technologies based on CdTe and Cu(In,Ga)Se(2). Metal sulphides are the ideal candidate materials, but their band gaps are usually too large to absorb significant fractions of visible light. However, by combining Cu(+) (low binding energy d(10) band) and Sb(3+)/Bi(3+) (low binding energy s(2) band), the ternary sulphides CuSbS(2) and CuBiS(2) are formed, which have been gathering recent interest for solar cell applications. Using a hybrid density functional theory approach, we calculate the structural and electronic properties of these two materials. Our results highlight the stereochemical activity of the Sb and Bi lone pair electrons, and predict that the formation of hole carriers will occur in the Cu d(10) band and hence will involve oxidation of Cu(I). PMID- 22514021 TI - A new "turn-on" chemodosimeter for Hg2+: ICT fluorophore formation via Hg(2+) induced carbaldehyde recovery from 1,3-dithiane. AB - A novel sensitive and specific Hg(2+) chemodosimeter, derived from 1',3'-dithiane substituted 2,1,3-benzoxadiazole, displays "turn-on" fluorescent and colorimetric responses via an Hg(2+)-triggered aldehyde recovery reaction. Its potential to monitor Hg(2+) in living organisms has been demonstrated using zebrafish larvae. PMID- 22514022 TI - O2 induced Cu surface segregation in Au-Cu alloys studied by angle resolved XPS and DFT modelling. AB - Surface segregation effects on polycrystalline Au-Cu alloys (Au(0.80)Cu(0.20), Au(0.85)Cu(0.15) and Au(0.90)Cu(0.10)) were studied at room temperature by angle resolved XPS (ARXPS) and density functional theory (DFT) before and after exposure to O(2). Au surface enrichment was found as predicted from calculations showing that this process is energetically favourable, with a segregation energy for Au in a Cu matrix of -0.37 eV atom(-1). Surface enrichment with Cu was observed after exposure to O(2) due to its dissociative adsorption, in agreement with DFT calculations that predicted an energy gain of -1.80 eV atom(-1) for the transfer of Cu atoms to a surface containing adsorbed oxygen atoms, thus leading to an inversion in surface population. PMID- 22514023 TI - New endoscopic thyroidectomy via a unilateral axillo-breast approach with gas insufflation: Preliminary report. AB - BACKGROUND: Invasiveness of endoscopic thyroidectomy has been in debate. The purpose of this study was to introduce new endoscopic thyroidectomy via a unilateral axillo-breast approach (UABA) with gas insufflation to lessen invasiveness. METHODS: We performed 68 cases of hemithyroidectomy via a UABA with gas insufflation from January to July 2011. The following variables were studied: operation time, pain score, drainage amount, drainage day, perioperative complications, pathological outcomes, and cosmetic satisfaction. RESULTS: Mean postoperative pain visual analogue scale (VAS) scores were 2.75 +/- 0.93 and 2.07 +/- 0.79 at 1 and 3 days after surgery. The mean amount of drainage over the first 3 postoperative days was 144.35 +/- 51.64 mL, and the mean time to drain removal was 3.75 +/- 0.81 days. Two cases (2.9%) of transient vocal cord palsy and 2 cases (2.9%) of seroma were identified. All patients were satisfied with the cosmetic results. CONCLUSION: Endoscopic thyroidectomy via a UABA with gas insufflation is a feasible and less invasive option for selected patients. PMID- 22514024 TI - Bridging QTAIM with vibrational spectroscopy: the energy of intramolecular hydrogen bonds in DNA-related biomolecules. AB - Physical properties of over 8000 intramolecular hydrogen bonds (iHBs), including 2901 ones of the types OH...O, OH...N, NH...O and OH...C, in 4244 conformers of the DNA-related molecules (four canonical 2'-deoxyribonucleotides, 1,2 dideoxyribose-5-phosphate, and 2-deoxy-D-ribose in its furanose, pyranose and linear forms) have been investigated using quantum theory of atoms in molecules (QTAIM) and vibrational analysis. It has been found that for all iHBs with positive red-shift of the proton donating group stretching frequency the shift value correlates with rho(cp)-the electron charge density at the (3,-1)-type bond critical point. Combining QTAIM and spectroscopic data new relationships for estimation of OH...O, OH...N, NH...O and OH...C iHB enthalpy of formation (kcal mol(-1)) with RMS error below 0.8 kcal mol(-1) have been established: E(OH...O) = -3.09 + 239.rho(cp), E(OH...N) = 1.72 + 142.rho(cp), E(NH...O) = -2.03 + 225.rho(cp), E(OH...C) = -0.29 + 288.rho(cp), where rho(cp) is in e a(0)(-3) (a(0)- the Bohr radius). It has been shown that XHY iHBs with red-shift values over 40 cm(-1) are characterized by the following minimal values of the XHY angle, rho(cp) and nubla(2)rho(cp): 112 degrees , 0.005 e a(0)(-3) and 0.016 e a(0)(-5), respectively. New relationships have been used to reveal the strongest iHBs in canonical 2'-deoxy- and ribonucleosides and the O(5')H...N(3) H-bond in ribonucleoside guanosine was found to have the maximum energy (8.1 kcal mol(-1)). PMID- 22514025 TI - Simple chiral sulfonamide primary amine catalysed highly enantioselective Michael addition of malonates to enones. AB - A chiral sulfonamide primary amine-organocatalysed, highly enantioselective Michael addition of malonates to enones has been developed. This reaction afforded the corresponding products in excellent yields (up to 99%) and excellent enantioselectivity (up to 99% ee). PMID- 22514026 TI - Novel methods for the quantification of changes in actin organization in chondrocytes using fluorescent imaging and linear profiling. AB - We present three novel reproducible methodologies for the quantification of changes in actin organization from microscope images. Striation and integrative analysis were devised for the investigation of trans-cellular filaments and F actin localization, respectively, in response to physiological or mechanical actin-modulatory conditions. Additionally, the Parker-Qusous (PQ) formula was developed as a measure of total quantity of F-actin, independent of cell volume changes, whereby fluorescence intensity was divided by the cube root of cell volume, squared. Values obtained were quantified in Mauricean Units (Mu; pixel/MUm(3)). Upon isolation, there was a 49% decrease in total F-actin fluorescence from 1.91 +/- 0.16 pixel/MUm(3) (Mu) to 0.95 +/- 0.55 Mu, whereas upon culture, an apparent increase in total fluorescence was deemed insignificant due to an increase in average cell volume, with a rise, however, in striation units (StU) from 1 +/- 1 to 5 +/- 1 StU/cell, and a decrease in percentage cortical fluorescence to 30.45% +/- 1.52% (P = 7.8 * 10(-5)). Freshly isolated chondrocytes exhibited a decrease in total F-actin fluorescence to 0.61 +/- 0.05 Mu and 0.32 +/- 0.02 Mu, 10 min posthypertonic and hypotonic challenges, respectively. Regulatory volume decrease was inhibited in the presence of REV5901 with maintenance of actin levels at 1.15 Mu. Following mechanical impact in situ, there was a reduction in total F-actin fluorescence to 0.95 +/- 0.08 Mu and 0.74 +/- 0.06 Mu under isotonic and hypotonic conditions, respectively, but not under hypertonic conditions. We report simple methodologies for quantification of changes in actin organization, which will further our understanding of the role of actin in various cellular stress responses. These techniques can be applied to better quantify changes in localization of various proteins using fluorescent labeling. PMID- 22514027 TI - Microenvironmental control of enantiodifferentiating photocyclization of 5 hydroxy-1,1-diphenylpentene through selective solvation. AB - For mechanistic elucidation of the photosensitized cyclization of 5-hydroxy-1,1 diphenylpentene (1), its methyl ether (4) was synthesized as an unreactive "dummy" substrate and used as a quencher of the sensitizer fluorescence to reveal the intervention of an exciplex intermediate that was unable to detect when reactive substrate 1 was used as a quencher/reactant In the enantiodifferentiating photocyclization of 1 to 2-(diphenylmethyl)tetrahydrofuran (2) sensitized by a chiral saccharide ester of 1,4-naphthalenedicarboxylate (3), the enantiomeric excess (ee) of chiral product 2 obtained in methylcyclohexane (MCH) at 25 degrees C was significantly enhanced from 20% to 35% upon 10-fold dilution of the sample solution by MCH, for which the reduced solvent polarity, discouraging dissociation of the intervening radical ionic exciplex, is likely to be responsible. Further attempts to microenvironmentally control the photochirogenic reaction and enhance the product's ee through selective solvation of polar cosolvent to the diastereomeric exciplex pair in nonpolar solvent were not successful probably due to the inherently high local polarity around the exciplex of saccharide-appended 3 with alcoholic substrate 1. PMID- 22514028 TI - CDH1 methylation in preoperative peritoneal washes is an independent prognostic factor for gastric cancer. AB - BACKGROUND AND OBJECTIVES: To investigate the clinical value of CDH1 methylation in preoperative peritoneal washes (PPW) from gastric cancer patients. METHODS: CDH1 methylation was detected by real-time methylation specific-PCR in tumor tissues and corresponding PPW from 92 gastric cancer patients, gastric mucosa from 40 chronic gastritis patients and 48 normal persons. RESULTS: CDH1 methylation was found in 75 of 92 (81.5%) gastric cancer tissues, which significantly correlated with size, growth pattern, differentiation, lymphatic invasion, venous invasion, invasion depth, lymph node metastasis, distant metastasis, and TNM stage of tumor (all P < 0.05), but its relationship to age, gender, tumor site, and H. pylori infection was not found (all P > 0.05). The percentage of CDH1 methylation in PPW was 48.9%, of which the Azeta value of ROC curve was 0.8 compared to that in gastric cancer tissues. Kaplan-Meier analysis showed that there was a significant difference in disease-free survival (DFS) between the patients with or without methylated CDH1 in their PPW (chi(2) = 109.64, P < 0.000). Cox regression analysis revealed CDH1 methylation in PPW was an independent risk factor for gastric cancer patients, with a remarkable decrease in DFS after postoperative 30 months. CONCLUSIONS: Methylated CDH1 in PPW predicts poor prognosis for gastric cancer patients. PMID- 22514029 TI - On random sample size, ignorability, ancillarity, completeness, separability, and degeneracy: sequential trials, random sample sizes, and missing data. AB - The vast majority of settings for which frequentist statistical properties are derived assume a fixed, a priori known sample size. Familiar properties then follow, such as, for example, the consistency, asymptotic normality, and efficiency of the sample average for the mean parameter, under a wide range of conditions. We are concerned here with the alternative situation in which the sample size is itself a random variable which may depend on the data being collected. Further, the rule governing this may be deterministic or probabilistic. There are many important practical examples of such settings, including missing data, sequential trials, and informative cluster size. It is well known that special issues can arise when evaluating the properties of statistical procedures under such sampling schemes, and much has been written about specific areas (Grambsch P. Sequential sampling based on the observed Fisher information to guarantee the accuracy of the maximum likelihood estimator. Ann Stat 1983; 11: 68-77; Barndorff-Nielsen O and Cox DR. The effect of sampling rules on likelihood statistics. Int Stat Rev 1984; 52: 309-326). Our aim is to place these various related examples into a single framework derived from the joint modeling of the outcomes and sampling process and so derive generic results that in turn provide insight, and in some cases practical consequences, for different settings. It is shown that, even in the simplest case of estimating a mean, some of the results appear counterintuitive. In many examples, the sample average may exhibit small sample bias and, even when it is unbiased, may not be optimal. Indeed, there may be no minimum variance unbiased estimator for the mean. Such results follow directly from key attributes such as non-ancillarity of the sample size and incompleteness of the minimal sufficient statistic of the sample size and sample sum. Although our results have direct and obvious implications for estimation following group sequential trials, there are also ramifications for a range of other settings, such as random cluster sizes, censored time-to-event data, and the joint modeling of longitudinal and time-to event data. Here, we use the simplest group sequential setting to develop and explicate the main results. Some implications for random sample sizes and missing data are also considered. Consequences for other related settings will be considered elsewhere. PMID- 22514030 TI - A transformation class for spatio-temporal survival data with a cure fraction. AB - We propose a hierarchical Bayesian methodology to model spatially or spatio temporal clustered survival data with possibility of cure. A flexible continuous transformation class of survival curves indexed by a single parameter is used. This transformation model is a larger class of models containing two special cases of the well-known existing models: the proportional hazard and the proportional odds models. The survival curve is modeled as a function of a baseline cumulative distribution function, cure rates, and spatio-temporal frailties. The cure rates are modeled through a covariate link specification and the spatial frailties are specified using a conditionally autoregressive model with time-varying parameters resulting in a spatio-temporal formulation. The likelihood function is formulated assuming that the single parameter controlling the transformation is unknown and full conditional distributions are derived. A model with a non-parametric baseline cumulative distribution function is implemented and a Markov chain Monte Carlo algorithm is specified to obtain the usual posterior estimates, smoothed by regional level maps of spatio-temporal frailties and cure rates. Finally, we apply our methodology to melanoma cancer survival times for patients diagnosed in the state of New Jersey between 2000 and 2007, and with follow-up time until 2007. PMID- 22514031 TI - Solar irradiation of the seed germination stimulant karrikinolide produces two novel head-to-head cage dimers. AB - Karrikinolide is a naturally derived potent seed germination stimulant that is responsible for triggering the germination of numerous plant species from various habitats around the world. We now report that solar irradiation of karrikinolide yields two novel head-to-head cage photodimers with the formation, stability and bioactivity of both presented herein. PMID- 22514032 TI - In vitro delivery, cytotoxicity, swelling, and degradation behavior of a liquid to-solid gelling polymer system for cerebral aneurysm embolization. AB - This study examines the in vitro characteristics of a crosslinking polymer system for cerebral aneurysm embolization. The polymeric material is composed of poly(propylene glycol)diacrylate (PPODA) and pentaerythritol tetrakis(3 mercaptopropionate) (QT), formulated with the liquid contrast agents ConrayTM or OmnipaqueTM 300. The PPODA-QT system was tested for delivery feasibility through mock delivery into a model aneurysm. Cytotoxicity was performed by exposing 3T3 cells to gel formulations, followed by a cell viability assay. Swelling was measured on samples submerged in 150 mM phosphate buffered saline at 37 or 50 degrees C. The same samples underwent compression testing to assess degradation, characterized by reduction in Young's modulus over time. The PPODA-QT system was easily deliverable to mock aneurysms. Cytotoxicity results indicated that Conray formulated gels are initially less toxic than Omnipaque-formulated gels, but show greater susceptibility to swelling and degradation over time. In general, these experiments represented more challenging conditions than would be present in vivo, and therefore, reported results are likely overestimations of in vivo outcomes. However, these results highlight potential issues with each PPODA-QT formulation. Given the desired outcome of neointimal tissue growth over the polymer material, initial cytotoxicity may be more important than long-term factors when choosing an optimal formulation for aneurysm embolization. PMID- 22514033 TI - Looking within and reaching out: bereavement counselor perceptions of grieving adults with ID. AB - The purpose of this qualitative study was to explore the grief and loss experience of adults with ID through the eyes of 18 hospice-affiliated bereavement counselors. The data included interviews with hospice affiliated counselors who had provided grief counseling to adults with ID. The interview data were analyzed using grounded theory. The participants voiced clearly that loss needs to be recognized and grief must be honored for all persons, including those with ID. The participating counselors described the long histories of unrecognized losses and the unintended consequences of protecting people with ID by avoiding informing them or including them in change, loss, and death scenarios. The interview data depicted individuals with ID being so "invisible" that they are often disregarded in times of crisis and loss. The findings from this study, along with existing published literature, point out a serious need for education and training for families and formal and informal caregivers as well as professionals. Palliative care and hospice workers have an obligation and opportunity to identify, support, and, if necessary, treat the grief of those with ID. The hope is that over time, there will be less need for end-of-life care providers to be the lone educators and supporters about death and grief for any individual. PMID- 22514034 TI - Measurement of distance with the nanoscale precise imaging by rapid beam oscillation method. AB - We discuss here the principles of a novel optical method in which the scanning of a laser spot around a fluorescent object is used to determine its shape, orientation, and fluorophore distribution. The scanning pattern is adapted to the shape of the object according to a feedback principle based on intensity modulation measurements. The modulation of the intensity with respect to the angular coordinate is used to keep the orbit centered on the object. The modulation induced by rapid oscillations of the orbit radius is used to measure the local distance from the surface with nanometer precision. We provide a model to describe the fundamental relationship between modulation and distance and discuss the range of validity of several approximate expressions. According to this model, the distance can be measured with a precision dependent on the steepness of the point spread function and the total number of detected photons. To test our findings, we performed experiments with one or two channels on fluorescent spheres of known size and characterized the modulation function of our microscope setup. We conclude that the method can be used to measure distances in the range 10-200 nm between two surfaces labeled with two different probes. PMID- 22514035 TI - A fluorescent chiral chemosensor for the recognition of the two enantiomers of chiral carboxylates. AB - A new 7-nitrobenz-2-oxa-1,3-diazole (NBD)-based fluorescent chiral chemosensor (NBD-1) was prepared and applied to the recognition of the two enantiomers of the tetrabutylammonium salts of N-t-Boc-alpha-amino acids and chiral carboxylic acids including naproxen. In particular, the chiral recognition by the new fluorescent chiral chemosensor for the two enantiomers of N-t-Boc-threonine (tetrabutylammonium salt) was quite excellent, the Stern-Volmer constant ratio (K(D)/K(L)) for the two enantiomers being as high as 4.89. PMID- 22514036 TI - Validation of the seventh edition of the American Joint Committee on cancer tumor node-staging system in patients with colorectal carcinoma in comparison with sixth classification. AB - BACKGROUND: The aim of this study was to compare survival rates assessed by the seventh-staging system with those by the sixth classification. METHODS: This was a retrospective study of 3,377 patients who underwent surgery for colorectal adenocarcinoma from three university hospitals. The overall survival (OS) and cancer-specific survival (CSS) rates were compared between patients whose stages according to the seventh-staging system remained the same and patients whose stages migrated, and between subgroups within each new stage (homogeneity analysis). RESULTS: In seventh edition, the 5-year OS and CSS rates of patients with T3n2 tumor were significantly greater in the downstaged patients (T3N2a) than in other patients (T3N2b) (OS, P = 0.010; CSS, P = 0.009). The 5-year survival rates for patients with T4a and T4b sub-classifications according to the seventh edition did not differ from those in patients with T4N0-1. Homogeneity analysis of subgroups classified using the new system showed that some subgroups of stage IIIB (T3N2a/T4aN1) had poorer survival rates compared with patients in other sub-categories in the same stage IIIB (P < 0.001). CONCLUSION: Overall, the seventh edition provides a more detailed classification of the prognosis than the old system. However, further study would be warranted to evaluate the validity of sub-classification in seventh TNM-staging system, especially for T4a-b and T3N2a tumors. PMID- 22514037 TI - Stereoselective hydrofluorination of ynamides: a straightforward synthesis of novel alpha-fluoroenamides. AB - alpha-Fluoroenamides, potent rigid fluorinated bioisosters of ureas, have been synthesized by a highly regio- and stereo-selective hydrofluorination of ynamides in anhydrous HF. This reaction provides the first general entry to alpha fluoroenamides and can easily be applied to a wide range of substrates. PMID- 22514038 TI - Evaluation of an automated sphygmomanometer for use in the office setting. AB - OBJECTIVE: To determine whether the WatchBP Office sphygmomanometer can be used to obtain automated office blood pressure (AOBP) readings that are similar to the awake ambulatory BP. METHODS: One hundred patients referred for 24 h ambulatory BP monitoring had BP recorded three times using the WatchBP Office fully automated sphygmomanometer in accordance with standard AOBP measurement guidelines. The mean AOBP was compared with the mean awake ambulatory BP. RESULTS: The mean (+/- SD) AOBP (138.6 +/- 13.7/79.7 +/- 9.0 mmHg) was similar to the mean awake ambulatory BP (136.8 +/- 12.4/79.0 +/- 10.8 mmHg). The small difference in systolic BP (1.8 mmHg) was statistically significant (P=0.03), but was within the accepted range (5 mmHg) recommended by guidelines for equivalence between BP readings. There was a strong correlation (P<0.001) between the systolic/diastolic AOBP and awake ambulatory BP readings (r=0.819/0.801). CONCLUSION: The WatchBP Office produces BP readings that closely approximate the awake ambulatory BP, confirming that this automated sphygmomanometer is suitable for recording AOBP in clinical practice. PMID- 22514039 TI - Relationship between sodium intake and blood pressure according to metabolic syndrome status in the Korean National Health and Nutrition Examination Survey. AB - OBJECTIVES: The relationship between sodium intake and blood pressure (BP) in population studies varies depending on the dietary habit and the characteristics of the population studied. Asian dietary patterns and salt sensitivity have been suggested to explain this association. Aging and metabolic syndrome (MS) are the most common reasons for salt sensitivity in populations. PARTICIPANTS AND METHODS: We therefore examined the dietary patterns in the Korean National Health and Nutrition Examination Survey. RESULTS: In a multiple regression model for 3757 patients, age, antihypertensive medication, BMI, family history of hypertension, and MS were positively associated with systolic BP, whereas female sex, income, educational status, and fruit intake were negatively associated with systolic BP. Fruit intake was the only dietary factor that was negatively associated with systolic BP (P=0.017). In MS (n=712), sodium and fruit intake was independently positively and negatively associated with systolic BP, respectively, discounting age and medication. In contrast, in normal individuals (n=3045), diet was not related to systolic BP. The relationship between diet and systolic BP is more clear-cut in MS. CONCLUSION: Dietary pattern and salt sensitivity at the population level could be a cause of the relationship between sodium intake and BP. PMID- 22514040 TI - Comparison of the electronic structure of different perylene-based dye aggregates. AB - Aggregates of functionalized polycyclic aromatic molecules like perylene derivatives differ in important optoelectronic properties such as absorption and emission spectra or exciton diffusion lengths. Although those differences are well known, it is not fully understood if they are caused by variations in the geometrical orientation of the molecules within the aggregates, variations in the electronic structures of the dye aggregates or interplay of both. As this knowledge is of interest for the development of materials with optimized functionalities, we investigate this question by comparing the electronic structures of dimer systems of representative perylene-based chromophores. The study comprises dimers of perylene, 3,4,9,10-perylene tetracarboxylic acid bisimide (PBI), 3,4,9,10-perylene tetracarboxylic acid dianhydride (PTCDA), and diindeno perylene (DIP). Potential energy curves (PECs) and characters of those electronic states are investigated which determine the optoelectronic properties. The computations use the spin-component-scaled approximate coupled-cluster second order method (SCS-CC2), which describes electronic states of predominately neutral excited (NE) and charge transfer (CT) character equally well. Our results show that the characters of the excited states change significantly with the intermolecular orientation and often represent significant mixtures of NE and CT characters. However, PECs and electronic structures of the investigated perylene derivatives are almost independent of the substitution patterns of the perylene core indicating that the observed differences in the optoelectronic properties mainly result from the geometrical structure of the dye aggregate. It also hints at the fact that optical properties can be computed from less-substituted model compounds if a proper aggregate geometry is chosen. PMID- 22514041 TI - Prey capture behavior of native vs. nonnative fishes: a case study from the Colorado River drainage basin (USA). AB - The Colorado River drainage basin is home to a diverse but imperiled fish fauna; one putative challenge facing natives is competition with nonnatives. We examined fishes from Colorado River tributaries to address the following questions: Do natives and nonnatives from the same trophic guild consume the same prey items? Will a given species alter its behavior when presented with different prey types? Do different species procure the same prey types via similar feeding behaviors? Roundtail chub (Gila robusta) and smallmouth bass (Micropterus dolomieu), midwater predators, and Sonora sucker (Catostomus insignis) and common carp (Cyprinus carpio), benthic omnivores, were offered six ecologically relevant prey types in more than 600 laboratory trials. Native species consumed a broader array of prey than nonnatives, and species from a given trophic guild demonstrated functional convergence in key aspects of feeding behavior. For example, roundtail chub and smallmouth bass consume prey attached to the substrate by biting, then ripping the prey from its point of attachment; in contrast, Sonora sucker remove attached prey via scraping. When presented with different prey types, common carp, roundtail chub, and smallmouth bass altered their prey capture behavior by modifying strike distance, gape, and angle of attack. Gape varied among the species examined here, with smallmouth bass demonstrating the largest functional and anatomical gape at a given body size. Because fish predators are gape limited, smallmouth bass will be able to consume a variety of large prey items in the wild, including large, invasive crayfish and young roundtail chub-their presumptive trophic competitors. PMID- 22514042 TI - Locomotor development of zebrafish (Danio rerio) under novel hydrodynamic conditions. AB - The kinematics, neuromuscular control, and hydrodynamic aspects of normal locomotor activity in larval zebrafish have been extensively studied. Although locomotion depends heavily on the fluid properties of water, we have little knowledge of what sensory and developmental cues zebrafish larvae receive from their interaction with the fluid medium in which they grow. In this study, I manipulate the viscosity of water in which larvae grow until 5 and 7 days postfertilization (dpf) and record the kinematics of routine turns in their growth medium. Larvae are then transferred to a new medium of different viscosity and filmed again after short and long acclimation periods. Four hypotheses are tested: (1) larval kinematics are constrained by muscle activation patterns, (2) larval kinematics are guided by kinematic objectives, (3) routine turning control is independent of early locomotor experience, and (4) response to novel fluid environment is independent of developmental stage. The results indicate that a kinematic parameter, stage 1 angle, correlates with the kinematics of stage 1 while muscle activation patterns likely constrain stage 2. Development of this behavior is not dependent on locomotor experience both at 5 and 7 dpf, although the two age groups respond differently to increased viscosity. PMID- 22514045 TI - Rhodium-catalyzed oxidative C2-acylation of indoles with aryl and alkyl aldehydes. AB - A rhodium-catalyzed oxidative C2-acylation of indoles with aryl and alkyl aldehydes via C-H bond activation is described. The reaction is highly atom economic and provides easy access to a wide variety of 2-aroylindoles. PMID- 22514046 TI - Altered expression of Alzheimer's disease-related proteins in male hypogonadal mice. AB - Age-related depletion of estrogens and androgens is associated with an increase in Alzheimer's disease (AD) brain pathology and diminished cognitive function. Here we investigated AD-associated molecular and cellular changes in brains of aged hypogonadal (hpg) male and female mice. hpg Mice have a spontaneous, inactivating genetic mutation in the GnRH gene resulting in life-long deficiency of gonadotropins and gonadal sex hormones. Western blot analysis revealed low levels of amyloid precursor protein and high levels of presenilin 1, amyloid precursor protein C-terminal fragment, and beta-amyloid 42 in brains of aged male, but not female, hpg mice. Changes were confined to the hippocampus and were not evident in the cerebellum or other brain tissues. Male hpg mice tended to have lower levels of IL-1beta protein than male littermate controls. Immunohistochemical staining of the basal forebrain revealed that male hpg mice had lower choline acetyltransferase levels per neuron compared with controls. These AD-like changes specific to male hpg mice supports a link between androgen depletion and the development of AD pathology. PMID- 22514047 TI - Nucleobindin-2 is a positive modulator of EGF-dependent signals leading to enhancement of cell growth and suppression of adipocyte differentiation. AB - Nucleobindin-2 is a 420-amino-acid EF-hand calcium-binding protein that undergoes proteolytic processing to generate an 82-amino-acid amino-terminal peptide termed nesfatin-1. To determine whether nucleobindin-2 has any biological function, nucleobindin-2 was either overexpressed or knocked down by short hairpin RNA in cultured CHO cells expressing the human insulin and epidermal growth factor (EGF) receptors (CHO/IE) and in 3T3-L1 cells. Reduction in nucleobindin-2 expression inhibited EGF-stimulated MAPK kinase (S217/S221) and Erk phosphorylation (T202/Y204). In contrast, there was no significant effect on EGF-stimulated EGF receptor phosphorylation, EGF receptor internalization, or 52-kDa Shc and c-Raf phosphorylation. Although kinase suppressor of Ras-1 and protein phosphatase 2A expression was not changed, intracellular calcium concentrations and PP2A activity was significantly increased in nucleobindin-2 knocked-down cells. Concomitant with these alterations in EGF-stimulated signaling, cell proliferation was significantly reduced in nucleobindin-2 knocked-down cells. Moreover, reduced nucleobindin-2 expression in 3T3-L1 preadipocytes resulted in a greater extent of 3T3-L1 cell adipocyte differentiation. Taken together, these data indicate that nucleobindin-2 regulates EGF-stimulated MAPK kinase/Erk signaling, cell proliferation, and adipocyte differentiation. PMID- 22514048 TI - Canadian breast implant cohort: extended follow-up of cancer incidence. AB - Cosmetic breast implants are not associated with increased breast cancer incidence, but variations of risk according to implant characteristics are still poorly understood. As well, the assessment of cancer risk for sites other than breast needs to be clarified. The purpose of this study was to fill these research gaps. This study presents an extended analysis of 10 more years of follow-up of a large Canadian cohort of women who received either cosmetic breast implants (n = 24,558) or other cosmetic surgery (15,893). Over 70% of the implant cohort was followed for over 20 years. Cancer incidence among implant women was compared to those of controls using multivariate Poisson models and the general female population using the standardized incidence ratios (SIRs). Women with breast implants had reduced rates of breast and endometrial cancers compared to other surgery women. Subglandular implants were associated to a reduced rate of breast cancer compared to submuscular implants [incidence rate ratio (IRR) = 0.78, 95% confidence interval (CI) = 0.63-0.96] and this reduction persisted over time. We observed a sevenfold increased rate (IRR = 7.36, 95% CI = 1.86-29.12) of breast cancer in the first 5 years after the date of surgery for polyurethane coated subglandular implant women but this IRR decreased progressively over time (p value for trend = 0.02). We also observed no increased risk of rarer forms of cancer among augmented women. A reduction in breast cancer incidence was observed for women with subglandular implants relative to women with submuscular implants. Possible increase of breast cancer incidence shortly after breast augmentation with polyurethane implants needs to be verified. PMID- 22514049 TI - Remote stereocontrol in reactions between 4- and 5-alkoxyalk-2-enylstannanes and 1-alkoxycarbonylimines and analogues: stereoselective approaches to novel alpha amino acids. AB - Reactions of the allyltin trichloride 45 generated from (4S)-4-benzyloxypent-2 enyl(tributyl)stannane 1 with imines prepared from glyoxylates proceed with useful levels of 1,5-stereocontrol in favour of (4E)-2,6-anti-2-(alkylamino)-6 benzyloxyhept-4-enoates 49. This stereoselectivity, controlled by the chirality of the stannane, dominates over any intrinsic stereochemical bias of the imine although a small amount of matching and mis-matching was observed. The allyltin trichloride 77 prepared from (4S)-4-(tert-butyldimethylsilyloxy)pent-2 enyl(tributyl)stannane 52 reacts with 1-alkoxycarbonylimines with the opposite 1,5-stereoselectivity to give the (4E)-2,6-syn-diastereoisomers 79. Matching and mismatching was more pronounced for tin(IV) chloride mediated reactions of (4R)-5 benzyloxy-4-methylpent-2-enyl(tributyl)stannane 80 with chiral 1 alkoxycarbonylimines but useful stereoselectivity in favour of (4E)-2,6-syn-2 alkyl- and arylthio-amino-7-benzyloxy-6-methylhept-4-enoates 177 was observed for reactions with achiral imines and similar, but reduced, stereoselectivity was observed for the 5-tert-butyldimethylsilyloxypentenylstannane 82. However, excellent 1,5-stereocontrol in favour of the (4E)-2,6-anti-isomers 179 was found using the 4,5-bis-alkoxypent-2-enylstannane 106. Modest (4E)-2,7-anti stereoselectivity was observed in the analogous tin(IV) bromide mediated reactions of (S)-5-methoxy- and (S)-5-hydroxyhex-2-enyl(tributyl)stannanes (S) 123 and (S)-122 with achiral 1-alkoxycarbonylimines but in this series the intrinsic stereochemical bias of the imine controls the facial selectivity of reactions of chiral 1-alkoxycarbonylimines. Useful (4E)-2,6-anti stereoselectivity was also observed in the tin(IV) chloride promoted reaction of the 4-benzyloxypent-2-enylstannane 1 with an oxime O-benzyl ether. PMID- 22514050 TI - Self-assembling peptide-based nanoparticles for siRNA delivery in primary cell lines. PMID- 22514051 TI - Mild rhodium(III)-catalyzed C-H activation and intermolecular annulation with allenes. AB - All(enes) great! A novel Rh(III)-catalyzed oxidative coupling with allenes under mild conditions provides heterocycles with exocyclic double bonds. This reaction features low catalyst loadings, high regio- and stereoselectivity, and excellent substrate scope. The products were derivatized and preliminary mechanistic studies were conducted. PMID- 22514052 TI - Differential responses of cortisol and corticosterone to adrenocorticotropic hormone (ACTH) in a subterranean rodent (Ctenomys talarum). AB - We aimed to evaluate the responses of cortisol, corticosterone, and blood glucose to adrenocorticotropic hormone (ACTH) in males and females of the subterranean rodent Ctenomys talarum and addressed interannual variations in the plasma levels of both hormones. The most important results indicate that: (1) cortisol positively responds to the ACTH signal but corticosterone does not, even though corticosterone levels were higher than cortisol concentrations, (2) plasma corticosterone concentrations in free-living animals were 20 times higher compared to values reported for the same population during previous annual periods and, as cortisol levels were similar, this resulted in much lower cortisol/corticosterone ratios, (3) cortisol and corticosterone differentiated in their relative proportions in plasma in free-living males and females. These results indicate that cortisol and corticosterone are differentially regulated in our study species and emphasize that a remarkable temporal variation in the relative proportions of these hormones may occur in natural populations. Therefore, the conclusions regarding the presence of cortisol and corticosterone in plasma of wild animals may differ substantially depending on the moment when the study is conducted. Recent data indicate that cortisol and corticosterone are not interchangeable hormones in species of free-living vertebrates. We suggest that, in addition to the classical roles of glucocorticoids (GCs), it is crucial that other physiological functions be kept in mind when interpreting GC data from wild species. PMID- 22514055 TI - A tubular macrocycle from covalently linked anthracenes and meta-phenylene spacers. AB - A novel tubular macrocycle containing four anthracene panels covalently linked by meta-phenylene spacers was synthesized. The tube is approximately 1 nm long with anthracene panels delimiting a columnar cavity with a diameter of ~1 nm and exhibits strong blue fluorescence. PMID- 22514053 TI - Screening of upregulated genes induced by high density in the vetch aphid Megoura crassicauda. AB - Aphids exhibit several polyphenisms in which discontinuous, alternative phenotypes are produced depending on environmental conditions. One representative example is the wing polyphenism, where winged and wingless females are produced through parthenogenesis. Previous work has shown that, in some aphid species, the density condition sensed by the mother aphid determines the developmental fate of embryos in her ovary, with high densities leading to winged progeny and low densities to wingless progeny. However, little is known about the molecular and physiological mechanisms underlying the wing polyphenism. To identify genes involved in the wing-morph determination in the vetch aphid, Megoura crassicauda, we compared maternal and embryonic transcripts between high- and low-density conditions using differential display, followed by quantitative real-time PCR (qRT-PCR). Under the high-density condition, two genes (Uba1 and Naca) were found to be upregulated in maternal tissues without ovaries, while one gene (ClpP) was upregulated in ovaries containing embryos. Uba1 and Naca encode factors that function in protein modification or transcriptional/translational regulation, respectively. In addition to differential display, candidate gene approaches focusing on morphogenetic and endocrine genes, i.e., wg, dpp, ap, hh, InR, IRS, Foxo, EcR, and USP, were also carried out. We found that wg was upregulated in maternal tissues under the high-density condition. The identified genes from both approaches are candidates for further study of their involvement in the transduction of density signals in mother aphids and/or the initial process of wing differentiation in embryos. PMID- 22514056 TI - Evaluation of epoxy resin sealer after three root canal filling techniques by confocal laser scanning microscopy. AB - The aim of this study was to evaluate the penetration of endodontic sealer into the dentin tubules, the integrity of the sealer layer perimeter, and the sealer area at the apical third after different filling techniques by confocal laser scanning microscopy (CLSM). Forty-five mandibular premolars were mechanically prepared with ProTaper files, until F5 file. Thereafter, they were filled with an epoxy-resin sealer (AH Plus) mixed with Rhodamine B dye (0.1% proportion) and allocated in three groups: Group 1, single master cone; Group 2, cold lateral compaction; and Group 3, Thermafil. For confocal laser scanning microscopy analysis, the specimens were transversely sectioned at 4 mm from the apex. The images at *10 and *40 were analyzed by Imagetool 3.0 software. Significant differences were not found among the three experimental groups according the dentin-impregnate area by the sealer (P = 0.68) and between the sealer and root canal perimeter (P = 0.18). However, root canal filling techniques were significantly different when apical sealer areas were compared (P = 0.001). Thermafil group showed smaller sealer areas (8.09%) while cold lateral compaction and gutta-percha master cone showed similar areas (17.37 and 21.18%, respectively). The dentin-impregnated area was not dependent on the root canal filling technique. Single master cone, cold lateral condensation and Thermafil techniques presented integrity of the sealer perimeter close to 100% and Thermafil resulted in a significantly thinner sealer layer. PMID- 22514057 TI - Synthesis of 2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-3 ((dimethylamino)methyl)camphor organocatalysts. AB - In a stereo-divergent synthesis, three novel camphor-derived bifunctional thiourea organocatalysts 7-9 have been prepared in five steps starting from (+) camphor. In addition, borneol-derived bifunctional thiourea organocatalysts 19/19' have been prepared in three steps from (1S)-(+)-camphorquinone. Novel organocatalysts 7-9, 19/19' have been evaluated in a model reaction of Michael addition of dimethyl malonate to trans-beta-nitrostyrene with low to moderate enantioselectivities (20%-60% ee). Configuration of all novel compounds has been meticulously determined using nuclear magnetic resonance (NMR) techniques. PMID- 22514058 TI - Clinical trials in gastric cancer and the future. AB - Following the first successful gastric resection for gastric cancer by Theodor Billroth in 1881 surgery has made tremendous progress leading to improved surgical mortality and morbidity. However, while treatment of early gastric cancer is frequently curative, 5-year survival rates for advanced gastric cancer remain dismal despite the application of perioperative multimodal treatment concepts. In this article we will outline key clinical trials that have lead to an improvement in treatment of gastric cancer patients with specific emphasis on the last 20 years. We will then outline recent concepts and key clinical trials that are currently being conducted in the field. Finally we will outline open questions that remain to be elucidated in the future. PMID- 22514059 TI - First-principles calculations on thermodynamic properties of BaTiO3 rhombohedral phase. AB - The calculations based on the linear combination of atomic orbitals have been performed for the low-temperature phase of BaTiO(3) crystal. Structural and electronic properties, as well as phonon frequencies were obtained using hybrid PBE0 exchange-correlation functional. The calculated frequencies and total energies at different volumes have been used to determine the equation of state and thermal contribution to the Helmholtz free energy within the quasiharmonic approximation. For the first time, the bulk modulus, volume thermal expansion coefficient, heat capacity, and Gruneisen parameters in BaTiO(3) rhombohedral phase have been estimated at zero pressure and temperatures form 0 to 200 K, based on the results of first-principles calculations. Empirical equation has been proposed to reproduce the temperature dependence of the calculated quantities. The agreement between the theoretical and experimental thermodynamic properties was found to be satisfactory. PMID- 22514060 TI - Characterization of thyroid nodules using the proposed thyroid imaging reporting and data system (TI-RADS). AB - BACKGROUND: The Thyroid Imaging Reporting and Data System (TI-RADS) was proposed based on a scheme similar to Breast Imaging Reporting and Data System (BI-RADS) lexicon used in breast lesions. The purpose of this study was to evaluate its interobserver variability and accuracy. METHODS: We included 498 nodules in 437 patients undergoing thyroidectomy. Two endocrine surgeons and 2 endocrinologists independently reviewed sonographic images. RESULTS: There was moderate to substantial interobserver agreement for final assessment category (kappa = 0.61). The overall sensitivity, specificity, and negative predictive value (NPV) were 94%, 43%, and 96%, respectively. Positive predictive values (PPVs) for categories 4 and 5 were 32% and 60%. The sensitivity was 92%, 99%, 96%, and 89%, whereas the specificity was 25%, 37%, 41%, and 62% for tumor sizes of <2, 2 to 3, 3 to 4, and >4 cm, respectively. CONCLUSION: TI-RADS is a helpful but not optimal reporting tool in characterizing thyroid lesions. Tumor size has a considerable impact on interobserver concordance and diagnostic performance. PMID- 22514061 TI - The use of comorbidities among adults experiencing care transitions: a systematic review and evolutionary analysis of empirical literature. AB - OBJECTIVE: To systematically review how comorbidities are employed in the empirical literature for adults coping with multiple chronic conditions during common episodes of acute illness that resulted in transition across health care setting. METHODS: Evolutionary concept analysis inductively identifies current consensus regarding the usage of a concept and results in exploring attributes and clarification of the concept. Sixty studies from 1965 to 2009 identified from MEDLINE, CINAHL, PsychINFO, and ISI Web of Science databases were analysed. RESULTS: Comorbidities were used heterogeneously among reviewed studies with most controlling for their presence (n=33) and lacking robust measurement (n=37). The designation of index or principal condition was equally heterogeneous with approximately half (n=26) representing the main disease or diagnosis of interest to the researcher. In this study comorbidities were associated with personal, disease or system level antecedents and consequences. A conceptual framework is proposed. DISCUSSION: The impact of comorbidities on the care and outcomes of adults coping with multiple chronic conditions is limited by heterogeneous and ambiguous usage. While analytic techniques have become more sophisticated, continued lack of meaningful conceptualization and instrument use has limited maturation of this important concept for research, practice and policy purposes. PMID- 22514063 TI - Parameters for temperature dependence of mean-square displacements for B-, Bi- and Tl-containing binary III-V compounds. AB - Mean-square displacements were computed within the harmonic approximation from ab initio force constants for binary B-, Tl- and Bi-containing III-V compounds in sphalerite crystal structures in the temperature range from 0 to 1000 K in steps of 1 K. An Einstein model with a temperature-dependent characteristic frequency was used to model the temperature dependence of the mean-square displacements. A Gaussian was fitted to the temperature dependence of the characteristic frequency and parameters of the Gaussian are given. Phonon dispersion relations and densities of states derived during the computation of the mean-square displacements are also shown. PMID- 22514062 TI - Enumeration of one-dimensional crystal structures obtained from a minimum of diffraction intensities. AB - A central problem in crystallography is crystal structure determination directly from diffraction intensities. For structures of small molecules, this problem has been addressed by probabilistic direct methods that allow one to obtain the structure coordinates with a high degree of certainty given a sufficiently large set of intensities. In contrast, deterministic algebraic methods that could guarantee a solution and may be applicable to macromolecules have not yet emerged. In this study a basic algebraic question is posed: how many crystal structures can be obtained from a given set of intensities? Recently, by using a new origin definition and the method of elementary symmetrical polynomials, all small (N <= 4 atoms) one-dimensional crystal structures that could be obtained from the minimum set of N - 1 lowest-resolution intensities were enumerated. Here, by using methods of modern algebraic geometry the maximum number of one dimensional crystal structures that can be determined from the minimum set of intensities for N > 4 is obtained. It is demonstrated that this ambiguity increases exponentially with the increasing number of atoms in the structure N (~4(N)/N(3/2) for N >> 1) and includes non-homometric structures. Therefore, a minimum set of intensities, even in principle, is insufficient for structure determination for all but very small structures. PMID- 22514064 TI - Bayesian analysis of the evidence for minor components in crystallographic models: an alternative to the Hamilton R test. AB - A simple test based on Bayesian statistics for the presence of minority populations in single-crystal structure refinement is presented. The test is illustrated by analysis of photocrystallographic experiments on single crystals of ruthenium-sulfur-dioxide-based complexes. In data sets collected after irradiation with light, conventional refinements of the populations of different metastable states to values below 4% are shown to be statistically significant. The results also confirm that the photo-induced states are absent from data collected in the dark. PMID- 22514066 TI - An improved experimental databank of transferable multipolar atom models--ELMAM2. Construction details and applications. AB - ELMAM2 is a generalized and improved library of experimentally derived multipolar atom types. The previously published ELMAM database is restricted mostly to protein atoms. The current database is extended to common functional groups encountered in organic molecules and is based on optimized local axes systems taking into account the local pseudosymmetry of the molecular fragment. In this approach, the symmetry-restricted multipoles have zero populations, while others take generally significant values. The various applications of the database are described. The deformation electron densities, electrostatic potentials and interaction energies calculated for several tripeptides and aromatic molecules are calculated using ELMAM2 electron-density parameters and compared with the former ELMAM database and density functional theory calculations. PMID- 22514065 TI - High-resolution study of (002, 113, 11-1) four-beam diffraction in Si. AB - The results of a high-resolution study of the (002, 113, 11 1) four-beam diffraction in Si are presented. The incident synchrotron radiation beam was highly monochromated and collimated with a multi-crystal arrangement in a dispersive setup in both vertical and horizontal planes, in an attempt to experimentally approach plane-wave incident conditions. The Renninger scheme was used with the forbidden reflection reciprocal-lattice vector 002 normal to the crystal surface. The azimuthal and polar rotations were performed in the crystal surface plane and the vertical plane correspondingly. The polar angular curves for various azimuthal angles were measured and found to be very close to theoretical computer simulations, with only a small deviation from the plane monochromatic wave. The effect of the strong two-beam 002 diffraction was observed for the first time with the maximum reflectivity close to 80%. The structure factor of the 002 reflection in Si was experimentally determined as zero. PMID- 22514067 TI - Refining structures against reflection rank: an alternative metric for electron crystallography. AB - A new metric is proposed to improve the fidelity of structures refined against precession electron diffraction data. The inherent dynamical nature of electron diffraction ensures that direct refinement of recorded intensities against structure-factor amplitudes can be prone to systematic errors. Here it is shown that the relative intensity of precessed reflections, their rank, can be used as an alternative metric for refinement. Experimental data from erbium pyrogermanate show that applying precession reduces the dynamical transfer of intensity between reflections and hence stabilizes their rank, enabling accurate and reliable structural refinements. This approach is then applied successfully to an unknown structure of an oxygen-deficient bismuth manganite resulting in a refined structural model that is similar to a calcium analogue. PMID- 22514068 TI - Density functional calculations of polysynthetic Brazil twinning in alpha-quartz. AB - Polysynthetic Brazil twinning in alpha-quartz, which occurs commonly in amethyst, is interpreted in the literature as having its composition planes parallel to one of the faces of the major rhombohedron r. It is shown that, instead, the composition planes are parallel to one of the faces of the minor rhombohedron z. The proposed translation 0.4547a between neighbouring lamellae leads to binding distances and binding angles across the composition plane that differ less from their bulk values than for the translation 0.5a proposed in the literature. Density functional calculations show that the energy of the unrelaxed polysynthetic twin is lower for the proposed translation. They also show that relaxation increases the thickness of the polytwin by 4 pm per composition plane. PMID- 22514069 TI - Classifying and assembling two-dimensional X-ray laser diffraction patterns of a single particle to reconstruct the three-dimensional diffraction intensity function: resolution limit due to the quantum noise. AB - A new two-step algorithm is developed for reconstructing the three-dimensional diffraction intensity of a globular biological macromolecule from many experimentally measured quantum-noise-limited two-dimensional X-ray laser diffraction patterns, each for an unknown orientation. The first step is classification of the two-dimensional patterns into groups according to the similarity of direction of the incident X-rays with respect to the molecule and an averaging within each group to reduce the noise. The second step is detection of common intersecting circles between the signal-enhanced two-dimensional patterns to identify their mutual location in the three-dimensional wavenumber space. The newly developed algorithm enables one to detect a signal for classification in noisy experimental photon-count data with as low as ~0.1 photons per effective pixel. The wavenumber of such a limiting pixel determines the attainable structural resolution. From this fact, the resolution limit due to the quantum noise attainable by this new method of analysis as well as two important experimental parameters, the number of two-dimensional patterns to be measured (the load for the detector) and the number of pairs of two-dimensional patterns to be analysed (the load for the computer), are derived as a function of the incident X-ray intensity and quantities characterizing the target molecule. PMID- 22514070 TI - Temperature diffuse scattering of nanocrystals. AB - The effects of thermal vibrations on X-ray powder diffraction patterns are discussed. Special considerations for extremely small crystallites are described, including the occurrence of surface and edge vibrational modes, and a restriction on the maximum phonon wavelength. In doing so, a complete temperature diffuse scattering (TDS) model is presented, which includes the influence of these features on: the Debye-Waller parameter; first-order TDS; and higher-order TDS terms. The importance of using an accurate TDS representation is studied as a function of temperature and crystallite size. It is found that a misrepresentation of the TDS for small crystallites can lead to an error in the determined Debye-Waller parameter on the order of 20-40% and a slight overestimation of the peak broadening. While the presented theory is primarily developed considering X-ray scattering, the same expressions are expected to describe the TDS in faster-than-sound neutron powder diffraction measurements. PMID- 22514071 TI - Topological complexity of crystal structures: quantitative approach. AB - The topological complexity of a crystal structure can be quantitatively evaluated using complexity measures of its quotient graph, which is defined as a projection of a periodic network of atoms and bonds onto a finite graph. The Shannon information-based measures of complexity such as topological information content, I(G), and information content of the vertex-degree distribution of a quotient graph, I(vd), are shown to be efficient for comparison of the topological complexity of polymorphs and chemically related structures. The I(G) measure is sensitive to the symmetry of the structure, whereas the I(vd) measure better describes the complexity of the bonding network. PMID- 22514072 TI - Patterson function and delta recycling: derivation of the phasing equations. AB - Two phasing equations based on the Fourier syntheses delta(P) = T(-1)[(E(2) - )exp(iphi)] and delta(M) = T(-1)[(E - )exp(iphi)] were recently described [Rius (2012). Acta Cryst. A 68, 77-81] (E is the quasi-normalized structure factor and is the average over all reflections). These equations were found by comparison with the direct methods origin-free modulus sum function and constitute the core of the 'delta recycling' phasing procedure. The derivation of these phasing equations from the minimization of a residual (R(P)) between two differently calculated density functions (one of them including the positivity constraint) is shown. PMID- 22514076 TI - Searching for new cell-penetrating agents: hybrid cyclobutane-proline gamma,gamma peptides. AB - Two generations of hybrid gamma,gamma-peptides containing cyclobutane amino acids and cis-gamma-amino-L-proline joined in alternation have been synthesized and their capacity to cross the eukaryotic cell membrane has been evaluated. The first generation consists of di-, tetra- and hexapeptides, and their properties have been analyzed as well as the influence of peptide length and chirality of the cyclobutane residues. Results have shown that the absolute configuration of the cyclobutane amino acid does not have a relevant influence. The second generation consists of hybrid gamma,gamma-hexapeptides with a common backbone and distinct side chains introduced with different linkage types through the alpha amino group (N(alpha)) of the proline monomers. These peptides have been shown to be non-toxic towards HeLa cells and to internalize them effectively, the best results being obtained for the peptides with a spacer of five carbons between the N(alpha) atom and the guanidinium group. The introduction of cyclobutane residues inside the sequence affords a good balance between charge and hydrophobicity, reducing the number of positive charges. This results in lower toxicity and similar cell-uptake properties when compared to previously described peptide agents. PMID- 22514078 TI - GPU accelerated numerical simulations of viscoelastic phase separation model. AB - We introduce a complete implementation of viscoelastic model for numerical simulations of the phase separation kinetics in dynamic asymmetry systems such as polymer blends and polymer solutions on a graphics processing unit (GPU) by CUDA language and discuss algorithms and optimizations in details. From studies of a polymer solution, we show that the GPU-based implementation can predict correctly the accepted results and provide about 190 times speedup over a single central processing unit (CPU). Further accuracy analysis demonstrates that both the single and the double precision calculations on the GPU are sufficient to produce high-quality results in numerical simulations of viscoelastic model. Therefore, the GPU-based viscoelastic model is very promising for studying many phase separation processes of experimental and theoretical interests that often take place on the large length and time scales and are not easily addressed by a conventional implementation running on a single CPU. PMID- 22514077 TI - Biological responses to spider silk-antibiotic fusion protein. AB - The development of a new generation of multifunctional biomaterials is a continual goal for the field of materials science. The in vivo functional behaviour of a new fusion protein that combines the mechanical properties of spider silk with the antimicrobial properties of hepcidin was addressed in this study. This new chimeric protein, termed 6mer + hepcidin, fuses spider dragline consensus sequences (6mer) and the antimicrobial peptide hepcidin, as we have recently described, with retention of bactericidal activity and low cytotoxicity. In the present study, mouse subcutaneous implants were studied to access the in vivo biological response to 6mer + hepcidin, which were compared with controls of silk alone (6mer), polylactic-glycolic acid (PLGA) films and empty defects. Along with visual observations, flow cytometry and histology analyses were used to determine the number and type of inflammatory cells at the implantation site. The results show a mild to low inflammatory reaction to the implanted materials and no apparent differences between the 6mer + hepcidin films and the other experimental controls, demonstrating that the new fusion protein has good in vivo biocompatibility, while maintaining antibiotic function. PMID- 22514079 TI - Microscopic vision based on the adaptive positioning of the camera coordinate frame. AB - Microscopic vision measurement precision has been largely limited by inaccurately calibrated model parameters, because image plane is near parallel to reference plane in the narrow depth of field. This article proposes a method of precise microscopic vision measurement based on the adaptive positioning of the camera coordinate frame. The microscopic vision measurement movably attaches the origin of the camera coordinate frame along the optical axis. By finding the optimal position, the nonlinearity of the objective function in calibration optimization is decreased and the optimization sensitivity to initial values is reduced. Therefore, we obtain a high calibration precision and eventually ensure a high measurement precision. Mathematical simulations illustrate that the calibration precision of the proposed microscopic vision measurement model is higher than that of the conventional vision measurement model. The experiment shows that with magnification of 3.024*, the presented system achieves a precision of 0.12% based on the proposed microscopic vision measurement model, which is two times higher than the one based on the conventional vision measurement model. PMID- 22514081 TI - Formation mechanism of LiFePO4 sticks grown by a microwave-assisted liquid-phase process. AB - A time-dependent study on the formation of LiFePO4 with olivine-type structure is presented. The material is synthesized through a non-aqueous route in benzyl alcohol assisted by microwave radiation. The LiFePO4 forms with an anisotropic morphology of microscale stick-like particles. The detailed structure of these particles and their evolution with reaction time is revealed by transmission electron microscopy; a 3D reconstruction of a particle by electron tomography provides insight into the formation mechanism of these sticks. Without applying a thermal post-annealing treatment or a carbon coating, the electrochemical behavior of the LiFePO4 microsticks is assessed for the preparation of cathodes in lithium-ion batteries. PMID- 22514083 TI - Semi-automated primary tumor volume measurements by dynamic contrast-enhanced MRI in patients with head and neck cancer. AB - BACKGROUND: Tumor volume is a significant prognostic factor in the treatment of malignant head and neck tumors. Unfortunately, it is not routinely measured because of the workload involved. METHODS: Twenty-one patients, between 2009 and 2010, were studied. Dynamic contrast-enhanced MRI (DCE-MRI) at 3.0T was performed. A workstation previously developed for semi-automated segmentation of breast cancers on DCE-MRI was used to segment the head and neck cancers. The Pearson correlation analysis was used to assess the agreement between volumetric measurements and the manually derived gross tumor volume (GTV). RESULTS: In 90.5% of the patients (19 of 21) correlation could be made between DCE-MRI and the manually derived GTV. The Pearson correlation coefficient between the automatically derived tumor volume at DCE-MRI and the manually derived GTVs was R(2) = 0.95 (p < .001). CONCLUSION: Semi-automated tumor volumes on DCE-MRI were representative of those derived from the manually derived GTV (R(2) = 0.95; p < .001). PMID- 22514082 TI - EGFR activation is a potential determinant of primary resistance of hepatocellular carcinoma cells to sorafenib. AB - Sorafenib is currently the medical treatment of reference for hepatocellular carcinoma (HCC), but it is not known whether sorafenib is equally active in all HCC. Here, our aim was to explore intrinsic differences in the response of HCC cells to sorafenib, to identify potential mechanisms leading to primary resistance to this treatment. We analyzed a panel of six human HCC cell lines and compared the activity of the main oncogenic kinase cascades, their clonogenic potential, proliferation and apoptosis upon exposure to sorafenib. We report that HCC cells present important differences in their response to sorafenib, and that some cell lines are more resistant to the actions of sorafenib than others. We identify the activated epidermal growth factor receptor (EGFR) as a parameter that promotes the resistance of HCC cells to sorafenib. In resistant cells, the efficacy of sorafenib was increased when EGFR was inhibited, as was demonstrated using two chemical inhibitors (erlotinib or gefitinib), a monoclonal antibody directed against EGFR (cetuximab), and RNA interference directed against EGFR. A combination of EGFR inhibitors and sorafenib affords a better control over HCC proliferation, most likely through an improved blockade of the RAF kinases. Our findings therefore confirm the importance of RAF kinases as therapeutic targets in HCC, and identify EGFR as a determinant of the sensitivity of HCC cells to sorafenib. Our findings bear possible implications for the improvement of the efficacy of sorafenib in HCC, and might be useful for the identification of predictive biomarkers in this context. PMID- 22514084 TI - Modular self-assembled multiporphyrin cages with tunable shape. AB - Three new molecular cages-a trigonal prism (2) and two cubic-shaped boxes of increasing size (3, 4)-featuring as many as 10 porphyrins were obtained in quantitative yields by self-assembly of a single bis-zincporphyrin metallacycle (1) with appropriate polytopic N-linkers: the trigonal planar tpt or the cruciform porphyrins 4'-TPyP and 4'-TPhPyP. PMID- 22514085 TI - Association between STAT1 activity and BRAF mutations in papillary thyroid carcinomas. AB - BACKGROUND: Signal transducer and activator of transcription-1 (STAT1) plays a critical role in tumorigenesis by controlling several functions in both tumor cells and the immune system, and is considered to be a tumor suppressor. The present study evaluated the activity of STAT1 in human papillary thyroid carcinomas (PTC). METHODS: STAT1 activity was measured in nuclear extracts of tumor tissues from 35 PTC patients using an ELISA-based kit. RESULTS: STAT1 activity was significantly lower in tumors than in the surrounding normal thyroid tissues (P < 0.01). The association between STAT1 activity and clinicopathologic factors was analyzed in PTC tissues. STAT1 activity was significantly lower in tumors that measured 2 cm or more than in tumors that measured 2 cm or less (P = 0.044). Moreover, tumor size was inversely correlated with STAT1 activity (Spearman's rank correlation coefficient (rho) = -0.34, P = 0.048). In addition, tumors with BRAF mutations showed lower STAT1 activity than wild-type BRAF tumors [0.064 (0.056-0.124) vs. 0.108 (0.073-0.153) arbitrary units, P = 0.048]. CONCLUSION: STAT1 activity is suppressed in PTCs (as measured by DNA-binding activities). The tumor with T1799A BRAF mutation and tumor sizes of 2 cm or more were clinicopathologic parameters associated with lower STAT1 activity. STAT1 activity of tumor might be one of potential biomarkers for PTC's. PMID- 22514086 TI - Enantioselective direct aldol reaction of alpha-keto esters catalyzed by (S(a)) binam-D-prolinamide under quasi solvent-free conditions. AB - (S(a))-Binam-D-prolinamide (20 mol%), instead of (S(a))-binam-L-prolinamide, in combination with chloroacetic acid (100 mol%) is an efficient organocatalyst for the direct aldol reaction between alpha-keto esters as electrophiles and alkyl and alpha-functionalised ketones, under quasi solvent-free conditions, providing access to highly functionalised chiral quaternary gamma-keto alpha-hydroxyesters with up to 92% ee. PMID- 22514087 TI - HAK transporters from Physcomitrella patens and Yarrowia lipolytica mediate sodium uptake. AB - The widespread presence of Na(+)-specific uptake systems across plants and fungi is a controversial topic. In this study, we identify two HAK genes, one in the moss Physcomitrella patens and the other in the yeast Yarrowia lipolytica, that encode Na(+)-specific transporters. Because HAK genes are numerous in plants and are duplicated in many fungi, our findings suggest that some HAK genes encode Na(+) transporters and that Na(+) might play physiological roles in plants and fungi more extensively than is currently thought. PMID- 22514088 TI - CRUMPLED LEAF (CRL) homologs of Physcomitrella patens are involved in the complete separation of dividing plastids. AB - Plastid division is controlled by numerous nuclear genes. Arabidopsis thaliana CRUMPLED LEAF (AtCRL) is a plastid division-related gene, and the crl mutant exhibits a dwarf phenotype with abnormal cell division and a significant reduction in plastid numbers. However, the function of AtCRL is not fully understood. Here, we identified and characterized two AtCRL homologs, PpCRL1 and PpCRL2, in the moss Physcomitrella patens. PpCRL1 and PpCRL2 shared 77% amino acid identity with each other and 47% identity with AtCRL. Single PpCRL1 or -2 gene knockout (KO) mutants could not be distinguished from the wild-type mosses, but PpCRL1 and -2 double KO mutants displayed growth retardation of protonemata and gametophores and harbored approximately 10 large chloroplasts per cell. This indicates that PpCRL1 and PpCRL2 have redundant functions in chloroplast division and plant growth. Unlike the A. thaliana crl mutants, however, the PpCRL double KO mutants did not display abnormal orientation of the cell division plane. Complementation experiments showed that AtCRL partially rescued the defects in chloroplast size and number of the PpCRL double KO mutant. This suggests that PpCRL has a similar, but not identical, function to AtCRL. Time-lapse microscopic observation of the double PpCRL KO mutants revealed that some dumbbell-shaped chloroplasts failed to complete division at the late stage of plastid division; enlarged chloroplasts were thus generated. This strongly suggests that PpCRLs are involved in the complete separation of dividing chloroplasts. PMID- 22514089 TI - Activation and epigenetic regulation of DNA transposon nDart1 in rice. AB - A large part of the rice genome is composed of transposons. Since active excision/reintegration of these mobile elements may result in harmful genetic changes, many transposons are maintained in a genetically or epigenetically inactivated state. However, some non-autonomous DNA transposons of the nDart1-3 subgroup, including nDart1-0, actively transpose in specific rice lines, such as pyl-v which carries an active autonomous element, aDart1-27, on chromosome 6. Although nDart1-3 subgroup elements show considerable sequence identity, they display different excision frequencies. The most active element, nDart1-0, had a low cytosine methylation status. The aDart1-27 sequence showed conservation between pyl-stb (pyl-v derivative line) and Nipponbare, which both lack autonomous activity for transposition of nDart1-3 subgroup elements. In pyl-v plants, the promoter region of the aDart1-27 transposase gene was more hypomethylated than in other rice lines. Treatment with the methylation inhibitor 5-azacytidine (5-azaC) induced transposition of nDart1-3 subgroup elements in both pyl-stb and Nipponbare plants; the new insertion sites were frequently located in genic regions. 5-AzaC treatment principally induced expression of Dart1-34 transposase rather than the other 38 aDart1-related elements in both pyl stb and Nipponbare treatment groups. Our observations show that transposition of nDart1-3 subgroup elements in the nDart1/aDart1 tagging system is correlated with the level of DNA methylation. Our system does not cause somaclonal variation due to an absence of transformed plants, offers the possibility of large-scale screening in the field and can identify dominant mutants. We therefore propose that this tagging system provides a valuable addition to the tools available for rice functional genomics. PMID- 22514090 TI - Interactions of CUP-SHAPED COTYLEDON and SPATULA genes control carpel margin development in Arabidopsis thaliana. AB - A characteristic feature of flowering plants is the fusion of carpels, which results in the formation of an enclosed gynoecium. In Arabidopsis thaliana, the gynoecium is formed by the fusion of two carpels along their margins, which also act as a meristematic site for the formation of internal structures such as ovules, the septum and transmitting tract. How gene interactions coordinate the fusion and differentiation of the marginal structures during gynoecium development is largely unknown. It was previously shown that the SPATULA (SPT) gene is required for carpel fusion, whereas overexpression of the CUP-SHAPED COTYLEDON genes CUC1 and CUC2 prevents it. Here we provide evidence that SPT promotes carpel fusion in the apical gynoecium partly through the negative regulation of CUC1 and CUC2 expression. In spt, transcripts of both CUC genes accumulated ectopically, and addition of cuc1 and cuc2 mutations to spt suppressed the split phenotype of carpels specifically along their lateral margins. In the basal gynoecium, on the other hand, all three genes promoted the formation of margin-derived structures, as revealed by the synergistic interactions of spt with each of the cuc mutations. Our results suggest that differential interactions among SPT, CUC1 and CUC2 direct the formation of domain specific structures of the Arabidopsis gynoecium. PMID- 22514091 TI - Difference in sodium spatial distribution in the shoot of two canola cultivars under saline stress. AB - Among different mechanisms of salt resistance, regulation of ion distribution among various tissues and intracellular compartmentation are of great importance. In this study, we investigated the effects of salt stress on growth, photosynthesis, and Na(+) accumulation and distribution in leaf apoplast and symplast of two canola (Brassica napus L.) cultivars (NYY 1 and BZY 1). The results showed that the declines in shoot dry mass, leaf water potential and net photosynthetic rate of BZY 1 (salt sensitive) were higher than those of NYY 1 (salt resistant) in response to salt stress. Stomatal limitation to photosynthesis was mainly affected under moderate salinity, whereas the reduction in assimilation rate under severe salt stress was due to both stomatal and non stomatal limitations. We also found that more Na(+) was distributed to leaf veins in NYY 1 than in BZY 1; simultaneously, less Na(+) accumulated in the leaf blade in NYY 1 than in BZY 1. The percentage of Na(+) in the leaf symplast in NYY 1 was markedly lower than that in BZY 1. Also, Na(+) diffusion in leaves through apoplastic and symplastic pathways of BZY 1 was stronger than that in NYY 1, and the transpiration rate in BZY 1, especially at the leaf edges, decreased more than in NYY 1. Our results showed that NYY 1 accumulated less Na(+) in the shoot, especially in leaf blades, and confined Na(+) to the apoplast to avoid leaf salt toxicity, which could be one reason for the higher resistance of NYY 1 than BZY 1 plants to salt stress. PMID- 22514092 TI - Functional characterization of residues involved in redox modulation of maize photosynthetic NADP-malic enzyme activity. AB - Two highly similar plastidic NADP-malic enzymes (NADP-MEs) are found in the C(4) species maize (Zea mays); one exclusively expressed in the bundle sheath cells (BSCs) and involved in C(4) photosynthesis (ZmC(4)-NADP-ME); and the other (ZmnonC(4)-NADP-ME) with housekeeping roles. In the present work, these two NADP MEs were analyzed regarding their redox-dependent activity modulation. The results clearly show that ZmC(4)-NADP-ME is the only one modulated by redox status, and that its oxidation produces a conformational change limiting the catalytic process, although inducing higher affinity binding of the substrates. The reversal of ZmC(4)-NADP-ME oxidation by chemical reductants suggests the presence of thiol groups able to form disulfide bonds. In order to identify the cysteine residues involved in the activity modulation, site-directed mutagenesis and MALDI-TOF (matrix-assisted laser desorption ionization-time of flight) analysis of ZmC(4)-NADP-ME were performed. The results obtained allowed the identification of Cys192, Cys246 (not conserved in ZmnonC(4)-NADP-ME), Cys270 and Cys410 as directly or indirectly implicated in ZmC(4)-NADP-ME redox modulation. These residues may be involved in forming disulfide bridge(s) or in the modulation of the oxidation of critical residues. Overall, the results indicate that, besides having acquired a high level of expression and localization in BSCs, ZmC(4)-NADP-ME displays a particular redox modulation, which may be required to accomplish the C(4) photosynthetic metabolism. Therefore, the present work could provide new insights into the regulatory mechanisms potentially involved in the recruitment of genes for the C(4) pathway during evolution. PMID- 22514093 TI - The electronic spectra and the H-bonding pattern of the sulfur and selenium substituted guanines. AB - The density functional theory (DFT) with B3LYP, M05-2x, and M06-2x functionals, along with the 6-311+G(d, p) basis set, were used in the study of the UV absorption spectra and the H-bonding pairing patterns of the sulfur and selenium substituted guanines. The time-dependent DFT calculations reveal that the red shifts of the transition energies predicted for guanine for the first gas-phase observable transition amount to 55 nm for S6mG and 86 nm for Se6mG, respectively. These changes in the transition energies are qualitatively comparable to the experimental data for substituted guanines in DNA. The density deformation map reveals that both sulfur and selenium atoms exhibit lesser conjugated with the purine ring, which leads to the small transition energies in S6mG and Se6mG. The decrease in binding energy (3 kcal/mol) of Se6mGmC as compared to that of mGmC is well related to the observation of the melting temperature difference DeltaT(m) ~3.9 degrees C for the Se-DNA versus DNA. The molecular recognition (mGmC pairing) pattern is found to be changed significantly due to the replacement of O6 by S or Se. The substantial base-base plane twisting revealed in this study suggests that the base stacking in the DNA might be interrupted. This study shows that the red-shifts of the transition energies predicted by the M05-2x and M06-2x functionals are close to those revealed by the B3LYP calculations. As M05-2x and M06-2x offer better descriptions for the dispersion interactions, they provide efficient approaches to investigate the influences of the base-stacking on the transition energies. PMID- 22514094 TI - Consumer preferences for hearing aid attributes: a comparison of rating and conjoint analysis methods. AB - Low utilization of hearing aids has drawn increased attention to the study of consumer preferences using both simple ratings (e.g., Likert scale) and conjoint analyses, but these two approaches often produce inconsistent results. The study aims to directly compare Likert scales and conjoint analysis in identifying important attributes associated with hearing aids among those with hearing loss. Seven attributes of hearing aids were identified through qualitative research: performance in quiet settings, comfort, feedback, frequency of battery replacement, purchase price, water and sweat resistance, and performance in noisy settings. The preferences of 75 outpatients with hearing loss were measured with both a 5-point Likert scale and with 8 paired-comparison conjoint tasks (the latter being analyzed using OLS [ordinary least squares] and logistic regression). Results were compared by examining implied willingness-to-pay and Pearson's Rho. A total of 56 respondents (75%) provided complete responses. Two thirds of respondents were male, most had sensorineural hearing loss, and most were older than 50; 44% of respondents had never used a hearing aid. Both methods identified improved performance in noisy settings as the most valued attribute. Respondents were twice as likely to buy a hearing aid with better functionality in noisy environments (p < .001), and willingness to pay for this attribute ranged from US$2674 on the Likert to US$9000 in the conjoint analysis. The authors find a high level of concordance between the methods-a result that is in stark contrast with previous research. The authors conclude that their result stems from constraining the levels on the Likert scale. PMID- 22514096 TI - Differentiation of human pluripotent stem cells to retinal pigmented epithelium in defined conditions using purified extracellular matrix proteins. AB - A potential application of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) is the generation of retinal pigmented epithelium (RPE) to treat age-related macular degeneration (AMD), a common but incurable retinal disease. RPE cells derived from hESCs (hESC-RPEs) and iPSCs (iPSC-RPEs) express essential RPE markers and can rescue visual function in animal models. However, standard differentiation protocols yield RPE cells at low frequency, especially from iPSC lines, and the common use of Matrigel and xenogeneic feeder cells is not compatible with clinical applications. The extracellular matrix (ECM) can affect differentiation, and therefore changes in ECM composition may improve the frequency of stem cell-RPE differentiation. We selected several purified ECM proteins and substrates, based on the in vivo RPE ECM environment, and tested their ability to support iPSC-RPE differentiation and maintenance. iPSCs differentiated on nearly all tested substrates developed pigmented regions, with Matrigel and mouse laminin-111 supporting the highest pigmentation frequencies. Although iPSC-RPEs cultured on the majority of the tested substrates expressed key RPE genes, only six substrates supported development of confluent monolayers with normal RPE morphology, including Matrigel and mouse laminin-111. iPSCs differentiated on mouse laminin-111 produced iPSC-RPEs expressing RPE proteins, and hESCs differentiated on mouse laminin-111 resulted in high yields of functional hESC-RPEs. This identification of key ECM proteins may assist with future scaffold designs and provide peptide sequences for use in synthetic, xeno free, GMP-compliant generation of RPE from human pluripotent stem cells relevant to clinical translation. PMID- 22514095 TI - Stem cell therapy for the inner ear: recent advances and future directions. AB - In vertebrates, perception of sound, motion, and balance is mediated through mechanosensory hair cells located within the inner ear. In mammals, hair cells are only generated during a short period of embryonic development. As a result, loss of hair cells as a consequence of injury, disease, or genetic mutation, leads to permanent sensory deficits. At present, cochlear implantation is the only option for profound hearing loss. However, outcomes are still variable and even the best implant cannot provide the acuity of a biological ear. The recent emergence of stem cell technology has the potential to open new approaches for hair cell regeneration. The goal of this review is to summarize the current state of inner ear stem cell research from a viewpoint of its clinical application for inner ear disorders to illustrate how complementary studies have the potential to promote and refine stem cell therapies for inner ear diseases. The review initially discusses our current understanding of the genetic pathways that regulate hair cell formation from inner ear progenitors during normal development. Subsequent sections discuss the possible use of endogenous inner ear stem cells to induce repair as well as the initial studies aimed at transplanting stem cells into the ear. PMID- 22514097 TI - Sensitive detection of spores using volume-amplified magnetic nanobeads. PMID- 22514099 TI - Comparison of 3 T MRI and CT for the measurement of visceral and subcutaneous adipose tissue in humans. AB - OBJECTIVE: CT is considered the gold standard imaging modality for measurement of visceral adipose tissue area. However, as CT imaging exposes subjects to ionising radiation, a comparable imaging technique without this exposure is desirable, such as MRI. Therefore, we compared the agreement of measures of visceral adipose tissue and subcutaneous adipose tissue area from single-slice images obtained at the umbilicus using a 3 T MRI scanner with single-slice images obtained via CT scan. METHODS: 64 images were obtained from 27 subjects who underwent MRI and CT scanning on the same day, after 10-12 hours of fasting. Visceral and subcutaneous adipose tissue depots were manually separated and quantified using a multimodality image-processing software program. RESULTS: We found good agreement between CT and MRI for the measurement of both visceral adipose tissue and subcutaneous adipose tissue. Bland-Altman difference analysis demonstrated a mean bias of -2.9% (as a portion of total abdominal area) for visceral adipose tissue and +0.4% for subcutaneous adipose tissue, as measured by MRI compared with CT. CONCLUSION: MRI is a safe, accurate and precise imaging modality for measuring both visceral and subcutaneous adipose tissue, making it a favourable alternative to CT for quantification of these adipose depots. PMID- 22514100 TI - Evaluation of coronary angiographic projections to balance the clinical yield with the radiation risk. AB - OBJECTIVE: Radiation safety principles dictate that imaging procedures should minimise the radiation risks involved, without compromising diagnostic performance. This study aims to define a core set of views that maximises clinical information yield for minimum radiation risk. Angiographers would supplement these views as clinically indicated. METHODS: An algorithm was developed to combine published data detailing the quality of information derived for the major coronary artery segments through the use of a common set of views in angiography with data relating to the dose-area product and scatter radiation associated with these views. RESULTS: The optimum view set for the left coronary system comprised four views: left anterior oblique (LAO) with cranial (Cr) tilt, shallow right anterior oblique (AP-RAO) with caudal (Ca) tilt, RAO with Ca tilt and AP-RAO with Cr tilt. For the right coronary system three views were identified: LAO with Cr tilt, RAO and AP-RAO with Cr tilt. An alternative left coronary view set including a left lateral achieved minimally superior efficiency (<5%), but with an ~8% higher radiation dose to the patient and 40% higher cardiologist dose. CONCLUSION: This algorithm identifies a core set of angiographic views that optimises the information yield and minimises radiation risk. This basic data set would be supplemented by additional clinically determined views selected by the angiographer for each case. The decision to use additional views for diagnostic angiography and interventions would be assisted by referencing a table of relative radiation doses for the views being considered. PMID- 22514101 TI - Perfusion CT to assess angiogenesis in colon cancer: technical limitations and practical challenges. AB - OBJECTIVE: Perfusion CT may have the potential to quantify the degree of angiogenesis of solid tumours in vivo. This study aims to identify the practical and technical challenges inherent to the technique, and evaluate its feasibility in colorectal tumours. METHODS: 51 patients from 2 institutions prospectively underwent a single perfusion CT on 2 different multidetector scanners. The patients were advised to breath-hold as long as possible, followed by shallow breathing, and were given intravenous buscopan to reduce movement. Numerous steps were explored to identify the challenges. RESULTS: 43 patients successfully completed the perfusion CT as per protocol. Inability to detect the tumour (n=3), misplacement of dynamic sequence co-ordinates (n=2), failure of contrast injection (n=2) and displacement of tumour (n=1) were the reasons for failure. In 14 cases excessive respiratory motion displaced the tumour out of the scanning field along the temporal sequence, leading to erroneous data capture. In nine patients, minor displacements of the tumour were corrected by repositioning the region of interest (ROI) to its original position after reviewing each dynamic sequence slice. In 20 patients the tumour was stable, and data captured from the ROI were representative, and could have been analysed by commercially available Body Tumor Perfusion 3.0(r) software (GE Healthcare, Waukesha, WI). Hence all data were manually analysed by MATLAB(r) processing software (MathWorks, Cambridge, UK). CONCLUSION: Perfusion CT in tumours susceptible to motion during acquisition makes accurate data capture challenging and requires meticulous attention to detail. Motion correction software is essential if perfusion CT is to be used routinely in colorectal cancer. PMID- 22514102 TI - Missed rib fractures on evaluation of initial chest CT for trauma patients: pattern analysis and diagnostic value of coronal multiplanar reconstruction images with multidetector row CT. AB - OBJECTIVE: The objective of this study was to review the prevalence and radiological features of rib fractures missed on initial chest CT evaluation, and to examine the diagnostic value of additional coronal images in a large series of trauma patients. METHODS: 130 patients who presented to an emergency room for blunt chest trauma underwent multidetector row CT of the thorax within the first hour during their stay, and had follow-up CT or bone scans as diagnostic gold standards. Images were evaluated on two separate occasions: once with axial images and once with both axial and coronal images. The detection rates of missed rib fractures were compared between readings using a non-parametric method of clustered data. In the cases of missed rib fractures, the shapes, locations and associated fractures were evaluated. RESULTS: 58 rib fractures were missed with axial images only and 52 were missed with both axial and coronal images (p=0.088). The most common shape of missed rib fractures was buckled (56.9%), and the anterior arc (55.2%) was most commonly involved. 21 (36.2%) missed rib fractures had combined fractures on the same ribs, and 38 (65.5%) were accompanied by fracture on neighbouring ribs. CONCLUSION: Missed rib fractures are not uncommon, and radiologists should be familiar with buckle fractures, which are frequently missed. Additional coronal imagescan be helpful in the diagnosis of rib fractures that are not seen on axial images. PMID- 22514103 TI - Imaging manifestations in Proteus syndrome: an unusual multisystem developmental disorder. AB - In this review we use images from an 11-year-old male to describe Proteus syndrome, a complex disorder with multisystem involvement and great clinical variability. Our aim is to enhance recognition of the typical imaging findings, which can aid diagnosis of this rare condition. PMID- 22514105 TI - Solid pseudopapillary tumours of the pancreas: spectrum of imaging findings with histopathological correlation. AB - Solid pseudopapillary tumour (SPT) is an uncommon cystic exocrine pancreatic neoplasm. The typical patient is a female in the third decade of life presenting with pain and/or palpable mass. Classic imaging characteristics include large size, mixed solid and cystic nature, encapsulation and haemorrhage. A pancreatic mass with these features in a young adult female should raise suspicion for an SPT. Although typically a non-aggressive neoplasm with surgery curative in most cases, SPT may exhibit more aggressive features such as local invasion, metastases or recurrence in up to 20% of cases. PMID- 22514104 TI - Radiological findings in 210 paediatric patients with viral pneumonia: a retrospective case study. AB - OBJECTIVE: The objective of this study was to assess the radiological presentations of different types of viral pneumonia in children. METHODS: Nasopharyngeal swab specimens and bronchial aspirate samples from children with acute respiratory infections were obtained and tested for influenza B, adenovirus, respiratory syncytial virus and parainfluenza (Types 1, 2 and 3) by direct immunofluorescence assay, or for influenza A (Subtype H1N1) by quantitative real-time polymerase chain reaction. The chest radiographs of the 210 confirmed cases of viral pneumonia were analysed retrospectively by two independent radiologists for the identification, characterisation and description of the distribution of imaging abnormalities. The cases were divided into six groups on the basis of confirmed causative viral agent, and radiographic findings were compared, analysed and presented. RESULTS: The abnormal chest radiograph findings consisted of bilateral patchy areas of consolidation (n=133), interstitial lung disease (n=33), diffuse areas of air space consolidation (n=29) and lobar consolidation (n=15). The abnormalities were distributed bilaterally in 195 cases and observed more frequently in the lower zones than in other regions. The radiological findings varied significantly among the six groups (p=0.0050). Pairwise comparison showed significant difference between influenza A (H1N1) and adenovirus (p=0.0031) only. CONCLUSION: The predominant radiological finding in paediatric viral pneumonia was bilateral patchy areas of consolidation. The radiological findings differed significantly only between adenovirus and influenza A pneumonia. The diagnosis of the specific causative organism requires laboratory confirmation. PMID- 22514106 TI - Comparative study of robotic versus endoscopic thyroidectomy by a gasless unilateral axillo-breast or axillary approach. AB - BACKGROUND: Robotic thyroidectomy and conventional endoscopic thyroidectomy have not been thoroughly compared. In this study, we compared the potential advantages of robotic versus endoscopic thyroidectomy. METHODS: We analyzed 218 consecutive patients who underwent endoscopic (105 cases) or robotic (113 cases) thyroidectomy using a gasless unilateral axillo-breast or gasless unilateral axillary approach. RESULTS: Because of the dexterity of robotic instruments and the improved surgical view, it was subjectively easier and took less time to perform a complete total thyroidectomy and central compartment neck dissection in robotic thyroidectomy. In the case of unilateral lobectomy, endoscopic and robotic thyroidectomy had quite similar surgical outcomes. Cosmetic satisfaction was excellent in both groups. CONCLUSION: In this series by a single surgeon, robotic thyroidectomy was superior to endoscopic thyroidectomy for performing total thyroidectomy and bilateral central compartment neck dissection. However, in terms of cost-effectiveness, endoscopic thyroidectomy was comparable to robotic thyroidectomy in patients who undergo unilateral lobectomy. PMID- 22514107 TI - Biological activity of probable/possible high-risk human papillomavirus types in cervical cancer. AB - Judging the carcinogenicity of human papillomavirus (HPV) types rarely found in cervical cancer (CxCa) is hindered by lack of studies of their biological activity in cancer tissues. To asses transcriptional activity of HPV types, we have developed ultra-short amplimer, splice-site specific, E6*I mRNA RT-PCR assays for 12 high-risk (HR)-HPV (IARC Group 1) and eight probable/possible high risk (pHR)-HPV types (IARC Group 2A/B carcinogens). Previously unreported E6*I splice sites of the six pHR-HPV types 26, 53, 67, 70, 73 and 82 were identified by cloning and sequencing. We analyzed 97 formalin-fixed paraffin-embedded (FFPE) Mongolian CxCa biopsies for presence of HPV DNA by two sensitive genotyping assays, for E6*I transcripts of all HR-/pHR-HPV types identified and for expression of HPV surrogate markers p16(INK4a), pRb and p53. E6*I of at least one HR-/pHR-HPV was expressed in 94 (98%) of cancer tissues including seven with pHR HPV types 26, 66, 70 or 82 as single transcribed types. Fifty-eight of E6*I mRNA transcribing cases were analyzable by immunohistochemistry and displayed p16(INK4a) overexpression in 57 (98%), pRb downregulation in 56 (97%) and p53 downregulation in 36 (62%) tissues. The newly developed E6*I mRNA RT-PCR assays appeared to be highly sensitive method to analyze HPV transcription in FFPE materials. Our finding of viral oncogene transcription of pHR-HPV types 26, 66, 70 and 82 in cervical tumors, in the absence of any other transcriptionally active HR-type and with p16(INK4a) overexpression and pRb downregulation, may support a reassessment of the carcinogenicity classification of these pHR-HPV types. PMID- 22514109 TI - The biology and the genetics of Hurthle cell tumors of the thyroid. AB - The biology and the genetics of Hurthle cell tumors are reviewed starting from the characterization and differential diagnosis of the numerous benign and malignant, neoplastic and nonneoplastic lesions of the thyroid in which Hurthle cell transformation is frequently observed. The clinicopathologic and molecular evidence obtained from the comparative study of the aforementioned conditions indicate that Hurthle cell appearance represents a phenotype that is superimposed on the genotypic and conventional histopathologic features of the tumors. Hurthle cell tumors differ from their non-Hurthle counterparts regarding the prevalence of large deletions of mitochondrial DNA (mtDNA), mutations of mtDNA genes coding for oxidative phosphorylation (OXPHOS) proteins (namely mutations of complex I subunit genes) and mutations of nuclear genes coding also for mitochondrial OXPHOS proteins. Such mitochondrial alterations lead to energy production defects in Hurthle cell tumors; the increased proliferation of mitochondria may reflect a compensatory mechanism for such defects and is associated with the overexpression of factors involved in mitochondrial biogenesis. The mitochondrial abnormalities are also thought to play a major role in the predisposition for necrosis instead of apoptosis which seems to be blocked in most Hurthle cell tumors. Finally, the results obtained in experimental models using cybrid cell lines and the data obtained from histopathologic and molecular studies of familial Hurthle cell tumors are used, together with the aforementioned genetic and epigenetic alterations, to progress in the understanding of the mechanisms through which mitochondrial abnormalities may be involved in the different steps of thyroid carcinogenesis, from tumor initiation to metastization. PMID- 22514110 TI - Androgens, diabetes and prostate cancer. AB - Metabolic disorders such as diabetes, obesity and the metabolic syndrome have been shown to modulate prostate cancer (PCa) risk and aggressiveness in population-based and experimental studies. While associations between these conditions are modest and complex, two consistent findings have emerged. First, there is observational evidence that obesity and associated insulin excess are linked to increased PCa aggressiveness and worse outcomes. Secondly and somewhat paradoxically, long-standing diabetes may be protective against PCa development. This apparent paradox may be due to the fact that long-standing diabetes is associated with insulin depletion and decreased IGF1 signalling. Men with obesity or diabetes have moderate reductions in their androgen levels. The interconnectedness of metabolic and androgen status complicates the dissection of the individual roles of these factors in PCa development and progression. Metabolic factors and androgens may promote prostate carcinogenesis via multiple mechanisms including inflammation, adipokine action, fatty acid metabolism and IGF signalling. Moreover, androgen deprivation, given to men with PCa, has adverse metabolic consequences that need to be taken into account when estimating the risk benefit ratio of this therapy. In this review, we will discuss the current epidemiological and mechanistic evidence regarding the interactions between metabolic conditions, sex steroids and PCa risk and management. PMID- 22514108 TI - Thyroid-specific ablation of the Carney complex gene, PRKAR1A, results in hyperthyroidism and follicular thyroid cancer. AB - Thyroid cancer is the most common endocrine malignancy in the population, and the incidence of this cancer is increasing at a rapid rate. Although genetic analysis of papillary thyroid cancer (PTC) has identified mutations in a large percentage of patients, the genetic basis of follicular thyroid cancer (FTC) is less certain. Thyroid cancer, including both PTC and FTC, has been observed in patients with the inherited tumor predisposition Carney complex, caused by mutations in PRKAR1A. In order to investigate the role of loss of PRKAR1A in thyroid cancer, we generated a tissue-specific knockout of Prkar1a in the thyroid. We report that the resulting mice are hyperthyroid and developed follicular thyroid neoplasms by 1 year of age, including FTC in over 40% of animals. These thyroid tumors showed a signature of pathway activation different from that observed in other models of thyroid cancer. In vitro cultures of the tumor cells indicated that Prkar1a-null thyrocytes exhibited growth factor independence and suggested possible new therapeutic targets. Overall, this work represents the first report of a genetic mutation known to cause human FTC that exhibits a similar phenotype when modeled in the mouse. In addition to our knowledge of the mechanisms of human follicular thyroid tumorigenesis, this model is highly reproducible and may provide a viable mechanism for the further clinical development of therapies aimed at FTC. PMID- 22514111 TI - Engaging basic scientists in translational research. PMID- 22514112 TI - Multimodal fluorescence modulation using molecular photoswitches and upconverting nanoparticles. AB - The intensity and colour of the light emitted from upconverting nanoparticles is controlled by the state of photoresponsive dithienylethene ligands decorated onto the surface of the nanoparticles. By selectively activating one or both ligands in a mixed, 3-component system, a multimodal read-out of the emitted light is achieved. PMID- 22514113 TI - Detection of fluticasone propionate in horse plasma and urine following inhaled administration. AB - Fluticasone propionate (FP) is an anti-inflammatory agent with topical and inhaled applications commonly used in the treatment of asthma in steroid dependent individuals. The drug is used in racehorses to treat Inflammatory Airway Disease; this work was performed in order to advise on its use and detect potential misuse close to racing. Methods were developed for the extraction and analysis of FP from horse plasma and a carboxylic acid metabolite (FP-17betaCOOH) from horse urine. The methods utilize ultra high performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) in order to detect the extremely low concentrations of analyte present in both matrices. The developed methods were used to analyse plasma and urine samples collected following inhaled administration of FP to six thoroughbred horses. FP was detected in plasma for a minimum of 72 h post-administration and FP-17betaCOOH was detected in urine for approximately 18 h post-administration. The results show that it is possible to detect FP in the horse following inhaled administration. PMID- 22514114 TI - An overview of the applications of graphene-based materials in supercapacitors. AB - Due to their unique 2D structure and outstanding intrinsic physical properties, such as extraordinarily high electrical conductivity and large surface area, graphene-based materials exhibit great potential for application in supercapacitors. In this review, the progress made so far for their applications in supercapacitors is reviewed, including electrochemical double-layer capacitors, pseudo-capacitors, and asymmetric supercapacitors. Compared with traditional electrode materials, graphene-based materials show some novel characteristics and mechanisms in the process of energy storage and release. Several key issues for improving the structure of graphene-based materials and for achieving better capacitor performance, along with the current outlook for the field, are also discussed. PMID- 22514115 TI - Labor-effective manipulation of marine and beetle luciferases for bioassays. AB - Engineering of luciferases with designed properties and functionalities collects great interest in bioassays. However, such an engineering including mutagenesis accompanies great consumption of time-and-labor. Here, I review an empirical approach to efficiently manipulate marine and beetle luciferases for bioassays, where a putative active site of luciferases is initially assigned with an in silico analysis, prior to the practical engineering, e.g. a hydrophilicity search reveals a characteristic hydrophilic region of luciferases as an engineering target. Amino acids in the hydrophilic region are recommended for a mutagenesis target to generate superluminescent variants of marine luciferases with prolonged bioluminescence. Empirical data suggest that a consecutive fragmentation to the assigned hydrophilic site greatly reduces time-and-labors on construction of single-chain probes. This review summarizes how to relieve the efforts for fabricating single-chain probes and potent variants of luciferases with excellent optical properties. PMID- 22514116 TI - Genotype analysis of tumor-initiating cells expressing CD133 in neuroblastoma. AB - Neuroblastoma (NB) is the most common and lethal extracranial solid tumor of childhood. Despite aggressive therapy, more than half of the children with advanced NB will die of uncontrolled metastatic disease. After chemotherapy, tumor-initiating cells (TICs) could persist, cause relapses and metastasis. The aim of this study is to demonstrate the tumor-initiating properties of CD133high NB cells and to identify new specific genetic abnormalities. Isolation of the CD133high cell population from NB cell lines was followed by neurosphere formation, soft agar assays, and orthotopic injections in NOD/SCID/IL2Rgammac null mice. A differential genotyping analysis was performed with Affymetrix SNP 6.0 arrays on CD133low and CD133high populations and the frequency of the abnormalities of 36 NB tumors was determined. Our results show that CD133high NB cells possess tumor-initiating properties, as CD133high cells formed significantly more neurospheres and produced significantly more colonies in soft agar than CD133low. Injection of 500 CD133high cells was sufficient to generate primary tumors and frequent metastases in mice. Differential genotyping analysis demonstrated two common regions with gains (16p13.3 and 19p13.3) including the gene EFNA2 in the CD133high population, and two with loss of heterozygosity (16q12.1 and 21q21.3) in the CD133low population. The gain of EFNA2 correlated with increased expression of the corresponding protein. These abnormalities were found in NB samples and some were significantly correlated with CD133 expression. Our results show that CD133high NB cells have TICs properties and present different genotyping characteristics compared to CD133low cells. Our findings reveal insights into new therapeutic targets in NB TICs. PMID- 22514118 TI - Single-cell protein as an alternative food for zebrafish, Danio rerio: a toxicological assessment. AB - Single-cell protein (SCP) refers to the dried cells of microorganisms. The aim of this research was to evaluate the nutrional characteristics and possible toxic effects of the SCP of Trichoderma harzianum. First, T. harzianum was grown on whey filtrate agar medium and the obtained SCP was analysed. It was rich in both total protein (34.21%) and ash (4.78%). Furthermore, the biomass contained all the essential amino acids, and the amino acid concentrations were very close to the FAO reference protein levels. Second, we exposed zebrafish (Danio rerio) embryos to diluted SCP at various concentrations for 96 hours postfertilization (hpf). Compared with the control group, we did not observe any developmental abnormalities, delayed hatching, and lethal effects on zebrafish embryos (96 hpf) found in the SCP group. To test diet effects on spawning success and growth of embryos, adult zebrafish were fed on SCP and flake feed diets for 10 weeks. The number of laid eggs, wet weight and diameter of eggs, and the percentages of hatched eggs from fish fed the flake diet and SCP diet were not significantly different from each other. Also, larval length and weight were not significantly affected by diets. Finally, SCP did not cause any toxic effect on zebrafish adults and their offsprings and could be useful as fish food or food additive. PMID- 22514119 TI - Early antioxidative defence responses in the aquatic worms (Limnodrilus sp.) in Porsuk Creek in Eskisehir (Turkey). AB - Certain oligochaeta specimens have been universally applied as bioindicators to reflect the organic and inorganic pollution in rivers and play a major role in the decomposition of pollutants. The aim of this study was to investigate the water quality in Porsuk Creek in Eskisehir (Turkey) through the specimens from two different species that belong to Limnodrilus genus, using their biomonitoring compatibilities for the accumulated trace element concentrations and to describe the applicability of antioxidative systems as biomarkers of pollution in Tubificinae. Therefore, some parameters that serve as biomarkers for antioxidative defence, total protein, glutathione (GSH) contents and glutathione S-transferase (GST) activities, were determined in Limnodrilus hoffmeisteri and Limnodrilus udekemianus. The study was completed with the chemical analysis of the trace elements from these specimens and also from the water samples. As a conclusion, the observed elevation in GSH levels and GST activities reflect the contribution of oxidative stress in toxicity mechanisms due to the accumulation of trace elements, and the study also suggests a general induction of detoxification metabolisms in the presence of several pollutants in benthic sediment-dwelling worms. According to the average value, the trace element levels for two species are as follows: Fe > Al > Zn > Mn > Pb > Cu > Ni > B > Cd = Cr = Hg. As Porsuk Creek is used for many purposes, such as irrigation, drinking water and fish production, discharges of all types of wastes should be under stringent control to avoid the unwanted health effects to its habitants and to humans. PMID- 22514120 TI - Antagonistic modulation of gliomagenesis by Pax6 and Olig2 in PDGF-induced oligodendroglioma. AB - Gliomas are aggressive tumors of the central nervous system originating from proliferating neural cells. Regulators of neural stem or progenitor cells biology may thus influence aspects of brain tumorigenesis, such as the maintenance of tumor-propagating potential. We investigated the role of Pax6, a neurogenic transcription factor already suggested as a positive prognostic marker for human gliomas, in a well-characterized in vivo model of PDGF-B-driven oligodendroglioma. In this system, the expression of Pax6 severely impairs tumor propagation by inducing a reduction of cell proliferation and the acquisition of differentiation traits in tumor-initiating cells. The overexpression of Pax6 correlates with a downregulation of Olig2, a bHLH transcription factor that normally antagonizes Pax6 in adult neurogenic niches and that plays a key role in the maintenance of neural stem and progenitor cells. Furthermore, we found that Olig2 is strictly required to maintain the malignancy of oligodendroglioma cells, since its silencing by interfering RNA abrogates tumor propagation. We finally show evidence that this function depends, at least in part, on the silencing of ID4, a dominant negative bHLH protein, whose upregulation follows Olig2 loss. In our model, the upregulation of ID4 mimics the loss of Olig2 in impairing the tumor-propagating potential of glioma cells. Our data, therefore, establish the relevance of physiological regulators of neural stem cell biology in regulating glial tumor malignancy and provide support for their functional interactions in this context. PMID- 22514121 TI - Surface chemistry of carbon nanotubes impacts the growth and expression of water channel protein in tomato plants. AB - Specific properties of carbon nanotubes, such as their level of agglomeration in the medium and their surface characteristics, can be critical for the physiological response of plants upon application of carbon nanotubes. The correlations among the level of aggregation, the type of functional group on the surface of the carbon nanotubes, and the growth performance of tomato plants are documented. PMID- 22514122 TI - Case studies on ESA-doping as revealed by the Biological Passport. AB - Blood doping, through the increase of red cells, induces changes of hematological parameters. The aim of the Biological Passport is first to analyse individual longitudinal profiles in order to identify, through variations of the specific parameters, doping manipulations. Additionally, on the basis of abnormal values or profiles, athletes can be targeted for traditional anti-doping tests in order to detect forbidden substances or methods. We report the experience of the International Cycling Union in applying the Biological Passport to target athletes for the presence of erythropoiesis stimulating agents. All positive results which have been reported between 2008 and 2010 concerning athletes enrolled in the Biological Passport program are presented. Four cases are discussed more in details. To conclude, we propose possible ways of using the Biological Passport in order to better understand athletes' doping modalities, so that testing programs efficiency can be improved. PMID- 22514123 TI - Rapid synthesis of polymer brush surfaces via microwave-assisted surface initiated radical polymerization. AB - Microwave-assisted surface-initiated radical polymerization (MUW-SIP) is demonstrated for the rapid synthesis of polymer brush surfaces on two-dimensional substrates. MUW-SIP is carried out at constant temperature and microwave power allowing comparison with conventional SIP carried out in an oil bath at the same effective solution temperature. We show MUW-SIP enables significant enhancements (up to 39-fold increase) in brush thickness at reduced reaction times for a range of monomer types (i.e. acrylamides, acrylates, methacrylates, and styrene). The effects of reaction time, monomer concentration, and microwave power on film thickness are explored. PMID- 22514124 TI - Fetal varicella - diagnosis, management, and outcome. AB - Fetal varicella syndrome (FVS) is due to transplacental infection by the Varicella zoster virus following maternal infection. The risks for the fetus and neonate depend on the timing. When varicella occurs around delivery, it often leads to disseminated neonatal varicella. When varicella occurs during pregnancy, transmission can occur, but is usually asymptomatic; some infants develop zoster postnatally and a few have FVS. Before 20 weeks' gestation, FVS can occur, with an incidence of about 1%. The lesions can affect the skin, limbs, central and autonomous nervous systems, eyes, cause calcifications, and growth retardation; mortality is high. Lesions typically follow one or several nerve territories, suggesting that damage results from in utero zoster following primary fetal infection. There has been little study of prenatal diagnosis of FVS. Serial ultrasound examination can detect various anomalies, magnetic resonance imaging can be of use to investigate for microphthamia and cerebral lesions, and amniocentesis can diagnose viral transmission. Prevention strategies include vaccination and post-exposure prophylaxis with immune globulin and/or antivirals. Perspectives for treating infected fetuses in utero require further research. PMID- 22514125 TI - Psychology and theology meet: illness appraisal and spiritual coping. AB - This descriptive exploratory study explored illness appraisal and spiritual coping of three groups of individuals with life-threatening illness. These were hospice clients with cancer (Ca; n = 10), clients with first myocardial infarction (MI; n = 6), and parents of children with cystic fibrosis (CF; n = 16). Qualitative data were collected by audiotaped face-to-face interviews (parents) and focus groups (MI and Ca). Similarities in illness appraisal and spiritual coping were found across the three groups except appreciation of crafts, which was found only in clients with Ca and causal meaning of parents (CF). Overall, illness was appraised negatively and positively, whereas spiritual coping incorporated existential and religious coping. These findings confirm the psychological theory (Lazarus & Folkman, 1984) and theological theory (Otto, 1950), which guided this study. Recommendations were proposed to integrate spirituality and religiosity in the curricula, clinical practice and to conduct cross-cultural comparative longitudinal research. PMID- 22514126 TI - Fireflies-on-a-chip: (ionic liquid)-aqueous microdroplets for biphasic chemical analysis. PMID- 22514127 TI - Metabolism and disposition of N,N-dimethyltryptamine and harmala alkaloids after oral administration of ayahuasca. AB - Ayahuasca is an Amazonian psychotropic plant tea obtained from Banisteriopsis caapi, which contains beta-carboline alkaloids, chiefly harmine, harmaline and tetrahydroharmine. The tea usually incorporates the leaves of Psychotria viridis or Diplopterys cabrerana, which are rich in N,N-dimethyltryptamine (DMT), a psychedelic 5-HT(2A/1A/2C) agonist. The beta-carbolines reversibly inhibit monoamine-oxidase (MAO), effectively preventing oxidative deamination of the orally labile DMT and allowing its absorption and access to the central nervous system. Despite increased use of the tea worldwide, the metabolism and excretion of DMT and the beta-carbolines has not been studied systematically in humans following ingestion of ayahuasca. In the present work, we used an analytical method involving high performance liquid chromatography (HPLC)/electrospray ionization (ESI)/selected reaction monitoring (SRM)/tandem mass spectrometry(MS/MS) to characterize the metabolism and disposition of ayahuasca alkaloids in humans. Twenty-four-hour urine samples were obtained from 10 healthy male volunteers following administration of an oral dose of encapsulated freeze dried ayahuasca (1.0 mg DMT/kg body weight). Results showed that less than 1% of the administered DMT dose was excreted unchanged. Around 50% was recovered as indole-3-acetic acid but also as DMT-N-oxide (10%) and other MAO-independent compounds. Recovery of DMT plus metabolites reached 68%. Harmol, harmalol, and tetrahydroharmol conjugates were abundant in urine. However, recoveries of each harmala alkaloid plus its O-demethylated metabolite varied greatly between 9 and 65%. The present results show the existence in humans of alternative metabolic routes for DMT other than biotransformation by MAO. Also that O-demethylation plus conjugation is an important but probably not the only metabolic route for the harmala alkaloids in humans. PMID- 22514128 TI - A parametric level-set approach to simultaneous object identification and background reconstruction for dual-energy computed tomography. AB - Dual-energy computerized tomography has gained great interest because of its ability to characterize the chemical composition of a material rather than simply providing relative attenuation images as in conventional tomography. The purpose of this paper is to introduce a novel polychromatic dual-energy processing algorithm, with an emphasis on detection and characterization of piecewise constant objects embedded in an unknown cluttered background. Physical properties of the objects, particularly the Compton scattering and photoelectric absorption coefficients, are assumed to be known with some level of uncertainty. Our approach is based on a level-set representation of the characteristic function of the object and encompasses a number of regularization techniques for addressing both the prior information we have concerning the physical properties of the object and the fundamental physics-based limitations associated with our ability to jointly recover the Compton scattering and photoelectric absorption properties of the scene. In the absence of an object with appropriate physical properties, our approach returns a null characteristic function and, thus, can be viewed as simultaneously solving the detection and characterization problems. Unlike the vast majority of methods that define the level-set function nonparametrically, i.e., as a dense set of pixel values, we define our level set parametrically via radial basis functions and employ a Gauss-Newton-type algorithm for cost minimization. Numerical results show that the algorithm successfully detects objects of interest, finds their shape and location, and gives an adequate reconstruction of the background. PMID- 22514129 TI - Rotation-invariant nonrigid point set matching in cluttered scenes. AB - This paper addresses the problem of rotation-invariant nonrigid point set matching. The shape context (SC) feature descriptor is used because of its strong discriminative nature, whereas edges in the graphs constructed by point sets are used to determine the orientations of SCs. Similar to lengths or directions, oriented SCs constructed this way can be regarded as attributes of edges. By matching edges between two point sets, rotation invariance is achieved. Two novel ways of constructing graphs on a model point set are proposed, aiming at making the orientations of SCs as robust to disturbances as possible. The structures of these graphs facilitate the use of dynamic programming (DP) for optimization. The strong discriminative nature of SC, the special structure of the model graphs, and the global optimality of DP make our methods robust to various types of disturbances, particularly clutters. The extensive experiments on both synthetic and real data validated the robustness of the proposed methods to various types of disturbances. They can robustly detect the desired shapes in complex and highly cluttered scenes. PMID- 22514130 TI - Local tetra patterns: a new feature descriptor for content-based image retrieval. AB - In this paper, we propose a novel image indexing and retrieval algorithm using local tetra patterns (LTrPs) for content-based image retrieval (CBIR). The standard local binary pattern (LBP) and local ternary pattern (LTP) encode the relationship between the referenced pixel and its surrounding neighbors by computing gray-level difference. The proposed method encodes the relationship between the referenced pixel and its neighbors, based on the directions that are calculated using the first-order derivatives in vertical and horizontal directions. In addition, we propose a generic strategy to compute nth-order LTrP using (n - 1)th-order horizontal and vertical derivatives for efficient CBIR and analyze the effectiveness of our proposed algorithm by combining it with the Gabor transform. The performance of the proposed method is compared with the LBP, the local derivative patterns, and the LTP based on the results obtained using benchmark image databases viz., Corel 1000 database (DB1), Brodatz texture database (DB2), and MIT VisTex database (DB3). Performance analysis shows that the proposed method improves the retrieval result from 70.34%/44.9% to 75.9%/48.7% in terms of average precision/average recall on database DB1, and from 79.97% to 85.30% and 82.23% to 90.02% in terms of average retrieval rate on databases DB2 and DB3, respectively, as compared with the standard LBP. PMID- 22514131 TI - Three-dimensional face reconstruction from a single image by a coupled RBF network. AB - Reconstruction of a 3-D face model from a single 2-D face image is fundamentally important for face recognition and animation because the 3-D face model is invariant to changes of viewpoint, illumination, background clutter, and occlusions. Given a coupled training set that contains pairs of 2-D faces and the corresponding 3-D faces, we train a novel coupled radial basis function network (C-RBF) to recover the 3-D face model from a single 2-D face image. The C-RBF network explores: 1) the intrinsic representations of 3-D face models and those of 2-D face images; 2) mappings between a 3-D face model and its intrinsic representation; and 3) mappings between a 2-D face image and its intrinsic representation. Since a particular face can be reconstructed by its nearest neighbors, we can assume that the linear combination coefficients for a particular 2-D face image reconstruction are identical to those for the corresponding 3-D face model reconstruction. Therefore, we can reconstruct a 3-D face model by using a single 2-D face image based on the C-RBF network. Extensive experimental results on the BU3D database indicate the effectiveness of the proposed C-RBF network for recovering the 3-D face model from a single 2-D face image. PMID- 22514132 TI - Effect of coronary occlusion on intracardiac electrogram morphology. AB - AIMS: The effect of coronary occlusion on the morphology of intracardiac electrograms (IKG) may be of diagnostic value in recipients of cardiac implantable electronic device (CIED) and in other patients at risk of ischaemic heart disease (IHD), but remains grossly uncharacterized. The aim of the current study was to examine the effect of total occlusions in the major coronary artery distributions on the IKG. METHODS AND RESULTS: Domestic crossbred pigs (n= 11, 20 30 kg) were implanted with dual-coil right ventricular defibrillators, and bipolar right atrial and left ventricular leads. Through the femoral approach, percutaneous balloon total occlusion of the major coronary arteries was performed in random order in the left anterior descending, left circumflex, and right coronary arteries. Each occlusion was maintained for 3-5 min with 30 min periods of reperfusion in between. Simultaneous 15-vector IKG and 12-lead surface electrocardiograms (ECG) were recorded and analysed at baseline and during coronary occlusions. With coronary occlusions, significant ST-segment disturbances are consistently seen on both surface ECG leads and IKG tracings compared with baseline recordings and are reproducible over time. Given the multiple intracardiac recording vectors, each occluded vessel has a specific signature, allowing coronary localization from the IKG. CONCLUSIONS: Total coronary occlusion induces consistent IKG changes with injury patterns that allow the detection and localization of the culprit coronary artery. If duplicated in patients with IHD, these changes are likely to improve the time to diagnosis of acute coronary syndromes and thus favourably impact clinical outcomes. PMID- 22514133 TI - Stabilization of pH-sensitive mPEG-PH-PLA nanoparticles by stereocomplexation between enantiomeric polylactides. AB - Methoxy poly(ethylene glycol)-poly(L-histidine)-poly(lactide) (mPEG(45)-PH(30) PLA(82)) triblock copolymers self-assemble into nanoparticles by sterocomplexation. The properties of the stereocomplex nanoparticles including morphology, stability, and biocompatibility are investigated. The results reveal that the stereocomplexation between PLLA and PDLA segments could prevent the aggregation of the nanoparticles when the pH value is around 6.8. The mean diameter of the stereocomplex nanoparticles is stabilized at about 100 nm when the pH values are changed from 7.9 to 5.0. The cytotoxicity of the stereocomplex nanoparticles is evaluated, and the results demonstrate that the stereocomplexation could decrease the cytotoxicity of the PDLA segments. PMID- 22514134 TI - Ultrasound estimated fetal weight slightly below the median is associated with increased risk of spontaneous preterm birth. AB - BACKGROUND: This study investigates the possible relationship between ultrasound estimated fetal weight (EFW) at third trimester and the risk of preterm birth following spontaneous preterm labor in otherwise uncomplicated pregnancies. METHODS: We performed a nested case-control study including 281 cases of spontaneous preterm labor with preterm delivery in the third trimester and 3372 matched controls within a cohort of 6207 consecutive pregnant women. Pregnancies with fetal growth restriction (birth weight <10th centile of population-based normograms) or fetal anomalies were not included. EFW was calculated by using Hadlock's formula and converted to fetal gender adjusted multiples of median (MoM) for each gestational age. RESULTS: EFW correlated with birth weight (r = 0.959, p < 0.0001) and was lower in preterm than in control fetuses (p < 0.0001). The odds ratios (95% confidence intervals) for preterm birth for fetuses below 0.9 MoM, 0.85 MoM, 0.80 MoM, and 0.75 MoM of EFW were, respectively, 4.6 (3.6 5.9), 5.7 (4.3-7.5), 8.5 (5.9-12.1), and 11.2 (6.8-18.3). The independent relationship between preterm birth and lower EFW was confirmed in multivariate analysis with adjustment for potential confounders, such as maternal age, parity, and fetal gender. CONCLUSION: In asymptomatic women between 28 and 36 weeks of gestation, an EFW lower than 0.90 MoM increases by 4.6 times the risk of spontaneous preterm birth, and the risk increases proportionally to the degree of weight reduction. PMID- 22514135 TI - Traceless tosylhydrazone-based triazole formation: a metal-free alternative to strain-promoted azide-alkyne cycloaddition. PMID- 22514136 TI - Plasma fibronectin deficiency impedes atherosclerosis progression and fibrous cap formation. AB - Atherosclerotic lesions are asymmetric focal thickenings of the intima of arteries that consist of lipids, various cell types and extracellular matrix (ECM). These lesions lead to vascular occlusion representing the most common cause of death in the Western world. The main cause of vascular occlusion is rupture of atheromatous lesions followed by thrombus formation. Fibronectin (FN) is one of the earliest ECM proteins deposited at atherosclerosis-prone sites and was suggested to promote atherosclerotic lesion formation. Here, we report that atherosclerosis-prone apolipoprotein E-null mice lacking hepatocyte-derived plasma FN (pFN) fed with a pro-atherogenic diet display dramatically reduced FN depositions at atherosclerosis-prone areas, which results in significantly smaller and fewer atherosclerotic plaques. However, the atherosclerotic lesions from pFN-deficient mice lacked vascular smooth muscle cells and failed to develop a fibrous cap. Thus, our results demonstrate that while FN worsens the course of atherosclerosis by increasing the atherogenic plaque area, it promotes the formation of the protective fibrous cap, which in humans prevents plaques rupture and vascular occlusion. PMID- 22514137 TI - A biomimetic potentiometric sensor based on molecularly imprinted polymer for the determination of memantine in tablets. AB - Memantine hydrochloride is one of the first novel class medications for treatment of Alzheimer's disease. In this work, a biomimetic potentiometric sensor, based on a non-covalent imprinted polymer, was fabricated for the recognition and determination of memantine in pure drug and tablet pharmaceutical form. The molecularly imprinted polymer was synthesized by precipitation polymerization, using memantine hydrochloride as a template molecule, methacrylic acid as a functional monomer, and ethylene glycol dimethacrylate as a cross-linking agent. The sensor was developed by dispersing the memantine imprinted polymer particles in dibutyl sebacate plasticizer and embedding in poly(vinyl chloride) matrix. The wide linear range (10(-5) -10(-1) M), with a near Nernstian response of 57.4 mV/decade, a limit of detection 6.0 * 10(-6) M, fast response time (~15 s) and a satisfactory long-term stability (4 months) are characterizations of the proposed sensor. The sensor showed a high selectivity and a sensitive response to the template in aqueous system. The standard electrode potentials were determined at different temperatures and used to calculate the isothermal coefficient of the electrode. It was used as indicator electrode in potentiometric determination of memantine in pharmaceutical formulations. PMID- 22514138 TI - One case of increased intracranial translucency during the first trimester associated with the Dandy-Walker variant. PMID- 22514139 TI - Determinants of heart failure self-care behaviour in community-based patients: a cross-sectional study. AB - BACKGROUND: Self-care behaviour in patients with heart failure (HF) represents a series of specific actions that patients should take, as an important treatment component. AIMS: The aim of this study was to identify potential determinants of HF self-care in ambulatory patients with stable systolic HF. METHODS: In a cross sectional study of 318 patients with chronic systolic HF recruited in 48 German primary care practices, we evaluated the patient-reported European HF Self-care Behaviour scale (EHFScBs) assessments (range 12-60, where lower scores indicate better self-care). Potential determinants included socio-demographic (e.g. age, living status), clinical (e.g. NYHA class, LVEF, NT-proBNP levels, co morbidities), behavioural (e.g. smoking and alcohol intake), psychosocial (SF-36 scales and KCCQ domains, e.g. quality of life and self-efficacy) and depression status (PHQ-D), plus previous health care utilisation. Mixed regression modelling was applied. RESULTS: Patients had a mean (SD) age of 69.0 (10.4) years and were 71% male. They had a good overall EHFScBs score of 24.7 (7.8) (n=274). In the final regression model (n=271), six determinants were retained (beta; descriptive p-value): self-efficacy (-0.24; <.001), age (-0.22; <.001), prosthetic heart valve (-0.14; .01), referrals to cardiologists (-0.14; .02), peripheral arterial disease (0.13; .03) and quality of life (0.16; .02). CONCLUSION: In this exploratory cross-sectional study, the potential non-modifiable and modifiable risk factors and resources involved in patients' HF self-care were at the individual and organisational level. Self-efficacy and quality of life are potentially modifiable, so these could be targeted for improvement by enhancing patient motivation, HF education and further supporting a collaborative care approach. PMID- 22514140 TI - Taking a back seat: support and self-preservation in close relatives of patients with left ventricular assist device. AB - BACKGROUND: As more patients with cardiac failure are being bridged to transplantation with left ventricular assist devices (LVAD), more insight into the lives of their close relatives is needed. AIMS: To explore the experiences and coping strategies of LVAD patients' close relatives during bridge to transplantation and to generate theory. METHODS: The study had a qualitative design using grounded theory and NVivo version 9 to analyse one paired interview (n=2) and one group interview (n=5) with LVAD patients' close relatives. RESULTS: The main finding was the importance of supporting the close relatives who support the LVAD patient. The core category was support and self-preservation in close relatives. We constructed the support cascade model illustrating support from close relatives to the patient (main obligation) and to other family members (other obligations), and support from personal and professional relations to the close relatives. CONCLUSIONS: Support from close relatives potentially benefits patients, family, healthcare providers, and society in general. Our study highlighted the importance of supporting the close relatives supporting the patient and we have suggested some modifiable factors to enable social support and ease transitions in the illness trajectory. We suggest that awareness of social support systems might be beneficial in comprehensive care planning for LVAD patients and their close relatives. PMID- 22514141 TI - Screening for mild cognitive impairment in patients with heart failure: Montreal cognitive assessment versus mini mental state exam. AB - BACKGROUND: Cognitive impairments occur frequently in patients with chronic heart failure (CHF), resulting in worse health outcomes than expected. These impairments can remain undetected unless specifically screened. There are limited sensitive screening measures available in nursing practice to identify mild cognitive impairment (MCI). AIM: To compare the Montreal Cognitive Assessment (MoCA) with the Mini Mental State Exam (MMSE) in screening for MCI in CHF patients. METHODS: The MMSE and MoCA were administered to 93 hospitalized CHF patients (70+/-11 years), without a history of neurocognitive problems. Patients with low MoCA scores (<26) were compared to those with low MMSE scores (<27). Two different parameters were examined between the MoCA and the MMSE: level of MCI agreement (Kappa coefficient) and task errors on assessed cognitive domains (chi2 test). RESULTS: Statistically more patients had low MoCA scores compared with low MMSE scores (66 vs. 30, p=0.02). The MoCA classified 38 (41%) patients as cognitively impaired that were not classified by the MMSE. A significantly low level of agreement was found (kappa=0.25, p=0.001) between the MMSE and MoCA in identifying patients with scores suggestive of MCI. More task errors were observed on the MoCA cognitive domains compared with the MMSE cognitive domains. In 68% of patients with low cognitive scores, visuospatial task errors were observed on tasks from the MoCA compared with 22% on a similar task of the MMSE. CONCLUSION: The MoCA, a screening tool for MCI, identified subtle but potentially clinically relevant cognitive dysfunctions with greater frequency than MMSE. PMID- 22514142 TI - The impact of comprehensibility and sense of coherence in the recovery of patients with myocardial infarction: a long-term follow-up study. AB - BACKGROUND: After being through a myocardial infarction (MI), a severe recovery period ensues for the patient. Long-term follow-ups are helpful, but what this should include differs between patients. Today there is no established approach to identify needs for support after an MI. AIM: The aim was to describe sense of coherence (SOC) over time in relation to sex, as well as further SOC in relation to quality of life (QoL) and treatment satisfaction in patients with an MI. METHODS: This study had an observational and longitudinal design and followed 18 women and 60 men with an acute MI for 49-67 months after the onset of MI. Instruments used were the SOC-13 and the Seattle angina questionnaire. RESULTS: Women scored lower SOC than men. A main effect of time was shown for comprehensibility which increased significantly from baseline to the long-term follow-up. Women increased from a lower level to an equal level as men at the long-term follow-up. The total SOC was significantly associated with QoL and treatment satisfaction. CONCLUSION: High comprehensibility and high SOC give the patient a better basis to handle life after MI. Thus, healthcare professionals should keep in mind that SOC and especially comprehensibility have meaning for the patient's ability to handle her or his recovery. Healthcare professionals need to together with the patient identify and work with lifestyle factors that contribute to increased comprehensibility about the disease, which gives the patient the foundation to preserve and promote her or his health both in the short and long term. PMID- 22514143 TI - Patients with a left ventricular assist device: the new chronic patient in cardiology. PMID- 22514144 TI - Novel APP/Abeta mutation K16N produces highly toxic heteromeric Abeta oligomers. AB - Here, we describe a novel missense mutation in the amyloid precursor protein (APP) causing a lysine-to-asparagine substitution at position 687 (APP770; herein, referred to as K16N according to amyloid-beta (Abeta) numbering) resulting in an early onset dementia with an autosomal dominant inheritance pattern. The K16N mutation is located exactly at the alpha-secretase cleavage site and influences both APP and Abeta. First, due to the K16N mutation APP secretion is affected and a higher amount of Abeta peptides is being produced. Second, Abeta peptides carrying the K16N mutation are unique in that the peptide itself is not harmful to neuronal cells. Severe toxicity, however, is evident upon equimolar mixture of wt and mutant peptides, mimicking the heterozygous state of the subject. Furthermore, Abeta42 K16N inhibits fibril formation of Abeta42 wild-type. Even more, Abeta42 K16N peptides are protected against clearance activity by the major Abeta-degrading enzyme neprilysin. Thus the mutation characterized here harbours a combination of risk factors that synergistically may contribute to the development of early onset Alzheimer disease. PMID- 22514145 TI - Paromomycin-loaded albumin microspheres: efficacy and stability studies. AB - In the present work, paromomycin-loaded albumin microspheres (PM-MS) have been formulated for passive targeting of paromomycin (PM) to macrophages, for the treatment of visceral leishmaniasis (VL). PM-MS were prepared by spray-drying method with a mean particle size of ~ 3 um. Thermal and chemical cross-linking methods were used for controlling drug release from the prepared microspheres (MS). PM-MS were then tested for efficacy and stability studies. In efficacy study, in vitro promastigote assay was carried out to assess the susceptibility of promastigote to PM in the concentration range of 5.0-150 ug/ml; cytotoxicity assay was performed to determine possible toxicity of PM for the host cells (peritoneal macrophages) and intracellular amastigote assay was carried out to determine the efficacy of free PM (PM solution) and encapsulated PM (PM-MS). Results obtained indicated a significant increase in efficacy of PM-MS in comparison to PM solution at equivalent concentration. Subsequently, stability studies of prepared formulation was carried out at various temperature and humidity conditions, these studies provided stability of formulation at all tested conditions including accelerated conditions. Thus, it can be concluded that present work provides an optimized formulation with stability and enhanced efficacy. PMID- 22514146 TI - 'To suddenly have a name for this thing... was wonderful': the patient's experience of receiving a diagnosis of systemic lupus erythematosus. AB - OBJECTIVES: The aim of this study was to explore the patient's perception of receiving a diagnosis of systemic lupus erythematosus (lupus) and reports on their experience of the period between onset of symptoms and receiving a definitive diagnosis. METHODS: Focus groups were conducted in seven rheumatology centres. Forty-three participants were purposively selected and data were subjected to thematic deductive analysis. RESULTS: Focus group data generated three major themes. 'Diagnostic uncertainty and misdiagnosis' describes the frustration for many of experiencing years of often debilitating symptoms that have gone unacknowledged by health professionals and misunderstood by themselves. Some experienced the trauma of being misdiagnosed, which impacted on how they adjusted to their final diagnosis of lupus. 'Consequences of receiving a diagnosis' highlights the feelings of relief for participants at finally having a diagnosis, despite its implications. However, the manner in which this knowledge was delivered was often inappropriate and unsupported, affecting how they adjusted to future management of their condition. 'Impact on individuals' lives' explores how many felt empowered by finally receiving recognition for their symptoms, but the diagnosis of a relatively unknown condition with often invisible symptoms impacted on the response and support they received from those around them. CONCLUSION: It is essential health professionals have a greater understanding of the patient experience prior to receiving a diagnosis of lupus. The individual experience from symptom onset to diagnosis has a direct impact on the patient's subsequent acceptance of their diagnosis and response to management and therefore justifies the need for further research in this field. PMID- 22514147 TI - Assessment of medication knowledge and adherence among patients under oral chronic medication treatment in community pharmacy settings. AB - PURPOSE: This study aimed to determine whether there is a relationship between the lack of medication knowledge and the self-reported rates of patient medication adherence. METHODS: Patients eligible to participate in the study had been taking oral medication at least once daily over the course of a minimum of three consecutive months before recruitment to the study. All participants were older than 18 years. The level of each patient's knowledge of his or her medication was randomly assessed by a trained fifth-year pharmacy student through an adapted questionnaire. In addition, patient adherence was evaluated via utilization of the Morisky Medication Adherence Scale. RESULTS: Of the 765 study participants (mean +/- SD age = 55.45 +/- 15.05 years, range = 20-91 years, 56.2% women), 58.0% reported adherence to their medication regimen and 64.5% professed optimal knowledge of their medication. The mean duration of medication utilization was 26.77 +/- 40.62 months (range = 3-504 years). A statistically significant correlation exists between the total medication knowledge score on the questionnaire and the level of medication adherence (r = -0.964, p < 0.001). CONCLUSION: Improvement in the patient's knowledge of medications taken would bear a positive effect on medication adherence. PMID- 22514148 TI - Persistence of humoral immunity to tetanus and diphtheria in hematopoietic stem cell transplant recipients after post-transplant immunization. AB - BACKGROUND: Persistence of humoral immunity was evaluated in 82 hematopoietic stem cell transplant recipients up to 12.5 years after post-transplant immunization against tetanus and diphtheria. PROCEDURE: New immunization, initiated at least 12 months after transplantation, consisted of an average three dose schedule of vaccine administration on day 1, month 3, and month 12. Serological data were collected at pre-transplant, post-transplant, vaccination, and post-vaccination time points. RESULTS: The first vaccination dose elicited a seroprotective response in most recipients, but the complete vaccine series (usually three-dose schedule) reinforced the specific immunity in most vaccinated cases, that is, 100% and 95.8% seroprotection against tetanus and diphtheria, respectively. Geometric mean concentration post-vaccination tetanus and diphtheria antibody levels persisted at 1.9 IU (95% CI: 1.23-2.94 IU/ml) and 0.20 IU (95% CI: 0.11-0.38 IU/ml) for 7 years, respectively. However, diphtheria antibodies were lost not significantly but much faster and more often than tetanus antibodies, though the seroprotection rates against tetanus and diphtheria remained favorable, that is, 100% (95% CI: 85.2-100%) and 87% (95% CI: 59.5-98.3%), respectively. CONCLUSIONS: Full post-transplant revaccination resulted in long-term persistence of humoral immunity against tetanus and diphtheria in SCT recipients, for an average of 8.6 and 9.0 years, respectively. PMID- 22514149 TI - Proximal and distal maximal luminal diameters as a guide to appropriate deployment of the ABSORB everolimus-eluting bioresorbable vascular scaffold: a sub-study of the ABSORB Cohort B and the on-going ABSORB EXTEND Single Arm Study. AB - OBJECTIVES: Due to the limited distensibility of the everolimus-eluting bioresorbable vascular scaffold (ABSORB) compared to metallic platform stents, quantitative coronary arteriography (QCA) is a mandatory requirement for ABSORB deployment in the on-going ABSORB EXTEND Single-Arm Study. Visual assessment of vessel size in the ABSORB Cohort B study often lead to under and over-sizing of the 3 mm ABSORB in coronary vessels (recommended range of the vessel diameter >= 2.5 mm and <= 3.3 mm), with an increased risk of spontaneous incomplete scaffold apposition post ABSORB deployment. We report whether mandatory QCA assessment of vessel size pre-implantation, utilizing the maximal luminal diameter (Dmax) and established interpolated reference vessel diameter (RVD) measurements, has improved device/vessel sizing. METHODS: Pre-implantation post-hoc QCA analyses of all 101 patients from ABSORB Cohort B (102 lesions) and first consecutive 101 patients (108 lesions) from ABSORB EXTEND were undertaken by an independent core laboratory; all patients had a 3 mm ABSORB implanted. Comparative analyses were performed. RESULTS: Within ABSORB Cohort B, a greater number of over-sized vessels (> 3.3 mm) were identified utilizing the Dmax compared to the interpolated RVD (17 vessels, 16.7% vs. 3 vessels, 2.9%; P = 0.002). Comparative analyses demonstrated a greater number of appropriate vessel-size selection (75 vessels, 69.4% vs. 48 vessels, 47.1%; P = 0.001), a trend towards a reduction in implantation in small (< 2.5 mm) vessels (29 vessels, 26.9% vs. 40 vessels, 39.2%; P = 0.057) and a significant decrease in the implantation in large (> 3.3 mm) vessels (4 vessels, 3.7% vs. 17 vessels, 16.7%; P = 0.002) in ABSORB EXTEND. Bland-Altman plots suggested a good agreement between operator and core laboratory calculated Dmax measurements. CONCLUSIONS: The introduction of mandatory Dmax measurements of vessel size prior to ABSORB implantation significantly reduced the under-sizing of the 3.0 mm scaffold in large vessels validating the use of this technique in vessel sizing prior to ABSORB implantation. PMID- 22514150 TI - Intensive statin therapy for Chinese patients with coronary artery disease undergoing percutaneous coronary intervention (ISCAP study): rationale and design. AB - BACKGROUND: Myocardial necrosis is related to higher incidence of cardiovascular events and higher mortality rates during follow-up. Statins have been demonstrated to lower the risk of periprocedural myocardial infarction. The aim of this study is to evaluate the safety and efficacy of intensive statin therapy and the long-term outcome of patients in the Asian population. STUDY DESIGN: Approximately 1,100 patients with stable angina or non-ST elevation acute coronary syndrome undergoing selective percutaneous coronary intervention (PCI) are enrolled in this study. Patients are randomized either to the experimental group (80 mg atorvastatin 80 mg/day * 2 days before and 40 mg/day * 30 days after PCI) or to the control group (usual care). Creatine kinase-MB (CK-MB), troponin I (cTnI), and serum creatine are measured at 24 hours after the procedure. The total follow-up period is 6 months. The primary objective is to evaluate the efficacy of intensive atorvastatin treatment compared with usual care in reducing 30-day primary cardiovascular endpoints in patients undergoing selective PCI. Secondary endpoints are changes in myocardial biomarkers (cTnI, CK-MB) and hs CRP, CIN morbidity, 6-month clinical outcomes, and safety. CONCLUSION: The result of the ISCAP study will provide important evidence on the efficacy and safety of periprocedural serial intensive statin treatment in Asian patients with coronary artery disease undergoing selective PCI. PMID- 22514151 TI - The interaction between BDNF and DRD2 in bipolar II disorder but not in bipolar I disorder. AB - Bipolar I (BP-I) and bipolar II (BP-II) disorders are the two most common subtypes of bipolar disorder. However, most studies have not differentiated bipolar disorder into BP-I and BP-II groups, for which the underlying etiology differentiating these two subtypes remains unclear. The genetic association between both subtypes is essential for improving our understanding. The dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1), one of the dopaminergic pathways, as well as the brain-derived neurotrophic factor (BDNF) gene, were reported as candidate genes in the etiology of bipolar disorder. Therefore, we examined the contribution of the BDNF and DRD2/ANKK1 genes and their interaction to the differentiation of BP-I and BP-II. Seven hundred ninety-two participants were recruited: 208 with BP-I, 329 with BP-II, and 255 healthy controls. The genotypes of the BDNF and DRD2/ANKK1 Taq1A polymorphisms were determined using polymerase chain reactions plus restriction fragment length polymorphism analysis. A significant main effect for the Val/Val genotype of the BDNF Val66Met polymorphism predicted BP-II patients. The significant interaction effect for the Val/Val genotype of the BDNF Val66Met polymorphism and A1/A2 genotype of DRD2/ANKK1 Taq1A polymorphism was found only in BP-II patients. We provide initial evidence that the BDNF Val66Me and DRD2/ANKK1 Taq1A polymorphisms interact only in BP-II disorder and that BP-I and BP-II are genetically distinct. PMID- 22514152 TI - Effect of body mass index on mortality and clinical status in rheumatoid arthritis. AB - OBJECTIVE: To study the relative risk (RR) of all-cause and cause-specific mortality in rheumatoid arthritis (RA) associated with body mass index (BMI), and to quantify the clinical and outcome consequences of abnormal BMI. METHODS: We studied mortality in 24,535 patients over 12.3 years, dividing patients into 3 age groups, <50, 50-70, and >70 years and fit Cox regression models separately within each age stratum. We used BMI categories of <18.5 kg/m(2) (underweight), 18.5 to <25 kg/m(2) (normal weight, reference category), 25 to <30 kg/m(2) (overweight), and >=30 kg/m(2) (obesity). RESULTS: BMI >=30 kg/m(2) was seen in 63-68% and underweight in ~2%. Reduction in the RR (95% confidence interval [95% CI]) for all-cause (AC) and cardiovascular mortality was seen for overweight (AC 0.8 [95% CI 0.8, 0.9]) and obese groups (AC 0.8 [95% CI 0.7, 0.8]), with and without comorbidity adjustment. Underweight was associated with increased mortality risk (AC 1.9 [95% CI 1.7, 2.3]). By contrast, obesity produced profound changes in clinical variables. Compared with normal weight, the odds ratio in the obese group was 4.8 for diabetes mellitus, 3.4 for hypertension, 1.3 for myocardial infarction, 1.4 for joint replacement, and 1.9 for work disability. Total semiannual direct medical costs were $1,683 greater, annual household income $6,481 less, pain scores 1.1 units higher, Health Assessment Questionnaire 0.28 higher, and EuroQol utility 0.7 units lower in the obese. CONCLUSION: Overweight and obesity reduce the RR of all-cause and cardiovascular mortality across different age groups and durations of RA. By contrast, overweight and obesity are associated with substantial increased risks of comorbidity, total joint replacement, greater pain, medical costs, and decreased quality of life. PMID- 22514153 TI - Molecular spintronics based on single-molecule magnets composed of multiple decker phthalocyaninato terbium(III) complex. AB - Unlike electronics, which is based on the freedom of the charge of an electron whose memory is volatile, spintronics is based on the freedom of the charge, spin, and orbital of an electron whose memory is non-volatile. Although in most GMR, TMR, and CMR systems, bulk or classical magnets that are composed of transition metals are used, this Focus Review considers the growing use of single molecule magnets (SMMs) that are composed of multinuclear metal complexes and nanosized magnets, which exhibit slow magnetic-relaxation processes and quantum tunneling. Molecular spintronics, which combines spintronics and molecular electronics, is an emerging field of research. Using molecules is advantageous because their electronic and magnetic properties can be manipulated under specific conditions. Herein, recent developments in [LnPc]-based multiple-decker SMMs on surfaces for molecular spintronic devices are presented. First, we discuss the strategies for preparing single-molecular-memory devices by using SMMs. Next, we focus on the switching of the Kondo signal of [LnPc]-based multiple-decker SMMs that are adsorbed onto surfaces, their characterization by using STM and STS, and the relationship between the molecular structure, the electronic structure, and the Kondo resonance of [TbPc(2)]. Finally, the field effect-transistor (FET) properties of surface-adsorbed [LnPc(2)] and [Ln(2)Pc(3)] cast films are reported, which is the first step towards controlling SMMs through their spins for applications in single-molecular memory and spintronics devices. PMID- 22514155 TI - A dual Atkinson measure of socioeconomic inequality of health. AB - The Atkinson index of income inequality is based on a comparison of the average income with the equivalent income, where the equivalent income is defined as the level of income that, if given to everyone, would generate the same social welfare as the existing distribution of income. This paper explores the possibility of extending this approach to the measurement of socioeconomic inequality of health. It assumes a social evaluation function that depends upon two variables: socioeconomic status as well as health status. With a general form of this function, an Atkinson measure is derived, which gives exactly the same result when applied to the socioeconomic variable and when applied to the health variable. The paper examines the properties of the index and suggests various extensions. PMID- 22514156 TI - Contribution of obesity to the rise in incidence of rheumatoid arthritis. AB - OBJECTIVE: Obesity is an underrecognized risk factor for rheumatoid arthritis (RA). In recent years, both the prevalence of obesity and the incidence of RA have been rising. Our objective was to determine whether the "obesity epidemic" could explain the recent rise in the incidence of RA. METHODS: An inception cohort of Olmsted County, Minnesota residents who fulfilled the 1987 American College of Rheumatology criteria for RA in 1980-2007 was compared to population based controls (matched on age, sex, and calendar year). Heights, weights, and smoking statuses were collected from medical records. Obesity was defined as a body mass index >=30 kg/m(2) . Conditional logistic regression was used to assess the influence of obesity on developing RA. Population attributable risk was used to estimate the incidence of RA in the absence of obesity. RESULTS: The study included 813 patients with RA and 813 controls. Both groups had extensive medical history available prior to the incidence/index date (mean 32.2 years), and ~30% of each group was obese at the incidence/index date. The history of obesity was significantly associated with developing RA (odds ratio 1.24, 95% confidence interval 1.01-1.53; adjusted for smoking status). In 1985-2007, the incidence of RA rose by an increment of 9.2 per 100,000 among women. Obesity accounted for 4.8 per 100,000 (52%) of this increase. CONCLUSION: Obesity is associated with a modest risk for developing RA. Given the rapidly increasing prevalence of obesity, this has had a significant impact on RA incidence and may account for much of the recent increase in the incidence of RA. PMID- 22514157 TI - In vitro and in vivo study of calcium polyphosphate fiber/calcium phosphate cement/micromorselized bone composite for bone defect repair. AB - The aim of this study was to develop a superior bone engineering material for repair of bone defects. A composite of calcium polyphosphate fiber (CPPF)/calcium phosphate cement (CPC)/micromorselized bone was prepared. A scanning electron microscope was used to observe the structure of the composite and measure its porosity. Seventy-two pieces of the material were placed in phosphate buffer solution and changes in pH were measured over time, and compressive strength was also measured. In vivo experiments were carried out on 72 rabbits divided into six groups: bone implantation with CPPF/CPC/micromorselized bone, CPC/micromorselized bone, micromorselized bone, CPPF/CPC, CPC, respectively; and no implantation (control). The implants were assessed with X-ray film and histologically, and bone density and biomechanical strength were measured. The study period was 12 weeks. The addition of CPPF increased apertures of the composite. The bone defects in the CPPF/CPC/micromorselized group compared with the other groups had significantly higher radiographic grading and significantly greater bone density (p < 0.05) and biomechanical strength (p < 0.05). The new composite improves the speed and quality of bone formation. The addition of CPPF improved the mechanical properties of the scaffold material and created higher porosity. PMID- 22514158 TI - The dynamics of income-related health inequality among American children. AB - We estimate and decompose income-related inequality in child health in the USA and analyze its dynamics using the recently introduced health mobility index. Data come from the 1997, 2002, and 2007 waves of the Child Development Supplement of the Panel Study of Income Dynamics. The findings show that income-related child health inequality remains stable as children grow up and enter adolescence. The main factor underlying income-related child health inequality is income itself, although other factors, such as maternal education, also play a role. Decomposition of income-related health mobility indicates that health changes over time are more favorable to children with lower initial family incomes versus children with higher initial family incomes. However, offsetting this effect, our findings also suggest that changes in income ranking over time are positively related to children's subsequent health status. PMID- 22514159 TI - Association of obesity with worse disease severity in rheumatoid arthritis as well as with comorbidities: a long-term followup from disease onset. AB - OBJECTIVE: To determine the association of obesity, defined as a body mass index (BMI) >=30 or >=28 kg/m(2) or by waist circumference (WC), with disease activity and severity, as well as its relationship to comorbidities in rheumatoid arthritis (RA). METHODS: The study population comprised 1,596 patients with early RA (mean +/- SD age 55.6 +/- 14.6 years, 67.8% women) who had been included in the Better Anti-Rheumatic Farmacotherapy observational study from 1992-2006. In 2010, data on lifestyle factors and comorbidities were collected through a postal questionnaire, answered by 1,391 patients. Clinical outcomes were the Disease Activity Score in 28 joints, sustained remission, physical function (Health Assessment Questionnaire [HAQ]), and pain and global health assessed on a visual analog scale, as well as predefined comorbidities. RESULTS: After a mean +/- SD of 9.5 +/- 3.7 years, the mean +/- SD BMI had increased from 25.4 +/- 4.2 to 26.0 +/- 4.5 kg/m(2) (P = 0.000). The prevalence of BMI >=30 kg/m(2) was 12.9% at baseline and 15.8% at followup. In multivariable regression, BMI and obesity, defined as a BMI >=30 or >=28 kg/m(2) , at both inclusion and the time of the survey were independently associated with higher disease activity, fewer patients in sustained remission, higher HAQ score, more pain, and worse general health. Also, BMI and obesity independently conferred to higher odds for being diagnosed with hypertension, diabetes mellitus, and chronic pulmonary disease. Further, BMI and WC were independently associated with angina pectoris/acute myocardial infarction/coronary revascularization. In contrast, none of the examined obesity variables was associated with the prevalence of stroke or transient ischemic attack. Lifestyle changes during the observational period, such as quitting smoking or diet change, had no impact on the outcomes. CONCLUSION: Obesity was associated with worse RA disease outcomes and a higher prevalence of comorbidities. Body measurements are recommended to improve prediction of the disease course. PMID- 22514161 TI - Anodic oxidation on a boron-doped diamond electrode mediated by methoxy radicals. PMID- 22514162 TI - Mapping spatial and field dependence of magnetic domain memory by soft X-ray speckle metrology. AB - The occurrence of magnetic domain memory has been observed in ferromagnets, either induced by structural defects or by exchange couplings. Being able to quantify the amount of memory as a function of length scale, field and temperature is both of fundamental and technological importance. A technique has been refined to statistically quantify the magnetic domain memory in ferromagnetic thin films by using coherent soft-X-ray scattering metrology. This technique, based on cross-correlating magnetic speckle patterns, provides a unique way to map out the behavior of domain memory. Here, the details of our correlation method and the necessary treatment of the X-ray scattering images to extract spatial and field dependences in the memory information are reviewed. The resulting correlation maps, measured on [Co/Pd]IrMn multilayers, show how magnetic domain memory evolves at various spatial scales, as a function of the field magnitude throughout magnetization cycles, but also as a function of field cycling and of temperature. This technique can easily be applied to a wide variety of systems presenting memory effects, in soft and hard matter, and also to dynamical studies. PMID- 22514160 TI - Long-term mechanical durability of dental nanocomposites containing amorphous calcium phosphate nanoparticles. AB - Half of all dental restorations fail within 10 years, with secondary caries and restoration fracture being the main reasons. Calcium phosphate (CaP) composites can release Ca and PO(4) ions and remineralize tooth lesions. However, there has been no report on their long-term mechanical durability. The objective of this study was to investigate the wear, thermal-cycling, and water-aging of composites containing amorphous calcium phosphate nanoparticles (NACP). NACP of 112-nm and glass particles were used to fabricate four composites: (1) 0% NACP+75% glass; (2) 10% NACP+65% glass; (3) 15% NACP+60% glass; and (4) 20% NACP+50% glass. Flexural strength and elastic modulus of NACP nanocomposites were not degraded by thermal-cycling. Wear depth increased with increasing NACP filler level. Wear depths of NACP nanocomposites after 4 * 10(5) cycles were within the range for commercial controls. Mechanical properties of all the tested materials decreased with water-aging time. After 2 years, the strengths of NACP nanocomposites were moderately higher than the control composite, and much higher than the resin modified glass ionomers. The mechanism of strength loss for resin-modified glass ionomer was identified as microcracking and air-bubbles. NACP nanocomposites and control composite were generally free of microcracks and air-bubbles. In conclusion, combining NACP nanoparticles with reinforcement glass particles resulted in novel nanocomposites with long-term mechanical properties higher than those of commercial controls, and wear within the range of commercial controls. These strong long-term properties, plus the Ca-PO(4) ion release and acid neutralization capability reported earlier, suggest that the new NACP nanocomposites may be promising for stress-bearing and caries-inhibiting restorations. PMID- 22514163 TI - High-energy transmission Laue micro-beam X-ray diffraction: a probe for intra granular lattice orientation and elastic strain in thicker samples. AB - An understanding of the mechanical response of modern engineering alloys to complex loading conditions is essential for the design of load-bearing components in high-performance safety-critical aerospace applications. A detailed knowledge of how material behaviour is modified by fatigue and the ability to predict failure reliably are vital for enhanced component performance. Unlike macroscopic bulk properties (e.g. stiffness, yield stress, etc.) that depend on the average behaviour of many grains, material failure is governed by 'weakest link'-type mechanisms. It is strongly dependent on the anisotropic single-crystal elastic plastic behaviour, local morphology and microstructure, and grain-to-grain interactions. For the development and validation of models that capture these complex phenomena, the ability to probe deformation behaviour at the micro-scale is key. The diffraction of highly penetrating synchrotron X-rays is well suited to this purpose and micro-beam Laue diffraction is a particularly powerful tool that has emerged in recent years. Typically it uses photon energies of 5-25 keV, limiting penetration into the material, so that only thin samples or near-surface regions can be studied. In this paper the development of high-energy transmission Laue (HETL) micro-beam X-ray diffraction is described, extending the micro-beam Laue technique to significantly higher photon energies (50-150 keV). It allows the probing of thicker sample sections, with the potential for grain-level characterization of real engineering components. The new HETL technique is used to study the deformation behaviour of individual grains in a large-grained polycrystalline nickel sample during in situ tensile loading. Refinement of the Laue diffraction patterns yields lattice orientations and qualitative information about elastic strains. After deformation, bands of high lattice misorientation can be identified in the sample. Orientation spread within individual scattering volumes is studied using a pattern-matching approach. The results highlight the inability of a simple Schmid-factor model to capture the behaviour of individual grains and illustrate the need for complementary mechanical modelling. PMID- 22514164 TI - Synchrotron-radiation phase-contrast imaging of human stomach and gastric cancer: in vitro studies. AB - The electron density resolution of synchrotron-radiation phase-contrast imaging (SR-PCI) is 1000 times higher than that of conventional X-ray absorption imaging in light elements, through which high-resolution X-ray imaging of biological soft tissue can be achieved. For biological soft tissue, SR-PCI can give better imaging contrast than conventional X-ray absorption imaging. In this study, human resected stomach and gastric cancer were investigated using in-line holography and diffraction enhanced imaging at beamline 4W1A of the Beijing Synchrotron Radiation Facility. It was possible to depict gastric pits, measuring 50-70 um, gastric grooves and tiny blood vessels in the submucosa layer by SR-PCI. The fine structure of a cancerous ulcer was displayed clearly on imaging the mucosa. The delamination of the gastric wall and infiltration of cancer in the submucosa layer were also demonstrated on cross-sectional imaging. In conclusion, SR-PCI can demonstrate the subtle structures of stomach and gastric cancer that cannot be detected by conventional X-ray absorption imaging, which prompt the X-ray diagnosis of gastric disease to the level of the gastric pit, and has the potential to provide new methods for the imageology of gastric cancer. PMID- 22514165 TI - Energy resolution of the CdTe-XPAD detector: calibration and potential for Laue diffraction measurements on protein crystals. AB - The XPAD3S-CdTe, a CdTe photon-counting pixel array detector, has been used to measure the energy and the intensity of the white-beam diffraction from a lysozyme crystal. A method was developed to calibrate the detector in terms of energy, allowing incident photon energy measurement to high resolution (approximately 140 eV), opening up new possibilities in energy-resolved X-ray diffraction. In order to demonstrate this, Laue diffraction experiments were performed on the bending-magnet beamline METROLOGIE at Synchrotron SOLEIL. The X ray energy spectra of diffracted spots were deduced from the indexed Laue patterns collected with an imaging-plate detector and then measured with both the XPAD3S-CdTe and the XPAD3S-Si, a silicon photon-counting pixel array detector. The predicted and measured energy of selected diffraction spots are in good agreement, demonstrating the reliability of the calibration method. These results open up the way to direct unit-cell parameter determination and the measurement of high-quality Laue data even at low resolution. Based on the success of these measurements, potential applications in X-ray diffraction opened up by this type of technology are discussed. PMID- 22514166 TI - Evaluating the peak-to-valley dose ratio of synchrotron microbeams using PRESAGE fluorescence. AB - Synchrotron-generated microbeam radiotherapy holds great promise for future treatment, but the high dose gradients present conventional dosimetry with a challenge. Measuring the important peak-to-valley dose ratio (PVDR) of a microbeam-collimated synchrotron source requires both a dosimeter and an analysis method capable of exceptional spatial resolution. The PVDR is of great interest since it is the limiting factor for potential application of the microbeam radiation therapy technique clinically for its tissue-sparing properties (i.e. the valley dose should be below the tolerance of normal tissue). In this work a new method of measuring the dose response of PRESAGE dosimeters is introduced using the fluorescence from a 638 nm laser on a confocal laser-scanning microscope. This fluorescent microscopy method produces dosimetry data at a pixel size as low as 78 nm, giving a much better spatial resolution than optical computed tomography, which is normally used for scanning PRESAGE dosimeters. Using this technique the PVDR of the BL28B2 microbeam at the SPring-8 synchrotron in Japan is estimated to be approximately 52:1 at a depth of 2.5 mm. The PVDR was also estimated with EBT2 GAFchromic films as 30.5:1 at the surface in order to compare the PRESAGE fluorescent results with a more established dosimetry system. This estimation is in good agreement with previously measured ratios using other dosimeters and Monte Carlo simulations. This means that it is possible to use PRESAGE dosimeters with confocal microscopy for the determination of PVDR. PMID- 22514167 TI - Study of radiation damage induced by 12 keV X-rays in MOS structures built on high-resistivity n-type silicon. AB - Imaging experiments at the European X-ray Free Electron Laser (XFEL) require silicon pixel sensors with extraordinary performance specifications: doses of up to 1 GGy of 12 keV photons, up to 10(5) 12 keV photons per 200 um * 200 um pixel arriving within less than 100 fs, and a time interval between XFEL pulses of 220 ns. To address these challenges, in particular the question of radiation damage, the properties of the SiO(2) layer and of the Si-SiO(2) interface, using MOS (metal-oxide-semiconductor) capacitors manufactured on high-resistivity n-type silicon irradiated to X-ray doses between 10 kGy and 1 GGy, have been studied. Measurements of capacitance/conductance-voltage (C/G-V) at different frequencies, as well as of thermal dielectric relaxation current (TDRC), have been performed. The data can be described by a dose-dependent oxide charge density and three dominant radiation-induced interface states with Gaussian-like energy distributions in the silicon band gap. It is found that the densities of the fixed oxide charges and of the three interface states increase up to dose values of approximately 10 MGy and then saturate or even decrease. The shapes and the frequency dependences of the C/G-V measurements can be quantitatively described by a simple model using the parameters extracted from the TDRC measurements. PMID- 22514168 TI - Improved count rate corrections for highest data quality with PILATUS detectors. AB - The PILATUS detector system is widely used for X-ray experiments at third generation synchrotrons. It is based on a hybrid technology combining a pixelated silicon sensor with a CMOS readout chip. Its single-photon-counting capability ensures precise and noise-free measurements. The counting mechanism introduces a short dead-time after each hit, which becomes significant for rates above 10(6) photons s(-1) pixel(-1). The resulting loss in the number of counted photons is corrected for by applying corresponding rate correction factors. This article presents the results of a Monte Carlo simulation which computes the correction factors taking into account the detector settings as well as the time structure of the X-ray beam at the synchrotron. The results of the simulation show good agreement with experimentally determined correction factors for various detector settings at different synchrotrons. The application of accurate rate correction factors improves the X-ray data quality acquired at high photon fluxes. Furthermore, it is shown that the use of fast detector settings in combination with an optimized time structure of the X-ray beam allows for measurements up to rates of 10(7) photons s(-1) pixel(-1). PMID- 22514169 TI - Development of a laser-based heating system for in situ synchrotron-based X-ray tomographic microscopy. AB - Understanding the formation of materials at elevated temperatures is critical for determining their final properties. Synchrotron-based X-ray tomographic microscopy is an ideal technique for studying such processes because high spatial and temporal resolutions are easily achieved and the technique is non destructive, meaning additional analyses can take place after data collection. To exploit the state-of-the-art capabilities at the tomographic microscopy and coherent radiology experiments (TOMCAT) beamline of the Swiss Light Source, a general-use moderate-to-high-temperature furnace has been developed. Powered by two diode lasers, it provides controlled localized heating, from 673 to 1973 K, to examine many materials systems and their dynamics in real time. The system can also be operated in various thermal modalities. For example, near-isothermal conditions at a given sample location can be achieved with a prescribed time dependent temperature. This mode is typically used to study isothermal phase transformations; for example, the formation of equiaxed grains in metallic systems or to nucleate and grow bubble foams in silicate melts under conditions that simulate volcanic processes. In another mode, the power of the laser can be fixed and the specimen moved at a constant speed in a user-defined thermal gradient. This is similar to Bridgman solidification, where the thermal gradient and cooling rate control the microstructure formation. This paper details the experimental set-up and provides multiple proofs-of-concept that illustrate the versatility of using this laser-based heating system to explore, in situ, many elevated-temperature phenomena in a variety of materials. PMID- 22514170 TI - Micrometre resolution of a charge integrating microstrip detector with single photon sensitivity. AB - A synchrotron beam has been used to test the spatial resolution of a single photon-resolving integrating readout-chip coupled to a 320 um-thick silicon strip sensor with a dedicated readout system. Charge interpolation methods have yielded a spatial resolution of sigma(x) ? 1.8 um for a 20 um-pitch strip. PMID- 22514171 TI - Aspherical lens shapes for focusing synchrotron beams. AB - Aspherical surfaces required for focusing collimated and divergent synchrotron beams using a single refractive element (lens) are reviewed. The Cartesian oval, a lens shape that produces perfect point-to-point focusing for monochromatic radiation, is studied in the context of X-ray beamlines. Optical surfaces that approximate ideal shapes are compared. Results are supported by ray-tracing simulations. Elliptical lenses, rather than parabolic, are preferred for nanofocusing X-rays because of the higher peak and lower tails in the intensity distribution. Cartesian ovals will improve the gain when using high demagnification lenses of high numerical aperture. PMID- 22514172 TI - Quantitative performance measurements of bent crystal Laue analyzers for X-ray fluorescence spectroscopy. AB - Third-generation synchrotron radiation sources pose difficult challenges for energy-dispersive detectors for XAFS because of their count rate limitations. One solution to this problem is the bent crystal Laue analyzer (BCLA), which removes most of the undesired scatter and fluorescence before it reaches the detector, effectively eliminating detector saturation due to background. In this paper experimental measurements of BCLA performance in conjunction with a 13-element germanium detector, and a quantitative analysis of the signal-to-noise improvement of BCLAs are presented. The performance of BCLAs are compared with filters and slits. PMID- 22514174 TI - Performance upgrade in the JAEA actinide science beamline BL23SU at SPring-8 with a new twin-helical undulator. AB - The soft X-ray beamline BL23SU at SPring-8 has undergone an upgrade with a twin helical undulator of in-vacuum type to enhance the experimental capabilities of the endstations. The new light source with a fast helicity-switching operation allows not only the data throughput but also the sensitivity in X-ray magnetic circular dichroism (XMCD) to be improved. The operational performance and potential are described by presenting XMCD results of paramagnetic beta-US(2) measured with a 10 T superconducting magnet. PMID- 22514173 TI - Transmission-mode diamond white-beam position monitor at NSLS. AB - Two transmission-mode diamond X-ray beam position monitors installed at National Synchrotron Light Source (NSLS) beamline X25 are described. Each diamond beam position monitor is constructed around two horizontally tiled electronic-grade (p.p.b. nitrogen impurity) single-crystal (001) CVD synthetic diamonds. The position, angle and flux of the white X-ray beam can be monitored in real time with a position resolution of 500 nm in the horizontal direction and 100 nm in the vertical direction for a 3 mm * 1 mm beam. The first diamond beam position monitor has been in operation in the white beam for more than one year without any observable degradation in performance. The installation of a second, more compact, diamond beam position monitor followed about six months later, adding the ability to measure the angular trajectory of the photon beam. PMID- 22514175 TI - XANES analysis of spectral properties and structures of arsenate adsorption on TiO(2) surfaces. AB - X-ray absorption near-edge structure (XANES) of arsenate adsorption on TiO(2) surfaces was calculated using self-consistent multiple-scattering methods, allowing a structural analysis of experimental spectra. A quantitative analysis of the effect of disorder revealed that the broadening and weakening of the characteristic absorption in experimental XANES was due to the structural disorder of the arsenate-TiO(2) adsorption system. The success with calculating the scattering amplitude of a specific set of paths using the path expansion approach enables the scattering contributions of different coordination shells to the XANES to be sorted out. The results showed that the scattering resonances from high-level shells inherently overlapped onto the first-shell scattering amplitudes, and formed the fine structures in the XANES region. A variation in one oscillatory feature could be due to several structural changes affecting specific single/multiple-scattering amplitudes. Therefore, direct assignments of spectral features with structural elements should be based on adequate theoretical analysis. PMID- 22514176 TI - Spectroelectrochemical cell for in situ studies of solid oxide fuel cells. AB - Solid oxide fuel cells (SOFCs) are able to produce electricity and heat from hydrogen- or carbon-containing fuels with high efficiencies and are considered important cornerstones for future sustainable energy systems. Performance, activation and degradation processes are crucial parameters to control before the technology can achieve breakthrough. They have been widely studied, predominately by electrochemical testing with subsequent micro-structural analysis. In order to be able to develop better SOFCs, it is important to understand how the measured electrochemical performance depends on materials and structural properties, preferably at the atomic level. A characterization of these properties under operation is desired. As SOFCs operate at temperatures around 1073 K, this is a challenge. A spectroelectrochemical cell was designed that is able to study SOFCs at operating temperatures and in the presence of relevant gases. Simultaneous spectroscopic and electrochemical evaluation by using X-ray absorption spectroscopy and electrochemical impedance spectroscopy is possible. PMID- 22514177 TI - Implementation of a beam deflection system for studies of liquid interfaces on beamline I07 at Diamond. AB - X-ray optics, based on a double-crystal deflection scheme, that enable reflectivity measurements from liquid surfaces/interfaces have been designed, built and commissioned on beamline I07 at Diamond Light Source. This system is able to deflect the beam onto a fixed sample position located at the centre of a five-circle diffractometer. Thus the incident angle can be easily varied without moving the sample, and the reflected beam is tracked either by a moving Pilatus 100K detector mounted on the diffractometer arm or by a stationary Pilatus 2M detector positioned appropriately for small-angle scattering. Thus the system can easily combine measurements of the reflectivity from liquid interfaces (Q(z) > 1 A(-1)) with off-specular data collection, both in the form of grazing-incidence small-angle X-ray scattering (GISAXS) or wider-angle grazing-incidence X-ray diffraction (GIXD). The device allows operation over the energy range 10-28 keV. PMID- 22514178 TI - The SAMBA quick-EXAFS monochromator: XAS with edge jumping. AB - Results and performances of the QEXAFS double monochromator of the SAMBA beamline (Synchrotron SOLEIL) are presented. The device is capable of speeds of up to 40 Hz, while giving the user the possibility to choose the amplitude of the scan from 0.1 degrees to 4 degrees in a few seconds. The device is composed of two independent units and it is possible to perform scans alternating between two different crystals, literally jumping from low (4 keV) to high (37 keV) energies. PMID- 22514179 TI - A unique approach to accurately measure thickness in thick multilayers. AB - X-ray optics called multilayer Laue lenses (MLLs) provide a promising path to focusing hard X-rays with high focusing efficiency at a resolution between 5 nm and 20 nm. MLLs consist of thousands of depth-graded thin layers. The thickness of each layer obeys the linear zone plate law. X-ray beamline tests have been performed on magnetron sputter-deposited WSi(2)/Si MLLs at the Advanced Photon Source/Center for Nanoscale Materials 26-ID nanoprobe beamline. However, it is still very challenging to accurately grow each layer at the designed thickness during deposition; errors introduced during thickness measurements of thousands of layers lead to inaccurate MLL structures. Here, a new metrology approach that can accurately measure thickness by introducing regular marks on the cross section of thousands of layers using a focused ion beam is reported. This new measurement method is compared with a previous method. More accurate results are obtained using the new measurement approach. PMID- 22514180 TI - An optimized side-cooling scheme for a collimation mirror at the SSRF. AB - Here, in order to reduce tangential slope errors along the centreline of a first mirror's surface, a side-cooling scheme is proposed. The length of the contact area between the mirror and cooling blocks should be smaller than the beam footprint along the mirror. By optimizing the length and the height of the contact area, reduced slope errors can be obtained. Using this scheme the maximum temperature is not located at the centre of the footprint but shifts to both sides, which fundamentally changes the temperature distribution and enhances the cooling effect compared with the traditional method. This paper presents a 'design of experiment' analysis for four kinds of cooling schemes. The structure of the mechanical clamps is also described. PMID- 22514181 TI - An integrated high-throughput data acquisition system for biological solution X ray scattering studies. AB - A fully automated high-throughput solution X-ray scattering data collection system has been developed for protein structure studies at beamline 4-2 of the Stanford Synchrotron Radiation Lightsource. It is composed of a thin-wall quartz capillary cell, a syringe needle assembly on an XYZ positioning arm for sample delivery, a water-cooled sample rack and a computer-controlled fluid dispenser. It is controlled by a specifically developed software component built into the standard beamline control program Blu-Ice/DCS. The integrated system is intuitive and very simple to use, and enables experimenters to customize data collection strategy in a timely fashion in concert with an automated data processing program. The system also allows spectrophotometric determination of protein concentration for each sample aliquot in the beam via an in situ UV absorption spectrometer. A single set of solution scattering measurements requires a 20-30 ul sample aliquot and takes typically 3.5 min, including an extensive capillary cleaning cycle. Over 98.5% of measurements are valid and free from artefacts commonly caused by air-bubble contamination. The sample changer, which is compact and light, facilitates effortless switching with other sample-handling devices required for other types of non-crystalline X-ray scattering experiments. PMID- 22514182 TI - I19, the small-molecule single-crystal diffraction beamline at Diamond Light Source. AB - The dedicated small-molecule single-crystal X-ray diffraction beamline (I19) at Diamond Light Source has been operational and supporting users for over three years. I19 is a high-flux tunable-wavelength beamline and its key details are described in this article. Much of the work performed on the beamline involves structure determination from small and weakly diffracting crystals. Other experiments that have been supported to date include structural studies at high pressure, studies of metastable species, variable-temperature crystallography, studies involving gas exchange in porous materials and structural characterizations that require analysis of the diffuse scattering between Bragg reflections. A range of sample environments to facilitate crystallographic studies under non-ambient conditions are available as well as a number of options for automation. An indication of the scope of the science carried out on the beamline is provided by the range of highlights selected for this paper. PMID- 22514183 TI - Facilities for macromolecular crystallography at the Helmholtz-Zentrum Berlin. AB - Three macromolecular crystallography (MX) beamlines at the Helmholtz-Zentrum Berlin (HZB) are available for the regional, national and international structural biology user community. The state-of-the-art synchrotron beamlines for MX BL14.1, BL14.2 and BL14.3 are located within the low-beta section of the BESSY II electron storage ring. All beamlines are fed from a superconducting 7 T wavelength-shifter insertion device. BL14.1 and BL14.2 are energy tunable in the range 5-16 keV, while BL14.3 is a fixed-energy side station operated at 13.8 keV. All three beamlines are equipped with CCD detectors. BL14.1 and BL14.2 are in regular user operation providing about 200 beam days per year and about 600 user shifts to approximately 50 research groups across Europe. BL14.3 has initially been used as a test facility and was brought into regular user mode operation during the year 2010. BL14.1 has recently been upgraded with a microdiffractometer including a mini-kappa goniometer and an automated sample changer. Additional user facilities include office space adjacent to the beamlines, a sample preparation laboratory, a biology laboratory (safety level 1) and high-end computing resources. In this article the instrumentation of the beamlines is described, and a summary of the experimental possibilities of the beamlines and the provided ancillary equipment for the user community is given. PMID- 22514184 TI - Beamline AR-NW12A: high-throughput beamline for macromolecular crystallography at the Photon Factory. AB - AR-NW12A is an in-vacuum undulator beamline optimized for high-throughput macromolecular crystallography experiments as one of the five macromolecular crystallography (MX) beamlines at the Photon Factory. This report provides details of the beamline design, covering its optical specifications, hardware set up, control software, and the latest developments for MX experiments. The experimental environment presents state-of-the-art instrumentation for high throughput projects with a high-precision goniometer with an adaptable goniometer head, and a UV-light sample visualization system. Combined with an efficient automounting robot modified from the SSRL SAM system, a remote control system enables fully automated and remote-access X-ray diffraction experiments. PMID- 22514185 TI - ID29: a high-intensity highly automated ESRF beamline for macromolecular crystallography experiments exploiting anomalous scattering. AB - ID29 is an ESRF undulator beamline with a routinely accessible energy range of between 20.0 keV and 6.0 keV (lambda = 0.62 A to 2.07 A) dedicated to the use of anomalous dispersion techniques in macromolecular crystallography. Since the beamline was first commissioned in 2001, ID29 has, in order to provide an improved service to both its academic and proprietary users, been the subject of almost continuous upgrade and refurbishment. It is now also the home to the ESRF Cryobench facility, ID29S. Here, the current status of the beamline is described and plans for its future are briefly outlined. PMID- 22514186 TI - Adapting federated cyberinfrastructure for shared data collection facilities in structural biology. AB - Early stage experimental data in structural biology is generally unmaintained and inaccessible to the public. It is increasingly believed that this data, which forms the basis for each macromolecular structure discovered by this field, must be archived and, in due course, published. Furthermore, the widespread use of shared scientific facilities such as synchrotron beamlines complicates the issue of data storage, access and movement, as does the increase of remote users. This work describes a prototype system that adapts existing federated cyberinfrastructure technology and techniques to significantly improve the operational environment for users and administrators of synchrotron data collection facilities used in structural biology. This is achieved through software from the Virtual Data Toolkit and Globus, bringing together federated users and facilities from the Stanford Synchrotron Radiation Lightsource, the Advanced Photon Source, the Open Science Grid, the SBGrid Consortium and Harvard Medical School. The performance and experience with the prototype provide a model for data management at shared scientific facilities. PMID- 22514188 TI - Catalytic azide reduction in biological environments. AB - In the quest for the identification of catalytic transformations to be used in chemical biology and medicinal chemistry, we identified iron(III) meso tetraarylporphines as efficient catalysts for the reduction of aromatic azides to their amines. The reaction uses thiols as reducing agents and tolerates water, air, and other biological components. A caged fluorophore was employed to demonstrate that the reduction can be performed even in living mammalian cells. However, in vivo experiments in nematodes (Caenorhabditis elegans) and zebrafish (Danio rerio) revealed a limitation to this method: the metabolic reduction of aromatic azides. PMID- 22514189 TI - Obesity and the prediction of minimal disease activity: a prospective study in psoriatic arthritis. AB - OBJECTIVE: We prospectively evaluated whether obesity impacts achievement of minimal disease activity (MDA) in subjects with psoriatic arthritis (PsA). METHODS: Among PsA subjects with an active disease and who were starting a treatment with tumor necrosis factor alpha blockers, 135 obese (body mass index [BMI] >30 kg/m(2) ) patients and 135 patients of normal weight (controls) were followed up for 24 months. At baseline and at the 12- and 24-month followup, all subjects underwent a clinical, rheumatologic, and laboratory assessment. RESULTS: With the exception of the prevalence of hypercholesterolemia and hypertriglyceridemia, case and control subjects were similar for all the clinical and demographic characteristics analyzed. At the 12-month followup, in both cases and controls, no significant changes in body weight were found (P > 0.05 for all). MDA was achieved by 98 (36.3%) of the 270 PsA individuals. The prevalence of obesity was higher in those that did not achieve MDA than in those that did (64.0% versus 25.5%; P < 0.001). After adjusting for all the other variables, obesity was associated with a higher risk of not achieving MDA (hazard ratio [HR] 4.90, 95% confidence interval [95% CI] 3.04-7.87; P < 0.001). The HR of not achieving MDA was 3.98 (95% CI 1.96-8.06, P < 0.001) and 5.40 (95% CI 3.09-9.43, P < 0.001) in subjects with first-degree (BMI <30 kg/m(2) ) and second-degree (BMI 30-35 kg/m(2) ) obesity, respectively. Among the 98 subjects who had achieved MDA at the 12-month followup, the presence of obesity was associated with a poor probability of sustained MDA at the 24-month followup (HR 2.04, 95% CI 1.015-3.61; P = 0.014). CONCLUSION: Obesity is a negative predictor of achieving and maintaining MDA. PMID- 22514190 TI - Does body mass index accurately reflect body fat? A comparison of anthropometric measures in the longitudinal assessment of fat mass. AB - OBJECTIVE: To determine which anthropometric measure best correlates with change in fat mass (FM) over time. METHODS: The authors performed a retrospective cohort study of 76 obese patients (mean body mass index [BMI] 38 kg/m(2) and mean age 13 years) presenting to an obesity clinic between 2005 and 2010. For each patient, during 2 visits, FM was measured by bioelectrical impedance analysis and the following measures obtained: BMI, waist circumference, hip circumference, and neck circumference. Correlation coefficients and linear regression analyses were calculated to examine the relationship between each measure and FM. RESULTS: Change in BMI correlated better with change in FM than any other measure and had the strongest effect on change in FM (P < .01, R (2) = .887). The best regression model included BMI only (R (2) = .891); without BMI, the model was significantly worse (R (2) = .521). DISCUSSION: In the clinical management of obese children, BMI is an adequate measure of change in FM. PMID- 22514191 TI - Addressing antimicrobial resistance to treat children with atopic dermatitis in a tertiary pediatric allergy clinic. AB - BACKGROUND: Secondary skin infection with Staphylococcus aureus is a significant problem in atopic dermatitis (AD) patients. OBJECTIVE: This study evaluated antimicrobial resistance patterns of S aureus isolates from skin lesions in AD patients and empiric antimicrobial prescribing patterns. METHODS: Resistance patterns from positive skin cultures obtained from AD patients in the Allergy/Immunology clinic from May 1, 2006, to December 31, 2008, were compared with all outpatient wound cultures over the same period. RESULTS: Fifty-nine cultures were obtained from 38 AD patients. S aureus was the most common pathogen cultured from AD patients (53/59 cultures). S aureus resistance to clindamycin and methicillin differed significantly between the study group and the outpatient reference population (37.7% vs 9.4% and 45.3% vs 76.4%). Clindamycin was the most commonly prescribed antimicrobial (59%). Overall, 31.4% of organisms showed resistance to the antimicrobial prescribed. CONCLUSIONS: Susceptibility profiles of S aureus isolates from AD patients vary significantly from that of the general population. PMID- 22514192 TI - Two siblings with prolonged fever and pneumonia. PMID- 22514194 TI - Identification and management of behavioral/mental health problems in primary care pediatrics: perceived strengths, challenges, and new delivery models. AB - This study describes the experiences of and barriers for pediatricians in Kentucky in providing behavioral/mental health (B-MH) services in primary care settings. These data will serve as a foundation for improving service delivery. An online survey was completed by 70 pediatricians. Descriptive data are presented. More than 90% of the respondents said that they saw at least one patient a month with 1 of 10 specific B-MH diagnoses. Physicians' comfort with diagnosing and treating disorders varied widely by diagnosis, age-group, and drug classification. Major barriers to providing optimal care were inaccessibility of mental health professionals for consultation and referral, lack of communication, and lack of knowledge. Respondents were more likely to favor consultation and co location models over an integration model of care delivery. Overall, the authors found that pediatricians are dealing with patients with B-MH problems for which they may not have been adequately trained. Communication and collaboration needs were identified. PMID- 22514193 TI - The health status of youth in Puerto Rico. AB - BACKGROUND: Few population-based studies have assessed health outcomes and health care access and use among youth in the US Commonwealth of Puerto Rico. METHODS: Data are from an island population-based sample of 337 youth, 10 to 17 years old, who participated in the Asthma, Depression, and Anxiety in Puerto Rican Youth Study. In-person interviews with youth and caregivers assessed self-rated physical and mental health, weight status, diagnosed health conditions, and health care access and use. RESULTS: Island Puerto Rican youth report slightly worse physical and mental health than mainland youth. Puerto Rican youth have high rates of asthma, headaches, and stomachaches. Also, 6 in 10 island youth use public health insurance, and 1 in 3 regularly receive care at the emergency department. CONCLUSIONS: Island Puerto Rican youth are at a health disadvantage compared with mainland youth. Public health research is needed to fully understand and combat health challenges among Puerto Rican youth. PMID- 22514195 TI - Active/inactive dual-probe system for selective photoaffinity labeling of small molecule-binding proteins. AB - Two are better than one: A new approach to selective photoaffinity labeling is described in which a bioactive probe is used in combination with its inactive analog as a scavenger of nonspecific proteins. PMID- 22514196 TI - A review of polyvinyl alcohol and its uses in cartilage and orthopedic applications. AB - Polyvinyl alcohol (PVA) is a synthetic polymer derived from polyvinyl acetate through partial or full hydroxylation. PVA is commonly used in medical devices due to its low protein adsorption characteristics, biocompatibility, high water solubility, and chemical resistance. Some of the most common medical uses of PVA are in soft contact lenses, eye drops, embolization particles, tissue adhesion barriers, and as artificial cartilage and meniscus. The purpose of this review is to evaluate the available published information on PVA with respect to its safety as a medical device implant material for cartilage replacement. The review includes historical clinical use of PVA in orthopedics, and in vitro and in vivo biocompatibility studies. Finally, the safety recommendation involving the further development of PVA cryogels for cartilage replacement is addressed. PMID- 22514197 TI - Association between polymyalgia rheumatica and vascular disease: a systematic review. AB - OBJECTIVE: To systematically identify and appraise the existing literature on the association between polymyalgia rheumatica (PMR) and vascular disease. METHODS: The Medline, Embase, CINAHL, and Cochrane databases were searched from inception to September 2010. Search criteria included observational studies containing patients with isolated PMR reporting on a vascular outcome. Data were extracted and articles were assessed for quality. RESULTS: The database search identified 545 articles. Eight articles reporting on 7 unique studies were included in the final review. Four studies reported on vascular mortality and 3 studies reported on other vascular outcomes. Four of the studies reported statistically significant positive associations between PMR and vascular disease and 3 studies reported no statistically significant results. The heterogeneity of the results was investigated; the strongest explanatory variable was that 2 of 3 studies that reported nonsignificant results were prospective, whereas all of those studies reporting significant results were retrospective. CONCLUSION: There is some evidence to suggest that, like other inflammatory rheumatic disorders, PMR may be linked to an increased risk of vascular disease. Further studies are required to quantify the level of risk to determine whether patients with PMR should be actively screened for cardiovascular disease and its risk factors. PMID- 22514198 TI - Synthesis of biodegradable poly(epsilon-caprolactone)-organosiloxane hybrid with carboxylate groups. AB - Biodegradable poly(epsilon-caprolactone)-organosiloxane hybrid with carboxylate groups was newly synthesized by a sol-gel method with the capacity to conjugate cell adhesion ligands for the potential applications as a bone tissue engineering scaffold material. An intermediate hybrid contained positively charged amine groups was synthesized by end-capping alpha,omega-hydroxyl poly(epsilon caprolactone) with (3-isocyanatopropyl)triethoxysilane and a subsequent sol-gel reaction with (3-aminopropyl)triethoxysilane. This resulted in a new hybrid composed of biodegradable organic poly(epsilon-caprolactone) segments connected by inorganic siloxane linkages containing positively charged amine groups. The successive succinlylation of amine groups created amide bonds and converted the cationic sites of succinic anhydride into negatively charged carboxylate groups. New formations of amine and carboxylate groups could be directly and indirectly confirmed using Fourier transformed infrared spectrometry, zeta potentials, and atomic force microscopy. Biodegradability of hybrid with carboxylate groups was also examined by weight loss in phosphate buffered saline, and it was about 14 wt % after 8 weeks. Conjugating capacity of a cell adhesion ligand was examined by comparing the relative fluorescent intensities of covalently and noncovalently immobilized synthetic GGGGRGDASSK-FITC oligopeptides onto the carboxylated groups of the hybrid using confocal laser scanning microscopy; the relative fluorescent intensity of covalently conjugated RGD peptide was about three times higher than that of noncovalently coated RGD peptide. The hybrid covalently conjugated by GGGGRGDASSK oligopeptides improved proliferation and differentiation activities of preosteoblastic MC3T3-E1 cells. The results suggest that this hybrid possesses an encouraging potential to be used as a bone tissue engineering scaffold material due to its biodegradability and high capacity for conjugating cell adhesion ligands. PMID- 22514199 TI - Usefulness of thoracic CT to diagnose tuberculosis disease in patients younger than 4 years of age. AB - BACKGROUND: There is controversy over the need of using thoracic CT (TCT) systematically for differentiating disease from tuberculosis infection in young children. This distinction is important when making a diagnosis of TB as the treatment changes from a single drug to a multidurug regimen with reported side effects. AIM: To determine the usefulness of using TCT to diagnose pulmonary tuberculosis (PTB) in patients younger than 4 years of age who have TB infection (IBI). MATERIALS AND METHODS: After the simultaneous detection of four cases of PTB in children who attended the same class, a study on the contact among workers and children was carried out. One hundred sixteen children younger than 4 years and 20 adults were included. The tuberculin skin test (TST) was performed on all of them. CHEST XR (CXR) and TCT were performed on children with positive TST and three samples of gastric acid were taken. CXR and sputum testing were performed on adults with positive TST. RESULTS: TST was positive in 28 children (24.1%). In 92.8% of children with positive TST and normal CXR, TCT showed features compatible with PTB. Out of the 28 children with positive TST, 27 (96.4%) were diagnosed with PTB and only one with latent TBI (4%). CONCLUSIONS: In children younger than 4-year old with positive TST and normal CXR, it would be advisable to perform a TCT since the findings could change the diagnosis from TBI to TB disease. PMID- 22514200 TI - Methods for automated identification of informative behaviors in natural bioptic driving. AB - Visually impaired people may legally drive if wearing bioptic telescopes in some developed countries. To address the controversial safety issue of the practice, we have developed a low-cost in-car recording system that can be installed in study participants' own vehicles to record their daily driving activities. We also developed a set of automated identification techniques of informative behaviors to facilitate efficient manual review of important segments submerged in the vast amount of uncontrolled data. Here, we present the methods and quantitative results of the detection performance for six types of driving maneuvers and behaviors that are important for bioptic driving: bioptic telescope use, turns, curves, intersections, weaving, and rapid stops. The testing data were collected from one normally sighted and two visually impaired subjects across multiple days. The detection rates ranged from 82% up to 100%, and the false discovery rates ranged from 0% to 13%. In addition, two human observers were able to interpret about 80% of targets viewed through the telescope. These results indicate that with appropriate data processing the low-cost system is able to provide reliable data for natural bioptic driving studies. PMID- 22514201 TI - Monitoring respiration and cardiac activity using fiber Bragg grating-based sensor. AB - This paper shows the design of a fiber-based sensor for living activities in human body and the results of a laboratory evaluation carried out on it. The authors have developed a device that allows for monitoring the vibrations of human body evoked by living activities--breathing and cardiac rhythm. The device consists of a Bragg grating inscribed into a single mode optical fiber and operating on a wavelength of around 1550 nm. The fiber Bragg grating (FBG) is mounted inside a pneumatic cushion to be placed between the backrest of the seat and the back of the monitored person. Deformations of the cushion, involving deformations of the FBG, are proportional to the vibrations of the body leaning on the cushion. Laboratory studies have shown that the sensor allows for obtaining dynamic strains on the sensing FBG in the range of 50-124 MU strain caused by breathing and approximately 8.3 MUstrain induced by heartbeat, which are fully measurable by today's FBG interrogation systems. The maximum relative measurement error of the presented sensor is 12%. The sensor's simple design enables it to be easily implemented in pilot's and driver's seats for monitoring the physiological condition of pilots and drivers. PMID- 22514202 TI - Reconstruction of fluorescence molecular tomography using a neighborhood regularization. AB - In fluorescence molecular tomography, the highly scattering property of biological tissues leads to an ill-posed inverse problem and reduces the accuracy of detection and localization of fluorescent targets. Regularization technique is usually utilized to obtain a stable solution. Conventional Tikhonov regularization is based on singular value decomposition (SVD) and L-curve strategy, which attempts to find a tradeoff between the residual norm and image norm. It is computationally demanding and may fail when there is no optimal turning point in the L-curve plot. In this letter, a neighborhood regularization method is presented. It achieves a reliable solution by computing the geometric mean of multiple regularized solutions. These solutions correspond to different regularization parameters with neighbor orders of magnitude. The main advantages lie in three aspects. First, it can produce comparable or better results in comparison with the conventional Tikhonov regularization with L-curve routine. Second, it replaces the time-consuming SVD computation with a trace-based pseudoinverse strategy, thus greatly reducing the computational cost. Third, it is robust and practical even when the L-curve technique fails. Results from numerical and phantom experiments demonstrate that the proposed method is easy to implement and effective in improving the quality of reconstruction. PMID- 22514203 TI - Dynamic sample size detection in learning command line sequence for continuous authentication. AB - Continuous authentication (CA) consists of authenticating the user repetitively throughout a session with the goal of detecting and protecting against session hijacking attacks. While the accuracy of the detector is central to the success of CA, the detection delay or length of an individual authentication period is important as well since it is a measure of the window of vulnerability of the system. However, high accuracy and small detection delay are conflicting requirements that need to be balanced for optimum detection. In this paper, we propose the use of sequential sampling technique to achieve optimum detection by trading off adequately between detection delay and accuracy in the CA process. We illustrate our approach through CA based on user command line sequence and naive Bayes classification scheme. Experimental evaluation using the Greenberg data set yields encouraging results consisting of a false acceptance rate (FAR) of 11.78% and a false rejection rate (FRR) of 1.33%, with an average command sequence length (i.e., detection delay) of 37 commands. When using the Schonlau (SEA) data set, we obtain FAR = 4.28% and FRR = 12%. PMID- 22514204 TI - A globally optimal estimator for the delta-lognormal modeling of fast reaching movements. AB - Fast reaching movements are an important component of our daily interaction with the world and are consequently under investigation in many fields of science and engineering. Today, useful models are available for such studies, with tools for solving the inverse dynamics problem involved by these analyses. These tools generally provide a set of model parameters that allows an accurate and locally optimal reconstruction of the original movements. Although the solutions that they generate may provide a data curve fitting that is sufficient for some pattern recognition applications, the best possible solution is often necessary in others, particularly those involving neuroscience and biomedical signal processing. To generate these solutions, we present a globally optimal parameter extractor for the delta-lognormal modeling of reaching movements based on the branch-and-bound strategy. This algorithm is used to test the impact of white noise on the delta-lognormal modeling of reaching movements and to benchmark the state-of-the-art locally optimal algorithm. Our study shows that, even with globally optimal solutions, parameter averaging is important for obtaining reliable figures. It concludes that physiologically derived rules are necessary, in addition to global optimality, to achieve meaningful ?Lambda extractions which can be used to investigate the control patterns of these movement primitives. PMID- 22514205 TI - Cycling induced by electrical stimulation improves muscle activation and symmetry during pedaling in hemiparetic patients. AB - A randomized controlled trial, involving 35 post-acute hemiparetic patients, demonstrated that a four-week treatment of cycling induced by functional electrical stimulation (FES-cycling) promotes motor recovery. Analyzing additional data acquired during that study, the present work investigated whether these improvements were associated to changes in muscle strength and motor coordination. Participants were randomized to receive FES-cycling or placebo FES cycling. Clinical outcome measures were: the Motricity Index (MI), the gait speed, the electromyography activation of the rectus femoris and biceps femoris, and the mechanical work produced by each leg during voluntary pedaling. To provide a comparison with normal values, healthy adults also carried out the pedaling test. Patients were evaluated before, after training, and at follow-up visits. A significant treatment effect in favor of FES-treated patients was found in terms of MI scores and unbalance in mechanical works, while differences in gait speed were not significant (ANCOVA). Significant improvements in the activation of the paretic muscles were highlighted in the FES group, while no significant change was found in the placebo group (Friedman test). Our findings suggested that improvements in motor functions induced by FES-cycling training were associated with a more symmetrical involvement of the two legs and an improved motor coordination. PMID- 22514206 TI - Comparison of single- and two-channel neuromuscular electrical stimulation sites for enhancing venous return. AB - Neuromuscular electrical stimulation (NMES) has previously been used to activate the musculature of the lower leg and increase venous return to the heart. However, there is little evidence to suggest the superiority of one particular stimulation site over another. In this paper, we aim to reveal the optimal stimulation site on the lower leg in a group of healthy adults. Doppler ultrasound measurements of venous blood volume expelled and peak venous velocity in response to various single and two-channel applications of NMES were taken for each subject. We found that soleus NMES is the most effective single-channel stimulation method, capable of expelling 58.3% of the blood achieved during a voluntary contraction, alternatively soleus plus tibialis posterior stimulation is capable of expelling 76.5%. Based on these and other factors we suggest that the soleus and soleus plus tibialis posterior are the most effective NMES sites for improving venous return. PMID- 22514207 TI - Development of a pressure control system for brace treatment of scoliosis. AB - Bracing is a common nonsurgical treatment for scoliosis, but its effectiveness has been debated. Some clinical studies have shown efficacy of brace treatment is correlated to how the brace has been worn. The more often the patients wear their braces to the prescribed tightness as well as the prescribed length of wear each day, the better the treatment outcome. A system of four wireless pressure control devices was developed to understand brace wear-time and regulate a target pressure range at the brace-body interface. Each pressure control device could function independently and be embedded in the brace at key pressure areas. Such a system could improve the quality of brace wear-making the treatment more effective and refining our understanding of the three-pressure-point brace treatment concept during daily activities. This paper reports the system development and validation. The system was tested on four healthy subjects for 2 h without pressure regulation and 2 h with regulation. The results show that the pressure regulation doubled the time spent in a desired pressure range on average (from 31% to 62%). Brace-wear time was logged correctly. The system was also validated through a seven-day continuous test, and a fully charged battery could run for 30 days without requiring recharge. PMID- 22514208 TI - A simulation-based analysis of motor unit number index (MUNIX) technique using motoneuron pool and surface electromyogram models. AB - Motor unit number index (MUNIX) measurement has recently achieved increasing attention as a tool to evaluate the progression of motoneuron diseases. In our current study, the sensitivity of the MUNIX technique to changes in motoneuron and muscle properties was explored by a simulation approach utilizing variations on published motoneuron pool and surface electromyogram (EMG) models. Our simulation results indicate that, when keeping motoneuron pool and muscle parameters unchanged and varying the input motor unit numbers to the model, then MUNIX estimates can appropriately characterize changes in motor unit numbers. Such MUNIX estimates are not sensitive to different motor unit recruitment and rate coding strategies used in the model. Furthermore, alterations in motor unit control properties do not have a significant effect on the MUNIX estimates. Neither adjustment of the motor unit recruitment range nor reduction of the motor unit firing rates jeopardizes the MUNIX estimates. The MUNIX estimates closely correlate with the maximum M-wave amplitude. However, if we reduce the amplitude of each motor unit action potential rather than simply reduce motor unit number, then MUNIX estimates substantially underestimate the motor unit numbers in the muscle. These findings suggest that the current MUNIX definition is most suitable for motoneuron diseases that demonstrate secondary evidence of muscle fiber reinnervation. In this regard, when MUNIX is applied, it is of much importance to examine a parallel measurement of motor unit size index (MUSIX), defined as the ratio of the maximum M-wave amplitude to the MUNIX. However, there are potential limitations in the application of the MUNIX methods in atrophied muscle, where it is unclear whether the atrophy is accompanied by loss of motor units or loss of muscle fiber size. PMID- 22514209 TI - Air pollution and symptoms of depression in elderly adults. AB - BACKGROUND: Although the effect of air pollution on various diseases has been extensively investigated, few studies have examined its effect on depression. OBJECTIVES: We investigated the effect of air pollution on symptoms of depression in an elderly population. METHODS: We enrolled 537 participants in the study who regularly visited a community center for the elderly located in Seoul, Korea. The Korean version of the Geriatric Depression Scale-Short Form (SGDS-K) was used to evaluate depressive symptomatology during a 3-year follow-up study. We associated ambient air pollutants with SGDS-K results using generalized estimating equations (GEE). We also conducted a factor analysis with items on the SGDS-K to determine which symptoms were associated with air pollution. RESULTS: SGDS-K scores were positively associated with interquartile range (IQR) increases in the 3-day moving average concentration of particulate matter with an aerodynamic diameter <= 10 MUm (PM10) [17.0% increase in SGDS-K score, 95% confidence interval (CI): 4.9%, 30.5%], the 0-7 day moving average of nitrogen dioxide [NO2; 32.8% (95% CI: 12.6%, 56.6%)], and the 3-day moving average of ozone [O3; 43.7% (95% CI: 11.5%, 85.2%)]. For these three pollutants, factor analysis showed that air pollution was more strongly associated with emotional symptoms such as feeling happy and satisfied than with somatic or affective symptoms. CONCLUSIONS: Our study suggests that increases in PM10, NO2, and O3 may increase depressive symptoms among the elderly. Of the symptoms evaluated, ambient air pollution was most strongly associated with emotional symptoms. PMID- 22514210 TI - Accelerated mammary tumor onset in a HER2/Neu mouse model exposed to DDT metabolites locally delivered to the mammary gland. AB - BACKGROUND: The association of DDT (dichlorodiphenyltrichloroethane) with breast cancer is controversial, but animal studies directly linking DDT to risk are lacking. Concerns with DDT reside in its environmental persistence, bioaccumulation in breast adipose tissue, and endocrine-disrupting actions. Whereas most attention has been focused on estrogenic congeners, we tested the cancer-inducing potential of the antiandrogen, p,p'-DDE [1,1-dichloro-2,2-bis(p chlorophenyl) ethylene], the most prevalent and persistent DDT metabolite. OBJECTIVES: We aimed to determine whether developmental exposure to p,p'-DDE stored in adipose tissue surrounding the cancer-prone mammary epithelium of MMTV Neu mice influences tumor development. METHODS: For localized delivery, Elvax 40P pellets containing p,p'-DDE were implanted into the mammary fat pads of prepubertal female mice. We compared mammary tumor development with p,p'-DDE with development in response to its estrogenic isomer, o,p'-DDE [1,1-dichloro-2-(o chlorophenyl)-2-(p-chlorophenyl) ethylene], and a mixture of both isomers. RESULTS: p,p'-DDE implants significantly accelerated mammary tumor onset compared with vehicle Elvax implants. o,p'-DDE had similar results, but only at <= 10 months of age. Lipid-adjusted levels of p,p'-DDE in mammary adipose tissue and serum in young mice were within the ranges of human exposure, whereas concentrations in aged mice were low to undetectable. Exposure to a 2:1 ratio of p,p'-DDE:o,p'-DDE did not result in the younger latency observed with the individual isomers. CONCLUSIONS: p,p'-DDE exposure at concentrations relevant to human exposure accelerates mammary carcinogenesis in mice, possibly through hormonal and/or other actions. These data suggest that DDE exposure would promote, but not cause, mammary tumorigenesis. Developmental exposure in immature mammary tissue continues to affect tumor onset even after p,p'-DDE levels have declined. Future studies are needed to determine whether early exposure to p,p' DDE correspondingly predisposes women to early-onset breast cancer. PMID- 22514212 TI - Determinants of risk factor control in subjects with coronary heart disease: a report from the EUROASPIRE III investigators. AB - The EUROASPIRE audits of risk factor control have indicated that, even in those with established coronary heart disease, risk factor control remains poor. We therefore analysed the EUROASPRE III data set to establish the factors associated with success or failure in risk factor control in order to inform future risk factor management strategies. University education, attendance at a specialist cardiology clinic, and participation in a cardiac rehabilitation programme were associated with improved risk factor control. Risk factor control was poorer in women, those with diabetes, and those undergoing coronary artery bypass surgery as opposed to medical therapy or percutaneous coronary intervention. Increasing age, depression, and anxiety were not associated with poorer risk factor control. PMID- 22514211 TI - Omega-3 fatty acid supplementation appears to attenuate particulate air pollution induced cardiac effects and lipid changes in healthy middle-aged adults. AB - BACKGROUND: Air pollution exposure has been associated with adverse cardiovascular health effects. Findings of a recent epidemiological study suggested that omega-3 fatty acid (fish oil) supplementation blunted cardiac responses to air pollution exposure. OBJECTIVES: We conducted a randomized, controlled exposure study to evaluate the efficacy of fish oil supplements in attenuating adverse cardiac effects of exposure to concentrated ambient fine and ultrafine particulate matter (CAP). METHODS: Twenty-nine healthy middle-aged participants (mean, 58 +/- 1 years of age) were supplemented in a randomized, double-blinded manner with 3 g/day of either fish oil or olive oil for 4 weeks before sequential chamber exposure to filtered air and CAP (mean mass concentration 278 +/- 19 ug/m3) for 2 hr. Cardiac responses were assessed by comparing time and frequency domain changes in heart rate variability (HRV) and electrocardiographic repolarization changes measured before, immediately after, and 20 hr after exposure. Changes in plasma lipids were also evaluated at these time points. RESULTS: Fish oil supplementation appeared to attenuate CAP-induced reductions in high-frequency/low-frequency ratio, as well as elevations in normalized low-frequency HRV and prolongation of the QT interval corrected for heart rate (QTc). Very low-density lipoprotein and triglyceride concentrations increased significantly immediately after exposure to CAP in participants supplemented with olive oil, but not in those supplemented with fish oil. CONCLUSIONS: Exposure of healthy middle-aged adults to CAP for 2 hr induced acute cardiac and lipid changes after supplementation with olive oil, but not fish oil. Our findings suggest that omega-3 fatty acid supplements offer protection against the adverse cardiac and lipid effects associated with air pollution exposure. PMID- 22514213 TI - Population-level changes to promote cardiovascular health. AB - BACKGROUND: Cardiovascular diseases (CVD) cause 1.8 million premature (<75 years) death annually in Europe. The majority of these deaths are preventable with the most efficient and cost-effective approach being on the population level. The aim of this position paper is to assist authorities in selecting the most adequate management strategies to prevent CVD. DESIGN AND METHODS: Experts reviewed and summarized the published evidence on the major modifiable CVD risk factors: food, physical inactivity, smoking, and alcohol. Population-based preventive strategies focus on fiscal measures (e.g. taxation), national and regional policies (e.g. smoke-free legislation), and environmental changes (e.g. availability of alcohol). RESULTS: Food is a complex area, but several strategies can be effective in increasing fruit and vegetables and lowering intake of salt, saturated fat, trans-fats, and free sugars. Tobacco and alcohol can be regulated mainly by fiscal measures and national policies, but local availability also plays a role. Changes in national policies and the built environment will integrate physical activity into daily life. CONCLUSION: Societal changes and commercial influences have led to the present unhealthy environment, in which default option in life style increases CVD risk. A challenge for both central and local authorities is, therefore, to ensure healthier defaults. This position paper summarizes the evidence and recommends a number of structural strategies at international, national, and regional levels that in combination can substantially reduce CVD. PMID- 22514215 TI - Tendering out general practice is bad for doctors--and patients. PMID- 22514214 TI - Early and current socio-economic position and cardiometabolic risk factors in the Indian Migration Study. AB - AIMS: The aim of this study is to estimate the associations of early and current socio-economic position (SEP) on adult cardiometabolic risk factors in the Indian Migration Study (N = 7,067). METHODS AND RESULTS: Linear mixed models were used to estimate associations between early and current SEP and cardiometabolic risk factors: systolic blood pressure (SBP), body fat and Homeostasis Model Assessment (HOMA) score. In males, high current SEP was associated with higher SBP. In both genders, high early and current SEP were associated with higher body fat, current SEP dominating the associations. High early SEP was associated with higher HOMA score in males only, and the effect size halved after adjustment for current SEP. High current SEP was associated with higher HOMA score more strongly in males than in females. CONCLUSION: Higher SEP, more importantly in adulthood than childhood, was associated with cardiometabolic risk factors in an Indian population. The relationship between SEP over the life course and urbanization should be considered in the Indian context when public health interventions to prevent cardiovascular disease are planned. PMID- 22514216 TI - Most Pinnacle cup implants have polyethylene or ceramic bearings. PMID- 22514217 TI - Guidelines can harm patients too. PMID- 22514218 TI - Good doctors being bad. PMID- 22514219 TI - How will minimum unit price for alcohol be enforced? PMID- 22514220 TI - Fortify minimum alcohol prices with excise tax. PMID- 22514221 TI - Invite all donors to participate in follow-up studies. PMID- 22514222 TI - In memoriam. PMID- 22514223 TI - Living donor registries are needed. PMID- 22514224 TI - For how much longer will we tolerate commercial screening? PMID- 22514225 TI - Routine monitoring of outcomes is needed. PMID- 22514226 TI - What is the objective of personal healthcare budgets? PMID- 22514227 TI - Healthcare professionals more knowledgeable about female genital mutilation but still some way to go. PMID- 22514228 TI - Taking dementia seriously. PMID- 22514229 TI - Investing in new services is key. PMID- 22514230 TI - What are the benefits of an early diagnosis? PMID- 22514232 TI - Streptococcus B in pregnancy: to screen or not to screen? PMID- 22514233 TI - Geographic location, sex and nutritional status play an important role in body image concerns among Brazilian adolescents. AB - This study compared body image concerns among adolescents from different geographic locations in Brazil, and the influence of sex and nutritional status. Seven hundred eighty-eight adolescents completed the Body Shape Questionnaire (BSQ) and had their weight and height measured. There were significant cross regional differences in BSQ scores. Also, body image concerns were more prevalent among girls and among overweight adolescents. It is suggested that sex and nutritional status may play an important role in body image concerns, which is more common between adolescents from urban areas. Furthermore, our findings contribute to the literature by examining patterns of body image concerns within subgroups of adolescents who have received little research attention on these issues. PMID- 22514234 TI - Landmark study classifies breast cancer into 10 genetic types. PMID- 22514235 TI - Airway disease and emphysema on CT: not just phenotypes of lung pathology. PMID- 22514238 TI - Delinquency, androgens, and the family: a test of evolutionary neuroandrogenic theory. AB - There is little doubt that family factors can influence involvement in delinquency, although the full nature and extent of their influences remain unclear. In recent decades, testosterone has been increasingly implicated as a contributor to adolescent offending. The present study sought to determine whether two important types of familial factors--parental socioeconomic status and amicable parent-child relationships--are interacting with testosterone (and possibly other androgens) to affect delinquency. A large sample of North American college students self-reported their involvement in eight categories of delinquency along with self-ratings of various androgen-promoted traits (e.g., muscularity and low-deep voice), parental social status, and the quality of the relationships they had with parents. In both sexes, parent-child relationships and androgens were significantly associated with delinquency but parental social status was not. Factor analysis revealed that the authors' measures of all four categories of variables exhibited strong loadings onto their respective factors. Androgens and amicable parent-child relationships were associated with delinquency but parental social status was not. About one third of the influence of parent-child relationships on delinquency appeared to be attributable to androgens. Findings are discussed from the perspective of the evolutionary neuroandrogenic theory of delinquent and criminal behavior. PMID- 22514239 TI - British doctor fabricated results of a non-existent experiment, US body finds. PMID- 22514237 TI - Key observations from the NHLBI Asthma Clinical Research Network. AB - The National Heart, Lung and Blood Institute (NHLBI) Asthma Clinical Research Network (ACRN) recently completed its work after 20 years of collaboration as a multicentre clinical trial network. When formed, its stated mission was to perform multiple controlled clinical trials for treating patients with asthma by dispassionately examining new and existing therapies, and to rapidly communicate its findings to the medical community. The ACRN conducted 15 major clinical trials. In addition, clinical data, manual of operations, protocols and template informed consents from all ACRN trials are available via NHLBI BioLINCC (https://biolincc.nhlbi.nih.gov/studies/). This network contributed major insights into the use of inhaled corticosteroids, short-acting and long-acting beta-adrenergic agonists, leukotriene receptor antagonists, and novel agents (tiotropium, colchicine and macrolide antibiotics). They also pioneered studies of the variability in drug response, predictors of treatment response and pharmacogenetics. This review highlights the major research observations from the ACRN that have impacted the current management of asthma. PMID- 22514240 TI - Alcohol strategy is short on targets and ambitions, MPs told. PMID- 22514241 TI - Gender as risk factor for 30 days post-discharge hospital utilisation: a secondary data analysis. AB - OBJECTIVE: In the 30 days after hospital discharge, hospital utilisation is common and costly. This study evaluated the association between gender and hospital utilisation within 30 days of discharge. DESIGN: Secondary data analysis using Poisson regression stratified by gender. PARTICIPANTS: 737 English-speaking hospitalised adults from general medical service in urban, academic safety-net medical centre who participated in the Project Re-Engineered clinical trial (clinicaltrials.gov identifier: NCT00252057). MAIN OUTCOME MEASURE: The primary end point was hospital utilisation, defined as total emergency department visits and hospital readmissions within 30 days after index discharge. RESULTS: Female subjects had a rate of 29 events for every 100 people and male subjects had a rate of 47 events for every 100 people (incident rate ratio (IRR) 1.62, 95% CI 1.28 to 2.06). Among men, risk factors included hospital utilisation in the 6 months prior to the index hospitalisation (IRR 3.55, 95% CI 2.38 to 5.29), being unmarried (IRR 1.72, 95% CI 1.12 to 2.64), having a positive depression screen (IRR 1.53, 95% CI 1.09 to 2.13) and no primary care physician (PCP) visit within 30 days (IRR 1.64, 95% CI 1.08 to 2.50). Among women, the only risk factor was hospital utilisation in the 6 months prior to the index hospitalisation (IRR 3.08, 95% CI 1.86 to 5.10). CONCLUSIONS: In our data, male subjects had a higher rate of hospital utilisation within 30 days of discharge than female subjects. For men-but not for women-risk factors were being retired, unmarried, having depressive symptoms and having no PCP visit within 30 days. Interventions addressing these factors might lower hospital utilisation rates observed among men. PMID- 22514236 TI - Relationship between quantitative CT metrics and health status and BODE in chronic obstructive pulmonary disease. AB - BACKGROUND: The value of quantitative CT (QCT) to identify chronic obstructive pulmonary disease (COPD) phenotypes is increasingly appreciated. The authors hypothesised that QCT-defined emphysema and airway abnormalities relate to St George's Respiratory Questionnaire (SGRQ) and Body-Mass Index, Airflow Obstruction, Dyspnea and Exercise Capacity Index (BODE). METHODS: 1200 COPDGene subjects meeting Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD with QCT analysis were included. Total lung emphysema was measured using the density mask technique with a -950 Hounsfield unit threshold. An automated programme measured mean wall thickness (WT), wall area percentage (WA%) and 10 mm lumenal perimeter (pi10) in six segmental bronchi. Separate multivariate analyses examined the relative influence of airway measures and emphysema on SGRQ and BODE. RESULTS: In separate models predicting SGRQ score, a 1 unit SD increase in each airway measure predicted higher SGRQ scores (for WT, 1.90 points higher, p=0.002; for WA%, 1.52 points higher, p=0.02; for pi10, 2.83 points higher p<0.001). The comparable increase in SGRQ for a 1 unit SD increase in emphysema percentage in these models was relatively weaker, significant only in the pi10 model (for emphysema percentage, 1.45 points higher, p=0.01). In separate models predicting BODE, a 1 unit SD increase in each airway measure predicted higher BODE scores (for WT, 1.07-fold increase, p<0.001; for WA%, 1.20 fold increase, p<0.001; for pi10, 1.16-fold increase, p<0.001). In these models, emphysema more strongly influenced BODE (range 1.24-1.26-fold increase, p<0.001). CONCLUSION: Emphysema and airway disease both relate to clinically important parameters. The relative influence of airway disease is greater for SGRQ; the relative influence of emphysema is greater for BODE. PMID- 22514242 TI - Intervention for control of hypertension in Catalonia, Spain (INCOTECA Project): results of a multicentric, non-randomised, quasi-experimental controlled intervention study. AB - OBJECTIVE: The purpose of this study was to assess the effectiveness of a quality improvement (QI) plan aimed at primary healthcare teams (PHCTs) to optimise hypertension control and to compare it with standard clinical care. METHODS: Design Multicentric, non-randomised, quasi-experimental controlled intervention study. Setting 5 PHCTs in the intervention and 13 in the standard care group in the province of Barcelona, Catalonia, Spain. Participants This is a population based study in which all patients over 18 years of age with a diagnosis of hypertension before 1 January 2006 were included (n=9877 in the intervention group and n=21 704 in the control group). Intervention A QI plan that targeted primary care professionals. The plan included training sessions, implementation of recommended clinical practice guidelines for the management of hypertensive patients and audit and feedback to health professionals. Main outcome measure Prevalence of hypertensive patients with an adequate blood pressure (BP) control. RESULTS: The adjusted difference between intervention and standard care groups in the odds of BP control was 1.3 (95% CI 1.1 to 1.6, p=0.003). Results of the mixed model on repeated measures showed that, on average, an individual in the intervention group had an increase of 92% in the odds of BP control (OR 1.9, 95% CI 1.7 to 2.1). CONCLUSIONS: The implementation of a QI plan can improve BP control. This strategy is potentially feasible for up-scaling within the existing PHCTs. TRIAL REGISTRATION: ClinicalTrials.gov MS: 1998275938244441. PMID- 22514243 TI - The trajectory to diagnosis with pulmonary arterial hypertension: a qualitative study. AB - OBJECTIVES: To investigate the patient's experience of the trajectory to receiving a diagnosis of pulmonary arterial hypertension (PAH) and inform the provision of care for this patient group. DESIGN: Qualitative study using in depth one-to-one interviews and pictorial representations. Data were analysed using thematic analysis. SETTING: Participants were interviewed in their own homes across England. PARTICIPANTS: 30 patients with a diagnosis of pulmonary hypertension (18 participants were women, mean age 56 and range 26-80 years and time since diagnosis ranged from a few months to more than 12 years) participated. RESULTS: All participants, regardless of the time since diagnosis, vividly described the process from manifestation of symptoms to receiving a confirmed diagnosis. The authors present data using three major themes: (i) making sense of symptoms, (ii) process of elimination and (iii) being diagnosed with PAH. Making sense of symptoms represented an early period of perseverance people tried to carry-on as usual despite 'unexplained breathlessness'. As time progressed, this period was punctuated by critical events that triggered seeking medical advice. Once medical contact had been made, patients described a period of 'elimination' and convoluted contact with the medical profession. Dyspnoea misdiagnosis was a key factor that delayed the PAH diagnosis. Diagnosis disclosure by some medical professionals was also viewed as lacking empathy. More positive experiences were relayed when the medical team disclosing the diagnosis acknowledged previous limitations. CONCLUSIONS: A lack of awareness of this illness from both the sufferer themselves and the medical profession emerged as a central theme and led to prolonged periods of being misdiagnosed. The application of a diagnostic pathway for unexplained dyspnoea that alerts practitioners to rare conditions could expedite the process of correct diagnosis. PMID- 22514244 TI - Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY): kidney substudy analytic protocol of an international randomised controlled trial. AB - INTRODUCTION: CORONARY is a large international randomised controlled trial comparing coronary artery bypass graft (CABG) surgery done with and without a bypass pump. Compared with on-pump, off-pump surgery may prevent acute kidney injury (AKI) in the short term and may better preserve kidney function 1 year following surgery. Secondary analyses may also clarify whether effects are similar in patients with and without pre-operative chronic kidney disease and whether AKI avoidance mediates preserved 1-year kidney function. METHODS AND ANALYSIS: With respect to the study schedule, the last of 4752 patients from 79 sites in 19 countries were randomised in November 2011 to cardiac surgery performed with an on-pump or off-pump procedure. The authors will use regression models to compare the groups in the outcome of peri-operative AKI (per cent change in serum creatinine, >=50% increase in serum creatinine) and 1-year kidney function (per cent change in estimated glomerular filtration rate (eGFR), >=20% eGFR loss 1 year after surgery). The authors will use interaction terms in regression models to determine if there is a differential impact of the intervention in those with and without pre-existing chronic kidney disease. The authors will use regression-based tests to determine the proportion of the total effect of surgery type (off-pump vs on-pump CABG) on 1-year eGFR that is mediated by peri-operative AKI. ETHICS AND DISSEMINATION: In the year 2009, the authors were competitively awarded a grant from the Canadian Institutes of Health Research to answer these kidney questions in CORONARY. Ethics approval was obtained for additional renal data collection in centres that agreed to study participation (>90% of participating centres). This collection began for patients enrolled after 1 January 2010. Remaining 1-year renal outcome data will be collected throughout 2012. Results will be reported in 2013. CLINICAL TRIAL REGISTRATION NUMBER: NCT 00463294. PMID- 22514245 TI - The efficacy of deterrent and punitive measures. PMID- 22514246 TI - Psychiatric advance statements: an Indian experience. AB - BACKGROUND: The psychiatric advance statement (PAS) is a document that outlines the preferences of patients in their future treatment. Formulating and writing a PAS has not been studied in low- and middle-income (LAMI) countries. AIM: To study the feasibility of writing a PAS in an Indian population. METHODS: Patients' diagnosed with schizophrenia or schizoaffective psychosis attending the outpatient clinic at the Schizophrenia Research Foundation (SCARF) or its community centres in 2011 were screened using the study criteria. After obtaining informed consent, stratified sampling was used to derive the final sample. RESULTS: Most patients consented to participate in the study (122/123 patients). Following interviews with research assistants, 93 patients were assessed to have the capacity to write a PAS and 92 completed one. The patients were mostly able to complete the PAS on their own. Major themes included choice of treatment facility, type of treatment and nomination of others to take decisions on their behalf. A third of the sample were either from rural areas or not exclusively urban. At the time of the study, about 45% of the sample was rated as being symptomatic. CONCLUSION: Psychotic patients with a long-term illness, a third of them from non-urban areas, were able to write a valid PAS. PMID- 22514247 TI - Do the spatial characteristics of myocardial scar tissue determine the risk of ventricular arrhythmias? AB - Sudden cardiac death is one of the main causes of mortality in patients with structural heart disease. Although an implantable cardioverter defibrillator significantly reduces the mortality rate, many patients never receive a shock. Identification of high-risk patients would reduce the costs associated with this therapy and prevent the deleterious effect of inappropriate discharges. As scar tissue is the substrate of ventricular arrhythmias in patients with structural heart disease, scar characterization could allow stratification of the risk. The objective of this article is to review the role of scar characteristics in the pathogenesis of ventricular arrhythmias in patients with structural heart disease. PMID- 22514248 TI - Pharmacological approaches to reperfusion therapy. AB - Despite the fact that numerous clinical trials investigating infarct size have been completed over the last two to three decades, the methods for treating lethal reperfusion injury efficiently have only become established very recently. After several years of accumulating evidence in experimental preparations that lethal reperfusion injury might exist, the description of the phenomenon of ischaemic post-conditioning in animal models has fully convinced us of the existence and importance of irreversible myocardial damage occurring after reflow. Transfer to the clinics was possible in small phase II trials, provided care was taken to assess the determinants of infarct size and, most importantly, to consider the timing of drug administration with respect to the time of reflow. Technical questions remain to be resolved regarding the assessment of the area at risk in the difficult setting of emergency care for reperfusion therapy. Nevertheless, convincing pharmacological trials are being performed that mark the start of a new era that will, in the future, improve the prognosis of patients with ST-segment elevation myocardial infarction through the prevention of lethal myocardial reperfusion injury. At present, while erythropoietin and adenosine have not proved efficient for alleviation of lethal reperfusion injury, a significant benefit has been reported for cyclosporin and exenatide. New pharmacological agents need to be identified and tested in phase II trials. In the meantime, clinical outcome studies are currently being conducted for cyclosporin. PMID- 22514249 TI - Contribution of screening and survival differences to racial disparities in colorectal cancer rates. AB - BACKGROUND: Considerable disparities exist in colorectal cancer (CRC) incidence and mortality rates between blacks and whites in the United States. We estimated how much of these disparities could be explained by differences in CRC screening and stage-specific relative CRC survival. METHODS: We used the MISCAN-Colon microsimulation model to estimate CRC incidence and mortality rates in blacks, aged 50 years and older, from 1975 to 2007 assuming they had: (i) the same trends in screening rates as whites instead of observed screening rates (incidence and mortality); (ii) the same trends in stage-specific relative CRC survival rates as whites instead of observed (mortality only); and (iii) a combination of both. The racial disparities in CRC incidence and mortality rates attributable to differences in screening and/or stage-specific relative CRC survival were then calculated by comparing rates from these scenarios to the observed black rates. RESULTS: Differences in screening accounted for 42% of disparity in CRC incidence and 19% of disparity in CRC mortality between blacks and whites. Thirty-six percent of the disparity in CRC mortality could be attributed to differences in stage-specific relative CRC survival. Together screening and survival explained a little more than 50% of the disparity in CRC mortality between blacks and whites. CONCLUSION: Differences in screening and relative CRC survival are responsible for a considerable proportion of the observed disparities in CRC incidence and mortality rates between blacks and whites. IMPACT: Enabling blacks to achieve equal access to care as whites could substantially reduce the racial disparities in CRC burden. PMID- 22514250 TI - Dynamic interactions between large-scale brain networks predict behavioral adaptation after perceptual errors. AB - Failures to perceive visual stimuli lead to errors in decision making. Different theoretical accounts implicate either medial frontal (MF) cognitive control processes or prestimulus occipital (OC) cortical oscillatory dynamics in errors during perceptual tasks. Here, we show that these 2 previously unconnected theoretical accounts can be reconciled, and the brain regions described by the 2 theories have complimentary and interactive roles in supporting error adaptation. Using a perceptual discrimination task and time-frequency network-based analyses of electroencephalography data, we show that perceptual anticipation and posterror top-down control mechanisms recruit distinct but interacting brain networks. MF sites were a hub for theta-band networks and theta-alpha coupling elicited after errors, whereas occipital sites were a network hub during stimulus anticipation and alpha-gamma coupling. Granger causality analyses revealed that these networks communicate in their preferred direction and frequency band: response-related MF -> OC interactions occurred in the theta band, whereas stimulus anticipation-related OC -> MF interactions occurred in the alpha band. Subjects with stronger network interactions were more likely to improve performance after errors. These findings demonstrate that multiple large-scale brain networks interact dynamically and in a directionally specific manner in different frequency bands to support flexible behavior adaptation during perceptual decision making. PMID- 22514251 TI - Periodontal disease and atherosclerotic vascular disease: does the evidence support an independent association?: a scientific statement from the American Heart Association. AB - A link between oral health and cardiovascular disease has been proposed for more than a century. Recently, concern about possible links between periodontal disease (PD) and atherosclerotic vascular disease (ASVD) has intensified and is driving an active field of investigation into possible association and causality. The 2 disorders share several common risk factors, including cigarette smoking, age, and diabetes mellitus. Patients and providers are increasingly presented with claims that PD treatment strategies offer ASVD protection; these claims are often endorsed by professional and industrial stakeholders. The focus of this review is to assess whether available data support an independent association between ASVD and PD and whether PD treatment might modify ASVD risks or outcomes. It also presents mechanistic details of both PD and ASVD relevant to this topic. The correlation of PD with ASVD outcomes and surrogate markers is discussed, as well as the correlation of response to PD therapy with ASVD event rates. Methodological issues that complicate studies of this association are outlined, with an emphasis on the terms and metrics that would be applicable in future studies. Observational studies to date support an association between PD and ASVD independent of known confounders. They do not, however, support a causative relationship. Although periodontal interventions result in a reduction in systemic inflammation and endothelial dysfunction in short-term studies, there is no evidence that they prevent ASVD or modify its outcomes. PMID- 22514252 TI - Net clinical benefit of warfarin in patients with atrial fibrillation: a report from the Swedish atrial fibrillation cohort study. AB - BACKGROUND: Known risk factors for bleeding during anticoagulant treatment are largely the same as those predicting thromboembolic events in patients with atrial fibrillation (AF). Our objective was to investigate how to maximize the likelihood of avoiding both stroke and bleeding. METHODS AND RESULTS: All 182 678 subjects with atrial fibrillation in the Swedish Hospital Discharge Register were studied for an average of 1.5 years (260 000 patient-years at risk). Patients were stratified according to risk scores with the use of historic International Classification of Disease diagnostic codes in the register. Information about medication was obtained from the Swedish Drug Registry. Our primary end point was net benefit defined as number of avoided ischemic strokes with anticoagulation minus the number of excess intracranial bleedings with a weight of 1.5 to compensate for the generally more severe outcome with intracranial bleedings. The adjusted net clinical benefit favored anticoagulation for almost all atrial fibrillation patients. The exceptions were patients at very low risk of ischemic stroke with a CHA(2)DS(2)-VASc score of 0 and moderately elevated bleeding risk ( 1.7%/y). The results were broadly similar with CHADS(2), except for patients with very low embolic risk; the CHA(2)DS(2)-VASc was able to identify those patients (n=6205, 3.9% of all patients) who had no net clinical benefit or even some disadvantage from anticoagulant treatment. CONCLUSIONS: In almost all patients with atrial fibrillation, the risk of ischemic stroke without anticoagulant treatment is higher than the risk of intracranial bleeding with anticoagulant treatment. Analysis of the net benefit indicates that more patients may benefit from anticoagulant treatment. PMID- 22514253 TI - Net clinical benefit of warfarin: extending the reach of antithrombotic therapy for atrial fibrillation. PMID- 22514254 TI - Late gadolinium enhancement as a potential marker of increased perioperative risk in aortic valve replacement. AB - OBJECTIVES Risk assessment of patients with aortic stenosis (AS) undergoing aortic valve replacement (AVR) is challenging. We set out to determine the impact of myocardial late gadolinium enhancement (LGE), as detected by cardiovascular magnetic resonance (CMR), on postoperative outcomes following AVR. METHODS A prospective observational study was conducted on patients undergoing CMR using the LGE technique within 1 year of subsequent AVR. Patients were categorized into absent, mid-wall or infarct patterns of LGE by independent observers blinded to all clinical data, and data were collected with regard to 30-day mortality, major adverse cardiac and cerebrovascular events (MACCE) and postoperative complications. RESULTS A total of 63 patients were studied. Twenty-five patients had no LGE; 20 had mid-wall LGE and 18 had an infarct pattern. The incidence of MACCE, cerebrovascular accident (CVA) and heart block were significantly higher in the mid-wall group compared with the other two groups (MACCE: 25 vs. 0 vs. 5%, P = 0.014; CVA: 20 vs. 0 vs. 0%, P = 0.013; heart block: 30 vs. 4 vs. 12%, P = 0.050). Patients with no LGE had no 30-day MACCE events and no deaths up to 2 years of follow-up. CONCLUSIONS The myocardial LGE holds promise as a means of predicting risk prior to AVR for AS. PMID- 22514255 TI - The tumour shape of lung adenocarcinoma is related to the postoperative prognosis. AB - We evaluated the tumour shape as a potential prognostic indicator in lung adenocarcinoma patients. Among 994 patients who underwent curative surgery, 78 cases of adenocarcinoma (N0M0) with tumours >= 31 mm in diameter were reviewed. The patients were divided into two groups based on the ratio between the longest and the smallest axis length. The patients who had tumours whose ratios were > 0.5 were defined as the globular shape group (GL) and the others, whose ratio was 0.5 or less, were defined as the ellipse shape group (EL). The 78 patients were divided into two subgroups (57 in the GL and 21 in the EL). The tumour shape was related to the prognosis, and the 5-year overall survival (OS) rate in the GL was 51.5%, and that in the EL was 85.5% (P = 0.018). The 5-year disease-free survival rate of the GL was 46.6% and that of the EL patients was 85.0% (P = 0.04). The multivariate analysis showed that the shape of the tumour and the presence of pleural invasion were the independent and significant factors predicting the OS (P = 0.04 and P < 0.01, respectively). In adenocarcinoma patients, the shape of the tumour is related to the postoperative survival. PMID- 22514256 TI - Comparative study of talc poudrage versus pleural abrasion for the treatment of primary spontaneous pneumothorax. AB - Primary spontaneous pneumothorax is a pathology mainly affecting healthy young patients. Clinical guidelines do not specify the type of pleurodesis that should be conducted, due to the lack of comparative studies on the different techniques. The aim of this study was to compare talc poudrage and pleural abrasion in the treatment of spontaneous pneumothorax. A retrospective comparative study was performed, including 787 patients with primary spontaneous pneumothorax. The 787 patients were classified into two groups: Group A (pleural abrasion) n = 399 and Group B (talc pleurodesis) n = 388. The variables studied were recurrence, surgical time, morbidity and in-hospital length of stay. Statistical analysis was done by an unpaired t-test and Fisher's exact test (SSPS 18.0). Statistically significant differences were observed in the variables: surgical time (A: 46 +/- 12.3; B: 37 +/- 11.8 min; P < 0.001); length of stay (A: 4.7 +/- 2.5; B: 4.3 +/- 1.8 days; P = 0.01); apical air camera (A: 25; B: 4; P < 0.001); pleural effusion (A: 6; B: 0; P = 0.05). Talc poudrage shows shorter surgical times and length of stay, and lower re-intervention rates. Morbidity is lower in patients with talc poudrage. Statistically significant differences were not observed in recurrence, persistent air leaks, atelectasis and haemothorax. PMID- 22514257 TI - Comparative evaluation of the effects of tranexamic acid and low-dose aprotinin on post-valvular heart surgery bleeding and allogenic transfusion. AB - Bleeding diathesis and allogenic transfusion after complex heart surgery, such as heart valve surgery, may result in complications such as transfusion reaction, viral infection, postoperative infection, haemodynamic disturbance, prolonged stay in the intensive care unit and hospital, renal and respiratory failure and mortality. In this prospective, double-blind, randomized, placebo-controlled clinical trial, 90 patients were randomly divided into three groups: aprotinin, tranexamic acid and control. Chest-tube drainage, transfusion requirements and renal and neurological complications were evaluated. We found that chest-tube drainage during the first (P < 0.0001) and second 24 h (P = 0.001) after admission to the intensive care unit were significantly lower in the aprotinin group. The amounts of transfused packed red blood cells (P < 0.0001) and platelets (P = 0.02) were significantly lower in the aprotinin and tranexamic acid groups. The quantity of transfused fresh frozen plasma (P = 0.034) was significantly lower in the aprotinin group only. We did not find any neurological complications or renal failure in the three groups. Our data suggest that in valvular heart surgery, low-dose aprotinin is significantly better than tranexamic acid or a placebo for reduction of postoperative bleeding and allogenic transfusion, without increasing adverse outcomes. PMID- 22514258 TI - Ablation for atrial fibrillation during mitral valve surgery: 1-year results through continuous subcutaneous monitoring. AB - Continuous monitoring of cardiac rhythm may play an important role in measuring the true symptomatic/asymptomatic atrial fibrillation (AF) burden and improve the management of anti-arrhythmic and anti-thrombotic therapies. Forty-seven patients with mitral valve disease and longstanding persistent AF (LSPAF) underwent a left atrial maze procedure with bipolar radiofrequency and valve surgery. The follow up data recorded by an implanted loop recorder were analysed after 3, 6 and 12 months. On discharge, 40 (85.1%) patients were in stable sinus rhythm, as documented by in-office electrocardiography (ECG), 4 (8.5%) were in pacemaker rhythm and 3 (6.4%) were in AF. One (2.1%) patient died after 7 months. On 12 month follow-up examination, 30 (65.2%) patients had an AF burden <0.5% and were classified as responders. Three (6.5%) of the 16 non-responders had atrial flutter and 13 (27.7%) had documented AF recurrences with an AF burden >0.5%. Two (4.3%) patients with AF recurrences were completely asymptomatic. Among the symptomatic events stored by the patients, only 27.6% was confirmed as genuine AF recurrences according to the concomitant ECG recorded by the implanted loop recorder. A concomitant bipolar maze procedure during mitral valve surgery is effective in treating AF, as proved by detailed 1-year continuous monitoring. PMID- 22514259 TI - Primary parosteal osteosarcoma of the rib. AB - Osteosarcoma is a common primary malignant tumour of bones that produces an osteoid matrix. Parosteal osteosarcoma is an uncommon neoplasm and principally affects the long bones, especially in the distal femur, proximal tibia and proximal humerus. Rarely, the tumour may arise in a flat bone, and rib involvement is very infrequent. An unusual case of primary parosteal osteosarcoma of the rib in an asymptomatic 28-year old female is presented here. A chest X-ray film suggested an intrapulmonary homogeneous mass, while a computed tomography scan revealed a broad-based calcified mass attached to the inner cortex of the right fourth anterior rib. The patient underwent a wide excision of the tumour together with adjacent intercostal muscles and chest wall reconstruction. Postoperative histopathological outcome was consistent with primary parosteal osteosarcoma. PMID- 22514260 TI - Prevalence of and risk factors associated with faecal carriage of CTX-M beta lactamase-producing Enterobacteriaceae in rural Thai communities. AB - OBJECTIVES: To determine the prevalence of CTX-M beta-lactamase-producing Enterobacteriaceae and to study the risk factors associated with faecal carriage in asymptomatic rural Thai people. METHODS: In all, 417 stool samples were obtained from rural Thai people and screened for extended-spectrum beta lactamases (ESBLs) using MacConkey agar supplemented with 2 mg/L cefotaxime. Results were confirmed using cefotaxime and ceftazidime with and without clavulanic acid. The bla(CTX-M) genes were identified and genotyped using PCR with bacterial DNA samples. Multivariate analysis was performed to investigate risk factors associated with the faecal carriage of CTX-M producers. RESULTS: The prevalence of CTX-M-type ESBL-producing Enterobacteriaceae was 65.7%. The CTX-M-9 group (60.6%) was dominant, followed by the CTX-M-1 group (38.7%). Most of the bacteria were Escherichia coli (85.4%) and Klebsiella pneumoniae (4.7%). Of a total of 234 E. coli strains, 48.7% belonged to phylogenetic group A, 28.6% to group B1, 15.8% to group D and 6.8% to group B2. Most CTX-M producers were susceptible to carbapenems and amikacin, but resistant to tetracycline and gentamicin. In a multivariate logistic regression model, better education status (OR 2.245; 95% CI 1.297-3.884), history of hospitalization (OR 1.643; 95% CI 1.036-2.603) and the use of antibiotics within the last 3 months (OR 1.883; 95% CI 1.221-2.903) were independently associated with faecal carriage. CONCLUSIONS: Faecal carriage of CTX-M-type ESBL-producing Enterobacteriaceae among asymptomatic individuals in rural Thailand remains alarmingly high, and previous antibiotic use and a history of hospitalization may contribute to its dissemination. PMID- 22514261 TI - Standardizing an in vitro procedure for the evaluation of the antimicrobial activity of wound dressings and the assessment of three wound dressings. AB - OBJECTIVES: A wide selection of wound dressings is available on the market with varying claims of antimicrobial efficacy. A valid standard method for evaluation of their antimicrobial activity in vitro has not been established. In this study we suggest a standardized time-kill assay procedure for antimicrobial activity evaluation of wound dressings in order to make studies more comparable and reproducible. We also tested two silver-containing dressings and one propolis containing dressing against Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli and Pseudomonas aeruginosa using our proposed procedure. METHODS: The following dressings were tested: the ionic silver-containing dressing (ISCD), nanocrystalline silver coated dressing (NSCD) and a propolis containing dressing (PCD) that is in development. A time-kill assay and the zone of inhibition test were used in the study. RESULTS: NSCD exhibited the most potent antibacterial activity against all organisms. ISDC also demonstrated good antibacterial activity although inferior to NSCD. PCD did not show any bactericidal effect. CONCLUSIONS: Based on our findings we suggest that a time kill assay with a 1 cm(2) dressing is used for evaluation of the antimicrobial activity of wound dressings, and that the dressings should be exposed to a standardized inoculum of 1-1.5 * 10(6) cfu/mL with Mueller-Hinton broth as the most appropriate medium. PCD requires further research to establish its clinical value. PMID- 22514262 TI - In vitro activity of phenylmercuric acetate against ocular pathogenic fungi. AB - OBJECTIVES: To determine the antifungal activity of phenylmercuric acetate against ocular pathogenic fungi in vitro and develop new antifungal eye drops to combat keratomycosis. METHODS: The in vitro activity of phenylmercuric acetate was assessed against 261 isolates of ocular pathogenic fungi that included 136 Fusarium spp. isolates, 98 Aspergillus spp. isolates, 10 Alternaria alternata isolates and 17 other pathogens. The activity of phenylmercuric acetate was compared with the activities of amphotericin B and natamycin. In vitro susceptibility testing was performed by broth microdilution assay, in accordance with the CLSI (formerly NCCLS) M38-A guidelines for filamentous fungi. RESULTS: MIC90s of phenylmercuric acetate were 0.0156, 0.0156, 0.0156 and 0.0156 mg/L for Fusarium spp., Aspergillus spp., A. alternata and other pathogens, respectively. MIC90s of amphotericin B were 2, 2, 1 and 1 mg/L for Fusarium spp., Aspergillus spp., A. alternata and other pathogens, respectively. MIC90s of natamycin were 8, 32, 4 and 4 mg/L for Fusarium spp., Aspergillus spp., A. alternata and other pathogens, respectively. CONCLUSIONS: Phenylmercuric acetate has promising antifungal activity, which is significantly superior to the activities of amphotericin B and natamycin against a wide variety of ocular pathogenic fungi based on comparative MIC values. Additional evaluation is required to determine its clinical utility. PMID- 22514263 TI - Transfer of quinolone resistance gene qnrA1 to Escherichia coli through a 50 kb conjugative plasmid resulting from the splitting of a 300 kb plasmid. AB - OBJECTIVES: To analyse the in vitro transfer of the qnrA1 gene by a 50 kb (pSZ50) self-transferable plasmid that derives from a 300 kb plasmid (pSZ300) and to determine the complete nucleotide sequence of plasmid pSZ50. METHODS: Extended spectrum beta-lactamase (ESBL) and plasmid-mediated quinolone resistance (PMQR) genes of an Escherichia coli clinical isolate were analysed. Plasmid analysis included conjugation and selection on seven antibiotics examined by antimicrobial susceptibility testing, RFLP comparison, Southern hybridization, incompatibility group identification and shotgun sequencing. RESULTS: The E. coli 5509 isolate carries the genes encoding the ESBL CTX-M-15 and the quinolone resistance determinants qnrA1, qnrB2 and aac(6')-Ib-cr on a 300 kb plasmid. Seven transfer resistances were analysed by conjugation under two conditions (30 and 37 degrees C), leading to two distinct transconjugant phenotypes with different resistances. Transconjugants of phenotype A harboured a 300 kb plasmid named pSZ300 that conferred resistance to eight antibiotics and harboured the qnrA1, aac(6')-Ib-cr and bla(CTX-M-15) genes. Transconjugants of phenotype B were resistant to three antibiotics and they harboured the qnrA1 gene on an ~ 50 kb plasmid named pSZ50. Both plasmids were self-transferable at a frequency of 1 * 10(-3). Plasmid pSZ300 was typed to be both an IncF and IncN plasmid, whereas pSZ50 corresponded only to type IncN. Fingerprinting and Southern hybridization showed that plasmid pSZ50 derived from pSZ300. The complete nucleotide sequence of plasmid pSZ50 was determined (51556 bp) and 55 open reading frames were predicted. The qnrA1 gene was identified in a tandem duplicate inside a sul1-type integron structure. CONCLUSIONS: The plasmid pSZ300 represented a fusion of two replicons (IncF and IncN), and our observations suggest that the plasmid pSZ50 (IncN) may split and transfer antibiotic resistance determinants. This mechanism could be advantageous in the dissemination of antibiotic resistance genes. PMID- 22514264 TI - Clinical predictors of community-genotype ST72-methicillin-resistant Staphylococcus aureus-SCCmec type IV in patients with community-onset S. aureus infection. AB - OBJECTIVES: Community-genotype methicillin-resistant Staphylococcus aureus (MRSA) clones have emerged in the community worldwide and recently have been spreading into the hospitals. To identify predictors of sequence type 72-MRSA-SCCmec type IV (ST72-MRSA-IV) in patients with community-onset (CO) S. aureus infection, a case-control study was conducted among CO S. aureus infections, including healthcare-associated infections. METHODS: Eighty-four patients with CO infections caused by ST72-MRSA-IV strains in Korea between 2007 and 2009 were selected as cases. Members of the control group were those with CO methicillin susceptible S. aureus infections and they were matched by the admission date in a 1 : 1 ratio. RESULTS: The most common type of infection was skin and soft tissue infection in both groups (48.8% versus 52.4%), followed by pneumonia. Female sex (OR 2.55, 95% CI 1.30-5.04), severe sepsis or septic shock (OR 3.05, 95% CI 1.09 8.55), prior hospitalization within the previous year (OR 2.18, 95% CI 1.10-4.32) and surgical site infection (SSI) (OR 4.63, 95% CI 1.38-15.59) were associated with ST72-MRSA-IV infections in multivariate analyses. CONCLUSIONS: Female sex, SSI, severe sepsis or septic shock and prior hospitalization within the previous year were predictors of ST72-MRSA-IV among patients with CO S. aureus infection. PMID- 22514265 TI - Detection and characterization of pCT-like plasmid vectors for blaCTX-M-14 in Escherichia coli isolates from humans, turkeys and cattle in England and Wales. AB - OBJECTIVES: To detect and characterize Escherichia coli strains and pCT-like plasmids implicated in the dissemination of the CTX-M-14 gene in animals and humans, in England and Wales. METHODS: UK CTX-M-14-producing E. coli (n=70) from cattle (n=33), turkeys (n=9), sheep (n=2) and humans (n=26) were screened using multiplex PCR for the detection of a previously characterized plasmid, pCT. Isolates found to be carrying two or more pCT genetic markers were further analysed using PFGE. Their antimicrobial-resistance genes and virulence genes were also determined. These plasmids were transferred to Salmonella enterica serotype Typhimurium 26R and further examined for incompatibility type, genetic environment of the bla(CTX-M-14) gene, size, restriction fragment length polymorphism (RFLP) and nikB sequence. RESULTS: The 25 E. coli isolates carrying pCT genetic markers generated 19 different PFGE profiles, and 23 isolates had different virulence and antimicrobial-resistance gene patterns. One isolate from cattle was a verotoxigenic E. coli ('VTEC'); the rest were commensal or extra intestinal pathogenic E. coli. pCT-like plasmids with similar molecular characteristics (size, replicon type, RFLP pattern, pCT markers and genetic environment of the bla(CTX-M-14) gene) were detected in 21/25 of the field isolates, which comprised those from cattle (n=9), turkeys (n=8) and humans (n=4). All pCT-like plasmids were conjugative, and most were IncK (n=21) and had the same local genetic environment flanking the bla(CTX-M-14) gene (n=23). RFLP analysis demonstrated >= 75% similarity among most plasmids (n=22). CONCLUSIONS: pCT-like plasmids were common vectors for horizontal dissemination of 30% of the bla(CTX-M-14) genes to different E. coli isolates from humans, cattle and turkeys. PMID- 22514268 TI - It is better to be in a clinical trial than not: lessons learnt from clinical neurology--the management of acute multiple sclerosis relapses. AB - OBJECTIVE: To compare being on-, or off-, a randomized controlled trial (RCT) for the same intervention. DESIGN: Cohort study. SETTING: Ambulatory outpatient clinic in a clinical neurosciences centre. SUBJECTS: Patients experiencing a clinically significant multiple sclerosis (MS) relapse, who received a 3-day regimen of intravenous methylprednisolone as an ambulatory outpatient, were compared with a similar group of patients who had previously been treated exactly in the same way while participating in a RCT. MAIN OUTCOME MEASURES: The Multiple Sclerosis Relapse Management Scale (MSRMS) was used to measure patients' experiences of relapse management in both groups. The two groups were compared under four main headings: interpersonal care, access to care, information and coordination of care. RESULTS: The principal finding was that interpersonal care was significantly worse in the off-trial group (P = 0.0001), implying a beneficial trial effect on patient experience. CONCLUSION: The effect observed is likely secondary to trial participation; both groups had similar baseline features, and were treated in the same way. Likely mechanisms for the differences are protocol, care and Hawthorne effects. The findings support the incorporation of structured RCT-style practice into routine clinical management, in order to deliver a more patient-centred care in the treatment of MS relapses. This may have implications for other chronic neurological diseases. PMID- 22514266 TI - Reconstitution of high-level micafungin resistance detected in a clinical isolate of Candida glabrata identifies functional homozygosity in glucan synthase gene expression. AB - OBJECTIVES: A mechanism for the acquisition of high-level echinocandin resistance in Candida glabrata was investigated. FKS mutants were constructed to: determine whether clinically significant micafungin resistance requires a hot-spot mutation in FKS1 and a premature stop codon in FKS2, as was observed in a clinical isolate; select for variants with reduced susceptibility and locate mutations in FKS genes; and assess the roles of FKS1 and FKS2. METHODS: A panel of FKS mutants was constructed using micafungin-susceptible parents by site-directed mutagenesis. Drug susceptibility, gene expression and glucan synthase activities were compared between mutants. Mutations acquired by selection were identified by DNA sequence analysis of FKS genes from selected variants. Single FKS deletants were constructed and their phenotypes examined. RESULTS: Introduction of the hot spot mutation in FKS1 alone conferred an intermediate reduction in susceptibility, and the premature stop codon in FKS2 alone had no effect on susceptibility, while severely reduced susceptibility equivalent to that of the clinical isolate required both mutations. Exposure of susceptible strains to micafungin yielded variants with an intermediate reduction in susceptibility that possessed a hot-spot mutation in FKS1. Further exposure to micafungin yielded variants with severely reduced susceptibility that acquired various single mutations in FKS2. The phenotypes of Deltafks1 and Deltafks2 mutants indicate that the two FKS genes are functionally redundant, while deletion of both FKS1 and FKS2 conferred synthetic lethality. CONCLUSIONS: In the laboratory mutants of C. glabrata, clinically significant reduced susceptibility to micafungin required single nucleotide changes in both FKS1 and FKS2, and both genes encoded beta-1,3 glucan synthase catalytic subunits. PMID- 22514269 TI - Neonatal hormone changes and growth in lambs born to dams receiving differing nutritional intakes and selenium supplementation during gestation. AB - To investigate the effects of maternal selenium (Se) supplementation and nutritional intake during gestation on hormone changes, percentage body weight (BW) change, and organ mass in neonatal lambs, ewes were allocated to differing Se levels (adequate Se (ASe, 11.5 MUg/kg BW) or high Se (HSe, 77.0 MUg/kg BW)) initiated at breeding and nutritional intake (60% (RES), 100% (CON), or 140% (HIGH) of NRC requirements) initiated at day 40 of gestation. At parturition, all lambs were removed from dams, fed common diets, and BW and blood samples were collected until day 19. There was a Se * nutritional intake * day interaction for percentage BW change from birth. Lambs born to ASe-HIGH ewes tended to have decreased BW change compared with ASe-CON and ASe-RES groups on day 7. Lambs from HSe-HIGH ewes tended to have increased BW change compared with HSe-RES and HSe CON groups from days 7 to 19. At birth, there was a Se * sex of offspring interaction, in which male lambs from HSe ewes had decreased cortisol concentrations compared with all other lambs. By 24 h, lambs from RES ewes had decreased cortisol compared with those from HIGH ewes, with lambs from CON ewes being intermediate. Lambs from RES- and CON-fed ewes had greater thyroxine than HIGH ewes at 24 h. Organ masses on day 19 were mainly impacted by maternal nutritional intake and sex of the offspring. Birth weight alone did not predict growth performance during neonatal life. Moreover, despite a similar postnatal diet, maternal nutritional plane and Se status did impact neonatal endocrine profiles. Exact mechanisms of how neonatal endocrine status can influence later growth and development need to be determined. PMID- 22514270 TI - Characterization of conformational changes and protein-protein interactions of rod photoreceptor phosphodiesterase (PDE6). AB - As the central effector of visual transduction, the regulation of photoreceptor phosphodiesterase (PDE6) is controlled by both allosteric mechanisms and extrinsic binding partners. However, the conformational changes and interactions of PDE6 with known interacting proteins are poorly understood. Using a fluorescence detection system for the analytical ultracentrifuge, we examined allosteric changes in PDE6 structure and protein-protein interactions with its inhibitory gamma-subunit, the prenyl-binding protein (PrBP/delta), and activated transducin. In solution, the PDE6 catalytic dimer (Palphabeta) exhibits a more asymmetric shape (axial ratio of 6.6) than reported previously. The inhibitory Pgamma subunit behaves as an intrinsically disordered protein in solution but binds with high affinity to the catalytic dimer to reconstitute the holoenzyme without a detectable change in shape. Whereas the closely related PDE5 homodimer undergoes a significant change in its sedimentation properties upon cGMP binding to its regulatory cGMP binding site, no such change was detected upon ligand binding to the PDE6 catalytic dimer. However, when Palphabeta was reconstituted with Pgamma truncation mutants lacking the C-terminal inhibitory region, cGMP dependent allosteric changes were observed. PrBP/delta bound to the PDE6 holoenzyme with high affinity (K(D) = 6.2 nm) and induced elongation of the protein complex. Binding of activated transducin to PDE6 holoenzyme resulted in a concentration-dependent increase in the sedimentation coefficient, reflecting a dynamic equilibrium between transducin and PDE6. We conclude that allosteric regulation of PDE6 is more complex than for PDE5 and is dependent on interactions of regions of Pgamma with the catalytic dimer. PMID- 22514271 TI - Cyclic AMP signaling inhibits megakaryocytic differentiation by targeting transcription factor 3 (E2A) cyclin-dependent kinase inhibitor 1A (CDKN1A) transcriptional axis. AB - Signaling via the intracellular second messenger cyclic AMP (cAMP) has long been implicated in the repression of megakaryocytic differentiation. However, the mechanisms by which cAMP signaling impairs megakaryopoiesis have never been elucidated. In a human CD34(+) cell culture model, we show that the adenylyl cyclase agonist forskolin inhibits megakaryocytic differentiation in a protein kinase A-dependent manner. Using this system to screen for downstream effectors, we identified the transcription factor E2A as a key target in a novel repressive signaling pathway. Specifically, forskolin acting through protein kinase A induced E2A down-regulation and enforced expression of E2A overrode the inhibitory effects of forskolin on megakaryopoiesis. The dependence of megakaryopoiesis on critical thresholds of E2A expression was confirmed in vivo in haploinsufficient mice and ex vivo using shRNA knockdown in human progenitors. Using a variety of approaches, we further identified p21 (encoded by CDKN1A) as a functionally important megakaryopoietic regulator residing downstream of E2A. These results thus implicate the E2A-CDKN1A transcriptional axis in the control of megakaryopoiesis and reveal the lineage-selective inhibition of this axis as a likely mechanistic basis for the inhibitory effects of cAMP signaling. PMID- 22514272 TI - Cooperation of nuclear fibroblast growth factor receptor 1 and Nurr1 offers new interactive mechanism in postmitotic development of mesencephalic dopaminergic neurons. AB - Experiments in mice deficient for Nurr1 or expressing the dominant-negative FGF receptor (FGFR) identified orphan nuclear receptor Nurr1 and FGFR1 as essential factors in development of mesencephalic dopaminergic (mDA) neurons. FGFR1 affects brain cell development by two distinct mechanisms. Activation of cell surface FGFR1 by secreted FGFs stimulates proliferation of neural progenitor cells, whereas direct integrative nuclear FGFR1 signaling (INFS) is associated with an exit from the cell cycle and neuronal differentiation. Both Nurr1 and INFS activate expression of neuronal genes, such as tyrosine hydroxylase (TH), which is the rate-limiting enzyme in dopamine synthesis. Here, we show that nuclear FGFR1 and Nurr1 are expressed in the nuclei of developing TH-positive cells in the embryonic ventral midbrain. Both nuclear receptors were effectively co immunoprecipitated from the ventral midbrain of FGF-2-deficient embryonic mice, which previously showed an increase of mDA neurons and enhanced nuclear FGFR1 accumulation. Immunoprecipitation and co-localization experiments showed the presence of Nurr1 and FGFR1 in common nuclear protein complexes. Fluorescence recovery after photobleaching and chromatin immunoprecipitation experiments demonstrated the Nurr1-mediated shift of nuclear FGFR1-EGFP mobility toward a transcriptionally active population and that both Nurr1 and FGFR1 bind to a common region in the TH gene promoter. Furthermore, nuclear FGFR1 or its 23-kDa FGF-2 ligand (FGF-2(23)) enhances Nurr1-dependent activation of the TH gene promoter. Transcriptional cooperation of FGFR1 with Nurr1 was confirmed on isolated Nurr1-binding elements. The proposed INFS/Nurr1 nuclear partnership provides a novel mechanism for TH gene regulation in mDA neurons and a potential therapeutic target in neurodevelopmental and neurodegenerative disorders. PMID- 22514273 TI - CTRP9 protein protects against myocardial injury following ischemia-reperfusion through AMP-activated protein kinase (AMPK)-dependent mechanism. AB - Ischemic heart disease is the major cause of death in Western countries. CTRP9 (C1q/TNF-related protein 9) is a fat-derived plasma protein that has salutary effects on glucose metabolism and vascular function. However, the functional role of CTRP9 in ischemic heart disease has not been clarified. Here, we examined the regulation of CTRP9 in response to acute cardiac injury and investigated whether CTRP9 modulates cardiac damage after ischemia and reperfusion. Myocardial ischemia-reperfusion injury resulted in reduced plasma CTRP9 levels and increased plasma free fatty acid levels, which were accompanied by a decrease in CTRP9 expression and an increase in NADPH oxidase component expression in fat tissue. Treatment of cultured adipocytes with palmitic acid or hydrogen peroxide reduced CTRP9 expression. Systemic administration of CTRP9 to wild-type mice, before the induction of ischemia or at the time of reperfusion, led to a reduction in myocardial infarct size following ischemia-reperfusion. Administration of CTRP9 also attenuated myocyte apoptosis in ischemic heart, which was accompanied by increased phosphorylation of AMP-activated protein kinase (AMPK). Treatment of cardiac myocytes with CTRP9 protein reduced apoptosis in response to hypoxia/reoxygenation and stimulated AMPK phosphorylation. Blockade of AMPK activity reversed the suppressive actions of CTRP9 on cardiomyocyte apoptosis. Knockdown of adiponectin receptor 1 diminished CTRP9-induced increases in AMPK phosphorylation and survival of cardiac myocytes. Our data suggest that CTRP9 protects against acute cardiac injury following ischemia-reperfusion via an AMPK dependent mechanism. PMID- 22514274 TI - Conformational selection and folding-upon-binding of intrinsically disordered protein CP12 regulate photosynthetic enzymes assembly. AB - Carbon assimilation in plants is regulated by the reduction of specific protein disulfides by light and their re-oxidation in the dark. The redox switch CP12 is an intrinsically disordered protein that can form two disulfide bridges. In the dark oxidized CP12 forms an inactive supramolecular complex with glyceraldehyde-3 phosphate dehydrogenase (GAPDH) and phosphoribulokinase, two enzymes of the carbon assimilation cycle. Here we show that binding of CP12 to GAPDH, the first step of ternary complex formation, follows an integrated mechanism that combines conformational selection with induced folding steps. Initially, a CP12 conformation characterized by a circular structural motif including the C terminal disulfide is selected by GAPDH. Subsequently, the induced folding of the flexible C-terminal tail of CP12 in the active site of GAPDH stabilizes the binary complex. Formation of several hydrogen bonds compensates the entropic cost of CP12 fixation and terminates the interaction mechanism that contributes to carbon assimilation control. PMID- 22514275 TI - LINGO-1, a transmembrane signaling protein, inhibits oligodendrocyte differentiation and myelination through intercellular self-interactions. AB - Overcoming remyelination failure is a major goal of new therapies for demyelinating diseases like multiple sclerosis. LINGO-1, a key negative regulator of myelination, is a transmembrane signaling protein expressed in both neurons and oligodendrocytes. In neurons, LINGO-1 is an integral component of the Nogo receptor complex, which inhibits axonal growth via RhoA. Because the only ligand binding subunit of this complex, the Nogo receptor, is absent in oligodendrocytes, the extracellular signals that inhibit myelination through a LINGO-1-mediated mechanism are unknown. Here we show that LINGO-1 inhibits oligodendrocyte terminal differentiation through intercellular interactions and is capable of a self-association in trans. Consistent with previous reports, overexpression of full-length LINGO-1 inhibited differentiation of oligodendrocyte precursor cells (OPCs). Unexpectedly, treatment with a soluble recombinant LINGO-1 ectodomain also had an inhibitory effect on OPCs and decreased myelinated axonal segments in cocultures with neurons from dorsal root ganglia. We demonstrated LINGO-1-mediated inhibition of OPCs through intercellular signaling by using a surface-bound LINGO-1 construct expressed ectopically in astrocytes. Further investigation showed that the soluble LINGO-1 ectodomain can interact with itself in trans by binding to CHO cells expressing full-length LINGO-1. Finally, we observed that soluble LINGO-1 could activate RhoA in OPCs. We propose that LINGO-1 acts as both a ligand and a receptor and that the mechanism by which it negatively regulates OPC differentiation and myelination is mediated by a homophilic intercellular interaction. Disruption of this protein-protein interaction could lead to a decrease of LINGO-1 inhibition and an increase in myelination. PMID- 22514276 TI - Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates cardiac sodium channel NaV1.5 gating by multiple phosphorylation sites. AB - The cardiac Na(+) channel Na(V)1.5 current (I(Na)) is critical to cardiac excitability, and altered I(Na) gating has been implicated in genetic and acquired arrhythmias. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is up-regulated in heart failure and has been shown to cause I(Na) gating changes that mimic those induced by a point mutation in humans that is associated with combined long QT and Brugada syndromes. We sought to identify the site(s) on Na(V)1.5 that mediate(s) the CaMKII-induced alterations in I(Na) gating. We analyzed both CaMKII binding and CaMKII-dependent phosphorylation of the intracellularly accessible regions of Na(V)1.5 using a series of GST fusion constructs, immobilized peptide arrays, and soluble peptides. A stable interaction between delta(C)-CaMKII and the intracellular loop between domains 1 and 2 of Na(V)1.5 was observed. This region was also phosphorylated by delta(C) CaMKII, specifically at the Ser-516 and Thr-594 sites. Wild-type (WT) and phosphomutant hNa(V)1.5 were co-expressed with GFP-delta(C)-CaMKII in HEK293 cells, and I(Na) was recorded. As observed in myocytes, CaMKII shifted WT I(Na) availability to a more negative membrane potential and enhanced accumulation of I(Na) into an intermediate inactivated state, but these effects were abolished by mutating either of these sites to non-phosphorylatable Ala residues. Mutation of these sites to phosphomimetic Glu residues negatively shifted I(Na) availability without the need for CaMKII. CaMKII-dependent phosphorylation of Na(V)1.5 at multiple sites (including Thr-594 and Ser-516) appears to be required to evoke loss-of-function changes in gating that could contribute to acquired Brugada syndrome-like effects in heart failure. PMID- 22514277 TI - p53 basic C terminus regulates p53 functions through DNA binding modulation of subset of target genes. AB - The p53 gene encodes a transcription factor that is composed of several functional domains: the N-terminal transactivation domain, the central sequence specific DNA binding domain, the tetramerization domain, and the highly basic C terminal regulatory domain (CTD). The p53 CTD is a nonspecific DNA binding domain that is subject to extensive post-translational modifications. However, the functional significance of the p53 CTD remains unclear. The role of this domain in the regulation of p53 functions is explored by comparing the activity of ectopically expressed wild-type (WT) p53 protein to that of a truncated mutant lacking the 24 terminal amino acids (Delta24). Using quantitative real time PCR and chromatin Immuno-Precipitation experiments, a p53 CTD deletion is shown to alter the p53-dependent induction of a subset of its target genes due to impaired specific DNA binding. Moreover, p53-induced growth arrest and apoptosis both require an intact p53 CTD. These data indicate that the p53 CTD is a positive regulator of p53 tumor suppressor functions. PMID- 22514279 TI - Novel actin-like filament structure from Clostridium tetani. AB - Eukaryotic F-actin is constructed from two protofilaments that gently wind around each other to form a helical polymer. Several bacterial actin-like proteins (Alps) are also known to form F-actin-like helical arrangements from two protofilaments, yet with varied helical geometries. Here, we report a unique filament architecture of Alp12 from Clostridium tetani that is constructed from four protofilaments. Through fitting of an Alp12 monomer homology model into the electron microscopy data, the filament was determined to be constructed from two antiparallel strands, each composed of two parallel protofilaments. These four protofilaments form an open helical cylinder separated by a wide cleft. The molecular interactions within single protofilaments are similar to F-actin, yet interactions between protofilaments differ from those in F-actin. The filament structure and assembly and disassembly kinetics suggest Alp12 to be a dynamically unstable force-generating motor involved in segregating the pE88 plasmid, which encodes the lethal tetanus toxin, and thus a potential target for drug design. Alp12 can be repeatedly cycled between states of polymerization and dissociation, making it a novel candidate for incorporation into fuel-propelled nanobiopolymer machines. PMID- 22514278 TI - Extracellular signal-regulated kinase (ERK) regulates cortactin ubiquitination and degradation in lung epithelial cells. AB - Cortactin, an actin-binding protein, is essential for cell growth and motility. We have shown that cortactin is regulated by reversible phosphorylation, but little is known regarding cortactin protein stability. Here, we show that lipopolysaccharide (LPS)-induced cortactin degradation is mediated by extracellular regulated signal kinase (ERK). LPS induces cortactin serine phosphorylation, ubiquitination, and degradation in mouse lung epithelia, an effect abrogated by ERK inhibition. Serine phosphorylation sites mutant, cortactin(S405A/S418A), enhances its protein stability. Cortactin is polyubiquitinated and degraded within the proteasome, whereas a cortactin(K79R) mutant exhibited proteolytic stability during cyclohexamide (CHX) or LPS treatment. The E3 ligase subunit beta-Trcp interacts with cortactin, and its overexpression reduced cortactin protein levels, an effect attenuated by ERK inhibition. Overexpression of beta-Trcp was sufficient to reduce the protective effects of exogenous cortactin on epithelial cell barrier integrity, an effect not observed after expression of a cortactin(K79R) mutant. These results provide evidence that LPS modulation of cortactin stability is coordinately regulated by stress kinases and the ubiquitin-proteasomal network. PMID- 22514280 TI - Lipodepsipeptide empedopeptin inhibits cell wall biosynthesis through Ca2+ dependent complex formation with peptidoglycan precursors. AB - Empedopeptin is a natural lipodepsipeptide antibiotic with potent antibacterial activity against multiresistant Gram-positive bacteria including methicillin resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae in vitro and in animal models of bacterial infection. Here, we describe its so far elusive mechanism of antibacterial action. Empedopeptin selectively interferes with late stages of cell wall biosynthesis in intact bacterial cells as demonstrated by inhibition of N-acetylglucosamine incorporation into polymeric cell wall and the accumulation of the ultimate soluble peptidoglycan precursor UDP-N-acetylmuramic acid-pentapeptide in the cytoplasm. Using membrane preparations and the complete cascade of purified, recombinant late stage peptidoglycan biosynthetic enzymes and their respective purified substrates, we show that empedopeptin forms complexes with undecaprenyl pyrophosphate containing peptidoglycan precursors. The primary physiological target of empedopeptin is undecaprenyl pyrophosphate-N-acetylmuramic acid(pentapeptide)-N-acetylglucosamine (lipid II), which is readily accessible at the outside of the cell and which forms a complex with the antibiotic in a 1:2 molar stoichiometry. Lipid II is bound in a region that involves at least the pyrophosphate group, the first sugar, and the proximal parts of stem peptide and undecaprenyl chain. Undecaprenyl pyrophosphate and also teichoic acid precursors are bound with lower affinity and constitute additional targets. Calcium ions are crucial for the antibacterial activity of empedopeptin as they promote stronger interaction with its targets and with negatively charged phospholipids in the membrane. Based on the high structural similarity of empedopeptin to the tripropeptins and plusbacins, we propose this mechanism of action for the whole compound class. PMID- 22514281 TI - Glycogen synthase kinase 3beta (GSK3beta) modulates antiviral activity of zinc finger antiviral protein (ZAP). AB - Zinc-finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses, including HIV-1, Ebola virus, and Sindbis virus. ZAP binds directly to specific viral mRNAs and recruits cellular mRNA degradation machinery to degrade the target RNA. ZAP has also been suggested to repress translation of the target mRNA. In this study, we report that ZAP is phosphorylated by glycogen synthase kinase 3beta (GSK3beta). GSK3beta sequentially phosphorylated Ser-270, Ser-266, Ser-262, and Ser-257 of rat ZAP. Inhibition of GSK3beta by inhibitor SB216763 or down-regulation of GSK3beta by RNAi reduced the antiviral activity of ZAP. These results indicate that phosphorylation of ZAP by GSK3beta modulates ZAP activity. PMID- 22514282 TI - JBP1 and JBP2 proteins are Fe2+/2-oxoglutarate-dependent dioxygenases regulating hydroxylation of thymidine residues in trypanosome DNA. AB - We have recently demonstrated that O-linked glucosylation of thymine in trypanosome DNA (base J) regulates polymerase II transcription initiation. In vivo analysis has indicated that base J synthesis is initiated by the hydroxylation of thymidine by proteins (JBP1 and JBP2) homologous to the Fe(2+)/2 oxoglutarate (2-OG)-dependent dioxygenase superfamily where hydroxylation is driven by the oxidative decarboxylation of 2-OG, forming succinate and CO(2). However, no direct evidence for hydroxylase activity has been reported for the JBP proteins. We now demonstrate recombinant JBP1 hydroxylates thymine specifically in the context of dsDNA in a Fe(2+)-, 2-OG-, and O(2)-dependent manner. Under anaerobic conditions, the addition of Fe(2+) to JBP1/2-OG results in the formation of a broad absorption spectrum centered at 530 nm attributed to metal chelation of 2-OG bound to JBP, a spectroscopic signature of Fe(2+)/2-OG dependent dioxygenases. The N-terminal thymidine hydroxylase domain of JBP1 is sufficient for full activity and mutation of residues involved in coordinating Fe(2+) inhibit iron binding and thymidine hydroxylation. Hydroxylation in vitro and J synthesis in vivo is inhibited by known inhibitors of Fe(2+)/2-OG-dependent dioxygenases. The data clearly demonstrate the JBP enzymes are dioxygenases acting directly on dsDNA, confirming the two-step J synthesis model. Growth of trypanosomes in hypoxic conditions decreases JBP1 and -2 activity, resulting in reduced levels of J and changes in parasite virulence previously characterized in the JBP KO. The influence of environment upon J biosynthesis via oxygen-sensitive regulation of JBP1/2 has exciting implications for the regulation of gene expression and parasite adaptation to different host niches. PMID- 22514283 TI - Mutation of conserved histidines alters tertiary structure and nanomechanics of consensus ankyrin repeats. AB - The conserved TPLH tetrapeptide motif of ankyrin repeats (ARs) plays an important role in stabilizing AR proteins, and histidine (TPLH)-to-arginine (TPLR) mutations in this motif have been associated with a hereditary human anemia, spherocytosis. Here, we used a combination of atomic force microscopy-based single-molecule force spectroscopy and molecular dynamics simulations to examine the mechanical effects of His -> Arg substitutions in TPLH motifs in a model AR protein, NI6C. Our molecular dynamics results show that the mutant protein is less mechanically stable than the WT protein. Our atomic force microscopy results indicate that the mechanical energy input necessary to fully unfold the mutant protein is only half of that necessary to unfold the WT protein (53 versus 106 kcal/mol). In addition, the ability of the mutant to generate refolding forces is also reduced. Moreover, the mutant protein subjected to cyclic stretch-relax measurements displays mechanical fatigue, which is absent in the WT protein. Taken together, these results indicate that the His -> Arg substitutions in TPLH motifs compromise mechanical properties of ARs and suggest that the origin of hereditary spherocytosis may be related to mechanical failure of ARs. PMID- 22514284 TI - Estrogen-induced expression of Fos-related antigen 1 (FRA-1) regulates uterine stromal differentiation and remodeling. AB - Concerted actions of estrogen and progesterone via their cognate receptors orchestrate changes in the uterine tissue, regulating implantation during early pregnancy. The uterine stromal cells undergo steroid-dependent differentiation into morphologically and functionally distinct decidual cells, which support embryonic growth and survival. The hormone-regulated pathways underlying this unique cellular transformation are not fully understood. Previous studies in the mouse revealed that, following embryo attachment, de novo synthesis of estrogen by the decidual cells is critical for stromal differentiation. In this study we report that Fos-related antigen 1 (FRA-1), a member of the Fos family of transcription factors, is a downstream target of regulation by intrauterine estrogen. FRA-1 expression was localized in the differentiating uterine stromal cells surrounding the implanted embryo. Attenuation of estrogen receptor alpha (Esr1) expression by siRNA mediated silencing in primary uterine stromal cells suppressed FRA-1 expression. Furthermore, chromatin immunoprecipitation demonstrated direct recruitment of ESR1 to an estrogen response element in the Fra-1 promoter. Down-regulation of Fra-1 expression during in vitro decidualization blocked stromal differentiation and resulted in a marked decrease in stromal cell migration. Interestingly, FRA-1 controls the expression of matrix metalloproteinases MMP9 and MMP13, which are critical modulators of stromal extracellular matrix remodeling. Collectively, these results suggest that FRA-1, induced in response to estrogen signaling via ESR1, is a key regulator of stromal differentiation and remodeling during early pregnancy. PMID- 22514285 TI - Forebrain organization representing baroreceptor gating of somatosensory afferents within the cortical autonomic network. AB - Somatosensory afferents are represented within the cortical autonomic network (CAN). However, the representation of somatosensory afferents, and the consequent cardiovascular effects, may be modified by levels of baroreceptor input. Thus, we examined the cortical regions involved with processing somatosensory inputs during baroreceptor unloading. Neuroimaging sessions (functional magnetic resonance imaging [fMRI]) recorded brain activity during 30 mmHg lower-body negative pressure (LBNP) alone and combined with somatosensory stimulation (LBNP+SS) of the forearm (n = 14). Somatosensory processing was also assessed during increased sympathetic outflow via end-expiratory apnea. Heart rate (HR), blood pressure (BP), cardiac output (Q), and muscle sympathetic nerve activity (MSNA) were recorded during the same protocols in a separate laboratory session. SS alone had no effect on any cardiovascular or MSNA variable at rest. Measures of HR, BP, and Q during LBNP were not different compared with LBNP+SS. The rise in MSNA burst frequency was attenuated during LBNP+SS versus LBNP alone (8 vs. 12 bursts/min, respectively, P < 0.05). SS did not affect the change in MSNA during apnea. Activations within the insula and dorsal anterior cingulate cortex (ACC) observed during LBNP were not seen during LBNP+SS. Anterior insula and ACC activations occurring during apnea were not modified by SS. Thus, the absence of insular and dorsal ACC activity during LBNP+SS along with an attenuation of MSNA burst frequency suggest sympathoinhibitory effects of sensory stimulation during decreased baroreceptor input by a mechanism that includes conjoint insula-dorsal ACC regulation. These findings reveal that the level of baroreceptor input influences the forebrain organization of somatosensory afferents. PMID- 22514287 TI - Spatial pattern of BOLD fMRI activation reveals cross-modal information in auditory cortex. AB - Recent findings suggest that neural representations in early auditory cortex reflect not only the physical properties of a stimulus, but also high-level, top down, and even cross-modal information. However, the nature of cross-modal information in auditory cortex remains poorly understood. Here, we used pattern analyses of fMRI data to ask whether early auditory cortex contains information about the visual environment. Our data show that 1) early auditory cortex contained information about a visual stimulus when there was no bottom-up auditory signal, and that 2) no influence of visual stimulation was observed in auditory cortex when visual stimuli did not provide a context relevant to audition. Our findings attest to the capacity of auditory cortex to reflect high level, top-down, and cross-modal information and indicate that the spatial patterns of activation in auditory cortex reflect contextual/implied auditory information but not visual information per se. PMID- 22514286 TI - How is a motor skill learned? Change and invariance at the levels of task success and trajectory control. AB - The public pays large sums of money to watch skilled motor performance. Notably, however, in recent decades motor skill learning (performance improvement beyond baseline levels) has received less experimental attention than motor adaptation (return to baseline performance in the setting of an external perturbation). Motor skill can be assessed at the levels of task success and movement quality, but the link between these levels remains poorly understood. We devised a motor skill task that required visually guided curved movements of the wrist without a perturbation, and we defined skill learning at the task level as a change in the speed-accuracy trade-off function (SAF). Practice in restricted speed ranges led to a global shift of the SAF. We asked how the SAF shift maps onto changes in trajectory kinematics, to establish a link between task-level performance and fine motor control. Although there were small changes in mean trajectory, improved performance largely consisted of reduction in trial-to-trial variability and increase in movement smoothness. We found evidence for improved feedback control, which could explain the reduction in variability but does not preclude other explanations such as an increased signal-to-noise ratio in cortical representations. Interestingly, submovement structure remained learning invariant. The global generalization of the SAF across a wide range of difficulty suggests that skill for this task is represented in a temporally scalable network. We propose that motor skill acquisition can be characterized as a slow reduction in movement variability, which is distinct from faster model-based learning that reduces systematic error in adaptation paradigms. PMID- 22514289 TI - A neuronal population in hypothalamus that dramatically resists acute ischemic injury compared to neocortex. AB - Pyramidal neurons (PyNs) of the cortex are highly susceptible to acute stroke damage, yet "lower" brain regions like hypothalamus and brain stem better survive global ischemia. Here we show for the first time that a "lower" neuron population intrinsically resists acute strokelike injury. In rat brain slices deprived of oxygen and glucose (OGD), we imaged anoxic depolarization (AD) as it propagated through neocortex or hypothalamus. AD, the initial electrophysiological event of stroke, is a front of depolarization that drains residual energy in compromised gray matter. The extent of AD reliably determines ensuing cortical damage, but do all CNS neurons generate a robust AD? During 10 min of OGD, PyNs depolarize without functional recovery. In contrast, magnocellular neuroendocrine cells (MNCs) in hypothalamus under identical stress generate a weak and delayed AD, resist complete depolarization, and rapidly repolarize when oxygen and glucose are restored. They recover their membrane potential, input resistance, and spike amplitude and can survive multiple OGD exposures. Two-photon microscopy in slices derived from a fluorescent mouse line confirms this protection, revealing PyN swelling and dendritic beading after OGD, whereas MNCs are not injured. Exposure to the Na(+)-K(+)-ATPase inhibitor ouabain (100 MUM) induces AD similar to OGD in both cell types. Moreover, elevated extracellular K(+) concentration ([K(+)](o)) evokes spreading depression (SD), a milder version of AD, in PyNs but not MNCs. Therefore overriding the pump by OGD, ouabain, or elevated [K(+)](o) evokes a propagating depolarization in higher gray matter but not in MNCs. We suggest that variation in Na(+)-K(+)-ATPase pump efficiency during ischemia injury determines whether a neuronal type succumbs to or resists stroke. PMID- 22514288 TI - A distributed, dynamic, parallel computational model: the role of noise in velocity storage. AB - Networks of neurons perform complex calculations using distributed, parallel computation, including dynamic "real-time" calculations required for motion control. The brain must combine sensory signals to estimate the motion of body parts using imperfect information from noisy neurons. Models and experiments suggest that the brain sometimes optimally minimizes the influence of noise, although it remains unclear when and precisely how neurons perform such optimal computations. To investigate, we created a model of velocity storage based on a relatively new technique--"particle filtering"--that is both distributed and parallel. It extends existing observer and Kalman filter models of vestibular processing by simulating the observer model many times in parallel with noise added. During simulation, the variance of the particles defining the estimator state is used to compute the particle filter gain. We applied our model to estimate one-dimensional angular velocity during yaw rotation, which yielded estimates for the velocity storage time constant, afferent noise, and perceptual noise that matched experimental data. We also found that the velocity storage time constant was Bayesian optimal by comparing the estimate of our particle filter with the estimate of the Kalman filter, which is optimal. The particle filter demonstrated a reduced velocity storage time constant when afferent noise increased, which mimics what is known about aminoglycoside ablation of semicircular canal hair cells. This model helps bridge the gap between parallel distributed neural computation and systems-level behavioral responses like the vestibuloocular response and perception. PMID- 22514290 TI - Detection of tactile inputs in the rat vibrissa pathway. AB - The rapid detection of sensory inputs is crucial for survival. Sensory detection explicitly requires the integration of incoming sensory information and the ability to distinguish between relevant information and ongoing neural activity. In this study, head-fixed rats were trained to detect the presence of a brief deflection of their whiskers resulting from a focused puff of air. The animals showed a monotonic increase in response probability and a decrease in reaction time with increased stimulus strength. High-speed video analysis of whisker motion revealed that animals were more likely to detect the stimulus during periods of reduced self-induced motion of the whiskers, thereby allowing the stimulus-induced whisker motion to exceed the ongoing noise. In parallel, we used voltage-sensitive dye (VSD) imaging of barrel cortex in anesthetized rats receiving the same stimulus set as those in the behavioral portion of this study to assess candidate codes that make use of the full spatiotemporal representation and to compare variability in the trial-by-trial nature of the cortical response and the corresponding variability in the behavioral response. By application of an accumulating evidence framework to the population cortical activity measured in separate animals, a strong correspondence was made between the behavioral output and the neural signaling, in terms of both the response probabilities and the reaction times. Taken together, the results here provide evidence for detection performance that is strongly reliant on the relative strength of signal versus noise, with strong correspondence between behavior and parallel electrophysiological findings. PMID- 22514291 TI - Effects of galvanic vestibular stimulation on postural limb reflexes and neurons of spinal postural network. AB - Quadrupeds maintain the dorsal side up body orientation due to the activity of the postural control system driven by limb mechanoreceptors. Binaural galvanic vestibular stimulation (GVS) causes a lateral body sway toward the anode. Previously, we have shown that this new position is actively stabilized, suggesting that GVS changes a set point in the reflex mechanisms controlling body posture. The aim of the present study was to reveal the underlying neuronal mechanisms. Experiments were performed on decerebrate rabbits. The vertebral column was rigidly fixed, whereas hindlimbs were positioned on a platform. Periodic lateral tilts of the platform caused postural limb reflexes (PLRs): activation of extensors in the loaded and flexing limb and a decrease in extensor activity in the opposite (unloaded and extending) limb. Putative spinal interneurons were recorded in segments L4-L5 during PLRs, with and without GVS. We have found that GVS enhanced PLRs on the cathode side and reduced them on the anode side. This asymmetry in PLRs can account for changes in the stabilized body orientation observed in normal rabbits subjected to continuous GVS. Responses to platform tilts (frequency modulation) were observed in 106 spinal neurons, suggesting that they can contribute to PLR generation. Two neuron groups were active in opposite phases of the tilt cycle of the ipsi-limb: F-neurons in the flexion phase, and E-neurons in the extension phase. Neurons were driven mainly by afferent input from the ipsi-limb. If one supposes that F- and E-neurons contribute, respectively, to excitation and inhibition of extensor motoneurons, one can expect that the pattern of response to GVS in F-neurons will be similar to that in extensor muscles, whereas E-neurons will have an opposite pattern. We have found that ~40% of all modulated neurons meet this condition, suggesting that they contribute to the generation of PLRs and to the GVS-caused changes in PLRs. PMID- 22514292 TI - Neural targets for relieving parkinsonian rigidity and bradykinesia with pallidal deep brain stimulation. AB - Clinical evidence has suggested that subtle changes in deep brain stimulation (DBS) settings can have differential effects on bradykinesia and rigidity in patients with Parkinson's disease. In this study, we first investigated the degree of improvement in bradykinesia and rigidity during targeted globus pallidus DBS in three 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus macaques. Behavioral outcomes of DBS were then coupled with detailed, subject-specific computational models of neurons in the globus pallidus internus (GPi), globus pallidus externus (GPe), and internal capsule (IC) to determine which neuronal pathways when modulated with high-frequency electrical stimulation best correlate with improvement in motor symptoms. The modeling results support the hypothesis that multiple neuronal pathways can underlie the therapeutic effect of DBS on parkinsonian bradykinesia and rigidity. Across all three subjects, improvements in rigidity correlated most strongly with spread of neuronal activation into IC, driving a small percentage of fibers within this tract (<10% on average). The most robust effect on bradykinesia resulted from stimulating a combination of sensorimotor axonal projections within the GP, specifically at the site of the medial medullary lamina. Thus the beneficial effects of pallidal DBS for parkinsonian symptoms may occur from multiple targets within and near the target nucleus. PMID- 22514293 TI - Sensory regulation of quadrupedal locomotion: a top-down or bottom-up control system? AB - Propriospinal pathways are thought to be critical for quadrupedal coordination by coupling cervical and lumbar central pattern generators (CPGs). However, the mechanisms involved in relaying information between girdles remain largely unexplored. Using an in vitro spinal cord preparation in neonatal rats, Juvin and colleagues (Juvin et al. 2012) have recently shown sensory inputs from the hindlimbs have greater influence on forelimb CPGs than forelimb sensory inputs on hindlimb CPGs, in other words, a bottom-up control system. However, results from decerebrate cats suggest a top-down control system. It may be that both bottom-up and top-down control systems exist and that the dominance of one over the other is task or context dependent. As such, the role of sensory inputs in controlling quadrupedal coordination before and after injury requires further investigation. PMID- 22514294 TI - How does the motor system correct for errors in time and space during locomotor adaptation? AB - Walking is a complex behavior for which the healthy nervous system favors a smooth, symmetric pattern. However, people often adopt an asymmetric walking pattern after neural or biomechanical damage (i.e., they limp). To better understand this aberrant motor pattern and how to change it, we studied walking adaptation to a split-belt perturbation where one leg is driven to move faster than the other. Initially, healthy adult subjects take asymmetric steps on the split-belt treadmill, but within 10-15 min people adapt to reestablish walking symmetry. Which of the many walking parameters does the nervous system change to restore symmetry during this complex act (i.e., what motor mappings are adapted to restore symmetric walking in this asymmetric environment)? Here we found two parameters that met our criteria for adaptive learning: a temporal motor output consisting of the duration between heel-strikes of the two legs (i.e., "when" the feet land) and a spatial motor output related to the landing position of each foot relative to one another (i.e., "where" the feet land). We found that when subjects walk in an asymmetric environment they smoothly change their temporal and spatial motor outputs to restore temporal and spatial symmetry in the interlimb coordination of their gait. These changes in motor outputs are stored and have to be actively deadapted. Importantly, the adaptation of temporal and spatial motor outputs is dissociable since subjects were able to adapt their temporal motor output without adapting the spatial output. Taken together, our results suggest that temporal and spatial control for symmetric gait can be adapted separately, and therefore we could potentially develop interventions targeting either temporal or spatial walking deficits. PMID- 22514295 TI - Auditory signals evolve from hybrid- to eye-centered coordinates in the primate superior colliculus. AB - Visual and auditory spatial signals initially arise in different reference frames. It has been postulated that auditory signals are translated from a head centered to an eye-centered frame of reference compatible with the visual spatial maps, but, to date, only various forms of hybrid reference frames for sound have been identified. Here, we show that the auditory representation of space in the superior colliculus involves a hybrid reference frame immediately after the sound onset but evolves to become predominantly eye centered, and more similar to the visual representation, by the time of a saccade to that sound. Specifically, during the first 500 ms after the sound onset, auditory response patterns (N = 103) were usually neither head nor eye centered: 64% of neurons showed such a hybrid pattern, whereas 29% were more eye centered and 8% were more head centered. This differed from the pattern observed for visual targets (N = 156): 86% were eye centered, <1% were head centered, and only 13% exhibited a hybrid of both reference frames. For auditory-evoked activity observed within 20 ms of the saccade (N = 154), the proportion of eye-centered response patterns increased to 69%, whereas the hybrid and head-centered response patterns dropped to 30% and <1%, respectively. This pattern approached, although did not quite reach, that observed for saccade-related activity for visual targets: 89% were eye centered, 11% were hybrid, and <1% were head centered (N = 162). The plainly eye-centered visual response patterns and predominantly eye-centered auditory motor response patterns lie in marked contrast to our previous study of the intraparietal cortex, where both visual and auditory sensory and motor-related activity used a predominantly hybrid reference frame (Mullette-Gillman et al. 2005, 2009). Our present findings indicate that auditory signals are ultimately translated into a reference frame roughly similar to that used for vision, but suggest that such signals might emerge only in motor areas responsible for directing gaze to visual and auditory stimuli. PMID- 22514297 TI - Friction-based stabilization of juxtacellular recordings in freely moving rats. AB - Virtually nothing is known about the activity of morphologically identified neurons in freely moving mammals. Here we describe stabilization and positioning techniques that allow juxtacellular recordings from labeled single neurons in awake, freely moving animals. This method involves the use of a friction-based device that allows stabilization of the recording pipette by friction forces. Friction is generated by a clamplike mechanism that tightens a sliding pipette holder to a preimplanted pipette guide. The interacting surfaces are smoothed to optical quality (<5-nm roughness) to enable micrometer stepping precision of the device during operation. Our method allows recordings from identified neurons in freely moving animals, and thus opens new perspectives for analyzing the role of identified neurons in the control of behavior. PMID- 22514296 TI - The role of the right presupplementary motor area in stopping action: two studies with event-related transcranial magnetic stimulation. AB - Rapidly stopping action engages a network in the brain including the right presupplementary motor area (preSMA), the right inferior frontal gyrus, and the basal ganglia. Yet the functional role of these different regions within the overall network still remains unclear. Here we focused on the role of the right preSMA in behavioral stopping. We hypothesized that the underlying neurocognitive function of this region is one or more of setting up a stopping rule in advance, modulating response tendencies (e.g., slowing down in anticipation of stopping), and implementing stopping when the stop signal occurs. We performed two experiments with magnetic resonance imaging (MRI)-guided, event-related, transcranial magnetic stimulation(TMS), during the performance of variants of the stop signal task. In experiment 1 we show that stimulation of the right preSMA versus vertex (control site) slowed the implementation of stopping (measured via stop signal reaction time) but had no influence on modulation of response tendencies. In experiment 2, we showed that stimulation of the right preSMA slowed implementation of stopping in a mechanistically selective form of stopping but had no influence on setting up stopping rules. The results go beyond the replication of prior findings by showing that TMS of the right preSMA impairs stopping behavior (including a behaviorally selective form of stopping) through a specific disruption of the implementation of stopping. Future studies are required to establish whether this was due to stimulation of the right preSMA itself or because of remote effects on the wider stopping network. PMID- 22514298 TI - Contralateral-noise effects on cochlear responses in anesthetized mice are dominated by feedback from an unknown pathway. AB - Suppression of ipsilateral distortion product otoacoustic emissions (DPOAEs) by contralateral noise is used in humans and animals to assay the strength of sound evoked negative feedback from the medial olivocochlear (MOC) efferent pathway. However, depending on species and anesthesia, contributions of other feedback systems to the middle or inner ear can cloud the interpretation. Here, contributions of MOC and middle-ear muscle reflexes, as well as autonomic feedback, to contra-noise suppression in anesthetized mice are dissected by selectively eliminating each pathway by surgical transection, pharmacological blockade, or targeted gene deletion. When ipsilateral DPOAEs were evoked by low level primaries, contra-noise suppression was typically ~1 dB with contra-noise levels around 95 dB SPL, and it always disappeared upon contralateral cochlear destruction. Lack of middle-ear muscle contribution was suggested by persistence of contra-noise suppression after paralysis with curare, tensor tympani cauterization, or section of the facial nerve. Contribution of cochlear sympathetics was ruled out by studying mutant mice lacking adrenergic signaling (dopamine beta-hydroxylase knockouts). Surprisingly, contra-noise effects on low level DPOAEs were also not diminished by eliminating the MOC system pharmacologically (strychnine), surgically, or by deletion of relevant cholinergic receptors (alpha9/alpha10). In contrast, when ipsilateral DPOAEs were evoked by high-level primaries, the contra-noise suppression, although comparable in magnitude, was largely eliminated by MOC blockade or section. Possible alternate pathways are discussed for the source of contra-noise-evoked effects at low ipsilateral levels. PMID- 22514299 TI - Relative disparity processing in the dorsal visual pathway. PMID- 22514300 TI - Functional dissociation within the entorhinal cortex for memory retrieval of an association between temporally discontiguous stimuli. AB - Anatomical connectivity and single neuron coding suggest a segregation of information representation within lateral (LEC) and medial (MEC) portions of the entorhinal cortex, a brain region serving as the primary input/output of the hippocampus and maintaining widespread connections to many association cortices. The present study aimed to expand this idea by examining whether these two subregions differentially contribute to memory retrieval for an association between temporally discontiguous stimuli. We found that reversible inactivation of the LEC, but not the MEC, severely impaired the retrieval of the recently and remotely acquired memory in rat trace eyeblink conditioning, in which a stimulus free interval was interposed between the conditioned and unconditioned stimulus. Conversely, inactivation of the LEC had no effect on retrieval in delay eyeblink conditioning, where two stimuli were presented without an interval. Therefore, the LEC, but not the MEC, plays a long-lasting role in the retrieval of a memory for an association between temporally discontiguous stimuli. PMID- 22514301 TI - c-Maf is required for the development of dorsal horn laminae III/IV neurons and mechanoreceptive DRG axon projections. AB - Establishment of proper connectivity between peripheral sensory neurons and their central targets is required for an animal to sense and respond to various external stimuli. Dorsal root ganglion (DRG) neurons convey sensory signals of different modalities via their axon projections to distinct laminae in the dorsal horn of the spinal cord. In this study, we found that c-Maf was expressed predominantly in the interneurons of laminae III/IV, which primarily receive inputs from mechanoreceptive DRG neurons. In the DRG, c-Maf+ neurons also coexpressed neurofilament-200, a marker for the medium- and large-diameter myelinated afferents that transmit non-noxious information. Furthermore, mouse embryos deficient in c-Maf displayed abnormal development of dorsal horn laminae III/IV neurons, as revealed by the marked reduction in the expression of several marker genes for these neurons, including those for transcription factors MafA and Rora, GABA(A) receptor subunit alpha5, and neuropeptide cholecystokinin. In addition, among the four major subpopulations of DRG neurons marked by expression of TrkA, TrkB, TrkC, and MafA/GFRalpha2/Ret, c-Maf was required selectively for the proper differentiation of MafA+/Ret+/GFRalpha2+ low-threshold mechanoreceptors (LTMs). Last, we found that the central and peripheral projections of mechanoreceptive DRG neurons were compromised in c-Maf deletion mice. Together, our results indicate that c-Maf is required for the proper development of MafA+/Ret+/GFRalpha2+ LTMs in the DRG, their afferent projections in the dorsal horn and Pacinian corpuscles, as well as neurons in laminae III/IV of the spinal cord. PMID- 22514302 TI - Ferritin stimulates oligodendrocyte genesis in the adult spinal cord and can be transferred from macrophages to NG2 cells in vivo. AB - Injured CNS tissue often contains elevated iron and its storage protein ferritin, which may exacerbate tissue damage through pro-oxidative mechanisms. Therefore, therapeutic studies often target iron reduction as a neuroprotective strategy. However, iron may be crucial for oligodendrocyte replacement and remyelination. For instance, we previously showed that intraspinal toll-like receptor 4 macrophage activation induced the generation of new ferritin-positive oligodendrocytes, and that iron chelation significantly reduced this oligodendrogenic response. Since macrophages can secrete ferritin, we hypothesize that ferritin is a macrophage-derived signal that promotes oligodendrogenesis. To test this, we microinjected ferritin into intact adult rat spinal cords. Within 6 h, NG2+ progenitor cells proliferated and accumulated ferritin. By 3 d, many of these cells had differentiated into new oligodendrocytes. However, acute neuron and oligodendrocyte toxicity occurred in gray matter. Interestingly, ferritin positive NG2 cells and macrophages accumulated in the area of cell loss, revealing that NG2 cells thrive in an environment that is toxic to other CNS cells. To test whether ferritin can be transferred from macrophages to NG2 cells in vivo, we loaded macrophages with fluorescent ferritin then transplanted them into intact spinal white matter. Within 3-6 d, proliferating NG2 cells migrated into the macrophage transplants and accumulated fluorescently labeled ferritin. These results show that activated macrophages can be an in vivo source of ferritin for NG2 cells, which induces their proliferation and differentiation into new oligodendrocytes. This work has relevance for conditions in which iron mediated injury and/or repair likely occur, such as hemorrhage, stroke, spinal cord injury, aging, Parkinson's disease, and Alzheimer's disease. PMID- 22514304 TI - Distinct subsets of Syt-IV/BDNF vesicles are sorted to axons versus dendrites and recruited to synapses by activity. AB - BDNF plays a critical role in the regulation of synaptic strength and is essential for long-term potentiation, a phenomenon that underlies learning and memory. However, whether BDNF acts in a diffuse manner or is targeted to specific neuronal subcompartments or synaptic sites to affect circuit function remains unknown. Here, using photoactivation of BDNF or syt-IV (a regulator of exocytosis present on BDNF-containing vesicles) in transfected rat hippocampal neurons, we discovered that distinct subsets of BDNF vesicles are targeted to axons versus dendrites and are not shared between these compartments. Moreover, syt-IV- and BDNF-harboring vesicles are recruited to both presynaptic and postsynaptic sites in response to increased neuronal activity. Finally, using syt-IV knockout mouse neurons, we found that syt-IV is necessary for both presynaptic and postsynaptic scaling of synaptic strength in response to changes in network activity. These findings demonstrate that BDNF-containing vesicles can be targeted to specific sites in neurons and suggest that syt-IV-regulated BDNF secretion is subject to spatial control to regulate synaptic function in a site-specific manner. PMID- 22514303 TI - Attention deficit/hyperactivity disorder-derived coding variation in the dopamine transporter disrupts microdomain targeting and trafficking regulation. AB - Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed disorder of school-age children. Although genetic and brain-imaging studies suggest a contribution of altered dopamine (DA) signaling in ADHD, evidence of signaling perturbations contributing to risk is largely circumstantial. The presynaptic, cocaine- and amphetamine (AMPH)-sensitive DA transporter (DAT) constrains DA availability at presynaptic and postsynaptic receptors following vesicular release and is targeted by the most commonly prescribed ADHD therapeutics. Using polymorphism discovery approaches with an ADHD cohort, we identified a hDAT (human DAT) coding variant, R615C, located in the distal C terminus of the transporter, a region previously implicated in constitutive and regulated transporter trafficking. Here, we demonstrate that, whereas wild-type DAT proteins traffic in a highly regulated manner, DAT 615C proteins recycle constitutively and demonstrate insensitivity to the endocytic effects of AMPH and PKC (protein kinase C) activation. The disrupted regulation of DAT 615C parallels a redistribution of the transporter variant away from GM1 ganglioside- and flotillin1-enriched membranes, and is accompanied by altered CaMKII (calcium/calmodulin-dependent protein kinase II) and flotillin-1 interactions. Using C-terminal peptides derived from wild-type DAT and the R615C variant, we establish that the DAT 615C C terminus can act dominantly to preclude AMPH regulation of wild-type DAT. Mutagenesis of DAT C-terminal sequences suggests that phosphorylation of T613 may be important in sorting DAT between constitutive and regulated pathways. Together, our studies support a coupling of DAT microdomain localization with transporter regulation and provide evidence of perturbed DAT activity and DA signaling as a risk determinant for ADHD. PMID- 22514305 TI - Different properties of visual relearning after damage to early versus higher level visual cortical areas. AB - The manipulation of visual perceptual learning is emerging as an important rehabilitation tool following visual system damage. Specificity of visual learning for training stimulus and task attributes has been used in prior work to infer a differential contribution of higher-level versus lower-level visual cortical areas to this process. The present study used a controlled experimental paradigm in felines to examine whether relearning of motion discrimination and the specificity of such relearning are differently influenced by damage at lower versus higher levels of the visual cortical hierarchy. Cats with damage to either early visual areas 17,18, and 19, or to higher-level, motion-processing lateral suprasylvian (LS) cortex were trained to perform visual tasks with controlled fixation. Animals with either type of lesion could relearn to discriminate the direction of motion of both drifting gratings and random dot stimuli in their impaired visual field. However, two factors emerged as critical for allowing transfer of learning to untrained motion stimuli: (1) an intact LS cortex and (2) more complex visual stimuli. Thus, while the hierarchical level of visual cortex damage did not seem to limit the ability to relearn motion discriminations, generalizability of relearning with a damaged visual system appeared to be influenced by both the areas damaged and the nature of the stimulus used during training. PMID- 22514306 TI - Spontaneous activity promotes synapse formation in a cell-type-dependent manner in the developing retina. AB - Spontaneous activity is thought to regulate synaptogenesis in many parts of the developing nervous system. In vivo evidence for this regulation, however, is scarce and comes almost exclusively from experiments in which normal activity was reduced or blocked completely. Thus, whether spontaneous activity itself promotes synaptogenesis or plays a purely permissive role remains uncertain. In addition, how activity influences synapse dynamics to shape connectivity and whether its effects among neurons are uniform or cell-type-dependent is unclear. In mice lacking the cone-rod homeobox gene (Crx), photoreceptors fail to establish normal connections with bipolar cells (BCs). Here, we find that retinal ganglion cells (RGCs) in Crx-/- mice become rhythmically hyperactive around the time of eye opening as a result of increased spontaneous glutamate release from BCs. This elevated neurotransmission enhances synaptogenesis between BCs and RGCs, without altering the overall circuit architecture. Using live imaging, we discover that spontaneous activity selectively regulates the rate of synapse formation, not elimination, in this circuit. Reconstructions of the connectivity patterns of three BC types with a shared RGC target further revealed that neurotransmission specifically promotes the formation of multisynaptic appositions from one BC type without affecting the maintenance or elimination of connections from the other two. Although hyperactivity in Crx-/- mice persists, synapse numbers do not increase beyond 4 weeks of age, suggesting closure of a critical period for synaptic refinement in the inner retina. Interestingly, despite their hyperactivity, RGC axons maintain normal eye-specific territories and cell-type specific layers in the dorsal lateral geniculate nucleus. PMID- 22514307 TI - G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation. AB - Learning triggers alterations in gene transcription in brain regions such as the hippocampus and the entorhinal cortex (EC) that are necessary for long-term memory (LTM) formation. Here, we identify an essential role for the G9a/G9a-like protein (GLP) lysine dimethyltransferase complex and the histone H3 lysine 9 dimethylation (H3K9me2) marks it catalyzes, in the transcriptional regulation of genes in area CA1 of the rat hippocampus and the EC during memory consolidation. Contextual fear learning increased global levels of H3K9me2 in area CA1 and the EC, with observable changes at the Zif268, DNMT3a, BDNF exon IV, and cFOS gene promoters, which occurred in concert with mRNA expression. Inhibition of G9a/GLP in the EC, but not in the hippocampus, enhanced contextual fear conditioning relative to control animals. The inhibition of G9a/GLP in the EC induced several histone modifications that include not only methylation but also acetylation. Surprisingly, we found that downregulation of G9a/GLP activity in the EC enhanced H3K9me2 in area CA1, resulting in transcriptional silencing of the non-memory permissive gene COMT in the hippocampus. In addition, synaptic plasticity studies at two distinct EC-CA1 cellular pathways revealed that G9a/GLP activity is critical for hippocampus-dependent long-term potentiation initiated in the EC via the perforant pathway, but not the temporoammonic pathway. Together, these data demonstrate that G9a/GLP differentially regulates gene transcription in the hippocampus and the EC during memory consolidation. Furthermore, these findings support the possibility of a role for G9a/GLP in the regulation of cellular and molecular cross talk between these two brain regions during LTM formation. PMID- 22514309 TI - Desert hedgehog links transcription factor Sox10 to perineurial development. AB - Schwann cells are the main glial cell type in the PNS. They develop along nerves during embryogenesis and rely on the HMG domain containing Sox10 transcription factor for specification, lineage progression, and terminal differentiation. Sox10 deletion in immature Schwann cells caused peripheral nerve defects in mice that were not restricted to this glial cell type, although expression in the nerve and gene loss were. Formation of the perineurium as the protecting sheath was, for instance, heavily compromised. This resembled the defect observed after loss of Desert hedgehog (Dhh) in mice. Here we show that Sox10 activates Dhh expression in Schwann cells via an enhancer that is located in intron 1 of the Dhh gene. Sox10 binds this enhancer in monomeric form via several sites. Mutation of these sites abolishes both Schwann-cell-specific activity and Sox10 responsiveness in vitro and in transgenic mouse embryos. This argues that Sox10 activates Dhh expression by direct binding to the enhancer and by increasing Dhh levels promotes formation of the perineurial sheath. This represents the first mechanism for a non-cell-autonomous function of Sox10 during peripheral nerve development. PMID- 22514308 TI - Columnar interactions determine horizontal propagation of recurrent network activity in neocortex. AB - The cortex is organized in vertical and horizontal circuits that determine the spatiotemporal properties of distributed cortical activity. Despite detailed knowledge of synaptic interactions among individual cells in the neocortex, little is known about the rules governing interactions among local populations. Here, we used self-sustained recurrent activity generated in cortex, also known as up-states, in rat thalamocortical slices in vitro to understand interactions among laminar and horizontal circuits. By means of intracellular recordings and fast optical imaging with voltage-sensitive dyes, we show that single thalamic inputs activate the cortical column in a preferential layer 4 (L4) -> layer 2/3 (L2/3) -> layer 5 (L5) sequence, followed by horizontal propagation with a leading front in supragranular and infragranular layers. To understand the laminar and columnar interactions, we used focal injections of TTX to block activity in small local populations, while preserving functional connectivity in the rest of the network. We show that L2/3 alone, without underlying L5, does not generate self-sustained activity and is inefficient propagating activity horizontally. In contrast, L5 sustains activity in the absence of L2/3 and is necessary and sufficient to propagate activity horizontally. However, loss of L2/3 delays horizontal propagation via L5. Finally, L5 amplifies activity in L2/3. Our results show for the first time that columnar interactions between supragranular and infragranular layers are required for the normal propagation of activity in the neocortex. Our data suggest that supragranular and infragranular circuits, with their specific and complex set of inputs and outputs, work in tandem to determine the patterns of cortical activation observed in vivo. PMID- 22514310 TI - Memory deficits of British dementia knock-in mice are prevented by Abeta precursor protein haploinsufficiency. AB - Familial British Dementia (FBD) is caused by an autosomal dominant mutation in the BRI2/ITM2B gene (Vidal et al., 1999). FBD(KI) mice are a model of FBD that is genetically congruous to the human disease, because they carry one mutant and one wild-type Bri2/Itm2b allele. Analysis of these mice has shown that the British mutation causes memory impairments due to loss of Bri2 function (Tamayev et al., 2010b). BRI2 is a physiologic inhibitor of processing of the Abeta-precursor protein (APP; Matsuda et al., 2008), a gene associated with Alzheimer's disease (Bertram et al., 2010). Here we show that APP haploinsufficiency prevents memory dysfunctions seen in FBD(KI) mice. This genetic suppression is consistent with a role for APP in the pathogenesis of memory deficits. Moreover, it provides compelling evidence that the memory dysfunctions caused by the British BRI2 mutant are dependent on endogenous APP and that BRI2 and APP functionally interact. This evidence establishes a mechanistic connection between Familial British and Alzheimer's dementias. PMID- 22514311 TI - Regulation of NMDA receptor transport: a KIF17-cargo binding/releasing underlies synaptic plasticity and memory in vivo. AB - Regulation of NMDA receptor trafficking is crucial to modulate neuronal communication. Ca(2+)/calmodulin-dependent protein kinase phosphorylates the tail domain of KIF17, a member of the kinesin superfamily, to control NMDA receptor subunit 2B (GluN2B) transport by changing the KIF17-cargo interaction in vitro. However, the mechanisms of regulation of GluN2B transport in vivo and its physiological significance are unknown. We generated transgenic mice carrying wild-type KIF17 (TgS), or KIF17 with S1029A (TgA) or S1029D (TgD) phosphomimic mutations in kif17(-/-) background. TgA/kif17(-/-) and TgD/kif17(-/-) mice exhibited reductions in synaptic NMDA receptors because of their inability to load/unload GluN2B onto/from KIF17, leading to impaired neuronal plasticity, CREB activation, and spatial memory. Expression of GFP-KIF17 in TgS/kif17(-/-) mouse neurons rescued the synaptic and behavioral defects of kif17(-/-) mice. These results suggest that phosphorylation-based regulation of NMDA receptor transport is critical for learning and memory in vivo. PMID- 22514312 TI - Motor deficits are triggered by reperfusion-reoxygenation injury as diagnosed by MRI and by a mechanism involving oxidants. AB - The early antecedents of cerebral palsy (CP) are unknown but are suspected to be due to hypoxia-ischemia (H-I). In our rabbit model of CP, the MRI biomarker, apparent diffusion coefficient (ADC) on diffusion-weighted imaging, predicted which fetuses will develop postnatal hypertonia. Surviving H-I fetuses experience reperfusion-reoxygenation but a subpopulation manifested a continued decline of ADC during early reperfusion-reoxygenation, which possibly represented greater brain injury (RepReOx). We hypothesized that oxidative stress in reperfusion reoxygenation is a critical trigger for postnatal hypertonia. We investigated whether RepReOx predicted postnatal neurobehavior, indicated oxidative stress, and whether targeting antioxidants at RepReOx ameliorated motor deficits, which included testing of a new superoxide dismutase mimic (MnTnHex-2-PyP). Rabbit dams, 79% gestation (E25), were subjected to 40 min uterine ischemia. Fetal brain ADC was followed during H-I, immediate reperfusion-reoxygenation, and 4-72 h after H-I. Endpoints were postnatal neurological outcome at E32, ADC at end of H I, ADC nadir during H-I and reperfusion-reoxygenation, and area under ADC curve during the first 20 min of reperfusion-reoxygenation. Antioxidants targeting RepReOx were administered before and/or after uterine ischemia. The new MRI-ADC biomarker for RepReOx improved prediction of postnatal hypertonia. Greater superoxide production, mitochondrial injury, and oligodendroglial loss occurred in fetal brains exhibiting RepReOx than in those without. The antioxidants, MnTnHex-2-PyP and Ascorbate and Trolox combination, significantly decreased postnatal motor deficits and extent of RepReOx. The etiological link between early injury and later motor deficits can thus be investigated by MRI, and allows us to distinguish between critical oxidative stress that causes motor deficits and noncritical oxidative stress that does not. PMID- 22514313 TI - Parallel coding of first- and second-order stimulus attributes by midbrain electrosensory neurons. AB - Natural stimuli often have time-varying first-order (i.e., mean) and second-order (i.e., variance) attributes that each carry critical information for perception and can vary independently over orders of magnitude. Experiments have shown that sensory systems continuously adapt their responses based on changes in each of these attributes. This adaptation creates ambiguity in the neural code as multiple stimuli may elicit the same neural response. While parallel processing of first- and second-order attributes by separate neural pathways is sufficient to remove this ambiguity, the existence of such pathways and the neural circuits that mediate their emergence have not been uncovered to date. We recorded the responses of midbrain electrosensory neurons in the weakly electric fish Apteronotus leptorhynchus to stimuli with first- and second-order attributes that varied independently in time. We found three distinct groups of midbrain neurons: the first group responded to both first- and second-order attributes, the second group responded selectively to first-order attributes, and the last group responded selectively to second-order attributes. In contrast, all afferent hindbrain neurons responded to both first- and second-order attributes. Using computational analyses, we show how inputs from a heterogeneous population of ON- and OFF-type afferent neurons are combined to give rise to response selectivity to either first- or second-order stimulus attributes in midbrain neurons. Our study thus uncovers, for the first time, generic and widely applicable mechanisms by which parallel processing of first- and second-order stimulus attributes emerges in the brain. PMID- 22514314 TI - Willingness to wait and altered encoding of time-discounted reward in the orbitofrontal cortex with normal aging. AB - Normal aging has been associated with cognitive changes, including shifts in responding for time-discounted rewards. The orbitofrontal cortex, an area previously associated with aging-related cognitive changes, is critical for normal discounting. Previously we have shown in a choice task that rats prefer immediate over delayed reward and that neural representations of delayed reward in orbitofrontal cortex were attenuated, whereas immediate reward elicited strong responses. Changes in choice performance were correlated with changes in firing rate in orbitofrontal neurons, suggesting that these reward representations were critical to the rats' ability to wait for reward. Here we asked whether age dependent changes in discounting behavior were related to changes in the representation of delayed reward in the orbitofrontal cortex. Young (3-6 months) and aged (22-26 months) rats were trained on the same discounting paradigm used previously. We found that aged rats showed less sensitivity to increasing delay preceding reward delivery, shifting behavior away from the delayed reward more slowly than younger rats. This sensitivity was specific to delay, since choice performance did not differ between the two groups when delay was held constant and reward size varied. Aged rats exhibited a corresponding increase in the prevalence of neurons that fired more strongly for delayed reward. Again this change was specific to delay; there was no change in encoding of different-sized rewards. These results suggest that natural aging results in altered representations of reward in orbitofrontal cortex. These changes may relate to the increased ability to delay gratification and reduced impulsivity associated with aging. PMID- 22514315 TI - Mechanisms of action selection and timing in substantia nigra neurons. AB - The timing of actions is critical for adaptive behavior. In this study we measured neural activity in the substantia nigra as mice learned to change their action duration to earn food rewards. We observed dramatic changes in single unit activity during learning: both dopaminergic and GABAergic neurons changed their activity in relation to behavior to reflect the learned instrumental contingency and the action duration. We found the emergence of "action-on" neurons that increased firing for the duration of the lever press and mirror-image "action off" neurons that paused at the same time. This pattern is especially common among GABAergic neurons. The activity of many neurons also reflected confidence about the just completed action and the prospect of reward. Being correlated with the relative duration of the completed action, their activity could predict the likelihood of reward collection. Compared with the GABAergic neurons, the activity of dopaminergic neurons was more commonly modulated by the discriminative stimulus signaling the start of each trial, suggesting that their phasic activity reflected sensory salience rather than any reward prediction error found in previous work. In short, these results suggest that (1) nigral activity is highly plastic and modified by the learning of the instrumental contingency; (2) GABAergic output from the substantia nigra can simultaneously inhibit and disinhibit downstream structures, while the dopaminergic output also provide bidirectional modulation of the corticostriatal circuits; (3) dopaminergic and GABAergic neurons show similar task-related activity, although DA neurons are more responsive to the trial start signal. PMID- 22514316 TI - Individual differences in nucleus accumbens activity to food and sexual images predict weight gain and sexual behavior. AB - Failures of self-regulation are common, leading to many of the most vexing problems facing contemporary society, from overeating and obesity to impulsive sexual behavior and STDs. One reason that people may be prone to engaging in unwanted behaviors is heightened sensitivity to cues related to those behaviors; people may overeat because of hyperresponsiveness to food cues, addicts may relapse following exposure to their drug of choice, and some people might engage in impulsive sexual activity because they are easily aroused by erotic stimuli. An open question is the extent to which individual differences in neural cue reactivity relate to actual behavioral outcomes. Here we show that individual differences in human reward-related brain activity in the nucleus accumbens to food and sexual images predict subsequent weight gain and sexual activity 6 months later. These findings suggest that heightened reward responsivity in the brain to food and sexual cues is associated with indulgence in overeating and sexual activity, respectively, and provide evidence for a common neural mechanism associated with appetitive behaviors. PMID- 22514317 TI - Social-cognitive deficits in normal aging. AB - A sizeable number of studies have implicated the default network (e.g., medial prefrontal and parietal cortices) in tasks that require participants to infer the mental states of others (i.e., to mentalize). Parallel research has demonstrated that default network function declines over the lifespan, suggesting that older adults may show impairments in social-cognitive tasks that require mentalizing. Older and younger human adults were scanned using functional magnetic resonance imaging while performing three different social-cognitive tasks. Across three mentalizing paradigms, younger and older adults viewed animated shapes in brief social vignettes, stories about a person's moral actions, and false belief stories. Consistent with predictions, older adults responded less accurately to stories about others' false beliefs and made less use of actors' intentions to judge the moral permissibility of behavior. These impairments in performance during social-cognitive tasks were accompanied by age-related decreases across all three paradigms in the BOLD response of a single brain region, the dorsomedial prefrontal cortex. These findings suggest specific task-independent age-related deficits in mentalizing that are localizable to changes in circumscribed subregions of the default network. PMID- 22514318 TI - Necdin controls Foxo1 acetylation in hypothalamic arcuate neurons to modulate the thyroid axis. AB - The forkhead transcription factor Foxo1 regulates energy homeostasis by modulating gene expression in the hypothalamus. Foxo1 undergoes post translational modifications such as phosphorylation and acetylation, which modulate its functional activities. Sirtuin1 (Sirt1), a nicotinamide adenine dinucleotide-dependent protein deacetylase, regulates the acetylation status of Foxo1 in mammalian cells. Necdin, a pleiotropic protein required for neuronal development and survival, interacts with both Sirt1 and p53 to facilitate p53 deacetylation. The necdin gene (Ndn), an imprinted gene transcribed only from the paternal allele, is strongly expressed in hypothalamic neurons. Here, we demonstrate that necdin controls the acetylation status of Foxo1 in vivo in hypothalamic arcuate neurons to modulate the thyroid function. Necdin forms a stable ternary complex with Sirt1 and Foxo1, diminishes Foxo1 acetylation, and suppresses the transcriptional activity of Foxo1 in vitro. Paternal Ndn mutant mice express high levels of acetylated Foxo1 and mRNAs encoding agouti-related protein and neuropeptide Y in the hypothalamus in vivo during the juvenile period. The mutant mice exhibit endocrine dysfunction characteristic of hypothalamic hypothyroidism. Chemically induced hyperthyroidism and hypothyroidism lead to hypothalamic responses similar to those under necdin deficient and excessive conditions, respectively, suggesting that thyroid hormone serves as a negative regulator of this system. These results suggest that necdin regulates Foxo1 acetylation and neuropeptide gene expression in the arcuate neurons to modulate the hypothalamic-pituitary-thyroid axis during development. PMID- 22514319 TI - Peroxynitrite donor SIN-1 alters high-affinity choline transporter activity by modifying its intracellular trafficking. AB - Sodium-coupled, high-affinity choline transporters (CHTs) are inhibited by 3 morpholinosydnonimine (SIN-1) [peroxynitrite (ONOO-) donor]; ONOO- can be produced from nitric oxide and reactive oxygen species during neurodegeneration. SIN-1 rapidly increases CHT internalization from the cell surface, and this correlates with decreased choline uptake. This study addresses mechanisms by which SIN-1 inhibits CHT function in human neuronal SH-SY5Y cells. Thus, mutant L531A-CHT, which does not constitutively internalize into cells by a clathrin mediated process, is resistant to SIN-1 effects. This suggests that CHT inhibition is not due to oxidative-nitrosative inactivation of the protein and that decreased levels of cell surface CHT in SIN-1-treated cells is related to alterations in its trafficking and subcellular disposition. Dominant-negative proteins AP180C and dynamin-K44A, which interfere with clathrin-mediated and dynamin-dependent endocytosis, respectively, attenuate CHT inhibition by SIN-1. CHT in both vehicle- and SIN-1-treated cells colocalizes with Rab7, Rab9, and Lamp-1 in late endosomes and lysosomes to a similar extent. Lysosome inhibitors increase choline uptake, suggesting that CHT proteins are normally degraded by lysosomes, and this is not altered by oxidative stress. Unexpectedly, inhibitors of proteasomes, but not lysosomes, attenuate SIN-1-mediated inhibition of choline uptake, indicating that proteasomal degradation plays a role in regulating CHT disposition in SIN-1-treated cells. SIN-1 treatment also enhances CHT ubiquitination. Thus, CHT inhibition in SIN-1-treated cells is mediated by proteasomal degradation, which differs from inhibitory mechanisms for some neurotransmitter transporters under similar conditions. Increased oxidative nitrosative stress in the microenvironment of cholinergic nerve terminals would diminish cholinergic transmission by reducing choline availability for ACh synthesis. PMID- 22514320 TI - Preclinical retinal neurodegeneration in a model of multiple sclerosis. AB - Neurodegeneration plays a major role in multiple sclerosis (MS), in which it is thought to be the main determinant of permanent disability. However, the relationship between the immune response and the onset of neurodegeneration is still a matter of debate. Moreover, recent findings in MS patients raised the question of whether primary neurodegenerative changes can occur in the retina independent of optic nerve inflammation. Using a rat model of MS that frequently leads to optic neuritis, we have investigated the interconnection between neurodegenerative and inflammatory changes in the retina and the optic nerves with special focus on preclinical disease stages. We report that, before manifestation of optic neuritis, characterized by inflammatory infiltration and demyelination of the optic nerve, degeneration of retinal ganglion cell bodies had already begun and ultrastructural signs of axon degeneration could be detected. In addition, we observed an early activation of resident microglia in the retina. In the optic nerve, the highest density of activated microglia was found within the optic nerve head. In parallel, localized breakdown in the integrity of the blood-retinal barrier and aberrations in the organization of the blood-brain barrier marker aquaporin-4 in the optic nerves were observed during the preclinical phase, before onset of optic neuritis. From these findings, we conclude that early and subtle inflammatory changes in the retina and/or the optic nerve head reminiscent of those suggested for preclinical MS lesions may initiate the process of neurodegeneration in the retina before major histopathological signs of MS become manifest. PMID- 22514321 TI - Neural correlates of long-term object memory in the mouse anterior cingulate cortex. AB - Damage to the hippocampal formation results in a profound temporally graded retrograde amnesia, implying that it is necessary for memory acquisition but not its long-term storage. It is therefore thought that memories are transferred from the hippocampus to the cortex for long-term storage in a process called systems consolidation (Dudai and Morris, 2000). Where in the cortex this occurs remains an open question. Recent work (Frankland et al., 2005; Vetere et al., 2011) suggests the anterior cingulate cortex (ACC) as a likely candidate area, but there is little direct electrophysiological evidence to support this claim. Previously, we demonstrated object-associated firing correlates in caudal ACC during tests of recognition memory and described evidence of neuronal responses to where an object had been following a brief delay. However, long-term memory requires evidence of more durable representations. Here we examined the activity of ACC neurons while testing for long-term memory of an absent object. Mice explored two objects in an arena and then were returned 6 h later with one of the objects removed. Mice continued to explore where the object had been, demonstrating memory for that object. Remarkably, some ACC neurons continued to respond where the object had been, while others developed new responses in the absent object's location. The incidence of absent-object responses by ACC neurons was greatly increased with increased familiarization to the objects, and such responses were still evident 1 month later. These data strongly suggest that the ACC contains neural correlates of consolidated object/place association memory. PMID- 22514322 TI - Spatial profile of excitatory and inhibitory synaptic connectivity in mouse primary auditory cortex. AB - The role of local cortical activity in shaping neuronal responses is controversial. Among other questions, it is unknown how the diverse response patterns reported in vivo-lateral inhibition in some cases, approximately balanced excitation and inhibition (co-tuning) in others-compare to the local spread of synaptic connectivity. Excitatory and inhibitory activity might cancel each other out, or, whether one outweighs the other, receptive field properties might be substantially affected. As a step toward addressing this question, we used multiple intracellular recording in mouse primary auditory cortical slices to map synaptic connectivity among excitatory pyramidal cells and the two broad classes of inhibitory cells, fast-spiking (FS) and non-FS cells in the principal input layer. Connection probability was distance-dependent; the spread of connectivity, parameterized by Gaussian fits to the data, was comparable for all cell types, ranging from 85 to 114 MUm. With brief stimulus trains, unitary synapses formed by FS interneurons were stronger than other classes of synapses; synapse strength did not correlate with distance between cells. The physiological data were qualitatively consistent with predictions derived from anatomical reconstruction. We also analyzed the truncation of neuronal processes due to slicing; overall connectivity was reduced but the spatial pattern was unaffected. The comparable spatial patterns of connectivity and relatively strong excitatory inhibitory interconnectivity are consistent with a theoretical model where either lateral inhibition or co-tuning can predominate, depending on the structure of the input. PMID- 22514324 TI - Controlling human striatal cognitive function via the frontal cortex. AB - Cognitive flexibility is known to depend on the striatum. However, the striatum does not act in isolation to bias cognitive flexibility. In particular, cognitive flexibility also implicates the frontal cortex. Here we tested the hypothesis that the human frontal cortex controls cognitive flexibility by regulating striatal function via topographically specific frontostriatal connections. To this end, we exploited a repetitive transcranial magnetic stimulation (TMS) protocol over frontal cortex that is known to increase dopamine release in the striatum. This intervention was combined with functional magnetic resonance imaging to determine the functional and topographic specificity of its consequences at the whole brain level. Participants were scanned both before and after off-line TMS while performing a cognitive switching task that is known to depend on a specific striatal substructure, the putamen. Frontal stimulation perturbed task-specific functional signals in the putamen, while reducing fronto striatal functional connectivity. There were no such effects of TMS over the medial parietal cortex. These data strengthen the hypothesis that cognitive flexibility involves topographic frontal control of striatal function. PMID- 22514325 TI - Neural circuit reconfiguration by social status. AB - The social rank of an animal is distinguished by its behavior relative to others in its community. Although social-status-dependent differences in behavior must arise because of differences in neural function, status-dependent differences in the underlying neural circuitry have only begun to be described. We report that dominant and subordinate crayfish differ in their behavioral orienting response to an unexpected unilateral touch, and that these differences correlate with functional differences in local neural circuits that mediate the responses. The behavioral differences correlate with simultaneously recorded differences in leg depressor muscle EMGs and with differences in the responses of depressor motor neurons recorded in reduced, in vitro preparations from the same animals. The responses of local serotonergic interneurons to unilateral stimuli displayed the same status-dependent differences as the depressor motor neurons. These results indicate that the circuits and their intrinsic serotonergic modulatory components are configured differently according to social status, and that these differences do not depend on a continuous descending signal from higher centers. PMID- 22514323 TI - Regulation of neuronal mRNA translation by CaM-kinase I phosphorylation of eIF4GII. AB - Ca2+/calmodulin-dependent kinases (CaMKs) are essential for neuronal development and plasticity, processes requiring de novo protein synthesis. Roles for CaMKs in modulating gene transcription are well established, but their involvement in mRNA translation is evolving. Here we report that activity-dependent translational initiation in cultured rat hippocampal neurons is enhanced by CaMKI-mediated phosphorylation of Ser1156 in eukaryotic initiation factor eIF4GII (4GII). Treatment with bicuculline or gabazine to enhance neuronal activity promotes recruitment of wild-type 4GII, but not the 4GII S1156A mutant or 4GI, to the heterotrimeric eIF4F (4F) complex that assembles at the 5' cap structure (m7GTP) of mRNA to initiate ribosomal scanning. Recruitment of 4GII to 4F is suppressed by pharmacological inhibition (STO-609) of CaM kinase kinase, the upstream activator of CaMKI. Post hoc in vitro CaMKI phosphorylation assays confirm that activity promotes phosphorylation of S1156 in transfected 4GII in neurons. Changes in cap-dependent and cap-independent translation were assessed using a bicistronic luciferase reporter transfected into neurons. Activity upregulates cap-dependent translation, and RNAi knockdown of CaMKIbeta and gamma isoforms, but not alpha or delta, led to its attenuation as did blockade of NMDA receptors. Furthermore, RNAi knockdown of 4GII attenuates cap-dependent translation and reduces density of dendritic filopodia and spine formation without effect on dendritic arborization. Together, our results provide a mechanistic link between Ca2+ influx due to neuronal activity and regulation of cap-dependent RNA translation via CaMKI activation and selective recruitment of phosphorylated 4GII to the 4F complex, which may function to regulate activity-dependent changes in spine density. PMID- 22514326 TI - Scene construction in amnesia: an FMRI study. AB - In recent years, there has been substantial interest in how the human hippocampus not only supports recollection of past experiences, but also the construction of fictitious and future events, and the leverage this might offer for understanding the operating mechanisms of the hippocampus. Evidence that patients with bilateral hippocampal damage and amnesia cannot construct novel or future scenes/events has been influential in driving this line of research forward. There are, however, some patients with hippocampal damage and amnesia who retain the ability to construct novel scenes. This dissociation may indicate that the hippocampus is not required for scene construction, or alternatively, there could be residual function in remnant hippocampal tissue sufficient to support the basic construction of scenes. Resolving this controversy is central to current theoretical debates about the hippocampus. To investigate, we used fMRI and a scene construction task to test patient P01, who has dense amnesia, ~50% bilateral hippocampal volume loss, and intact scene construction. We found that scene construction in P01 was associated with increased activity in a set of brain areas, including medial temporal, retrosplenial, and posterior parietal cortices, that overlapped considerably with the regions engaged in control participants performing the same task. Most notably, the remnant of P01's right hippocampus exhibited increased activity during scene construction. This suggests that the intact scene construction observed in some hippocampal-damaged amnesic patients may be supported by residual function in their lesioned hippocampus, in accordance with theoretical frameworks that ascribe a vital role to the hippocampus in scene construction. PMID- 22514327 TI - Neurogenic subventricular zone stem/progenitor cells are Notch1-dependent in their active but not quiescent state. AB - The adult mammalian forebrain contains neural stem/progenitor cells (NSCs) that generate neurons throughout life. As in other somatic stem cell systems, NSCs are proposed to be predominantly quiescent and proliferate only sporadically to produce more committed progeny. However, quiescence has recently been shown not to be an essential criterion for stem cells. It is not known whether NSCs show differences in molecular dependence based on their proliferation state. The subventricular zone (SVZ) of the adult mouse brain has a remarkable capacity for repair by activation of NSCs. The molecular interplay controlling adult NSCs during neurogenesis or regeneration is not clear but resolving these interactions is critical in order to understand brain homeostasis and repair. Using conditional genetics and fate mapping, we show that Notch signaling is essential for neurogenesis in the SVZ. By mosaic analysis, we uncovered a surprising difference in Notch dependence between active neurogenic and regenerative NSCs. While both active and regenerative NSCs depend upon canonical Notch signaling, Notch1-deletion results in a selective loss of active NSCs (aNSCs). In sharp contrast, quiescent NSCs (qNSCs) remain after Notch1 ablation until induced during regeneration or aging, whereupon they become Notch1-dependent and fail to fully reinstate neurogenesis. Our results suggest that Notch1 is a key component of the adult SVZ niche, promoting maintenance of aNSCs, and that this function is compensated in qNSCs. Therefore, we confirm the importance of Notch signaling for maintaining NSCs and neurogenesis in the adult SVZ and reveal that NSCs display a selective reliance on Notch1 that may be dictated by mitotic state. PMID- 22514328 TI - Spatiotemporal dynamics of bimanual integration in human somatosensory cortex and their relevance to bimanual object manipulation. AB - Little is known about the spatiotemporal dynamics of cortical responses that integrate slightly asynchronous somatosensory inputs from both hands. This study aimed to clarify the timing and magnitude of interhemispheric interactions during early integration of bimanual somatosensory information in different somatosensory regions and their relevance for bimanual object manipulation and exploration. Using multi-fiber probabilistic diffusion tractography and MEG source analysis of conditioning-test (C-T) median nerve somatosensory evoked fields in healthy human subjects, we sought to extract measures of structural and effective callosal connectivity between different somatosensory cortical regions and correlated them with bimanual tactile task performance. Neuromagnetic responses were found in major somatosensory regions, i.e., primary somatosensory cortex SI, secondary somatosensory cortex SII, posterior parietal cortex, and premotor cortex. Contralateral to the test stimulus, SII activity was maximally suppressed by 51% at C-T intervals of 40 and 60 ms. This interhemispheric inhibition of the contralateral SII source activity correlated directly and topographically specifically with the fractional anisotropy of callosal fibers interconnecting SII. Thus, the putative pathway that mediated inhibitory interhemispheric interactions in SII was a transcallosal route from ipsilateral to contralateral SII. Moreover, interhemispheric inhibition of SII source activity correlated directly with bimanual tactile task performance. These findings were exclusive to SII. Our data suggest that early interhemispheric somatosensory integration primarily occurs in SII, is mediated by callosal fibers that interconnect homologous SII areas, and has behavioral importance for bimanual object manipulation and exploration. PMID- 22514329 TI - An activity-regulated microRNA, miR-188, controls dendritic plasticity and synaptic transmission by downregulating neuropilin-2. AB - MicroRNAs (miRNAs) have recently come to be viewed as critical players that modulate a number of cellular features in various biological systems including the mature CNS by exerting regulatory control over the stability and translation of mRNAs. Despite considerable evidence for the regulatory functions of miRNAs, the identities of the miRNA species that are involved in the regulation of synaptic transmission and plasticity and the mechanisms by which these miRNAs exert functional roles remain largely unknown. In the present study, the expression of microRNA-188 (miR-188) was found to be upregulated by the induction of long-term potentiation (LTP). The protein level of neuropilin-2 (Nrp-2), one of the possible molecular targets for miR-188, was decreased during LTP induction. We also confirmed that the luciferase activity of the 3'-UTR of Nrp-2 was diminished by treatment with a miR-188 oligonucleotide but not with a scrambled miRNA oligonucleotide. Nrp-2 serves as a receptor for semaphorin 3F, which is a negative regulator of spine development and synaptic structure. In addition, miR-188 specifically rescued the reduction in dendritic spine density induced by Nrp-2 expression in hippocampal neurons from rat primary culture. Furthermore, miR-188 counteracted the decrease in the miniature EPSC frequency induced by Nrp-2 expression in hippocampal neurons from rat primary culture. These findings suggest that miR-188 serves to fine-tune synaptic plasticity by regulating Nrp-2 expression. PMID- 22514331 TI - Dimension-specific signal modulation in visual search: evidence from inter stimulus surround suppression. AB - A fundamental task for the visual system is to determine where to attend next. In general, attention is guided by visual saliency. Computational models suggest that saliency values are estimated through an iterative process in which each visual item suppresses each other item's saliency, especially for those with close proximity. To investigate this proposal, we tested the effect of two salient distractors on visual search for a size target. While fixing the target to-distractor distance, we manipulated the distance between two distractors. If two salient distractors suppressed each other when they were close together, they should interfere with search less; this was exactly what we found. However, we observed such a distance effect only for distractors of the same dimension (e.g., both defined in color) but not for those of different dimensions (e.g., one defined in color and the other in shape), displaying specificity to a perceptual dimension. Therefore, we conclude that saliency in visual search is calculated through a surround suppression process that occurs at a dimension-specific level. PMID- 22514330 TI - IkappaB kinase/nuclear factor kappaB-dependent insulin-like growth factor 2 (Igf2) expression regulates synapse formation and spine maturation via Igf2 receptor signaling. AB - Alterations of learning and memory in mice with deregulated neuron-specific nuclear factor kappaB (NF-kappaB) activity support the idea that plastic changes of synaptic contacts may depend at least in part on IkappaB kinase (IKK)/NF kappaB-related synapse-to-nucleus signaling. There is, however, little information on the molecular requirements and mechanisms regulating this IKK/NF kappaB-dependent synapse development and remodeling. Here, we report that the NF kappaB inducing IKK kinase complex is localized at the postsynaptic density (PSD) and activated under basal conditions in the adult mouse brain. Using different models of conditional genetic inactivation of IKK2 function in mouse principal neurons, we show that IKK/NF-kappaB signaling is critically involved in synapse formation and spine maturation in the adult brain. IKK/NF-kappaB blockade in the forebrain of mutant animals is associated with reduced levels of mature spines and postsynaptic proteins PSD95, SAP97, GluA1, AMPAR-mediated basal synaptic transmission and a spatial learning impairment. Synaptic deficits can be restored in adult animals within 1 week by IKK/NF-kappaB reactivation, indicating a highly dynamic IKK/NF-kappaB-dependent regulation process. We further identified the insulin-like growth factor 2 gene (Igf2) as a novel IKK/NF-kappaB target. Exogenous Igf2 was able to restore synapse density and promoted spine maturation in IKK/NF-kappaB signaling-deficient neurons within 24 h. This process depends on Igf2/Igf2R-mediated MEK/ERK activation. Our findings illustrate a fundamental role of IKK/NF-kappaB-Igf2-Igf2R signaling in synapse formation and maturation in adult mice, thus providing an intriguing link between the molecular actions of IKK/NF-kappaB in neurons and the memory enhancement factor Igf2. PMID- 22514332 TI - Spatiotemporal dynamics of perisaccadic remapping in humans revealed by classification images. AB - We actively scan our environment with fast ballistic movements called saccades, which create large and rapid displacements of the image on the retina. At the time of saccades, vision becomes transiently distorted in many ways: Briefly flashed stimuli are displaced in space and in time, and spatial and temporal intervals appear compressed. Here we apply the psychophysical technique of classification images to study the spatiotemporal dynamics of visual mechanisms during saccades. We show that saccades cause gross distortions of the classification images. Before the onset of saccadic eye movements, the positive lobes of the images become enlarged in both space and in time and also shifted in a systematic manner toward the pre-saccadic fixation (in space) and anticipated in time by about 50 ms. The transient reorganization creates a spatiotemporal organization oriented in the direction of saccadic-induced motion at the time of saccades, providing a potential mechanism for integrating stimuli across saccades, facilitating stable and continuous vision in the face of constant eye movements. PMID- 22514335 TI - Cigarette smoking, coffee drinking, and ingestion of charcoal-broiled beef as potential modifiers of drug therapy and confounders of clinical trials. AB - A pathway of research is described, leading from the finding of an inhibitory effect of 3-methylcholanthrene on the carcinogenicity of an aminoazo dye, to the induction of drug-metabolizing enzymes by 3-methylcholanthrene, benzo[a]pyrene, and other polycyclic aromatic hydrocarbons, to the demonstration of enhanced drug metabolism in cigarette smokers, coffee drinkers, and people who eat charcoal broiled beef. The results of these studies indicate that cigarette smoking, coffee drinking, and the ingestion of charcoal-broiled beef (all resulting in exposure to polycyclic aromatic hydrocarbons) can influence the dosing regimen needed for proper drug therapy and are potential confounders of clinical trials with drugs metabolized by polycyclic aromatic hydrocarbon-inducible enzymes. PMID- 22514334 TI - The novel reversible fatty acid amide hydrolase inhibitor ST4070 increases endocannabinoid brain levels and counteracts neuropathic pain in different animal models. AB - The effect of the enol carbamate 1-biphenyl-4-ylethenyl piperidine-1-carboxylate (ST4070), a novel reversible inhibitor of fatty acid amide hydrolase (FAAH), was investigated for acute pain sensitivity and neuropathic pain in rats and mice. Brain enzymatic activity of FAAH and the endogenous levels of its substrates, anandamide (AEA; N-arachidonoylethanolamine), 2-arachidonoylglycerol (2-AG), and N-palmitoylethanolamine (PEA), were measured in control and ST4070-treated mice. ST4070 (10, 30, and 100 mg/kg) was orally administered to assess mechanical nociceptive thresholds and allodynia by using the Randall-Selitto and von Frey tests, respectively. Neuropathy was induced in rats by either the chemotherapeutic agent vincristine or streptozotocin-induced diabetes, whereas the chronic constriction injury (CCI) model was chosen to evaluate neuropathy in mice. ST4070 produced a significant increase of nociceptive threshold in rats and counteracted the decrease of nociceptive threshold in the three distinct models of neuropathic pain. In diabetic mice, ST4070 inhibited FAAH activity and increased the brain levels of AEA and PEA, without affecting that of 2-AG. The administration of ST4070 generated long-lasting pain relief compared with pregabalin and the FAAH inhibitors 1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL135) and cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-ylester (URB597) in CCI neuropathic mice. The antiallodynic effects of ST4070 were prevented by pretreatment with cannabinoid type 1 and cannabinoid type 2 receptor antagonists and by the selective peroxisome proliferator-activated receptor alpha antagonist [(2S)-2-[[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl]amino]-3 [4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-carbamic acid ethyl ester (GW6471). The administration of ST4070 generated long-lasting neuropathic pain relief compared with pregabalin and the FAAH inhibitors OL135 and URB597. Taken together, the reversible FAAH inhibitor ST4070 seems to be a promising novel therapeutic agent for the management of neuropathic pain. PMID- 22514333 TI - Effects of alterations in cannabinoid signaling, alone and in combination with morphine, on pain-elicited and pain-suppressed behavior in mice. AB - Inhibitors of fatty acid amide hydrolase (FAAH) and anandamide (AEA) uptake, which limit the degradation of endogenous cannabinoids, have received interest as potential therapeutics for pain. There is also evidence that endogenous cannabinoids mediate the antinociceptive effects of opioids. Assays of pain elicited and pain-suppressed behavior have been used to differentiate the effects of drugs that specifically alter nociception from drugs that alter nociception caused by nonspecific effects such as catalepsy or a general suppression of activity. Using such procedures, this study examines the effects of the direct cannabinoid type 1 (CB1) agonist (-)-cis-3-[2-hydroxy-4-(1,1 dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940), the FAAH inhibitor cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (URB597), and the AEA uptake inhibitor N-(4-hydroxyphenyl) arachidonylamide (AM404). Additional experiments examined these compounds in combination with morphine. CP55940 produced antinociception in assays of pain-elicited, but not pain-suppressed, behavior and disrupted responding in an assay of schedule-controlled behavior. URB597 and AM404 produced antinociception in assays of pain-elicited and pain suppressed behavior in which acetic acid was the noxious stimulus, but had no effect on the hotplate and schedule-controlled responding. CP55940 in combination with morphine resulted in effects greater than those of morphine alone in assays of pain-elicited and scheduled-controlled behavior but not pain-suppressed behavior. URB597 in combination with morphine resulted in enhanced morphine effects in assays of pain-elicited and pain-suppressed behavior in which diluted acetic acid was the noxious stimulus, but did not alter morphine's effects on the hotplate or schedule-controlled responding. These studies suggest that, compared with direct CB1 agonists, manipulations of endogenous cannabinoid signaling have enhanced clinical potential; however, their effects depend on the type of noxious stimulus. PMID- 22514336 TI - Capsid structure and its stability at the late stages of bacteriophage SPP1 assembly. AB - The structure of the bacteriophage SPP1 capsid was determined at subnanometer resolution by cryo-electron microscopy and single-particle analysis. The icosahedral capsid is composed of the major capsid protein gp13 and the auxiliary protein gp12, which are organized in a T=7 lattice. DNA is arranged in layers with a distance of ~24.5 A. gp12 forms spikes that are anchored at the center of gp13 hexamers. In a gp12-deficient mutant, the centers of hexamers are closed by loops of gp13 coming together to protect the SPP1 genome from the outside environment. The HK97-like fold was used to build a pseudoatomic model of gp13. Its structural organization remains unchanged upon tail binding and following DNA release. gp13 exhibits enhanced thermostability in the DNA-filled capsid. A remarkable convergence between the thermostability of the capsid and those of the other virion components was found, revealing that the overall architecture of the SPP1 infectious particle coevolved toward high robustness. PMID- 22514337 TI - Initial HIV-1 antigen-specific CD8+ T cells in acute HIV-1 infection inhibit transmitted/founder virus replication. AB - CD8-mediated virus inhibition can be detected in HIV-1-positive subjects who naturally control virus replication. Characterizing the inhibitory function of CD8(+) T cells during acute HIV-1 infection (AHI) can elucidate the nature of the CD8(+) responses that can be rapidly elicited and that contribute to virus control. We examined the timing and HIV-1 antigen specificity of antiviral CD8(+) T cells during AHI. Autologous and heterologous CD8(+) T cell antiviral functions were assessed longitudinally during AHI in five donors from the CHAVI 001 cohort using a CD8(+) T cell-mediated virus inhibition assay (CD8 VIA) and transmitted/founder (T/F) viruses. Potent CD8(+) antiviral responses against heterologous T/F viruses appeared during AHI at the first time point sampled in each of the 5 donors (Fiebig stages 1/2 to 5). Inhibition of an autologous T/F virus was durable to 48 weeks; however, inhibition of heterologous responses declined concurrent with the resolution of viremia. HIV-1 viruses from 6 months postinfection were more resistant to CD8(+)-mediated virus inhibition than cognate T/F viruses, demonstrating that the virus escapes early from CD8(+) T cell-mediated inhibition of virus replication. CD8(+) T cell antigen-specific subsets mediated inhibition of T/F virus replication via soluble components, and these soluble responses were stimulated by peptide pools that include epitopes that were shown to drive HIV-1 escape during AHI. These data provide insights into the mechanisms of CD8-mediated virus inhibition and suggest that functional analyses will be important for determining whether similar antigen-specific virus inhibition can be induced by T cell-directed vaccine strategies. PMID- 22514338 TI - Feline tetherin is characterized by a short N-terminal region and is counteracted by the feline immunodeficiency virus envelope glycoprotein. AB - Tetherin (BST2) is the host cell factor that blocks the particle release of some enveloped viruses. Two putative feline tetherin proteins differing at the level of the N-terminal coding region have recently been described and tested for their antiviral activity. By cloning and comparing the two reported feline tetherins (called here cBST2(504) and cBST2*) and generating specific derivative mutants, this study provides evidence that feline tetherin has a shorter intracytoplasmic domain than those of other known homologues. The minimal tetherin promoter was identified and assayed for its ability to drive tetherin expression in an alpha interferon-inducible manner. We also demonstrated that cBST2(504) is able to dimerize, is localized at the cellular membrane, and impairs human immunodeficiency virus type 1 (HIV-1) particle release, regardless of the presence of the Vpu antagonist accessory protein. While cBST2(504) failed to restrict wild-type feline immunodeficiency virus (FIV) egress, FIV mutants, bearing a frameshift at the level of the envelope-encoding region, were potently blocked. The transient expression of the FIV envelope glycoprotein was able to rescue mutant particle release from feline tetherin-positive cells but did not antagonize human BST2 activity. Moreover, cBST2(504) was capable of specifically immunoprecipitating the FIV envelope glycoprotein. Finally, cBST2(504) also exerted its function on HIV-2 ROD10 and on the simian immunodeficiency virus SIVmac239. Taken together, these results show that feline tetherin does indeed have a short N-terminal region and that the FIV envelope glycoprotein is the predominant factor counteracting tetherin restriction. PMID- 22514339 TI - Extensive mutagenesis of the conserved box E motif in duck hepatitis B virus P protein reveals multiple functions in replication and a common structure with the primer grip in HIV-1 reverse transcriptase. AB - Hepadnaviruses, including the pathogenic hepatitis B virus (HBV), replicate their small DNA genomes through protein-primed reverse transcription, mediated by the terminal protein (TP) domain in their P proteins and an RNA stem-loop, epsilon, on the pregenomic RNA (pgRNA). No direct structural data are available for P proteins, but their reverse transcriptase (RT) domains contain motifs that are conserved in all RTs (box A to box G), implying a similar architecture; however, experimental support for this notion is limited. Exploiting assays available for duck HBV (DHBV) but not the HBV P protein, we assessed the functional consequences of numerous mutations in box E, which forms the DNA primer grip in human immunodeficiency virus type 1 (HIV-1) RT. This substructure coordinates primer 3'-end positioning and RT subdomain movements during the polymerization cycle and is a prime target for nonnucleosidic RT inhibitors (NNRTIs) of HIV-1 RT. Box E was indeed critical for DHBV replication, with the mutations affecting the folding, epsilon RNA interactions, and polymerase activity of the P protein in a position- and amino acid side chain-dependent fashion similar to that of HIV 1 RT. Structural similarity to HIV-1 RT was underlined by molecular modeling and was confirmed by the replication activity of chimeric P proteins carrying box E, or even box C to box E, from HIV-1 RT. Hence, box E in the DHBV P protein and likely the HBV P protein forms a primer grip-like structure that may provide a new target for anti-HBV NNRTIs. PMID- 22514340 TI - Elite controllers with low to absent effector CD8+ T cell responses maintain highly functional, broadly directed central memory responses. AB - Analyses of the breadth and specificity of virus-specific CD8(+) T cell responses associated with control of HIV have largely relied on measurement of cytokine secretion by effector T cells. These have resulted in the identification of HIV elite controllers with low or absent responses in which non-T-cell mechanisms of control have been suggested. However, successful control of HIV infection may be associated with central memory T cells, which have not been consistently examined in these individuals. Gag-specific T cells were characterized using a peptide based cultured enzyme-linked immunosorbent spot assay (ELISpot). Peripheral blood mononuclear cells from HIV elite controllers (n = 10), progressors (n = 12), and antiretroviral-treated individuals (n = 9) were cultured with overlapping peptides for 12 days. Specificity was assessed by tetramer staining, functional features of expanded cells were assessed by cytokine secretion, and virus inhibition and phenotypic characteristics were assessed by cell sorting and coculture assays. After peptide stimulation, elite controllers showed a greater number of previously undetectable (new) responses compared to progressors (P = 0.0008). These responses were highly polyfunctional, with 64.5% of responses having 3 to 5 functions. Expandable epitope-specific CD8(+) T cells from elite controllers had strong virus inhibitory capacity and predominantly displayed a central memory phenotype. These data indicate that elite controllers with minimal T cell responses harbor a highly functional, broadly directed central memory T cell population that is capable of suppressing HIV in vitro. Comprehensive examination of this cell population could provide insight into the immune responses associated with successful containment of viremia. PMID- 22514341 TI - Genomic sequences of Australian bluetongue virus prototype serotypes reveal global relationships and possible routes of entry into Australia. AB - Bluetongue virus (BTV) is transmitted by biting midges (Culicoides spp.). It causes disease mainly in sheep and occasionally in cattle and other species. BTV has spread into northern Europe, causing disease in sheep and cattle. The introduction of new serotypes, changes in vector species, and climate change have contributed to these changes. Ten BTV serotypes have been isolated in Australia without apparent associated disease. Simplified methods for preferential isolation of double-stranded RNA (dsRNA) and template preparation enabled high throughput sequencing of the 10 genome segments of all Australian BTV prototype serotypes. Phylogenetic analysis reinforced the Western and Eastern topotypes previously characterized but revealed unique features of several Australian BTVs. Many of the Australian BTV genome segments (Seg-) were closely related, clustering together within the Eastern topotypes. A novel Australian topotype for Seg-5 (NS1) was identified, with taxa spread across several serotypes and over time. Seg-1, -2, -3, -4, -6, -7, -9, and -10 of BTV_2_AUS_2008 were most closely related to the cognate segments of viruses from Taiwan and Asia and not other Australian viruses, supporting the conclusion that BTV_2 entered Australia recently. The Australian BTV_15_AUS_1982 prototype was revealed to be unusual among the Australian BTV isolates, with Seg-3 and -8 distantly related to other BTV sequences from all serotypes. PMID- 22514342 TI - Pellino-1 selectively regulates epithelial cell responses to rhinovirus. AB - Pellino-1 has recently been identified as a regulator of interleukin-1 (IL-1) signaling, but its roles in regulation of responses of human cells to human pathogens are unknown. We investigated the potential roles of Pellino-1 in the airways. We show for the first time that Pellino-1 regulates responses to a human pathogen, rhinovirus minor group serotype 1B (RV-1B). Knockdown of Pellino-1 by small interfering RNA (siRNA) was associated with impaired production of innate immune cytokines such as CXCL8 from human primary bronchial epithelial cells in response to RV-1B, without impairment in production of antiviral interferons (IFN), and without loss of control of viral replication. Pellino-1 actions were likely to be independent of interleukin-1 receptor-associated kinase-1 (IRAK-1) regulation, since Pellino-1 knockdown in primary epithelial cells did not alter responses to IL-1 but did inhibit responses to poly(I.C), a Toll-like receptor 3 (TLR3) activator that does not signal via IRAK-1 to engender a response. These data indicate that Pellino-1 represents a novel target that regulates responses of human airways to human viral pathogens, independently of IRAK signaling. Neutralization of Pellino-1 may therefore provide opportunities to inhibit potentially harmful neutrophilic inflammation of the airways induced by respiratory viruses, without loss of control of the underlying viral infection. PMID- 22514343 TI - Aptamer that binds to the gD protein of herpes simplex virus 1 and efficiently inhibits viral entry. AB - The ectodomain of the gD protein of herpes simplex viruses (HSVs) plays an important role in viral entry by binding to specific cellular coreceptors and mediating viral entry to the host cells. In the present study, we isolated RNA aptamers (aptamer-1 and aptamer-5) that specifically bind to the gD protein of HSV-1 with high affinity and are able to discriminate the gD protein of a different virus, HSV-2. Aptamer-1 efficiently interfered with the interaction between the gD protein and the HSV-1 target cell receptor (HVEM) in a dose dependent manner. The 50% effective concentration (EC(50)) of aptamer-1 was estimated to be in the nanomolar range (60 nM). Furthermore, aptamer-1 was analyzed for anti-HSV-1 activity by using plaque assays, and it efficiently inhibited viral entry with an estimated K(i) of 0.8 MUM. To expand the future applications of aptamer-1, a shorter variant was designed by using both mapping and boundary analyses, resulting in the mini-1 aptamer (44-mer). Compared to the full-length aptamer, mini-1 had at least as high an affinity, specificity, and ability to interfere with gD-HVEM interactions. These studies suggest that the mini-1 aptamer could be explored further as an anti-HSV-1 topical therapy designed to prevent the risk of acquiring HSV-1 infection through physical contact. PMID- 22514344 TI - Glycoprotein B of herpes simplex virus 2 has more than one intracellular conformation and is altered by low pH. AB - The crystal structure of herpes simplex virus (HSV) gB identifies it as a class III fusion protein, and comparison with other such proteins suggests this is the postfusion rather than prefusion conformation, although this is not proven. Other class III proteins undergo a pH-dependent switch between pre- and postfusion conformations, and a low pH requirement for HSV entry into some cell types suggests that this may also be true for gB. Both gB and gH undergo structural changes at low pH, but there is debate about the extent and significance of the changes in gB, possibly due to the use of different soluble forms of the protein and different assays for antigenic changes. In this study, a complementary approach was taken, examining the conformations of full-length intracellular gB by quantitative confocal microscopy with a panel of 26 antibodies. Three conformations were distinguished, and low pH was found to be a major influence. Comparison with previous studies indicates that the intracellular conformation in low-pH environments may be the same as that of the soluble form known as s-gB at low pH. Interestingly, the antibodies whose binding was most affected by low pH both have neutralizing activity and consequently must block either the function of a neutral pH conformation or its switch from an inactive form to an activated form. If one of the intracellular conformations is the fusion-active form, another factor required for fusion is presumably absent from wherever that conformation is present in infected cells so that inappropriate fusion is avoided. PMID- 22514345 TI - The ubiquitin-specific protease USP7 modulates the replication of Kaposi's sarcoma-associated herpesvirus latent episomal DNA. AB - Kaposi's sarcoma herpesvirus (KSHV) belongs to the gamma-2 Herpesviridae and is associated with three neoplastic disorders: Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). The viral latency-associated nuclear antigen 1 (LANA) is expressed in all latently KSHV infected cells and is involved in viral latent replication and maintenance of the viral genome. We show that LANA interacts with the ubiquitin-specific protease USP7 through its N-terminal TRAF (tumor necrosis factor [TNF] receptor-associated factor) domain. This interaction involves a short sequence (amino acids [aa] 971 to 986) within the C-terminal domain of LANA with strong similarities to the USP7 binding site of the Epstein-Barr virus (EBV) EBNA-1 protein. A LANA mutant with a deletion of the identified USP7 binding site showed an enhanced ability to replicate a plasmid containing the KSHV latent origin of replication but was comparable to the wild-type LANA (LANA WT) with regard to the regulation of viral and cellular promoters. Furthermore, the LANA homologues of two other gamma-2 herpesviruses, MHV68 and RRV, also recruit USP7. Our findings suggest that recruitment of USP7 to LANA could play a role in the regulation of viral latent replication. The recruitment of USP7, and its role in herpesvirus latent replication, previously described for the latent EBNA-1 protein of the gamma-1 herpesvirus (lymphocryptovirus) EBV (M. N. Holowaty et al., J. Biol. Chem. 278:29987-29994, 2003), may thereby be a conserved feature among gammaherpesvirus latent origin binding proteins. PMID- 22514346 TI - TP-RT domain interactions of duck hepatitis B virus reverse transcriptase in cis and in trans during protein-primed initiation of DNA synthesis in vitro. AB - The hepadnavirus reverse transcriptase (RT) has the unique ability to initiate viral DNA synthesis using RT itself as a protein primer. Protein priming requires complex interactions between the N-terminal TP (terminal protein) domain, where the primer (a specific Y residue) resides, and the central RT domain, which harbors the polymerase active site. While it normally utilizes the cis-linked TP to prime DNA synthesis (cis-priming), we found that the duck hepatitis B virus (DHBV) RT domain, in the context of the full-length RT protein or a mini-RT construct containing only truncated TP and RT domains, could additionally use a separate TP or RT domain in trans as a primer (trans-priming). trans interaction could also be demonstrated by the inhibitory effect (trans-inhibition) on cis priming by TP and RT domain sequences provided in trans. Protein priming was further shown to induce RT conformational changes that resulted in TP-RT domain dissociation, altered priming site selection, and a gain of sensitivity to a pyrophosphate analog inhibitor. trans-priming, trans-inhibition, and trans complementation, which requires separate TP and RT domains to reconstitute a functional RT protein, were employed to define the sequences in the TP and RT domains that could mediate physical or functional inter- and intradomain interactions. These results provide new insights into TP-RT domain interactions and conformational dynamics during protein priming and suggest novel means to inhibit protein priming by targeting these interactions and the associated conformational transitions. PMID- 22514347 TI - Differential impact of interferon regulatory factor 7 in initiation of the type I interferon response in the lymphocytic choriomeningitis virus-infected central nervous system versus the periphery. AB - Interferon (IFN) regulatory factors (IRFs) are a family of transcription factors involved in regulating type I IFN genes and other genes participating in the early antiviral host response. To better understand the mechanisms involved in virus-induced central nervous system (CNS) inflammation, we studied the influence of IRF1, -3, -7, and -9 on the transcriptional activity of key genes encoding antiviral host factors in the CNS of mice infected with lymphocytic choriomeningitis virus (LCMV). A key finding is that neither IRF3 nor IRF7 is absolutely required for induction of a type I IFN response in the LCMV-infected CNS, whereas concurrent elimination of both factors markedly reduces the virus induced host response. This is unlike the situation in the periphery, where deficiency of IRF7 almost eliminates the LCMV-induced production of the type I IFNs. This difference is seemingly related to the local environment, as peripheral production of type I IFNs is severely reduced in intracerebrally (i.c.) infected IRF7-deficient mice, which undergo a combined infection of the CNS and peripheral organs, such as spleen and lymph nodes. Interestingly, despite the redundancy of IRF7 in initiating the type I IFN response in the CNS, the response is not abolished in IFN-beta-deficient mice, as might have been expected. Collectively, these data demonstrate that the early type I IFN response to LCMV infection in the CNS is controlled by a concerted action of IRF3 and -7. Consequently this work provides strong evidence for differential regulation of the type I IFN response in the CNS versus the periphery during viral infection. PMID- 22514348 TI - Epstein-Barr virus latent membrane protein 2A promotes invasion of nasopharyngeal carcinoma cells through ERK/Fra-1-mediated induction of matrix metalloproteinase 9. AB - Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is highly metastatic, and this malignant feature may be promoted by an EBV oncoprotein, latent membrane protein 2A (LMP2A). Acting as a signal regulator, LMP2A can enhance invasiveness and motility of epithelial cells. Downstream from the LMP2A triggered signaling events, it is largely unknown what key effector proteins are induced and essentially promote cell invasion. In the present study, we found that in NPC cells, LMP2A upregulated matrix metalloproteinase 9 (MMP9), a metastasis-associated protease. LMP2A increased MMP9 expression at both the mRNA and protein levels. It also activated the MMP9 promoter, in which two AP-1 elements were required for the promoter activation. Among AP-1 transcription factors, Fra-1 was induced by LMP2A and is essential for LMP2A-triggered MMP9 expression. Induction of Fra-1 was dependent on the LMP2A-activated ERK1/2 pathway, and induction of the ERK1/2-Fra-1-MMP9 axis required PY motifs in the amino-terminal domain of LMP2A. Notably, LMP2A-promoted invasion of NPC cells was blocked when MMP9 expression, Fra-1 induction, or ERK1/2 activation was inhibited. In addition, we found an association of LMP2A with MMP9 expression in NPC tumor biopsy specimens, where Fra-1 was a major mediation factor. This study reveals an underlying mechanism of LMP2A-induced cell invasion, from signal transduction to upregulation of a critical protease. Considering that MMP9 can also be upregulated by another EBV oncoprotein, LMP1, this protease may be a pivotal effector at which the EBV-induced, invasion-promoting mechanisms converge, serving as an attractive therapeutic target for NPC treatment. PMID- 22514349 TI - Structural analysis of coxsackievirus A7 reveals conformational changes associated with uncoating. AB - Coxsackievirus A7 (CAV7) is a rarely detected and poorly characterized serotype of the Enterovirus species Human enterovirus A (HEV-A) within the Picornaviridae family. The CAV7-USSR strain has caused polio-like epidemics and was originally thought to represent the fourth poliovirus type, but later evidence linked this strain to the CAV7-Parker prototype. Another isolate, CAV7-275/58, was also serologically similar to Parker but was noninfectious in a mouse model. Sequencing of the genomic region encoding the capsid proteins of the USSR and 275/58 strains and subsequent comparison with the corresponding amino acid sequences of the Parker strain revealed that the Parker and USSR strains are nearly identical, while the 275/58 strain is more distant. Using electron cryomicroscopy and three-dimensional image reconstruction, the structures of the CAV7-USSR virion and empty capsid were resolved to 8.2-A and 6.1-A resolutions, respectively. This is one of the first detailed structural analyses of the HEV-A species. Using homology modeling, reconstruction segmentation, and flexible fitting, we constructed a pseudoatomic T = 1 (pseudo T = 3) model incorporating the three major capsid proteins (VP1 to VP3), addressed the conformational changes of the capsid and its constituent viral proteins occurring during RNA release, and mapped the capsid proteins' variable regions to the structure. During uncoating, VP4 and RNA are released analogously to poliovirus 1, the interfaces of VP2 and VP3 are rearranged, and VP1 rotates. Variable regions in the capsid proteins were predicted to map mainly to the surface of VP1 and are thus likely to affect the tropism and pathogenicity of CAV7. PMID- 22514350 TI - Identification of the galactose binding domain of the adeno-associated virus serotype 9 capsid. AB - Adeno-associated virus serotype 9 (AAV9) vectors show promise for gene therapy of a variety of diseases due to their ability to transduce multiple tissues, including heart, skeletal muscle, and the alveolar epithelium of the lung. In addition, AAV9 is unique compared to other AAV serotypes in that it is capable of surpassing the blood-brain barrier and transducing neurons in the brain and spinal cord. It has recently been shown that AAV9 uses galactose as a receptor to transduce many different cell types in vitro, as well as cells of the mouse airway in vivo. In this study, we sought to identify the specific amino acids of the AAV9 capsid necessary for binding to galactose. By site-directed mutagenesis and cell binding assays, plus computational ligand docking studies, we discovered five amino acids, including N470, D271, N272, Y446, and W503, which are required for galactose binding that form a pocket at the base of the protrusions around the icosahedral 3-fold axes of symmetry. The importance of these amino acids for tissue tropism was also confirmed by in vivo studies in the mouse lung. Identifying the interactions necessary for AAV9 binding to galactose may lead to advances in vector engineering. PMID- 22514351 TI - Mutations in the GM1 binding site of simian virus 40 VP1 alter receptor usage and cell tropism. AB - Polyomaviruses are nonenveloped viruses with capsids composed primarily of 72 pentamers of the viral VP1 protein, which forms the outer shell of the capsid and binds to cell surface oligosaccharide receptors. Highly conserved VP1 proteins from closely related polyomaviruses recognize different oligosaccharides. To determine whether amino acid changes restricted to the oligosaccharide binding site are sufficient to determine receptor specificity and how changes in receptor usage affect tropism, we studied the primate polyomavirus simian virus 40 (SV40), which uses the ganglioside GM1 as a receptor that mediates cell binding and entry. Here, we used two sequential genetic screens to isolate and characterize viable SV40 mutants with mutations in the VP1 GM1 binding site. Two of these mutants were completely resistant to GM1 neutralization, were no longer stimulated by incorporation of GM1 into cell membranes, and were unable to bind to GM1 on the cell surface. In addition, these mutant viruses displayed an infection defect in monkey cells with high levels of cell surface GM1. Interestingly, one mutant infected cells with low cell surface GM1 more efficiently than wild-type virus, apparently by utilizing a different ganglioside receptor. Our results indicate that a small number of mutations in the GM1 binding site are sufficient to alter ganglioside usage and change tropism, and they suggest that VP1 divergence is driven primarily by a requirement to accommodate specific receptors. In addition, our results suggest that GM1 binding is required for vacuole formation in permissive monkey CV-1 cells. Further study of these mutants will provide new insight into polyomavirus entry, pathogenesis, and evolution. PMID- 22514352 TI - Evasion of the innate immune response: the Old World alphavirus nsP2 protein induces rapid degradation of Rpb1, a catalytic subunit of RNA polymerase II. AB - The Old World alphaviruses are emerging human pathogens with an ability to cause widespread epidemics. The latest epidemic of Chikungunya virus, from 2005 to 2007, affected over 40 countries in Africa, Asia, and Europe. The Old World alphaviruses are highly cytopathic and known to evade the cellular antiviral response by inducing global inhibition of transcription in vertebrate cells. This function was shown to be mediated by their nonstructural nsP2 protein; however, the detailed mechanism of this phenomenon has remained unknown. Here, we report that nsP2 proteins of Sindbis, Semliki Forest, and Chikungunya viruses inhibit cellular transcription by inducing rapid degradation of Rpb1, a catalytic subunit of the RNAPII complex. This degradation of Rpb1 is independent of the nsP2 associated protease activity, but, instead, it proceeds through nsP2-mediated Rpb1 ubiquitination. This function of nsP2 depends on the integrity of the helicase and S-adenosylmethionine (SAM)-dependent methyltransferase-like domains, and point mutations in either of these domains abolish Rpb1 degradation. We go on to show that complete degradation of Rpb1 in alphavirus-infected cells occurs within 6 h postinfection, before other previously described virus-induced changes in cell physiology, such as apoptosis, autophagy, and inhibition of STAT1 phosphorylation, are detected. Since Rpb1 is a subunit that catalyzes the polymerase reaction during RNA transcription, degradation of Rpb1 plays an indispensable role in blocking the activation of cellular genes and downregulating cellular antiviral response. This indicates that the nsP2-induced degradation of Rpb1 is a critical mechanism utilized by the Old World alphaviruses to subvert the cellular antiviral response. PMID- 22514353 TI - Profound amplification of pathogenic murine polytropic retrovirus release from coinfected cells. AB - Previous studies indicate that mice infected with mixtures of mouse retroviruses (murine leukemia viruses [MuLVs]) exhibit dramatically altered pathology compared to mice infected with individual viruses of the mixture. Coinoculation of the ecotropic virus Friend MuLV (F-MuLV) with Fr98, a polytropic MuLV, induced a rapidly fatal neurological disease that was not observed in infections with either virus alone. The polytropic virus load in coinoculated mice was markedly enhanced, while the ecotropic F-MuLV load was unchanged. Furthermore, pseudotyping of the polytropic MuLV genome within ecotropic virions was nearly complete in coinoculated mice. In an effort to better understand these phenomena, we examined mixed retrovirus infections by utilizing in vitro cell lines. Similar to in vivo mixed infections, the polytropic MuLV genome was extensively pseudotyped within ecotropic virions; polytropic virus release was profoundly elevated in coinfected cells, and the ecotropic virus release was unchanged. A reduced level of polytropic SU protein on the surfaces of coinfected cells was observed and correlated with a reduced level of nonpseudotyped polytropic virion release. Marked amplification and pseudotyping of the polytropic MuLV were also observed in mixed Fr98-F-MuLV infections of cell lines derived from the central nervous system (CNS), the target for Fr98 pathogenesis. Additional experiments indicated that pseudotyping contributed to the elevated polytropic virus titer by increasing the efficiency of packaging and release of the polytropic genomes within ecotropic virions. Mixed infections are the rule rather than the exception in retroviral infection, and the ability to examine them in vitro should facilitate a more thorough understanding of retroviral interactions in general. PMID- 22514354 TI - Modulation of the myxoma virus plaque phenotype by vaccinia virus protein F11. AB - Vaccinia virus (VACV) produces large plaques consisting of a rapidly expanding ring of infected cells surrounding a lytic core, whereas myxoma virus (MYXV) produces small plaques that resemble a focus of transformed cells. This is odd, because bioinformatics suggests that MYXV carries homologs of nearly all of the genes regulating Orthopoxvirus attachment, entry, and exit. So why does MYXV produce foci? One notable difference is that MYXV-infected cells produce few of the actin microfilaments that promote VACV exit and spread. This suggested that although MYXV carries homologs of the required genes (A33R, A34R, A36R, and B5R), they are dysfunctional. To test this, we produced MYXV recombinants expressing these genes, but we could not enhance actin projectile formation even in cells expressing all four VACV proteins. Another notable difference between these viruses is that MYXV lacks a homolog of the F11L gene. F11 inhibits the RhoA-mDia signaling that maintains the integrity of the cortical actin layer. We constructed an MYXV strain encoding F11L and observed that, unlike wild-type MYXV, the recombinant virus disrupted actin stress fibers and produced plaques up to 4-fold larger than those of controls, and these plaques expanded ~6-fold faster. These viruses also grew to higher titers in multistep growth conditions, produced higher levels of actin projectiles, and promoted infected cell movement, although neither process was to the extent of that observed in VACV-infected cells. Thus, one reason for why MYXV produces small plaques is that it cannot spread via actin filaments, although the reason for this deficiency remains obscure. A second reason is that leporipoxviruses lack vaccinia's capacity to disrupt cortical actin. PMID- 22514355 TI - The Interactions Between Rapeseed Lipoxygenase and Native Polyphenolic Compounds in a Model System. AB - The focus of the present research was to study inhibition of lipoxygenase activity by rapeseed native polyphenols and the interactions between those compounds and the enzyme. The enzyme and polyphenolic compounds (polyphenols, phenolic acids) were extracted from rapeseed (Brassica napus) varieties Aviso and PR45DO3. The total phenolic compounds concentration in tested rapeseed was 1,485 1,691 mg/100 g d.m. (dry matter) and the free phenolic acids content in both rapeseed varieties was about 76 MUg/100 g d.m. The isolated proteins showed lipoxygenase activity. Prooxidant properties of phenolic compounds in the presence of lipoxygenase and linoleic acid were observed rather in the case of extracts containing a relatively high concentration of miscellaneous polyphenols. Antioxidant properties were recorded in the case of phenolic acid extracts which contain only 1.4-1.9% of phenolics present in raw phenolic extracts. We propose that the prooxidant effect of phenolic compounds comes from quinone and oxidized polyphenols formation. The observed antioxidant activity of phenolic acid extracts is probably due to their ability to scavenge free radicals formed from linoleic acid. However, reduction of lipoxygenase ferric to ferrous ions, which prevent the activation of the enzyme and inhibited its activity, was also observed. PMID- 22514356 TI - Uncovering the fruit bat bushmeat commodity chain and the true extent of fruit bat hunting in Ghana, West Africa. AB - Harvesting, consumption and trade of bushmeat are important causes of both biodiversity loss and potential zoonotic disease emergence. In order to identify possible ways to mitigate these threats, it is essential to improve our understanding of the mechanisms by which bushmeat gets from the site of capture to the consumer's table. In this paper we highlight the previously unrecognized scale of hunting of the African straw-colored fruit bat, Eidolon helvum, a species which is important in both ecological and public health contexts, and describe the commodity chain in southern Ghana for its trade. Based on interviews with 551 Ghanaians, including bat hunters, vendors and consumers, we estimate that a minimum of 128,000 E. helvum bats are sold each year through a commodity chain stretching up to 400 km and involving multiple vendors. Unlike the general bushmeat trade in Ghana, where animals are sold in both specialized bushmeat markets and in restaurants, E. helvum is sold primarily in marketplaces; many bats are also kept by hunters for personal consumption. The offtake estimated in this paper raises serious conservation concerns, while the commodity chain identified in this study may offer possible points for management intervention. The separation of the E. helvum commodity chain from that of other bushmeat highlights the need for species-specific research in this area, particularly for bats, whose status as bushmeat is largely unknown. PMID- 22514358 TI - Characterizations of ordered semigroups in terms of (?, ? ?q)-fuzzy interior ideals. AB - In this paper, we give characterizations of ordered semigroups in terms of (?, ? ?q)-fuzzy interior ideals. We characterize different classes regular (resp. intra regular, simple and semisimple) ordered semigroups in terms of (?, ? ?q)-fuzzy interior ideals (resp. (?, ? ?q)-fuzzy ideals). In this regard, we prove that in regular (resp. intra-regular and semisimple) ordered semigroups the concept of (?, ? ?q)-fuzzy ideals and (?, ? ?q)-fuzzy interior ideals coincide. We prove that an ordered semigroup S is simple if and only if it is (?, ? ?q)-fuzzy simple. We characterize intra-regular (resp. semisimple) ordered semigroups in terms of (?, ? ?q)-fuzzy ideals (resp. (?, ? ?q)-fuzzy interior ideals). Finally, we consider the concept of implication-based fuzzy interior ideals in an ordered semigroup, in particular, the implication operators in Lukasiewicz system of continuous-valued logic are discussed. PMID- 22514357 TI - The Effect of an Executive Functioning Training Program on Working Memory Capacity and Intrusive Thoughts. AB - Recurrent intrusive thoughts are apparent across numerous clinical disorders, including depression (i.e., rumination) and anxiety disorders (e.g., worry, obsessions; Brewin et al. 2010). Theoretical accounts of intrusive thoughts suggest that individual differences in executive functioning, specifically poor inhibitory control, may account for the persistence of these thoughts in some individuals (e.g., Anderson and Levy 2009). The present study examined the causal effect of inhibitory control on intrusive thoughts by experimentally manipulating inhibition requirements in a working memory capacity (WMC) task and evaluating the effect of this training on intrusive thoughts during a thought suppression task. Unselected undergraduate participants were randomly assigned to repeatedly practice a task requiring either high inhibitory control (training condition) or low inhibitory control (control condition). Results indicated that individuals in the training condition demonstrated significantly greater WMC performance improvements from pre to post assessment relative to the control group. Moreover, individuals in the training group experienced fewer intrusions during a thought suppression task. These results provide support for theoretical accounts positing a relationship between inhibitory control and intrusive thoughts. Moreover, improving inhibitory control through computerized training programs may have clinical utility in disorders characterized by recurrent intrusive thoughts (e.g., depression, PTSD). PMID- 22514360 TI - Using 3-D dense packing models to predict surface tension change due to protein adsorption. AB - Protein adsorption modeling primarily focuses on the role of the complexities and differences in the role of the protein constituents. However, experimental evidence suggests that adsorption of human blood-borne protein molecules of widely varying size and purpose is more similar than different. A model, which treats proteins as hard, non-interacting spheres, explains the observed regularity of human blood borne protein adsorption as a result of the dominant role of the solvent in the adsorption process. Here we independently evaluate the efficacy of this model, and adjust the model to a dependence on molecular volume as opposed to molecular weight. In addition, we explore the role of adsorption induced conformation or orientation changes, and demonstrate that volume invariant changes are well represented by this model and changes that include changes in the molecular volume are not. By focusing on molecular volume, the model can be applied to non-spherical molecules such as fibrinogen and accurately captures differences between BSA, multi-layer, and HSA, monolayer, adsorption. These findings confirm the importance of the solvent in protein adsorption, elucidate the importance of molecular volume on surface tension change, and suggest that this model is generally applicable. PMID- 22514361 TI - A Model of Community-Based Behavioral Intervention for Depression in Diabetes: Program ACTIVE. AB - Depression affects one in four people with diabetes and significantly affects diabetes health. Earlier studies of the treatment of depression have documented that cognitive behavioral therapy (CBT) and exercise have each been found to be effective in treating depression in people with and without diabetes in the context of medical settings. Individuals in rural areas lack regular access to medical centers and require treatment options that may be adapted for local communities. To date, no studies have combined CBT and exercise for people with diabetes. This article presents a translational behavioral depression intervention study designed for individuals with type 2 diabetes in a rural Appalachian region as a model of an interdisciplinary approach to the treatment of depression in diabetes. PMID- 22514362 TI - Risk of acquiring cytomegalovirus infection while working in out-of-home child care centres. PMID- 22514363 TI - Recent developments in genital herpes. PMID- 22514364 TI - Initial therapy of bacterial meningitis with cefuroxime: Experience in 167 children. AB - The morbidity and mortality of patients with bacterial meningitis treated initially with cefuroxime were studied and compared with the results of a previous prospective study of patients treated initially with ampicillin plus chloramphenicol in the same institution from 1979 to 1983. A retrospective chart review was completed in all cases of microbiologically confirmed bacterial meningitis admitted to the Hospital for Sick Children in Toronto, Ontario between January 1, 1984 and August 1, 1988. During this period all patients were treated initially with intravenous cefuroxime. The 167 children reviewed ranged in age from six weeks to 17.1 years (median 11.6 months). The case fatality rate was 7.8% and the rate of hearing deficit 13%. There were no statistically significant differences in abnormal neurological outcome (20 versus 20%, respectively), hearing loss (12.9 versus 13%, respectively), and case fatality rate (6.4 versus 7.8%, respectively) between the cohort of 1979-83 and the present study. The rate of hearing loss following meningitis caused by Haemophilus influenzae type b increased from 7.3 to 11.7% (P=0.26). PMID- 22514365 TI - Evaluation of a Candida antigen detection method (Cand-Tec): Experience from a university teaching hospital. AB - The usefulness of a rapid latex agglutination method for the detection of Candida antigen (Cand-Tec; Ramco Laboratories. Texas) was retrospectively assessed in a university teaching hospital over a one year period. Patients were enrolled when the managing physician requested Cand-Tec testing for confirmation of possible invasive candidal infection. The majority of patients were critically ill; 56% were in the intensive care unit, and 30% subsequently died. Analyses were available from 79 patients and 125 samples. Thirty-three patients were diagnosed as having either definite invasive candidiasis or a high probability of infection based upon clinical, microbiological and tissue criteria. The sensitivity and specificity of Candida antigen detection was determined for doubling titres >=1:4 to >=1:16. If a titre of >=1:4 was used as the diagnostic cut-off level for definite candidal infection, overall sensitivity and specificity were 77% and 69%, respectively, while the positive predictive value was 48%, and the negative predictive value 89%. When patients with a high probability of invasive candidal infection were included in analyses for a cut-off titre of >=1:4, overall sensitivity and specificity were 70% and 69%, respectively, while the positive predictive value was 68%, and the negative predictive value 71%. The usefulness of the Cand-Tec test was not improved further for any subgroup of patients (including those in the intensive care unit), nor by following serial titres in individual patients. In this experience, the Cand-Tec test did not add enough information to include definitively or exclude invasive candidiasis in this high risk general patient population. PMID- 22514366 TI - Comparative activity of daptomycin and teicoplanin against enterococci isolated from blood and urine. AB - The authors compared the activity of daptomycin with that of ampicillin, penicillin, teicoplanin and vancomycin against 304 strains of Enterococcus species isolated from blood and urine. Daptomycin was as active as penicillin against Enterococcus faecalis: 90% of strains were inhibited by 2 mg/L. Daptomycin was more active than vancomycin (90% minimal inhibitory concentration [MIC(90)] 2 mg/L; 90% minimal bactericidal concentration [MBC(90)] 8 mg/L) but was less active than teicoplanin (MIC(50) 0.25; MBC(90) 8 mg/L) or ampicillin (MIC(90) 1 mg/L; MBC(90) 2 mg/L) against E faecalis. In time-kill studies daptomycin was not more rapidly bactericidal than ampicillin or penicillin but was significantly more rapidly bactericidal than either teicoplanin or vancomycin. In combination with gentamicin, daptomycin has activity similar to that of penicillin, vancomycin and teicoplanin. Daptomycin may be a suitable alternative to penicillin in patients allergic to penicillins or for the treatment of enterococcal infections caused by beta-lactamase-producing enterococci. PMID- 22514367 TI - Seroprevalence of antibodies against human herpesvirus 6 in the Quebec City area. AB - Seroprevalence of antibodies against human herpesvirus 6 was determined in a sample of 303 randomly selected individuals from the Quebec City area. The influence of different variables on antibody litres was also evaluated. Human herpesvirus 6 was grown in the HSB-2 cell line, and antibody litres were measured by indirect immunofluorescence. Serum samples were collected from 177 females and 126 males ranging in age from two months to 88 years. Ninety-nine per cent (300 of 303) of this population had an antibody titre of at least 1:10, whereas 75% had a titre of at least 1:80. Women had a higher geometric mean litre than men (P=0.06). This difference between sexes varied according to age and became statistically significant in subjects older than 20 years of age (P=0.04). It was found that this difference was attributable to higher antibody litres in women in the 15 to 40 year age group who had previously had children. PMID- 22514368 TI - Bacteremic pneumonia caused by penicillin-resistant pneumococci: Case report and review with a Canadian perspective. AB - A Canadian adult with bacteremic pneumonia caused by a relatively penicillin resistant (minimal inhibitory concentration 0.25 MUg/mL) Streptococcus pneumoniae is reported, and the published literature regarding penicillin-resistant pneumococci in Canada reviewed. Although penicillin resistance has been reported infrequently to date, this case emphasizes the need for routine antimicrobial sensitivity testing of all pneumococci isolated from normally sterile sites, and for ongoing systematic surveillance for penicillin and other antibiotic resistance in Canada. PMID- 22514369 TI - Molecular epidemiological characterization of respiratory isolates of Moraxella catarrhalis in a pediatric intensive care unit. AB - A perceived increase in the number of isolates of Moraxella catarrhalis from the respiratory secretions of patients intubated in the pediatric intensive care unit prompted a review of the clinical profiles of such patients and restriction enzyme analysis of the strains involved. Over two months, of 192 patients admitted to the unit, 154 were intubated. Of the 46 for whom endotracheal tube specimens were submitted to the laboratory, M catarrhalis was isolated in 12. M catarrhalis was not felt to be a significant respiratory pathogen by the attending medical staff in any of the patients from whom it was isolated. In only two patients (17%) could nosocomial acquisition be firmly invoked. Restriction enzyme analysis of the 12 strains ruled out the presence of an epidemic strain. Isolation of M catarrhalis from intubated children does not necessarily imply pathogenicity nor an outbreak situation. PMID- 22514371 TI - National microbiological surveillance of the susceptibility of gonococcal isolates to antimicrobial agents. PMID- 22514370 TI - Subinhibitory antimicrobial concentrations: A review of in vitro and in vivo data. AB - Antimicrobial activity is not an 'all or none' effect. An increase in the rate and extent of antimicrobial action is usually observed over a wide range of antimicrobial concentrations. Subinhibitory antimicrobial concentrations are well known to produce significant antibacterial effects, and various antimicrobials at subinhibitory concentrations have been reported to inhibit the rate of bacterial growth. Bacterial virulence may be increased or decreased by subinhibitory antimicrobial concentrations by changes in the ability of bacteria to adhere to epithelial cells or by alterations in bacterial susceptibility to host immune defences. Animal studies performed in rats, hamsters and rabbits demonstrate decreased bacterial adherence, reduced infectivity and increased survival of animals treated with subinhibitory antimicrobial concentrations compared to untreated controls. The major future role of investigation of subinhibitory antimicrobial concentrations will be to define more fully, at a molecular level, how antimicrobials exert their antibacterial effects. PMID- 22514372 TI - Pharmacodynamics and alternative antimicrobial dosing regimens. PMID- 22514373 TI - Update: Intravenous immune globulin in children. PMID- 22514374 TI - Mefloquine dangers - fact or fancy? PMID- 22514375 TI - An improved immunofluorescent reagent for rapid, direct detection of Bordetella pertussis. PMID- 22514376 TI - Hepatitis E: Canada welcomes the world. PMID- 22514377 TI - Antimicrobial activity of ceftriaxone compared with cefotaxime in the presence of serum albumin. AB - The effect of serum albumin on the antimicrobial activity of ceftriaxone, cefotaxime, and a 1:1 ratio of cefotaxime and its desacetyl metabolite against nonpseudomonal Gram-negative bacilli was determined. Antimicrobial activity of drugs was evaluated by measuring minimum inhibitory (mic) and bactericidal (mbc) concentrations in broth with and without human serum albumin. The analysis of logarithmically transformed mean mics and mbcs showed that there was a highly significant interaction between drug and serum albumin (P<0.0001). The inhibitory and bactericidal activities were greatest for cefotaxime followed by cefotaxime/desacetylcefotaxime and ceftriaxone (P<0.01). Time-kill kinetics demonstrated that ceftriaxone was less bactericidal than cefotaxime in broth with albumin. On the basis of these results it was concluded that the in vitro antimicrobial activity of ceftriaxone compared with that of cefotaxime was significantly diminished in the presence of serum albumin. PMID- 22514378 TI - Therapeutic potential for cytokine antagonists: Thalidomide and pentoxifylline in Hansen's disease. AB - Cytokine antagonists are a group of drugs defined by their actions on specific cytokines. Cytokine antagonists can inhibit action of cytokines by acting directly on receptors, by affecting production of cytokines or by binding to cytokines and preventing their subsequent action. Recent evidence suggests that Hansen's disease, which is characterized by reactional states, is associated with elevated serum levels of tumour necrosis factor-alpha (tnf-alpha) and interleukin 1beta during these reactional states. Thalidomide, a drug used to treat reactional states in Hansen's disease, has been reported to enhance degradation of tnf-alpha mrna. Pentoxifylline has also been reported to alter tnf-alpha mrna levels by inhibiting tnf-a transcription. Combination of these two drugs as cytokine antagonists may prove to be beneficial as therapeutic agents in the treatment of reactional states in Hansen's disease. Pentoxifylline may prove to be beneficial in the treatment of reactional states in Hansen's disease patients who are female and of childbearing age. Cytokine antagonists alone or in combination will likely fill a niche in future therapeutics. PMID- 22514379 TI - Hepatitis E: A newcomer to the hepatitis alphabet - Case report and review of the literature. AB - The first Canadian case of hepatitis E is described in a patient who travelled to Asia for a six-month period and spent most of his time in India. Hepatitis E shares some similarities with hepatitis A, notably the mode of transmission and the absence of chronic course. However, a few important differences have been noted, including a higher mortality rate and a high fatality rate in pregnant women. Hepatitis E is very common in developing countries and should be suspected more often in individuals with gastrointestinal complaints returning from endemic areas. PMID- 22514380 TI - Hepatitis E in a Canadian traveller. AB - Hepatitis E is clinically indistinguishable from hepatitis A and is caused by an enterically transmitted rna virus that is endemic in developing countries of Asia, Africa, the Middle East and North America. This report describes a Canadian traveller to Nepal, Thailand and India with one of the first confirmed cases of hepatitis E reported in Canada. Although this disease is usually self-limited with no known sequelae, it may produce fulminant hepatitis with a high case fatality rate in pregnancy. Diagnosis can be confirmed by serological tests. Apart from strict food and beverage hygiene, there are presently no prophylactic measures against this disease, and pregnant women in the third trimester should avoid travel to endemic areas. PMID- 22514381 TI - Transient in vivo selection of a constitutively cephalosporin resistant Enterobacter cloacae causing ventriculitis. AB - A case of neonatal ventriculitis complicating a ventriculoperitoneal shunt and caused by one strain of Enterobacter cloacae (as shown on pulsed field gel electrophoresis) is presented. Daily ventricular fluid cultures from day 1 to 9 revealed inducible cephalosporin resistance in all isolates except on days 3, 4 and 5 of therapy when isolates were constitutively resistant. This emergence of resistance due to constitutive Bush class 1 beta-lactamase production is an excellent example of the rapid emergence of a predominant strain of bacteria depending on antibiotic selection pressures in vivo. The transient nature of the predominant resistant phenotype may have been due to missing a dose of cefotaxime on day 5 or in vivo factors allowing persistence of sensitive organisms in antibiotic protected sites. Caution is advised in the use of cephalosporins alone for serious Enterobacter species infections. Repeat culture and sensitivity should be done in severe infections that are slow to respond to cephalosporin therapy. PMID- 22514382 TI - Moving towards a universal hepatitis B vaccine program for Canadian children. PMID- 22514384 TI - Poststreptococcal arthritis. PMID- 22514383 TI - Confronting antibiotic-resistant organisms - A Canadian perspective. PMID- 22514385 TI - Immune response to verotoxin 1 and 2 in children with Escherichia coli O157:H7 hemorrhagic colitis and classic hemolytic uremic syndrome. AB - OBJECTIVES: To compare neutralizing antibody titres against verotoxin (vt)-1 and vt-2 between children with uncomplicated hemorrhagic colitis (hc) and those with classic hemolytic uremic syndrome (hus). vt antibody titres were also compared in children with hc who received trimethoprim-sulfamethoxazole with those who did not. DESIGN: Prospective study. SETTING: Tertiary pediatric hospital. POPULATION STUDIED: Children with hc (n=41) or classic hus (n=12). INTERVENTIONS: Serum antibodies against vt-1 and vt-2 were determined by quantitative neutralization. MAIN RESULTS: Antibodies were detected in 40% (21 of 53) of serum samples for vt 1 and in 100% (53 of 53) of samples for vt-2. A positive immune response, defined as a fourfold increase in vt antibody titres or as a single titre of 1/64 or greater, was found in 0% (0 of 12) of patients with hus compared with 7% (three of 41) of those with hc for vt-1 (P=0.4); and in 17% (two of 12) of patients with hus compared with 22% (nine of 41) of those with hc for vt-2 (P=0.3). The rate of seroconversion against either vt-1 or vt-2 was comparable in treated and untreated patients with uncomplicated hc. CONCLUSIONS: There was no evidence that neutralizing antibody levels against vt-1 or vt-2 in classic hus or after antibiotic therapy are substantially different from those in patients with uncomplicated hc. PMID- 22514386 TI - Epidemiological typing of Moraxella catarrhalis by pulsed field gel electrophoresis. AB - Pulsed field gel electrophoresis (pfge) was used to compare 59 strains of Moraxella catarrhalis to evaluate pfge for the epidemiological typing of this organism. pfge-generated patterns were compared with those obtained by small fragment restriction enzyme analysis (rea) and species-specific probe hybridization. The strains used in the study were isolated from various geographic locations and included proven epidemiologically related strains. pfge yielded more unique patterns than dna-dna hybridization - 30 versus 18, respectively - but fewer than rea, which generated 45 unique patterns. Strains that demonstrated the same rea pattern or dna-dna hybridization pattern did not always demonstrate the same pfge pattern. For example, in 23 epidemiologically unrelated strains that shared six rea patterns, pfge differentiated the isolates into 12 patterns. Conversely, strains that demonstrated the same pfge pattern did not always demonstrate the same rea pattern or hybridization pattern. For example, in 42 strains that shared 13 pfge patterns, rea differentiated the isolates into 31 patterns and dna-dna hybridization differentiated them into 16 patterns. However, compared with rea, pfge yielded less complex patterns that were more easily comparable, and compared with dna-dna hybridization, pfge was technically easier. PMID- 22514387 TI - Blastomycosis presenting as multiple splenic masses. AB - Blastomyces dermatitidis is a fungus that causes a wide spectrum of disease in humans. The clinical and pathological entity of splenic abscess due to blastomycosis is extremely rare. A case of splenic blastomycosis is reported, and its cytopathological and radiological features are described. PMID- 22514388 TI - Cutaneous Corynebacterium diphtheriae: A traveller's disease? AB - A Canadian soldier incurred a nonhealing traumatic skin ulcer while on duty in Somalia. The diagnosis of localized cutaneous diphtheria was confirmed by isolation of a toxigenic strain of Corynebacterium diphtheriae from the ulcer. The patient was placed in isolation and treated with erythromycin and penicillin for 10 days without antitoxin. He was released when two consecutive daily cultures were negative. Public health officials evaluated his wife, two children and close contacts for carriage, but no carriers or secondary cases were identified. Cutaneous diphtheria as a diagnostic and management patient problem and potential public health problem are discussed. PMID- 22514389 TI - Diagnosis? PMID- 22514390 TI - Human to human transmission of Brucella melitensis. AB - Human brucellosis is acquired mainly through contact with infected animal tissues, ingestion of unpasteurized dairy products or infected aerosols. Person to person transmission is still considered uncertain. The case of a woman diagnosed with proven brucellosis after her husband suffered a relapse of bacteremia with Brucella melitensis biotype 3, which was originally acquired abroad by eating goat cheese, is described. It was postulated that person to person spread of brucellosis is a likely mode of transmission in this case. PMID- 22514391 TI - Emergence of penicillin-resistant Streptococcus pneumoniae in southern Ontario, 1993-94. AB - OBJECTIVE: To determine the prevalence of resistance of Streptococcus pneumoniae to penicillin and other antimicrobial agents in metropolitan Toronto. DESIGN: Consecutive pneumococcal isolates from different patients were obtained from two private community-based laboratories and from patients assessed in the emergency department of a tertiary-care teaching hospital in Toronto, Ontario between June and December 1993, and between March and October 1994. In vitro susceptibility testing was done by broth microdilution in accordance with National Committee for Clinical Laboratory Standards guidelines. RESULTS: Twenty (7.3+/-3.1%) of 274 pneumococcal isolates were resistant to penicillin; six (30%) isolates had high level resistance (minimal inhibitory concentration [mic] 2.0 MUg/mL or greater); and 14 isolates had intermediate resistance (mic 0.1 to 1.0 MUg/mL). Penicillin resistant strains were also frequently resistant to tetracycline (55%), cotrimoxazole (50%), erythromycin (40%) and cefuroxime (35%). Resistant strains comprised several serotypes: 19F (six isolates), 9V (three), 23F (three), and one each of 6A, 6B, 14, and 19A; four isolates were nontypeable. CONCLUSIONS: There has been a recent emergence of penicillin-resistant S pneumoniae in southern Ontario. National and regional surveillance is warranted to determine the extent of the problem elsewhere in Canada. PMID- 22514392 TI - Communicable disease surveillance: Strengthening the national perspective. PMID- 22514393 TI - Emerging in Canada. PMID- 22514394 TI - Hantavirus pulmonary syndrome: Report of four Alberta cases. AB - Four Alberta cases of hantavirus pulmonary syndrome are reported. Three cases required intensive care, with one experiencing a fulminant course resulting in death. A fourth case with milder illness was identified after epidemiological investigations. Ribavirin was used in one patient who experienced a successful outcome. A recent open label trial has not supported the efficacy of this drug. The epidemiology of Peromyscus maniculatus, the primary rodent host, and the clinical features of this syndrome are summarized. PMID- 22514395 TI - Diagnosis? PMID- 22514396 TI - Chlamydia pneumoniae pneumonia: An evolving clinical spectrum. AB - Chlamydia pneumoniae is a recently recognized respiratory tract pathogen. It accounts for 6 to 10% of all cases of community acquired pneumonia requiring admission to hospital. Two patients hospitalized with C pneumoniae pneumonia are presented to illustrate its range of severity and the extrapulmonary manifestations. PMID- 22514397 TI - Laboratory diagnosis of Chlamydia pneumoniae infections. AB - Chlamydia pneumoniae is an important cause of respiratory illness. There is a need for accurate and rapid laboratory diagnostic methods that will lead to improved patient care, appropriate use of antimicrobial therapy and a better understanding of the epidemiology of this emerging pathogen. Culture is highly specific but is technically demanding, expensive, has a long turnaround time and its sensitivity is highly dependent on transport conditions. Antigen detection tests such as enzyme immunoassay and direct fluorescent antibody assay, and molecular detection methods such as the polymerase chain reaction assay, may provide a rapid diagnosis without the requirement for stringent transport conditions. The results of these tests should be interpreted with caution until more thorough evaluation is available. Serology remains the method of choice. The limitations of different serological methods for the laboratory diagnosis of C pneumoniae are discussed. PMID- 22514398 TI - Cefixime use in children: When and why. PMID- 22514399 TI - Emerging zoonotic diseases. PMID- 22514400 TI - The impact of global tuberculosis in Canada: We are our brothers' keepers. PMID- 22514401 TI - Typhoid vaccination - Update. PMID- 22514402 TI - The use of Bacille Calmette-Guerin vaccination in children. PMID- 22514403 TI - Dash for DOT. PMID- 22514404 TI - Risk of hepatitis C virus infection from tattooing and other skin piercing services. PMID- 22514405 TI - Evaluation and follow-up of infectious tuberculosis at the University of Ottawa. AB - A case of active infectious pulmonary tuberculosis (tb) in a recent immigrant to Canada was identified at the University of Ottawa. The student was attending classes regularly and coughing for six months before the diagnosis of infectious pulmonary tb was made. Investigation carried out by the Ottawa-Carleton Health Department identified 871 student contacts. Of the 871 contacts, 773 (89%) were available for testing and follow-up. Initial skin testing with purified protein derivative (ppd) was positive in 149 contacts. Of the 602 contacts testing negative initially 399 (66%) returned for 12-week retesting. Eleven skin test converters were identified. All 160 contacts with positive ppd had negative chest x-ray and were given isoniazid prophylaxis for six months. The estimated cost of the process of contact tracing, testing, follow-up and treatment was $34,036. Although pre-immigration screening policies for tb do exist, additional pre- and postimmigration measures could help in the early detection of active tb and the prevention of its spread. PMID- 22514406 TI - Diagnosis? PMID- 22514408 TI - Comparative activity of cefepime with several antimicrobials against aerobic Gram negative and Gram-positive organisms isolated from patients across Canada in 1993. AB - To compare the activity of cefepime, a fourth-generation cephalosporin, with several available antimicrobials, in vitro susceptibility studies were carried out on bacteria commonly associated with various infections, including sepsis. Ten tertiary care hospital laboratories in six provinces provided 1276 clinically relevant isolates of aerobic Gram-negative bacilli and Gram-positive cocci during 1993. When the activity of each of the antimicrobials was determined against all isolates submitted, cefepime, piperacillin/tazobactam, imipenem and ciprofloxacin all had minimal inhibitory concentrations for 90% of the organisms (mic(90)) two or more dilutions below the mic resistant category. Gentamicin's mic(90) against all organisms tested was one dilution below the mic resistant category. The mic(90)s of the third-generation cephalosporins, piperacillin and ticarcillin/clavulanate, for Enterobacter species fell in the resistant category. This is presumably due to constitutive high level chromosomal cephalosporinase production. The mic(90)s of cefepime for Enterobacter species was three or more dilutions below the mic resistant category. The mic(90)s of all antimcrobials against Staphylococcus aureus, with the exception of ceftazidime and piperacillin, had mic(90) categories two or more dilutions below the resistant category. The activity of cefepime, piperacillin/tazobactam, imipenem, ciprofloxacin and gentamicin make them excellent candidates for the empirical therapy of serious infections due to aerobic Gram-negative bacilli and S aureus. PMID- 22514409 TI - Street youth: Provision of medical care. PMID- 22514410 TI - Varicella zoster immune globulin use in neonates and infants. PMID- 22514407 TI - Screening and treatment of immigrants and refugees to Canada for tuberculosis: Implications of the experience of Canada and other industrialized countries. AB - OBJECTIVE: To assess the incidence of tuberculosis in immigrants and refugees in Canada and other industrialized countries; the effectiveness of the screening process; the incidence of drug resistance; recommendations for prophylaxis and therapy; and indications for and effectiveness of directly observed therapy. DATA SOURCES: medline search of literature published from 1985 to 1995 with the key words 'tuberculosis', 'Canada', 'screening', 'drug resistance', 'drug resistance, multiple', 'immigration and emigration', and the title words 'directly observed therapy'. STUDY SELECTION: All studies reporting data on incidence, the outcomes of screening, drug resistance, therapy and directly observed therapy were selected. DATA SYNTHESIS AND CONCLUSIONS: Data synthesis led to the conclusions that immigrants and refugees to Canada have five times the nonimmigrant and non Aboriginal rate of tuberculosis; that screening programs discover new cases of tuberculosis on and after arrival and that up to 20% of those scheduled to attend a tuberculosis clinic after arrival may never attend; that drug resistance is widespread in countries from which Canada receives immigrants; and that directly observed therapy for active cases can result in 100% conversion rates. PMID- 22514411 TI - And then there were eight... PMID- 22514412 TI - Surveillance for Streptococcus pneumoniae in Latin American children. PMID- 22514413 TI - Chemotherapy of drug-resistant malaria. AB - OBJECTIVE: To review the impact of drug-resistant malaria on current management of plasmodial infections. DATA SOURCES: A MEDLINE search of the English-language medical literature from 1985 to 1995; bibliographies of selected papers; international malaria advisory experts. DATA SYNTHESIS: Combinations of artemisinin derivatives and mefloquine or atovaquone plus proguanil appear to be the most active drug regimens against multidrug-resistant falciparum malaria from Southeast Asia. The optimal therapy for chloroquine-resistant Plasmodium vivax is unknown, but recent data indicate that halofantrine or chloroquine plus high doses of primaquine are efficacious. CONCLUSIONS: The incidence of drug-resistant malaria continues to increase at a rate that exceeds new drug development. Ultimately the control of malaria will require more creative approaches than just the development of additional inhibitory drugs. These might include the identification of biochemical pathways unique to the parasite (such as drug efflux and heme polymerization), making it possible to design new classes of antimalarial agents that are selectively toxic to the parasite; methods to block parasite development in the mosquito vector; and multistage vaccines against asexual and sexual stages to block both the pathophysiology and the transmission of disease. PMID- 22514414 TI - Incidence and susceptibility of aerobic Gram-negative bacilli from 20 Canadian intensive care units: 1989-1993. AB - OBJECTIVE: To assess the prevalence of antibiotic resistance in Canadian intensive care units. DESIGN: The antimicrobial profiles of 1939 Gram-negative bacilli isolated in 20 Canadian intensive care units were analyzed using a custom designed MicroScan panel. SETTING: The majority of the hospitals were tertiary care institutions, but some community hospitals were included. PATIENTS: Adult intensive care unit patients were the sources of isolates. MAIN RESULTS: Pseudomonas aeruginosa was the most frequently isolated microorganism overall, with Escherichia coli the most common initial isolate. Comparison of initial and repeat isolates showed that P aeruginosa readily acquired resistance to all antibiotic classes except the aminoglycosides. Enterobacter aerogenes developed resistance to ciprofloxacin and Enterobacter cloacae demonstrated resistance to all beta-lactam antibiotics except for imipenem on repeat isolation. Other Enterobacteriaceae remained susceptible. Historical comparison with data derived four years previously from 15 of the centres showed increased resistance of P aeruginosa and Acinetobacter species to ciprofloxacin while other susceptibility patterns remained stable. CONCLUSIONS: The prevalence of Gram-negative resistance in Canadian hospitals is less than that reported in surveys done in some other countries, and was relatively stable over four years. PMID- 22514415 TI - Animals with Coxiella burnetii infection demonstrate a Western immunoblot profile of chronic Q fever in humans. AB - Western immunoblotting was used to compare the immune response to Coxiella burnetii phase I and phase II antigens of humans with acute and chronic Q fever with that of infected cats, rabbits, cows and raccoons. The cats, rabbits, cows and raccoons had an immunoblot profile similar to that of the human with chronic Q fever. PMID- 22514416 TI - Chlamydia infection in street youth: Need for more aggressive screening programs. AB - OBJECTIVES: To determine, first, the sexual practices among street youth in the Ottawa-Carleton, Ontario region; second, the percentage of street youth who report previous sexually transmitted disease (STD) screening; and third, the rate of previous infection with Chlamydia trachomatis in this population. METHODS: This prospective street youth pilot study was cross-sectional in design. Street youth aged 15 to 20 years were recruited through a drop-in centre or shelter in Ottawa, Ontario between August and October 1993. Information on demographics, substance use, current sexual practices and STD screening and infection history were obtained through a structured face to face interview and a 75-item questionnaire. Past C trachomatis infection was determined by microimmunofluorescence assay with purified antigens of C trachomatis (serovars A to K), Chlamydia psittaci (avian strain 6BC) and Chlamydia pneumoniae (TW-183 strain). RESULTS: Ninety-eight per cent of the youth approached participated. Of the 100 street youth (61 males, mean age 17.8 years; 39 females, mean age 17.1 years), 94% were sexually active, with 21% of males and 26% of females having had four or more different sexual partners in the previous year. Only 27% of males and 8% of females reported consistent condom use with all partners all of the time. Thirty per cent of males and 50% of females reported previous STD testing. Of the 100 street youth, 22 (16 males and six females) had had previous C trachomatis infection by serotesting, but only three of 16 (19%) of these males and three of six (50%) of these females reported previous STD testing. None of the 22 recalled previous diagnosis or treatment for any STD. CONCLUSIONS: These street youth reported a high prevalence of risky sexual behaviour, and this supports the national STD guidelines for targeted screening in this population. The current screening guidelines for C trachomatis in this population do not reach the majority of street youth. PMID- 22514417 TI - Public knowledge about hepatitis B-related issues in Korea. AB - Hepatitis B infection is endemic in many parts of the world, including Korea. Basic knowledge of the hepatitis B virus by the public is a prerequisite for the development of a successful vaccination program. A survey was conducted in rural Korea to examine public knowledge of hepatitis B etiology, symptoms, transmission, risk factors and prevention. It was found that knowledge independently correlated with education and female sex, but that overall knowledge of hepatitis B was poor. The preferred information sources in order of preference were physicians, television and public health nurses. This information may be useful in designing public health education and vaccination programs in developing populations. PMID- 22514418 TI - Bacterial peritonitis caused by Listeria monocytogenes: Case report and review of the literature. AB - Although Listeria monocytogenes has been isolated from the gastrointestinal tract, it is an infrequent cause of bacterial peritonitis. Since 1963 only 23 cases of peritonitis caused by listeria have been reported. This report describes another case in a patient with cirrhosis and chronic renal failure and presents a review of the literature. Most (16) of the previous cases were cirrhotic while six were undergoing chronic ambulatory peritoneal dialysis. Eight patients were on immunosuppressive therapy. Blood cultures were positive in fewer than half (42%) of the cases and Gram stain of peritoneal fluid was positive only twice. The peritoneal fluid protein concentration was relatively high compared with other causes of bacterial peritonitis. Ampicillin was the drug most commonly used for treatment, and the majority of patients survived the acute infection. PMID- 22514420 TI - Subcutaneous dirofilariasis in Nova Scotia. AB - A case of dirofilariasis in a 78-year-old woman from Nova Scotia is described along with the histological findings and the basis of identification of the parasite. The patient developed a subcutaneous nodule, which was excised. Dirofilaria ursi and ursi-like nematodes are a rare cause of subcutaneous nodules. This is the first time dirofilariasis has been diagnosed in an adult in Atlantic Canada. PMID- 22514419 TI - Pseudomonas aeruginosa blepharitis in a patient with vancomycin induced neutropenia. AB - A patient who developed a necrotizing pseudomonas blepharitis as a complication of drug induced neutropenia is reported. Although the patient's neutrophil count recovered and he survived his infection, radical reconstructive surgery of his eyelids was required. Clinicians should keep in mind that in patients with predisposing risk factors, even commonly encountered infections such as blepharoconjunctivitis may be caused by atypical pathogens. PMID- 22514421 TI - First reported case of bacterial endocarditis attributable to Actinomyces meyeri. AB - A 48-year-old man presented to the Victoria General Hospital, Halifax, Nova Scotia in severe congestive heart failure. Echocardiographic studies revealed significant aortic valve insufficiency. Two anaerobic blood cultures performed two weeks apart were both positive for Actinomyces meyeri. The patient was treated with high dose intravenous penicillin. Three weeks after antibiotics were begun, he underwent aortic valve replacement. Intraoperative cultures were negative. Histopathological examination revealed findings in keeping with subacute bacterial endocarditis. The patient completed a six-week course of penicillin and was doing well three months after surgery. This is the first case of endocarditis attributable to A meyeri reported in the literature. PMID- 22514422 TI - Taking control. PMID- 22514423 TI - Reinforcing surveillance for vaccine-associated adverse events: The Advisory Committee on Causality Assessment. PMID- 22514424 TI - Pseudo-, Xantho-, and now Stenotrophomonas maltophilia: New kid on the block. PMID- 22514425 TI - Laboratory perspectives: Population biology and the 'new' enterococcus. PMID- 22514426 TI - A multidisciplinary hospital-based antimicrobial use program: Impact on hospital pharmacy expenditures and drug use. AB - The authors' hospital embarked on a three-component, multidisciplinary, hospital based antimicrobial use program to cut costs and reduce inappropriate antimicrobial use. Initially, antimicrobial use patterns and costs were monitored for 12 months. For the next two years, an antimicrobial use program was implemented consisting of three strategies: automatic therapeutic interchanges; antimicrobial restriction policies; and parenteral to oral conversion. The program resulted in a reduction in the antimicrobial portion of the total pharmacy drug budget from 41.6% to 28.2%. Simultaneously, the average cost per dose per patient day dropped from $11.88 in 1991 to $10.16 in 1994. Overall, mean monthly acquisition cost savings rose from $6,810 in 1992 to $27,590 in 1994. This study demonstrates that a multidisciplinary antimicrobial use program in a Canadian hospital can effect dramatic cost savings and serve as a quality assurance activity of physician antimicrobial prescribing behaviour. PMID- 22514427 TI - Short-course itraconazole in the treatment of candida vulvovaginitis: A multicentre Canadian study. AB - OBJECTIVE: To determine the clinical and mycological effectiveness of oral itraconazole in the treatment of acute candida vulvovaginitis. DESIGN: A prospective, randomized and single-blinded, multicentre trial of 221 women, comparing a one-day course of oral itraconazole 200 mg bid with vaginal clotrimazole 500 mg single-dose therapy. MAIN OUTCOME MEASURES: Symptoms, signs and mycological results were assessed up to two months following treatment. Adverse events were recorded and evidence of hepatotoxicity sought. RESULTS: At 10 and 30 days post-treatment, clinical and mycological cure rates were similar (61.3% clinical and 88.6% mycological 10 days after, and 67.7% clinical and 79.5 mycological 30 days after itraconazole; 64.0 clinical and 85.9% mycological 10 days after, and 62.1% clinical and 78.6 mycological 30 days after clotrimazole) with the majority of both treatment groups free from infection. A total of 69 patients reported adverse events, which were generally transient and mild. Itraconazole was more often associated with gastrointestinal or central nervous system complaints, while clotrimazole recipients more often had genitourinary symptoms. No evidence of hepatotoxicity was found. A higher incidence of relapse was noted among women on the birth control pill and among those who were symptomatic for longer than 10 days before treatment. CONCLUSIONS: A one-day course of oral itraconazole is as effective as intravaginal clotrimazole in the treatment of acute yeast vulvovaginitis. The number of patients reporting adverse events was similar for the treatment groups, although the side effect profile differed. No hepatotoxicity was observed. PMID- 22514428 TI - HIV-related non-Hodgkin's lymphoma in Calgary. AB - OBJECTIVE: To determine the incidence of human immunodeficiency virus (HIV) associated non-Hodgkin's lymphoma (NHL) in a cohort of patients from a distinct geographic region (southern Alberta). The type and location of NHL as well as how it affected the survival of these patients was examined. PATIENTS AND METHODS: The Southern Alberta HIV Clinic in Calgary serves all of southern Alberta, which has an estimated population of one million. The clinic has provided primary care for 1086 patients from January 1983 to August 1995. Data were obtained by reviewing the clinic's database and patients' charts. RESULTS: Over a 12-year period, 39 cases of NHL were diagnosed in a group of 1086 HIV-infected patients. Presentation of NHL was at an extranodal site in all but four cases, with the most common sites being the bowel and central nervous system. The mean CD4 count on presentation with NHL was 143.4+/-37.4*10(6)/L (range 1 to 1219*10(6)/L). Mean survival was 1.25+/-0.25 years with a range from 0 (diagnosed on autopsy) to 6.45 years. Patients with a CD4 count of less than 200*10(6)/L and/or diagnosed with an AIDS-defining illness before development of NHL had significantly reduced survival (0.85 years versus 2.48 years, P<0.02 and 0.57 years versus 2.09 years, P<0.001, respectively). Patients who presented with NHL involving either nodes alone or central nervous system had significantly decreased survival (0.28 years and 0.29 years, respectively, P<0.05). Patients with NHL involving the gastrointestinal tract had a longer mean survival than those with NHL elsewhere (P<0.05). All but seven cases received therapy for NHL including chemotherapy, radiotherapy, surgery or combined therapy. Fifteen patients (47% of treated) achieved a complete response that led to improved survival (P<0.01). Patients tolerated surgery, chemotherapy and radiotherapy well and no deaths were due to NHL therapy. CONCLUSIONS: These data suggest that development of NHL in HIV is associated with reduced survival, and that survival is predominantly determined by CD4 count and site of involvement at the time of diagnosis of NHL. PMID- 22514429 TI - Skeletal cryptococcosis: Case report and review of the literature. AB - A case of isolated cryptococcal skull infection is presented in a patient with unexplained CD4 lymphopenia and chronic hepatitis B. All cases of this disease reported in the English literature from 1956 to the present are reviewed. The literature suggests that skeletal cryptococcosis is manifested in only 5% to 10% of recognized cases of disseminated cryptococcosis and that isolated skeletal disease without evidence of other tissue involvement is even less common. When isolated bony disease does occur it tends to occur in immunocompromised hosts, particularly those with defects of cell mediated immunity. Any bony site can be involved, most commonly the vertebrae, with the presentation often being a soft tissue swelling and pain in the affected area. Systemic constitutional symptoms occur in a minority of patients. Radiographic investigations are nonspecific and the gold standard of diagnosis remains culture isolation from bone tissue. The most commonly employed therapy for isolated bone disease is amphotericin alone or combined with surgical debridement. The new azoles may have a role in future therapy. PMID- 22514430 TI - Pasteurella multocida osteomyelitis: An unusual case presentation. AB - A healthy male farm employee developed an unusual infection caused by Pasteurella multocida. Atypical features included the chronic nature of the infection, the development of osteomyelitis of the tibia without direct animal inoculation, and lack of fever and leukocytosis. Radiographic appearance of P multocida osteomyelitis may be the result of osteoclast activation and can be confused with musculoskeletal tumour. P multocida infection requires a high degree of suspicion, and should be considered in cases of farm- or animal-related injuries even if there is no history of direct animal contact. PMID- 22514431 TI - Dacochordodes bacescui Capuse, 1966: Report of the first two isolations from humans. AB - This report describes two cases of isolation of Dacochordodes bacescui Capuse, 1966 from human intestinal infections. In the first case, two adult worms were identified in the vomitus of a man suffering from abdominal pain and nausea. In the second case, a worm was passed in the stool of a woman suffering from abdominal pain and pruritus. Human gastrointestinal infection with this parasite has not previously been reported. PMID- 22514433 TI - Antimicrobial resistance: Implications for therapy of infections with common childhood pathogens. PMID- 22514432 TI - Human and canine blastomycosis: A common source infection. AB - In fall 1993 a man and a dog developed blastomycosis after visiting an island off Bayfield Inlet, Georgian Bay, located near Parry Sound, Ontario. The man recovered but the dog died of blastomycosis. It was hypothesized that the common source of exposure was the island since the permanent residences of the two cases were in different cities. One further case of human infection, based on positive serology, and four additional cases of probable canine blastomycosis were identified. All cases had travelled to Bayfield Inlet during summer and early fall 1993. To the authors' knowledge this is the first Canadian report of a common source of infection of human and canine blastomycosis. This report also provides evidence for a new endemic area of blastomycosis infection. PMID- 22514434 TI - Summary of the national consensus conference on foodborne, waterborne and enteric disease surveillance: november 28 to 30, 1995, citadel hotel and convention centre, Ottawa, ontario. PMID- 22514435 TI - Where is the varicella vaccine? PMID- 22514436 TI - A B C d e f g ... PMID- 22514437 TI - The role of ganciclovir for the management of cytomegalovirus retinitis in HIV patients: Pharmacological review and update on new developments. AB - OBJECTIVE: To review the pharmacology and pharmacokinetics of intravenous, oral and intraocular ganciclovir, and to discuss the role of these various formulations in the management of cytomegalovirus (CMV) retinitis in AIDS patients. DATA SOURCES: A MEDLINE search (1987 through November 1995) of English language literature using the main medical subject headings 'ganciclovir' and 'cytomegalovirus', and the subheading 'acquired immunodeficiency syndrome'. Relevant articles were also selected from references of identified articles. Abstracts from recent medical conferences of infectious diseases, pharmacology and human immunodeficiency virus were screened for additional data. STUDY SELECTION AND DATA EXTRACTION: All articles and abstracts discussing the use of ganciclovir for the management or prophylaxis of CMV retinitis in AIDS patients were considered for inclusion. Pertinent information, as judged by the authors, was selected and synthesized for discussion. DATA SYNTHESIS: Ganciclovir has demonstrated virustatic activity against CMV, and is often administered 5 mg/kg intravenously every 12 h as first-line therapy for CMV retinitis. Intravenous maintenance therapy at 5 mg/kg daily is usually effective at delaying retinitis progression for approximately 60 to 70 days. Neutropenia and thrombocytopenia are observed frequently, often necessitating interruption or discontinuation of therapy. Local drug administration may delay disease progression even further, and may be considered for patients who are intolerant to or failing intravenous therapy. However, systemic ganciclovir should be encouraged to reduce the risk of developing contralateral eye or end-organ CMV disease. Oral ganciclovir at 1 g tid is almost as effective as intravenous ganciclovir 5 mg/kg/day in delaying retinitis progression and is associated with fewer line-related complications. Absorption, drug interactions, cost and compliance should also be considered. CONCLUSIONS: Until recently, ganciclovir was available only for intravenous use. Recent developments allow for intraocular and oral administration of this agent. A clear understanding of the advantages and disadvantages of these new formulations is required in order to select the most appropriate product for managing CMV retinitis in AIDS patients. PMID- 22514438 TI - Evaluation of routine enteric pathogens in hospitalized patients: A Canadian perspective. AB - Diarrhea is a frequently encountered problem in hospitalized patients. Since nosocomial spread of routine enteric pathogens such as Salmonella species, Shigella species, Campylobacter species and Escherichia coli O:157 H:7 seldom occurs, testing for these organisms in patients hospitalized for longer than three days has been questioned. The goal of this study was to determine the length of hospitalization preceding detection of routine enteric pathogens and Clostridium difficile cytotoxin, and to develop guidelines for enteric cultures from hospitalized patients. The enteric pathogens detected in 1991 were C difficile toxin B(+), 77%; Campylobacter species, 10%; Salmonella species, 9%; E coli O:157 H:7, 3%; and Shigella species, 1%. For 1992, these numbers were 86%, 9%, 3%, 2% and 0%, respectively. None of the routine enteric pathogens isolated in 1991 or 1992 was detected in patients after their second day of hospitalization. Routine cultures for enteric pathogens on hospitalized patients were eliminated in February 1993, and physician ordering practices were monitored. With the exception of one campylobacter isolate per year, all routine enteric pathogens isolated in 1993 and 1994 were detected by the second day of hospitalization. Compliance with the changed protocol was 76% measured over a four-month period in 1993 and 74% over the year 1994. Savings of $3,648.10 were associated with rejecting 191 'inappropriate' specimens in 1994. It was concluded that routine enteric cultures are unnecessary for patients hospitalized more than two days, and that appreciable financial savings can be achieved if revised protocols for processing stool cultures are instituted. However, when enteric protocol changes are in place compliance must be evaluated to ensure appropriate utilization. PMID- 22514439 TI - Meningitis in a Canadian adult due to high level penicillin-resistant, cefotaxime intermediate Streptococcus pneumoniae. AB - Invasive penicillin-resistant pneumococcal (PRSP) infections are increasing worldwide. In Canada, the incidence of penicillin resistance among Streptococcus pneumoniae isolates is estimated at greater than 6%. In Quebec, only one case of PRSP meningitis has been reported and involved an infant. An adult patient is described who presented with meningitis caused by high level penicillin resistant, cefotaxime-intermediate S pneumoniae. PMID- 22514440 TI - Herpes simplex mastitis: Case report and review of the literature. AB - The most common sites of herpes simplex virus (HSV) infection are around the oral cavity and the genitalia. However, HSV can infect any skin or mucous membrane surface. One uncommon site of HSV infection is the breast. Reports of herpetic breast infections are predominantly cases of transmission from a systemically HSV infected neonate to the mother during breast-feeding. A review of the literature identified only six reports suggesting HSV breast lesions acquired by means other than through an infected infant. Of these, only one report suggests HSV transmission to the breast from a male sexual partner. A second case of clinically unsuspected symptomatic herpes mastitis presumably acquired from sexual contact in a 46-year-old woman is presented. Herpes simplex type 1 was isolated by using polymerase chain reaction and restriction fragment length polymerization techniques. The purpose of this report is to alert physicians to HSV mastitis. PMID- 22514441 TI - Assuring quality in Canada's microbiology laboratories. PMID- 22514442 TI - In search of the amazing technicolour dream coat for amphotericin B. PMID- 22514443 TI - Measles vaccination: Weighing the benefits and risks of a live viral vaccine for HIV-infected children. PMID- 22514444 TI - An assessment of the utilization of diagnostic parasitology laboratory services in Ontario. AB - OBJECTIVE: Diagnostic parasitology services in Ontario were assessed to determine whether the reduction in the number of provider laboratories from 209 to 70 over the period 1977 to 1994 has affected the availability and quality of service. DESIGN: A questionnaire on parasitology practice was distributed to all laboratories. Responses were validated against data from the requisitions, work cards and reports submitted by licensed parasitology laboratories in a pattern-of practice survey. SETTING AND PARTICIPANTS: Laboratories in Ontario are licensed by the provincial Ministry of Health and subjected to mandatory proficiency testing. Laboratories not licensed in parasitology may receive specimens for referral to another facility for processing. MAIN OUTCOME MEASURES: Assessment included receipt of fecal specimens for parasitology, on-site testing, the limitation of testing, work referred elsewhere for primary investigation or confirmation, laboratory to which work was referred, and the turnaround time for both on-site and referred work. RESULTS: Ninety-eight per cent of 338 laboratories returned the questionnaire. Three hundred and six received specimens for parasitology. Sixty-four performed the testing. Of the remainder, 235 referred to 40 laboratories. Approximately 31,000 specimens were processed monthly, with 78% examined within private laboratories and 62% having a turnaround time of at least three days. The yield of positive findings was 3% or more of patients. CONCLUSIONS: The presence of fecal parasites has been reliably determined and the genus, species and stage of the organism correctly identified. Utilization must be improved through understanding of the factors increasing the pretest likelihood of a positive finding. PMID- 22514445 TI - Diversity of urine bacteriology practice in Ontario: An external quality assessment. AB - OBJECTIVE: Assessment of urine bacteriology practice in Ontario regarding appropriateness of quantification and the accuracy and Systeme International d'Unites (SI) conformity in the reporting of results. DESIGN AND SETTING: A simulated urine specimen with Escherichia coli at a target of 100*10 colony forming units (CFU)/L was submitted to licensed Ontario bacteriology laboratories. Data on the isolation and quantification of the pathogen were required within a stipulated time. Reference values were determined by consensus agreement of the findings of seven designated laboratories. PARTICIPANTS: The challenge was administered to 182 Ontario laboratories licensed to perform urine bacteriological assessment. There was no stratification by type or complexity of facility. MAIN OUTCOMES: Samples were processed by routine procedures. Date and time of receipt of the sample, date tested, bacterial count, associated quantification units and the method used were the data required. A copy of the report using the laboratory's normal reporting format to user-physicians was requested. RESULTS: The organism was isolated and correctly identified by 179 laboratories. Only 58% of laboratories reported a count of 100*10(3) CFU/L or more, with 42% reporting a count of between 10 and 100*10(3) CFU/L. The majority used a standard 0.001 mL loop method. Only 87 participants reported using the correct notation of SI units, although a further 65 reported as CFU/L. CONCLUSION: The variety of reporting formats is of concern. Processing and reporting should be standardized. Laboratories should provide an explanatory note or interpretation when nomenclature or format of a report is changed. PMID- 22514446 TI - Variability in urine culture reporting by Canadian microbiology laboratories. AB - OBJECTIVE: To determine the ability of microbiology laboratories to perform and to report urine colony counts. DESIGN: Clinical Microbiology Proficiency Testing program participants received stabilized simulated urine samples. Laboratories were asked to perform the appropriate test and report results. PARTICIPANTS: One hundred and nine clinical microbiology laboratories in British Columbia, Alberta and Nova Scotia. OUTCOME MEASURES: Consistency of reporting was compared with standards for reporting results as described in the SI Manual in Health Care, 2nd edition. RESULTS: The study demonstrated a wide variation in units used for the reporting of results. Ninety-five (87.2%) laboratories reported quantitative urine results in a variety of unit styles. Of those laboratories providing results with units, 80 (84.2%) used one of 10 variations of SI reporting styles. Fifteen (16.8%) laboratories reported metric units in three different styles. Eleven (10.0%) laboratories reported semiquantitative values without stating units. The remaining three (2.8%) did not respond to the survey. CONCLUSIONS: Many clinical microbiology laboratories have not adopted a consistent form of SI units for reporting quantitative urine culture results. This lack of consistency could potentially lead to interpretation confusion. PMID- 22514447 TI - Diagnosis? PMID- 22514448 TI - Comparison of community-acquired pneumonia requiring admission to hospital in HIV and non-HIV-infected patients. AB - OBJECTIVE: To compare community-acquired pneumonia (CAP) in hospitalized human immunodeficiency virus (HIV)-infected patients with that in hospitalized non-HIV infected patients by assessing presenting characteristics, etiology and outcomes. DESIGN: Retrospective chart review. SETTING: A tertiary care centre in Halifax, Nova Scotia. POPULATION STUDIED: Thirty-two HIV-infected patients requiring hospitalization for treatment of CAP were identified from September 1991 to October 1993 and compared with 33 age-matched non-HIV-infected patients who presented with pneumonia during the same period. MAIN RESULTS: The two populations were comparable in age, sex and race. Fifty per cent of the HIV infected and 20.8% of the non-HIV-infected patients had had a previous episode of pneumonia. Pneumocystis carinii pneumonia (PCP) accounted for 16 of the 32 episodes of CAP in the HIV-infected patients, while none of the non-HIV-infected patients had PCP. Pneumonia secondary to Streptococcus pneumoniae was more common in the non-HIV-infected patients (five versus one, P=0.02). Vital signs and initial PO(2) did not differ between the two groups. White blood cell count was lower at admission for the HIV population (5.7*10(9)/L versus 12.7*10(9)/L, P=0.003). The HIV patients were more likely to undergo bronchoscopy (27.7% versus 0%, P<0.001). The length of stay in hospital, transfer to the intensive care unit and necessity for intubation were the same for both groups. The in-hospital mortality for HIV-infected patients was eight of 32 (25%) while for the non-HIV infected patients it was none of 33 (P=0.002). CONCLUSIONS: Patients with HIV infection who present with CAP are more likely to have PCP, to have had a past episode of pneumonia and to die while in hospital than age- and sex-matched non HIV-infected patients with CAP. PMID- 22514449 TI - A cost-benefit analysis of prenatal screening for toxoplasmosis. AB - The objective of this study was to examine critically the validity of a toxoplasma prenatal screening program, in the context of a cost-benefit analysis, as it relates to the Canadian experience. Recently, studies have suggested that early treatment of infected infants with a combination of pyrimethamine and sulfadiazine is effective in reducing the sequelae of toxoplasmosis. It was concluded that a carefully planned screening program for detecting and treating infants infected with Toxoplasma gondii during pregnancy is cost beneficial. The cost of delivering a screening and treatment program is less than half of what it would cost to provide comprehensive long term medical, educational and other social services for the estimated 1000 children born each year with congenital toxoplasmosis. Even if an incidence as low as two infected infants per 1000 pregnancies is assumed and only 400 children were affected, the screening and preventive therapy program would be justified. PMID- 22514450 TI - Immunization against influenza and pneumococcal disease in residents of long term care facilities. PMID- 22514451 TI - Egg allergy and MMR vaccine: New recommendations from the National Advisory Committee on Immunization. PMID- 22514452 TI - Communicable disease surveillance: Notification of infectious diseases in Canada. PMID- 22514453 TI - Influenza and pneumococcal vaccination in long term care facilities in two regions of Quebec. AB - OBJECTIVES: To evaluate the use of influenza and pneumococcal vaccines in long term care facilities. DESIGN: Cross-sectional survey in a random sample of 30 facilities in two regions of Quebec. Information was collected from the general manager or the chief of nursing, all consultant physicians and a random sample of 20 residents in each facility. RESULTS: Twenty-nine centres agreed to participate. The mean influenza vaccination rate was 70%, and was not influenced by differences in the types of facilities or the organization of the programs for immunization. The main obstacle to influenza vaccination reported by physicians was nonacceptance by a significant proportion of residents. Of the residents who did not initially request influenza vaccine, only 64% accepted vaccination when it was offered. The vast majority of residents were satisfied with the information they had received and the respect shown for their freedom of choice. Forty per cent of residents were unfit to provide a valid consent and the vaccination rate was 76% in this group. Only one-third of the physicians regularly obtained authorization from a relative or the legal guardian before prescribing vaccination for incompetent residents. None of the facilities studied had an effective program for pneumococcal vaccination, only 43% of the physicians reported any use of pneumococcal vaccine and 98% of residents had never heard of the vaccine. CONCLUSIONS: The national objective of 95% coverage with influenza vaccine will be difficult to achieve in long term care facilities, mainly because a minority of residents are not likely to be convinced of the benefit of immunization. Much remains to be done to promote and administer pneumococcal vaccine in this setting. PMID- 22514454 TI - Antibody response in seropositive multiple sclerosis patients vaccinated with attenuated live varicella zoster virus. AB - OBJECTIVE: To determine the safety and effectiveness of live attenuated varicella zoster virus (VZV) vaccine (OKA/Merck) on 50 patients with chronic progressive multiple sclerosis (MS), based on the hypothesis that VZV might be the antigen or antigen mimic of MS plus the fact that repeated high antigen doses have produced 'antigen paralysis' in experimental allergic encephalomyelitis mice. DESIGN: Fifty patients were randomly selected without controls. They were assessed clinically at entry and on four other occasions over 14 months. Enhanced cranial magnetic resonance imaging (MRI) was performed at entry and at six and 12 months post entry. All were vaccinated after initial assessment and again six weeks later. SETTING: All clinical and laboratory assessments were performed at the Health Sciences Centre, Winnipeg, in the out-patient department. All MRI examinations were performed at the St Boniface General Hospital, Winnipeg, Manitoba. Both are tertiary care hospitals. POPULATION STUDIED: Fifty randomly selected patients with chronic progressive MS, age 18 to 60 years, and a disability status scale of 2.0 or greater were included. Forty-five patients completed the study. INTERVENTIONS: Two vaccinations with attenuated live VZV six weeks apart. RESULTS: All patients were VZV seropositive at entry and all showed an increased antibody level following vaccination. No one was harmed by the vaccine. There may have been some changes in the MS of 15 patients. CONCLUSIONS: It may be reasonable and safe to challenge the process of MS using large doses of the immunogenic proteins of the VZV to induce 'immune paralysis'. PMID- 22514455 TI - Low prevalence of gastrointestinal colonization with antimicrobial-resistant bacteria in high risk units in a Canadian tertiary care centre. AB - OBJECTIVE: To determine the prevalence of antimicrobial-resistant bacteria among patients receiving care in high risk units in a Canadian tertiary care centre. DESIGN: Prevalence study over a four-month period in 1995 with rectal swab or freshly passed stool specimen collected from each patient included in study. Standardized record data extraction for selected patient variables was used. SETTING: Units at high risk for antimicrobial-resistant organisms at the Health Sciences Centre, Winnipeg, including neonatal (NICU), pediatric (PICU), surgical (SICU) and medical intensive care units (MICU), central dialysis unit (CDU), and the in-patient oncology ward (ONC). PATIENTS: One hundred and fifty-seven patients admitted to the high risk care units for at least 72 h were screened. Ward distribution was NICU 13 (8.3%), PICU nine (5.7%), SICU 24 (15.3%), MICU 19 (12.1%), CDU 62 (39.5%) and ONC 30 (19.1%). Fifty-one of 157 (32.5%) patients had urinary drainage devices, 108 (68.8%) had invasive vascular devices, and 57 (36.3%) had had a surgical procedure within the month before specimen collection. In the month before sampling, 114 (72.6%) had received antimicrobial therapy, including 21 (13.3%) who had received vancomycin, and 81 (51.5%) were receiving antimicrobials, seven (10.8%) vancomycin, on the day of sampling. RESULTS: Antimicrobial susceptibilities were performed on 371 bacterial isolates. There were no vancomycin-resistant enterococci or methicillin-resistant Staphylococcus aureus. Eleven (10.8%) enterococci were resistant to ampicillin, none of which were beta-lactamase producers, 19 (18.6%) and five (4.9%) demonstrated high level resistance to gentamicin and streptomycin, respectively. One (0.7%) Escherichia coli was resistant to ciprofloxacin and another to gentamicin. Six (20.7%) Enterobacter cloacae samples were resistant to cefotaxime. One (2.4%) Klebsiella species was resistant to ciprofloxacin and another to cefotaxime. Two (16.6%) Citrobacter species were resistant to cefotaxime. One of 11 (9%) Pseudomonas aeruginosa isolates was resistant to ceftazidime; none were resistant to piperacillin, aminoglycosides, ciprofloxacin or imipenem. CONCLUSIONS: The prevalence of antimicrobial-resistant organisms colonizing the gastrointestinal tract in patients in these high risk units is low. The reasons for this low prevalence of antimicrobial resistance require further exploration. PMID- 22514456 TI - Seroprevalence of immunoglobulin G antibody to parvovirus B19 in Ontario. AB - The prevalence of antibody to parvovirus B19 was assessed in two populations. In a group of 494 residents from Ontario and the Maritimes, virus-specific immunoglobulin (Ig) M antibody, a marker of acute infection, was found throughout the year but was most prevalent during the late winter and early spring months. The overall prevalence of IgG antibody in this group was 30.3%. In an effort to examine age-specific prevalence in this population, a second group of sera from 210 pediatric patients at The Hospital for Sick Children, Toronto, Ontario and from Red Cross blood donors was tested for the presence of B19-specific IgG, and of these, 31.4% of the samples were positive. This prevalence varied from 3.3% in the under five-year-old age group to 66.7% in the 35- to 45-year-old age group. Eighty per cent of sera from females of this group were seropositive. This study provides insight into the prevalence of parvovirus B19 IgG antibody in the population. PMID- 22514457 TI - New concepts in the diagnosis and pathogenesis of Trichomonas vaginalis. AB - Trichomonas vaginalis infection is the most commonly encountered sexually transmitted disease. There is a need for more accurate and rapid laboratory diagnostic methods, leading to better control and treatment strategies. Various virulence factors such as adherence, contact-independent factors, hemolysis and acquisition of host macromolecules have been shown to play a role in the pathogenesis of this infection. Detection of the factors that are only present in the pathogenic isolates of trichomonads will lead to a better understanding of the epidemiology of this pathogen. Culture technique is highly specific compared with microscopic techniques, but it is time consuming. Immunological techniques lack proper correlation with clinical manifestations. The application of monoclonal antibodies, either singly or in a group that recognizes a common antigen, along with methods such as detection of common DNA fragment from clinical specimens, may have a promising future in the laboratory diagnosis of trichomoniasis. PMID- 22514458 TI - Seroprevalence of toxoplasma antibody in a Toronto population. AB - OBJECTIVE: To determine the prevalence of infection with toxoplasmosis by country of birth and age in a sample of convenience. DESIGN: Banked sera and the computerized data base of demographic and other factors from an earlier epidemiological study were retrieved. SETTING: Thirty-eight infant-toddler day care centres in Toronto. POPULATION: Day care providers from whom informed consent was obtained and banked sera were available. MAIN RESULTS: Of the 124 providers whose serum was tested, 16 (12.9%) were seropositive. Of those providers born in Canada, 8.2% were seropositive, while of those born outside of Canada, 19.6% were positive (P=0.067, OR 2.68, 95% CI 0.91, 7.94). While there was no significant association of seropositivity with age, the association of seropositivity with country of birth was different in the providers under 30 years of age. Among those born in Canada, 4.6% were seropositive, while among those born outside of Canada 23.1% were seropositive. CONCLUSIONS: The data supplement the limited existing data on toxoplasmosis infection in Canada. Among Canadians, those born outside of Canada were more likely to be seropositive than those born in Canada, suggesting that there may be a differential risk of congenital infection for infants whose parents were born outside of Canada. PMID- 22514459 TI - Streptococcus suis meningitis: First case reported in Quebec. AB - Very few Streptococcus suis infections in humans have been reported in Canada, although the condition is frequent in pigs. Meningitis, often accompanied by severe hearing loss, is the most common clinical manifestation. The disease is an occupational illness affecting persons in contact with pigs and may be underdiagnosed because of misidentification of the responsible bacterium. Since Quebec is the leading province for swine production in Canada, physicians and microbiologists should be aware of this infection, especially when a streptococcal meningitis is diagnosed in swine workers. The first case of S suis type 2 meningitis reported in Quebec is described. PMID- 22514460 TI - Candida albicans epididymo-orchitis and fungemia in a patient with chronic myelogenous leukemia. AB - The fourth reported case of candidal epididymo-orchitis in the literature and the first reported case successfully cured with only low dose amphotericin B is described. A 75-year-old male with chronic myelogenous leukemia presented with acute testicular and epididymal swelling and pain. Subsequent investigations suggested the diagnosis of epididymo-orchitis due to Candida albicans. This was successfully treated with intravenous amphotericin B (total dose of 500 mg). Based on the three previous case reports and the current case several characteristic features that increased the suspicion of this entity were identified. These features include an immunocompromised state, candiduria, specific epididymal ultrasonographic appearance, as well as typical clinical features of epididymo-orchitis. PMID- 22514461 TI - Avoid becoming road kill alongside the information highway... PMID- 22514462 TI - Treatment of cytomegalovirus retinitis: A growing number of options. PMID- 22514463 TI - Proficiency testing of drug susceptibility results in the Canadian Network of Public Health TB laboratories. PMID- 22514464 TI - Acellular pertussis vaccines have arrived. PMID- 22514465 TI - Importance of Q fever in community acquired pneumonia. AB - Coxiella burnetii appears to be endemic in animals in the Mauricie region of Quebec, and causes some human cases of Q fever annually. Unlike in other rural areas, patients in this study experienced few respiratory symptoms. To determine whether C burnetii pneumonia is underdiagnosed, adults admitted to hospital for community acquired pneumonia were included in a one-year serological study. Significant immunofluorescent antibody (IFA) titres in four of 118 patients with pneumonia (fewer than 4%) were studied. Clinical presentation, standard laboratory tests and epidemiological data did not allow identification of these cases; however, Q fever increased during the warm months. There were no detectable complement fixing (CF) antibodies in these four cases. C burnetii causes few cases of pneumonia in Mauricie. IFA seems to be a more sensitive test than CF. PMID- 22514466 TI - Oligella infections: Case report and review of the literature. AB - A case of Oligella ureolytica infection of a cervical lymph node is presented and previous cases of oligella infection reported in the literature are reviewed. Underlying malignancy and urinary tract obstruction were observed in many of the cases. All patients responded to antimicrobial therapy and, in those cases associated with urinary tract obstruction, surgical relief of the obstruction. The microbiology and clinical features of oligella infections are reviewed. PMID- 22514467 TI - Plesiomonas shigelloides septicemia and meningitis in a neonate. AB - A newborn infant is described who presented with septicemia and meningoencephalitis caused by Plesiomonas shigelloides, a Gram-negative rod belonging to the family Vibrionaceae. This appears to be the first documented case in a neonate in Canada. Despite prompt treatment with appropriate antibiotics, he developed endophthalmitis and lytic brain lesions. PMID- 22514469 TI - Decision analysis: A toy or a tool for clinical practice? PMID- 22514468 TI - Disseminated soft tissue infection and sepsis with Stenotrophomonas maltophilia in a bone marrow transplant patient. AB - A 32-year-old female presented with aplastic anemia and subsequently underwent a one-antigen mismatched bone marrow transplant from her brother. She failed to engraft and a second graft was attempted. Protracted neutropenia of three months' duration despite the use of broad spectrum antibiotics occurred. Stenotrophomonas (Xanthomonas) maltophilia metastatic cellulitis developed that did not respond to appropriate antibiotics. PMID- 22514470 TI - Immunizing for health - Achieving our national goals, the 1996 Canadian National Immunization Conference. PMID- 22514472 TI - Treatment of group A streptococcal pharyngitis. PMID- 22514471 TI - Creutzfeldt-Jakob disease, new variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy - An update. PMID- 22514473 TI - Decision analysis modelling of costs and outcomes following cefepime monotherapy in Canada. AB - OBJECTIVE: To evaluate the comparative cost of treatment and intermediate outcomes (percentage resistant organisms, days in hospital, etc) among cefepime and alternative parenteral antibiotics used for empiric monotherapy. DESIGN: Decision analysis model, based on published literature, clinical trial results and information from infectious disease clinicians. SETTING: A Canadian tertiary care hospital. INTERVENTION: Comparison of cefepime, ceftazidime, ceftriaxone, cefotaxime and ciprofloxacin in the treatment of lower respiratory tract infections, urinary tract infections, skin/soft tissue infections, septicemia and febrile neutropenia. MAIN RESULTS: Cefepime treatment results in the lowest average cost per patient when used as initial empiric therapy for lower respiratory tract infections and for skin/soft tissue infections. Cefepime therapy is among the lowest cost treatments for the other infectious disease conditions and has the lowest cost for a weighted 'average' condition. Sensitivity analysis indicates that model results are most sensitive to duration of hospitalization. CONCLUSIONS: Initial empiric monotherapy with cefepime for serious infectious disease conditions may result in cost savings compared with alternative parenteral agents. PMID- 22514474 TI - [Not Available]. AB - To review the epidemiology, risk factors, clinical features and outcomes of Listeria monocytogenes infection in the Eastern Townships of Quebec, a retrospective study was completed over the period 1976 to 1995. Cases were identified from positive cultures and diagnosis given by the infectious diseases service of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec. A total of 12 cases were in the study. Septicemia not related to pregnancy (four of 12) and meningitis (six of 12) were the major clinical presentations. There was one case of listeriosis associated with pregnancy and one case of granulomatosis infanti septica. Ten patients had at least one predisposing underlying condition. Only one death was related to L monocytogenes infection. Neurological sequelae were observed in half of the cases of meningitis, whereas no sequelae were noted in cases of septicemia. In conclusion, listeriosis is predominantly a disease of elderly and immunosuppressed patients. The clinical presentation and outcome are not different from those reported in other industrialized countries. PMID- 22514475 TI - Laboratory diagnosis for Giardia lamblia infection: A comparison of microscopy, coprodiagnosis and serology. AB - OBJECTIVE: To evaluate newer techniques such as coproantigen detection and serology in the diagnosis of symptomatic Giardia lamblia infection. DESIGN: Blinded comparison of copro-antigen detection (by ELISA), serology (immunoglobulin IgG and IgM anti-G lamblia by ELISA, and IgG, IgM and IgA by immunoblot) and microscopy in clinical samples. Microscopic findings for three preserved stools were considered the gold standard. SETTING: Travel medicine clinic. POPULATION STUDIED: Adults, post-travel, with gastrointestinal symptomatology. MAIN RESULTS: For 152 previously collected stools, copro-antigen detection had a sensitivity of 73 of 74 (98.6%) and a specificity of 78 of 78 (100%). In clinical samples of 62 patients, eight of the 62 patients (13%) were diagnosed with G lamblia infection on microscopy. Copro-antigen diagnosis was accurate in symptomatic patients, with sensitivity of seven of eight (87.5%) and specificity of 52 of 54 (96.8%). Serology was less accurate. IgG response to G lamblia had sensitivity of four of seven and specificity of 24 of 50 (48%), and IgM response had sensitivity of three of six and specificity 27 of 48 (56%). Western blot had a sensitivity of five of seven and a specificity of 38 of 49 (78%). CONCLUSIONS: Copro-antigen diagnosis of G lamblia is highly accurate in patients with chronic gastrointestinal complaints, while serology is less accurate and appears to be less useful diagnostically. PMID- 22514477 TI - Parvovirus B19-induced constellation of acute renal failure, elevated aminotransferases and congestive heart failure. AB - This report details a case of acute renal failure and elevated aminotransferases with subsequent development of congestive heart failure in a patient with history of exposure to parvovirus B19 and serological evidence of acute infection with this agent. This constellation of organ involvement has not been previously reported in the literature. PMID- 22514478 TI - Broadening horizons: Integrating quantitative and qualitative research. PMID- 22514476 TI - Cat scratch disease: The story continues. AB - OBJECTIVE: To present a perspective on the current state of knowledge of cat scratch disease (CSD), including the evidence for Bartonella henselae as the etiological agent, epidemiological and clinical characteristics of the disease, available diagnostic tests and current therapeutic options. DATA SOURCES: MEDLINE search of the literature published from 1966 to 1995 using 'cat scratch disease', 'Bartonella henselae', 'Rochalimaea henselae' as key words and bibliographies of selected papers. DATA EXTRACTION: Selected studies reporting data on etiology, epidemiology, clinical characteristics, diagnosis and therapy of CSD were evaluated. DATA SYNTHESIS AND CONCLUSIONS: Evidence accumulated to date supports B henselae as the etiological agent of CSD. The most significant risk factors for CSD are being licked on the face, scratched or bitten by a kitten and owning a kitten with fleas. Available serological tests can confirm classic CSD and identify B henselae as the cause of more atypical presentations, such as fever of unknown origin, granulomatous hepatitis, encephalitis and osteomyelitis. Symptomatic management is appropriate for isolated lymphadenopathy caused by CSD in healthy individuals; however, antibiotic therapy may be indicated for patients with more severe manifestations of the disease and immunocompromised hosts. Further study of CSD, in particular the epidemiology and therapy, is warranted. A better understanding of the pathogenesis of B henselae infection will have important implications in both immunocompetent and immunocompromised individuals. PMID- 22514479 TI - Prevention of perinatal group B streptococcal infection: Management strategies. PMID- 22514480 TI - Vancomycin-resistant enterococci (VRE) in Canada - Results of the Canadian Nosocomial Infection Surveillance Program 1996 VRE point prevalence surveillance project. PMID- 22514481 TI - Rubella antibody levels in school-aged children in Newfoundland: Implications for a two-dose rubella vaccination strategy. AB - OBJECTIVE: To determine the prevailing levels of rubella immunity among school aged children who received a single dose of measles-mumps-rubella (MMR) vaccine at one year of age. DESIGN: Cross-sectional study with a two stage cluster sampling of randomly picked schools across the province of Newfoundland. STUDY POPULATION AND METHODS: A total of 1053, five to 17-year-old children were enrolled; vaccination history was verified through official records; and a sample of blood was taken. Rubella immunity was determined by enzyme immunoassay based on a serum antibody protective cut-off titre of more than 10 IU. RESULTS: A total of 145 (13.8%) were found to be nonimmune. The rate of susceptibility ranged from 3.2% to 25.9% for different age groups. The proportion susceptible was significantly higher at 16.5% in the age group eight to 17 years old versus 3.9% for the age group five to eight years old (chi(2)=24.08; df=1, P<0.001). There was a significant regression of logarithm titre values on the age of children with an average decline in titre values of 8.1% per annum. CONCLUSIONS: A substantial number of those who were given a single dose of MMR II vaccine may not have protective immunity against rubella as they reach prime reproductive age. There is a definite need to consider a two-dose rubella vaccination strategy in Canada, and these data suggest the second dose given after eight years of age will be most beneficial. In the move towards a routine two-dose measles vaccination strategy in Canada, the MMR II vaccine is being used for the second dose and given either at 18 months of age or at school entry. While this approach will have an overall beneficial effect, the impact of the above timing of the second dose on long term rubella immunity cannot be predicted at this time. These data also underscore the continuing need for prenatal rubella screening program. PMID- 22514482 TI - Prospective, randomized comparison of intravenous and oral ciprofloxacin with intravenous ceftazidime in the treatment of nosocomial pneumonia. AB - OBJECTIVE: To compare the efficacy of intravenous and oral ciprofloxacin and intravenous ceftazidime in the treatment of nosocomial pneumonia. DESIGN: Randomized, nonblinded, multicentre comparative trial. SETTING: Seven Canadian university hospitals. POPULATION: Adult patients with moderate to severe pneumonia developing 72 h or longer after hospitalization. METHODS: After informed consent was obtained, patients were randomized to receive intravenous ciprofloxacin 300 mg every 12 h or ceftazidime 2 g every 8 h. After three days, patients in the ciprofloxacin arm could be switched to oral ciprofloxacin, 750 mg every 12 h. Concomitant clindamycin was allowed for three days in patients with syndromes consistent with Gram-positive or anaerobic infection. Erythromycin could be used if cultures revealed no pathogen. RESULTS: A total of 149 patients were enrolled, of whom 124 were eligible for efficacy analysis. Of 119 pathogens identified in 87 patients, 84 were Gram-negative, and 35 Gram-positive. The mean duration of ciprofloxacin therapy was 12.1 days, of which 9.2 days were given intravenously. Ceftazidime was given for a mean of 9.8 days. There was eradication or reduction of pathogens in 75.7% of ciprofloxacin patients and 70.6% of the ceftazidime group. Clinical resolution or improvement occurred in 87.1% of ciprofloxacin recipients and 87.3% of the ceftazidime group. Eight ciprofloxacin and six ceftazidime patients died. Overall outcomes were considered to be successful in 85.2% of ciprofloxacin patients and 87.1% of ceftazidime recipients. Adverse events were mild. CONCLUSIONS: There were similar efficacy and safety of intravenous and oral ciprofloxacin and intravenous ceftazidime in the treatment of patients with hospital-acquired pneumonia. Physicians were reluctant to use oral therapy in patients. PMID- 22514483 TI - Survey of physicians concerning the use of chest radiography in the diagnosis of pneumonia in out-patients. AB - OBJECTIVE: To determine how physicians use chest radiography in the diagnosis of pneumonia in ambulatory patients. STUDY POPULATION: A convenience sample of 176 Nova Scotia family physicians and internists selected to represent all geographic areas of the province proportional to population. STUDY INSTRUMENT: A 35-item questionnaire covering demographics, experience with out-patients with pneumonia, use of chest radiographs to make this diagnosis and factors that were considered important in the decision to perform initial and follow-up chest radiographs. Two skill-testing questions were also included. RESULTS: One hundred and fourteen of 176 (64.7%) responded; 88% had treated out-patients with pneumonia in the previous three months. Fifty-seven per cent of physicians requested chest radiographs on 90% to 100% of out-patients in whom they had made a clinical diagnosis of pneumonia. These physicians were more likely to be internists and to have graduated before 1970. Factors that ranked most important in the decision to request the initial chest radiograph were clinical appearance, respiratory distress and physical findings, while age and smoking history contributed most to the decision to perform a follow-up chest radiograph. CONCLUSIONS: There is considerable variability among physicians in requesting chest radiographs on out patients with a clinical diagnosis of pneumonia. Physician and patient factors contribute to this variability. PMID- 22514484 TI - Apoptosis: Molecular mechanisms, regulation and role in pathogenesis. AB - OBJECTIVE: To review the current state of knowledge of apoptosis, with an emphasis on identifying potential and established roles for apoptosis in the pathogenesis of infectious diseases. DATA SOURCES: MEDLINE and the University of British Columbia library system were searched using the search subject, "apoptosis", for the years 1992 to 1996. Further search terms (eg, "pathogenesis") were used to narrow the results. These review articles and reference books were used as the basis for locating original articles on particular studies. DATA SELECTION: Approximately 40 studies were reviewed, with the criterion for selection being the relevance to either the molecular mechanisms behind apoptosis or roles for apoptosis in the pathogenesis of infectious diseases. DATA EXTRACTION: Relevant information from each study was collated into categories specific to morphological and biochemical characterization, and the regulation and molecular mechanisms of apoptosis and its role in the pathogenesis of infectious diseases. DATA SYNTHESIS AND CONCLUSIONS: Apoptosis is characterized by distinct morphological and biochemical changes that distinguish it from cell necrosis. Different signal transduction events and transcription factors can promote or inhibit apoptosis, although where and how these tie into the cell death pathway is still poorly understood. Apoptosis has been implicated in the pathogenesis of infectious diseases in two distinct ways: first, multicellular organisms use apoptosis to combat viral infections; and second, pathogens can alter the normal process of apoptosis in host cells by abnormal upregulation or downregulation. Many diseases have been shown to implicate apoptosis in their pathogenesis, raising the possibility of novel treatments for some disorders by therapeutically altering the occurrence and course of apoptosis. Therefore, further study of apoptosis in both health and disease needs to be rigorously pursued. PMID- 22514485 TI - Rhomboencephalitis caused by Listeria monocytogenes. AB - Listerial rhomboencephalitis is a rare, devastating treatable disease. A previously well 72-year-old man presented with a one-week history of fever and headache. Four days before admission he developed right facial numbness and ataxia. Diagnosis and treatment are described, including the relevant clinical, laboratory and radiological findings. PMID- 22514486 TI - Invasion of eukaryotic cells by Legionella pneumophila: A common strategy for all hosts? AB - Legionella pneumophila is an environmental micro-organism capable of producing an acute lobar pneumonia, commonly referred to as Legionnaires' disease, in susceptible humans. Legionellae are ubiquitous in aquatic environments, where they survive in biofilms or intracellularly in various protozoans. Susceptible humans become infected by breathing aerosols laden with the bacteria. The target cell for human infection is the alveolar macrophage, in which the bacteria abrogate phagolysosomal fusion. The remarkable ability of L pneumophila to infect a wide range of eukaryotic cells suggests a common strategy that exploits very fundamental cellular processes. The bacteria enter host cells via coiling phagocytosis and quickly subvert organelle trafficking events, leading to formation of a replicative phagosome in which the bacteria multiply. Vegetative growth continues for 8 to 10 h, after which the bacteria develop into a short, highly motile form called the 'mature form'. The mature form exhibits a thickening of the cell wall, stains red with the Gimenez stain, and is between 10 and 100 times more infectious than agar-grown bacteria. Following host cell lysis, the released bacteria infect other host cells, in which the mature form differentiates into a Gimenez-negative vegetative form, and the cycle begins anew. Virulence of L pneumophila is considered to be multifactorial, and there is growing evidence for both stage specific and sequential gene expression. Thus, L pneumophila may be a good model system for dissecting events associated with the host-parasite interactions. PMID- 22514487 TI - Study of the comparative activity of piperacillin/tazobactam with currently available antibiotics against 8206 aerobic isolates. AB - OBJECTIVES: To compare the activity of piperacillin-tazobactam with piperacillin and other parenterally administered antibiotics against aerobic Gram-negative bacilli and Gram-positive cocci isolated from across Canada, and to determine the prevalence of resistance mediated by extended-spectrum cephalosporinases. METHODS: Sixty-one laboratories participated. Disk diffusion testing was performed in accordance with methods outlined by the National Committee for Clinical Laboratory Standards. Susceptibilities were performed on 8206 strains. Escherichia coli and Klebsiella pneumoniae with reduced susceptibilities to third generation cephalosporins were screened for extended-spectrum beta-lactamases (ESBLs). RESULTS: Piperacillin-tazobactam was active against 92% of the strains, piperacillin against 81% and ticarcillin-clavulanic acid against 88%. Few differences were observed in the relative susceptibility of strains from teaching or community hospitals, from different anatomic sites or from different regions of the country. Aerobic Gram-negative bacilli tested tended to be more susceptible to all the agents than was recently reported in a similar American study. Only 43% of Enterococcus faecium were susceptible to ampicillin and 42% to piperacillin piperacillin with and without tazobactam. Only two enterococcal strains were resistant to vancomycin, and 19 had intermediate zone sizes. Of the 10 strains of E coli and eight strains of K pneumoniae with reduced susceptibility to extended spectrum cephalosporins, only one demonstrated typical ESBL activity. CONCLUSIONS: Canadian aerobic Gram-positive cocci and Gram negative bacilli remain highly susceptible to many currently available antibiotics. The findings confirm a broad spectrum of activity of piperacillin tazobactam and indicate that the pattern of susceptibility is quite uniform from different body sites, in both teaching and community hospitals, and across the country. PMID- 22514488 TI - Reduction in the nephrotoxicity of amphotericin B when administered in 20% intralipid. AB - The administration of amphotericin B (AmB) is often limited by the development of nephrotoxicity. In a pilot crossover trial, aqueous AmB followed by a new preparation of a mixture of AmB with 20% intralipid (AmB-IL) was administered to 10 immunocompromised patients for systemic fungal infections caused by Candida species. Mean total dose and duration of therapy with AmB-IL exceeded that of aqueous AmB (649+/-165 mg versus 394+/-105 mg, P=0.061 and 13.2+/-2.5 days versus 9+/-2.1 days, P=0.31). However, mean creatinine clearance of the patients rose during AmB-IL therapy by 10.7+/-7.7 mL/min (P=0.03). AmB-IL warrants further investigation to assess its stability and efficacy for treating serious fungal infections. PMID- 22514490 TI - Disappearing breast cancers. PMID- 22514489 TI - Short course monotherapy with clarithromycin for localized Mycobacterium marinum skin infection. AB - In vitro studies have shown that Mycobacterium marinum is usually susceptible to clarithromycin. However, there are limited published data on the clinical use of clarithromycin for the treatment of M marinum infections. This report describes a previously healthy 58-year-old man who developed a chronic soft tissue infection of his right hand caused by M marinum. He responded to four weeks' therapy with clarithromycin. Follow-up at six months showed no relapse. Our experience and review of the literature suggest that short course monotherapy with clarithromycin may be quite effective for uncomplicated soft issue infections caused by M marinum. PMID- 22514491 TI - Improving cancer control in Canada through knowledge translation: from in-the field projects to policy initiatives in a new standing section in Current Oncology. PMID- 22514492 TI - Alternative and orthodox medicine and the "odd" principle. PMID- 22514493 TI - Accelerating knowledge to action: the pan-Canadian cancer control strategy. AB - BACKGROUND: In 2006, the federal government committed funding of $250 million over 5 years for the Canadian Partnership Against Cancer Corporation to begin implementation of the Canadian Strategy for Cancer Control (CSCC). The Partnership was established as a not-for-profit corporation designed to work actively with a broad range of stakeholders and organizations that had been engaged in the development of the CSCC and with the public more broadly. A policy experiment unto itself, the Partnership was the first disease-based organization funded at the federal level outside of government. It was charged with a mandate to enable transfer of knowledge and to catalyze coordinated and accelerated action across the country to reduce the burden of cancer. IMPLEMENTATION: Implementation has involved establishing shared goals, objectives, and plans with participating partners. Knowledge management-incorporating pan-Canadian approaches to the identification of content, processes, technology, and culture change-was used to enable that work across the federated health care delivery system. Evaluation of the organization through independent review, the ability to achieve initiative-level targets by 2012, and progress measured using indicators of system performance was used to examine the effectiveness of the strategy and approach overall. DISCUSSION AND CONCLUSIONS: Evaluation findings support the conclusions that Canada has made progress in achieving immediate outcomes (achievable in <5 years) associated with advancing its cancer control goals and that there is evidence that, with sustained effort, those goals will translate into a long-term (>25 years) impact on cancer. The mechanism of funding the Partnership to develop collaboration among stakeholders in cancer control to achieve coordinated action has been possible and has been enabled through the Partnership's knowledge-to-action mandate. Opportunities are available to further engage and clarify the roles of stakeholders in action, to clearly define outcomes, and to further quantify the economic benefits that have resulted from a coordinated approach. With the ongoing funding commitment to support coordinated action within a federated environment of health care delivery, there is opportunity to reduce the impact that cancer may have in the long term in Canada. PMID- 22514494 TI - A personalized approach to treatment: use of EGFR tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer in Canada. AB - Lung cancer is one of the most commonly diagnosed malignancies and the leading cause of cancer-related mortality in Canada. The heterogeneity of nsclc and the importance of linking new targeted agents to the appropriate disease subtype require an individualized approach to treatment. In patients with EGFR (epidermal growth factor receptor gene) mutations, EGFR tyrosine kinase inhibitors (TKIs) provide a highly effective treatment option, with improved toxicity compared with standard chemotherapy. However, the identification of mutation-positive patients is limited by a lack of funding for testing. The length of time required to receive test results and insufficient tissue from biopsies are additional limitations. In Canada, the use of EGFR-TKIs varies based on differences in provincial funding for both testing and treatment. With improvements in testing and access to funding for treatment, targeted use of EGFR-TKIs may greatly improve outcomes in NSCLC. PMID- 22514496 TI - A mixed-methods cohort study to determine perceived patient benefit in providing custom breast prostheses. AB - BACKGROUND: Of all mastectomy patients, 90% will use an external prosthesis where the standard of care uses a stock prosthesis that is purchased "off the shelf." Our objectives were to determine patient demand for and perceived value of a custom breast prosthesis. The information obtained will influence future research and program direction. METHODS: We asked 65 women who had undergone lumpectomy or mastectomy to participate before exploring rehabilitation options. The quantitative outcome measures were the European Organisation for Research and Treatment of Cancer QLQ-C30 general and -BR23 breast cancer-specific quality of life questionnaires, and the Ambulatory Oncology Patients Satisfaction Tool. The QLQ results were analyzed using the Mann-Whitney U-test. Results of the satisfaction tool were compared using the Fisher exact and chi-square tests. A descriptive qualitative approach-involving in-depth interviews exploring the experiences of the women-was used to establish the perceived value of the services to the patients. The analysis of the interview transcripts was conducted using a standardized content method to describe the experiences of the women. RESULTS: All the women had had previous experiences with a conventional prosthesis, and they reported that wearing a custom prosthesis was more satisfying for them. They reported comfort and ease in wearing it, coupled with a sense of feeling less like a victim. Comparison of the QLQ and patient satisfaction scores showed no significant difference between the women wearing the conventional prosthesis and those wearing the custom prosthesis. CONCLUSIONS: The qualitative data provide a strong case in support of the new device. Patient demand, perceived benefit, and experience wearing the prosthesis were documented. Suggestions for improvements in the device and in the program operations were gathered and will influence future development of this service. PMID- 22514495 TI - Advances in the management of metastatic breast cancer: options beyond first-line chemotherapy. AB - This article provides an overview of recent advances in chemotherapy that may be used for the treatment of patients with locally advanced or metastatic breast cancer (MBC). Key phase ii and iii trial data for eribulin mesylate, ixabepilone, and nab-paclitaxel, published since 2006, are discussed on the basis of recency, depth, and quality.Eribulin mesylate is the first monotherapy to significantly increase overall survival in patients with pretreated MBC, but nab-paclitaxel offers a novel and safer mode of delivery in comparison with standard taxanes. By contrast, the use of ixabepilone will be limited for now, until the associated neurotoxicity can be better managed. Alongside a brief overview of the other major chemotherapies currently in use, we have aimed to provide a Canadian context for how these novel agents may be integrated into clinical practice. PMID- 22514497 TI - Characterizing distress, the 6th vital sign, in an oncology pain clinic. AB - CONTEXT: The delineation of populations of cancer patients with complex symptoms can inform the planning and delivery of supportive care services. OBJECTIVES: We explored the physical, psychosocial, and practical concerns experienced by patients attending an ambulatory oncology symptom control clinic. METHODS: Patients attending a Pain Clinic at a large tertiary cancer centre were invited to complete screening measures assessing distress, pain, fatigue, anxiety, depression, and practical and psychosocial problems. A matched sample of patients who did not attend the Pain Clinic were selected as a comparison group. RESULTS: Of all eligible Pain Clinic patients, 46 (77%) completed the measures; so did 46 comparison group patients. The percentages of patients reporting distress (78.3%), pain (93.5%), and fatigue (93.5%) were higher among Pain Clinic patients than among the comparison patients. A higher percentage of Pain Clinic patients also reported multiple, severe, concurrent symptoms: 87% scored 7 or higher in at least one of the pain, fatigue, or distress scales, and 30.4% of the patients scored 7 or higher on all three. The most common problem areas were feeling a burden to others, trouble talking with friends and family, spirituality, and sleep difficulties. CONCLUSIONS: Higher levels of multiple, concurrent symptoms and psychosocial problems were found in Pain Clinic patients than in a group of patients who did not attend the Pain Clinic. Routine screening and triaging of cancer patients using a comprehensive and standardized panel of questions can facilitate symptom assessment and management, and can inform program planning. PMID- 22514498 TI - What is the optimal management of dysphagia in metastatic esophageal cancer? AB - BACKGROUND: The palliation of dysphagia in metastatic esophageal cancer remains a challenge, and the optimal approach for this difficult clinical scenario is not clear. We therefore sought to define and determine the efficacy of various treatment options used at our institution for this condition. METHODS: We reviewed a prospective database for all patients managed in an esophageal cancer referral centre over a 5-year period. All patients receiving palliation of malignant dysphagia were reviewed for demographics, palliative treatment modalities, complications, and dysphagia scores (0 = none to 4 = complete). The Wilcoxon signed rank test was used to determine significance (p < 0.05). RESULTS: During 2004-2009, 63 patients with inoperable esophageal cancer were treated for palliation of dysphagia. The primary treatment was radiotherapy in 79% (brachytherapy in 18 of 50; external-beam in 10 of 50; both types in 22 of 50), and stenting in 21%. Mean wait time from diagnosis to treatment was 22 days in the stent group and 54 days in the radiotherapy group (p = 0.003). Mean duration of treatment was 1 day in the stent group and 40 days in the radiotherapy group (p = 0.001). In patients treated initially by stenting, dysphagia improved within 2 weeks of treatment in 85% of patients (dysphagia score of 0 or 1). However, 20% of patients presented with recurrence of dysphagia at 10 weeks of treatment. In the radiotherapy group, the onset of palliation was slower, with only 50% of patients palliated at 2 weeks (dysphagia score of 0 or 1). However, long-term palliation was more satisfactory, with 90% of patients remaining palliated after 10 weeks of treatment. CONCLUSIONS: In inoperable esophageal cancer at our centre, radiation treatment provided durable long-term relief, but came at a high price of a long wait time for initiation of treatment and a long lag time between initiation of treatment and relief of symptoms. On the other hand, endoluminal stenting provided more rapid and effective early relief from symptoms, but was affected by recurrence of dysphagia in the long-term. It is now time for a prospective randomized trial to assess the safety and efficacy of combined modality treatment with both endoluminal stenting and radiation therapy compared with either treatment alone. PMID- 22514499 TI - EGFR tyrosine kinase mutation testing in the treatment of non-small-cell lung cancer. AB - BACKGROUND: Non-small-cell lung cancer (nsclc) tumours with activating mutations of the epidermal growth factor receptor (efgr) tyrosine kinase are highly sensitized to the effects of oral tyrosine kinase inhibitors such as gefitinib and erlotinib, suggesting the possibility of targeted treatment of nsclc based on EFGR mutation status. However, no standardized method exists for assessing the EGFR mutation status of tumours. Also, it is not known if available methods are feasible for routine screening. To address that question, we conducted a validation study of methods used for detecting EGFR mutations in exons 19 and 21 at molecular laboratories located in five specialized Canadian cancer centres. METHODS: The screening methods were first optimized using cell lines harbouring the mutations in question. A validation phase using anonymized patient samples followed. RESULTS: The methods used at the sites were highly specific and sensitive in detecting both mutations in cell-line dna (specificity of 100% and sensitivity of at least 1% across all centres). In the validation phase, we observed excellent concordance between the laboratories for detecting mutations in the patient samples. Concordant results were obtained in 26 of 30 samples (approximately 87%). In general, the samples for which results were discordant were also less optimal, containing small amounts of tumour. CONCLUSIONS: Our results suggest that currently available methods are capable of reliably detecting exon 19 and exon 21 mutations of EFGR in tumour samples (provided that sufficient tumour material is available) and that routine screening for those mutations is feasible in clinical practice. PMID- 22514500 TI - Phase ii trial of a metronomic schedule of docetaxel and capecitabine with concurrent celecoxib in patients with prior anthracycline exposure for metastatic breast cancer. AB - BACKGROUND: This phase ii clinical trial examined the activity of a metronomic dosing schedule of docetaxel and capecitabine chemotherapy in patients with advanced breast cancer. Patients also received daily oral celecoxib in an effort to improve outcome measures and to ameliorate some of the common side effects of chemotherapy. METHODS: Patients received docetaxel at a starting dose of 15 mg/m2 weekly, oral capecitabine 1250 mg/m2 once daily, and oral celecoxib 200 mg twice daily. The primary endpoint was clinical benefit: percentage of patients experiencing either an objective response or stable disease (sd) for more than 6 months. In the absence of significant neutropenia, the dose of docetaxel was escalated after 4 and 8 weeks of treatment. Therapy was given until disease progression or development of unacceptable toxicity. The level of thymidine phosphorylase expression in peripheral white blood cells of patients was measured before and during treatment to determine the effect on this capecitabine activating enzyme. RESULTS: Of 47 patients enrolled, 38 (81%) completed treatment to a disease endpoint. No complete responses were achieved, but 13 of the 38 patients (34%) experienced a partial response, and another 3 patients (8%) experienced sd for more than 6 months. The clinical benefit rate was therefore 42% (95% confidence interval: 27% to 57%). The median time to disease progression for all evaluable patients was 3.6 months (range: 0.9-21.7 months). The most common nonhematologic toxicities were diarrhea, plantar- palmar erythrodysesthesia, fatigue, mucositis, and vomiting. Most patients (89%) received combination chemotherapy until disease progression. CONCLUSIONS: The present study demonstrates that metronomic docetaxel-capecitabine chemotherapy with daily celecoxib can produce significant anticancer activity, with predictable toxicity. Efficacy fell short of expectations, with outcome measures being similar to those obtained when the study agents are given in conventional dosing. Furthermore, there is mounting evidence to indicate that a low dose of taxanes fails to induce thymidine phosphorylase expression, an effect believed to be important in achieving therapeutic synergism when taxanes are given concurrently with capecitabine. PMID- 22514501 TI - Editor's letter. PMID- 22514502 TI - Update to "Beyond Citation Analysis: A Model for Assessment of Research Impact". PMID- 22514503 TI - Identities and relationships: parallels between metadata and professional relevance. PMID- 22514504 TI - Redesigning a library-based genetics class research project through instructional theory and authentic experience. AB - QUESTION: How can the library-based research project of a genetics course be reinvigorated and made sustainable without sacrificing educational integrity? SETTING: The University of Florida's Health Science Center Library provides the case study. METHODS: Since 1996, the librarian has codeveloped, supported, and graded all components of the project. In 2009, the project evolved from a single authored paper to a group-work poster, with graded presentations hosted by the library. In 2010, students were surveyed regarding class enhancements. RESULTS: Responses indicated a preference for collaborative work and the poster format and suggested the changes facilitated learning. Instructors reported that the poster format more clearly documented students' understanding of genetics. CONCLUSION: Results suggest project enhancements contributed to greater appreciation, understanding, and application of classroom material and offered a unique and authentic learning experience, without compromising educational integrity. The library benefitted through increased visibility as a partner in the educational mission and development of a sustainable instructional collaboration. PMID- 22514505 TI - Pay-per-view in interlibrary loan: a case study. AB - QUESTION: Can purchasing articles from publishers be a cost-effective method of interlibrary loan (ILL) for libraries owing significant copyright royalties? SETTING: The University of Nebraska Medical Center's McGoogan Library of Medicine provides the case study. METHOD: Completed ILL requests that required copyright payment were identified for the first quarter of 2009. The cost of purchasing these articles from publishers was obtained from the publishers' websites and compared to the full ILL cost. A pilot period of purchasing articles from the publisher was then conducted. RESULTS: The first-quarter sample data showed that approximately $500.00 could have been saved if the articles were purchased from the publisher. The pilot period and continued purchasing practice have resulted in significant savings for the library. CONCLUSION: Purchasing articles directly from the publisher is a cost-effective method for libraries burdened with high copyright royalty payments. PMID- 22514506 TI - Provision of pandemic disease information by health sciences librarians: a multisite comparative case series. AB - OBJECTIVE: The research provides an understanding of pandemic information needs and informs professional development initiatives for librarians in disaster medicine. METHODS: Utilizing a multisite, comparative case series design, the researchers conducted semi-structured interviews and examined supplementary materials in the form of organizational documents, correspondence, and websites to create a complete picture of each case. The rigor of the case series was ensured through data and investigator triangulation. Interview transcripts were coded using NVivo to identify common themes and points of comparison. RESULTS: Comparison of the four cases revealed a distinct difference between "client initiated" and "librarian-initiated" provision of pandemic information. Librarian initiated projects utilized social software to "push" information, whereas client initiated projects operated within patron-determined parameters to deliver information. Health care administrators were identified as a key audience for pandemic information, and news agencies were utilized as essential information sources. Librarians' skills at evaluating available information proved crucial for selecting best-quality evidence to support administrative decision making. CONCLUSIONS: Qualitative analysis resulted in increased understanding of pandemic information needs and identified best practices for disseminating information during periods of high organizational stress caused by an influx of new cases of an unknown infectious disease. PMID- 22514507 TI - Rethinking information delivery: using a natural language processing application for point-of-care data discovery. AB - OBJECTIVE: This paper examines the use of Semantic MEDLINE, a natural language processing application enhanced with a statistical algorithm known as Combo, as a potential decision support tool for clinicians. Semantic MEDLINE summarizes text in PubMed citations, transforming it into compact declarations that are filtered according to a user's information need that can be displayed in a graphic interface. Integration of the Combo algorithm enables Semantic MEDLINE to deliver information salient to many diverse needs. METHODS: The authors selected three disease topics and crafted PubMed search queries to retrieve citations addressing the prevention of these diseases. They then processed the citations with Semantic MEDLINE, with the Combo algorithm enhancement. To evaluate the results, they constructed a reference standard for each disease topic consisting of preventive interventions recommended by a commercial decision support tool. RESULTS: Semantic MEDLINE with Combo produced an average recall of 79% in primary and secondary analyses, an average precision of 45%, and a final average F-score of 0.57. CONCLUSION: This new approach to point-of-care information delivery holds promise as a decision support tool for clinicians. Health sciences libraries could implement such technologies to deliver tailored information to their users. PMID- 22514509 TI - Using an automated tool to calculate return on investment and cost benefit figures for resources: the Health Sciences and Human Services Library experience. PMID- 22514508 TI - Comparing patient characteristics, type of intervention, control, and outcome (PICO) queries with unguided searching: a randomized controlled crossover trial. AB - BACKGROUND: Translating a question into a query using patient characteristics, type of intervention, control, and outcome (PICO) should help answer therapeutic questions in PubMed searches. The authors performed a randomized crossover trial to determine whether the PICO format was useful for quick searches of PubMed. METHODS: Twenty-two residents and specialists working at the Radboud University Nijmegen Medical Centre were trained in formulating PICO queries and then presented with a randomized set of questions derived from Cochrane reviews. They were asked to use the best query possible in a five-minute search, using standard and PICO queries. Recall and precision were calculated for both standard and PICO queries. RESULTS: Twenty-two physicians created 434 queries using both techniques. Average precision was 4.02% for standard queries and 3.44% for PICO queries (difference nonsignificant, t(21) = -0.56, P = 0.58). Average recall was 12.27% for standard queries and 13.62% for PICO queries (difference nonsignificant, t(21) = -0.76, P = 0.46). CONCLUSIONS: PICO queries do not result in better recall or precision in time-limited searches. Standard queries containing enough detail are sufficient for quick searches. PMID- 22514510 TI - Failure or success of electronic search strategies to identify adverse effects data. PMID- 22514512 TI - Promoting and teaching the history of medicine in a medical school curriculum. PMID- 22514511 TI - Does Bradford's Law of Scattering predict the size of the literature in Cochrane Reviews? PMID- 22514513 TI - The role of medical librarians in medical education review articles. PMID- 22514514 TI - The impact of indoor residual spraying on malaria incidence in East Shoa Zone, Ethiopia. AB - BACKGROUND: In Ethiopia, nearly 70% of the population resides in areas prone to malaria infection. The objective of this study is to evaluate the impact of indoor residual spraying (IRS) on the incidence of malaria in East Shoa Zone of Ethiopia. METHODS: Data from the registers of malaria cases at Debrezeit Malaria Control Center in East Shoa Zone of Ethiopia were collected and analyzed. Records of 22 villages with no previous rounds of spraying that were entirely covered with IRS using DDT during the peak malaria transmission season of 2001 and 2002 and other 22 adjacent villages with similar malaria incidence but remained unsprayed were used for the analyses. RESULTS: The incidence of malaria in 2011 and 2002 among the sprayed villages was lower than the respective preceding years for both Plasmodium species (incidence rate ratio 0.60; CI 0.35 to 0.95; p < 0.0001). After the focal spray, there was significant reduction in malaria incidence in the villages sprayed. Spraying was associated with a 62% reduction in malaria incidence. CONCLUSIONS: This study demonstrated that IRS with DDT was effective in reducing malaria incidence in highland epidemic-prone areas in the East Shoa Zone of Ethiopia. A larger scale study should evaluate the effectiveness of DDT in reducing malaria incidence against its environmental impact and alternative strategies for malaria prevention. PMID- 22514515 TI - The origins of options. AB - Most research on decision making has focused on how human or animal decision makers choose between two or more options, posed in advance by the researchers. The mechanisms by which options are generated for most decisions, however, are not well understood. Models of sequential search have examined the trade-off between continued exploration and choosing one's current best option, but still cannot explain the processes by which new options are generated. We argue that understanding the origins of options is a crucial but untapped area for decision making research. We explore a number of factors which influence the generation of options, which fall broadly into two categories: psycho-biological and socio cultural. The former category includes factors such as perceptual biases and associative memory networks. The latter category relies on the incredible human capacity for culture and social learning, which doubtless shape not only our choices but the options available for choice. Our intention is to start a discussion that brings us closer toward understanding the origins of options. PMID- 22514517 TI - Acetylcholinesterase involvement in apoptosis. AB - To date, more than 40 different types of cells from primary cultures or cell lines have shown AChE expression during apoptosis and after the induction apoptosis by different stimuli. It has been well-established that increased AChE expression or activity is detected in apoptotic cells after apoptotic stimuli in vitro and in vivo, and AChE could be therefore used as a marker of apoptosis. AChE is not an apoptosis initiator, but the cells in which AChE is overexpressed undergo apoptosis more easily than controls. Interestingly, cells with downregulated levels of AChE are not sensitive to apoptosis induction and AChE deficiency can protect against apoptosis. Some tumor cells do not express AChE, but when AChE is introduced into a tumor cell, the cells cease to proliferate and undergo apoptosis more readily. Therefore, AChE can be classified as a tumor suppressor gene. AChE plays a pivotal role in apoptosome formation, and silencing of the AChE gene prevents caspase-9 activation, with consequent decreased cell viability, nuclear condensation, and poly (adenosine diphosphate-ribose) polymerase cleavage. AChE is translocated into the nucleus, which may be an important event during apoptosis. Several questions still need to be addressed, and further studies that address the non-classical function of AChE in apoptosis are needed. PMID- 22514516 TI - The essential role of AMPA receptor GluR2 subunit RNA editing in the normal and diseased brain. AB - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are comprised of different combinations of GluA1-GluA4 (also known asGluR1-GluR4 and GluR-A to GluR-D) subunits. The GluA2 subunit is subject to RNA editing by the ADAR2 enzyme, which converts a codon for glutamine (Gln; Q), present in the GluA2 gene, to a codon for arginine (Arg; R) found in the mRNA. AMPA receptors are calcium (Ca(2+))-permeable if they contain the unedited GluA2(Q) subunit or if they lack the GluA2 subunit. While most AMPA receptors in the brain contain the edited GluA2(R) subunit and are therefore Ca(2+)-impermeable, recent evidence suggests that Ca(2+)-permeable AMPA receptors are important in synaptic plasticity, learning, and disease. Strong evidence supports the notion that Ca(2+)-permeable AMPA receptors are usually GluA2-lacking AMPA receptors, with little evidence to date for a significant role of unedited GluA2 in normal brain function. However, recent detailed studies suggest that Ca(2+)-permeable AMPA receptors containing unedited GluA2 do in fact occur in neurons and can contribute to excitotoxic cell loss, even where it was previously thought that there was no unedited GluA2.This review provides an update on the role of GluA2 RNA editing in the healthy and diseased brain and summarizes recent insights into the mechanisms that control this process. We suggest that further studies of the role of unedited GluA2 in normal brain function and disease are warranted, and that GluA2 editing should be considered as a possible contributing factor when Ca(2+)-permeable AMPA receptors are observed. PMID- 22514518 TI - Memory, plasticity and sleep - A role for calcium permeable AMPA receptors? AB - Experience shapes and molds the brain throughout life.These changes in neuronal circuits are produced by a myriad of molecular and cellular processes. Simplistically, circuits are modified through changes in neurotransmitter release or through neurotransmitter detection at synapses. The predominant neurotransmitter receptor in excitatory transmission, the AMPA-type glutamate receptor (AMPAR), is exquisitely sensitive to changes in experience and synaptic activity. These ion channels are usually impermeable to calcium, a property conferred by the GluA2 subunit. However, GluA2-lacking AMPARs are permeable to calcium and have recently been shown to play a unique role in synaptic function. In this review, I will describe new findings on the role of calcium permeable AMPARs (CP-AMPARs) in experience-dependent and synaptic plasticity.These studies suggest that CP-AMPARs play a prominent role in maintaining circuits in a labile state where further plasticity can occur, thus promoting metaplasticity. Moreover, the abnormal expression of CP-AMPARs has been implicated in drug addiction and memory disorders and thus may be a novel therapeutic target. PMID- 22514519 TI - Tuning synaptic transmission in the hippocampus by stress: the CRH system. AB - To enhance survival, an organism needs to remember-and learn from-threatening or stressful events. This fact necessitates the presence of mechanisms by which stress can influence synaptic transmission in brain regions, such as hippocampus, that subserve learning and memory. A major focus of this series of monographs is on the role and actions of adrenal-derived hormones, corticosteroids, and of brain-derived neurotransmitters, on synaptic function in the stressed hippocampus. Here we focus on the contribution of hippocampus-intrinsic, stress activated CRH-CRH receptor signaling to the function and structure of hippocampal synapses. Corticotropin-releasing hormone (CRH) is expressed in interneurons of adult hippocampus, and is released from axon terminals during stress. The peptide exerts time- and dose-dependent effects on learning and memory via modulation of synaptic function and plasticity. Whereas physiological levels of CRH, acting over seconds to minutes, augment memory processes, exposure to presumed severe stress levels of the peptide results in spine retraction and loss of synapses over more protracted time-frames. Loss of dendritic spines (and hence of synapses) takes place through actin cytoskeleton collapse downstream of CRHR(1) receptors that reside within excitatory synapses on spine heads. Chronic exposure to stress levels of CRH may promote dying-back (atrophy) of spine-carrying dendrites. Thus, the acute effects of CRH may contribute to stress-induced adaptive mechanisms, whereas chronic or excessive exposure to the peptide may promote learning problems and premature cognitive decline. PMID- 22514520 TI - Neural stem/progenitor cells as a promising candidate for regenerative therapy of the central nervous system. AB - Neural transplantation is a promising therapeutic strategy for neurodegenerative diseases and other disorders of the central nervous system (CNS) such as Parkinson and Huntington diseases, multiple sclerosis or stroke. Although cell replacement therapy already went through clinical trials for some of these diseases using fetal human neuroblasts, several significant limitations led to the search for alternative cell sources that would be more suitable for intracerebral transplantation.Taking into account logistical and ethical issues linked to the use of tissue derived from human fetuses, and the immunologically special status of the CNS allowing the occurrence of deleterious immune reactions, neural stem/progenitor cells (NSPCs) appear to be an interesting cell source candidate. In addition to their ability for replacing cell populations lost during the pathological events, NSPCs also display surprising therapeutic effects of neuroprotection and immunomodulation. A better knowledge of the mechanisms involved in these specific characteristics will hopefully lead in the future to a successful use of NSPCs in regenerative medicine for CNS disorders. PMID- 22514521 TI - Segregated anatomical input to sub-regions of the rodent superior colliculus associated with approach and defense. AB - The superior colliculus (SC) is responsible for sensorimotor transformations required to direct gaze toward or away from unexpected, biologically salient events. Significant changes in the external world are signaled to SC through primary multisensory afferents, spatially organized according to a retinotopic topography. For animals, where an unexpected event could indicate the presence of either predator or prey, early decisions to approach or avoid are particularly important. Rodents' ecology dictates predators are most often detected initially as movements in upper visual field (mapped in medial SC), while appetitive stimuli are normally found in lower visual field (mapped in lateral SC). Our purpose was to exploit this functional segregation to reveal neural sites that can bias or modulate initial approach or avoidance responses. Small injections of Fluoro-Gold were made into medial or lateral sub-regions of intermediate and deep layers of SC (SCm/SCl). A remarkable segregation of input to these two functionally defined areas was found. (i) There were structures that projected only to SCm (e.g., specific cortical areas, lateral geniculate and suprageniculate thalamic nuclei, ventromedial and premammillary hypothalamic nuclei, and several brainstem areas) or SCl (e.g., primary somatosensory cortex representing upper body parts and vibrissae and parvicellular reticular nucleus in the brainstem). (ii) Other structures projected to both SCm and SCl but from topographically segregated populations of neurons (e.g., zona incerta and substantia nigra pars reticulata). (iii) There were a few brainstem areas in which retrogradely labeled neurons were spatially overlapping (e.g., pedunculopontine nucleus and locus coeruleus). These results indicate significantly more structures across the rat neuraxis are in a position to modulate defense responses evoked from SCm, and that neural mechanisms modulating SC-mediated defense or appetitive behavior are almost entirely segregated. PMID- 22514523 TI - Molecular compartmentalization of lateral geniculate nucleus in the gray squirrel (Sciurus carolinensis). AB - Previous research has suggested that the three physiologically defined relay cell types in mammalian lateral geniculate nucleus (LGN)-called parvocellular (P), magnocellular (M), and koniocellular (K) cells in primates and X, Y, and W cells in other mammals-each express a unique combination of cell-type marker proteins. However, some of the relationships among physiological classification and protein expression found in primates, prosimians, and tree shrews do not apply to carnivores and murid rodents. It remains unknown whether these are exceptions to a common rule for all mammals, or whether these relationships vary over a wide range of species. To address this question, we examined protein expression in the gray squirrel (Sciurus carolinensis), a highly visual rodent. Unlike many rodents, squirrel LGN is well laminated, and the organization of X-like, Y-like, and W-like cells relative to the LGN layers has been characterized physiologically. We labeled tissue sections through visual thalamus with antibodies to calbindin and parvalbumin, the antibody Cat-301, and the lectin WFA. Calbindin expression was found in W-like cells in LGN layer 3, just adjacent to the optic tract. These results suggest that calbindin is a common marker for the konicellular pathway in mammals. However, while parvalbumin expression characterizes P and M cells in primates and X and Y cells in tree shrews, here it identifies only about half of the X-like cells in LGN layers 1 and 2. Putative Y/M cell markers did not differentiate relay cells in this animal. Together, these results suggest that protein expression patterns among LGN relay cell classes are variable across mammals. PMID- 22514522 TI - Profound morphological and functional changes of rodent Purkinje cells between the first and the second postnatal weeks: a metamorphosis? AB - Between the first and the second postnatal week, the development of rodent Purkinje cells is characterized by several profound transitions. Purkinje cells acquire their typical dendritic "espalier" tree morphology and form distal spines. During the first postnatal week, they are multi-innervated by climbing fibers and numerous collateral branches sprout from their axons, whereas from the second postnatal week, the regression of climbing fiber multi-innervation begins, and Purkinje cells become innervated by parallel fibers and inhibitory molecular layer interneurons. Furthermore, their periods of developmental cell death and ability to regenerate their axon stop and their axons become myelinated. Thus a Purkinje cell during the first postnatal week looks and functions differently from a Purkinje cell during the second postnatal week. These fundamental changes occur in parallel with a peak of circulating thyroid hormone in the mouse. All these features suggest to some extent an interesting analogy with amphibian metamorphosis. PMID- 22514524 TI - The role of the lateral amygdala in the retrieval and maintenance of fear memories formed by repeated probabilistic reinforcement. AB - The lateral nucleus of the amygdala (LA) is a key element in the neural circuit subserving Pavlovian fear-conditioning, an animal model of fear and anxiety. Most studies have focused on the role of the LA in fear acquisition and extinction, i.e., how neural plasticity results from changing contingencies between a neutral conditioned stimulus (CS) (e.g., a tone) and an aversive unconditioned stimulus (US) (e.g., a shock). However, outside of the lab, fear-memories are often the result of repeated and unpredictable experiences. Examples include domestic violence, child abuse or combat. To better understand the role of the LA in the expression of fear resulting from repeated and uncertain reinforcement, rats experienced a 30% partial reinforcement (PR) fear-conditioning schedule four days a week for four weeks. Rats reached asymptotic levels of conditioned-fear expression after the first week. We then manipulated LA activity with drug (or vehicle) (VEH) infusions once a week, for the next three weeks, before the training session. LA infusions of muscimol (MUSC), a GABA-A agonist that inhibits neural activity, reduced CS evoked fear-behavior to pre-conditioning levels. LA infusions of pentagastrin (PENT), a cholecystokinin-2 (CCK) agonist that increases neural excitability, resulted in CS-evoked fear-behavior that continued past the offset of the CS. This suggests that neural activity in the LA is required for the retrieval of fear memories that stem from repeated and uncertain reinforcement, and that CCK signaling in the LA plays a role in the recovery from fear after the removal of the fear-evoking stimulus. PMID- 22514525 TI - Enhancing memory performance with rTMS in healthy subjects and individuals with Mild Cognitive Impairment: the role of the right dorsolateral prefrontal cortex. AB - A debated question in the literature is the degree of anatomical and functional lateralization of the executive control processes sub-served by the dorsolateral prefrontal cortex (DLPFC) during recognition memory retrieval. We investigated if transient inhibition and excitation of the left and right DLPFC at retrieval by means of repetitive transcranial magnetic stimulation (rTMS) modulate recognition memory performance in 100 healthy controls (HCs) and in eight patients with Mild Cognitive Impairment (MCI). Recognition memory tasks of faces, buildings, and words were used in different experiments. rTMS-inhibition of the right DLPFC enhanced recognition memory in both HCs and MCIs. rTMS-excitation of the same region in HCs deteriorated memory performance. Inhibition of the right DLPFC could modulate the excitability of a network of brain regions, in the ipsilateral as well as in the contralateral hemisphere, enhancing function in HCs or restoring an adaptive equilibrium in MCI. PMID- 22514526 TI - Richer concepts are better remembered: number of features effects in free recall. AB - Many models of memory build in a term for encoding variability, the observation that there can be variability in the richness or extensiveness of processing at encoding, and that this variability has consequences for retrieval. In four experiments, we tested the expectation that encoding variability could be driven by the properties of the to-be-remembered item. Specifically, that concepts associated with more semantic features would be better remembered than concepts associated with fewer semantic features. Using feature listing norms we selected sets of items for which people tend to list higher numbers of features (high NoF) and items for which people tend to list lower numbers of features (low NoF). Results showed more accurate free recall for high NoF concepts than for low NoF concepts in expected memory tasks (Experiments 1-3) and also in an unexpected memory task (Experiment 4). This effect was not the result of associative chaining between study items (Experiment 3), and can be attributed to the amount of item-specific processing that occurs at study (Experiment 4). These results provide evidence that stimulus-specific differences in processing at encoding have consequences for explicit memory retrieval. PMID- 22514527 TI - Oscillatory power decreases and long-term memory: the information via desynchronization hypothesis. AB - The traditional belief is that brain oscillations are important for human long term memory, because they induce synchronized firing between cell assemblies which shapes synaptic plasticity. Therefore, most prior studies focused on the role of synchronization for episodic memory, as reflected in theta (~5 Hz) and gamma (>40 Hz) power increases. These studies, however, neglect the role that is played by neural desynchronization, which is usually reflected in power decreases in the alpha and beta frequency band (8-30 Hz). In this paper we present a first idea, derived from information theory that gives a mechanistic explanation of how neural desynchronization aids human memory encoding and retrieval. Thereby we will review current studies investigating the role of alpha and beta power decreases during long-term memory tasks and show that alpha and beta power decreases play an important and active role for human memory. Applying mathematical models of information theory, we demonstrate that neural desynchronization is positively related to the richness of information represented in the brain, thereby enabling encoding and retrieval of long-term memories. This information via desynchronization hypothesis makes several predictions, which can be tested in future experiments. PMID- 22514528 TI - Is there a critical lesion site for unilateral spatial neglect? A meta-analysis using activation likelihood estimation. AB - The critical lesion site responsible for the syndrome of unilateral spatial neglect has been debated for more than a decade. Here we performed an activation likelihood estimation (ALE) to provide for the first time an objective quantitative index of the consistency of lesion sites across anatomical group studies of spatial neglect. The analysis revealed several distinct regions in which damage has consistently been associated with spatial neglect symptoms. Lesioned clusters were located in several cortical and subcortical regions of the right hemisphere, including the middle and superior temporal gyrus, inferior parietal lobule, intraparietal sulcus, precuneus, middle occipital gyrus, caudate nucleus, and posterior insula, as well as in the white matter pathway corresponding to the posterior part of the superior longitudinal fasciculus. Further analyses suggested that separate lesion sites are associated with impairments in different behavioral tests, such as line bisection and target cancellation. Similarly, specific subcomponents of the heterogeneous neglect syndrome, such as extinction and allocentric and personal neglect, are associated with distinct lesion sites. Future progress in delineating the neuropathological correlates of spatial neglect will depend upon the development of more refined measures of perceptual and cognitive functions than those currently available in the clinical setting. PMID- 22514529 TI - Gestural coupling and social cognition: Mobius Syndrome as a case study. AB - Social cognition researchers have become increasingly interested in the ways that behavioral, physiological, and neural coupling facilitate social interaction and interpersonal understanding. We distinguish two ways of conceptualizing the role of such coupling processes in social cognition: strong and moderate interactionism. According to strong interactionism (SI), low-level coupling processes are alternatives to higher-level individual cognitive processes; the former at least sometimes render the latter superfluous. Moderate interactionism (MI) on the other hand, is an integrative approach. Its guiding assumption is that higher-level cognitive processes are likely to have been shaped by the need to coordinate, modulate, and extract information from low-level coupling processes. In this paper, we present a case study on Mobius Syndrome (MS) in order to contrast SI and MI. We show how MS-a form of congenital bilateral facial paralysis-can be a fruitful source of insight for research exploring the relation between high-level cognition and low-level coupling. Lacking a capacity for facial expression, individuals with MS are deprived of a primary channel for gestural coupling. According to SI, they lack an essential enabling feature for social interaction and interpersonal understanding more generally and thus ought to exhibit severe deficits in these areas. We challenge SI's prediction and show how MS cases offer compelling reasons for instead adopting MI's pluralistic model of social interaction and interpersonal understanding. We conclude that investigations of coupling processes within social interaction should inform rather than marginalize or eliminate investigation of higher-level individual cognition. PMID- 22514530 TI - MEG dual scanning: a procedure to study real-time auditory interaction between two persons. AB - Social interactions fill our everyday life and put strong demands on our brain function. However, the possibilities for studying the brain basis of social interaction are still technically limited, and even modern brain imaging studies of social cognition typically monitor just one participant at a time. We present here a method to connect and synchronize two faraway neuromagnetometers. With this method, two participants at two separate sites can interact with each other through a stable real-time audio connection with minimal delay and jitter. The magnetoencephalographic (MEG) and audio recordings of both laboratories are accurately synchronized for joint offline analysis. The concept can be extended to connecting multiple MEG devices around the world. As a proof of concept of the MEG-to-MEG link, we report the results of time-sensitive recordings of cortical evoked responses to sounds delivered at laboratories separated by 5 km. PMID- 22514531 TI - Emergent bursting and synchrony in computer simulations of neuronal cultures. AB - Experimental studies of neuronal cultures have revealed a wide variety of spiking network activity ranging from sparse, asynchronous firing to distinct, network wide synchronous bursting. However, the functional mechanisms driving these observed firing patterns are not well understood. In this work, we develop an in silico network of cortical neurons based on known features of similar in vitro networks. The activity from these simulations is found to closely mimic experimental data. Furthermore, the strength or degree of network bursting is found to depend on a few parameters: the density of the culture, the type of synaptic connections, and the ratio of excitatory to inhibitory connections. Network bursting gradually becomes more prominent as either the density, the fraction of long range connections, or the fraction of excitatory neurons is increased. Interestingly, biologically prevalent values of parameters result in networks that are at the transition between strong bursting and sparse firing. Using principal components analysis, we show that a large fraction of the variance in firing rates is captured by the first component for bursting networks. These results have implications for understanding how information is encoded at the population level as well as for why certain network parameters are ubiquitous in cortical tissue. PMID- 22514532 TI - Shortest Loops are Pacemakers in Random Networks of Electrically Coupled Axons. AB - High-frequency oscillations (HFOs) are an important part of brain activity in health and disease. However, their origins remain obscure and controversial. One possible mechanism depends on the presence of sparsely distributed gap junctions that electrically couple the axons of principal cells. A plexus of electrically coupled axons is modeled as a random network with bi-directional connections between its nodes. Under certain conditions the network can demonstrate one of two types of oscillatory activity. Type I oscillations (100-200 Hz) are predicted to be caused by spontaneously spiking axons in a network with strong (high conductance) gap junctions. Type II oscillations (200-300 Hz) require no spontaneous spiking and relatively weak (low-conductance) gap junctions, across which spike propagation failures occur. The type II oscillations are reentrant and self-sustained. Here we examine what determines the frequency of type II oscillations. Using simulations we show that the distribution of loop lengths is the key factor for determining frequency in type II network oscillations. We first analyze spike failure between two electrically coupled cells using a model of anatomically reconstructed CA1 pyramidal neuron. Then network oscillations are studied by a cellular automaton model with random network connectivity, in which we control loop statistics. We show that oscillation periods can be predicted from the network's loop statistics. The shortest loop, around which a spike can travel, is the most likely pacemaker candidate. The principle of one loop as a pacemaker is remarkable, because random networks contain a large number of loops juxtaposed and superimposed, and their number rapidly grows with network size. This principle allows us to predict the frequency of oscillations from network connectivity and visa versa. We finally propose that type I oscillations may correspond to ripples, while type II oscillations correspond to so-called fast ripples. PMID- 22514533 TI - Can Quality be Extracted from Quantification of Interactions by NBS? PMID- 22514534 TI - Sub-Regional Hippocampal Injury is Associated with Fornix Degeneration in Alzheimer's Disease. AB - We examined in vivo evidence of axonal degeneration in association with neuronal pathology in Alzheimer's disease (AD) through analysis of fornix microstructural integrity and measures of hippocampal subfield atrophy. Based on known anatomical topography, we hypothesized that the local thickness of subiculum and CA1 hippocampus fields would be associated with fornix integrity, reflecting an association between AD-related injury to hippocampal neurons and degeneration of associated axon fibers. To test this hypothesis, multi-modal imaging, combining measures of local hippocampal radii with diffusion tensor imaging (DTI), was applied to 44 individuals clinically diagnosed with AD, 44 individuals clinically diagnosed with mild cognitive impairment (MCI), and 96 cognitively normal individuals. Fornix microstructural degradation, as measured by reduced DTI-based fractional anisotropy (FA), was prominent in both MCI and AD, and was associated with reduced hippocampal volumes. Further, reduced fornix FA was associated with reduced anterior CA1 and antero-medial subiculum thickness. Finally, while both lesser fornix FA and lesser hippocampal volume were associated with lesser episodic memory, only the hippocampal measures were significant predictors of episodic memory in models including both hippocampal and fornix predictors. The region-specific association between fornix integrity and hippocampal neuronal death may provide in vivo evidence for degenerative white matter injury in AD: axonal pathology that is closely linked to neuronal injury. PMID- 22514535 TI - Autonomic Regulation during Quiet and Active Sleep States in Very Preterm Neonates. AB - The immature autonomic nervous system (ANS) in premature infants regulates heart rate (HR) and respiration different during quiet sleep (QS) and active sleep (AS). Little information is available about ANS regulation in these subjects. The aim of this study was to investigate changes in autonomic regulation and cardiorespiratory coupling during AS and QS in five very preterm neonates with gestational age (GA) 26-31 weeks, applying univariate and bivariate linear and non-linear dynamics methods to the recorded cardiorespiratory signals. During QS univariate linear indices revealed lower standard deviations and entropies, indicating decreased heart rate (HR) variability. More balanced sympatho-vagal behavior of the ANS was revealed by decreased low frequency (LF), increased high frequency (HF), and a trend toward lower ratio LF/HF in QS. Applied non-linear indices (probabilities, entropies, and fractal measures) quantifying the complexity and scaling behavior of HR regulation processes were significantly altered in QS in comparison to AS. This reflects a lower short-term variability, less complexity, and a loss of fractal-like correlation properties of HR dynamics in QS. One major finding is that cardiorespiratory coupling is not yet completely developed in very preterm neonates with 26-31 weeks GA. Significantly different regulation patterns in bivariate oscillations of HR and respiration during AS and QS could be recognized. These patterns were characterized on the one hand by predominant monotonous regulating sequences originating from respiration independently from HR time series in AS, and to a minor degree in QS, and on the other hand by some prominent HR regulation sequences in QS independent of respiratory regulation. We speculate that these findings might be suitable for monitoring preterm neonates and for detecting disorders in the developing cardiorespiratory system. PMID- 22514536 TI - Receptors responsive to protein breakdown products in g-cells and d-cells of mouse, swine and human. AB - Monitoring the luminal content in the stomach is of vital importance for adjusting the gastric activities, including the release of gastric hormones such as gastrin. Our previous studies have shown that in mice the gastrin-secreting G cells express receptor types which are responsive to amino acids. Since the pig is considered as more suitable model for studying gastro-physiological aspects relevant for men, in this study we have analyzed the distribution of G-cells and D-cells in the gastric antrum of men, swine, and mouse and the expression of receptor types which may render these cells responsiveness to protein breakdown products. The results indicate that the number of G-cells per antral invagination was significantly higher in swine and human compared to mice and also the distribution pattern of G-cells differed between the species. The molecular phenotyping revealed that the receptors GPRC6A and CaSR were also expressed in G cells and in a subpopulation of D-cells from swine and men. As an additional receptor type, the peptone-receptor GPR92, was found to be expressed in G-cells and a subpopulation of D-cells; this receptor type may be particular suitable for sensing protein breakdown products and thus be a key element to adjust the activity of G-cells and D-cells according to the progress of the digestive processes in the stomach. In search for elements of an intracellular signaling cascade it was found that G-cells express the G-protein subunit Galphaq as well as the phospholipase C subtype PLCbeta3; in contrast, D-cells expressed the subtype PLCbeta2 and neither Galphaq. These results indicate that there are significant species differences concerning the number and distribution pattern, but not concerning the molecular phenotype of the gastric endocrine cells. However, G-cells and D-cells significantly differ from each other regarding the repertoire of receptors and signaling elements. PMID- 22514537 TI - Multifaceted roles of tunneling nanotubes in intercellular communication. AB - Cell-to-cell communication and exchange of materials are vital processes in multicellular organisms during cell development, cell repair, and cell survival. In neuronal and immunological cells, intercellular transmission between neighboring cells occurs via different complex junctions or synapses. Recently, long distance intercellular connections in mammalian cells called tunneling nanotubes (TNTs) have been described. These structures have been found in numerous cell types and shown to transfer signals and cytosolic materials between distant cells, suggesting that they might play a prominent role in intercellular trafficking. However, these cellular connections are very heterogeneous in both structure and function, giving rise to more questions than answers as to their nature and role as intercellular conduits. To better understand and characterize the functions of TNTs, we have highlighted here the latest discoveries regarding the formation, structure, and role of TNTs in cell-to-cell spreading of various signals and materials. We first gathered information regarding their formation with an emphasis on the triggering mechanisms observed, such as stress and potentially important proteins and/or signaling pathways. We then describe the various types of transfer mechanisms, in relation to signals and cargoes that have been shown recently to take advantage of these structures for intercellular transfer. Because a number of pathogens were shown to use these membrane bridges to spread between cells we also draw attention to specific studies that point toward a role for TNTs in pathogen spreading. In particular we discuss the possible role that TNTs might play in prion spreading, and speculate on their role in neurological diseases in general. PMID- 22514538 TI - Fatigue is a Brain-Derived Emotion that Regulates the Exercise Behavior to Ensure the Protection of Whole Body Homeostasis. AB - An influential book written by A. Mosso in the late nineteenth century proposed that fatigue that "at first sight might appear an imperfection of our body, is on the contrary one of its most marvelous perfections. The fatigue increasing more rapidly than the amount of work done saves us from the injury which lesser sensibility would involve for the organism" so that "muscular fatigue also is at bottom an exhaustion of the nervous system." It has taken more than a century to confirm Mosso's idea that both the brain and the muscles alter their function during exercise and that fatigue is predominantly an emotion, part of a complex regulation, the goal of which is to protect the body from harm. Mosso's ideas were supplanted in the English literature by those of A. V. Hill who believed that fatigue was the result of biochemical changes in the exercising limb muscles - "peripheral fatigue" - to which the central nervous system makes no contribution. The past decade has witnessed the growing realization that this brainless model cannot explain exercise performance. This article traces the evolution of our modern understanding of how the CNS regulates exercise specifically to insure that each exercise bout terminates whilst homeostasis is retained in all bodily systems. The brain uses the symptoms of fatigue as key regulators to insure that the exercise is completed before harm develops. These sensations of fatigue are unique to each individual and are illusionary since their generation is largely independent of the real biological state of the athlete at the time they develop. The model predicts that attempts to understand fatigue and to explain superior human athletic performance purely on the basis of the body's known physiological and metabolic responses to exercise must fail since subconscious and conscious mental decisions made by winners and losers, in both training and competition, are the ultimate determinants of both fatigue and athletic performance. PMID- 22514540 TI - Chiropractic treatment as a primary care intervention for better musculoskeletal health in the aging population in the United kingdom: an opinion and positioning paper. PMID- 22514539 TI - Implications of TGFbeta on Transcriptome and Cellular Biofunctions of Palatal Mesenchyme. AB - Development of the palate comprises sequential stages of growth, elevation, and fusion of the palatal shelves. The mesenchymal component of palates plays a major role in early phases of palatogenesis, such as growth and elevation. Failure in these steps may result in cleft palate, the second most common birth defect in the world. These early stages of palatogenesis require precise and chronological orchestration of key physiological processes, such as growth, proliferation, differentiation, migration, and apoptosis. There is compelling evidence for the vital role of TGFbeta-mediated regulation of palate development. We hypothesized that the isoforms of TGFbeta regulate different cellular biofunctions of the palatal mesenchyme to various extents. Human embryonic palatal mesenchyme (HEPM) cells were treated with TGFbeta1, beta2, and beta3 for microarray-based gene expression studies in order to identify the roles of TGFbeta in the transcriptome of the palatal mesenchyme. Following normalization and modeling of 28,869 human genes, 566 transcripts were detected as differentially expressed in TGFbeta treated HEPM cells. Out of these altered transcripts, 234 of them were clustered in cellular biofunctions, including growth and proliferation, development, morphology, movement, cell cycle, and apoptosis. Biological interpretation and network analysis of the genes active in cellular biofunctions were performed using IPA. Among the differentially expressed genes, 11 of them are known to be crucial for palatogenesis (EDN1, INHBA, LHX8, PDGFC, PIGA, RUNX1, SNAI1, SMAD3, TGFbeta1, TGFbeta2, and TGFbetaR1). These genes were used for a merged interaction network with cellular behaviors. Overall, we have determined that more than 2% of human transcripts were differentially expressed in response to TGFbeta treatment in HEPM cells. Our results suggest that both TGFbeta1 and TGFbeta2 orchestrate major cellular biofunctions within the palatal mesenchyme in vitro by regulating expression of 234 genes. PMID- 22514542 TI - The major transitions of life from a network perspective. AB - Many attempts have been made to understand the origin of life and biological complexity both at the experimental and theoretical levels but neither is fully explained. In an influential work, Maynard Smith and Szathmary (1995) argued that the majority of the increase in complexity is not gradual, but it is associated with a few so-called major transitions along the way of the evolution of life. For each major transition, they identified specific mechanisms that could account for the change in complexity related to information transmission across generations. In this work, I propose that the sudden and unexpected improvement in the functionality of an organism that followed a major transition was enabled by a phase transition in the network structure associated with that function. The increase in complexity following a major transition is therefore directly linked to the emergence of a novel structure-function relation which altered the course of evolution. As a consequence, emergent phenomena arising from these network phase transitions can serve as a common organizing principle for understanding the major transitions. As specific examples, I analyze the emergence of life, the emergence of the genetic apparatus, the rise of the eukaryotic cells, the evolution of movement and mechanosensitivity, and the emergence of consciousness. Finally, I discuss the implications of network associated phase transitions to issues that bear relevance to the history, the immediate present and perhaps the future, of life. PMID- 22514541 TI - Testosterone and vascular function in aging. AB - Androgen receptors are widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Through classic cytosolic androgen receptors or membrane receptors, testosterone induces genomic and non-genomic effects, respectively. Testosterone interferes with the vascular function by increasing the production of pro-inflammatory cytokines and arterial thickness. Experimental evidence indicates that sex steroid hormones, such as testosterone modulate the synthesis and bioavailability of NO and, consequently, endothelial function, which is key for a healthy vasculature. Of interest, aging itself is accompanied by endothelial and vascular smooth muscle dysfunction. Aging-associated decline of testosterone levels is accompanied by age-related diseases, such as metabolic and cardiovascular diseases, indicating that very low levels of androgens may contribute to cardiovascular dysfunction observed in these age-related disorders or, in other words, that testosterone may have beneficial effects in the cardiovascular system. However, testosterone seems to play a negative role in the severity of renal disease. In this mini-review, we briefly comment on the interplay between aging and testosterone levels, the vascular actions of testosterone and its implications for vascular aging. Renal effects of testosterone and the use of testosterone to prevent vascular dysfunction in elderly are also addressed. PMID- 22514543 TI - The role of words in cognitive tasks: what, when, and how? AB - The current review focuses on how exposure to linguistic input, and count nouns in particular, affect performance on various cognitive tasks, including individuation, categorization and category learning, and inductive inference. We review two theoretical accounts of effects of words. Proponents of one account argue that words have top-down effects on cognitive tasks, and, as such, function as supervisory signals. Proponents of the other account suggest that early in development, words, just like any other perceptual feature, are first and foremost part of the stimulus input and influence cognitive tasks in a bottom-up, non-supervisory fashion. We then review evidence supporting each account. We conclude that, although much research is needed, there is a large body of evidence indicating that words start out like other perceptual features and become supervisory signals in the course of development. PMID- 22514544 TI - French college students' sports practice and its relations with stress, coping strategies and academic success. AB - College students at university have to face several stress factors. Although sports practice has been considered as having beneficial effects upon stress and general health, few studies have documented its influence on this specific population. The aim of this comparative study was to determine whether the intensity of the college students' sports practice (categorized into three groups: rare, regular, or intensive) would influence their levels of stress and self-efficacy, their coping strategies, and their academic success/failure. Three self-completion questionnaires were administered to 1071 French freshmen during their compulsory medical visit at the preventive medicine service of the university. Results indicated that students with intensive sport practice reported lower scores of general stress, academic stress, and emotion-focused coping strategies, and higher scores of self-efficacy than those with rare practice. However, the proportion of successful students did not differ significantly between the three groups of sports practice. PMID- 22514545 TI - Evaluative conditioning induces changes in sound valence. AB - Through evaluative conditioning (EC) a stimulus can acquire an affective value by pairing it with another affective stimulus. While many sounds we encounter daily have acquired an affective value over life, EC has hardly been tested in the auditory domain. To get a more complete understanding of affective processing in auditory domain we examined EC of sound. In Experiment 1 we investigated whether the affective evaluation of short environmental sounds can be changed using affective words as unconditioned stimuli (US). Congruency effects on an affective priming task for conditioned sounds demonstrated successful EC. Subjective ratings for sounds paired with negative words changed accordingly. In Experiment 2 we investigated whether extinction occurs, i.e., whether the acquired valence remains stable after repeated presentation of the conditioned sound without the US. The acquired affective value remained present, albeit weaker, even after 40 extinction trials. These results provide clear evidence for EC effects in the auditory domain. We will argue that both associative as well as propositional processes are likely to underlie these effects. PMID- 22514546 TI - Writing direction affects how people map space onto time. AB - What determines which spatial axis people use to represent time? We investigate effects of writing direction. English, like Mandarin Chinese in mainland China, is written left to right and then top to bottom. But in Taiwan, characters are written predominantly top to bottom and then right to left. Because being a fluent reader-writer entails thousands of hours of experience with eye and hand movement in the direction dictated by one's writing system, it could be that writing system direction affects the axis used to represent time in terms of space. In a behavioral experiment, we had native speakers of English, Mandarin Chinese from mainland China, and Mandarin Chinese from Taiwan place sets of cards in temporal order. These cards depicted stages of development of plants and animals, for instance: tadpole, froglet, frog. Results showed that English speakers always represented time as moving from left to right (LR). Mainland Chinese participants trended in the same direction, but a small portion laid the cards out from top to bottom. Taiwanese participants were just as likely to depict time as moving from LR as from top to bottom, with a large minority depicting it as moving from right to left. Native writing system affects how people represent time spatially. PMID- 22514548 TI - The influence of extracellular superoxide on iron redox chemistry and bioavailability to aquatic microorganisms. AB - Superoxide, the one-electron reduced form of dioxygen, is produced in the extracellular milieu of aquatic microbes through a range of abiotic chemical processes and also by microbes themselves. Due to its ability to promote both oxidative and reductive reactions, superoxide may have a profound impact on the redox state of iron, potentially influencing iron solubility, complex speciation, and bioavailability. The interplay between iron, superoxide, and oxygen may also produce a cascade of other highly reactive transients in oxygenated natural waters. For microbes, the overall effect of reactions between superoxide and iron may be deleterious or beneficial, depending on the organism and its chemical environment. Here I critically discuss recent advances in understanding: (i) sources of extracellular superoxide in natural waters, with a particular emphasis on microbial generation; (ii) the chemistry of reactions between superoxide and iron; and (iii) the influence of these processes on iron bioavailability and microbial iron nutrition. PMID- 22514547 TI - Concepts and principles of photodynamic therapy as an alternative antifungal discovery platform. AB - Opportunistic fungal pathogens may cause superficial or serious invasive infections, especially in immunocompromised and debilitated patients. Invasive mycoses represent an exponentially growing threat for human health due to a combination of slow diagnosis and the existence of relatively few classes of available and effective antifungal drugs. Therefore systemic fungal infections result in high attributable mortality. There is an urgent need to pursue and deploy novel and effective alternative antifungal countermeasures. Photodynamic therapy (PDT) was established as a successful modality for malignancies and age related macular degeneration but photodynamic inactivation has only recently been intensively investigated as an alternative antimicrobial discovery and development platform. The concept of photodynamic inactivation requires microbial exposure to either exogenous or endogenous photosensitizer molecules, followed by visible light energy, typically wavelengths in the red/near infrared region that cause the excitation of the photosensitizers resulting in the production of singlet oxygen and other reactive oxygen species that react with intracellular components, and consequently produce cell inactivation and death. Antifungal PDT is an area of increasing interest, as research is advancing (i) to identify the photochemical and photophysical mechanisms involved in photoinactivation; (ii) to develop potent and clinically compatible photosensitizers; (iii) to understand how photoinactivation is affected by key microbial phenotypic elements multidrug resistance and efflux, virulence and pathogenesis determinants, and formation of biofilms; (iv) to explore novel photosensitizer delivery platforms; and (v) to identify photoinactivation applications beyond the clinical setting such as environmental disinfectants. PMID- 22514549 TI - A Role for Sigma Factor sigma(E) in Corynebacterium pseudotuberculosis Resistance to Nitric Oxide/Peroxide Stress. AB - Pathogenic intracellular bacteria can respond to antimicrobial mechanisms of the host cell through transient activation of stress-responsive genes by alternative sigma (sigma) factors of the RNA polymerase. We evaluated the contribution of the extracytoplasmic function sigma factor sigma(E) for Corynebacterium pseudotuberculosis resistance to stress conditions resembling those found intracellularly during infection. A sigE-null mutant strain (DeltasigE) of this bacterium was more susceptible in vitro to acidic pH, cell surface stressors, and biologically relevant concentrations of nitric oxide (NO). The same mutant strain was unable to persist in C57BL/6 mice but remained infective in mice lacking inducible nitric oxide synthase (iNOS), confirming the significance of sigma(E) for resistance to nitric oxide/peroxide stress in vivo. High-throughput proteomic analysis identified NO-responsive extracellular proteins of C. pseudotuberculosis and demonstrated the participation of sigma(E) in composition of this bacterium's exoproteome. PMID- 22514550 TI - Excretion of antibiotic resistance genes by dairy calves fed milk replacers with varying doses of antibiotics. AB - Elevated levels of antibiotic resistance genes (ARGs) in soil and water have been linked to livestock farms and in some cases feed antibiotics may select for antibiotic resistant gut microbiota. The purpose of this study was to examine the establishment of ARGs in the feces of calves receiving milk replacer containing no antibiotics versus subtherapeutic or therapeutic doses of tetracycline and neomycin. The effect of antibiotics on calf health was also of interest. Twenty eight male and female dairy calves were assigned to one of the three antibiotic treatment groups at birth and fecal samples were collected at weeks 6, 7 (prior to weaning), and 12 (5 weeks after weaning). ARGs corresponding to the tetracycline (tetC, tetG, tetO, tetW, and tetX), macrolide (ermB, ermF), and sulfonamide (sul1, sul2) classes of antibiotics along with the class I integron gene, intI1, were monitored by quantitative polymerase chain reaction as potential indicators of direct selection, co-selection, or horizontal gene transfer of ARGs. Surprisingly, there was no significant effect of antibiotic treatment on the absolute abundance (gene copies per gram wet manure) of any of the ARGs except ermF, which was lower in the antibiotic-treated calf manure, presumably because a significant portion of host bacterial cells carrying ermF were not resistant to tetracycline or neomycin. However, relative abundance (gene copies normalized to 16S rRNA genes) of tetO was higher in calves fed the highest dose of antibiotic than in the other treatments. All genes, except tetC and intI1, were detectable in feces from 6 weeks onward, and tetW and tetG significantly increased (P < 0.10), even in control calves. Overall, the results provide new insight into the colonization of calf gut flora with ARGs in the early weeks. Although feed antibiotics exerted little effect on the ARGs monitored in this study, the fact that they also provided no health benefit suggests that the greater than conventional nutritional intake applied in this study overrides previously reported health benefits of antibiotics. The results suggest potential benefit of broader management strategies, and that cost and risk may be avoided by minimizing incorporation of antibiotics in milk replacer. PMID- 22514552 TI - Honey's Ability to Counter Bacterial Infections Arises from Both Bactericidal Compounds and QS Inhibition. AB - The ability of honey to kill bacterial pathogens in vitro and quickly clear even chronic or drug-resistant infections has been demonstrated by several studies. Most current research is focused on identifying the bactericidal compounds in honey, but the action of the compounds discovered is not sufficient to explain honey's activity. By diluting honey to sub-inhibitory levels, we were able to study its impact on bacterial coordinated behavior, and discovered that honey inhibits bacterial quorum sensing (QS). Experiments to characterize and quantify honey's effect on the QS networks of Pseudomonas aeruginosa revealed that low concentrations of honey inhibited the expression of MvfR, las, and rhl regulons, including the associated virulence factors. This research also establishes that inhibition of QS is associated with honey's sugar content. Therefore, honey combats infections by two independent mechanisms acting in tandem: bactericidal components, which actively kill cells, and disruption of QS, which weakens bacterial coordination and virulence. PMID- 22514551 TI - Mining genomes of marine cyanobacteria for elements of zinc homeostasis. AB - Zinc is a recognized essential element for the majority of organisms, and is indispensable for the correct function of hundreds of enzymes and thousands of regulatory proteins. In aquatic photoautotrophs including cyanobacteria, zinc is thought to be required for carbonic anhydrase and alkaline phosphatase, although there is evidence that at least some carbonic anhydrases can be cambialistic, i.e., are able to acquire in vivo and function with different metal cofactors such as Co(2+) and Cd(2+). Given the global importance of marine phytoplankton, zinc availability in the oceans is likely to have an impact on both carbon and phosphorus cycles. Zinc concentrations in seawater vary over several orders of magnitude, and in the open oceans adopt a nutrient-like profile. Most studies on zinc handling by cyanobacteria have focused on freshwater strains and zinc toxicity; much less information is available on marine strains and zinc limitation. Several systems for zinc homeostasis have been characterized in the freshwater species Synechococcus sp. PCC 7942 and Synechocystis sp. PCC 6803, but little is known about zinc requirements or zinc handling by marine species. Comparative metallo-genomics has begun to explore not only the putative zinc proteome, but also specific protein families predicted to have an involvement in zinc homeostasis, including sensors for excess and limitation (SmtB and its homologs as well as Zur), uptake systems (ZnuABC), putative intracellular zinc chaperones (COG0523) and metallothioneins (BmtA), and efflux pumps (ZiaA and its homologs). PMID- 22514553 TI - Acclimation of the Global Transcriptome of the Cyanobacterium Synechococcus sp. Strain PCC 7002 to Nutrient Limitations and Different Nitrogen Sources. AB - The unicellular, euryhaline cyanobacterium Synechococcus sp. strain PCC 7002 is a model organism for laboratory-based studies of cyanobacterial metabolism and is a potential platform for biotechnological applications. Two of its most notable properties are its exceptional tolerance of high-light intensity and very rapid growth under optimal conditions. In this study, transcription profiling by RNAseq has been used to perform an integrated study of global changes in transcript levels in cells subjected to limitation for the major nutrients CO(2), nitrogen, sulfate, phosphate, and iron. Transcriptional patterns for cells grown on nitrate, ammonia, and urea were also studied. Nutrient limitation caused strong decreases of transcript levels of the genes encoding major metabolic pathways, especially for components of the photosynthetic apparatus, CO(2) fixation, and protein biosynthesis. Uptake mechanisms for the respective nutrients were strongly up-regulated. The transcription data further suggest that major changes in the composition of the NADH dehydrogenase complex occur upon nutrient limitation. Transcripts for flavoproteins increased strongly when CO(2) was limiting. Genes involved in protection from oxidative stress generally showed high, constitutive transcript levels, which possibly explains the high-light tolerance of this organism. The transcriptomes of cells grown with ammonia or urea as nitrogen source showed increased transcript levels for components of the CO(2) fixation machinery compared to cells grown with nitrate, but in general transcription differences in cells grown on different N-sources exhibited surprisingly minor differences. PMID- 22514556 TI - The impact of recent alcohol use on genome wide DNA methylation signatures. AB - Chronic alcohol intake is associated with a wide variety of adverse health outcomes including depression, diabetes, and heart disease. Unfortunately, the molecular mechanisms through which these effects are conveyed are not clearly understood. To examine the potential role of epigenetic factors in this process, we examined the relationship of recent alcohol intake to genome wide methylation patterns using the Illumina 450 Methylation Bead Chip and lymphoblast DNA derived from 165 female subjects participating in the Iowa Adoption Studies. We found that the pattern of alcohol use over the 6-months immediately prior to phlebotomy was associated with, severity-dependent changes in the degree of genome wide methylation that preferentially hypermethylate the central portion of CpG islands with methylation at cg05600126, a probe in ABR, and the 5' untranslated region of BLCAP attaining genome wide significance in two point and sliding window analyses of probe methylation data, respectively. We conclude that recent alcohol use is associated with widespread changes in DNA methylation in women and that further study to confirm these findings and determine their relationship to somatic function are in order. PMID- 22514554 TI - Understanding Alcoholism Through microRNA Signatures in Brains of Human Alcoholics. AB - Advances in the fields of genomics and genetics in the last decade have identified a large number of genes that can potentially influence alcohol drinking behavior in humans as well as animal models. Consequently, the task of identifying efficient molecular targets that could be used to develop effective therapeutics against the disease has become increasingly daunting. One of the reasons for this is the fact that each of the many alcohol-responsive genes only contributes a small effect to the overall mechanism and disease phenotype, as is characteristic of complex traits. Current research trends are hence shifting toward the analysis of gene networks rather than emphasizing individual genes. The discovery of microRNAs and their mechanisms of action on regulation of transcript level and protein translation have made evident the utility of these small non-coding RNA molecules that act as central coordinators of multiple cross communicating cellular pathways. Cells exploit the fact that a single microRNA can target hundreds of mRNA transcripts and that a single mRNA transcript can be simultaneously targeted by distinct microRNAs, to ensure fine-tuned and/or redundant control over a large number of cellular functions. By the same token, we can use these properties of microRNAs to develop novel, targeted strategies to combat complex disorders. In this review, we will focus on recent discoveries of microRNA signatures in brain of human alcoholics supporting the hypothesis that changes in gene expression and regulation by microRNAs are responsible for long term neuroadaptations occurring during development of alcoholism. We also discuss insights into the potential modulation of epigenetic regulators by a subset of microRNAs. Taken together, microRNA activity may be controlling many of the cellular mechanisms already known to be involved in the development of alcoholism, and suggests potential targets for the development of novel therapeutic interventions. PMID- 22514557 TI - A rare cause of the pulmonary-renal syndrome: a case of atypical haemolytic uraemic syndrome complicated by pulmonary haemorrhage. AB - Pulmonary haemorrhage is a potentially life-threatening event that may occur in patients with pulmonary-renal syndromes. These syndromes have typically been thought to occur in small-vessel vasculitides, such as ANCA-mediated disease, Goodpasture's disease and other autoimmune conditions including systemic lupus erythematosus or anti-phospholipid antibody syndrome. Here, we present a rare cause for pulmonary haemorrhage with associated renal failure-atypical haemolytic uraemic syndrome. In this case, renal biopsy was integral to providing a diagnosis and guiding therapy. PMID- 22514558 TI - Combination of the deacetylase inhibitor panobinostat and the multi-kinase inhibitor sorafenib for the treatment of metastatic hepatocellular carcinoma - review of the underlying molecular mechanisms and first case report. AB - Advanced hepatocellular carcinoma still represents an unmet medical need that has only a limited overall survival despite the introduction of the multi-kinase inhibitor sorafenib. Recently, inhibitors of histone and other protein deacetylases have been established as novel therapeutic approaches to cancer diseases. We here review the molecular rationale for combining these two novel targeted therapies and report a patient with metastasized hepatocellular carcinoma who showed a partial remission of primary and metastatic lesions for five months after a combination therapy with sorafenib and the orally available pan-deacetylase inhibitor panobinostat. PMID- 22514555 TI - Genome-Wide Analyses of Metal Responsive Genes in Caenorhabditis elegans. AB - Metals are major contaminants that influence human health. Many metals have physiologic roles, but excessive levels can be harmful. Advances in technology have made toxicogenomic analyses possible to characterize the effects of metal exposure on the entire genome. Much of what is known about cellular responses to metals has come from mammalian systems; however the use of non-mammalian species is gaining wider attention. Caenorhabditis elegans is a small round worm whose genome has been fully sequenced and its development from egg to adult is well characterized. It is an attractive model for high throughput screens due to its short lifespan, ease of genetic mutability, low cost, and high homology with humans. Research performed in C. elegans has led to insights in apoptosis, gene expression, and neurodegeneration, all of which can be altered by metal exposure. Additionally, by using worms one can potentially study mechanisms that underline differential responses to metals in nematodes and humans, allowing for identification of novel pathways and therapeutic targets. In this review, toxicogenomic studies performed in C. elegans exposed to various metals will be discussed, highlighting how this non-mammalian system can be utilized to study cellular processes and pathways induced by metals. Recent work focusing on neurodegeneration in Parkinson's disease will be discussed as an example of the usefulness of genetic screens in C. elegans and the novel findings that can be produced. PMID- 22514559 TI - Stemness of the CT-2A Immunocompetent Mouse Brain Tumor Model: Characterization In Vitro. AB - Evidence has pointed to brain tumor stem cells (BTSC) as culprits behind human high-grade glioma (hHGG) resistance to standard therapy. Pre-clinical rodent models are the mainstay for testing of new therapeutic strategies. The typical model involves the intracranial injection of human glioma cells into immunocompromised hosts, hindering the evaluation of tumor-host responses and resulting in non-infiltrative tumors. The CT-2A model is an immunocompetent mouse model with potential to overcome these disadvantages. In this study, we confirmed the highly infiltrative nature of intracranial CT-2A tumors and optimized reproducible injection parameters. We then generated neurospheres and established, for the first time, the stemness of this model. CT-2A expression of the BTSC marker, CD133, increased from 2% in monolayer cells to 31% in fully formed neurospheres. Investigation of three stem cell markers (Oct4, Nanog and Nestin) revealed a distinct stemness signature with monolayer cells expressing Oct4 and Nestin (no Nanog), and neurospheres expressing all three. Additionally, CT-2A cells were more proliferative and invasive than U87 cells, while CT-2A neurospheres were significantly more proliferative and invasive than either monolayer cells in vitro. Taken together, our results show that this model is a valuable tool for pre-clinical testing of novel therapeutics against hHGG and also affords the opportunity for investigation of BTSC in an immunocompetent setting. PMID- 22514560 TI - ASPN and GJB2 Are Implicated in the Mechanisms of Invasion of Ductal Breast Carcinomas. AB - The mechanism of progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) remains largely unknown. We compared gene expression in tumors with simultaneous DCIS and IDC to decipher how diverse proteins participate in the local invasive process.Twenty frozen tumor specimens with concurrent, but separated, DCIS and IDC were microdissected and evaluated. Total RNA was extracted and microarray analysis was performed using Affymetrix GeneChip(r) Human Gene 1.0 ST Arrays. Microarray data were validated by quantitative real time reverse transcription-PCR (qRT-PCR) and immunohistochemistry. Controls included seven pure in situ carcinomas, eight fragments from normal breast tissue, and a series of mouse breast carcinomas (MMTV-PyMT).Fifty-six genes were differentially expressed between DCIS and IDC samples. The genes upregulated in IDC samples, and probably associated with invasion, were related to the epithelial-mesenchymal transition (ASPN, THBS2, FN1, SPARC, and COL11A1), cellular adhesion (GJB2), cell motility and progression (PLAUR, PLAU, BGN, ADAMTS16, and ENPP2), extracellular matrix degradation (MMP11, MMP13, and MMP14), and growth/proliferation (ST6GAL2). qRT-PCR confirmed the expression patterns of ASPN, GJB2, ENPP2, ST6GAL2, and TMBS10. Expression of the ASPN and GJB2 gene products was detected by immunohistochemistry in invasive carcinoma foci. The association of GJB2 protein expression with invasion was confirmed by qRT-PCR in mouse tumors (P < 0.05). CONCLUSIONS: The upregulation of ASPN and GJB2 may play important roles in local invasion of breast ductal carcinomas. PMID- 22514562 TI - Minimally invasive treatment for female stress urinary incontinence - Romanian highlights. AB - RATIONALE: Stress urinary incontinence is still a "battlefield" for many minimally invasive therapies, but, unfortunately, few can restore the anatomical and functional background of this disorder. OBJECTIVE: Assessing the latest minimally invasive procedures of intra and perisphincterian injection of autologous stem cells. METHOD AND RESULT: The first stem cell implantation (myoblasts and /or mature fibroblasts grown and multiplied in the laboratory from biopsy samples taken from the pectoralis muscle) in the urethral sphincter was performed on October 18, 2010, in "Fundeni" Clinic of Urology and Renal Transplantation, in Romania. DISCUSSION: The follow-up at six weeks with the quality of life questionnaires, micturition diary and clinical examination revealed a decrease of urine loss from six pads/ day at one per day, which significantly improved the patient's quality of life according to visual analogue scale. Clinical and urodynamic evaluations will continue and will be future scientific topics. PMID- 22514563 TI - Intramedullary osteosynthesis versus plate osteosynthesis in subtrochanteric fractures. AB - Due to an ever-aging population and a growing prevalence of osteoporosis and motor vehicle accidents, the number of subtrochanteric fractures is increasing worldwide. The choice of the appropriate implant continues to be critical for fixation of unstable hip fractures. The subtrochanteric region has certain anatomical and biomechanical features that can make fractures in this region difficult to treat. The preferred type of device is a matter of debate. Increased understandings of biomechanical characteristics of the hip and improvement of the implant materials have reduced the incidence of complications. The surgeons choose between the two methods according to Seinsheimer's classification and also to their personal preferences. As a general principle, the open reduction and internal fixation were performed in stable fractures, and the closed reduction and internal fixation were performed in unstable fractures. The advantages of intramedullary nailing consist in a small skin incision, lower operating times, preservation of fracture hematoma and the possibility of early weight bearing. The disadvantages consist in a difficult closed reduction due to important muscular forces, although the nail can be used as a reduction instrument, and higher implant cost. In open reduction internal fixation techniques, the advantage is represented by anatomical reduction which, in our opinion, is not necessary. The disadvantages are represented by: higher operating time, demanding surgery, large devascularization, higher infection rates, late weight bearing, medial instability, refracture after plate removal and inesthetic approach. PMID- 22514564 TI - Cardiac magnetic resonance imaging in ischemic heart disease: a clinical review. AB - Cardiac magnetic resonance imaging (MRI) has emerged as a prime player in the clinical and preclinical detection of ischemic heart disease (IHD) as well in the prognosis assessment by offering a comprehensive approach for all spectrums of coronary artery disease (CAD) patients. The aim of this review is to provide the reader a state-of-the art on how the newest cardiac MRI techniques can be used to study IHD patients. In patients with suspected/stable CAD, functional and perfusion imaging both at rest and during vasodilatatory stress (adenosine, dypiridamole)/dobutamine stress can accurately depict ischemic myocardium secondary to significant coronary artery stenosis. In patients with acute MI, MRI is a robust tool for differentiating and sizing the jeopardized and the infarcted myocardium by using a combination of functional, edema, perfusion and Gd contrast imaging. Moreover, important prognostic factors like myocardial salvage, the presence of microvascular obstruction (MVO), post reperfusion myocardial hemorrhage, RV involvement and infarct related complications can be assessed in the same examination. In patients with chronic ischemic cardiomyopathy, the role of the MRI extends from diagnosis by means of Gadolinium contrast scar imaging to therapy and prognosis by functional assessment and viability testing with rest and dobutamine stress imaging. In all the circumstances mentioned, MRI derived information has been proven valuable in every day clinical decision making and prognosis assessment. Thus, MRI is becoming more and more an accepted alternative to other imaging modalities both in the acute and chronic setting. PMID- 22514565 TI - Can ageing be slowed?: Hormetic and redox perspectives. AB - Redox metabolism has long been considered to play important roles in aging and the development of age-related diseases. Both dietary and pharmacological manipulations of redox metabolism have been associated with the extension of lifespan. Increasing new evidence s also suggests that the process of aging may derive from imperfect clearance of oxidatively damaged material. The accumulation of this molecular "garbage", relatively indigestible, further hinders cellular functions, induces progressive failure of maintenance and repair and increases the probability of death. One important trend in anti-aging strategy is, therefore, to prevent or even revert the accumulation of these oxidatively altered molecules by stimulating the maintenance and repair systems through hormesis. A promising approach for slowing down ageing and achieving a healthy senescence is represented by repeated exposure to various mild stresses (caloric restriction, moderate exercise, nutritional or pharmacological hormetins). This article reviews the potential therapeutic tools available to date for increasing longevity and obtaining and successful ageing from the redox and hormetic perspective. PMID- 22514566 TI - Right atrium thrombosis in nonvalvular permanent atrial fibrillation. AB - Nonvalvular atrial fibrillation is the most common sustained arrhythmia in adults, and it is described as a relationship between it and right atrium thrombosis. A case of a 76-year-old man who presented with severe recent-onset dyspnea and several co-morbidities, such as permanent atrial fibrillation, with no anticoagulant therapy is reported here. Echocardiography showed a massive thrombus in right atrium, without any clinical or echographic signs of peripheral veins thrombosis. This article is also a review of the cases from literature. PMID- 22514567 TI - Questionnaire about psychology/disease correlation - II. AB - OBJECTIVE: To further evaluate the adequacy of the items in our questionnaire aimed at unraveling the possible correlations between psychological features and internal disorders. This paper is dedicated to the items exploring the individual's interaction with other people. METHOD: The items are divided into several subdomains. For each subdomain, we have calculated the correlations between the items of the respective subdomain (inner associations) and with the items in other subdomains (outer associations) by means of chi square test or Fisher exact test as dictated by statistical reasons. We examined the answers from our first 10192 respondents. RESULTS AND CONCLUSIONS: Many inter-item correlations are the consequence of higher or lesser degrees of synonymy. Those within a given subdomain confirm the adequate allocation of items. Those bridging different subdomains may point either to incorrect assignments, or to semantic inclusion relations. Other results are not explicable by semantic similarity, and probably reveal psychological subtleties, such as: most individuals have a sense of undeservedness when badly treated by other people; those easily hurt by insults and humiliations have a propensity to timidity and/or emotivity; the subjects who shun conflicts are more prone to persistent thoughts, brooding people are more sensitive and more prone to conflicts, injustice-indignant people frequently get into conflict although they declare to be bothered by dissent etc. But at the heart of all the PFs in the Interaction-with-other-people domain there seems to be the sense of being undervalued, which should probably be the key issue to be addressed by any therapeutic interventions for diseases psychoemotionally determined by disturbed interpersonal relationships. PMID- 22514568 TI - Management of gall bladder perforation evaluation on ultrasonography: report of six rare cases with review of literature. AB - BACKGROUND: Perforation of the gall bladder with cholecystohepatic communication is a rare cause of liver abscess. We are reporting here six rare cases of gall bladder perforation with variable clinical presentations. MATERIALS AND METHODS: Most patients presented with right hypochondrium pain and fever but two patients presented with only pain in the abdomen. Ultrasonography (USG) and Computed Tomography (CT) were used for diagnosis. The patients were also successfully treated. RESULTS: There was a gall bladder perforation with cholecystohepatic communication, leading to liver abscess formation in most cases on USG and CT. The final diagnosis was confirmed on surgery. CONCLUSION: The perforation of the gall bladder which leads to liver abscess is a rare complication of acute, chronic or empyema gall bladder. USG and CT scans are the most important diagnostic tool in diagnosing this rare complication. In the set up, where advanced options are not available, the only treatment of choice is the conservative one or surgery, according to the status of the patients. PMID- 22514569 TI - New application of diffusion tensor imaging in neurosurgery. AB - Diffusion tensor imaging is a MRI technique that enables the measurement of the diffusion of water in tissue in order to produce neural tract images. Advanced methods such as color coding and tractography (fiber tracking) have been used to investigate the directionality. The localization of tumors in relation to the white matter tracts (infiltration, deflection), has been one the most important initial applications. A non invasive technique for assessing tumor tissue characteristics, like tumor cell density, is required to assist preoperative surgical planning for malignant brain tumors and help better define the target for tumor biopsy, resulting in more accurate diagnosis and grading of malignant brain tumors. One possible source of this information is diffusion tensor imaging. Date studies have focused on its ability to delineate white matter fiber tracks by fiber tracking and to detect tumor infiltration around the tumor and normal white matter interface. Relationships between cell density and the two key values that diffusion tensor imaging provides, fractional anisotropy and mean diffusivity, still need to be investigated. Mean diffusivity has a good negative correlation and fractional anisotropy has a good positive correlation with tumor cell density within the tumor core. Similar correlation was observed between the Ki-67, on the one hand and fractional anisotropy and mean diffusivity, on the other hand. Thus, measurement of both fractional anisotropy and mean diffusivity within the tumor core has a potential to provide detailed information on tumor cell density within the tumor. PMID- 22514570 TI - Modern risk stratification in coronary heart disease. AB - The prevalence and impact of cardiovascular diseases in the world are growing. There are 2 million deaths due to cardiovascular disease each year in the European Union; the main cause of death being the coronary heart disease responsible for 16% of deaths in men and 15% in women. Prevalence of cardiovascular disease in Romania is estimated at 7 million people, of which 2.8 million have ischemic heart disease. In this epidemiological context, risk stratification is required for individualization of therapeutic strategies for each patient. The continuing evolution of the diagnosis and treatment techniques combines personalized medicine with the trend of therapeutic management leveling, based on guidelines and consensus, which are in constant update. The guidelines used in clinical practice have involved risk stratification and identification of patient groups in whom the risk-benefit ratio of using new diagnostic and therapeutic techniques has a positive value. Presence of several risk factors may indicate a more important total risk than the presence / significant increase from normal values of a single risk factor. Modern trends in risk stratification of patients with coronary heart disease are polarized between the use of simple data versus complex scores, traditional data versus new risk factors, generally valid scores versus personalized scores, depending on patient characteristics, type of coronary artery disease, with impact on the suggested therapy. All known information and techniques can be integrated in a complex system of risk assessment. The current trend in risk assessment is to identify coronary artery disease in early forms, before clinical manifestation, and to guide therapy, particularly in patients with intermediate risk, which can be classified in another class of risk based on new obtained information. PMID- 22514571 TI - Probiotics and periodontal health. AB - Periodontitis is one of the most common chronic inflammatory diseases. The etiology is clearly bacterial and a number of putative bacterial pathogens have been associated with the disease, including Aggregatibacter actinomycetemcomitans, Tannerella forsythus and Porphyromonas gingivalis. Comparatively, little attention has been paid to the identification of health associated and potentially beneficial bacterial species that may reside in the gingival sulcus. Probiotic technology represents a breakthrough approach to maintaining oral health by using natural beneficial bacteria, commonly found in healthy mouths, to provide a natural defense against those bacteria which are thought to be harmful to teeth and gums. This article endeavors to introduce the concepts of probiotics in periodontics. PMID- 22514572 TI - The news of treatment of variceal upper gastrointestinal bleeding. AB - Variceal bleeding is one of the dreaded complications of portal hypertension. Although its prognosis has improved over the last several decades, it still carries substantial mortality. Although most portal hypertensive bleeds result from the ruptured distal esophageal varices, bleeding from other sources such gastric varices, portal hypertensive gastropathy, and ectopic varices can lead to clinically significant bleeding. Variceal bleeding typically presents as massive gastrointestinal (GI) bleeding with hematemesis, melena or hematochezia. In general, the terapeutic aims of management are to initially correct hypovolemia, to control bleeding, to prevent complications of bleeding, such as infection and renal failure and to prevent early rebleeding. The treatment of bleeding esophageal varices differs substantially foom the treatment of other lesions of the upper gastrointestinal tract. Moreover, patients with esophageal varices typically have severe liver disease and thus are likely from poor nutrition, blood clotting disorders, and encephalopathy, all of which can adversaly affect morbidity and mortality. PMID- 22514574 TI - Survey on quality of life related factors in patients with peptic ulcer based on PRECEDE model in Yazd, Iran. AB - BACKGROUND: Peptic ulcer is one of the most prevalent diseases. Its prevalence is estimated between 6-15% and, about 10% of the people, experience its symptom in a period of their life. Studies showed that quality of life and health status of peptic ulcer patients is affected by disease. OBJECTIVES: The aim of this study was to determine the Quality of life Related Factors in patients with peptic ulcer based on Precede Model. CONTEXT: A cross-sectional study with 120 subject patients, who were referred to Shahid Sadoghi Hospital of Yazd. METHODS: The patients were selected by simple Random sampling and data were collected by researchers making questionnaire. The validity and reliability of the questionnaire was approved. The data collected were transferred directly into SPSS. For data analysis, correlations, T-test, One way - ANOVA were used. RESULTS AND CONCLUSION: Results showed that there was a significant difference between the Quality of Life and Self-Management (p=0.05) and Quality of Life with Health Status (p=0.01). Pearson correlation showed that there was a significant correlation between the Quality of Life and Reinforcing factors (P=0.01). Totally, it was found that the health status, Self-Management, Predisposing and Enabling factors predicted 0.64 of the quality of life variance, among which, the Health Status was the strongest predictor (beta=0.575). What should be taken into account is the cultural situation of Iran and the fact that the PRECEDE model is a model for planning intervention. It can be used as a framework for planning intervention in order to promote the quality of life of ulcer peptic patients in Iran. PMID- 22514573 TI - The use of growth factors to modulate the activities of antigen-specific CD8+ T cells in vitro. AB - RATIONALE: Adoptive T cell therapy depends on the harvesting of the cells from the host, their activation in vitro, and their infusion back to the same host. The way of activating the T cells in vitro is a critical factor for their homing, survival and function in vivo. Sustaining T cell homing molecules, particularly CD62L, is benefic for the trafficking of the adoptive transferred cells. OBJECTIVE: The aim of the present study is to test whether insulin-like growth factor-1 (IGF-1), thymosin- alpha1 (T-alpha1) as well as all-trans retinoid acid (ATRA) alone or in combination with IL-2, IL-12, IL-15 can enhance the activation and survival phenotypes of antigen-activated T cells in vitro. METHODS & RESULTS: To this end, OT-1 transgenic T cells were used as a model. These CD8+ T cells recognize OVA peptide presented by MHC class-I. The results showed that antigen stimulation of OT1 cells resulted in their activation as evidenced by the decrease in surface expression of CD62L, analyzed for 3 days after antigen stimulation and was more pronounced on day 5. The addition of IL-12 or IGF-1 alone but not of IL-2, IL-15 augmented OT-1 cell activation measured on day 5. Interestingly, the combination of IL-12 with IGF-1 sustained the expression of CD62L on OT1 cells. Although the addition of ATRA alone or in combination with IL 12 resulted in decreases in CD62L expression on day 3, they showed a dose dependent effect on the restoration of CD62L expression on day 5. The analysis of the activation-induced cell death (apoptosis) of OT1 cells showed an increased rate of death on day 5 than on day 3-post antigen stimulation. The addition of only IL-12 or IGF-1 alone, but not of IL-2, IL-15 or T- alpha1, decreased OT1 cell apoptosis on day 3. These anti-apoptotic effects of IL-12 and IGF- 1, however, were recovered on day 5-post stimulation. DISCUSSION: In conclusion, these results indicate that the activation phenotype and the survival of antigen specific T cells can be differently modulated by immunomodulatory factors, where, interleukin-12 and IGF-1 induced the favorable effect. These results have a significant implication for T cell adoptive immunotherapy in different settings. PMID- 22514575 TI - Tinnitus in elderly population: clinic correlations and impact upon QoL. AB - INTRODUCTION: Tinnitus is a common health problem that affects between 10 - 30% of the population, approximately 3 - 4% presenting to the doctor at least once in their life. There are many causes that lead to tinnitus in elderly population, including otology, metabolic, neurologic or cardiovascular conditions. The aim of this study was to determine the association of tinnitus with these chronic comorbidities among elderly community and its impact upon their quality of life. MATERIALS AND METHODS: We performed a clinical retrospective study on 471 ENT patients hospitalized for various diseases, up to 60 years old, for a period of 24 months. All subjects were assessed for subjective tinnitus, neuro-vascular comorbidities and QoL by use of the brief version of the World Health Organization QoL instrument. RESULTS: Tinnitus was reported in 114 patients, giving a prevalence of 24,2%. Variables like gender, residence, economic status, alcohol or smoking were not significantly associated with tinnitus. On the other hand, otic and sinonasal pathology, dizziness, hypertension, arteriosclerosis or diabetes were significantly correlated. All patients with tinnitus presented a more negative perception of their overall health and a poorer QoL, compared to those without. CONCLUSIONS: Tinnitus is a common pathology among elderly community. Its association with chronic treatable health comorbidities reduces QoL and highlights the need of cooping strategies among this group population. PMID- 22514576 TI - Left atrial thrombus: a case report. AB - RATIONALE: Echocardiography is essential in establishing the diagnosis in patients with cardiac masses. The differentiation between myxomas and thrombi is sometimes difficult, but is critical in making the right therapeutical decision. OBJECTIVE: A 70-year-old female presented to the Emergency Department with palpitations, dyspnea and anterior epistaxis. She had a 3 years history of atrial fibrillation and chronic heart failure NYHA class III. METHOD AND RESULT: Two dimensional transthoracic echocardiography showed the thickening of the mitral valves with moderate mitral insufficiency and a mobile round mass in the left atrium, heterogeneous, inhomogeneous, 18 mm in size, attached with a narrow stalk to the interatrial septum, reaching mitral annular plane; tricuspid insufficiency with a maximum 30 mmHg gradient, intact interatrial septum, akinesia of two thirds of basal inferior wall, 42% ejection fraction. DISCUSSION: The two dimensional transesophageal echocardiography confirmed the intraatrial mass. Epistaxis was considered to be due to heart failure and the increased venous pressure. The patient was referred to the cardiovascular surgery clinic, but refused surgery. Anticoagulation with fraxiparine 0,6 ml/day was started and continued for 3 weeks, after cessation of epistaxis by nasal tamponament. Then echocardiography was repeated, with no remnant mass in the left atrium. The conclusion was that the mass must have been a thrombus that has melted away. In this particular case, the left intraatrial thrombus may have been due to the presence of atrial fibrillation. PMID- 22514577 TI - Complete spontaneous regression of a total pneumothorax in a patient with chronic obstructive lung disease. AB - A 61-year old man presented with a sudden onset of breathlessness. The total left pneumothorax was overlooked on the initial chest radiograph. One month later, the patient had a partial pneumothorax less than 20% on the radiograph, although he did not receive any therapy against pneumothorax, such as oxygen inhalation or needle aspiration. After the observation for one month, the lungs totally expanded. Pulmonary function tests demonstrated severe chronic obstructive pulmonary disease. To our knowledge, this is the first case in which the total secondary pneumothorax showed a spontaneous remission. PMID- 22514578 TI - Influence of the acute alcoholism on the phagocytic function of the mononuclear phagocytic system. AB - RATIONALE: Alcoholics are more likely to have infections, mainly in the respiratory system. Alcohol seems to inhibit the immune system. Despite the extensive literature related to alcoholism, data related to the immune system are still not conclusive. OBJECTIVE: The purpose of this study was to verify the influence of acute alcohol intake on colloid distribution in the organs of the mononuclear phagocyte system. METHODS AND RESULTS: Thirteen male Swiss mice were divided into two groups: Group 1 (n = 5) - control, and Group 2 (n = 8) - animals that received 0.5 ml ethanol 50%, 30 minutes before the experiment. Colloidal sulphur labeled with 99mTc was used to evaluate colloid distribution in the liver, spleen and lungs. Colloid clearance was assessed as well. A gamma camera was used to measure the radioactivity of these organs and of a blood clot. No difference was found in the presence of colloid in the organs of both groups. The liver showed the highest phagocytic intake, followed by the spleen and lungs (p = 0.021 for Group 1 and p = 0.003 for Group 2). A minimum amount of radiation remained in the blood of both groups. DISCUSSION: According to the experiential conditions of this work, acute ingestion of alcohol did not interfere with the phagocytic function of the mononuclear phagocyte system in mice. PMID- 22514579 TI - Actual concepts in scaphocephaly : (an experience of 98 cases). AB - Craniosynostoses are recognized as a group of birth defects that impair the skull structures by early closure of one or more sutures, causing an abnormal cranial shape. Among the "simple" craniosynostoses, (a single closed suture) the most common is scaphocephaly. The 3D CT scan is the most relevant and rapid diagnostic test. The authors present the personal experience of 98 scaphocephaly cases diagnosed and surgically treated in the Neurosurgical Department of "Bagdasar Arseni" Emergency Hospital during a period of 10 years (2000 - 2009). The procedure of choice was the Stein & Schut (1977) extensive craniotomy that removes the early closed suture. There were no post-operatory death cases and no abnormally closed sutures. The routine use of the craniotome facilitates the lateral osteotomy that allows a normal brain growth and a normal symmetrical skull shape development. The authors advocate for early surgery during the first 6 months of life. PMID- 22514580 TI - How much do antiretroviral drugs penetrate into the central nervous system? AB - The central nervous system can act as a compartment in which HIV can replicate independently from plasma, and also as a sanctuary in which, under suboptimal drug pressure, HIV antiretroviral genetic variants can occur. Continuous replication of HIV in brain can contribute to neurocognitive impairment. Therefore, reaching adequate concentrations of antiretrovirals in the central nervous system might be essential in providing neuroprotection and improving neurocognition. Antiretrovirals have a restricted entry into the brain, due to several factors: the unique structure of the blood-brain barrier, and the existence of efficient efflux mechanisms. However, there is a high variability of antiretrovirals in reaching therapeutic drug concentrations in cerebrospinal fluid, that depend on the characteristics of the antiretrovirals (molecular weight, lipophilicity, protein binding) and on their capacity to be substrate for efflux transporters. The review aims to discuss the main mechanisms that interfere with antiretroviral penetration into central nervous system, and to summarize the current data concerning the penetrability of different antiretrovirals into the cerebrospinal fluid. PMID- 22514581 TI - A case of oral mucosal melanoma. Clinical and dermoscopic correlation. AB - BACKGROUND: Most patients with oral mucosal melanoma have had a mucosal hyper pigmented area for months or even years before the diagnosis, it is important to consider the differential diagnosis of mucosal melanoma, which in many cases is a difficult diagnosis and because of the aggressive biological behavior of mucosal melanoma it is important to do a quick diagnosis. MAIN OBSERVATION: A 40-year-old Mexican male patient, presented with a lesion on the lower right half of the lip covering almost the entire vermillion border, 1 mm below the white roll. The lesion was a 1.5 x 4 cm pigmented macule with asymmetric and irregular borders and colors. Dermoscopy showed a multi component pattern. An incision biopsy was performed under the impression of mucosal melanoma. The pathologic report described a Clark I vermillion edge mucosal melanoma in situ. CONCLUSIONS: This case had confounding clinical signs that could have misguided the clinician. But dermoscopy proved to be useful when suspecting a malignant lesion, which prompted a biopsy and a correct diagnosis. PMID- 22514582 TI - Melanoma diagnosed 27 years after a benoxaprofen-induced photosensitivity reaction. AB - BACKGROUND: The propionic acid derivative Benoxaprofen was introduced for the treatment of rheumatic disorders in 1980. Its product license was then withdrawn 2 years later due to concerns over serious dermatologic, hepatic and renal side effects. Photosensitivity was the most common side effect with reported incidence of up to 50%. MAIN OBSERVATIONS: We present the first case report of a patient who presented with a melanoma diagnosed 27 years after a benoxaprofen-induced photosensitivity reaction. With an estimated 1.5 million patients previously on benoxaprofen, a large number of patients may potentially face increased risk of developing malignant melanoma. This case report can only suggest an association between solar injury secondary to benoxaprofen-related photosensitivity and subsequent melanoma. However the primary factor that improves survival from melanoma is early diagnosis, and so clinicians treating this group of patients should be aware of this risk. CONCLUSION: Although benoxaprofen is no longer in clinical use, the long-term sequelae to its photosensitizing effects may still be clinically important. Clinicians treating this group of patients should be vigilant, and consider a low threshold for diagnostic biopsy of suspicious skin lesions. PMID- 22514583 TI - Variable clinical presentations of Classic Kaposi Sarcoma in Turkish patients. AB - BACKGROUND: Kaposi sarcoma (KS) is a vascular neoplasm with multicentric cutanenous and extracutaneous involvements, which was first described by Moriz Kaposi in 1872. Since then, different epidemiological clinical and histopathological variants of this neoplasm have been identified. Classic Kaposi sarcoma (CKS) is one of four main clinico-epidemiologiologic variants. characteristics of the disease. MATERIALS AND METHODS: Four Turkish inpatients with CKS were evaluated in the study. All medical history and clinical data were noted. A screening immunodeficiency workup were performed for all patients. HHV-8 immunofluorescence testing on the specimens and ELISA test for human immunodeficiency virus (HIV 1 and 2) were performed. Pulmonary X ray graphies and computurized tomography (CT) scan were applied. Stage of the tumor was determined, in each case, according to the classification system proposed by Brambilla et al in 2003. RESULTS: All patients are positive for HHV-8. They were all immunocompetent and negative for HIV1 and HIV2. The first patient was unusual for morphological presentation of several verrucoid lesions that was evaluated as verrucoid KS. He was considered stage IB CKS. The patient 2 was a young man and the course of KS seemed unexpectedly aggressive for CKS. His clinical appearence seemed us to be a patient with AIDSassociated KS. The patient was evaluated as stage IVB CKS. Our third patient had also prominent lymphedema associated with bluish discoloration on the toes and fingers, suggesting a diagnosis of peripheral vascular disorder. He was diagnosed as stage IIIB CKS. The fourth case was interesting for very extensive lesions involving big sized plaques and also the existence of mucosal lesion. The patient was diagnosed as stage IVB CKS. CONCLUSIONS: It seems that the reports of exceptional cases of KS are accumulating. Data from various cases should be collected and perhaps, novel clinical classifications should be considered. PMID- 22514585 TI - Acute periungueal dermatitis induced by application of urea-containing cream under occlusion. AB - BACKGROUND: Urea containing topical products are extensively marked for treatment of nail diseases. Side effects are rare and mainly include irritation of the periungual skin, when topicals with high urea concentration are applied too widely on the digit, or covered by tape. MAIN OBSERVATION: We report a case of a 84-year-old man with an erosive-bullous eruption of the 1st and the 2nd left toes due to application of an urea-containing cream, that he had regularly applied every night covering the digit with a plastic bandage. Suspecting an allergic contact dermatitis, we performed patch test with the Italian Standard series called SIDAPA and the product (Xerial 50 Extreme cream(r)) itself. Patch test readings showed a positive reaction to colophony contained in the plastic band and to the cream. CONCLUSION: Our case is the first report of allergic contact dermatitis to a cream containing a high concentration urea utilized for treatment of nail thickening under occlusion. PMID- 22514584 TI - Atrophic dermatofibrosarcoma protuberans. AB - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is an uncommon malignant mesenchymal tumor that arises in the dermis and is characterised by latency in its initial detection. As a rare form, atrophic or morphea-like DFSP has been documented. Atrophic DFSP resemble other benign lesions such as morphea, idiopathic atrophoderma, atrophic scar, anetoderma or lipoatrophy. It behaves like classic DFSP. It commonly favours young to middle aged adults. It has a slow infiltrative growth and a high rate of local recurrence if not completely excised. Metastases are rare and occur after repeated local recurrence. Surgical excision is the best line of treatment. Long term follow up is required to detect recurrence. MAIN OBSERVATIONS: We report a case of atrophic DFSP in a 52-year-old female patient. Diagnosis was achieved according to clinical, histopathological and immunohistochemical findings. Tumor was surgically excised with safety margin and the patient is still under follow up. CONCLUSIONS: Atrophic DFSP is a rare variant of DFSP. It is a tumor of low to moderate grade malignancy. Surgical excision is the best line of management. Long term follow up is necessary. PMID- 22514586 TI - Mucosal fixed drug eruption in a patient treated with ornidazole. AB - BACKGROUND: Therapeutic drugs have been observed to cause a wide spectrum of adverse oral effects such as dry mouth, gingival enlargement, taste disturbance, oral mucosal ulceration, halitosis, etc. OBSERVATIONS: A rare case of intra-oral fixed drug eruption (FDE) induced by ornidazole presenting on the hard palate, an extremely rare site for FDE, in a 40-year-old male is reported. CONCLUSIONS: Ornidazole is a relatively newer 5-nitroimidazole derivative commonly prescribed for Amoebic dysentery in developing countries. FDE is a rare adverse drug effect characterized by onset of round/oval, erythematous macules on the skin or mucosa that can be associated with itching and burning sensation. The exact mechanism causing FDE is unknown. PMID- 22514587 TI - Adams-Oliver Syndrome. A case with isolated aplasia cutis congenita and skeletal defects. AB - BACKGROUND: Adams-Oliver Syndrome is characterized by the combination of aplasia cutis congenita and limb anomalies. It was initially described in 1945 by Adams and Oliver. MAIN OBSERVATIONS: We report a case of a 10-year-old girl with Adams Oliver Syndrome with aplasia cutis congenita and limb defects only with no internal organ anomalies. CONCLUSIONS: Adams-Oliver Syndrome is a rare multisystem disorder of unknown etiology. It may be presented by isolated aplasia cutis congenita and limb anomalies. PMID- 22514589 TI - Photoletter to the editor: Scarring alopecia resulting from pyoderma gangrenosum of the scalp. AB - Pyoderma gangrenosum is an uncommon ulcerative cutaneous condition of uncertain aetiology. It is a disease that causes tissue to become necrotic, leading to deep ulcers. We report a case of pyoderma gangrenosum localized at the scalp, which is an unusual location. After 16 months of treatment with prednisolone 40 mg daily, methotrexate 15 mg weekly, ciprofloxacin 500 mg and honey dressing the indurated elevated ulcer margins flattened and the ulcer healed with scarring of the entire scalp. PMID- 22514588 TI - Clinical and laboratory findings in 8 patients with Bloom's syndrome. AB - Bloom's syndrome is a rare autosomal recessive disorder caused by germline mutation of the BLM gene. The objective of this study was to illustrate the clinical, biological and genetic characteristics of this syndrome through Tunisian series. We report in a retrospective study 8 case of bloom's syndrome observed during 20 years. RESULTS: Our patients were 4 males and 4 females issued from 5 families. For all patients, the parents were consanguineous. The age was 13 to 39 years. The telangiectatic erythema was developed in all the patients between 6 months and 2 years old on the cheeks, on the nose, on the lips and the lower eyebrows. The photosensitivity was constant and was complicated by vesicules and bullae for 5 patients who had extensive lesions, three patients noted accentuation of their telangiectasic erythema. An improvement with the age was noticed for the first four patients. The growth deficiency was observed for all patients. It was marked, between -2 and -4 DS (standard deviation). The number of sister chromatid exchange was increased to twelve fold comparatively to normal subjects. Two patients developed a breast cancer; the evolution was fatal in one. Another patient developed a leukaemia, the evolution was also fatal. CONCLUSION: Bloom's syndrome is a rare genodermatitis. All the patients presented three symptoms: telangiectatic erythema, growth delay and photosensitivity associated with immunodeficiency. There is significant risk of cancer, so that follow up of patients is mandatory. PMID- 22514590 TI - ASSOCIATION BETWEEN DE NOVO DONOR SPECIFIC HLA ANTIBODY, C4D STAINING IN RENAL GRAFT BIOPSY AND GRAFT OUTCOME: A SINGLE CENTER EXPERIENCE. AB - In 69 renal transplant recipients (RTR), all had a functioning graft (SCr < 2.0) at one year. After one year, transplant dysfunction was observed and these 69 RTR were biopsied, tested for C4d deposition and donor specific antibodies (DSA). Of these 69 RTR, 29 (42%) showed C4d negativity, 27 (39%) were C4d positive and 13 (19%) were not diagnostic. Forty-nine (71%) recipients had HLA antibodies and 41 (59%) had DSA. The proportion of C4d positivity was significantly higher in patients with DSA (HLA Class I only, II only, and I & II) in comparison to patients without post-transplant HLA antibodies. The incidence of graft failure (including current SCr > 4.0) in RTR with HLA Class II antibodies (Class II only or I & II) was significantly higher than in RTR without post-transplant HLA antibodies (P=0.03).Even after amelioration of rejection, the RTR with Class II DSA group continued to fail beyond 2 years after transplantation when compared with the other 2 groups (None/NDSA or HLA Class I only), however, the difference in graft survival between HLA Class II and None/NDSA groups did not reach statistical significance (log-rank P=0.32). Significant association between C4d staining, post-transplant HLA Class II antibodies and graft failure strongly suggests the importance of post-transplant HLA antibodies. HLA Class II DSAs may be an indicator of chronic allograft nephropathy (CAN) proceeding to graft loss. We propose that amelioration of CAN graft loss may be affected by monitoring and identification of DSA with appropriate immunosuppression of these antibodies. PMID- 22514596 TI - Caffeine consumption prevents diabetes-induced memory impairment and synaptotoxicity in the hippocampus of NONcZNO10/LTJ mice. AB - Diabetic conditions are associated with modified brain function, namely with cognitive deficits, through largely undetermined processes. More than understanding the underlying mechanism, it is important to devise novel strategies to alleviate diabetes-induced cognitive deficits. Caffeine (a mixed antagonist of adenosine A(1) and A(2A) receptors) emerges as a promising candidate since caffeine consumption reduces the risk of diabetes and effectively prevents memory deficits caused by different noxious stimuli. Thus, we took advantage of a novel animal model of type 2 diabetes to investigate the behavioural, neurochemical and morphological modifications present in the hippocampus and tested if caffeine consumption might prevent these changes. We used a model closely mimicking the human type 2 diabetes condition, NONcNZO10/LtJ mice, which become diabetic at 7-11 months when kept under an 11% fat diet. Caffeine (1 g/l) was applied in the drinking water from 7 months onwards. Diabetic mice displayed a decreased spontaneous alternation in the Y-maze accompanied by a decreased density of nerve terminal markers (synaptophysin, SNAP25), mainly glutamatergic (vesicular glutamate transporters), and increased astrogliosis (GFAP immunoreactivity) compared to their wild type littermates kept under the same diet. Furthermore, diabetic mice displayed up-regulated A(2A) receptors and down-regulated A(1) receptors in the hippocampus. Caffeine consumption restored memory performance and abrogated the diabetes-induced loss of nerve terminals and astrogliosis. These results provide the first evidence that type 2 diabetic mice display a loss of nerve terminal markers and astrogliosis, which is associated with memory impairment; furthermore, caffeine consumption prevents synaptic dysfunction and astrogliosis as well as memory impairment in type 2 diabetes. PMID- 22514598 TI - Annotation of the transcriptome from Taenia pisiformis and its comparative analysis with three Taeniidae species. AB - BACKGROUND: Taenia pisiformis is one of the most common intestinal tapeworms and can cause infections in canines. Adult T. pisiformis (canines as definitive hosts) and Cysticercus pisiformis (rabbits as intermediate hosts) cause significant health problems to the host and considerable socio-economic losses as a consequence. No complete genomic data regarding T. pisiformis are currently available in public databases. RNA-seq provides an effective approach to analyze the eukaryotic transcriptome to generate large functional gene datasets that can be used for further studies. METHODOLOGY/PRINCIPAL FINDINGS: In this study, 2.67 million sequencing clean reads and 72,957 unigenes were generated using the RNA seq technique. Based on a sequence similarity search with known proteins, a total of 26,012 unigenes (no redundancy) were identified after quality control procedures via the alignment of four databases. Overall, 15,920 unigenes were mapped to 203 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Through analyzing the glycolysis/gluconeogenesis and axonal guidance pathways, we achieved an in-depth understanding of the biochemistry of T. pisiformis. Here, we selected four unigenes at random and obtained their full-length cDNA clones using RACE PCR. Functional distribution characteristics were gained through comparing four cestode species (72,957 unigenes of T. pisiformis, 30,700 ESTs of T. solium, 1,058 ESTs of Eg+Em [conserved ESTs between Echinococcus granulosus and Echinococcus multilocularis]), with the cluster of orthologous groups (COG) and gene ontology (GO) functional classification systems. Furthermore, the conserved common genes in these four cestode species were obtained and aligned by the KEGG database. CONCLUSION: This study provides an extensive transcriptome dataset obtained from the deep sequencing of T. pisiformis in a non-model whole genome. The identification of conserved genes may provide novel approaches for potential drug targets and vaccinations against cestode infections. Research can now accelerate into the functional genomics, immunity and gene expression profiles of cestode species. PMID- 22514597 TI - Identification of spectral modifications occurring during reprogramming of somatic cells. AB - Recent technological advances in cell reprogramming by generation of induced pluripotent stem cells (iPSC) offer major perspectives in disease modelling and future hopes for providing novel stem cells sources in regenerative medicine. However, research on iPSC still requires refining the criteria of the pluripotency stage of these cells and exploration of their equivalent functionality to human embryonic stem cells (ESC). We report here on the use of infrared microspectroscopy to follow the spectral modification of somatic cells during the reprogramming process. We show that induced pluripotent stem cells (iPSC) adopt a chemical composition leading to a spectral signature indistinguishable from that of embryonic stem cells (ESC) and entirely different from that of the original somatic cells. Similarly, this technique allows a distinction to be made between partially and fully reprogrammed cells. We conclude that infrared microspectroscopy signature is a novel methodology to evaluate induced pluripotency and can be added to the tests currently used for this purpose. PMID- 22514599 TI - White matter development in early puberty: a longitudinal volumetric and diffusion tensor imaging twin study. AB - White matter microstructure and volume show synchronous developmental patterns in children. White matter volume increases considerably during development. Fractional anisotropy, a measure for white matter microstructural directionality, also increases with age. Development of white matter volume and development of white matter microstructure seem to go hand in hand. The extent to which the same or different genetic and/or environmental factors drive these two aspects of white matter maturation is currently unknown. We mapped changes in white matter volume, surface area and diffusion parameters in mono- and dizygotic twins who were scanned at age 9 (203 individuals) and again at age 12 (126 individuals). Over the three-year interval, white matter volume (+6.0%) and surface area (+1.7%) increased, fiber bundles expanded (most pronounced in the left arcuate fasciculus and splenium), and fractional anisotropy increased (+3.0%). Genes influenced white matter volume (heritability ~85%), surface area (~85%), and fractional anisotropy (locally 7% to 50%) at both ages. Finally, volumetric white matter growth was negatively correlated with fractional anisotropy increase (r = 0.62) and this relationship was driven by environmental factors. In children who showed the most pronounced white matter growth, fractional anisotropy increased the least and vice-versa. Thus, white matter development in childhood may reflect a process of both expansion and fiber optimization. PMID- 22514601 TI - A putative plant aminophospholipid flippase, the Arabidopsis P4 ATPase ALA1, localizes to the plasma membrane following association with a beta-subunit. AB - Plasma membranes in eukaryotic cells display asymmetric lipid distributions with aminophospholipids concentrated in the inner leaflet and sphingolipids in the outer leaflet. This unequal distribution of lipids between leaflets is, amongst several proposed functions, hypothesized to be a prerequisite for endocytosis. P4 ATPases, belonging to the P-type ATPase superfamily of pumps, are involved in establishing lipid asymmetry across plasma membranes, but P4 ATPases have not been identified in plant plasma membranes. Here we report that the plant P4 ATPase ALA1, which previously has been connected with cold tolerance of Arabidopsis thaliana, is targeted to the plasma membrane and does so following association in the endoplasmic reticulum with an ALIS protein beta-subunit. PMID- 22514600 TI - Retinoids regulate the formation and degradation of gap junctions in androgen responsive human prostate cancer cells. AB - The retinoids, the natural or synthetic derivatives of Vitamin A (retinol), are essential for the normal development of prostate and have been shown to modulate prostate cancer progression in vivo as well as to modulate growth of several prostate cancer cell lines. 9-cis-retinoic acid and all-trans-retinoic acid are the two most important metabolites of retinol. Gap junctions, formed of proteins called connexins, are ensembles of intercellular channels that permit the exchange of small growth regulatory molecules between adjoining cells. Gap junctional communication is instrumental in the control of cell growth. We examined the effect of 9-cis-retinoic acid and all-trans retinoic acid on the formation and degradation of gap junctions as well as on junctional communication in an androgen-responsive prostate cancer cell line, LNCaP, which expressed retrovirally introduced connexin32, a connexin expressed by the luminal cells and well-differentiated cells of prostate tumors. Our results showed that 9-cis retinoic acid and all-trans retinoic acid enhanced the assembly of connexin32 into gap junctions. Our results further showed that 9-cis-retinoic acid and all trans-retinoic acid prevented androgen-regulated degradation of gap junctions, post-translationally, independent of androgen receptor mediated signaling. Finally, our findings showed that formation of gap junctions sensitized connexin32-expressing LNCaP cells to the growth modifying effects of 9-cis retinoic acid, all-trans-retinoic acid and androgens. Thus, the effects of retinoids and androgens on growth and the formation and degradation of gap junctions and their function might be related to their ability to modulate prostate growth and cancer. PMID- 22514602 TI - Role of fibronectin in the adhesion of Acinetobacter baumannii to host cells. AB - Adhesion to host cells is an initial and important step in Acinetobacter baumannii pathogenesis. However, there is relatively little information on the mechanisms by which A. baumannii binds to and interacts with host cells. Adherence to extracellular matrix proteins, such as fibronectin, affords pathogens with a mechanism to invade epithelial cells. Here, we found that A. baumannii adheres more avidly to immobilized fibronectin than to control protein. Free fibronectin used as a competitor resulted in dose-dependent decreased binding of A. baumannii to fibronectin. Three outer membrane preparations (OMPs) were identified as fibronectin binding proteins (FBPs): OMPA, TonB-dependent copper receptor, and 34 kDa OMP. Moreover, we demonstrated that fibronectin inhibition and neutralization by specific antibody prevented significantly the adhesion of A. baumannii to human lung epithelial cells (A549 cells). Similarly, A. baumannii OMPA neutralization by specific antibody decreased significantly the adhesion of A. baumannii to A549 cells. These data indicate that FBPs are key adhesins that mediate binding of A. baumannii to human lung epithelial cells through interaction with fibronectin on the surface of these host cells. PMID- 22514603 TI - Ghrelin attenuates the osteoblastic differentiation of vascular smooth muscle cells through the ERK pathway. AB - Vascular calcification results from osteoblastic differentiation of vascular smooth muscle cells (VSMCs) and is a major risk factor for cardiovascular events. Ghrelin is a newly discovered bioactive peptide that acts as a natural endogenous ligand of the growth hormone secretagog receptor (GHSR). Several studies have identified the protective effects of ghrelin on the cardiovascular system, however research on the effects and mechanisms of ghrelin on vascular calcification is still quite rare. In this study, we determined the effect of ghrelin on osteoblastic differentiation of VSMCs and investigated the mechanism involved using the two universally accepted calcifying models of calcifying vascular smooth muscle cells (CVSMCs) and beta-glycerophosphate (beta-GP)-induced VSMCs. Our data demonstrated that ghrelin inhibits osteoblastic differentiation and mineralization of VSMCs due to decreased alkaline phosphatase (ALP) activity, Runx2 expression, bone morphogenetic protein-2 (BMP-2) expression and calcium content. Further study demonstrated that ghrelin exerted this suppression effect via an extracellular signal-related kinase (ERK)-dependent pathway and that the suppression effect of ghrelin was time dependent and dose dependent. Furthermore, inhibition of the growth hormone secretagog receptor (GHSR), the ghrelin receptor, by siRNA significantly reversed the activation of ERK by ghrelin. In conclusion, our study suggests that ghrelin may inhibit osteoblastic differentiation of VSMCs through the GHSR/ERK pathway. PMID- 22514605 TI - Dynamic resource allocation in disaster response: tradeoffs in wildfire suppression. AB - Challenges associated with the allocation of limited resources to mitigate the impact of natural disasters inspire fundamentally new theoretical questions for dynamic decision making in coupled human and natural systems. Wildfires are one of several types of disaster phenomena, including oil spills and disease epidemics, where (1) the disaster evolves on the same timescale as the response effort, and (2) delays in response can lead to increased disaster severity and thus greater demand for resources. We introduce a minimal stochastic process to represent wildfire progression that nonetheless accurately captures the heavy tailed statistical distribution of fire sizes observed in nature. We then couple this model for fire spread to a series of response models that isolate fundamental tradeoffs both in the strength and timing of response and also in division of limited resources across multiple competing suppression efforts. Using this framework, we compute optimal strategies for decision making scenarios that arise in fire response policy. PMID- 22514604 TI - The effect of chronic antipsychotic drug on hypothalamic expression of neural nitric oxide synthase and dopamine D2 receptor in the male rat. AB - Antipsychotic-induced sexual dysfunction is a common and serious clinical side effect. It has been demonstrated that both neuronal nitric oxide (nNOS) and dopamine D2 receptor (DRD2) in the medial preoptic area (MPOA) and the paraventricular nucleus (PVN) of the hypothalamus have important roles in the regulation of sexual behaviour. We investigated the influences of 21 days' antipsychotic drug administration on expression of nNOS and DRD2 in the rat hypothalamus. Haloperidol (0.5 mg/kg/day i.p.) significantly decreased nNOS integrated optical density in a sub-nucleus of the MPOA, medial preoptic nucleus (MPN), and decreased the nNOS integrated optical density and cell density in another sub-nucleus of the MPOA, anterodorsal preoptic nucleus (ADP). Risperidone (0.25 mg/kg) inhibited the nNOS integrated optical density in the ADP. nNOS mRNA and protein in the MPOA but not the PVN was also significantly decreased by haloperidol. Haloperidol and risperidone increased DRD2 mRNA and protein expression in both the MPOA and the PVN. Quetiapine (20 mg/kg/day i.p.) did not influence the expression of nNOS and DRD2 in either the MPOA or the PVN. These findings indicate that hypothalamic nNOS and DRD2 are affected to different extents by chronic administration of risperidone and haloperidol, but are unaffected by quetiapine. These central effects might play a role in sexual dysfunction induced by certain antipsychotic drugs. PMID- 22514606 TI - Comparative proteomic analysis of Streptococcus suis biofilms and planktonic cells that identified biofilm infection-related immunogenic proteins. AB - Streptococcus suis (SS) is a zoonotic pathogen that causes severe disease symptoms in pigs and humans. Biofilms of SS bind to extracellular matrix proteins in both endothelial and epithelial cells and cause persistent infections. In this study, the differences in the protein expression profiles of SS grown either as planktonic cells or biofilms were identified using comparative proteomic analysis. The results revealed the existence of 13 proteins of varying amounts, among which six were upregulated and seven were downregulated in the Streptococcus biofilm compared with the planktonic controls. The convalescent serum from mini-pig, challenged with SS, was applied in a Western blot assay to visualize all proteins from the biofilm that were grown in vitro and separated by two-dimensional gel electrophoresis. A total of 10 immunoreactive protein spots corresponding to nine unique proteins were identified by MALDI-TOF/TOF-MS. Of these nine proteins, five (Manganese-dependent superoxide dismutase, UDP-N acetylglucosamine 1-carboxyvinyltransferase, ornithine carbamoyltransferase, phosphoglycerate kinase, Hypothetical protein SSU05_0403) had no previously reported immunogenic properties in SS to our knowledge. The remaining four immunogenic proteins (glyceraldehyde-3-phosphate dehydrogenase, hemolysin, pyruvate dehydrogenase and DnaK) were identified under both planktonic and biofilm growth conditions. In conclusion, the protein expression pattern of SS, grown as biofilm, was different from the SS grown as planktonic cells. These five immunogenic proteins that were specific to SS biofilm cells may potentially be targeted as vaccine candidates to protect against SS biofilm infections. The four proteins common to both biofilm and planktonic cells can be targeted as vaccine candidates to protect against both biofilm and acute infections. PMID- 22514607 TI - Photodegradation of the Mycobacterium ulcerans toxin, mycolactones: considerations for handling and storage. AB - BACKGROUND: Mycolactones are toxins secreted by M. ulcerans, the etiological agent of Buruli ulcer. These toxins, which are the main virulence factors of the bacilli, are responsible for skin lesions. Considering their specificity for M. ulcerans and their presence in skin lesions even at early stages, mycolactones are promising candidates for the development of a diagnostic tool for M. ulcerans infection. Stability of purified mycolactones towards light and heat has not yet been investigated, despite the importance of such parameters in the selection of strategies for a diagnosis tool development. In this context, the effects of UV, light and temperature on mycolactone stability and biological activity were studied. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the effect of these physical parameters, mycolactones were exposed to different wavelengths in several solvents and temperatures. Structural changes and biological activity were monitored. Whilst high temperature had no effect on mycolactones, UV irradiation (UV-A, UV-B and UV-C) and sunlight exposure caused a considerable degradation, as revealed by LC-MS and NMR analysis, correlated with a loss of biological activity. Moreover, effect of UVs on mycolactone caused a photodegradation rather than a phototransformation due to the identification of degradation product. CONCLUSION/SIGNIFICANCE: This study demonstrates the high sensitivity of mycolactones to UVs as such it defines instructions for storage and handling. PMID- 22514608 TI - Transcriptional and proteomic analysis of the Aspergillus fumigatus DeltaprtT protease-deficient mutant. AB - Aspergillus fumigatus is the most common opportunistic mold pathogen of humans, infecting immunocompromised patients. The fungus invades the lungs and other organs, causing severe damage. Penetration of the pulmonary epithelium is a key step in the infectious process. A. fumigatus produces extracellular proteases to degrade the host structural barriers. The A. fumigatus transcription factor PrtT controls the expression of multiple secreted proteases. PrtT shows similarity to the fungal Gal4-type Zn(2)-Cys(6) DNA-binding domain of several transcription factors. In this work, we further investigate the function of this transcription factor by performing a transcriptional and a proteomic analysis of the DeltaprtT mutant. Unexpectedly, microarray analysis revealed that in addition to the expected decrease in protease expression, expression of genes involved in iron uptake and ergosterol synthesis was dramatically decreased in the DeltaprtT mutant. A second finding of interest is that deletion of prtT resulted in the upregulation of four secondary metabolite clusters, including genes for the biosynthesis of toxic pseurotin A. Proteomic analysis identified reduced levels of three secreted proteases (ALP1 protease, TppA, AFUA_2G01250) and increased levels of three secreted polysaccharide-degrading enzymes in the DeltaprtT mutant possibly in response to its inability to derive sufficient nourishment from protein breakdown. This report highlights the complexity of gene regulation by PrtT, and suggests a potential novel link between the regulation of protease secretion and the control of iron uptake, ergosterol biosynthesis and secondary metabolite production in A. fumigatus. PMID- 22514609 TI - An emperor penguin population estimate: the first global, synoptic survey of a species from space. AB - Our aim was to estimate the population of emperor penguins (Aptenodytes fosteri) using a single synoptic survey. We examined the whole continental coastline of Antarctica using a combination of medium resolution and Very High Resolution (VHR) satellite imagery to identify emperor penguin colony locations. Where colonies were identified, VHR imagery was obtained in the 2009 breeding season. The remotely-sensed images were then analysed using a supervised classification method to separate penguins from snow, shadow and guano. Actual counts of penguins from eleven ground truthing sites were used to convert these classified areas into numbers of penguins using a robust regression algorithm.We found four new colonies and confirmed the location of three previously suspected sites giving a total number of emperor penguin breeding colonies of 46. We estimated the breeding population of emperor penguins at each colony during 2009 and provide a population estimate of ~238,000 breeding pairs (compared with the last previously published count of 135,000-175,000 pairs). Based on published values of the relationship between breeders and non-breeders, this translates to a total population of ~595,000 adult birds.There is a growing consensus in the literature that global and regional emperor penguin populations will be affected by changing climate, a driver thought to be critical to their future survival. However, a complete understanding is severely limited by the lack of detailed knowledge about much of their ecology, and importantly a poor understanding of their total breeding population. To address the second of these issues, our work now provides a comprehensive estimate of the total breeding population that can be used in future population models and will provide a baseline for long-term research. PMID- 22514611 TI - Groundwater nitrogen pollution and assessment of its health risks: a case study of a typical village in rural-urban continuum, China. AB - Protecting groundwater from nitrogen contamination is an important public-health concern and a major national environmental issue in China. In this study, we monitored water quality in 29 wells from 2009 to 2010 in a village in Shanghai city, whick belong to typical rural-urban continuum in China. The total N and NO(3)-N exhibited seasonal changes, and there were large fluctuations in NH(4)-N in residential areas, but without significant seasonal patterns. NO(2)-N in the water was not stable, but was present at high levels. Total N and NO(3)-N were significantly lower in residential areas than in agricultural areas. The groundwater quality in most wells belonged to Class III and IV in the Chinese water standard, which defines water that is unsuitable for human consumption. Our health risk assessments showed that NO(3)-N posed the greatest carcinogenic risk, with risk values ranging from 19*10(-6) to 80*10(-6), which accounted for more than 90% of the total risk in the study area. PMID- 22514610 TI - Genetic resistance to rhabdovirus infection in teleost fish is paralleled to the derived cell resistance status. AB - Genetic factors of resistance and predisposition to viral diseases explain a significant part of the clinical variability observed within host populations. Predisposition to viral diseases has been associated to MHC haplotypes and T cell immunity, but a growing repertoire of innate/intrinsic factors are implicated in the genetic determinism of the host susceptibility to viruses. In a long-term study of the genetics of host resistance to fish rhabdoviruses, we produced a collection of double-haploid rainbow trout clones showing a wide range of susceptibility to Viral Hemorrhagic Septicemia Virus (VHSV) waterborne infection. The susceptibility of fibroblastic cell lines derived from these clonal fish was fully consistent with the susceptibility of the parental fish clones. The mechanisms determining the host resistance therefore did not associate with specific host immunity, but rather with innate or intrinsic factors. One cell line was resistant to rhabdovirus infection due to the combination of an early interferon IFN induction--that was not observed in the susceptible cells--and of yet unknown factors that hamper the first steps of the viral cycle. The implication of IFN was well consistent with the wide range of resistance of this genetic background to VSHV and IHNV, to the birnavirus IPNV and the orthomyxovirus ISAV. Another cell line was even more refractory to the VHSV infection through different antiviral mechanisms. This collection of clonal fish and isogenic cell lines provides an interesting model to analyze the relative contribution of antiviral pathways to the resistance to different viruses. PMID- 22514612 TI - Genetic variations and haplotype diversity of the UGT1 gene cluster in the Chinese population. AB - Vertebrates require tremendous molecular diversity to defend against numerous small hydrophobic chemicals. UDP-glucuronosyltransferases (UGTs) are a large family of detoxification enzymes that glucuronidate xenobiotics and endobiotics, facilitating their excretion from the body. The UGT1 gene cluster contains a tandem array of variable first exons, each preceded by a specific promoter, and a common set of downstream constant exons, similar to the genomic organization of the protocadherin (Pcdh), immunoglobulin, and T-cell receptor gene clusters. To assist pharmacogenomics studies in Chinese, we sequenced nine first exons, promoter and intronic regions, and five common exons of the UGT1 gene cluster in a population sample of 253 unrelated Chinese individuals. We identified 101 polymorphisms and found 15 novel SNPs. We then computed allele frequencies for each polymorphism and reconstructed their linkage disequilibrium (LD) map. The UGT1 cluster can be divided into five linkage blocks: Block 9 (UGT1A9), Block 9/7/6 (UGT1A9, UGT1A7, and UGT1A6), Block 5 (UGT1A5), Block 4/3 (UGT1A4 and UGT1A3), and Block 3' UTR. Furthermore, we inferred haplotypes and selected their tagSNPs. Finally, comparing our data with those of three other populations of the HapMap project revealed ethnic specificity of the UGT1 genetic diversity in Chinese. These findings have important implications for future molecular genetic studies of the UGT1 gene cluster as well as for personalized medical therapies in Chinese. PMID- 22514613 TI - The crest phenotype in chicken is associated with ectopic expression of HOXC8 in cranial skin. AB - The Crest phenotype is characterised by a tuft of elongated feathers atop the head. A similar phenotype is also seen in several wild bird species. Crest shows an autosomal incompletely dominant mode of inheritance and is associated with cerebral hernia. Here we show, using linkage analysis and genome-wide association, that Crest is located on the E22C19W28 linkage group and that it shows complete association to the HOXC-cluster on this chromosome. Expression analysis of tissues from Crested and non-crested chickens, representing 26 different breeds, revealed that HOXC8, but not HOXC12 or HOXC13, showed ectopic expression in cranial skin during embryonic development. We propose that Crest is caused by a cis-acting regulatory mutation underlying the ectopic expression of HOXC8. However, the identification of the causative mutation(s) has to await until a method becomes available for assembling this chromosomal region. Crest is unfortunately located in a genomic region that has so far defied all attempts to establish a contiguous sequence. PMID- 22514614 TI - Negative regulation of EGFR/MAPK pathway by Pumilio in Drosophila melanogaster. AB - In Drosophila melanogaster, specification of wing vein cells and sensory organ precursor (SOP) cells, which later give rise to a bristle, requires EGFR signaling. Here, we show that Pumilio (Pum), an RNA-binding translational repressor, negatively regulates EGFR signaling in wing vein and bristle development. We observed that loss of Pum function yielded extra wing veins and additional bristles. Conversely, overexpression of Pum eliminated wing veins and bristles. Heterozygotes for Pum produced no phenotype on their own, but greatly enhanced phenotypes caused by the enhancement of EGFR signaling. Conversely, over expression of Pum suppressed the effects of ectopic EGFR signaling. Components of the EGFR signaling pathway are encoded by mRNAs that have Nanos Response Element (NRE)-like sequences in their 3'UTRs; NREs are known to bind Pum to confer regulation in other mRNAs. We show that these NRE-like sequences bind Pum and confer repression on a luciferase reporter in heterologous cells. Taken together, our evidence suggests that Pum functions as a negative regulator of EGFR signaling by directly targeting components of the pathway in Drosophila. PMID- 22514615 TI - Refugee and migrant women's views of antenatal ultrasound on the Thai Burmese border: a mixed methods study. AB - BACKGROUND: Antenatal ultrasound suits developing countries by virtue of its versatility, relatively low cost and safety, but little is known about women's or local provider's perspectives of this upcoming technology in such settings. This study was undertaken to better understand how routine obstetric ultrasound is experienced in a displaced Burmese population and identify barriers to its acceptance by local patients and providers. METHODOLOGY/PRINCIPAL FINDINGS: Qualitative (30 observations, 19 interviews, seven focus group discussions) and quantitative methods (questionnaire survey with 644 pregnant women) were used to provide a comprehensive understanding along four major themes: safety, emotions, information and communication, and unintended consequences of antenatal ultrasound in refugee and migrant clinics on the Thai Burmese border. One of the main concerns expressed by women was the danger of childbirth which they mainly attributed to fetal malposition. Both providers and patients recognized ultrasound as a technology improving the safety of pregnancy and delivery. A minority of patients experienced transitory shyness or anxiety before the ultrasound, but reported that these feelings could be ameliorated with improved patient information and staff communication. Unintended consequences of overuse and gender selective abortions in this population were not common. CONCLUSIONS/SIGNIFICANCE: The results of this study are being used to improve local practice and allow development of explanatory materials for this population with low literacy. We strongly encourage facilities introducing new technology in resource poor settings to assess acceptability through similar inquiry. PMID- 22514616 TI - Mind the gap: investigating toddlers' sensitivity to contact relations in predictive events. AB - Toddlers readily learn predictive relations between events (e.g., that event A predicts event B). However, they intervene on A to try to cause B only in a few contexts: When a dispositional agent initiates the event or when the event is described with causal language. The current studies look at whether toddlers' failures are due merely to the difficulty of initiating interventions or to more general constraints on the kinds of events they represent as causal. Toddlers saw a block slide towards a base, but an occluder prevented them from seeing whether the block contacted the base; after the block disappeared behind the occluder, a toy connected to the base did or did not activate. We hypothesized that if toddlers construed the events as causal, they would be sensitive to the contact relations between the participants in the predictive event. In Experiment 1, the block either moved spontaneously (no dispositional agent) or emerged already in motion (a dispositional agent was potentially present). Toddlers were sensitive to the contact relations only when a dispositional agent was potentially present. Experiment 2 confirmed that toddlers inferred a hidden agent was present when the block emerged in motion. In Experiment 3, the block moved spontaneously, but the events were described either with non-causal ("here's my block") or causal ("the block can make it go") language. Toddlers were sensitive to the contact relations only when given causal language. These findings suggest that dispositional agency and causal language facilitate toddlers' ability to represent causal relationships. PMID- 22514617 TI - Accuracy of rapid tests for malaria and treatment outcomes for malaria and non malaria cases among under-five children in rural Ghana. AB - BACKGROUND: WHO now recommends test-based management of malaria across all transmission settings. The accuracy of rapid diagnostic test (RDT) and the outcome of treatment based on the result of tests will influence acceptability of and adherence to the new guidelines. METHOD: We conducted a study at the Kintampo hospital in rural Ghana to evaluate the performance of CareStart, a HRP-2 based RDT, using microscopy as reference. We applied IMCI treatment guidelines, restricted ACT to RDT-positive children and followed-up both RDT-positive (malaria) and RDT-negative (non-malaria) cases over 28 days. RESULTS: 436 children were enrolled in the RDT evaluation and 391 (children with haemoglobin >8.0 gm/dl) were followed-up to assess treatment outcomes. Mean age was 25.4 months (s.d. 14.6). Sensitivity and specificity of the RDT were 100.0% and 73.0% respectively. Over the follow-up period, 32 (18.5%) RDT-negative children converted to positive, with 7 (4.0%) of them presenting with fever. More children in the non-malaria group made unscheduled visits than children in the malaria group (13.3% versus 7.7%) On all scheduled follow-up visits, proportion of children having a temperature higher than that recorded on day 0 was higher in the non-malaria group compared to the malaria group. Reports of unfavourable treatment outcomes by caregivers were higher among the non-malaria group than the malaria group. CONCLUSIONS: The RDT had good sensitivity and specificity. However a minority of children who will not receive ACT based on RDT results may develop clinical malaria within a short period in high transmission settings. This could undermine caregivers' and health workers' confidence in the new guidelines. Improving the quality of management of non-malarial febrile illnesses should be a priority in the era of test-based management of malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT00832754. PMID- 22514618 TI - Changes to airborne pollen counts across Europe. AB - A progressive global increase in the burden of allergic diseases has affected the industrialized world over the last half century and has been reported in the literature. The clinical evidence reveals a general increase in both incidence and prevalence of respiratory diseases, such as allergic rhinitis (common hay fever) and asthma. Such phenomena may be related not only to air pollution and changes in lifestyle, but also to an actual increase in airborne quantities of allergenic pollen. Experimental enhancements of carbon dioxide (CO[Formula: see text]) have demonstrated changes in pollen amount and allergenicity, but this has rarely been shown in the wider environment. The present analysis of a continental scale pollen data set reveals an increasing trend in the yearly amount of airborne pollen for many taxa in Europe, which is more pronounced in urban than semi-rural/rural areas. Climate change may contribute to these changes, however increased temperatures do not appear to be a major influencing factor. Instead, we suggest the anthropogenic rise of atmospheric CO[Formula: see text] levels may be influential. PMID- 22514619 TI - The macroeconomic consequences of renouncing to universal access to antiretroviral treatment for HIV in Africa: a micro-simulation model. AB - AIM: Previous economic literature on the cost-effectiveness of antiretroviral treatment (ART) programs has been mainly focused on the microeconomic consequences of alternative use of resources devoted to the fight against the HIV pandemic. We rather aim at forecasting the consequences of alternative scenarios for the macroeconomic performance of countries. METHODS: We used a micro simulation model based on individuals aged 15-49 selected from nationally representative surveys (DHS for Cameroon, Tanzania and Swaziland) to compare alternative scenarios : 1-freezing of ART programs to current levels of access, 2 universal access (scaling up to 100% coverage by 2015, with two variants defining ART eligibility according to previous or current WHO guidelines). We introduced an "artificial" ageing process by programming methods. Individuals could evolve through different health states: HIV negative, HIV positive (with different stages of the syndrome). Scenarios of ART procurement determine this dynamics. The macroeconomic impact is obtained using sample weights that take into account the resulting age-structure of the population in each scenario and modeling of the consequences on total growth of the economy. RESULTS: Increased levels of ART coverage result in decreasing HIV incidence and related mortality. Universal access to ART has a positive impact on workers' productivity; the evaluations performed for Swaziland and Cameroon show that universal access would imply net cost-savings at the scale of the society, when the full macroeconomic consequences are introduced in the calculations. In Tanzania, ART access programs imply a net cost for the economy, but 70% of costs are covered by GDP gains at the 2034 horizon, even in the extended coverage option promoted by WHO guidelines initiating ART at levels of 350 cc/mm(3) CD4 cell counts. CONCLUSION: Universal Access ART scaling-up strategies, which are more costly in the short term, remain the best economic choice in the long term. Renouncing or significantly delaying the achievement of this goal, due to "legitimate" short term budgetary constraints would be a misguided choice. PMID- 22514620 TI - Reaching the hard-to-reach: a probability sampling method for assessing prevalence of driving under the influence after drinking in alcohol outlets. AB - Drinking alcoholic beverages in places such as bars and clubs may be associated with harmful consequences such as violence and impaired driving. However, methods for obtaining probabilistic samples of drivers who drink at these places remain a challenge--since there is no a priori information on this mobile population--and must be continually improved. This paper describes the procedures adopted in the selection of a population-based sample of drivers who drank at alcohol selling outlets in Porto Alegre, Brazil, which we used to estimate the prevalence of intention to drive under the influence of alcohol. The sampling strategy comprises a stratified three-stage cluster sampling: 1) census enumeration areas (CEA) were stratified by alcohol outlets (AO) density and sampled with probability proportional to the number of AOs in each CEA; 2) combinations of outlets and shifts (COS) were stratified by prevalence of alcohol-related traffic crashes and sampled with probability proportional to their squared duration in hours; and, 3) drivers who drank at the selected COS were stratified by their intention to drive and sampled using inverse sampling. Sample weights were calibrated using a post-stratification estimator. 3,118 individuals were approached and 683 drivers interviewed, leading to an estimate that 56.3% (SE = 3,5%) of the drivers intended to drive after drinking in less than one hour after the interview. Prevalence was also estimated by sex and broad age groups. The combined use of stratification and inverse sampling enabled a good trade-off between resource and time allocation, while preserving the ability to generalize the findings. The current strategy can be viewed as a step forward in the efforts to improve surveys and estimation for hard-to-reach, mobile populations. PMID- 22514621 TI - Selenium toxicity to honey bee (Apis mellifera L.) pollinators: effects on behaviors and survival. AB - We know very little about how soil-borne pollutants such as selenium (Se) can impact pollinators, even though Se has contaminated soils and plants in areas where insect pollination can be critical to the functioning of both agricultural and natural ecosystems. Se can be biotransferred throughout the food web, but few studies have examined its effects on the insects that feed on Se-accumulating plants, particularly pollinators. In laboratory bioassays, we used proboscis extension reflex (PER) and taste perception to determine if the presence of Se affected the gustatory response of honey bee (Apis mellifera L., Hymenoptera: Apidae) foragers. Antennae and proboscises were stimulated with both organic (selenomethionine) and inorganic (selenate) forms of Se that commonly occur in Se accumulating plants. Methionine was also tested. Each compound was dissolved in 1 M sucrose at 5 concentrations, with sucrose alone as a control. Antennal stimulation with selenomethionine and methionine reduced PER at higher concentrations. Selenate did not reduce gustatory behaviors. Two hours after being fed the treatments, bees were tested for sucrose response threshold. Bees fed selenate responded less to sucrose stimulation. Mortality was higher in bees chronically dosed with selenate compared with a single dose. Selenomethionine did not increase mortality except at the highest concentration. Methionine did not significantly impact survival. Our study has shown that bees fed selenate were less responsive to sucrose, which may lead to a reduction in incoming floral resources needed to support coworkers and larvae in the field. If honey bees forage on nectar containing Se (particularly selenate), reductions in population numbers may occur due to direct toxicity. Given that honey bees are willing to consume food resources containing Se and may not avoid Se compounds in the plant tissues on which they are foraging, they may suffer similar adverse effects as seen in other insect guilds. PMID- 22514622 TI - Highly pathogenic influenza A(H5N1) virus survival in complex artificial aquatic biotopes. AB - BACKGROUND: Very little is known regarding the persistence of Highly Pathogenic Avian Influenza (HPAI) H5N1 viruses in aquatic environments in tropical countries, although environmental materials have been suggested to play a role as reservoirs and sources of transmission for H5N1 viruses. METHODOLOGY/PRINCIPAL FINDINGS: The survival of HPAI H5N1 viruses in experimental aquatic biotopes (water, mud, aquatic flora and fauna) relevant to field conditions in Cambodia was investigated. Artificial aquatic biotopes, including simple ones containing only mud and water, and complex biotopes involving the presence of aquatic flora and fauna, were set up. They were experimentally contaminated with H5N1 virus. The persistence of HPAI H5N1 virus (local avian and human isolates) was determined by virus isolation in embryonated chicken eggs and by real-time reverse-polymerase chain reaction. Persistence of infectious virus did not exceed 4 days, and was only identified in rain water. No infectious virus particles were detected in pond and lake water or mud even when high inoculum doses were used. However, viral RNA persisted up to 20 days in rain water and 7 days in pond or lake water. Viral RNA was also detected in mud samples, up to 14 days post contamination in several cases. Infectious virus and viral RNA was detected in few cases in the aquatic fauna and flora, especially in bivalves and labyrinth fish, although these organisms seemed to be mostly passive carriers of the virus rather than host allowing virus replication. CONCLUSIONS/SIGNIFICANCE: Although several factors for the survival and persistence of HPAI viruses in the environment are still to be elucidated, and are particularly hard to control in laboratory conditions, our results, along with previous data, support the idea that environmental surveillance is of major relevance for avian influenza control programs. PMID- 22514623 TI - Diversity of matriptase expression level and function in breast cancer. AB - Overexpression of matriptase has been reported in a variety of human cancers and is sufficient to trigger tumor formation in mice, but the importance of matriptase in breast cancer remains unclear. We analysed matriptase expression in 16 human breast cancer cell lines and in 107 primary breast tumors. The data revealed considerable diversity in the expression level of this protein indicating that the significance of matriptase may vary from case to case. Matriptase protein expression was correlated with HER2 expression and highest expression was seen in HER2-positive cell lines, indicating a potential role in this subgroup. Stable overexpression of matriptase in two breast cancer cell lines had different consequences. In MDA-MB-231 human breast carcinoma cells the only noted consequence of matriptase overexpression was modestly impaired growth in vivo. In contrast, overexpression of matriptase in 4T1 mouse breast carcinoma cells resulted in visible changes in morphology, actin staining and cell to cell contacts. This correlated with downregulation of the cell-cell adhesion molecule E-cadherin. These results suggest that the functions of matriptase in breast cancer are likely to be variable and cell context dependent. PMID- 22514625 TI - Epcam, CD44, and CD49f distinguish sphere-forming human prostate basal cells from a subpopulation with predominant tubule initiation capability. AB - BACKGROUND: Human prostate basal cells expressing alpha-6 integrin (CD49f(Hi)) and/or CD44 form prostaspheres in vitro. This functional trait is often correlated with stem/progenitor (S/P) activity, including the ability to self renew and induce differentiated tubules in vivo. Antigenic profiles that distinguish tubule-initiating prostate stem cells (SCs) from progenitor cells (PCs) and mature luminal cells (LCs) with less regenerative potential are unknown. METHODOLOGY/PRINCIPLE FINDINGS: Prostasphere assays and RT-PCR analysis was performed following FACS separation of total benign prostate cells based upon combinations of Epcam, CD44, and/or CD49f expression. Epithelial cell fractions were isolated, including Epcam(+)CD44(+) and Epcam+CD44+CD49f(Hi) basal cells that formed abundant spheres. When non-sphere-forming Epcam(+)CD44(-) cells were fractionated based upon CD49f expression, a distinct subpopulation (Epcam(+)CD44( )CD49f(Hi)) was identified that possessed a basal profile similar to Epcam(+)CD44(+)CD49f(Hi) sphere-forming cells (p63(+)AR(Lo)PSA(-)). Evaluation of tubule induction capability of fractionated cells was performed, in vivo, via a fully humanized prostate tissue regeneration assay. Non-sphere-forming Epcam(+)CD44(-) cells induced significantly more prostate tubular structures than Epcam(+)CD44(+) sphere-forming cells. Further fractionation based upon CD49f co expression identified Epcam(+)CD44(-)CD49f(Hi) (non-sphere-forming) basal cells with significantly increased tubule induction activity compared to Epcam(+)CD44( )CD49f(Lo) (true) luminal cells. CONCLUSIONS/SIGNIFICANCE: Our data delineates antigenic profiles that functionally distinguish human prostate epithelial subpopulations, including putative SCs that display superior tubule initiation capability and induce differentiated ductal/acini structures, sphere-forming PCs with relatively decreased tubule initiation activity, and terminally differentiated LCs that lack both sphere-forming and tubule-initiation activity. The results clearly demonstrate that sphere-forming ability is not predictive of tubule-initiation activity. The subpopulations identified are of interest because they may play distinct roles as cells of origin in the development of prostatic diseases, including cancer. PMID- 22514624 TI - Association between serum interleukin-6 concentrations and mortality in older adults: the Rancho Bernardo study. AB - BACKGROUND: Interleukin-6 (IL-6) may have a protective role in acute liver disease but a detrimental effect in chronic liver disease. It is unknown whether IL-6 is associated with risk of liver-related mortality in humans. AIMS: To determine if IL-6 is associated with an increased risk of all-cause, cardiovascular disease (CVD), cancer, and liver-related mortality. METHODS: A prospective cohort study included 1843 participants who attended a research visit in 1984-87. Multiple covariates were ascertained including serum IL-6. Multivariable-adjusted Cox proportional hazards regression analyses were used to examine the association between serum IL-6 as a continuous (log transformed) variable with all-cause, CVD, cancer, and liver-related mortality. Patients with prevalent CVD, cancer and liver disease were excluded for cause-specific mortality. RESULTS: The mean (+/- standard deviation) age and body-mass-index (BMI) of participants was 68 (+/- 10.6) years and 25 (+/- 3.7) Kg/m(2), respectively. During the 25,802 person-years of follow-up, the cumulative all cause, CVD, cancer, and liver-related mortality were 53.1% (N = 978), 25.5%, 11.3%, and 1.3%, respectively. The median (+/- IQR) length of follow-up was 15.3 +/- 10.6 years. In multivariable analyses, adjusted for age, sex, alcohol, BMI, diabetes, hypertension, total cholesterol, HDL, and smoking, one-SD increment in log-transformed serum IL-6 was associated with increased risk of all-cause, CVD, cancer, and liver-related mortality, with hazard ratios of 1.48 (95% CI, 1.33 1.64), 1.38 (95% CI, 1.16-1.65), 1.35 (95% CI, 1.02-1.79), and 1.88 (95% CI, 0.97 3.67), respectively. CRP adjustment attenuated the effects but the association between IL-6 and all-cause and CVD mortality remained statistically significant, independent of CRP levels. CONCLUSIONS: In community-dwelling older adults, serum IL-6 is associated with all-cause, CVD, cancer, and liver-related mortality. PMID- 22514626 TI - Repeated methamphetamine administration differentially alters fos expression in caudate-putamen patch and matrix compartments and nucleus accumbens. AB - BACKGROUND: The repeated administration of psychostimulant drugs produces a persistent and long-lasting increase ("sensitization") in their psychomotor effects, which is thought to be due to changes in the neural circuitry that mediate these behaviors. One index of neuronal activation used to identify brain regions altered by repeated exposure to drugs involves their ability to induce immediate early genes, such as c-fos. Numerous reports have demonstrated that past drug experience alters the ability of drugs to induce c-fos in the striatum, but very few have examined Fos protein expression in the two major compartments in the striatum--the so-called patch/striosome and matrix. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we used immunohistochemistry to investigate the effects of pretreatment with methamphetamine on the ability of a subsequent methamphetamine challenge to induce Fos protein expression in the patch and matrix compartments of the dorsolateral and dorsomedial caudate-putamen and in the ventral striatum (nucleus accumbens). Animals pretreated with methamphetamine developed robust psychomotor sensitization. A methamphetamine challenge increased the number of Fos-positive cells in all areas of the dorsal and ventral striatum. However, methamphetamine challenge induced Fos expression in more cells in the patch than in the matrix compartment in the dorsolateral and dorsomedial caudate putamen. Furthermore, past experience with methamphetamine increased the number of methamphetamine-induced Fos positive cells in the patch compartment of the dorsal caudate putamen, but not in the matrix or in the core or shell of the nucleus accumbens. CONCLUSIONS/SIGNIFICANCE: These data suggest that drug-induced alterations in the patch compartment of the dorsal caudate-putamen may preferentially contribute to some of the enduring changes in brain activity and behavior produced by repeated treatment with methamphetamine. PMID- 22514627 TI - PHYRN: a robust method for phylogenetic analysis of highly divergent sequences. AB - Both multiple sequence alignment and phylogenetic analysis are problematic in the "twilight zone" of sequence similarity (<= 25% amino acid identity). Herein we explore the accuracy of phylogenetic inference at extreme sequence divergence using a variety of simulated data sets. We evaluate four leading multiple sequence alignment (MSA) methods (MAFFT, T-COFFEE, CLUSTAL, and MUSCLE) and six commonly used programs of tree estimation (Distance-based: Neighbor-Joining; Character-based: PhyML, RAxML, GARLI, Maximum Parsimony, and Bayesian) against a novel MSA-independent method (PHYRN) described here. Strikingly, at "midnight zone" genetic distances (~7% pairwise identity and 4.0 gaps per position), PHYRN returns high-resolution phylogenies that outperform traditional approaches. We reason this is due to PHRYN's capability to amplify informative positions, even at the most extreme levels of sequence divergence. We also assess the applicability of the PHYRN algorithm for inferring deep evolutionary relationships in the divergent DANGER protein superfamily, for which PHYRN infers a more robust tree compared to MSA-based approaches. Taken together, these results demonstrate that PHYRN represents a powerful mechanism for mapping uncharted frontiers in highly divergent protein sequence data sets. PMID- 22514628 TI - P67-phox (NCF2) lacking exons 11 and 12 is functionally active and leads to an extremely late diagnosis of chronic granulomatous disease (CGD). AB - Two brothers in their fifties presented with a medical history of suspected fungal allergy, allergic bronchopulmonary aspergillosis, alveolitis, and invasive aspergillosis and pulmonary fistula, respectively. Eventually, after a delay of 50 years, chronic granulomatous disease (CGD) was diagnosed in the index patient. We found a new splice mutation in the NCF2 (p67-phox) gene, c.1000 + 2T -> G, that led to several splice products one of which lacked exons 11 and 12. This deletion was in frame and allowed for remarkable residual NADPH oxidase activity as determined by transduction experiments using a retroviral vector. We conclude that p67-phox which lacks the 34 amino acids encoded by the two exons can still exert considerable functional activity. This activity can partially explain the long-term survival of the patients without adequate diagnosis and treatment, but could not prevent progressing lung damage. PMID- 22514629 TI - The effects of spatially heterogeneous prey distributions on detection patterns in foraging seabirds. AB - Many attempts to relate animal foraging patterns to landscape heterogeneity are focused on the analysis of foragers movements. Resource detection patterns in space and time are not commonly studied, yet they are tightly coupled to landscape properties and add relevant information on foraging behavior. By exploring simple foraging models in unpredictable environments we show that the distribution of intervals between detected prey (detection statistics) is mostly determined by the spatial structure of the prey field and essentially distinct from predator displacement statistics. Detections are expected to be Poissonian in uniform random environments for markedly different foraging movements (e.g. Levy and ballistic). This prediction is supported by data on the time intervals between diving events on short-range foraging seabirds such as the thick-billed murre (Uria lomvia). However, Poissonian detection statistics is not observed in long-range seabirds such as the wandering albatross (Diomedea exulans) due to the fractal nature of the prey field, covering a wide range of spatial scales. For this scenario, models of fractal prey fields induce non-Poissonian patterns of detection in good agreement with two albatross data sets. We find that the specific shape of the distribution of time intervals between prey detection is mainly driven by meso and submeso-scale landscape structures and depends little on the forager strategy or behavioral responses. PMID- 22514630 TI - Zebrafish Agr2 is required for terminal differentiation of intestinal goblet cells. AB - BACKGROUND: Mammalian Anterior Gradient 2 (AGR2) is a protein disulfide isomerase that is required for the production of intestinal mucus and Paneth and goblet cell homeostasis. However, whether increased endoplasmic reticulum (ER) stress occurs in Agr2(-/-) mice remains a controversial issue. METHODOLOGY/PRINCIPAL FINDINGS: We characterized the function of zebrafish agr2 by both morpholino antisense oligomer-mediated knockdown and agr2 mRNA overexpression. Fluorescent whole-mount double in situ hybridization indicated that in the intestine, agr2 was only expressed in goblet cells. Significantly increased numbers of immature Alcian blue-stained goblet cells were observed in the intestines of 104- and 120 hours post fertilization (hpf) agr2 morphants. Transmission electron microscopy analyses further confirmed the existence of immature pre-goblet cells containing few mucous granules in the mid-intestines of 104- and 120-hpf agr2 morphants. agr2 expression was not significantly induced by an ER stress inducer, tunicamycin. Expression of the ER chaperone gene hspa5, the spliced form of xbp1s, c/enhancer binding protein homologous protein chop, and the activating transcription factor 4b1 atf4b1 were not significantly induced in either 104-hpf agr2 morphants or agr2-overexpressed embryos. Similar percentages of P-Histone H3 stained M phase cells were identified in intestines of 104-hpf agr2 morphants and control embryos. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that in contrast to mouse AGR2, zebrafish Agr2 is expressed in only one intestinal secretory cell type - the goblet cells. Agr2 is essential for terminal differentiation of intestinal goblet cells in zebrafish embryos. Either knockdown of agr2 function or agr2 overexpression could not extensively induce expression of members of the unfolded protein response pathway. PMID- 22514631 TI - Isolation of two strong poly (U) binding proteins from moderate halophile Halomonas eurihalina and their identification as cold shock proteins. AB - Cold shock proteins (Csp) are known to be expressed in response to sudden decrease in temperature. They are thought to be involved in a number of cellular processes viz., RNA chaperone activity, translation, transcription, nucleoid condensation. During our studies on ribosomal protein S1 in moderate halophile Halomonas eurihalina, we observed the presence of two strong poly (U) binding proteins in abundance in cell extracts from cells grown under normal growth conditions. The proteins can be isolated in a single step using Poly (U) cellulose chromatography. The proteins were identified as major cold shock proteins belonging to Csp A family by MALDI-TOF and bioinformatic analysis. Csp 12 kDa was found in both exponential and stationary phases whereas Csp 8 kDa is found only in exponential phase. PMID- 22514632 TI - MLN64 transport to the late endosome is regulated by binding to 14-3-3 via a non canonical binding site. AB - MLN64 is an integral membrane protein localized to the late endosome and plasma membrane that is thought to function as a mediator of cholesterol transport from endosomal membranes to the plasma membrane and/or mitochondria. The protein consists of two distinct domains: an N-terminal membrane-spanning domain that shares homology with the MENTHO protein and a C-terminal steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain that binds cholesterol. To further characterize the MLN64 protein, full-length and truncated proteins were overexpressed in cells and the effects on MLN64 trafficking and endosomal morphology were observed. To gain insight into MLN64 function, affinity chromatography and mass spectrometric techniques were used to identify potential MLN64 interacting partners. Of the 15 candidate proteins identified, 14-3-3 was chosen for further characterization. We show that MLN64 interacts with 14-3-3 in vitro as well as in vivo and that the strength of the interaction is dependent on the 14-3-3 isoform. Furthermore, blocking the interaction through the use of a 14 3-3 antagonist or MLN64 mutagenesis delays the trafficking of MLN64 to the late endosome and also results in the dispersal of endocytic vesicles to the cell periphery. Taken together, these studies have determined that MLN64 is a novel 14 3-3 binding protein and indicate that 14-3-3 plays a role in the endosomal trafficking of MLN64. Furthermore, these studies suggest that 14-3-3 may be the link by which MLN64 exerts its effects on the actin-mediated endosome dynamics. PMID- 22514633 TI - The role of innate APOBEC3G and adaptive AID immune responses in HLA-HIV/SIV immunized SHIV infected macaques. AB - The AID/APOBEC family (activation induced deaminase/apolipoprotein B mRNA editing cytokine deaminase) in B cells play important roles in adaptive and innate immunity. Whereas APOBEC3G has been studied in CD4+ T cells and myeloid cells its functional potential in B cells has received little attention. AID combines two critical functions of antibodies, class switching and affinity maturation and may serve as a functional surrogate of protection. These functions were studied following systemic immunization of rhesus macaques with recombinant HLA constructs, linked with HIV and SIV antigens and HSP70 to dextran. The results showed significant upregulation of AID in CD20+ B cells, APOBEC 3G in CD27+ memory B cells and CD4+ effector memory T cells. After immunization the upregulated APOBEC 3G and AID were directly correlated in B cells (p<0.0001). Following challenge with SHIV SF162.P4 the viral load was inversely correlated with AID in B cells and APOBEC 3G in B and T cells, suggesting that both deaminases may have protective functions. Investigation of major interactions between DC, T cells and B cells showed significant increase in membrane associated IL-15 in DC and CD40L in CD4+ T cells. IL-15 binds the IL-15 receptor complex in CD4+ T and B cells, which may reactivate the DC, T and B cell interactions. The overall results are consistent with AID inhibiting pre-entry SHIV by eliciting IgG and IgA antibodies, whereas APOBEC 3G may contribute to the post-entry control of SHIV replication and cellular spread. PMID- 22514634 TI - Role of misfolded N-CoR mediated transcriptional deregulation of Flt3 in acute monocytic leukemia (AML)-M5 subtype. AB - The nuclear receptor co-repressor (N-CoR) is a key component of the generic multi protein complex involved in transcriptional control. Flt3, a key regulator of hematopoietic cell growth, is frequently deregulated in AML (acute myeloid leukemia). Here, we report that loss of N-CoR-mediated transcriptional control of Flt3 due to misfolding, contributes to malignant growth in AML of the M5 subtype (AML-M5). An analysis of hematopoietic genes in AML cells led to the identification of Flt3 as a transcriptional target of N-CoR. Flt3 level was inversely related to N-CoR status in various leukemia cells. N-CoR was associated with the Flt3 promoter in-vivo, and a reporter driven by the Flt3 promoter was effectively repressed by N-CoR. Blocking N-CoR loss with Genistein; an inhibitor of N-CoR misfolding, significantly down-regulated Flt3 levels regardless of the Flt3 receptor mutational status and promoted the differentiation of AML-M5 cells. While stimulation of the Flt3 receptor with the Flt3 ligand triggered N-CoR loss, Flt3 antibody mediated blockade of Flt3 ligand-receptor binding led to N-CoR stabilization. Genetic ablation of N-CoR potentiated Flt3 ligand induced proliferation of BA/F3 cells. These findings suggest that N-CoR-induced repression of Flt3 might be crucial for limiting the contribution of the Flt3 signaling pathway on the growth potential of leukemic cells and its deregulation due to N-CoR loss in AML-M5, could contribute to malignant growth by conferring a proliferative advantage to the leukemic blasts. Therapeutic restoration of N-CoR function could thus be a useful approach in restricting the contribution of the Flt3 signaling pathway in AML-M5 pathogenesis. PMID- 22514635 TI - Modelling and analysis of central metabolism operating regulatory interactions in salt stress conditions in a L-carnitine overproducing E. coli strain. AB - Based on experimental data from E. coli cultures, we have devised a mathematical model in the GMA-power law formalism that describes the central and L-carnitine metabolism in and between two steady states, non-osmotic and hyperosmotic (0.3 M NaCl). A key feature of this model is the introduction of type of kinetic order, the osmotic stress kinetic orders (g(OSn)), derived from the power law general formalism, which represent the effect of osmotic stress in each metabolic process of the model.By considering the values of the g(OSn) linked to each metabolic process we found that osmotic stress has a positive and determinant influence on the increase in flux in energetic metabolism (glycolysis); L-carnitine biosynthesis production; the transformation/excretion of Acetyl-CoA into acetate and ethanol; the input flux of peptone into the cell; the anabolic use of pyruvate and biomass decomposition. In contrast, we found that although the osmotic stress has an inhibitory effect on the transformation flux from the glycolytic end products (pyruvate) to Acetyl-CoA, this inhibition is counteracted by other effects (the increase in pyruvate concentration) to the extent that the whole flux increases. In the same vein, the down regulation exerted by osmotic stress on fumarate uptake and its oxidation and the production and export of lactate and pyruvate are reversed by other factors up to the point that the first increased and the second remained unchanged.The model analysis shows that in osmotic conditions the energy and fermentation pathways undergo substantial rearrangement. This is illustrated by the observation that the increase in the fermentation fluxes is not connected with fluxes towards the tricaboxylic acid intermediates and the synthesis of biomass. The osmotic stress associated with these fluxes reflects these changes. All these observations support that the responses to salt stress observed in E. coli might be conserved in halophiles.Flux evolution during osmotic adaptations showed a hyperbolic (increasing or decreasing) pattern except in the case of peptone and fumarate uptake by the cell, which initially decreased. Finally, the model also throws light on the role of L-carnitine as osmoprotectant. PMID- 22514636 TI - Reproductive schedules in southern bluefin tuna: are current assumptions appropriate? AB - Southern bluefin tuna (SBT) appear to comprise a single stock that is assumed to be both mixed across its distribution and having reproductive adults that are obligate, annual spawners. The putative annual migration cycle of mature SBT consists of dispersed foraging at temperate latitudes with migration to a single spawning ground in the tropical eastern Indian Ocean. Spawning migrations have been assumed to target two peaks in spawning activity; one in September-October and a second in February-March. SBT of sizes comparable to that of individuals observed on the spawning ground were satellite tagged in the Tasman Sea region (2003-2008) and demonstrated both migrations to the spawning grounds and residency in the Tasman Sea region throughout the whole year. All individuals undertaking apparent spawning migrations timed their movements to coincide with the second recognised spawning peak or even later. These observations suggest that SBT may demonstrate substantial flexibility in the scheduling of reproductive events and may even not spawn annually as currently assumed. Further, the population on the spawning grounds may be temporally structured in association with foraging regions. These findings provide new perspectives on bluefin population and spatial dynamics and warrant further investigation and consideration of reproductive schedules in this species. PMID- 22514637 TI - The notch ligand delta-like 4 regulates multiple stages of early hemato-vascular development. AB - BACKGROUND: In mouse embryos, homozygous or heterozygous deletions of the gene encoding the Notch ligand Dll4 result in early embryonic death due to major defects in endothelial remodeling in the yolk sac and embryo. Considering the close developmental relationship between endothelial and hematopoietic cell lineages, which share a common mesoderm-derived precursor, the hemangioblast, and many key regulatory molecules, we investigated whether Dll4 is also involved in the regulation of early embryonic hematopoiesis. METHODOLOGY/PRINCIPAL FINDINGS: Using Embryoid Bodies (EBs) derived from embryonic stem cells harboring hetero- or homozygous Dll4 deletions, we observed that EBs from both genotypes exhibit an abnormal endothelial remodeling in the vascular sprouts that arise late during EB differentiation, indicating that this in vitro system recapitulates the angiogenic phenotype of Dll4 mutant embryos. However, analysis of EB development at early time points revealed that the absence of Dll4 delays the emergence of mesoderm and severely reduces the number of blast-colony forming cells (BL-CFCs), the in vitro counterpart of the hemangioblast, and of endothelial cells. Analysis of colony forming units (CFU) in EBs and yolk sacs from Dll4(+/-) and Dll4(-/-) embryos, showed that primitive erythropoiesis is specifically affected by Dll4 insufficiency. In Dll4 mutant EBs, smooth muscle cells (SMCs) were seemingly unaffected and cardiomyocyte differentiation was increased, indicating that SMC specification is Dll4-independent while a normal dose of this Notch ligand is essential for the quantitative regulation of cardiomyogenesis. CONCLUSIONS/SIGNIFICANCE: This study highlights a previously unnoticed role for Dll4 in the quantitative regulation of early hemato-vascular precursors, further indicating that it is also involved on the timely emergence of mesoderm in early embryogenesis. PMID- 22514638 TI - An essential regulatory role of downstream of kinase-1 in the ovalbumin-induced murine model of asthma. AB - The downstream of kinase (DOK)-1 is involved in the protein tyrosine kinase (PTK) pathway in mast cells, but the role of DOK-1 in the pathogenesis of asthma has not been defined. In this study, we have demonstrated a novel regulatory role of DOK-1 in airway inflammation and physiologic responses in a murine model of asthma using lentiviral vector containing DOK-1 cDNA or DOK-1-specific ShRNA. The OVA-induced inflammatory cells, airway hyperresponsiveness, Th2 cytokine expression, and mucus response were significantly reduced in DOK-1 overexpressing mice compared to OVA-challenged control mice. The transgenic introduction of DOK 1 significantly stimulated the activation and expression of STAT-4 and T-bet, while impressively inhibiting the activation and expression of STAT-6 and GATA-3 in airway epithelial cells. On the other hand, DOK-1 knockdown mice enhanced STAT 6 expression and its nuclear translocation compared to OVA-challenged control mice. When viewed in combination, our studies demonstrate DOK-1 regulates allergen-induced Th2 immune responses by selective stimulation and inhibition of STAT-4 and STAT-6 signaling pathways, respectively. These studies provide a novel insight on the regulatory role of DOK-1 in allergen-induced Th2 inflammation and airway responses, which has therapeutic potential for asthma and other allergic diseases. PMID- 22514639 TI - Decreased serologic response in vaccinated military recruits during 2011 correspond to genetic drift in concurrent circulating pandemic A/H1N1 viruses. AB - BACKGROUND: Population-based febrile respiratory illness surveillance conducted by the Department of Defense contributes to an estimate of vaccine effectiveness. Between January and March 2011, 64 cases of 2009 A/H1N1 (pH1N1), including one fatality, were confirmed in immunized recruits at Fort Jackson, South Carolina, suggesting insufficient efficacy for the pH1N1 component of the live attenuated influenza vaccine (LAIV). METHODOLOGY/PRINCIPAL FINDINGS: To test serologic protection, serum samples were collected at least 30 days post-vaccination from recruits at Fort Jackson (LAIV), Parris Island (LAIV and trivalent inactivated vaccine [TIV]) at Cape May, New Jersey (TIV) and responses measured against pre vaccination sera. A subset of 78 LAIV and 64 TIV sera pairs from recruits who reported neither influenza vaccination in the prior year nor fever during training were tested by microneutralization (MN) and hemagglutination inhibition (HI) assays. MN results demonstrated that seroconversion in paired sera was greater in those who received TIV versus LAIV (74% and 37%). Additionally, the fold change associated with TIV vaccination was significantly different between circulating (2011) versus the vaccine strain (2009) of pH1N1 viruses (ANOVA p value = 0.0006). HI analyses revealed similar trends. Surface plasmon resonance (SPR) analysis revealed that the quantity, IgG/IgM ratios, and affinity of anti HA antibodies were significantly greater in TIV vaccinees. Finally, sequence analysis of the HA1 gene in concurrent circulating 2011 pH1N1 isolates from Fort Jackson exhibited modest amino acid divergence from the vaccine strain. CONCLUSIONS/SIGNIFICANCE: Among military recruits in 2011, serum antibody response differed by vaccine type (LAIV vs. TIV) and pH1N1 virus year (2009 vs. 2011). We hypothesize that antigen drift in circulating pH1N1 viruses contributed to reduce vaccine effectiveness at Fort Jackson. Our findings have wider implications regarding vaccine protection from circulating pH1N1 viruses in 2011 2012. PMID- 22514640 TI - Genomic, proteomic and physiological characterization of a T5-like bacteriophage for control of Shiga toxin-producing Escherichia coli O157:H7. AB - Despite multiple control measures, Escherichia coli O157:H7 (STEC O157:H7) continues to be responsible for many food borne outbreaks in North America and elsewhere. Bacteriophage therapy may prove useful for controlling this pathogen in the host, their environment and food. Bacteriophage vB_EcoS_AKFV33 (AKFV33), a T5-like phage of Siphoviridae lysed common phage types of STEC O157:H7 and not non-O157 E. coli. Moreover, STEC O157:H7 isolated from the same feedlot pen from which the phage was obtained, were highly susceptible to AKFV33. Adsorption rate constant and burst size were estimated to be 9.31 * 10(-9) ml/min and 350 PFU/infected cell, respectively. The genome of AKVF33 was 108,853 bp (38.95% G+C), containing 160 open reading frames (ORFs), 22 tRNA genes and 32 strong promoters recognized by host RNA polymerase. Of 12 ORFs without homologues to T5 like phages, 7 predicted novel proteins while others exhibited low identity (<60%) to proteins in the National Centre for Biotechnology Information database. AKVF33 also lacked the L-shaped tail fiber protein typical of T5, but was predicted to have tail fibers comprised of 2 novel proteins with low identity (37 41%) to tail fibers of E. coli phage phiEco32 of Podoviridae, a putative side tail fiber protein of a prophage from E. coli IAI39 and a conserved domain protein of E. coli MS196-1. The receptor-binding tail protein (pb5) shared an overall identify of 29-72% to that of other T5-like phages, with no region coding for more than 6 amino acids in common. Proteomic analysis identified 4 structural proteins corresponding to the capsid, major tail, tail fiber and pore-forming tail tip (pb2). The genome of AKFV33 lacked regions coding for known virulence factors, integration-related proteins or antibiotic resistance determinants. Phage AKFV33 is a unique, highly lytic STEC O157:H7-specific T5-like phage that may have considerable potential as a pre- and post-harvest biocontrol agent. PMID- 22514643 TI - Dressed for sex: red as a female sexual signal in humans. AB - BACKGROUND: In many non-human primate species, a display of red by a female serves as a sexual signal to attract male conspecifics. Red is associated with sex and romance in humans, and women convey their sexual interest to men through a variety of verbal, postural, and behavioral means. In the present research, we investigate whether female red ornamentation in non-human primates has a human analog, whereby women use a behavioral display of red to signal their sexual interest to men. METHODOLOGY/PRINCIPAL FINDINGS: Three studies tested the hypothesis that women use red clothing to communicate sexual interest to men in profile pictures on dating websites. In Study 1, women who imagined being interested in casual sex were more likely to display red (but not other colors) on their anticipated web profile picture. In Study 2, women who indicated interest in casual sex were more likely to prominently display red (but not other colors) on their actual web profile picture. In Study 3, women on a website dedicated to facilitating casual sexual relationships were more likely to prominently exhibit red (but not other colors) than women on a website dedicated to facilitating marital relationships. CONCLUSIONS/SIGNIFICANCE: These results establish a provocative parallel between women and non-human female primates in red signal coloration in the mating game. This research shows, for the first time, a functional use of color in women's sexual self-presentation, and highlights the need to extend research on color beyond physics, physiology, and preference to psychological functioning. PMID- 22514642 TI - Comparison of DNA extraction methods for microbial community profiling with an application to pediatric bronchoalveolar lavage samples. AB - Barcoded amplicon sequencing is rapidly becoming a standard method for profiling microbial communities, including the human respiratory microbiome. While this approach has less bias than standard cultivation, several steps can introduce variation including the type of DNA extraction method used. Here we assessed five different extraction methods on pediatric bronchoalveolar lavage (BAL) samples and a mock community comprised of nine bacterial genera to determine method reproducibility and detection limits for these typically low complexity communities. Additionally, using the mock community, we were able to evaluate contamination and select a relative abundance cut-off threshold based on the geometric distribution that optimizes the trade off between detecting bona fide operational taxonomic units and filtering out spurious ones. Using this threshold, the majority of genera in the mock community were predictably detected by all extraction methods including the hard-to-lyse Gram-positive genus Staphylococcus. Differences between extraction methods were significantly greater than between technical replicates for both the mock community and BAL samples emphasizing the importance of using a standardized methodology for microbiome studies. However, regardless of method used, individual patients retained unique diagnostic profiles. Furthermore, despite being stored as raw frozen samples for over five years, community profiles from BAL samples were consistent with historical culturing results. The culture-independent profiling of these samples also identified a number of anaerobic genera that are gaining acceptance as being part of the respiratory microbiome. This study should help guide researchers to formulate sampling, extraction and analysis strategies for respiratory and other human microbiome samples. PMID- 22514641 TI - Purification and structural characterization of siderophore (corynebactin) from Corynebacterium diphtheriae. AB - During infection, Corynebacterium diphtheriae must compete with host iron sequestering mechanisms for iron. C. diphtheriae can acquire iron by a siderophore-dependent iron-uptake pathway, by uptake and degradation of heme, or both. Previous studies showed that production of siderophore (corynebactin) by C. diphtheriae is repressed under high-iron growth conditions by the iron-activated diphtheria toxin repressor (DtxR) and that partially purified corynebactin fails to react in chemical assays for catecholate or hydroxamate compounds. In this study, we purified corynebactin from supernatants of low-iron cultures of the siderophore-overproducing, DtxR-negative mutant strain C. diphtheriae C7(beta) DeltadtxR by sequential anion-exchange chromatography on AG1-X2 and Source 15Q resins, followed by reverse-phase high-performance liquid chromatography (RP HPLC) on Zorbax C8 resin. The Chrome Azurol S (CAS) chemical assay for siderophores was used to detect and measure corynebactin during purification, and the biological activity of purified corynebactin was shown by its ability to promote growth and iron uptake in siderophore-deficient mutant strains of C. diphtheriae under iron-limiting conditions. Mass spectrometry and NMR analysis demonstrated that corynebactin has a novel structure, consisting of a central lysine residue linked through its alpha- and epsilon- amino groups by amide bonds to the terminal carboxyl groups of two different citrate residues. Corynebactin from C. diphtheriae is structurally related to staphyloferrin A from Staphylococcus aureus and rhizoferrin from Rhizopus microsporus in which d ornithine or 1,4-diaminobutane, respectively, replaces the central lysine residue that is present in corynebactin. PMID- 22514644 TI - Regulation of tumor suppressor p53 and HCT116 cell physiology by histone demethylase JMJD2D/KDM4D. AB - JMJD2D, also known as KDM4D, is a histone demethylase that removes methyl moieties from lysine 9 on histone 3 and from lysine 26 on histone 1.4. Here, we demonstrate that JMJD2D forms a complex with the p53 tumor suppressor in vivo and interacts with the DNA binding domain of p53 in vitro. A luciferase reporter plasmid driven by the promoter of p21, a cell cycle inhibitor and prominent target gene of p53, was synergistically activated by p53 and JMJD2D, which was dependent on JMJD2D catalytic activity. Likewise, overexpression of JMJD2D induced p21 expression in U2OS osteosarcoma cells in the absence and presence of adriamycin, an agent that induces DNA damage. Furthermore, downregulation of JMJD2D inhibited cell proliferation in wild-type and even more so in p53(-/-) HCT116 colon cancer cells, suggesting that JMJD2D is a pro-proliferative molecule. JMJD2D depletion also induced more strongly apoptosis in p53(-/-) compared to wild-type HCT116 cells. Collectively, our results demonstrate that JMJD2D can stimulate cell proliferation and survival, suggesting that its inhibition may be helpful in the fight against cancer. Furthermore, our data imply that activation of p53 may represent a mechanism by which the pro-oncogenic functions of JMJD2D become dampened. PMID- 22514645 TI - Genome-wide transcription analysis of clinal genetic variation in Drosophila. AB - Clinal variation in quantitative traits is widespread, but its genetic basis awaits identification. Drosophila melanogaster shows adaptive, clinal variation in traits such as body size along latitudinal gradients on multiple continents. To investigate genome wide transcription differentiation between North and South that might contribute to the clinal phenotypic variation, we compared RNA expression patterns during development of D. melanogaster from tropical northern and temperate southern populations using whole genome tiling arrays. We found that genes that were differentially expressed between the cline ends were generally associated with metabolism and growth, and experimental alteration of expression of a sample of them generally resulted in altered body size in the predicted direction, sometimes significantly so. We further identified the serpent (srp) transcription factor binding sites to be enriched near genes up regulated in expression in the south. Analysis of clinal populations revealed a significant cline in the expression level of srp. Experimental over-expression of srp increased body size, as predicted from its clinal expression pattern, suggesting that it may be involved in regulating adaptive clinal variation in Drosophila. This study identified a handful of genes that contributed to clinal phenotypic variation through altered gene expression level, yet misexpression of individual gene led to modest body size change. PMID- 22514646 TI - Multishot versus single-shot pulse sequences in very high field fMRI: a comparison using retinotopic mapping. AB - High-resolution functional MRI is a leading application for very high field (7 Tesla) human MR imaging. Though higher field strengths promise improvements in signal-to-noise ratios (SNR) and BOLD contrast relative to fMRI at 3 Tesla, these benefits may be partially offset by accompanying increases in geometric distortion and other off-resonance effects. Such effects may be especially pronounced with the single-shot EPI pulse sequences typically used for fMRI at standard field strengths. As an alternative, one might consider multishot pulse sequences, which may lead to somewhat lower temporal SNR than standard EPI, but which are also often substantially less susceptible to off-resonance effects. Here we consider retinotopic mapping of human visual cortex as a practical test case by which to compare examples of these sequence types for high-resolution fMRI at 7 Tesla. We performed polar angle retinotopic mapping at each of 3 isotropic resolutions (2.0, 1.7, and 1.1 mm) using both accelerated single-shot 2D EPI and accelerated multishot 3D gradient-echo pulse sequences. We found that single-shot EPI indeed led to greater temporal SNR and contrast-to-noise ratios (CNR) than the multishot sequences. However, additional distortion correction in postprocessing was required in order to fully realize these advantages, particularly at higher resolutions. The retinotopic maps produced by both sequence types were qualitatively comparable, and showed equivalent test/retest reliability. Thus, when surface-based analyses are planned, or in other circumstances where geometric distortion is of particular concern, multishot pulse sequences could provide a viable alternative to single-shot EPI. PMID- 22514647 TI - Angiopreventive efficacy of pure flavonolignans from milk thistle extract against prostate cancer: targeting VEGF-VEGFR signaling. AB - The role of neo-angiogenesis in prostate cancer (PCA) growth and metastasis is well established, but the development of effective and non-toxic pharmacological inhibitors of angiogenesis remains an unaccomplished goal. In this regard, targeting aberrant angiogenesis through non-toxic phytochemicals could be an attractive angiopreventive strategy against PCA. The rationale of the present study was to compare the anti-angiogenic potential of four pure diastereoisomeric flavonolignans, namely silybin A, silybin B, isosilybin A and isosilybin B, which we established previously as biologically active constituents in Milk Thistle extract. Results showed that oral feeding of these flavonolignans (50 and 100 mg/kg body weight) effectively inhibit the growth of advanced human PCA DU145 xenografts. Immunohistochemical analyses revealed that these flavonolignans inhibit tumor angiogenesis biomarkers (CD31 and nestin) and signaling molecules regulating angiogenesis (VEGF, VEGFR1, VEGFR2, phospho-Akt and HIF-1alpha) without adversely affecting the vessel-count in normal tissues (liver, lung, and kidney) of tumor bearing mice. These flavonolignans also inhibited the microvessel sprouting from mouse dorsal aortas ex vivo, and the VEGF-induced cell proliferation, capillary-like tube formation and invasiveness of human umbilical vein endothelial cells (HUVEC) in vitro. Further studies in HUVEC showed that these diastereoisomers target cell cycle, apoptosis and VEGF-induced signaling cascade. Three dimensional growth assay as well as co-culture invasion and in vitro angiogenesis studies (with HUVEC and DU145 cells) suggested the differential effectiveness of the diastereoisomers toward PCA and endothelial cells. Overall, these studies elucidated the comparative anti-angiogenic efficacy of pure flavonolignans from Milk Thistle and suggest their usefulness in PCA angioprevention. PMID- 22514648 TI - Simultaneous identification of DNA and RNA viruses present in pig faeces using process-controlled deep sequencing. AB - BACKGROUND: Animal faeces comprise a community of many different microorganisms including bacteria and viruses. Only scarce information is available about the diversity of viruses present in the faeces of pigs. Here we describe a protocol, which was optimized for the purification of the total fraction of viral particles from pig faeces. The genomes of the purified DNA and RNA viruses were simultaneously amplified by PCR and subjected to deep sequencing followed by bioinformatic analyses. The efficiency of the method was monitored using a process control consisting of three bacteriophages (T4, M13 and MS2) with different morphology and genome types. Defined amounts of the bacteriophages were added to the sample and their abundance was assessed by quantitative PCR during the preparation procedure. RESULTS: The procedure was applied to a pooled faecal sample of five pigs. From this sample, 69,613 sequence reads were generated. All of the added bacteriophages were identified by sequence analysis of the reads. In total, 7.7% of the reads showed significant sequence identities with published viral sequences. They mainly originated from bacteriophages (73.9%) and mammalian viruses (23.9%); 0.8% of the sequences showed identities to plant viruses. The most abundant detected porcine viruses were kobuvirus, rotavirus C, astrovirus, enterovirus B, sapovirus and picobirnavirus. In addition, sequences with identities to the chimpanzee stool-associated circular ssDNA virus were identified. Whole genome analysis indicates that this virus, tentatively designated as pig stool-associated circular ssDNA virus (PigSCV), represents a novel pig virus. CONCLUSION: The established protocol enables the simultaneous detection of DNA and RNA viruses in pig faeces including the identification of so far unknown viruses. It may be applied in studies investigating aetiology, epidemiology and ecology of diseases. The implemented process control serves as quality control, ensures comparability of the method and may be used for further method optimization. PMID- 22514649 TI - Molecular mechanism underlying persistent induction of LCN2 by lipopolysaccharide in kidney fibroblasts. AB - The neutrophil gelatinase-associated lipocalin 2 (LCN2) is a critical inflammatory mediator persistently induced during endotoxemia, contributing to tubular damage and kidney failure. The intracellular process responsible for persistent induction of LCN2 by bacterial endotoxin Lipopolysaccharide (LPS) is not well understood. Using primary kidney fibroblasts, we observed that LPS induced LCN2 expression requires a coupled circuit involving an early transient phase of AP-1 path and a late persistent phase of C/EBPdelta path, both of which are dependent upon the interleukin 1 receptor associated kinase 1 (IRAK-1). Using immunoprecipitation analysis we observed transient binding of AP-1 to the promoters of both TNFalpha and C/ebpdelta. On the other hand, we only observed persistent binding of C/EBPdelta to its own promoter but not on TNFalpha. Blockage of new protein synthesis using cyclohexamide significantly reduced the expression of C/EBPdelta as well as LCN2. By chromatin immunoprecipitation analyses, we demonstrated that LPS recruited C/EBPdelta to the Lcn2 promoter in WT, but not IRAK-1 deficient fibroblasts. A differential equation-based computational model captured the dynamic circuit leading to the persistent induction of LCN2. In vivo, we observed elevated levels of LCN2 in kidneys harvested from LPS-injected WT mice as compared to IRAK-1 deficient mice. Taken together, this study has identified an integrated intracellular network involved in the persistent induction of LCN2 by LPS. PMID- 22514650 TI - Differential requirement for c-Jun N-terminal kinase 1 in lung inflammation and host defense. AB - The c-Jun N-terminal kinase (JNK) - 1 pathway has been implicated in the cellular response to stress in many tissues and models. JNK1 is known to play a role in a variety of signaling cascades, including those involved in lung disease pathogenesis. Recently, a role for JNK1 signaling in immune cell function has emerged. The goal of the present study was to determine the role of JNK1 in host defense against both bacterial and viral pneumonia, as well as the impact of JNK1 signaling on IL-17 mediated immunity. Wild type (WT) and JNK1 -/- mice were challenged with Escherichia coli, Staphylococcus aureus, or Influenza A. In addition, WT and JNK1 -/- mice and epithelial cells were stimulated with IL-17A. The impact of JNK1 deletion on pathogen clearance, inflammation, and histopathology was assessed. JNK1 was required for clearance of E. coli, inflammatory cell recruitment, and cytokine production. Interestingly, JNK1 deletion had only a small impact on the host response to S. aureus. JNK1 -/- mice had decreased Influenza A burden in viral pneumonia, yet displayed worsened morbidity. Finally, JNK1 was required for IL-17A mediated induction of inflammatory cytokines and antimicrobial peptides both in epithelial cells and the lung. These data identify JNK1 as an important signaling molecule in host defense and demonstrate a pathogen specific role in disease. Manipulation of the JNK1 pathway may represent a novel therapeutic target in pneumonia. PMID- 22514651 TI - DotU and VgrG, core components of type VI secretion systems, are essential for Francisella LVS pathogenicity. AB - The Gram-negative bacterium Francisella tularensis causes tularemia, a disease which requires bacterial escape from phagosomes of infected macrophages. Once in the cytosol, the bacterium rapidly multiplies, inhibits activation of the inflammasome and ultimately causes death of the host cell. Of importance for these processes is a 33-kb gene cluster, the Francisella pathogenicity island (FPI), which is believed to encode a type VI secretion system (T6SS). In this study, we analyzed the role of the FPI-encoded proteins VgrG and DotU, which are conserved components of type VI secretion (T6S) clusters. We demonstrate that in F. tularensis LVS, VgrG was shown to form multimers, consistent with its suggested role as a trimeric membrane puncturing device in T6SSs, while the inner membrane protein DotU was shown to stabilize PdpB/IcmF, another T6SS core component. Upon infection of J774 cells, both DeltavgrG and DeltadotU mutants did not escape from phagosomes, and subsequently, did not multiply or cause cytopathogenicity. They also showed impaired activation of the inflammasome and marked attenuation in the mouse model. Moreover, all of the DotU-dependent functions investigated here required the presence of three residues that are essentially conserved among all DotU homologues. Thus, in agreement with a core function in T6S clusters, VgrG and DotU play key roles for modulation of the intracellular host response as well as for the virulence of F. tularensis. PMID- 22514652 TI - Deletion of FoxN1 in the thymic medullary epithelium reduces peripheral T cell responses to infection and mimics changes of aging. AB - Aging increases susceptibility to infection, in part because thymic involution culminates in reduced naive T-lymphocyte output. Thymic epithelial cells (TECs) are critical to ensure normal maturation of thymocytes and production of peripheral T cells. The forkhead-class transcription factor, encoded by FoxN1, regulates development, differentiation, and function of TECs, both in the prenatal and postnatal thymus. We recently showed that expression of FoxN1, by keratin 14 (K14)-expressing epithelial cells is essential for maintenance of thymic medullary architecture, and deletion of FoxN1 in K14 promoter-driven TECs inhibited development of mature TECs and reduced the number of total thymocytes. These findings are reminiscent of changes observed during normal thymic aging. In the current report, we compared the effects of K14-driven FoxN1 deletion on peripheral T cell function in response to influenza virus infection with those associated with normal aging in a mouse model. FoxN1-deleted mice had reduced numbers of peripheral CD62L+CD44- naive T-cells. In addition, during influenza infection, these animals had reduced antigen-specific CD8+ T-cell and IgG responses to influenza virus, combined with increased lung injury, weight loss and mortality. These findings paralleled those observed in aged wild type mice, providing the first evidence that K14-mediated FoxN1 deletion causes changes in T cell function that mimic those in aging during an immune response to challenge with an infectious agent. PMID- 22514653 TI - Effective DNA/RNA co-extraction for analysis of microRNAs, mRNAs, and genomic DNA from formalin-fixed paraffin-embedded specimens. AB - BACKGROUND: Retrospective studies of archived human specimens, with known clinical follow-up, are used to identify predictive and prognostic molecular markers of disease. Due to biochemical differences, however, formalin-fixed paraffin-embedded (FFPE) DNA and RNA have generally been extracted separately from either different tissue sections or from the same section by dividing the digested tissue. The former limits accurate correlation whilst the latter is impractical when utilizing rare or limited archived specimens. PRINCIPAL FINDINGS: For effective recovery of genomic DNA and total RNA from a single FFPE specimen, without splitting the proteinase-K digested tissue solution, we optimized a co-extraction method by using TRIzol and purifying DNA from the lower aqueous and RNA from the upper organic phases. Using a series of seven different archived specimens, we evaluated the total amounts of genomic DNA and total RNA recovered by our TRIzol-based co-extraction method and compared our results with those from two commercial kits, the Qiagen AllPrep DNA/RNA FFPE kit, for co extraction, and the Ambion RecoverAllTM Total Nucleic Acid Isolation kit, for separate extraction of FFPE-DNA and -RNA. Then, to accurately assess the quality of DNA and RNA co-extracted from a single FFPE specimen, we used qRT-PCR, gene expression profiling and methylation assays to analyze microRNAs, mRNAs, and genomic DNA recovered from matched fresh and FFPE MCF10A cells. These experiments show that the TRIzol-based co-extraction method provides larger amounts of FFPE DNA and -RNA than the two other methods, and particularly provides higher quality microRNAs and genomic DNA for subsequent molecular analyses. SIGNIFICANCE: We determined that co-extraction of genomic DNA and total RNA from a single FFPE specimen is an effective recovery approach to obtain high-quality material for parallel molecular and high-throughput analyses. Our optimized approach provides the option of collecting DNA, which would otherwise be discarded or degraded, for additional or subsequent studies. PMID- 22514654 TI - Proteasome inhibition is partially effective in attenuating pre-existing immunity against recombinant adeno-associated viral vectors. AB - Pre-existing immunity against adeno-associated virus (AAV) remains a major challenge facing the clinical use of systemic administration of recombinant AAV vectors for the treatment of genetic and acquired diseases using gene therapy. In this study, we evaluated the potential of bortezomib (marketed under trade name Velcade) to abrogate a pre-existing immunity to AAV in mice, thereby allowing subsequent transduction by a recombinant AAV vector of the same serotype. We demonstrate that bortezomib efficiently reduces AAV-specific IgG titres and moderates the cytotoxic T cell response in mice that have a pre-existing immunity to AAV2/8. Significant depletion of AAV2/8-specific IgG-producing plasma cells in secondary lymphoid organs and bone marrow was observed. However, this inhibition of the immune response by bortezomib was insufficient to allow subsequent re infection with a recombinant AAV vector of a similar serotype. We show that this shortcoming is probably due to the combination of residual antibody levels and the inability of bortezomib to completely deplete the memory B cells that are re activated in response to a repeated infection with a recombinant AAV vector. Taken together, the results of this study argue for the use of immunosuppressive therapies that target both plasma and memory B cells for the efficient elimination of pre-existing immunity against AAV2/8 vectors. PMID- 22514655 TI - Systematic analysis of stability patterns in plant primary metabolism. AB - Metabolic networks are characterized by complex interactions and regulatory mechanisms between many individual components. These interactions determine whether a steady state is stable to perturbations. Structural kinetic modeling (SKM) is a framework to analyze the stability of metabolic steady states that allows the study of the system Jacobian without requiring detailed knowledge about individual rate equations. Stability criteria can be derived by generating a large number of structural kinetic models (SK-models) with randomly sampled parameter sets and evaluating the resulting Jacobian matrices. Until now, SKM experiments applied univariate tests to detect the network components with the largest influence on stability. In this work, we present an extended SKM approach relying on supervised machine learning to detect patterns of enzyme-metabolite interactions that act together in an orchestrated manner to ensure stability. We demonstrate its application on a detailed SK-model of the Calvin-Benson cycle and connected pathways. The identified stability patterns are highly complex reflecting that changes in dynamic properties depend on concerted interactions between several network components. In total, we find more patterns that reliably ensure stability than patterns ensuring instability. This shows that the design of this system is strongly targeted towards maintaining stability. We also investigate the effect of allosteric regulators revealing that the tendency to stability is significantly increased by including experimentally determined regulatory mechanisms that have not yet been integrated into existing kinetic models. PMID- 22514656 TI - A synthetic chloride channel restores chloride conductance in human cystic fibrosis epithelial cells. AB - Mutations in the gene-encoding cystic fibrosis transmembrane conductance regulator (CFTR) cause defective transepithelial transport of chloride (Cl(-)) ions and fluid, thereby becoming responsible for the onset of cystic fibrosis (CF). One strategy to reduce the pathophysiology associated with CF is to increase Cl(-) transport through alternative pathways. In this paper, we demonstrate that a small synthetic molecule which forms Cl(-) channels to mediate Cl(-) transport across lipid bilayer membranes is capable of restoring Cl(-) permeability in human CF epithelial cells; as a result, it has the potential to become a lead compound for the treatment of human diseases associated with Cl(-) channel dysfunction. PMID- 22514657 TI - Body integrity identity disorder. AB - INTRODUCTION: Body Integrity Identity Disorder (BIID) is a rare, infrequently studied and highly secretive condition in which there is a mismatch between the mental body image and the physical body. Subjects suffering from BIID have an intense desire to amputate a major limb or severe the spinal cord in order to become paralyzed. Aim of the study is to broaden the knowledge of BIID amongst medical professionals, by describing all who deal with BIID. METHODS: Somatic, psychiatric and BIID characteristic data were collected from 54 BIID individuals using a detailed questionnaire. Subsequently, data of different subtypes of BIID (i.e. wish for amputation or paralyzation) were evaluated. Finally, disruption in work, social and family life due to BIID in subjects with and without amputation were compared. RESULTS: Based on the subjects' reports we found that BIID has an onset in early childhood. The main rationale given for their desire for body modification is to feel complete or to feel satisfied inside. Somatic and severe psychiatric co-morbidity is unusual, but depressive symptoms and mood disorders can be present, possibly secondary to the enormous distress BIID puts upon a person. Amputation and paralyzation variant do not differ in any clinical variable. Surgery is found helpful in all subjects who underwent amputation and those subjects score significantly lower on a disability scale than BIID subjects without body modification. CONCLUSIONS: The amputation variant and paralyzation variant of BIID are to be considered as one of the same condition. Amputation of the healthy body part appears to result in remission of BIID and an impressive improvement of quality of life. Knowledge of and respect for the desires of BIID individuals are the first steps in providing care and may decrease the huge burden they experience. PMID- 22514658 TI - Differential effects of UCHL1 modulation on alpha-synuclein in PD-like models of alpha-synucleinopathy. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by genetic and environmental factors. Abnormal accumulation and aggregation of alpha synuclein (a-syn) within neurons, and mutations in the a-syn and UCH-L1 genes have been shown to play a role in the pathogenesis of PD. In light of recent reports suggesting an interaction between a-synuclein and UCH-L1, we investigated the effects of UCH-L1 inhibition on a-syn distribution and expression levels in primary neurons and hippocampal tissues derived from non transgenic (non tg) and a-syn over expressing tg mice. We show that suppression of UCH-L1 activity increased a-syn levels in control, non tg neurons, and resulted in a concomitant accumulation of presynaptic a-syn in these neurons. In contrast, blocking UCH-L1 activity in a-syn over expressing neurons decreased a-syn levels, and enhanced its synaptic clearance. In vitro studies verified the LDN-induced inhibition of UCH-L1 had minimal effect on LC3 (a marker of autophagy) in control cells, in cells over expressing a-syn UCH-L1 inhibition resulted in increased LC3 activity. These findings suggest a possible differential role of UCH-L1 function under normal and pathological conditions. Furthermore, in the context of a-syn-induced pathology, modulation of UCH-L1 activity could serve as a therapeutic tool to enhance the autophagy pathway and induce clearance of the observed accumulated/aggregated a-syn species in the PD brain. PMID- 22514659 TI - Resident cardiac immune cells and expression of the ectonucleotidase enzymes CD39 and CD73 after ischemic injury. AB - BACKGROUND: The ectoenzymes CD39 and CD73 are expressed by a broad range of immune cells and promote the extracellular degradation of nucleotides to anti inflammatory adenosine. This study explored the abundance of CD73 and CD39 on circulating and resident cardiac leukocytes and coronary endothelial cells under control conditions and in response to inflammation following myocardial ischemia and reperfusion (I/R). METHODS AND RESULTS: A method was elaborated to permit FACS analysis of non-myocardial cells (resident leukocytes, coronary endothelium and CD31(-) CD45(-) cells) of the unstressed heart. Under control conditions the murine heart contained 2.3 * 10(3) resident leukocytes/mg tissue, the most prominent fraction being antigen-presenting mononuclear cells (CD11b(+) CD11c(+) F4/80(+) MHCII(+)) followed by B-cells, monocytes and T-cells. CD73 was highly expressed on circulating and resident cardiac lymphoid cells with little expression on myeloid cells, while the opposite was true for CD39. Cardiomyocytes and erythrocytes do not measurably express CD39/CD73 and CD39 dominates on coronary endothelium. Three days after I/R, CD73 was significantly upregulated on invading granulocytes (2.8-fold) and T-cells (1.5-fold). Compared with coronary endothelial cells, CD73 associated with leukocytes comprised 2/3 of the total cardiac CD73. CONCLUSION: Our study suggests that extracellular ATP formed during I/R is preferentially degraded by CD39 present on myeloid cells, while the formation of immunosuppressive adenosine is mainly catalysed by CD73 present on granulocytes and lymphoid cells. Upregulated CD73 on granulocytes and T-cells infiltrating the injured heart is consistent with the existence of an autocrine adenosinergic loop which may promote the healing process. PMID- 22514660 TI - Multiserotype protection elicited by a combinatorial prime-boost vaccination strategy against bluetongue virus. AB - Bluetongue virus (BTV) belongs to the genus Orbivirus within the family Reoviridae. The development of vector-based vaccines expressing conserved protective antigens results in increased immune activation and could reduce the number of multiserotype vaccinations required, therefore providing a cost effective product. Recent recombinant DNA technology has allowed the development of novel strategies to develop marker and safe vaccines against BTV. We have now engineered naked DNAs and recombinant modified vaccinia virus Ankara (rMVA) expressing VP2, VP7 and NS1 proteins from BTV-4. IFNAR((-/-)) mice inoculated with DNA/rMVA-VP2,-VP7-NS1 in an heterologous prime boost vaccination strategy generated significant levels of antibodies specific of VP2, VP7, and NS1, including those with neutralizing activity against BTV-4. In addition, vaccination stimulated specific CD8(+) T cell responses against these three BTV proteins. Importantly, the vaccine combination expressing NS1, VP2 and VP7 proteins of BTV-4, elicited sterile protection against a lethal dose of homologous BTV-4 infection. Remarkably, the vaccine induced cross-protection against lethal doses of heterologous BTV-8 and BTV-1 suggesting that the DNA/rMVA VP2,-VP7,-NS1 marker vaccine is a promising multiserotype vaccine against BTV. PMID- 22514661 TI - Motor fatigue measurement by distance-induced slow down of walking speed in multiple sclerosis. AB - BACKGROUND AND RATIONALE: Motor fatigue and ambulation impairment are prominent clinical features of people with multiple sclerosis (pMS). We hypothesized that a multimodal and comparative assessment of walking speed on short and long distance would allow a better delineation and quantification of gait fatigability in pMS. Our objectives were to compare 4 walking paradigms: the timed 25-foot walk (T25FW), a corrected version of the T25FW with dynamic start (T25FW(+)), the timed 100-meter walk (T100MW) and the timed 500-meter walk (T500MW). METHODS: Thirty controls and 81 pMS performed the 4 walking tests in a single study visit. RESULTS: The 4 walking tests were performed with a slower WS in pMS compared to controls even in subgroups with minimal disability. The finishing speed of the last 100-meter of the T500MW was the slowest measurable WS whereas the T25FW(+) provided the fastest measurable WS. The ratio between such slowest and fastest WS (Deceleration Index, DI) was significantly lower only in pMS with EDSS 4.0-6.0, a pyramidal or cerebellar functional system score reaching 3 or a maximum reported walking distance <= 4000 m. CONCLUSION: The motor fatigue which triggers gait deceleration over a sustained effort in pMS can be measured by the WS ratio between performances on a very short distance and the finishing pace on a longer more demanding task. The absolute walking speed is abnormal early in MS whatever the distance of effort when patients are unaware of ambulation impairment. In contrast, the DI-measured ambulation fatigability appears to take place later in the disease course. PMID- 22514662 TI - Accuracy of using visual identification of white sharks to estimate residency patterns. AB - Determining the residency of an aquatic species is important but challenging and it remains unclear what is the best sampling methodology. Photo-identification has been used extensively to estimate patterns of animals' residency and is arguably the most common approach, but it may not be the most effective approach in marine environments. To examine this, in 2005, we deployed acoustic transmitters on 22 white sharks (Carcharodon carcharias) in Mossel Bay, South Africa to quantify the probability of detecting these tagged sharks by photo identification and different deployment strategies of acoustic telemetry equipment. Using the data collected by the different sampling approaches (detections from an acoustic listening station deployed under a chumming vessel versus those from visual sightings and photo-identification), we quantified the methodologies' probability of detection and determined if the sampling approaches, also including an acoustic telemetry array, produce comparable results for patterns of residency. Photo-identification had the lowest probability of detection and underestimated residency. The underestimation is driven by various factors primarily that acoustic telemetry monitors a large area and this reduces the occurrence of false negatives. Therefore, we propose that researchers need to use acoustic telemetry and also continue to develop new sampling approaches as photo-identification techniques are inadequate to determine residency. Using the methods presented in this paper will allow researchers to further refine sampling approaches that enable them to collect more accurate data that will result in better research and more informed management efforts and policy decisions. PMID- 22514664 TI - Neuronal variability during handwriting: lognormal distribution. AB - We examined time-dependent statistical properties of electromyographic (EMG) signals recorded from intrinsic hand muscles during handwriting. Our analysis showed that trial-to-trial neuronal variability of EMG signals is well described by the lognormal distribution clearly distinguished from the Gaussian (normal) distribution. This finding indicates that EMG formation cannot be described by a conventional model where the signal is normally distributed because it is composed by summation of many random sources. We found that the variability of temporal parameters of handwriting--handwriting duration and response time--is also well described by a lognormal distribution. Although, the exact mechanism of lognormal statistics remains an open question, the results obtained should significantly impact experimental research, theoretical modeling and bioengineering applications of motor networks. In particular, our results suggest that accounting for lognormal distribution of EMGs can improve biomimetic systems that strive to reproduce EMG signals in artificial actuators. PMID- 22514663 TI - Comparative pharmacology of cholecystokinin induced activation of cultured vagal afferent neurons from rats and mice. AB - Cholecystokinin (CCK) facilitates the process of satiation via activation of vagal afferent neurons innervating the upper gastrointestinal tract. Recent findings indicate CCK acts on these neurons via a ruthenium red (RuR) sensitive pathway that involves members of the vanilloid (V) subfamily of transient receptor potential (TRP) channels. To further test this mechanism, the mouse provides an ideal model in which genetic tools could be applied. However, whether CCK acts by similar mechanism(s) in mice has not been determined. In the present study we explored the actions of CCK on nodose neurons isolated from Sprague Dawley (SD) rat and two strains of mice; C57BL/6 and BalbC using fluorescence based calcium imaging. With minor exceptions nodose neurons isolated from all species/strains behaved similarly. They all respond to brief depolarization with a large calcium transient. A significant subset of neurons responded to capsaicin (CAP), a TRPV1 agonist, although neurons from C57BL/6 were 10-fold more sensitive to CAP than SD rats or BalbC mice, and a significantly smaller fraction of neurons from BalbC mice responded to CAP. CCK-8 dose-dependently activated a subpopulation of neurons with similar dose dependency, percent responders, and overlap between CCK and CAP responsiveness. In all species/strains CCK-8 induced activation was significantly attenuated (but not completely blocked) by pretreatment with the TRPV channel blocker RuR. Surprisingly, the CCK analogue JMV-180, which is reported to have pure antagonistic properties in rat but mixed agonist/antagonist properties in mice, behaved as a pure antagonist to CCK in both rat and mouse neurons. The pure antagonistic action of JMV-180 in this in vitro preparation suggests that prior reported differential effects of JMV-180 on satiation in rats versus mouse must be mediated by a site other than vagal afferent activation. PMID- 22514665 TI - Oral cancer development in patients with leukoplakia--clinicopathological factors affecting outcome. AB - BACKGROUND: Oral leukoplakia (OL) is the best-known potentially malignant disorder. The objective of the current study was to evaluate the clinicopathological factors predictive of outcome in a large cohort of patients with OL, and report our experience in the early detection of malignant events. METHODS: A total of 320 patients with biopsy-proven OL were retrospectively reviewed from the study institution who had a mean follow-up of 5.1 years. Data on patient and lesion at initial diagnosis and patient underwent sequential biopsies were reviewed. Multiple biopsies indicates > = 3 times sequential biopsies. Oral cancer-free survival rate (OCFS) was determined by the Kaplan Meier method and significant factors were identified by Cox regression analysis. RESULTS: The 3-year and 5-year OCFS was 86.6% and 82.0%, respectively. A new binary system of grading oral dysplasia was performed and Kaplan-Meier analysis indicated that high-grade dysplasia had significantly higher malignant incidence than low-grade dysplasia (5-year OCFS, 90.5% vs 59.0%; P<0.001), especially during the first 2-3 years of follow-up. Multivariate analysis revealed that the 4 factors including patient aged >60 years, lesion located at lateral/ventral tongue, non-homogenous lesion, high-grade dysplasia were independent significant indicators for OL malignant transformation. In addition, significant positive correlation between the multiple biopsies and these 4 factors and malignant outcome was established. CONCLUSIONS: Elderly patients with OL located at lateral/ventral tongue and who had non-homogenous lesion with high-grade dysplasia correlated much higher risk of transformation. This high-risk subpopulation was suggested to undergo sequential biopsies and histologic examination contributing to early detection of malignant event. PMID- 22514666 TI - Fatigue-associated alterations of cognitive function and electroencephalographic power densities. AB - Fatigue is a common problem in modern society. We attempted to identify moderate- to long-term fatigue-related alterations in the central nervous system using cognitive tasks and electroencephalography (EEG) measures. The study group consisted of 17 healthy male participants. After saliva samples were collected to measure copy number of human herpesvirus (HHV)-6 DNA to assess the level of moderate- to long-term fatigue, subjects were evaluated using EEG, with their eyes open for 2 min, then closed for 1 min sitting quietly. Thereafter, they completed cognitive task trials to evaluate simple selective attention for 3 min (Task 1) and conflict-controlling selective attention for 6 min (Task 2, which included Stroop trials). The percent error of Task 2 for Stroop trials was positively associated with the copy number of saliva HHV-6 DNA, although the simple selective attention measures in Task 1 did not differ significantly. EEG power densities (especially the alpha power density) during the eye-closed condition were negatively associated with the saliva HHV-6 DNA level. Impaired high-level information processing such as that required for conflict-controlling selective attention in the central nervous system may be a characteristic feature of moderate- to long-term fatigue. PMID- 22514667 TI - Social determinants of self-reported health in women and men: understanding the role of gender in population health. AB - BACKGROUND: Women and men share similar health challenges yet women report poorer health. The study investigates the social determinants of self-reported health in women and men, and male-female differences in health. METHODS: Data on 103154 men and 125728 women were analysed from 57 countries in the World Health Survey 2002 2004. Item Response Theory was used to construct a composite measure of health. Associations between health and determinants were assessed using multivariate linear regression. Blinder-Oaxaca decomposition partitioned the inequality in health between women and men into an "explained" component that arises because men and women differ in social and economic characteristics, and an "unexplained" component due to the differential effects of these characteristics. Decomposition was repeated for 18 countries in the World Health Organization (WHO) African region and 19 countries in the WHO European region. RESULTS: Women's health was significantly lower than men's. Health was associated with education, household economic status, employment, and marital status after controlling for age. In the pooled analysis decomposition showed that 30% of the inequality was "explained", of which almost 75% came from employment, education, marital status. The differential effects of being in paid employment increased the inequality. When countries in Africa and Europe were compared, the "explained" component (31% and 39% respectively) was largely attributed to the social determinants in the African countries and to women's longevity in the European countries. Being in paid employment had a greater positive effect on the health of males in both regions. CONCLUSIONS: Ways in which age and the social determinants contribute to the poorer health status of women compared with men varies between groups of countries. This study highlights the need for action to address social structures, institutional discrimination and harmful gender norms and roles that differently influence health with ageing. PMID- 22514668 TI - Proteomic analysis of chikungunya virus infected microgial cells. AB - Chikungunya virus (CHIKV) is a recently re-emerged public health problem in many countries bordering the Indian Ocean and elsewhere. Chikungunya fever is a relatively self limiting febrile disease, but the consequences of chikungunya fever can include a long lasting, debilitating arthralgia, and occasional neurological involvement has been reported. Macrophages have been implicated as an important cell target of CHIKV with regards to both their role as an immune mediator, as well evidence pointing to long term viral persistence in these cells. Microglial cells are the resident brain macrophages, and so this study sought to define the proteomic changes in a human microglial cell line (CHME-5) in response to CHIKV infection. GeLC-MS/MS analysis of CHIKV infected and mock infected cells identified some 1455 individual proteins, of which 90 proteins, belonging to diverse cellular pathways, were significantly down regulated at a significance level of p<0.01. Analysis of the protein profile in response to infection did not support a global inhibition of either normal or IRES-mediated translation, but was consistent with the targeting of specific cellular pathways including those regulating innate antiviral mechanisms. PMID- 22514669 TI - Long term results of anterior corpectomy and fusion for cervical spondylotic myelopathy. AB - BACKGROUND: Results showed good clinical outcomes of anterior corpectomy and fusion (ACCF) for patients with cervical spondylotic myelopathy (CSM) during a short term follow-up; however, studies assessing long term results are relatively scarce. In this study we intended to assess the long term clinical and radiographic outcomes, find out the factors that may affect the long term clinical outcome and evaluate the incidence of adjacent segment disease (ASD). METHODS: This is a retrospective study of 145 consecutive CSM patients on ACCF treatment with a minimum follow-up of 5 years. Clinical data were collected from medical and operative records. Patients were evaluated by using the Japanese Orthopedic Association (JOA) scoring system preoperatively and during the follow up. X-rays results of cervical spine were obtained from all patients. Correlations between the long term clinical outcome and various factors were also analyzed. FINDINGS: Ninety-three males and fifty-two females completed the follow up. The mean age at operation was 51.0 years, and the mean follow-up period was 102.1 months. Both postoperative sagittal segmental alignment (SSA) and the sagittal alignment of the whole cervical spine (SACS) increased significantly in terms of cervical lordosis. The mean increase of JOA was 3.8 +/- 1.3 postoperatively, and the overall recovery rate was 62.5%. Logistic regression analysis showed that preoperative duration of symptoms >12 months, high-intensity signal in spinal cord and preoperative JOA score <= 9 were important predictors of the fair recovery rate (<= 50%). Repeated surgery due to ASD was performed in 7 (4.8%) cases. CONCLUSIONS: ACCF with anterior plate fixation is a reliable and effective method for treating CSM in terms of JOA score and the recovery rate. The correction of cervical alignment and the repeated surgery rate for ASD are also considered to be satisfactory. PMID- 22514670 TI - Rapid spread of tomato yellow leaf curl virus in China is aided differentially by two invasive whiteflies. AB - BACKGROUND: Tomato yellow leaf curl virus (TYLCV) was introduced into China in 2006, approximately 10 years after the introduction of an invasive whitefly, Bemisia tabaci (Genn.) B biotype. Even so the distribution and prevalence of TYLCV remained limited, and the economic damage was minimal. Following the introduction of Q biotype into China in 2003, the prevalence and spread of TYLCV started to accelerate. This has lead to the hypothesis that the two biotypes might not be equally competent vectors of TYLCV. METHODOLOGY/PRINCIPAL FINDINGS: The infection frequency of TYLCV in the field-collected B. tabaci populations was investigated, the acquisition and transmission capability of TYLCV by B and Q biotypes were compared under the laboratory conditions. Analysis of B. tabaci populations from 55 field sites revealed the existence of 12 B and 43 Q biotypes across 18 provinces in China. The acquisition and transmission experiments showed that both B and Q biotypes can acquire and transmit the virus, however, Q biotype demonstrated superior acquisition and transmission capability than its B counterparts. Specifically, Q biotype acquired significantly more viral DNA than the B biotype, and reached the maximum viral load in a substantially shorter period of time. Although TYLCV was shown to be transmitted horizontally by both biotypes, Q biotype exhibited significantly higher viral transmission frequency than B biotype. Vertical transmission result, on the other hand, indicated that TYLCV DNA can be detected in eggs and nymphs, but not in pupae and adults of the first generation progeny. CONCLUSIONS/SIGNIFICANCE: These combined results suggested that the epidemiology of TYLCV was aided differentially by the two invasive whiteflies (B and Q biotypes) through horizontal but not vertical transmission of the virus. This is consistent with the concomitant eruption of TYLCV in tomato fields following the recent rapid invasion of Q biotype whitefly in China. PMID- 22514671 TI - Molecular etiology of atherogenesis--in vitro induction of lipidosis in macrophages with a new LDL model. AB - BACKGROUND: Atherosclerosis starts by lipid accumulation in the arterial intima and progresses into a chronic vascular inflammatory disease. A major atherogenic process is the formation of lipid-loaded macrophages in which a breakdown of the endolysomal pathway results in irreversible accumulation of cargo in the late endocytic compartments with a phenotype similar to several forms of lipidosis. Macrophages exposed to oxidized LDL exihibit this phenomenon in vitro and manifest an impaired degradation of internalized lipids and enhanced inflammatory stimulation. Identification of the specific chemical component(s) causing this phenotype has been elusive because of the chemical complexity of oxidized LDL. METHODOLOGY/PRINCIPAL FINDINGS: Lipid "core aldehydes" are formed in oxidized LDL and exist in atherosclerotic plaques. These aldehydes are slowly oxidized in situ and (much faster) by intracellular aldehyde oxidizing systems to cholesteryl hemiesters. We show that a single cholesteryl hemiester incorporated into native, non-oxidized LDL induces a lipidosis phenotype with subsequent cell death in macrophages. Internalization of the cholesteryl hemiester via the native LDL vehicle induced lipid accumulation in a time- and concentration-dependent manner in "frozen" endolysosomes. Quantitative shotgun lipidomics analysis showed that internalized lipid in cholesteryl hemiester-intoxicated cells remained largely unprocessed in those lipid-rich organelles. CONCLUSIONS/SIGNIFICANCE: The principle elucidated with the present cholesteryl hemiester-containing native-LDL model, extended to other molecular components of oxidized LDL, will help in defining the molecular etiology and etiological hierarchy of atherogenic agents. PMID- 22514672 TI - Thalamic activation modulates the responses of neurons in rat primary auditory cortex: an in vivo intracellular recording study. AB - Auditory cortical plasticity can be induced through various approaches. The medial geniculate body (MGB) of the auditory thalamus gates the ascending auditory inputs to the cortex. The thalamocortical system has been proposed to play a critical role in the responses of the auditory cortex (AC). In the present study, we investigated the cellular mechanism of the cortical activity, adopting an in vivo intracellular recording technique, recording from the primary auditory cortex (AI) while presenting an acoustic stimulus to the rat and electrically stimulating its MGB. We found that low-frequency stimuli enhanced the amplitudes of sound-evoked excitatory postsynaptic potentials (EPSPs) in AI neurons, whereas high-frequency stimuli depressed these auditory responses. The degree of this modulation depended on the intensities of the train stimuli as well as the intervals between the electrical stimulations and their paired sound stimulations. These findings may have implications regarding the basic mechanisms of MGB activation of auditory cortical plasticity and cortical signal processing. PMID- 22514673 TI - Identification and characterization of novel mutations in the human gene encoding the catalytic subunit Calpha of protein kinase A (PKA). AB - The genes PRKACA and PRKACB encode the principal catalytic (C) subunits of protein kinase A (PKA) Calpha and Cbeta, respectively. Calpha is expressed in all eukaryotic tissues examined and studies of Calpha knockout mice demonstrate a crucial role for Calpha in normal physiology. We have sequenced exon 2 through 10 of PRKACA from the genome of 498 Norwegian donors and extracted information about PRKACA mutations from public databases. We identified four interesting nonsynonymous point mutations, Arg45Gln, Ser109Pro, Gly186Val, and Ser263Cys, in the Calpha1 splice variant of the kinase. Calpha variants harboring the different amino acid mutations were analyzed for kinase activity and regulatory (R) subunit binding. Whereas mutation of residues 45 and 263 did not alter catalytic activity or R subunit binding, mutation of Ser(109) significantly reduced kinase activity while R subunit binding was unaltered. Mutation of Calpha Gly(186) completely abrogated kinase activity and PKA type I but not type II holoenzyme formation. Gly(186) is located in the highly conserved DFG motif of Calpha and mutation of this residue to Val was predicted to result in loss of binding of ATP and Mg(2+), which may explain the kinetic inactivity. We hypothesize that individuals born with mutations of Ser(109) or Gly(186) may be faced with abnormal development and possibly severe disease. PMID- 22514674 TI - Adaptation to aridity in the malaria mosquito Anopheles gambiae: chromosomal inversion polymorphism and body size influence resistance to desiccation. AB - Chromosomal inversions are thought to confer a selective advantage in alternative habitats by protecting co-adapted alleles from recombination. The frequencies of two inversions (2La and 2Rb) of the afro-tropical malaria mosquito Anopheles gambiae change gradually along geographical clines, increasing in frequency with degree of aridity. Such clines can result from gene flow and local selection acting upon alternative karyotypes along the cline, suggesting that these inversions may be associated with tolerance to xeric conditions. Since water loss represents a major challenge in xeric habitats, it can be supposed that genes inside these inversions are involved in water homeostasis. To test this hypothesis, we compared the desiccation resistance of alternative karyotypes from a colonised 2Rb/2La polymorphic population of A. gambiae from Cameroon. The strain included only the molecular form S, one of the genetic units marking incipient speciation in this taxon. Day-old mosquitoes of both sexes were assayed individually for time to death in a dry environment and the karyotype of each was determined post-mortem using molecular diagnostic assays for each inversion. In agreement with expectations based on their eco-geographical distribution, we found that 2La homokaryotypes survived significantly longer (1.3 hours) than the other karyotypes. However, there was weak support for the effect of 2Rb on desiccation resistance. Larger mosquitoes survived longer than smaller ones. Median survival of females was greater than males, but the effect of sex on desiccation resistance was weakly supported, indicating that differential survival was correlated to differences between sexes in average size. We found weak evidence for a heterotic effect of 2La karyotype on size in females. These results support the notion that genes located inside the 2La inversion are involved in water balance, contributing towards local adaptation of A. gambiae to xeric habitats, beyond the adaptive value conferred by a larger body size. PMID- 22514675 TI - Cellular basis for response diversity in the olfactory periphery. AB - An emerging idea in olfaction is that temporal coding of odor specificity can be intrinsic to the primary olfactory receptor neurons (ORNs). As a first step towards understanding whether lobster ORNs are capable of generating odor specific temporal activity and what mechanisms underlie any such heterogeneity in discharge pattern, we characterized different patterns of activity in lobster ORNs individually and ensemble using patch-clamp recording and calcium imaging. We demonstrate that lobster ORNs show tonic excitation, tonic inhibition, phaso tonic excitation, and bursting, and that these patterns are faithfully reflected in the calcium signal. We then demonstrate that the various dynamic patterns of response are inherent in the cells, and that this inherent heterogeneity is largely determined by heterogeneity in the underlying intrinsic conductances. PMID- 22514676 TI - Phosphorylation by Dyrk1A of clathrin coated vesicle-associated proteins: identification of the substrate proteins and the effects of phosphorylation. AB - Dyrk1A phosphorylated multiple proteins in the clathrin-coated vesicle (CCV) preparations obtained from rat brains. Mass spectrometric analysis identified MAP1A, MAP2, AP180, and alpha- and beta-adaptins as the phosphorylated proteins in the CCVs. Each protein was subsequently confirmed by [(32)P]-labeling and immunological methods. The Dyrk1A-mediated phosphorylation released the majority of MAP1A and MAP2 and enhanced the release of AP180 and adaptin subunits from the CCVs. Furthermore, Dyrk1A displaced adaptor proteins physically from CCVs in a kinase-concentration dependent manner. The clathrin heavy chain release rate, in contrast, was not affected by Dyrk1A. Surprisingly, the Dyrk1A-mediated phosphorylation of alpha- and beta-adaptins led to dissociation of the AP2 complex, and released only beta-adaptin from the CCVs. AP180 was phosphorylated by Dyrk1A also in the membrane-free fractions, but alpha- and beta-adaptins were not. Dyrk1A was detected in the isolated CCVs and was co-localized with clathrin in neurons from mouse brain sections and from primary cultured rat hippocampus. Previously, we proposed that Dyrk1A inhibits the onset of clathrin-mediated endocytosis in neurons by phosphorylating dynamin 1, amphiphysin 1, and synaptojanin 1. Current results suggest that besides the inhibition, Dyrk1A promotes the uncoating process of endocytosed CCVs. PMID- 22514677 TI - MAPPIN'SDM--the multifocal approach to sharing in shared decision making. AB - BACKGROUND: The wide scale permeation of health care by the shared decision making concept (SDM) reflects its relevance and advanced stage of development. An increasing number of studies evaluating the efficacy of SDM use instruments based on various sub-constructs administered from different viewpoints. However, as the concept has never been captured in operable core definition it is quite difficult to link these parts of evidence. This study aims at investigating interrelations of SDM indicators administered from different perspectives. METHOD: A comprehensive inventory was developed mapping judgements from different perspectives (observer, doctor, patient) and constructs (behavior, perception) referring to three units (doctor, patient, doctor-patient-dyad) and an identical set of SDM-indicators. The inventory adopted the existing approaches, but added additional observer foci (patient and doctor-patient-dyad) and relevant indicators hitherto neglected by existing instruments. The complete inventory comprising a doctor-patient-questionnaire and an observer-instrument was applied to 40 decision consultations from 10 physicians from different medical fields. Convergent validities were calculated on the basis of Pearson correlation coefficients. RESULTS: Reliabilities for all scales were high to excellent. No correlations were found between observer and patients or physicians neither for means nor for single items. Judgements of doctors and patients were moderately related. Correlations between the observer scales and within the subjective perspectives were high. Inter-perspective agreement was not related to SDM performance or patient activity. CONCLUSION: The study demonstrates the contribution to involvement made by each of the relevant perspectives and emphasizes the need for an inter-subjective approach regarding SDM measurement. PMID- 22514678 TI - Acquisition of complement inhibitor serine protease factor I and its cofactors C4b-binding protein and factor H by Prevotella intermedia. AB - Infection with the Gram-negative pathogen Prevotella intermedia gives rise to periodontitis and a growing number of studies implies an association of P. intermedia with rheumatoid arthritis. The serine protease Factor I (FI) is the central inhibitor of complement degrading complement components C3b and C4b in the presence of cofactors such as C4b-binding protein (C4BP) and Factor H (FH). Yet, the significance of complement inhibitor acquisition in P. intermedia infection and FI binding by Gram-negative pathogens has not been addressed. Here we show that P. intermedia isolates bound purified FI as well as FI directly from heat-inactivated human serum. FI bound to bacteria retained its serine protease activity as shown in degradation experiments with (125)I-labeled C4b. Since FI requires cofactors for its activity we also investigated the binding of purified cofactors C4BP and FH and found acquisition of both proteins, which retained their activity in FI mediated degradation of C3b and C4b. We propose that FI binding by P. intermedia represents a new mechanism contributing to complement evasion by a Gram-negative bacterial pathogen associated with chronic diseases. PMID- 22514679 TI - Insulin signaling as a mechanism underlying developmental plasticity: the role of FOXO in a nutritional polyphenism. AB - We investigated whether insulin signaling, known to mediate physiological plasticity in response to changes in nutrition, also facilitates discrete phenotypic responses such as polyphenisms. We test the hypothesis that the gene FOXO--which regulates growth arrest under nutrient stress--mediates a nutritional polyphenism in the horned beetle, Onthophagus nigriventris. Male beetles in the genus Onthophagus vary their mating strategy with body size: large males express horns and fight for access to females while small males invest heavily in genitalia and sneak copulations with females. Given that body size and larval nutrition are linked, we predicted that 1) FOXO expression would differentially scale with body size (nutritional status) between males and females, and 2) manipulation of FOXO expression would affect the nutritional polyphenism in horns and genitalia. First, we found that FOXO expression varied with body size in a tissue- and sex-specific manner, being more highly expressed in the abdominal tissue of large (horned) males, in particular in regions associated with genitalia development. Second, we found that knockdown of FOXO through RNA interference resulted in the growth of relatively larger copulatory organs compared to control-injected individuals and significant, albeit modest, increases in relative horn length. Our results support the hypothesis that FOXO expression in the abdominal tissue limits genitalia growth, and provides limited support for the hypothesis that FOXO regulates relative horn length through direct suppression of horn growth. Both results support the idea that tissue specific FOXO expression may play a general role in regulating scaling relationships in nutritional polyphenisms by signaling traits to be relatively smaller. PMID- 22514680 TI - Similarities and differences in Chinese and Caucasian adults' use of facial cues for trustworthiness judgments. AB - BACKGROUND: All cultural groups in the world place paramount value on interpersonal trust. Existing research suggests that although accurate judgments of another's trustworthiness require extensive interactions with the person, we often make trustworthiness judgments based on facial cues on the first encounter. However, little is known about what facial cues are used for such judgments and what the bases are on which individuals make their trustworthiness judgments. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we tested the hypothesis that individuals may use facial attractiveness cues as a "shortcut" for judging another's trustworthiness due to the lack of other more informative and in-depth information about trustworthiness. Using data-driven statistical models of 3D Caucasian faces, we compared facial cues used for judging the trustworthiness of Caucasian faces by Caucasian participants who were highly experienced with Caucasian faces, and the facial cues used by Chinese participants who were unfamiliar with Caucasian faces. We found that Chinese and Caucasian participants used similar facial cues to judge trustworthiness. Also, both Chinese and Caucasian participants used almost identical facial cues for judging trustworthiness and attractiveness. CONCLUSIONS/SIGNIFICANCE: The results suggest that without opportunities to interact with another person extensively, we use the less racially specific and more universal attractiveness cues as a "shortcut" for trustworthiness judgments. PMID- 22514681 TI - Macrophage inhibitory cytokine 1 (MIC-1/GDF15) decreases food intake, body weight and improves glucose tolerance in mice on normal & obesogenic diets. AB - Food intake and body weight are controlled by a variety of central and peripheral factors, but the exact mechanisms behind these processes are still not fully understood. Here we show that that macrophage inhibitory cytokine-1 (MIC 1/GDF15), known to have anorexigenic effects particularly in cancer, provides protection against the development of obesity. Both under a normal chow diet and an obesogenic diet, the transgenic overexpression of MIC-1/GDF15 in mice leads to decreased body weight and fat mass. This lean phenotype was associated with decreased spontaneous but not fasting-induced food intake, on a background of unaltered energy expenditure and reduced physical activity. Importantly, the overexpression of MIC-1/GDF15 improved glucose tolerance, both under normal and high fat-fed conditions. Altogether, this work shows that the molecule MIC 1/GDF15 might be beneficial for the treatment of obesity as well as perturbations in glucose homeostasis. PMID- 22514682 TI - QTL analysis for transgressive resistance to root-knot nematode in interspecific cotton (Gossypium spp.) progeny derived from susceptible parents. AB - The southern root-knot nematode (RKN, Meloidogyne incognita) is a major soil inhabiting plant parasite that causes significant yield losses in cotton (Gossypium spp.). Progeny from crosses between cotton genotypes susceptible to RKN produced segregants in subsequent populations which were highly resistant to this parasite. A recombinant inbred line (RIL) population of 138 lines developed from a cross between Upland cotton TM-1 (G. hirsutum L.) and Pima 3-79 (G. barbadense L.), both susceptible to RKN, was used to identify quantitative trait loci (QTLs) determining responses to RKN in greenhouse infection assays with simple sequence repeat (SSR) markers. Compared to both parents, 53.6% and 52.1% of RILs showed less (P<0.05) root-galling index (GI) and had lower (P<0.05) nematode egg production (eggs per gram root, EGR). Highly resistant lines (transgressive segregants) were identified in this RIL population for GI and/or EGR in two greenhouse experiments. QTLs were identified using the single-marker analysis nonparametric mapping Kruskal-Wallis test. Four major QTLs located on chromosomes 3, 4, 11, and 17 were identified to account for 8.0 to 12.3% of the phenotypic variance (R(2)) in root-galling. Two major QTLs accounting for 9.7% and 10.6% of EGR variance were identified on chromosomes 14 and 23 (P<0.005), respectively. In addition, 19 putative QTLs (P<0.05) accounted for 4.5-7.7% of phenotypic variance (R(2)) in GI, and 15 QTLs accounted for 4.2-7.3% of phenotypic variance in EGR. In lines with alleles positive for resistance contributed by both parents in combinations of two to four QTLs, dramatic reductions of >50% in both GI and EGR were observed. The transgressive segregants with epistatic effects derived from susceptible parents indicate that high levels of nematode resistance in cotton may be attained by pyramiding positive alleles using a QTL mapping approach. PMID- 22514683 TI - Functional interaction between CFTR and the sodium-phosphate co-transport type 2a in Xenopus laevis oocytes. AB - BACKGROUND: A growing number of proteins, including ion transporters, have been shown to interact with Cystic Fibrosis Transmembrane conductance Regulator (CFTR). CFTR is an epithelial chloride channel that is involved in Cystic Fibrosis (CF) when mutated; thus a better knowledge of its functional interactome may help to understand the pathophysiology of this complex disease. In the present study, we investigated if CFTR and the sodium-phosphate co-transporter type 2a (NPT2a) functionally interact after heterologous expression of both proteins in Xenopus laevis oocytes. METHODOLOGY/FINDINGS: NPT2a was expressed alone or in combination with CFTR in X. laevis oocytes. Using the two-electrode voltage-clamp technique, the inorganic phosphate-induced current (IPi) was measured and taken as an index of NPT2a activity. The maximal IPi for NPT2a substrates was reduced when CFTR was co-expressed with NPT2a, suggesting a decrease in its expression at the oolemna. This was consistent with Western blot analysis showing reduced NPT2a plasma membrane expression in oocytes co expressing both proteins, whereas NPT2a protein level in total cell lysate was the same in NPT2a- and NPT2a+CFTR-oocytes. In NPT2a+CFTR- but not in NPT2a oocytes, IPi and NPT2a surface expression were increased upon PKA stimulation, whereas stimulation of Exchange Protein directly Activated by cAMP (EPAC) had no effect. When NPT2a-oocytes were injected with NEG2, a short amino-acid sequence from the CFTR regulatory domain that regulates PKA-dependent CFTR trafficking to the plasma membrane, IPi values and NPT2a membrane expression were diminished, and could be enhanced by PKA stimulation, thereby mimicking the effects of CFTR co-expression. CONCLUSION/PERSPECTIVES: We conclude that when both CFTR and NPT2a are expressed in X. laevis oocytes, CFTR confers to NPT2a a cAMPi-dependent trafficking to the membrane. This functional interaction raises the hypothesis that CFTR may play a role in phosphate homeostasis. PMID- 22514684 TI - Worrying affects associative fear learning: a startle fear conditioning study. AB - A valuable experimental model for the pathogenesis of anxiety disorders is that they originate from a learned association between an intrinsically non-aversive event (Conditioned Stimulus, CS) and an anticipated disaster (Unconditioned Stimulus, UCS). Most anxiety disorders, however, do not evolve from a traumatic experience. Insights from neuroscience show that memory can be modified post learning, which may elucidate how pathological fear can develop after relatively mild aversive events. Worrying--a process frequently observed in anxiety disorders--is a potential candidate to strengthen the formation of fear memory after learning. Here we tested in a discriminative fear conditioning procedure whether worry strengthens associative fear memory. Participants were randomly assigned to either a Worry (n = 23) or Control condition (n = 25). After fear acquisition, the participants in the Worry condition processed six worrisome questions regarding the personal aversive consequences of an electric stimulus (UCS), whereas the Control condition received difficult but neutral questions. Subsequently, extinction, reinstatement and re-extinction of fear were tested. Conditioned responding was measured by fear-potentiated startle (FPS), skin conductance (SCR) and UCS expectancy ratings. Our main results demonstrate that worrying resulted in increased fear responses (FPS) to both the feared stimulus (CS(+)) and the originally safe stimulus (CS(-)), whereas FPS remained unchanged in the Control condition. In addition, worrying impaired both extinction and re extinction learning of UCS expectancy. The implication of our findings is that they show how worry may contribute to the development of anxiety disorders by affecting associative fear learning. PMID- 22514685 TI - Pseudomonas aeruginosa overrides the virulence inducing effect of opioids when it senses an abundance of phosphate. AB - The gut during critical illness represents a complex ecology dominated by the presence of healthcare associated pathogens, nutrient scarce conditions, and compensatory host stress signals. We have previously identified key environmental cues, opioids and phosphate depletion that independently activate the virulence of Pseudomonas aeruginosa. Opioids induce quinolone signal production (PQS), whereas phosphate depletion leads to a triangulated response between MvfR-PQS, pyoverdin, and phosphosensory/phosphoregulatory systems (PstS-PhoB). Yet how P. aeruginosa manages its response to opioids during nutrient scarce conditions when growth is limited and a quorum is unlikely to be achieved is important in the context of pathogenesis in gut during stress. To mimic this environment, we created nutrient poor conditions and exposed P. aeruginosa PAO1 to the specific k opioid receptor agonist U-50,488. Bacterial cells exposed to the k-opioid expressed a striking increase in virulence- and multi-drug resistance-related genes that correlated to a lethal phenotype in C. elegans killing assays. Under these conditions, HHQ, a precursor of PQS, rather than PQS itself, became the main inducer for pqsABCDE operon expression. P. aeruginosa virulence expression in response to k-opioids required PqsE since DeltaPqsE was attenuated in its ability to activate virulence- and efflux pumps-related genes. Extracellular inorganic phosphate completely changed the transcriptional response of PAO1 to the k- opioid preventing pqsABCDE expression, the activation of multiple virulence- and efflux pumps-related genes, and the ability of P. aeruginosa to kill C. elegans. These results indicate that when P. aeruginosa senses resource abundance in the form of phosphate, it overrides its response to compensatory host signals such as opioids to express a virulent and lethal phenotype. These studies confirm a central role for phosphate in P. aeruginosa virulence that might be exploited to design novel anti- virulence strategies. PMID- 22514686 TI - Pre-existing vector immunity does not prevent replication deficient adenovirus from inducing efficient CD8 T-cell memory and recall responses. AB - Adenoviral vectors have shown a great potential for vaccine development due to their inherent ability to induce potent and protective CD8 T-cell responses. However, a critical issue regarding the use of these vectors is the existence of inhibitory immunity against the most commonly used Ad5 vector in a large part of the human population. We have recently developed an improved adenoviral vaccine vector system in which the vector expresses the transgene tethered to the MHC class II associated invariant chain (Ii). To further evaluate the potential of this system, the concept of pre-existing inhibitory immunity to adenoviral vectors was revisited to investigate whether the inhibition previously seen with the Ad5 vector also applied to the optimized vector system. We found this to be the case, and antibodies dominated as the mechanism underlying inhibitory vector immunity. However, presence of CD8 T cells directed against epitopes in the adenoviral vector seemed to correlate with repression of the induced response in re-vaccinated B-cell deficient mice. More importantly, despite a repressed primary effector CD8 T-cell response in Ad5-immune animals subjected to vaccination, memory T cells were generated that provided the foundation for an efficient recall response and protection upon subsequent viral challenge. Furthermore, the transgene specific response could be efficiently boosted by homologous re-immunization. Taken together, these studies indicate that adenoviral vectors can be used to induce efficient CD8 T-cell memory even in individuals with pre-existing vector immunity. PMID- 22514687 TI - An anillin-Ect2 complex stabilizes central spindle microtubules at the cortex during cytokinesis. AB - Cytokinesis occurs due to the RhoA-dependent ingression of an actomyosin ring. During anaphase, the Rho GEF (guanine nucleotide exchange factor) Ect2 is recruited to the central spindle via its interaction with MgcRacGAP/Cyk-4, and activates RhoA in the central plane of the cell. Ect2 also localizes to the cortex, where it has access to RhoA. The N-terminus of Ect2 binds to Cyk-4, and the C-terminus contains conserved DH (Dbl homologous) and PH (Pleckstrin Homology) domains with GEF activity. The PH domain is required for Ect2's cortical localization, but its molecular function is not known. In cultured human cells, we found that the PH domain interacts with anillin, a contractile ring protein that scaffolds actin and myosin and interacts with RhoA. The anillin-Ect2 interaction may require Ect2's association with lipids, since a novel mutation in the PH domain, which disrupts phospholipid association, weakens their interaction. An anillin-RacGAP50C (homologue of Cyk-4) complex was previously described in Drosophila, which may crosslink the central spindle to the cortex to stabilize the position of the contractile ring. Our data supports an analogous function for the anillin-Ect2 complex in human cells and one hypothesis is that this complex has functionally replaced the Drosophila anillin-RacGAP50C complex. Complexes between central spindle proteins and cortical proteins could regulate the position of the contractile ring by stabilizing microtubule-cortical interactions at the division plane to ensure the generation of active RhoA in a discrete zone. PMID- 22514688 TI - Optical coherence tomography in parkinsonian syndromes. AB - BACKGROUND/OBJECTIVE: Parkinson's disease (PD) and the atypical parkinsonian syndromes multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are movement disorders associated with degeneration of the central nervous system. Degeneration of the retina has not been systematically compared in these diseases. METHODS: This cross-sectional study used spectral-domain optical coherence tomography with manual segmentation to measure the peripapillar nerve fiber layer, the macular thickness, and the thickness of all retinal layers in foveal scans of 40 patients with PD, 19 with MSA, 10 with CBS, 15 with PSP, and 35 age- and sex-matched controls. RESULTS: The mean paramacular thickness and volume were reduced in PSP while the mean RNFL did not differ significantly between groups. In PSP patients, the complex of retinal ganglion cell- and inner plexiform layer and the outer nuclear layer was reduced. In PD, the inner nuclear layer was thicker than in controls, MSA and PSP. Using the ratio between the outer nuclear layer and the outer plexiform layer with a cut-off at 3.1 and the additional constraint that the inner nuclear layer be under 46 um, we were able to differentiate PSP from PD in our patient sample with a sensitivity of 96% and a specificity of 70%. CONCLUSION: Different parkinsonian syndromes are associated with distinct changes in retinal morphology. These findings may serve to facilitate the differential diagnosis of parkinsonian syndromes and give insight into the degenerative processes of patients with atypical parkinsonian syndromes. PMID- 22514689 TI - Association of spermatogenic failure with the b2/b3 partial AZFc deletion. AB - Infertility affects around 1 in 10 men and in most cases the cause is unknown. The Y chromosome plays an important role in spermatogenesis and specific deletions of this chromosome, the AZF deletions, are associated with spermatogenic failure. Recently partial AZF deletions have been described but their association with spermatogenic failure is unclear. Here we screened a total of 339 men with idiopathic spermatogenic failure, and 256 normozoospermic ancestry-matched men for chromosome microdeletions including AZFa, AZFb, AZFc, and the AZFc partial deletions (gr/gr, b1/b3 and b2/b3).AZFa and AZFc deletions were identified in men with severe spermatogenic failure at similar frequencies to those reported elsewhere. Gr/gr deletions were identified in case and control populations at 5.83% and 6.25% respectively suggesting that these deletions are not associated with spermatogenic failure. However, b2/b3 deletions were detected only in men with spermatogenic failure and not in the normospermic individuals. Combined with our previous data this shows an association of the b2/b3 deletion (p = 0.0318) with spermatogenic failure in some populations. We recommend screening for this deletion in men with unexplained spermatogenic failure. PMID- 22514690 TI - Association of sedentary behaviour with metabolic syndrome: a meta-analysis. AB - BACKGROUND: In recent years there has been a growing interest in the relationship between sedentary behaviour (sitting) and health outcomes. Only recently have there been studies assessing the association between time spent in sedentary behaviour and the metabolic syndrome. The aim of this study is to quantify the association between sedentary behaviour and the metabolic syndrome in adults using meta-analysis. METHODOLOGY/PRINCIPAL FINDINGS: Medline, Embase and the Cochrane Library were searched using medical subject headings and key words related to sedentary behaviours and the metabolic syndrome. Reference lists of relevant articles and personal databases were hand searched. Inclusion criteria were: (1) cross sectional or prospective design; (2) include adults >= 18 years of age; (3) self-reported or objectively measured sedentary time; and (4) an outcome measure of metabolic syndrome. Odds Ratio (OR) and 95% confidence intervals for metabolic syndrome comparing the highest level of sedentary behaviour to the lowest were extracted for each study. Data were pooled using random effects models to take into account heterogeneity between studies. Ten cross-sectional studies (n = 21393 participants), one high, four moderate and five poor quality, were identified. Greater time spent sedentary increased the odds of metabolic syndrome by 73% (OR 1.73, 95% CI 1.55-1.94, p<0.0001). There were no differences for subgroups of sex, sedentary behaviour measure, metabolic syndrome definition, study quality or country income. There was no evidence of statistical heterogeneity (I(2) = 0.0%, p = 0.61) or publication bias (Eggers test t = 1.05, p = 0.32). CONCLUSIONS: People who spend higher amounts of time in sedentary behaviours have greater odds of having metabolic syndrome. Reducing sedentary behaviours is potentially important for the prevention of metabolic syndrome. PMID- 22514691 TI - Mitochondria-specific accumulation of amyloid beta induces mitochondrial dysfunction leading to apoptotic cell death. AB - Mitochondria are best known as the essential intracellular organelles that host the homeostasis required for cellular survival, but they also have relevance in diverse disease-related conditions, including Alzheimer's disease (AD). Amyloid beta (Abeta) peptide is the key molecule in AD pathogenesis, and has been highlighted in the implication of mitochondrial abnormality during the disease progress. Neuronal exposure to Abeta impairs mitochondrial dynamics and function. Furthermore, mitochondrial Abeta accumulation has been detected in the AD brain. However, the underlying mechanism of how Abeta affects mitochondrial function remains uncertain, and it is questionable whether mitochondrial Abeta accumulation followed by mitochondrial dysfunction leads directly to neuronal toxicity. This study demonstrated that an exogenous Abeta(1-42) treatment, when applied to the hippocampal cell line of mice (specifically HT22 cells), caused a deleterious alteration in mitochondria in both morphology and function. A clathrin-mediated endocytosis blocker rescued the exogenous Abeta(1-42)-mediated mitochondrial dysfunction. Furthermore, the mitochondria-targeted accumulation of Abeta(1-42) in HT22 cells using Abeta(1-42) with a mitochondria-targeting sequence induced the identical morphological alteration of mitochondria as that observed in the APP/PS AD mouse model and exogenous Abeta(1-42)-treated HT22 cells. In addition, subsequent mitochondrial dysfunctions were demonstrated in the mitochondria-specific Abeta(1-42) accumulation model, which proved indistinguishable from the mitochondrial impairment induced by exogenous Abeta(1 42)-treated HT22 cells. Finally, cellular toxicity was directly induced by mitochondria-targeted Abeta(1-42) accumulation, which mimics the apoptosis process in exogenous Abeta(1-42)-treated HT22 cells. Taken together, these results indicate that mitochondria-targeted Abeta(1-42) accumulation is the necessary and sufficient condition for Abeta-mediated mitochondria impairments, and leads directly to cellular death rather than along with other Abeta-mediated signaling alterations. PMID- 22514692 TI - MS4A1 dysregulation in asbestos-related lung squamous cell carcinoma is due to CD20 stromal lymphocyte expression. AB - Asbestos-related lung cancer accounts for 4-12% of lung cancers worldwide. We have previously identified ADAM28 as a putative oncogene involved in asbestos related lung adenocarcinoma (ARLC-AC). We hypothesised that similarly gene expression profiling of asbestos-related lung squamous cell carcinomas (ARLC-SCC) may identify candidate oncogenes for ARLC-SCC. We undertook a microarray gene expression study in 56 subjects; 26 ARLC-SCC (defined as lung asbestos body (AB) counts >20AB/gram wet weight (gww) and 30 non-asbestos related lung squamous cell carcinoma (NARLC-SCC; no detectable lung asbestos bodies; 0AB/gww). Microarray and bioinformatics analysis identified six candidate genes differentially expressed between ARLC-SCC and NARLC-SCC based on statistical significance (p<0.001) and fold change (FC) of >2-fold. Two genes MS4A1 and CARD18, were technically replicated by qRT-PCR and showed consistent directional changes. As we also found MS4A1 to be overexpressed in ARLC-ACs, we selected this gene for biological validation in independent test sets (one internal, and one external dataset (2 primary tumor sets)). MS4A1 RNA expression dysregulation was validated in the external dataset but not in our internal dataset, likely due to the small sample size in the test set as immunohistochemical (IHC) staining for MS4A1 (CD20) showed that protein expression localized predominantly to stromal lymphocytes rather than tumor cells in ARLC-SCC. We conclude that differential expression of MS4A1 in this comparative gene expression study of ARLC-SCC versus NARLC-SCC is a stromal signal of uncertain significance, and an example of the rationale for tumor cell enrichment in preparation for gene expression studies where the aim is to identify markers of particular tumor phenotypes. Finally, our study failed to identify any strong gene candidates whose expression serves as a marker of asbestos etiology. Future research is required to determine the role of stromal lymphocyte MS4A1 dysregulation in pulmonary SCCs caused by asbestos. PMID- 22514693 TI - Collaborative enhancement of antibody binding to distinct PECAM-1 epitopes modulates endothelial targeting. AB - Antibodies to platelet endothelial cell adhesion molecule-1 (PECAM-1) facilitate targeted drug delivery to endothelial cells by "vascular immunotargeting." To define the targeting quantitatively, we investigated the endothelial binding of monoclonal antibodies (mAbs) to extracellular epitopes of PECAM-1. Surprisingly, we have found in human and mouse cell culture models that the endothelial binding of PECAM-directed mAbs and scFv therapeutic fusion protein is increased by co administration of a paired mAb directed to an adjacent, yet distinct PECAM-1 epitope. This results in significant enhancement of functional activity of a PECAM-1-targeted scFv-thrombomodulin fusion protein generating therapeutic activated Protein C. The "collaborative enhancement" of mAb binding is affirmed in vivo, as manifested by enhanced pulmonary accumulation of intravenously administered radiolabeled PECAM-1 mAb when co-injected with an unlabeled paired mAb in mice. This is the first demonstration of a positive modulatory effect of endothelial binding and vascular immunotargeting provided by the simultaneous binding a paired mAb to adjacent distinct epitopes. The "collaborative enhancement" phenomenon provides a novel paradigm for optimizing the endothelial targeted delivery of therapeutic agents. PMID- 22514694 TI - 3,3'-Diindolylmethane induces G1 arrest and apoptosis in human acute T-cell lymphoblastic leukemia cells. AB - Certain bioactive food components, including indole-3-carbinol (I3C) and 3,3' diindolylmethane (DIM) from cruciferous vegetables, have been shown to target cellular pathways regulating carcinogenesis. Previously, our laboratory showed that dietary I3C is an effective transplacental chemopreventive agent in a dibenzo[def,p]chrysene (DBC)-dependent model of murine T-cell lymphoblastic lymphoma. The primary objective of the present study was to extend our chemoprevention studies in mice to an analogous human neoplasm in cell culture. Therefore, we tested the hypothesis that I3C or DIM may be chemotherapeutic in human T-cell acute lymphoblastic leukemia (T-ALL) cells. Treatment of the T-ALL cell lines CCRF-CEM, CCRF-HSB2, SUP-T1 and Jurkat with DIM in vitro significantly reduced cell proliferation and viability at concentrations 8- to 25-fold lower than the parent compound I3C. DIM (7.5 uM) arrested CEM and HSB2 cells at the G(1) phase of the cell cycle and 15 uM DIM significantly increased the percentage of apoptotic cells in all T-ALL lines. In CEM cells, DIM reduced protein expression of cyclin dependent kinases 4 and 6 (CDK4, CDK6) and D-type cyclin 3 (CCND3); DIM also significantly altered expression of eight transcripts related to human apoptosis (BCL2L10, CD40LG, HRK, TNF, TNFRSF1A, TNFRSF25, TNFSF8, TRAF4). Similar anticancer effects of DIM were observed in vivo. Dietary exposure to 100 ppm DIM significantly decreased the rate of growth of human CEM xenografts in immunodeficient SCID mice, reduced final tumor size by 44% and increased the apoptotic index compared to control-fed mice. Taken together, our results demonstrate a potential for therapeutic application of DIM in T-ALL. PMID- 22514695 TI - Complement C1 esterase inhibitor levels linked to infections and contaminated heparin-associated adverse events. AB - Activation of kinin-kallikrein and complement pathways by oversulfated chondroitin-sulfate (OSCS) has been linked with recent heparin-associated adverse clinical events. Given the fact that the majority of patients who received contaminated heparin did not experience an adverse event, it is of particular importance to determine the circumstances that increase the risk of a clinical reaction. In this study, we demonstrated by both the addition and affinity depletion of C1inh from normal human plasma, that the level of C1inh in the plasma has a great impact on the OSCS-induced kallikrein activity and its kinetics. OSCS-induced kallikrein activity was dramatically increased after C1inh was depleted, while the addition of C1inh completely attenuated kallikrein activity. In addition, actual clinical infection can lead to increased C1inh levels. Plasma from patients with sepsis had higher average levels of functional C1inh and decreased OSCS-induced kallikrein activity. Lastly, descriptive data on adverse event reports suggest cases likely to be associated with contaminated heparin are inversely correlated with infection. Our data suggest that low C1inh levels can be a risk factor and high levels can be protective. The identification of risk factors for contact system-mediated adverse events may allow for patient screening and clinical development of prophylaxis and treatments. PMID- 22514696 TI - Tibial loading increases osteogenic gene expression and cortical bone volume in mature and middle-aged mice. AB - There are conflicting data on whether age reduces the response of the skeleton to mechanical stimuli. We examined this question in female BALB/c mice of different ages, ranging from young to middle-aged (2, 4, 7, 12 months). We first assessed markers of bone turnover in control (non-loaded) mice. Serum osteocalcin and CTX declined significantly from 2 to 4 months (p<0.001). There were similar age related declines in tibial mRNA expression of osteoblast- and osteoclast-related genes, most notably in late osteoblast/matrix genes. For example, Col1a1 expression declined 90% from 2 to 7 months (p<0.001). We then assessed tibial responses to mechanical loading using age-specific forces to produce similar peak strains (-1300 uepsilon endocortical; -2350 uepsilon periosteal). Axial tibial compression was applied to the right leg for 60 cycles/day on alternate days for 1 or 6 weeks. qPCR after 1 week revealed no effect of loading in young (2-month) mice, but significant increases in osteoblast/matrix genes in older mice. For example, in 12-month old mice Col1a1 was increased 6-fold in loaded tibias vs. controls (p = 0.001). In vivo microCT after 6 weeks revealed that loaded tibias in each age group had greater cortical bone volume (BV) than contralateral control tibias (p<0.05), due to relative periosteal expansion. The loading induced increase in cortical BV was greatest in 4-month old mice (+13%; p<0.05 vs. other ages). In summary, non-loaded female BALB/c mice exhibit an age-related decline in measures related to bone formation. Yet when subjected to tibial compression, mice from 2-12 months have an increase in cortical bone volume. Older mice respond with an upregulation of osteoblast/matrix genes, which increase to levels comparable to young mice. We conclude that mechanical loading of the tibia is anabolic for cortical bone in young and middle-aged female BALB/c mice. PMID- 22514697 TI - Discovery and genomic characterization of a novel bat sapovirus with unusual genomic features and phylogenetic position. AB - Sapovirus is a genus of caliciviruses that are known to cause enteric disease in humans and animals. There is considerable genetic diversity among the sapoviruses, which are classified into different genogroups based on phylogenetic analysis of the full-length capsid protein sequence. While several mammalian species, including humans, pigs, minks, and dogs, have been identified as animal hosts for sapoviruses, there were no reports of sapoviruses in bats in spite of their biological diversity. In this report, we present the results of a targeted surveillance study in different bat species in Hong Kong. Five of the 321 specimens from the bat species, Hipposideros pomona, were found to be positive for sapoviruses by RT-PCR. Complete or nearly full-length genome sequences of approximately 7.7 kb in length were obtained for three strains, which showed similar organization of the genome compared to other sapoviruses. Interestingly, they possess many genomic features atypical of most sapoviruses, like high G+C content and minimal CpG suppression. Phylogenetic analysis of the viral proteins suggested that the bat sapovirus descended from an ancestral sapovirus lineage and is most closely related to the porcine sapoviruses. Codon usage analysis showed that the bat sapovirus genome has greater codon usage bias relative to other sapovirus genomes. In summary, we report the discovery and genomic characterization of the first bat calicivirus, which appears to have evolved under different conditions after early divergence from other sapovirus lineages. PMID- 22514698 TI - Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. AB - Cancer cells acquire drug resistance via various mechanisms including enhanced cellular cytoprotective and antioxidant activities. Heme oxygenase-1 (HO-1) is a key enzyme exerting potent cytoprotection, cell proliferation and drug resistance. We aimed to investigate roles of HO-1 in human cholangiocarcinoma (CCA) cells for cytoprotection against chemotherapeutic agents. KKU-100 and KKU M214 CCA cell lines with high and low HO-1 expression levels, respectively, were used to evaluate the sensitivity to chemotherapeutic agents, gemcitabine (Gem) and doxorubicin. Inhibition of HO-1 by zinc protoporphyrin IX (ZnPP) sensitized both cell types to the cytotoxicity of chemotherapeutic agents. HO-1 gene silencing by siRNA validated the cytoprotective effect of HO-1 on CCA cells against Gem. Induction of HO-1 protein expression by stannous chloride enhanced the cytoprotection and suppression of apoptosis caused by anticancer agents. The sensitizing effect of ZnPP was associated with increased ROS formation and loss of mitochondrial transmembrane potential, while Gem alone did not show any effects. A ROS scavenger, Tempol, abolished the sensitizing effect of ZnPP on Gem. Combination of ZnPP and Gem enhanced the release of cytochrome c and increased p21 levels. The results show that HO-1 played a critical role in cytoprotection in CCA cells against chemotherapeutic agents. Targeted inhibition of HO-1 may be a strategy to overcome drug resistance in chemotherapy of bile duct cancer. PMID- 22514699 TI - Two homologous putative protein tyrosine phosphatases, OsPFA-DSP2 and AtPFA-DSP4, negatively regulate the pathogen response in transgenic plants. AB - Protein phosphatases, together with protein kinases, regulate protein phosphorylation and dephosphorylation, and play critical roles in plant growth and biotic stress responses. However, little is known about the biological functions of plant protein tyrosine dual-specificity phosphatase (PFA-DSP) in biotic stresses. Here, we found that OsPFA-DSP2 was mainly expressed in calli, seedlings, roots, and young panicles, and localized in cytoplasm and nucleus. Ectopic overexpression of OsPFA-DSP2 in rice increased sensitivity to Magnaporthe grisea (M. grisea Z1 strain), inhibited the accumulation of hydrogen peroxide (H(2)O(2)) and suppressed the expression of pathogenesis-related (PR) genes after fungal infection. Interestingly, transgenic Arabidopsis plants overexpressing AtPFA-DSP4, which is homologous to OsPFA-DSP2, also exhibited sensitivity to Pseudomonas syringae pv. tomato DC3000 (Pst DC3000), reduced accumulation of H(2)O(2) and decreased photosynthesic capacity after infection compared with Col 0. These results indicate that OsPFA-DSP2 and AtPFA-DSP4 act as negative regulators of the pathogen response in transgenic plants. PMID- 22514700 TI - Identification of BC005512 as a DNA damage responsive murine endogenous retrovirus of GLN family involved in cell growth regulation. AB - Genotoxicity assessment is of great significance in drug safety evaluation, and microarray is a useful tool widely used to identify genotoxic stress responsive genes. In the present work, by using oligonucleotide microarray in an in vivo model, we identified an unknown gene BC005512 (abbreviated as BC, official full name: cDNA sequence BC005512), whose expression in mouse liver was specifically induced by seven well-known genotoxins (GTXs), but not by non-genotoxins (NGTXs). Bioinformatics revealed that BC was a member of the GLN family of murine endogenous retrovirus (ERV). However, the relationship to genotoxicity and the cellular function of GLN are largely unknown. Using NIH/3T3 cells as an in vitro model system and quantitative real-time PCR, BC expression was specifically induced by another seven GTXs, covering diverse genotoxicity mechanisms. Additionally, dose-response and linear regression analysis showed that expression level of BC in NIH/3T3 cells strongly correlated with DNA damage, measured using the alkaline comet assay,. While in p53 deficient L5178Y cells, GTXs could not induce BC expression. Further functional studies using RNA interference revealed that down-regulation of BC expression induced G1/S phase arrest, inhibited cell proliferation and thus suppressed cell growth in NIH/3T3 cells. Together, our results provide the first evidence that BC005512, a member from GLN family of murine ERV, was responsive to DNA damage and involved in cell growth regulation. These findings could be of great value in genotoxicity predictions and contribute to a deeper understanding of GLN biological functions. PMID- 22514701 TI - Comparative transcriptional network modeling of three PPAR-alpha/gamma co agonists reveals distinct metabolic gene signatures in primary human hepatocytes. AB - AIMS: To compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR)-alpha/gamma agonist, aleglitazar, with tesaglitazar (a dual PPAR-alpha/gamma agonist) or a combination of pioglitazone (Pio; PPAR-gamma agonist) and fenofibrate (Feno; PPAR-alpha agonist) in human hepatocytes. METHODS AND RESULTS: Gene expression microarray profiles were obtained from primary human hepatocytes treated with EC(50)-aligned low, medium and high concentrations of the three treatments. A systems biology approach, Causal Network Modeling, was used to model the data to infer upstream molecular mechanisms that may explain the observed changes in gene expression. Aleglitazar, tesaglitazar and Pio/Feno each induced unique transcriptional signatures, despite comparable core PPAR signaling. Although all treatments inferred qualitatively similar PPAR-alpha signaling, aleglitazar was inferred to have greater effects on high- and low-density lipoprotein cholesterol levels than tesaglitazar and Pio/Feno, due to a greater number of gene expression changes in pathways related to high-density and low-density lipoprotein metabolism. Distinct transcriptional and biologic signatures were also inferred for stress responses, which appeared to be less affected by aleglitazar than the comparators. In particular, Pio/Feno was inferred to increase NFE2L2 activity, a key component of the stress response pathway, while aleglitazar had no significant effect. All treatments were inferred to decrease proliferative signaling. CONCLUSIONS: Aleglitazar induces transcriptional signatures related to lipid parameters and stress responses that are unique from other dual PPAR-alpha/gamma treatments. This may underlie observed favorable changes in lipid profiles in animal and clinical studies with aleglitazar and suggests a differentiated gene profile compared with other dual PPAR-alpha/gamma agonist treatments. PMID- 22514702 TI - Activity of clinically relevant antimalarial drugs on Plasmodium falciparum mature gametocytes in an ATP bioluminescence "transmission blocking" assay. AB - BACKGROUND: Current anti-malarial drugs have been selected on the basis of their activity against the symptom-causing asexual blood stage of the parasite. Which of these drugs also target gametocytes, in the sexual stage responsible for disease transmission, remains unknown. Blocking transmission is one of the main strategies in the eradication agenda and requires the identification of new molecules that are active against gametocytes. However, to date, the main limitation for measuring the effect of molecules against mature gametocytes on a large scale is the lack of a standardized and reliable method. Here we provide an efficient method to produce and purify mature gametocytes in vitro. Based on this new procedure, we developed a robust, affordable, and sensitive ATP bioluminescence-based assay. We then assessed the activity of 17 gold-standard anti-malarial drugs on Plasmodium late stage gametocytes. METHODS AND FINDINGS: Difficulties in producing large amounts of gametocytes have limited progress in the development of malaria transmission blocking assays. We improved the method established by Ifediba and Vanderberg to obtain viable, mature gametocytes en masse, whatever the strain used. We designed an assay to determine the activity of antimalarial drugs based on the intracellular ATP content of purified stage IV V gametocytes after 48 h of drug exposure in 96/384-well microplates. Measurements of drug activity on asexual stages and cytotoxicity on HepG2 cells were also obtained to estimate the specificity of the active drugs. CONCLUSIONS: The work described here represents another significant step towards determination of the activity of new molecules on mature gametocytes of any strain with an automated assay suitable for medium/high-throughput screening. Considering that the biology of the forms involved in the sexual and asexual stages is very different, a screen of our 2 million-compound library may allow us to discover novel anti-malarial drugs to target gametocyte-specific metabolic pathways. PMID- 22514704 TI - Categorial compositionality III: F-(co)algebras and the systematicity of recursive capacities in human cognition. AB - Human cognitive capacity includes recursively definable concepts, which are prevalent in domains involving lists, numbers, and languages. Cognitive science currently lacks a satisfactory explanation for the systematic nature of such capacities (i.e., why the capacity for some recursive cognitive abilities-e.g., finding the smallest number in a list-implies the capacity for certain others finding the largest number, given knowledge of number order). The category theoretic constructs of initial F-algebra, catamorphism, and their duals, final coalgebra and anamorphism provide a formal, systematic treatment of recursion in computer science. Here, we use this formalism to explain the systematicity of recursive cognitive capacities without ad hoc assumptions (i.e., to the same explanatory standard used in our account of systematicity for non-recursive capacities). The presence of an initial algebra/final coalgebra explains systematicity because all recursive cognitive capacities, in the domain of interest, factor through (are composed of) the same component process. Moreover, this factorization is unique, hence no further (ad hoc) assumptions are required to establish the intrinsic connection between members of a group of systematically-related capacities. This formulation also provides a new perspective on the relationship between recursive cognitive capacities. In particular, the link between number and language does not depend on recursion, as such, but on the underlying functor on which the group of recursive capacities is based. Thus, many species (and infants) can employ recursive processes without having a full-blown capacity for number and language. PMID- 22514703 TI - Complete mitochondrial genome sequencing reveals novel haplotypes in a Polynesian population. AB - The high risk of metabolic disease traits in Polynesians may be partly explained by elevated prevalence of genetic variants involved in energy metabolism. The genetics of Polynesian populations has been shaped by island hoping migration events which have possibly favoured thrifty genes. The aim of this study was to sequence the mitochondrial genome in a group of Maoris in an effort to characterise genome variation in this Polynesian population for use in future disease association studies. We sequenced the complete mitochondrial genomes of 20 non-admixed Maori subjects using Affymetrix technology. DNA diversity analyses showed the Maori group exhibited reduced mitochondrial genome diversity compared to other worldwide populations, which is consistent with historical bottleneck and founder effects. Global phylogenetic analysis positioned these Maori subjects specifically within mitochondrial haplogroup--B4a1a1. Interestingly, we identified several novel variants that collectively form new and unique Maori motifs--B4a1a1c, B4a1a1a3 and B4a1a1a5. Compared to ancestral populations we observed an increased frequency of non-synonymous coding variants of several mitochondrial genes in the Maori group, which may be a result of positive selection and/or genetic drift effects. In conclusion, this study reports the first complete mitochondrial genome sequence data for a Maori population. Overall, these new data reveal novel mitochondrial genome signatures in this Polynesian population and enhance the phylogenetic picture of maternal ancestry in Oceania. The increased frequency of several mitochondrial coding variants makes them good candidates for future studies aimed at assessment of metabolic disease risk in Polynesian populations. PMID- 22514705 TI - Waterfowl: potential environmental reservoirs of the chytrid fungus Batrachochytrium dendrobatidis. AB - Infections with Batrachochytrium dendrobatidis (B. dendrobatidis), the causal agent of chytridiomycosis, have been shown to play an important role in the decline of amphibians worldwide. Spread of the fungus is poorly understood. Bird movement might possibly contribute to the spread of B. dendrobatidis in the environment. Therefore, 397 wild geese in Belgium were screened for presence of B. dendrobatidis on their toes using real-time quantitative PCR (qPCR). In addition, chemotaxis towards, adhesion, survival after desiccation and proliferation of B. dendrobatidis on keratinous toe scales from waterfowl were examined in vitro. qPCR revealed that 76 geese (15%) were positive for B. dendrobatidis. Results of the in vitro tests showed that B. dendrobatidis is attracted to the keratinous toes of aquatic birds on which they can adhere and even proliferate. However, desiccation is poorly tolerated. This suggests waterfowl are potential environmental reservoirs for B. dendrobatidis. PMID- 22514706 TI - Heterogeneous glycation of cancellous bone and its association with bone quality and fragility. AB - Non-enzymatic glycation (NEG) and enzymatic biochemical processes create crosslinks that modify the extracellular matrix (ECM) and affect the turnover of bone tissue. Because NEG affects turnover and turnover at the local level affects microarchitecture and formation and removal of microdamage, we hypothesized that NEG in cancellous bone is heterogeneous and accounts partly for the contribution of microarchitecture and microdamage on bone fragility. Human trabecular bone cores from 23 donors were subjected to compression tests. Mechanically tested cores as well as an additional 19 cores were stained with lead-uranyl acetate and imaged to determine microarchitecture and measure microdamage. Post-yield mechanical properties were measured and damaged trabeculae were extracted from a subset of specimens and characterized for the morphology of induced microdamage. Tested specimens and extracted trabeculae were quantified for enzymatic and non enzymatic crosslink content using a colorimetric assay and Ultra-high Performance Liquid Chromatography (UPLC). Results show that an increase in enzymatic crosslinks was beneficial for bone where they were associated with increased toughness and decreased microdamage. Conversely, bone with increased NEG required less strain to reach failure and were less tough. NEG heterogeneously modified trabecular microarchitecture where high amounts of NEG crosslinks were found in trabecular rods and with the mechanically deleterious form of microdamage (linear microcracks). The extent of NEG in tibial cancellous bone was the dominant predictor of bone fragility and was associated with changes in microarchitecture and microdamage. PMID- 22514707 TI - Aragonite precipitation by "proto-polyps" in coral cell cultures. AB - The mechanisms of coral calcification at the molecular, cellular and tissue levels are poorly understood. In this study, we examine calcium carbonate precipitation using novel coral tissue cultures that aggregate to form "proto polyps". Our goal is to establish an experimental system in which calcification is facilitated at the cellular level, while simultaneously allowing in vitro manipulations of the calcifying fluid. This novel coral culturing technique enables us to study the mechanisms of biomineralization and their implications for geochemical proxies. Viable cell cultures of the hermatypic, zooxanthellate coral, Stylophora pistillata, have been maintained for 6 to 8 weeks. Using an enriched seawater medium with aragonite saturation state similar to open ocean surface waters (Omega(arag)~4), the primary cell cultures assemble into "proto polyps" which form an extracellular organic matrix (ECM) and precipitate aragonite crystals. These extracellular aragonite crystals, about 10 um in length, are formed on the external face of the proto-polyps and are identified by their distinctive elongated crystallography and X-ray diffraction pattern. The precipitation of aragonite is independent of photosynthesis by the zooxanthellae, and does not occur in control experiments lacking coral cells or when the coral cells are poisoned with sodium azide. Our results demonstrate that proto-polyps, aggregated from primary coral tissue culture, function (from a biomineralization perspective) similarly to whole corals. This approach provides a novel tool for investigating the biophysical mechanism of calcification in these organisms. PMID- 22514708 TI - Micro-Raman spectroscopy of silver nanoparticle induced stress on optically trapped stem cells. AB - We report here results of a single-cell Raman spectroscopy study of stress effects induced by silver nanoparticles in human mesenchymal stem cells (hMSCs). A high-sensitivity, high-resolution Raman Tweezers set-up has been used to monitor nanoparticle-induced biochemical changes in optically-trapped single cells. Our micro-Raman spectroscopic study reveals that hMSCs treated with silver nanoparticles undergo oxidative stress at doping levels in excess of 2 ug/ml, with results of a statistical analysis of Raman spectra suggesting that the induced stress becomes more dominant at nanoparticle concentration levels above 3 ug/ml. PMID- 22514709 TI - Alteration of proteins and pigments influence the function of photosystem I under iron deficiency from Chlamydomonas reinhardtii. AB - BACKGROUND: Iron is an essential micronutrient for all organisms because it is a component of enzyme cofactors that catalyze redox reactions in fundamental metabolic processes. Even though iron is abundant on earth, it is often present in the insoluble ferric [Fe (III)] state, leaving many surface environments Fe limited. The haploid green alga Chlamydomonas reinhardtii is used as a model organism for studying eukaryotic photosynthesis. This study explores structural and functional changes in PSI-LHCI supercomplexes under Fe deficiency as the eukaryotic photosynthetic apparatus adapts to Fe deficiency. RESULTS: 77K emission spectra and sucrose density gradient data show that PSI and LHCI subunits are affected under iron deficiency conditions. The visible circular dichroism (CD) spectra associated with strongly-coupled chlorophyll dimers increases in intensity. The change in CD signals of pigments originates from the modification of interactions between pigment molecules. Evidence from sucrose gradients and non-denaturing (green) gels indicates that PSI-LHCI levels were reduced after cells were grown for 72 h in Fe-deficient medium. Ultrafast fluorescence spectroscopy suggests that red-shifted pigments in the PSI-LHCI antenna were lost during Fe stress. Further, denaturing gel electrophoresis and immunoblot analysis reveals that levels of the PSI subunits PsaC and PsaD decreased, while PsaE was completely absent after Fe stress. The light harvesting complexes were also susceptible to iron deficiency, with Lhca1 and Lhca9 showing the most dramatic decreases. These changes in the number and composition of PSI LHCI supercomplexes may be caused by reactive oxygen species, which increase under Fe deficiency conditions. CONCLUSIONS: Fe deficiency induces rapid reduction of the levels of photosynthetic pigments due to a decrease in chlorophyll synthesis. Chlorophyll is important not only as a light-harvesting pigment, but also has a structural role, particularly in the pigment-rich LHCI subunits. The reduced level of chlorophyll molecules inhibits the formation of large PSI-LHCI supercomplexes, further decreasing the photosynthetic efficiency. PMID- 22514710 TI - Acute activation of AMP-activated protein kinase prevents H2O2-induced premature senescence in primary human keratinocytes. AB - We investigated the effects of AMPK on H(2)O(2)-induced premature senescence in primary human keratinocytes. Incubation with 50 uM H(2)O(2) for 2 h resulted in premature senescence with characteristic increases in senescence-associated beta galactosidase (SA-gal) staining 3 days later and no changes in AMPK or p38 MAPK activity. The increase in SA-gal staining was preceded by increases in both p53 phosphorylation (S15) (1 h) and transactivation (6 h) and the abundance of the cyclin inhibitor p21(CIP1) (16 h). Incubation with AICAR or resveratrol, both of which activated AMPK, prevented the H(2)O(2)-induced increases in both SA-Gal staining and p21 abundance. In addition, AICAR diminished the increase in p53 transactivation. The decreases in SA-Gal expression induced by resveratrol and AICAR were prevented by the pharmacological AMPK inhibitor Compound C, expression of a DN-AMPK or AMPK knock-down with shRNA. Likewise, both knockdown of AMPK and expression of DN-AMPK were sufficient to induce senescence, even in the absence of exogenous H(2)O(2). As reported by others, we found that AMPK activation by itself increased p53 phosphorylation at S15 in embryonic fibroblasts (MEF), whereas under the same conditions it decreased p53 phosphorylation in the keratinocytes, human aortic endothelial cells, and human HT1080 fibrosarcoma cells. In conclusion, the results indicate that H(2)O(2) at low concentrations causes premature senescence in human keratinocytes by activating p53-p21(CIP1) signaling and that these effects can be prevented by acute AMPK activation and enhanced by AMPK downregulation. They also suggest that this action of AMPK may be cell or context-specific. PMID- 22514711 TI - Comparative study on the therapeutic potential of neurally differentiated stem cells in a mouse model of multiple sclerosis. AB - BACKGROUND: Transplantation of neural stem cells (NSCs) is a promising novel approach to the treatment of neuroinflammatory diseases such as multiple sclerosis (MS). NSCs can be derived from primary central nervous system (CNS) tissue or obtained by neural differentiation of embryonic stem (ES) cells, the latter having the advantage of readily providing an unlimited number of cells for therapeutic purposes. Using a mouse model of MS, we evaluated the therapeutic potential of NSCs derived from ES cells by two different neural differentiation protocols that utilized adherent culture conditions and compared their effect to primary NSCs derived from the subventricular zone (SVZ). METHODOLOGY/PRINCIPAL FINDINGS: The proliferation and secretion of pro-inflammatory cytokines by antigen-stimulated splenocytes was reduced in the presence of SVZ-NSCs, while ES cell-derived NSCs exerted differential immunosuppressive effects. Surprisingly, intravenously injected NSCs displayed no significant therapeutic impact on clinical and pathological disease outcomes in mice with experimental autoimmune encephalomyelitis (EAE) induced by recombinant myelin oligodendrocyte glycoprotein, independent of the cell source. Studies tracking the biodistribution of transplanted ES cell-derived NSCs revealed that these cells were unable to traffic to the CNS or peripheral lymphoid tissues, consistent with the lack of cell surface homing molecules. Attenuation of peripheral immune responses could only be achieved through multiple high doses of NSCs administered intraperitoneally, which led to some neuroprotective effects within the CNS. CONCLUSION/SIGNIFICANCE: Systemic transplantation of these NSCs does not have a major influence on the clinical course of rMOG-induced EAE. Improving the efficiency at which NSCs home to inflammatory sites may enhance their therapeutic potential in this model of CNS autoimmunity. PMID- 22514712 TI - Gremlin-1 induces BMP-independent tumor cell proliferation, migration, and invasion. AB - Gremlin-1, a bone morphogenetic protein (BMP) antagonist, is overexpressed in various cancerous tissues but its role in carcinogenesis has not been established. Here, we report that gremlin-1 binds various cancer cell lines and this interaction is inhibited by our newly developed gremlin-1 antibody, GRE1. Gremlin-1 binding to cancer cells was unaffected by the presence of BMP-2, BMP-4, and BMP-7. In addition, the binding was independent of vascular endothelial growth factor receptor-2 (VEGFR2) expression on the cell surface. Addition of gremlin-1 to A549 cells induced a fibroblast-like morphology and decreased E cadherin expression. In a scratch wound healing assay, A549 cells incubated with gremlin-1 or transfected with gremlin-1 showed increased migration, which was inhibited in the presence of the GRE1 antibody. Gremlin-1 transfected A549 cells also exhibited increased invasiveness as well as an increased growth rate. These effects were also inhibited by the addition of the GRE1 antibody. In conclusion, this study demonstrates that gremlin-1 directly interacts with cancer cells in a BMP- and VEGFR2-independent manner and can induce cell migration, invasion, and proliferation. PMID- 22514713 TI - Artemisinin attenuates lipopolysaccharide-stimulated proinflammatory responses by inhibiting NF-kappaB pathway in microglia cells. AB - Microglial activation plays an important role in neuroinflammation, which contributes to neuronal damage, and inhibition of microglial activation may have therapeutic benefits that could alleviate the progression of neurodegeneration. Recent studies have indicated that the antimalarial agent artemisinin has the ability to inhibit NF-kappaB activation. In this study, the inhibitory effects of artemisinin on the production of proinflammatory mediators were investigated in lipopolysaccharide (LPS)-stimulated primary microglia. Our results show that artemisinin significantly inhibited LPS-induced production of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1) and nitric oxide (NO). Artemisinin significantly decreased both the mRNA and the protein levels of these pro-inflammatory cytokines and inducible nitric oxide synthase (iNOS) and increased the protein levels of IkappaB-alpha, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. Artemisinin treatment significantly inhibited basal and LPS-induced migration of BV-2 microglia. Electrophoretic mobility shift assays revealed increased NF kappaB binding activity in LPS-stimulated primary microglia, and this increase could be prevented by artemisinin. The inhibitory effects of artemisinin on LPS stimulated microglia were blocked after IkappaB-alpha was silenced with IkappaB alpha siRNA. Our results suggest that artemisinin is able to inhibit neuroinflammation by interfering with NF-kappaB signaling. The data provide direct evidence of the potential application of artemisinin for the treatment of neuroinflammatory diseases. PMID- 22514714 TI - Breast cancer cells induce stromal fibroblasts to secrete ADAMTS1 for cancer invasion through an epigenetic change. AB - Microenvironment plays an important role in cancer development. We have reported that the cancer-associated stromal cells exhibit phenotypic and functional changes compared to stromal cells neighboring to normal tissues. However, the molecular mechanisms as well as the maintenance of these changes remain elusive. Here we showed that through co-culture with breast cancer cells for at least three to four passages, breast normal tissue-associated fibroblasts (NAFs) gained persistent activity for promoting cancer cell invasion, partly via up-regulating ADAM metallopeptidase with thrombospondin type 1 motif, 1 (ADAMTS1). Furthermore, we demonstrated that the DNA methylation pattern in the ADAMTS1 promoter has no alteration. Instead, the loss of EZH2 binding to the ADAMTS1 promoter and the resulting decrease of promoter-associated histone H3K27 methylation may account for the up-regulation of ADAMTS1. Importantly, the lack of EZH2 binding and the H3K27 methylation on the ADAMTS1 promoter were sustained in cancer cell precocultured NAFs after removal of cancer cells. These results suggest that cancer cells are capable of inducing stromal fibroblasts to secrete ADAMTS1 persistently for their invasion and the effect is epigenetically inheritable. PMID- 22514715 TI - Testicular development in mice lacking receptors for follicle stimulating hormone and androgen. AB - Post-natal testicular development is dependent on gonadotrophin and androgen stimulation. Follicle stimulating hormone (FSH) acts through receptors (FSHR) on the Sertoli cell to stimulate spermatogenesis while androgens promote testis growth through receptors (AR) on the Sertoli cells, Leydig cells and peritubular myoid cells. In this study we have examined the effects on testis development of ablating FSHRs (FSHRKO mice) and/or ARs ubiquitously (ARKO mice) or specifically on the Sertoli cells (SCARKO mice). Cell numbers were measured using stereological methods. In ARKO mice Sertoli cell numbers were reduced at all ages from birth until adulthood. FSHR ablation also caused small reductions in Sertoli cell numbers up to day 20 with more marked effects seen in the adult. Germ cell numbers were unaffected by FSHR and/or AR ablation at birth. By day 20 ubiquitous AR or FSHR ablation caused a marked reduction in germ cell numbers with a synergistic effect of losing both receptors (germ cell numbers in FSHRKO.ARKO mice were 3% of control). Germ cell numbers in SCARKO mice were less affected. By adulthood, in contrast, clear synergistic control of germ cell numbers had become established between the actions of FSH and androgen through the Sertoli cells. Leydig cell numbers were normal on day 1 and day 5 in all groups. By day 20 and in adult animals total AR or FSHR ablation significantly reduced Leydig cell numbers but Sertoli cell specific AR ablation had no effect. Results show that, prior to puberty, development of most testicular parameters is more dependent on FSH action than androgen action mediated through the Sertoli cells although androgen action through other cells types is crucial. Post-pubertally, germ cell numbers and spermatogenesis are dependent on FSH and androgen action through the Sertoli cells. PMID- 22514716 TI - Characterization of common carp transcriptome: sequencing, de novo assembly, annotation and comparative genomics. AB - BACKGROUND: Common carp (Cyprinus carpio) is one of the most important aquaculture species of Cyprinidae with an annual global production of 3.4 million tons, accounting for nearly 14% of the freshwater aquaculture production in the world. Due to the economical and ecological importance of common carp, genomic data are eagerly needed for genetic improvement purpose. However, there is still no sufficient transcriptome data available. The objective of the project is to sequence transcriptome deeply and provide well-assembled transcriptome sequences to common carp research community. RESULT: Transcriptome sequencing of common carp was performed using Roche 454 platform. A total of 1,418,591 clean ESTs were collected and assembled into 36,811 cDNA contigs, with average length of 888 bp and N50 length of 1,002 bp. Annotation was performed and a total of 19,165 unique proteins were identified from assembled contigs. Gene ontology and KEGG analysis were performed and classified all contigs into functional categories for understanding gene functions and regulation pathways. Open Reading Frames (ORFs) were detected from 29,869 (81.1%) contigs with an average ORF length of 763 bp. From these contigs, 9,625 full-length cDNAs were identified with sequence length from 201 bp to 9,956 bp. Comparative analysis revealed that 27,693(75.2%) contigs have significant similarity to zebrafish Refseq proteins, and 24,371(66.2%), 24,501(66.5%) and 25,025(70.0%) to teraodon, medaka and three-spined stickleback refseq proteins. A total of 2,064 microsatellites were initially identified from 1,730 contigs, and 1,639 unique sequences had sufficient flanking sequences on both sides for primer design. CONCLUSION: The transcriptome of common carp had been deep sequenced, de novo assembled and characterized, providing the valuable resource for better understanding of common carp genome. The transcriptome data will facilitate future functional studies on common carp genome, and gradually apply in breeding programs of common carp, as well as closely related other Cyprinids. PMID- 22514717 TI - Prognostic significance of miR-205 in endometrial cancer. AB - PURPOSE: microRNAs have emerged as key regulators of gene expression, and their altered expression has been associated with tumorigenesis and tumor progression. Thus, microRNAs have potential as both cancer biomarkers and/or potential novel therapeutic targets. Although accumulating evidence suggests the role of aberrant microRNA expression in endometrial carcinogenesis, there are still limited data available about the prognostic significance of microRNAs in endometrial cancer. The goal of this study is to investigate the prognostic value of selected key microRNAs in endometrial cancer by the analysis of archival formalin-fixed paraffin-embedded tissues. EXPERIMENTAL DESIGN: Total RNAs were extracted from 48 paired normal and endometrial tumor specimens using Trizol based approach. The expression of miR-26a, let-7g, miR-21, miR-181b, miR-200c, miR-192, miR-215, miR 200c, and miR-205 were quantified by real time qRT-PCR expression analysis. Targets of the differentially expressed miRNAs were quantified using immunohistochemistry. Statistical analysis was performed by GraphPad Prism 5.0. RESULTS: The expression levels of miR-200c (P<0.0001) and miR-205 (P<0.0001) were significantly increased in endometrial tumors compared to normal tissues. Kaplan Meier survival analysis revealed that high levels of miR-205 expression were associated with poor patient overall survival (hazard ratio, 0.377; Logrank test, P = 0.028). Furthermore, decreased expression of a miR-205 target PTEN was detected in endometrial cancer tissues compared to normal tissues. CONCLUSION: miR-205 holds a unique potential as a prognostic biomarker in endometrial cancer. PMID- 22514718 TI - Optimal design of intervention studies to prevent influenza in healthy cohorts. AB - BACKGROUND: Influenza cohort studies, in which participants are monitored for infection over an epidemic period, are invaluable in assessing the effectiveness of control measures such as vaccination, antiviral prophylaxis and non pharmaceutical interventions (NPIs). Influenza infections and illnesses can be identified through a number of approaches with different costs and logistical requirements. METHODOLOGY AND PRINCIPAL FINDINGS: In the context of a randomized controlled trial of an NPI with a constrained budget, we used a simulation approach to examine which approaches to measuring outcomes could provide greater statistical power to identify an effective intervention against confirmed influenza. We found that for a short epidemic season, the optimal design was to collect respiratory specimens at biweekly intervals, as well as following report of acute respiratory illness (ARI), for virologic testing by reverse transcription polymerase chain reaction (RT-PCR). Collection of respiratory specimens only from individuals reporting ARI was also an efficient design particularly for studies in settings with longer periods of influenza activity. Collection of specimens only from individuals reporting a febrile ARI was less efficient. Collection and testing of sera before and after influenza activity appeared to be inferior to collection of respiratory specimens for RT-PCR confirmation of acute infections. The performance of RT-PCR was robust to uncertainty in the costs and diagnostic performance of RT-PCR and serological tests. CONCLUSIONS AND SIGNIFICANCE: Our results suggest that unless the sensitivity or specificity of serology can be increased RT-PCR will remain as the preferable outcome measure in NPI studies. Routine collection of specimens for RT PCR testing even when study participants do not report acute respiratory illness appears to be the most cost efficient design under most scenarios. PMID- 22514719 TI - Oval cell response is attenuated by depletion of liver resident macrophages in the 2-AAF/partial hepatectomy rat. AB - BACKGROUND/AIMS: Macrophages are known to play an important role in hepatocyte mediated liver regeneration by secreting inflammatory mediators. However, there is little information available on the role of resident macrophages in oval cell mediated liver regeneration. In the present study we aimed to investigate the role of macrophages in oval cell expansion induced by 2 acetylaminofluorene/partial hepatectomy (2-AAF/PH) in rats. METHODOLOGY/PRINCIPAL FINDINGS: We depleted macrophages in the liver of 2-AAF/PH treated rats by injecting liposome encapsulated clodronate 48 hours before PH. Regeneration of remnant liver mass, as well as proliferation and differentiation of oval cells were measured. We found that macrophage-depleted rats suffered higher mortality and liver transaminase levels. We also showed that depletion of macrophages yielded a significant decrease of EPCAM and PCK positive oval cells in immunohistochemical stained liver sections 9 days after PH. Meanwhile, oval cell differentiation was also attenuated as a result of macrophage depletion, as large foci of small basophilic hepatocytes were observed by day 9 following hepatectomy in control rats whereas they were almost absent in macrophage depleted rats. Accordingly, real-time polymerase chain reaction analysis showed lower expression of albumin mRNA in macrophage depleted livers. Then we assessed whether macrophage depletion may affect hepatic production of stimulating cytokines for liver regeneration. We showed that macrophage-depletion significantly inhibited hepatic expression of tumor necrosis factor-alpha and interleukin-6, along with a lack of signal transducer and activator of transcription 3 phosphorylation during the early period following hepatectomy. CONCLUSIONS: These data indicate that macrophages play an important role in oval cell mediated liver regeneration in the 2-AAF/PH model. PMID- 22514720 TI - Role of active site rigidity in activity: MD simulation and fluorescence study on a lipase mutant. AB - Relationship between stability and activity of enzymes is maintained by underlying conformational flexibility. In thermophilic enzymes, a decrease in flexibility causes low enzyme activity while in less stable proteins such as mesophiles and psychrophiles, an increase in flexibility is associated with enhanced enzyme activity. Recently, we identified a mutant of a lipase whose stability and activity were enhanced simultaneously. In this work, we probed the conformational dynamics of the mutant and the wild type lipase, particularly flexibility of their active site using molecular dynamic simulations and time resolved fluorescence techniques. In contrast to the earlier observations, our data show that active site of the mutant is more rigid than wild type enzyme. Further investigation suggests that this lipase needs minimal reorganization/flexibility of active site residues during its catalytic cycle. Molecular dynamic simulations suggest that catalytically competent active site geometry of the mutant is relatively more preserved than wild type lipase, which might have led to its higher enzyme activity. Our study implies that widely accepted positive correlation between conformation flexibility and enzyme activity need not be stringent and draws attention to the possibility that high enzyme activity can still be accomplished in a rigid active site and stable protein structures. This finding has a significant implication towards better understanding of involvement of dynamic motions in enzyme catalysis and enzyme engineering through mutations in active site. PMID- 22514721 TI - Fast, multiphase volume adaptation to hyperosmotic shock by Escherichia coli. AB - All living cells employ an array of different mechanisms to help them survive changes in extra cellular osmotic pressure. The difference in the concentration of chemicals in a bacterium's cytoplasm and the external environment generates an osmotic pressure that inflates the cell. It is thought that the bacterium Escherichia coli use a number of interconnected systems to adapt to changes in external pressure, allowing them to maintain turgor and live in surroundings that range more than two-hundred-fold in external osmolality. Here, we use fluorescence imaging to make the first measurements of cell volume changes over time during hyperosmotic shock and subsequent adaptation on a single cell level in vivo with a time resolution on the order of seconds. We directly observe two previously unseen phases of the cytoplasmic water efflux upon hyperosmotic shock. Furthermore, we monitor cell volume changes during the post-shock recovery and observe a two-phase response that depends on the shock magnitude. The initial phase of recovery is fast, on the order of 15-20 min and shows little cell-to cell variation. For large sucrose shocks, a secondary phase that lasts several hours adds to the recovery. We find that cells are able to recover fully from shocks as high as 1 Osmol/kg using existing systems, but that for larger shocks, protein synthesis is required for full recovery. PMID- 22514722 TI - Elevated mortality among birds in Chernobyl as judged from skewed age and sex ratios. AB - BACKGROUND: Radiation has negative effects on survival of animals including humans, although the generality of this claim is poorly documented under low-dose field conditions. Because females may suffer disproportionately from the effects of radiation on survival due to differences in sex roles during reproduction, radiation-induced mortality may result in male-skewed adult sex ratios. METHODOLOGY/PRINCIPAL FINDING: We estimated the effects of low-dose radiation on adult survival rates in birds by determining age ratios of adults captured in mist nets during the breeding season in relation to background radiation levels around Chernobyl and in nearby uncontaminated control areas. Age ratios were skewed towards yearlings, especially in the most contaminated areas, implying that adult survival rates were reduced in contaminated areas, and that populations in such areas could only be maintained through immigration from nearby uncontaminated areas. Differential mortality in females resulted in a strongly male-skewed sex ratio in the most contaminated areas. In addition, males sang disproportionately commonly in the most contaminated areas where the sex ratio was male skewed presumably because males had difficulty finding and acquiring mates when females were rare. The results were not caused by permanent emigration by females from the most contaminated areas because none of the recaptured birds had changed breeding site, and the proportion of individuals with morphological abnormalities did not differ significantly between the sexes for areas with normal and higher levels of contamination. CONCLUSIONS/SIGNIFICANCE: These findings are consistent with the hypothesis that the adult survival rate of female birds is particularly susceptible to the effects of low-dose radiation, resulting in male skewed sex ratios at high levels of radiation. Such skewed age ratios towards yearlings in contaminated areas are consistent with the hypothesis that an area exceeding 30,000 km(2) in Chernobyl's surroundings constitutes an ecological trap that causes dramatic excess mortality. PMID- 22514723 TI - alpha7-Nicotinic acetylcholine receptor: role in early odor learning preference in mice. AB - Recently, we have shown that mice with decreased expression of alpha7-nicotinic acetylcholine receptors (alpha7) in the olfactory bulb were associated with a deficit in odor discrimination compared to wild-type mice. However, it is unknown if mice with decreased alpha7-receptor expression also show a deficit in early odor learning preference (ELP), an enhanced behavioral response to odors with attractive value observed in rats. In this study, we modified ELP methods performed in rats and implemented similar conditions in mice. From post-natal days 5-18, wild-type mice were stroked simultaneously with an odor presentation (conditioned odor) for 90 s daily. Control mice were only stroked, exposed to odor, or neither. On the day of testing (P21), mice that were stroked in concert with a conditioned odor significantly investigated the conditioned odor compared to a novel odor, as observed similarly in rats. However, mice with a decrease in alpha7-receptor expression that were stroked during a conditioned odor did not show a behavioral response to that odorant. These results suggest that decreased alpha7-receptor expression has a role in associative learning, olfactory preference, and/or sensory processing deficits. PMID- 22514724 TI - Predicting Anatomical Therapeutic Chemical (ATC) classification of drugs by integrating chemical-chemical interactions and similarities. AB - The Anatomical Therapeutic Chemical (ATC) classification system, recommended by the World Health Organization, categories drugs into different classes according to their therapeutic and chemical characteristics. For a set of query compounds, how can we identify which ATC-class (or classes) they belong to? It is an important and challenging problem because the information thus obtained would be quite useful for drug development and utilization. By hybridizing the informations of chemical-chemical interactions and chemical-chemical similarities, a novel method was developed for such purpose. It was observed by the jackknife test on a benchmark dataset of 3,883 drug compounds that the overall success rate achieved by the prediction method was about 73% in identifying the drugs among the following 14 main ATC-classes: (1) alimentary tract and metabolism; (2) blood and blood forming organs; (3) cardiovascular system; (4) dermatologicals; (5) genitourinary system and sex hormones; (6) systemic hormonal preparations, excluding sex hormones and insulins; (7) anti infectives for systemic use; (8) antineoplastic and immunomodulating agents; (9) musculoskeletal system; (10) nervous system; (11) antiparasitic products, insecticides and repellents; (12) respiratory system; (13) sensory organs; (14) various. Such a success rate is substantially higher than 7% by the random guess. It has not escaped our notice that the current method can be straightforwardly extended to identify the drugs for their 2(nd)-level, 3(rd)-level, 4(th)-level, and 5(th)-level ATC-classifications once the statistically significant benchmark data are available for these lower levels. PMID- 22514725 TI - Identification and characterization of small RNAs in the hyperthermophilic archaeon Sulfolobus solfataricus. AB - The term RNA silencing (RNA interference, RNAi) describes a set of mechanisms that regulate gene expression in eukaryotes. Small interfering RNAs (siRNA) and microRNAs (miRNAs) are two major types of RNAi-associated small RNAs (smRNAs) found in most eukaryotic organisms. Despite the presence of a plethora of non coding RNAs longer than 50-nucleotide (nt) in length in various species of Archaea, little is known about smRNAs in archaea that resemble the 20-24-nt long smRNAs found in eukaryotes, which have been implicated in the post transcriptional control of gene expression. Here, we report the finding of a large number of smRNAs approximatelly 20-nt in length, including phased smRNAs and potential miRNAs, from the hyperthermophilic archaeon Sulfolobus solfataricus p2 (Ssp2) based on deep sequencing. The expression of some of the miRNA candidates in Ssp2 was confirmed. Consistent with the Ssp2 hyperthermophilic properties, we found that higher temperatures more efficiently induced the production of the miRNA candidates in an in vitro system using the putative foldback precursor transcripts incubated with Ssp2 extract. Although we initially predicted putative target genes of some miRNA candidates, further analysis mapped the cleavage sites downstream of the miRNA candidate complementary regions, similar to those involved in plant miRNA-mediated TAS transcript cleavage. We also identified smRNAs from clustered, regularly interspaced, short palindromic repeat (CRISPR) loci, which play important roles in prokaryotic microbial defense systems. Archaea represent a unique life form next to Bacteria and Eukarya, and our results may provide a useful resource for further in-depth study on the regulation and evolution of smRNAs in this special organism. PMID- 22514726 TI - Endothelial and smooth muscle cells from abdominal aortic aneurysm have increased oxidative stress and telomere attrition. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is a complex multi-factorial disease with life-threatening complications. AAA is typically asymptomatic and its rupture is associated with high mortality rate. Both environmental and genetic risk factors are involved in AAA pathogenesis. Aim of this study was to investigate telomere length (TL) and oxidative DNA damage in paired blood lymphocytes, aortic endothelial cells (EC), vascular smooth muscle cells (VSMC), and epidermal cells from patients with AAA in comparison with matched controls. METHODS: TL was assessed using a modification of quantitative (Q)-FISH in combination with immunofluorescence for CD31 or alpha-smooth muscle actin to detect EC and VSMC, respectively. Oxidative DNA damage was investigated by immunofluorescence staining for 7, 8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG). RESULTS AND CONCLUSIONS: Telomeres were found to be significantly shortened in EC, VSMC, keratinocytes and blood lymphocytes from AAA patients compared to matched controls. 8-oxo-dG immunoreactivity, indicative of oxidative DNA damage, was detected at higher levels in all of the above cell types from AAA patients compared to matched controls. Increased DNA double strand breaks were detected in AAA patients vs controls by nuclear staining for gamma-H2AX histone. There was statistically significant inverse correlation between TL and accumulation of oxidative DNA damage in blood lymphocytes from AAA patients. This study shows for the first time that EC and VSMC from AAA have shortened telomeres and oxidative DNA damage. Similar findings were obtained with circulating lymphocytes and keratinocytes, indicating the systemic nature of the disease. Potential translational implications of these findings are discussed. PMID- 22514727 TI - Evolutionary plasticity of habenular asymmetry with a conserved efferent connectivity pattern. AB - The vertebrate habenulae (Hb) is an evolutionary conserved dorsal diencephalic nuclear complex that relays information from limbic and striatal forebrain regions to the ventral midbrain. One key feature of this bilateral nucleus is the presence of left-right differences in size, cytoarchitecture, connectivity, neurochemistry and/or gene expression. In teleosts, habenular asymmetry has been associated with preferential innervation of left-right habenular efferents into dorso-ventral domains of the midbrain interpeduncular nucleus (IPN). However, the degree of conservation of this trait and its relation to the structural asymmetries of the Hb are currently unknown. To address these questions, we performed the first systematic comparative analysis of structural and connectional asymmetries of the Hb in teleosts. We found striking inter-species variability in the overall shape and cytoarchitecture of the Hb, and in the frequency, strength and to a lesser degree, laterality of habenular volume at the population level. Directional asymmetry of the Hb was either to the left in D. rerio, E. bicolor, O. latipes, P. reticulata, B. splendens, or to the right in F. gardneri females. In contrast, asymmetry was absent in P. scalare and F. gardneri males at the population level, although in these species the Hb displayed volumetric asymmetries at the individual level. Inter-species variability was more pronounced across orders than within a single order, and coexisted with an overall conserved laterotopic representation of left-right habenular efferents into dorso-ventral domains of the IPN. These results suggest that the circuit design involving the Hb of teleosts promotes structural flexibility depending on developmental, cognitive and/or behavioural pressures, without affecting the main midbrain connectivity output, thus unveiling a key conserved role of this connectivity trait in the function of the circuit. We propose that ontogenic plasticity in habenular morphogenesis underlies the observed inter-species variations in habenular asymmetric morphology. PMID- 22514728 TI - Derivation of myoepithelial progenitor cells from bipotent mammary stem/progenitor cells. AB - There is increasing evidence that breast and other cancers originate from and are maintained by a small fraction of stem/progenitor cells with self-renewal properties. Recent molecular profiling has identified six major subtypes of breast cancer: basal-like, ErbB2-overexpressing, normal breast epithelial-like, luminal A and B, and claudin-low subtypes. To help understand the relationship among mammary stem/progenitor cells and breast cancer subtypes, we have recently derived distinct hTERT-immortalized human mammary stem/progenitor cell lines: a K5(+)/K19(-) type, and a K5(+)/K19(+) type. Under specific culture conditions, bipotent K5(+)/K19(-) stem/progenitor cells differentiated into stable clonal populations that were K5(-)/K19(-) and exhibit self-renewal and unipotent myoepithelial differentiation potential in contrast to the parental K5(+)/K19(-) cells which are bipotent. These K5(-)/K19(-) cells function as myoepithelial progenitor cells and constitutively express markers of an epithelial to mesenchymal transition (EMT) and show high invasive and migratory abilities. In addition, these cells express a microarray signature of claudin-low breast cancers. The EMT characteristics of an un-transformed unipotent mammary myoepithelial progenitor cells together with claudin-low signature suggests that the claudin-low breast cancer subtype may arise from myoepithelial lineage committed progenitors. Availability of immortal MPCs should allow a more definitive analysis of their potential to give rise to claudin-low breast cancer subtype and facilitate biological and molecular/biochemical studies of this disease. PMID- 22514729 TI - Lasp-1 regulates podosome function. AB - Eukaryotic cells form a variety of adhesive structures to connect with their environment and to regulate cell motility. In contrast to classical focal adhesions, podosomes, highly dynamic structures of different cell types, are actively engaged in matrix remodelling and degradation. Podosomes are composed of an actin-rich core region surrounded by a ring-like structure containing signalling molecules, motor proteins as well as cytoskeleton-associated proteins. Lasp-1 is a ubiquitously expressed, actin-binding protein that is known to regulate cytoskeleton architecture and cell migration. This multidomain protein is predominantely present at focal adhesions, however, a second pool of Lasp-1 molecules is also found at lamellipodia and vesicle-like microdomains in the cytosol.In this report, we show that Lasp-1 is a novel component and regulator of podosomes. Immunofluorescence studies reveal a localization of Lasp-1 in the podosome ring structure, where it colocalizes with zyxin and vinculin. Life cell imaging experiments demonstrate that Lasp-1 is recruited in early steps of podosome assembly. A siRNA-mediated Lasp-1 knockdown in human macrophages affects podosome dynamics as well as their matrix degradation capacity. In summary, our data indicate that Lasp-1 is a novel component of podosomes and is involved in the regulation of podosomal function. PMID- 22514730 TI - Consequences of gestational malaria on birth weight: finding the best timeframe for intermittent preventive treatment administration. AB - To investigate the consequences of intermittent preventive treatment (IPTp) timing on birth weight, we pooled data from two studies conducted in Benin between 2005 and 2010: a prospective cohort of 1037 pregnant women and a randomised trial comparing sulfadoxine-pyrimethamine (SP) to mefloquine in 1601 women. A total of 1439 women (752 in the cohort and 687 in the SP arm of the randomised trial) who delivered live singletons were analysed. We showed that an early intake of the first SP dose (4 months of gestation) was associated with a lower risk of LBW compared to a late intake (6-7 months of gestation) (aOR = 0.5 p = 0.01). We also found a borderline increased risk of placental infection when the first SP dose was administered early in pregnancy (aOR = 1.7 p = 0.1). This study is the first to investigate the timing of SP administration during pregnancy. We clearly demonstrated that women who had an early intake of the first SP dose were less at risk of LBW compared to those who had a late intake. Pregnant women should be encouraged to attend antenatal visits early to get their first SP dose and a third dose of SP could be recommended to cover the whole duration of pregnancy and to avoid late infections of the placenta. PMID- 22514731 TI - Dynamics of mechanical signal transmission through prestressed stress fibers. AB - Transmission of mechanical stimuli through the actin cytoskeleton has been proposed as a mechanism for rapid long-distance mechanotransduction in cells; however, a quantitative understanding of the dynamics of this transmission and the physical factors governing it remains lacking. Two key features of the actin cytoskeleton are its viscoelastic nature and the presence of prestress due to actomyosin motor activity. We develop a model of mechanical signal transmission through prestressed viscoelastic actin stress fibers that directly connect the cell surface to the nucleus. The analysis considers both temporally stationary and oscillatory mechanical signals and accounts for cytosolic drag on the stress fibers. To elucidate the physical parameters that govern mechanical signal transmission, we initially focus on the highly simplified case of a single stress fiber. The results demonstrate that the dynamics of mechanical signal transmission depend on whether the applied force leads to transverse or axial motion of the stress fiber. For transverse motion, mechanical signal transmission is dominated by prestress while fiber elasticity has a negligible effect. Conversely, signal transmission for axial motion is mediated uniquely by elasticity due to the absence of a prestress restoring force. Mechanical signal transmission is significantly delayed by stress fiber material viscosity, while cytosolic damping becomes important only for longer stress fibers. Only transverse motion yields the rapid and long-distance mechanical signal transmission dynamics observed experimentally. For simple networks of stress fibers, mechanical signals are transmitted rapidly to the nucleus when the fibers are oriented largely orthogonal to the applied force, whereas the presence of fibers parallel to the applied force slows down mechanical signal transmission significantly. The present results suggest that cytoskeletal prestress mediates rapid mechanical signal transmission and allows temporally oscillatory signals in the physiological frequency range to travel a long distance without significant decay due to material viscosity and/or cytosolic drag. PMID- 22514732 TI - The intracellular transport and secretion of calumenin-1/2 in living cells. AB - Calumenin isoforms 1 and 2 (calu-1/2), encoded by the CALU gene, belong to the CREC protein family. Calu-1/2 proteins are secreted into the extracellular space, but the secretory process and regulatory mechanism are largely unknown. Here, using a time-lapse imaging system, we visualized the intracellular transport and secretory process of calu-1/2-EGFP after their translocation into the ER lumen. Interestingly, we observed that an abundance of calu-1/2-EGFP accumulated in cellular processes before being released into the extracellular space, while only part of calu-1/2-EGFP proteins were secreted directly after attaching to the cell periphery. Moreover, we found the secretion of calu-1/2-EGFP required microtubule integrity, and that calu-1/2-EGFP-containing vesicles were transported by the motor proteins Kif5b and cytoplasmic dynein. Finally, we determined the export signal of calu-1/2-EGFP (amino acid positions 20-46) and provided evidence that the asparagine at site 131 was indispensable for calu-1/2-EGFP stabilization. Taken together, we provide a detailed picture of the intracellular transport of calu-1/2-EGFP, which facilitates our understanding of the secretory mechanism of calu-1/2. PMID- 22514733 TI - BMP4 was associated with NSCL/P in an Asian population. AB - BACKGROUND: The Bone Morphogenetic Protein 4 gene (BMP4) is located in chromosome 14q22-q23 which has shown evidence of linkage for isolated nonsyndromic cleft lip with or without cleft palate (NSCL/P) in a genome wide linkage analysis of human multiplex families. BMP4 has been shown to play crucial roles in lip and palatal development in animal models. Several candidate gene association analyses also supported its potential risk for NSCL/P, however, results across these association studies have been inconsistent. The aim of the current study was to test for possible association between markers in and around the BMP4 gene and NSCL/P in Asian and Maryland trios. METHODOLOGY/PRINCIPAL FINDINGS: Family Based Association Test was used to test for deviation from Mendelian assortment for 12 SNPs in and around BMP4. Nominal significant evidence of linkage and association was seen for three SNPs (rs10130587, rs2738265 and rs2761887) in 221 Asian trios and for one SNP (rs762642) in 76 Maryland trios. Statistical significance still held for rs10130587 after Bonferroni correction (corrected p = 0.019) among the Asian group. Estimated odds ratio for carrying the apparent high risk allele at this SNP was 1.61 (95%CI = 1.20, 2.18). CONCLUSIONS: Our results provided further evidence of association between BMP4 and NSCL/P. PMID- 22514734 TI - Multistep ion channel remodeling and lethal arrhythmia precede heart failure in a mouse model of inherited dilated cardiomyopathy. AB - BACKGROUND: Patients with inherited dilated cardiomyopathy (DCM) frequently die with severe heart failure (HF) or die suddenly with arrhythmias, although these symptoms are not always observed at birth. It remains unclear how and when HF and arrhythmogenic changes develop in these DCM mutation carriers. In order to address this issue, properties of the myocardium and underlying gene expressions were studied using a knock-in mouse model of human inherited DCM caused by a deletion mutation DeltaK210 in cardiac troponinT. METHODOLOGY/PRINCIPAL FINDINGS: By 1 month, DCM mice had already enlarged hearts, but showed no symptoms of HF and a much lower mortality than at 2 months or later. At around 2 months, some would die suddenly with no clear symptoms of HF, whereas at 3 months, many of the survivors showed evident symptoms of HF. In isolated left ventricular myocardium (LV) from 2 month-mice, spontaneous activity frequently occurred and action potential duration (APD) was prolonged. Transient outward (I(to)) and ultrarapid delayed rectifier K(+) (I(Kur)) currents were significantly reduced in DCM myocytes. Correspondingly, down-regulation of Kv4.2, Kv1.5 and KChIP2 was evident in mRNA and protein levels. In LVs at 3-months, more frequent spontaneous activity, greater prolongation of APD and further down-regulation in above K(+) channels were observed. At 1 month, in contrast, infrequent spontaneous activity and down-regulation of Kv4.2, but not Kv1.5 or KChIP2, were observed. CONCLUSIONS/SIGNIFICANCE: Our results suggest that at least three steps of electrical remodeling occur in the hearts of DCM model mice, and that the combined down-regulation of Kv4.2, Kv1.5 and KChIP2 prior to the onset of HF may play an important role in the premature sudden death in this DCM model. DCM mice at 1 month or before, on the contrary, are associated with low risk of death in spite of inborn disorder and enlarged heart. PMID- 22514735 TI - Local microenvironment provides important cues for cell differentiation in lingual epithelia. AB - Transgenic Keratin14-rtTA-PTR mice specifically express Keratin14 (K14) in the tongue epithelia, as well as co-express EGFP and the dominant negative DeltaTgfbr2 genes upon treatment with Doxycycline (Dox). As TGF-beta signaling negatively regulates the stem cell cycle and proliferation, its disruption by Dox induction in these transgenic mice shortens the cell cycle and allows observation of the final fate of those mutated cell lineages within a short period of time. Here, we used inducible transgenic mice to track the K14+ cells through the cell migration stream by immunohistochemical an immunofluorescent imaging. We showed that these cells have different development patterns from the tip to posterior of the tongue, achieved presumably by integrating positional information from the microenvironment. The expression of the K14 gene was variable, depending on the location of the tongue and papillae. Disruption of TGF-beta signaling in K14+ progenitor cells resulted in proliferation of stem cell pools. PMID- 22514736 TI - Structural basis of the chromodomain of Cbx3 bound to methylated peptides from histone h1 and G9a. AB - BACKGROUND: HP1 proteins are highly conserved heterochromatin proteins, which have been identified to be structural adapters assembling a variety of macromolecular complexes involved in regulation of gene expression, chromatin remodeling and heterochromatin formation. Much evidence shows that HP1 proteins interact with numerous proteins including methylated histones, histone methyltransferases and so on. Cbx3 is one of the paralogues of HP1 proteins, which has been reported to specifically recognize trimethylated histone H3K9 mark, and a consensus binding motif has been defined for the Cbx3 chromodomain. METHODOLOGY/PRINCIPAL FINDINGS: Here, we found that the Cbx3 chromodomain can bind to H1K26me2 and G9aK185me3 with comparable binding affinities compared to H3K9me3. We also determined the crystal structures of the human Cbx3 chromodomain in complex with dimethylated histone H1K26 and trimethylated G9aK185 peptides, respectively. The complex structures unveil that the Cbx3 chromodomain specifically bind methylated histone H1K26 and G9aK185 through a conserved mechanism. CONCLUSIONS/SIGNIFICANCE: The Cbx3 chromodomain binds with comparable affinities to all of the methylated H3K9, H1K26 and G9aK185 peptides. It is suggested that Cbx3 may regulate gene expression via recognizing both histones and non-histone proteins. PMID- 22514737 TI - Oxidation of HMGB1 causes attenuation of its pro-inflammatory activity and occurs during liver ischemia and reperfusion. AB - High mobility group box 1 (HMGB1) is a nuclear transcription factor. Once HMGB1 is released by damaged cells or activated immune cells, it acts as danger molecule and triggers the inflammatory signaling cascade. Currently, evidence is accumulating that posttranslational modifications such as oxidation may modulate the pro-inflammatory potential of danger signals. We hypothesized that oxidation of HMGB1 may reduce its pro-inflammatory potential and could take place during prolonged ischemia and upon reperfusion.Liver grafts were cold preserved for 24 h and flushed with saline in hourly intervals to collect the effluent. Liver grafts, cold-preserved for 6 h, were transplanted into syngeneic recipients to obtain serum and liver samples 24 h after initiation of reperfusion. Addition of the effluent to a macrophage culture induced the synthesis of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6. The stimulatory activity of graft effluent was reduced after depletion of HMGB1 via immunoprecipitation. Oxidation of the effluent HMGB1 using H(2)O(2) attenuated its stimulatory activity as well. Liver transplantation of cold preserved grafts caused HMGB1 translocation and release as determined by immunohistochemistry and ELISA-assay, respectively. Using Western blot with non-reducing conditions revealed the presence of oxidized HMGB1 in liver samples obtained after 12 h and in effluent samples after 16 h of cold preservation as well as in liver and serum samples obtained 24 h after reperfusion.These observations confirm that post translational oxidation of HMGB1 attenuates its pro-inflammatory activity. Oxidation of HMGB1 as induced during prolonged ischemia and by reoxygenation during reperfusion in vivo might also attenuate its pro-inflammatory activity. Our findings also call for future studies to investigate the mechanism of the inhibitory effect of oxidized HMGB1 on the pro-inflammatory potential. PMID- 22514739 TI - Dissociation of immune responses from pathogen colonization supports pattern recognition in C. elegans. AB - Caenorhabditis elegans has been used for over a decade to characterize signaling cascades controlling innate immune responses. However, what initiates these responses in the worm has remained elusive. To gain a better understanding of the initiating events we delineated genome-wide immune responses to the bacterial pathogen Pseudomonas aeruginosa in worms heavily-colonized by the pathogen versus worms visibly not colonized. We found that infection responses in both groups were identical, suggesting that immune responses were not correlated with colonization and its associated damage. Quantitative RT-PCR measurements further showed that pathogen secreted factors were not able to induce an immune response, but exposure to a non-pathogenic Pseudomonas species was. These findings raise the possibility that the C.elegans immune response is initiated by recognition of microbe-associated molecular patterns. In the absence of orthologs of known pattern recognition receptors, C. elegans may rely on novel mechanisms, thus holding the potential to advance our understanding of evolutionarily conserved strategies for pathogen recognition. PMID- 22514738 TI - Highly efficient amplification of chronic wasting disease agent by protein misfolding cyclic amplification with beads (PMCAb). AB - Protein misfolding cyclic amplification (PMCA) has emerged as an important technique for detecting low levels of pathogenic prion protein in biological samples. The method exploits the ability of the pathogenic prion protein to convert the normal prion protein to a proteinase K-resistant conformation. Inclusion of Teflon(r) beads in the PMCA reaction (PMCAb) has been previously shown to increase the sensitivity and robustness of detection for the 263 K and SSLOW strains of hamster-adapted prions. Here, we demonstrate that PMCAb with saponin dramatically increases the sensitivity of detection for chronic wasting disease (CWD) agent without compromising the specificity of the assay (i.e., no false positive results). Addition of Teflon(r) beads increased the robustness of the PMCA reaction, resulting in a decrease in the variability of PMCA results. Three rounds of serial PMCAb allowed detection of CWD agent from a 6.7 * 10(-13) dilution of 10% brain homogenate (1.3 fg of source brain). Titration of the same brain homogenate in transgenic mice expressing cervid prion protein (Tg(CerPrP)1536(+/-) mice) allowed detection of CWD agent from the 10(-6) dilution of 10% brain homogenate. PMCAb is, thus, more sensitive than bioassay in transgenic mice by a factor exceeding 10(5). Additionally, we are able to amplify CWD agent from brain tissue and lymph nodes of CWD-positive white-tailed deer having Prnp alleles associated with reduced disease susceptibility. PMID- 22514740 TI - Scalable purification and characterization of the anticancer lunasin peptide from soybean. AB - Lunasin is a peptide derived from the soybean 2S albumin seed protein that has both anticancer and anti-inflammatory activities. Large-scale animal studies and human clinical trials to determine the efficacy of lunasin in vivo have been hampered by the cost of synthetic lunasin and the lack of a method for obtaining gram quantities of highly purified lunasin from plant sources. The goal of this study was to develop a large-scale method to generate highly purified lunasin from defatted soy flour. A scalable method was developed that utilizes the sequential application of anion-exchange chromatography, ultrafiltration, and reversed-phase chromatography. This method generates lunasin preparations of >99% purity with a yield of 442 mg/kg defatted soy flour. Mass spectrometry of the purified lunasin revealed that the peptide is 44 amino acids in length and represents the original published sequence of lunasin with an additional C terminal asparagine residue. Histone-binding assays demonstrated that the biological activity of the purified lunasin was similar to that of synthetic lunasin. This study provides a robust method for purifying commercial-scale quantities of biologically-active lunasin and clearly identifies the predominant form of lunasin in soy flour. This method will greatly facilitate the development of lunasin as a potential nutraceutical or therapeutic anticancer agent. PMID- 22514741 TI - Loop diuretics have anxiolytic effects in rat models of conditioned anxiety. AB - A number of antiepileptic medications that modulate GABA(A) mediated synaptic transmission are anxiolytic. The loop diuretics furosemide (Lasix) and bumetanide (Bumex) are thought to have antiepileptic properties. These drugs also modulate GABA(A) mediated signalling through their antagonism of cation-chloride cotransporters. Given that loop diuretics may act as antiepileptic drugs that modulate GABAergic signalling, we sought to investigate whether they also mediate anxiolytic effects. Here we report the first investigation of the anxiolytic effects of these drugs in rat models of anxiety. Furosemide and bumetanide were tested in adult rats for their anxiolytic effects using four standard anxiety models: 1) contextual fear conditioning; 2) fear-potentiated startle; 3) elevated plus maze, and 4) open-field test. Furosemide and bumetanide significantly reduced conditioned anxiety in the contextual fear-conditioning and fear potentiated startle models. At the tested doses, neither compound had significant anxiolytic effects on unconditioned anxiety in the elevated plus maze and open field test models. These observations suggest that loop diuretics elicit significant anxiolytic effects in rat models of conditioned anxiety. Since loop diuretics are antagonists of the NKCC1 and KCC2 cotransporters, these results implicate the cation-chloride cotransport system as possible molecular mechanism involved in anxiety, and as novel pharmacological target for the development of anxiolytics. In view of these findings, and since furosemide and bumetanide are safe and well tolerated drugs, the clinical potential of loop diuretics for treating some types of anxiety disorders deserves further investigation. PMID- 22514742 TI - Fenofibrate reduces mortality and precludes neurological deficits in survivors in murine model of Japanese encephalitis viral infection. AB - BACKGROUND: Japanese encephalitis (JE), the most common form of viral encephalitis occurs periodically in endemic areas leading to high mortality and neurological deficits in survivors. It is caused by a flavivirus, Japanese encephalitis virus (JEV), which is transmitted to humans through mosquitoes. No effective cure exists for reducing mortality and morbidity caused by JEV infection, which is primarily due to excessive inflammatory response. Fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist is known to resolve inflammation by repressing nuclear factor-kappaB (NF kappaB) and enhancing transcription of anti-oxidant and anti-inflammatory genes. In addition, fenofibrate also up-regulates a class of proteins, cytochrome P4504Fs (Cyp4fs), which are involved in detoxification of the potent pro inflammatory eicosanoid, leukotriene B(4) (LTB(4)) to 20-hydroxy LTB(4). METHODOLOGY/PRINCIPAL FINDINGS: The neuroprotective effect of fenofibrate was examined using in vitro (BV-2 microglial cell line) and in vivo (BALB/c mice) models of JEV infection. Mice were treated with fenofibrate for 2 or 4 days prior to JEV exposure. Pretreatment with fenofibrate for 4 but not 2 days reduced mortality by 80% and brain LTB(4) levels decreased concomitantly with the induction of Cyp4f15 and 4f18, which catalyze detoxification of LTB(4) through hydroxylation. Expression of cytokines and chemokine decreased significantly as did microglial activation and replication of the JEV virus. CONCLUSIONS/SIGNIFICANCE: Fenofibrate confers neuroprotection against Japanese encephalitis, in vivo, in mouse model of JEV infection. Thus, fenofibrate, a PPARalpha agonist that is commonly used as a hypolipidemic drug could potentially be used for prophylaxis during JE epidemics to reduce mortality and morbidity. PMID- 22514743 TI - A novel network integrating a miRNA-203/SNAI1 feedback loop which regulates epithelial to mesenchymal transition. AB - BACKGROUND: The majority of human cancer deaths are caused by metastasis. The metastatic dissemination is initiated by the breakdown of epithelial cell homeostasis. During this phenomenon, referred to as epithelial to mesenchymal transition (EMT), cells change their genetic and trancriptomic program leading to phenotypic and functional alterations. The challenge of understanding this dynamic process resides in unraveling regulatory networks involving master transcription factors (e.g. SNAI1/2, ZEB1/2 and TWIST1) and microRNAs. Here we investigated microRNAs regulated by SNAI1 and their potential role in the regulatory networks underlying epithelial plasticity. RESULTS: By a large-scale analysis on epithelial plasticity, we highlighted miR-203 and its molecular link with SNAI1 and the miR-200 family, key regulators of epithelial homeostasis. During SNAI1-induced EMT in MCF7 breast cancer cells, miR-203 and miR-200 family members were repressed in a timely correlated manner. Importantly, miR-203 repressed endogenous SNAI1, forming a double negative miR203/SNAI1 feedback loop. We integrated this novel miR203/SNAI1 with the known miR200/ZEB feedback loops to construct an a priori EMT core network. Dynamic simulations revealed stable epithelial and mesenchymal states, and underscored the crucial role of the miR203/SNAI1 feedback loop in state transitions underlying epithelial plasticity. CONCLUSION: By combining computational biology and experimental approaches, we propose a novel EMT core network integrating two fundamental negative feedback loops, miR203/SNAI1 and miR200/ZEB. Altogether our analysis implies that this novel EMT core network could function as a switch controlling epithelial cell plasticity during differentiation and cancer progression. PMID- 22514744 TI - Altered metabolic signature in pre-diabetic NOD mice. AB - Altered metabolism proceeding seroconversion in children progressing to Type 1 diabetes has previously been demonstrated. We tested the hypothesis that non obese diabetic (NOD) mice show a similarly altered metabolic profile compared to C57BL/6 mice. Blood samples from NOD and C57BL/6 female mice was collected at 0, 1, 2, 3, 4, 5, 6, 7, 9, 11, 13 and 15 weeks and the metabolite content was analyzed using GC-MS. Based on the data of 89 identified metabolites OPLS-DA analysis was employed to determine the most discriminative metabolites. In silico analysis of potential involved metabolic enzymes was performed using the dbSNP data base. Already at 0 weeks NOD mice displayed a unique metabolic signature compared to C57BL/6. A shift in the metabolism was observed for both strains the first weeks of life, a pattern that stabilized after 5 weeks of age. Multivariate analysis revealed the most discriminative metabolites, which included inosine and glutamic acid. In silico analysis of the genes in the involved metabolic pathways revealed several SNPs in either regulatory or coding regions, some in previously defined insulin dependent diabetes (Idd) regions. Our result shows that NOD mice display an altered metabolic profile that is partly resembling the previously observation made in children progressing to Type 1 diabetes. The level of glutamic acid was one of the most discriminative metabolites in addition to several metabolites in the TCA cycle and nucleic acid components. The in silico analysis indicated that the genes responsible for this reside within previously defined Idd regions. PMID- 22514745 TI - Computer simulation on the cooperation of functional molecules during the early stages of evolution. AB - It is very likely that life began with some RNA (or RNA-like) molecules, self replicating by base-pairing and exhibiting enzyme-like functions that favored the self-replication. Different functional molecules may have emerged by favoring their own self-replication at different aspects. Then, a direct route towards complexity/efficiency may have been through the coexistence/cooperation of these molecules. However, the likelihood of this route remains quite unclear, especially because the molecules would be competing for limited common resources. By computer simulation using a Monte-Carlo model (with "micro-resolution" at the level of nucleotides and membrane components), we show that the coexistence/cooperation of these molecules can occur naturally, both in a naked form and in a protocell form. The results of the computer simulation also lead to quite a few deductions concerning the environment and history in the scenario. First, a naked stage (with functional molecules catalyzing template-replication and metabolism) may have occurred early in evolution but required high concentration and limited dispersal of the system (e.g., on some mineral surface); the emergence of protocells enabled a "habitat-shift" into bulk water. Second, the protocell stage started with a substage of "pseudo-protocells", with functional molecules catalyzing template-replication and metabolism, but still missing the function involved in the synthesis of membrane components, the emergence of which would lead to a subsequent "true-protocell" substage. Third, the initial unstable membrane, composed of prebiotically available fatty acids, should have been superseded quite early by a more stable membrane (e.g., composed of phospholipids, like modern cells). Additionally, the membrane-takeover probably occurred at the transition of the two substages of the protocells. The scenario described in the present study should correspond to an episode in early evolution, after the emergence of single "genes", but before the appearance of a "chromosome" with linked genes. PMID- 22514746 TI - Premature senescence and increased TGFbeta signaling in the absence of Tgif1. AB - Transforming growth factor beta (TGFbeta) signaling regulates cell cycle progression in several cell types, primarily by inducing a G1 cell cycle arrest. Tgif1 is a transcriptional corepressor that limits TGFbeta responsive gene expression. Here we demonstrate that primary mouse embryo fibroblasts (MEFs) lacking Tgif1 proliferate slowly, accumulate increased levels of DNA damage, and senesce prematurely. We also provide evidence that the effects of loss of Tgif1 on proliferation and senescence are not limited to primary cells. The increased DNA damage in Tgif1 null MEFs can be partially reversed by culturing cells at physiological oxygen levels, and growth in normoxic conditions also partially rescues the proliferation defect, suggesting that in the absence of Tgif1 primary MEFs are less able to cope with elevated levels of oxidative stress. Additionally, we show that Tgif1 null MEFs are more sensitive to TGFbeta-mediated growth inhibition, and that treatment with a TGFbeta receptor kinase inhibitor increases proliferation of Tgif1 null MEFs. Conversely, persistent treatment of wild type cells with low levels of TGFbeta slows proliferation and induces senescence, suggesting that TGFbeta signaling also contributes to cellular senescence. We suggest that in the absence of Tgif1, a persistent increase in TGFbeta responsive transcription and a reduced ability to deal with hyperoxic stress result in premature senescence in primary MEFs. PMID- 22514747 TI - Effect of fructooligosaccharide metabolism on chicken colonization by an extra intestinal pathogenic Escherichia coli strain. AB - Extra-intestinal pathogenic Escherichia coli (ExPEC) strains cause many diseases in humans and animals. While remaining asymptomatic, they can colonize the intestine for subsequent extra-intestinal infection and dissemination in the environment. We have previously identified the fos locus, a gene cluster within a pathogenicity island of the avian ExPEC strain BEN2908, involved in the metabolism of short-chain fructooligosaccharides (scFOS). It is assumed that these sugars are metabolized by the probiotic bacteria of the microbiota present in the intestine, leading to a decrease in the pathogenic bacterial population. However, we have previously shown that scFOS metabolism helps BEN2908 to colonize the intestine, its reservoir. As the fos locus is located on a pathogenicity island, one aim of this study was to investigate a possible role of this locus in the virulence of the strain for chicken. We thus analysed fos gene expression in extracts of target organs of avian colibacillosis and performed a virulence assay in chickens. Moreover, in order to understand the involvement of the fos locus in intestinal colonization, we monitored the expression of fos genes and their implication in the growth ability of the strain in intestinal extracts of chicken. We also performed intestinal colonization assays in axenic and Specific Pathogen-Free (SPF) chickens. We demonstrated that the fos locus is not involved in the virulence of BEN2908 for chickens and is strongly involved in axenic chicken cecal colonization both in vitro and in vivo. However, even if the presence of a microbiota does not inhibit the growth advantage of BEN2908 in ceca in vitro, overall, growth of the strain is not favoured in the ceca of SPF chickens. These findings indicate that scFOS metabolism by an ExPEC strain can contribute to its fitness in ceca but this benefit is fully dependent on the bacteria present in the microbiota. PMID- 22514748 TI - DNA fingerprinting validates seed dispersal curves from observational studies in the neotropical legume parkia. AB - BACKGROUND: Determining the distances over which seeds are dispersed is a crucial component for examining spatial patterns of seed dispersal and their consequences for plant reproductive success and population structure. However, following the fate of individual seeds after removal from the source tree till deposition at a distant place is generally extremely difficult. Here we provide a comparison of observationally and genetically determined seed dispersal distances and dispersal curves in a Neotropical animal-plant system. METHODOLOGY/PRINCIPAL FINDINGS: In a field study on the dispersal of seeds of three Parkia (Fabaceae) species by two Neotropical primate species, Saguinus fuscicollis and Saguinus mystax, in Peruvian Amazonia, we observationally determined dispersal distances. These dispersal distances were then validated through DNA fingerprinting, by matching DNA from the maternally derived seed coat to DNA from potential source trees. We found that dispersal distances are strongly right-skewed, and that distributions obtained through observational and genetic methods and fitted distributions do not differ significantly from each other. CONCLUSIONS/SIGNIFICANCE: Our study showed that seed dispersal distances can be reliably estimated through observational methods when a strict criterion for inclusion of seeds is observed. Furthermore, dispersal distances produced by the two primate species indicated that these primates fulfil one of the criteria for efficient seed dispersers. Finally, our study demonstrated that DNA extraction methods so far employed for temperate plant species can be successfully used for hard-seeded tropical plants. PMID- 22514749 TI - Mouse estrous cycle identification tool and images. AB - The efficiency of producing timed pregnant or pseudopregnant mice can be increased by identifying those in proestrus or estrus. Visual observation of the vagina is the quickest method, requires no special equipment, and is best used when only proestrus or estrus stages need to be identified. Strain to strain differences, especially in coat color can make it difficult to determine the stage of the estrous cycle accurately by visual observation. Presented here are a series of images of the vaginal opening at each stage of the estrous cycle for 3 mouse strains of different coat colors: black (C57BL/6J), agouti (CByB6F1/J) and albino (BALB/cByJ). When all 4 stages (proestrus, estrus, metestrus, and diestrus) need to be identified, vaginal cytology is regarded as the most accurate method. An identification tool is presented to aid the user in determining the stage of estrous when using vaginal cytology. These images and descriptions are an excellent resource for learning how to determine the stage of the estrous cycle by visual observation or vaginal cytology. PMID- 22514751 TI - What's Good about Being Gay?: Perspectives from Youth. AB - This article explores gay and bisexual male adolescents' positive perceptions of their sexual orientation identity. In-depth qualitative interviews were conducted with an ethnically diverse sample of 63 gay/bisexual male adolescents in Chicago (N=42) and Miami (N=21). Data revealed two major conceptual categories: 1) positive personal conceptualizations of being gay/bisexual, and 2) resiliency in the face of gay-related oppression. Additional primary themes and sub-themes were identified within each category that further illustrate how gay/bisexual youth were able to develop positive conceptualizations of their sexual orientation despite experiencing negative societal messages about being gay/bisexual. Implications for the development of interventions to promote the health and well being of gay/bisexual male youth are discussed. PMID- 22514750 TI - Real-time PCR demonstrates Ancylostoma duodenale is a key factor in the etiology of severe anemia and iron deficiency in Malawian pre-school children. AB - BACKGROUND: Hookworm infections are an important cause of (severe) anemia and iron deficiency in children in the tropics. Type of hookworm species (Ancylostoma duodenale or Necator americanus) and infection load are considered associated with disease burden, although these parameters are rarely assessed due to limitations of currently used diagnostic methods. Using multiplex real-time PCR, we evaluated hookworm species-specific prevalence, infection load and their contribution towards severe anemia and iron deficiency in pre-school children in Malawi. METHODOLOGY AND FINDINGS: A. duodenale and N. americanus DNA loads were determined in 830 fecal samples of pre-school children participating in a case control study investigating severe anemia. Using multiplex real-time PCR, hookworm infections were found in 34.1% of the severely anemic cases and in 27.0% of the non-severely anemic controls (p<0.05) whereas a 5.6% hookworm prevalence was detected by microscopy. Prevalence of A. duodenale and N. americanus was 26.1% and 4.9% respectively. Moderate and high load A. duodenale infections were positively associated with severe anemia (adjusted odds ratio: 2.49 (95%CI 1.16 5.33) and 9.04 (95%CI 2.52-32.47) respectively). Iron deficiency (assessed through bone marrow examination) was positively associated with intensity of A. duodenale infection (adjusted odds ratio: 3.63 (95%CI 1.18-11.20); 16.98 (95%CI 3.88-74.35) and 44.91 (95%CI 5.23-385.77) for low, moderate and high load respectively). CONCLUSIONS/SIGNIFICANCE: This is the first report assessing the association of hookworm load and species differentiation with severe anemia and bone marrow iron deficiency. By revealing a much higher than expected prevalence of A. duodenale and its significant and load-dependent association with severe anemia and iron deficiency in pre-school children in Malawi, we demonstrated the need for quantitative and species-specific screening of hookworm infections. Multiplex real-time PCR is a powerful diagnostic tool for public health research to combat (severe) anemia and iron deficiency in children living in resource poor settings. PMID- 22514752 TI - Hypoxia promotes growth of stem cells in dental follicle cell populations. AB - Adult stem cells (ASC) have been found in many tissues and are of great therapeutic potential due to their capability of differentiation. However, ASC comprise only a small fraction of the tissues. In order to use ASC for therapeutic purposes, it is important to obtain relatively pure stem cells in large quantities. Current methods for stem cell purification are mainly based on marker-dependent cell sorting techniques, which have various technical difficulties. In this study, we have attempted to develop novel conditions to favor the growth of the dental follicle stem cells (DFSC) such that the resultant cell populations are enriched in stem cells. Specifically, a heterogeneous dental follicle cell (H-DFC) population containing stem cells and homogenous non-stem cell dental follicle cell population were cultured at 1% or 5% hypoxic conditions. Only the heterogeneous population could increase proliferation in the hypoxic condition whereas the homogenous DFC did not change their proliferation rate. In addition, when the resultant cells from the heterogonous population were subjected to differentiation, they appeared to have a higher capacity of adipogenesis and osteogenesis as compared to the controls grown in the normal atmosphere (normoxic condition). These hypoxia-treated cells also express higher levels of some stem cell markers. Together, these data suggest that stem cells are enriched by culturing the heterogeneous cell populations in a reduced O(2) condition. PMID- 22514753 TI - Assessment of biosafety precautions in Khartoum state diagnostic laboratories, Sudan. AB - BACKGROUND: This study was conducted to evaluate the biosafety precautions that applied by diagnostic laboratories in Khartoum state, 2009. METHODS: A total number of 190 laboratories were surveyed about their compliance with standard biosafety precautions. These laboratories included 51 (27%) laboratories from government, 75 (39%) from private sectors and 64 (34%) laboratories belong to organization providing health care services. RESULTS: The study found that 32 (16.8%) of laboratories appointed biosafety officers. Only, ten (5.2%) participated in training about response to fire emergency, and 28 (14.7%) reported the laboratory accident occurred during work. 45 (23.7%) laboratories had a written standard operation procedures (SOPs), and 35 (18.4%) had written procedures for the lean-up of spills. Moreover, biosafety cabinet was found in 11 (5.8%) laboratories, autoclave in 28 (14.7%) and incinerator in only two (1.1%) laboratories. Sharp disposable containers were found in 84 (44.2%). Fire alarm system was found in 2 (1.1%) laboratories, fire extinguisher in 39 (20.5%) laboratories, and fire emergency exit found in 14 (7.4%) laboratories. Furthermore, 19 (10%) laboratories had a hepatitis B virus vaccination programme, 5 (6.2%) applied BCG vaccine, and 2 (1.1%0) vaccinated the staff against influenza. CONCLUSION: The study concluded that the standards biosafety precautions adopted by the diagnostic laboratories in Khartoum state was very low. Further, the laboratory personnel awareness towards biosafety principles implementation was very low too. PMID- 22514754 TI - ["Limb body wall complex": about a rather unusual observation]. PMID- 22514755 TI - Bone scintigraphy elucidates different metabolic stages of melorheostosis. AB - Melorheostosis is a rare benign non-hereditary sclerosing dysplasia involving the bone, often in a sclerotomal distribution. we report the case of a 27 years old lady with painful swelling of the left hand and forearm lasting for almost 15 years. The patient experienced aggravation of symptoms and limitation of motion during the past two months. Radiographic assessment revealed hyperostosis involving the left 3(rd) and 4(th) metacarpal bones and corresponding digits as well as the left ulna and distal humerus, with no soft tissue ossification. Angiographic and blood pool images of bone scintigraphy showed increased activity of mid-metacarpal region, corresponding to the sclerotom C-8. Delayed static views showed increased radiotracer uptake of the left 4(th) metacarpal bone and the corresponding digit as well as the left ulna and humerus, but no abnormal osteoblastic activity of the 3(rd) left metacarpal and digit. Histopathologic assessment confirmed the diagnosis of Melorheostosis. The case confirms that even in the same sclerotomal distribution, the multiple foci of involvement can present in different metabolic stages. In fact, the disease does not progress uniformly and different lesions can be seen in dissimilar stages of activity. Hence, metabolic imaging can be important to unmask which of the radiographically detected bony lesions are metabolically active and have the potential to be the source of current patient's symptoms and which of them are old, metabolically inactive and silent lesions, which are not clinically relevant to the patient's complaints. PMID- 22514757 TI - [Domestic violence in Antananarivo (Madagascar): a public health issue]. PMID- 22514756 TI - New Delhi Metallo-beta lactamase-1 containing enterobacteriaceae: origin, diagnosis, treatment and public health concern. AB - One of the biggest problems associated with the antibiotic therapy is resistance. Recently published studies have revealed that enterobacteriaceae, like E. coli and Klebsiella, isolated from several Indian centers are resistant to many antibiotics including some highly potent antibiotics like carbapenems. It has been proposed that this resistance is because of a carbapenemase enzyme called NDM-1 (New Delhi Metallo-betalactamase-1). This carbapenemase is class B carbapenemase also called metallolactamases as they require zinc at their active site. This enzyme is coded by a gene called bla-NDM-1 or gene NDM-1. NDM-1 containing enterobacteriaceae can be screened in laboratory by few techniques. Metallolactamase production can be detected by disk approximation test or Modified Hodge test and NDM-1 gene can be detected by polymerase chain reaction by the use of specific primer targeting the gene. Infections caused by such bacteria are associated with high morbidity and mortality. Two classes of antibiotics i.e., polymyxins (colistin) and glycylcyclines (tigecyclines), have shown in vitro activity against NDM-1 harboring enterobacteriaceae. The safety profile of both of these antibiotics is questionable. There is a need for active screening of microorganisms for NDM-1 and research should be directed towards the development of safe antibiotics for the treatment of these kinds of infections. PMID- 22514758 TI - [Accidents to AVK: a retrospective study of 30 cases]. PMID- 22514759 TI - [Prevalence of smoking among staff of the General Hospital of Douala, Cameroon]. PMID- 22514760 TI - [Association of neonatal fat necrosis, hypertriglyceridemia and hypercalcemia: report of an observation]. PMID- 22514761 TI - Knowledge of HIV/AIDS and use of mandatory premarital HIV testing as a prerequisite for marriages among religious leaders in Sokoto, North Western Nigeria. AB - BACKGROUND: In Sub-Saharan Africa, an estimated 1.8 million became infected with the HIV in 2009 and Nigeria currently has about 3.4 million people living with HIV. Measures put in place by religious organizations to combat HIV/AIDS in Nigeria include mandatory premarital HIV testing. The knowledge of HIV/AIDS amongst religious leaders in Nigeria has not been sufficiently explored . In this study, we assessed the knowledge of HIV/AIDS amongst religious leaders in Sokoto and if they routinely demand for mandatory premarital HIV testing for all intending couples. METHODS: This was a descriptive cross-sectional study involving 158 religious leaders (30 Christians and 128 Muslims) who officiate or assist during marriages. Data was collected using interviewer and self administered questionnaire which sought such information as biodata, knowledge of HIV/AIDS , speaking to congregation about AIDS and using Premarital HIV status as a pre-requisite for contracting marriages. Data was entered into and analysed using Epi-info computer soft ware program. Level of statistical significance was put at P = 0.05. RESULTS: The ages of the respondents ranged from 35 to 78 years with a mean age of 26.3 +/- 20.3 years. Forty nine percent of the respondents had adequate knowledge of HIV/AIDS with more Christian clerics compared to Muslim Clerics having better knowledge of HIV/AIDS (P < 0.0001). All the Christian clerics opined that they would insist on mandatory premarital HIV testing for their subjects before joining them in marriages. CONCLUSION: The results of the study have shown that most of the religious leaders lacked adequate knowledge of HIV/AIDS and the use of mandatory premarital HIV testing is yet to be adopted by the Muslim clerics. Awareness campaigns should be intensified for the religious leaders to improve their knowledge of HIV/AIDS. PMID- 22514762 TI - Knowledge, attitudes, beliefs, behaviour and breast cancer screening practices in Ghana, West Africa. AB - BACKGROUND: Late presentation has been observed as the hallmark of breast cancer in Ghanaian women where over 60% of patients report with either stage 3 or 4 of the disease. This cross-sectional study aimed at exploring breast cancer related knowledge and practices in order to develop an appropriate socio-economic and cultural specific model to improve breast cancer care in Ghana. METHODS: The study which was conducted in Accra and Sunyani in Ghana used both quantitative and qualitative methods and employed the theory of planned behavior as a communication and educational model. Information was collected from 474 women using questionnaires. In addition semi-structured interviews were conducted on 10 breast cancer patients; 10 breast clinic attendants; 3 Oncology Consultants and 2 herbalists. RESULTS: Generally, the respondents displayed knowledge deficit about the disease. However, higher levels of education was associated with better appreciation of the disease (rs = 0.316, N = 465, p < 0.001). The respondents' attitudes include fear of the disease which was linked to death in most cases; denial and guilt; as well as supernatural attributes. The self-reported breast cancer screening rate (BSE 32%, CBE 12% and mammogram 2%) was poor, however, higher educational of the respondents was very significant for breast cancer screening practices. CONCLUSION: The study found that routine mammography screening is not feasible in Ghana at the moment which therefore requires a different approach. PMID- 22514763 TI - Critical reflections on the principle of beneficence in biomedicine. AB - Medical ethics as a scholarly discipline and a system of moral principles that apply values and judgments to the practice of medicine encompasses its practical application in clinical settings as well as work on its history, philosophy, theology, anthropology and sociology. As such there are a number of values in medical ethics such as autonomy, non-maleficence, confidentiality, dignity, honesty, justice and beneficence, among others. These values act as guidelines for professionals in the medical fraternity and are therefore used to judge different cases in the fraternity. For purposes of this work, this paper examines the principle of beneficence in biomedicine. Using both hypothetical cases and others in real life situations, the paper reflects on the implications of beneficence in biomedicine. It argues that the principle of beneficence is a prima facie obligation that should "always be acted upon unless it conflicts on a particular occasion with an equal or stronger principle". PMID- 22514764 TI - [HELLP syndrome: report of 61 cases and literature review]. PMID- 22514765 TI - A wandering spleen presenting as a hypogastric mass: case report. AB - Wandering spleen is a rare condition characterized by the absence or underdevelopment of one or all of the ligaments that hold the spleen in its normal position in the left upper quadrant of the abdomen. It is an uncommon clinical entity that mainly affects children. Among adults it most frequently affects women of reproductive age, in whom acquired laxity of the splenic ligaments is usually the cause. Patients with a wandering spleen may be asymptomatic, present with a movable mass in the abdomen, or have chronic or intermittent abdominal pain because of partial torsion and spontaneous detorsion of the spleen. A 26-year-old woman was admitted to our hospital with vomiting and abdominal pain. Abdominal examination revealed a large ovoid hypogastric mass. A CT scan showed a wandering spleen in the hypogastric region. Exploratory laparotomy revealed an ischemic spleen. A total splenectomy was performed. PMID- 22514766 TI - Soft-tissue metastasis revealing a pancreatic adenocarcinoma: one case report and a review of literature. AB - Soft tissue metastases from pancreatic adenocarcinoma are rare lesions and can be the source of diagnostic confusion both clinically and pathologically. To our knowledge, one patient has been reported on with soft tissue lesions that ultimately disclose a pancreatic adenocarcinoma. We report here on a patient who presented with a metastatic soft tissue lesion in the trochanter, and the buttocks, as the initial manifestation of pancreatic adenocarcinoma. Soft tissue metastasis from pancreatic carcinoma is a rare finding. Clinicians should be aware that metastatic soft tissue lesions could be the initial presenting sign for pancreatic cancer. Also, the immunohistochemical staining for CK 7 and 19 may be helpful for the diagnosis of metastatic pancreatic adenocarcinoma. PMID- 22514767 TI - [Sternal tuberculosis: report of 2 cases]. PMID- 22514768 TI - [Congenital bilateral eversion of the eyelids: management of a case according to the conservative approach at the University Hospital of Yaounde, Cameroon]. PMID- 22514769 TI - [Reaction to Mujahid et al: Hydatid cysts of the liver ruptured into the biliary tracts: report of 120 cases]. PMID- 22514770 TI - [Severe forms of influenza A (H1N1) 2009 in pregnant women: experience of the University Hospital of Fez, Morocco and literature review]. PMID- 22514771 TI - [Tetanus in older children in a pediatric hospital in Yaounde, Cameroon]. PMID- 22514772 TI - Neuroplasty. PMID- 22514773 TI - Use of hypnosis in the treatment of pain. AB - Hypnosis is an altered state of consciousness that comprises of heightened absorption in focal attention, dissociation of peripheral awareness, and enhanced responsiveness to social cues. Hypnosis has a long tradition of effectiveness in controlling somatic symptoms, such as pain. Pain, the most common symptom in clinical practice, is a multi-dimensional experience, which includes sensory discriminative, affective-emotional, cognitive and behavioral components. There is a growing recognition for hypnosis and related techniques in pain management. Psychological approaches to pain control, such as hypnosis, can be highly effective analgesics, but are underused in Korea. In this article, we would like to review the basic concepts of hypnosis, the mechanism, and the outcome data of the analgesic effects of hypnosis, and also, its limitations. PMID- 22514774 TI - Evaluation of an Experimentally Designed Stereotactic Guidance System for Determining Needle Entry Point during Uniplanar Fluoroscopy-guided Intervention. AB - BACKGROUND: In discography performed during percutaneous endoscopic lumbar discectomy (PELD) via the posterolateral approach, it is difficult to create a fluoroscopic tunnel view because a long needle is required for discography and the guide-wire used for consecutive PELD interrupts rotation of fluoroscope. A stereotactic system was designed to facilitate the determination of the needle entry point, and the feasibility of this system was evaluated during interventional spine procedures. METHODS: A newly designed stereotactic guidance system underwent a field test application for PELD. Sixty patients who underwent single-level PELD at L4-L5 were randomly divided into conventional or stereotactic groups. PELD was performed via the posterolateral approach using the entry point on the skin determined by premeasured distance from the midline and angles according to preoperative magnetic resonance imaging (MRI) findings. Needle entry accuracy provided by the two groups was determined by comparing the distance and angle measured by postoperative computed tomography with those measured by preoperative MRI. The duration and radiation exposure for determining the entry point were measured in the groups. RESULTS: The new stereotactic guidance system and the conventional method provided similarly accurate entry points for discography and consecutive PELD. However, the new stereotactic guidance system lowered the duration and radiation exposure for determining the entry point. CONCLUSIONS: The new stereotactic guidance system under fluoroscopy provided a reliable needle entry point for discography and consecutive PELD. Furthermore, it reduced the duration and radiation exposure associated with determining needle entry. PMID- 22514775 TI - Ischiorectal block with bupivacaine for post hemorrhoidectomy pain. AB - BACKGROUND: Hemorrhoid is one of the most common surgical diseases occurring in the anorectal region. In this study, we evaluated the effect of ischiorectal fossa block on alleviating post hemorrhoidectomy pain. METHODS: In this study, 90 patients suffering from hemorrhoids were evaluated. They were randomly divided into 3 groups. The first group had no block, the second group an ischiorectal block with placebo (normal saline), and the third group a preemptive ischiorectal block with bupivacaine. Postoperative variables such as pain intensity, pethidine consumption, nausea, and vomiting were compared between the groups. RESULTS: The postoperative pain score in group 1 was 8.5 +/- 1.3 and 8.1 +/- 0.9 (P = NS) in group 2. The post operative analgesic demand was 3.1 +/- 1.5 and 3.3 +/- 1.8 hours in groups 1 and 2, respectively (P = NS). The post operative pain score and analgesic demand were 4.2 +/- 2.1 and 9.3 +/- 2.7 hours, respectively, in group 3 (P < 0.0001). CONCLUSIONS: Preemptive ischiorectal block reduces the posthemorrhoidectomy pain and opioid demand. PMID- 22514776 TI - Effect of intravenous lidocaine on the neuropathic pain of failed back surgery syndrome. AB - BACKGROUND: An intravenous infusion of lidocaine has been used on numerous occasions to produce analgesia in neuropathic pain. In the cases of failed back surgery syndrom, the pain generated as result of abnormal impulse from the dorsal root ganglion and spinal cord, for instance as a result of nerve injury may be particularly sensitive to lidocaine. The aim of the present study was to identify the effects of IV lidocaine on neuropathic pain items of FBSS. METHODS: The study was a randomized, prospective, double-blinded, crossover study involving eighteen patients with failed back surgery syndrome. The treatments were: 0.9% normal saline, lidocaine 1 mg/kg in 500 ml normal saline, and lidocaine 5 mg/kg in 500 ml normal saline over 60 minutes. The patients underwent infusions on three different appointments, at least two weeks apart. Thus all patients received all 3 treatments. Pain measurement was taken by visual analogue scale (VAS), and neuropathic pain questionnaire. RESULTS: Both lidocaine (1 mg/kg, 5 mg/kg) and placebo significantly reduced the intense, sharp, hot, dull, cold, sensitivity, itchy, unpleasant, deep and superficial of pain. The amount of change was not significantly different among either of the lidocaine and placebo, or among the lidocaine treatments themselves, for any of the pain responses, except sharp, dull, cold, unpleasant, and deep pain. And VAS was decreased during infusion in all 3 group and there were no difference among groups. CONCLUSIONS: This study shows that 1 mg/kg, or 5 mg/kg of IV lidocaine, and palcebo was effective in patients with neuropathic pain attributable to FBSS, but effect of licoaine did not differ from placebo saline. PMID- 22514777 TI - Ultrasonographic measurement of the ligamentum flavum depth; is it a reliable method to distinguish true and false loss of resistance? AB - BACKGROUND: Previous studies have shown that if performed without radiographic guidance, the loss of resistance (LOR) technique can result in inaccurate needle placement in up to 30% of lumbar epidural blocks. To date, no study has shown the efficacy of measuring the depth of the posterior complex (ligamentum flavum, epidural space, and posterior dura) ultrasonographically to distinguish true and false LOR. METHODS: 40 cervical epidural blocks were performed using the LOR technique and confirmed by epidurograms. Transverse ultrasound images of the C6/7 area were taken before each cervical epidural block, and the distances from the skin to the posterior complex, transverse process, and supraspinous ligament were measured on each ultrasound view. The number of LOR attempts was counted, and the depth of each LOR was measured with a standard ruler. Correlation of false and true positive LOR depth with ultrasonographically measured depth was also statistically analyzed. RESULTS: 76.5% of all cases (26 out of 34) showed false positive LOR. Concordance correlation coefficients between the measured distances on ultrasound (skin to ligamentum flavum) and actual needle depth were 0.8285 on true LOR. Depth of the true positive LOR correlated with height and weight, with a mean of 5.64 +/- 1.06 cm, while the mean depth of the false positive LOR was 4.08 +/- 1.00 cm. CONCLUSIONS: Ultrasonographic measurement of the ligamentum flavum depth (or posterior complex) preceding cervical epidural block is beneficial in excluding false LOR and increasing success rates of cervical epidural blocks. PMID- 22514778 TI - Treatment of idiopathic persistent hiccups with positive pressure ventilation -a case report-. AB - A 41-year-old male patient presented with idiopathic persistent hiccups. The hiccups did not respond to pharmacologic treatments including cisapride, omeprazole, and baclofen. Phrenic nerve block was also ineffective. However, the persistent hiccups were successfully treated with short-term positive pressure ventilation using a short-acting muscle relaxant. PMID- 22514779 TI - Extradigit glomus tumor causing abdominal pain -a case report-. AB - Glomus tumors are small vascular tumors that are usually benign and rarely occur. They originate from glomus bodies and present in the reticular dermis. They are clinically distinguished by their small size and their ability to cause extreme pain. Most of these tumors are subungually located. However, atypical locations of the tumors sometimes cause misdiagnosis, particularly when the lesion is rarely reported. Therefore, we report a case of glomus tumor which presented with chronic abdominal pain, found in the abdominal wall that has never been reported before. PMID- 22514780 TI - Epidural Blood Patch for the Treatment of Abducens Nerve Palsy due to Spontaneous Intracranial Hypotension -A Case Report-. AB - Intracranial hypotension is characterized by a postural headache which is relieved in a supine position and worsened in a sitting or standing position. Although less commonly reported than postural headache, sixth nerve palsy has also been observed in intracranial hypotension. The epidural blood patch (EBP) has been performed for postdural puncture headache, but little is known about the proper timing of EBP in the treatment of sixth nerve palsy due to intracranial hypotension. This article reports a case of sixth nerve palsy due to spontaneous intracranial hypotension which was treated by EBP 10 days after the onset of palsy. PMID- 22514781 TI - Psoas compartment blockade in a laterally herniated disc compressing the psoas muscle -a case report-. AB - A psoas compartment block has been used to provide anesthesia for orthopedic surgical procedures and analgesia for post-operative pain. Currently, this block is advocated for relieving pain in the lower extremity and pelvic area resulting from various origins. We report a case of a 69-year-old male patient who had gait abnormality with posterior pelvic and hip pain, which were both aggravated by hip extension. From the magnetic resonance image, the patient was found to have a laterally herniated intervertebral disc at the L2/3 level, which compressed the right psoas muscle. This was thought to be the origin of the pain, so a psoas compartment block was performed using 0.25% chirocaine with triamcinolone 5mg, and the pain in both the pelvis and hip were relieved. PMID- 22514782 TI - Spinal cord stimulation for refractory angina pectoris -a case report-. AB - Refractory angina pectoris is defined as angina refractory to optimal medical treatment and standard coronary revascularization procedures. Despite recent therapeutic advances, patients with refractory angina pectoris are not adequately treated. Spinal cord stimulation is a minimally invasive and reversible technique which utilizes electrical neuromodulation by means of an electrode implanted in the epidural space. It has been reported to be an effective and safe treatment for refractory angina pectoris. We report a case of spinal cord stimulation which has effectively relieved chest pain due to coronary artery disease in a 40-year old man. This is the first report of spinal cord stimulation for treatment of refractory angina pectoris in South Korea. PMID- 22514783 TI - Aspiration pneumonitis caused by delayed respiratory depression following intrathecal morphine administration. AB - Opioid analgesia is the primary pharmacologic intervention for managing pain. However, opioids can cause various adverse effects including pruritus, nausea, constipation, and sedation. Respiratory depression is the most fatal side effect. Therefore, cautious monitoring of respiratory status must be done after opioid administration. Here, we report a patient who suffered from respiratory depression with deep sedation and aspiration pneumonitis after intrathecal morphine administration. PMID- 22514784 TI - Radiation safety for pain physicians. PMID- 22514785 TI - Cannula-induced Vertebral Reduction during Kyphoplasty in a Patient with Kummell's Disease. PMID- 22514786 TI - Is epidurogram a reliable tool for the diagnosis of epidural adhesion? PMID- 22514787 TI - Seed germination and seedling development ecology in world-wide populations of a circumboreal Tertiary relict. AB - BACKGROUND AND AIMS: Temperate forests are disjunct in the Northern Hemisphere, having become fragmented from the earlier widespread (Tertiary) boreotropical forest. We asked 'What are the contemporary patterns of population variation in ecological traits of a Tertiary relict in a macroecological context?'. This issue underpins our understanding of variation in populations occurring in the same biome but on different continents. METHODOLOGY: We examined characters associated with root and shoot emergences among populations of Viburnum opulus in temperate forests of Asia, North America and Europe. This species has complex seedling emergence extending over several years and requiring various temperature cues. PRINCIPAL RESULTS: Populations varied in germination responses and clustered into groups that were only partly related to varietal status. Whereas roots (at warm temperatures) and shoots (following a cold period) simultaneously emerged from seeds of all populations when simulated dispersal occurred in winter, they were delayed in some populations when dispersal occurred in summer. CONCLUSIONS: Viburnum opulus populations, some separated by 10 300 km, showed high similarity in seedling development and in germination phenology, and we suggest that stabilizing selection has played a key role in maintaining similar dormancy mechanisms. Nevertheless, there was some degree of variation in other germination characters, suggesting local adaptation. PMID- 22514788 TI - A Review of Varenicline's Efficacy and Tolerability in Smoking Cessation Studies in Subjects with Schizophrenia. AB - Schizophrenia is a severe psychiatric disorder affecting 1% of the world's population. Nicotine addiction is one of the most important health concerns for patients with schizophrenia. An extensive body of evidence points to a high prevalence rate of comorbid nicotine addiction in people with schizophrenia (70 90%), which contributes to significant cardiovascular and cancer risks in this vulnerable population. Therefore, effective smoking cessation strategies could play a major role in preventing significant morbidity and mortality in this population. Two of the most common pharmacological approaches to smoking cessation, bupropion and nicotine replacement therapy (NRT), have been used in psychiatric patients to reduce their smoking. In 2006, varenicline, a partial agonist of alpha4beta2 acetylcholine receptor, was approved for smoking cessation by the FDA. This drug not only has the beneficial effects on withdrawal symptoms, but also reduces craving and rewarding effects of smoking. While varenicline has been shown to be an effective, safe medication for the general population, its efficacy and safety for subjects with schizophrenia is less well characterized. A number of case studies have prompted FDA warnings about the potential exacerbation of psychiatric symptoms. However, other case studies and pilot studies have shown varenicline to be a safe and effective treatment for smoking cessation in subjects with schizophrenia. Varenicline has the potential to reduce smoking in subjects with schizophrenia, however, clinicians should carefully monitor patients receiving varenicline for potential exacerbation of psychiatric symptoms. PMID- 22514789 TI - Design of "smart" probes for optical imaging of apoptosis. AB - Apoptosis is a mode of programmed cell death in multicellular organisms and plays a central role in controlling embryonic development, growth and differentiation and monitoring the induction of tumor cell death through anticancer therapy. Since the most effective chemotherapeutics rely on apoptosis, imaging apoptotic processes can be an invaluable tool to monitor therapeutic intervention and discover new drugs modulating apoptosis. The most attractive target for developing specific apoptosis imaging probes is caspases, crucial mediators of apoptosis. Up to now, various optical imaging strategies for apoptosis have been developed as an easy and economical modality. However, current optical applications are limited by poor sensitivity and specificity. A subset of molecular imaging contrast agents known as "activatable" or "smart" molecular probes allow for very high signal-to-background ratios compared to conventional targeted contrast agents and open up the possibility of imaging intracellular targets. In this review, we will discuss the unique design strategies and applications of activatable probes recently developed for fluorescence and bioluminescence imaging of caspase activity. PMID- 22514790 TI - Support group processes: Perspectives from HIV-infected women in South Africa. AB - This study examined the experiences and perceived benefits of support group participation among HIV-infected women in South Africa. From a qualitative analysis of responses, key psychological processes through which support groups are potentially beneficial were identified. These processes included: identification; modeling; acceptance; and empowerment. The participants' consequent life changes were explored in order to associate these processes with the positive outcomes of support group participation. Through understanding the relationship between the psychological processes within a support group setting and the potential benefits, and by targeting these processes in the development and implementation of future support group interventions, a framework is provided for achieving positive outcomes associated with support group participation. PMID- 22514791 TI - Synthesis of cycloheptanoid natural products via tandem 5-exo cyclization/Claisen rearrangement process. AB - This article describes the development of microwave-assisted oxyanionic 5-exo-dig cyclization-Claisen rearrangement sequence as a convenient "one-pot" route to a variety of seven-membered carbocyclic ring systems. This process was used as the key transformation for the construction of several natural products, including frondosins A, B, and C. PMID- 22514792 TI - The pharmacology of neurotrophic treatment with Cerebrolysin: brain protection and repair to counteract pathologies of acute and chronic neurological disorders. AB - Neurotrophic factors are considered as part of the therapeutic strategy for neurological disorders like dementia, stroke and traumatic brain injury. Cerebrolysin is a neuropeptide preparation which mimics the action of endogenous neurotrophic factors on brain protection and repair. In dementia models, Cerebrolysin decreases beta-amyloid deposition and microtubule-associated protein tau phosphorylation by regulating glycogen synthase kinase-3beta and cyclin dependent kinase 5 activity, increases synaptic density and restores neuronal cytoarchitecture. These effects protect integrity of the neuronal circuits and thus result in improved cognitive and behavioral performance. Furthermore, Cerebrolysin enhances neurogenesis in the dentate gyrus, the basis for neuronal replacement therapy in neurodegenerative diseases. Experimental studies in stroke animal models have shown that Cerebrolysin stabilizes the structural integrity of cells by inhibition of calpain and reduces the number of apoptotic cells after ischemic lesion. Cerebrolysin induces restorative processes, decreases infarct volume and edema formation and promotes functional recovery. Stroke-induced neurogenesis in the subventricular zone was also promoted by Cerebrolysin, thus supporting the brain's self-repair after stroke. Both, traumatic brain and spinal cord injury conditions stimulate the expression of natural neurotrophic factors to promote repair and regeneration processes -axonal regeneration, neuronal plasticity and neurogenesis- that is considered to be crucial for the future recovery. Neuroprotective effects of Cerebrolysin on experimentally induced traumatic spinal cord injury have shown that Cerebrolysin prevents apoptosis of lesioned motoneurons and promotes functional recovery. This section summarizes the most relevant data on the pharmacology of Cerebrolysin obtained from in vitro assays (biochemical and cell cultures) and in vivo animal models of acute and chronic neurological disorders. PMID- 22514793 TI - Cerebrolysin improves symptoms and delays progression in patients with Alzheimer's disease and vascular dementia. AB - Dementia is the result of various cerebral disorders, leading to an acquired loss of memory and impaired cognitive ability. The most common forms are Alzheimer's disease (AD) and vascular dementia (VaD). Neurotrophic factors are essential for the survival and differentiation of developing neurons and protecting them against damage under pathologic conditions. Cerebrolysin is a peptide preparation that mimics the pleiotropic effects of neurotrophic factors. Several clinical trials investigating the therapeutic efficacy of Cerebrolysin in AD and VaD have confirmed the proof of concept. The results of these trials have shown statistically significant and clinically relevant treatment effects of Cerebrolysin on cognitive, global and functional domains in mild to moderately severe stages of dementia. Doses of 10 and 30 mL were the most effective, but higher doses of up to 60 mL turned out to be most effective in improving neuropsychiatric symptoms, which become relevant at later stages of the disease. Combining treatment with cholinesterase inhibitors and Cerebrolysin indicated long-term synergistic treatment effects in mild to moderate AD. The efficacy of Cerebrolysin persisted for up to several months after treatment suggesting Cerebrolysin has not merely symptomatic benefits, but a disease-delaying potential. This paper reviews the clinical efficacy of Cerebrolysin in the treatment of dementia. Data were obtained from international, multicenter, randomized clinical trials performed in compliance with Good Clinical Practice and the principles of the Declaration of Helsinki (1964) and subsequent revisions. PMID- 22514794 TI - Accelerated recovery from acute brain injuries: clinical efficacy of neurotrophic treatment in stroke and traumatic brain injuries. AB - Stroke is one of the most devastating vascular diseases in the world as it is responsible for almost five million deaths per year. Almost 90% of all strokes are ischemic and mainly due to atherosclerosis, cardiac embolism and small-vessel disease. Intracerebral or subarachnoid hemorrhage can lead to hemorrhagic stroke, which usually has the poorest prognosis. Cerebrolysin is a peptide preparation which mimics the action of a neurotrophic factor, protecting stroke-injured neurons and promoting neuroplasticity and neurogenesis. Cerebrolysin has been widely studied as a therapeutic tool for both ischemic and hemorrhagic stroke, as well as traumatic brain injury. In ischemic stroke, Cerebrolysin given as an adjuvant therapy to antiplatelet and rheologically active medication resulted in accelerated improvement in global, neurological and motor functions, cognitive performance and activities of daily living. Cerebrolysin was also safe and well tolerated when administered in patients suffering from hemorrhagic stroke. Traumatic brain injury leads to transient or chronic impairments in physical, cognitive, emotional and behavioral functions. This is associated with deficits in the recognition of basic emotions, the capacity to interpret the mental states of others, and executive functioning. Pilot clinical studies with adjuvant Cerebrolysin in the acute and postacute phases of the injury have shown faster recovery, which translates into an earlier onset of rehabilitation and shortened hospitalization time. PMID- 22514795 TI - Safety profile of Cerebrolysin: clinical experience from dementia and stroke trials. AB - The safety of Cerebrolysin has been shown through many years of clinical use, observations from postmarketing surveillance studies, and safety data from randomized, controlled clinical trials. The reported events showed that adverse reactions to Cerebrolysin were generally mild and transient. Most common adverse events included vertigo, agitation and feeling hot. In the controlled clinical trials analyzed for this report, the incidence of adverse events was similar in Cerebrolysin- and placebo-treated groups. Cerebrolysin seems to be safe when used in combination with recombinant tissue-type plasminogen activator or cholinesterase inhibitors such as donepezil or rivastigmine. To our knowledge, Cerebrolysin was not associated with major changes in vital signs or laboratory parameters. PMID- 22514796 TI - Carpe diem: nursing making inroads to improve mental health for elders. PMID- 22514797 TI - The official journal for the Council for the Advancement of Nursing Science (CANS). PMID- 22514798 TI - Prioritizing association strength versus value: the influence of self-regulatory modes on means evaluation in single goal and multigoal contexts. AB - Means of goal attainment are said to be multifinal when they are capable of attaining more than 1 goal at the same time. Such means have an advantage over unifinal means because they have the potential to attain greater overall value. However, they have the disadvantage (relative to unifinal means) of diluting the association between the means and each of the goals (Zhang, Fishbach, & Kruglanski, 2007). In turn,diluted association strength is often interpreted as reduced means' instrumentality. Given these tradeoffs between value (favoring a multifinal option) and instrumentality (favoring the unifinal option), the question is under what conditions 1 or the other would be selected. Based on regulatory mode theory(Higgins, Kruglanski, & Pierro, 2003; Kruglanski et al., 2000), we predicted and found in 5 experiments that individuals operating in a locomotion self-regulatory mode prefer a unifinal to multifinal means,whereas individuals operating in an assessment mode prefer multifinal to unifinal means. Implications of these findings for self-regulatory phenomena are discussed. PMID- 22514799 TI - The beginning of a new editorial term at the Attitudes and Social Cognition section of the Journal of Personality and Social Psychology (JPSP) is a natural occasion for reflection on this journal's mission. Introduction. PMID- 22514800 TI - Quantification of phytochelatins and their metal(loid) complexes: critical assessment of current analytical methodology. AB - Whilst there are a variety of methods available for the quantification of biothiols in sample extracts, each has their own inherent advantages and limitations. The ease with which thiols readily oxidise not only hinders their quantification but also alters the speciation profile. The challenge faced by the analyst is not only to preserve the speciation of the sample, but also to select a method which allows the retrieval of the desired information. Given that sulfur is not a chromophore and that it cannot easily be monitored by ICP-MS, a number of direct and indirect methods have been developed for this purpose. In order to assess these methods, they are compared in the context of the measurement of arsenic-phytochelatin complexes in plant extracts. The inherent instability of such complexes, along with the instabilities of reduced glutathione and phytochelatin species,necessitates a rapid and sensitive analytical protocol. Whilst being a specific example, the points raised and discussed in this review will also be applicable to the quantification of biothiols and thiol-metal(loid) species in a wide range of systems other than just the analysis of arsenic phytochelatin species in plant extracts. PMID- 22514801 TI - Four alleles of AtCESA3 form an allelic series with respect to root phenotype in Arabidopsis thaliana. AB - Plant cell shape is determined by the orientation of cellulose microfibrils in the primary cell wall. Consequently, mutations that affect genes encoding the enzymes responsible for the synthesis of cellulose, namely, the cellulose synthase catalytic subunits, can alter cell shape substantially, particularly in the roots of affected plants. The multiple response expansion1 (mre1) mutant of Arabidopsis thaliana results from a point mutation in the AtCESA3 gene, which encodes one of the three isoforms of the cellulose synthase catalytic subunit required for synthesis of cellulose in the primary cell wall. Phenotypic comparison of the mre1 mutant with three other alleles (ectopic lignification1-1, ectopic lignification1-2 and constitutive expression of vsp1) showed that these four alleles form an allelic series with respect to their root phenotypes, with mre1 being the weakest allele identified to date. These analyses demonstrated that sucrose affects a significant alteration of cell shape in the roots of these mutants and likely suppresses root cell division in them as well, and that the chemical aminoisobutyric acid can suppress these effects of sucrose. Interestingly, the cell walls in the roots of these four AtCESA3 alleles contain different percentages of cellulose, and these percentages correlate with the lengths of the roots and cortex cells in these roots when grown on media containing high levels of sucrose. PMID- 22514867 TI - From closed ranks to open doors: Elaine and John Cummings' mental health education experiment in 1950s Saskatchewan. AB - During late 1951 and early 1952, married couple, social biologist Elaine Cumming and psychiatrist John Cumming, led a mental health education experiment in Indian Head, Saskatchewan. The study, which was intended to inform strategies toward deinstitutionalization, sought to determine if attitudes regarding mental illness could be changed through commonly used educational practices. It was shaped by the shared interests of powerful philanthropic, charitable, psychiatric, academic and governmental bodies to create healthier citizens and a stronger democratic nation through expert knowledge. However, in addition to the disappointing findings indicating that attitudes remained unchanged, the town appeared to close ranks against the research team. Nonetheless, the Cummings' later association with sociologists at Harvard University enabled them to interpret the results in a way that lent the study credibility and themselves legitimacy, thus opening the door to their careers as very successful researchers and policy-makers. PMID- 22514868 TI - Visiting the mentally ill: volunteer visitors at Saskatchewan hospital, Weyburn 1950-1965. AB - This article offers a glimpse into the lives and activities of some of the patients, volunteers and staff in the Saskatchewan mental health system during the period of deinstitutionalization. Drawing on her own experience as a patient in psychiatric wards as well as ongoing research in the history of mental health, it features the role of Regina Volunteer Visitors in Saskatchewan Hospital, Weyburn and examines the importance of occupational and recreational therapies and activities in improving the lives of the patients in that institution. It emphasizes the perspectives of patients and volunteers who actively worked to develop recreational activities, with the intention of helping individuals connect with the surrounding communities. The views and perspectives presented here are drawn from a variety of historical and oral interview sources, including views from visitors to the asylum and patients who lived within its walls. The author has also been a consumer of mental health services, and spent time in the Provincial Mental Hospital in North Battleford. The article therefore makes an important contribution to enhancing our understanding of the social history of deinstitutionalization, not only for its unique source base, but also because those sources have been examined and explained to readers through the perspectives of a former patient herself. This article draws significant attention to the changing opportunities for patients as they interacted with the women's volunteer groups, as well as to how the changes brought about by the encroaching deinstitutionalization, care in the community, and decisions from "above" affected the individuals on the ground. PMID- 22514870 TI - [Abstract of the branch meetings of the Japanese Society of Legal Medicine. 2010, Japan]. PMID- 22514869 TI - A house divided: deinstitutionalization, medicare and the Canadian Mental Health Association in Saskatchewan, 1944-1964. AB - Defined as a set of distinct processes that included the declining use of large psychiatric institutions and the increasing use of outpatient services and general hospitals, deinstitutionalization occurred earlier in Saskatchewan than other provinces in Canada. It was led by a CCF government dedicated to major change across a number of sectors including mental health, assisted by one of the most influential and well-organized social movement organizations of the 1950s, the Saskatchewan Division of the Canadian Mental Health Association (SCMHA). However, by the late 1950s and early 1960s, the SCMHA opposed the CCF government's policy priority on medicare which it felt came at the expense of mental health care, in particular the implementation of a regional psychiatric hospital system called the Saskatchewan Plan. As a consequence, the SCMHA, once such a powerful ally of the CCF government in health reform, formed a strategic and temporary coalition with the anti-medicare forces in the province. Given the fact that a number of medical staff within the government's department of public health were prominent members of the SCMHA, the CCF government found that it occupied an increasingly divided house at the very time it was struggling to introduce medicare in the midst of civil unrest and a doctors' strike. PMID- 22514872 TI - [Abstracts of the meeting of the Hokkaido medical society, Hokkaido, Japan, 2011]. PMID- 22514871 TI - Unusual morphological damage of Purkinje cells following postnatal BrdU administration in the cerebellar cortex of mouse. AB - Postnatal development of the cerebellum lasts for weeks in rodents and can be disturbed by systemic 5-bromo-2'-deoxyuridine (BrdU) administration. This thymidine analogue incorporates into the DNA of proliferating cells, and result in more or less serious damage or death granule cells, the most actively dividing neuronal population in the developing cerebellar cortex. Further consequences of postnatal BrdU administration are the interrupted postnatal migration and integrations as well as partial loss of cerebellar Purkinje cells. In the present study, C57B16 mice were administered with 50 MUg/g body weight BrdU, one sc. injection daily, between P0 and P11 postnatal days, respectively.Large "cavities" appeared in the cytoplasm of a subpopulation of Purkinje cells by P7 in about one third of administered animals, their number are size of the cavities (and PCs exhibiting unusual morphology) decreased. EM studies revealed that the unusual Purkinje cells received numerous axonal inputs of unknown origin, first of all on their somatic and dendritic spines. The transitory appearance of a subpopulation of Purkinje cells possessing unusual morphology refers to the influence of other (neuronal, glial, or both) cells on their regular differentiation. PMID- 22514873 TI - [Backstreet cuisine]. PMID- 22514874 TI - [Again on the cancer risk for those who were in military service in the Balkans]. PMID- 22514875 TI - [Not Available]. PMID- 22514876 TI - [Not Available]. PMID- 22514877 TI - Effect of Schlafen 2 on natural killer and T cell development from common T/natural killer progenitors. AB - Natural Killer (NK) cells are thought to develop from common lymphoid progenitors in the bone marrow. Even though thymus is not essential for NK cell development, T-cell/natural killer-cell (T/NK) precursors, DN1 (CD44+CD25-) and DN2 (CD44+CD25+) when cultured on an OP9 stroma, give rise to some NK1.1 cells. Genes of the Schlafen (Slfn) family are involved in hematopoietic and immune processes. The contribution of the Slfn genes in NK cell development from Double Negative (DN) cells is unknown. We transduced DN1 and DN2 progenitors prepared from C57BL/6 (B6) mouse thymus with Schlafen 1 (Slfnl) and Schlafen 2 (Slfn2) genes using Mig retroviral vector containing the Green Fluorescent Protein (GFP) gene and cultured those transduced progenitors on OP9 and OP9 stroma expressing the Notch ligand Delta-like 1 (OP9-DL 1) with appropriate cytokines to see if they affect generating NK and T-cells differently. Maturation of both NK and T cells from immature T/NK thymocytes hampered by Slfn1 and Slfn2 transduction but we got a small number of Slfn1 and Slfn2 expressing cells upon culture of transduced DN progenitors on stroma cells. There was no difference between Slfn1 expressing (GFP+) and none expressing T cells regarding CD3 expression but all mature NK cells were from Slfn1 negative population. Slfn2 completely blocked maturation of T cells but there was no difference between Slfn2 expressing and none expressing NK cells. Based on our findings both Slfn1 and Slfn2 interfere with maturation of DN2 progenitors but T cell development is more sensitive to Slfn2 expression than NK cell. PMID- 22514878 TI - Optimization of process parameters influencing the submerged fermentation of extracellular lipases from Pseudomonas aeruginosa, candida albicans and Aspergillus flavus. AB - The present study was aimed at optimization, production and partial purification of lipases from Pseudomonas aeruginosa, Candida albicans and Aspergillus flavus. Various nutritional and physical parameters affecting lipase production such as carbon and nitrogen supplements, pH, temperature, agitation speed and incubation time were studied. Refined sunflower oil (1% v/v) and tryptone at a pH of 6.2 favored maximum lipase production in Pseudomonas at 30 degrees C and 150 rpm, when incubated for 5 days. In C. albicans refined sunflower oil (3% v/v) and peptone resulted in maximum lipase production at pH 5.2, 30 degrees C and 150 rpm, when incubated for 5 days. In A. flavus coconut oil (3% v/v) and peptone yielded maximum lipase at pH 6.2, 37 degrees C, 200 rpm after an incubation period of 5 days. The lipases were partially purified by ammonium sulphate precipitation and dialysis. In P. aeruginosa enzyme activity of the dialyzed fraction was found to be 400 U mL-' and for C. albicans 410 U mL(-1). The dialysed lipase fraction from A. flavus demonstrated an activity of 460 U mL(-1). The apparent molecular weights of the dialyzed lipases were determined by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). The dialyzed lipase fraction obtained from P. aeruginosa revealed molecular weights of 47, 49 and 51 kDa, whereas, lipases from C. albicans and A. flavus demonstrated 3 bands (16.5, 27 and 51 kDa) and one band (47 kDa), respectively. These extracellular lipases may find wide industrial applications. PMID- 22514879 TI - Screening of endophytic fungi having ability for antioxidative and alpha glucosidase inhibitor activities isolated from Taxus sumatrana. AB - Endophytic microbes are considered as an important source of natural products. They show antibiotic, anticancer, antioxidative and antidiabetic activities. Therefore, there are many reports on the isolation and bioactivity screening of endophytic fungi from various plants including Taxus species. Taxus sumatrana (Miq.) de Laub is found in Indonesia. The objective of this study is to conduct an in vitro screening of 14 endophytic fungi isolated from Taxus sumatrana having antioxidative and alpha-glucosidase inhibitor activities. Each endophytic fungus was cultured for 7 days and the fungal mycelium and medium were extracted with methanol and ethyl acetate, respectively, to produce each extract. The antioxidative activity of each extract was tested by DPPH free radical scavenging activity and beta-carotene bleaching assays, whereas antidiabetic activity was tested based on alpha-glucosidase inhibitor activity. The screening results showed that fungal mycelia of TSC 13 had the best alpha-glucosidase inhibitor activity and TSC 24 had the best antioxidative activity. Isolation of bioactive compounds from TSC 13 and TSC 24 is being conducted. This is the first report that endophytic fungi isolated from T. sumatrana exhibited anti alpha-glucosidase inhibitory and anti oxidative activities. PMID- 22514880 TI - Effects of pyrethroid insecticide exposure on haematological and haemostatic profiles in rats. AB - High malaria burden has led to the increase use of insecticides in the tropics and subtropics. This study thus aimed at assessing the haematological effects and associated haemostatic alteration of pyrethroid insecticide exposure using experimental animal model. Rats of comparable ages and weights were randomized into four groups (A-D). Rats in groups B, C and D were exposed to pyrethroid insecticide by inhalation for 1, 2 and 3 min daily respectively for three weeks. Rats in group A (control) were not exposed. Haematological and haemostatic variables were comparable in all groups (< 0.05). Results from the study show that minimal exposure to pyrethroids is safe. PMID- 22514881 TI - Intensifying groundnut production in the Sudan savanna zone of Nigeria: including groundnut in the irrigated cropping systems. AB - Inadequate and erratic rainfall pattern and extreme temperature variations induced by climate change being experienced in Sudan savanna areas have compromised the cropping systems of these areas. A change in the cropping patterns is required to maintain and improve upon crop output levels. The pod yield ha(-1) and other growth and yield components of three varieties of groundnut grown under irrigated conditions were measured in a field experiment conducted at the Irrigation Research Station of the Institute for Agricultural Research, Zaria, from 2003 to 2006 dry seasons. Treatments consisted of three plant populations (50,000, 100,000 and 200,000 plants ha(-1)), three varieties (Samnut 23, Samnut 21 and Samnut 11) and three basin sizes (3 x 3, 3 x 4 and 3 x 5 m) arranged in a split plot design with population and variety as main plot and basin size as sub plot. Treatments were randomly assigned and replicated three times. Plant populations significantly affected plant height and canopy spread but had no effect on number of branches plant. Plants grew significantly taller at 200,000 plants ha(-1) while plant canopy spread was significantly widest at 50,000 plants ha(-1). Samnut 23 grew significantly taller than Samnut 21 and 11 although they exhibited wider canopies. Pod yield ha(-1) and 100 seed weight were significantly highest at 200,000 plants ha(-1). Samnut 23 produced the significantly highest pod yield ha(-1) and number of pods plant(-1). Samnut 11 produced significantly highest 100 seed weight. Samnut 23 planted at 200,000 plants ha(-1) in 3 x 4 m basins is most promising for irrigated groundnut cultivation in the Sudan savanna of Nigeria. PMID- 22514882 TI - Pluripotent stem cells: a new approach to tendon therapy. PMID- 22514883 TI - A comparison of Fumaria parviflora Lam. and Momordica balsamina Linn. hepatoprotection. PMID- 22514884 TI - APACHE II scoring and antibiotics significance against VAP associated risks. PMID- 22514885 TI - A comprehensive review of vaginitis phytotherapy. AB - To overview phytotherapy of vaginitis in order to identify new approaches for new pharmacological treatments. All related literature databases were searched for herbal medicinal treatment in vaginitis. The search terms were plant, herb, herbal therapy, phytotherapy, vaginitis, vaginal, anti-candida, anti-bacterial and anti-trichomonas. All of the human, animal and in vitro studies were included. Anti-candida, anti-bacterial and anti-trichomonas effects were the key outcomes. The plants including carvacrol, 1,8-cineole, geranial, germacrene-D, limonene, linalool, menthol, terpinen-4-ol and thymol exhibited anti-candida effects. A very low concentration of geranium oil and geraniol blocked mycelial growth, but not yeast. Tea tree oil including terpinen-4-ol, alpha-terpinene, gamma-terpinene and alpha-terpineol showed anti-bacterial, anti-fungal and anti protozoal properties against trichomonas. Allium hirtifolium (persian shallot) comparable to metronidazole exhibited anti-trichomonas activity due to its components such as allicin, ajoene and other organosulfides. The plants having beneficial effects on vaginitis encompass essential oils that clear the pathway that future studies should be focused to standardize theses herbs. PMID- 22514886 TI - Salinity induced changes in photosynthetic pigment and antioxidant responses in Sesuvium portulacastrum. AB - The production of leaf and root antioxidant changes when exposed to saline conditions were investigated in the perennial halophyte Sesuvium portulacastrum L. Plants were grown with a nonsterilized soil and sterilized soil with 50 and 100% of sterilized seawater on 25, 55 and 85 Days After Planting (DAP). The plants were harvested on 30th, 60th and 90th DAP and used for analyzing the photosynthetic pigments, antioxidant enzyme activities viz., Superoxide dismutase (SOD; EC1.15.1.1) Ascorbate peroxidase (APX, EC 1.11.1.11) and non enzymatic antioxidant contents like ascorbic acid, alpha-tocopherol, reduced glutathione were determined. Plants exposed to salinity, either alone (SSW) sterilized seawater/unsterilized soil (USS) along with higher pigments, antioxidative enzymes and Na+ ions response. This tendency was generally more marked in SSW/USS plants when compared to SSW/SS plants. The concentration of SSW/SS was negatively correlated with the antioxidative capacity of the plant, either enzymatic or non enzymatic and K+ ions. These data suggest that the enhancement of the antioxidative response is of crucial significance for S. portulacastrum plants growing under saline conditions. PMID- 22514887 TI - Expression of p53 during apoptosis induced by D-galactosamine and the protective role of PGE1 in cultured rat hepatocytes. AB - p53 is a critical player in the prevention of tumor development. It can contribute directly to DNA repair and inhibition of angiogenesis and subsequently to the induction of apoptosis. The regulation of p53 expression is mediated by the transcription factor NF-kappaB. This includes regulation of p53 protein stability, control of its subcellular localization and conformational changes that allow activation of the DNA binding activity of p53. Rat hepatocytes were isolated from male Wistar rats following collagenase perfusion of liver. We examined the change in the expression level of p53 by western blotting in hepatocytes and its effect on apoptosis as a response of treatment with D galactosamine, prostaglandin E1 and/or the Proteosome Inhibitor (PSI). A kinetic study of the extracellular lactate dehydrogenase activity, NF-kappaB activation, induced nitric oxide synthase expression and nitric oxide production was carried out in hepatocytes. The addition of prostaglandin E1 to control and D galactosamine-treated hepatocytes increased p53 expression in the cytoplasm during 24 h. While the addition of PSI in the absence of prostaglandin E1 decreased p53 expression at 5 mM D-galactosamine. This inhibition is reversed in the presence of prostaglandin E1 at 5 and 40 mM D-galactosamine. The protective action of prostaglandin E1 against the apoptotic effect of D-galactosamine is mediated by NF-kappaB activation, induced nitric oxide synthase and p53 expression. PMID- 22514888 TI - Antidiabetic activity evaluation of glimepiride and Nerium oleander extract on insulin, glucose levels and some liver enzymes activities in experimental diabetic rat model. AB - The present study is aimed to assess the therapeutic potential of sulfonylurea drug glimepiride in comparison with Nerium oleander plant extract on insulin, glucose levels and some liver enzymes activities in streptozotocin-induced diabetic rats. Rats were rendered diabetic by intraperitoneal injection of a single dose of 50 mg kg(-1) body weight streptozotocin. Rats with serum glucose levels > 200 mg dL(-1) were subdivided into three sub-groups: the first sub-group were remained without treatment and considered as diabetics. The second and third subgroups were orally administered 0.1 mg kg(-1) body weight/day glimepiride and 250 mg kg(-1) body weight/day Nerium oleander, respectively for 4 weeks. Streptozotocin-induced diabetic rats showed hypoinsulinemia and hyperglycemia compared to controls. Strong negative correlation (r = -0.8) was found between serum insulin and glucose levels in diabetic rats. This correlation was +0.4 and 0.3 in glimepiride and Nerium olender-treated rats, respectively implying that glimepiride and plant extract improved insulin and glucose levels with the former was more efficient. The activities of serum aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase were significantly increased in streptozotocin-induced diabetic rats compared to controls. Treatment of diabetic rats with glimepiride or Nerium oleander extract also improved liver enzymes activities. PMID- 22514889 TI - Effects of spiracle-blocking insecticides and microbial insecticides on the predator mirid bug, Nesidiocoris tenuis (reuter) (heteroptera: miridae). AB - Spiracle-blocking insecticides and microbial insecticides are widely used for Integrated Pest Management (IPM) in Japan while Nesidiocoris tenuis is used for the control of thrips and whiteflies in Kochi Prefecture, Japan. However, the effects of the insecticides mentioned above on N. tenuis were unclear. This study investigated the effects of five spiracle-blocking insecticides and two microbial insecticides on the nymphs and adults ofN. tenuis. Propylene glycol fatty acid monoester was slightly harmful to both the nymphs and adults. Hydroxypropyl starch was slightly harmful to the nymphs, while sodium oleate was slightly harmful to the adults. Decanoyloctanoylglycerol and hydrogenated starch hydrolysate were not harmful to either the nymphs or adults. Beauveria bassiana was extremely harmful to the adults and was moderately harmful to the nymphs. Lecanicillium muscarium was slightly harmful to the adults. Therefore, decanoyloctanoylglycerol and hydrogenated starch hydrolysate can be used in combination with N. tenuis to establish an IPM program. PMID- 22514890 TI - Steroidal ester of Cassia nigricans have antibacterial potential. PMID- 22514891 TI - Modified CTAB method for high quality genomic DNA extraction from medicinal plants. PMID- 22514892 TI - Ocimum sanctum may overcome fatigue stress. PMID- 22514893 TI - Protective effect of berberine on expression pattern of apoptotic, cell proliferative, inflammatory and angiogenic markers during 7,12 dimethylbenz(a)anthracene induced hamster buccal pouch carcinogenesis. AB - Investigation of expression pattern of molecular markers in oral epithelial tissues would help to assess the cell differentiation and proliferation as well as early diagnosis of precancerous and cancerous lesions of the oral cavity. Aim of the present study was to investigate the protective effect of berberine on expression pattern of apoptotic, cell proliferative, inflammatory and angiogenic markers during 7,12-dimethylbenz(a)anthracene (DMBA) induced hamster buccal pouch carcinogenesis. Immunohistochemical staining [p53, Bcl-2, Bax, Proliferating Cell Nuclear Antigen (PCNA) and Vascular Endothelial Growth Factor (VEGF)], Enzyme Linked Immuno Sorbent Assay (ELISA) [c-fos, COX-2, caspase-3 and -9] and Real Time PCR [Cyclin D1 and NFkappaB] were utilized to assess the expression pattern of molecular markers in DMBA induced hamster buccal pouch carcinogenesis. Over expression of mutant p53, PCNA, Bcl-2 and VEGF were noticed in hamsters treated with DMBA alone. Decreased expression of Bax protein was noticed in hamsters treated with DMBA alone. Increased expression of C-fos, COX-2, NFkappaB and Cyclin D1 and decreased activities of caspase-3 and -9 were also noticed in hamsters treated with DMBA alone. Oral administration ofberberine at a dose of 75 mg kg(-1) b.w. brought back the expression of above mentioned molecular markers to near normal pattern in hamsters treated with DMBA. The present results thus suggest that berberine has potent anti-inflammatory, anti-angiogenic, anti-cell proliferative and apoptosis inducing properties in DMBA induced oral carcinogenesis. PMID- 22514894 TI - Protein improvement in Gari by the use of pure cultures of microorganisms involved in the natural fermentation process. AB - The ability of microorganisms involved in cassava mash fermentation to produce and improve protein value by these microorganisms during fermentation was studied. Standard microbiological procedures were used to isolate, identify and determine the numbers of the organisms. Alcaligenes faecalis, Lactobacillus plantarum, Bacillus subtilis, Leuconostoc cremoris, Aspergillus niger, A. tamari, Geotrichum candidum and Penicillium expansum were isolated and identified from cassava waste water while standard analytical methods were used to determine the ability of the isolates to produce linamarase and the proximate composition, pH and titrable acidity of the fermenting mash. The linamarase activity of the isolates ranged from 0.0416 to 0.2618 micromol mL(-1) nmol(-1). Bacillus subtilis, A. niger, A. tamari and P. expansum did not express any activity for the enzyme. Protein content of mash fermented with mixed fungal culture had the highest protein value (15.4 mg/g/dry matter) while the raw cassava had the least value (2.37 mg/g/dry matter). The naturally fermented sample had the least value for the fermented samples (3.2 mg/g/dry matter). Carbohydrate and fat contents of naturally fermented sample were higher than values obtained from the other fermented samples. Microbial numbers of the sample fermented with mixed bacterial culture was highest and got to their peak at 48 h (57 x 10(8) cfu g(-1)). pH decreased with increase in fermentation time with the mash fermented by the mixed culture of fungi having the lowest pH of 4.05 at the end of fermentation. Titrable acidity increased with increase in fermentation time with the highest value of 1.32% at 96 h of fermentation produced by the mixed culture of fungi. Thus fermentation with the pure cultures significantly increased the protein content of mash. PMID- 22514895 TI - Saffron (Crocus sativus) ethanolic extract and its constituent, safranal, inhibits morphine-induced place preference in mice. AB - The effects of saffron ethanolic extract and its constituent, safranal, on the acquisition and expression of morphine-induced place preference (CPP) in male Swiss Webster mice (20-25 g) were investigated in the present study. An unbiased place conditioning method was applied for assessment of morphine reward properties. The saffron extract and safranal were administered intraperitoneally (i.p.) during (acquisition) or after induction (expression) of morphine CPP. In a pilot study, the extract and safranal were alone administered to the animals to assess if they have any reward properties. Subcutaneous (s.c.) of morphine (4 and 8 mg kg(-1)) and extract (50 mg kg(-1); i.p.) induced CPP. Extract (10, 50 and 100 mg kg(-1); i.p.) reduced the acquisition and expression of morphine CPP. The same results were obtained when safranal (1, 5 and 10 mg kg(-1), i.p.) was used. It may be concluded that both ethanolic saffron extract and safranal can inhibit the acquisition and expression of morphine-induced CPP in the mice. PMID- 22514897 TI - Comparison study of therapeutic results of closed tibial shaft fracture with intramedullary nails inserted with and without reaming. AB - Tibia fractures are the most common type of long bone fractures in US. This study aimed at comparing the therapeutic results of closed tibial shaft fracture with intramedullary nails inserted with and without reaming. In this randomized clinical trial study, 60 patients with a fracture of the tibia were examined. The patients were randomly divided into two groups. Thirty patients treated through inserting intramedullary nail with reaming technique (group A). The other 30 patients treated through inserting intramedullary nail without reaming technique (group B). After operation physical examination and control radiography were taken up to 6 month and results were compared. Sixty patients suffering from closed tibial diaphysis fractures were studied. Mean age of the group A and B were 40.24 +/- 12.32 and 38.42 +/- 14.28, respectively. Group A consisted of 24 (80%) males and 6 (20%) females while group B consisted of 24% females and 76% males. Considering fracture based on OTA criteria (p = 0.4) and severity of soft tissue damage based on Tscherne classification (p = 0.6), there was no statistically meaningful difference between groups A and B. The study demonstrated that degree of horizontal displacement, mean time of surgery, post operation infection, organ shortness at the end of the follow-up period, organ deviation in patients of the group A was significantly more than that of the group B. Time required for callus formation (mean time of union), mean time of full weight bearing time and mean time of return to normal activities in group B was significantly more than that of the group A. PMID- 22514896 TI - Comparative in vitro study of the intestinal absorption of titanium and iron in rats. AB - Rat Everted Gut Sac (EGS) model was employed to study the intestinal uptake of titanium and iron. Incubation of freshly prepared rat EGS in Earle's medium pH = 7.4 containing titanium showed that the absorption of titanium as well as iron was a dose dependent process. Ascorbic acid enhanced the absorption of both metal ions, while NaF (1 mM) as an inhibitor of glycolytic energy supply, decreased their absorption. The Na+-K+ ATPase inhibitor, ouabain (1 mM) reduced intestinal absorption of Titanium. This suggests that titanium uptake is an active transport process as is iron uptake. Iron absorption was reduced approximate by 17% when titanium was presented to incubation medium EGS whereas, the absorption of titanium was decreased by 35% when iron was added to the reaction mixture. PMID- 22514898 TI - An analgesic and hepatoprotective plant: Ocimum gratissimum. PMID- 22514899 TI - Antioxidant potential of dried Enicostemma littorale. PMID- 22514900 TI - Aloe barbadensis provides antiviral defense to tasar silkworm. PMID- 22514902 TI - [The mediating roles of cognition and behavior in the process of maintaining anger]. AB - Relationships were investigated between the sense of unintegration of thoughts, recurrent thinking, and avoidance behavior, which are considered to be factors in maintaining anger. Undergraduate students (N = 990) were asked to write about anger episodes that they had experienced a week or more ago. Then, they completed a questionnaire assessing their sense of unintegration of thoughts at the present time and just after the episode, their present recurrent thinking, their avoidance behavior after the episode, and their present degree of anger. The results of covariance structure analysis indicated that the sense of unintegration of thoughts just after the episode maintained anger through recurrent thinking. Recurrent thinking also intensified their present sense of unintegration of thoughts, which directly maintained anger. Moreover, the sense of unintegration of thoughts just after the episode led to an increase in avoidance behavior, which was related to recurrent thinking. PMID- 22514903 TI - [Psychological effects of emotional crying in adults: events that elicit crying and social reactions to crying]. AB - This research focused on both the psychological benefits and costs of crying. We investigated the relationships of intrapersonal and interpersonal consequences of crying. Female nurses (N = 300) were requested to describe one of the most impressive negative episodes where they had cried. Then, they were asked to complete a questionnaire including a scale of their psychological changes after the crying episode and the social reactions when they cried. Factor analysis revealed five components of the psychological changes scale. Solitary crying had greater effects for both psychological benefits and costs after crying than crying in front of others. Factor analysis revealed three components of the scale of social reactions. When they cried in front of others, "catharsis", "positive attitude", and "recognition of the relationship with others" after crying were associated with "empathy and social support" from others. The factors of "recognition of negative reality" and "negative attitude" were associated with "criticism and slander" from others. These results were discussed in terms of the communicative functions and the reflective functions of adult crying. PMID- 22514901 TI - [Analyzing consumer preference by using the latest semantic model for verbal protocol]. AB - This paper examines consumers' preferences for competing brands by using a preference model of verbal protocols. Participants were 150 university students, who reported their opinions and feelings about McDonalds and Mos Burger (competing hamburger restaurants in Japan). Their verbal protocols were analyzed by using the singular value decomposition method, and the latent decision frames were estimated. The verbal protocols having a large value in the decision frames could be interpreted as showing attributes that consumers emphasize. Based on the estimated decision frames, we predicted consumers' preferences using the logistic regression analysis method. The results indicate that the decision frames projected from the verbal protocol data explained consumers' preferences effectively. PMID- 22514904 TI - [The effects of crime information and response effectiveness on behavioral intentions of coping with crime]. AB - A survey and an experiment were conducted about the promotion of behavioral intentions for preventing sexual assaults by strangers. The study focused on the "identifiable victim effect", where contextual descriptions of a single victim resulted in the collection of more donations than statistical descriptions of victims. A survey of 42 police websites that made recommendation for preventing sexual assaults revealed that only 3.3% of the threat messages described identifiable victims, whereas 50.0% referred to statistical figures. Additionally, only 9.5% of the coping recommendations mentioned the effectiveness of the recommendation. In the experiment, 207 female university students were randomly presented with one of four threat messages featuring victims (statistical, identifiable, combination, or none), followed by recommendation of high-efficacy or low-efficacy response. ANOVA indicated interaction effects of threat type and response efficacy on behavioral intentions. The effect of threat messages was statistically significant only when a high-efficacy response was recommended. The difference in behavioral intentions for different types of threats partly replicated the findings in donation. These results suggest that current threat appeals for crime prevention need refinements regarding both the threat description and response the efficacy. PMID- 22514905 TI - [Studies regarding the goals of indirect request]. AB - Why do people make requests indirectly? We examined the goals of indirect requests in order to answer this question. In study 1, 162 university students completed a questionnaire regarding the goals of indirect requests. Exploratory factor analysis indicated that the goals of indirect requests could be classified into five types: concern for the listener, making an effective request, avoidance of explicit refusal, self-impression management, or conveyance of indebtedness. In study 2, we examined whether these goals actually affect the use of indirect requests by conducting a questionnaire study with 25 university students. The results indicated that some goals (making an effective request, avoidance of explicit refusal, self-impression management, and conveyance of indebtedness) have positive effects on indirect requests, whereas the goal of concern for the listener has no effect. Therefore, we concluded that these four goals which have positive effects are reasonable goals for indirect requests. PMID- 22514906 TI - [The relationship between state anxiety and the impression of sandplay productions in terms of factors of the makers and raters]. AB - This study investigated the relationship between the state anxiety of Sandplay makers and raters, and the raters' impressions of the Sandplay productions. The S Anxiety subscale of the STAI was administered to college students. One group (N = 20) created Sandplay productions which were photographed. Three works were selected from higher S-Anxiety subjects (H-works) and three from lower S-Anxiety subjects (L-works). Then another group of 58 college students were asked to rate these Sandplay productions using the SD method. Factor analysis extracted three factors of Flexibility, Integration, and Activity. The raters were divided into two groups based on their S-Anxiety scores, and their subscale scores were examined using ANOVA. Significant main effects for the makers involved Flexibility and Activity (L-works < H-works). This suggests that the S-Anxiety and ego function of the makers influence their works. Furthermore, an interaction was found with Integration. Higher S-Anxiety raters rated the Integration of L works lower than did the lower S-Anxiety raters. This indicates that higher S Anxiety raters observed the free expression of lower S-anxiety makers from a partial perspective. PMID- 22514907 TI - [Reliability and validity of the Japanese revised version of the television affinity scale]. AB - The purpose of this study was to improve the Japanese version of the Television Affinity Scale (TAS), and to examine the relationship between affinity for television and viewing behavior. Data was based on a random sample of 552 people in Hachioji City (Tokyo, Japan); the response rate was 55.2%. The results revealed the following: (a) the TAS 6-item version had sufficient reliability and validity, (b) the TAS provided information which could not be explained directly by demographic factors, and (c) affinity for television was positively correlated with unplanned and non-concentrated television viewing. These results are consistent with the findings of Erikawa, Yamada, Kawabata, and Numazaki (2007). In addition, the TAS scores correlated positively with entertainment program viewing. This is consistent with the findings of Rubin (1984) that television affinity correlated with ritualized television viewing. The implications of these results for contemporary television viewing are discussed. PMID- 22514908 TI - [Individual differences in strategy use in the Japanese reading span test]. AB - Working memory is a system for processing and storing information. The Reading Span Test (RST), developed by Daneman and Carpenter (1980), is well-known for assessing individual difference in working memory. In the present investigation, we used the Japanese version of the RST (Osaka, 2002) and analyzed individual differences in strategy use from the viewpoint of strategy type (rehearsal, chaining, word-image, scene-image, and initial letter) and frequency of use (used in almost all trials, in half the trials, or not used). Data from the participants (N = 132) were assigned to groups according to the scores, for the total number of words correctly recalled and the proportion correct. The results showed that the frequency of word-image strategy use differed significantly between high-scoring subjects (HSS) and low-scoring subjects (LSS). HSS mainly used word-image and chaining strategies, while LSS used rehearsal and chaining strategies. This indicates that HSS used both verbal and visual strategies, whereas LSS relied only on verbal strategies. The use of the word-image is important for effective retention of words in memory. PMID- 22514909 TI - [How to explain the effects of radiations exactly to your patients?]. PMID- 22514910 TI - [Effects of radiation exposure on human body]. AB - There are two types of radiation health effect; acute disorder and late on-set disorder. Acute disorder is a deterministic effect that the symptoms appear by exposure above a threshold. Tissues and cells that compose the human body have different radiation sensitivity respectively, and the symptoms appear in order, from highly radiosensitive tissues. The clinical symptoms of acute disorder begin with a decrease in lymphocytes, and then the symptoms appear such as alopecia, skin erythema, hematopoietic damage, gastrointestinal damage, central nervous system damage with increasing radiation dose. Regarding the late on-set disorder, a predominant health effect is the cancer among the symptoms of such as cancer, non-cancer disease and genetic effect. Cancer and genetic effect are recognized as stochastic effects without the threshold. When radiation dose is equal to or more than 100 mSv, it is observed that the cancer risk by radiation exposure increases linearly with an increase in dose. On the other hand, the risk of developing cancer through low-dose radiation exposure, less 100 mSv, has not yet been clarified scientifically. Although uncertainty still remains regarding low level risk estimation, ICRP propound LNT model and conduct radiation protection in accordance with LNT model in the low-dose and low-dose rate radiation from a position of radiation protection. Meanwhile, the mechanism of radiation damage has been gradually clarified. The initial event of radiation-induced diseases is thought to be the damage to genome such as radiation-induced DNA double-strand breaks. Recently, it is clarified that our cells could recognize genome damage and induce the diverse cell response to maintain genome integrity. This phenomenon is called DNA damage response which induces the cell cycle arrest, DNA repair, apoptosis, cell senescence and so on. These responses act in the direction to maintain genome integrity against genome damage, however, the death of large number of cells results in acute disorder, and then DNA mis-repair and mutation is speculated to cause cancer. The extent to which this kind of cellular response could reduce the low-dose radiation risk is a major challenge for future research. PMID- 22514911 TI - [History of health management for radiation accident and disaster]. AB - According to the chronological evidences of radiation accident and disaster in the world, we can easily learn the valuable lessons on radiation health effects and also a necessity of well preparatory and organized system and network of emergency radiation medicine. Especially countermeasures on emergency radiation medicine have been categorized simply into two groups: acute and chronic effects, and high-dose and low-dose consequences. Based on the identification of potential impacts on radiation health and environmental effects, referring the past accidents and disasters, comprehensive risk analysis including risk estimation, risk management and risk communication is really required for maintaining healthy lives and safeguards in the unavoidable nuclear age of the 21st century. PMID- 22514912 TI - [Ionizing radiation-induced DNA damage and repair]. AB - Ionizing radiation has been shown to induce various types of chromosomal DNA damages. Among these DNA damages, DNA double strand breaks(DSBs) are the most severe damages resulting in cell death or chromosome abnormalities. Proteins associated with DNA repair, such as phosphorylated form of histone H2AX, a histone variant of H2A, and a DNA recombinase RAD51, has been shown to form radiation-induced repair foci at sites containing DNA damage. Reorganization of damaged chromatin by protein modifications or exchange of histones has been shown to play an important role in the formation of radiation induced repair foci. PMID- 22514913 TI - [Radiation-induced cell death]. AB - Elucidation of the molecular mechanism(s) of cell death induced by ionizing radiation is a main topic in the field of radiation biology. Radiation-induced cell death has been classified as interphase death estimated by vital cell counting and reproductive death estimated by colony forming assay. Recently, many modes of cell death, such as apoptosis, autophagy, mitotic catastrophe, senescence-like cell death, etc. have been reported. In this review, (1) classification of modes of cell death induced by ionizing radiation, (2) radiation-induced apoptosis and its molecular mechanism, (3) significance of radiation-induced cell death are summarized. Discussion on radiation-induced cell death will also focus on radiation-induced normal tissue damage and strategies in radiation cancer PMID- 22514914 TI - [Radiation measurement and dose assessment]. AB - In order to assess an effective dose, it is necessary to evaluate the external exposure caused by gamma ray or neutron, and the internal exposure caused by ingestion from contaminated food or soil and inhalation from radioactive fallout. It is also necessary to consider the equivalent dose of the skin in case of the existence of a high density surface contamination by beta emitters. An early evaluation on the effective dose should be indispensable by a dose calculation using easy expression and by a suitable radiation measurement for the radiation emergency. The accuracy of the effective dose may not be significant at the first stage, but the true value should be included in the range of the fluctuation. Here, radiation measurement is the most effective means to be able to avoid the misjudgment. PMID- 22514915 TI - [Cohort studies of the atomic bomb survivors at the Radiation Effects Research Foundation]. AB - The Radiation Effects Research Foundation has been evaluating the risk of atomic bomb radiation for various diseases since the beginning of its former organization, the Atomic Bomb Casualty Commission. Cohorts of atomic-bomb survivors, in-utero survivors, and survivors' offspring have been followed up. The risk of all solid cancers at 1 Gy was estimated as ERR = 0.47 and EAR = 52/10,000 person-years for people who were exposed at 30 years of age and had reached 70 years of age, based on the cancer incidence during 1958-1998. The risk seemed to be increased in the in-utero survivors, but was rather lower than the risk for the survivors exposed at a young age. Effects on the offspring of survivors have not been shown to be significant. Continuing the research is important in order to more accurately estimate and understand radiation-induced health effects. PMID- 22514916 TI - [Chernobyl nuclear power plant accident and Tokaimura criticality accident]. AB - It is clear from inspection of historical incidents that the scale of disasters in a nuclear power plant accident is quite low level overwhelmingly compared with a nuclear explosion in nuclear war. Two cities of Hiroshima and Nagasaki were destroyed by nuclear blast with about 20 kt TNT equivalent and then approximately 100,000 people have died respectively. On the other hand, the number of acute death is 30 in the Chernobyl nuclear reactor accident. In this chapter, we review health hazards and doses in two historical nuclear incidents of Chernobyl and Tokaimura criticality accident and then understand the feature of the radiation accident in peaceful utilization of nuclear power. PMID- 22514917 TI - [Epidemiological findings on health effects of medical radiation exposures]. AB - Various epidemiological studies have been conducted in relation to medical exposures to therapeutic or diagnostic radiation. These studies provide strong evidence for increased risks of breast, thyroid, and other cancers after exposures to several Gy to several tens of Gy from therapeutic radiation. As for exposures to diagnostic radiation, however, there is much less evidence for increased risks of cancer except for those among patients with tuberculosis and scoliosis, as well as thorotrast patients who received moderate dose of radiation (approximately a hundred mGy or more) to organs or sites of interest. Epidemiological studies on medical exposures continue to provide a unique opportunity to look at the possible health effects from fractionated exposures to low to high dose of radiation which the studies of atomic bomb survivors cannot address. PMID- 22514918 TI - [Acute radiation injury]. AB - Cell death due to DNA damage by ionizing radiation causes acute radiation injury of tissues and organs. Frequency and severity of the injuries increase according to dose increase, when the dose becomes more than threshold dose. The threshold dose of acute human radiation death is 1 Gy and LD50 of human is 4 Gy. Human dies due to the cerebrovascular syndrome, the gastrointestinal syndrome or the hematopoetic syndrome, when he received more than 20 Gy, 10-20 Gy or 3-8 Gy to his total body, respectively. Any tissue or organ, including embryo and fetus, does not show the acute injury, when it received less than 100 mSv. Acute injuries are usually reversible, and late injuries are sometimes irreversible. PMID- 22514919 TI - [Radiation induced carcinogenesis]. AB - Intense research after Hiroshima and Nagasaki atomic bomb (A-bomb) tragedy and Chernobyl nuclear plant accident revealed that ionizing radiation (IR) more than 100 mSv induces cancers that are indistinguishable from sporadic tumors. It remains controversial whether low dose IR (less than 100 mSv) is oncogenic or not. Among IR-induced malignancies, leukemia (A-bomb) and thyroid cancers (Chernobyl), in which chimeric(fusion) oncogenes formed by chromosome translocations play a critical role, develop with relatively short latency. All other cancers develop after long latency. Age-related epigenetic changes, as well as additional genetic alterations, would contribute to IR-induced carcinogenesis. PMID- 22514920 TI - [Radiation-induced skin injuries]. AB - Early radiation dermatitis develops after large doses of X-radiation. Inflammatory erythema develops within about a week. This may heal with desquamation and pigmentation. If the dose was high enough, painful blisters may develop at the site of erythema. In that case, healing usually takes place with atrophy, teleangiectasia, and irregular hyperpigmentation. Subsequent to very large doses, ulceration occurs, generally within 2 months. Such an ulcer may heal ultimately with severe atrophic scarring. Chronic radiation dermatitis occurs from a few months to many years. The skin shows atrophy, teleangiectasia, and irregular hyper- and hypopigmentation. Ulceration may be seen within the areas of atrophy. Radiation ulcerations should be studied by biopsy if they have been present for three or more months. After a long latent period, various malignant neoplasms may form. Most frequent is the basal cell carcinoma, followed by squamous cell carcinoma. PMID- 22514921 TI - [Radiation associated leukemia and myelodysplastic syndrome]. AB - Leukemias including acute myeloid leukemia (AML), acute lymphocytic leukemia, and chronic myeloid leukemia as well as myelodysplastic syndrome (MDS), male non Hodgkin lymphoma and MGUS are statistically significant radiation-associated hematopoietic neoplasms. Recently, MDS has been confirmed to increase among atomic bomb survivors. AML/RUNX1 is a critical transcription factor of differentiation and proliferation of hematopoietic stem cells. AML1 point mutations, especially N-terminal RUNT domain in-frame type, are frequently detected in radiaton-associated and therapy-related (rad-t-) MDS/AML. In addition, the point mutations, are frequently associated with additional mutations in receptor tyrosine kinase (RTK)-RAS pathway, including FLT3, N-RAS, SHP2 and NF1. The combination of AML1/RUNX1 mutation and RTK-RAS pathway mutation in hematopoietic stem cells is considered responsible for the oncogenesis of rad t- MDS/AML. PMID- 22514922 TI - [Thyroid cancer]. AB - The thyroid glands are a vulnerable organ to ionizing radiation. Indeed the epidemiological studies have revealed an increase in the incidences of thyroid cancer among atomic bomb survivors in Hiroshima and Nagasaki and radiation casualties in Chernobyl. The carcinogenic risk for the thyroids is dependent on radiation dose, and higher in younger people. Recent advances in molecular biology contribute to clarify the mechanisms for thyroid carcinogenesis at genetic and molecular levels. Here radiation-induced thyroid carcinogenesis is reviewed from epidemiological data to basic research. PMID- 22514923 TI - [Cataract: based on A-bomb survivor studies]. AB - Until now, the radiation protection community had assumed that only high doses of 2 Gy or more cause cataracts. However, new data from the atomic-bomb (A-bomb) survivors suggest that the dose threshold for both minor opacities and vision limiting cataracts may be below 1 Gy. Other studies have shown similar results in recent years. In 2011, the International Commission on Radiological Protection (ICRP) revised their guidelines for permissible occupational and medical exposures to the eye. PMID- 22514924 TI - [Assessment, diagnosis and treatment of internal or body surface contamination]. AB - Contamination with radioactive materials is classified into surface contamination and internal contamination. Measures for radiation protection to prevent dispersion of the radioactive materials and to protect the medical staffs are essential. Surface contamination is measured by surface survey meter such as a G M counter. Washing or wiping is a choice for treatment. For internal contamination, direct(external) measurement and bioassay are the two methods for dose assessment. Estimation of the committed effective dose is necessary based on the activity inside the body. General treatment to reduce the absorption of radioactive materials, such as laxatives can be used. Stable iodine, Prussian Blue, and DTPA are three well-known and effective drugs for prophylaxis or de cooperation against internal contamination. PMID- 22514925 TI - [Radiation effects on pregnant women, fetuses, and children]. AB - We conducted a review of literature related to radiation effects on pregnant women, fetuses, and children from the perspective of epidemiology, pathology, and radiobiology. During 8-25 weeks post-conception the central nervous system is particularly sensitive to radiation. Fetal doses in excess of 100 mGy can result in some reduction of IQ (intelligence quotient). Fetal doses in the range of 1000 mGy can lead to severe mental retardation and microcephaly, particularly during 8 15 weeks and to a lesser extent 16-25 weeks after conception. Recent studies of cancers and chromosome aberrations indicated less radiosensitivity in prenatally exposed A-bomb survivors compared with postnatally exposed survivors, for which we provide possible hypotheses as an explanation. PMID- 22514926 TI - [Genetic effects of radiation]. AB - This paper is a short review of genetic effect of radiation. This includes methods and results of a large-scale genetic study on specific loci in mice and of various studies in the offspring of atomic-bomb survivors. As for the latter, there is no results obtained which suggest the effect of parental exposure to radiation. Further, in recent years, studies are conducted to the offspring born to parents who were survivors of childhood cancers. In several reports, the mean gonad dose is quite large whereas in most instances, the results do not indicate genetic effect following parental exposure to radiation. Possible reasons for the difficulties in detecting genetic effect of radiation are discussed. PMID- 22514927 TI - [Radiological protection: its concept and principles]. AB - Main concepts and principles of radiation protection system are reviewed. Especially, the concept of LNT model and its background are discussed. Also, the major principles, i.e., (i) justification, (ii) optimization, and (iii) the application of dose limits, are reviewed with emphasis on the existing situation, which is mostly related to the current situation in Fukushima. PMID- 22514928 TI - [Radiation emergency medical preparedness in Japan--lessons learned from the Fukushima accident]. AB - Although radiation exposure accidents fortunately occur only rarely, potential sources for exposure accidents can be found anywhere. When persons are accidentally exposed to radiation, physicians may be involved in their assessment and care; of course, their early diagnosis and dose assessment are crucial. After the criticality accident at Tokaimura in 1999, the system of radiation emergency medical preparedness has been further strengthened for nuclear facilities in Japan. In the revised system, hospitals involved were classified into three levels, depending on their locations and capabilities. The Great East Japan Earthquake attacked the Pacific coast area of eastern Japan on 11 March 2011. This earthquake and tsunami caused serious damage to the nuclear power plants of Tokyo Electric Power Co.(TEPCO) in Fukushima Prefecture; a large amount of radionuclides such as iodine and cesium were released into the environment. Since the revised system was focused on treatment of heavily exposed patients and knowledge on radiation was not enough for medical staff, many problems were raised at hospitals and fire departments in this disaster. PMID- 22514929 TI - [Radiological clinical practice and its safety in hospital]. AB - Medical radiation exposures are increasing world-wide and especially in Japan, because of the progress in medical care. In order to keep the patients safe from medical exposure, we should know not only possible radiation injuries through the radiological interventions provided to the patients, but also the factors which increase or decrease medical exposure. In addition, we have to keep aware of the radiation dose level exposed to the patients, every time we use medical radiation to our patients. Continuing educations and guidelines on medical exposure and consciousness of the dose level are helpful in decreasing the patients' medical exposures, and in consequences, also in protecting ourselves from occupational exposures. PMID- 22514930 TI - [Medical and occupational radiation exposure: present situation and countermeasures]. AB - This paper describes the present status and countermeasures for patient dose and occupational exposure in Japan. The patient radiation dose resulting from a large number of diagnostic radiological procedures presents no substantial risk(deterministic and stochastic effects). Nevertheless, some procedures (e.g., interventional radiology: IVR) carry a risk of deterministic effects, such as skin injury. The regulatory dose limit of the occupational dose for most medical workers was not exceeded. Nevertheless, radiation injuries, such as cataracts, to physicians performing IVR have been reported recently, although not many cases. When radiation protection/optimization issues are addressed adequately, medical exposure will decrease without decreasing the diagnostic benefit to the patient. Consequently, decreasing the patient dose will also decrease occupational exposure. PMID- 22514931 TI - [Initial medical management in radiological accidents and nuclear disaster]. AB - Major radiological emergencies include criticality in nuclear power plants or terrorist attacks using dirty bombs or nuclear device detonation. Because irradiation itself does not cause any immediate death of the victims, and there is a minimum risk of secondary irradiation to medical personnel during decontamination procedures, lifesaving treatments should be prioritized. When a major radiological accident occurs, information is scarce and/or becomes intricate. We might face with significant difficulties in determining the exact culprits of the event, i.e., radiological or chemical or others. Therefore, it is strongly recommended for the national and local governments, related organizations and hospitals to develop comprehensive systems to cope with all hazards(chemical, biological, radiation, nuclear, and explosion) under the common incident command system. PMID- 22514932 TI - [Prevention of radiation damage in interventional radiology (IVR)]. AB - With the development of interventional radiology, radiation protection has become increasingly important for both patients and medical staff in interventional radiology. Sometimes, long fluoroscopy times and repeated angiography lead to higher radiation doses, limited to a small area of the patient's skin surface. This becomes the potential for deterministic effects of the skin and also may lead to an increased risk of stochastic effects. The entrance skin dose and effective dose can be deduced from the dose area product. It should be noted that minimizing patient dose leads to reduction of staff dose. Here we briefly explain radiation protection in interventional radiology. PMID- 22514933 TI - [Ingestion of contaminated foods and drinks and internal radiation]. AB - Many international agencies have evaluated radiation effects to humans. However, reports on effects of international radiation are not so many. Internal exposure of radiation depends on both physical and chemical properties of the radioactive material. Therefore, we combine several methods for the exposure estimation, including environmental measurements and questionnaires to individual subjects. Then, we must select quantitative effect estimates from actual case examples of internal radiation including all age strata, especially children. Among the residents exposed to radiation from the Chernobyl accident in 1986, increased incidence of thyroid cancer and leukemia has been reported. Quantitative effect estimates were also presented in some of the reports. The estimates may be also useful for individual protection for the Fukushima case. PMID- 22514934 TI - [The role of hematopoietic stem cell transplantation in the treatment of acute radiation injury]. AB - The magnitude 9.0 Great East Japan Earthquake on March 11, 2011 brought devastating the world's largest nuclear accidents at the Fukushima Daiichi Nuclear Power Plant. When the mass exposure, hematopoietic tissue, destroyed more quickly with fewer radiation doses compared to other organs. More exposure completely destroys hematopoietic tissues and requires hematopoietic stem cell transplantation. Immunosuppressive therapy as GVHD prophylaxis continues at least 3 months after transplantation and GVHD attacks the same organ as radiation injury in skin, gut and lungs, which makes the treatment so complicated in allogeneic transplantation. If we store autologous stem cells for workers, hematopoietic system can be easily restored. Our conclusion is that we recommend autologous stem cell collection for nuclear power plant workers. PMID- 22514935 TI - [Bullous dermatosis--treatment up-to-date]. AB - Blistering dermatosis are generally known to be constructed of two groups, autoimmune blistering dermatosis and genodermatosis. Autoantibodies are determined in autoimmune blistering dermatosis including pemhigus and bullous pemphigoid. We used to treat them with systemic corticosteroids and various immunosuppressants, with attention to side effects. Apheresis or intravenous immunoglobulin (IVIG) therapy is recommended as a combination therapy with systemic corticosteroids and various immunosuppressants. Some of responsible genes have been elucidated in blistering genodermatosis such as epidermolysis bullosa. Although no specific treatment is available, cell-based therapies using bone marrow cells and fibroblasts improve the quality of life in these patients. In this review, we present an overview of the treatment of blistering dermatosis. PMID- 22514936 TI - [Clinical implications from the results of the CASE-J extension]. AB - The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was conducted to compare the effects of the angiotensin II receptor blocker (ARB) candesartan and the calcium channel blocker (CCB) amlodipine on the incidence of cardiovascular events in Japanese high-risk hypertensive patients. The CASE-J Extension (CASE-J Ex) was an observational study designed to evaluate the long term effects of ARB candesartan and CCB amlodipine, incorporating an additional 3 year follow-up of the CASE-J trial. As in the CASE-J trial, no statistically significant difference was observed in the incidence of primary cardiovascular events, all-cause mortality, or cardiovascular death between the two groups. The superiority of candesartan over amlodipine in reducing new-onset diabetes was sustained in the three-year-long CASE-J Ex, thereby corroborating the results of the CASE-J trial. PMID- 22514937 TI - [Examination of onset cases in contact investigation]. AB - OBJECTIVES: To analyze and evaluate onset cases of tuberculosis detected in contact investigations and to apply the results to future countermeasures. METHODS: Index and secondary cases in contact investigations in which the secondary cases occurred in Osaka City between 2005 and 2008 were enrolled. The tuberculin skin test or QFT (QuantiFERON-TB Gold) was conducted to diagnose whether the contacts were infected with tuberculosis. X-ray examination of the chest was conducted to determine whether tuberculosis had developed, immediately or 6 months, 1 year or 2 years after the contact investigation. RESULTS: (1) Index cases: Index cases followed by secondary cases numbered 131 patients. Regarding the chest X-ray findings, a cavity was observed in 67.7% of the index cases, and a sputum smear of 3 + was observed in 51.5% of the index cases. A 3 month or longer delay in index case-finding was noted in 50.4% of the index cases. (2) Secondary cases: Secondary cases numbered 177 patients, consisting of 107 patients who showed an onset of less than 6 months after their last contact with index cases. Of 70 secondary cases in whom tuberculosis was detected in the investigation conducted 6 months to 2 years after the contact investigation, 50% of them were not tested for infection due to their older age, consisting of 11 patients in their 40's, 8 in their 50's, and 16 in their 60's or over, and 17.1% of them refused or discontinued the treatment for latent tuberculosis infection, leading to onset. DISCUSSION: Many secondary cases were detected immediately after the contact investigation, suggesting the importance of reducing the delay in index case-finding. Regarding the onset of secondary cases who showed an onset 6 months after the last contact with index cases, many cases showed an onset without being tested for infection due to their older age. More attention should be paid to the cases who refused or discontinued the treatment for latent tuberculosis infection, leading to onset. PMID- 22514938 TI - [Molecular epidemiology of rifampicin mono-resistant Mycobacterium tuberculosis]. AB - PURPOSE: We aimed to investigate the prevalence and possible transmission routes of rifampicin (RFP) mono-resistant Mycobacterium tuberculosis strains. METHODS: Drug susceptibility testing was used to identify 15 RFP-resistant strains out of 4633 M. tuberculosis isolates. Sequencing of the rpoB gene and VNTR analysis were performed to further confirm the genetic classification. RESULTS: Resistance conferring mutations in the RFP resistance-determining region (RRDR) of the rpoB gene were found in 14 of the 15 strains with phenotypic RFP mono-resistance. VNTR analysis revealed 2 clusters of 5 identical strains each. CONCLUSIONS: Although the community prevalence of RFP mono-resistant M. tuberculosis is low, the results of VNTR analysis suggested that rather than being recently transmitted, these strains may have been widely transmitted as latent infections in the population. PMID- 22514939 TI - [Two cases of pulmonary tuberculosis with an intra-familial transmission route]. AB - Two patients with smear-positive adult-type pulmonary tuberculosis (TB) were admitted to our hospital. The patients in case 1 and case 2 were a 33-year-old woman and a 33-year-old man, respectively. None of the patients' family members had any apparent symptom indicating TB. However, the father of patient 1 was found to have recurrent TB with a positive smear in the contact investigation. The mother of patient 2 was then admitted to a hospital with acute respiratory failure caused by recurrence of TB. Her sputum sample also turned out to be smear positive. Restriction fragment length polymorphism (RFLP) analysis of the isolates revealed identical DNA patterns in each pair of family members. These cases were typical examples of intra-familial infections involving young adults and their parents. This route of transmission is still important in areas with low prevalence of the disease. PMID- 22514940 TI - [Nationwide survey of the use of class 2 infectious disease beds for in-hospital care of tuberculosis patients]. AB - PURPOSE: To investigate the possibility of employing in-hospital care for tuberculosis (TB) patients in beds meant for patients with Class 2 infectious diseases and determine the obstacles facing the same. SUBJECTS & METHODS: We conducted a questionnaire survey of all 225 hospitals that had beds meant for patients with Class 2 infectious disease but did not have tuberculosis wards. RESULT: Responses were obtained from 83.1% of the targeted hospitals. Around 60% of the hospitals had used these beds for patients other than those with Class 2 infectious disease (including TB patients). Around 50% and 30% of the hospitals had used these beds for suspected TB patients to ensure hospital infection control, and for treatment of patients diagnosed with TB, respectively. In response to the question on how they would use these hospital beds for TB or suspected TB patients if the regulations allowed such use, around 60% of the hospitals answered that the beds will be used for suspected TB patients until their diagnosis was confirmed, and 25% of the hospitals responded that they will never use their beds for TB patients. Only 10% of the hospitals answered that the beds will be used for in-hospital care of TB patients. With regard to the reasons why the beds cannot be easily used for in-hospital care of TB patients, several issues were pointed out, such as difficulty in appointing sufficient staff for care of TB patients, and a lack of doctors who had sufficient experience in TB medicine. However, there was no single predominant reason. CONCLUSION: To ensure that hospital beds for patients with Class 2 infectious diseases are utilized for in-hospital TB care, we need a flexible policy, which is suited to the specific conditions in each community and hospital. PMID- 22514941 TI - [Tuberculosis annual report 2009--series 8. Treatment of TB(1)]. AB - The standard treatment of tuberculosis (TB) is the key to its control. Here we report the statistics of treatment history and the initial regimen for treating TB in 2009. In 2009, 24,170 TB patients were newly notified. Of those, 1751 cases were reported as having had previous treatment and 410 cases were reported as having an unknown treatment history. The proportion of patients receiving retreatment was 7.4%, excluding those of unknown treatment history. The proportion of those receiving retreatment among newly notified TB patients increased with age from those at 20-24 years old (3.2%) to those at 80-84 years old (9.3%). The frequency of retreatment among newly notified TB patients might be partly an indicator of previous insufficient treatment. Regarding the year of previous treatment, the greatest number of cases reported having received previous treatment in 2008 (n=194). The total number of cases whose previous treatment had begun in 2008 or 2009 was 224, i.e. 12.8% of all retreatment cases in 2009. On the other hand, the number of cases having received previous treatment in the 1950s was also significant (n=219, 12.5%). As the initial treatment regimen, the combination of INH (isoniazid), RFP (rifampicin), PZA (pyrazinamide)+EB (ethambutol) or SM (streptomycin) is recommended by the Japanese Society for Tuberculosis. This regimen was initially used in 80.8% of all forms of TB patients aged 15-79 years old, excluding those cases whose treatment regimen was unknown. The data on duration of having actually received PZA was added to the central TB surveillance database starting in 2007. The number of cases who started TB treatment including PZA in 2008 was 15,146. Of those, 11,997 cases had completed TB treatment by the end of 2009, but 9.9% of them could not take PZA fully for 2 months. PMID- 22514942 TI - [Recent advances in tuberculosis immunity]. AB - Primary tuberculosis infection is acquired by the inhalation of droplets containing Mycobacterium tuberculosis (MTB) bacilli. Only 5-10% of those individuals infected by MTB develop clinical diseases, and disease presentation itself is heterogeneous, suggesting that host factors play a large role in disease susceptibility. Protective immunity in the lung against MTB consist of the innate immunity in which alveolar macrophages play an central role, and the acquired immunity including various type of effector T cells. Recent studies show that the important roles of the receptors which recognize MTB for the development of protective immunity, the difference in the anti-MTB activity of macrophages between human and mice, the macrophage-heterogeneity that affects the anti-MTB activity, the role of IL-10 in the activation of anti-MTB activity of human macrophages, and the role of Th17/IL-17, Th22/ IL-22 and TNF in the protective immunity against human tuberculosis. In this review, these recent advances in tuberculosis immunity will be described. PMID- 22514943 TI - Analytical challenges for forensic screening of drugs of abuse. PMID- 22514944 TI - Sample preparation for drugs-of-abuse analysis: a new perspective. PMID- 22514945 TI - Screening for heroin and chronic alcohol abuse. PMID- 22514946 TI - Viral hepatitis: targeted tests and therapies contribute to improved outcomes. PMID- 22514947 TI - How does your salary measure up? PMID- 22514948 TI - Lean lab in action. PMID- 22514949 TI - Laboratory diagnostics for celiac disease. PMID- 22514950 TI - At the crossroads? Molecular diagnostics and stool testing. PMID- 22514951 TI - Great expectations--or how to focus on prevention for all. PMID- 22514952 TI - How do dihydropyridine and nondihydropyridine CCBs differ? PMID- 22514953 TI - A facial lesion concerns an at-risk patient. Sclerosing basal cell carcinoma. PMID- 22514954 TI - Health care: the quality chasm 10 years later. PMID- 22514955 TI - Urinary tract infection: consistent therapy to reduce resistance. PMID- 22514956 TI - Evaluating a neck mass: narrowing the differential diagnosis. PMID- 22514957 TI - Individualizing revascularization for peripheral arterial disease. PMID- 22514958 TI - Renal artery stenosis: a correctable cause of resistant hypertension. PMID- 22514959 TI - Factors that influence physician assistant choice of practice location. AB - OBJECTIVE: Certain US rural areas have inadequate access to health care providers. Health care educational institutions have made nationwide efforts to recruit students from rural areas, in the hope that they will return upon graduation. This 2009 study focused on the physician assistant (PA) profession's endeavors in this effort. METHODOLOGY: A cross-sectional survey used a random sample of 2000 practicing PAs from the United States. Factor analysis was used to categorize the responses to 20 Likert-type questions about possible reasons behind the PA's choice of first practice location. RESULTS: Respondents who graduated from a rural high school were significantly more likely to practice in a rural setting. Six identifiable factors emerged from the factor analysis. Chi square analyses determined that significant relationships existed between these factors and demographic variables. Gender influenced the greatest number of items; specialty and PA degree level influenced the fewest items. Factor 2 (support of/for significant other) held the most sway in the decision about first employment location. CONCLUSION: Respondents felt that support of and for the significant other was the most important factor in their first practice-location choice. Recruiters searching for health care professionals in areas needing medical services may wish to pay closer attention to spousal opportunities and should not underestimate the impact of family in the decision about work location. PMID- 22514960 TI - The diagnosis and pharmacologic management of low back pain. PMID- 22514961 TI - A neck mass in a patient with fever and sore throat. Parapharyngeal abscess. PMID- 22514962 TI - Hereditary breast and ovarian cancer. PMID- 22514963 TI - Fast food medicine. PMID- 22514964 TI - Case of the month. Mature cystic teratoma. PMID- 22514965 TI - Making the effort. PMID- 22514966 TI - Viewing art imitates life, part 2. PMID- 22514967 TI - Can I bill a diagnostic angiogram? How about a Cath code? PMID- 22514968 TI - ICD-10: pregnancy. PMID- 22514969 TI - Benefits of cloud computing for PACS and archiving. AB - The goal of cloud-based services is to provide easy, scalable access to computing resources and IT services. The healthcare industry requires a private cloud that adheres to government mandates designed to ensure privacy and security of patient data while enabling access by authorized users. Cloud-based computing in the imaging market has evolved from a service that provided cost effective disaster recovery for archived data to fully featured PACS and vendor neutral archiving services that can address the needs of healthcare providers of all sizes. Healthcare providers worldwide are now using the cloud to distribute images to remote radiologists while supporting advanced reading tools, deliver radiology reports and imaging studies to referring physicians, and provide redundant data storage. Vendor managed cloud services eliminate large capital investments in equipment and maintenance, as well as staffing for the data center--creating a reduction in total cost of ownership for the healthcare provider. PMID- 22514971 TI - Sustainable differentiation. PMID- 22514972 TI - Equipment leasing and imaging: what's going on? AB - In the fall of 2011, a survey of AHRA members was conducted to find out what is going on with leasing in imaging. This article discusses the survey findings as well as provides some background and definitions about leasing. Existing users of leasing are interested in becoming more sophisticated in their understanding of the economics of leasing. And non-users are seeking to learn more than just about how leases are structured. This growing interest suggests that increased utilization may be the outcome. The results of this survey were presented in detail at the Equipment Leasing and Financing Association (ELFA) Annual Convention. Attendees were encouraged to reflect on the survey results and design leasing products that satisfy the needs and requirements that the survey revealed. PMID- 22514970 TI - The power of engagement: implementation of a career ladder program. AB - At Baystate Health in Massachusetts, the development and implementation of a career ladder program was implemented to reduce turnover and to improve employee satisfaction, morale, and recruitment efforts. There was significant initial expenditure in the program, as a result of promoting the large number of employees with significant experience and seniority. A smaller number of staff are expected to apply for advancement during successive cycles, allowing for decreased incremental expense going forward. Critical to the success of the program was understanding the time commitment, getting senior organizational support and staff buy-in, and justifying the associated expenses. The development and initiation of the program has done much to support a positive work environment with increased morale and higher performance among significant numbers of staff at all levels. PMID- 22514973 TI - Doing more with less and keeping staffing levels the same. PMID- 22514974 TI - Generation revelation. PMID- 22514975 TI - [The mock ECN of La Revue du Practicien]. PMID- 22514976 TI - [Lupus panniculitis]. PMID- 22514977 TI - [Transposition of the great arteries: a curable congenital heart defect?]. AB - Transposition of the great arteries (TGA) is a common congenital heart malformation, involving the inversion of both great vessels (aorta and pulmonary artery). It is not compatible with life in the absence of surgical treatment. The prognosis of this malformation has been transformed by the development of neonatal cardiac surgery. "Anatomic" repair has been introduced in the 80s; its goal is to provide near-normal cardiac anatomy. The mid-term results of anatomic repair of TGA can be summarized as follows: overall mortality is 5% (most deaths occur during the first postoperative year and are related to coronary complications), 5% of patients need reoperation for various reasons (mainly, coronary obstruction and pulmonary stenosis), major sequelae are rare (1-2%), minor sequelae are frequent (15-20%) and require strict surveillance, most patients (70-75%) are leading a normal life and can be considered as "cured". Very long-term results remain to be determined. The management of TGA includes several steps: prenatal diagnosis, planned delivery close to a pediatric cardiology center, immediate treatment with Rashkind maneuver and/or PGE1 infusion, anatomic repair during the first week of life, life-long surveillance by a congenital cardiologist. This complex multidisciplinary approach emphasizes the need for specialized centers of congenital cardiology from fetal life to adulthood. PMID- 22514978 TI - [How to adjust the dose of drugs in chronic kidney disease?]. AB - Renal insufficiency is a common disease, in the general population as well as in some specific diseases such as HIV infection or cancer. The vast majority of medicines require a dosage adjustment in case of renal dysfunction, it is thus of a crucial importance to know how to evaluate appropriately renal function, on one hand, but also to have access to reliable information sources on how to handle the drugs in such cases. Most often, the Summary of Drug Characteristics (SmPC) only provides partial information, which may even be false in some cases as compared to the most recent data from the literature. However, some information sources exist, reliable, updated, and easily accessible. PMID- 22514979 TI - [Antiphospholipid syndrome, systemic lupus erythematosus: endocarditis and glomerulopathy]. PMID- 22514980 TI - [Smoking: 2012, the year of change?]. PMID- 22514982 TI - [Emergence and consequences of tobacco use in developing countries]. PMID- 22514981 TI - [Tobacco epidemiology]. AB - The World Health Organisation attributed to tobacco 5.1 million deaths worldwide in 2004 which represents 9% of the total number of deaths. In France, the number of deaths attributable to tobacco in 2004 is 73 000 which represents 14% of the total mortality. It includes 85% of lung cancer mortality, 70% of chronic obstructive lung disease mortality and 10% of cardiovascular disease mortality. Tobacco is the cause of 22% of the deaths among French men and 5% of the deaths among French women in 2004. Because of the time lag of several decades between smoking initiation in a population and the occurrence of tobacco induced cancers or chronic respiratory diseases, tobacco attributable mortality will continue to increase in France among the female population for at least 20 years, even if tobacco consumption decreases in the next 10 years. The risk of death from lung cancer will exceed the risk of death from breast cancer in 2 or 3 years, a catastrophe observed in the US in 1987 and predicted for France many years ago! PMID- 22514983 TI - [Smoking: what are the health risks?]. AB - Smoking is the primary cause of avoidable deaths in developing countries; it is the principal cause of many illnesses and is risk factor or aggravated cause. Cigarettes or smokeless tobacco have a direct or indirect toxicity effect on practically every organ. The induced diseases are cardiovascular, cancers, respiratory complaints and many consequences less well known but often serious. There is no smoking without risk; however, stopping smoking at any age is beneficial. PMID- 22514984 TI - [Tobacco use in HIV infection]. PMID- 22514985 TI - [Smoking and cardiovascular diseases]. AB - Smoking is a major cardiovascular risk factor and smoking cessation is essential in any approach to cardiovascular prevention. Events occurring wthout any threshold of intensity or duration of consumption, smoking is the essential and often isolated factor in the acute coronary events of the young subjects. The mechanisms involved are mainly thrombosis and spasm. Smoking cessation provides a rapid and very important cardiovascular benefit and has the best cost/benefit ratio for cardiovascular prevention. The main objective is an early, total and definitive cessation. Nicotine replacement therapy can be prescribed in patients with coronary artery disease, including immediately after a myocardial infarction. Passive smoking must also be considered as a cardiovascular risk factor and should be avoided by collective and individual measures. PMID- 22514986 TI - [Smoking and pregnancy]. PMID- 22514987 TI - [Current therapeutic strategies for tobacco dependence]. AB - Smoking remains the first preventable cause of premature death worldwide. Despite the knowledge of adverse consequences of smoking, many smokers have difficulties to quit for good. This is due to the addictive nature of tobacco, at least as strong as the one of illicit drugs. The mechanisms of nicotine dependence are very similar to those of other addictive behaviors, and are based on disequilibrium of the meso-cortico-limbic reward system. The withdrawal syndrome responds well to nicotine replacement therapy, bupropion, and varenicline. Recent guidelines stress the responsibility of all health care professional to address the smoking problem of every patient through the 5 A model: Ask - Advise - Assess - Assist - Arrange. PMID- 22514988 TI - [Smoking cessation among patients with mental disorders]. PMID- 22514989 TI - [Perioperative smoking cessation]. PMID- 22514990 TI - [From nicotine dependence to addictology]. AB - The concept of addiction has developed in France since the beginning of the 2000s. It has justified by common clinical aspects, high level of co-morbidities between addictions to psychoactive drugs, common cognitive and behavioral mechanisms, the impact of comparable psychological and genetic factors, the same neurobiological mechanisms and the same therapy options in many cases. Although some specificities remain in smoking management: absence of intoxication and abuse diagnosis in DSM-IV, less consensual politics of harm reduction, and own pharmacotherapy solutions. Despite what is commonly thought, tobacco is the most addictive amongst all psycho-active-substances in Western countries. PMID- 22514991 TI - [Outcomes of premature infants]. PMID- 22514992 TI - [Epidemiology of preterm births]. AB - The frequency of preterm birth is about 12-13% in the USA and 5-7% in European countries. In France, almost 13,000 births (1.5%) occur before 32 weeks, 7,000 (0.8%) at 32-33 weeks and 40,000 (5%) between 34 and 36 weeks. Neonatal mortality rates are 10%, 2-3% and 0.5-1% for very, moderate and late preterm infants respectively. Risks of motor and cognitive deficiencies are higher among very (10% and 15% respectively), moderate (4% and 10%) and late preterm children (0.5% and 5%) than among children born at term. Preterm births account for 50% of disabilities from perinatal origin, i.e 3,500 children each year in France. Thus, all preterm infants should be carefully monitored to ensure prompt detection and management of neurodevelopmental impairments. Additional research exploring pathophysiology of preterm birth and its consequences is obviously needed, which will hopefully lead to the development of new therapeutic approaches. PMID- 22514993 TI - [Prediction of preterm birth]. PMID- 22514994 TI - [Psychological, developmental and relational consequences of prematurity]. AB - The authors of the present article, all physicians engaged in a multidisciplinary perinatal collaboration in the Institut de puericulture de Paris-Necker-Enfants malades, propose an up to date view of the traumatic experience, for infants, parents and clinicians, inherent to prematurity, based on literature review. Their focus questions the impact and consequences of this experience over development, interactions and parenthood. PMID- 22514995 TI - [Neurological consequences of prematurity]. AB - Very preterm infants are at risk of neurodevelopmental impairment. Severe disabilities (cerebral palsy, mental retardation) occur in around 10% of cases. The most frequent impairments concern cognitive and neurobehavioral development which usually express at school age. These disorders involve behavior, executive function, attention and speech development. All of these deficiencies can compromise learning functions, social interactions and school integration. Near 40% of very preterm infants need special therapies: psychological therapy, physiotherapy, speech therapy... Environmental, educative and health conditions largely influence the neurodevelopmental outcome. These infants need a special medical and social follow-up. PMID- 22514996 TI - [Respiratory outcome in preterm infants]. PMID- 22514997 TI - [Eye diseases of prematurity]. PMID- 22514998 TI - [Nutrition and growth follow-up in the preterm infant]. AB - The nutrition of premature babies is an important issue to improve their short and long-term growth and development. After birth, our target is to achieve the same growth as a foetus of similar gestational age. The recent recommendations insist on the early introduction of enteral and parenteral nutrition, with optimization of protein and energy intakes to avoid the appearance of extra uterine failure to thrive. The human milk is always the best nutrition for premature babies but it should be adequatly fortified. After hospital discharge, undoubtly breast-feeding still the best choice, but the nutritional intakes should be individualised according to the nutrition state of the baby. A fortification of expressed breat milk or a complement with premature milk formula should be recommended for small for gestational age babies. Then, we should closely follow-up the growth on the regular basis and for a long period, to note that the catch up will be reached frequently at the end of the first year of age. PMID- 22514999 TI - [Immunization of the preterm infant]. PMID- 22515000 TI - [PubMed in 10 lessons: no 3: Pair term/subheading]. PMID- 22515001 TI - [From health education to health sciences faculty]. PMID- 22515002 TI - [The thyroid nodules revisited]. PMID- 22515003 TI - [Fracture of the proximal end of the femur: the loss of autonomy a central concern]. PMID- 22515004 TI - [Admission decisions in psychiatric care]. PMID- 22515005 TI - [Menopause]. PMID- 22515006 TI - [Distal radius fractures in adults]. PMID- 22515007 TI - [Giant cell arteritis and polymyalgia rheumatica]. PMID- 22515008 TI - [Mood disorders. Manic-depressive illness or bipolar disorders]. PMID- 22515009 TI - [The museum of the Treasury of the hotel-Dieu of Chateau-Thierry]. PMID- 22515010 TI - [Morphology and etiopathogenesis of the abdominal aortic aneurysm]. AB - The paper summarizes the latest research on the abdominal aorta aneurysm etiopathogenesis and compares normal aorta morphology with changes in the aortic aneurysm wall. The role of risk factors, especially hemodynamic and genetic, is discussed in detail. Special attention is paid to inflammatory processes including cytokines and matrix degrading proteases that contribute to the development of aneurysm. The role of thrombus and the current results of research into biomarkers indicating the risks and progression of the disease are analysed. Finally, a review of pharmacomodulation of the aortic aneurysm using statins, antibiotics, antihypertensive and nonsteroidal antiinflammatory drugs is presented. PMID- 22515011 TI - [Relapsing polychondritis]. AB - Relapsing polychondritis (RP) is an unusually rare disease involving multiple organs. It has an episodic course, occasionally also progressing. Typically, inflammation of cartilaginous tissues and tissues rich in glycosaminoglycans is present. Clinical symptoms are concentrated in auricula, nose, larynx, upper respiratory tract, joints, heart, blood vessels, inner ear, cornea and sclera. Manifestations include: (1) chondritis of auricular, nasal, laryngotracheal, costal and joint cartilages, (2) inflammation of the eyes and inner ear, (3) collapse of laryngotracheal structures and structures in the subglottic area resulting in increased susceptibility to upper respiratory tract infections, (4) diversity of clinical manifestations, of the disease course and also of the treatment response. Concurrent systemic vasculitis or glomerulonephritis may contribute to higher morbidity and premature mortality. In about 30% of cases the RP is secondary, accompanied by other systemic connective tissue disorders as RA, SLE, Sjogren's syndrome, thyroiditis, ulcerative colitis, psoriasis and Behcet's syndrome. Diagnosis is based on 1986 diagnostic criteria from Minnesota and RP has to be suspected when the inflammatory bouts involve at least two of the typical sites - auricular, nasal, laryngotracheal or one of the typical sites and two other--ocular, statoacoustic disturbances (hearing loss and/or vertigo) and arthritis. In the treatment are, apart from corticoids and nonsteroidal anti inflammatory drugs, also corticoids combined with immunosuppressive therapy (cyclophosphamide, azathioprine, chlorambucil, cyclosporine) used. More recently, also biologic therapy is used in RP (infliximab, adalimumab, ethanercept, tocilizumab, rituximab). It is necessary to underscore that biologic therapy for RP is only a research modality used in very severe refractory forms of RP. Preliminary results suggest that biologic therapy will have its place in severe refractory relapsing forms of RP. PMID- 22515012 TI - [Male hypogonadism and civilization diseases]. AB - Male hypogonadism and civilization diseases Age dependant decrease of testosterone levels leads in many men to hypogonadism called as late-onset hypogonadism. Morbidity and mortality of men with subnormal testosterone levels is higher than that of men sufficiently supplied with androgens. Cardiovascular diseases, obesity or diabetes take often part in these events. Low testosterone level is risk factor for these diseases. However, it is until now not clear whether testosterone deficiency is a cause or consequence of atherosclerosis or metabolic syndrome. A handful of symptoms and metabolic parameters present in hypogonadal men can be ameliorated by testosterone supplementation. Testosterone has a beneficial effect on cardiovascular risk factors, but it is not clear whether it can reduce mortality. PMID- 22515013 TI - [Prevalence of thrombophilic mutations of FV Leiden, prothrombin G20210A and PAl 1 4G/5G and their combinations in a group of 1450 healthy middle-aged individuals in the Prague and Central Bohemian regions (results of FRET real-time PCR assay)]. AB - BACKGROUND: Factor V Leiden (G1691A) and prothrombin gene (FII G20210A) mutations are independent risk factors of venous thrombosis and this risk is further increased by the combined genotype 4G/4G PAI-1. AIM: The primary objective was to identify the frequency of mutations of minor alleles and genotypes of FVL, FII G20210A and PAI-1 4G/5G in healthy Caucasians in the Prague and Central Bohemia regions. The secondary objective was to identify the occurrence of their mutual combinations. METHOD: Genotyping was performed in 1,450 healthy individuals (blood donors, 981 men and 469 women) using robotic DNA isolation and subsequent PCR and melting curve analysis (Light Cycler 480 System, Roche). RESULTS: The minor allele frequencies in FV Leiden and FII G20210A mutations were 4.5% and 1.3% respectively. The frequency of the 4G PAI-1 allele was 55.9%. The genotype frequencies were as follows: GG 91.10%, GA 8.83% and AA 0.07% for FV Leiden; GG 97.38%, GA 2.55% and AA 0.07% for FII G20210A and 4G/4G 30.69%, 4G/5G 50.34% and 5G/5G 18.97% for PAI-1. No differences in these frequencies were found between the genders. The occurrence of the combined heterozygous FII and heterozygous FV Leiden mutations was 0.14%. The PAI-1 4G/4G genotype was combined with the heterozygous FV leiden mutation in 2.83% of cases and with the heterozygous FII mutation in 0.62% of cases. CONCLUSIONS: The found frequencies of genotypes and alleles confirm a relatively high prevalence of hereditary thrombophilia in the Czech Republic. PMID- 22515014 TI - [Polarization in activities of ethics committees]. AB - BACKGROUND: The goal of this work was to acquire data concerning characteristics, ways of assessing presented documentation, publishing attitudes and other related activities of ethics committees established according to the Act No. 378/2007 Coll., on Pharmaceuticals, and to use evaluated data subsequently for mapping actual state of assessing clinical trial projects with emphasis to observance of legislation, as well as description of differences between individual ethics committees. METHODS AND RESULTS: An on-line questionnaire, comprised of 36 questions, was filled in by 66 ethics committees. That is 64% out of 104 approached active ethics committees. All participating ethics committees continue working in 2011. 74% of the ethics committees work in accordance with the legislation. 62% ethics committees also apply ethical recommendations above the scope of law and only 26% ethics committees break some part of the legislation. CONCLUSIONS: Being able to focus only on a formal part of ethics committees' activity, it is possible to say that individual ethics committees differ from each other particularly in the general characteristics, conditions made for their work and in some trial aspect, but it doesn't automatically mean serious law breach and the immediate need of rectification. It seems that not all members of ethics committees realize adequately the seriousness of their actions from the ethical point of view at current research done with human subjects. PMID- 22515015 TI - [Project for collaboration and categorization of stations for the treatment of tobacco dependency in Europe]. PMID- 22515016 TI - [Nobel Prize laureates. Julius Axelrod (1912-2004)]. PMID- 22515017 TI - Surveys show support for green 'activities'. AB - Two independently conducted surveys on sustainability - one into the 'views and values' of NHS 'leaders', and the other questioning the public about the importance of the 'green agenda' in the NHS, and their opinions on how the service might most effectively reduce its carbon footprint, form the basis of Sustainability in the NHS: Health Check 2012, a new NHS Sustainable Development Unit (NHS SDU) publication. As HEJ editor Jonathan Baillie reports, the new document also presents updated data on the 'size' of the carbon footprint of the NHS in England, showing that, although good work by a number of Trusts in the past two years has seen healthcare-generated carbon emissions start to 'level off', the biggest contributors have been the current health service spending review, and the increased national availability of renewable energy. PMID- 22515018 TI - Energy centre's immediate impact. AB - A new CHP-based Energy Centre completed in 2010 at London's King's College Hospital helped the south London facility cut its overall carbon emissions by 12% in the first financial year of operation, and reduce by pounds sterling 254,000 its energy costs over the same period, reports HEJ editor, Jonathan Baillie. Based on the experience gained during the first year's operation, subsequent 'fine tuning' of the plant by Dalkia--the company which designed and managed the Energy Centre's construction, and is now operating and maintaining it under a 15 year contract with the King's College Hospital NHS Foundation Trust--saw site CO2 emissions at the hospital reduced by 550 tonnes more in the first seven months of the 2011-2012 financial year than in the corresponding period the previous year, enabling the Trust to achieve its 374-tonne 2011-2012 carbon reduction target with five months to spare. PMID- 22515019 TI - Fighting the scourge of metal theft. AB - Last December one acute hospital in south Wales, the University Hospital Llandough near Cardiff, was forced to cancel eight operations, with 81 patients affected in total, after thieves stole copper cabling from a back-up generator. HEJ editor, Jonathan Baillie, reports on the growing theft of cabling, pipework, and other vital supply infrastructure, from the healthcare estate, and asks senior estates personnel what lessons have been learned that might be useful in combating this lucrative, opportunistic, and also potentially highly dangerous, practice, in the future. PMID- 22515020 TI - Biomass heating--how the benefits stack up. AB - Neil Turner, business development manager at Wood Energy, a specialist supplier of high efficiency automatic biomass boilers throughout the UK and Ireland, and part of the Renewable Energy System (RES) Group, outlines the case for such boilers, and sets out the key considerations for organisations considering investing in a technology he says is now beginning to 'flourish' and gain popularity, thanks largely to the support and incentives for its use provided through the Renewable Heat Incentive (RHI). PMID- 22515021 TI - Significant growth in. LED use predicted. AB - Although LED lighting has its critics, a number of whom (see article 'LED- panacea or marketing hype', HEJ--February 2012) are concerned about what they claim are some manufacturers' 'exaggerated claims' about lighting efficiency and lamp lifetime, Philips Lighting believes that, such are the advances being made in this innovative lighting technology, that LED's overall share of the European lighting market will have risen from around 7% in 2008 to 25% by 2020 and that, a decade later, it will account for a remarkable 75% of lighting sales. In the UK, Philips' technical and design director for Lighting, Mike Simpson, told HEJ editor, Jonathan Baillie, healthcare estates and facilities managers are increasingly recognising the potential to save energy, reduce carbon emissions, and cut maintenance costs, using LED. PMID- 22515022 TI - CRC: staying on top by identifying priorities. AB - In an article in the May 2011 issue of Health Estate Journal, Debbie Hobbs, principal at environmental consultancy, Environ, explained the steps that organisations obligated under the Carbon Reduction Commitment (CRC) scheme needed to take over the following 3-4 years, and set out a checklist of actions to help. Here Gordon Lee, manager, and Malcolm Hanna, senior manager, at the firm, provide an update, and highlight the priorities for the coming few months as the scheme progresses to its next stages. PMID- 22515023 TI - Tackling violence and aggression in A & E. PMID- 22515024 TI - Pre-wired systems prove their worth. AB - The 'new generation' of modular wiring systems from Apex Wiring Solutions have been specified for two of the world's foremost teaching hospitals - the Royal London and St Bartholomew's Hospital, as part of a pounds sterling 1 billion redevelopment project, to cut electrical installation times, reduce on-site waste, and provide a pre-wired, factory-tested, power and lighting system. HEJ reports. PMID- 22515025 TI - [Highly ciprofloxacin resistant Salmonella enterica serovar Kentucky isolates in turkey meat and a human patient]. AB - In recent years in France, England, Wales, Denmark and the USA about 500 human infections occurred, which were caused by multidrug-resistant Salmonella enterica Serovar (S.) Kentucky isolates displaying high-level resistance to fluoroquinolones (ciprofloxacin, MIC > or = 4 mg/l). The responsible clone was referred to as ST198-X1.To determine whether this clone is also present in German S. Kentucky isolates, the National Reference Laboratory for Salmonella (NRL-Salm) at the BfR analyzed the trend of S. Kentucky isolates received over the past years. Since 2010 the first entries of highly ciprofloxacin resistant S. Kentucky isolates, especially from turkey meat products, were recorded. 15 isolates originating from animal or food as well as one human isolate displayed MIC values of > or = 8 mg/l to ciprofloxacin. Molecular biological typing methods showed the in Germany isolated S. Kentucky isolates to be identical to the clone described by Le Hello et al. (2011) and to carry a multidrug resistance conferring region (SGI1). Since fluoroquinolones are considered by the WHO in human and veterinary medicine as drugs of critical importance, this trend demands attention. The implementation of mitigation strategies for this highly resistant clone seems to be required. PMID- 22515027 TI - Production of viral vaccines for veterinary use. AB - This review provides inside information on the production of vaccines for veterinary use. The vaccines against rinderpest as well as foot and mouth disease are considered milestones in the history of veterinary vaccine production. Modern vaccines are based on the scientific progress in virology, cell biology and immunology. While naturally occurring attenuated viruses or viruses obtained after passage in different animal species or cell culture were used as vaccine strains in the early vaccines, nowadays targeted mutagenesis can be applied to generate vaccine virus strains. In principle, the antigen production process is the same for live and inactivated vaccines. The vaccine virus is usually grown in cell culture, either in roller bottles or bioreactors. Most live vaccines are freeze-dried in order to enable storage in the refridgerator for a longer period. To this end, a so-called stabilizer is added to the culture medium. The inactivation of the vaccine virus for the production of killed vaccines is done by physical or chemical treatments that lead to denaturation of the proteins or damage of the nucleic acids. The inactivated antigen may be further purified and mixed with an adjuvant. The quality standards for vaccines are layed down in international regulations and laws. Numerous tests are performed during the different production steps and on the final product in order to warrant the quality of each batch. PMID- 22515026 TI - [Evaluation of perioperative analgesia by nociceptive flexor reflex in pigs under ketamine-azaperone-general anaesthesia]. AB - The objective of the investigation was to evaluate quantitatively the analgesic efficacy of the Ketamine-Azaperone-general anesthesia during surgical procedures on pigs by nociceptive flexor reflexes (NFR). The study was performed in 30 four to five month old male pigs which were castrated. The NFR was evoked every minute over the N. ulnaris by multiple electrical stimulation consisting of five single stimuli (2 Hz). The reflex response was derived electromyographically (EMG) by surface electrodes placed over the M. deltoideus. The root-mean-square amplitude within the time interval of 80-240 ms after the last stimulus was calculated as measure for the reflex size. The threshold was fixed at 40 microV. Beside electrical NFR recording the surgical tolerance was determined by the traditional interdigital reflex and the defense reaction to defined surgical test stimuli which were incisisions in the scrotal skin, in the tunica vaginalis and in the testis, pulling off the spermatic cord, clamping and cutting off the spermatic cord and final wound disinfection. All surgical pain stimuli were performed simultaneously with the electrical stimuli. After induction of anesthesia the NFR amplitude declined from 3500 microV below the threshold of 40 microV. At 98% of the surgical stimuli without defense reaction were below the reflex threshold. At 93% with defense reactions demonstrated reflex amplitudes above the threshold. When the interdigital reflex was suppressed, 89% of the NFR values fell below the threshold of 40 microV. These findings demonstrate a good correlation of NFR amplitudes with reactions to traditional controls of analgesia. PMID- 22515028 TI - Contact structure and potential risk factors for avian influenza transmission among open-sided chicken farms in Kamalia, an important poultry rearing area of Pakistan. AB - Since 1994, the domestic poultry in Pakistan has experienced several outbreaks due to avian influenza viruses of subtypes H7N3, H5N1, and H9N2. This paper reveals horizontal contacts and potential risk factors for the spread of avian influenza infection between open-sided chicken farms in Kamalia, a sub-district of Punjab province. Between April and June 2009, an interview-based questionnaire was administered to a sample of 78 growers. The survey identified the following potential biosecurity risks for outbreak propagation: i) short buffer distances between farms, ii) disposal of carcasses and other organic wastes into the environment, iii) entry of feral birds into poultry sheds, iv) visits of poultry farmers to possible cross-contamination sites, v) absence of boundary walls, vi) incomplete biosecurity on high-risk visitors (i. e. those going inside the poultry houses), essential vehicles and equipment used by vaccination crews vii) visits of intermediaries and service providers and, viii) sharing of egg trays between farms at production. For most of the variables, there was no significant difference between the broiler and layer type of farms (p < or = 0.05). The risk of an extensive outbreak in Kamalia was concluded to be due to its high poultry density, ubiquitous small-scale, market-oriented poultry production with medium to low biosecurity, and the affiliation of the farmers to multiple service providers. To reduce the risk of having an outbreak, farm-specific biosecurity gaps should be identified and appropriate action taken to close these gaps. Improvement in biosecurity and targeted surveillance are therefore considered critical to limit the spread of infection should an outbreak occur. PMID- 22515029 TI - Performance of complement fixation test and confirmatory immunoblot as two cascade testing approach for serodiagnosis of glanders in an endemic region of South East Asia. AB - Various serological tests were used for the diagnosis of glanders in the past but still complement fixation test (CFT) is the internationally prescribed test for trading equines. A new immunoblot (IB) technique has recently been introduced to overcome the well known shortcomings of CFT i. e. a considerable number of false positive and negative results and anticomplementary effects of sera. The objective of this study was the comparative evaluation of two glanders CFT antigens commercially available at Central Veterinary Institute ofWageningen UR, Lelystad, NL (CIDC) and at c.c.pro GmbH, Oberdorla, DE (c.c.pro) in a glanders endemic area regarding specificity and sensitivity. A total of 1678 serum samples from the endemic region (Province Punjab, Pakistan) and a non-endemic area (Germany) were analysed. All sera tested positive or suspicious with CFT were analysed by the confirmatory IB to exclude CFT false positive results. Both CFT antigens showed 100% sensitivity. The use of CIDC or c.c.pro antigen resulted in specificities of 77.45% or 75.71% for sera from endemic area and 93.75% or 94.79% for sera from non-endemic areas, respectively. The results demonstrate the different performances of identical tests in different epidemiologically settings. Based on these results, the combined use of CFT and IB is highly suggestive for the serodiagnosis of glanders. Good agreement was calculated between CFT (using either c.c.pro or CIDC antigen) and immunoblot. PMID- 22515030 TI - [Acute pasteurellosis in fallow deer, cattle and pigs in a region of Eastern Germany]. AB - Hemorrhagic septicaemia, an acute disease caused by P multocida capsular type B which is rarely detected in Europe, caused considerable losses in fallow deer, cattle and pigs within a region along the border of the federal states Brandenburg and Saxony-Anhalt in the summer of 2010. Clinical appearances and diagnostic findings are presented and possible triggering influences discussed. Pasteurella multocida capsular type B has not been cultivated from clinically healthy cattle and pigs of the region. Examination of fallow deer and roe deer in the region revealed the presence of singular carriers, which may act as a source of clinical infections. PMID- 22515031 TI - Prevalence of Salmonella spp. in Austrian broiler flocks in the context of the EU wide baseline survey 2005-2006. AB - In Austria an EU-wide baseline survey on the prevalence of Salmonella spp. in broilers organized by the EU commission was conducted from October 2005 to September 2006. The aim of this study was to produce comparable data on the prevalence of Salmonella in broiler flocks and holdings for all member states and for the EU-Commission to set EU-wide targets for the control of Salmonella in the broiler populations. A randomised sampling plan was designed according to EU commission parameters (p = 50%; CI = 95%, a = 5%). Sampling was carried out regularly throughout the whole year. On every farm one flock was sampled with five pairs of boot swabs and analysed in the lab according to appendix D of ISO 6579 (2002). In Austria, 363 flocks on farms consisting of at least 5000 broilers each were tested. 28 flocks (7.7%) showed infections with Salmonella spp., eight flocks (2.2%) had either S. Enteritidis (six flocks) or S. Typhimurium (two flocks). In detail, S. Enteritidis (1.7%), S. Typhimurium (0.6%), S. Montevideo (4.1%), S. Infantis 0.6%, S. Senftenberg, S. Tennessee and S. Virchow (0.3% each) have been found. Data indicated that the risk of vertical transmission of Salmonella spp. to broiler flocks has almost been kept at bay; however, the risk of horizontal transmission still needs attention. Contamination of feeding stuff, possible persistence, spreading between barns of a farm as well as introduction of Salmonella spp. through individuals or materials are important factors for future control strategies. PMID- 22515032 TI - Investigations concerning the prevalence of Coxiella burnetii and Chlamydia abortus in sheep in correlation with management systems and abortion rate in Lower Saxony in 2004. AB - The intracellular bacteria Coxiella (C) burnetii and Chlamydia (Chl) abortus induce abortion in sheep and also affect humans. While Chl. abortus only infrequently infects humans, C burnetii is the aetiological agent of numerous Q fever outbreaks during the last decades. There is only limited knowledge about the prevalence of both pathogens in sheep, although sheep are involved in almost all Q fever outbreaks in Germany. The aim of our study was to investigate the prevalence of both pathogens in flocks located in Lower Saxony, Germany, in correlation to the management form and abortion rate. Serum samples of 1714 sheep from 95 flocks located in Lower Saxony were investigated by ELISA. 2.7% of these samples were positive, 1.3% showed inconclusive results in the C. burnetii-ELISA. Elevated intra-flock seroprevalences were only detected in three migrating flocks. Chlamydia-specific antibodies could be detected in 15.1% serum samples of mainly shepherded and migrating flocks. In one of these flocks with a high intra flock seroprevalence for C burnetii (27%) and Chlamydia (44.9%), C burnetii was detected in 21.6% of the placenta samples of normal births and in 12.5% of the colostrum samples by PCR. Aborted fetuses and the corresponding placentas were negative in C burnetii-PCR, but in most of them and also in many other placenta samples Chl. abortus could be detected by PCR and DNA microarray. This survey shows a low overall prevalence of C. burnetii in sheep in Lower Saxony in the year 2004. However, three migrating flocks with a high intra-flock prevalence are localized in the southern parts of Lower Saxony. Spreading of C burnetii could occur, because of the large radius of grazing of all three flocks. PMID- 22515033 TI - First insights into the protective effects of a recombinant swinepox virus expressing truncated MRP of Streptococcus suis type 2 in mice. AB - To explore the potential of the swinepox virus (SPV) as vector for Streptococcus suis vaccines, a vector system was developed for the construction of a recombinant SPV carrying bacterial genes. Using this system, a recombinant virus expressing truncated muramidase-released protein (MRP) of S. suis type 2 (SS2), designated rSPV-MRP, was produced and identified by PCR, western blotting and immunofluorescence assays. The rSPV-MRP was found to be only slightly attenuated in PK-15 cells, when compared with the wild-type virus. After immunization intramuscularly with rSPV-MRP, SS2 inactive vaccine (positive control), wild-type SPV (negative control) and PBS (blank control) respectively, all CD1 mice were challenged with a lethal dose or a sublethal dose of SS2 highly virulent strain ZY05719. While SS2 inactive vaccine protected all mice, immunization with rSPV MRP resulted in 60% survival and protected mice against a lethal dose of the highly virulent SS2 strain, compared with the negative control (P < 0.05). Our data indicate that animals immunized with rSPV-MRP had a significantly reduced bacterial burden in all organs examined, compared to negative controls and blank controls (P <0.05). Antibody titers of the rSPV-MRP-vaccinated group were significantly higher (P <0.001), when compared to negative controls and blank controls. Antibody titers were also significantly higher in the vaccinated group at all time points post-vaccination (P <0.001), compared with the positive controls. These initial results demonstrated that the rSPV-MRP provided mice with protection from systemic SS2 infection. If SPV recombinants have the potential as S. suis vaccines for the use in pigs has to be evaluated in further studies. PMID- 22515034 TI - An unusual outbreak of histomonosis in a commercial turkey flock. AB - In the past histomonosis was very well controlled with Dimetridazole as a treatment and/or Nifursol as feed additive. In the European Union both products were banned in 1995 and 2003, respectively. This was followed by the re-emergence of the disease in the recent years. In the present case a farm with two houses was affected by the disease. In each house 2620 hens and 2620 toms were kept, separated by wire mesh. At the 53rd day of age the toms in house 1 showed general clinical symptoms, accompanied by a slightly raised mortality, which sharply increased in the following days. At necropsy all dead birds showed lesions typical for histomonosis in caeca and liver. Histomonosis was diagnosed by histopathology and PCR. Within five days cumulative mortality was 25.1%.The hens kept at the same house didn't show any symptoms. At day 57 two toms, which were kept in house 2, died and showed similar symptoms and lesions. Within the next three days 48 more birds died. Again the hens in house 2 showed neither clinical signs nor mortality. Treatment trials using herbal products and a change of litter directly after the onset of clinical signs did not reduce the mortality. On day 62 the toms of both houses were euthanized by CO2 in closed containers. The hens were kept until they were slaughtered in week 16 and did not show any evidence of histomonosis. PMID- 22515036 TI - Seroprevalence and bacteremia [corrected] of Anaplasma phagocytophilum in cats from Bavaria and Lower Saxony (Germany). AB - Anaplasma (A.) phagocytophilum is a tick-transmitted obligate intracellular bacterium and has been identified in a wide range of mammalian species, causing febrile disease in some. Few reports show that it can also cause granulocytic anaplasmosis in cats. As data on the occurrence of A. phagocytophilum in cats from Germany is limited, a total of 326 serum and 306 EDTA-blood samples from cats from Germany were screened by direct (Giemsa-stained blood/buffy coat smears, real-time PCR) and indirect (IFAT) methods. Of 274 Giemsa-stained blood smears which could be evaluated none was positive for morulae, but one blood sample (< or =0.1%; 1/306) was positive for A. < or = phagocytophilum-DNA in PCR. Antibodies (cutoff > or = 1:64) were detected in 53 out of 326 samples (16.2%). Altogether, the results show a high seroprevalence rate of anti-A. phagocytophilum antibodies in cats in Germany while the low detection rate of this bacterial agent by direct methods is similar to those of other studies on A. phagocytophilum infections in cats. PMID- 22515035 TI - [Corynebacterium ulcerans infection in roe deer (Capreolus capreolus)]. AB - This is the first report of a Corynebacterium (C) ulcerans-infection in European roe deer (Capreolus capreolus). The bacterium was isolated from a grapefruit sized abscess of an animal that had been shot. In addition to biochemical tests, the isolate was identified by Fourier transform infrared spectroscopy (FT-IR) and partial sequencing of the rpoB gene. The isolated bacteria showed phospholipase D activity that could be demonstrated by reverse CAMP-test. A tox-gene could be detected by PCR but the Elek-test specific for diphtheria toxin failed.The isolate was compared to two C. ulcerans-strains isolated from wild boar (Sus scrofa) from the state of Baden-Wuerttemberg described recently. PMID- 22515037 TI - [The prevalence of Babesia canis canis in marsh ticks (Dermacentor reticulatus) in the Saarland]. AB - An accumulation of autochthonous cases of canine babesiosis caused by Babesia canis has been registered in a small animal clinic in the Saarland since the beginning of 2006, some cases with fatal outcome. This study aims to contribute to the explanation of strong focal occurrence of infections with B. canis in this region.Therefore, patient owners who had presented their dogs in the years 2006 and 2007 because of babesiosis and who had claimed not having left the Saarland with their dogs at least six months before the outbreak of Babesiosis, were asked for their dog walking habits. Accordingly, a selection often tick collection sites of various landscape structures was made.Tick sampling by flagging the vegetation took place every month from March to December 2008. The collected ticks were identified morphologically. In eight of ten collecting sites a total of 397 adult Dermacentor reticulatus ticks were collected from March to December with the highest frequencies during the months of May, October and November. All collected specimens were examined by genus-specific conventional PCR for the presence of Babesia-DNA. In positive samples, the PCR-products were differentiated by sequencing. ten D. reticulatus (2.5%) ticks examined were found positive for DNA of B. canis canis originating from three out of eight collection sites. Consequently, an endemic distribution of D. reticulatus was confirmed and a natural PMID- 22515038 TI - Regional intravenous gentamicin administration for treatment of postoperative tarso-metatarsal infection in a dog--a case report. AB - The regional intravenous antibiotic administration has been used to achieve high local concentrations of antibiotics into the extremities. The goal of this case report was to describe a known, but not often used technique of local administration of antibiotics for treatment of acute soft tissue, joint or bone infection in a dog, which suffered from chronic renal failure. In a seven years old Great Dane tarso-metatarsal arthrodesis was performed and three days after surgery infection was obvious. Gentamicin-sensitive E. co i was found by antibiogram. A tourniquet was tightened on the affected limb and gentamicin was administered in a dosage of 0,5 mg/kg every twelve hours via an intravenous catheter placed in the saphenous vein. The therapy lasted for ten days and wound healing was progressive. Regional intravenous gentamicin administration was very effective in treating distal extremity infection. PMID- 22515039 TI - Enamel of primary teeth--morphological and chemical aspects. AB - Enamel is one of the most important structures of the tooth, both from a functional and esthetic point of view. Primary enamel carries registered information regarding metabolic and physiological events that occurred during the period around birth and the first year of life. Detailed knowledge of normal development and the structure of enamel is important for the assessment of mineralization defects. The aim of the thesis is to add more detailed information regarding the structure of primary enamel. The structural appearance of the neonatal line and the quantitative developmental enamel defect, enamel hypoplasia, was thoroughly investigated with a polarized light microscope, microradiography and scanning electron microscope. X-ray microanalysis of some elements was also performed across the enamel and the neonatal line. Postnatal mineralization of enamel at different ages and from different individuals was studied regarding the chemical content, by using secondary ion mass spectrometry. The enamel's response to demineralization was investigated in relation to the individual chemical content and the degree of mineralization of the enamel, by using polarized light microscope, microradiography, scanning electron microscope and X-ray microanalysis. The neonatal line is a hypomineralized structure seen as a step-like rupture in the enamel matrix. The neonatal line is due to disturbances in the enamel secretion stage. The enamel prisms in the postnatal enamel appeared to be smaller than the prenatal prisms. The hypoplasias showed a rough surface at the base and no aprismatic surface layer was seen in the defect. The enamel of the rounded border of hypoplasia appeared to be hypomineralized, with the bent prisms not being densely packed. Mineralization of enamel is a gradual process, still continuous at 6 months postnatally in the primary mandibular incisors. The thickness of the buccal enamel is reached at 3-4 months of age. Demineralization of enamel depends on the degree of mineralization and the chemical content of the enamel exposed. In a more porous enamel, deeper lesions will develop. The posteruptive maturation has a beneficial effect on the enamel's resistance to demineralization. PMID- 22515040 TI - Analysis of capital spending and capital financing among large US nonprofit health systems. AB - This article examines the recent trends (2006 to 2009) in capital spending among 25 of the largest nonprofit health systems in the United States and analyzes the financing sources that these large nonprofit health care systems used to fund their capital spending. Total capital spending for these 25 nonprofit health entities exceeded $41 billion for the four-year period of this study. Less than 3 percent of total capital spending resulted in mergers and acquisition activities. Total annual capital spending grew at an average annual rate of 17.6 percent during the first three year of this study's period of analysis. Annual capital spending for 2009 fell by more than 22 percent over prior year's level due to the impact of widespread disruption in US tax-exempt variable rate debt markets. While cash inflow from long-term debt issues was a significant source of capital financing, this study's primary finding was that operating cash flow was the predominant source of capital spending funding. Key words: nonprofit, mergers and acquisitions (M&A), capital spending, capital financing. PMID- 22515041 TI - New requirements for hospitals to maintain tax-exempt status. AB - Tax-exempt hospitals are now facing more legislative requirements to maintain tax exempt status. This article outlines each of these requirements imposed by the Patient Protection Act of 2010. Health care administrators, executives, and consultants must be aware of these new laws to ensure each facility is capable of maintaining tax-exempt status. Despite the issuance of new requirements, a conclusive definition of charity does not exist. Therefore, the debate surrounding charity care and the justification for tax-exempt status will continue. PMID- 22515042 TI - Inner-city hospital closures: financial decision or impediment to access? AB - This article applies a financial ratio model and a behavioral model of health services use' to examine inner-city hospital closures. We use Medicare Cost Report financial information and demographics to find evidence that hospitals with high debt, less severity of illness, and lower occupancy rates are more likely to close, as expected. We also find that urban hospitals with a high elderly population are more likely to remain open. However, hospitals in our study with a high proportion of Medicare patients and a high minority population are more likely to close. This last finding may have important public policy consequences for access to health care for vulnerable populations, particularly in a recessionary economy under health care reform. PMID- 22515043 TI - The financial impact of hospital-acquired conditions. AB - CONTEXT: This article investigates the financial impact of the Centers for Medicare & Medicaid Services' hospital-acquired conditions (HACs). METHODS: Data from 2007-2008 was analyzed using New York State Department of Health's Statewide Planning and Research Cooperative System (SPARCS), using regression analysis and descriptive statistics for each condition. RESULTS: Of 4,853,800 patient discharges, the development of decubitus ulcers was the most prevalent condition, associated with an annual cost of nearly $680 million and 376,546 hospital days. Mediastinitis after Coronary Artery Bypass Graft (CABG) had the highest marginal impact for both length of stay (LOS) and total costs, but this condition had a relatively low frequency. Extrapolation of the results suggests that HACs represent a major burden to US hospitals. CONCLUSIONS: HACs have a significant financial impact on the US health care system. Hospitals would benefit from better understanding the impact and frequency of these conditions in order to best target preventative strategies. PMID- 22515044 TI - The association between the hospital quality alliance's pneumonia measures and discharge costs. AB - OBJECTIVE: This article examines the association between performance on the Hospital Quality Alliance's (HQA's) pneumonia measures and costs associated with pneumonia discharges. STUDY POPULATION: Patients with pneumonia discharges (primary pneumonia diagnosis, ICD-9 codes 480-487) in New York hospitals (n = 189) during 2005 (n = 48,574). Discharges were excluded if the patient was younger than 18, discharged dead, or was transferred in from or out to an acute care facility. STUDY DESIGN: The study is cross-sectional. MEASURES: The study outcome measure was hospital-level pneumonia discharges-related costs. The main independent variable comprised hospitals' performance on the three HQA pneumonia measures that are part of the "starter set." The hospital was the unit of analysis. RESULTS: The use of a composite score measure, as well as the three individual measures, allowed for the identification of some differential impact among the measures. For example, optimal performance on the oxygenation assessment measure was found to be negatively associated with discharge costs, whereas there was no significant association between the composite scores or each of the other two measures and costs. An observation worth noting is the borderline, significant inverse relationship between being in the top 10 percent performance category of the oxygenation assessment measures and reduced discharge costs, which persisted even after controlling for length of stay. CONCLUSIONS: Providers should not be dissuaded from actively engaging in quality improvement efforts due to concerns over the costs required to provide high quality care. There is some evidence, albeit modest, that top performers may actually witness cost savings. PMID- 22515045 TI - Financial position and adoption of electronic health records: a retrospective longitudinal study. AB - AIM: Financial barriers are a major factor of slow electronic health record (EHR) adoption among US hospitals. All existing literature focuses on relationships between current or short-term financial position and EHR adoption. This study examines relationship between financial position in previous years and the current level of EHR adoption. METHODS: Retrospective longitudinal data were extracted from (1) the 2009 American Hospital Association (AHA) EHR implementation survey; (2) the 2002 and 2006 Centers for Medicare & Medicaid Cost Reports; and (3) the 2002 and 2006 AHA Annual Survey containing organizational and operational data. The final sample was 2,701 acute care hospitals in the United States. General ordinal logistic regression was used for data analysis with a three-level dependent variable to measure adoption, five independent variables to measure financial position, and 11 control variables to measure structure and environment. RESULTS: For 2006, higher total margin was significantly and positively associated with EHR adoption, but higher asset turnover was significantly and negatively associated with EHR adoption. For 2002, higher total margin was significantly and positively associated with EHR adoption, but higher asset turnover and higher equity multiplier were both significantly and negatively associated with EHR adoption. In addition, lower net days revenue in accounts receivable was significantly and positively associated with EHR adoption. For both the 2002 and 2006 control variables, human resource intensity and bed size were significant and positively related to adoption, and percentage Medicare patients and investor ownership were significant and negatively related to adoption. CONCLUSIONS: Financial position does relate to EHR adoption in mid-term and long-term planning. PMID- 22515046 TI - Can more use of supporting primary care health practitioners increase efficiency of health clinics? Evidence from California's San Joaquin Valley. AB - This study examined 67 primary health care centers operating in the San Joaquin Valley, California, and explored the factors that may have contributed to productive efficiency gains. The study used the data envelopment analysis (DEA) technique to measure efficiency of the clinics and then used tobit regression analysis to understand the factors that affected efficiency. It was found that clinics that employed relatively more "unlicensed" supporting practitioners compared to "licensed" practitioners were more likely to be efficient. The results also showed that clinics that employed fewer physicians compared to all "licensed" practitioners were likely to be more efficient. In addition, providing transportation services to patients also enhanced clinics' efficiency. PMID- 22515047 TI - Watson, I presume?. PMID- 22515048 TI - Solution helps shorten referral wait times. University health system uses referral-automation and decision-support software to reduce wait times for specialty care. PMID- 22515049 TI - Don't roll the dice on data loss. Implement smart recovery to reduce disaster recovery costs in healthcare. PMID- 22515050 TI - Improving disaster recovery outcomes. Healthcare data ust be protected to conform to HIPAA requirements, which active archive supports through the expanded role of tape. PMID- 22515051 TI - Navigating regulations. How Edward Hospital & Health Services is achieving secure document management. PMID- 22515052 TI - Taking an enterprise view of content management. PMID- 22515053 TI - Filling the skills gap. PMID- 22515054 TI - RTLS solves patient-tracking emergency. PMID- 22515055 TI - Focus less on technology, more on workflow and people. Intel-GE care innovations has developed a four-phase approach to help healthcare organizations prepare for and implement new technology. PMID- 22515056 TI - Unifying anesthesia documentation. Central Washington Hospital implements solutions to automate all aspects of perioperative care. PMID- 22515057 TI - Developing standards for unstructured documents. Creating a strategy for managing unstructured documents does not have to be an onerous task. PMID- 22515058 TI - A comparative study of the removal of 3-indolebutyric acid using advanced oxidation processes. AB - In this study, advanced oxidation technologies, namely Fenton Process (FP), Fenton-Like Process (FLP), ozonation (O3) and O3/H2O2 processes, were applied to synthetic wastewater containing 3-indolebutyric acid (IBA). The effectiveness of each process was investigated at different pH values, Fe(+2), Fe(+3), O3 and H2O2 concentrations with respect to the removal efficiencies for chemical oxygen demand (COD) and total organic carbon (TOC). The best removal efficiencies were seen at pH 3 and 2 mM Fe concentration in both FP and FLP, in which the optimum H2O2 concentrations were 6 mM for FP and 10 mM for FLP. Optimum process conditions were pH 12 for the O3 process, pH 9 for the O3/H2O2 process and 1:1 O3/H2O2 molar ratio. The highest COD removal efficiency was 86 percent, obtained in the O3/H2O2 process and the highest TOC removal efficiency was obtained at 77 percent in the FP. PMID- 22515060 TI - How to optimize hollow-fiber submerged membrane bioreactors. AB - Membrane fouling is linked to reversible or irreversible accumulation of macromolecules and solids on membrane surfaces and to the irreversible adsorption inside pores. If reversible accumulation can be controlled by filtering in subcritical conditions, then adsorption could also be minimized by reducing the soluble organic matter [extracellular polymeric substances, soluble microbial products (SMP)]. This research shows how the choice of operating parameters related to biological reaction (solid retention time and the organic loading rate) can influence the process rate and the by-product (SMP) production. It also illustrates how suspension characteristics and membrane aeration can influence membrane fouling control according to the hollow fiber configuration and to the different scales of observation. The investigations were based on the definition of different fouling level and fine-tuning of a model to better understand the effects of operating parameters on membrane bioreactor filtration. PMID- 22515061 TI - Characteristics of biosolids in dimethyl ether dewatering method. AB - In this study, a method for removing water from biosolids that uses dimethyl ether (DME) as an extractant was considered. This study evaluates the applicability of the DME dewatering method to biosolid cakes by using a DME flow type experimental apparatus. It was found that a high dewatering ratio is clearly achieved by increasing the liquefied DME/biosolid ratio and lowering the liquefied DME linear velocity. As the liquefied DME/biosolid ratio was increased, the carbon content in dewatered biosolid showed a slight decrease and the TOC concentration in separated liquid increased significantly. Finally, the input energy Es to remove 1 kg of water from the biosolid cake, using both the DME dewatering method and the conventional drying method was estimated. The calculation shows that Es for the DME dewatering process is approximately a third of Es for the conventional thermal drying process. PMID- 22515059 TI - Effects of different methods of DNA extraction for activated sludge on the subsequent analysis of bacterial community profiles. AB - The effect of different DNA extraction protocols on activated sludge DNA yield and bacterial community composition was evaluated by temperature gradient gel electrophoresis (TGGE). Nine different procedures to extract DNA were compared sonication (30s), sonication (40s), sonication (50s), freezing-thawing, bead milling, sodium dodecyl sulfate (SDS)-lysozyme, SDS-proteinase K, SDS-lysozyme proteinase, and a commercial extraction kit. It was found that the TGGE profiles and the DNA band numbers made significant differences via various extraction methods. The yield and purity of DNA extracted by sonication and other physical methods were not satisfactory, while the DNA purity extracted by SDS and other chemical-biological methods were better. Crude DNA extracts isolated by sonication and other physical methods passed the polymerase chain reaction, despite the absence of purification and acquired affluent DNA bands in TGGE. The affluence of bands in TGGE was not consistent with the yield and purification of DNA, but was correlative with extraction protocols. To analyze the activated sludge bacterial community by TGGE fingerprint, it is necessary to make a synthesis of the TGGE fingerprint profiles of chemical and physical DNA extraction methods to overcome the representative bias. PMID- 22515062 TI - A cascade of anoxic and oxic fluidized bed biofilm reactors for treatment of synthetic municipal wastewater. AB - In this study, a cascade of anoxic and oxic fluidized bed biofilm reactors system was carried out to treat synthetic municipal wastewater. The parameters of the influent flow rates and C/N ratios were discussed. System performance was acceptable for chemical oxygen demand (COD), ammonia, and total nitrogen removal. A decrease of ammonia and total nitrogen removal efficiencies, however, was observed when the influent flow rates increased to 5.04 and 6.12 1 h(-1). Total nitrogen removal decreased at the influent C/N ratio of 3:1. The measured ratios of COD reduction in the anoxic column to nitrogen removal through nitrification denitrification were 3.7, 3.5, 3.3, and 3.1 g COD/g(-1) N on average when the influent C/N ratios changed from 6:1 to 3:1. The observed sludge yield (Yobs) was 0.169 g VSS g COD(-1) because of perfect denitrification in the anoxic column and the relatively long solids retention time. PMID- 22515063 TI - Metal ion and other key water quality constituent attenuation in soil columns. AB - A set of soil columns was constructed to simulate discharge of disinfected tertiary treated wastewater to a river via nearby land application or indirect discharge. The system was primarily designed to observe the fate of metal ions and nutrients. The following three experiments were conducted: (1) flow through saturated soils only, which simulates indirect discharge where water is directly applied to groundwater; (2) flow through unsaturated soil followed by saturated flow, which simulates vadose then saturated zone transport; and (3) saturated flow only using ethylene diamine tetraacetic acid-metal chelates, which determined effects of metal organic complexes on metal mobility through the soil. Metal ion attenuation was substantial but not complete in experiments 1 and 2 (removal: 68% Cu2+, 43% Ni2+, 98% Pb2+, and 96% Hg2+), which was somewhat contrary to modeling results. Cyanide attenuation was also monitored (92% removal). In experiment 3, lead attenuation was somewhat reduced (92% removal) and delayed (requiring additional residence time); copper attenuation was significantly reduced (38% removal) and delayed; and nickel concentrations were higher in the 28-day sample (> 80 microg/L) than in the column feed water (58 microg/L). Near-complete denitrification and total phosphorus attenuation were observed. For the water quality constituents studied, unsaturated (vadose zone) transport did not appear to add additional benefit. PMID- 22515064 TI - Electrocatalytic reduction of nitrate ions from water using polyaniline nanofibers modified gold electrode. AB - Polyaniline (PANI) nanofibers were electrochemically synthesized on gold electrode using ethanol as soft template by the cyclic voltammetry technique. The PANI nanofibers were characterized by Fourier transform infrared spectroscopy, UV visible spectroscopy, and scanning electron microscopy. Linear sweep voltammetry was used to investigate electrocatalytic activity of the PANI nanofibers modified electrode toward the reduction of nitrate ions. Results showed that the electroreduction process strongly depends on the applied potential. At the potential value of about -0.8 V vs Ag/AgCl, the electroreduction of nitrate anions to nitrite anions was identified as the rate-determining step of the electroreduction process. In the potential range of -0.8 to -1.0 V, reduction of nitrite to hydroxylamine occurs, followed by the reduction to ammonia. At potentials more negative than -1.0 V, nitrite is directly reduced to ammonia. This study demonstrates the effectiveness of PANI nanofibers modified electrode in the electroreduction of nitrate ions compared to traditional reduction methods. PMID- 22515065 TI - Preliminary findings on the antimony levels of Quiroga river water in the vicinity of a long-abandoned stibnite mine. AB - A UV-Vis spectrophotometric method was developed as a preliminary approach to the determination of antimony in water samples from a river that flows very close to an abandoned mining site. The analyte is complexed with ammonium pyrrolidinedithiocarbamate and absorbance of the complex is measured at 291.06 nm. The standard additions method is mandatory in view of the matrix effect observed, and the response is linear at least up to 9.3 microg/mL of antimony. The sensitivity of the method is 2.609 x 10(-2) mL/microg, whereas the limits of detection and quantification are, respectively, 0.2 and 0.6 microg/mL. The repeatability, expressed as mean relative standard deviation of the measurements within the calibration range, is 2.0%, whereas the repeatability of the entire procedure is 0.3%. The mean analytical recovery within the calibration range was 102.6%. The method was successfully applied to river water samples. PMID- 22515066 TI - Performance evaluation of sequencing batch reactor for beverage industrial wastewater treatment. AB - Attempts were made in this study to examine the effectiveness of sequencing batch reactor (SBR) for the treatment of beverage industrial wastewater. The SBR was operated at three different organic loading rates (OLRs): 2, 1.7 and 1.1 kg COD/m3 d. Results of continuous long-term operation showed that by decreasing OLR from 2 to 1.7 kg COD/m3 day, the removal efficiency was increased from 95.5 to 99.3% for COD, from 95.3 to 98.1% for BOD and from 87 to 97.7% for TSS. While further decreasing of the OLR to 1.1 kg COD/m3 day, there is no significant adverse effect on organics removal. Also, residual total nitrogen (TN) concentration decreased by decreasing the OLR. However, increasing the OLRs exerted a slightly negative effect on the removal of total phosphorous. On the other hand, the experimental data indicated that the substrate utilization kinetic followed Monod's kinetics model approximately. The maximum specific substrate utilization rate (micro(max), half velocity coefficient (Ks), growth yield coefficient (Y) and decay coefficient (Kd) were 2.94 d(-1), 15.22 mg/L, 0.2384 g VSS/g COD and 0.2019 h(-1), respectively. PMID- 22515067 TI - Removal of cationic dyes from aqueous solutions using microspherical particles of fly ash. AB - Batch sorption experiments were carried out for the removal of cationic dyes (methylene blue and malachite green) from their aqueous solutions using sorbent made from fly ash-a waste material. Effects of various experimental parameters: initial dye concentration, contact time, pH, adsorbent dosage, solution temperature, surfactant addition and ionic strength on the fly ash sorption of dyes were evaluated. The isothermal data for sorption followed the Langmuir model. The maximum sorption capacity obtained for methylene blue and malachite green was 36.05 mg/g and 40.65 mg/g, respectively. Kinetic studies indicate that sorption on fly ash follows the pseudo-second order kinetics. Present research suggests that fly ash could be an appropriate adsorbent for the removal of basic dyes from aqueous solutions. PMID- 22515068 TI - Improving nutrient removal while reducing energy use at three Swiss WWTPs using advanced control. AB - Aeration consumes about 60% of the total energy use of a wastewater treatment plant (WWTP) and therefore is a major contributor to its carbon footprint. Introducing advanced process control can help plants to reduce their carbon footprint and at the same time improve effluent quality through making available unused capacity for denitrification, if the ammonia concentration is below a certain set-point. Monitoring and control concepts are cost-saving alternatives to the extension of reactor volume. However, they also involve the risk of violation of the effluent limits due to measuring errors, unsuitable control concepts or inadequate implementation of the monitoring and control system. Dynamic simulation is a suitable tool to analyze the plant and to design tailored measuring and control systems. During this work, extensive data collection, modeling and full-scale implementation of aeration control algorithms were carried out at three conventional activated sludge plants with fixed pre denitrification and nitrification reactor zones. Full-scale energy savings in the range of 16-20% could be achieved together with an increase of total nitrogen removal of 40%. PMID- 22515069 TI - A special issue on the developments in biomedical nanotechnology in Latin America. PMID- 22515070 TI - Magnetic nanoparticles and rapamycin encapsulated into polymeric nanocarriers. AB - PURPOSE: The objective of this study was to develop nanocapsules and nanospheres of polylactide-co-glycolide (PLGA) containing magnetic nanoparticles and rapamycin. METHOD: Magnetic nanoparticles (MP) were obtained by the co precipitation of Fe(ll) and Fe(III) salts by addition of ammonium hydroxide. Nanocapsules (NC) and nanospheres (NS) containing either uncoated magnetic nanoparticles (MP), MP coated with oleic acid monolayer (MPOA) or MP coated with oleic acid bilayer (MPOA-OA) were prepared by the emulsion evaporation method. Rapamycin was also encapsulated into NC and NS. Morphology, size, size distribution, entrapment efficiency, stability and magnetization characteristics were determined. RESULTS: Non-contact AFM images showed that the composite nanoparticles were almost spherical in shape. The resulting polymeric nanocarriers were found to have a mean diameter of approximately 120 nm with a narrow size distribution. The influence of some experimental parameters on the entrapment efficiency and stability was determined. Nanocapsules and nanospheres prepared with uncoated magnetic nanoparticles exhibited higher entrapment efficiency and stability. Superparamagnetic behavior of the magnetic nanocomposite was demonstrated by magnetization data. These findings may contribute to the development of potential controlled release drug targeting devices based on magnetic polymeric nanocarriers. PMID- 22515071 TI - Poly(ethylene glycol) hydroxystearate-based nanosized emulsions: effect of surfactant concentration on their formation and ability to solubilize quercetin. AB - Quercetin is a natural compound that has shown several biological activities. However, it displays poor water solubility and, therefore, low bioavailability. In this study, oil-in-water nanosized emulsions were obtained by the hot solvent diffusion method, using castor oil as oily phase and poly(ethylene glycol) (660) 12-hydroxystearate (PEG 660-stearate) and lecithin as surfactants. The effect of the PEG 660-stearate concentration on the droplet size of the nanosized emulsions and on the ability of these systems to load quercetin was investigated. Dynamic light scattering (DLS), transmission electron microscopy (TEM), cryo-TEM, and small-angle X-ray scattering (SAXS) were used to characterize the systems. We have demonstrated that a critical concentration of PEG 660-stearate (2.5 wt%) was needed to obtain colloidal dispersions displaying microemulsion characteristics. This colloidal dispersion, that was not optically birefringent, was constituted by a monodisperse population of 20 nm-large droplets, and exhibited excellent stability. Besides, this system was able to solubilize five times more quercetin than nanoemulsions prepared using 0.25 wt% PEG 660-stearate. SAXS results suggest that the spherical droplets have a core-shell structure. With regard to the hot solvent diffusion method, both diffusion of the solvent towards the aqueous phase and increase of the temperature above the phase inversion temperature (PIT) of PEG 660-stearate appeared to be required for obtaining clear and isotropic colloidal dispersions. PMID- 22515072 TI - Mesenchymal stem cell adherence on poly(D, L-lactide-co-glycolide) nanofibers scaffold is integrin-beta 1 receptor dependent. AB - Tissue engineering is a potential approach to regenerate damaged tissue by the combination and synergism among the scaffolding material, cell source and signaling factors. In the present study, mesenchymal stem cells (MSCs) were isolated from C57BL/6 mice, cultured on poly(D, L-lactide-co-glycolide) (PLGA) scaffold produced by electrospinning technique and differentiated into chondrogenic lineage. After seeding, MSCs were responsive and became flattened with fibroblast-like morphology demonstrated by the presence of actin stress fibers. Integrin-beta1 receptor blockage reduced significantly cell adhesion with loss of actin stress fibers, demonstrating the ability of PLGA nanofiber to trigger integrin receptor-mediated cell adhesion. Present data contribute to the understanding of MSCs' behavior on these biodegradable and biocompatible scaffolds that can be used as carriers in treatments involving cell transplantation. PMID- 22515073 TI - Development of cationic solid lipid nanoparticles with factorial design-based studies for topical administration of doxorubicin. AB - Topical chemotherapy using doxorubicin, a powerful anticancer drug, can be used as an alternative with reduced systemic toxicity when treating skin cancer. The aim of the present work was to use factorial design-based studies to develop cationic solid lipid nanoparticles containing doxorubicin; further investigations into the influence of these particles on the drug's cytotoxicity and cellular uptake in B16F10 murine melanoma cells were performed. A 32 full factorial design was applied for two different lipid phases; one phase used stearic acid and the other used a 1:2 mixture of stearic acid and glyceryl behenate. The two factors investigated included the ratio between the lipid and the water phase and the ratio between the surfactant (poloxamer) and the co-surfactant (cetylpyridinium chloride). It was observed that the studied factors did not affect the mean diameter or the polydispersity of the obtained nanoparticles; however, they did significantly affect the zeta potential values. Optimised formulations with particle sizes ranging from 251 to 306 nm and positive zeta potentials were selected for doxorubicin incorporation. High entrapment efficiencies were achieved (97%) in formulations with higher amounts of stearic acid, suggesting that cationic charges on doxorubicin molecules may interact with the negative charges in stearic acid. Melanoma culture cell experiments showed that cationic solid lipid nanoparticles without drug were not cytotoxic to melanoma cells. The encapsulation of doxorubicin significantly increased cytotoxicity, indicating the potential of these nanoparticles for the treatment of skin cancer. PMID- 22515074 TI - Acute toxicity study of cisplatin loaded long-circulating and pH-sensitive liposomes administered in mice. AB - Cisplatin (CDDP) is a very active and cytotoxic agent but causes severe side effects, namely nephrotoxicity, which limits the therapy. The present study aimed to evaluate the acute toxicity of long-circulating and pH-sensitive liposomes containing cisplatin (SpHL-CDDP), as compared to free CDDP, after their intravenous administration in mice. After the administration of free CDDP or SpHL CDDP at different doses, the body weight was recorded and the LD50 and the maximum tolerated dose (MTD) were calculated. Blood samples were collected for hematological and biochemical analysis. Kidneys, liver, spleen, and bone marrow were removed for histopathological examination. A reduction of body weight of less than 15% could be observed in male and female mice after treatment with free CDDP and SpHL-CDDP at doses of < or = 10 mg/kg and 20 mg/kg, respectively. The LD50 and MTD values obtained after SpHL-CDDP administration were approximately two and three times higher, respectively, than those obtained using free CDDP. Changes in hematological parameters and hematopoietic tissue morphology showed the appearance of toxicity induced by free CDDP. By contrast, the absence of mielotoxicity after SpHL-CDDP treatment could be observed. As regards nephrotoxicity, no alteration in blood urea and creatinine levels, nor morphological change in kidneys, could be observed in mice treated with SpHL CDDP, as compared to saline-treatment control group. The results showed that SpHL CDDP at its MTD (20 mg/kg), as compared to the administration of free CDDP at its MTD (7.5 mg/kg), significantly reduced the renal toxicity. Thus, SpHL-CDDP can eliminate CDDP-induced toxicity and is a promising candidate for the intravenous therapy of solid tumors. PMID- 22515075 TI - Chitosan coated liposomes as an innovative nanocarrier for drugs. AB - Chitosomes are chitosan coated liposomes that represent an alternative to conventional liposomes since they present better stability and bioadhesivity. The aim of this work was to develop and evaluate the physico-chemical stability of melatonin (MEL)-loaded chitosomes as well as to compare their properties with that of MEL loaded liposomes. Structural characteristics of nanovesicles were also studied by dynamic light scattering and small angle X-ray scattering. The liposome and chitosome suspensions presented mean diameters between 150 nm and 254 nm, polydispersity indexes around 0.4, zeta potential values between -38 mV and -28 mV, pH values close to 4.0, MEL content close to 100% and encapsulation efficiency between 34.4% and 60.8%. Small angle X-rays scattering showed the presence of unilamelar structures, which were also observed by transmission electronic microscopy. Stability studies focusing on the particle diameter indicated that, within 90 days, the liposome suspensions had a decrease in mean diameter values and in polydispersity indexes, but no alterations were detected in zeta potentials and MEL content. The chitosome suspensions remained stable in relation to these parameters during 90 days. Multiple light scattering analysis (Turbiscan LAb) corroborated the the findings in the stability studies. The result sets pointed out the physico-chemical stability of chitosomes and the chitosan influence in their supramolecular structure. PMID- 22515076 TI - Aluminum-chloride-phthalocyanine encapsulated in liposomes: activity against naturally occurring dog breast cancer cells. AB - Breast tumors represent the most common malignant tumors. Current treatments for humans and pets rely on tumor excision and adjuvant chemotherapy, which may affect both cancer cells and normal cells. Photodynamic therapy (PDT) is an approved treatment modality for a variety of cancers and was recently recommended as a first-line treatment for non-melanoma skin cancers for humans. The main purpose of the present study was to determine the efficacy of PDT using aluminum chloride-phthalocyanine that is encapsulated in liposomes and LED as a light source to kill naturally occurring female dog breast cancer in vitro. The cytotoxicity behavior of the encapsulated photosensitizer in the dark and under irradiation using the 670 nm laser were investigated using classical trypan blue and MTT cell viability tests, acridine orange and ethidium bromide staining to label organelles, and cell morphology. Cell morphology was evaluated using light and electron microscopy. Our results demonstrate a reduced cell viability that is associated with morphologic alterations. The neoplasic cell destruction was predominantly mediated via a necrotic process, which was assayed using acridine orange and ethidium bromide staining. These findings were confirmed using light and electronic microscopy. The photosensitizer or laser irradiation alone did not induce cytotoxicity or morphological alterations, indicating the safety and efficacy of PDT with chloro-aluminum-phthalocyanine that was encapsulated in liposomes for the treatment of breast cancer cells in vitro. PMID- 22515077 TI - Isotretinoin-loaded nanocapsules: stability and cutaneous penetration by tape stripping in human and pig skin. AB - The cutaneous penetration of isotretinoin-loaded poly(epsilon-caprolactone) nanocapsules (GEL-NCISO) was compared to that of free isotretinoin (GEL-FREE) incorporated in hydrogels by tape stripping in excised human and pig skin. The physicochemical stability of isotretinoin-loaded nanocapsules and a nanoemulsion (used as a control) was evaluated using multiple light scattering, quantifying drug content and determining particle size, polydispersion index, zeta potential and pH for 60 days. A photostability study was also carried out. GEL-FREE and GEL NCISO were applied to human and pig skin and penetration was assessed by tape stripping in Franz diffusion cells. The isotretinoin-loaded nanocapsules showed suitable physicochemical characteristics for topical administration, physical stability for 2 months at room temperature and under UVA radiation. In vitro tape stripping in human and pig skin showed that no isotretinoin reaches the receptor compartment for both formulations up to 8 h. Nanoencapsulation increased isotretinoin skin penetration for both skin stratum corneum. Pig skin was more permeable than human since higher isotretinoin concentrations were found at human upper skin layers for both formulations. Similar proportion of cutaneous penetration for human and pig skin were observed although different amounts of drug were detected in the stratum corneum of both skin specimens in vitro. A positive Pearson product moment correlation coefficient (0.79) between human and pig skin penetration in vitro was obtained, thus, pig skin can be considered suitable for predicting cutaneous penetration of isotretinoin in humans in vitro. PMID- 22515078 TI - Amphiphilic diblock copolymer and polycaprolactone blends to produce new vesicular nanocarriers. AB - New Melatonin-loaded vesicular nanocarriers were prepared by interfacial deposition using a blend of an amphiphilic diblock copolymer, poly(methyl methacrylate)-block-poly(2-(dimethylamino)ethyl methacrylate), PMMA-b-PDMAEMA, with poly(epsilon-caprolactone), PCL. Particle size and morphology of the nanocarriers was evaluated. Dynamic light scattering shows that the nanocarriers have hydrodynamic radii between 100 and 180 nm, with unimodal particle size distribution for each formulation. Shape and structure were visualized by transmission electron microscopy (TEM), cryogenic TEM and scanning electron microscopy. Standard TEM for nanocapsules showed an oily core surrounded by a thin layer composed by PCL/PMMA-b-PDMAEMA. Cryo-TEM also indicated the presence of spherical nano-objects with a diffuse polymer corona. Encapsulation efficiencies were determined assaying the nanoparticles by HPLC and higher values of ca. 25% are shown by the nanocapsules. We could successfully incorporate platinum nanoparticles into the nanocarrier as evidenced by TEM, which opens up the possibility for promising applications like monitoring the encapsulated drug in the body. PMID- 22515079 TI - Rheological, mechanical and adhesive properties of surfactant-containing systems designed as a potential platform for topical drug delivery. AB - In the last few decades, nanotechnology has led to an advance in the development of topical drug delivery. Nanostructured drug delivery systems enable the compartmentalization of drugs in restricted environments, modifying the release profile and maintaining the required drug concentration for prolonged periods at the site of action and/or absorption. The development of nanostructured systems containing surfactants has evolved rapidly. Mixtures of surfactant, oil and water can self-associate to form structures, such as microemulsions and liquid crystal phases, which can be exploited as drug delivery systems because their nanostructured organization can control drug release. Therefore, the purpose of this study was to assess the potential of systems containing polyoxypropylene (5) polyoxyethylene (20) cetyl ether as surfactant, oleic acid or mineral oil as the oily phase, and water to be used as a platform in the development of topical drug delivery systems. Physicochemical characterization of the systems was performed by polarized light microscopy (PLM), small-angle X-ray scattering (SAXS), rheological tests and texture profile analysis. The ternary phase diagrams showed that combinations of surfactant/mineral oil/water and surfactant/oleic acid/water could form various thermodynamically stable structures, such as microemulsions and liquid crystals. The oily phases, oleic acid and mineral oil, changed the rheological, mechanical and adhesive properties of systems containing polyoxypropylene (5) polyoxyethylene (20) cetyl ether. PMID- 22515080 TI - Amphotericin B microemulsion reduces toxicity and maintains the efficacy as an antifungal product. AB - Amphotericin B remains the drug of choice for the treatment of most of the systemic fungal infections in immunodeficient patients. Because of the high incidence of adverse drug reactions the clinical use of Amphotericin B is rather limited. To reduce its toxicity new drug delivery systems has been suggested. Nevertheless, these carriers present several technological drawbacks that impair the development of a marketable product. The aim of this work was to develop an Amphotericin B microemulsion in order to increase its efficacy and decrease its toxicity compared to Fungizon, the widely know inexpensive micellar system of Amphotericin B. Amphotericin B loaded microemulsion showed an average size close to 300 nm by photon correlation spectroscopy. In the UV spectrum, the observation of the monomeric peak at 405 nm, which was independent of the sample dilution, revealed that the Amphotericin B molecules were strongly and individually bound to the microemulsion droplets. The new microemulsion formulation had the same efficacy than Fungizon against C. albicans. Concerning toxicity, Amphotericin B loaded microemulsion showed lower toxicity against human red blood cells compared to the commercial product. Taken together, these results suggested that microemulsion is an eligible drug carrier for Amphotericin B or other water insoluble molecules, and it has potential applications to targeting fungal cells. Additionally, a novel formulation of Amphotericin B-loaded microemulsion was prepared by a straightforward and fast procedure. PMID- 22515081 TI - Long-term biodistribution and biocompatibility investigation of dextran-coated magnetite nanoparticle using mice as the animal model. AB - Magnetic resonance is used to investigate biodistribution aspects of dextran coated magnetite nanoparticles (9.4 nm core diameter) in both liver and spleen from 5 minutes up to 6 months after intravenous administration of a magnetic fluid sample in female Swiss mice. Using magnetic resonance data important parameters such as the absorption half-life (t 1/2 = 12 +/- 2 min in the liver and t 1/2 = 11 +/- 2 min in the spleen), the peak time (1.7 +/- 0.2 h in the liver and 1.9 +/- 0.2 h in the spleen), and the disposition half-life of the dextran-coated magnetite nanoparticles in mice organs (t 1/2 = 70 +/- 10 h in the liver and t 1/2 = 32 +/- 7 h in the spleen) were assessed. In addition, light and electron microscopy showed several aspects that may be related to the iron metabolism. Microscopic analysis also revealed that although magnetite nanoparticles or iron released from them are retained in the organism for a long period of time, no morphologic alteration is induced by the intravenous administration of the magnetic fluid sample, evidencing its biocompatibility. The used tests may represent an adequate methodology for nanotoxicology evaluation. PMID- 22515082 TI - Natural lipid nanoparticles containing nimesulide: synthesis, characterization and in vivo antiedematogenic and antinociceptive activities. AB - Lipid nanoparticles are drug delivery systems able to increase bioavailability of poorly soluble drugs. They can be prepared with different lipid materials, especially natural lipids. Shea butter is a natural lipid obtained from the Butyrospermum parkii seed and rich in oleic and stearic acids. Nimesulide is a COX 2 selective anti-inflammatory that is poorly soluble in water. The purpose of this study was to develop and characterize shea butter lipid nanoparticles using a new technique and evaluate the in vivo activity of these nanoparticles. Lipid nanoparticles were prepared by melting shea butter and mixing with an aqueous phase using a high shear mixer. The nanoparticles presented pH of 6.9 +/- 0.1, mean particle size of 90 nm and a narrow polydispersity (0.21). Zeta potential was around -20 mV and the encapsulation efficiency was 97.5%. Drug release was evaluated using dialysis bags and presented monoexponential profile with t50% of 4.80 h (free drug t50% was only 2.86 h). Antinociceptive activity was performed by the acetic acid model. Both nimesulide and nimesulide-loaded nanoparticles presented significant activity compared to the control. The in vivo anti inflammatory activity was evaluated by paw edema and was statistically different for the nanoparticles containing nimesulide compared to free nimesulide, blank nanoparticles and saline. In conclusion, the use of shea butter as encapsulating lipid was very successful and allowed nanoparticles to be prepared with a very simple technique. The nanoparticles presented significant pharmacological effects that were not seen for free drug administration. PMID- 22515083 TI - Safety and efficacy of antioxidants-loaded nanoparticles for an anti-aging application. AB - The aim of this work was to perform a pilot study on the safety and efficacy of nanoparticle formulation for cosmetic application. The encapsulated actives in the nanoparticles were a blend of coenzyme Q10, retinyl palmitate, tocopheryl acetate, grape seed oil and linseed oil. The nanoparticle suspension was characterized in terms of pH and particle size. For the safety assessment, alternative methods as cytotoxicity and HET CAM were used. The clinical skin compatibility tests were also performed. The efficacy was evaluated in healthy volunteers presenting different degrees of periorbital wrinkles. Skin hydration was performed by corneometry. The nanoparticles presented narrow size around 140 nm and pH close to neutral and were suitable to cutaneous application. The alternative tests demonstrated that the nanoparticles did not present potential to induce skin irritant effects, cytotoxicity or generate oxidative stress. The clinical assays confirmed the in vitro results, demonstrating the safety of the nanoparticles, which were not irritant, sensitizing and comedogenic. Furthermore, the exposure to UVA light did not cause photoxicity. Regarding the efficacy, nanoparticles presented significant reduction in wrinkle degree after 21 days of application compared to the control. The volunteers could differentiate the nanoparticles and the control product by means of subjective analyses. In conclusion, the nanoparticles containing antioxidant actives were safe for topical use and presented anti-aging activity in vivo and are suitable to be used as cosmetic ingredient. PMID- 22515084 TI - Amphotericin B-loaded nanocarriers for topical treatment of cutaneous leishmaniasis: development, characterization, and in vitro skin permeation studies. AB - Topical treatment of cutaneous leishmaniasis represents an exciting alternative for reducing toxicity associated with parenteral administration of conventional amphotericin B. This work aims to develop and to characterize amphotericin B loaded new carriers and to investigate their potential for topical delivery by conducting permeation studies with pig ear skin in comparison with marketed formulations. Among other formulations, nanoemulsions were developed and characterized for size, encapsulation efficiency, and zeta potential. To mimic use conditions in topical therapy of cutaneous leishmaniasis, in vitro skin permeation experiments were conducted using a damaged skin model. High encapsulation efficiency (95%) and low particle size (239 nm) were obtained for amphotericin B-loaded nanoemulsion by employing an ion pairing between the drug and stearylamine. Amphotericin B permeation after 24 h across the dermal membrane was low, regardless of the type of formulation tested. In contrast, amphotericin B penetration into dermal membranes (microg/cm2) from solution (control), aqueous Amphocil, hydroalcoholic Amphocil, Fungizone, mixture Fungizone-Lipofundin, and NE was 17.5 +/- 4, 15.2 +/- 3, 9.6 +/- 3, 3.5 +/- 1, 1.7 +/- 0.3, and 1.1 +/- 0.1, respectively. Amphocil provided the best results, highlighted by its high improvement of dermal penetration of amphotericin B. PMID- 22515085 TI - Development of topical hydrogels containing genistein-loaded nanoemulsions. AB - This article describes the development of topical hydrogels containing genistein loaded nanoemulsions, obtained by means of spontaneous emulsification. This procedure yielded monodisperse nanoemulsions in a sub 250 nm range exhibiting negative zeta-potential and low viscosity. The formulations were incorporated into acrylic-acid hydrogels in order to have their viscosity adjusted for topical application. The semisolid formulations exhibit non-Newtonian pseudoplastic behavior. The skin permeation/retention of genistein from formulations was carried out using porcine ear skin mounted in Franz diffusion cells under sink conditions. The results showed a slow flow of genistein through the skin. Higher amount of genistein was detected into the skin from the formulation composed by medium chain triglycerides as oily core when compared to the octyldodecanol one. The overall results show that hydrogels containing genistein-loaded nanoemulsions could be considered as a promising formulation to delivery isoflavones into the skin. PMID- 22515086 TI - Effects of the composite nanovesicles on the physical properties and cellular adhesion of chitosan films. AB - Chitosan films were prepared by the casting of a chitosan gel in absence and presence of composite nanovesicles. The microscopy images showed the occurrence of agglomerates on the surface and internal pores when the nanovesicles were added to the films, differently from the smooth surface of the pure chitosan films. Despite the hydrophobic character that composite nanovesicles gave to the chitosan films, as showed by the reduction of the water permeation at prolonged times, there was a reduction on the contact angle values for these samples related to the roughness of the surface. The peak of water desorption observed on calorimetric analysis of chitosan was shifted to higher values when the nanovesicles were added to the films. Furthermore, the desappearance of Tg on the films containing nanovesicles denoted their plastifier effect in the chitosan film. The swelling results showed higher water diffusion at the first times for the films containing nanovesicles because of the pores observed by microscopy. However, at prolonged times, there was a reduction on the swelling because of the lipofilic composition of the nanovesicles. Furthermore, the presence of nanovesicles led to a reduction on the water content in the chitosan films. Due to the effect on the physical properties of the chitosan films, the addition of nanovesicles on discrete concentrations contributed to the cell adhesion. PMID- 22515087 TI - Carbon nanostructures interacting with vitamins A, B3 and C: ab initio simulations. AB - The energetic and structural properties of fullerenes, carbon nanotubes and graphene interacting with vitamins A, B3 and C were studied by first principles simulations. These vitamins, which have antioxidant activities, give support to the cellular metabolism, have biochemical, therapeutic and cosmetic functions, and when combined with carbon nanostructures may have their chemical instability controlled. In this work, the results illustrate that the strongest interaction is between vitamin A and graphene. The binding energies found for the interactions between carbon nanostructures and these vitamins range from 0.10 to 0.93 eV. For all the configurations studied, a physisorption regime is observed without significant changes in the chemical and physical properties of the adsorbed vitamins, which is relevant for a drug delivery system. PMID- 22515088 TI - Structural properties induced by the composition of biocompatible phospholipid based microemulsion and amphotericin B association. AB - Anionic microemulsions (MEs) containing soya phosphatidylcholine, Tween-20, sodium oleate as surfactant, and cholesterol as oil phase were investigated as drug carriers for amphotericin B. Depending on the composition of the microemulsion, various structures, which differently interact with amphotericin B, can be formed. The nanostructured systems were characterized by photon correlation spectroscopy, rheological behavior, and polarized light microscopy. The results reveal that the droplet diameters increased with amphotericin B incorporation for all ranges of surfactant and oil phase. For both amphotericin B unloaded and amphotericin B-loaded microemulsions, the profile of the oil droplet diameter decreased with increasing the surfactant concentration, demonstrating the stabilizing effect of the surfactant. The increase in the oil phase proportions led to the growth of the droplet diameter, clearly demonstrating the limit of the surfactant organization in the oil-water interface. The amphotericim B incorporation into microemulsion increased with the fraction volume of the oil phase and the surfactant concentration reaching a plateau at high contents. This profile could be quantitatively analyzed by the framework of the pseudo-phase model that considers the amphotericim B distribution between the oil and the aqueous phases. The rheological analysis showed a pseudoplastic behavior with little thixotropic characteristic. Under polarized light, the system of interest showed a dark background characteristic of dispersed droplets. However, for both amphotericim B-loaded and amphotericim B unloaded microemulsions, the increase in the O/S ratio led to the formation of ordered structures with lamellar arrangements. PMID- 22515089 TI - Electrospun fibers and tissue engineering. AB - Electrospinning is an exciting technique attracting more and more attention as a potential solution to the current challenges in the field of tissue engineering. This technique can be used to produce fibrous scaffolds with excellent biocompatibility and biodegradability, as well as suitable micro-/nanostructure to induce desired cellular activities and to guide tissue regeneration. In order to develop electrospun fibrous scaffolds for these applications, different biocompatible materials including natural polymers, synthetic polymers and inorganic substances and preparations have been used to fabricate electrospun fibers with different structures and morphologies. This review briefly describes the development of the technique, focusing on several typically electrospun materials, surface modification of electrospun fibers, and current applications in tissue engineering. PMID- 22515090 TI - In vivo experiments and numerical investigations on nanocryosurgical freezing of target tissues with large blood vessels. AB - This study presented the first in vivo animal experiments of using nano cryosurgical modality to completely freezing tumor tissues embedded with large blood vessels, which is a tough issue to tackle otherwise. Three-dimensional theoretical simulations were also performed on the complex freezing problems by considering flow and heat transfer of blood flow in large vessels. According to the experimental measurements and numerical predictions, injecting the nanoparticles with high thermal conductivity into the freezing target can significantly reduce the heating effect of blood vessel, shorten the freezing time, and enlarge the freezing range. Most importantly, the introduction of nanoparticles successfully overcomes the classical challenges in completely ablating the tumor region with large blood vessel and enhancing the freezing efficacy of cryosurgery. This investigation consolidates the practical and theoretical foundation for nano-cryosurgery which suggests a highly efficient freezing strategy for treating late stage tumor. PMID- 22515091 TI - Polyelectrolyte coated polymeric nanoparticles for controlled release of docetaxel. AB - Polyelectrolyte coatings are effective means of minimizing the rate of release of small molecules from a nanoparticle system. The current investigation aim at developing biodegradable drug delivery carriers composed of three types of polymers viz poly(lactide-co-glycolic) acid [PLGA], poly(lactide-co-glycolic) acid-polyethylene imine [PLGA-PEI] and poly lactic acid [PLA]. The PLGA and PLGA PEI nanoparticles were in the size range approximately 150 nm while PLA nanoparticles were approximately 80 nm in size respectively. The nanoparticles were found to encapsulate 66%, 62% and 65% of the hydrophobic drug, Docetaxel (DOCE) respectively. "Layer by Layer (LbL)" self assembly technique was then performed to coat these particles with polyelectrolyte thin films (PEs). DLS studies showed hydrodynamic diameter of 330 nm, 350 nm and 310 nm for the coated PLGA, PLGA-PEI and PLA nanoparticles respectively, while SEM and TEM studies demonstrated that after coating the particle sizes were approximately 200 nm for all the three nanoparticles. In vitro drug release studies demonstrated that at the end of 24 hours, about 83%, 90% and 88% of drug was released from uncoated PLA, PLGA-PEI and PLGA nanoparticles respectively. Using LbL coating, the same amount of the drug was found to be released in a sustained way for up to 7 days for PLGA and up to 6 days for PLGA-PEI and PLA nanoparticles. In vitro cytocompatibility studies were carried out with each system and the cell viability at end of 48 hours was found to be in the range of 70% to 100%. Current approach of sustained drug delivery can help in improving the therapeutic efficiency of the breast cancer drug, DOCE. PMID- 22515092 TI - 5-flourouracil loaded N,O-carboxymethyl chitosan nanoparticles as an anticancer nanomedicine for breast cancer. AB - Chitosan and its carboxymethyl derivatives are smart biopolymers that are non toxic, biocompatible, biodegradable and hence found applications in biomedical field. In the current work, we have developed 5-fluorouracil (5-FU) loaded N,Ocarboxymethyl chitosan (N,O-CMC) nanoparticles (mean diameter: 80 +/- 20 nm, zeta potential: +52.47 +/- 2 mV) for cancer drug delivery. Drug entrapment efficiency (65%) and in vitro drug release studies were carried out spectrophotometricaly. Cellular internalization of the drug loaded nanoparticles was confirmed by fluorescent microscopy and flow cytometric analysis. Results of anticancer activity via MTT, apoptosis and caspase 3 assays showed the toxicity of the drug loaded nanoparticles towards breast cancer cells. As a whole these results indicates the potential of 5-FU loaded N,O-CMC nanoparticles in breast cancer chemotherapy in which the side effects of conventional chemo treatment could be reduced. Furthermore, the results of in vitro hemolytic assay and coagulation assay substantiate the blood compatibility of the system as well. PMID- 22515093 TI - Gelatin nanocarrier enables efficient delivery and phototoxicity of hypocrellin B against a mice tumour model. AB - Nanoparticles formulated from biodegradable and natural polymer gelatin, were investigated for their potential to enable efficient delivery and enhanced efficacy of a well-known photodynamic agent, Hypocrellin B (HB). The HB-loaded poly(ethylene glycol) modified gelatin nanoparticles (HB-PEG-GNP) possessed near spherical shape, with particle size in the range of 292 +/- 42 nm, and demonstrated characteristic optical properties for photodynamic therapy (PDT). Photophysical studies of the HB-PEG-GNP demonstrated photogeneration of reactive oxygen species (ROS). The nanoparticles were tested for cellular uptake in vitro, on Daltons' Lymphoma Ascites (DLA) cells and demonstrated dose dependent phototoxicity upon visible light treatment. HB-PEG-GNP induced mitochondrial damage, as investigated by JC-1 staining, leading to apoptotic cell death. Biodistribution measurements revealed that nanoformulation reduces liver uptake of HB-PEG-GNP and increases tumour uptake with time. In vivo PDT studies in solid tumour bearing mice showed markedly significant regression (38.5 +/- 2.2%, p < 0.05) for HB-PEG-GNP treated mice in contrast to those treated with free HB (29.36 +/- 1.62%). The present study reveals gelatin nanocarrier to be an effective drug delivery system for enhancement of therapeutic efficacy of the PDT agent, HB. PMID- 22515094 TI - Carbosilane dendrimers are a non-viral delivery system for antisense oligonucleotides: characterization of dendriplexes. AB - The success of gene therapy depends on the development of suitable carriers, and because of their architecture dendrimers are promising tools for gene delivery. This research concerns the use of second generation carbosilane dendrimers as carriers for anti-HIV oligodeoxynucleotides (ODNs). The aim was to characterize complexes formed by positively charged dendrimers and negatively charged oligonucleotides using a fluorescence method, laser Doppler electrophoresis, dynamic light scattering (DLS), atomic force microscopy (AFM), transmission electron microscopy (TEM) and molecular modeling. The zeta-potential of ODNs increased from -25 mV to positive values after the addition of dendrimers. DLS and TEM revealed that the diameters of dendriplexes ranged from 75 to 240 nm and from 50 to 260 nm, respectively, and this was dependent on the type of dendrimer and the molar ratios of the complexes formed; complexes were stable for between 100 and 300 minutes. AFM measurements and molecular modeling studies were carried out to determine the structure and size of dendriplexes. The physicochemical properties of the dendriplexes studied and data from previous research suggest that carbosilane dendrimers are good candidates for nucleic acid delivery. PMID- 22515095 TI - Monitoring of bystander effect of herpes simplex virus thymidine kinase/acyclovir system using fluorescence resonance energy transfer technique. AB - Cytotoxic gene therapy mediated by gene transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene followed by acyclovir (ACV) treatment has been reported to inhibit malignant tumor growth in a variety of studies. The magnitude of "bystander effect" is an essential factor for this anti-tumor approach in vivo. However, the mechanism by which HSV-tk/ACV brings "bystander effect" is poorly understood. In this report, the plasmid CD3 (ECFP-CRS-DsRed) and TK-GFP were transferred to the human adenoid cystic carcinoma line ACC-M cell line. The CD3-expressing cells apoptosis was monitored using fluorescence resonance energy transfer (FRET) technique. First, CD3 and TK-GFP co-expressing ACC-M cells apoptosis was monitored using FRET technique. The apoptosis was induced by ACV and initiated by caspase3. The FRET efficient was remarkably decreased and then disappeared during cellular apoptosis, which indicated that the TK-GFP expressing ACC-M cells apoptosis, induced by ACV, was via a caspase3-dependent pathway. Secondly, CD3 and TK-GFP mixed expressing ACC-M cells apoptosis, induced by ACV, were monitored using FRET technique. The apoptotic phenomena appeared in the CD3 expressing ACC-M cells. The results show that HSV-tk/ACV system killed ACC-M cells using its bystander effect. These results confirm that HSV-tk/ACV system is potential for cancer gene therapy. PMID- 22515096 TI - Biodegradable self-assembled MPEG-PCL micelles for hydrophobic oridonin delivery in vitro. AB - The great potential of oridonin (ORI) for clinical application in cancer therapy is greatly limited due to its poor water-solubility. The purpose of this study was to increase the water solubility of oridonin using monomethoxy poly(ethylene glycol)-poly(epsilon-caprolactone) (MPEG-PCL) as drug carrier. The ORI-loaded MPEG-PCL micelles were prepared by thin film hydration method. The obtained ORI micelles could be lyophilized into powder form, which could be re-dissolved in water to form homogeneous solution. This study showed that ORI was successfully incorporated in the core-shell structure of MPEG-PCL micelles and maintained its anticancer activity. The average particle size was 25.55 +/- 0.10 nm and the mean zeta potential was -4.71 +/- 0.05 mV. The actual drug loading and encapsulation efficiency were 7.99 +/- 0.03% and 99.51 +/- 0.34%, respectively. ORI could be released from MPEG-PCL micelles in a sustained manner in vitro. The permeation profiles of ORI from ORI-micelles and ORI water saturated solution through excised mouse skin demonstrated that ORI-micelles showed much better transdermal penetration performance than ORI water saturated solution. The prepared ORI micelles have great potential for both direct intravascular administration and being further developed as a transdermal drug delivery system in cancer chemotherapy. PMID- 22515097 TI - The in vitro and in vivo study on self-nanoemulsifying drug delivery system (SNEDDS) based on insulin-phospholipid complex. AB - Self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the absorption of insulin after oral administration, where insulin was complexed with phospholipid to achieve a better liposolubility in the form of insulin phospholipid complex (IPC). IPC was formulated into the oil phase of SNEDDS by solvent-evaporation method. The formula of IPC-SNEDDS was optimized and characterized. Data showed that SNEDDS as a drug vehicle did not exhibit an obvious inhibition over MDCK cells, and it can facilitate the transport of IPC across MDCK cell monolayer. IPC-SNEDDS could enhance the absorption of insulin after oral administration and yielded a pronounced hypoglycemic effect on diabetic Wistar rats. All these suggested that IPC-SNEDDS has a great potential for oral delivery of insulin. PMID- 22515098 TI - Synthesis, characterization and preliminary in vitro evaluation of PTH 1-34 loaded chitosan nanoparticles for osteoporosis. AB - Human Parathyroid hormone 1-34 (PTH1-34) loaded chitosan nanoparticles (PTH 1-34 chitosan nanoparticles) via simple ionic gelation technique were prepared which can improve the bioavailability and half-life of the peptide. Chitosan nanoparticles and PTH 1-34 chitosan nanoparticles were synthesised and characterized by DLS, SEM, AFM, FT-IR and TG/DTA. Chitosan nanoparticles (40-60 nm) and PTH 1-34 chitosan nanoparticles (60-80 nm) with zeta potential of +60 and +40 mV respectively were subjected to haemolysis assay and tested for agglomeration in blood. MTT and LDH was performed assay using Saos-2, UMR 106, L929, NIH3T3. The in vitro peptide release profile at pH 7.5 for 144 h was quantified using PTH 1-34 ELISA Kit. Effect of released PTH 1-34 on Saos-2 was determined with ALP and BCA assay. These preliminary results pave way for the prospective use of such a carrier for the delivery of PTH 1-34 by multiple routes for the benefit of patients undergoing treatment for osteoporosis. PMID- 22515099 TI - Design and optimization of polyphosphazene functionalized fiber matrices for soft tissue regeneration. AB - Electrospun polycaprolactone nanofiber matrices surface functionalized with poly[(ethyl alanato), (p-methyl phenoxy),] phosphazene were fabricated for the purpose of soft skeletal tissue regeneration. This preliminary study reports the effect of fiber diameter and polyphosphazene surface functionalization on significant scaffold properties such as morphology, surface hydrophilicity, porosity, tensile properties, human mesenchymal stem cell adhesion and proliferation. Six fiber matrices comprised of average fiber diameters in the range of 400-500, 900-1000, 1400-1500, 1900-2000, 2900-3000 and 3900-4000 nm were considered for primary evaluation. After achieving the greatest proliferation while maintaining moderate tensile modulus, matrices in the diameter range of 2900-3000 nm were selected to examine the effect of coating with 1%, 2% and 3% (weight/volume) polyphosphazene solutions. Polyphosphazene functionalization resulted in rougher surfaces that correlated with coating solution concentration. Analytical techniques such as energy dispersive X-ray analysis, Fourier transform infrared spectroscopy, elemental analysis, differential scanning calorimetry, water contact angle goniometry and confocal microscopy confirmed the presence of polyphosphazene and its distribution on the functionalized fiber matrices. Functionalization achieved through 2% polymer solutions did not affect average pore diameter, tensile modulus, suture retention strength or cell proliferation compared to PCL controls. Surface polyphosphazene functionalization significantly improved the matrix hydrophilicity evidenced through decreased water contact angle of PCL matrices from 130 degrees to 97 degrees. Further, enhanced total protein synthesis by cells during in vitro culture was seen on 2% PPHOS functionalized matrices over controls. Improving PCL matrix hydrophilicity via proposed surface functionalization may be an efficient method to improve cell-PCL matrix interactions. PMID- 22515100 TI - Silver-loaded biomimetic hydroxyapatite grafted poly(epsilon-caprolactone) composite nanofibers: a cytotoxicity study. AB - We report on poly(epsilon-caprolactone) (PCL) containing biomimetic hydroxyapatite (HA) and hydroxyapatite-silver (HA-Ag) composite nanofibers prepared via an electrospinning process for the biomedical applications. The morphology, structure and thermal properties of the PCL, PCL/HA and PCL/HA-Ag composite nanofibers were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive X-ray (EDX) spectroscopy, X-ray diffraction (XRD) and thermogravimetry (TGA). SEM images revealed that the nanofibers were well-oriented and incorporated the HA-Ag nanoparticles well. The adhesion, viability and proliferation properties of composite nanofibers and differentiation of osteoblast were carried out to study the in vitro cell compatibility of the PCL/HA/HA-Ag composite nanofibers. Our results showed that pristine PCL and PCL/HA composite nanofibers scaffold can be utilized for the bone regeneration applications, however, PCL/HA-Ag composite nanofibers results in mild cytotoxic effect to human cells. PMID- 22515101 TI - Urinary proteome analysis by matrix-assisted laser desorption/ionization time-of flight mass spectrometry with magnetic beads for identifying the pathologic presentation of clinical early IgA nephropathy. AB - IgA nephropathy is the most common type of chronic glomerulonephritis which leads eventually to end-stage renal disease (ESRD). The duration of clinical early stage IgA nephropathy to ESRD varies a lot. The pathologic presentation may have detrimental effect on outcome. But the renal biopsy is a high-risk invasive operation not able to be accepted by all patients. In this study, we tried to find biomarkers in urine as a non-invasive approach to diagnose different pathologic presentations of clinical early stage IgA nephropathy. A total of 56 patients with IgA nephropathy were included in this study, with 23 patients having severe pathologic presentation and the other 33 having mild ones. The control group consisted of 14 normal subjects. The urinary proteomic spectra from those three groups were generated by Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with weak cationic exchange magnetic beads. The total experiment data was handled by the Zhejiang University ProteinChip Data Analysis System. We found that the urine protein/peptide spectra patterns could be established to distinguish severe IgA nephropathy from the mild IgA nephropathy group and the normal group. Several potential biomarkers were found and the diagnostic system could distinguish between severe IgA nephropathy from the mild IgA nephropathy with a sensitivity of 90.48% and specificity of 96.77%. We conclude that, using MALDI-TOF-MS with magnetic beads to detect urine proteomic patterns shows great potential in identifying early IgA nephropathy with different pathologic prognosis. PMID- 22515102 TI - Antibacterial and antioxidant activity of protein capped silver and gold nanoparticles synthesized with Escherichia coli. AB - Escherichia coli is used for eco-friendly extra cellular synthesis of metallic silver and gold nanoparticles. This is achieved by reducing AgNO3 and HAuCl4 solutions respectively under ambient conditions by using the extra cellular protein produced by the microorganism. The proteins act as reducing as well as capping agent. The nanoparticles were characterized by UV-Visible spectroscopy, X Ray diffraction (XRD), Fourier transform infra-red spectroscopy (FT-IR) and transmission electron microscopy (TEM). Both the nanoparticles are polydisperse. Gold particles predominantly exhibit flat and plate like morphology. These nanoparticles are stable in water for more than three months. The silver nanoparticles are able to inhibit the growth of several Gram positive and negative microorganisms, and the gold nanoparticles exhibit good antioxidant activity. This approach is simple, does not use toxic chemicals and is amenable for large scale commercial production. PMID- 22515103 TI - Synthesis and characterization of chitosan/chondroitin sulfate/nano-SiO2 composite scaffold for bone tissue engineering. AB - Chitosan, a natural polymer, is a biomaterial which is known to be osteoconductive but lacking in mechanical strength. In this work, to further enhance the mechanical property and biocompatibility of chitosan, we combined it with both chondroitin sulfate, a natural glycosaminoglycan found in bone, and nano-SiO2. The composite scaffold of chitosan/chondroitin sulfate/nano-SiO2 was fabricated by lyophilization. The nanocomposite scaffold showed enhanced porosity, degradation, mechanical integrity, biomineralization and protein adsorption. Biocompatibility and cell attachment-proliferation studies performed using MG-63 cells, advocate its better performance in vitro. To improve the cell seeding efficiency, we coated the scaffold surface with fibrin, which enhanced the initial cell attachment. The cumulative results suggest this novel nanocomposite scaffold to be a suitable candidate for bone tissue engineering. PMID- 22515104 TI - Antitumor effect of novel gallium compounds and efficacy of nanoparticle-mediated gallium delivery in lung cancer. AB - The widespread application of gallium (Ga) in cancer therapy has been greatly hampered by lack of specificity resulting in poor tumor accumulation and retention. To address the challenge, two lipophilic gallium (III) compounds (gallium hexanedione; GaH and gallium acetylacetonate; GaAcAc) were synthesized and antitumor studies were conducted in human lung adenocarcinoma (A549) cells. Nanoparticles (NPs) containing various concentrations of the Ga compounds were prepared using a binary mixture of Gelucire 44/14 and cetyl alcohol as matrix materials. NPs were characterized based on size, morphology, stability and biocompatibility. Antitumor effects of free or NP-loaded Ga compounds were investigated based on cell viability, production of reactive oxygen species and reduction of mitochondrial potential. Compared to free Ga compounds, cytotoxicity of NP-loaded Ga (5-150 microg/ml) was less dependent on concentration and incubation time (exposure) with A549 cells. NP-mediated delivery (5-150 microg Ga/ml) enhanced antitumor effects of Ga compounds and the effect was pronounced at: (i) shorter incubation times; and (ii) at low concentrations of gallium (approximately 50 microg/ml) (p < 0.0006). Additional studies showed that NP mediated Ga delivery was not dependent on transferrin receptor uptake mechanism (p > 0.13) suggesting the potential in overcoming gallium resistance in some tumors. In general, preparation of stable and biocompatible NPs that facilitated Ga tumor uptake and antitumor effects could be effective in gallium-based cancer therapy. PMID- 22515105 TI - Preparation and characterization of monensin loaded PLGA nanoparticles: in vitro anti-malarial activity against Plasmodium falciparum. AB - PLGA nanoparticles loaded with monensin (carboxylic ionophore) were prepared by emulsion solvent evaporation method using PLGA of molecular weight (Mw.) 19000 and 110000 Da. The nanoparticles were characterized by applying dynamic light scattering (DLS), atomic force microscopy (AFM), differential scanning calorimetry (DSC) and Fourier transformed infrared spectroscopy (FTIR). Negatively charged and spherical smooth surfaced nanoparticles of size range between 147-167 nm were obtained. The nanoparticles of monensin-PLGA showed no chemical interaction between monensin and the polymer molecules. The release kinetics in vitro studies exhibited biphasic release profile characterized by an initial fast release followed by a slower release. The antimalarial efficacy of monensin-PLGA nanoparticles was also examined. Monensin loaded in nanoparticles was 10-fold more effective in inhibiting the growth of P. falciparum in vitro as compared to free monensin. The antimalarial efficacy of monensin-PLGA nanoparticles was significantly dependent on the Mw. of the polymer. PMID- 22515106 TI - Successful strategy for targeting the central nervous system using magnetic albumin nanospheres. AB - This study reports on the successful use of magnetic albumin nanosphere (MAN), consisting of maghemite nanoparticles hosted by albumin-based nanosphere, to target different sites within the central nervous system (CNS). Ultrastructural analysis by transmission electron microscopy (TEM) of the material collected from the mice was performed in the time window of 30 minutes up to 30 days after administration. Evidence found that the administered MAN was initially internalized and transported by erythrocytes across the blood-brain-barrier and transferred to glial cells and neuropils before internalization by neurons, mainly in the cerebellum. We hypothesize that the efficiency of MAN in crossing the BBB with no pathological alterations is due to the synergistic effect of its two main components, the iron-based nanosized particles and the hosting albumin based nanospheres. We found that the MAN in targeting the CNS represents an important step towards the design of nanosized materials for clinical and diagnostic applications. PMID- 22515109 TI - Process of physical disability among older adults--contribution of frailty in the super-aged society. AB - One of the critical issues that Japan, well known for the world's highest proportion of older adults, a super-aged society, is currently confronting is how to prevent physical disability in old age. This issue is particularly important not only from a medical perspective such as functional prognoses but also from a socio-economic angle in view of reducing the rapid rise in the cost of medical and long-term care insurance services. Functional decline in old age results not only from acute diseases but also from frailty. Such a common and important syndrome that is increasingly prevalent with advancing age can be the cause. The present article intends to review what is known about frailty, including its definition, epidemiology, and pathophysiology, and to examine potential areas of future research. PMID- 22515107 TI - Physiology and pathophysiology of bicarbonate secretion by pancreatic duct epithelium. AB - HCO3- -rich fluid in the pancreatic juice (2-3 L/day) is secreted by epithelial cells lining the pancreatic duct tree, while digestive enzymes are secreted by acinar cells with a small amount of Cl- -rich fluid. Ductal HCO3- secretion is not only regulated by gastrointestinal hormones and cholinergic nerves but is also influenced by luminal factors: intraductal pressure, Ca2+ concentration, pathological activation of protease and bile reflux. The maximum HCO3- concentration of the juice under secretin stimulation reaches 140-150 mM. Thus pancreatic duct cells secrete HCO3- against a approximately 7-fold concentration gradient. HCO3- secretion critically depends on the activity of CFTR, a cAMP dependent anion channel localized in the apical membrane of various epithelia. In the proximal part of pancreatic ducts close to acinar cells HCO3 secretion across the apical membrane is largely mediated by SLC26A6 CI- -HCO3- exchanger. In distal ducts where the luminal HCO3- concentration is already high, most of the HCO3- secretion is mediated by HCO3- conductance of CFTR. CFTR is the causative gene for cystic fibrosis. Loss of function due to severe mutations in both alleles causes typical cystic fibrosis characterized by dehydrated, thick, and viscous luminal fluid/mucus in the respiratory and gastrointestinal tract, pancreatic duct, and vas deferens. A compound heterozygote of mutations/polymorphisms (causing a mild dysfunction of CFTR) involves a risk of developing CFTR-related diseases such as chronic pancreatitis. In cystic fibrosis and certain cases of chronic pancreatitis, the pancreatic duct epithelium secretes a small amount of fluid with neutral-acidic pH, which causes an obstruction of the duct lumen by a protein plug or viscous mucus. PMID- 22515108 TI - Adipocytokines and obesity-linked disorders. AB - Obesity is closely associated with an increased risk for metabolic and cardiovascular diseases. Adipose tissue produces a number of secretory bioactive substances, also known as adipocytokines or adipokines, which directly affect adjacent or distant organs. Most adipocytokines are pro-inflammatory, thereby promoting the obesity-linked disorders. In contrast, there are a small number of adipocytokines that exhibit antiinflammatory properties. It is now recognized that dysregulated production or secretion of adipocytokines caused by adipocyte dysfunction leads to the development of obesity-linked complications. In this review, we focus on the functional role of several adipocytokines in metabolic and cardiovascular diseases. PMID- 22515110 TI - Determination of ferritin and hemosiderin iron in patients with normal iron stores and iron overload by serum ferritin kinetics. AB - We attempted to clarify the storage iron metabolism from the change in the serum ferritin level. We assumed that the nonlinear decrease in serum ferritin was caused by serum ferritin increase in iron mobilization. Under this assumption, we determined both ferritin and hemosiderin iron levels by computer-assisted simulation of the row of decreasing assay-dots of serum ferritin in 11 patients with normal iron stores free of both iron deficiency and iron overload; chronic hepatitis C (CHC) and iron deficiency anemia after treatment, and 11 patients with iron overload; hereditary hemochromatosis (HH) and transfusion-dependent anemias (TD). We determined the iron removal rates of 20 and 17 mg/day by administering mean doses of deferasirox at 631 and 616 mg/day in 2 TD during the period of balance of iron addition and removal as indicated by the serum ferritin returned to the previous level. The ferritin-per-hemosiderin ratio was almost the same in both HH and CHC. This matched the localized hepatic hemosiderin deposition in CHC with normal iron stores. We detected the ferritin increased by utilizing the hemosiderin iron in iron removal and the ferritin reduced by transforming ferritin into hemosiderin in iron additions. The iron storing capacity of hemosiderin was limitless, while that of ferritin was suppressed when ferritin iron exceeded around 5 grams. We confirmed the pathway of iron from hemosiderin to ferritin in iron mobilization, and that from ferritin to hemosiderin in iron deposition. Thus, serum ferritin kinetics enabled us to be the first to clinically clarify storage iron metabolism. PMID- 22515111 TI - Cardiovascular disease risk factors among rural Kazakh population. AB - Cardiovascular diseases (CVDs) have remained a leading cause of mortality in Kazakhstan. The objectives of the present study were to estimate the prevalence of CVD risk factors (RFs) among the Kazakh population, and their ability to identify those CVD RFs. We interviewed 611 subjects aged 25-65 years using a structured self-administered questionnaire from April to July, 2008. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated to determine associations between CVD RFs and its correlations, such as socioeconomic status and level of knowledge of CVD RFs through a logistic regression model. Mean age of the respondents was 43.2 years, and 49.8% were male. Tobacco smoking, overweight (body mass index > or = 25.0), hypertension (systolic blood pressure > or =140 mm Hg and diastolic blood pressure > or =90 mm Hg), and alcohol drinking were identified as important CVD RFs. Risk of overweight was greatest among the population aged 45-54 years, with an OR of 5.3 (95% CI = 3.1-9.2). The overweight population was significantly associated with higher income (OR = 1.6, 95% CI = 1.1-2.4) and knowledge of RF (OR = 1.7, 95% CI = 1.2-2.4), with p < 0.05. Only 25.0% of respondents had good knowledge about CVD RFs. Alcohol drinking was inversely related to the level of knowledge about CVD RFs (OR = 0.7, 95% CI = 0.5 0.9). We concluded that CVD RFs were very high among the Kazakh population, although their level of knowledge to identify those RFs was very low. Increasing knowledge about CVD RFs through awareness campaign activities can reduce CVD related morbidity and mortality and ensure a better quality of life for the Kazakh population. PMID- 22515112 TI - Prevalence of Helicobacter pylori infection measured with urinary antibody in an urban area of Japan, 2008-2010. AB - Helicobacter pylori (H. pylori) has expanded to infect about half the world's population. Although there were many studies on the prevalence of H. pylori infection for defined areas in the 1990s throughout the world, there were only limited sources tracking its latest prevalence among large populations. In the present study, we estimated the prevalence of H. pylori among the inhabitants of Nagoya, an urban area of Japan. Study subjects were 5167 participants (1467 males and 3700 females) aged 35 to 69 years from the Daiko Study, a part of the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). A urinary anti-H. pylori antibody was used to detect H. pylori infection. The history of eradication treatments for H. pylori infection was obtained using self administered questionnaires. The prevalence detected by the urinary test included 19.6% (95% confidence interval; 16.8-22.6%) for those aged 35-39 years, 25.8% (23.5-28.2%) for 40-49 years, 39.4% (36.8-42.1%) for 50-59 years, 50.3% (47.8 52.7%) for 60-69 years, and 36.4% (35.1-37.7%). Among 5167 participants, 266 (5.1%) stated that they had received an eradication treatment. Since 167 subjects with negative urinary tests replied that they had been seropositive for H. pylori in the past, they were included among the ever-infected inhabitant group. Consequently, the overall rate of those with a history of persistent infection was 39.6% (38.3-40.9%). The prevalence of H. pylori infection observed in Nagoya seemed to be lower than the corresponding prevalence reported in other studies of Japan. That lower rate might be due to the reduced exposure from improved urban sanitary conditions. PMID- 22515113 TI - Elderly health and its correlations among Uzbek population. AB - This study was conducted from November, 2007 to May, 2008 to evaluate the health status of the elderly and correlated factors affecting their health. We collected data from 682 individuals 65 years or older (214 male) from greater Tashkent City in Uzbekistan. The study revealed that 75.4% of the respondents were aged <75 years and that 16.8% of them were not educated. About three-quarters of the respondents rated themselves as 'healthy'. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated through a logistic regression model to determine correlations of elderly health, and adjusted for age and sex. The elderly who had additional income were 2.6 times (95% CI = 1.8-4.0) more likely to be healthy. Similarly, those <75 years old (OR = 1.5, 95% CI = 1.0-2.2), were able to do everyday duties (OR = 6.0, 95% CI = 3.8-9.3), and those who were married (OR = 4.1, 95% CI = 1.7-9.7) were also healthy. Conversely, males (OR = 0.6, 95% CI = 0.4-0.9) and the elderly who were supported by sources other than their own income from work were not healthy. We concluded that having a strong family relationship and adhering to a traditional lifestyle are important for protecting elderly health in Uzbekistan. Substantial financial support and personal care are necessary for the elderly. Creating a healthy atmosphere for them at an individual and family level could ensure a better quality life for the elderly in Uzbekistan. PMID- 22515114 TI - The impact of maternal obesity on mother and neonatal health: study in a tertiary hospital of Astana, Kazakhstan. AB - This study was aimed to investigate the impact of maternal obesity on mothers and their neonatal health. Our study population consisted of 157 women with completed singleton pregnancies, which included both obese (Body mass index, BMI > or =30) and non-obese women (BMI < 30). Data were collected from case histories, and ante and postnatal records at the tertiary hospital in Astana, Kazakhstan between January and February of 2008. Associations between pregnancy and delivery-related complications, outcomes, and maternal obesity were estimated as odds ratios (ORs) and 95% confidence intervals (CIs) using a logistic regression model. Women aged 30 years or more were at higher risk of obesity (OR = 3.1, 95% CI = 0.8-11.6) than women less than 30 years old. Multiparous women were also at higher risk of obesity (OR = 4.1, 95% CI = 0.9-19.6) than primiparous ones. Obese women were also more likely to have longer hospital stays of more than 10 days (OR=2.2, 95% CI = 0.8-6.2), and were more prone to eclampsia/preeclampsia (OR = 24.7, 95% CI = 2.2-44.8), cesarean sections (OR = 2.1, 95% CI-0.7-6.2), and abnormal labor (OR = 8.1, 95% CI = 1.0-63.8) compared to non-obese women. Neonatal complications such as pneumonia (OR = 3.4, 95% CI = 0.6-20.2) and fetal macrosomia (OR = 2.2, 95% CI = 0.6-8.0) were also more common among babies born to obese mothers. Congenital baby birth defects were strongly associated with maternal obesity (P = 0.016). We concluded that maternal obesity is associated with increased risks of both maternal and neonatal complications, and that such risks increase with advanced age and parity of the mother. Hence, medical practices must take these complications into account by ensuring an adaptable and early management in order to improve mothers and their neonatal health. PMID- 22515115 TI - A permission system for carbapenem use reduced incidence of drug-resistant bacteria and cost of antimicrobials at a general hospital in Japan. AB - Some drug management systems have been established in Japanese hospitals to reduce medical costs and regulate drug usage. Among the many available prescription drugs, antimicrobials should be given special attention because their inappropriate use often leads to sudden outbreaks of resistant bacteria. As drug specialists, pharmacists should monitor the use of all drugs, particularly antimicrobials. Carbapenems are a class of broad-spectrum antimicrobials that are widely used to treat infections worldwide. However, their inappropriate use has led to an increase in the incidence of drug-resistant bacteria and consequently, medical costs, at hospitals. To reduce inappropriate use and drug resistance, we have established a permission system to control the use of carbapenems at the Japanese Red Cross Nagoya Daiichi Hospital. In this study, we retrospectively evaluated the applicability of the new permission system compared to that of the notification system and the non control system for 14 months each. The two management systems were able to maintain total antibiotic use density and control the outbreak of drug-resistant bacteria (P. aeruginosa, E. coli, and K. pneumoniae). The number of carbapenem prescriptions was decreased dramatically when this permission system was enforced. Compared to the non control system, the cost of antimicrobials was reduced by $757,470 for the 14-month study period using the permission system. These results suggest that our system to control the use of antimicrobials can efficiently suppress the incidence of drug-resistant bacteria and medical costs at hospitals. PMID- 22515117 TI - Preventive medical services not covered by public health insurance at Daiko Medical Center in Japan, 2004-2011. AB - Preventive medical services not covered by public health insurance started in the Daiko Medical Center of Nagoya University in June, 2004. Those services included: (1) Helicobacter pylori (H. pylori) diagnosis and eradication treatments, for which CYP2C19 genotyping was introduced in November 2005; (2) smoking cessation support with genotype tests of CYP1A1 Ile462Val, GSTM1 present/null, GSTT1 present/null, and NQO1 Pro187Ser; (3) advice on alcohol consumption with genotype tests of ADH Arg47His and ALDH2 Glu487Lys; (4) advice on folate-associated diseases with a genotype test of MTHFR C677T; (5) advice on a tumor marker CA19-9 with genotype tests of Lewis and Secretor genes; and (6) raloxifene prescription aimed to prevent breast cancer for high-risk postmenopausal women. A total of 683 patients visited the Center until it closed in March 2011. Those given diagnoses and eradication treatments for H. pylori numbered 567, followed by 44 for smoking cessation support, 35 for advice on folate-associated diseases, 26 for advice on alcohol consumption, 8 for CA19-9, and 3 for raloxifene prescription. Around 2004, public interest in H. pylori was relatively high, but thereafter patient numbers dropped markedly. The Center closed in March 2011 due to the reduction in patient visits. Our unique trial showed that continuing to provide uninsured preventive services at a clinic was difficult in Japan without the affiliation of hospitals/clinics providing medical services covered by public health insurance. PMID- 22515116 TI - Risk factors for extended-spectrum beta-lactamase-producing Escherichia coli infection in hospitalized patients. AB - The incidence of nosocomial infection caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria is increasing worldwide. Infections caused by ESBL producers have been associated with severe adverse clinical outcomes that have led to increased mortality, prolonged hospitalization, and rising medical costs. To avoid such adverse events and ineffective treatment, an appropriate use of drugs for infectious diseases is needed. To suppress the emergence and spread of drug-resistant bacteria in hospitals, it is important to be vigilant about ESBL producing Escherichia coli (E. coli). In this study, we examined and compared seven items in a blood test between patients with ESBL-producing E. coli and non ESBL-producing E. coli among febrile patients. We examined the levels of serum albumin, hemoglobin, and C-reactive protein (CRP), and the numbers of leucocytes, neutrophils, lymphocytes, and platelets in blood on the day of admission, the screening day during hospitalization, and the day immediately before discharge from the hospital. There were no significant differences in clinical background characteristics between the two groups of patients. In patients with invasive infections caused by ESBL-producing E. coli, serum albumin levels and the number of lymphocytes were significantly lower than those in patients not infected with ESBL producers. These values recovered to their baseline levels on the day of hospital discharge. This retrospective study suggests that serum albumin levels and the number of lymphocytes may serve as risk factors for infection by ESBL producing E. coli, thereby supporting the appropriate use of antimicrobials in hospitals. PMID- 22515118 TI - Geranylgeranylacetone attenuates cisplatin-induced reductions in cell viability by suppressing the elevation of intracellular p53 content without heat shock protein induction. AB - Geranylgeranylacetone (GGA) was originally used as an anti-ulcer drug to protect gastric mucosa from various stresses, and it is also known to induce heat shock proteins (HSPs), especially HSP70. However, it remains unclear how GGA affects cellular functions in the presence of anti-cancer drugs. We investigated the effects of GGA on cellular viability, caspase-3 activation, HSP induction and p53 content in the presence of cisplatin (CDDP). Rat intestinal epithelium-derived IEC-18 cells and human colon cancer-derived CW-2 cells were incubated with GGA in the presence of CDDP, and we observed that GGA attenuated CDDP-induced viability reductions. GGA also suppressed CDDP-induced caspase-3 activation. However, GGA induced neither HSP70 nor GRP78 expression in the presence of CDDP. We found that GGA suppressed the CDDP-induced elevation of intracellular p53 content. In conclusion, GGA attenuates viability reductions and caspase-3 activation in CDDP treated cells by suppressing the elevation of intracellular p53 content without HSP induction. PMID- 22515120 TI - Prognostic factors for tumor recurrence after gamma knife radiosurgery of partially resected and recurrent craniopharyngiomas. AB - A study was conducted to clarify the prognostic factors related to recurrence of craniopharyngioma and to improve the quality of life of patients by the treatment with intentional partial removal and gamma knife radiosurgery. One hundred cases of craniopharyngioma have been treated at Komaki City Hospital since 1991. In a mean follow-up period of 65.5 months, the tumor control rate was 79.5%. The 5- and 10-year actuarial survival rates were 94.1% and 91%, respectively. However, the recurrence-free survival rates were 73.6% at 5 years and 60.2% at 10 years. Nine factors thought to be related to the recurrence were selected from past references and previous studies, including gender, age, pediatric (< or =17 years) or adult patient, partial removal or recurrence, mean tumor diameter, tumor type (solid or cyst), pathological types (squamous cell or adamantinoma), number of previous treatments, and radiation dose. Statistical analysis was performed to determine which factors had a significant prognostic impact. Multivariate analysis showed that mean tumor diameter and radiation dose were independent predictors of outcome. To maximize the prognostic power of these factors, cut-off levels were determined using ROC analysis. These levels were 19 mm for tumor diameter and 13.2 Gy for marginal dose. Significant prognostic factors related to recurrence of craniopharyngioma are tumor diameter and radiation dose. A tumor diameter of <19 mm and a marginal dose of > or =13.2 Gy are favorable prognostic factors for gamma knife radiosurgery. PMID- 22515119 TI - Genetic polymorphisms of the adenosine triphosphate-binding cassette transporters (ABCG2, ABCB1) and gefitinib toxicity. AB - The purpose of this study is to investigate associations between allelic variations of ABCG2 and ABCB1 with skin toxicity, diarrhea, liver injury and interstitial lung disease (ILD) in gefitinib-treated patients. A prospective clinical study of 83 Japanese patients with non-small-cell lung cancer was performed. Polymorphic loci in ABCG2 and ABCB1 were genotyped, and their effects on gefitinib toxicities were evaluated. ABCG2 34G>A was statistically associated with occurrence of skin rash; 13 (42%) of the 32 patients with at least one variant ABCG2 34G>A allele (G/A and A/A) developed grade 2 or worse skin rash, whereas only 10 (19%) of 51 patients homozygous for the reference allele (G/G) for the wild-type sequence for both alleles did so (P=0.046). There was no significant association between severe toxicities and polymorphisms of ABCG2 421C>A nor ABCB1 3435C>T. The results suggested that ABCG2 34G>A would be useful for predicting grade 2 or worse skin rash. PMID- 22515121 TI - Incidence of young onset insulin-requiring diabetes mellitus among 18- to 30-year olds in Dhaka, Bangladesh (1994-2003). AB - Little information is available regarding the epidemiology of young onset insulin requiring diabetes mellitus (IRDM). We described the incidence of young onset IRDM and its trend in males and females of Dhaka, Bangladesh. Subsequently, factors related to possible sex difference were investigated. Young onset IRDM was defined as diabetic patients aged 18-30 years who required three months or more insulin treatment but presented no ketonuria. Between 1994 to 2003, 1804 cases were registered. Incidence rates were calculated with denominators based on the population census 2001. The overall annual incidence of young onset IRDM for the period 1994-2003 was 8.5 per 100,000 persons (95% CI: 7.2-7.9), and the corresponding value for females (10.9 per 100,000 persons, 95% CI: 9.2-12.1) was higher than that in males (6.7 per 100,000 persons, 95% CI 5.6-7.9). The incidence rate significantly increased in females during the investigated period, but not in males (p for sex interaction < 0.01). There was a significantly higher increment of female cases with a body mass index > or = 25.0 kg/m2 (overweight/obesity) (19 percentage point) compared to that of males (3 percentage point) between 1994-1998 and 1999-2003 (p for sex interaction < 0.01). The incidence of young onset IRDM is increasing in the Dhaka City population among females, which is attributed to the increase in overweight/obese female cases. PMID- 22515122 TI - Establishment and optimal culture conditions of microrna-induced pluripotent stem cells generated from HEK293 cells via transfection of microrna-302s expression vector. AB - Induced pluripotent stem cells (iPSCs) have been directly generated from fibroblast cultures though retrovirus- or lentivirus-mediated ectopic overexpression of only a few defined transcriptional factors. This remarkable achievement has greatly enhanced our ability to explore the causes of, and potential cures for, many genetic diseases, and strengthened the promise of regenerative medicine. In fact, to date, many kinds of somatic cells from different tissues have exhibited a capacity for reprogramming toward an embryonic stem cell-like state, but major bottlenecks in iPSC derivation and therapeutic use remain, including low reprogramming efficiencies and the tumorigenesis of the generated iPSC. Here, we successfully generated miR-302s-induced pluripotent stem cells (mirPS cells) from human embryonic kidney (HEK) 293 cells via transfection of the miR-302s expression vector. We also determined the optimal culture conditions to generate mirPS on feeder cells, which included the use of serum free N2B27 medium. The mirPS cells generated by our improved conditions showed the expression of pluripotent marker genes such as OCT3/4, NANOG, and SOX2 under growth conditions via reverse transcription-PCR, whereas no expression of these genes was observed in HEK293 cells. On the other hand, under differentiation conditions, mirPS cells formed ball-shaped structures (embryoid bodies), and showed the ability to differentiate into three germ layers (ectoderm, mesoderm, and endoderm) in vitro. The results suggested that our generated mirPS cells are actually functional as a cell resource to apply to regenerative medicine, and mirPS cells are suitable materials to clarify the mechanism underlying the reprogramming from somatic cells. PMID- 22515123 TI - Tilt of the radius from forearm rotational axis reliably predicts rotational improvement after corrective osteotomy for malunited forearm fractures. AB - Forearm rotation occurs around an axis connecting the center of the radial head and the fovea of the distal ulna. The purpose of the present study was to demonstrate the usefulness of the difference between forearm and proximal radial axis in the treatment of malunited forearm fractures. We reviewed the results of eight corrective osteotomies for malunited fractures of the forearm without dislocations of the wrist or elbow. Subjects were 6 men and 2 women (mean age, 15 years; range, 10-21 years). Corrective osteotomy was performed at the fracture site. Preoperatively and at final follow-up, the are of forearm rotation was recorded and anteroposterior and lateral X-rays were taken. Proximal radius tilt was defined as the angle between the rotational axis of the forearm and the axis of the proximal radius. Corrective osteotomy improved proximal radius tilt in all cases. Three patients were considered to have malrotation. Postoperative rotational are correlated with proximal radial tilt (r = -0.83). No significant difference in rotational arc was evident between malunited cases and the remaining cases. To improve forearm rotation, corrective osteotomy should be planned to minimize proximal radius tilt. PMID- 22515124 TI - Simultaneous surgical resections of two distant metastatic malignant melanoma lesions--case report. AB - A 41-year-old woman presented with disturbance of consciousness, right hemiparesis, and symptoms of Gerstmann syndrome. She had a history of malignant melanoma resections of an ear mole and her right neck lymph nodes and parotid gland, with subsequent chemotherapy and radiotherapy. Computed tomography showed two large lesions in the right frontal and left parietal lobes surrounded by severe brain edema. Magnetic resonance images revealed that the two lesions were strongly enhanced with cystic change, and a small round lesion was located in the left head of the caudate nucleus. (18F) fluoro-2-deoxyglucose positron emission tomography showed high accumulation in both lesions, and no sign of metastatic lesions except within the brain. The two lesions were large, causing increased intracranial pressure. Simultaneous surgical resections were performed using two approaches. The patient's neurological symptoms were greatly improved after surgery, and her Karnofsky Performance Status improved from 20% to 90%. She was discharged to her home almost completely free of neurological deficits. Although, simultaneous one-stage tumor resections for multiple metastatic brain tumors do not extend the survival period, they improve the quality of the patient's limited remaining life, and may be a treatment choice for young patients with well controlled systemic disease. PMID- 22515125 TI - Postoperative recovery from unilateral blindness caused by tuberculum sellae meningioma. AB - A 47-year-old female had noticed diminished visual acuity in both eyes 2 months previously. The patient had vision loss (no light perception) in her right eye on admission. Her left visual acuity was 1.2 (naked vision) and an upper temporal quadrant hemianopsia was revealed in her left eye. Optic disc atrophy was also found bilaterally during a fundus examination. The tumor was located at the tuberculum sella. The first operation was performed using a right pterional approach. The right optic nerve was thin and atrophic and was severely encased by the tumor. Considering the deterioration of her visual evoked potential, the operation was terminated in the remaining major part of the tumor. Postoperatively, the patient suffered visual loss in her right eye (no light perception), decreased visual acuity (naked: 0.6 (corrected: 1.0)), and deteriorated visual field defects (upper temporal quadrant hemianopsia) in her left eye. The tumor remnant was resected again 2 weeks later using the right frontobasal and pterional approaches. The tumor around the bilateral internal carotid arteries and optic nerves was not resected. Light perception in the right eye appeared 2 weeks after the operation. Although an opthalmological examination revealed right optic atrophy, finger counting was possible in the upper nasal visual field of the right eye three months after the second operation. Her visual acuity was 0.7 (1.0), and the upper temporal quadrant hemianopia of the left eye improved in comparison with the preoperative one. Our case demonstrated the possibility of a recovery from blindness. PMID- 22515126 TI - Extravasation of pegylated-liposomal doxorubicin: favorable outcome after immediate subcutaneous administration of corticosteroids. AB - A massive extravasation of pegylated-liposomal doxorubicin (Doxil) accidentally occurred, affecting the right forearm of a 54-year-old woman with metastatic ovarian cancer who was receiving an intravenous infusion of the drug. In accordance with the institutional guidelines for vesicant drugs, a corticosteroid preparation was immediately injected subcutaneously into the surrounding tissues. Clobetasol propionate and an ice pack were then topically applied to the affected region. There were no serious complications at the extravasation site, such as tissue necrosis or severe pain, and only a transient erythema of the skin and desquamation remained after 2 months. PMID- 22515127 TI - Repair of carotid blow-out using a carotid sheath in a patient with recurrent thyroid cancer. AB - The patient had thyroid cancer and underwent subtotal thyroidectomy. Local recurrence occurred on both sides 5 years and 6 months later. The sterno-hyoid muscle and sterno-thyroid muscle were severed and the tumor around the cricoid cartilage was removed. The tumor extended into the space between the right common carotid artery and internal jugular vein and was located under the right common carotid artery and vagus nerve on the lateral side. The carotid sheath was peeled off of the carotid artery quite easily. The right common carotid artery ruptured abruptly at the distal side during this procedure. The right common carotid artery had two layers, which were very fragile, so the direct suture or repair with a graft was impossible. The carotid artery could not be trapped with ligation because the cerebral vascular supply was not examined preoperatively. This portion was repaired using the remaining carotid sheath. However, re bleeding occurred at the proximal portion of the previous laceration spontaneously. Fibrin glue with oxidized cellulose was initially used to seal the second small hole in this lesion. The second ruptured section was repaired using the remaining sterno-thyroid and sterno-hyoid muscles. The proximal portion of the right common carotid artery was reinforced with the harvested external jugular vein. These procedures resulted in hemostasis. Three-dimensional CT angiography showed irregular stenosis just after the operation, but it recovered 11 days later. No cerebral infarction occurred after the operation and the patient's general condition was good. PMID- 22515128 TI - Schwannoma originating from lower cranial nerves: report of 4 cases. AB - Four cases of schwannoma originating from the lower cranial nerves are presented. Case 1 is a schwannoma of the vagus nerve in the parapharyngeal space. The operation was performed by the transcervical approach. Although the tumor capsule was not dissected from the vagus nerve, hoarseness and dysphagia happened transiently after the operation. Case 2 is a schwannoma in the jugular foramen. The operation was performed by the infralabyrinthine approach. Although only the intracapsular tumor was enucleated, facial palsy, hoarseness, dysphagia and paresis of the deltoid muscle occurred transiently after the operation. The patient's hearing had also slightly deteriorated. Case 3 is a dumbbell-typed schwannoma originating from the hypoglossal nerve. The hypoglossal canal was markedly enlarged by the tumor. As the hypoglossal nerves were embedded in the tumor, the tumor around the hypoglossal nerves was not resected. The tumor was significantly enlarged for a while after stereotactic irradiation. Case 4 is an intracranial cystic schwannoma originating from the IXth or Xth cranial nerves. The tumor was resected through the cerebello-medullary fissure. The tumor capsule attached to the brain stem was not removed. Hoarseness and dysphagia happened transiently after the operation. Cranial nerve palsy readily occurs after the removal of the schwannoma originating from the lower cranial nerves. Mechanical injury caused by retraction, extension and compression of the nerve and heat injury during the drilling of the petrous bone should be cautiously avoided. PMID- 22515129 TI - A spinal epidural hematoma with symptoms mimicking cerebral stroke. AB - A spontaneous cervical epidural hematoma (SCEH) is a rare condition, which usually requires urgent treatment. However, unusual manifestations, such as hemiparesis, may lead to a misdiagnosis. We herein report a case of SCEH that presented with pure motor hemiparesis to discuss the appropriate and prompt diagnosis and treatment of such cases. An 84-year-old female was brought to our emergency department complaining of nuchal pain, followed by right hemiparesis. A contrast-enhanced computed tomography (CT) scan of the neck demonstrated a spinal epidural hematoma right posterolateral to the spinal cord, extending from C2 to C3. She was managed conservatively and her symptoms improved significantly. The authors emphasize that cervical spinal lesions should be considered in the differential diagnosis for patients with acute onset of hemiparesis, when they are associated with neck pain. Even though magnetic resonance imaging is the gold standard, a CT scan is also useful for quick screening for SCEH. PMID- 22515131 TI - Screening: tell the truth. PMID- 22515130 TI - Surgical results of parasagittal and falx meningioma. AB - Sixteen operative cases of parasagittal and falx meningioma were analyzed retrospectively. Parasagittal meningioma totaled 12 cases and falx meningioma numbered 4 cases. Preoperative symptoms were paresis of a lower extremity in 7 cases and disturbed consciousness or mentality in 6 cases. Paresis and/or consciousness deteriorated just after the operation in 11 cases. The deterioration was identified in paresis (6 cases), consciousness (3 cases), paresis and consciousness (2 cases). Motor function further deteriorated postoperatively when the patients had shown preoperative paresis. The cause of postoperative deterioration of motor function and/or consciousness level was intracerebral hematoma in 1 case, and newly-developed brain edema in 1 case. There was no obvious explanation for the symptomatic exacerbation in the other 9 cases. At discharge, 5 cases showed deterioration of motor function in comparison to their preoperative condition, and 3 cases showed an improvement. Eleven cases showed no change of consciousness in comparison to the preoperative condition, and 5 cases showed improvement at discharge. Surgical result was good for consciousness or mentality, but was relatively poor for motor function. It was considered that surgery should be performed carefully in patients with preoperative paresis. PMID- 22515132 TI - Boceprevir. AB - Standard treatment for patients with genotype 1 chronic hepatitis C consists of a combination of peginterferon alfa and ribavirin, taken for 24 to 48 weeks. Boceprevir, a drug that inhibits the hepatitis C virus NS3/4A serine protease, is now authorised in the European Union as an adjunct to this standard treatment. In clinical trials, addition of boceprevir did not increase efficacy when the peginterferon alfa-2b + ribavirin combination reduced viral load during the first 4 weeks of treatment. A double-blind, randomised trial including 1097 previously untreated patients showed that adding boceprevir after 4 weeks of peginterferon alfa-2b + ribavirin combination therapy increased the rate of sustained virological response compared with adding placebo after 44 weeks of triple-agent therapy (66.1% versus 37.7%). In early responders, the rates of sustained virological response were similar after 24 weeks and 44 weeks of triple-agent therapy. After failure of standard therapy, a double-blind randomised trial in 403 patients showed that a new 44-week course of treatment induced a significantly higher rate of sustained virological response when boceprevir was added rather than placebo (66% versus 21%). In early responders, the rates of sustained virological response were not reduced by shortening treatment duration to 32 weeks. The main adverse effect of adding boceprevir was an increased incidence of haematological disorders, including anaemia (48% versus 28% with placebo add-on), neutropenia (23% versus 18%), and thrombocytopenia (32% versus 14%). Boceprevir is a potent inhibitor of cytochrome P450 isoenzyme CYP3A4; clinically relevant pharmacokinetic interactions can be thus anticipated when boceprevir is combined with drugs that have a narrow therapeutic margin. Boceprevirtherapy involves taking 4 capsules 3 times daily for 24 to 32 weeks. In practice, adding boceprevir to the peginterferon alfa + ribavirin combination is justified both for first-line treatment and after failure of standard treatment. The impact of the added virological efficacy on morbidity and mortality remains to be determined. PMID- 22515133 TI - Telaprevir. AB - The standard treatment for genotype 1 chronic hepatitis C consists of the peginterferon alfa + ribavirin combination taken for 24 to 48 weeks. When added to this combination, boceprevir, an inhibitor of hepatitis C virus (HCV) NS3/4A serine protease, increases virological efficacy at a cost of generally acceptable adverse effects (mainly anaemia). However, more trials are needed to assess its impact on morbidity and mortality. Telaprevir was authorised in the European Union soon after boceprevir, also as an adjunct to standard therapy. A double blind randomised trial in 1088 previously untreated patients showed that adding telaprevir to the peginterferon alfa-2a + ribavirin combination, as compared with adding placebo, led to a significantly higher rate of sustained virological response (about 79% versus 46%). In another randomised but unblinded trial in 540 patients, the rates of sustained virological response did not differ whether patients who had an early virological response were treated for 24 or 48 weeks. A double-blind randomised trial including 662 patients in whom initial treatment with peginterferon alfa-2a + ribavirin had failed showed that further treatment with the standard regimen plus telaprevir resulted in a significantly higher rate of sustained virological response compared to adding placebo, regardless of the type of failure (relapse: 86% versus 22%; partial response: 59% versus 15%; nonresponse: 32% versus 5%). There are no head-to-head comparisons between telaprevir and boceprevir. No firm conclusions on respective efficacy can be drawn from an indirect comparison of the data. The most common adverse effects associated with the addition of telaprevir, as compared to adding placebo, were rash (55.2% versus 32.7%), anaemia (32.1% versus 14.8%), and anorectal disorders (26% versus 5%). Severe rash occurred in 0.4% of patients receiving telaprevir, and severe anaemia in 4.9%. Telaprevir is metabolised by and inhibits cytochrome P450 isoenzyme CYP 3A4. Telaprevir is also a P-glycoprotein substrate, resulting in a high risk of pharmacokinetic interactions. The adverse effects of telaprevir are more difficult to manage than those of boceprevir. This means that telaprevir should be reserved for patients in whom boceprevir fails, at least until the respective long-term effects of the two drugs are better documented. PMID- 22515134 TI - Bupropion: congenital heart defects (continued). AB - Bupropion, an amphetamine, is authorised as an aid to smoking cessation, despite its negative harm-benefit balance. In 2004, data from a registry of pregnancies exposed to bupropion drew attention to an increased risk of congenital heart defects. In 2010, a case-control study including more than 10 000 children showed a higher incidence of in utero exposure to bupropion among children who had congenital left heart defects. Other, less reliable studies did not show such a link. In practice, this risk of congenital heart defects is yet another reason to avoid using bupropion, including during pregnancy, and to monitor the cardiac status of exposed fetuses and newborns. PMID- 22515136 TI - Publicly accessible pharmacovigilance databases. PMID- 22515135 TI - Opioids and hypogonadism. AB - Detailed reports of hypogonadotropic hypogonadism in patients receiving morphine analgesia were published in 2010. Symptoms included flushing and sweating, amenorrhoea, impotence and decreased libido. Epidemiological studies have examined a possible link between hypogonadism and opioid use, in both patients and drug addicts. Statistically significant decreases in plasma hormone concentrations were found, with lower testosterone and LH levels in men, and lower oestradiol, progesterone, LH and FSH levels in women. Animal studies have provided consistent results. It is suspected that opioids affect the hypothalamic pituitary axis, inhibiting LH secretion. Patients should be warned of this risk. If signs of hypogonadism occur in a patient taking an opioid, the benefits and harms of treatment should be reassessed. If possible, the dose should be reduced or the opioid withdrawn. PMID- 22515137 TI - Fingolimod: cardiovascular deaths. PMID- 22515138 TI - HIV exposure through contact with body fluids. AB - A variety of situations, either accidental or linked to high-risk behaviour, raise concerns about potential infection from contact with the blood or genital secretions of a person who may be HIV-infected. Antiretroviral post-exposure prophylaxis is offered to prevent establishment of HIV infection. As of 2011, what is the evidence for the efficacy of antiretroviral post-exposure prophylaxis? Under what circumstances is this treatment justified? To answer these questions, we reviewed the available evidence, based on the standard Prescrire methodology. The evidence for the efficacy of rapidly initiated prophylaxis following exposure comes mainly from one case-control study on health professionals injured while treating HIV-positive patients. Treatment with zidovudine for 3 to 4 weeks was associated with a risk of HIV seroconversion that was 5 times lower than among those not treated. The main clinical practice guidelines recommend the use of antiretroviral treatments that are already well established for chronic HIV infection as post-exposure prophylaxis. A typical regimen combines HIV-protease inhibitors (ideally lopinavir + ritonavir) with a fixed-dose combination of two nucleoside (or nucleotide) reverse transcriptase inhibitors (emtricitabine + tenofovir or lamivudine + zidovudine). Certain antiretrovirals are best avoided as first-choice therapy due to their adverse effects: abacavir due to the risk of serious allergic reactions; atazanavir due to the risk of jaundice and torsades de pointes. Non-nucleoside reverse transcriptase inhibitors (such as efavirenz) frequently cause adverse cutaneous and neurosensory adverse effects, especially during the first weeks of treatment. The main adverse effects of antiretrovirals are gastrointestinal. Diarrhoea is common with lopinavir. Antiretrovirals interact with many other drugs. HIV protease inhibitors reduce the efficacy of hormonal contraceptives. The Iopinavir + ritonavir + zidovudine + lamivudine combination has been used for a long time to treat pregnant women. No evidence of teratogenicity has been shown.The antiretrovirals atazanavir, emtricitabine, nelfinavir, nevirapine and tenofovir can also be used but there is less experience with their use during pregnancy. Post-exposure treatment should be started as soon as possible: wash and rinse the wound; initiate antiretroviral therapy within 48 to 72 hours, without waiting to obtain all the information required for risk assessment; reassess the infection risk 2 to 4 days later. Risk assessment should be based on the type and circumstances of exposure, and the source person's serological HIV status and viral load if the individual is known to be HIV-infected and receiving treatment.This information should be obtained urgently or estimated on the basis of HIV infection is still possible despite post-exposure prophylaxis.Therefore, in order to avoid transmitting the virus to others, anyone exposed and potentially infected should be advised against unprotected sex or blood donation for 3 months, until serological evidence has been obtained that they have not been infected. In practice, the many situations in which the risk of infection is uncertain should be managed on a case-by-case basis, with the patient's involvement, weighing the probability of HIV transmission against the adverse effects of a one-month course of antiretroviral therapy. PMID- 22515139 TI - Assessing the risk of HIV infection after an isolated exposure incident. AB - The higher the plasma viral load of an HIV-infected person, the greater the risk that their blood, sperm and vaginal secretions are infectious. The risk of infection from splashes onto non-intact skin or a mucous membrane is virtually non-existent if the exposed area is washed within 15 minutes. There is almost no risk of HIV transmission from nasal secretions, saliva, urine and vomit, unless they contain visible blood. The risk associated with sexual exposure to HIV varies enormously, depending on the type of sexual activity: almost non-existent for insertive fellatio; estimated at 1.5% for passive (receptive) anal intercourse with ejaculation inside the rectum. The risk of HIV transmission following injury from a sharp object contaminated with blood has been estimated at about 0.3%. PMID- 22515140 TI - The French procedure for emergency management of HIV exposure. PMID- 22515141 TI - New drugs and indications in 2011. France is better focused on patients' interests after the Mediator scandal, but stagnation elsewhere. AB - Progress in the pharmaceutical sector accounted for only a tiny proportion of the hundred or so new products and indications analysed by Prescrire in 2011. About 1 in 6 new products had more harms than benefits, while more than half of all new products provided no advantages over existing options. One worrisome trend was the expansion of "umbrella" ranges for self-medication. As in previous years, drug regulatory agencies continued to grant marketing authorisation prematurely or on the basis of inadequate evaluation. This was especially true for paediatric medicines, despite some limited progress. In the wake of the Mediator disaster, the French health authorities in charge of patient protection, including the drug regulatory agency, finally reacted by withdrawing many old drugs with negative harm-benefit balances and made an effort to increase transparency and to provide better information on drug-related harms. European authorities showed no signs of similar improvements in early 2012. Drug companies continue to promote their products aggressively, which is not in patients' best interests. The medicalisation of life continues apace, with more and more direct-to-consumer advertising. The Mediator disaster was a wake-up call for French policy makers. In late 2011, several new regulations serving patients' interests were adopted, including greater transparency and better management of conflicts of interest, but as yet, with no major breakthrough in attitudes and procedures. PMID- 22515142 TI - Drugs best avoided yet still on the market in early 2012. PMID- 22515143 TI - In the wake of the Mediator scandal: some progress in France, but apathy at the European level. PMID- 22515144 TI - Novel promising IAP antagonist on the horizon for clinical translation. PMID- 22515145 TI - Amphiphilic polybetaines: the effect of side-chain hydrophobicity on protein adsorption. AB - Novel amphiphilic polybetaines were synthesized and used as the base material for nonfouling coatings. The amphiphilicity of these polybetaines was systematically tuned by coupling chains of increasing hydrophobicity to the zwitterionic functionality side at the repeat unit level. An oligoethylene glycol (OEG) moiety was selected to yield the most hydrophilic coating, while octyl (C(8)) and fluorinated (F) groups were used to impart lipophilicity and lipophobicity to the coatings, respectively. This unique design allowed us to investigate the effect of the lipophilicity/lipophobicity of the side chain on the nonfouling properties of these zwitterionic systems. Adsorption studies, performed using six different proteins, showed that the fluorinated polybetaine, Poly[NFZI-co-NSi], resisted nonspecific adsorption as effectively as, and in some cases even better than, the most hydrophilic Poly[NOEGZI-co-NSi] coating. The comparison of Poly[NFZI-co-NSi] to its noncharged analog demonstrated the essential nature of the zwitterionic functionality in imparting nonfouling character to the coating. PMID- 22515146 TI - Reactions of anionic oxygen nucleophiles with C60 revisited. AB - Reactions of C(60) with oxygen nucleophiles of HO(-) and CH(3)O(-) are revisited in PhCN in the presence of PhCH(2)Br. Different from previous results that such reactions lead to the formation of complex mixtures, well-structured C(60) oxazolines are obtained when HO(-) is involved, while di- and tetraadducts with methoxy and benzyl addends are obtained when CH(3)O(-) is engaged. The reactions are followed by in situ vis-near-IR spectroscopy, which reveals further information for the reactions. PMID- 22515147 TI - Should postactivation potentiation be the goal of your warm-up? AB - Athletes expect improved high-intensity performance following warm-up, and postactivation potentiation (PAP) is assumed to contribute to this improvement. However, the scientific evidence supporting this assumption is incomplete. PAP is known to result from prior muscle activation, and should enhance maximal effort contractions of very short duration. However, PAP dissipates over 4-6 min after the PAP-inducing contraction, so PAP should not contribute to enhanced performance more than 5 min after the warm-up. PMID- 22515148 TI - Trends in aerobic fitness among Canadians, 1981 to 2007-2009. AB - Public health surveillance systems often monitor physical activity trends, but fitness assessment is relatively rare. This study investigated secular changes in aerobic fitness among Canadian adults and children. Participants aged 8-69 years were from 2 nationally representative surveys, conducted in-home in 1981 and in mobile examination centers in 2007-2009. In both surveys, submaximal step tests using progressive age- and sex-specific exercise stages were completed after initial screening (Physical Activity Readiness Questionnaire, heart rate, blood pressure). Between surveys, the step-test protocol had been modified to reduce underestimation of fitness among fitter and older individuals. Maximal oxygen uptake was estimated for adults using validated historical and updated prediction equations, adjusted to reflect protocol differences. Because these equations are not validated for young people, maximal aerobic power was predicted at a heart rate of 200 beats.min(-1) by regressing observed heart rates on the oxygen costs of stepping for children and youth who completed at least 2 exercise stages. Overall, despite protocol differences, we found that the aerobic fitness levels of Canadians were lower in 2007-2009 than in 1981, with declines apparent in all age and both sex groups, thereby increasing the number of those at risk of adverse health outcomes. Future work is required to validate prediction equations of aerobic fitness for young people to make it possible to compare fitness levels over the lifespan and across time. PMID- 22515150 TI - Effects of embedded carbon nanotube on properties of biomembrane. AB - We investigated the interaction between embedded nanotube and biomembrane using molecular dynamics (MD) simulations. The effects of embedded nanotube on biomembrane were characterized by investigating the influence on the conformational fluctuation of individual lipid molecules, the organization of membrane molecules, the diffusion behavior of lipid molecules, and the diffusion behavior of penetrants inside biomembrane. The steric interaction with the nanotube leads to an entropy reduction of interfacial membrane molecules, while the long-range electrostatic interaction with the N-DWCNT enhances the conformational fluctuation of lipid molecules. The curvature of embedded nanotube could also influence the flexibility of lipid molecules. When the interaction between nanotube and the membrane molecules is weak, the packing density of the membrane is almost unaffected. On the contrary, when the attraction between nanotube and the membrane molecules significantly increases, the attraction among the membrane molecules decreases effectively, which leads to a relaxation of the organization of membrane. With the increase of the strength of electrostatic interaction between nanotube and small polar molecules, interaction-modified friction increases, which leads to the decrease of the diffusion constant of penetrants inside the biomembrane. PMID- 22515151 TI - Exploring the influence of students' attributions for success on their self regulation in pathophysiology. AB - Pathophysiology is a difficult course both for students to take and for instructors to teach. However, little research has explored learner characteristics that teachers may address through targeted instruction to make both the teaching and learning experience better. This study examined the influence of students' causal attributions for success on their self-regulated learning, which is strongly associated with positive learning outcomes. Results indicated that ability, effort, and luck attributions for success collectively influenced Pathophysiology students' self-regulated learning and that ability was the most potent influence. The findings and the implication for teaching are discussed. PMID- 22515152 TI - Cultivation of a highly enriched ammonia-oxidizing archaeon of thaumarchaeotal group I.1b from an agricultural soil. AB - Nitrification of excess ammonia in soil causes eutrophication of water resources and emission of atmospheric N(2) O gas. The first step of nitrification, ammonia oxidation, is mediated by Archaea as well as Bacteria. The physiological reactions mediated by ammonia-oxidizing archaea (AOA) and their contribution to soil nitrification are still unclear. Results of non-culture-based studies have shown the thaumarchaeotal group I.1b lineage of AOA to be dominant over both AOA of group I.1a and ammonia-oxidizing bacteria in various soils. We obtained from an agricultural soil a highly enriched ammonia-oxidizing culture dominated by a single archaeal population [c. 90% of total cells, as determined microscopically (by fluorescence in situ hybridization) and by quantitative PCR of its 16S rRNA gene]. The archaeon (termed 'strain JG1') fell within thaumarchaeotal group I.1b and was related to the moderately thermophilic archaeon, Candidatus Nitrososphaera gargensis, and the mesophilic archaeon, Ca. Nitrososphaera viennensis with 97.0% and 99.1% 16S rRNA gene sequence similarity respectively. Strain JG1 was neutrophilic (growth range pH 6.0-8.0) and mesophilic (growth range temperature 25-40 degrees C). The optimum temperature of strain JG1 (35-40 degrees C) is > 10 degrees C higher than that of ammonia-oxidizing bacteria (AOB). Membrane analysis showed that strain JG1 contained a glycerol dialkyl glycerol tetraether, GDGT-4, and its regioisomer as major core lipids; this crenarchaeol regioisomer was previously detected in similar abundance in the thermophile, Ca. N. gargensis and has been frequently observed in tropical soils. Substrate uptake assays showed that the affinity of strain JG1 for ammonia and oxygen was much higher than those of AOB. These traits may give a competitive advantage to AOA related to strain JG1 in oligotrophic environments. (13) C bicarbonate incorporation into archaeal lipids of strain JG1 established its ability to grow autotrophically. Strain JG1 produced a significant amount of N(2) O gas - implicating AOA as a possible source of N(2) O emission from soils. Sequences of archaeal amoA and 16S rRNA genes closely related to those of strain JG1 have been retrieved from various terrestrial environments in which lineage of strain JG1 is likely engaged in autotrophic nitrification. PMID- 22515153 TI - Hemato-nationalism: the past, present, and future of "Japanese blood". AB - In Japan, citizenship is based on the principle of jus sanguinis. Naturalized citizenship is a possibility, but there is a tacit understanding at large that really real, or "pure," Japaneseness is qualified (and circumscribed) by "blood" (chi, ketsu). Blood, in this sense, is understood as an active agent responsible for catalyzing an ethos, or a national-cultural identity. For many Japanese today, blood is understood in terms of blood type, which, despite its controversial serological history, prevails as a popular mode of horoscopy, match making, and personality analysis. I interrogate the compelling fiction of something called "Japanese blood"-a multi-authored "hemato-narrative" that has been nurtured and sustained for more than a century. To this end, I assemble a comprehensive account of the constructive and deconstructive aspects of blood and blood type that considers the cuteness industry, eugenics, blood donation, and national identity. PMID- 22515154 TI - Mobile migrants, mobile germs: migration, contagion, and boundary-building in Shenzhen, China after SARS. AB - Shenzhen, a city located on the border between Mainland China and Hong Kong, is populated primarily by internal Chinese migrants. After the 2003 SARS epidemic, the pressure in Shenzhen to contain infectious disease has been considerable. By engaging with issues of global biosecurity, migration and citizenship, and intersubjectivity in medicine, I argue that in their attempts to prevent another SARS and protect their own subject positions as modern, urban citizens, Shenzhen's public health professionals worked to maintain precarious boundaries between themselves and their city's majority migrant population. However, by establishing the migrants as dangerous, biological noncitizens, by denying connections between the migrants' experiences and their own experiences of migration, by failing to engage with the migrants as subjects, and by defending structures that institutionalized these exclusions, they undermined both the health of the migrants and the stability of the city they were trying to protect. PMID- 22515155 TI - First do no harm? Female hysteria, trauma, and the (bio)logic of violence in Iraq. AB - In Iraq, women are frequently rushed to the hospital in severe anxiety, diagnosed by medical professionals in local hospitals as "hysterical." The treatments proffered are often disturbingly violent in their own right, indicating the normalization of violence in the conflict zone and the rationalizing discourses of biomedicine to this end. Based on fieldwork in the northern Kurdish region, held to be a prosperous beacon of "postconflict" stability in an otherwise war torn country, I consider the ways in which neoliberal interventionist agendas, medical technologies in the aftermath of war, and gendered narratives of the Kurdish nation coalesce to valorize particular forms of suffering while devaluing others as both inherently "feminine" and devoid of either agency or recuperative value. I argue that the violence of such biomedical beliefs forms a "natural" rationalized corollary of wider logics of violence in the war zone, and that both inscribe non-normative expressions of trauma in gendered terms. PMID- 22515156 TI - "The Adopted Children of ART": expert clients and role tensions in ART provision in Uganda. AB - The implementation of the greater involvement of people living with HIV (GIPA) principle in Ugandan AIDS care is described by focusing on the engagement of expert clients in two rural health centers during a time of antiretroviral therapy (ART) scale-up. We contrast how the expert clients help overburdened nurses to manage the well-attended ART programs in the public and in the nongovernmental organization clinic. They are unpaid, but acquire preferential status in the ART program because of their knowledge of AIDS medicines (and its adverse effects) and because of the compassionate care that they provide. Despite the assistance provided, nurses in the public facility felt threatened in their professional status by these expert clients, who were seen to overstep the boundaries of their role. We pay particular attention to the double burden for HIV-positive nurses, who fear stigma, and (unlike the expert patients) keep their HIV status secret. PMID- 22515157 TI - Winter Texans and the re-creation of the American medical experience in Mexico. AB - Rising medical costs and decreasing health insurance coverage are fueling the health care crisis in the United States. Often, patients have to make tough decisions about whether to forgo care or risk bankruptcy. This conundrum has encouraged some patients to use Mexican health care as an alternative to the high costs in the United States. While medical travel enables some patients to access affordable care, others perceive it as risky and thus not a viable option. This article explores how those concerns are mitigated and Mexican health care usage is increased by (1) outlining how Mexican health care information is disseminated and used within a community of winter Texans living along the US/Mexico border; and (2) discussing how Mexican pharmacies and dental clinics have broadened their appeal through association with US health care standards and practices. Research for this article was conducted during 11 months of fieldwork in the Lower Rio Grande Valley. PMID- 22515158 TI - Impact of surface functionalization on bacterial cytotoxicity of single-walled carbon nanotubes. AB - The addition of surface functional groups to single-walled carbon nanotubes (SWNTs) is realized as an opportunity to achieve enhanced functionality in the intended application. At the same time, several functionalized SWNTs (fSWNTs), compared to SWNTs, have been shown to exhibit decreased cytotoxicity. Therefore, this unique class of emerging nanomaterials offers the potential enhancement of SWNT applications and potentially simultaneous reduction of their negative human health and environmental impacts depending on the specific functionalization. Here, the percent cell viability loss of Escherichia coli K12 resulting from the interaction with nine fSWNTs, n-propylamine, phenylhydrazine, hydroxyl, phenydicarboxy, phenyl, sulfonic acid, n-butyl, diphenylcyclopropyl, and hydrazine SWNT, is presented. The functional groups range in molecular size, chemical composition, and physicochemical properties. While physiochemical characteristics of the fSWNTs did not correlate, either singularly or in combination, with the observed trend in cell viability, results from combined light scattering techniques (both dynamic and static) elucidate that the percent loss of cell viability can be correlated to fSWNT aggregate size distribution, or dispersity, as well as morphology. Specifically, when the aggregate size polydispersity, quantified as the width of the distribution curve, and the aggregate compactness, quantified by the fractal dimension, are taken together, we find that highly compact and narrowly distributed aggregate size are characteristics of fSWNTs that result in reduced cytotoxicity. The results presented here suggest that surface functionalization has an indirect effect on the bacterial cytotoxicity of SWNTs through the impact on aggregation state, both dispersity and morphology. PMID- 22515159 TI - Chronic illness and patient satisfaction. AB - OBJECTIVE: To examine how the relationship between patient characteristics, patient experience with the health care system, and overall satisfaction with care varies with illness complexity. DATA SOURCES/STUDY SETTING: Telephone survey in 14 U.S. geographical areas. STUDY DESIGN: Structural equation modeling was used to examine how relationships among patient characteristics, three constructs representing patient experience with the health care system, and overall satisfaction with care vary across patients by number of chronic illnesses. DATA COLLECTION/EXTRACTION METHODS: Random digital dial telephone survey of adults with one or more chronic illnesses. PRINCIPAL FINDINGS: Patients with more chronic illnesses report higher overall satisfaction. The total effects of better patient-provider interaction and support for patient self-management are associated with higher satisfaction for all levels of chronic illness. The latter effect increases with illness burden. Older, female, or insured patients are more satisfied; highly educated patients are less satisfied. CONCLUSIONS: Providers seeking to improve their patient satisfaction scores could do so by considering patient characteristics when accepting new patients or deciding who to refer to other providers for treatment. However, our findings suggest constructive actions that providers can take to improve their patient satisfaction scores without selection on patient characteristics. PMID- 22515160 TI - Clinicopathological features of fatal cardiomyopathy in childhood: an autopsy series. AB - AIM: Cardiomyopathy, a group of primary myocardial disorders, is an uncommon, but important, cause of death in childhood. This study examines the demographic, clinical and pathological features of fatal cardiomyopathy in childhood with particular reference to its classification and autopsy findings. METHOD: The method of this study was a retrospective structured review of all paediatric autopsies performed at a single specialist centre from 1995 to 2009 inclusive, in order to determine the demographic, clinical and pathological features of fatal cardiomyopathy. RESULTS: From a total of 2229 autopsies performed at the centre during the study period on live-born infants and children, 34 confirmed cases of cardiomyopathy were identified (1.5%). More than half (59%) of these cases occurred in infants (less than 1 year of age). Heart weight of cardiomyopathy cases was significantly greater than those with normal hearts (P < 0.001), and 77% had heart weights above the 95th percentile of the normal expected range for age, including all of those over 1 year age. Of cardiomyopathy cases, 50% were primary dilated cardiomyopathy and 27% were primary hypertrophic cardiomyopathy. Twelve of 34 cases (35%) presented as sudden unexpected death, the diagnosis of cardiomyopathy being only made at autopsy. CONCLUSION: Cardiomyopathy is an uncommon cause of death in infancy and childhood. It can present as sudden unexpected death and encompasses a range of aetiologies. Heart weight above the 95th percentile at autopsy is present in most cases but heart weight may be within the normal range in infants. PMID- 22515161 TI - Problems of primary T-cell lymphoma of the thyroid gland--a case report. AB - In the following report we discuss a very rare case of malignant T-cell lymphoma of the thyroid gland that developed in a 70-year-old woman with a past history of hypothyroidism due to chronic thyroiditis. The chief complaint was a rapidly growing neck mass. CT and ultrasonographic examination revealed a diffuse large thyroid gland without a nodule extending up to 13 cm. Although presence of abnormal lymphoid cells in the peripheral blood was not found, the sIL-2 Receptor antibody and thyroglobulin measured as high as 970 U/ml and 600 ng/mL respectively. Fine needle aspiration cytology diagnosed chronic thyroiditis. A preoperative diagnosis of suspicious malignant lymphoma of the thyroid gland accompanied by Hashimoto's thyroiditis was made, and a right hemithyroidectomy was performed to definite diagnosis. Histological examination revealed diffuse small lymphocytic infiltration in the thyroid gland associated with Hashimoto's thyroiditis. Immunohistochemical examination showed that the small lymphocytes were positive for T-cell markers with CD3 and CD45RO. The pathological diagnosis was chronic thyroiditis with atypical lymphocytes infiltration. However, Southern blot analysis of tumor specimens revealed only a monoclonal T-cell receptor gene rearrangement. Finally, peripheral T cell lymphoma was diagnosed. Therefore, the left hemithyroidectomy was also performed one month later. No adjuvant therapy was performed due to the tumor stage and its subtype. The patient is well with no recurrence or metastasis 22 months after the surgical removal of the thyroid. As malignant T-cell lymphoma of the thyroid gland with Hashimoto's thyroiditis was difficult to diagnose, gene rearrangement examination needed to be performed concurrently. PMID- 22515166 TI - Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with SCO2 mutations. AB - BACKGROUND: Mutations in SCO2 cause cytochrome c oxidase deficiency (COX) and a fatal infantile cardioencephalomyopathy. SCO2 encodes a protein involved in COX copper metabolism; supplementation with copper salts rescues the defect in patients' cells. Bezafibrate (BZF), an approved hypolipidemic agent, ameliorates the COX deficiency in mice with mutations in COX10, another COX-assembly gene. METHODS: We have investigated the effect of BZF and copper in cells with SCO2 mutations using spectrophotometric methods to analyse respiratory chain activities and a luciferase assay to measure ATP production.. RESULTS: Individual mitochondrial enzymes displayed different responses to BZF. COX activity increased by about 40% above basal levels (both in controls and patients), with SCO2 cells reaching 75-80% COX activity compared to untreated controls. The increase in COX was paralleled by an increase in ATP production. The effect was dose-dependent: it was negligible with 100 MUM BZF, and peaked at 400 MUM BZF. Higher BZF concentrations were associated with a relative decline of COX activity, indicating that the therapeutic range of this drug is very narrow. Combined treatment with 100 MUM CuCl2 and 200 MUM BZF (which are only marginally effective when administered individually) achieved complete rescue of COX activity in SCO2 cells. CONCLUSIONS: These data are crucial to design therapeutic trials for this otherwise fatal disorder. The additive effect of copper and BZF will allow to employ lower doses of each drug and to reduce their potential toxic effects. The exact mechanism of action of BZF remains to be determined. PMID- 22515167 TI - Low levels of food involvement and negative affect reduce the quality of diet in women of lower educational attainment. AB - BACKGROUND: Women of lower educational attainment tend to have poorer quality diets and lower food involvement (an indicator of the priority given to food) than women of higher educational attainment. The present study reports a study of the role of food involvement in the relationship between educational attainment and quality of diet in young women. METHODS: The first phase uses six focus group discussions (n = 28) to explore the function of food involvement in shaping the food choices of women of lower and higher educational attainment with young children. The second phase is a survey that examines the relationship between educational attainment and quality of diet in women, and explores the role of mediating factors identified by the focus group discussions. RESULTS: The focus groups suggested that lower food involvement in women of lower educational attainment might be associated with negative affect (i.e. an observable expression of negative emotion), and that this might mean that they did not place a high priority on eating a good quality diet. In support of this hypothesis, the survey of 1010 UK women found that 14% of the effect of educational attainment on food involvement was mediated through the woman's affect (P <= 0.001), and that 9% of the effect of educational attainment on quality of diet was mediated through food involvement (P <= 0.001). CONCLUSIONS: Women who leave school with fewer qualifications may have poorer quality diets than women with more qualifications because they tend to have a lower level of food involvement, partly attributed to a more negative affect. Interventions to improve women's mood may benefit their quality of diet. PMID- 22515169 TI - Characterization of homologous and heterologous adaptive immune responses in porcine reproductive and respiratory syndrome virus infection. AB - The present study characterized the homologous and heterologous immune response in type-I porcine reproductive and respiratory syndrome virus (PRRSV) infection. Two experiments were conducted: in experiment 1, eight pigs were inoculated with PRRSV strain 3262 and 84 days post-inoculation (dpi) they were challenged with either strain 3262 or strain 3267 and followed for the next 14 days (98 dpi). In experiment 2, eight pigs were inoculated with strain 3267 and challenged at 84 dpi as above. Clinical course, viremia, humoral response (neutralizing and non neutralizing antibodies, NA) and virus-specific IFN-gamma responses (ELISPOT) were evaluated all throughout the study. Serum levels of IL-1, IL-6, IL-8, TNF alpha and TGF-beta were determined (ELISA) after the second challenge. In experiment 1 primo-inoculation with strain 3262 induced viremia of <= 28 days, low titres of homologous NA but strong IFN-gamma responses. In contrast, strain 3267 induced longer viremias (up to 56 days), higher NA titres (<= 6 log2) and lower IFN-gamma responses. Inoculation with 3267 produced higher serum IL-8 levels. After the re-challenge at 84 dpi, pigs in experiment 1 developed mostly a one week viremia regardless of the strain used. In experiment 2, neither the homologous nor the heterologous challenge resulted in detectable viremia although PRRSV was present in tonsils of some animals. Homologous re-inoculation with 3267 produced elevated TGF-beta levels in serum for 7-14 days but this did not occur with the heterologous re-inoculation. In conclusion, inoculation with different PRRSV strains result in different virological and immunological outcomes and in different degrees of homologous and heterologous protection. PMID- 22515171 TI - Balancing participation and risks in children's Internet use: the role of internet literacy and parental mediation. AB - This study analyzed the survey data from 566 Korean children between the ages of 10 and 15 to examine the role of Internet literacy and parental mediation in solving the dilemma of children's Internet use. According to the findings, children's online participation was associated with increased exposure to online risks. The association was moderated by Internet skills and parental restrictive mediation; that is, for children with a high level of Internet skills and for children who received more restrictive mediation, the positive association between online participation and online risks weakened, but was still significant. The limited roles of Internet skills and parental restrictive mediation in children's Internet use were discussed in the context of media education. PMID- 22515170 TI - Defending the doomed: implicit strategies concerning protection of first-person shooter games. AB - Censorship of violent digital games, especially first-person shooter (FPS) games, is broadly discussed between generations. While older people are concerned about possible negative influences of these games, not only players but also nonplayers of the younger net-generation seem to deny any association with real aggressive behavior. Our study aimed at investigating defense mechanisms players and nonplayers use to defend FPS and peers with playing habits. By using a lexical decision task, we found that aggressive concepts are activated by priming the content of FPS but suppressed afterward. Only if participants were instructed to actively suppress aggressive concepts after priming, thought suppression was no longer necessary. Young people still do have negative associations with violent video games. These associations are neglected by implicitly applying defense strategies--independent of own playing habits--to protect this specific hobby, which is common for the net-generation. PMID- 22515172 TI - Joint position sense is not altered during shoulder medial and lateral rotations in female assembly line workers with shoulder impingement syndrome. AB - This study evaluated joint position sense (JPS) during medial and lateral rotations of the shoulder in female workers with and without shoulder impingement syndrome (SIS). Three groups were assessed. The case group consisted of 15 female assembly line workers (35.5, SD 5.8 years) with unilateral SIS. Control group 1 consisted of 15 female assembly line workers asymptomatic for SIS (34.4, SD 5.5 years) and control group 2 consisted of 15 female subjects (33.1, SD 6.2 years) asymptomatic for SIS and with no exposure to activities with the upper limbs. The JPS was evaluated bilaterally during passive (2 degrees /sec) and active (5 degrees /sec) repositioning tests using an isokinetic dynamometer. The target angles were 45 degrees of lateral rotation (achieved by medially rotating the shoulder from 90 degrees of lateral rotation) and 75 degrees of lateral rotation (achieved by laterally rotating the shoulder from neutral rotation). There were no differences between sides for all groups (p > 0.05). There were no differences in any of the variables between the case group and the control groups (p > 0.05). The results of this study suggest that JPS during medial and lateral rotations of the shoulder is not altered in female assembly line workers with SIS. PMID- 22515173 TI - Evaluation of the effect of storage medium on fragment reattachment. AB - BACKGROUND/AIM: Fragment reattachment is a conservative and a valid alternative to a direct composite restoration. The aim of this study was to evaluate the effect of commonly available storage media on the fracture resistance of reattached fragments. MATERIAL AND METHODS: Sixty sound human maxillary incisors were divided into three groups, the teeth were then sectioned and the fragments were kept dry (Group A), stored in milk (Group B) and in saline (Group C) for 24 h. The fragments were then reattached using simple reattachment technique with flowable composite resin. These teeth were then subjected to thermocycling and the fracture resistance of these reattached fragments were recorded. The mode of fracture was also recorded. RESULTS: Group C (saline) recorded the highest mean fracture resistance (76.9 N) followed by Group B (milk) and Group C (dry), (38.7 N and 27.2 N, respectively). Most of the samples in Group A (65%) and Group C (70%) showed adhesive fracture, whereas 50% of the samples in Group B showed adhesive fracture. CONCLUSIONS: Fragments stored in saline and milk showed greater fracture resistance than those kept dried. PMID- 22515175 TI - Factors related to health locus of control among lung transplant candidates. AB - As the number of individuals pursuing lung transplantation to treat lung disease increases, transplant team members have an opportunity to maximize patients' chances for post-transplant success through identifying and addressing psychosocial factors that have been previously associated with patients' post transplant survival, such as health locus of control (HLC). The purpose of this cross-sectional study was to understand the factors associated with HLC in lung transplant candidates. The aims were to (i) identify the demographic factors associated with internal (IHLC), chance (CHLC), and powerful others (PHLC) HLC; (ii) examine the associations between HLC and anxiety, depression, and optimism; and (iii) determine whether these factors explain a significant proportion of variance in HLC. Hierarchical regression analyses indicated that age, education, trait anxiety, and optimism explained 20% of the variance in CHLC; gender, trait anxiety, and depression accounted for 9% of the variance in IHLC; and lower education accounted for 5% of the variance in PHLC. Helping transplant team members understand the factors that influence patients' perceptions that their own behaviors impact their health status is important for maximizing post transplant success. PMID- 22515174 TI - Characterization of the dog lipocalin allergen Can f 6: the role in cross reactivity with cat and horse. AB - BACKGROUND: Allergy to the domestic dog (Canis familiaris) affects 5-10% of the population in affluent countries. Three of four patients are allergic to more than one pet, which can only partially be explained by cross-reactivity between serum albumins. The lipocalin protein family harbours allergens in mammalian species. METHODS: We set out to clone and characterize a novel dog allergen, and investigate its potential role in cross-sensitization between dog, cat and horse. The gene encoding Can f 6 was amplified from dog skin and bladder cDNA libraries. The corresponding allergen was produced and purified by recombinant techniques and evaluated by SDS-PAGE, size exclusion chromatography, circular dichroism spectra, ELISA and basophil activation test. RESULTS: IgE antibodies to Can f 6 were found in serum from 38% of dog-sensitized subjects. Sequence similarities between the lipocalin allergens Can f 6, Fel d 4 (cat) and Equ c 1 (horse) suggested a probability for cross-reactivity, which was demonstrated by competitive ELISA. The biological relevance of Can f 6 was confirmed by basophil activation test in dog-allergic patients. CONCLUSION: Can f 6 is a new lipocalin dog allergen that cross-reacts with lipocalins from horse and cat. Can f 6 and homologous allergens may contribute to multisensitization and symptoms in individuals allergic to mammals. PMID- 22515176 TI - The many facets of cell injury: angiogenesis to autophagy. PMID- 22515177 TI - Stability of therapeutic retreatment of corneal wavefront customized ablation with the SCHWIND CAM: 4-year data. AB - PURPOSE: To evaluate the long-term outcomes of aspheric corneal wavefront ablation profiles for excimer laser retreatment. METHODS: Eighteen eyes that had previously undergone LASIK or photorefractive keratectomy (PRK) were retreated with LASIK using the corneal wavefront ablation profile. Custom Ablation Manager (SCHWIND eye-tech-solutions, Kleinostheim, Germany) software and the ESIRIS flying spot excimer laser system (SCHWIND) were used to perform the ablations. Refractive outcomes and wavefront data are reported up to 4 years after retreatment. Pre- and postoperative data were compared with Student t tests and (multivariate) correlation tests. P<.05 was considered statistically significant. A bilinear correlation of various postoperative wavefront aberrations versus planned correction and preoperative aberration was performed. RESULTS: Mean manifest refraction spherical equivalent (MRSE) before retreatment was -0.38+/ 1.85 diopters (D) and -0.09+/-0.22 D at 6 months and -0.10+/-0.38 D at 4 years postoperatively. The reduction in MRSE was statistically significant at both postoperative time points (P<.005). Postoperative aberrations were statistically lower (spherical aberration P<.05; coma P<.005; root-mean-square higher order aberration P<.0001) at 4 years postoperatively. Distribution of the postoperative uncorrected distance visual acuity (P<.0001) and corrected distance visual acuity (P<.01) were statistically better than preoperative values. CONCLUSIONS: Aspheric corneal wavefront customization with the ESIRIS yields visual, optical, and refractive results comparable to those of other wavefront-guided customized techniques for the correction of myopia and myopic astigmatism. The corneal wavefront customized approach shows its strength in cases where abnormal optical systems are expected. Systematic wavefront customized corneal ablation appears safe and efficacious for retreatment cases. PMID- 22515178 TI - Delayed presentation of traumatic dislocation of a Visian Implantable Collamer Lens. AB - PURPOSE: To report traumatic dislocation of a Visian Implantable Collamer Lens (ICL, STAAR Surgical Co) discovered on routine examination. METHODS: A 26-year old man was found to have ICL subluxation into the anterior chamber with pupillary capture on routine screening examination. The patient reported being punched near the left eye 2 weeks earlier. He noted mild blurry vision, no pain, and uncorrected distance visual acuity (UDVA) was 20/30, which was decreased from his baseline of 20/20 in the affected eye. RESULTS: Surgical repositioning was performed under pupillary dilation without complication. Postoperatively, UDVA was 20/20(-2). Persistent pigment on the ICL, slight pupillary margin peaking, and anterior chamber inflammation were noted. CONCLUSIONS: Traumatic ICL dislocation may occur with minimal signs and symptoms. Education of patients about the necessity for examination after ocular trauma and need to wear eye protection during activities at high risk of ocular trauma are important. PMID- 22515180 TI - Standing balance in patients with whiplash-associated neck pain and idiopathic neck pain when compared with asymptomatic participants: A systematic review. AB - Neck proprioception is one of the information sources that helps regulate postural balance. However, it is believed to be impaired as patients with both idiopathic neck pain (INP) and whiplash-associated disorders (WAD) have been shown to have a more unstable balance than healthy controls. This systematic review aims to determine if there are significant differences in balance between patients with INP and healthy controls and between patients with WAD and healthy controls. Studies were sought from PubMed, Cinahl, Physiotherapy Evidence Database, Web of Science, Academic Search Complete, Science Direct, and Scielo. Two reviewers independently screened titles and abstracts, assessed full reports for potentially eligible studies, and extracted information on participants' characteristics, pain characteristics, study methods, study results, and study quality. Twelve studies were included in this systematic review. Of these, six compared INP and healthy controls and eight compared WAD and healthy controls. All but one study (11/12) found a statistically significant difference for at least one measurement between patients with INP and WAD and healthy controls. The results of this systematic review suggest that both patients with INP and patients with WAD have poorer balance than healthy controls. PMID- 22515179 TI - From signal transduction to signal interpretation: an alternative model for the molecular function of insulin receptor substrates. AB - The insulin receptor (IR) recruits adaptor proteins, so-called insulin receptor substrates (IRS), to connect with downstream signalling pathways. A family of IRS proteins was defined based on three major common structural elements: Amino terminal PH and PTB domains that mediate protein-lipid or protein-protein interactions, mostly carboxy-terminal multiple tyrosine residues that serve as binding sites for proteins that contain one or more SH2 domains and serine/threonine-rich regions which may be recognized by negative regulators of insulin action. The current model for the role of IRS proteins therefore combines an adaptor function with the integration of mostly negative input from other signal transduction cascades allowing for modulation of signalling amplitude. In this review we propose an extended version of the adaptor model that can explain how signalling specificity could be implemented at the level of IRS proteins. PMID- 22515181 TI - Interleukin-12: clinical usage and molecular markers of cancer susceptibility. AB - The last decade has seen the emergence of immunomodulators as therapeutic agents in cancer treatment. Interleukins (ILs) are a category of small cell-signaling molecules that organize communication and interaction between immune cells and therefore they could be used as perfect immunomodulators. IL-12 is a promising candidate for cancer immunotherapy since it plays a major role in development of antitumor immune response. Numerous studies report that IL-12 promotes an effective destruction of cancer cells both in vivo and in vitro. In addition, IL 12 has anti-angiogenic activity and it is able to dramatically decrease tumor supportive activities of tumor-associated macrophages. The first part of the review is devoted to immunobiology of IL-12. Signaling pathways of IL-12 as well as clinical trials of this cytokine are discussed. The second part of the review is concerned on the inherited variations in IL-12A and IL-12B genes that could modulate cancer susceptibility, and as a consequence, possess predictive, therapeutic, or prognostic significance. It is known that functional single nucleotide polymorphisms (SNPs) in IL-12A and IL-12B genes may dramatically affect on protein expression level, or alter its functions, which may lead to immune disorders, autoimmune diseases, and eventually contribute to cancer occurrence. The list of genetic polymorphisms for further investigations might include the following: IL-12B_+1188A/C (rs3212227), IL-12A_+277G/A (rs568408), IL 12A_-798T/A (rs582054), IL-12A_-504T/G (rs190533), IL-12A_-1148T/C (rs2243123), and IL-12B_+16974 A/C. Perhaps, some of these SNPs may become an attractive target for oncogenomics and possibly could be used in programs of early cancer diagnosis as well as cancer prevention in the nearest future. PMID- 22515182 TI - Polyphosphoric acid promoted synthesis of 10,11-dihydrobenzo[j]fluoranthen-12 one. AB - A straightforward synthesis of 3,8-dimethoxy-10,11-dihydrobenzo[j]fluoranthen-12 ones 1 is reported in a seven-step route from biphenyl-4,4'-diol 2 via the transformation of a double Claisen rearrangement, cross metathesis with ethyl acrylate, and polyphosphoric acid (PPA)-promoted Friedel-Crafts electrophilic benzannulation in good yields. PMID- 22515183 TI - Pharmacological management of pain during orthodontic treatment: a meta-analysis. AB - OBJECTIVES: To evaluate the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) in managing pain arising from orthodontic interventions, such as archwire or separators placement. DATA SOURCES: Medline and Cochrane databases searched in February 2010 and updated in July 2010 using orthodontics and pain as the search terms. Additional studies located from Google Scholar, Clinical Trials and the reference lists of retrieved articles. STUDY SELECTION: Randomized controlled trials comparing NSAID to placebo using visual analogue scale (VAS) scores. DATA SYNTHESIS: Of the 1127 studies identified through database searches, seven were included for meta-analysis. Treatment effects (Hedges' g using random effects model) and 95% confidence intervals (CI) of the pain VAS scores were evaluated at 2, 6 and 24 h after intervention, during chewing and biting activities. Pain level at 2 h differed between the ibuprofen and placebo groups during biting (95% CI: -0.178 to -0.046), but not during chewing (95% CI: -0.551 to 0.148). At 6 h, the ibuprofen group exhibited lower pain levels during both activities (chewing 95% CI: -0.640 to -0.123, biting 95% CI: -0.857 to -0.172). At 24 h, no statistically significant difference could be detected between ibuprofen and placebo (chewing 95% CI: -0.642 to 0.112, biting 95% CI: -0.836 to 0.048). No statistically significant difference was found between ibuprofen and acetaminophen at any time point. CONCLUSION: Ibuprofen appears to lower orthodontic pain compared to placebo at 2 and 6 h after separators or archwire placement, but not at 24 h, when pain peaks. PMID- 22515184 TI - Histological study of the nasal septal cartilage in BALB/c-bm/bm mouse which spontaneously induces malocclusion. AB - OBJECTIVES: The BALB/c-bm/bm mouse is characterized by short limbs and short tail attributed to undersulfated glycosaminoglycans. Anterior transverse crossbite sometimes spontaneously appears in BALB/c-bm/bm mice. The BALB/c-bm/bm mouse shows a short nose and cranium. The reason for hypo-growth of anterior craniofacial structures has not been clarified, although the nasal septal cartilage might be related to the growth of anterior craniofacial structures. Therefore, the purpose of this study was to evaluate histological findings of the nasal septal cartilage at the border region of the ethmoid and sphenoid bone in BALB/c-bm/bm mice. MATERIALS AND METHODS: BALB/c mice (wild type) and BALB/c bm/bm mice with normal occlusion (bm/bm) were used. Sagittal sections of female mice aged 2, 4, and 8 weeks were stained with hematoxylin and eosin for histological analysis. RESULTS: At the border region between the nasal septal cartilage and the ethmoid bone in bm/bm, the area of proliferative zone was significantly smaller than that in wild type. At the border regions between the nasal septal cartilage and both the ethmoid and sphenoid bones, the number of proliferative chondrocytes was significantly smaller. Normal endochondral ossification was not observed at the border region between the nasal septal cartilage and the sphenoid bone in bm/bm. CONCLUSION: The findings suggest that disorder of endochondral ossification in the nasal septal cartilage contributes to the hypo-growth of anterior craniofacial structures in bm/bm. PMID- 22515185 TI - Statistical modelling of lip movement in the clinical context. AB - OBJECTIVE: To establish three-dimensional (3D) reference data on average lip movement in normal healthy subjects using statistical shape analysis techniques. SETTING AND SAMPLE POPULATION: School of Dentistry and Cardiff School of Computer Science, Cardiff University, United Kingdom. One hundred and fifteen white subjects. MATERIAL AND METHODS: Subjects performed four reproducible verbal gestures (puppy, rope, baby and bob) in a normal relaxed manner, which were captured using a non-invasive, 3D motion scanner (3dMDFaceTM Dynamic System). Six landmarks were manually placed around the lips of the 3D facial shells showing maximum lip displacement. Generalized procrustes analysis followed by principal component analysis was applied to the landmark coordinates to characterize lip movement for each word. RESULTS: The first four principal components (PCs) describe the majority of variation in lip movement for the four words involving a complex interaction of lip movements in three dimensions. Bilateral landmarks were paired within PCs showing that movement was largely symmetrical. Female resting lip shape was narrower and shorter in height than males. During motion, females preferred a more protrusive articulation than males. CONCLUSION: Statistical shape analysis techniques can be used to characterize lip movement during articulation. Data from this study can act as a reference for average lip movement to compare similar population groups. PMID- 22515186 TI - Reference values for three-dimensional surface cephalometry in children aged 3-6 years. AB - OBJECTIVE: This prospective cross-sectional study design was performed to define reference values for the facial surfaces of 3-6-year-old boys and girls using three-dimensional surface cephalometry. MATERIAL AND METHODS: A total of 2290 standardized three-dimensional facial images from 3 to 6-year-old preschool children were separated by gender and assigned to four age categories. All children were Caucasian and revealed no evidence of dentofacial abnormalities. On each image, 31 cephalometric landmarks were marked, resulting in 35 (19 frontal, six lateral, 10 paired) distances and eight angles. Differences between age groups and genders were calculated and significances detected. RESULTS: A base table with reference values was compiled, which indicated that boys showed higher values than age-matched girls and that measured distances increased with age. CONCLUSION: The mean values from this study could be compiled as a reference table for three-dimensional facial analysis in Caucasian children aged 3-6 years. Such a reference table could be used in comparative studies with other populations or children with craniofacial malformations. PMID- 22515187 TI - Dental arch relationship in 5-year-olds with complete unilateral cleft lip and palate after early alveolar bone grafting. AB - OBJECTIVE: To evaluate dental arch relationship in preschoolers with unilateral cleft lip and palate after early alveolar bone grafting (ABG). MATERIALS AND METHODS: Three raters blindly assessed the dental arch relationship with the GOSLON Yardstick (using a 5-point scale, from 1--very good to 5--very poor outcome) in Early-grafted group (27 boys and 15 girls; mean age = 5.2 years, SD 0.5) and Non-grafted group (17 boys and 12 girls; mean age = 5.8 years, SD 0.8). The groups differed regarding the age when ABG was performed: between 2 and 4 years (mean = 2.4, SD 0.6) in the Early-grafted group and after 9 years in the Non-grafted group. The strength of agreement of rating was evaluated with kappa statistics. RESULTS: The intra- and inter-rater agreement was high (kappa > 0.800). The mean GOSLON score in the Early-grafted group was 2.72 and in the Non grafted group -2.64. The distribution of the GOSLON grades in the Early-grafted group was: 54.8% had a score 1 or 2, 23.8%--3, and 21.4%--4 or 5; in the Non grafted group, 38.0% subjects scored 1 or 2, 41.4%--3, and 20.6%--4 or 5 (p = 0.023). CONCLUSIONS: Early alveolar bone grafting carried out between the ages of 2 and 4 years was not found to negatively affect dental arch relationship by the age of 5 years. However, it is possible that such a negative effect could be found if a longer observation period (e.g. at age 10 years or age 15 years) was allowed. PMID- 22515188 TI - Effect of light-cure initiation time on polymerization efficiency and orthodontic bond strength with a resin-modified glass-ionomer. AB - OBJECTIVES: The polymerization and acid-base reactions in resin-modified glass ionomers (RMGI) are thought to compete with and inhibit one another. To examine the effect of visible light-cure (VLC) delay on the polymerization efficiency and orthodontic bond strength of a dual-cured RMGI. SETTING AND SAMPLE POPULATION: The Orthodontics Graduate Program at Marquette University. An in vitro study utilizing 72 freshly extracted human bicuspid teeth. MATERIALS AND METHODS: A RMGI light-cured immediately, 2.5, 5, or 10 min after mixing comprised the experimental groups. Isothermal and dynamic temperature scan differential scanning calorimetry (DSC) analysis of the RMGI was performed to determine extents of VLC polymerization and acid-base reaction exotherms. Human premolars (n = 18/group) were bonded with the RMGI. Shear bond strength and adhesive remnant index (ARI) scores were determined. RESULTS: Differential scanning calorimetry results showed the 10-min-delay RMGI group experienced significantly (p < 0.05) lower VLC polymerization compared with the other groups. Acid-base reaction exotherms were undetected in all groups except the 10-min delay group. No significant differences (p > 0.05) were noted among the groups for mean shear bond strength. A chi-square test showed no significant difference (p = 0.428) in ARI scores between groups. CONCLUSIONS: Delay in light-curing may reduce polymerization efficiency and alter the structure of the RMGI, but orthodontic shear bond strength does not appear to be compromised. PMID- 22515191 TI - Association between fatigue and Internet addiction in female hospital nurses. AB - AIMS: To report a study conducted to examine the association between fatigue and Internet addiction among female hospital nurses. BACKGROUND: The Internet provides unprecedented convenience for social interaction and information retrieval. Although excessive Internet use has been demonstrated to correlate with fatigue in adolescents, no studies have examined whether it is associated with fatigue in nurses. DESIGN: Cross-sectional survey. METHODS: The study was conducted in August 2010. Female Registered Nurses working in a regional teaching hospital in southern Taiwan were asked to complete a paper-based questionnaire. The questionnaire included questions on demographics, the Chen Internet Addiction Scale and the Chalder Fatigue Scale. Multiple linear regression analysis was performed using Chalder fatigue scale as the dependent variable. RESULTS: Of the 564 (79% response) valid questionnaires returned, 6 and 10% of the participants were classified as diagnostic cases and possible cases of Internet addiction, respectively. Fatigue levels, adjusting for other potential confounders including work unit, shift work, regular self-medication, and self-perceived health status, was significantly associated with both possible cases of Internet addiction and diagnostic cases of Internet addiction. CONCLUSION: This study is the first in reporting a statistically significant association between fatigue levels and Internet addiction in female hospital nurses. RELEVANCE TO CLINICAL PRACTICE: Nurses should pay attention to their Internet activity and whether it adds to their fatigue levels. Addictive behaviour should promptly be dealt with to ensure that the best care is provided to patients. PMID- 22515192 TI - Study on cerium-doped nano-TiO2 coatings for corrosion protection of 316 L stainless steel. AB - Many methods have been reported on improving the photogenerated cathodic protection of nano-TiO2 coatings for metals. In this work, nano-TiO2 coatings doped with cerium nitrate have been developed by sol-gel method for corrosion protection of 316 L stainless steel. Surface morphology, structure, and properties of the prepared coatings were investigated by X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy and energy dispersive X ray spectroscopy. The corrosion protection performance of the prepared coatings was evaluated in 3 wt% NaCl solution by using electrochemical techniques in the presence and absence of simulated sunlight illumination. The results indicated that the 1.2% Ce-TiO2 coating with three layers exhibited an excellent photogenerated cathodic protection under illumination attributed to the higher separation efficiency of electron-hole pairs and higher photoelectric conversion efficiency. The results also showed that after doping with an appropriate concentration of cerium nitrate, the anti-corrosion performance of the TiO2 coating was improved even without irradiation due to the self-healing property of cerium ions. PMID- 22515190 TI - Looking to the future: incorporating genomic information into disparities research to reduce measurement error and selection bias. AB - OBJECTIVE: To extend recent conceptual and methodological advances in disparities research to include the incorporation of genomic information in analyses of racial/ethnic disparities in health care and health outcomes. DATA SOURCES: Published literature on human genetic variation, the role of genetics in disease and response to treatment, and methodological developments in disparities research. STUDY DESIGN: We present a conceptual framework for incorporating genomic information into the Institute of Medicine definition of racial/ethnic disparities in health care, identify key concepts used in disparities research that can be informed by genomics research, and illustrate the incorporation of genomic information into current methods using the example of HER-2 mutations guiding care for breast cancer. PRINCIPAL FINDINGS: Genomic information has not yet been incorporated into disparities research, though it has direct relevance to concepts of race/ethnicity, health status, appropriate care, and socioeconomic status. The HER-2 example demonstrates how available genetic information can be incorporated into current disparities methods to reduce selection bias and measurement error. Advances in health information infrastructure may soon make standardized genetic information more available to health services researchers. CONCLUSION: Genomic information can refine measurement of racial/ethnic disparities in health care and health outcomes and should be included wherever possible in disparities research. PMID- 22515193 TI - Non-thermal DNA damage of cancer cells using near-infrared irradiation. AB - Previously, we reported that near-infrared irradiation that simulates solar near infrared irradiation with pre- and parallel-irradiational cooling can non thermally induce cytocidal effects in cancer cells. To explore these effects, we assessed cell viability, DNA damage response pathways, and the percentage of mitotic cancer cells after near-infrared treatment. Further, we evaluated the anti-cancer effects of near-infrared irradiation compared with doxorubicin in xenografts in nude mice by measuring tumor volume and assessing protein phosphorylation by immunoblot analysis. The cell viability of A549 lung adenocarcinoma cells was significantly decreased after three rounds of near infrared irradiation at 20 J/cm(2). Apoptotic cells were observed in near infrared treated cells. Moreover, near-infrared treatment increased the phosphorylation of ataxia-telangiectasia mutated (ATM) at Ser(1981), H2AX at Ser(139), Chk1 at Ser(317), structural maintenance of chromosome (SMC) 1 at Ser(966), and p53 at Ser(15) in A549 cells compared with control. Notably, near infrared treatment induced the formation of nucleic foci of gammaH2AX. The percentage of mitotic A549 cells, as measured by histone H3 phosphorylation, decreased significantly after three rounds of near-infrared irradiation at 20 J/cm(2). Both near-infrared and doxorubicin inhibited the tumor growth of MDA MB435 melanoma cell xenografts in nude mice and increased the phosphorylation of p53 at Ser(15), Chk1 at Ser(317), SMC1 at Ser(966), and H2AX at Ser(139) compared with control mice. These results indicate that near-infrared irradiation can non thermally induce cytocidal effects in cancer cells as a result of activation of the DNA damage response pathway. The near-infrared irradiation schedule used here reduces discomfort and side effects. Therefore, this strategy may have potential application in the treatment of cancer. PMID- 22515194 TI - Effect of thiol pendant conjugates on plasmid DNA binding, release, and stability of polymeric delivery vectors. AB - Polymers have attracted much attention as potential gene delivery vectors due to their chemical and structural versatility. However, several challenges associated with polymeric carriers, including low transfection efficiencies, insufficient cargo release, and high cytotoxicity levels have prevented clinical implementation. Strong electrostatic interactions between polymeric carriers and DNA cargo can prohibit complete cargo release within the cell. As a result, cargo DNA never reaches the cell's nucleus where gene expression takes place. In addition, highly charged cationic polymers have been correlated with high cytotoxicity levels, making them unsuitable carriers in vivo. Using poly(allylamine) (PAA) as a model, we investigated how pH-sensitive disulfide cross-linked polymer networks can improve the delivery potential of cationic polymer carriers. To accomplish this, we conjugated thiol-terminated pendant chains onto the primary amines of PAA using 2-iminothiolane, developing three new polymer vectors with 5, 13, or 20% thiol modification. Unmodified PAA and thiol conjugated polymers were tested for their ability to bind and release plasmid DNA, their capacity to protect genetic cargo from enzymatic degradation, and their potential for endolysosomal escape. Our results demonstrate that polymer plasmid complexes (polyplexes) formed by the 13% thiolated polymer demonstrate the greatest delivery potential. At high N/P ratios, all thiolated polymers (but not unmodified counterparts) were able to resist decomplexation in the presence of heparin, a negatively charged polysaccharide used to mimic in vivo polyplex protein interactions. Further, all thiolated polymers exhibited higher buffering capacities than unmodified PAA and, therefore, have a greater potential for endolysosomal escape. However, 5 and 20% thiolated polymers exhibited poor DNA binding-release kinetics, making them unsuitable carriers for gene delivery. The 13% thiolated polymers, on the other hand, displayed high DNA binding efficiency and pH-sensitive release. PMID- 22515196 TI - Well-differentiated papillary mesothelioma of the epididymis in a man with recurrent haematospermia. AB - We present a case of well-differentiated papillary mesothelioma of the epididymis occurring in a 60-year-old man who came to urologic consult after recurrent episodes of haematospermia. The patient denied pain, fever and trauma in genitals. Local examination revealed indolent swelling at the right testicle and ecography localised a well-circumscribed nodule at the epididymis tail, measuring 2 cm in greater diameter, with associated haemorrhagic hydrocele. A nodulectomy was performed and the patient is alive with no evidence of disease 17 months following surgery. PMID- 22515195 TI - The extradomain a of fibronectin enhances the efficacy of lipopolysaccharide defective Salmonella bacterins as vaccines in mice. AB - The Extradomain A from fibronectin (EDA) has an immunomodulatory role as fusion protein with viral and tumor antigens, but its effect when administered with bacteria has not been assessed. Here, we investigated the adjuvant effect of EDA in mice immunizations against Salmonella enterica subspecies enterica serovar Enteritidis (Salmonella Enteritidis). Since lipopolysaccharide (LPS) is a major virulence factor and the LPS O-polysaccharide (O-PS) is the immunodominant antigen in serological diagnostic tests, Salmonella mutants lacking O-PS (rough mutants) represent an interesting approach for developing new vaccines and diagnostic tests to differentiate infected and vaccinated animals (DIVA tests). Here, antigenic preparations (hot-saline extracts and formalin-inactivated bacterins) from two Salmonella Enteritidis rough mutants, carrying either intact (SEDeltawaaL) or deep-defective (SEDeltagal) LPS-Core, were used in combination with EDA. Biotinylated bacterins, in particular SEDeltawaaL bacterin, decorated with EDAvidin (EDA and streptavidin fusion protein) improved the protection conferred by hot-saline or bacterins alone and prevented significantly the virulent infection at least to the levels of live attenuated rough mutants. These findings demonstrate the adjuvant effect of EDAvidin when administered with biotinylated bacterins from Salmonella Enteritidis lacking O-PS and the usefulness of BEDA-SEDeltawaaL as non-live vaccine in the mouse model. PMID- 22515198 TI - Amorphous/crystalline (A/C) thermodynamic "rules of thumb": estimating standard thermodynamic data for amorphous materials using standard data for their crystalline counterparts. AB - Standard thermochemical data (in the form of Delta(f)H degrees and Delta(f)G degrees ) are available for crystalline (c) materials but rarely for their corresponding amorphous (a) counterparts. This paper establishes correlations between the sets of data for the two material forms (where known), which can then be used as a guideline for estimation of missing data. Accordingly, Delta(f)H degrees (a)/kJ mol(-1) ~ 0.993Delta(f)H degrees (c)/kJ mol(-1) + 12.52 (R(2) = 0.9999; n = 50) and Delta(f)G degrees /kJ mol(-1) ~ 0.988Delta(f)H degrees (c)/kJ mol(-1) + 0.70 (R(2) = 0.9999; n = 10). Much more tentatively, we propose that S degrees (298)(c)/J K(-1) mol(-1) ~ 1.084S degrees (298)(c)/J K(-1) mol(-1) + 6.54 (R(2) = 0.9873; n = 11). An amorphous hydrate enthalpic version of the Difference Rule is also proposed (and tested) in the form [Delta(f)H degrees (M(p)X(q).nH(2)O,a) - Delta(f)H degrees (M(p)X(q),a)]/kJ mol(-1) ~ Theta(Hf)n ~ 302.0n, where M(p)X(q).nH(2)O represents an amorphous hydrate and M(p)X(q) the corresponding amorphous anhydrous parent salt. PMID- 22515197 TI - Endocytosis-like uptake of surface-modified drug nanocarriers into giant unilamellar vesicles. AB - We had previously developed surface-modified poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) for use as a cellular drug delivery system. The cellular uptake of PLGA-NPs was mediated predominantly by endocytosis, and this uptake was increased by surface modifications with polymers, such as chitosan (CS) and polysorbate 80 (P80). In the present study, we prepared a cell-sized giant unilamellar vesicle (GUV) that mimics a cell membrane to investigate the interaction between cell membranes and NPs. Endocytosis-like uptake of NPs into a GUV was observed when the NPs were modified with nonionic surfactant P80 probably due to change in viscoelasticity and enhanced fusion activity of the membrane induced by P80. In contrast, unmodified NPs and those modified with CS were not internalized into a GUV. These results suggest that surface properties of PLGA NPs are an important formulation parameter for their interaction with lipid membranes. PMID- 22515199 TI - Electrochemistry and electrogenerated chemiluminescence of BODIPY dyes. AB - BODIPY (boron dipyrromethene) dyes are unique materials with spectroscopic and electrochemical properties comparable to those of aromatic hydrocarbons. Electrochemical studies are useful in understanding the redox properties of these materials and finding structure-stability relations for the radical ions; along with spectroscopy, these studies help researchers design novel compounds with desired properties. This Account represents our attempt at a full description of the electrochemical and electrogenerated chemiluminescence (ECL) properties of the BODIPY dyes. When the dyes are completely substituted with alkyl or other groups, the radical ions of BODIPY dyes are highly stable. But if they include unsubstituted positions, the radical ions can undergo dimerization or other reactions. BODIPY dyes also show unusually large separations, ~1.0 V, between the first and second cyclic voltammetric (CV) waves for both oxidation and reduction half-reactions. Alkyl-substituted BODIPY dyes show good photoluminescence (PL) quantum efficiencies, and radical ion electron transfer annihilation in these molecules produces electrogenerated chemiluminescence (ECL), the intensity of which depends on the structure of the dye. The large separation between waves and the presence of strong ECL signals are both important in the design of stable ECL based materials. The ECL spectra provide a fast method of monitoring the electrochemical formation of dimers and aggregates from the monomers. BODIPY dyes are particularly good systems for studying stepwise electron transfer in their chemically synthesized oligomers and polymers because of the small separation between the first oxidation and first reduction waves, generally about 2.0-2.4 V, and their relative ease of reduction compared with many other aromatic compounds. The larger separation between consecutive waves for oxidation compared with reduction is noticeable for all BODIPY dimers and trimers. We also observe a more difficult addition or extraction of a third electron compared with the second for the trimers, signaling the importance of electrostatic interactions. In general, BODIPY dyes combine interesting electrochemical and spectroscopic properties that suggest useful analytical applications. PMID- 22515200 TI - Monozygotic twins discordant for intermittent allergic rhinitis differ in mRNA and protein levels. AB - Monozygotic (MZ) twins discordant for complex diseases may help to find disease mechanisms that are not due to genetic variants. Intermittent allergic rhinitis (IAR) is an optimal disease model because it occurs at defined time points each year, owing to known external antigens. We hypothesized that MZ twins discordant for IAR could help to find gene expression differences that are not dependent on genetic variants. We collected blood outside of the season from MZ twins discordant for IAR, challenged their peripheral blood mononuclear cells (PBMC) with pollen allergen in vitro, collected supernatants and isolated CD4+ T cells. We identified disease-relevant mRNAs and proteins that differed between the discordant MZ twins. By contrast, no differences in microRNA expression were found. Our results indicate that MZ twins discordant for IAR is an optimal model to identify disease mechanisms that are not due to genetic variants. PMID- 22515201 TI - Pre- and postnatal exposure to kynurenine causes cognitive deficits in adulthood. AB - Levels of kynurenic acid (KYNA), an endogenous product of tryptophan degradation, are elevated in the brain and cerebrospinal fluid of individuals with schizophrenia (SZ). This increase has been implicated in the cognitive dysfunctions seen in the disease, as KYNA is an antagonist of the alpha7 nicotinic acetylcholine receptor and the N-methyl-d-aspartate receptor, both of which are critically involved in cognitive processes and in a defining neurodevelopmental period in the pathophysiology of SZ. We tested the hypothesis that early developmental increases in brain KYNA synthesis might cause biochemical and functional impairments in adulthood. To this end, we stimulated KYNA formation by adding the KYNA precursor kynurenine (100 mg/day) to the chow fed to rat dams from gestational day 15 to postnatal day 21 (PD 21). This treatment raised brain KYNA levels in the offspring by 341% on PD 2 and 210% on PD 21. Rats were then fed normal chow until adulthood (PD 56-80). In the adult animals, basal levels of extracellular KYNA, measured in the hippocampus by in vivo microdialysis, were elevated (+12%), whereas extracellular glutamate levels were significantly reduced (-13%). In separate adult animals, early kynurenine treatment was shown to impair performance in two behavioral tasks linked to hippocampal function, the passive avoidance test and the Morris water maze test. Collectively, these studies introduce a novel, naturalistic rat model of SZ, and also suggest that increases in brain KYNA during a vulnerable period in brain development may play a significant role in the pathophysiology of the disease. PMID- 22515203 TI - Gastrocnemius-derived BDNF promotes motor function recovery in spinal cord transected rats. AB - This study evaluated the role of gastrocnemius-derived brain-derived neurotrophic factor (BDNF) and possible mechanism in motor improvement in T10 spinal cord transection (SCT) rats. There was complete paralysis in hindlimbs immediately after SCT, followed by partial functional restoration with time going. The level of BDNF but not its mRNA gradually increased in caudal stump after SCT, whereas a significant increase in both BDNF and its mRNA was simultaneously seen in gastrocnemius. Injection of BDNF antibody into the gastrocnemius significantly decreased hindlimb locomotor function, downregulated the level of BDNF and its mRNA together with extracellular signal-regulated kinase 1/2 (Erk1/2). Moreover, ventral root ligation led to decrease both BDNF and Erk in caudal stump, indicating BDNF transportation from gastrocnemius into the spinal cord. We concluded that gastrocnemius-derived BDNF reduced motor functional deficits in SCT rats through Erk signaling pathway. These novel findings suggested the usage of BDNF in muscle for the treatment of spinal cord injury in clinic. PMID- 22515204 TI - A clinical audit of antithrombin concentrate use in a tertiary paediatric centre. AB - AIM: The aim of this study was to investigate the clinical use of antithrombin concentrate (ATC) in children and specifically to determine the current practice of ATC administration, including dosing and indications for administration. METHODS: A clinical audit was performed of patients treated with ATC during two 12-month periods: 1 June 1999-1 June 2000 and 1 June 2009-1 June 2010. RESULTS: Thirty-seven patients whose age ranged from 1 day to 13.5 years (median 30 days) received a median of two doses (range 1-15) with a median dose of 40 units/kg (range 1-200 units). The majority (90%) of patients were located in the intensive care unit, and the major indication (76%) for use of the ATC was in the setting of unfractionated heparin (UFH) resistance. Post-ATC administration, 32% of the doses given resulted in antithrombin levels reaching age-specific normative levels. Of the patients administered ATC with the aim of optimising UFH therapy, 28% of patients had their UFH dose reduced without any measurement of UFH effect. CONCLUSIONS: This data provides the basis for future investigations of the specific biochemical changes accompanying ATC administration and the development of paediatric-specific evidence-based guidelines for ATC use. PMID- 22515202 TI - Evaluation of vascular lesions using circulating endothelial cells in renal transplant patients. AB - OBJECTIVE: To investigate the correlation between circulating endothelial cells (CECs) and vascular lesions in renal allografts. METHODOLOGY: Sixty-two renal transplant patients were divided into four groups according to biopsy data. CECs were isolated from peripheral blood with anti-CD136-coated immunomagnetic Dynabeads and counted by microscopy during biopsy. CEC numbers were compared in each group, as well as the correlation between CECs and C4d and vascular changes in different groups. RESULT: CECs counts were higher in the acute rejection (AR) with endarteritis group than in the normal group (p < 0.01), acute tubular necrosis (ATN) group (p < 0.01) and chronic allograft nephropathy (CAN) group (p < 0.01), there were no difference among ATN, normal and CAN) group (p = 0.587). There was no difference among the normal group without hyaline, normal group with hyaline and CAN with hyaline group. An increasing CECs count was related to C4d positive AR (p = 0.008; kappa score = 0.519) and infiltration of inflammatory cells (p = 0.002, kappa score = 0.573) in proximal tubule cells (PTCs). The CECs count decreased after intensive therapy in five patients (p = 0.001). CONCLUSION: Elevation of the CEC count in blood was related to endarteritis. Elevation of CEC count was related to C4d deposition and infiltration of inflammatory cells in PTCs. PMID- 22515205 TI - Modeling the dimensionality of DSM-IV alcohol use disorder criteria in a nationally representative sample of college students. AB - This study examined the dimensionality of DSM-IV alcohol use disorder (AUD) criteria in a nationally representative sample of college students (N = 4,605) using latent variable techniques. We used data from the 2009 National Survey of Drug Use and Health and selected those who were currently enrolled in college and current drinkers. Confirmatory factor analysis provided support for a one-factor solution of the AUD criteria. Item Response Theory analyses indicated that the alcohol abuse and dependence criteria severity parameters were intermixed along the AUD severity continuum with high discrimination parameters. Findings support reformulating the current AUD diagnostic system for the DSM-V. Study's limitations are noted. PMID- 22515206 TI - Detection of helicobacter pylori in benign laryngeal lesions by polymerase chain reaction: a cross sectional study. AB - BACKGROUND: Although Helicobacter Pylori (HP) was detected in some cases of chronic laryngitis, the results were not confirmed by polymerase chain reaction (PCR). By this time, it has not been found in laryngeal lesions by in house PCR, the most sensitive method for detecting the genome tracks. Regarding the previous results and also few numbers of studies about the presence of HP in benign laryngeal lesions, specifically by PCR, we aimed to investigate the presence of HP in benign laryngeal lesions by in-house PCR. METHODS: The samples were taken from 55 patients with benign laryngeal lesions and frozen in -20 degrees C. One milliliter (ml) of lysis buffer was added to 100 mg (mg) of each sample and the tube was placed in 56 degrees C overnight. Then DNA extraction was carried out. RESULTS: To find HP DNA, in-house PCR was performed that revealed 5 positive results among 55 patients with benign laryngeal lesions. Of them, 3 were polyp, 1 was nodule and 1 was papilloma. CONCLUSION: Although the number of positive results was not a lot in this study, it was in contrast with previous studies which could not find any HP tracks in benign laryngeal lesions by other methods. More studies about the prevalence of HP in benign laryngeal lesions improve judging about the effect of this infection on benign laryngeal lesions. PMID- 22515207 TI - Structure of mitochondrial DNA control region of Fenneropenaeus chinensis and phylogenetic relationship among different populations. AB - This paper deals with the structure of mitochondrial DNA control region of Fenneropenaeus chinensis. The termination-associated sequence (TAS), cTAS, CSB-D CSB-F, and CSB-1 are detected in the species. The results indicate that the structures of these parts are similar to those of most marine organisms. Two conserved regions and many stable conserved boxes are found in the extended TAS area, central sequences blocks, and conserved sequences blocks (CSBs). This is the special character of F. chinensis. All the mtDNA control region sequences do not have CSB2 and CSB3 blocks, which is quite different from most vertebrates. In addition, the complete mtDNA control region sequences are used to analyze the phylogenetic relationships of F. chinensis. The phylogenetic trees show a lack of genetic structure among populations, which is similar to many previous studies. PMID- 22515208 TI - Repetitive sequences in Eurasian lynx (Lynx lynx L.) mitochondrial DNA control region. AB - Mitochondrial DNA (mtDNA) control region (CR) of numerous species is known to include up to five different repetitive sequences (RS1-RS5) that are found at various locations, involving motifs of different length and extensive length heteroplasmy. Two repetitive sequences (RS2 and RS3) on opposite sides of mtDNA central conserved region have been described in domestic cat (Felis catus) and some other felid species. However, the presence of repetitive sequence RS3 has not been detected in Eurasian lynx (Lynx lynx) yet. We analyzed mtDNA CR of 35 Eurasian lynx (L. lynx L.) samples to characterize repetitive sequences and to compare them with those found in other felid species. We confirmed the presence of 80 base pairs (bp) repetitive sequence (RS2) at the 5' end of the Eurasian lynx mtDNA CR L strand and for the first time we described RS3 repetitive sequence at its 3' end, consisting of an array of tandem repeats five to ten bp long. We found that felid species share similar RS3 repetitive pattern and fundamental repeat motif TACAC. PMID- 22515209 TI - Complete mitochondrial genome of the seven-spotted lady beetle, Coccinella septempunctata (Coleoptera: Coccinellidae). AB - The complete mitochondrial genome (mitogenome) of the seven-spotted lady beetle, Coccinella septempunctata (Coleoptera: Coccinellidae), which is one of the best known insects capable of predation, is described with an emphasis on the noteworthy composition of the A+T-rich region. The C. septempunctata genome consists of 2 rRNAs, 22 tRNAs, 13 protein-coding genes, and 1 control region, designated as the A+T-rich region in insects. Along with an unusually long A+T rich region (4469 bp), the 18,965-bp long C. septempunctata mitogenome was the largest in Coleoptera. The A+T-rich region is composed of a 2214-bp long non repeat region composed of 80.17% A/T nucleotides and a 2256-bp long repeat region composed of 65.71% A/T nucleotides. The repeat region harbors 32 identical 70-bp long tandem repeats plus one 15-bp long incomplete first repeat. These repeat sequences may possibly have been caused by slipped-strand mispairing and unequal crossing-over events during DNA replication. PMID- 22515210 TI - Complete mitochondrial genome sequences of two Chiroptera species (Rhinolophus luctus and Hipposideros armiger). PMID- 22515211 TI - Complete mitochondrial genome of the groundhopper Alulatettix yunnanensis (Insecta: Orthoptera: Tetrigoidea). AB - In this work, we sequenced the first complete mitochondrial genome of Tetrigoidea species, Alulatettix yunnanensis. The circle genome (15,104 bp) consists of 13 protein-coding, 22 transfer RNA, and 2 ribosomal RNA genes, and an A+T-rich region. It has the typical invertebrate mitochondrial gene arrangement. PMID- 22515212 TI - Complete mitochondrial genome sequence of the dragonet Callionymus curvicornis (Perciformes: Callionymoidei: Callionymidae). AB - We determined the complete mitochondrial genome (mitogenome) sequence of the dragonet Callionymus curvicornis. The total length of C. curvicornis mitogenome is 16,406 bp, which consists of 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and 1 control region. It has the typical vertebrate mitochondrial gene arrangement. This is the first report of a complete mitochondrial genome in the fish suborder Callionymoidei. PMID- 22515213 TI - Association of 3D reconstruction and conventional radiography for the description of the appendicular skeleton of Chelonoidis carbonaria (Spix, 1824). AB - In this study, we associated imaging modalities, such as computed tomography (CT) and standard radiography, with anatomical specimens to describe the anatomy of the appendicular skeleton of red-footed tortoises (Chelonoidis carbonaria), using animals of different sizes, ages, sexes and weights. Manus and pes bones were described from conventional radiography and osteological specimens, because they have small structures that could not be reconstructed. The main anatomical feature that differentiates C. carbonaria from others Testudines is the ischial pubic tuberculum. The pectoral girdle is formed by the union of two bones, the scapula and the coracoid, showing no bone connection with the shell. Carpal and tarsal bones can be fused or not and include: carporadial and central carpus, carpoulnar and V carpal, central tarsal and fibular tarsal, distal tarsal I and II. The phalangeal formula is 2:2:2:2:2 in the forelimb and 2:2:2:2:1 in the hind limb. Imaging examinations are important tools in anatomical description and can be used in living individuals, replacing or aiding the study with anatomical specimens. PMID- 22515214 TI - Structural tuning of photoluminescence in nanoporous anodic alumina by hard anodization in oxalic and malonic acids. AB - We report on an exhaustive and systematic study about the photoluminescent properties of nanoporous anodic alumina membranes fabricated by the one-step anodization process under hard conditions in oxalic and malonic acids. This optical property is analysed as a function of several parameters (i.e. hard anodization voltage, pore diameter, membrane thickness, annealing temperature and acid electrolyte). This analysis makes it possible to tune the photoluminescent behaviour at will simply by modifying the structural characteristics of these membranes. This structural tuning ability is of special interest in such fields as optoelectronics, in which an accurate design of the basic nanostructures (e.g. microcavities, resonators, filters, supports, etc.) yields the control over their optical properties and, thus, upon the performance of the nanodevices derived from them (biosensors, interferometers, selective filters, etc.). PMID- 22515216 TI - Effect of axially projected oligothiophene pendants and nitro-functionalized diimine ligands on the lowest excited state in cationic Ir(III) bis cyclometalates. AB - The novel terthiophene (3T) oligomer 6 and a series of cationic Ir(III) bis cyclometalates [Ir(C^N)(2)(N^N)]PF(6) 9-12 were prepared. The synthesis, characterization, electrochemical, and photophysical properties are reported. The cyclometalating ligands (C^N) are 2-phenylpyridinato (ppy) or the 3T oligomer (3T ppy), asymmetrically capped in the 5 and 5" positions with the ppy and mesityl groups. The diimine ligands (N^N) are 2,2'-bipyridine (bpy) or 4-NO(2)-bipyridine (4-NO(2)-bpy). Hybrid metal-organic complexes 11 and 12 bear 3T-pendants ligated through the ppy cap, 10 and 12 contain NO(2) functionalized diimines, whereas 9 contains neither. Structural characterization of 10 by single crystal X-ray diffraction confirms the presence of the NO(2) substituent and pseudo-octahedral coordination geometry about the Ir(III) ion. Cyclic voltammetry highlights the large electron withdrawing effect of the NO(2) substituent, providing an 850 mV shift toward lower potentials for the first diimine centered reduction of 10 and 12. Strong overlap of the intense pi -> pi* absorptions of the 3T-pendants with Ir(III) charge transfer bands is evident in complexes of 11 and 12, precluding the possibility for selective excitation of either chromophore. Photoexcitation (lambda(ex) = 400 nm) of the series affords strong luminescence from the 3T oligomer 6 and the unsubstituted 9, with phi(em) = 0.11. In stark contrast the NO(2) and 3T functionalized complexes 10-12 display near total quenching of luminescence. Computations of the ground and excited state electronic structure using density functional theory (DFT) and time-dependent DFT (TD-DFT) indicate that both the NO(2) and 3T substituents play an important role in excited state deactivation of complexes 10-12. A substantial electronic contribution of the NO(2) substituent results in stabilization of the diimine based molecular orbital (MO) and offers an efficient nonradiative decay pathway for the excited state. Spin-orbit coupling effects of the Ir(III) ion lead to efficient population of the low lying, nonluminescent, triplet states centered on the 3T-pendants. PMID- 22515215 TI - Analysis of the microbial gene landscape and transcriptome for aromatic pollutants and alkane degradation using a novel internally calibrated microarray system. AB - Despite various efforts to develop tools to detect and compare the catabolic potential and activity for pollutant degradation in environmental samples, there is still a need for an open-source, curated and reliable array method. We developed a custom array system including a novel normalization strategy that can be applied to any microarray design, allowing the calculation of the reliability of signals and make cross-experimental comparisons. Array probes, which are fully available to the scientific community, were designed from knowledge-based curated databases for key aromatic catabolic gene families and key alkane degradation genes. This design assigns signals to the respective protein subfamilies, thus directly inferring function and substrate specificity. Experimental procedures were optimized using DNA of four genome sequenced biodegradation strains and reliability of signals assessed through a novel normalization procedure, where a plasmid containing four artificial targets in increased copy numbers and co amplified with the environmental DNA served as an internal calibration curve. The array system was applied to assess the catabolic gene landscape and transcriptome of aromatic contaminated environmental samples, confirming the abundance of catabolic gene subfamilies previously detected by functional metagenomics but also revealing the presence of previously undetected catabolic groups and specifically their expression under pollutant stress. PMID- 22515218 TI - Granular cell angiosarcoma. PMID- 22515219 TI - Caveat emptor. PMID- 22515220 TI - Broad range of adverse cutaneous eruptions in patients on TNF-alpha antagonists. AB - Biologic therapies targeting tumor necrosis factor (TNF)-alpha have become a mainstay in the management of a number of autoimmune diseases. We report a series of adverse skin eruptions in six patients (four females, two males, age: 21-58 years, mean: 39) receiving 4 months to 10 years (mean 3.1 years) of anti-TNF alpha therapies (infliximab, n = 4; adalimumab, n = 1 or etanercept, n = 1). The following drug-associated diagnoses were made in eight skin biopsies performed at Massachusetts General Hospital between 3/2007 and 10/2010: pustular folliculitis, psoriasis, interface dermatitis, neutrophilic eccrine hidradenitis, Sweet's syndrome, lupus, vasculitis and palmoplantar pustulosis. The descriptions of neutrophilic eccrine hidradenitis-like and Sweet's-like hypersensitivity eruptions induced by anti-TNF-alpha therapies are the first such cases described in the literature. Each cutaneous eruption improved or resolved with switching to a different TNF-alpha inhibitor, discontinuation of the anti-TNF-alpha agent, and/or topical or systemic steroids. There was a clear chronologic relationship with, and clinical remission upon withdrawal or steroid suppression of the anti TNF-alpha agents. The mechanism for such diverse cutaneous eruptions among this class of medications remains poorly understood. The cutaneous adverse reaction profile of TNF-alpha inhibitors is broad and should be considered in the histopathologic differential in this clinical setting. PMID- 22515222 TI - Scleromyxedema and the dermato-neuro syndrome: case report and review of the literature. AB - Scleromyxedema is a generalized form of lichen myxedematosus which is characterized by a papular and sclerodermoid skin eruption resulting from dermal fibroblast proliferation and mucin deposition. The majority of patients with scleromyxedema have a monoclonal gammopathy, and other systemic manifestations are common. Herein we describe a case of the 'dermato-neuro syndrome', a rare and sometimes fatal neurologic manifestation of scleromyxedema which consists of fever, convulsions and coma, often preceded by a flu-like prodrome. In addition, we provide a comprehensive summary of previously published cases of the dermato neuro syndrome and discuss the current etiopathogenic theories and treatment options for this rare disease. PMID- 22515221 TI - Increased Twist expression in advanced stage of mycosis fungoides and Sezary syndrome. AB - BACKGROUND: The mechanisms of tumor progression in mycosis fungoides (MF) and Sezary syndrome (SS) are poorly understood. Twist, a transcription factor, is thought to promote solid tumor progression by blocking p53 and inhibiting c-myc induced apoptosis. Whether Twist expression is correlated to MF/SS stages remains unknown. METHODS: Twist, c-myc and p53 proteins in 68 MF/SS lesions across all T stages were examined by immunohistochemistry, and mRNA levels in peripheral blood CD4+ T-cells from SS patients were measured by real-time quantitative polymerase chain reaction. RESULTS: Positive staining for Twist was found in 12.5% (2/16) of T1 and 33.3% (7/21) of T2 early stage patches/plaques compared to 50.0% (9/18) of T3 tumors and 84.6% (11/13) of T4 erythroderma. Most T4 erythroderma were positive for Twist in dermal lymphocytes, with the strongest staining. Positive staining for c-myc was higher in T3/T4 lesions (29/31, 93.5%) than T1/T2 lesions (25/37, 67.6%, p < 0.05), with strongest staining in T3 tumors. Aberrant p53 expression was more common in T3/T4 lesions (8/31, 25.8%) than in T1/T2 lesions (2/37, 5.4%, p < 0.05). Twist mRNA was detected in all CD4+ T cells from SS patients but not in normal donors. CONCLUSIONS: Increased Twist protein expression in advanced MF/SS lesions suggests that Twist expression may correlate with MF/SS stages. PMID- 22515223 TI - Alopecia with perineural lymphocytes: a clue to linear scleroderma en coup de sabre. AB - Linear scleroderma en coup de sabre ('the stroke of the sword') is an uncommon form of morphea with onset typically in childhood or adolescence. Involvement is usually located on the paramedian forehead and is associated with alopecia. It is microscopically indistinguishable from other forms of scleroderma. We present a 51-year-old woman who presented with alopecia and subsequently developed linear scleroderma en coup de sabre on her adjacent forehead. Histopathology revealed a strikingly perineural lymphocytic and plasmacytic infiltrate, extending deeply into the subcutis and fascia. To our knowledge, this is the first report of alopecia with perineural lymphocytic inflammation as a presenting sign of linear scleroderma en coup de sabre. PMID- 22515224 TI - Metastatic basal cell carcinoma of the posterior neck: case report and review of the literature. AB - Although primary basal cell carcinoma (BCC) represents an extremely common malignancy, metastases derived from BCC are exceedingly rare. The prognosis for metastatic BCC is poor, and little consensus exists regarding predictive factors or optimal treatment strategies. Here, we present the case of a 63-year-old man with BCC of the neck who subsequently developed multiple metastases to subcutaneous tissue, lymph nodes, and the parotid gland. Risk factors and clinical features of metastatic BCC are reviewed, as is the relationship of histopathologic subtype to metastatic behavior. Current chemotherapeutic and targeted therapies also are discussed in the context of recent advances in molecular biology. PMID- 22515225 TI - Annular hypopigmented mycosis fungoides: a novel ringed variant. AB - Hypopigmented mycosis fungoides (MF) is a relatively uncommon variant of cutaneous lymphoma that is mostly seen in darker skin types. We present a novel and unique clinical presentation in an African-American female patient, consisting of regular hypopigmented annular rings in areas of normal skin and in more typical hypopigmented patches of MF. The lesions appeared diffusely on all extremities, anterior chest and back. Histopathologic examination showed an atypical lymphocytic infiltrate at the dermal-epidermal junction with epidermotropism and few Pautrier's collections. The patient was otherwise healthy and improved with narrowband ultraviolet (UV)-B. This case represents a presentation of a most unusual variant of hypopigmented MF, for which we propose the name 'annular hypopigmented MF'. PMID- 22515226 TI - Nevoid hyperkeratosis of the areola misinterpreted as mycosis fungoides. AB - Nevoid hyperkeratosis of the nipple and areola is a benign condition with fewer than 70 cases reported in the literature. We report a case of unilateral nevoid hyperkeratosis of the areola with intraepidermal lymphocytes that resembled Pautrier's microabscesses on histological examination. This is the third report of mycosis fungoides-like changes in nevoid hyperkeratosis of the nipple and areola. In addition, this is the first case to present immunohistochemical and T cell gene rearrangement studies of the intraepidermal lymphocytes. This case highlights a potential histopathological pitfall in the diagnosis of nevoid hyperkeratosis of the nipple and areola. PMID- 22515227 TI - Reactive granular histiocytosis secondary to arthroplasty prosthesis: a novel reaction pattern. AB - A reactive histiocytic infiltrate can be seen as an incidental finding in a lymph node biopsy from a patient with a history of joint arthroplasty. We report the case of a 74-year-old female who underwent surgical revision of a polyethylene based right total knee prosthesis due to chronic wear. At the time of surgery, a soft tissue mass adjacent to the tibial prosthetic insert was noted and excised. Histopathologic examination revealed a sheet-like proliferation of large, histiocytoid cells within the subcutis and superficial fascia. The cells showed abundant eosinophilic, granular cytoplasm and small round bland nuclei. Immunohistochemical evaluation revealed the cells to be positive only for CD68. In addition, abundant PAS-positive cytoplasmic granules were found, and minute particles of polarizable material were noted intracellularly and scattered throughout the interstitium of the infiltrate. These findings were interpreted as consistent with a reactive, non-Langerhans cell histiocytosis secondary to the patient's polyethylene knee prosthesis. This finding appears to be a local correlate of the process previously described in regional lymph nodes as reactive granular histiocytosis. Dermatopathologists should be cognizant of this uncommon reaction pattern to avoid mistaking it for a neoplastic process. PMID- 22515229 TI - Stereoselective synthesis of the macrolactone core of (+)-neopeltolide. AB - A stereoselective synthesis of the macrolactone core of the potent anticancer agent neopeltolide is disclosed. The key steps of the synthesis include asymmetric allylation using Krische' protocol, conjugate reduction using MacMillan's methodology, and an asymmetric hetero-Diels-Alder reaction using Jacobsen's catalyst. Substrate controlled diastereoselective 1,3-anti reduction of a keto alcohol, Luche reduction followed by Ireland-Claisen rearrangement, oxymercuration, and reductive lithiation are other key steps. PMID- 22515230 TI - Establishing desirable fortificant levels for calcium, iron and zinc in foods for infant and young child feeding: examples from three Asian countries. AB - We used the World Health Organization's recommended procedures to establish desirable fortificant levels for three problem micronutrients in children's diets, based on dietary data collected earlier from Filipino (n = 1374; 6-36 months), Mongolian (n = 179; 12-36 months) and Cambodian (n = 177; 12-36 months) children. Prevalence of inadequate and excessive intakes of calcium and zinc (via cut-point method) and iron (via full-probability approach) was assessed after adjusting usual intake distributions with pc-side using internal or external within-person variances from Filipino (calcium and iron) and US National Health And Nutrition Examination Survey III (zinc) national surveys. Fortificant levels were determined by repositioning usual intake distributions so that the 2.5th percentile of the targeted populations equalled the estimated average requirement (calcium, zinc) or so that full-probability prevalence was no larger than 2.5% (iron). Prevalence of inadequate intakes was >=70% for calcium and iron, except Filipino infants (30% for Ca) and Cambodian toddlers (41% for Fe); but <1% for zinc for toddlers in Mongolia and 20% in Cambodia. Prevalence of excessive intakes was <1% for zinc, calcium and iron, except for Mongolian toddlers (11% for Zn). Desirable fortificant levels, although apparently negligible for zinc, were 530-783 mg for calcium and 10.8-22.8 mg for iron (per 100 g). Fortificant levels can be estimated from 24-h recalls, preferably by applying internal within person variances. Fortification with calcium and iron was necessary, but seemingly not for zinc, despite a high prevalence of low serum zinc, suggesting the need for better defined cut-offs for population risk of zinc deficiency based on dietary zinc intake and/or serum zinc. PMID- 22515231 TI - Germination of Aspergillus fumigatus inside avian respiratory macrophages is associated with cytotoxicity. AB - Although aspergillosis is one of the most common diseases in captive birds, the pathogenesis of avian aspergillosis is poorly known. We studied the role of avian respiratory macrophages as a first line of defense against avian aspergillosis. The phagocytic and killing capacities of avian respiratory macrophages were evaluated using pigeon respiratory macrophages that were inoculated with Aspergillus fumigatus conidia. On average, 25% of macrophage-associated conidia were phagocytosed after one hour. Sixteen percents of these cell-associated conidia were killed after 4 h and conidial germination was inhibited in more than 95% of the conidia. A. fumigatus conidia were shown to be cytotoxic to the macrophages. Intracellularly germinating conidia were located free in the cytoplasm of necrotic cells, as shown using transmission electron microscopy. These results suggest that avian respiratory macrophages may prevent early establishment of infection, unless the number of A. fumigatus conidia exceeds the macrophage killing capacity, leading to intracellular germination and colonization of the respiratory tract. PMID- 22515233 TI - Synthetic high-charge organomica: effect of the layer charge and alkyl chain length on the structure of the adsorbed surfactants. AB - A family of organomicas was synthesized using synthetic swelling micas with high layer charge (Na(n)Si(8-n)Al(n)Mg(6)F(4)O(20).XH(2)O, where n = 2, 3, and 4) exchanged with dodecylammonium and octadecylammonium cations. The molecular arrangement of the surfactant was elucidated on the basis on XRD patterns and DTA. The ordering conformation of the surfactant molecules into the interlayer space of micas was investigated by (13)C, (27)Al, and (29)Si MAS NMR. The arrangement of alkylammonium ions in these high-charge synthetic micas depends on the combined effects of the layer charge of the mica and the chain length of the cation. In the organomicas with dodecylammonium, a transition from a parallel layer to a bilayer-paraffin arrangement is observed when the layer charge of the mica increases. However, when octadecylammonium is the interlayer cation, the molecular arrangement of the surfactant was found to follow the bilayer-paraffin model for all values of layer charge. The amount of ordered conformation all trans is directly proportional of layer charge. PMID- 22515232 TI - Phase I trial of gemcitabine and candesartan combination therapy in normotensive patients with advanced pancreatic cancer: GECA1. AB - Our retrospective study showed inhibition of the renin-angiotensin system was associated with better outcomes in patients with advanced pancreatic cancer receiving gemcitabine. The primary objective of this phase I study was to determine the recommended dose of candesartan in combination with gemcitabine in normotensive patients with advanced pancreatic cancer. Candesartan was given orally at an escalating dose (4, 8, 16, and 32 mg) q.d. daily, and gemcitabine was given 1000 mg/m(2) 30 min i.v. on days 1, 8, and 15, repeated every 4 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicities, grade 2 hypotension, abnormal creatinine or potassium, and grade 3 or 4 other non hematological toxicities. A standard "3+3" phase I dose-escalation design was used. A total of 14 patients (candesartan 4 mg, three patients; 8 mg, three patients; 16 mg, six patients; 32 mg, two patients) were enrolled. One of six patients at 16 mg showed DLT of grade 4 neutropenia and two of two patients at 32 mg showed DLT of grade 2 hypotension. Response rate and disease control rate were 0% and 79%, respectively. Progression-free survival and overall survival were 7.6 and 22.9 months, respectively. Candesartan 16 mg is the recommended dose in combination with gemcitabine in the treatment of advanced pancreatic cancer. (UMIN CTR: UMIN000002152). PMID- 22515234 TI - In situ inactivation of polyphenol oxidase in mamey fruit (Pouteria sapota) by microwave treatment. AB - Polyphenol oxidase (PPO) is the enzyme responsible for quality loss in most fruits and vegetables. Quality loss is mainly because of oxidative chemical reactions which generate the darkening of tissues. Mamey fruit (Pouteria sapota) after harvesting suffers a rapid quality decay trough activation of PPO. However, PPO may be inactivated in situ by chemical or thermal treatment. In food processing, microwave treatment (MT) has been used recently as an alternative for PPO inactivation. In this study, it was observed that mamey fruit pulp subjected to a gently MT resulted in a higher PPO activity as the generated heat induced in situ the increase in PPO activity. In contrast, PPO was completely inactivated after long MT by using a high microwave power. Temperature in mamey pulp after MT reached a maximum of 79 degrees C; although PPO was active up to 60 degrees C. PPO was completely inactivated when conventional blanching treatment was performed but required a higher temperature (92 degrees C/300 s). The optimum energy intensity (E(opt)) for PPO inactivation by MT was 0.51 kJ/g or 937 W/165 s. Under this condition, the remaining PPO activity was inversely proportional to energy intensity (E). Interestingly, MT resulted in a negligible damage in microstructure of mamey pulp, although blanching treatment resulted in large damaging effects on tissue organization and shape. Therefore, MT is proposed as an effective way to completely inactivate PPO without causing any significant damage to fruit tissues and shape; as preservation of color, flavor, and taste would be favored. PMID- 22515235 TI - The role of salivary proteins in the mechanism of astringency. AB - Understanding astringency has focused on the interaction of tannins with the salivary proline-rich proteins (PRPs), although it remains unclear if other astringents precipitate the PRPs or how this interaction relates to sensory perceptions of astringency. We used 2 approaches to compare how distinct classes of astringent compounds interacted with the salivary PRPs and mucins. Using sodium dodecyl sulfate polyacrylamide gel electrophoresis, we evaluated protein patterns and characterized the salivary proteins present in the supernatants and pellets of pooled saliva assayed with tannin, alum, and hydrochloric acid solutions. Tannins and alum precipitated many of the PRPs, but acid did not. Mucins were precipitated by both the acid and alum, but not by the tannins. From our research, it appears that the precipitation of salivary proteins may be involved in the mechanism of astringency, but the precipitation of PRPs is not requisite for the development of astringency. We also measured mucin and deoxyribonucleic acid content of expectorated solutions of astringents that panelists swished in their mouths to determine if astringency was associated with a loss of oral lubricating films. PMID- 22515237 TI - Potential role of native pickling cucumber polygalacturonase in softening of fresh pack pickles. AB - This study examined the potential involvement of polygalacturonase (PG) in commercial pickling cucumbers on gradual softening of refrigerated and pasteurized fresh pack pickle products that adversely affects their market-life. PG activity was detected in all sources of commercial pickling cucumbers and refrigerated pickle spears, and activity was detected in some sources of pasteurized spears. Polygalacturonic acid hydrolysis determined from changes in fluidity, reducing groups and oligogalacturonides indicated involvement of both exo- and endo-PG. Treatment of pasteurized pickle mesocarp tissues with concentrated extracts from pickling cucumbers resulted in rapid softening and alteration of pectic substances. D-values for thermal inactivation of pickling cucumber PG at 75, 80, 85, and 90 degrees C were 22.0, 19.5, 14.5, and 4.2 min, respectively, indicating that residual activity would be expected in commercially pasteurized pickle products. It is concluded that residual cucumber PG could be responsible for softening of processed pickle products, and it is suspected that variations in textural quality of given products are caused by differences in residual types and levels of native PG. PRACTICAL APPLICATION: Since enzyme extracts from commercial pickling cucumbers were demonstrated to be capable of softening pickle tissues and that PG activity was present in some processed fresh pack products, methods that inactivate or eliminate the enzyme(s) should reduce softening of products during storage and marketing. PMID- 22515236 TI - Starch characteristics of transgenic wheat (Triticum aestivum L.) overexpressing the Dx5 high molecular weight glutenin subunit are substantially equivalent to those in nonmodified wheat. AB - The effects of engineering higher levels of the High Molecular Weight Glutenin Dx5 subunit on starch characteristics in transgenic wheat (Triticum aestivum L.) grain were evaluated. This is important because of the interrelationship between starch and protein accumulation in grain, the strong biotechnological interest in modulating Dx5 levels and the increasing likelihood that transgenic wheat will be commercialized in the U.S. Unintended effects of Dx5 overexpression on starch could affect wheat marketability and therefore should be examined. Two controls with native levels of Dx5 were used: (i) the nontransformed Bobwhite cultivar, and (ii) a transgenic line (Bar-D) expressing a herbicide resistant (bar) gene, and they were compared with 2 transgenic lines (Dx5G and Dx5J) containing bar and additional copies of Dx5. There were few changes between Bar-D and Dx5G compared to Bobwhite. However, Dx5J, the line with the highest Dx5 protein (*3.5) accumulated 140% more hexose, 25% less starch and the starch had a higher frequency of longer amylopectin chains. These differences were not of sufficient magnitude to influence starch functionality, because granule morphology, crystallinity, amylose-to-amylopectin ratio, and the enthalpy of starch gelatinization and the amylose-lipid complex melting were similar to the control (P > 0.05). This overall similarity was borne out by Partial Least Squares Discriminant Function Analysis, which could not distinguish among genotypes. Collectively our data imply that higher Dx5 can affect starch accumulation and some aspects of starch molecular structure but that the starches of the Dx5 transgenic wheat lines are substantially equivalent to the controls. PRACTICAL APPLICATION: Transgenic manipulation of biochemical pathways is an effective way to enhance food sensory quality, but it can also lead to unintended effects. These spurious changes are a concern to Government Regulatory Agencies and to those Industries that market the product. In this study we examined if making "specific" changes to the composition of gluten proteins in wheat seeds would simultaneously alter starch, as their synthesis is interrelated and the molecular structure of both determine flour functionality. This information may be used to address issues of "substantial equivalence" and to inform Industrial End-Users of possible changes in product performance. PMID- 22515238 TI - Enzymatic interesterification of palm stearin with Cinnamomum camphora seed oil to produce zero-trans medium-chain triacylglycerols-enriched plastic fat. AB - It is known that Cinnamomum camphora seed oil (CCSO) is rich in medium-chain fatty acids (MCFAs) or medium-chain triacylglycerols (MCTs). The purpose of the present study was to produce zero-trans MCTs-enriched plastic fat from a lipid mixture (500 g) of palm stearin (PS) and CCSO at 3 weight ratios (PS:CCSO 60:40, 70:30, 80:20, wt/wt) by using lipase (Lipozyme TL IM, 10% of total substrate) as a catalyst at 65 degrees C for 8 h. The major fatty acids of the products were palmitic acid (C16:0, 42.68% to 53.42%), oleic acid (C18:1, 22.41% to 23.46%), and MCFAs (8.67% to 18.73%). Alpha-tocopherol (0.48 to 2.51 mg/100 g), gamma tocopherol (1.70 to 3.88 mg/100 g), and delta-tocopherol (2.08 to 3.95 mg/100 g) were detected in the interesterified products. The physical properties including solid fat content (SFC), slip melting point (SMP), and crystal polymorphism of the products were evaluated for possible application in shortening or margarine. Results showed that the SFCs of interesterified products at 25 degrees C were 9% (60:40, PS:CCSO), 18.50% (70:30, PS:CCSO), and 29.2% (80:20, PS:CCSO), respectively. The beta' crystal form was found in most of the interesterified products. Furthermore, no trans fatty acids were detected in the products. Such zero-trans MCT-enriched fats may have a potential functionality for shortenings and margarines which may become a new type of nutritional plastic fat for daily diet. PMID- 22515239 TI - Volatile compounds of black cumin seeds (Nigella sativa L.) from microwave heating and conventional roasting. AB - The volatile compounds in raw, conventionally roasted and microwave roasted black cumin (Nigella sativa L.) seeds at 0.45 kW for 2, 4, and 8 min, were analyzed by headspace-SPME gas chromatography-mass spectrometry. Among the 38 volatile compounds identified, the major compounds were thymoquinone and p-cymene in all samples. The levels of these compounds decreased with roasting. However, concentrations of pyrazines and furans increased significantly as a result of roasting and these compounds may affect the flavor of roasted black cumin seeds. Methyl pyrazine and 2,5-dimethylpyrazine were major pyrazines, formed at high concentration in seeds roasted for 8 min and in conventional roasting. PMID- 22515240 TI - Precipitation of salivary proteins after the interaction with wine: the effect of ethanol, pH, fructose, and mannoproteins. AB - Astringency is a complex sensation mainly caused by the precipitation of salivary proteins with polyphenols. In wine it can be enhanced or reduced depending on the composition of the medium. In order to investigate the effect of ethanol, tartaric acid, fructose, and commercial mannoproteins (MPs) addition on the precipitation of salivary proteins, the saliva precipitation index (SPI) was determined by means of the sodium dodecyl sulphate polyacrylamide gel electrophoresis of human saliva after the reaction with Merlot wines and model solutions. Gelatin index, ethanol index, and Folin-Ciocalteu index were also determined. As resulted by Pearson's correlation, data on SPI were well correlated with the sensory analysis performed on the same samples. In a second experiment, increasing the ethanol (11%-13%-17%), MPs (0-2-8 g/L), fructose (0-2 6 g/L) level, and pH values (2.9-3.0-3.6), a decrease in the precipitation of salivary proteins was observed. A difference in the SPI between model solution and red wine stated that an influence of wine matrix on the precipitation of salivary proteins occurred. PRACTICAL APPLICATION: Results provide interesting suggestions for enologists, which could modulate the astringency of red wine by: (i) leaving some residual reducing sugars (such as fructose) in red wine during winemaking of grapes rich in tannins; (ii) avoiding the lowering of pH; (iii) adding commercial mannoproteins or promoting a "sur lie" aging; and (iv) harvesting grapes at high technological maturity in order to obtain wines with a satisfactory alcoholic content when possible. PMID- 22515241 TI - Chitosan-based edible coatings for quality preservation of postharvest whiteleg shrimp (Litopenaeus vannamei). AB - Postharvest shrimp is highly susceptible to both microbiological spoilage and endogenous enzymatic browning, so it should be preserved properly using effective and appropriate methods. The effects of 1.0% and 1.5% O-carboxymethyl chitosan (CMC) and 1.0% and 1.5% chitosan (CH) coatings on the quality changes of whiteleg shrimp (Litopenaeus vannamei) during refrigerated storage (0 +/- 1 degrees C) of 10 d were investigated. The pretreatment with CMC and CH solution (1.0% or 1.5%) retarded growth of psychrophilic bacteria throughout storage in comparison with the control (P < 0.05). The lower increases in pH and total volatile base (TVB) content were obtained in the shrimp treated with CMC and CH solution at both levels, compared with the control samples (P < 0.05). Loss in freshness and melanosis decreased after the shrimp was treated with CMC and CH. In addition, CMC and CH (1.0% or 1.5%) showed inhibitory activity toward total viable bacteria counts of white shrimp in a dose-dependent manner. Therefore, chitosan and O carboxymethyl chitosan can be used as promising melanosis inhibitors as well as antimicrobial agents during refrigerated storage. PRACTICAL APPLICATION: The main practical application behind the development of chitosan (CH) and O-carboxymethyl chitosan (CMC) used to preserve postharvest whiteleg shrimp lies with the fact that these polysaccharides represent a renewable source of natural biodegradable polymers and meet with the emergence of more and more food safety problems. Both CMC and CH can be used as food preservatives to extend shrimp shelf life. However, CMC is more convenient due to its solubility. In the future, CMC will be used in the food processing industry because of its soluble, compatible, antimicrobial, and antioxidative characteristics. PMID- 22515242 TI - The impact of anthocyanin-rich red raspberry extract (ARRE) on the properties of edible soy protein isolate (SPI) films. AB - To modify the properties of edible soy protein isolate (SPI) films, 0.5% anthocyanin-rich red raspberry (Rubus strigosus) extract (ARRE) (0.5 g raspberry powder in 95% ethyl alcohol/water/85% lactic acid [80:19:1. v/v/v]) was incorporated into film-forming solutions. ARRE resulted in an SPI film having significantly enhanced tensile strength (P < 0.05) and % elongation at break (P < 0.05), as well as increased water swelling ratio (P < 0.05) and in vitro pepsin digestibility (P < 0.05). The resultant films also showed significantly decreased water solubility and water vapor permeability (P < 0.05). In addition, ARRE increased darkness, redness, and yellowness film appearance as evidenced by a lower L* (P < 0.05), greater positive a* (P < 0.05), and a higher b* (P < 0.05) than the control film. Scanning electron microscopy images revealed that extract added films had denser and more compact cross-section microstructure. Fourier transform infrared spectra illustrated that ARRE-created hydrogen bonding involved conformational changes of soy protein without destroying its backbone structure. SDS-PAGE electrophoretograms revealed that the extract induced intermolecular interaction of the soy protein monomers. Natural plant extracts would be a promising ingredient to make SPI films with different physicochemical properties and applications. PRACTICAL APPLICATION: This study characterizes the potential physicochemical changes of SPI film with incorporated raspberry extract. Upon the above modification, the resultant film was found to enhance the applications of pure SPI film in food packaging. For example, SPI-ARRE film could prolong the usage life of SPI film due to increased strength, or could be useful as a desiccant (drying agent) such as a water-absorbing sheet for preserving dried foods due to its increased hydrophilic surface and water-swelling ratio. SPI-ARRE film could also be alternately used as a food wrap with unique color. PMID- 22515243 TI - Improved microbial quality of buckwheat using antimicrobial solutions in a fluidized bed. AB - Buckwheat (Fagopyrum esculentum, Moench) is a specialty crop of interest because of its numerous nutritional, health, and agronomic benefits. A high microbial load on the seed often limits its export and use in functional foods; therefore, these generally recognized as safe antimicrobial treatments were evaluated for buckwheat disinfection: ozone gas, ozonated water, acetic acid (AA), acidic calcium sulfate (ACS), and combinations thereof. The liquid treatments were sprayed on buckwheat grain in a fluidized bed and the treated buckwheat was analyzed for aerobic plate count (APC) and yeast and mold count (YMC). Ozone gas and ozonated water treatments were not significantly (P < 0.05) effective in reducing the microbial load, and AA + ozonated water had significant but low effectiveness. Electron microscopic imaging suggested that rough surfaces and crevices in the seed hull shielded microbes from ozone treatments. Effectiveness of treatments was also limited by the industry limits on the amount of moisture that can be added to buckwheat grain. The ACS (50 mL/L) treatment was most effective with 3.9-log10 reduction in APC and complete elimination of YMC. ACS (50 mL/L) caused bleaching and increased redness. Sufficient reduction of microbes could be achieved at a lower concentration of ACS, thereby reducing the effect on color. PMID- 22515246 TI - Transmission electron microscopic analysis showing structural changes to bacterial cells treated with electrolyzed water and an acidic sanitizer. AB - The effects of various sanitizers on the viability and cellular injury to structures of Escherichia coli and Listeria innocua were investigated. A food grade organic acidic formulation (pH 2.5) and acidic, neutral, and basic electrolyzed water [AEW (pH 2.7, oxidation reduction potential; ORP: 1100 mV, free available chlorine; FAC: 150 ppm), NEW (pH 6.9, ORP: 840 mV, FAC: 150 ppm), BEW (pH 11.6, ORP: -810 mV)] were used to treat E. coli and L. innocua cells. After 10 min of exposure to the sanitizers, changes to the bacterial numbers and cell structures were evaluated by plate counting and transmission electron microscopy (TEM), respectively. It was concluded from the results that the sanitizers reduced the E. coli cells between 2 and 3 log CFU/mL. Except for the BEW treatment, reductions in L. innocua population were greater (>1 log CFU/mL) than that of E. coli for all treatments. Data from the TEM showed that all sanitizers caused changes to the cell envelope and cytoplasm of both organisms. However, smaller changes were observed for L. innocua cells. Decrease in the integrity of the cell envelope and aggregation of the cytoplasmic components appeared to be mainly because of exposure to the sanitizers. The organic acid formulation and AEW were the most effective sanitizers against bacterial cells, indicating that penetration of acidic substances effectively caused the cell inactivation. PRACTICAL APPLICATION: An understanding of the method in which E water and an acidic sanitizer cause injury to E. coli and L. innocua would be helpful in selecting an effective chemical agent as a food safety tool. This will allow a scientist to target similar microorganisms such as food borne bacteria with structures that are vulnerable to the sanitizer. PMID- 22515247 TI - Attachment of Escherichia coli O157:H7 to abiotic surfaces of cooking utensils. AB - We examined the attachment of enterohemorrhagic Escherichia coli O157:H7 to abiotic surfaces of cooking utensils. When the cell suspension in 0.85% NaCl (about 100 cells/mL, 10 mL) was contacted with various abiotic surfaces (square pieces, 25 cm2) at 25 degrees C for 20 min, the number of attached cells varied depending on the types of abiotic materials. The pathogen well attached to stainless steel (about 50 cells/25 cm2), pure titanium (35 to 45 cells/25 cm2), and glass (about 20 cells/25 cm2), but little attached to aluminum foil and plastics, irrespective of strains used. Fewer cells (below 10 cells/25 cm2) attached to stainless steel, pure titanium, and glass surfaces conditioned with aseptically sliced beef (sirloin) and autoclaved beef tallow at 25 degrees C for 20 min, but bovine serum albumin did not reduce the number of attached cells. The cells grown at 15 degrees C to the stationary phase (OD660 = about 2.8) less attached to the abiotic surfaces than those grown at 25 degrees C and 37 degrees C. When we pretreated the cells at 37 degrees C for 2 h with 50 MUM N hexanoyl-L-homoserine lactone (HHL), the number of cells attached to stainless steel was reduced by 70%. The number of cells attached to cooking utensils seemed to change depending on types of abiotic materials, adhesion of beef tallow to abiotic surfaces, growth temperature of the pathogen, and HHL-producing bacteria. PMID- 22515248 TI - Mathematical modeling of growth of non-O157 Shiga toxin-producing Escherichia coli in raw ground beef. AB - The objective of this study was to investigate the growth of Shiga toxin producing Escherichia coli (STEC, including serogroups O45, O103, O111, O121, and O145) in raw ground beef and to develop mathematical models to describe the bacterial growth under different temperature conditions. Three primary growth models were evaluated, including the Baranyi model, the Huang 2008 model, and a new growth model that is based on the communication of messenger signals during bacterial growth. A 5 strain cocktail of freshly prepared STEC was inoculated to raw ground beef samples and incubated at temperatures ranging from 10 to 35 degrees C at 5 degrees C increments. Minimum relative growth (<1 log10 cfu/g) was observed at 10 degrees C, whereas at other temperatures, all 3 phases of growth were observed. Analytical results showed that all 3 models were equally suitable for describing the bacterial growth under constant temperatures. The maximum cell density of STEC in raw ground beef increased exponentially with temperature, but reached a maximum of 8.53 log10 cfu/g of ground beef. The specific growth rates estimated by the 3 primary models were practically identical and can be evaluated by either the Ratkowsky square-root model or a Belehradek-type model. The temperature dependence of lag phase development for all 3 primary models was also developed. The results of this study can be used to estimate the growth of STEC in raw ground beef at temperatures between 10 and 35 degrees C. PRACTICAL APPLICATION: Incidents of foodborne infections caused by non O157 Shiga toxin-producing Escherichia coli (STEC) have increased in recent years. This study reports the growth kinetics and mathematical modeling of STEC in ground beef. The mathematical models can be used in risk assessment of STEC in ground beef. PMID- 22515249 TI - Development and application of reverse transcription loop-mediated isothermal amplification for detecting live Shewanella putrefaciens in preserved fish sample. AB - Given that live Shewanella putrefaciens is one of the major causes of spoilage for aquatic products even in chill storage, the rapid and accurate detection process is the first priority. In the present study, a novel reverse transcription loop-mediated isothermal amplification (RT-LAMP) detecting assay was developed by targeting internal transcribed spacer (ITS) sequence between 16S and 23S rRNA. At the same time, a new procaryotic mRNA isolation strategy was also established by introducing a polyA tail to RNA during cDNA synthesis step. Under the optimal reaction time (60 min) and temperature (64.1 degrees C), S. putrefaciens could be specially identified from a variety of other tested bacteria by RT-LAMP. The sensitivity analysis showed that RT-LAMP could be identified as lower as 5.4 copies per reaction, which is over 200-fold higher than that of standard PCR (1.08 * 103 copies per reaction). The method could be effectively identified S. putrefaciens in artificially contaminated or spoilaged fish samples with dose-dependent manners. To our knowledge, this is the first report using RT-LAMP assay to detect live S. putrefaciens in fish. PRACTICAL APPLICATION: The study provided a rapid and accurate detection method for live bacteria in aquatic food and established a new procaryotic mRNA isolation strategy at the same time, which will be useful for food preservation. PMID- 22515250 TI - Application of proanthocyanidins from peanut skins as a natural yeast inhibitory agent. AB - Proanthocyanidins were extracted from peanut skins and investigated for their antimicrobial activity against Saccharomyces cerevisiae, Zygosaccharomyces bailii, and Zygosaccharomyces bisporus in traditional growth media (Sabouraud Dextrose and Maltose broth) and a simulated apple juice beverage. Peanut skins extracts (PSE) were prepared through a multisolvent extraction procedure. The PSE extended the lag phase growth of the 3 yeasts studied at a concentration of 1 mg/mL and at 10 mg/mL yeast growth was totally inhibited for 120 h. PSE was fractionated by normal phase high performance liquid chromatography and the active components/fractions were determined. Compounds present in the fractions were identified by liquid chromatography-mass spectrometry to determine the compounds responsible for inhibition. Fractions consisting mostly of A-type proanthocyanidin dimers, trimers, and tetramers showed the highest percent inhibition toward the yeasts tested in this study. Both optical density (OD) and standard enumeration plating methods were performed in this study. The OD method led to an overestimation of the inhibitory effects of PSE, the 2 methods agreed in respect to treatment effects but not the severity of the inhibition. PRACTICAL APPLICATION: There is a growing consumer demand for "fresh like" products containing reduced amounts of chemical preservatives without compromising food safety and quality. Therefore, the goal of this study was to determine if an extract of peanut skins containing flavonoid rich compounds could function as a natural antimicrobial in a model beverage system. Proteins were removed through the process of producing the peanut skin extract, thus it is unlikely to contain peanut allergens. The antimicrobial compounds mentioned in this study were successfully integrated into a model beverage system, and were found to have antimicrobial effect. However, the incorporation of these compounds would likely lead to negative sensory attributes at the concentration needed to achieve an appreciable antimicrobial effect alone. PMID- 22515251 TI - Microbial composition of the Korean traditional food "kochujang" analyzed by a massive sequencing technique. AB - Kochujang is a traditional Korean fermented food that is made with red pepper, glutinous rice, salt, and soybean. Kochujang is fermented by naturally occurring microorganisms through which it obtains various health-promoting properties. In this study, the bacterial diversities of 9 local and 2 commercial brands of kochujang were analyzed with a barcoded pyrosequencing technique targeting the hyper-variable regions V1/V2 of the 16S rRNA gene. Through the analysis of 13524 bacterial pyrosequences, 223 bacterial species were identified, most of which converged on the phylum Firmicutes (average 93.1%). All of the kochujang samples were largely populated (>90.9% of abundance) by 12 bacterial families, and Bacillaceae showed the highest abundance in all but one sample. Bacillus subtilis and B. licheniformis were the most dominant bacterial species and were broadly distributed among the kochujang samples. Each sample contained a high abundance of region-specific bacterial species, such as B. sonorensis, B. pumilus, Weissella salipiscis, and diverse unidentified Bacillus species. Phylotype- and phylogeny-based community comparison analysis showed that the microbial communities of the two commercial brands were different from those of the local brands. Moreover, each local brand kochujang sample had region-specific microbial community reflecting the manufacturing environment. PMID- 22515252 TI - State of knowledge on amaranth grain: a comprehensive review. AB - Amaranth grain is a highly nutritional pseudocereal with a superior amount of proteins when compared to true cereals. It is a reasonably well-balanced food with functional properties that have been shown to provide medicinal benefits. The health benefits attributed include decreasing plasma cholesterol levels, stimulating the immune system, exerting an antitumor activity, reducing blood glucose levels and improving conditions of hypertension and anemia. In addition, it has been reported to possess anti-allergic and antioxidant activities. The present article provides a comprehensive overview of amaranth grain that focuses on recent research reporting its use in the clinical practice and its possible benefits to human health. PMID- 22515253 TI - Perceptual changes and drivers of liking in high protein extruded snacks. AB - Increasing the amount of protein in snack foods can add to their satiating ability, which aligns with many health-based trends currently seen in the food industry. Understanding the effect of adding high levels of protein in a food matrix is essential for product development. The objective for this research was to determine the effects of varying protein type and level on the sensory-related aspects of a model extruded snack food. Independent variables in the design of the snacks were the level of total protein and the protein type in the formulation. The level of protein ranged from 28% to 43% (w/w) in 5% increments. The protein type varied in the ratio of whey to soy protein ranging from 0: 100 to 100: 0, in 25% increments. Descriptive analysis was conducted on the samples to profile their sensory characteristics. Protein type was found to be the predominant variable in differentiating the sensory characteristics of the samples. Soy protein imparted nutty, grainy aromas-by-mouth, and increased expansion during processing, resulting in a lighter, crispier texture. Whey protein imparted dairy related aromas-by-mouth and inhibited expansion during processing, resulting in a more dense, crunchy texture. Separately, 100 consumers rated their acceptance of the samples using the 9-point hedonic scale. It was found that protein type was also the predominant variable in affecting acceptance, with some clusters of consumers preferring samples comprised of soy protein, and others preferring samples with whey. Food product developers can use these findings to predict changes in a similar food product by varying protein level or protein type. PRACTICAL APPLICATION: This work shows how the perceivable appearance, aroma, and texture characteristics of puffed snack foods change when adding protein or changing the protein type. The type of protein incorporated was shown to have major effects on the characteristics of the snacks, partially because of their impact on how much the snacks puffed during processing. The findings from this research can help develop acceptable products that incorporate high levels of protein to be aligned with current health trends in the market. PMID- 22515254 TI - Dry fermented sausages of Southern Italy: a comparison of free amino acids and biogenic amines between industrial and homemade products. AB - This paper compares some important parameters and the free amino acid and biogenic amine contents of cured industrial and homemade meat products. To this aim, industrial and homemade "soppressata" and "salsiccia", typical dry fermented sausages produced in Southern Italy, were analyzed. The homemade sausages showed a higher level of free biogenic amines than that manufactured industrially, most likely because biogenic amine formation in industrial products is limited by the use of starter cultures. The industrial sausages are characterized by a higher total free amino acid content than the homemade products. Overall, free amino acid and biogenic amine contents demonstrated that appreciable differences exist between homemade and industrial sausages. PMID- 22515256 TI - Alkaloids from areca (betel) nuts and their effects on human sperm motility in vitro. AB - An improved high-performance liquid chromatography (HPLC) method was established to rapidly and simultaneously determine 3 main alkaloids (arecoline, arecaidine, and guvacine) in areca (betel) nuts (AN), and 12 AN samples from the main betel palm growing areas on the Chinese Mainland were collected and determined. Semen samples from acceptable volunteers were treated in vitro with different concentrations of the 3 alkaloids to evaluate the effects on sperm motility (SM). Highly motile spermatozoa were selected from the samples and divided into 5 equal fractions. Various concentrations of each alkaloid were added to 4 of the 5 fractions, and 1 fraction was used as a control. All fractions were incubated for 4 h. A computer-aided sperm analysis system was used to measure 5 SM parameters, motility, average path velocity, straight-line velocity, curvilinear velocity, linearity, and amplitude of lateral head displacement. The results showed that the contents of the amount of alkaloids in AN differed markedly in different places in China and were higher in the kernel than in the husk, and higher in dried AN than in fresh AN. Arecoline had the strongest reduction effect on human SM and the effect was strongly dose dependent. Arecaidine had a much weaker reduction effect than arecoline, and guvacine had the least reduction effect. These findings also demonstrate that betel quid could have adverse effects on the gonadal functions of betel quid consumers. PMID- 22515255 TI - Establishment and optimization of monoclonal antibody-based heterologous dcELISA for 19-nortestosterone residue in bovine edible tissue. AB - This paper presents the generation of monoclonal antibodies (mAbs) with high specificity against 19-nortestosterone (NT) through cell fusion procedures, and the development of mAb-based heterologous direct competitive enzyme-linked immunoabsorbent assay (dcELISA) methods to detect NT residue using one of these hybridomas (clone 3B8-E6). Under optimal experimental conditions, this assay exhibited a working range of 0.004 to 19 ng/mL with IC50 and limit of detection values of 0.28 and 0.002 ng/mL, respectively, when it was run in 0.01M phosphate buffered saline (pH 7.4). Except for minor cross-reactivity with beta-boldenone (6.9%) and trenbolone (1.2%), other interference to the assay was negligible (<0.05%). No significant differences (P > 0.05) were found for IC50 values when the pH of the assay buffer ranged from 6 to 8 and phosphate ion concentration was less than 20 mM. The dcELISA can tolerate higher concentrations of methanol than other organic solvents tested. When applied to bovine sample, the correlation coefficients (R) of the dcELISA and GC-MS data were 0.9918 in muscle, 0.9834 in liver, and 0.9976 in kidney. Therefore, this assay has the potential to be incorporated into a quantitative monitoring program for the rapid screening of NT residue in food. PMID- 22515258 TI - It has been my pleasure! PMID- 22515257 TI - Distribution and spatial trends of PCBs in commercial scallops from Galician littoral (NW, Spain). Possible influence of biometric parameters. AB - Levels and profiles of 10 individual congeners of polychlorinated biphenyls (PCBs) were studied in 3 species of commercial scallops (Pecten maximus, Chlamys varia, and Chlamys opercularis) from several Rias in Galician littoral (NW, Spain). SigmaPCBs levels ranged from 2.21 to 41.0 ng/g wet weight for P. maximus, from 13.9 to 24.9 ng/g wet weight for C. varia, and from 1.58 to 24.3 ng/g wet weight for C. opercularis. The possible influence between biometric parameters (lipid content, condition index, and shell size) and PCBs levels were studied using statistical analysis (ANOVA). No relationship between biometric parameters could be established in the studied samples. Multivariate analysis showed there were differences in bioaccumulation of some PCBs congeners. Principal component analysis classifies clearly the 3 studied Rias (Ria de Ferrol, Ria de Arousa, and Ria de Vigo) taking into account PCBs levels found in the shellfish. PRACTICAL APPLICATIONS: We investigated levels and profiles of 10 congeners of PCBs in 3 commercial scallop species from the Galician littoral zone. The influence of 3 biometric parameters on polychlorinated biphenyls (PCBs) levels was also studied in order to assess results from the monitoring programs of production areas. According to PCBs levels, geographical differences were observed in commercial scallops from the 3 studied estuarine bays (Ria de Ferrol, Ria de Arousa, and Ria de Vigo). PMID- 22515259 TI - Honored and looking forward to the challenge. PMID- 22515260 TI - Prevention of relapse using DLI can increase survival following HLA-identical transplantation in patients with advanced-stage acute leukemia: a multi-center study. AB - A total of 123 consecutive patients with advanced-stage, acute leukemia undergoing HSCT from HLA-identical sibling donors were analyzed. A G-CSF-primed DLI was planned within day 60 post-transplantation before hematologic relapse was diagnosed. Fifty of the 123 individuals received prophylactic DLI, and 73 individuals received no prophylactic treatment. The incidence of grades II-IV acute graft-versus-host disease (GVHD) was 17% for patients receiving DLI and 23% for patients not receiving DLI (p = 0.35). The incidence of chronic GVHD was 38% for patients receiving DLI and 17% for patients not receiving DLI (p = 0.021). The two-yr cumulative incidence of relapse was significantly lower in patients who received prophylactic DLI (46%) compared with patients who did not receive prophylactic DLI (66%) (p = 0.02). The three-yr probability of overall survival was higher in patients who received prophylactic DLI (36%) than in patients who did not receive prophylactic DLI (11%) (p = 0.001). The leukemia-free survival was also higher in patients who received prophylactic DLI (29%) than in patients who did not receive prophylactic DLI (9%) (p = 0.001). Our comparisons suggest that the prophylactic use of DLI can significantly increase survival of patients with advanced-stage, acute leukemia who receive HLA-identical sibling HSCT. PMID- 22515261 TI - Fibrillation mechanism of a model intrinsically disordered protein revealed by 2D correlation deep UV resonance Raman spectroscopy. AB - Understanding of numerous biological functions of intrinsically disordered proteins (IDPs) is of significant interest to modern life science research. A large variety of serious debilitating diseases are associated with the malfunction of IDPs including neurodegenerative disorders and systemic amyloidosis. Here we report on the molecular mechanism of amyloid fibrillation of a model IDP (YE8) using 2D correlation deep UV resonance Raman spectroscopy. YE8 is a genetically engineered polypeptide, which is completely unordered at neutral pH yet exhibits all properties of a fibrillogenic protein at low pH. The very first step of the fibrillation process involves structural rearrangements of YE8 at the global structure level without the detectable appearance of secondary structural elements. The formation of beta-sheet species follows the global structural changes and proceeds via the simultaneous formation of turns and beta strands. The kinetic mechanism revealed is an important new contribution to understanding of the general fibrillation mechanism proposed for IDP. PMID- 22515262 TI - Buccal spray insulin (Oralgen) for type 2 diabetes: what evidence? AB - INTRODUCTION: The achievement of a good glycemic control and, in particular, the management of postprandial hyperglycemia represent the most significant treatment target for the management of diabetes. Multiple daily insulin injections are often still required to gain the treatment goals. Since the noncompliance with injected insulin therapy causes a slowdown in the process of glycemic compensation, novel non-injectable insulin formulations have been developed. Oral spray insulin (Oralgen) is a tasteless liquid formulation that provides insulin absorption via buccal mucosa. AREAS COVERED: To elucidate the current status of Oralgen in type 2 diabetes patients, studies of pharmacodynamic and pharmacokinetic and clinical trials are reviewed. EXPERT OPINION: The 'psychological insulin resistance,' represented by the reluctance of both patients and health-care professionals to initiate insulin therapy, could be won by alternative routes of insulin administration, improving patients' compliance. In particular, Oralgen seems to be suitable to manage the postprandial hyperglycemia without hypoglycemic risk, although no comparative studies with rapid-acting insulin analogs and no randomized controlled trials in large cohort subjects with type 2 diabetes are available to date. PMID- 22515263 TI - Mechanisms for the reaction of thiophene and methylthiophene with singlet and triplet molecular oxygen. AB - Mechanisms for the reaction of thiophene and 2-methylthiophene with molecular oxygen on both the triplet and singlet potential energy surfaces (PESs) have been investigated using ab initio methods. Geometries of various stationary points involved in the complex reaction routes are optimized at the MP2/6-311++G(d, p) level. The barriers and energies of reaction for all product channels were refined using single-point calculations at the G4MP2 level of theory. For thiophene, CCSD(T) single point energies were also determined for comparison with the G4MP2 energies. Thiophene and 2-methylthiophene were shown to react with O(2) via two types of mechanisms, namely, direct hydrogen abstraction and addition/elimination. The barriers for reaction with triplet oxygen are all significantly large (i.e., >30 kcal mol(-1)), indicating that the direct oxidation of thiophene by ground state oxygen might be important only in high temperature processes. Reaction of thiophene with singlet oxygen via a 2 + 4 cycloaddition leading to endoperoxides is the most favorable channel. Moreover, it was found that alkylation of the thiophene ring (i.e., methyl-substituted thiophene) is capable of lowering the barrier height for the addition pathway. The implication of the current theoretical results may shed new light on the initiation mechanisms for combustion of asphaltenes. PMID- 22515266 TI - Genetic testing registry launched. PMID- 22515264 TI - A highly efficient beta-glucosidase from the buffalo rumen fungus Neocallimastix patriciarum W5. AB - BACKGROUND: Cellulose, which is the most abundant renewable biomass on earth, is a potential bio-resource of alternative energy. The hydrolysis of plant polysaccharides is catalyzed by microbial cellulases, including endo-beta-1,4 glucanases, cellobiohydrolases, cellodextrinases, and beta-glucosidases. Converting cellobiose by beta-glucosidases is the key factor for reducing cellobiose inhibition and enhancing the efficiency of cellulolytic enzymes for cellulosic ethanol production. RESULTS: In this study, a cDNA encoding beta glucosidase was isolated from the buffalo rumen fungus Neocallimastix patriciarum W5 and is named NpaBGS. It has a length of 2,331 bp with an open reading frame coding for a protein of 776 amino acid residues, corresponding to a theoretical molecular mass of 85.1 kDa and isoelectric point of 4.4. Two GH3 catalytic domains were found at the N and C terminals of NpaBGS by sequence analysis. The cDNA was expressed in Pichia pastoris and after protein purification, the enzyme displayed a specific activity of 34.5 U/mg against cellobiose as the substrate. Enzymatic assays showed that NpaBGS was active on short cello-oligosaccharides from various substrates. A weak activity in carboxymethyl cellulose (CMC) digestion indicated that the enzyme might also have the function of an endoglucanase. The optimal activity was detected at 40 degrees C and pH 5 ~ 6, showing that the enzyme prefers a weak acid condition. Moreover, its activity could be enhanced at 50 degrees C by adding Mg2+ or Mn2+ ions. Interestingly, in simultaneous saccharification and fermentation (SSF) experiments using Saccharomyces cerevisiae BY4741 or Kluyveromyces marxianus KY3 as the fermentation yeast, NpaBGS showed advantages in cell growth, glucose production, and ethanol production over the commercial enzyme Novo 188. Moreover, we showed that the KY3 strain engineered with the NpaNGS gene can utilize 2 % dry napiergrass as the sole carbon source to produce 3.32 mg/ml ethanol when Celluclast 1.5 L was added to the SSF system. CONCLUSION: Our characterizations of the novel beta-glucosidase NpaBGS revealed that it has a preference of weak acidity for optimal yeast fermentation and an optimal temperature of ~40 degrees C. Since NpaBGS performs better than Novo 188 under the living conditions of fermentation yeasts, it has the potential to be a suitable enzyme for SSF. PMID- 22515267 TI - A survey of public health and consumer health informatics programmes and courses in Canadian universities and colleges. AB - INTRODUCTION: As information technology becomes more widely used by people for health-care decisions, training in consumer and public health informatics will be important for health practitioners working directly with the public. METHODS: Using information from 74 universities and colleges across Canada, we searched websites and online calendars for programmes (undergraduate, graduate) regarding availability and scope of education in programmes, courses and topics geared to public health and/or consumer health informatics. RESULTS: Of the 74 institutions searched, 31 provided some content relevant to health informatics (HI) and 8 institutions offered full HI-related programmes. Of these 8 HI programmes, only 1 course was identified with content relevant to public health informatics and 1 with content about consumer health informatics. Some institutions (n = 22) - which do not offer HI-degree programmes - provide health informatics-related courses, including one on consumer health informatics. We found few programmes, courses or topic areas within courses in Canadian universities and colleges that focus on consumer or public health informatics education. DISCUSSION: Given the increasing emphasis on personal responsibility for health and health-care decision-making, skills training for health professionals who help consumers navigate the Internet should be considered in health informatics education. PMID- 22515268 TI - Development of the Tobacco Tactics logo: From thumb prints to press. AB - BACKGROUND: The purpose of this study was to describe the development and evaluation of the image-based Veterans Affairs (VA) Tobacco Tactics program logo and campaign character using principles of social marketing. METHODS: Four cross sectional surveys with open- and closed-ended questions were used to gather participant demographic information, smoking behavior, and feedback on the development and evaluation of the Tobacco Tactics program logo and campaign character. The first 3 surveys were conducted with 229 veterans, visitors, and staff to obtain feedback for the final logo and character choice. The fourth survey was conducted with 47 inpatient veteran smokers to evaluate the Tobacco Tactics manual which was illustrated with the logo and campaign character. Descriptive statistics and bivariate analyses comparing demographic characteristics and tobacco use variables to opinions about the pictures for each round of testing were computed. RESULTS: After three rounds of testing to modify the logo and character choices based on participant feedback and survey data, the bulldog logo was chosen to represent the VA Tobacco Tactics program as it was viewed as strong and tough by the majority of participants. About 80% of the participants rated the manual highly on items such as logo, color, and pictures/illustrations. Almost 90% said they would recommend the manual to someone trying to quit smoking. CONCLUSION: Social marketing techniques that include consumer feedback to develop appealing tobacco cessation campaigns can increase consumer engagement and enhance the development of compelling tobacco cessation campaigns to compete with the influential marketing of tobacco companies. PMID- 22515269 TI - Interaction proteomics suggests a new role for the Tfs1 protein in yeast. AB - The PEBP (phosphatidylethanolamine-binding protein) family is a large group of proteins whose human member, hPEBP1, has been shown to play multiple functions, influencing intracellular signaling cascades, cell cycle regulation, neurodegenerative processes, and reproduction. It also acts, by an unknown mechanism, as a metastasis suppressor in a number of cancers. A more complete understanding of its biological role is thus necessary. As the yeast Saccharomyces cerevisiae is a powerful and easy to handle model organism, we focused on Tfs1p, the yeast ortholog of hPEBP1. In a previous study based on a two-hybrid approach, we showed that Tfs1p interacts and inhibits Ira2p, a GTPase Activating Protein (GAP) of the small GTPase Ras. To further characterize the molecular functions of Tfs1p, we undertook the identification of protein complexes formed around Tfs1p using a targeted proteomics approach. Complexed proteins were purified by tandem-affinity, cleaved with trypsin, and identified by nanoflow liquid chromatography coupled with tandem mass spectrometry. Overall, 14 new interactors were identified, including several proteins involved in intermediate metabolism. We confirmed by co-immunoprecipitation that Tfs1p interacts with Glo3p, a GAP for Arf GTPases belonging to the Ras superfamily of small GTPases, indicating that Tfs1p may be involved in the regulation of another GAP. We similarly confirmed the binding of Tfs1p with the metabolic enzymes Idp1p and Pro1p. Integration of these results with known functional partners of Tfs1p shows that two subnetworks meet through the Tfs1p node, suggesting that it may act as a bridge between cell signaling and intermediate metabolism in yeast. PMID- 22515270 TI - Controlled synthesis of ZnS quantum dots and ZnS quantum flakes with graphene as a template. AB - Novel ZnS quantum dots (QDs) and ZnS quantum flakes (QFs) were successfully prepared with graphene nanosheets (GNs) as a special template, and two unique heterostructures of ZnS/GNs were also obtained. Due to the structure-directing template effect of GNs, the as-synthesized ZnS with different morphologies, dots or flakes, were uniformly distributed on the surface of GNs by controlling nucleation and growth. The two different heterostructures of ZnS/GNs exhibited obvious photovoltaic response, and ZnS/GN QFs-on-sheet heterostructures show higher photovoltage than that of ZnS/GN QDs-on-sheet. PMID- 22515271 TI - Neuronal caspase 2 activity and function requires RAIDD, but not PIDD. AB - Caspase 2 was initially identified as a neuronally expressed developmentally down regulated gene (HUGO gene nomenclature CASP2) and has been shown to be required for neuronal death induced by several stimuli, including NGF (nerve growth factor) deprivation and Abeta (beta-amyloid). In non-neuronal cells the PIDDosome, composed of caspase 2 and two death adaptor proteins, PIDD (p53 inducible protein with a death domain) and RAIDD {RIP (receptor-interacting protein)-associated ICH-1 [ICE (interleukin-1beta-converting enzyme)/CED-3 (cell death determining 3) homologue 1] protein with a death domain}, has been proposed as the caspase 2 activation complex, although the absolute requirement for the PIDDosome is not clear. To investigate the requirement for the PIDDosome in caspase-2-dependent neuronal death, we have examined the necessity for each component in induction of active caspase 2 and in execution of caspase-2 dependent neuronal death. We find that both NGF deprivation and Abeta treatment of neurons induce active caspase 2 and that induction of this activity depends on expression of RAIDD, but is independent of PIDD expression. We show that treatment of wild-type or PIDD-null neurons with Abeta or NGF deprivation induces formation of a complex of caspase 2 and RAIDD. We also show that caspase-2 dependent execution of neurons requires RAIDD, not PIDD. Caspase 2 activity can be induced in neurons from PIDD-null mice, and NGF deprivation or Abeta use caspase 2 and RAIDD to execute death of these neurons. PMID- 22515272 TI - Electrosensitive polyacrylic acid/fibrin hydrogel facilitates cell seeding and alignment. AB - Three-dimensional cell culture and conditioning is an effective means to guide cell distribution and patterning for tissue engineered constructs such as vascular grafts. Polyacrylic acid is known as an electroresponsive polymer, capable of transforming environmental stimuli like electrical energy to mechanical forces. In this study, we developed an electrosensitive and biocompatible hydrogel-based smart device composed of acrylic acid and fibrin as a tissue engineered construct to mechanically stimulate cells. Structural properties of the hydrogel were assessed by FTIR-ATR, scanning electron microscopy, prosimetry, and swelling measurement. Distribution and alignment of porcine smooth muscle cells (pSMCs) seeded on the surface of lyophilized hydrogels were evaluated and quantified by two-photon laser scanning microscopy. Smooth muscle cell tissue constructs exposed to 2 h of pulsatile electrical stimulation showed significantly enhanced cell penetration and alignment due to dynamic changes produced by alternative swelling and deswelling, in comparison with static samples. On the basis of the results, this hydrogel under electrical stimulation works as a mechanical pump, which can direct SMC alignment and facilitate infiltration and distribution of cells throughout the structure. PMID- 22515273 TI - Identifying priorities to improve maternal and child nutrition among the Khmu ethnic group, Laos: a formative study. AB - Chronic malnutrition in children remains highly prevalent in Laos, particularly among ethnic minority groups. There is limited knowledge of specific nutrition practices among these groups. We explored nutritional status, cultural beliefs and practices of Laos' Khmu ethnic group to inform interventions for undernutrition as part of a Primary Health Care (PHC) project. Mixed methods were used. For background, we disaggregated anthropometric and behavioural indicators from Laos' Multiple Indicator Cluster Survey. We then conducted eight focus group discussions and 33 semi-structured interviews with Khmu villagers and health care workers, exploring beliefs and practices related to nutrition. The setting was two rural districts in Luang Prabang province, in one of which the PHC project had been established for 3 years. There was a higher prevalence of stunting in the Khmu than in other groups. Disaggregation showed nutrition behaviours were associated with ethnicity, including exclusive breastfeeding. Villagers described strong adherence to post-partum food restrictions for women, while little change was described in intake during pregnancy. Most children were breastfed, although early introduction of pre-lacteal foods was noted in the non-PHC district. There was widespread variation in introduction and diversity of complementary foods. Guidance came predominantly from the community, with some input from health care workers. Interventions to address undernutrition in Khmu communities should deliver clear, consistent messages on optimum nutrition behaviours. Emphasis should be placed on dietary diversity for pregnant and post-partum mothers, encouraging exclusive breastfeeding and timely, appropriate complementary feeding. The impact of wider governmental policies on food security needs to be further assessed. PMID- 22515274 TI - Association of u-opioid receptor (OPRM1) gene polymorphism with response to naltrexone in alcohol dependence: a systematic review and meta-analysis. AB - Previous studies have suggested that the effect of naltrexone in patients with alcohol dependence may be moderated by genetic factors. In particular, the possession of the G allele of the A118G polymorphism of the u-opioid receptor gene (OPRM1) has been associated with a better response to naltrexone, although controversial results have been reported. The aim of this paper is to combine previous findings by means of a systematic review and a meta-analysis. We retrieved studies on the relationship between A118G polymorphism in OPRM1 gene and response to treatment with naltrexone in patients with alcohol dependence by means of electronic database search. A meta-analysis was conducted using a random effects model. Calculations of odds ratio (OR) and their confidence intervals (CI) and tests for heterogeneity of the results have been performed. Six previous studies have analyzed the role of A118G polymorphism in response to naltrexone for alcohol dependence. After meta-analysis, we found that naltrexone-treated patients carrying the G allele had lower relapse rates than those who were homozygous for the A allele (OR: 2.02, 95% CI 1.26-3.22; P = 0.003). There were no differences in abstinence rates. Our results support the fact that the G allele of A118G polymorphism of OPRM1 moderates the effect of naltrexone in patients with alcohol dependence. This genetic marker may therefore identify a subgroup of individuals more likely to respond to this treatment. PMID- 22515277 TI - Photooxidations of 2-(gamma,epsilon-dihydroxyalkyl) furans in water: synthesis of DE-bicycles of the pectenotoxins. AB - Photooxygenations of 2-(gamma,epsilon-dihydroxyalkyl) furans in H(2)O followed by in situ reduction and ketalization affords, in one synthetic operation, DE bicyclic ketals of the pectenotoxins. PMID- 22515278 TI - Titanium(IV) complexes of disulfide-linked Schiff bases. AB - With the goal of preparing Ti(IV) complexes bearing a sulfur-based redox function of possible use in electrocatalytic oxidations of alcohols at electrode surfaces, a series of seven 2,2'-dithiodianiline Schiff-base derivatives, including two new variations, were tested in reactions with Ti(OR)(4) (R = (i)Pr, (t)Bu). Instead of the expected dimetallic products of general formula [LTi(OR)(2)](2), mononuclear species LTi(OR)(2) were obtained, confirmed by crystallographic determinations to have an unprecedented, symmetrical, and macrocyclic arrangement with four-point binding to the metal center and with the disulfide moieties remaining uncoordinated. Cyclic voltammetry performed in CH(2)Cl(2) displayed oxidations at potentials useful for fuel cells (+1.1-1.5 V vs Ag/AgCl), but despite the uncoordinated disulfide moieties, the complexes were reticent to engage in reduction processes. PMID- 22515275 TI - The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety. AB - The role of kappa-opioid receptors (KOR) in the regulation of alcohol-related behaviors is not completely understood. For example, alcohol consumption has been reported to increase following treatment with KOR antagonists in rats, but was decreased in mice with genetic deletion of KOR. Recent studies have further suggested that KOR antagonists may selectively decrease alcohol self administration in rats following a history of dependence. We assessed the effects of the KOR antagonist JDTic on alcohol self-administration, reinstatement of alcohol seeking induced by alcohol-associated cues or stress, and acute alcohol withdrawal-induced anxiety ('hangover anxiety'). JDTic dose-dependently reversed hangover anxiety when given 48 hours prior to testing, a time interval corresponding to the previously demonstrated anxiolytic efficacy of this drug. In contrast, JDTic decreased alcohol self-administration and cue-induced reinstatement of alcohol seeking when administered 2 hours prior to testing, but not at longer pre-treatment times. For comparison, we determined that the prototypical KOR antagonist nor-binaltorphimine can suppress self-administration of alcohol at 2 hours pre-treatment time, mimicking our observations with JDTic. The effects of JDTic were behaviorally specific, as it had no effect on stress induced reinstatement of alcohol seeking, self-administration of sucrose, or locomotor activity. Further, we demonstrate that at a 2 hours pre-treatment time JDTic antagonized the antinociceptive effects of the KOR agonist U50,488H but had no effect on morphine-induced behaviors. Our results provide additional evidence for the involvement of KOR in regulation of alcohol-related behaviors and provide support for KOR antagonists, including JDTic, to be evaluated as medications for alcoholism. PMID- 22515279 TI - Linking selenium biogeochemistry to the sulfur-dependent biological detoxification of arsenic. AB - Geochemistry often reveals unexpected (anti)correlations. Arsenic (As) and selenium (Se) are cases in point. We explore the hypothesis that bacteria living in an As-replete environment recruited a biological process involving Se and sulfur to fulfil their need for As detoxification. In analogy with the formation of arsenolipids and arsenosugars, which are common non-toxic As metabolites derived from microbial and plant metabolism, we attempt to explain the prevalence of novel sulfur-containing As derivatives, in particular monothioarsenate, in the aqueous environment. Thiolated-As species have been overlooked so far mainly because of the difficulty of their identification. Based on comparative genomics, we propose a scenario where SelD and SelU proteins, commonly used to make selenophosphate and modify transfer RNA, have been recruited to make monothioarsenate, a relatively innocuous arsenical. This hypothesis is discussed in terms of the relative geochemical distribution of Se and As. PMID- 22515280 TI - High-temperature rate constant determination for the reaction of OH with iso butanol. AB - This work presents the first direct experimental study of the rate constant for the reaction of OH with iso-butanol (2-methyl-1-propanol) at temperatures from 907 to 1147 K at near-atmospheric pressures. OH time-histories were measured behind reflected shock waves using a narrow-linewidth laser absorption method during reactions of dilute mixtures of tert-butylhydroperoxide (as a fast source of OH) with iso-butanol in excess. The title reaction's overall rate constant (OH + iso-butanol ->(k(overall)) all products) minus the rate constant for the beta radical-producing channel (OH + iso-butanol ->(k(beta)) 1-hydroxy-2-methyl-prop-2 yl radical + H(2)O) was determined from the pseudo-first-order rate of OH decay. A two-parameter Arrhenius fit of the experimentally determined rate constant in the current temperature range yields the expression (k(overall) - k(beta)) = 1.84 * 10(-10) exp(-2350/T[K]) cm(3) molecule(-1) s(-1). A recommendation for the overall rate constant, including k(beta), is made, and comparisons of the results to rate constant recommendations from the literature are discussed. PMID- 22515281 TI - Characterization of C-strain "Riems" TAV-epitope escape variants obtained through selective antibody pressure in cell culture. AB - Classical swine fever virus (CSFV) C-strain "Riems" escape variants generated under selective antibody pressure with monoclonal antibodies and a peptide specific antiserum in cell culture were investigated. Candidates with up to three amino acid exchanges in the immunodominant and highly conserved linear TAV epitope of the E2-glycoprotein, and additional mutations in the envelope proteins ERNS and E1, were characterized both in vitro and in vivo.It was further demonstrated, that intramuscular immunization of weaner pigs with variants selected after a series of passages elicited full protection against lethal CSFV challenge infection. These novel CSFV C-strain variants with exchanges in the TAV epitope present potential marker vaccine candidates. The DIVA (differentiating infected from vaccinated animals) principle was tested for those variants using commercially available E2 antibody detection ELISA. Moreover, direct virus differentiation is possible using a real-time RT-PCR system specific for the new C-strain virus escape variants or using differential immunofluorescence staining. PMID- 22515282 TI - Does restriction of mandibular movements during sleep influence jaw-muscle activity? AB - To investigate the effect of restriction of mandibular movements during sleep on jaw-muscle electromyographic (EMG) activity. Eleven healthy subjects (four men and seven women; age, 25.9 +/- 3.1 years) with self-reports of sleep bruxism participated in three randomised sessions with three different types of oral appliances: (i) full-arch maxillary and mandibular appliances which did not allow any mandibular movement, that is, restrictive oral appliance (restrict-MMOA), (ii) full-arch maxillary and mandibular oral appliances (free-MMOA) with no restrictions of mandibular movements and (iii) conventional full-arch flat stabilisation appliance, that is, maxillary oral appliance (free-MOA). Baseline recordings (1st EMG recording) of jaw-muscle activity during sleep without any oral appliance were performed and followed by 1 week of nightly use of each oral appliance (three sessions). During the last night in each session, jaw-muscle activity was recorded (2nd, 3rd and 4th EMG recordings) and compared to baseline values. All EMG data were analysed in accordance with the gold-standard diagnostic method. The average jaw-muscle activity expressed as number of EMG episodes and bursts per hour sleep was significantly reduced during any combination of appliance compared to baseline values. The inhibitory effect of the appliances was specific to the number of phasic EMG episodes and bursts (P < 0.01), with no effects on tonic EMG bursts or episodes (P > 0.30). The results indicated that restriction of mandibular movements with oral appliances do not have any major influence on jaw-muscle activity during sleep but rather that the immediate effect of any combination of oral appliances lead to a suppression of phasic EMG bursts and episodes. PMID- 22515284 TI - Commentary on: Dudley MH, Fleming SW, Garg U, Edwards JM. Fatality involving complications of bupivacaine toxicity and hypersensitivity reaction. J Forensic Sci 2011;56(5):1376-9. PMID- 22515285 TI - Commentary on: Dudley MH, Fleming SW, Garg U, Edwards JM. Fatality involving complications of bupivacaine toxicity and hypersensitivity reaction. J Forensic Sci 2011;56(5):1376-9. PMID- 22515287 TI - Commentary on: Nuzzolese E, Borrini M. Forensic approach to an archaeological casework of "vampire" skeletal remains in Venice: odontological and anthropological prospectus. J Forensic Sci 2010; 55(6):1634-37. PMID- 22515289 TI - Nuclear expression of S-phase kinase-associated protein 2 predicts poor prognosis of hepatocellular carcinoma. AB - The S-phase kinase-associated protein 2 (Skp2), which ubiquitinates the cell cycle inhibitor p27(Kip1) and targets it for degradation, is commonly overexpressed in human cancers and is associated with poor prognosis in several cancers. The aim of this study was to investigate Skp2 expression and its clinicopathologic significance in surgically resected hepatocellular carcinomas. We collected 359 hepatocellular carcinoma samples and evaluated Skp2 protein expression in cytoplasmic and nuclear fractions by immunohistochemistry using a tissue microarray method. Among the 359 patients, nuclear expression of Skp2 was observed in 41 (10.38%), and cytoplasmic expression of Skp2 was observed in 195 (49.37%). Of the several clinicopathologic variables examined, high Edmonson Steiner grade and early recurrence correlated with nuclear expression of Skp2 (p = 0.000 and 0.022, respectively). Cytoplasmic expression of Skp2 correlated negatively with microvascular and macrovascular invasion, tumor size, histologic grade, and overall survival. Multivariate analysis revealed that nuclear expression of Skp2 correlated with short disease-free survival. Our findings suggest that nuclear expression of Skp2 may be used as an independent predictor of poor prognosis for hepatocellular carcinoma, whereas cytoplasmic expression of Skp2 may indicate less aggressive disease. PMID- 22515290 TI - Expression and mutational status of RON in neoplastic lesions of the breast: analysis of MSP/RON signaling in ductal carcinoma in situ and invasive ductal carcinoma. AB - Recepteur d'origine nantais (RON) is a receptor tyrosine kinase closely related to MET and involved in tumorigenesis. We investigated the roles of aberrations in RON and its ligand, macrophage-stimulating protein (MSP), in invasive ductal carcinoma (IDC, n = 81), ductal carcinoma in situ (DCIS, n = 26), and in benign lesions (n = 20) of mammary gland. Expression of RON and MSP was evaluated by immunohistochemistry and the mutational status of a region containing the proteolytic cleavage site in exon 1 and each exon of the kinase domain (exon 14 20) of RON was screened by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis. The proportion of cases positive for RON expression was significantly different between malignant [86% (92/107)] and benign [40% (8/20)] lesions. RON expression was positive in both IDC and DCIS [90% (73/81) and 73% (19/26), respectively], whereas MSP expression was present in 54% (44/81) of IDC and absent in DCIS. RON expression correlated significantly with the histological grade of DCIS. No mutations were detected in the examined regions of RON in breast cancer samples as confirmed by PCR-SSCP. The findings suggest the involvement of RON expression in the development of breast cancer, and that an autocrine/paracrine loop of RON seems to affect tumor invasiveness. PMID- 22515291 TI - Combined immunohistochemistry for thyroid peroxidase, galectin-3, CK19 and HBME-1 in differential diagnosis of thyroid tumors. AB - We evaluated some proposed molecular thyroid tumor markers: thyroid peroxidase (TPO), galectin-3, cytokeratin-19, and HBME-1, individually and in combination, by immunohistochemistry in a total of 242 archival thyroid tissue sections. The expression of each individual marker was most helpful for the diagnosis of papillary carcinoma and its follicular variant. However, none of them was sensitive and specific enough to discriminate between Hurthle adenoma and carcinoma. Galectin-3 and HBME-1 could be used as single discriminators between follicular thyroid adenoma and carcinoma, but HBME-1 is the better choice. As a single test, all analyzed tumor markers had sufficient power to predict differentiated thyroid cancer, with sensitivities ranging from 66.5% to 82.2%. The sensitivity was improved by using combinations of some proposed markers. Only two antigens, HBME-1 and TPO, had distinct predictive values for different diagnostic alternatives i.e. a sequential combination improved diagnostic accuracy between follicular thyroid adenoma and the follicular variant of papillary thyroid carcinoma to 92.6% and consequently, between overall benign and malignant thyroid tumors to 89.1%. HBME-1 is the most accurate ancillary stain in discriminating well-differentiated thyroid carcinomas from benign tumors, although the addition of TPO did improve accuracy and served as a useful confirmatory marker. PMID- 22515292 TI - BRAF V600E mutation does not predict recurrence after long-term follow-up in TNM stage I or II papillary thyroid carcinoma patients. AB - The BRAF V600E mutation may serve as a marker of disease recurrence in well differentiated papillary thyroid cancer (PTC). Our aim was to study if TNM stage I or II PTC patients, with and without recurrence after long-term follow-up would differ in BRAF status. BRAF status was retrospectively determined in tumour tissue from a cohort of low-risk PTC patients (n = 461) with and without recurrence after 16 years of follow-up. Initial treatment was total thyroidectomy (TTE) and radioiodine remnant ablation (RRA). Forty-six patients (9.9%) experienced disease recurrence. BRAF mutation was positive in 66% (17/26) of patients with and 68% (17/25) without recurrence (p = NS). Fifty per cent of BRAF positive and 53% of BRAF negative patients experienced disease recurrence (p = NS). Time to recurrence was 52 (range 18-144) and 36 (range 16-71) months, respectively (p = NS). Primary tumour size, nodal metastasis and local infiltration at presentation did not differ between BRAF positive and negative patients (2.0 vs 2.2 cm, 21% vs 35% and 6% vs 12%, respectively, all p = NS). Taken together, BRAF V600E is common in Finnish patients with low-risk PTC but does not predict recurrence after long-term follow-up after initial treatment with TTE and RRA. PMID- 22515293 TI - FoxP3 mRNA splice forms in synovial CD4+ T cells in rheumatoid arthritis and psoriatic arthritis. AB - Our aim was to elucidate the relative amount of the different splice forms of FoxP3 mRNA in CD4+ T cells in peripheral blood (PB) compared to synovial fluid (SF) in RA and PsA patients. FoxP3 mRNA was measured using a quantitative real time PCR method. CD4+ T cells were isolated from 17 paired samples of PB and SF from RA and PsA patients, and PB from 10 controls. FoxP3fl and FoxP3Delta2 mRNA was significantly increased (6.7 and 2.1-fold, respectively) in PB CD4+ T cells from RA patients compared to controls. FoxP3fl and Delta2 mRNA in SF CD4+ T cells was increased compared to controls in sero-negative RA and PsA, but not in sero positive RA patients, who had a high FoxP3 expression in both PB and SF. The FoxP3Delta2Delta7 mRNA was barely detectable in patient samples, and not at all in healthy individuals. We provide evidence of an increased expression of FoxP3 splice forms in synovial CD4+ T cells from RA patients. A skewed, high expression profile of FoxP3, but not CTLA-4, in sero-negative RA and PsA, indicates that synovial CD4+ T cells may represent unique subsets of T cells which have been induced locally or selectively recruited to the joint. PMID- 22515294 TI - Polyomavirus-induced pilomatricomas in mice: from viral inoculation to tumour development. AB - Polyomavirus has been used extensively to study tumour induction in mice. Although most neoplasms are well characterized, those arising from hair follicles have been referred to by different names during the last four decades. The purpose of this research was to contribute to a more accurate histological characterization of these tumours as well as to study the viral progression from the onset of infection to the development of neoplasms. Polyomavirus A2 was inoculated into newborn C3H/BiDa mice, and at different time-points (from 5 to 70 days post-inoculation) the mice were sacrificed and studied using histological, immunocytochemical, ultrastructural and virological methods. The fully developed hair follicle tumours consisted of a proliferation of matrix cells that evolved into 'shadow' cells with empty nuclei and finally into amorphous keratin; the tumours were therefore diagnosed as pilomatricomas. Viral VP-1 was observed only in fully differentiated cells and not in proliferating-cell-nuclear-antigen (PCNA)-positive cells in the same tumour. In conclusion, Polyomavirus first replicated in the skin, and then disseminated through the blood and reached the outer sheath of the hair follicles and finally infected matrix cells, leading to the development of pilomatricomas from which infectious virus was isolated. PMID- 22515295 TI - The GenoType(r) MTBDRplus assay for detection of drug resistance in Mycobacterium tuberculosis in Sweden. AB - The performance of the GenoType((r)) MTBDRplus assay was compared with conventional drug susceptibility testing (DST) in 604 patients with tuberculosis. The study comprised 477 Mycobacterium tuberculosis complex isolates and 127 preparations of DNA from clinical specimens which had been tested positive for M. tuberculosis by COBAS((r))TaqMan((r)) 48. By DST, isoniazid (INH) monoresistance was diagnosed in 56 (9.3%), rifampicin (RMP) monoresistance in 2 (0.3%) and multidrug resistance (MDR) in 21 (3.5%) of the cases. The sensitivity of the MTBDRplus assay was 87.5%, 100% and 95.2% for INH resistance, RMP resistance and MDR respectively. The specificity was 100% for all resistance patterns. The dominating mutations in RMP and INH resistant isolates were in codon 531 of the rpoB gene and codon 315 of the KatG gene. The turnaround time for detection of drug resistance can be shortened from a median of 21 days for DST to 7 days for the MTBDRplus assay. This may have a significant impact on routine work flow of a mycobacteriology laboratory. PMID- 22515296 TI - Biofilm formation by bacteria isolated from upper respiratory tract before and after adenotonsillectomy. AB - Failure of antibiotics to eradicate the microbial pathogens primarily responsible for otorhinolaryngological diseases has led to the hypothesis that these microorganisms may be structured in a biolfilm. Aim of the study was to evaluate the ability to produce biofilm among bacteria isolated from tonsils and/or adenoids and nasopharynx. Biopsies and swabs were collected during surgery and after 3 and 6 months in 32 children undergoing adenoidectomy and/or tonsillectomy. Production of biofilm by Staphylococcus aureus, Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae was evaluated in vitro by means of spectrophotometry after growth in microplates and staining with crystalviolet. Of the isolates from intraoperative samples, 44.7% were either moderate or strong biofilm producers compared with 27% of isolates at 6 months after surgery. A decrease in biofilm production was observed for H. influenzae and S. aureus. In conclusion, the rate of isolation and ability to form biofilm decreased in bacteria isolated subsequent to adenoidectomy and/or tonsillectomy. This suggests a role for biofilm in pathogenesis of recurrent and chronic pharyngeal diseases and rhinopharingitis. PMID- 22515297 TI - The cell envelope-associated protein, LytR, regulates the cysteine protease SpeB in Streptococcus pyogenes. AB - The LytR family of cell envelope-associated transcriptional attenuators in bacteria has been brought into focus of scientific interest on the expression of various virulence factors, as well as bacterial cell envelope maintenance. However, this protein of Streptococcus pyogenes has been only described as cell surface-associated protein, and its function is completely unknown. We created lytR mutant strains from two independent S. pyogenes strains to analyze the function of LytR. The protease assay in culture supernatant showed that lytR mutant had the higher cysteine protease activity than wild-type. Two-dimensional gel electrophoresis and western blotting analysis revealed that the amount of cysteine protease, SpeB in lytR mutant was more compared with that in wild-type. The level of speB mRNA in lytR mutant also increased compared with that of wild type. The membrane integrity and potential in lytR mutant also were decreased compared with that of wild-type. Murine infection model showed that less survival was detected in mice inoculated with lytR mutant than that with wild-type, and the size of wound lesion of mice with lytR mutant was larger than that with wild type. Our data suggest that the lytR regulates the expression of SpeB in S. pyogenes with relation to membrane integrity. PMID- 22515298 TI - Real-time multiplex PCR for direct detection of methicillin-resistant Staphylococcus aureus (MRSA) in clinical samples enriched by broth culture. AB - A real-time multiplex PCR using the orfX and staphylococcal cassette chromosome (SCC) mec of Staphylococcus aureus was developed. The aim was to achieve a rapid and sensitive high-throughput method for direct detection of heterogeneous methicillin-resistant S. aureus (MRSA) in clinical samples, present in a low endemic population, such as in Sweden. Consecutive broth enriched pooled clinical screening samples (nares, throat and/or perineum/groin) (n = 541 pools), broth enriched clinical samples showing growth of methicillin-sensitive S. aureus (MSSA) (n = 95 pools), clinical MRSA isolates (n = 173), MRSA reference strains (n = 43) and various coagulase-negative staphylococcal isolates (n = 33) were analyzed. The multiplex PCR detected all heterogeneous MRSA strains (n = 173) obtained in our area as well as all pooled consecutive broth enriched clinical samples with MRSA, i. e. 36 of 541 pools. None of the CoNS were positive. However, 18 out of 541 pools (3.3%) were positive in the multiplex PCR but no growth of MRSA could be detected by subculture and were regarded as false positive. Furthermore, the assay is rapid and reliable negative results can be delivered to the clinician within 18 h that will facilitate the infection control management of patients and hospital staff. PMID- 22515299 TI - Molecular phylogeny of Pacific Archigregarines (Apicomplexa), including descriptions of Veloxidium leptosynaptae n. gen., n. sp., from the sea cucumber Leptosynapta clarki (Echinodermata), and two new species of Selenidium. AB - Although archigregarines are poorly understood intestinal parasites of marine invertebrates, they are critical for understanding the earliest stages in the evolution of the Apicomplexa. Previous studies suggest that archigregarines are a paraphyletic stem group from which other lineages of gregarines, and possibly all other groups of apicomplexans, evolved. However, substantiating this inference is difficult because molecular phylogenetic data from archigregarines, in particular, and other gregarines, in general, are severely limited. In an attempt to help fill gaps in our knowledge of archigregarine diversity and phylogeny, we set out to discover and characterize novel lineages of archigregarines with high resolution light and scanning electron microscopy and analyses of small subunit (SSU) rDNA sequences derived from single-cell (SC) PCR techniques. Here, we describe two novel species of Selenidium, namely Selenidium idanthyrsae n. sp. and S. boccardiellae n. sp., and demonstrate the surface morphology and molecular phylogenetic position of the previously reported species S. cf. mesnili. We also describe a novel genus of archigregarine, Veloxidium leptosynaptae n. gen., n. sp., which branches with an environmental sequence and, together, forms the nearest sister lineage to a diverse clade of marine eugregarines (i.e. lecudinids and urosporids). This molecular phylogenetic result is consistent with the hypothesis that archigregarines are deeply paraphyletic within apicomplexans, and suggests that convergent evolution played an important role in shaping the diversity of eugregarine trophozoites. PMID- 22515300 TI - Activation of spinal TDAG8 and its downstream PKA signaling pathway contribute to bone cancer pain in rats. AB - Bone cancer pain is difficult to treat and has a strong impact on the quality of life of patients. Few therapies have emerged because the molecular mechanisms underlying bone cancer pain are poorly understood. Recently, T-cell death associated gene 8 (TDAG8) has been shown to participate in complete Freund's adjuvant-induced chronic inflammatory pain. In this study, we aimed to examine whether TDAG8 and its downstream protein kinase A (PKA) pathway are involved in bone cancer pain. A bone cancer pain model was made by inoculation of Walker 256 cells into the intramedullary space of rat tibia. Spinal TDAG8 expression was increased after inoculation with tumor cells. Intrathecal TDAG8 siRNA attenuated bone cancer pain behaviors during the initiation and maintenance phases; there were also concomitant decreases in TDAG8 mRNA and protein levels in spinal cord. Moreover, we found spinal PKA and phosphorylated cAMP response element-binding (pCREB) protein levels were up-regulated in the rat model of bone cancer pain. Knockdown of TDAG8 resulted in reduced bone cancer pain-induced spinal PKA and pCREB protein expression in two procedures. Furthermore, intrathecal H-89 (a PKA inhibitor) significantly attenuated bone cancer pain behaviors in rats. Our results suggest a causal relationship between TDAG8 expression and the initiation and maintenance of bone cancer pain. Activation of spinal TDAG8 contributes to bone cancer pain through the PKA signaling pathway in rats. These findings may lead to novel strategies for the treatment of bone cancer pain. PMID- 22515301 TI - In vivo stratum corneum over-hydration and water diffusion coefficient measurements using opto-thermal radiometry and TEWL Instruments. AB - Skin over-hydration is a common problem that affects many people who wear incontinence pads or diapers. The aim of this study is to develop a new method for stratum corneum (SC) over-hydration and SC water diffusion coefficient measurements using opto-thermal transient emission radiometry (OTTER) and evaporimetry. With OTTER, we can measure the SC surface hydration and hydration gradient. With evaporimetry, we can measure the time-dependent evaporative drying curves of water vapour flux density (WVFD). The combination of hydration results and WVFD results can yield information on the SC water diffusion coefficient and how it depends on the SC surface hydration level. The results show that SC water diffusion coefficient is non-linearly proportional to the SC surface hydration level. The results also show strong correlations between evaporative drying flux measured using the Evaporimeter and surface hydration estimated from OTTER measurements. PMID- 22515304 TI - Structure of [C4mpyr][NTf2] room-temperature ionic liquid at charged gold interfaces. AB - The structure of 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide ([C(4)mpyr][NTf(2)]) room-temperature ionic liquid at an electrified gold interface was studied using neutron reflectometry, cyclic voltammetry, and differential capacitance measurements. Subtle differences were observed between the reflectivity data collected on a gold electrode at three different applied potentials. Detailed analysis of the fitted reflectivity data reveals an excess of [C(4)mpyr](+) at the interface, with the amount decreasing at increasingly positive potentials. A cation rich interface was found even at a positively charged electrode, which indicates a nonelectrostatic (specific) adsorption of [C(4)mpyr](+) onto the gold electrode. PMID- 22515302 TI - The complicated relationship between obstructive sleep apnea and inflammation biomarkers. PMID- 22515305 TI - Teachers who study and students who teach: are we really so different? PMID- 22515306 TI - Predicting who applies to study medicine: implication for diversity in UK medical schools. AB - AIMS: Widening access to medical school is a priority in medical selection. If disadvantaged students do not apply, interventions cannot be effective. To date, no studies have examined factors that predict who chooses to apply to medicine and if socio-demographics influence the profile of those who apply to study medicine. METHODS: A large database provided by the UK University and Colleges Admissions Service on all 1,225,156 applicants to UK universities over a 3-year period (2002-2004) was analysed. The relationship between demographics, preference to study medicine and academic performance prior to entry (A level score) were explored using logistic and linear regression and path modelling. RESULTS: Those applying to study medicine were more likely to be female, non white, of higher socio-economic status and from fee-paying schools. Applying to study medicine was associated with increased academic entrance performance over and above socio-demographic factors. Importantly, in those applying to study medicine socio-demographic inequalities in entrance exam performance was either reduced (for ethnicity and SES) or abolished (for sex and schooling). CONCLUSIONS: It is argued that early interventions are needed to increase applications for certain groups to help to reduce socio-demographic inequalities in entrance exam performance and hence medical school admissions. PMID- 22515307 TI - eMedical teacher. PMID- 22515309 TI - Program evaluation models and related theories: AMEE guide no. 67. AB - This Guide reviews theories of science that have influenced the development of common educational evaluation models. Educators can be more confident when choosing an appropriate evaluation model if they first consider the model's theoretical basis against their program's complexity and their own evaluation needs. Reductionism, system theory, and (most recently) complexity theory have inspired the development of models commonly applied in evaluation studies today. This Guide describes experimental and quasi-experimental models, Kirkpatrick's four-level model, the Logic Model, and the CIPP (Context/Input/Process/Product) model in the context of the theories that influenced their development and that limit or support their ability to do what educators need. The goal of this Guide is for educators to become more competent and confident in being able to design educational program evaluations that support intentional program improvement while adequately documenting or describing the changes and outcomes-intended and unintended-associated with their programs. PMID- 22515310 TI - Medical students' perceptions of the factors influencing their academic performance: an exploratory interview study with high-achieving and re-sitting medical students. AB - BACKGROUND: Little is known about medical students' perceptions of the factors that influence their academic performance. AIM: To detect factors medical students, in the final years of their undergraduate medical studies, believe affect their academic performance. METHODS: We conducted semi-structured interviews with high-achieving and re-sitting students in the final two years of their studies in a London medical school. Interviews were recorded and transcribed. Thematic content analysis was conducted. Similarities and differences in factors perceived to affect the academic performance of high achieving and re-sitting students were identified. RESULTS: Eight re-sitting and ten high-achieving students were interviewed. Three core themes were identified: engagement with learning; reflections on learning methods and experiences and the application of learning to future practice. High-achieving students showed a greater awareness of what worked in terms of their approaches to learning and coping with difficulty than re-sitting students. There were also differences in the degree of positive engagement with peers, suggesting the positive contribution of socialising with other medical students. CONCLUSIONS: This exploratory qualitative study identified attitudes, behaviours and motivations that appeared to contribute to success or failure at medical school. Our findings suggest ways to improve appraisal, remediation and support mechanisms for students. PMID- 22515311 TI - Unexpected multivalent display of proteins by temperature triggered self-assembly of elastin-like polypeptide block copolymers. AB - We report herein the unexpected temperature triggered self-assembly of proteins fused to thermally responsive elastin-like polypeptides (ELPs) into spherical micelles. A set of six ELP block copolymers (ELP(BC)) differing in hydrophilic and hydrophobic block lengths were genetically fused to two single domain proteins, thioredoxin (Trx) and a fibronectin type III domain (Fn3) that binds the alpha(v)beta(3) integrin. The self-assembly of these protein-ELP(BC) fusions as a function of temperature was investigated by UV spectroscopy, light scattering, and cryo-TEM. Self-assembly of the ELP(BC) was unexpectedly retained upon fusion to the two proteins, resulting in the formation of spherical micelles with a hydrodynamic radius that ranged from 24 to 37 nm, depending on the protein and ELP(BC). Cryo-TEM images confirmed the formation of spherical particles with a size that was consistent with that measured by light scattering. The bioactivity of Fn3 was retained when presented by the ELP(BC) micelles, as indicated by the enhanced uptake of the Fn3-decorated ELP(BC) micelles in comparison to the unimer by cells that overexpress the alpha(v)beta(3) integrin. The fusion of single domain proteins to ELP(BC)s may provide a ubiquitous platform for the multivalent presentation of proteins. PMID- 22515313 TI - The challenge of psychiatric nosology and diagnosis. PMID- 22515312 TI - Surgical management of primary appendiceal malignancy. AB - AIM: Primary appendiceal neoplasms are rare, with carcinoid being more common than carcinoma. Preoperative diagnosis is infrequent. We report a series of 24 primary appendiceal neoplasms treated over a 5-year period. METHOD: All primary appendiceal neoplasms diagnosed in a university teaching hospital between April 2003 and June 2008 were identified from the prospective histopathology database. Patient records were reviewed for clinical, operative and pathological data. RESULTS: Fourteen carcinomas and 10 carcinoids were identified in the 5-year period. The former presented at median age 55.8 years with median symptom duration of 35 days, compared with 48 years and 3 days, respectively, for carcinoids. An abdominal mass was commoner in carcinomas (8/14 vs 1/10). Six patients with carcinoma underwent appendicectomy followed by completion right hemicolectomy, two of whom had residual disease; seven underwent primary right hemicolectomy and one had abscess drainage. Five patients with appendiceal carcinoma died of the disease during a median follow-up of 633 (256-1158) days. Six patients underwent appendicectomy for acute appendicitis, one had a primary right-hemicolectomy for a caecal mass. Three had a subsequent right-hemicolectomy for a high-risk carcinoid. An appendiceal carcinoid was an incidental finding in three right-hemicolectomy specimens removed for other indications. No metastases or deaths were recorded at median follow-up 451 (51-975) days. CONCLUSION: Appendiceal carcinomas follow a more protracted clinical course than carcinoids, which usually present as acute appendicitis. Caution is needed when diagnosing simple appendicitis in older patients with longer symptom duration, particularly if a mass is present. Patients with appendiceal carcinoma should be offered completion right-hemicolectomy. Carcinoma has a poor prognosis. PMID- 22515314 TI - Prevalence of Neoehrlichia mikurensis in ticks and rodents from North-west Europe. AB - BACKGROUND: Neoehrlichia mikurensis s an emerging and vector-borne zoonosis: The first human disease cases were reported in 2010. Limited information is available about the prevalence and distribution of Neoehrlichia mikurensis in Europe, its natural life cycle and reservoir hosts. An Ehrlichia-like schotti variant has been described in questing Ixodes ricinus ticks, which could be identical to Neoehrlichia mikurensis. METHODS: Three genetic markers, 16S rDNA, gltA and GroEL, of Ehrlichia schotti-positive tick lysates were amplified, sequenced and compared to sequences from Neoehrlichia mikurensis. Based on these DNA sequences, a multiplex real-time PCR was developed to specifically detect Neoehrlichia mikurensis in combination with Anaplasma phagocytophilum in tick lysates. Various tick species from different life-stages, particularly Ixodes ricinus nymphs, were collected from the vegetation or wildlife. Tick lysates and DNA derived from organs of wild rodents were tested by PCR-based methods for the presence of Neoehrlichia mikurensis. Prevalence of Neoehrlichia mikurensis was calculated together with confidence intervals using Fisher's exact test. RESULTS: The three genetic markers of Ehrlichia schotti-positive field isolates were similar or identical to Neoehrlichia mikurensis. Neoehrlichia mikurensis was found to be ubiquitously spread in the Netherlands and Belgium, but was not detected in the 401 tick samples from the UK. Neoehrlichia mikurensis was found in nymphs and adult Ixodes ricinus ticks, but neither in their larvae, nor in any other tick species tested. Neoehrlichia mikurensis was detected in diverse organs of some rodent species. Engorging ticks from red deer, European mouflon, wild boar and sheep were found positive for Neoehrlichia mikurensis. CONCLUSIONS: Ehrlichia schotti is similar, if not identical, to Neoehrlichia mikurensis. Neoehrlichia mikurensis is present in questing Ixodes ricinus ticks throughout the Netherlands and Belgium. We propose that Ixodes ricinus can transstadially, but not transovarially, transmit this microorganism, and that different rodent species may act as reservoir hosts. These data further imply that wildlife and humans are frequently exposed to Neoehrlichia mikurensis-infected ticks through tick bites. Future studies should aim to investigate to what extent Neoehrlichia mikurensis poses a risk to public health. PMID- 22515315 TI - Altered handwriting suggests cognitive impairment and may be relevant to posthumous evaluation. AB - Judging the validity of a disputed will is complex; however, one of the main issues is what the mental status of the testator was at the time of the will. If the will is handwritten, a handwriting analysis can provide information on the mental status of the testator. We tested how two writing parameters (the "writing score," a novel evaluation scale that we previously described, and the percentage of spelling mistakes) are capable to identify cognitively impaired persons. These parameters are especially helpful because they can be used to evaluate the mental status of a deceased person. We found a significant correlation between either parameter and established scales of neuropsychological evaluation (Mini Mental State Examination and Milan Overall Dementia Assessment scale). Specifically, a poor score on either parameter reliably identified a compromised cognitive status. These may represent helpful additions to existing techniques in posthumously identifying persons with severe cognitive impairment. PMID- 22515316 TI - Alkali-ion microsolvation with benzene molecules. AB - The target of this investigation is to characterize by a recently developed methodology, the main features of the first solvation shells of alkaline ions in nonpolar environments due to aromatic rings, which is of crucial relevance to understand the selectivity of several biochemical phenomena. We employ an evolutionary algorithm to obtain putative global minima of clusters formed with alkali-ions (M(+)) solvated with n benzene (Bz) molecules, i.e., M(+)-(Bz)(n). The global intermolecular interaction has been decomposed in Bz-Bz and in M(+)-Bz contributions, using a potential model based on different decompositions of the molecular polarizability of benzene. Specifically, we have studied the microsolvation of Na(+), K(+), and Cs(+) with benzene molecules. Microsolvation clusters up to n = 21 benzene molecules are involved in this work and the achieved global minimum structures are reported and discussed in detail. We observe that the number of benzene molecules allocated in the first solvation shell increases with the size of the cation, showing three molecules for Na(+) and four for both K(+) and Cs(+). The structure of this solvation shell keeps approximately unchanged as more benzene molecules are added to the cluster, which is independent of the ion. Particularly stable structures, so-called "magic numbers", arise for various nuclearities of the three alkali-ions. Strong "magic numbers" appear at n = 2, 3, and 4 for Na(+), K(+), and Cs(+), respectively. In addition, another set of weaker "magic numbers" (three per alkali-ion) are reported for larger nuclearities. PMID- 22515318 TI - Quality of care for severe acute malnutrition delivered by community health workers in southern Bangladesh. AB - This study assessed the quality of care provided by community health workers (CHWs) in managing cases of severe acute malnutrition (SAM) according to a treatment algorithm. A mixed methods approach was employed to provide perspectives on different aspects of quality of care, including technical competence and acceptability to caretakers. CHWs screened children at community level using a mid-upper arm circumference measurement, and treated cases without medical complications. Fifty-five case management observations were conducted using a quality of care checklist, with 89.1% (95% confidence interval: 77.8 95.9%) of CHWs achieving 90% error-free case management or higher. Caretakers perceived CHWs' services as acceptable and valuable, with doorstep delivery of services promoting early presentation in this remote area of Bangladesh. Integration of the treatment of SAM into community-based health and nutrition programs appears to be feasible and effective. In this setting, well-trained and supervised CHWs were able to effectively manage cases of SAM. These findings suggest the feasibility of further decentralization of treatment from current delivery models for community-based management of acute malnutrition. PMID- 22515319 TI - SprayQc: a real-time LC-MS/MS quality monitoring system to maximize uptime using off the shelf components. AB - With the advent of high-throughput mass spectrometry (MS)-based proteomics, the magnitude and complexity of the performed experiments has increased dramatically. Likewise, investments in chromatographic and MS instrumentation are a large proportion of the budget of proteomics laboratories. Guarding measurement quality and maximizing uptime of the LC-MS/MS systems therefore requires constant care despite automated workflows. We describe a real-time surveillance system, called SprayQc, that continuously monitors the status of the peripheral equipment to ensure that operational parameters are within an acceptable range. SprayQc is composed of multiple plug-in software components that use computer vision to analyze electrospray conditions, monitor the chromatographic device for stable backpressure, interact with a column oven to control pressure by temperature, and ensure that the mass spectrometer is still acquiring data. Action is taken when a failure condition has been detected, such as stopping the column oven and the LC flow, as well as automatically notifying the appropriate operator. Additionally, all defined metrics can be recorded synchronized on retention time with the MS acquisition file, allowing for later inspection and providing valuable information for optimization. SprayQc has been extensively tested in our laboratory, supports third-party plug-in development, and is freely available for download from http://sourceforge.org/projects/sprayqc . PMID- 22515321 TI - gamma-Aminobutyric acid receptor A-mediated inhibition in the honeybee's antennal lobe is necessary for the formation of configural olfactory percepts. AB - Complex odours often possess perceptual qualities that are distinct from their components. Previous studies in humans, rodents, and insects indicate that the perception of complex odour blends depends on the concentration of the components and the mixture's complexity. However, we know relatively little about the way that an odour mixture 'gestalt' is produced by the olfactory system. Here, using an assay for olfactory conditioning in the honeybee (Apis mellifera), we examine the role of gamma-aminobutyric acid receptor A (GABA(A) )-ergic inhibition within the olfactory primary relay, the antennal lobe, in the formation of a unique odour percept for complex odours. We found that honeybees perceive odour mixtures as configural stimuli when the mixtures were of low concentration and when they were composed of more than two odorants. When GABA(A) receptors were disrupted using the antagonist, picrotoxin, injected directly into the antennal lobe, we observed that bees no longer perceived the mixture as a configural stimulus. Our results imply that synchronization of antennal lobe projection neurons mediated by GABA(A) receptors is the mechanism responsible for the formation of unique olfactory percepts for complex odours. PMID- 22515322 TI - New layered compounds with honeycomb ordering: Li3Ni2BiO6, Li3NiM'BiO6 (M' = Mg, Cu, Zn), and the delafossite Ag3Ni2BiO6. AB - The new layered compound Li(3)Ni(2)BiO(6) has been prepared by a solid-state reaction. It crystallizes in the monoclinic C2/m space group; its lamellar structure is characterized by a honeycomb ordering between Ni(2+) and Bi(5+) within the slabs, while Li(+) ions occupy octahedral sites in the interslab space. Stacking defects weakly alter the XRD pattern. By substitution of half of the nickel ions, the new phases Li(3)NiM'BiO(6) (M' = Mg, Cu, Zn) isostructural with Li(3)Ni(2)BiO(6) have been synthesized under similar conditions. All these compounds demonstrate paramagnetic behavior at high temperature, and Li(3)Ni(2)BiO(6) exhibits an antiferromagnetic ordering at 5.5 K. By topotactic molten salt ionic exchange, the new delafossite compound Ag(3)Ni(2)BiO(6) has been also obtained and characterized. PMID- 22515320 TI - A simple and effective method to generate lentiviral vectors for ex vivo gene delivery to mature human peripheral blood lymphocytes. AB - Human ex vivo gene therapy protocols have been used successfully to treat a variety of genetic disorders, infectious diseases, and cancer. Murine oncoretroviruses (specifically, gammaretroviruses) have served as the primary gene delivery vehicles for these trials. However, in some cases, such vectors have been associated with insertional mutagenesis. As a result, alternative vector platforms such as lentiviral vectors (LVVs) are being developed. LVVs may provide advantages compared with gammaretroviral vectors, including the ability to transduce large numbers of nondividing cells, resistance to gene silencing, and a potentially safer integration profile. The aim of this study was to develop a simplified process for the rapid production of clinical-grade LVVs. To that end, we used a self-inactivating bicistronic LVV encoding an MART (melanoma antigen recognized by T cells)-1-reactive T cell receptor containing oPRE, an optimized and truncated version of woodchuck hepatitis virus posttranslational regulatory element (wPRE). Using our simplified clinical production process, 293T cells were transiently transfected in roller bottles. The LVV supernatant was collected, treated with Benzonase, and clarified by modified step filtration. LVV produced in this manner exhibited titers and a biosafety profile similar to those of cGMP (current Good Manufacturing Practices) LVVs previously manufactured at the Indiana University Vector Production Facility in support of a phase I/II clinical trial. We describe a simple, efficient, and low-cost method for the production of clinical-grade LVV for ex vivo gene therapy protocols. PMID- 22515323 TI - Dual-mode control of PET process in a ferrocene-functionalized [2]rotaxane with high-contrast fluorescence output. AB - The shuttling motion of the ferrocene-functionalized macrocycle between the dibenzylammonium and the N-methyltriazolium recognition sites in a bistable [2]rotaxane, as well as the photoinduced electron transfer process occurring between ferrocene units and the morpholin-naphthalimide fluorescent stopper, can be adjusted not only by acid-base stimuli but also addition-removal of the fluoride anion, along with remarkable, high-contrast fluorescent intensity changes. PMID- 22515325 TI - Neotypification and ontogenesis of Leptopharynx costatus costatus Mermod, 1914. AB - Using standard methods, we studied the morphology and ontogenesis of a German Leptopharynx costatus costatus. This population makes two morphs: microstomes with a size of 40 * 25 MUm, about 190 basal bodies, and 5 MUm wide oral basket; and macrostomes with a size of 55 * 40 MUm, about 264 basal bodies, and 15 MUm wide oral basket. Because the identity is threatened, this population is designated as the neotype of L. costatus costatus. Ontogenesis is complex due to the preoral kineties and the postoral complex produced by kineties 9 and 10. Stomatogenesis is mixokinetal: the opisthe membranelles 1 and 2 are formed by the oral primordium, whereas membranelle 3 is produced by the posterior portion of somatic kinety 1. The nasse kinetosomes are generated by the anterior portion of the oral primordium. Preoral kineties 1 and 3 develop de novo, while kinety 2 originates by intrakinetal proliferation of kinety 8; preoral kinety 4 is produced by the postoral complex, thus being a somatic kinety. Kinety 6 has two anterior kinetids in line with kinety 7. These observations require changes in the descriptive morphology, support the classification of Leptopharynx into the Microthoracidae, and sustain the nonmonophyly of the Nassophorea. PMID- 22515324 TI - Bioinformatic identification of proteins with tissue-specific expression for biomarker discovery. AB - BACKGROUND: There is an important need for the identification of novel serological biomarkers for the early detection of cancer. Current biomarkers suffer from a lack of tissue specificity, rendering them vulnerable to non disease-specific increases. The present study details a strategy to rapidly identify tissue-specific proteins using bioinformatics. METHODS: Previous studies have focused on either gene or protein expression databases for the identification of candidates. We developed a strategy that mines six publicly available gene and protein databases for tissue-specific proteins, selects proteins likely to enter the circulation, and integrates proteomic datasets enriched for the cancer secretome to prioritize candidates for further verification and validation studies. RESULTS: Using colon, lung, pancreatic and prostate cancer as case examples, we identified 48 candidate tissue-specific biomarkers, of which 14 have been previously studied as biomarkers of cancer or benign disease. Twenty-six candidate biomarkers for these four cancer types are proposed. CONCLUSIONS: We present a novel strategy using bioinformatics to identify tissue-specific proteins that are potential cancer serum biomarkers. Investigation of the 26 candidates in disease states of the organs is warranted. PMID- 22515326 TI - Facial swelling and discharging lesions associated with abnormalities of the mandible in kunekune pigs. AB - CASE HISTORIES: Four adult kunekune pigs developed facial swelling at the base of the right ear that ruptured and discharged food material. A further six pigs that had similar clinical signs were reported by members of the New Zealand Kunekune Association who responded to an email survey, one of which was confirmed by post mortem examination. CLINICAL FINDINGS: Inside the mouth of each pig there was an opening at the junction of the body and ramus of the mandible just lateral to the most caudal visible molar that was impacted with masticated feed. The food packed into the mandible resulted in infection and progressive erosion of the medullary cavity of the bone until it reached the ramus where it eroded through the lateral cortex. The feed material then tracked through the soft tissues to form a subcutaneous abscess, which eventually ruptured resulting in a draining lesion. In Case 2, which had had the lesion for 2 years, the cavity in the mandible was lined with mucosa that had healed to the skin to produce a fistula. In all four pigs there was also a lesion in the left side of the mandible that was not as developed as that on the right side. DIAGNOSIS: The facial swellings were produced by feed material that had impacted into the mandible through an opening immediately caudal to the cheek teeth and then emerged through one or more lesions in the lateral aspect of the ramus of the mandible. CLINICAL RELEVANCE: Although it has not been previously reported, anecdotal reports and our survey suggest that this condition may occur relatively frequently in kunekune pigs. It should be considered as a differential diagnosis for facial swellings and discharging lesions in these animals. PMID- 22515327 TI - A prospective study on MRI findings and prognostic factors in athletes with MTSS. AB - In medial tibial stress syndrome (MTSS) bone marrow and periosteal edema of the tibia on the magnetic resonance imaging (MRI) is frequently reported. The relationship between these MRI findings and recovery has not been previously studied. This prospective study describes MRI findings of 52 athletes with MTSS. Baseline characteristics were recorded and recovery was related to these parameters and MRI findings to examine for prognostic factors. Results showed that 43.5% of the symptomatic legs showed bone marrow or periosteal edema. Absence of periosteal and bone marrow edema on MRI was associated with longer recovery (P = 0.033 and P = 0.013). A clinical scoring system for sports activity (SARS score) was significantly higher in the presence of bone marrow edema (P = 0.027). When clinical scoring systems (SARS score and the Lower Extremity Functional Scale) were combined in a model, time to recovery could be predicted substantially (explaining 54% of variance, P = 0.006). In conclusion, in athletes with MTSS, bone marrow or periosteal edema is seen on MRI in 43,5% of the symptomatic legs. Furthermore, periosteal and bone marrow edema on MRI and clinical scoring systems are prognostic factors. Future studies should focus on MRI findings in symptomatic MTSS and compare these with a matched control group. PMID- 22515329 TI - Enhanced cellular uptake of a new, in silico identified antitubercular candidate by peptide conjugation. AB - Mycobacterium tuberculosis is a successful pathogen, and it can survive in infected macrophages in dormant phase for years and decades. The therapy of tuberculosis takes at least six months, and the slow-growing bacterium is resistant to many antibiotics. The development of novel antimicrobials to counter the emergence of bacteria resistant to current therapies is urgently needed. In silico docking methods and structure-based drug design are useful bioinformatics tools for identifying new agents. A docking experiment to M. tuberculosis dUTPase enzyme, which plays a key role in the bacterial metabolism, has resulted in 10 new antitubercular drug candidates. The uptake of antituberculars by infected macrophages is limited by extracellular diffusion. The optimization of the cellular uptake by drug delivery systems can decrease the used dosages and the length of the therapy, and it can also enhance the bioavailability of the drug molecule. In this study, improved in vitro efficacy was achieved by attaching the TB5 antitubercular drug candidate to peptide carriers. As drug delivery components, (i) an antimicrobial granulysin peptide and (ii) a receptor specific tuftsin peptide were used. An efficient synthetic approach was developed to conjugate the in silico identified TB5 coumarone derivative to the carrier peptides. The compounds were effective on M. tuberculosis H37Rv culture in vitro; the chemical linkage did not affect the antimycobacterial activity. Here, we show that the OT20 tuftsin and GranF2 granulysin peptide conjugates have dramatically enhanced uptake into human MonoMac6 cells. The TB5-OT20 tuftsin conjugate exhibited significant antimycobacterial activity on M. tuberculosis H37Rv infected MonoMac6 cells and inhibited intracellular bacteria. PMID- 22515328 TI - N-(2-oxo-3-oxetanyl)carbamic acid esters as N-acylethanolamine acid amidase inhibitors: synthesis and structure-activity and structure-property relationships. AB - The beta-lactone ring of N-(2-oxo-3-oxetanyl)amides, a class of N acylethanolamine acid amidase (NAAA) inhibitors endowed with anti-inflammatory properties, is responsible for both NAAA inhibition and low compound stability. Here, we investigate the structure-activity and structure-property relationships for a set of known and new beta-lactone derivatives, focusing on the new class of N-(2-oxo-3-oxetanyl)carbamates. Replacement of the amide group with a carbamate one led to different stereoselectivity for NAAA inhibition and higher intrinsic stability, because of the reduced level of intramolecular attack at the lactone ring. The introduction of a syn methyl at the beta-position of the lactone further improved chemical stability. A tert-butyl substituent in the side chain reduced the reactivity with bovine serum albumin. (2S,3R)-2-Methyl-4-oxo-3 oxetanylcarbamic acid 5-phenylpentyl ester (27, URB913/ARN077) inhibited NAAA with good in vitro potency (IC(50) = 127 nM) and showed improved stability. It is rapidly cleaved in plasma, which supports its use for topical applications. PMID- 22515330 TI - Update 1 of: Sensitivity analysis for chemical models. PMID- 22515331 TI - KCNH2 gene mutation: a potential link between epilepsy and long QT-2 syndrome. AB - Long QT syndrome (LQTS) is closely associated with syncope, seizure, and sudden death but LQTS is frequently misdiagnosed as epilepsy. LQTS and epilepsy both belong to the group of ion channelopathies that manifest in the heart and brain. Therefore, genetic analysis of genes associated with potassium and sodium homeostasis and electrical disorders may reveal a link between epilepsy and lethal cardiac arrhythmia. Here, the authors report a young woman who suffered recurrent seizure episodes and syncopes that occurred while walking and also during rest. She showed electroencephalogram abnormalities and a pathological prolonged QTc interval in electrocardiogram. The patient and the patient's asymptomatic family members underwent genetic screening of the three genes most frequently associated with LQTS: KCNQ1, KCNH2, and SCN5A. The patient and the family members did not show DNA alterations in the genes KCNQ1 and SCN5A associated with LQT-1 and LQT-3, respectively. However, the patient showed a de novo mutation 2587T->C in exon 10 of KCNH2 gene associated with LQT-2. The mutation caused a stop codon substitution (R863X) in the HERG channel, leading to a 296-amino acid deletion. The patient's asymptomatic relatives did not show the KCNH2 gene mutation. R863X alteration in HERG channel may be involved in both prolonged QTc interval and epilepsy. This fact raises the possibility that R863X alteration in KCNH2-encoded potassium channel may confer susceptibility for epilepsy and cardiac LQT-2 arrhythmia. PMID- 22515332 TI - Adhesin contribution to nanomechanical properties of the virulent Bordetella pertussis envelope. AB - Adherence to a biological surface allows bacteria to colonize and persist within the host and represents an essential first step in the pathogenesis of most bacterial diseases. Consequently, the physicochemical properties of the outer membrane in bacteria play a key role for attachment to surfaces and therefore for biofilm formation. Bordetella pertussis is a Gram-negative bacterium that colonizes the respiratory tract of humans, producing whooping cough or pertussis, a highly infectious disease. B. pertussis uses various adhesins exposed on its surface to promote cell-surface and cell-cell interactions. The most dominant adhesin function is displayed by filamentous hemagglutinin (FHA). B. pertussis Tohama I wild-type (Vir+) strain and two defective mutants, an avirulent (Vir-) and a FHA-deficient (FHA-) B. pertussis strains were studied by AFM under physiological conditions to evaluate how the presence or absence of adhesins affects the mechanical properties of the B. pertussis cell surface. Quantitative information on the nanomechanical properties of the bacterial envelope was obtained by AFM force-volume analysis. These studies suggested that the presence of virulence factors is correlated with an increase in the average membrane rigidity, which is largely influenced by the presence of FHA. Moreover, for this system we built a nanoscale stiffness map that reveals an inhomogeneous spatial distribution of Young modulus as well as the presence of rigid nanodomains on the cell surface. PMID- 22515333 TI - A study of menopausal symptoms in relation to habits of smoking and make-up using in Japanese women aged 35-59. AB - We conducted a survey to elucidate the influence with menopause symptoms and the impact of not only smoking but also using make-up among for Japanese women, included ages above and below the menopausal generation. The subjects of this study were 335 Japanese women from 35 to 59 years of age who were examined for the first time in the specialized women's outpatient clinic of our institution from July 2010 to June 2011 for 1 year period. We used the items of the Menopause Specific Quality of Life Questionnaire. Similarly, we analysed the scores in relation to menopausal symptoms and whether the subject smoked, whether the subject used make-up depend on women (including foundation, lip rouge, brush one's eyebrows), how frequently she used make-up. The JMP version 9.0 software program was used to statistically analyse the score data. Significant associations were observed in psychosocial (P = 0.0196), tended to be more severe in women before menopause and after climacteric. Furthermore, the frequency of using make-up were negative relations with menopause symptoms (P = 0.0251) after climacteric. Smoking had made worse for physical symptoms (P < 0.001). Menopause symptoms are already experienced by younger women, especially, psychological symptoms. Also, physical conditions were influenced by smoking. Using make-up frequently was often seen after climacteric because of appearance changes by oestrogen dynamic decline. PMID- 22515335 TI - Improving response rate and quality of survey data with a scratch lottery ticket incentive. AB - BACKGROUND: The quality of data collected in survey research is usually indicated by the response rate; the representativeness of the sample, and; the rate of completed questions (item-response). In attempting to improve a generally declining response rate in surveys considerable efforts are being made through follow-up mailings and various types of incentives. This study examines effects of including a scratch lottery ticket in the invitation letter to a survey. METHOD: Questionnaires concerning oral health were mailed to a random sample of 2,400 adults. A systematically selected half of the sample (1,200 adults) received a questionnaire including a scratch lottery ticket. One reminder without the incentive was sent. RESULTS: The incentive increased the response rate and improved representativeness by reaching more respondents with lower education. Furthermore, it reduced item nonresponse. The initial incentive had no effect on the propensity to respond after the reminder. CONCLUSION: When attempting to improve survey data, three issues become important: response rate, representativeness, and item-response. This study shows that including a scratch lottery ticket in the invitation letter performs well on all the three. PMID- 22515336 TI - Dismembered laparoscopic Anderson-Hynes pyeloplasty versus nondismembered laparoscopic Y-V pyeloplasty in the treatment of patients with primary ureteropelvic junction obstruction: a prospective study. AB - PURPOSE: An attempt has been made to prospectively compare the results of two laparoscopic pyeloplasties: Dismembered Anderson-Hynes (A-H) plasty and nondismembered Y-V plasty. Complications following the procedures have been studied as well. PATIENTS AND METHODS: Fifty patients with primary ureteropelvic junction obstruction (UPJO) were prospectively selected at random to undergo dismembered A-H (25 patients-even numbers) and nondismembered Y-V (25 patients odd numbers) laparoscopic pyeloplasty. UPJO was diagnosed on the basis of ultrasonography, excretory urography, and diuretic renography (DR). The intensity of pain was assessed according to a visual analog pain scale (VAS). Success was defined by three factors taken collectively: 80% or greater pain relief in comparison with the preoperative VAS score, no obstruction on DR (decreasing renographic excretion curve, T(1/2) <12 min), and improved or stable differential renal function. The mean follow-up was 26.2 months for the A-H group and 26.6 months for Y-V group (P=0.865). RESULTS: Both groups were comparable in terms of preoperative data, except for the presence of the crossing vessel, which was more often observed in the Y-V group. No statistically significant differences between the studied groups were found in operative times, morbidity, and hospitalization length. The success rate in the A-H group was 95% and 86% in the Y-V group, the difference being not statistically significant. CONCLUSIONS: Laparoscopic A-H pyeloplasty achieved a higher success rate then Y-V pyeloplasty; however, the difference was not statistically significant. PMID- 22515334 TI - Prevalence of canine leishmaniasis in Beichuan County, Sichuan, China and phylogenetic evidence for an undescribed Leishmania sp. in China based on 7SL RNA. AB - BACKGROUND: Leishmaniasis is a vector-borne disease, which is still endemic in the west and northwest area of China. Canines are the major reservoirs of Leishmania, the etiological agent of human visceral leishmaniasis. Phlebotomus chinensis is the main transmission vector of zoonotic visceral leishmaniasis (ZVL). METHODS: In this study, rK39 dip-stick, ELISA and PCR methods were used to investigate the prevalence of canine leishmaniasis (CanL) in Beichuan County, Sichuan Province, China. RESULTS: Among the 86 dogs which were included in the study, 13 dogs were positive using the dip-stick test (15.12%), while 8 dogs were positive using ELISA (9.30%) and 19 dogs were positive for PCR (22.03%). In total, 32 dogs were positive for one or more tests (37.21%). Interestingly, phylogenetic analysis based on the partial 7SL RNA fragment provided evidence that an undescribed Leishmania species, which is clearly a causative agent of CanL and human visceral leishmaniasis, does exist in China. This result is consistent with our previous study. CONCLUSIONS: Our work confirmed that canine leishmaniasis is still prevalent in Beichuan County. Further control is urgently needed, as canine leishmaniasis is of great public health importance. The phylogenetic analysis based on 7SL RNA segment provides evidence for the existence of an undescribed Leishmania sp. in China. PMID- 22515337 TI - Palliative resection of the primary tumour in stage IV rectal cancer: response to Verberne et al. PMID- 22515338 TI - The knowledge levels of health personnel in Turkey regarding forensic evidence. AB - It is important that health personnel have extensive and adequate knowledge and practice regarding forensic evidence. This article describes the knowledge and practices of health personnel, who work in emergency rooms and health centers, regarding forensic evidence. The health personnel in a city in Central Anatolia, Turkey, constitute the population of this descriptive study and 233 personnel constitute its sample. It was determined that 31.3% stated that the practices of forensic evidence collection are inadequate. It was determined that average knowledge scores of health personnel with respect to forensic evidence are 23.5 +/- 7.28 of 40. It was found that there was a statistically significant difference between knowledge scores on the subject of forensic with respect to duty (p = 0.005), level of education (p = 0.005), and institution of health personnel (p = 0.015). It was determined that the scores of the health personnel, who work in emergency services and health centers, on the subject of forensic evidence, are not at a desirable level. PMID- 22515339 TI - Theoretical studies on the unimolecular decomposition of propanediols and glycerol. AB - Polyols, a typical type of alcohol containing multiple hydroxyl groups, are being regarded as a new generation of a green energy platform. In this paper, the decomposition mechanisms for three polyol molecules, i.e., 1,2-propanediol, 1,3 propanediol, and glycerol, have been investigated by quantum chemistry calculations. The potential energy surfaces of propanediols and glycerol have been built by the QCISD(T) and CBS-QB3 methods, respectively. For the three molecules studied, the H(2)O-elimination and C-C bond dissociation reactions show great importance among all of the unimolecular decomposition channels. Rate constant calculations further demonstrate that the H(2)O-elimination reactions are predominant at low temperature and pressure, whereas the direct C-C bond dissociation reactions prevail at high temperature and pressure. The temperature and pressure dependence of calculated rate constants was demonstrated by the fitted Arrhenius equations. This work aims to better understand the thermal decomposition process of polyols and provide useful thermochemical and kinetic data for kinetic modeling of polyols-derived fuel combustion. PMID- 22515340 TI - Effects of hyperthermia on Hsp27 (HSPB1), Hsp72 (HSPA1A) and DNA repair proteins hMLH1 and hMSH2 in human colorectal cancer hMLH1-deficient and hMLH1-proficient cell lines. AB - PURPOSE: The objective of the present study was to examine the consequences of a mild hyperthermia in human tumour cell lines deficient and proficient in the DNA mismatch repair system (MMR) to advance our understanding on the relationship between MMR and heat shock proteins (HSPs). MATERIALS AND METHODS: The human colon carcinoma cell lines HCT116 (parent cells), HCT116 + ch2 (MMR-deficient), and HCT116 + ch3 (MMR-proficient) were used. Cells were incubated at 41 degrees C and 42 degrees C for 1 h and then at 37 degrees C for 4 and 24 h. The expression of Hsp27 and Hsp72 was evaluated by immunocytochemistry. Hsp27, Hsp72, hMLH1 and hMSH2 levels were assessed by western blotting in nuclear and cytoplasmic fractions. The alkaline comet assay was used to evaluate the DNA damage. RESULTS: The mild hyperthermia significantly increased the protein expression levels of Hsp27 and Hsp72 in all cell lines, which was higher in the cytoplasm and nucleus of HCT116 + ch3 cells. We also observed that heat induced translocation of hMLH1 and hMSH2 proteins from the nucleus to the cytoplasm in HCT116 + ch3 cells. The comet assay revealed that HCT116 parent cells were more resistant to heat-induced DNA damage. However, the MMR-proficient and deficient cell lines repaired the DNA damage at the same rate. CONCLUSIONS: The present study demonstrates that hyperthermia induced the nuclear accumulation of Hsp27 and Hsp72 and affected the subcellular localisation of hMLH1 and hMSH2 in HCT116 + ch3 cells. Our findings suggest that the MMR system is not a direct determining factor for the different heat shock response in HCT116 cells. PMID- 22515342 TI - Determining a minimal safe distance to prevent thermal injury to intrahepatic bile ducts in radiofrequency ablation of the liver: a study in dogs. AB - PURPOSE: To determine a minimal safe distance between the radiofrequency ablation (RFA) electrode tip and major intrahepatic bile ducts to prevent thermal injury during hepatic RFA in a canine model. MATERIALS AND METHODS: Forty healthy mongrel dogs were randomised equally into four groups based on the distance between the electrode and large intrahepatic bile ducts during RFA of the liver, as follows: 1.0-2.9 mm, 3.0-4.9 mm, 5.0-7.9 mm, or 8.0-10.0 mm. The RFA electrodes were opened uniformly at 2 cm. During RFA, energy was sequentially raised, starting at 5 W and increasing by 5 W increments every minute to a maximum of 95 W. Animals were monitored for a maximum of 14 days post-RFA for complications and by bilirubin testing, after which they were euthanised and their livers were surgically removed for cholangiographic and pathological examination. RESULTS: When the electrodes were less than 5.0 mm from the bile ducts during RFA, either full or partial-thickness bile duct necrosis occurred, leading to a variety of serious complications. In contrast, when the distance was more than 5.0 mm between the RFA electrode and bile ducts, serious complications occurred rarely, with pathological examinations showing either normal bile ducts or vacuolar changes of the biliary ductal epithelium. CONCLUSION: A minimum safe distance of 5.0 mm between the RFA electrode and intrahepatic bile ducts was effective in preventing serious complications secondary to bile duct injury in a canine model. PMID- 22515341 TI - Luciferase-based protein denaturation assay for quantification of radiofrequency field-induced targeted hyperthermia: developing an intracellular thermometer. AB - BACKGROUND: Several studies have reported targeted hyperthermia at the cellular level using remote activation of nanoparticles by radiofrequency waves. To date, methods to quantify intracellular thermal dose have not been reported. In this report we study the relationship between radio wave exposure and luciferase denaturation with and without intracellular nanoparticles. The findings are used to devise a strategy to quantify targeted thermal dose in a primary human liver cancer cell line. METHODS: Water bath or non-invasive external Kanzius RF generator (600 W, 13.56 MHz) was used for hyperthermia exposures. Luciferase activity was measured using a bioluminescence assay and viability was assessed using Annexin V-FITC and propidium iodide staining. Heat shock proteins were analysed using western blot analysis. RESULTS: Duration-dependent luciferase denaturation was observed in SNU449 cells exposed to RF field that preceded measurable loss in viability. Loss of luciferase activity was higher in cetuximab conjugated gold nanoparticle (C225-AuNP) treated cells. Using a standard curve from water bath experiments, the intracellular thermal dose was calculated. Cells treated with C225-AuNP accumulated 6.07 times higher intracellular thermal dose than the untreated controls over initial 4 min of RF exposure. CONCLUSION: Cancer cells when exposed to an external RF field exhibit dose-dependent protein denaturation. Luciferase denaturation assay can be used to quantify thermal dose delivered after RF exposures to cancer cells with and without nanoparticles. PMID- 22515343 TI - Percutaneous microwave ablation for liver cancer adjacent to the diaphragm. AB - PURPOSE: The aim of the study was to prospectively evaluate the safety and effectiveness of percutaneous microwave (MW) ablation for liver cancer adjacent to the diaphragm. MATERIALS AND METHODS: From May 2005 to June 2008, 89 patients with 96 hepatic lesions adjacent to the diaphragm (the shortest distance from the lesion margin to the diaphragm less than 5 mm), who underwent ultrasound (US) guided percutaneous MW ablation, were included in the study group. A total of 100 patients with 127 hepatic lesions not adjacent to the diaphragm (the shortest distance from the lesion to the diaphragm and the first or second branch of the hepatic vessels more than 10 mm), who underwent US-guided percutaneous MW ablation, were included in the control group. During the ablation the temperature of marginal ablation tissue proximal to the diaphragm was monitored and controlled at 50 degrees -60 degrees C for more than 10 min in the study group. We compared the results of ablation between the two groups. RESULTS: A total of 91 of 96 tumours (94.8%) in the study group and 123 of 127 tumours (96.9%) in the control group achieved complete ablation (P > 0.05). Local tumour progression was found in 18 of 96 tumours (18.8%) in the study group and 21 of 127 tumours (16.5%) in the control group during follow-up after MW ablation (P > 0.05). No major complications occurred in either group. CONCLUSIONS: Under strict temperature monitoring, percutaneous MW ablation is safe and can achieve a high complete ablation rate for the treatment of hepatic tumours adjacent to the diaphragm. PMID- 22515344 TI - Comparison of percutaneous radiofrequency ablation and open partial nephrectomy for the treatment of size- and location-matched renal masses. AB - PURPOSE: To compare percutaneous radiofrequency ablation (RFA) and open partial nephrectomy (OPN) for the treatment of renal cell carcinoma (RCC) with respect to renal function and mid-term oncological outcome. MATERIALS AND METHODS: From January 2006 to December 2008, 40 (RFA group) and 110 (OPN group) patients underwent RFA and OPN for sporadic RCC, respectively. The sizes and locations of RCCs were matched between the two groups. To determine the lesion size, the maximum transverse diameter was measured. Estimated glomerular filtration rates (eGFR) before and after treatment and overall three-year recurrence-free survival rates were calculated and compared. RESULTS: Tumours in the RFA and OPN groups ranged from 9-76 mm (24.4 +/- 13.1 mm) and from 6-60 mm (22.3 +/- 10.2 mm), respectively (p = 0.962). The locations of RCCs were not significantly different (p = 0.101-0.508). The mean reductions of eGFR in the RFA and OPN groups were 2.3 +/- 8.6 mL/min/1.73 m2 (range, -23 to +17.5 mL/min/1.73 m2) and 7.4 +/- 10.9 mL/min/1.73 m2 (-23.6 to +42.8 mL/min/1.73 m2, respectively (p = 0.013). Overall three-year recurrence-free survival rates in the RFA and OPN groups were 94.7% and 98.9%, respectively (p = 0.266). CONCLUSION: For treating size- and location matched RCCs, RFA is superior to OPN with respect to the preservation of renal function. Furthermore, RFA can achieve excellent mid-term outcomes that are equivalent to those of OPN. PMID- 22515345 TI - Temperature superposition for fast computation of 3D temperature distributions during optimization and planning of interstitial ultrasound hyperthermia treatments. AB - PURPOSE: A temperature superposition method has been developed for fast optimisation and planning of interstitial hyperthermia treatments with convectively cooled multi-transducer ultrasound applicators integrated within high dose rate (HDR) brachytherapy catheters. METHODS: Steady-state temperature distributions produced by individual tubular transducers capable of directional heating were pre-computed using finite element models (FEM) methods. The composite temperature distributions generated by multi-applicator implants were approximated as superposition sums of the pre-computed temperature profiles. Composite temperature distributions produced by the multi-applicator implants were also computed using accurate but computationally expensive FEM methods (considered here as the validation standard). Both methods were used for temperature calculation on a range of test implant geometries and representative patient cases (HDR implants in prostate (n = 13) and cervix (n = 2)), with optimised treatment plans created for the latter. RESULTS: Difference between temperatures calculated by the superposition and FEM methods was below 0.37 degrees C (95% confidence interval) in test implants at clinically relevant acoustic intensities (0.3-2.0 W/cm2) and blood perfusion (2 kg/m3/s). Difference in 41 degrees C isothermal volumes was below 8.3%. Superposition-based optimisations followed by FEM forward calculations (hybrid plans) were completed 4-7 times faster than FEM-only plans (FEM optimisation + FEM forward). Mean T90, T50 and T10 values from both plans were within 0.3 degrees C, 0.4 degrees C and 0.45 degrees C respectively, and the mean acoustic intensities were within 0.23 W/cm2. CONCLUSIONS: Temperature superposition provides a fast technique for forward or optimised planning of interstitial ultrasound hyperthermia treatments with calculations comparable to more accurate but time consuming FEM methods. PMID- 22515346 TI - A pilot study for clinical feasibility of the near-harmonic 2D referenceless PRFS thermometry in liver under free breathing using MR-guided LITT ablation data. AB - OBJECTIVES: The conventional implementations of proton resonance frequency shift (PRFS) magnetic resonance thermometry (MRT) require the subtraction of single or multiple temporal references, a motion sensitive critical feature. A pilot study was conducted here to investigate the clinical feasibility of near-harmonic two dimensional (2D) referenceless PRFS MRT, using patient data from MR-guided laser ablation of liver malignancies. METHODS: PRFS MRT with respiratory-triggered multi-slice gradient-recalled (GRE) acquisition was performed under free breathing in six patients. The precision of the novel referenceless MRT was compared with the reference phase subtraction. Coupling the referenceless MRT with a model-based, real-time compatible regularisation algorithm was also investigated. RESULTS: The precision of MRT was improved by a factor of 3.3 when using the referenceless method as compared to the reference phase subtraction. The approach combining referenceless PRFS MRT and model-based regularisation yielded an estimated precision of 0.7 degrees to 2.1 degrees C, resulting in millimetre-range agreement between the calculated thermal dose and the 24 h post treatment unperfused regions in liver. CONCLUSIONS: The application of the near harmonic 2D referenceless MRT method was feasible in a clinical scenario of MR guided laser-induced thermal therapy (LITT) ablation in liver and permitted accurate prediction of the thermal lesion under free breathing in conscious patients, obviating the need for a controlled breathing under general anaesthesia. PMID- 22515347 TI - The tolerance of reirradiation and hyperthermia in breast cancer patients with reconstructions. AB - BACKGROUND: Breast cancer recurrences in previously irradiated areas are treated with reirradiation (reRT) and hyperthermia (HT). The aim of this retrospective study is to quantify the toxicity of HT in breast cancer patients with reconstruction. METHODS: Between 1992 and 2009, 36 patients were treated with reRT with a scheme of 8 fractions of 4.0 Gy in 4 weeks, and HT on a total of 37 tissue reconstructions. The types of reconstructions were: split-thickness skin graft (15), transverse rectus abdominis myocutaneous flap (1), latissimus dorsi flap (14), rhomboid flap (1) or a combination of grafts and flaps (6). Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Patient, tumour, and treatment characteristics predictive for the endpoints were identified in univariate and multivariate analyses. The primary endpoint was HT toxicity. Secondary endpoints were acute and late radiotherapy (RT) toxicity, complete response (CR), local control (LC) and overall survival (OS). RESULTS: The median follow-up time was 64 months. Grade 2 HT toxicity occurred in four patients and grade 3 in three. The three patients with grade 3 HT toxicity required reoperation. None of the evaluated parameters showed a significant relationship with HT toxicity. The CR rate in 15 patients with macroscopic disease was 80%. The 3 and 5 year LC rates were 74% and 69%; the median OS was 55 months. CONCLUSIONS: Combined reRT and HT in breast cancer patients with reconstruction is safe and effective. PMID- 22515348 TI - A big smile for spring. PMID- 22515349 TI - HELLP syndrome with postpartum hepatic infarction and subcapsular bleeding. PMID- 22515351 TI - Site-selective catalysis: toward a regiodivergent resolution of 1,2-diols. AB - This paper demonstrates that the secondary hydroxyl can be functionalized in preference to the primary hydroxyl of a 1,2-diol. The site selectivity is achieved by using an enantioselective organic catalyst that is able to bond to the diol reversibly and covalently. The reaction has been parlayed into a divergent kinetic resolution on a racemic mixture, providing access to highly enantioenriched secondary-protected 1,2-diols in a single synthetic step. PMID- 22515352 TI - 2,6-Bis(5-(2,2-dimethylpropyl)-1H-pyrazol-3-yl)pyridine as a ligand for efficient actinide(III)/lanthanide(III) separation. AB - The N-donor complexing ligand 2,6-bis(5-(2,2-dimethylpropyl)-1H-pyrazol-3 yl)pyridine (C5-BPP) was synthesized and screened as an extracting agent selective for trivalent actinide cations over lanthanides. C5-BPP extracts Am(III) from up to 1 mol/L HNO(3) with a separation factor over Eu(III) of approximately 100. Due to its good performance as an extracting agent, the complexation of trivalent actinides and lanthanides with C5-BPP was studied. The solid-state compounds [Ln(C5-BPP)(NO(3))(3)(DMF)] (Ln = Sm(III), Eu(III)) were synthesized, fully characterized, and compared to the solution structure of the Am(III) 1:1 complex [Am(C5-BPP)(NO(3))(3)]. The high stability constant of log beta(3) = 14.8 +/- 0.4 determined for the Cm(III) 1:3 complex is in line with C5 BPP's high distribution ratios for Am(III) observed in extraction experiments. PMID- 22515354 TI - Single nucleotide polymorphisms of Helicobacter pylori dupA that lead to premature stop codons. AB - BACKGROUND: The detection of the putative disease-specific Helicobacter pylori marker duodenal ulcer promoting gene A (dupA) is currently based on PCR detection of jhp0917 and jhp0918 that form the gene. However, mutations that lead to premature stop codons that split off the dupA leading to truncated products cannot be evaluated by PCR. METHODS: We directly sequence the complete dupA of 75 dupA-positive strains of H. pylori isolated from patients with gastritis (n = 26), duodenal ulcer (n = 29), and gastric carcinoma (n = 20), to search for frame shifting mutations that lead to stop codon. RESULTS: Thirty-four strains had single nucleotide mutations in dupA that lead to premature stop codon creating smaller products than the predicted 1839 bp product and, for this reason, were considered as dupA-negative. Intact dupA was more frequently observed in strains isolated from duodenal ulcer patients (65.5%) than in patients with gastritis only (46.2%) or with gastric carcinoma (50%). In logistic analysis, the presence of the intact dupA independently associated with duodenal ulcer (OR = 5.06; 95% CI = 1.22-20.96, p = .02). CONCLUSION: We propose the primer walking methodology as a simple technique to sequence the gene. When we considered as dupA-positive only those strains that carry dupA gene without premature stop codons, the gene was associated with duodenal ulcer and, therefore, can be used as a marker for this disease in our population. PMID- 22515355 TI - Expression of adhesion and activation molecules on circulating monocytes in children with Helicobacter pylori infection. AB - OBJECTIVES: The aim of this study was to assess the cell surface expression of adhesion (CD11a, CD11b, CD11c, CD18, CD54, and CD58) and activation (CD14, HLA DR, and CD16) molecules on the circulating monocytes in Helicobacter pylori (H. pylori)-infected and noninfected children with gastritis, with the goal of comparing the results with those obtained from the controls. MATERIALS AND METHODS: Ninety-four children were studied: 47 of them with H. pylori infection (of those 25 children after the failure of eradication therapy) and 26 children with gastritis where H. pylori infection was excluded, as well as 21 controls. H. pylori infection status was assessed based on [13C] urea breath test, rapid urease test, and histology. Analysis of the monocyte surface molecule expression was carried out by flow cytometry. RESULTS: H. pylori-infected children and children who experienced a failure of the eradication therapy differed significantly in the expression of adhesion and activation molecule on circulating monocytes. A decrease, both in the proportion of CD11c- and CD14 bearing monocytes, and the expression of CD11c and CD14 molecules on circulating monocytes, was found in children in whom the eradication therapy failed (p < .05). Low expression of CD11b (p = .04) and CD18 (p = .02) integrins on monocytes was also observed. Additionally, the percentage of HLA-DR-bearing monocytes was decreased (p = .04), while the CD16 density receptor was increased (p = .02). Compared with the controls, low percentage of CD16-positive monocytes was noted in noninfected children with gastritis (p = .01). CONCLUSION: H. pylori eradication therapy in children causes inhibition of inflammatory response via a reduction in CD11b, CD11c, and CD18 beta2 integrin monocyte expression. PMID- 22515353 TI - The association between Barrett's esophagus and Helicobacter pylori infection: a meta-analysis. AB - OBJECTIVE: The effect of Helicobacter pylori on Barrett's esophagus is poorly understood. We conducted a meta-analysis to summarize the existing literature examining the effect that H. pylori has on Barrett's esophagus. DESIGN: We performed a comprehensive search to identify studies pertaining to the association between H. pylori and Barrett's esophagus. We conducted meta regression analyses to identify sources of variation in the effect of H. pylori on Barrett's esophagus. RESULTS: Our analysis included a total of 49 studies that examined the effect of H. pylori on Barrett's esophagus and seven studies that examined the effect of cag A positivity on Barrett's esophagus. Overall, H. pylori, and even more so cag A, tended to be protective for Barrett's esophagus in most studies; however, there was obvious heterogeneity across studies. The effect of H. pylori on Barrett's esophagus varied by geographic location and in the presence of selection and information biases. Only four studies were found without obvious selection and information bias, and these showed a protective effect of H. pylori on Barrett's esophagus (Relative risk = 0.46 [95% CI: 0.35, 0.60]). CONCLUSIONS: Estimates for the effect of H. pylori on Barrett's esophagus were heterogeneous across studies. We identified selection and information bias as potential sources of this heterogeneity. Few studies without obvious selection and information bias have been conducted to examine the effect of H. pylori on Barrett's esophagus, but in these, H. pylori infection is associated with a reduced risk of Barrett's esophagus. PMID- 22515356 TI - Fragmented CagA protein is highly immunoreactive in Japanese patients. AB - BACKGROUND: High-molecular-weight cell-associated proteins (HM-CAP) assay is the most popular serological immunoassay worldwide and has been developed from US isolates as the antigens. The accuracy is reduced when the sera are from adults and children in East Asia including Japan. To overcome the reduced accuracy, an enzyme immunoassay using Japanese strain-derived HM-CAP (JHM-CAP) was developed, in which the antigens were prepared by exactly the same procedure as HM-CAP. The performance of JHM-CAP was better than that of HM-CAP in Japanese adults as well as in children. The higher sensitivity was because of the presence of 100-kDa protein that was absent in the preparation of HM-CAP antigen. MATERIALS AND METHODS: Immunoblot analysis and peptide mass fingerprinting methods were used to identify the distinctive 100-kDa protein present in JHM-CAP antigens. The peptide sequence and identification were analyzed by Mascot Search on the database of Helicobacter pylori. The identified protein was confirmed by immunoblot with a specific antibody and inhibition assay by the sera. RESULTS: The distinctive 100-kDa protein was a fragment of CagA derived from Japanese clinical isolates, and the sera of Japanese patients had strongly reacted to the protein, probably to the exposed epitope on the fragmented CagA. The fragmentation of CagA had occurred in the process of antigen preparation in Japanese isolates, not in US isolates even under the same preparation. CONCLUSION: The distinctive 100-kDa protein was a fragment of CagA protein of H. pylori derived from Japanese clinical isolates, and Japanese patients including children are likely to react strongly to the exposed epitopes on fragmented CagA. PMID- 22515357 TI - Helicobacter pylori-associated regulation of forkhead transcription factors FoxO1/3a in human gastric cells. AB - BACKGROUND: Interaction of Helicobacter pylori with gastric mucosa leads to marked cellular and humoral host immunologic responses. The signaling pathways initiated by bacteria-host interaction that result in perturbations in cell structure and function remain unclear. Forkhead transcription factors of class O (FoxO) are implicated in the regulation of apoptosis, cell survival, and pathogenesis. H. pylori infection of gastric epithelial cells induces phosphoinositide-3 kinase (PI3K)-dependent Akt activation and cell survival signaling. We investigated the role of H. pylori-activated PI3K/Akt in the regulation of FoxO1/3a in gastric cells. METHODS: Immunoblot, immunoprecipitation, and fluorescence microscopy were used to assess the effect of infection of gastric epithelial cells with wild-type H. pylori and their isogenic cag pathogenicity island (PAI) or oipA mutants on the FoxO1/3a signaling pathways. Interleukin-8 release was determined by enzyme-linked immunosorbent assays. RESULTS: H. pylori infection resulted in activation of the PI3K p85 subunit and inactivation of FoxO1 and FoxO3a by their phosphorylation and translocation of from the nucleus to the cytoplasm. Inhibition of PI3K or Akt kinase activity reduced FoxO1/3a phosphorylation. Akt, FoxO1, or FoxO3a siRNA reduced H. pylori-induced interleukin-8 production. Infection with oipA mutants reduced PI3K/Akt activation and inhibited FoxO1/3a phosphorylation, whereas infection with cag PAI mutants reduced PI3K/Akt activity but did not inhibit FoxO1/3a activation. CONCLUSIONS: FoxO1 and FoxO3a are novel nuclear substrates of H. pylori-induced PI3K/Akt cell survival signaling pathways that partially control interleukin-8 production. OipA-regulated interleukin-8 release through PI3K/Akt is dependent on FoxO1/3a inactivation, whereas cag PAI-mediated interleukin-8 production employs FoxO1/3-independent signaling. PMID- 22515358 TI - Length of thymidine homopolymeric repeats modulates promoter activity of sabA in Helicobacter pylori. AB - BACKGROUND: Helicobacter pylori uses SabA to interact with sialyl-Lewis x on the gastric mucosal surface to establish persistent colonization. The number of CT repeats in sabA is variable and thus influences SabA translation, but the expression of SabA determined by Western blotting does not fully match with a CT sequence-based prediction. Furthermore, a homopolymeric thymidine (polyT) tract located upstream of sabA has been observed, but its role in regulating sabA expression is still unknown. METHODS: The transcriptional start site (TSS) of sabA in strains J99 and Hp258 was determined by 5' RACE. One hundred and fifteen clinical isolates were sequenced to analyze the distribution of the polyT tract length and promoter sequence. Finally, RT-PCR and an E. coli-lux reporter system were used to determine the sabA promoter activity with different lengths of the polyT tract. RESULTS: The TSS of sabA was located at 66 or 64 bp upstream of the translational start codon in J99 and Hp258, respectively. The polyT tract close to the -35 element varied from T10 to T28 in 115 clinical isolates, and 70% of the isolates contained a stretch of 14-19 Ts. The sabA gene displayed slipped strand mispairing (SSM) of the polyT tract, generating varying genotypes in J99 (16-18 Ts) and Hp258 (14-15 Ts). Furthermore, J99 with lengths of T16 and T30, had higher sabA promoter activity than the common length of T18. CONCLUSION: Our findings indicate that the sabA promoter region modulates its transcriptional activity through a variable polyT tract, and SSM generates mixed genotypes in the population. PMID- 22515360 TI - Randomized comparison of two non-bismuth-containing second-line rescue therapies for Helicobacter pylori. AB - BACKGROUND: Classical second-line anti-Helicobacter pylori includes proton-pump inhibitor, tetracycline, metronidazole, and bismuth salts, but alternative therapies are required owing to the restricted availability of the latter. Levofloxacin-containing triple therapy is recommended but is expensive. Besides, quinolone resistance in an endemic tuberculosis infection area like Taiwan is concerned. The low in vitro antibiotic resistance to amoxicillin and tetracycline in Taiwanese H. pylori strains implies that in vivo esomeprazole/amoxicillin/tetracycline (EAT) second-line rescue therapy may be effective. This study compared the efficacy of esomeprazole/amoxicillin/levofloxacin (EAL) and EAT second-line eradication therapies and determines the clinical factors influencing the efficacy of salvage regimens. MATERIALS AND METHODS: One hundred and twenty-eight patients who failed H. pylori eradication using the standard triple therapy for 7 days are randomly assigned to either EAL group (esomeprazole 40 mg twice daily, amoxicillin 1 g twice daily, and levofloxacin 500 mg once daily) for 7 days or EAT group (esomeprazole 40 mg twice daily, amoxicillin 1 g twice daily, tetracycline 500 mg four times daily) for 14 days. Follow-up endoscopy or urea breath test was performed 8 weeks later to assess treatment response. RESULTS: The eradication rates of EAL and EAT groups were 78.1 versus 75.0%, p = .676 (in intention-to treat analysis) and 80.3 versus 80%, p = .0964 (per-protocol analysis). Both groups exhibited similar drug compliance (95.3 vs 96.9%, p = .952) but more adverse events in the EAT group (6.3 vs 12.5%, p = .225). CONCLUSIONS: Despite low in vitro drug resistances to amoxicillin and tetracycline, the efficacy of 14 day EAT regimens attained an unacceptable report card of 75% eradication rates in intention-to-treat analysis and was not even superior to the 7-day EAL regimen. Drug-drug interaction between combined antibiotics should be considered other than in vivo drug resistances. PMID- 22515359 TI - Gemifloxacin can partially overcome quinolone resistance of H. pylori with gyrA mutation in Taiwan. AB - BACKGROUNDS: The levofloxacin resistance caused by gyrA gene mutation is rising rapidly to limit wide application for Helicobacter pylori eradication. We investigated whether gemifloxacin has a superior antimicrobial activity to levofloxacin against H. pylori. MATERIALS AND METHODS: Forty-four consecutive clinical H. pylori isolates with levofloxacin resistance and 80 randomly selected levofloxacin-sensitive controls were tested for gemifloxacin sensitivity by E test. The resistance to levofloxacin or gemifloxacin was defined as minimal inhibitory concentration (MIC) > 1 mg/L. The clinical features and GyrA mutation patterns checked by direct sequencing were also analyzed to assess its association with the H. pylori gemifloxacin resistance. RESULTS: All levofloxacin-sensitive H. pylori isolates were sensitive to gemifloxacin. Eight strains (18.2%) resistant to levofloxacin could be still sensitive to gemifloxacin. Gemifloxacin achieved a 5-time lower in MIC levels against levofloxacin-resistant isolates. Nearly all levofloxacin-resistant isolates (97.7%, 43/44) had GyrA mutation at amino acid position 87 or 91. Double mutation sites may play dual roles in quinolone resistance, as N87K plus H57Y or D91N plus V77A mutations showed high-level resistance to both quinolones; whereas D91Y plus A97V or D91N plus A97V mutations showed low level levofloxacin resistance to become sensitive to gemifloxacin. In H. pylori isolates with single N87K, D91Y or D91N mutation, near 20% was gemifloxacin-sensitive and levofloxacin-resistant. The gemifloxacin-resistant rate of H. pylori was higher in patients with gastric ulcer than in those without (p <.05). CONCLUSION: Gemifloxacin is superior to levofloxacin in antimicrobial activity against clinical H. pylori isolates, and even overcome some levofloxacin resistance. PMID- 22515361 TI - Comprehensive investigation of areae gastricae pattern in gastric corpus using magnifying narrow band imaging endoscopy in patients with chronic atrophic fundic gastritis. AB - BACKGROUND: Barium radiographic studies have suggested the importance of evaluating areae gastricae pattern for the diagnosis of gastritis. Significance of endoscopic appearance of areae gastricae in the diagnosis of chronic atrophic fundic gastritis (CAFG) was investigated by image-enhanced endoscopy. MATERIALS AND METHODS: Endoscopic images of the corpus lesser curvature were studied in 50 patients with CAFG. Extent of CAFG was evaluated with autofluorescence imaging endoscopy. The areae gastricae pattern was evaluated with 0.2% indigo carmine chromoendoscopy. Micro-mucosal structure was examined with magnifying chromoendoscopy and narrow band imaging. RESULTS: In patients with small extent of CAFG, polygonal areae gastricae separated by a narrow intervening part of areae gastricae was observed, whereas in patients with wide extent of CAFG, the size of the areae gastricae decreased and the width of the intervening part of areae gastricae increased (p < 0.001). Most areae gastricae showed a foveola-type micro-mucosal structure (82.7%), while intervening part of areae gastricae had a groove-type structure (98.0%, p < 0.001). Groove-type mucosa had a higher grade of atrophy (p < 0.001) and intestinal metaplasia (p < 0.001) compared with foveola type. CONCLUSIONS: As extent of CAFG widened, multifocal groove-type mucosa that had high-grade atrophy and intestinal metaplasia developed among areae gastricae and increased along the intervening part of areae gastricae. Our observations facilitate our understanding of the development and progression of CAFG. PMID- 22515363 TI - What is the definition of Helicobacter pylori-negative gastric cancer? Comment on: Helicobacter pylori-negative gastric cancer in South Korea: incidence and clinicopathologic characteristics. Helicobacter 2011; 16(5): 382-8. PMID- 22515362 TI - The impact of Helicobacter pylori on atopic disorders in childhood. AB - BACKGROUND: The prevalence of Helicobacter pylori in Western populations has steadily decreased. This has been suggested as one of the factors involved in the recent increase of asthma and allergy. Some studies have reported a negative association between H. pylori and asthma and allergy, but data are inconsistent and there are a few studies in children. AIM: We investigated whether the prevalence of H. pylori was associated with asthma symptoms, allergic rhinitis, and atopic dermatitis in childhood. METHODS: We determined IgG anti-H. pylori and CagA antibodies in serum of Dutch children, who took part in the PIAMA birth cohort study. Serum was collected from 545 children, aged 7-9 years (Dutch ethnicity 91.5%). Symptoms of asthma and atopy were assessed by yearly questionnaires. Chi-square tests and logistic regression were used. RESULTS: We found 9%H. pylori and 0.9% CagA seropositivity. Twelve (5.9%) children with reported wheezing ever were H. pylori positive, compared to 37 (10.9%) of the non wheezers (p = .05). No significant differences in H. pylori prevalence were found between children with or without allergic rhinitis (8.5% vs 9.5%), atopic dermatitis (8.7% vs 9.2%), and physician-diagnosed asthma (7.1% vs 9.4%). Multivariate analysis showed no significant associations between H. pylori seropositivity and wheezing (OR 0.52; 95% CI 0.25-1.06), allergic rhinitis (OR 0.96; 95% CI 0.51-1.81), atopic dermatitis (OR 1.05; 95% CI 0.56-1.98) or physician-diagnosed asthma (OR 0.87; 95% CI 0.37-2.08). CONCLUSION: We found a borderline significantly lower H. pylori seropositivity in children with wheezing compared to non-wheezers, but no association between H. pylori serum-antibody status and allergic rhinitis, atopic dermatitis, or asthma. PMID- 22515365 TI - Second-site suppressors of HIV-1 capsid mutations: restoration of intracellular activities without correction of intrinsic capsid stability defects. AB - BACKGROUND: Disassembly of the viral capsid following penetration into the cytoplasm, or uncoating, is a poorly understood stage of retrovirus infection. Based on previous studies of HIV-1 CA mutants exhibiting altered capsid stability, we concluded that formation of a capsid of optimal intrinsic stability is crucial for HIV-1 infection. RESULTS: To further examine the connection between HIV-1 capsid stability and infectivity, we isolated second-site suppressors of HIV-1 mutants exhibiting unstable (P38A) or hyperstable (E45A) capsids. We identified the respective suppressor mutations, T216I and R132T, which restored virus replication in a human T cell line and markedly enhanced the fitness of the original mutants as revealed in single-cycle infection assays. Analysis of the corresponding purified N-terminal domain CA proteins by NMR spectroscopy demonstrated that the E45A and R132T mutations induced structural changes that are localized to the regions of the mutations, while the P38A mutation resulted in changes extending to neighboring regions in space. Unexpectedly, neither suppressor mutation corrected the intrinsic viral capsid stability defect associated with the respective original mutation. Nonetheless, the R132T mutation rescued the selective infectivity impairment exhibited by the E45A mutant in aphidicolin-arrested cells, and the double mutant regained sensitivity to the small molecule inhibitor PF74. The T216I mutation rescued the impaired ability of the P38A mutant virus to abrogate restriction by TRIMCyp and TRIM5alpha. CONCLUSIONS: The second-site suppressor mutations in CA that we have identified rescue virus infection without correcting the intrinsic capsid stability defects associated with the P38A and E45A mutations. The suppressors also restored wild type virus function in several cell-based assays. We propose that while proper HIV-1 uncoating in target cells is dependent on the intrinsic stability of the viral capsid, the effects of stability-altering mutations can be mitigated by additional mutations that affect interactions with host factors in target cells or the consequences of these interactions. The ability of mutations at other CA surfaces to compensate for effects at the NTD-NTD interface further indicates that uncoating in target cells is controlled by multiple intersubunit interfaces in the viral capsid. PMID- 22515366 TI - Synthesis and antitumor efficacy of a beta-glucuronidase-responsive albumin binding prodrug of doxorubicin. AB - In this paper we describe the synthesis and biological evaluation of the first beta-glucuronidase-responsive albumin-binding prodrug designed for the selective delivery of doxorubicin at the tumor site. This prodrug leads to superior antitumor efficacy in mice compared to HMR 1826, a well-known glucuronide prodrug of doxorubicin that cannot bind covalently to circulating albumin. Furthermore, this compound inhibits tumor growth in a manner similar to that of doxorubicin while avoiding side effects induced by the free drug. PMID- 22515367 TI - Kinetic control of translation initiation in bacteria. AB - Translation initiation is a crucial step of protein synthesis which largely defines how the composition of the cellular transcriptome is converted to the proteome and controls the response and adaptation to environmental stimuli. The efficiency of translation of individual mRNAs, and hence the basal shape of the proteome, is defined by the structures of the mRNA translation initiation regions. Initiation efficiency can be regulated by small molecules, proteins, or antisense RNAs, underscoring its importance in translational control. Although initiation has been studied in bacteria for decades, many aspects remain poorly understood. Recent evidence has suggested an unexpected diversity of pathways by which mRNAs can be recruited to the bacterial ribosome, the importance of structural dynamics of initiation intermediates, and the complexity of checkpoints for mRNA selection. In this review, we discuss how the ribosome shapes the landscape of translation initiation by non-linear kinetic processing of the transcriptome information. We summarize the major pathways by which mRNAs enter the ribosome depending on the structure of their 5' untranslated regions, the assembly and the structure of initiation intermediates, the individual and synergistic roles of initiation factors, and the mechanisms of mRNA and initiator tRNA selection. PMID- 22515368 TI - Photopatterning of multilayer n-alkylsilane films. AB - Surface photopatterning of organosilane self-assembled monolayers (SAM) has received increasing attention since its introduction 20 years ago. Herein we report for the first time a cost-efficient soft photopatterning technique affording amplified 3D multilayer structures. The essential chemistry relies on a spatially controlled photoacid-catalyzed hydrolysis and polycondensation of n alkyltrimethoxysilane precursors (n-C(12)H(25)Si(OCH(3))(3),). Amphiphilic siloxane species are photogenerated locally and are able to self-assemble spontaneously into a long-range-ordered lamellar mesostructure. PMID- 22515369 TI - Constraints and facilitators to participation in physical activity in teenagers with Developmental Co-ordination Disorder: an exploratory interview study. AB - BACKGROUND: Despite their movement difficulties, youngsters with Developmental Co ordination Disorder (DCD) generally have sufficient capability for physical activity. However, they tend to be less physically active and less physically fit than their well co-ordinated age peers. The aim of this study was to use qualitative research methods to understand which factors constrain and facilitate participation in physical activity in teenagers with DCD, in order to help inform future health promotion programmes. METHOD: Semi-structured interviews were conducted with eight teenagers with DCD (aged 13-15) and their parents. The interviews focused on how much physical activity was typically undertaken by the child and the perceived constraints and facilitators to being physically active. Interviews were transcribed and subjected to categorical-content analysis. RESULTS: Half of the children and all but one of the parents reported that the children did little physical activity. Although most children disliked competitive team games, they reported many physical activities that they did enjoy and they reported wanting to be more physically active. Perceived internal constraints to participation included poor motor skill, lack of motivation and reports of fatiguing easily. Perceived external constraints included difficulty travelling to activities, negative comments from peers and teachers' lack of understanding of DCD. CONCLUSIONS: Reports of low levels of physical activity support previous literature and are a cause for concern for this group. The teenagers expressed the desire to be more active, yet the interviews revealed both personal and environmental constraints to engagement in physical activity. It is clear that these factors interact in a dynamic way and that teachers, schools and communities play an important role in creating a motivational environment for youngsters with DCD to engage in physical activity and learn to maintain an active lifestyle as they move into adulthood. PMID- 22515371 TI - A retrospective, deformable registration analysis of the impact of PET-CT planning on patterns of failure in stereotactic body radiation therapy for recurrent head and neck cancer. AB - BACKGROUND: Stereotactic body radiation therapy (SBRT) has seen increasing use as a salvage strategy for selected patients with recurrent, previously-irradiated squamous cell carcinoma of the head and neck (rSCCHN). PET-CT may be advantageous for tumor delineation and evaluation of treatment failures in SBRT. We analyzed the patterns of failure following SBRT for rSCCHN and assessed the impact of PET CT treatment planning on these patterns of failure. METHODS: We retrospectively reviewed 96 patients with rSCCHN treated with SBRT. Seven patients (7%) were treated after surgical resection of rSCCHN and 89 patients (93%) were treated definitively. PET-CT treatment planning was used for 45 patients whereas non-PET CT planning was used for 51 patients. Categories of failure were assigned by comparing recurrences on post-treatment scans to the planning target volume (PTV) from planning scans using the deformable registration function of VelocityAITM. Failures were defined: In-field (>75% inside PTV), Overlap (20-75% inside PTV), Marginal (<20% inside PTV but closest edge within 1cm of PTV), or Regional/Distant (more than 1cm from PTV). RESULTS: Median follow-up was 7.4 months (range, 2.6-52 months). Of 96 patients, 47 (49%) developed post-SBRT failure. Failure distribution was: In-field-12.3%, Overlap-24.6%, Marginal-36.8%, Regional/Distant-26.3%. There was a significant improvement in overall failure free survival (log rank p = 0.037) and combined Overlap/Marginal failure-free survival (log rank p = 0.037) for those receiving PET-CT planning vs. non-PET-CT planning in the overall cohort (n = 96). Analysis of the definitive SBRT subgroup (n = 89) increased the significance of these findings (overall failure: p = 0.008, Overlap/Marginal failure: p = 0.009). There were no significant differences in age, gender, time from prior radiation, dose, use of cetuximab with SBRT, tumor differentiation, and tumor volume between the PET-CT and non-PET CT groups. CONCLUSIONS: Most failures after SBRT treatment for rSCCHN were near misses, i.e. Overlap/Marginal failures (61.4%), suggesting an opportunity to improve outcomes with more sensitive imaging. PET-CT treatment planning showed the lowest rate of overall and near miss failures and is beneficial for SBRT treatment planning. PMID- 22515370 TI - Stratum corneum dysfunction in dandruff. AB - Dandruff is characterized by a flaky, pruritic scalp and affects up to half the world's population post-puberty. The aetiology of dandruff is multifactorial, influenced by Malassezia, sebum production and individual susceptibility. The commensal yeast Malassezia is a strong contributory factor to dandruff formation, but the presence of Malassezia on healthy scalps indicates that Malassezia alone is not a sufficient cause. A healthy stratum corneum (SC) forms a protective barrier to prevent water loss and maintain hydration of the scalp. It also protects against external insults such as microorganisms, including Malassezia, and toxic materials. Severe or chronic barrier damage can impair proper hydration, leading to atypical epidermal proliferation, keratinocyte differentiation and SC maturation, which may underlie some dandruff symptoms. The depleted and disorganized structural lipids of the dandruff SC are consistent with the weakened barrier indicated by elevated transepidermal water loss. Further evidence of a weakened barrier in dandruff includes subclinical inflammation and higher susceptibility to topical irritants. We are proposing that disruption of the SC of the scalp may facilitate dandruff generation, in part by affecting susceptibility to metabolites from Malassezia. Treatment of dandruff with cosmetic products to directly improve SC integrity while providing effective antifungal activity may thus be beneficial. PMID- 22515373 TI - The meta-language of psychiatry as cross-disciplinary effort: in response to Zachar (2012). PMID- 22515374 TI - Advancing science and improving outcomes. PMID- 22515372 TI - Biomonitoring of aristolactam-DNA adducts in human tissues using ultra performance liquid chromatography/ion-trap mass spectrometry. AB - Aristolochic acids (AAs) are a structurally related family of nephrotoxic and carcinogenic nitrophenanthrene compounds found in Aristolochia herbaceous plants, many of which have been used worldwide for medicinal purposes. AAs have been implicated in the etiology of so-called Chinese herbs nephropathy and of Balkan endemic nephropathy. Both of these disease syndromes are associated with carcinomas of the upper urinary tract (UUC). 8-Methoxy-6-nitrophenanthro-[3,4-d] 1,3-dioxolo-5-carboxylic acid (AA-I) is a principal component of Aristolochia herbs. Following metabolic activation, AA-I reacts with DNA to form aristolactam (AL-I)-DNA adducts. We have developed a sensitive analytical method, using ultraperformance liquid chromatography-electrospray ionization/multistage mass spectrometry (UPLC-ESI/MS(n)) with a linear quadrupole ion-trap mass spectrometer, to measure 7-(deoxyadenosin-N(6)-yl) aristolactam I (dA-AL-I) and 7 (deoxyguanosin-N(2)-yl) aristolactam I (dG-AL-I) adducts. Using 10 MUg of DNA for measurements, the lower limits of quantitation of dA-AL-I and dG-AL-I are, respectively, 0.3 and 1.0 adducts per 10(8) DNA bases. We have used UPLC ESI/MS(n) to quantify AL-DNA adducts in tissues of rodents exposed to AA and in the renal cortex of patients with UUC who reside in Taiwan, where the incidence of this uncommon cancer is the highest reported for any country in the world. In human tissues, dA-AL-I was detected at levels ranging from 9 to 338 adducts per 10(8) DNA bases, whereas dG-AL-I was not found. We conclude that UPLC-ESI/MS(n) is a highly sensitive, specific and robust analytical method, positioned to supplant (32)P-postlabeling techniques currently used for biomonitoring of DNA adducts in human tissues. Importantly, UPLC-ESI/MS(n) could be used to document exposure to AA, the toxicant responsible for AA nephropathy and its associated UUC. PMID- 22515375 TI - Gerontological Nursing Academic Capacity: Annual Survey 2012. PMID- 22515376 TI - A carbaboranylmercuric salt catalyzed reaction; highly regioselective cycloisomerization of 1,3-dienes. AB - The combination of carbaboranylmercuric chloride (new type of bulky Lewis acid) and silver triflate efficiently catalyzes cycloisomerization of 1,3-dienes at room temperature. The catalytic system gives allyl-substituted azacycles and cycloalkanes in excellent yields with high to complete regioselectivity. PMID- 22515377 TI - DEET (N,N-diethyl-meta-toluamide) induced delay of blowfly landing and oviposition rates on treated pig carrion (Sus scrofa L.). AB - The question of whether the insect repellent N,N-Diethyl-meta-toluamide (DEET) affected fly attraction, oviposition, and larval development was investigated; in part, to determine whether the common habit of wearing DEET as a repellent could affect the rate of human decomposition. Experiments using pig surrogates of human decedents were carried out in a rural environment. Dead piglets were sprayed with DEET, and fly behavior, colonization levels, and maggot development were compared with those in nonsprayed controls. Piglets treated with DEET experienced significant delays in fly visitation and oviposition and delayed appearance of each larval instar, as well as reduced total larval numbers (p < 0.01 for all variables), with subsequently reduced decomposition (p < 0.05). Such changes in fly behavior and larval population development would significantly impact the estimation of the period following the death from entomological evidence in decedents wearing DEET at the time of their death. PMID- 22515378 TI - Lower extremity neuropathies after robot-assisted laparoscopic prostatectomy on a split-leg table. AB - BACKGROUND AND PURPOSE: Lower extremity neuropathies from prolonged lithotomy positioning have been well documented. When we initiated our robot-assisted laparoscopic prostatectomy (RALP) program in December 2002, we chose to use the split-leg table that allows patient support in a more anatomic position, hypothesizing that this would reduce risk of neurologic compression injuries. We report our incidence of lower extremity neuropathies associated with RALP using split-leg positioning and review patient and surgical variables associated with this complication. PATIENTS AND METHODS: We retrospectively reviewed records of 377 patients who underwent RALP using a split-leg table. Patient data including height, weight, body mass index, age, and smoking status; surgical variables such as surgeon operative experience and intraoperative times were also assessed. Intraoperative time was defined as anesthesia induction to anesthesia emergence to more accurately measure total time patients spent in the split-leg position. RESULTS: Of 377 patients, lower extremity neuropathies developed in 5 (1.3%) in the immediate postoperative period. Of all variables examined, only increased intraoperative time was identified as a potential risk factor for the development of this complication (496.2 +/- 34.8 min vs 366.3 +/- 96.1 min, P<0.001). Overall mean operative time for all patients was 368.0 +/- 96.6 minutes. Three of the five patients had symptoms suggestive of a femoral mononeuropathy. CONCLUSIONS: Intraoperative time as defined in our study is a significant risk factor for development of postoperative neuropathy. We also found that split-leg positioning appears to put the femoral nerve at risk for injury, instead of the common peroneal nerve as has been previously reported from prolonged lithotomy positioning. PMID- 22515379 TI - Cambodian patients' and health professionals' views regarding the allocation of antiretroviral drugs. AB - The way Cambodian patients and health professionals judge the priority of HIV infected patients in relation to the allocation of antiretroviral drugs was examined. Participants were either HIV-infected patients attending the HIV/AIDS Care and Support Centre for People Living with HIV/AIDS in Phnom Penh (29 females and 21 males) or members of the staff (9 physicians, 6 pharmacists and 15 health counsellors and health educators). They were presented with stories of a few lines depicting a patient's situation and were instructed to judge the extent to which the patient should be given priority for HIV drugs. The stories were composed according to a four within-subject factor design: (a) the patient's family responsibilities, (b) the severity of infection, (c) the time elapsed since the first consultation, and (d) the financial difficulties of the family. Most patients expressed the view that the drugs should be used for the patients who are most important from a familial point of view, namely, when the family contains small children and/or is already in a precarious financial condition. PMID- 22515380 TI - Validation of a new LC-MS/MS method for the detection and quantification of phenolic metabolites from tomato sauce in biological samples. AB - Tomato is a good source of bioactive molecules such as vitamin C, carotenoids, and phenolic compounds. Up to now, only a few studies have evaluated the bioavailability of phenolic compounds from tomato. This paper presents the optimization of a method for the determination of phenolics in tomato and their metabolites in human urine and plasma after ingestion of tomato sauce. The sample preparation includes a SPE step to obtain cleaner extracts for injection in the LC-MS/MS system. The mean recovery of analytes ranged from 73 to 104% in plasma and from 65 to 106% in urine, the accuracy was between 90.3 and 115.0% in urine and between 85.7 and 115.0% in plasma, and the precision coefficient of variation was <15%. The method allowed detection and quantification limits of 0.5-29 and 2.0-90 ng mL-1 in urine, respectively, and 0.5-30 and 2.0-105 ng mL-1 in plasma, respectively, for the same phenolic compounds. PMID- 22515382 TI - Design of polydiacetylene-phospholipid supramolecules for enhanced stability and sensitivity. AB - We present polydiacetylene (PDA) liposome assemblies with various phospholipids that have different headgroup charges and phase transition temperatures (T(m)). 10,12-Pentacosadiynoic acid (PCDA)-epoxy was used as a base PDA monomer and the insertion of highly charged phospholipids resulted in notable changes in the size of liposome and reduction of the aggregation of PDA liposome. Among the various phospholipids, the phospholipid with a moderate T(m) demonstrated enhanced stability and sensitivity, as measured by the size and zeta potential over storage time, thermochoromic response, and transmission electron microscopy images. By combining these results, we were able to detect immunologically an antibody of bovine viral diarrhea virus over a wide dynamic range of 0.001 to 100 MUg/mL. PMID- 22515383 TI - Special issue on severe asthma. PMID- 22515384 TI - Obesity as a risk factor for increased asthma severity and allergic inflammation; cause or effect? PMID- 22515386 TI - What is severe asthma? AB - Asthma is common, and some individuals are severely affected by it. Learned institutions have sought to provide a definition of 'severe asthma' to facilitate research and clinical care. This is a challenging undertaking given the difficulty in defining asthma and the lack of supportive evidence for a distinct severe asthma phenotype. In this review, we discuss the rationale for a definition of severe asthma and the relative merits of the sequential attempts that have been made to produce such a definition. The difficulty in disentangling control and severity is highlighted, as is the heterogeneity of phenotype in severe asthma, and potential for misclassification. We conclude that the search for a singular definition of severe asthma is problematic, though likely to continue. We suggest the alternative strategy of using classifiers with a specific aim related to symptoms, pathophysiology or service provision. PMID- 22515385 TI - Nitric oxide and asthma severity: towards a better understanding of asthma phenotypes. PMID- 22515387 TI - Pathogenesis of severe asthma. AB - Patients with severe asthma have asthma symptoms which are difficult to control, require high dosages of medication, and continue to experience persistent symptoms, asthma exacerbations or airflow obstruction. Epidemiological and clinical evidences point to the fact that severe asthma is not a single phenotype. Cluster analyses have identified subclasses of severe asthma using parameters such as patient characteristics, and cytokine profiles have also been useful in classifying moderate and severe asthma. The IL-4/IL-13 signalling pathway accounts for the symptoms experienced by a subset of severe asthmatics with allergen-associated symptoms and high serum immunoglobulin E (IgE) levels, and these patients are generally responsive to anti-IgE treatment. The IL-5/IL-33 signalling pathway is likely to play a key role in the disease pathogenesis of those who are resistant to high doses of inhaled corticosteroid but responsive to systemic corticosteroids and anti-IL5 therapy. The IL-17 signalling pathway is thought to contribute to 'neutrophilic asthma'. Although traditionally viewed as players in the defence mechanism against viral and intracellular bacterial infection, mounting evidence supports a role for Th1 cytokines such as IL-18 and IFN-gamma in severe asthma pathogenesis. Furthermore, these cytokine signalling pathways interact to contribute to the spectrum of clinical pathological outcomes in severe asthma. To date, glucocorticoids are the most effective anti-asthma drugs available, yet severe asthma patients are typically resistant to the effects of glucocorticoids. Glucocorticoid receptor dysfunction and histone deacetylase activity reduction are likely to contribute to glucocorticoid resistance in severe asthma patients. This review discusses recent development in different cytokine signalling pathways, their interactions and steroid resistance, in the context of severe asthma pathogenesis. PMID- 22515389 TI - Exacerbations of severe asthma. AB - Exacerbations occur frequently in severe asthma. They result in significant morbidity and can lead to hospitalization and death. Severe exacerbations can also lead to an accelerated decline in lung function. Phenotyping severe asthma can aid with both prognostication of exacerbation risk and maintenance treatment selection to minimize future risks of exacerbations in severe asthma. The rate of exacerbations differs by phenotype, and is most frequent in refractory eosinophilic asthma and early onset allergic asthma. Phenotype specific therapy can reduce exacerbations in both these forms of severe asthma. Exacerbations are multi-component events. Each exacerbation represents an opportunity to assess and target treatment to the domains of airway pharmacotherapy, self-management behaviour, risk factors, and relevant co-morbidities. PMID- 22515390 TI - The investigation of severe asthma to define phenotypes. AB - Severe asthmatics often exhibit poor control despite high doses of inhaled corticosteroids with or without systemic corticosteroids and suffer from persistent symptoms and/or recurrent exacerbations. Five to ten percentage of the asthmatic population falls within this category. Patients with severe asthma are a heterogeneous group and should be investigated to confirm the diagnosis, identify comorbidities, exclude alternative diagnoses, together with an evaluation of treatment adherence and side-effects from medications. Optimization of asthma medications and monitoring the control and pattern of asthma usually takes place over a period of 6 months. In patients with confirmed severe refractory asthma, further evaluation is needed in terms of detailed lung function, of airway and lung structure using high resolution computed tomographic scanning, and of airway inflammatory processes and biomarkers using induced sputum or bronchial biopsies. Patients with severe asthma are best investigated and managed with a multidisciplinary team. Severe asthma consists of different phenotypes that need defining. Investigation of severe asthma should bring into the open the various characteristics of the disease that could point to particular phenotype. Inclusion of investigations based on transcriptomics and proteomics should expand, improve classification and understanding of severe asthma, with the ultimate hope of finding more effective treatments and a step towards personalized medicine. PMID- 22515391 TI - Severe asthma: future treatments. AB - BACKGROUND: Patients with severe refractory asthma have not achieved asthma control, even with high doses of ICS, usually in combination with LABAs and other maintenance treatments. OBJECTIVE: The most promising approaches currently under investigation are those which reduce airway eosinophils in patients with severe refractory asthma and a persisting airway eosinophilia. RESULTS: Monoclonal antibodies against IL-5 have been shown to improve lung function, improve asthma control, reduce exacerbation risk and allow reduction or elimination of maintenance oral corticosteroids in this subset of patients. Bronchial thermoplasty may provide benefit in improving control and reducing exacerbations in selected patients. The addition of the muscarinic antagonist, tiotropium also improves airflow obstruction, but its benefit on exacerbation risk is not yet established. Other developments being evaluated in severe refractory asthma are CXCR2 antagonists in patients with a persisting neutrophilic airway inflammation, and CRTh2 antagonists, both of which are small molecule antagonists, and hMabs against IL4 and IL-13. Finally, other approaches to reduce receptor numbers, using inhaled anti-sense, has shown to reduce allergen-induced airway eosinophilia, and combining different anti-sense against different targets may become a feasible treatment option. CONCLUSIONS: A variety of new treatment options are being investigated to help improve overall asthma control in patients with severe refractory asthma. These include medications to optimize lung function; bronchial thermoplasty to reduce airway smooth muscle in central airways; and those which target specific inflammatory cells or receptors of inflammatory mediators. CLINICAL RELEVANCE: Patients with severe refractory asthma have the greatest unmet treatment needs to improve asthma control and reduce exacerbation risk. New treatment approaches have been identified which will benefit subsets of these patients. Phenotyping patients is necessary to select those likely to benefit. PMID- 22515388 TI - The role of allergy in severe asthma. AB - The classification of asthma to identify forms which have different contributing causes is useful for all cases in which the disease requires regular treatment, but it is essential for the management of severe asthma. Many forms of the disease can occur, and complex mixtures are not uncommon; here we artificially separated the cases into four groups: (i) inhalant allergy, (ii) fungal sensitization with or without colonization (including ABPA); (iii) severe sinusitis with or without aspirin-exacerbated respiratory disease (AERD), and (iv) non-inflammatory cases, including those associated with severe obesity and vocal cord dysfunction (VCD). The reason for focusing on these groups is because they illustrate how much the specific management depends upon correct classification. Inhalant allergy can present as chronically severe asthma. However, severe attacks of asthma requiring hospital admission can occur in cases which are generally only mild or moderate. The best recognized and probably the most common cause of these acute episodes is acute infection with a rhinovirus. Recent evidence suggests that high titre IgE, particularly to dust mite, correlates to exacerbations of asthma related to rhinovirus infection. Although it is well recognized that the fungus Aspergillus can colonize the lungs and cause severe disease, it is less well recognized that those cases may not have full criteria for diagnosis of ABPA or may involve other fungi. Identifying fungal cases is important, because treatment with imidazole antifungals can provide significant benefit. Taken together, specific treatment using allergen avoidance, immunotherapy, anti-IgE, or antifungal treatment is an important part of the successful management of severe asthma, and each of these requires correctly identifying specific sensitization. PMID- 22515392 TI - Non-atopic males with adult onset asthma are at risk of persistent airflow limitation. AB - BACKGROUND: Patients with asthma have on average a more rapid decline in FEV (1) as compared with the general population. Recent cluster analysis has revealed different asthma phenotypes that can be distinguished by age of onset and reversibility of airflow limitation. OBJECTIVE: This study aimed at detecting risk factors associated with persistent airflow limitation in patients with the adult onset asthma phenotype. METHODS: We recruited 88 patients with adult onset (>= 18 years) asthma from an academic pulmonary outpatient clinic in the Netherlands. The associations of age, age of asthma onset, asthma duration, gender, race, atopy, smoking pack-years, BMI, use of oral corticosteroids with post-bronchodilator FEV (1) /FVC were investigated. RESULTS: Multiple linear regression analysis showed an association of absence of atopy (r = -0.27, B = 0.26, P = 0.01) and male gender (r = 0.31, B = 0.30, P = 0.004) with post bronchodilator FEV (1) /FVC. Multiple logistic regression analysis showed that male patients were 10.8 (CI: 2.6-45.2) times the odds than women to have an FEV (1) /FVC < 0.7, and non-atopic patients were 5.2 (CI: 1.3-20.3) times the odds to have an FEV (1) /FVC < 0.7 than atopic patients. CONCLUSIONS AND CLINICAL RELEVANCE: We conclude that in patients with adult onset asthma, male gender and absence of atopy are associated with persistent airflow limitation. This might suggest that amongst patients with adult onset asthma, non-atopic male patients are at increased risk of accelerated decline in lung function. PMID- 22515393 TI - Associated demographics of persistent exhaled nitric oxide elevation in treated asthmatics. AB - BACKGROUND: The fraction of exhaled nitric oxide (FENO) is reduced by anti inflammatory treatment in asthma. However, the FENO level is also regulated by individual demographics and there is considerable variation among clinically stable patients. OBJECTIVE: We hypothesized that some demographics may be responsible for persistent FENO elevation despite inhaled corticosteroids (ICS) therapy in asthma. METHODS: This was a prospective observational study. We initially screened 250 stable asthmatics and determined the FENO cut-off point for identifying poorly controlled asthma defined by one of the following criteria: Asthma control test <20, or forced expiratory volume in one-second % of predicted <80%, or peak expiratory flow variability <80% (Study 1). After 12 weeks, 229 patients who maintained high or low FENO were selected and the independent factors which might contribute to a high FENO were examined (Study 2). RESULTS: A FENO level >39.5 p.p.b. yielded 67% sensitivity and 76% specificity for identifying the patients with poorly controlled asthma. The persistent high FENO group (>= 40 p.p.b.) was more likely to be ex-smokers, to show evidence of atopy (positive specific IgE, higher serum IgE and blood eosinophils), and to have allergic comorbidities. Especially, past smoking history, blood eosinophils, and chronic rhinosinusitis were identified to be independent predictors of high FENO. Neither the dose of ICS nor other medication use showed any difference between the groups. CONCLUSIONS AND CLINICAL RELEVANCE: These results suggested that past smoking history, blood eosinophilia, and chronic rhinosinusitis are involved in the persistent airway inflammation detected by FENO. Although their relative contributions on FENO values should be further quantified, clarification of the features of the subjects with high FENO might provide clues for adjustment of the treatment approach in asthma. PMID- 22515395 TI - Prediction of asthma exacerbations in children: results of a one-year prospective study. AB - BACKGROUND: Underdiagnosis and low levels of asthma control are frequent occurring problems in patients with asthma. OBJECTIVE: The study aim was to evaluate the ability of non-invasive inflammatory markers in exhaled breath to predict exacerbations of childhood asthma, and to assess the time course of changes in these exhaled markers before, during and after exacerbations. METHODS: The design was a prospective one-year longitudinal study. Regular two-month visits at the outpatient clinic were performed. Forty children with asthma (aged 6-16 years) participated. The primary outcome measure was the occurrence of an exacerbation. Assessment was made of the presence and severity of pulmonary symptoms, use of medication, and measurements of forced expiratory volume in 1 s using home monitor. The following independent parameters were assessed during outpatient visits: (1) exhaled nitric oxide, (2) inflammatory markers in exhaled breath condensate: acidity, nitrite, hydrogen peroxide, interleukin-1alpha, -5, 13, interferon-gamma, (3) lung function, (4) asthma control score. RESULTS: Thirty-eight of 40 children completed the study. Sixteen children developed exacerbations, of which ten were moderate and six severe. Univariate Cox regression analysis revealed that condensate acidity, interleukin-5 and asthma control score were significant predictors of an asthma exacerbation (P < 0.05). In the multivariate Cox regression analysis, exacerbations were best predicted by the asthma control score and by the level of interleukin-5 in exhaled breath condensate (Wald scores of 7.19 and 4.44, P = 0.007 and P = 0.035 respectively). The predicted survival curve of this multivariate model showed a two times reduced risk on exacerbations in the category of children with the 10% most optimal values of IL-5 and asthma control score. CONCLUSIONS AND CLINICAL RELEVANCE: Both exhaled breath condensate interleukin-5 level and asthma control score were significant predictors of asthma exacerbations. These findings open up the possibility of assessing the potential of such parameters to titrate asthma treatment in future studies. PMID- 22515396 TI - The role of seasonal grass pollen on childhood asthma emergency department presentations. AB - BACKGROUND: Few studies have focused on the role of grass pollen on asthma emergency department (ED) presentations among children. None have examined whether a dose-response effect exists between grass pollen levels and these asthma exacerbations. OBJECTIVES: To examine the association between increasing ambient levels of grass pollen and asthma ED presentations in children. To determine whether these associations are seen only after a thunderstorm, or whether grass pollen levels have a consistent influence on childhood asthma ED visits during the season. METHODS: A short time series ecological study was conducted for asthma presentations to ED among children in Melbourne, Victoria, and grass pollen, meteorological and air quality measurements recorded during the selected 2003 period. A semi-parametric Poisson regression model was used to examine dose-response associations between daily grass pollen levels and mean daily ED attendance for asthma. RESULTS: A smoothed plot suggested a dose response association. As ambient grass pollen increased to about 19 grains/m(3) , the same day risk of childhood ED presentations also increased linearly (P < 0.001). Grass pollen levels were also associated with an increased risk in asthma ED presentations on the following day (lag 1, P < 0.001). CONCLUSION: This is the first study to establish a clear relationship between increased risk of childhood asthma ED attendance and levels of ambient grass pollen below 20 grains/m(3) , independent of any impact of thunderstorm-associated asthma. These findings have important implications for patient care, such as asthma management programs that notify the general public regarding periods of high grass pollen exposure, as well as defining the timing of initiation of pollen immunotherapy. PMID- 22515394 TI - Isolation of filamentous fungi from sputum in asthma is associated with reduced post-bronchodilator FEV1. AB - BACKGROUND: Fungal sensitization is common in severe asthma, but the clinical relevance of this and the relationship with airway colonization by fungi remain unclear. The range of fungi that may colonize the airways in asthma is unknown. OBJECTIVE: To provide a comprehensive analysis on the range of filamentous fungi isolated in sputum from people with asthma and report the relationship with their clinico-immunological features of their disease. METHODS: We recruited 126 subjects with a diagnosis of asthma, 94% with moderate-severe disease, and 18 healthy volunteers. At a single stable visit, subjects underwent spirometry; sputum fungal culture and a sputum cell differential count; skin prick testing to both common aeroallergens and an extended fungal panel; specific IgE to Aspergillus fumigatus. Fungi were identified by morphology and species identity was confirmed by sequencing. Four patients had allergic bronchopulmonary aspergillosis. RESULTS: Forty-eight percent of asthma subjects were IgE sensitized to one fungal allergen and 22% to >= 2. Twenty-seven different taxa of filamentous fungi were isolated from 54% of their sputa, more than one species being detected in 17%. This compared with 3 (17%) healthy controls culturing any fungus (P < 0.01). Aspergillus species were most frequently cultured in isolation followed by Penicillium species. Post-bronchodilator FEV (1) (% predicted) in the subjects with asthma was 71(+/- 25) in those with a positive fungal culture vs. 83 (+/- 25) in those culture-negative, (P < 0.01). CONCLUSION AND CLINICAL RELEVANCE: Numerous thermotolerant fungi other than A. fumigatus can be cultured from sputum of people with moderate-to-severe asthma; a positive culture is associated with an impaired post-bronchodilator FEV (1) , which might be partly responsible for the development of fixed airflow obstruction in asthma. Sensitization to these fungi is also common. PMID- 22515397 TI - Re: The average Adjusted Symptom Score, a new primary efficacy end-point for specific allergen immunotherapy trials. PMID- 22515402 TI - Magnetic interactions in A-site-ordered perovskites LnCu3(Ge(3/4)Ga(1/4))4O12 (Ln = La, Dy). AB - A-site-ordered perovskites LaCu(3)(Ge(3/4)Ga(1/4))(4)O(12) and DyCu(3)(Ge(3/4)Ga(1/4))(4)O(12) were synthesized, and their magnetism was investigated. Ferromagnetic ordering of the square-planar-coordinated Cu(2+) spins was observed at 12-13 K in both compounds, and the Dy(3+) moment in DyCu(3)(Ge(3/4)Ga(1/4))(4)O(12) stayed paramagnetic below T(C). The decoupling of the magnetic behavior of Cu(2+) and Dy(3+) sublattices revealed the weak magnetic interaction between Cu(2+) and Dy(3+). PMID- 22515401 TI - Finding out what matters: validity of quality of life measurement in young people with ASD. AB - BACKGROUND: Compared with other conditions there has been a lack of focus on quality of life (QoL) as an outcome measure for children and young people with Autism Spectrum Disorder (ASD). This pilot study aimed to evaluate the validity of existing QoL questionnaires for use with children with ASD aged 8-12 years. METHODS: A literature review (1990-2011) identified the PedsQL (Pediatric Quality of Life Inventory) and Kidscreen as robust measures used with children with neurodevelopmental disorders. These measures were completed by 10 children and 11 parents. In addition semi-structured interviews were conducted with 10 parents and four children to explore their experience of completing the QoL questionnaires. RESULTS: Young people with ASD, and their parents, report lower child QoL compared with a normative sample. Framework analysis of the data highlighted six key themes which may affect the validity of generic QoL measures when administered within an ASD sample and which warrant further investigation. CONCLUSIONS: Our results indicate that a new condition-specific measure of QoL, grounded in ASD children's own perspectives of their lives, is needed and that such a measure should assess experiences of anxiety and access to special interests when measuring QoL of children with ASD. Active involvement of young people and their families is critical for the development of a theoretical framework for QoL within ASD, and any future development of an ASD-specific measure. PMID- 22515400 TI - The risk of AIDS-defining events is decreasing over time in the German HIV-1 Seroconverter Cohort. AB - BACKGROUND: With ageing of the HIV-infected population, long-term exposure to treatment, varying adherence, emerging resistance and complications to therapies, effectiveness of Highly Active Antiretroviral Therapy (HAART) needs to be monitored continuously at the population level. The German HIV-1 Seroconverter Cohort is a multi-centre, open, long-term observational cohort including patients with a known or reliably estimated date of HIV-infection i.e. last negative and first positive HIV antibody test within a maximum three-year interval or laboratory evidence of seroconversion. Our study aims to investigate survival improvements and changes in AIDS risk over calendar periods in the German HIV-1 Seroconverter Cohort. METHODS: Retrospective (for the pre-1997 period) and prospective (since 1997) data from the German HIV-1 Seroconverter Cohort were used. Time from seroconversion to first AIDS-defining event over calendar periods was analysed by using Cox models adjusting for age at seroconversion, sex, transmission groups and short HIV test interval. Kaplan-Meier methods were used to determine expected survival (remaining AIDS-free) by calendar period. RESULTS: 2162 seroconverters with 8976 person-years of observation were included in our analysis (up to 31.12.2010). A total of 196 first AIDS defining events were reported. Two periods i.e. 19972000 and 2007-2010 were statistically associated with a reduction in the risk of AIDS, accounting for an overall reduction of 80%. Compared to1997-2000, hazard ratios were 2.6 (95%CI, 1.6-4.8; p=0.000) in pre 1997 and 0.5 (95%CI, 0.3-0.8; p=0.007) in 20072010. Independent risk factor for AIDS progression was age at seroconversion (HR, 1.3 per 10 year-increase; p=0.001). CONCLUSION: HAART effectiveness has improved in the German HIV-1 Seroconverter Cohort. The risk to develop AIDS decreased significantly in 19972000 and in 20072010. However, elderly may require particular monitoring in view of their faster progression to AIDS. PMID- 22515403 TI - LTBP-2 acts as a novel marker in human heart failure - a preliminary study. AB - BACKGROUND: We have observed increased expression of latent TGF-beta binding protein (LTBP)-2 mRNA in human failing hearts. This study was aimed to further confirm LTBP-2 act as a novel marker in human acute heart failure. METHODS AND RESULTS: We demonstrated that median level of LTBP-2 in myocardial samples from heart failure patients was significantly elevated, and TGF-beta1 significantly promoted LTBP-2 expression in neonatal rat cardiomyocytes. To investigate the potential of LTBP-2 as a biomarker to diagnose heart failure with reduced ejection fraction (HFREF), another cohort of 133 consecutive patients with dyspnea were enrolled. In receiver operating characteristic (ROC) curve analyses to detect HFREF, LTBP-2 achieved an area under curve (AUC) of 0.67 (95% confidence intervals (CI) 0.58-0.75), comparable to the diagnostic ability of NT proBNP 0.68 (95% CI 0.59-0.77). CONCLUSION: The serum LTBP-2 levels might act as a promising biomarker in HFREF. PMID- 22515404 TI - Feasibility of implementing magnesium sulphate for neuroprotection in a tertiary obstetric unit. AB - BACKGROUND: It is important to establish whether research recommendations regarding magnesium sulphate for neuroprotection can be readily translated into clinical practice and achieve the dual objectives of good coverage of the target group, while minimising unnecessary or prolonged exposure to treatment. METHODS: This retrospective cohort study included all women admitted to a tertiary obstetric centre at 23-32 weeks gestation in the first 12 months following implementation of the guideline 'Magnesium sulphate for the prevention of cerebral palsy'. We determined the number triaged to receive magnesium sulphate, the proportion of infants who received magnesium sulphate prior to delivery and the total number of doses administered. RESULTS: A total of 330 women were admitted at a mean gestational age of 28.2 weeks, and 132/330 (40%) were prescribed magnesium sulphate, of whom 123/132 (93%) delivered. 142/191 (74%) infants born at <32 weeks' gestation received magnesium sulphate prior to delivery, with no significant differences seen by plurality or gestational age. Of the 145 doses administered, only 13 women received more than one dose, and only nine of 145 (7%) doses proved to be unnecessary. The median treatment duration was 3 h 58 min. The infusion was discontinued as result of side effects in 2% of women. CONCLUSION: Research recommendations regarding administration of magnesium sulphate with neuroprotective intent can be successfully translated into clinical practice. Appropriate triaging of women at high risk of imminent preterm birth is feasible, enabling a high level of magnesium sulphate coverage for infants that deliver prior to 32 weeks gestation, with minimal toxicity and a low rate of unnecessary maternal exposure. PMID- 22515405 TI - Thiophene bioisosteres of spirocyclic sigma receptor ligands: relationships between substitution pattern and sigma receptor affinity. AB - On the basis of the 6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] framework, a series of more than 30 sigma ligands with versatile substituents in 1-, 2'-, and 6'-position has been synthesized and pharmacologically evaluated in order to find novel structure-affinity relationships. It was found that a cyclohexylmethyl residue at the piperidine N-atom instead of a benzyl moiety led to increased sigma(2) affinity and therefore to decreased sigma(1)/sigma(2) selectivity. Small substituents (e.g., OH, OCH(3), CN, CH(2)OH) in 6'-position adjacent to the O-atom were well tolerated by the sigma(1) receptor. Removal of the substituent in 6'-position resulted in very potent but unselective sigma ligands (13). A broad range of substituents with various lipophilic and H-bond forming properties was introduced in 2'-position adjacent to the S-atom without loss of sigma(1) affinity. However, very polar and basic substituents in both 2'- and 6'-position decreased the sigma(1) affinity considerably. It is postulated that the electron density of the thiophene moiety has a big impact on the sigma(1) affinity. PMID- 22515406 TI - Visible skin colouration predicts perception of male facial age, health and attractiveness. AB - Although there is evidence that perception of facial age, health and attractiveness is informed by shape characteristics as well as by visible skin condition, studies on the latter have focused almost exclusively on female skin. Recent research, however, suggests that a decrease in skin colour homogeneity leads to older, less healthy and less attractive ratings of facial skin in both women and men. Here, we elaborate on the significance of the homogeneity of visible skin colouration in men by testing the hypothesis that perception of age, health and attractiveness of (non-contextual) digitally isolated fields of cheek skin only can predict that of whole facial images. Facial digital images of 160 British men (all Caucasian) aged between 10 and 70 were blind-rated for age, health and attractiveness by a total of 147 men and 154 women (mean age = 22.95, SD = 4.26), and these ratings were related to those of corresponding images of cheek skin reported by Fink et al. (J. Eur. Acad. Dermatol. Venereol. in press). Linear regression analysis showed that age, health and attractiveness perception of men's faces could be predicted by the ratings of cheek skin only, such that older men were viewed as older, less healthy and less attractive. This result underlines once again the potent signalling role of skin in its own right, independent of shape or other factors and suggests strongly that visible skin condition, and skin colour homogeneity in particular, plays a significant role in the perception of men's faces. PMID- 22515407 TI - Effect of soccer footwear on landing mechanics. AB - Lower-extremity injury is common in soccer. A number of studies have begun to assess why specific lower-extremity injuries occur. However, currently few studies have examined how footwear affects lower-extremity mechanics. In order to address this question, 14 male (age: 22.1 +/- 3.9 years, height: 1.77 +/- 0.06 m, and mass: 73.3 +/- 11.5 kg) and 14 female (age: 22.8 +/- 3.1 years, height: 1.68 +/- 0.07 m and mass: 64.4 +/- 9.2 kg) competitive soccer players underwent a motion analysis assessment while performing a jump heading task. Each subject performed the task in three different footwear conditions (running shoe, bladed cleat, and turf shoe). Two-way analyses of variance were used to examine statistical differences in landing mechanics between the footwear conditions while controlling for gender differences. These comparisons were made during two different parts (prior to and following) of a soccer-specific jump heading task. A statistically significant interaction for the peak dorsiflexion angle (P = 0.02) and peak knee flexion angle (P = 0.05) was observed. Male soccer players exhibited a degree increase in dorsiflexion in the bladed cleat while female soccer players exhibited a three-degree reduction in peak knee flexion in the bladed cleat condition. Other main effects for gender and footwear were also observed. The results suggest that landing mechanics differ based upon gender, footwear, and the type of landing. Therefore, training interventions aimed at reducing lower-extremity injury should consider utilizing sport-specific footwear when assessing movement patterns. PMID- 22515408 TI - Early life adversity is associated with brain changes in subjects at family risk for depression. AB - OBJECTIVE: The interplay of genetic and early environmental factors is recognized as an important factor in the aetiology of major depressive disorder (MDD). The aim of the present study was to examine whether reduced volume of hippocampus and frontal brain regions involved in emotional regulation are already present in unaffected healthy individuals at genetic risk of suffering MDD and to investigate whether early life adversity is a relevant factor interacting with these reduced brain structures. METHOD: Twenty unaffected first-degree relatives of patients with MDD (FHP: family history positive) and 20 healthy controls (FHN: family history negative) underwent high-resolution magnetic resonance imaging. Manual tracing of hippocampal sub-regions and voxel-based morphometry was used to compare groups and find association to early life adversity. RESULTS: FHP subjects with history of emotional abuse had significantly smaller left and right hippocampal heads. VBM also showed smaller dorsolateral prefrontal cortices (DLPFC), medial prefrontal cortices (MPFC) and anterior cortex cinguli in FHP who had a previous history of emotional abuse. CONCLUSION: High risk individuals for depression have reduced volume of brain regions related to emotional processing in particular when they additionally suffered childhood abuse, indicating that genetic and environmental factors like early life adversity influence brain structure possibly via epigenetic mechanisms and thus structural anomalies may precede the onset of the illness. PMID- 22515409 TI - Simian retroviruses in African apes. AB - It is now well established that simian immunodeficiency viruses (SIVs) from chimpanzees (SIVcpz) and gorillas (SIVgor) from west Central Africa are at the origin of HIV-1/AIDS. Apes are also infected with other retroviruses, notably simian T-cell lymphotropic viruses (STLVs) and simian foamy viruses (SFVs), that can be transmitted to humans. We discuss the actual knowledge on SIV, STLV and SFV infections in chimpanzees, gorillas, and bonobos. We especially elaborate on how the recent development of non-invasive methods has allowed us to identify the reservoirs of the HIV-1 ancestors in chimpanzees and gorillas, and increased our knowledge of the natural history of SIV infections in chimpanzees. Multiple cross species events with retroviruses from apes to humans have occurred, but only one transmission of SIVcpz from chimpanzees in south-eastern Cameroon spread worldwide, and is responsible for the actual HIV pandemic. Frequent SFV transmissions have been recently reported, but no human-to-human transmission has been documented yet. Because humans are still in contact with apes, identification of pathogens in wild ape populations can signal which pathogens may be cause risk for humans, and allow the development of serological and molecular assays with which to detect transmissions to humans. Finally, non invasive sampling also allows the study of the impact of retroviruses and other pathogens on the health and survival of endangered species such as chimpanzees, gorillas, and bonobos. PMID- 22515410 TI - Li-O2 battery with a dimethylformamide electrolyte. AB - Stability of the electrolyte toward reduced oxygen species generated at the cathode is a crucial challenge for the rechargeable nonaqueous Li-O(2) battery. Here, we investigate dimethylformamide as the basis of an electrolyte. Although reactions at the O(2) cathode on the first discharge-charge cycle are dominated by reversible Li(2)O(2) formation/decomposition, there is also electrolyte decomposition, which increases on cycling. The products of decomposition at the cathode on discharge are Li(2)O(2), Li(2)CO(3), HCO(2)Li, CH(3)CO(2)Li, NO, H(2)O, and CO(2). Li(2)CO(3) accumulates in the electrode with cycling. The stability of dimethylformamide toward reduced oxygen species is insufficient for its use in the rechargeable nonaqueous Li-O(2) battery. PMID- 22515411 TI - Effects of zinc supplementation on diabetes mellitus: a systematic review and meta-analysis. AB - The number of people with diabetes and pre-diabetes are exponentially increasing. Studies on humans have shown the beneficial effects of Zinc supplementation in patients with diabetes. The present study aims to systematically evaluate the literature and meta-analyze the effects of Zinc supplementation on diabetes. A systematic review of published studies reporting the effects of Zinc supplementations on diabetes mellitus was undertaken. The literature search was conducted in the following databases; PubMed, Web of Science and SciVerse Scopus. A meta-analysis of studies examining the effects of Zinc supplementation on clinical and biochemical parameters in patients with diabetes was performed. The total number of articles included in the present review is 25, which included 3 studies on type-1 diabetes and 22 studies on type 2 diabetes. There were 12 studies comparing the effects of Zinc supplementation on fasting blood glucose in patients with type-2 diabetes. The pooled mean difference in fasting blood glucose between Zinc supplemented and placebo groups was 18.13mg/dl (95%CI:33.85,2.41; p<0.05). 2-h post-prandial blood sugar also shows a similar distinct reduction in (34.87mg/dl [95%CI:75.44; 5.69]) the Zinc treated group. The reduction in HbA1c was 0.54% (95%CI:0.86;0.21) in the Zinc treated group. There were 8 studies comparing the effects of Zinc supplementation on lipid parameters in patients with type-2 diabetes. The pooled mean difference for total cholesterol between Zinc supplemented and placebo groups was 32.37mg/dl (95%CI:57.39,7.35; p<0.05). Low-density lipoprotein cholesterol also showed a similar distinct reduction in the Zinc treated group, the pooled mean difference from random effects analysis was 11.19mg/dl (95%CI:21.14,1.25; p<0.05). Studies have also shown a significant reduction in systolic and diastolic blood pressures after Zinc supplementation. This first comprehensive systematic review and meta analysis on the effects of Zinc supplementation in patients with diabetes demonstrates that Zinc supplementation has beneficial effects on glycaemic control and promotes healthy lipid parameters. Further studies are required to identify the exact biological mechanisms responsible for these results. PMID- 22515412 TI - The predictive validity of implicit measures of self-determined motivation across health-related behaviours. AB - OBJECTIVE: Research on health-related behaviour has typically adopted deliberative models of motivation and explicit measures. However, growing support for implicit processes in motivation and health-related behaviour has caused a shift towards developing models that incorporate implicit and explicit processes. METHODS: The current research advances this area by comparing the predictive validity of a newly developed implicit measure of motivation from self determination theory (SDT) with explicit measures of motivation for 20 health related behaviours, in a sample of undergraduate students (N= 162). A dual systems model was developed to test whether implicit motivation provided unique prediction of behaviour. RESULTS: Structural equation models for each behaviour indicated some support for the role of implicit measures; explicit measures and intention provided more consistent, significant prediction across most behaviours. CONCLUSIONS: This study provides some support for dual systems models, and offers an important contribution to understanding why some behaviours may be better predicted by either implicit or explicit measures. Future implications for implicit processes and SDT are outlined. STATEMENT OF CONTRIBUTION: WHAT IS ALREADY KNOWN ON THIS SUBJECT? : Previous research has highlighted the unique effects of implicit processes on goal-directed behaviour. Several studies have supported the role of implicit processes in motivation. WHAT DOES THIS STUDY ADD? : The current study adds to the previous literature by investigating the role of implicit processes and self-determination theory. Furthermore, the current study uses a relatively novel implicit measure across a wide range of behaviours. Finally, the current study incorporates a dual-systems model to provide a conceptual understanding of the findings. PMID- 22515413 TI - Functioning and effectiveness of electronic control devices such as the TASER(r) M- and X-series: a review of the current literature. AB - Conducted electrical weapons (CEWs) such as the TASER((r)) M- and X-series deliver short high-voltage, low-current energy pulses to temporarily paralyze a person by causing electrical interruption of the body's normal energy pulses. Despite many scientific publications, which classify the health risks of an appropriate use of the TASER device as minor, there still is a continuous uncertainty about possible side effects with human application. Based on a literature search of the National Library of Medicine's MEDLINE database's PubMed system of current publications, the following article describes the mechanisms by which the device operates and discusses possible pathophysiological consequences. The majority of current human literature has not found evidence of clinical relevant pathophysiological effects during and after an exposure of professionally applied CEWs. However, to be able to exclude possible health risks, a medical checkup of people who have been exposed to CEWs is essential. PMID- 22515414 TI - Docosahexaenoic acid ameliorates palmitate-induced lipid accumulation and inflammation through repressing NLRC4 inflammasome activation in HepG2 cells. AB - BACKGROUND: N-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA; 22:6n-3), has clinical significance in the prevention and reversal of nonalcoholic steatohepatitis (NASH). However, the precious mechanism underlying remains unclear. The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR) family members, has been recently shown to be activated in NASH and promote the cleavage of the pro-inflammatory cytokines to their maturation forms. METHODS: HepG2 cells were exposed to different dose of PA for 24 h with or without the preincubation of 50 MUM DHA for another 24 h and then lipid deposition was assessed with Oil red O staining and intracellular triglyceride (TG) determination. Secretory levels of inflammatory cytokines and Caspase-1 activity were determined by ELISA assays. Gene expression and protein levels were determined by quantitative RCR and western blotting, respectively. RESULTS: Palmitate (PA) dose-dependently increased lipid accumulation, TG content and induced the secretion of interleukin-1beta (IL-1beta), IL-18, TNF-alpha and MCP-1 from HepG2 cells. Preincubation with DHA significantly alleviated PA-induced lipid accumulation and inflammatory agents. DHA was also found to attenuate PA induced NOD-like receptor protein 4 (NLRC4) mRNA expression. Furthermore, PA induced caspase-1 activation in a dose-dependent manner, resulting in exacerbating of procaspase-1 and pro-IL-1beta processing. Knockdown of NLRC4 partially abrogated PA-induced caspase-1 activation and IL-1beta maturation and completely abolished these events in the presence of DHA. CONCLUSIONS: Our findings indicate DHA attenuates PA-induced lipid accumulation and inflammation through suppressing NLRC4 inflammasome activation, caspase-1 activation and IL 1beta cleavage. PMID- 22515415 TI - The effect of work shift and sleep duration on various aspects of police officers' health. AB - Police officers are prone to cardiovascular disease, overweight, and obesity. Because night-shift work affects sleep, a modifiable risk factor linked to chronic disease, the researchers explored the relationship among shift work, sleep, and wellness for police officers. Sleep, C-reactive protein (CRP) levels, stress, fatigue, and body mass index were used to compare officers who worked primarily day shifts to those who worked primarily evening or night shifts, and officers who slept less than 6 hours per day to those who slept at least 6 hours per day. A cross-sectional study of 85 male officers, 20 to 63 years old, was completed at three Midwestern police departments. The Pittsburgh Sleep Quality Index was used to assess sleep. A questionnaire was used to collect officer demographics and work hours. Other measurements included serum CRP, height, weight, perceived stress, and vital exhaustion. The relative risk of sleeping less than 6 hours per day for officers who primarily worked non-day shifts, compared to those who worked day shifts, was 14.27 (95% confidence interval [CI], 1.98-102.95, p < .001), and the relative risk of overall poor sleep quality for officers who slept less than 6 hours per day, compared to those who slept more hours, was 2.44 (95% CI, 1.15-5.20, p = .027). CRP was not associated with shift or sleep duration, even when adjusted for officers' ages. PMID- 22515416 TI - Effects of valsartan or ramipril addition to amlodipine/hydrochlorothiazide combination on left ventricular mass in diabetic hypertensive patients with left ventricular hypertrophy. AB - OBJECTIVE: The objective of this study was to compare valsartan or ramipril addition to amlodipine + hydrochlorothiazide (HCTZ) on blood pressure (BP) and left ventricular hypertrophy (LVH) in hypertensive diabetic patients with LVH. RESEARCH DESIGN AND METHODS: 293 patients were treated with amlodipine 10 mg + HCTZ 12.5 combination and then randomized to receive valsartan 160 mg or ramipril 5 mg, in addition to the previous therapy, for 1 year. MAIN OUTCOME MEASURES: Clinic BP was measured every month; echocardiographic assessments were performed at the end of the placebo period, both before the randomization and after 1-year of triple combination therapy. RESULTS: Both triple regimens similarly reduced SBP/DBP values (-13.5/10.9 mm Hg in the valsartan group and -13.4/10.4 mm Hg in the ramipril group). Triple combination including valsartan better reduced LVMI ( 20.1%, p < 0.001), interventricular septal thickness (IVST) (-20.3%, p < 0.001) and left ventricular posterior wall thickness (PWT) (-16.3%, p < 0.001), compared with triple combination including ramipril (-14%, p < 0.01; -16.2%, p < 0.001 and -9%, p < 0.01, respectively); the difference between treatments being statistically significant (p < 0.05). Triple combination with valsartan gave a greater increase of E/A ratio (p < 0.05 between groups). CONCLUSIONS: Valsartan addition to dual therapy with amlodipine + HCTZ was more effective than ramipril addition in reducing LVH. PMID- 22515417 TI - Technology-based programs to improve walking behavior of persons with multiple disabilities: two single-case studies. AB - PURPOSE: Assessing two technology-based programs for reducing toe walking and breaks during walking of two men with multiple disabilities, respectively. METHOD: The men were involved in separate single-case studies, each of which was carried out according to an ABAB design. The technology included a microprocessor with specific software, optic sensors, and visual plus vibrotactile or auditory systems for presenting preferred stimuli. In Study I, the man received 1 s of preferred flickering lights and vibratory input for each step performed with the heel of the left foot touching the ground or coming close to it (i.e. within a 2 mm distance). In Study II, the other man received 10 s of preferred music anytime he crossed one of the small marks present along the travel routes. RESULTS: The B phases showed that (a) the man included in Study I increased the percentages of left- and right-foot steps performed with the heels touching or nearing the ground to above 85% and 70%, respectively, and (b) the man included in Study II walked with very few breaks. CONCLUSION: Technology-based programs can be highly effective in helping persons with multiple disabilities improve their walking behavior. PMID- 22515418 TI - Effect of additives on subcritical water hydrolysis of whey protein isolate. AB - The objective was to examine the effect of the additives acetic acid, lactic acid, sodium bicarbonate, sodium chloride, and sodium hydroxide on the hydrolysis of whey protein isolate with subcritical water. A screening experimental design was used to study the effect of temperature, time, and additives. The most influential additive, sodium bicarbonate, along with temperature and time was used in a second experimental design to predict the treatment conditions to maximize the degree of hydrolysis and production of free amino acids. The maximum degree of hydrolysis achieved was 50% at a concentration of 1.24 M sodium bicarbonate, 291 degrees C, and 28 min. The highest concentration of total amino acids was 83.0 mg/g of whey protein isolate with 0.83 M sodium bicarbonate at 264 degrees C for 29 min. Compared to water alone, sodium bicarbonate increased the degree of hydrolysis 4-fold and the production of amino acids by 44% and decreased peptides' molecular weight. PMID- 22515419 TI - Dinuclear Cu(II) complexes of isomeric bis-(3-acetylacetonate)benzene ligands: synthesis, structure, and magnetic properties. AB - Highly versatile coordinating ligands are designed and synthesized with two beta diketonate groups linked at the carbon 3 through a phenyl ring. The rigid aromatic spacer is introduced in the molecules to orient the two acetylacetone units along different angles and coordination vectors. The resulting para, meta, and ortho bis-(3-acetylacetonate)benzene ligands show efficient chelating properties toward Cu(II) ions. In the presence of 2,2'-bipyridine, they promptly react and yield three dimers, 1, 2, and 3, with the bis-acetylacetonate unit in bridging position between two metal centers. X-ray single crystal diffraction shows that the compounds form supramolecular chains in the solid state because of intermolecular interactions. Each of the dinuclear complexes shows a magnetic behavior which is determined by the combination of structural parameters and spin polarization effects. Notably, the para derivative (1) displays a moderate antiferromagnetic coupling (J = -3.3 cm(-1)) along a remarkably long Cu...Cu distance (12.30 A). PMID- 22515420 TI - Sensing micelle hydration by proton-transfer dynamics of a 3-hydroxychromone dye: role of the surfactant headgroup and chain length. AB - The dynamics of the excited-state intramolecular proton-transfer (ESIPT) reaction of 2-(2'-furyl)-3-hydroxychromone (FHC) was studied in micelles by time-resolved fluorescence. The proton-transfer dynamics of FHC was found to be sensitive to the hydration and charge of the micelles, demonstrated through a decrease of the ESIPT rate constant (k(PT)) in the sequence cationic -> nonionic -> anionic micelles. A remarkably slow ESIPT with a time constant (tau(PT)) of ~100 ps was observed in the anionic sodium dodecyl sulfate and sodium tetradecyl sulfate micelles, whereas it was quite fast (tau(PT) ~ 15 ps) in the cationic cetyltrimethylammonium bromide and tetradecyltrimethylammonium bromide micelles. In the nonionic micelles of Brij-78, Brij-58, Tween-80, and Tween-20, ESIPT occurred with time constants (tau(PT) ~ 35-65 ps) intermediate between those of the cationic and anionic micelles. The slower ESIPT dynamics in the anionic micelles than the cationic micelles is attributed to a relatively stronger hydration of the negatively charged headgroups of the former than the positively charged headgroups of the latter, which significantly weakens the intramolecular hydrogen bond of FHC in the Stern layer of the anionic micelles compared to the latter. In addition, electrostatic attraction between the positively charged N(CH(3))(3)(+) headgroups and the negatively charged 4-carbonyl moiety of FHC effectively screens the intramolecular hydrogen bond from the perturbation of water molecules in the micelle-water interface of the cationic micelles, whereas in the anionic micelles, this screening of the intramolecular hydrogen bond is much less efficient due to an electrostatic repulsion between its negatively charged -OSO(3)(-) headgroups and the 4-carbonyl moiety. As for the nonionic micelles, a moderate level of hydration, and the absence of any charged headgroups, causes an ESIPT dynamics faster than that of the anionic but slower than that of the cationic micelles. Furthermore, the ESIPT rate decreased with a decrease of the hydrophobic chain length of the surfactants due to the stronger hydration of the micelles of shorter chain surfactants than those of longer chain surfactants, arising from a less compact packing of the former surfactants compared to the latter surfactants. PMID- 22515421 TI - Low serum MMP-1 in breast cancer: a negative prognostic factor? AB - In this study we investigated the prognostic significance of serum matrix metalloproteinase (MMP)-1 levels in early-stage breast cancer patients and correlated these levels with various clinicopathologic parameters. MMP-1 levels were determined by enzyme-linked immunosorbent assay. MMP-1 serum levels in patients (n = 60) were significantly lower than in healthy subjects (n = 20, p < 0.0001). We found significant negative correlation between serum levels of MMP-1 and several negative prognostic factors of breast cancer. Kaplan-Meier analysis showed significantly shorter 5-year survival in patients with lower values of MMP 1 compared to those with high levels of MMP-1 (p = 0.0147). Our results suggest a negative prognostic role of low serum MMP-1. PMID- 22515422 TI - Recognition of dextran-superparamagnetic iron oxide nanoparticle conjugates (Feridex) via macrophage scavenger receptor charged domains. AB - Dextran-coated superparamagnetic iron oxide nanoparticles (dextran-SPIO conjugates) offer the attractive possibility of enhancing MRI imaging sensitivity so that small or diffuse lesions can be detected. However, systemically injected SPIOs are rapidly removed by macrophages. We engineered embryonic cells (HEK293T) to express major macrophage scavenger receptor (SR) subtypes including SR-AI, MARCO, and endothelial receptor collectin-12. These SRs possess a positively charged collagen-like (CL) domain and they promoted SPIO uptake, while the charge neutral lipoprotein receptor SR-BI did not. In silico modeling indicated a positive net charge on the CL domain and a net negative charge on the cysteine rich (CR) domain of MARCO and SR-AI. In vitro experiments revealed that CR domain deletion in SR-AI boosted uptake of SPIO 3-fold, while deletion of MARCO's CR domain abolished this uptake. These data suggest that future studies might productively focus on the validation and further exploration of SR charge fields in SPIO recognition. PMID- 22515423 TI - US IRBs confronting research in the developing world. AB - Increasingly, US-sponsored research is carried out in developing countries, but how US Institutional Review Boards (IRBs) approach the challenges they then face is unclear. METHODS: I conducted in-depth interviews of about 2 hours each, with 46 IRB chairs, directors, administrators and members. I contacted the leadership of 60 IRBs in the United States (US) (every fourth one in the list of the top 240 institutions by National Institutes of Health (NIH) funding), and interviewed IRB leaders from 34 (55%). RESULTS: US IRBs face ethical and logistical challenges in interpreting and applying principles and regulations in developing countries, given economic and health disparities, and limited contextual knowledge. These IRBs perceive wide variations in developing world IRBs/RECs' quality, resources and training; and health systems in some countries may have long-standing practices of corruption. These US IRBs often know little of local contexts, regulations and standards of care, and struggle with understandings of other cultures' differing views of autonomy, and risks and benefits of daily life. US IRBs thus face difficult decisions, including how to interpret principles, how much to pay subjects and how much sustainability to require from researchers. IRB responses and solutions include trying to maintain higher standards for developing world research, obtain cultural expertise, build IRB infrastructure abroad, communicate with foreign IRBs, and 'negotiate' for maximum benefits for participants and fearing 'worst-case scenarios'. CONCLUSIONS: US and foreign IRBs confront a series of tensions and dilemmas in reviewing developing world research. These data have important implications for increased education of IRBs/RECs and researchers in the US and abroad, and for research and practice. PMID- 22515425 TI - Fine needle aspiration cytology diagnosis of metastatic adult granulosa cell tumour showing Call-Exner bodies. PMID- 22515426 TI - The effectiveness of local child weight management programmes: an audit study. AB - BACKGROUND: Many different child weight management programmes exist, with varying degrees of evaluation to provide evidence of their success. The purpose of this research was to use a standardized approach to audit the effectiveness of weight management intervention programmes in the West Midlands region of the UK, specifically to assess the benefits to participating children in terms of health improvement and behaviour change. METHODS: An audit of seven family-based intervention programmes currently in place in the West Midlands. Programmes were audited against the Standard Evaluation Framework. RESULTS: The programmes provided a partial data set relating to a change in weight from the baseline to the end of the programme; none of the programmes provided all of the measures indicated by the Standard Evaluation Form as being essential for evaluation. Weight change ranged from an increase in group mean of 0.4 kg to a decrease of 0.9 kg. Body Mass Index SD decreased by 0.1-0.2 points in four programmes and remained unchanged in two programmes. Four programmes collected long-term follow up data at 6 months. This was often limited because of participant dropout. Improvement in diet and exercise were reported by participants in all programmes which measured these behaviours. CONCLUSIONS: Ongoing evaluation of all programmes, using a standard approach, is essential in order to improve the evidence base and support future commissioning. PMID- 22515424 TI - Pharmacokinetics and pharmacodynamics of medication in asphyxiated newborns during controlled hypothermia. The PharmaCool multicenter study. AB - BACKGROUND: In the Netherlands, perinatal asphyxia (severe perinatal oxygen shortage) necessitating newborn resuscitation occurs in at least 200 of the 180 185.000 newly born infants per year. International randomized controlled trials have demonstrated an improved neurological outcome with therapeutic hypothermia. During hypothermia neonates receive sedative, analgesic, anti-epileptic and antibiotic drugs. So far little information is available how the pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs are influenced by post resuscitation multi organ failure and the metabolic effects of the cooling treatment itself. As a result, evidence based dosing guidelines are lacking. This multicenter observational cohort study was designed to answer the question how hypothermia influences the distribution, metabolism and elimination of commonly used drugs in neonatal intensive care. METHODS/DESIGN: Multicenter cohort study. All term neonates treated with hypothermia for Hypoxic Ischemic Encephalopathy (HIE) resulting from perinatal asphyxia in all ten Dutch Neonatal Intensive Care Units (NICUs) will be eligible for this study. During hypothermia and rewarming blood samples will be taken from indwelling catheters to investigate blood concentrations of several antibiotics, analgesics, sedatives and anti-epileptic drugs. For each individual drug the population PK will be characterized using Nonlinear Mixed Effects Modelling (NONMEM). It will be investigated how clearance and volume of distribution are influenced by hypothermia also taking maturation of neonate into account. Similarly, integrated PK-PD models will be developed relating the time course of drug concentration to pharmacodynamic parameters such as successful seizure treatment; pain assessment and infection clearance. DISCUSSION: On basis of the derived population PK-PD models dosing guidelines will be developed for the application of drugs during neonatal hypothermia treatment. The results of this study will lead to an evidence based drug treatment of hypothermic neonatal patients. Results will be published in a national web based evidence based paediatric formulary, peer reviewed journals and international paediatric drug references. TRIAL REGISTRATION: NTR2529. PMID- 22515427 TI - The effect of negative wound pressure therapy on haemodynamics in a laparostomy wound model. AB - We have recently shown that negative pressure wound therapy (NPWT) induces a decrease in microvascular blood flow in the small intestinal loop close to the dressing. The effect of NPWT is thus thought to be local. In this study, we investigate whether the application of NPWT in laparostomy affects the haemodynamics. Midline incisions were made in six pigs followed by NPWT at -120 mmHg for 20 minutes. The cardiac output, mean systemic arterial pressure, mean pulmonary artery pressu re, central venous pressure, left atrial pressure and superior mesenteric artery blood flow were recorded. The blood flow in a small branch of the superior mesenteric artery was then recorded under NPWT between -50 and -175 mmHg. Cardiac output was not affected by NPWT [P = not significant (n.s.)]. Neither the mean arterial pressure nor the mean pulmonary artery pressure was affected by NPWT (P = n.s.). Negative pressures of -50, -75, -100 and -125 mmHg did not alter the blood flow in the small branch of the superior mesenteric artery (P = n.s.). After application of -150 mmHg, a significant decrease in blood flow was seen (P < 0.01), while the application of -175 mmHg resulted in only a slight decrease in blood flow (P = n.s.). The effect of NPWT in laparotomy seems to be local and to have no influence on central haemodynamics or the blood flow to the superior mesenteric artery. PMID- 22515428 TI - In vitro and in vivo role of heat shock protein 90 in Amphotericin B resistance of Aspergillus terreus. AB - Aspergillus terreus (A. terreus) is of serious concern because of a high propensity to dissemination and in vitro and in vivo resistance to Amphotericin B (AmB). The underlying molecular mechanism of AmB is not known yet and here we want to explore whether fungal heat shock protein 90 (HSP90) is involved in polyene resistance in A. terreus. AmB-susceptible (ATS) and AmB-resistant (ATR) A. terreus and AmB-susceptible Aspergillus fumigatus (AFS) were investigated in response to AmB with a special focus on HSP90. HSP90 inhibitors resulted in significant improvement of AmB activity against ATR as minimum inhibitory concentrations (MIC) decreased from 32 to 0.38 mg/L. Gene expression profiling showed a greater basal amount of HSP90 levels in ATR and ATS when compared with AFS. HSP90 blockers in combination with AmB were evaluated in a murine model of disseminated aspergillosis. HSP90 inhibitors were not beneficial for mice infected with ATR, and neither mono- nor combination treatment with AmB yielded clinical improvement. HSP90 inhibition with 17-allylamino-17 demethoxygeldanamycin (17-AAG) was harmful. HSP90 seems to play a vital role in antifungal stress response in all aspergilli tested, whereas HSP90 does not substantiate the origin of AmB resistance in ATR. PMID- 22515429 TI - Ianthelliformisamines A-C, antibacterial bromotyrosine-derived metabolites from the marine sponge Suberea ianthelliformis. AB - A high-throughput screening campaign using a prefractionated natural product library and an in vitro Pseudomonas aeruginosa (PAO200 strain) assay identified two antibacterial fractions derived from the marine sponge Suberea ianthelliformis. Mass-directed isolation of the CH(2)Cl(2)/CH(3)OH extract from S. ianthelliformis resulted in the purification of three new bromotyrosine derived metabolites, ianthelliformisamines A-C (1-3), together with the known natural products aplysamine 1 (4) and araplysillin I (5). The structures of 1-3 were determined following analysis of 1D and 2D NMR and MS spectroscopic data. This is the first report of chemistry from the marine sponge S. ianthelliformis. Ianthelliformisamine A (1) showed inhibitory activity against the Gram-negative bacterium P. aeruginosa with an IC(50) value of 6.8 MUM (MIC = 35 MUM). PMID- 22515430 TI - Dramatically enhanced cleavage of the C-C bond using an electrocatalytically coupled reaction. AB - This paper describes a generalized approach for the selective electrocatalytic C C bond splitting in aliphatic alcohols at low temperature in aqueous state, with ethanol as an example. We show that selective C-C bond cleavage, leading to carbon dioxide, is possible in high pH aqueous media at low overpotentials. This improved selectivity and activity is achieved using a solution-born co-catalyst based on Pb(IV) acetate, which controls the mode of the ethanol adsorption so as to facilitate direct activation of the C-C bond. The simultaneously formed under potentially deposited (UPD) Pb and surface lead hydroxide change the functionality of the catalyst surface for efficient promotion of CO oxidation. The resulting catalyst retains an unprecedented ability to sustain the full oxidation reaction pathway on an extended time scale of hours as opposed to minutes without addition of Pb(IV) acetate. PMID- 22515431 TI - Plateable cryopreserved human hepatocytes for the assessment of cytochrome P450 inducibility: experimental condition-related variables affecting their response to inducers. AB - 1. RATIONALE: The aim of the present study was to assess the stability of cryopreserved human hepatocytes over 5 years and to explore experimental condition-related variables such as seeding density, culture matrix and medium, start and duration of treatment that could potentially affect the quality of cultures and their response to cytochrome P450 (CYP) inducers. 2. RESULTS: 63/125 batches of cryopreserved human hepatocytes were plateable after thawing. Of those, 17 batches showed reproducible recovery, viability and plateability (less than 5% intra-batch variability) up to 5 years. When cultured in collagen home coated 48-well plates at a seeding density allowing 70% confluence, cryopreserved human hepatocytes display activities equivalent to fresh counterparts. Their response to CYP inducers is maximal and equivalent to fresh counterpart for an incubation of 72 h starting at Day 2 or Day 3 after plating when cultured in modified Hepatocyte Maintenance Medium (HMM). The number of cryopreserved human hepatocytes can be further reduced by using a cocktail of CYP substrates for the assessment of their inducibility. 3. CONCLUSIONS: Experimental condition-related variables, such as seeding density, culture matrix and medium, start and duration of treatment, affecting the response of plateable thawed cryopreserved human hepatocytes to cytochrome P450 inducers can be reduced by optimizing critical steps of the protocols. PMID- 22515432 TI - When effects of the universal psychological need for autonomy on health behaviour extend to a large proportion of individuals: a field experiment. AB - OBJECTIVE: Based on tenets of self-determination theory, the present manuscript examined the hypothesis that a physical activity intervention programme that supported the universal psychological need for autonomy would motivate a large proportion of young individuals to engage in physical activity. In contrast, we hypothesized that interventions that did not support the universal psychological need for autonomy would motivate a smaller proportion of young individuals to endorse the physical activity programme. METHOD: A field experiment was conducted. Participants were randomly allocated to an intervention that supported the psychological need for autonomy and two conditions that did not support the psychological need for autonomy (rationale-only or forced-choice conditions). RESULTS: It was demonstrated that more young individuals initiated and completed a physical activity intervention programme when the programme supported the psychological need for autonomy than when the programme did not support the psychological need for autonomy. CONCLUSIONS: Results of the present study provide additional evidence to a growing body of literature recognizing the importance of universal psychological needs in motivating health-related behaviours. PMID- 22515435 TI - Rethinking the war on cancer: multidisciplinary collaborations between biologists and physical scientists. PMID- 22515434 TI - Salivary uric acid as a noninvasive biomarker of metabolic syndrome. AB - BACKGROUND: Elevated serum uric acid is associated with obesity, hypertension and metabolic syndrome. Because a linear relationship exists between serum and salivary uric acid (SUA) concentration, saliva testing may be a useful noninvasive approach for monitoring cardiometabolic risk. The goal of this pilot study was to determine if SUA is increased in patients with metabolic syndrome and to investigate correlations between SUA and individual cardiometabolic risk factors. FINDINGS: Volunteers between the ages of 18 and 65 without conditions known to affect serum uric acid levels were recruited. Height, weight, blood pressure and waist circumference were measured and a full lipid panel along with fasting blood glucose was obtained. Saliva samples were collected and uric acid levels were determined. 78 volunteers, 35% of whom had metabolic syndrome, completed the study. SUA was significantly elevated in patients with metabolic syndrome (p=.002). The incidence of metabolic syndrome in the 4th quartile for SUA was 67% compared to 25% in quartiles1-3 combined. Significant correlations were seen between SUA and systolic blood pressure (r=.440, p=.000), diastolic blood pressure ( r=.304, p=.007), waist circumference (r=.332, p=.003), BMI ( r=.269, p=.018), fasting blood glucose ( r=.341, p=.002), triglycerides (r=.410, p=.000), HDL ( r=.237, p=.036) and the number of cardiometabolic risk factors present (r=0.257, p=.023). CONCLUSIONS: These results suggest that SUA may be a useful biomarker for noninvasive monitoring of cardiometabolic risk. Larger studies are needed to validate this approach. PMID- 22515433 TI - The effect of minocycline on the masticatory movements following the inferior alveolar nerve transection in freely moving rats. AB - BACKGROUND: To determine the effects of inferior alveolar nerve transection (IAN X) on masticatory movements in freely moving rats and to test if microglial cells in the trigeminal principal sensory nucleus (prV) or motor nucleus (motV) may be involved in modulation of mastication, the effects of microglial cell inhibitor minocycline (MC) on masticatory jaw movements, microglia (Iba1) immunohistochemistry and the masticatory jaw movements and related masticatory muscle EMG activities were studied in IAN-X rats. RESULTS: The number of Iba1 immunoreactive (IR) cells both in prV and motV was significantly larger in IAN-X rats compared with sham rats on day 3 after IAN-X. The intraperitoneal (i.p.) administration of MC caused a significant reduction of the number of Iba1-IR cells both in prV and motV that was evident on day 14 after IAN-X. Furthermore, a significant reduction of the number of Iba1-IR cells could be observed in motV but not in prV after microinjection (m.i.) of MC into the motV of IAN-X rats. The rats also exhibited a significant decrease in the head-withdrawal threshold on the side ipsilateral to the IAN-X compared to the threshold before IAN-X and it lasted to day 14. In addition, IAN-X markedly affected the ability to rat to carry out mastication. The number of complete masticatory sequences was significantly decreased. Furthermore, the total masticatory sequence time and food preparatory (PP) period duration was significantly elongated in compared to sham rats. Although IAN-X significantly affected the total number of chewing cycles within the RC period of a masticatory sequence, it had no effect on the duration of the chewing cycles. On the other hand, systemic administration of MC (both i.p. and m.i.) in IAN-X rats significantly improved decreased head withdrawal threshold and the impaired masticatory jaw movements. CONCLUSIONS: The present findings reveal that the strong modulation of masticatory jaw movements occurs following microglial cell activation after IAN-X, and the modulation recovers after inhibition of the microglial cell activation by MC, suggesting that microglial cell activation in the motV as well as in the prV has a pivotal role in modulating mastication following trigeminal nerve injury associated with orofacial neuropathic pain. PMID- 22515436 TI - Future approaches for the therapy of malignant glioma: targeting genes mediating invasion. PMID- 22515438 TI - Efficacy of tosedostat, a novel, oral agent for elderly patients with relapsed or refractory acute myeloid leukemia: a review of the Phase II OPAL trial. AB - Acute myeloid leukemia is most often diagnosed in patients older than 60 years of age. Overall, these patients have a poor prognosis, partly because they are typically unable to tolerate intensive chemotherapy regimens traditionally offered to younger individuals. Furthermore, responses attained in these older patients are not durable, with most experiencing relapse within 1-2 years. Therefore, new strategies are needed to improve the outcome of older patients with acute myeloid leukemia. Tosedostat is an orally available aminopeptidase inhibitor shown to have activity in leukemia. This commentary discusses the background and results of an ongoing Phase II evaluation of tosedostat in elderly patients with relapsed or refractory acute myeloid leukemia. The data available to date is analyzed and future perspectives regarding the development of this agent is discussed. PMID- 22515440 TI - Panitumumab: a summary of clinical development in colorectal cancer and future directions. AB - Panitumumab is a fully human, monoclonal antibody targeting the EGF receptor with proven clinical activity in KRAS wild-type metastatic colorectal carcinoma. Treatment with panitumumab has been shown to significantly improve response rate and progression-free survival in this subgroup of patients, with a manageable toxicity profile. Panitumumab's first worldwide indication was as a single agent in chemorefractory patients. Recently, the EMA approved its use as part of a chemotherapy regimen in first- and second-line settings, following the encouraging results of large randomized Phase III trials. In order to identify patients with higher chances of benefiting from the treatment, additional molecular aberrations in the EGF receptor signaling pathway are being investigated as predictive biomarkers. In this article we review 10 years of drug development, focusing on the clinical evidence for panitumumab's indication in metastatic colorectal cancer and future strategies of investigation. PMID- 22515439 TI - Bortezomib: a proteasome inhibitor with an evolving role in select subtypes of B cell non-Hodgkin's lymphoma. AB - Bortezomib is a novel proteasome inhibitor initially approved for use in multiple myeloma and currently under continued investigation as a treatment for numerous subtypes of non-Hodgkin's lymphoma. One postulated mechanism of action in non Hodgkin's lymphoma is the ability of bortezomib to ameliorate molecular dysregulation in NF-kappaB activation and regain cell cycle control. Results of clinical trials have varied widely based on lymphoma subtype. While response to bortezomib has been dismal in chronic lymphocytic leukemia and small lymphocytic lymphoma, reasonable responses have been attained in mantle cell lymphoma leading to its US FDA approval as a second-line agent for the treatment of mantle cell lymphoma in 2006. Bortezomib in combination with R-CHOP has also been suggested to improve response in certain molecular subgroups of diffuse large B-cell lymphoma. The role of bortezomib in follicular and marginal zone lymphomas remains less clear. PMID- 22515441 TI - New developments in the treatment of hepatic tumors. AB - The International Association of Surgeons, Gastroenterologists and Oncologists (IASGO) hosted their annual world congress under the auspices of president Masatoshi Makuuchi from Japan and the general secretary Nicolas J Lygidakis. This year the congress was held in Tokyo, and the president was Wataru Kimura of Yamagata University. It is common knowledge that a major triple disaster struck Japan in March 2011. It was thought, for a time, that the congress would not take place, but the great courage and determination of the hosts allowed the conference to continue as scheduled. This congress was one of the most interesting hosted by the IASGO, evidenced by the presence of 909 participants from 59 countries, including invited speakers from Europe, America, Africa and Asia. The congress provided an opportunity to exchange knowledge of new techniques, methods of diagnosis and therapy. The program included symposiums, video presentations, free papers and poster presentations. This manuscript highlights presentations of the newest and most original material concerning the treatment of liver tumors, especially hepatocellular carcinoma. PMID- 22515442 TI - PKM2: a new player in the beta-catenin game. AB - beta-catenin is a key player in the regulation of gene expression during morphogenesis and tumorigenesis. Although its transactivation often results from stimulation of the Wnt signaling pathway, Wnt-independent regulation of beta catenin has also been observed in cancer cells. This study discloses a new mechanism for the transactivation of beta-catenin upon EGF receptor activation that relies on the binding of beta-catenin to the PKM2 isoform in the nucleus. This interaction requires phosphorylation of beta-catenin on the Y333 residue by c-Src and the PKM2 domain that binds phosphotyrosine. Importantly, the authors demonstrated that EGF-induced transactivation of beta-catenin is necessary for brain tumor growth and that high levels of c-Src activity, Y333 beta-catenin phosphorylation and nuclear localization of PKM2 altogether correlate with high aggressiveness of tumors in glioblastoma multiforme. Remarkably, this study reveals a novel role for PKM2 in cancer cells where PKM2 appears to be, in addition to its established role in aerobic glycolysis, a major coactivator of beta-catenin transactivation. This nuclear function of PKM2 is shared with other transcription factors such as HIF-1alpha and OCT4, and highlights the nonmetabolic role of PKM2 during tumorigenesis. PMID- 22515443 TI - Elevated levels of HSF1 indicate a poor prognosis in breast cancer. AB - HSF1 is the transcriptional activator of heat shock protein genes in both cell stress and cancer. The studies of Santagata et al. clearly establish that HSF1 levels are increased in the nuclei of mammary cancer cells, both at the in situ and invasive stages, and that these levels are closely correlated with increased mortality. HSF1 levels were elevated in estrogen receptor-positive cells, as well as HER2-expressing and triple-negative breast cancer cells, and higher levels of nuclear HSF1 were associated with a poor prognosis. These studies establish a clear role for HSF1 in human mammary carcinoma and suggest the potential for targeting HSF1 in breast cancer treatment. PMID- 22515445 TI - Preclinical imaging of the cellular and molecular events in the multistep process of bone metastasis. AB - Bone metastasis is a complex process that ultimately leads to devastating metastatic bone disease. It is therefore of key interest to unravel the mechanisms underlying the multistep process of skeletal metastasis and cancer induced bone disease, and to develop better treatment and management of patients with this devastating disease. Fortunately, novel technologies are rapidly emerging that allow real-time imaging of molecules, pathogenic processes, drug delivery and drug response in preclinical in vivo models. The outcome of these experimental studies will facilitate clinical cancer research by improving the detection of cancer cell invasion, metastasis and therapy response. PMID- 22515446 TI - GPR56 in cancer progression: current status and future perspective. AB - Cell adhesion is a critical process during cancer progression and is mediated by transmembrane receptors. Recently, GPR56, a member of the adhesion family of G protein-coupled receptors, was established as a new type of adhesion receptor that binds to extracellular matrix proteins and shown to play inhibitory roles in melanoma progression. Further studies revealed that the extracellular portion and the seven transmembrane domains of GPR56 function antagonistically to regulate VEGF production and angiogenesis via a signaling pathway mediated by PKCalpha. Tissue transglutaminase was identified as the first extracellular matrix protein that binds to GPR56. It is a crosslinking enzyme in the extracellular matrix but is also expressed in the cytosol. Tissue transglutaminase plays pleiotropic roles in cancer progression. Whether and how it might mediate GPR56-regulated cancer progression awaits further investigation. PMID- 22515447 TI - Germline copy number variations and cancer predisposition. AB - We present an overview of the role of germline copy number variations (CNVs) in cancer predisposition. CNVs represent a significant source of genetic diversity, although the mechanisms by which they influence cancer susceptibility still remain largely unknown. Approximately 100 highly penetrant germline mutant genes are now known to cause cancer predisposition inherited in a Mendelian fashion; in this review, we show that nearly half of these genes have also been observed as rare CNVs associated with cancer. However, these highly penetrant alleles seem to account for less than 5% of all familial cancers. We surmise that most of the genetic risk of cancer in the general population must largely involve genes of low or moderate penetrance. In the last 5 years, studies have demonstrated that although common low penetrant CNVs are modest contributors to cancer individually, their combined impact on cancer predisposition must be taken into account in estimating cancer risk. PMID- 22515444 TI - Bevacizumab and breast cancer: what does the future hold? AB - Breast cancer is a major health concern for many women, but despite the current standard therapies, many women still die of metastatic disease. Angiogenesis has been evaluated as a possible target for therapy and bevacizumab (Avastin((r)), Genentech/Roche, CA, USA), a monoclonal antibody against VEGF-A, has been developed to target this. Current clinical trials utilizing bevacizumab have shown an increase in progression-free survival, but this has not translated to an increase in overall survival in breast cancer patients. In this article, we summarize the currently published trials utilizing bevacizumab in the treatment of breast cancer and describe various methods of measuring angiogenesis in vitro and in vivo. We also describe the related process of lymphangiogenesis, as this may contribute to the mechanism of cancer progression and may be a potential target for therapy in the future. Understanding these processes may help us develop new treatments for breast cancer. PMID- 22515448 TI - Differences in outcome and toxicity between Asian and caucasian patients with lung cancer treated with systemic therapy. AB - It is increasingly recognized that differences in overall survival and toxicity exist between Asian and caucasian patients with small-cell and non-small-cell lung cancer, with a longer survival, higher response rates and greater toxicity to chemotherapy and targeted therapy reported in Asian patients. Two global studies are used to illustrate how the proportions of Asian patients can influence survival outcome. Ethnicity is an important and complex characteristic that should considered in the design and conduct of a global clinical study, as the safety, tolerability and response may vary between Asian and caucasian patients. Whether ethnic differences in lung cancer survival are attributed to genetic differences among races or are simply a surrogate marker of differences in access to healthcare because of socioeconomic differences is unclear. Carefully designed prospective studies investigating ethnic-specific determinants of sensitivity and toxicity to systemic therapy are warranted. PMID- 22515450 TI - Complete response to exemestane in a patient with a desmoid tumor. AB - Desmoid tumors are rare mesenchymal neoplasms without metastatic potential. Despite the benign nature of this condition, some patients develop disease progression despite all locoregional options for care. Aggressive forms of desmoid tumors may induce morbidity that can lead to physical impairment and mortality that is occasionally observed as a result of local infiltrative growth and tissue invasion, in particular with abdominal disease. Few therapeutic options are available for patients with recurrent/unresectable desmoid tumors. Several studies have suggested the potential benefit of antiestrogens such as tamoxifen in this setting. Here we report the first description of the efficacy of an aromatase inhibitor in a patient with a desmoid tumor. PMID- 22515452 TI - Characterization of FerC, a MarR-type transcriptional regulator, involved in transcriptional regulation of the ferulate catabolic operon in Sphingobium sp. strain SYK-6. AB - Sphingobium sp. strain SYK-6 is able to degrade various lignin-derived aromatic compounds including ferulate, vanillate, and syringate. In the SYK-6 cells, ferulate is converted to vanillin and acetyl-coenzyme A (acetyl-CoA) through the reactions catalyzed by feruloyl-CoA synthetase and feruloyl-CoA hydratase/lyase encoded by ferA and ferB, respectively. Here, we characterized the transcriptional regulation of ferBA controlled by a MarR-type transcriptional regulator, FerC. The ferC gene is located upstream of ferB. Reverse transcription (RT)-PCR analysis suggested that the ferBA genes form an operon. Quantitative RT PCR analyses of SYK-6 and its mutant cells revealed that the transcription of the ferBA operon is negatively regulated by FerC, and feruloyl-CoA was identified as an inducer. The transcription start site of ferB was mapped at 30 nucleotides upstream from the ferB initiation codon. Purified His-tagged FerC bound to the ferC-ferB intergenic region. This region contains an inverted repeat sequence, which overlaps with a part of the -10 sequence and the transcriptional start site of ferB. The binding of FerC to the operator sequence was inhibited by the addition of feruloyl-CoA, indicating that FerC interacts with feruloyl-CoA as an effector molecule. Furthermore, hydroxycinnamoyl-CoAs, including p-coumaroyl-CoA, caffeoyl-CoA, and sinapoyl-CoA also acted as effector. PMID- 22515453 TI - Families, functioning and therapies. PMID- 22515454 TI - Family therapy in Brazil: current status. AB - In the last three decades there has been a noticeable trend in the redefinition of the nuclear family in Brazil. A recent increase in the rates of divorces and paradoxically also in the rates of marriages, the legalization of same-sex unions and adoption by these couples, and the phenomenon of teenage pregnancy are some of the aspects that reflect on the current Brazilian family. This review highlights these changes and describes how family therapists in Brazil are facing the challenge of assisting these families, in a continental-sized country with uneven distribution of training courses and healthcare assistance. PMID- 22515455 TI - The framework of family therapy in clinical practice and research in Serbia. AB - In the last two decades, Serbia has had to deal with multiple social and economic problems reflecting on society's demographics and seemed to weaken its core cell the family. The paper describes the framework of family therapy in clinical practice and research, within the recent transition of the Serbian family. Family therapy treatment in Serbia uses the systemic family therapy (SFT) approach, applied according to the standards of the European Association for Psychotherapy. A large number of professionals who practise in Serbia hold European qualifications, setting high standards in education, clinical practice, and research. Although SFT is also available in the private sector, the majority of patients are still treated in state institutions. Family therapy is often used for adults and adolescents with psychosis and addictions in psychiatric hospital settings. However, in counselling centres it is used for marital and relationship problems. Interestingly, family therapy has recently started to emerge as a more frequent tool in consultation-liaison, particularly psycho-oncology but also in correctional institutions. The clinical practice and research interests are interlinked with changes in social settings. PMID- 22515456 TI - Treating troubled families: therapeutic scenario in India. AB - India, a country of diverse cultures, languages, life styles, and ethnicities, is becoming a land of economic change, political stability, technological advancement, and changing traditional structures of relationships as well as health consciousness. Being known for its ancient traditions, rituals, religious orientation, spiritual outlook and folk beliefs, Indian families attempt to continue certain healthy and traditional elements such as warmth, strong bond, hierarchy, extended support, cultural orientation, shared values and time, tolerance, respect for the aged and inculcation of religious teachings and traditions in families. These factors, or practices, in fact have strong therapeutic value in supplementing the growth and development of individuals in the family system in spite of its transitional position. This paper deals with the review of family-based mental health services and focuses on the changing trends of those practices in India and the advancement of Indian families in their engaging ability with mentally ill members as well as with the treating team. PMID- 22515457 TI - Which family--what therapy: Maori culture, families and family therapy in New Zealand. AB - New Zealand is a relatively young and small country which has seen steady migration for nearly seven centuries. Despite a long history of rivalry and hostility between Maori and European values, the country has also seen some significant synergism between the two cultures. For the last three decades Asians have also migrated at a significant pace. The country faces the challenge of delivering quality mental health services to such cultures which are bifurcated in being socio-centric (Maori, Pacific Islanders and Asian total 32% combined) or ego-centric (European total 68%). Significant progress has been made in including families of the mentally ill in their treatment and care planning. Legislative requirements have been introduced for the family to be consulted in the treatment of those who are being compelled to receive psychiatric care under the Mental Health Act. Models of family therapy developed through innovation meeting the unique local needs or adaptation of existing models from overseas are being used. An overview of such family therapy modalities is presented. PMID- 22515458 TI - Family environment, expressed emotion and adolescent self-harm: a review of conceptual, empirical, cross-cultural and clinical perspectives. AB - Self-harm in young people is a complex and pervasive problem with a number of co existing risk factors. Although research has implicated a range of family variables in understanding the onset, maintenance and prevention of adolescent self-harm, relatively little attention has been given to the expressed emotion (EE) construct. Based on a narrative review and synthesis of peer-reviewed literature up to and including 2011, this paper considers the conceptual background and empirical evidence for the role of family environment in the expression of adolescent self-harm, with a particular focus on EE. The clinical implications of this literature for working with young people and families from different cultures are also addressed. In summary, the surveyed research provides insufficient evidence for a direct causal link between family environment and adolescent self-harm, with questions raised about the temporal sequencing of measured variables, specificity of implicated family risk factors, and the nature and role of protective factors in families. Emerging evidence for an association between high EE and adolescent self-harm requires replication in well-controlled, prospective studies. There is also a lack of empirically-supported, family-based treatment modalities for adolescents who self-harm. Intervention strategies should be guided by personalised formulation, taking into account individual vulnerabilities, strengths and social contexts, as well as cultural norms for family environment. PMID- 22515449 TI - Inactivation of X-linked tumor suppressor genes in human cancer. AB - Cancer cells silence autosomal tumor suppressor genes by Knudson's two-hit mechanism in which loss-of-function mutations and then loss of heterozygosity occur at the tumor suppressor gene loci. However, the identification of X-linked tumor suppressor genes has challenged the traditional theory of 'two-hit inactivation' in tumor suppressor genes, introducing the novel concept that a single genetic hit can cause loss of tumor suppressor function. The mechanism through which these genes are silenced in human cancer is unclear, but elucidating the details will greatly enhance our understanding of the pathogenesis of human cancer. Here, we review the identification of X-linked tumor suppressor genes and discuss the potential mechanisms of their inactivation. In addition, we also discuss how the identification of X-linked tumor suppressor genes can potentially lead to new approaches in cancer therapy. PMID- 22515459 TI - Families and family therapy in Hong Kong. AB - Family therapy views humans not as separate entities, but as embedded in a network of relationships, highlighting the reciprocal influences of one's behaviours on one another. This article gives an overview of family demographics and the implementation of family therapy in Hong Kong. We start with a review of the family demographics in Hong Kong and brief notes on families in mainland China. Demographics show that the landscape has changed markedly in the past decade, with more cross-border marriages, an increased divorce rate, and an ageing overall population - all of which could mean that there is increasing demand for professional family therapy interventions. However, only a limited number of professionals are practising the systems-based approach in Hong Kong. Some possible reasons as to why family therapy is not well disseminated and practised are discussed. These reasons include a lack of mental health policy to support family therapy, a lack of systematic family therapy training, and a shortage of skilled professionals. Furthermore, challenges in applying the western model in Chinese culture are also outlined. We conclude that more future research is warranted to investigate how family therapy can be adapted for Chinese families. PMID- 22515460 TI - Family and family therapy in Russia. AB - This article represents the information about family and family therapy in the context of culture, traditions and contemporary changes of social situations in Russia. The legislation of family rights are mentioned within items about marriage and family in the Constitution, Civil Code and Family Code of the Russian Federation which has changed during recent years. The definition of family and description of family structure are given through the prism of the current demographic situation, dynamics of statistics of marriage and divorce rates, mental disorders, disabilities and such phenomena as social abandonment. The actual curriculum, teaching of family therapy and its disadvantages, system of continuous education, supervision and initiatives of the Institute of Integrative Family Therapy in improvement of preparing of specialists who can provide qualified psychosocial assistance for the family according to the actual needs of society are noted. The directions of state and private practice of family counselling and therapy both for psychiatric patients and medical patients, for adults and children in a family systemic approach are highlighted with an indication of the spectrum of techniques and methods used by Russian professionals. The main obstacles and perspectives of development of family therapy in Russia are summarized. PMID- 22515461 TI - Demographics and treatment of the American family. AB - There have been numerous changes to the US family over the past several decades. Traditional family roles have changed, and the conception of what Americans consider a 'family' has likewise shifted with differing societal views regarding gender, gender roles, race, and ethnicity. This review examines demographics of the American family as well as a number of family therapies that have been historically and are presently used to treat family problems. We expect that with the changes present in US society, family therapies will need to continue to be sensitive and adaptive to these shifts in order to be effective. PMID- 22515462 TI - Interpersonal communication in and through family: structure and therapy in Turkey. AB - It is essential for professionals in the mental health sector to identify and understand the different family models and the effects of social transformations. Historically and at present, however, Turkish families live in a 'culture of relatedness', with emotional and/or material interdependence between generations. Marriage and family therapy is a newly emerging discipline in Turkey. Although studies on family structure and common problems in families have been made, data on the practice of family therapy are limited. To our knowledge, this is the first paper aiming to describe the practice of family therapies in Turkey, situating them against a backdrop of sociological and social/psychological studies in family structure. PMID- 22515463 TI - The family in Romania: cultural and economic context and implications for treatment. AB - The study of family structures, functioning, roles and values is fundamental in family therapist's activities for better understanding the psychological, cultural and social specificity of different clients and interventions. In this paper we describe the Romanian family and the family therapies which are available in Romania. We illustrate basic needs using demographic data and research available from Romania. The nuclear family remains dominant instead of other alternatives, the age of marriage is earlier than in western European countries and celibate and consensual living are exceptions or only for the transitional period before marriage. The role of marriage and childbirth within the marital setting is still important. The model of a single child appears increasingly common due to an improvement in financial resources and better living conditions. Relations with family of origin remain close. The difficulties for children with parents working in different countries raise problems and have implications for the extended family, educators and psychotherapists as well as mental health service providers. Family therapists should keep in mind the structure, function, role and values of the Romanian family for better understanding the issues and resources and use these accordingly in therapy. Policy-makers should be aware of the difficulties concerning availability and access to this therapeutic approach. PMID- 22515464 TI - Family and family therapy in the Netherlands. AB - This article describes how families are functioning in the Netherlands, and how family therapy is used in mental healthcare. In the open Dutch society, new ideas are easily incorporated, as exemplified by the rapid introduction and growth of family therapy in the 1980s. In recent decades, however, family therapy has lost ground to other treatment models that are more individually orientated, and adhere to stricter protocols. This decline of family therapy has been exacerbated by recent budget cuts in mental healthcare. In regular healthcare institutes family therapy now has a marginal position at best, although family treatment models are used in specific areas such as forensic treatments. In addition, the higher trained family therapists have found their own niches to work with couples and families. We argue that a stronger position of family therapy would be beneficial for patients and for families, in order to counteract the strong individualization of Dutch society. PMID- 22515465 TI - The family in Italy: cultural changes and implications for treatment. AB - In Italy family is characterized by strong ties and is based on mutual aid of all its members. In the last 20 years, the structure of families has been significantly influenced by demographic, economic and professional changes, determining a transition from a patriarchal to a nuclear family model, with a higher number of single-parent families, single-person households, childless couples, same-sex couples. However, this transition has been slower than that occurring in other countries, probably as an ongoing impact of prevalent Catholic ideology. Major demographic changes in Italian families include, 1) a decrease in the number of marriages, delays in getting married and an high number of civil ceremonies, 2) a reduced birth rate; Italy is becoming one of the European countries with lowest growth rate, and with an increasing number of births out of wedlock, 3) an increased marital instability, with a constantly growing number of legal separations. Like many countries, relatives in Italy are highly involved in the care of patients with physical and mental disorders. There are a number of psychosocial interventions used in Italy including the 'Milan Systemic Approach' and family psycho-educational interventions. However, there are difficulties in implementing these interventions which are highlighted in this paper. We recommend research strategies to identify the best options to involve families in the care of mentally ill patients and to adequately support them. PMID- 22515466 TI - Family therapy in the Czech Republic. AB - Political, economic and cultural transformations in the Czech Republic after 1989 were reflected in a number of demographic indicators, including those that characterize family behaviour. The main features of these changes are declining birth and marriage rates, postponement of first marriage and first birth ages, and a growing proportion of children born outside of marriage. These changes are comparable to those that have taken place in western Europe since the 1960s; however, some of them are abrupt and cause rapid shift in the family structure. Over the last two decades, significant changes have also occurred in the organization of family therapy. Earlier less coordinated activities underwent institutionalization, and guidelines for training and supervision were established. Family therapy in the Czech Republic is covered by a national organization, the Society of Family Therapy (SOFT). Standards of training and supervision correspond to European standards. The problem remains the lack of support for family therapy from state institutions, especially in the health service. There are only a few healthcare facilities providing family therapy for the treatment of psychiatric disorders or chronic somatic diseases. The capacity of these centres is substantially inadequate. PMID- 22515467 TI - Overview of the family structure in Egypt and its relation to psychiatry. AB - The family is the basic unit of any society and culture. The concept, structure, and function of the family unit vary considerably across different cultures; however, its role continues to be imperative to the development of individuals and their psychological make-up. All societies have a concept of 'family', its relative importance, structure, and functions; however, this varies according to the particular culture. In the Arabic culture, as well as other collectivistic cultures, the extended family is often regarded as the basic unit. The family is the foundational and basic social unit that fosters the stability, well-being and sustainability of society. The quality of family relationships shapes and influences the social, psychological, and biological development and functioning of its members. This may be especially relevant to individuals with mental health problems. The people of ancient Egypt valued family life highly, and this is the case even now. They treasured children and regarded them as a great blessing. If a couple had no children, they would pray to the gods and goddesses for help. They would also place letters at the tombs of dead relatives asking them to use their influence with the gods. The importance of family has not changed dramatically even though the structures are beginning to. In this paper we highlight changes in family set-up and the state of family therapy in Egypt. PMID- 22515468 TI - Families in Bollywood cinema: changes and context. AB - With increasing and rapid urbanization and population changes in India, a growing number of people are migrating from rural areas to urban areas, which brings about major changes in support systems. As a result, the portrayal of families has also changed in Hindi cinema over the last 50 years. Recent family melodramas have focused on an idealized version of joint and extended families. In this paper we use some key Hindi films of the 1960s and of the last two decades to compare how films have changed and how, in view of changing audiences, they have created a version of the family which is far from real. Clinicians need to be aware of these changes while dealing with patients and their families (the latter may have unrealistic expectations of their own family members). PMID- 22515469 TI - Lemon (Citrus limon, Burm.f.) essential oil enhances the trans-epidermal release of lipid-(A, E) and water-(B6, C) soluble vitamins from topical emulsions in reconstructed human epidermis. AB - Topical bioavailability of lipid- and water-soluble vitamins is a critical issue for protecting or anti-ageing formulations. Using 17-day-old SkinEthic((r)) reconstructed human epidermis, we investigated (at 34 degrees C) the role of lemon EO in enhancing the penetration of alpha-tocopherol (E) and retinyl acetate (A), pyridoxine (B(6)) and ascorbic acid (C), released from O/W or W/O emulsions. D-limonene, alpha-pinene and p-cymene (65.9, 2.2 and 0.5%w/w of the oil) had skin permeability coefficients Ps (10(-3) cm h(-1)) of 0.56 +/- 0.03 (or 0.73 +/- 0.02), 0.72 +/- 0.05 (or 0.98 +/- 0.05) and 0.84 +/- 0.04 (or 1.14 +/- 0.04), respectively, when incorporated in a W/O (or O/W) emulsion. Vitamins B6, C and A had Ps values of (3.0 +/- 0.4) * 10(-3), (7.9 +/- 0.6) * 10(-3) and (0.37 +/- 0.02) * 10(-5) cm h(-1), respectively, and their flux through the skin was enhanced by a factor of 4.1, 3.4 and 5.8, respectively, in the presence of lemon EO. The penetration of vitamin E was nine-fold enhanced. Lemon EO produced only reversible modification of TEWL, and it is a safe and effective penetration enhancer for topical administration of lipid- and water-soluble vitamins. PMID- 22515471 TI - Giant core-shell nanospherical clusters composed of 32 Co or 32 Ni atoms held by 6 p-tert-butylthiacalix[4]arene units. AB - Using combinations of p-tert-butylthiacalix[4]arene (TCA) and [M(DMSO)(6)(BF(4))(2)] salts (M = Co(II) or Ni(II)), two almost isostructural core-shell-type thermally stable giant nanoclusters, composed of 32 metal centers, 6 deprotonated calix units binding the metal centers by both their O and S atoms, 24 MU-oxo or MU-hydroxo bridging groups, and 6 MeOH molecules, have been prepared under mild and reproducible conditions. For both giant clusters, the oxidation state II [M(II)(32)O(16)(OH)(8)(CH(3)OH)(6)TCA(6) (M = Co or Ni)] for the metal center was demonstrated by X-ray photoelectron and electronic absorption spectroscopies. PMID- 22515470 TI - Ammosamide D, an oxidatively ring opened ammosamide analog from a marine-derived Streptomyces variabilis. AB - Ammosamide D (1), an oxidized analog of the ammosamide family, was isolated from a marine-derived Streptomyces variabilis. Pyrroloquinoline containing alkaloids are a growing class of natural products, with 1 being the first example of an oxidized analog resulting in a 5,6-dioxo-5,6-dihydroquinoline ring system. Attempts at chemical conversion of ammosamide B to ammosamide D revealed that a strong chemical oxidant is required. Ammosamide D has modest cytotoxicity to the MIA PaCa-2 pancreatic cancer cell line. PMID- 22515472 TI - Role of lymphadenectomy in the management of urothelial carcinoma of the bladder and the upper urinary tract. AB - The role of lymphadenectomy has been controversial in urological malignancies. Urothelial carcinoma of the bladder and upper urinary tract has a high potential to spread through the lymphatic network compared with other malignancies, including renal cell carcinoma or prostate cancer. In urothelial carcinoma of the bladder, lymphadenectomy of pelvic nodes had been considered as the standard procedure when radical cystectomy was carried out. Recently, many investigators have examined the influence of its extent, and the majority of the studies have supported the beneficial role of extended lymphadenectomy in accurate staging or in improving patient survival. Although randomized controlled trials are required to establish a greater level of evidence, more urological surgeons have already noticed the necessity for extended lymphadenectomy in bladder cancer. In contrast to bladder cancer, there have been far fewer studies on urothelial carcinoma of the upper urinary tract. This might be because of the smaller number of the patients with urothelial carcinoma of the upper urinary tract and the lack of understanding of regional nodes. However, studies of lymph node mapping and the retrospective analyses with respect to the benefit of lymphadenectomy have been carried out in urothelial carcinoma of the upper urinary tract by some investigators, although the results are still controversial. However, the results from multi-institutional studies by high volume centers have supported the beneficial role of lymphadenectomy in urothelial carcinoma of the upper urinary tract, as it has been proposed in bladder cancer. Thus, lymphadenectomy for urothelial carcinoma of the bladder and the upper urinary tract might have a potential role in staging and improving the oncological outcomes. PMID- 22515473 TI - Impaired pitch identification as a potential marker for depression. AB - BACKGROUND: Impaired auditory performance has been considered as marker for depression. The present study tested whether pitch perception is affected in depression and whether the impairment is task-specific or reflects global dysfunction. METHODS: Twelve depressive in-patients and 12 non-depressive participants, half of the sample women, volunteered. The participants performed pitch identification using a four-choice reaction task, pitch contour perception, and pitch discrimination. RESULTS: During pitch identification but not during pitch contour perception or pitch discrimination, depressive patients responded less accurate than non-depressive participants (F = 3.3, p = 0.047). An analysis of covariates revealed that only female but not male depressive patients identified pitches poorly (Z = -2.2, p = 0.025) and inaccurate pitch identification correlated with high scores in the Beck Depression Inventory in women (r = -0.8, p = 0.001) but not in men (r = -0.1, p = 0.745). Patients did not differ from controls in reaction time or responsiveness. CONCLUSIONS: Impaired pitch perception in depression is task-specific. Therefore, cognitive deficits in depression are circumscribed and not global. Reduced pitch identification in depression was associated with female sex. We suggest that impaired pitch identification merits attention as a potential marker for depression in women. PMID- 22515474 TI - Optical properties of the products of alpha-dicarbonyl and amine reactions in simulated cloud droplets. AB - Secondary organic aerosol makes up a significant fraction of the total aerosol mass, and a growing body of evidence indicates that reactions in the atmospheric aqueous phase are important contributors to aerosol formation and can help explain observations that cannot be accounted for using traditional gas-phase chemistry. In particular, aqueous phase reactions between small organic molecules have been proposed as a source of light absorbing compounds that have been observed in numerous locations. Past work has established that reactions between alpha-dicarbonyls and amines in evaporating water droplets produces particle phase products that are brown in color. In the present study, the complex refractive indices of model secondary organic aerosol formed by aqueous phase reactions between the alpha-dicarbonyls glyoxal and methylglyoxal and the primary amines glycine and methylamine have been determined. The reaction products exhibit significant absorption in the visible, and refractive indices are similar to those for light absorbing species isolated from urban aerosol. However, the optical properties are different from the values used in models for secondary organic aerosol, which typically assume little to no absorption of visible light. As a result, the climatic cooling effect of such aerosols in models may be overestimated. PMID- 22515475 TI - Reduction of mercury from mackerel fillet using combined solution of cysteine, EDTA, and sodium chloride. AB - An acidic solution containing mercury chelating agents to eliminate mercury in raw fish (mackerel) fillet was developed. The solution contained hydrochloric acid, sodium hydroxide, cysteine, EDTA, and NaCl. The optimum conditions for mercury reduction were achieved using response surface methodology (RSM) at cysteine concentration of 1.25%, EDTA of 275 mg/L, NaCl of 0.5%, pH of 3.75, and exposure time of 18 min. The optimized conditions produced a solution which can remove up to 91% mercury from raw fish fillet. Cysteine and EDTA were identified as potential chelating agents with the greatest potential for use. The solution can be employed in fish industries to reduce mercury in highly contaminated fish. PMID- 22515476 TI - Implementation of pressure ulcer prevention best practice recommendations in acute care: an observational study. AB - Pressure ulcers are a common but preventable problem in hospitals. Implementation of best practice guideline recommendations can prevent ulcers from occurring. This 9-year cohort study reports prevalence data from point prevalence surveys during the observation period, and three practice metrics to assess implementation of best practice guideline recommendations: (i) nurse compliance with use of a validated pressure ulcer risk assessment and intervention checklist; (ii) accuracy of risk assessment scoring in usual-care nurses and experienced injury prevention nurses; and (iii) use of pressure ulcer prevention strategies. The prevalence of hospital-acquired pressure ulcers decreased following implementation of an evidence-based prevention programme from 12.6% (2 years preprogramme implementation) to 2.6% (6 years postprogramme implementation) (P < 0.001). Audits between 2003 and 2011 of 4368 patient medical records identified compliance with pressure ulcer prevention documentation according to best practice guidelines was high (>84%). A sample of 270 patients formed the sample for the study of risk assessment scoring accuracy and use of prevention strategies. It was found usual-care nurses under-estimated patients' risk of pressure ulcer development and under-utilised prevention strategies compared with experienced injury prevention nurses. Despite a significant reduction in prevalence of hospital-acquired pressure ulcers and high documentation compliance, use of prevention strategies could further be improved to achieve better patient outcomes. Barriers to the use of prevention strategies by nurses in the acute hospital setting require further examination. This study provides important insights into the knowledge translation of pressure ulcer prevention best practice guideline recommendations at The Northern Hospital. PMID- 22515477 TI - Quality of life domains affected in children with developmental coordination disorder: a systematic review. AB - The quality of life (QOL) of children with developmental coordination disorder (DCD) is largely unknown, but evidence suggests that multiple QOL domains are affected by the disorder. While DCD is primarily considered a motor disorder, multiple studies have reported psychological and social concerns in children with this condition. Our primary aim was to present the current state of the evidence regarding the physical, psychological, and social QOL domains that can be affected in children with DCD. Systematic review of articles from seven databases through November 2010 (MEDLINE, EMBASE, CINAHL, PsycINFO, ERIC, CDSR, DARE) was conducted. Search terms included developmental coordination disorder, dyspraxia, quality of life, life satisfaction, well-being, activities of daily living, and participation. Two independent reviewers screened titles, abstracts, and full text articles. Studies meeting the following criteria were selected: (1) sample comprised solely of individuals with coordination difficulties consistent with DCD; (2) outcome measures related to physical, psychological, or socials domains of QOL; and (3) articles published in English. Data were extracted by one author and verified by a second. Outcomes were categorized according to physical, psychological and social domains of QOL and study quality was rated by case definitions of DCD based on diagnostic criteria as per the Diagnostic and Statistical Manual - 4th edition. Forty-one articles were included. Most studies reported significantly poorer results in physical, psychological and social functioning in children with DCD compared with peers. Despite the impact of DCD on multiple domains, only one study used a QOL measure as an outcome. Although DCD impacts several QOL domains, the QOL of children with this disorder remains largely unknown. The next critical step is for clinicians and researchers to use QOL measures to gather information on how DCD may affect the QOL of children with this disorder. PMID- 22515478 TI - Synthesis and assembly of conjugates bearing specific numbers of DNA strands per gold nanoparticle. AB - Here, we present a relatively simple, efficient, and high-yielding polymerase based method for the synthesis of 15 nm gold nanoparticle conjugates bearing a specific number of 25 base oligonucleotide strands. We have shown that the conjugates bearing one or two oligonucleotide strands per particle, with the conjugates comprising a single complementary strand, self-assemble into nanoparticle dimers and trimers, respectively. Incubation of fully coated AuNPs, containing tens of oligonucleotide strands, with a conjugate bearing a single complementary strand leads to the formation of flower-shaped structures. The assembly of particles into nanoparticle structures shown here is a prerequisite for more complex controlled assembly of particles into three-dimensional macrostructures. PMID- 22515479 TI - Harvesting highly electronically excited energy to triplet manifolds: state dependent intersystem crossing rate in Os(II) and Ag(I) complexes. AB - A series of newly synthesized Os(II) and Ag(I) complexes exhibit remarkable ratiometric changes of intensity for phosphorescence versus fluorescence that are excitation wavelength dependent. This phenomenon is in stark contrast to what is commonly observed in condensed phase photophysics. While the singlet to triplet intersystem crossing (ISC) for the titled complexes is anomalously slow, approaching several hundred picoseconds in the lowest electronic excited state (S(1) -> T(1)), higher electronic excitation leads to a much accelerated rate of ISC (10(11)-10(12) s(-1)), which is competitive with internal conversion and/or vibrational relaxation, as commonly observed in heavy transition metal complexes. The mechanism is rationalized by negligible metal d orbital contribution in the S(1) state for the titled complexes. Conversely, significant ligand-to-metal charge transfer character in higher-lying excited states greatly enhances spin orbit coupling and hence the ISC rate. The net result is to harvest high electronically excited energy toward triplet states, enhancing the phosphorescence. PMID- 22515480 TI - Characterisation of the dissimilatory reduction of Fe(III)-oxyhydroxide at the microbe-mineral interface: the application of STXM-XMCD. AB - A combination of scanning transmission X-ray microscopy and X-ray magnetic circular dichroism was used to spatially resolve the distribution of different carbon and iron species associated with Shewanella oneidensis MR-1 cells. S. oneidensis MR-1 couples the reduction of Fe(III)-oxyhydroxides to the oxidation of organic matter in order to conserve energy for growth. Several potential mechanisms may be used by S. oneidensis MR-1 to facilitate Fe(III)-reduction. These include direct contact between the cell and mineral surface, secretion of either exogenous electron shuttles or Fe-chelating agents and the production of conductive 'nanowires'. In this study, the protein/lipid signature of the bacterial cells was associated with areas of magnetite (Fe3O4), the product of dissimilatory Fe(III) reduction, which was oversaturated with Fe(II) (compared to stoichiometric magnetite). However, areas of the sample rich in polysaccharides, most likely associated with extracellular polymeric matrix and not in direct contact with the cell surface, were undersaturated with Fe(II), forming maghemite like (gamma-Fe2O3) phases compared to stoichiometric magnetite. The reduced form of magnetite will be much more effective in environmental remediation such as the immobilisation of toxic metals. These findings suggest a dominant role for surface contact-mediated electron transfer in this study and also the inhomogeneity of magnetite species on the submicron scale present in microbial reactions. This study also illustrates the applicability of this new synchrotron based technique for high-resolution characterisation of the microbe-mineral interface, which is pivotal in controlling the chemistry of the Earth's critical zone. PMID- 22515481 TI - Are recently reported biomarkers helpful for early and accurate diagnosis of acute kidney injury? AB - Over the past few years and with the use of innovative genomic and proteomic tools, several molecules that their urinary concentration is modified during acute kidney injury have been identified and proposed as biomarkers. Among the most studied biomarkers are neutrophil gelatinase-associated lipocalin-2, kidney injury molecule-1, interleukin-18, cystatin C, N-acetyl-beta-D-glucosaminidase, liver fatty-acid binding protein, and heat shock protein 72. Here, we reviewed and compared the sensitivity and specificity of each biomarker for the appropriate diagnosis of acute kidney injury, as well as its ability to stratify renal injury and to monitor a renoprotective pharmacologic strategy. PMID- 22515482 TI - Self-assembly of colloidal cubes via vertical deposition. AB - The vertical deposition technique for creating crystalline microstructures is applied for the first time to nonspherical colloids in the form of hollow silica cubes. Controlled deposition of the cubes results in large crystalline films with variable symmetry. The microstructures are characterized in detail with scanning electron microscopy and small-angle X-ray scattering. In single layers of cubes, distorted square to hexagonal ordered arrays are formed. For multilayered crystals, the intralayer ordering is predominantly hexagonal with a hollow site stacking, similar to that of the face centered cubic lattice for spheres. Additionally, a distorted square arrangement in the layers is also found to form under certain conditions. These crystalline films are promising for various applications such as photonic materials. PMID- 22515483 TI - Direct (13)C NMR detection in HPLC hyphenation mode: analysis of Ganoderma lucidum terpenoids. AB - Solid phase extraction (SPE) was introduced as a crucial step in the HPLC-SPE-NMR technique to enable online analyte enrichment from which proton-detected NMR experiments on submicrogram amounts from complex mixtures were possible. However, the significance of direct-detected (13)C NMR experiments is indubitable in simplifying structural elucidations. In the current study, we demonstrated direct (13)C NMR detection of triterpenoids from a Ganoderma lucidum extract in hyphenation mode. The combined advantage of a cryogenically cooled probe, miniaturization, and multiple trapping enabled the first reported application of HPLC-SPE-NMR analysis using direct-detected (13)C NMR spectra. HPLC column loading, accumulative SPE trappings, and the effect of different elution solvents were evaluated and optimized. A column loading of approximately 600 MUg of a prefractionated triterpenoid mixture, six trappings, and an acquisition time of 13 h resulted in spectra with adequate signal-to-noise ratios to detect all C-13 signals. PMID- 22515484 TI - Vascular calcification in South African dialysis patients: ethnic variation, prevalence, detection and haemodynamic correlates. AB - AIM: Studies from the US have shown little effect of ethnicity on vascular calcification in dialysis patients. This has not been examined in the multi ethnic population of South Africa where genetic and environmental differences may exist. We assessed the extent and severity of vascular calcification in South African dialysis patients according to race and known risk factors. We further evaluated the association of abdominal aorta calcification with coronary artery calcification. METHOD: Seventy-five CKD-5D patients and 20 healthy controls were enrolled consecutively. All subjects underwent chest computed tomography for coronary calcium score and abdominal X-ray for abdominal aorta calcium score. Ambulatory blood pressure monitoring was generated via radial artery applanation tonometry. RESULTS: Coronary calcification was present in 38.6% of patients and was associated with age and prior cardiovascular disease on multivariate analyses. The median coronary calcium score in black patients was 0 (IQR 0) and 66 in non-Blacks (IQR 383, P < 0.001); controls had a coronary calcium score of 0 (IQR 0). Black race remained a significant negative predictor for coronary calcification after adjustment, prevalence ratio = 0.14 and 95% confidence interval (CI): 0.0-0.53. Vascular calcification was not associated with any ambulatory blood pressure parameter. Using receiver operator characteristic curves, an abdominal aorta calcification score of >=1 showed an area under the curve of 0.83 to predict a coronary calcium score >= 10. CONCLUSION: Black race appears to protect from vascular calcification in South African CKD-5D patients and this warrants further study regarding the underlying mechanism. The abdominal X-ray is a useful screening tool for coronary calcification. PMID- 22515486 TI - Computation of fractal features based on the fractal analysis of surface electromyogram to estimate force of contraction of different muscles. AB - This research study investigates the fractal properties of surface Electromyogram (sEMG) to estimate the force levels of contraction of three muscles with different cross-sectional areas (CSA): m. quadriceps--vastus lateralis, m. biceps brachii, andm. flexor digitorum superficialis. The fractal features were computed based on the fractal analysis of sEMG, signal recorded while performing sustained muscle contraction at different force levels. A comparison was performed between the fractal features and five other features reported in the literature. Linear regression analysis was carried out to determine the relationship between the force of contraction (20-100%) and features of sEMG. The results from the coefficients of regression r2 show that the new fractal feature, maximum fractal length of the signal has highest correlation (range 0.88-0.90) when compared with other features which ranges from 0.34 to 0.74 for the three different muscles. This study suggests that the estimation of various levels of sustained contraction of muscles with varied CSA will provide a better insight into the biomechanics model that involves muscle properties and muscle activation. PMID- 22515485 TI - A novel virus genome discovered in an extreme environment suggests recombination between unrelated groups of RNA and DNA viruses. AB - BACKGROUND: Viruses are known to be the most abundant organisms on earth, yet little is known about their collective origin and evolutionary history. With exceptionally high rates of genetic mutation and mosaicism, it is not currently possible to resolve deep evolutionary histories of the known major virus groups. Metagenomics offers a potential means of establishing a more comprehensive view of viral evolution as vast amounts of new sequence data becomes available for comparative analysis. RESULTS: Bioinformatic analysis of viral metagenomic sequences derived from a hot, acidic lake revealed a circular, putatively single stranded DNA virus encoding a major capsid protein similar to those found only in single-stranded RNA viruses. The presence and circular configuration of the complete virus genome was confirmed by inverse PCR amplification from native DNA extracted from lake sediment. The virus genome appears to be the result of a RNA DNA recombination event between two ostensibly unrelated virus groups. Environmental sequence databases were examined for homologous genes arranged in similar configurations and three similar putative virus genomes from marine environments were identified. This result indicates the existence of a widespread but previously undetected group of viruses. CONCLUSIONS: This unique viral genome carries implications for theories of virus emergence and evolution, as no mechanism for interviral RNA-DNA recombination has yet been identified, and only scant evidence exists that genetic exchange occurs between such distinct virus lineages. REVIEWERS: This article was reviewed by EK, MK (nominated by PF) and AM. For the full reviews, please go to the Reviewers' comments section. PMID- 22515487 TI - SoxS-dependent coregulation of ompN and ydbK in a multidrug-resistant Escherichia coli strain. AB - SoxS, MarA, and Rob are homologous transcriptional activators of numerous superoxide- and antibiotic resistance genes but many of the regulated genes are yet to be characterized. In this study, microarrays and RT-PCR analysis were used to show the overexpression of the ompN porin and its upstream gene, ydbK, in an Escherichia coli multidrug-resistant mutant and in a strain constitutive for SoxS. However, transcriptional fusions revealed that SoxS (not MarA or Rob) only activated the ydbK promoter but not the ompN upstream region. RT-PCR experiments showed the overexpression of a combined ydbK - ompN transcript in the SoxS overexpressing strain. Surprisingly, a bioinformatic approach revealed no soxbox upstream of the ydbK promoter. Thus, the ydbK and ompN genes are coexpressed in an operon and are likely activated by SoxS indirectly. It is known that YdbK is involved in superoxide resistance. Thus, individual ompN and ydbK mutants were tested for superoxide susceptibility. Nonetheless, only the ydbK mutant was susceptible to paraquat, a superoxide generator. These mutants, as well as an OmpN-overproducing strain, were further tested for antibiotic resistance. No significant decreased susceptibility was observed. Thus, ydbK plays a role in superoxide resistance but no role for either gene is found in resistance to the antibiotics tested. PMID- 22515488 TI - Elevated interferon regulatory factor 4 levels in patients with allergic asthma. AB - OBJECTIVE: Allergic asthma is a common inflammatory disease regulated by the T helper (Th) cells. Interferon regulatory factor 4 (IRF4) plays an important role in the differentiation of Th cells. This study investigated whether IRF4 is involved in the systemic immune responses in allergic asthma patients. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from allergic asthmatics (n = 29) and healthy controls (n = 12). The mRNA and protein levels of IRF4 in PBMCs were measured by quantitative RT-PCR and western blotting. The frequencies of Th1, Th2, and Th17 cells were analyzed by flow cytometry. The related cytokine (interferon-gamma, interleukin-4 (IL-4), and IL-17) concentrations in plasma and culture supernatants were measured by ELISA. The levels of GATA binding protein 3 (GATA3), retinoic acid-related orphan receptor gammat (RORgammat), and forkhead box P3 (FOXP3), the master transcription factors controlling Th2, Th17, and T regulatory cells differentiation, respectively, were examined by quantitative RT PCR. RESULTS: The levels of IRF4 were elevated in allergic asthmatics compared with those in healthy controls. The frequencies of Th2 and Th17 cells as well as the concentrations of Th2- and Th17-related cytokines were higher in plasma from asthma patients than those from healthy controls; similar results were observed in culture supernatants. IRF4 mRNA levels were positively correlated with GATA3, RORgammat, and FOXP3 mRNA levels in allergic asthmatics but not in healthy controls. CONCLUSIONS: Our results suggested that IRF4 may play a role in the systemic inflammation of allergic asthma patients by facilitating the differentiation of Th2 and Th17 cells at least at the transcriptional level. PMID- 22515489 TI - Trunk muscle fatigue during a lateral isometric hold test: what are we evaluating? AB - BACKGROUND: Side bridge endurance protocols have been suggested to evaluate lateral trunk flexor and/or spine stabilizer muscles. To date, no study has investigated muscle recruitment and fatigability during these protocols. Therefore the purpose of our study was to quantify fatigue parameters in various trunk muscles during a modified side bridge endurance task (i.e. a lateral isometric hold test on a 45 degrees roman chair apparatus) and determine which primary trunk muscles get fatigued during this task. It was hypothesized that the ipsilateral external oblique and lumbar erector spinae muscles will exhibit the highest fatigue indices. METHODS: Twenty-two healthy subjects participated in this study. The experimental session included left and right lateral isometric hold tasks preceded and followed by 3 maximal voluntary contractions in the same position. Surface electromyography (EMG) recordings were obtained bilaterally from the external oblique, rectus abdominis, and L2 and L5 erector spinae. Statistical analysis were conducted to compare the right and left maximal voluntary contractions (MVC), surface EMG activities, right vs. left holding times and decay rate of the median frequency as the percent change from the initial value (NMFslope). RESULTS: No significant left and right lateral isometric hold tests differences were observed neither for holding times (97.2 +/ 21.5 sec and 96.7 +/- 24.9 sec respectively) nor for pre and post fatigue root mean square during MVCs. However, participants showed significant decreases of MVCs between pre and post fatigue measurements for both the left and right lateral isometric hold tests. Statistical analysis showed that a significantly NMFslope of the ipsilateral external oblique during both conditions, and a NMFslope of the contralateral L5 erector spinae during the left lateral isometric hold test were steeper than those of the other side's respective muscles. Although some participants presented positive NMFslope for some muscles, each muscle presented a mean negative NMFslope significantly different from 0. CONCLUSIONS: Although the fatigue indices suggest that the ipsilateral external oblique and contralateral L5 erector spinae show signs of muscle fatigue, this task seems to recruit a large group of trunk muscles. Clinicians should not view this task as evaluating specifically lateral trunk flexors, but rather as providing an indication of the general endurance and stabilisation capacity of the trunk. PMID- 22515490 TI - A survey of women and health providers about information regarding the timing of driving a car after experiencing a caesarean section. AB - BACKGROUND: In NSW, around 30% of women experience a caesarean section. Anecdotally, few receive consistent information regarding driving after a caesarean delivery. AIMS: The aims were to determine the information provided to women following caesarean section and by whom it was given, and compare this with women's actual driving behaviour. METHOD: Prior to hospital discharge, 101 consenting women completed a survey of five questions documenting the information they received about when to commence driving. They were telephoned 6-8 weeks postpartum and asked when they drove and whether they experienced any problems. Following this, a staff survey was conducted to establish what information was given to women. Insurance companies and government departments were contacted for relevant polices about when women can drive postcaesarean. RESULTS: 100 women completed both surveys (99% of recruits); 65% were advised to wait for 6 weeks or longer before driving. However, 72% of women reported they had driven by 6 weeks, and 35% by 3 weeks. In our sample, women reported minimal discomfort and rarely discontinued driving. Returned staff surveys (n = 138) revealed inconsistent advice ranging from no advice to 8 weeks of driving abstinence. Other recommendations included following insurance company guidelines (of which there were none specific to postcaesarean) (34%), 'listen to your body and be able to perform an emergency stop' (27%). CONCLUSION: Women receive conflicting advice, and current recommendations are not reflected in women's behaviour. Women are driving earlier than advised with minimal reported complications. PMID- 22515491 TI - Initial operative experience of single-port retroperitoneal laparoscopic nephrectomy. AB - This paper reports our early experience with single-port laparoscopic nephrectomy via the retroperitoneal approach. Since April 2010, 23 patients have undergone single-port laparoscopic surgery for simple nephrectomy (n = 11 patients) and radical nephrectomy (n = 12) by an experienced laparoscopic surgeon. The mean operative time was 265.2 min and the mean estimated blood loss was 96.7 mL. The procedure was completed in all patients without conversion to standard laparoscopy or open surgery. No intraoperative or acute postoperative complications occurred. When the single-port retroperitoneal laparoscopic nephrectomy group was retrospectively compared with the group that had undergone standard retroperitoneal laparoscopic nephrectomy, no significant difference was noted with respect to age, body mass index, operation time, time to eat, catheter removal or length of hospitalization (P > 0.05). A significant difference in favor of the single-port retroperitoneal laparoscopic nephrectomy group was noted with respect to the estimated blood loss (P = 0.027) and the visual analog pain scale score at discharge (P = 0.016). Although our findings show that retroperitoneal single-port laparoscopic nephrectomy is feasible with advanced techniques and optimal instrumentation, further study is required to determine the future extent of its clinical application. PMID- 22515492 TI - Chronic infusion of amyloid-beta peptide and sustained attention altered alpha7 nicotinic receptor density in the rat brain. AB - It is already known that progressive degeneration of cholinergic neurons in brain areas such as the hippocampus and the cortex leads to memory deficits, as observed in Alzheimer's disease. This work verified the effects of the infusion of amyloid-beta (Abeta) peptide associated to an attentional rehearsal on the density of alpha7 nicotinic cholinergic receptor (nAChR) in the brain of male Wistar rats. Animals received intracerebroventricular infusion of Abeta or vehicle (control - C) and their attention was stimulated weekly (Stimulated Abeta group: S-Abeta and Stimulated Control group: SC) or not (Non- Stimulated Abeta group: N-SAbeta and Non-Stimulated Control group: N-SC), using an active avoidance apparatus. Conditioned avoidance responses (CAR) were registered. Chronic infusion of Abeta caused a 37% reduction in CAR for N-SAbeta. In S-Abeta, this reduction was not observed. At the end, brains were extracted and autoradiography for alpha7 nAChR was conducted using [125I]-alpha-bungarotoxin. There was an increase in alpha7 density in hippocampus, cortex and amygdala of SAbeta animals, together with the memory preservation. In recent findings from our lab using mice infused with Abeta and the alpha7 antagonist methyllycaconitine, and stimulated weekly in the same apparatus, it was observed that memory maintenance was abolished. So, the increase in alpha7 density in brain areas related to memory might be related to a participation of this receptor in the long-lasting change in synaptic plasticity, which is important to improve and maintain memory consolidation. PMID- 22515493 TI - Pretreatment with memantine prevents Alzheimer-like alterations induced by intrahippocampal okadaic acid administration in rats. AB - Cerebral okadaic acid (OA) administration induces Alzheimer's disease (AD)-like phenotype in rats. Alterations in glutamate levels associated with hyperactivation of cyclin dependent kinase 5 (Cdk5) signaling pathway downstream Tau phosphorylation may participate in the genesis of this pathological phenotype. Here, we examined the efficacy of memantine (MN) pretreatment on reducing OA-induced AD-like phenotypes in rats. Wistar rats were given daily intraperitoneal injections of MN for 3 days and then given an intrahippocampal infusion of OA. Animals were divided into four groups: control (CO), MN, OA and MN/OA. Spontaneous locomotion and spatial memory performance were assessed by open field and Morris water maze respectively. Additionally, we measured glutamate levels in the cerebrospinal fluid (CSF) and the immunocontent of Cdk5, p35, p25 and phosphorylated Tau (pTauSer199/202) in the hippocampus. Spontaneous locomotion did not differ between groups. The OA group showed a significant decrease in spatial memory performance compared to all groups. The OA infusion also increased CSF glutamate levels and the immunocontents of Cdk5, p25 and pTauSer199/202 in the hippocampus. Conversely, pretreatment with MN prevented OA induced spatial memory deficits and the increment of CSF glutamate level; which paralleled with normal immunocontents of Cdk5, p25 and pTau- Ser199/202 proteins. There were positive correlations between spatial memory performance and the neurochemical parameters. In summary, pretreatment with MN prevents spatial memory deficits induced by intrahippocampal OA administration in rats. The prevention of increase CSF glutamate levels, along with the reduced hippocampal phosphorylation of TauSer199/202 by Cdk5/p25 signaling pathway, are the mechanisms proposed to participate in the prophylactic effects of MN in this AD like model. PMID- 22515494 TI - Multi-target inhibitors for proteins associated with Alzheimer: in silico discovery using fragment-based descriptors. AB - Alzheimer disease (AD) is one of the most common and serious neurodegenerative disorders in humans. For this reason, the search for new anti-AD treatments is a very active area. Only few biological receptors associated with AD have been well studied. The efficacy of the current drugs is limited by the fact that they inhibit only one target like protein. Thus, the rational design of new drug candidates as versatile inhibitors for different proteins associated with AD, constitutes a major goal. With the aim to overcome this problem, we developed here the first fragment-based approach by exploring quantitative-structure activity relationships (QSAR). The principal purpose was the in silico design of multitarget (mt) inhibitors against five proteins associated with AD. Our approach was focused on the construction of an mt- QSAR discriminant model using a large and heterogeneous database of compounds and substructural descriptors, which permitted the simultaneous classification and prediction of inhibitors against five proteins associated with AD. The model correctly classified more than 90% of active and inactive compounds in both, training and prediction series. As principal advantage, this mt-QSAR discriminant model was used for the automatic and fast extraction of fragments responsible for the inhibitory activity against the five proteins under study, and new molecular entities were suggested as possible versatile inhibitors for these proteins. PMID- 22515495 TI - Magnetic resonance imaging in Alzheimer's disease: from diagnosis to monitoring treatment effect. AB - Quantitative outcome variables in Alzheimer's disease (AD) are of interest because of their low longitudinal variability compared with that of repeated clinical and cognitive measurements. Conventional MR-based volumetry of structures within and beyond the medial temporal lobe has proven to be useful in the diagnostic work up of early AD patients, and measures of atrophy have the potential to monitor the efficacy of disease-modifying agents. The extensive application of new non-conventional MR-based techniques to the study of AD, such as proton magnetic resonance spectroscopy, diffusion tensor MRI, and functional MRI, has undoubtedly improved our understanding of the pathophysiology of the disease, and might lead to the identification of additional useful markers of disease progression. This review summarizes the main results obtained from the application of conventional and non-conventional MRI in AD patients, and supports their more extensive use in studies of disease evolution and clinical trials. PMID- 22515497 TI - Design, synthesis, and antimycobacterial property of PEG-bis(INH) conjugates. AB - Poly(ethylene glycol) derivatives of isoniazid with varying molecular weight of poly(ethylene glycol) were designed as antimycobacterial agents. Poly(ethylene glycol)-diacrylate of three different molecular weights (MW 258, 575, and 700) was conjugated with isoniazid by the Michael addition approach. The poly(ethylene glycol)-bis(isoniazid) conjugates thus obtained were completely characterized by FT-IR, (1)H and (13)C NMR, and ESI-MS spectroscopic techniques. Comparative MTT assay of the poly(ethylene glycol)-bis(isoniazid) conjugates showed much lower cytotoxicity than the neat isoniazid. MIC studies on Mycobaterium tuberculosis H37Rv showed potential antimycobacterial activity than the free isoniazid on a molar basis. The poly(ethylene glycol)-bis(isoniazid) conjugates were successfully radiolabeled with 99m-Technetium with more than 97% efficiency and stability to assess their in vivo fate. The (99m)Tc labeled poly(ethylene glycol) bis(isoniazid) conjugates showed higher blood retention time in New Zealand rabbits which increased with increasing molecular weight of poly(ethylene glycol). Biodistribution studies in infection-induced murine models (BALB/c mice) showed significant retention of these conjugates at the site of infection for 72 h. The results of this study illustrate the potential utility of the PEGylated isoniazid conjugates as long circulating carriers for improved antitubercular drug therapy. PMID- 22515498 TI - Oxidation of phenol by tris(1,10-phenanthroline)osmium(III). AB - Outer-sphere oxidation of phenols is under intense scrutiny because of questions related to the dynamics of proton-coupled electron transfer (PCET). Oxidation by cationic transition-metal complexes in aqueous solution presents special challenges because of the potential participation of the solvent as a proton acceptor and of the buffers as general base catalysts. Here we report that oxidation of phenol by a deficiency of [Os(phen)(3)](3+), as determined by stopped-flow spectrophotometry, yields a unique rate law that is second order in [osmium(III)] and [phenol] and inverse second order in [osmium(II)] and [H(+)]. A mechanism is inferred in which the phenoxyl radical is produced through a rapid PCET preequilibrium, followed by rate-limiting phenoxyl radical coupling. Marcus theory predicts that the rate of electron transfer from phenoxide to osmium(III) is fast enough to account for the rapid PCET preequilibrium, but it does not rule out the intervention of other pathways such as concerted proton-electron transfer or general base catalysis. PMID- 22515496 TI - The effectiveness and cost evaluation of pain exposure physical therapy and conventional therapy in patients with complex regional pain syndrome type 1. Rationale and design of a randomized controlled trial. AB - BACKGROUND: Pain Exposure Physical Therapy is a new treatment option for patients with Complex Regional Pain Syndrome type 1. It has been evaluated in retrospective as well as in prospective studies and proven to be safe and possibly effective. This indicates that Pain Exposure Physical Therapy is now ready for clinical evaluation. The results of an earlier performed pilot study with an n = 1 design, in which 20 patients with Complex Regional Pain Syndrome type 1 were treated with Pain Exposure Physical Therapy, were used for the design and power calculation of the present study.After completion and evaluation of this phase III study, a multi-centre implementation study will be conducted.The aim of this study is to determine whether Pain Exposure Physical Therapy can improve functional outcomes in patients with Complex Regional Pain Syndrome type 1. METHODS/DESIGN: This study is designed as a single-blinded, randomized clinical trial. 62 patients will be randomized with a follow-up of 9 months to demonstrate the expected treatment effect. Complex Regional Pain Syndrome type 1 is diagnosed in accordance with the Bruehl/International Association for the Study of Pain criteria. Conventional therapy in accordance with the Dutch guideline will be compared with Pain Exposure Physical Therapy. Primary outcome measure is the Impairment level SumScore, restricted version. DISCUSSION: This is the first randomized controlled study with single blinding that has ever been planned in patients with Complex Regional Pain Syndrome type 1 and does not focus on a single aspect of the pain syndrome but compares treatment strategies based on completely different pathophysiological and cognitive theories. PMID- 22515499 TI - Iodinated photosensitizing chitosan: self-assembly into tumor-homing nanoparticles with enhanced singlet oxygen generation. AB - A novel iodinated chitosan-backboned conjugate (GC-I-Ce6) was designed and prepared to fabricate self-assembled biopolymeric nanoparticles with heavy atom effected enhanced singlet oxygen generation as well as biological merits. The heavy atom-rich nature of the hydrophobic particle interior was characterized with X-ray absorption and the modified photophysical properties of a chemically embedded photosensitizer, chlorin e6 (Ce6). From the comparative spectroscopic studies as well as cellular and animal experiments, it has been shown that the self-assembled GC-I-Ce6 nanoparticles have enhanced capability of singlet oxygen generation by the intraparticle heavy-atom effect, along with high tumor targetability in vitro and in vivo thanks to the glycol chitosan-surfaced exterior with biocompatible, positively charged and tumor-homing characteristics. Actual efficacy improvement in the photodynamic therapy of a human breast cancer cell line (MDA-MB-231) demonstrates potential of our photophysically and pharmaceutically motivated hybrid bioconjugate approach for nanomedicine applications. PMID- 22515500 TI - Intramolecular charge resonance in dimer radical anions of di-, tri-, tetra-, and pentaphenylalkanes. AB - Intramolecular dimer radical anions of di-, tri-, tetra-, and pentaphenylalkanes were investigated on the basis of absorption spectral measurements during gamma radiolysis in 2-methyltetrahydrofuran (MTHF) glassy matrix at 77 K and theoretical calculations. The absorption spectrum of 1,1,2,2-tetraphenylethane (1,1,2,2-Ph(4)E) radical anion showed two bands in the near-infrared (NIR) region (900-2600 nm). One band observed at shorter wavelength than 2000 nm is assigned to the intramolecular charge resonance (CR) band between two phenyl groups of the 1,1-diphenylmethyl chromophore (1,1-dimer radical anion). The intramolecular CR band of the 1,1-dimer radical anion was observed for various alkanes having 1,1 diphenylmethyl chromophore such as 1,1,1-triphenylmethane (1,1,1-Ph(3)M), 1,1,1,1 tetraphenylmethane (1,1,1,1-Ph(4)M), and so on. The other intramolecular CR band observed at longer wavelength than 2200 nm is assigned to intramolecular dimer radical anion between two phenyl groups of the 1,2-diphenylethyl chromophore (1,2 dimer radical anion). The intramolecular CR band of the 1,2-dimer radical anion was observed for various alkanes having a 1,2-diphenylethyl chromophore, such as 1,1,2-triphenylethane (1,1,2-Ph(3)E), 1,1,2,2-Ph(4)E, and 1,1,1,2,2 pentaphenylethane (1,1,1,2,2-Ph(5)E) and so on. No dimer radical anion was observed for 1,n-diphenylalkanes (n > 2) without 1,1-diphenylmethyl chromophore. The relationship between the structure and negative charge delocalization over two phenyl groups connected by an sp(3) carbon is discussed. PMID- 22515501 TI - Usefulness of continuous renal replacement therapy for correcting hypernatremia in a patient with severe congestive heart failure. AB - Continuous renal replacement therapy (CRRT) is used as an alternative to intermittent hemodialysis (IHD) in patients who have acute kidney injury (AKI) and cannot tolerate IHD. Several studies have reported the usefulness of CRRT in treating sepsis, which is a non-renal indication for CRRT. Recently, CRRT was also introduced as a useful tool for treating severe congestive heart failure (CHF). By using CRRT, we successfully treated hypernatremia in a patient with severe CHF, without observing any fluid overload. Therefore, we report this case to suggest that CRRT should be considered for the treatment of hypernatremia in patients with severe CHF. PMID- 22515502 TI - Serological antibodies against LY6K as a diagnostic biomarker in esophageal squamous cell carcinoma. AB - OBJECTIVES: To evaluate the diagnostic values of autoantibodies against lymphocyte antigen 6 complex locus K (LY6K) in esophageal squamous cell carcinoma (ESCC). METHODS: After cloning, expressing, and purifying LY6K as fusion proteins, LY6K autoantibodies were measured in 62 patient and 58 control serum samples using enzyme-linked immunosorbent assay (ELISA). Reverse transcription polymerase chain reaction (RT-PCR) was used to measure the LY6K mRNA levels in ESCC and adjacent tissues. RESULTS: LY6K autoantibodies were found significantly higher in patients than controls. The area under the receiver-operating characteristic (ROC) curve (AUC) was 0.85, and the optimal sensitivity and specificity for ESCC detection were 80.6 and 78.7%, respectively. LY6K mRNA expressions in patients were upregulated. CONCLUSIONS: Autoantibodies against LY6K may be a good diagnostic biomarker for ESCC. PMID- 22515503 TI - Comparison of three DNA extraction methods for feed products and four amplification methods for the 5'-junction fragment of Roundup Ready soybean. AB - Three methods of DNA extraction from feed products and four detection methods for the 5'-junction fragment of genetically modified (GM) Roundup Ready soybean (RRS) were compared and evaluated. The DNA extraction methods, including cetyltrimethylammonium bromide (CTAB), sodium dodecyl sulfate (SDS), and guanidine hydrochloride (Kit), were assessed for their yields and purity of DNA, extraction time, and reagent cost. The DNA yields of CTAB, SDS, and Kit were 52 694, 164-1750 and 23-105 ng/mg sample, and their extraction time was 2.5-3, 2 2.5, and 1.5-2 h with reagent cost about US dollar 0.24, 0.13, and 1.9 per extraction, respectively. The SDS method was generally well suited to all kinds of feed matrices tested. The limits of detection for the four amplification protocols, including loop-mediated isothermal amplification (LAMP), hyperbranched rolling circle amplification (HRCA), conventional polymerase chain reaction (PCR), and real-time PCR, were 48.5, 4.85, 485, and 9 copies of the pTLH10 plasmid, respectively. The ranked results of the four detection methods were based on multiattribute utility theory as follows (from best to worse): HRCA, LAMP, PCR, and real-time PCR. This comparative evaluation was specifically useful for selection of a highly efficient DNA extraction or amplification method for detecting different GM ingredients. PMID- 22515504 TI - Staphylococcus pseudintermedius in the dog: taxonomy, diagnostics, ecology, epidemiology and pathogenicity. AB - The dog is the natural host of Staphylococcus pseudintermedius. Many research efforts are currently being undertaken to expand our knowledge and understanding of this important canine commensal and opportunistic pathogen. The objective of this review is to summarize the current knowledge of the species, including the latest research outcomes, with emphasis on taxonomy, diagnostics, ecology, epidemiology and pathogenicity. Despite the important taxonomic changes that have occurred over the past few years, the risk of misidentification in canine specimens is low and does not have serious consequences for clinical practice. Staphylococcus pseudintermedius carriage in the dog is more frequent and genetically heterogeneous compared with that of Staphylococcus aureus in man. It appears that these staphylococcal species have evolved separately through adaptation to their respective natural hosts and differ with regard to various aspects concerning ecology, population structure and evolution of antibiotic resistance. Further understanding of the ecology and epidemiology of S. pseudintermedius is hampered by the lack of a standard method for rapid and discriminatory typing and by the limited data available on longitudinal carriage and population structure of meticillin-susceptible strains. With regard to pathogenicity, it is only now that we are starting to explore the virulence potential of S. pseudintermedius based on genomic and proteomic approaches, and more research is needed to assess the importance of individual virulence factors and the possible existence of hypervirulent strains. PMID- 22515505 TI - Tuning the potentials of "extra" electrons in colloidal n-type ZnO nanocrystals via Mg2+ substitution. AB - Colloidal reduced ZnO nanocrystals are potent reductants for one-electron or multielectron redox chemistry, with reduction potentials tunable via the quantum confinement effect. Other methods for tuning the redox potentials of these unusual reagents are desired. Here, we describe synthesis and characterization of a series of colloidal Zn(1-x)Mg(x)O and Zn(0.98-x)Mg(x)Mn(0.02)O nanocrystals in which Mg(2+) substitution is used to tune the nanocrystal reduction potential. The effect of Mg(2+) doping on the band-edge potentials of ZnO was investigated using electronic absorption, photoluminescence, and magnetic circular dichroism spectroscopies. Mg(2+) incorporation widens the ZnO gap by raising the conduction band potential and lowering the valence-band potential at a ratio of 0.68:0.32. Mg(2+) substitution is far more effective than Zn(2+) removal in raising the conduction-band potential and allows better reductants to be prepared from Zn(1 x)Mg(x)O nanocrystals than can be achieved via quantum confinement of ZnO nanocrystals. The increased conduction-band potentials of Zn(1-x)Mg(x)O nanocrystals compared to ZnO nanocrystals are confirmed by demonstration of spontaneous electron transfer from n-type Zn(1-x)Mg(x)O nanocrystals to smaller (more strongly quantum confined) ZnO nanocrystals. PMID- 22515506 TI - Transcutaneous electrical nerve stimulation and placental vascularization in cases of uterine blood flow restriction. AB - Studies report transcutaneous electrical nerve stimulation (TENS) as a treatment for placental insufficiency. To induce utero-placental insufficiency in rats, the uterine artery was ligated. Transcutaneous electrical nerve stimulation was applied with a frequency of 80 Hz, pulse duration of 200 MUs, and low intensity. Placental blood vessels were analyzed after immunohistochemistry. The number, caliber and area occupied by placental vessels, fetal weight and length, and placental volume were lower in cases stimulated by TENS. The interaction between ligation and stimulation by TENS was associated with reduction of all these measurements, suggesting that TENS use during pregnancy may have harmful effects on intra-uterine development. PMID- 22515507 TI - Dynein and dynactin components modulate neurodegeneration induced by excitotoxicity. AB - Glutamate excitotoxicity causes neuronal dysfunction and degeneration. It is implicated in chronic disorders, including Alzheimer's disease, and in acute CNS insults such as ischemia. These disorders share prominent morphological features, including axon degeneration and cell body death. However, the molecular mechanism underlying excitotoxicity-induced neurodegeneration remains poorly understood. A key molecular feature of neurodegeneration is deficits in microtubule-based cargo transport that plays a pivotal role in maintaining the balance of survival and stress signaling in the axon. We developed an excitotoxicity-induced neurodegeneration system in primary neuronal cultures. We find that excitotoxicity generates a C-terminal truncated form of p150Glued, a major component of the dynactin complex, which exacerbates axon degeneration. This p150Glued truncated form was identified in brain tissues of patients with Alzheimer's disease. Overexpression of wild-type (WT) dynein intermediate chain (DIC), a dynein component that interacts with p150Glued and links dynein and dynactin complexes, DIC (S84D) mutant, and WT p150Glued suppressed axon degeneration. These modulating effects of p150Glued and DIC on excitotoxicity induced axon degeneration are also observed in apoptosis and cell body death. Thus, our findings identify retrograde transport proteins, p150Glued and DIC, as novel modulators of neurodegeneration induced by glutamate excitotoxicity. PMID- 22515508 TI - Facile method for the fabrication of robust polyelectrolyte multilayers by post photo-cross-linking of azido groups. AB - In this letter, we have developed a facile method to enhance the stability of polyelectrolyte multilayers. We fabricate conventional polyelectrolyte multilayers of PAH/PAA through electrostatic layer-by-layer (LbL) assembly and then postinfiltrate photosensitive cross-linking agent 4,4'-diazostilbene-2,2' disulfonic acid disodium salt into the LbL films. After cross-linking by UV irradiation, the stability of the photo-cross-linked multilayer is highly improved as evidenced by the lack of dissolution under ultrasonication in saturated SDS aqueous solutions for 10 min. Moreover, by taking advantage of the different stability of the LbL film before and after UV irradiation, a patterned surface can be achieved. PMID- 22515509 TI - Mobile connected dermatoscope and confocal laser scanning microscope: a useful combination applied in facial simple sensitive skin. AB - Little is known as the effects of mobile connected dermatoscope services on diagnostic accuracy for sensitive skin. Confocal laser scanning microscope (CLSM) can non-invasively measure the thickness of epidermis. Combination of the two devices to observe sensitive skin may receive unexpected effects. To evaluate the application effect on sensitive skin with the combination of Handyscope and confocal laser scanning microscope. Twenty simple sensitive-skinned patients and 20 volunteers participated in the study. Cheek, typically, dermoscopic images were obtained from patients, and the changes in the skin texture were observed. Their epidermis thicknesses as well as the volunteers' were measured so that the thicknesses of the two groups were compared. Dermoscopic pictures of the skin texture obviously showed that dilated capillaries looked like earthworms with pigmented patches more or less floating above, and skin roughness as well as deepened dermatoglyph were also conspicuously present in some patients. The mean epidermal thickness of the patients was 79.01 MUm and the volunteers' was 85.78 MUm. The difference between the two groups reached 6.77 MUm. There was a statistical significance (P = 0.001). Mobile connected dermatoscope and confocal laser scanning microscope might be the choice for simple sensitive skin investigation. PMID- 22515510 TI - Treatment of endometriosis in different ethnic populations: a meta-analysis of two clinical trials. AB - Approaches to the treatment of endometriosis vary worldwide, but studies comparing endometriosis medications in different ethnic groups are rare. A systematic literature search identified two studies directly comparing dienogest (DNG) versus gonadotropin-releasing hormone (GnRH) analogues in European and Japanese populations. Meta-analysis of visual analogue scale scores revealed no heterogeneity in response between the trials, indicating equivalent efficacy of DNG and GnRH analogues for endometriosis-related pain across populations. DNG was significantly superior to GnRH analogues for bone mineral density change in both trials, but significant heterogeneity between the studies may indicate ethnic differences in physiology. PMID- 22515511 TI - Survival analysis of pediatric dialysis patients in Taiwan. AB - AIM: The long-term survival of Taiwanese children with end-stage renal disease (ESRD) has not been reported before. This study aimed to determine the long-term survival, mortality hazards and causes of death in paediatric patients receiving dialysis. METHODS: Paediatric patients (aged 19 years and younger) with incident ESRD who were reported to the Taiwan Renal Registry from 1995 to 2004 were included. A total of 319 haemodialysis (HD) and 156 peritoneal dialysis (PD) patients formed the database. After stratification by dialysis modality, multivariate Cox proportional-hazards model was constructed with age, sex and co morbidity as predictive variables. RESULTS: The annual paediatric ESRD incidence rate was 8.12 per million of age-related populations. The overall 1-, 5-, and 10 year survival rates for PD patients were 98.1%, 88.0% and 68.4%, respectively, and were 96.9%, 87.3% and 78.5% for HD patients. The survival analysis showed no significant difference between HD and PD (P = 0.4878). Using '15-19 years' as a reference group, the relative risk (RR) of the youngest group (0-4 years) was 6.60 (95% CI: 2.50-17.38) for HD, and 5.03 (95% CI: 1.23-20.67) for PD. The death rate was 24.66 per 1000 dialysis patient-years. The three major causes of death were infection (23.4%), cardiovascular disease (13.0%) and cerebrovascular disease (10.4%). Hemorrhagic stroke (87.5%) was the main type of foetal cerebrovascular accident. CONCLUSION: We conclude that there was no significant difference of paediatric ESRD patient survival between HD and PD treatment in Taiwan. The older paediatric ESRD patients had better survival than younger patients. PMID- 22515512 TI - Unknown aspects of self-assembly of PbS microscale superstructures. AB - A lot of interesting and sophisticated examples of nanoparticle (NP) self assembly (SA) are known. From both fundamental and technological standpoints, this field requires advancements in three principle directions: (a) understanding the mechanism and driving forces of three-dimensional (3D) SA with both nano- and microlevels of organization; (b) understanding disassembly/deconstruction processes; and (c) finding synthetic methods of assembly into continuous superstructures without insulating barriers. From this perspective, we investigated the formation of well-known star-like PbS superstructures and found a number of previously unknown or overlooked aspects that can advance the knowledge of NP self-assembly in these three directions. The primary one is that the formation of large seemingly monocrystalline PbS superstructures with multiple levels of octahedral symmetry can be explained only by SA of small octahedral NPs. We found five distinct periods in the formation PbS hyperbranched stars: (1) nucleation of early PbS NPs with an average diameter of 31 nm; (2) assembly into 100-500 nm octahedral mesocrystals; (3) assembly into 1000-2500 nm hyperbranched stars; (4) assembly and ionic recrystallization into six-arm rods accompanied by disappearance of fine nanoscale structure; (5) deconstruction into rods and cuboctahedral NPs. The switches in assembly patterns between the periods occur due to variable dominance of pattern-determining forces that include van der Waals and electrostatic (charge-charge, dipole-dipole, and polarization) interactions. The superstructure deconstruction is triggered by chemical changes in the deep eutectic solvent (DES) used as the media. PbS superstructures can be excellent models for fundamental studies of nanoscale organization and SA manufacturing of (opto)electronics and energy-harvesting devices which require organization of PbS components at multiple scales. PMID- 22515513 TI - Comparative pharmacokinetics of HD203, a biosimilar of etanercept, with marketed etanercept (Enbrel(r)): a double-blind, single-dose, crossover study in healthy volunteers. AB - OBJECTIVE: HD203 is a biosimilar of etanercept, a fusion protein of the ligand binding portion of the human tumor necrosis factor receptor II linked to the Fc portion of human immunoglobulin G1. Since HD203 is under clinical development, this study was conducted to compare the pharmacokinetics of HD203 with Enbrel(r), the first marketed etanercept. METHODS: A double-blind, randomized, single-dose, two-period, two-sequence, crossover study was conducted in 37 healthy volunteers. In each period, 25 mg/mL of reconstituted lyophilized reference (Enbrel(r)) or test product (HD203) was administered subcutaneously, either the reference product followed by the test product, or vice versa. Serial blood samples for pharmacokinetic analysis were taken for 480 hours after dosing, and serum concentrations of the products were determined using a commercial enzyme-linked immunosorbent assay. The geometric mean ratios with 90% confidence intervals for the maximum concentration (C(max)) and the area under the concentration-time curve from time 0 to the last measurable time point (AUC(0-t)) were estimated. RESULTS: A total of 35 subjects completed the study; serious adverse events were not observed. The mean serum concentration-time profiles of the two products were similar. The C(max) and AUC(0-t) values of the reference product (mean +/- standard deviation) were 1.25 +/- 0.45 mg/L and 283.15 +/- 98.57 mg*h/L, respectively, while those of the test drug were 1.35 +/- 0.47 mg/L and 315.78 +/- 99.38 mg*h/L, respectively. The geometric mean ratios (90% confidence intervals) of the test to the reference for C(max) and AUC(0-t) were 1.08 (1.00, 1.16) and 1.13 (1.05, 1.21), respectively. CONCLUSIONS: A single subcutaneous injection of HD203 or Enbrel(r) into healthy volunteers appeared to be safe and well tolerated. Comparative pharmacokinetics demonstrated that reconstituted lyophilized HD203 has bioavailability similar to that of Enbrel(r). PMID- 22515515 TI - Na(2/7)Gd(4/7)MoO4: a modulated scheelite-type structure and conductivity properties. AB - Scheelite-type compounds with the general formula (A1,A2)(n)[(B1,B2)O(4)](m) (2/3 <= n/m <= 3/2) are the subject of large interest owing to their stability, relatively simple preparation, and optical properties. The creation of cation vacancies (?) in the scheelite-type framework and the ordering of A cations and vacancies can be a new factor in controlling the scheelite-type structure and properties. For a long time, cation-deficient Nd(3+):M(2/7)Gd(4/7)?(1/7)MoO(4) (M = Li, Na) compounds were considered as potential lasers with diode pumping. They have a defect scheelite-type 3D structure (space group I4(1)/a) with a random distribution of Li(+)(Na(+)), Gd(3+), and vacancies in the crystal. A Na(2/7)Gd(4/7)MoO(4) single crystal with scheelite-type structure has been grown by the Czochralski method. Transmission electron microscopy revealed that Na(2/7)Gd(4/7)MoO(4) has a (3 + 2)D incommensurately modulated structure. The (3 + 2)D incommensurately modulated scheelite-type cation-deficient structure of Na(2/7)Gd(4/7)MoO(4) [super space group I4 (alpha-beta0,betaalpha0)00] has been solved from single-crystal diffraction data. The solution of the (3 + 2)D incommensurately modulated structure revealed the partially disordered distribution of vacancies and Na and Gd cations. High-temperature conductivity measurements performed along the [100] and [001] orientation of the single crystal revealed that the conductivity of Na(2/7)Gd(4/7)MoO(4) at T = 973 K equals sigma = 1.13 * 10(-5) Omega(-1) cm(-1). PMID- 22515514 TI - Preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra during retropubic radical prostatectomy: description of the technique. AB - We describe our technique for preservation of the smooth muscular internal (vesical) sphincter and proximal urethra during radical retropubic prostatectomy. The first steps of the prostatectomy reflect the standard retropubic prostatectomy; whereas for the final phases, the procedure continues in an anterograde manner with incision of the fibers of the detrusor muscle at the insertion of the ventral surface of the base of the prostate. At this level, the inner circular muscle of the bladder neck forms a sphincteric ring of smooth muscle that covers the longitudinally-oriented smooth muscle component of the urethra that extends distally to the verumontanum; these two proximal structures represent the internal sphincter that envelops and locks the proximal urethra. A blunt dissection is continued until the ring-shaped vesical sphincter is separated from the prostate and the longitudinally-oriented smooth muscle component of the urethral musculature is identified. The base of the prostate is then gently separated from the urethra and from the bladder until the maximal length of the urethral musculature is isolated and preserved. Finally, a urethra urethral anastomosis is carried out and the ventral stitches are placed through the circular fibres of the bladder neck. In all cases we carry out circumferential biopsies of the proximal urethra and of the base of the prostate. The described technique is a feasible and safe method for preservation of the internal urethral sphincter. Despite the enthusiasm regarding our positive functional results, further studies with larger series are required to confirm these findings. PMID- 22515516 TI - Potential application of hydrogen in traumatic and surgical brain injury, stroke and neonatal hypoxia-ischemia. AB - This article summarized findings of current preclinical studies that implemented hydrogen administration, either in the gas or liquid form, as treatment application for neurological disorders including traumatic brain injury (TBI), surgically induced brain injury (SBI), stroke, and neonatal hypoxic-ischemic brain insult (HI). Most reviewed studies demonstrated neuroprotective effects of hydrogen administration. Even though anti-oxidative potentials have been reported in several studies, further neuroprotective mechanisms of hydrogen therapy remain to be elucidated. Hydrogen may serve as an adjunct treatment for neurological disorders. PMID- 22515517 TI - Micro-mechanical damage of trabecular bone-cement interface under selected loading conditions: a finite element study. AB - In this study, two micro finite element models of trabecular bone-cement interface developed from high resolution computed tomography (CT) images were loaded under compression and validated using the in situ experimental data. The models were then used under tension and shear to examine the load transfer between the bone and cement and the micro damage development at the bone-cement interface. In addition, one models was further modified to investigate the effect of cement penetration on the bone-cement interfacial behaviour. The simulated results show that the load transfer at the bone-cement interface occurred mainly in the bone cement partially interdigitated region, while the fully interdigitated region seemed to contribute little to the mechanical response. Consequently, cement penetration beyond a certain value would seem to be ineffective in improving the mechanical strength of trabecular bone-cement interface. Under tension and shear loading conditions, more cement failures were found in denser bones, while the cement damage is generally low under compression. PMID- 22515518 TI - Novel and emerging drugs for chronic lymphocytic leukemia. AB - During the last decades advanced treatment options for chronic lymphocytic leukemia have enabled the shift from rather ineffective palliative treatment to therapies that are aiming for long lasting complete remission and prolongation of survival. This remarkable progress was achieved by combining conventional chemotherapy with monoclonal antibodies such as rituximab and alemtuzumab. Despite this improvement, CLL remains an incurable disease and all patients will eventually relapse and become refractory to treatment. Allogeneic stem cell transplantation is the only curative option but is feasible only in a minority of patients due to the comorbidity and impaired physical fitness of many patients, since the mean age at first diagnosis lies between 70 and 75 years. Therefore, novel less-toxic therapeutic agents are needed, particularly for patients with comorbidities or high-risk cytogenetic abnormalities. Research in the field of CLL and growing understanding of the pathogenesis of B-cell lymphomas has produced a wide variety of new substances for different targets, e.g. different novel monoclonal antibodies, immunomodulatory agents and inhibitors targeting different kinases of B-cell receptor signalling cascade, such as Bruton tyrosine kinase (BTK) and phosphatidylinositol-3-kinase (PI3K). This article reviews novel drugs that were recently developed for the use in CLL. The agents discussed in this article were selected for having already shown preliminary evidence of clinical activity. PMID- 22515519 TI - Acid ceramidase as a chemotherapeutic target to overcome resistance to the antitumoral effect of choline kinase alpha inhibition. AB - We have analyzed the response of primary cultures derived from tumor specimens of non small cell lung cancer (NSCLC) patients to choline kinase alpha (ChoKalpha) inhibitors. ChoKalpha inhibitors have been demonstrated to increase ceramides levels specifically in tumor cells, and this increase has been suggested as the mechanism that explain its proapoptotic effect in cancer cells. Here, we have investigated the molecular mechanism associated to the intrinsic resistance, and found that other enzyme involved in lipid metabolism, acid ceramidase (ASAH1), is specifically upregulated in resistant tumors. NSCLC cells with acquired resistance to ChoKalpha inhibitors also display increased levels of ASAH1. Accordingly, ASAH1 inhibition synergistically sensitizes lung cancer cells to the antiproliferative effect of ChoKalpha inhibitors. Thus, the determination of the levels of ASAH1 predicts sensitivity to targeted therapy based on ChoKalpha specific inhibition and represents a model for combinatorial treatments of ChoKalpha inhibitors and ASAH1 inhibitors. Considering that ChoKalpha inhibitors have been recently approved to enter Phase I clinical trials by the Food and Drug Administration (FDA), these findings are anticipating critical information to improve the clinical outcome of this family of novel anticancer drugs under development. PMID- 22515520 TI - A molecular signature for oncogenic BRAF in human colon cancer cells is revealed by microarray analysis. AB - Sporadic colorectal cancer develops through a number of functional mutations. Key events are mutually exclusive mutations in BRAF or RAS oncogenes. Signatures for BRAF oncogene have been revealed in melanoma. In a previous study we have reported a molecular signature for HRAS and KRAS mutations in colorectal cell lines that also showed an EMT phenotype for HRAS. In this study we report a molecular profile for a BRAF oncogenic mutation BRAFV600E in colon using the Illumina 45,000 gene microarray. Key differentially expressed genes have been identified from the array analysis further verified by qPCR analysis. Ingenuity pathway analysis such as microsatellite instability, kinase signalling, apoptosis, WNT and Integrin signalling is presented. MutBRAF transforms cells through cross talk with developmental pathways Hedgehog and Wnt, as well as by deregulation of colorectal cancer related kinase pathways, like PI3K. Differential gene expression of BRAFV600E in colon as compared to those associated with RAS oncogenes is presented, as well as similarities and differences between oncogenic BRAF signatures in colon as compared to thyroid and melanoma are highlighted. Novel selected genes/pathways are validated in cell lines and clinical samples bearing BRAFV600E and may serve as markers/targets for personalised diagnosis/therapy/resistance of colorectal cancer. PMID- 22515522 TI - Emerging roles for modulation of microRNA signatures in cancer chemoprevention. AB - miRNAs are small endogenous non-coding RNAs, approximately 21-nucleotides in length, which are shown to regulate an array of cellular processes such as differentiation, cell cycle, cell proliferation, apoptosis, and angiogenesis which are important in cancer. miRNAs can function as both tumor promoters (oncomiRs) or tumor suppressors by their ability to target numerous biomolecules that are important in carcinogenesis. Aberrant expression of miRNAs is correlated with the development and progression of tumors, and the reversal of their expression has been shown to modulate the cancer phenotype suggesting the potential of miRNAs as targets for anti-cancer drugs. Several chemopreventive phytochemicals like epigallocatechin-3-gallate, curcumin, isoflavones, indole-3 carbinol, resveratrol, and isothiocyanate have been shown to modulate the expression of numerous miRNAs in cancer cells that lead to either abrogation of tumor growth or sensitization of cancer cells to chemotherapeutic agents. This review focuses on the putative role(s) of miRNAs in different aspects of tumorigenesis and at various stages of early drug discovery that makes them a promising class of drug targets for chemopreventive intervention in cancer. We summarize the current progress in the development of strategies for miRNA-based anti-cancer therapies. We also explore the modulation of miRNAs by various cancer chemopreventive agents and the role of miRNAs in drug metabolism. We will discuss the role of miRNAs in cancer stem cells and epithelial-to-mesenchymal transition; and talk about how modulation of miRNA expression relates to altered glycosylation patterns in cancer cells. In addition, we consider the role of altered miRNA expression in carcinogenesis induced by various agents including genotoxic and epigenetic carcinogens. Finally, we will end with a discussion on the potential involvement of miRNAs in the development of cancer chemoresistance. Taken together, a better understanding of the complex role(s) of miRNAs in cancer may help in designing better strategies for biomarker discovery or drug targeting of miRNAs and/or their putative protein targets. PMID- 22515521 TI - A comprehensive overview of targeted therapy in metastatic renal cell carcinoma. AB - Chemotherapy and immunotherapy failed to deliver decisive results in the systemic treatment of metastatic renal cell carcinoma. Agents representing the current standards operate on members of the RAS signal transduction pathway. Sunitinib (targeting vascular endothelial growth factor), temsirolimus (an inhibitor of the mammalian target of rapamycin - mTOR) and pazopanib (a multi-targeted receptor tyrosine kinase inhibitor) are used in the first line of recurrent disease. A combination of bevacizumab (inhibition of angiogenesis) plus interferon alpha is also first-line therapy. Second line options include everolimus (another mTOR inhibitor) as well as tyrosine kinase inhibitors for patients who previously received cytokine. We review the results of clinical investigations focusing on survival benefit for these agents. Additionally, trials focusing on new agents, including the kinase inhibitors axitinib, tivozanib, dovitinib and cediranib and monoclonal antibodies including velociximab are also discussed. In addition to published outcomes we also include follow-up and interim results of ongoing clinical trials. In summary, we give a comprehensive overview of current advances in the systemic treatment of metastatic renal cell carcinoma. PMID- 22515523 TI - The impact of proteomics in the understanding of the molecular basis of Paclitaxel-resistance in ovarian tumors. AB - The current therapy for ovarian cancer has advanced from alkylating agents, to a combination of carboplatinum and paclitaxel offering increased survival. Although most patients respond to this first-line therapy, initially, the majority of these patients relapse within 2 years. The mechanisms responsible for acquired drug resistance in ovarian cancer have been elucidated only in part. They include i) enhanced drug export, ii) activation/inhibition of intracellular signalling pathways, iii) molecular alterations in tubulin isotype composition. A better understanding of these mechanisms is needed, in order to develop new approaches, aimed at overcoming resistance to anticancer agents, and to reveal the complexity of causes, which contribute to drug resistance. In this review we offer an updated overview of proteomic studies on the molecular mechanisms of paclitaxel resistance. These proteomic studies also identify potential targets for modulating drug resistance, that could be predictive of response to chemotherapy in ovarian carcinomas. PMID- 22515524 TI - Increased expression of matrix metalloproteinases mediates thromboxane A2-induced invasion in lung cancer cells. AB - Thromboxane A(2) receptor (TP) has been shown to play an important role in multiple aspects of cancer development including regulation of tumor growth, survival and metastasis. Here we report that TP mediates cancer cell invasion by inducing expression of matrix metalloproteinases (MMPs). TP agonist, I-BOP, significantly elevated MMP-1, MMP-3, MMP-9 and MMP-10 mRNA levels in A549 human lung adenocarcinoma cells overexpressing TPalpha or TPbeta. The secretion of MMP 1 and MMP-9 in conditioned media was determined using Western blot analysis and zymographic assay. Signaling pathways of I-BOP-induced MMP-1 expression were examined in further detail as a model system for MMPs induction. Signaling molecules involved in I-BOP-induced MMP-1 expression were identified by using specific inhibitors including small interfering (si)-RNAs of signaling molecules and promoter reporter assay. The results indicate that I-BOP-induced MMP-1 expression is mediated by protein kinase C (PKC), extracellular signal-regulated kinase (ERK)-activator protein-1(AP-1) and ERK-CCAAT/enhancer-binding protein beta (C/EBPbeta) pathways. I-BOP-induced cellular invasiveness of A549 cells expressing TPalpha or TPbeta was determined by invasion assay. GM6001, a general inhibitor of MMPs, decreased basal and I-BOP-induced cell invasion. Knockdown of MMP-1 and MMP-9 by their respective siRNA partially reduced I-BOP-stimulated cell invasion suggesting that other MMPs induced by I-BOP were also involved. Our studies establish the relationship between TP and MMPs in cancer cell invasion and suggest that the thromboxane A(2) (TXA(2))-TP signaling is a potential therapeutic target for cancer invasion and metastasis. PMID- 22515525 TI - anti-tumor effect of AlkB homolog 3 knockdown in hormone- independent prostate cancer cells. AB - Castrate resistant prostate cancer (CRPC) is a disease that is resistant to both hormone therapy and chemotherapy. At present, no curative therapy for CRPC has been established. Therefore, it is necessary to determine a novel molecular target for the development of therapeutic agents. We previously reported that AlkB homolog 3 (ALKBH3) is highly expressed in prostate cancer but not in benign prostatic hyperplasia or in normal prostate epithelium and that the expression levels of ALKBH3 protein are significantly correlated with the hormone independent state of prostate cancer. Moreover, ALKBH3 regulates the invasion of prostate cancer cells via the regulation of matrix metalloproteinase 9. Here, we show that ALKBH3 gene silencing markedly induces apoptosis in hormone-independent prostate cancer cell line DU145 but not in the normal prostate epithelial cell line PNT2. Moreover, the in vivo tumorigenicity of DU145 cells was significantly inhibited by the administration of ALKBH3 siRNA. Furthermore, the anchorage independent growth of DU145 cells was inhibited by ALKBH3 knockdown and promoted by ALKBH3 overexpression, significantly. ALKBH3 shRNA-expressing prostate cancer cells formed significantly smaller tumors than those of control shRNA transfectants in an in vivo xenograft model. These findings suggest that ALKBH3 is a promising target molecule for the development of CRPC therapeutic agents. PMID- 22515526 TI - Retrospective record review of canine postclipping hair follicle arrest. PMID- 22515527 TI - Bronchial thermoplasty: therapeutic success in severe asthma associated with persistent airflow obstruction. AB - INTRODUCTION: Severe persistent asthma is a disabling condition associated with significant morbidity and rising mortality worldwide. The recent advent of bronchial thermoplasty (BT) has offered a revolutionary therapeutic option for the treatment of severe persistent asthma. This minimally invasive bronchoscopic procedure focuses on anatomical manipulation of bronchial smooth muscle to attenuate airway hyperresponsiveness. CASE REPORT: This case report describes treatment of a 42-year-old female with BT for her debilitating asthma. Following a complicated treatment course of BT, she attained significant relief from her symptoms and had noticeably improved functionality. CONCLUSION: This case represents BT success and a change to the traditional paradigm governing the treatment of refractory asthma. PMID- 22515529 TI - Continued progress of Avian Pathology. PMID- 22515530 TI - The long view: a selective review of 40 years of coccidiosis research. AB - This selective review of 40 years of coccidiosis research is one of a number on important diseases of poultry to celebrate the 40th anniversary of the birth of Avian Pathology, the journal of the World Veterinary Poultry Association, and is written for the non-specialist. The intention is to provide a flavour of the field problems and intellectual challenges, with emphasis in the areas of immunology and vaccinology that drove research in the 1970s, and to reflect on research progress since. PMID- 22515531 TI - Thomas K. Jeffers: pioneer of coccidiosis research. AB - Thomas K. Jeffers has made many significant contributions to our understanding of the biology of the parasite Eimeria, the cause of coccidiosis in poultry. His work has had direct practical application for the control of this widespread disease. Topics discussed include Jeffers' pioneering work concerned with genetics of the host response to infection, the nature of biological and immunological intraspecific variation, drug resistance and discovery, field surveys of resistance, and his most recognized achievement-the demonstration that the lifecycle of coccidia may be altered by artificial selection. Parasites so modified are attenuated but retain their immunogenicity, a discovery that has led to the development of live vaccines that are inherently non-pathogenic. This article provides a brief biography and describes the contributions that Jeffers has made to our knowledge of coccidiosis. PMID- 22515528 TI - The effect of telephone-based interpersonal psychotherapy for the treatment of postpartum depression: study protocol for a randomized controlled trial. AB - BACKGROUND: Substantial data indicate potential health consequences of untreated postpartum depression (PPD) on the mother, infant, and family. Studies have evaluated interpersonal psychotherapy (IPT) as treatment for PPD; however, the results are questionable due to methodological limitations. A comprehensive review of maternal treatment preferences suggests that mothers favor 'talking therapy' as a form of PPD treatment. Unfortunately, IPT is not widely available, especially in rural and remote areas. To improve access to care, telepsychiatry has been introduced, including the provision of therapy via the telephone. METHODS/DESIGN: The purpose of this randomized controlled trial is to evaluate the effect of telephone-based IPT on the treatment of PPD. Stratification is based on self-reported history of depression and province. The target sample is 240 women. Currently, women from across Canada between 2 and 24 weeks postpartum are able to either self-identify as depressed and refer themselves to the trial or they may be referred by a health professional based on a score >12 on the Edinburgh Postnatal Depression Scale (EPDS). Following contact by the trial coordinator, a detailed study explanation is provided. Women who fulfill the eligibility criteria (including a positive diagnostic assessment for major depression) and consent to participate are randomized to either the control group (standard postpartum care) or intervention group (standard postpartum care plus 12 telephone-based IPT sessions within 12 to 16 weeks, provided by trained nurses). Blinded research nurses telephone participants at 12, 24, and 36 weeks post-randomization to assess for PPD and other outcomes including depressive symptomatology, anxiety, couple adjustment, attachment, and health service utilization. Results from this ongoing trial will: (1) develop the body of knowledge concerning the effect of telephone-based IPT as a treatment option for PPD; (2) advance our understanding of training nurses to deliver IPT; (3) provide an economic evaluation of an IPT intervention; (4) investigate the utility of the EPDS in general clinical practice to identify depressed mothers; and (5) present valuable information regarding PPD, along with associated couple adjustment, co morbid anxiety and self-reported attachment among a mixed rural and urban Canadian population. TRIAL REGISTRATION: Current Controlled Trials Ltd. ISRCTN88987377. PMID- 22515532 TI - Current status of vaccines against infectious bursal disease. AB - Infectious bursal disease virus (IBDV) is the aetiological agent of the acute and highly contagious infectious bursal disease (IBD) or "Gumboro disease". IBD is one of the economically most important diseases that affects commercially produced chickens worldwide. Along with strict hygiene management of poultry farms, vaccination programmes with inactivated and live attenuated viruses have been used to prevent IBD. Live vaccines show a different degree of attenuation; many of them may cause bursal atrophy and thus immunosuppression with poor immune response to vaccination against other pathogens and an increase in vulnerability to various types of infections as possible consequences. Depending on their intrinsic characteristics or on the vaccination procedures, some of the vaccines may not induce full protection against the very virulent IBDV strains and antigenic variants observed in the last three decades. As chickens are most susceptible to IBDV in their first weeks of life, active immunity to the virus has to be induced early after hatching. However, maternally derived IBDV-specific antibodies may interfere with early vaccination with live vaccines. Thus new technologies and second-generation vaccines including rationally designed and subunit vaccines have been developed. Recently, live viral vector vaccines have been licensed in several countries and are reaching the market. Here, the current status of IBD vaccines is discussed. PMID- 22515533 TI - Longitudinal field study on the occurrence of Mycoplasma synoviae in Dutch turkey flocks with lameness and experimental induction of the condition. AB - Four meat turkey farms with a history of lameness were investigated for the presence of Mycoplasma synoviae by testing one flock per farm for antibodies with the rapid plate agglutination (RPA) test and/or for M. synoviae DNA by polymerase chain reaction (PCR). Flocks were sampled every 2 weeks from 6 weeks of age until slaughter. If PCR results were positive, tracheal swabs were taken for mycoplasma isolation and swollen joints were sampled for general bacteriology, mycoplasma culture and virology. In one flock, all M. synoviae diagnostic tests were negative but reovirus was isolated. In the other flocks, M. synoviae was the only pathogen associated with lameness due to joint disease. M. synoviae RPA tests became positive 6 to 8 weeks later than PCR. An experimental infection was then conducted in male meat turkeys in which a negative control group was sham inoculated at 8 weeks of age, while three other groups were inoculated intravenously with M. synoviae. Turkeys in group LCh were given 10(5) colony forming units (CFU) of an arthropathic M. synoviae chicken strain at 8 weeks; group LHCh was given a low (10(5) CFU) dose at 8 weeks, followed by a high (10(8) CFU) dose at 12 weeks, of the same chicken strain; and group HTu was inoculated with 10(8) CFU of a M. synoviae turkey joint isolate from the field study. Post mortem examination, histopathology, serology, bacteriology and mycoplasma culture were performed at 19 weeks of age. A dose effect was found after comparing the LCh and the LHCh groups. No significant difference was observed between the HTu (10(8) CFU/bird) and the LCh (10(5) CFU/bird) group regarding the number of turkeys with arthritis, the number of M. synoviae reisolations and the mean microscopic lesion scores of joints, indicating that the M. synoviae chicken strain has greater arthropathogenic potential and that infection of turkeys in the field with such a strain may possibly have a greater clinical and economic impact. PMID- 22515534 TI - Capsid protein sequence diversity of chicken astrovirus. AB - The complete capsid gene sequences of 24 chicken astroviruses (CAstVs), collected in the UK, Germany, the Netherlands and South Africa from the 1980s to 2008, were determined and compared with that of a US CAstV (UGA-2006). Pairwise comparisons and phylogenetic analysis demonstrated the existence of two major capsid groups, designated A and B, which shared 38 to 40% amino acid identity. CAstVs from groups A and B shared capsid protein identities ranging from 26 to 38% with other avian astroviruses. The group A CAstVs comprised three subgroups, which displayed inter-subgroup identities ranging from 77 to 82%, while group B comprised two clearly separated subgroups, Bi and Bii, which displayed intra-subgroup identities of 97 to 99% and 94 to 99%, respectively, and shared inter-subgroup identities of 84 to 85%. Phylogenetic analyses performed with contiguous open reading frame 1b (polymerase) and open reading frame 2 (capsid) CAstV sequences showed that CAstVs from capsid subgroup Bi had polymerase genes that differed from those possessed by CAstVs belonging to group A and subgroup Bii. The N terminal capsid regions (residues 1 to 415) were more conserved than the C terminal regions, with the C-terminal regions of the subgroup Bi and Bii CAstVs sharing 76 to 78% amino acid identity, while the C-terminal regions of the A subgroups displayed identities less than 75%. CAstVs representative of both capsid groups and more than one subgroup were detected within the same broiler flock. The high level of capsid sequence diversity observed in this study has important implications for both the control and diagnosis of CAstV infections. PMID- 22515535 TI - Pathotyping of Australian isolates of Marek's disease virus and association of pathogenicity with meq gene polymorphism. AB - We report the pathotyping of six Australian isolates of Marek's disease virus-1 (MDV1) isolated between 1992 and 2004 and association of virulence with meq gene polymorphism. Unvaccinated and herpesvirus of turkeys (HVT)-vaccinated specific pathogen free chickens were challenged at day 5 with 500 plaque forming units of Marek's disease virus. The isolates induced gross Marek's disease lesions in 53 to 94% of unvaccinated chickens, and HVT induced a protective index ranging from 38 to 100% by 56 days post challenge. This experiment provides evidence that current Australian isolates of MDV1 vary significantly in pathogenicity. However, there was no clear evidence that the most virulent recent isolates were more pathogenic than isolates from the 1980s or that any of the isolates belong to the highest pathotype category of very virulent plus. Evidence is presented that virulence can be predicted by measurements taken as early as 13 days post challenge. The meq gene sequences of five of the isolates used in the experiment were determined. When compared with the very virulent US isolate Md5, there was a 177 base-pair insertion and distinct point mutations in each of the five isolates. There were no individual mutations in the meq sequences that correlated with levels of virulence. However, amino acid alignment of the five Australian and 14 international isolates revealed that the number of repeat sequences of four prolines (PPPP repeats) in the meq gene (overall range 2 to 8) was strongly associated with virulence across all isolates, with the most pathogenic isolates having the fewest number of repeats. The results suggest that the presence of the 177 base-pair insertion alone is not an indicator of attenuation. Rather, the number of PPPP repeats, independent of the presence of the insertion, is a better indicator of pathogenicity. PMID- 22515536 TI - Challenges for accurate and prompt molecular diagnosis of clades of highly pathogenic avian influenza H5N1 viruses emerging in Vietnam. AB - Forty-six chickens and 48 ducks were sampled from four Vietnamese poultry premises in 2009 infected with H5N1 highly pathogenic avian influenza (HPAI) clade 2.3.2 and 2.3.4 viruses, which also differed by cleavage site (CS) sequences in their haemagglutinin (HA) genes. All clinical specimens (n=282), namely tracheal and cloacal swabs plus feathers, were tested by five Eurasian reverse-transcriptase AI RealTime polymerase chain reaction (RRT-PCR) methods. Bayesian modelling showed similar high sensitivity for the validated H5 HA2 RRT PCR and a new modified M-gene RRT-PCR that utilizes lyophilized reagents. Both were more sensitive than the validated "wet" M-gene RRT-PCR. Another RRT-PCR, which targeted the H5-gene CS region, was effective for clade 2.3.4 detection, but severely compromised for clade 2.3.2 viruses. Reduced sensitivity of the H5 CS and "wet" M-gene RRT-PCRs correlated with mismatches between the target and the primer and/or probe sequences. However, the H5 HA2 RRT-PCR sensitively detected both clade 2.3.2 and 2.3.4 viruses, and agreed with N1 RRT-PCR results. Feather testing from diseased chicken and duck flocks by AI RRT-PCRs resulted in the most sensitive identification of H5N1 HPAI-infected birds. Evolution of new H5N1 HPAI clades remains a concern for currently affected Asian countries, but also for more distant regions where it is important to be prepared for new incursions of H5N1 HPAI viruses. Genetic evidence for adamantane resistance and sensitivity was also observed in isolates from both clades. PMID- 22515537 TI - Comparison of the replication and transmissibility of two infectious laryngotracheitis virus chicken embryo origin vaccines delivered via drinking water. AB - Infectious laryngotracheitis (ILT) is an acute infectious viral disease that affects chickens, causing respiratory disease, loss of production and mortality in severe cases. Biosecurity measures and administration of attenuated viral vaccine strains are commonly used to prevent ILT. It is notable that most recent ILT outbreaks affecting the intensive poultry industry have been caused by vaccine-related virus strains. The purpose of this study was to characterize and compare viral replication and transmission patterns of two attenuated chicken embryo origin ILT vaccines delivered via the drinking water. Two groups of specific pathogen free chickens were each inoculated with SA-2 ILT or Serva ILT vaccine strains. Unvaccinated birds were then placed in contact with vaccinated birds at regular intervals. Tracheal swabs were collected every 4 days over a period of 60 days and examined for the presence and amount of virus using a quantitative polymerase chain reaction. A rapid increase in viral genome copy numbers was observed shortly after inoculation with SA-2 ILT virus. In contrast, a comparatively delayed virus replication was observed after vaccination with Serva ILT virus. Transmission to in-contact birds occurred soon after exposure to Serva ILT virus but only several days after exposure to SA-2 ILT virus. Results from this study demonstrate in vivo differences between ILT vaccine strains in virus replication and transmission patterns. PMID- 22515538 TI - Pathomorphological, immunohistochemical and bacteriological findings in budgerigars (Melopsittacus undulatus) naturally infected with S. Gallinarum. AB - The present study describes the pathological and bacteriological findings and diagnosis by immunoperoxidase and immunofluorescence methods in budgerigars (Melopsittacus undulatus) naturally infected with Salmonella gallinarum obtained from three commercial budgerigar rearing farms. The course of the disease in young budgerigars was peracute or acute, whereas in adult budgerigars the disease was acute or chronic. Clinically, yellow-white diarrhoea was observed in the young budgerigars with the acute form. In the adult budgerigars with the acute and chronic forms, a decrease in feed and water consumption with loss in body condition together with greenish-yellow diarrhoea was generally noted. Peritonitis and pericarditis were the most common findings in young budgerigars at necropsy, while in adult budgerigars scattered grey-white necrotic foci were found in the livers. Histopathologically, the lesions in young budgerigars were characterized with fibrinonecrotic peritonitis and/or pericarditis and necrotic hepatitis. In adult budgerigars with acute infection, hepatic necrosis with focal heterophil infiltration was present; whilst lesions in the chronic cases were granulomatous in nature with the infiltration of macrophages, lymphocytes and histiocytes. For the detection of S. Gallinarum in formalin-fixed, paraffin embedded tissues, the avidin-biotin peroxidase complex and immunofluorescence methods were used. Both methods showed bacteria to be localized in the liver, kidney, peritoneum, heart, spleen and intestines of both young and adult budgerigars. The results of the present study indicate that the avidin-biotin peroxidase complex method was more sensitive than the immunofluorescence method in the detection of the bacteria. PMID- 22515539 TI - Immunohistochemical examination of plexiform-like complex vascular lesions in the lungs of broiler chickens selected for susceptibility to idiopathic pulmonary arterial hypertension. AB - Idiopathic pulmonary arterial hypertension (IPAH) is a disease of unknown cause that is characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance, and by extensive vascular remodelling. In human IPAH patients, remodelling of the pulmonary vasculature results in the formation of plexiform lesions in the terminal pulmonary arterioles. Various molecules are expressed in the human plexiform lesions, including alpha smooth muscle actin, von Willebrand factor, vascular endothelial growth factor, vascular endothelial growth factor receptor type 2, hypoxia inducible factor-1alpha, survivin, tenascin, collagen, fibronectin, and various immune/inflammatory cells such as, cytotoxic lymphocytes, B lymphocytes, MHC class II cells, and monocytes/macrophages are also present. Plexiform lesions rarely develop in the lungs of laboratory animals, but plexiform-like complex vascular lesions (CVL) do develop spontaneously in the lungs of broiler chickens from an IPAH-susceptible line. To examine angioproliferative and immune-system-related activities associated with CVL in broiler lungs, paraformaldehyde-fixed, paraffin-embedded lung sections from 8-week-old to 24-week-old broiler chickens were stained immunohistochemically using monoclonal or polyclonal antibodies specific for angioproliferative molecules and immune/inflammatory cells. The CVL in the lungs of broiler chickens exhibited positive staining for both angioproliferative molecules and immune/inflammatory cells. These observations combined with the close histological resemblance of broiler CVL to the plexiform lesions of human IPAH patients further validates chickens from our IPAH-susceptible line as an excellent animal model of spontaneous plexogenic arteriopathy. PMID- 22515540 TI - Distribution of Salmonella serovars and antimicrobial susceptibility of Salmonella Enteritidis from poultry in Zimbabwe. AB - A study was carried out to determine the distribution and antimicrobial susceptibility profiles of Salmonella serovars from chickens from large-scale commercial (LSC), small-scale commercial (SSC), and rural free-range (RFR) farms of Zimbabwe. Pooled cloacal swabs were collected for culture and isolation of Salmonella spp. A chi-square test was used to assess distribution differences of salmonellas among the farming sectors. Approximately 10% (283/2833) of the swabs were positive for Salmonella enterica, with only subspecies enterica (98.6%) and arizonae (1.4%) being detected. The prevalence of S. enterica varied significantly (P<0.05) among areas, with Harare (27.8%) and Buhera (1.3%) recording the highest and the least prevalence, respectively. S. enterica was only isolated from LSC and SSC farms, with the former having a significantly (P<0.001; chi(2)=155.3) higher prevalence than the latter. S. arizonae was only isolated from the SSC farms while none were obtained from the RFR farms. The serovars isolated were Salmonella Enteritidis (72.8%), Group C (20.1%), Group B (4.2%), Salmonella Typhimurium (1.1%) and Salmonella Gallinarum (0.4%). S. Enteritidis predominated in the urban/periurban areas. Approximately 26% (53/206) of S. Enteritidis isolates were resistant to one or more antimicrobial agents. Resistance to tetracycline was the most common, while no resistance was detected for furazolidone, neomycin and trimethoprim-sulfamethoxazole. There were 12.1% multi-drug-resistant S. Enteritidis isolates, and the resistance to ampicillin/kanamycin was predominant. The identification of multi-drug-resistant S. Enteritidis is of public health concern. Thus, stringent control of S. Enteritidis will reduce the public health risk of human salmonellosis. PMID- 22515541 TI - Non-soluble fibres and narasin reduce spontaneous gizzard erosion and ulceration in broiler chickens. AB - The prevalence and severity of gizzard erosion and ulceration syndrome (GEU) in broilers is affected by a number of predisposing and preventive factors. Two broiler experiments with almost identical basal diets were conducted to investigate the effect of dietary oat hulls, access to litter and the antimicrobial compound narasin on GEU. The effects on particle size of duodenal digesta, ileal starch concentration, caecal Clostridium perfringens counts, necrotic enteritis and production performance were also examined. Oat hulls reduced GEU severity and starch levels in the ileum in both experiments. Access to litter reduced GEU scores when oat hulls were included in the feed. Access to litter also improved feed efficiency and reduced C. perfringens counts. Narasin reduced GEU severity when the feed was supplemented with oat hulls. Oat hulls were associated with improved feed efficiency in Experiment 1 and impaired feed efficiency in Experiment 2. The inconsistent effect of oat hulls on production performance appeared to be related to an association between oat hulls and high C. perfringens counts in Experiment 2; an association that was absent in Experiment 1. In general, oat hulls interacted with litter access and narasin in exerting a positive effect on gizzard health. However, the association between oat hulls and necrotic enteritis detected in Experiment 2 suggests that the positive effect of oat hulls on GEU occasionally may be outweighed by a negative effect on gut health. In conclusion, our findings demonstrate that the severity of GEU in broilers was influenced by non-soluble fibres and narasin. PMID- 22515543 TI - Variance in Bacillus anthracis virulence assessed through Bayesian hierarchical dose-response modelling. AB - AIMS: To develop a predictive dose-response model for describing the survival of animals exposed to Bacillus anthracis to support risk management options. METHODS AND RESULTS: Dose-response curves were generated from a large dose-mortality data set (>11,000 data points) consisting of guinea pigs exposed via the inhalation route to 76 different product preparations of B. anthracis. Because of the predictive nature of the Bayesian hierarchical approach (BHA), this method was used. The utility of this method in planning for a variety of scenarios from best case to worst case was demonstrated. CONCLUSIONS: A wide range of expected virulence was observed across products. Median estimates of virulence match well with previously published statistical estimates, but upper bound values of virulence are much greater than previous statistical estimates. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first meta-analysis in open literature to estimate the dose-response relationship for B. anthracis from a very large data set, generally a rare occurrence for highly infectious pathogens. The results are also the first to suggest the extent of variability, which is contributed by product preparation and/or dissemination methods, information needed for health based risk management decisions in response to a deliberate release. A set of possible benchmark values produced through this analysis can be tied to the risk tolerance of the decision-maker or available intelligence. Further, the substantial size of the data set led to the ability to assess the appropriateness of the assumed distributional form of the prior, a common limitation in Bayesian analysis. PMID- 22515544 TI - p38beta MAP kinase as a therapeutic target for pancreatic cancer. AB - Pancreatic cancer is very difficult to diagnose in its early stage. Molecular marker and imaging have not proven to be accurate modalities for screening of pancreatic cancer. This study aims to develop p38beta as a protein marker for pancreatic cancer and to design peptide inhibitor against the same. The serum p38beta level of pancreatic cancer (n = 35; 5.06 MUg/mL) was twofold higher compared to that of the chronic pancreatitis (n = 10; 2.92 MUg/mL) and matched normal control (n = 10; 2.86 MUg/ml) (p < 0.0005). Peptide inhibitors were designed to inhibit the activity of p38beta and the kinetic assay had shown the dissociation constant, (K(D)) to be 3.16 * 10(-8) M and IC(50), 25 nM by Surface Plasmon Resonance (SPR) and Enzyme-Linked Immunosorbent Assay (ELISA), respectively. The peptide inhibitor also significantly reduced viability and induced cytotoxicity in Human Pancreatic carcinoma epithelial-like cell line (PANC-1) cells. PMID- 22515545 TI - Hybrid semiconducting polymer dot-quantum dot with narrow-band emission, near infrared fluorescence, and high brightness. AB - This communication describes a new class of semiconducting polymer nanoparticle quantum dot hybrid with high brightness, narrow emission, near-IR fluorescence, and excellent cellular targeting capability. Using this approach, we circumvented the current difficulty with obtaining narrow-band-emitting and near-IR fluorescing semiconducting polymer nanoparticles while combining the advantages of both semiconducting polymer nanoparticles and quantum dots. We further demonstrated the use of this new class of hybrid nanomaterial for effective and specific cellular and subcellular labeling without any noticeable nonspecific binding. This hybrid nanomaterial is anticipated to find use in a variety of in vitro and in vivo biological applications. PMID- 22515546 TI - Asymmetric chemoenzymatic synthesis of ramatroban using lipases and oxidoreductases. AB - A chemoenzymatic asymmetric route for the preparation of enantiopure (R) ramatroban has been developed for the first time. The action of lipases and oxidoreductases has been independently studied, and both were found as excellent biocatalysts for the production of adequate chiral intermediates under very mild reaction conditions. CAL-B efficiently catalyzed the resolution of (+/-)-2,3,4,9 tetrahydro-1H-carbazol-3-ol that was acylated with high stereocontrol. On the other hand, ADH-A mediated bioreduction of 4,9-dihydro-1H-carbazol-3(2H)-one provided an alternative access to the same enantiopure alcohol previously obtained through lipase-catalyzed resolution, a useful synthetic building block in the synthesis of ramatroban. Inversion of the absolute configuration of (S) 2,3,4,9-tetrahydro-1H-carbazol-3-ol has been identified as a key point in the synthetic route, optimizing this process to avoid racemization of the azide intermediate, finally yielding (R)-ramatroban in enantiopure form by the formation of the corresponding amine and the convenient functionalization of both exocyclic and indole nitrogen atoms. PMID- 22515547 TI - Phenolic, polysaccharidic, and lipidic fractions of mushrooms from northeastern Portugal: chemical compounds with antioxidant properties. AB - Mushrooms do not constitute a significant portion of the human diet, but their consumption continues to increase due to their functional benefits and presence of bioactive compounds. Some of those compounds can be found in the phenolic, polysaccharidic, and lipidic fractions of edible and inedible species. Herein, those fractions of five wild mushrooms (Coprinopsis atramentaria, Lactarius bertillonii, Lactarius vellereus, Rhodotus palmatus, and Xerocomus chrysenteron) from northeastern Portugal were studied for their chemical composition and antioxidant properties. Protocatechuic, p-hydroxybenzoic, p-coumaric, and cinnamic acids were found in the phenolic fraction; rhamnose, xylose, fucose, arabinose, fructose, glucose, manose, mannitol, sucrose, maltose, and trehalose were quantified in polysaccharidic fraction; and linoleic and stearic (only in Lactarius sp.) acids, and beta- and gamma-tocopherols were the main compounds in the lipidic fraction. C. atramentaria and X. chrysenteron phenolic fractions gave the highest free radical scavenging activity, reducing properties, and lipid peroxidation inhibition in brain homogenates, which is in agreement with its highest content in total phenolics. Furthermore, among the polysaccharidic fractions C. atramentaria also gave the highest antioxidant activity, which is in agreement with its highest total polysaccharides content and sugars obtained after hydrolysis. PMID- 22515548 TI - "Double trouble" or an amplification of the triploidy phenotype? AB - Triploidy occurs in about 1 to 3% of clinically recognizable pregnancies and is typically associated with growth restriction, craniofacial dysmorphisms and congenital anomalies. We report the case of a female fetus with prenatal diagnosis of complete triploidy, polysplenia, bilateral cleft-palate, horseshoe kidneys and bilateral club-feet. Whereas bilateral cleft-palate, horseshoe kidneys and bilateral club feet are known to be part of the triploidy-associated malformation spectrum, polysplenia, which usually occurs as part of the heterotaxia spectrum, has never been associated with triploidy. An amplification of the triploidy phenotype or a "double trouble". PMID- 22515549 TI - Association between the markers of FIRS and the morphologic alterations in the liver of neonates autopsied in the perinatal period. AB - Markers of fetal inflammatory response syndrome (FIRS) can influence the morphologic alterations in liver of autopsied neonates. The IL-6, TNF-alpha, and C-reactive protein (CRP) expression in liver fragments were marked by immunohistochemistry and the intensity of steatosis, percentage of fibrosis, and the number of foci of extramedullary erythropoiesis were evaluated. The degree of steatosis correlated positively with IL-6 (p = 0.06), positively with CRP (p <= 0.001), and negatively with TNF-alpha (p = 0.06). The collagen percentage correlated positively with IL-6 (p = 0.055) and positively with TNF-alpha (p <= 0.001). Erythropoiesis correlated positively with IL-6 (p <= 0.001) and negatively with CRP (p = 0.00754). The analyzed markers of FIRS have an important role in triggering hepatic morphologic alterations. PMID- 22515550 TI - Epidemiology of end-stage renal disease and hemodialysis treatment in Serbia at the turn of the millennium. AB - The study presents the epidemiological features of patients treated with renal replacement therapy (RRT) in Serbia from 1997 to 2009 and compares the results of hemodialysis treatment in 1999 and 2009. Epidemiological data were obtained from the National Registry of RRT patients and data on hemodialysis treatment from special surveys conducted in 1999 and 2009. Within the period 1997-2009 the incidence of patients on RRT increased from 108 to 179 per million population (pmp), prevalence rose from 435 to 699 pmp, while mortality rate fell from 20.7% to 16.7%. The frequency of patients with glomerulonephritis decreased, while that of patients with diabetes and hypertensive nephropathy increased. In late 2009 there were 5208 patients receiving RRT in Serbia. Within the examined period new hemodialysis and reverse osmosis equipment were purchased, high-flux dialyzers with synthetic membranes were increasingly used and the number of patients receiving hemodiafiltration increased to 17.6%. Kt/V greater than 1.2 was recorded in 16% of the patients in 1999 but 52% in 2009. Options for correction of anemia and mineral disorders have also improved. The percentage of patients with HbsAg (13.8% vs. 4.8%) as well as anti-hepatitis C virus antibodies positive patients (23.2% vs. 12.7%) was significantly lower in 2009 than in 1999. Both the incidence and prevalence of RRT patients in Serbia are rising continuously, while the mortality rate is falling. More favorable conditions for dialysis treatment have brought about significant improvement in the results over the last 10 years. PMID- 22515551 TI - Maternal perceptions of children's weight status. AB - BACKGROUND: Several studies have addressed mothers' perceptions of their children's weight status; however, there is no investigation on Portuguese children (a country with one of the highest levels of children's overweight and obesity in Europe). The aim of this study was to quantify maternal misclassification of child weight status in a sample of Portuguese children aged 9 to 12 years, according to gender, family income, and maternal weight status, education level and age. METHODS: Data were collected in a school-based study (school year 2009/2010) in northern Portugal with 499 urban children (236 girls; 47.3%). Body mass index was calculated from measurements of height and weight [body mass (kg)/height (m(2))]. Mothers' perceptions of child's weight status, age, height and weight were accessed by a questionnaire. Children's age, gender and socio-economic status were extracted from the schools' administrative record systems. Cohen's Kappa was used to analyse the misperceptions and the agreement between children's objectively measured weight status and mothers' perception of their child's weight status. RESULTS: The prevalence of underweight, overweight and obesity in children was 4.6%, 25.5% and 6.4%, respectively. A proportion of 65.2% of underweight and 61.6% of overweight/obese children were misclassified by their mothers. For the majority of variables presented, the values of agreement were fair (k ranged from 0.257 to 0.486), but were statistically significant. Significant differences in the percentages of mothers who correctly classified their children's weight status were only found among the most educated in the overweight/obese group and among the normal-weight mothers in the underweight group. CONCLUSIONS: Many mothers do not properly recognize their children's weight status and frequently underestimate their children's body size. PMID- 22515552 TI - In situ measurement of bovine serum albumin interaction with gold nanospheres. AB - We present in situ observations of adsorption of bovine serum albumin (BSA) on citrate-stabilized gold nanospheres. We implemented scattering correlation spectroscopy as a tool to quantify changes in the nanoparticle brownian motion resulting from BSA adsorption onto the nanoparticle surface. Protein binding was observed as an increase in the nanoparticle hydrodynamic radius. Our results indicate the formation of a protein monolayer at similar albumin concentrations as those found in human blood. Additionally, by monitoring the frequency and intensity of individual scattering events caused by single gold nanoparticles passing the observation volume, we found that BSA did not induce colloidal aggregation, a relevant result from the toxicological viewpoint. Moreover, to elucidate the thermodynamics of the gold nanoparticle-BSA association, we measured an adsorption isotherm which was best described by an anticooperative binding model. The number of binding sites based on this model was consistent with a BSA monolayer in its native state. In contrast, experiments using poly(ethylene glycol)-capped gold nanoparticles revealed no evidence for adsorption of BSA. PMID- 22515553 TI - Keratin-based peptide: biological evaluation and strengthening properties on relaxed hair. AB - A peptide based on a fragment of hair keratin type II cuticular protein, keratin peptide (KP), was studied as a possible strengthening agent for weakened relaxed hair. The peptide was prepared both in aqueous water formulation (WF) and organic solvent formulations (OF), to determine the effect of organic solvents on peptide interaction with hair and the differences in hair recovery. Both peptide formulations were shown to improve mechanical and thermal properties of weakened hair with peptide in OF showing the stronger effect. As a potential new hair care product, and so would necessitate contact with skin, the cytotoxicity and genotoxicity of the peptide were also evaluated through different methodologies (Alamar Blue assay, 2'-7'-dichlorofluorescein probe, cell morphology and growth and evaluation of DNA damage by an alkaline version of the comet assay) in skin fibroblasts. These tests are indicators of the potential of peptide to cause irritation on skin or to be carcinogenic, respectively. The peptide in WF did not cause cytotoxicity or genotoxicity in any of the concentrations tested. The presence of OF, however, induced a 20% decrease in cell viability in all of the range of concentrations used after 72-h incubation. Moreover, OF inhibited cell growth and was considered genotoxic at first contact with cells. The peptide was therefore considered a promising strengthening agent for hair and was shown to be innocuous when applied in WF. PMID- 22515555 TI - Anatomical, physiological and metabolic changes with gestational age during normal pregnancy: a database for parameters required in physiologically based pharmacokinetic modelling. AB - BACKGROUND: Pregnancy is associated with considerable changes in the physiological, anatomical and biochemical attributes in women. These may alter the exposure to xenobiotics between pregnant and non-pregnant women who receive similar doses, with implications for different susceptibility to environmental pollutants or therapeutic agents. Physiologically based pharmacokinetic (PBPK) models together with in vitro in vivo extrapolation (IVIVE) of absorption, distribution, metabolism and excretion (ADME) characteristics may capture the likely changes. However, such models require comprehensive information on the longitudinal variations of PBPK parameter values; a set of data that are as yet not available from a singular source. AIM: The aim of this article was to collect, integrate and analyse the available time-variant parameters that are needed for the PBPK modelling of xenobiotic kinetics in a healthy pregnant population. METHODS: A structured literature search was carried out on anatomical, physiological and biochemical parameters likely to change in pregnancy and alter the kinetics of xenobiotics. Collated data were carefully assessed, integrated and analysed for trends with gestational age. Algorithms were generated to describe the changes in parameter values with gestational age. These included changes in maternal weight, the individual organ volumes and blood flows, glomerular filtration rates, and some drug-metabolising enzyme activities. RESULTS: Articles were identified using relevant keywords, quality appraised and data were extracted by two investigators. Some parameters showed no change with gestational age and for others robust data were not available. However, for many parameters significant changes were reported during the course of pregnancy, e.g. cardiac output, protein binding and expression/activity of metabolizing enzymes. The trend for time-variant parameters was not consistent (with respect to direction and mono-tonicity). Hence, various mathematical algorithms were needed to describe individual parameter values. CONCLUSION: Despite the limitations identified in the availability of some values, the collected data presented in this paper provide a potentially useful singular resource for key parameters needed for PBPK modelling in pregnancy. This facilitates the risk assessment of environmental chemicals and therapeutic drug dose adjustments in the pregnant population. PMID- 22515556 TI - Pharmacokinetics and pharmacodynamics of ticagrelor in patients with stable coronary artery disease: results from the ONSET-OFFSET and RESPOND studies. AB - BACKGROUND AND OBJECTIVES: Ticagrelor, the first reversibly binding oral P2Y(12) receptor antagonist, improves outcomes in patients with acute coronary syndromes (ACS) compared with clopidogrel. In the ONSET-OFFSET study (parallel group trial) and the RESPOND study (crossover trial), the pharmacodynamic effects of ticagrelor were compared with clopidogrel in patients with coronary artery disease (CAD). We now report the pharmacokinetic analyses of ticagrelor, and the exposure-inhibition of platelet aggregation (IPA) relationships from these studies. PATIENTS AND METHODS: Patients were treated with ticagrelor (180 mg loading dose, 90 mg twice daily maintenance dose) or clopidogrel (600 mg loading dose, 75 mg once daily maintenance dose) in addition to aspirin (acetylsalicylic acid) [75-100 mg once daily]. Ticagrelor administration was for 6 weeks in ONSET OFFSET. In RESPOND, ticagrelor was given for 14 days before or after 2 weeks of clopidogrel in patients classified as clopidogrel responders or non-responders. Pharmacokinetics and IPA were evaluated following the loading and last maintenance doses. Exposure-IPA relationships were evaluated using a sigmoid maximum effect (E(max)) model. OUTCOME MEASURES: The outcome measures were ticagrelor and AR-C124910XX (active metabolite) pharmacokinetics and exposure-IPA relationships in both trials, including the effect of prior clopidogrel exposure, and effects in clopidogrel responders and non-responders in RESPOND. RESULTS: In ONSET-OFFSET, maximum (peak) plasma concentration (C(max)), time to C(max) (t(max)) and area under the plasma concentration-time curve from time 0 to 8 hours (AUC(8)) for ticagrelor were 733 ng/mL, 2.0 hours and 4130 ng . h/mL, respectively; and for AR-C124910XX were 210 ng/mL, 2.1 hours and 1325 ng . h/mL, respectively. E(max) estimates were IPA >97%. Trough plasma ticagrelor (305 ng/mL) and AR-C124910XX (121 ng/mL) concentrations were 5.2 and 7.7 times higher than respective concentration producing 50% of maximum effect (EC(50)) estimates. In RESPOND, ticagrelor mean C(max) and AUC(8) following 2-week dosing were comparable between clopidogrel responders (724 ng/mL and 3983 ng . h/mL, respectively) and non-responders (764 ng/mL and 3986 ng . h/mL, respectively). Pharmacokinetics of ticagrelor were unaffected by prior clopidogrel dosing. E(max) estimates were IPA >96% for both responders and non-responders. Trough plasma concentrations were sufficient to achieve high IPA. CONCLUSIONS: Ticagrelor pharmacokinetics in stable CAD patients were comparable to previous findings in stable atherosclerotic and ACS patients, and were not affected by prior clopidogrel exposure or clopidogrel responsiveness. Ticagrelor effectively inhibited platelet aggregation, and trough plasma concentrations of ticagrelor and AR-C124910XX were sufficient to result in high IPA in stable CAD patients. PMID- 22515557 TI - Clinical pharmacokinetics and therapeutic efficacy of esmolol. AB - Esmolol is a unique cardioselective beta(1)-receptor blocking agent with a rapid onset and short duration of action. Since our previous review in 1995, the pharmacokinetics and efficacy of esmolol have been investigated in a number of acute care settings. Three studies investigated the pharmacokinetics and safety of esmolol in the paediatric population. The disposition of esmolol in children was found to be linear with plasma concentrations increasing in proportion to dose over the ranges studied. The pharmacokinetic estimates for esmolol showed a shorter elimination half-life (t(½)) [2.7-4.8 minutes] and a higher clearance (281 mL/kg/min) in newborns and infants than that found in children (>2 years old) and adults. Dosing requirements to achieve targeted blood pressure in post-coarctectomy patients were substantially higher (mean 700 MUg/kg/min) than that used in adults. Esmolol was effective in controlling hypertension following cardiac surgery and terminating supraventricular arrhythmias in children. The efficacy of esmolol has been established in a variety of patients, including those with unstable angina, myocardial ischaemia, supraventricular arrhythmias, peri- and postoperative tachycardia and hypertension, and electroconvulsive therapy. With careful titration and monitoring, esmolol can be used effectively in patients with congestive heart failure and chronic obstructive lung disease because of its unique short t(½) and beta(1)-selectivity. Different dosage schedules have been developed depending on clinical setting and diagnosis. Generally, a loading dose of <=500 MUg/kg/min over 1 minute is administered followed by a continuous infusion of 25-300 MUg/kg/min. Hypotension, being the primary adverse effect, can be minimized by careful dosage titration and patient monitoring. In the perioperative setting involving tracheal intubation and extubation, a number of recent studies have suggested that titration of esmolol to a haemodynamic endpoint can be safe and effective, resulting in a decreased incidence of myocardial ischaemia. The most effective regimen in attenuating the response to heart rate and blood pressure after laryngeal tracheal intubation was a loading dose of 500 MUg/kg/min for 4 minutes followed by a continuous infusion of 200-300 MUg/kg/min. In cardiac and non-cardiac surgical patients esmolol has been shown to decrease episodes of myocardial ischaemia and arrhythmias. In the perioperative period for non-cardiac surgery routine use of beta-blockers (beta adrenoceptor antagonists) is no longer recommended. However, in patients at high risk for myocardial ischaemia or undergoing high-risk surgery where a beta blocker is indicated, esmolol is the ideal perioperative agent to minimize the risk of hypotension and bradycardia based on its pharmacodynamic and pharmacokinetic characteristics. For postoperative patients in atrial fibrillation, esmolol achieves rapid ventricular rate control. However, for the prevention of postoperative atrial fibrillation esmolol provides no advantage over oral beta-blockers. In other situations where emergent beta-blockade is required, such as electroconvulsive therapy, esmolol has been shown to effectively control haemodynamic response. After more than 2 decades of use esmolol continues to provide an important therapeutic option in the acute care setting. PMID- 22515558 TI - The use of complementary and alternative medicine (CAM) in children: a telephone based survey in Korea. AB - BACKGROUND: The purpose of this study was to estimate the prevalence and patterns of CAM use in Korean children via a telephone based survey. We also investigated parent satisfaction, a proxy for their child, with CAM therapy and determined the factors affecting satisfaction with CAM use. METHODS: This study used a landline telephone-based survey to examine a random sample representative of Korean children, aged 0 to 18 years. We assigned and surveyed 2,000 subjects according to age group, gender, and geographical distributions by proportionate quota and systematic sampling of children throughout Korea in 2010. A household of 1,184 with a 18.6% response rate was projected to yield 2,077 completed data. We performed statistical analyses using sampling weight. RESULTS: The prevalence of CAM use was 65.3% for the Korean children in our sample population. The most commonly used CAM category was natural products (89.3%). More than half of CAM user's parents reported satisfaction with their therapies (52.7%), but only 29.1% among them had consulted a Western trained doctor regarding the CAM therapies used. Doctor visits were associated with lower satisfaction with CAM use but not with consultation rate with a doctor. CONCLUSIONS: Our study suggests that CAM is widely used among children in Korea. Medical doctors should actively discuss the use of CAM therapies with their patients and provide information on the safety and efficacy of diverse CAM modalities to guide the choices of CAM users. PMID- 22515554 TI - Potential for pharmacological manipulation of human embryonic stem cells. AB - The therapeutic potential of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) is vast, allowing disease modelling, drug discovery and testing and perhaps most importantly regenerative therapies. However, problems abound; techniques for cultivating self-renewing hESCs tend to give a heterogeneous population of self-renewing and partially differentiated cells and general include animal-derived products that can be cost-prohibitive for large-scale production, and effective lineage-specific differentiation protocols also still remain relatively undefined and are inefficient at producing large amounts of cells for therapeutic use. Furthermore, the mechanisms and signalling pathways that mediate pluripotency and differentiation are still to be fully appreciated. However, over the recent years, the development/discovery of a range of effective small molecule inhibitors/activators has had a huge impact in hESC biology. Large-scale screening techniques, coupled with greater knowledge of the pathways involved, have generated pharmacological agents that can boost hESC pluripotency/self-renewal and survival and has greatly increased the efficiency of various differentiation protocols, while also aiding the delineation of several important signalling pathways. Within this review, we hope to describe the current uses of small molecule inhibitors/activators in hESC biology and their potential uses in the future. PMID- 22515560 TI - Role of the alkali-metal cation size in the self-assembly of polyoxometalate monolayer shells on gold nanoparticles. AB - Polyoxometalate (POM)-monolayer stability constants, K, for three POM anions vary with the cation size, in the same order as that for increasing ion-pair formation with alpha-SiW(11)O(39)(8-) (1) in the early nucleation phase of monolayer self-assembly: Li(+) < Na(+) < K(+) < Cs(+). Cryo-TEM images demonstrating the use of the cation size to rationally control monolayer formation provide definitive evidence that the POM monolayers are electrostatically stabilized (ionic) shells, analogous in that respect to the monolayer walls of "hollow" POM-macroanion vesicles. PMID- 22515559 TI - Quantitative comparison of immunohistochemical staining measured by digital image analysis versus pathologist visual scoring. AB - Immunohistochemical (IHC) assays performed on formalin-fixed paraffin-embedded (FFPE) tissue sections traditionally have been semi-quantified by pathologist visual scoring of staining. IHC is useful for validating biomarkers discovered through genomics methods as large clinical repositories of FFPE specimens support the construction of tissue microarrays (TMAs) for high throughput studies. Due to the ubiquitous availability of IHC techniques in clinical laboratories, validated IHC biomarkers may be translated readily into clinical use. However, the method of pathologist semi-quantification is costly, inherently subjective, and produces ordinal rather than continuous variable data. Computer-aided analysis of digitized whole slide images may overcome these limitations. Using TMAs representing 215 ovarian serous carcinoma specimens stained for S100A1, we assessed the degree to which data obtained using computer-aided methods correlated with data obtained by pathologist visual scoring. To evaluate computer aided image classification, IHC staining within pathologist annotated and software-classified areas of carcinoma were compared for each case. Two metrics for IHC staining were used: the percentage of carcinoma with S100A1 staining (%Pos), and the product of the staining intensity (optical density [OD] of staining) multiplied by the percentage of carcinoma with S100A1 staining (OD*%Pos). A comparison of the IHC staining data obtained from manual annotations and software-derived annotations showed strong agreement, indicating that software efficiently classifies carcinomatous areas within IHC slide images. Comparisons of IHC intensity data derived using pixel analysis software versus pathologist visual scoring demonstrated high Spearman correlations of 0.88 for %Pos (p < 0.0001) and 0.90 for OD*%Pos (p < 0.0001). This study demonstrated that computer-aided methods to classify image areas of interest (e.g., carcinomatous areas of tissue specimens) and quantify IHC staining intensity within those areas can produce highly similar data to visual evaluation by a pathologist. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1649068103671302. PMID- 22515561 TI - More evidence that spirits can be more dangerous: Homicide in Russia and suicide in Japan. PMID- 22515562 TI - Short-day response in Djungarian hamsters of different circadian phenotypes. AB - In Djungarian hamsters (Phodopus sungorus) bred at the authors' institute, a certain number of animals show activity patterns incompatible with proper entrainment of their endogenous circadian pacemaker to the environmental light dark (LD) cycle. Even though the activity-offset in these animals is stably coupled to "light-on," activity-onset is increasingly delayed, leading to a compression of the activity time (alpha). If alpha falls below a critical value, the circadian rhythm in these so called delayed activity-onset (DAO) hamsters starts to free-run and finally breaks down. Animals then show an arrhythmic activity pattern (AR hamsters). Previous studies revealed the mechanisms of photic entrainment have deteriorated (DAO) or the suprachiasmatic nucleus (SCN) does not generate a rhythmic signal (AR). The aim of the present study was to investigate the consequences that these deteriorations have upon photoperiodic time measurement. Animals were bred and kept under standardized housing conditions with food and water ad libitum and a 14L/10D (long day, LD) regimen. Locomotor activity was recorded continuously using passive infrared motion detectors. Body mass, testes size, and fur coloration were measured weekly or biweekly to further quantify the photoperiodic reaction. In a first experiment, adult male wild-type (WT), DAO, and AR hamsters were transferred initially to a 16L/8D cycle. After 3-4 wks, the light period was shortened symmetrically by 8 h. After 14 wks, none of the DAO and AR hamsters, and only 1 of 8 WT hamsters showed short-day (SD) traits. Therefore, in a second experiment, hamsters were transferred to SD conditions (8L/16D cycle) for 8 wks directly from standard LD conditions. In 6 of 7 WT hamsters, activity time expanded, body mass and testes size decreased, and fur coloration changed from summer to winter pelage. In contrast, none of the DAO and AR hamsters displayed an SD response. In a third experiment, DAO and AR hamsters were kept in constant darkness (DD) for 8 and 14 wks. After 8 wks, DAO hamsters showed a similar photoperiodic reaction to WT hamsters that had been kept for 8 wks under SD conditions. However, the level of adaptation was still less compared to WT hamsters, but this difference was not apparent after 14 wks. In contrast, AR animals did not display any photoperiodic reaction, even after 14 wks in DD. Type VI phase response curves (PRCs) were constructed to better understand the mechanism behind the SD response. In WT hamsters, the photosensitive phase, where light pulses induce phase shifts, was lengthened in SD condition. In DAO hamsters, in contrast, the PRCs were similar under LD and SD conditions with a compressed photosensitive phase corresponding to alpha. Also, "light-on" induced only weak phase advances of activity-onset, insufficient to compensate for the long endogenous period. The results show that physiological mechanisms necessary for seasonal adaptation are working in DAO hamsters and that it is the inadequate interaction of the LD cycle with the SCN that prevents the photoperiodic reaction. AR hamsters, on the other hand, are incapable of measuring photoperiodic time due to a complete disruption of circadian rhythmicity. PMID- 22515564 TI - Sodium citrate induces apoptosis in biocontrol yeast Cryptococcus laurentii. AB - AIM: To provide the observation that sodium citrate induced apoptosis in biocontrol yeast Cryptococcus laurentii. METHODS AND RESULTS: The viability of the yeast cells was evaluated using the percentage of colony-forming units (CFU) of treated cells. The induction of cell death was dependent on the concentration of sodium citrate and exhibited typical apoptotic markers such as phosphatidylserine (PS) translocation as shown by annexin V coupled with fluorescein isothiocyanate (FITC) labelling and DNA fragmentation as detected by TdT-mediated dUTP-biotin nick end labelling (TUNEL) assay. The annexin V-positive cells reached the maximum (14.8%) on the third day, whereas TUNEL-positive cells increased gradually from 5.92 to 27.9% within 5 days of incubation in sodium citrate. In addition, confocal laser microscopy and flow cytometric analysis revealed that the induction of apoptosis was associated with the production of reactive oxygen species (ROS) that reached the highest intracellular level in the first day, before the peak of the early event (PS exposure) in apoptosis. The apoptosis was delayed by the addition of antioxidant glutathione (GSH), suggesting that ROS generated in this process plays a key role in the regulation of the apoptosis in C. laurentii cells. CONCLUSIONS: This study indicated that the apoptotic signals in C. laurentii are dependent on citrate ions and/or sodium ions, the concentration and initial acidity of sodium citrate. Induction of ROS in response to sodium citrate plays a significant role in apoptosis. SIGNIFICANCE AND IMPACT OF THE STUDY: Yeast Cryptococcus laurentii has been selected as an effective biocontrol indicator for the postharvest diseases because of its competition for nutrients and space with the pathogen in the wound of fruits. This study presents a convenient method for commercial production of yeast as biocontrol agent. PMID- 22515565 TI - Effects of serum adsorption on cellular uptake profile and consequent impact of titanium dioxide nanoparticles on human lung cell lines. AB - Exposure to fetal bovine serum (FBS) is shown herein to reduce the aggregate size of titanium dioxide (TiO(2)) nanoparticles, affecting uptake and consequent effect on A549 and H1299 human lung cell lines. Initially, the cellular uptake of the FBS-treated TiO(2) was lower than that of non-FBS-treated TiO(2). Expulsion of particles was then observed, followed by a second phase of uptake of FBS treated TiO(2), resulting in an increase in the cellular content of FBS-treated TiO(2), eventually exceeding the amount by cells exposed to non-FBS-treated TiO(2). Surface adsorbed vitronectin and the clathrin-mediated endocytosis pathway were shown to regulate the uptake of TiO(2) into A549 cells, while the endocytosis mechanism responsible remains elusive for H1299. Intriguingly, nystatin treatment was shown to have the unexpected effect of increasing nanoparticle uptake into the A549 cells via an alternate endocytic pathway. The surface adsorbed serum components were found to provide some protection from the cytotoxic effect of endocytosed TiO(2) nanoparticles. PMID- 22515566 TI - What parents find important in the support of a child with profound intellectual and multiple disabilities. AB - BACKGROUND: The importance of a partnership between parents and professionals in the support of children with disabilities is widely acknowledged and is one of the key elements of 'family-centred care'. To what extent family-centred principles are also applied to the support of persons with profound intellectual and multiple disabilities (PIMD) is not yet known. AIM: The purpose of this exploratory study was to examine what parents with a child with PIMD find important in the support of their child. In addition, we examined which child or parent characteristics influence these parental opinions. METHOD: In total, 100 parents completed an adapted version of the Measure of Processes of Care. Mean unweighted and weighted scale scores were computed. Non-parametric tests were used to examine differences in ratings due to child (gender, age, type and number of additional disabilities, type of services used and duration of service use) and parent characteristics (gender, involvement with support and educational level). RESULTS: Parents rated situations related to 'Respectful and Supportive Care' and 'Enabling and Partnership' with averages of 7.07 and 6.87 respectively on a scale from 1 to 10. They were generally satisfied with the services provided, expressed in a mean score of 6.88 overall. The age of the child significantly affected the scores for 'Providing Specific Information about the Child'. Parents of children in the '6-12 years' age group gave significantly higher scores on this scale than did parents of children in the '>=17 years' age group (U = 288, r = -0.34). CONCLUSION: This study shows that parents with children with PIMD find family-centred principles in the professional support of their children important. Although the majority of parents are satisfied with the support provided for their children, a substantial minority of the parents indicated that they did not receive the support they find important. PMID- 22515567 TI - Ecosystem protection, integrated management and infrastructure are vital for improving water quality in Africa. PMID- 22515569 TI - Generation of receptor structural ensembles for virtual screening using binding site shape analysis and clustering. AB - Accounting for protein flexibility is an essential yet challenging component of structure-based virtual screening. Whereas an ideal approach would account for full protein and ligand flexibility during the virtual screening process, this is currently intractable using available computational resources. An alternative is ensemble docking, where calculations are performed on a set of individual rigid receptor conformations and the results combined. The primary challenge associated with this approach is the choice of receptor structures to use for the docking calculations. In this work, we show that selection of a small set of structures based on clustering on binding site volume overlaps provides an efficient and effective way to account for protein flexibility in virtual screening. We first apply the method to crystal structures of cyclin-dependent kinase 2 and HIV protease and show that virtual screening for ensembles of four cluster representative structures yields consistently high enrichments and diverse actives. We then apply the method to a structural ensemble of the androgen receptor generated with molecular dynamics and obtain results that are in agreement with those from the crystal structures of cyclin-dependent kinase 2 and HIV protease. This work provides a step forward in the incorporation of protein flexibility into structure-based virtual screening. PMID- 22515568 TI - Inflammation and cancer: chemical approaches to mechanisms, imaging, and treatment. AB - The inflammatory response represents a first line of defense against invading pathogens and is important to human health. Chronic inflammation contributes to the etiology of multiple diseases, especially those associated with aging, such as cancer and cardiovascular disease. The chemistry of the inflammatory response is complex and involves the generation of highly reactive oxidants and electrophiles designed to kill the pathogen as well as the release of small molecule and protein mediators of intercellular signaling, chemotaxis, vasoconstriction, and wound-healing. Oxidation of unsaturated fatty acids--either nonenzymatic or enzymatic--contributes to the inflammatory response and associated cellular pathologies. The current perspective summarizes our research on unsaturated fatty acid oxidation in the context of inflammation and cancer. In addition to understanding the consequences of DNA and protein modification by lipid electrophiles, our research has focused on the development of molecularly targeted agents to image and treat cancer. PMID- 22515570 TI - The influence of gender, ethnicity, class, race, the women's and labour movements on the development of nursing in Sri Lanka. AB - The paper reveals that historically various socio-political factors, including gender, class, ethnicity, race, waves of colonization, decolonization, the civil and ethnic wars, the women's and labour movements, have influenced the development of nursing in Sri Lanka. However, literature presenting the development of nursing in Sri Lanka is sparse. All relevant journals and books published in the English and Sinhalese languages on nursing in Sri Lanka between the years 1878-2011 were examined. Because there are no nursing journals currently produced in Sri Lanka, CINAHL and Medline databases were accessed and relevant literature published in the English language on Sri Lanka was examined. Government, nurses' union and association reports, other unpublished reports and websites such as Google were also searched to access information related to the influence of gender, race, class, ethnicity, women's and labour movements in Sri Lanka. Poor pay, shortages of resources, failure in recruitment and retention and limited opportunity for career progression have acted as deterrents to persons entering and remaining in the nursing profession. Being non-British was a key issue in terms of race. Further, the shift from a colonized state to a welfare state resulted in a class shift from upper middle class to middle and lower class persons entering into nursing. Although there is a paucity of information available in the nursing literature, this analysis offers an intriguing insight into an angle that may be used to examine the influence of gender, ethnicity, class, race and the women's and labour movements in other contextual situations. PMID- 22515571 TI - An incompletely penetrant novel mutation in COL7A1 causes epidermolysis bullosa pruriginosa and dominant dystrophic epidermolysis bullosa phenotypes in an extended kindred. AB - Epidermolysis bullosa pruriginosa (EBP) is a rare subtype of dystrophic epidermolysis bullosa (DEB) characterized by intense pruritus, nodular or lichenoid lesions, and violaceous linear scarring, most prominently on the extensor extremities. Remarkably, identical mutations in COL7A1, which encodes an anchoring fibril protein present at the dermal-epidermal junction, can cause both DEB and EBP with either autosomal dominant or recessive inheritance. We present one family with both dystrophic and pruriginosa phenotypes of epidermolysis bullosa. The proband is a 19-year-old Caucasian woman who initially presented in childhood with lichenoid papules affecting her extensor limbs and intense pruritus consistent with EBP. Her maternal grandmother saw a dermatologist for similar skin lesions that developed without any known triggers at age 47 and mostly resolved spontaneously after approximately 10 years. The proband's younger brother developed a small crop of pruritic papules on his elbows, dorsal hands, knees, and ankles at age 13. Her second cousin once removed, however, reported a mild blistering disease without pruritus consistent with DEB. Genetic sequencing of the kindred revealed a single dominant novel intron 47 splice site donor G>A mutation, c.4668 + 1 G>A, which we predict leads to exon skipping. Incomplete penetrance is confirmed in her clinically unaffected mother, who carries the same dominant mutation. The wide diversity of clinical phenotypes with one underlying genotype demonstrates that COL7A1 mutations are incompletely penetrant and strongly suggests that other genetic and environmental factors influence clinical presentation. PMID- 22515572 TI - Low incidence of benign lesions in resected suspicious renal masses greater than 2 cm: Single-center experience from Japan. AB - OBJECTIVE: To assess the incidence of benign renal lesions in our Japanese clinical experience with surgical resection. METHODS: A total of 411 renal masses harvested by radical or partial nephrectomy between January 1991 and April 2011 at our institution were retrospectively assessed. The incidence of benign lesions in 1-cm increments in diameter was determined, and a logistic regression model was used to assess relationships between the incidence of benign lesions and other factors. RESULTS: Histological examination confirmed a total of 18 (4.4%) benign lesions. The incidence of benign lesions was 42.8% for nodules <1 cm and 10.0% for nodules 1 to <2 cm. In contrast, the incidence of benign lesions in each 1-cm increment between 2 and 6 cm was 4.1-4.9%. The incidence of benign lesions 2 to <4 cm was 4.8% and of benign nodules >=6 cm was just 0-1.0%. The incidence of benign lesions >=2 cm (3.5%) was significantly lower than that of masses <2 cm (16.2%; P < 0.001). Multivariate analysis showed that female gender (odds ratio 3.68) and smaller mass size (<2 cm; odds ratio 4.84) were significant predictors for benign lesions. CONCLUSIONS: The incidence of benign lesions among renal masses >=2 cm in diameter was found to be much lower than previously reported. This should be taken into account when designing strategies for the management of suspicious small renal masses. PMID- 22515573 TI - Mechanisms and management of exercise-induced asthma in elite athletes. AB - OBJECTIVE AND METHODS: Asthma is often reported by elite athletes, especially endurance athletes. The aim of this article is to review current knowledge of mechanisms and management of exercise-induced asthma (EIA) in adult elite athletes. RESULTS: The mechanisms underlying EIA is incompletely understood, but the two prevailing hypotheses are the hyper-osmolarity and the thermal hypothesis. Both hypotheses consider inflammation and activation of mast cells as being crucial for the development of EIA, although the assumed mechanisms triggering the inflammatory response differ. Objective testing is of utmost importance in the diagnosis of EIA in elite athletes. Management of EIA can be divided into pharmacologic and non-pharmacologic treatment. The basic principles for the treatment of EIA in elite athletes should be as for any asthmatic individual, including use of inhaled corticosteroids (ICS), beta(2)-agonists, and leukotriene antagonists. However, evidence suggests that daily use of beta(2) agonists might lead to the development of tolerance. ICS therapy is, due to its anti-inflammatory effects, the recommended primary therapy for EIA also in elite athletes. All doctors treating individuals with asthma, especially elite athletes, should remain updated on doping aspects of asthma therapy. Non pharmacologic management of EIA in elite athletes includes physical warm-up, which takes advantage of the refractory period following an attack of EIA, whereas high intake of antioxidants may reduce airway inflammation. Wearing heat masks, specially designed for outdoor winter athletes, might protect against bronchoconstriction triggered by inhalation of cold and dry air. CONCLUSION: EIA in elite athletes should be managed as in any individual with asthma, but the risk of developing tolerance to bronchodilators as well as doping aspects should always be taken into account. PMID- 22515574 TI - Work partitioning of transversally loaded muscle: experimentation and simulation. AB - Skeletal muscles are surrounded by other muscles, connective tissue and bones, which may transfer transversal forces to the muscle belly. Simple Hill-type muscle models do not consider transversal forces. Thus, the aim of this study was to examine and model the influence of transversal muscle loading on contraction dynamics, e.g. on the rate of force development and on the maximum isometric muscle force (Fim). Isometric experiments with and without transversal muscle loading were conducted on rat muscles. The muscles were loaded (1.3 N cm-2) by a custom-made plunger which was able to move in transversal direction. Then the muscle was fully stimulated, the isometric force was measured at the distal tendon and the movement of the plunger was captured with a high-speed camera. The interaction between the muscle and the transversal load was modelled based on energy balance between the (1) work done by the contractile component (CC) and (2) the work done to lift the load, to stretch the series elastic structures and to deform the muscle. Compared with the unloaded contraction, the force rate was reduced by about 25% and Fim was reduced by 5% both in the experiment and in the simulation. The reduction in Fim resulted from using part of the work done by the CC to lift the load and deform the muscle. The response of the muscle to transversal loading opens a window into the interdependence of contractile and deformation work, which can be used to specify and validate 3D muscle models. PMID- 22515575 TI - Trypanosoma cruzi infection: a review with emphasis on cutaneous manifestations. AB - Chagas disease, an infection caused by the protozoan Trypanosoma cruzi and transmitted by the Reduuvid insect vector, remains a major cause of morbidity in Central and South America over a century after its discovery in 1909. Though major advances in preventing the spread of this disease have been made in recent decades, millions of individuals remain chronically infected due to prior exposure to T. cruzi and are at risk for future complications from the disease. Dermatologic manifestations of acute infection may include localized swelling at the site of inoculation (chagoma), conjunctivitis (Romana's sign), and a generalized morbilliform eruption (schizotrypanides). Reactivation of quiescent infection in immunocompromised hosts due to the acquired immunodeficiency syndrome or organ transplantation can present with fever and skin lesions including panniculitis. The widespread emigration of chronic carriers of T. cruzi to North America, Europe, and Australia makes it imperative that dermatologists worldwide be familiar with this entity to ensure proper diagnosis and treatment. PMID- 22515577 TI - The many faces of nickel allergy. AB - Hypersensitivity reactions to nickel are one of the most common in the modern world. Nickel allergy prevalence is constantly growing in many countries and represents a major health and socioeconomic issue. Herein the current understanding on nickel allergy is summarized with a practical approach to the dermatologist, allergist, and general practitioner. The personal experience with some practical clinical cases of nickel dermatitis is shared. A special emphasis is put on the possible strategies for treatment and prevention of the disease. PMID- 22515576 TI - Geriatric dermatoses: a clinical review of skin diseases in an aging population. AB - Geriatric dermatoses are a challenging job for the physician in terms of diagnosis, management, and followup. Since skin of the elderly population is going through a lot of changes from both an intrinsic and extrinsic point of view, it is imperative for the physician to have a better understanding of the pathophysiology of geriatric skin disorders and their specific management, which differs slightly from an adult population. This review focuses on a brief introduction to the pathophysiological aspects of skin disorders in elderly, the description of some common geriatric skin disorders and their management and the new emerging role of psychodermatological aspects of geriatric dermatoses is also discussed. At the end, ten multiple choice questions are also added to further enhance the knowledge base of the readers. PMID- 22515578 TI - Clinicopathologic challenge: acral lymphomatoid papulosis. PMID- 22515579 TI - Hydroxyurea-induced dermatomyositis: true amyopathic dermatomyositis or dermatomyositis-like eruption? AB - BACKGROUND: Hydroxyurea-induced dermatomyositis is a rare adverse reaction of long-term hydroxyurea therapy. It has been reported under different names; however, the exact classification and nomenclature of this eruption have been the subject of much debate, and a more precise term is still awaiting. Herein, we review the different aspects of this reaction and suggest a new term that might help to minimize the confusion about its nomenclature. MATERIALS AND METHODS: We describe a 68-year-old woman who had been on long-term hydroxyurea therapy for the treatment of chronic myeloid leukemia for nine years. She presented with typical dermatomyositis-like lesions and many of the other mucocutaneous adverse effects of hydroxyurea. RESULTS: Skin examination revealed typical Gottron's papules on the dorsa of the hands, atrophy, xerosis, acquired ichthyosis, photosensitivity, cutaneous, oral and nail hyperpigmentation, acral erythema, palmoplantar keratoderma, actinic keratoses, and leg ulcers. There was no clinical or laboratory evidence of proximal muscle weakness. Cessation of hydroxyurea was associated with remarkable improvement of the skin lesions. CONCLUSION: Hydroxyurea-induced dermatomyositis is a rare drug-induced dermatomyositis characterized by skin lesions identical to classic dermatomyositis without clinical or laboratory evidence of myositis. We propose that the term hydroxyurea-induced amyopathic dermatomyositis that adequately describes the findings reported in this subset of patients would be more precise and specific. PMID- 22515580 TI - The investigation of autonomic functions in patients with psoriasis. AB - BACKGROUND: Psoriasis is a common Th1-mediated skin disease whose etiology remains obscure. Loss of sweating caused by retention hyperkeratosis is seen in psoriasis plaques, which is likely to have resulted from autonomic dysfunction. OBJECTIVE: In the present study, we aimed to evaluate autonomic nervous system (ANS) functions with regard to psoriasis and to examine whether there is an underlying ANS dysfunction. MATERIALS AND METHODS: Fifty adult patients with plaque-type psoriasis and 20 healthy controls were enrolled in the present study. RESULTS In this study, R-R interval variation (RRIV) was used to evaluate the parasympathetic system. No statistically significant difference was detected when RRIV values of the patient and the control groups were evaluated during normal and deep breathing (P > 0.05). It was determined that parasympathetic activity in the patient group remained unaffected. The sympathetic skin response (SSR) method was used for the evaluation of the sympathetic system. It was found that SSR latency and amplitude values of upper and lower extremities of the patient group were prolonged in comparison to those of the control group. The change in SSR latency of the upper extremity was found to be statistically significant (P < 0.05), whereas the changes in hand amplitude, foot latency, and foot amplitude values were not statistically significant (P > 0.05). It was determined that sympathetic activity in the patient group was affected. CONCLUSION: In conclusion, we detected that a dysfunction was present in sympathetic nervous systems of patients with psoriasis. The parasympathetic nervous system functions were normal in patients with psoriasis. PMID- 22515581 TI - Acquired patch-type blue nevus with overlying vitiligo: a case report. AB - BACKGROUND: Blue nevi are a group of congenital and acquired dermal melanocytoses characterized by a blue-gray appearance on the skin. The common blue nevus and cellular blue nevus are the most common subtypes. Patch-type blue nevus is rather rare. OBSERVATIONS: We describe a 77-year-old Chinese male with a 6 * 8-cm non palpable blue patch overlaid by a depigmented patch on the back of the left scalp. Histological examination of the blue-gray patch showed numerous spindled and elongated bipolar dendritic melanocytes in the upper reticular dermis and an absence of epidermal melanocytes. Immunohistochemically, these dendritic melanocytes were positive for S-100 and HMB-45. A diagnosis of a patch-type blue nevus with overlying vitiligo was made after the biopsy. CONCLUSIONS: The patient presents an unusual manifestation of patch-type blue nevi with overlying vitiligo. To the best of our knowledge, these features have not been previously described. PMID- 22515582 TI - Tumor necrosis factor alpha promoter-308G/A polymorphism in Mexican patients with patchy alopecia areata. AB - BACKGROUND: Alopecia areata (AA) is a chronic inflammatory condition characterized by hair loss, most frequently from the scalp. Its etiopathogenesis is currently unknown, but inflammatory traits and associations with autoimmune diseases suggest that AA shares a similar origin. The tumor necrosis factor alpha (TNFalpha) gene, located on chromosome 6 within the major histocompatibility complex class III gene, may carry previously described polymorphisms- particularly in the promoter region, such as TNFalpha-308G/A--known to be risk factors in a wide variety of inflammatory pathologies. In Mexican populations, this polymorphism has been associated with augmented TNFalpha production and, thus, renders carriers more susceptible to developing autoimmune diseases; however, as yet it has not been associated with AA. OBJECTIVES: To assess a possible association between the presence of TNFalpha-308G/A and patchy AA. MATERIALS AND METHODS: Blood samples were taken from 59 patients affected by patchy AA and 103 control subjects without AA, all from the northeastern Mexican population. Genomic DNA was isolated using the phenol-chloroform method and samples subjected to polymerase chain reaction-restriction fragment length polymorphism in order to detect the TNFalpha-308G/A polymorphism. RESULTS: TNFalpha-308G/A (TNF2) allele [odds ratio (OR) = 3.22, P = 0.026, 95% confidence interval (CI) = 0.99-11.61], when segregated in the heterozygous (TNF1/TNF2) genotype (OR = 3.53, P = 0.023, 95% CI = 1.01-12.89) confers a significant risk for developing AA, compared with the genotype TNF1/TNF1 observed in controls (OR = 0.28, P = 0.023, 95% CI = 0.08-0.99). CONCLUSIONS: Our data suggest that there is a plausible association between the presence of the TNFalpha-308G/A polymorphism and a higher susceptibility for developing patchy AA. This risk might be due to overproduction of TNFalpha, which would facilitate an autoimmune response against the hair follicle. PMID- 22515583 TI - Prevalence survey of dermatological conditions in mountainous north India. AB - BACKGROUND: Dermatological conditions account for a substantial proportion of the global burden of disease in low and middle income countries (Bickers D, Lim H, Margolis D, et al. The burden of skin diseases: 2004. A joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol 2006; 55: 490-500) and place major pressures on primary healthcare centers (Satimia F, McBride S, Leppard B. Prevalence of skin disease in rural Tanzania and factors influencing the choice of health care, modern or traditional. Arch Dermatol 1998; 134: 1363-1366). In mountainous North India, where limited resources are available for skin care, no dermatological data exists on prevalence, treatment patterns, or associations. The study aimed to measure prevalence and treatment of dermatological conditions and associated factors in Uttarakhand so to inform delivery of dermatological care and prevention programs in India. METHODS: Single stage cluster randomized sampling generated seven cluster units or villages. Household members (n = 1275) from each cluster were interviewed, and where possible, examined and offered treatment. RESULTS: Dermatological conditions were prevalent (45.3%), with 33% being of infectious etiology. Atopic dermatitis (9.2%), scabies (4.4%), tinea corporis (4.1%), and pityriasis alba (3.6%) were most prevalent. Multivariate analysis showed that cohabitation with animals (OR = 1.62, 95% CI-1.35, 1.95) was a predictor of any skin diseases. A health practitioner was not consulted in 64.7% of dermatological conditions, and where consulted, approximately 69% received inappropriate or ineffective treatments. Excessive spending on dermatological care was commonplace. Limitations associated with cross-sectional cluster methodology included the underrepresentation of seasonal conditions and conditions of short duration. Caste proved difficult to randomize across clusters given villages were often composed according to caste. CONCLUSION: These results demonstrate a high prevalence of dermatological conditions and a pattern of conditions somewhat distinctive to this mountainous area of North India. These findings will assist development of appropriate and cost-effective dermatological services in these mountainous regions. PMID- 22515584 TI - Parotid tuberculosis: a forgotten suspicion (a case report and literature review). PMID- 22515585 TI - Concurrence of linear epidermal nevus and nevus flammeus in a man with optic pathway glioma: coincidence or phacomatosis? PMID- 22515586 TI - A case of vesiculobullous dermatomyositis: a marker of internal malignancy. PMID- 22515587 TI - Clinical comparison of two hyaluronic acid-derived fillers in the treatment of nasolabial folds: Mesoglow(r) and IAL System(r). AB - Hyaluronic acid (HA) dermal fillers are widely used to reduce the appearance of aging. However, comparative research on the efficacy and safety of products of similar composition is limited. We compared outcomes achieved with two non-cross linked HA fillers of almost identical composition, Mesoglow(r) and IAL System(r) . Forty subjects with visible nasolabial folds (NLFs) were enrolled in a randomized study. Wrinkle severity was rated using the 5-point Wrinkle Severity Rating Scale (WSRS). Each subject was injected with Mesoglow(r) in one NLF and IAL System(r) in the other. An optimal cosmetic result was established at two weeks after a second treatment. Participants were then reassessed at 2, 6, and 12 weeks, respectively, post-optimal cosmetic result using the WSRS. The degree of improvement was also assessed by subjects and investigators using the Global Aesthetic Improvement Scale (GAIS). At baseline, the mean WSRS score was 3.20 +/- 0.41. At the optimal cosmetic result, 98% of subjects showed a 1- or 2-point change in WSRS score with either treatment. All subsequent WSRS scores were significantly improved over baseline for both treatments. There was no significant difference between treatments or improvement in WSRS score at any point in time. Investigator GAIS scores at weeks 4 and 6 were slightly but not significantly higher for Mesoglow(r)-treated skin. There was no significant difference in the frequency of local adverse responses. No serious systemic adverse events occurred. This study indicates that Mesoglow(r) and IAL System(r) are equally effective in achieving short-term correction of NLFs, but the longevity of their effects is limited. PMID- 22515589 TI - Living with familial melanoma syndrome: coping with the anxiety of three melanomas. PMID- 22515588 TI - Efficacy and safety of non-laser, targeted UVB phototherapy alone and in combination with psoralen gel or calcipotriol ointment in the treatment of localized, chronic, plaque-type psoriasis. AB - BACKGROUND: Topical drugs enhance the therapeutic effects of ultraviolet (UV) based therapy for psoriasis. However, their efficacy has yet to be established in a clinical trial. OBJECTIVES: This study aimed to compare the efficacy of targeted microphototherapy alone and in combination with psoralen or calcipotriol in the treatment of plaque-type psoriasis. METHODS: Thirty individuals, affected by plaque-type psoriasis, were treated with targeted narrowband UVB phototherapy alone (Group 1), in combination with psoralen gel (Group 2), or in combination with calcipotriol ointment (Group 3) three times per week based on predetermined minimal erythema doses for 10 weeks. RESULTS: All patients in each group completed the study. The percentages of improvement in Psoriasis Area and Severity Index (PASI) and Psoriasis Severity Index (PSI) scores were 33.9% and 38.3% in Group 1, 29.9% and 29.8% in Group 2, and 67.2% and 59% in Group 3, respectively. There was no statistically significant difference in improvement between Groups 1 and 2 (P > 0.05). Outcomes in Group 3 were found to be superior compared with those in the other groups. CONCLUSIONS: The addition of calcipotriol ointment in targeted phototherapy enhances the therapeutic effects of phototherapy in the treatment of plaque-type psoriasis. PMID- 22515590 TI - A solitary fibrofolliculoma on the concha of the ear. PMID- 22515591 TI - Comparison between in vivo measurement of the Montenegro skin test and paper recording. PMID- 22515592 TI - Malignant adnexal tumors: diagnostic and therapeutic challenges in Calabar, Nigeria. PMID- 22515595 TI - Oxidized low-density lipoprotein and lipoprotein(a) levels in chronic kidney disease patients under hemodialysis: influence of adiponectin and of a polymorphism in the apolipoprotein(a) gene. AB - Chronic kidney disease (CKD) has been associated with an abnormal lipid profile. Our aim was to study the interplay between oxidized low-density lipoprotein (ox LDL), adiponectin, and blood lipids and lipoproteins in Portuguese patients with CKD under hemodialysis (HD); the influence of the pentanucleotide repeat polymorphism in the apolipoprotein(a) (apo [a]) gene upon lipoprotein(a) (Lp[a]) levels in these patients. We studied 187 HD patients and 25 healthy individuals. ox-LDL and adiponectin were measured using enzyme-linked immunoassays. Apo(a) genotyping was performed by polymerase chain reaction, followed by electrophoresis in polyacrylamide gel. Compared with controls, patients presented with significantly higher levels of adiponectin, Lp(a), and ox-LDL/low-density lipoprotein cholesterol (LDLc) ratio; significantly lower levels of total cholesterol (TC), LDLc, apo A-I, apo B, ox-LDL, and TC/high-density lipoprotein cholesterol (HDLc) ratio were also observed. Similar changes were observed for patients with or without statin therapy, as compared with controls, except for Lp(a). Multiple linear regression analysis showed that body mass index, HDLc, time on HD, and triglycerides (TG) were independent determinants of adiponectin levels, and that apo B, TG and LDLc were independent determinants of ox-LDL concentration. Concerning the apo(a) genotype, the homozygous (TTTTA)8/8 repeats was the most prevalent (50.8%). A raised proportion of LDL particles that are oxidized was observed. Adiponectin almost doubled its values in patients and seems to be an important determinant in HDLc and TG levels, improving the lipid profile in these patients. Apo(a) alleles with a lower number of repetitions are more frequent in patients with higher Lp(a). PMID- 22515594 TI - In vivo proton magnetic resonance spectroscopy of breast cancer: a review of the literature. AB - An emerging clinical modality called proton magnetic resonance spectroscopy ((1)H MRS) enables the non-invasive in vivo assessment of tissue metabolism and is demonstrating applications in improving the specificity of MR breast lesion diagnosis and monitoring tumour responsiveness to neoadjuvant chemotherapies. Variations in the concentration of choline-based cellular metabolites, detectable with (1)H-MRS, have shown an association with malignant transformation of tissue in in vivo and in vitro studies. (1)H-MRS exists as an adjunct to the current routine clinical breast MR examination. This review serves as an introduction to the field of breast (1)H-MRS, discusses modern high-field strength and quantitative approaches and technical considerations, and reviews the literature with respect to the application of (1)H-MRS for breast cancer. PMID- 22515596 TI - Studying the potential impact of automated document classification on scheduling a systematic review update. AB - BACKGROUND: Systematic Reviews (SRs) are an essential part of evidence-based medicine, providing support for clinical practice and policy on a wide range of medical topics. However, producing SRs is resource-intensive, and progress in the research they review leads to SRs becoming outdated, requiring updates. Although the question of how and when to update SRs has been studied, the best method for determining when to update is still unclear, necessitating further research. METHODS: In this work we study the potential impact of a machine learning-based automated system for providing alerts when new publications become available within an SR topic. Some of these new publications are especially important, as they report findings that are more likely to initiate a review update. To this end, we have designed a classification algorithm to identify articles that are likely to be included in an SR update, along with an annotation scheme designed to identify the most important publications in a topic area. Using an SR database containing over 70,000 articles, we annotated articles from 9 topics that had received an update during the study period. The algorithm was then evaluated in terms of the overall correct and incorrect alert rate for publications meeting the topic inclusion criteria, as well as in terms of its ability to identify important, update-motivating publications in a topic area. RESULTS: Our initial approach, based on our previous work in topic-specific SR publication classification, identifies over 70% of the most important new publications, while maintaining a low overall alert rate. CONCLUSIONS: We performed an initial analysis of the opportunities and challenges in aiding the SR update planning process with an informatics-based machine learning approach. Alerts could be a useful tool in the planning, scheduling, and allocation of resources for SR updates, providing an improvement in timeliness and coverage for the large number of medical topics needing SRs. While the performance of this initial method is not perfect, it could be a useful supplement to current approaches to scheduling an SR update. Approaches specifically targeting the types of important publications identified by this work are likely to improve results. PMID- 22515597 TI - Structural characterization of lignin in the process of cooking of cornstalk with solid alkali and active oxygen. AB - A novel, efficient, and environmentally friendly technology is used in cornstalk cooking, active oxygen (O2 and H2O2) cooking with solid alkali (MgO). After the cooking, the milled wood lignin in the raw material and pulp and the water soluble and insoluble lignin in the yellow liquor were all characterized by attenuated total reflectance Fourier transform infrared spectroscopy and two dimensional heteronuclear single-quantum coherence NMR. The results showed that the cooking procedure with solid alkali and active oxygen had a high selectivity for delignification, which could remove 85.5% of the lignin from the raw material. The syringyl (S/S'/S') units could be dissolved preferentially because of their high reactivity, and a novel guaiacyl unit with a carbonyl group (G') was generated in the cooking process. Moreover, during the cooking, the beta-O-4' (A/A'/A") structures as the main side-chain linkages in all the lignins could be partly broken and the beta-O-4' (A') with a ring-conjugated structure was readily attacked by oxygen, whereas the H unit and beta-5' and beta-beta' structures were found to stay stable without characteristic reaction. PMID- 22515598 TI - Fullerene/cobalt porphyrin hybrid nanosheets with ambipolar charge transporting characteristics. AB - A novel supramolecular nanoarchitecture, comprising C(60)/Co porphyrin nanosheets, was prepared by a simple liquid-liquid interfacial precipitation method and fully characterized by means of optical microscopy, AFM, STEM, TEM, and XRD. It is established that the highly crystalline C(60)/Co porphyrin nanosheets have a simple (1:1) stoichiometry, and when incorporated in bottom gate, bottom-contact field-effect transistors (FETs), they show ambipolar charge transport characteristics. PMID- 22515599 TI - Characterization and emulsifying property of a novel bioemulsifier by Aeribacillus pallidus YM-1. AB - AIMS: Biosurfactants and bioemulsifiers commonly have the advantages of biodegradability, low toxicity, selectivity and biocompatibility over chemically synthesized surfactants. The goal of the study is to present a novel bioemulsifier with great application potential. METHODS AND RESULTS: Aeribacillus pallidus YM-1, isolated from crude oil contaminated soil, was found to produce a novel high molecular bioemulsifier with an emulsification index of 60 +/- 1% without remarkable surface tension reduction (45.7 +/- 0.1 mN m(-1) ). The number-average molecular weight was determined as 526 369 Da by gel permeation chromatography analysis. Bioemulsifier was subjected to FT-IR and a complex of carbohydrates (41.1%), lipids (47.6%) and proteins (11.3%) was determined. CONCLUSIONS: The bioemulsifier of A. pallidus YM-1 was isolated from the glucose-based culture medium and characterized with the help of chemical analytical techniques. The bioemulsifier exhibited a promising emulsifying property for biotechnology application potential in bioremediation and microbial enhanced oil recovery. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report of the bioemulsifier production by A. pallidus. The potential emulsifying activity of the bioemulsifier in the present study may be explored in various biotechnological and industrial applications. PMID- 22515601 TI - [W(bipy)(CN)6]-: a suitable metalloligand in the design of heterotrimetallic complexes. The first Cu(II)Ln(III)W(V) trinuclear complexes. AB - The first 3d-4f-5d heterotrimetallic complexes using [W(V)(bipy)(CN)(6)](-) as a metalloligand were synthesized (bipy = 2,2'-bipyridine). The structural and magnetic properties of three [Cu(II)Ln(III)W(V)] complexes (Ln = Gd, Ho, Tb) are discussed. PMID- 22515600 TI - Gossypol-enhanced P450 gene pool contributes to cotton bollworm tolerance to a pyrethroid insecticide. AB - Cotton plants accumulate phytotoxins, including gossypol and related sesquiterpene aldehydes, to resist insect herbivores and pathogens. To counteract these defensive plant secondary metabolites, cotton bollworms (Helicoverpa armigera) elevate their production of detoxification enzymes, including cytochrome P450 monooxygenases (P450s). Besides their tolerance to phytotoxin, cotton bollworms have quickly developed resistance to deltamethrin, a widely used pyrethroid insecticide in cotton field. However, the relationship between host plant secondary metabolites and bollworm insecticide resistance is poorly understood. Here, we show that exogenously expressed CYP6AE14, a gossypol inducible P450 of cotton bollworm, has epoxidation activity towards aldrin, an organochlorine insecticide, indicating that gossypol-induced P450s participate in insecticide metabolism. Gossypol-ingested cotton bollworm larvae showed higher midgut P450 enzyme activities and exhibited enhanced tolerance to deltamethrin. The midgut transcripts of bollworm larvae administrated with different phytochemicals and deltamethrin were then compared by microarray analysis, which showed that gossypol and deltamethrin induced the most similar P450 expression profiles. Gossypol-induced P450s exhibited high divergence and at least five of them (CYP321A1, CYP9A12, CYP9A14, CYP6AE11 and CYP6B7) contributed to cotton bollworm tolerance to deltamethrin. Knocking down one of them, CYP9A14, by plant mediated RNA interference (RNAi) rendered the larvae more sensitive to the insecticide. These data demonstrate that generalist insects can take advantage of secondary metabolites from their major host plants to elaborate defence systems against other toxic chemicals, and impairing this defence pathway by RNAi holds a potential for reducing the required dosages of agrochemicals in pest control. PMID- 22515602 TI - Breast cancer pharmacogenomics: where we are going. PMID- 22515603 TI - Recent advances in pharmacogenomics of ABC transporters involved in breast cancer therapy. PMID- 22515604 TI - Next-generation sequencing in breast cancer: translational science and clinical integration. PMID- 22515606 TI - Highlights from the latest articles in breast cancer pharmacogenomics. PMID- 22515607 TI - An interview with Pharmacogenomics for the breast cancer special focus issue. PMID- 22515608 TI - An interview with Pharmacogenomics for the breast cancer special focus issue. PMID- 22515609 TI - The pharmacogenomics of sex hormone metabolism: breast cancer risk in menopausal hormone therapy. AB - With women in western countries spending nearly one-third of their lifetime beyond menopause and a substantial number of these women facing severe menopausal symptoms, the goal of sex hormone pharmacogenomics is to promote the safe use of hormone replacement therapy (HRT). This could be achieved by providing molecular predictors for the upfront stratification of women in need of relief from menopausal symptoms into those with a likely benefit from HRT and those with a contraindication due to an HRT-associated breast cancer risk or other adverse effects. An increasing knowledge base of sex hormone metabolism and its variability, HRT outcomes and breast cancer susceptibility, as well as emerging examples of pharmacogenomic predictors, underscore the potential relevance of genetic variations for HRT outcome. The genes responsible for the metabolism, signaling and action of sex hormones are at the heart of this research; however, pharmacogenomic investigation of their therapeutic effects due to the enormous complexity of the biological pathways involved is still in its infancy. This article discusses the current knowledge, challenges and potential future directions towards the goal of genotype-guided safer HRT use. PMID- 22515610 TI - Pharmacogenetics of chemotherapy efficacy in breast cancer. AB - Large differences are observed in chemotherapy response between breast cancer patients, with a substantial part of this variability being explained by genetic factors. Polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters and drug targets influence the pharmacokinetics and pharmacodynamics of these anticancer drugs, leading to differences in therapeutic efficacy. Pharmacogenetic investigations of breast cancer therapeutics focused on these candidate loci have been performed. This article summarizes the status of research to identify polymorphisms in genes that influence response to the chemotherapeutic agents used in breast cancer treatment and suggests future directions for this line of research. Understanding the genetic factors that predispose patients to poor treatment outcomes will help guide individualized therapeutic strategies to obtain maximal benefit. PMID- 22515611 TI - Use of CYP2D6 genotyping in practice: tamoxifen dose adjustment. AB - Tamoxifen is a selective estrogen-receptor modulator that is commonly utilized in the treatment and prevention of endocrine receptor-positive breast cancer. Ultimate conversion of the parent drug by the enzyme CYP2D6 to the active metabolite, endoxifen, is required for tamoxifen to exert its anticancer effects. CYP2D6 exists in varying concentrations across individuals due, in part, to genetic variation. Lower concentrations of endoxifen have been associated with inferior breast cancer outcomes in numerous retrospective trials. In an effort to increase the endoxifen concentrations, three prospective trials have assessed different methods of increasing tamoxifen dose based on patient CYP2D6 genotypes. All three demonstrated the ability to increase endoxifen concentrations using tamoxifen at a dose of 30 or 40 mg daily. These positive findings support future investigations to determine, not only the clinical benefit of genotype-guided therapy, but also the optimal dose needed for individual patients. PMID- 22515612 TI - Pharmacogenetics of aromatase inhibitors. AB - Aromatase inhibitors (AIs) are an important class of endocrine drugs used in the treatment of early and advanced breast cancer in postmenopausal women. A number of studies have taken candidate approaches to assess the role of variants in genes encoding enzymes important in AI metabolism, notably CYP19A1 (aromatase), in AI response. These studies have shown conflicting, but interesting, results suggesting that CYP19A1 variants may be important in both the efficacy and toxicity of AIs. A recent genome-wide association study has identified a variant, creating an estrogen response element in TCL1A, which is associated with an increased risk of the musculoskeletal side effects associated with AI use. As breast cancer incidence increases, predictive biomarkers of response to AIs will become more important to ensure the most effective use of endocrine treatments. PMID- 22515613 TI - miRNAs in breast cancer: ready for real time? AB - Over the past decade, major advances in our comprehension of breast cancer biology have led to improved diagnostic and prognostic techniques and the development of novel targeted therapies. However, the efficacy of new treatments remains limited by a combination of drug toxicity, resistance and persisting insufficiencies in our understanding of tumor-signaling pathways; furthermore, the reliability of identified biomarkers is contentious. Following their recent discovery, miRNAs have been established as critical regulators of gene expression, and their putative roles as oncogenes and tumor-suppressor genes has provided a potential new dimension to our clinical approach to breast cancer diagnosis and treatment. Their role as biomarkers and therapeutic targets is appealing; however, several barriers have limited our ability to translate this potential into a clinical reality. This review focuses on the currently accepted roles of miRNAs in breast cancer pathogenesis, and highlights the clinical challenges and breakthroughs in this field to date. PMID- 22515614 TI - The importance of nonpharmacogenetic factors in endocrine therapy. AB - Nonpharmacogenetic factors may play a key role in the success of oral endocrine therapy for breast cancer. Adherence, defined as following medical advice as well as persistence and duration of use for patients prescribed endocrine therapy, may impact significantly on recurrence and survival. Side effects from tamoxifen or aromatase inhibitors may lead to patients stopping or switching therapy, while comorbidities, consequent coprescribing and patient perceptions may also influence outcomes. Interventions to improve adherence and persistence are required and could have as great an effect on survival as applying pharmacogenetic principles to the endocrine management of breast cancer. PMID- 22515617 TI - Palladium-catalyzed desulfitative conjugate addition of aryl sulfinic acids and direct ESI-MS for mechanistic studies. AB - A new and efficient method for palladium(II) catalytic desulfitative conjugate addition of arylsulfinic acids with alpha,beta-unsaturated carbonyl compound has been developed. The key reacting intermediates including aryl Pd(II) sulfinic intermediate, aryl Pd(II), and C?O-Pd complexes were captured by ESI-MS/MS, which provide new experimental evidence for the understanding of addition mechanism. PMID- 22515616 TI - A rare case of malignant triton tumor in the cerebellopontine angle. AB - Malignant triton tumor (MTT) is defined as malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation. Intracranial MTT is extremely rare, and only four cases have been reported in the literature. Here, we report a case of MTT occurring in the cerebellopontine angle, and describe its histopathological characteristics, immunohistochemical features, and prognosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1336227313684480. PMID- 22515618 TI - Screening for attention-deficit/hyperactivity disorder (ADHD): can high-risk children be identified in first grade? AB - AIM: Recent studies have demonstrated the beneficial long-term effects of an indicated parent support programme for acting out behaviour in pre-school children with attention-deficit/hyperactivity disorder (ADHD) traits. In this study we wanted to assess different thresholds for screening with the Conners scale for hyperactive-inattentive behaviours in first grade for ADHD in grade four. METHOD: The study population consisted of 422 first graders (6- to 7-year olds) in one municipality in Stockholm County who were screened with Conners 10 item scale and followed up by ADHD assessment in grade four. Sensitivity, specificity, likelihood ratios, and positive predictive value (PPV) of the screening by parents and teachers in first grade for being diagnosed with ADHD in fourth grade were calculated. RESULTS: The prevalence of pervasive and situational ADHD was 5.7% and 5.9% respectively. A score >= 10 on the Conners scale in first grade in teachers' reports identified 63% [95% confidence interval (CI): 43-79] of children diagnosed with pervasive ADHD in grade four (P < 0.001) with a PPV of 29% and a positive likelihood ratio (LR+) of 6.72. Parental reports of a score >= 10 yielded a lower sensitivity (29%; 95% CI: 15-49), PPV of 20% and LR+ of 4.24 for pervasive ADHD. The best predictor was a combination of parent and teacher scores >= 10 with a PPV of 50% and LR+ of 16.63. Associations with situational ADHD were weak with LR+ of 1.81 and 2.49, respectively, for teachers' and parental scores >= 10. CONCLUSIONS: This study indicates a strong association between a teacher's report of a score >= 10 on the Conners scale in first grade and pervasive ADHD in grade four, while parental reports were less predictive. PMID- 22515619 TI - Dihydroartemisinin/Piperaquine: a review of its use in the treatment of uncomplicated Plasmodium falciparum malaria. AB - Artemisinin-based combination regimens are recommended by WHO for the treatment of uncomplicated Plasmodium falciparum malaria. One such combination comprises the artemisinin derivative dihydroartemisinin and the bisquinolone piperaquine. Eurartesim(r) is the only dihydroartemisinin/piperaquine formulation that meets international good manufacturing practice standards. This article reviews the pharmacological properties of dihydroartemisinin and piperaquine, and the therapeutic efficacy and tolerability of dihydroartemisinin/piperaquine in the treatment of uncomplicated P. falciparum malaria. A number of trials have shown dihydroartemisinin/piperaquine to be highly effective in the treatment of uncomplicated P. falciparum malaria. Two pivotal, randomized, open-label, multicentre trials demonstrated the Eurartesim(r) formulation of dihydroartemisinin/piperaquine to be noninferior to artesunate plus mefloquine in children and adults in Asia and noninferior to artemether/lumefantrine in children in Africa, in terms of polymerase chain reaction-corrected cure rates. In both trials, dihydroartemisinin/piperaquine recipients were significantly less likely than artesunate plus mefloquine recipients or artemether/lumefantrine recipients to experience reinfection. Gametocyte carriage was greater in patients receiving dihydroartemisinin/piperaquine than in those receiving comparator antimalarial regimens. The Eurartesim(r) formulation of dihydroartemisinin/piperaquine was generally well tolerated in the treatment of uncomplicated P. falciparum malaria, and was associated with significantly less nausea, vomiting and dizziness than artesunate plus mefloquine. Although prolongation of the corrected QT interval has been reported in patients receiving dihydroartemisinin/piperaquine, there are currently no clinical data signalling that it is associated with clinically significant arrhythmias. In conclusion, dihydroartemisinin/piperaquine is a valuable option for use in the first-line treatment of uncomplicated P. falciparum malaria. PMID- 22515620 TI - Bevacizumab combination therapy: for the first-line treatment of advanced epithelial ovarian, fallopian tube or primary peritoneal cancer. AB - Bevacizumab is a recombinant, humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody that neutralizes the biological activity of VEGF and inhibits tumour angiogenesis. In two pivotal, well designed, phase III, clinical trials (GOG-0218 and ICON7) in women with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer, first-line treatment with bevacizumab in combination with standard chemotherapy (carboplatin plus paclitaxel) followed by maintenance treatment with bevacizumab alone significantly prolonged progression free survival relative to standard chemotherapy. A subgroup analysis of ICON7 suggested that bevacizumab therapy may also be beneficial in patients at high risk of disease progression. In GOG-0218, health-related quality of life (HR-QOL) deteriorated temporarily (during the chemotherapy phase) and slightly, although statistically significantly, with bevacizumab in combination with standard chemotherapy followed by bevacizumab maintenance relative to standard chemotherapy plus placebo maintenance. In ICON7, HR-QOL did not differ to a clinically significant extent between patients receiving bevacizumab plus standard chemotherapy followed by bevacizumab maintenance and those receiving standard chemotherapy alone. Bevacizumab combination therapy had generally acceptable tolerability in these studies, with the nature of adverse events generally similar to that observed in previous clinical trials in patients with other solid tumours. PMID- 22515622 TI - Climate change. PMID- 22515623 TI - Thoughts on humaneness. PMID- 22515624 TI - What is your diagnosis? Avulsion fracture of the insertion of the round ligament of the head of the femur. PMID- 22515625 TI - What is your diagnosis? Hypereosinophilia in a dog with multicentric B-cell lymphoma. PMID- 22515626 TI - Pathology in practice. Primary hepatic chondroblastic osteosarcoma. PMID- 22515627 TI - Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs. AB - OBJECTIVE: To compare efficacy and safety of treatment with phenobarbital or bromide as the first-choice antiepileptic drug (AED) in dogs. DESIGN: Double blinded, randomized, parallel, clinical trial. ANIMALS: 46 AED-naive dogs with naturally occurring epilepsy. PROCEDURES: Study inclusion was based on age, history, findings on physical and neurologic examinations, and clinicopathologic test results. For either phenobarbital treatment (21 dogs) or bromide treatment (25), a 7-day loading dose period was initiated along with a maintenance dose, which was adjusted on the basis of monthly monitoring. Efficacy and safety outcomes were compared between times (baseline and study end [generally 6 months]) and between drugs. RESULTS: Phenobarbital treatment resulted in eradication of seizures (17/20 [85%]) significantly more often than did bromide (12/23 [52%]); phenobarbital treatment also resulted in a greater percentage decrease in seizure duration (88 +/- 34%), compared with bromide (49 +/- 75%). Seizure activity worsened in 3 bromide-treated dogs only. In dogs with seizure eradication, mean +/- SD serum phenobarbital concentration was 25 +/- 6 MUg/mL (phenobarbital dosage, 4.1 +/- 1.1 mg/kg [1.9 +/- 0.5 mg/lb], p.o., q 12 h) and mean serum bromide concentration was 1.8 +/- 0.6 mg/mL (bromide dosage, 31 +/- 11 mg/kg [14 +/- 5 mg/lb], p.o., q 12 h). Ataxia, lethargy, and polydipsia were greater at 1 month for phenobarbital-treated dogs; vomiting was greater for bromide-treated dogs at 1 month and study end. CONCLUSIONS AND CLINICAL RELEVANCE: Both phenobarbital and bromide were reasonable first-choice AEDs for dogs, but phenobarbital was more effective and better tolerated during the first 6 months of treatment. PMID- 22515628 TI - Comparison of two assays for detection of antibodies against canine parvovirus and canine distemper virus in dogs admitted to a Florida animal shelter. AB - OBJECTIVE: To compare 2 assays for use in the identification of dogs with a protective antibody titer (PAT) against canine parvovirus (CPV) and canine distemper virus (CDV). DESIGN: Prospective cross-sectional study. ANIMALS: 431 dogs admitted to a municipal animal shelter in north central Florida. PROCEDURES: Blood samples were collected from dogs on the day of admission to the shelter. Serum was obtained, criterion-referenced assays were used to identify dogs that had PATs against CPV (titers >= 80; hemagglutination inhibition assay) and CDV (titers >= 32; virus neutralization assay), and results were compared with results of a semiquantitative ELISA and an immunofluorescence assay (IFA). RESULTS: For correct identification of dogs that had PATs against viruses, the ELISA had significantly higher specificity for CPV (98%) and CDV (95%) than did the IFA (82% and 70%, respectively) and had significantly lower sensitivity for CDV (88%) than did the IFA (97%); the sensitivity for CPV was similar (ELISA, 98%; IFA, 97%). Overall diagnostic accuracy was significantly greater with the ELISA than with the IFA. Predictive value of a positive result for PATs was significantly higher with the ELISA for CPV (99%) and CDV (93%) than with the IFA (92% and 71%, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: The ELISA had fewer false-positive results than did the IFA and could be performed on-site in shelters in < 1 hour. Accuracy and practicality of the ELISA may be useful for identifying the infection risk of dogs exposed during outbreaks attributable to CPV and CDV infections in shelters. PMID- 22515629 TI - Comparison of three-view thoracic radiography and computed tomography for detection of pulmonary nodules in dogs with neoplasia. AB - OBJECTIVE: To compare the detection of pulmonary nodules by use of 3-view thoracic radiography and CT in dogs with confirmed neoplasia. DESIGN: Prospective case series. ANIMALS: 33 dogs of various breeds. PROCEDURES: 3 interpreters independently evaluated 3-view thoracic radiography images. The location and size of pulmonary nodules were recorded. Computed tomographic scans of the thorax were obtained and evaluated by a single interpreter. The location, size, margin, internal architecture, and density of pulmonary nodules were recorded. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for thoracic radiography (with CT as the gold standard). RESULTS: 21 of 33 (64%) dogs had pulmonary nodules or masses detected on CT. Of the dogs that had positive CT findings, 17 of 21 (81%) had pulmonary nodules or masses detected on radiographs by at least 1 interpreter. Sensitivity of radiography ranged from 71% to 95%, and specificity ranged from 67% to 92%. Radiography had a positive predictive value of 83% to 94% and a negative predictive value of 65% to 89%. The 4 dogs that were negative for nodules on thoracic radiography but positive on CT were all large-breed to giant-breed dogs with osteosarcoma. CONCLUSIONS AND CLINICAL RELEVANCE: CT was more sensitive than radiography for detection of pulmonary nodules. This was particularly evident in large-breed to giant-breed dogs. Thoracic CT is recommended in large-breed to giant-breed dogs with osteosarcoma if the detection of pulmonary nodules will change treatment. PMID- 22515630 TI - Relationship between paradoxical breathing and pleural diseases in dyspneic dogs and cats: 389 cases (2001-2009). AB - OBJECTIVE: To determine the strength of the relationship between paradoxical breathing (PB) and spontaneous pleural diseases in dyspneic dogs and cats. DESIGN: Cross-sectional study. ANIMALS: Dogs (n = 195) and cats (194) with a recorded diagnosis of dyspnea examined at the National Veterinary Schools of Alfort and Toulouse (France) between January 2001 and October 2009. PROCEDURES: Dogs and cats were divided into 2 groups according to the presence or absence of PB. Stratified analysis by species was performed. Signalment of affected animals and occurrence of PB were recorded. The relationship between PB and pleural diseases among dyspneic dogs and cats was analyzed. RESULTS: A strong relationship between PB and pleural diseases was highlighted in multivariate analysis (dogs, OR = 12.6 and 95% confidence interval = 4.6 to 31.2; cats, OR = 14.1 and 95% confidence interval = 6.0 to 33.5). Paradoxical breathing prevalence among dyspneic dogs and cats was 27% and 64%, respectively. Occurrence of pleural diseases in dyspneic animals with and without PB was 49% and 9% in dogs and 66% and 13% in cats, respectively. The sensitivity and specificity of PB as a predictor of pleural diseases were 0.67 and 0.83 in dyspneic dogs and 0.90 and 0.58 in dyspneic cats, respectively. The positive and negative predictive values of PB were 0.49 and 0.91 in dyspneic dogs and 0.66 and 0.87 in dyspneic cats, respectively. Age, sex, feline breeds, and canine morphotypes in patients with PB were not significantly different from those of other dyspneic animals. CONCLUSIONS AND CLINICAL RELEVANCE: PB was strongly associated with pleural diseases in dyspneic dogs and cats. The presence of this clinical sign should prompt small animal practitioners to implement appropriate emergency procedures and guide their diagnostic strategy. PMID- 22515631 TI - Gastroesophageal reflux and laryngeal dysfunction in a dog. AB - CASE DESCRIPTION: A 7-year-old neutered male Saint Bernard was evaluated because of a 6-month history of coughing, gagging, change in phonation, excessive panting, and chronic intermittent vomiting and diarrhea. CLINICAL FINDINGS: Physical examination revealed no remarkable findings other than panting. Total thyroxine concentration and results of a CBC, serum biochemistry analysis, urinalysis, and thoracic radiography were within reference limits. A laryngeal examination revealed edema, erythema, and ulceration of the larynx and pharynx, with normal laryngeal movement. Results of bronchoscopy and cytologic examination of bronchoalveolar lavage fluid were diagnostic only for distal tracheitis. Esophagoscopy and an esophagography revealed esophagitis consistent with gastroesophageal reflux. Gastroduodenoscopy and histologic examination of biopsy specimens revealed Helicobacter colonization and lymphocytic or plasmacytic enteritis. TREATMENT AND OUTCOME: Following treatment for gastroesophageal reflux and suspected Helicobacter infection with combination antacid and antimicrobial treatment, the dog's respiratory signs resolved but vomiting continued. Gastroduodenoscopy revealed complete resolution of the previous laryngitis, pharyngitis, and esophagitis. Treatment for the lymphocytic or plasmacytic enteritis was initiated with prednisone (1 mg/kg [0.45 mg/lb], p.o., q 12 h) and a novel protein diet. The previous treatment was also continued. Complete resolution of clinical signs was maintained 4 months after initiation of appropriate treatment. CLINICAL RELEVANCE: Laryngeal dysfunction induced by gastroesophageal reflux as occurred in the patient described in this report is a previously undocumented association in the veterinary literature. This association could be a potential consideration in dogs with concurrent respiratory and gastrointestinal signs. The present report may provide a basis for further studies investigating this association. PMID- 22515632 TI - Treatment of dematiaceous fungal keratitis in a dog. AB - CASE DESCRIPTION: A 9-year-old castrated male Bichon Frise was evaluated because of a 3-week history of a nonhealing corneal ulcer and corneal pigmentation of the left eye. CLINICAL FINDINGS: Ophthalmic examination of the left eye revealed conjunctival hyperemia, corneal neovascularization, corneal edema, corneal ulceration, and central corneal pigmentation. Intraocular structures of the left eye could not be visually examined because of the diffuse nature of the corneal lesions. The right eye had anterior cortical incipient cataracts, nuclear sclerosis, and an inactive chorioretinal scar. TREATMENT AND OUTCOME: Superficial lamellar keratectomy of the left eye was performed for both therapeutic and diagnostic purposes. Histologic evaluation of corneal biopsy specimens revealed dematiaceous fungal keratitis of the left eye, and topical administration of voriconazole was used to successfully resolve the keratitis. Seven months after diagnosis of dematiaceous fungal keratitis, the dog had no clinical signs or history of recurrence of the keratitis. CLINICAL RELEVANCE: Dematiaceous fungal keratitis should be considered as a possible cause of nonhealing corneal ulceration with heavy pigment deposition in dogs. Results suggested that lamellar keratectomy along with topical administration of voriconazole can be used successfully to treat dematiaceous fungal keratitis in dogs. PMID- 22515633 TI - Comparison of radiography, nuclear scintigraphy, and magnetic resonance imaging for detection of specific conditions of the distal tarsal bones of horses: 20 cases (2006-2010). AB - OBJECTIVE: To describe pathological findings identified with MRI in the distal tarsal bones of horses with unilateral hind limb lameness attributable to tarsal pain and to compare the usefulness of MRI with that of radiography and nuclear scintigraphy in evaluation of this region. DESIGN: Retrospective case series. ANIMALS: 20 lame horses. PROCEDURES: In all horses, MRI, radiography (4 standard projections), and nuclear scintigraphy of the tarsus had been performed. Horses were excluded if the results of all 3 imaging modalities were not available or if lameness was detected in more than 1 limb. Pathological changes identified with MRI were cross-referenced with the findings determined with other imaging modalities. RESULTS: Compared with MRI findings, the following lesions were identified with radiography: medullary and subchondral bone sclerosis in 9 of 16 horses, pathological changes related to osseous hyperintensity in 0 of 10 horses, and osteoarthritis in 5 of 8 horses. Standard radiographic projections did not aid in the identification of fracture of the distal tarsal bones (3 horses). Location of increased radiopharmaceutical uptake with nuclear scintigraphy corresponded with the location of pathological changes detected with MRI in all horses. The intensity of the radiopharmaceutical uptake on nuclear scintigraphic images did not correspond with the severity of the pathological changes identified with MRI. CONCLUSIONS AND CLINICAL RELEVANCE: Radiography was unreliable for the detection of pathological changes related to osseous hyperintensity identified with MRI, fracture, and subchondral bone sclerosis in the equine tarsus. Nuclear scintigraphy was effective in localizing pathological changes, but MRI provided superior anatomic detail. PMID- 22515634 TI - Improving the assembly speed, quality, and tunability of thin conductive multilayers. AB - While inhomogeneous thin conductive films have been sought after for their flexibility, transparency, and strength, poor control in the processing of these materials has restricted their application. The versatile layer-by-layer assembly technique allows greater control over film deposition, but even this has been hampered by the traditional dip-coating method. Here, we employ a fully automated spin-spray layer-by-layer system (SSLbL) to rapidly produce high-quality, tunable multilayer films. With bilayer deposition cycle times as low as 13 s (~50% of previously reported) and thorough characterization of film conductance in the near percolation region, we show that SSLbL permits nanolevel control over film growth and efficient formation of a conducting network not available with other methods of multilayer deposition. The multitude of variables from spray time, to spin rate, to active drying available with SSLbL makes films generated by this technique inherently more tunable and expands the opportunity for optimization and application of composite multilayers. A comparison of several polymer-CNT systems deposited by both spin-spray and dip-coating exemplifies the potential of SSLbL assembly to allow for rapid screening of multilayer films. Ultrathin polymer-CNT multilayers assembled by SSLbL were also evaluated as lithium-ion battery electrodes, emphasizing the practical application of this technique. PMID- 22515635 TI - Wealth effect and dental care utilization in the United States. AB - OBJECTIVE: The purpose of this article is to examine the relationship of wealth and income and the relative impact of each on dental utilization in a population of older Americans, using data from the Health and Retirement Study (HRS). METHODS: Data from the HRS were analyzed for US individuals aged 51 years and older during the 2008 wave of the HRS. The primary focus of the analysis is the relationship between wealth, income, and dental utilization. We estimate a multivariable model of dental use controlling for wealth, income, and other potentially confounding covariates. RESULTS: We find that both wealth and income each have a strong and independent positive effect on dental care use of older Americans (P < 0.05). A test of the interaction between income and wealth in our model failed to show that the impact on dental care utilization as wealth increases depends on a person's income level or, alternatively, that the impact on dental use as income increases depends on a person's household wealth status (P > 0.05). CONCLUSIONS: Relative to those living in the wealthiest US households, the likelihood of utilizing dental care appears to decrease with a decline in wealth. The likelihood of utilizing dental care also appears to decrease with a decline in income as well. PMID- 22515636 TI - Microdeletions detected using chromosome microarray in children with suspected genetic movement disorders: a single-centre study. AB - AIM: Chromosome microarray (CMA) can determine copy number variants such as microdeletions or microduplications. Microdeletions of movement disorder genes including epsilon-sarcoglycan (SGCE) and thyroid transcription factor-1 (TITF1) have been described in patients with myoclonus dystonia and benign hereditary chorea respectively. We examined whether CMA is a valuable tool in the investigation of children with suspected genetic movement disorders. METHOD: A genetic movement disorder was suspected if there was a positive first-degree family history, or two or more of the following factors: normal or near-normal magnetic resonance imaging, negative history of brain injury, and negative investigations for metabolic disorders. Tic disorders were excluded. Twenty-five patients (18 males, seven females) with a mean age at movement disorder onset of 4 years 5 month (range 1 mo-14 y) were prospectively recruited with the following primary movement disorders: dystonia (n=10), paroxysmal kinesigenic dyskinesia (n=5), tremor (n=4), chorea (n=3), myoclonus (n=2), and paroxysmal non kinesigenic dyskinesia (n=1). Comorbid associated features were common, particularly developmental delay or intellectual disability (19 out of 25) and attention-deficit-hyperactivity disorder (six out of 25). CMA was performed using Agilent aCGH 60K array. RESULTS: Seven out of twenty-five patients had a microdeletion determined by CMA. None of the microdeletions were considered benign variants. Four patients had a deletion of a known movement disorder gene including paroxysmal kinesigenic dyskinesia (PRRT2; n=2), SGCE (myoclonus dystonia, n=1), and TITF1 (benign hereditary chorea, n=1). Three patients had novel microdeletions of unknown but potential significance including 14q13.3 (chorea, n=1), 19p13.12 (tremor, n=1), and 19q13.12 (progressive dystonia). All seven patients had associated neurodevelopmental or behavioural problems. INTERPRETATION: Assays that determine copy number variants may be a valuable first-tier investigation in patients with suspected genetic movement disorders, particularly when associated with intellectual disability or developmental disorders. Microdeletion syndromes may help the search for new movement disorder genes. PMID- 22515637 TI - Response interference between functional and structural object-related actions is increased in patients with ideomotor apraxia. AB - We report data from two left hemisphere stroke patients with moderate-to-severe ideomotor apraxia who exhibited deficits in positioning their hands to use 'conflict' objects (objects grasped and used with different hand postures) relative to controls and patients with mild apraxia. These novel data support the claim that actions to common objects are subject to interference between multiple responses, and suggest that errors in apraxia may be attributed to deficient resolution of competition between appropriate and inappropriate actions. PMID- 22515639 TI - Alkylthiol-enabled Se powder dissolution in oleylamine at room temperature for the phosphine-free synthesis of copper-based quaternary selenide nanocrystals. AB - Enhancement of Se solubility in organic solvents without the use of alkylphosphine ligands is the key for phosphine-free synthesis of selenide semiconductor nanocrystals (NCs). In this communication, we demonstrate the dissolution of elemental Se in oleylamine by alkylthiol reduction at room temperature, which generates soluble alkylammonium selenide. This Se precursor is highly reactive for hot-injection synthesis of selenide semiconductor NCs, such as Cu(2)ZnSnSe(4), Cu(InGa)Se(2), and CdSe. In the case of Cu(2)ZnSnSe(4), for example, the as-synthesized NCs possessed small size, high size monodispersity, strong absorbance in the visible region, and in particular a promising increase in photocurrent under AM1.5 illumination. The current preparation of the Se precursor is simple and convenient, which will promote the synthesis and practical applications of selenide NCs. PMID- 22515638 TI - Baseline comparison of three health utility measures and the feeling thermometer among participants in the Action to Control Cardiovascular Risk in Diabetes trial. AB - BACKGROUND: Health utility (HU) measures are used as overall measures of quality of life and to determine quality adjusted life years (QALYs) in economic analyses. We compared baseline values of three HUs including Short Form 6 Dimensions (SF-6D), and Health Utilities Index, Mark II and Mark III (HUI2 and HUI3) and the feeling thermometer (FT) among type 2 diabetes participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. We assessed relationships between HU and FT values and patient demographics and clinical variables. METHODS: ACCORD was a randomized clinical trial to test if intensive controls of glucose, blood pressure and lipids can reduce the risk of major cardiovascular disease (CVD) events in type 2 diabetes patients with high risk of CVD. The health-related quality of life (HRQOL) sub-study includes 2,053 randomly selected participants. Interclass correlations (ICCs) and agreement between measures by quartile were used to evaluate relationships between HU's and the FT. Multivariable regression models specified relationships between patient variables and each HU and the FT. RESULTS: The ICCs were 0.245 for FT/SF-6D, 0.313 for HUI3/SF-6D, 0.437 for HUI2/SF-6D, 0.338 for FT/HUI2, 0.337 for FT/HUI3 and 0.751 for HUI2/HUI3 (P < 0.001 for all). Common classification by quartile was found for the majority (62%) of values between HUI2 and HUI3, which was significantly (P < 0.001) higher than between other HUs and the FT: SF-6D/HUI3 = 40.8%, SF 6D/HUI2 = 40.9%, FT/HUI3 = 35.0%, FT/HUI2 = 34.9%, and FT/SF-6D = 31.9%. Common classification was higher between SF-6D/HUI2 and SF-6D/HUI3 (P < 0.001) than between FT/SF-6D, FT/HUI2, and FT/HUI3. The mean difference in HU values per patient ranged from -0.024 +/- 0.225 for SF-6D/ HUI3 to -0.124 +/- 0.133 for SF 6D/HUI2. Regression models were significant; clinical and demographic variables explained 6.1% (SF-6D) to 7.7% (HUI3) of the variance in HUs. CONCLUSIONS: The agreements between the different HUs were poor except for the two HUI measures; therefore HU values derived different measures may not be comparable. The FT had low agreement with HUs. The relationships between HUs and demographic and clinical measures demonstrate how severity of diabetes and other clinical and demographic factors are associated with HUs and FT measures. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00000620. PMID- 22515641 TI - Engineering tyrosine-based electron flow pathways in proteins: the case of aplysia myoglobin. AB - Tyrosine residues can act as redox cofactors that provide an electron transfer ("hole-hopping") route that enhances the rate of ferryl heme iron reduction by externally added reductants, for example, ascorbate. Aplysia fasciata myoglobin, having no naturally occurring tyrosines but 15 phenylalanines that can be selectively mutated to tyrosine residues, provides an ideal protein with which to study such through-protein electron transfer pathways and ways to manipulate them. Two surface exposed phenylalanines that are close to the heme have been mutated to tyrosines (F42Y, F98Y). In both of these, the rate of ferryl heme reduction increased by up to 3 orders of magnitude. This result cannot be explained in terms of distance or redox potential change between donor and acceptor but indicates that tyrosines, by virtue of their ability to form radicals, act as redox cofactors in a new pathway. The mechanism is discussed in terms of the Marcus theory and the specific protonation/deprotonation states of the oxoferryl iron and tyrosine. Tyrosine radicals have been observed and quantified by EPR spectroscopy in both mutants, consistent with the proposed mechanism. The location of each radical is unambiguous and allows us to validate theoretical methods that assign radical location on the basis of EPR hyperfine structure. Mutation to tyrosine decreases the lipid peroxidase activity of this myoglobin in the presence of low concentrations of reductant, and the possibility of decreasing the intrinsic toxicity of hemoglobin by introduction of these pathways is discussed. PMID- 22515640 TI - Sex, outcrossing and mating types: unsolved questions in fungi and beyond. AB - Variability in the way organisms reproduce raises numerous, and still unsolved, questions in evolutionary biology. In this study, we emphasize that fungi deserve a much greater emphasis in efforts to address these questions because of their multiple advantages as model eukaryotes. A tremendous diversity of reproductive modes and mating systems can be found in fungi, with many evolutionary transitions among closely related species. In addition, fungi show some peculiarities in their mating systems that have received little attention so far, despite the potential for providing insights into important evolutionary questions. In particular, selfing can occur at the haploid stage in addition to the diploid stage in many fungi, which is generally not possible in animals and plants but has a dramatic influence upon the structure of genetic systems. Fungi also present several advantages that make them tractable models for studies in experimental evolution. Here, we briefly review the unsolved questions and extant hypotheses about the evolution and maintenance of asexual vs. sexual reproduction and of selfing vs. outcrossing, focusing on fungal life cycles. We then propose how fungi can be used to address these long-standing questions and advance our understanding of sexual reproduction and mating systems across all eukaryotes. PMID- 22515642 TI - Expression features of SOX9 associate with tumor progression and poor prognosis of hepatocellular carcinoma. AB - BACKGROUND: SOX9 as a member of the SOX (SRY [sex determining region Y] box) gene superfamily has been previously demonstrated to be a proto-oncogene in a variety of malignancies. However, the clinical significance of SOX9 expression in hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to investigate the expression of SOX9 in HCC and determine its correlation with tumor progression and prognosis. METHODS: One-hundred and thirty HCC patients who had undergone curative liver resection were selected and immunohistochemistry, Western blotting, and quantitative real time polymerase chain reaction (Q-PCR) were performed to analyze SOX9 expression in the respective tumors. RESULTS: Immunohistochemistry, Western blotting, and Q-PCR consistently confirmed SOX9 overexpression in HCC tissues compared with their adjacent nonneoplastic tissues (P ? 0.01). Additionally, immunostaining showed more SOX9 positive cells in the higher tumor stage (T3 ~ 4) and tumor grade (G3) than in the lower tumor stage (T1 ~ 2, P = 0.03) and tumor grade (G1 ~ 2, P = 0.01), respectively. Moreover, HCC patients with high SOX9 expression were significantly associated with lower 5 year overall survival (P ? 0.01) and lower 5-year disease-free survival (P ? 0.01), respectively. The Cox proportional hazards model further showed that SOX9 over-expression was an independent poor prognostic factor for both 5-year disease free survival (hazards ratio [HR] = 2.621, 95% confidence interval[CI] = 1.548 5.829, P = 0.01) and 5-year overall survival (HR = 3.825, CI = 1.638-7.612, P = 0.003) in HCC. CONCLUSION: Our data suggest for the first time that the overexpression of SOX9 protein in HCC tissues is of predictive value on tumor progression and poor prognosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9029740396926377. PMID- 22515643 TI - Optimal fluid control can normalize cardiovascular risk markers and limit left ventricular hypertrophy in thrice weekly dialysis patients. AB - Increased hemodialysis frequency can make fluid overload easier to treat, although most patients are still treated thrice weekly. Chronic fluid overload is associated with left ventricular hypertrophy and elevated serum cardiac biomarkers, recognized as mortality risk factors. Serum cardiac troponin T (cTnT), N-terminal prohormone brain natriuretic peptide (NT-proBNP), left ventricular mass index by cardiac magnetic imaging, and ambulatory blood pressure was measured in 30 thrice weekly hemodiafiltration patients. Time-averaged fluid overload (TAFO) was quantified by bioimpedance spectroscopy. In the study group, left ventricular hypertrophy was found to be 26% by cardiac magnetic resonance. Ambulatory blood pressure was 130 mmHg (112-151) requiring a low equivalent dose of medication of 0.25 units (0-1). Significantly, lower levels of left ventricular mass index (P < 0.05) were associated in those patients with TAFO <1 L or NT-proBNP <1200 pg/mL or cTnT <0.1 ug/L. In the subgroups, 16 patients had normal cTnT (<0.03 ug/L), 16 patients had NT-proBNP <400 pg/mL, and 20 patients had TAFO <1 L. Nine patients had both cTnT <0.03 ug/L and NT-proBNP <400 pg/mL. Normally hydrated thrice-weekly hemodiafiltration patients can have cardiac biomarker and TAFO levels indistinguishable from the normal healthy population. Obtaining TAFO by bioimpedance monitoring can offer a practical alternative to serum cardiac biomarkers. PMID- 22515644 TI - Effect of animal sera on Bacillus anthracis Sterne spore germination and vegetative cell growth. AB - AIMS: The aims of this work were to investigate the effects of sera on B. anthracis Sterne germination and growth. Sera examined included human, monkey and rabbit sera, as well as sera from eight other species. METHODS AND RESULTS: Standard dilution plate assay (with and without heat kill) was used as a measure of germination, and spectroscopy was used to measure growth. In addition, a Coulter Counter particle counter was used to monitor germination and growth based on bacterial size. Spores germinated best in foetal bovine and monkey sera, moderately with human sera and showed limited germination in the presence of rabbit or rat sera. Vegetative bacteria grew best in foetal bovine sera and moderately in rabbit sera. Human and monkey sera supported little growth of vegetative bacteria. CONCLUSION: The data suggested sera can have a significant impact on germination and growth of Sterne bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: These data should be considered when conducting in vitro cell culture studies and may aid in interpreting in vivo infection studies. PMID- 22515645 TI - Chemical composition and hepatoprotective effects of polyphenol-rich extract from Houttuynia cordata tea. AB - This study was designed to investigate the antioxidant activity, hepatoprotective effect, and phenolic composition of the ethyl acetate fraction (EAF) extracted from Houttuynia cordata tea. EAF was shown to exhibit strong ferric-reducing antioxidant power (FRAP) and scavenging activity against DPPH radical in vitro, and the antioxidant effects were further verified by suppressing CCl4-induced oxidative stress in mouse liver at three tested doses of EAF (250, 500, and 1000 mg/kg bw). Pretreatment with EAF (1000 mg/kg bw) prior to CCl4 administration significantly (p < 0.001) decreased the CCl4-elevated levels of serum AST, ALT, alkaline phosphatase, total bilirubin, and hepatic MDA in mice and prevented the increases in GSH, SOD, and CAT caused by CCl4. HPLC analysis revealed that three predominantly polyphenolic compounds present in EAF were quercitrin (111.7 MUg/mg), quercetin (43.8 MUg/mg), and hyperoside (29.1 MUg/mg). These results combined with liver histopathology indicate that EAF possesses a significant protective effect against acute hepatotoxicity induced by CCl4, which may be due to the strong antioxidant activity of phenolic components. PMID- 22515646 TI - Integrated pharmacokinetics and pharmacodynamics of epoprostenol in healthy subjects. AB - AIM: The aim of the study was to report the first thorough characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of epoprostenol in an integrated manner. METHOD: Twenty healthy male subjects received two formulations of i.v. epoprostenol, in a crossover design, in sequential infusions of 2, 4, 6 and 8 ng kg(-1) min(-1) for 2 h each. A sensitive assay was developed which allowed accurate PK characterization of epoprostenol via analysis of the concentration-time profiles of its two primary metabolites, 6-keto-prostacyclin F(1alpha) and 6,15-diketo-13,14-dihydro-prostacyclin F(1alpha) . PD parameters included cardiac output (CO), cardiac index (CIn) and heart rate (HR). RESULTS: The pharmacokinetics of epoprostenol deviated slightly from dose-proportionality, probably due to a food effect. After infusion of the two formulations of epoprostenol, the t(1/2) values expressed as geometric mean (95% confidence interval) were 0.25 h (0.14, 0.46) and 0.22 h (0.13, 0.38) for 6-keto prostacyclin F(1alpha) , and 0.32 h (0.22, 0.45) and 0.34 h (0.26, 0.46) for 6,15 diketo-13,14-dihydro-prostacyclin F(1alpha) . A single compartment infusion model with first order elimination adequately described the PK of 6-keto-prostacyclin F(1alpha) . This model also characterized the food effect. Stepwise infusions with epoprostenol resulted in a progressive increase in CO, CIn and HR. CONCLUSION: Of the two metabolites analyzed, the appearance of 6-keto prostacyclin F(1alpha) in plasma was more closely associated with the haemodynamic effects of i.v. epoprostenol. PK and PD profiles showed that CIn relates proportionally and linearly to the plasma concentrations of 6-keto prostacyclin F(1alpha) . These results suggest that 6-keto-prostacyclin F(1alpha) is a suitable surrogate marker of plasma concentrations of epoprostenol. PMID- 22515647 TI - Uncertainty in environmental health impact assessment: quantitative methods and perspectives. AB - Environmental health impact assessment models are subjected to great uncertainty due to the complex associations between environmental exposures and health. Quantifying the impact of uncertainty is important if the models are used to support health policy decisions. We conducted a systematic review to identify and appraise current methods used to quantify the uncertainty in environmental health impact assessment. In the 19 studies meeting the inclusion criteria, several methods were identified. These were grouped into random sampling methods, second order probability methods, Bayesian methods, fuzzy sets, and deterministic sensitivity analysis methods. All 19 studies addressed the uncertainty in the parameter values but only 5 of the studies also addressed the uncertainty in the structure of the models. None of the articles reviewed considered conceptual sources of uncertainty associated with the framing assumptions or the conceptualisation of the model. Future research should attempt to broaden the way uncertainty is taken into account in environmental health impact assessments. PMID- 22515649 TI - Acoustic reflectometry for an in vitro model of a human upper airway using sinusoidal wave packets and the Ware-Aki algorithm. AB - Acoustic reflectometry is often used for estimating the cross-sectional area of a cylindrical cavity when used in combination with an acoustic pulse. The objective of this research is to sweep a spectral bandwidth from 50 Hz to 10 kHz at steps of 50 Hz, with Gaussian sinusoidal wave packets, and to apply the Ware-Aki algorithm. In practice, not only it is difficult to generate a broad spectral bandwidth, but also robust methods are required to compensate for attenuation in the propagating wave and to eliminate a DC offset component generated in its impulse response. This paper looks at using numerical techniques to compute the impulse response and estimate the cross-sectional area as a function of an increment in the frequency response. Preliminary results show that both simulated and reconstructed cross-sectional areas for an in vitro model of a human upper airway may be estimated with an appropriate resolution, suggesting that this method is suitable for such applications. PMID- 22515648 TI - Deficiency of the p53/p63 target Perp alters mammary gland homeostasis and promotes cancer. AB - INTRODUCTION: Perp is a transcriptional target of both p53 during DNA damage induced apoptosis and p63 during stratified epithelial development. Perp-/- mice exhibit postnatal lethality associated with dramatic blistering of the epidermis and oral mucosa, reflecting a critical role in desmosome-mediated intercellular adhesion in keratinocytes. However, the role of Perp in tissue homeostasis in other p63-dependent stratified epithelial tissues is poorly understood. Given that p63 is essential for proper mammary gland development and that cell adhesion is fundamental for ensuring the proper architecture and function of the mammary epithelium, here we investigate Perp function in the mammary gland. METHODS: Immunofluorescence and Western blot analysis were performed to characterize Perp expression and localization in the mouse mammary epithelium throughout development. The consequences of Perp deficiency for mammary epithelial development and homeostasis were examined by using in vivo mammary transplant assays. Perp protein levels in a variety of human breast cancer cell lines were compared with those in untransformed cells with Western blot analysis. The role of Perp in mouse mammary tumorigenesis was investigated by aging cohorts of K14 Cre/+;p53fl/fl mice that were wild-type or deficient for Perp. Mammary tumor latency was analyzed, and tumor-free survival was assessed using Kaplan-Meier analysis. RESULTS: We show that Perp protein is expressed in the mammary epithelium, where it colocalizes with desmosomes. Interestingly, although altering desmosomes through genetic inactivation of Perp does not dramatically impair mammary gland ductal development, Perp loss affects mammary epithelial homeostasis by causing the accumulation of inflammatory cells around mature mammary epithelium. Moreover, we show reduced Perp expression in many human breast cancer cell lines compared with untransformed cells. Importantly, Perp deficiency also promotes the development of mouse mammary cancer. CONCLUSIONS: Together, these observations demonstrate an important role for Perp in normal mammary tissue function and in mammary cancer suppression. In addition, our findings highlight the importance of desmosomes in cancer suppression and suggest the merit of evaluating Perp as a potential prognostic indicator or molecular target in breast cancer therapy. PMID- 22515652 TI - Combination therapy using maxacalcitol and corticosteroid lotions preliminary to monotherapy with maxacalcitol lotion for scalp psoriasis. AB - Topical treatment with betamethasone butyrate propionate lotion on 37 patients with scalp psoriasis was replaced with a combination therapy using maxacalcitol lotion (on weekdays) and BBP (on the weekends). This combination therapy was later switched to MXA monotherapy. To identify the optimum duration of the combination therapy, the patients were divided into two groups: a 4-week group and an 8-week group, which were given combination therapy and monotherapy. In both groups, the total mean scores for the skin symptoms had significantly improved in comparison with that obtained at the outset of the study (p < 0.01). In terms of overall improvement, 20.0% of the 4-week group and 72.7% of the 8 week group yielded scores reflecting moderate or greater improvement. The treatment administered to the 8-week group was significantly more effective than that given to the 4-week group at the end of the trial (p < 0.01). This study also suggests that a 4-week combination therapy is an option before switching to monotherapy, but that an 8-week therapy is preferable in severe cases. PMID- 22515653 TI - Immunogenicity and efficacy of an anthrax/plague DNA fusion vaccine in a mouse model. AB - The efficacy of multi-agent DNA vaccines consisting of a truncated gene encoding Bacillus anthracis lethal factor (LFn) fused to either Yersinia pestis V antigen (V) or Y . pestis F1 was evaluated. A/J mice were immunized by gene gun and developed predominantly IgG1 responses that were fully protective against a lethal aerosolized B. anthracis spore challenge but required the presence of an additional DNA vaccine expressing anthrax protective antigen to boost survival against aerosolized Y. pestis. PMID- 22515655 TI - Cytokine profile of bronchoalveolar lavage fluid in patients with combined pulmonary fibrosis and emphysema. AB - BACKGROUND AND OBJECTIVE: Combined pulmonary fibrosis and emphysema (CPFE) is characterized by upper lobe emphysema together with lower lobe fibrosis. The aim of this study was to examine whether cytokine levels in the alveolar space are associated with emphysematous changes superimposed on pulmonary fibrosis. METHODS: Consecutive patients (n = 102), diagnosed with pulmonary fibrosis were retrospectively evaluated. Cytokine levels and differential cell counts in bronchoalveolar lavage (BAL) fluid, pulmonary function, computed tomography (CT) scores and levels of serum markers were compared between patients with or without emphysema. RESULTS: Among the 102 patients (14 females, mean age 68 years), 38 (37%) had evidence of upper lobe emphysema on computed tomography (CT). Levels of epithelial neutrophil activating peptide 78 (ENA-78/CXCL5) and interleukin (IL) 8/CXCL8 in BAL fluid were significantly higher in patients with emphysema. Vital capacity (VC, % predicted) was greater, and ratio of forced expiratory volume in 1 s/forced vital capacity and diffusing capacity of carbon monoxide (DL(CO))/alveolar volume (V(A)) were lower in patients with emphysema. CXCL8 and CXCL5 levels were associated with percentage or absolute numbers of neutrophils in BAL fluid. In addition, CXCL8 levels were inversely correlated with VC and DL(CO)/V(A), and positively correlated with composite physiological index (CPI) and the extent of areas of low attenuation on CT. CONCLUSIONS: Increased CXC chemokine levels in the airspaces may be associated with emphysematous lung changes in patients with pulmonary fibrosis. PMID- 22515656 TI - Prevalence and severity of dental caries among American Indian and Alaska Native preschool children. AB - OBJECTIVES: To describe the Indian Health Service (IHS) oral health surveillance system and the oral health status of American Indian and Alaska Native (AI/AN) children aged 1-5 years. METHODS: A stratified probability sample of IHS/tribal sites was selected. Children were screened by trained examiners at community based locations including medical clinics, Head Start, preschools, kindergarten, and Women, Infants, and Children (WIC). Data collection was limited to the primary dentition and included number of teeth present plus number of teeth with cavitated lesions, restorations, and extracted because of decay. Number of molars with sealants and urgency of need for dental care data were also obtained. Statistical analyses were performed with SAS (SAS Institute Inc., Cary, NC, USA). Sample weights were used to produce population estimates based on selection probabilities. RESULTS: A total of 8,461 AI/AN children 12-71 months of age were screened at 63 IHS/tribal sites, approximately 7 percent of the estimated IHS user population of the same age. Overall, 54 percent of the children had decay experience, 39 percent had untreated decay, 7 percent had primary molar sealants, 36 percent needed early or urgent dental care, and 6 percent needed urgent dental care. The mean of decayed, missing, or filled teeth was 3.5 (95 percent confidence interval, 3.1-3.9). The prevalence of decay experience increased with age; 21 percent of 1-year-olds and 75 percent of 5-year-olds had a history of caries. When stratified by IHS area, there were substantial differences in the oral health of preschool children. CONCLUSIONS: The results confirm that in the United States, AI/AN children served by IHS/tribal programs are one of the racial/ethnic groups at highest risk of caries. PMID- 22515657 TI - Effective enhancement of Pseudomonas stutzeri D-phenylglycine aminotransferase functional expression in Pichia pastoris by co-expressing Escherichia coli GroEL GroES. AB - BACKGROUND: D-phenylglycine aminotransferase (D-PhgAT) of Pseudomonas stutzeri ST 201 catalyzes the reversible stereo-inverting transamination potentially useful in the application for synthesis of D-phenylglycine and D-4-hydroxyphenylglycine using L-glutamate as a low cost amino donor substrate in one single step. The enzyme is a relatively hydrophobic homodimeric intracellular protein difficult to express in the soluble functionally active form. Over-expression of the dpgA gene in E. coli resulted in the majority of the D-PhgAT aggregated into insoluble inclusion bodies that failed to be re-natured. Expression in Pichia pastoris was explored as an alternative route for high level production of the D-PhgAT. RESULTS: Intracellular expression of the codon-optimized synthetic dpgA gene under the PAOX1 promoter in P. pastoris resulted in inactive D-PhgAT associated with insoluble cellular fraction and very low level of D-PhgAT activity in the soluble fraction. Manipulation of culture conditions such as addition of sorbitol to induce intracellular accumulation of osmolytes, addition of benzyl alcohol to induce chaperone expression, or lowering incubation temperature to slow down protein expression and folding rates all failed to increase the active D-PhgAT yield. Co-expression of E. coli chaperonins GroEL-GroES with the D-PhgAT dramatically improved the soluble active enzyme production. Increasing gene dosage of both the dpgA and those of the chaperones further increased functional D-PhgAT yield up to 14400-fold higher than when the dpgA was expressed alone. Optimization of cultivation condition further increased D-PhgAT activity yield from the best co-expressing strain by 1.2-fold. CONCLUSIONS: This is the first report on the use of bacterial chaperones co-expressions to enhance functional intracellular expression of bacterial enzyme in P. pastoris. Only two bacterial chaperone genes groEL and groES were sufficient for dramatic enhancement of functionally active D-PhgAT expression in this yeast. With the optimized gene dosage and chaperone combinations, P. pastoris can be attractive for intracellular expression of bacterial proteins since it can grow to a very high cell density which is translated into the higher volumetric product yield than the E. coli or other bacterial systems. PMID- 22515659 TI - Road trauma perceptions and the potential influence of the media. AB - The United Nations Decade of Action for Road Safety (2011-2020) recognises the urgency of addressing global road trauma. Road crashes and attempts to reduce risky driving, including public education campaigns, receive media attention in many countries. In Australia, road fatalities have declined significantly. However, the extent of awareness about this success and of fatalities overall is unclear. A survey of 833 Australian drivers revealed the majority of participants under-estimated fatalities. Unexpectedly, some under-estimates appear based on recollections of media reports. The findings suggest lack of awareness of the extent of road deaths and that, paradoxically, media reports might contribute to under-estimations. This represents a major public health challenge. Engaging community support for road safety, relative to other health/safety messages, may prove difficult if the extent of road trauma is misunderstood. Misperceptions about fatality levels may be a barrier to road users adopting safety precautions or supporting further road safety countermeasures. PMID- 22515658 TI - Circulating biomarkers of response to sunitinib in gastroenteropancreatic neuroendocrine tumors: current data and clinical outlook. AB - After years of limited progress in the treatment of patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs), strategies using targeted agents have been developed on the basis of increased knowledge of the biology of these tumors. Some of these agents, targeting vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway, have shown efficacy in randomized clinical trials. The tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus have received international approval for the treatment of advanced well differentiated pancreatic NETs after showing survival benefit in randomized phase III trials. There is now an imperative need to identify biomarkers of the biologic activity of such targeted therapies in specific disease contexts, as well as new markers of response and prognosis. This approach may allow rational development of drugs and early identification of patients who may obtain benefit from treatments. In this article, we review recent developments in circulating biomarkers of the clinical benefit of targeted therapies for GEP-NET, including soluble proteins and circulating cells, with an emphasis on sunitinib. No validated molecular biomarkers are yet integrated into clinical practice for sunitinib in NET, although some markers have shown correlation with clinical outcomes and may be implicated in resistance. The VEGF pathway proteins and interleukin-8 (IL-8) are possibly prognostic in GEP-NET; other possible soluble markers of the activity of sunitinib and everolimus include stromal cell-derived factor 1alpha, chromogranin A, and neuron-specific enolase. We additionally discuss treatment-induced modulation of circulating endothelial cells and progenitors and subpopulations of cells of the myeloid lineage. These candidate markers should be considered in the development of future combination or sequential therapies. PMID- 22515660 TI - Sperm competition roles and ejaculate investment in a promiscuous mammal. AB - Theoretical models of sperm competition predict how males should allocate sperm and seminal fluid components to ejaculates according to their mating role (dominant vs. subordinate). Here, we present a detailed analysis of ejaculate expenditure according to male roles in the bank vole (Myodes glareolus). Sperm competition occurs regularly in this species, and dominant males typically achieve higher fertilization success than subordinates. Contrary to theoretical predictions, we found that dominant male bank voles invest more sperm per ejaculate than subordinates, both absolutely and relative to body and testes mass. The testes of dominant males were also absolutely (although not relatively) larger than those of subordinates. However, we found no evidence that subordinate males compensate for lower sperm numbers per ejaculate by increasing ejaculation frequency or sperm velocity. Similarly, we found no evidence for differential investment in copulatory plug size according to male roles in sperm competition, although dominant males had significantly larger seminal vesicles (both absolutely and relative to body mass) compared with subordinates. We conclude that sperm competition roles can have significant but unexpected influences on ejaculate investment in mammals with clearly defined differences in male social status. PMID- 22515661 TI - Type IV secretion system core component VirB8 from Brucella binds to the globular domain of VirB5 and to a periplasmic domain of VirB6. AB - Type IV secretion systems are macromolecular assemblies in the cell envelopes of bacteria that function in macromolecular translocation. Structural biology approaches have provided insights into the interaction of core complex components, but information about proteins that undergo transient interactions with membrane components has not been forthcoming. We have pursued an unbiased approach using peptide arrays and phage display to identify interaction partners and interaction domains of type IV secretion system assembly factor VirB8. These approaches identified the globular domain from the VirB5 protein to interact with VirB8. This interaction was confirmed in cross-linking, pull-down, and fluorescence resonance energy transfer (FRET)-based interaction assays. In addition, using phage display analysis, we identified different regions of VirB6 as potential interaction partners of VirB8. Using a FRET-based interaction assay, we provide the first direct experimental evidence of the interaction of a VirB6 periplasmic domain with VirB8. These results will allow us to conduct directed structural biological work and structure-function analyses aimed at defining the molecular details and biological significance of these interactions with VirB8 in the future. PMID- 22515662 TI - Safety and tolerability of theta-burst transcranial magnetic stimulation in children. AB - AIM: Theta-burst stimulation (TBS) is a lower intensity, high-frequency repetitive transcranial magnetic stimulation technique developed recently for quantifying and modulating cerebral cortical function. Nearly all published studies have involved adults. The aim of this study was to obtain safety data as a basis for evaluating potential risks versus benefits of TBS research in children. METHOD: Forty participants under 18 years: 16 with Tourette syndrome (five females, 11 males; mean age 12y, SD 2y 10mo) and 24 typically developing children (12 females, 12 males; mean age 12y 11mo, SD 2y 10mo) underwent intermittent or continuous TBS over the left motor cortex. Open questions, a structured 16-question review of systems, and visual analog mood scale (VAMS) were administered before and after TBS. A Wilcoxon signed-rank sum test was used to analyze differences in VAMS scores before and after TBS. RESULTS: There were no serious adverse events. Five of the 40 children reported mild, self-limited adverse events: a subjective sensation of finger twitching (n=1), neck stiffness (n=1), and mild headache (n=3). The total adverse event rate was 11.6%. There was no significant change in VAMS score in either group after one session of TBS. INTERPRETATION: A single session of TBS in children appears to be safe and well tolerated. PMID- 22515663 TI - Realist synthesis: illustrating the method for implementation research. AB - BACKGROUND: Realist synthesis is an increasingly popular approach to the review and synthesis of evidence, which focuses on understanding the mechanisms by which an intervention works (or not). There are few published examples of realist synthesis. This paper therefore fills a gap by describing, in detail, the process used for a realist review and synthesis to answer the question 'what interventions and strategies are effective in enabling evidence-informed healthcare?' The strengths and challenges of conducting realist review are also considered. METHODS: The realist approach involves identifying underlying causal mechanisms and exploring how they work under what conditions. The stages of this review included: defining the scope of the review (concept mining and framework formulation); searching for and scrutinising the evidence; extracting and synthesising the evidence; and developing the narrative, including hypotheses. RESULTS: Based on key terms and concepts related to various interventions to promote evidence-informed healthcare, we developed an outcome-focused theoretical framework. Questions were tailored for each of four theory/intervention areas within the theoretical framework and were used to guide development of a review and data extraction process. The search for literature within our first theory area, change agency, was executed and the screening procedure resulted in inclusion of 52 papers. Using the questions relevant to this theory area, data were extracted by one reviewer and validated by a second reviewer. Synthesis involved organisation of extracted data into evidence tables, theming and formulation of chains of inference, linking between the chains of inference, and hypothesis formulation. The narrative was developed around the hypotheses generated within the change agency theory area. CONCLUSIONS: Realist synthesis lends itself to the review of complex interventions because it accounts for context as well as outcomes in the process of systematically and transparently synthesising relevant literature. While realist synthesis demands flexible thinking and the ability to deal with complexity, the rewards include the potential for more pragmatic conclusions than alternative approaches to systematic reviewing. A separate publication will report the findings of the review. PMID- 22515664 TI - Non-ablative fractional resurfacing in combination with topical tretinoin cream as a field treatment modality for multiple actinic keratosis: a pilot study and a review of other field treatment modalities. AB - BACKGROUND: Actinic keratoses (AK) are premalignant lesions occurring mainly in sun-damaged skin. Current topical treatment options for AK and photo-damaged skin such as liquid nitrogen and electrosurgery are not suitable for field treatment. Otherwise, therapies suitable for field treatment bring along considerable patient discomfort. Non-ablative fractional resurfacing has emerged as a logical treatment option especially for field treatment of AK. OBJECTIVES: To evaluate the clinical efficacy of fractional laser therapy for clearing AK and improving skin quality. To compare patient friendliness of the "fractional" therapy with those reported for other field treatment modalities. MATERIALS & METHODS: Ten patients with Fitzpatrick skin type I to III with multiple AK and extensive sun damaged skin, received 5-10 sessions with a 4-week interval using a 1550 nm Erbium-Glass Fractionated laser (Sellas, Korea). Four weeks and 24 weeks after the last treatment the clinical results were evaluated by an independent physician. RESULTS: The mean degree of improvement, in terms of reduction in the number of AK and improvement of skin texture, was 54% on a 4 point PGA scale, and persisted for approximately 6 months. The biggest advantage of fractional laser treatment, besides the eradication of AK and a clear rejuvenation effect, is the absence of "downtime". CONCLUSION: Fractional non-ablative resurfacing induces significant reduction in the number of AK and improves the skin quality. Also all patients preferred fractional laser therapy above other AK treatment modalities. PMID- 22515665 TI - Can a single inflammatory marker adequately predict resistance to erythropoiesis stimulating agents in hemodialysis patients? PMID- 22515666 TI - Surgical complications. PMID- 22515667 TI - Medical legal complications of cutaneous surgery. AB - Complications in surgery are an unfavorable outcome as a result of a procedure. These can occur intraoperatively, immediately after or in the distant future. Minimizing the risk and prompt treatment of complications is important to avoid potentially disastrous outcomes. This article will review the more common complications of cutaneous surgery and then analyze the legal consequences of these complications. PMID- 22515668 TI - Complications of injectable fillers and neurotoxins. AB - All cosmetic injectable products are associated with the risk of both early and delayed complications. Early and expected side effects include swelling, bruising, and erythema at the injection. It is of utmost importance that patients are educated on the treatment they are consenting to receive and the potential risk of these therapies. Side effects of the various cosmetic injectable products, including both injectable neurotoxins and soft tissue fillers, are often technique associated, such as placing the filler too superficial or unintentional paralysis of facial muscles. Other complications, such as necrosis, intravascular injections, and infection may not be entirely technique-dependent, and must be managed swiftly and effectively. Finally, immunologic phenomena, such as delayed-type hypersensitivity reactions and foreign body granulomas, are complications that have no relationship to technique, and thus proper counseling and knowledge of management is required. PMID- 22515670 TI - Complications of tissue ischemia in dermatologic surgery. AB - Ischemic complications in cutaneous surgery can be devastating. Tissue ischemia can result from improper technique or closure design (i.e., increased tension), inadequate hemostasis, or infection, all of which result in decreased blood supply to the surgical site. Knowledge of patient characteristics that affect blood supply to the surgical site, including comorbid conditions, medications and behaviors (i.e., tobacco and alcohol use), is essential. Also, a thorough understanding of cutaneous anatomy, principles of surgical design, coupled with meticulous technique will minimize the likelihood of ischemic complications. Prompt recognition of hematoma, infection and impending ischemia/necrosis, and proper treatment of such complications, can minimize poor outcomes. PMID- 22515669 TI - Hemorrhagic complications in dermatologic surgery. AB - The ability to recognize, manage, and, most importantly, prevent hemorrhagic complications is critical to performing dermatologic procedures that have safe and high quality outcomes. This article reviews the preoperative, intraoperative, and postoperative factors and patient dynamics that are central to preventing such an adverse outcome. Specifically, the role that anticoagulants and anti platelet agents, hypertension, and other medical conditions play in the development of postoperative hemorrhage are discussed. In addition, this article provides practical guidelines on managing bleeding during and after surgery. PMID- 22515671 TI - Infectious complications of dermatologic procedures. AB - Although the infection rate of dermatologic procedures is extremely low, it is important to understand the serious complications that may result from one of these rare events. With the ever increasing number of dermatologic procedures performed, research continues to build regarding cutaneous infections. In order to properly treat a surgical site infection, the etiology and course of the infection must be known. The common microbes, types of infections, prophylaxis, and treatments involved in dermatologic surgery are reviewed. PMID- 22515672 TI - Complications of lasers and light treatments. AB - Cutaneous lasers and lights, and also more novel cutaneous energy modalities like radiofrequency and ultrasound, are in general very safe interventions with an associated rapid healing time. Posttreatment sequelae are usually mild and spontaneously resolving, with erythema and edema lasting hours to days. More troublesome, less common short-term adverse events include urticaria, erosions, crusting, ecchymoses, blistering, and infection. Medium-term adverse events include hyperpigmentation, hypopigmentation, a line of demarcation, burns, textural imperfections, and delayed reepithelialization. Long-term to permanent adverse events, which are fortunately rare, include indentation, scar, and ocular damage. With few exceptions, there are management strategies for avoiding laser adverse events, and, if they do occur, for mitigating their impact. PMID- 22515673 TI - Acitretin in management of diffuse common warts: a case report. AB - Warts are among the most commonly observed dermatological diseases, caused by human papilloma virus (HPV), usually HPV1-2 subtypes; HPV4-7 are rarely found and mostly related to professional exposure (butchers and dairy workers). Different therapeutical approaches are possible, depending on extension and severity of lesions. The present authors describe the case of 32-year-old Caucasian man, who came to our attention for the presence of numerous exophytic papules on the back of both hands and over periungual regions, which appeared about 6 months before. Histological examination confirmed the clinical suspicion of common warts (HPV4). The patient underwent therapy by acitretin for 12 weeks, obtaining during the 8th week of therapy complete resolution of skin lesions. The present authors present this case for the unusual local aggressiveness of viral warts in an immunocompetent patient successfully treated with acitetrin. PMID- 22515674 TI - Clinical effectiveness of intense pulsed light therapy for solar lentigines of the hands. AB - Intense pulsed light (IPL) treatment, as a nonablative phototherapy, is known to improve various signs of facial photoaging skin, e.g., solar lentigines, fine wrinkles, and telangiectasias. The purpose of the present study was to investigate the efficacy and tolerability of IPL with a 515-nm filter in patients with solar lentigines on the back of hands. An open study was performed in 31 patients who were treated with a 1-month interval up to five times. Sixty-two percent of patients had more than 50% improvement and 23% had more than 75% improvement. No patients discontinued due to adverse effects, and no patients showed hyperpigmentation or scarring after the treatments. Phototherapy using this IPL source was effective and well tolerated in the patients, suggesting that this phototherapy may be an appropriate modality for the treatment of solar lentigines of the hands. PMID- 22515675 TI - Psoriatic erythroderma coexisting with erythema multiforme-like lesions induced by retinoids or retinoids combined with an antibiotic: case report. AB - Psoriasis is currently considered a multifactorial disease, which can coexist with many somatic and psychological disorders. We present the case of a 50-year old woman referred to our department due to erythroderma with concomitant peculiar violaceous, polycyclic lesions most likely induced by medications. Past medical history revealed numerous systemic disorders, including metabolic syndrome, hypertension, cardiac insufficiency, obesity, and depression. Additional examinations and consultations demonstrated dyslipidemia, xanthelasma, incomplete block of the right branch of His bundle, thyreocardiac syndrome, benign adrenal tumor, and delusions. Recently, psoriasis has been intensively studied. We present the case in which erythroderma was most likely triggered by acitretin combined with ceftriaxone. Treatment of many diseases and psychiatric disturbances coexisting with psoriasis is extremely difficult and requires cooperation of various specialists. PMID- 22515677 TI - Inspirational airflow patterns in deviated noses: a numerical study. AB - This study attempts to evaluate the effects of deviation of external nose to nasal airflow patterns. Four typical subjects were chosen for model reconstruction based on computed tomography images of undeviated, S-shaped deviated, C-shaped deviated and slanted deviated noses. To study the hypothetical influence of deviation of external nasal wall on nasal airflow (without internal blockage), the collapsed region along the turbinate was artificially reopened in all the three cases with deviated noses. Computational fluid dynamics simulations were carried out in models of undeviated, original deviated and reopened nasal cavities at both flow rates of 167 and 500 ml/s. The shape of the anterior nasal roof was found to be collapsed on one side of the nasal airways in all the deviated noses. High wall shear stress region was found around the collapsed anterior nasal roof. The nasal resistances in cavities with deviated noses were considerably larger than healthy nasal cavity. Patterns of path-line distribution and wall shear stress distribution were similar between original deviated and reopened models. In conclusion, the deviation of an external nose is associated with the collapse of one anterior nasal roof. The crooked external nose induced a larger nasal resistance compared to the undeviated case, while the internal blockage of the airway along the turbinates further increased it. PMID- 22515676 TI - Use of patch testing for the diagnosis of abacavir-related hypersensitivity reaction in HIV patients. AB - BACKGROUND: The use of antiretroviral drug abacavir (ABC) has been often associated with cutaneous hypersensitivity reactions, the majority being severe. OBJECTIVE: The present study discusses the issues of patch testing associated with pharmacogenetic screening in light of the development of abacavir hypersensitivity reactions (HSRs). METHODS: The present authors classified 100 patients into three groups: 20 patients (group A) had experienced a hypersensitivity reaction when treated with highly active antiretroviral therapy (HAART) including ABC; 60 HIV-positive patients (group B) were receiving HAART scheme including ABC; 20 HIV-negative patients acted as control group (group C). Patients of group A and B were patch tested with ABC as such, then with an ABC extract diluted to 1 and 10% in petrolatum. Group C patients underwent patches with petrolatum only. A biopsy of the lesion was performed in those patients who showed a positive skin reaction. All patients had been tested for HLA-B5701. RESULTS: A correlation between positive ABC-patch testing and HLA-B5701 was found in 50% of patients enrolled in group A, while in group B and C, all patients tested negative for both genetic marker and ABC-patch testing. Histopathology findings confirmed a vigorous CD4+ and CD8+ cellular response that is compatible with HSR. CONCLUSIONS: Patch testing is a safe and sensitive method that can be used for to confirm or exclude any correlation between abacavir and hypersensitivity skin reactions in patients who have been previously treated with abacavir during HAART. Correlation between patch test, immunohistochimical, and genetic tests results shows that genetic testing increases the possibility to identify patients with a true reaction. PMID- 22515678 TI - Psychophysiological responses to cooperation: the role of outcome and gender. AB - Instances of sustained cooperative behaviour in humans can be considered as an adaptive strategy that enhances the probability of reaching a goal. This study investigates psychophysiological responses to cooperation in healthy subjects, while considering outcome and gender as potential moderators of these responses. Salivary cortisol levels (Csal), heart rate (HR), skin conductance level (SCL), nonspecific skin conductance responses (NSRs), and mood states were measured at different points before, during and after a Lego house-building task in undergraduate men (n = 22) and women (n = 20). Once the task was finished, the experimenter informed the participants about the outcome obtained (positive or negative). Cooperation produces an increase in HR, SCL, and NSR responses. When the outcome is positive it produces a gradual diminution in Csal levels, but when the outcome is negative there is a significant increase in Csal levels after the task followed by a progressive decrease. Men with positive outcomes showed a lower area under curve (AUC) in Csal than women with a negative outcome. Men had more NSR responses in all periods other than the rest period. Several mood states are differently affected by the combined effect of outcome and gender. Our laboratory results can be generalized to other situations in which negotiation, mediation, and cooperative strategies are relevant for taking decisions and/or solving problems. The authors wish to thank Dr Tinca Polderman and John Rawlins for the revision of the English text. This study was supported by the Ministry of Business, Research and Science of the Valencia Regional Government (GVPRE/2008/260, GVACOMP/2010/250, and PROMETEO/2011/048) and the Ministry of Science and Education of the Spanish Government (PSI2008-04408/PSIC). PMID- 22515680 TI - Si-compatible cleaning process for graphene using low-density inductively coupled plasma. AB - We report a novel cleaning technique for few-layer graphene (FLG) by using inductively coupled plasma (ICP) of Ar with an extremely low plasma density of 3.5 * 10(8) cm(-3). It is known that conventional capacitively coupled plasma (CCP) treatments destroy the planar symmetry of FLG, giving rise to the generation of defects. However, ICP treatment with extremely low plasma density is able to remove polymer resist residues from FLG within 3 min at a room temperature of 300 K while retaining the carbon sp(2)-bonding of FLG. It is found that the carrier mobility and charge neutrality point of FLG are restored to their pristine defect-free state after the ICP treatment. Considering the application of graphene to silicon-based electronic devices, such a cleaning method can replace thermal vacuum annealing, electrical current annealing, and wet-chemical treatment due to its advantages of being a low-temperature, large area, high-throughput, and Si-compatible process. PMID- 22515679 TI - Efficacy and safety of venous thromboembolism prophylaxis with fondaparinux or low molecular weight heparin in a large cohort of consecutive patients undergoing major orthopaedic surgery - findings from the ORTHO-TEP registry. AB - AIMS: In large randomized trials, thromboprophylaxis with fondaparinux in major orthopaedic surgery (MOS) has been shown to be superior to low molecular weight heparin (LMWH) prophylaxis with comparable safety. However, patients treated under trial conditions are different from unselected patients and efficacy and safety outcomes may be different in unselected patients in daily practice. We performed a retrospective cohort study to compare the efficacy and safety of venous thromboembolism (VTE) prophylaxis with fondaparinux or LMWH in 3896 consecutive patients undergoing major orthopaedic surgery at our centre. METHODS: All patients undergoing MOS between January 2006 and December 2009 were retrospectively analyzed using patient charts, hospital admission and discharge database, quality management database, transfusion unit database and VTE event documentation. VTE standard prophylaxis at our institution was LMWH (3000-6000 aXa units once daily) from January 2006 to December 2007 or fondaparinux 2.5 mg from January 2008 to December 2009. In these two large cohorts of unselected consecutive patients, in-hospital incidences of VTE, surgical complications, severe bleeding and death were evaluated. RESULTS: Symptomatic VTE was found in 4.1% of patients in the LMWH group (62/1495 patients; 95% CI 0.032, 0.052) compared with 5.6% of patients receiving fondaparinux (112/1994 patients, 95% CI 0.047, 0.067; P= 0.047). Distal deep vein thrombosis (DVT) was significantly more frequent in the fondaparinux group (3.9%, 95% CI 0.031, 0.048; vs. 2.5%; 95% CI 0.018, 0.034; P= 0.021). No significant differences in the rates of major VTE or death were found. Rates of severe bleeding, transfusion of RBC concentrates, plasma and platelet concentrates were comparable between both treatment groups. However, patients receiving fondaparinux had significantly lower rates of surgical revisions (1.6%, 95% CI 0.011, 0.022 vs. 3.7%, 95% CI 0.028, 0.047; P < 0.001). Multivariate analysis revealed previous VTE (HR 18.2, 95% CI 11.6, 28.5; P < 0.001) and female gender (HR 1.9, 95% CI 1.3, 2.7; P < 0.001), but not fondaparinux prophylaxis (HR1.3, 95% CI 0.9, 1.7; P= 0.184) to be associated with significantly increased VTE risk. DISCUSSION: Thromboprophylaxis with fondaparinux is less effective to prevent distal VTE than LMWH in unselected patients undergoing MOS, but is equally effective with regard to rates of major VTE and death. However, differences in efficacy of LMWH or fondaparinux are of little relevance compared with a history of VTE or female gender, which were found to be the main VTE risk factors in MOS. The safety profile of fondaparinux was comparable with LMWH with regard to rates of severe bleeding complications, but patients receiving fondaparinux had significantly less surgical complications requiring surgical revisions. Both our efficacy and safety findings differ from data derived from large phase III trials testing fondaparinux against LMWH in MOS, where overall rates of symptomatic VTE were lower and the safety profile of fondaparinux was different. CONCLUSION: We conclude that the strict patient selection and surveillance in phase-III trials results in lower VTE and bleeding event rates compared with unselected routine patients. Consequently, the efficacy and safety profile of thromboprophylaxis regimens needs to be confirmed in large registries or phase IV trials of unselected patients. PMID- 22515682 TI - Minimal fluorous tagging strategy that enables the synthesis of the complete stereoisomer library of SCH725674 macrolactones. AB - Four mixtures of four fluorous-tagged quasiisomers have been synthesized, demixed, and detagged to make all 16 stereoisomers of the macrocyclic lactone natural product Sch725674. A new bare-minimum tagging pattern needs only two tags -one fluorous and one nonfluorous--to encode four isomers. The structure of Sch725674 is assigned as (5R,6S,8R,14R,E)-5,6,8-trihydroxy-14 pentyloxacyclotetradec-3-en-2-one. Various comparisons of spectra of 32 lactones (16 with tags, 16 without) and 16 ester precursors (8 with tags, 8 without) provide insights into when and why related compounds have the same or different spectra. PMID- 22515681 TI - Prospective evaluation of artemether-lumefantrine for the treatment of non falciparum and mixed-species malaria in Gabon. AB - BACKGROUND: The recommendation of artemisinin combination therapy (ACT) as first line treatment for uncomplicated falciparum malaria is supported by a plethora of high quality clinical trials. However, their recommendation for the treatment of mixed-species malaria and the large-scale use for the treatment of non-falciparum malaria in endemic regions is based on anecdotal rather than systematic clinical evidence. METHODS: This study prospectively observed the efficacy of artemether lumefantrine for the treatment of uncomplicated non-falciparum or mixed-species malaria in two routine district hospitals in the Central African country of Gabon. RESULTS: Forty patients suffering from uncomplicated Plasmodium malariae, Plasmodium ovale or mixed-species malaria (including Plasmodium falciparum) presenting at the hospital received artemether-lumefantrine treatment and were followed up. All evaluable patients (n=38) showed an adequate clinical and parasitological response on Day 28 after oral treatment with artemether lumefantrine (95% confidence interval: 0.91,1). All adverse events were of mild to moderate intensity and completely resolved by the end of study. CONCLUSIONS: This first systematic assessment of artemether-lumefantrine treatment for P. malariae, P. ovale and mixed-species malaria demonstrated a high cure rate of 100% and a favourable tolerability profile, and thus lends support to the practice of treating non-falciparum or mixed-species malaria, or all cases of malaria without definite species differentiation, with artemether-lumefantrine in Gabon. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00725777. PMID- 22515683 TI - Production of melatonin by Saccharomyces strains under growth and fermentation conditions. AB - Melatonin is a bioactive compound that is present in wine because it is contained in vinification grapes and synthesized by yeast during alcoholic fermentation. The purpose of this study was to determine the capacity of various Saccharomyces strains to form melatonin during its growth and alcoholic fermentation. A selection of yeasts including six S. cerevisiae (Lalvin CLOS, Lalvin ICV-D254, Enoferm QA23 Viniferm ARM, Viniferm RVA, and Viniferm TTA), one S. uvarum (Lalvin S6U) and one S. cerevisiae var. bayanus (Uvaferm BC) were tested to determine whether they produce melatonin in yeast extract peptose dextrose and synthetic must media in a variety of conditions. Two S. cerevisiae strains (ARM, and QA23), the S. uvarum and the S. cerevisiae var. bayanus, synthesized melatonin. The conditions in which they did so, however, were different: the QA23 strain produced melatonin best in a medium with a low concentration of reducing sugars and Lalvin S6U and Uvaferm BC required a synthetic must under fermentation conditions. Melatonin synthesis largely depended on the growth phase of the yeasts and the concentration of tryptophan, reducing sugars and the growth medium. These results indicate that melatonin may have a role as a yeast growth signal molecule. PMID- 22515684 TI - Variations in the chemical composition of cassava ( Manihot esculenta Crantz) leaves and roots as affected by genotypic and environmental variation. AB - The purpose of this study was to assess the quality of cassava cultivars, in terms of cyanogenic potential and composition of macro- and micronutrients, sampled from different locations in rural Mozambique. Total cyanide concentrations in fresh cassava tissues were measured using portable cyanide testing kits, and elemental nutrients were later analyzed from dried plant tissue. Variation in cyanogenic potential and nutrient composition occurred both among cultivars and across locations. The majority of cultivars contained >100 ppm total cyanide, fresh weight, and are therefore considered to be dangerously poisonous unless adequately processed before consumption. Leaf cyanogenic and nutrient content varied with plant water status, estimated using carbon isotope discrimination (delta(13)C). The colonization of roots of all cultivars by arbuscular mycorrhizal fungi was also quantified and found to be high, indicating that mycorrhizas could play a key role in plant nutrient acquisition in these low input farming systems. PMID- 22515686 TI - SNPpath: characterizing cattle SNPs by enriched pathway terms. AB - High-density single nucleotide polymorphism (SNP) microarrays have made large scale genome-wide association studies (GWAS) and genomic selection (GS) feasible. Valuable insight into the genetic basis underlying complex polygenic traits will likely be gained by considering functionally related sets of genes simultaneously. SNPpath, a suite of computer-generated imagery-based web servers has been developed to automatically annotate and characterize cattle SNPs by enriched KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway terms. The SNPpath allows users to navigate and analysis large SNP sets and is the only web server currently providing pathway annotations of cattle SNPs in National Center for Biotechnology Information's dbSNP database and three commercial platforms. Hence, we describe SNPpath and provide details of the query options, as well as biological examples of use. The SNPpath may be favorable for the analysis of combining SNP association analysis with pathway-driven gene set enrichment analysis and is freely available at http://klab.sjtu.edu.cn/SNPpath. PMID- 22515685 TI - Exploring polymorphisms and their effects on reproductive traits of the INHA and INHbetaA genes in three goat breeds. AB - In this study, we report the analysis of INHA and INHbetaA gene polymorphisms in 786 goats of three breeds: Xinong Saanen (SN), Guanzhong (GZ) and Boer (BG). We identified three new allelic variants: P1-C80G and/126G (GenBank accession no. HQ202573) in the three goat breeds and P2-C936T (GenBank accession no. HQ202572) in SN and GZ goat breeds. At P1 locus, AA, AB and BB genotypes were found in the three goat breeds. At P2 locus, CC and CT genotypes were found in SN and GZ goat breeds. After comparing genotype distribution within the three goat breeds, BG had conspicuous differences from SN and GZ (P < 0.001) at P2 locus. The SNP locus was in Hardy-Weinberg disequilibrium at P1 locus in the three goat breeds (P < 0.05). At P2 locus, the SNP locus was in Hardy-Weinberg disequilibrium in SN and GZ goat breeds (P < 0.05). Association of polymorphisms with litter size was done at P1 locus in the three goat breeds. The result showed that AA genotype had remarkable litter size at P1 locus in the three goat breeds (P < 0.05). Therefore, these results suggest that INHA gene is a strong candidate gene that affects litter size in goats. PMID- 22515687 TI - Association between energy status early postpartum and subsequent embryonic mortality in high-yielding recipient cows. AB - High-yielding Holstein-Friesian recipients (n = 43) were used in order to investigate the relation between energy balance status during the early postpartum period and subsequent embryonic mortality after transferring good quality frozen embryos. Blood samples were collected during the second, third, fourth, fifth, sixth and seventh weeks postpartum in order to measure energy status indicators. These indicators include beta hydroxyl butyric acid (BHBA), non-esterified fatty acid (NEFA), total cholesterol (T-chol), glucose and blood urea nitrogen (BUN). Moreover, body condition scores (BCS) were assessed during the same period. Pregnancy diagnosis by ultrasonography at the 28th day postestrus and embryo viability was ascertained until 45 days postestrus in order to detect late embryonic mortality (LEM). The pregnancy rate on day 28 was 44.2% (19/43); however, five cows (11.6%) experienced LEM by day 45. Based on the non return rate at day 24, non-pregnant animals, as diagnosed by ultrasonography, were allocated into animals with longer estrus intervals than 24 days (32.5%; mid embryonic mortality (MEM) group) and animals returning to estrus by day 24 postestrus (23.5%; early embryonic mortality (EEM) group). At week 5 postpartum, BCS was significantly (P < 0.05) lower in the LEM group than that of pregnant (PREG), EEM and MEM groups. NEFA was significantly higher in animals that experienced LEM (LEM group) at week 7 postpartum (289.6 +/- 47.0 uEq/L; P < 0.01) than that of PREG (196.8 +/- 16.0 uEq/L), EEM (157.2 +/- 18.6 uEq/L) and MEM groups (191.5 +/- 14.4 uEq/L). In conclusion, lower BCS at week 5 postpartum and higher NEFAs at week 7 postpartum may be associated with subsequent LEM in high yielding recipient cows. PMID- 22515688 TI - Transgenic chimera quail production by microinjecting lentiviral vector into the blood vessel of the early embryo. AB - In the past, several strategies have been used to generate transgenic birds. The most successful method has proven to be injection of lentiviral vector into the subgerminal cavity of the newly laid egg. In this study, we directly injected lentiviral vector into the blood vessel of HH13-15 quail embryos to produce transgenic chimeras. In the manipulated, hatched birds, the green fluorescent protein (GFP) gene driven by a cytomegalovirus (CMV) promoter was extensively expressed. All tissues analyzed were GFP-positive, and gonad cells from some of the manipulated embryos expressed GFP. The semen genome of 21.4% of mature male birds was determined to be GFP-positive by PCR, indicating these male birds were transgenic chimeras. PMID- 22515689 TI - Variation in chemical composition of corn dried distillers grains with solubles in relation to in situ protein degradation profiles in the rumen. AB - Chemical composition and in situ degradation profiles were analyzed for 27 samples of dried distillers grains with solubles (DDGS) distributed in Japan, and a wide variation was found in neutral detergent fiber (NDF) content, which had positive relationships to detergent-insoluble crude proteins such as neutral detergent-insoluble crude protein (NDICP) and acid detergent-insoluble CP (ADICP). Samples with lower NDF (< 35% on dry matter (DM)) showed higher soluble fractions of protein, but the degradation rate of microbially degradable protein in the rumen was not different in comparison with the samples with higher NDF, and no difference was shown between samples with higher and lower NDF after 24 and 48 h of in situ incubation for DM and CP degradation, respectively. The NDICP content in the digestion residue decreased with time of incubation, especially for samples with higher NDF, while the ADICP content increased. These results suggest that a part of the soluble fraction of CP in DDGS would be incorporated into NDICP by the heating process in bio-ethanol production, which is still highly degradable, whereas another part of the fraction incorporated into ADICP would proceed to the advanced steps of irreversible amino-carbonyl reaction. PMID- 22515690 TI - Fermentation quality and chemical composition of shrub silage treated with lactic acid bacteria inoculants and cellulase additives. AB - Effects of lactic acid bacteria (LAB) inoculants and cellulase additives on fermentation quality and chemical compositions of shrub silages were studied by using a small-scale fermentation system. Two LAB inoculants of Qingbao (Lactobacillus plantarum, Pediococcus acidilacticii, Lactobacillus casei and Clostridium phage) and Caihe (Lactobacillus plantarum, Lactobacillus brevis and Pediococcus acidilactici) and a commercial cellulase made from Trichoderma reesei were used as additives for intermediate pea-shrub, rush bushclover, arborescent ceratoides and shrubby silage preparation. The crude protein, neutral detergent fiber and water-soluble carbohydrate contents of the four shrub materials were 10.1-14.2, 62.6-67.2 and 1.9-3.5% on a dry matter basis, respectively. All shrub silages had pH 3.40-4.43, ammonia-N 0.1-0.2% g/kg and lactic acid 1.3-2.9% on a fresh matter basis. The silage quality of LAB-inoculated silages did not have a greater effect than control silages, except shrubby silage preparation. Silages treated with the cellulase, the pH of rush bushclover and shrubby sweetvetch silage were significantly (P < 0.05) lower and the lactic acid content were significantly (P < 0.05) higher than the control silages. The results confirmed that shrub contained a relatively high content of crude protein; its silages can be preserved in good quality, and they are new potential resources for livestock feed. PMID- 22515691 TI - Effects of feeding dried distillers grains with solubles (DDGS) on meat quality at the late stage of the fattening period of Holstein steers. AB - Feeding dried distillers grains with solubles (DDGS) during the late stage of the fattening period of Holstein steers was studied in regard to the influence on meat quality. Sixteen Holstein steers approximately 18 months old were used in this study. Eight animals were fed commercial concentrated feed for the entire fattening period. The other eight animals were fed 15% DDGS in the concentrated feed for 3 months before slaughtering. The moisture, ether extract and crude protein from both groups was approximately the same. The thiobarbituric acid reactive substance (TBA) value of storage for 7 days at 5 degrees C from the animals fed DDGS showed a tendency to be lower (P = 0.059). The change in the TBA value during storage was also lower for the animals not fed DDGS (P < 0.05). There were no differences in the subcutaneous fat color between the two groups. The a*(measure of redness) and b*(measure of yellowness) of the M. longissimus from the animals fed DDGS showed a tendency to be lower (P = 0.051, 0.070). The fatty acid composition of the M. longissimus, subcutaneous and perirenal fat were not widely influenced by the feeding of DDGS. It is suggested that feeding 15% DDGS during the late stage of the fattening period for Holstein steers reduced the oxidation of the beef. PMID- 22515692 TI - Identification and characterization of lactic acid bacteria isolated from mixed pasture of timothy and orchardgrass, and its badly preserved silage. AB - In order to understand the relationship between lactic acid bacteria (LAB) species and silage fermentation, a total of 65 LAB strains isolated from mixed pasture of timothy (Phleum pratense L.) and orchardgrass (Dactylis glomerata L.), and its badly preserved silages were subjected to phenotypic and genetic analysis. According to these analyses, the isolates were divided into 13 groups, including Enterococcus gallinarum, Lactobacillus acidipiscis, L. coryniformis subsp. coryniformis, L. coryniformis subsp. torquens, L. curvatus, L. paraplantarum, L. plantarum subsp. argentoratensis, L. plantarum subsp. plantarum, L. sakei subsp. carnosus, Lactococcus garvieae, Lactococcus lactis subsp. cremoris, Leuconostoc pseudomesenteroides, Pediococcus acidilactici, Pediococcus pentosaceus, Weissella hellenica, Weissella paramesenteroides and Carnobacterium divergens. This is the first report to document that C. divergens, L. acidipiscis, L. sakei subsp. carnosus, L. garvieae, phenotypically novel L. lactis subsp. cremoris, E. gallinarum and W. hellenica are present in vegetative forage crops. L. plantarum group strains were most frequently isolated from the badly preserved silages. Some isolates showed a wide range of growth preferences for carbohydrate utilization, optimal growth pH and temperature in vitro, indicating that they have a high growth potential. These results are useful in understanding the diversity of LAB associated with decayed silage of timothy and orchardgrass. PMID- 22515693 TI - Increased expression of NOR-1 mRNA in the skeletal muscles of cold-exposed neonatal chicks. AB - Nuclear receptor subfamily 4, group A (NR4A) subgroup orphan receptors are rapidly induced by various physiological stimuli and have been suggested to regulate oxidative metabolism and muscle mass in mammalian skeletal muscle. The results showed that the NR4A subgroup orphan receptor, NOR-1 (NR4A3), was acutely increased in skeletal muscles of neonatal chicks in response to short-term cold exposure. The increased NOR-1 gene expression was concomitant with cold-induced changes in gene expression of both myostatin and proliferator-activated receptor gamma coactivator-1 (PGC-1alpha), and the increase in skeletal muscle mass. These observations suggest that NOR-1 might play a role in controlling skeletal muscle growth in cold-exposed neonatal chicks. PMID- 22515694 TI - Increased intramuscular fat improves both 'chewiness' and 'hardness' as defined in ISO5492:1992 of beef Longissimus muscle of Holstein * Japanese black F1 steers. AB - It is considered that high-fat beef is more 'tender' than low-fat beef in Japanese consumers. However, 'tenderness' which has been an important beef characteristic, has not been commonly defined. ISO5492:1992 provides internationally established items for sensory texture analysis with simple definitions, and the items classified under 'chewiness' and 'hardness' as defined in the international standard are characterized as useful texture descriptors for beef. The aim of this study was to investigate the effects of intramuscular fat on beef texture using the ISO5492 texture vocabulary. Longissimus muscles were harvested from Holstein * Japanese black F1 beef steers with different intramuscular fat levels and were subjected to sensory tests by a trained panel using ISO5492:1992 texture terms. Correspondence analysis indicated that the intramuscular fat level was related to both 'chewiness' and 'hardness' and the intensities of these characteristics decreased as intramuscular fat increased. These findings suggest that intramuscular fat improves both 'chewiness' and 'hardness' as defined in ISO5492:1992. PMID- 22515695 TI - Changes in the milk composition of okapi (Okapia johnstoni) during the first 6 months of lactation. AB - We collected 17 milk samples at 1 day to 6 months post partum from one captive okapi (Okapia johnstoni). Milks were examined for nutrient composition, including water, fat, crude protein, carbohydrates, ash and five minerals. The average values of the concentrations were 79.2 +/- 3.0% SD water, 8.5 +/- 3.4% fat, 7.5 +/- 1.1% crude protein, 3.6 +/- 0.6% carbohydrate, 1.2 +/- 0.1% ash, 263.7 +/- 47.3 mg/100 g calcium, 183.0 +/- 40.0 mg/100 g phosphorus, 95.2 +/- 17.6 mg/100 g sodium, 74.4 +/- 34.3 mg/100 g potassium and 28.4 +/- 4.4 mg/100 g magnesium, respectively. The protein concentration increased at late lactation (P < 0.01). The contents of sodium and potassium were rather high in the early lactation period, while those of calcium and phosphorus were rather low in the early lactation period. During the course of lactation in the first week post partum and the protein concentration was high at 1 day post partum. We compare our findings with the American Association of Zoos & Aquariums's Okapi Species Survival Plan Hand-rearing Protocol, and recommend that nutrient composition of the formula for okapi calves is developed using the present study as a guide. PMID- 22515696 TI - Effects of moisture content in quail litter on the physical characteristics after pelleting using a Siriwan Model machine. AB - Quail litter (QL), a combination of accumulated quail manures, feathers, spilled feed and bedding materials, is a potential plant fertilizer, ruminant feed ingredient and other value-added applications. In general, utilization of this litter has been limited to within a few kilometers of quail farms, because it has low density. Pelleting is one possible way to enhance storage, transportation and off-site utilization. The purposes of this study were to show the procedures of pelleting and determine the effects of moisture content in fresh QL on the values of physical characteristics. Results obtained showed that bulk and particle densities of QL pellets decreased and increased, respectively, with an increase in moisture content. Porosity, durability, rupture force and decomposition were also affected by moisture content. Pelleting increased the bulk density of QL. Thus, this method more economically transported the litter from the quail farm to distant areas. PMID- 22515698 TI - Pediatric pharmacology in Japan. PMID- 22515697 TI - Cytotoxicity of all-trans-retinal increases upon photodegradation. AB - All-trans-retinal (AtRal) can accumulate in the retina as a result of excessive exposure to light. The purpose of this study was to compare cytotoxicity of AtRal and photodegraded AtRal (dAtRal) on cultured human retinal pigment epithelial cells in dark and upon exposure to visible light. AtRal was degraded by exposure to visible light. Cytotoxicity was monitored by imaging of cell morphology, propidium iodide staining of cells with permeable plasma membrane and measurements of reductive activity of cells. Generation of singlet oxygen photosensitized by AtRal and dAtRal was monitored by time-resolved measurements of characteristic singlet oxygen phosphorescence. Photodegradation of AtRal resulted in a decrease in absorption of visible light and accumulation of the degradation products with absorption maximum at ~330 nm. Toxicity of dAtRal was concentration-dependent and was greater during irradiation with visible light than in dark. DAtRal was more cytotoxic than AtRal both in dark and during exposure to visible light. Photochemical properties of dAtRal indicate that it may be responsible for the maximum in the action spectra of retinal photodamage recorded in animals. In conclusion, photodegradation products of AtRal may impose a significant threat to the retina and therefore their roles in retinal pathology need to be explored. PMID- 22515700 TI - Insulin resistance in the early stages of renal failure: implications for cardiovascular risk. AB - An elevated risk of cardiovascular events is present in patients with mild-to moderate renal function impairment. Similar to patients with end-stage renal disease, this elevated risk can be accounted for by high prevalence of classic and emergent cardiovascular risk factors and additional conditions that are more specifically related to the organ failure, such as anemia and electrolyte disturbances. Among emergent cardiovascular risk factors, insulin resistance has been demonstrated to contribute significantly to the cardiovascular risk in the general population and it is known that abnormalities of glucose metabolism and hyperinsulinemia due to insulin resistance are present in patients with renal failure. Because patients with more advanced disease stage have several abnormalities that might affect the cellular action of insulin acting as important confounders, the relationship between insulin sensitivity and renal function should be better evaluated in the early stages of renal failure. This article overviews the evidence supporting the presence of increased cardiovascular morbidity and mortality in patients with early stages of renal disease, and examines the potential for insulin resistance to contribute to cardiovascular risk in these patients. PMID- 22515701 TI - Anti-vascular endothelial growth factor drug treatment of diabetic macular edema: the evolution continues. AB - Diabetic mellitus is the leading cause of blindness in working aged patients in developing nations. Due to the buildup of abnormal metabolites from several overactive biochemical pathways, chronic hyperglycemia causes oxidative stress in the retina which upregulates vascular endothelial growth factor (VEGF). Together with other growth factors and metabolites, VEGF causes endothelial cell proliferation, vasodilation, recruitment of inflammatory cells, and increased vascular permeability, leading to breakdown of the blood-retinal barrier. This allows trans-cellular exudation into the interstitial space resulting in diabetic macular edema (DME). For over 3 decades the standard treatment for DME has been laser photocoagulation. Though laser reduces the incidence of vision loss by 50%, few eyes with diffuse edema experience improved vision. This has led physicians to use the VEGF-binding drugs pegaptanib, ranibizumab, and aflibercept, each of which has been approved for the treatment of exudative macular degeneration, and bevacizumab which is commonly used off-label for a variety of chorioretinal disorders. Intravitreal administration of each drug frequently causes rapid improvement of DME with sustained improvement in vision through 2 years. Though these drugs significantly outperform laser photocoagulation over treatment periods of 1 year of less, the advantages appear to lessen when trials approach 2 years. Further studies to better determine relative efficacies of anti-VEGF drugs and laser photocoagulation are continuing. PMID- 22515702 TI - Pharmacotherapy in type 2 diabetes: a functional schema for drug classification. AB - With growing awareness that long-term hyperglycemia is directly implicated in the tissue damage characteristic of diabetes, there has been a corresponding increase in clinicians' willingness to employ intensive treatment to achieve euglycemia, which may require diabetes drugs in combination. The expanding array of drugs with different mechanisms of action calls for a clear method of classification to guide rational combination therapy. Contemporary and historical literature was surveyed to document changes in awareness of toxicity from hyperglycemia and consequent changes in treatment strategy. References were selected for clinical applicability and explanation of drug mechanisms of action, with the goal of proposing a useful schema for classification. Diabetes drugs may be classified in the following categories: insulin providers, which increase the supply of insulin through administration of exogenous human insulin or analogues or drugs that stimulate endogenous insulin secretion (sulfonylureas and meglitinides are direct insulin secretagogues, whereas glucagon- like peptide-1 analogues and dipeptidyl peptidase-4 inhibitors act to increase the supply of insulin); insulin sensitizers (metformin, thiazolidinediones), which offset the effects of insulin resistance; and insulin-independent drugs, which work in the gut to impede intestinal absorption of glucose into the circulation (alpha-glucosidase inhibitors) or in the kidney to prevent renal reabsorption of glucose back into the circulation (sodium-glucose cotransporter 2 inhibitors, currently investigational). Awareness of these categories facilitates rational combinations of drugs with differing mechanisms of action to address hyperglycemia from separate directions, in accordance with current treatment guidelines. PMID- 22515703 TI - Management strategies in SSRI-associated sexual dysfunction in women at midlife. AB - The prevalence of major depression disorder in women is double that seen in men, with the menopause transition being associated with increased vulnerability to depression. Selective serotonin reuptake inhibitors (SSRIs), which constitute 70 80% of antidepressant prescriptions, are associated with secondary sexual dysfunction in 35-70% of users. Different strategies for approaching sexual dysfunction secondary to SSRI medication have been investigated. Most interventions fail to show significant benefit on sexual function compared to placebo; moreover, adjuvant therapies commonly result in side-effects and tolerability problems. While antidepressant-associated sexual dysfunction in women has been a concern for many years, there remains a need for more research into the optimal management of antidepressant-associated sexual dysfunction in women, including multidisciplinary approaches. Further randomized, controlled trials assessing multidisciplinary approaches are required before clinicians or patients can be confident of the benefits of any intervention. Despite the efficacy of testosterone in improving sexual function in non-depressed women, there is no information regarding the efficacy of testosterone in treating antidepressant-associated sexual dysfunction in women. PMID- 22515699 TI - Inflammation and clinical presentation in neurodegenerative disease: a volatile relationship. AB - A proposed immune mechanism that potentially modifies or exacerbates neurodegenerative disease presentation in older adults has received considerable attention in the past decade, with recent studies demonstrating a strong link between pro-inflammatory markers and neurodegeneration. The overarching aim of the following review is to synthesize recent research that supports a possible relationship between inflammation and clinical features of neurodegenerative diseases, including risk of development, cognitive and clinical correlates, and progression of the specified diseases. Specific emphasis is placed on providing a temporal context for the association between inflammation and neurodegeneration. PMID- 22515704 TI - Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines. AB - BACKGROUND: TAK733 is a novel allosteric, non-ATP-binding, inhibitor of the BRAF substrates MEK-1/2. METHODS: The growth inhibitory effects of TAK733 were assessed in a panel of 27 cutaneous and five uveal melanoma cell lines genotyped for driver oncogenic mutations. Flow cytometry, Western blots and metabolic tracer uptake assays were used to characterize the changes induced by exposure to TAK733. RESULTS: Fourteen cutaneous melanoma cell lines with different driver mutations were sensitive to the antiproliferative effects of TAK733, with a higher proportion of BRAFV600E mutant cell lines being highly sensitive with IC50s below 1 nM. The five uveal melanoma cell lines had GNAQ or GNA11 mutations and were either moderately or highly sensitive to TAK733. The tested cell lines wild type for NRAS, BRAF, GNAQ and GNA11 driver mutations were moderately to highly resistant to TAK733. TAK733 led to a decrease in pERK and G1 arrest in most of these melanoma cell lines regardless of their origin, driver oncogenic mutations and in vitro sensitivity to TAK733. MEK inhibition resulted in increase in pMEK more prominently in NRASQ61L mutant and GNAQ mutant cell lines than in BRAFV600E mutant cell lines. Uptake of the metabolic tracers FDG and FLT was inhibited by TAK733 in a manner that closely paralleled the in vitro sensitivity assays. CONCLUSIONS: The MEK inhibitor TAK733 has antitumor properties in melanoma cell lines with different oncogenic mutations and these effects could be detectable by differential metabolic tracer uptake. PMID- 22515705 TI - Constant, cycling, hot and cold thermal environments: strong effects on mean viability but not on genetic estimates. AB - It has frequently been suggested that trait heritabilities are environmentally sensitive, and there are genetic trade-offs between tolerating different environments such as hot and cold or constant and fluctuating temperatures. Future climate predictions suggest an increase in both temperatures and their fluctuations. How species will respond to these changes is uncertain, particularly as there is a lack of studies which compare genetic performances in constant vs. fluctuating environments. In this study, we used a nested full sib/half-sib breeding design to examine how the genetic variances and heritabilities of egg-to-adult viability differ at high and low temperatures with and without daily fluctuations in temperatures using Drosophila melanogaster as a model organism. Although egg-to-adult viability was clearly sensitive to developmental temperatures, heritabilities were not particularly sensitive to developmental temperatures. Moreover, we found that egg-to-adult viabilities at different developmental temperatures were positively correlated, suggesting a common genetic background for egg-to-adult viability at different temperatures. Finding both a uniform genetic background coupled with rather low heritabilities insensitive to temperatures, our results suggest evolutionary responses are unlikely to be limited by temperature effects on genetic parameters or negative genetic correlations, but by the direct effects of stressful temperatures on egg to-adult viability accompanied with low heritabilities. PMID- 22515706 TI - Acute haemodynamic response in relation to plasma vardenafil concentrations in patients with pulmonary hypertension. AB - AIMS: To evaluate the acute haemodynamic effects of a single oral dose of vardenafil and to study the drug concentration in relation to haemodynamic effects in patients with pulmonary hypertension (PH). METHODS: Sixteen patients with PH (aged 29-85? years), received one single oral dose of vardenafil (5, 10 or 20 mg). The haemodynamic effect was assessed over a 60 min period. Vardenafil plasma concentrations were measured after 15, 30, 45 and 60 min using liquid chromatography-tandem mass spectrometry. RESULTS: At 60 min a reduction in mPAP with a median % decrease of -20.3% (range -48.3 to 3.0; P < 0.001) and an increase in cardiac output and the cardiac index with a median % change of 10.6% (range -25.0 to 88.1; P = 0.015) and 12.1% (range -24.0 to 94.4; P = 0.01) respectively was observed. The pulmonary vascular resistance (PVR) was reduced with a median % decrease of -28.9% (range -61.5 to -5.9; P < 0.001), and pulmonary selectivity was reflected by a median percent reduction of -16.9% (range -49.0 to 16.5; P = 0.002; n = 14) in the PVR/systemic vascular resistance ratio. There was a correlation between the plasma concentrations of vardenafil and change in mPAP (r = -0.579, P = 0.019) and between vardenafil concentrations and change in PVR (r = -0.662, P = 0.005). CONCLUSIONS: Vardenafil causes rapid changes in cardiopulmonary haemodynamics and there is a correlation between plasma vardenafil drug concentration and the acute changes in mPAP as well as PVR in patients with PH. PMID- 22515711 TI - Who will have the 'guts' to quantify the decline in surgical skills of older surgeons? A commentary on the paper that shows that this occurs in thyroid surgeons. PMID- 22515707 TI - A computational model of in vitro angiogenesis based on extracellular matrix fibre orientation. AB - Recent interest in the process of vascularisation within the biomedical community has motivated numerous new research efforts focusing on the process of angiogenesis. Although the role of chemical factors during angiogenesis has been well documented, the role of mechanical factors, such as the interaction between angiogenic vessels and the extracellular matrix, remains poorly understood. In vitro methods for studying angiogenesis exist; however, measurements available using such techniques often suffer from limited spatial and temporal resolutions. For this reason, computational models have been extensively employed to investigate various aspects of angiogenesis. This paper outlines the formulation and validation of a simple and robust computational model developed to accurately simulate angiogenesis based on length, branching and orientation morphometrics collected from vascularised tissue constructs. Microvessels were represented as a series of connected line segments. The morphology of the vessels was determined by a linear combination of the collagen fibre orientation, the vessel density gradient and a random walk component. Excellent agreement was observed between computational and experimental morphometric data over time. Computational predictions of microvessel orientation within an anisotropic matrix correlated well with experimental data. The accuracy of this modelling approach makes it a valuable platform for investigating the role of mechanical interactions during angiogenesis. PMID- 22515712 TI - Interpretation of CT data in the management of paediatric neck abscess: our experience in 24 patients. PMID- 22515713 TI - The application of modified guidelines for epistaxis management: our experience in 30 patients before and 32 patients after audit. PMID- 22515714 TI - Assessing the role of chronic hyperventilation in patients with nasal congestion: our experience in 118 patients. PMID- 22515715 TI - The down-up bone bridge approach for cochlear and middle ear implants: our experience in 34 patients. PMID- 22515716 TI - RE: The use of ice lollies for pain relief post-paediatric tonsillectomy. PMID- 22515717 TI - Response to Hanna Re: The diagnosis of infectious mononucleosis by Lennon et al. in a previous issue. PMID- 22515718 TI - Re: Endonasal phototherapy for the treatment of allergic rhinitis/hay fever. PMID- 22515719 TI - Advances in consenting: the rule of 3 and its modifications for the surgeon. PMID- 22515720 TI - Re: Wedge resection & modified mattress suture for correcting anterior septal deviation: how we do it. PMID- 22515721 TI - 'Scratch pad' technique for refinement of cartilage grafts in rhinoplasty and ear reconstructive surgery: a technical innovation. PMID- 22515722 TI - Nasal bolster or sling: a technical innovation. PMID- 22515723 TI - Introducing the Sophono Alpha 1 abutment free bone conduction hearing system. PMID- 22515724 TI - Meniere's disease and driving. PMID- 22515725 TI - The influence of the redox state of follicular fluid albumin on the viability of aspirated human oocytes. AB - A number of reports have suggested that the oxidative state of human albumin in serum and in some body fluids is associated with cell damage. However there are no reports on the redox state of human follicular fluid (FF) and its influence on oocyte viability. The aim of this study was to examine the relationship between the redox state of FF and serum on oocyte viability. The cytoplasmic condition of oocytes was evaluated microscopically at collection in 117 women. Deteriorating oocytes were recognized by degenerative changes in their cytoplasm. The redox state of FFs that yielded degenerated oocytes was evaluated and compared with fluids containing normal oocytes. The redox state of the corresponding FF and serum, at the time of oocyte retrieval, was analyzed by high performance liquid chromatography. The redox state of FF that contained degenerated oocytes was found to have a significantly elevated oxidized state compared with the FFs that yielded normal oocytes. Also the albumin in the FF of patients was found to be predominantly in the reduced state compared with that in their serum at the time of oocyte retrieval. In addition, increasing age and endometriosis were found to shift the redox of serum to the oxidative state. We propose that the reduced state of albumin in FF may play an important role in protecting oocytes from oxidative damage. PMID- 22515727 TI - Abstracts of the RACP (Royal Australasian College of Physicians) Future Directions in Health Congress 2012. May 6-9, 2012. Brisbane, Queensland, Australia. PMID- 22515726 TI - Influence of helium-neon laser irradiation on seed germination in vitro and physico-biochemical characters in seedlings of brinjal (Solanum melongena L.) var. Mattu Gulla. AB - In the present study, the seeds of brinjal (Solanum melongena L.) var. Mattu Gulla were irradiated with single exposure of He-Ne laser at different doses of 5 40 J cm(-2) and germinated aseptically. Thirty day old seedlings were harvested and the germination, growth, physiological and biochemical parameters were estimated and compared with un-irradiated control seedlings. A significant enhancement in growth characters were noted with respect to length, fresh and dry weight of shoots and roots. In addition, chlorophyll (a and b), carotenoid content, anthocyanin and amylases (alpha and beta) activities were found to be altered. Significant alterations in percentage of seed germination (P < 0.001) and time to 50% germination (P < 0.001) were observed in the irradiated seeds compared with the un-irradiated controls. In conclusion, the results of the present study demonstrated that low dose (5-30 J cm(-2) ) of He-Ne laser irradiation enhanced the germination process and altered growth, by positively influencing physiological and biochemical parameters of the brinjal seedlings compared with un-irradiated control under in vitro conditions. PMID- 22515728 TI - Assessing therapeutic effectiveness of scalp treatments for dandruff and seborrheic dermatitis, part 1: a reliable and relevant method based on the adherent scalp flaking score (ASFS). AB - BACKGROUND: Dandruff and seborrheic dermatitis (D/SD) are common and troublesome scalp conditions with the primary signs and symptoms being presence of skin flakes, pruritus, a tight feeling, and sometimes erythema. AIM: To demonstrate the reliability and relevance of a clinical model for the assessment of therapeutic efficacy of a treatment using the Adherent Scalp Flaking Score (ASFS) method to quantitate the flaking severity. METHODS: Six randomized, double-blind, parallel design studies were conducted in either North America or Asia with subjects suffering from dandruff using the ASFS grading method before and after a 3-week test product treatment period. RESULTS: Treatment with a commercial potentiated 1% zinc pyrithione (ZPT) shampoo resulted in statistically significant (p < 0.0001) improvements in total ASFS compared with the placebo cosmetic shampoo. Results were consistent across all studies, geographies, and product usage protocols (controlled on-site versus home use conditions), and were associated with statistically significant improvements in self-perception of scalp condition. CONCLUSION: The ASFS-based clinical model was demonstrated to be a reliable and proven methodology to assess the effectiveness of widely used anti dandruff treatments. The results are consistent with patient self-assessments, establishing this methodology as relevant to patient perception of product benefits. PMID- 22515729 TI - The clinical utility of chromosomal microarray in childhood neurological disorders. PMID- 22515730 TI - Aging of theory of mind: the influence of educational level and cognitive processing. AB - Previous studies of theory of mind (ToM) in old age have provided mixed results. We predicted that educational level and cognitive processing are two factors influencing the pattern of the aging of ToM. To test this hypothesis, a younger group who received higher education (mean age 20.46 years), an older group with an education level equal to that of the young group (mean age 76.29 years), and an older group with less education (mean age 73.52 years) were recruited. ToM tasks included the following tests: the second-order false-belief task, the faux pas task, the eyes test, and tests of fundamental aspects of cognitive function that included two background tests (memory span and processing speed) and three subcomponents of executive function (inhibition, updating, and shifting). We found that the younger group and the older group with equally high education outperformed the older group with less education in false-belief and faux-pas tasks. However, there was no significant difference between the two former groups. The three groups of participants performed equivalently in the eyes test as well as in control tasks (false-belief control question, faux-pas control question, faux-pas control story, and Eyes Test control task). The younger group outperformed the other two groups in the cognitive processing tasks. Mediation analyses showed that difficulties in inhibition, memory span, and processing speed mediated the age differences in false-belief reasoning. Also, the variables of inhibition, updating, memory span, and processing speed mediated age-related variance in faux-pas. Discussion focused on the links between ToM aging, educational level, and cognitive processing. Supported by Chinese National Natural Science Foundation (number: 30870766) and Anhui Province Natural Science Foundation (number: 11040606M166). PMID- 22515731 TI - A case of apathy due to frontotemporal dementia responsive to memantine. AB - OBJECTIVE: To study the effect of memantine on apathy, a common symptom of behavioral variant frontotemporal dementia (bvFTD). DESIGN: The patient underwent an off-label trial of memantine with behavioral inventories and [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) scans performed at baseline, 7 weeks and 6 months. SUBJECT: The patient was a 66-year-old male whose main manifestation of bvFTD was affective, behavioral and cognitive apathy. INTERVENTION: The patient began memantine at an oral dose of 5 mg per morning and titrated up by 5 mg per week to the maintenance dose of 10 mg PO bid. RESULTS: Informants reported reduction of the apathy. The insula and cerebellum, both involved in the salience network, showed improved metabolism. CONCLUSION: Further study to correlate the effects of memantine on apathy and the salience network in bvFTD are warranted. PMID- 22515732 TI - Efficacy of preventing hemodialysis catheter infections with citrate lock. AB - Prevalent use of tunneled dialysis catheters can reach 30%. Infection remains the most serious catheter-related problem. Catheter locks are increasingly used for prevention, but are not yet recommended either by the Food and Drug Association or European Medicines Agency, on the basis of increasing bacterial resistance or lock toxicity. The aim was to test safety and effectiveness of citrate. A prospective, interventional study was conducted to assess the safety and efficacy of a 30% citrate lock in preventing catheter-related bacteremia (CRB). A total of 157 prevalent tunneled catheters were locked with citrate and prospectively followed during a 1-year period. The primary endpoint was first CRB diagnosed according to two of the diagnostic criteria for Catheter Infection of Centers for Disease Control and Prevention (CDC), namely definite and probable infection. The CDC criterion of possible but not proved infection was not considered. This citrate lock cohort (n = 157) had 10 episodes of CRB. We observed 0.49 CRB episodes/1000 patient-days and the mean infection-free catheter day was 130.6 +/- 100.9. No clinically relevant adverse events were observed. No proved tunnel or exit site infection was observed and no patients died because of CRB. Catheter obstruction episodes were reported on 69 occasions out of 14 catheters. These results were compared with an historical cohort from a previous study of catheter locking with low-dose gentamicin and did not show significant difference in efficacy. Citrate lock is effective in preventing CRB. No toxicity was observed. The use of citrate lock may have advantages over antibiotic locks: no reported bacterial resistance, lower industrial cost, and less manipulation. PMID- 22515734 TI - NMR, HPLC-ESI-MS, and MALDI-TOF MS analysis of condensed tannins from Delonix regia (Bojer ex Hook.) Raf. and their bioactivities. AB - The structures of the condensed tannins isolated from leaf, fruit, and stem bark of Delonix regia (Bojer ex Hook.) Raf. have been investigated with (13)C nuclear magnetic resonance ((13)C NMR) and high performance liquid chromatography electrospray ionization mass spectrometry (HPLC-ESI-MS) coupled with thiolysis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analyses. The results showed that these condensed tannins from D. regia possessed structural heterogeneity in monomer units and degree of polymerization. Propelargonidin (PP) and procyanidin (PC) were found in the leaf, fruit, and stem bark of D. regia, while prodelphinidin (PD) was found only in the leaves. The polymer chain lengths of condensed tannins from leaf and fruit organs were detected to be trimers to hexadecamers but from trimers to tridecamers for stem bark. B-type linkages were present in all these compounds. Condensed tannins from different parts of D. regia can be explored as tyrosinase inhibitors and food antioxidants because of their potent antityrosinase and antioxidant activities. The inhibitor concentration leading to 50% enzyme activity (IC(50)) was estimated to be 38 +/- 1, 73 +/- 2, and 54 +/- 1.5 MUg/mL for the condensed tannins of leaf, fruit, and stem bark. Condensed tannins extracted from stem bark exhibited the highest antioxidant activity; the DPPH scavenging activity (IC(50)) and the FRAP values were 90 +/- 2 MUg/mL and 5.42 +/- 0.09 mmol AAE/g, respectively. PMID- 22515735 TI - The quorum-sensing protein TraR of Agrobacterium tumefaciens is susceptible to intrinsic and TraM-mediated proteolytic instability. AB - TraR of Agrobacterium tumefaciens is a LuxR-type transcription factor that regulates genes required for replication and conjugation of the tumour-inducing plasmid. TraR binds the pheromone 3-oxo-octanoylhomoserine lactone (OOHL) and requires this molecule for folding into a protease-resistant, soluble conformation. Even after binding to OOHL, TraR is degraded at readily detectable rates. Here we show that the N-terminal domain of TraR, which binds OOHL, is more resistant to degradation than the full length protein, suggesting that sites on the C-terminal DNA binding domain [TraR(170-234)] enhance protein turnover. A fusion between GFP and TraR(170-234) was poorly fluorescent, and truncations of this fusion protein allowed us to identify residues in this domain that contribute to protein degradation. TraR activity was previously shown to be inhibited by the antiactivator TraM. These proteins form 2:2 complexes that fail to bind DNA sequences. Here we show that TraM sharply decreased the accumulation of TraR in whole cells, indicating that TraM facilitates proteolysis of TraR. The TraM component of these complexes is spared from proteolysis, and could therefore act catalytically. PMID- 22515733 TI - Conformational change in rhomboid protease GlpG induced by inhibitor binding to its S' subsites. AB - Rhomboid protease conducts proteolysis inside the hydrophobic environment of the membrane. The conformational flexibility of the protease is essential for the enzyme mechanism, but the nature of this flexibility is not completely understood. Here we describe the crystal structure of rhomboid protease GlpG in complex with a phosphonofluoridate inhibitor, which is covalently bonded to the catalytic serine and extends into the S' side of the substrate binding cleft. Inhibitor binding causes subtle but extensive changes in the membrane protease. Many transmembrane helices tilt and shift positions, and the gap between S2 and S5 is slightly widened so that the inhibitor can bind between them. The side chain of Phe-245 from a loop (L5) that acts as a cap rotates and uncovers the opening of the substrate binding cleft to the lipid bilayer. A concurrent turn of the polypeptide backbone at Phe-245 moves the rest of the cap and exposes the catalytic serine to the aqueous solution. This study, together with earlier crystallographic investigation of smaller inhibitors, suggests a simple model for explaining substrate binding to rhomboid protease. PMID- 22515737 TI - Atom probe tomography of a-axis GaN nanowires: analysis of nonstoichiometric evaporation behavior. AB - GaN nanowires oriented along the nonpolar a-axis were analyzed using pulsed laser atom probe tomography (APT). Stoichiometric mass spectra were achieved by optimizing the temperature, applied dc voltage, and laser pulse energy. Local variations in the measured stoichiometry were observed and correlated with facet polarity using scanning electron microscopy. Fewer N atoms were detected from nonpolar and Ga-polar surfaces due to uncorrelated evaporation of N(2) ions following N adatom diffusion. The observed differences in Ga and N ion evaporation behaviors are considered in detail to understand the influence of intrinsic materials characteristics on the reliability of atom probe tomography analysis. We find that while reliable analysis of III-N alloys is possible, the standard APT procedure of empirically adjusting analysis conditions to obtain stoichiometric detection of Ga and N is not necessarily the best approach for this materials system. PMID- 22515739 TI - Editorial: neurodegeneration with brain iron accumulation. PMID- 22515736 TI - Trust, confidentiality, and the acceptability of sharing HIV-related patient data: lessons learned from a mixed methods study about Health Information Exchanges. AB - BACKGROUND: Concerns about the confidentiality of personal health information have been identified as a potential obstacle to implementation of Health Information Exchanges (HIEs). Considering the stigma and confidentiality issues historically associated with human immunodeficiency virus (HIV) disease, we examine how trust-in technology, processes, and people-influenced the acceptability of data sharing among stakeholders prior to implementation of six HIEs intended to improve HIV care in parts of the United States. Our analyses identify the kinds of concerns expressed by stakeholders about electronic data sharing and focus on the factors that ultimately facilitated acceptability of the new exchanges. METHODS: We conducted 549 surveys with patients and 66 semi structured interviews with providers and other stakeholders prior to implementation of the HIEs to assess concerns about confidentiality in the electronic sharing of patient data. The patient quantitative data were analyzed using SAS 9.2 to yield sample descriptive statistics. The analysis of the qualitative interviews with providers and other stakeholders followed an open coding process, and convergent and divergent perspectives emerging from those data were examined within and across the HIEs. RESULTS: We found widespread acceptability for electronic sharing of HIV-related patient data through HIEs. This acceptability appeared to be driven by growing comfort with information technologies, confidence in the security protocols utilized to protect data, trust in the providers and institutions who use the technologies, belief in the benefits to the patients, and awareness that electronic exchange represents an enhancement of data sharing already taking place by other means. HIE acceptability depended both on preexisting trust among patients, providers, and institutions and on building consensus and trust in the HIEs as part of preparation for implementation. The process of HIE development also resulted in forging shared vision among institutions. CONCLUSIONS: Patients and providers are willing to accept the electronic sharing of HIV patient data to improve care for a disease historically seen as highly stigmatized. Acceptability depends on the effort expended to understand and address potential concerns related to data sharing and confidentiality, and on the trust established among stakeholders in terms of the nature of the systems and how they will be used. PMID- 22515738 TI - Ruthenium-catalyzed transfer oxygenative cyclization of alpha,omega-diynes: unprecedented [2 + 2 + 1] route to bicyclic furans via ruthenacyclopentatriene. AB - A novel oxygen-atom-transfer process enables the catalytic [2 + 2 + 1] synthesis of bicyclic furans from alpha,omega-diynes with DMSO. [CpRu(AN)(3)]PF(6) catalyzed the transfer oxygenative cyclization of diynes with aryl terminal groups, while those of diynes with alkyl terminal groups were effectively promoted by the corresponding Cp* complex. A mechanism for bicyclic furan formation via a ruthenacyclopentatriene was proposed on the basis of both experimental and theoretical studies. PMID- 22515740 TI - Aceruloplasminemia. AB - Ceruloplasmin contains 95% of the copper in human serum and plays an important role in iron efflux from mammalian cells, including brain cells, due to the activity of ferroxidase, which oxidizes ferrous iron following its transfer to the cell surface via the iron transporter, ferroportin, and delivers ferric iron to extracellular transferrin. In the central nervous system, a glycosylphosphatidylinositol (GPI)-anchored ceruloplasmin bound to the cell membranes of astrocytes was found to be the major isoform of this protein. Inherited loss of the protein causes aceruloplasminemia, which is an autosomal recessive disorder characterized by progressive neurodegeneration of the retina and basal ganglia associated with specific inherited mutations in the ceruloplasmin gene. Aceruloplasminemia is classified as an inherited neurodegenerative disorder called "neurodegeneration with brain iron accumulation" (NBIA) due to genetic defects associated with iron metabolism. Clinical and pathologic studies in patients with aceruloplasminemia and ceruloplasmin knockout mice revealed increased lipid peroxidation due to iron mediated cellular radical injury which is caused by a marked accumulation of iron in the affected parenchymal tissues such as the retina, liver, pancreas and brain. In the following review of aceruloplasminemia, the ceruloplasmin gene expression, structure and function will be presented, and the role of ceruloplasmin in iron metabolism will be discussed. The pathogenesis of aceruloplasminemia provides valuable insights into the mechanisms regulating iron homeostasis and also identified models that can be used to further dissect the role of this metal in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, in which iron is accumulated. PMID- 22515741 TI - Pantothenate kinase-associated neurodegeneration. AB - Pantothenate kinase-associated neurodegeneration (PKAN) is a hereditary progressive disorder and the most frequent form of neurodegeneration with brain iron accumulation (NBIA). PKAN patients present with a progressive movement disorder, dysarthria, cognitive impairment and retinitis pigmentosa. In magnetic resonance imaging, PKAN patients exhibit the pathognonomic "eye of the tiger" sign in the globus pallidus which corresponds to iron accumulation and gliosis as shown in neuropathological examinations. The discovery of the disease causing mutations in PANK2 has linked the disorder to coenzyme A (CoA) metabolism. PANK2 is the only one out of four PANK genes encoding an isoform which localizes to mitochondria. At least two other NBIA genes (PLA2G6, C19orf12) encode proteins that share with PANK2 a mitochondrial localization and all are suggested to play a role in lipid homeostasis. With no causal therapy available for PKAN until now, only symptomatic treatment is possible. A multi-centre retrospective study with bilateral pallidal deep brain stimulation in patients with NBIA revealed a significant improvement of dystonia. Recently, studies in the PANK Drosophila model "fumble" revealed improvement by the compound pantethine which is hypothesized to feed an alternate CoA biosynthesis pathway. In addition, pilot studies with the iron chelator deferiprone that crosses the blood brain barrier showed a good safety profile and some indication of efficacy. An adequately powered randomized clinical trial will start in 2012. This review summarizes clinical presentation, neuropathology and pathogenesis of PKAN. PMID- 22515742 TI - Neuroferritinopathy: update on clinical features and pathogenesis. AB - Neuroferritinopathy is an autosomal dominant extra - pyramidal movement disorder caused by mutations in the ferritin light chain gene (FTL). The most frequent presentation is with chorea (50%), followed by dystonia (42.5 %) and parkinsonism (7.5%). Seven different mutations are known; 6 insertions in exon 4 and a missense mutation in exon 3 with the 460insA mutation in exon 4 being the most common. Brain magnetic resonance imaging demonstrates iron deposition in the basal ganglia and cavitation. Neuropathological studies have shown neuronal loss in the cerebral cortex, cerebellum and basal ganglia. Ferritin inclusion bodies were demonstrated within neurons and glia. Studies of patient derived fibroblasts and HeLa cells expressing mutant ferritin demonstrate increased iron levels and oxidative stress. These abnormalities have been recapitulated in mouse models of neuroferritinopathy. There is no disease modifying treatement for neuroferritinopathy but benzodiazepines and botulinum toxin may palliate dystonia and tetrabenazine may relieve chorea and facial tics. There is no role for iron chelation. PMID- 22515743 TI - PLA2G6 mutations and other rare causes of neurodegeneration with brain iron accumulation. AB - There is a wide variety of genetic and sporadic causes for neurodegenerative disorders with apparent brain iron accumulation on magnetic resonance imaging. Rare recessive causes include PLA2G6 mutations (infantile neuroaxonal dystrophy), and mutations of ATP13A2 (Kufor Rakeb syndrome) and FA2H. A variety of sporadic neurological disorders can present brain iron accumulation on imaging, including multiple sclerosis and neurological manifestations of HIV infection. The relevant clinical and imaging features will be discussed. PMID- 22515744 TI - The effect of calcification on the structural mechanics of the costal cartilage. AB - The costal cartilage often undergoes progressive calcification with age. This study sought to investigate the effects of calcification on the structural mechanics of whole costal cartilage segments. Models were developed for five costal cartilage specimens, including representations of the cartilage, the perichondrium, calcification, and segments of the rib and sternum. The material properties of the cartilage were determined through indentation testing; the properties of the perichondrium were determined through optimisation against structural experiments. The calcified regions were then expanded or shrunk to develop five different sensitivity analysis models for each. Increasing the relative volume of calcification from 0% to 24% of the cartilage volume increased the stiffness of the costal cartilage segments by a factor of 2.3-3.8. These results suggest that calcification may have a substantial effect on the stiffness of the costal cartilage which should be considered when modelling the chest, especially if age is a factor. PMID- 22515745 TI - Maternal and infant characteristics by mode of vitamin K prophylaxis administration. AB - AIM: The aim of this study was to compare maternal and infant characteristics by mode of VK administration. METHODS: De-identified computerised birth files of all babies born in New South Wales (NSW), Australia between January 2007 and December 2009 (when VK prophylaxis was measured) were included in the present study. The outcome variable, mode of VK prophylaxis, was recorded by checkbox as oral, IM injection, none or not stated. RESULTS: We analysed population-based birth data from 2007 to 2009 in NSW, Australia and found that IM injection was the most prevalent mode of administration (96.3%, n = 263, 555), followed by oral (2.6%, n = 7023) and none (1.2%, n = 3136). Compared to neonates receiving IM VK, those with oral or none were more likely to have vaginal births without medical interventions at birth centres or planned home births and were less likely to receive hepatitis B vaccination. Among neonates administered oral VK, a larger proportion were preterm births and breastfed at discharge compared to neonates administered VK as an IM injection. Neonates with no VK recorded were more likely to be admitted to neonatal intensive care, but may have received VK later in the birth admission. CONCLUSIONS: A small proportion of the Australian neonates may be at risk of inadequate protection from VKBD due to parental concerns about the safety of IM injection of VK to neonates. PMID- 22515746 TI - Detection of influenza A virus in live bird markets in Kenya, 2009-2011. AB - BACKGROUND: Surveillance for influenza viruses within live bird markets (LBMs) has been recognized as an effective tool for detecting circulating avian influenza viruses (AIVs). In Sub-Saharan Africa, limited data exist on AIVs in animal hosts, and in Kenya the presence of influenza virus in animal hosts has not been described. OBJECTIVES: This surveillance project aimed to detect influenza A virus in poultry traded in five LBMs in Kenya. METHODS: We visited each market monthly and collected oropharyngeal and cloacal specimens from poultry and environmental specimens for virological testing for influenza A by real time RT-PCR. On each visit, we collected information on the number and types of birds in each market, health status of the birds, and market practices. RESULTS: During March 24, 2009-February 28, 2011, we collected 5221 cloacal and oropharyngeal swabs. Of the 5199 (99.6%) specimens tested, influenza A virus was detected in 42 (0.8%), including 35/4166 (0.8%) specimens from chickens, 3/381 (0.8%) from turkeys, and 4/335 (1.2%) from geese. None of the 317 duck specimens were positive. Influenza was more commonly detected in oropharyngeal [33 (1.3%)] than in cloacal [9 (0.4%)] specimens. None of the 485 environmental specimens were positive. Virus was detected in all five markets during most (14/22) of the months. Ducks and geese were kept longer at the market (median 30 days) than chickens (median 2days). CONCLUSIONS: Influenza A was detected in a small percentage of poultry traded in LBMs in Kenya. Efforts should be made to promote practices that could limit the maintenance and transmission of AIVs in LBMs. PMID- 22515747 TI - French-language version of the World Health Organization quality of life spirituality, religiousness and personal beliefs instrument. AB - BACKGROUND: A valid assessment of spirituality and religiousness is necessary for clinical and research purposes. We developed and assessed the validity of a French-language version of the World Health Organization Quality of Life Spirituality, Religiousness and Personal Beliefs Instrument (WHOQOL-SRPB). METHODS: The SRPB was translated into French according to the methods recommended by the WHOQOL group. An Internet survey was conducted in 561 people in 2010, with follow-up 2 weeks later (n = 231, 41%), to assess reliability, factor structure, social desirability bias and construct validity of this scale. Tests were performed based on item-response theory. RESULTS: A modal score of 1 (all answers="not at all") was observed for Faith (in 34% of participants), Connectedness (27%), and Spiritual Strength (14%). All scales had test-retest reliability coefficients >=0.7. Cronbach's alpha coefficients were high for all subscales (0.74 to 0.98) and very high (>0.9) for three subscales (Connectedness, Spiritual Strength and Faith). Scores of Faith, Connectedness, Spiritual Strength and Meaning of Life were higher for respondents with religious practice than for those who had no religious practice. No association was found between SRPB and age or sex. The Awe subscale had a low information function for all levels of the Awe latent trait and may benefit from inclusion of an additional item. CONCLUSIONS: The French language version of the SRPB retained many properties of the original version. However, the SRPB could be improved by trimming redundant items. The strength of SRPB relies on its multinational development and validation, allowing for cross-cultural comparisons. PMID- 22515749 TI - 'Jump out of your comfort zone and into the learning zone': the challenge point framework and its application to medical education. PMID- 22515750 TI - Challenging the challenge point framework. PMID- 22515751 TI - Understanding clinical reasoning: the next step in working out how it really works. PMID- 22515752 TI - The application of the challenge point framework in medical education. AB - OBJECTIVES: The current paper describes a model of learning that has been used to produce efficient learning, thus yielding greater retention of information and superior performance under stress. In this paper, the model is applied to the learning of technical skills. STRUCTURE: After a brief review of the learning performance paradox and other relevant literature from the field of movement science, the benefits of challenge and adversity for learning are discussed in the context of a framework for learning known as the challenge point framework (CPF). The framework is based on laboratory and field studies of methods that have been shown to consistently enhance learning, and is used to model and generate insight into the relationships between practice protocols and the learning that results from them. APPLICATION: The practical application of the CPF to simulation-based medical education and training is described. Firstly, a simple conceptual model that utilises three key elements to adjust the functional difficulty of the tasks to be learned is outlined. Secondly, a number of assessment strategies that may be necessary to ensure that the trainee remains in the optimal learning zone are proposed. Thirdly, a practical example is used to demonstrate how to utilise this conceptual model to design simulation environments suitable for teaching an endotracheal intubation task to beginners and more advanced trainees. PMID- 22515753 TI - Clinical reasoning processes: unravelling complexity through graphical representation. AB - CONTEXT: Clinical reasoning is a core skill in medical practice, but remains notoriously difficult for students to grasp and teachers to nurture. To date, an accepted model that adequately captures the complexity of clinical reasoning processes does not exist. Knowledge-modelling software such as mot Plus (Modelling using Typified Objects [MOT]) may be exploited to generate models capable of unravelling some of this complexity. OBJECTIVES: This study was designed to create a comprehensive generic model of clinical reasoning processes that is intended for use by teachers and learners, and to provide data on the validity of the model. METHODS: Using a participatory action research method and the established modelling software (mot Plus), knowledge was extracted and entered into the model by a cognitician in a series of encounters with a group of experienced clinicians over more than 250 contact hours. The model was then refined through an iterative validation process involving the same group of doctors, after which other groups of clinicians were asked to solve a clinical problem involving simulated patients. RESULTS: A hierarchical model depicting the multifaceted processes of clinical reasoning was produced. Validation rounds suggested generalisability across disciplines and situations. CONCLUSIONS: The MOT model of clinical reasoning processes has potentially important applications for use within undergraduate and graduate medical curricula to inform teaching, learning and assessment. Specifically, it could be used to support curricular development because it can help to identify opportune moments for learning specific elements of clinical reasoning. It could also be used to precisely identify and remediate reasoning errors in students, residents and practising doctors with persistent difficulties in clinical reasoning. PMID- 22515754 TI - Reflection as a strategy to foster medical students' acquisition of diagnostic competence. AB - OBJECTIVES: Developing diagnostic competence in students is a major goal of medical education, but there is little empirical evidence on instructional strategies that foster the acquisition of this competence. The aim of this study was to investigate the effects of structured reflection compared with the generation of immediate or differential diagnosis while practising with clinical cases on learning clinical diagnosis. METHODS: This was a three-phase experimental study. During a learning phase, 46 Year 4 students diagnosed six clinical cases under different experimental conditions: structured reflection, immediate diagnosis, or differential diagnosis. This was followed by an immediate test and a delayed test administered 1 week later. Each test consisted of diagnosing four different cases of diseases presented in the learning phase. Performance in diagnosing these new cases was used as a measure of learning. RESULTS: Repeated-measures analysis of variance on the mean diagnostic accuracy scores (range: 0-1) showed a significant interaction between performance moment (i.e. performance in the learning phase and on each test) and instructions followed during the learning phase (p=0.003). Follow-up analyses of this interaction showed that diagnostic performance did not differ between conditions in the learning phase. On the immediate test, scores in the reflection condition (mean=0.48, 95% confidence interval [CI] 0.38-0.58) were significantly lower than scores in the differential diagnosis condition (mean=0.62, 95% CI 0.54-0.70; p=0.012) and marginally lower than those in the immediate diagnosis condition (mean=0.61, 95% CI 0.52-0.70; p=0.04). One week later, however, scores in the reflection condition (mean=0.66, 95% CI 0.56-0.76) significantly outperformed those in the other conditions (differential diagnosis: mean=0.48, 95% CI 0.37 0.58 [p<0.01]; immediate diagnosis: mean=0.52, 95% CI 0.43-0.60 [p=0.01]). Comparisons within experimental conditions showed that performance from the immediate to the delayed test decreased in the immediate and differential diagnosis conditions (immediate diagnosis: p=0.042; differential diagnosis: p=0.012), but increased in the reflection condition (p=0.003). CONCLUSIONS: Structured reflection while practising with cases appears to foster the learning of clinical knowledge more effectively than the generation of immediate or differential diagnoses and therefore seems to be an effective instructional approach to developing diagnostic competence in students. PMID- 22515755 TI - Associations between medical school and career preferences in Year 1 medical students in Scotland. AB - OBJECTIVES: Little is known about the relationship between the career preferences of medical students and the medical schools at which they are enrolled. Our aim was to explore this relationship early in students' medical training. METHODS: Year 1 (2009-2010) medical students at the five Scottish medical schools were invited to take part in a career preference questionnaire survey. Questions were asked about demographic factors, career preferences and influencing factors. RESULTS: The response rate was 87.9% (883/1005). No significant differences were found among medical schools with regard to first-choice specialty. Surgery (22.5%), medicine (19.0%), general practice (17.6%) and paediatrics (16.1%) were the top career choices. Work-life balance, perceived aptitude and skills, intellectual satisfaction, and amount of patient contact were rated as the most important job-related factors by most respondents. Few differences were found among schools in terms of the impact of job-related factors on future career preferences. Students for whom the work-life balance was extremely important (odds ratio [OR]=0.6) were less likely to prefer surgery. Students for whom the work-life balance (OR=2.2) and continuity of care (OR=2.1) were extremely important were more likely to prefer general practice. CONCLUSIONS: Students' early career preferences were similar across the five medical schools. These preferences result from the interplay among demographic factors and the perceived characteristics of the various specialties. Maintaining a satisfactory work-life balance is very important to tomorrow's doctors, and the data hint that this may be breaking down some of the traditional gender differences in specialty choice. Longitudinal work is required to explore whether students' career preferences change as they progress through medical school and training. PMID- 22515756 TI - Faking good: self-enhancement in medical school applicants. AB - OBJECTIVES: The problem of dissimulation by applicants when self-report tests of personality are used for job selection has received considerable attention in non medical contexts. Personality testing is not yet widely used in medical student selection, but this may change in the light of recent research demonstrating significant relationships between personality and performance in medical school. This study therefore aimed to assess the extent of self-enhancement in a sample of medical school applicants. METHODS: A within-subjects design compared personality test scores collected in 2007 for 83 newly enrolled medical students with scores for the same students obtained on the same personality test administered during the selection process 4 months previously. Five factors of personality were measured using the International Personality Item Pool and mean differences in scores were assessed using paired t-tests. RESULTS: At the time of selection, the personality scores of successful applicants were similar to those of candidates who were not accepted (n=271). Once selected, the medical students achieved significantly lower scores on four of the five personality factors (conscientiousness, extroversion, openness to experience, agreeableness) and higher scores on the fifth factor (neuroticism). Of the selected students, 62.7% appeared to have 'faked good' on at least one of the five factors measured. CONCLUSIONS: Applicants to medical school are likely to dissimulate when completing self-report tests of personality used for selection. The authors review the evidence as to whether such dissimulation reduces construct and predictive validity and summarise methods used to reduce self-enhancement in applicant samples. PMID- 22515757 TI - Residency selection: do the perceptions of US programme directors and applicants match? AB - OBJECTIVES: This study sought to evaluate the practices and perceptions of US residency programme directors (PDs) and residency applicants with reference to the use of social media and Internet resources in the resident doctor selection process. METHODS: A survey was distributed via e-mail (SurveyMonkey(r)) to 2592 PDs of programmes in 22 specialties accredited by the Accreditation Council for Graduate Medical Education. A separate survey was distributed to all residency candidates applying for postgraduate year 1 (PGY1) positions at the Saint Barnabas Medical Center, Livingston, New Jersey. RESULTS: A total of 1200 (46.3%) PDs completed the survey. Overall, 16.3% (n=196) of respondents reported visiting Internet resources to gain more information about applicants, 38.1% (74 of 194) of whom had ranked an applicant lower as a result. American medical graduates (AMGs), US international medical graduates (USIMGs) and non-USIMGs all felt that performance on Step 1 of the US Medical Licensing Examination (USMLE) was a critical aspect of a residency application. More AMGs than USIMGs and non-USIMGs believed that PDs made use of social media resources when evaluating applicants and that their online profiles might influence their rankings. CONCLUSIONS: Residency candidates universally understand the importance of USMLE Step 1 scores in maintaining a competitive application. However, significant differences exist among AMGs, USIMGs and non-USIMGs in their perceptions of the value of other applicant criteria, which may place some applicants at a disadvantage. A small but growing number of PDs currently use Internet resources to learn more about applicants and base their recruitment decisions in part on the information they encounter. At present, applicants are generally unaware of the implications their online activity may have on their selection for residency. Content guideline programmes that raise awareness of the possible impact of social media on the residency recruitment process are needed and should be delivered early in medical education. PMID- 22515758 TI - A peer-reviewed collection of reports on innovative approaches to medical education. PMID- 22515759 TI - Using Google Docs to enhance medical student reflection. PMID- 22515760 TI - Critical reflection: lessons learned from a communication skills assessment. PMID- 22515761 TI - Using hospital art in medical student reflection. PMID- 22515762 TI - Students accompany acute hospital admissions from primary care. PMID- 22515763 TI - 'The Game': student 'teaching' objective structured clinical examinations in South Africa. PMID- 22515764 TI - Web-based blog supplement to evidence-based physical examination teaching. PMID- 22515765 TI - Communication gaps in a teaching paediatric out-patient scenario. PMID- 22515766 TI - 'Care Factor': engaging medical students with their well-being. PMID- 22515767 TI - A novel student-selected component in medical admissions. PMID- 22515768 TI - Empowering students to become involved in medical education. PMID- 22515769 TI - Medical students teach basic life support in hospital. PMID- 22515770 TI - Framework for feedback: the peer mini-clinical examination as a formative assessment tool. PMID- 22515771 TI - Course evaluation respondents: are 'low-performing retaliators' really over represented? PMID- 22515772 TI - Da Vinci's notebook: a novel learning tool. PMID- 22515773 TI - Oriented paediatric resuscitation: a new training approach. PMID- 22515774 TI - Providing support to preceptors with resident doctors in difficulty. PMID- 22515775 TI - E-learning strategies to improve general practitioners' knowledge of age-related macular degeneration. PMID- 22515776 TI - Themed monthly evaluations: a focus on individual competencies. PMID- 22515777 TI - The ambulatory morbidity and mortality conference meets the morning report. PMID- 22515778 TI - Evaluation of electronic versus traditional format poster presentations. PMID- 22515779 TI - A Parisian-style salon addressing social determinants of health. PMID- 22515780 TI - An innovative medical Spanish curriculum for resident doctors. PMID- 22515781 TI - Broadening horizons: looking beyond disability. PMID- 22515782 TI - 'Imitating Art': ethics, humanities and professionalism in undergraduate medical education. PMID- 22515783 TI - Enhancing medical professionalism through interactive seminars. PMID- 22515784 TI - Medical professionalism adapted to faith and cultural beliefs. PMID- 22515785 TI - Addressing complex multi-dimensional health problems using interprofessional education. PMID- 22515786 TI - Teaching ethics: are students getting the answers? PMID- 22515787 TI - The ethics script concordance test in assessing ethical reasoning. PMID- 22515789 TI - On 'Medical students' illness-related cognitions'. PMID- 22515790 TI - Lectures and the hidden curriculum. PMID- 22515791 TI - Predicting present and future intra-specific genetic structure through niche hindcasting across 24 millennia. AB - Paleoclimatic reconstructions coupled with species distribution models and identification of extant spatial genetic structure have the potential to provide insights into the demographic events that shape the distribution of intra specific genetic variation across time. Using the globeflower Trollius europaeus as a case-study, we combined (1) Amplified Fragment Length Polymorphisms, (2) suites of 1000-years stepwise hindcasted species distributions and (3) a model of diffusion through time over the last 24,000 years, to trace the spatial dynamics that most likely fits the species' current genetic structure. We show that the globeflower comprises four gene pools in Europe which, from the dry period preceding the Last Glacial Maximum, dispersed while tracking the conditions fitting its climatic niche. Among these four gene pools, two are predicted to experience drastic range retraction in the near future. Our interdisciplinary approach, applicable to virtually any taxon, is an advance in inferring how climate change impacts species' genetic structures. PMID- 22515792 TI - Take-up of public insurance and crowd-out of private insurance under recent CHIP expansions to higher income children. AB - OBJECTIVE: To analyze the effects of states' expansions of Children's Health Insurance Program (CHIP) eligibility to children in higher income families on health insurance coverage outcomes. DATA SOURCES: 2002-2009 Current Population Survey linked to multiple secondary data sources. STUDY DESIGN: Instrumental variables estimation of linear probability models. Outcomes are whether the child had any public insurance, any private insurance, or no insurance coverage during the year. PRINCIPAL FINDINGS: Among children in families with incomes between two and four times the federal poverty line (FPL), four enrolled in CHIP for every 100 who became eligible. Roughly half of the newly eligible children who took up public insurance were previously uninsured. The upper bound "crowd-out" rate was estimated to be 46 percent. CONCLUSIONS: The CHIP expansions to children in higher income families were associated with limited uptake of public coverage. Our results additionally suggest that there was crowd-out of private insurance coverage. PMID- 22515793 TI - Differentiation of stages in joke comprehension: evidence from an ERP study. AB - This study aimed to investigate the mechanisms underlying joke comprehension using event-related potentials (ERPs). Fourteen healthy college students were presented with the context of a story without its joke or nonjoke ending, and then, when the story ending was presented, they were asked to make a funny/unfunny judgment about these endings. The behavioral results showed that there was no significant difference between funny and unfunny items, which meant that subjects could understand funny items as easily as unfunny ones. However, the ERP results showed that funny items initially elicited a more negative ERP deflection (N350-450) over frontocentral scalp regions. Dipole analysis localized the generators in the left temporal gyrus and the left medial frontal gyrus; it is suggested that these areas might be involved in detecting the incongruent element in joke comprehension. Between 600 and 800 ms, funny items subsequently elicited a more negative ERP deflection (N600-800) over frontocentral scalp regions and a more positive ERP deflection (P600-800) over posterior scalp regions. Dipole analysis localized the generator in the anterior cingulate cortex (ACC), an area involved in the breaking of mental set/expectation and the forming of novel associations. Finally, funny items elicited a more positive ERP deflection (P1250-1400) over anterior and posterior scalp regions. Dipole analysis localized the generators in the middle frontal gyrus and the fusiform gyrus, areas that might be related to the affective appreciation stage in joke process. Unlike that of Coulson and Kutas (2001), the present study might support the hypothesis of a three stage model of humor processing (humor detection, resolution of incongruity and humor appreciation). PMID- 22515794 TI - Reduction in nausea and vomiting in children undergoing cancer chemotherapy by either appropriate or sham auricular acupuncture points with standard care. AB - BACKGROUND: Over 40% of children with cancer have reported that chemotherapy induced nausea and vomiting (CINV) are the two most distressing side-effects of treatment even when antiemetic drugs have been used. OBJECTIVES: The purpose of this article is to report the findings from a feasibility and pilot study using auricular point acupressure point for CINV in a small group of children in Taiwan. METHODS: This was a crossover randomized design study. CINV symptoms were assessed on 10 patients just prior to and for 7 days following each of three rounds of chemotherapy drugs (CTX). They received standard care (SC) and were not entered into a test treatment group until they completed the baseline assessment, which was conducted during their first round of chemotherapy after entering the study. Just prior to receiving the second round of CTX, patients were randomized into one of two treatment conditions: auricular acupressure intervention, in addition to standard care (AAP) or auricular acupressure using sham auricular points (SAP) in addition to standard care. For the third round of CTX, they were switched to the other treatment group. RESULTS: The enrollment rate for this study was 77% of the children invited to participate and of those, 88% provided completed data sets for all three treatment conditions. Patients in the AAP group reported significantly lower occurrence and severity of nausea and vomiting than patients in the SC group (p<0.05). There were no significant differences of nausea and vomiting for patients between the AAP and SAP groups. All of the patients took antiemetic medication on the day they received CTX, and 80% of patients reported that the antiemetics did not help to treat CINV. CONCLUSIONS: These preliminary findings did show evidence that AAP is acceptable to the children and their parents to prevent/treat CINV. However, there were no statistically significant differences between the AAP and SAP groups in the prevention/treatment of CINV. There were clinical trend differences between the groups, which may due to the small sample size. In a larger study, it would be important to determine whether the effects of the AAP and SAP treatment are independent of any psychologic effects, such as the researcher's increased presence in both treatment groups. PMID- 22515795 TI - A review of tensions and risks in naturopathic education and training in Australia: a need for regulation. AB - OBJECTIVES: In line with increasing complementary medicine (CAM) use, the Australian government has committed considerable resources to the training of CAM practitioners. However, it has generally failed to complement this support with regulation or accountability measures. This is particularly true in Australia's largest CAM profession (naturopaths), which remains entirely unregulated but attracts approximately AUD$40 million each year in government funding for its education sector. This article explores the consequences of such unfettered support on professional outcomes. DESIGN: Data on Australian government funding for naturopathic student places were collated and compared with various outcome measures including research and professional outcomes. RESULTS: Lack of accountability measures attached to government support has enabled the proliferation of commercial education providers in the sector. This is often at the expense of the university sector, which is financially disadvantaged in naturopathic education delivery through extra academic and research obligations not shared by private for-profit providers. The major beneficiaries of government funding have facilitated few formal contributions to naturopathic research or professional development, whereas those with the highest research, professional, and academic output attracted the least government funding. Course content has declined in the previous 5 years, and government funding is still directed to courses that do not meet the minimum education levels for the prescribed government definition of naturopath. Unfettered support has also resulted in a significant increase in student numbers growth, which significantly outstrips growth in utilization, potentially affecting the profession's sustainability. CONCLUSIONS: Lack of regulation in naturopathic education has resulted in significant risks to patients (through reduced standards) as well as the naturopathic profession itself. Although CAM advocates often focus on pushing for government support for the development CAM, support without the development of appropriate regulatory and accountability measures can ultimately be detrimental to the development of CAM. PMID- 22515796 TI - Policy implications of complementary and alternative medicine use in Australia: data from the National Health Survey. AB - OBJECTIVES: The objective of this study was to investigate the drivers of complementary and alternative medicine (CAM) use in the general population in Australia and to identify key policy implications. DATA AND METHODS: The National Health Survey 2007/2008, a representative survey of the Australian population, provides information on CAM use (practitioners and products) in the last 12 months. All adult respondents (N=15,779) aged 18 years or older are included in this study. Logistic regression is employed to determine the effect of socio economic, condition-specific, health behavior variables, and private health insurance status on CAM use. RESULTS: In addition to socio-economic variables known to affect CAM use, individuals who have a chronic condition, particularly a mental health condition, are more likely to use CAM. There does not appear to be a correlation between CAM use and more frequent General Practitioner use; however, ancillary private health insurance is correlated with a greater likelihood of CAM use, as expected. CONCLUSIONS: The Australian government does not currently intervene in the CAM market in a systematic way. CAM is clearly considered to be a legitimate and important component of health care for many Australians, despite the limited availability of clinical evidence for its efficacy and safety. Policy interventions may include the regulation of CAM products, practitioners, and information as well as providing subsidies for cost effective modalities. PMID- 22515797 TI - The Buddha relics and evidence of physical space conditioning with unimprinted intention host devices. AB - OBJECTIVES: The objective of this study was to experimentally determine whether an unimprinted intention host device (IHD), electrically activated in the near presence of the Maitreya Buddhist relics for about 72 hours (3 nights), could be imprinted by its loving kindness essence into the IHD. This will be referred to as a "first-degree relic IHD." DESIGN: This first-degree relic IHD was placed in an unused, unconditioned room in a Scottsdale, AZ home in the presence of a water vessel (pH ~ 5.6) being continuously monitored via a pH-sensor system that was computer recorded. This particular IHD was electrically switched on. Initially, no intention instructions were given to the system. After about 2200 hours, an intention statement was written to respectfully ask the first-degree relic IHD that the excess thermodynamic free energy aspect of this loving kindness essence be made manifest in this space so that its thermodynamic magnitude could be experimentally measured via the pH-sensor reading. RESULTS: It was shown that during the first 3 months, only a small increase in water pH was recorded. However, during the postintention period, the pH increased by about +2.5 pH units or ~ 60 meV increase in the thermodynamic free energy of the physical space, a very significant change. The excess thermodynamic free energy suggests that a fundamental change of the gauge symmetry state of the unconditioned room had occurred to a higher state. CONCLUSIONS: The following were concluded in this study: (1) Imprinting meaningful information onto a simple unimprinted IHD via passive exposure to the Buddha relics is possible. (2) Activating this IHD information to, in turn, imprint itself onto the space of a particular room so that a quantitative thermodynamic measure of its energetic essence can be physically realized is also possible. (3) Crucially, a verbal request from a deep meditative state by four humans appeared to be a necessary condition for this "imbedded loving kindness essence" to manifest itself in this way. PMID- 22515799 TI - Chinese herbal medicine Danshen formulations for preventing renal disease in Henoch-Schonlein Purpura: a systematic review and meta-analysis. AB - OBJECTIVES: The study objective was to evaluate the use of Danshen formulations in preventing renal disease in Henoch-Schonlein Purpura (HSP) either as sole agents or in combination with other drug regimens. METHODS: Search strategy- Databases searched were the Cochrane Central Register of Controlled Trials, PubMed, Embase (Excerpta Medica Database), the Chinese Biomedicine Database, CNKI (Chinese National Knowledge Infrastructure), and VIP-database for all relevant studies without any language restriction. The cut-off date for the search was October 2010. Selection criteria--All randomized controlled trials with enrolled patients of all ages without renal disease before random assignment were included. The primary outcomes were the number of patients who developed renal disease and the incidence of adverse effects of drugs. Data collection and analysis--For dichotomous outcomes, the incidence of renal disease in patients with HSP was calculated as a relative risk with 95% confidence intervals. For continuous outcomes, the weighted mean difference with 95% confidence intervals was used. RESULTS: A total of five trials (513 children aged 2-14 years old) were included in the meta-analyses, which indicated that Danshen formulations (injections or tablets) with symptomatic therapy significantly reduced the risk of developing renal disease in children with HSP compared to symptomatic therapy alone 6-12 months after treatment (relative risk: 0.35, 95% confidence interval: 0.20-0.61). Adverse effects of Danshen formulations were not explicitly reported in these studies. CONCLUSIONS: Danshen formulations may help prevent renal disease in children with HSP without serious side-effects. However, the evidence is of low quality (as assessed using the GRADE approach), and thus there is insufficient proof to strongly recommend the use of Danshen formulations in children with HSP. Large, properly randomized, placebo-controlled, double-blind studies are needed to substantiate its use. PMID- 22515798 TI - Capturing amplitude changes of low-frequency fluctuations in functional magnetic resonance imaging signal: a pilot acupuncture study on NeiGuan (PC6). AB - OBJECTIVES: This study aims to examine amplitude changes of low-frequency oscillations (fALFF) in the blood-oxygen level-dependent (BOLD) signal associated with acupuncture on NeiGuan (PC6). EXPERIMENTAL DESIGN: Ten (10) healthy adults participated in a functional magnetic resonance imaging (i.e., nuclear medicine; fMRI) study. During the brain-imaging procedure, the participants were instructed to lie quietly; they did not perform any cognitive task. MAIN OUTCOME MEASURES: Three (3) fMRI scans were conducted for each participant: a first resting-state scan (R1), a stimulating-acupoint scan (AP), and a second resting-state scan (R2) after AP. Individual fALFF maps were calculated for each scan. RESULTS: During R1, consistent with previous studies, the default network regions showed significantly detectable fALFF amplitudes. Acupuncture on PC6 increased fALFF amplitudes within the anterior cingulate cortex (ACC), occipital fusiform gyrus, posterior cingulate cortex, and precuneus (PCC/PCU). In contrast, during R2, fALFF within PCC is still significantly higher than R1 while ACC and cerebellum showed decreased fALFF. CONCLUSIONS: These findings imply that stimulating PC6 can change the amplitude of the intrinsic cortical activity of the brain. In particular, a continuous and temporally consistent effect of acupuncture within PCC not the common brain circuit of pain including ACC and cerebellum was observed. Considering the cognitive functions and deficits of the relevant areas in mild cognitive impairment and Alzheimer disease, acupuncture on PC6 could potentially affect both psychiatric and neurological disorders. Thus, stimulating PC6 may be a candidate method for improving cognitive impairment. PMID- 22515800 TI - Hypertonic dextrose injections (prolotherapy) for knee osteoarthritis: results of a single-arm uncontrolled study with 1-year follow-up. AB - OBJECTIVE: The objective of this study was to determine whether prolotherapy, an injection-based complementary treatment for chronic musculoskeletal conditions, improves pain, stiffness, and function in adults with symptomatic knee osteoarthritis (KOA) compared to baseline status. DESIGN: This was a prospective, uncontrolled study with 1-year follow-up. SETTING: The study was conducted in an outpatient setting. PARTICIPANTS: Adults with at least 3 months of symptomatic KOA, recruited from clinical and community settings, participated in the study. INTERVENTIONS: Participants received extra-articular injections of 15% dextrose and intra-articular prolotherapy injections of 25% dextrose at 1, 5, and 9 weeks, with as-needed treatments at weeks 13 and 17. OUTCOME MEASURES: Primary outcome measure was the validated Western Ontario McMaster University Osteoarthritis Index (WOMAC). Secondary outcome measure was the validated Knee Pain Scale (KPS). Tertiary outcome measure was procedure-related pain severity and participant satisfaction. RESULTS: Thirty-six (36) participants (60 +/- 8.7 years old, 21 female) with moderate-to-severe KOA received an average of 4.3 +/- 0.7 prolotherapy injection sessions over a 17-week treatment period and reported progressively improved scores during the 52-week study on WOMAC and KPS measures. Participants reported overall WOMAC score improvement 4 weeks after the first injection session (7.6 +/- 2.4 points, 17.2%), and continued to improve through the 52-week follow-up (15.9 +/- 2.5 points, p<0.001, 36.1%). KPS scores improved in both injected (p<0.001) and uninjected knees (p<0.05). Prescribed low-dose opioid analgesia effectively treated procedure-related pain. Satisfaction was high and there were no adverse events. Female gender, age 46-65 years old, and body-mass index of 25 kg/m(2) or less were associated with greater improvement on the WOMAC instrument. CONCLUSIONS: In adults with moderate to severe KOA, dextrose prolotherapy may result in safe, significant, sustained improvement of knee pain, function, and stiffness scores. Randomized multidisciplinary effectiveness trials including evaluation of potential disease modification are warranted to further assess the effects of prolotherapy for KOA. PMID- 22515801 TI - Systemic effects of conjugated equine estrogen vaginal cream on bone turnover markers in postmenopausal women. AB - OBJECTIVE: To evaluate the systemic effect of therapy with conjugated equine estrogen (CEE) vaginal cream on bone turnover markers in postmenopausal women. METHODS: This study was conducted in 40 spontaneously menopausal women aged 40-60 years who complained of vulvovaginal symptoms. Subjects were instructed to self administer 1 g CEE vaginal cream (CEE 0.625 mg) once daily for 12 weeks (continuous phase), then twice weekly for the next 12 consecutive weeks (intermittent phase). Serum levels of bone turnover markers and estradiol and the vaginal maturation index were evaluated at baseline, 12 and 24 weeks after treatment initiation. RESULTS: Levels of C-terminal cross-linked telopeptide of type I collagen (CTx) were significantly decreased at 12 weeks and 24 weeks when compared to baseline values (median (range) 0.435 (0.171-0.859) and 0.391 (0.122 0.714) vs. 0.562 (0.250-1.290) ng/ml (p < 0.001 and < 0.001), respectively), but there was no significant difference between the levels at 12 and 24 weeks. Levels of procollagen type I N-terminal propeptide (P1NP) and osteocalcin levels were significantly decreased after 24 weeks when compared to pretreatment levels (mean (standard deviation) 41.74 (11.76) vs. 50.02 (17.71) ng/ml (p = 0.002) for P1NP and 23.91 (7.11) vs. 27.54 (8.67) ng/ml (p < 0.001) for osteocalcin, respectively). Estradiol levels were significantly increased and the vaginal maturation index was significantly improved after 12 and 24 weeks when compared to baseline. CONCLUSIONS: CEE vaginal cream significantly decreased the bone resorption marker (CTx) in postmenopausal women after completion of the continuous-treatment phase. There was no significant further decrease after the intermittent phase. The effects on the markers of bone formation and bone turnover (P1NP and osteocalcin) were apparent only at 24 weeks. The two treatment phases moderately increased serum estradiol levels and significantly improved the vaginal maturation index. PMID- 22515802 TI - Potential mechanisms for the association between fall birth and food allergy. AB - BACKGROUND: Season of birth has been reported as a risk factor for food allergy, but the mechanisms by which it acts are unknown. METHODS: Two populations were studied: 5862 children from the National Health and Nutrition Examination Survey (NHANES) III and 1514 well-characterized food allergic children from the Johns Hopkins Pediatric Allergy Clinic (JHPAC). Food allergy was defined as self-report of an acute reaction to a food (NHANES), or as milk, egg, and peanut allergy. Logistic regression compared fall or nonfall birth between (i) food allergic and nonallergic subjects in NHANES, adjusted for ethnicity, age, income, and sex, and (ii) JHPAC subjects and the general Maryland population. For NHANES, stratification by ethnicity and for JHPAC, eczema were examined. RESULTS: Fall birth was more common among food allergic subjects in both NHANES (OR, 1.91; 95% CI, 1.31-2.77) and JHPAC/Maryland (OR, 1.31; 95% CI, 1.18-1.47). Ethnicity interacted with season (OR, 2.34; 95% CI, 1.43-3.82 for Caucasians; OR, 1.19; 95% CI, 0.77-1.86 for non-Caucasians; P = 0.04 for interaction), as did eczema (OR, 1.47; 95% CI, 1.29-1.67 with eczema; OR, 1.00; 95% CI, 0.80-1.23 without eczema; P = 0.002 for interaction). CONCLUSIONS: Fall birth is associated with increased risk of food allergy, and this risk is greatest among those most likely to have seasonal variation in vitamin D during infancy (Caucasians) and those at risk for skin barrier dysfunction (subjects with a history of eczema), suggesting that vitamin D and the skin barrier may be implicated in seasonal associations with food allergy. PMID- 22515804 TI - Is the dendritic cell a missing piece in the pathogenesis model of post infectious irritable bowel syndrome? PMID- 22515803 TI - Conservation of oxidative protein stabilization in an insect homologue of parkinsonism-associated protein DJ-1. AB - DJ-1 is a conserved, disease-associated protein that protects against oxidative stress and mitochondrial damage in multiple organisms. Human DJ-1 contains a functionally essential cysteine residue (Cys106) whose oxidation is important for regulating protein function by an unknown mechanism. This residue is well conserved in other DJ-1 homologues, including two (DJ-1alpha and DJ-1beta) in Drosophila melanogaster. Because D. melanogaster is a powerful model system for studying DJ-1 function, we have determined the crystal structure and impact of cysteine oxidation on Drosophila DJ-1beta. The structure of D. melanogaster DJ 1beta is similar to that of human DJ-1, although two important residues in the human protein, Met26 and His126, are not conserved in DJ-1beta. His126 in human DJ-1 is substituted with a tyrosine in DJ-1beta, and this residue is not able to compose a putative catalytic dyad with Cys106 that was proposed to be important in the human protein. The reactive cysteine in DJ-1 is oxidized readily to the cysteine-sulfinic acid in both flies and humans, and this may regulate the cytoprotective function of the protein. We show that the oxidation of this conserved cysteine residue to its sulfinate form (Cys-SO(2)(-)) results in considerable thermal stabilization of both Drosophila DJ-1beta and human DJ-1. Therefore, protein stabilization is one potential mechanism by which cysteine oxidation may regulate DJ-1 function in vivo. More generally, most close DJ-1 homologues are likely stabilized by cysteine-sulfinic acid formation but destabilized by further oxidation, suggesting that they are biphasically regulated by oxidative modification. PMID- 22515805 TI - "Is it effective?" to "How to use it?": the era has changed in probiotics and functional food products against Helicobacter pylori infection. PMID- 22515806 TI - Anti-inflammatories and the gastrointestinal tract: Victores et Victis. PMID- 22515807 TI - Education and Imaging. Gastrointestinal: benign cystic schwannoma localized in the gastroduodenal ligament; a rare case. PMID- 22515808 TI - Education and Imaging. Gastrointestinal: balloon pancreatitis. PMID- 22515809 TI - Education and Imaging. Gastrointestinal: gastric mucosa-associated lymphoid tissue (MALT) lymphoma observed by magnifying endoscopy with narrow band imaging. PMID- 22515810 TI - Education and Imaging. Hepatobiliary and pancreatic: autoimmune cholangitis, pancreatitis and sialadenitis. PMID- 22515811 TI - Education and Imaging. Hepatobiliary and pancreatic: pancreatic vascular malformations in hereditary hemorrhagic telangiectasia. PMID- 22515814 TI - Hemolysis-induced acute kidney injury following cardiac surgery: a case report and review of the literature. AB - Acute kidney injury is a common complication following cardiac surgery. Even small increases in creatinine levels are associated with increases in morbidity and mortality. Numerous factors such as hemolysis can contribute to the development of acute kidney injury after cardiac surgery. We present a rare case of severe hemolysis related to cardiopulmonary bypass resulting in kidney injury and requiring dialysis. The patient's renal function gradually recovered when hemolysis was improved. After follow-up for 3 months, his creatinine levels returned to normal. We discussed the pathogenesis of this hemolysis-related kidney dysfunction, the causes of hemolysis during cardiac surgery, and a new treatment option. PMID- 22515815 TI - YeeU enhances the bundling of cytoskeletal polymers of MreB and FtsZ, antagonizing the CbtA (YeeV) toxicity in Escherichia coli. AB - All free-living bacteria carry the toxin-antitoxin (TA) systems controlling cell growth and death under stress conditions. YeeU-YeeV (CbtA) is one of the Escherichia coli TA systems, and the toxin, CbtA, has been reported to inhibit the polymerization of bacterial cytoskeletal proteins, MreB and FtsZ. Here, we demonstrate that the antitoxin, YeeU, is a novel type of antitoxin (type IV TA system), which does not form a complex with CbtA but functions as an antagonist for CbtA toxicity. Specifically, YeeU was found to directly interact with MreB and FtsZ, and enhance the bundling of their filamentous polymers in vitro. Surprisingly, YeeU neutralized not only the toxicity of CbtA but also the toxicity caused by other inhibitors of MreB and FtsZ, such as A22, SulA and MinC, indicating that YeeU-induced bundling of MreB and FtsZ has an intrinsic global stabilizing effect on their homeostasis. Here we propose to rename YeeU as CbeA for cytoskeleton bundling-enhancing factor A. PMID- 22515817 TI - Highly sensitive diagnostic assay for the detection of protein biomarkers using microresonators and multifunctional nanoparticles. AB - We developed a novel gravimetric immunoassay for sensitive detection of multiple protein biomarkers using silicon microcantilever arrays and multifunctional hybrid nanoparticles. Magnetic-photocatalytic hybrid nanoparticles with a highly crystalline TiO(2) shell were synthesized using a solvothermal reaction without a calcination process. After functionalizing the hybrid nanoparticles and silicon cantilevers with antibodies, the nanoparticles were used to magnetically separate target biomarkers from human serum. Frequency changes of the microcantilevers due to the binding of the nanoparticles were measured using a dip-and-dry method. Frequency changes were further amplified using a photocatalytic silver reduction reaction. Several biomarkers, including interleukin-6, interferon-gamma, and alpha-fetoprotein, were selectively detected using arrays of eight silicon microcantilevers. The detection limit of this assay was ~0.1 pg/mL, which is superior to the clinical threshold of the biomarkers. PMID- 22515816 TI - HIV-related eye disease in patients presenting to a tertiary care government hospital in Turkey. AB - AIM: To document the ocular involvement in HIV-infected individuals in Turkey and to compare the findings with those from other centers throughout the world. METHODS: In this cross-sectional study, patients with HIV infection being monitored in a tertiary hospital in Istanbul were enrolled. Ocular examination was performed, and the prevalence of ocular manifestations determined. RESULTS: In total, 93 patients were enrolled, of whom 37.6% had ocular pathology. HIV retinopathy was the most frequent retinal finding, affecting 8.6% of the enrolled patients, but none of the affected individuals had any ophthalmic complaints. There were no ocular lesions suggestive of cytomegalovirus (CMV) retinitis. DISCUSSION: In contrast to the case in the developed world, sight-threatening infections are uncommon in Turkish HIV(+) patients. The reasons for this are not clear, but it is possible that there are some genetic or environmental protective factors against CMV retinitis in the population studied. PMID- 22515818 TI - Treatment of 28 patients with sclerosing hemangioma (SH) of the lung. AB - BACKGROUND: Sclerosing hemangioma (SH) of the lung is a kind of rare pulmonary tumor. Preoperative diagnosis of this tumor is difficult and it is now generally accepted that SH of the lung is benign lesions and surgical excision alone is curative. Herein, we present our experiences of treating 28 patients with SH. METHODS: The medical records of 28 patients with SH from 1994 to 2010 at the Department of Thoracic Surgery in Beijing Chest Hospital were retrospectively reviewed. RESULTS: There were 3 male and 25 female patients with sclerosing hemangioma and 50% of the patients were asymptomatic. Preoperatively, all the patients had undergone CT of chest and 5 patients had undergone PET scan but 4 patients were misdiagnosed as malignancy. There was no operative mortality or tumor recurrence despite that three different operative methods were undertaken. CONCLUSIONS: SH has a high incidence in middle-aged women. Most of SH is asymptomatic and the symptoms of SH are not related to the tumor size and distribution. The features of chest CT and PET are not specific. Bilateral or multiple lesions should not exclude the possibility of SH. Complete excision of lesion is a curable treatment method and there is no evidence to verify the need of adjuvant therapy. PMID- 22515819 TI - Optimal dosages of fluoxetine in the treatment of hypoxic brain injury induced by 3-nitropropionic acid: implications for the adjunctive treatment of patients after acute ischemic stroke. AB - AIM: The serotonin selective reuptake inhibitor fluoxetine (Flx) has tried to treat patients suffered acute ischemic stroke because of its possible neuroprotective actions. However, besides the neuroprotective effect, Flx at high concentration also induces some actions in contradiction to neuroprotection in the brain. The purpose of this study was to investigate whether Flx presents neuroprotective effect against 3-nitropropionic acid (3-NP)-induced hypoxic brain injury, and what is the most suitable dosage of Flx. METHODS: Mouse model was established by subacute systemic administration of 3-NP. Rotarod and pole tests were used to evaluate motor deficit. The oxidative stress and oxidative DNA damage were assessed respectively by measuring malondialdehyde and 8 hydroxydeoxyguanosine content in brain homogenates. RESULTS: According to measurements in the rotarod test, 7 days pretreatment plus 5 days treatment of Flx at low (2.5 mg/kg/day) and, to a lesser degree, medium (5 mg/kg/day) doses exerted a rapid and strong protection against the neurotoxicity induced by 3-NP, whereas Flx at high dose (10mg/kg/day) showed a much late and light effect. Similarly, in the pole test, Flx at 2.5 mg/kg/day had the strongest protective effects. Again, only Flx administration at 2.5 mg/kg/day canceled out the enhancement of malondialdehyde and 8-hydroxydeoxyguanosine in striatum following 3-NP neurotoxication. CONCLUSIONS: Flx attenuated the motor deficits induced by 3 NP in a dose-dependent manner. In contrary to the high dose, Flx at the lower doses had a more remarkable effect against 3-NP insult, similar to acute ischemic stroke. PMID- 22515820 TI - Mechanistic insight into the structure and dynamics of entangled and hydrated lambda-phage DNA. AB - Intrinsic dynamics of DNA plays a crucial role in DNA-protein interactions and has been emphasized as a possible key component for in vivo chromatin organization. We have prepared an entangled DNA microtube above the overlap concentration by exploiting the complementary cohesive ends of lambda-phage DNA, which is confirmed by atomic force microscopy and agarose gel electrophoresis. Photon correlation spectroscopy further confirmed that the entangled solutions are found to exhibit the classical hydrodynamics of a single chain segment on length scales smaller than the hydrodynamic length scale of single lambda-phage DNA molecule. We also observed that in 41.6% (gm water/gm DNA) hydrated state, lambda-phage DNA exhibits a dynamic transition temperature (T(dt)) at 187 K and a crossover temperature (T(c)) at 246 K. Computational insight reveals that the observed structure and dynamics of entangled lambda-phage DNA are distinctively different from the behavior of the corresponding unentangled DNA with open cohesive ends, which is reminiscent with our experimental observation. PMID- 22515821 TI - NMR solution structure of a photoswitchable apoptosis activating Bak peptide bound to Bcl-xL. AB - The Bcl-2 family of proteins includes the major regulators and effectors of the intrinsic apoptosis pathway. Cancers are frequently formed when activation of the apoptosis mechanism is compromised either by misregulated expression of prosurvival family members or, more frequently, by damage to the regulatory pathways that trigger intrinsic apoptosis. Short peptides derived from the pro apoptotic members of the Bcl-2 family can activate mechanisms that ultimately lead to cell death. The recent development of photocontrolled peptides that are able to change their conformation and activity upon irradiation with an external light source has provided new tools to target cells for apoptosis induction with temporal and spatial control. Here, we report the first NMR solution structure of a photoswitchable peptide derived from the proapoptotic protein Bak in complex with the antiapoptotic protein Bcl-x(L). This structure provides insight into the molecular mechanism, by which the increased affinity of such photopeptides compared to their native forms is achieved, and offers a rationale for the large differences in the binding affinities between the helical and nonhelical states. PMID- 22515822 TI - Tackling perinatal loss, a participatory action research approach: research protocol. AB - AIM: The aim of this study was to promote changes to improve the care provided to parents who have experienced a perinatal loss through participatory action research. BACKGROUND: The birth of a child is a joyful event for most families, however, unfortunately some pregnancies end in loss. Perinatal loss creates a heavy emotional impact not only on parents but also on health professionals, where in most cases there is an evident lack of skills, strategies and resources to cope with these kinds of situations. DESIGN: Participatory action research is the methodology proposed to achieve the purpose of this study. METHODS: Participatory action research consists of five stages: outreach and awareness, induction, interaction, implementation and systematization. The working group will include professionals from the Mother and Child Unit for patients at a tertiary level public hospital in Spain. The duration of the study will be 3 years since the approval of the protocol in January 2011. The qualitative techniques used will include group dynamics such as the SWOT analysis the nominal group technique, focus groups and brainstorming, among others that will be recorded and transcribed, generating reports throughout the evolution of the group sessions and about the consensus reached. Content analysis will be conducted on the field diaries kept by the participants and researchers. This project has been funded by the Andalusian Regional Ministry of Health. DISCUSSION: Participatory action research is a methodological strategy that allows changes in clinical practice to conduct a comprehensive transformative action in the care process for perinatal loss. PMID- 22515823 TI - Editorial: capturing developmental trajectories of change in persons with intellectual and developmental disability. PMID- 22515824 TI - Foreword: development is not about studying children: the importance of longitudinal approaches. PMID- 22515825 TI - Heart activity and autistic behavior in infants and toddlers with fragile X syndrome. AB - The present study contrasted physiological arousal in infants and toddlers with fragile X syndrome to typically developing control participants and examined physiological predictors early in development to autism severity later in development in fragile X syndrome. Thirty-one males with fragile X syndrome (ages 8-40 months) and 25 age-matched control participants were included. The group with fragile X syndrome showed shorter interbeat intervals (IBIs), lower vagal tone (VT), and less modulation of IBI. Data suggested a nonlinear effect with IBI and autistic behavior; however, a linear effect with VT and autistic behavior emerged. These findings suggest that atypical physiological arousal emerges within the first year and predicts severity of autistic behavior in fragile X syndrome. These relationships are complex and dynamic, likely reflecting endogenous factors assumed to reflect atypical brain function secondary to reduced fragile X mental retardation protein. This research has important implications for the early identification and treatment of autistic behaviors in young children with fragile X syndrome. PMID- 22515826 TI - Does attention constrain developmental trajectories in fragile x syndrome? A 3 year prospective longitudinal study. AB - Basic attentional processes and their impact on developmental trajectories in fragile X syndrome were assessed in a 3-year prospective study. Although fragile X syndrome is a monogenic X-linked disorder, there is striking variability in outcomes even in young boys with the condition. Attention is a key factor constraining interactions with the environment, so it is a perfect candidate to predict trajectories in cognitive and behavioral outcomes. In this study, 48 boys with fragile X syndrome were assessed 3 times over 24 months. Although nonverbal IQ declined, there were significant improvements in nonverbal growth scores and in cognitive attention. In contrast, behavioral difficulties (i.e., autistic symptomatology, hyperactivity-inattention) remained stable over this time frame. Attentional markers in the visual and auditory modalities predicted intellectual abilities and classroom behavior, whereas auditory markers alone predicted autistic symptomatology. PMID- 22515827 TI - Trajectory of behavior and emotional problems in autism. AB - High rates of behavior and emotional problems have been consistently reported in children and adolescents with autism. Elevated rates of mental health problems have also been reported in adults with autism. Little is known, however, about the longitudinal development of behavior and emotional problems in autism. This study followed a cohort of children and adolescents over 18 years. Outcomes were evaluated in terms of behavior and emotional problems and autism symptomatology. The role of childhood factors (age, gender, IQ, behavior, and emotional problems) and the environment (socioeconomic disadvantage) were considered in terms of adult outcomes. Overall, improvements in comorbid behavior and emotional problems and autism symptomatology were observed. However, rates of comorbid behavior and emotional problems in adulthood remained high. PMID- 22515828 TI - Longitudinal assessment of intellectual abilities of children with Williams syndrome: multilevel modeling of performance on the Kaufman Brief Intelligence Test-Second Edition. AB - Multilevel modeling was used to address the longitudinal stability of standard scores (SSs) measuring intellectual ability for children with Williams syndrome (WS). Participants were 40 children with genetically confirmed WS who completed the Kaufman Brief Intelligence Test-Second Edition (KBIT-2; A. S. Kaufman & N. L. Kaufman, 2004 ) 4-7 times over a mean of 5.06 years. Mean age at first assessment was 7.44 years (range = 4.00-13.97 years). On average, KBIT-2 Composite IQ, Verbal SS, and Nonverbal SS were stable from 4 to 17 years, although there were significant individual differences in intercept (Composite IQ, Verbal SS, Nonverbal SS) and slope (Composite IQ, Nonverbal SS). Maternal education was significantly related to Verbal SS intercept. No significant sex differences were found. Implications for studies of genotype/phenotype correlations in WS are discussed. PMID- 22515829 TI - Do autistic symptoms persist across time? Evidence of substantial change in symptomatology over a 3-year period in cognitively able children with autism. AB - This study investigated the extent and nature of changes in symptomatology in cognitively able children with autism over a 3-year period. Thirty-seven children diagnosed with an autism spectrum condition involved in an earlier study (M age = 5 years, 7 months) were followed and reassessed 3 years later (M age = 8 years, 4 months). Scores on the Social Communication Questionnaire (SCQ; M. Rutter, A. Bailey, & C. Lord, 2003 ) decreased significantly over time in all symptom domains but especially in the social domain, and correlational findings suggested the presence of 2 distinct developmental trajectories-social communication and repetitive behaviors-that interact across time. Furthermore, 7 children (19% of sample) made substantial changes to the extent that they failed to meet criteria on diagnostic instruments (the Autism Diagnostic Observation Schedule-Generic [ADOS-G; C. Lord, M. Rutter, P. C. DiLavore, & S. Risi, 1999 ] and the SCQ) 3 years later. Children showing diagnostic discontinuity were distinguishable from those who fulfilled ADOS-G criteria only in terms of the age at which they began receiving intervention. The presence of a significant proportion of children showing considerable progress over the 3-year period challenges assumptions of diagnostic continuity and highlights the potential long term benefits of early intervention. PMID- 22515830 TI - Developmental trajectories in syndromes with intellectual disability, with a focus on Wolf-Hirschhorn and its cognitive-behavioral profile. AB - Few studies exist of developmental trajectories in children with intellectual disability, and none for those with subtelomeric deletions. We compared developmental trajectories of children with Wolf-Hirschhorn syndrome to other genetic disorders. We recruited 106 children diagnosed with fragile X, Williams Beuren syndrome, or Wolf-Hirschhorn syndrome, assessing their intellectual and adaptive behavior abilities. We retested 61 children 2 years later. We compared Time 1 and Time 2 difference scores related to genetic disorder, age, initial IQ, or adaptive behavior composite. Results show genetic disorder and initial IQ score were significant factors for IQ differences, but only genetic disorder affected adaptive behavior differences. Results suggest different gene-brain behavior pathways likely exist for these genetic disorders. Different developmental trajectories will influence the type and intensity of intervention implemented by caregivers. PMID- 22515832 TI - Characterization of the key odorants in raw Italian hazelnuts ( Corylus avellana L. var. Tonda Romana) and roasted hazelnut paste by means of molecular sensory science. AB - The concentrations of 19 odorants, recently characterized by GC-olfactometry and aroma extract dilution analysis as the most odor-active compounds in raw hazelnuts, were quantitated by stable isotope dilution assays (SIDA). Calculation of odor activity values (OAV) on the basis of odor thresholds in oil revealed high OAVs, in particular for linalool, 5-methyl-4-heptanone, 2-methoxy-3,5 dimethylpyrazine, and 4-methylphenol. A model mixture in sunflower oil containing the 13 odorants showing OAVs above 1 in their natural concentrations resulted in a good similarity compared to the overall nut-like, fruity aroma of the raw hazelnuts. Quantitation of the 25 most odor-active compounds in roasted hazelnut paste by SIDA showed clear changes in the concentrations of most odorants, and formation of new odor-active compounds induced by the roasting process was observed. The highest OAVs were calculated for 3-methylbutanal (malty), 2,3 pentanedione (buttery), 2-acetyl-1-pyrroline (popcorn), and (Z)-2-nonenal (fatty), followed by dimethyl trisulfide, 2-furfurylthiol, 2,3-butanedione, and 4 hydroxy-2,5-dimethyl-3(2H)-furanone. The aroma of a model mixture containing the 19 odorants with OAVs above 1 in their actual concentrations in the roasted nut material was judged to elicit a very good similarity to the popcorn-like, coffee like, and sweet-smoky aroma of the roasted hazelnut paste. New SIDAs were developed for the quantitation of 5-methyl-4-heptanone, 5-methyl-(E)-2-hepten-4 one, 2-thenylthiol, and 3,5,5-trimethyl-2(5H)-furanone. PMID- 22515833 TI - Selection for Dutch postgraduate GP training; time for improvement. AB - BACKGROUND: In the Netherlands we select candidates for the postgraduate GP training by assessing personal qualities in interviews. Because of differences in the ratio of number of candidates and number of vacancies between the eight departments of GP training we questioned whether the risk of being rejected diverged amongst them. OBJECTIVE: The research question of this study was to which degree department of choice, candidates' characteristics and qualities assessed during interviews explain admission into GP training. METHODS: A nationwide observational study was conducted of all candidates who applied for postgraduate GP training in 2009/ 2010. Application ratio per department, candidates' characteristics (gender, age, region of medical school and times of application) and qualities (motivation, orientation on the job, personal attributes and learning needs) were collected. Outcome measures were admission to interview and admission to GP training. RESULTS: The study population addressed 542 candidates. Sixty three candidates were rejected on application letter (11.6%). So 479 candidates were admitted to the interview, of which 340 were admitted to the GP training (71%). Gender and region of medical school outside North West Europe were associated with admission to the interview. Department of choice had a strong association with admission in both stages (RR: 0.30 to 0.74; 0.20 to 0.79 respectively), while candidates' qualities explained admission (RR: 1.09- 1.25) as well. CONCLUSION: The influence of department of choice yields doubts about fairness of the procedure. So advantages and disadvantages of a national procedure are discussed as well as those of a competency based procedure. PMID- 22515834 TI - Social support on international assignments: the relevance of socioemotional support from locals. AB - The first author received funding from the Commission of the European Communities as a Marie Curie International Reintegration Grant (FP/-PEOPLE-2007-4-3-IRG) under grant agreement number PIRG02-GA-224818 for data analysis and write-up. We want to thank our anonymous reviewers for their valuable comments and suggestions, and Ruth Lamont and Jaimee Stuart for their help with the preparation of the manuscript. PMID- 22515836 TI - Diblock-copolymer-coated water- and oil-repellent cotton fabrics. AB - A diblock copolymer consisting of a sol-gel-forming block and a fluorinated block was used to coat cotton fabrics, yielding textiles that were highly oil- and water-repellent. The coating procedure was simple. At grafted polymer amounts of as low as 1.0 wt %, water, diodomethane, hexadecane, cooking oil, and pump oil all had contact angles surpassing 150 degrees on the coated cotton fabrics and were readily rolled. The liquids were not drawn into the interfiber space by the coated fabrics. Rather, droplets of the nonvolatile liquids such as cooking oil retained their beaded shapes for months with minimal contact angle changes. When forced into water, the coated fabrics trapped an air or plastron layer and this plastron layer was stable for months. In addition, the coating had high stability against simulated washing, and the mechanical properties were essentially identical to those of uncoated cotton fabrics. PMID- 22515835 TI - COBRA ARRA subsidies: was the carrot enticing enough? AB - OBJECTIVE: To help preserve continuity of health insurance coverage during the recent recession, the American Recovery and Reinvestment Act provided a 65 percent Consolidated Omnibus Budget Reconciliation Act (COBRA) premium subsidy for workers laid off in 2008-2010. We examined COBRA enrollment levels with the subsidy and the health, access, and financial consequences of enrollment decisions. STUDY DESIGN/DATA COLLECTION: Telephone interviews linked with health system databases for 561 respondents who were laid off in 2009 and eligible for the COBRA subsidy (80 percent response rate). PRINCIPAL FINDINGS: Overall, 38 percent reported enrolling in COBRA and 54 percent reported having some gaps in insurance coverage since being laid off. After adjustments, we found that those who had higher cost-sharing, who had higher incomes, were older, or were sicker were more likely to enroll in COBRA. COBRA enrollees less frequently reported access problems or that their health suffered because of poor access, but they reported greater financial stress due to health care spending. CONCLUSION: Despite the substantial subsidy, a majority of eligible individuals did not enroll in COBRA, and many reported insurance coverage gaps. Nonenrollees reported more access problems and that their health worsened. Without a mandate, subsidies may need to be widely publicized and larger to encourage health insurance enrollment among individuals who suffer a negative income shock. PMID- 22515837 TI - Excited state structure and dynamics of the neutral and anionic flavin radical revealed by ultrafast transient mid-IR to visible spectroscopy. AB - Neutral and anionic flavin radicals are involved in numerous photochemical processes and play an essential part in forming the signaling state of various photoactive flavoproteins such as cryptochromes and BLUF domain proteins. A stable neutral radical flavin has been prepared for study in aqueous solution, and both neutral and anion radical states have been stabilized in the proteins flavodoxin and glucose oxidase. Ultrafast transient absorption measurements were performed in the visible and mid-infrared region in order to characterize the excited state dynamics and the excited and ground state vibrational spectra and to probe the effect of the protein matrix on them. These data are compared with the results of density functional theory calculations. Excited state decay dynamics were found to be a strong function of the protein matrix. The ultrafast electron transfer quenching mechanism of the excited flavin moiety in glucose oxidase is characterized by vibrational spectroscopy. Such data will be critical in the ongoing analysis of the photocycle of photoactive flavoproteins. PMID- 22515838 TI - Pigs as natural hosts of Dientamoeba fragilis genotypes found in humans. AB - Dientamoeba fragilis is a common intestinal parasite in humans. Transmission routes and natural host range are unknown. To determine whether pigs are hosts, we analyzed 152 fecal samples by microscopy and molecular methods. We confirmed that pigs are a natural host and harbor genotypes found in humans, suggesting zoonotic potential. PMID- 22515839 TI - Risk factors for intestinal invasive amebiasis in Japan, 2003-2009. AB - We determined yearly change in prevalence and risk factors for amebic colitis caused by intestinal invasive amebiasis among persons who underwent endoscopy and assessed differences between HIV-positive and HIV-negative persons in Japan. A total of 10,930 patients were selected for analysis, of whom 54 had amebic colitis. Prevalence was in 2009 (0.88%, 12/1360) compared with 2003 (0.16%, 3/1904). Male sex (odds ratio [OR] 8.39, 95% CI 1.99-35.40), age <50 years (OR 4.73, 95% CI 2.43-9.20), history of syphilis (OR 2.90, 95% CI 1.40-5.99), and HIV infection (OR 15.85, 95% CI 7.93-31.70) were independent risk factors. No differences in risk factors were identified between HIV-positive and HIV-negative patients. Contact with commercial sex workers was a new risk factor among HIV negative patients. Homosexual intercourse, rather than immunosuppressed status, appears to be a risk factor among HIV-positive patients. PMID- 22515840 TI - Partner relationships and long-term sick leave among female workers: consequences and impact on dimensions of health and return to work. AB - Few efforts have been made to prospectively identify resources and obstacles outside work that may predict regained work ability and return to work when workers are on sick leave. This study investigates the association between partner relationships and sick leave. Our research questions were as follows: (i) What is the influence of sick leave, pain, stress and domestic strain on the quality of the dyadic partner relationship?, and (ii) What is the influence of the partner and social relationship on pain, stress, work ability, self-rated health and return to work? A cohort of female workers (n = 225) on long-term sick leave (>60 days), all in a partner relationship, at 6-month intervals completed a questionnaire based on the Quality of Dyadic Relationship (QDR) instrument, the Interview Schedule of Social Interaction (ISSI), the Work Ability Index (WAI) and the Copenhagen Psychosocial Questionnaire (COPSOQ). Univariate and multivariate analyses of baseline and prospective data were performed. The results showed that decreased partner relationship quality was related to having major responsibility for household work despite being on sick leave, having pain and having decreased social integration. Among younger individuals on sick leave, a reduction in the quality of the partner relationship was shown already at the first (6-month) follow-up, while among middle-aged women, such a reduction was seen only at the 12-month follow-up. No dimensions of partner relationship quality at baseline were related to dimensions of return to work, either as a resource or as an obstacle. Consequently, our results show that a good relationship does not keep the woman from returning to work. Having main responsibility for household work, which implies domestic strain while on sick leave, predicts lower partner relationship quality. The practical implications are that healthcare professionals treating women on sick leave should emphasize the importance of keeping a social network as well as making sufficient adjustments at home for the relationship quality to be safeguarded. Special attention should be given to the young woman on sick leave as being on sick leave seems to influence her partner relationship considerably. PMID- 22515841 TI - Comparison of oral and transdermal administration of rasagiline mesylate on human melanoma tumor growth in vivo. AB - BACKGROUND/AIMS: Transdermal patch administration results in a locally high concentration of drug that induce local toxicity, including tumorogenicity. As a worst-case scenario for consequences of repeated application on neoplastic growth, the melanin-binding drug, rasagiline, was used in a transdermal formulation applied directly to a human-derived melanoma to determine the effects on tumor growth. MATERIALS AND METHODS: Rasagiline mesylate was administered either orally or transdermally to athymic mice implanted with human melanoma (SKMEL28) to determine the effects on tumor growth and survival. Over a 21-day period, animals were administered daily oral gavage (15 mg/kg) or one or two rasagiline mesylate transdermal patches every 3 days. After the last dose administration, blood samples were collected to confirm drug exposure. RESULTS: All animals from the untreated, vehicle and rasagiline groups survived to the end of the study; however, 7 out of the 10 cisplatin-treated animals died before the end of the study. Rasagiline mesylate dosed either via the oral or transdermal routes had comparable plasma exposure and, unexpectedly, significantly reduced absolute tumor volumes and tumor growth rates in the nude mouse SKMEL28 xenograft model. CONCLUSION: Transdermal delivery of melanin-binding rasagiline does not increase melanoma growth in the xenograft model. Because rasagiline decreases melanoma growth, it may be candidate for combination therapy for melanoma. PMID- 22515843 TI - A review of Platelet Derived Growth Factor playing pivotal role in bone regeneration. AB - Abstract : In this article we have tried to review the available literature and also the recent advances in the field of bone grafting which has involved platelet derived growth factor (PDGF) as one of the facilitating factor in bone regeneration. Here we have described the mechanism how PDGF can be used in surgeries where bone grafting is required. The importance of describing the molecular mechanism is that it will provide future application for faster bone regeneration and also the inhibitory mechanism in condition for bone regeneration as in osteosarcoma. The important specific activities of PDGF include mitogenesis (increase in the cell populations of healing cells), angiogenesis (endothelial mitoses into functioning capillaries) and macrophage activation (debridement of the wound site and a second phase source of growth factors for continued repair and bone regeneration). Thus PDGF can be utilized in wound with bone defect to conceal the wound with repair of bony defect. PMID- 22515842 TI - Chest trauma experience over eleven-year period at al-mouassat university teaching hospital-Damascus: a retrospective review of 888 cases. AB - BACKGROUND: Thoracic trauma is one of the leading causes of morbidity and mortality in developing countries. In this study, we present our 11-year experience in the management and clinical outcome of 888 chest trauma cases as a result of blunt and penetrating injuries in our university hospital in Damascus, Syria. METHODS: We reviewed files of 888 consequent cases of chest trauma between January 2000 and January 2011. The mean age of our patients was 31 +/- 17 years mostly males with blunt injuries. Patients were evaluated and compared according to age, gender, etiology of trauma, thoracic and extra-thoracic injuries, complications, and mortality. RESULTS: The leading cause of the trauma was violence (41%) followed by traffic accidents (33%). Pneumothorax (51%), Hemothorax (38%), rib fractures (34%), and lung contusion (15%) were the most common types of injury. Associated injuries were documented in 36% of patients (extremities 19%, abdomen 13%, head 8%). A minority of the patients required thoracotomy (5.7%), and tube thoracostomy (56%) was sufficient to manage the majority of cases. Mean hospital LOS was 4.5 +/- 4.6 days. The overall mortoality rate was 1.8%, and morbidity (n = 78, 8.7%). CONCLUSIONS: New traffic laws (including seat belt enforcement) reduced incidence and severity of chest trauma in Syria. Violence was the most common cause of chest trauma rather than road traffic accidents in this series, this necessitates epidemiologic or multi institutional studies to know to which degree violence contributes to chest trauma in Syria. The number of fractured ribs can be used as simple indicator of the severity of trauma. And we believe that significant neurotrauma, traffic accidents, hemodynamic status and GCS upon arrival, ICU admission, ventilator use, and complication of therapy are predictors of dismal prognosis. PMID- 22515844 TI - The new label for erythropoiesis stimulating agents: the FDA'S sentence. AB - On June 24, 2011, the U.S. Food and Drug Administration (FDA) revised the prescribing instructions (the label) for erythropoiesis-stimulating agents. The new label, the second revision since publication of the TREAT Study, placed new restrictions on the use of these agents, and increased the strength of warnings. We believe that the new label language may deprive patients of the full benefits of erythropoiesis-stimulating agent treatment and impair the opportunity to individualize treatment through shared decision making. Diminished discovery and innovation in the treatment of one of the most common and important complications of kidney disease may also be an unintended consequence of the label change. PMID- 22515845 TI - High anti-phenolic glycolipid-I IgM titers and hidden leprosy cases, Amazon region. PMID- 22515846 TI - Splicing modulation mediated by small nuclear RNAs as therapeutic approaches for muscular dystrophies. AB - Splice-modulation therapy aiming at correcting genetic defects by molecular manipulation of the premessenger RNA is a promising novel therapeutic approach for genetic diseases. In recent years, these new RNA based strategies, mostly mediated by antisense oligonucleotides (AO), have demonstrated encouraging results for muscular dystrophies, a heterogeneous group of genetic disorders characterized by muscle weakness and wasting. In particular, the clinical evaluation of antisense-mediated exon-skipping for the treatment of Duchenne muscular dystrophy has shown convincing data and therefore raised hopes and expectations for neuromuscular disorders therapy. However, AO-mediated splicing modulation still faces major hurdles such as low efficacy in specific tissues, poor cellular uptake and relatively rapid clearance from circulation, which means repeated administrations are required to achieve some therapeutic efficacy. To overcome these limitations, small nuclear RNAs (snRNA) have been used to shuttle the antisense sequences, offering the advantage of a correct subcellular localization with pre-mRNAs and the potential of a permanent correction when introduced into viral vectors. Here we review the recent progress in the development of snRNA mediated splicing modulation for muscular dystrophies, focusing on the advantages offered by this technology over classical AOs but also the challenges limiting their clinical application. PMID- 22515847 TI - Characterization of a Tembusu virus isolated from naturally infected house sparrows (Passer domesticus) in Northern China. AB - The house sparrow (Passer domesticus) is one of the most widely distributed wild birds in China. Tembusu virus (TMUV) strain, TMUV-SDHS, was isolated from house sparrows living around the poultry farms in Shandong Province, Northern China. Genetic analysis of E and NS5 genes showed that it had a close relationship with that of the YY5 strain, which can cause severe egg drop in ducks. Pathogenicity studies showed that the virus is highly virulent when experimentally inoculated into the ducks. These findings show that house sparrows carrying the Tembusu virus may play an important role in transmitting the virus among other species. PMID- 22515848 TI - Finding consensus on cervical cancer prevention. PMID- 22515849 TI - Quality improvement with pay-for-performance incentives in integrated behavioral health care. AB - OBJECTIVES: We evaluated a quality improvement program with a pay-for-performance (P4P) incentive in a population-focused, integrated care program for safety-net patients in 29 community health clinics. METHODS: We used a quasi-experimental design with 1673 depressed adults before and 6304 adults after the implementation of the P4P program. Survival analyses examined the time to improvement in depression before and after implementation of the P4P program, with adjustments for patient characteristics and clustering by health care organization. RESULTS: Program participants had high levels of depression, other psychiatric and substance abuse problems, and social adversity. After implementation of the P4P incentive program, participants were more likely to experience timely follow-up, and the time to depression improvement was significantly reduced. The hazard ratio for achieving treatment response was 1.73 (95% confidence interval=1.39, 2.14) after the P4P program implementation compared with pre-program implementation. CONCLUSIONS: Although this quasi-experiment cannot prove that the P4P initiative directly caused improved patient outcomes, our analyses strongly suggest that when key quality indicators are tracked and a substantial portion of payment is tied to such quality indicators, the effectiveness of care for safety net populations can be substantially improved. PMID- 22515850 TI - The status of legal authority for injury prevention practice in state health departments. AB - Despite the potential for public health strategies to decrease the substantial burden of injuries, injury prevention infrastructure in state health departments is underdeveloped. We sought to describe the legal support for injury prevention activities at state health departments. We searched the Lexis database for state laws providing authority for those activities, and categorized the scope of those laws. Only 10 states have authority that covers the full scope of injury prevention practice; in the others, legal authority is piecemeal, nonspecific, or nonexistent. More comprehensive legal authority could help health departments access data for surveillance, work with partners, address sensitive issues, and garner funding. Efforts should be undertaken to enhance legal support for injury prevention activities across the country. PMID- 22515851 TI - Safety belt laws and disparities in safety belt use among US high-school drivers. AB - OBJECTIVES: We compared reported safety belt use, for both drivers and passengers, among teenagers with learner's permits, provisional licenses, and unrestricted licenses in states with primary or secondary enforcement of safety belt laws. METHODS: Our data source was the 2006 National Young Driver Survey, which included a national representative sample of 3126 high-school drivers. We used multivariate, log-linear regression analyses to assess associations between safety belt laws and belt use. RESULTS: Teenaged drivers were 12% less likely to wear a safety belt as drivers and 15% less likely to wear one as passengers in states with a secondary safety belt law than in states with a primary law. The apparent reduction in belt use among teenagers as they progressed from learner to unrestricted license holder occurred in only secondary enforcement states. Groups reporting particularly low use included African American drivers, rural residents, academically challenged students, and those driving pickup trucks. CONCLUSIONS: The results provided further evidence for enactment of primary enforcement provisions in safety belt laws because primary laws are associated with higher safety belt use rates and lower crash-related injuries and mortality. PMID- 22515852 TI - Swimming upstream. PMID- 22515853 TI - Payment source and emergency management of deliberate self-harm. AB - OBJECTIVES: We investigated whether health insurance type (private vs Medicaid) influences the delivery of acute mental health care to patients with deliberate self-harm. METHODS: Using National Medicaid Analytic Extract Files (2006) and MarketScan Research Databases (2005-2007), we analyzed claims focusing on emergency episodes of deliberate self-harm of Medicaid- (n=8,228) and privately (n=2,352) insured adults. We analyzed emergency department mental health assessments and outpatient mental health visits in the 30 days following the emergency visit for discharged patients. RESULTS: Medicaid-insured patients were more likely to be discharged (62.7%), and among discharged patients they were less likely to receive a mental health assessment in the emergency department (47.8%) and more likely to receive follow-up outpatient mental health care (52.9%) than were privately insured patients (46.9%, 57.3%, and 41.2%, respectively). CONCLUSIONS: Acute emergency management of deliberate self-harm is less intensive for Medicaid- than for privately insured patients, although discharged Medicaid-insured patients are more likely to receive follow-up care. Programmatic reforms are needed to improve access to emergency mental health services, especially in hospitals that serve substantial numbers of Medicaid insured patients. PMID- 22515854 TI - A prospective investigation of physical health outcomes in abused and neglected children: new findings from a 30-year follow-up. AB - OBJECTIVES: We investigated whether abused and neglected children are at risk for negative physical health outcomes in adulthood. METHODS: Using a prospective cohort design, we matched children (aged 0-11 years) with documented cases of physical and sexual abuse and neglect from a US Midwestern county during 1967 through 1971 with nonmaltreated children. Both groups completed a medical status examination (measured health outcomes and blood tests) and interview during 2003 through 2005 (mean age=41.2 years). RESULTS: After adjusting for age, gender, and race, child maltreatment predicted above normal hemoglobin, lower albumin levels, poor peak airflow, and vision problems in adulthood. Physical abuse predicted malnutrition, albumin, blood urea nitrogen, and hemoglobin A1C. Neglect predicted hemoglobin A1C, albumin, poor peak airflow, and oral health and vision problems, Sexual abuse predicted hepatitis C and oral health problems. Additional controls for childhood socioeconomic status, adult socioeconomic status, unhealthy behaviors, smoking, and mental health problems play varying roles in attenuating or intensifying these relationships. CONCLUSIONS: Child abuse and neglect affect long-term health status-increasing risk for diabetes, lung disease, malnutrition, and vision problems-and support the need for early health care prevention. PMID- 22515855 TI - All public health is local. Revisiting the importance of local sanitation through the eyes of youth. PMID- 22515858 TI - Integrating biodiversity management and indigenous biopiracy protection to promote environmental justice and global health. AB - Many potentially useful medicines arise from developing countries' biodiverse environments and indigenous knowledge. However, global intellectual property rules have resulted in biopiracy, raising serious ethical concerns of environmental justice, exploitation, and health disparities in these populations. Furthermore, state-based approaches have not led to adequate biodiversity protection, management, or resource sharing, which affect access to lifesaving drugs. In response, country delegates adopted the Nagoya Protocol, which aims at promoting biodiversity management, combating biopiracy, and encouraging equitable benefits sharing with indigenous communities. However, the effectiveness of this framework in meeting these objectives remains in question. To address these challenges, we propose a policy building on the Nagoya Protocol that employs a World Health Organization-World Trade Organization Joint Committee on Bioprospecting and Biopiracy. PMID- 22515857 TI - Injury surveillance in New York City jails. AB - To characterize injuries occurring in jails, we analyzed injury report forms from the New York City jail system. We abstracted data from 4695 injury report forms representing 3863 patients. Of the injuries reported, 66% were classified as intentional. The 2 leading causes of injuries were inmate-on-inmate aggression (40%) and slips and falls (27%). Injuries place a considerable burden on jail health care systems, and there is a need for more studies on this problem and development of injury prevention programs. PMID- 22515856 TI - Geographic poverty and racial/ethnic disparities in cervical cancer precursor rates in Connecticut, 2008-2009. AB - OBJECTIVES: We examined associations of geographic measures of poverty, race, ethnicity, and city status with rates of cervical intraepithelial neoplasia grade 2 or higher and adenocarcinoma in situ (CIN2+/AIS), known precursors to cervical cancer. METHODS: We identified 3937 cases of CIN2+/AIS among women aged 20 to 39 years in statewide surveillance data from Connecticut for 2008 to 2009. We geocoded cases to census tracts and used census data to calculate overall and age specific rates. Poisson regression determined whether rates differed by geographic measures. RESULTS: The average annual rate of CIN2+/AIS was 417.6 per 100,000 women. Overall, higher rates of CIN2+/AIS were associated with higher levels of poverty and higher proportions of Black residents. Poverty was the strongest and most consistently associated measure. However, among women aged 20 to 24 years, we observed inverse associations between poverty and CIN2+/AIS rates. CONCLUSIONS: Disparities in cervical cancer precursors exist for poverty and race, but these effects are age dependent. This information is necessary to monitor human papillomavirus vaccine impact and target vaccination strategies. PMID- 22515859 TI - Community health workers as drivers of a successful community-based disease management initiative. AB - In 2005, local leaders in New York City developed the Washington Heights/Inwood Network for Asthma Program to address the burden of asthma in their community. Bilingual community health workers based in community organizations and the local hospital provided culturally appropriate education and support to families who needed help managing asthma. Families participating in the yearlong care coordination program received comprehensive asthma education, home environmental assessments, trigger reduction strategies, and clinical and social referrals. Since 2006, 472 families have enrolled in the yearlong program. After 12 months, hospitalizations and emergency department visits decreased by more than 50%, and caregiver confidence in controlling the child's asthma increased to nearly 100%. Key to the program's success was the commitment and involvement of community partners from program inception to date. PMID- 22515860 TI - Sudden unexpected infant deaths: sleep environment and circumstances. AB - OBJECTIVES: We sought to describe the characteristics and sleep circumstances of infants who die suddenly and unexpectedly and to examine similarities and differences in risk factors among infants whose deaths are classified as resulting from sudden infant death syndrome (SIDS), suffocation, or undetermined causes. METHODS: We used 2005 to 2008 data from 9 US states to assess 3136 sleep related sudden unexpected infant deaths (SUIDs). RESULTS: Only 25% of infants were sleeping in a crib or on their back when found; 70% were on a surface not intended for infant sleep (e.g., adult bed). Importantly, 64% of infants were sharing a sleep surface, and almost half of these infants were sleeping with an adult. Infants whose deaths were classified as suffocation or undetermined cause were significantly more likely than were infants whose deaths were classified as SIDS to be found on a surface not intended for infant sleep and to be sharing that sleep surface. CONCLUSIONS: We identified modifiable sleep environment risk factors in a large proportion of the SUIDs assessed in this study. Our results make an important contribution to the mounting evidence that sleep environment hazards contribute to SUIDs. PMID- 22515861 TI - A dynamic model of US adolescents' smoking and friendship networks. AB - OBJECTIVES: We investigated the associations between smoking and friend selection in the social networks of US adolescents. METHODS: We used a stochastic actor based model to simultaneously test the effects of friendship networks on smoking and several ways that smoking can affect the friend selection process. Data are from 509 US high school students in the National Longitudinal Study of Adolescent Health, 1994-1996 (46.6% female, mean age at outset=15.4 years). RESULTS: Over time, adolescents' smoking became more similar to their friends. Smoking also affected who adolescents selected as friends; adolescents were more likely to select friends whose smoking level was similar to their own, and smoking enhanced popularity such that smokers were more likely to be named as friends than were nonsmokers, after controlling for other friend selection processes. CONCLUSIONS: Both friend selection and peer influence are associated with smoking frequency. Interventions to reduce adolescent smoking would benefit by focusing on selection and influence mechanisms. PMID- 22515862 TI - The safe routes to school program in California: an update. AB - Despite efforts to combat increasing rates of childhood obesity, the problem is worsening. Safe Routes to School (SRTS), an international movement motivated by the childhood obesity epidemic, seeks to increase the number of children actively commuting (walking or biking) to school by funding projects that remove barriers preventing them from doing so. We summarize the evaluation of the first phase of an ongoing SRTS program in California and discuss ways to enhance data collection. PMID- 22515863 TI - Increasing cell phone usage among Hispanics: implications for telephone surveys. AB - OBJECTIVES: We examined whether the widespread assumption that Hispanics are subject to greater noncoverage bias in landline telephone surveys because they are more likely than other ethnic groups to use cell phones exclusively was supported by data. METHODS: Data came from the 2010 National Health Interview Survey and the 2009 California Health Interview Survey. We considered estimates derived from surveys of adults with landline telephones biased and compared them with findings for all adults. Noncoverage bias was the difference between them, examined separately for Hispanics and non-Hispanic Whites. RESULTS: Differences in demographic and health characteristics between cell-only and landline users were larger for non-Hispanic Whites than Hispanics; cell usage was much higher for Hispanics than non-Hispanic Whites. The existence, pattern, and magnitude of noncoverage bias were comparable between the groups. CONCLUSIONS: We found no evidence to support a larger noncoverage bias for Hispanics than non-Hispanic Whites in landline telephone surveys. This finding should be considered in the design and interpretation of telephone surveys. PMID- 22515864 TI - Addressing the implementation gap in global road safety: exploring features of an effective response and introducing a 10-country program. AB - Yearly, more than 1.2 million people are killed by road traffic injuries (RTIs) around the globe, and another 20 to 50 million are injured. The global burden of RTIs is predicted to rise. We explored the need for concerted action for global road safety and propose characteristics of an effective response to the gap in addressing RTIs. We propose that a successful response includes domains such as strong political will, capacity building, use of evidence-based interventions, rigorous evaluation, increased global funding, multisectoral action, and sustainability. We also present a case study of the global Road Safety in 10 Countries project, which is a new, 5-year, multipartner initiative to address the burden of RTIs in 10 low- and middle-income countries. PMID- 22515865 TI - Chronic and acute exposures to the world trade center disaster and lower respiratory symptoms: area residents and workers. AB - OBJECTIVES: We assessed associations between new-onset (post-September 11, 2001 [9/11]) lower respiratory symptoms reported on 2 surveys, administered 3 years apart, and acute and chronic 9/11-related exposures among New York City World Trade Center-area residents and workers enrolled in the World Trade Center Health Registry. METHODS: World Trade Center-area residents and workers were categorized as case participants or control participants on the basis of lower respiratory symptoms reported in surveys administered 2 to 3 and 5 to 6 years after 9/11. We created composite exposure scales after principal components analyses of detailed exposure histories obtained during face-to-face interviews. We used multivariate logistic regression models to determine associations between lower respiratory symptoms and composite exposure scales. RESULTS: Both acute and chronic exposures to the events of 9/11 were independently associated, often in a dose-dependent manner, with lower respiratory symptoms among individuals who lived and worked in the area of the World Trade Center. CONCLUSIONS: Study findings argue for detailed assessments of exposure during and after events in the future from which potentially toxic materials may be released and for rapid interventions to minimize exposures and screen for potential adverse health effects. PMID- 22515866 TI - "Here man learns about himself": visual education and the rise and fall of the American Museum of Health. AB - When the American Museum of Health (AMH) opened in 1939 at the World's Fair, its popularity convinced its organizers that the AMH was merely the first in a nationwide network of health museums. The AMH's organizers had imported an approach to health education developed in Germany, which promoted health as a positive attribute through interactive, visually impressive displays that relied on clarity and simplicity-as epitomized by the "Transparent Man"-to encourage a feeling of wonder among exhibit goers. However, other museum professionals rejected this approach, and the AMH failed to catalyze a broad health museum movement. Nevertheless, the notion that presenting the body as an object of wonder will improve the public's health has reappeared in the more recent past, as popular anatomical shows claim that exposing the interior of the human body will convince viewers to live healthier lives. PMID- 22515867 TI - Supporting the integration of HIV testing into primary care settings. AB - OBJECTIVES: We examined the efforts of the US network of AIDS Education and Training Centers (AETCs) to increase HIV testing capacity across a variety of clinical settings. METHODS: We used quantitative process data from 8 regional AETCs for July 1, 2008, to June 30, 2009, and qualitative program descriptions to demonstrate how AETC education helped providers integrate HIV testing into routine clinical care with the goals of early diagnosis and treatment. RESULTS: Compared with other AETC training, HIV testing training was longer and used a broader variety of strategies to educate more providers per training. During education, providers were able to understand their primary care responsibility to address public health concerns through HIV testing. CONCLUSIONS: AETC efforts illustrate how integration of the principles of primary care and public health can be promoted through professional training. PMID- 22515868 TI - Rampage violence requires a new type of research. AB - Tragedies such as school shootings and the assault on Congresswoman Gabrielle Giffords share features that define them as acts of "rampage violence." These types of events can lead to despair about their inevitability and unpredictability. To understand and prevent rampage violence, we need to acknowledge that current discipline-based violence research is not well suited to this specific challenge. There are numerous important, unanswered research questions that can inform policies designed to prevent rampage violence. It is time to develop alternative research approaches to reduce the risk of rampage violence. Such approaches should incorporate transdisciplinary research models; flexible, outcomes-focused organizational structures similar to those used to investigate other catastrophic events; and an expanded inventory of analytic tools. PMID- 22515869 TI - Neighborhood social inequalities in road traffic injuries: the influence of traffic volume and road design. AB - OBJECTIVES: We examined the extent to which differential traffic volume and road geometry can explain social inequalities in pedestrian, cyclist, and motor vehicle occupant injuries across wealthy and poor urban areas. METHODS: We performed a multilevel observational study of all road users injured over 5 years (n=19,568) at intersections (n=17,498) in a large urban area (Island of Montreal, Canada). We considered intersection-level (traffic estimates, major roads, number of legs) and area-level (population density, commuting travel modes, household income) characteristics in multilevel Poisson regressions that nested intersections in 506 census tracts. RESULTS: There were significantly more injured pedestrians, cyclists, and motor vehicle occupants at intersections in the poorest than in the richest areas. Controlling for traffic volume, intersection geometry, and pedestrian and cyclist volumes greatly attenuated the event rate ratios between intersections in the poorest and richest areas for injured pedestrians (-70%), cyclists (-44%), and motor vehicle occupants (-44%). CONCLUSIONS: Roadway environment can explain a substantial portion of the excess rate of road traffic injuries in the poorest urban areas. PMID- 22515870 TI - The global dimensions of public health preparedness and implications for US action. AB - The globalization of public health is both real and relevant throughout the United States and to Americans traveling or residing abroad. US public policy responses are evolving, but a crisper and more comprehensive global perspective is needed. I suggest four timely US actions to address today's competing realities of globalization and economic austerity: raise awareness among clinicians and local health departments; capture and share exemplary disaster management practices across countries; ensure that US global health investments are effective, efficient, and sustainable; and think globally while acting locally to enhance US health security. The reauthorization of the Pandemic and All-Hazards Preparedness Act of 2006 provides an opportunity to more clearly address the global dimensions of domestic preparedness. PMID- 22515871 TI - Implementing rapid HIV testing with or without risk-reduction counseling in drug treatment centers: results of a randomized trial. AB - OBJECTIVES: We examined the effectiveness of risk reduction counseling and the role of on-site HIV testing in drug treatment. METHODS: Between January and May 2009, we randomized 1281 HIV-negative (or status unknown) adults who reported no past-year HIV testing to (1) referral for off-site HIV testing, (2) HIV risk reduction counseling with on-site rapid HIV testing, or (3) verbal information about testing only with on-site rapid HIV testing. RESULTS: We defined 2 primary self-reported outcomes a priori: receipt of HIV test results and unprotected anal or vaginal intercourse episodes at 6-month follow-up. The combined on-site rapid testing participants received more HIV test results than off-site testing referral participants (P<.001; Mantel-Haenszel risk ratio=4.52; 97.5% confidence interval [CI]=3.57, 5.72). At 6 months, there were no significant differences in unprotected intercourse episodes between the combined on-site testing arms and the referral arm (P=.39; incidence rate ratio [IRR]=1.04; 97.5% CI=0.95, 1.14) or the 2 on-site testing arms (P=.81; IRR=1.03; 97.5% CI=0.84, 1.26). CONCLUSIONS: This study demonstrated on-site rapid HIV testing's value in drug treatment centers and found no additional benefit from HIV sexual risk-reduction counseling. PMID- 22515873 TI - A method for partitioning the attributable fraction of multiple time-dependent coexisting risk factors for an adverse health outcome. AB - OBJECTIVES: We decomposed the total effect of coexisting diseases on a timed occurrence of an adverse outcome into additive effects from individual diseases. METHODS: In a cohort of older adults enrolled in the Precipitating Events Project in New Haven County, Connecticut, we assessed a longitudinal extension of the average attributable fraction method (LE-AAF) to estimate the additive and order free contributions of multiple diseases to the timed occurrence of a health outcome, with right censoring, which may be useful when relationships among diseases are complex. We partitioned the contribution to death into additive LE AAFs for multiple diseases. RESULTS: The onset of heart failure and acute episodes of pneumonia during follow-up contributed the most to death, with the overall LE-AAFs equal to 13.0% and 12.1%, respectively. The contribution of preexisting diseases decreased over the years, with a trend of increasing contribution from new onset of diseases. CONCLUSIONS: LE-AAF can be useful for determining the additive and order-free contribution of individual time-varying diseases to a time-to-event outcome. PMID- 22515875 TI - Refining (not narrowing) notions of program sustainability. PMID- 22515874 TI - The health care home model: primary health care meeting public health goals. AB - In November 2010, the American Public Health Association endorsed the health care home model as an important way that primary care may contribute to meeting the public health goals of increasing access to care, reducing health disparities, and better integrating health care with public health systems. Here we summarize the elements of the health care home (also called the medical home) model, evidence for its clinical and public health efficacy, and its place within the context of health care reform legislation. The model also has limitations, especially with regard to its degree of involvement with the communities in which care is delivered. Several actions could be undertaken to further develop, implement, and sustain the health care home. PMID- 22515878 TI - Ludwig Teleky (1872-1957): a leader in social and occupational medicine. PMID- 22515877 TI - H1N1 influenza vaccination during pregnancy and fetal and neonatal outcomes. AB - OBJECTIVES: We evaluated the relationship between maternal H1N1 vaccination and fetal and neonatal outcomes among singleton births during the 2009-2010 H1N1 pandemic. METHODS: We used a population-based perinatal database in Ontario, Canada, to examine preterm birth (PTB), small-for-gestational-age (SGA) births, 5 minute Apgar score below 7, and fetal death via multivariable regression. We compared outcomes between women who did and did not receive an H1N1 vaccination during pregnancy. RESULTS: Of the 55,570 mothers with a singleton birth, 23,340 (42.0%) received an H1N1 vaccination during pregnancy. Vaccinated mothers were less likely to have an SGA infant based on the 10th (adjusted risk ratio [RR]=0.90; 95% confidence interval [CI]=0.85, 0.96) and 3rd (adjusted RR=0.81; 95% CI=0.72, 0.92) growth percentiles; PTB at less than 32 weeks' gestation (adjusted RR=0.73; 95% CI=0.58, 0.91) and fetal death (adjusted RR=0.66; 95% CI=0.47, 0.91) were also less likely among these women. CONCLUSIONS: Our results suggest that second- or third-trimester H1N1 vaccination was associated with improved fetal and neonatal outcomes during the recent pandemic. Our findings need to be confirmed in future studies with designs that can better overcome concerns regarding biased estimates of vaccine efficacy. PMID- 22515879 TI - Which factors predict unsuccessful outcome in a weight management intervention for obese children? AB - BACKGROUND: Many obese children attending weight management interventions experience positive changes; however, not all are successful and little is known about what factors influence treatment outcome. The present study aimed to assess which baseline characteristics may predict unsuccessful treatment outcome in a weight management intervention for obese children. METHODS: WATCH IT is a community weight management intervention for obese children and their families. Data collected during the pilot phase were visited retrospectively and secondary analysis was performed on the dataset. Inclusion criterion prioritised independent variables for the statistical model aiming to detect those that were exerting a significant effect. Logistic regression was used to assess the ability of these independent variables to predict unsuccessful treatment outcome. RESULTS: Seventy-eight children (mean age 11.9 years) who attended the WATCH IT weight management intervention for at least 6 months were included in the analysis. Multivariable regression analysis showed that children from families where both parents reported having a weight problem were six times more likely to be unsuccessful compared to children from families where neither parent reported weight problems (odds ratio = 6.1; 95% confidence interval = 1.2-32.0; P = 0.032). Age, gender, severity of obesity and duration of previous weight management attempts were not predictive of treatment outcome. CONCLUSIONS: To increase the overall success rate of children's weight management interventions such as WATCH IT, current approaches to behaviour change may need to be adapted or tailored for those families who are less likely to be successful. Supporting overweight parents to make their own successful lifestyle changes may be one way of improving the child's likelihood of weight management success. PMID- 22515880 TI - Effect of nitrous oxide on the efficacy of the inferior alveolar nerve block in patients with symptomatic irreversible pulpitis. AB - INTRODUCTION: The inferior alveolar nerve (IAN) block does not always result in successful pulpal anesthesia. Anesthetic success rates might be affected by increased anxiety. Nitrous oxide has been shown to have both anxiolytic and analgesic properties. Therefore, the purpose of this prospective, randomized, double-blind, placebo-controlled study was to determine the effect of nitrous oxide on the anesthetic success of the IAN block in patients experiencing symptomatic irreversible pulpitis. METHODS: One hundred emergency patients diagnosed with symptomatic irreversible pulpitis of a mandibular posterior tooth were enrolled in this study. Each patient was randomly assigned to receive an inhalation regimen of nitrous oxide/oxygen mix or room air/oxygen mix (placebo) 5 minutes before the administration of the IAN block. Endodontic access was begun 15 minutes after completion of the IAN block, and all patients had profound lip numbness. Success was defined as no or mild pain (visual analog scale recordings) on access or instrumentation. RESULTS: The success rate for the IAN block was 50% for the nitrous oxide group and 28% for the placebo group. There was a statistically significant difference between the 2 groups (P = .024). CONCLUSIONS: For mandibular teeth diagnosed with symptomatic irreversible pulpitis, administration of 30%-50% nitrous oxide resulted in a statistically significant increase in the success of the IAN block compared with room air/oxygen. PMID- 22515881 TI - Five-year longitudinal assessment of the prognosis of apical microsurgery. AB - INTRODUCTION: Apical surgery is an important treatment option for teeth with post treatment apical periodontitis. Knowledge of the long-term prognosis is necessary when weighing apical surgery against alternative treatments. This study assessed the 5-year outcome of apical surgery and its predictors in a cohort for which the 1-year outcome was previously reported. METHODS: Apical microsurgery procedures were uniformly performed using SuperEBA (Staident International, Staines, UK) or mineral trioxide aggregate (MTA) (ProRoot MTA; Dentsply Tulsa Dental Specialties, Tulsa, OK) root-end fillings or alternatively Retroplast capping (Retroplast Trading, Rorvig, Denmark). Subjects examined at 1 year (n = 191) were invited for the 5-year clinical and radiographic examination. Based on blinded, independent assessment by 3 calibrated examiners, the dichotomous outcome (healed or nonhealed) was determined and associated with patient-, tooth-, and treatment related variables using logistic regression. RESULTS: At the 5-year follow-up, 9 of 191 teeth were unavailable, 12 of 191 teeth were extracted, and 170 of 191 teeth were examined (87.6% recall rate). A total of 129 of 170 teeth were healed (75.9%) compared with 83.8% at 1 year, and 85.3% were asymptomatic. Two significant outcome predictors were identified: the mesial-distal bone level at <= 3 mm versus >3 mm from the cementoenamel junction (78.2% vs 52.9% healed, respectively; odds ratio = 5.10; confidence interval, 1.67-16.21; P < .02) and root-end fillings with ProRoot MTA versus SuperEBA (86.4% vs. 67.3% healed, respectively; odds ratio = 7.65; confidence interval, 2.60-25.27; P < .004). CONCLUSIONS: This study suggested that the 5-year prognosis after apical microsurgery was 8% poorer than assessed at 1 year. It also suggested that the prognosis was significantly impacted by the interproximal bone levels at the treated tooth and by the type of root-end filling material used. PMID- 22515882 TI - Response of pulp sensibility test is strongly influenced by periodontal attachment loss and gingival recession. AB - INTRODUCTION: To assess, in vivo, the influence of periodontal attachment loss and gingival recession on responses to pulp sensibility tests (PSTs) with cold stimuli in mandibular incisors in adult patients. METHODS: This cross-sectional study included 45 patients aged 30 to 60 years treated at a university dental health service. In each patient, 1 mandibular incisor was randomly selected for analysis. One calibrated dentist performed all periodontal assessments. Periodontal attachment loss and gingival recession were measured at 6 sites of the selected tooth followed by application of the PST on the buccal surface of the tooth by an independent operator. Each patient was asked to indicate a score for pain intensity on a numeric visual analog scale. The Pearson correlation coefficient was used to investigate and quantify the correlation between predictor variables (periodontal attachment loss and gingival recession) and reported pain. Simple and multiple linear regression analyses were performed to determine the impact of periodontal attachment loss and gingival recession on PST pain scores. RESULTS: Multivariate analysis showed that periodontal attachment loss contributed significantly to the prediction of pain in response to the PST (P < .001). Increases of 1 mm in periodontal attachment loss resulted in a decrease of approximately 0.5 score on the pain scale. Gingival recession also contributed as a predictor of the outcome (P < .001) with a decrease of approximately 0.7 in pain scores for every 1-mm increase in gingival recession. The correlations were in the opposite direction than expected. CONCLUSIONS: Periodontal attachment loss and gingival recession strongly influenced reported pain in response to PST with cold stimuli. The effect of both variables was constant (ie, responses to PST decreased gradually with increases in periodontal attachment loss and gingival recession). PMID- 22515883 TI - Tobacco smoking and radiographic periapical status: a retrospective case-control study. AB - INTRODUCTION: The aim of this study was to investigate radiographically the relationship of tobacco smoking and periapical status by using a retrospective case-control study design. METHODS: The records of 79 controls and 79 age- and sex-matched cases were examined. Case was defined as a patient who has at least 1 radiographically detectable periapical lesion in a tooth. Control was defined as a patient who has no radiographically detectable periapical lesion in any teeth. Periapical status was assessed by using panoramic radiographs and the periapical index score. The history of smoking and diabetes, the number of teeth and root filled teeth, and the quality of root fillings were recorded. Statistical analyses were conducted by using the Cohen kappa test, chi(2) test, Student's t test, and logistic regression analysis. RESULTS: Among the case subjects, 75% had antecedents of smoking, whereas in the control group only 13% had been smokers (odds ratio, 20.4; 95% confidence interval, 8.8-46.9; P = .0000). After multivariate logistic regression analysis adjusting for covariates (age, gender, number of teeth, root-filled teeth, root-filled teeth with a root filling technically unsatisfactory, and diabetes), a strong association was observed between the presence of at least 1 radiographically detectable periapical lesion and antecedents of smoking (odds ratio, 32.4; 95% confidence interval, 11.7-89.8; P = .0000). CONCLUSIONS: After adjusting for age, gender, number of teeth, endodontic status, quality of root filling, and diabetic status, tobacco smoking is strongly associated with the presence of radiographically diagnosed periapical lesions. PMID- 22515884 TI - Validity of self-reported history of endodontic treatment in the Baltimore Longitudinal Study of Aging. AB - INTRODUCTION: Self-reported history of endodontic treatment (SRHET) has been used as a simplified method to estimate the history of endodontic disease and treatment. This study aimed to quantify the validity of SRHET, as reported in the Baltimore Longitudinal Study of Aging (BLSA), as a method to identify individuals who experienced endodontic treatment (ET) and to identify individuals who present with apical periodontitis (AP). METHODS: SRHET was collected through the BLSA questionnaire in 247 participants. Data on ET and AP were determined from panoramic radiographs. The total number of ET, AP, and missing teeth were recorded for each individual. The validity of SRHET was determined based on ET and AP separately. Accuracy, efficiency, sensitivity, specificity, positive and negative predictive values (+PV and -PV), and positive and negative likelihood ratios (+LR and -LR) were calculated according to standard methods. RESULTS: After exclusions, 229 participants were available for ET analysis and 129 for AP analysis. The SRHET validity values were sensitivity (ET = 0.915, AP = 0.782), specificity (ET = 0.891, AP = 0.689), +PV (ET = 0.824, AP = 0.353), -PV (ET = 0.949, AP = 0.936), +LR (ET = 8.394, AP = 2.514), and -LR (ET = 0.095, AP = 0.316). CONCLUSIONS: SRHET was found to be a highly accurate method to predict ET but a weak predictor of the presence of AP among participants in the BLSA. PMID- 22515885 TI - Comparison of the anesthetic efficacy between bupivacaine and lidocaine in patients with irreversible pulpitis of mandibular molar. AB - INTRODUCTION: The purpose of this study was to compare the anesthetic efficacy of 0.5% bupivacaine with 1:200,000 epinephrine with that of 2% lidocaine with 1:100,000 epinephrine during pulpectomy in patients with irreversible pulpitis in mandibular posterior teeth. METHODS: Seventy volunteers, patients with irreversible pulpitis admitted to the Emergency Center of the School of Dentistry at the University of Sao Paulo, randomly received a conventional inferior alveolar nerve block containing 3.6 mL of either 0.5% bupivacaine with 1:200,000 epinephrine or 2% lidocaine with 1:100,000 epinephrine. During the subsequent pulpectomy, we recorded the patients' subjective assessments of lip anesthesia, the absence/presence of pulpal anesthesia through electric pulp stimulation, and the absence/presence of pain through a verbal analog scale. RESULTS: All patients reported lip anesthesia after the application of either inferior alveolar nerve block. By measuring pulpal anesthesia success with the pulp tester, lidocaine had a higher success rate (42.9%) than bupivacaine (20%). For patients reporting none or mild pain during pulpectomy, the success rate of bupivacaine was 80% and lidocaine was 62.9%. There were only statistically significant differences to the success of pulpal anesthesia. CONCLUSIONS: Neither of the solutions resulted in an effective pain control during irreversible pulpitis treatments of mandibular molars. PMID- 22515886 TI - Anesthetic efficacy of combinations of 0.5 mol/L mannitol and lidocaine with epinephrine for inferior alveolar nerve blocks in patients with symptomatic irreversible pulpitis. AB - INTRODUCTION: The purpose of these 2 prospective, randomized, single-blind studies was to determine the anesthetic efficacy of lidocaine with epinephrine compared with a combination lidocaine with epinephrine plus 0.5 mol/L mannitol for inferior alveolar nerve (IAN) blocks in patients experiencing symptomatic irreversible pulpitis. METHODS: In study one, 55 emergency patients randomly received IAN blocks by using a 3.18-mL formulation containing 63.6 mg of lidocaine with 31.8 MUg epinephrine or a 5-mL formulation containing 63.6 mg of lidocaine with 31.8 MUg epinephrine (3.18 mL) plus 1.82 mL of 0.5 mol/L mannitol. In study two, 51 emergency patients randomly received IAN blocks by using a 1.9 mL formulation containing 76.4 mg of lidocaine with 36 MUg epinephrine or a 3-mL formulation containing 76.4 mg of lidocaine with 36 MUg epinephrine (1.9 mL) plus 1.1 mL of 0.5 mol/L mannitol. Endodontic access was begun 15 minutes after the IAN block, and all patients had profound lip numbness. Success was defined as no or mild pain (visual analogue scale recordings) on endodontic access or instrumentation. RESULTS: The 1.9 mL of lidocaine (76.4 mg) with epinephrine plus 0.5 mol/L mannitol had a significantly (P = .04) better success rate of 39% when compared with the lidocaine formulation without mannitol (13% success rate). CONCLUSIONS: For mandibular posterior teeth in patients with symptomatic irreversible pulpitis, the addition of 0.5 mol/L mannitol to 1.9 mL of lidocaine (76.4 mg) with epinephrine resulted in a statistically higher success rate. However, the combination lidocaine/mannitol formulation would not result in predictable pulpal anesthesia. PMID- 22515887 TI - Genetic susceptibility to periapical disease: conditional contribution of MMP2 and MMP3 genes to the development of periapical lesions and healing response. AB - INTRODUCTION: It has been proposed that individual genetic predisposition may contribute to a persistent apical periodontitis condition. Matrix metalloproteinases (MMPs) are associated with levels of inflammation and are involved in caries, pulpal, and periapical tissue destruction. MMPs also play a major role in bone resorption. In this study, we hypothesized that polymorphisms in MMP genes and their regulators may contribute to an individual's increased susceptibility to apical tissue destruction in response to deep carious lesions. METHODS: Sixteen hundred radiographic records obtained through the University of Pittsburgh School of Dental Medicine Dental Registry and DNA Repository were screened for subjects with deep carious lesions in dentin with or without periapical lesions (>= 3 mm). DNA samples of 268 patients were sorted into 2 groups: 158 cases with deep carious lesions but no periapical lesions (controls) and 110 cases with periapical lesions and deep carious lesions (cases). Sixteen SNP markers in MMP2, MMP3, MMP9, MMP13, MMP14, and TIMP2, were selected for genotyping. Genotypes were generated by endpoint analysis in a real-time polymerase chain reaction instrument. Analyses were performed comparing cases and controls. Allele and genotypic frequencies and haplotype analysis were calculated using the PLINK program. RESULTS: An association was found for MMP3 rs639752 (P = .03) and rs679620 (P = .004) genotypes in individuals with periapical lesions. We also observed altered transmission of MMP2 marker haplotypes (P = .000004) in these individuals. CONCLUSIONS: Variations in MMP2 and MMP3 are associated with periapical lesion formation in individuals with untreated deep carious lesions. Future studies could help predict host susceptibility to developing periapical lesions. PMID- 22515888 TI - Low-intensity low-frequency ultrasound promotes proliferation and differentiation of odontoblast-like cells. AB - INTRODUCTION: Ultrasound is a potential therapeutic tool for dental tissue repair, but its biological effects on odontoblasts have not been well characterized. In this study, the effects of low-intensity low-frequency ultrasound on the viability, proliferation, and differentiation of odontoblast like cells were investigated. METHODS: Cell viability and proliferation were assessed after the treatment of adherent clonal MDPC-23 odontoblast-like cells with a 25-mW/cm(2) 45-kHz ultrasound. An in vitro scratch wound healing assay was used to investigate the ultrasound effects on cell migration. Long-term cultures were used to study odontogenic differentiation and extracellular mineralization. RESULTS: Ultrasound exposure for up to 30 minutes did not significantly affect odontoblast-like cell viability but significantly increased cell numbers after 2 days in culture. Ultrasound did not influence the scratch wound closure rate in the absence or presence of the mitogen inhibitor mitomycin C, indicating that ultrasound did not influence cellular migration. Single and consecutive exposures to ultrasound resulted in the enhancement of in vitro mineralization after 14 days in culture with an osteogenic differentiation medium. This coincided with the up-regulation of gene expression of collagen type I, osteoadherin, dentine matrix protein 1, and osteocalcin as well as the expression of cell markers alkaline phosphatase and nestin. CONCLUSIONS: These findings indicate that low frequency ultrasound is able to influence proliferation and differentiation of odontoblast-like cells and may potentially be considered as a therapeutic tool for dental pulp and dentine repair. PMID- 22515889 TI - Basic fibroblast growth factor enhances stemness of human stem cells from the apical papilla. AB - INTRODUCTION: Stem cells from the apical papilla (SCAP) are a type of mesenchymal stem cells found in the developing tissue, apical papilla, of immature permanent teeth. Studies have shown that SCAP are likely to be a source of primary odontoblasts that are responsible for the formation of root dentin. Basic fibroblast growth factor (bFGF) is a signaling molecule and pleiotropic growth factor involved in tooth root development, and it promotes proliferation of a variety of cell types. The effects of bFGF on SCAP, however, have not been examined. METHODS: We investigated the regulatory effects of bFGF on the proliferation and differentiation potential of human SCAP in vitro. Changes in the cell cycle and proliferation, colony-forming unit-fibroblastic formation, alkaline phosphatase (ALP) activity, osteogenic/dentinogenic differentiation, and stem cell gene makers of SCAP, cultured in the presence or absence of bFGF, were evaluated. RESULTS: Treatment with 5 ng/mL bFGF significantly increased SCAP proliferation and their colony-forming unit-fibroblastic formation efficiency. The growth factor also increased the expression of STRO-1 and the stem cell gene makers Nanog, Oct4, Sox2, and Rex1 in SCAP. In contrast, bFGF reduced the ALP activity, mineral nodule formation, and the expression of ALP, osteocalcin, bone sialoprotein, and dentin sialophosphoprotein. When SCAP cultures were expanded in the presence of bFGF for 1 week, subsequent stimulation of the osteogenic/dentinogenic condition resulted in enhanced differentiation. CONCLUSIONS: Under certain conditions, bFGF enhances SCAP stemness by up regulating stem cell gene expression, increasing proliferation ability, and potentiating differentiation potency. PMID- 22515890 TI - Lipopolysaccharide-induced stem cell factor messenger RNA expression and production in odontoblast-like cells. AB - INTRODUCTION: This study was done to evaluate the mechanism involved in stem cell factor (SCF) expression and production by lipopolysaccharide (LPS)-stimulated odontoblast (OD)-like cells and to investigate the signal transduction pathway activated in the process. METHODS: ODs-like cells (MDPC-23) were stimulated with different LPS concentrations for 1, 6, and 24 hours. SCF expression in OD-like cells was analyzed by reverse-transcriptase polymerase chain reaction, and SCF production was assessed by enzyme-linked immunosorbent assay. In another set of experiments, OD-like cells were pretreated with dexamethasone (DEX), MK886 (MK), p42/44 inhibitor (PD 98059 [PD]), p38 inhibitor (SB 202190 [SB]), or PI3K inhibitor (wortmannin [Wort]) for 30 minutes followed by stimulation with LPS (0.1 MUg/mL) for 1 hour. RESULTS: OD-like cells stimulated with LPS (0.1 MUg/mL) for 1 hour expressed SCF, but SCF production decreased with increasing LPS concentrations (1, 10, and 100 MUg/mL). DEX and MK were able to inhibit SCF messenger RNA (mRNA) expression. PD, SB, and Wort inhibited the SCF mRNA expression. CONCLUSIONS: LPS-induced SCF mRNA expression and production in OD like cells occur via leukotriene production or cytokine and/or chemokine formation, activating the p42/44, p38, and PI3K pathways. Data suggest that SCF released by OD-like cells may act as immune response modulators. PMID- 22515891 TI - Vascular endothelial growth factors and receptors are up-regulated during development of apical periodontitis. AB - INTRODUCTION: Apical periodontitis is a common inflammatory disease caused by persistent root canal infection and is characterized by bone resorption. Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) have been described in many pathologic and inflammatory conditions, but their involvement in the development of apical periodontitis has not been thoroughly investigated. The aim of this study was to quantify gene expression and localize VEGF-A, VEGF C, and VEGF-D and VEGFR-2 and VEGFR-3 in a rat model of apical periodontitis. METHODS: Molar pulps were unilaterally exposed to the oral cavity for 10 or 21 days. Jaw sections were used for localization of VEGFs and VEGFRs with immunohistochemistry and identification of cells with double immunofluorescence. Gene expression analysis for VEGF-A, VEGF-C, and VEGFR-3 of periapical tissues was performed with quantitative real-time polymerase chain reaction. RESULTS: All investigated factors and receptors were expressed immunohistochemically in blood vessels at the periodontal ligament of control teeth and were up-regulated during lesion development. In apical lesions, macrophages and neutrophils expressed all studied factors and receptors, with macrophages being an important source of VEGF C and VEGF-D. Osteoclasts expressed VEGFR-2 and VEGFR-3, and the latter was also identified in fibroblast-like cells in the lesions. VEGF-A and VEGFR-3 gene expression was up-regulated at days 10 and 21 (P < .05). CONCLUSIONS: The current findings indicate that the VEGF family and receptors are involved in vascular remodeling and immune functions during disease development. The presence of VEGFR 2 and VEGFR-3 on osteoclasts indicates that bone resorbing activity is influenced by VEGFs. PMID- 22515892 TI - No evidence for DNA double-strand breaks caused by endodontic sealers. AB - INTRODUCTION: On extrusion, endodontic sealers might come into close contact with the periapical tissues for long periods. The objective of this study was to test possible mutagenicity of resin-based endodontic sealers by evaluating their potential to induce DNA double-strand breaks (DSBs). METHODS: Human gingival fibroblasts were exposed to subtoxic concentrations of eluates from 1 epoxy resin based endodontic sealer (AH Plus Jet) and 2 methacrylate-based endodontic sealers (EndoRez and Real Seal). As control, Calcicur, a Ca(OH)(2)-based sealer, was used. The gamma-H2AX immunofluorescence assay was used to microscopically detect DNA DSBs, and a custom algorithm was developed to quantify them. RESULTS: The cytotoxicity of the 24-hour eluates could be ranked in the following order: AH Plus Jet > Real Seal > EndoRez >> Calcicur. The gamma-H2AX assay revealed that 1.3%-4.3% of the cell nucleus was occupied by foci when the cells were exposed to the eluates of the endodontic sealers. This was not significantly different from the negative control group in which the cells had been exposed to medium (2.1%). CONCLUSIONS: No indications for increased risk of genotoxicity of resin-based root canal sealers caused by the induction of DNA DSBs were found in this study. PMID- 22515893 TI - Proliferation and multilineage potential of CXCR4-positive human dental pulp cells in vitro. AB - INTRODUCTION: Although the results of our previous studies showed that the stromal cell-derived factor (SDF)-1alpha-CXC chemokine receptor 4 (CXCR4) axis may play a role in the recruitment of CXCR4-positive dental pulp cells (CXCR4(+) DPCs) toward the damaged sites, the specific function of CXCR4(+) DPCs in the injured dental pulp was still unknown. The purpose of this study was to verify whether CXCR4(+) DPCs possessed stem cells properties so that we can understand their role in area of injury. METHODS: CXCR4(+) DPCs were isolated from normal DPCs with magnetic-activated cell sorting. The characteristics of the cells from the 3 groups of cells (ie, CXCR4(+) DPCs, CXCR4(-) DPCs, or nonsorted DPCs) were analyzed in colony formation, proliferation, and multilineage differentiation including odontogenic and adipogenic lineages. RESULTS: The results showed that CXCR4(+) DPCs were the most dominant population in colony formation, proliferation, alkaline phosphatase activity, calcium content, and adipogenic differentiation among the 3 groups. CONCLUSIONS: CXCR4(+) DPCs may contain more stem cells than nonsorted DPCs. PMID- 22515894 TI - Gene expression analysis of membrane transport proteins in normal and lipopolysaccharide-inflamed rat dental pulp. AB - INTRODUCTION: Membrane transport proteins (transporters) play a crucial role in the transmembrane uptake and/or efflux of various compounds such as inorganic ions, endogenous bioactive substances such as prostaglandins (PGs), and drugs such as nonsteroidal anti-inflammatory drugs. This study aimed to analyze mRNA expression of selected transporters related to drug disposition and PG transport in normal and lipopolysaccharide (LPS)-inflamed rat incisor pulp. METHODS: Pulp tissues were subjected to reverse transcription-polymerase chain reaction (PCR) detection for transporter isoforms belonging to organic anion transporting polypeptide (Oatp), organic anion transporter (Oat), organic cation transporter (Oct), multidrug resistance-associated protein (Mrp), and multidrug resistance protein (Mdr) families. The levels of mRNA expression for PG transporters (Oatp1a5, Oatp1b2, Oatp2a1, Oatp2b1, and Oatp3a1) were compared in normal and LPS inflamed pulps by using real-time PCR. RESULTS: The pulp tissue expressed mRNAs for various transporters belonging to the Oatp, Oat, Oct, Mrp, and Mdr families. LPS inflammation caused significant up-regulation of Oatp2a1 (P < .01) and significant down-regulation of Oatp1a5, Oatp2b1 (P < .01), and Oatp3a1 (P < .05). CONCLUSIONS: Rat incisor dental pulp expressed mRNAs for various transporter isoforms. The levels of mRNA expression for PG transporters were significantly up regulated or down-regulated in LPS-inflamed dental pulp. PMID- 22515895 TI - Resistance to vertical root fracture of endodontically treated teeth with MetaSEAL. AB - INTRODUCTION: The purpose of this in vitro study was to assess the influence of MetaSEAL and AH Plus on the resistance to vertical root fracture of endodontically treated teeth when either the matched-taper single-cone or lateral condensation technique was used. METHODS: Ninety extracted single-canal mandibular premolar teeth were sectioned, leaving a standard root length of 13 mm. The buccolingual and mesiodistal diameters were measured, and the teeth were randomly divided into 6 groups (n = 15). There were no statistically significant differences between the groups in terms of the diameters. In group 1, no instrumentation or obturation was performed. The rest of the roots were chemomechanically prepared with nickel-titanium ProTaper rotary instruments up to size F3 at the working length. Group 2 was left unobturated. Groups 3 and 4 were obturated with AH Plus used with the matched-taper single-cone and lateral condensation techniques, respectively. In groups 5 and 6, MetaSEAL was used instead of AH Plus. All of the roots were mounted vertically in self-curing acrylic resin blocks that exposed 8 mm of the coronal part. Then the roots were subjected to a vertical loading force (1 mm/min). The force required to produce a fracture was recorded in newtons. The data were analyzed by using Kruskal-Wallis and post hoc Dunn multiple comparison tests (P < .05). RESULTS: Although we did not detect statistical significance, there was a substantial difference between the fracture resistance values of the intact and instrumented but not obturated roots. The groups in which AH Plus and MetaSEAL were used with the matched-taper single-cone technique showed significantly higher fracture resistance values than the instrumented but not obturated roots (P < .05). There were no significant differences between the groups submitted to the matched-taper single-cone technique. The force required to fracture the roots in the group treated with AH Plus and the lateral condensation technique was similar to that required to fracture intact roots, whereas the group treated with MetaSEAL and the lateral condensation technique revealed comparable values to the instrumented but not obturated roots. CONCLUSIONS: When used with the matched-taper single-cone technique, MetaSEAL and AH Plus have the potential to reinforce endodontically treated teeth. PMID- 22515896 TI - Irrigant flow beyond the insertion depth of an ultrasonically oscillating file in straight and curved root canals: visualization and cleaning efficacy. AB - INTRODUCTION: The purpose of this study was to evaluate the influence of the insertion depth of an ultrasonically oscillating file on the ability to remove dentin debris from simulated canal irregularities in an extracted tooth model of a straight root canal and its influence on the flow of irrigant in both straight and curved canals. METHODS: A tooth model with artificial depressions in 1 canal wall at 0.5, 2, 4, and 6 mm from the working length was used. Ultrasonic activated irrigation was performed with the file inserted 1, 2, 3, 4, or 5 mm short of the working length. Dye penetration and high-speed recordings of the flow in straight and curved canals showed the static and dynamic behavior of the flow during ultrasonic activation. RESULTS: The overall cleaning efficacy decreased with increasing distance between the file and the apex, with the depressions next to the file and within 3 mm in front of the file being the cleanest. The flow observed from the visualization experiments matched this distance, suggesting a direct relation between flow and cleaning. The observed flow depth increased with increasing power setting; the curvature of the root canal had no influence on the flow depth. High-speed imaging showed a start-up phase with deeper fluid activation than in the steady phase afterward. CONCLUSIONS: The ultrasonically oscillating file could remove dentin debris up to 3 mm in front of the file tip, coinciding with the extent of the observed flow. The root canal curvature had no influence on the irrigant flow. PMID- 22515897 TI - In vitro evaluation of dentin tubule occlusion by Denshield and Neodymium-doped yttrium-aluminum-garnet laser irradiation. AB - INTRODUCTION: This in vitro study evaluated the efficacy of bioglass (Denshield; Novamin Technology, Alachua, FL) and Neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser irradiation on dentinal tubuli orifice occlusion (DOO) by comparing samples examined under environmental scanning electron microscope (ESEM) after applying each desensitizing approach separately and in combination. METHODS: Forty-eight human molars were collected, randomly organized in 4 equal groups, and had their cervical dentin exposed. Additionally, in half of the specimens of each experimental group, the smear layer was removed (subgroups A1, B1, C1, and D1). Group A received NovaMin paste treatment for 5 minutes (NM) to the experimental surface. Group B received Nd:YAG laser irradiation (0.5 w, 10 Hz, and 50 mJ) (L). Group C received NM followed by L. Group D was treated with L followed by NM. All specimens were stored for 24 hours and evaluated for DOO under ESEM by 4 blinded observers. RESULTS: The presence of a smear layer significantly contributed to DOO regardless of the treatment modality (ordinal logistic regression, P < .001). Compared with group A, all other treatments delivered significantly more occluded dentin orifices (P < .001 for groups B and D and P < .05 for group C). A layer formation was observed in subgroups C2 and D2. CONCLUSIONS: Under these experimental conditions, a smear layer was essential for successful DOO. Laser irradiation alone and combined with NovaMin proved superior to NovaMin alone on DOO. This combined approach has the potential to improve the outcome of treatment for cervical dentin hypersensitivity. The biological significance of this newly formed layer needs to be elucidated. PMID- 22515898 TI - Resistance to cyclic fatigue failure of a new endodontic rotary file. AB - INTRODUCTION: A new nickel-titanium (NiTi) rotary file called the ProFile Vortex (PV; Denstply, Tulsa Dental Specialties, Tulsa, OK) has recently been released for endodontic use. The purpose of this study was to compare cyclic fatigue resistance of the new size 30 PV files with size 30 files of other popular brands. Other files tested include Twisted File (TF; Sybron Dental Specialties, Orange, CA), ProFile (PF; Denstply Tulsa Dental Specialties, Tulsa, OK), GTX (GTX, Denstply Tulsa Dental Specialties), and EndoSequence (ES; Brasseler, Savannah, GA). METHODS: Size 30 files with a constant .06-mm/mm taper were rotated at manufacturer-recommended speed and torque settings in a simulated canal until failure. RESULTS: Significant differences were found between the various brands of files. The differences between file brands may be because of a different manufacturing process or differences in file design. CONCLUSIONS: Based on a simulated canal model, the PV, TF, and GTX files appear to offer greater cyclic fatigue resistance than ES and PF files. PMID- 22515899 TI - A micro-computed tomography evaluation of mineral trioxide aggregate root canal fillings. AB - INTRODUCTION: The aim of this study was to assess the effect of indirect ultrasonic activation on the incidence of voids within mineral trioxide aggregate (MTA) root canal fillings and at their interface with the canal walls by using a nondestructive 3-dimensional (3D) micro-computed tomography (micro-CT) analysis. METHODS: Extracted human teeth with single canals and minimal curvatures were decoronated, instrumented to size 50/05 apically, and randomly allocated into 4 groups (n = 12). MTA was compacted manually by using hand pluggers in group A (MC). Indirect ultrasonic activation was applied to each increment of manually compacted MTA for 1 second in group B (1 sec-UC), 5 seconds in group C (5 sec UC), and 10 seconds in group D (10 sec-UC). Filled roots were scanned with a micro-CT device, and 3D analysis of void incidence was carried out by using the SkyScan software. RESULTS: Statistical analysis showed a significantly lower incidence of voids (P < .05) in the manual compaction (MC) group (0.7%) compared with the ultrasonic activation for 1 second (3.8%), 5 seconds (1.7%), and 10 seconds (1.6%) groups. CONCLUSIONS: Manual compaction produced significantly denser root fillings than those achieved with ultrasonic activation. PMID- 22515900 TI - Effect of nitrogen ion implantation on the flexibility of rotary nickel-titanium instruments. AB - INTRODUCTION: The aim of this study was to assess the effect of nitrogen ion implantation on the flexibility of rotary nickel-titanium (NiTi) instruments as measured by the load required to bend implanted and nonimplanted instruments at a 30 degrees angle. METHODS: Thirty K3 files, size #40, 0.02 taper and 25-mm length, were allocated into 2 groups as follows: group A, 15 files exposed to nitrogen ion implantation at a dose of 2.5 * 10(17) ions/cm(2), voltage 200 KeV, current density 1 MUA/cm(2), temperature 130 degrees C, and vacuum conditions of 10 * 10(-6) mm Hg for 6 hours; and group B, 15 nonimplanted files. One extra file was used for process control. All instruments were subjected to bend testing on a modified troptometer, with measurement of the load required for flexure to an angle of 30 degrees . The Mann-Whitney U test was used for statistical analysis. Findings with P <.05 were considered significant. RESULTS: The mean load required to bend instruments at a 30 degrees angle was 376.26 g for implanted instruments and 383.78 g for nonimplanted instruments. The difference was not statistically significant. CONCLUSIONS: Our findings show that nitrogen ion implantation has no appreciable effect on the flexibility of NiTi instruments. PMID- 22515901 TI - Ability of gutta-percha and Resilon to fill simulated lateral canals by using the Obtura II system. AB - INTRODUCTION: The aim of this study was to evaluate the ability of Resilon (Resilon Research, LLC, North Branford, CT) and 2 types of gutta-percha to fill simulated lateral canals when using the Obtura II system (Model 823-700; Obtura Spartan, Fenton, MO). METHODS: Forty-five human single-rooted teeth were selected and subjected to root canal preparation. After that, simulated lateral canals were made at 2, 5, and 8 mm from the working length (WL). The specimens were divided into 3 groups (n = 15) according to the filling material used: Obtura Flow 150 gutta-percha (Obtura flow), Odous Endo Flow gutta-percha (Odous; Odous De Deus Ind e Com. Ltda Belo Horizonte, MG, Brazil), and Resilon pellets (Resilon). Root canals were filled using the Obtura II system with the tip inserted to 3 mm from the WL. No sealer was used for root canal obturation. Specimens were subjected to a tooth decalcification and clearing method, and filling of the lateral canals was analyzed by digital radiography and photographs. The measurement of lateral canal filling was done using Image Tool software (UTHSCSA Image Tool for Windows version 3.0, San Antonio, TX). Data were statistically analyzed with the Kruskal-Wallis test at 5% significance. RESULTS: All materials showed an ability to penetrate into the simulated lateral canals, with a minimum percentage of 73% in all thirds of the root canal. CONCLUSIONS: It was concluded that gutta-percha and Resilon are solid core materials with a lateral canal filling ability when used with the Obtura II system. PMID- 22515902 TI - Effects of calcium silicate-based materials on the flexural properties of dentin. AB - INTRODUCTION: Prolonged exposure of root dentin to calcium hydroxide alters the fracture resistance of dentin. Calcium silicate-based materials (CSMs) used in endodontics release calcium hydroxide on setting. This study examined whether prolonged contact of dentin with CSMs adversely affects its mechanical properties. METHODS: Dentin beams prepared from extracted human molars (7 * 3 * 0.3 mm) were divided into 3 groups on the basis of the material to which dentin was exposed (Biodentine, MTA Plus, and untreated control beams). Three-point flexure to failure was performed for each beam at designated exposure times (24 hours, 1, 2, and 3 months; n = 10). Data were analyzed with 2-factor repeated measures analyses of variance to determine the effects of material and aging time on flexural modulus, flexural strength, and modulus of toughness (alpha = 0.05). RESULTS: For flexural modulus, there was no significant difference for material (P = .947) or aging time (P = .064) when compared with baseline control. For flexural strength, significant differences were associated with aging time (P < .001) but not with material (P = .349). Flexural strength of dentin exposed to Biodentine decreased significantly after 2 and 3 months, whereas that exposed to MTA Plus decreased significantly after 3 months of aging (P < .05). For modulus of toughness, significant declines were observed for both material (P < .004) and aging time (P < .001). CONCLUSIONS: Both CSMs alter material toughness more than the strength and stiffness of dentin after aging in 100% relative humidity. Because dentin toughness is attributed to its collagen matrix, the amount of collagen extracted from mineralized dentin and changes in collagen ultrastructure should be further examined after exposure of dentin to CSMs. PMID- 22515903 TI - Resistance to flexural fatigue of Reciproc R25 files under continuous rotation and reciprocating movement. AB - INTRODUCTION: The aim of the present work was to evaluate the resistance to flexural fatigue of Reciproc R25 nickel-titanium files, 25 mm, used in continuous rotation motion or reciprocation motion, in dynamic assays device. METHODS: Thirty-six Reciproc R25 files were divided into 2 groups (n = 18) according to kinematics applied, continuous rotary (group CR) and reciprocation motion (group RM). The files were submitted to dynamic assays device moved by an electric engine with 300 rpm of speed that permitted the reproduction of pecking motion. The files run on a ring's groove of temperate steel, simulating instrumentation of a curved root canal with 40 degrees and 5 mm of curvature radius. The fracture of file was detected by sensor of device, and the time was marked. The data were analyzed statistically by Student's t test, with level of significance of 95%. RESULTS: The instruments moved by reciprocating movement reached significantly higher numbers of cycles before fracture (mean, 1787.78 cycles) when compared with instruments moved by continuous rotary (mean, 816.39 cycles). CONCLUSIONS: The results showed that the reciprocation motion improves flexural fatigue resistance in nickel-titanium instrument Reciproc R25 when compared with continuous rotation movement. PMID- 22515904 TI - In vitro comparison of passive and continuous ultrasonic irrigation in simulated lateral canals of extracted teeth. AB - INTRODUCTION: Complete endodontic system disinfection requires the removal of vital and necrotic pulp tissue, microorganisms, and toxins. The purpose of this study was to compare the effects of 2 ultrasonic irrigation techniques on the penetration of sodium hypochlorite into the main canal and simulated lateral canals of extracted teeth. METHODS: Two simulated lateral canals each were created 2, 4, and 6 mm from the working length in 60 single-rooted teeth (6 canals/tooth, n = 360). To resemble the clinical situation, a closed system was created in each tooth. The teeth were randomly assigned to 3 experimental irrigation groups: group 1 (n = 20), positive pressure irrigation (PPI); group 2 (n = 20), passive ultrasonic irrigation (PUI); and group 3 (n = 20), continuous ultrasonic irrigation (CUI). Samples were evaluated by direct observation of still images recorded under a dental operating microscope. To examine irrigating solution penetration, 20% Chinese ink (Sanford Rotring GmbH, Hamburg, Germany) was added to a 5% sodium hypochlorite solution and delivered into the root canals. RESULTS: The results showed a significantly higher (P < .05) penetration of irrigant into the lateral canals in the CUI group. PUI and CUI did not differ significantly in solution penetration into the apical thirds of the main canals. The PPI group showed a significantly lower penetration of sodium hypochlorite into the main and lateral canals compared with the CUI and PUI groups. CONCLUSIONS: CUI as a final rinse significantly increased the penetration of irrigating solution into simulated lateral canals. PMID- 22515905 TI - Reduction of hard-tissue debris accumulation during rotary root canal instrumentation by etidronic acid in a sodium hypochlorite irrigant. AB - INTRODUCTION: Hard-tissue debris is accumulated during rotary instrumentation. This study investigated to what extent a calcium-complexing agent that has good short-term compatibility with sodium hypochlorite (NaOCl) could reduce debris accumulation when applied in an all-in-one irrigant during root canal instrumentation. METHODS: Sixty extracted mandibular molars with isthmuses in the mesial root canal system were selected based on prescans using a micro-computed tomography system. Thirty teeth each were randomly assigned to be instrumented with a rotary system and irrigated with either 2.5% NaOCl or 2.5% NaOCl containing 9% (wt/vol) etidronic acid (HEBP). Using a side-vented irrigating tip, 2 mL of irrigant was applied by 1 blinded investigator to the mesial canals after each instrument. Five milliliters of irrigant was applied per canal as the final rinse. Mesial root canal systems were scanned at high resolution before and after treatment, and accumulated hard-tissue debris was calculated as vol% of the original canal anatomy. Values between groups were compared using the Student's t test (alpha < .05). RESULTS: Irrigation with 2.5% NaOCl resulted in 5.5 +/- 3.6 vol% accumulated hard-tissue debris compared with 3.8 +/- 1.8 vol% when HEBP was contained in the irrigant (P < .05). CONCLUSIONS: A hypochlorite-compatible chelator can reduce but not completely prevent hard-tissue debris accumulation during rotary root canal instrumentation. PMID- 22515907 TI - Effects of bone graft materials on the microhardness of mineral trioxide aggregate. AB - INTRODUCTION: Large through-and-through lesions have been reported to heal faster and better when filled with bone graft material at the time of an apicoectomy. It is unknown what effect these have on retrograde filling materials such as white mineral trioxide aggregate (WMTA). In this study, the null hypothesis was tested that the presence of bone graft materials does not affect the microhardness of WMTA. METHODS: Freshly mixed WMTA was condensed into acrylic cylinders and preincubated aerobically at 37 degrees C for 1 hour. Cylinders were immersed in simulated body fluid in close proximity to graft materials: xenograft (Bio-Oss, n = 60), freeze-dried bone allograft (MinerOss, n = 60), demineralized freeze-dried bone allograft (OraGraft, n = 40), and allograft (Puros, n = 60). Knoop microhardness of half the samples in each group was evaluated after 2 weeks of incubation and the remainder at 4 weeks. The values for each group were then compared with 2-way analysis of variance and Bonferroni post hoc tests. RESULTS: WMTA microhardness values for Bio-Oss, MinerOss, and Puros groups were lower than those for OraGraft and control groups regardless of incubation period (P < .001); values for the OraGraft group were higher than those for the control group at 2 weeks (P < .001), with no difference at 4 weeks. Microhardness values were higher at 4 weeks compared with 2 weeks for MinerOss (P < .05), OraGraft (P < .01), and control (P < .001), with no differences for Bio-Oss and Puros groups. The null hypothesis was rejected. CONCLUSIONS: Demineralized and mineralized graft materials appear to have a differential effect on the microhardness of WMTA. PMID- 22515906 TI - The effect of prior calcium hydroxide intracanal placement on the bond strength of two calcium silicate-based and an epoxy resin-based endodontic sealer. AB - INTRODUCTION: The aim of this study was to investigate the effect of prior calcium hydroxide (Ca[OH](2)) intracanal placement on the bond strength of AH Plus (Dentsply DeTrey GmbH, Konstanz, Germany), iRoot SP (Innovative Bioceramix, Vancouver, BC, Canada), and MTA Fillapex (Angelus Solucoes Odontologicas, Londrina, PR, Brazil). METHODS: The root canals of 90 human incisor teeth were prepared with the ProTaper System (Dentsply Maillefer, Ballaigues, Switzerland) up to a master apical file size of F5. Canals were filled using the single-cone technique either immediately (the control group, n = 30) or after a 7-day Ca(OH)(2) placement. Ca(OH)(2) removal was performed either manually using F5 with distilled water irrigation (the Ca[OH](2) group, n = 30) or manually using Protaper F5 followed by passive ultrasonic irrigation with 2.5 % NaOCl with a final flush of 17 % EDTA and then distilled water (the PUI group, n = 30). After obturation, a 2-mm-thick middle section of each root was then subjected to push out testing. RESULTS: Using 1-way analysis of variance, AH Plus showed a higher bond strength than iRoot SP and MTA Fillapex in the control group (P < .05). With prior Ca(OH)(2) placement, AH Plus and iRoot SP showed a similar bond strength (P > .05), which was higher than MTA Fillapex (P < .05). CONCLUSIONS: Prior Ca(OH)(2) placement seemed to improve the dislodgment resistance of iRoot SP but did not affect AH Plus and MTA Fillapex. PMID- 22515908 TI - The effect of surfactant addition to EDTA on microhardness of root dentin. AB - INTRODUCTION: The aim of this study was to investigate the effect of different concentrations of cetrimide with or without 5% EDTA solution on the microhardness of human root dentin in vitro. METHODS: Twenty-five recently extracted single rooted human teeth were selected. The roots were split longitudinally into 2 parts. The specimens were randomly divided into the following 5 groups and were treated with 5% EDTA, 5% EDTA + 0.25% cetrimide, 5% EDTA + 0.50% cetrimide, 0.25% cetrimide, and 0.50% cetrimide immediately after the initial baseline microhardness measurements. A standardized volume of 50 mL of each solution was used for 1 minute. The reference microhardness values of untreated specimens were initially measured with a Vickers indenter under a 50-g load and a 10-second dwell time at the midroot level of the root dentin. Post-treatment microhardness values were obtained in the same manner as the initial ones. The decrease in microhardness was calculated as a percentage. Data were analyzed statistically by 1-way analysis of variance (P = .05) and the post hoc Tukey test for multiple comparisons at the same level of significance. RESULTS: All solutions significantly decreased the microhardness of root dentin (P < .05). Although there was no significant difference among the solutions (P > .05), the specimens in the EDTA + 0.50% cetrimide solution group showed the highest change in microhardness. The plain EDTA and plain 0.50% cetrimide groups had similar values. CONCLUSIONS: The use of surfactants higher than 0.25% in concentration is questionable for clinical conditions. PMID- 22515910 TI - Simulations of solvation and solvation dynamics in an idealized ionic liquid model. AB - Equilibrium and nonequilibrium molecular dynamics simulations of solvation and solvation dynamics of a variety of solutes have been performed in the coarse grained ionic liquid model ILM2 (Roy, D.; Maroncelli, M. J. Phys. Chem. B 2010, 114, 12629). Some comparisons are made between ionic and dipolar solvation using parallel simulations in CH(3)CN. Despite the fact that the multipolar character of electrostatic interactions and their spatial extent differ in the two solvents, solvation energies are equal to within about 10% in ILM2 and CH(3)CN. This near equality also holds with reduced accuracy in the case of reorganization energies. Solvation energies of spherical solutes in ILM2 and its variants can be correlated as a function of solute and solvent size using a Born-type expression with an effective cavity size. Solvation time correlation functions in ILM2 exhibit a subpicosecond inertial component followed by a broadly distributed component related to solvent viscosity, comparable to what has been observed in experiment. Direct comparison of simulation to experiment using the solute coumarin 153 (C153) shows general agreement on the time scales and character of the fast and slow components, but the amplitude of the fast component is overestimated by the simulations. Solute motion can significantly increase the speed of solvation, even in the case of large solutes such as C153. Good agreement is found between linear response estimates and the nonequilibrium dynamics associated with electronic excitation of C153. In contrast, perturbations involving changes of a full electron charge in atomic solutes lead to local heating which greatly hastens solvation compared to linear response predictions. The mechanism of charge solvation in atomic solutes is examined in some detail. It is found that ion translation dominates the inertial dynamics. The rotational contribution only becomes comparable to the translation contribution in the tail of the response. Adjustments of ion positions over distances of ~30% of their diameters are all that is required to relax the solvation energy in these systems. PMID- 22515909 TI - Ag2S quantum dot: a bright and biocompatible fluorescent nanoprobe in the second near-infrared window. AB - Ag(2)S quantum dots (QDs) emitting in the second near-infrared region (NIR-II, 1.0-1.4 MUm) are demonstrated as a promising fluorescent probe with both bright photoluminescence and high biocompatibility for the first time. Highly selective in vitro targeting and imaging of different cell lines are achieved using biocompatible NIR-II Ag(2)S QDs with different targeting ligands. The cytotoxicity study illustrates the Ag(2)S QDs with negligible effects in altering cell proliferation, triggering apoptosis and necrosis, generating reactive oxygen species, and causing DNA damage. Our results have opened up the possibilities of using these biocompatible Ag(2)S QDs for in vivo anatomical imaging and early stage tumor diagnosis with deep tissue penetration, high sensitivity, and elevated spatial and temporal resolution owing to their high emission efficiency in the unique NIR-II imaging window. PMID- 22515911 TI - Economic approach to assess the forest carbon implications of biomass energy. AB - There is widespread concern that biomass energy policy that promotes forests as a supply source will cause net carbon emissions. Most of the analyses that have been done to date, however, are biological, ignoring the effects of market adaptations through substitution, net imports, and timber investments. This paper uses a dynamic model of forest and land use management to estimate the impact of United States energy policies that emphasize the utilization of forest biomass on global timber production and carbon stocks over the next 50 years. We show that when market factors are included in the analysis, expanded demand for biomass energy increases timber prices and harvests, but reduces net global carbon emissions because higher wood prices lead to new investments in forest stocks. Estimates are sensitive to assumptions about whether harvest residues and new forestland can be used for biomass energy and the demand for biomass. Restricting biomass energy to being sourced only from roundwood on existing forestland can transform the policy from a net sink to a net source of emissions. These results illustrate the importance of capturing market adjustments and a large geographic scope when measuring the carbon implications of biomass energy policies. PMID- 22515912 TI - Invasive Haemophilus influenzae serotype e and f disease, England and Wales. AB - Haemophilus influenzae infection causes serious invasive disease, but incidence of the most virulent serotype, Hib, has dropped since introduction of routine Hib vaccination. In England and Wales, the incidence of 2 other serotypes, Hie and Hif, is increasing; during 2001-2010, there was an 11.0% year-on-year increase in Hif and a 7.4% increase in Hie. In 2009-2010, Hif incidence was 0.090/100,000 persons and Hie incidence 0.030/100,000, with higher rates among infants and older adults. Hie had a more severe clinical course; although outcome at 6 months was comparable for the 2 serotypes, case-fatality rate within 7 days of diagnosis was higher for Hie, even after adjustment for age and comorbidities. Multilocus sequence typing revealed a single major circulating clone for both Hif (sequence type 124; 89/99 isolates, 90%) and Hie (sequence type 18; 21/33, 64%), but no association between type and clinical disease or outcome was found. PMID- 22515913 TI - SOS: a screening instrument to identify children with handwriting impairments. AB - Poor handwriting has been shown to be associated with developmental disorders such as Developmental Coordination Disorder, Attention Deficit Hyperactivity Disorder, autism, and learning disorders. Handwriting difficulties could lead to academic underachievement and poor self-esteem. Therapeutic intervention has been shown to be effective in treating children with poor handwriting, making early identification critical. The SOS test (Systematic Screening for Handwriting Difficulties) has been developed for this purpose. A child copies a sample of writing within 5 min. Handwriting quality is evaluated using six criteria and writing speed is measured. The Dutch SOS test was administered to 860 Flemish children (7-12 years). Inter- and intrarater reliability was excellent. Test retest reliability was moderate. A correlation coefficient of 0.70 between SOS and "Concise Assessment Methods of Children Handwriting" test (Dutch version) confirmed convergent validity. The SOS allowed discrimination between typically developing children and children in special education, males and females, and different age groups. PMID- 22515914 TI - Two additional cases of metformin-associated encephalopathy in patients with end stage renal disease undergoing hemodialysis. AB - We report on two additional cases of metformin-associated encephalopathy in patients with end-stage renal disease (ESRD) undergoing hemodialysis. Two patients were seen at our hospital with abnormal neurological signs and symptoms. Magnetic resonance imaging (MRI) revealed the same pattern of high signal intensity in both basal ganglia in T2-weighted images in the two patients. The two patients had started taking metformin 5 and 6 weeks earlier at the same dose of 1000 mg per day. Metformin was immediately stopped, and regular hemodialysis was conducted. Their signs and symptoms resolved completely after these measures. The high signal intensity in both ganglia in T2-weighted MRI also disappeared. We should suspect metformin-induced encephalopathy and withdraw the drug when presented with diabetic patients with chronic kidney disease and neurological signs and symptoms of unknown cause. PMID- 22515915 TI - Single molecule directivity enhanced Raman scattering using nanoantennas. AB - Single molecule detection by directivity enhanced Raman scattering is demonstrated using nanoantennas. Bianalyte Raman scattering is used to confirm the detection of single molecules of Rhodamine 6G and Nile Blue A in aqueous solution. Calculations show that Raman enhancement factors of 10(13) can be achieved by combined optimization of the local field enhancement (hotspot with 10(11) enhancement) and antenna directionality (with 10(2) enhancement). PMID- 22515916 TI - [Keloid scars of the head and neck]. AB - A keloid scar is a benign proliferative lesion of dermic collagen. It is predominant in black skin patients. It is most commonly located on the head and neck. Skin trauma and a genetic predisposition may be responsible for the keloid scar. Nevertheless, the pathogenesis of keloid scar is still unclear, and no currently available treatment is 100% effective. The authors had for aim to review the current data on keloid scar pathogenesis and treatment for an optimal management of this condition. PMID- 22515918 TI - Efficient liquid chromatographic analysis of mono-, di-, and triglycerols using silver thiolate stationary phase. AB - We show that the characterization of mono-, di- and triglycerols can be readily accomplished by high performance liquid chromatography (HPLC) with silver(I) mercaptopropyl modified silica gel, or silver thiolate chromatographic material (AgTCM), which can be used with evaporative light scattering detection (ELSD) or atmospheric pressure chemical ionization mass spectroscopy (APCI-MS). Separation of triglycerols varying by degrees of unsaturation and cis/trans configuration in common oil samples can be achieved using a simple linear gradient of hexane and acetone. In addition to double bonds, AgTCM also displays major selectivity for compounds with different levels of polarity, allowing for efficient separation between mono-, di- and triglycerols. In comparison to conventional reversed phase columns, AgTCM produces simple chromatograms for rapid assessment of degrees of unsaturation and the amount of trans fats in triglycerides, which are central issues to food quality determination. In comparison to previous silver-ion based HPLC separations, AgTCM-HPLC based column offers greatly enhanced stability, inertness, durability, and reproducibility allowing routine coupling of the HPLC with a mass spectrometer for detection. PMID- 22515919 TI - [Postchemotherapy retroperitoneal lymphadenectomy for testicular cancer. Literature review by the Oncology Committee of the French Association of Urology, External Genitalia Group]. AB - INTRODUCTION: Postchemotherapy retroperitoneal lymphadenectomy (PC RPLDN) leads to an overall survival rate for testicular cancer exceeding 75%. Several questions still persist concerning: preoperative assessment of residual masses, reducing templates of dissection, choosing surgical approaches or including RPLND in high-risk patients' management. METHOD: The main series in the literature of the past 20 years were analyzed and selected to address these issues and reach a consensual diagnostic and therapeutic approach. RESULTS: Forty-eight original articles (1992 to 2011) were selected. They confirm that no preoperative tool can predict the histological nature of residual masses. The unilateral modified template is a valid option for selected patients but the full bilateral dissection remains the standard but more morbid. The laparoscopic approach is being evaluated. The LDNRP PC is indicated in "high risk" situations especially after salvage chemotherapy. CONCLUSION: The bilateral lymphadenectomy by laparotomy of any supracentimeter residual mass, 6 weeks after chemotherapy, for germ cell tumors of the testicle is a standard of care. PMID- 22515920 TI - [Prospective study of the results of ureterointestinal anastomosis in 100 patients after the Hautmann ileal neobladder with double chimney]. AB - PURPOSE: We attempted to determine the results of the ureterointestinal anastomosis in the Hautmann orthotopic ileal neobladder. This study was conducted prospectively and focused on ureteral stricture, which occurs mainly during the 2 years after surgery. PATIENTS AND METHODS: Between January1999 and June 2009, a total of 100 consecutive patients (five women and 95 men) with bladder cancer underwent cystectomy followed by construction of a Hautmann neobladder. The median age of the patients was 62 (36-78) years. The mean follow-up was 63 (+/ 28) months and included physical examination, serum creatinine values, urine cytology, CT scans and renal ultrasonography. RESULTS: A total of 197 renal units (RU) were included. In eleven RU, hydronephrosis was present preoperatively and improved postoperatively. In ten others RU, hydronephrosis persisted postoperatively without symptoms. The anastomotic stricture rate was 4%, concerning eight RU by seven patients. Five inflammatory strictures (2.5%) occurred early on the 5th, 6th, 8th and 13th postoperative weeks and were revealed by pyelonephritis. Three strictures were tumors in nature and were revealed by urine cytology and radiology on the 6th, 7th and the 14th month respectively. The five inflammatory strictures were treated with percutaneous nephrostomy, balloon dilatation and ureteral stenting. For three of these four patients, surgical reimplantation was necessary on the 4th, 5th and 7th months, like in the case of the three tumoral strictures. CONCLUSION: With a minimal 2 years follow-up, ureterointestinal anastomosis with double chimney had, in this study, a 4% rate of anastomotic stenosis. The surgical modification avoiding tension seemed to preserve ureteral vascularization. PMID- 22515921 TI - [Epidemiology of urologic cancers at the university teaching hospital of Cotonou, Benin. Review of about 158 cases of urologic cancers]. AB - OBJECTIVE: To study the epidemiological profile of urologic cancers in the department of urology at the teaching hospital of Cotonou. METHODOLOGY: We analysed the course of all urological cancer data over a 42-month period, from January the 1st 2008 to 30th June 2011. RESULTS: Urologic cancers were frequent in our hospital practice with a frequency of 17.38%. They are dominated by prostatic cancer (69%), the cancer of bladder (28.5%), the cancer of the kidney (8.5%) and cancers of the external genitals (testis and scrotum) which are marginal in our review. We did not report any case of penis cancer and urethral cancer. They occured at an advanced age with an average age 62.89+/-15.51 years. Urologic cancers were the prerogative of the subjects of male sex with a sex ratio of 9/10. Specific mortality rate which is attached to them was high. CONCLUSION: The epidemiologic profile of urologic cancers in our practice had some essential characteristic for the primary prevention. The improvement of the quality of data, the installation of a cancer register and the improvement of the technical skills will allowed a better approach of urologic cancer in our urology unit. PMID- 22515922 TI - [Tolerance and effectiveness of Memokath(r) 051 ureteral stents : a prospective 3 year follow-up study]. AB - OBJECTIVE: To assess the effectiveness and tolerance of the metallic stent Memokath(r) 051 in the management of patients with chronic ureteral stricture treated by JJ stenting. PATIENTS AND METHODS: A prospective observational study included 16 patients with chronic ureteral stricture managed with JJ stents. They were all treated with Memokath(r) 051 metallic stents. The primary endpoint was the medium durability of the stent. Adverse events and complications were prospectively collected. The evolution of the irritative urinary symptoms and lumbar pain after stent insertion were also assessed. RESULTS: Sixteen patients (mean age: 62, standard deviation: 11,4) had a total of 20 stents inserted. It was technically impossible to insert the stent in two patients and one stent was removed one day after insertion. The medium durability of the stents was 13 months (standard deviation: 10,9). Eight stents (40%) were still functioning at the end of the study. Complications were: six migrations (30%) and four obstructions (20%) of the stents. Thirteen of the 14 patients with a Memokath(r) stent experienced significant improvement of their JJ stent-related symptoms. CONCLUSION: The Memokath(r) 051 stent was an interesting alternative to JJ stents in the management of chronic ureteral strictures. Their tolerance was good and complications were easily managed without threatening the urologic prognosis of the patients. Larger studies are required to identify the risk factors of complications and the best indications for stent insertion. PMID- 22515923 TI - [Is statin use associated with D'Amico risk groups and biochemical recurrence after radical prostatectomy?]. AB - OBJECTIVE: To examine the association between statin use and prostate cancer (PC) stratified with D'Amico risk groups and biochemical recurrence (BR) in patients undergoing radical prostatectomy (RP). PATIENTS AND METHODS: All medical charts of patients managed from 2004 to 2008 for PC with RP were reviewed retrospectively. The use and the type of statin were identified. Patients were split according to the use (S+) or not (S-) of statin. The two groups were compared using the Chi(2) test. A logistic regression was performed for multivariate analysis. RESULTS: Overall, 377 patients were included. Mean age was 64 (48-76) (median, range). Ninety-seven patients (27.5%) used statin for at least a year. Groups S- and S+ were comparable in terms of age, obesity, diabetes, preoperative PSA, biopsy Gleason score or clinical stage. The use of statin was statistically associated with D'Amico risk groups (P=0.003). The number of high-risk PC was higher in Group S+ (23.7% vs. 10.7%) with an odds ratio of 2.4 (P=0.009). With a mean follow up of 33+/-10 months, the overall 2 years-BR was 89%. The 2-years-BR was higher in the S+ (93% vs. 88%, P=0.16). After adjustment, this difference was statistically significant with a hazard ratio of 0.46 (P=0.036). CONCLUSION: The use of statin was associated with high risk PC in this study. Surprisingly, the statin use seem also to be associated with better disease-free survival, independently of other risk factors. PMID- 22515924 TI - [Use of [-2] pro PSA and phi index for early detection of prostate cancer: a prospective of 452 patients]. AB - INTRODUCTION: Early detection of prostate cancer (Pca) is a real challenge to reduce morbidity and mortality while avoiding over-diagnosis and over-treatment. The prostate specific antigen (PSA) is characterized by its imperfections justifying the evaluation of new serum or urinary specific markers allowing a better selection of patients at risk of developing aggressive Pca. AIM: To compare the value of -2pro PSA and phi index to total and free PSA. METHODS: Serum sampled from 452 patients from two university centers were used to determine levels of PSA before performing biopsies. The patients were included in this study based on the PSA serum concentration between 1.6 ng/mL and 8 ng/mL according to the WHO international standard. All biopsies were performed according to a standardized protocol consisting of 12 cores or more. Sera were analyzed centrally in one of the two institutions with on a single analyzer. Sera from 243 prostate cancer and 208 negative biopsies patients have been taken into account. RESULTS: Sera were analyzed blinded for total PSA, free PSA and [-2] proPSA using Access((r)) immunoassay method from Beckman Coulter. The Prostate Health Index (phi) was calculated using the formula phi=([-2] proPSA/fPSA)*sqrt (PSA). The median value of the phi index is significantly (P>0.0001) higher for patients with cancer (phi=65.8) compared to patients with negative biopsies (phi=40.6). At a given sensitivity, the phi index significantly increases the specificity of detection of prostate cancer compared to other markers. CONCLUSION: The phi index currently appears as the best predictor of prostate cancer for patients with a total PSA between 1.6 and 8 ng/mL according to the WHO standard. The improvement in specificity of the phi index over tPSA could reduce significantly the numbers of unnecessary biopsies. Whether this new biomarker could be an indicator of aggressive prostate cancer remains to be confirmed. PMID- 22515925 TI - [Muscularis mucosae invasion: prognostic factor for intravesical BCG immunotherapy failure for T1 bladder carcinoma]. AB - OBJECTIVES: To study the prognostic impact of muscularis mucosae (MM) invasion for pT1 bladder cancer treated by transurethral resection (TUR) and adjuvant Bacille Calmette-Guerin (BCG) intravesical immunotherapy. METHODS: Sixty-six patients treated by BCG intravesical instillations were substaged into pT1a and pT1b, regarding Muscularis Mucosae invasion. Tumor grade, associated carcinoma in situ (CIS), multifocality, tumoral size up to 3cm, BCG maintenance were noted. With a mean follow-up of 50.5+/-38 months, we studied recurrence, progression, overall and specific survival. Cox's model method was used for multivariate analysis. RESULTS: Tumor recurrence was observed in 30+/-7% and 43+/-10% (P=0.29) and tumor progression in 16.3+/-5% and 39+/-10% (P=0.04) for pT1a and pT1b. The rate of progression was higher (P=0.04) and progression free survival was decreased (P=0.04) for pT1b. Specific death rates were 11+/-5% and 21+/-9% (P=0.28), median overall survival was 80.9 [1.5-92] and 48.2 [12-93] months for pT1a and pT1b. Overall and specific survival weren't different between the two populations (P=0.38; P=0.3). Cystectomy rates were 2.3+/-2% and 30+/-9% for pT1a and PT1b (P=0.0006). For pT1a patients, recurrence (P=0.8) or progression rates (P=0.64) were no different regarding BCG maintenance immunotherapy but pT1b population had a better progression free survival with BCG maintenance than without (P=0.0051). Only CIS had prognostic value in multivariate analysis. CONCLUSIONS: Tumors with Muscularis Mucosae invasion have a higher risk of progression and BCG failure. Maintenance immunotherapy should be given to improve results with these patients. PMID- 22515926 TI - [Bladder and bowel function in children with congenital spinal lipomatus malformations. A retrospective study of 114 cases]. AB - OBJECTIVE: To clarify bladder and bowel function of children with lipomas of the conus, without, before and after neurosurgery. PATIENTS AND METHODS: Retrospective analysis of 114 children with a lipomas of the conus, followed in our pediatric neuro-urology department from 1993 to 2010. Several data were collected: bladder and bowel symptoms, bladder and anorectal continence, neurosurgical indication and age, clinical modification after neurosurgery, investigations carried out in pre- and post-surgery treatment, associated bladder and bowel treatment. RESULTS: Forty-nine of the 77 children (63.6%) operated on had never been seen before surgery in our neuro-urology department. Seventy-seven children (67.5%) underwent a neuro-surgery, 60% indicated due to a neurogenic bladder. Before neurosurgery, 66 children (85.7%) had spontaneous miction. Five children (6.5%) had bladder intermittent catheterization. Forty of these patients (56.3%) were continent. After neurosurgery and a specialized consultation in neuro-urology, 54 children (70.1%) were continent. Thirty-seven children (48%) had spontaneous miction. Thirty-seven children (48%) had bladder intermittent catheterization and drug of overactive detrusor. Fifty-two children (67.5%) were constipated after surgery. Seventy-seven percent of the treatments for bowel symptoms were effective in terms of continence. CONCLUSION: The existence of a neurogenic bladder was one of the main indications for neurosurgery. These results suggest that the complexity of care requires neurosurgical, urological surgeon and neuro-urology physician to achieve the explorations and urinary and digestive treatment in order to preserve renal function and both continences. PMID- 22515927 TI - [Evaluation of sexuality among Afro-Caribbean patients homozygous SS sickle cell disease followed in Martinique]. AB - OBJECTIVES: To evaluate and compare retrospectively the sexuality of homozygous sickle cell patients from Martinique related to priapismic events using the IIEF 15 questionnary. PATIENTS AND METHODS: Retrospective survey of 68 patients with sickle cell disease regularly followed up at sickle cell disease's center of Lamentin's hospital according to the occurrence and the type of priapism (intermittent or acute). We shared patients in three groups: no priapism (group 1), intermittent priapism (group 2) and acute priapism (group 3). Information regarding specific and preventive treatments to the disease, and events related to priapism have been gathered for all patients. Each patient's sexuality has been studied with the IIEF-15 questionnary and results have been compared between the groups to show the priapism's impact on sexual activity of these young men. RESULTS: In 37.3%, priapism was observed. The group 1 and 2 had better results than the group 3 on the EF score. There was no significative difference between the group 1 and 2. There was also no significative difference between the three groups on the SD, FO, IS and OS score. The increase of the priapism duration and the repetition of the episodes were associated to a decrease of the EF score. CONCLUSION: Our study showed the lack of major impairment of erectile function in patients with intermittent priapism in opposition to the patients with acute priapism. PMID- 22515928 TI - [Solitary laryngeal metastasis from renal cell carcinoma of the kidney: clinical case and review of the literature]. AB - Metastasis from renal cell carcinoma may reach head and neck region in 14-16% of cases. In this region, the most involved areas are thyroid gland, nose, paransal sinuses and parotid gland. Secondary localization to the larynx is a very rare occurrence. We report a case of solitary laryngeal metastasis from clear cell carcinoma of the kidney, occurring several months after removal of the primary tumour. PMID- 22515929 TI - [Erdheim-Chester disease: report of a case and literature review]. AB - The Erdheim-Chester disease is a rare non-Langerhans hystiocytose acquired in adults. It results from a xanthogranulomatous infiltration, consists of histioccytes foamy and is characterized by heterogeneous systemic manifestations. The most frequent clinical manifestations of the disease are the bone with a long bone uptake on bone scintigraphy99Tc (Dion et al., 2006) and urological damage with an array of pseudo retroperitoneal fibrosis. We report the case of a 64-year old man in whom was founded in the course of acute obstructive renal disease with Erdheim-Chester pseudofibrose retroperitoneal. PMID- 22515930 TI - Neurological comorbidity affects prognosis in left ventricular hypertrabeculation/noncompaction. AB - OBJECTIVE: Left ventricular hypertrabeculation/noncompaction (LVHT) is a cardiac abnormality frequently associated with neuromuscular disorders (NMDs). Whether differences exist between LVHT patients with and without NMDs remains unknown. This study compared the baseline characteristics and prognoses of LVHT patients with and without NMDs. METHODS: This prospective, observational study included patients in whom LVHT was diagnosed at one echocardiographic laboratory between June 1995 and June 2011. Patients underwent a baseline cardiologic examination, and were invited to participate in a neurological investigation. In June 2011, patients were contacted by telephone. RESULTS: One hundred and seventy-two patients received a diagnosis of LVHT (53 female; mean age, 53 standard deviation [SD] +/- 16 years). One hundred and twenty-three patients (72%) were investigated neurologically. A specific NMD was diagnosed in 25, including metabolic myopathy (n = 16), Leber's hereditary optic neuropathy (n = 3), myotonic dystrophy (n = 3), Becker muscular dystrophy (n = 1), postpoliomyelitis syndrome (n = 1), and Duchenne muscular dystrophy (n = 1). An NMD of unknown etiology was diagnosed in 79 patients, and the neurological investigation produced normal results in 19 patients. During a follow-up of 64 months, the mortality amounted to 4.84%/year. Baseline data did not differ between patients with and without NMDs. No deaths occurred among patients without NMDs, even though their observation periods were much longer (8 vs. 4 years, P = .01) than those of patients who were not investigated neurologically. CONCLUSIONS: The presence or absence of NMDs influences the prognosis of patients with LVHT. Patients should be investigated by a neurologist when LVHT is diagnosed. Patients with LVHT and an NMD should be educated about the symptoms of arrhythmias and heart failure. They should be closely followed, and the implantation of cardiac electronic devices should be considered. PMID- 22515931 TI - Association of the PPARG Pro12Ala polymorphism with type 2 diabetes and incident coronary heart disease in a Hong Kong Chinese population. AB - AIMS: We examined the risk association between single nucleotide polymorphisms (SNPs) in eleven candidate genes with type 2 diabetes (T2D). T2D-associated polymorphisms were also examined for prediction of incident CHD. METHODS: 113 tagging SNPs were genotyped in stage 1 (467 T2D cases, 290 controls), and 15 SNPs were analyzed in the final cohort (1462 T2D cases, 600 controls). Three T2D associated SNPs were further tested for prediction of CHD within a subset of 1417 T2D cases free of CHD at enrolment. RESULTS: In the case-control analysis, PPARG rs1801282 (Pro12Ala) (OR=1.48 (1.02-2.16)), ADIPOQ rs1063539 (OR=1.17 (1.01 1.35)), and HNF4A rs1884614 (OR=1.16 (1.00-1.32) were associated with T2D (P(allelic)<0.05). Joint analysis of rs1801282-C, rs1063539-G, and rs1884614-T risk alleles showed an additive dosage effect (P for trend=0.001). Moreover, carriers with two PPARG rs1801282-C risk alleles were associated with an increased risk of incident CHD (HR=4.38 (1.03-18.57), P=0.045) in T2D patients in the prospective analysis. CONCLUSIONS: Genetic variants of PPARG, ADIPOQ and HNF4A were individually and jointly associated with T2D in Hong Kong Chinese. The PPARG Pro12 risk allele contributed to increased risk for both T2D and CHD. PMID- 22515932 TI - Functional polysaccharide conjugates for the preparation of microarrays. AB - A method for the immobilization of functional molecules on cellulose surfaces was developed. The irreversible deposition of the water-soluble polyelectrolyte carboxymethyl cellulose (CMC) on solid cellulose surfaces was used as a basis for this immobilization. CMC was modified using aminofluorescein (AMF) as a model compound for a functional molecule. The carbodiimide mediated coupling efficiency of AMF to CMC was studied in detail, and the functional conjugates were isolated. A quartz crystal microbalance with dissipation was employed to study the immobilization of the functionalized CMC onto cellulose model films in situ. The influence of the carbodiimide concentration, the degree of substitution, and the molecular weight of CMC on the immobilization process was investigated. Atomic force microscopy was used to characterize the changes in the surface morphology of the modified cellulose films. Finally, microspotted arrays of AMF-CMC conjugates were prepared with the knowledge obtained from the basic interaction studies. The successful deposition of AMF-CMC conjugates onto cellulose surfaces was proven by fluorescence microscopy. The conjugation of functional molecules to CMC and the subsequent deposition of these products on cellulose can be seen as a versatile method to immobilize these molecules for applications in the field of microarrays and other sensor surfaces. It offers the possibility to introduce new properties on a variety of cellulosic materials. PMID- 22515935 TI - Novel prion protein in BSE-affected cattle, Switzerland. PMID- 22515933 TI - Elucidating the role of place in health care disparities: the example of racial/ethnic residential segregation. AB - OBJECTIVE: To develop a conceptual framework for investigating the role of racial/ethnic residential segregation on health care disparities. DATA SOURCES AND SETTINGS: Review of the MEDLINE and the Web of Science databases for articles published from 1998 to 2011. STUDY DESIGN: The extant research was evaluated to describe mechanisms that shape health care access, utilization, and quality of preventive, diagnostic, therapeutic, and end-of-life services across the life course. PRINCIPAL FINDINGS: The framework describes the influence of racial/ethnic segregation operating through neighborhood-, health care system-, provider-, and individual-level factors. Conceptual and methodological issues arising from limitations of the research and complex relationships between various levels were identified. CONCLUSIONS: Increasing evidence indicates that racial/ethnic residential segregation is a key factor driving place-based health care inequalities. Closer attention to address research gaps has implications for advancing and strengthening the literature to better inform effective interventions and policy-based solutions. PMID- 22515936 TI - Plasmodium vivax malaria-associated acute kidney injury, India, 2010-2011. AB - Plasmodium vivax is causing increasingly more cases of severe malaria worldwide. Among 25 cases in India during 2010-2011, associated conditions were renal failure, thrombocytopenia, jaundice, severe anemia, acute respiratory distress syndrome, shock, cerebral malaria, hypoglycemia, and death. Further studies are needed to determine why P. vivax malaria is becoming more severe. PMID- 22515937 TI - [Prediction of fluid responsiveness: a new step towards a totally non invasive assessment]. PMID- 22515938 TI - Evaluation of canting correction of the maxillary transverse occlusal plane and change of the lip canting in Class III two-jaw orthognathic surgery. AB - OBJECTIVE: To compare the effect of canting correction in anterior maxillary transverse occlusal planes (AMTOP) and posterior maxillary transverse occlusal planes (PMTOP) on the change of lip canting (LC) in two-jaw surgery (TJS) cases. MATERIALS AND METHODS: The samples consisted of eight young adult patients (three males and five females, mean age = 24.1 +/- 4.5 years) who had skeletal Class III malocclusion (CIII), facial asymmetry (FA), and LC and who underwent TJS. Two dimensional lateral and posteroanterior cephalograms and three-dimensional facial scanning taken 1 week before (T1) and 6 months after TJS (T2) were combined using the Morpheus 3D program. Six linear and angular variables were measured and statistically analyzed. RESULTS: When comparing the values of the linear and angular variables at the T1 and T2 stages there was significant canting correction of AMTOP (1.7 mm vs -0.3 mm; 3.0 degrees vs 0.1 degrees ), PMTOP (3.5 mm vs 0.1 mm, 3.3 degrees vs -0.1 degrees ), and LC (3.0 mm vs 0.7 mm, 4.7 degrees vs 2.1 degrees ) (all P < .05). Although the angular change ratios (DeltaLC/DeltaAMTOP and DeltaLC/DeltaPMTOP) did not exhibit a significant difference (0.99 vs 0.83), the linear change ratio of DeltaLC/DeltaAMTOP was significantly higher than that of DeltaLC/DeltaPMTOP (1.67 vs 0.74, P < .05). The angular change of DeltaLC showed a significant correlation with DeltaAMTOP (r(2) = 0.64; P < .05). However, the linear change of DeltaLC was significantly correlated with both the angular and linear changes of DeltaAMTOP (r(2) = 0.62 and 0.66; both P < .05). Therefore, the amount of LC change was more related to the canting correction of AMTOP than to that of PMTOP. CONCLUSION: In TJS cases with CIII, FA, and LC, the amount of canting correction of the AMTOP should be considered to predict the actual LC change. PMID- 22515939 TI - Right ventricular rupture and tamponade caused by malposition of the Avalon cannula for venovenous extracorporeal membrane oxygenation. AB - Placement of the Avalon Elite bicaval dual lumen cannula for venovenous extracorporeal membrane oxygenation (VV-ECMO) via the internal jugular vein requires precise positioning of the cannula tip in the inferior vena cava with echocardiography or fluoroscopy guidance. Correct guidewire placement is clearly the key first step in assuring proper advancement of the cannula. We report a case of unexpected wire migration into the right ventricle at the time of final cannula advancement, resulting in right ventricular rupture and tamponade. Transesophageal echocardiography is an important monitoring modality for appropriate placement of the VV-ECMO guidewire and Avalon cannula, and in particular, for early identification of potential complications. PMID- 22515940 TI - Controlling nanoscale friction through the competition between capillary adsorption and thermally activated sliding. AB - We demonstrate measurement and control of nanoscale single-asperity friction by using cantilever probes featuring an in situ solid-state heater in contact with silicon oxide substrates. The heater temperature was varied between 25 and 790 degrees C. By using a low thermal conductivity sample, silicon oxide, we are able to vary tip temperatures over a broad range from 25 +/- 2 to 255 +/- 25 degrees C. In ambient atmosphere with ~30% relative humidity, the control of friction forces was achieved through the formation of a capillary bridge whose characteristics exhibit a strong dependence on temperature and sliding speed. The capillary condensation is observed to be a thermally activated process, such that heating in ambient air caused friction to increase due to the capillary bridge nucleating and growing. Above tip temperatures of ~100 +/- 10 degrees C, friction decreased drastically, which we attribute to controllably evaporating water from the contact at the nanoscale. In contrast, in a dry nitrogen atmosphere, friction was not affected appreciably by temperature changes. In the presence of a capillary, friction decreases at higher sliding speeds due to disruption of the capillary; otherwise, friction increases in accordance with the predictions of a thermally assisted sliding model. In ambient atmospheres, the rate of increase of friction with sliding speed at room temperature is sufficiently strong that the friction force changes from being smaller than the response at 76 +/- 8 degrees C to being larger. Thus, an appropriate change in temperature can cause friction to increase at one sliding speed, while it decreases at another speed. PMID- 22515941 TI - Clinical trial: Efficacy of a low or modified fat diet for the prevention of gastrointestinal toxicity in patients receiving radiotherapy treatment for pelvic malignancies. AB - BACKGROUND: Inflammatory responses to pelvic radiotherapy can result in severe changes to normal gastrointestinal function with potentially severe long-term effects. Reduced or modified fat diets may confer benefit. METHODS: This randomised controlled trial recruited patients with gynaecological, urological or lower gastrointestinal malignancy due to receive radical radiotherapy. Patients were randomised to a low fat (20% total energy from long chain triglycerides), modified fat (20% from long chain triglycerides and 20% from medium chain triglycerides) or normal fat diet (40% total energy from long chain triglycerides). The primary outcome was a difference in change in Inflammatory Bowel Disease Questionnaire--Bowel (IBDQ-B) score, from the start to end of radiotherapy. RESULTS: A total of 117 patients with pelvic tumours (48% urological; 32% gastrointestinal; 20% gynaecological), with mean (SD) age: 65 (11.0) years, male:female ratio: 79:38, were randomised. The mean (SE) fall in paired IBDQ-B score was -7.3 (0.9) points, indicating a worsening toxicity. Differences between groups were not significant: P = 0.914 (low versus modified fat), P = 0.793 (low versus normal fat) and P = 0.890 (modified versus normal fat). The difference in fat intake between low and normal fat groups was 29.5 g [1109 kJ (265 kcal)] amounting to 11% (of total energy intake) compared to the planned 20% differential. Full compliance with fat prescription was only 9% in the normal fat group compared to 93% in the low fat group. CONCLUSIONS: A low or modified fat diet during pelvic radiotherapy did not improve gastrointestinal symptom scores compared to a normal fat intake. An inadequate differential in fat intake between the groups may have confounded the results. PMID- 22515942 TI - Membrane lipid raft organization is uniquely modified by n-3 polyunsaturated fatty acids. AB - Fish oil, enriched in bioactive n-3 polyunsaturated fatty acids (PUFA), has been shown to play a role in prevention of colon cancer. The effects of n-3 PUFA are pleiotropic and multifaceted, resulting in an incomplete understanding of their molecular mechanisms of action. Here, we focus on a highly conserved mechanism of n-3 PUFA, which is the alteration of the organization of the plasma membrane. We highlight recent work demonstrating that enrichment of n-3 PUFA in the plasma membrane alters the lateral organization of membrane signaling assemblies (i.e. lipid rafts). This mechanism is central for n-3 PUFA regulation of downstream signaling, T-cell activation, transcriptional activation, and cytokine secretion. We conclude that these studies provide strong evidence for a predominant mechanism by which n-3 PUFA function in colon cancer prevention. PMID- 22515944 TI - Epidemic of invasive pneumococcal disease, western Canada, 2005-2009. AB - In Canada before 2005, large outbreaks of pneumococcal disease, including invasive pneumococcal disease caused by serotype 5, were rare. Since then, an epidemic of serotype 5 invasive pneumococcal disease was reported: 52 cases during 2005, 393 during 2006, 457 during 2007, 104 during 2008, and 42 during in 2009. Of these 1,048 cases, 1,043 (99.5%) occurred in the western provinces of Canada. Median patient age was 41 years, and most (659 [59.3%]) patients were male. Most frequently representing serotype 5 cases (compared with a subset of persons with non-serotype 5 cases) were persons who were of First Nations heritage or homeless. Restriction fragment-length polymorphism typing indicated that the epidemic was caused by a single clone, which multilocus sequence typing identified as sequence type 289. Large pneumococcal epidemics might go unrecognized without surveillance programs to document fluctuations in serotype prevalence. PMID- 22515943 TI - Docosahexaenoic acid synthesis from alpha-linolenic acid is inhibited by diets high in polyunsaturated fatty acids. AB - The conversion of the plant-derived omega-3 (n-3) alpha-linolenic acid (ALA, 18:3n-3) to the long-chain eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) can be increased by ALA sufficient diets compared to ALA deficient diets. Diets containing ALA above an optimal level result in no further increase in DHA levels in animals and humans. The present study evaluates means of maximizing plasma DHA accumulation by systematically varying both linoleic acid (LA, 18:2n-6) and ALA dietary level. Weanling rats were fed one of 54 diets for three weeks. The diets varied in the percentage of energy (en%) of LA (0.07-17.1 en%) and ALA (0.02-12.1 en%) by manipulating both the fat content and the balance of vegetable oils. The peak of plasma phospholipid DHA (>8% total fatty acids) was attained as a result of feeding a narrow dietary range of 1-3 en% ALA and 1-2 en% LA but was suppressed to basal levels (~2% total fatty acids) at dietary intakes of total polyunsaturated fatty acids (PUFA) above 3 en%. We conclude it is possible to enhance the DHA status of rats fed diets containing ALA as the only source of n-3 fatty acids but only when the level of dietary PUFA is low (<3 en%). PMID- 22515945 TI - Effects of motor cortex modulation and descending inhibitory systems on pain thresholds in healthy subjects. AB - Pain modulation can be achieved using neuromodulatory tools that influence various levels of the nervous system. Transcranial direct current stimulation (tDCS), for instance, has been shown to reduce chronic pain when applied to the primary motor cortex. In contrast to this central neuromodulatory technique, diffuse noxious inhibitory controls (DNIC) refers to endogenous analgesic mechanisms that decrease pain following the introduction of heterotopic noxious stimuli. We examined whether combining top-down motor cortex modulation using anodal tDCS with a bottom-up DNIC induction paradigm synergistically increases the threshold at which pain is perceived. The pain thresholds of 15 healthy subjects were assessed before and after administration of active tDCS, sham tDCS, cold-water-induced DNIC, and combined tDCS and DNIC. We found that both tDCS and the DNIC paradigm significantly increased pain thresholds and that these approaches appeared to have additive effects. Increase in pain threshold following active tDCS was positively correlated with baseline N-acetylaspartate in the cingulate cortex and negatively correlated with baseline glutamine levels in the thalamus as measured by magnetic resonance spectroscopy. These results suggest that motor cortex modulation may have a greater analgesic effect when combined with bottom-up neuromodulatory mechanisms, presenting new avenues for modulation of pain using noninvasive neuromodulatory approaches. PERSPECTIVE: This article demonstrates that both noninvasive motor cortex modulation and a descending noxious inhibitory controls paradigm significantly increase pain thresholds in healthy subjects and appear to have an additive effect when combined. These results suggest that existing pain therapies involving DNIC may be enhanced through combination with noninvasive brain stimulation. PMID- 22515946 TI - Sadness enhances the experience of pain and affects pain-evoked cortical activities: an MEG study. AB - Pain is a multidimensional phenomenon. Previous psychological studies have shown that a person's subjective pain threshold can change when certain emotions are recognized. We examined this association with magnetoencephalography. Magnetic field strength was recorded with a 306-channel neuromagnetometer while 19 healthy subjects (7 female, 12 male; age range = 20-30 years) experienced pain stimuli in different emotional contexts induced by the presentation of sad, happy, or neutral facial stimuli. Subjects also rated their subjective pain intensity. We hypothesized that pain stimuli were affected by sadness induced by facial recognition. We found: 1) the intensity of subjective pain ratings increased in the sad emotional context compared to the happy and the neutral contexts, and 2) event-related desynchronization of lower beta bands in the right hemisphere after pain stimuli was larger in the sad emotional condition than in the happy emotional condition. Previous studies have shown that event-related desynchronization in these bands could be consistently observed over the primary somatosensory cortex. These findings suggest that sadness can modulate neural responses to pain stimuli, and that brain processing of pain stimuli had already been affected, at the level of the primary somatosensory cortex, which is critical for sensory processing of pain. PERSPECTIVE: We found that subjective pain ratings and cortical beta rhythms after pain stimuli are influenced by the sad emotional context. These results may contribute to understanding the broader relationship between pain and negative emotion. PMID- 22515948 TI - How preview space/time translates into preview cost/benefit for fixation durations during reading. AB - Eye-movement control during reading depends on foveal and parafoveal information. If the parafoveal preview of the next word is suppressed, reading is less efficient. A linear mixed model (LMM) reanalysis of McDonald (2006) confirmed his observation that preview benefit may be limited to parafoveal words that have been selected as the saccade target. Going beyond the original analyses, in the same LMM, we examined how the preview effect (i.e., the difference in single fixation duration, SFD, between random-letter and identical preview) depends on the gaze duration on the pretarget word and on the amplitude of the saccade moving the eye onto the target word. There were two key results: (a) The shorter the saccade amplitude (i.e., the larger preview space), the shorter a subsequent SFD with an identical preview; this association was not observed with a random letter preview. (b) However, the longer the gaze duration on the pretarget word, the longer the subsequent SFD on the target, with the difference between random letter string and identical previews increasing with preview time. A third pattern-increasing cost of a random-letter string in the parafovea associated with shorter saccade amplitudes-was observed for target gaze durations. Thus, LMMs revealed that preview effects, which are typically summarized under "preview benefit", are a complex mixture of preview cost and preview benefit and vary with preview space and preview time. The consequence for reading is that parafoveal preview may not only facilitate, but also interfere with lexical access. PMID- 22515949 TI - Modeling drug-induced anorexia by molecular topology. AB - Molecular topology (MT) has demonstrated to be a very good technique for describing molecular structures and to predict physical, chemical, and biological properties of compounds. In this paper, a topological-mathematical model based on MT has been developed for identifying drug compounds showing anorexia as a side effect. An external validation (test set) has been carried out, yielding over an 80% correct classification in the active and inactive compounds. These results reinforce the role of MT as a potential useful tool for predicting drug side effects. PMID- 22515950 TI - Adsorption of lipid liquid crystalline nanoparticles on cationic, hydrophilic, and hydrophobic surfaces. AB - Investigation of nonlamellar nanoparticles formed by dispersion of self-assembled lipid liquid crystalline phases is stimulated by their many potential applications in science and technology; resulting from their unique solubilizing, encapsulating, and space-dividing nature. Understanding the interfacial behavior of lipid liquid crystalline nanoparticles (LCNPs) at surfaces can facilitate the exploitation of such systems for a number of potentially interesting uses, including preparation of functional surface coatings and uses as carriers of biologically active substances. We have studied the adsorption of LCNP, based on phosphatidylcholine/glycerol dioleate and Polysorbate 80 as stabilizers, at different model surfaces by use of in situ ellipsometry. The technique allows time-resolved monitoring of the layer thickness and the amount adsorbed, thereby providing insights into the restructuring of the lipid nanoparticle upon adsorption. The effects of solvent condition, electrolyte concentration, particle size, and surface chemistry on adsorbed layer properties were investigated. Furthermore, the internal structures of the particles were investigated by cryo transmission electron microscopy and small angle X-ray diffraction on the corresponding liquid crystalline phases in excess water. LCNPs are shown to form well-defined layers at the solid-liquid interface with a structure and coverage that are determined by the interplay between the self-assembly properties of the lipids and lipid surface interactions, respectively. At the hydrophobic surface, hydrophobic interaction results in a structural transition from the original LCNP morphology to a monolayer structure at the interface. In contrast, at cationic and hydrophilic surfaces, relaxation is a relatively slow process, resulting in much thicker adsorbed layers, with thickness and adsorption behavior that to a greater extent reflect the original bulk LCNP properties. PMID- 22515947 TI - Associations between pro- and anti-inflammatory cytokine genes and breast pain in women prior to breast cancer surgery. AB - The purposes of this study were to determine the occurrence rate for preoperative breast pain; describe the characteristics of this pain; evaluate for differences in demographic and clinical characteristics; and evaluate for variations in pro- and anti-inflammatory cytokine genes between women who did and did not report pain. Patients (n = 398) were recruited prior to surgery and completed self report questionnaires on a number of pain characteristics. Genotyping was done using a custom genotyping array. Women (28.2%) who reported breast pain were significantly younger (P < .001); more likely to be nonwhite (P = .032); reported significantly lower Karnofsky Performance Status scores (P = .008); were less likely to be postmenopausal (P = .012); and had undergone significantly more biopsies (P = .006). Carriers of the minor allele for a single nucleotide polymorphism in interleukin (IL)1-receptor 1 (IL1R1) (rs2110726) were less likely to report breast pain prior to surgery (P = .007). Carriers of the minor allele for a single nucleotide polymorphism in IL13 (rs1295686) were more likely to report breast pain prior to surgery (P = .019). Findings suggest that breast pain occurs in over a quarter of women who are about to undergo breast cancer surgery. Based on phenotypic and genotypic characteristics found, inflammatory mechanisms contribute to preoperative breast pain. PERSPECTIVE: In women with breast cancer, preoperative pain may be associated with increases in inflammatory responses associated with an increased number of biopsies. In addition, differences in cytokine genes may contribute to this preoperative breast pain. PMID- 22515951 TI - Nurse staffing levels and the incidence of mortality and morbidity in the adult intensive care unit: a literature review. AB - BACKGROUND: Studies have shown that nurse staffing levels, among many other factors in the hospital setting, contribute to adverse patient outcomes. Concerns about patient safety and quality of care have resulted in numerous studies being conducted to examine the relationship between nurse staffing levels and the incidence of adverse patient events in both general wards and intensive care units. AIM: The aim of this paper is to review literature published in the previous 10 years which examines the relationship between nurse staffing levels and the incidence of mortality and morbidity in adult intensive care unit patients. METHODS: A literature search from 2002 to 2011 using the MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, and Australian digital thesis databases was undertaken. The keywords used were: intensive care; critical care; staffing; nurse staffing; understaffing; nurse patient ratios; adverse outcomes; mortality; ventilator-associated pneumonia; ventilator-acquired pneumonia; infection; length of stay; pressure ulcer/injury; unplanned extubation; medication error; readmission; myocardial infarction; and renal failure. A total of 19 articles were included in the review. Outcomes of interest are patient mortality and morbidity, particularly infection and pressure ulcers. RESULTS: Most of the studies were observational in nature with variables obtained retrospectively from large hospital databases. Nurse staffing measures and patient outcomes varied widely across the studies. While an overall statistical association between increased nurse staffing levels and decreased adverse patient outcomes was not found in this review, most studies concluded that a trend exists between increased nurse staffing levels and decreased adverse events. CONCLUSION: While an overall statistical association between increased nurse staffing levels and decreased adverse patient outcomes was not found in this review, most studies demonstrated a trend between increased nurse staffing levels and decreased adverse patient outcomes in the intensive care unit which is consistent with previous literature. While further more robust research methodologies need to be tested in order to more confidently demonstrate this association and decrease the influence of the many other confounders to patient outcomes; this would be difficult to achieve in this field of research. PMID- 22515952 TI - Report on the International Symposium on Hepatitis E, Seoul, South Korea, 2010. PMID- 22515953 TI - The validity of race and ethnicity in enrollment data for Medicare beneficiaries. AB - OBJECTIVE: To assess the validity of race/ethnicity in Medicare databases for studies of racial/ethnic disparities. DATA SOURCES: The 2010 Medicare Consumer Assessments of Healthcare Providers and Systems (CAHPS((r))) survey was linked to Medicare enrollment data and local area characteristics from the 2000 Census. STUDY DESIGN: Race/ethnicity was cross-tabulated for CAHPS and Medicare data. Within each self-reported category, demographic, geographic, health, and health care variables were compared between those that were and were not similarly identified in Medicare data. DATA COLLECTION METHODS: The Medicare CAHPS survey included 343,658 responses from elderly participants (60 percent response rate). Data were weighted for sampling and nonresponse to be representative of the national population of elderly Medicare beneficiaries. PRINCIPAL FINDINGS: Self reported Hispanics, Asians, Pacific Islanders, and American Indians were underidentified in Medicare enrollment data. Individuals in these groups who were identified in Medicare data tended to be more strongly identified with their group, poorer, and in worse health and to report worse health care experiences than those who were not so identified. CONCLUSIONS: Self-reported members of racial and ethnic groups other than Whites and Blacks who are identified in Medicare data differ substantially from those who are not so identified. These differences should be considered in assessments of disparities in health and health care among Medicare beneficiaries. PMID- 22515954 TI - Doing it the Gadamerian way--using philosophical hermeneutics as a methodological approach in nursing science. AB - While several authors are referring to Gadamer's philosophy, the operationalization of his thinking into practical use in nursing science is less common. The goal of this paper is to systematize some of the basic key concepts in Gadamer's hermeneutics into a methodological approach to the interpretation of texts. This is a somewhat different approach to his work from those described in earlier commentaries and should be useful for nursing science. In this paper, Gadamer's hermeneutics is explored with a particular focus on some of the basic concepts of his philosophy. A four-step approach is proposed that may be used to develop a research plan in the Gadamerian hermeneutic tradition. Gadamer himself did not develop a method of interpretation, but elaborated upon the old hermeneutic tradition, of an inner fusion of subtilitas intelligendi (understanding), subtilitas explicandi (interpretation) and subtilitas applicandi (application). Hence, the analyses are not open and accessible, but inherent in the interpretation (auslegung). To use Gadamer's philosophy as a methodological approach, the interpreter must acquire a comprehensive understanding of the basic ideas and key concepts of his philosophy. These concepts may be used as a framework upon which to develop a research plan. PMID- 22515955 TI - Novel human adenovirus strain, Bangladesh. AB - We report a novel human adenovirus D (HAdV-65) isolated from feces of 4 children in Bangladesh who had acute gastroenteritis. Corresponding genes of HAdV-65 were related to a hexon gene of HAdV-10, penton base genes of HAdV-37 and HAdV-58, and a fiber gene of HAdV-9. This novel virus may be a serious threat to public health. PMID- 22515957 TI - Which roles for autophagy in Toxoplasma gondii and related apicomplexan parasites? AB - Autophagy is a life-sustaining process by which cytoplasmic components are sequestered in double-membrane vesicles called autophagosomes, and degraded after fusion with a lytic compartment. This process can be triggered under cellular stress conditions in order to recycle damaged organelles or provide nutrients to the cell, but may also be involved in cell remodelling during normal development. This catabolic process is conserved among most eukaryotes and characterisation of its molecular machinery has benefited greatly from functional genetic studies in yeast and mammalian models. Until recently, not much was known about the functions of autophagy in Apicomplexa, but recent data obtained in Toxoplasma have shed light on a very important role for this machinery, potentially at the crossroads between life and death decisions for the parasite. The possible roles for autophagy during the life cycles of other medically important apicomplexan parasites and the perspectives for discovering new drug targets in this pathway for combating these parasites are discussed in this review. PMID- 22515958 TI - Variability in the analysis of 25-hydroxyvitamin D by liquid chromatography tandem mass spectrometry: the devil is in the detail. AB - BACKGROUND: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is increasingly used in clinical laboratories for the analysis of 25-hydroxyvitamin D (25OHD), but measurement is not straightforward. Importantly, LC-MS/MS is not a single technique: variables in sample preparation, chromatography and ionisation/fragmentation should each be considered. METHODS: We analysed results from a survey organised by the international Vitamin D External Quality Assessment Scheme (DEQAS), to determine the influence of such variables on the results for two DEQAS distributions. RESULTS: 65 laboratories returned questionnaires. 346 (57%) individual results were from laboratories using electrospray ionisation (ESI), and 259 (43%) from laboratories using atmospheric pressure chemical ionisation (APCI). Although the mean ratio of results was not significantly different between ESI and APCI (P=0.5828), there was greater variation (P<0.0001) in results obtained by laboratories using ESI. Greater variation (P<0.05) was also observed between results from laboratories monitoring non-specific water-loss transitions. Only 3 laboratories (5%) could resolve the isobaric metabolite 3-epi-25OHD(3) from 25OHD(3). CONCLUSIONS: There are many variables to consider when using LC-MS/MS, including assay standardisation/calibration, chromatography and MS conditions. MS/MS alone cannot distinguish isobaric metabolites such as 3-epi-25OHD(3). Interference can also occur if non-specific transitions are used. Laboratories should always subscribe to an EQA scheme for 25OHD analysis. PMID- 22515959 TI - XAGE-1a and XAGE-1d are potential biomarkers of lung squamous cell carcinoma. AB - BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide. We evaluated the diagnostic potential of sera XAGE-1a and XAGE-1d in lung cancer, both of which are variants of the X antigen family, member 1. METHODS: The expression levels of XAGE-1a and XAGE-1d in cell lines were determined using western blot analysis. Competitive ELISA was used to analyze XAGE-1a and XAGE-1d levels in culture supernatants and sera from 194 lung cancer patients and 194 healthy sex- and age-group-matched controls. To evaluate the diagnostic performance of these proteins, we also analyzed carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) in culture supernatants and 388 sera using commercial ELISA kits. RESULTS: XAGE-1a and XAGE-1d proteins were expressed in both breast cancer and lung cancer cell lines, but they were only secreted by the latter. The areas under the curves (AUCs) for XAGE-1a and XAGE-1d were 0.787 and 0.806, respectively. The cutoff values (sensitivity, specificity) for XAGE-1a and XAGE-1d were 1.62 ng/ml (0.866, 0.572) and 2.51 ng/ml (0.871, 0.613), respectively. The diagnostic performance was improved for patients with squamous cell carcinoma. The AUC values for XAGE-1a and XAGE-1d for patients with squamous cell carcinoma versus a group containing all healthy participants and patients with any illness other than squamous cell carcinoma were similar to those for CEA and CYFRA 21-1. Better performance (AUC: 0.914) for all patients was obtained when using a combination of four markers (Random Forest). CONCLUSIONS: Sera XAGE 1a and XAGE-1d are potential biomarkers for lung cancer; they display a diagnostic performance comparable to that of CEA or CYFRA 21-1. Further studies are needed to evaluate the diagnostic and prognostic potential of XAGE-1a and XAGE-1d in lung cancer. PMID- 22515961 TI - Evaluation of commutability of several materials for harmonization alkaline phosphatase catalytic concentration measurements. AB - BACKGROUND: The International Standard ISO 18153 establish that one of the requirements to assure the metrological traceability of values for catalytic concentration of enzymes is the commutability of calibrator and control materials used in the reference measurement systems. This approach was applied to verify the commutability of several commercial stabilized materials using the recently published alkaline phosphatase IFCC primary reference procedure and two routine procedures. METHODS: ALP catalytic activity was measured in 50 serum samples and 16 commercial materials, including control materials from EQAS programs, using primary reference measurement procedure and two routine measurement procedures with AMP and DEA as buffers. Calibration materials with a value assigned by reference procedure which were proved to be commutable were used to recalculate the serum values obtained by routine procedures. RESULTS: All commercial materials showed a similar behaviour to the patient specimens when AMP vs IFCC procedures were compared. For DEA vs IFCC comparison only one calibration material and two quality control materials were commutable. Recalculation of serum results with a commutable common calibrator improves the agreement between methods changing the ratio AMP vs IFCC from 1.44 to 1.04 and DEA vs IFCC from 3.02 to 1.05. CONCLUSIONS: The use of a common commutable calibration material allows harmonizing ALP measurements and made traceable patient results to reference procedure. PMID- 22515960 TI - Comparison of Sebia Capillarys Flex capillary electrophoresis with the BioRad Variant II high pressure liquid chromatography in the evaluation of hemoglobinopathies. AB - BACKGROUND: There are multiple biochemical screening techniques for assessing hemoglobinopathies. Here we compare a new instrument, the Sebia Capillarys Flex (capillary zone electrophoresis (CE)), with the BioRad Variant II (high pressure liquid chromatography (HPLC) in the evaluation of hemoglobinopathies. METHODS: This was a retrospective study using 174 whole blood samples encompassing the 5 most common (Hb A, A2', S, C, and E) and 10 rare (Hb G(Philidelphia), D, H, Bart's, O(Arab), S/G(Philidelphia), Hasharoon, Q(India), N(Baltimore), and Malmo) hemoglobin variants. An additional 126 samples were used to establish a CE reference interval for Hb A2. RESULTS: Hb A measurements agreed well between the 2 methods (bias=-0.06;r=0.999). The agreement of Hb F was also very good (bias= 0.17; r=0.994). When samples with the highest Hb F concentration were excluded, agreement was less precise (bias=-0.44; r=0.811). When no variant was present, the Hb A2 concentrations showed excellent agreement (bias=0.00; r=0.994). Positive bias for Hb A2 is seen when Hb C is present using CE. The Hb A2 reference interval using CE was <3.2%. CONCLUSION: The Capillarys Flex is capable of identifying and quantifying hemoglobin species, consistent with existing HPLC methods. PMID- 22515962 TI - Expanding the medicinally relevant chemical space with compound libraries. AB - Analysis of marketed drugs and commercial vendor libraries used in high throughput screening suggests that the medicinally relevant chemical space may be expanded to unexplored regions. Novel regions of the chemical space can be conveniently explored with structurally unique molecules with increased complexity and balanced physicochemical properties. As a case study, we discuss the chemoinformatic profile of natural products in the Traditional Chinese Medicine (TCM) database and a large collection assembled from 30 small-molecule combinatorial libraries with emphasis on assessing molecular complexity. The herein surveyed combinatorial libraries have been successfully used over the past 20 years to identify novel bioactive compounds across different therapeutic areas. Combinatorial libraries and natural products are suitable sources to expand the traditional relevant medicinal chemistry space. PMID- 22515964 TI - Flexible low-voltage polymer thin-film transistors using supercritical CO2 deposited ZrO2 dielectrics. AB - The fabrication of low-voltage flexible organic thin film transistors using zirconia (ZrO(2)) dielectric layers prepared via supercritical fluid deposition was studied. Continuous, single-phase films of approximately 30 nm thick ZrO(2) were grown on polyimide (PI)/aluminum (Al) substrates at 250 degrees C via hydrolysis of tetrakis(2,2,6,6-tetramethyl-3,5-heptane-dionato) zirconium in supercritical carbon dioxide. This dielectric layer showed a high areal capacitance of 317 nF cm(-2) at 1 kHz and a low leakage current of 1.8 * 10(-6) A cm(-2) at an applied voltage of -3 V. By using poly(3-hexylthiophene) (P3HT) as a semiconductor, we have fabricated flexible thin film transistors operating at V(DS) = -0.5 V and V(G) in a range from 0.5 V to -4 V, with on/off ratios on the order of 1 * 10(3) and mobility values higher than 0.1 cm(2)/(V s). PMID- 22515965 TI - Impacts of low doses of pesticide mixtures on liver cell defence systems. AB - Low amounts of residual pesticides are present in the environment, often as mixtures of chemicals which contaminate drinking water and food, being a source of chronic exposure for humans and a growing matter of concern in public health policy. Despite of the needs and growing investigation, little is known about the impact of low doses and mixtures of these chemicals on human health. The purpose of this study was to enlighten if modifications of liver cell metabolic- and/or defence-related capacities could occur under such exposures. In vitro perturbations of several metabolic, stress and survival pathways in human and mice cultured hepatocytes and liver cells were evaluated under exposure to low doses of single molecules or equimolecular combinations of the three pesticides, atrazine, chlorpyrifos and endosulfan. Mainly phases I and II enzymes of detoxification were found modulated, together with apoptotic process deregulation. Hence, CYP3A4 and CYP3A11 were upregulated in primary cultured human and mouse hepatocytes, respectively. These inductions were correlated to an anti-apoptotic process (increased Bcl-xL/Bax ratio, inhibition of the PARP protein cleavage). Such disturbances in pathways involved in cell protection may possibly account for initiation of pathologies or decrease in drugs efficiency in humans exposed to multiple environmental contaminants. PMID- 22515956 TI - Identification of the immune expressed sequence tags of pearl oyster (Pinctada martensii, Dunker 1850) responding to Vibrio alginolyticus challenge by suppression subtractive hybridization. AB - One hemolymph subtracted cDNA library of pearl oyster (Pinctada martensii, Dunker 1837) was constructed using the suppression subtractive hybridization (SSH) in response to Vibrio alginolyticus. A total of 1089 clones were sequenced. All the consensuses were recognized based on the BLAST searches in NCBI, and revealed that 376 (58%) of them had no significant matches to reported sequences in the database. 267 ESTs were in significant matches after homologous sequence searches. Hypothesized genes inferred from EST sequences were categorized into six groups according to their putative biological functions: replication, transcription and translation; cellular processes; responded to stimuli; metabolism and biosynthesis; signal transduction genes; "other" category. The five genes, pearlin gene promoter PGPPm, serine/threonine kinase STKPm, limbic system-associated membrane protein LSAMPPm, nacrein gene intron 6 NGIPm6 and ferritin-like protein FLPPm, were analyzed using real-time PCR. All these genes were significantly expressed after V. alginolyticus challenge. PMID- 22515966 TI - Low concentrations of bisphenol A induce lipid accumulation mediated by the production of reactive oxygen species in the mitochondria of HepG2 cells. AB - Bisphenol A (BPA) is an endocrine-disrupting chemical that leaches from polycarbonate plastics that consequently leads to low-dose human exposure. In addition to its known xenoendocrine action, BPA exerts a wide variety of metabolic effects, but no data are available on its actions on the functions of liver mitochondrial. To assess these effects, HepG2 cells were exposed to BPA (10(-4)-10(-12)M) and physiological parameters were measured by flow cytometry. We demonstrated a significant mitochondrial dysfunction including ROS production, DeltaPsi(M) hyperpolarization, lipid accumulation, lipoperoxidation and the release of pro-inflammatory cytokines. In conclusion, we showed that low concentrations of BPA promote lipid accumulation in hepatic cells triggered by disturbances in mitochondrial function, alterations in lipid metabolism and by inflammation that can therefore contribute to steatosis. PMID- 22515967 TI - Comparative analysis of perturbed molecular pathways identified in in vitro and in vivo toxicology studies. AB - The development of in vitro toxicological testing strategies are hampered by the difficulty in extrapolation to the intact organism. Academic toxicological literature contains a wealth of mechanistically rich information, especially arising from omic studies, which could potentially be utilized to uncover commonalities between in vitro and in vivo observations on the cellular level. Using a literature mining strategy, we identified 1221 unique human genes as being associated to nephrotoxicity, hepatotoxicity, or CNS toxicity, either linked to in vitro, in vivo, or both experimental conditions. Among this large set of relevant molecular features four genes were found in common to all tissues and experimental conditions analyzed, namely heme oxygenase-1, nitric oxide synthetase 2, NFkappaB1 and p53. Pathway enrichment revealed 17 relevant pathways for kidney, 26 for liver, and 30 for CNS bridging in vitro and in vivo toxicity effects. Such joint markers and pathways may serve as indicators for extrapolating from in vitro results to in vivo. PMID- 22515968 TI - Antimicrobial drug resistance in Escherichia coli from humans and food animals, United States, 1950-2002. AB - We conducted a retrospective study of Escherichia coli isolates recovered from human and food animal samples during 1950-2002 to assess historical changes in antimicrobial drug resistance. A total of 1,729 E. coli isolates (983 from humans, 323 from cattle, 138 from chickens, and 285 from pigs) were tested for susceptibility to 15 antimicrobial drugs. A significant upward trend in resistance was observed for ampicillin (p<0.001), sulfonamide (p<0.001), and tetracycline (p<0.001). Animal strains showed increased resistance to 11/15 antimicrobial agents, including ampicillin (p<0.001), sulfonamide (p<0.01), and gentamicin (p<0.001). Multidrug resistance (>=3 antimicrobial drug classes) in E. coli increased from 7.2% during the 1950s to 63.6% during the 2000s. The most frequent co-resistant phenotype observed was to tetracycline and streptomycin (29.7%), followed by tetracycline and sulfonamide (29.0%). These data describe the evolution of resistance after introduction of new antimicrobial agents into clinical medicine and help explain the range of resistance in modern E. coli isolates. PMID- 22515969 TI - Readiness to be physically active and self-reported physical activity in low income Latinas, California WISEWOMAN, 2006-2007. AB - INTRODUCTION: Latinas are more likely to be inactive than non-Hispanic white women. Although 74% of Latinas report no leisure-time activity, few interventions have been designed to promote physical activity among these women. The objective of this study was to assess the effect of the California WISEWOMAN program on low income Latinas's readiness to change physical activity and on self-reported physical activity behaviors. METHODS: We screened 1,332 women for cardiovascular disease risk factors and randomly assigned 1,093 women to 2 groups: an enhanced intervention (n = 552) or usual care (n = 541). The enhanced intervention was delivered by community health workers in one-on-one counseling sessions. We examined self-reported readiness to change and physical activity at baseline and 12-month follow-up among participants who completed both assessments (n = 868). RESULTS: Mean age of participants was 52 years (standard deviation, 6 y); most (65%) were Mexican or Mexican American, and most (81%) were not high school graduates. A higher percentage (67%) of the enhanced intervention group was in the action/maintenance stage for vigorous physical activity at follow-up compared with baseline (47%). We found no such change among women in usual care (52%, baseline; 58%, follow-up). A higher percentage of the enhanced intervention group also reported significant increases in moderate (71%, baseline; 84%, follow-up) and vigorous (13% to 33%) physical activity at follow-up than at baseline. Women in usual care reported no changes. CONCLUSION: A culturally tailored adaptation of the WISEWOMAN program that used community health workers significantly improved both self-reported readiness to engage in physical activity and vigorous physical activity among low-income Latinas. PMID- 22515970 TI - Racial/ethnic differences in the percentage of gestational diabetes mellitus cases attributable to overweight and obesity, Florida, 2004-2007. AB - INTRODUCTION: Gestational diabetes mellitus (GDM) affects 3% to 7% of pregnant women in the United States, and Asian, black, American Indian, and Hispanic women are at increased risk. Florida, the fourth most populous US state, has a high level of racial/ethnic diversity, providing the opportunity to examine variations in the contribution of maternal body mass index (BMI) status to GDM risk. The objective of this study was to estimate the race/ethnicity-specific percentage of GDM attributable to overweight and obesity in Florida. METHODS: We analyzed linked birth certificate and maternal hospital discharge data for live, singleton deliveries in Florida from 2004 through 2007. We used logistic regression to assess the independent contributions of women's prepregnancy BMI status to their GDM risk, by race/ethnicity, while controlling for maternal age and parity. We then calculated the adjusted population-attributable fraction of GDM cases attributable to overweight and obesity. RESULTS: The estimated GDM prevalence was 4.7% overall and ranged from 4.0% among non-Hispanic black women to 9.9% among Asian/Pacific Islander women. The probability of GDM increased with increasing BMI for all racial/ethnic groups. The fraction of GDM cases attributable to overweight and obesity was 41.1% overall, 15.1% among Asians/Pacific Islanders, 39.1% among Hispanics, 41.2% among non-Hispanic whites, 50.4% among non-Hispanic blacks, and 52.8% among American Indians. CONCLUSION: Although non-Hispanic black and American Indian women may benefit the most from prepregnancy reduction in obesity, interventions other than obesity prevention may be needed for women from other racial/ethnic groups. PMID- 22515971 TI - State-specific synthetic estimates of health status groups among inactive older adults with self-reported diabetes, 2000-2009. AB - INTRODUCTION: Physical activity helps diabetic older adults who have physical impairments or comorbid conditions to control their disease. To enable state planners to select physical activity programs for these adults, we calculated synthetic state-specific estimates of inactive older adults with diabetes, categorized by defined health status groups. METHODS: Using data from the 2000 through 2009 National Health Interview Survey (NHIS) and the Behavioral Risk Factor Surveillance System (BRFSS), we calculated synthetic state-specific estimates of inactive adults with diabetes who were aged 50 years or older for 5 mutually exclusive health status groups: 1) homebound, 2) frail (functional difficulty in walking one-fourth mile, climbing 10 steps, standing for 2 hours, and stooping, bending, and kneeling), 3) functionally impaired (difficulty in 1 to 3 of these functions), 4) having 1 or more comorbid conditions (with no functional impairments), and 5) healthy (no impairments or comorbid conditions). We combined NHIS regional proportions for the health status groups of inactive, older diabetic adults with BRFSS data of older diabetic adults to estimate state specific proportions and totals. RESULTS: State-specific estimates of health status groups among all older adults ranged from 2.2% to 3.0% for homebound, 5.8% to 8.8% for frail, 20.1% to 26.1% for impaired, 34.9% to 43.7% for having comorbid conditions, and 4.0% to 6.9% for healthy; the remainder were older active diabetic adults. Except for the homebound, the percentages in these health status groups varied significantly by region and state. CONCLUSION: These state specific estimates correspond to existing physical activity programs to match certain health status characteristics of groups and may be useful to program planners to meet the needs of inactive, older diabetic adults. PMID- 22515972 TI - An epidemiologic transition of cardiovascular disease risk in Carriacou and Petite Martinique, Grenada: the Grenada Heart Project, 2005-2007. AB - INTRODUCTION: The epidemiologic transition has made chronic disease a major health threat in the Caribbean and throughout the world. Our objective was to examine the pattern of lifestyle factors associated with cardiovascular disease (CVD) in Grenada and to determine whether the prevalence of CVD risk factors differs by subgroups. METHODS: We conducted a cross-sectional study of adult Grenadians between 2005 and 2007. We used a population-wide, community-based approach by adapting the World Health Organization's STEPwise Approach to the Surveillance of Chronic Disease survey for a local context. We collected behavioral, anthropometric, and blood sample data to assess the prevalence of CVD risk factors. RESULTS: An estimated 64% (n = 2,017) of 3,167 eligible adults participated in our study (60% women). With increasing age, consumption of fried foods declined, whereas fish intake increased. Adults aged 45 to 54 years had the highest obesity rate (39%). Large waist circumference was more common among women than among men. According to National Cholesterol Education Program criteria, 29% of participants had metabolic syndrome (47% >= 65 y; 36% women vs 17% men). Approximately one-fifth of participants had lived outside Grenada for more than 10 years. Participants who had migrated tended to be older and have different CVD risk factors than those who had never migrated. CONCLUSION: In the midst of an epidemiologic transition in the Caribbean nation of Grenada in which CVD risk is increasing, dietary risk factors are most prevalent among women and among all adults younger than 55. PMID- 22515973 TI - Pluripotent and multipotent stem cells in adult tissues. AB - One of the most intriguing questions in stem cell biology is whether pluripotent stem cells exist in adult tissues. Several groups of investigators employing i) various isolation protocols, ii) detection of surface markers, and iii) experimental in vitro and in vivo models, have reported the presence of cells that possess a pluripotent character in adult tissues. Such cells were assigned various operational abbreviations and names in the literature that added confusion to the field and raised the basic question of whether these are truly distinct or overlapping populations of the same primitive stem cells. Unfortunately, these cells were never characterized side-by-side to address this important issue. Nevertheless, taking into consideration their common features described in the literature, it is very likely that various investigators have described overlapping populations of developmentally early stem cells that are closely related. These different populations of stem cells will be reviewed in this paper. PMID- 22515974 TI - Unexpected cure from cutaneous leukocytoclastic vasculitis in a patient treated with N-butyldeoxynojirimycin (miglustat) for Gaucher disease. AB - Cutaneous leukocytoclastic vasculitis (CLV) is a necrotizing inflammation of the small vessels in the dermis. We report the case of a Swedish man with an untreated N370S/L444P Gaucher disease who developed CLV at the age of 79 years. The patient has been treated for CLV with topical and oral corticosteroids, moisturizing agents, and periodically with antibiotics for 3 years without improvement. Administration of miglustat (N-butyldeoxynojirimycin; Zavesca(r)) because of progress of Gaucher disease resulted in a prompt and durable cure of the CLV. PMID- 22515975 TI - Rhabdomyolysis associated with antimicrobial drug-resistant Mycoplasma pneumoniae. AB - We describe a case of rhabdomyolysis in a patient infected with antimicrobial drug-resistant Mycoplasma pneumoniae The patient's acute-phase serum levels of interleukin-18 and tumor necrosis factor-alpha were high, which suggests a pathogenic role for M. pneumoniae. In an era of increasing antimicrobial drug resistance, a system for rapidly identifying resistant M. pneumoniae would be beneficial. PMID- 22515976 TI - Blood pressure control among US veterans: a large multiyear analysis of blood pressure data from the Veterans Administration health data repository. AB - BACKGROUND: Hypertension treatment and control remain low worldwide. Strategies to improve blood pressure control have been implemented in the United States and around the world for several years. This study was designed to assess improvement in blood pressure control over a 10-year period in a large cohort of patients in the Department of Veterans Affairs. METHODS AND RESULTS: A cohort of 582 881 hypertensive patients and 260 924 normotensive individuals treated in 15 Department of Veterans Affairs medical centers between 2000 and 2010 were examined. Strategies used system-wide included blood pressure control as a performance measure, automatic notification to healthcare providers, electronic reminders, and a systematic revisit schedule. The main outcome measure was the percentage of hypertensive patients whose hypertension was controlled and the level of blood pressure each month. In the hypertensive cohort (mean age 62.9+/ 13.4 years, 96.0% male), 52.3% of patients were white, 25.1% were black, and 21.1% were Hispanic. Blood pressure control rates improved from 45.7% in September 2000 to 76.3% in August 2010. Improvements were similar across ethnic, racial, age, and sex groups. Average systolic/diastolic blood pressure decreased from 142.6/77.1 mm Hg in 2000 to 131.2/74.8 mm Hg in 2010, a decrease of 11.3/2.3 mm Hg (P<0.0001 for both). Systolic and diastolic blood pressures were lower in summer than in winter, and this trend continued through 2010. On average, control rates increased by 3.0% per year and were 6.8% higher in summer than in winter. CONCLUSIONS: High rates of blood pressure control can be achieved in all age and ethnic groups and in both sexes. PMID- 22515978 TI - Th17-related cytokines in inflammatory bowel diseases: friends or foes? AB - T helper (Th)17 cells and other interleukin (IL)-17-producing cells are supposed to play critical roles in several human immune-mediated diseases, including Crohn's disease (CD) and ulcerative colitis (UC), the main forms of inflammatory bowel diseases (IBD) in man. Th17 cells infiltrate massively the inflamed intestine of IBD patients and in vitro and in vivo studies have shown that Th17 type cytokines may trigger and amplify multiple inflammatory pathways. Nonetheless, some Th17-related cytokines, such as interleukin (IL)-17A and IL-22, may target gut epithelial cells and promote the activation of counter-regulatory mechanisms. This observation together with the demonstration that Th17 cells are not stable and can be converted into either regulatory T cells or Th1 cells if stimulated by immune-suppressive (e.g. TGF-beta1) or inflammatory (e.g. IL-12, IL 23) cytokines have contributed to advance our understanding of mechanisms that regulate mucosal homeostasis and inflammation in the gut. PMID- 22515977 TI - Neuroprotective strategies for the treatment of inherited photoreceptor degeneration. AB - Photoreceptor degeneration is the hallmark of several groups of inherited neurodegenerative diseases causing blindness in humans. These diseases are a major cause of visual handicap and to date no satisfactory treatment is available. Here, we briefly review different approaches for the treatment of photoreceptor degeneration, to then focus on neuroprotection. Up to date, translation of experimental neuroprotection into a clinical setting has faced major obstacles, which are in part due to an incomplete understanding of the regulation of pro-survival as well as neurodegenerative mechanisms. Previous approaches were often based on the hypothesis that photoreceptor cell death was governed by a single, apoptotic cell death mechanism. This perception has turned out too simple as recent work has demonstrated that photoreceptor cell death is governed by non-apoptotic mechanisms as well. Moreover, there is evidence, that several different destructive processes are executed in parallel. Briefly reviewing the complexity of degenerative mechanisms, this review discusses relevant pathways, options to target signaling cascades, final common denominators of cell death, and the interplay of events executing cell death. In particular, we focus on cGMP-signaling, epigenetic and proteolytic processes and the corresponding enzymatic activities that were recently shown to be causally related to retinal degeneration. Finally, we illustrate how a better understanding of destructive mechanisms may enable identification and validation of novel targets for neuroprotection, and allow development of next generation neuroprotective treatments as well as combination therapy. PMID- 22515979 TI - Immunosuppressive properties of mesenchymal stem cells: advances and applications. AB - Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, such as bone marrow, skeletal muscle, dental pulp, bone, umbilical cord and adipose tissue. MSCs are used in regenerative medicine mainly based on their capacity to differentiate into specific cell types and also as bioreactors of soluble factors that will promote tissue regeneration from the damaged tissue cellular progenitors. In addition to these regenerative properties, MSCs hold an immunoregulatory capacity, and elicit immunosuppressive effects in a number of situations. Not only are they immunoprivileged cells, due to the low expression of class II Major Histocompatibilty Complex (MHC-II) and costimulatory molecules in their cell surface, but they also interfere with different pathways of the immune response by means of direct cell-to-cell interactions and soluble factor secretion. In vitro, MSCs inhibit cell proliferation of T cells, B-cells, natural killer cells (NK) and dendritic cells (DC), producing what is known as division arrest anergy. Moreover, MSCs can stop a variety of immune cell functions: cytokine secretion and cytotoxicity of T and NK cells; B cell maturation and antibody secretion; DC maturation and activation; as well as antigen presentation. It is thought that MSCs need to be activated to exert their immunomodulation skills. In this scenario, an inflammatory environment seems to be necessary to promote their effect and some inflammation-related molecules such as tumor necrosis factor-alpha and interferon-gamma might be implicated. It has been observed that MSCs recruit T-regulatory lymphocytes (Tregs) to both lymphoid organs and graft. There is great controversy concerning the mechanisms and molecules involved in the immunosuppressive effect of MSCs. Prostaglandin E2, transforming growth factor-beta, interleukins- 6 and 10, human leukocyte antigen G5, matrix metalloproteinases, indoleamine-2,3-dioxygenase and nitric oxide are all candidates under investigation. In vivo studies have shown many discrepancies regarding the immunomodulatory properties of MSCs. These studies have been designed to test the efficacy of MSC therapy in two different immune settings: the prevention or treatment of allograft rejection episodes, and the ability to suppress abnormal immune response in autoimmune and inflammatory diseases. Preclinical studies have been conducted in rodents, rabbits and baboon monkeys among others for bone marrow, skin, heart, and corneal transplantation, graft versus host disease, hepatic and renal failure, lung injury, multiple sclerosis, rheumatoid arthritis, diabetes and lupus diseases. Preliminary results from some of these studies have led to human clinical trials that are currently being carried out. These include treatment of autoimmune diseases such as Crohn's disease, ulcerative colitis, multiple sclerosis and type 1 diabetes mellitus; prevention of allograft rejection and enhancement of the survival of bone marrow and kidney grafts; and treatment of resistant graft versus host disease. We will try to shed light on all these studies, and analyze why the results are so contradictory. PMID- 22515980 TI - Beyond the cardiac myofilament: hypertrophic cardiomyopathy- associated mutations in genes that encode calcium-handling proteins. AB - Traditionally regarded as a genetic disease of the cardiac sarcomere, hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease and a significant cause of sudden cardiac death. While the most common etiologies of this phenotypically diverse disease lie in a handful of genes encoding critical contractile myofilament proteins, approximately 50% of patients diagnosed with HCM worldwide do not host sarcomeric gene mutations. Recently, mutations in genes encoding calcium-sensitive and calcium-handling proteins have been implicated in the pathogenesis of HCM. Among these are mutations in TNNC1- encoded cardiac troponin C, PLN-encoded phospholamban, and JPH2-encoded junctophilin 2 which have each been associated with HCM in multiple studies. In addition, mutations in RYR2-encoded ryanodine receptor 2, CASQ2-encoded calsequestrin 2, CALR3-encoded calreticulin 3, and SRI-encoded sorcin have been associated with HCM, although more studies are required to validate initial findings. While a relatively uncommon cause of HCM, mutations in genes that encode calcium-handling proteins represent an emerging genetic subset of HCM. Furthermore, these naturally occurring disease-associated mutations have provided useful molecular tools for uncovering novel mechanisms of disease pathogenesis, increasing our understanding of basic cardiac physiology, and dissecting important structure-function relationships within these proteins. PMID- 22515982 TI - Spinophilin: a new tumor suppressor at 17q21. AB - The scaffold protein spinophilin (SPN) is a regulatory subunit of phosphatase 1a (PP1a) located at 17q21.33. This region is frequently associated with microsatellite instability and LOH and contains a relatively high density of known tumor suppressor genes, and several unidentified candidate tumor suppressor genes located distal to BRCA1. Spn is located in this locus and proposed to be a new tumor suppressor. Loss of Spn induces a proliferative response by increasing pRb phosphorylation, which in turn activates p53, thereby, neutralizing the proliferative response. The absence of p53 bypasses this barrier and enhances the malignant phenotype. Furthermore, the ectopic expression of SPN in human tumor cells from different types of malignancies greatly reduced cell growth. Spn knock out mice had decreased lifespan with increased cellular proliferation in tissues such as the mammary ducts and early appearance of tumors. Furthermore, the combined loss of Spn and mutant p53 activity led to increased mammary carcinomas, confirming the functional relationship between p53 and Spn. In human tumors, Spn is absent in 20% and reduced in another 37% of human lung tumors. Spn reduction correlates with malignant grade and p53 mutations. Furthermore, Spn mRNA is lost in a percentage of renal carcinomas and lung adenocarcinomas. Finally, lower levels of Spn mRNA correlate with higher grade of ovarian carcinoma and chronic myelogenous leukemia. Therefore, Spn may be the tumor suppressor gene that is located at 17q21.33 and that its tumor suppressive function is dependent on the absence of p53. PMID- 22515984 TI - Human adenovirus type 7 outbreak in Police Training Center, Malaysia, 2011. AB - In March 2011, an outbreak of acute respiratory disease was reported at the Kuala Lumpur (Malaysia) Police Training Centre. Approximately 100 trainees were hospitalized and 5 were admitted to the intensive care unit. Three of these 5 trainees died. Human adenovirus type 7 was identified as the etiologic agent. PMID- 22515983 TI - Novel strain of Andes virus associated with fatal human infection, central Bolivia. AB - To better describe the genetic diversity of hantaviruses associated with human illness in South America, we screened blood samples from febrile patients in Chapare Province in central Bolivia during 2008-2009 for recent hantavirus infection. Hantavirus RNA was detected in 3 patients, including 1 who died. Partial RNA sequences of small and medium segments from the 3 patients were most closely related to Andes virus lineages but distinct (<90% nt identity) from reported strains. A survey for IgG against hantaviruses among residents of Chapare Province indicated that 12.2% of the population had past exposure to >1 hantaviruses; the highest prevalence was among agricultural workers. Because of the high level of human exposure to hantavirus strains and the severity of resulting disease, additional studies are warranted to determine the reservoirs, ecologic range, and public health effect of this novel strain of hantavirus. PMID- 22515981 TI - GADD45 proteins: central players in tumorigenesis. AB - The Growth Arrest and DNA Damage-inducible 45 (GADD45) proteins have been implicated in regulation of many cellular functions including DNA repair, cell cycle control, senescence and genotoxic stress. However, the pro-apoptotic activities have also positioned GADD45 as an essential player in oncogenesis. Emerging functional evidence implies that GADD45 proteins serve as tumor suppressors in response to diverse stimuli, connecting multiple cell signaling modules. Defects in the GADD45 pathway can be related to the initiation and progression of malignancies. Moreover, induction of GADD45 expression is an essential step for mediating anti-cancer activity of multiple chemotherapeutic drugs and the absence of GADD45 might abrogate their effects in cancer cells. In this review, we present a comprehensive discussion of the functions of GADD45 proteins, linking their regulation to effectors of cell cycle arrest, DNA repair and apoptosis. The ramifications regarding their roles as essential and central players in tumor growth suppression are also examined. We also extensively review recent literature to clarify how different chemotherapeutic drugs induce GADD45 gene expression and how its up-regulation and interaction with different molecular partners may benefit cancer chemotherapy and facilitate novel drug discovery. PMID- 22515986 TI - Lymphocytic choriomeningitis virus-associated meningitis, southern Spain. AB - Lymphocytic choriomeningitis virus (LCMV) was detected in 2 patients with acute meningitis in southern Spain within a 3-year period. Although the prevalence of LCMV infection was low (2 [1.3%] of 159 meningitis patients), it represents 2.9% of all pathogens detected. LCMV is a noteworthy agent of neurologic illness in immunocompetent persons. PMID- 22515987 TI - Publication bias: what are the challenges and can they be overcome? PMID- 22515985 TI - Health care professionals' beliefs about using wiki-based reminders to promote best practices in trauma care. AB - BACKGROUND: Wikis are knowledge translation tools that could help health professionals implement best practices in acute care. Little is known about the factors influencing professionals' use of wikis. OBJECTIVES: To identify and compare the beliefs of emergency physicians (EPs) and allied health professionals (AHPs) about using a wiki-based reminder that promotes evidence-based care for traumatic brain injuries. METHODS: Drawing on the theory of planned behavior, we conducted semistructured interviews to elicit EPs' and AHPs' beliefs about using a wiki-based reminder. Previous studies suggested a sample of 25 EPs and 25 AHPs. We purposefully selected participants from three trauma centers in Quebec, Canada, to obtain a representative sample. Using univariate analyses, we assessed whether our participants' gender, age, and level of experience were similar to those of all eligible individuals. Participants viewed a video showing a clinician using a wiki-based reminder, and we interviewed participants about their behavioral, control, and normative beliefs-that is, what they saw as advantages, disadvantages, barriers, and facilitators to their use of a reminder, and how they felt important referents would perceive their use of a reminder. Two reviewers independently analyzed the content of the interview transcripts. We considered the 75% most frequently mentioned beliefs as salient. We retained some less frequently mentioned beliefs as well. RESULTS: Of 66 eligible EPs and 444 eligible AHPs, we invited 55 EPs and 39 AHPs to participate, and 25 EPs and 25 AHPs (15 nurses, 7 respiratory therapists, and 3 pharmacists) accepted. Participating AHPs had more experience than eligible AHPs (mean 14 vs 11 years; P = .04). We noted no other significant differences. Among EPs, the most frequently reported advantage of using a wiki-based reminder was that it refreshes the memory (n = 14); among AHPs, it was that it provides rapid access to protocols (n = 16). Only 2 EPs mentioned a disadvantage (the wiki added stress). The most frequently reported favorable referent was nurses for EPs (n = 16) and EPs for AHPs (n = 19). The most frequently reported unfavorable referents were people resistant to standardized care for EPs (n = 8) and people less comfortable with computers for AHPs (n = 11). The most frequent facilitator for EPs was ease of use (n = 19); for AHPs, it was having a bedside computer (n = 20). EPs' most frequently reported barrier was irregularly updated wiki-based reminders (n = 18); AHPs' was undetermined legal responsibility (n = 10). CONCLUSIONS: We identified EPs' and AHPs' salient beliefs about using a wiki-based reminder. We will draw on these beliefs to construct a questionnaire to measure the importance of these determinants to EPs' and AHPs' intention to use a wiki-based reminder promoting evidence-based care for traumatic brain injuries. PMID- 22515988 TI - Will lithium damage my kidneys? PMID- 22515989 TI - Transmission dynamics, border entry screening, and school holidays during the 2009 influenza A (H1N1) pandemic, China. AB - Pandemic influenza A (H1N1) 2009 virus spread rapidly around the world in 2009. We used multiple data sources from surveillance systems and specific investigations to characterize the transmission patterns of this virus in China during May-November 2009 and analyze the effectiveness of border entry screening and holiday-related school closures on transmission. In China, age distribution and transmission dynamic characteristics were similar to those in Northern Hemisphere temperate countries. The epidemic was focused in children, with an effective reproduction number of ~1.2-1.3. The 8 days of national holidays in October reduced the effective reproduction number by 37% (95% credible interval 28%-45%) and increased underreporting by ~20%-30%. Border entry screening detected at most 37% of international travel-related cases, with most (89%) persons identified as having fever at time of entry. These findings suggest that border entry screening was unlikely to have delayed spread in China by >4 days. PMID- 22515990 TI - Temporal trends in Bordetella pertussis populations, Denmark, 1949-2010. AB - We used multilocus variable-number tandem repeat analysis and multiple antigen sequence typing to characterize isolates of Bordetella pertussis strains circulating in Denmark during periods with and without pertussis vaccination coverage. Our results show substantial shifts in the B. pertussis population over time and a reduction in genetic diversity. These changes might have resulted from the introduction of pertussis vaccines in Denmark and other parts of Europe. The predominant strains currently circulating in Denmark resemble those in other European countries. PMID- 22515991 TI - Diversity of parvovirus 4-like viruses in humans, chimpanzees, and monkeys in hunter-prey relationships. AB - During 2010-2011, we investigated interspecies transmission of partetraviruses between predators (humans and chimpanzees) and their prey (colobus monkeys) in Cote d'Ivoire. Despite widespread infection in all species investigated, no interspecies transmission could be detected by PCR and genome analysis. All sequences identified formed species- or subspecies (chimpanzee)-specific clusters, which supports a co-evolution hypothesis. PMID- 22515992 TI - Diagnosis of soil-transmitted helminthiasis in an Amazonic community of Peru using multiple diagnostic techniques. AB - An observational descriptive study was conducted in a Shipibo-Conibo/Ese'Eja community of the rainforest in Peru to compare the Kato-Katz method and the spontaneous sedimentation in tube technique (SSTT) for the diagnosis of intestinal parasites as well as to report the prevalence of soil-transmitted helminth (STH) infections in this area. A total of 73 stool samples were collected and analysed by several parasitological techniques, including Kato Katz, SSTT, modified Baermann technique (MBT), agar plate culture, Harada-Mori culture and the direct smear examination. Kato-Katz and SSTT had the same rate of detection for Ascaris lumbricoides (5%), Trichuris trichiura (5%), hookworm (14%) and Hymenolepis nana (26%). The detection rate for Strongyloides stercoralis larvae was 16% by SSTT and 0% by Kato-Katz, but 18% by agar plate culture and 16% by MBT. The SSTT also had the advantage of detecting multiple intestinal protozoa such as Blastocystis hominis (40%), Giardia intestinalis (29%) and Entamoeba histolytica/E. dispar (16%). The most common intestinal parasites found in this community were B. hominis, G. intestinalis, H. nana, S. stercoralis and hookworm. In conclusion, the SSTT is not inferior to Kato-Katz for the diagnosis of common STH infections but is largely superior for detecting intestinal protozoa and S. stercoralis larvae. PMID- 22515993 TI - Arsenic(III) sorption on nanostructured cerium incorporated manganese oxide (NCMO): a physical insight into the mechanistic pathway. AB - Arsenic(III) sorption was investigated with nanostructured cerium incorporated manganese oxide (NCMO). The pH between 6.0 and 8.0 was optimized for the arsenic(III) sorption. Kinetics and equilibrium data (pH=7.0+/-0.2, T=303+/-1.6 K, and I=0.01 M) of arsenic(III) sorption by NCMO described, respectively, the pseudo-second order and the Freundlich isotherm equations well. The sorption process was somewhat complicated in nature and divided into two different segments, initially very fast sorption followed by slow intraparticle diffusion process. Sorption reaction of arsenic(III) on NCMO was endothermic (DeltaH degrees =+13.46 kJ mol(-1)) and spontaneous (DeltaG degrees =-24.75 to -30.15 kJ mol(-1) at T=283-323 K), which took place with increasing entropy (DeltaS degrees =+0.14 kJ mol(-1)K(-1)) at solid-liquid interface. Energy of arsenic(III) sorption estimated by analyzing the equilibrium data using the D-R isotherm model was 15.4 kJ mol(-1), indicating the ion-exchange type mechanism. Raman, FT-IR, pH effect, desorption, etc. studies indicated that arsenic(III) was oxidized to arsenic(V) during the sorption process. PMID- 22515994 TI - Upconversion emission enhancement of Gd3+ ions induced by surface plasmon field in Au@NaYF4 nanostructures codoped with Gd(3+)-Yb(3+)-Tm(3+) ions. AB - Au nanoparticles (NPs) attached beta-NaYF(4) nanocrystals codoped with Gd(3+) Yb(3+)-Tm(3+) were synthesized by a facial solution method. The UV-vis-near infrared absorption spectrum shows typical surface plasmon resonance band of Au NPs in addition to the characteristic absorption peaks of Yb(3+) ion. X-ray diffraction and selected area electron diffraction results indicate the existence of Au NPs. The transmission electron microscopic image reveals the formation of Au@NaYF(4) nanostructures. Enhanced ultraviolet (UV) upconversion luminescence (UCL) was observed in the nanostructures under the excitation of 980-nm infrared laser. The largest enhancement factor was obtained as 76 for the (6)I(J) >(8)S(7/2) emission of Gd(3+) ions, which was much larger than those emission enhancement factors of Tm(3+). It is for the first time to our knowledge that the emission enhancement of Gd(3+) ions was obtained. Local field enhancement induced by Au NPs was found to be responsible for the UCL enhancement, which is the further experimental evidence of local field enhancement theory. Magnetic measurements of the Au@NaYF(4) nanostructure indicated it would have potential application in magnetic resonance imaging. PMID- 22515995 TI - Mixed aggregate formation in gemini surfactant/1,2-dialkyl-sn-glycero-3 phosphoethanolamine systems. AB - An evaluation of the physical interactions between gemini surfactants, DNA, and 1,2-dialkyl-sn-glycero-3-phosphoethanolamine helper lipid is presented in this work. Complexation between gemini surfactants and DNA was first investigated using surface tensiometry where the surface tension profiles obtained were found to be consistent with those typically observed for mixed surfactant-polymer systems; that is, there is a synergistic lowering of the surface tension, followed by a first (CAC) and second (CMC) break point in the plot. The surfactant alkyl tail length was observed to exhibit a significant effect on the CAC, thus demonstrating the importance of hydrophobic interactions during complexation between gemini surfactants and DNA. The second study presented is an investigation of the mixing interactions between gemini surfactants and DOPE using Clint's, Rubingh's, and Motomura's theories for mixed micellar formation. The mixing interactions between the 16-3-16/16-7-16/16-12-16/16-7NH-16 gemini surfactants and DOPE were observed to be antagonistic, where the strength of antagonism was found to be dependent upon the gemini surfactant spacer group and the solution composition. PMID- 22515996 TI - Investigations and application in piezoelectric phenol sensor of Langmuir-Schafer films of a copper phthalocyanine derivative functionalized with bulky substituents. AB - An octa-substituted copper phthalocyanine was dissolved in chloroform and spread on ultrapure water subphase in a Langmuir trough. The floating films were characterized at the air-water interface by the Langmuir isotherm, Brewster angle microscopy, and UV-Vis reflection spectroscopy and transferred by Langmuir Schafer technique on a silicon substrate, and thickness, refractive index, and extinction coefficient of the phthalocyanine derivative thin film were calculated by means of spectroscopic ellipsometry. A different number of layers were deposited using Langmuir-Schafer method onto QCM crystals, and the active layers were tested as sensors for the detection of phenols in aqueous solution. The piezoelectric sensor response, totally reversible, is influenced by the number of transferred layers and by the nature of the substituent; on the contrary, the pK(a) value of the injected analytes slightly affects the device performances. Repeatability of the sensor responses was tested, and the frequency variation appears unchanged at least for 100 days. PMID- 22515997 TI - Controllable synthesis of MnS nanocrystals from a single-source precursor. AB - A facile single-source precursor method has been applied for the selective synthesis of MnS nanocrystals (NCs) with well-defined shapes and crystal structures such as hexapod, octahedral, hexagonal shaped alpha-MnS NCs, and pencil-shaped gamma-MnS NCs. The effects of the composition of precursor, reaction temperature, and the heating rate on the morphologies, and crystal structures of MnS NCs were systematically studied for the first time. PMID- 22515998 TI - Modic changes: prevalence, distribution patterns, and association with age in white men. AB - BACKGROUND CONTEXT: Suspected as a cause of back pain, Modic changes (MCs) have received increasing attention in spine research and care. Yet, epidemiologic knowledge of MCs based on the general population, which may provide an important clinical reference, is limited. PURPOSE: To investigate the prevalence and distribution patterns of MCs in the lumbosacral spine and their associations with age in a large population-based sample of men. STUDY DESIGN: An epidemiologic investigation of lumbar magnetic resonance images (MRIs). PATIENT SAMPLE: This study was based on the Twin Spine Study database, comprising a sample of male twins shown to be largely representative of the base Finnish population. Lumbar spine MRIs (1.5 Tesla Magnetom; Siemens AG, Erlangen, Germany) of 561 subjects (mean age, 49.8 years; range, 35-70 years) were included in the present study. METHODS: For each spine, all 11 end plates (L1-S1) in the lumbar region were evaluated using both T1- and T2-weighted images to identify MCs, which were classified into Type 1, 2, 3, and mixed types. Furthermore, the number and location of MCs were recorded, as well as the anteroposterior (AP) and transverse sizes, to explore the prevalence and distribution pattern of MCs in the lumbar region and associations with age. RESULTS: Modic changes were identified in 55.6% (312) of individuals and 13.5% (830) of end plates studied. Among these MCs, 64.2% (533) were Type 2, 16.0% (133) were Type 1, 18.1% (150) were Mixed Type 1/2, and the remaining 1.6% (13) were noted as Type 3 or Mixed Type 2/3. Modic changes were more common in the lower (74.5%) than in the upper lumbar region (25.5%), and 77.9% (642) of MCs presented in pairs at opposing end plates of a disc. Moreover, the specific type of MCs on opposing end plates was usually concordant. The presence of MCs in the lumbar region was associated with age (odds ratio=1.05-1.08 for each additional year of age, depending on type of MCs, p<.001). In addition, greater age was associated with a greater number of end plates affected and MCs of larger size (p<.001). CONCLUSIONS: Modic changes are common MRI findings in the lumbar spines of middle-aged white men, with Type 2 MCs predominating. Mainly present in the lower lumbar region, MCs tend to affect both end plates adjacent to a disc simultaneously, and they commonly involve the entire AP diameter of the vertebral end plate. The presence and size of MCs are clearly related to age, suggesting that aging or associated factors may play an essential role in the pathogenesis of MCs. PMID- 22515999 TI - [Acute myocarditis]. AB - Myocarditis is defined as inflammation of the myocardium accompanied by myocellular necrosis. Acute myocarditis must be considered in patients who present with recent-onset of cardiac failure or arrhythmia. Fulminant myocarditis is a distinct entity characterized by sudden onset of severe congestive heart failure or cardiogenic shock, usually following a flu-like illness, parvovirus B19, human herpesvirus 6, coxsackievirus and adenovirus being the most frequently viruses responsible for the disease. Treatment of myocarditis remains largely supportive, since immunosuppression has not been proven to be beneficial for acute lymphocytic myocarditis. Trials of antiviral therapies, or immunostimulants such as interferons, suggest a potential therapeutic role but require further investigation. Lastly, early recognition of patients rapidly progressing to refractory cardiac failure and their immediate transfer to a medical-surgical center experienced in mechanical circulatory support is warranted. In this setting, ECMO should be the first-line mechanical assistance. For highly unstable patients, a Mobile Cardiac Assistance Unit, that rapidly travels to primary care hospitals with a portable ECMO system and hooks it up before refractory multiorgan failure takes hold, is the preferred option. PMID- 22516000 TI - [Relation between creatinine level and kalaemia in patients with digitalis poisoning]. PMID- 22516001 TI - [Multifocal hydatidosis with extended vertebral and spinal cord localization]. PMID- 22516002 TI - Influenza outbreaks in nursing homes with high vaccination coverage in Navarre, Spain, 2011/12. AB - In the 2011/12 season, three influenza outbreaks were studied in nursing homes with high vaccination coverage in Navarre, Spain. Attack rates ranged from 2.9% to 67%. Influenza A/Stockholm/18/2011(H3N2) virus strain was isolated from the three outbreaks. Vaccination should be complemented with other hygiene measures in nursing homes. Early detection of influenza outbreaks in nursing homes can aid in their control. PMID- 22516003 TI - Excess mortality among the elderly in 12 European countries, February and March 2012. AB - In February and March 2012, excess deaths among the elderly have been observed in 12 European countries that carry out weekly monitoring of all-cause mortality. These preliminary data indicate that the impact of influenza in Europe differs from the recent pandemic and post-pandemic seasons. The current excess mortality among the elderly may be related to the return of influenza A(H3N2) virus, potentially with added effects of a cold snap. PMID- 22516004 TI - Influenza A(H1N1)pdm09 in England, 2009 to 2011: a greater burden of severe illness in the year after the pandemic than in the pandemic year. AB - Influenza pandemics are often perceived as single-year events, but the burden of previous influenza pandemics has in reality been spread over a number of years. The aim of this paper is to compare the burden of influenza in the pandemic year 2009/10 with that in the year immediately after (2010/11) in England. We compared four measures of disease. There was a greater burden of severe illness in 2010/11 compared with 2009/10: more deaths (474 vs 361), more critical care admissions (2,200 vs 1,700), and more hospital admissions (8,797 vs 7,879). In contrast, there were fewer general practice consultations in 2010/11 compared with 2009/10 (370,000 vs 580,000). There was also much less public interest in influenza, as assessed by number of Google searches. This is a worrying finding, as by the time of the second influenza season, much had been learnt about the potential impact of the influenza A(H1N1)pdm09 virus and an effective vaccine developed. We suggest that a widespread assumption of 'mildness' led to insufficient ongoing action to prevent influenza and hence to avoidable influenza-related deaths. This offers a lesson to all countries, both for future influenza seasons and for pandemic preparedness planning. PMID- 22516005 TI - European Food Safety Authority publishes its second report on the Schmallenberg virus. PMID- 22516007 TI - The human vestibular cortex revealed by coordinate-based activation likelihood estimation meta-analysis. AB - The vestibular system contributes to the control of posture and eye movements and is also involved in various cognitive functions including spatial navigation and memory. These functions are subtended by projections to a vestibular cortex, whose exact location in the human brain is still a matter of debate (Lopez and Blanke, 2011). The vestibular cortex can be defined as the network of all cortical areas receiving inputs from the vestibular system, including areas where vestibular signals influence the processing of other sensory (e.g. somatosensory and visual) and motor signals. Previous neuroimaging studies used caloric vestibular stimulation (CVS), galvanic vestibular stimulation (GVS), and auditory stimulation (clicks and short-tone bursts) to activate the vestibular receptors and localize the vestibular cortex. However, these three methods differ regarding the receptors stimulated (otoliths, semicircular canals) and the concurrent activation of the tactile, thermal, nociceptive and auditory systems. To evaluate the convergence between these methods and provide a statistical analysis of the localization of the human vestibular cortex, we performed an activation likelihood estimation (ALE) meta-analysis of neuroimaging studies using CVS, GVS, and auditory stimuli. We analyzed a total of 352 activation foci reported in 16 studies carried out in a total of 192 healthy participants. The results reveal that the main regions activated by CVS, GVS, or auditory stimuli were located in the Sylvian fissure, insula, retroinsular cortex, fronto-parietal operculum, superior temporal gyrus, and cingulate cortex. Conjunction analysis indicated that regions showing convergence between two stimulation methods were located in the median (short gyrus III) and posterior (long gyrus IV) insula, parietal operculum and retroinsular cortex (Ri). The only area of convergence between all three methods of stimulation was located in Ri. The data indicate that Ri, parietal operculum and posterior insula are vestibular regions where afferents converge from otoliths and semicircular canals, and may thus be involved in the processing of signals informing about body rotations, translations and tilts. Results from the meta-analysis are in agreement with electrophysiological recordings in monkeys showing main vestibular projections in the transitional zone between Ri, the insular granular field (Ig), and SII. PMID- 22516006 TI - Timing of audiovisual inputs to the prefrontal cortex and multisensory integration. AB - A number of studies have demonstrated that the relative timing of audiovisual stimuli is especially important for multisensory integration of speech signals although the neuronal mechanisms underlying this complex behavior are unknown. Temporal coincidence and congruency are thought to underlie the successful merging of two intermodal stimuli into a coherent perceptual representation. It has been previously shown that single neurons in the non-human primate prefrontal cortex integrate face and vocalization information. However, these multisensory responses and the degree to which they depend on temporal coincidence have yet to be determined. In this study we analyzed the response latency of ventrolateral prefrontal (VLPFC) neurons to face, vocalization and combined face-vocalization stimuli and an offset (asynchronous) version of the face-vocalization stimulus. Our results indicate that for most prefrontal multisensory neurons, the response latency for the vocalization was the shortest, followed by the combined face vocalization stimuli. The face stimulus had the longest onset response latency. When tested with a dynamic face-vocalization stimulus that had been temporally offset (asynchronous) one-third of multisensory cells in VLPFC demonstrated a change in response compared to the response to the natural, synchronous face vocalization movie. Our results indicate that prefrontal neurons are sensitive to the temporal properties of audiovisual stimuli. A disruption in the temporal synchrony of an audiovisual signal which results in a change in the firing of communication related prefrontal neurons could underlie the loss in intelligibility which occurs with asynchronous speech stimuli. PMID- 22516009 TI - Immunohistochemical determination of the site of hypotensive effects of glucagon like peptide-2 in the rat brain. AB - Proglucagon-derived glucagon-like peptide-2 (GLP-2) is released from enteroendocrine cells and neurons. GLP-2 regulates energy absorption and epithelial integrity in the gastrointestinal tract, but its effect on blood pressure regulation remains unknown. In the present study, we found that GLP-2 administered both peripherally and centrally dose-dependently reduced mean arterial blood pressure (MAP) in male Wistar rats anesthetized with urethane and alpha-chloralose. Immunohistochemical detection of the c-fos protein (Fos) revealed that the peripherally and centrally administered GLP-2 induced Fos immunoreactivity (Fos-IR) in the nucleus of the solitary tract (NTS) and the caudal ventrolateral medulla (CVLM). In contrast, Fos-IR in brainstem catecholamine neurons decreased after the administration of GLP-2. These results suggest that GLP-2 acts on specific brain nuclei to inhibit sympathetic nerve activity and this leads to hypotension. PMID- 22516008 TI - Multisensory dysfunction accompanies crossmodal plasticity following adult hearing impairment. AB - Until now, cortical crossmodal plasticity has largely been regarded as the effect of early and complete sensory loss. Recently, massive crossmodal cortical reorganization was demonstrated to result from profound hearing loss in adult ferrets (Allman et al., 2009a). Moderate adult hearing loss, on the other hand, induced not just crossmodal reorganization, but also merged new crossmodal inputs with residual auditory function to generate multisensory neurons. Because multisensory convergence can lead to dramatic levels of response integration when stimuli from more than one modality are present (and thereby potentially interfere with residual auditory processing), the present investigation sought to evaluate the multisensory properties of auditory cortical neurons in partially deafened adult ferrets. When compared with hearing controls, partially-deaf animals revealed elevated spontaneous levels and a dramatic increase (~2 times) in the proportion of multisensory cortical neurons, but few of which showed multisensory integration. Moreover, a large proportion (68%) of neurons with somatosensory and/or visual inputs was vigorously active in core auditory cortex in the absence of auditory stimulation. Collectively, these results not only demonstrate multisensory dysfunction in core auditory cortical neurons from hearing impaired adults but also reveal a potential cortical substrate for maladaptive perceptual effects such as tinnitus. PMID- 22516010 TI - The amnesic effect of intra-central amygdala administration of a cannabinoid CB1 receptor agonist, WIN55,212-2, is mediated by a beta-1 noradrenergic system in rat. AB - In this study, we investigated effects of intra-central amygdala (intra-CeA) administrations of a cannabinoid agonist, WIN55,212-2 by itself and its interaction with beta1-adrenoceptor agents on memory consolidation. We used a step-through inhibitory avoidance (IA) task to assess memory in male Wistar rats. The results showed that post-training intra-CeA administrations of different doses of WIN55,212-2 at doses of 0.1 and 0.25 MUg/rat impaired memory consolidation (or induced amnesia) as revealed by a decrease in step-through latency on the test day. Post-training intra-CeA injections of a beta1 adrenoceptor agonist, isoprenaline (0.01, 0.025, 0.05 MUg/rat) by itself had no significant effect on memory consolidation, while at all doses prevented the amnesia induced by post-training injections of WIN55,212-2 (0.25 MUg/rat). Although, post-training intra-CeA administrations of beta1-adrenoceptor antagonist, atenolol alone at different doses (0.01, 0.025, 0.05 and 0.1 MUg/rat) had no significant effect, but its co-administrations at doses of 0.05 and 0.1 MUg/rat along with an ineffective dose of WIN55,212-2 (0.05 MUg/rat) induced amnesia, and at dose of 0.1 MUg/rat along with an effective dose of WIN55,212-2 (0.25 MUg/rat) increased amnesia that induced by the later drug. Moreover, the improving effect of isoprenaline (0.025 MUg/rat) on amnesia induced by WIN55,212 2 (0.25 MUg/rat) was prevented by intra-CeA co-injections of atenolol at doses of 0.01 and 0.025 MUg/rat. The present results suggest that a beta1-adrenoeceptor mechanism in the central amygdala (CeA) is involved in amnesia induced by post training intra-CeA injections of WIN55,212-2. PMID- 22516011 TI - Swimming exercise increases the level of nerve growth factor and stimulates neurogenesis in adult rat hippocampus. AB - We investigated the effects of swimming and treadmill exercise on the level of nerve growth factor (NGF) protein and neurogenesis in the hippocampus, and cognitive function of adult rats over a period of 8 weeks. We divided 144 male Sprague-Dawley rats into 3 groups: (1) a control group (COG; total n=48, n=8 for each time-point), (2) a swimming exercise group (SEG; total n=48; n=8 for each time-point), and (3) a treadmill exercise group (TEG; total n=48, n=8 for each time-point). The SEG and TEG were made to perform their respective exercise type for 5 days per week over a period of 8 weeks. The level of NGF on the second day, and after the first, second, and fourth weeks increased significantly in the SEG and TEG, compared to the COG (p<0.001 for each time-point). Specifically, a significant increase was observed in the SEG at the 2-day, 2-week, and 4-week time-points. A significant difference in the number of BrdU-positive cells was found between groups at all time-points (6 months: p<0.05; 2 days, 2 weeks, 4 weeks, and 3 months: p<0.01; 1 week: p<0.001). Specifically, a significant increase was observed in the SEG at the 1-week and 4-week time-points. The number of NeuN-positive cells in the SEG increased significantly at all time-points (2 weeks: p<0.01; 2 days, 1 week, 4 weeks, 3 months, and 6 months: p<0.001). The number of DCX-positive cells between groups was also significantly different at all time-points, except for the fourth week, (6 months: p<0.05; 2 days: p<0.01; 1 week, 2 weeks, 3 months: p<0.001). Specifically, a significant increase was observed in the SEG at the 3-month time-point. These results show that regular exercise in adult rats increased the level of NGF in the hippocampus, increased the number of newly proliferated nerve cells, and extended the period of neuron survival and maintenance. Furthermore, this phenomenon was more apparent when the exercise form was swimming. PMID- 22516013 TI - Sensorimotor integration during stance: processing time of active or passive addition or withdrawal of visual or haptic information. AB - Vision (V) and touch (T) help stabilize our standing body, but little is known on the time-interval necessary for the brain to process the sensory inflow (or its removal) and exploit the new information (or counteract its removal). We have estimated the latency of onset and the time-course of the changes in postural control mode following addition or withdrawal of sensory information and the effect of anticipation thereof. Ten subjects stood in tandem position. They wore LCD goggles that allowed or removed vision, or lightly touched (eyes-closed) with the index finger (haptic stimulation) a pad that could be suddenly lowered (passive task). In different sessions, sensory shifts were deliberately produced by opening (or closing) the eyes or touching the pad (or lifting the finger) (active task). We recorded eyelid movement and finger force (<1N), sway of center of foot pressure (CoP), electromyogram (EMG) of soleus, tibialis and peroneus muscle, bilaterally, and of extensor indicis. The latency of the CoP and EMG changes following the shifts were statistically estimated on the averaged traces of 50 repetitions per condition. Muscle activity and sway adaptively decreased in amplitude on adding stabilizing visual or haptic information. The time-interval from the sensory shift to decrease in EMG and sway was ~0.5-2 s under both conditions. It was shorter for tibialis than peroneus or soleus and shorter for visual than haptic shift. CoP followed the tibialis by ~0.2 s. Slightly shorter intervals were observed following active sensory shifts. Latencies of EMG and postural changes were the shortest on removal of both haptic and visual information. Subsequently, the time taken to reach the steady-state was ~1-3 s under both active and passive tasks. A startle response at ~100 ms could precede EMG changes. Reaction-time contractions in response to sensory shifts appeared at ~200 ms, earlier than the adaptive changes. Changes in postural behavior require a finite amount of time from visual or haptic shift, much longer than reflexes or rapid voluntary responses, suggesting a time-consuming central integration process. This process is longer on addition than removal of haptic information, indicating a heavier computational load. These findings should be taken into account when considering problems of sensorimotor integration in elderly subjects or patients and when designing simulation models of human balance. PMID- 22516012 TI - Morphometric classification and spatial organization of spiral ganglion neurons in the human cochlea: consequences for single fiber response to electrical stimulation. AB - The unique, unmyelinated perikarya of spiral ganglion cells (SGCs) in the human cochlea are often arranged in functional units covered by common satellite glial cells. This micro anatomical peculiarity presents a crucial barrier for an action potential (AP) travelling from the sensory receptors to the brain. Confocal microscopy was used to acquire systematically volumetric data on perikarya and corresponding nuclei in their full dimension along the cochlea of two individuals. Four populations of SGCs within the human inner ear of two different specimens were identified using agglomerative hierarchical clustering, contrary to the present distinction of two groups of SGCs. Furthermore, we found evidence of a spatial arrangement of perikarya and their accordant nuclei along the cochlea spiral. In this arrangement, the most uniform sizes of cell bodies are located in the middle turn, which represents the majority of phonational frequencies. Since single-cell recordings from other mammalians may not be representative to humans and human SGCs are not accessible for physiological measurements, computer simulation has been used to quantify the effect of varying soma size on single neuron response to electrical micro stimulation. Results show that temporal parameters of the spiking pattern are affected by the size of the cell body. Cathodic stimulation was found to induce stronger variations of spikes while also leading to the lowest thresholds and longest latencies. Therefore, anodic stimulation leads to a more uniform excitation profile among SGCs with different cell body size. PMID- 22516014 TI - Dietary omega-3 polyunsaturated fatty acids improves learning performance of diabetic rats by regulating the neuron excitability. AB - Previous research has demonstrated that diabetes induced learning and memory deficits. However, the mechanism of memory impairment induced by diabetes is poorly understood. Dietary fatty acids, especially polyunsaturated fatty acids (PUFA), have been shown to enhance learning and memory and prevent memory deficits in various experimental conditions. Sprague-Dawley rats were used in the present study to investigate the effect of fish oil supplementation on spatial learning and memory of streptozotocin (STZ)-induced diabetic rats with the Morris Water Maze. The excitability of CA1 pyramidal neurons and the related ionic currents was also examined. Diabetes impaired spatial learning and memory of rats. Diabetes decreased the sodium currents and increased the potassium currents, and further led to the reduction of excitability of CA1 pyramidal neurons, effects which may contribute to the behavioral deficits. Fish oil dietary supplementation decreased the transient currents and Kv4.2 expression in the hippocampus and partially improved learning performance of diabetic rats. The results of the present study suggested that sodium and potassium currents contributed to the inhibitory effect of diabetes on neuron excitability, further influencing learning and memory processing. Dietary fish oil may modulate the membrane excitability and is a possible strategy for preventing the impairments of diabetes on hippocampal function. PMID- 22516016 TI - Changes in event-related potentials associated with postural adaptation during floor oscillation. AB - The event-related potential (ERP) mainly reflecting activation of the frontal lobe was measured during periodic floor oscillation, and changes in postural preparation and attention to the postural disturbance according to this adaptation were investigated. The experiment consisted of two tasks with eyes closed: adaptation to floor oscillation and finger flexion coinciding with the anterior and posterior reversals of oscillation. Subjects were 20 healthy young adults. They maintained a standing posture for 1 min (1 trial) on the force platform which oscillated in the anteroposterior direction at 0.5 Hz and an amplitude of 2.5 cm. ERP from a Cz electrode, activity of postural muscles and the center of foot pressure in the anteroposterior direction (CoPy) were analyzed. In the adaptation task, the speeds of CoPy fluctuation gradually decreased and reached a plateau between 4th and 14th trials, with inter-subject differences. Posterior postural muscles were activated in response to the anterior reversal of oscillation according to adaptation and also in the finger flexion task, with the largest activation of the gastrocnemius (GcM). A negative ERP peak was observed to occur locally around the anterior reversal of oscillation after adaptation. The peak ERP time had the strongest positive correlation with the peak activation time of the GcM, and the amplitude of the negative peak decreased with adaptation. In the finger flexion task, a negative ERP peak was observed around each target point. This negative peak was related to the anticipatory attention directed to the reversal point and to motor preparation for finger flexion. It is conceivable that the increasing negative ERP in the adaptation task reflects the dynamics of motor preparation and attention mainly for the anterior reversal, where the negative ERP peak is closely related to anticipatory information processing of somatosensory stimuli arising around the time of the reversal. PMID- 22516015 TI - Strength-duration relationship for intra- versus extracellular stimulation with microelectrodes. AB - Chronaxie, a historically introduced excitability time parameter for electrical stimulation, has been assumed to be closely related to the time constant of the cell membrane. Therefore, it is perplexing that significantly larger chronaxies have been found for intracellular than for extracellular stimulation. Using compartmental model analysis, this controversy is explained on the basis that extracellular stimulation also generates hyperpolarized regions of the cell membrane hindering a steady excitation as seen in the intracellular case. The largest inside/outside chronaxie ratio for microelectrode stimulation is found in close vicinity of the cell. In the case of monophasic cathodic stimulation, the length of the primarily excited zone which is situated between the hyperpolarized regions increases with electrode-cell distance. For distant electrodes this results in an excitation process comparable to the temporal behavior of intracellular stimulation. Chronaxie also varies along the neural axis, being small for electrode positions at the nodes of Ranvier and axon initial segment and larger at the soma and dendrites. As spike initiation site can change for short and long pulses, in some cases strength-duration curves have a bimodal shape, and thus, they deviate from a classical monotonic curve as described by the formulas of Lapicque or Weiss. PMID- 22516017 TI - Repeated longitudinal in vivo imaging of neuro-glio-vascular unit at the peripheral boundary of ischemia in mouse cerebral cortex. AB - Understanding the cellular events evoked at the peripheral boundary of cerebral ischemia is critical for therapeutic outcome against the insult of cerebral ischemia. The present study reports a repeated longitudinal imaging for cellular scale changes of neuro-glia-vascular unit at the boundary of cerebral ischemia in mouse cerebral cortex in vivo. Two-photon microscopy was used to trace the longitudinal changes of cortical microvasculature and astroglia following permanent middle cerebral artery occlusion (MCAO). We found that sulforhodamine 101 (SR101), a previously-known marker of astroglia, provide a bright signal in the vessels soon after the intraperitoneal injection, and that intensity was sufficient to detect the microvasculature up to a depth of 0.8 mm. After 5-8 h from the injection of SR101, cortical astroglia was also imaged up to a depth of 0.4 mm. After 1 day from MCAO, some microvessels showed a closure of the lumen space in the occluded MCA territory, leading to a restructuring of microvascular networks up to 7 days after MCAO. At the regions of the distorted microvasculature, an increase in the number of cells labeled with SR101 was detected, which was found as due to labeled neurons. Immunohistochemical results further showed that ischemia provokes neuronal uptake of SR101, which delineate a boundary between dying and surviving cells at the peripheral zone of ischemia in vivo. Finally, reproducibility of the MCAO model was evaluated with magnetic resonance imaging (MRI) in a different animal group, which showed the consistent infarct volume at the MCA territory over the subjects. PMID- 22516018 TI - Sleep homeostasis and depression: studies with the rat clomipramine model of depression. AB - Neonatal treatment of rat pups with clomipramine (CLI) has been shown to cause long-lasting and persistent depression-related behaviors and changes in sleep architecture and in brain-derived neurotrophic factor (BDNF) signaling in adult animals, producing an animal model of depression. However, the molecular mechanisms which mediate these effects of early-life CLI treatment on adult animals remain largely unknown. In order to characterize these further, we investigated in neonatally CLI-treated rats the sleep architecture as well as the extracellular and cellular levels of sleep regulators (nitric oxide, adenosine) and BDNF, respectively, in the basal forebrain (BF), i.e. the brain area which is implicated in sleep and depression. We found that CLI-treated rats exhibited a disturbed sleep architecture (REM sleep fragmentation was increased and NREM periods preceding REM were shorter) and reduced levels of BDNF and adenosine in the BF, whereas the levels of nitric oxide were elevated. Next, we examined sleep deprivation (SD)-induced homeostatic responses on sleep regulation and brain BDNF levels in CLI-treated rats. Compared to control rats, 3h of SD induced a smaller increase in the amount of NREM sleep during sleep recovery. At the molecular level, the normal homeostatic response was dissociated: the rise in the adenosine level was not accompanied by a rise in the nitric oxide concentration. Moreover, while BF BDNF levels decreased during SD in control rats, such a decline was not observed in CLI rats. Taken together, neonatal CLI treatment produces long lasting functional changes in the sleep architecture and sleep regulation in adult rats, accompanied by dysregulated BDNF signaling in the BF. PMID- 22516019 TI - The negative effects of alcohol hangover on high-anxiety phenotype rats are influenced by the glutamate receptors of the dorsal midbrain. AB - Alcoholism is a chronic disorder characterized by the appearance of a withdrawal syndrome following the abrupt cessation of alcohol intake that includes symptoms of physical and emotional disturbances, anxiety being the most prevalent symptom. In humans, it was shown that anxiety may increase the probability of relapse. In laboratory animals, however, the use of anxiety to predict alcohol preference has remained difficult. Excitatory amino acids as glutamate have been implicated in alcohol hangover and may be responsible for the seizures and anxiety observed during withdrawal. The dorsal periaqueductal gray (DPAG) is a midbrain region critical for the modulation/expression of anxiety- and fear-related behaviors and the propagation of seizures induced by alcohol withdrawal, the glutamate neurotransmission being one of the most affected. The present study was designed to evaluate whether low- (LA) and high-anxiety rats (HA), tested during the alcohol hangover phase, in which anxiety is the most prevalent symptom, are more sensitive to the reinforcing effects of alcohol when tested in a voluntary alcohol drinking procedure. Additionally, we were interested in investigating the main effects of reducing the excitatory tonus of the dorsal midbrain, after the blockade of the ionotropic glutamate receptors into the DPAG, on the voluntary alcohol intake of HA and LA motivated rats that were made previously experienced with the free operant response of alcohol drinking. For this purpose, we used local infusions of the N-metil D-Aspartato (NMDA) and alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA)-kainate receptors antagonist DL-2-Amino-7 phosphonoheptanoic acid - DL-AP7 (10 nmol/0.2 MUl) and l-glutamic acid diethyl ester - GDEE (160 nmol/0.2 MUl), respectively. Alcohol intoxication was produced by 10 daily bolus intraperitonial (IP) injections of alcohol (2.0 g/kg). Peak blood alcohol levels were determined by gas-chromatography analysis in order to assess blood-alcohol content. Unconditioned and conditioned anxiety-like behavior was assessed by the use of the fear-potentiated startle procedure (FPS). Data collected showed that anxiety and alcohol drinking in HA animals are positively correlated in animals that were made previously familiarized with the anxiolytic effects of alcohol. In addition, anxiety-like behavior induced during alcohol hangover seems to be an effect of changes in glutamatergic neurotransmission into DPAG possibly involving AMPA/kainate and NMDA receptors, among others. PMID- 22516020 TI - beta functional connectivity modulation during the maintenance of motion information in working memory: importance of the familiarity of the visual context. AB - The purpose of this study was to examine whether mechanisms, involved during the maintenance of familiar movement information in memory, were influenced by the degree of familiarity of the display in which the movements were embedded. Twelve gymnasts who possessed high visual and motor familiarity with the movements employed in this study, were recruited. They were invited to retain for a short period of time familiar movements viewed previously and presented under different displays with the aim of recognizing them at a later stage. The first display was a realistic, familiar display which presented videos of movements. The second display was an unfamiliar impoverished display never experienced in every day life which showed point-light movements. Activity during the maintenance period was considered in five frequency bands (4-8 Hz, 8-10 Hz, 10-13 Hz, 13-20 Hz, 20 30 Hz) using a non-linear measure of functional connectivity. The results in the 13-20 Hz frequency band showed that functional connectivity was greater within the frontal and right temporal areas during the unfamiliar display (i.e., point light maintenance condition) compared to the familiar display (i.e., video maintenance condition). Differences in functional connectivity between the two maintenance conditions in the beta frequency band are mainly discussed in the light of the process of anticipation. Subjects' perception of the expected difficulty of the upcoming recognition task is discussed. PMID- 22516021 TI - Electron cryotomography of postsynaptic densities during development reveals a mechanism of assembly. AB - Postsynaptic densities (PSDs) are responsible for organizing receptors and signaling proteins that regulate excitatory transmission in the mammalian brain. To better understand the assembly and 3D organization of this synaptic structure, we employed electron cryotomography to visualize general and fine structural details of PSDs isolated from P2, P14, P21 and adult forebrain in the absence of fixatives and stains. PSDs at P2 are a loose mesh of filamentous and globular proteins and during development additional protein complexes are recruited onto the mesh. Quantitative analysis reveals that while the surface area of PSDs is relatively constant, the thickness and protein occupancy of the PSD volume increase dramatically between P14 and adult. One striking morphological feature is the appearance of lipid raft-like structures, first evident in PSDs from 14 day old animals. These detergent-resistant membranes stain for GM1 ganglioside and their terminations can be clearly seen embedded in protein "bowls" within the PSD complex. In total, these results lead to the conclusion that the PSD is assembled by the gradual recruitment and stabilization of proteins within an initial mesh that systematically adds complexity to the structure. PMID- 22516023 TI - 3D navigation and monitoring for spinal milling operation based on registration between multiplanar fluoroscopy and CT images. AB - Milling operations in spinal surgery demand much experience and skill for the surgeon to perform the procedure safely. A 3D navigation method is introduced aiming at providing a monitoring system with enhanced safety and minimal intraoperative interaction. An automatic registration method is presented to establish the 3D-3D transformation between the preoperative CT images and a common reference system in the surgical space, and an intensity-based similarity metric adapted for the multi-planar configuration is introduced in the registration procedure. A critical region is defined for real-time monitoring in order to prevent penetration of the lamina and avoid violation of nerve structures. The contour of the spinal canal is reconstructed as the critical region, and different levels of warning limits are defined. During the milling procedure, the position of the surgical instrument relative to the critical region is provided with augmented display and audio warnings. Timely alarm is provided for surgeons to prevent surgical failure when the mill approaches the critical region. Our validation experiment shows that real-time 3D navigation and monitoring is advantageous for improving the safety of the milling operation. PMID- 22516022 TI - Neurodegeneration and early lethality in superoxide dismutase 2-deficient mice: a comprehensive analysis of the central and peripheral nervous systems. AB - The contribution of oxidative stress to diabetic complications including neuropathy is widely known. Mitochondrial and cellular damage are associated with the overproduction of reactive oxygen species and decreased levels or function of the cellular antioxidant mitochondrial manganese superoxide dismutase (SOD2). We hypothesized that targeted SOD2 deletion in the peripheral nervous system using cre-lox technology under control of the nestin promoter would accelerate neuropathy in a type 2 model of diabetes, the BKS.db/db mouse. SOD2-deficient mice, however, demonstrated severe gait deformities and seizures and died by 20 days of age. Examination of SOD2 expression levels revealed that SOD2 was lost in brain and reduced in the spinal cord, but appeared normal in dorsal root ganglia and peripheral nerves in SOD2-deficient mice. These findings indicate incomplete targeted knockout of SOD2. Morphological examination revealed cortical lesions similar to spongiform encephalopathy in the brain of SOD2-deficient mice. No lesions were evident in the spinal cord, but changes in myelin within the sciatic and sural nerves including a lack of cohesion between layers of compact myelin were observed. Together, these results indicate that targeted neuronal SOD2 knockout using the nestin promoter results in severe central nervous system degeneration and perinatal lethality in mice. A specific peripheral nervous system-targeting construct is required to examine the consequences of SOD2 knockout in diabetic neuropathy. PMID- 22516025 TI - Interrelationship and limitations of conventional radiographic assessments of skeletal maturation. AB - Assessments of skeletal maturation (ASM) are used by clinicians to optimize treatments for each patient. This study examines the interrelationship between and limitations of hand-wrist and cervical vertebrae maturation methods in adolescent patients. Radiographs (hand-wrist and lateral cephalometric) were obtained from patients (n=62, 11 to 17 years of age) at two-time periods (T1/T2) with time intervals of 9.75 to 16.50 months. Radiographs were scored using cervical vertebral maturation staging (CS) and Fishman's skeletal maturation indices (SMI). Functional data analysis was used to visually assess maturational changes of the cervical vertebrae. Both SMI and CS increased over the period of observation. Age was moderately correlated with SMI (0.707/0.651 at T1/T2) and mildly correlated with CS (0.431/0.314 at T1/T2). There was some evidence of gender variability in SMI. The correlations between SMI and CS were 0.513 and 0.372 at T1 and T2, respectively. Functional data analysis illustrated the difficulty in differentiating contiguous cervical stages. Discrepancies exist between both scoring methods. Further studies are needed to overcome the difficulties encountered with CS. Clinicians are advised to use ASM methods with caution in adolescent patients given the aforementioned discrepancies. Separate references for boys and girls are not required. PMID- 22516027 TI - Post-orthodontic intra- and interarch changes at 1 year: a retrospective study assessing the impact of anterior fixed retention. AB - OBJECTIVES: The aim of this study is to evaluate intra- and interarch changes over the year following active treatment appliance removal, and to analyze the impact of anterior fixed retention on these changes. PATIENTS AND METHODS: This study is based on casts taken at appliance removal (T1) and one year after removal (T2) in two groups of 15 privately-treated adolescent patients. One group received anterior fixed retention (G2), and the other did not (G1). We applied the seven criteria of the American Board of Orthodontics Objective Grading System: alignment (anterior/posterior), vertical positioning of the posterior marginal ridges, interproximal contacts, buccolingual inclination of the posterior teeth, posterior occlusal contacts, sagittal occlusal relationships, and overjet (anterior/posterior). RESULTS: G1 and G2 together showed significant improvement in occlusal contacts, interproximal contacts, marginal ridges, and maxillary posterior alignment, but also a deterioration in anterior alignment, anterior overjet, and sagittal occlusal relationships. However, significant differences were found between the two groups, notably in terms of anterior alignment, which deteriorated more in G1. CONCLUSION: The relapse observed in anterior overjet and sagittal relationships seems independent of the retention modality, whereas the deterioration in anterior alignment was specific to the group without fixed retention. At the same time, there were spontaneous adjustments in posterior occlusion, favorable to treatment stability. PMID- 22516028 TI - Vascularization of the trapeziometacarpal joint and its clinical importance: anatomical study. AB - Few studies have investigated the vascular anatomy of the trapeziometacarpal (TM) joint of the thumb. The aim of our study was to describe the supplying arteries of the trapezium and the TM joint since this knowledge is essential for trapezium osteotomies. Ten anatomical dissections in ten different cadavers using two different techniques (four macerations, six classic dissections) were performed. The arteries of the TM joint originated from the radial artery and the princeps pollicis artery. Four important branches were identified. The arteries formed a vascular network around the joint. The dorsoradial surface of the joint contained the richest arterial network. These findings present an important consideration when performing an osteotomy of the trapezium. PMID- 22516029 TI - Tetanus - still a scourge in the 21st century: a paediatric hospital-based study in India. AB - Tetanus remains endemic in India. A retrospective hospital-based study was conducted to review the profile of all children admitted with diagnosis of tetanus between January 2009 and December 2010. A total of 140 cases of tetanus were admitted; 45 cases of neonatal tetanus (NT) and 77 cases of post-neonatal tetanus (PNT) were studied. Age of presentation of NT was 9.4 +/- 1.2 days. Home delivered children accounted for 86.7% of cases, with 77.8% being attended by untrained birth attendants. Unimmunized mothers accounted for 93.4%. In PNT, otogenic route of infection and trauma were present in 58.4% and 23.3% of cases, respectively. The rate of hospital admission of tetanus remains high. Unlike previously published reports, otogenic route is the most common mode of PNT infection in this study. Improving immunization, increasing deliveries by skilled birth attendants and prompt treatment of suppurative otitis media are the main areas in which public health initiatives need to be focused. PMID- 22516030 TI - Plasmodium vivax remains responsive to chloroquine with primaquine treatment regimen: a prospective cohort study from tertiary care teaching hospital in southern India. AB - We conducted this prospective study among 110 symptomatic Plasmodium vivax patients attending the Kasturba Hospital, Manipal, India, in order to evaluate their clinico-laboratory profile during July 2007-July 2009. Complications observed among patients were: anaemia (46.4%; 95% confidence interval [CI], 37.08 55.72%); thrombocytopenia (68.2%; 95% CI, 59.5-76.9%); leucopenia (29.1%; 95% CI, 20.61-37.59%); hyperbilirubinaemia (20%; 95% CI, 12.53-27.47%); non-oliguric renal failure (10.9%; 95% CI, 5.08-16.72%); elevated serum transaminases (33.6%; 95% CI, 24.77-42.43%); hypotension (8.2%; 95% CI, 3.07-13.33%); hepatomegaly (27.3%; 95% CI, 18.97-35.63%); and splenomegaly and jaundice in 12.7% (95% CI, 6.48-18.92%). The 99% chloroquine response and zero mortality observed in this study of vivax malaria are encouraging points for practicing physicians. PMID- 22516031 TI - Raynaud's phenomenon, cytokines and acupuncture: a case report. AB - A 30-year-old African-American woman diagnosed in 2006 with primary Raynaud's phenomenon (RP) was seen in the clinic in 2010 and the diagnosis confirmed excluding underlying disorders. Acupuncture was administered bilaterally at the LI4 Hegu acupuncture points for 5 min twice weekly for 2 months, which resulted in improvement in pain severity, joint stiffness and the colour of her fingers and toes. The literature reveals that acupuncture is effective in improving pain severity and joint stiffness in RP. The patient's serum proinflammatory cytokines were compared with those from an ongoing study in our institution and the results indicated that acupuncture therapy might be anti-inflammatory. Acupuncture is relatively safe and should be considered as an alternative treatment or non pharmacological therapy for pain associated with RP. PMID- 22516032 TI - Combined standard medication and acupuncture for COPD: a case series. AB - BACKGROUND: Traditional acupuncture has been used in patients with chronic obstructive pulmonary disease (COPD). However, only a few studies have been performed to determine the efficacy of this treatment. OBJECTIVE: To observe changes in the symptoms of COPD during acupuncture treatment in patients with COPD stratified according to the severity of the disease. METHODS: A prospective case series of 26 patients with dyspnoea on exertion due to COPD was followed from October 2004 to October 2008 in the Departments of Respiratory Internal Medicine, Gifu University of Medicine and Meiji University of Integrative Medicine, Japan. All participants received acupuncture treatments once a week for 10 weeks in addition to standard medication therapy. The main outcome measure was the modified Borg dyspnoea scale after the 6 min walk test (6MWT) and the secondary outcome measure was the BODE index. RESULTS: All 26 patients showed significant improvement in the Borg dyspnoea scale after 10 weeks of acupuncture treatment (from 4.02 (2.85) to 1.96 (1.97), mean difference -2.06, 95% CI -3.03 to -1.09, p=0.0002, paired t test). Improvements in the BODE index, 6MWT and oxygen saturation during exercise, which indicates better reduced dyspnoea on exertion and prognosis, were also found. CONCLUSION: The results of this study suggest that acupuncture treatment has clinically useful effects, at least in the short term, in reducing dyspnoea on exercise in patients with COPD, particularly in those more severely affected. PMID- 22516033 TI - Comparison of cryopreservation methods for the long term storage of the marine diatom Haslea ostrearia (simonsen). AB - Long term maintenance of microalgal strains by serial subculturing is often expensive and time-consuming. Alternative methods, such as cryopreservation, present several benefits and thus seem more relevant. Our study aimed at comparing two cryopreservation procedures applied to the marine diatom Haslea ostrearia (Simonsen): (1) a two-step freezing method in liquid media using 5%, 10% and 20% MeOH, Me2SO or Glycerol, and (2) an immobilization-dehydration method consisting in an algal cell entrapped in 0.7 M sucrose dehydrated and air-flow desiccated calcium alginate beads before "direct" or "two-step" freezing. Our results showed that the cryopreservation of H. ostrearia was feasible. With the two-step freezing protocol only Me2SO maintained cell viability without contamination but the low percentage of viability (<10%) prevents its use. Conversely, the immobilization-dehydration methods tested in this study were effective. Average viability of 57% and 77% were obtained with the "direct" and the "two step" cooling assays respectively, ensuring preservation of the genetic traits of H. ostrearia. PMID- 22516034 TI - Hypothermic reconditioning by gaseous oxygen persufflation after cold storage of porcine kidneys. AB - BACKGROUND: Delayed graft function still represents a major complication in clinical kidney transplantation. Here we tested the possibility to improve functional outcome of cold stored kidneys a posteriori by hypothermic reconditioning using retrograde oxygen persufflation (ROP) immediately prior to reperfusion. METHODS: Kidneys from female German Landrace pigs were flushed with Histidine-Tryptophan-Ketoglutarate (HTK) solution and cold-stored for 18 h (control). Some grafts were subsequently subjected to 90 min of retrograde oxygen persufflation (ROP) via the renal vein during cold preservation. Early graft function of all kidneys was assessed thereafter by warm reperfusion in vitro (n=6, resp.). RESULTS: Renal function upon reperfusion was significantly enhanced by ROP with an approximately twofold increase in renal clearances of creatinine and urea. ROP also led to higher renal vascular flow rates, enhanced urine output and mitigated histological alterations. CONCLUSION: It is concluded that initial graft function can be improved by 90 min of hypothermic gaseous oxygenation after arrival of the preserved organ in the transplantation clinic. PMID- 22516035 TI - [Urinary incontinence and obesity]. AB - Obesity, defined as a body mass index (BMI) more than or equal to 30kg/m(2), promotes pelvic floor disorders such as urinary incontinence (UI) and genital prolapse. Datas from cohort studies found an association between high BMI and the onset of UI. This association seems to be predominant with for mixed UI and stress UI. For the urge UI and overactive bladder syndrome, the analysis of the literature found a weaker association. The weight is therefore the only modifiable risk factor. Thus, the weight loss by a hypocaloric diet associated with pelvic floor muscle training should be the front line treatment in the obese patient suffering from UI. Bariatric surgery can be discussed in the most obese patient, even if the risk/benefit balance should be weighed because of significant morbidity of this surgery. The results of sub urethral sling (by retropubic tension-free vaginal tape or transobturator sling) in obese patients appear to be equivalent to those obtained in patients of normal weight. Datas on per- and postoperative complications for suburethral slings are reassuring. PMID- 22516036 TI - Apigenin ameliorates gamma radiation-induced cytogenetic alterations in cultured human blood lymphocytes. AB - The aim of the present study was to assess the protective effect of apigenin, a dietary flavone, against cytogenetic alterations in human peripheral blood lymphocytes (HPBL) induced by Cobalt-60 radiation (3Gy). Results of MTT [3-(4, 5 dimethyl-2-thiaozolyl)-2,5-diphenyl-2H tetrazolium bromide] assay revealed that 37.2MUM of apigenin was found to be non-toxic in HPBL. At this dose (37.2MUM) of apigenin, the LD(50) radiation dose of HPBL increased from 2.9Gy to 3.4Gy, which resulted in a DMF of 1.17. Apigenin (37.2MUM) treatment 1h before irradiation significantly (p<0.05) reduced DNA damage in irradiated HPBL as measured by comet assay (% tail DNA, tail length, tail moment, and olive tail moment). Moreover, apigenin treatment significantly decreased the frequencies of dicentric (DC), acentric fragments (AF), and acentric rings (AR) in irradiated HPBL. Apigenin pretreatment also reduced the radiation-induced CBMN (cytokinesis blocked micronuclei) anomalies such as micronuclei (MNi), nucleoplasmic bridges (NPB) and nuclear buds (NBUD) in HPBL. These results also showed that there was a significant correlation between NPB and DC frequencies and MNi and AF+AR. Treatment with apigenin alone had no significant effect on DNA damage and chromosomal aberrations in HPBL. Thus, the current studies indicate that apigenin protects HPBL from radiation-induced cytogenetic alterations. PMID- 22516037 TI - Identification of CK2 inhibitors with new scaffolds by a hybrid virtual screening approach based on Bayesian model; pharmacophore hypothesis and molecular docking. AB - Protein kinase casein kinase 2 (CK2), a member of the serine/threonine kinase family, has been established as one of the most attractive targets for molecularly targeted cancer therapy. The discovery of CK2 inhibitors has thus attracted much attention in recent years. In this investigation, a hybrid virtual screening approach based on Bayesian classification model, pharmacophore hypothesis and molecular docking was proposed and employed to identify CK2 inhibitors. We first established a naive Bayes classification model of CK2 inhibitors/non-inhibitors and pharmacophore hypotheses of CK2 inhibitors. The docking parameters and scoring functions were also optimized in advance. The three virtual screening methods were sequentially used to screen two large chemical libraries, Specs and Enamine, for retrieving new CK2 inhibitors. Finally 30 compounds were selected from the final hits for in vitro CK2 kinase inhibitory assays. Five compounds with completely novel scaffolds showed a good inhibitory potency against CK2, which have good potentials for a future hit-to-lead optimization. PMID- 22516039 TI - A randomized, double-blind, parallel, single-site pilot trial to compare two different starting doses of methotrexate in methotrexate-naive adult patients with rheumatoid arthritis. AB - BACKGROUND: Methotrexate (MTX) is a cornerstone in the treatment of rheumatoid arthritis. Despite its widespread use, expert opinions differ about the optimal MTX starting dosage to achieve rapid onset of action while averting increased occurrence of adverse effects. Plasma concentrations have not been assessed in previous studies that monitored clinical efficacy. OBJECTIVE: This study was performed to compare the pharmacokinetic parameters and clinical response of a standard (15 mg) and an accelerated (25 mg) dosing regimen, each administered orally once a week. METHODS: This randomized, controlled, double-blind, parallel, single-site study included 19 MTX-naive patients older than 18 years with rheumatoid arthritis. Patients participated for 16 weeks. Disease activity was assessed using the Disease Activity Score in 28 joints (DAS-28) as the primary outcome parameter. Plasma MTX concentrations were measured using HPLC at weeks 1, 5, 10, and 16. Tolerability was assessed via routine blood analysis (hematology and clinical chemistry) and a patient questionnaire to monitor adverse events. Reported or observed adverse events were recorded along with information about their severity and causal relationship to the study medication. RESULTS: Nineteen white patients (13 women and 6 men; mean age, 56 years; and mean weight, 74 kg) participated. At study entry, mean (SD) DAS-28-4v (erythrocyte sedimentation rate) was 4.73 (1.02). Health Assessment Questionnaire scores were 1.45 (0.85); for C-reactive protein, 11.45 (10.04) mg/dL; for alkaline phosphatase, 73.58 (19.91) U/L; for aspartate aminotransferase, 23.32 (7.13) U/L; and for creatinine, 0.87 (0.22) mg/dL. Although pharmacokinetic parameters such as AUC and C(max) were significantly higher after the accelerated dosing regimen, clinical activity scores (DAS-28) and inflammation parameters (C-reactive protein) did not indicate a significant benefit of an accelerated starting regimen. Considering toxicity, no elevation in liver function enzymes and no decrease in renal function were observed using the accelerated dosing (statistical significance set at P <= 0.05). No serious adverse events were noted. All observed adverse events were classified as study related. Overall, adverse events were noted in 58% of patients. Comparison of the two doses revealed that 60% of patients receiving the standard dosing regimen and 56% of patients receiving the accelerated dosing regimen reported adverse events, the most frequent being gastrointestinal. These events were generally self-limiting. CONCLUSIONS: Differences in clinical response between these two small selected patient groups who received an initial oral dose of either 15 or 25 mg MTX per week did not reach the level of statistical significance. The overall incidence of adverse effects, all classified as study related, was 58%, with 60% of patients receiving the standard dosage and 56% of patients receiving the accelerated dosing regimen reporting adverse effects. However, because of the small sample size, this study was not powered to detect differences in the incidence of adverse events between the two dosing groups. ClinicalTrials.gov identifier: NCT00695188. PMID- 22516038 TI - A spatial analysis of individual- and neighborhood-level determinants of malaria incidence in adults, Ontario, Canada. AB - Malaria, once endemic in Canada, is now restricted to imported cases. Imported malaria in Canada has not been examined recently in the context of increased international mobility, which may influence incidence of imported and autochthonous cases. Surveillance of imported cases can highlight high-risk populations and help target prevention and control measures. To identify geographic and individual determinants of malaria incidence in Ontario, Canada, we conducted a descriptive spatial analysis. We then compared characteristics of case-patients and controls. Case-patients were significantly more likely to be male and live in low-income neighborhoods that had a higher proportion of residents who had emigrated from malaria-endemic regions. This method's usefulness in clarifying the local patterns of imported malaria in Ontario shows its potential to help identify areas and populations at highest risk for imported and emerging infectious disease. PMID- 22516040 TI - Low prevalence of pulmonary involvement in children with inflammatory bowel disease. AB - BACKGROUND: Since extraintestinal sites of inflammation have been demonstrated in patients with Crohn's disease (CD) and ulcerative colitis (UC), both entities are regarded as systemic disorders. There are only scarce data on the prevalence of inflammatory bowel disease (IBD)-associated lung involvement in children. OBJECTIVES: The aim of our study was to investigate pulmonary involvement in pediatric patients with IBD. MATERIAL AND METHODS: Fifty children with IBD (25 UC and 25 CD, mean age 14.2 +/- 3.2 yrs) and 39 age-matched, healthy, control subjects were included in the study. Pulmonary function testing, methacholine bronchial challenge, fractional exhaled nitric oxide (FeNO) and high resolution computed tomography (HRCT) were used to detect functional and/or structural pulmonary involvement. RESULTS: There were no differences in spirometric parameters, lung volumes or lung diffusion capacity for carbon monoxide between IBD patients and control subjects. Highly significant differences were found in FeNO between CD, UC and control patients (mean 9.3 +/- 3.3, 27.7 +/- 14.8 and 16.6 +/- 9.28, respectively; p = 0.000). Bronchial hyperresponsiveness was diagnosed in six IBD cases (14.6%). HRCT (performed in 32 patients from the study group) revealed mild bilateral bronchiectasis in one patient. CONCLUSIONS: The prevalence of pulmonary involvement in children with IBD is low. Screening for pulmonary involvement in children and young adults with IBD may enable early detection of IBD-related pulmonary diseases which, seems to be notably more common in adult patients. Elevated FeNO could probably be regarded as a marker of airway involvement in non-smoking UC pediatric patients. This requires further studies. PMID- 22516041 TI - Fetal bisphenol A exposure: concentration of conjugated and unconjugated bisphenol A in amniotic fluid in the second and third trimesters. AB - Bisphenol A (BPA) is an estrogenic compound widely used in polycarbonate plastics. The placental enzyme beta-glucuronidase may deconjugate BPA into its "free" active form. We sought to quantify levels of conjugated and free BPA in second and third trimester amniotic fluid. Liquid chromatography coupled with mass spectrometry was used to measure BPA concentrations in 20 second trimester and 20 third trimester amniotic fluid specimens. Total BPA was detected in 16/20 second trimester samples; levels ranged from non-detectable to 0.75ng/mL (median 0.47ng/mL). Free BPA was detected in 9/20 second trimester samples; levels ranged from 0.31 to 0.43ng/mL (median 0.38ng/mL). Total BPA was detected in 2/20 third trimester samples. Free BPA was detected in 1/20 (0.42ng/mL). When detected, free BPA comprised 83% and 91% of total BPA in second and third trimester amniotic fluid, respectively. Placental beta-glucuronidase may deconjugate BPA, increasing fetal exposure to free BPA. PMID- 22516042 TI - Corpus callosum morphology in children who stutter. AB - Multiple studies have reported both functional and neuroanatomical differences between adults who stutter and their normally fluent peers. However, the reasons for these differences remain unclear although some developmental data suggest that structural brain differences may be present in school-age children who stutter. In the present study, the corpus callosum of children with persistent stuttering, children who recovered from stuttering and typically developing children between 9 and 12 years of age was compared to test if the presence of aberrant callosal morphology is implicated in this disorder. The total corpus callosum midsagittal area and area of each subsection consisting of the rostrum, anterior midbody, posterior midbody and splenium were measured using MIPAV (Medical Image Processing, Analysis, and Visualization). Voxel-based morphometry (VBM) was also used to compare white matter volume. No differences were detected in the corpus callosum area or white matter volume between children with persistent stuttering, children who recovered from stuttering and typically developing children. These results agree with dichotic listening studies that indicate children who stutter show the typical right ear advantage. Therefore, the neural reorganization across the midline shown in adults who stutter may be the result of long-term adaptations to persistent stuttering. LEARNING OUTCOMES: EDUCATIONAL OBJECTIVES: After reading this article, the reader will be able to: (1) summarize research findings on corpus callosum development; and (2) discuss the characteristics of corpus callosum anatomy in stuttering. PMID- 22516043 TI - Emergency department visits for influenza A(H1N1)pdm09, Davidson County, Tennessee, USA. AB - To determine the number of emergency department visits attributable to influenza A(H1N1)pdm09 in Davidson County, Tennessee, USA, we used active, population-based surveillance and laboratory-confirmed influenza data. We estimated ~10 visits per 1,000 residents during the pandemic period. This estimate should help emergency departments prepare for future pandemics. PMID- 22516045 TI - Q fever outbreak in the village of Nocaj, Srem County, Vojvodina Province, Serbia, January to February 2012. AB - From 27 January to 10 February 2012, a total of 43 cases of Q fever were notified in the village of Nocaj, Srem county, Autonomous Province of Vojvodina, Republic of Serbia. Q fever was laboratory confirmed in 37 notified cases. Alhough, the outbreak is considered over, the outbreak investigation is still ongoing in order to identify aetiologic factors relevant for this outbreak. PMID- 22516044 TI - Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression. AB - BACKGROUND: Ketamine has rapid antidepressant effects lasting as long as 1 week in patients with major depressive disorder (MDD) and bipolar depression (BD). Ketamine is extensively metabolized. This study examined the relationship between ketamine metabolites and response, diagnosis, and psychotomimetic symptoms in MDD and BD patients. METHODS: Following a 40-minute ketamine infusion (.5 mg/kg), plasma samples were collected at 40, 80, 110, and 230 minutes and day 1 postinfusion in 67 patients currently experiencing a major depressive episode (MDD, n = 45; BD, n = 22). Concentrations of ketamine, norketamine (NK), dehydronorketamine (DHNK), six hydroxynorketamine metabolites (HNK), and hydroxyketamine (HK) were measured. Plasma concentrations were analyzed by diagnostic group and correlated with patients' depressive, psychotic, and dissociative symptoms. The relationship between cytochrome P450 gene polymorphisms and metabolites, response, and diagnosis was also examined. RESULTS: Ketamine, NK, DHNK, four of six HNKs, and HK were present during the first 230 minutes postinfusion. Patients with BD had higher plasma concentrations of DHNK, (2S,6S;2R,6R)-HNK, (2S,6R;2R,6S)-HNK, and (2S,5S;2R,5R)-HNK than patients with MDD, who, in turn, had higher concentrations of (2S,6S;2R,6R)-HK. Higher (2S,5S;2R,5R)-HNK concentrations were associated with nonresponse to ketamine in BD patients. Dehydronorketamine, HNK4c, and HNK4f levels were significantly negatively correlated with psychotic and dissociative symptoms at 40 minutes. No relationship was found between cytochrome P450 genes and any of the parameters examined. CONCLUSIONS: A diagnostic difference was observed in the metabolism and disposition of ketamine. Concentrations of (2S,5S;2R,5R)-HNK were related to nonresponse to ketamine in BD. Some hydroxylated metabolites of ketamine correlated with psychotic and dissociative symptoms. PMID- 22516046 TI - Early estimates of seasonal influenza vaccine effectiveness in Europe among target groups for vaccination: results from the I-MOVE multicentre case-control study, 2011/12. AB - To provide an early estimate of 2011/12 influenza vaccine effectiveness (VE), we conducted a multicentre case-control study based on seven sentinel surveillance networks. We included influenza-like illness cases up to week 7/2012 from the vaccination target groups, swabbed less than eight days after symptom onset. Laboratory-confirmed influenza A(H3) cases were compared to negative controls. Adjusted VE was 43% (95% confidence interval: -0.4 to 67.7), suggesting low to moderate VE against influenza A(H3) in the early 2011/12 season. PMID- 22516047 TI - Health professions and risk of sporadic Creutzfeldt-Jakob disease, 1965 to 2010. AB - In 2009, a pathologist with sporadic Creutzfeldt-Jakob Disease (sCJD) was reported to the Spanish registry. This case prompted a request for information on health-related occupation in sCJD cases from countries participating in the European Creutzfeldt Jakob Disease Surveillance network (EuroCJD). Responses from registries in 21 countries revealed that of 8,321 registered cases, 65 physicians or dentists, two of whom were pathologists, and another 137 healthcare workers had been identified with sCJD. Five countries reported 15 physicians and 68 other health professionals among 2,968 controls or non-cases, suggesting no relative excess of sCJD among healthcare professionals. A literature review revealed: (i) 12 case or small case-series reports of 66 health professionals with sCJD, and (ii) five analytical studies on health-related occupation and sCJD, where statistically significant findings were solely observed for persons working at physicians' offices (odds ratio: 4.6 (95 CI: 1.2-17.6)). We conclude that a wide spectrum of medical specialities and health professions are represented in sCJD cases and that the data analysed do not support any overall increased occupational risk for health professionals. Nevertheless, there may be a specific risk in some professions associated with direct contact with high human infectivity tissue. PMID- 22516048 TI - Description and analysis of 12 years of surveillance for Creutzfeldt-Jakob disease in Denmark, 1997 to 2008. AB - Prospective surveillance of Creutzfeldt-Jakob disease (CJD) was initiated in Denmark in 1997, following the observation of variant CJD in the United Kingdom. Demographic, clinical and diagnostic information was collected for each patient with clinical suspicion of CJD. Here we describe the methods for surveillance and the observed outcomes between 1 January 1997 and 31 December 2008. A total of 83 patients were classified as sporadic CJD, 47 were definite diagnoses, 34 probable and two possible. This resulted in a mean incidence of 1.26 patients with probable and definite sporadic CJD per million inhabitants. Two sporadic CJD patients were found to have a genetic variant of unknown significance: Thr201Ser and Glu200Asp. One patient was diagnosed with Gerstmann-Straussler-Scheinker syndrome. No patients were classified as having variant, iatrogenic or familial CJD. The Danish surveillance system, like those in other countries, has a multidisciplinary approach, which is labour-intensive and time-consuming but ensures the most complete set of information possible. With this approach we think that patients with variant CJD would have been detected had they occurred in Denmark. Certain aspects of CJD surveillance need further discussion at European level and beyond, in order to find a balance between efficiency of the systems and accuracy of surveillance data. PMID- 22516049 TI - A human metapneumovirus outbreak at a community hospital in England, July to September 2010. AB - We describe an outbreak of human metapneumovirus (hMPV) which occurred in July September 2010 at a community hospital in the East of England. Based on the medical and nursing records, cases were retrospectively defined as suspected if they had had an influenza-like illness (ILI), and probable if they had had an ILI and an epidemiological link to a laboratory-confirmed case. Of a total of 17 symptomatic inpatients, five were classified as probable cases, five were laboratory confirmed and seven were suspected. The attack rate was 29.4% for confirmed and probable cases combined. The median age of symptomatic inpatients was 85 years-old (range 68-96) and the majority (16/17) of symptomatic inpatients had an underlying medical condition. Control measures introduced appeared to restrict further exposure of susceptible patients to infection although modelling suggested that up to four of 10 confirmed and probable cases (40%) could have been prevented through more timely diagnosis and recognition of an outbreak. These findings suggest that there should be increased awareness of hMPV infection within healthcare settings, particularly when the population at risk has a high prevalence of underlying co-morbidities. PMID- 22516050 TI - [Latest developments on risk factors and prophylaxis of thromboembolic disease in obstetrics]. AB - Venous thromboembolic disease and placental vascular pathology are responsible for an important maternal and foetal morbi-mortality with a modification of the hemostasis parameters. As these biological factors combined with particular clinical features can increase or reduce the risk of occurrence of these diseases, knowing the risk factors would help to prevent problems during the pregnancy. Several antithrombotic therapies exist, including very recent ones. Furthermore, a lot of recommendations are available in the literature. A lot of data are thus at our disposal but their synthesis is necessary to be really useful. We review here the risk factors, therapies and recommendations to help improve the management of these women. PMID- 22516052 TI - Prediction of copper transport protein 1 (CTR1) genotype on severe cisplatin induced toxicity in non-small cell lung cancer (NSCLC) patients. AB - BACKGROUND: Cisplatin toxicity severely obstacles successful chemotherapy in lung cancer patients. Cisplatin uptake is considered as one of the major factors contributing to the side effects of cisplatin. Genetic variances of core genes also affect cisplatin toxicity. It has been identified that CTR1, copper transporter protein 1, plays an essential role in cisplatin uptake. The purpose of this study is to investigate whether CTR1 polymorphism is associated with platinum toxicity in non-small cell lung cancer (NSCLC) patients. METHOD: 204 incident NSCLC patients from three different institutions were enrolled and followed up. These patients were histologically confirmed with non-small cell lung cancer. All patients have accepted cisplatin-based chemotherapy for at least two cycles. Twenty SNPs of CTR1 were detected in these patients. RESULT: CTR1 rs10981694 A>C polymorphism is associated with cisplatin induced severe toxicity in NSCLC patients. C-carrier subjects presented poorer tolerance to ototoxicity (p<0.05). The survival times of patients with different rs10981694 genetic polymorphism were not significantly different. CONCLUSION: NSCLC patients carrying C allele of CTR1 rs10981694 presented more sensitivity to ototoxicity after cisplatin treatment. CTR1 plays an essential role in cisplatin toxicity and could be considered as a predictor for pretreatment evaluation in lung cancer patients. PMID- 22516051 TI - Tumor cell and carcinoma-associated fibroblast interaction regulates matrix metalloproteinases and their inhibitors in oral squamous cell carcinoma. AB - Co-culture of periodontal ligament (PDL) fibroblasts and SCC-25 oral squamous carcinoma cells (OSCC), results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs). Paracrin circuits between CAFs and OSCC cells were hypothesized to regulate the gene expression of matrix remodeling enzymes in their co-culture, which was performed for 7days, followed by analysis of the mRNA/protein expression and activity of metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and other relevant genes. Interleukin1-beta, transforming growth factor-beta1, fibronectin and alphavbeta6 integrin have shown to be involved in the regulation of the MMP and TIMP gene expression in co-culture of CAFs and tumor cells. In addition, these cells also cooperated in activation of MMP pro-enzymes. It is particularly interesting that the fibroblast-produced inactive MMP-2 has been activated by the tumor-cell-produced membrane-type 1 matrix metalloproteinase (MT1-MMP). The crosstalk between cancer- and the surrounding fibroblast stromal-cells is essential for the fine tuning of cancer cells invasivity. PMID- 22516054 TI - Extensive dental caries in patients with oral chronic graft-versus-host disease. AB - The oral cavity is one of the sites most frequently affected by chronic graft versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (alloHCT) and can be a significant source of patient morbidity due to both mucosal and salivary gland involvement. The development of dental decay is a potentially devastating oral complication that has only rarely been reported in the transplantation literature. The purpose of this study was to comprehensively characterize a cohort of patients with cGVHD who subsequently developed extensive dental caries. A retrospective case-record review was conducted for patients who had undergone alloHCT at Dana-Farber/Brigham and Women's Cancer Center between 1990 and 2010 and developed cGVHD-associated rampant dental decay. All patients underwent dental evaluation, involving soft and hard tissue examination and dental radiography, before and after alloHCT. Any dental caries diagnosed at the pre-alloHCT evaluation were treated definitively, such that all patients were considered free of caries at the time of admission for alloHCT. A total of 21 patients were identified, with a median time of cGVHD onset of 5.4 months (range, 2.2-18.5 months) after alloHCT. All patients were diagnosed with oral cGVHD, with 90% demonstrating mucosal involvement and 95% demonstrating salivary gland involvement. Post-alloHCT dental evaluation was performed at a median of 22 months (range, 4-81) after alloHCT, when 10 patients were diagnosed with gross caries and 8 patients had 4 or more affected teeth. Cervical and interproximal patterns of dental caries were frequently diagnosed. The proportions of patients with gross caries, one surface caries, and more than one surface caries (classified as 0, 1-3, and >=4, respectively) were significantly higher after alloHCT than before alloHCT, with at least 50% of patients experiencing an increase. Patients with oral cGVHD who were free of caries at the time of transplantation developed extensive areas of cervical decay at a median of less than 2 years after alloHCT. This is the first comprehensive characterization of this severe late complication of alloHCT and oral cGVHD. Greater awareness by transplantation oncologists and dentists, as well as more aggressive preventive measures, are needed, as are further prospective studies to better elucidate the incidence of this complication, identify risk factors, and evaluate the effectiveness of preventive interventions. PMID- 22516053 TI - Selective purging of human multiple myeloma cells from autologous stem cell transplantation grafts using oncolytic myxoma virus. AB - Autologous stem cell transplantation and novel therapies have improved overall survival of patients with multiple myeloma; however, most patients relapse and eventually succumb to their disease. Evidence indicates that residual cancer cells contaminate autologous grafts and may contribute to early relapses after autologous stem cell transplantation. Here, we demonstrate that ex vivo treatment with an oncolytic poxvirus called myxoma virus results in specific elimination of human myeloma cells by inducing rapid cellular apoptosis while fully sparing normal hematopoietic stem and progenitor cells. The specificity of this elimination is based on strong binding of the virus to myeloma cells coupled with an inability of the virus to bind or infect CD34(+) hematopoietic stem and progenitor cells. These 2 features allow myxoma to readily identify and distinguish even low levels of myeloma cells in complex mixtures. This ex vivo rabbit-specific oncolytic poxvirus called myxoma virus treatment also effectively inhibits systemic in vivo engraftment of human myeloma cells into immunodeficient mice and results in efficient elimination of primary CD138(+) myeloma cells contaminating patient hematopoietic cell products. We conclude that ex vivo myxoma treatment represents a safe and effective method to selectively eliminate myeloma cells from hematopoietic autografts before reinfusion. PMID- 22516055 TI - Comparison of allogeneic stem cell transplantation from familial mismatched/haploidentical donors and from unrelated donors in adults with high risk acute myelogenous leukemia. AB - To weigh the pros and cons of familial-mismatched/haploidentical transplantation (FMT) in patients with high-risk acute myelogenous leukemia, we assessed outcomes of 23 patients who underwent FMT, using reduced-intensity conditioning with total body irradiation 800 cGy/busulfan/fludarabine/antithymocyte globulin without ex vivo T cell depletion, compared to 33 patients who underwent well-matched unrelated donor transplantation (WM-UDT) and 13 who underwent partially matched unrelated donor transplantation (PM-UDT) during the same period. The FMT patients had not only a similar pattern of engraftment and immune reconstitution as the WM UDT and PM-UDT patients but also comparable incidences and severity of acute and chronic graft-versus-host disease. The FMT patients did not experience any form of engraftment failure. However, the cumulative incidence of cytomegalovirus DNAemia was significantly higher in the FMT group compared with the other groups (P = .036). After a median follow-up of 28 months, overall survival, disease-free survival, relapse, and nonrelapse mortality were 83%, 74%, 20%, and 7%, respectively, for WM-UDT; 51%, 51%, 31%, and 18% for PM-UDT; and 66%, 64%, 26%, and 10% for FMT. This demonstrates a trend for favorable survival outcomes of WM UDT over FMT and of FMT over PM-UDT. However, we found no significant statistical differences in survival according to donor type. These data need to be interpreted cautiously because of limited power calculations due to the small number of each donor group. This pilot study suggests the feasibility of FMT using our novel regimen with careful evaluation of CMV DNAemia compared with WM UDT and PM-UDT. Further trials with larger numbers of patients, comparing FMT directly with transplantation with other donor types, are needed. PMID- 22516056 TI - Methylglyoxal has deleterious effects on thioredoxin in human aortic endothelial cells. AB - Methylglyoxal (MG), a precursor of advanced glycation end products (AGEs), is elevated in diabetic patient's plasma. Some studies have demonstrated that MG induces oxidative stress and apoptosis. Thioredoxin (Trx) is a cytoprotective protein with anti-oxidative and anti-apoptosis functions. In this study, we examined the effects of MG on Trx in human aortic endothelial cells (HAECs). MG increased oxidized-hydroethidine fluorescence intensity, suggesting intracellular accumulation of reactive oxygen species. Flow cytometric analyses with annexin V/propidium iodide double staining revealed that cells incubated with MG displayed features characteristic of apoptosis. The condensation of chromatin, the release of cytochrome c into cytosol, and the collapse of mitochondrial membrane potential by MG were observed. The exposure to MG decreased Trx protein levels through transcription regulation. MG induced the oxidative damage of peroxiredoxin, a Trx-dependent peroxidase. These results suggest that MG has deleterious effects on Trx in HAECs, which may be contribute to oxidative stress and apoptosis. PMID- 22516057 TI - Mechanism investigation of dioscin against CCl4-induced acute liver damage in mice. AB - The mechanisms of the ameliorating effects of dioscin against CCl(4) induced acute liver damage are investigated in this study. Dioscin significantly inhibited (p<0.01) the increases of serum ALT and AST activities compared with the CCl(4)-treated animals. The hepatic lipid peroxidation formation and, concentrations of TNF-alpha and IL-6 were also decreased. Liver histopathologic studies and a DNA laddering assay indicated that dioscin protected hepatocytes against CCl(4)-induced apoptosis and necrosis. Furthermore, dioscin decreased the protein expressions of Fas/FasL, increased Bcl-2/Bax ratio, inhibited the release of cytochrome c from mitochondrion to cytosol and attenuated CCl(4)-induced caspase-3 and -8 activities. The expressions of ICAM-1, vimentin, prohibitin, HGF, c-MET and GSTA1 were also regulated by dioscin and iNOS was also involved in the effects of this agent. These protective effects against CCl(4) induced acute liver damage might be through inhibiting lipid peroxidation, inflammatory cytokines, necrosis and apoptosis, and dioscin shows promise for development toward the treatment of acute chemically mediated liver injury. PMID- 22516058 TI - Effects of sub-chronic exposure to cadmium on some parameters of calcium and iodine metabolisms in the Shaw's jird Meriones shawi. AB - In the present work we determined effects of a sub-chronic exposure to cadmium on some parameters of calcium and iodine metabolisms in Meriones shawi, a desert rodent species occupying the arid steppes of Tunisia and other countries. Fourteen jirds of both sex were equally divided into a control group receiving diet without cadmium and a treated group receiving cadmium in the diet during 30, 45, 60 and 90 days. At the end of each period, 5 jirds from each group were sacrificed. In cadmium-treated group, cadmium accumulation and total metallothioneins synthesis in the liver and kidneys were high and dependant on the duration of treatment. Cadmium caused significant modifications in the body weight and in the relative weights of the liver, femur and thyroids, in parallel to a decrease in calcium content in serum and in femur. Cadmium also decreased iodine content in serum and in the thyroids. Several impairments were dependant on the duration of exposure and were more pronounced at the end of the experiment. In conclusion, a sub-chronic exposure to cadmium induces perturbations in calcium and iodine metabolisms in Meriones shawi. However, effects on calcium seem to be more evident. We can conclude also that Meriones shawi is an indicator of cadmium presence in arid environments. PMID- 22516059 TI - Impact of collimation on radiation exposure during interventional electrophysiology. AB - AIMS: Fluoroscopy remains a cornerstone imaging technique in contemporary electrophysiology practice. We evaluated the impact of collimation to the 'minimal required field size' on clinically significant parameters of radiation exposure. METHODS AND RESULTS: Radiation dose measured by dose area product (DAP) and radiation dose rate measured by DAP per minute of fluoroscopy were determined for all 571 electrophysiology procedures performed in a single electrophysiology laboratory from January 2010 to December 2010. Data from 205 procedures performed by one interventional electrophysiologist, who instituted a practice of routinely collimating to the minimum required visual fluoroscopy field on a case-by-case basis, were compared with data from 366 procedures performed by the three other experienced interventional electrophysiologists using the laboratory who continued their existing practice of ad hoc collimation. Significant reductions in radiation exposure were seen with the practice of routine maximal collimation. The largest reductions were seen during 'simple' ablation procedures. CONCLUSION: A practice of routinely collimating to the minimum required visual fluoroscopy field results in significant reductions in radiation exposure when compared with a usual approach to collimation. This may have important implications for risk of malignancy in patients and operators. PMID- 22516060 TI - Vasovagal syncope: poorly understood, but well handled. PMID- 22516061 TI - Conventional and biventricular pacing in patients with first-degree atrioventricular block. AB - Recent reports suggest that first-degree atrioventricular block is not benign. However, there is no evidence that shortening of the PR interval can improve outcome except for symptomatic patients with a very long PR interval >=0.3 s. Because these patients require continual forced pacing, biventricular pacing should be used according to accepted guidelines for third-degree AV block. Functional atrial undersensing may occur in patients with conventional dual chamber pacing and first-degree AV block because the sinus P-wave tends to be displaced into the post-ventricular atrial refractory period (PVARP) an arrangement that may cause a pacemaker syndrome. Prevention requires programming a shorter AV and PVARP that is feasible because retrograde conduction is rare in first-degree AV block patients. A relatively new pacing mode to minimize right ventricular stimulation has been designed by eliminating the traditional AV interval but with dual-chamber backup. This pacing mode permits the establishment of very long AV intervals that may cause pacemaker syndrome. About 50% of patients undergoing cardiac resynchronization therapy (CRT) have a PR interval >=200 ms. The CRT patients with first-degree AV block are prone to develop electrical desynchronization more easily than those with a normal PR interval. The duration of desynchronization after exceeding the upper rate on exercise is also more pronounced. AV junctional ablation is rarely necessary in patients with first-degree AV block but should be considered for symptomatic functional atrial undersensing or when the disturbances caused by first-degree AV block during CRT cannot be managed by programming. PMID- 22516062 TI - Osteoprotegerin is associated with aneurysm diameter and proteolysis in abdominal aortic aneurysm disease. AB - OBJECTIVE: Serum osteoprotegerin (OPG) concentrations have previously been associated with growth of abdominal aortic aneurysms (AAAs). In vitro experiments showed that OPG promotes matrix metalloprotease (MMP) release from monocytes and vascular smooth muscle cells. We hypothesized that OPG expression is increased in human AAAs and is associated with proteolysis. METHODS AND RESULTS: AAA biopsies were collected from 329 patients. We assessed the concentrations of OPG, cathepsins A, B, and S as well as the activity of MMP-2 and MMP-9. The AAA wall infiltration by macrophages, lymphocytes, and plasma cells was estimated by immunohistochemistry. The concentration of OPG correlated positively with aortic diameter (<55 mm: 16.1 [5.8-28.7], 55-70 mm: 21.9 [10.2-36.0], >70 mm: 24.0 [13.5 52.9] ng OPG/mg total amount of protein, P=0.020), cathepsin A (r=0.221, P=0.005), B (r=0.384, P<0.001), and S (r=0.467, P<0.001), MMP-2 (r=0.180, P<0.001), MMP-9 (r=0.178, P<0.001), and the number of lymphocytes (P<0.001) and plasma cells (P=0.001). OPG immunostaining was predominantly demonstrated in plasma cells. CONCLUSIONS: The concentration of aortic wall OPG is positively associated with established markers of AAA severity and pathogenesis. OPG appeared to be associated with lymphocytes and plasma cells. These human data support previous experimental data suggesting a role for OPG in AAA pathogenesis. PMID- 22516063 TI - Attenuation of early atherogenesis in low-density lipoprotein receptor-deficient mice by proteasome inhibition. AB - OBJECTIVE: Low and nontoxic proteasome inhibition has anti-inflammatory, antiproliferative, and antioxidative effects on vascular cells in vitro and in vivo. We hypothesized that low-dose inhibition of the proteasome could provide antiatherogenic protection. The present study investigated the effect of low-dose proteasome inhibition on early lesion formation in low-density lipoprotein receptor-deficient mice fed a Western-type diet. METHODS AND RESULTS: Male low density lipoprotein receptor-deficient mice, 10 weeks old, were fed a Western type diet for 6 weeks with intraperitoneal injections of bortezomib or solvent. Bortezomib was injected at a dose of 50 MUg/kg body weight. Cholesterol plasma levels were not affected by bortezomib treatment. En face Oil Red O staining of aortae and aortic root cryosections demonstrated significant reduction of atherosclerotic lesion coverage in bortezomib-treated animals. Bortezomib significantly reduced vascular cellular adhesion molecule-1 expression and macrophage infiltration as shown by histological analysis. Bortezomib treatment resulted in a significant reduction of superoxide content, lipid peroxidation and protein oxidation products, serum levels of monocyte chemoattractant protein-1, and interleukin-6. Gene expression microarray analysis showed that expressional changes induced by Western-type diet were attenuated by treatment with low-dose bortezomib. CONCLUSIONS: Low-dose proteasome inhibition exerts antioxidative and anti-inflammatory effects and attenuates development of atherosclerotic lesions in low-density lipoprotein receptor-deficient mice. PMID- 22516064 TI - Intense physiological light upregulates vascular endothelial growth factor and enhances choroidal neovascularization via peroxisome proliferator-activated receptor gamma coactivator-1alpha in mice. AB - OBJECTIVE: Toxicity of intense light to facilitate the development of neovascular age-related macular degeneration has been a health concern although the mechanism remains unclear. METHODS AND RESULTS: Effects of intense, but within physiological range, light on retinal pigment epithelium, a major pathogenic origin of age-related macular degeneration were studied in mice. Intense physiological light upregulated vascular endothelial growth factor (VEGF) expression in retinal pigment epithelium, independent of circadian rhythm, which resulted in enhancement of choroidal neovascularization. In rd1/rd1 mice or Crx( /-) mice that do not possess outer segment structure, light exposure did not induce VEGF, indicating that VEGF upregulation by light depended on increased outer segment phagocytosis by retinal pigment epithelium. In retinal pigment epithelium cells phagocytosing increased amount of outer segment, peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) not hypoxia inducible factor-1alpha was induced, leading to VEGF upregulation. The VEGF upregulation and choroidal neovascularization enhancement were abrogated in PGC 1alpha(-/-) mice and estrogen-related receptor-alpha(-/-) mice, indicating the involvement of PGC-1alpha/estrogen-related receptor-alpha pathway. CONCLUSIONS: Intense physiological light is involved in choroidal neovascularization through excess outer segment phagocytosis and VEGF upregulation mediated by PGC-1alpha in vivo. PMID- 22516065 TI - The synaptic proteins beta-neurexin and neuroligin synergize with extracellular matrix-binding vascular endothelial growth factor a during zebrafish vascular development. AB - OBJECTIVE: The goal of this study was to determine the in vivo functions of the synaptic proteins neurexins and neuroligins in embryonic vascular system development using zebrafish as animal model. METHODS AND RESULTS: In the present study, we show that the knockdown of the alpha-form of neurexin 1a induces balance defects and reduced locomotory activity, whereas beta-neurexin 1a and neuroligin 1 morphants present defects in sprouting angiogenesis and vascular remodeling, in particular in the caudal plexus and subintestinal vessels. Coinjection of low doses of morpholinos for beta-neurexin 1a and neuroligin 1 together or in combination with morpholinos targeting the -heparin--binding isoforms of vascular endothelial growth factor A (encoded by the VEGFAb gene) recapitulates the observed abnormalities, suggesting synergistic activity of these molecules. Similar coinjection experiments with morpholinos, targeting the enzyme heparan sulfate 6-O-sulfotransferase 2, confirm the presence of a functional correlation between extracellular matrix maturation and beta-neurexin 1a or neuroligin 1. CONCLUSIONS: Our data represent the first in vivo evidence of the role of neurexin and neuroligin in embryonic blood vessel formation and provide insights into their mechanism of action. PMID- 22516066 TI - Role of Src tyrosine kinases in experimental pulmonary hypertension. AB - OBJECTIVE: Pulmonary arterial hypertension is a progressive pulmonary vascular disorder with high morbidity and mortality. Compelling evidence suggests that receptor tyrosine kinases, such as platelet-derived growth factor (PDGF) are closely involved in the pathogenesis of pulmonary arterial hypertension. We investigated the effects of 2 novel PDGF inhibitors, nilotinib/AMN107 (Abl kinases/PDGF receptor inhibitor) and dasatinib/BMS-354825 (Abl kinases/PDGF receptor/Src inhibitor), on the proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) and on the hemodynamics and pulmonary vascular remodeling in experimental pulmonary hypertension, and determined the expression and regulation of Src family kinases. METHODS AND RESULTS: Human PASMCs were stimulated by PDGF alone or multiple growth factors to induce proliferation and migration in vitro. Dasatinib (0.03 MUmol/L), nilotinib (0.3 MUmol/L), and imatinib (1 MUmol/L) potently inhibited PDGF-induced signal transducer and activator of transcription 3 and Akt phosphorylation. All 3 inhibitors decreased PDGF-induced proliferation, cell cycle gene regulation, and migration. In contrast, only dasatinib inhibited multiple growth factor-induced PASMC proliferation, and this was associated with the inhibition of Src phosphorylation. Combination of specific Src inhibitors (phosphoprotein phosphatase 1, phosphoprotein phosphatase 2) with either imatinib or nilotinib reduced multiple growth factor-induced proliferation to a similar extent as dasatinib. Importantly, Src phosphorylation increased in pulmonary arterial hypertension PASMCs compared with control PASMCs. Finally, in vivo dasatinib (15 mg/kg per body weight) treatment caused a complete reversal of pulmonary vascular remodeling and achieved similar effectiveness as imatinib (100 mg/kg per body weight) in both monocrotaline- and hypoxia-induced pulmonary hypertension models. CONCLUSIONS: We suggest that dual inhibition of PDGF receptor and Src kinases potently inhibits mitogenic and motogenic responses to growth factors in PASMCs and pulmonary vascular remodeling in vivo so that dual inhibition may represent an alternative therapeutic approach for pulmonary arterial hypertension. PMID- 22516067 TI - Development of a magnetic resonance imaging protocol for the characterization of atherosclerotic plaque by using vascular cell adhesion molecule-1 and apoptosis targeted ultrasmall superparamagnetic iron oxide derivatives. AB - OBJECTIVE: Acute ischemic events are often caused by the disruption of lipid-rich plaques, which are frequently not angiographically visible. Vascular cell adhesion molecule-1 and apoptotic cell-targeted peptides studied during our previous work were conjugated to ultrasmall superparamagnetic iron oxide (USPIO) (USPIO-R832 for vascular cell adhesion molecule-1 targeting; USPIO-R826 for apoptosis targeting) and assessed by magnetic resonance imaging. METHODS AND RESULTS: Apolipoprotein E knockout mice were injected with 0.1 mmol Fe/kg body weight and were imaged on a 4.7-T Bruker magnetic resonance imaging until 24 hours after contrast agent administration. Aortic samples were then harvested and examined by histochemistry, and the magnetic resonance images and histological micrographs were analyzed with ImageJ software. The plaques enhanced by USPIO R832 contained macrophages concentrated in the cap and a large necrotic core, whereas USPIO-R826 produced a negative enhancement of plaques rich in macrophages and neutral fats concentrated inside the plaque. Both USPIO derivatives colocalized with their target on histological sections and were able to detect plaques with a vulnerable morphology, but each one is detecting a specific environment. CONCLUSIONS: Our vascular cell adhesion molecule-1 and apoptotic cell targeted USPIO derivatives seem to be highly promising tools for atherosclerosis imaging contributing to the detection of vulnerable plaques. They are able to attain their target in low doses and as fast as 30 minutes after administration. PMID- 22516068 TI - Thioredoxin-1 promotes anti-inflammatory macrophages of the M2 phenotype and antagonizes atherosclerosis. AB - OBJECTIVE: Oxidative stress is believed to play a key role in cardiovascular disorders. Thioredoxin (Trx) is an oxidative stress-limiting protein with anti inflammatory and antiapoptotic properties. Here, we analyzed whether Trx-1 might exert atheroprotective effects by promoting macrophage differentiation into the M2 anti-inflammatory phenotype. METHODS AND RESULTS: Trx-1 at 1 MUg/mL induced downregulation of p16(INK4a) and significantly promoted the polarization of anti inflammatory M2 macrophages in macrophages exposed to interleukin (IL)-4 at 15 ng/mL or IL-4/IL-13 (10 ng/mL each) in vitro, as evidenced by the expression of the CD206 and IL-10 markers. In addition, Trx-1 induced downregulation of nuclear translocation of activator protein-1 and Ref-1, and significantly reduced the lipopolysaccharide-induced differentiation of inflammatory M1 macrophages, as indicated by the decreased expression of the M1 cytokines, tumor necrosis factor alpha and monocyte chemoattractant protein-1. Consistently, Trx-1 administered to hyperlipoproteinemic ApoE2.Ki mice at 30 MUg/30 g body weight challenged either with lipopolysaccharide at 30 MUg/30 g body weight or with IL-4 at 500 ng/30 g body weight significantly induced the M2 phenotype while inhibiting differentiation of macrophages into the M1 phenotype in liver and thymus. ApoE2.Ki mice challenged once weekly with lipopolysaccharide for 5 weeks developed severe atherosclerotic lesions enriched with macrophages expressing predominantly M1 over M2 markers. In contrast, however, daily injections of Trx-1 shifted the phenotype pattern of lesional macrophages in these animals to predominantly M2 over M1, and the aortic lesion area was significantly reduced (from 100%+/-18% to 62.8%+/-9.8%; n=8; P<0.01). Consistently, Trx-1 colocalized with M2 but not with M1 macrophage markers in human atherosclerotic vessel specimens. CONCLUSIONS: The ability of Trx-1 to promote differentiation of macrophages into an alternative, anti-inflammatory phenotype may explain its protective effects in cardiovascular diseases. These data provide novel insight into the link between oxidative stress and cardiovascular diseases. PMID- 22516069 TI - Genetic evidence that lipoprotein(a) associates with atherosclerotic stenosis rather than venous thrombosis. AB - OBJECTIVE: The aim of the present study was to determine whether lipoprotein(a) [Lp(a)], considered a causal risk factor for cardiovascular disease, primarily promotes thrombosis or atherosclerosis. METHODS AND RESULTS: Using a Mendelian randomization study design, we measured plasma Lp(a) and genetically elevated Lp(a) levels through the LPA kringle IV type 2 repeat genotype in 41231 individuals. We included 2 general population studies of both venous thrombosis and combined thrombosis and atherosclerosis in coronary arteries (=myocardial infarction), and 3 -case--control studies of atherosclerotic stenosis. Neither Lp(a) tertiles nor LPA kringle IV type 2 tertiles associated with the risk of venous thrombosis in general population studies (trend: P=0.12-0.76), but did each associate with risk of coronary, carotid, and femoral atherosclerotic stenosis in -case--control studies (trend: P<0.001 to 0.04). Lp(a) and LPA kringle IV type 2 tertiles also associated with the risk of myocardial infarction in general population studies (trend: P<0.001 to 0.003). For doubling of Lp(a) levels, instrumental variable estimates of hazard/odds ratios were 1.02 (95% CI 0.90-1.15) and 1.04 (0.93-1.16) for venous thrombosis in the 2 general population studies, 1.12 (1.01-1.25), 1.17 (1.05-1.32), and 1.16 (1.01-1.35), respectively, for coronary, carotid, and femoral atherosclerotic stenosis in -case-control studies, and 1.21 (1.10-1.33) and 1.17 (1.05-1.29) for myocardial infarction in general population studies. CONCLUSIONS: This supports that Lp(a) primarily promotes atherosclerotic stenosis rather than venous thrombosis. PMID- 22516070 TI - Thrombus growth and embolism on tissue factor-bearing collagen surfaces under flow: role of thrombin with and without fibrin. AB - OBJECTIVE: At sites of vascular injury, thrombin is an important mediator in thrombus growth and stability. Using microfluidic flow devices as well as patterned surfaces of collagen and tissue factor (TF), we sought to determine the role that fibrin plays in clot stability without interfering with the production of thrombin. METHODS AND RESULTS: We deployed an 8-channel microfluidic device to study coagulation during corn trypsin inhibitor-treated (XIIa-inhibited) whole blood perfusion over lipidated TF linked to a fibrillar collagen type 1 surface. Clot growth and embolization were measured at initial inlet venous (200 s(-1)) or arterial (1000 s(-1)) wall shear rates under constant flow rate or pressure relief mode in the presence or absence of Gly-Pro-Arg-Pro (GPRP) to block fibrin polymerization. Numerical calculations for each mode defined hemodynamic forces on the growing thrombi. In either mode at inlet venous flow, increasing amounts of TF on the surface led to a modest dose-dependent increase (up to 2-fold) in platelet deposition, but resulted in massive fibrin accumulation (>50-fold) only when exceeding a critical TF threshold. At a venous inlet flow, GPRP led to a slight 20% increase in platelet accumulation (P<0.01) in pressure relief mode with thrombi resisting ~1500 s(-1) before full channel occlusion. GPRP-treated thrombi were unstable under constant flow rate, where shear forces caused embolization at a maximum shear rate of ~2300 s(-1) (69 dynes/cm2). In constant flow rate mode, the nonocclusive platelet-fibrin deposits (no GPRP) withstood maximum shear rates of ~29 000 s(-1) (870 dyne/cm2) at ~95% of full channel occlusion. For arterial inlet shear rate, embolization was marked for either mode with GPRP present when shear forces reached 87 dynes/cm2 (~2900 s(-1)). Under constant flow rate, platelet-fibrin deposits (no GPRP) withstood maximums of 2400 dynes/cm2 (80,000 s(-1)) at ~90% of full channel occlusion prior to embolization. CONCLUSIONS: Fibrin increased clot strength by 12- to 28-fold. Under pressure relief mode, ~2-fold more fibrin was produced under venous flow (P<0.001). These studies define embolization criteria for clots formed with surface TF-triggered thrombin production (+/-fibrin) under venous and arterial flows. PMID- 22516071 TI - A decade at the forefront of clinical neurology. PMID- 22516073 TI - Spreading depolarisations and traumatic brain injury: time course and mechanisms. PMID- 22516074 TI - Epilepsy nurse specialists are a vital resource. PMID- 22516075 TI - UK High Court case to reignite debate over assisted death. PMID- 22516076 TI - Eelco Wijdicks: a neurocritical appraisal. PMID- 22516078 TI - Treatment of motor and non-motor features of Parkinson's disease with deep brain stimulation. AB - Deep brain stimulation (DBS) is an established procedure for the symptomatic treatment of Parkinson's disease. Several deep brain nuclei have been stimulated, producing a wide range of effects on the motor and non-motor symptoms of Parkinson's disease. Long-term, high-quality evidence is available for stimulation of the subthalamic nucleus and globus pallidus internus, both of which uniformly improve motor features, and for stimulation of the thalamic ventralis intermedius, which improves tremor. Short-term data are available for stimulation of other deep brain targets, such as the pedunculopontine nucleus and the centremedian/parafascicular thalamic complex. Some non-motor symptoms improve after DBS, partly because of motor benefit or reduction of drug treatment, and partly as a direct effect of stimulation. More evidence on the effects of DBS on non-motor symptoms is needed and specifically designed studies are warranted. PMID- 22516079 TI - Childhood spinal muscular atrophy: controversies and challenges. AB - Spinal muscular atrophy is an autosomal recessive disorder characterised by degeneration of motor neurons in the spinal cord and is caused by mutations of the survival of motor neuron 1 gene SMN1. The severity of spinal muscular atrophy is highly variable and no cure is available at present. Consensus has been reached on several aspects of care, the availability of which can have a substantial effect on prognosis, but controversies remain. The development of standards of care for children with the disorder and the identification of promising treatment strategies have changed the natural history of spinal muscular atrophy, and the prospects are good for further improvements in function, quality of life, and survival. A long-term benefit for patients will be the development of effective interventions (such as antisense oligonucleotides), some of which are in clinical trials. The need to be prepared for clinical trials has been the impetus for a remarkable and unprecedented cooperation between clinicians, scientists, industry, government, and volunteer organisations on an international scale. PMID- 22516081 TI - Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects. AB - Many of the available disability outcome measures used in clinical trials of multiple sclerosis are insensitive to change over time, inadequately validated, or insensitive to patient-perceived health status or quality of life. Increasing focus on therapies that slow or reverse disability progression makes it essential to refine existing measures or to develop new tools. Major changes to the expanded disability status scale should be avoided to prevent the loss of acceptance by regulators as a measure for primary outcomes in trials that provide substantial evidence of effectiveness. Rather, we recommend practical refinements. Conversely, although substantial data support the multiple sclerosis functional composite as an alternative measure, changes to its component tests and scoring method are needed. Novel approaches, including the use of composite endpoints, patient-reported outcomes, and measurement of biomarkers, show promise as adjuncts to the current disability measures, but are insufficiently validated to serve as substitutes. A collaborative approach that involves academic experts, regulators, industry representitives, and funding agencies is needed to most effectively develop disability outcome measures. PMID- 22516080 TI - Neurology of inherited glycosylation disorders. AB - Congenital disorders of glycosylation comprise most of the nearly 70 genetic disorders known to be caused by impaired synthesis of glycoconjugates. The effects are expressed in most organ systems, and most involve the nervous system. Typical manifestations include structural abnormalities (eg, rapidly progressive cerebellar atrophy), myopathies (including congenital muscular dystrophies and limb-girdle dystrophies), strokes and stroke-like episodes, epileptic seizures, developmental delay, and demyelinating neuropathy. Patients can also have neurological symptoms associated with coagulopathies, immune dysfunction with or without infections, and cardiac, renal, or hepatic failure, which are common features of glycosylation disorders. The diagnosis of congenital disorder of glycosylation should be considered for any patient with multisystem disease and in those with more specific phenotypic features. Measurement of concentrations of selected glycoconjugates can be used to screen for many of these disorders, and molecular diagnosis is becoming more widely available in clinical practice. Disease-modifying treatments are available for only a few disorders, but all affected individuals benefit from early diagnosis and aggressive management. PMID- 22516083 TI - Evidence of selective packaging and different alpha-granule subtypes in canine platelets. AB - Platelets are circulating megakaryocytic cytoplasmic fragments that are required to maintain vascular integrity and prevent haemorrhage. During activation, platelets release hundreds of bioactive proteins, mainly by secretion of alpha granule content. These proteins include von Willebrand factor (vWF) and fibrinogen, major adhesive proteins involved in haemostasis. Human and mouse platelet alpha-granules are packaged selectively to contain different molecules and platelets can differentially release these proteins on specific receptor activation. Confocal laser scanning microscopy was used to analyse vWF and fibrinogen localization within canine platelet alpha-granules. In resting canine platelets, the majority of platelet vWF and fibrinogen is located in separate alpha-granule populations. These findings provide evidence that canine platelets contain different alpha-granule subtypes, suggesting that selective protein packaging occurs during canine platelet ontology. PMID- 22516082 TI - B cell receptor light chain repertoires show signs of selection with differences between groups of healthy individuals and SLE patients. AB - We have developed a microarray to study the expression of L-chain V genes (V(L) genes) in healthy and SLE patient peripheral kappa- and lambda-sorted B cells. In all repertoires tested, one V(L) gene accounts for over 10% of all gene V(L) expression, consistent with positive selection acting on L-chains. While a few V(L) genes were highly expressed in all individuals, most V(L) genes were expressed at different levels. Some V(L) genes (5 out of a total of 78) were not detected. We attribute their absence from the repertoire to negative selection. Positive selection and negative selection were also found in SLE repertoires, but expression of V(L) genes was different; the differences point to less regulation of V(L) gene repertoires in SLE. Our data shows that V(L) gene expression is variable and supports a model where the L-chain repertoire is generated by both positive and negative selection on L-chains. PMID- 22516084 TI - Purulent meningoventriculitis caused by Streptococcus equi subspecies zooepidemicus in a snow leopard (Panthera uncia). AB - Streptococcus equi subspecies zooepidemicus (SEZ) is a zoonotic pathogen that causes respiratory tract infections in man and animals. SEZ infections are very rare in felids. This report describes purulent meningoventriculitis caused by SEZ in an approximately 16-year-old male snow leopard (Panthera uncia). The animal exhibited neurological signs and died 1 month after their onset. On necropsy examination, the surface blood vessels of the brain were swollen and there was an increased volume and turbidity of cerebrospinal fluid (CSF). Microscopically, suppurative inflammation accompanied by gram-positive cocci was observed in the meninges and near the ventricles. SEZ was isolated from the brain tissue and CSF. This is the first report of infection with SEZ in a felid other than a domestic cat. This animal had not had direct contact with horses, but it had been fed horse flesh that may have been the source of infection. PMID- 22516085 TI - Cutaneous and systemic pathogenicity of a clinical isolate of Cladosporium sphaerospermum in a murine model. AB - The pathogenicity of a clinical isolate of Cladosporium sphaerospermum was determined in a murine model. BALB/c mice were given two intraperitoneal injections of 150 mg/kg cyclophosphamide or normal saline on days 4 and 1 preinoculation, and were then challenged with 0.2 ml of C. sphaerospermum inoculum (2 * 10(7) CFU/ml) by topical application on an abrasive wound or by subcutaneous or intravenous injection. Histopathology and inverse fungal culture were performed on the skin lesions and viscera, and pulmonary fungal burden was also determined. Inoculated skin developed localized infections after dermabrasive or subcutaneous challenge in all mice, but the maximum area and number of positive cultures from skin lesions were higher for immunocompromised mice. In the intravenously inoculated mice, all immunocompetent animals survived for the 4-week period of the experiment, while 60% of immunocompromised animals died by 5 days postinoculation. The incidence of disseminated infection and the pulmonary fungal burden of immunosuppressed mice were higher than those of immunocompetent animals. Cutaneous and systemic infections can be established by subcutaneous and intravenous challenge with C. sphaerospermum in BALB/c mice, with the lungs being the most susceptible tissue in systemic infection. PMID- 22516086 TI - Malignant mesenchymoma of the heart base in a dog with infiltration of the pericardium and metastasis to the lung. AB - A 9-year-old male rottweiler was presented with abdominal distension, ascites and respiratory distress and marked bulging in the perineal region. At necropsy examination the animal had profuse ascites and hydropericardium and a multinodular mass in the right auricle of the heart infiltrating the epicardium and pericardium and metastasizing to the caudal lobe of the left lung. Microscopically and immunohistochemically the tumour was composed of neoplastic cells with muscular, cartilaginous and adipose differentiation. A diagnosis of malignant mesenchymoma with leiomyosarcomatous (~ 50%), rhabdomyosarcomatous (~ 30%), chondrosarcomatous (25%) and liposarcomatous (5%) components was made. Metastatic malignant mesenchymoma has not been reported previously at this site in the dog. PMID- 22516087 TI - Minimal involvement of the circumventricular organs in the pathogenesis of spontaneously arising and experimentally induced classical bovine spongiform encephalopathy. AB - In sheep infected experimentally with the bovine spongiform encephalopathy (BSE) agent, amplification of infectivity in peripheral organs during early preclinical stages is thought to contribute to high titres of the agent being detected in blood, with subsequent haematogenous neuroinvasion through the circumventricular organs (CVOs). In contrast, little disease-associated prion protein (PrP(d)) or infectivity is detected in the peripheral tissues of cattle during the preclinical and clinical stages of BSE. The aim of this study was to investigate immunohistochemically the role of haematogenous neuroinvasion in cattle with spontaneously arising and experimentally induced BSE. There was almost complete absence of PrP(d) in the peripheral organs of BSE infected cattle. Additionally, there was minimal involvement of the CVOs during preclinical disease and there was progressive caudorostral accumulation of PrP(d) in the brain. These findings do not support haematogenous neuroinvasion in the bovine disease. PMID- 22516088 TI - Cell entry of cell penetrating peptides: tales of tails wagging dogs. AB - Cell penetrating peptides hold considerable potential for academic and pharmaceutical remits with an interest in delivering macromolecules to the insides of cells. Hundreds of sequences now fall within the cell penetrating peptide classification and HIV-Tat, penetratin, transportan, and octaarginine represent extensively studied variants. The process by which membrane translocation is achieved has received significant interest in an aim to exploit new mechanistic knowledge to gain higher efficiency of penetration. There is evidence that many of the most well studied peptides are able to deliver themselves, relatively small cargo and possibly large macromolecular structures directly across the plasma membrane but there is also support for the involvement of an endocytic pathway or pathways. This review focuses on recent findings relating to experimental protocols and cell penetrating peptide modifications or extensions that yield significant effects on penetration capability. Relatively small changes in extracellular peptide concentrations, the inclusion or absence of serum from the incubation medium and the in vitro model exemplify variables that significantly influence the capacity of CPPs to penetrate membranes. Attachment of any type of cargo to these entities has the potential to affect their interaction with cells. There is increasing evidence to suggest that this is true for relatively small molecules such as fluorescent probes and hydrophobic adducts such as lipids and short peptide sequences designed as peptide therapeutics. Information gained from these findings will improve our knowledge of, and capacity to study the interactions of CPPs with cells, and this will accelerate their translation as efficient vectors from the in vitro setting into the clinical arena. PMID- 22516089 TI - Microneedle delivery of plasmid DNA to living human skin: Formulation coating, skin insertion and gene expression. AB - Microneedle delivery of nucleic acids, in particular plasmid DNA (pDNA), to the skin represents a potential new approach for the clinical management of genetic skin diseases and cutaneous cancers, and for intracutaneous genetic immunisation. In this study excised human skin explants were used to investigate and optimise key parameters that will determine stable and effective microneedle-facilitated pDNA delivery. These include (i) high dose-loading of pDNA onto microneedle surfaces, (ii) stability and functionality of the coated pDNA, (iii) skin penetration capability of pDNA-coated microneedles, and (iv) efficient gene expression in human skin. Optimisation of a dip-coating method enabled significant increases in the loading capacity, up to 100MUg of pDNA per 5 microneedle array. Coated microneedles were able to reproducibly perforate human skin at low (<1N) insertion forces. The physical stability of the coated pDNA was partially compromised on storage, although this was improved through the addition of saccharide excipients without detriment to the biological functionality of pDNA. The pDNA-coated microneedles facilitated reporter gene expression in viable human skin. The efficiency of gene expression from coated microneedles will depend upon suitable DNA loading, efficient and reproducible skin puncture and rapid in situ dissolution of the plasmid at the site of delivery. PMID- 22516090 TI - Triggering of drug release of particles in hair follicles. AB - Particulate drug delivery via hair follicles represents a promising concept, although requirements are high. This process must be realized at the desired depth and at the appropriate time, due to the fact that the particles themselves are not able to overcome the follicular skin barrier. In the present study, a novel triggering concept for the release of a model drug from the delivering particles is presented based on the application of two different particle types of the same size, where one particle type is the drug carrier, and the second one is loaded with a protease. The latter particle type is supposed to interact with the drug-carrying particles to trigger the drug release. A mixture of both particles was applied onto porcine skin samples, followed by follicular analysis. As a control, the particles were applied unaided without protease, whereas one skin area remained untreated. The investigations revealed that the protease was able to release the model drug from the delivering particles in significant depths within the hair follicle (866+/-62nm). Additionally, an uptake of the model drug in the sebaceous gland was observed after release providing a promising novel approach for the development of treatment strategies for different skin diseases. PMID- 22516091 TI - Transcutaneous immunization using a dissolving microneedle array protects against tetanus, diphtheria, malaria, and influenza. AB - Transcutaneous immunization (TCI) is an attractive alternative vaccination route compared to the commonly used injection systems. We previously developed a dissolving microneedle array for use as a TCI device, and reported that TCI with the dissolving microneedle array induced an immune response against model antigens. In the present study, we investigated the vaccination efficacy against tetanus and diphtheria, malaria, and influenza using this vaccination system. Our TCI system induced substantial increases in toxoid-specific IgG levels and toxin neutralizing antibody titer and induced the production of anti-SE36 IgG, which could bind to malaria parasite. On influenza HA vaccination, robust antibody production was elicited in mice that provided complete protection against a subsequent influenza virus challenge. These findings demonstrate that TCI using a dissolving microneedle array can elicit large immune responses against infectious diseases. Based on these results, we are now preparing translational research for human clinical trials. PMID- 22516092 TI - Low-frequency ac electroporation shows strong frequency dependence and yields comparable transfection results to dc electroporation. AB - Conventional electroporation has been conducted by employing short direct current (dc) pulses for delivery of macromolecules such as DNA into cells. The use of alternating current (ac) field for electroporation has mostly been explored in the frequency range of 10kHz-1MHz. Based on Schwan equation, it was thought that with low ac frequencies (10Hz-10kHz), the transmembrane potential does not vary with the frequency. In this report, we utilized a flow-through electroporation technique that employed continuous 10Hz-10kHz ac field (based on either sine waves or square waves) for electroporation of cells with defined duration and intensity. Our results reveal that electropermeabilization becomes weaker with increased frequency in this range. In contrast, transfection efficiency with DNA reaches its maximum at medium frequencies (100-1000Hz) in the range. We postulate that the relationship between the transfection efficiency and the ac frequency is determined by combined effects from electrophoretic movement of DNA in the ac field, dependence of the DNA/membrane interaction on the ac frequency, and variation of transfection under different electropermeabilization intensities. The fact that ac electroporation in this frequency range yields high efficiency for transfection (up to ~71% for Chinese hamster ovary cells) and permeabilization suggests its potential for gene delivery. PMID- 22516093 TI - The efficacy of aerosol treatment with non-ionic surfactant vesicles containing amphotericin B in rodent models of leishmaniasis and pulmonary aspergillosis infection. AB - Amphotericin B (AMB) is used to treat both fungal and leishmanial infections, which are of major significance to human health. Clinical use of free AMB is limited by its nephrotoxicity, whereas liposomal AMB is costly and requires parenteral administration, thus development of novel formulations with enhanced efficacy, minimal toxicity and that can be applied via non-invasive routes is required. In this study we analysed the potential of non-ionic surfactant vesicles (NIV) given by nebulisation to deliver AMB to the lungs, liver and skin. Treatment with AMB-NIV resulted in significantly higher drug levels in the lungs and skin (p<0.05) compared to similar treatment with AMB solution but significantly lower plasma levels (p<0.05). Treatment with AMB-NIV resulted in a significant reduction in fungal lung burdens in a rat model of invasive pulmonary aspergillosis (p<0.05) compared to treatment with the carrier alone. Treatment with AMB-NIV but not AMB solution significantly suppressed Leishmania donovani liver parasite burdens (p<0.05) but could not inhibit the growth of cutaneous Leishmania major lesions. The results of this study indicate that aerosolised NIV enhanced pulmonary and hepatic delivery whilst minimising systemic exposure and toxicity. PMID- 22516095 TI - Virus-mediated gene delivery for human gene therapy. AB - After over 20 years from the first application of gene transfer in humans, gene therapy is now a mature discipline, which has progressively overcome several of the hurdles that prevented clinical success in the early stages of application. So far, the vast majority of gene therapy clinical trials have exploited viral vectors as very efficient nucleic acid delivery vehicles both in vivo and ex vivo. Here we summarize the current status of viral gene transfer for clinical applications, with special emphasis on the molecular properties of the major classes of viral vectors and the information so far obtained from gene therapy clinical trials. PMID- 22516094 TI - Controlled release of Pantoea agglomerans E325 for biocontrol of fire blight disease of apple. AB - Microencapsulation and controlled release of the biocontrol agent Pantoea agglomerans strain E325 (E325), an antagonist to the bacterial plant pathogen Erwinia amylovora that causes fire blight, a devastating disease of apple and pear, have been investigated. Uniform core-shell alginate microcapsules (AMCs), 60-300 MUm in diameter, were fabricated to encapsulate E325 within the core, along with nutrients, to preserve viability and promote proliferation. Controlled release of E325 was achieved by separately adjusting alginate concentrations in the shell and core solutions, and by modifying the AMC size. Viability of E325 was monitored via fluorescent staining, revealing either lack of or minimal stress during or after encapsulation. Proliferation of E325 within AMCs, followed by their subsequent release, and colonization activities within confines of apple flowers were studied under different encapsulation conditions using rfp-labeled E325 to obtain highly promising results. This study provided a 'proof of concept' of the successful use of a microencapsulated biocontrol agent, E325, against E. amylovora, and could serve as a model for further studies on the development of effective plant disease management strategies. PMID- 22516096 TI - Effect of unsaturated alkyl chains on transfection activity of poly(amidoamine) dendron-bearing lipids. AB - In an earlier study, we developed a new type of gene vector using poly(amidoamine) (PAMAM) dendron-bearing lipids and reported that their transfection activity was affected by their structures, such as dendron generation and alkyl chain length. In this study, for improvement of their performance as gene vectors, we examined the effect of unsaturated chains of the dendron-bearing lipids using DL-G1-2C(18), which consists of PAMAM G1 dendron moiety and two octadecyl chains, and achieved the most efficient transfection activity among the dendron-bearing lipids having saturated alkyl chains, and DL G1-2C(18)-U2, which consists of the same dendron-moiety and two octadecenyl chains. DL-G1-2C(18)-U2 showed a higher ability to form lipoplexes with plasmid DNA than DL-G1-2C(18). The DL-G1-2C(18)-U2 lipoplexes exhibited much smaller particle sizes than the DL-G1-2C(18). In addition, the DL-G1-2C(18)-U2 lipoplexes exhibited more efficient transfection of HeLa cells than DL-G1-2C(18) did. Results demonstrate the importance of unsaturated chains for the production of the dendron-bearing lipids having excellent gene transfection performance. Without the help of additional fusogenic lipids such as dioleoylphosphatidylethanolamine, DL-G1-2C(18)-U2 lipoplexes achieved the highly efficient transfection of the cells without marked cellular toxicity, in the presence of serum. Therefore, DL-G1-2C(18)-U2 might be promising as a potent gene vector. PMID- 22516097 TI - Designing the nanoparticle-biomolecule interface for "targeting and therapeutic delivery". AB - The endogenous transport mechanisms which occur in living organisms have evolved to allow selective transport and processing operate on a scale of tens of nanometers. This presents the possibility of unprecedented access for engineered nanoscale materials to organs and sub-cellular locations, materials which may in principle be targeted to precise locations for diagnostic or therapeutic gain. For this reason, nano-architectures could represent a truly radical departure as delivery agents for drugs, genes and therapies to treat a host of diseases. Thus, for active targeting, unlike the case of small molecular drugs where molecular structure has evolved to promote higher physiochemical affinity to specific sites, one aims to exploit these energy dependant endogenous processes. Many active targeting strategies have been developed, but despite this truly remarkable potential, in applications they have met with mixed success to date. This situation may have more to do with our current understanding and integration of knowledge across disciplines, than any intrinsic limitation on the vision itself. In this review article we suggest that much more fundamental and detailed control of the nanoparticle-biomolecule interface is required for sustained and general success in this field. In the simplest manifestation, pristine nanoparticles in biological fluids act as a scaffold for biomolecules, which adsorb rapidly to the nanoparticles' surface, conferring a new biological identity to the nanoparticles. It is this nanoparticle-biomolecule interface that is 'read' and acted upon by the cellular machinery. Moreover, where targeting moieties are grafted onto nanoparticles, they may not retain their function as a result of poor orientation, and structural or conformational disruption. Further surface adsorption of biomolecules from the surrounding environment i.e. the formation of a biomolecule corona may also obscure specific surface recognition. To transfer the remarkable possibilities of nanoscale interactions in biology into therapeutics one may need a more focused and dedicated approach to the understanding of the in situ (in vivo) interface between engineered nanomaedicines and their targets. PMID- 22516098 TI - Bartonella spp. bacteremia and rheumatic symptoms in patients from Lyme disease endemic region. AB - Bartonella spp. infection has been reported in association with an expanding spectrum of symptoms and lesions. Among 296 patients examined by a rheumatologist, prevalence of antibodies against Bartonella henselae, B. koehlerae, or B. vinsonii subsp. berkhoffii (185 [62%]) and Bartonella spp. bacteremia (122 [41.1%]) was high. Conditions diagnosed before referral included Lyme disease (46.6%), arthralgia/arthritis (20.6%), chronic fatigue (19.6%), and fibromyalgia (6.1%). B. henselae bacteremia was significantly associated with prior referral to a neurologist, most often for blurred vision, subcortical neurologic deficits, or numbness in the extremities, whereas B. koehlerae bacteremia was associated with examination by an infectious disease physician. This cross-sectional study cannot establish a causal link between Bartonella spp. infection and the high frequency of neurologic symptoms, myalgia, joint pain, or progressive arthropathy in this population; however, the contribution of Bartonella spp. infection, if any, to these symptoms should be systematically investigated. PMID- 22516099 TI - Thermal conversion of municipal solid waste via hydrothermal carbonization: comparison of carbonization products to products from current waste management techniques. AB - Hydrothermal carbonization (HTC) is a novel thermal conversion process that may be a viable means for managing solid waste streams while minimizing greenhouse gas production and producing residual material with intrinsic value. HTC is a wet, relatively low temperature (180-350 degrees C) thermal conversion process that has been shown to convert biomass to a carbonaceous residue referred to as hydrochar. Results from batch experiments indicate HTC of representative waste materials is feasible, and results in the majority of carbon (45-75% of the initially present carbon) remaining within the hydrochar. Gas production during the batch experiments suggests that longer reaction periods may be desirable to maximize the production of energy-favorable products. If using the hydrochar for applications in which the carbon will remain stored, results suggest that the gaseous products from HTC result in fewer g CO(2)-equivalent emissions than the gases associated with landfilling, composting, and incineration. When considering the use of hydrochar as a solid fuel, more energy can be derived from the hydrochar than from the gases resulting from waste degradation during landfilling and anaerobic digestion, and from incineration of food waste. Carbon emissions resulting from the use of the hydrochar as a fuel source are smaller than those associated with incineration, suggesting HTC may serve as an environmentally beneficial alternative to incineration. The type and extent of environmental benefits derived from HTC will be dependent on hydrochar use/the purpose for HTC (e.g., energy generation or carbon storage). PMID- 22516100 TI - Wet landfill decomposition rate determination using methane yield results for excavated waste samples. AB - An increasing number of landfills are operated to accelerate waste decomposition through liquids addition (e.g., leachate recirculation) as a wet landfill. Landfill design and regulation often depend on utilizing landfill gas production models that require an estimate of a first-order gas generation rate constant, k. Consequently, several studies have estimated k using collected gas volumes from operating wet landfills. Research was conducted to examine an alternative approach in which k is estimated not from collected landfill gas but from solid waste samples collected over time and analyzed for remaining gas yield. To achieve this goal, waste samples were collected from 1990 through 2007 at two full-scale landfills in Florida that practiced liquids addition. Methane yields were measured from waste samples collected over time, including periods before and after leachate recirculation, and the results were applied to a first-order decay model to estimate rate constants for each of the sites. An initial, intensive processing step was conducted to exclude non-biodegradable components from the methane yield testing procedure. The resulting rate constants for the two landfills examined were 0.47 yr(-1) and 0.21 yr(-1). These results expectedly exceeded the United States Environmental Protection Agency's rate constants for dry and conventional landfills (0.02-0.05 yr(-1)), but they are comparable to wet landfill rate constants derived using landfill gas data (0.1-0.3 yr(-1)). PMID- 22516101 TI - LCA for household waste management when planning a new urban settlement. AB - When planning for a new urban settlement, industrial ecology tools like scenario building and life cycle assessment can be used to assess the environmental quality of different infrastructure solutions. In Trondheim, a new greenfield settlement with carbon-neutral ambitions is being planned and five different scenarios for the waste management system of the new settlement have been compared. The results show small differences among the scenarios, however, some benefits from increased source separation of paper and metal could be found. The settlement should connect to the existing waste management system of the city, and not resort to decentralised waste treatment or recovery methods. However, as this is an urban development project with ambitious goals for lifestyle changes, effort should be put into research and initiatives for proactive waste prevention and reuse issues. PMID- 22516102 TI - DGKzeta is degraded through the cytoplasmic ubiquitin-proteasome system under excitotoxic conditions, which causes neuronal apoptosis because of aberrant cell cycle reentry. AB - Recent reports have described the involvement of the diacylglycerol kinase (DGK) family in various pathological conditions. In an animal model of transient ischemia, DGKzeta containing a nuclear localization signal (NLS) is shown to translocate quickly from the nucleus to the cytoplasm in hippocampal neurons and to disappear gradually after reperfusion. Those neurons die a delayed neuronal death because of glutamate excitotoxicity. This study investigated the molecular mechanism and functional relation linking DGKzeta and neuronal death. In primary cultured neurons, transient exposure to excitotoxic concentration of glutamate led to cytoplasmic accumulation of DGKzeta followed by its down-regulation. Results showed that DGKzeta down-regulation was caused by proteolytic degradation through the ubiquitin-proteasome system (UPS) rather than transcriptional inhibition. DGKzeta polyubiquitination was inhibited in the presence of nuclear export inhibitor leptomycin B. Furthermore, NLS-deleted mutant DGKzetaDeltaNLS, which mainly localizes to the cytoplasm, was ubiquitinated more heavily than wild type DGKzeta. From a functional perspective, in vitro gene silencing of DGKzeta via specific siRNA enhanced DNA fragmentation in cultured neurons after glutamate exposure. At the organismal level, hippocampal neurons of DGKzeta-deficient mice showed vulnerability to kainate-induced seizures. In addition, DGKzeta-deficient hippocampus exhibited a significant increase in Ser807/811 phosphorylated retinoblastoma protein levels together with up-regulation of the expression of type D and E cyclins, indicative of cell cycle reentry. Collectively, these results suggest that 1) glutamate excitotoxicity induces nucleocytoplasmic translocation of DGKzeta followed by its degradation through the cytoplasmic UPS in hippocampal neurons and that 2) DGKzeta-deficient neurons do not succumb directly to apoptosis, although they are more vulnerable to excitotoxicity because of aberrant cell cycle reentry. PMID- 22516103 TI - [Visceral leishmaniasis in immunocompetent adults. About six cases]. AB - OBJECTIVE: Studying the epidemiological variations of visceral leishmaniasis in Tunisia and proving the importance of parasitological investigations to raise the diagnosis. PATIENTS AND METHODS: Six patients hospitalised during the period between January 1998 and January 2009 at Fattouma Bourguiba Teaching Hospital in Monastir, five men and an only one woman, aged from 26 to 70 years old, originating from the central and eastern regions of the country. Epidemiological, clinical, biological and therapeutic data were obtained from the patient's medical files. RESULTS: The major clinical symptoms were fever, weakness and spleen enlargement. Biological data revealed the presence of anaemia in every case and leucopoenia associated or not associated with thrombopenia in four cases. The diagnosis of visceral leishmaniasis was confirmed by the identification of the parasite in the blood or in the bone marrow. All patients were treated with two courses of antimoniate of meglumine separated by a 6-week interval. The outcome was positive and the patients were cured. CONCLUSION: Visceral leishmaniasis is increasing among adults in Tunisia. Moreover, it is spreading outside its epidemiological area in the north to reach the central and southern regions. It should be raised when fever and spleen enlargement occur. Biological data are hardly specific. Diagnosis is based on finding the parasite in human fluids, mainly by molecular techniques. The rapid establishment of a specific treatment is vital. PMID- 22516104 TI - Deciphering chondrocyte behaviour in matrix-induced autologous chondrocyte implantation to undergo accurate cartilage repair with hyaline matrix. AB - Since the emergence in the 1990s of the autologous chondrocytes transplantation (ACT) in the treatment of cartilage defects, the technique, corresponding initially to implantation of chondrocytes, previously isolated and amplified in vitro, under a periosteal membrane, has greatly evolved. Indeed, the first generations of ACT showed their limits, with in particular the dedifferentiation of chondrocytes during the monolayer culture, inducing the synthesis of fibroblastic collagens, notably type I collagen to the detriment of type II collagen. Beyond the clinical aspect with its encouraging results, new biological substitutes must be tested to obtain a hyaline neocartilage. Therefore, the use of differentiated chondrocytes phenotypically stabilized is essential for the success of ACT at medium and long-term. That is why researchers try now to develop more reliable culture techniques, using among others, new types of biomaterials and molecules known for their chondrogenic activity, giving rise to the 4th generation of ACT. Other sources of cells, being able to follow chondrogenesis program, are also studied. The success of the cartilage regenerative medicine is based on the phenotypic status of the chondrocyte and on one of its essential component of the cartilage, type II collagen, the expression of which should be supported without induction of type I collagen. The knowledge accumulated by the scientific community and the experience of the clinicians will certainly allow to relief this technological challenge, which influence besides, the validation of such biological substitutes by the sanitary authorities. PMID- 22516105 TI - Screening for influenza A(H1N1)pdm09, Auckland International Airport, New Zealand. AB - Entry screening for influenza A(H1N1)pdm09 at Auckland International Airport, New Zealand, detected 4 cases, which were later confirmed, among 456,518 passengers arriving April 27-June 22, 2009. On the basis of national influenza surveillance data, which suggest that ~69 infected travelers passed through the airport, sensitivity for screening was only 5.8%. PMID- 22516106 TI - What are young patients doing after hip reconstruction? AB - We assessed primary hip arthroplasty patients younger than 50 years in terms of activity and function. We hypothesized that young patients are more active than previously thought. Physician activity recommendations were compared with patient reported participation levels in activities. Sixty-one patients (65.3%) were reached by telephone. Average age was 43.18 years; body mass index, 29.46. "Recommended activities" increased by 33%. High-Activity Arthroplasty Score and University of California at Los Angeles scores were 11.69 and 6.87, respectively. Patients were 98% satisfied with their postoperative function, and 95% would redo the procedure. Activities stopped due to fear of injury (29%), physician recommendation (26%), hip pain (14%), early fatigue (17%), and decreased interest (14%). The average period to postoperative survey administration was 30.06 months (range, 10-81 months). Postoperative recommendations for the young total hip arthroplasty patient should be a balance between joint prosthesis preservation and regular activity participation. PMID- 22516107 TI - The intercalated paracapsular islands as a module for integration of signals regulating anxiety in the amygdala. AB - The intercalated paracapsular (IPC) islands are clusters of dopamine-D1-and MU opioid 1-receptor rich GABAergic neurons which surround the rostral half of the basolateral complex of the amygdala (BLA) giving rise to several subgroups which can be further subdivided. IPC cells are small-sized and have an axonal and dendritic pattern which differs according to the group they belong. Functionally, IPC neurons are endowed with unique properties that set them apart from other amygdaloid interneurons and allow them to participate in integrative functions. Consistent with this role IPC cells usually remain confined within the amygdala where they receive BLA and cortical inputs and interact synaptically with each other. They project into both the central (CeA) and medial (MeA) amygdaloid nuclei. Their main effect at the network level seems to control the trafficking of nerve impulses to the main input (BLA) and output (CeA) stations of the amygdala. Such a task seems to be accomplished by providing feedforward inhibition to BLA neurons from putative inputs of the medial prefrontal cortex (mPFC) and to CeA from both mPFC and BLA projections. Current experimental evidence will be discussed suggesting that through feedforward inhibitory effects on specific amygdaloid nuclei IPC neurons participate in the maintenance of basal anxiety as well as in the modulation of unconditioned and conditioned fear, and in the process of fear extinction. This article is part of a Special Issue entitled: Brain Integration. PMID- 22516108 TI - Neuroprotection of GluK1 kainate receptor agonist ATPA against ischemic neuronal injury through inhibiting GluK2 kainate receptor-JNK3 pathway via GABA(A) receptors. AB - It is well known that GluK2-containing kainate receptors play essential roles in seizure and cerebral ischemia-induced neuronal death, while GluK1-containing kainate receptors could increase tonic inhibition of post-synaptic pyramidal neurons. This research investigated whether GluK1 could inhibit activation of c Jun N-terminal kinase 3 (JNK3) signaling pathway mediated by the GluK2 in cerebral ischemia-reperfusion. The results show that GluK1 activation by (RS)-2 amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA) at 1nmol per rat could inhibit the assembly of GluK2.Postsynaptic density 95.mixed lineage kinase 3 signaling module, activation of JNK3 and its downstream signal molecules. However, the inhibition of ATPA could be prevented by GluK1 antagonist NS3763, GluK1 antisense, and GABA(A) receptor antagonist bicuculline. In addition, ATPA played a neuroprotective role against cerebral ischemia. In sum, the findings indicate that activation of GluK1 by ATPA at specific dosages may promote GABA release, which then suppresses post-synaptic GluK2-JNK3 signaling mediated cerebral ischemic injury via GABA(A)R. PMID- 22516109 TI - Abnormal microglial-neuronal spatial organization in the dorsolateral prefrontal cortex in autism. AB - Microglial activation and alterations in neuron number have been reported in autism. However, it is unknown whether microglial activation in the disorder includes a neuron-directed microglial response that might reflect neuronal dysfunction, or instead indicates a non-directed, pro-activation brain environment. To address this question, we examined microglial and neuronal organization in the dorsolateral prefrontal cortex, a region of pronounced early brain overgrowth in autism, via spatial pattern analysis of 13 male postmortem autism subjects and 9 controls. We report that microglia are more frequently present near neurons in the autism cases at a distance interval of 25 MUm, as well as 75 and 100 MUm. Many interactions are observed between near-distance microglia and neurons that appear to involve encirclement of the neurons by microglial processes. Analysis of a young subject subgroup preliminarily suggests that this alteration may be present from an early age in autism. We additionally observed that neuron-neuron clustering, although normal in cases with autism as a whole, increases with advancing age in autism, suggesting a gradual loss of normal neuronal organization in the disorder. Microglia-microglia organization is normal in autism at all ages, indicating that aberrantly close microglia-neuron association in the disorder is not a result of altered microglial distribution. Our findings confirm that at least some microglial activation in the dorsolateral prefrontal cortex in autism is associated with a neuron-specific reaction, and suggest that neuronal organization may degrade later in life in the disorder. PMID- 22516110 TI - Tail nerve electrical stimulation combined with scar ablation and neural transplantation promotes locomotor recovery in rats with chronically contused spinal cord. AB - To date, few treatment strategies applying cellular transplantation to the chronically injured spinal cord have yielded significant functional improvement in animal experiments. Here we report that significant improvement of locomotor function was achieved in rats with chronic spinal cord injury (SCI) by the application of combination treatments with tail nerve electrical stimulation (TANES), which can activate the central pattern generator, inducing active weight supported stepping. Contusion injury (25 mm) to spinal cord T10 was produced by using the NYU impactor device in female, adult Long-Evans rats. Rats in 2 of 4 groups with SCI received basic treatments (scar ablation followed by transplantation of lamina propria of olfactory mucosa and cultured olfactory ensheathing cells into the lesion cavity) 6 weeks after SCI. Rats both with and without basic treatments were subjected to TANES one week after secondary surgery or 7 weeks after SCI. Sixteen weeks after secondary surgery or 22 weeks after SCI rats in two groups receiving TANES significantly improved their functional recovery compared with those without TANES, when evaluated with BBB open field rating scale (p<0.01). Among them, however, rats with basic treatments performed better than those without basic treatments. TANES may contribute to the activity dependent plasticity below the injury level, which is critical for functional recovery. Additionally, TANES may promote axonal regeneration, including those from supraspinal level. Since TANES demonstrated considerable potential for achieving improvement of functional recovery in rat model, it would suggest a new strategy for chronic SCI. PMID- 22516111 TI - Corrosion protection by sonoelectrodeposited organic films on zinc coated steel. AB - A variety of coatings based on electrosynthesized polypyrrole were deposited on zinc coated steel in presence or absence of ultrasound, and studied in terms of corrosion protection. Cr III and Cr VI commercial passivation were used as references. Depth profiling showed a homogeneous deposit for Cr III, while SEM imaging revealed good surface homogeneity for Cr VI layers. These chromium-based passivations ensured good protection against corrosion. Polypyrrole (PPy) was also electrochemically deposited on zinc coated steel with and without high frequency ultrasound irradiation in aqueous sodium tartrate-molybdate solution. Such PPy coatings act as a physical barrier against corrosive species. PPy electrosynthesized in silent conditions exhibits similar properties to Cr VI passivation with respect to corrosion protection. Ultrasound leads to more compact and more homogeneous surface structures for PPy, as well as to more homogeneous distribution of doping molybdate anions within the film. Far better corrosion protection is exhibited for such sonicated films. PMID- 22516113 TI - Topical propranolol for treatment of superficial infantile hemangiomas. AB - BACKGROUND: "Wait-and-see" is a common principle for most superficial infantile hemangiomas (IHs) because of their expected involution. Topical propranolol has recently been reported to be an effective treatment for superficial IHs. OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of 1% propranolol ointment in the treatment of superficial IHs. METHODS: A retrospective chart review was performed on 25 children (21 female and 4 male) with a median age of 4 months (range, 1-10 months). A total of 28 lesions were treated with 1% propranolol ointment. Topical propranolol was applied thrice daily for a mean duration of 21 weeks (range, 5-59 weeks). Changes in the size, texture, and color of the tumor were monitored and recorded at regular intervals. The treatment response was evaluated using a 3-point scale system: good, partial, and no response. Adverse effects after medication were evaluated and managed accordingly. RESULTS: Of the 28 hemangiomas, 16 (57%) demonstrated good response, 9 (33%) showed a partial response, and 3 (10%) had no response. Among all the IHs, 90% showed either good or partial responses to topical 1% propranolol ointment treatment. No systemic complication was observed in any of the patients. LIMITATIONS: This report is a retrospective uncontrolled study. CONCLUSIONS: Topical therapy with 1% propranolol ointment may be a safe and effective method for the treatment of superficial IHs and can be used as an adjuvant treatment measure during the wait-and-see period. PMID- 22516112 TI - Ultrasound imaging velocimetry of the human vitreous. AB - Knowledge of vitreous motion in response to saccades is a prerequisite for understanding vitreous rheology. Purpose of present paper is to introduce Ultrasound Image Velocimetry of the human eye, measure scleral and vitreous velocity fields and test the reproducibility of the proposed technique. Twelve patients with varying diagnosis underwent Ocular Dynamic Ultrasound; scleral angular velocity (V(S)) was measured by 2 different operators and reproducibility calculated. Squared velocity of the vitreous (E), which is representative of kinetic energy per unit mass, was computed from velocity. The time evolution of the energy of the vitreous was described by its spatial average (E(S)), whereas spatial distribution was described by its time average (E(T)). Peak and average E(S), the ratio K(p) of the peak of the spatially averaged kinetic energy per unit mass to the maximum squared scleral angular velocity, vitreous motion onset time (T(O)) and vitreous motion decay time (T(D)) were also defined. Inter operator reproducibility coefficient was 0.043 and correlation between operators was significant. V(S), peak and average E(S), K(p) ratio and T(D) differed among patients but not among operators. V(S) correlated with E(S) and T(D). E(S) and T(D) but not V(S), were significantly different in patients with Posterior Vitreous Detachment. Patients with retinal detachment showed significantly higher V(S) and E(S). K(p) was inversely correlated to age and refraction. Measures proved accurate and reproducible. E is related to V(S), retinal traction and mechanical stimulation. Identified variables varied with age, refraction pathologic conditions. PMID- 22516114 TI - Theoretical and experimental vibrational study of the phenyl urea herbicide 1-(4 bromo-3-chlorophenyl)-3-methoxy-3-methylurea. AB - FT-Raman and IR spectra of the herbicidal compound chlorbromuron have been recorded and analyzed. The detailed interpretation of the vibrational spectra has been carried out with the aid of normal coordinate analysis (NCA) following the scaled quantum mechanical force field methodology. The various intramolecular interactions which are responsible for the stabilization of the molecule were revealed by natural bond orbital analysis. The Mulliken population analysis on atomic charges and the HOMO-LUMO energy were also calculated. The presence of strong NH?O intermolecular hydrogen bonding was clearly exposed from the IR spectrum by the red shifting of NH stretching wavenumber. PMID- 22516115 TI - Vibrational spectroscopic studies, NLO, HOMO-LUMO and electronic structure calculations of alpha,alpha,alpha-trichlorotoluene using HF and DFT. AB - FT-IR and FT-Raman spectra of alpha,alpha,alpha-trichlorotoluene have been recorded and analyzed. The geometry, fundamental vibrational frequencies are interpreted with the aid of structure optimizations and normal coordinate force field calculations based on density functional theory (DFT) B3LYP/6-311++G(d,p) method and a comparative study between HF level and various basis sets combination. The fundamental vibrational wavenumbers as well as their intensities were calculated and a good agreement between observed and scaled calculated wavenumbers has been achieved. The complete vibrational assignments of wavenumbers are made on the basis of potential energy distribution (PED). The effects due to the substitutions of methyl group and halogen were investigated. The absorption energy and oscillator strength are calculated by time-dependent density functional theory (TD-DFT). The electric dipole moment, polarizability and the first hyperpolarizability values of the alpha,alpha,alpha trichlorotoluene have been calculated. (1)H NMR chemical shifts were calculated by using the gauge independent atomic orbital (GIAO) method with HF and B3LYP methods with 6-311++G(d,p) basis set. Moreover, molecular electrostatic potential (MEP) and thermodynamic properties were performed. Mulliken and natural charges of the title molecule were also calculated and interpreted. PMID- 22516116 TI - Crystal structure, spectra properties and comparative studies on a 2-pyrazoline derivative. AB - A 2-pyrazoline derivation of 1-phenyl-3-(4-methylphenyl)-5-(3,4-dimethyl phenyl) 2-pyrazoline has been characterized by X-ray single crystal diffraction, UV-vis and fluorescence spectroscopy. For the title compound, density functional theory (DFT) calculations of the structure and natural population atomic charge analysis have been performed at B3LYP/6-311G** level of theory. By using TD-DFT method, electron spectra of the title compound have been predicted, which suggest the B3LYP/6-311G** method can approximately simulate the electron spectra for the system presented here. Comparative studies on the title compound with 1-phenyl-3 (4-methylphenyl)-5-phenyl-2-pyrazoline indicate that introducing electron donating groups in 5-phenyl ring of pyrazoline ring influences the peak location and intensity in electronic and fluorescence spectra. PMID- 22516118 TI - Growth, spectroscopy, dielectric and nonlinear optical studies of novel organic NLO crystal: L-Threonine formate. AB - An efficient, novel, organic nonlinear optical (NLO) crystal of L-threonine formate (LTF), with dimensions 15mm*9mm*3mm was grown by slow evaporation technique at ambient temperature. Solubility and metastable zone-width measurements have been carried out for LTF sample. The metastable zone-width studies have been carried out for different cooling rates. The grown crystals were subjected to single crystal X-ray diffraction to determine the unit cell dimensions and morphology. The formation of the new crystal has been confirmed by NMR and mass spectroscopic analysis. The dielectric constant and dielectric loss measurements of the as grown crystal at different temperatures and frequencies of the applied field are measured and reported. The existence of SHG conversion efficiency was measured using an Nd:YAG laser (1064nm). PMID- 22516117 TI - Spectrofluorimetric study of the interaction of ciprofloxacin with amino acids in aqueous solution following solvatochromic studies. AB - Complexation of a fluoroquinolone derivative (ciprofloxacin), L, and some amino acids has been studied using spectrofluorimetric method. Results indicated that ciprofloxacin have a greater tendency to form a 1:1 complex with aspartic acid and arginine than the other tested molecules. The fluorescence of ciprofloxacin exhibits quenching process while it has been titrated with these amino acids. Formation constant values (K(f)) for complex formed between ciprofloxacin and amino acids were also calculated. Thermodynamic parameters such as DeltaG degrees , DeltaH degrees and DeltaS degrees were studied too. Possible reasons for the observed stability sequence were discussed based on the structures proposed for the resulting complexes. Besides the solution studies, solvatochromic properties of the ciprofloxacin are discussed by studying its spectra in a selection of different solvents. PMID- 22516119 TI - Spectral and electrochemical study of host-guest inclusion complex between 2,4 dinitrophenol and beta-cyclodextrin. AB - The formation of host-guest inclusion complex of 2,4-dinitrophenol (2,4-DNP) with nano-hydrophobic cavity of beta-cyclodextrin (beta-CD) in solution phase was studied by UV-visible spectrophotometer and electrochemical method (cyclic voltammetry, CV). The prototropic behaviors of 2,4-DNP with and without beta-CD and the ground state acidity constant (pK(a)) of host-guest inclusion complex (2,4-DNP-beta-CD) were studied. The binding constant of inclusion complex at 303K was calculated using Benesi-Hildebrand plot and thermodynamic parameter (DeltaG) was also calculated. The solid inclusion complex formation between beta-CD and 2,4-DNP was confirmed by (1)H NMR, FT-IR, XRD and SEM analysis. A schematic representation of this inclusion process is proposed by molecular docking studies using PatchDock server. PMID- 22516120 TI - A theoretical study on the molecular structure and vibrational (FT-IR and Raman) spectra of cyano-bridged heteronuclear polymeric complex of triethylenetetramine. AB - The cyano bridged complex of triethylenetetramine was characterized by FT-IR, Raman spectroscopy and X-ray single crystal diffraction analysis. The molecular geometry and vibrational frequencies of the complex in the ground state have been calculated by using B3LYP density functional method with LANL2DZ basis set. A good correlation was found via comparison of the experimental and theoretical vibrational frequencies of complex. The complex of the type [Zn(teta)Ni(MU CN)(2)(CN)(2)](n) has been studied in the 4000-250cm(-1) region and assignment of all the observed bands were made. The analysis of the FT-IR and Raman spectra indicates that there are some structure spectra correlations. PMID- 22516121 TI - Theoretical and experimental investigation of the oxidized and oxygenated forms of pyrocatechuic acid (2,3-dihydroxybenzoic acid). AB - The catecholic derivative 2,3-dihydroxybenzoic acid (2,3-DHBA or pyrocatechuic acid) represents a diversity of actions in enzymatic processes. In the present study DFT calculations (at the B3LYP/TZVP level of theory) have been performed for neutral 2,3DHBA and its dimer (models 1-1a), several semiquinone forms of 2,3 DHBA, namely the neutral (models 2-4), the monoionized (models 5-7), the di ionized (models 8) and the dimer 7a. The more stable species in each case are those with the carboxyl group protonated. Oxygenated adducts were also constructed (models 10-15) in which the dioxygen is either H-bonded to the catecholic or carboxylic hydrogen or it is concerned to act on the intradiol or extradiol carbon atoms. The side-on placement of O(2) on C(2) facilitates the intradiol C-C cleavage. Protonation of the oxygenated on C(1) adduct leads to decarboxylation of 2,3-DHBA. Isolation in the solid state and characterization by ESMS, IR, NMR, electronic spectra of the blue-green oxidized product of 2,3-DHBA (solid 1) supports the possibility of the existence of the semiquinone form or the hydroperoxide-adduct. Experimental spectroscopic data are correlated to the calculated spectroscopic parameters. In the ESMS the decarboxylation and degradation products as well a peroxo-adduct have been detected. Oxygenated species may also account for the plethora of redox signals in the cyclic voltammograms of solid 1 (in DMSO solutions). PMID- 22516122 TI - Study on Tb3+ containing high silica and low silica calcium aluminate glasses: Impact of optical basicity. AB - Two series of glasses based on high silica (CAS) and low silica calcium aluminates (LSCA) have been investigated for their structural, optical and Tb(3+) luminescence properties. The compositional modification reduces host phonon energy in LSCA glasses. Still, LSCA glasses exhibit Tb(3+) green luminescence quenching, whereas no quenching observed in CAS glasses. Material property influence on this behaviour has been discussed with an insight into the redox state of active ions. PMID- 22516123 TI - Following 18O uptake in scCO2-H2O mixtures with Raman spectroscopy. AB - The uptake of (18)O by scC(16)O(2) in mixtures containing liquid H(2)(18)O was followed with Raman spectroscopy using a specially designed high-pressure optical cell. Characteristic bands from the C(16)O(18)O and C(18)O(2) molecules were identified in the supercritical phase and measured in the spectra as a function of time after introducing the liquid H(2)(18)O into the scC(16)O(2). Temporal dependence indicated the process was diffusion-limited in our cell for both C(16)O(18)O and C(18)O(2). The ratio of concentrations of the (18)O-labeled CO(2) molecules, C(18)O(2)/C(16)O(18)O, was much higher than a random distribution of the isotopes for the system expected at equilibrium. The results are consistent with previous studies showing both rapid kinetics for oxygen exchange in aqueous solutions and the role of CO(2) transport at liquid water interfaces. More importantly, they demonstrate the potential for using Raman spectroscopy with (18)O isotopic labeling in scCO(2) reaction studies with the recently determined frequency and intensity characteristics of the Fermi dyad peaks from (18)O containing CO(2) molecules. PMID- 22516124 TI - Single stranded helical chains of C-H?pi interactions further connected by halogen-halogen interactions of type I to construct supramolecular structure of (E)-5-(diethylamino)-2-[(4-iodophenylimino)methyl]phenol compound. AB - In this study, (E)-5-(diethylamino)-2-[(4-iodophenylimino)methyl]phenol compound was investigated from the point of stacking interactions assembling the supramolecular network, conformational isomerism and tautomerism. For this purpose, X-ray diffraction, FT-IR and UV/Vis spectroscopic techniques were used, giving the following structural and spectroscopic properties of the compound: The title compound has two conformers (anti and eclipsed) in the crystal structure resulting from rotation about C-N single bond of ethyl group. Both conformers prefer enol form in the solid state, adopting E configuration about the CN double bond. The supramolecular architecture of the compound is constructed by two non covalent interactions as C-H?pi and halogen-halogen interactions. The repetition of C-H?pi interactions is resulted in a single-stranded helical structure. The helical structures are further connected by C-I?I-C interactions of Type I to construct the two dimensional supramolecular network defined as (6,3)-net in Wells nomenclature. The title compound adopts both enol and keto forms in EtOH (a polar and protic solvent) while enol form is preferred in the solid state. PMID- 22516125 TI - DFT/TD-DFT study of the spin transition complex [Fe(pmea)(NCS)2]. AB - The spin crossover (SCO) compound [Fe(pmea)(NCS)(2)] (where pmea symbolizes the ligand bis[(2-pyridyl)methyl]-2-(2-pyridyl)ethylamine) has been studied by DFT/TD DFT methods. Several density functionals and basis sets were used in the calculations to obtain optimized geometries of the compound in the low-(LS), intermediate-(IS) and high-spin (HS) states. The vibrational modes and IR spectra, spin splittings energies, excited states and UV/vis absorption spectra were calculated. From the TD-DFT calculations, it can be inferred that this complex may act as a reversible optical switch via the LIESST effect and its reverse process. PMID- 22516126 TI - Solvatochromic behavior of the electronic absorption spectra of gallic acid and some of its azo derivatives. AB - The electronic absorption spectra of gallic acid and its azo derivatives have been studied in various solvents of different polarities. Multiple regression techniques were applied to calculate the regression and correlation coefficients based on an equation that relates the wavenumbers of the absorption band maxima (upsilon(max)(-)) to the solvent parameters; refractive index (n), dielectric constant (D), empirical Kamlet-Taft solvent parameters, pi*(dipolarity/polarizability), alpha (solvent hydrogen-bond donor acidity) and beta (solvent hydrogen-bond acceptor basicity). The fitting coefficient obtained from this analysis allows estimating the contribution of each type of interactions relative to total spectral shifts in solution. The dependence of upsilon(max)(-) on the solvent parameters indicates that the obtained bands are affected by specific and non-specific solute-solvent interactions. PMID- 22516127 TI - The experience of rural midwives in dual roles as nurse and midwife: "I'd prefer midwifery but I chose to live here". AB - OBJECTIVE: To explore and describe the experiences of working in the dual role as nurse and midwife in rural areas of far north Queensland, Australia. METHOD: The methodology was informed by Heidegger's interpretive phenomenological philosophy and data analysis was guided by van Manen's analytical approach. Data was generated by conversational interviews. Eight midwives working in a dual role as midwife and nurse were interviewed individually. FINDINGS: Three themes were identified: Making choices between professional role and lifestyle: "Because I choose to live here"; Integration of maternity and general nursing: "All in together this fine weather" and: "That's part of working in a small place". CONCLUSION: Participants recognized that in rural areas it is important to be a multi-skilled generalist; however they were concerned that midwifery skills could be eroded or even lost with the diminishing amounts of midwifery work available. Appropriate re-structuring of maternity services could provide better use of the midwifery workforce in rural centres, and reduce the current problems associated with transferring birthing mothers to larger facilities. Further research is needed to examine the extent to which the requirement to work in a dual, or multifaceted role is an impediment to the recruitment and retention of midwives to rural areas. PMID- 22516128 TI - Comparative effectiveness of antibiotics for uncomplicated urinary tract infections: network meta-analysis of randomized trials. AB - BACKGROUND: The efficacies and adverse effects of different antibiotics for uncomplicated urinary tract infections (UTIs) have been studied by standard meta analytic methods using pairwise direct comparisons of antimicrobial treatments: the effects of one treatment are compared to those of either another treatment or placebo. However, for clinical decisions, we need to know the effectiveness of each possible treatment in comparison with all relevant alternatives, not with just one. OBJECTIVES: To compare the efficacies and adverse effects of all relevant antibiotics for UTI treatment simultaneously by performing a network meta-analysis using direct and indirect treatment comparisons. METHODS: Using logistic regression analysis, we performed a network meta-analysis of randomized controlled trials (RCTs) published after 1999 that compared different oral antibiotic or placebo regimens for UTI treatment in general practice or outpatient settings. We looked at five binary outcomes: early clinical, early bacteriological, late clinical and late bacteriological outcomes, as well as adverse effects. Consequently, a ranking of the antibiotic regimens could be composed. RESULTS: Using a network structure, we could compare and rank nine treatments from 10 studies. Overall, ciprofloxacin and gatifloxacin appeared the most effective treatments, and amoxicillin-clavulanate appeared the least effective treatment. In terms of adverse effects, there were no significant differences. DISCUSSION: Network meta-analysis shows some clear efficacy differences between different antibiotic treatments for UTI in women. It provides a useful tool for clinical decision making in everyday practice. Moreover, the method can be used for meta-analyses of RCTs across primary care and beyond. PMID- 22516129 TI - Characterization of coagulase-negative staphylococci isolated from hospital indoor air and a comparative analysis between airborne and inpatient isolates of Staphylococcus epidermidis. AB - A total of 108 coagulase-negative staphylococci (CoNS) were collected from hospital indoor air. The majority of the isolates were able to produce biofilms and displayed multiresistance profiles. The most frequent species identified were Staphylococcus epidermidis (n=27) and Staphylococcus haemolyticus (n=17). Potential virulence traits (icaAD, aap, hld, atlE and sesB) and genotypic profiles were compared for S. epidermidis isolates from indoor air (n=27) and from patients (n=26) who had been admitted to the hospital 8-34 months after air sampling. Overall, the virulence factors tested were more frequently found among S. epidermidis recovered from clinical origin than from air sources (P=0.003). Indeed, the group of patient isolates exhibited superior ability to accumulate biofilms (P<0.0001). Despite this, genotyping using PFGE revealed that identical clones of S. epidermidis could be recovered from both patient and indoor air samples. In addition, some airborne isolates displayed virulence profiles and levels of biofilm accumulation similar to those found in patient isolates. Therefore, further studies are necessary to clarify the importance of hospital indoor air as a route of transmission for CoNS isolates (mainly S. epidermidis). PMID- 22516130 TI - Quantitative expression of cholera toxin mRNA in Vibrio cholerae isolates with different CTX cassette arrangements. AB - Cholera toxin (CT) is the major virulence factor produced by Vibrio cholerae. Several genomic arrangements within the CTX cassette have been elucidated in V. cholerae. Previously, it was shown that three different CTX cassette arrangements, one complete CTX cassette (arrangement A), one complete and two incomplete CTX cassettes (arrangement B), and two complete CTX cassettes (arrangement C), exist within V. cholerae isolates. In the present study, the level of CT expression by V. cholerae isolates carrying different CTX cassette arrangements was evaluated. Real-time quantitative PCR analysis showed unequal production of CT mRNA in V. cholerae isolates with different CTX arrangements. V. cholerae with the CTX arrangement C expressed more CT mRNA than isolates with the other CTX arrangements. In addition, CT mRNA was expressed more in the isolates with CTX arrangement B than in those with arrangement A. Overall, these results suggest that the arrangement and number of regulatory elements (rstA) within the CTX cassette could affect the level of expression of CT. PMID- 22516131 TI - Chelating agents exert distinct effects on biofilm formation in Staphylococcus aureus depending on strain background: role for clumping factor B. AB - Staphylococcus aureus is a leading cause of catheter infections, and biofilm formation plays a key role in the pathogenesis. Metal ion chelators inhibit bacterial biofilm formation and viability, making them attractive candidates as components in catheter lock solutions. The goal of this study was to characterize further the effect of chelators on biofilm formation. The effect of the calcium chelators ethylene glycol tetraacetic acid (EGTA) and trisodium citrate (TSC) on biofilm formation by 30 S. aureus strains was tested. The response to subinhibitory doses of EGTA and TSC varied dramatically depending on strain variation. In some strains, the chelators prevented biofilm formation, in others they had no effect, and they actually enhanced biofilm formation in others. The molecular basis for this phenotypic variability was investigated using two related strains: Newman, in which biofilm formation was inhibited by chelators, and 10833, which formed strong biofilms in the presence of chelators. It was found that deletion of the gene encoding the surface adhesin clumping factor B (clfB) completely eliminated chelator-induced biofilm formation in strain 10833. The role of ClfB in biofilm formation activity in chelators was confirmed in additional strains. It was concluded that biofilm-forming ability varies strikingly depending on strain background, and that ClfB is involved in biofilm formation in the presence EGTA and citrate. These results suggest that subinhibitory doses of chelating agents in catheter lock solutions may actually augment biofilm formation in certain strains of S. aureus, and emphasize the importance of using these agents appropriately so that inhibitory doses are achieved consistently. PMID- 22516132 TI - Pulmonary Actinomyces graevenitzii infection presenting as organizing pneumonia diagnosed by PCR analysis. AB - We report what is believed to be the first case of pulmonary Actinomyces graevenitzii infection presenting as organizing pneumonia. Fever and night sweats developed in a 69-year-old male. The only abnormal laboratory data were an elevated erythrocyte sedimentation rate and C-reactive protein level. On chest images, multiple consolidations with air bronchograms were seen in the bilateral lungs. Histological examination from lung biopsy revealed a pattern of organizing pneumonia with microabscesses, but definitive diagnosis was not obtained because culture from lung specimen was negative. A. graevenitzii was eventually identified in the lung biopsy specimen by detection of an Actinomyces-specific PCR product followed by 16S rRNA gene sequencing. The patient was treated with high-dose ampicillin intravenously for 1 month, followed by oral amoxicillin and clarithromycin for 6 months, and recovered. We suggest that actinomycosis can present as organizing pneumonia, and identification of infection by PCR analysis and rRNA gene sequencing is a useful strategy in cases that are difficult to diagnose. PMID- 22516133 TI - Rising incidence of Pneumocystis jirovecii pneumonia suggests iatrogenic exposure of immune-compromised patients may be becoming a significant problem. AB - Against a background of point-source outbreaks of Pneumocystis pneumonia (PCP) in renal transplant units in Europe, we undertook a retrospective 3 year observational review of PCP in Northern Ireland. This showed an unexpected increase in incidence, with a mortality rate of 30 %. Fifty-one cases were confirmed compared to 10 cases confirmed in the preceding 7 years. Where undiagnosed HIV infection had previously been the main risk factor for PCP, this was now equally matched by chemotherapy for haematological and non-haematological malignancy and immune suppression for a range of autoimmune conditions. Congenital immunodeficiency and transplantation were less common predisposing factors, but renal grafts also showed a rising incidence. Asymptomatic carriage was uncommon. At presentation both upper and lower respiratory samples were of equal use in establishing the diagnosis, and treatment resulted in rapid clearance. These data suggest the need for considering PCP in at-risk patients, reviewing its mode of acquisition and whether iatrogenic colonization is a treatable pre-condition. PMID- 22516134 TI - Recent developments in bacterial protein glycan coupling technology and glycoconjugate vaccine design. AB - The discovery of the Campylobacter jejuni N-linked glycosylation system combined with its functional expression in Escherichia coli marked the dawn of a new era in glycoengineering. The process, termed protein glycan coupling technology (PGCT), has, in particular, been applied to the development of glycoconjugate vaccines. In this review, we highlight recent technical developments in this area, including the first structural determination of the coupling enzyme PglB, the use of glycotags for optimal glycan attachment and the possible applications of other glycosylation systems and how these may improve and extend PGCT. PMID- 22516135 TI - Assessment of a real-time PCR for the detection and characterization of verocytotoxigenic Escherichia coli. AB - The European Union Reference Laboratory (EU-RL) has produced guidelines for a real-time PCR for the detection of verocytotoxigenic Escherichia coli (VTEC). In this study, we validated the EU-RL assay on 545 strains of VTEC and evaluated the utility of the assay for the detection of VTEC from stool specimens. The validation study on cultures showed that the EU-RL VTEC PCR was 99.3% sensitive for the detection of vtx genes; only strains harbouring vtx2f genes were not detected. The assay was 100% sensitive and 100% specific for the detection of both the eae and O157 rfbE genes. In a prospective study involving 500 stool samples, the EU-RL VTEC PCR detected vtx genes in 12.4% of specimens, compared to 3.8% specimens found to be culture-positive for E. coli O157 using the Health Protection Agency national standard culture method. This study showed that the EU RL VTEC assay was reliable and robust, and an effective rapid screening method for the detection of VTEC from stool specimens. PMID- 22516136 TI - Oral administration of paclitaxel with pegylated poly(anhydride) nanoparticles: permeability and pharmacokinetic study. AB - The aim of this work was to study the potential of pegylated poly(anhydride) nanoparticles as carriers for the oral delivery of paclitaxel (PTX). Paclitaxel is an anticancer drug, ascribed to the class IV of the Biopharmaceutical Classification system, characterised for its low aqueous solubility and to act as a substrate of the P-glycoprotein and cytochrome P450. For the pegylation of nanoparticles, three different poly(ethylene glycol) (PEG) were used: PEG 2000 (PTX-NP2), PEG 6000 (PTX-NP6) and PEG 10,000 (PTX-NP10). The transport and permeability of paclitaxel through the jejunum mucosa of rats was determined in Ussing chambers, whereas its oral bioavailability was studied in rats. The loading of PTX in pegylated nanoparticles increased between 3 and 7 times the intestinal permeability of paclitaxel through the jejunum compared with the commercial formulation Taxol. Interestingly, the permeability of PTX was significantly higher for PTX-NP2 and PTX-NP6 than for PTX-NP10. In the in vivo studies, similar results were obtained. When PTX-NP2 and PTX-NP6 were administered to rats by the oral route, sustained and therapeutic plasma levels of paclitaxel for at least 48 h were observed. The relative oral bioavailability of paclitaxel delivered in nanoparticles was calculated to be 70% for PTX-NP2, 40% for PTX-NP6 and 16% in case of PTX-NP10. All of these observations would be related with both the bioadhesive properties of these carriers and the inhibitory effect of PEG on the activity of both P-gp and P450 cytochrome. PMID- 22516139 TI - Elucidating second coordination sphere effects in heme proteins using low temperature magnetic circular dichroism spectroscopy. AB - This paper reviews recent findings on how the second coordination sphere of heme proteins fine-tunes the properties of the heme active site via hydrogen bonding. This insight is obtained from low-temperature magnetic circular dichroism (MCD) spectroscopy. In the case of high-spin ferric hemes, MCD spectroscopy allows for the identification of a multitude of charge-transfer (CT) transitions. Using optically-detected magnetic saturation curves, out-of-plane polarized CT transitions between the heme and its axial ligand(s) can be identified. In the case of ferric Cytochrome P450cam, the corresponding S(sigma)->Fe(III) CT transition can be used as a probe for the {Fe(III)-axial ligand} interaction, indicating that the hydrogen bonding network of the proximal Cys only plays a limited role for fine-tuning the Fe(III)-S(Cys) interaction. In the case of high spin ferrous hemes with axial His/imidazole coordination, our MCD-spectroscopic investigations have uncovered a direct correlation between the strength of the hydrogen bond to the proximal imidazole ligand and the ground state of the complexes. With neutral imidazole coordination, the doubly occupied d-orbital of high-spin iron(II) is of d(pi) character, located orthogonal to the heme plane. As the strength of the hydrogen bond increases, this orbital rotates into the heme plane, changing the ground state of the complex. PMID- 22516137 TI - The VP1 subunit of JC polyomavirus recapitulates early events in viral trafficking and is a novel tool to study polyomavirus entry. AB - JC polyomavirus (JCV) is an important human pathogen that causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). In this study we further delineate the early events of JCV entry in human glial cells and demonstrate that a pentameric subunit of the viral capsid is able to recapitulate early events in viral trafficking. We show that JCV traffics to the endoplasmic reticulum (ER) by 6h post infection, and that VP1 pentamers arrive at the ER with similar kinetics. Further, this JCV localization to the ER is critical for infection, as treatment of cells with agents that prevent ER trafficking, ER function, or ER quality control reduce JCV infectivity. These pentamers represent a new tool to study polyomavirus entry, and will be particularly useful in studying recently identified polyomaviruses that are difficult to propagate. PMID- 22516138 TI - Disulfide-bond formation by a single cysteine mutation in adenovirus protein VI impairs capsid release and membrane lysis. AB - The internal capsid protein VI mediates adenovirus (AdV) endosome penetration during cell entry. Essential to this process is the release of protein VI from the AdV capsid and subsequent membrane targeting and insertion by the liberated VI molecules within the endocytic vesicle. In this study, we describe a human AdV (HAdV) substitution mutant (AdV VI-G48C) within the critical N-terminal amphipathic alpha-helical domain of protein VI. The VI-G48C virus displays altered capsid stability that impacts protein VI release, membrane disruption and virus infectivity. This is due in part to aberrant disulfide-bonding of protein VI molecules within the AdV particle. Our results provide insight into the structural organization of protein VI in the virus particle, as well as highlight the role of protein VI in cell entry. PMID- 22516140 TI - Ventriculoatrial conduction in complete atrioventricular block. AB - The case of a patient with complete atrioventricular block with capability of rapid ventriculoatrial conduction with unusual behavior is presented. Potential mechanisms are discussed. PMID- 22516141 TI - Hypothermia masquerading as pericarditis: an unusual electrocardiographic analogy. AB - Hypothermia is one of the most common environmental emergencies encountered by physicians that can be associated with a variety of electrocardiographic (ECG) abnormalities. The classic and well-known ECG manifestations of hypothermia include the presence of J (Osborne) waves, interval (PR, QRS, QT) prolongation, varied T-wave abnormalities, and atrial and ventricular arrhythmias. There are less well-defined and known ECG signs of hypothermia that, in fact, may simulate findings of acute coronary ischemia. We describe a case of hypothermia with associated ECG findings mimicking pericarditis. Especially interesting was the challenging presentation and several associated important learning points. Herewith, we also discuss some important ECG and clinical factors that may be used in differentiating the genesis of ST elevations. PMID- 22516142 TI - Implantable enzyme amperometric biosensors. AB - The implantable enzyme amperometric biosensor continues as the dominant in vivo format for the detection, monitoring and reporting of biochemical analytes related to a wide range of pathologies. Widely used in animal studies, there is increasing emphasis on their use in diabetes care and management, the management of trauma-associated hemorrhage and in critical care monitoring by intensivists in the ICU. These frontier opportunities demand continuous indwelling performance for up to several years, well in excess of the currently approved seven days. This review outlines the many challenges to successful deployment of chronically implantable amperometric enzyme biosensors and emphasizes the emerging technological approaches in their continued development. The foreign body response plays a prominent role in implantable biotransducer failure. Topics considering the approaches to mitigate the inflammatory response, use of biomimetic chemistries, nanostructured topographies, drug eluting constructs, and tissue-to-device interface modulus matching are reviewed. Similarly, factors that influence biotransducer performance such as enzyme stability, substrate interference, mediator selection and calibration are reviewed. For the biosensor system, the opportunities and challenges of integration, guided by footprint requirements, the limitations of mixed signal electronics, and power requirements, has produced three systems approaches. The potential is great. However, integration along the multiple length scales needed to address fundamental issues and integration across the diverse disciplines needed to achieve success of these highly integrated systems, continues to be a challenge in the development and deployment of implantable amperometric enzyme biosensor systems. PMID- 22516143 TI - What is the best method for estimating the burden of severe sepsis in the United States? AB - PURPOSE: The aim of the study was to compare estimates of hospitalizations, outcomes, and costs produced by 2 approaches for defining severe sepsis. METHODS: We used the Nationwide Inpatient Sample to study adults hospitalized in the United States in 2007. We defined severe sepsis using 2 previously published algorithms: (1) the presence of a principal or secondary diagnosis of septicemia combined with organ dysfunction or (2) the presence of a principal or secondary diagnosis of septicemia or another infection (eg, pneumonia) combined with organ dysfunction. For each approach, we calculated the weighted frequency of hospitalizations, population-based mortality rates, and geometric mean costs. RESULTS: A total of 719099 (SD, 16676) hospitalizations had a diagnosis of septicemia and a diagnosis of organ dysfunction. A total of 2.5 million hospitalizations were recorded, with a diagnosis code for either septicemia or infection combined with a diagnosis code for organ dysfunction. Hospitalizations without a diagnosis code for septicemia had lower rates of respiratory failure (35% vs 51%, P < .001) or shock (20% vs 46%, P < .001), lower in-hospital mortality (8% vs 29%, P < .001), and lower mean costs. CONCLUSIONS: An approach that requires a diagnosis code for septicemia and a diagnosis code for organ dysfunction yields estimates of disease burden and outcomes that are more consistent with chart-based studies. PMID- 22516144 TI - Exposure keratopathy in sedated and ventilated patients. AB - PURPOSE: The purpose of this study is to determine the frequency of exposure keratopathy in sedated/mechanically ventilated patients in the intensive care unit and its risk factors. MATERIALS AND METHODS: This is a prospective cohort study including all patients admitted to an adult intensive care unit department between March and October 2010 who were sedated and mechanically ventilated. Patients were examined by an ophthalmologist 1 to 5 days after commencing ventilation and subsequently every day. Examination included assessment of lid position, conjunctival edema (chemosis), and corneal changes. RESULTS: Of the 74 patients included in the study, 57% had exposure keratopathy. Fifty-four percent of patients developed chemosis, and 31% of patients developed lagophthalmos. Frequency of exposure keratopathy differed significantly according to degree of chemosis and lagophthalmos (P < .0001); lagophthalmos was also significantly related to chemosis (P < .0001). For lagophthalmos score of 3, the odds ratio of association with higher exposure keratopathy score was 136 (95% confidence interval [CI], 14.97-1242.6); for lagophthalmos score of 2, it was 14.4 (95% CI, 2.67-77.2). For any edema, the odds ratio of association with exposure keratopathy was 5.50 (95% CI, 2.02-15.00). CONCLUSION: The frequency of exposure keratopathy in sedated/mechanically ventilated patients is high with lagophthalmos and chemosis as the main risk factors. PMID- 22516145 TI - The role of craving in AUDs: dimensionality and Differential Functioning in the DSM-5. AB - BACKGROUND: The dimensionality and the contribution of the proposed diagnostic criteria for the DSM-5 model of alcohol-use disorders (AUDs) which will provide guidelines for future diagnoses have not been examined in depth. METHOD: Data from past year drinkers in the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), Wave 2 (n=22 177) were analysed. Severity and discrimination of DSM-5 diagnostic criteria was determined using a two-parameter logistic Item Response Theory model. Comparative analyses were conducted on the DSM-IV criteria. Differential functioning of the criteria across a number of socio-demographic variables was assessed. RESULTS: The proposed criteria supported a unidimensional AUD model, with a factor loading range of 0.625-0.914 (craving=0.818). The model measured intermediate severity of AUDs with 'reduced time on important/pleasurable activities' and 'failure to meet major role obligations' criteria having the highest severity and discrimination. Craving, endorsed by 4.2% of the general population, was in the mid-range for both severity (sixth) and discrimination (seventh). Significant measurement bias was found on four criteria across socio-demographic subgroups. CONCLUSIONS: Application of the proposed DSM-5 changes yields an improved one-factor model of AUD over the existing DSM-IV model. Inclusion of a craving criterion improves the application of the diagnostic criteria in a general population sample, covering a previously unrepresented problem area. Additionally, criteria measuring the milder end of the AUD continuum remain absent and some criteria exhibit measurement non-invariance. The AUD classification may require further refinement to enhance validity and reliability. PMID- 22516146 TI - Changes in drinking behavior among control group participants in early intervention studies targeting unhealthy alcohol use recruited in general hospitals and general practices. AB - BACKGROUND: This study aims to analyze the influence of setting variables on drinking behavior in patients with unhealthy alcohol consumption recruited proactively in general medical practices (GP) and internal and surgical wards of two general hospitals (GH) assigned to control groups. METHOD: This analysis compared two control groups of RCTs targeting unhealthy alcohol consumption: one outpatient sample (GP; n=99) with one inpatient sample (GH; n=173). Both groups were recruited via systematic screening of all patients aged between 18 and 64 years and were included in the studies if drank above the at-risk criteria of the British Medical Association (20/30 g alcohol/daily) and/or fulfilled criteria of alcohol abuse or - dependence according to DSM-IV. Both samples received a non alcohol specific brochure on healthy living after study inclusion and were re assessed 12 months later. RESULTS: GH patients were significantly older, included of more males, had received less schooling and had a higher readiness to change at baseline than GP patients. Groups did not differ concerning alcohol-related diagnoses or smoking status. At the 12-month follow-up, significantly more GH patients revealed abstinence or drinking below the inclusion criteria (50.0% vs. 26.1%, p<.001). In a multivariate analysis, medical setting (GH vs. GP) remained a significant predictor for non-problematic drinking or abstinence even after controlling for baseline differences between groups. CONCLUSIONS: Findings suggest that untreated change from problematic alcohol use may be more intense after non-alcohol-related inpatient treatment than after having been a GP patient. Implications for brief interventions in inpatients are discussed. PMID- 22516147 TI - The validity of the 16-item version of the Prodromal Questionnaire (PQ-16) to screen for ultra high risk of developing psychosis in the general help-seeking population. AB - In order to bring about implementation of routine screening for psychosis risk, a brief version of the Prodromal Questionnaire (PQ; Loewy et al., 2005) was developed and tested in a general help-seeking population. We assessed a consecutive patient sample of 3533 young adults who were help-seeking for nonpsychotic disorders at the secondary mental health services in The Hague with the PQ. We performed logistic regression analyses and CHi-squared Automatic Interaction Detector decision tree analysis to shorten the original 92 items. Receiver operating characteristic curves were used to examine the psychometric properties of the PQ-16. In the general help-seeking population, a cutoff score of 6 or more positively answered items on the 16-item version of the PQ produced correct classification of Comprehensive Assessment of At-Risk Mental State (Yung et al., 2005) psychosis risk/clinical psychosis in 44% of the cases, distinguishing Comprehensive Assessment of At-Risk Mental States (CAARMS) diagnosis from no CAARMS diagnosis with high sensitivity (87%) and specificity (87%). These results were comparable to the PQ-92. The PQ-16 is a good self report screen for use in secondary mental health care services to select subjects for interviewing for psychosis risk. The low number of items makes it quite appropriate for screening large help-seeking populations, thus enhancing the feasibility of detection and treatment of ultra high-risk patients in routine mental health services. PMID- 22516148 TI - Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. AB - Gluten can cause extraintestinal manifestations with or without gastrointestinal symptoms and elevated antitissue transglutaminase 2 (tTG2) autoantibodies. Organ specific gluten reaction involves immune response toward other transglutaminase (TG) isoforms including tTG3 (expressed in the skin, leading to dermatitis herpetiformis) and tTG6 (expressed in the brain, causing gluten ataxia). This analysis focuses on tTG6 antibodies, which have never been studied before in schizophrenia (SZ) and its relationships to tTG2 and to antigliadin antibodies. We previously showed an increased prevalence of tTG2 antibodies in gluten sensitive SZ patients compared with healthy controls (HC) that was not paralleled by an increased prevalence of antiendomysial antibody. To elucidate this discrepancy, we examined those tTG2 positive SZ patients for the presence of tTG6 antibody. We also searched for tTG6 antibodies in our sample of antigliadin (AGA) positive and AGA and tTG2 negative SZ patients. Seventy-four tTG2 positive SZ patients were compared with 148 age and gender-matched HC. Of the 74 tTG2 positive SZ patients, 16 were positive for tTG6 IgA for a prevalence of 22%. Only 4 HC were positive for tTG6 IgA for a prevalence of 2.7%. Among the AGA positive SZ patients, the prevalence of tTG6 IgA was 21.3% while 13.1% of the AGA and tTG2 negative SZ patients were positive for tTG6 IgA. The HC had a prevalence of 6%. Our results indicate a higher prevalence of tTG6 antibodies in SZ that may represent a biomarker useful to identify SZ patients who would benefit from a gluten-free diet. PMID- 22516149 TI - Making meaning. PMID- 22516150 TI - Glaucoma filtration surgery: trabeculectomy or tube shunt? PMID- 22516151 TI - Corneal collagen cross-linking with riboflavin and ultraviolet-A irradiation in patients with thin corneas. PMID- 22516154 TI - Ocular surface disease and quality of life in patients with glaucoma. PMID- 22516155 TI - Combined intravitreal ranibizumab and photodynamic therapy for retinal angiomatous proliferation. PMID- 22516157 TI - Intralesional triamcinolone acetonide injection versus incision and curettage for primary chalazia: a prospective, randomized study. PMID- 22516159 TI - Keratocyte density 3 months, 15 months, and 3 years after corneal surface ablation with mitomycin C. PMID- 22516161 TI - Prophylactic selective laser trabeculoplasty in the prevention of intraocular pressure elevation after intravitreal triamcinolone acetonide injection. PMID- 22516162 TI - Aqueous humor levels of vascular endothelial growth factor before and after intravitreal bevacizumab in type 3 versus type 1 and 2 neovascularization: a prospective, case-control study. PMID- 22516165 TI - Antibiotic use and antimicrobial resistance. PMID- 22516167 TI - Novel set of vectorcardiographic parameters for the identification of ischemic patients. AB - New signal processing techniques have enabled the use of the vectorcardiogram (VCG) for the detection of cardiac ischemia. Thus, we studied this signal during ventricular depolarization in 80 ischemic patients, before undergoing angioplasty, and 52 healthy subjects with the objective of evaluating the vectorcardiographic difference between both groups so leading to their subsequent classification. For that matter, seven QRS-loop parameters were analyzed, i.e.: (a) Maximum Vector Magnitude; (b) Volume; (c) Planar Area; (d) Maximum Distance between Centroid and Loop; (e) Angle between XY and Optimum Plane; (f) Perimeter and, (g) Area-Perimeter Ratio. For comparison, the conventional ST-Vector Magnitude (ST(VM)) was also calculated. Results indicate that several vectorcardiographic parameters show significant differences between healthy and ischemic subjects. The identification of ischemic patients via discriminant analysis using ST(VM) produced 73.2% Sensitivity (Sens) and 73.9% Specificity (Spec). In our study, the QRS-loop parameter with the best global performance was Volume, which achieved Sens=64.5% and Spec=74.6%. However, when all QRS-loop parameters and ST(VM) were combined, we obtained Sens=88.5% and Spec=92.1%. In conclusion, QRS loop parameters can be accepted as a complement to conventional ST(VM) analysis in the identification of ischemic patients. PMID- 22516168 TI - Quantification of glucose, xylose, arabinose, furfural, and HMF in corncob hydrolysate by HPLC-PDA-ELSD. AB - Lignocellulose and other carbohydrates are being studied extensively as potential renewable carbon sources for liquid biofuels and other valuable chemicals. In the present study, a simple, sensitive, selective, and reliable HPLC method using a photodiode array (PDA) detector and an evaporative light scattering detector (ELSD) was developed for the simultaneous determination of important sugars (D(+) cellobiose, glucose, xylose, and arabinose), furfural and 5-hydroxymethylfurfural (5-HMF) in lignocellulose hydrolysate. The analysis was carried out on an Aminex HPX-87H column (250 mm * 4.6 mm, 5 MUm particle size). Ultra-pure water with 0.00035 M H(2)SO(4) was used as the mobile phase with a flow rate of 0.6 mL/min. The temperature of the ELSD drift tube was kept at 50 degrees C, the carrier gas pressure was 350 kPa, and the gain was set at 7. Furfural and 5-HMF were quantified on a PDA detector at 275 nm and 284 nm, respectively. The sugar concentrations were determined by ELSD. This method was validated for accuracy and precision. The regression equation revealed a good linear relationship (r(2) = 0.9986 +/- 0.0012) within the test ranges. The method showed good reproducibility for the quantification of six analytes in corncob hydrolysate, with intra- and inter-day variations less than 1.12%. This method is also convenient because it allows the rapid analysis of the primary products of biomass hydrolysis and carbohydrate degradation. PMID- 22516169 TI - Guidelines for preventing catheter infection: assessment of knowledge and practice among paediatric and neonatal intensive care healthcare workers. AB - We analysed knowledge of and adherence to guidelines for the prevention of catheter-related infection (CRI) among Spanish healthcare workers (HCWs) from paediatric and neonatal intensive care units by distributing 357 questionnaires to 31 Spanish hospitals. The overall mean scores for individual knowledge and daily practice were 5.61 and 5.78, respectively. Our results reveal room for improvement in Spanish HCWs' knowledge of prevention of CRI. Continuing education programmes and implementation of care bundles must be introduced to improve prevention and management of CRI. PMID- 22516170 TI - Hepatitis E virus infection among solid organ transplant recipients, the Netherlands. AB - We screened 1,200 living heart, lung, liver, and kidney transplant recipients for hepatitis E virus infection by reverse transcription PCR. In 12 (1%) patients, hepatitis E virus infection was identified; in 11 patients, chronic infection developed. This immunocompromised population is at risk for hepatitis E virus infection. PMID- 22516171 TI - Helicobacter pylori infection and nonsteroidal anti-inflammatory drug use: eradication, acid-reducing therapy, or both? PMID- 22516172 TI - Multiple polyposis of the esophagus: mantle cell lymphoma. PMID- 22516173 TI - Characterization of virulent West Nile virus Kunjin strain, Australia, 2011. AB - To determine the cause of an unprecedented outbreak of encephalitis among horses in New South Wales, Australia, in 2011, we performed genomic sequencing of viruses isolated from affected horses and mosquitoes. Results showed that most of the cases were caused by a variant West Nile virus (WNV) strain, WNV(NSW2011), that is most closely related to WNV Kunjin (WNV(KUN)), the indigenous WNV strain in Australia. Studies in mouse models for WNV pathogenesis showed that WNV(NSW2011) is substantially more neuroinvasive than the prototype WNV(KUN) strain. In WNV(NSW2011), this apparent increase in virulence over that of the prototype strain correlated with at least 2 known markers of WNV virulence that are not found in WNV(KUN). Additional studies are needed to determine the relationship of the WNV(NSW2011) strain to currently and previously circulating WNV(KUN) strains and to confirm the cause of the increased virulence of this emerging WNV strain. PMID- 22516174 TI - Electricity assisted anaerobic treatment of salinity wastewater and its effects on microbial communities. AB - High salinity wastewater is often difficult to treat using common anaerobic technologies. Considering that high conductivity of salinity wastewater may enhance electrodes reaction to accelerate the decomposition of volatile fatty acids produced in anaerobic digestion, a pair of electrodes was packed into an anaerobic reactor (R1) with the aim to enhance the treatment of salinity wastewater. With increasing the salt concentration (NaCl) gradually from 0 to 50 g/L in 137 days' operation, COD removal in this reactor under the voltage for the electrodes of 1.2 V was well maintained at 93%, while the COD removal in a reference anaerobic reactor without electrodes (R2) decreased to 53%. When the voltage for R1 was cut off, about 10% COD removal was declined, which was still 30 percentage points higher than that in R2. The electrodes enhanced the biodegradation of volatile fatty acids, especially propionate. Fluorescence in situ hybridization analysis confirmed that the relative abundance of propionate utilizing bacteria in R1 was significantly higher than that in R2. PCR-DGGE analysis of bacteria and archaea domains indicated that the electric field stimulation effectively enriched salt-adapted microorganisms during the treatment. PMID- 22516176 TI - Variability of trace organic chemical concentrations in raw wastewater at three distinct sewershed scales. AB - The site-specific daily fluctuations and scale-dependent variability of influent water quality, particularly concentrations of trace organic chemicals (TOrCs), have not yet been well described. In this study, raw wastewater from three distinct sewershed scales was sampled including a centralized wastewater treatment facility in Boulder, Colorado (population ~125,000) and two decentralized wastewater catchments in Golden, Colorado (clustered system population 400, and septic system population 32). Each site was sampled hourly for 26 h and samples were subsequently analyzed in triplicate for 32 TOrCs using liquid chromatography with tandem mass spectrometry and stable isotope dilution. Detection frequency (DF) of the various TOrCs was positively correlated with sewershed size with the greatest DF of the targeted TOrCs at the Boulder site and with decreasing DF with decreasing sewershed size. Site-specific fluctuations were both scale and compound-specific. The 11 TOrCs detected greater than 75% of the time across all three sites were used to further investigate and quantify variability and to develop a statistical model to investigate the flow-dependence and time-dependence of TOrC variability. Sewershed scale was inversely correlated to variability with coefficients of variation ranging from 0.24 to 0.96, 0.39 to 2.22, and 0.32 to 3.93 for the Boulder, cluster, and septic sites, respectively. A significant linear relationship was observed between concentration and flow and concentration and the concentration at prior time points for most TOrCs at the Boulder site. This suggests less variable influent concentrations result from dispersion and mixing in the conveyance system and a larger number of discrete inputs. A notable exception was the chlorinated flame retardant TCPP, which is likely associated with a high concentration, low-flow industrial input. A significant linear relationship between flow and concentration and sequential time points was not common at the decentralized sites. Scientists and engineers developing decentralized treatment systems must consider a larger range of influent qualities, particularly with respect to TOrCs. PMID- 22516175 TI - Chlorate reduction capacity and characterisation of chlorate reducing bacteria communities in sediments of the rio Cruces wetland in southern Chile. AB - This study investigated chlorate reduction kinetics in multiple samples of sediments from a longitudinal profile of a wetland located downstream of the effluent discharge of a cellulose plant, including characterisation of the bacterial communities involved. The sediments were exposed to different initial chlorate concentrations in microcosm tests, with and without the addition of acetate as an external electron donor, and in a matrix of natural water or a defined medium. At a high initial chlorate concentration of 100 mg/L, in the absence of an external electron source, the degradation curves presented first order kinetics, influenced by electron donor availability. The first-order kinetic constant varied between 0.05 and 0.17 day(-1). Subsequently, when the initial chlorate concentration was reduced to 7 mg/L, a zero-order kinetic was obtained, with the kinetic constant presenting values between 1.1 and 1.3 mg/L day. No correlation was observed between chlorate degradation kinetics and the location of the sampling points or the previous history of exposure to chlorate. Other factors evaluated, such as the availability of organic matter or the chlorate reducing bacteria count, also proved not to have any incidence on the results. The richness of chlorate reducing bacteria species in the different samples analysed were also similar, with the greatest similarity being found between cld genes in the samples from the upstream or downstream sampling points. Additionally, cld genes most similar to those present in PCRB like Dechlorospirillum sp., Alicycliphilus denitrificans, Dechloromonas agitata, Dechloromonas sp. LT1 and Ideonella dechloratans were detected. This study showed that the anaerobic sediments of the Cruces river wetland present a high potential for chlorate natural attenuation, regardless of the previous history of exposure to chlorate. This capacity is associated with the presence of a diverse community of chlorate reducing bacteria. PMID- 22516177 TI - Inhibitory and antimicrobial activities of OGTI and HV-BBI peptides, fragments and analogs derived from amphibian skin. AB - A series of linear and cyclic fragments and analogs of two peptides (OGTI and HV BBI) isolated from skin secretions of frogs were synthesized by the solid-phase method. Their inhibitory activity against several serine proteinases: bovine beta trypsin, bovine alpha-chymotypsin, human leukocyte elastase and cathepsin G from human neutrophils, was investigated together with evaluation of their antimicrobial activities against Gram-negative bacteria (Escherichia coli) and Gram-positive species isolated from patients (Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus sp., Streptococcus sp.). The cytotoxicity of the selected peptides toward an immortal human skin fibroblast cell line was also determined. Three peptides: HV-BBI, its truncated fragment HV BBI(3-18) and its analog [Phe(8)]HV-BBI can be considered as bifunctional compounds with inhibitory as well as antibacterial properties. OGTI, although it did not display trypsin inhibitory activity as previously reported in the literature, exerted antimicrobial activity toward S. epidermidis. In addition, under our experimental conditions, this peptide did not show cytotoxicity. PMID- 22516178 TI - Are enemas given before cesarean section useful? A prospective randomized controlled study. AB - OBJECTIVE: To assess the effect of preoperative enemas on the postoperative recovery of bowel habits in women undergoing elective cesarean section. STUDY DESIGN: A prospective randomized controlled study with a standard two-group parallel design. The study was registered at the Protocol Registration System of the National Institute of Health (NCT00391599). With an alpha of 0.05, and a beta of 0.1 (power of 90%) 65 participants were required in each group. The inclusion criteria were elective cesarean section and no history of previous abdominal operations except for cesarean delivery. Randomization was done by random number generator. The study group (n=65) was given a Fleet enema and the controls (n=65) had no preoperative intestinal preparation. The primary outcome measures were postoperative return of bowel sounds, gas passage and first spontaneous feces. Care givers and those assessing the outcomes were blinded to group assignment. RESULTS: On postoperative day 1, among women who had a preoperative enema, 35.3% had bowel sounds, 47.2% had gas passage and 1.5% had spontaneous feces, compared to 47.2%, 52.8%, and 10.8%, respectively, among those who had no enema. The differences were not statistically significant. CONCLUSION: As we could not demonstrate any benefit for preoperative enema, we recommend against routine use of preoperative enema prior to elective cesarean delivery. PMID- 22516179 TI - Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life. AB - Humans are exposed to potentially harmful agents (bacteria, viruses, toxins) throughout our lifespan; the consequences of such exposure can alter central nervous system development. Exposure to immunogens during pregnancy increases the risk of developing neurological disorders such as schizophrenia and autism. Further, sex hormones, such as estrogen, have strong modulatory effects on immune function and have also been implicated in the development of neuropathologies (e.g., schizophrenia and depression). Similarly, animal studies have demonstrated that immunogen exposure in utero or during the neonatal period, at a time when the brain is undergoing maturation, can induce changes in learning and memory, as well as dopamine-mediated behaviors in a sex-specific manner. Literature that covers the effects of immunogens on innate immune activation and ultimately the development of the adult brain and behavior is riddled with contradictory findings, and the addition of sex as a factor only adds to the complexity. This review provides evidence that innate immune activation during critical periods of development may have effects on the adult brain in a sex-specific manner. Issues regarding sex bias in research as well as variability in animal models of immune function are discussed. PMID- 22516180 TI - Dynamics in multi-domain protein recognition of RNA. AB - Protein-RNA interactions play essential roles in gene regulation and RNA metabolism. While high-resolution structures have revealed principles of RNA recognition by individual RNA binding domains (RBDs), the presence of multiple RBDs in many eukaryotic proteins suggests additional modes of RNA recognition by combination and cooperation of these interactions. Recent structures, together with biochemical and biophysical studies have revealed novel principles of RNA recognition by multi-domain proteins. These examples highlight an important role for dynamics in RNA recognition, with mechanisms including fly-casting and conformational selection, and advocate the use of solution techniques for their analysis. PMID- 22516182 TI - Transcriptome and full-length cDNA resources for the mountain pine beetle, Dendroctonus ponderosae Hopkins, a major insect pest of pine forests. AB - Bark beetles (Coleoptera: Curculionidae: Scolytinae) are major insect pests of many woody plants around the world. The mountain pine beetle (MPB), Dendroctonus ponderosae Hopkins, is a significant historical pest of western North American pine forests. It is currently devastating pine forests in western North America- particularly in British Columbia, Canada--and is beginning to expand its host range eastward into the Canadian boreal forest, which extends to the Atlantic coast of North America. Limited genomic resources are available for this and other bark beetle pests, restricting the use of genomics-based information to help monitor, predict, and manage the spread of these insects. To overcome these limitations, we generated comprehensive transcriptome resources from fourteen full-length enriched cDNA libraries through paired-end Sanger sequencing of 100,000 cDNA clones, and single-end Roche 454 pyrosequencing of three of these cDNA libraries. Hybrid de novo assembly of the 3.4 million sequences resulted in 20,571 isotigs in 14,410 isogroups and 246,848 singletons. In addition, over 2300 non-redundant full-length cDNA clones putatively containing complete open reading frames, including 47 cytochrome P450s, were sequenced fully to high quality. This first large-scale genomics resource for bark beetles provides the relevant sequence information for gene discovery; functional and population genomics; comparative analyses; and for future efforts to annotate the MPB genome. These resources permit the study of this beetle at the molecular level and will inform research in other Dendroctonus spp. and more generally in the Curculionidae and other Coleoptera. PMID- 22516183 TI - Comparing capsule exposure using extracapsular dissection with partial superficial parotidectomy for pleomorphic adenoma. AB - The aim of this study was to compare capsule exposure using extracapsular dissection (ECD) with partial superficial parotidectomy (PSP) for pleomorphic adenoma. PURPOSE: Long-term favorable results for recurrence and facial nerve function have been reported for ECD and PSP for parotid pleomorphic adenoma. Extracapsular dissection is distinguished from PSP in that the facial nerve is dissected in PSP but not in ECD. This article attempts to answer the following hypothesis: the margin of normal parotid tissue surrounding a parotid pleomorphic adenoma is less for ECD compared with PSP. MATERIAL AND METHODS: This is a retrospective individual case-control study. Twelve consecutive parotidectomy procedures with a final pathology report of pleomorphic adenoma were retrospectively measured for margin (the percent of capsule exposure around the tumor). In 8 highly selected patients, ECD was performed. Four parotid surgical procedures not meeting strict criteria underwent PSP and served as controls. RESULTS: The eight patients with ECD had a mean of 80% (71%-99%) of the capsule exposed. The 4 PSP procedures had 21% (4%-50%) of the capsule exposed (P < .05). CONCLUSIONS: Extracapsular dissection results in higher capsule exposure. PMID- 22516181 TI - A Toll-Spatzle pathway in the tobacco hornworm, Manduca sexta. AB - Insects synthesize a battery of antimicrobial peptides (AMPs) and expression of AMP genes is regulated by the Toll and Imd (immune deficiency) pathways in Drosophila melanogaster. Drosophila Toll pathway is activated after Spatzle (Spz) is cleaved by Spatzle processing enzyme (SPE) to release the active C-terminal C106 domain (DmSpz-C106), which then binds to the Toll receptor to initiate the signaling pathway and regulate expression of AMP genes such as drosomycin. Toll and Spz genes have been identified in other insects, but interaction between Toll and Spz and direct evidence for a Toll-Spz pathway in other insect species have not been demonstrated. Our aim is to investigate a Toll-Spz pathway in Manduca sexta, and compare M. sexta and D. melanogaster Toll-Spz pathways. Co immunoprecipitation (Co-IP) assays showed that MsToll(ecto) (the ecto-domain of M. sexta Toll) could interact with MsSpz-C108 (the active C-terminal C108 domain of M. sexta Spz) but not with full-length MsSpz, and DmToll(ecto) could interact with DmSpz-C106 but not DmSpz, suggesting that Toll receptor only binds to the active C-terminal domain of Spz. Co-expression of MsToll-MsSpz-C108, but not MsToll-MsSpz, could up-regulate expression of drosomycin gene in Drosophila S2 cells, indicating that MsToll-MsSpz-C108 complex can activate the Toll signaling pathway. In vivo assays showed that activation of AMP genes, including cecropin, attacin, moricin and lebocin, in M. sexta larvae by purified recombinant MsSpz C108 could be blocked by pre-injection of antibody to MsToll, further confirming a Toll-Spz pathway in M. sexta, a lepidopteran insect. PMID- 22516184 TI - Simulator training reduces radiation exposure and improves trainees' performance in placing electrophysiologic catheters during patient-based procedures. AB - BACKGROUND: Currently, training in interventional electrophysiology is based on conventional methodologies, and a paucity of data on the usefulness of simulation in this field is available. OBJECTIVE: The purpose of this study was to evaluate the impact of simulator training on trainees' performance in electrophysiologic catheter placement during the early phase of their learning curve. METHODS: Inexperienced electrophysiology fellows were considered. A hybrid high-fidelity simulator (Procedicus VIST, version 7.0, Mentice AB Gothenburg, Sweden for Biosense Webster) was used. The following parameters were evaluated in 3 consecutive patient-based procedures before and after two training sessions of at least 1.5 hours on the simulator: (1) ability to place catheters in conventional recording/pacing sites (coronary sinus, His-bundle area, high right atrium, and right ventricular apex); (2) amount of help provided by the supervisor (scale from 1-3; 3 for maximal help); (3) fluoroscopy time; and (4) positioning time. RESULTS: Seven fellows performed 168 catheter placements during 42 patient-based procedures with no complications. Comparing parameters before and after simulator training, there was a significant reduction in the mean amount of help and in fluoroscopy and positioning times per placement: from 1.71 +/- 1.24 to 0.42 +/- 0.68 (P <.001), from 121 +/- 88 seconds to 76 +/- 54 seconds (P <.001), and from 175 +/- 138 seconds to 102 +/- 74 seconds (P <.001), respectively. Overall fluoroscopy time per patient decreased from 567 +/- 220 seconds to 305 +/- 111 seconds (P <.0001). Improvement appeared to be related to simulator training alone and not to the previously performed patient-based procedures. CONCLUSION: During the early phase of the trainees' learning curve, simulator training significantly improves the independent trainees' performance with reduction in radiation exposure. PMID- 22516185 TI - The course of the sinus node artery and its impact on achieving linear block at the left atrial roof in patients with persistent atrial fibrillation. AB - BACKGROUND: Linear block at the left atrial (LA) roof may be challenging in some patients undergoing an ablation procedure for atrial fibrillation. OBJECTIVE: To identify factors that may influence the likelihood of achieving roof block. METHODS: Seventy-four patients (61 +/- 10 years; 59 men [80%); LA diameter, 46 +/ 6 mm; ejection fraction 0.55 +/- 0.10) underwent linear ablation at the LA roof for persistent atrial fibrillation. The morphology of the roof and its anatomical relationship to adjacent structures were analyzed on a preprocedure computed tomography scan. RESULTS: Complete block along the LA roof was achieved in 61 of the 74 patients (82%). There was no significant difference in the myocardial thickness, length, or other morphological aspects of the LA roof between patients with and without complete block. The sinus node artery (SNA) originated from the right coronary artery in 52 patients (70%) and the left circumflex artery in 22 patients (30%). The prevalence of a left SNA (from the circumflex) among patients with and without linear block at the roof was 21% and 69%, respectively (P = .001). On multivariate analysis, a left SNA was the only independent predictor of incomplete conduction block at the LA roof (odds ratio 6.8; 95% confidence interval 1.7-28; P = .007). CONCLUSIONS: A left SNA identifies patients in whom conduction block at the roof is more difficult to achieve. A left SNA may act as an epicardial heat sink, preventing adequate heating of the LA roof during linear ablation. PMID- 22516186 TI - Spontaneous baroreflex sensitivity: prospective validation trial of a novel technique in survivors of acute myocardial infarction. AB - BACKGROUND: Low baroreflex sensitivity (BRS) indicates poor prognosis after acute myocardial infarction. Noninvasive BRS assessment is complicated by nonstationarities and noise in electrocardiogram and pressure signals. Phase rectified signal averaging is a novel signal processing technology overcoming these problems. OBJECTIVE: To prospectively validate a BRS measure (baroreflex sensitivity assessed by means of phase-rectified signal averaging [BRS(PRSA)]) based on this technology. METHODS: Nine hundred forty-one consecutive acute myocardial infarction survivors aged 80 years or younger in sinus rhythm were prospectively enrolled at 2 German university hospitals. All patients underwent 30-minute recordings of electrocardiogram and arterial blood pressures (Portapres; TNO-TPD Biomedical Instrumentation, Amsterdam, Netherlands) within the first 2 weeks after myocardial infarction. BRS(PRSA) was prospectively dichotomized at 1.58 ms/mm Hg. Primary end point was all-cause mortality at 5 years. Multivariable analyses included Global Registry of Acute Coronary Events score (dichotomized at >=120), sex, BRS(PRSA), left ventricular ejection fraction (dichotomized at <=35%), and diabetes mellitus. BRS(PRSA) was compared with 3 standard noninvasive BRS measures, that is, the sequence method, the transfer function method, and the correlation method. RESULTS: During follow-up, 72 patients (7.7%) died. BRS(PRSA) stratified the study population into a high-risk group of 405 patients (<=1.58 ms/mm Hg) with an estimated 5-year mortality of 14.2% and a low-risk group of 536 patients (>1.58 ms/mm Hg) with a 5-year mortality of 2.8% (P <.0001). On multivariable analysis, BRS(PRSA) <= 1.58 ms/mm Hg was associated with a hazard ratio of 3.1 (confidence interval 1.7-5.6; P = .001). Predictive power of BRS(PRSA) <= 1.58 ms/mm Hg was particularly strong in patients with a Global Registry of Acute Coronary Events score of >=120 or with a left ventricular ejection fraction of <=35%. CONCLUSION: BRS(PRSA) is a powerful and independent predictor of mortality in postinfarction patients especially when assessed in patients with a Global Registry of Acute Coronary Events score of >=120 or a left ventricular ejection fraction of <=35%. PMID- 22516187 TI - CT imaging of primary pleuropulmonary synovial sarcoma. AB - AIM: To evaluate the computed tomography (CT) imaging findings of primary pleuropulmonary synovial sarcoma. MATERIALS AND METHODS: Five cases of synovial sarcoma confirmed by histopathology and cytogenetic study were retrospectively analysed. All patients had undergone chest radiography and unenhanced and contrast-enhanced CT examinations, and three had also undergone multiphase CT enhancement examinations. Image characteristics, including shape, size, margin, and attenuation of each lesion before and after contrast enhancement, were analysed. RESULTS: The chest radiographs of the five patients showed well-defined or partly well-defined masses, which were homogeneous and without associated calcification or lymphadenopathy. Pneumothorax was present in one patient. The unenhanced CT images showed well-defined, heterogeneous masses with patchy low density in all five patients. The contrast-enhanced CT images showed heterogeneous enhancement in all cases, three of which demonstrated cystic and necrotic areas. The tumour showed no prolonged or delayed enhancement in three cases using multiphase CT. There were small pleural effusions in four cases. No calcification was observed in any of the cases. There was no evidence of hilar or mediastinal lymphadenopathy. CONCLUSIONS: In these five patients, primary pleuropulmonary synovial sarcoma presented as a well-defined mass with patchy low density and heterogeneous enhancement, with no evidence of regional lymphadenopathy. It should be included in the differential diagnosis of regional tumours. PMID- 22516188 TI - An integrated system of ABO typing and multiplex STR testing for forensic DNA analysis. AB - A new amplification system for ABO and STR genotyping in a single reaction has been successfully developed. Two types of information can be obtained from a biological sample at one time. One is the classical information of ABO blood group typing for screening suspects and the other is STR information for individual identification. The system allows for the simultaneous detection of 15 autosomal STR loci (containing all CODIS STR loci as well as Penta D and Penta E), six ABO genotypes (O/O, B/B, A/A, A/O, A/B, and B/O) and the gender determining locus Amelogenin. Primers are designed so that the amplicons are distributed ranging from 75bp to 500bp within a four-dye fluorescent design, leaving a fourth dye for the internal size standard. With 30 cycles, the results showed that the optimal amount of DNA template for this multiplex ranges from 250pg to 2ng and the lowest detection threshold is 125pg (as low as 63pg for ABO loci). For the DNA template outside the optimal detection range, we could adjust the number of cycles to obtain the robust profiles. Mixture studies showed that over 83% of minor alleles were detected at 1:9 ratios. The full profiles were still observed when 4ng of degraded DNA was digested by DNase I and 1ng undegraded DNA was added to 40MUM haematin. Polymerase chain reaction (PCR)-based conditions including the concentrations of primers, magnesium and the Taq polymerase as well as volume, cycle numbers and annealing temperature were examined and optimised. In addition, the system was validated by 364 bloodstain samples and 32 common casework samples. According to the Chinese National Standards and Scientific Working Group on DNA Analysis Methods (SWGDAM) guidelines, our system demonstrates good detection performance and is an ideal tool for forensic DNA typing with potential application. PMID- 22516190 TI - Organ distribution of Schmallenberg virus RNA in malformed newborns. AB - A novel orthobunyavirus was first detected in German dairy cows in autumn 2011 and was subsequently found in the brains of malformed lambs, kids and calves in the Netherlands, Germany, Belgium, France, Italy, Great Britain, Luxembourg and Spain. For rapid detection of this novel virus, named Schmallenberg virus, a real time quantitative reverse transcription PCR (RT-qPCR) was developed at the Friedrich-Loeffler-Institut and provided to the federal veterinary state laboratories in Germany. For diagnostic purposes, the organ distribution of this new virus was analyzed in several organs and body fluids of 15 lambs and two calves showing typical malformations. Spleen, cerebrum, meconium, spinal cord, rib cartilage, umbilical cord, placental fluid out of the stomach as well as external placental fluid scraped from the coat of the foetuses were collected during necropsy. All animals were tested RT-qPCR positive in the external placental fluid, and all but one were also RT-qPCR positive in the cerebrum, the umbilical and the spinal cord. Our results suggest that both the external placental fluid and the umbilical cord could be suitable sample materials for the confirmation of an infection with Schmallenberg virus in malformed newborns, at least in lambs. This is of special interest since those samples can be collected very easily on the farm without the need of a necropsy. PMID- 22516189 TI - No association between 2008-09 influenza vaccine and influenza A(H1N1)pdm09 virus infection, Manitoba, Canada, 2009. AB - We conducted a population-based study in Manitoba, Canada, to investigate whether use of inactivated trivalent influenza vaccine (TIV) during the 2008-09 influenza season was associated with subsequent infection with influenza A(H1N1)pdm09 virus during the first wave of the 2009 pandemic. Data were obtained from a provincewide population-based immunization registry and laboratory-based influenza surveillance system. The test-negative case-control study included 831 case-patients with confirmed influenza A(H1N1)pdm09 virus infection and 2,479 controls, participants with test results negative for influenza A and B viruses. For the association of TIV receipt with influenza A(H1N1)pdm09 virus infection, the fully adjusted odds ratio was 1.0 (95% CI 0.7-1.4). Among case-patients, receipt of 2008-09 TIV was associated with a statistically nonsignificant 49% reduction in risk for hospitalization. In agreement with study findings outside Canada, our study in Manitoba indicates that the 2008-09 TIV neither increased nor decreased the risk for infection with influenza A(H1N1)pdm09 virus. PMID- 22516191 TI - Genetic relatedness and netB prevalence among environmental Clostridium perfringens strains associated with a broiler flock affected by mild necrotic enteritis. AB - In a previous study we investigated pulsed-field gel electrophoresis (PFGE) genotype diversity and prevalence of the netB toxin gene in Clostridium perfringens (CP) isolates recovered from a broiler flock (flock 1) affected by necrotic enteritis (NE). In this follow-up work, we examined samples collected before placement of flock 1, to see if NE during rearing could be traced back to the cleaned and empty building or the day-old chicks. Litter from the next flock in the same building (flock 2) was also examined. We detected 25 different PFGE genotypes, five of which were found only in litter from flock 2. Six genotypes which had been found in flock 1 during rearing were detected in samples collected before placement. NetB positive isolates belonging to two of these genotypes had been recovered from NE lesions during rearing, suggesting that virulent strains were transmitted from the cleaned and disinfected broiler house. NetB frequency among isolates from the empty building was 45%, indicating that netB positive strains were prevalent in a building that previously had housed a healthy flock offered in-feed narasin (flock 0). NetB frequency among isolates from litter used by flock 2 was 22%, indicating that netB positive strains were present in the environment of a 14-days-old healthy flock offered in-feed narasin. Two prevalent genotypes were consistently either netB negative or netB positive. However, the presence of genotypes represented by both negative and positive isolates may suggest that the gene can spread horizontally among different CP strains. PMID- 22516192 TI - Light-mediated seed germination: connecting phytochrome B to gibberellic acid. AB - In this issue of Developmental Cell, Cho et al. (2012) uncover the mechanisms linking the light-regulated trigger and hormone-mediated induction of seed germination in Arabidopsis. When phytochrome B is activated by red light, seed germination is promoted by epigenetic transcriptional activation of gibberellic acid biosynthetic enzymes via histone demethylation. PMID- 22516193 TI - Alternative cells for regeneration. AB - Normally, in fish fin regeneration, bone regenerates from bone. But what happens when there is no bone? Singh et al. (2012) show in this issue of Developmental Cell that the bony rays still regenerate from an alternative cell source. PMID- 22516194 TI - Membrane fission: curvature-sensitive proteins cut it both ways. AB - Boucrot et al. (2012) demonstrate a membrane fission mechanism independent of nucleotide hydrolysis that is based on membrane insertion of amphipathic helices. They show that, for N-BAR domain proteins, which promote membrane curvature but also contain amphipathic helices, fission is opposed by the BAR domain that stabilizes tubular membrane structures. PMID- 22516195 TI - Ciliary and nuclear transport: different places, similar routes? AB - Cilia and flagella are membrane-sheathed, microtubule-based protrusions that decorate the surface of many eukaryotic cells. At their base, they form a selective barrier that concentrates certain proteins within the cilia but excludes others. Kee et al. (2012) now propose that nuclear pore complex proteins form a fundamental part of this diffusion barrier. PMID- 22516196 TI - Growth control by committee: intercellular junctions, cell polarity, and the cytoskeleton regulate Hippo signaling. AB - Over the past decade, the Hippo tumor suppressor pathway has emerged as a central regulator of growth in epithelial tissues. Research in Drosophila and in mammals has shown that this kinase signaling cascade regulates the activity of the transcriptional coactivator and oncoprotein Yorkie/Yap. In this review, we discuss recent findings that emphasize the cell cortex-specifically the actin cytoskeleton, intercellular junctions, and protein complexes that determine cell polarity-as a key site for Hippo pathway regulation. We also highlight where additional research is needed to integrate known functional interactions between Hippo pathway components. PMID- 22516197 TI - The tumor suppressor merlin controls growth in its open state, and phosphorylation converts it to a less-active more-closed state. PMID- 22516198 TI - The Sec7 Arf-GEF is recruited to the trans-Golgi network by positive feedback. AB - Arf GTPases are key regulators of both retrograde and anterograde traffic at the Golgi complex. The Golgi-localized Arf activators, Arf-GEFs (guanine exchange factor) of the BIG/GBF family, are poorly understood in terms of both their regulatory and localization mechanisms. We have performed a detailed kinetic characterization of a functional Golgi Arf-GEF, the trans-Golgi network (TGN) localized Sec7 protein from yeast. We demonstrate that Sec7 is regulated by both autoinhibition and positive feedback. We show that positive feedback arises through the stable recruitment of Sec7 to membranes via its HDS1 domain by interaction with its product, activated Arf1. This interaction mediates localization of Sec7 to the TGN, because deletion of the HDS1 domain or mutation of the HDS1 domain in combination with deletion of Arf1 significantly increases cytoplasmic localization of Sec7. Our results lead us to propose a model in which Arf-GEF recruitment is linked to Golgi maturation via Arf1 activation. PMID- 22516199 TI - The clathrin adaptor AP-1A mediates basolateral polarity. AB - Clathrin and the epithelial-specific clathrin adaptor AP-1B mediate basolateral trafficking in epithelia. However, several epithelia lack AP-1B, and mice knocked out for AP-1B are viable, suggesting the existence of additional mechanisms that control basolateral polarity. Here, we demonstrate a distinct role of the ubiquitous clathrin adaptor AP-1A in basolateral protein sorting. Knockdown of AP 1A causes missorting of basolateral proteins in MDCK cells, but only after knockdown of AP-1B, suggesting that AP-1B can compensate for lack of AP-1A. AP-1A localizes predominantly to the TGN, and its knockdown promotes spillover of basolateral proteins into common recycling endosomes, the site of function of AP 1B, suggesting complementary roles of both adaptors in basolateral sorting. Yeast two-hybrid assays detect interactions between the basolateral signal of transferrin receptor and the medium subunits of both AP-1A and AP-1B. The basolateral sorting function of AP-1A reported here establishes AP-1 as a major regulator of epithelial polarity. PMID- 22516200 TI - Chemokine signaling directs trunk lymphatic network formation along the preexisting blood vasculature. AB - The lymphatic system is crucial for fluid homeostasis, immune responses, and numerous pathological processes. However, the molecular mechanisms responsible for establishing the anatomical form of the lymphatic vascular network remain largely unknown. Here, we show that chemokine signaling provides critical guidance cues directing early trunk lymphatic network assembly and patterning. The chemokine receptors Cxcr4a and Cxcr4b are expressed in lymphatic endothelium, whereas chemokine ligands Cxcl12a and Cxcl12b are expressed in adjacent tissues along which the developing lymphatics align. Loss- and gain-of-function studies in zebrafish demonstrate that chemokine signaling orchestrates the stepwise assembly of the trunk lymphatic network. In addition to providing evidence for a lymphatic vascular guidance mechanism, these results also suggest a molecular basis for the anatomical coalignment of lymphatic and blood vessels. PMID- 22516201 TI - Atypical E2F repressors and activators coordinate placental development. AB - The evolutionarily ancient arm of the E2f family of transcription factors consisting of the two atypical members E2f7 and E2f8 is essential for murine embryonic development. However, the critical tissues, cellular processes, and molecular pathways regulated by these two factors remain unknown. Using a series of fetal and placental lineage-specific cre mice, we show that E2F7/E2F8 functions in extraembryonic trophoblast lineages are both necessary and sufficient to carry fetuses to term. Expression profiling and biochemical approaches exposed the canonical E2F3a activator as a key family member that antagonizes E2F7/E2F8 functions. Remarkably, the concomitant loss of E2f3a normalized placental gene expression programs, corrected placental defects, and fostered the survival of E2f7/E2f8-deficient embryos to birth. In summary, we identified a placental transcriptional network tightly coordinated by activation and repression through two distinct arms of the E2F family that is essential for extraembryonic cell proliferation, placental development, and fetal viability. PMID- 22516202 TI - Snf2l regulates Foxg1-dependent progenitor cell expansion in the developing brain. AB - Balancing progenitor cell self-renewal and differentiation is essential for brain development and is regulated by the activity of chromatin remodeling complexes. Nevertheless, linking chromatin changes to specific pathways that control cortical histogenesis remains a challenge. Here we identify a genetic interaction between the chromatin remodeler Snf2l and Foxg1, a key regulator of neurogenesis. Snf2l mutant mice exhibit forebrain hypercellularity arising from increased Foxg1 expression, increased progenitor cell expansion, and delayed differentiation. We demonstrate that Snf2l binds to the Foxg1 locus at midneurogenesis and that the phenotype is rescued by reducing Foxg1 dosage, thus revealing that Snf2l and Foxg1 function antagonistically to regulate brain size. PMID- 22516203 TI - Regeneration of amputated zebrafish fin rays from de novo osteoblasts. AB - Determining the cellular source of new skeletal elements is critical for understanding appendage regeneration in amphibians and fish. Recent lineage tracing studies indicated that zebrafish fin ray bone regenerates through the dedifferentiation and proliferation of spared osteoblasts, with limited if any contribution from other cell types. Here, we examined the requirement for this mechanism by using genetic ablation techniques to destroy virtually all skeletal osteoblasts in adult zebrafish fins. Animals survived this injury and restored the osteoblast population within 2 weeks. Moreover, amputated fins depleted of osteoblasts regenerated new fin ray structures at rates indistinguishable from fins possessing a resident osteoblast population. Inducible genetic fate mapping confirmed that new bone cells do not arise from dedifferentiated osteoblasts under these conditions. Our findings demonstrate diversity in the cellular origins of appendage bone and reveal that de novo osteoblasts can fully support the regeneration of amputated zebrafish fins. PMID- 22516204 TI - Sapovirus outbreaks in long-term care facilities, Oregon and Minnesota, USA, 2002 2009. AB - We tested fecal samples from 93 norovirus-negative gastroenteritis outbreaks; 21 outbreaks were caused by sapovirus. Of these, 71% were caused by sapovirus genogroup IV and 66% occurred in long-term care facilities. Future investigation of gastroenteritis outbreaks should include multi-organism testing. PMID- 22516206 TI - Formation of dioxins during exposure of pesticide formulations to sunlight. AB - Chlorinated pesticides can contain impurities of dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), and their precursors, as a result of various manufacturing processes and conditions. As precursor formation of PCDD/Fs can also be mediated by ultraviolet light (UV), this study investigated whether PCDD/Fs are formed when currently used pesticides are exposed to natural sunlight. Formulations containing pentachloronitrobenzene (PCNB; n=2) and 2,4 dichlorophenoxyacetic acid (2,4-D; n=1) were exposed to sunlight in quartz tubes, and the concentration of 93 PCDD/F congeners were monitored over time. Considerable formation of PCDD/Fs was observed in both PCNB formulations (by up to 5600%, to a maximum concentration of 57000 MUg ?PCDD/F kg(-1)) as well as the 2,4-D formulation (by 3000%, to 140 MUg ?PCDD/F kg(-1)). TEQ also increased by up to 980%, to a maximum concentration of 28 MUg kg(-1) in PCNB, but did not change in the 2,4-D formulation. Assuming similar yields as observed in the present study as a worst case scenario the use of PCNB in Australia may result in the formation of 155 g TEQ annum(-1), contributed primarily by OCDD formation. This warrants detailed evaluations on the contemporary release of PCDD/Fs to the environment after the use of pesticides. Changes in congener profiles (including the ratio of PCDDs to PCDFs (DF ratio)) suggest that pesticide sources of PCDD/Fs after sunlight exposure may not be recognized based on matching source fingerprints established from manufacturing impurities. These changes also provide preliminary insights into the possible formation routes and types of precursors involved. PMID- 22516207 TI - Transport of silver nanoparticles (AgNPs) in soil. AB - The effect of soil properties on the transport of silver nanoparticles (AgNPs) was studied in a set of laboratory column experiments, using different combinations of size fractions of a Mediterranean sandy clay soil. The AgNPs with average size of ~30nm yielded a stable suspension in water with zeta potential of -39mV. Early breakthrough of AgNPs in soil was observed in column transport experiments. AgNPs were found to have high mobility in soil with outlet relative concentrations ranging from 30% to 70%, depending on experimental conditions. AgNP mobility through the column decreased when the fraction of smaller soil aggregates was larger. The early breakthrough pattern was not observed for AgNPs in pure quartz columns nor for bromide tracer in soil columns, suggesting that early breakthrough is related to the nature of AgNP transport in natural soils. Micro-CT and image analysis used to investigate structural features of the soil, suggest that soil aggregate size strongly affects AgNP transport in natural soil. The retention of AgNPs in the soil column was reduced when humic acid was added to the leaching solution, while a lower flow rate (Darcy velocity of 0.17cm/min versus 0.66cm/min) resulted in higher retention of AgNPs in the soil. When soil residual chloride was exchanged by nitrate prior to column experiments, significantly improved mobility of AgNPs was observed in the soil column. These findings point to the importance of AgNP-soil chemical interactions as a retention mechanism, and demonstrate the need to employ natural soils rather than glass beads or quartz in representative experimental investigations. PMID- 22516205 TI - Twist factor regulation of non-cardiomyocyte cell lineages in the developing heart. AB - The heart is a complex organ that is composed of numerous cell types, which must integrate their programs for proper specification, differentiation and cardiac morphogenesis. During cardiogenesis members of the Twist-family of basic helix loop-helix (bHLH) transcription factors play distinct roles within cardiac lineages such as the endocardium and extra-cardiac lineages such as the cardiac neural crest (cNCC) and epicardium. While the study of these cell populations is often eclipsed by that of cardiomyocytes, the contributions of non-cardiomyocytes to development and disease are increasingly being appreciated as both dynamic and essential. This review summarizes what is known regarding Twist-family bHLH function in extra-cardiac cell populations and the endocardium, with a focus on regulatory mechanisms, downstream targets, and expression profiles. Improving our understanding of the molecular pathways that Twist-family bHLH factors mediate in these lineages will be necessary to ascertain how their dysfunction leads to congenital disease and adult pathologies such as myocardial infarctions and cardiac fibroblast induced fibrosis. Indeed, this knowledge will prove to be critical to clinicians seeking to improve current treatments. PMID- 22516208 TI - Formaldehyde personal exposure measurements and time weighted exposure estimates in children. AB - Residential concentrations of formaldehyde have been associated with poor respiratory health in children, where formaldehyde has been measured using stationary monitors inside homes. Although children spend most of their time indoors at home, there are few studies of children's personal exposure to formaldehyde. The aim of this study was to investigate the relationship between personal exposure formaldehyde concentrations, microenvironmental concentrations and time weighted exposure estimates in children. Forty-one primary school children (aged between 9 and 12 years) wore a personal passive sampler over two 24h periods in two seasons and completed 24h daily activity diaries and a questionnaire about lifestyle and behaviour. Samplers were co located indoors at home, outdoors at centralised locations and indoors at school for the corresponding period. Personal exposure formaldehyde concentrations in this group of children were generally low with a geometric mean concentration of 9.1 ppb (range 100ml). High risk tumours (HR, histological poor response >30% residual cells or clinical poor response <50% for unresectable tumours), received IE prior high dose busulfan/melphalan with stem cell rescue. RESULTS: From 1993 to 1999, 214 patients were enrolled. 5 y-EFS and OS were 60% (95% confidence interval (CI), 53-66) and 69% (95% CI, 63-75), respectively. 116 (54%), 46 (21%), 48 (22%) patients were considered as SR, IR and HR of relapse, respectively. No advantage to IE was observed in the IR group. As compared to previous study, tumour with poor histological response to induction chemotherapy seemed to benefit from the consolidation strategy including busulfan/melphalan: EFS were 45% (95% CI, 30-60) and 20% (95% CI, 7-43) for EW93 and EW88, respectively. Despite a risk-adapted strategy, histological response to chemotherapy remains the main prognostic factor in resected tumours, while initial tumour volume is the main prognostic factor for unresected tumours. CONCLUSION: These results showing a potential benefit of a consolidation strategy including busulfan/melphalan as compared to conventional chemotherapy needed confirmation by a randomised trial and were one of the bases of the ongoing EuroEwing99. PMID- 22516210 TI - Population-based evidence of increased survival in human papillomavirus-related head and neck cancer. AB - BACKGROUND: Evidence from clinical, population-based and molecular studies has shown that human papillomavirus (HPV) infection can be a causal risk factor for a subset of head and neck squamous cell carcinomas (HNSCC). It is proposed that HPV associated oropharyngeal cancer is a new disease entity that requires treatment and prevention strategies distinct from present recommendations. METHODS: In our population-based study we estimated incidence and survival trends in 8270 patients with HPV-related HNSCC (HPV(+)HNSCC) and HPV-unrelated HNSCC (HPV( )HNSCC) in Norway over the past three decades. RESULTS: In the period 1981-1995, patients with HPV(+)HNSCC had poorer survival than HPV(-)HNSCC (adjusted hazard ratio (HR) 1.3, 95% confidence interval (CI): 1.14-1.44). By 1996-2007, survival had increased in both groups, but the increase was significantly greater among HPV(+)HNSCC patients (HR 0.57, 95% CI: 0.48-0.67). During the same period, incidence also increased, but only for HPV(+)HNSCCs. From 1981-1995 to 1996-2007, median age at diagnosis for HPV(+)HNSCC decreased from 63.2 to 59.8 years, while for HPV(-)HNSCC median age at diagnosis of 66.6 years remained unchanged. CONCLUSIONS: We demonstrate a population level improvement in survival among patients with oropharyngeal squamous cell cancers commonly related to infection with HPV. In contrast, patients with HNSCC not related to HPV only showed a modest improvement in survival in the period 1981-2007. A concomitant increase in incidence and survival was observed for HPV-related cancers only. This trend cannot be explained by changes in treatment, cancer registration nor screening, but is most likely due to an increased prevalence of HPV-positive tumours. PMID- 22516211 TI - Evaluation of an improved rapid neutralizing antibody detection test (RAPINA) for qualitative and semiquantitative detection of rabies neutralizing antibody in humans and dogs. AB - Using the principle of immunochromatography, we previously developed a method called RAPINA (Rapid Neutralizing Antibody detection test) that can measure the level of rabies virus -neutralizing antibody (VNA) in serum samples [Shiota S, Mannen K, Matsumoto T, Yamada K, Yasui T, Takayama K, et al. Development and evaluation of a rapid neutralizing antibody test for rabies. J Virol Methods 2009;161:58-62]. RAPINA is faster, simpler, and easier to perform compared with a virus-neutralizing test or enzyme-linked immunosorbent assay (ELISA). The improved version of RAPINA has greater positive and negative predictive values corresponding to a VNA level of 0.5 IU/mL, as recommended by the World Health Organization and the World Organization for Animal Health. To verify the efficacy of this improved method, serum samples were collected from humans and dogs before and after immunization against rabies and were tested in Japan, Sri Lanka, and Thailand. The results were compared between RAPINA and the true VNA levels measured by the Rapid Fluorescent Focus Inhibition Test (RFFIT). The improved RAPINA accurately predicted seropositivity for 182 of 183 seropositive human samples as assessed by RFFIT (99.5%) and for 138 of 140 RFFIT-negative human samples (98.6%). In dog serum samples, the positive and negative predictive values were 99.7% (345/355) and 95.6% (174/182), respectively. RAPINA was also used to estimate VNA levels in a semiquantitative manner by using serial dilution of serum samples. Our results show that RAPINA is an easy and rapid method for measuring VNA levels before and after immunization with the rabies vaccine and does not need a high skill level or sophisticated equipment. RAPINA can be used to monitor the success of preexposure prophylaxis in at-risk persons, vaccine coverage, and animal control. It can also be used in laboratories with modest facilities and where a large number of samples are screened. PMID- 22516212 TI - Prevalence of human papillomavirus (HPV) infections in sexually active adolescents and young women in England, prior to widespread HPV immunisation. AB - INTRODUCTION: The introduction of an HPV immunisation programme in England should result in a significant reduction in the prevalence of vaccine type infections in young women. Here we describe type-specific HPV prevalence in three samples of the young female population in England, prior to the beginning of mass immunisation in 2008. METHODS: Residual vulva-vaginal swab samples from females aged under 25 years undergoing chlamydia testing as part of the National Chlamydia Screening Programme (NCSP) or Prevention of Pelvic Infection (POPI) trial were collected from sites across England, together with available demographic and sexual behaviour data. Residual samples were screened for HPV infection using the Hybrid Capture 2 (hc2) HPV DNA Test, including the high-risk (HR) and low-risk (LR) probes. Hc2 positive samples were genotyped using the Roche Linear Array (LA) HPV Genotyping Test. RESULTS: A total of 3829 samples were included: 2369 from 16 to 24 year old NCSP participants, 275 from 13 to 15 year old NCSP participants and 1185 from 16 to 24 year old POPI participants. Variations in HPV prevalence between and within the different samples followed a pattern largely consistent with differences in sexual behaviour. The prevalence of total HR HPV infection, of HPV 16 and/or 18 (16/18) infection and of five HR HPV types closely related to HPV 16/18 (HPV 31, 33, 45, 52 or 58) amongst 16-24 year old NCSP participants was 35% (95% CI 33-37%), 18% (95% CI 16-19%), and 16% (95% CI 14-18%), respectively. Risk of HR HPV infection increased with age during the teen years and was higher in women who reported two or more sexual partners in the last year and in women with chlamydia infection. Approximately half of women with HPV 16/18 infection also had another non-vaccine HR HPV type present. CONCLUSIONS: Prior to HPV immunisation, there was a high prevalence of HPV infections in the lower genital tract of young, sexually active females in England. The overall, type-specific, and multiple infection prevalence closely reflected age and sexual activity. These data provide a baseline against which the early impact of HPV immunisation on the prevalence of HPV 16/18 and closely related types in young women can be measured, in order to inform immunisation and cervical screening policies. PMID- 22516213 TI - Acute neurogenic pulmonary edema following electroconvulsive therapy: a case report. AB - OBJECTIVE: We report the case of a 47-year-old man with depression who developed acute dyspnea, hypoxemia, and mild hemoptysis after electroconvulsive therapy (ECT). METHOD: Intravenous carbazochrome sodium sulfate hydrate as a hemostatic drug (100 mg/day) was prescribed for 2 days. On the day of ECT, oxygen inhalation (4 L/min) was continued, and SpO2 was maintained at 94-96%. RESULTS: Chest radiography showed improvement in alveolar infiltration. Chest CT 6 days after ECT also confirmed the disappearance of ground glass opacities in the lung fields. CONCLUSION(S): NPE is life threatening and should be recognized as an uncommon adverse event associated with ECT. PMID- 22516214 TI - Metoprolol-induced psychosis in a young patient. AB - Metoprolol is widely used in cardiology for the treatment of hypertension and arrhythmia. The neuropsychiatric adverse reactions associated with the use of beta-blockers are relatively uncommon, but sometimes take place when poisoning or overdosing on elderly patients. We present a case of a young patient with low dose metoprolol which induced acute delirium and in whom the symptoms disappeared within 3 days after metoprolol was ceased. The results illustrated that the neuropsychiatric adverse reactions of metoprolol could be developed not only in elderly patients but also in young patients, which has great significance to direct physicians in their clinical practice. PMID- 22516215 TI - Bottlenecks in the emergency department: the psychiatric clinicians' perspective. AB - OBJECTIVE: To ask psychiatric clinicians for their perspectives on the rate limiting steps (RLS) in patient care in the Emergency Department (ED) and to compare them to the patient's actual length of stay. METHOD: Prospective cohort study of clinicians' perspectives on the RLS among 1092 adult ED patients. Medical records were abstracted for ED time and other data. RESULTS: Clinicians identified five RLS: limited availability of staff, limited availability of beds after discharge, need for clinical stability, need for additional history and patient's financial issues. The last RLS was the only one not associated with increased wait times in the ED. There were significant differences in the patterns of RLS by trainee status and hospital. For example, significantly higher proportions of trainees reported that RLS in patient care were due to the need for clinical stability and additional history and lack of bed availability. In contrast, non-trainee clinicians were more likely to cite problems with the availability of ED staff as an RLS. CONCLUSIONS: Most of the RLS in patient care identified by clinicians were associated with actual increases in ED wait time for their patients. Next steps include asking clinicians for possible solutions to the delays their patients experience. PMID- 22516217 TI - Clozapine-induced stuttering: a case report and analysis of similar case reports in the literature. AB - There is limited literature reporting clozapine-associated stuttering. In this case report, we present a case of a young male who developed stuttering with clozapine, which improved with dose reduction. Computer-assisted searches on clozapine-induced stuttering yielded 16 cases, and analysis of these case reports suggests that stuttering may be linked to seizures or movement disorders, but other putative mechanisms may be at work, which need further research. PMID- 22516216 TI - Eight-year trends of cardiometabolic morbidity and mortality in patients with schizophrenia. AB - OBJECTIVE: We examined cardiometabolic disease and mortality over 8 years among individuals with and without schizophrenia. METHOD: We compared 65,362 patients in the Veteran Affairs (VA) health system with schizophrenia to 65,362 VA patients without serious mental illness (non-SMI) matched on age, service access year and location. The annual prevalence of diagnosed cardiovascular disease, diabetes, dyslipidemia, hypertension, obesity, and all-cause and cause-specific mortality was compared for fiscal years 2000-2007. Mean years of potential life lost (YPLLs) were calculated annually. RESULTS: The cohort was mostly male (88%) with a mean age of 54 years. Cardiometabolic disease prevalence increased in both groups, with non-SMI patients having higher disease prevalence in most years. Annual between-group differences ranged from <1% to 6%. Annual mortality was stable over time for schizophrenia (3.1%) and non-SMI patients (2.6%). Annual mean YPLLs increased from 12.8 to 15.4 in schizophrenia and from 11.8 to 14.0 for non-SMI groups. CONCLUSIONS: VA patients with and without schizophrenia show increasing but similar prevalence rates of cardiometabolic diseases. YPLLs were high in both groups and only slightly higher among patients with schizophrenia. The findings highlight the complex population served by the VA while suggesting a smaller mortality impact from schizophrenia than previously reported. PMID- 22516218 TI - Pityriasis rosea-like eruption associated with clozapine: a case report. AB - Adverse cutaneous drug reactions (ACDRs) are common in clinical practice and occur in about 5% of antipsychotic-treated patients. Most ACDRs are benign, but a small percentage of them are serious and life threatening. Pityriasis rosea (PR) like eruption is a common cutaneous adverse reaction related to many drugs. Clozapine, a complex neurotransmitter receptor-binding in antipsychotic agent, is usually used for treatment-resistant schizophrenia. Clozapine-related ACDRs have been reported frequently, but clozapine-induced PR-like eruption has been reported once in the literature. We report a 54-year-old male patient with chronic schizophrenia who had received clozapine for 28 days and developed generalized skin rashes, high fever, and elevated values in liver function tests. His clozapine was immediately discontinued. He received acute managements with steroid and antihistamine, and his symptoms were relieved after treatment. This case report can be used to remind clinicians of keeping in mind the potential of clozapine-associated ACDRs. PMID- 22516219 TI - Symptom profile of delirium in children and adolescent--does it differ from adults and elderly? AB - OBJECTIVE: The objective was to evaluate the phenomenology, etiology and outcome of delirium in children and adolescents (8-18 years of age) seen in a consultation-liaison psychiatric service in India. Additionally, an attempt was made to compare the phenomenology with adult and elderly patients with delirium. METHOD: Thirty children and adolescents (age 8-18 years) diagnosed with delirium by the consultation-liaison psychiatry team were rated on the Delirium Rating Scale-Revised-98 (DRS-R-98) and compared with DRS-R-98 data on 120 adults and 109 elderly patients. RESULTS: The commonly observed symptoms in children and adolescents with delirium were disturbance in attention, orientation, sleep-wake cycle disturbances, fluctuation of symptoms, disturbance of short-term memory and motor agitation. The least commonly seen symptoms included delusions and motor retardation. Compared to adults, children and adolescents had lower frequency of long-term memory and visuospatial disturbances. Compared to the elderly, children and adolescents had higher frequency of lability of affect. For severity of symptoms, compared to adults, the children and adolescents had lower severity of sleep-wake disturbances, abnormality of thought, motor agitation, orientation, attention, short-term memory, long-term memory and visuospatial abilities. When compared to elderly patients, children and adolescents had higher severity of lability of affect and lower severity of language disturbances, short-term memory and visuospatial abilities. CONCLUSIONS: In general, phenomenology, of delirium in children and adolescents (age 8-18 years) is similar to that seen in adults and elderly patients. PMID- 22516220 TI - The use of short message service (SMS) among hospitalized coronary patients. AB - OBJECTIVE: The use of cell phones and short message service (SMS, also called "texting") has become pervasive in Western society and increasingly throughout the world. Despite the importance of this technology in everyday life, little is known about how patients draw on SMS to keep in contact with family and friends during their hospitalization. METHODS: A questionnaire was distributed to patients with coronary artery disease discharged from a Norwegian university hospital during the period from June 2005 to June 2006. In addition to questions pertaining to demographics, illness and treatment, mental distress, personality traits, perceived control, Internet usage and lifestyle, respondents were asked if they had contact with family and friends by SMS while in the hospital. RESULTS: Four hundred twelve responded (59%), of which 216 had undergone surgery and 196 had undergone percutaneous coronary interventions. Sixty-three percent had used SMS to keep in touch with family and friends during their stay at the hospital. Use of SMS was positively predicted by Internet usage, gender and the personality trait of Openness, and was negatively predicted by the belief that illness and health were caused by luck or destiny. CONCLUSIONS: SMS is an important means of communication during hospitalization for a majority of coronary disease inpatients. PMID- 22516221 TI - FgVelB globally regulates sexual reproduction, mycotoxin production and pathogenicity in the cereal pathogen Fusarium graminearum. AB - The velvet genes are conserved in ascomycetous fungi and function as global regulators of differentiation and secondary metabolism. Here, we characterized one of the velvet genes, designated FgVelB, in the plant-pathogenic fungus Fusarium graminearum, which causes fusarium head blight in cereals and produces mycotoxins within plants. FgVelB-deleted (DeltaFgVelB) strains produced fewer aerial mycelia with less pigmentation than those of the wild-type (WT) during vegetative growth. Under sexual development conditions, the DeltaFgVelB strains produced no fruiting bodies but retained male fertility, and conidiation was threefold higher compared with the WT strain. Production of trichothecene and zearalenone was dramatically reduced compared with the WT strain. In addition, the DeltaFgVelB strains were incapable of colonizing host plant tissues. Transcript analyses revealed that FgVelB was highly expressed during the sexual development stage, and may be regulated by a mitogen-activated protein kinase cascade. Microarray analysis showed that FgVelB affects regulatory pathways mediated by the mating-type loci and a G-protein alpha subunit, as well as primary and secondary metabolism. These results suggest that FgVelB has diverse biological functions, probably by acting as a member of a possible velvet protein complex, although identification of the FgVelB-FgVeA complex and the determination of its roles require further investigation. PMID- 22516222 TI - Identification of a high-molecular-mass Lactobacillus epithelium adhesin (LEA) of Lactobacillus crispatus ST1 that binds to stratified squamous epithelium. AB - Lactobacilli belong to the normal gastrointestinal and genital tract microbiota of human and animal hosts. Adhesion is important for bacterial colonization; however, only a few Lactobacillus adhesins have been identified so far. We studied extracted surface proteins from an adhesive Lactobacillus crispatus strain, ST1, which efficiently colonizes the chicken alimentary tract, for their binding to tissue sections of the chicken crop, and identified a novel high molecular-mass repetitive surface protein that shows specific binding to stratified squamous epithelium. The adhesin binds to both crop epithelium and epithelial cells from human vagina, and was named Lactobacillus epithelium adhesin (LEA). Expression of LEA is strain-specific among L. crispatus strains and corresponds directly to in vitro bacterial adhesion ability. The partial sequence of the lea gene predicts that the LEA protein carries an N-terminal YSIRK signal sequence and a C-terminal LPxTG anchoring motif, as well as a highly repetitive region harbouring 82 aa long repeats with non-identical sequences that show similarity to Lactobacillus Rib/alpha-like repeats. LEA-mediated epithelial adherence may improve bacterial colonization in the chicken crop and the human vagina, which are the natural environments for L. crispatus. PMID- 22516223 TI - A dual signalling pathway for the hypoxic expression of lipid genes, dependent on the glucose sensor Rag4, is revealed by the analysis of the KlMGA2 gene in Kluyveromyces lactis. AB - In the respiratory yeast Kluyveromyces lactis, little is known about the factors regulating the metabolic response to oxygen shortage. After searching for homologues of characterized Saccharomyces cerevisiae regulators of the hypoxic response, we identified a gene that we named KlMGA2, which is homologous to MGA2. The deletion of KlMGA2 strongly reduced both the fermentative and respiratory growth rate and altered fatty acid composition and the unsaturation index of membranes. The reciprocal heterologous expression of MGA2 and KlMGA2 in the corresponding deletion mutant strains suggested that Mga2 and KlMga2 are functional homologues. KlMGA2 transcription was induced by hypoxia and the glucose sensor Rag4 mediated the hypoxic induction of KlMGA2. Transcription of lipid biosynthetic genes KlOLE1, KlERG1, KlFAS1 and KlATF1 was induced by hypoxia and was dependent on KlMga2, except for KlOLE1. Rag4 was required for hypoxic induction of transcription for both KlMga2-dependent (KlERG1) and KlMga2 independent (KlOLE1) structural genes. PMID- 22516224 TI - Self-association of the Shigella flexneri IcsA autotransporter protein. AB - The IcsA autotransporter protein is a major virulence factor of the human intracellular pathogen Shigella flexneri. IcsA is distributed at the poles in the outer membrane (OM) of S. flexneri and interacts with components of the host actin-polymerization machinery to facilitate intracellular actin-based motility and subsequent cell-to-cell spreading of the bacterium. We sought to characterize the biochemical properties of IcsA in the bacterial OM. Chemical cross-linking data suggested that IcsA exists in a complex in the OM. Furthermore, reciprocal co-immunoprecipitation of differentially epitope-tagged IcsA proteins indicated that IcsA is able to self-associate. The identification of IcsA linker-insertion mutants that were negatively dominant provided genetic evidence of IcsA-IcsA interactions. From these results, we propose a model whereby IcsA self association facilitates efficient actin-based motility. PMID- 22516225 TI - Computational identification of interplay between phosphorylation and O-beta glycosylation of human occludin as potential mechanism to impair hepatitis C virus entry. AB - Hepatitis C virus (HCV) is one of the leading causes of liver diseases. Several host factors that facilitate the attachment and entry of HCV have been discovered, of which human occludin seems to be the most promising. Studies have shown that activity of occludin is dependent upon its phosphorylation status, and that during HCV infection deregulation of phosphorylated occludin collectively leads to a reduction in tight junction (TJ) integrity of hepatocytes and favors HCV entry. However, detailed information of the posttranslational modifications (PTMs) of occludin still remains largely unknown. In addition to phosphorylation, serine/threonine residues of several proteins are also regulated by a unique type of modification known as O-beta-glycosylation and this crosstalk serves as a functional switch. To identify the O-beta-glycosylation potential and how interplay between phosphorylation and O-beta-glycosylation can be exploited for the inhibition of HCV entry, here we report a computational analysis of PTMs of human occludin. Several conserved phosphorylation residues and kinases that can alter the ability of occludin to regulate the integrity of TJs were identified. In addition to previously reported Tyr residues, two additional Tyr residues (Tyr29 and Tyr287) were identified as target sites of Src kinase. To our knowledge, this is the first study to report the O-beta-GlcNAc potential of occludin and target sites of ERK (Ser8, Ser310, and Thr345), GSK-3 (Ser8, Ser341) and Cdk5 (Thr376). Furthermore, based on findings from this study, a potential novel interplay between phosphorylation and O-beta-glycosylation at the two Yin Yang sites (Ser408 and Ser490) is also proposed. PMID- 22516226 TI - Evolution of the Leishmania braziliensis species complex from amplified fragment length polymorphisms, and clinical implications. AB - In order to get more insight into its evolution and geographical distribution, we investigated the Leishmania (Viannia) braziliensis species complex using amplified fragment length polymorphisms and sequencing of a heat-shock protein 70 gene fragment. Previously, several assays had alluded to the high genetic diversity of the group, and single-locus assays typically identified two species, i.e. L. braziliensis and Leishmania peruviana, with occasional genetic signatures of both in the same strain. By analysis of 53 parasite isolates from Peru, and eight additional ones from other countries, we identified an atypical L. braziliensis cluster, and confirmed the origin of L. peruviana from the L. braziliensis cluster during the colonization of the western Andean coastal valleys. We discuss the clinical and taxonomical implications of our findings in relation to currently used species typing assays. PMID- 22516227 TI - Effect of two intracellular calcium modulators on sperm motility and heparin induced capacitation in cryopreserved bovine spermatozoa. AB - Spermatozoa require a preparatory process called capacitation to fertilize mature oocytes. Two events related to capacitation of mammalian spermatozoa are an increase in intracellular Ca(2+) and protein tyrosine phosphorylation. The sites that regulate intracellular Ca(2+) concentration are plasma membrane and mitochondria. There are different systems for mitochondrial Ca(2+) influx and efflux. Our aim was to study the involvement of mitochondrial Ca(2+) cycle during heparin-induced capacitation in cryopreserved bovine spermatozoa. Samples were incubated at 38 degrees C for 45 min, in TALP medium, in the presence of: (a) heparin (H), a well known capacitation inducer; (b) H+CGP 37157, a specific inhibitor of mitochondrial Ca(2+) efflux; (c) H+RU 360, a specific inhibitor of Ca(2+) influx to the mitochondria and (d) H+CGP 37157+RU 360. In every treatment, capacitation (by CTC), progressive motility (by optical microscopy), viability (by the eosin/nigrosin technique) and protein tyrosine phosphorylation (by Western Immuno-blotting), were evaluated. The addition of CGP 37157 (20 MUM) decreased progressive motility (p<0.05), without affecting capacitation or protein tyrosine phosphorylation, indicating the importance of calcium efflux for maintaining progressive motility. RU 360 (5 MUM) significantly reduced capacitation without affecting progressive motility, sperm viability or protein tyrosine phosphorylation, showing that inhibition of the mitochondrial calcium uptake, negatively affect the capacitation process. The addition of both inhibitors showed the effect of RU 360. According with these results, there would exist a differential participation of the income and outcome mitochondrial calcium carriers, in the capacitation process. In conclusion, this research demonstrates the importance of normal mitochondrial calcium cycle in the achievement of sperm capacitation and the maintenance of progressive motility in cryopreserved bovine spermatozoa. PMID- 22516228 TI - Relationships between the ovarian status and superovulatory responses in dairy cattle. AB - The aim of this study was to determine the influence of follicular profiles over 4 days prior to superovulation on superovulatory responses. Eighty-eight Holstein cows were synchronized by two prostaglandin F(2)alpha injections given 11 days apart and conventionally superovulated between days 8 and 12 of the estrous cycle with 400 mg Folltropin-V given in decreasing doses over 4 days. Luteolysis was induced by 2 im injections of cloprostenol (2 ml) with the sixth and seventh injections of Folltropin-V. The ovaries of all cows were examined by ultrasonography with a real-time linear scanning ultrasound diagnostic system (Ls 300-A: Tokyo Keiki Co., Tokyo, Japan; 7.5 MHz Transducer) on days -3, -2, -1, 0 (initiation day of the superovulatory treatment=day 0). Data were analyzed by the GLM procedure of the SAS. Animals with a greater diameter of the largest follicle (F1; 13.4 vs 9.8 and 10.1 mm; p<0.007) and with a greater difference in the diameter of the first and second largest follicles (7.6 vs 4.5 and 3.8 mm; p<0.001) had the greater superovulatory response and produced the greater number of quality I embryos. In conclusion, the diameter of the F1 and the F1-F2 follicles were higher over a 4-day period prior to superovulation in animals yielding a high than a medium and a low number of quality I and I+II embryos. PMID- 22516229 TI - GDF-9 and bFGF enhance the effect of FSH on the survival, activation, and growth of cattle primordial follicles. AB - This study aims to investigate the effects of follicle stimulating hormone (FSH) in combination with growth and differentiation factor-9 (GDF-9) or basic fibroblast growth factor (bFGF) on the activation, survival and growth of cattle primordial follicles. Ovarian tissues were cultured for 3, 7, 14, 22 days in alpha minimum essential medium (alpha-MEM) supplemented with FSH, FSH+GDF-9 or FSH+bFGF. Non-cultured and cultured ovarian fragments were processed for histological and TUNEL analysis. Compared to the FSH medium, the results showed FSH+GDF-9 medium increased the percentage of primary follicles in all culture periods and secondary follicles after 14 days of culture (P<0.05), meanwhile the diameter of primary and secondary follicles were also observed to increase in this medium after 7 days of cultures (P<0.05). FSH+bFGF medium appeared to increase the percentage of primary follicles after 14 days of culture and secondary follicles at day 14 of culture than FSH medium (P<0.05). Furthermore, the FSH+GDF-9 and FSH+bFGF mediums had a greater percentage of normal follicles, and lesser apoptotic cell rates than FSH medium. The results first indicated that FSH in combination with GDF-9 or bFGF can improve the survival, activation, and growth of cattle primordial follicles after the long-term culture of ovarian cortex. PMID- 22516230 TI - Development of corpus luteum susceptibility to an analog of prostaglandin F2alpha, throughout the luteal phase in llamas (Lama glama). AB - The aim of the present study was to evaluate the susceptibility of the corpus luteum to d-cloprostenol (synthetic analog of PGF(2alpha)) throughout the luteal phase in llamas. Female llamas (n=43) were induced to ovulate by GnRH injection in the presence of an ovulatory follicle and randomly assigned into one of six groups: control and treated with an injection of d-cloprostenol on Day 3, 4, 5, 6 or 8 post GnRH. Blood samples were collected to determine plasma progesterone concentrations. There was no effect of treatment on animals injected on Day 3 or 4 post-GnRH. In animals treated on Day 5, different responses were observed. No effect of treatment was recorded in 27% of the animals whereas 55% of the llamas showed a transitory decrease followed by a recovery in plasma progesterone concentrations after d-cloprostenol injection, indicative of a resurgence of the corpus luteum, extending the luteal phase a day more than in control animals. In the remaining 18% of the animals injected on Day 5, (corresponding to those exhibiting the greatest plasma progesterone concentrations at the day of injection), complete luteolysis was observed. Plasma progesterone concentrations decreased to below 1 ng ml(-1) 24 h after d-cloprostenol in llamas injected on Day 6 or 8 post-GnRH. In conclusion, the corpus luteum of llamas is completely refractory to PGF(2alpha) until Day 4 after induction of ovulation, being partially sensitive by Day 5 and fully responsive to PGF(2alpha), by Day 6 after induction of ovulation. PMID- 22516231 TI - Effects of cold storage on plasma membrane, DNA integrity and fertilizing ability of feline testicular spermatozoa. AB - This study examined the effects of cold storage on plasma membrane, DNA integrity, and fertilizing ability of domestic cat spermatozoa. Intact cat testes were stored at 4 degrees C in Dulbecco's phosphate buffered saline (DPBS) for 7 days. Membrane integrity (experiment 1) and DNA integrity (experiment 2) of extracted spermatozoa were assessed over time during storage. Testicular spermatozoa were also tested for their fertilizing ability via intracytoplasmic sperm injection (ICSI) in term of gamete activation and early embryonic development at 18 h (experiment 3). The membrane integrity of testicular spermatozoa was well preserved in DPBS for 4 days compared to non-preserved control (Day 0) (P<0.05). The incidence of testicular sperm DNA fragmentation was <1% after 7 days of cold storage and was not significantly affected by the duration of cold storage (P>0.05). Finally, testicular spermatozoa could form pronuclei and sustain embryo development following ICSI regardless of the storage time (P>0.05). In conclusion, cat testicular spermatozoa can be preserved at 4 degrees C for up to 7 days without severely compromising of plasma membrane and DNA integrity while retaining a normal fertilizing ability. PMID- 22516232 TI - NK cytotoxicity and alloreactivity against neuroblastoma cell lines in vitro: comparison of Europium fluorometry assay and quantification by RT-PCR. AB - New therapies for children with high risk neuroblastoma are needed, and haploidentical stem cell transplantation with NK post-graft injections is a potential option. To develop this strategy, we compared and correlated two methods of NK cytotoxicity assay. The aim of this work is to optimize in vitro NK cytotoxicity assays, investigate the effect of interleukin stimulation on NK cells and use of antiGD2 antibodies against tumor target cells and finally establish an in vitro model for haploidentical stem cell transplantation. EXPERIMENTAL DESIGN: We evaluated NK cell cytotoxicity in vitro against NB cell lines (IMR-32 and SK-NSH) in different culture conditions using a Europium BATDA fluorescence test, and correlated the results with quantification of TH, Phox2B, and DCX transcripts evaluated by RT-PCR. RESULTS: Both IMR-32 and SK-N-SH neuroblastoma cell lines were sensitive to NK cells and particularly when NK cells were stimulated by interleukin IL-2 and IL-15 or when using anti-GD2 antibodies against tumor target cells. All these results were observed either with Europium fluorometry assay or with RT-PCR quantification. There is a clear correlation between the two methods, for the three transcripts at the ratio effector/target 50/1 (TH r=0.75, Phox2B r=0.79 and DCX r=0.8), for all the values whatever the cell line. Besides for all three transcripts, the correlations were significantly independent of the cell line and the ratio E/T (all p values non significant) even if the best correlation was observed for the ratio 50/1. After prolonged incubation times of effector and target cells (24 h), which could be evaluated only by RT-PCR, all the transcripts clearly decreased, confirming the haploidentical effect of NK against the two neuroblastoma cell lines in our two in vitro haploidentical models but no advantage of mismatch. CONCLUSIONS: NK cytotoxicity against neuroblastoma cell lines can be evaluated by Europium assay and by RT-PCR with clear correlation for the three transcripts TH, Phox2B and DCX whatever the ratio E/T and cell line used. This new method of RT-PCR is simple and suitable for large-scale conditions like study of adherent tumor cells or prolonged incubations of target/effector cells which allowed us to observe haploidentical effect. PMID- 22516233 TI - Abdominal compartment syndrome after laparoscopic Roux-en-Y gastric bypass: a case report. PMID- 22516234 TI - Comment on: Effect of primary versus revisional Roux-en-Y gastric bypass: inferior weight loss of revisional surgery after gastric banding. PMID- 22516235 TI - The location and trafficking routes of the neuronal retromer and its role in amyloid precursor protein transport. AB - The retromer complex plays an important role in intracellular transport, is highly expressed in the hippocampus, and has been implicated in the trafficking of the amyloid precursor protein (APP). Nevertheless, the trafficking routes of the neuronal retromer and the role it plays in APP transport in neuronal processes remain unknown. Here we use hippocampal neuronal cultures to address these issues. Using fluorescence microscopy, we find that Vps35, the core element of the retromer complex, is in dendrites and axons, is enriched in endosomes and trans-Golgi network, and is found in APP-positive vesicles. Next, to identify the role the neuronal retromer plays in cargo transport, we infected hippocampal neurons with a lentivirus expressing shRNA to silence Vps35. By live fluorescence imaging, Vps35 deficiency was found to reduce the frequency, but not the kinetics, of long-range APP transport within neuronal processes. Supporting the interpretation that retromer promotes long-range transport, Vps35 deficiency led to increased APP in the early endosomes, in processes but not the soma. Finally, Vps35 deficiency was associated with increased levels of Abeta, a cleaved product of APP, increased colocalization of APP with its cleaving enzyme BACE1 in processes, and caused an enlargement of early endosomes. Taken together, our studies clarify the function of the neuronal retromer, and suggest specific mechanisms for how retromer dysfunction observed in Alzheimer's disease affects APP transport and processing. PMID- 22516236 TI - Use of spatial information to predict multidrug resistance in tuberculosis patients, Peru. AB - To determine whether spatiotemporal information could help predict multidrug resistance at the time of tuberculosis diagnosis, we investigated tuberculosis patients who underwent drug susceptibility testing in Lima, Peru, during 2005 2007. We found that crude representation of spatial location at the level of the health center improved prediction of multidrug resistance. PMID- 22516237 TI - Possible nosocomial transmission of Pneumocystis jirovecii. PMID- 22516238 TI - The cortical language circuit: from auditory perception to sentence comprehension. AB - Over the years, a large body of work on the brain basis of language comprehension has accumulated, paving the way for the formulation of a comprehensive model. The model proposed here describes the functional neuroanatomy of the different processing steps from auditory perception to comprehension as located in different gray matter brain regions. It also specifies the information flow between these regions, taking into account white matter fiber tract connections. Bottom-up, input-driven processes proceeding from the auditory cortex to the anterior superior temporal cortex and from there to the prefrontal cortex, as well as top-down, controlled and predictive processes from the prefrontal cortex back to the temporal cortex are proposed to constitute the cortical language circuit. PMID- 22516239 TI - Understanding all inconsistency compensation as a palliative response to violated expectations. AB - It has been repeatedly shown that, when people have experiences that are inconsistent with their expectations, they engage in a variety of compensatory efforts. Although there have been many superficially different accounts for these behaviors, a potentially unifying inconsistency compensation perspective is currently coalescing. Following from a common prediction error/conflict monitoring mechanism, any given inconsistency is understood as evoking a common syndrome of aversive arousal. In turn, this aversive arousal is understood to motivate palliative efforts, which manifest as the analogous compensation behaviors reported within different psychological literatures. Based on this perspective, compensation efforts following both 'high-level' (e.g., attitudinal dissonance) and 'low-level' (e.g., Stroop task color/word mismatches) inconsistencies can now be understood in terms of a common motivational account. PMID- 22516240 TI - Success of endovenous saphenous and perforator ablation in patients with symptomatic venous insufficiency receiving long-term warfarin therapy. AB - BACKGROUND: Endovenous ablation of great (GSV) and short saphenous vein (SSV) reflux has become the initial procedure for most patients with symptomatic venous insufficiency, and perforator ablation is increasingly used to assist in healing venous ulceration. Many patients have comorbid conditions, which require long term anticoagulation with warfarin; however, the impact of a long-term anticoagulation therapy on endovenous ablation procedures is not understood. This study aims to determine the effects of chronic anticoagulation on the outcomes of endovenous ablation procedures in patients with chronic venous insufficiency (CVI). METHODS: Consecutive patients undergoing endovenous ablation for to Clinical severity (CEAP) class 2 through 6 CVI between January 1, 2005 and May 1, 2011 were evaluated; 781 patients with chronic venous reflux underwent 1,180 endovenous ablation procedures. We identified 45 patients receiving long-term anticoagulation therapy who underwent 71 endovenous ablation procedures, including 37 GSVs, 12 SSVs, and 22 perforator vein procedures. All patients underwent wound examination and duplex ultrasonography within 48 to 72 hours. Outcomes evaluated included closure rate and postoperative complications. RESULTS: The mean age of the patients was 69.7 +/- 13 years. Most patients treated presented with active venous ulceration (59% CEAP 6). Indications for anticoagulation included atrial fibrillation (n = 9, 20%), previous deep venous thrombosis (n = 16, 36%), hypercoagulable state (n = 9, 20%), prosthetic valve (n = 2, 4%), and others (n = 9, 20%). All patients receiving warfarin therapy (100%) underwent a postprocedure ultrasonography, which confirmed the successful closure of the GSVs and SSVs; successful initial perforator closure was achieved in 59% of patients (13/22). Repeat perforator ablation yielded a closure rate of 77%. Compared with a matched cohort group of 35 patients (61 perforators) undergoing perforator ablation without anticoagulation, treated during the same period, there was no significant difference in the rates of successful closure between the groups. No patients developed postoperative deep venous thrombosis or pulmonary embolus. No additional thrombotic complications were noted. Three patients (4.2%) developed a small hematoma after the procedure, which resolved with conservative treatment. No patients required postoperative hospital admission, and no postprocedure deaths occurred. CONCLUSIONS: Based on our protocol, patients with severe CVI who were receiving long-term warfarin therapy can be treated safely and effectively with endovenous radiofrequency ablation for incompetent GSVs, SSVs, and perforator veins. Long-term warfarin therapy did not have a significant effect on perforator closure rates compared with no anticoagulation. PMID- 22516241 TI - Open and endovascular repair of popliteal artery aneurysms: tabular review of the literature. AB - Popliteal artery aneurysms (PAAs) have been referred to as "the silent killer" because of the devastating thromboembolic events they can cause without warning symptoms. Open surgical repair of PAA remains the gold standard, although the endovascular approach has being increasingly reported during the past years. Open repair can be performed over the medial or posterior approach, depending on the extent of the aneurysm and surgeon's preference. The goal of the present article is to summarize the clinical results of open and endovascular repair of PAA and to serve as a practical and prompt literature search tool for all surgeons and endovascular specialists who encounter this disease process in their practices. PMID- 22516242 TI - Combined metallothioneins and p53 proteins expression as a prognostic marker in patients with Dukes stage B and C colorectal cancer. AB - Our study aimed to evaluate metallothionein and p53 expression in colorectal cancer and to correlate their combined expression with selected clinical and pathologic variables of the disease, to define their prognostic significance. Colorectal cancer specimens from 99 patients were retrospectively analyzed by immunohistochemistry for metallothionein and p53 expression. Survival curves were generated according to the Kaplan-Meier method, and univariate survival distributions were compared with the use of the log-rank test. Multivariate models were computed using Cox proportional hazards regression. This research was approved by the institutional review boards of all centers. Tumors showing concomitant high metallothionein expression and negative p53 (metallothionein(H)/p53(-)) were significantly inversely related to depth of invasion, frequency of nodal metastasis, and Dukes stage (P < .01). In univariate analysis, patients with metallothionein(H)/p53(-) phenotype showed a better overall survival (hazard ratio [HR], 2.83; P < .05) and disease-free survival (HR, 2.03; P < .05). In multivariate analysis, considering staging, metallothionein, and metallothionein + p53 variables, in 83 patients with Dukes stages B and C, metallothionein(H)/p53(-) combination was the sole factor showing an independent prognostic value for overall survival (HR, 3.88; P < .1) and disease-free survival (HR, 2.56; P < .1). In conclusion, the combined analysis of metallothionein and p53 may enhance the prognostic power of each individual marker by predicting the progression of the disease and contributing to a better identification of patients at low risk for mortality, especially for those with Dukes stage B and C colorectal cancer. PMID- 22516243 TI - Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature. AB - Immunohistochemical detection of DNA mismatch repair proteins and polymerase chain reaction detection of microsatellite instability have enhanced the recognition of mismatch repair-deficient neoplasms in patients with Lynch syndrome and, consequently, led to the identification of tumors that have not been included in the currently known Lynch syndrome tumor spectrum. Here, we report 4 such unusual tumors. Three of the 4, a peritoneal mesothelioma, a pancreatic acinar cell carcinoma, and a pancreatic well-differentiated neuroendocrine tumor, represented tumor types that, to the best of our knowledge, have not been previously reported in Lynch syndrome. The fourth tumor was an adrenocortical carcinoma, which has rarely been reported previously in Lynch syndrome. Three of our 4 patients carried a pathogenic germ-line mutation in a mismatch repair gene. The unusual tumor in each of the 3 patients showed loss of the mismatch repair protein corresponding to the mutation. The fourth patient did not have mutation information but had a history of colonic and endometrial carcinomas; both lacked MSH2 and MSH6 proteins. Interestingly, none of the 4 unusual tumors revealed microsatellite instability on polymerase chain reaction testing, whereas an appendiceal carcinoma from 1 of the study patients who was tested simultaneously did. The recognition of such tumors expands the repertoire of usable test samples for the workup of high-risk families. As yet, however, there are no data to support the inclusion of these tumors into general screening guidelines for detecting Lynch syndrome, nor are there data to warrant surveillance for these tumors in patients with Lynch syndrome. PMID- 22516244 TI - Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer. AB - Neoadjuvant chemotherapy or preoperative systemic therapy is increasingly considered for patients with operable breast cancer. Patients with breast cancer were examined for pathologic factors predictive of response to neoadjuvant chemotherapy, using an anthracycline-based regimen. For clinical histomorphology and biomarkers, factors were compared among 16 pathologically complete responses and 52 nonpathologically complete responses, using univariate analysis and multivariate regression analysis of principal components, using preneoadjuvant chemotherapy needle biopsy samples as follows: degree of tumor-infiltrating lymphocytes, histologic grade, biology-based tumor type (hormone receptors and HER2 [human epidermal growth factor receptor type 2]), age, clinical TNM stage, and TNM staging. In univariate analysis, high tumor-infiltrating lymphocyte, high histologic grade, and hormone receptors(-)/HER2(+) were significantly associated with pathologically complete responses (93.7%, P < .0001; 81.3%, P = .0206; 43.7%, P = .014, respectively). In multivariate principal component regression analysis, high tumor-infiltrating lymphocytes were the best independent predictor for pathologically complete responses (odds ratio, 4.7; confidence interval, 2.2 10.06; P < .0001). Among tumor-infiltrating lymphocytes and biology-based tumor types, patients with high tumor-infiltrating lymphocytes had pathologically complete responses more than nonpathologically complete responses, especially in the hormone receptors(-)/HER2(+) group. Among high tumor-infiltrating lymphocyte cases, T lymphocytes showed more predominant tendency than B lymphocytes in the pathologically complete responses cases, compared with nonpathologically complete responses cases. These findings indicate that high tumor-infiltrating lymphocytes are important predictors of pathologically complete responses to neoadjuvant chemotherapy, especially in the hormone receptors(-)/HER2(+) group. PMID- 22516245 TI - alpha-Fetoprotein-producing gastric carcinoma and combined hepatocellular and cholangiocarcinoma show similar morphology but different histogenesis with respect to SALL4 expression. AB - alpha-Fetoprotein is expressed in hepatocellular carcinoma, yolk sac tumor, and some gastric carcinomas. The alpha-fetoprotein-producing gastric carcinoma composed of hepatoid and common adenocarcinoma shows morphological similarities to combined hepatocellular and cholangiocarcinoma. In this study, the expression of putative hepatic stem/progenitor markers (EpCAM, OV-6, DLK-1, and NCAM/CD56), hepatocyte markers (HepParI, alpha-fetoprotein, glypican 3), and the germ cell marker SALL4 was examined in alpha-fetoprotein-producing gastric carcinoma (20 cases) and combined hepatocellular and cholangiocarcinoma (20 cases) for evaluation of pathologic differentiation and also the histogenesis of both tumors. The SALL4 protein was expressed in 95% of alpha-fetoprotein-producing gastric carcinoma, including the hepatoid component (hepatoid gastric carcinoma), but was absent in combined hepatocellular and cholangiocarcinoma. Glypican 3 and alpha-fetoprotein were detected in all hepatoid-type alpha-fetoprotein-producing gastric carcinoma but variably in combined hepatocellular and cholangiocarcinoma. NCAM/CD56 was expressed focally in combined hepatocellular and cholangiocarcinoma but was rare in hepatoid gastric carcinoma. EpCAM, DLK-1, and OV6 were variably expressed in hepatoid gastric carcinoma and combined hepatocellular and cholangiocarcinoma. SALL4 was a useful differential marker for combined hepatocellular and cholangiocarcinoma and hepatoid gastric carcinoma. The histogenesis of hepatoid gastric carcinoma expressing SALL4 seems to reflect fetal gut differentiation or involve the germ cell lineage and may be different from that of combined hepatocellular and cholangiocarcinoma involving the hepatic stem cell or progenitor cell lineages. In conclusion, hepatoid gastric carcinoma and combined hepatocellular and cholangiocarcinoma shared morphologies, whereas the distinction of hepatoid gastric carcinoma from combined hepatocellular and cholangiocarcinoma is possible by immunostaining for SALL4. These 2 tumors seem to differ in their histogenesis with respect to SALL4 expression.1. PMID- 22516246 TI - Effects of antipsychotic medications on quality of life and psychosocial functioning in patients with early-stage schizophrenia: 1-year follow-up naturalistic study. AB - BACKGROUND: The relative effects of the atypical antipsychotic drugs and conventional agent on quality of life and psychosocial functioning in patients with early-stage schizophrenia is still uncertain because of an insufficient number of studies examining this issue. METHODS: In a 12 months open-label, prospective observational, multicenter study, 1029 subjects with schizophrenia or schizophreniform disorder within 5 years of onset were monotherapy with chlorpromazine, sulpiride, clozapine, risperidone, olanzapine, quetiapine or aripiprazole. The health-related quality of life and psychosocial functioning were assessed using Medical Outcomes Study 36-Item Short Form Health Survey (SF 36), the Global Assessment Scale (GAS) and the Activities of Daily Living Scale (ADL), respectively. RESULTS: At 12 months, treatment resulted in significant improvements in all 8 domain scores of SF-36, GAS and ADL score (all P-values< .001). However, only olanzapine and quetiapine groups demonstrated greater improvement in the role-psychical score of SF-36 and GAS score than did the chlorpromazine group (all P-values <= .002). CONCLUSIONS: All antipsychotics may improve quality of life and social function in patients with early-stage schizophrenia, but further studies are needed to determine whether atypical antipsychotics are superior to conventional agents. PMID- 22516247 TI - Direct lactic acid fermentation of Jerusalem artichoke tuber extract using Lactobacillus paracasei without acidic or enzymatic inulin hydrolysis. AB - Lactic acid fermentation of Jerusalem artichoke tuber was performed with strains of Lactobacillus paracasei without acidic or enzymatic inulin hydrolysis prior to fermentation. Some strains of L. paracasei, notably KCTC13090 and KCTC13169, could ferment hot-water extract of Jerusalem artichoke tuber more efficiently compared with other Lactobacillus spp. such as L. casei type strain KCTC3109. The L. paracasei strains could utilize almost completely the fructo-oligosaccharides present in Jerusalem artichoke. Inulin-fermenting L. paracasei strains produced c.a. six times more lactic acid compared with L. casei KCTC3109. Direct lactic fermentation of Jerusalem artichoke tuber extract at 111.6g/L of sugar content with a supplement of 5 g/L of yeast extract by L. paracasei KCTC13169 in a 5L jar fermentor produced 92.5 ce:hsp sp="0.25"/>g/L of lactic acid with 16.8 g/L fructose equivalent remained unutilized in 72 h. The conversion efficiency of inulin-type sugars to lactic acid was 98% of the theoretical yield. PMID- 22516248 TI - Metabolic profiling of a Rhizopus oryzae fumaric acid production mutant generated by femtosecond laser irradiation. AB - Femtosecond laser irradiation was employed to induce mutations in Rhizopus oryzae, leading to increases in fumaric acid production. Compared to the parental strain, mutant strain FM19 exhibited an increase in titer and yield of 56.3% and 36.6%, respectively, corresponding to a titer of 49.4 g/L and a yield of 0.56 g fumaric acid per g glucose. Metabolic profiling by gas chromatography-mass spectrometry revealed that higher levels of carbon (Embden-Meyerhof-Parnas and tricarboxylic acid cycle) and amino acid metabolism were operating in the high yielding strain; particularly, 4-aminobutyric acid and 5-aminolevulinic acid were increased 10.33- and 7.22-fold, respectively, compared with parental strain during stationary phase. These findings provided new insights into metabolic characterization of high-yielding fumaric acid R. oryzae. PMID- 22516249 TI - Fungal pretreatment of cornstalk with Phanerochaete chrysosporium for enhancing enzymatic saccharification and hydrogen production. AB - The feasibility of fungal pretreatment of cornstalk with Phanerochaete chrysosporium for enzymatic saccharification and H(2) production was investigated in this study. Firstly, cornstalk was pretreated with P. chrysosporium at 29 degrees C under static condition for 15 d, lignin reduction was up to 34.3% with holocellulose loss less than 10%. Microscopic structure observation combined FTIR analysis further demonstrated that the lignin and crystallinity were decreased. Subsequently, the fungal-pretreated cornstalk was subjected to enzymatic hydrolysis by the crude cellulase from Trichoderma viride to produce fermentable sugars which were then fermented to bio-H(2) using Thermoanaerobacterium thermosaccharolyticum W16. The maximum enzymatic saccharification was found to be 47.3% which was 20.3% higher than the control without pretreatment. Upon fermentation of enzymatic hydrolysate, the yield of H(2) was calculated to be 80.3 ml/g-pretreated cornstalk. The present results suggested the potential of using hydrogen-producing bacteria for high-yield conversion of cornstalk into bio H(2) integrate with biological pretreatment and enzymatic saccharification. PMID- 22516250 TI - Populus seed fibers as a natural source for production of oil super absorbents. AB - The genus Populus, which includes poplars, cottonwoods and aspen trees, represents a huge natural source of fibers with exceptional physical properties. In this study, the oil absorption properties of poplar seed hair fibers obtained from Populus nigra italica when tested with high-density motor oil and diesel fuel are reported. Poplar seed hair fibers are hollow hydrophobic microtubes with an external diameter between 3 and 12 MUm, an average length of 4+/-1 mm and average tube wall thickness of 400+/-100 nm. The solid skeleton of the hollow fibers consists of lignocellulosic material coated by a hydrophobic waxy coating. The exceptional chemical, physical and microstructural properties of poplar seed hair fibers enable super-absorbent behavior with high absorption capacity for heavy motor oil and diesel fuel. The absorption values of 182-211 g heavy oil/g fiber and 55-60 g heavy oil/g fiber for packing densities of 0.005 g/cm(3) and 0.02 g/cm(3), respectively, surpass all known natural absorbents. Thus, poplar seed hair fibers obtained from Populus nigra italica and other trees of the genus Populus are an extremely promising natural source for the production of oil super absorbents. PMID- 22516251 TI - The effect of paliperidone extended release on subjective well-being and responses in patients with schizophrenia. AB - OBJECTIVE: This study aimed to evaluate the subjective well-being and attitudes toward antipsychotic medication of patients with schizophrenia who had switched to paliperidone extended release (ER). METHODS: A total of 291 patients with schizophrenia treated with antipsychotics participated in this open-label, 24 week switching study. The primary outcome measures were the Subjective Well-Being under Neuroleptic Treatment Scale-short version (SWN-K) and the Drug Attitude Inventory (DAI). The Krawiecka scale, Clinical Global Impression-Schizophrenia (CGI-SCH), Personal and Social Performance scale (PSP) were used to evaluate psychopathology and psychosocial functioning, respectively. RESULTS: Data from a total of 243 subjects who received the study medication and had at least one follow-up assessment without a major protocol violation were analyzed. Scores on the DAI and SWN-K showed significant improvement between baseline and end-point measurements beginning during the second week. Scores on the Krawiecka scale, all five subscales of the CGI-SCH scale, and the PSP scale were also significantly improved at the end point compared with the baseline. Significant predictors of improvements in the SWN-K and DAI after a switch to paliperidone ER were baseline scores, reductions in scores on the Krawiecka scale, and previous risperidone use. A clinically relevant increase in body weight (>=7% weight gain) occurred in one-fourth of the participants who completed the 24-week study. CONCLUSION: Switching to paliperidone ER improved the subjective well-being and attitudes towards antipsychotic medication in patients with schizophrenia. Exploratory analyses revealed that these improvements were particularly pronounced in patients who had been treated with risperidone before treatment with paliperidone ER. PMID- 22516252 TI - Tobacco smoking produces greater striatal dopamine release in G-allele carriers with mu opioid receptor A118G polymorphism. AB - OBJECTIVE: To determine if carriers of the allelic expression of the G variant of the human mu opioid receptor (OPRM1) A118G polymorphism have greater increases in striatal dopamine (DA) release after tobacco smoking. METHODS: Nineteen of 20 genotyped male tobacco smokers, after overnight abstinence, smoked denicotinized (denic) and average nicotine (nic) containing tobacco cigarettes in a PET brain imaging study using [(11)C]raclopride. RESULTS: The right striatum had more free D(2) receptors than the left striatum pre- and post-tobacco smoking. After smoking the nic cigarettes, mean decreased DA binding was observed in the left dorsal caudate (-14 6 11; t=3.77), left and right ventral putamen (-26 3-8; t=4.27; 28 2 1; t=4.25, respectively), and right caudate (17 18 1; t=3.92). The effects of A118G genotype on the binding potentials for these four regions were then analyzed. Carriers of the G allele had larger magnitudes of DA release in response to nic smoking than those homozygous for the more prevalent AA allele in the right caudate and right ventral pallidum (t=3.03; p=0.008 and t=3.91; p=0.001). A voxel by voxel whole brain SPM analysis using an independent samples t test did not reveal any other differences between genotype groups. In addition, the venous plasma cortisol levels of the volunteers from 8:30 a.m. to 12:40 p.m. were lower in the AG/GG allele carriers. Nic smoking increased plasma cortisol in both groups, but they were higher in the AA group. CONCLUSION: This preliminary study indicates a difference in both brain striatal DA release and plasma cortisol in A118G polymorphic male tobacco smokers. PMID- 22516253 TI - Calming down T cell acute leukemia. AB - Signaling from class I phosphoinositide 3-kinase (PI3K) is often deregulated in leukemia and lymphoma, but which isoforms are involved in T cell acute lymphoblastic leukemia (T-ALL) was not known. In this issue of Cancer Cell, Subramaniam et al. show that T-ALL can be tamed by inhibiting gamma and delta PI3K isoforms. PMID- 22516254 TI - Breaking the LSD1/KDM1A addiction: therapeutic targeting of the epigenetic modifier in AML. AB - KDM1A/LSD1, a histone H3K4/K9 demethylase and epigenetic regulator with roles in both gene activation and repression, has increased expression in multiple cancer types. Harris et al., in this issue of Cancer Cell, and Schenk et al. show that KDM1A may be a viable therapeutic target in treating AML. PMID- 22516255 TI - Hijacking T cell differentiation: new insights in TLX function in T-ALL. AB - TLX1 and TLX3 are two closely-related homeobox transcriptional repressors frequently misexpressed and translocated in T cell acute lymphoblastic leukemia (T-ALL). In this issue of Cancer Cell, Dadi et al. provide new insights into how these factors are recruited by ETS-1 to the TCRalpha enhancer and actively repress differentiation. PMID- 22516256 TI - Personalized medicine: patient-predictive panel power. AB - Two recent papers published in Nature demonstrate the power of systematic high throughput pharmacologic profiling of very large, diverse, molecularly characterized human cancer cell line panels to reveal linkages between genetic profile and targeted-drug sensitivity. Known oncogene addictions are confirmed while surprising complexities and biomarker relationships with clinical potential are revealed. PMID- 22516257 TI - Targeting nonclassical oncogenes for therapy in T-ALL. AB - Constitutive phosphoinositide 3-kinase (PI3K)/Akt activation is common in T cell acute lymphoblastic leukemia (T-ALL). Although four distinct class I PI3K isoforms (alpha, beta, gamma, delta) could participate in T-ALL pathogenesis, none has been implicated in this process. We report that in the absence of PTEN phosphatase tumor suppressor function, PI3Kgamma or PI3Kdelta alone can support leukemogenesis, whereas inactivation of both isoforms suppressed tumor formation. The reliance of PTEN null T-ALL on the combined activities of PI3Kgamma/delta was further demonstrated by the ability of a dual inhibitor to reduce disease burden and prolong survival in mice as well as prevent proliferation and promote activation of proapoptotic pathways in human tumors. These results support combined inhibition of PI3Kgamma/delta as therapy for T-ALL. PMID- 22516258 TI - Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. AB - Little is known about the dynamics of cancer cell death in response to therapy in the tumor microenvironment. Intravital microscopy of chemotherapy-treated mouse mammary carcinomas allowed us to follow drug distribution, cell death, and tumor stroma interactions. We observed associations between vascular leakage and response to doxorubicin, including improved response in matrix metalloproteinase 9 null mice that had increased vascular leakage. Furthermore, we observed CCR2 dependent infiltration of myeloid cells after treatment and that Ccr2 null host mice responded better to treatment with doxorubicin or cisplatin. These data show that the microenvironment contributes critically to drug response via regulation of vascular permeability and innate immune cell infiltration. Thus, live imaging can be used to gain insights into drug responses in situ. PMID- 22516259 TI - Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. AB - Increased translocation of intestinal bacteria is a hallmark of chronic liver disease and contributes to hepatic inflammation and fibrosis. Here we tested the hypothesis that the intestinal microbiota and Toll-like receptors (TLRs) promote hepatocellular carcinoma (HCC), a long-term consequence of chronic liver injury, inflammation, and fibrosis. Hepatocarcinogenesis in chronically injured livers depended on the intestinal microbiota and TLR4 activation in non-bone-marrow derived resident liver cells. TLR4 and the intestinal microbiota were not required for HCC initiation but for HCC promotion, mediating increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis. Gut sterilization restricted to late stages of hepatocarcinogenesis reduced HCC, suggesting that the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease. PMID- 22516260 TI - DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo. AB - Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe mechanism mediated by the DNA damage response (DDR) machinery that results in activation of the ATR/ATM Chk1/Chk2-p53/p21(CIP1) checkpoint and cellular senescence at early stages of cellular transformation caused by a regulatable MLL-ENL-ERtm in mice. Furthermore, we identified the transcription program underlying this intrinsic anticancer barrier, and DDR-induced inflammatory regulators that fine-tune the signaling toward senescence, thereby modulating the fate of MLL-ENL-immortalized cells in a tissue-environment-dependent manner. Our results indicate that DDR is a rate-limiting event for acquisition of stem cell-like properties in MLL-ENL ERtm-mediated transformation, as experimental inhibition of the barrier accelerated the transition to immature cell states and acute leukemia development. PMID- 22516261 TI - VHL-regulated MiR-204 suppresses tumor growth through inhibition of LC3B-mediated autophagy in renal clear cell carcinoma. AB - The von Hippel-Lindau tumor-suppressor gene (VHL) is lost in most clear cell renal cell carcinomas (ccRCC). Here, using human ccRCC specimens, VHL-deficient cells, and xenograft models, we show that miR-204 is a VHL-regulated tumor suppressor acting by inhibiting macroautophagy, with MAP1LC3B (LC3B) as a direct and functional target. Of note, higher tumor grade of human ccRCC was correlated with a concomitant decrease in miR-204 and increase in LC3B levels, indicating that LC3B-mediated macroautophagy is necessary for RCC progression. VHL, in addition to inducing endogenous miR-204, triggered the expression of LC3C, an HIF regulated LC3B paralog, that suppressed tumor growth. These data reveal a function of VHL as a tumor-suppressing regulator of autophagic programs. PMID- 22516262 TI - Chemical genomics identifies small-molecule MCL1 repressors and BCL-xL as a predictor of MCL1 dependency. AB - MCL1, which encodes the antiapoptotic protein MCL1, is among the most frequently amplified genes in human cancer. A chemical genomic screen identified compounds, including anthracyclines, that decreased MCL1 expression. Genomic profiling indicated that these compounds were global transcriptional repressors that preferentially affect MCL1 due to its short mRNA half-life. Transcriptional repressors and MCL1 shRNAs induced apoptosis in the same cancer cell lines and could be rescued by physiological levels of ectopic MCL1 expression. Repression of MCL1 released the proapoptotic protein BAK from MCL1, and Bak deficiency conferred resistance to transcriptional repressors. A computational model, validated in vivo, indicated that high BCL-xL expression confers resistance to MCL1 repression, thereby identifying a patient-selection strategy for the clinical development of MCL1 inhibitors. PMID- 22516263 TI - TLX homeodomain oncogenes mediate T cell maturation arrest in T-ALL via interaction with ETS1 and suppression of TCRalpha gene expression. AB - Acute lymphoblastic leukemias (ALLs) are characterized by multistep oncogenic processes leading to cell-differentiation arrest and proliferation. Specific abrogation of maturation blockage constitutes a promising therapeutic option in cancer, which requires precise understanding of the underlying molecular mechanisms. We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) alpha enhanceosome activity and blocked TCR Jalpha rearrangement. TLX1/TLX3 abrogation or enforced TCRalphabeta expression leads to TCRalpha rearrangement and apoptosis. Importantly, the autoextinction of clones carrying TCRalpha-driven TLX1 expression supports TLX "addiction" in TLX positive leukemias and provides further rationale for targeted therapy based on disruption of TLX1/TLX3. PMID- 22516264 TI - Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. AB - We characterized leukemia stem cells (LSC) in chronic phase chronic myelogenous leukemia (CML) using a transgenic mouse model. LSC were restricted to cells with long-term hematopoietic stem cell (LTHSC) phenotype. CML LTHSC demonstrated reduced homing and retention in the bone marrow (BM), related to decreased CXCL12 expression in CML BM, resulting from increased G-CSF production by leukemia cells. Altered cytokine expression in CML BM was associated with selective impairment of normal LTHSC growth and a growth advantage to CML LTHSC. Imatinib (IM) treatment partially corrected abnormalities in cytokine levels and LTHSC growth. These results were validated using human CML samples and provide improved understanding of microenvironmental regulation of normal and leukemic LTHSC and their response to IM in CML. PMID- 22516265 TI - Comparison of gaseous cryotherapy with more traditional forms of cryotherapy following total knee arthroplasty. AB - OBJECTIVE: The aim of this study was to assess the efficacy of gaseous cryotherapy following total knee arthroplasty (TKA) and to compare it to routinely used strategies for applying cold therapy. PATIENTS AND METHODS: Sixty six patients undergoing primary unilateral TKA were randomized into three groups and received "gaseous cryotherapy (GC)", "cold pack" and "cryocuff" applications, respectively throughout the hospital stay. Primary outcomes (knee pain intensity, mobility and girth measurements) were recorded on preoperative day 1 as well as on postoperative day (POD) 7. Cutaneous temperature of the knee sides were also measured on POD7 just before and immediately after cold application. RESULTS: Although skin temperature dropped to 14 degrees C following GC versus 22 to 24 degrees C for the other two applications (P<0,05), the three groups did not differ at POD7 regarding the three primary outcomes. No adverse effects were observed with any of the ways of application. CONCLUSIONS: Gaseous cryotherapy was not more beneficial than routinely used strategies for applying cold therapy. Further studies with larger sample size and with a more frequent and closer gaseous cryotherapy applications are needed to confirm our results. PMID- 22516266 TI - NO modulation of carotid body chemoreception in health and disease. AB - Nitric oxide (NO), at physiological concentrations, is a tonic inhibitory modulator of carotid body (CB) chemosensory discharges. NO modulates the chemoreception process by several mechanisms, indirectly by modifying the vascular tone and oxygen delivery, and directly through the modulation of the excitability of glomus cells and petrosal neurons. In addition to the inhibitory effect, at high concentrations NO has a dual dose-dependent effect on CB chemoreception that depends on the P(O(2)). In hypoxic conditions, NO is primarily an inhibitory modulator of CB chemoreception, while in normoxia NO increases the chemosensory discharges. In this review, we will examine new evidence supporting the idea that NO is involved in the CB chemosensory potentiation induced by congestive heart failure (CHF) and chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea (OSA). Evidence from patients and experimental animal models indicates that CHF and OSA, as well as CIH, potentiate the carotid hypoxic chemoreflexes, contributing to enhance the sympathetic tone. Moreover, animals exposed to CIH or to pacing-induced CHF showed enhanced baseline CB discharges in normoxia and potentiated chemosensory responses to acute hypoxia. Several molecules and pathways are altered in CHF, OSA and CIH, but the available evidence suggests that a reduced NO production in the CB plays an essential role in both diseases, contributing to enhance the CB chemosensory discharges. PMID- 22516267 TI - Gas biology: tiny molecules controlling metabolic systems. AB - It has been recognized that gaseous molecules and their signaling cascades play a vital role in alterations of metabolic systems in physiologic and pathologic conditions. Contrary to this awareness, detailed mechanisms whereby gases exert their actions, in particular in vivo, have been unclear because of several reasons. Gaseous signaling involves diverse reactions with metal centers of metalloproteins and thiol modification of cysteine residues of proteins. Both the multiplicity of gas targets and the technical limitations in accessing local gas concentrations make dissection of exact actions of any gas mediator a challenge. However, a series of advanced technologies now offer ways to explore gas responsive regulatory processes in vivo. Imaging mass spectrometry combined with quantitative metabolomics by capillary-electrophoresis/mass spectrometry reveals spatio-temporal profiles of many metabolites. Comparing the metabolic footprinting of murine samples with a targeted deletion of a specific gas producing enzyme makes it possible to determine sites of actions of the gas. In this review, we intend to elaborate on the ideas how small gaseous molecules interact with metabolic systems to control organ functions such as cerebral vascular tone and energy metabolism in vivo. PMID- 22516268 TI - [Quality of life in patients with schizophrenia: a study of 100 cases]. AB - OBJECTIVE: The aim of the present study was to evaluate the quality of life (QOL) in outpatients with schizophrenia, and to identify factors correlated to an impaired QOL among them. SUBJECTS AND METHODS: A transversal study, in the form of an inquiry, was conducted in 100 outpatients, during seven months, in the psychiatric department of the Hedi Chaker teaching hospital in Sfax - Tunisia. We used the "36 item Short-Form Health Survey" (SF-36) to assess the QOL; this has been considered as impaired when the global medium score was inferior to 66.7. For the global assessment of functioning and the global assessment of the interference by existing side effects with the patient's daily performance, we have used respectively the Global Assessment of Functioning scale (GAF) and the Udvalg of Kliniske Undersogelser (UKU) side effect rating scale. The positive and negative symptoms added to the general psychopathology were assessed using the Positive and Negative syndrome scale (PANSS). RESULTS: The QOL was impaired in 34% of the cases. The analysis of the scores of the eight dimensions by the scale SF-36 has shown that the most affected dimensions were, in decreasing order: mental health (MH), general health perceptions (GH), vitality (VT), role limitations due to physical health problems (RP) and role limitations due to emotional problems (RE). The standardization revealed that six dimensions were impaired; these were, in decreasing order: mental health (MH), social functioning (SF), role limitations due to emotional problems (RE), role limitations due to physical health problems (RP), general health perceptions (GH) and physical functioning (PF). The standardization has also revealed an impairment of the psychological component, while the physical component has been conserved. After analysis by multiple linear regression, four factors appeared strongly correlated with the impaired QOL: the professional inactivity, the episodic course with interepisode residual symptoms, the presence of side effects moderately influencing the daily performance, and a general psychopathology score for 26 at least. These four factors affected, in decreasing order of importance, social functioning (SF) (related to two factors), general health perceptions (GH) and role limitations due to emotional problems (RE) (each related to one factor). None of the factors appeared to affect the other dimensions: physical functioning (PF), role limitations due to the physical health problems (RP), bodily pain (BP), mental health (MH) and vitality (VT). The bivariate analysis revealed three other factors correlated, to a lesser degree, to the impairment of the QOL: the disorganized sub-type, a score of (GAF) inferior or equal to 30 and the negative type of schizophrenia. CONCLUSION: Management of schizophrenic patients should go beyond the remission of the symptoms; it has also to target the improvement in QOL. This needs an action over the factors that affect the QOL, among which residual symptoms and side effects. The atypical antipsychotics would contribute preciously in this way, due to their efficacy on negative symptoms and their better tolerance than the conventional ones. PMID- 22516269 TI - ["Suicidal intentions": literature review and perspectives]. AB - INTRODUCTION: Fifteen years ago, Baechler presented his "strategic theory of suicide". Following a viewpoint initiated at the end of the 1950's by Stengel and Cook, he proposed the more accomplished theoretical development of suicidal functions. We propose a critical review of international empiric literature following this approach. METHOD: We carried out a bibliographic research on PsychINFO((r)) databank, crossing terms of suicide attempt, deliberate self-harm and parasuicide, to reasons, motivations, functions, intentions. Thirty-one articles were selected. They cover a period ranging from 1971 to 2008, and from Europe to the USA. RESULTS: Few studies have been conducted in France, but international literature has grown since 1970, and some questionnaires have been created: e.g. the Motives for Parasuicide Questionnaire (MPQ, Kerkhof et al., 1993 [28]) and the Reasons for Attempting Suicide Questionnaire (RASQ, Holden et al., 1998 [24]). The first intentions mentioned are internal perturbations type: to get relief, to escape, cannot endure situation or thoughts any longer, loss of control. They are often blended with interpersonal intentions: to make people understand what they felt, to seek help, to make things easier for others, while more aggressive, punitive or manipulative functions are seldom reported. Women report more reasons than men, but do not differ in their pattern of intentions. Suicide attempters report varying desire to die across studies. Some inconsistent distinctions can be made from age and gender but few from subjects' suicidal history. DISCUSSION: One can wonder if subject's answers are really honest, particularly in regards to social desirability. Links between internal perturbations and suicidal intent, hopelessness, and depression are logically found, which aims to give evidence that, at least for this dimension, subjects give true answers, but which also point out the redundant aspect of some items of the suicidant functions scales (e.g. "to die"). Today, it turns out that this kind of research should be managed in France, by creating tools and questionnaires, validating existing ones and, internationally, by taking into account gender, age, and subjects' suicidal history to obtain more clear results. CONCLUSION: So far, to our knowledge, this kind of review has never been conducted. Suicidal functions appear to be a rich and relevant approach to better understand suicide attempts, notably in a "suicidal crisis" perspective. In the future, some links with coping strategies and cathartic effect of the attempts could be made. We also point out that it could be relevant for psychotherapeutic care. PMID- 22516270 TI - [Methodological approach to inter "guideline" variability in the management of bipolar disorders]. AB - INTRODUCTION: In recent decades, an increasing number of pharmacologic agents have become available in bipolar disorder treatment. These therapeutic advances provide a new challenge for clinicians in the choice of medication for patients with bipolar disorder. In this context, tools have been developed for making medical decisions in the management of bipolar disorder: guidelines. METHODS: Guidelines for bipolar disorder were compared on the basis of their construction methodology (evidence-based treatment guidelines or consensus-based treatment guidelines), results and recommendations for clinical practice. RESULTS: There are differences between guidelines for treating bipolar disorder. For the American Psychiatric Association (APA), the severity of the manic episode is a primary endpoint of the decision-making tree for the choice of therapy. On the other hand, the National Institute for Health and Clinical Excellence (NICE) ruled that the choice of the initial treatment, in the case of manic episode, should be based first on the current patient's treatment (history of anti-manic therapy) while the World Federation of Societies of Biological Psychiatry (WFSBP) emphasizes the clinical classification of the type of mania. The sequencing of medication in the guidelines may vary according to the construction methodology, the date of elaboration, the geocultural context and experts' position. Recent guidelines consider the last randomized controlled trials (RCT) as those of aripiprazole in the treatment of mania, recommending it in first line as anti manic agent. The recent updated WFSBP guidelines changed in its construction methodology taking into account the negative studies or those showing non superiority compared to placebo. Thus, a recent study of non-superiority of lithium monotherapy compared to placebo in the treatment of bipolar depression downgraded lithium from level of evidence B to D. During recent years, a large number of RCT have demonstrated superior efficacy (particularly in mania treatment) of lithium or valproate combined with second-generation antipsychotic compared with lithium or valproate monotherapy. Consequently, according to geocultural context or experts' position, some guidelines recommended medication combinations in first line (Canadian Network for Mood and Anxiety Treatment) and other guidelines considered monotherapy in first line (except for particular cases) to promote tolerance and good therapeutic alliance (WFSBP). Malhi et al. recommended a sequencing of medication based on the benefit risk ratio for the management of each phase of bipolar disorder. These differences between guidelines may cause difficulties for clinicians in choosing clinical practice guidelines. CONCLUSION: While there are a large number of guidelines for bipolar disorder, the recommendations may vary depending on multiple factors. It seems interesting to conduct a comparative study of guidelines for bipolar disorder on the basis of a validated scale (AGREE) or completed by other items such as date of elaboration and number of proposed recommendations. However, the methodological understanding of guidelines remains the central element for practitioners in their choice of guidelines. Thus, the initial objective of guidelines "to develop statements to assist clinician and patient decisions about the most appropriate health care for specific clinical situations" could be implemented in clinical practice. PMID- 22516271 TI - [Assessment of a new law for sex offenders implemented in France in 1998]. AB - OBJECTIVES: Most people recognize that incarceration alone will not solve sexual violence. Treating the offenders is critical in an approach to preventing sexual violence and reducing victimization. The Law of June 17, 1998, on the prevention and repression of sexual offences, as well as the protection of minors, makes a provision for the possibility of medical and psychological monitoring adapted to these particular individuals. Sex offenders may well be constrained, after their incarceration, to social and judicial follow-up, which may include coerced treatment in order to reduce the risk of recidivism. In order to control this follow-up, the legislature has created the position of medical coordinator, who acts as an interface between justice and care in conjunction with the treating physician. This study is the first attempt to evaluate the activity of physician coordinators conducted in France since the implementation in 2004 of the 1998 law on monitoring sex offenders. METHODS: An interview of all the physician coordinators in Upper Normandy was conducted. The files of all sex offenders subjected to coerced treatment were studied. RESULTS: In our sample of 100 sex offenders who were subjected to coerced treatment (any kind of treatment) (99% men, 60% of sexual assaults on minors, 14% of cases of indecent exposure), minor victims of sexual assault were: 78% females; in 90% of cases the victim was aged under 14 years (under 10 in 52% of cases), 60% of cases were intrafamilial incest; the victim was an unknown aggressor in only one case out of 60. The constraint follow-up contributed to reducing the risk of recidivism (three cases of recidivism in 100 individuals over an average duration of follow-up of five years), although it remains difficult to assess the recidivism over a duration of time as short as five years. A diagnosis of paraphilia was only applied in 19% of cases (in 10 cases pedophilia, exhibitionism in nine cases). Only six subjects were receiving antiandrogen treatment. A diagnosis based on Axis I DSM was established in 57% of cases. Personality disorders were mentioned in the medical records in 65% of cases. An antisocial personality disorder was not prominent (20%). In 56 cases, the individuals had been victims of physical, psychological or sexual abuse. Nearly half of the individuals had a past history of sexual or non sexual offences, among those, 16 subjects had previously been convicted at least three times. The seniority of the prior conviction was more than 10 years in 43% of cases. Physician coordinators interviewed were satisfied with their work and felt they had contributed to improving the care of patients who had committed sexual offences. CONCLUSION: However, this study shows the need to create a national reference centre, which could enable a multidisciplinary evaluation of difficult cases and could also boost the development of research in this area where many questions remain unanswered, particularly regarding the determinants of deviant sexual behaviour and risk factors for recidivism. PMID- 22516272 TI - [Cannabis cessation interventions offered to young French users: predictors of follow-up]. AB - INTRODUCTION: Cannabis use is very problematic among young French people, because of the young age of first consumption and its health consequences. Indeed, the average age of cannabis experimentation is about 15 in France and 49.5% of 17 year-olds report having used cannabis in their lives. To prevent this problem, tobacco and cannabis cessation services are dedicated to handle patients who want to stop tobacco and/or cannabis. Moreover, in 2004, specific medical outpatient services have been implemented to address the problem of young cannabis users. Since their establishment, some studies have reported demographic and clinical characteristics of the patients attending these services, but we still lack data on their follow-up and their medical and psychological care. OBJECTIVE: The aim of this study is to describe the clinical and psychiatric characteristics of young patients referred to tobacco/cannabis cessation consultations or specific young cannabis users' consultations and to evaluate their medical care and monitoring. PATIENTS AND METHODS: We designed a retrospective study in seven cessation clinics in the Paris area between 2005 and 2007. Eligible patients were regular cannabis users aged under 40. An electronic medical database was completed using patients' medical records. Medical files reported demographic and clinical data. Psychiatric disorders were assessed using the HAD and the Beck scores. Nicotine dependence was evaluated by Fagerstrom's score. The history of addictions, and data about consumption of cannabis, tobacco, alcohol and other drugs were recorded in the medical file. The follow-up of patients was defined by having at least two visits at the medical outpatient services. Tobacco and cannabis cessations were assessed at one-month follow-up. Univariate and multivariate logistic models were used to assess factors associated with patients' follow up and monitoring. RESULTS: Four cessation clinics accepted to participate in our study. One hundred and eight eligible patients were listed during the study period. One hundred and eleven patients (75%) were males and seventy-nine (53%) were employed. The average age of patients was 26 years old (+/-6.8). Fifty patients (34%) came to the clinic on their own decision, thirty three (22%) were referred by a hospital and twenty-eight (19%) came because of their family's advice. The mean age of first cannabis consumption was 16 years old (+/-7.3) and cannabis consumption was most often associated with tobacco use. Fifty-nine percent of patients had anxiety disorders and 28% had depression according to D-HAD score. The dropout rate after first visit was about 40%. The most frequent therapy proposed to young cannabis users was nicotine replacement therapy. Follow-up data were collected for 135 patients and only 85 (37%) patients made at least two visits at the outpatient services. The average number of consultations was five (+/-3.8). Multivariate analysis found an association between follow-up and previous cannabis cessation (P=0.04), pharmacological treatment of tobacco withdrawal (P=0.04), and antidepressant treatment (P=0.04). Only one quarter of patients had quit cannabis and/or tobacco at one-month follow up. DISCUSSION: This study describes clinical characteristics of patients attending cannabis consultations in France. As reported in other studies, anxiety disorders and depression are important problems in this population and should be considered during their medical care. The efficacy of specific French medical outpatient services is difficult to evaluate because of the high rate of dropout. Some patients' characteristics seem linked to their monitoring but other studies should be assessed to confirm these results. As pharmacological treatments seem associated with patients' follow-up, new research should be implemented to develop therapeutic solutions for cannabis addiction. PMID- 22516273 TI - [The measurement of electrodermal activity]. AB - INTRODUCTION: Electrodermal activity (EDA) is an early physiological index and the subject of constant interest, in spite of the bad reputation attached to "lie detectors". This interest is expected to increase in the future, following the development of research related to the neurobiological aspect of emotions of which it is an index. Recent data provided by functional cerebral imaging has added to the significance of this index and should result in further interest. AIM: The authors thus re-examined the various notions related to measuring EDA, and its practical aspect as well as its mechanisms. EDA should be useful both for authors wishing to use this variable and for readers wishing to form their own critical point of view. LITERATURE FINDINGS: The article first defines the various terms used to qualify EDA. Then, it analyses the mechanisms occurring at the sweat glands' level, showing that a distinct innervation of the sweat glands causes sweat to be released in the excretory channels, thereby allowing the recording of a negative surface potential in parallel to the lowering of skin conductance. Arguments are then pointed out to illustrate that the potential's positive phase following this first answer occurs in the case of high intensity stimulations. The study of the central command of sudation demonstrates that, several areas are involved and that different functions such as thermal regulation and motricity may interfere with emotive reactions. Difficulties regarding the mode of measurement of these answers as to their number and amplitude are also brought to light. DISCUSSION: A particular interest of measuring EDA is its ability to highlight individual characteristic and unconscious emotional reactivity. Subjects who constitutionally present many spontaneous and therefore habitual EDA can indeed be opposed to subjects whose EDA reflexes are very few and hardly habitual. A theory suggests that for the first category, whose subjects are named labiles, emotional control may be at the origin of EDA. This characteristic brings to mind the case of antisocial subjects whose rate of EDA is also reduced, although for the latter a primitive drop in behavioral inhibition is involved. The production of EDA in response to non conscious emotive stimulations can be objectified in the rare cases of prosopagnosia. These subjects who are unable to recognize familiar faces can produce EDA when presented faces with an emotional load. These cases contrast with the delusional denial of the Capgras syndrome where subjects do not present EDA, suggesting that the dysfunction of visual analysis occurs at a different level. There are other rare cases represented by cortical blindness where EDA shows that an unconscious emotional analysis is preserved. These subjects are known however to be capable of unconscious visual discriminations, which are possibly accompanied by EDA. This possibility of a "blind vision" is experimentally studied via subliminal vision testing (backward masking tests). These demonstrate that a rudimentary visual analysis is carried out in the subcortical circuits while taking into account the affective aspect of stimulations. CONCLUSION: Present or future data should allow a greater comprehension of electrodermal signals, making it possible to overcome the difficulties related to their interpretation and facilitate their applications. PMID- 22516274 TI - [Psychopathology in online pathological gamblers: a preliminary study]. AB - INTRODUCTION: The rapidly expanding gambling offline and online have resulted in an increasing number of gamblers and the problem is likely to get worse in the future. However, online pathological gambling is a not well known. This rapidly developing modality of gambling, which requires to be studied, notably in its links with regular pathological gambling and Internet addiction. Depression and personality disorders are known to be often associated with pathological gambling. Personality disorders have an influence on pathological gambling, increasing its severity. Online gamblers seem to have a particular personality profile, compared to offline gamblers, and could present different personality disorders. Depression is a common comorbidity among online gamblers, as well as offline gamblers. Both types of gamblers have personality disorders, but the nature of these disorders differs: prevalency of personality disorders of cluster B (dramatic, emotional or erratic disorders) is more important in offline gamblers, whereas cluster C (anxious or fearful disorders) is more present in online pathological gamblers. In France, few studies have specifically examined this subject. AIMS: The objective of the study is to evaluate scores on depression, personality disorders and internet addiction in online pathological gamblers. METHOD: The South Oaks Gambling Screen (SOGS) is used to assess pathological gambling, Beck's Depression Inventory (BDI) to measure depression, the Personality Disorders Questionnaire (PDQ 4) to assess personality disorders and the Internet Addiction Test (IAT) to assess internet addiction. Participants completed the self-report scales. Questionnaires were strictly confidential. POPULATION: The participants were recruited in gambling places (cafes) and Internet forums. Two groups of pathological gamblers were formed: online gamblers (N=15) and offline gamblers (N=15). Participants gave their informed consent. Participation was voluntary and anonymous and no payment was made. ANALYSIS OF THE DATA: The data collection was carried out with an anonymous file and then placed in a data bank. The statistical analysis was carried out using traditional techniques: averages, frequency, standard deviations. Differences among groups were tested using the t-test. RESULTS: The results showed that the majority of subjects met diagnostic criteria for at least one personality disorder. The majority of pathological online gamblers evidenced personality of cluster C grouping avoidant, dependant and obsessive-compulsive personalities. Personality disorders differ according to the type of gambling: offline gamblers have more disorders of cluster B, while online gamblers have more disorders of cluster C. Some personality disorders, in particular borderline and narcissistic personality disorders, are often associated with pathological gambling and seem to have an increasing effect on depression and pathological gambling's intensity. Pathological gambling is strongly correlated to depression. Online pathological gambling, Internet addiction and offline pathological gambling appear to be strongly correlated. DISCUSSION/CONCLUSION: This study opens new perspectives of questioning and research, in particular for existing links between online and offline pathological gambling and internet addiction, and in existent differences between online and offline pathological gamblers. Online pathological gambling shares common characteristics with pathological gambling and Internet addiction, without being able to be assimilated with one or the other. This type of gambling, therefore, requires to be studied to adapt the actions of prevention and treatment intended for online pathological gamblers. PMID- 22516275 TI - [Humour and the theory of mind in schizophrenia: a review of the literature]. AB - Humour is a universal phenomenon, a daily fact holding positive aspects valued in society. The sense of humour is subjective, inherent in each and everyone and difficult to assess. We could qualify it as an indefinable sense set by an absence of norms. This intangible notion occupies a primordial social role of communication, confidence, shared by all with both therapeutic and physical benefit. Scientists started researching this theme in schizophrenic patients from 1950. Studies show a net deficit of humour capabilities between healthy subjects and patients. The hypothesis of a deficit of the theory of mind in the evaluation of humour in schizophrenics is currently the object of several experiments. Nowadays, cognitive functions are also taken into account in humour perception studies. However the little or few studies relevant to this subject are a definite obstacle to the understanding of this complex phenomenon. PMID- 22516276 TI - [Dependent patient and interpersonal dependency: psychotherapeutic strategies]. AB - OBJECTIVES: This article is a review of psychotherapies for patients suffering from dependent personality and interpersonal dependency. METHOD: We synthesized articles making reference to this question, notably those written by Bornstein, author who refers to the dependent personality. We highlighted the psychotherapies that have been the object of an evaluation. The research on the subject is sparse: only eight studies permitting assessment of psychotherapies in this indication in 2005. Besides these psychotherapies, we detailed other approaches which are used by practitioners in these indications. RESULTS: The therapy does not aim at autonomy "at all costs", but that the patient finds a dependence "adapted" to his/her environment. Before starting a therapy, an evaluation is useful to specify the type of dependence. First of all, is there a "pathological" dependence? Is the suffering of the patient secondary to his personality or not supportive enough? Does insight exist? What is the reaction of the patient if we suggest the hypothesis of a dependence on his/her part? Does he/she consider this idea or reject it? Finally, is the dependence primary or secondary? For that purpose, it is necessary to study the biography of the patient and the appearance of the comorbidity over time. The primary dependence is seen in childhood and precedes the other psychological disorders. The secondary dependence follows after the comorbidity and events of life that alter self-esteem (depression, for example). Various therapeutic strategies arise from various currents. The therapies of analytical inspiration recommend replaying the relationship of object and explicitly evoking the transfer. The behavioural and cognitive psychotherapies aim at making the patient identify the cognitions which underlie the dependence, then leading the patient to modify his/her cognition and to behave in a more autonomous way, using the theory of learning. The humanist therapies aim at a therapeutic relationship of acceptance and respect for the patient, so that he/she increases self-esteem and finds autonomy. The brief systemic therapy develops tools to deviate from the relationship of dependence in the therapy. It aims at the change through a modification in the beliefs of the patient. The dependence can be envisaged as a way of adapting itself, of compensating for altered self-esteem. In this way, the psychotherapy must also attempt to restore self-esteem in an implicit or explicit way. CONCLUSION: The evaluation of the type of dependence helps the therapeutic approach. It is necessary to look for the comorbidity and its appearance over time with regard to the dependence. So, in primary dependence, the therapy focuses on the increase of self-esteem. In the secondary dependence, the therapy focuses on the adaptation to this event, the treatment of the mental illness, and then to the accompaniment in restoring and autonomy. If the patient doesn't have insight, it is necessary either to enhance it, or to work in an indirect way. PMID- 22516277 TI - [Reform of mental health legislation: a practical tool]. AB - INTRODUCTION: It was widely agreed that the June 27, 1990 law needed to be changed. The new mental health legislation provides new procedures, which challenge our work habits and balance the rights of individual patient with the need to ensure public safety. In view of the very short time between the publication of the law in the Bulletin Officiel (July 6, 2011) and its application (August 1, 2011), the changes in legislation have led to concrete modifications of our practices. AIM AND METHOD: The scope of this article is to provide a practical tool, which will help to better understand the new measures in the law and to provide an accessible guide of use in relation to mental health care decisions. For the purpose of involuntary admissions, we provide two flow charts outlining the changes in the legislation in its various aspects. We propose to summarize the points, which are not modified by this legislation, and we further develop the several new aspects of the law. Notably, procedures involving compulsory detention including the care and observation period of 72 hours, medical certificates, care in an emergency situation, the panel of caregivers, systematic review of each decision to detain by the Juge de la Detention et des Libertes (JLD), the particular case of patients under a criminal procedure or subjects who were hospitalized in units for dangerous patients, planned discharges, and disagreements between psychiatrists and the civil servant responsible. DISCUSSION: The aim of this article is not to criticize the law. It simply sets out the new measures for the compulsory admission of patients in hospital and defines the new procedures for continued detention or discharge. Due to its recent implementation, we don't have any feedback concerning long-term implications of this reform of mental health legislation, and it is premature to fully appreciate its advantages or disadvantages. PMID- 22516278 TI - Phytoestrogens for menopausal symptoms: a review. AB - OBJECTIVE: To review the evidence that isoflavones are effective treatments for menopausal symptoms and to present the safety data. METHODS: The databases Scopus, ScienceDirect and Primo Central Index were searched and preference was given to systematic reviews and meta-analyses. RESULTS: The available evidence suggests that isoflavones do not relieve menopausal vasomotor symptoms any better than placebo. Long-term safety studies suggest that women who consume a diet high in isoflavones may have a lower risk of endometrial and ovarian cancer. CONCLUSIONS: Isoflavones cannot be recommended for the relief of hot flushes. PMID- 22516279 TI - Will heartburn break your leg? PMID- 22516280 TI - Visual ratings of atrophy in MCI: prediction of conversion and relationship with CSF biomarkers. AB - Medial temporal lobe atrophy (MTA) and cerebrospinal fluid (CSF) markers of Alzheimer's disease (AD) pathology may aid the early detection of AD in mild cognitive impairment (MCI). However, the relationship between structural and pathological markers is not well understood. Furthermore, while posterior atrophy (PA) is well recognized in AD, its value in predicting conversion from late-onset amnestic MCI to AD is unclear. In this study we used visual ratings of MTA and PA to assess their value in predicting conversion to AD in 394 MCI patients. The relationship of atrophy patterns with CSF Abeta1-42, tau, and p-tau(181) was further investigated in 114 controls, 192 MCI, and 99 AD patients. There was a strong association of MTA ratings with conversion to AD (p < 0.001), with a weaker association for PA ratings (p = 0.047). Specific associations between visual ratings and CSF biomarkers were found; MTA was associated with lower levels of Abeta1-42 in MCI, while PA was associated with elevated levels of tau in MCI and AD, which may reflect widespread neuronal loss including posterior regions. These findings suggest both that posterior atrophy may predict conversion to AD in late-onset MCI, and that there may be differential relationships between CSF biomarkers and regional atrophy patterns. PMID- 22516281 TI - Practical access to four stereoisomers of naftidrofuryl and their binding affinity towards 5-hydroxytryptamine 2A receptor. AB - Naftidrofuryl oxalate (Praxilene(r), 1) has been used for the treatment of intermittent claudication for more than 30 years. It selectively blocks vascular and platelet 5-hydroxytryptamine 2 (5-HT(2)) receptors. This drug is marketed as a mixture of four stereoisomers, and so far there is no individual biological evaluation on the single isomers. The purpose of this study is to provide an improved method for the preparation of all four stereoisomers of naftidrofuryl, and more importantly, to distinguish them in terms of their binding affinity to 5 hydroxytryptamine 2A (5-HT(2A)) receptor. The bioassay results revealed that the C-2S configuration of naftidrofuryl was crucial for the binding affinity with 5 HT(2A) receptor, and the C-2' configuration was less important for binding. In conclusion, our study may pave the way to develop single naftidrofuryl isomers with C-2S configuration as inhibitors of 5-HT(2A) receptor that have clinical significance as vasodilators and CNS agents. PMID- 22516282 TI - Synthesis and biological activity of 2-aminothiazoles as novel inhibitors of PGE2 production in cells. AB - This Letter presents the synthesis and biological evaluation of a collection of 2 aminothiazoles as a novel class of compounds with the capability to reduce the production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 36 analogs were synthesized and assayed for PGE(2) reduction, and those with potent cellular activity were counter screened for inhibitory activity against COX-2 in a cell free assay. In general, analogs bearing a 4-phenoxyphenyl substituent in the R(2) position were highly active in cells while maintaining negligible COX-2 inhibition. Specifically, compound 5l (R(1)=Me, R(2)=4-OPh-Ph, R(3)=CH(OH)Me) exhibited the most potent cellular PGE(2) reducing activity of the entire series (EC(50)=90 nM) with an IC(50) value for COX-2 inhibition of >5 MUM in vitro. Furthermore, the anti-tumor activity of analog 1a was analyzed in xenograft mouse models exhibiting promising anti-cancer activity. PMID- 22516283 TI - Solvent effect on copper-catalyzed azide-alkyne cycloaddition (CuAAC): synthesis of novel triazolyl substituted quinolines as potential anticancer agents. AB - A regioselective route to novel mono triazolyl substituted quinolines has been developed via copper-catalyzed azide-alkyne cycloaddition (CuAAC) of 2,4 diazidoquinoline with terminal alkynes in DMF. The reaction provided bis triazolyl substituted quinolines when performed in water in the presence of Et(3)N. A number of the compounds synthesized showed promising anti-proliferative properties when tested in vitro especially against breast cancer cells. PMID- 22516284 TI - Frequent hemodialysis: a way to improve physical function? PMID- 22516285 TI - What is the role of vaptans in routine clinical nephrology? PMID- 22516287 TI - Predicting baseline creatinine in hospitalized patients. PMID- 22516286 TI - Bone mineral density and fracture risk in older individuals with CKD. AB - BACKGROUND AND OBJECTIVES: Kidney Disease Improving Global Outcomes guidelines recommend against bone mineral density (BMD) screening in CKD patients with mineral bone disease, due to a lack of association of BMD with fractures in cross sectional studies in CKD. We assessed whether BMD is associated with fractures in participants with and without CKD in the Health, Aging, and Body Composition study, a prospective study of well functioning older individuals. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Hip BMD was measured by dual-energy x-ray absorptiometry. Osteoporosis was defined as a femoral neck BMD (FNBMD) T score below -2.5 and CKD as an estimated GFR <60 ml/min per 1.73 m(2). The association of BMD with incident nonspine, fragility fractures to study year 11 was analyzed using Cox proportional hazards analyses, adjusting for age, race, sex, body mass index, hyperparathyroidism, low vitamin D level, and CKD. Interaction terms were used to assess whether the association of BMD with fracture differed in those with and without CKD. RESULTS: There were 384 incident fractures in 2754 individuals (mean age 73.6 years). Lower FNBMD was associated with greater fracture, regardless of CKD status. After adjustment, the hazard ratios (95% confidence intervals) were 2.74 (1.99, 3.77) and 2.15 (1.80, 2.57) per lower SD FNBMD for those with and without CKD, respectively (interaction P=0.68), and 2.10 (1.23, 3.59) and 1.63 (1.18, 2.23) among those with osteoporosis in patients with and without CKD, respectively (interaction P=0.75). CONCLUSIONS: BMD provides information on risk for fracture in older individuals with or without moderate CKD. PMID- 22516289 TI - Influence of decisions related to business and regulatory considerations on therapeutic development for kidney diseases. PMID- 22516288 TI - Renal replacement therapy in the elderly population. AB - ESRD has become an important problem for elderly patients. The segment of the ESRD population age 65 years or older has grown considerably, and this growth is expected to accelerate in coming years. Nephrologists caring for the elderly with advanced kidney disease will encounter patients with comorbid conditions common in younger patients, as well as physical, psychological, and social challenges that occur with increased frequency in the aging population. These challenging factors must be addressed to help inform decisions regarding the option to initiate dialysis, the choice of dialysis modality, whether to pursue kidney transplantation, and end-of-life care. This article will highlight some common problems encountered by elderly patients with ESRD and review data on the clinical outcomes of elderly patients treated with different modalities of dialysis, outcomes of kidney transplantation in the elderly, and nondialytic management of CKD stage 5. PMID- 22516290 TI - Vasopressin, copeptin, and renal concentrating capacity in patients with autosomal dominant polycystic kidney disease without renal impairment. AB - BACKGROUND AND OBJECTIVES: Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary renal disease, characterized by cyst formation in the kidneys leading to end stage kidney failure. It is clinically acknowledged that ADPKD patients have impaired urine concentrating capacity, but the mechanism behind this observation is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fifteen ADPKD patients (estimated GFR >=60 ml/min per 1.73 m(2)) and 15 age- and sex-matched healthy controls underwent a standard prolonged water deprivation test in which urine and plasma osmolality, vasopressin, and copeptin were measured. The effect of a synthetic vasopressin analog (desmopressin) injected at the moment of maximal urine concentrating capacity was also studied. RESULTS: After 14 hours of water deprivation, ADPKD patients tended to have higher plasma osmolality (P=0.07) and significantly higher vasopressin and copeptin levels (both P<0.05), whereas urine osmolality was similar in ADPKD patients and controls (710 versus 742 mOsmol/kg; P=0.61). Maximal urine concentrating capacity was lower in ADPKD patients (758 versus 915 mOsmol/kg in controls; P<0.001). At maximal urine concentrating capacity, plasma osmolality, vasopressin, and copeptin levels were significantly higher in ADPKD patients. The median increase in urine osmolality after desmopressin administration in ADPKD patients was less than in healthy controls. CONCLUSIONS: Already early in their disease, ADPKD patients have impaired maximal urine concentrating capacity brought out upon dehydration, with no evidence of impaired hypothalamic response. To maintain fluid balance, vasopressin concentration increases, which is hypothesized to play a role in ADPKD disease progression. PMID- 22516291 TI - Clinical consequences of mutations in sodium phosphate cotransporters. AB - Three families of sodium phosphate cotransporters have been described. Their specific roles in human health and disease have not been defined. Review of the literature reveals that the type II sodium phosphate cotransporters play a significant role in transepithelial transport in a number of tissues including kidney, intestine, salivary gland, mammary gland, and lung. The type I transporters seem to play a major role in renal urate handling and mutations in these proteins have been implicated in susceptibility to gout. The ubiquitously expressed type III transporters play a lesser role in phosphate homeostasis but contribute to cellular phosphate uptake, mineralization, and inflammation. The recognition of species differences in the expression, regulation, and function of these transport proteins suggests an urgent need to find ways to study them in humans. PMID- 22516292 TI - CKD and coronary collateral supply in individuals undergoing coronary angiography after myocardial infarction. AB - BACKGROUND AND OBJECTIVES: CKD patients have high mortality risk after myocardial infarction (MI). An adequate supply of coronary collaterals to the culprit vessel responsible for MI is associated with reduced risks of death and complications. Whether a diminished supply of collaterals contributes to the high risk in CKD patients is uncertain. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Quantitative coronary angiography was performed in a consecutive series of individuals with (n=58) and without (n=165) CKD (estimated GFR <60 ml/min per 1.73 m(2)) who underwent coronary angiography at the time of MI. Collateral supply was analyzed and candidate predictors were assessed in patient-level and individual artery-level models using logistic regression and ordered categorical regression, respectively. RESULTS: There were no significant differences in collateral supply among 58 CKD patients and 165 individuals with preserved renal function. Culprit artery collaterals were present in 25.0% of CKD patients compared with 27.2% of individuals with preserved renal function (P=0.76). The odds of having an adequate supply of culprit vessel collaterals were also not significantly different in individuals with and without CKD, respectively. CKD patients were 2.22-fold more likely to have visible collaterals to the nonculprit vessels in unadjusted analyses. The difference was not significant after correction for percent stenosis and comorbid factors. CONCLUSIONS: Our results do not support an independent association between CKD and diminished collateral supply to either the culprit or nonculprit vessels in MI. Additional studies are warranted to better define associations between myocardial capillary supply, collateral supply, and the full range of human CKD. PMID- 22516293 TI - Rural and micropolitan residence and mortality in patients on dialysis. AB - BACKGROUND AND OBJECTIVES: Micropolitan and rural patients face challenges when initiating dialysis, including healthcare access. Previous studies have shown little association of nonurban residence with dialysis outcomes but have not examined the association of dialysis modality with residence location. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study used data from the U.S. Renal Data System. Adults who initiated maintenance dialysis between January 1, 2006, and December 31, 2007, were classified as rural, micropolitan, or urban. Early and long-term mortality and kidney transplantation were examined with Cox regression stratified by dialysis modality. RESULTS: Of 204,463 patients, 80% were urban; 10.2%, micropolitan; and 9.8%, rural. Micropolitan and rural patients were older, were less racially diverse, had more comorbid conditions, and were more likely to start peritoneal dialysis (PD). Median follow-up was 2.0 years. Early mortality or long-term hemodialysis (HD) mortality did not significantly differ by geographic residence. After adjustment, micropolitan and rural PD patients had higher risk for long-term mortality (hazard ratio [HR], 1.21 [95% confidence interval (CI), 1.09-1.35] and 1.12 [95% CI, 1.01-1.24], respectively) than urban PD patients. After adjustment, kidney transplantation was more likely in micropolitan and rural HD patients (HR, 1.19 [95% CI, 1.11-1.28] and 1.30 [CI, 1.21-1.40]) than urban HD patients, and micropolitan PD patients (HR, 1.31 [95%, CI 1.13-1.51]) than urban PD patients. CONCLUSIONS: Micropolitan and rural residence is associated with higher mortality in PD patients and similar or higher likelihood of kidney transplantation among HD and PD patients. Studies examining the underlying mechanisms of these associations are warranted. PMID- 22516294 TI - GRK2 contribution to the regulation of energy expenditure and brown fat function. AB - Obesity is a major health problem and an important risk factor for the development of multiple disorders. Previous studies in our laboratory have revealed that down-regulation of GRK2 decreases age-related adiposity, but the physiological and molecular mechanisms underlying this outcome remain unclear. We evaluate whether the lean phenotype results from a direct effect of GRK2 on energy homeostasis. The study of white adipose tissue (WAT) in wild-type (WT) and GRK2(+/-) littermates showed a reduced expression of lipogenic enzymes and enhanced lipolytic rate in adult GRK2(+/-) mice. Moreover, hemizygous mice display higher energy expenditure and lower respiratory exchange ratio. Analysis of brown adipose tissue (BAT) from adult GRK2(+/-) mice showed a less deteriorated morphology associated with age compared to WT, which is correlated with a higher basal core temperature. BAT from young GRK2(+/-) mice showed an increase in gene expression of thermogenesis-related genes. Accordingly, hemizygous mice displayed better thermogenic capacity and exhibited a more oxidative phenotype in both BAT and WAT than WT littermates. Overexpression of GRK2 in brown adipocytes corroborated the negative effect of this kinase in BAT function and differentiation. Collectively, our data point to GRK2 inhibition as a potential tool for the enhancement of brown fat activity, which may have important therapeutic implications for the treatment of obesity and associated metabolic disorders. PMID- 22516295 TI - Microglia and mast cells: two tracks on the road to neuroinflammation. AB - One of the more important recent advances in neuroscience research is the understanding that there is extensive communication between the immune system and the central nervous system (CNS). Proinflammatory cytokines play a key role in this communication. The emerging realization is that glia and microglia, in particular, (which are the brain's resident macrophages), constitute an important source of inflammatory mediators and may have fundamental roles in CNS disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Microglia respond also to proinflammatory signals released from other non-neuronal cells, principally those of immune origin. Mast cells are of particular relevance in this context. These immunity-related cells, while resident in the CNS, are capable of migrating across the blood-spinal cord and blood-brain barriers in situations where the barrier is compromised as a result of CNS pathology. Emerging evidence suggests the possibility of mast cell-glia communications and opens exciting new perspectives for designing therapies to target neuroinflammation by differentially modulating the activation of non-neuronal cells normally controlling neuronal sensitization, both peripherally and centrally. This review aims to provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of microglia, neuroimmune interactions involving mast cells, in particular, and the possibility that mast cell-microglia crosstalk may contribute to the exacerbation of acute symptoms of chronic neurodegenerative disease and accelerate disease progression, as well as promote pain transmission pathways. We conclude by considering the therapeutic potential of treating systemic inflammation or blockade of signaling pathways from the periphery to the brain in such settings. PMID- 22516296 TI - Conversion of human 5-lipoxygenase to a 15-lipoxygenase by a point mutation to mimic phosphorylation at Serine-663. AB - The enzyme 5-lipoxygenase (5-LOX) initiates biosynthesis of the proinflammatory leukotriene lipid mediators and, together with 15-LOX, is also required for synthesis of the anti-inflammatory lipoxins. The catalytic activity of 5-LOX is regulated through multiple mechanisms, including Ca(2+)-targeted membrane binding and phosphorylation at specific serine residues. To investigate the consequences of phosphorylation at S663, we mutated the residue to the phosphorylation mimic Asp, providing a homogenous preparation suitable for catalytic and structural studies. The S663D enzyme exhibits robust 15-LOX activity, as determined by spectrophotometric and HPLC analyses, with only traces of 5-LOX activity remaining; synthesis of the anti-inflammatory lipoxin A(4) from arachidonic acid is also detected. The crystal structure of the S663D mutant in the absence and presence of arachidonic acid (in the context of the previously reported Stable-5 LOX) reveals substantial remodeling of helices that define the active site so that the once fully encapsulated catalytic machinery is solvent accessible. Our results suggest that phosphorylation of 5-LOX at S663 could not only down regulate leukotriene synthesis but also stimulate lipoxin production in inflammatory cells that do not express 15-LOX, thus redirecting lipid mediator biosynthesis to the production of proresolving mediators of inflammation. PMID- 22516297 TI - Molecular modulation of airway epithelial ciliary response to sneezing. AB - Our purpose was to evaluate the effect of the mechanical force of a sneeze on sinonasal cilia function and determine the molecular mechanism responsible for eliciting the ciliary response to a sneeze. A novel model was developed to deliver a stimulation simulating a sneeze (55 mmHg for 50 ms) at 26 degrees C to the apical surface of mouse and human nasal epithelial cells. Ciliary beating was visualized, and changes in ciliary beat frequency (CBF) were determined. To interrogate the molecular cascades driving sneeze-induced changes of CBF, pharmacologic manipulation of intra- and extracellular calcium, purinergic, PKA, and nitric oxide (NO) signaling were performed. CBF rapidly increases by >=150% in response to a sneeze, which is dependent on the release of adenosine triphosphate (ATP), calcium influx, and PKA activation. Furthermore, apical release of ATP is independent of calcium influx, but calcium influx and subsequent increase in CBF are dependent on the ATP release. Lastly, we observed a blunted ciliary response in surgical specimens derived from patients with chronic rhinosinusitis compared to control patients. Apical ATP release with subsequent calcium mobilization and PKA activation are involved in sinonasal ciliary response to sneezing, which is blunted in patients with upper-airway disease. PMID- 22516299 TI - A hierarchical model for automatic nuchal translucency detection from ultrasound images. AB - The nuchal translucency (NT) thickness is an important parameter in the diagnosis of fetuses. The previous computerized methods often require manual operations to select the NT region, which leads to the time-consuming problem and the detection variability. In the paper, a hierarchical model is proposed for the automated detection of the NT region. Three discriminative classifiers are first trained with Gaussian pyramids to represent the NT, head and body of fetuses respectively. Then a spatial model is proposed to denote the spatial constrains among them. Finally the dynamic programming and generalized distance transform are applied for the inference from the proposed model, which ensures that the optimal solution can be obtained for the NT detection. The direction problem of fetuses is resolved by the introduced "OR" node. The performance of the proposed model is verified by the experimental results of 690 clinical NT ultrasound images. PMID- 22516300 TI - Molecular cloning, expression pattern and antimicrobial activity of a new isoform of anti-lipopolysaccharide factor from the swimming crab Portunus trituberculatus. AB - A new isoform of anti-lipopolysaccharide factor (PtALF5) was cloned from eyestalk cDNA library of swimming crab Portunus trituberculatus. The full-length cDNA of PtALF5 was 1045 bp encoding 120 amino acids. PtALF5 shared lower amino acid similarity with other ALFs, yet it contained the conserved LPS-binding domain and was clearly member of the ALF family. The genomic fragment of PtALF5 contained two exons separated by one intron. Several tandem repeats were found in intron. The mRNA transcript of PtALF5 was predominantly expressed in the hemocytes but barely detectable in muscle. After challenge with Vibrio alginolyticus, a main pathogen causing high mortality in P. trituberculatus, the PtALF5 transcript in hemocytes showed a clear time-dependent response expression pattern with obvious decrease at 6 h and significant increase at 24 h. The recombinant PtALF5 protein revealed antimicrobial activity against Gram-negative bacteria V. alginolyticus and Pseudomonas aeruginosa, but did not inhibit the growth of the tested Gram positive bacteria and fungus. These results together suggest that PtALF5 is a potent antibacterial protein against Gram-negative bacteria infection, and might function as a promising therapeutic agent in disease control of crab aquaculture. PMID- 22516298 TI - A high-fat diet regulates gastrin and acid secretion through primary cilia. AB - The role of primary cilia in the gastrointestinal tract has not been examined. Here we report the presence of primary cilia on gastric endocrine cells producing gastrin, ghrelin, and somatostatin (Sst), hormones regulated by food intake. During eating, cilia in the gastric antrum decreased, whereas gastric acid and circulating gastrin increased. Mice fed high-fat chow showed a delayed decrease in antral cilia, increased plasma gastrin, and gastric acidity. Mice fed high-fat chow for 3 wk showed lower cilia numbers and acid but higher gastrin levels than mice fed a standard diet, suggesting that fat affects gastric physiology. Ex vivo experiments showed that cilia in the corpus responded to acid and distension, whereas cilia in the antrum responded to food. To analyze the role of gastric cilia, we conditionally deleted the intraflagellar transport protein Ift88 (Ift88(-/fl)). In fed Ift88(-/fl) mice, gastrin levels were higher, and gastric acidity was lower. Moreover, gastrin and Sst gene expression did not change in response to food as in controls. At 8 mo, Ift88(-/fl) mice developed foveolar hyperplasia, hypergastrinemia, and hypochlorhydria associated with endocrine dysfunction. Our results show that components of food (fat) are sensed by antral cilia on endocrine cells, which modulates gastrin secretion and gastric acidity. PMID- 22516301 TI - Fatal human co-infection with Leptospira spp. and dengue virus, Puerto Rico, 2010. PMID- 22516302 TI - Influenza virus A (H10N7) in chickens and poultry abattoir workers, Australia. AB - In March 2010, an outbreak of low pathogenicity avian influenza A (H10N7) occurred on a chicken farm in Australia. After processing clinically normal birds from the farm, 7 abattoir workers reported conjunctivitis and minor upper respiratory tract symptoms. Influenza virus A subtype H10 infection was detected in 2 workers. PMID- 22516303 TI - Safety evaluation of fibermalt. AB - Fibermalt is a new soluble fiber food ingredient produced with the use of an alternansucrase enzyme from Leuconostoc mesenteroides expressed in a non pathogenic strain of Escherichia coli. Fibermalt is predominantly composed of indigestible maltose alternan oligosaccharides (>= 80%). Fibermalt was non mutagenic in a bacterial reverse mutation test. In a 13-week dietary rat study, fibermalt was administered at 0 (control), 50,000, 100,000 or 150,000 ppm. Statistically significant increases in food consumption were generally observed throughout the study in males receiving 100,000 or 150,000 ppm and in females receiving 100,000 ppm. However, there was no effect of fibermalt on mean body weight, body weight gain or food efficiency. All animals survived to scheduled termination and no adverse clinical signs were attributed to administration of fibermalt. There were no toxicologically relevant changes in hematology, clinical chemistry or urinalysis parameters or organ weights in males or females ingesting any concentration of fibermalt. Any macroscopic or microscopic findings were considered incidental, of normal variation and/or of minimal magnitude for test substance association. Based on these results, fibermalt is not mutagenic as evaluated in a bacterial reverse mutation test and has an oral subchronic (13 week) no observable adverse effect level (NOAEL) of 150,000 ppm in rats. PMID- 22516304 TI - A 15-day oral dose toxicity study of aspirin eugenol ester in Wistar rats. AB - The subchronic toxicity of aspirin eugenol ester (AEE) was evaluated after 15-day intragastrically administration in rats at daily doses of 50, 1000, and 2000 mg/kg. AEE at low-dose showed no toxicity to the tested rats. Following repeated exposure to medium- or high-dose of AEE, apparent changes were observed in the levels of blood glucose, AST, ALP, ALT and TB in both male and female rats, and appeared to be dose-independent. There were no significant gender differences in most indexes of subchronic toxicity throughout the experimental period with the exception of food consumption and body weight. The no-observed-adverse-effect level (NOAEL) of AEE was considered to be 50 mg/kg/day under the present study conditions. PMID- 22516305 TI - New human fossil to the last Neanderthals in central Spain (Jarama VI, Valdesotos, Guadalajara, Spain). PMID- 22516307 TI - [Oncodermatologic surgery. Editorial]. PMID- 22516306 TI - Global Wolbachia prevalence, titer fluctuations and their potential of causing cytoplasmic incompatibilities in tsetse flies and hybrids of Glossina morsitans subgroup species. AB - We demonstrate the high applicability of a novel VNTR-based (Variable-Number Tandem-Repeat) molecular screening tool for fingerprinting Wolbachia-infections in tsetse flies. The VNTR-141 locus provides reliable and concise differentiation between Wolbachia strains deriving from Glossina morsitans morsitans, Glossina morsitans centralis, and Glossina brevipalpis. Moreover, we show that certain Wolbachia-infections in Glossina spp. are capable of escaping standard PCR screening methods by 'hiding' as low-titer infections below the detection threshold. By applying a highly sensitive PCR-blot technique to our Glossina specimen, we were able to enhance the symbiont detection limit substantially and, consequently, trace unequivocally Wolbachia-infections at high prevalence in laboratory-reared G. swynnertoni individuals. To our knowledge, Wolbachia persistence was reported exclusively for field-collected samples, and at low prevalence only. Finally, we highlight the substantially higher Wolbachia titer levels found in hybrid Glossina compared to non-hybrid hosts and the possible impact of these titers on hybrid host fitness that potentially trigger incipient speciation in tsetse flies. PMID- 22516308 TI - Evolution of antibiotic resistance at non-lethal drug concentrations. AB - Human use of antimicrobials in the clinic, community and agricultural systems has driven selection for resistance in bacteria. Resistance can be selected at antibiotic concentrations that are either lethal or non-lethal, and here we argue that selection and enrichment for antibiotic resistant bacteria is often a consequence of weak, non-lethal selective pressures - caused by low levels of antibiotics - that operates on small differences in relative bacterial fitness. Such conditions may occur during antibiotic therapy or in anthropogenically drug polluted natural environments. Non-lethal selection increases rates of mutant appearance and promotes enrichment of highly fit mutants and stable mutators. PMID- 22516309 TI - Four hygienic-dietary recommendations as add-on treatment in depression: a randomized-controlled trial. AB - BACKGROUND: Modifying diet, exercise, sunlight exposure and sleep patterns may be useful in the treatment of depression. METHOD: Eighty nonseasonal depressive outpatients on anti-depressant treatment were randomly assigned either to the active or control group. Four hygienic-dietary recommendations were prescribed together. Outcome measures were blinded assessed before and after the six month intervention period. RESULTS: A better evolution of depressive symptoms, a higher rate of responder and remitters and a lesser psychopharmacological prescription was found in the active group. LIMITATIONS: Small sample size. Lacked homogeneity concerning affective disorders (major depression, dysthimia, bipolar depression). CONCLUSIONS: This study suggests lifestyle recommendations can be used as an effective antidepressant complementary strategy in daily practice. PMID- 22516310 TI - Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: randomized double-blind placebo controlled study. AB - BACKGROUND: It has been proposed that the mechanism of the antidepressant effect of celecoxib is linked to its anti-inflammatory action and particularly its inhibitory effect on pro-inflammatory cytokines (e.g. interleukin-6(IL-6)). We measured changes in serum IL-6 concentrations and depressive symptoms following administration of celecoxib in patients with major depressive disorder (MDD). METHODS: In a randomized double-blind placebo-controlled study, 40 patients with MDD and Hamilton Depression Rating Scale-17 items (Ham-D) score >=18 were randomly assigned to either celecoxib (200mg twice daily) or placebo in addition to sertraline (200mg/day) for 6 weeks. Outcome measures were serum IL-6 concentrations at baseline and week 6, and Ham-D scores at baseline and weeks 1, 2, 4, and 6. RESULTS: The celecoxib group showed significantly greater reduction in serum IL-6 concentrations (mean difference (95%CI)=0.42(0.30 to 0.55) pg/ml, t(35)=6.727, P<0.001) as well as Ham-D scores (mean difference (95%CI)=3.35(1.08 to 5.61), t(38)=2.99, P=0.005) than the placebo group. The patients in the celecoxib group experienced more response (95%) and remission (35%) than the placebo group (50% and 5%, P=0.003 and 0.04 respectively). Baseline serum IL-6 levels were significantly correlated with baseline Ham-D scores (r=0.378, P=0.016). Significant correlation was observed between reduction of Ham-D scores and reduction of serum IL-6 levels at week 6 (r=0.673, P<0.001). LIMITATIONS: We did not measure other inflammatory biomarkers. CONCLUSIONS: We showed that the antidepressant activity of celecoxib might be linked to its capability of reducing IL-6 concentrations. Moreover, supporting previous studies we showed that celecoxib is both safe and effective as an adjunctive antidepressant (Registration number: IRCT138903124090N1). PMID- 22516312 TI - Materials of acoustic analysis: sustained vowel versus sentence. AB - OBJECTIVES: Sustained vowel is a widely used material of acoustic analysis. However, vowel phonation does not sufficiently demonstrate sentence-based real life phonation, and biases may occur depending on the test subjects intent during pronunciation. The purpose of this study was to investigate the differences between the results of acoustic analysis using each material. STUDY DESIGN: An individual prospective study. MATERIALS AND METHODS: Two hundred two individuals (87 men and 115 women) with normal findings in videostroboscopy were enrolled. Acoustic analysis was done using the speech pattern element acquisition and display program. Fundamental frequency (Fx), amplitude (Ax), contact quotient (Qx), jitter, and shimmer were measured with sustained vowel-based acoustic analysis. Average fundamental frequency (FxM), average amplitude (AxM), average contact quotient (QxM), Fx perturbation (CFx), and amplitude perturbation (CAx) were measured with sentence-based acoustic analysis. Corresponding data of the two methods were compared with each other. SPSS (Statistical Package for the Social Sciences, Version 12.0; SPSS, Inc., Chicago, IL) software was used for statistical analysis. RESULTS: FxM was higher than Fx in men (Fx, 124.45 Hz; FxM, 133.09 Hz; P=0.000). In women, FxM seemed to be lower than Fx, but the results were not statistically significant (Fx, 210.58 Hz; FxM, 208.34 Hz; P=0.065). There was no statistical significance between Ax and AxM in both the groups. QxM was higher than Qx in men and women. Jitter was lower in men, but CFx was lower in women. Both Shimmer and CAx were higher in men. CONCLUSIONS: Sustained vowel phonation could not be a complete substitute for real-time phonation in acoustic analysis. Characteristics of acoustic materials should be considered when choosing the material for acoustic analysis and interpreting the results. PMID- 22516313 TI - Functional reinnervation of vocal folds after selective laryngeal adductor denervation-reinnervation surgery for spasmodic dysphonia. AB - Selective laryngeal adductor denervation-reinnervation surgery (SLAD-R) offers a viable surgical alternative for patients with adductor spasmodic dysphonia refractory to botulinum toxin injections. SLAD-R selectively denervates the symptomatic thyroarytenoid muscle by dividing the distal adductor branch of the recurrent laryngeal nerve (RLN), and preventing reinnervation, by the proximal RLN and maintaining vocal fold bulk and tone by reinnervating the distal RLN with the ansa cervicalis. We present a patient who had previously undergone successful SLAD-R but presented 10 years postoperatively with a new regional dystonia involving his strap muscles translocated to his reinnervated larynx by his previous ansa-RLN neurorraphy. The patient's symptomatic vocal fold adduction resolved completely on division of the ansa-RLN neurorraphy confirming successful selective functional reinnervation of vocal fold adductors by the ansa cervicalis. PMID- 22516314 TI - The interrater reliability of stroboscopy evaluations. AB - OBJECTIVES/HYPOTHESES: To investigate the interrater reliability of stroboscopy evaluations assessed using Poburka's Stroboscopy Evaluation Rating Form (SERF). STUDY DESIGN: Single-factor experiment with repeated measures on the same element. METHODS: Evaluations of nine experts pertaining to 68 stroboscopy recordings and 16 SERF variables were analyzed. For the 14 SERF variables possessing interval scale level, interrater reliability was investigated using the intraclass correlations for absolute agreement (ICC-a) and consistency (ICC c). ICCs-c were computed for both original values and values standardized with respect to raters' means and standard deviations (ipsative values). For the two nominally scaled SERF variables, "vertical level" and "glottal closure" interrater reliability was investigated using kappa coefficients. RESULTS: For evaluations of single raters, ICCs-a ranged from 0.32 to 0.71, ICCs-c for original values from 0.41 to 0.72, and ICCs-c for ipsative values from 0.43 to 0.72. For mean evaluations of two raters, the corresponding values were 0.48 to 0.83 for ICCs-a, 0.58 to 0.84 for ICCs-c for original values, and 0.60 to 0.84 for ICCs-c for ipsative values. The interval scale variables with the lowest interrater reliabilities were phase closure, phase symmetry, and regularity. The kappa coefficients for vertical level and glottal closure were 0.15 and 0.38, respectively. CONCLUSIONS: The interrater reliabilities for vertical level, glottal closure, phase closure, phase symmetry, and regularity are so low that these variables should not be assessed via stroboscopy. For the remaining variables, adequate reliability can be obtained by aggregating evaluations from at least two raters. PMID- 22516316 TI - Epidemiology of voice disorders in teachers and nonteachers in Brazil: prevalence and adverse effects. AB - PURPOSE: This epidemiological study compared the frequency and adverse effects of voice disorders in Brazilian teachers and nonteachers. METHODS: A standardized interview/questionnaire was administered to 3,265 participants; 1,651 teachers; and 1,614 nonteachers recruited from all 27 Brazilian states. RESULTS: Prevalence of reporting a current voice disorder was 11.6% for teachers and 7.5% for nonteachers, respectively (chi2(1)=16.1, P<0.001). Sixty-three percent of teachers and 35.8% of nonteachers reported having experienced a voice problem at some point during their lifetime (chi2(1)=246.6, P<0.001). Teachers reported a higher number of current (3.7) and past (3.6) voice symptoms as compared with nonteachers (1.7 current, 2.3 past) and more often attributed these symptoms to their occupation (P<0.001). Teachers, as compared with nonteachers (1) more frequently reported that their voice limited their ability to do certain tasks within their current occupation (29.9% of teachers vs 5.4% of nonteachers; P<0.001); (2) experienced more voice-related absenteeism over the past year (12.1% of teachers missed 5 or more days of work vs 2.4% of nonteachers; P<0.001); and (3) more often considered changing occupations in the future because of voice problems (16.7% of teachers vs 0.9% of nonteachers; P<0.001). The magnitude of voice-related dysfunction among teachers was similar across Brazilian states, and regional characteristics did not appear to significantly influence the results. CONCLUSION: This large epidemiological study comparing teachers and nonteachers confirms that teaching at school is a high-risk occupation for developing voice disorders. These voice disorders contribute to reduced job performance, attendance, and force many Brazilian teachers to consider changing occupations in the future because of their voice. PMID- 22516315 TI - Nonlinear dynamic-based analysis of severe dysphonia in patients with vocal fold scar and sulcus vocalis. AB - OBJECTIVE: The primary goal of this study was to evaluate a nonlinear dynamic approach to the acoustic analysis of dysphonia associated with vocal fold scar and sulcus vocalis. STUDY DESIGN: Case-control study. METHODS: Acoustic voice samples from scar/sulcus patients and age-/sex-matched controls were analyzed using correlation dimension (D2) and phase plots, time-domain based perturbation indices (jitter, shimmer, signal-to-noise ratio [SNR]), and an auditory perceptual rating scheme. Signal typing was performed to identify samples with bifurcations and aperiodicity. RESULTS: Type 2 and 3 acoustic signals were highly represented in the scar/sulcus patient group. When data were analyzed irrespective of signal type, all perceptual and acoustic indices successfully distinguished scar/sulcus patients from controls. Removal of type 2 and 3 signals eliminated the previously identified differences between experimental groups for all acoustic indices except D2. The strongest perceptual-acoustic correlation in our data set was observed for SNR and the weakest correlation was observed for D2. CONCLUSIONS: These findings suggest that D2 is inferior to time-domain based perturbation measures for the analysis of dysphonia associated with scar/sulcus; however, time-domain based algorithms are inherently susceptible to inflation under highly aperiodic (ie, type 2 and 3) signal conditions. Auditory-perceptual analysis, unhindered by signal aperiodicity, is therefore a robust strategy for distinguishing scar/sulcus patient voices from normal voices. Future acoustic analysis research in this area should consider alternative (e.g., frequency- and quefrency-domain based) measures alongside additional nonlinear approaches. PMID- 22516317 TI - Individually customized implants for laryngoplasty--are they possible? AB - OBJECTIVE: To standardize the design of individually fitted implants based on computed tomographic (CT) images for use in medialization laryngoplasty without intraoperative voice monitoring. STUDY DESIGN: Prospective tomographic and anatomical experimental study of 10 human cadaveric larynges. METHODS: CT scans of 10 excised human larynges were analyzed to define the shape and size of ideal implants for medialization laryngoplasty. Silicone implants were designed according to CT parameters and used in simulated laryngoplasties in the laryngeal specimens. The efficacy of each implant in providing adequate medialization of the vocal fold was evaluated. RESULTS: Diverse shapes and sizes of implants were obtained, reflecting variations in laryngeal anatomy. The implants enabled regular medialization of the entire extent of the free border of the vocal fold, including its posterior aspect. Medialization was considered adequate in all cases. CONCLUSIONS: This method proved to be a simple and efficient way to design individualized implants for medialization laryngoplasty, regardless of the size and shape of the larynx. LEVEL OF EVIDENCE: Not available. PMID- 22516319 TI - Atrazine and PCB 153 and their effects on the proteome of subcellular fractions of human MCF-7 cells. AB - Several man-made organic pollutants including polychlorinated biphenyls (PCBs) and several pesticides may exhibit endocrine disrupting (ED) properties. These ED molecules can be comparatively persistent in the environment, and have shown to perturb hormonal activity and several physiological functions. The objective of this investigation was to study the impact of PCB 153 and atrazine on human MCF-7 cells, and to search for marker proteins of their exposure. Cells were exposed to environmentally high but relevant concentrations of atrazine (200ppb), PCB 153 (500ppb), 17-beta estradiol (positive control, 10nM) and DMSO (0.1%, negative control) for t=36h (n=3 replicates/exposure group). Proteins from cell membrane and cytosol were isolated, and studied by 2D-DiGE. Differentially regulated proteins were trypsin-digested and identified by MALDI-ToF-ToF and NCBInr database. A total of 36 differentially regulated proteins (>|1.5| fold change, P<0.05) were identified in the membrane fraction and 22 in the cytosol, and were mainly involved in cell structure and in stress response, but also in xenobiotic metabolism. 67% (membrane) and 50% (cytosol) of differentially regulated proteins were more abundant following atrazine exposure whereas nearly 100% (membrane) and 45% (cytosol) were less abundant following PCB 153 exposure. Western blots of selected proteins (HSBP1, FKBP4, STMN1) confirmed 2D-DiGE results. This study emphasizes the numerous potential effects that ED compounds could have on exposed humans. PMID- 22516318 TI - Adenosylcobalamin enzymes: theory and experiment begin to converge. AB - Adenosylcobalamin (coenzyme B(12)) serves as the cofactor for a group of enzymes that catalyze unusual rearrangement or elimination reactions. The role of the cofactor as the initiator of reactive free radicals needed for these reactions is well established. Less clear is how these enzymes activate the coenzyme towards homolysis and control the radicals once generated. The availability of high resolution X-ray structures combined with detailed kinetic and spectroscopic analyses have allowed several adenosylcobalamin enzymes to be computationally modeled in some detail. Computer simulations have generally obtained good agreement with experimental data and provided valuable insight into the mechanisms of these unusual reactions. Importantly, atomistic modeling of the enzymes has allowed the role of specific interactions between protein, substrate and coenzyme to be explored, leading to mechanistic predictions that can now be tested experimentally. This article is part of a Special Issue entitled: Radical SAM enzymes and Radical Enzymology. PMID- 22516320 TI - An examination of the Clinical Impairment Assessment among women at high risk for eating disorder onset. AB - Identifying measures that reliably and validly assess clinical impairment has important implications for eating disorder (ED) diagnosis and treatment. The current study examined the psychometric properties of the Clinical Impairment Assessment (CIA) in women at high risk for ED onset. Participants were 543 women (20.6 +/- 2.0 years) who were classified into one of three ED categories: clinical ED, high risk for ED onset, and low risk control. Among high risk women, the CIA demonstrated high internal consistency (alpha = 0.93) and good convergent validity with disordered eating attitudes (rs = 0.27-0.68, ps < 0.001). Examination of the CIA's discriminant validity revealed that CIA global scores were highest among women with a clinical ED (17.7 +/- 10.7) followed by high risk women (10.6 +/- 8.5) and low risk controls (3.0 +/- 3.3), respectively (p < 0.001). High risk women reporting behavioral indices of ED psychopathology (objective and/or subjective binge episodes, purging behaviors, driven exercise, and ED treatment history) had higher CIA global scores than those without such indices (ps < 0.05), suggesting good criterion validity. These data establish the first norms for the CIA in a United States sample. The CIA is psychometrically sound among high risk women, and heightened levels of impairment among these individuals as compared to low risk women verify the relevance of early intervention efforts. PMID- 22516321 TI - A pilot randomised controlled trial of an Internet-based cognitive behavioural therapy self-management programme (MS Invigor8) for multiple sclerosis fatigue. AB - The majority of people affected by Multiple Sclerosis (paMS) experience severe and disabling fatigue. A recent randomised controlled trial (RCT) showed that cognitive behaviour therapy with a clinical psychologist was an effective treatment for MS fatigue. An Internet-based version of this intervention, MS Invigor8, was developed for the current study using agile design and input from paMS. MS Invigor8 includes eight tailored, interactive sessions. The aim was to test the feasibility and potential efficacy and cost-effectiveness of the programme in a pilot RCT. 40 patients were randomised to MS Invigor8 (n=23) or standard care (n=17). The MS Invigor8 group accessed sessions over 8-10 weeks and received up to three 30-60min telephone support sessions. Participants completed online standardised questionnaires assessing fatigue, mood, quality of life and service use at baseline and 10 weeks follow-up. Large between group treatment effects were found for the primary outcomes of fatigue severity (d=1.19) and impact (d=1.02). The MS Invigor8 group also reported significantly greater improvements in anxiety, depression and quality-adjusted life years. These data suggest that Internet-based CBT may be a clinically and cost-effective treatment for MS fatigue. A larger RCT with longer term follow-up is warranted. PMID- 22516328 TI - Several neuroradiological features can help distinguish abusive and non-abusive head trauma. PMID- 22516322 TI - Are pediatric grand rounds dead? PMID- 22516329 TI - Hand sanitizer and cough hygiene can reduce the number of influenza A infections in school children. PMID- 22516330 TI - Daily and intermittent corticosteroids have similar impact on recurrent wheezing in young children. PMID- 22516331 TI - Pure-tone threshold testing is better at detecting high-frequency hearing loss in adolescents. PMID- 22516332 TI - Chest pain in children referred to cardiology clinic does not increase risk of sudden cardiac death. PMID- 22516333 TI - Heliox is of minimal benefit in bronchiolitis but is more costly. PMID- 22516334 TI - Antibiotic exposure is associated with necrotizing enterocolitis in premature infants. PMID- 22516335 TI - Rapid rehydration is not better than standard IV hydration in dehydrated pediatric patients with gastroenteritis. PMID- 22516344 TI - Positive margin rates following breast-conserving surgery for stage I-III breast cancer: palpable versus nonpalpable tumors. AB - BACKGROUND: Margin status is a significant risk factor for local recurrence. We sought to examine whether the method of tumor localization predicted the margin status and the need for re-excision for both nonpalpable and palpable breast cancer. METHODS: We identified 358 consecutive breast cancer patients who were treated with breast-conserving therapy (BCT) from 1999 to 2006. Data included patient and tumor characteristics, method of localization (needle versus palpation), and pathologic outcomes. Descriptive statistics were used for data summary and data were compared using chi(2). RESULTS: Of 358 patients undergoing BCT, 234 (65%) underwent needle localization for a nonpalpable tumor and 124 (35%) underwent a palpation-guided procedure. Patients undergoing palpation guided procedures were younger and had larger tumors at a more advanced pathologic stage of disease than those undergoing needle localization procedures (P < 0.05 for each). Patient race, tumor grade, presence of lymphovascular invasion, biomarker profile, and nodal status were not significantly different between the two groups (P > 0.05). Overall, 137 patients (38%) had one or more positive margins: 90 of 234 (38%) who had a needle localization procedure and 47 of 124 (38%) who had a palpation-guided procedure (P > 0.05). The number of margins affected did not differ significantly between the two groups. CONCLUSION: Although patients with palpable breast cancer had larger tumors than those with nonpalpable breast cancer, the incidence and number of positive margins was similar to those who had needle localization for nonpalpable tumors. Improved methods of localization are needed to reduce the rate of positive margins and the need for re-excision. PMID- 22516345 TI - Involvement of signaling molecules in the prediction of response to imatinib treatment in metastatic GIST patients. AB - Imatinib therapy has undoubtedly contributed to the treatment of metastatic gastrointestinal stromal (GIST) tumors that were previously untreatable. However, disease progression during treatment with tyrosine kinase inhibitors remains an issue in clinical practice not fully explained by KIT and PDGFRA mutation status. We investigated the role of three important signaling molecules (insulin-like growth factor 1 receptor [IGF1R], protein kinase C-theta [PKCtheta], and Raf kinase inhibitor protein [RKIP]) that have been implicated in GIST pathogenesis as potential biomarkers for prediction of response to imatinib treatment. We retrospectively reviewed 76 patients with metastatic GIST submitted to imatinib treatment between 2002 and 2007, and analyzed 63 of them. Insulin-like growth factor 1, total PKCtheta, phosphorylated PKCtheta, and RKIP immunohistochemical expression were correlated with objective response to imatinib treatment and progression-free and overall survival. Median follow-up was 31.2 mo (95% confidence interval, 26.3-36.1 mo). There was a statistically significant association between IGF1R expression and type of response to imatinib treatment (P = 0.05)-that is, higher IGF1R expression was related to lower objective response. However, IGF1R higher expression did not affect progression-free and overall survival. Insulin-like growth factor 1, but not PKCtheta and RKIP, emerges as a potential biomarker for prediction of response to imatinib treatment in metastatic GISTs. Validation studies are warranted. PMID- 22516346 TI - Intravascular retained surgical items: a multicenter study of risk factors. AB - INTRODUCTION: Retained surgical items (RSIs) have been previously studied in patients undergoing major surgical procedures. This is the first study that specifically examines potential risk factors for intravascular RSI (ivRSI). METHODS: Multicenter retrospective review of 83 RSIs was performed. Among these, 13 cases involved ivRSI. Cases in the ivRSI group were compared with a group of similar control cases to determine potential risk factors for ivRSI, including procedural factors (urgency and complicating factors), patient factors (body mass index), equipment failure (structural or functional), and safety variances. Fisher's exact testing was performed. RESULTS: Thirteen ivRSI cases and 14 controls were examined. There were no differences between the two groups with regard to age, gender, or body mass index. ivRSI items included guide wires (8/13), catheter/catheter fragments (4/13), and a coil (1/13). The incidence of unexpected procedural factors was significantly higher among ivRSI cases (10/13) than among controls (3/14) (P < 0.007). Equipment failure occurred in five ivRSI cases, with none among controls (P < 0.016). There were no differences between the two groups with regard to number of urgent procedures, bleeding >500 mL, evening procedures, or trainee involvement. Both groups had a very high proportion of safety variances (8 in ivRSI and 11 in control group, P = not significant). In addition, seven of 13 ivRSIs were missed on initial confirmatory postprocedural imaging. DISCUSSION: Unexpected procedural factors and equipment failure are significantly associated with ivRSI. Of concern, over half of all ivRSIs were missed on confirmatory postprocedural imaging. Strict adherence to established protocols and stringent radiographic review for intravascular procedures is required to prevent ivRSI. PMID- 22516347 TI - Hypoxia stabilizes GAS6/Axl signaling in metastatic prostate cancer. AB - The receptor tyrosine kinase Axl is overexpressed in a variety of cancers and is known to play a role in proliferation and invasion. Previous data from our laboratory indicate that Axl and its ligand growth arrest-specific 6 (GAS6) may play a role in establishing metastatic dormancy in the bone marrow microenvironment. In the current study, we found that Axl is highly expressed in metastatic prostate cancer cell lines PC3 and DU145 and has negligible levels of expression in a nonmetastatic cancer cell line LNCaP. Knockdown of Axl in PC3 and DU145 cells resulted in decreased expression of several mesenchymal markers including Snail, Slug, and N-cadherin, and enhanced expression of the epithelial marker E-cadherin, suggesting that Axl is involved in the epithelial-mesenchymal transition in prostate cancer cells. The Axl-knockdown PC3 and DU145 cells also displayed decreased in vitro migration and invasion. Interestingly, when PC3 and DU145 cells were treated with GAS6, Axl protein levels were downregulated. Moreover, CoCl(2), a hypoxia mimicking agent, prevented GAS6-mediated downregulation of Axl in these cell lines. Immunochemical staining of human prostate cancer tissue microarrays showed that Axl, GAS6, and hypoxia-inducible factor-1alpha (Hif-1alpha; indicator of hypoxia) were all coexpressed in prostate cancer and in bone metastases compared with normal tissues. Together, our studies indicate that Axl plays a crucial role in prostate cancer metastasis and that GAS6 regulates the expression of Axl. Importantly, in a hypoxic tumor microenvironment Axl expression is maintained leading to enhanced signaling. PMID- 22516349 TI - [Coexistence of Peutz-Jeghers' syndrome and Lynch's syndrome in the same patient]. AB - Peutz-Jeghers' syndrome is an uncommon polyposis syndrome characterized by the presence of hamartomatous polyps in the gastrointestinal tract and mucocutaneous pigmentation (especially in the oral-nasal and perianal areas and hands and feet). Inheritance is autosomal dominant, caused by a germline mutation in the STK11 (LKB1) gene. The risk of breast and gastrointestinal cancer is increased in this syndrome. Lynch's syndrome is also known as hereditary non-polyposis colorectal cancer. This syndrome is caused by a mutation in DNA mismatch repair genes and increases the risk of colon and endometrial cancer, as well as that of other neoplasms (ovary, upper urological tract, gastric, small intestine, pancreas, skin and brain). We present the case of a young woman with colorectal cancer and the coexistence of both syndromes. This association has not previously been reported in the literature. PMID- 22516350 TI - Influenza A and B virus attachment to respiratory tract in marine mammals. AB - Patterns of virus attachment to the respiratory tract of 4 marine mammal species were determined for avian and human influenza viruses. Attachment of avian influenza A viruses (H4N5) and (H7N7) and human influenza B viruses to trachea and bronchi of harbor seals is consistent with reported influenza outbreaks in this species. PMID- 22516348 TI - Somatic mutations in CCK2R alter receptor activity that promote oncogenic phenotypes. AB - The roles of cholecystokinin 2 receptor (CCK2R) in numerous physiologic processes in the gastrointestinal tract and central nervous system are well documented. There has been some evidence that CCK2R alterations play a role in cancers, but the functional significance of these alterations for tumorigenesis is unknown. We have identified six mutations in CCK2R among a panel of 140 colorectal cancers and 44 gastric cancers. We show that these mutations increase receptor activity, activate multiple downstream signaling pathways, increase cell migration, and promote angiogenesis. Our findings suggest that somatic mutations in CCK2R may promote tumorigenesis through deregulated receptor activity and highlight the importance of evaluating CCK2R inhibitors to block both the normal and mutant forms of the receptor. PMID- 22516353 TI - Editorial comment. PMID- 22516351 TI - Association between history and physical examination factors and change in lumbar multifidus muscle thickness after spinal manipulation in patients with low back pain. AB - Understanding the clinical characteristics of patients with low back pain (LBP) who display improved lumbar multifidus (LM) muscle function after spinal manipulative therapy (SMT) may provide insight into a potentially synergistic interaction between SMT and exercise. Therefore, the purpose of this study was to identify the baseline historical and physical examination factors associated with increased contracted LM muscle thickness one week after SMT. Eighty-one participants with LBP underwent a baseline physical examination and ultrasound imaging assessment of the LM muscle during submaximal contraction before and one week after SMT. The relationship between baseline examination variables and 1 week change in contracted LM thickness was assessed using correlation analysis and hierarchical multiple linear regression. Four variables best predicted the magnitude of increases in contracted LM muscle thickness after SMT. When combined, these variables suggest that patients with LBP, (1) that are fairly acute, (2) have at least a moderately good prognosis without focal and irritable symptoms, and (3) exhibit signs of spinal instability, may be the best candidates for a combined SMT and lumbar stabilization exercise (LSE) treatment approach. PMID- 22516354 TI - Matched comparison of robotic-assisted and open radical cystectomy. AB - OBJECTIVE: To evaluate our initial robotic-assisted radical cystectomy (RARC) experience compared with a robust open radical cystectomy (ORC) series performed at a single institution using a matched-pair analysis. Although early results suggest that RARC is safe, with favorable perioperative and early oncologic outcomes, limited data exist comparing ORC and RARC. METHODS: RARC and ORC patients were identified through a prospectively maintained institutional review board-approved bladder cancer database. RARC and ORC cases performed from September 2007 to November 2010 were matched 1:2 by age, sex, urinary diversion, and clinical stage. The perioperative, complication, and pathologic outcomes were compared. RESULTS: A total of 50 RARC and 100 ORC cases were reviewed, with a median follow-up of 8 and 13.5 months, respectively. No differences in the demographic parameters were present between the 2 groups. RARC was associated with a significantly decreased median estimated blood loss (350 vs 475 mL) and 30 day transfusion rate (2% vs 24%) but with longer operative times (454.9 vs 349.1 minutes). No difference was found in the rate of 30-day minor or major Clavien complications, length of stay, or 30-day readmissions between groups. The 90-day mortality rate was 3% versus 0% for ORC and RARC, respectively. No difference in the final pathologic findings, number of lymph nodes removed, or margin status was identified. CONCLUSION: Early experience with RARC compared with a robust ORC experience demonstrated similar perioperative and pathologic outcomes. Continued experience with RARC has the potential to bring improved perioperative results. PMID- 22516355 TI - Effect of partial ureteral obstruction and bacterial virulence on the occurrence of renal scarring in a mouse model. AB - OBJECTIVE: To evaluate the effect of the infection and the obstruction of urinary tract on renal parenchyma, we developed a model of ascending urinary infection in mice with partial unilateral obstructive uropathy. METHODS: Six week-old CBA/J mice were operated on to perform a right partial ureteral obstruction and challenged transurethrally with Escherichia coli CFT073 (high virulent strain) or E. coli Mez (low virulent strain). Level of infection of urine and kidneys, score of inflammation and fibrosis of kidneys, and kidney weight ratio (KWR) in the short and long term were studied. RESULTS: At short-term (72 hours) experimentation, partial ureteral obstruction does not influence the level of kidney infection in terms of bacterial count, and the score of inflammation regardless of whether a virulent or low virulent strain was used. At long-term (42 days) experimentation, E. coli Mez was eliminated from all mice kidneys, but CFT073 persisted in almost all; obstruction did not influence the level of kidney infection with CFT073 but a significant difference of KWR and the inflammation and fibrosis score between obstructed and unobstructed kidneys was found (P = .0078; P = .036, respectively). Although the E. coli Mez strain did not persist in renal parenchyma, severe damage of the renal parenchyma was observed. CONCLUSION: The proposed model is similar to the obstructive uropathy in children in which ureteral obstruction is present before the onset of infection. The association of obstruction and urinary infection impairs kidney growth and favors the occurrence of renal damage. PMID- 22516356 TI - Editorial comment. PMID- 22516357 TI - Second multicenter, randomized, double-blind, parallel-group evaluation of effectiveness and safety of intravesical sodium chondroitin sulfate compared with inactive vehicle control in subjects with interstitial cystitis/bladder pain syndrome. AB - OBJECTIVE: To gain additional safety and effectiveness information regarding intravesical 2% chondroitin sulfate in subjects with interstitial cystitis/bladder pain syndrome (IC/BPS) in a controlled clinical trial. METHODS: Women with IC/BPS were randomized to receive either 8 weekly bladder instillations of 20 mL of 2% chondroitin sulfate or 20 mL of inactive control solution. The primary effectiveness endpoint was the number of positive results using the Global Response Assessment at week 11 (4 weeks after the last instillation). The secondary effectiveness endpoint was a positive response to the Interstitial Cystitis Symptom Index (ICSI) at week 11. Additional effectiveness endpoints were changes from baseline at week 11 in the total ICSI score voiding diary, and visual analog scale for pain. RESULTS: A total of 98 eligible women with a diagnosis of IC/BPS met the inclusion criteria and were the intention to treat population. Of the 98 women, 83% completed the study. More patients in the chondroitin sulfate group (38.0%) reported moderate or marked improvement (considered responders) compared with the inactive control group (31.3%) at the 11-week endpoint visit. Similarly, more subjects in the active treatment group were classified as ICSI and VAS pain responders and reported a greater decrease in ICSI and VAS pain scores than the control group. None of these differences were statistically significant. CONCLUSION: Intravesical chondroitin sulfate therapy for IC/BPS might result in minor improvements in IC/BPS-related symptom and pain. However, the magnitude of benefit in our small pilot study does not support its use as monotherapy for this condition. Better strategies for selecting patients with a bladder-specific clinical phenotype might improve the overall response to this type of intravesical therapy. PMID- 22516358 TI - Performance characteristics of prostate-specific antigen in patients undergoing radical prostatectomy. AB - OBJECTIVE: To assess the performance characteristics of prostate-specific antigen (PSA) for predicting the volume of total or high-grade cancer in men undergoing radical prostatectomy. It is known that the performance characteristics of PSA are improved for predicting the presence of high-grade prostate cancer. METHODS: We identified 1459 patients from the Stanford Radical Prostatectomy Database with clinical Stage T1c (n = 783) and T2 (n = 676) disease who underwent surgery from 1988 to 2003 with detailed morphometric mapping. We generated receiver operating characteristic curves for PSA levels according to the total and high-grade (Gleason score 4 or 5) cancer volume and compared the areas under the curve (AUC) for the various total and high-grade cancer volumes. RESULTS: For patients with Stage T1c disease, the AUC for the PSA ROC curve increased in a stepwise fashion as both the total cancer volume and the high-grade cancer volume increased. Significant differences between the AUCs for low and high volumes of total and high-grade disease were observed. For T2 disease, the AUCs for predicting high grade cancer volume were generally greater than the corresponding AUCs for T1c disease, although no incremental increase was observed. CONCLUSION: In patients with Stage T1c disease, in whom the PSA level was the driving force for biopsy, the PSA performance improved in a stepwise fashion with greater total and high grade cancer volumes as evidenced by improved ROC. Previous studies have shown that PSA performs better for detecting the presence of high-grade disease. We have shown that PSA performs better in predicting greater volumes of high-grade disease in radical prostatectomy specimens. PMID- 22516359 TI - Effect of varicocelectomy on testicular volume in children and adolescents: a meta-analysis. AB - OBJECTIVE: To evaluate the effect of surgical intervention on catch-up growth as determined by a decreased testicular volume discrepancy in children and adolescents with varicocele. METHODS: A systematic search was performed using MEDLINE and the PubMed database and cross-referenced as of October 28, 2011 using the terms "varicocele," "children," "adolescent," "surgery," and "testicular volume." All relevant studies were of the testicular volume discrepancy variance before and after surgical repair. The outcomes included the number of patients with initial testicular atrophy and those with catch-up growth after surgical repair. The database search, quality evaluation, and data extraction were independently performed by 2 reviewers. RESULTS: Of 75 studies, 14 were included for analysis and involved 1475 patients. The combined analysis showed that the testicular volume discrepancy was significantly reduced after surgery in the >=10% group (P < .00001) and >=20% group (P < .00001), respectively. No difference was found between the 2 groups (P = .70). Taken together, the number of patient with testicular volume disproportion in all pediatric and adolescent varicocele patients significantly decreased after surgery (P < .00001). The average proportion of catch-up growth was 76.4% (range 52.6%-93.8%). CONCLUSION: The meta-analysis suggested clear advantages of surgical intervention on reducing testicular hypotrophy when the discrepancy is >=10% in children and adolescents with varicocele. Additional prospective and controlled studies are warranted to elucidate the treatment of children and adolescents with varicocele. PMID- 22516360 TI - Expression and clinical significance of von Hippel-Lindau downstream genes: Jade 1 and beta-catenin related to renal cell carcinoma. AB - OBJECTIVE: To investigate the expression of Jade-1 and beta-catenin and their effect in the development of renal cell carcinoma (RCC). METHODS: The expression of Jade-1 and beta-catenin in 11 normal kidney tissue specimens (normal group) and 60 RCC specimens (RCC group) was determined using real-time polymerase chain reaction and immunohistochemistry. Also, their effect on early relapses of RCC was analyzed after 5 years of follow-up. RESULTS: The expression of Jade-1 protein in the RCC group was significantly lower than that in the normal group (0.1655 vs 0.7438, P < .05), and the expression of beta-catenin protein was significantly greater than that in the normal group (0.2756 vs 0.0855, P < .05). The expression of Jade-1 mRNA in the RCC group was 0.202 times that in the normal group, which were lower (P < .05). The expression of beta-catenin mRNA was 1.014 times that in the normal group (P > .05). The expression of Jade-1 protein and beta-catenin protein in poorly differentiated RCC specimens was significantly lower and higher than the expression in the well-differentiated RCC specimen (P < .05), respectively. Patients with negative Jade-1 expression and positive beta catenin expression were found to have shorter survival on univariate analysis (P < .05). CONCLUSION: RCC with a low expression of Jade-1 and high expression of beta-catenin is associated with a poor outcome and decreased survival. PMID- 22516361 TI - Urinary diversion in early childhood: indications and outcomes in the exstrophy patients. AB - OBJECTIVE: To evaluate indications and applicability of continent and incontinent urinary diversion (CUD and IUD, respectively) in early childhood in patients with classic bladder exstrophy (CBE). METHODS: Using an institutionally approved exstrophy database, patients with CBE born after 1980 who underwent CUD or IUD by 2 surgeons within the first 5 years of life were identified. All aspects of their care and clinical outcomes were studied. RESULTS: In the CUD group (n = 14), only 21% had successful primary closure. Indications were desire to be dry (7), persistent hydronephrosis (4), urinary tract infections (UTIs) (1), repeat CUD (1), and inaccessible proper follow-up (1). Three patients had neobladder creation, 10 had bladder augmentation with continent stomas, and 2 underwent ureterosigmoidostomy. Currently, all patients are dry with clean intermittent catheterization (CIC). In the IUD group (n = 5), only 1 had successful primary closure. In addition to small, noncontractile bladders, the indications for IUD were severe hydronephrosis (2), recurrent UTIs (2), and noncompliance with catheterization (1). Four patients were re-diverted to CUD after a mean of 9.4 years and 1 has colon conduit. All are socially dry via catheterization. There was no case of renal function loss or malignant transformation. CONCLUSION: The need for early diversion in CBE is primarily driven by upper tract changes after secondary closure and social factors. Urinary diversion can be safe in younger children with a favorable continence outcome. PMID- 22516362 TI - Complete resolution of tumoral calcinosis after renal transplantation. AB - A 41-year-old male receiving hemodialysis for 10 years was referred to our hospital for multiple masses progressively growing in multiple joints and buttocks, which were diagnosed as giant tumoral calcinosis (TC) by radiographic findings. He had been hypercalcemic and hyperphosphatemic with high doses of vitamin D for chronic kidney disease-mineral and bone disorder. We then stopped vitamin D to manage the hypercalcemia and hyperphosphatemia; however, the TC did not regress after 1.5 years, thus the patient underwent renal transplantation. Subsequently, the TC gradually but almost completely disappeared over the next 1.5 years. A renal transplantation was thus found to be useful for the successful treatment of TC. PMID- 22516363 TI - Proteomic study of renal uric acid stone. AB - OBJECTIVE: To analyze urinary uric acid stone matrix proteins (SMP) with mass spectrometry (MS) to evaluate the mechanisms of uric acid stone formation. SMP plays an important role in urinary stone formation. Several proteomic studies apply to calcium-containing stones have been reported; however no proteomic study for urinary uric acid stone has been reported. METHODS: Pure kidney uric acid stones from 5 individuals were demineralized, and SMPs were isolated. The obtained proteins were analyzed with reverse-phase liquid chromatography-tandem MS. The acquired data were searched against a Swiss Prot human protein database using Matrix Science, Mascot. The identified proteins were submitted to the AmiGO Web site for gene ontology analysis. They were also sumitted to Metacore software and Kyoto Encyclopedia of Genes and Genomes website (KEGG) for pathway analysis. MS-determined protein expressions were verified by immunoblot. RESULTS: MS analysis identified 242 proteins from 5 proteomic results and the number of the identified protein of each result ranged from 52 to 156. Metacore software analysis suggested that inflammation may play an important role for kidney uric acid stone formation. Endogenous metabolic pathways were also analyzed and submitted to KEGG Web site, which revealed that these proteins may participate in fat metabolism. Five identified proteins were selected for immunoblot validation, and 3 proteins were confirmed. CONCLUSION: Our results suggest that inflammatory process may play a role in kidney uric acid stone formation. Our endogenous metabolic pathway analysis data revealed that these proteins may participate in lipid metabolism. Whether this finding implies a relation between lipotoxicity and kidney uric acid stone former requires further investigation. PMID- 22516364 TI - Late revelation of a subphrenic extralobar pulmonary sequestration as a suprarenal mass. AB - Pulmonary sequestrations are some rare congenital anomalies. The incidence was estimated of 0.15% to 1.7%. They are characterized by a mass of non functioning pulmonary tissue that has no communication to the normal bronchial tree. The vascularisation is supplied by systemic arteries. They are classified further as intralobar and extralobar types. Extralobar sequestration, so-called accessory lung, is separated from the normal lung. We present a rare case of subphrenic extralobar pulmonary sequestration in a 57 years old patient. The lesion was initially presented as a non-typical suprarenal mass discovered on CT scan. The approach by laparatomy permitted the resection and the definitive diagnosis. PMID- 22516365 TI - Age-related divergent remodeling of the cardiac extracellular matrix in heart failure: collagen accumulation in the young and loss in the aged. AB - The incidence of heart failure (HF) increases with age. This study sought to determine whether aging exacerbates structural and functional remodeling of the myocardium in HF. HF was induced in young (~18 months) and aged sheep (>8 years) by right ventricular tachypacing. In non-paced animals, aging was associated with increased left ventricular (LV) end diastolic internal dimensions (EDID, P<0.001), reduced fractional shortening (P<0.01) and an increase in myocardial collagen content (P<0.01). HF increased EDID and reduced fractional shortening in both young and aged animals, although these changes were more pronounced in the aged (P<0.05). Age-associated differences in cardiac extracellular matrix (ECM) remodeling occurred in HF with collagen accumulation in young HF (P<0.001) and depletion in aged HF (P<0.05). MMP-2 activity increased in the aged control and young HF groups (P<0.05). Reduced tissue inhibitor of metalloproteinase (TIMP) expression (TIMPs 3 and 4, P<0.05) was present only in the aged HF group. Secreted protein acidic and rich in cysteine (SPARC) was increased in aged hearts compared to young controls (P<0.05) while serum procollagen type I C-pro peptide (PICP) was increased in both young failing (P<0.05) and aged failing (P<0.01) animals. In conclusion, collagen content of the cardiac ECM changes in both aging and HF although; whether collagen accumulation or depletion occurs depends on age. Changes in TIMP expression in aged failing hearts alongside augmented collagen synthesis in HF provide a potential mechanism for the age-dependent ECM remodeling. Aging should therefore be considered an important factor when elucidating cardiac disease mechanisms. PMID- 22516366 TI - Serologic evidence of West Nile virus infection among humans, Morocco. PMID- 22516367 TI - Cerebral integration of verbal and nonverbal emotional cues: impact of individual nonverbal dominance. AB - Emotional communication is essential for successful social interactions. Emotional information can be expressed at verbal and nonverbal levels. If the verbal message contradicts the nonverbal expression, usually the nonverbal information is perceived as being more authentic, revealing the "true feelings" of the speaker. The present fMRI study investigated the cerebral integration of verbal (sentences expressing the emotional state of the speaker) and nonverbal (facial expressions and tone of voice) emotional signals using ecologically valid audiovisual stimulus material. More specifically, cerebral activation associated with the relative impact of nonverbal information on judging the affective state of a speaker (individual nonverbal dominance index, INDI) was investigated. Perception of nonverbally expressed emotions was associated with bilateral activation within the amygdala, fusiform face area (FFA), temporal voice area (TVA), and the posterior temporal cortex as well as in the midbrain and left inferior orbitofrontal cortex (OFC)/left insula. Verbally conveyed emotions were linked to increased responses bilaterally in the TVA. Furthermore, the INDI correlated with responses in the left amygdala elicited by nonverbal and verbal emotional stimuli. Correlation of the INDI with the activation within the medial OFC was observed during the processing of communicative signals. These results suggest that individuals with a higher degree of nonverbal dominance have an increased sensitivity not only to nonverbal but to emotional stimuli in general. PMID- 22516368 TI - Modulation of somatosensory evoked magnetic fields by intensity of interfering stimuli in human somatosensory cortex: an MEG study. AB - Somatosensory evoked responses are known to be modulated by previous interfering stimuli. Here, we first investigated the modulatory effects of interfering stimuli with different intensities on somatosensory evoked magnetic field in human primary (S1) and secondary (S2) somatosensory cortices. In the control condition of the study, test stimulus, set to strong intensity, was delivered to the left median nerve. Interfering stimuli with three different levels of intensity from weak (WI) through moderate (MI) and finally to strong (SI) were interspersed to the left median nerve between the test stimuli in each interfering condition. The cortical responses to the test stimulus were modeled with equivalent current dipoles in the contralateral S1 and bilateral S2 cortices from 17 subjects. The amplitude of the N20m deflection from the S1 was not changed by any interfering stimuli, whereas the amplitude of later P35m deflection was reduced by MI stimulus. The amplitude of P60m deflection was reduced by MI and SI stimuli. The extent of amplitude reduction of the bilateral S2 response was markedly increased as intensity of interfering stimuli increased from weak to moderate, but further reduction by the SI stimuli compared to MI stimuli was not observed. Those results indicated that somatosensory cortical activation in the S1 (P35m and P60m) and S2 were modulated by intensity of interfering stimuli. Our findings of a greater gating effect on the bilateral S2 compared to the contralateral S1 indicate that S2 may play an important role in temporal integration of different intensity levels of somatosensory inputs. PMID- 22516369 TI - Nonverbal spatially selective attention in 4- and 5-year-old children. AB - Under some conditions 4- and 5-year-old children can differentially process sounds from attended and unattended locations. In fact, the latency of spatially selective attention effects on auditory processing as measured with event-related potentials (ERPs) is quite similar in young children and adults. However, it is not clear if developmental differences in the polarity, distribution, and duration of attention effects are best attributed to acoustic characteristics, availability of non-spatial attention cues, task demands, or domain. In the current study adults and children were instructed to attend to one of two simultaneously presented soundscapes (e.g., city sounds or night sounds) to detect targets (e.g., car horn or owl hoot) in the attended channel only. Probes presented from the same location as the attended soundscape elicited a larger negativity by 80 ms after onset in both adults and children. This initial negative difference (Nd) was followed by a larger positivity for attended probes in adults and another negativity for attended probes in children. The results indicate that the neural systems by which attention modulates early auditory processing are available for young children even when presented with nonverbal sounds. They also suggest important interactions between attention, acoustic characteristics, and maturity on auditory evoked potentials. PMID- 22516370 TI - Immediate breast reconstruction with prostheses after conservative treatment plus intraoperative radiotherapy. long term esthetic and oncological outcomes. AB - Electron intraoperative radiotherapy (ELIOT) has been introduced for breast conservative treatment (BCT) with promising oncological outcome. Thus, immediate breast reconstruction with prosthesis after BCT became possible due to minimal radiation effect on local tissue from ELIOT. We reported oncological and esthetical results of 29 BCT patients who had immediate implant reconstruction plus 21 Gy-ELIOT as the sole radiation treatment. All patients had prosthesis in ipsilateral breast and had simultaneous contralateral augmentation for symmetrical procedure. The average age was 52.3 years. There were stage Ia thirteen cases, stage Ib seven cases, stage IIa six cases and stage IIIb one case and two cases of intraepithelial neoplasia. From 54.2 (36-88) months follow up, the capsular contracture grading in the reconstructed breast from ELIOT-side is comparable with non-irradiated contralateral side. There was one patient who developed local recurrence (LR) and later on dead with breast related event (LR=0.76% per year). There was no primary ipsilateral carcinomas and distant metastasis. PMID- 22516371 TI - Axillary and systemic treatment of patients with breast cancer and micrometastatic disease or isolated tumor cells in the sentinel lymph node. AB - BACKGROUND: After introduction of sentinel node biopsy (SNB) in patients with breast cancer a higher proportion of micrometastases and isolated tumor cells are being detected. Prognostic impact and clinical relevance of this minimal nodal involvement is under debate and substantial variation in the use of axillary surgery and/or systemic adjuvant treatment could be expected. METHODS: Data from the population-based Eindhoven Cancer Registry were used on all (n = 9038) women who underwent SNB for invasive breast cancer from 1996 to 2008 and medical files were studied to determine the role of minimal nodal involvement in the decision to use adjuvant systemic treatment. RESULTS: Forty-five percent of 172 patients with isolated tumor cells and 76% of 605 patients with micrometastases received adjuvant systemic treatment. Thirty-five of 59 patients with isolated tumor cells and 153 of 193 patients with micrometastases received systemic therapy based on primary tumor characteristics. The remainder probably received adjuvant therapy based on presence of minimal nodal involvement. Thirty-seven percent of the patients with isolated tumor cells underwent an axillary lymph node dissection compared to 75% when micrometastases were present. Multivariate analyses showed a significantly higher chance of receiving systemic treatment when isolated tumor cells (OR 1.5 (95% CI, 1.05-2.15)) or micrometastases (OR 10.7 (95% CI, 8.56 13.27)) were present, compared to a negative lymph node status. CONCLUSION: The debate on necessity of performing completion ALND and administration of systemic therapy in patients with minimal nodal involvement is reflected by the treatment patterns observed in our population-based study. SYNOPSIS: Describing time-trends and predictors of axillary and systemic treatment of patients with breast cancer and micrometastases or isolated tumor cells in their sentinel lymph node(s). PMID- 22516372 TI - Nutritional therapy in acute pancreatitis--time to take stock. PMID- 22516373 TI - Accuracy of anthropometric measurements in estimating fat mass in individuals with 21-hydroxylase deficiency. AB - OBJECTIVE: The use of anthropometric measurements to estimate the percentage of body fat (%BF) is easy and inexpensive. However, the accuracy of these methods in patients with 21-hydroxylase deficiency (21OHD) has not been explored. The objective of this study was to evaluate the accuracy of skinfold-based models, body mass index (BMI), and waist circumference (WC) in estimations of %BF using dual-energy X-ray absorptiometry (DXA) as the reference method in individuals with 21OHD. METHODS: Fifty-four 21OHD patients (32 women and 22 men), aged 7 to 20 y, were recruited for the study. DXA was used to determine %BF; four predictive skinfold equations, BMI, and WC were assessed for accuracy in determining %BF. RESULTS: All predictive skinfold equations were highly associated (R, range: 0.82-0.89) with DXA %BF values. In women, BMI and WC showed moderate correlations (R = 0.69 for both BMI and WC) with DXA values. In contrast, among men there was a low explanatory power for BMI (13%) and WC (4%) and high errors (BMI, 6.9%; WC, 7.4%). All predictive equations significantly underestimated %BF (range of differences, -4.1 to -8.9) compared with DXA (women, 31.3 +/- 6.1; men, 24.4 +/- 7.3), and large limits of agreement were observed (range, -15.3 to 1.7 and -15.5 to 4.2 for women and men, respectively). CONCLUSION: In children and adolescents with 21OHD, %BF as estimated by skinfold measurements was associated more strongly with DXA-assessed %BF than both BMI and WC. However, still, the skinfold-based assessment underestimated DXA %BF and showed moderate agreement. PMID- 22516374 TI - [Presentation of the editorial fellowship "Dr. Calatayud" 2012]. PMID- 22516375 TI - One-step nucleic acid amplification for detecting lymph node metastasis of head and neck squamous cell carcinoma. AB - OBJECTIVES: Lymph node stage is an important prognostic factor in head and neck squamous cell carcinoma (HNSCC). We previously reported the clinical usefulness of sentinel lymph node biopsy diagnosed by genetic analysis using quantitative RT PCR. However, this method takes about 3h. In this study, we attempted to develop a more efficient method for the intraoperative genetic detection of lymph node metastasis in HNSCC. MATERIALS AND METHODS: A total of 312 lymph nodes (65 patients) were diagnosed by the one-step nucleic acid amplification (OSNA) method using GD-100. OSNA consists of a short homogenization step followed by amplification of cytokeratin 19 (CK19) mRNA directly from the lysate. Each lymph node was divided into two to diagnose metastasis. One half was used for the OSNA assay, and the other was subjected to semi-serial sectioning, sliced at 200-MUm intervals and examined by H&E and cytokeratin AE1/AE3 immunohistochemical staining. The accuracy of OSNA assay was evaluated based on histopathological diagnosis. RESULTS: Sixty-one of 312 lymph nodes were pathologically metastasis positive. The overall concordance rate between the OSNA assay using breast cancer criteria and histopathology was 94.2%. The optimal cut-off for the copy number of CK19 mRNA in assessing lymph node metastasis of HNSCC was 300 copies/MUl, which had the highest diagnostic accuracy (95.2%). The OSNA assay can be completed within 30 min. CONCLUSION: The OSNA assay, which shows high sensitivity and specificity, suggests the possibility to be used as a novel tool for the genetic detection of lymph node metastasis in HNSCC patients. PMID- 22516376 TI - Distant metastases from head and neck squamous cell carcinoma. Part III. Treatment. AB - Distant metastases from head and neck squamous cell carcinoma (HNSCC), though rare at initial presentation, remain an important manifestation of cancer recurrence and mortality. Although generally considered incurable with a dismal prognosis despite palliative therapy, highly selected patients with distant metastases may have a long term survival benefit from aggressive surgery or radiotherapy. Advances in systemic treatments also may improve patient survival. This article reviews the current state of management of HNSCC patients with distant metastases. PMID- 22516377 TI - Primary chemoradiotherapy for oral cavity squamous cell carcinoma. AB - OBJECTIVES: To evaluate the survival of patients with oral cavity squamous cell carcinoma (SCC) treated with chemoradiotherapy (CRT) or radiotherapy (RT). To record the rate of osteoradionecrosis (ORN) and need for alternative feeding of patients with oral cavity cancer treated with CRT or RT. MATERIALS AND METHODS: All patients with first presentation of oral cavity SCC treated with CRT or RT only at the Royal Brisbane & Women's Hospital (RBWH) between 2000 and 2007 were included. Patient Demographics (age, sex), ACE-27 Co-morbidity index, Staging (TNM staging system), Type of Chemotherapy and Dose of RT, Overall Survival (OS) and Disease-Specific Survival (DSS), Attempt at Salvage, development of distant metastases, development of ORN and success of treatment for ORN and requirement for alternative feeding (PEG/NGT) were recorded. RESULTS: Fifty-four patients met the inclusion criteria. One patient died due to toxicity of treatment. The 5-year OS was 29%. The 5-year DSS was 30%. The rate of ORN amongst survivors was 36%. CONCLUSIONS: CRT is successful in a small number of patients with oral cavity SCC. When compared to the published literature, surgery with or without post operative RT has better survival rates. Salvage surgery does not appear to be a viable option for management of recurrence post CRT. The consequences of treatment, namely ORN and need for alternative feeding, are high. PMID- 22516378 TI - c-Myb interacts with the glucocorticoid receptor and regulates its level in pre-B acute lymphoblastic leukemia cells. AB - Glucocorticoid (GC) hormones are used in the treatment of hematopoietic malignancies. When the GC binds to the glucocorticoid receptor (GR) protein, c Myb and GR are recruited at the Glucocorticoid Response Unit in the DNA. Here we demonstrate that c-Myb interacts with the GR and that decreasing c-Myb amounts reduces the levels of GR transcripts and protein in 697 pre-B-acute lymphoblastic leukemia (ALL) cells. Furthermore, the auto-upregulation of GR promoter 1C and promoter 1D is blunted at reduced c-Myb levels. Taken together, these data show that c-Myb is a direct, key regulator of the GR. Unexpectedly, the reduction in c Myb levels increased the sensitivity of the cells to steroid-mediated apoptosis. This was because the reduction in c-Myb itself decreases cell viability, and the residual GR remained above the threshold needed to trigger apoptosis. These studies show the mutual importance of c-Myb and the GR in controlling survival of pre-B ALL cells. PMID- 22516380 TI - Global reluctance to practice evidence-based medicine continues in the treatment of uncomplicated painful bone metastases despite level 1 evidence and practice guidelines. PMID- 22516379 TI - Coxsackievirus A21, enterovirus 68, and acute respiratory tract infection, China. AB - During August 2006-April 2010, in Beijing, China, 2 rare human enterovirus serotypes, coxsackievirus A21 and enterovirus 68, were detected most frequently in human enterovirus-positive adults with acute respiratory tract infections. Thus, during some years, these 2 viruses cause a substantial proportion of enterovirus-associated adult acute respiratory tract infections. PMID- 22516381 TI - A tribute to Malcolm A. Bagshaw--an innovative physician who soared to success. PMID- 22516382 TI - Effect of increasing experience on dosimetric and clinical outcomes in the management of malignant pleural mesothelioma with intensity-modulated radiation therapy. AB - PURPOSE: To assess the impact of increasing experience with intensity-modulated radiation therapy (IMRT) after extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM). METHODS AND MATERIALS: The records of all patients who received IMRT following EPP at Duke University Medical Center between 2005 and 2010 were reviewed. Target volumes included the preoperative extent of the pleural space, chest wall incisions, involved nodal stations, and a boost to close/positive surgical margins if applicable. Patients were typically treated with 9-11 beams with gantry angles, collimator rotations, and beam apertures manually fixed to avoid the contalateral lung and to optimize target coverage. Toxicity was graded retrospectively using National Cancer Institute common toxicity criteria version 4.0. Target coverage and contralateral lung irradiation were evaluated over time by using linear regression. Local control, disease-free survival, and overall survival rates were estimated using the Kaplan-Meier method. RESULTS: Thirty patients received IMRT following EPP; 21 patients also received systemic chemotherapy. Median follow-up was 15 months. The median dose prescribed to the entire ipsilateral hemithorax was 45 Gy (range, 40-50.4 Gy) with a boost of 8-25 Gy in 9 patients. Median survival was 23.2 months. Two-year local control, disease-free survival, and overall survival rates were 47%, 34%, and 50%, respectively. Increasing experience planning MPM cases was associated with improved coverage of planning target volumes (P=.04). Similarly, mean lung dose (P<.01) and lung V5 (volume receiving 5 Gy or more; P<.01) values decreased with increasing experience. Lung toxicity developed after IMRT in 4 (13%) patients at a median of 2.2 months after RT (three grade 3-4 and one grade 5). Lung toxicity developed in 4 of the initial 15 patients vs none of the last 15 patients treated. CONCLUSIONS: With increasing experience, target volume coverage improved and dose to the contralateral lung decreased. Rates of pulmonary toxicity were relatively low. However, both local and distant control rates remained suboptimal. PMID- 22516383 TI - Safety and efficacy of thoracic external beam radiotherapy after airway stenting in malignant airway obstruction. AB - PURPOSE: We retrospectively evaluated the outcome and toxicity of external beam radiotherapy (EBRT) after airway stents were placed in patients treated for malignant airway obstruction. METHODS AND MATERIALS: Between 2004 and 2009, we performed airway stenting followed by EBRT in 43 patients for symptomatic primary lung cancer (n = 31) or other thoracic malignancies (n = 12). The median time interval between stent placement and first irradiation was 14 days. A median total dose of 50 Gy was delivered. Sixty-seven percent of the patients had reduced performance status (Karnofsky performance score, <=70). RESULTS: EBRT had to be stopped prematurely in 16 patients (37%), at a median total dose of 17 Gy, for various reasons. In this group of patients, the survival was poor, with a median overall survival (OS) of only 21 days. Twenty-seven patients (63%) completed radiotherapy as planned, with a median OS of 8.4 months. Fourteen of 43 patients (33%) developed at least one Common Terminology Criteria for Adverse Event of grade 3 to 5. The most common event was a malignant restenosis of the stent leading to asphyxia (n = 7), followed by fistula formation (n = 4), necrosis (n = 3), mediastinitis with abscess (n = 1), secondary nonmalignant airway stenosis (n = 1), and hemoptysis (n = 1). With the exception of one event, all events were associated with a local progression of the tumor. CONCLUSIONS: Although the long-term prognosis for patients with malignant airway obstruction is poor, airway stenting combined with EBRT offers a possible therapeutic option, achieving fast relief of acute respiratory distress with an associated antitumor effect, resulting in a potential survival benefit. However, due to local advanced tumor growth, increased rates of adverse events are to be expected, necessitating careful monitoring. PMID- 22516384 TI - On-line use of three-dimensional marker trajectory estimation from cone-beam computed tomography projections for precise setup in radiotherapy for targets with respiratory motion. AB - PURPOSE: To develop and evaluate accurate and objective on-line patient setup based on a novel semiautomatic technique in which three-dimensional marker trajectories were estimated from two-dimensional cone-beam computed tomography (CBCT) projections. METHODS AND MATERIALS: Seven treatment courses of stereotactic body radiotherapy for liver tumors were delivered in 21 fractions in total to 6 patients by a linear accelerator. Each patient had two to three gold markers implanted close to the tumors. Before treatment, a CBCT scan with approximately 675 two-dimensional projections was acquired during a full gantry rotation. The marker positions were segmented in each projection. From this, the three-dimensional marker trajectories were estimated using a probability based method. The required couch shifts for patient setup were calculated from the mean marker positions along the trajectories. A motion phantom moving with known tumor trajectories was used to examine the accuracy of the method. Trajectory-based setup was retrospectively used off-line for the first five treatment courses (15 fractions) and on-line for the last two treatment courses (6 fractions). Automatic marker segmentation was compared with manual segmentation. The trajectory-based setup was compared with setup based on conventional CBCT guidance on the markers (first 15 fractions). RESULTS: Phantom measurements showed that trajectory-based estimation of the mean marker position was accurate within 0.3 mm. The on-line trajectory-based patient setup was performed within approximately 5 minutes. The automatic marker segmentation agreed with manual segmentation within 0.36 +/- 0.50 pixels (mean +/- SD; pixel size, 0.26 mm in isocenter). The accuracy of conventional volumetric CBCT guidance was compromised by motion smearing (<=21 mm) that induced an absolute three-dimensional setup error of 1.6 +/- 0.9 mm (maximum, 3.2) relative to trajectory-based setup. CONCLUSIONS: The first on-line clinical use of trajectory estimation from CBCT projections for precise setup in stereotactic body radiotherapy was demonstrated. Uncertainty in the conventional CBCT-based setup procedure was eliminated with the new method. PMID- 22516385 TI - Randomized control trial: evaluating aluminum-based antiperspirant use, axilla skin toxicity, and reported quality of life in women receiving external beam radiotherapy for treatment of Stage 0, I, and II breast cancer. AB - PURPOSE: Standard skin care instructions regarding the use of antiperspirants during radiotherapy to the breast varies across North America. Women have articulated that when instructed to not use antiperspirant, the potential for body odor is distressing. Historical practices and individual opinions have often guided practice in this field. The present study had 2 purposes. To evaluate whether the use of aluminum-based antiperspirant while receiving external beam radiotherapy for stage 0, I, or II breast cancer will increase axilla skin toxicity and to evaluate whether the use of antiperspirant during external beam radiotherapy improves quality of life. METHODS: A total of 198 participants were randomized to either the experimental group (antiperspirant) or control group (standard care-wash only). The skin reactions in both groups were measured weekly and 2 weeks after treatment using the National Cancer Institute Common Toxicity Criteria Adverse Events, version 3, toxicity grading criteria. Both groups completed the Functional Assessment for Chronic Illness Therapy's questionnaire for the breast population quality of life assessment tool, with additional questions evaluating the effect of underarm antiperspirant use on quality of life before treatment, immediately after treatment, and 2 weeks after treatment during the study. RESULTS: The skin reaction data were analyzed using the generalized estimating equation. No statistically significant difference was seen in the skin reaction between the 2 groups over time. The quality of life data also revealed no statistically significant difference between the 2 groups over time. CONCLUSIONS: Data analysis indicates that using antiperspirant routinely during external beam radiotherapy for Stage 0, I, or II breast cancer does not affect the intensity of the skin reaction or the self-reported quality of life. This evidence supports that in this particular population, there is no purpose to restrict these women from using antiperspirants during their treatment, and the decision to use an antiperspirant or not in this setting should be left to the discretion of the patient. PMID- 22516386 TI - Gefitinib radiosensitizes stem-like glioma cells: inhibition of epidermal growth factor receptor-Akt-DNA-PK signaling, accompanied by inhibition of DNA double strand break repair. AB - PURPOSE: We compared radiosensitivity of brain tumor stem cells (BTSCs) with matched nonstem glioma cells, and determined whether gefitinib enhanced BTSC radiosensitivity by inhibiting epidermal growth factor receptor (EGFR)-Akt-DNA dependent protein kinase (DNA-PK) signaling, followed by enhanced DNA double stand breaks (DSBs) and inhibition of DSB repair. METHODS AND MATERIALS: Radiosensitivity of stem-like gliomaspheres and nonstem glioma cells (obtained at patient neurosurgical resection) were evaluated by clonogenic assays, gamma H(2)AX immunostaining and cell cycle distribution. Survival of irradiated and nonirradiated NOD-SCID mice intracranially implanted with stem-like gliomaspheres were monitored. Glioma cells treated with gefitinib, irradiation, or both were assayed for clonogenic survival, gamma-H(2)AX immunostaining, DNA-PKcs expression, and phosphorylation of EGFR and Akt. RESULTS: Stem-like gliomaspheres displayed BTSC characteristics of self-renewal; differentiation into lineages of neurons, oligodendrocytes, and astrocytes; and initiation of glioma growth in NOD SCID mice. Irradiation dose-dependently reduced clonogenic survival, induced G(2)/M arrest and increased gamma-H(2)AX immunostaining of nonstem glioma cells, but not stem-like gliomaspheres. There was no difference in survival of irradiated and nonirradiated mice implanted with stem-like gliomaspheres. The addition of gefitinib significantly inhibited clonogenic survival, increased gamma-H(2)AX immunostaining, and reduced DNA-PKcs expression of irradiated stem like gliomaspheres, without affecting irradiated-nonstem glioma cells. Gefitinib alone, and when combined with irradiation, inhibited phosphorylation of EGFR (Y1068 and Y1045) and Akt (S473) in stem-like gliomaspheres. In nonstem glioma cells, gefitinib alone inhibited EGFR Y1068 phosphorylation, with further inhibition by combined gefitinib and irradiation. CONCLUSIONS: Stem-like gliomaspheres are resistant to irradiation-induced cytotoxicity, G(2)/M arrest, and DNA DSBs, compared with nonstem glioma cells. Gefitinib differentially enhances radiosensitivity of stem-like gliomaspheres by reducing EGFR-Akt activation and DNA-PKcs expression, accompanied by enhanced irradiation-induced DNA DSBs and inhibition of DSB repair. PMID- 22516387 TI - Current dosing paradigm for stereotactic radiosurgery alone after surgical resection of brain metastases needs to be optimized for improved local control. AB - PURPOSE: To describe the use of radiosurgery (RS) alone to the resection cavity after resection of brain metastases as an alternative to adjuvant whole-brain radiotherapy (WBRT). METHODS AND MATERIALS: Sixty-two patients with 64 cavities were treated with linear accelerator-based RS alone to the resection cavity after surgical removal of brain metastases between March 2007 and August 2010. Fifty two patients (81%) had a gross total resection. Median cavity volume was 8.5 cm(3). Forty-four patients (71%) had a single metastasis. Median marginal and maximum doses were 18 Gy and 20.4 Gy, respectively. Sixty-one cavities (95%) had gross tumor volume to planning target volume expansion of >=1 mm. RESULTS: Six month and 1-year actuarial local recurrence rates were 14% and 22%, respectively, with a median follow-up period of 9.7 months. Six-month and 1-year actuarial distant brain recurrence, total intracranial recurrence, and freedom from WBRT rates were 31% and 51%, 41% and 63%, and 91% and 74%, respectively. The symptomatic cavity radiation necrosis rate was 8%, with 2 patients (3%) undergoing surgery. Of the 11 local failures, 8 were in-field, 1 was marginal, and 2 were both (defined as in-field if >=90% of recurrence within the prescription isodose and marginal if >=90% outside of the prescription isodose). CONCLUSIONS: The high rate of in-field cavity failure suggests that geographic misses with highly conformal RS are not a major contributor to local recurrence. The current dosing regimen derived from Radiation Therapy Oncology Group protocol 90-05 should be optimized in this patient population before any direct comparison with WBRT. PMID- 22516388 TI - Normal tissue complication probability analysis of acute gastrointestinal toxicity in cervical cancer patients undergoing intensity modulated radiation therapy and concurrent cisplatin. AB - PURPOSE: To test the hypothesis that increased bowel radiation dose is associated with acute gastrointestinal (GI) toxicity in cervical cancer patients undergoing concurrent chemotherapy and intensity-modulated radiation therapy (IMRT), using a previously derived normal tissue complication probability (NTCP) model. METHODS: Fifty patients with Stage I-III cervical cancer undergoing IMRT and concurrent weekly cisplatin were analyzed. Acute GI toxicity was graded using the Radiation Therapy Oncology Group scale, excluding upper GI events. A logistic model was used to test correlations between acute GI toxicity and bowel dosimetric parameters. The primary objective was to test the association between Grade >=2 GI toxicity and the volume of bowel receiving >=45 Gy (V(45)) using the logistic model. RESULTS: Twenty-three patients (46%) had Grade >=2 GI toxicity. The mean (SD) V(45) was 143 mL (99). The mean V(45) values for patients with and without Grade >=2 GI toxicity were 176 vs. 115 mL, respectively. Twenty patients (40%) had V(45) >150 mL. The proportion of patients with Grade >=2 GI toxicity with and without V(45) >150 mL was 65% vs. 33% (p = 0.03). Logistic model parameter estimates V50 and gamma were 161 mL (95% confidence interval [CI] 60-399) and 0.31 (95% CI 0.04-0.63), respectively. On multivariable logistic regression, increased V(45) was associated with an increased odds of Grade >=2 GI toxicity (odds ratio 2.19 per 100 mL, 95% CI 1.04-4.63, p = 0.04). CONCLUSIONS: Our results support the hypothesis that increasing bowel V(45) is correlated with increased GI toxicity in cervical cancer patients undergoing IMRT and concurrent cisplatin. Reducing bowel V(45) could reduce the risk of Grade >=2 GI toxicity by approximately 50% per 100 mL of bowel spared. PMID- 22516389 TI - Elective lymph node irradiation with intensity-modulated radiotherapy: is conventional dose fractionation necessary? AB - PURPOSE: Intensity-modulated radiation therapy (IMRT) is the standard of care for head-and-neck cancer (HNC). We treated patients with HNC by delivering either a moderate hypofractionation (MHF) schedule (66 Gy at 2.2 Gy per fraction to the gross tumor [primary and nodal]) with standard dose fractionation (54-60 Gy at 1.8-2.0 Gy per fraction) to the elective neck lymphatics or a conventional dose and fractionation (CDF) schedule (70 Gy at 2.0 Gy per fraction) to the gross tumor (primary and nodal) with reduced dose to the elective neck lymphatics. We analyzed these two cohorts for treatment outcomes. METHODS AND MATERIALS: Between November 2001 and February 2009, 89 patients with primary carcinomas of the oral cavity, larynx, oropharynx, hypopharynx, and nasopharynx received definitive IMRT with or without concurrent chemotherapy. Twenty patients were treated using the MHF schedule, while 69 patients were treated with the CDF schedule. Patient characteristics and dosimetry plans were reviewed. Patterns of failure including local recurrence (LR), regional recurrence (RR), distant metastasis (DM), disease free survival (DFS), overall survival (OS), and toxicities, including rate of feeding tube placement and percentage of weight loss, were reviewed and analyzed. RESULTS: Median follow-up was 31.2 months. Thirty-five percent of patients in the MHF cohort and 77% of patients in the CDF cohort received chemotherapy. No RR was observed in either cohort. OS, DFS, LR, and DM rates for the entire group at 2 years were 89.3%, 81.4%, 7.1%, and 9.4%, respectively. Subgroup analysis showed no significant differences in OS (p = 0.595), DFS (p = 0.863), LR (p = 0.833), or DM (p = 0.917) between these two cohorts. Similarly, no significant differences were observed in rates of feeding tube placement and percentages of weight loss. CONCLUSIONS: Similar treatment outcomes were observed for MHF and CDF cohorts. A dose of 50 Gy at 1.43 Gy per fraction may be sufficient to electively treat low risk neck lymphatics. PMID- 22516390 TI - Computational fluid dynamic simulations for determination of ventricular workload in aortic arch obstructions. AB - OBJECTIVE: The cardiac workload associated with various types of aortic obstruction was determined using computational fluid dynamic simulations. METHODS: Computed tomography image data were collected from 4 patients with 4 distinct types of aortic arch obstructions and 4 controls. The categorization of arch hypoplasia corresponded to the "A, B, C" nomenclature of arch interruption; a type "D" was added to represent diffuse arch hypoplasia. Measurements of the vessel diameter were compared against the normal measurements to determine the degree of narrowing. Three-dimensional models were created for each patient, and additional models were created for type A and B hypoplasia to represent 25%, 50%, and 75% diameter narrowing. The boundary conditions for the computational simulations were chosen to achieve realistic flow and pressures in the control cases. The simulations were then repeated after changing the boundary conditions to represent a range of cardiac and vascular adaptations. The resulting cardiac workload was compared with the control cases. RESULTS: Of the 4 patients investigated, 1 had aortic coarctation and 3 had aortic hypoplasia. The cardiac workload of the patients with 25% narrowing type A and B hypoplasia was not appreciably different from that of the control. When comparing the different arch obstructions, 75% type A, 50% type B, and 50% type D hypoplasia required a greater workload increase than 75% coarctation. CONCLUSIONS: The present study has determined the hemodynamic significance of aortic arch obstruction using computational simulations to calculate the cardiac workload. These results suggest that all types of hypoplasia pose more of a workload challenge than coarctation with an equivalent degree of narrowing. PMID- 22516391 TI - Right anterior minithoracotomy versus conventional aortic valve replacement: a propensity score matched study. AB - OBJECTIVE: Minimally invasive aortic valve surgery by way of a right anterior minithoracotomy has shown excellent results in terms of mortality, morbidities, and patient satisfaction. The aim of the present study was to compare minimally invasive aortic valve surgery by way of a right anterior minithoracotomy with conventional full sternotomy on early outcomes and midterm survival. METHODS: A retrospective, observational, cohort study was undertaken of prospectively collected data from 637 consecutive patients undergoing isolated aortic valve surgery from January 2005 to July 2010. Of the 637 patients, 192 (30%) underwent minimally invasive aortic valve surgery by way of a right anterior minithoracotomy. Of these, 138 patients (right anterior minithoracotomy group) were matched to a control group (full sternotomy group) using propensity score analysis. RESULTS: The baseline characteristics were similar in both groups. The overall in-hospital mortality was 0.7% (2/276), with no difference between the 2 groups. Minimally invasive aortic valve surgery by way of a right anterior minithoracotomy was associated with a lower incidence of postoperative atrial fibrillation (25 [18.1%] vs 41 [29.7%]; P = .003) and blood transfusions (26 [18.8%] vs 47 [34.1%]; P = .0006). In addition, patients in the right anterior minithoracotomy group had a shorter mechanical ventilation time (median, 6 vs 8 hours; P = .004) and postoperative length of stay (median, 5 vs 6 days; P = .02). The occurrence of stroke, renal failure, reexploration for bleeding, and wound infection was similar in both groups. At a median follow-up of 30 months (range, 17-54 months), survival was 96% +/- 2% vs 88% +/- 4% (P = .3). CONCLUSIONS: Right anterior minithoracotomy in patients undergoing isolated aortic valve surgery is associated with a lower incidence of postoperative atrial fibrillation and blood transfusion and shorter ventilation time and hospital length of stay. Prospective randomized trials are needed to confirm our data. PMID- 22516392 TI - A percutaneous treatment algorithm for crossing coronary chronic total occlusions. AB - Coronary chronic total occlusions (CTOs) are frequently identified during coronary angiography and remain the most challenging lesion group to treat. Patients with CTOs are frequently left unrevascularized due to perceptions of high failure rates and technical complexity even if they have symptoms of coronary disease or ischemia. In this review, the authors describe a North American contemporary approach for percutaneous coronary interventions for CTO. Two guide catheters are placed to facilitate seamless transition between antegrade wire-based, antegrade dissection re-entry-based, and retrograde (wire or dissection re-entry) techniques, the "hybrid" interventional strategy. After dual coronary injection is performed, 4 angiographic parameters are assessed: 1) clear understanding of location of the proximal cap using angiography or intravascular ultrasonography; 2) lesion length; 3) presence of branches, as well as size and quality of the target vessel at the distal cap; and 4) suitability of collaterals for retrograde techniques. On the basis of these 4 characteristics, an initial strategy and rank order hierarchy for technical approaches is established. Radiation exposure, contrast utilization, and procedure time are monitored throughout the procedure, and thresholds are established for intraprocedural strategy conversion to maximize safety, efficiency, and effectiveness. PMID- 22516393 TI - Successful recanalization of chronic total occlusions is associated with improved long-term survival. AB - OBJECTIVES: This study investigated the impact of procedural success on mortality following chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in a large cohort of patients in the drug-eluting stent era. BACKGROUND: Despite advances in expertise and technologies, many patients with CTO are not offered PCI. METHODS: A total of 6,996 patients underwent elective PCI for stable angina at a single center (2003 to 2010), 836 (11.9%) for CTO. All-cause mortality was obtained to 5 years (median: 3.8 years; interquartile range: 2.0 to 5.4 years) and stratified according to successful chronic total occlusion (sCTO) or unsuccessful chronic total occlusion (uCTO) recanalization. Major adverse cardiac events (MACE) included myocardial infarction (MI), urgent revascularization, stroke, or death. RESULTS: A total of 582 (69.6%) procedures were successful. Stents were implanted in 97.0% of successful procedures (mean: 2.3 +/- 0.1 stents per patient, 73% drug-eluting). Prior revascularization was more frequent among uCTO patients: coronary artery bypass grafting (CABG) (16.5% vs. 7.4%; p < 0.0001), PCI (36.0% vs. 21.2%; p < 0.0001). Baseline characteristics were otherwise similar. Intraprocedural complications, including coronary dissection, were more frequent in unsuccessful cases (20.5% vs. 4.9%; p < 0.0001), but did not affect in-hospital MACE (3% vs. 2.1%; p = NS). All-cause mortality was 17.2% for uCTO and 4.5% for sCTO at 5 years (p < 0.0001). The need for CABG was reduced following sCTO (3.1% vs. 22.1%; p < 0.0001). Multivariate analysis demonstrated that procedural success was independently predictive of mortality (hazard ratio [HR]: 0.32 [95% confidence interval (CI): 0.18 to 0.58]), which persisted when incorporating a propensity score (HR: 0.28 [95% CI: 0.15 to 0.52]). CONCLUSIONS: Successful CTO PCI is associated with improved survival out to 5 years. Adoption of techniques and technologies to improve procedural success may have an impact on prognosis. PMID- 22516394 TI - Percutaneous revascularization of chronic total coronary occlusions: are the benefits underappreciated? PMID- 22516395 TI - Use of a novel crossing and re-entry system in coronary chronic total occlusions that have failed standard crossing techniques: results of the FAST-CTOs (Facilitated Antegrade Steering Technique in Chronic Total Occlusions) trial. AB - OBJECTIVES: This study sought to examine the efficacy and safety of 3 novel devices to recanalize coronary chronic total occlusions (CTOs). BACKGROUND: Successful percutaneous coronary intervention (PCI) of CTOs improves clinical outcome in appropriately selected patients. CTO PCI success, however, remains suboptimal. METHODS: A new crossing catheter and re-entry system was evaluated in a prospective, multicenter, single-arm trial of CTO lesions refractory to standard PCI techniques. The primary efficacy endpoint was the frequency of true lumen guidewire placement distal to the CTO (technical success). RESULTS: Enrollment included 147 patients with 150 CTOs. The mean lesion length was 41 +/- 17 mm. A crossing catheter crossed 56 lesions into the distal true lumen, and a re-entry catheter facilitated tapered-wire cannulation of the distal lumen in 59 CTOs initially crossed subintimally (77% technical success). Success in the first 75 CTOs was 67%, rising to 87% in the last 75 CTOs. Mean fluoroscopy and procedure times were 45 +/- 16 min and 90 +/- 12 min, respectively, each significantly shorter than in historical controls (p < 0.0001 for both). Coronary perforation occurred in 14 cases (9.3%), requiring treatment in 3 cases (prolonged balloon inflation, with additional coil embolization in 1 case). No tamponade or hemodynamic instability occurred. Six patients had periprocedural non-ST-segment elevation myocardial infarction. No emergency surgery, ST-segment elevation myocardial infarction, or cardiac reintervention occurred. Two deaths occurred within 30 days, neither as a direct result of the procedure. The 30-day major adverse cardiac event rate was 4.8%. CONCLUSIONS: In CTOs failing standard techniques, use of a new crossing and re-entry system results in a high success rate without increasing complications. PMID- 22516396 TI - Maximal hyperemia in the assessment of fractional flow reserve: intracoronary adenosine versus intracoronary sodium nitroprusside versus intravenous adenosine: the NASCI (Nitroprussiato versus Adenosina nelle Stenosi Coronariche Intermedie) study. AB - OBJECTIVES: This study sought to compare increasing doses of intracoronary (i.c.) adenosine or i.c. sodium nitroprusside versus intravenous (i.v.) adenosine for fractional flow reserve (FFR) assessment. BACKGROUND: Maximal hyperemia is the critical prerequisite for FFR assessment. Despite i.v. adenosine currently representing the recommended approach, i.c. administration of adenosine or other coronary vasodilators constitutes a valuable alternative in everyday practice. However, it is surprisingly unclear which i.c. strategy allows the achievement of FFR values comparable to i.v. adenosine. METHODS: Fifty intermediate coronary stenoses (n = 45) undergoing FFR measurement were prospectively and consecutively enrolled. Hyperemia was sequentially induced by incremental boli of i.c. adenosine (ADN) (60 MUg ADN60, 300 MUg ADN300, 600 MUg ADN600), by i.c. sodium nitroprusside (NTP) (0.6 MUg/kg bolus) and by i.v. adenosine infusion (IVADN) (140 MUg/kg/min). FFR values, symptoms, and development of atrioventricular block were recorded. RESULTS: Incremental doses of i.c. adenosine and NTP were well tolerated and associated with fewer symptoms than IVADN. Intracoronary adenosine doses (0.881 +/- 0.067, 0.871 +/- 0.068, and 0.868 +/- 0.070 with ADN60, ADN300, and ADN600, respectively) and NTP (0.892 +/- 0.072) induced a significant decrease of FFR compared with baseline levels (p < 0.001). Notably, ADN600 only was associated with FFR values similar to IVADN (0.867 +/- 0.072, p = 0.28). Among the 10 patients with FFR values <=0.80 with IVADN, 5 were correctly identified also by ADN60, 6 by ADN300, 7 by ADN600, and 6 by NTP. CONCLUSIONS: Intracoronary adenosine, at doses higher than currently suggested, allows obtaining FFR values similar to i.v. adenosine. Intravenous adenosine, which remains the gold standard, might thus be reserved for those lesions with equivocal FFR values after high (up to 600 MUg) i.c. adenosine doses. PMID- 22516397 TI - Relationship between fractional flow reserve and angiographic and intravascular ultrasound parameters in ostial lesions: major epicardial vessel versus side branch ostial lesions. AB - OBJECTIVES: This study sought to assess the relationship of coronary angiography, intravascular ultrasound (IVUS) and fractional flow reserve (FFR) between major epicardial vessel (MV) and side branch (SB) ostial lesions. BACKGROUND: Evaluation of ostial lesions is clinically very important. However, anatomical parameters have limitations in the prediction of the functional significance of coronary stenoses. METHODS: IVUS and FFR measurement were performed in 93 lesions (MV: 38, SB: 55). Optimal angiographic and IVUS criteria and their diagnostic accuracy for functionally significant stenoses (FFR <=0.8) were assessed. RESULTS: In MV ostial lesions, FFR had correlation with angiographic percent diameter stenosis (r = -0.68, p < 0.001), minimum lumen area (MLA) by IVUS (r = 0.55, p < 0.001), percent plaque burden (r = -0.42, p = 0.011), and percent area stenosis (r = -0.49, p = 0.003). Meanwhile, FFR had no correlation with angiographic percent diameter stenosis (r = -0.067, p = 0.635) and weak correlation with MLA (r = 0.30, p = 0.026) in SB ostial lesions. In MV ostial lesions, best cutoff value of angiographic percent diameter stenosis, MLA, percent plaque burden, and percent area stenosis to determine the functional significance was 53%, 3.5 mm(2), 70%, and 50%. However, a statistically significant cutoff value of percent diameter stenosis and MLA could not be found in SB ostial lesions. CONCLUSIONS: The relations between angiographic/IVUS parameters and FFR were different between MV and SB ostial lesions. Angiographic and IVUS parameters had poor diagnostic accuracy in predicting the functional significance of SB ostial lesions. (Main Branch Versus Side Branch Ostial Lesion; NCT01335659). PMID- 22516398 TI - Provoked exercise desaturation in patent foramen ovale and impact of percutaneous closure. AB - OBJECTIVES: This study was designed to assess the prevalence of provoked exercise desaturation (PED) in patients with patent foramen ovale (PFO) referred for cardiovascular evaluation and to evaluate the impact of PFO closure. BACKGROUND: Platypnea orthodeoxia syndrome is a rare, mechanistically obscure consequence of PFO that results in oxygen desaturation during postural changes. In our clinical experience, however, it is far less common than desaturation during exercise. METHODS: This was a single-center prospective study of 50 patients with newly diagnosed PFO. Each patient underwent standardized assessment for arterial oxygen saturation with pulse oximetry during postural changes and stair climbing exercise. Provoked exercise desaturation was defined as a desaturation of at least 8% from baseline to <90%. All patients who underwent closure were reevaluated 3 months after the procedure. Those with baseline PED were similarly reassessed for desaturation at follow-up. RESULTS: Mean age of the cohort was 46 +/- 17 years, 74% were female, 30% had migraines, and 48% had experienced a cerebrovascular event. Seventeen patients (34%) demonstrated PED. Provoked exercise desaturation patients seemed demographically similar to non-PED patients. Ten PED patients underwent PFO closure (2 surgical, and 8 percutaneous). Drop in oxygen saturation was improved by an average of 10.1 +/- 4.2% after closure (p < 0.001), and New York Heart Association functional class improved by a median of 1.5 classes (interquartile range: 0.75 to 2.00, p = 0.008). CONCLUSIONS: One-third of patients referred for assessment of PFO experience oxygen desaturation during stair exercise. Closure of PFO seems to ameliorate this phenomenon and improve functional status. PMID- 22516399 TI - Some air for closure of the patent foramen ovale. PMID- 22516400 TI - Risk factors and outcomes of post-procedure heart blocks after transcatheter device closure of perimembranous ventricular septal defect. AB - OBJECTIVES: The aim of this study was to analyze the risk factors and mid-term outcomes associated with post-procedure heart blocks (PPHBs) after transcatheter closure of perimembranous ventricular septal defect (pmVSD). BACKGROUND: The development of heart blocks remains a major challenge for transcatheter closure of pmVSD. METHODS: Transcatheter closure of pmVSD was carried out in 228 patients. Electrocardiography and 24-h Holter monitoring were performed before the procedure, within 1 week after the procedure, then 1, 3, 6, and 12 months, and every year thereafter. RESULTS: Thirty-three patients (14.5%) who received transcatheter closure of pmVSD developed PPHBs. PPHBs included right bundle branch block (57.6%), left bundle branch block (24.2%), and atrioventricular block (18.2%). High-degree atrioventricular blocks occurred in 4 patients and recovered to normal conduction after intravenous administration of hydrocortisone. PPHBs recovered to normal conduction in 21 patients by the time of hospital discharge. Compared with the patients without PPHBs, the patients suffering PPHBs were characterized by a significantly longer distance between the aortic valve and the defect (DAVD), a shorter distance from the lower rim of the defect to the septal leaflet of the tricuspid valve (DLRD-SLTV), and a larger diameter difference between the occluder and ventricular septal defect (DDOV). The earlier the PPHBs developed after the procedure, the more difficult the recovery to normal conduction. CONCLUSIONS: The outcome of PPHBs after transcatheter closure of pmVSD was satisfactory, as most patients recovered to normal conduction. Measurements of DLRD-SLTV, DAVD, and DDOV may be useful in predicting the incidence of PPHBs. PMID- 22516401 TI - Differences in neointimal thickness between the adluminal and the abluminal sides of malapposed and side-branch struts in a polylactide bioresorbable scaffold: evidence in vivo about the abluminal healing process. AB - OBJECTIVES: The goal of this study was to describe the neointimal healing on the abluminal side (ABL) of malapposed (ISA) struts and nonapposed side-branch (NASB) struts in terms of coverage by optical coherence tomography (OCT) and in comparison with the adluminal side (ADL). BACKGROUND: The neointimal healing on the ABL of ISA and NASB struts has never to our knowledge been explored in vivo and could be involved in the correction of acute malapposition. The bioresorbable vascular scaffold (BVS) is made of a translucent polymer that enables imaging of the ABL with OCT. METHODS: Patients enrolled in the ABSORB B (ABSORB Clinical Investigation Cohort B) study were treated with implantation of a BVS and imaged with OCT at 6 months. Thickness of coverage on the ADL and ABL of ISA and NASB struts was measured by OCT. RESULTS: Twenty-eight patients were analyzed; 114 (2.4%) struts were malapposed or at side branches. In 76 ISA struts (89.4%) and 29 NASB struts (100%), the thickness of ABL coverage was >30 MUm. Coverage was thicker on the ABL than on the ADL side (101 vs. 71 MUm; 95% confidence interval [CI] of the difference: 20 to 40 MUm). In 70 struts (60.7%, 95% CI: 50.6% to 70.0%), the neointimal coverage was thicker on the ABL, versus only 20 struts (18.5%, 95% CI: 11.6% to 28.1%) with thicker neointimal coverage on the ADL side (odds ratio: 3.35, 95% CI: 2.22 to 5.07). CONCLUSIONS: Most of the malapposed and side-branch struts are covered on the ABL side 6 months after BVS implantation, with thicker neointimal coverage than on the ADL side. The physiological correction of acute malapposition involves neointimal growth from the strut to the vessel wall or bidirectional. (ABSORB Clinical Investigation, Cohort B [ABSORB B]; NCT00856856). PMID- 22516402 TI - Nobori stent shows less vascular inflammation and early recovery of endothelial function compared with Cypher stent. AB - OBJECTIVES: The current study sought to examine inflammation at the stented segments of Nobori (Terumo Corporation, Tokyo, Japan) and Cypher (Cordis, Miami, Florida) drug-eluting stents (DES), as well as free radical production and endothelial function of the adjacent nonstented segments in a pig coronary model. BACKGROUND: Nobori is a novel DES, incorporating a biolimus A9-eluting biodegradable polymer coated only on the abluminal surface of the stent. These unique features may favorably affect inflammation and endothelial function, as compared to the currently marketed DES. Presently, pre-clinical data on direct comparison of the various generations of DES are not available. METHODS: A total of 18 DES were implanted in pig coronary arteries and subsequently explanted at 1 month. Stented segments were assessed by angiography and histology. Ex vivo vasomotor function and superoxide production in segments proximal and distal to the stent were determined. The vasoconstriction, endothelial-dependent relaxation, and endothelial-independent relaxation of proximal and distal nonstented segments were measured. RESULTS: Histological evaluation revealed lower inflammatory response with Nobori than with Cypher DES. There is trend for lower angiographic percentage diameter stenosis in Nobori versus Cypher groups (p = 0.054). There was increased endothelium-dependent relaxation, decreased endothelin-1-mediated contraction, and less superoxide production in the vessel segments proximal and distal to Nobori versus Cypher stents. CONCLUSIONS: Our data show significantly lower inflammatory response in the stented segments, and rapid recovery of endothelial function of peristent segments in the Nobori group compared with Cypher DES group at 1 month in porcine coronary artery model. PMID- 22516404 TI - Amplatzer septal occluder sealed the complicating aortic root perforation during transseptal procedure. PMID- 22516403 TI - Reduction of operator radiation dose by a pelvic lead shield during cardiac catheterization by radial access: comparison with femoral access. AB - OBJECTIVES: This study sought to determine the efficacy of patient pelvic lead shielding for the reduction of operator radiation exposure during cardiac catheterization via the radial access in comparison with the femoral access. BACKGROUND: Cardiac catheterization via the radial access is associated with significantly increased radiation dose to the patient and the operator. Improvements in radiation protection are needed to minimize this drawback. Pelvic lead shielding has the potential to reduce operator radiation dose. METHODS: We randomly assigned 210 patients undergoing elective coronary angiography by the same operator to a radial and femoral access with and without pelvic lead shielding of the patient. Operator radiation dose was measured by a radiation dosimeter attached to the outside breast pocket of the lead apron. RESULTS: For radial access, operator dose decreased from 20.9 +/- 13.8 MUSv to 9.0 +/- 5.4 MUSv, p < 0.0001 with pelvic lead shielding. For femoral access, it decreased from 15.3 +/- 10.4 MUSv to 2.9 +/- 2.7 MUSv, p < 0.0001. Pelvic lead shielding significantly decreased the dose-area product-normalized operator dose (operator dose divided by the dose-area product) by the same amount for radial and femoral access (0.94 +/- 0.28 to 0.39 +/- 0.19 MUSv * Gy(-1) * cm(-2) and 0.70 +/- 0.26 to 0.16 +/- 0.13 MUSv * Gy(-1) * cm(-2), respectively). CONCLUSIONS: Pelvic lead shielding is highly effective in reducing operator radiation exposure for radial as well as femoral procedures. However, despite its use, radial access remains associated with a higher operator radiation dose. PMID- 22516405 TI - Endovascular imaging of angiographically invisible spontaneous coronary artery dissection. PMID- 22516406 TI - More positive fluid balance could explain lower risk of contrast nephropathy. PMID- 22516407 TI - Hydration is critical for prevention of contrast-induced nephropathy. PMID- 22516410 TI - Quality control and the learning curve of transcatheter aortic valve implantation. PMID- 22516411 TI - Chronic total occlusion: a job for the "heart team". PMID- 22516412 TI - Fibromuscular dysplasia of the left anterior descending coronary artery. PMID- 22516413 TI - Anterior ST-segment elevation myocardial infarction in a patient with an L-I type single coronary artery. PMID- 22516414 TI - Intraosseous lipoma of the skull base, involving the sphenoclival region: case report. PMID- 22516415 TI - Anti-cholinergics for axial symptoms in Parkinson's disease after subthalamic stimulation. AB - OBJECTIVE: We studied the effect of anti-cholinergic therapy on axial symptoms that show a tendency to worsen over time after deep brain stimulation of the subthalamic nucleus (STN-DBS) in patients with Parkinson's disease (PD). PATIENTS AND METHODS: We conducted a prospective study of 20 consecutive patients treated with the anti-cholinergic agent trihexyphenidyl after bilateral STN-DBS and assessed the effect of anti-cholinergic therapy on parkinsonism 1 month after its initiation using the Unified Parkinson's Disease Rating Scale (UPDRS). RESULTS: After a mean post-operative follow-up period of 22.3 months, the scores of axial symptoms on UPDRS part II (ADL score) and part III (motor score) deteriorated by 87% and 54% (baseline), respectively, compared with the pre-operative scores (P < 0.001 for both comparisons). After adding trihexyphenidyl to dopaminergic medication with stimulation, the scores of axial symptoms on UPDRS part II and part III improved from baseline by 33% and 39%, respectively (P < 0.001 for both comparisons). CONCLUSIONS: Our findings demonstrated that the anti-cholinergic agent trihexyphenidyl shows positive effect for a patient population developing deterioration of axial symptoms after STN-DBS. The results in the present study may provide insights into the mechanism of emergence or progression of axial symptoms in patients with PD after STN-DBS. PMID- 22516416 TI - Glioblastoma research 2006-2010: pattern of citation and systematic review of highly cited articles. AB - High and continuously increasing research activity related to different aspects of pathogenesis, epidemiology, diagnosis and treatment of glioblastoma has been performed between 2006 and 2010. Different measures of impact, visibility and quality of published research are available, each with its own pros and cons. For this review, article citation rate was chosen. Articles were identified through systematic search of the abstract database PubMed followed by analyses of total number of citations and proportion of highly cited articles, arbitrarily defined as those with >=100, 50-99, and 25-49 citations, respectively (citation database Scopus). Overall 5831 scientific articles on the subject were published during this time period. 1.5% of all articles accumulated at least 100 citations, 3.2% were cited between 50 and 99 times, and 7.5% were cited between 25 and 49 times. Among the 10 most cited articles, 7 reported on genomic analyses, molecular subclasses of glioblastoma and/or stem cells. Overall, 18 randomized clinical trials were published between 2006 and 2010, including those with phase II design. Thirty-nine percent of them accumulated at least 50 citations and 72% were cited at least 25 times. In general, annual citation rate appeared to gradually increase during the first 2-3 years after publication before reaching high levels. A large variety of preclinical and clinical topics achieved at least 25 citations. However, areas such as quality of life, side effects, and end-of life care were underrepresented. Efforts to increase their visibility might be warranted. PMID- 22516417 TI - High-dose methotrexate and temozolomide associated with intrathecal liposomal cytarabine for the treatment of primary or secondary central nervous system lymphoma: a preliminary experience. PMID- 22516418 TI - Intrahepatic bile duct recurrence of hepatocellular carcinoma without a detectable liver tumor. AB - INTRODUCTION: Invasion of the portal and hepatic veins by hepatocellular carcinoma (HCC) is common, but macroscopic bile duct invasion is rare. Once a tumor thrombus completely obstructs the main bile duct, it causes obstructive jaundice. This type of HCC, known as icteric-type HCC (IHCC), has a poor prognosis. PRESENTATION OF CASE: A 72-year-old woman had been treated for chronic hepatitis C since 1997. In 2002, percutaneous ethanol injection therapy was performed for HCC in segment 8. HCC recurrence occurred in 2004, and she underwent transarterial embolization (TAE) and radiofrequency ablation (RFA). In 2006, an S8 segmentectomy was performed for re-recurrence of HCC. Three years after surgery, computed tomography (CT) revealed a tumor occupying the right anterior intrahepatic bile duct and extending into its right main branch. With a preoperative diagnosis of HCC recurrence in the bile duct, we performed a right hepatectomy and thrombectomy. Histological examination showed moderately to poorly differentiated HCC. No tumor tissue other than the intrahepatic bile duct tumor was detected in the resected liver specimen. DISCUSSION: HCC with biliary tumor thrombus is associated with a poor prognosis. In general, IHCC is difficult to diagnose and treat in the early stages. A characteristic radiological finding for this type of IHCC is the hypervascularity of the tumor thrombus. CONCLUSION: To the best of our knowledge, this is a rare case of IHCC recurrence as a tumor thrombus without recurrence in the resected liver specimen. PMID- 22516420 TI - Early migration of fully covered double-layered metallic stents for post-gastric bypass anastomotic strictures. AB - INTRODUCTION: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is well recognized for its efficiency in morbidly obese patients. Anastomotic strictures present in 5-15% of cases and have a significant impact on the patient's quality of life. Endoscopic balloon dilation is the recommended treatment but management of refractory cases is challenging. PRESENTATION OF CASE: Two patients with anastomotic stenoses refractory to dilations were treated with fully covered esophageal stents. Both cases presented early stent migration. The first patient finally underwent surgical revision of the anastomosis. For the second patient, a double-layered stent was installed after the first incident. After the migration of this second stent, three sessions of intralesional injection of triamcinolone acetonide were performed. Both patients were free of obstructive symptoms at a follow-up of 9 months. DISCUSSION: Treatment of post-gastric bypass strictures with stents is based on years of successful experience with endoscopic stenting of malignant esophageal strictures, gastric outlet obstruction in addition to anastomotic stenoses after esophageal cancer surgery. The actual prosthesis are however inadequate for the particularities of the LRYGB anastomosis with a high migration rate. Intralesional corticosteroid injection therapy has been reported to be beneficial in the management of refractory benign esophageal strictures and seems to have prevented recurrence of the stenosis in this post-LRYGB. CONCLUSION: Stents are aimed at preventing a complex surgical reintervention but are not yet specifically designed for that indication. Local infiltration of corticosteroids at the time of dilation may prevent recurrence of the anastomotic stricture. PMID- 22516419 TI - Laparoscopic approach to a large adrenocortical oncocytoma: A case report and review of the literature. AB - INTRODUCTION: Adrenocortical oncocytomas are extremely rare tumors, considered to be non-functional and of low malignant potential. Despite the great advance in laparoscopic techniques, there are extremely limited reports of laparoscopic approach of adrenocortical oncocytomas. Herein is presented a challenging case of laparoscopic approach to a large adrenocortical oncocytoma, underlining the safety and feasibility of laparoscopy in the surgical management of these extremely rare adrenal tumors. PRESENTATION OF CASE: A 34 year-old male was referred for surgical evaluation after the incidental discovery of a large right adrenal mass, during ultrasound examination due to renal colic. Further imaging evaluation revealed a well circumscribed capsule around the mass was demonstrated, with no evidence of infiltration of the neoplasm to periadrenal tissues. The patient was scheduled for laparoscopic right adrenalectomy, running an uneventful postoperative period. Histopathology revealed the presence of an adrenal oncocytoma. DISCUSSION: Recent studies have demonstrated that approximately one third of adrenocortical oncocytomas are associated with hormonal hypersecretion, as well as that one fifth of them demonstrate malignant biological behavior. From this point of view, there is emerging evidence in favor of the necessity of surgical excision as the treatment of choice. In spite of the progress of laparoscopic surgery, only three cases of laparoscopic excision of these tumors have been reported up to date. CONCLUSION: Laparoscopic surgery offers a safe alternative in confronting adrenocortical neoplasms, even when the biological behavior of the tumors cannot be pre-operatively evaluated in a definite way. PMID- 22516421 TI - Benign fibrous histiocytoma arising from the right shoulder: Is immunohistochemical staining always required for a definitive diagnosis? AB - INTRODUCTION: Fibrous histiocytomas are divided into two subgroups: malignant and benign fibrous histiocytomas (BFHs). BFH is one of the most common tumors of the superficial and deep soft tissues; it is commonly found on the skin and presents as a slow-growing solitary nodule made up of a mixture of fibroblastic and histiocytic cells. PRESENTATION OF CASE: In this study, we present the case of a 45-year-old female who was histopathologically diagnosed with dermatofibrosarcoma protuberans (DFSP) and received radiotherapy, but whose diagnosis was changed to BFH based on subsequent immunohistochemical analyses. DISCUSSION: BFH is a mesenchymal soft-tissue tumor with fibroblastic and histiocytic differentiation. Differential diagnosis for BFH found in deeper tissues includes other aggressive fibrohistiocytic lesions, such as DFSP and malignant fibrous histiocytoma. Differentiating among these tumors is crucial in selecting the correct surgical strategy and patient management in the postoperative period. In most cases, the pleomorphism and atypical mitotic activity seen histopathologically are sufficient for the differentiation between benign and malignant tumors. Immunohistochemical staining methods should be used in cases that are difficult to diagnose. The treatment of choice for BFH is wide resection of the tumor, which results in an excellent prognosis and low recurrence rate. In agreement with cases reported in the literature, our case confirms that wide excision is adequate to prevent the recurrence of the tumor. CONCLUSION: Although benign fibrous histiocytomas is rare, it must be considered in the differential diagnosis of tumors arising from the soft-tissue. PMID- 22516422 TI - Enterovirus 104 infection in adult, Japan, 2011. PMID- 22516423 TI - Streptococcus suis serotype 9 bacterin immunogenicity and protective efficacy. AB - Streptococcus suis diseases in pigs, most importantly meningitis, are worldwide responsible for major economic losses in the pig industry. About one fourth of invasive S. suis diseases are caused by S. suis serotype 9 strains in Europe. However, little is known about serotype 9 since most studies were performed with serotype 2. The objective of this study was to determine the immunogenicity and protective efficacy of a serotype 9 bacterin in piglets. Challenge was conducted with a reference serotype 9 strain, belonging to the same clonal complex but to a different sequence type as the bacterin strain. The bacterin induced protection against mortality but not morbidity. Eleven days post infection, 3 of 7 vaccinated survivors were not fully convalescent and had not eliminated the challenge strain from inner organs completely. In accordance with the clinical findings, the majority of piglets showed fibrinous-suppurative lesions in at least one inner organ or tissue. In contrast to the placebo group such lesions were not detected in one third of bacterin-vaccinated piglets. Determination of specific serum IgG titers revealed that the bacterin elicited seroconversion against muramidase-released protein and basic membrane lipoprotein. Furthermore, vaccination was associated with induction of opsonizing antibodies against the serotype 9 challenge strain. However, titers of opsonizing antibodies were rather low in comparison to those found in our previous serotype 2 vaccination trial. Piglets developed substantially higher titers of opsonizing antibodies after challenge. Opsonizing antibodies were absorbable with the serotype 9 challenge strain but not with an unencapsulated isogenic mutant of a serotype 2 strain indicating their specificity. The results indicate that a serotype 9 bacterin is less protective than a serotype 2 bacterin, most likely due to inducing only low titers of opsonizing antibodies. This might contribute to emergence of serotype 9 strains, in particular strains of this clonal complex, in Europe. PMID- 22516424 TI - The synthesis of 2,5-bis(4-amidinophenyl)thiophene derivatives providing submicromolar-range inhibition of the botulinum neurotoxin serotype A metalloprotease. AB - Botulinum neurotoxins (BoNTs), composed of a family of seven serotypes (categorized A-G), are the deadliest of known biological toxins. The activity of the metalloprotease, light chain (LC) component of the toxins is responsible for causing the life-threatening paralysis associated with the disease botulism. Herein we report significantly more potent analogs of novel, lead BoNT serotype A LC inhibitor 2,5-bis(4-amidinophenyl)thiophene (K(i) = 10.88 MUM +/- 0.90 MUM). Specifically, synthetic modifications involved simultaneously replacing the lead inhibitor's terminal bis-amidines with secondary amines and the systematic tethering of 4-amino-7-chloroquinoline substituents to provide derivatives with K(i) values ranging from 0.302 MUM (+/- 0.03 MUM) to 0.889MUM (+/- 0.11 MUM). PMID- 22516425 TI - Synthesis and characterization of some new complexes of Cu(II), Ni(II) and V(IV) with Schiff base derived from indole-3-carboxaldehyde. Biological activity on prokaryotes and eukaryotes. AB - Six new Cu(II), Ni(II), and VO(II) complexes (1-6) with Schiff base 1-phenyl-2,3 dimethyl-4-(1H-indole-3-carboxaldehyde)-3-pyrazolin-5-one (HL) were synthesized. The Schiff base was prepared through the condensation of 1-phenyl-2,3-dimethyl-4 amino-3-pyrazolin-5-one (antipyrine) with 1H-indole-3-carboxaldehyde. The new obtained compounds were characterized by (1)H NMR, (13)C NMR, UV-VIS, IR, EPR spectroscopy, elemental analysis, molar electric conductibility, magnetic susceptibility and thermal gravimetric analysis. In addition, the structure of the ligand HL has been determined by X-ray diffraction methods. The biological activity of complex compounds was investigated in terms of antibacterial effect on prokaryotic cells, by using paper disc diffusion technique, and for antiproliferative effect on eukaryotic cells, by monitoring mitotic activity in timelapse videomicroscopy experiments. The compounds were screened for their antibacterial activity against gram-positive bacteria (Staphylococcus aureus var. Oxford 6538, Klebsielle pneumoniae ATCC 100131 and Legionella monocytogenes ATCC 35182), gram-negative bacteria (Escherichia coli ATCC 10536, Pseudomonas aeruginosa ATCC 9027 and Salmonella typhimurium ATCC 14028) and anti-fungal activity (Candida albicans and Aspergillus flavus) using paper disc diffusion technique. The minimum inhibitory concentrations (MICs) of the compounds were also determined by agar streak dilution method. Compounds 3 and 4 proved to be the most effective as antibacterial agents. The antiproliferative activity was investigated by counting the number of mitoses for HeLa, and MCF7 cells. No significant antiproliferative effect was noted for HL and complex 2, for both used cell types. For complexes 1 and 3 complete inhibition of cell proliferation was observed in the case of HeLa cells, while the effects on MCF7 cell proliferation were lower. In conclusion, six new complex compounds were synthesized, and their biological activity investigated on both prokaryotic and eukaryotic cells, proving that some of them could be putative therapeutic substances. PMID- 22516426 TI - Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as antibacterial, antifungal and antituberculosis agents. AB - To affiliate multiple bioactivities in a compact heteronuclei, two series of benzimidazole based 1,3,4-oxadiazoles were synthesized and assessed in vitro for their efficacy as antimicrobial agents against eight bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Proteus vulgaris, Shigella flexneri), four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus clavatus, Candida albicans) and Mycobacterium tuberculosis H37Rv and best results were observed amongst the N-benzothiazolyl aetamide series. The lipophilicity (LogP) influence on the biological profile (MICs) of the prepared products was also discussed. Upon biological screening, it was observed that the majority of the compounds were found to possess a significant broad spectrum antimicrobial (3.12-25 MUg/mL of MIC) and antitubercular (6.25-25 MUg/mL of MIC) potential. The structural assignments of the new products were done on the basis of IR, (1)H NMR, (13)C NMR spectroscopy and elemental analysis. PMID- 22516428 TI - Balance of symptomatic pulmonary embolism and symptomatic intracerebral hemorrhage with low-dose anticoagulation in recent ischemic stroke: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: The current consensus is that anticoagulation therapy has no role acutely in the management of ischemic stroke, although there is still debate for specific conditions, such as cerebral venous thrombosis and cervical dissection. In addition, anticoagulation is used in the prevention of venous thromboembolic events. We assess the balance between preventing symptomatic pulmonary embolism (sPE) and causing symptomatic intracerebral hemorrhage (sICH) in patients with recent stroke who were randomized to low-dose subcutaneous anticoagulation in trials. METHODS: We systematically searched the Cochrane Library, Medline, Embase, and Science Citation Index for prospective randomized controlled trials assessing the effect of heparin and other antithrombotic therapies in patients with acute/early ischemic stroke. Included trials had to record information on pulmonary embolism and sICH. Risk ratios (RRs) were calculated for sICH per sPE for each trial using a random effects model. RESULTS: We identified 15 trials of low-dose subcutaneous anticoagulation. The trials studied low molecular weight heparin, heparinoids, and unfractionated heparin. The ratio of sICH to sPE was increased with low molecular weight heparin (RR 2.1; 95% confidence interval [CI] 1.03-4.28), but was in approximated unity with heparinoids (RR 1.27; 95% CI 0.31 5.17) and unfractionated heparin (RR 0.99; 95% CI 0.65-1.52). CONCLUSIONS: Prophylactic/low-dose heparin increased sICH by more than they reduced sPE in patients with recent ischemic stroke. Therefore, their routine acute use cannot be recommended, but they may still be relevant in patients at very high risk of PE (eg, morbid obesity, previous venous thromboembolism, and inherited thrombophilia) or if started later, although trials have not assessed these issues. PMID- 22516427 TI - Clinical features and racial/ethnic differences among the 3020 participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial. AB - This study examined the baseline characteristics, racial/ethnic differences, and geographic differences among participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) study. The SPS3 trial enrolled patients who experienced a symptomatic small subcortical stroke (lacunar stroke) within the previous 6 months and an eligible lesion on detected on magnetic resonance imaging. The patients were randomized, in a factorial design, to antiplatelet therapy (aspirin 325 mg daily plus clopidogrel 75 mg daily vs aspirin 325 mg daily plus placebo) and to one of two levels of systolic blood pressure targets ("intensive" [<130 mmHg] or "usual" [130-149 mmHg]). A total of 3020 participants were recruited from 81 clinical sites in 8 countries. In this cohort, the mean age was 63 years, 63% were men, 75% had a history of hypertension, and 37% had diabetes. The racial distribution was 51% white, 30% Hispanic, and 16% black. Compared with white subjects, black subjects were younger (mean age, 58 years vs 64 years; P <.001) and had a higher prevalence of hypertension (87% vs 70%; P <.001). The prevalence of diabetes was higher in the Hispanic and black subjects compared with the white subjects (42% and 40% vs 32%; both P <.001). Tobacco smoking at the time of qualifying stroke was much more frequent in the Spanish participants than in subjects from North America and from Latin America (32%, 22%, and 9%, respectively; P <.001). Mean systolic blood pressure at study entry was 4 mmHg lower in the Spanish subjects compared with the North American subjects (P <.01). The SPS3 cohort is the largest magnetic resonance imaging defined series of patients with S3. Among the racially/ethnically diverse SPS3 participants, important differences in patient features and vascular risk factors could influence prognosis for recurrent stroke and response to interventions. PMID- 22516429 TI - Study of hemostatic biomarkers in acute ischemic stroke by clinical subtype. AB - BACKGROUND: We studied the usefulness of hemostatic biomarkers in assessing the pathology of thrombus formation, subtype diagnosis, prognosis in the acute phase of cerebral infarction, and differences between various hemostatic biomarkers. METHODS: Our study included 69 patients with acute cerebral infarction who had been hospitalized within 2 days of stroke onset. Fibrin monomer complex (FMC), soluble fibrin (SF), D-dimer, thrombin-antithrombin III complex, fibrinogen, antithrombin III, and fibrin/fibrinogen degradation products (FDPs) were assayed as hemostatic biomarkers on days 1, 2, 3, and 7 of hospitalization. RESULTS: In the cardioembolic (CE) stroke group, FMC and SF levels were significantly higher on days 1 and 2 of hospitalization, and D-dimer levels were significantly higher on day 1 of hospitalization, compared to the noncardioembolic (non-CE) stroke group. FDP levels were significantly higher at all times in the CE group compared to the non-CE group. Neither the National Institute of Health Stroke Scale (NIHSS) used during hospitalization nor the modified Rankin Scale (mRS) used at discharge found any significant correlations to hemostatic biomarkers, but the NIHSS score during hospitalization was significantly higher in the CE group than in the non-CE group. CONCLUSIONS: Measurements of hemostatic biomarkers, such as FMC, SF, and D-dimer on the early stage of cerebral infarction are useful for distinguishing between CE and non-CE stroke. PMID- 22516430 TI - Phylogenetics of the millipede genus Brachycybe Wood, 1864 (Diplopoda: Platydesmida: Andrognathidae): patterns of deep evolutionary history and recent speciation. AB - The genus Brachycybe Wood is a little known group of millipedes comprising eight nominal species distributed throughout North America, Japan, South Korea, Taiwan, and China. The group's species are relatively morphologically homogenous and have been described primarily on the basis of differences in somatic morphology largely ignoring the often-used characters in millipede taxonomy and systematics male genitalia (the gonopods). The objectives of this study were to survey male gonopods with the aim of evaluating inter-specific variation, assess existing species boundaries and phylogeny using molecular characters, examine the historical biogeography of the genus, and estimate the timing of lineage divergence using a molecular clock. We surveyed two mitochondrial genes (cytochrome c oxidase I and cytochrome b) and one nuclear protein-coding gene (glutamyl and prolyl-tRNA synthetase) each comprising 952, 746, and 555 aligned base pairs respectively. Phylogenetic inference coupled with an analysis of species delimitation using a generalized mixed Yule coalescent model recovered eight species, two of which were considered to be cryptic. Molecular dating analyses coupled with ancestral range reconstructions indicate that the group is quite ancient (age>50 million years) and its origins are likely traced back geographically to the mountains of California's Sierra Nevada and Coastal Ranges. The genus Brachycybe appears to have expanded its range at least twice out of present day California into eastern North America and at least once into Asia. This study highlights the need for integrative approaches to describe biodiversity and furthers the evidence for cryptic diversity even in groups where genitalia are generally thought to be rapidly evolving, diagnostic features. PMID- 22516431 TI - Site-specific phosphorylation of protein phosphatase 1 regulatory subunit 12A stimulated or suppressed by insulin. AB - Protein phosphatase 1 (PP1) is one of the major phosphatases responsible for protein dephosphorylation in eukaryotes. So far, only few specific phosphorylation sites of PP1 regulatory subunit 12A (PPP1R12A) have been shown to regulate the PP1 activity. The effect of insulin on PPP1R12A phosphorylation is largely unknown. Utilizing a mass spectrometry based phosphorylation identification and quantification approach, we identified 21 PPP1R12A phosphorylation sites (7 novel sites, including Ser20, Thr22, Thr453, Ser478, Thr671, Ser678, and Ser680) and quantified 16 of them under basal and insulin stimulated conditions in hamster ovary cells overexpressing the insulin receptor (CHO/IR), an insulin sensitive cell model. Insulin stimulated the phosphorylation of PPP1R12A significantly at Ser477, Ser478, Ser507, Ser668, and Ser695, while simultaneously suppressing the phosphorylation of PPP1R12A at Ser509 (more than 2 fold increase or decrease compared to basal). Our data demonstrate that PPP1R12A undergoes insulin stimulated/suppressed phosphorylation, suggesting that PPP1R12A phosphorylation may play a role in insulin signal transduction. The novel PPP1R12A phosphorylation sites as well as the new insulin-responsive phosphorylation sites of PPP1R12A in CHO/IR cells provide targets for investigation of the regulation of PPP1R12A and the PPP1R12A-PP1cdelta complex in insulin action and other signaling pathways in other cell models, animal models, and humans. PMID- 22516433 TI - Proteomic analysis of microvesicles from plasma of healthy donors reveals high individual variability. AB - Healthy blood plasma is required for several therapeutic procedures. To maximize successful therapeutic outcomes it is critical to control the quality of blood plasma. Clearly initiatives to improve the safety of blood transfusions will have a high economical and social impact. A detailed knowledge of the composition of healthy blood plasma is essential to facilitate such improvements. Apart from free proteins, lipids and metabolites, blood plasma also contains cell-derived microvesicles, including exosomes and microparticles from several different cellular origins. In this study, we have purified microvesicles smaller than 220nm from plasma of healthy donors and performed proteomic, ultra-structural, biochemical and functional analyses. We have detected 161 microvesicle-associated proteins, including many associated with the complement and coagulation signal transduction cascades. Several proteases and protease inhibitors associated with acute phase responses were present, indicating that these microvesicles may be involved in these processes. There was a remarkably high variability in the protein content of plasma from different donors. In addition, we report that this variability could be relevant for their interaction with cellular systems. This work provides valuable information on plasma microvesicles and a foundation to understand microvesicle biology and clinical implications. PMID- 22516432 TI - Translational plant proteomics: a perspective. AB - Translational proteomics is an emerging sub-discipline of the proteomics field in the biological sciences. Translational plant proteomics aims to integrate knowledge from basic sciences to translate it into field applications to solve issues related but not limited to the recreational and economic values of plants, food security and safety, and energy sustainability. In this review, we highlight the substantial progress reached in plant proteomics during the past decade which has paved the way for translational plant proteomics. Increasing proteomics knowledge in plants is not limited to model and non-model plants, proteogenomics, crop improvement, and food analysis, safety, and nutrition but to many more potential applications. Given the wealth of information generated and to some extent applied, there is the need for more efficient and broader channels to freely disseminate the information to the scientific community. This article is part of a Special Issue entitled: Translational Proteomics. PMID- 22516434 TI - Sonographic evaluation of supraspinatus cross-sectional area in collegiate baseball players. AB - OBJECTIVE: To establish the normal thickness of the supraspinatus tendon in collegiate baseball players with the use of ultrasound and to determine whether there are any significant differences between the dominant and nondominant supraspinatus thickness. DESIGN: A cross-sectional observational study. SETTING: An outpatient clinical setting. PARTICIPANTS: Twelve healthy, asymptomatic collegiate pitchers between the ages of 19 and 22 years. METHODS: Sonographic evaluation of 12 asymptomatic pitchers (9 right-hand dominant and 3 left-hand dominant) between the ages of 19 and 22 years was performed in a transverse plane (short axis) and longitudinal view (long axis) of their right and left shoulders. Maximum thickness was measured in both the long- and short-axis views. On the long-axis view, measurement was taken at the point where there was maximal height observed at the footprint insertion. Mixed-model analysis of variance was used to test for differences in tendon thickness across factors. Post hoc contrasts were performed with a Tukey adjustment for the P values. The mean +/- SD values, side to-side difference, and difference between dominant and nondominant values were calculated and statistically analyzed for differences. RESULTS: An ultrasound examination showed a significant 3-way interaction (P = .038) for view by side of hand dominance. Post hoc contrasts revealed that supraspinatus tendon thickness for right-handed pitchers in the long-axis view on the right side showed a mean value of 8.0 +/- 0.32 mm versus the long-axis view on the left side of 6.5 +/- 0.34 mm (P = .006) and the short-axis view on the right of 7.4 +/- 0.40 mm versus the short-axis view on the left of 6.1 +/- 0.26 mm (P = .036). Supraspinatus tendon thickness for left-handed pitchers in the long-axis view on the left side showed a mean value of 7.5 +/- 0.59 mm versus the long-axis view on the right side of 5.9 +/- 0.56 mm (P = .137) and the short-axis view on the left of 6.5 +/- 0.45 mm versus the short-axis view on the right of 6.5 +/- 0.68 mm (P = .999). CONCLUSIONS: A database of normal values for supraspinatus tendon thickness in collegiate baseball pitchers has been developed. The results are consistent with expectations when the dominant side is compared with the nondominant side for right-handed pitchers with increased tendon thickness noted on the dominant side. There was no side-to-side difference found in left-hand dominant pitchers. PMID- 22516435 TI - Exceptional neurologic recovery in a teenage football player after second impact syndrome with a thin subdural hematoma. PMID- 22516437 TI - Confounding factors in brain death: cardiogenic ventilator autotriggering and implications for organ transplantation. AB - Brain death is characterised by a flaccid, areflexic neurological examination; fixed, dilated and midpoint pupils and total absence of intrinsic respiratory drive. A non-reversible clinical state or brain lesion must also be identified. Integral to brain death diagnosis is loss of respiratory drive. Following terminal brainstem herniation, a cardiovascular hyperdynamic state often occurs. This hyperdynamic state causes cyclical volume displacement within the chest in phase with the cardiac cycle, causing oscillations in gas flow patterns and may be reflected in ventilator airway pressure and flow waveforms. When these flow/pressure waveform oscillations meet or exceed ventilator flow or pressure trigger sensitivity, ventilator breaths may be triggered in the total absence of intrinsic respiratory drive. In a patient with no apparent neurological function who is still triggering ventilator breaths, detailed analysis of ventilator pressure/flow waveforms in context with neurological assessment findings can identify cardiac autotriggering in a brain-dead patient. Undetected, cardiogenic ventilator autotriggering results in prolonged ICU stay and potential loss of transplantable organs. Collaborative practice and aggressive surveillance to determine loss of all neurologic function and evaluate possible autotriggering in this population is paramount and can minimise ICU stay, reduce costs of care, decrease family stress and facilitate recovery of transplantable organs. PMID- 22516436 TI - Fear avoidance beliefs predict disability in older adults with chronic low back pain. AB - OBJECTIVES: To determine whether fear avoidance beliefs (FABs) in older adults with chronic low back pain (CLBP) are significantly associated with gait speed decline and/or self-report of greater disability. DESIGN: Cross-sectional analysis. SETTING: An academic medical center (single site). PARTICIPANTS: Two hundred English-speaking participants aged 65 years and older with CLBP every day or almost every day of moderate or greater intensity for >=3 months. MAIN OUTCOME MEASUREMENTS: The physical activity portion of the FAB questionnaire assessed FABs. Disability was measured with gait speed and the Roland Morris Questionnaire. Covariates measured included age, gender, body mass index, chronic disease (Cumulative Illness Rating Scale), depression (Geriatric Depression Scale), and pain (McGill Pain Questionnaire Short Form). RESULTS: FABs were significantly associated with the Roland Morris Questionnaire (P < .0001) and gait speed (P = .002) after controlling for all covariates. CONCLUSION: FABs related to physical activity in older adults with CLBP were significantly associated with both self-reported and performance-based disability after controlling for known confounders. Previous studies have reported similar associations between self-reported measures of disabling back pain and FABs. Ours is the first study to examine the relationship between FAB and gait speed, a powerful predictor of morbidity and mortality. Future work should examine whether targeting fear avoidance in addition to other psychosocial measures in older adults with CLBP improves gait speed and functional independence. PMID- 22516438 TI - Seed storage oil catabolism: a story of give and take. AB - The transition from seed to seedling is an important step in the life cycle of plants, which is fuelled primarily by the breakdown of triacylglycerol (TAG) in 'oilseed' species. TAG is stored within cytosolic oil bodies, while the pathway for fatty acid beta-oxidation resides in the peroxisome. Although the enzymology of fatty acid beta-oxidation has been relatively well characterised, the processes by which fatty acids are liberated from oil bodies and enter the peroxisome are less well understood and, together with metabolite, cofactor and co-substrate transporters, represent key targets for future research in order to understand co-ordination of peroxisomal metabolism with that of other subcellular compartments. PMID- 22516439 TI - The impact of case reports in oral and maxillofacial surgery. AB - This review examines the effect of publishing case reports on journal impact factor and future research. All case reports published in the four major English language oral and maxillofacial surgery journals in the two year period, 2007 2008, were searched manually. The citation data of each case report were retrieved from the ISI online database. The number, percentage and mean citations received by case reports and their relation to the 2009 journal impact factor were analysed. Case reports which received more than 5 citations were also identified and all of the citing articles retrieved and analysed. Thirty-one percent of all articles published in major oral and maxillofacial journals in 2007-2008 were case reports. Case reports had a low citation rate with a mean citation of less than 1. There were 38 (7.2%) case reports with more than 5 citations and 30% of the citing articles were also case reports. The publication of case reports negatively affected journal impact factor which correlated directly with the percentage of case reports published within a journal. Case reports reporting recent topics, describing new treatment/diagnosis method and with a literature review were more likely to receive citations. PMID- 22516440 TI - The year in interventional cardiology. PMID- 22516443 TI - How to supplement endpoints of ventricular tachycardia ablation: is there a role for noninvasive programmed ventricular stimulation? PMID- 22516441 TI - On-treatment non-high-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and lipid ratios in relation to residual vascular risk after treatment with potent statin therapy: JUPITER (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). AB - OBJECTIVES: The goal of this study was to determine whether residual risk after high-dose statin therapy for primary prevention individuals with reduced levels of low-density lipoprotein cholesterol (LDL-C) is related to on-treatment apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), trigylcerides, or lipid ratios, and how they compare with on-treatment LDL-C. BACKGROUND: Guidelines focus on LDL-C as the primary target of therapy, yet residual risk for cardiovascular disease (CVD) among statin-treated individuals remains high and not fully explained. METHODS: Participants in the randomized placebo-controlled JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial were adults without diabetes or CVD, with baseline LDL-C levels <130 mg/dl, high-sensitivity C-reactive protein levels >=2 mg/l, and triglyceride concentrations <500 mg/dl. Individuals allocated to receive rosuvastatin 20 mg daily with baseline and on-treatment lipids and lipoproteins were examined in relation to the primary endpoint of incident CVD (nonfatal myocardial infarction or stroke, hospitalization for unstable angina, arterial revascularization, or cardiovascular death). RESULTS: Using separate multivariate Cox models, statistically significant associations of a similar magnitude with residual risk of CVD were found for on-treatment LDL-C, non-HDL-C, apolipoprotein B, total cholesterol/HDL-C, LDL-C/HDL-C, and apolipoprotein B/A-I. The respective adjusted standardized hazard ratios (95% confidence intervals) for each of these measures were 1.31 (1.09 to 1.56), 1.25 (1.04 to 1.50), 1.27 (1.06 to 1.53), 1.22 (1.03 to 1.44), 1.29 (1.09 to 1.52), and 1.27 (1.09 to 1.49). The overall residual risk and the risk associated with these measures decreased among participants achieving on-treatment LDL-C <=70 mg/dl, on-treatment non-HDL-C <=100 mg/dl, or on-treatment apolipoprotein B <=80 mg/dl. In contrast, on-treatment triglycerides showed no association with CVD. CONCLUSIONS: In this primary prevention trial of nondiabetic individuals with low LDL-C and elevated high-sensitivity C-reactive protein, on-treatment LDL-C was as valuable as non-HDL-C, apolipoprotein B, or ratios in predicting residual risk. (JUPITER-Crestor 20mg Versus Placebo in Prevention of Cardiovascular [CV] Events; NCT00239681). PMID- 22516442 TI - Noninvasive programmed ventricular stimulation early after ventricular tachycardia ablation to predict risk of late recurrence. AB - OBJECTIVES: The goal of this study was to evaluate the ability of noninvasive programmed stimulation (NIPS) after ventricular tachycardia (VT) ablation to identify patients at high risk of recurrence. BACKGROUND: Optimal endpoints for VT ablation are not well defined. METHODS: Of 200 consecutive patients with VT and structural heart disease undergoing ablation, 11 had clinical VT inducible at the end of ablation and 11 recurred spontaneously. Of the remaining 178 patients, 132 underwent NIPS through their implantable cardioverter-defibrillator 3.1 +/- 2.1 days after ablation. At 2 drive cycle lengths, single, double, and triple right ventricular extrastimuli were delivered to refractoriness. Clinical VT was defined by comparison with 12-lead electrocardiograms and stored implantable cardioverter-defibrillator electrograms from spontaneous VT episodes. Patients were followed for 1 year. RESULTS: Fifty-nine patients (44.7%) had no VT inducible at NIPS; 49 (37.1%) had inducible nonclinical VT only; and 24 (18.2%) had inducible clinical VT. Patients with inducible clinical VT at NIPS had markedly decreased 1-year VT-free survival compared to those in whom no VT was inducible (<30% vs. >80%; p = 0.001), including 33% recurring with VT storm. Patients with inducible nonclinical VT only, had intermediate 1-year VT-free survival (65%). CONCLUSIONS: When patients with VT and structural heart disease have no VT or nonclinical VT only inducible at the end of ablation or their condition is too unstable to undergo final programmed stimulation, NIPS should be considered in the following days to further define risk of recurrence. If clinical VT is inducible at NIPS, repeat ablation may be considered because recurrence over the following year is high. PMID- 22516444 TI - Coronary arterial 18F-sodium fluoride uptake: a novel marker of plaque biology. AB - OBJECTIVES: With combined positron emission tomography and computed tomography (CT), we investigated coronary arterial uptake of 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) as markers of active plaque calcification and inflammation, respectively. BACKGROUND: The noninvasive assessment of coronary artery plaque biology would be a major advance particularly in the identification of vulnerable plaques, which are associated with specific pathological characteristics, including micro-calcification and inflammation. METHODS: We prospectively recruited 119 volunteers (72 +/- 8 years of age, 68% men) with and without aortic valve disease and measured their coronary calcium score and 18F-NaF and 18F-FDG uptake. Patients with a calcium score of 0 were used as control subjects and compared with those with calcific atherosclerosis (calcium score >0). RESULTS: Inter-observer repeatability of coronary 18F-NaF uptake measurements (maximum tissue/background ratio) was excellent (intra-class coefficient 0.99). Activity was higher in patients with coronary atherosclerosis (n = 106) versus control subjects (1.64 +/- 0.49 vs. 1.23 +/- 0.24; p = 0.003) and correlated with the calcium score (r = 0.652, p < 0.001), although 40% of those with scores >1,000 displayed normal uptake. Patients with increased coronary 18F-NaF activity (n = 40) had higher rates of prior cardiovascular events (p = 0.016) and angina (p = 0.023) and higher Framingham risk scores (p = 0.011). Quantification of coronary 18F-FDG uptake was hampered by myocardial activity and was not increased in patients with atherosclerosis versus control subjects (p = 0.498). CONCLUSIONS: 18F-NaF is a promising new approach for the assessment of coronary artery plaque biology. Prospective studies with clinical outcomes are now needed to assess whether coronary 18F-NaF uptake represents a novel marker of plaque vulnerability, recent plaque rupture, and future cardiovascular risk. (An Observational PET/CT Study Examining the Role of Active Valvular Calcification and Inflammation in Patients With Aortic Stenosis; NCT01358513). PMID- 22516445 TI - 18F-sodium fluoride positron emission tomography: an in vivo window into coronary atherosclerotic plaque biology. PMID- 22516448 TI - Medicine in free market economies. PMID- 22516447 TI - Reimbursement and the practice of cardiology. PMID- 22516446 TI - Heparanase regulates thrombosis in vascular injury and stent-induced flow disturbance. AB - OBJECTIVES: The purpose of this study was to examine the role of heparanase in controlling thrombosis following vascular injury or endovascular stenting. BACKGROUND: The use of endovascular stents are a common clinical intervention for the treatment of arteries occluded due to vascular disease. Both heparin and heparan sulfate are known to be potent inhibitors of thrombosis. Heparanase is the major enzyme that degrades heparan sulfate in mammalian cells. This study examined the role of heparanase in controlling thrombosis following vascular injury and stent-induced flow disturbance. METHODS: This study used mice overexpressing human heparanase and examined the time to thrombosis using a laser induced arterial thrombosis model in combination with vascular injury. An ex vivo system was used to examine the formation of thrombus to stent-induced flow disturbance. RESULTS: In the absence of vascular injury, wild type and heparanase overexpressing (HPA Tg) mice had similar times to thrombosis in a laser-induced arterial thrombosis model. However, in the presence of vascular injury, the time to thrombosis was dramatically reduced in HPA Tg mice. An ex vivo system was used to flow blood from wild type and HPA Tg mice over stents and stented arterial segments from both animal types. These studies demonstrate markedly increased thromboses on stents with blood isolated from HPA Tg mice in comparison to blood from wild type animals. We found that blood from HPA Tg animals had markedly increased thrombosis when applied to stented arterial segments from either wild type or HPA Tg mice. CONCLUSIONS: Taken together, this study's results indicate that heparanase is a powerful mediator of thrombosis in the context of vascular injury and stent-induced flow disturbance. PMID- 22516449 TI - Intravascular ultrasound-guided endovascular stenting for celiac artery complicated with hepatic hypoperfusion after acute type B aortic dissection. PMID- 22516450 TI - The D-dimer approach for troponin in the diagnosis of myocardial infarction: is it really useful? PMID- 22516451 TI - Dichotomizing high-sensitivity cardiac troponin T results and important analytical considerations. PMID- 22516453 TI - Microvolt T-wave alternans testing has a role in arrhythmia risk stratification. PMID- 22516454 TI - Serial images of right atrial hematoma after catheter ablation for supraventricular tachycardia. PMID- 22516455 TI - Unsuspected rickettsioses among patients with acute febrile illness, Sri Lanka, 2007. AB - We studied rickettsioses in southern Sri Lanka. Of 883 febrile patients with paired serum samples, 156 (17.7%) had acute rickettsioses; rickettsioses were unsuspected at presentation. Additionally, 342 (38.7%) had exposure to spotted fever and/or typhus group rickettsioses and 121 (13.7%) scrub typhus. Increased awareness of rickettsioses and better tests are needed. PMID- 22516456 TI - Imaging of genitourinary cancers: progress on all fronts. PMID- 22516457 TI - [Management of metastatic castration-resistant prostate cancer following docetaxel]. AB - Abiraterone acetate and cabazitaxel have shown an overall survival benefit in patients with metastatic castration-resistant prostate cancer following docetaxel failure. Both have been approved in this indication. The search, follow-up and characterisation of circulating tumor cells should help for the response evaluation and the choice between the two treatments. Recently, alpharadin (radium-223 chloride) has demonstrated also an overall survival advantage in a large phase III trial. Other hormone therapies as MDV3100 or TAK700 are very promising. In undifferentiated cancers with neuroendocrine features, etoposide and platinum salts combinations have shown low efficiency. PMID- 22516458 TI - The effect of DISC1 on regional gray matter density of schizophrenia in Han Chinese population. AB - Schizophrenia is thought to arise in part from abnormal gray matter (GM), which are partly shared by the relatives of the probands. DISC1 is one of the most promising susceptibility genes of schizophrenia and a SNP rs821597 (A) in the gene was associated with schizophrenia in Han Chinese population. In this study, 61 healthy controls and 72 with schizophrenic patients were genotyped at rs821597, and underwent T1-weighted MRI for the density of GM. The results showed that the risk allele (A) carriers had higher GM density in regional left parahippocampal gyrus and right orbitofrontal cortex in schizophrenic patients, but had reduced GM density of these brain regions in healthy controls. The DISC1 variant rs821597 may confer risk for schizophrenia by its effects on the regional GM in left parahippocampal gyrus and right orbitofrontal cortex with other risk factors for schizophrenia. PMID- 22516459 TI - Telocytes in meninges and choroid plexus. AB - Telocytes (TCs) are a recently identified type of interstitial cells present in a wide variety of organs in humans and mammals (www.telocytes.com). They are characterized by a small cell body, but extremely long cell processes - telopodes (Tp), and a specific phenotype. TCs establish close contacts with blood capillaries, nerve fibers and stem cells. We report here identification of TCs by electron microscopy and immunofluorescence in rat meninges and choroid plexus/subventricular zone, in the vicinity of putative stem cells. The presence of TCs in brain areas involved in adult neurogenesis might indicate that they have a role in modulation of neural stem cell fate. PMID- 22516461 TI - The tDCS effect on alpha brain oscillation for correct vs. incorrect object use. The contribution of the left DLPFC. AB - Representation of the instrumentally incorrect use of an object was explored in the present research taking into account the role of the dorsolateral prefrontal cortex (DLPFC). Specifically the "inhibitory" effect performed by tDCS (transcranial Direct Current Stimulation) on DLPFC was analyzed by measuring alpha frequency band modulation when subjects processed congruous/incongruous object-related action. Thirty-four subjects performed the congruence detection task within a dynamic context (a sequence of four action frames), where the final one could be congruous or incongruous. The stimulation effect (cathode applied on the DLPFC and anode on the control site) was analyzed comparing the RTs (response times) and alpha modifications before and after the stimulation. A significant alpha increasing was found for incongruous actions in case of cathodic stimulation of DLPFC compared with the pre-stimulation condition. Moreover, RTs showed a significant reduction in response to incongruous condition after tDCS stimulation. It was suggested that the inhibition of DLPFC may limit the "incongruence effect" induced by the semantic anomaly. Secondly, the contribution of the frontal area for the semantic processing of action was demonstrated. Finally, tDCS influence on cortical oscillations was largely supported, showing alpha modulation induced by DLPFC inhibition. PMID- 22516460 TI - Possible roles of Plexin-A4 in positioning of oligodendrocyte precursor cells in developing cerebral cortex. AB - Molecular mechanisms regulating positions of oligodendrocyte precursor cells (OPCs) remain unclear in developing cerebral cortex. To explore the mechanisms, we investigated how Plexin-A4, receptor of Semaphorin in OPCs, is involved in the positioning. We found that Plexin-A4 knockout mice exhibited (1) an increased number of OPCs in both the upper- and middle-regions of the cortical plate, where both indirect- and direct-ligands of Plexin-A4, Sema3A and Sema6A, respectively, were continuously expressed, and (2) aberrant distributions of OPCs in both the intermediate zone and corpus callosum, where Plexin-A4 was richly expressed in wild-type mice. These results suggest that Plexin-A4 is involved in the precise positioning of OPCs in developing cerebral cortex. PMID- 22516462 TI - NMDAR2B tyrosine phosphorylation is involved in thermal nociception. AB - Previous studies found that the NMDA receptor-mediated signaling regulates thermal nociception, though the underlying molecular mechanism remains unclear. The GluN2B subunit of the NMDA receptor is tyrosine-phosphorylated, Tyr-1472 being the major phosphorylation site. In this study, we have found that homozygous knock-in mice that express a Tyr-1472-Phe mutant of GluN2B display defects in the nociceptive response in the hot plate test. Expression of the neurotensin receptor subtype 2 (NTSR2), which is relevant to the regulation of thermal nociception, is decreased in the amygdala of GluN2B Tyr-1472-Phe knock-in mice. In addition, NTSR2-mediated c-fos induction is impaired in the amygdala of these mice. These data suggest that Tyr-1472 phosphorylation on GluN2B is involved in thermal nociception through regulating the NTSR2 mRNA expression in the amygdala. PMID- 22516464 TI - Ghrelin promotes reorganization of dendritic spines in cultured rat hippocampal slices. AB - Recent evidence suggests ghrelin may up-regulate the number of spine synapses. However, it is not completely understood whether an increased number of synapses are expressed on existing spines or accommodated in newly generated spines. We examined if ghrelin might have promoted the generation of new dendritic spines. Localization of polymerized actin (F-actin), highly expressed in dendritic spines, was assayed using phalloidin, a mushroom toxin that has a high affinity to F-actin. Alexa 488-conjugated phalloidin was visualized and relative changes in fluorescing puncta were quantified using a confocal microscope. Ghrelin was applied to cultured hippocampal slices for either 60 min or 23 h. Ghrelin increased the phalloidin fluorescent signals. The antagonist of the ghrelin receptor, D-Lys3-GHSR-6, blocked the ghrelin's effect of increasing the phalloidin signal, suggesting that the ghrelin's effect was mediated by the ghrelin receptor (GHSR1a). The ghrelin-mediated increase in phalloidin signals remained elevated while ghrelin was present in the culture media for 23 h. However, removal of ghrelin from culture media restored the phalloidin signal to control level. Our results suggest ghrelin may have a stimulating effect on the generation or remodeling of dendritic spines, and the spine change persists in the presence of ghrelin. The serum ghrelin level is high when the stomach is empty, and the ghrelin level remains high until metabolic demands are fulfilled. Thus, ghrelin may be involved in food-related and appetite-related learning in the hippocampus. PMID- 22516463 TI - Dantrolene ameliorates cognitive decline and neuropathology in Alzheimer triple transgenic mice. AB - Disruption of intracellular calcium homeostasis via abnormal and excessive activation of ryanodine receptors plays an important role in the neuropathology of Alzheimer's disease. We investigated the therapeutic effect of dantrolene, a ryanodine receptor antagonist, on cognitive dysfunction and neuropathology in the triple transgenic Alzheimer mouse model (3xTg-AD). 3xTg-AD mice were treated with dantrolene from 2 to 13 months of age. Learning and memory were measured with the Morris Water Maze at 6, 10, and 13 months of age. Amyloid and tau neuropathology and biomarkers for synaptic dysfunction and neurodegeneration were examined in the brain using immunoblotting or immunohistochemistry. Dantrolene treatment for 11 months significantly reduced both memory deficits and amyloid plaque load in the hippocampus in 13-month-old 3xTg-AD mice. Dantrolene treatment, however, had no effect on phosphorylated tau, phosphorylated or total GSK-3beta, synaptic markers, or mitochondrial or cytosolic cytochrome C. Our results suggest that dantrolene significantly improves cognition in a murine model of Alzheimer's disease and is associated with a reduction in amyloid plaque burden, forming the basis for a novel therapeutic approach for Alzheimer's disease. PMID- 22516465 TI - Complex regulation of capsaicin on intracellular second messengers by calcium dependent and independent mechanisms in primary sensory neurons. AB - Intracellular second messengers play an important role in capsaicin- and analogous-induced sensitization and desensitization in pain. Fluorescence Ca2+ imaging, enzyme immunoassay and PKC assay kit were used to determine a novel mechanism of different Ca2+ dependency in the signal transduction of capsaicin induced desensitization. On the average, capsaicin increased cAMP, cGMP concentration and SP release in bell-shaped concentration-dependent manner, with the maximal responses at concentrations around 1 MUM, suggesting acute desensitization of TRPV1 receptor activation. Capsaicin-induced intracellular Ca2+ concentration ([Ca2+](i)) increase depended on extracellular Ca2+ influx as an initial trigger. The Ca2+ influx by capsaicin increased PKC activation and SP release. These increases were completely abolished in Ca2+-free solution, suggesting that the modulation of capsaicin on PKC and SP are Ca2+-dependent. Interestingly, the maximal cAMP increase by TRPV1 activation was not blocked Ca2+ removal, suggesting at least in part a Ca2+-independent pathway is involved. Further study showed that cAMP increase was totally abolished by G-protein and adenylate cyclase (AC) antagonist, suggesting a G-protein-dependent pathway in cAMP increase. However, SP release was blocked by inhibiting PKC, but not G protein or AC, suggesting a G-protein independent pathway in SP release. These results suggest that both Ca2+-dependent and independent mechanisms are involved in the regulation of capsaicin on second messengers systems, which could be a novel mechanism underlying distinct desensitization of capsaicin and might provide additional opportunities in the development of effective analgesics in pain treatment. PMID- 22516466 TI - Preventable risk factors for acute kidney injury in patients undergoing cardiac surgery. PMID- 22516467 TI - Atrial fibrillation complicating left pneumothorax after malpositioning of a double-lumen tube. PMID- 22516468 TI - Retromolar placement of a double-lumen tube: novel approach for a difficult airway. PMID- 22516469 TI - CASE 6--2012: suspected amiodarone hepatotoxicity after cardiac surgery. PMID- 22516470 TI - An unusual radio-opaque shadow in the chest radiograph after coronary artery bypass surgery. PMID- 22516471 TI - Clonal spread of Geomyces destructans among bats, midwestern and southern United States. PMID- 22516473 TI - Negative electro-mechanical windows are required for drug-induced Torsades de Pointes in the anesthetized guinea pig. AB - INTRODUCTION: Assessment of the propensity of novel drugs to cause proarrhythmia is essential in the drug development process. It is increasingly recognized, however, that QT prolongation alone is an imperfect surrogate marker for Torsades de Pointes (TdP) arrhythmia prediction. In the present study we investigated the behavior of a novel surrogate marker for TdP, the electro-mechanical (E-M) window, prior to triggering of TdP episodes with sympathetic stimulation after administration of a number of reference compounds. METHODS: Experiments were carried out in closed chest pentobarbital anesthetized guinea pigs. Test compounds were administered intravenously together with a specific I(Ks) blocker (JNJ303; 0.2 mgkg(-1)min(-1) for 3 min) and adrenaline (0.06 mgkg(-1)min(-1) for 2 min) was applied to trigger TdP. ECG, blood- and left ventricular pressure signals were measured continuously throughout the experiments. The E-M window i.e. the duration of the mechanical systole (QLVP(end) interval) minus the duration of the electrical activity (QT interval) was assessed for individual beats. RESULTS: Drugs with documented TdP liability (quinidine, haloperidol, domperidone, terfenadine, moxifloxacin, ciprofloxacin and dofetilide) produced TdP in the protocol after adrenaline infusion, whereas negative control compounds (verapamil, ranolazine, amiodarone and saline) did not cause TdP arrhythmia, even though increases in repolarization times were observed. TdP were typically preceded by large (greater than -50 ms) negative electro-mechanical windows and were accompanied by aftercontractions. DISCUSSION: The present study in anesthetized guinea pigs indicates that negative E-M windows are a prerequisite for sympathetically-driven TdP induction after the administration of various agents with known proarrhythmic potential. These data are a first step in the validation of this novel protocol; however we believe that this proarrhythmia model in small animals might be a valuable additional tool in the prediction of TdP risk of new chemical entities at the early stages of drug discovery. PMID- 22516472 TI - IL-33 blockade suppresses the development of experimental autoimmune encephalomyelitis in C57BL/6 mice. AB - IL-33 is a recently described member of the IL-1 family that has been reported to have a pathogenic role in several inflammatory diseases. In this study, we evaluated the role of IL-33 in a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). We showed that the expression of IL-33 and its receptor, ST2, was markedly elevated in the spinal cord of mice during myelin oligodendrocyte glycoprotein (MOG)(35-55) peptide-induced EAE. Administration of a blocking anti-IL-33 antibody in mice of EAE during the induction phase significantly inhibited the onset and severity of EAE and reduced MOG(35-55) induced IFN-gamma and IL-17 production. In contrast, treatment with recombinant IL-33 worsened the disease course of EAE in association with increased induction of both IFN-gamma and IL-17. Furthermore, anti-IL-33 treatment caused a remarkable decrease in expression of IL-17, IFN-gamma, T-bet and RORgammat, and an upregulation of IL-10 and TGF-beta in the spinal cord of EAE mice. These results demonstrate that endogenous IL-33 plays a pivotal role in the pathogenesis of EAE and indicate that blockade of IL-33 has a significant protective effect against EAE. PMID- 22516474 TI - Babies born at the threshold of viability: changes in survival and workload over 20 years. AB - OBJECTIVE: To assess the care given to the babies born at the threshold of viability over the last 20 years using regional and national data. DESIGN: Population-based retrospective study. SETTING: Former 'Trent' health region. PARTICIPANTS: Babies born between 1 January 1991 and 31 December 2010 at 22(+0) to 25(+6) weeks gestational age. MAIN OUTCOME MEASURE: Survival and use of respiratory support. METHODS: Data of all babies born between 1 January 1991 and 31 December 2010 with a gestational age of 22(+0) to 25(+6) weeks and admitted to a neonatal unit were extracted from The Neonatal Survey. Use of respiratory support in terms of ventilation and continuous positive airway pressure (CPAP) for this group of babies was calculated as a proportion of the total used by the whole neonatal intensive care population within the defined study area. RESULTS: The proportion of babies surviving to discharge increased significantly over time in those born at 24 and 25 weeks (p<0.01) but failed to achieve statistical significance for those at 23 weeks (p=0.08). No babies born at 22 weeks survived. The babies born at 22-25 weeks accounted for 26.3% of all ventilation and 21.5% of CPAP given. CONCLUSION: Our work concurs with the current UK guidelines. There could be advantages in focusing the care of babies born at 23 weeks to a small number of intensive care units to allow specialist expertise to develop in all aspects of the management of these babies. However, focusing care will not necessarily improve survival or reduce morbidity. PMID- 22516475 TI - Early lactation failure and formula adoption after elective caesarean delivery: cohort study. AB - OBJECTIVE: To investigate the effects of elective primary and elective repeat caesarean deliveries on lactation at hospital discharge. DESIGN: Cohort study. SETTING: Four Italian teaching hospitals - Padua, Brescia, L'Aquila and Udine. INTERVENTIONS: Deliveries were classified as vaginal, elective caesarean (primary and repeat) or emergency caesarean. A total of 2296 (24.7%) infants born by caesarean section (CS), 816 of which (35.5%) classified as primary elective CS and 796 (34.7%) as repeat elective CS, were studied. Moreover, 30.2% of the elective CS deliveries took place before 39 weeks. MAIN OUTCOME MEASURES: Feeding modalities at discharge: formula, complementary and breastfeeding. RESULTS: At discharge, 6.9% of the vaginal delivery mothers, 8.3% of the emergency CS mothers, 18.6% of the elective CS mothers, 23.3% of the primary CS mothers and 13.9% of the repeat CS mothers were using infant formula exclusively. Multivariate analysis (OR; 95% CI) identified primary elective delivery (3.74; 3.0 to 4.60), lower gestational age (1.16; 1.10 to 1.23), and place L'Aquila versus Udine (1.42; 1.01 to 2.09) and of Brescia versus Udine hospitals (6.16; 4.53 to 8.37) as independent predictors of formula feeding at discharge. CONCLUSIONS: These findings provide new information about the risks of breastfeeding failure connected to elective CS delivery, particularly if primary and scheduled before 39 weeks of gestation. PMID- 22516476 TI - Randomised weaning trial comparing assist control to pressure support ventilation. AB - OBJECTIVES: To determine if the work of breathing was lower, respiratory muscle strength greater, but the degree of asynchrony higher during weaning by assist control ventilation (ACV) rather than pressure support ventilation (PSV) and if any differences were associated with a shorter duration of weaning. DESIGN: Randomised trial SETTING: Tertiary neonatal unit PATIENTS: Thirty-six infants, median gestational age 29 (range 24 to 39) weeks INTERVENTION: Weaning by either ACV or PSV. MAIN OUTCOME MEASURES: At baseline, 24 hours after entering the study and immediately prior to extubation, the work of breathing (PTPdi), thoracoabdominal asynchrony (TAA) and respiratory muscle strength (Pimax) were assessed and weaning duration recorded. RESULTS: There were no significant differences in the median PTPdi, TAA and Pimax results at any time point. The inflation times during ACV and PSV were similar. The median duration of weaning was 34 (range 7-100) hours in the ACV group and 27 (range 10-169) hours in the PSV group (p=0.88). CONCLUSION: No significant differences were found between weaning by PSV and ACV when similar inflation times were used. PMID- 22516477 TI - Local allergic rhinitis: concept, pathophysiology, and management. AB - Local allergic rhinitis (LAR) is a localized nasal allergic response in the absence of systemic atopy characterized by local production of specific IgE (sIgE) antibodies, a T(H)2 pattern of mucosal cell infiltration during natural exposure to aeroallergens, and a positive nasal allergen provocation test response with release of inflammatory mediators (tryptase and eosinophil cationic protein). Although the prevalence remains to be established, a number of patients previously given a diagnosis of nonallergic rhinitis or idiopathic rhinitis are now being classified as having LAR. Culprit allergens responsible include house dust mite, grass and olive pollens, and many others. For the diagnosis of LAR, neither skin prick testing nor determination of the presence of serum sIgE antibodies is useful, and a nasal allergen provocation test is needed to identify the culprit allergen or allergens. In a certain proportion of cases, local sIgE can be detected, and conjunctivitis, asthma, or both can be associated. Whether patients with LAR will have systemic atopy in the future is a matter of debate. Further studies are needed for examine the prevalence of this phenomenon in different areas, to improve the diagnostic methods to better identify these patients, and to develop therapeutic approaches, including the use of immunotherapy. PMID- 22516479 TI - Light-regulated stomatal aperture in Arabidopsis. AB - The stomatal pores of plant leaves, situated in the epidermis and surrounded by a pair of guard cells, allow CO2 uptake for photosynthesis and water loss through transpiration. Blue light is one of the dominant environmental signals that control stomatal movements in leaves of plants in a natural environment. This blue light response is mediated by blue/UV A light-absorbing phototropins (phots) and cryptochromes (crys). Red/far-red light-absorbing phytochromes (phys) also play a role in the control of stomatal aperture. The signaling components that link the perception of light signals to the stomatal opening response are largely unknown. This review discusses a few newly discovered nuclear genes, their function with respect to the phot-, cry-, and phy-mediated signal transduction cascades, and possible involvement of circadian clock. PMID- 22516478 TI - The Arabidopsis homolog of the mammalian OS-9 protein plays a key role in the endoplasmic reticulum-associated degradation of misfolded receptor-like kinases. AB - The endoplasmic reticulum-associated degradation (ERAD) is a highly conserved mechanism to remove misfolded membrane/secretory proteins from the endoplasmic reticulum (ER). While many of the individual components of the ERAD machinery are well characterized in yeast and mammals, our knowledge of a plant ERAD process is rather limited. Here, we report a functional study of an Arabidopsis homolog (AtOS9) of an ER luminal lectin Yos9 (OS-9 in mammals) that recognizes a unique asparagine-linked glycan on misfolded proteins. We discovered that AtOS9 is an ER localized glycoprotein that is co-expressed with many known/predicted ER chaperones. A T-DNA insertional atos9-t mutation blocks the degradation of a structurally imperfect yet biochemically competent brassinosteroid (BR) receptor bri1-9, causing its increased accumulation in the ER and its consequent leakage to the cell surface responsible for restoring the BR sensitivity and suppressing the dwarfism of the bri1-9 mutant. In addition, we identified a missense mutation in AtOS9 in a recently discovered ERAD mutant ems-mutagenized bri1 suppressor 6 (ebs6-1). Moreover, we showed that atos9-t also inhibits the ERAD of bri1-5, another ER-retained BR receptor, and a misfolded EFR, a BRI1-like receptor for the bacterial translation elongation factor EF-Tu. Furthermore, we found that AtOS9 interacted biochemically and genetically with EBS5, an Arabidopsis homolog of the yeast Hrd3/mammalian Sel1L known to collaborate with Yos9/OS-9 to select ERAD clients. Taken together, our results demonstrated a functional role of AtOS9 in a plant ERAD process that degrades misfolded receptor-like kinases. PMID- 22516480 TI - A case report of primary small cell carcinoma of the breast and review of the literature. AB - Primary small cell carcinoma (SCC) of the breast, an exceedingly rare and aggressive tumor, is often characterized by rapid progression and poor prognosis. We report a case of primary SCC of the breast that was diagnosed through pathologic and immunohistochemical examinations. Computed tomography (CT) scans failed to reveal a non-mammary primary site. Due to the scant number of relevant case summaries, this type of tumor is proved to be a diagnostic and therapeutic challenge. Therefore, we also reviewed relevant literature to share expertise in diagnosis, clinicopathologic characteristics, treatment, and prognosis of this type of tumor. Future studies with more cases are required to define more appropriate treatment indications for this disease. PMID- 22516482 TI - Reaching the healthy people goals for reducing childhood obesity: closing the energy gap. AB - BACKGROUND: The federal government has set measurable goals for reducing childhood obesity to 5% by 2010 (Healthy People 2010), and 10% lower than 2005 2008 levels by 2020 (Healthy People 2020). However, population-level estimates of the changes in daily energy balance needed to reach these goals are lacking. PURPOSE: To estimate needed per capita reductions in youths' daily "energy gap" (calories consumed over calories expended) to achieve Healthy People goals by 2020. METHODS: Analyses were conducted in 2010 to fit multivariate models using National Health and Nutrition Examination Surveys 1971-2008 (N=46,164) to extrapolate past trends in obesity prevalence, weight, and BMI among youth aged 2 19 years. Differences in average daily energy requirements between the extrapolated 2020 levels and Healthy People scenarios were estimated. RESULTS: During 1971-2008, mean BMI and weight among U.S. youth increased by 0.55 kg/m(2) and by 1.54 kg per decade, respectively. Extrapolating from these trends to 2020, the average weight among youth in 2020 would increase by ~1.8 kg from 2007-2008 levels. Averting this increase will require an average reduction of 41 kcal/day in youth's daily energy gap. An additional reduction of 120 kcal/day and 23 kcal/day would be needed to reach Healthy People 2010 and Healthy People 2020 goals, respectively. Larger reductions are needed among adolescents and racial/ethnic minority youth. CONCLUSIONS: Aggressive efforts are needed to reverse the positive energy imbalance underlying the childhood obesity epidemic. The energy-gap metric provides a useful tool for goal setting, intervention planning, and charting progress. PMID- 22516481 TI - Propofol participates in gastric mucosal protection through inhibiting the toll like receptor-4/nuclear factor kappa-B signaling pathway. AB - AIMS: Propofol has demonstrated protective effects against digestive injury. Toll like receptor-4 (TLR4) is involved in gastric mucosal injury. However, it has not yet been clarified whether propofol protects gastric mucosa from ethanol-induced injury and whether the mechanism involved is related to TLR4 activation. Therefore, this prospective study was carried out to address the issue. METHODS: Gastric mucosal injury was induced in mice by intragastric administration of ethanol. Propofol was given intraperitoneally 30 min before ethanol intragastric administration and, 1h later, gastric specimens were studied using hematoxylin- eosin staining, quantitative real-time RT-PCR, immunohistochemical staining and Western blot assays; serum specimens were studied using ELISA kits. RESULTS: Propofol at 25mg/kg significantly attenuated ethanol-induced gastric mucosal injury. In addition, propofol pretreatment significantly inhibited the upregulated expression of high-mobility group box-1 (HMGB1) protein, TLR4 and its downstream signaling molecules--myeloid differentiation factor 88 (MyD88) and nuclear factor kappa-B (NF-kappaB)--in gastric mucosa, while suppressing the increased release of tumor neurosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) in serum. Furthermore, upregulation of the Bax/Bcl-2 ratio in gastric mucosa was clearly depressed by propofol. CONCLUSION: Propofol can inhibit HMGB1 expression and TLR4/MyD88/NF-kappaB-mediated inflammatory responses, and hamper apoptosis, which may contribute to its protective action against ethanol-induced gastric mucosal injury. PMID- 22516483 TI - Physical activity, sedentary behavior, and adiposity in English children. AB - BACKGROUND: The importance of variation in total volume of physical activity or moderate- to vigorous-intensity physical activity (MVPA) to development of body fatness in childhood is unclear, and it is unclear if physical activity has a greater influence on adiposity in boys than girls. PURPOSE: To assess relationships between 2-year changes in objectively measured physical activity, sedentary behavior, and adiposity in English children. METHODS: Prospective cohort study, set in Northeast England, of a socioeconomically representative sample of 403 children. Measures were change in accelerometer-determined physical activity and sedentary behavior from age 7 to 9 years (data collected 2006/2007 and 2008/2009; analyzed in 2010) and concurrent change in adiposity (fat mass index derived from bioelectric impedance) and change in BMI Z-score. RESULTS: Decline in MVPA was associated with a greater increase in fat mass index in boys but not girls. Declining MVPA was associated with increased BMI Z-score in boys but not girls. Increased sedentary behavior was not associated with increased BMI Z-score in either gender. CONCLUSIONS: Avoiding mid-late childhood reductions in MVPA may reduce excessive fat gain, although such strategies may have greater impact on boys than girls. PMID- 22516484 TI - Physical education policy compliance and children's physical fitness. AB - BACKGROUND: Physical education policies have received increased attention as a means for improving physical activity levels, enhancing physical fitness, and contributing to childhood obesity prevention. Although compliance at the school and district levels is likely to be critical for the success of physical education policies, few published studies have focused on this issue. PURPOSE: This study investigated whether school district-level compliance with California physical education policies was associated with physical fitness among 5th-grade public-school students in California. METHODS: Cross-sectional data from FITNESSGRAM((r)) 2004-2006, district-level compliance with state physical education requirements for 2004-2006, school- and district-level information, and 2000 U.S. Census data were combined to examine the association between district level compliance with physical education policies and children's fitness levels. The analysis was completed in 2010. RESULTS: Of the 55 districts with compliance data, 28 (50%) were in compliance with state physical education mandates; these districts represented 21% (216) of schools and 18% (n=16,571) of students in the overall study sample. Controlling for other student-, school-, and district-level characteristics, students in policy-compliant districts were more likely than students in noncompliant districts to meet or exceed physical fitness standards (AOR=1.29, 95% CI=1.03, 1.61). CONCLUSIONS: Policy mandates for physical education in schools may contribute to improvements in children's fitness levels, but their success is likely to depend on mechanisms to ensure compliance. PMID- 22516485 TI - Cardiorespiratory fitness, alcohol, and mortality in men: the Cooper Center longitudinal study. AB - BACKGROUND: Studies have found that higher levels of cardiorespiratory fitness and light to moderate alcohol intake reduce the risk for premature death. Scant evidence, however, exists assessing the joint effects of both measures on all cause and cardiovascular disease (CVD) mortality. PURPOSE: This study aims to examine the independent and joint effects of alcohol consumption and cardiorespiratory fitness on all-cause and cardiovascular-related mortality in a large cohort of men. METHODS: This prospective study included 29,402 men who came to the Cooper Clinic (Dallas, TX) for a preventive medicine visit from 1973 to 2006. Data were analyzed in 2011. The primary exposure variables were tertiles of cardiorespiratory fitness and four categories of alcohol consumption, and the outcomes were all-cause and CVD mortality. Cox proportional hazards regression was used to model the association between alcohol intake, cardiorespiratory fitness, and all-cause and CVD mortality, controlling for potential confounders. RESULTS: A total of 1830 (all-cause) and 523 (CVD) deaths occurred in men over an average follow-up period of 17.4 years (SD=9.1). A linear relationship was observed (p<0.001) between increased fitness and reduced all-cause and CVD mortality. Specifically, moderate and high levels of fitness reduced the risk for all-cause mortality (HR=0.67, 95% CI=0.60, 0.74, and HR=0.57, 95% CI=0.49, 0.67, respectively) and CVD mortality in comparison to the low-fitness reference group (HR=0.70, 95% CI=0.57, 0.85; HR=0.54, 95% CI=0.40, 0.75, respectively), while controlling for alcohol intake and other covariates. A significant curvilinear relationship was found (p=0.01) between alcohol intake and all-cause mortality (but not CVD mortality), while controlling for fitness and other covariates. In a categoric examination of alcohol intake and mortality, adjusting for fitness and other confounders, there was no statistically significant effect of light drinking compared to heavy drinking on all-cause mortality or CVD mortality. An examination of the joint effects of fitness and alcohol on all-cause mortality showed that moderate and high fitness levels were protective against mortality irrespective of alcohol consumption levels. Few significant combined effects for CVD mortality reduction were found. CONCLUSIONS: Alcohol consumption did not significantly modify the association between fitness and mortality in this large cohort of men. PMID- 22516486 TI - Safe in the city: effective prevention interventions for human immunodeficiency virus and sexually transmitted infections. AB - BACKGROUND: The public health literature documents the efficacy-effectiveness gap between research and practice resulting from the research priority of demonstrating efficacy at the expense of testing for effectiveness. PURPOSE: The Safe in the City video-based HIV/sexually transmitted infection (STI) prevention intervention designed for sexually transmitted disease (STD) clinic waiting rooms is presented as a case study to demonstrate the application of a new framework to bridge efficacy and effectiveness. The goal of the study is to determine the extent to which clinics are implementing the intervention. METHODS: As part of the case study, data were collected from a convenience sample of 81 publicly funded STD clinics during program implementation to determine whether clinics were showing the video. A baseline telephone survey was administered to clinic directors from November to December 2008, and a follow-up was conducted from March to May 2009. Data analysis was completed in 2009. RESULTS: At baseline, 41% of STD clinics were showing Safe in the City, which increased to 58% at follow up. None reported previous implementation of behavioral interventions delivered in waiting rooms. Almost one fourth of clinics adapted the intervention by showing the video on laptop computers in examination rooms or in other venues with different audiences. CONCLUSIONS: The Safe in the City intervention was implemented by the majority of STD clinics and adapted for implementation. The framework for HIV/STI prevention intervention illustrates how measures of effectiveness were increased in the development, evaluation, dissemination, implementation and sustainability phases of research and program. PMID- 22516487 TI - Health indicators for military, veteran, and civilian women. AB - BACKGROUND: Women who have served in the military are a rapidly growing population. No previous studies have compared directly their health status to that of civilians. PURPOSE: To provide estimates of several leading U.S. health indicators by military service status among women. METHODS: Data were obtained from the 2010 Behavioral Risk Factor Surveillance Survey, a U.S. population-based study. Health outcomes were compared by military status using multivariable logistic regression among the female participants (274,399 civilians, 4221 veterans, 661 active duty, and 995 National Guard or Reserves [NG/R]). Data were analyzed in August 2011. RESULTS: Veterans reported poorer general health and greater incidence of health risk behaviors, mental health conditions, and chronic health conditions than civilian women. Active duty women reported better access to health care, better physical health, less engagement in health risk behaviors, and greater likelihood of having had a recent Pap than civilian women. Women from the NG/R were comparable to civilians across most health domains, although they had a greater likelihood of being overweight or obese and reporting a depressive and anxiety disorder. CONCLUSIONS: Compared with civilian women, NG/R women rated their health and access to health care similarly and active duty women rated theirs better on several domains, but veterans consistently reported poorer health. PMID- 22516488 TI - Successful weight loss among obese U.S. adults. AB - BACKGROUND: Little is known about weight control strategies associated with successful weight loss among obese U.S. adults in the general population. PURPOSE: To identify strategies associated with losing at least 5% and 10% of body weight. METHODS: Multivariable analysis of data from obese adult (BMI >=30) participants in the 2001-2006 NHANES to identify strategies associated with losing >=5% and >=10% of body weight (conducted in 2009-2011). RESULTS: Of 4021 obese adults, 2523 (63%) reported trying to lose weight in the previous year. Among those attempting weight loss, 1026 (40%) lost >=5% and 510 (20%) lost >=10% weight. After adjustment for potential confounders, strategies associated with losing >=5% weight included eating less fat (OR=1.41, 95% CI=1.14, 1.75); exercising more (OR=1.29, 95% CI=1.05, 1.60); and using prescription weight loss medications (OR=1.77, 95% CI=1.00, 3.13). Eating less fat (OR=1.37, 95% CI=1.04, 1.79); exercising more (OR=1.36, 95% CI=1.12, 1.65); and using prescription weight loss medications (OR=2.05, 95% CI=1.09, 3.86) were also associated with losing >=10% weight, as was joining commercial weight loss programs (OR=1.72, 95% CI=1.00, 2.96). Adults eating diet products were less likely to achieve 10% weight loss (OR=0.48, 95% CI=0.31, 0.72). Liquid diets, nonprescription diet pills, and popular diets had no association with successful weight loss. CONCLUSIONS: A substantial proportion of obese U.S. adults who attempted to lose weight reported weight loss, at least in the short term. Obese adults were more likely to report achieving meaningful weight loss if they ate less fat, exercised more, used prescription weight loss medications, or participated in commercial weight loss programs. PMID- 22516490 TI - Active transport, physical activity, and body weight in adults: a systematic review. AB - CONTEXT: Physical activity has various health benefits. Active transport can contribute to total physical activity and thus affect body weight because of increased energy expenditure. This review summarizes published evidence on associations of active transport, general physical activity, and body weight in adults. EVIDENCE ACQUISITION: A systematic review of the literature was conducted in October 2010 using eight databases. A total of 14,216 references were screened; full texts were retrieved for 95 articles. Forty-six articles (36 unique studies) were included: 20 (17) from Europe; 18 (13) from North America, Australia, and New Zealand; and eight (six) from other countries. Analyses of the retrieved papers were carried out between November 2010 and March 2011. EVIDENCE SYNTHESIS: Of 15 studies assessing active transport and physical activity, five found associations in the expected direction (more active transport associated with more physical activity) for all or most variables studied, nine found some associations, and one reported no associations. Of 30 studies assessing active transport and body weight, 13 reported associations in the expected direction (more active transport associated with lower body weight) for all or most variables studied, 12 found some associations, two presented some associations in the expected and some in the opposite direction, and three reported no associations. CONCLUSIONS: There is limited evidence that active transport is associated with more physical activity as well as lower body weight in adults. However, study heterogeneity, predominantly cross-sectional designs, and crude measures for active transport and physical activity impede quantitative conclusions. PMID- 22516489 TI - Physical activity and physical fitness: standardizing assessment with the PhenX Toolkit. AB - The focus of the PhenX (Phenotypes and eXposures) Toolkit is to provide researchers whose expertise lies outside a particular area with key measures identified by experts for uniform use in large-scale genetic studies and other extensive epidemiologic efforts going forward. The current paper specifically addresses the PhenX Toolkit research domain of physical activity and physical fitness (PA/PF), which are often associated with health outcomes. A Working Group (WG) of content experts completed a 6-month consensus process in which they identified a set of 14 high-priority, low-burden, and scientifically supported measures. During this process, the WG considered self-reported and objective measures that included the latest technology (e.g., accelerometers, pedometers, and heart-rate monitors). They also sought the input of measurement experts and other members of the research community during their deliberations. A majority of the measures include protocols for children (or adolescents), adults, and older adults or are applicable to all ages. Measures from the PA/PF domain and 20 other domains are publicly available and found at the PhenX Toolkit website, www.phenxtoolkit.org. The use of common measures and protocols across large studies enhances the capacity to combine or compare data across studies, benefiting both PA/PF experts and non-experts. Use of these common measures by the research community should increase statistical power and enhance the ability to answer scientific questions that previously might have gone unanswered. PMID- 22516491 TI - Retail grocery store marketing strategies and obesity: an integrative review. AB - CONTEXT: In-store food marketing can influence food-purchasing behaviors and warrants increased attention given the dramatic rise in obesity. Descriptive and experimental studies of key marketing components have been conducted by consumer scientists, marketing researchers, and public health experts. This review synthesizes research and publications from industry and academic sources and provides direction for developing and evaluating promising interventions. EVIDENCE ACQUISITION: Literature sources for the review were English-language articles published from 1995 to 2010, identified from multidisciplinary search indexes, backward searches of cited articles, review articles, industry reports, and online sources. Only articles that focused on physical grocery stores and food products were included. Data collection occurred in 2010 and 2011. EVIDENCE SYNTHESIS: Articles were classified in the categories of product, price, placement, and promotion and divided into controlled laboratory experiments, observation, and field experiments; 125 primary peer-reviewed articles met the inclusion criteria. Narrative synthesis methods were used. Key findings were synthesized by category of focus and study design. Evidence synthesis was completed in 2011. CONCLUSIONS: Findings suggest several strategies for in-store marketing to promote healthful eating by increasing availability, affordability, prominence, and promotion of healthful foods and/or restricting or de-marketing unhealthy foods. Key results of research in controlled laboratory studies should be adapted and tested in real-world in-store settings. Industry methods for assessing consumer behavior, such as electronic sales data and individually linked sales information from loyalty card holders, can help public health researchers increase the scientific rigor of field studies. PMID- 22516492 TI - The role of the geographic information systems infrastructure in childhood obesity prevention: perspective from the Robert Wood Johnson Foundation. PMID- 22516493 TI - Thinking about place, spatial behavior, and spatial processes in childhood obesity. PMID- 22516494 TI - Recommendation from the community preventive services task force for use of collaborative care for the management of depressive disorders. AB - The Community Preventive Services Task Force recommends collaborative care for management of depressive disorders, based on strong evidence of effectiveness in improving depression symptoms, adherence to treatment, response to treatment, and remission and recovery from depression. PMID- 22516496 TI - Economics of collaborative care for management of depressive disorders: a community guide systematic review. AB - CONTEXT: Major depressive disorders are frequently underdiagnosed and undertreated. Collaborative Care models developed from the Chronic Care Model during the past 20 years have improved the quality of depression management in the community, raising intervention cost incrementally above usual care. This paper assesses the economic efficiency of collaborative care for management of depressive disorders by comparing its economic costs and economic benefits to usual care, as informed by a systematic review of the literature. EVIDENCE ACQUISITION: The economic review of collaborative care for management of depressive disorders was conducted in tandem with a review of effectiveness, under the guidance of the Community Preventive Services Task Force, a nonfederal, independent group of public health leaders and experts. Economic review methods developed by the Guide to Community Preventive Services were used by two economists to screen, abstract, adjust, and summarize the economic evidence of collaborative care from societal and other perspectives. An earlier economic review that included eight RCTs was included as part of the evidence. The present economic review expanded the evidence with results from studies published from 1980 to 2009 and included both RCTs and other study designs. EVIDENCE SYNTHESIS: In addition to the eight RCTs included in the earlier review, 22 more studies of collaborative care that provided estimates for economic outcomes were identified, 20 of which were evaluations of actual interventions and two of which were based on models. Of seven studies that measured only economic benefits of collaborative care in terms of averted healthcare or productivity loss, four found positive economic benefits due to intervention and three found minimal or no incremental benefit. Of five studies that measured both benefits and costs, three found lower collaborative care cost because of reduced healthcare utilization or enhanced productivity, and one found the same for a subpopulation of the intervention group. One study found that willingness to pay for collaborative care exceeded program costs. Among six cost-utility studies, five found collaborative care was cost effective. In two modeled studies, one showed cost effectiveness based on comparison of $/disability-adjusted life-year to annual per capita income; the other demonstrated cost effectiveness based on the standard threshold of $50,000/quality-adjusted life year, unadjusted for inflation. Finally, six of eight studies in the earlier review reported that interventions were cost effective on the basis of the standard threshold. CONCLUSIONS: The evidence indicates that collaborative care for management of depressive disorders provides good economic value. PMID- 22516495 TI - Collaborative care to improve the management of depressive disorders: a community guide systematic review and meta-analysis. AB - CONTEXT: To improve the quality of depression management, collaborative care models have been developed from the Chronic Care Model over the past 20 years. Collaborative care is a multicomponent, healthcare system-level intervention that uses case managers to link primary care providers, patients, and mental health specialists. In addition to case management support, primary care providers receive consultation and decision support from mental health specialists (i.e., psychiatrists and psychologists). This collaboration is designed to (1) improve routine screening and diagnosis of depressive disorders; (2) increase provider use of evidence-based protocols for the proactive management of diagnosed depressive disorders; and (3) improve clinical and community support for active client/patient engagement in treatment goal-setting and self-management. EVIDENCE ACQUISITION: A team of subject matter experts in mental health, representing various agencies and institutions, conceptualized and conducted a systematic review and meta-analysis on collaborative care for improving the management of depressive disorders. This team worked under the guidance of the Community Preventive Services Task Force, a nonfederal, independent, volunteer body of public health and prevention experts. Community Guide systematic review methods were used to identify, evaluate, and analyze available evidence. EVIDENCE SYNTHESIS: An earlier systematic review with 37 RCTs of collaborative care studies published through 2004 found evidence of effectiveness of these models in improving depression outcomes. An additional 32 studies of collaborative care models conducted between 2004 and 2009 were found for this current review and analyzed. The results from the meta-analyses suggest robust evidence of effectiveness of collaborative care in improving depression symptoms (standardized mean difference [SMD]=0.34); adherence to treatment (OR=2.22); response to treatment (OR=1.78); remission of symptoms (OR=1.74); recovery from symptoms (OR=1.75); quality of life/functional status (SMD=0.12); and satisfaction with care (SMD=0.39) for patients diagnosed with depression (all effect estimates were significant). CONCLUSIONS: Collaborative care models are effective in achieving clinically meaningful improvements in depression outcomes and public health benefits in a wide range of populations, settings, and organizations. Collaborative care interventions provide a supportive network of professionals and peers for patients with depression, especially at the primary care level. PMID- 22516497 TI - Collaborative depression care models: from development to dissemination. PMID- 22516498 TI - Systemic organizational change for the collaborative care approach to managing depressive disorders. PMID- 22516499 TI - Clinical and community prevention and treatment service for depression: a whole greater than the sum of its parts. PMID- 22516500 TI - Innovative methods for improving measures of the personal environment. PMID- 22516501 TI - Implications of the energy gap for the prevention and treatment of childhood obesity. PMID- 22516502 TI - Obesogenic environments in youth: concepts and methods from a longitudinal national sample. AB - To effectively prevent and reduce childhood obesity through healthy community design, it is essential to understand which neighborhood environment features influence weight gain in various age groups. However, most neighborhood environment research is cross-sectional, focuses on adults, and is often carried out in small, nongeneralizable geographic areas. Thus, there is a great need for longitudinal neighborhood environment research in diverse populations across the life cycle. This paper describes (1) insights and challenges of longitudinal neighborhood environment research and (2) advancements and remaining gaps in measurement and study design that examine individuals and neighborhoods within the context of the broader community. Literature-based research and findings from the Obesity and Neighborhood Environment Database (ONEdata), a unique longitudinal GIS that is spatially and temporally linked to data in the National Longitudinal Study of Adolescent Health (N=20,745), provide examples of current limitations in this area of research. Findings suggest a need for longitudinal methodologic advancements to better control for dynamic sources of bias, investigate and capture appropriate temporal frameworks, and address complex residential location processes within families. Development of improved neighborhood environment measures that capture relevant geographic areas within complex communities and investigation of differences across urbanicity and sociodemographic composition are needed. Further longitudinal research is needed to identify, refine, and evaluate national and local policies to most effectively reduce childhood obesity. PMID- 22516503 TI - Objective assessment of obesogenic environments in youth: geographic information system methods and spatial findings from the Neighborhood Impact on Kids study. AB - BACKGROUND: GIS-based walkability measures designed to explain active travel fail to capture "playability" and proximity to healthy food. These constructs should be considered when measuring potential child obesogenic environments. PURPOSE: The aim of this study was to describe the development of GIS-based multicomponent physical activity and nutrition environment indicators of child obesogenic environments in the San Diego and Seattle regions. METHODS: Block group-level walkability (street connectivity, residential density, land-use mix, and retail floor area ratio) measures were constructed in each region. Multiple sources were used to enumerate parks (~900-1600 per region) and food establishments (~10,000 per region). Physical activity environments were evaluated on the basis of walkability and presence and quality of parks. Nutrition environments were evaluated based on presence and density of fast-food restaurants and distance to supermarkets. Four neighborhood types were defined using high/low cut points for physical activity and nutrition environments defined through an iterative process dependent on regional counts of fast-food outlets and overall distance to parks and grocery stores from census block groups where youth live. RESULTS: To identify sufficient numbers of children aged 6-11 years, high physical activity environment block groups had at least one high-quality park within 0.25 miles and were above median walkability, whereas low physical activity environment groups had no parks and were below median walkability. High nutrition environment block groups had a supermarket within 0.5 miles, and fewer than 16 (Seattle) and 31 (San Diego) fast-food restaurants within 0.5 miles. Low nutrition environments had either no supermarket, or a supermarket and more than 16 (Seattle) and 31 (San Diego) fast-food restaurants within 0.5 miles. Income, educational attainment, and ethnicity varied across physical activity and nutrition environments. CONCLUSIONS: These approaches to defining neighborhood environments can be used to study physical activity, nutrition, and obesity outcomes. Findings presented in a companion paper validate these GIS methods for measuring obesogenic environments. PMID- 22516504 TI - Obesogenic neighborhood environments, child and parent obesity: the Neighborhood Impact on Kids study. AB - BACKGROUND: Identifying neighborhood environment attributes related to childhood obesity can inform environmental changes for obesity prevention. PURPOSE: To evaluate child and parent weight status across neighborhoods in King County (Seattle metropolitan area) and San Diego County differing in GIS-defined physical activity environment (PAE) and nutrition environment (NE) characteristics. METHODS: Neighborhoods were selected to represent high (favorable) versus low (unfavorable) on the two measures, forming four neighborhood types (low on both measures, low PAE/high NE, high PAE/low NE, and high on both measures). Weight and height of children aged 6-11 years and one parent (n=730) from selected neighborhoods were assessed in 2007-2009. Differences in child and parent overweight and obesity by neighborhood type were examined, adjusting for neighborhood-, family-, and individual-level demographics. RESULTS: Children from neighborhoods high on both environment measures were less likely to be obese (7.7% vs 15.9%, OR=0.44, p=0.02) and marginally less likely to be overweight (23.7% vs 31.7%, OR=0.67, p=0.08) than children from neighborhoods low on both measures. In models adjusted for parent weight status and demographic factors, neighborhood environment type remained related to child obesity (high vs low on both measures, OR=0.41, p<0.03). Parents in neighborhoods high on both measures (versus low on both) were marginally less likely to be obese (20.1% vs 27.7%, OR=0.66, p=0.08), although parent overweight did not differ by neighborhood environment. The lower odds of parent obesity in neighborhoods with environments supportive of physical activity and healthy eating remained in models adjusted for demographics (high vs low on the environment measures, OR=0.57, p=0.053). CONCLUSIONS: Findings support the proposed GIS-based definitions of obesogenic neighborhoods for children and parents that consider both physical activity and nutrition environment features. PMID- 22516506 TI - Fast food and obesity: a spatial analysis in a large United Kingdom population of children aged 13-15. AB - BACKGROUND: The childhood obesity epidemic is a current public health priority in many countries, and the consumption of fast food has been associated with obesity. PURPOSE: This study aims to assess the relationship between fast-food consumption and obesity as well as the relationship between fast-food outlet access and consumption in a cohort of United Kingdom teenagers. METHODS: A weighted accessibility score of the number of fast-food outlets within a 1-km network buffer of the participant's residence at age 13 years was calculated. Geographically weighted regression was used to assess the relationships between fast-food consumption at age 13 years and weight status at ages 13 and 15 years, and separately between fast-food accessibility and consumption. Data were collected from 2004 to 2008. RESULTS: The consumption of fast food was associated with a higher BMI SD score (beta=0.08, 95% CI=0.03, 0.14); higher body fat percentage (beta=2.06, 95% CI=1.33, 2.79); and increased odds of being obese (OR=1.23, 95% CI=1.02, 1.49). All these relationships were stationary and did not vary over space in the study area. The relationship between the accessibility of outlets and consumption did vary over space, with some areas (more rural areas) showing that increased accessibility was associated with consumption, whereas in some urban areas increased accessibility was associated with lack of consumption. CONCLUSIONS: There is continued need for nutritional education regarding fast food, but public health interventions that place restrictions on the location of fast-food outlets may not uniformly decrease consumption. PMID- 22516505 TI - Patterns of obesogenic neighborhood features and adolescent weight: a comparison of statistical approaches. AB - BACKGROUND: Few studies have addressed the potential influence of neighborhood characteristics on adolescent obesity risk, and findings have been inconsistent. PURPOSE: Identify patterns among neighborhood food, physical activity, street/transportation, and socioeconomic characteristics and examine their associations with adolescent weight status using three statistical approaches. METHODS: Anthropometric measures were taken on 2682 adolescents (53% female, mean age=14.5 years) from 20 Minneapolis/St. Paul MN schools in 2009-2010. Neighborhood environmental variables were measured using GIS data and by survey. Gender-stratified regressions related to BMI z-scores and obesity to (1) separate neighborhood variables; (2) composites formed using factor analysis; and (3) clusters identified using spatial latent class analysis in 2012. RESULTS: Regressions on separate neighborhood variables found a low percentage of parks/recreation, and low perceived safety were associated with higher BMI z scores in boys and girls. Factor analysis found five factors: away-from-home food and recreation accessibility, community disadvantage, green space, retail/transit density, and supermarket accessibility. The first two factors were associated with BMI z-score in girls but not in boys. Spatial latent class analysis identified six clusters with complex combinations of both positive and negative environmental influences. In boys, the cluster with highest obesity (29.8%) included low SES, parks/recreation, and safety; high restaurant and convenience store density; and nearby access to gyms, supermarkets, and many transit stops. CONCLUSIONS: The mix of neighborhood-level barriers and facilitators of weight related health behaviors leads to difficulties disentangling their associations with adolescent obesity; however, statistical approaches including factor and latent class analysis may provide useful means for addressing this complexity. PMID- 22516507 TI - Spatial classification of youth physical activity patterns. AB - BACKGROUND: Physical activity is an essential element in reducing the prevalence of obesity, but much is unknown about the intensity and location of physical activity among youth-this is important because adolescent health behaviors are predictive of behaviors in adults. PURPOSE: This study aims to identify the locations where youth moderate-to-vigorous physical activity (MVPA) occurs, and to examine how MVPA varies according to urbanicity (urban, suburban, rural). METHODS: Participants included adolescent students (N=380, aged 12-16 years) from Halifax, Nova Scotia. Locations of MVPA were measured using accelerometers and GPS data loggers for up to 7 days. Specialized software was developed to integrate and process the data. Frequencies of MVPA by location were determined, and differences in MVPA were assessed for association with urbanicity. RESULTS: Active commuting accounted for the largest proportion of time in MVPA among urban and suburban students. Rural students achieved most MVPA at school. Other residential locations, shopping centers, and green spaces accounted for a majority of the remaining MVPA. Minutes in MVPA varied significantly overall (196.6 +/- 163.8, 84.9 +/- 103.2, 81.7 +/- 98.2); at school (45.7 +/- 45.2, 18.6 +/- 28.0, 29.8 +/- 39.7); while commuting (110.3 +/- 107.1, 31.5 +/- 55.2, 19.5 +/- 39.7); and at other activity locations (19.7 +/- 27.1, 14.8 +/- 26.8, 12.0 +/ 22.1) and by urbanicity. CONCLUSIONS: Findings reveal that the journeys between locations are as important as home and school settings in contributing to greater MVPA in adolescent youth. The relative importance of context as a contributor to MVPA varies with urbanicity. Combining actimetry and GPS data provides a precise link between physical activity measurements and contexts of the built environment. PMID- 22516509 TI - Successful pregnancy in vitrified/warmed blastocyst intrafallopian transfer. AB - OBJECTIVE: To analyze whether the use of blastocyst intrafallopian transfer is a feasible option in a case of repeated difficult ET. DESIGN: Case report. SETTING: Public hospital. PATIENT(S): Forty-year old nulliparous patient. INTERVENTION(S): Transfer of two vitrified/warmed blastocysts into the right tube by means of laparoscopy. MAIN OUTCOME MEASURE(S): Successful ET, clinical pregnancy. RESULT(S): Successful ET procedure resulting in positive beta-hCG and clinical pregnancy. CONCLUSION(S): In cases of repeated difficult ETs (regardless of whether the patient shows cervical adhesions or any type of genital malformations), blastocyst intrafallopian transfer can be a successful alternative approach. PMID- 22516510 TI - Is chromosome testing of the second miscarriage cost saving? A decision analysis of selective versus universal recurrent pregnancy loss evaluation. AB - OBJECTIVE: To compare the cost of selective recurrent pregnancy loss (RPL) evaluation, which is defined as RPL evaluation if the second miscarriage is euploid, versus universal RPL evaluation, which is defined as RPL evaluation after the second miscarriage. Traditionally, an RPL evaluation is instituted after the third miscarriage. However, recent studies suggest evaluation after the second miscarriage, which dramatically increases health care costs. Alternatively, chromosome testing of the second miscarriage, to determine whether an RPL evaluation is required, has been proposed. DESIGN: Decision-analytic model. SETTING: Academic medical center. PATIENT(S): Couples experiencing a second miscarriage of less than 10 weeks size. INTERVENTION(S): Selective versus universal RPL evaluation after the second miscarriage. MAIN OUTCOME MEASURE(S): Estimated cost for selective versus universal RPL evaluation. RESULT(S): The estimated cost of selective RPL evaluation after the second miscarriage was $3,352, versus $4,507 for universal RPL evaluation, resulting in a cost savings of $1,155. With stratification by maternal age groups, selective RPL evaluation resulted in increased cost savings with advancing maternal age groups. CONCLUSION(S): Selective RPL evaluation, which is based upon chromosome testing of the second miscarriage, is a cost-saving strategy for couples with RPL when compared with universal RPL evaluation. With advancing maternal age groups, the cost savings increased. PMID- 22516508 TI - Levetiracetam extended release conversion to monotherapy for the treatment of patients with partial-onset seizures: a double-blind, randomised, multicentre, historical control study. AB - This double-blind, randomised, multicentre, conversion to monotherapy, historical control study (N01280; NCT00419094) evaluated the efficacy, safety and tolerability of levetiracetam extended release (LEV XR) 2000mg/day once daily for the treatment of patients with partial-onset seizures compared with a historical control. Patients aged 12-75 years with 2-40 partial-onset seizures per 4 weeks, taking 1-2 antiepileptic drugs (AEDs) and receiving a stable dosage for >=4 weeks prior to screening were randomised in a 3:1 ratio to LEV XR 2000 or 1000 mg/day. The study comprised baseline (8 weeks), LEV XR up-titration (2 weeks), baseline AED tapering (6 weeks), LEV XR monotherapy (10 weeks), and entry into open-label follow-up study or down-titration (1 week). The primary efficacy variable was the cumulative exit rate at Day 112 due to predefined exit criteria compared with the historical control. Of the 171 patients randomised to LEV XR 2000 mg/day and 57 randomised to 1000 mg/day, 141 (82.5%) and 50 (87.7%) completed the study. The cumulative exit rate for patients on LEV XR 2000 mg/day (0.375 [95% CI 0.297, 0.453]) was significantly lower than historical control (0.653). Both LEV doses were well tolerated. The most common adverse events during the treatment period were somnolence (21.9%), headache (19.7%) and convulsion (14.9%). PMID- 22516512 TI - Survival trends of Staphylococcus aureus, Pseudomonas aeruginosa, and Clostridium perfringens in a sandy South Florida beach. AB - The search for alternative indicators of disease-risk from non-enteric pathogens at the beach revealed high densities of targeted bacteria. To explain the high numbers of potential non-enteric pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, in beach sand, we investigated factors affecting their survival and distribution, as well as those of a potential fecal indicator, Clostridium perfringens. Results indicated greater S. aureus and P. aeruginosa survival and proliferation in sterile beach sand, than seawater, with diminished numbers upon exposure to natural micro-predators. C. perfringens remained relatively consistent with initial numbers. Intermediate sand particles (850 MUm-2 mm) constituted the major micro-niche; creating implications for beach classification programs. Colonization of sterile sand boxes at the beach by S. aureus and P. aeruginosa confirmed the filtering action (>100*) of beach sand. The use of these potential pathogens in periodic sanitary evaluation of beach sand quality is indicated, regardless of the factors influencing their abundance. PMID- 22516511 TI - Cystic fibrosis research in allied health and nursing professions. AB - This report is the result of the "Allied Health and Nursing Professions Working Group" meeting which took place in Verona, Italy, November 2009, which was organised by the European Cystic Fibrosis Society, and involved 32 experts. The meeting was designed to provide a "roadmap" of high priority research questions that can be addressed by Allied Health Professionals (AHP) and nursing. The other goal was to identify research skills that would be beneficial to AHP and nursing researchers and would ultimately improve the research capacity and capability of these professions. The following tasks were accomplished: 1) a Delphi survey was used to identify high priority research areas and themes, 2) common research designs used in AHP and nursing research were evaluated in terms of their strengths and weaknesses, 3) methods for assessing the clinimetric and psychometric properties, as well as feasibility, of relevant outcome measures were reviewed, and 4) a common skill set for AHPs and nurses undertaking clinical research was agreed on and will guide the planning of future research opportunities. This report has identified important areas and themes for future research which include: adherence; physical activity/exercise; nutritional interventions; interventions for the newborn with CF and evaluation of outcome measures for use in AHP and nursing research. It has highlighted the significant challenges AHPs and nurses experience in conducting clinical research, and proposes strategies to overcome these challenges. It is hoped that this report will encourage research initiatives that assess the efficacy/effectiveness of AHP and nursing interventions in order to improve the evidence base. This should increase the quality of research conducted by these professions, justify services they currently provide, and expand their skills in new areas, with the ultimate goal of improving care for patients with CF. PMID- 22516513 TI - Mercury distribution, speciation and bioavailability in sediments from the Pearl River Estuary, Southern China. AB - Surface sediments and sediment cores collected from the Pearl River Estuary (PRE) were analyzed for total mercury (THg) concentrations and speciation using a sequential extraction method. The mobility of Hg in sediments was also assessed using a series of single extraction methods. The surface sediments from the PRE showed slightly elevated levels of Hg, with concentrations ranging from 109 to 453 ng/g. The vertical profile of THg in sediment cores indicated an accelerated input of Hg over the past decades. The organo-chelated and strong-complexed Hg species were the dominant Hg species in the sediments, while the more mobile phases of Hg made up less than 0.5% of THg. Less than 10% of the Hg in the sediments was extracted by single extraction, depending on the extractant employed. Significant relationships were found between the total organic carbon and THg, geochemical speciation, and extractability, indicating the important role of organic matter in controlling the distribution, mobility, and bioavailability of Hg in sediments. PMID- 22516514 TI - Origin of human T-lymphotropic virus type 1 in rural Cote d'Ivoire. AB - Simian T-lymphotropic virus type 1 (STLV-1) strains occasionally infect humans. However, the frequency of such infections is unknown. We show that direct transmission of STLV-1 from nonhuman primates to humans may be responsible for a substantial proportion of human T-lymphotropic virus type 1 infections in rural Cote d'Ivoire, where primate hunting is common. PMID- 22516516 TI - [Prostate cancer and chemotherapy: standards care and perspectives]. AB - Docetaxel is a reference treatment of metastatic prostate cancer castration resistant. Until now, the different associations were studied without benefit when compared to docetaxel as monotherapy. Cabazitaxel showed efficacy in second line in patients with progressive disease during or after docetaxel chemotherapy. Other molecules are being evaluated in second-line post-docetaxel. Abiraterone acetate is an alternative treatment to cabazitaxel in metastatic second-line resistant to castration. Predictive factors to choice treatment must be evaluated and proposed to personalize treatment in the future. Docetaxel activity was also studied in early stage of prostate cancer and seems to be promising. A cabazitaxel activity in early stage of cancer is also being evaluated. PMID- 22516515 TI - Perfusion status of the stroke-like lesion at the hyperacute stage in MELAS. AB - Hypoperfusion on single-photon emission computed tomography (SPECT) of the stroke like lesion (SLL) at the hyperacute stage of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) is considered to be a supportive evidence of the mitochondrial angiopathy theory. Our objectives were to examine whether other neuroimages, especially transcranial color-coded sonography (TCCS), done at the hyperacute stage of stroke-like episode (SLE) is consistent with hypoperfusion of the SLL. We reviewed the magnetic resonance imaging (MRI), SPECT, cerebral angiography, and TCCS of a patient with MELAS syndrome, all of which were performed at the hyperacute stage of one SLE. MRI on the 1st day post SLE showed right temporoparietal lesion with vasogenic edema. SPECT on the 2nd day showed focal decreased uptake of technetium-99m hexamethylpropyleneamine oxime ((99m)Tc-HMPAO) in the same region, but cerebral angiography and TCCS on the 3rd day showed increased regional cerebral blood flow (rCBF) and distal arteriole dilation in the same region. TCCS can delineate increased rCBF of the SLL at the hyperacute stage of SLE. We propose that the discrepancy between the decreased (99m)Tc-HMPAO uptake and increased rCBF might be caused by mitochondrial dysfunction. The phenomenon of "hypoperfusion" on SPECT might be caused by cell dysfunction but not decreased rCBF. We suggest that SPECT can be complemented by angiography and TCCS in future studies to delineate the perfusion status of SLLs. PMID- 22516518 TI - Less urgent (UNOS 1B and 2) listings in pediatric heart transplantation: a vanishing breed. PMID- 22516517 TI - Seroconversion and avidity maturation of cytomegalovirus-specific IgG in D+/R- lung transplant patients receiving different prophylactic anti-viral regimens. PMID- 22516519 TI - Electronic school absenteeism monitoring and influenza surveillance, Hong Kong. PMID- 22516521 TI - Utilization of multiple organisms in a proposed early-warning biomonitoring system for real-time detection of contaminants: preliminary results and modeling. AB - During past decades, biomonitors were deployed in lakes and rivers to rapidly detect hazardous chemicals by measuring the endpoints of a single aquatic species at defined short intervals. Most biomonitors, however, are only capable of indicating a departure from baseline water conditions without identifying the cause. In order to provide a more comprehensive assessment, a biomonitoring system which features a library of stereotyped responses of multiple aquatic species in various water conditions is proposed. A preliminary library was constructed by characterizing the behavioural and physiological responses of Daphnia magna, Hyalella azteca, Lumbriculus variegatus, and Pseudokirchneriella subcapitata to various concentrations of atrazine and tributyltin. By employing multivariate statistical tools such as principal component analysis (PCA) and discriminant analysis, this library (which contained responses after 6h of exposure to contaminants) was used as a template to classify and to model other sets of earlier measurements at 2 and 4h, resulting in an accuracy of 73 and 97%, respectively. These findings demonstrated the potential capability of the proposed early-warning biomonitoring system to provide real-time water quality assessment and early-warning contaminant detection. PMID- 22516520 TI - Temporal changes in c-Fos activation patterns induced by conditioned fear. AB - Mechanisms underlying shock-induced conditioned fear - a paradigm frequently used to model posttraumatic stress disorder, PTSD - are usually studied shortly after shocks. Some of the brain regions relevant to conditioned fear were activated in all the c-Fos studies published so far, but the overlap between the activated regions was small across studies. We hypothesized that discrepant findings were due to dynamic neural changes that followed shocks, and a more consistent picture would emerge if consequences were studied after a longer interval. Therefore, we exposed rats to a single session of footshocks and studied their behavioral and neural responses one and 28 days later. The neuronal activation marker c-Fos was studied in 24 brain regions relevant for conditioned fear, e.g. in subdivisions of the prefrontal cortex, hippocampus, amygdala, hypothalamic defensive system, brainstem monoaminergic nuclei and periaqueductal gray. The intensity of conditioned fear (as shown by the duration of contextual freezing) was similar at the two time-points, but the associated neuronal changes were qualitatively different. Surprisingly, however, Multiple Regression Analyses suggested that conditioned fear-induced changes in neuronal activation patterns predicted the duration of freezing with high accuracy at both time points. We suggest that exposure to electric shocks is followed by a period of plasticity where the mechanisms that sustain conditioned fear undergo qualitative changes. Neuronal changes observed 28 days but not 1 day after shocks were consistent with those observed in human studies performed in PTSD patients. PMID- 22516522 TI - Effect of methanol on the biofiltration of n-hexane. AB - This study investigated the removal of recalcitrant compounds in the presence of a hydrophilic compound. n-Hexane is used as a model compound to represent hydrophobic compounds. Methanol has been introduced in mixture with n-hexane in order to increase the bioavailability of n-hexane in trickle-bed-air-biofilters (TBABs). The mixing ratios investigated were: 70% methanol:30% n-hexane, and 80% methanol:20% n-hexane by volume. n-Hexane loading rates (LRs) ranged from 0.9 to 13.2 g m(-3) h(-1). Methanol LRs varied from 4.6 to 64.5 g m(-3) h(-1) and from 2.3 to 45.2 g m(-3) h(-1) depending upon the mixing ratio used. Biofilter performance, effect of mixing ratios of methanol to n-hexane, removal profile along biofilter depth, COD/nitrogen consumption and CO(2) production were studied under continuous loading operation conditions. Results have shown that the degradation of n-hexane is significantly enhanced by the presence of methanol for n-hexane LRs less than 13.2 g m(-3) h(-1). For n-hexane LR greater than 13.2 g m( 3) h(-1), even though methanol had impacted n-hexane biodegradation, its removal efficiency was higher than our previous study for biodegradation of n-hexane alone, in presence of surfactant, or in presence of benzene. On the other hand, the degradation of methanol was not impacted by the presence of n-hexane. PMID- 22516524 TI - Performance of the Seattle Heart Failure Model in implantable defibrillator patients treated with cardiac resynchronization therapy. AB - The Seattle Heart Failure Model (SHFM) is a validated multivariate risk prediction model for mortality in patients with heart failure, using widely available clinical variables. The aim of this study was to assess the performance of the SHFM when applied to patients with heart failure who received cardiac resynchronization therapy devices with defibrillation. A total of 413 patients were identified from 2 prospective implantable cardioverter-defibrillator registries who received cardiac resynchronization therapy devices with defibrillation for the primary prevention of sudden death. Baseline laboratory and clinical data were entered in the SHFM to calculate predicted survival. The end point was all-cause mortality. During a median follow-up period of 2.8 years, 78 patients died and 9 underwent heart transplantation. Observed versus predicted 5-year mortality rates were 11.6% versus 11.4%, 21.5% versus 22.1%, and 41.4% versus 46.1% by ascending tertile of Seattle Heart Failure Score, respectively. No systematic or substantial errors of risk estimation were observed. Discrimination was excellent; the C-statistic ranged from 0.78 at 1-year follow up to 0.70 at 5-year follow-up, and the Hosmer-Lemeshow chi-square statistic was 0.87 (p = 0.65). In conclusion, in patients with heart failure who received cardiac resynchronization therapy devices with defibrillation, the SHFM offers adequate discrimination of risk for all-cause mortality and estimation of mortality risk without substantial or systematic errors. PMID- 22516523 TI - PNGase F catalyzes de-N-glycosylation in a domestic microwave. AB - Common de-N-glycosylation protocols usually require a lengthy incubation time. Although pressure cycling technology or scientific microwave reactors can accelerate this enzyme reaction, they may not be easily accessible. In this brief report, we employed an alternative strategy using a standard domestic microwave oven to perform the de-N-glycosylation. Model glycoproteins (bovine RNase B, bovine fetuin, and human IgG) and a complex mixture from human plasma were fully deglycosylated in 20 min, without any apparent adverse affects on the glycans or protein backbones. This new method provides a simple and inexpensive solution to achieve rapid de-N-glycosylation. PMID- 22516525 TI - Long-term compliance with nonpharmacologic treatment of patients with heart failure. AB - The aim of this study was to examine long-term compliance with nonpharmacologic treatment of patients with heart failure (HF) and its associated variables. Data from 648 hospitalized patients with HF (mean age 69 +/- 12 years, 38% women, mean left ventricular ejection fraction 33 +/- 14%) were analyzed. Compliance was assessed by means of self-report at baseline and 1, 6, 12, and 18 months after discharge. Patients completed questionnaires on depressive symptoms, HF knowledge, and physical functioning at baseline. Logistic regression analyses were performed to examine independent associations with low long-term compliance. From baseline to 18-month follow-up, long-term compliance with diet and fluid restriction ranged from 77% to 91% and from 72% to 89%, respectively. In contrast, compliance with daily weighing (34% to 85%) and exercise (48% to 64%) was lower. Patients who were in New York Heart Association functional class II were more often noncompliant with fluid restriction (odds ratio [OR] 1.97, 95% confidence interval [CI] 1.25 to 3.08). A lower level of knowledge on HF was independently associated with low compliance with fluid restriction (OR 0.78, 95% CI 0.71 to 0.86) and daily weighing (OR 0.86, 95% CI 0.79 to 0.94). Educational support improved compliance with these recommendations. Female gender (OR 1.91, 95% CI 1.26 to 2.90), left ventricular ejection fraction >=40% (OR 1.55, 95% CI 1.03 to 2.34), a history of stroke (OR 3.55, 95% CI 1.54 to 8.16), and less physical functioning (OR 0.99, 95% CI 0.98 to 0.99) were associated with low compliance with exercise. In conclusion, long-term compliance with exercise and daily weighing was lower than long-term compliance with advice on diet and fluid restriction. Although knowledge on HF and being offered educational support positively affected compliance with weighing and fluid restriction, these variables were not related to compliance with exercise. Therefore, new approaches to help patients with HF stay physically active are needed. PMID- 22516526 TI - Bleeding risk and major adverse events in patients with previous ulcer on oral anticoagulation therapy. AB - Bleeding is the major concern for patients receiving oral anticoagulation therapy (OAT), especially those with histories of gastrointestinal ulcer. The aim of this study was to evaluate the efficacy and safety of OAT in patients with nonvalvular atrial fibrillation with histories of ulcer. A composite end point, including major adverse cardiac events or major bleeding, was compared between patients with AF with previous ulcers who were (OAT+; n = 200) and were not (OAT- n = 230) receiving OAT. During the follow-up period of 3.3 +/- 2.7 years, 28 (14%) and 66 (29%) OAT+ and OAT- patients, respectively, had major adverse cardiac events (p = 0.001). Major bleeding occurred in 46 OAT+ patients (23%) and 25 OAT- patients (11%) (p = 0.001). There was no significant difference in the composite end point between OAT+ and OAT- patients (29% vs 36%, p = 0.08). The incidence of major bleeding was significantly lower, decreasing from 30% to 14%, when OAT began after endoscopic confirmation of ulcer healing (p = 0.02). OAT+ patients who achieved time in the therapeutic range >=60% for international normalized ratio (2.0 to 3.0) demonstrated better cumulative survival free from the composite end point than OAT- patients (p = 0.01). In conclusion, OAT in patients with nonvalvular AF with histories of gastrointestinal ulcer made no difference in the composite end point compared to absence of OAT. In OAT+ patients, maintaining an optimal international normalized ratio reduced the composite end point, and the confirmation of ulcer healing reduced the incidence of bleeding. PMID- 22516527 TI - Association between retinopathy and cardiovascular disease in patients with chronic kidney disease (from the Chronic Renal Insufficiency Cohort [CRIC] Study). AB - Patients with chronic kidney disease experience co-morbid illnesses, including cardiovascular disease (CVD) and retinopathy. The purpose of the present study was to assess the association between retinopathy and self-reported CVD in a subgroup of the participants in the Chronic Renal Insufficiency Cohort study. For this observational, ancillary investigation, 2,605 Chronic Renal Insufficiency Cohort participants were invited to participate in the present study, and nonmydriatic fundus photographs in both eyes were obtained for 1,936 subjects. The photographs were reviewed in a masked fashion at a central photograph reading center. The presence and severity of retinopathy (diabetic, hypertensive, or other) and vessel diameter caliber were assessed using standard protocols by trained graders who were masked to the information about the study participants. A history of self-reported CVD was obtained using a medical history questionnaire. Kidney function measurements and traditional and nontraditional risk factors for CVD were obtained from the Chronic Renal Insufficiency Cohort study. A greater severity of retinopathy was associated with a greater prevalence of any CVD, and this association persisted after adjustment for the traditional risk factors for CVD. The presence of vascular abnormalities usually associated with hypertension was also associated with increased prevalence of CVD. We found a direct relation between CVD prevalence and mean venular caliber. In conclusion, the presence of retinopathy was associated with CVD, suggesting that retinovascular pathology might indicate macrovascular disease, even after adjustment for renal dysfunction and traditional CVD risk factors. This would make the assessment of retinal morphology a valuable tool in CKD studies of CVD outcomes. PMID- 22516528 TI - Usefulness of desirable lifestyle factors to attenuate the risk of heart failure among offspring whose parents had myocardial infarction before age 55 years. AB - Heart failure (HF) is one of the leading causes of hospitalization and death in the United States and throughout Europe. Although a higher risk for HF with antecedent myocardial infarction (MI) has been reported in offspring whose parents had MIs before age 55 years, it is unclear whether adherence to healthful behaviors can mitigate that risk. The aim of the present study was therefore to prospectively examine if adherence to healthy weight, regular exercise, moderate alcohol consumption, and abstinence from smoking can attenuate such increased HF risk. Information on parental history of MI and lifestyle factors was collected using questionnaires. Subjects adhering to >=3 healthy lifestyle factors were classified as having good versus poor lifestyle scores. Incident HF was assessed via yearly follow-up questionnaires and validated in a subsample. During an average follow up of 21.7 +/- 6.5 years, 1,323 new HF cases (6.6%), of which 190 (14.4%) were preceded by MI, occurred. Compared to subjects with good lifestyle scores and no parental histories of premature MI, multivariate adjusted hazard ratios for incident HF with antecedent MI were 3.21 (95% confidence interval 1.74 to 5.91) for subjects with good lifestyle score and parental histories of premature MI, 1.52 (95% confidence interval 1.12 to 2.07) for those with poor lifestyle score and no parental histories of premature MI, and 4.60 (95% confidence interval 2.55 to 8.30) for those with poor lifestyle scores and parental histories of premature MI. In conclusion, our data suggest that even in subjects at higher risk for HF because of genetic predisposition, adherence to healthful lifestyle factors may attenuate such an elevated HF risk. PMID- 22516530 TI - Toe amputation: a predictor of future limb loss? AB - BACKGROUND: Digital toe amputation is a relatively minor surgical procedure but there is a historical view that it is the "first stage in a predictable clinical course" leading to eventual limb loss. There is a paucity of contemporaneous data on the long-term outcomes of patients undergoing toe amputation. We aim to study the experience from our institution, focussing on the risk factors for progression to future limb loss, by conducting a retrospective review of our practice. METHODS: Sixty-three patients undergoing toe amputation within our institution were identified and the clinical notes retrospectively reviewed. A database of vascular risk factors and co-morbidity was constructed and correlation with future limb loss was analysed with Chi-squared testing and a logistic regression model. RESULTS: Sixty-three patients with a mean age of 69 (IQR 62-76.5) years were identified. Thirty-five (55.6%) of these patients went on to have a further surgical amputation; 22 major amputations (16 below-knee and 6 above-knee amputations) and 23 minor amputations were performed in total. Forty three (68.3%) patients had diabetes and 31 (49.2%) patients had one or more revascularisation procedures undertaken. There was a significant correlation between patients who did not have diabetes and future limb loss (Chi squared=4.31, p=0.038), however no other identified risk factor predicted the need for major amputation. CONCLUSION: Toe amputation is a significant predictor of future limb loss. Our study identified that patients with diabetes are significantly less likely to progress to further limb loss than those with the disease. We hypothesise that this difference is due to the more intensive, multi disciplinary foot care follow-up that diabetic patients receive. These results highlight the significance of toe amputation and contribute to the evidence for a more intensive out-patient service for these high risk patients. PMID- 22516529 TI - Relation of the severity of obstructive sleep apnea in response to anti arrhythmic drugs in patients with atrial fibrillation or atrial flutter. AB - Atrial fibrillation (AF) is more common in those with obstructive sleep apnea (OSA) than in unaffected subjects and recurs more frequently in the presence of severe OSA after electrical cardioversion and AF ablation. However, it is unknown whether the severity of OSA influences the efficacy of antiarrhythmic drug (AAD) therapy in patients with OSA and AF. The aim of this study was to examine the impact of OSA severity on the treatment of patients with symptomatic AF using AADs. Sixty-one patients (mean age 62 +/- 15 years, 21 women) treated with AADs for symptomatic AF who underwent overnight polysomnography were studied. Rhythm control was prospectively defined as successful if a patient remained on the same AAD therapy for >=6 months with >=75% reduction in symptomatic AF burden. Twenty four patients (40%) had severe OSA. Thirty patients (49%) were rhythm controlled with AADs. Nonresponders to AADs were more likely to have severe OSA than milder disease (52% vs 23%, p <0.05); those with severe OSA were less likely to respond to AADs than participants with nonsevere OSA (39% vs 70%, p = 0.02). Nonresponders had higher apnea-hypopnea indexes than responders (34 +/- 25 vs 22 +/- 18 events/hour, p = 0.05), but there were no differences between these groups in minimum oxygen saturation or percentage of time spent in rapid eye movement sleep. In conclusion, patients with severe OSA are less likely to respond to AAD therapy for AF than those with milder forms of OSA. PMID- 22516531 TI - Sensitive and robust method for anabolic agents in human urine by gas chromatography-triple quadrupole mass spectrometry. AB - A rapid, sensitive and robust gas chromatography-triple quadrupole mass spectrometry method was developed for the determination of seven anabolic agents in human urine. The selection of analytes includes the main metabolites of all anabolics with higher sensitivity requirements. After optimizing the fragmentation conditions for each compound, a validation procedure for qualitative analysis was performed. The selectivity of the method showed that no interfering peaks were observed at the retention time of the compound. Adequate intermediate precision, below 14%, was observed for all of the compounds at the lower concentration tested. The concentrations assayed were in accordance with the performance limits required by the World Anti-Doping Agency (WADA). Unlike a previously published GC/QqQ method, detection of 17alpha-methyl-5beta-androstane 3alpha,17beta-diol (the main metabolites of methyltestosterone) at 2 ng/mL was accomplished under routine conditions. The qualitative method was applied to the analysis of 1367 samples in the span of 2 weeks, as part of the doping control of the XVI Pan American Games which took place in Mexico (14th-30th October, 2011). The high sensitivity was maintained during the analysis of all analytical batches, proving for the first time the excellent ruggedness of GC/QqQ methods. PMID- 22516532 TI - Analysis of SIR epidemic models with nonlinear incidence rate and treatment. AB - This paper deals with the nonlinear dynamics of a susceptible-infectious recovered (SIR) epidemic model with nonlinear incidence rate, vertical transmission, vaccination for the newborns of susceptible and recovered individuals, and the capacity of treatment. It is assumed that the treatment rate is proportional to the number of infectives when it is below the capacity and constant when the number of infectives reaches the capacity. Under some conditions, it is shown that there exists a backward bifurcation from an endemic equilibrium, which implies that the disease-free equilibrium coexists with an endemic equilibrium. In such a case, reducing the basic reproduction number less than unity is not enough to control and eradicate the disease, extra measures are needed to ensure that the solutions approach the disease-free equilibrium. When the basic reproduction number is greater than unity, the model can have multiple endemic equilibria due to the effect of treatment, vaccination and other parameters. The existence and stability of the endemic equilibria of the model are analyzed and sufficient conditions on the existence and stability of a limit cycle are obtained. Numerical simulations are presented to illustrate the analytical results. PMID- 22516533 TI - Vascular complications of infective endocarditis. AB - The complications of infective endocarditis (IE) are frequent and severe. Our objectives were to analyze the clinical, paraclinical, and prognostic features of IE vascular complications observed in two cardiology units, in Dakar. PATIENTS AND METHODS: We retrospectively studied 90 patients presenting with of IE, hospitalized between January 2005 and February 2011. The diagnostic criteria for IE were modified Duke University criteria. We selected in our study population, patients with vascular complications. RESULTS: Seventeen patients (18.8%) presented with one or more vascular complications of IE: eight male and nine female patients, with a mean age of 28 years. Infective endocarditis occurred on an abnormal valve in 15 cases. We identified 22 vascular lesions: ten neurological complications, seven arterial complications in the limbs, two myocardial infarctions, two cases of pulmonary embolism, and one splenic infarction. The vascular complication revealed an IE in seven cases. The vascular complication occurred during antibiotic treatment, in 15 cases including seven cases before the 14th day, nine of the 17 patients died. Death was related to vascular complications in six cases, in one case it was related to septic shock. CONCLUSION: Vascular complications of IE are frequent, the most common are neurological. Their prevention requires early and adequate management of IE. PMID- 22516534 TI - Survey of vaccination policies in French healthcare institutions. AB - OBJECTIVE: The survey was implemented to describe vaccination policies for healthcare professionals in French healthcare institutions. METHODS: A cross sectional survey based on questionnaires was sent to occupational physicians and chairpersons of hospital infection prevention and control committees (HIPC) of 38 institutions between November 2010 and January 2011. RESULTS: Twenty-nine occupational physicians and 26 hospital infection prevention and control committees chairpersons (HIPC), from 30 institutions answered (response rate: 79%), 70% of the institutions were university hospitals. Overall, 76% of occupational physicians and 85% of HIPC chairpersons reported that information and awareness campaigns about vaccination recommendations for healthcare professionals were usually conducted in their establishment. Fifty-nine percent of occupational physicians and 31% of HIPC chairpersons reported that they were aware of the vaccine coverage rates of professionals in their institution. The occupational physicians reported that they suggested diphtheria, tetanus, polio, influenza, and acellular pertussis vaccination to all staff at their annual visit in 100%, 97%, and 62% of cases, respectively. Varicella and measles vaccinations were never suggested in 31% and 17% of cases, respectively. Among respondents, 55% of physicians reported that they had already managed a pertussis epidemic, and 42% a measles epidemic, and in both of these cases an awareness campaigns were usually conducted (93% and 96%). CONCLUSIONS: The vaccine coverage rates of healthcare professionals in French healthcare institutions remain insufficiently documented and could be improved. PMID- 22516537 TI - Endothelial keratoplasty: a revolution in evolution. AB - Endothelial keratoplasty (EK) is continually evolving both in surgical technique and clinical outcomes. Descemet's stripping endothelial keratoplasty (DSEK) has replaced penetrating keratoplasty (PK) as the treatment of choice for corneal endothelial dysfunction. It is safe and predictable and offers early visual rehabilitation. Newer iterations include Descemet's membrane endothelial keratoplasty, Descemet's membrane automated endothelial keratoplasty, and other hybrid techniques. Early data on these newer EK techniques suggests that they provide significantly better visual outcomes compared to DSEK. Initial 5-year survival data indicates that EK is at least comparable to PK, and more widespread survival data is anticipated. Further work is needed to simultaneously optimize visual outcomes, refractive predictability, and endothelial cell survival, as well as surgical techniques of donor preparation and insertion. PMID- 22516536 TI - Nontuberculous mycobacterial ocular and adnexal infections. AB - The nontuberculous (also called "atypical") mycobacteria have become increasingly important causes of systemic as well as ocular morbidity in recent decades. All ocular tissues can become infected with these organisms, particularly in patients who are predisposed following ocular trauma, surgery, use of corticosteroids, or are immunocompromised. Because of their relative resistance to available antibiotics, multidrug parenteral therapy continues to be the mainstay of treatment of more serious ocular and adnexal infections caused by nontuberculous mycobacteria (NTM). Periocular cutaneous, adnexal, and orbital NTM infections remain rare and require surgical debridement and long-term parenteral antibiotic therapy. NTM scleritis may occur after trauma or scleral buckling and can cause chronic disease that responds only to appropriate antibiotic therapy and, in some cases, surgical debridement and explant removal. NTM infectious keratitis following trauma or refractive surgical procedures is commonly confused with other infections such as Herpes simplex keratitis and requires aggressive topical therapy and possible surgical debridement, particularly in those cases occuring after laser in situ keratomileusis. Only 18 cases of endophthalmitis due to NTM have been reported. Systemic and intraocular antibiotic therapy and multiple vitrectomies may be needed in NTM endophthalmitis; the prognosis remains poor, however. Disseminated NTM choroiditis in acquired immune deficiency syndrome patients with immune reconstitution during highly active anti-retroviral therapy is a rare infection that can present as a necrotizing chorioretinitis with dense vitritis, mimicking many other entities and needs to be recognized so that timely, life-saving treatment can be administered. Regardless of which ocular tissue is infected, all NTM ocular infections present similar challenges of recognition and of therapeutic intervention. We clarify diagnosis and delineate modern, effective therapy for these conditions. PMID- 22516538 TI - Scleral buckle removal: indications and outcomes. AB - Primary scleral buckling has been an effective means to reattach the retina for over 50 years. After surgery, complications may arise that require scleral buckle (SB) removal. The most common indications for SB removal are extrusion, infection, and pain. I review the pertinent literature in an effort to develop guidelines for when to remove a SB. PMID- 22516539 TI - [Immunotherapy: an emerging strategies against prostate castration resistant cancer]. AB - Castration resistant prostate cancer occurs when patients experience disease progression despite appropriate hormonal manipulations. In these patients, chemotherapy remains standard treatment. Preclinical and clinical data have demonstrated the potential utility of an immunotherapy-based approach for the treatment of prostate cancer (PC). The phase III trial (IMPACT) has recently reported an advantage for Sipuleucel-T over placebo, with an overall survival 4.1 months superior to placebo. Sipuleucel-T is also the first FDA-approved immunotherapy for prostate cancer. These promising results need to be confirmed with other large studies and within previous step of PC. Neoplasic cells can escape immune responses by multiple mechanisms. A better knowledge of these mechanisms is of major concern for the future development of new immunotherapies approach. PMID- 22516540 TI - Human infections with novel reassortant influenza A(H3N2)v viruses, United States, 2011. AB - During July-December 2011, a variant virus, influenza A(H3N2)v, caused 12 human cases of influenza. The virus contained genes originating from swine, avian, and human viruses, including the M gene from influenza A(H1N1)pdm09 virus. Influenza A(H3N2)v viruses were antigenically distinct from seasonal influenza viruses and similar to proposed vaccine virus A/Minnesota/11/2010. PMID- 22516541 TI - A new asymmetric diamide from the seed cake of Jatropha curcas L. AB - A new asymmetric diamide (E)-N-(3-acetamidopropyl)-cinnamamide named curcamide (1) has been isolated from the ethanol extract of the seed cake of Jatropha curcas L. along with 7 known compounds identified as isoamericanin (2), isoprincepin (3), caffeoylaldehyde (4), isoferulaldehyde (5), glycerol monooleate (6), syringaldehyde (7), and beta-ethyl-d-glucopyranoside (8). The synthesis and antibacterial activity of the new compound have been also studied. PMID- 22516542 TI - Effects of resveratrol on the ultrastructure of Botrytis cinerea conidia and biological significance in plant/pathogen interactions. AB - Many roles have been ascribed to stilbenes, namely as antimicrobial, deterrent or repellent compounds in plants, protecting them from attacks by fungi, bacteria, nematodes or herbivores, acting both as constitutive and active defense (phytoalexin) compounds. More recently, stilbenes (especially resveratrol and its derivatives) were acclaimed for their wondrous effects and wide range of purported healing and preventive powers as cardioprotective, antitumor, neuroprotective and antioxidant agents. Although there is a huge number of works concerning the role of resveratrol in human health, reports on the antifungal activity of this compound are still scarce. This study was thus conducted in order to investigate the toxicity of resveratrol at an ultra- structural level to dormant conidia of Botrytis cinerea, the causal microorganism for gray mold. In grapevine particularly, this disease can affect all the green organs but is particularly damaging for ripening berries. Observations using transmission electron microscopy showed the occurrence of damages on conidia treated with sub lethal doses, that is, 60MUg/mL (2.6*10(-4)M) of resveratrol, a concentration usually reached in grapevine leaves and grape berries challenged by this pathogen. These results provide further data about the overall mode of action of this phytoalexin and its role in the B. cinerea/grapevine interaction. PMID- 22516543 TI - Anti-gastric adenocarcinoma activity of 2-Methoxy-1,4-naphthoquinone, an anti Helicobacter pylori compound from Impatiens balsamina L. AB - 2-Methoxy-1,4-naphthoquinone (MeONQ) from Impatiens balsamina L. exhibited strong anti-H. pylori activity in our previous study. In this study, we investigated the cytotoxicity of MeONQ against gastric adenocarcinoma (MKN45 cell line) and propose the relevant mechanisms. MeONQ resulted in serious necrosis via superoxide anion catastrophe when the treatment doses were higher than 50MUM, whereas apoptosis occurred at low treatment doses (25-50MUM) through the caspase dependent apoptosis pathway. Necrosis is the dominant mode of cell death. MeONQ exhibited high ability to induce gastric adenocarcinoma necrosis, showing good potential as a candidate agent for H. pylori infection related disease therapy. PMID- 22516544 TI - Functional outcome prediction following intracerebral hemorrhage. AB - The ICH score is a validated method of assessing the risk of mortality and morbidity after intracerebral hemorrhage (ICH). We sought to compare the ability of the ICH score to predict outcome assessed with three of the most widely used scales: the Barthel Index (BI), modified Rankin Scale (mRS), and Glasgow Outcome Score (GOS). All patients with ICH treated at our institution between February 2009 and March 2011 were followed-up at three months using the mRS, GOS, and BI. The ICH score was highly correlated with the three-month mRS (rho=0.59, p<0.001), BI (rho=-0.57, p<0.001) and GOS (rho=0.61, p<0.001). The ICH score also predicted dependency for each measure well, with areas under the curve falling between 0.826 and 0.833. Our results suggest that future clinical studies that use the ICH score to stratify patients may employ any of the three outcome scales and expect good discrimination of disability. PMID- 22516545 TI - A novel murine model of human renal cell carcinoma spinal metastasis. AB - There is currently no reproducible animal model of renal cell carcinoma (RCC) spinal metastasis that allows for laboratory study of the human disease. In this report, we describe an animal model that reliably reproduces RCC spinal metastasis using a human tumor cell line. A posterior surgical approach was used to implant tumor cells into the lamina of immunosuppressed mice. Histology sections were analyzed 12 weeks after tumor cell implantation to quantify the location and extent of tumor growth. RCC xenografts grew in treated animals (8 mice) with a reproducible pattern of growth. After implantation, tumor growth occurred primarily in the antero-posterior dimension. At 8 weeks after tumor cell implantation, there was visible tumor growth in all treated mice. Histologic correlation at 12 weeks after tumor cell implantation confirmed tumor growth involving primarily the paraspinal region and lamina. Our investigation resulted in an orthotopic model of human RCC spinal metastasis. Ultimately this will allow testing of targeted therapies for RCC with spinal involvement. Furthermore, this model can be expanded to develop similar spinal metastasis models for other tumor cell lines. PMID- 22516546 TI - A clinicopathological study of the significance of the proportion of choroid morphology in chordoid meningioma. AB - Chordoid meningiomas (CM) account for approximately 0.5% to 1.0% of intracranial meningiomas. This tumor has a strong risk of recurrence and aggressive growth (World Health Organization grade II). Histological analysis of CM tumors shows that the tissue is often dominated by chordoid morphology; however, the exact relationship between the percentage of the chordoid component and other clinicopathological features is unknown. We collected 26 surgical specimens from 17 patients who had a histological diagnosis of CM between January 1986 and June 2010. The chordoid elements constituted 30% to 98% of the area of the tumor. In 12 of 17 (70.6%) primary tumors, over 50% of the area displayed the chordoid pattern. Recurrence was noted in nine of these patients and five underwent a second operation. These five patients showed a histopathological progression of aggressive features. The proportion of chordoid elements in each recurrent tumor also increased. Thus, the chordoid proportion in CM is associated with a greater likelihood of recurrence. PMID- 22516548 TI - Risk factors for recurrent shunt infections in children. AB - Risk factors for recurrent shunt-related cerebrospinal fluid (CSF) infections were analyzed. A total of 58 children were treated for initial shunt infections (ISI): all children were treated with antibiotics and CSF drainage, either by removal of the shunt system and insertion of an external ventricular drainage (EVD) catheter (44 children, 75.9%) or by externalization of the existing ventricular catheter (14 children, 24.1%). Recurrent shunt infections (RSI) were detected in 15 children: nine had been treated with shunt removal and insertion of a new EVD catheter and six had been treated with externalization of the existing ventricular catheter. There was a statistically significant increase in the number of RSI in children treated with externalization of the existing ventricular catheter. Thus, to reduce the risk of RSI, total shunt removal and insertion of a new EVD catheter is preferred. PMID- 22516547 TI - A novel adenoviral vector labeled with superparamagnetic iron oxide nanoparticles for real-time tracking of viral delivery. AB - In vivo tracking of gene therapy vectors challenges the investigation and improvement of biodistribution of these agents in the brain, a key feature for their targeting of infiltrative malignant gliomas. The glioma-targeting Ad5/3 cRGD gene therapy vector was covalently bound to super-paramagnetic iron oxide (Fe(3)O(4)) nanoparticles (SPION) to monitor its distribution by MRI. Transduction of labeled and unlabeled vectors was assessed on the U87 glioma cell line and normal human astrocytes (NHA), and was higher in U87 compared to NHA, but was similar between labeled and unlabeled virus. An in vivo study was performed by intracranial subcortical injection of labeled-Ad5/3-cRGD particles into a pig brain. The labeled vector appeared in vivo as a T2-weighted hyperintensity and a T2-gradient echo signal at the injection site, persisting up to 72 hours post-injection. We describe a glioma-targeting vector that is labeled with SPION, thereby allowing for MRI detection with no change in transduction capability. PMID- 22516550 TI - Neuroprotective effects of anti-tumor necrosis factor-alpha antibody on apoptosis following subarachnoid hemorrhage in a rat model. AB - Recent studies have emphasized the importance of apoptosis in subarachnoid hemorrhage (SAH) and the subsequent early brain injury. However, the apoptotic pathways induced by SAH in different brain regions are not fully understood. We investigated gene expression levels of classical apoptosis-related molecules (caspase-3, bax, and bcl-2) following SAH in the hippocampus of male Wistar rats. Temporally specific changes were found in caspase-3 and bax messenger RNA only. Interestingly, we found increased expression of bax, but not caspase-3, in the prefrontal cortex, which indicates different molecular mechanisms of apoptosis in distinct brain regions. Most important, changes in expression were reversed by functional blockade of tumor necrosis factor-alpha, which has a critical role in brain injury. In addition, we found that apoptosis induced by SAH may be associated with a relative elevation of pro-brain derived neurotrophic factor. PMID- 22516549 TI - Chromosomal anomalies and prognostic markers for intracranial and spinal ependymomas. AB - Ependymomas are neoplasms that can occur anywhere along the craniospinal axis. They are the third most common brain tumor in children, representing 10% of pediatric intracranial tumors, 4% of adult brain tumors, and 15% of all spinal cord tumors. As the heterogeneity of ependymomas has severely limited the prognostic value of the World Health Organization grading system, numerous studies have focused on genetic alterations as a potential basis for classification and prognosis. However, this endeavor has proven difficult due to variations of findings depending on tumor location, tumor grade, and patient age. While many have evaluated chromosomal abnormalities for ependymomas as a whole group, others have concentrated their efforts on specific subsets of populations. Here, we review modern findings of chromosomal analyses, their relationships with various genes, and their prognostic implications for intracranial and spinal cord ependymomas. PMID- 22516551 TI - LA Sprouts: a garden-based nutrition intervention pilot program influences motivation and preferences for fruits and vegetables in Latino youth. AB - Garden-based approaches to nutrition education may be effective for improving nutrition habits in adolescents. A quasi-experimental, garden-based intervention for Latino youth (LA Sprouts) was piloted and assessed for its influence on behavior associated with dietary intake and psychosocial factors. Study participants were 104 predominately Latino fourth and fifth grade students in Los Angeles (mean age, 9.8+/-0.7 years; n=70 control subjects, n=34 LA Sprouts participants); more than half (n=61, 59.8%) were overweight or obese (body mass index >=85th percentile). LA Sprouts participants received an intervention of weekly 90-minute culturally tailored, interactive classes for 12 consecutive weeks at a community garden during the spring of 2010; control participants received an abbreviated delayed intervention. Questionnaire data were obtained before and after the intervention. Compared with control subjects, LA Sprouts participants had an increased preference for vegetables overall, increased preferences for three target fruits and vegetables, as well as improved perceptions that "vegetables from the garden taste better than vegetables from the store." In the overweight/obese subgroup (n=61), LA Sprouts participants had a 16% greater increase in their preference for vegetables compared with control subjects (P=0.009). Results from this pilot study suggest that a cooking, nutrition, and gardening after-school program in a garden-based setting can improve attitudes and preferences for fruits and vegetables in Latino youth, which may lead to improved nutritional habits and dietary intake and reduced health disparities. PMID- 22516552 TI - Antipsychotic drug effects on left prefrontal phospholipid metabolism: a follow up 31P-2D-CSI study of haloperidol and risperidone in acutely ill chronic schizophrenia patients. AB - INTRODUCTION: 31Phosphorous magnetic resonance spectroscopy (2D chemical shift imaging, CSI) allows multiregional study of membrane phospholipids and high energy phosphates in vivo. Increased membrane lipid turnover and impaired energy supply have repeatedly been shown in first-episode schizophrenia patients, and might be a target of drug actions other than dopamine receptors. Here, we explored differential metabolic effects of a typical vs. an atypical antipsychotic on brain phospholipids. METHODS: We applied 2D-CSI MR spectroscopy in 17 recurrent-episode schizophrenia patients off antipsychotics at baseline and at follow-up after 6 weeks, during which 7 patients were treated with haloperidol (10-16 mg/d) and 10 with risperidone (4-6 mg/d). Psychopathology changes were assessed using PANSS, BPRS and CGI scores. RESULTS: Follow-up analysis using repeated measure ANOVA revealed different effects of both antipsychotic agents: while risperidone generally increased metabolite levels, haloperidol showed a tendency to decrease them. This diverging effect was significant for ATP levels in the left lateral frontal cortex. Furthermore, risperidone increased ATP in the left dorsolateral prefrontal cortex, left anterior temporal cortex and left insular cortex, basal ganglia, and anterior cerebellum, along with left frontal and prefrontal increase of PCr, PDE and PME in these brain regions. CONCLUSION: Risperidone seems to stimulate neuronal and synaptic phospholipid remodeling in left frontal and prefrontal regions, and to a lesser extent also in temporal and insular cortices. We discuss these effects with respect to clinical effects on negative and cognitive symptoms, as well as interaction of phospholipid metabolism with glutamatergic neurotransmission. PMID- 22516554 TI - Epidemic genotype of Coxiella burnetii among goats, sheep, and humans in the Netherlands. PMID- 22516553 TI - Different level, but a similar day pattern of physical activity in workers and sick-listed people with chronic nonspecific musculoskeletal pain. AB - OBJECTIVE: To investigate whether physical activity (PA) levels and day patterns of sick-listed workers with chronic nonspecific musculoskeletal pain (CMP) admitted for multidisciplinary rehabilitation are different from those of workers with CMP. DESIGN: Cross-sectional. SETTING: Outpatient rehabilitation center and general community. PARTICIPANTS: A convenience sample of sick-listed patients with CMP (n=27) referred for multidisciplinary pain rehabilitation, and a volunteer sample of workers with CMP (n=107; <5% sick leave in year before participation). INTERVENTION: Participants wore an accelerometer for 5 to 7 consecutive days. MAIN OUTCOME MEASURE: PA, expressed as activity counts. All analyses were corrected for confounders. RESULTS: PA levels of workers with CMP were higher than those of sick-listed patients (P=.01). After correction for confounders, work status explained 3.5% of the variance observed in activity counts (F(change)=5.27, P=.024). In the mornings, group status significantly contributed to the variance in mean activity counts (F(change)=5.32, P=.02). In afternoons (F(change)=3.29, P=.07) and evenings (F(change)=2.41, P=.12), the effect of group status on PA level was nonsignificant. No significant interaction was observed between time and group status (Wilks' lambda=.92, F(14,104)=.66, P=.80). CONCLUSIONS: Workers with CMP have a higher PA level compared with sick listed patients. The PA day pattern did not differ significantly between the 2 groups. PMID- 22516555 TI - Physics and medicine--two tips for a long and happy marriage. PMID- 22516556 TI - A call for recognition of the medical physics profession. PMID- 22516557 TI - Physics and medicine: a historical perspective. AB - Nowadays, the term medical physics usually refers to the work of physicists employed in hospitals, who are concerned mainly with medical applications of radiation, diagnostic imaging, and clinical measurement. This involvement in clinical work began barely 100 years ago, but the relation between physics and medicine has a much longer history. In this report, I have traced this history from the earliest recorded period, when physical agents such as heat and light began to be used to diagnose and treat disease. Later, great polymaths such as Leonardo da Vinci and Alhazen used physical principles to begin the quest to understand the function of the body. After the scientific revolution in the 17th century, early medical physicists developed a purely mechanistic approach to physiology, whereas others applied ideas derived from physics in an effort to comprehend the nature of life itself. These early investigations led directly to the development of specialties such as electrophysiology, biomechanics, and ophthalmology. Physics-based medical technology developed rapidly during the 19th century, but it was the revolutionary discoveries about radiation and radioactivity at the end of the century that ushered in a new era of radiation based medical diagnosis and treatment, thereby giving rise to the modern medical physics profession. Subsequent developments in imaging in particular have revolutionised the practice of medicine. We now stand on the brink of a new revolution in post-genomic personalised medicine, with physics-based techniques again at the forefront. As before, these techniques are often the unpredictable fruits of earlier investment in basic physics research. PMID- 22516558 TI - Diagnostic imaging. AB - Physical techniques have always had a key role in medicine, and the second half of the 20th century in particular saw a revolution in medical diagnostic techniques with the development of key imaging instruments: x-ray imaging and emission tomography (nuclear imaging and PET), MRI, and ultrasound. These techniques use the full width of the electromagnetic spectrum, from gamma rays to radio waves, and sound. In most cases, the development of a medical imaging device was opportunistic; many scientists in physics laboratories were experimenting with simple x-ray images within the first year of the discovery of such rays, the development of the cyclotron and later nuclear reactors created the opportunity for nuclear medicine, and one of the co-inventors of MRI was initially attempting to develop an alternative to x-ray diffraction for the analysis of crystal structures. What all these techniques have in common is the brilliant insight of a few pioneering physical scientists and engineers who had the tenacity to develop their inventions, followed by a series of technical innovations that enabled the full diagnostic potential of these instruments to be realised. In this report, we focus on the key part played by these scientists and engineers and the new imaging instruments and diagnostic procedures that they developed. By bringing the key developments and applications together we hope to show the true legacy of physics and engineering in diagnostic medicine. PMID- 22516559 TI - The importance of physics to progress in medical treatment. AB - Physics in therapy is as diverse as it is substantial. In this review, we highlight the role of physics--occasionally transitioning into engineering- through discussion of several established and emerging treatments. We specifically address minimal access surgery, ultrasound, photonics, and interventional MRI, identifying areas in which complementarity is being exploited. We also discuss some of the fundamental physical principles involved in the application of each treatment to medical practice. PMID- 22516560 TI - Future medicine shaped by an interdisciplinary new biology. AB - The projected effects of the new biology on future medicine are described. The new biology is essentially the result of shifts in the way biological research has progressed over the past few years, mainly through the involvement of physical scientists and engineers in biological thinking and research with the establishment of new teams and task forces to address the new challenges in biology. Their contributions go well beyond the historical contributions of mathematics, physical sciences, and engineering to medical practice that were largely equipment oriented. Over the next generation, the entire fabric of the biosciences will change as research barriers between disciplines diminish and eventually cease to exist. The resulting effects are starting to be noticed in front-line medicine and the prospects for the future are immense and potentially society changing. The most likely disciplines to have early effects are outlined and form the main thrust of this paper, with speculation about other disciplines and emphasis that although physics-based and engineering-based biology will change future medicine, the physical sciences and engineering will also be changed by these developments. Essentially, physics is being redefined by the need to accommodate these new views of what constitutes biological systems and how they function. PMID- 22516561 TI - The importance of quantitative systemic thinking in medicine. AB - The study and practice of medicine could benefit from an enhanced engagement with the new perspectives provided by the emerging areas of complexity science and systems biology. A more integrated, systemic approach is needed to fully understand the processes of health, disease, and dysfunction, and the many challenges in medical research and education. Integral to this approach is the search for a quantitative, predictive, multilevel, theoretical conceptual framework that both complements the present approaches and stimulates a more integrated research agenda that will lead to novel questions and experimental programmes. As examples, the importance of network structures and scaling laws are discussed for the development of a broad, quantitative, mathematical understanding of issues that are important in health, including ageing and mortality, sleep, growth, circulatory systems, and drug doses. A common theme is the importance of understanding the quantifiable determinants of the baseline scale of life, and developing corresponding parameters that define the average, idealised, healthy individual. PMID- 22516562 TI - Freezing or adding trypsin inhibitor to equine intestinal contents extends the lifespan of Clostridium perfringens beta toxin for diagnostic purposes. AB - Clostridium perfringens type C causes necrotizing enteritis mostly in neonatal animals of several species, including horses. The virulence of C. perfringens type C is mostly mediated by beta toxin (CPB). This toxin is highly sensitive to the action of trypsin and other proteases, which explains the increased susceptibility of neonatal animals to type C infections. Final confirmation of type C disease diagnosis should be based on detection of CPB in the intestinal content of affected animals. However, because CPB is so sensitive to the action of proteases, it is believed that this toxin persists for only a limited period of time in specimens of intestinal content of animals collected for diagnostic purposes. This study was therefore performed to determine the stability of CPB in intestinal content of horses stored at different temperatures and to evaluate the use of trypsin inhibitor to extend the lifespan of CPB in intestinal content of horses. When the intestinal content of horses that had been spiked with different amounts of CPB was tested by a capture ELISA technique to detect CPB, 319 LD(50) of CPB per milliliter was the lowest amount that could be detected. When equine intestinal content spiked with 319 LD(50)/ml was stored at 4 degrees C, CPB was detected by ELISA until day 8 after spiking. Samples spiked with the same amount of CPB and stored at -20 degrees C were positive for at least 5 weeks after spiking. When intestinal samples spiked with 319 LD(50)/ml of CPB were mixed with 0.1 mg/ml or 1.0 mg/ml of trypsin inhibitor and stored at 4 degrees C, all the samples were positive for at least 5 weeks after spiking. This study demonstrates that C. perfringens CPB present in equine intestinal samples stored at 4 degrees C cannot be detected by ELISA for more than 8 days. Freezing the samples at -20 degrees C or adding trypsin inhibitor before storage at 4 degrees C preserves the lifespan of CPB for at least 5 weeks. PMID- 22516563 TI - The use of PiezosurgeryTM for external dacryocystorhinostomy. PMID- 22516564 TI - Risk of chronic dialysis and death following acute kidney injury. AB - BACKGROUND: Acute kidney injury frequently arises within an acute care hospitalization. Outcomes among acute kidney injury survivors following hospital discharge are poorly documented. METHODS: We conducted a population-based cohort study between 1996 and 2006 of all adult patients in Ontario with acute kidney injury who did not require in-hospital dialysis, and who survived free of dialysis >=30 days after discharge. Those with acute kidney injury (n=41,327) were matched 1:1 to patients without acute kidney injury during their index hospitalization. Matching was by age (+/-1 year), sex, history of chronic kidney disease, receipt of mechanical ventilation during the index hospitalization, and a propensity score for developing acute kidney injury. The primary outcome was subsequent need for chronic dialysis. The secondary outcomes were all-cause mortality and rehospitalization. RESULTS: Mean age was 70 years, and median follow-up was 2 years (maximum 10 years). The incidence of chronic dialysis was 1.78 per 100 person-years among those with acute kidney injury and 0.74 per 100 person-years among unaffected controls (adjusted hazard ratio [HR]; 2.70, 95% confidence interval [CI], 2.42-3.00). Rates also were higher for all-cause mortality (15.34 vs 14.51 per-100 person-years; adjusted HR 1.10; 95% CI, 1.07 1.13) and rehospitalization (44.93 vs 37.18 per 100 person-years; adjusted HR 1.21; 95% CI, 1.18-1.24). CONCLUSION: Even when acute dialysis is not required, survivors of acute kidney injury remain at higher risk of receipt of chronic dialysis thereafter. The absolute risk of death was more than 8 times the rate of chronic dialysis. PMID- 22516565 TI - What a man wants: understanding the challenges and motivations to physical activity participation and healthy eating in middle-aged Australian men. AB - Little attention has been paid to the physical activity (PA) and nutrition behaviors of middle-aged men; thus, the aim of this study was to gather information and gain insight into the PA and nutrition behaviors of these men. Six focus group sessions were undertaken with middle-aged men (N = 30) from regional Australia to explore the challenges and motivations to PA participation and healthy eating. Men had a good understanding of PA and nutrition; however, this was sometimes confounded by inconsistent media messages. Work commitments and family responsibilities were barriers to PA, while poor cooking skills and abilities were barriers to healthy eating. Disease prevention, weight management, and being a good role model were motivators for PA and healthy eating. By understanding what a man wants, PA and nutrition interventions can be designed and delivered to meet the needs of this hard-to-reach population. PMID- 22516566 TI - Are podcasts effective at educating African American men about diabetes? AB - Education is a critical component of the National Blueprint to eliminate racial disparities in diabetes. Research indicates that traditional methods of diabetes education has had limited effectiveness with minority populations and suggests that different educational approaches be explored. The purpose of the research was to explore the effectiveness of an emergent technology (podcast) for use in educating inner-city, African American men about diabetes prevention. Thirty African American men participated in self-administered, pretest-posttest surveys in August 2009. Surveys collected information on demographic characteristics, perceptions of diabetes, and diabetes knowledge. Paired samples t test was computed to evaluate pretest-posttest changes in overall knowledge. McNemar or binomial tests were computed to evaluate pretest-posttest knowledge changes on each of the 15 individual knowledge items. Diabetes knowledge scores for the sample increased from 8.27 at pretest to 10.47 at posttest (p = .001). Posttest knowledge scores increased for 77% of men, stayed the same for 13%, and decreased for 10%. Men who listened to the podcast correctly answered 40% more knowledge questions on their posttest assessments. Results from this exploratory study suggest that podcasts are useful for helping inner-city, African American men recall diabetes prevention information. Additional research is recommended with larger randomly selected samples using more rigorous research designs. PMID- 22516567 TI - A new technique for stabilizing adolescent posteriorly displaced physeal medial clavicular fractures. AB - BACKGROUND: Adolescent posteriorly displaced physeal injuries of the medial clavicle are uncommon. Up to 50% of conservatively treated patients remain symptomatic, and late surgery is hazardous. Stability is rarely achieved with closed or open reduction alone, and internal fixation is usually required. Previously described options for fixation achieve stability of the medial clavicle by securing it to the intact epiphysis. Because the epiphyseal fragment is small, fixation is achieved using sutures or wires. This relies on the size and structural integrity of the medial fragment, which in our experience can be variable. We hypothesized that a novel technique of operative stabilization of these injuries, which does not require fixation to the epiphyseal fragment and uses no metalwork, is safe and effective in treating these injuries. MATERIALS AND METHODS: The operative technique involves suturing the medial clavicle to the anterior platysmal and periosteal layer using absorbable sutures passed through drill holes in the medial clavicle. Patients were assessed clinically an average of 9 months after surgery. RESULTS: We treated 7 patients with this method. There were no intraoperative complications. All patients were pain-free and symptom free and had a full range of movement at follow-up. All patients had returned to their preinjury level of sports. CONCLUSIONS: We recommend this technique for treating these uncommon injuries. It is simple, safe, and reproducible and it produces good results. PMID- 22516568 TI - The role of negative intraarticular pressure and the long head of biceps tendon on passive stability of the glenohumeral joint. AB - BACKGROUND: The purpose of this study was to determine the effect of intraarticular pressure and the long head of biceps (LHB) tendon on passive translations of the glenohumeral (GH) joint. Tenotomy or tenodesis of the LHB are common procedures but the consequences on shoulder stability are unclear. METHODS: A novel shoulder laxity testing rig permitting six degrees of freedom of motion was used to test passive translations in anterior, posterior, superior, and inferior directions in 10 cadaveric shoulders. Specimens were tested in neutral rotation with 0 degrees , 30 degrees , 60 degrees , or 90 degrees of GH abduction in the scapular plane. Translation loads up to 30N were applied, and displacements measured in an intact joint, vented joint and with the biceps tendon loaded (20N). RESULTS: The GH joint was most lax at 30 degrees GH abduction. Venting of the joint increased translations in all positions and directions (mean +/- standard error of the mean), the greatest difference was 12.5 (3.9) mm in the anterior-posterior direction and 7.5 (3.9) mm in the SI direction. Loading the LHB tendon with 20N decreased translations in all directions. The largest difference was observed in the anterior direction, 13.9 (2.8) mm (P < .0005) and inferior direction, 12.0 (2.8) mm (P < .0005). CONCLUSION: Negative intraarticular pressure and the LHB contribute significantly to overall passive stability of the GH joint. Surgical division or transfer of the LHB tendon may impact on joint stability and function. PMID- 22516569 TI - Milch versus Stimson technique for nonsedated reduction of anterior shoulder dislocation: a prospective randomized trial and analysis of factors affecting success. AB - BACKGROUND: The shoulder is regarded as the most commonly dislocated major joint in the human body. Most dislocations can be reduced by simple methods in the emergency department, whereas others require more complicated approaches. We compared the efficacy, safety, pain, and duration of the reduction between the Milch technique and the Stimson technique in treating dislocations. We also identified factors that affected success rate. METHODS: All enrolled patients were randomized to either the Milch technique or the Stimson technique for dislocated shoulder reduction. RESULTS: The study cohort consisted of 60 patients (mean age, 43.9 years; age range, 18-88 years) who were randomly assigned to treatment by either the Stimson technique (n = 25) or the Milch technique (n = 35). Oral analgesics were available for both groups. The 2 groups were similar in demographics, patient characteristics, and pain levels. The first reduction attempt in the Milch and Stimson groups was successful in 82.8% and 28% of cases, respectively (P < .001), and the mean reduction time was 4.68 and 8.84 minutes, respectively (P = .007). The success rate was found to be affected by the reduction technique, the interval between dislocation occurrence and first reduction attempt, and the pain level on admittance. CONCLUSIONS: The success rate and time to achieve reduction without sedation were superior for the Milch technique compared with the Stimson technique. Early implementation of reduction measures and low pain levels at presentation favor successful reduction, which- in combination with oral pain medication--constitutes an acceptable and reasonable management alternative to reduction with sedation. PMID- 22516571 TI - Fractures of the coronoid: morphology based upon computer tomography scanning. AB - HYPOTHESIS/BACKGROUND: Coronoid fractures have traditionally been described by the Regan-Morrey classification system, based upon lateral plain film radiographs. However, use of computer tomography (CT) scans to determine fracture morphology, define associated injuries, and make treatment plans is now commonplace. In addition, it is increasingly recognized that classification systems based upon plain film imaging studies may not be adequate to describe complex fracture patterns. The purpose of the present investigation was to review CT scans obtained for elbow trauma to describe coronoid fracture morphology and determine inter- and intra-observer reliability. METHODS: CT scans performed for elbow trauma over a 2-year period were examined to identify coronoid fractures, and recurring patterns were sought. After patterns were identified, the scans were reviewed by 3 observers to determine inter- and intra-observer reliability. RESULTS: Of 373 CT scans, 52 identified coronoid fractures were appropriate for review. Five common patterns were identified, including a tip type, mid transverse type, basal type, anteromedial oblique fractures, and an anterolateral oblique type fracture that has not been well described previously. Inter- and intra-observer reliability ranged from good to very good in this series. DISCUSSION/CONCLUSION: In this series, we describe anatomic patterns by which coronoid fractures break. Five common patterns were noted: a "tip" type fracture seen in 29% of the cases; a "mid-transverse" type fracture (24%); a "basal" type fracture (23); and 2 "oblique" type fracture patterns (24%), including an "anteromedial" type fracture (17%) and an "anterolateral" type (7%). There was a high rate of intra- and inter-observer reliability between and within 3 observers. PMID- 22516570 TI - Periprosthetic infections after total shoulder arthroplasty: a 33-year perspective. AB - BACKGROUND: To examine the rates and predictors of deep periprosthetic infections after primary total shoulder arthroplasty (TSA). METHODS: We used prospectively collected data on all primary TSA patients from 1976-2008 at Mayo Clinic Medical Center. We estimated survival free of deep periprosthetic infections after primary TSA using Kaplan-Meier survival. Univariate and multivariable Cox regression was used to assess the association of patient-related factors (age, gender, body mass index), comorbidity (Deyo-Charlson index), American Society of Anesthesiologists class, implant fixation, and underlying diagnosis with risk of infection. RESULTS: A total of 2,207 patients, with a mean age of 65 years (SD, 12 years), 53% of whom were women, underwent 2,588 primary TSAs. Mean follow-up was 7 years (SD, 6 years), and the mean body mass index was 30 kg/m(2) (SD, 6 kg/m(2)). The American Society of Anesthesiologists class was 1 or 2 in 61% of cases. Thirty-two confirmed deep periprosthetic infections occurred during follow up. In earlier years, Staphylococcus predominated; in recent years, Propionibacterium acnes was almost as common. The 5-, 10-, and 20-year prosthetic infection-free rates were 99.3% (95% confidence interval [CI], 98.9-99.6), 98.5% (95% CI, 97.8-99.1), and 97.2% (95% CI, 96.0-98.4), respectively. On multivariable analysis, a male patient had a significantly higher risk of deep periprosthetic infection (hazard ratio, 2.67 [95% CI, 1.22-5.87]; P = .01) and older age was associated with lower risk (hazard ratio, 0.97 [95% CI, 0.95-1.00] per year; P = .05). CONCLUSIONS: The periprosthetic infection rate was low at 20 year follow-up. Male gender and younger age were significant risk factors for deep periprosthetic infections after TSA. Future studies should investigate whether differences in bone morphology, medical comorbidity, or other factors are underlying these associations. PMID- 22516572 TI - Diagnostic accuracy of 2- and 3-dimensional imaging and modeling of distal humerus fractures. AB - PURPOSE: This investigation used prospectively recorded intraoperative evaluation as the reference standard for distal humerus fracture type and characteristics, in order to measure the diagnostic performance characteristics of computed tomography (CT) and physical models. In secondary analyses, we assessed the reliability of classification. METHODS: Thirty-five fractures were evaluated by the treating surgeon and first assistant on radiographs and 2-dimensional CT (2DCT) images first; a second time based on radiographs and 2- and 3-dimensional CT (3DCT) images; a third time based on 2- and 3DCT as well as 3D physical models; and a fourth time based on intraoperative visualization of the fracture characteristics. The intraoperative evaluation of the attending surgeon was used as the reference standard. RESULTS: The addition of 3DCT and the 3D models to 2DCT and radiographs led to significant improvements in sensitivity, but not specificity, in the diagnosis and proposed treatment, and improved the interobserver agreement with respect to specific fracture characteristics but not classification. CONCLUSION: Increasingly sophisticated imaging and modeling leads to slight but significant improvements in diagnostic performance characteristics and interobserver agreement on fracture characteristics. PMID- 22516573 TI - Will laboratory markers replace kidney biopsy in patients with nephrotic syndrome? PMID- 22516574 TI - Anti-PLA2R antibodies in membranous nephropathy: ready for routine clinical practice? AB - The identification of circulating autoantibodies against the M-type phospholipase A2 receptor (anti-PLA2R) in patients with idiopathic membranous nephropathy (iMN) has been a major discovery. Anti-PLA2R can be measured by a commercially available test. It is suggested that measurement of anti-PLA2R will change the diagnostic strategy in patients with nephrotic syndrome and may guide treatment in patients with iMN. We review the available evidence and caution against the immediate injudicious use of the assay in routine clinical practice. PMID- 22516575 TI - New insights into pathways that determine the link between infection and thrombosis. AB - Severe infection is often linked to prothrombotic events. Indeed, haemostatic abnormalities are encountered in most cases of infection, ranging from an increase in sensitive markers for coagulation activation or insignificant laboratory changes to gross activation of coagulation that may result in localised thrombotic complications or disseminated intravascular coagulation. Systemic inflammation as a consequence of infection results in activation of coagulation, due to tissue factor-mediated thrombin generation, down-regulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Pro inflammatory cytokines, immune cells and the endothelium form the interface on which differential effects on the coagulation and fibrinolysis pathways may ensue. Conversely, activation of the coagulation system may importantly affect inflammatory responses by direct and indirect mechanisms. Apart from the general coagulation response to inflammation associated with severe infection, specific infections may cause distinct features, such as haemorrhagic fever or thrombotic microangiopathy. PMID- 22516576 TI - A new era in the diagnosis and treatment of atypical haemolytic uraemic syndrome. AB - The haemolytic uraemic syndrome (HUS) is characterised by haemolytic anaemia, thrombocytopenia and acute renal failure. The majority of cases are seen in childhood and are preceded by an infection with Shiga-like toxin producing Escherichia coli (STEC-HUS; so-called typical HUS). Non-STEC or atypical HUS (aHUS) is seen in 5 to 10% of all cases and occurs at all ages. These patients have a poorer outcome and prognosis than patients with STEC-HUS. New insights into the pathogenesis of aHUS were revealed by the identification of mutations in genes encoding proteins of the alternative pathway of the complement system in aHUS patients. Specific information of the causative mutation is important for individualised patient care with respect to choice and efficacy of therapy, the outcome of renal transplantation, and the selection of living donors. This new knowledge about the aetiology of the disease has stimulated the development of more specific treatment modalities. Until now, plasma therapy was used with limited success in aHUS, but recent clinical trials have demonstrated that patients with aHUS can be effectively treated with complement inhibitors, such as the monoclonal anti-C5 inhibitor eculizumab. PMID- 22516577 TI - Common alternative diagnoses in general practice when deep venous thrombosis is excluded. AB - BACKGROUND: In patients initially suspected of deep venous thrombosis (DVT) the diagnosis can be confirmed in approximately 10 to 30% of cases. For the majority of patients this means that eventually an alternative diagnosis is assigned. OBJECTIVE: To assess the frequency distribution of alternative diagnoses and subsequent management of patients in primary care after initial exclusion of DVT. In addition, assess the value of ultrasound examination for the allocation of alternative diagnoses. METHODS: Data were recorded by general practitioners alongside a diagnostic study in primary care in the Netherlands (AMUSE). Additional data were retrieved from a three-month follow-up questionnaire. A descriptive analysis was performed using these combined data. RESULTS: The most prevalent diagnoses were muscle rupture (18.5%), chronic venous insufficiency (CVI) (14.6%), erysipelas/cellulitis (12.6%) and superficial venous thrombosis (SVT) (10.9%). Alternative diagnoses were based mainly on physical examination; ultrasound examination (US) did not improve the diagnostic yield for the allocation of alternative diagnoses. In about 30% of all cases, a wait and see approach was used (27 to 41%). During the three-month follow-up nine patients were diagnosed with venous thromboembolic disease, three of which occurred in patients with the working diagnosis of SVT (p=0.026). CONCLUSIONS: We found that after exclusion of DVT in general practice a wait and see policy in the primary care setting is uneventful for almost one third of patients, but with the alternative diagnosis of SVT, patients may require closer surveillance since we found a significant association with thrombosis in these patients. PMID- 22516578 TI - Isolated elevated aspartate aminotransferase: a surprising outcome for clinicians. AB - In this report a case of macro-aspartate aminotransferase in a 34-year-old pregnant woman is presented. Awareness of the existence of a macroenzyme is important because of their ability to cause diagnostic confusion, which leads to unnecessary investigations. Confirmation with a polyethylene glycol precipitation test is simple to perform and not expensive. PMID- 22516579 TI - A case of abdominal tamponade. PMID- 22516580 TI - Dripping candle wax. PMID- 22516581 TI - Life thru a lens. PMID- 22516583 TI - Lyme disease--the challenge for patients. PMID- 22516582 TI - Real-life costs of hepatitis C treatment. AB - BACKGROUND: Hepatitis C virus infection is a serious health threat in today's society. Improved identification strategies have increased the number of patients undergoing the expensive treatment with ribavirin and peg-interferon, inducing a substantial economic burden. METHODS: In a retrospective cohort study in three treatment centres in the Netherlands, files of patients treated between 2001 and 2010 were systematically searched for all cost-inducing treatment details. Costs of treatment resulting in sustained viral response (SVR), relapse, non-response and the costs per cured patient were specified for genotype and treatment setting. Determinants of costs were determined by multivariate linear regression. RESULTS: The mean 'real-life' treatment costs excluding side effects for genotype 1/4 and genotype 2/3 were approximately ? 12,900 and ? 9900 for all patients, ? 15,500 and ? 10,100 for treatment resulting in SVR and ? 16,800 and ? 12,100 for relapse, respectively. Costs per cured patient were ? 28,500 and ? 15,400 respectively. The costs of non-response were approximately ? 8000 for all genotypes. Costs of side effects can be high and are mainly caused by incidental treatment for neutropenia. Medication is the main component of treatment costs. Treatment costs were higher in the academic setting due to longer duration and higher costs of side effects. Regression analysis confirms duration as the main determinant of treatment costs excluding side effects. CONCLUSION: The 'real life' costs of treatment are mainly determined by treatment duration, medication costs and costs of side effects. The costs of unsuccessful treatment are considerable as are the costs of side effects. Therefore, future research should aim at increasing SVR rates, reducing treatment duration and preventing side effects. PMID- 22516584 TI - Valproic acid-induced DRESS syndrome with acute liver failure. PMID- 22516585 TI - Molecular pathology. AB - Molecular pathology as applied to neoplasia is a rapidly expanding component of the discipline of pathology that uses molecular biology tools in addition to conventional morphologic, immunohistochemical and chemical analyses of abnormalities in tissues and cells to understand the etiology and pathogenesis of tumors, establish their diagnosis, and contribute to prognostication and therapeutic decisions for cancer patient care. Biomarkers are a fundamental component of personalized cancer care, and the discipline of molecular pathology therefore contributes throughout the continuum from biomarker research to use in standard-of-care personalized cancer therapy. This brief review addresses some of the specific roles of molecular pathology in that continuum. PMID- 22516587 TI - Medial amygdaloid nucleus 5-HT2c receptors are involved in the hypophagic effect caused by zimelidine in rats. AB - The medial amygdaloid nucleus (MeA) is a sub-region of the amygdaloid complex that has been described as participating in food intake regulation. Serotonin has been known to play an important role in appetite and food intake regulation. Moreover, serotonin 5-HT(2C) and 5-HT(1A) receptors appear to be critical in food intake regulation. We investigated the role of the serotoninergic system in the MeA on feeding behavior regulation in rats. The current study examined the effects on feeding behavior regulation of the serotonin reuptake inhibitor, zimelidine, administered directly into the MeA or given systemically, and the serotoninergic receptors mediating its effect. Our results showed that microinjection of zimelidine (0.2, 2 and 20 nmol/100 nL) into the MeA evoked dose dependent hypophagic effects in fasted rats. The selective 5-HT(1A) receptor antagonist WAY-100635 (18.5 nmol/100 nL) or the 5-HT(1B) receptor antagonist SB 216641 microinjected bilaterally into the MeA did not change the hypophagic effect evoked by local MeA zimelidine treatment. However, microinjection of the selective 5-HT(2C) receptor antagonist SB-242084 (10 nmol/100 nL) was able to block the hypophagic effect of zimelidine. Moreover, microinjection of the 5 HT(2C) receptor antagonist SB-242084 into the MeA also blocked the hypophagic effect caused by zimelidine administered systemically. These results suggest that MeA 5-HT(2C) receptors modulate the hypophagic effect caused by local MeA administration as well as by systemic zimelidine administration. Furthermore, 5 HT(2C) into the MeA could be a potential target for systemic administration of zimelidine. PMID- 22516588 TI - Cortical thickness correlates of pain and temperature sensitivity. AB - It is well established that there is individual variability in pain and temperature sensitivity. Functional brain imaging studies have found that interindividual heat pain variability correlates with brain activity in sensory and pain modulation areas. Thus, it is possible that these individual differences are associated with variability in gray matter thickness of cortical regions involved in thermoreception and pain. To test this, we investigated the relationship between thermal thresholds and cortical thickness in 80 healthy subjects. Subjects underwent a psychophysical session to determine their cool detection (CD), warm detection (WD), cold pain (CP), and heat pain (HP) threshold. A high-resolution structural magnetic resonance imaging scan was acquired for each subject. We correlated each threshold measure to cortical thickness of regions associated with thermoreception and pain. The mean (+/- SD) thresholds were 30.7 degrees C (+/- 0.8) for CD, 33.8 degrees C (+/- 0.7) for WD, 11.7 degrees C (+/- 9.7) for CP, and 45.3 degrees C (+/- 2.8) for HP. The brain gray matter analysis revealed a strong correlation between greater thermal and pain sensitivity and cortical thickening of the primary somatosensory cortex. Additionally, greater sensitivity to cool stimuli correlated with cortical thickening in the paracentral lobule, and greater WD correlated with cortical thinning in the anterior midcingulate cortex. We also found that greater HP sensitivity correlated with thickening in the posterior midcingulate cortex and the orbitofrontal cortex. These cortical gray matter correlates of thermal and pain sensitivity provide a neural basis for individual differences in thermal sensitivity. PMID- 22516586 TI - Differential modulation of cocaine's discriminative cue by repeated and variable stress exposure: relation to monoamine transporter levels. AB - Discriminative stimulus functions of drugs of abuse play an important role in the acquisition, maintenance and reinstatement of drug-taking behavior. The present study tested whether two different schedules of stressor presentation, i.e., repeated and variable, for 10 days, can modify the discriminative stimulus effects of cocaine in male rats trained to discriminate cocaine (10 mg/kg, i.p.) from saline. Dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporter levels in mesocorticolimbic areas were also measured using western blotting after stress exposure to determine if the relative ratio of these proteins may explain differences in behavior. Rats exposed to both repeated and variable stress displayed shifts in the cocaine dose-response curve but with different patterns of responding. In handled controls, ED(50) values for cocaine like responding were stable after 10 days of handling compared to baseline. Repeated stress produced a transient left-ward shift in cocaine-like responding, indicating increased sensitivity to the cocaine cue. ED(50) values after variable stress did not differ from baseline, although maximal cocaine-like responding was lower at the two highest doses of cocaine tested at which variably stressed rats exhibited more saline-like responding. Alterations in DAT and NET were found in the Repeated Stress group and DAT and SERT in the Variable Stress group in select brain regions which may be responsible for differences in behavior. PMID- 22516589 TI - Worry and catastrophizing about pain in youth: a reappraisal. PMID- 22516590 TI - [Association of radiotherapy and hormonotherapy in locally advanced prostate cancer]. AB - Combination of radiotherapy and androgen deprivation is now considered as the standard of care for patients with a localized prostate cancer but poor prognostic factors. Two groups of randomized trials have led to this recommendation. Some have compared radiotherapy alone versus hormonal treatment and radiotherapy: these trials demonstrated, now with a long follow-up, an improvement in 10-year survival for the combined treatment. Three recent trials compared androgen deprivation alone or combined with radiotherapy; a benefit in survival was also demonstrated in favour of the combination. Some questions remained concerning the optimal duration of hormonal treatment, in view of its potential side effects. Patients in the intermediate prognostic groups could receive a short-term androgen deprivation, but those with a high Gleason score must be treated with a long-term hormonal treatment. Modalities of radiotherapy, regarding volumes and dose must also be precised in the next years. PMID- 22516591 TI - [Clinical study to obtain true view of the glenohumeral joint on scapula-45]. AB - Scapula-45 is an original roentogenographical technique to clarify objectively the function of the rotator cuff and scapulothoracic joint. This examination enables assessment of the function of the rotator cuff and scapulothoracic joint utilizing the radiographs of the glenohumeral joint. However, in the former technique, it was difficult for the technician to properly align the patient for the view of the true glenohumeral joint because of the individual postural difference of the patients, such as kyphosis. In the present study, we reported a new technique with the use of the acromion, coracoid process, and inferior angle of the scapula as a landmark to obtain the consistent radiographs of the glenohumeral joint. PMID- 22516592 TI - [Image quality evaluation of new image reconstruction methods applying the iterative reconstruction]. AB - The purpose of this study was to evaluate the image quality of an iterative reconstruction method, the iterative reconstruction in image space (IRIS), which was implemented in a 128-slices multi-detector computed tomography system (MDCT), Siemens Somatom Definition Flash (Definition). We evaluated image noise by standard deviation (SD) as many researchers did before, and in addition, we measured modulation transfer function (MTF), noise power spectrum (NPS), and perceptual low-contrast detectability using a water phantom including a low contrast object with a 10 Hounsfield unit (HU) contrast, to evaluate whether the noise reduction of IRIS was effective. The SD and NPS were measured from the images of a water phantom. The MTF was measured from images of a thin metal wire and a bar pattern phantom with the bar contrast of 125 HU. The NPS of IRIS was lower than that of filtered back projection (FBP) at middle and high frequency regions. The SD values were reduced by 21%. The MTF of IRIS and FBP measured by the wire phantom coincided precisely. However, for the bar pattern phantom, the MTF values of IRIS at 0.625 and 0.833 cycle/mm were lower than those of FBP. Despite the reduction of the SD and the NPS, the low-contrast detectability study indicated no significant difference between IRIS and FBP. From these results, it was demonstrated that IRIS had the noise reduction performance with exact preservation for high contrast resolution and slight degradation of middle contrast resolution, and could slightly improve the low contrast detectability but with no significance. PMID- 22516593 TI - [MRI image reconstruction using polar-coordinates conversion of k-space data]. AB - In this study, we proposed the new reconstruction techniques for magnetic resonance imaging (MRI) using filtered back projection (FBP) or simultaneous reconstruction technique (SIRT). We converted the k-space which was acquired by conventional phase-encoding schemes from Cartesian coordinates to polar coordinates and created the projection. The linear interpolation and the sinc interpolation were used in the conversion. The accuracy of the reconstructed image using projection was evaluated by the relative error in comparison with the standard image which was reconstructed by the two-dimensional Fourier transform (2DFT) with conventional Cartesian k-space. The relative error reconstructed both FBP and SIRT from projection with sinc interpolation is 0.013. The maximum value of standard image is 1.501451, FBP is 1.47921, and SIRT with iteration 100 is 1.44858 and with iteration 200 is 1.579442. The minimum value of both the standard image and the others is about 0. Visually, there is no margin between the standard image and the reconstructed image from projection with FBP or SIRT. PMID- 22516594 TI - [Development of image quality assurance support system using image recognition technology in radiography in lacked images of chest and abdomen]. AB - In order to provide a precise radiography for diagnosis, it is required that we avoid radiography with defects by having enough evaluation. Conventionally, evaluation was performed only by observation of a radiological technologist (RT). The evaluation support system was developed for providing a high quality assurance without depending on RT observation only. The evaluation support system, called as the Image Quality Assurance Support System (IQASS), is characterized in that "image recognition technology" for the purpose of diagnostic radiography of chest and abdomen areas. The technique of the system used in this study. Of the 259 samples of posterior-anterior (AP) chest, lateral chest, and upright abdominal x-rays, the sensitivity and specificity was 93.1% and 91.8% in the chest AP, 93.3% and 93.6% in the chest lateral, and 95.0% and 93.8% in the upright abdominal x-rays. In the light of these results, it is suggested that AIQAS could be applied to practical usage for the RT. PMID- 22516595 TI - [Physics properties of non-helical scan using 320-row multi detector computed tomography]. AB - Recently, clinical applications utilizing 320-row multi detector computed tomography (320MDCT) have increased, and the physical image properties of 320MDCT have been more concerned. We evaluated the spatial resolution in scan plane and z direction, image noise and low-contrast sensitivity of non-helical mode (320NH), 640 slices mode by a double slice reconstruction technology (640DS), and 64-row helical mode (64HE) by using a 320MDCT. The spatial resolution in z-direction was evaluated by the section sensitivity profile (SSP) measurement with the micro coin phantom and the contrast transfer ratio (CTR) with the 0.5-mm comb phantom. The in-plane spatial resolution of 320NH was uniform over all the slice positions. The spatial resolution in z-direction decreased from the cathode side toward the anode side. The image noise of the anode side was higher than that of the cathode side. The contrast to noise ratio as index of the low contrast sensitivity was uniform over all the slice position. The CTR of 320NH fluctuated in the z-position, and the fluctuation was improved by 640DS except for the center of rotation. PMID- 22516596 TI - [Comparison of dose accuracy between 2D array detectors for pre-treatment IMRT QA]. AB - The dosimetric properties between various 2D array detectors were compared and were evaluated with regard to the accuracy in absolute dose and dose distributions for clinical treatment fields. We used to check the dose accuracy: 2D array detectors; MapCHECK (Sun Nuclear), EPID (Varian Medical Systems), EPID based dosimetry (EPIDose, Sun Nuclear), COMPASS (IBA) and conventional system; EDR2 film (Eastman Kodak), Exradin A-14SL ion chamber (0.016 cc, Standard Imaging). First, we compared the dose linearity, dose rate dependence, and output factor between the 2D array detectors. Next, the accuracy of the absolute dose and dose distributions were evaluated for clinical fields. All detector responses for the dose linear were in agreement within 1%, and the dose rate dependence and output factor agreed within a standard deviation of +/-1.2%, except for EPID. This is because EPID is fluence distributions. In all the 2D array detectors, the point dose agreed within 5% with treatment planning system (TPS). Pass rates of each detector for TPS were more than 97% in the gamma analysis (3 mm/3%). EPIDose was in a good agreement with TPS. All 2D array detectors used in this study showed almost the same accuracy for clinical fields. EPIDose has better resolution than other 2D array detectors and thus this is expected for dose distributions with a small field. PMID- 22516597 TI - [A design of two-dimensional time-of-flight using the multi echo collection]. AB - In general, gradient echo (GRE) is used for the echo acquisition of two dimensional time-of-flight (2D-TOF). It takes time to the image acquisition by 2D TOF. Then, we designed the use of GRE-echo planar imaging (EPI) to the echo collections of 2D-TOF. We compared two pulse sequences using the following: contrast, signal to noise ratio, the distortions, and magnetic resonance angiography (MRA) images. The signal intensity ratio between blood vessel and fat was superior to the GRE-EPI. Signal to noise ratio of GRE-EPI was inferior to GRE. When the number of collection echoes of GRE-EPI is carried out by four, there was no distortion. The contrast of the blood vessel has improved when GRE EPI was used. Image acquisition time improved to about 23 percent earlier. The blood vessel of the parent trunk was able to be described in the image of the lower limbs blood vessel. However, the description of the peripheral vessel was dominant 2D-TOF that used GRE. In clinical, the description of the peripheral vessel may not be important. With such a case, this method is effective. Moreover, shortening the image acquisition time brings a reduction to the load of the patient. PMID- 22516598 TI - [Usefulness of imaging posture using anterior view of the half supine position for sentinel lymphscintigraphy in patients with breast cancer]. AB - OBJECTIVES: Sentinel lymphoscintigraphy(SLSG) is focused on the visualization of an injection site and lymph nodes. Therefore, an anterior view is effective in identifying the location of a lymph node easily. For this reason, we devised a new imaging method of anterior view (Modified Anterior View; MAV), and the usefulness was assessed. METHODS: SLSG was obtained in 166 patients with breast cancer. In MAV imaging, patients were laid in an oblique position on a triangular styrene foam elevating the target axillary side. The detector was also leaned. Just after the MAV were imaged, the patient was shifted to the supine position and the SAV imaging was also performed using the same acquisition times. RESULTS: The detectability of MAV and SAV was 92.42% and 81.99%, respectively. However, the detectability of SAV showed the better value for the few cases which the lymph node detected by the inside of injection site. CONCLUSION: MAV may improve detectability of SLN. However, SAV is still required for a few cases in which lymph node is detected by the inside of injection site. PMID- 22516599 TI - [Estimation of cost-saving for reducing radioactive waste from nuclear medicine facilities by implementing decay in storage (DIS) in Japan]. AB - DIS has not yet been implemented in Japan as of 2011. Therefore, even if risk was negligible, medical institutions have to entrust radioactive temporal waste disposal to Japan Radio Isotopes Association (JRIA) in the current situation. To decide whether DIS should be implemented in Japan or not, cost-saving effect of DIS was estimated by comparing the cost that nuclear medical facilities pay. By implementing DIS, the total annual cost for all nuclear medical facilities in Japan is estimated to be decreased to 30 million yen or less from 710 million yen. DIS would save 680 million yen (96%) per year. PMID- 22516600 TI - [What is cloud?]. PMID- 22516601 TI - [Feasibility of Mo-99/Tc-99m production by using countrywide cyclotrons as an alternative]. PMID- 22516602 TI - [Quantitative evaluation of magnetic resonance image: SNR, CNR, signal detectability]. PMID- 22516603 TI - [3. CT--current status of CT mammography]. PMID- 22516604 TI - [Image evaluation in digital age: what is the different from analog image]. PMID- 22516605 TI - [The outline of the document "Manufacturer Disclosure Statement for Medical Information Security"]. PMID- 22516606 TI - The effects of human platelet lysate on dental pulp stem cells derived from impacted human third molars. AB - Human platelet lysate (PL) has been suggested as a substitute for fetal bovine serum (FBS) in the large-scale expansion of dental pulp stem cells (DPSCs). However, the biological effects and the optimal concentrations of PL for the proliferation and differentiation of human DPSCs remain unexplored. We isolated and expanded stem cells from the dental pulp of extracted third molars and evaluated the effects of PL on the cells' proliferative capacity and differentiation potential in vitro and in vivo. Before testing, immunocytochemical staining and flow cytometry-based cell sorting showed that the cells derived from human dental pulp contained mesenchymal stem cell populations. Cells were grown on tissue culture plastic or on hydroxyapatite-tricalcium phosphate (HA/TCP) biomaterials and were incubated with either normal or odontogenic/osteogenic media in the presence or absence of various concentrations of human PL for further investigation. The proliferation of DPSCs was significantly increased when the cells were cultured in 5% PL under all testing conditions (P < 0.05). However, this enhancement was inconsistent when the cells were cultured in 1% PL or in 10% PL; 10% PL significantly inhibited cell proliferation and was therefore excluded from further differentiation testing. Culture medium containing 5% PL also significantly promoted the mineralized differentiation of DPSCs, as indicated by the measurement of alkaline phosphatase activity and calcium deposition under mineral-conditioned media (P < 0.05). Scanning electron microscopy and modified Ponceau trichrome staining showed that the cells treated with 5% PL and mineralizing media were highly capable of integrating with the HA/TCP biomaterials and had fully covered the surface of the scaffold with an extensive sheet-like structure 14 d after seeding. In addition, 5% PL showed significantly positive effects on tissue regeneration in two in vivo transplantation models. We conclude that the appropriate concentration of PL enhances the proliferation and mineralized differentiation of human DPSCs both in vitro and in vivo, which supports the use of PL as an alternative to FBS or a nonzoonotic adjuvant for cell culture in future clinical trials. However, the elucidation of the molecular complexity of PL products and the identification of both the essential growth factors that determine the fate of a specific stem cell and the criteria to establish dosing require further investigation. PMID- 22516607 TI - Nanotopography as modulator of human mesenchymal stem cell function. AB - Nanotopography changes human mesenchymal stem cells (hMSC) from their shape to their differentiation potential; however little is known about the underlying molecular mechanisms. Here we study the culture of hMSC on polydimethylsiloxane substrates with 350 nm grating topography and investigate the focal adhesion composition and dynamics using biochemical and imaging techniques. Our results show that zyxin protein plays a key role in the hMSC response to nanotopography. Zyxin expression is downregulated on 350 nm gratings, leading to smaller and more dynamic focal adhesion. Since the association of zyxin with focal adhesions is force-dependent, smaller zyxin-positive adhesion as well as its higher turnover rate suggests that the traction force in focal adhesion on 350 nm topography is decreased. These changes lead to faster and more directional migration on 350 nm gratings. These findings demonstrate that nanotopography decreases the mechanical forces acting on focal adhesions in hMSC and suggest that force-dependent changes in zyxin protein expression and kinetics underlie the focal adhesion remodeling in response to 350 nm grating topography, resulting in modulation of hMSC function. PMID- 22516608 TI - Bacteraemia in adult patients presenting with malaria in India. AB - Severe falciparum malaria is a major health problem in Odisha, India, contributing to high mortality. Multi organ dysfunction is a predominant manifestation of severe disease in Odisha, unlike in Africa, where cerebral malaria and anaemia are common. There are several studies implicating bacteraemia with severe malaria in African children while there are no reports in adults in India. This study has addressed this issue by enrolling 67 P. falciparum infected adult patients categorized into severe and uncomplicated malaria. Blood culture failed to confirm bacteraemia in any sample with the exception of one case of uncomplicated malaria. Study is inconclusive with regard to use of antibiotics in adult patients. PMID- 22516609 TI - The association between the Framingham risk score and sleep: a Sao Paulo epidemiological sleep study. AB - BACKGROUND: Sleep is an important factor in the maintenance of cardiovascular integrity. It seems that cardiovascular injury and sleep impairment is another chicken or egg puzzle and we hypothesized that the higher the cardiovascular risk factors the higher the sleep impairment. Therefore, the goal of this study is to analyze the sleep profile of a general population based on cardiovascular risk stratification. METHODS: This population-based survey used a probabilistic three stage cluster sample of Sao Paulo inhabitants to represent the population. A sample size of 1056 volunteers was defined in order to allow for prevalence estimates with 3% precision. From the 1101 selected and interviewed participants, a complete full-night polysomnogram (PSG) was performed in 1042 participants as well as clinical evaluation and blood samples analyses to assess Framingham risk score. RESULTS: Nine hundred four subjects were classified according the Framingham score and were included in the analyses. A total of 91.7% were classified as a low risk, 5.8% in the intermediate, and 2.4% in the high risk groups according to Framingham score. All polisomnographic parameters were different between groups, except those related to REM sleep parameters. AHI were greater in the high risk compared to the intermediate and low risk groups (23.9 +/- 2.8; 17.7 +/- 1.8; 7.2 +/- 0.5, respectively, p<0.001), as well as a lower total sleep time in minutes (295.3 +/- 16.2; 338.4 +/- 10.2; 347.4 +/- 2.6, respectively, p=0.01). Sleep efficiency in percentage also exhibits a reduction between groups (67.6 +/- 2.5; 78.4 +/- 1.6; 82.9 +/- 0.4, respectively, p<0.001). After adjustment for confounder factors age (p<0.001) and sleep efficiency (p=0.06) remained strongly associated with high risk population. CONCLUSION: High Framingham risk score was associated with poor sleep efficiency and aging. PMID- 22516610 TI - The flexion gap preparation does not disturb the modified gap technique in posterior stabilized total knee arthroplasty. AB - PURPOSE: Preparation of the flexion gap (resection of the posterior femoral condyle and removal of the osteophytes on the posterior aspect of the femur to re establish the posterior capsular recess) during modified gap technique might change the soft-tissue balancing and disturb the preparation of equal and rectangular extension and flexion joint gaps. The purpose of this study was to measure the change in the extension and flexion gaps using tension device during posterior stabilized TKA with modified gap technique. METHODS: We examined changes in the extension gap and flexion gap during posterior stabilized TKA using modified gap technique in 100 consecutive varus osteoarthritis knees. The extension gap was first prepared and then the distance and angle of both extension and flexion gaps were measured before and after preparation of the flexion gap using a tension device. RESULTS: Although both the extension and flexion gaps significantly increased during the operation, the amount of the increase was very small, and the difference between the increase in the extension gap (0.9 +/- 0.1mm [mean +/- SE]) and that in the flexion gap (0.7 +/- 0.1mm) was not statistically significant. Mean angular changes in extension and flexion gaps during the operation were less than 1 degrees . CONCLUSIONS: The preparation of the flexion gap in posterior stabilized TKA did not disturb the modified gap technique in terms of equal and rectangular extension and flexion gaps. PMID- 22516611 TI - Structural comparison of mouse and human alpha-synuclein amyloid fibrils by solid state NMR. AB - Fibrillar alpha-synuclein (AS) is the major component of Lewy bodies, the pathological hallmark of Parkinson's disease. Mouse AS (mAS) aggregates much faster than human AS (hAS), although mAS differs from hAS at only seven positions in its primary sequence. Currently, little is known about the site-specific structural differences between mAS and hAS fibrils. Here, we applied state-of-the art solid-state nuclear magnetic resonance (ssNMR) methods to structurally characterize mAS fibrils. The assignment strategy employed a set of high resolution 2D and 3D ssNMR spectra recorded on uniformly [(13)C, (15)N], [1 (13)C]glucose, and [2-(13)C]glucose labeled mAS fibrils. An almost complete resonance assignment (96% of backbone amide (15)N and 93% of all (13)C nuclei) was obtained for residues from Gly41 to Val95, which form the core of mAS fibrils. Six beta-strands were identified to be within the fibril core of mAS based on a secondary chemical shift and NHHC analysis. Intermolecular (13)C:(15)N labeled restraints obtained from mixed 1:1 (13)C/(15)N-labeled mAS fibrils reveal a parallel, in-register supramolecular beta-sheet arrangement. The results were compared in detail to recent structural studies on hAS fibrils and indicate the presence of a structurally conserved motif comprising residues Glu61-Lys80. PMID- 22516614 TI - The structure of subunit E of the Pyrococcus horikoshii OT3 A-ATP synthase gives insight into the elasticity of the peripheral stalk. AB - A(1)A(O) ATP synthases are the major energy converters of archaea. They are composed of an A(1) region that synthesizes ATP and an integral part A(O) that conducts ions. Subunit E is a component of the peripheral stalk that links the A(1) with the A(O) part of the A-ATP synthase. We have determined the crystal structure of the entire subunit E (PhE) of the Pyrococcus horikoshii OT3 A-ATP synthase at 3.6 A resolution. The structure reveals an extended S-shaped N terminal alpha-helix with 112.29 A in length, followed by a globular head group. The S-shaped feature, common in elastic connectors and spacers, would facilitate the storage of transient elastic energy during rotary motion in the enzyme. The structure has been superimposed into the asymmetric peripheral stalks of the three-dimensional reconstruction of the Pyrococcus furiosus enzyme, revealing that the S-shaped subunit PhE fits well into the bent peripheral stalk, whereas the previously solved E subunit structure (3.1 A resolution) of Thermus thermophilus A-ATP synthase is well accommodated in the density of the straight stator domain. The different features of the two stalk subunits are discussed in light of a novel coupling mechanism in A-ATP synthases proposed to differ from the Wankel engine of F-ATP synthases. PMID- 22516613 TI - Structural and functional characterization of microcin C resistance peptidase MccF from Bacillus anthracis. AB - Microcin C (McC) is heptapeptide adenylate antibiotic produced by Escherichia coli strains carrying the mccABCDEF gene cluster encoding enzymes, in addition to the heptapeptide structural gene mccA, necessary for McC biosynthesis and self immunity of the producing cell. The heptapeptide facilitates McC transport into susceptible cells, where it is processed releasing a non-hydrolyzable aminoacyl adenylate that inhibits an essential aminoacyl-tRNA synthetase. The self-immunity gene mccF encodes a specialized serine peptidase that cleaves an amide bond connecting the peptidyl or aminoacyl moieties of, respectively, intact and processed McC with the nucleotidyl moiety. Most mccF orthologs from organisms other than E. coli are not linked to the McC biosynthesis gene cluster. Here, we show that a protein product of one such gene, MccF from Bacillus anthracis (BaMccF), is able to cleave intact and processed McC, and we present a series of structures of this protein. Structural analysis of apo-BaMccF and its adenosine monophosphate complex reveals specific features of MccF-like peptidases that allow them to interact with substrates containing nucleotidyl moieties. Sequence analyses and phylogenetic reconstructions suggest that several distinct subfamilies form the MccF clade of the large S66 family of bacterial serine peptidases. We show that various representatives of the MccF clade can specifically detoxify non-hydrolyzable aminoacyl adenylates differing in their aminoacyl moieties. We hypothesize that bacterial mccF genes serve as a source of bacterial antibiotic resistance. PMID- 22516612 TI - The three-dimensional structural basis of type II hyperprolinemia. AB - Type II hyperprolinemia is an autosomal recessive disorder caused by a deficiency in Delta(1)-pyrroline-5-carboxylate dehydrogenase (P5CDH; also known as ALDH4A1), the aldehyde dehydrogenase that catalyzes the oxidation of glutamate semialdehyde to glutamate. Here, we report the first structure of human P5CDH (HsP5CDH) and investigate the impact of the hyperprolinemia-associated mutation of Ser352 to Leu on the structure and catalytic properties of the enzyme. The 2. 5-A resolution crystal structure of HsP5CDH was determined using experimental phasing. Structures of the mutant enzymes S352A (2.4 A) and S352L (2.85 A) were determined to elucidate the structural consequences of altering Ser352. Structures of the 93% identical mouse P5CDH complexed with sulfate ion (1.3 A resolution), glutamate (1.5 A), and NAD(+) (1.5 A) were determined to obtain high resolution views of the active site. Together, the structures show that Ser352 occupies a hydrophilic pocket and is connected via water-mediated hydrogen bonds to catalytic Cys348. Mutation of Ser352 to Leu is shown to abolish catalytic activity and eliminate NAD(+) binding. Analysis of the S352A mutant shows that these functional defects are caused by the introduction of the nonpolar Leu352 side chain rather than the removal of the Ser352 hydroxyl. The S352L structure shows that the mutation induces a dramatic 8-A rearrangement of the catalytic loop. Because of this conformational change, Ser349 is not positioned to interact with the aldehyde substrate, conserved Glu447 is no longer poised to bind NAD(+), and Cys348 faces the wrong direction for nucleophilic attack. These structural alterations render the enzyme inactive. PMID- 22516615 TI - Hypogonadotropic hypogonadism in a male with McCune-Albright syndrome. PMID- 22516616 TI - [Liver abscess caused by Klebsiella pneumoniae in a diabetic patient]. PMID- 22516617 TI - Molecular interactions underlying the specification of sensory neurons. AB - Sensory neurons of the dorsal root ganglion (DRG) respond to many different kinds of stimulus. The ability to discriminate between the diverse types of sensation is reflected by the existence of functionally and morphologically specialized sensory neurons. This neuronal diversity is created in a step-wise process extending well into postnatal life. Here, we review the hierarchical organization and the molecular process involving interactions between environmental growth factors, used and reused in different developmental contexts in self-reinforcing and cross-inhibitory mechanisms, and intrinsic gene programs that underlie the progressive diversification of sensory progenitors into specialized neurons. The recent advance in knowledge of sensory neuron specification may provide mechanistic principles that could extend to other parts of the nervous system. PMID- 22516618 TI - EphBs: an integral link between synaptic function and synaptopathies. AB - The assembly and function of neuronal circuits rely on selective cell-cell interactions to control axon targeting, generate pre- and postsynaptic specialization and recruit neurotransmitter receptors. In neurons, EphB receptor tyrosine kinases mediate excitatory synaptogenesis early during development, and then later coordinate synaptic function by controlling synaptic glutamate receptor localization and function. EphBs direct synapse formation and function to regulate cellular morphology through downstream signaling mechanisms and by interacting with glutamate receptors. In humans, defective EphB-dependent regulation of NMDA receptor (NMDAR) localization and function is associated with neurological disorders, including neuropathic pain, anxiety disorders and Alzheimer's disease (AD). Here, we propose that EphBs act as a central organizer of excitatory synapse formation and function, and as a key regulator of diseases linked to NMDAR dysfunction. PMID- 22516621 TI - Memristive tri-stable resistive switching at ruptured conducting filaments of a Pt/TiO2/Pt cell. AB - A tri-stable memristive switching was demonstrated on a Pt/TiO2/Pt device and its underlying mechanism was suggested through a series of electrical measurements. Tri-stable switching could be initiated from a device in unipolar reset status. The unipolar reset status was obtained by performing an electroforming step on a pristine cell which was then followed by unipolar reset switching. It was postulated that tri-stable switching occurred at the location where the conductive filament (initially formed by the electroforming step) was ruptured by a subsequent unipolar reset process. The mechanism of the tri-stable memristive switching presented in this article was attributed to the migration of oxygen ions through the ruptured filament region and the resulting modulation of the Schottky-like interfaces. The assertion was further supported by a comparison study performed on a Pt/TiO2/TiO(2-x)/Pt cell. PMID- 22516620 TI - Unforeseen consequences of the increasing rate of cesarean deliveries: early placenta accreta and cesarean scar pregnancy. A review. AB - This review concentrates on 2 consequences of cesarean deliveries that may occur in a subsequent pregnancy. They are the pathologically adherent placenta and the cesarean scar pregnancy. We explored their clinical and diagnostic as well as therapeutic similarities. We reviewed the literature concerning the occurrence of early placenta accreta and cesarean section scar pregnancy. The review resulted in several conclusions: (1) the diagnosis of placenta accreta and cesarean scar pregnancy is difficult; (2) transvaginal ultrasound seems to be the best diagnostic tool to establish the diagnosis; (3) an early and correct diagnosis may prevent some of their complications; (4) curettage and systemic methotrexate therapy and embolization as single treatments should be avoided if possible; and (5) in the case of cesarean scar pregnancy, local methotrexate- and hysteroscopic directed procedures had the lowest complication rates. PMID- 22516619 TI - The Sturm und Drang of anabolic steroid use: angst, anxiety, and aggression. AB - Anabolic androgenic steroids (AAS) are illicitly administered to enhance athletic performance and body image. Although conferring positive actions on performance, steroid abuse is associated with changes in anxiety and aggression. AAS users are often keenly invested in understanding the biological actions of these drugs. Thus, mechanistic information on AAS actions is important not only for the biomedical community, but also for steroid users. Here we review findings from animal studies on the impact of AAS exposure on neural systems that are crucial for the production of anxiety and aggression, and compare the effects of the different classes of AAS and their potential signaling mechanisms, as well as context-, age- and sex-dependent aspects of their actions. PMID- 22516622 TI - Functional electrical stimulation elliptical stepping versus cycling in spinal cord-injured individuals. AB - BACKGROUND: The cardiorespiratory responses and mechanical efficiencies of two modalities of functional electrical stimulation augmented leg exercises - isokinetic cycling and isokinetic elliptical stepping - were compared amongst individuals with spinal cord injury. METHODS: Five subjects performed seated isokinetic evoked cycling and elliptical stepping leg exercise at 10, 20 and 30rev.min(-1) pedal cadences. 3-D motion analysis and force transducers attached onto the foot pedals quantified the external forces and power outputs developed by each lower extremity. Hip, knee and ankle joints power were derived via inverse dynamics analysis. The subjects' cardiorespiratory responses during exercise were measured by respiratory gas analysis. FINDINGS: Ensemble-averaged oxygen uptakes across pedal cadences were higher during stepping (448 (75) ml.min(-1)) compared to cycling (422 (54) ml.min(-1)). External power outputs and metabolic efficiencies during stepping (9.9 (8.3) W, 2.9 (3.2) %) were double those observed during cycling (5.3 (6.3) W, 1.6 (1.9) %). Cumulative internal and external leg joint powers during stepping were twice higher than cycling, but the stepping mechanical efficiencies derived from inverse dynamics analysis were comparable to cycling (76.3 (21.2) % and 63.6 (12.3) % respectively). Heart rate responses were similar between cycling and stepping, while carbon dioxide production and expired ventilation were slightly higher during elliptical stepping. INTERPRETATION: Both exercise modalities could deliver appropriate training stimuli for improving the aerobic fitness and leg pedalling strength of spinal cord-injured individuals. However electrical stimulation-enhanced elliptical stepping might provide greater exercise dose-potency for leg muscle strengthening than electrically-enhanced cycling due to the higher power outputs observed. PMID- 22516623 TI - Recovery from ischemic acute kidney injury by spironolactone administration. AB - BACKGROUND: Prophylactic mineralocorticoid receptor (MR) antagonism with spironolactone (Sp) in rats completely prevents renal damage induced by ischemia. Because acute renal ischemia cannot typically be predicted, this study was designed to investigate whether Sp could prevent renal injury after an ischemic/reperfusion insult. METHODS: Six groups of male Wistar rats were studied: rats that received a sham abdominal operation (S); rats that underwent 20 min of ischemia and reperfusion for 24 h (I/R) and four groups of rats treated with Sp (20 mg/kg) 0, 3, 6 or 9 h after ischemia. RESULTS: As expected, I/R resulted in renal dysfunction characterized by a fall in renal blood flow and glomerular filtration rate and severe tubular injury which was confirmed by a significant increase in tubular damage biomarkers including kidney injury molecule-1, heat shock protein 72 and urinary protein excretion. The renal injury induced by I/R was in part due to Rho-kinase, endothelin and angiotensin II type 1 receptor upregulation. Interestingly, Sp administration at 0 and 3 h after ischemia completely reversed and prevented the damage induced by I/R. The protection induced by Sp given 6 h after ischemia was partial, but no protection was observed by administering Sp 9 h after ischemia. CONCLUSION: Our results show that MR antagonism administered, either immediately or 3 h after I/R, effectively prevented ischemic acute renal injury, indicating that spironolactone is a promising agent for preventing acute kidney injury once an ischemic insult has occurred. PMID- 22516624 TI - Hypoalbuminaemia, systemic albumin leak and endothelial dysfunction in peritoneal dialysis patients. AB - BACKGROUND: Inflammation, hypoalbuminaemia and peritoneal protein clearance are important predictors of survival in patients treated with peritoneal dialysis (PD). We hypothesized that the common link is abnormal endothelial barrier function. To test this, we explored associations between hypoalbuminaemia, systemic albumin leak and soluble markers of systemic inflammation and endothelial injury. METHODS: This was a cross-sectional study of 41 prevalent PD patients. Endothelial barrier function was measured as transcapillary escape rate of (125)I albumin [transcapillary escape rate of albumin (TER(alb))]. Seventeen plasma biomarkers including pro-inflammatory cytokines, endothelial biomarkers and metalloproteinases were measured. Hierarchical clustering analysis (HCA) and principal component analysis (PCA) were used to explore the hypothesis. RESULTS: The mean TER(alb) was 13.7 +/- 8.9 (%/h), higher than in non-uraemic subjects 8.22 +/- 5.8 (%/h). Three patient clusters were defined from HCA according to their biomarker patterns. Cluster 1 was characterized by inflammation, hypoalbuminaemia, overhydration and intermediate TER(alb). Cluster 2 was non inflamed, preserved muscle mass and more normal TER(alb). Cluster 3 had highest TER(alb), platelet activation, preserved plasma albumin and intermediate high sensitivity C-reactive protein levels. Two principal components (PCs) were identified from the biomarker matrix, PC1, indicating platelet activation and PC2, pro-inflammatory. TER(alb) was positively related to PC1 but not PC2. Diabetes and ischaemic heart disease were associated with PC1 and PC2, respectively. CONCLUSIONS: This exploratory analysis indicates that endothelial barrier function is decreased in PD patients and is associated with diabetic status and markers of platelet activation more than inflammation. In contrast, hypoalbuminaemia is associated more with inflammation and atherosclerotic disease indicating a more complex relationship between systemic endothelial barrier function, inflammation and hypoalbuminaemia which requires further validation. PMID- 22516625 TI - Chronic renal denervation increases renal tubular response to P2X receptor agonists in rats: implication for renal sympathetic nerve ablation. AB - BACKGROUND: Kidney noradrenergic innervation regulates tubular function. Adenosine triphosphate (ATP)-a co-transmitter of norepinephrine-acts on purinoceptors, including ion channel receptor, P2X. P2X receptor agonists, alpha,beta-methylene ATP (alpha,beta-meATP) and beta,gamma-methylene ATP (beta,gamma-meATP), induce natriuresis. Regarding the functional co-localization of adrenoceptors and P2X receptors, we evaluated rat renal tubular system sensitivity to natriuretic action of P2X receptor agonists in chronically denervated kidney. METHODS: Clearance studies with alpha,beta-meATP and beta,gamma-meATP (intravenous infusion rate, 2 umol/kg + 20 nmol/kg/min) were performed after bilateral surgical kidney denervation (DNx) and sham-operation (Sham). Na/K-ATPase activity was measured in isolated rat renal proximal tubules. RESULTS: In DNx compared with Sham, saline infusion significantly increased renal sodium and urine excretion and P2X receptor agonist infusion was significantly more natriuretic and diuretic. In DNx and Sham, respectively, alpha,beta-meATP increased fractional excretion of sodium (FE(Na)) by 2 +/- 0.3 and 0.6 +/- 0.1% and urine (FE(V)) by 1.6 +/- 0.3 and 0.9 +/- 0.2%; beta,gamma-meATP had similar effects. In both groups of rats, natriuretic and diuretic actions were abolished by P2 receptor blocker (pyridoxal-phosphate-6-azophenyl-2',4'-disulphonate, PPADS), mean arterial blood pressure and glomerular filtration rate remained unchanged during infusion of P2X receptor agonists and antagonist and basal Na/K ATPase activities in isolated proximal tubules were similar. Both alpha,beta meATP and beta,gamma-me-ATP decreased the Na/K-ATPase activity, with 20% inhibition (P < 0.05) in denervated and innervated rats; these inhibitory effects were abolished in the presence of PPADS. CONCLUSIONS: Decreased renal sympathetic activity enhances the natriuretic effect of P2X receptor stimulation. This effect is probably not related to altered Na/K-ATPase activity in renal proximal tubules. PMID- 22516626 TI - The elusive erythropoietin receptor. PMID- 22516627 TI - How do banded mongooses locate and select anvils for cracking encased food items? AB - Banded mongooses (Mungos mungo) extract encased food items by throwing them against anvils. Observations indicate that their chosen anvils are generally hard enough to crack open casings, suggesting an understanding of the physical properties that render an anvil suitable for cracking. We report results from two field experiments investigating spatial and physical aspects of anvil selection in a wild group of banded mongooses. Mongooses rapidly carried prey items to nearby anvils in their environment, without simply returning to the last anvil they passed, suggesting a detailed knowledge of anvil locations. Moreover, in choice experiments with hard or soft anvils, they always chose the appropriate anvil when both anvils were natural but chose indiscriminately when they were synthetic. These results support a recent suggestion that mongooses lack a generalized understanding of the functional properties of anvils but also indicate that they may mediate their decisions on the basis of familiarity. Together, our experiments suggest that mongooses employ simple rules of thumb that, in most cases, result in the selection of appropriate anvils. Where environmental problems are limited and predictable, selection will favor the evolution of such rules of thumb rather than a more generalized understanding of functional properties. PMID- 22516628 TI - The persistence of flood-borne pathogens on building surfaces under drying conditions. AB - Previous research into microbial persistence on material surfaces following flooding has produced a wide range of results due to differing experimental conditions, including the temperature and humidity conditions of the experimental material and/or surrounding air. However, investigations to identify and quantify these factors and their links to the hygrothermal properties of building materials and the transient environmental conditions are rarely reported. This paper examines the viability of bacterial species on drying material surfaces that have been saturated with water or synthetic sewage. Escherichia coli and Enterococcus faecalis were inoculated on brick, wood, or plaster and allowed to dry at the conditions intended to mimic the remediation environments commonly found in domestic dwellings following a flood event. The inactivation rates were compared between environmental conditions, water type and the material properties of the surfaces. Significant differences were found in the declines in E. coli according to water type, the surface relative humidity and air relative humidity and between drying rates for sewage floods. Simulations using hygrothermal software were performed to illustrate the wide variation in material drying rates under different scenarios, taking into account material size, wall composition, and ventilation. The significantly differing rates of microbial death on flooded building materials under different drying regimes suggest that building simulation models can be useful tools for predicting the level and duration of microbial contamination in buildings following a flood event. A better understanding of microbial survival on drying surfaces can be used to assess the health risks to occupants in flood affected properties. PMID- 22516629 TI - The local structure of image discontinuities in one dimension. AB - The detailed structure of intensities in the local neighborhood of an edge can often indicate the nature of the physical event givinig rise to that edge. We argue that the limit, as we approach arbitrarily close to either side of an edge, of such image parameters as type of texture, texture gradient, color, appropriate directional derivatives of intensity, etc., is a key aspect of this structure. However, the general problem of capturing this local structure is surprisingly complex. Thus, we restrict ourselves in this paper to a relatively simple domain?one-dimensional cuts through idealized images modeled by piecewise smooth (C1) functions corrupted by Gaussian noise. Within this domain, we define local structure to be the limit of the uncorrupted intensity and of its derivatives as we approach arbitrarily close to either side of a discontinuity. We develop a technique that captures this local structure while simultaneously locating the discontinuities, and demonstrate that these tasks are in fact inseparable. The technique is an extension, using estimation theory, of the classical definition of discontinuity. It handles, in a consistent fashion, both jump discontinuities in the function and jump discontinuities in its first derivative (so-called step edges are a special case of the former and roof-edges of the latter). It also integrates, again in a consistent fashion, information derived from a number of different neighborhood sizes. PMID- 22516630 TI - Motion stereo using ego-motion complex logarithmic mapping. AB - Stereo information can be obtained using a moving camera. If a dynamic scene is acquired using a translating camera and the camera motion parameters are known, then the analysis of the scene may be facilitated by ego-motion complex logarithmic mapping (ECLM). It is shown in this paper that by using the complex logarithmic mapping (CLM) with respect to the focus of expansion, the depth of stationary components can be determined easily in the transformed image sequence. The proposed approach for depth recovery avoids the difficult problems of establishing correspondence and computation of optical flow, by using the ego motion information. An added advantage of the CLM will be the invariances it offers. We report our experiments with synthetic data to show the sensitivity of the depth recovery, and show results of real scenes to demonstrate the efficacy of the proposed motion stereo in applications such as autonomous navigation. PMID- 22516631 TI - 3-d motion estimation, understanding, and prediction from noisy image sequences. AB - This paper presents an approach to understanding general 3-D motion of a rigid body from image sequences. Based on dynamics, a locally constant angular momentum (LCAM) model is introduced. The model is local in the sense that it is applied to a limited number of image frames at a time. Specifically, the model constrains the motion, over a local frame subsequence, to be a superposition of precession and translation. Thus, the instantaneous rotation axis of the object is allowed to change through the subsequence. The trajectory of the rotation center is approximated by a vector polynomial. The parameters of the model evolve in time so that they can adapt to long term changes in motion characteristics. The nature and parameters of short term motion can be estimated continuously with the goal of understanding motion through the image sequence. The estimation algorithm presented in this paper is linear, i.e., the algorithm consists of solving simultaneous linear equations. Based on the assumption that the motion is smooth, object positions and motion in the near future can be predicted, and short missing subsequences can be recovered. Noise smoothing is achieved by overdetermination and a leastsquares criterion. The framework is flexible in the sense that it allows both overdetermination in number of feature points and the number of image frames. PMID- 22516632 TI - Matching perspective views of a polyhedron using circuits. AB - We present a novel approach for finding corresponding points between two line drawings extracted from perspective views of a moving object whose surface is composed of planar polygons. In our approach, each circuit of the drawings is encoded with a boundary shape code which we call the RLCC code (run length code of convex and concave strings), then a clustering technique is used to obtain the matching result recursively. A series of measures are taken to make the algorithm tolerate considerable dissimilarities which may exist between the two drawings, such as missing lines, scale differences, rotation, perspective shape distortions, etc. Experimental results are presented. PMID- 22516633 TI - New methods for matching 3-d objects with single perspective views. AB - In this paper we analyze the ability of a computer vision system to derive properties of the three-dimensional (3-D) physical world from viewing two dimensional (2-D) images. We present a new approach which consists of a model based interpretation of a single perspective image. Image linear features and linear feature sets are backprojected onto the 3-D space and geometric models are then used for selecting possible solutions. The paper treats two situations: 1) interpretation of scenes resulting from a simple geometric structure (orthogonality) in which case we seek to determine the orientation of this structure relatively to the viewer (three rotations) and 2) recognition of moderately complex objects whose shapes (geometrical and topological properties) are provided in advance. The recognition technique is limited to objects containing, among others, straight edges and planar faces. In the first case the computation can be carried out by a parallel algorithm which selects the solution that has received the largest number of votes (accumulation space). In the second case an object is uniquely assigned to a set of image features through a search strategy. As a by-product, the spatial position and orientation (six degrees of freedom) of each recognized object is determined as well. The method is valid over a wide range of perspective images and it does not require perfect low-level image segmentation. It has been successfully implemented for recognizing a class of industrial parts. PMID- 22516634 TI - Iconic indexing by 2-d strings. AB - In this paper, we describe a new way of representing a symbolic picture by a two dimensional string. A picture query can also be specified as a 2-D string. The problem of pictorial information retrieval then becomes a problem of 2-D subsequence matching. We present algorithms for encoding a symbolic picture into its 2-D string representation, reconstructing a picture from its 2-D string representation, and matching a 2-D string with another 2-D string. We also prove the necessary and sufficient conditions to characterize ambiguous pictures for reduced 2-D strings as well as normal 2-D strings. This approach thus allows an efficient and natural way to construct iconic indexes for pictures. PMID- 22516635 TI - Polyhedra recognition by hypothesis accumulation. AB - A new method is presented for the recognition of polyhedra in range data. The method is based on a hypothesis accumulation scheme which allows parallel implementations. The different objects to be recognized are modeled by a set of local geometrical patterns. Local patterns of the same nature are extracted from the scene. For the recognition of an object, local scene and model patterns having the same geometrical characteristics are matched. For each of the possible matches, the geometric transformations (i.e., rotations and translations) are computed, which allows the overlapping of the model elements with those from the scene. This transformation permits the establishment of a hypothesis on the location of the object in the scene and the determination of a point in the transformation space. The presence of an object similar to a model involves the generation of several compatible hypotheses and creates a compact cluster in the transformation space. The recognition of the object is based on the detection of this cluster. The cluster coordinates give the values of the rotations and the translations to be applied to the model such that it corresponds to the object in the scene. The exact location of this object is given by the transformed model. PMID- 22516636 TI - Forward/Backward contour tracing with feedback. AB - This correspondence describes a contour extraction algorithm which can gradually improve its results until the extracted contours are closed. This is achieved by an architecture with a feedback path for local smoothing. The feedback path is activated only when one or more contours obtained are not closed in order to initiate smoothing in noisy areas of the image to remove local irregularities that cause the problems. A forward/backward boundary tracing mechanism is employed to facilitate locating any troubled areas. A smoothing method appropriate for reducing local irregularities is discussed. The proposed algorithm is very suitable for those applications that demand closed contours, such as character recognition and blob detection. PMID- 22516637 TI - Edge-detector resolution improvement by image interpolation. AB - Most step-edge detectors are designed to detect locally straight edge-segments which can be isolated within the operator kernel. While it can easily be demonstrated that a cross-sectional support of at least 4 pixels is required for the unambiguous detection of a stepedge, edges which cannot be isolated within windows having this width can nevertheless be resolved. This is achieved by preceding the stepedge detection process by image-intensity interpolation. Although resolution can be improved in this fashion, the step-edge position and intensity estimates thus determined may be subject to systematic biases. Also, the higher resolution performance is accompanied by lower robustness to noise. PMID- 22516638 TI - A robust filtering algorithm for subpixel reconstruction of chain coded line drawings. AB - A robust algorithm is presented for smoothing and achieving subpixel accuracy in the reconstruction of chain coded line drawings. The algorithm does not remove sharp corners and does not need a priori knowledge of curvature statistics. A fast on-line implementation can be achieved using a table look-up. A simplified algorithm can be used for reconstructing digitized polygons. PMID- 22516639 TI - Stochastic model utilizing spectral and spatial characteristics. AB - In remote sensing, because of physical properties of targets, sensor pixels in spatial proximity to one another are class conditionally correlated. Our main objective is to exploit this spatial correlation. Therefore, a two-dimensional causal first order Markov model was used to extract the spatial and spectral information and, based upon it, new object classifiers with improved performance were developed. First, the minimum distance (MT) and the maximum likelihood (ML) object classifiers are discussed. Then, based on the proposed model, these two classifiers are modified, and a linear object classifier is introduced. Finally, experimental results are presented. PMID- 22516640 TI - Recursive algorithms for implementing digital image filters. AB - The B-spline functions are used to develop recursive algorithms for the efficient implementation of two-dimensional linear digital image filters. These filters may be spatially varying. The B-splines are used in a representation of the desired point spread function. We show that this leads to recursive algorithms and hardware implementations which are more efficient than either direct spatial domain filter realizations or FFT implementations. The Z-transform is used to develop a discrete version of Duhamel's theorem. A computer architecture for B spline image filters is proposed and a complexity analysis and comparison to other approaches is provided. PMID- 22516641 TI - [Iron deficiency and anemia in oncology]. AB - Anemia in oncology is no longer seen only as a side effect of chemotherapies. This comorbidity may be multifactorial, clinically and, for example, may be rather chronic when the patient has chronic renal failure associated, resulting in renal anemia. Similarly, the presence of iron deficiency, which can be solely responsible or contributing factor of anemia, is also a factor to be taken into account in both the diagnosis and exploration of anemia and in its treatment, requiring the use of injectable iron complexes for treatment, if necessary in combination with an erythropoiesis agent stimulating. PMID- 22516642 TI - The ubiquitin/proteasome system-dependent control of mitochondrial steps in apoptosis. AB - Insights into the role of ubiquitin-dependent signaling in the regulation of apoptosis have provided one of the most significant breakthroughs in recent years for cell death research. It has been revealed that all steps in the apoptotic cascade, including transcriptional regulation of apoptotic gene expression, outer mitochondrial membrane permeabilization and caspase activation, are under the control of the ubiquitin/proteasome system. This makes ubiquitin signaling one on the most critical life and death decision checkpoints in mammalian cells. Here we discuss the ubiquitylation-dependent regulation of the mitochondrial steps in apoptosis, with a focus on the role of regulated protein degradation in this process. The newly identified ubiquitylation-dependent processes in the Bcl-2 family-regulated outer mitochondrial membrane permeabilization, as well as the role of mitochondria-associated ubiquitin ligases and other molecular components of the ubiquitin/proteasome system in the control of mitochondrial steps in apoptosis, are discussed. PMID- 22516643 TI - Use of a Real Time PCR for detecting subspecies of Babesia canis. AB - This paper reports the development and use of a Real Time PCR for detection of Babesia canis canis, B. canis rossi, and B. canis vogeli in endemic areas of Brazil. The sequences of the internal transcribed spacer (ITS) of several organisms were aligned and five primers and four probes were designed for amplification of a fragment (around 125 bp) which differentiates subspecies of B. canis. Blood samples collected from dogs living in farms in three distinct rural regions within the State of Minas Gerais (Lavras, Belo Horizonte and Nanuque) were tested. Blood samples had been collected during a dry season (Lavras, n=100; Belo Horizonte, n=50; Nanuque, n=102); the dogs were re-sampled in the subsequent rainy season (Lavras, n=71; Belo Horizonte, n=29; Nanuque, n=66). From each sample, DNA was extracted and Giemsa stained smears were microscopically examined for direct detection of Babesia parasites. B. canis vogeli was the only subspecies found, with an overall prevalence of 9.9% during the dry season and 10.8% during the rainy season. Dogs living in Nanuque and Belo Horizonte showed significantly higher prevalence rates than those living in Lavras (13.7%, 12.0% and 5.0%, respectively). The Real Time PCR developed proved to be appropriate to detect B. canis subspecies in endemic areas. PMID- 22516644 TI - Syringe test (modified larval immersion test): a new bioassay for testing acaricidal activity of plant extracts against Rhipicephalus microplus. AB - We report a new bioassay "syringe test" (modified larval immersion test) for in vitro evaluation of acaricidal activity of crude plant extracts. Prepared syringes, containing eggs of tick, were incubated until 14 d after hatching of eggs, when the bioassay was performed on the larvae. Lethal concentrations for 50% of larvae (LC(50)), LC(90) and LC(99) values were calculated for each tested product. 95% confidence intervals for LC(50) were very narrow, indicating a high degree of repeatability for the new bioassay on larvae of R. microplus. Bioassays were applied to six crude aqueous-methanol extracts from five plants (Acacia nilotica, Buxus papillosa, Fumaria parviflora, Juniperus excelsa, and Operculina turpethum), of which three showed discernible effects. Twenty-four hours post exposure, LC(99) values were 11.9% (w/v) for F. parviflora, 20.8% (w/v) and 29.2% (w/v) for B. papillosa and A. nilotica, respectively. After six days of exposure these values were; 9.1% (w/v), 9.2% (w/v) and 15.5 (w/v) for F. parviflora, A. nilotica and B. papillosa, respectively. PMID- 22516645 TI - Dicer-dependent miRNAs provide an endogenous restraint on cytotrophoblast proliferation. AB - Mature microRNAs (miRNAs) are processed from non-functional (pre)-miRNAs by the enzyme Dicer. In this study, manipulation of Dicer level was used to explore the influence of miRNAs on cytotrophoblast proliferation in human placenta. Immunohistochemistry (IHC) showed Dicer in cytotrophoblast, but not in terminally differentiated syncytiotrophoblast. siRNA-mediated knockdown of Dicer was used to effect a global reduction in miRNA in first trimester placental explants, as a result of which cytotrophoblast proliferation was significantly enhanced. QPCR and IHC analysis following Dicer knockdown revealed that the expression of two nodal pro-mitogenic signalling molecules expressed within cytotrophoblast, ERK and SHP-2, was significantly enhanced. Studies are now required to identify individual miRNAs involved in regulating trophoblast proliferation. PMID- 22516646 TI - Detecting carried objects from sequences of walking pedestrians. AB - This paper proposes a method for detecting objects carried by pedestrians, such as backpacks and suitcases, from video sequences. In common with earlier work [14], [16] on the same problem, the method produces a representation of motion and shape (known as a temporal template) that has some immunity to noise in foreground segmentations and phase of the walking cycle. Our key novelty is for carried objects to be revealed by comparing the temporal templates against view specific exemplars generated offline for unencumbered pedestrians. A likelihood map of protrusions, obtained from this match, is combined in a Markov random field for spatial continuity, from which we obtain a segmentation of carried objects using the MAP solution. We also compare the previously used method of periodicity analysis to distinguish carried objects from other protrusions with using prior probabilities for carried-object locations relative to the silhouette. We have reimplemented the earlier state-of-the-art method [14] and demonstrate a substantial improvement in performance for the new method on the PETS2006 data set. The carried-object detector is also tested on another outdoor data set. Although developed for a specific problem, the method could be applied to the detection of irregularities in appearance for other categories of object that move in a periodic fashion. PMID- 22516647 TI - Intrinsic dimensionality predicts the saliency of natural dynamic scenes. AB - Since visual attention-based computer vision applications have gained popularity, ever more complex, biologically inspired models seem to be needed to predict salient locations (or interest points) in naturalistic scenes. In this paper, we explore how far one can go in predicting eye movements by using only basic signal processing, such as image representations derived from efficient coding principles, and machine learning. To this end, we gradually increase the complexity of a model from simple single-scale saliency maps computed on grayscale videos to spatiotemporal multiscale and multispectral representations. Using a large collection of eye movements on high-resolution videos, supervised learning techniques fine-tune the free parameters whose addition is inevitable with increasing complexity. The proposed model, although very simple, demonstrates significant improvement in predicting salient locations in naturalistic videos over four selected baseline models and two distinct data labeling scenarios. PMID- 22516648 TI - Monocular 3D reconstruction of locally textured surfaces. AB - Most recent approaches to monocular nonrigid 3D shape recovery rely on exploiting point correspondences and work best when the whole surface is well textured. The alternative is to rely on either contours or shading information, which has only been demonstrated in very restrictive settings. Here, we propose a novel approach to monocular deformable shape recovery that can operate under complex lighting and handle partially textured surfaces. At the heart of our algorithm are a learned mapping from intensity patterns to the shape of local surface patches and a principled approach to piecing together the resulting local shape estimates. We validate our approach quantitatively and qualitatively using both synthetic and real data. PMID- 22516649 TI - Prototype-based Domain Description for one-class classification. AB - This work introduces the Prototype-based Domain Description rule (PDD) one-class classifier. PDD is a nearest neighbor-based classifier since it accepts objects on the basis of their nearest neighbor distances in a reference set of objects, also called prototypes. For a suitable choice of the prototype set, the PDD classifier is equivalent to another nearest neighbor-based one-class classifier, namely, the NNDD classifier. Moreover, it generalizes statistical tests for outlier detection. The concept of a PDD consistent subset is introduced, which exploits only a selected subset of the training set. It is shown that computing a minimum size PDD consistent subset is, in general, not approximable within any constant factor. A logarithmic approximation factor algorithm, called the CPDD algorithm, for computing a minimum size PDD consistent subset is then introduced. In order to efficiently manage very large data sets, a variant of the basic rule, called Fast CPDD, is also presented. Experimental results show that the CPDD rule sensibly improves over the CNNDD classifier, namely the condensed variant of NNDD, in terms of size of the subset while guaranteeing a comparable classification quality, that it is competitive over other one-class classification methods and is suitable to classify large data sets. PMID- 22516650 TI - Reading between the lines: object localization using implicit cues from image tags. AB - Current uses of tagged images typically exploit only the most explicit information: the link between the nouns named and the objects present somewhere in the image. We propose to leverage "unspoken" cues that rest within an ordered list of image tags so as to improve object localization. We define three novel implicit features from an image's tags-the relative prominence of each object as signified by its order of mention, the scale constraints implied by unnamed objects, and the loose spatial links hinted at by the proximity of names on the list. By learning a conditional density over the localization parameters (position and scale) given these cues, we show how to improve both accuracy and efficiency when detecting the tagged objects. Furthermore, we show how the localization density can be learned in a semantic space shared by the visual and tag-based features, which makes the technique applicable for detection in untagged input images. We validate our approach on the PASCAL VOC, LabelMe, and Flickr image data sets, and demonstrate its effectiveness relative to both traditional sliding windows as well as a visual context baseline. Our algorithm improves state-of-the-art methods, successfully translating insights about human viewing behavior (such as attention, perceived importance, or gaze) into enhanced object detection. PMID- 22516651 TI - Rhythmic brushstrokes distinguish van Gogh from his contemporaries: findings via automated brushstroke extraction. AB - Art historians have long observed the highly characteristic brushstroke styles of Vincent van Gogh and have relied on discerning these styles for authenticating and dating his works. In our work, we compared van Gogh with his contemporaries by statistically analyzing a massive set of automatically extracted brushstrokes. A novel extraction method is developed by exploiting an integration of edge detection and clustering-based segmentation. Evidence substantiates that van Gogh's brushstrokes are strongly rhythmic. That is, regularly shaped brushstrokes are tightly arranged, creating a repetitive and patterned impression. We also found that the traits that distinguish van Gogh's paintings in different time periods of his development are all different from those distinguishing van Gogh from his peers. This study confirms that the combined brushwork features identified as special to van Gogh are consistently held throughout his French periods of production (1886-1890). PMID- 22516652 TI - Spatiotemporal stereo and scene flow via stequel matching. AB - This paper is concerned with the recovery of temporally coherent estimates of 3D structure and motion of a dynamic scene from a sequence of binocular stereo images. A novel approach is presented based on matching of spatiotemporal quadric elements (stequels) between views, as this primitive encapsulates both spatial and temporal image structure for 3D estimation. Match constraints are developed for bringing stequels into correspondence across binocular views. With correspondence established, temporally coherent disparity estimates are obtained without explicit motion recovery. Further, the matched stequels also will be shown to support direct recovery of scene flow estimates. Extensive algorithmic evaluation with ground truth data incorporated in both local and global correspondence paradigms shows the considerable benefit of using stequels as a matching primitive and its advantages in comparison to alternative methods of enforcing temporal coherence in disparity estimation. Additional experiments document the usefulness of stequel matching for 3D scene flow estimation. PMID- 22516653 TI - Medial spheres for shape approximation. AB - We study the problem of approximating a 3D solid with a union of overlapping spheres. In comparison with a state-of-the-art approach, our method offers more than an order of magnitude speedup and achieves a tighter approximation in terms of volume difference with the original solid while using fewer spheres. The spheres generated by our method are internal and tangent to the solid's boundary, which permits an exact error analysis, fast updates under local feature size preserving deformation, and conservative dilation. We show that our dilated spheres offer superior time and error performance in approximate separation distance tests than the state-of-the-art method for sphere set approximation for the class of (sigma,theta)-fat solids. We envision that our sphere-based approximation will also prove useful for a range of other applications, including shape matching and shape segmentation. PMID- 22516654 TI - Spin probe analysis of microtubules structure and formation. AB - Microtubules (MTs) control cell replication, material transport and motion in eukaryotic cells, but MT role in several pathologies is still unknown. These functions are related to the MT physico-chemical properties and MT formation mode starting from tubulin molecules. This study describes a new method, based on the computer aided analysis of the electron paramagnetic resonance (EPR) spectra of selected spin probes to obtain structural and dynamical information on tubulins and MTs and the kinetics of MTs formation promoted by guanosine-5'-triphosphate (GTP). It was found that tubulin and MTs avoid radical quenching caused by ethylene glycol tetraacetic acid (EGTA). MT formation showed different kinetics as a function of tubulin concentration. At 5 mg/mL of tubulin, MTs were formed in 8 min. These results are also useful for getting information on MT-drug interactions. PMID- 22516655 TI - The reaction mechanisms of heme catalases: an atomistic view by ab initio molecular dynamics. AB - Catalases are ubiquitous enzymes that prevent cell oxidative damage by degrading hydrogen peroxide to water and oxygen (2H(2)O(2) -> 2H(2)O+O(2)) with high efficiency. The enzyme is first oxidized to a high-valent iron intermediate, known as Compound I (Cpd I, Por(.+)-Fe(IV)=O) which, at difference from other hydroperoxidases, is reduced back to the resting state by further reacting with H(2)O(2). The normal catalase activity is reduced if Cpd I is consumed in a competing side reaction, forming a species named Cpd I*. In recent years, Density Functional Theory (DFT) methods have unraveled the electronic configuration of these high-valent iron species, helping to assign the intermediates trapped in the crystal structures of oxidized catalases. It has been demonstrated that the a priori assumption that the H(+)/H(-) type of mechanism for Cpd I reduction leads to the generation of singlet oxygen is not justified. Moreover, it has been shown by ab initio metadynamics simulations that two pathways are operative for Cpd I reduction: a His-mediated mechanism (described as H./H(+) + e(-)) in which the distal His acts as an acid-base catalyst and a direct mechanism (described as H./H.) in which the distal His does not play a direct role. Independently of the mechanism, the reaction proceeds by two one-electron transfers rather than one two-electron transfer, as previously assumed. Electron transfer to Cpd I, regardless of whether the electron is exogenous or endogenous, facilitates protonation of the oxoferryl group, to the point that formation of Cpd I* may be controlled by the easiness of protonation of reduced Cpd I. PMID- 22516656 TI - Structural and immunological characterization of Amadori-rich human serum albumin: role in diabetes mellitus. AB - Proteins modifications in diabetes may lead to early glycation products (EGPs) as well as advanced glycation end products (AGEs). Whereas no extensive studies have been carried out to assess the role of EGPs in secondary complications of diabetes, numerous investigators have demonstrated the role of AGEs. Early glycation involves attachment of glucose on epsilon-NH2 of lysine residues of proteins leading to generation of the Amadori product (an early glycation species). This study reports the structural and immunological characterization of EGPs of HSA because we believe that during persistent hyperglycemia the HSA, one of the major blood proteins, can undergo fast glycation. Glucose mediated generation of EGPs of HSA was quantitated as Amadori products by NBT assay and authenticated by boronate affinity chromatography and LC/MS. Compared to native HSA changes in glycated-HSA were characterized by hyperchromicity, loss in fluorescence intensity and a new peak in the FTIR profile. Immunogenicity of native- and glycated-HSA was evaluated by inducing antibodies in rabbits. Results suggest generation of neo-epitopes on glycated-HSA rendering it highly immunogenic compared to native HSA. Quantization of EGPs of HSA by authentic antibodies against HSA-EGPs can be used as marker for early detection of the initiation/progression of secondary complications of diabetes. PMID- 22516657 TI - Direct intracellular selection and biochemical characterization of a recombinant anti-proNGF single chain antibody fragment. AB - proNGF, the precursor of the neurotrophin NGF, is widely expressed in central and peripheral nervous system. Its physiological functions are still largely unknown, although it emerged from studies in the last decade that proNGF has additional and distinct functions with respect to NGF, besides acting chaperone-like for NGF folding during its biogenesis. The regulation of proNGF/NGF ratio represents a crucial process for homeostasis of brain and other tissues, and understanding the molecular aspects of these differences is important. We report the selection and characterization of a recombinant monoclonal anti-proNGF antibody in single chain Fv fragment (scFv) format. The selection exploited the Intracellular Antibody Capture Technology (IACT), starting from a naive mouse SPLINT (Single Pot Library of INTracellular antibodies) library. This antibody (scFv FPro10) was expressed recombinantly in Escherichia coli, was proven to be highly soluble and stable, and thoroughly characterized from the biochemical-biophysical point of view. scFv FPro10 displays high affinity and specificity for proNGF, showing no cross reactivity with other pro-neurotrophins. A structural model was obtained by SAXS. scFv FPro10 represents a new tool to be exploited for the selective immunoanalysis of proNGF, both in vitro and in vivo, and might help in understanding the molecular function of proNGF in neurodegeneration. PMID- 22516658 TI - High-speed multiresolution scanning probe microscopy based on Lissajous scan trajectories. AB - A novel scan trajectory for high-speed scanning probe microscopy is presented in which the probe follows a two-dimensional Lissajous pattern. The Lissajous pattern is generated by actuating the scanner with two single-tone harmonic waveforms of constant frequency and amplitude. Owing to the extremely narrow frequency spectrum, high imaging speeds can be achieved without exciting the unwanted resonant modes of the scanner and without increasing the sensitivity of the feedback loop to the measurement noise. The trajectory also enables rapid multiresolution imaging, providing a preview of the scanned area in a fraction of the overall scan time. We present a procedure for tuning the spatial and the temporal resolution of Lissajous trajectories and show experimental results obtained on a custom-built atomic force microscope (AFM). Real-time AFM imaging with a frame rate of 1 frame s-1 is demonstrated. PMID- 22516659 TI - A novel approach to the treatment of lower extremity lymphedema by transferring a vascularized submental lymph node flap to the ankle. AB - OBJECTIVE: Vascularized groin lymph node flaps have been successfully transferred to the wrist to treat postmastecomy upper limb lymphedema. This study investigated the anatomy, mechanism and outcome of a novel vascularized submental lymph node (VSLN) flap transfer for the treatment of lower limb lymphedema. METHODS: Bilateral regional submental flaps were dissected from three fresh adult cadavers for histological study. A unilateral submental flap was dissected in another six fresh cadavers after latex injection. The VSLN flap was transferred to the ankles of seven lower extremities in six patients with chronic lower extremity lymphedema. The mean patient age was 61 +/- 9.4 years. The average duration of lymphedema symptoms was 71 +/- 42.2 months. RESULTS: There was a mean of 3.3 +/- 1.5 lymph nodes around the submental artery typically at the junction with the facial artery, on the six cadaveric histological sections. Mean of 2.3 +/- 0.8 sizable lymph nodes were dissected and supplied by the submental artery in six cadaveric latex-injected submental flaps. All seven VSLN flaps survived. One flap required re-exploration for venous congestion but was successfully salvaged. There was no donor site morbidity. At a mean follow-up of 8.7 +/- 4.2 months, the mean reduction of the leg circumference was 64 +/- 11.5% above the knee, 63.7 +/- 34.3% below the knee and 67.3 +/- 19.2% above the ankle. CONCLUSION: The transfer of a vascularized submental lymph node flap to the ankle is a novel approach for the effective treatment of lower extremity lymphedema. PMID- 22516660 TI - Long-term sexual function in survivors of vulvar cancer: a cross-sectional study. AB - OBJECTIVES: To assess sexual function of vulvar cancer survivors who received extensive and less extensive treatment. To explore associations between sexual function and patient, disease, treatment, and psychological variables. METHODS: Sexual function (Female Sexual Function Index, FSFI), mental and physical well being (SF36 Health Survey), body image (Body Image Scale), and optimism (Life Orientation Test) were assessed in vulvar cancer survivors treated in the period January 1997-January 2007. Demographic, disease and treatment characteristics were collected from medical files. Radical local excision with inguinal lymph node dissection and radical vulvectomy were considered extensive treatments; radical local excision, with or without sentinel node dissection, was considered less extensive treatment. Univariate and multivariate linear regression analyses were performed. RESULTS: Of 120 eligible patients, 76 (63%) responded. Eighteen women with a male partner (43%) reported having sexual intercourse. FSFI domain scores did not differ between extensively and less extensively treated women. Age was negatively associated with "Arousal" and "Desire", having a partner was positively associated with "Satisfaction", and optimism and physical well-being were positively associated with "Desire" and "Orgasm". Adjuvant inguinal radiotherapy was negatively associated with "Orgasm". One woman reported having better sexual function after than before treatment, 50% reported a similar sexual function, and 42% a worse sexual function. CONCLUSIONS: 43% of women who survived vulvar cancer and who had a male partner were sexually active. Treatment-related variables had a limited influence on long-term sexual function in these patients. Having a partner, good physical well-being, and being optimistic were positively associated with sexual function. PMID- 22516661 TI - A model for prediction of parametrial involvement and feasibility of less radical resection of parametrium in patients with FIGO stage IB1 cervical cancer. AB - OBJECTIVE: The objective of this study was to evaluate the potential risk factors associated with parametrial invasion and to identify preoperatively a subgroup of patients at low risk for parametrial involvement who could be appropriate candidates for less radical surgery in FIGO stage IB1 cervical cancer. METHODS: We retrospectively reviewed the medical records of 317 FIGO stage IB1 cervical cancer patients undergoing class III radical hysterectomy and bilateral pelvic lymphadenectomy. Clinocopathologic factors associated with parametrial invasion were analyzed and the risk criteria predicting parametrial involvement were calculated using a logistic regression model. RESULTS: Of 317 patients, 17 patients (5.4%) had parametrial involvement. Tumor size >3 cm (OR, 3.80; [95% CI, 1.19-12.06]; p=0.02) and pelvic lymph node metastasis (OR, 3.02; [95% CI, 1.04 8.79]; p=0.04) were independent pathologic factors for parametrial invasion on multivariate analysis. Significant preoperative factors associated with parametrial involvement were tumor size >3 cm (OR, 4.29; [95% CI, 1.43-12.89]; p<0.01) and serum SCC Ag level >1.40 ng/mL (OR, 3.27; [95% CI, 1.11-9.69]; p=0.03). We identified 185 low-risk (tumor size <= 3 cm and SCC <= 1.4 ng/mL) and 132 high-risk (tumor size>3 cm and/or SCC>1.4 ng/mL) patients. The rates of parametrial involvement in low- and high-risk patients were 1.1% and 11.4%, respectively (p<0.01). CONCLUSIONS: In this dataset, a model using tumor size and SCC Ag level is highly predictive of parametrial involvement in patients with stage IB1 cervical cancer and may identify candidates for less radical parametrial resection. PMID- 22516665 TI - Evaluation of hands-on training in colonoscopy: is a computer-based simulator useful? AB - BACKGROUND AND AIMS: The advantages of using a computer-based simulator during colonoscopy training are debated. We aimed to explore its usefulness in objectively measuring trainees' competence in colonoscopy. METHODS: Twelve colonoscopy trainees (fully trained in upper GI endoscopy) were evaluated using a computer-based simulator (GI-Mentor, Symbionix) before and during hands-on training (i.e. after 60 colonoscopies); the controls were 15 experts (>90% of caecal intubation). Both trainees and experts performed two "screening" simulations (easy and difficult) in a randomised order, and the time to reach the caecum and withdrawal time was assessed. RESULTS: The percentage of caecal intubation progressively increased during hands-on training. All of the trainees intubated the caecum during the easy and difficult simulations, both before and during hands-on training. The median time (interquartile range) to reach the caecum upon easy simulation was the only variable influenced by hands-on training: 2.7 min (2.1-3.2) before and 1.9 min (1.6-2) during training (p<0.01). Withdrawal time was >=6 min in the case of five trainees before training, and three during hands-on training. Computer-based simulator performance did not correlate with hands-on training performance. CONCLUSIONS: The computer-based simulator was not found to be useful in evaluating competence during hands-on training in colonoscopy. PMID- 22516664 TI - Identification of a circuit-based endophenotype for familial depression. AB - Frontal and parietal lesions may cause depression, and cortical thinning of the right frontal and parietal lobes has been shown to be a marker of risk for familial major depression. We studied biological offspring within a three generation cohort, in which risk was defined by the depression status of the first generation, to identify regional volume differences associated with risk for depression throughout the cerebrum. We found reduced frontal and parietal white matter volumes in the high-risk group, including in persons without any personal history of depression, suggesting that hypoplasia of frontal and parietal white matter is an endophenotype for familial depression. In addition, white matter volumes in these regions correlated with current severity of symptoms of depression, inattention, and impulsivity. White matter volumes also correlated strongly with the degree of thinning in the right parietal cortex. These findings support a model of pathogenesis in which hypoplasia within a neural network for attention and emotional processing predisposes to depression. PMID- 22516666 TI - Evaluation of the effects of venlafaxine and pregabalin on the carbon dioxide inhalation models of Generalised Anxiety Disorder and panic. AB - Previous studies have shown that subjective and objective symptoms of anxiety induced by 7.5% CO(2) inhalation can be attenuated by anxiolytics such as lorazepam and, to a lesser extent, paroxetine. Venlafaxine and pregabalin, two other licensed treatments for Generalised Anxiety Disorder, were used to further investigate the 7.5% and 35% CO(2) models of anxiety in healthy volunteers. Fifty four participants were randomised to receive either placebo, venlafaxine or pregabalin. Study treatments were dosed incrementally over a three week period, to reach daily doses of 150 mg venlafaxine and 200mg pregabalin by the CO(2) challenge test day. Participants inhaled air 7.5% CO(2) for 20 minutes (single blind presentation), and a non-blinded single vital capacity of 35% CO(2). Subjective ratings were recorded before and after each inhalation. Both 7.5% and 35% CO(2) inhalations produced the expected effects of increased ratings of symptoms of panic and anxiety, with increased blood pressure and heart rate. No significant treatment effects were found, although there were trends towards a reduction in feeling tense and nervous by both drugs compared with placebo during the 7.5% CO(2) challenge, and a reduction in alertness generally in the venlafaxine group compared with the pregabalin group. In contrast with the clear anxiolytic effects of benzodiazepines reported in several previous CO(2) studies, these findings suggest that the anxiogenic effects of CO(2) challenges are not significantly influenced by these serotonergic and GABAergic anxiolytics. This may be due to a lack of sensitivity of the CO(2) challenges in healthy volunteers to these drug types. PMID- 22516667 TI - Cannabinoid exposure in adolescent female rats induces transgenerational effects on morphine conditioned place preference in male offspring. AB - In the United States, marijuana is one of the drugs most abused by adolescents, with females representing a growing number of users. In previous studies, treatment of adolescent female rats with morphine significantly altered brain reward systems in future offspring. As both cannabinoid and opioid systems develop during adolescence, it was hypothesized that early exposure to cannabinoids would induce similar transgenerational effects. In the current study, female rats were treated with the cannabinoid receptor (CB1/CB2) agonist WIN 55,212-2 or its vehicle for three consecutive days during adolescent development (30 days of age), and were subsequently mated in adulthood (60 days of age). The adolescent and adult male offspring of these WIN 55,212-2 (WIN-F1)- or vehicle (VEH-F1)-treated females were tested for their response to morphine using the conditioned place preference (CPP) paradigm. Both adolescent and adult WIN-F1offspring exhibited greater sensitivity to morphine CPP than their VEH-F1 counterparts. Collectively, the findings provide additional evidence of transgenerational effects of adolescent drug use. PMID- 22516669 TI - The Bayesian brain: phantom percepts resolve sensory uncertainty. AB - Phantom perceptions arise almost universally in people who sustain sensory deafferentation, and in multiple sensory domains. The question arises 'why' the brain creates these false percepts in the absence of an external stimulus? The model proposed answers this question by stating that our brain works in a Bayesian way, and that its main function is to reduce environmental uncertainty, based on the free-energy principle, which has been proposed as a universal principle governing adaptive brain function and structure. The Bayesian brain can be conceptualized as a probability machine that constantly makes predictions about the world and then updates them based on what it receives from the senses. The free-energy principle states that the brain must minimize its Shannonian free energy, i.e. must reduce by the process of perception its uncertainty (its prediction errors) about its environment. As completely predictable stimuli do not reduce uncertainty, they are not worthwhile of conscious processing. Unpredictable things on the other hand are not to be ignored, because it is crucial to experience them to update our understanding of the environment. Deafferentation leads to topographically restricted prediction errors based on temporal or spatial incongruity. This leads to an increase in topographically restricted uncertainty, which should be adaptively addressed by plastic repair mechanisms in the respective sensory cortex or via (para)hippocampal involvement. Neuroanatomically, filling in as a compensation for missing information also activates the anterior cingulate and insula, areas also involved in salience, stress and essential for stimulus detection. Associated with sensory cortex hyperactivity and decreased inhibition or map plasticity this will result in the perception of the false information created by the deafferented sensory areas, as a way to reduce increased topographically restricted uncertainty associated with the deafferentation. In conclusion, the Bayesian updating of knowledge via active sensory exploration of the environment, driven by the Shannonian free-energy principle, provides an explanation for the generation of phantom percepts, as a way to reduce uncertainty, to make sense of the world. PMID- 22516670 TI - A comparative study of HRCT image metrics and PFT values for characterization of ILD and COPD. AB - RATIONALE AND OBJECTIVES: The aim of this study was to compare the performance of various image-based metrics computed from thoracic high-resolution computed tomography (HRCT) with data from pulmonary function testing (PFT) in characterizing interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: Fourteen patients with ILD and 11 with COPD had undergone both PFT and HRCT within 3 days. For each patient, 93 image based metrics were computed, and their relationships with the 21 clinically used PFT parameters were analyzed using a minimal-redundancy-maximal-relevance statistical framework. The first 20 features were selected among the total of 114 mixed image metrics and PFT values in the characterization of ILD and COPD. RESULTS: Among the best-performing 20 features, 14 were image metrics, derived from attenuation histograms and texture descriptions. The highest relevance value computed from PFT parameters was 0.47, and the highest from image metrics was 0.52, given the theoretical bound as [0, 0.69]. The ILD or COPD classifier using the first four features achieved a 1.92% error rate. CONCLUSIONS: Some image metrics are not only as good discriminators as PFT for the characterization of ILD and COPD but are also not redundant when PFT values are provided. Image metrics of attenuation histogram statistics and texture descriptions may be valuable for further investigation in computer-assisted diagnosis. PMID- 22516668 TI - Choice of randomization to clozapine versus other second generation antipsychotics in the CATIE schizophrenia trial. AB - There is evidence to suggest that clozapine is underutilized in treatment refractory schizophrenia. Data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), a multi-phase, randomized comparative effectiveness trial for schizophrenia, were used to identify factors associated with choosing randomization to clozapine. Two pathways were available in phase 2 of CATIE: randomization to clozapine or an untried atypical antipsychotic (2E), or randomization to an untried atypical antipsychotic (2T). We examined the proportion of entrants who chose to enter phase 2E due to the lack of efficacy of the phase 1 treatment, along with their demographic and clinical characteristics. Only 31.2% who discontinued phase 1 for lack of efficacy entered phase 2E. In multivariable analysis, males showed significantly increased odds of choosing phase 2E (adjusted odds ratio (AOR) = 2.38; confidence interval (CI) = 1.20, 4.70) as did patients with higher Positive and Negative Syndrome Scale total scores (AOR = 1.01; CI = 1.00, 1.03), more inpatient days (AOR = 1.06; CI = 1.02, 1.10) and more outpatient visits, (AOR = 1.06; CI = 1.02, 1.11). More effort examining the decision-making process of patients and providers is needed in order to increase the utilization of this effective treatment. PMID- 22516671 TI - Hepatitis C RNA-dependent RNA polymerase inhibitors: a review of structure activity and resistance relationships; different scaffolds and mutations. AB - Hepatitis C virus (HCV), like many other flaviviruses, is widely distributed worldwide with estimated chronically infected victims between 170 and 200 million. HCV inherent error-prone RNA-dependent RNA polymerase (RdRp) is an attractive target for medicinal chemists because of the conservative nature of NS5B nucleotide-binding site. In addition, the availability of several crystal structures for HCV RdRp paved the road for conducting rational-based drug design. At the same time, RdRp is responsible for high mutation rate and rapid development of resistance to the clinically-used therapeutics. To improve the viral response, combination therapy is regularly used. The success of co-therapy disciplines depends on targeting two different active sites. This review provides an overview about different scaffolds that target HCV RdPp with insights about their binding modes and possible induced mutant strains. PMID- 22516672 TI - Synthesis, biological evaluation and molecular modeling study of pyrazole and pyrazoline derivatives as selective COX-2 inhibitors and anti-inflammatory agents. Part 2. AB - New pyrazole and pyrazoline derivatives have been synthesized and their ability to inhibit ovine COX-1/COX-2 isozymes was evaluated using in vitro cyclooxygenase (COX) inhibition assay. Among the tested compounds, N-((5-(4-chlorophenyl)-1 phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methylene)-3,5 bis(trifluoromethyl)aniline 8d exhibit optimal COX-2 inhibitory potency (IC(50)=0.26 lM) and selectivity (SI)=>192.3] comparable with reference drug celecoxib (IC(50) value of 0.28 lM and selectivity index of 178.57). Moreover, the anti-inflammatory activity of selected compounds, which are the most selective COX-2 inhibitors in the COX inhibition assay, was investigated in vivo using carrageenan-induced rat paw edema model. Molecular modeling was conducted to study the ability of the active compounds to bind into the active site of COX 2 which revealed a similar binding mode to SC-558, a selective COX-2 inhibitor. PMID- 22516673 TI - Impact of copper exposure on Pseudo-nitzschia spp. physiology and domoic acid production. AB - Microalgae have differing sensitivities to copper toxicity. Some species within the genus Pseudo-nitzschia produce domoic acid (DA), a phycotoxin that has been hypothesised to chelate Cu and ameliorate Cu toxicity to the cells. To better characterise the effect of Cu on Pseudo-nitzschia, a toxic strain of P. multiseries and a non-toxic strain of P. delicatissima were exposed to Cu(II) for 96 h (50 MUg l(-1) for P. delicatissima and 50, 100 and 150 MUg l(-1) for P. multiseries). Physiological measurements were performed daily on Pseudo-nitzschia cells using fluorescent probes and flow cytometry to determine the cell density, lipid concentration, chlorophyll autofluorescence, esterase activity, percentage of dead algal cells, and number of living and dead bacteria. Photosynthetic efficiency and O(2) consumption and production of cells were also measured using pulse amplitude modulated fluorometry and SDR Oxygen Sensor dish. The DA content was measured using ELISA kits. After 48 h of Cu exposure, P. delicatissima mortality increased dramatically whereas P. multiseries survival was unchanged (in comparison to control cells). Cellular esterase activity, chlorophyll autofluorescence, and lipid content significantly increased upon Cu exposure in comparison to control cells (24h for P. delicatissima, up to 96 h for P. multiseries). Bacterial concentrations in P. multiseries decreased significantly when exposed to Cu, whereas bacterial concentrations were similar between control and exposed populations of P. delicatissima. DA concentrations in P. multiseries were not modified by Cu exposure. Addition of DA to non-toxic P. delicatissima did not enhance cells survival; hence, extracellular DA does not protect Pseudo nitzschia spp. against copper toxicity. Results suggested that cells of P. delicatissima are much more sensitive to Cu than P. multiseries. This difference is probably not related to the ability of P. multiseries to produce DA but could be explained by species differences in copper sensitivity, or a difference of bacterial community between the algal species. PMID- 22516674 TI - Haematological and ion regulatory effects of nitrite in the air-breathing snakehead fish Channa striata. AB - The tolerance and effects of nitrite on ion balance and haematology were investigated in the striped snakehead, Channa striata Bloch 1793, which is an air breathing fish with reduced gills of importance for aquaculture in South East Asia. C. striata was nitrite tolerant with a 96 h LC50 of 4.7 mM. Effects of sub lethal exposures to nitrite (0mM, 1.4mM, and 3.0mM) were determined during a 7 day exposure period. Plasma nitrite increased, but the internal concentration remained well below ambient levels. Extracellular nitrate rose by several mM, indicating that a large proportion of the nitrite taken up was converted to nitrate. Nitrite reacted with erythrocyte haemoglobin (Hb) causing methaemoglobin (metHb) to increase to 30% and nitrosylhaemoglobin (HbNO) to increase to 10% of total Hb. Both metHb and HbNO stabilised after 4 days, and functional Hb levels accordingly never fell below 60% of total Hb. Haematocrit and total Hb were unaffected by nitrite. Although the effects of nitrite exposure seemed minor in terms of plasma nitrite and metHb increases, ion balance was strongly affected. In the high exposure group, total osmolality decreased from 320 mOsm to 260 mOsm, and plasma sodium from 150 mM to 120 mM, while plasma chloride fell from 105 mM to 60mM and plasma bicarbonate rose from 12 mM in controls to 20mM in exposed fish. The extreme changes in ion balance in C. striata are different from the response reported in other fish, and further studies are needed to investigate the mechanism behind the observed changes in regulation. PMID- 22516675 TI - Effects of a triazole fungicide and a pyrethroid insecticide on the decomposition of leaves in the presence or absence of macroinvertebrate shredders. AB - Previously, laboratory experiments have revealed that freely diluted azole fungicides potentiate the direct toxic effect of pyrethroid insecticides on Daphnia magna. More ecologically relevant exposure scenarios where pesticides are adsorbed have not been addressed. In this study we exposed beech leaves (Fagus sylvatica) to the azole fungicide propiconazole (50 or 500 MUg L(-1)), the pyrethroid insecticide alpha-cypermethrin (0.1 or 1 MUg L(-1)) or any combination of the two for 3h. Exposed leaves were transferred to aquaria with or without an assemblage of macroinvertebrate shredders, and we studied treatment effects on rates of microbial leaf decomposition, microbial biomass (using C:N ratio as a surrogate measure) and macroinvertebrate shredding activity during 26 days post exposure. Microbial leaf decomposition rates were significantly reduced in the propiconazole treatments, and the reduction in microbial activity was significantly correlated with loss of microbial biomass (increased C:N ratio). Macroinvertebrate shredding activity was significantly reduced in the alpha cypermethrin treatments. In addition, the macroinvertebrate assemblage responded to the propiconazole treatments by increasing their consumption of leaf litter with lower microbial biomass, probably to compensate for the reduced nutritional quality of this leaf litter. We found no interaction between the two pesticides on macroinvertebrate shredding activity, using Independent Action as a reference model. In terms of microbial leaf decomposition rates, however, alpha cypermethrin acted as an antagonist on propiconazole. Based on these results we emphasise the importance of considering indirect effects of pesticides in the risk assessment of surface water ecosystems. PMID- 22516676 TI - The role of the breast cancer surgeon in personalized cancer care: clinical utility of the 21-gene assay. AB - BACKGROUND: Breast cancer surgeons represent the first line of defense for many patients battling this disease. They often have the first contact to discuss treatment options with the patient after diagnosis. However, the potential impact of this consultation has evolved with the arrival of commercialized multigene prognostic and predictive tests that continue to reshape the landscape of breast cancer management, including modern surgical practice. METHOD: This review was compiled from peer-reviewed literature indexed in PubMed. CONCLUSIONS: The advent of genomic analysis has advanced the treatment and management of breast cancer toward the goal of personalized care. Therefore, the role of the surgeon now extends beyond extirpation of the tumor and includes an understanding of the biology of the disease as well as an appreciation of this new technology. Breast cancer surgeons should seize this opportunity to provide patients and colleagues with this information in an expeditious manner to optimize clinical outcomes. PMID- 22516677 TI - Real-time CartoSound imaging of the esophagus: a comparison to computed tomography. PMID- 22516678 TI - Late onset of coronary vasospasm after administration of methyl-ergometrine for gynecologic bleeding. PMID- 22516679 TI - Structural elucidation of impurities in 5-n-butyl-4-{4-[2-(1H-tetrazole-5-yl)-1H pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6-dichlorophenyl)-3H-1,2,4-triazol-3 one (Ib), a novel nonpeptide angiotensin AT1 receptor antagonist. AB - 5-n-butyl-4-{4-[2-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2 (2,6-dichlorophenyl)-3H-1,2,4-triazol-3-one (Ib), a new nonpeptide angiotensin AT1-receptor antagonist, has been observed to play a positive role in the treatment of hypertension in preclinical tests. Four process impurities of Ib were detected by LC-UV and LC/ESI-MS, and the impurities isolated by preparative HPLC chromatography were characterized by LC-MS/MS, high resolution MS (HRMS), NMR and IR analyses. The structures of impurities were confirmed as 5-n-butyl-4 {4-[2-chloro-5-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2 (2,6-dichlorophenyl)-3H-1,2,4-triazol-3-one (I), 5-n-butyl-4-{4-[2-bromo-5-(1H tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6-dichlorophenyl) 3H-1,2,4-triazol-3-one (II), 5-n-butyl-4-{4-[4-chloro-2-(1H-tetrazole-5-yl)-1H pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6-dichlorophenyl)-3H-1,2,4-triazol-3 one (III) and 5-n-butyl-4-{4-[4-bromo-2-(1H-tetrazole-5-yl)-1H-pyrrol-1 yl]phenylmethyl}-2,4-dihydro-2-(2,6-dichlorophenyl)-3H-1,2,4-triazol-3-one (IV), respectively. All of the four impurities were produced as the by-products of the bromination reaction by NBS (N-bromosuccinimide) in the synthesis of Ib. PMID- 22516680 TI - Development and validation of an HPLC/UV assay for separation and quantification of peptide antigens from a liposomal vaccine delivery platform. AB - The development and validation of an HPLC method for the quantification of eight peptide antigens from the therapeutic cancer vaccine DPX-0907 is described. The antigens were formulated in DepoVaxTM, a patented liposomal vaccine delivery platform used in a phase 1 study for breast, ovarian, and prostate cancers. A gradient reversed-phase method with UV detection was optimized for separating and quantifying the peptide mixture. Several extraction methods investigated to extract the peptides from the lipids led to poor recovery of one or more of the peptides. A simple, reproducible, and high-recovery extraction procedure for the simultaneous quantification of hydrophilic and hydrophobic peptides was discovered using a liquid-liquid extraction with water-saturated n-butanol and sodium bicarbonate (0.1 M). The method was found to be specific, linear, accurate, precise, and reliable within the range of 50-150% of the nominal concentration for DPX-0907. The validated method was successfully applied to the assay of peptide content in pre-clinical and clinical batches of DPX-0907. PMID- 22516681 TI - Development of a monoclonal antibody-based ELISA for the hedgehog inhibitors cyclopamine and KAAD-cyclopamine. AB - Cyclopamine (1) was isolated from the plant Veratrum californicum Durand (Liliacea) and identified as the teratogen responsible for severe craniofacial birth defects including cyclops in the offspring of sheep grazing on mountain ranges in central Idaho. More recently, cyclopamine (1) was found to inhibit the hedgehog (Hh) signaling pathway which plays a critical role in embryonic development and is implicated in several types of cancer. Thus, cyclopamine (1) and cyclopamine derivatives have been targeted as potential pharmaceutical treatments for certain cancers and other diseases associated with the Hh signaling pathway. A monoclonal antibody-based competitive inhibition enzyme linked immunosorbent assay was developed to detect and measure cyclopamine (1) and cyclopamine derivatives in biological samples. The limits of detection of the assay for cyclopamine (1), 3-keto-N-aminoethyl aminocaproyl digyrocinnamoyl cyclopamine (8), and N-(4-l-rhamnopyranosyl-1H-1,2,3-triazol-1-yl) methylcyclopamine (11) were 2.9 pg, 0.41 pg and 2.6 pg, respectively. This assay was also found to be useful for the detection and measurement of cyclopamine (1) in sera from mice that had been dosed with cyclopamine (1). The simple ELISA method described herein demonstrates the potential of using these techniques for the rapid screening of biological samples for the presence and levels of cyclopamine (1) and other cyclopamine derivatives that are Hh inhibitors with anticancer potential. PMID- 22516682 TI - Effect of theophylline on prevention of contrast-induced acute kidney injury: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Whether treatment with adenosine receptor antagonists such as theophylline can prevent contrast-induced acute kidney injury (AKI) remains controversial. STUDY DESIGN: We conducted a meta-analysis of randomized controlled trials using MEDLINE (1966 to July 2011), EMBASE (1980 to July 2011), Web of Science (1986 to July 2011), and the Cochrane Central Register of Controlled Trials (1996 to July 2011), without language restriction. SETTING & POPULATION: Patients undergoing contrast procedures. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials assessing adenosine antagonists versus control for prevention of contrast-induced AKI. INTERVENTION: Adenosine antagonists with or without N-acetylcysteine versus control with or without N acetylcysteine. OUTCOMES: Contrast-induced AKI, change in serum creatinine level, requirement of dialysis, and in-hospital mortality. RESULTS: 16 trials (1,412 participants) were included. Theophylline significantly decreased the risk of contrast-induced AKI (13 trials, 1,222 patients; risk ratio, 0.48; 95% CI, 0.26 0.89; P = 0.02; I(2) = 45%) and had a protective effect on the absolute change in serum creatinine concentration (13 trials, 1,170 patients; standardized mean difference, -0.31 mg/dL; 95% CI, -0.50 to -0.11; P = 0.002; I(2) = 60%). Meta regression showed a significant relation between the relative risk of contrast nephropathy and baseline serum creatinine level or Jadad score. No clear effects of treatment on risk of dialysis and in-hospital mortality were identified. LIMITATIONS: Power to assess clinical end points was limited. CONCLUSIONS: Theophylline treatment significantly reduced the incidence of contrast-induced AKI and had a modest improvement on kidney function after contrast exposure in the general population. However, beneficial effects of theophylline were not observed in patients with high baseline creatinine values (serum creatinine >=1.5 mg/dL). In addition, the long-term effect of this agent on more clinically important outcomes was not established. Future large-scale high-quality multicenter trials in participants with different underlying risks of contrast induced AKI and that incorporate the evaluation of clinically relevant outcomes are required. PMID- 22516683 TI - Membranous nephropathy with renal salt wasting: role of neurohumoral factors in sodium retention. AB - The role of neurohumoral factors in the sodium retention of nephrotic syndrome is controversial. We report a case with abrupt onset of severe nephrotic-range proteinuria and hypoalbuminemia due to membranous glomerulonephritis that was associated with renal salt wasting and hypovolemia without edema. Further evaluation showed hypoaldosteronism, hyporeninemia, and primary autonomic failure principally affecting the sympathetic nervous system, determined by the Valsalva maneuver. Administration of exogenous mineralocorticoid and oral salt caused edema and accelerated hypertension. The severe hypoaldosteronism likely was due to use of the angiotensin-converting enzyme inhibitor lisinopril, and it improved after this drug treatment was discontinued. The nephrotic proteinuria resolved after treatment with cyclosporine and prednisone, but the primary autonomic failure with hyporeninemic hypoaldosteronism persisted. The case shows that intratubular factors activated by nephrotic proteinuria are not sufficient to produce sodium retention in the absence of aldosterone and an intact sympathetic nervous system. PMID- 22516684 TI - Excess of melanocytic nevi in a patient treated with natalizumab for multiple sclerosis. PMID- 22516685 TI - Food deprivation induces chronic stress and affects thyroid hormone metabolism in Senegalese sole (Solea senegalensis) post-larvae. AB - In vertebrates, stress and thyroid systems interact closely, most likely because of the involvement of both systems in energy metabolism. However, studies on these interactions, especially during larval development, are scarce. Recently, cDNAs coding for corticotropin-releasing hormone (CRH) and CRH-binding protein (CRH-BP), two key players in the regulation of the neuroendocrine stress response, were characterized for the flatfish Senegalese sole (Solea senegalensis). To investigate the involvement of stress and thyroid systems in this species, the effects of food deprivation during early development of S. senegalensis were assessed. Growth was arrested in food-deprived post-larvae, which was also reflected by decreased carbon and nitrogen contents, indicating increased catabolism. Food deprivation induces chronic stress, as illustrated by enhanced whole-body cortisol levels, as well as an up regulation of crh and a decrease of crh-bp expression levels. Furthermore, whole-body total T3 concentrations of food-deprived post-larvae were reduced, although tshbeta subunit expression levels remained unaffected. Our results show that food deprivation is a chronic stressor that induces energy-releasing catabolic processes that compensate for the reduced energy intake, and inhibits anabolic processes via the peripheral thyroid system. PMID- 22516686 TI - Product-controlled steady-state kinetics between cytochrome aa(3) from Rhodobacter sphaeroides and equine ferrocytochrome c analyzed by a novel spectrophotometric approach. AB - Cytochrome c oxidase (CcO) catalyzes the reduction of molecular oxygen to water using ferrocytochrome c (cyt c(2+)) as the electron donor. In this study, the oxidation of horse cyt c(2+) by CcO from Rhodobacter sphaeroides, was monitored using stopped-flow spectrophotometry. A novel analytic procedure was applied in which the spectra were deconvoluted into the reduced and oxidized forms of cyt c by a least-squares fitting method, yielding the reaction rates at various concentrations of cyt c(2+) and cyt c(3+). This allowed an analysis of the effects of cyt c(3+) on the steady-state kinetics between CcO and cyt c(2+). The results show that cyt c(3+) exhibits product inhibition by two mechanisms: competition with cyt c(2+) at the catalytic site and, in addition, an interaction at a second site which further modulates the reaction of cyt c(2+) at the catalytic site. These results are generally consistent with previous reports, indicating the reliability of the new procedure. We also find that a 6*His-tag at the C-terminus of the subunit II of CcO affects the binding of cyt c at both sites. The approach presented here should be generally useful in spectrophotometric studies of complex enzyme kinetics. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012). PMID- 22516687 TI - Anionic lipids in Ca(2+)-triggered fusion. AB - Anionic lipids are native membrane components that have a profound impact on many cellular processes, including regulated exocytosis. Nonetheless, the full nature of their contribution to the fast, Ca(2+)-triggered fusion pathway remains poorly defined. Here we utilize the tightly coupled quantitative molecular and functional analyses enabled by the cortical vesicle model system to elucidate the roles of specific anionic lipids in the docking, priming and fusion steps of regulated release. Studies with cholesterol sulfate established that effectively localized anionic lipids could contribute to Ca(2+)-sensing and even bind Ca(2+) directly as effectors of necessary membrane rearrangements. The data thus support a role for phosphatidylserine in Ca(2+) sensing. In contrast, phosphatidylinositol would appear to serve regulatory functions in the physiological fusion machine, contributing to priming and thus the modulation and tuning of the fusion process. We note the complexities associated with establishing the specific roles of (anionic) lipids in the native fusion mechanism, including their localization and interactions with other critical components that also remain to be more clearly and quantitatively defined. PMID- 22516688 TI - Postabortion contraceptive use and method continuation in India. AB - OBJECTIVE: To investigate the patterns and determinants of postabortion contraceptive use and the rates of method continuation in India. METHODS: Population-level retrospective calendar data on 5135 married women who had their last abortion during the 60 months preceding the survey were drawn from 2005-2006 Indian National Family Health Surveys. Multinomial logistic regression was used to model the factors associated with postabortion method choices. Method discontinuation rates were estimated using proportional hazard models. RESULTS: Overall, 70.4% of women reported not using any method following abortion, and the levels varied considerably across states. Significant differences were observed in the type of method adopted by women living in large cities, small towns, and rural areas. Poor and socially excluded women were less likely to use any method after abortion, particularly modern reversible methods. Method discontinuation rates were considerably higher among socially disadvantaged groups. CONCLUSION: Postabortion contraceptive adoption is exceptionally low in India. Reproductive health interventions should urgently consider implementing comprehensive postabortion care policies, integrating family planning with sexual and reproductive healthcare services, and in particular targeting women from disadvantaged communities. PMID- 22516689 TI - Telomere maintenance mechanisms in malignant peripheral nerve sheath tumors: expression and prognostic relevance. AB - This study investigated the prevalence and the prognostic relevance of the 2 known telomere maintenance mechanisms (TMMs), telomerase activity (TA) and alternative lengthening of telomeres (ALT), in malignant peripheral nerve sheath tumors (MPNST). In 57 specimens from 49 patients with MPNST (35 sporadic, 14 neurofibromatosis type 1-related), TA was determined using the telomeric repeat amplification protocol, and ALT was detected by assaying ALT-associated promyelocytic leukemia bodies (APB) and terminal restriction fragment (TRF) length distribution. TA or ALT (defined on the basis of APB) alone was found in 24.6% or 26.3% of the lesions, respectively, whereas 6 cases (10.5%) were TA+/ALT+. A concordance between APB and TRF results in defining the ALT status was observed in 44 of 57 cases (77.2%; P < .0001). TA was more frequently expressed in samples from patients with neurofibromatosis type 1 than in those with sporadic disease (60% vs 29.4%, P = 0.087). In the overall series, TA proved to be prognostic for 5-year disease-specific death (hazard ratio, 3.78; 95% confidence interval [CI], 1.60-8.95; P = .002), even when adjusted for the presence of neurofibromatosis type 1 (hazard ratio, 4.22; 95% CI, 1.804-9.874; P = .001) and margin status after surgery (hazard ratio, 5.78; 95% CI, 2.19-15.26; P < .001). Conversely, ALT did not significantly affect clinical outcome of MPNST using either APB expression (hazard ratio, 1.25; 95% CI 0.54-2.89; P = 0.605) or TRF distribution (hazard ratio, 0.57; 95% CI, 0.17-1.96; P = .375) as the detection approach. Our results indicate for the first time that both TMMs, TA and ALT, are present in MPNST and differentially affect patient prognosis. PMID- 22516690 TI - Extended scrapie incubation time in goats singly heterozygous for PRNP S146 or K222. AB - Scrapie is the transmissible spongiform encephalopathy (TSE) of sheep and goats, and scrapie eradication in sheep is based in part on strong genetic resistance to classical scrapie. Goats may serve as a scrapie reservoir, and to date there has been no experimental inoculation confirming strong genetic resistance in goats. Two prion protein variants (amino acid substitutions S146 and K222) in goats have been significantly underrepresented in scrapie cases though present in scrapie exposed flocks, and have demonstrated low cell-free protein conversion efficiency to the disease form (PrP(D)). To test degree of genetic resistance conferred in live animals with consistent exposure, we performed the first oral scrapie challenge of goats singly heterozygous for either PRNP S146 or K222. All N146 Q222 homozygotes became clinically scrapie positive by an average of 24months, but all S146 and K222 heterozygotes remain scrapie negative by both rectal biopsy and clinical signs at significantly longer incubation times (P<0.0001 for both comparisons). Recent reports indicate small numbers of S146 and K222 heterozygous goats have become naturally infected with scrapie, suggesting these alleles do not confer complete resistance in the heterozygous state but rather extend incubation. The oral challenge results presented here confirm extended incubation observed in a recent intracerebral challenge of K222 heterozygotes, and to our knowledge provide the first demonstration of extended incubation in S146 heterozygotes. These results suggest longer relevant trace-back histories in scrapie-eradication programs for animals bearing these alleles and strengthen the case for additional challenge experiments in both homozygotes to assess potential scrapie resistance. PMID- 22516691 TI - Sprint speed characteristics of high-level American female soccer players: Female Athletes in Motion (FAiM) study. AB - OBJECTIVES: Sprint speed is important in soccer and while descriptions of male players are plentiful relatively few data exist for high-level female players. The aim of this study was to determine speed characteristics of high-level American female soccer players and evaluate if speed could distinguish between players selected (n=56) and those not selected (n=84) in a professional draft. DESIGN: A cross-sectional study design. METHODS: One hundred and forty women participating in a try-out for a professional soccer league had speed assessed over 35 m with splits at 5, 10 and 20 m. Speeds for the static start distances (5, 10, 20 and 35 m) as well as for 'flying' splits (flying 5, 10, 25 and 30 m; also first 15 and final 15 m) were determined. RESULTS: Mean speed over 5, 10, 20 and 35 m was 15.1+/-1.1, 18.0+/-0.9, 21.2+/-0.9 and 23.4+/-0.9 km h-1, respectively. Mean peak speed was 27.3+/-1.4 km h-1 and occurred during the final 15m of the sprint (20-35 m). Speed for all flying splits exceeded 21.0 km h-1, with maximum values observed in excess of 30.0 km h-1. All speeds, except for the flying 5m split, were faster in the drafted players compared to non-drafted players. CONCLUSIONS: These data indicate that elite female soccer players achieve speeds ranging between 22 and 26 km h-1 over distances of 15-20 m and can reach 27 km h-1 when evaluated over 35 m. Sprint speed was able to distinguish between drafted and non-drafted players. PMID- 22516692 TI - Influence of the MCT1-T1470A polymorphism (rs1049434) on blood lactate accumulation during different circuit weight trainings in men and women. AB - OBJECTIVES: To analyze the effect of the MCT1 T1470A polymorphism (rs1049434) on venous blood lactate levels in men and women, during three different circuit weight training protocols. DESIGN: Cross-sectional laboratory study. METHODS: 14 women and 15 men, all caucasian and moderately active, performed three circuit training sessions (Weight Machine Protocol, Free Weight Protocol and Combined Protocol) at 70% of the 15 repetition maximum and 70% of the heart rate reserve, in non-consecutive days. The sessions included three sets of a circuit of eight exercises. Venous lactate measurements were obtained after each set and during the recoveries between sets (i.e. in min 3, 5, 7 and 9). One-way analysis of covariance and one-way analysis of covariance with repeated measures were used to determine differences among genotypes (AA, TA and TT) in lactate levels. RESULTS: In men, the AA group had higher lactate values than the TT group in all the measures (p <= 0.03) except for the average lactate during the Weight Machine Protocol, in which a borderline significant difference was found (p=0.07). We did not observe differences across genotypes in females. CONCLUSIONS: Our data suggest an influence of the MCT1 polymorphism on lactate transport across sarcolemma in males. Future studies on lactate transport and metabolism should take into account the gender-specific results. PMID- 22516693 TI - Fowl adenoviruses isolated from chickens with inclusion body hepatitis in Japan, 2009-2010. AB - Nine fowl adenoviruses (FAdVs) isolated from chickens with inclusion body hepatitis (IBH) in Japan from 2009 to 2010 were characterized serologically and genetically. These isolates were all neutralized by antisera against the SR-48 strain (FAdV-2). Phylogenetic analysis based on the part of the hexon gene that included the L1 region revealed that all isolates were almost identical except one isolate in 2009. This suggests a common ancestor for the FAdVs obtained from chickens with IBH in Japan in 2010. PMID- 22516694 TI - The in vitro activity of 15 antimicrobial agents against bacterial isolates from dogs. AB - The in vitro activity of 15 antimicrobial agents against clinical isolates of Staphylococcus pseudintermedius, Staphylococcus aureus, Escherichia coli, Pasteurella spp. and Streptococcus canis from dogs was investigated. For Staphylococcus spp., the highest frequency of resistance was observed for penicillin, followed by ampicillin, tetracycline and chloramphenicol. The highest frequency of resistance in E. coli isolates was recorded for tetracycline and streptomycin. Pasteurella spp. and S. canis had the highest resistance rate for tetracycline and chloramphenicol. Most isolates showed full susceptibility to low level resistance to colistin, florfenicol and fluoroquinolones. Further studies using larger number of isolates from both healthy and diseased dogs would provide a broader picture of antimicrobial resistance at a national level and promote prudent use of antimicrobial agents in companion animals. PMID- 22516695 TI - Relationship between pH and temperature in the ruminal fluid of cows, based on a radio-transmission pH-measurement system. AB - To assess the relationship between pH and temperature in the ruminal bottom fluid, circadian changes were monitored using cows fed a control diet (C diet) or a rumen acidosis-inducing diet (RAI diet) by using a wireless radio-transmission pH- measurement system. These two parameters were measured simultaneously at 10 min intervals on day 14 after commencement of feeding. Compared to the mean ruminal pH for 60 min immediately after the morning feeding (0 hr), significantly lower pH was noted 3-13 hr later (P<0.05) and 4-19 hr later (P<0.01) in cows fed the C and RAI diets, respectively, although the reduction in the latter was much higher than that in the former. In contrast, significantly higher ruminal temperature was found at 8 and 12-14 hr later (P<0.05) and 6, 8, and 10-19 hr later (P<0.01) in cows fed the C and RAI diets, respectively. A significant negative correlation was observed between the lowest ruminal pH and its corresponding ruminal temperature in cows fed the C and RAI diets (r=-0.722 and 0.650, P<0.01, respectively), suggesting active fermentation and volatile fatty acid production in the rumen. However, ruminal pH profiles may not be predictable by measuring only ruminal temperature because decreases in ruminal pH were preceded by increases in ruminal temperature, and circadian changes in pH and temperature were associated with ruminal fermentation. PMID- 22516696 TI - Synthesis and characterization of PbSe nanoparticles obtained by a colloidal route using Extran as a surfactant at low temperature. AB - Lead selenide nanoparticles (PbSe NPs) have been obtained through an easy and low cost route using colloidal synthesis in aqueous solution. The synthesis was carried out at room temperature using Extran (Na5P3O10, NaOH and H2O) as surfactant. Hydrochloric acid (HCl) was used to eliminate the generated by products. The size of PbSe NPs was varied by changing the Pb:Se molar concentration. The PbSe NPs were characterized by powder x-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive x-ray analysis (EDAX), high resolution transmission electron microscopy (HRTEM) and Raman spectroscopy. The XRD measurements showed that the PbSe NPs have the face-centered cubic phase structure. The crystal size was found to be between 14 and 20 nm as calculated from the XRD patterns and these values were corroborated with SEM and TEM. Additionally, HRTEM micrographs showed crystalline planes at (200), (220) and (111) of the PbSe NPs, in agreement with the XRD results. PMID- 22516697 TI - [Nutrition and fertility]. AB - There is a growing body of evidence that nutritional habits may have a significant effect on both male and female fertility. Maintenance of normal body mass may be effective in the prevention of infertility resulting from ovulatory disorders. Underweight and, to a larger degree, overweight and/or obesity, are related to the enhanced risk of infertility. Insulin resistance is an important pathogenic mechanism that may impair ovulation. Adequate intake of monounsaturated fatty acids, derived mainly from vegetable fats, as well as avoidance of trans isomers of unsaturated fatty acids which are present in industrially produced cakes and sweets, crisps, fast-foods, powdered soups and hard margarines, may be effective in the prevention of infertility in females. Choice of plant rather than animal sources of proteins, decrease in glycemic load of the diet, use of dietary supplements containing iron and folic acid, could also be beneficial. Avoidance of vitamin B12 deficiency and its supplementation seem to be important in the prevention of early miscarriages. Sufficient intake of antioxidants also promotes female reproductive functions. Free radical processes play an important role in the development of male factor infertility. It was shown that proper intake or supplementation with antioxidants may be effective in its prevention and treatment. Such nutrients as zinc, selenium and folic acid act beneficially on sperm quality. A well-balanced diet seems to play an important role in the prevention of infertility in both sexes. PMID- 22516698 TI - [Alpha-thalassemia/mental retardation syndrome (ATR-X) in two brothers - clinical characteristics, diagnostics and genetic counselling issues]. AB - Alpha-thalassemia/mental retardation syndrome (ATR-X) is a neurodevelopmental disorder with characteristic clinical picture as well as presence of pathognomonic haemoglobin H inclusions (HbH) on peripheral blood examination. Typical features of this condition are: severe intellectual impairment, muscular hypotonia, delay of growth, genitourinary/skeletal abnormalities and characteristic facial dysmorphism. Molecular basis of the syndrome constitute mutations in ATR-X gene located on the long arm of X chromosome (Xq13). In this work, clinical characteristics of the molecularly confirmed case of ATR-X syndrome in two brothers are presented. The mother of both affected boys is an asymptomatic mutation carrier. In one of the brothers additional studies revealed the presence of de novo 1q21.1 microdeletion. ATR-X syndrome symptomatology, differential diagnostics issues as well as the aims of genetic counselling are described. PMID- 22516699 TI - [Rett syndrome. Classical form and preserved speech variant as a different phenotype effect of deletion with the same starting point in MeCP2 gene - report of 2 cases]. AB - BACKGROUND: Rett syndrome is a common cause of mental retardation in girls. Characteristic features of RS include: profound impairment of cognitive abilities, impaired communication skills, stereotypic movements, seizures, respiratory disorders, dystonia. Classical Rett syndrome as well as variants such as forme fruste and variant with preserved speech were observed. Mutation in the MeCP2 gene is found in about 90% of RS. OBJECTIVE: This paper describes two cases of Rett syndrome (RS) caused by the presence of different size deletion in the MeCP2 gene. MATERIALS AND METHODS: DNA was isolated from peripheral blood lymphocytes of two patients: 2.5 years-old and 12 years-old, in whom Rett syndrome was suspected. For this study, PCR-RFLP method and sequencing were used. RESULTS: Patient 1 had a deletion of 35 nucleotides: del35 nt c.1159-1193 in one allele of the MeCP2 gene. Patient 2 had a deletion of 44 nucleotides in one allele of the MeCP2 gene del44 nt c.1159-1202. Both described girls with Rett syndrome had a deletion leading to frameshift at the C-terminal region of the MeCP2 gene, which begins at the same point (c.1159), but, the phenotypes are different. The patient with a smaller deletion of 35 nucleotides has the classical form of RS, the second patient with a deletion of 44 nucleotides has a variant with preserved speech. CONCLUSIONS: There is a significant phenotypic variation in Rett syndrome associated with deletions of the C-terminal region of the MeCP2 gene and it only partly depends on the location and type of mutation. Presumably, other mechanisms, such as non-random X chromosome inactivation and/or the effect of interaction between different genes may play an important role in shaping the phenotype in Rett syndrome. PMID- 22516700 TI - [Freeman-Sheldon syndrome - phenotype and course of disease on the base of two cases confirmed by molecular study]. AB - Freeman-Sheldon syndrome is characterized by typical dysmorphic features of the face (microstomia with putting lips and H-shaped dimpling of the chin, giving the appearance of a whistling face) and symmetrical hands and feet defects (camptodactyly, joint contractures). The intelligence quotient is usually within the normal range. Mutations in the MYH3 gene at 17p13 have been shown to cause the syndrome, inherited as an autosomal dominant trait. Two patients with clinical diagnosis of Freeman- Sheldon syndrome, confirmed by molecular study were described in this article. Additionally, clinical aspects, differential diagnosis and genetic basis of the disease were described as well as medical problems concerning patients with Freeman-Sheldon syndrome were discussed such as anesthetic aspects, malignant hyperthermia and pulmonary complications after surgery. The authors highlight the significance of dysmorphic features in patients with developmental delay and congenital defects as well as indicate the role of multidisciplinary approach in the diagnostic and therapeutic process. PMID- 22516701 TI - Congenital intramedullary spinal cord tumours: a report of two cases. AB - We present two different cases of congenital intramedullary tumours, one of a patient in whom treatment was started without pathological confirmation of a malignant tumour and the other of a primitive neuroectodermal tumour. Magnetic resonance imaging is the most useful tool in the diagnosis of malignant intramedullary tumours and differentiation from other types of spinal cord lesions. PMID- 22516702 TI - [Rare case of congenital cystic adenomatoid malformation associated with polycystic kidney disease]. AB - Congenital cystic adenomatoid malformation (CCAM) is a rare pulmonary abnormality that results from aberrant fetal lung development. It about 4-26% of cases it can be associated with other congenital abnormalities. We describe a case of congenital cystic adenomatoid malformation 2 associated with polycystic kidney disease. The association of these two congenital malformations is exceptional. Only four similar cases have been reported in the literature. A 2-year-old girl was referred to the Department of Paediatric Surgery and Oncology Medical University of Lodz with pneumonia and left pneumothorax. For three weeks prior to referral the patient was treated with antibiotics. Chest x-ray revealed hyperinflation of left upper lobe with mediastinal shift to right. Computer tomographic scan of the lung revealed multiple cyst in the left upper lobe, left site pneumothorax and mediastinal shift to the right. The patient underwent thoracotomy. Intraoperatively, multiple cysts in the left upper lobe were found and left upper lobectomy was performed. Histologic study was compatible with type 2 congenital cystic adenomatoid malformation. Ultrasound examination showed multilocular cysts in both kidneys. The dimensions of the cysts were: MWR4. 54x45x45 mm and 25x21x24 mm on the left and right sides, respectively. Significant increase in cyst size on the left side was observed. Ten months after first hospitalization resection of the cystic lower pole of the left kidney was performed. The presence of even a single renal cyst in a child with CCAM is an indication for further follow up examinations. PMID- 22516704 TI - [Coexistence of Crohn disease and Wegener granulomatosis in a 15-year-old patient]. AB - Crohn disease is being diagnosed more and more frequently in children and teenagers. Clinical symptoms are mainly related to the gastrointestinal tract, however there are many reports in the literature about the coexistence of Crohn disease with other autoimmunological disorders such as celiac disease, autoimmune hypothyroidism, systemic lupus erythematosus and Wegener granulomatosis. We report a 15-year-old patient with Crohn disease who also developed Wegener granulomatosis. The presented case illustrates the difficulties in establishing the diagnosis when symptoms of the original disease are superimposed on symptoms of a different disorder. PMID- 22516703 TI - [Frequency and causes for hospitalization of children with cholelithiasis - own observations]. AB - THE AIM: of this study was to assess the incidence and the cause of hospitalization of children with cholecystolithiasis. MATERIAL AND METHODS: A retrospective analysis was carried out using medical data of children and adolescents treated in the Department of Pediatrics, Gastroenterology, and Pediatric Allergology of Bialystok Medical University. The analysis included causes of hospitalization, its course and accompanying illnesses. During the 4 years of analysis, 47 children (17 boys, 30 girls), aged from 7 months to 18 years, with the diagnosis of cholecystolithiasis were treated. The comprised 1.18% of children hospitalized with gastrointestinal disorders. RESULTS: Cholecystolithiasis without complications was diagnosed in 29 children (61.7%), with cholecystitis in 13 (27.7%), choledocholithiasis was diagnosed in 5 children (10.6%). In 11 children (23.4%) the complication presented in form of acute pancreatitis. In 23 children (48.9%) factors predisposing to chorocholelithiasis were identified. In 20, the following were considered to be a possible significant factor: in 7 children there was a positive family history (14.9%), in 6 children (12.8%) - it was obesity, in 3 children (6.4%) lipid metabolic errors: prematurity and parenteral feeding in 2 children (4.3%) and spherocytosis in 2 children (4.3%). Apart from the above, cholelithiasis was diagnosed in two children with hypothyreosis and in two with Down's Syndrome. In treatment of 20 children (42.6%) antibiotics were prescribed and in 4 children (8.5%) endoscopic sphincterotomy was performed. 25 children (53.2%) were referred for laparoscopic cholecystectomy. In 16 children (34.0%), treatment with ursodeoxycholic acid was recommended. CONCLUSIONS: Cholecystolithiasis is a rare cause of hospitalization in pediatric departments. However, it occurs in even the youngest children. It usually runs without complications, but there is a certain risk of serious complications. In the differential diagnosis of abdominal pain, cholelithiasis should be taken into account, even in the youngest children. Special consideration should be given to the premature, with low birth weight and extremely low birth weight. PMID- 22516705 TI - [Congenital diarrhoea]. AB - Congenital diarrhoea of heterogenic etiology is a rare cause of chronic diarrhoea. Characteristic features are: onset in the first weeks of life, life threatening severe dehydratation and electrolyte disorders leading to a necessity of long-term parenteral nutrition. The clinical onset may be delayed and the degree of diarrhoea may be modest, making the diagnosis difficult. The main causes of congenital diarrhoea such as intestine electrolytes, carbohydrates, lipid and protein transport disorders and congenital enzymatic deficiencies, enterocyte polarization disorders, hormonal, immunological, metabolic, genetic and congenital anatomic disorders are presented in the paper. Some of them, such as: microvillus inclusion disease, tufting enteropathy, intestinal anedocrynosis, IPEX syndrome (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome) have been described recently. One of the basic investigations, when congenital diarrhea is suspected, is general examination of the stool, its electrolyte concentration and serum electrolytes and blood gas analysis. Often, small bowel biopsy with histological examination (with the use of electronic microscopy and PAS staining) is indicated. In some cases molecular examination is possible and indicated. In differential diagnosis other, more frequent causes of chronic diarrhea of infancy, have to be excluded. In most of the cases of congenital diarrhoea there is no casual treatment available - usually long-term parenteral nutrition is necessary. PMID- 22516706 TI - Breastfeeding in primary prevention of atopic diseases - is it really protective? AB - The role of human milk in the development of allergic sensitization remains controversial, especially in view of the difficulty to perform randomized clinical trials as well as methodological differences in the existing data. The incapability of human milk to prevent from allergic phenotype may be ascribed to genetic predisposition, environmental factors and also to differences in the immune contents of human milk, resulting in a lack of oral tolerance development. This article presents controversial results of recently published studies and current recommendations regarding the role of breastfeeding in allergy prevention. PMID- 22516707 TI - [Evaluation of infant feeding practices after implementation of recommendations for coeliac disease prophylaxis - pilot study]. AB - Recent research data concerning the risk of coeliac disease confirm that introduction of food containing gluten during breast-feeding not later than 6 months of life is justified. According to ESPGHAN and EFSA introduction of solid foods in the diet of infants between 4-6 months of age is safe. AIM OF STUDY: Evaluation of feeding practices in healthy full-term infants after implementation of the recommendations of coeliac disease prevention. MATERIAL AND METHODS: Conducted analysis concerned 54 healthy full-term infants, living in Warsaw, aged 6 to 12 months. Of these, 27 children were exclusively breastfed for the first 6 months of life and 27 children were non-breastfed. The differences between selected parameters of nutritional status and diets of breastfed and nonbreastfed infants were evaluated by using t-Student test. Relations between quantitative variables were assessed by chi2 test. RESULTS: Products containing gluten were introduced into the breastfed children's diet in the 5th month of life in 22% of studied subgroup, in the 6th month - in 15%, in the 7th or 8th month - in 30%, between 9th and 11th month - in 22% and 11% of these children have not received food containing gluten in the first year of life. In the group of non-breastfed infants 15% received products with gluten before 5th month of life, 15% in 5th month, 11% at age of 6 months, 22% between 7th and 8th month, 15% in 11th month and 22% of children have not received food containing gluten in the first 12 months of life. An average daily intake of foods with varying content of gluten amounted to 55 g in breastfed infants and 70.5 g in non-breastfed infants (p <0.05). CONCLUSIONS: In the pilot study it was found out that nutritional recommendations concerning prophylaxis of coeliac disease were not implemented correctly by the majority of mothers of studied infants. Products containing gluten were introduced to the infant's diet too early or too late and mostly in larger quantities than it was recommended. Due to the small number of studied children it is important to carry out the investigation on a larger sample. At the same time it is necessary to introduce more effective methods of implementing nutritional recommendations concerning prophylaxis of celiac disease. PMID- 22516708 TI - [Folic acid supplementation as prophylaxis of neural tube defect in the Lower Silesia region: fact or fiction?]. AB - AIM: To assess the efficacy of nationwide programme of prophylaxis of neural tube defects in the Lower Silesia region. MATERIAL AND METHODS: A questionnaire study was conducted among all mothers of infants admitted between 2001 and 2010 to the Department of Pediatric Surgery and Urology in Wroclaw Medical Academy. The data regarding pregnancy and delivery, newborn's medical condition, family history, parental health, profession and education, and finally folic acid supplementation by mothers were analysed. RESULTS: Among 1278 newborn infants, in 148 children (11.6%) central nervous system (CNS) defects were diagnosed. Among 894 mothers (69.9%) who took part in the study, 159 of them (17.8%) confirmed taking folic acid before becoming pregnant. The rate of supplementation with folic acid showed a rising trend in the study period and increased from 7.1% in 2001 to 35.8% in 2010. Folic acid was taken more frequently by the women living in urban areas (24.2%) than by those living in rural regions (9.2%). With regard to the educational level, the highest rate of supplementation with folic acid was noted among the women with high education (37.8%). Forty-eight percent of mothers were informed about prevention of neural tube defects by their physician, while in 32% of them the family or media were the source of information. Mothers of 255 infants confirmed that they knew about prevention of congenital defects by vitamin intake, but they had not taken folic acid before pregnancy. CONCLUSION: 1. Realization of the programme of prevention of neural tube defects in Lower Silesia region is highly unsatisfactory. 2. The actions undertaken on the national and local level and aimed to popularize the knowledge about prevention of CNS defects among women are assessed to be ineffective in the Lower Silesia region and need urgent verification. PMID- 22516709 TI - [Energy drinks and health - progress of the knowledge]. AB - For young people energy drinks have become the new fashion and also a quick way to increase the fitness of the body. Lack of legal regulations gives freedom in active ingredients concentration, based sometimes on the principle "the more the better". In the literature there are increasing data about adverse effects of energy drinks consumption. Children and adolescents are the risk group for negative health consequences. This article is a comprehensive literature review on the effects of energy drinks on the developing human body and its health safety. PMID- 22516710 TI - Bioacumulation and ultrastructural effects of Cd, Cu, Pb and Zn in the moss Scorpiurum circinatum (Brid.) Fleisch. & Loeske. AB - This paper tested if culturing the moss Scorpiurum circinatum (Brid.) Fleisch. & Loeske with metal solutions (Cd, Cu, Pb and Zn) for 30 days causes metal bioaccumulation and ultrastructural changes. The results showed that despite the high heavy metal concentrations in treatment solutions, treated samples did not show severe ultrastructural changes and cells were still alive and generally well preserved. Bioaccumulation highlighted that moss cells survived to heavy metal toxicity by immobilizing most toxic ions extracellularly, likely in binding sites of the cell wall, which is the main site of metal detoxification. PMID- 22516711 TI - Induction of mouthpart deformities in chironomid larvae exposed to contaminated sediments. AB - The aim of the present study was to improve the cause-effect relationship between toxicant exposure and chironomid mouthpart deformities, by linking induction of mouthpart deformities to contaminated field sediments, metal mixtures and a mutagenic polycyclic aromatic compound metabolite (acridone). Mouthpart deformities in Chironomus riparius larvae were induced by both the heavy metal mixture and by acridone. A clear correlation between metal concentrations in the sediment and deformities incidence was only observed when the contaminated field sediments were left out of the analysis, probably because these natural sediments contained other toxic compounds, which could be responsible for a higher incidence of deformities than predicted by the measured metal concentrations only. The present study clearly improved the cause-effect relationship between toxicant exposure and the induction of mouthpart deformities. It is concluded that the incidence of mouthpart deformities may better reflect the potential toxicity of contaminated sediments than chemical analysis. PMID- 22516712 TI - Application of XAD-resin based passive air samplers to assess local (roadside) and regional patterns of persistent organic pollutants. AB - We used XAD-resin based passive air samplers (PAS) to measure atmospheric levels of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) at five ombrotrophic bogs in Eastern Canada. The aims of our study were to investigate the influence of local roads on contaminant levels in the bogs, to derive the regional pattern of atmospheric concentrations, and to assess the uncertainties of the method. Expanded uncertainties based on the duplicate PAS deployed at 24 sites were good for the PAHs, while the deployment period of approx. 100 days was too short to yield acceptable uncertainties for PCBs. The regional PAH distribution was in good agreement with the calculated source proximity of the sampled bogs. We conclude that XAD-resin based PAS deployed for comparatively short periods are well suited for measuring atmospheric concentrations of volatile PAHs, while in remote regions longer deployment is necessary for less volatile PAHs and for PCBs. PMID- 22516714 TI - Outcomes after radical prostatectomy for patients with clinical stages T1-T2 prostate cancer with pathologically positive lymph nodes in the prostate-specific antigen era. AB - OBJECTIVES: To evaluate the outcomes of radical prostatectomy (RP) and pelvic lymph node dissection (PLND) for clinically organ confined prostate cancer (CaP) with regional lymph node metastases (pN1) treated in the era of prostate-specific antigen (PSA) screening. MATERIALS AND METHODS: A single institution cohort of 2,487 men with cT1-T2 CaP treated with open radical prostatectomy and pelvic lymph node dissection between 1988 and 2008 were analyzed. Kaplan-Meier and Cox proportional regression models were used to analyze overall survival (OS), clinical recurrence-free survival (cRFS), and biochemical recurrence-free survival (bRFS). RESULTS: Overall, 150 out of 2,487 patients (6%) had pN1 disease, with a median follow-up of 10.4 years. The predicted 10-year OS, cRFS, and bRFS rates for patients with pN0 and pN1 were 86% and 74% (Log rank P < 0.001), 97% and 84% (Log rank P < 0.001), and 88% and 57% (Log rank P < 0.001), respectively. In the subset of pN1 patients treated with surgery only (n = 49), the predicted 10-year OS, cRFS, and bRFS rates were 81%, 80%, and 59%, respectively. Exploratory univariate regression analysis showed that age (P = 0.003), total number of lymph nodes identified (P = 0.040), and total number of positive lymph nodes identified (P = 0.004) were associated with OS. Total number of positive lymph nodes (LNs) identified was also significantly associated with cRFS (P = 0.05). CONCLUSIONS: The incidence of pN1 in patients with cT1-T2 CaP treated with surgery in the era of PSA screening was low. RP and PLND demonstrated therapeutic efficacy in a subset of pN1 patients treated with surgery alone. PMID- 22516713 TI - Thermosensitive hydrogel based on poly(ether-ester anhydride) nanoparticle as drug delivery system: preparation, characterization and biocompatibility. AB - A novel temperature-response hydrogel was developed for drug-delivery applications. The hydrogel matrix (PES) was synthesized by melt polycondensation of poly(ether-ester) diacid based on PEG with low molecular weight and sebacic acid. The sol-gel-sol phase transitions of PES nanoparticle (NP) hydrogel were investigated. In vitro erosion of hydrogel was characterized by Fourier transform infrared spectroscopy, environmental scanning electron microscopy and dynamic light scattering. In vitro release behaviors of hydrophilic and hydrophobic drugs and in vivo histopathological evaluation were studied in detail. The study results revealed that an aqueous dispersion of PES nanoparticle freeze-dried powder exhibited reversible sol-gel transition behavior with increasing temperature. The hydrogel could maintain steadily at least a month during in vitro erosion process. There were sustained release behaviors of hydrophilic and hydrophobic drugs from PES NP hydrogel and histopathological studies confirmed that the PES NP hydrogel only provoked an acceptable modest inflammatory response. Thus, PES NP hydrogel is biodegradable, biocompatible and promising in controlling the incorporated drugs for sustained release. PMID- 22516715 TI - Molecular identification and functional characterisation of uncoupling protein 4 in larva and pupa fat body mitochondria from the beetle Zophobas atratus. AB - Uncoupling protein 4 (UCP4) is a member of the UCP subfamily that mediates mitochondrial uncoupling, and sequence alignment predicts the existence of UCP4 in several insects. The present study demonstrates the first molecular identification of a partial Zophobas atratus UCP4-coding sequence and the functional characterisation of ZaUCP4 in the mitochondria of larval and pupal fat bodies of the beetle. ZaUCP4 shows a high similarity to predicted insect UCP4 isoforms and known mammalian UCP4s, both at the nucleotide and amino acid sequence levels. Bioenergetic studies clearly demonstrate UCP function in mitochondria from larval and pupal fat bodies. In non-phosphorylating mitochondria, ZaUCP activity was stimulated by palmitic acid and inhibited by the purine nucleotide GTP. In phosphorylating mitochondria, ZaUCP4 activity decreased the yield of oxidative phosphorylation. ZaUCP4 was immunodetected with antibodies raised against human UCP4 as a single 36-kDa band. A lower expression of ZaUCP4 at the level of mRNA and protein and a decreased ZaUCP4 activity were observed in the Z. atratus pupal fat body compared with the larval fat body. The different expression patterns and activity of ZaUCP4 during the larval-pupal transformation indicates an important physiological role for UCP4 in insect fat body development and function during insect metamorphosis. PMID- 22516716 TI - Testing of a prototype of calibration facility for noble gas monitoring using 41Ar. AB - A prototype of a calibration facility for noble gas monitoring using (41)Ar in the PTKMR-BATAN has been tested. The facility was designed in such a way that the standard source of gas can be reused. The radioactive (41)Ar source was obtained by thermal neutron reaction of (40)Ar(n, gamma)(41)Ar using a thermal neutron flux of 4.8*10(13) neutrons per cm(2) per second in two minutes on the multipurpose G.A. Siwabessy Reactor (Batan, Serpong, Indonesia). Gamma spectrometry was used to measure the radioactivity and purity of (41)Ar. The spectrum of the (41)Ar observed yields an energy of 1294 keV because of the highest intensity (99.2%). The activity of (41)Ar was 2821 kBq and 4% of the expanded uncertainty. The time required for (41)Ar to reach homogeneity was 7 min, and the effectiveness of resuse was 53%. PMID- 22516717 TI - A semi-automated system for the routine production of copper-64. AB - An automated system for the production of high specific activity (64)Cu via the irradiation of electroplated enriched (64)Ni targets has been developed. We have been operating this system continually on a biweekly or weekly basis for more than two years. Since the inception of this automated production system, (October 1, 2008), we have had 145 productions, produced 53562 mCi and shipped out 25629 mCi of this isotope to external users. We routinely produce over 400 mCi of this isotope per batch with a specific activity of 14,000 +/- 7600 mCi/MUmol for distribution to some 12-15 centers each production. PMID- 22516718 TI - Development and characterization of a laboratory based X-ray diffraction imaging system for material and tissue characterization. AB - Soft tissues feature a degree of short-range order, giving rise to diffraction patterns with broader peaks than crystalline materials. For this reason, an X-ray diffraction system (XRD) for characterization of soft tissue has less stringent requirements in terms of momentum transfer resolution than the one aimed at characterizing crystalline materials. We present results on the characterization of two energy-dispersive XRD systems. The first was based on conical collimation at 5.9 degrees and the second was based on linear collimation at varying angles between 2 degrees and 10 degrees . The systems include a CdTe detector and a W anode X-ray source. The angular resolution was measured as a function of sample thickness and scattering angle. Preliminary results confirm the effectiveness of the method for the characterization of biological tissues, showing insensitivity to small changes in angular acceptance and sample thickness, also showing it is possible to combine scattering data obtained at different angles. PMID- 22516719 TI - Skeletal muscle responses to negative energy balance: effects of dietary protein. AB - Sustained periods of negative energy balance decrease body mass due to losses of both fat and skeletal muscle mass. Decreases in skeletal muscle mass are associated with a myriad of negative consequences, including suppressed basal metabolic rate, decreased protein turnover, decreased physical performance, and increased risk of injury. Decreases in skeletal muscle mass in response to negative energy balance are due to imbalanced rates of muscle protein synthesis and degradation. However, the underlying physiological mechanisms contributing to the loss of skeletal muscle during energy deprivation are not well described. Recent studies have demonstrated that consuming dietary protein at levels above the current recommended dietary allowance (0.8 g . kg(-1) . d(-1)) may attenuate the loss of skeletal muscle mass by affecting the intracellular regulation of muscle anabolism and proteolysis. However, the specific mechanism by which increased dietary protein spares skeletal muscle through enhanced molecular control of muscle protein metabolism has not been elucidated. This article reviews the available literature related to the effects of negative energy balance on skeletal muscle mass, highlighting investigations that assessed the influence of varying levels of dietary protein on skeletal muscle protein metabolism. Further, the molecular mechanisms that may contribute to the regulation of skeletal muscle mass in response to negative energy balance and alterations in dietary protein level are described. PMID- 22516720 TI - Mechanisms of gene regulation by fatty acids. AB - Consumption of specific dietary fatty acids has been shown to influence risk and progression of several chronic diseases, such as cardiovascular disease, obesity, cancer, and arthritis. In recent years, insights into the mechanisms underlying the biological effects of fatty acids have improved considerably and have provided the foundation for the emerging concept of fatty acid sensing, which can be interpreted as the property of fatty acids to influence biological processes by serving as signaling molecules. An important mechanism of fatty acid sensing is via stimulation or inhibition of DNA transcription. Here, we focus on fatty acid sensing via regulation of gene transcription and address the role of peroxisome proliferator-activated receptors, sterol regulatory element binding protein 1, Toll-like receptor 4, G protein-coupled receptors, and other putative mediators. PMID- 22516721 TI - Vitamin K oxygenation, glutamate carboxylation, and processivity: defining the three critical facets of catalysis by the vitamin K-dependent carboxylase. AB - The vitamin K-dependent carboxylase uses vitamin K oxygenation to drive carboxylation of multiple glutamates in vitamin K-dependent proteins, rendering them active in a variety of physiologies. Multiple carboxylations of proteins are required for their activity, and the carboxylase is processive, so that premature dissociation of proteins from the carboxylase does not occur. The carboxylase is unique, with no known homology to other enzyme families, and structural determinations have not been made, rendering an understanding of catalysis elusive. Although a model explaining the relationship of oxygenation to carboxylation had been developed, until recently almost nothing was known of the function of the carboxylase itself in catalysis. In the past decade, discovery and analysis of naturally occurring carboxylase mutants has led to identification of functionally relevant residues and domains. Further, identification of nonmammalian carboxylase orthologs has provided a basis for bioinformatic analysis to identify candidates for critical functional residues. Biochemical analysis of rationally chosen carboxylase mutants has led to breakthroughs in understanding vitamin K oxygenation, glutamate carboxylation, and maintenance of processivity by the carboxylase. Protein carboxylation has also been assessed in vivo, and the intracellular environment strongly affects carboxylase function. The carboxylase is an integral membrane protein, and topological analysis, coupled with biochemical determinations, suggests that interaction of the carboxylase with the membrane is an important facet of function. Carboxylase homologs, likely acquired by horizontal transfer, have been discovered in some bacteria, and functional analysis of these homologs has the potential to lead to the discovery of new roles of vitamin K in biology. PMID- 22516722 TI - Vitamin K-dependent carboxylation of osteocalcin: friend or foe? AB - Osteocalcin originates from osteoblastic synthesis and is deposited into bone or released into circulation, where it correlates with histological measures of bone formation. The presence of 3 vitamin K-dependent gamma carboxyglutamic acid residues is critical for osteocalcin's structure, which appears to regulate the maturation of bone mineral. In humans, the percentage of the circulating osteocalcin that is not gamma-carboxylated (percent ucOC) is used as a biomarker of vitamin K status. In contrast, when ucOC is not corrected for total osteocalcin, the interpretation of this measure is confounded by osteoblastic activity, independent of vitamin K. Observational studies using percent ucOC have led to the conclusion that vitamin K insufficiency leads to age-related bone loss. However, clinical trials do not provide overall support for the suggestion that vitamin K supplementation of the general population will reduce bone loss or fracture risk. More recently, results from in vitro and in vivo studies using animal models indicate that ucOC is an active hormone with a positive role in glucose metabolism. By inference, vitamin K, which decreases ucOC, would have a detrimental effect. However, in humans this hypothesis is not supported by the limited data available, nor is it supported by what has been established regarding osteocalcin chemistry. In summary, the specific function of osteocalcin in bone and glucose metabolism has yet to be elucidated. PMID- 22516723 TI - Vitamin K status and vascular calcification: evidence from observational and clinical studies. AB - Vascular calcification occurs when calcium accumulates in the intima (associated with atherosclerosis) and/or media layers of the vessel wall. Coronary artery calcification (CAC) reflects the calcium burden within the intima and media of the coronary arteries. In population-based studies, CAC independently predicts cardiovascular disease (CVD) and mortality. A preventive role for vitamin K in vascular calcification has been proposed based on its role in activating matrix Gla protein (MGP), a calcification inhibitor that is expressed in vascular tissue. Although animal and in vitro data support this role of vitamin K, overall data from human studies are inconsistent. The majority of population-based studies have relied on vitamin K intake to measure status. Phylloquinone is the primary dietary form of vitamin K and available supplementation trials, albeit limited, suggest phylloquinone supplementation is relevant to CAC. Yet observational studies have found higher dietary menaquinone, but not phylloquinone, to be associated with less calcification. Vascular calcification is highly prevalent in certain patient populations, especially in those with chronic kidney disease (CKD), and it is plausible vitamin K may contribute to reducing vascular calcification in patients at higher risk. Subclinical vitamin K deficiency has been reported in CKD patients, but studies linking vitamin K status to calcification outcomes in CKD are needed to clarify whether or not improving vitamin K status is associated with improved vascular health in CKD. This review summarizes the available evidence of vitamin K and vascular calcification in population-based studies and clinic-based studies, with a specific focus on CKD patients. PMID- 22516724 TI - The role of vitamin K in soft-tissue calcification. AB - Seventeen vitamin K-dependent proteins have been identified to date of which several are involved in regulating soft-tissue calcification. Osteocalcin, matrix Gla protein (MGP), and possibly Gla-rich protein are all inhibitors of soft tissue calcification and need vitamin K-dependent carboxylation for activity. A common characteristic is their low molecular weight, and it has been postulated that their small size is essential for calcification inhibition within tissues. MGP is synthesized by vascular smooth muscle cells and is the most important inhibitor of arterial mineralization currently known. Remarkably, the extrahepatic Gla proteins mentioned are only partly carboxylated in the healthy adult population, suggesting vitamin K insufficiency. Because carboxylation of the most essential Gla proteins is localized in the liver and that of the less essential Gla proteins in the extrahepatic tissues, a transport system has evolved ensuring preferential distribution of dietary vitamin K to the liver when vitamin K is limiting. This is why the first signs of vitamin K insufficiency are seen as undercarboxylation of the extrahepatic Gla proteins. New conformation specific assays for circulating uncarboxylated MGP were developed; an assay for desphospho-uncarboxylated matrix Gla protein and another assay for total uncarboxylated matrix Gla protein. Circulating desphospho-uncarboxylated matrix Gla protein was found to be predictive of cardiovascular risk and mortality, whereas circulating total uncarboxylated matrix Gla protein was associated with the extent of prevalent arterial calcification. Vitamin K intervention studies have shown that MGP carboxylation can be increased dose dependently, but thus far only 1 study with clinical endpoints has been completed. This study showed maintenance of vascular elasticity during a 3-y supplementation period, with a parallel 12% loss of elasticity in the placebo group. More studies, both in healthy subjects and in patients at risk of vascular calcification, are required before conclusions can be drawn. PMID- 22516725 TI - Gla-rich protein, a new player in tissue calcification? AB - A novel gamma-carboxyglutamate (Gla)-containing protein, named Gla-rich protein (GRP) after its high content in Gla residues or upper zone of growth plate and cartilage matrix associated protein after its preferential expression by cartilage chondrocyte, was recently identified in sturgeon, mice, and humans through independent studies. GRP is the most densely gamma-carboxylated protein identified to date and its structure has been remarkably conserved throughout vertebrate evolution but is apparently absent from bird genomes. Several transcript and genomic variants affecting key protein features or regulatory elements were described and 2 paralogs were identified in the teleost fish genome. In the skeleton, most relevant levels of GRP gene expression were observed in cartilaginous tissues and associated with chondrocytes, suggesting a role in chondrogenesis. But GRP expression was also detected in bone cells, indicative of a more widespread role for the protein throughout skeletal formation. Although the molecular function of GRP is yet unknown, the high content of Gla residues and its accumulation at sites of pathological calcification in different human pathologies affecting skin or the vascular system and in breast cancer tumors suggest that GRP may function as a modulator of calcium availability. Because of its association with fibrillar collagens, GRP could also be involved in the organization and/or stabilization of cartilage matrix. Although transgenic mice did not reveal obvious phenotypic alterations in skeletal development or structure, zebrafish morphants lack craniofacial cartilage and exhibit limited calcification, suggesting a role for GRP during skeletal development, but additional functional data are required to understand its function. PMID- 22516726 TI - Vitamin K nutrition, metabolism, and requirements: current concepts and future research. AB - In 2001, the US Food and Nutrition Board concluded that there were insufficient data with which to establish a RDA for vitamin K, in large part because of a lack of robust endpoints that reflected adequacy of intake. Knowledge of the relative bioavailability of multiple vitamin K forms was also poor. Since then, stable isotope methodologies have been applied to the assessment of the bioavailability of the major dietary form of vitamin K in its free state and when incorporated into a plant matrix. There is a need for stable isotope studies with enhanced sensitivity to expand knowledge of the bioavailability, absorption, disposition, and metabolism of different molecular forms of vitamin K. Another area for future research stems from evidence that common polymorphisms or haplotypes in certain key genes implicated in vitamin K metabolism might affect nutritional requirements. Thus far, much of this evidence is indirect via effects on warfarin dose requirements. In terms of clinical endpoints, vitamin K deficiency in early infancy continues to be a leading cause of intracranial bleeding even in developed countries and the reasons for its higher prevalence in certain Asian countries has not been solved. There is universal consensus for the need for vitamin K prophylaxis in newborns, but the effectiveness of any vitamin K prophylactic regimen needs to be based on sound nutritional principles. In contrast, there is still a lack of suitable biomarkers or clinical endpoints that can be used to determine vitamin K requirements among adults. PMID- 22516727 TI - Growth arrest-specific gene 6 (gas6) and vascular hemostasis. AB - Gas6 (growth arrest-specific 6) belongs structurally to the family of plasma vitamin K-dependent proteins. Gas6 has a high structural homology with the natural anticoagulant protein S, sharing the same modular composition. Interestingly, despite the presence of a gamma-carboxyglutamic acid domain in its structure, no role in the coagulation cascade has been identified for gas6. Gas6 has been shown to be involved in vascular homeostasis and more precisely is involved in proliferation, apoptosis, efferocytosis, leukocyte migration, and sequestration and platelet aggregation. It is also involved in the activation of different cell types, from platelets to endothelial and vascular smooth muscle cells. Thus, it has been shown to play a role in several pathophysiological processes such as atherosclerosis, cancer, and thrombosis. Interestingly, studies using gas6 null mice highlighted that gas6 may represent a novel potential target for anticoagulant therapy, because these animals are protected from lethal venous thromboembolism without excessive bleeding. However, the mechanism in thrombus occurrence remains to be further explored. In the present review, we will focus on the role of gas6 in innate immunity, atherosclerosis, thrombosis, and cancer related events. PMID- 22516729 TI - Biotin. PMID- 22516728 TI - Vitamin K and the nervous system: an overview of its actions. AB - The role of vitamin K in the nervous system has been somewhat neglected compared with other physiological systems despite the fact that this nutrient was identified some 40 y ago as essential for the synthesis of sphingolipids. Present in high concentrations in brain cell membranes, sphingolipids are now known to possess important cell signaling functions in addition to their structural role. In the past 20 y, additional support for vitamin K functions in the nervous system has come from the discovery and characterization of vitamin K-dependent proteins that are now known to play key roles in the central and peripheral nervous systems. Notably, protein Gas6 has been shown to be actively involved in cell survival, chemotaxis, mitogenesis, and cell growth of neurons and glial cells. Although limited in number, studies focusing on the relationship between vitamin K nutritional status and behavior and cognition have also become available, pointing to diet and certain drug treatments (i.e., warfarin derivatives) as potential modulators of the action of vitamin K in the nervous system. This review presents an overview of the research that first identified vitamin K as an important nutrient for the nervous system and summarizes recent findings that support this notion. PMID- 22516730 TI - WHO Guideline: Vitamin A supplementation in pregnant women. Geneva: WHO, 2011; WHO Guideline: Vitamin A supplementation in postpartum women. Geneva: WHO, 2011. PMID- 22516731 TI - Protection by flavanol-rich foods against vascular dysfunction and oxidative damage: 27th Hohenheim Consensus Conference. AB - Criteria for assessing the purported protection by flavanol-rich foods against vascular dysfunction and oxidative damage to biomolecules was the subject of the 27th Hohenheim Consensus Conference held on July 11, 2011. State-of-the-art evidence was put into perspective, focusing on several questions that were followed by a consensus answer. Among the topics addressed were the major sources of flavanols in the human diet, the bioavailability of flavanols, biomarkers for "health benefit," and the biological function of flavanols. Consensus was reached on these topics. No conclusion was reached on the design of randomized, controlled trials for substantiation of health claims for flavanol-rich foods as to the necessity of a study arm with an isolated pharmacologically active compound, e.g., (-)-epicatechin. PMID- 22516732 TI - Building convergence in science, programs, and policy actions on child undernutrition: symposium rationale and overview. AB - Childhood stunting and wasting are often portrayed as relatively distinct manifestations of undernutrition. Little is known about how children progress from one manifestation of undernutrition to another as they grow older, nor how intervention strategies need to consider the potential overlap of these manifestations of undernutrition. While much is known about the causes of growth faltering in general, much less is known about which pre-disposing contextual and biological factors cause children to become stunted as opposed to wasted or both. Increasingly, nutrition researchers have tended to focus on one form of malnutrition or the other, lacking an integrated framework for understanding both phenomena. Similarly, some practitioner communities focus on prevention of stunting while others focus on recuperative treatment of wasting. The fragmentation of interests and perspectives on childhood undernutrition has negative consequences for advocacy efforts that aim to bring attention and resources to child nutrition across the globe. It also has serious implications for how children worldwide receive nutrition interventions and services. The symposium aimed to bring together a set of speakers from academic, practice and policy communities to discuss and debate these issues. PMID- 22516733 TI - Patterns of stunting and wasting: potential explanatory factors. AB - We investigated the causes of stunting and wasting using nationally representative data on preschool children from India (2005-2006, N = 41,306) and Guatemala (2008-2009, N = 10,317). We estimated stunting and wasting using the 2006 WHO standard and the 1976 WHO/National Center for Health Statistics (NCHS) reference. India and Guatemala had high levels of stunting; wasting was common in India but rare in Guatemala. Use of the WHO standard (based on breast-fed children) increased the prevalence of stunting in both countries but dramatically changed the pattern of wasting by age in India. In Indian children 0-5 mo of age, wasting more than tripled, from 8% to 30%, leading to the highest prevalence of wasting. Using the NCHS reference, the lowest and highest prevalence among Indian children occurred in children 0-5 and 12-23 mo, respectively. Also, we showed that household wealth and the condition of women were related to both stunting and wasting; review of the literature on wasting failed to identify factors that were not also related to stunting (e.g., seasonality, infections, and intrauterine growth retardation). Possible explanations for high levels of wasting in India include the poor status of women, the "thin-fat" infant phenotype, chronic dietary insufficiency, poor dietary quality, marked seasonality, and poor levels of sanitation. Use of the WHO standard calls for urgent attention to improving prenatal and infant nutrition and uncovers an alarming level of wasting in the young infant in India that use of the NCHS growth reference (based on bottle-fed infants) had masked. PMID- 22516734 TI - Promoting healthy growth: what are the priorities for research and action? AB - Healthy growth from conception through the first 2 y of life is the foundation for adequate organ formation and function, a strong immune system, physical health, and neurological and cognitive development. Recent studies identified several low-cost interventions to address undernutrition during this age period and noted the lower returns on investment of intervening after this critical period. Although these interventions should be implemented widely, it is recognized that existing nutrition solutions, even if universally applied, would only avert a minority fraction of the estimated death and disability due to undernutrition. This paper reviews some of the knowledge and learning needed to close this "impact gap." Five areas are prioritized for future research: 1) study healthy growth from a lifecycle perspective, because maternal, fetal, and newborn outcomes are connected; 2) understand why growth faltering begins so early in breast-fed infants in the developing world; 3) apply new tools and technologies to study long-recognized problems such as the interaction between nutrition and infection; 4) explore new hypotheses for understanding nutrient assimilation and use to discover and develop intervention leads; and 5) understand the role of the environment in healthy growth and the potential synergistic benefits of multi sectoral interventions. Policymakers are urged to invest in nutrition-specific and -sensitive interventions to promote healthy growth from conception through the first 2 y of life because of their immediate and long-term health and development benefits. PMID- 22516735 TI - Program responses to acute and chronic malnutrition: divergences and convergences. AB - Program approaches for addressing acute malnutrition and those for addressing chronic malnutrition have grown in different directions. Their specialization has led to productive advances in the efficacy of specific interventions but has also created divergences in implementation. Greater convergence and integration between the 2 sets of approaches would help programs respond to the diversity of conditions faced in the field and enable a more comprehensive continuum of care from prevention to treatment. After reviewing the causes of the differences in approach, this paper examines programmatic and scientific challenges to greater convergence and suggests steps to promote effective integration of acute and chronic malnutrition services. Steps include strengthening community linkages between program platforms, assessing the degree and type of integration needed in various situations, identifying cost efficiencies, and developing joint tools where possible. PMID- 22516736 TI - Revisiting the relationship of weight and height in early childhood. AB - Ponderal and linear growth of children has been widely studied; however, epidemiologic evidence of a relationship between the two is inconsistent. Child undernutrition in the form of low height for age and low weight for height continues to burden the developing world. A downward shift in the distribution of height for age in the first 2 y of life is commonly observed in many developing countries and is usually summarized as the percentage stunted (height for age Z score <-2). Similar shifts are seen in weight for height; however, weight-for height shifts are often less extreme, perhaps because weight for height is more tightly biologically controlled. Low height for age and low weight for height in childhood share some common factors, including food insecurity, infectious diseases, and inappropriate feeding practices. Reductions in weight for height, generally seen as a short-term response to inadequate dietary intake or utilization, are thought to precede decreases in height for age; however, given an adequate diet and no further insults, catch-up linear growth can occur. Serial instances of decreased weight for height, however, are thought to limit the degree of catch-up growth attained, contributing to linear growth retardation. Additional research is needed to identify the factors associated with recovery of linear growth after a child experiences decreased weight for height. Although the direct relationship between weight for height and height for age is likely limited, each of these measurements indicates important information about the general health of children and their risk of the development of illness or dying; therefore, eliminating the downward shift of height for age and weight for height in developing countries should be prioritized as a public policy. PMID- 22516738 TI - Prevention of aortic valve stenosis: a realistic therapeutic target? AB - Aortic valve stenosis (AS) is the most common form of valvular heart disease in the Western world, affecting ~40% of the population over the age of 80; to date the only established treatment is valve replacement. However, AS progression occurs over many years, and is associated from its earliest stages with increased risk of coronary events. Recent insight into the pathophysiology of AS has included central roles for angiotensin II, for diminished nitric oxide effect at the level of valve endothelium and matrix, and for inflammatory activation/redox stress culminating in activation of pro-calcific stimuli. Despite the presence of atheroma within the stenotic valve, hyperlipidemia per se does not play a critic role in the development of obstructive disease. We review emerging options for pharmacotherapy of AS, including in particular retardation of disease progression. The various clinical evaluations of lipid-reducing therapy have been uniformly unsuccessful in slowing AS progression. However, recent studies in animal models and retrospective evaluations in humans suggest that ACE inhibitors and/or angiotensin receptor blockers may be effective in this regard. Furthermore, agents normally utilized to treat osteoporosis also offer promise in retarding AS. Given the considerable morbidity, mortality and health care costs associated with AS, such therapeutic developments should be expedited. PMID- 22516739 TI - Prospective associations between meth/amphetamine (speed) and MDMA (ecstasy) use and depressive symptoms in secondary school students. AB - BACKGROUND: Research has raised significant concern regarding the affective consequences of synthetic drug use. However, little evidence from well-controlled longitudinal studies exists on these consequences. The aim of this study was to determine whether use of meth/amphetamine (speed) and +/-3,4 methylenedioxymethamphetamine (MDMA, ecstasy) is independently predictive of subsequent depressive symptoms in adolescents. METHODS: A sample of 3880 adolescents from secondary schools in disadvantaged areas of Quebec, Canada, were followed over time (2003-2008). Logistic regression was used to test the association between meth/amphetamine and MDMA use in grade 10 (ages 15-16 years) and elevated depressive symptoms on an abridged Center for Epidemiologic Studies Depression scale in grade 11, controlling for pre-existing individual and contextual characteristics. RESULTS: After adjustment, both MDMA use (OR 1.7, 95% CI 1.1 to 2.6) and meth/amphetamine use (OR 1.6, 95% CI 1.1 to 2.3) in grade 10 significantly increased the odds of elevated depressive symptoms in grade 11. These relationships did not vary by gender or pre-existing depressive symptoms. Increased risk was particularly observed in concurrent usage (OR 1.9, 95% CI 1.2 to 2.9). CONCLUSIONS: Adolescent use of meth/amphetamine and MDMA (particularly concurrent use) is independently associated with subsequent depressive symptoms. Further enquiry must determine whether these associations reflect drug-induced neurotoxicity and whether adolescence is a period of increased vulnerability to the hazards of synthetic drug exposure. PMID- 22516740 TI - Differential tissue distribution of metabolites in Jacobaea vulgaris, Jacobaea aquatica and their crosses. AB - Plants are attacked by many different herbivores. Some will consume whole leaves or roots, while others will attack specific types of tissue. Thus, insight into the metabolite profiles of different types of leaf tissues is necessary to understand plant resistance against herbivores. Jacobaea vulgaris, J. aquatica and three genotypes of their crossings were used to study the variation in metabolomic profiles between epidermis and mesophyll tissues. Extracts of epidermis and mesophyll tissues were obtained using carborundum abrasion (CA). Subsequently, (1)H nuclear magnetic resonance (NMR) spectroscopy and multivariate data analyses were applied to compare the metabolome profiles. Orthogonal partial least-squares-discriminant analysis (OPLS-DA) resulted in a clear separation of epidermis and mesophyll extracts. The epidermis contained significantly higher amounts of jacaranone and phenylpropanoids, specifically chlorogenic (5-O-CQA) and feruloyl quinic (FQA) acids compared to the mesophyll. In contrast, the mesophyll showed significantly higher concentrations of pyrrolizidine alkaloids (PAs), specifically jacobine and jaconine. The tissue specific distribution of these compounds was constant over all genotypes tested. Phenylpropanoids, 5-O-CQA and FQA, as well as PAs are known for their inhibitory effect on herbivores, especially against thrips. Thrips feeding commences with the penetration of the epidermis, followed by ingestion of sub-epidermal or mesophyll. Thrips thus may have to encounter phenylpropanoids in the epidermis as the first line of defence, before encountering the PAs as the ultimate defence in the mesophyll. The finding of tissue specific defense may have a major impact on studies of plant resistance. We cannot judge resistance using analyses of a whole roots, leafs or flowers. In such a whole-organism approach, the levels of potential defense compounds are far below the real ones encountered in tissues involved in the first line of defense. Instead, it is of great importance to study the defence compounds in the specific tissue to which the herbivore is confined. PMID- 22516741 TI - Aphid antixenosis in cotton is activated by the natural plant defence elicitor cis-jasmone. AB - Upon insect herbivory, plants can release blends of volatile organic compounds (VOCs) that modify herbivore and natural enemy behaviour. We have shown recently that cotton, Gossypium hirsutum, emits a blend of defence VOCs that repels the cotton aphid, Aphis gossypii, upon herbivory by this notorious crop pest, including (Z)-3-hexenyl acetate, (E)-4,8-dimethyl-1,3,7-nonatriene (DMNT), methyl salicylate and (E,E)-4,8,12-trimethyl-1,3,7,11-tridecatetraene (TMTT). In this study, we investigated changes in the defence VOC profile of G. hirsutum induced by the naturally-occurring plant elicitor cis-jasmone (CJ) and whether these changes modify the behaviour of A. gossypii. In four-arm olfactometer assays, VOCs from untreated plants were significantly attractive (P<0.05), whilst VOCs from CJ-treated plants were significantly repellent (P<0.05). The VOCs induced by CJ appeared to comprise (Z)-3-hexenyl acetate, DMNT, methyl salicylate and TMTT. In quantitative VOC collection studies, sustained release of DMNT and TMTT was observed in CJ-treated plants over a period of five days, with levels becoming statistically significantly higher than for control treated plants on the fifth day in most cases. Despite earlier indications, no statistically significant differences were observed in levels of (Z)-3-hexenyl acetate or methyl salicylate between CJ and control treatments on any day. Furthermore, DMNT and TMTT emissions from CJ-treated plants were further enhanced by subsequent addition of A. gossypii. CJ treatment induced statistically significantly higher DMNT and TMTT expression levels as early as day three, when A. gossypii was present. The results in this study show that CJ can induce the production of A. gossypii induced VOCs from G. hirsutum, with potential for deployment in novel crop protection strategies. PMID- 22516742 TI - Distributed computation: the new wave of synthetic biology devices. AB - Synthetic biology (SB) offers a unique opportunity for designing complex molecular circuits able to perform predefined functions. But the goal of achieving a flexible toolbox of reusable molecular components has been shown to be limited due to circuit unpredictability, incompatible parts or random fluctuations. Many of these problems arise from the challenges posed by engineering the molecular circuitry: multiple wires are usually difficult to implement reliably within one cell and the resulting systems cannot be reused in other modules. These problems are solved by means of a nonstandard approach to single cell devices, using cell consortia and allowing the output signal to be distributed among different cell types, which can be combined in multiple, reusable and scalable ways. PMID- 22516743 TI - Next-generation sequencing offers new insights into DNA degradation. AB - The processes underlying DNA degradation are central to various disciplines, including cancer research, forensics and archaeology. The sequencing of ancient DNA molecules on next-generation sequencing platforms provides direct measurements of cytosine deamination, depurination and fragmentation rates that previously were obtained only from extrapolations of results from in vitro kinetic experiments performed over short timescales. For example, recent next generation sequencing of ancient DNA reveals purine bases as one of the main targets of postmortem hydrolytic damage, through base elimination and strand breakage. It also shows substantially increased rates of DNA base-loss at guanosine. In this review, we argue that the latter results from an electron resonance structure unique to guanosine rather than adenosine having an extra resonance structure over guanosine as previously suggested. PMID- 22516744 TI - Autoimmune manifestations in patients with visceral leishmaniasis. AB - Visceral leishmaniasis (VL) is a vector-borne protozoal infection caused by replication of Leishmania species in macrophages. VL is characterized by fever, hepatosplenomegaly and cytopenia. Apart from those classic clinical characteristics, VL has been associated with autoimmune clinical and laboratory features. Reported herein are 16 consecutive patients with VL who were checked for laboratory autoimmune manifestations. A variety of autoimmune antibodies including elevated titers of antinuclear antibodies and rheumatoid factor were detected in all patients. Of note, no laboratory autoimmune manifestations were detected in the seven patients who were re-evaluated 3 months after therapy. It is concluded that autoimmune laboratory manifestations during VL infection are common. These may mistakenly lead to diagnosis of an autoimmune disorder. PMID- 22516745 TI - Brevundimonas vesicularis bacteremia resistant to trimethoprim-sulfamethoxazole and ceftazidime in a tertiary hospital in southern Taiwan. AB - BACKGROUND: Over the past 20 years, Brevundimonas vesicularis has rarely been reported as a pathogen causing human infection. The clinical manifestations of B. vesicularis bacteremia and its susceptibility to antibiotics has not been characterized. METHODS: A retrospective study was conducted between 2006 and 2009 in a tertiary-care hospital in southern Taiwan. RESULTS: A total of 22 cases of B. vesicularis bacteremia were identified during the study with 86% being community-acquired primary bloodstream infections. Of the 22 patients, 15 (68%) presented with fever, fewer comorbidities, shorter hospital stays, lower mean creatinine levels (1.10 mg/dL vs. 1.74 mg/dL), lower aspartate aminotransferase levels (29.1 IU/L vs. 79.0 IU/L), and lower alanine aminotransferase levels (16.4 IU/L vs. 67.0 IU/L) when compared to afebrile patients. Among the bacterial isolates, 90.9% were susceptible to cefpirome, imipenem and piperacillin/tazobactam while 86.4% were susceptible to gentamicin, amikacin and ciprofloxacin. However, 63.6% of the bacterial isolates were susceptible to ceftazidime, and only 59.1% were susceptible to trimethoprim-sulfamethoxazole (TMP-SMX). The 30-day mortality rate from all causes was 4.5%. CONCLUSION: B. vesicularis is able to cause community-acquired and low-mortality primary bloodstream infections. The resistance of B. vesicularis to trimethoprim sulfamethoxazole and ceftazidime limits the choice of available antibiotics for treatment. PMID- 22516746 TI - Study of the endoparasitic fauna of commensal rats and shrews caught in traditional wet markets in Taichung City, Taiwan. AB - BACKGROUND: Rats live in close proximity to human populations. Feral rodents are known to transmit diseases and act as reservoir hosts to many zoonotic parasites that pose health risks to humans. The aim of this study is to investigate endoparasitic infections in commensal rats and shrews caught in traditional wet markets in Taichung City, Taiwan. METHODS: A total of 51 commensal wild rodents and shrews were caught in traditional wet markets in Taichung City, including 32 Rattus norvegicus, 11 R. rattus, and eight Suncus murinus. All tissues, organs, and intestinal contents were carefully examined after euthanasia for the detection of parasites. RESULTS: The overall prevalence of infection was 94.1%, and the infection rates in R. norvegicus, R. rattus, and S. murinus were 93.8%, 90.9%, and 100.0%, respectively. Four cestodes (Taenia taeniaeformis, Hymenolepis diminuta, H. nana, and Raillietina celebensis), seven nematodes (Angiostrongylus cantonensis, Capillaria hepatica, Heterakis spumosa, Nippostrongylus brasiliensis, Strongyloides ratti, Syphacia muris, and Trichosomoides crassicauda), and one protozoan (Sarcocystis spp.) were detected. CONCLUSION: Our findings indicate that commensal rodents and shrews found in the traditional wet markets of Taichung City are hosts to various zoonotic parasites and, therefore, pose a serious health risk to humans and domestic animals in Taiwan. PMID- 22516747 TI - Expression profiles of six novel C-type lectins in response to bacterial and 20E injection in the cotton bollworm (Helicoverpa armigera). AB - C-type lectins can act as pattern recognition receptors (PRRs) and play an important role in innate immunity. Two C-type lectins (HaCTL1 and HaCTL2) have been previously identified in the cotton bollworm (Helicoverpa armigera). Here we isolate six C-type lectins from H. armigera (HaCTL3, 4, 5, 6, 7 and 8). All six new HaCTLs encode a signal peptide (or partial signal peptide) and complete tandem carbohydrate-recognition domains (CRDs). HaCTL4, 5, 6, 7 and 8 mRNA increased in the fat body after injection with both killed Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus, whereas HaCTL3 mRNA was upregulated following E. coli injection only. Recombinant HaCTL3 exhibited agglutinating activity against both Gram-negative and Gram-positive bacteria in a calcium-dependent manner. Agglutination inhibitory analysis indicated that rHaCTL3 recognizes maltose, trehalose, peptidoglycan and lipopolysaccharides. HaCTL3 and HaCTL8 mRNA showed upregulation while HaCTL4, 5, and 6 mRNA downregulation post 20-Hydroxyecdysone (20E) injection. Our results indicate that the six novel C-type lectins of H. armigera may play important roles in defending against bacteria as PRRs and the hormone 20E can function in regulating immunity through lectins. PMID- 22516748 TI - Molecular cloning and functional study of calreticulin from a lepidopteran pest, Pieris rapae. AB - Insects have an effective innate immune system to protect themselves from exogenous invaders. Calreticulin is a multifunctional protein mainly involved in directing proper conformation of proteins, controlling calcium level, and participating in immune responses. Previous suppression subtractive hybridization assay showed that the expression of Pieris rapae calreticulin (PrCRT) was suppressed after injection of Pteromalus puparum venom. In this study, we obtained a full length cDNA of PrCRT and expressed recombinant wild type and the N-domain deleted mutant PrCRT in bacteria. Real time quantitative PCR and western blot analyses showed that PrCRT mRNA and protein were expressed in hemocytes, Malpighian tubule, midgut, epidermis and fat body, with a higher level in hemocytes. PrCRT was probably located in endoplasmic reticulum distributing in the cytoplasm of hemocytes. Recombinant PrCRT was first able to attach and then enter the hemocytes by endocytosis. PrCRT mRNA in hemocytes was significantly induced after injection of yeast or beads, but did not change noticeably after injection of Escherichia coli or Micrococcus lysodeikticus. Recombinant PrCRT enhanced cellular encapsulation by P. rapae hemocytes in vitro, and the N-domain of PrCRT was required for encapsulation. RNAi of PrCRT by dsRNA injection impaired the ability of hemocytes to encapsulate beads. After parasitization by P. puparum, PrCRT mRNA and protein levels in P. rapae pupal hemocytes were significantly suppressed compared to non-parasitized control. Our results suggest that PrCRT is involved in cellular encapsulation and the pupal parasitoid P. puparum can decrease PrCRT expression to impair host cellular immune response. PMID- 22516749 TI - Identification of a putative nuclear export signal motif in human NANOG homeobox domain. AB - NANOG is a homeobox-containing transcription factor that plays an important role in pluripotent stem cells and tumorigenic cells. To understand how nuclear localization of human NANOG is regulated, the NANOG sequence was examined and a leucine-rich nuclear export signal (NES) motif ((125)MQELSNILNL(134)) was found in the homeodomain (HD). To functionally validate the putative NES motif, deletion and site-directed mutants were fused to an EGFP expression vector and transfected into COS-7 cells, and the localization of the proteins was examined. While hNANOG HD exclusively localized to the nucleus, a mutant with both NLSs deleted and only the putative NES motif contained (hNANOG HD-DeltaNLSs) was predominantly cytoplasmic, as observed by nucleo/cytoplasmic fractionation and Western blot analysis as well as confocal microscopy. Furthermore, site-directed mutagenesis of the putative NES motif in a partial hNANOG HD only containing either one of the two NLS motifs led to localization in the nucleus, suggesting that the NES motif may play a functional role in nuclear export. Furthermore, CRM1-specific nuclear export inhibitor LMB blocked the hNANOG potent NES-mediated export, suggesting that the leucine-rich motif may function in CRM1-mediated nuclear export of hNANOG. Collectively, a NES motif is present in the hNANOG HD and may be functionally involved in CRM1-mediated nuclear export pathway. PMID- 22516750 TI - Salvianolic acid A protects human SH-SY5Y neuroblastoma cells against H2O2 induced injury by increasing stress tolerance ability. AB - Salvianolic acid A (Sal A) is a polyphenol extracted from the root of the Salvia miltiorrhiza bunge. Hydrogen peroxide (H(2)O(2)) is a major reactive oxygen species (ROS), which has been implicated in stroke and other neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. In this study, we investigated the neuroprotective effects of Sal A in human SH-SY5Y neuroblastoma cells against H(2)O(2)-induced injury. Our results showed that cells pretreated with Sal A exhibited enhanced neuronal survival and that this protection was associated with an increase in adenosine triphosphate (ATP) and the stabilization of mitochondrial membrane potential. In addition, Sal A markedly decreased the excessive activation AMP-activated protein kinase (AMPK) and the serine-threonine protein kinase, Akt, in SH-SY5Ycells induced by H(2)O(2). In conclusion, our results demonstrated that Sal A protects SH-SY5Y cells against H(2)O(2)-induced oxidative stress and these protective effects are related to stress tolerance and not energy depletion via inhibition of the AMPK and Akt signaling pathway. PMID- 22516751 TI - NOK/STYK1 has a strong tendency towards forming aggregates and colocalises with epidermal growth factor receptor in endosomes. AB - Our previous studies showed that the overexpression of Novel Oncogene with Kinase domain (NOK)/STYK1 led to cellular transformation, tumorigenesis and metastasis. This report characterises the subcellular distribution of NOK in HeLa cells and its localisation in early endosomes. Confocal immunolocalisation studies indicated that NOK had structural subtypes and was distributed into two distinct expression patterns: a dot pattern (DP) and an aggregation pattern (AP). The results of an immunohistochemistry (IHC) analysis of pathological tissues also showed that high expression level of endogenous NOK was expressed in an aggregate like structure in vivo. Importantly, we found that NOK was localised in endosomes and colocalised with epidermal growth factor receptor (EGFR) in activated endosomal vesicles. However, as the stimulation time increased, NOK and EGFR began to progress through different pathways. EGFR was gradually degraded after treatment with EGF for approximately 20 min, whereas NOK levels were not reduced. This result suggests that NOK mainly plays a role in facilitating the trafficking of EGFR from early endosomes to later endosomes/lysosomes. Taken together, NOK has a strong tendency towards forming aggregates, which may have physiological implications and provide the first evidence that this novel receptor kinase is colocalised with EGFR in endosomes to participate in a post-internalisation step of EGFR. PMID- 22516752 TI - Live free or die: stretch-induced apoptosis occurs when adaptive reorientation of annulus fibrosus cells is restricted. AB - High matrix strains in the intervertebral disc occur during physiological motions and are amplified around structural defects in the annulus fibrosus (AF). It remains unknown if large matrix strains in the human AF result in localized cell death. This study investigated strain amplitudes and substrate conditions where AF cells were vulnerable to stretch-induced apoptosis. Human degenerated AF cells were subjected to 1 Hz-cyclic tensile strains for 24h on uniformly collagen coated substrates and on substrates with 40 MUm stripes of collagen that restricted cellular reorientation. AF cells were capable of responding to stretch (stress fibers and focal adhesions aligned perpendicular to the direction of stretch), but were vulnerable to stretch-induced apoptosis when cytoskeletal reorientation was restricted, as could occur in degenerated states due to fibrosis and crosslink accumulation and at areas where high strains occur (around structural defects, delaminations, and herniations). PMID- 22516754 TI - microRNA-27b suppresses mouse MSC migration to the liver by targeting SDF 1alphain vitro. AB - The SDF-1/CXCR4 axis is critical for inducing stem cell mobilization into the circulation, for homing stem cells to the site of injury, and for stem cell participation in the regeneration of liver tissue. In this study, we have gained insight into the molecular mechanisms involved in regulating the expression of SDF-1alpha by miRNAs. Using microarray and bioinformatics approaches, we identified six miRNAs with differential expression in damaged liver tissue (21 days after liver injury) compared to normal C57BL/6 murine liver tissue and further confirmed these observations by qPCR; miR-23a, which was identified by other researchers, was also included for comparative purposes. We found that miR 23a, miR-27a and miR-27b expression was significantly lower in the damaged liver than in the normal liver (p<0.05). We further confirmed that miR-27b could directly interact with the 3'UTR of SDF-1alpha to suppress SDF-1alpha protein expression using a luciferase reporter assay and Western blot analysis. In addition, we found that the over-expression of miR-27b significantly reduced the directional migration of primary cultured CRCX4-positive murine mesenchymal stem cells (mMSCs) in vitro using a transwell assay. These results suggest that miR 27b may be a unique signature of the stem cell niche in the damaged mouse liver and that mir-27b can suppress the directional migration of mMSCs by down regulating SDF-1alpha expression by binding directly to the SDF-1alpha 3'UTR. PMID- 22516753 TI - ABCA1 upregulating apolipoproein M expression mediates via the RXR/LXR pathway in HepG2 cells. AB - We have previously reported that liver X receptor (LXR) agonist, TO901317, could significantly inhibit hepatic apolipoprotein M (apoM) expression. It has been reported that TO901317 could activate the ATP-binding cassette transporter A1 (ABCA1) that mediates cholesterol efflux to the lipid-poor apoAI, which is an essential step for the high-density lipoprotein (HDL) formation. It is unknown if ABCA1 may regulate hepatic apoM expression. In the present study, HepG2 cells were cultured with the synthetic LXR agonists, TO901317 or GW3965 in the presence or absence of ABCA1 antagonist, disodium 4,4'-diisothiocyanatostilbene- 2,2' disulfonate (DIDS). The mRNA levels of ABCA1, apoM and liver receptor homolog-1 (LRH-1) determined by the real-time RT-PCR. It demonstrated that both TO901317 and GW3965 could significantly enhance ABCA1 expression, and simultaneously, inhibit LRH1 expression. However, TO901317 alone could significantly inhibit apoM expression, while GW3965 alone did not influence apoM expression. ABCA1 antagonist, DIDS, have no effects on GW3965 induced upregulation of ABCA1 and downregulation of LRH1. However, apoM mRNA level was significantly decreased when the cells cultured with GW3965 together with DIDS. The present study demonstrated that apoM expression could be elevated by ABCA1 via the RXR/LXR pathway and LRH1 does not involve in the regulation of apoM by the activation of ABCA1, although the direct regulative pathway(s) between ABCA1 and apoM gene is still unknown yet. The detailed mechanism needs further investigation. PMID- 22516755 TI - The social determinants of health. PMID- 22516756 TI - Non-acid-fastness in Mycobacterium tuberculosis DeltakasB mutant correlates with the cell envelope electron density. AB - The acid-fastness is the most important and the most specific characteristics in mycobacteria, the mechanism of which is not clear but may be attributed to the lipid rich cell wall of this bacterium. While the exact component(s) responsible for this staining method remained unidentified, a Mycobacterium tuberculosis mutant, attenuated strain that produced shorter mycolic acids with defects in trans-cyclopropanation was shown to be acid fast negative. In this study, we examined the ultrastructure of the cell envelope (CE) of the mutant strain DeltakasB (missing a beta-ketoacyl-ACP synthase involved in mycolic acid biosynthesis), the parental CDC1551 (wild type strain) and kasB complemented strain, and compared ultrastructural differences among them with conventional transmission electron microscopy (TEM) and cryo-transmission electron microscopy (CEM). Conventional TEM revealed that there were no detectable differences in the thickness of the cell envelope among three strains (wild-type: 43.35 +/- 6.13 nm; DeltakasB: 45.98 +/- 11.32 nm; complement: 40.71 +/- 6.3 nm). However, CEM data demonstrated that the region between the inner and outer membranes of the mutant strain, which is composed mainly of cell wall anchored mycolic acids (MA), showed a significant decrease in electron density as compared to the wild type and kasB complement strain (567.1 +/- 372.7 vs. 301.4 +/- 262.1, or vs. 235.2 +/- 174.9, p < 0.02 or p < 0.001, respectively). These results suggested that altered MA patterns in the kasB mutant may have affected the packing of the lipid rich layer of the M. tuberculosis cell envelope, resulting in a reduced electron density of this layer as seen by CEM and loss of acid-fastness in light microscopical observation, and we propose a novel model of the cell envelope structure in tubercle bacilli. PMID- 22516757 TI - Influence of activated carbon and biochar on phytotoxicity of air-dried sewage sludges to Lepidium sativum. AB - The goal of the research was to determine the phytotoxicity (using Lepidium sativum) of two activated carbon/biochar-amended sewage sludges. Apart from the impact of the AC/biochar dose, the influence of biochar particle diameter (<300, 300-500 and >500 MUm) and the influence of the contact time (7, 60, 90 days) between AC/biochar and sewage sludges on their phytotoxicity was also assessed. No negative impact of sewage sludges on seed germination was observed (P>0.05). The application of AC or biochar to the sludges positively affected root growth by reducing the harmful effect by 7.8 to 42% depending on the material used. Furthermore, the reduction range clearly depended on the type of sewage sludge. No differences were observed in the inhibition of the toxic effect between both biochar types used and the biochar particle size. The extension of the contact time between AC/biochar and sewage sludges had a negative impact on root growth. PMID- 22516758 TI - Superimposed lateralized exanthema of childhood: a proposed explanation for an enigmatic disorder. PMID- 22516760 TI - Chloropicrin induces endoplasmic reticulum stress in human retinal pigment epithelial cells. AB - Chloropicrin is an aliphatic volatile nitrate compound that is mainly used as a pesticide. It has several toxic effects in animals and can cause irritating and other health problems in exposed humans. Since the mode of chloropicrin action is poorly understood, the aim of this study was to investigate molecular responses underlying chloropicrin toxicity. We used human retinal pigment epithelial cells (ARPE-19) as a model cell type because the eyes are one of the main target organs affected by chloropicrin exposure. Transmission electron microscopy images revealed that exposure to a chloropicrin concentration that decreased cell viability by 50%, evoked the formation of numerous electron-lucent, non-autophagy vacuoles in the cytoplasm with dilatation of the endoplasmic reticulum (ER). Lower concentrations led to the appearance of more electron-dense vacuoles, which contained cytoplasmic material and were surrounded by a membrane resembling autophagy vacuoles. According to immunoblotting analyses chloropicrin increased the amount of the ER-stress related proteins, Bip (about 3-fold compared to the controls), IRE1alpha (2.5-fold) and Gadd 153/Chop (2.5-fold), evidence for accumulation of misfolded proteins in the ER. This property was further confirmed by the increase of reactive oxygen species (ROS) production (2-2.5-fold), induction of heme oxygenase-1 (about 6-fold), and increase in the level of the tumour suppressor protein p53 (2-fold). Thus, the cytotoxicity of chloropicrin in the retinal pigment epithelium is postulated to be associated with oxidative stress and perturbation of the ER functions, which are possibly among the mechanisms involved in oculotoxicity of chloropicrin. PMID- 22516759 TI - In vitro cytotoxicity and mutagenicity of mainstream waterpipe smoke and its functional consequences on alveolar type II derived cells. AB - INTRODUCTION: While waterpipe tobacco smoking has become a global phenomenon, its potential health consequences are poorly understood. In this manuscript, we report the in vitro mutagenicity of waterpipe smoke condensate (WSC), the alteration in cellular parameters of lung alveolar cells in response to WSC exposure and discuss the implication of cellular responses in the pathophysiology of chronic obstructive pulmonary disease (COPD). METHODS: The mainstream WSC was generated using a standard laboratory machine protocol. We assessed its mutagenicity using Ames test. In addition, we studied the effect of WSC on the proliferation and cell cycle of alveolar type II cells and vascular endothelial cells. We also assessed the effect of WSC on the expression of genes involved in cell cycle arrest and inflammation. RESULTS: Within the range of tested doses, WSC did not elicit sufficient response to be considered mutagenic in any of the strains tested (TA98, TA100, TA102, and TA97a) but were found to be toxic for strains TA97a and TA102 at the highest tested doses. However, WSC induced cell cycle arrest and cellular senescence mediated by the p53-p21 pathway. Also our study indicated that WSC induced an increase in the transcriptional expression of matrix metalloproteinases, MMP-2 and MMP-9 and an immune response regulator, Toll Like Receptor-4. CONCLUSION: The data reported here represent the first in vitro demonstration of the effect of waterpipe smoke on cellular parameters providing evidence of the potential involvement of WPS in the pathogenesis of COPD through impairing cellular growth and inducing inflammation. PMID- 22516761 TI - Lipid and colour stability of M. longissimus muscle from lambs fed camelina or linseed as oil or seeds. AB - Colour and lipid stability of M. longissimus dorsi (LD) from sheep fed diets containing different lipid sources (Megalac (MG), camelina oil (CO), linseed oil (LO), NaOH-treated camelina seed (CS), NaOH-treated linseed (LS) or CO treated with ethanolamine (CA)) were examined. After 100 days on-feed, samples of LD were collected, fatty acid profile determined and colour and lipid oxidation (2 thiobarbituric acid reactive substances; TBARS) measured during retail display in high oxygen packaging. The LS ration was most effective in increasing the 18:3n-3 and conjugated linoleic acid (CLA) concentration in muscle. Within camelina, CA resulted in the highest 18:3n-3 and lowest CLA concentration in muscle. There was no difference in colour stability. Oil (seed) supplementation increased TBARS compared to MG in the early part of display while linseed-based rations tended to cause higher TBARS than camelina-based rations. Higher muscle 18:3n-3 concentration was associated with higher oxidation during early retail display but this was not reflected in a loss of colour stability. PMID- 22516762 TI - Is travel-time to a specialist centre a risk factor for non-referral, non attendance and loss to follow-up among patients with hepatitis C (HCV) infection? AB - Little is known about why many people diagnosed with hepatitis C virus (HCV) infection fail to reach and stay within specialist care services. We used a Geographic Information System and logit regression to investigate whether travel time to a specialist centre was associated with an increased likelihood of non referral, non-attendance and loss to follow-up among persons diagnosed with HCV between 1991 and 2003 in Tayside, Scotland (UK). Information was available on referral to, and utilisation of, the single HCV specialist centre in Tayside between 1991 and 2006. Longer travel-time to a specialist centre was associated with an increased likelihood of non-referral to a specialist centre following diagnosis (Odds Ratio: 1.25, 95% Confidence Interval: 1.09, 1.44). Patients living further from an HCV specialist centre were less likely to be referred to it for treatment that could cure their HCV infection. Neither a history of intravenous drug use (IDU), nor area deprivation predicted non-referral. Subsequent to referral, travel-time to a specialist centre was not associated with either non-attendance (0.83 (0.56, 1.21)) or loss to follow-up (0.98 (0.78, 1.22)), although a history of IDU was a strong predictor of both non-attendance and loss to follow-up. Non-attendance was less likely among older patients, while loss to follow-up was more common among those living in deprived areas. Once referred, patients appear able to cope with stress and financial cost of long and frequent journeys to hospital. However, as rates of referral improve from more geographically remote areas, long travel-times to an HCV specialist centre may become an important factor determining future utilisation. PMID- 22516763 TI - Corticotroph deficiency. AB - Corticotroph deficiency usually results from exogenous glucocorticoid therapy or, more rarely, from hypothalamopituitary damages. Its diagnostic may be difficult, especially when the deficit in ACTH secretion is partial. Stimulation tests are then necessary to investigate the integrity of the hypothalamopituitary-adrenal axis. The insulin tolerance test has become the gold standard, but its utilization is limited by several contra-indications. The metyrapone and cosyntropin tests represent currently used alternatives but their sensitivity is not optimal. Measurement of basal plasma dehydroepiandrosterone sulfate may allow excluding corticotroph deficiency when normal. Finally, cortisol replacement in patients with corticotropic deficiency is based on hydrocortisone administration. However, the dose regimens employed in clinical practice do not allow mimicking the nycthemeral rhythm of cortisol secretion and are still disputed. PMID- 22516764 TI - [MRI of hypophysitis]. AB - The pattern of adenohypophysitis is that of an enlarged pituitary gland in a normal sized sellar turcica with intense enhancement after gadolinium injection. The pattern of infundibulo-neurohypophysitis is that of a diabetes insipidus, i.e. enlargement of the pituitary stalk without any storage of the antidiuretic hormone. PMID- 22516765 TI - Dissemination of multidrug-resistant Escherichia coli in Korean veterinary hospitals. AB - This study was performed to investigate the prevalence of rectal colonization with multidrug-resistant Escherichia coli in dogs hospitalized at veterinary hospitals in Korea and to assess the molecular epidemiologic traits of this organism. A total of 63 unique E. coli isolates obtained from the rectal swabs of hospitalized dogs were analyzed. Genes encoding CTX-M extended-spectrum beta lactamases (ESBLs) and AmpC enzymes were detected in 21 (33.3%) and 15 (23.8%) canine E. coli isolates, respectively. Twelve canine E. coli isolates harbored both the genes encoding the CTX-M and AmpC enzymes. Six ESBL-producing E. coli isolates also carried the rmtB gene. All 24 E. coli isolates producing CTX-M ESBL and/or CMY-2 were resistant to ciprofloxacin. Furthermore, mutations were found in the gyrA and the parC genes. In most cases, the bla genes of the CTX-M ESBL and AmpC enzymes and the rmtB gene were localized to incompatibility group F (IncF) plasmids. Possible small clonal outbreaks are suggested because some E. coli isolates recovered in the same veterinary hospital were identified as identical sequence types and showed identical banding patterns in repetitive sequence-based polymerase chain reaction. The horizontal transfer of IncF plasmids and the clonal transfer of E. coli strains are suggested to play a role in the dissemination of antimicrobial resistance genes, and this transfer may occur across host species (i.e., between humans and dogs). PMID- 22516766 TI - Team-based learning, a learning strategy for clinical reasoning, in students with problem-based learning tutorial experiences. AB - Acquiring clinical reasoning skills in lectures may be difficult, but it can be learnt through problem-solving in the context of clinical practice. Problem finding and solving are skills required for clinical reasoning; however, students who underwent problem-based learning (PBL) still have difficulty in acquiring clinical reasoning skills. We hypothesized that team-based learning (TBL), a learning strategy that provides the opportunity to solve problems by repeatedly taking tests, can enhance the clinical reasoning ability in medical students with PBL experiences during the pre-clinical years. TBL courses were designed for 4(th) year students in a 6-year program in 2008, 2009, and 2010. TBL individual scores, consisting of a combination of individual and group tests, were compared with scores of several examinations including computer-based testing (CBT), an original examination assessing clinical reasoning ability (problem-solving ability test; P-SAT), term examinations, and Objective Structured Clinical Examination (OSCE). CBT, OSCE and P-SAT scores were compared with those of students who learned clinical reasoning only through PBL tutorials in 2005, 2006, and 2007 (non-TBL students). Individual TBL scores of students did not correlate with scores of any other examination. Assessments on clinical reasoning ability, such as CBT, OSCE, and P-SAT scores, were significantly higher in TBL students compared with non-TBL students. Students found TBL to be effective, particularly in areas of problem solving by both individuals and teams, and feedback from specialists. In conclusion, TBL for clinical reasoning is useful in improving clinical reasoning ability in students with PBL experiences with limited clinical exposure. PMID- 22516767 TI - High-rate production of functional nanostructured films and devices by coupling flame spray pyrolysis with supersonic expansion. AB - The fabrication of functional thin films and devices by direct deposition of nanoparticles from the gas phase is a promising approach enabling, for instance, the integration of complex analytical and sensing capabilities on microfabricated platforms. Aerosol-based techniques ensure large-scale nanoparticle production and they are potentially suited for this goal. However, they are not adequate in terms of fine control over the lateral resolution of the coatings, mild processing conditions (avoiding high temperature and aggressive chemicals), low contamination and compatibility with microfabrication processes. Here we report the high-rate and efficient production of functional nanostructured films by nanoparticle assembling obtained by the combination of flame spray pyrolysis and supersonic expansion. Our approach merges the advantages of flame spray pyrolysis for bulk nanopowders such as process stability and wide material library availability with those of supersonic cluster beam deposition in terms of lateral resolution and of direct integration of nanomaterials on devices. We efficiently produced nanostructured films and devices (such as gas sensors) using metal oxide, pure noble metal and oxide-supported noble metal nanoparticles. PMID- 22516768 TI - [The impact of dysglycemia on brain function in children with type 1 diabetes mellitus]. AB - Diabetes is a metabolic disease defined by increased blood glucose level above the references value. Insulin therapy is mandatory for all patients with type 1 diabetes melitus (T1DM). However, the insulin therapy is also the potential factor of hyperglycemia as well as hypoglycemia condition called dysglycemia. Moreover, T1DM leads to late organ changes such as retinopathy and nephropathy primarily due to diabetic angiopathy. Neuropathy is one of diabetic complications which can occur from the beginning of the disease. The pathogenesis of diabetic neuropathy, a structural and morphological abnormality, has been well described. In adults with T1DM diagnosed in childhood more frequent incidence of epilepsy, abnormal EEG and impaired cognitive functions were diagnosed. In children with type I diabetes further in depth studies are needed concerning the structural and functional damage of the central nervous system (cns). Research studies carried out in children have shown that the metabolic and morphological cns changes are the result of both hypo- and hyperglycemia. PMID- 22516769 TI - [Prospective Polish insulin pump therapy programme in children with type 1 diabetes]. AB - BACKGROUND: Continuous subcutaneous insulin infusion (CSII) in pre-pubertal children with type 1 diabetes (T1DM) has been introduced in Polish Diabetic Centres since 2000. Due to the lack of education and treatment standards for CSII we have initiated the National Prospective Pump Programme (OPPLP) in the 16 Diabetic Centres in Poland. AIM: The aim of this programme was to prepare the paediatric diabetic centres for implementation of insulin pump treatment in children and assessment of the effectiveness of this treatment as compared to multiple daily injections. METHOD: The Programme has been conducted in 16 centres in two stages - the first from 2003 to2005 - included the education of Health Care Providers (HCP), and the second clinical data collection of patients and evaluation of treatment effectiveness on the basis of estimation of HbA1c in the Central Laboratory. Electronic net-work system - enCapture with central server was used. RESULTS: The HCP' education as well as the data collection system were assessed positively. CONCLUSION: The OPPLP can be the basis of a National Register of children with T1DM. The Register could be used also for cost effectiveness assessment of the patients with T1DM treatment. PMID- 22516770 TI - [Quality of treatment in children with type 1 diabetes based on the Polish Prospective Pump Programme]. AB - BACKGROUND: In pediatric patients with type 1 diabetes mellitus, the value of HbA1c is a predictor of the risk of late systemic complications in adulthood. In the last years significant changes in the method of treatment in pre-pubertal children with T1DM have taken place. However, there is lack of precise data concerning the results of metabolic control of this group of patients. THE AIM: was to assess the impact of the Polish Prospective Insulin Pump Programme (OPPLP) on the quality of metabolic control in prepubertal children with T1DM. The OPPLP included also education for diabetological staff (HPC) from the Polish Diabetic Centres as well as standardization of continuous subcutaneous insulin infusion (CSII) implementation procedures. MATERIAL AND METHODS: Population studies were conducted in the years: 2005-2008. 920 patients were enrolled at age from 1.2 to 14.6 years (median 8.5 years). 71.75 % of patients were in pre-pubertal age. 734 patients received CSII therapy. The cross sectional, prospective study, conducted according to the protocol of the OPPLP with clinical data collection from 2005 to 2008. We analyzed the data obtained during 1657 visits and assessed 1657 blood samples for HbA1c value in the Central Laboratory. The clinical data were recorded in the electronic net-database. RESULTS: In whole group the median of HbA1c was 7.46 % (min. 5% - max. 12.1%); 60.1% patients has HbA1c below 7.5%. The quality of treatment was comparable among the centres: med. HbA1c ranged from min. 6.5% to max. 8.0%. During the period from 2005 to 2008 effective results were obtained in glycemic control: med. HbA1c: 2005 - 7.6%, 2006 - 7.2%, 2007 - 7.0% and 2008 - 7.5%. Slightly higher HbA1c was observed in children with longer duration of diabetes (r=0.17, p<0.005). CONCLUSIONS: The OPPLP, including HCP education, enabled optimalization of metabolic control in the prepubertal children switched pump therapy. Moreover, the programme brought about an even level of treatment between the Polish Diabetic Centres irrespective of their size. It is important to continue the programme and to develop a country level register of children with T1DM. PMID- 22516771 TI - [Type 1 diabetes-associated autoimmune diseases: screening, diagnostic principles and management]. AB - Type 1 diabetes (T1DM) is often associated with autoimmune diseases such as: autoimmune thyroid disease (ATD), celiac disease (CD), autoimmune gastritis (AIG), pernicious anemia (PA) and vitiligo. Autoimmune thyroid disease is the most prevalent endocrinopathy among diabetic patients. Hypothyroidism, celiac disease or Addison's disease in patients with type 1 diabetes may deteriorate glycemic control and can lead to an increased rate of hypoglycemia. Autoimmune gastritis, pernicious anemia and celiac disease can cause malabsorption and anemia which additionally impair the quality of life in patients with T1DM. The presence of organ-specific autoantibodies can be used to screen patients who are at higher risk of developing autoimmune diseases. Such procedure can help to identify patients, who need to undergo treatment in order to decrease the rate of possible complications in the future. In this clinical review we present current opinions in terms of diagnosis, management and screening in the most common type 1 diabetes-associated autoimmune diseases. PMID- 22516772 TI - [Self-esteem predictors in adolescents with diabetes]. AB - INTRODUCTION: Self-esteem is the conviction concerning self-satisfaction and self assessment of one's competence. It can influence the overall emotional state, and determine the motivation to take actions of characteristic teenagers. OBJECTIVE: Presentation of the results of research on predictors of self-esteem in healthy adolescents and their peers with diabetes. Is was investigated whether there were differences in factors that determine directly and indirectly the self-esteem within these groups. METHODS: The survey was conducted during the school year 2010/2011 as a part of cultural and linguistic adaptation of the CHIP-AE questionnaire (Child Health and Illness Profile - Adolescent Edition). Data were collected from 1177 students with average age of 15.4 years, who attended junior high and high schools of different types, in five provinces of Poland. In this group there were 117 adolescents with diabetes and 1060 healthy peers. The CHIP AE questionnaire consists of six main dimensions: satisfaction, complaints, protective factors, risk factors, achievements and illness. Students are asked to respond mostly from the perspective of the last 4 weeks. Predictors of self esteem were selected from the following fields of CHIP-AE questionnaire: physical health, self-efficiency, limitation of daily activities, academic achievement, burden of school work, social support, capability of solving social problems, family relationships, relationships with peers and with teachers. Multivariate regression models and structural equitation models were estimated for both the healthy and the ill adolescents. RESULTS: It has been proved that self-esteem of healthy adolescents was determined differently than that of their peers with diabetes. The most important elements forming self-esteem of adolescents with diabetes were as follows: self-assessment of physical fitness, academic achievements and social support. In the studied group an indirect impact of limitations of physical activity on self-perceived fitness and influence of physical activity on academic achievement has also been found. CONCLUSIONS: The self-esteem of teenagers with diabetes mellitus may be considered as a determinant of ability to cope with the constraints of the disease. More precise knowledge on predictors of self-esteem of teenagers with diabetes may help to improve their psychosocial functioning, and thus improve their health. PMID- 22516773 TI - [Biological role of obestatin in physiology and pathophysiology]. AB - Obestatin is a 23 amino acid peptide encoded by the same gene as ghrelin and synthetized in the gastrointestinal tract. The first results of the investigations on the physiological function of obestatin pointed to its role in the reduction of appetite, delay of stomach emptying and decrease of body weight gains which may testify the fact that this peptide is an endogenous antagonist for ghrelin. The results of the last 5 years investigations on the physiological role of obestatin presented in this paper contradict such a statement and prove that obestatin is an independent hormone, participating in many physiological processes in the organism which may include the development of the gastrointestinal tract in the early postnatal period. PMID- 22516774 TI - [Polymorphism rs9939609 of FTO gene is related to the body mass index in children from Podlaskie voievodship]. AB - INTRODUCTION: The presence of obesity and the features of metabolic syndrome plays a predictive role in cardiovascular diseases (CVD) in adults. It seems reasonable to seek new risk factors in the development of CVD. Defining the genetic background of obesity could help to select patients from a high risk group and help to introduce prevention and treatment, which, in consequence, lead to the lowering of morbidity and mortality. One of the genes probably related to the body weight is the Fat Mass and Obesity Associated Gene (FTO). THE AIM: of the study was an attempt to assess the relationship between the FTO polymorphism rs9939609 and body mass index in children from Podlaskie voievodship. MATERIAL AND METHODS: 405 children aged 4-18 were selected for the study. The examination included body mass index, waist circumference, blood pressure and lipid profile analysis. FTO rs9939609 polymorphism was assessed using a discrimination allele method with the application of ABI 7900HT Fast Real-Time PCR System. RESULTS: FTO rs9939609 polymorphism was related to the standarized body mass index and the AA genotype carriers had a higher risk of obesity. This polymorphism was also associated with waist circumference, systolic blood pressure and triglycerides concentration. It was not correlated with diastolic blood pressure and total HDL- and LDL-cholesterol concentrations. CONCLUSIONS: Our results demonstrate that rs9939609 FTO gene polymorphism is related to the body mass index in children. Our results should be confirmed in studies on a large cohort of healthy Polish children. PMID- 22516775 TI - [Effects of elimination diets on bone metabolism in children and adolescents with phenylketonuria, galactosemia and celiac disease]. AB - Phenylketonuria, galactosemia and celiac disease are disorders in which elimination diets are the only known therapy, which reverses many clinical manifestations of acute phase in the patients. Unfortunately, most of them develop long-term complications, including bone turnover impairment and low bone mineral density. These disturbances are not only observed in adulthood but also in childhood and adolescence. Insufficient accumulation of peak bone mass in these periods is a risk factor for osteoporosis and fractures in later life. The pathological mechanisms leading to a diminished bone mineral content in these disorders are not well known. The patients might be at risk for a decreased bone mineral content because of either dietary deficiencies secondary to the elimination diets and/or unknown intrinsic factors. This article overviews bone metabolism disturbances in phenylketonuria, galactosemia and celiac disease during childhood and adolescence, when growth and bone turnover are most intensive. The available data and own results concerning bone markers in children with these disorders and proposal for the prevention of osteoporosis in pediatric patients treated with elimination diets are discussed. PMID- 22516776 TI - NTCP models for patient-rated xerostomia and sticky saliva after treatment with intensity modulated radiotherapy for head and neck cancer: the role of dosimetric and clinical factors. AB - PURPOSE: The purpose of this multicentre prospective study was to develop multivariable logistic regression models to make valid predictions about the risk of moderate-to-severe patient-rated xerostomia (XER(M6)) and sticky saliva 6 months (STIC(M6)) after primary treatment with intensity modulated radiotherapy (IMRT) with or without chemotherapy for head and neck cancer (HNC). METHODS AND MATERIALS: The study population was composed of 178 consecutive HNC patients treated with IMRT. All patients were included in a standard follow up programme in which acute and late side effects and quality of life were prospectively assessed, prior to, during and after treatment. The primary endpoints were XER(M6) and STIC(M6) as assessed by the EORTC QLQ-H&N35 after completing IMRT. Organs at risk (OARs) potentially involved in salivary function were delineated on planning-CT, including the parotid, submandibular and sublingual glands and the minor glands in the soft palate, cheeks and lips. Patients with moderate-to severe xerostomia or sticky saliva, respectively, at baseline were excluded. The optimal number of variables for a multivariate logistic regression model was determined using a bootstrapping method. RESULTS: Eventually, 51.6% of the cases suffered from XER(M6). The multivariate analysis showed that the mean contralateral parotid gland dose and baseline xerostomia (none vs. a bit) were the most important predictors for XER(M6). For the multivariate NTCP model, the area under the receiver operating curve (AUC) was 0.68 (95% CI 0.60-0.76) and the discrimination slope was 0.10, respectively. Calibration was good with a calibration slope of 1.0. At 6 months after IMRT, 35.6% of the cases reported STIC(M6). The mean contralateral submandibular gland dose, the mean sublingual dose and the mean dose to the minor salivary glands located in the soft palate were most predictive for STIC(M6). For this model, the AUC was 0.70 (95% CI 0.61 0.78) and the discrimination slope was 0.12. Calibration was good with a calibration slope of 1.0. CONCLUSIONS: The multivariable NTCP models presented in this paper can be used to predict patient-rated xerostomia and sticky saliva. The dose volume parameters included in the models can be used to further optimise IMRT treatment. PMID- 22516777 TI - EGFR-mediated stimulation of sodium/glucose cotransport promotes survival of irradiated human A549 lung adenocarcinoma cells. AB - BACKGROUND AND PURPOSE: Solid tumor cells may adapt to an ischemic microenvironment by upregulation of sodium/glucose cotransport (SGLT) in the plasma membrane which supplies the tumor cell with glucose even at very low extracellular glucose concentration. Since SGLT activity has been shown to depend on the epithelial growth factor receptor (EGFR) and EGFR reportedly is activated by ionizing radiation, we tested for irradiation-induced SGLT activity. MATERIALS AND METHODS: A549 lung adenocarcinoma and FaDu head and neck squamous cancer cells were irradiated with 0 and 4 Gy X-ray and electrogenic SGLT transport activity was recorded by patch clamp current clamp in the presence and absence of extracellular glucose (5mM), the SGLT inhibitor phlorizin (500 MUM), and the inhibitor of the EGFR tyrosine kinase activity erlotinib (1 MUM). In addition, the effect of phlorizin and erlotinib on glucose uptake and clonogenic survival was tested in irradiated and control cells by tracer flux and colony formation assays, respectively. RESULTS: Irradiated A549 cells exhibited a significantly lower membrane potential 3h after irradiation than the control cells. Phlorizin, erlotinib or removal of extracellular glucose, hyperpolarized the irradiated A549 cells to a significantly higher extent than the control cells. Similarly, but less pronounced, glucose removal hyperpolarized irradiated FaDu cells. In addition, irradiated A549 cells exhibited a highly increased (3)H-glucose uptake which was sensitive to phlorizin. Finally, phlorizin radiosensitized the A549 and FaDu cells as evident from the colony formation assays. CONCLUSIONS: Taken together, these data suggest an irradiation-stimulated and EGFR-mediated increase in SGLT-generated glucose uptake which is required for the survival of the genotoxically stressed tumor cells. PMID- 22516778 TI - Multiscale functional connectivity estimation on low-density neuronal cultures recorded by high-density CMOS Micro Electrode Arrays. AB - We used electrophysiological signals recorded by CMOS Micro Electrode Arrays (MEAs) at high spatial resolution to estimate the functional-effective connectivity of sparse hippocampal neuronal networks in vitro by applying a cross correlation (CC) based method and ad hoc developed spatio-temporal filtering. Low density cultures were recorded by a recently introduced CMOS-MEA device providing simultaneous multi-site acquisition at high-spatial (21 MUm inter-electrode separation) as well as high-temporal resolution (8 kHz per channel). The method is applied to estimate functional connections in different cultures and it is refined by applying spatio-temporal filters that allow pruning of those functional connections not compatible with signal propagation. This approach permits to discriminate between possible causal influence and spurious co activation, and to obtain detailed maps down to cellular resolution. Further, a thorough analysis of the links strength and time delays (i.e., amplitude and peak position of the CC function) allows characterizing the inferred interconnected networks and supports a possible discrimination of fast mono-synaptic propagations, and slow poly-synaptic pathways. By focusing on specific regions of interest we could observe and analyze microcircuits involving connections among a few cells. Finally, the use of the high-density MEA with low density cultures analyzed with the proposed approach enables to compare the inferred effective links with the network structure obtained by staining procedures. PMID- 22516779 TI - Preliminary studies of (99m)Tc-memantine derivatives for NMDA receptor imaging. AB - INTRODUCTION: Novel technetium-labeled ligands, (99m)Tc-NCAM and (99m)Tc-NHAM were developed from the N-methyl-d-aspartate (NMDA) receptor agonist memantine as a lead compound by coupling with N(2)S(2). This study evaluated the binding affinity and specificity of the ligands for the NMDA receptor. METHODS: Ligand biodistribution and uptake specificity in the brain were investigated in mice. Binding affinity and specificity were determined by radioligand receptor binding assay. Three antagonists were used for competitive binding analysis. In addition, uptake of the complexes into SH-SY5Y nerve cells was evaluated. RESULTS: The radiochemical purity of (99m)Tc-labeled ligands was more than 95%. Analysis of brain regional uptake showed higher concentration in the frontal lobe and specific uptake in the hippocampus. (99m)Tc-NCAM reached a higher target to nontarget ratio than (99m)Tc-NHAM. The results indicated that (99m)Tc-NCAM bound to a single site on the NMDA receptor with a K(d) of 701.21 nmol/l and a B(max) of 62.47 nmol/mg. Specific inhibitors of the NMDA receptor, ketamine and dizocilpine, but not the dopamine D(2) and 5HT(1A) receptor partial agonist aripiprazole, inhibited specific binding of (99m)Tc-NCAM to the NMDA receptor. Cell physiology experiments showed that NCAM can increase the viability of SH SY5Y cells after glutamate-induced injury. CONCLUSIONS: The new radioligand (99m)Tc-NCAM has good affinity for and specific binding to the NMDA receptor, and easily crosses the blood-brain barrier; suggesting that it might be a potentially useful tracer for NMDA receptor expression. PMID- 22516780 TI - [Progres Pelvi-Perineologie, the new journal of the SIFUD-PP]. PMID- 22516781 TI - [Female overactive bladder syndrome and autonomic nervous system]. AB - PURPOSE: To analyse the hypothesis of an autonomic nervous system dysfunction in the female's idiopathic overactive bladder syndrome, by a literature review. METHOD: A systematic literature review (Pubmed, Medline, Cochrane database) concerning women presenting with overactive bladder syndrome and cardiovascular explorations of the autonomic nervous system (heart rate variability and cardiovascular tests). Keywords used for search: overactive bladder syndrome, female urinary incontinence, urge incontinence, autonomic nervous system. RESULTS: Heart rate variability (HRV) analysis among women with overactive bladder syndrome and controls has shown a difference between both, with is a global decrease of the heart rate variability parameters, or a relative increase of the sympathetic tone in overactive bladder syndrome. The sympathetic cardiovascular tests were more frequently abnormal among women presenting with overactive bladder syndrome than controls. CONCLUSION: All these studies suggest a sympathetic dysfunction of the autonomic nervous system in female's overactive bladder syndrome, but methodologies are too variable and the studies population too small to establish a pathophysiological link. PMID- 22516782 TI - [Metabolic syndrome and urinary disorders]. AB - OBJECTIVE: The goal of this article is to review and discuss the various and numerous links between metabolic syndrome (MetS) and bladder, specially overactive bladder syndrome. METHODS: Pubmed/Medline analysis, without date or language limits, was conducted using the following keywords: "metabolic syndrome" and "bladder (or "incontinence" or "overactive bladder"). All types of papers were analysed (117). RESULTS: MetS is defined as the presence of three or more of the following five characteristics: 1) waist circumference greater than 102 cm; 2) systolic blood pressure 130 mmHg or greater or diastolic blood pressure 85 mmHg or greater, or antihypertensive medication use; 3) HDL cholesterol less than 40 mg/dL or lipid medication use; 4) self- reported type 2 diabetes or increased blood sugar or diabetes medication use; 5) triglycerides greater than 150 mg/dL. In regard of epidemiolgy, there is a strong correlation between MetS and overactive bladder. Pathophysiological mechanisms to explain the relationship of storage symptoms rather than voiding phase symptoms with MetS include the influence of sustained hyperglycemia on the viability of parasympathetic neurons in the pelvic ganglion. A link or overlaps between MetS and alteration of autonomic nervous system can be hypothezised. CONCLUSION: Links between Mets and urinary disorders are frequent and common pathophysiological factors can be frequently observed, particularly autonomic nervous system alterations. PMID- 22516783 TI - [Botulinum toxin A intradetrusor injections in consultation: single center experience during 2 years]. AB - OBJECTIVES: In departments of urology, intradetrusor botulinum toxin injections are routinely performed in ambulatory outpatient clinic. The aim of the study was to assess the satisfaction level of patients treated with this technique. PATIENTS AND METHODS: A satisfaction questionnaire was carried out by telephone for all patients treated in ambulatory outpatient clinic from 2009 to 2010. RESULTS: Twenty-six patients were treated in consultation during the studied period for a total of 46 sessions of injections. The average age was 48.81 (+/ 16.78) years. An injection programme containing 20 or 30 points was performed after a local anesthetic. Twenty patients answered the questionnaire. As regards the organization of the injections, 12 patients (60%) declared to have been satisfied and seven very satisfied (35%). Eight patients (40%) were very satisfied with the management of the pain and six (30%) satisfied versus only one (5%) not satisfied at all. For the time spent in the hospital during the injections, 10 (50%) were satisfied and seven (35%) very satisfied. Only 4 patients (20%) would have preferred to be hospitalized in an outpatient facility. In cases of new injections, 18 (90%) patients would have preferred an identical coverage. Finally, 17 (85%) would recommend this procedure to one of their close relations. CONCLUSION: Our results showed that the majority of patients were completely satisfied with the injection programme. However, as patients are not currently covered by the national health system for these injections, this might hinder the development of this procedure. PMID- 22516784 TI - [Evidence of pudendal neuropathy in Proctalgia Fugax: perineal neurophysiological assessment in 55 patients]. AB - OBJECTIVE: Proctalgia fugax (PF) is a very common condition especially in women. Causes and pathophysiological mechanisms of PF are unknown. Recently, a pudendal neuropathy was clinically suspected in women with PF. The goal of our study was to demonstrate, or not, such abnormalities by means electrophysiological testing. PATIENTS AND METHODS: Fifty-five patients with PF (45 female and 10 male, mean age 50.2 years) were evaluated. EMG testing with motor unit potential analysis of pelvic floor muscles (bulbocavernosus muscle and striated external anal sphincter), study of bulbocavernosus reflex and pudendal nerve terminal motor latencies (PNTML) were performed. RESULTS: EMG testing was altered in two males out of 10 (20%) and 29/45 females (64%). In women, denervation was found bilateral in 25/29 (86%). Sacral latency was delayed in eight out of 29 (bilateral in five cases, unilateral in three cases) and PNTML altered in 17 cases (13 bilateral alteration, four unilateral). A significant difference (P<0.002 Chi(2) test) was demonstrated between male and female concerning pelvic floor muscles denervation. CONCLUSION: Pelvic floor muscles denervation was a common feature in women suffering from PF, due to a stretch bilateral pudendal neuropathy. Distal lesions of the pudendal nerves, principally due to a stretch perineal neuropathy, can be imagined as a factor or co-factor of PF. PMID- 22516785 TI - Late post-partum dyspareunia: does delivery play a role? AB - OBJECTIVE: To study whether post-partum dyspareunia one year after a delivery is associated with characteristics of delivery: perineal trauma, obstetric interventions and women's experience. METHODS: A self-administered questionnaire on post-partum sexual function was mailed in May 2002 to all consecutive women who gave birth to a live-born term infant in a maternity unit, between January 2001 and June 2001. Obstetric data were abstracted from the hospital computerized medical database. Late dyspareunia was defined as pain during intercourse, one year after delivery. Multiple logistic regression modeling was used to select independent predictors of late post-partum dyspareunia. RESULTS: Seventy (27.6%) of the 254 women studied experienced late dyspareunia. There was no relation between late post-partum dyspareunia and neither the mode of delivery nor state of the perineum, including perineal laceration or episiotomy. Multiple logistic regression analysis showed that late post-partum dyspareunia was associated with dyspareunia before pregnancy, low satisfaction with delivery, and employment status. CONCLUSIONS: Late post-partum dyspareunia seemed to be linked more with the mother's experience of childbirth than with perineal trauma. This hypothesis should be investigated further. PMID- 22516786 TI - [Widespread of clinical practice guidelines, concerning urinary incontinence in women]. AB - OBJECTIVE: Recommendations for good clinical practice concerning the treatment of urinary incontinence in women are available from the HAS (Haute Autorite de sante or French National Authority for Health), the College national des gynecologues obstetriciens francais (French national college of gynaecologists and obstetricians) and Association francaise des urologues (French association of urologists). We wanted to conduct the first investigation of these recommendations to primary care physicians (GPs) and gynaecologists in the cities located in the same area of health. METHODS: A questionnaire was sent to GPs and gynaecologists (French administrative divisions 78 and 92), with questions on the recommendations, as well as the methods of dissemination of these recommendations. Response rate: 22%. RESULTS: A total of 72 questionnaires were usable from 51 (71%) GPs and 21 (29%) gynaecologists. Of these, 76% of gynecologists and 47% of GPs were aware of recommendations from the HAS for clinical practice for urinary incontinence in women (P=0.04). Only 56% of doctors prescribed a urinalysis (dipstick or bacteriological urinalysis) and evaluated the residual urine in women seeking care for symptoms of urinary incontinence. Training for one or two days was the most desirable/popular method of dissemination of the recommendations (30 out of 72 doctors), followed by journals such as Prescrire, then the mailing and forms provided by the HAS, especially when combined with office visits from a representative of the HAS. CONCLUSION: This study provided an interesting perspective on the knowledge, dissemination and application of recommendations for good clinical practice concerning urinary incontinence in women. PMID- 22516787 TI - [Rectocele repair with porcine dermal collagen implant associated with infracoccygeal sacropexy]. AB - OBJECTIVES: To evaluate an infracoccygeal colpopexy procedure by tension-free synthetic tape for vaginal apical prolapse associated with a posterior mesh procedure using porcine dermal graft for rectocele repair. METHODS: A retrospective study concerning 35 women. The surgical procedure included rectocele repair with porcine dermal collagen implant (porcine dermal matrix, native) associated with transgluteal infracoccygeal sacropexy using a polypropylene sling. RESULTS: Median follow up was 48 months (42-54). A vaginal hysterectomy was associated in 43% and a cure of cystocele was associated in 63% of cases. No intra-operative complication was noted. The prevalence of dyschesia decreased from 25% (eight patients) preoperatively to 3% (one patient) postoperatively. No cases of de novo dyspareunia was noted. Five (14%) patients had a recurrent prolapse (two cases of rectocele stage 2, one case of grade 3 rectocele associated with a cystocele, a case of uterine prolapse associated with cystocele and one case of recurrent isolated uterine prolapse). Among them, three patients (9%) required a re-intervention for prolapse recurrence. No vaginal mesh exposure was observed. Perineal pain was reported by 12 (33%) patients at one month follow-up, but no patient complained with perineal pain one year follow-up. CONCLUSION: Infracoccygeal sacropexy associated with rectocele repair using porcine dermal collagen implant was associated with satisfactory results at medium term follow-up. PMID- 22516788 TI - Incomplete activation of human eosinophils via the histamine H4-receptor: evidence for ligand-specific receptor conformations. AB - Eosinophils play a crucial role in the pathogenesis of allergic diseases. Histamine activates eosinophils via the H(4)-receptor (H(4)R). However, pharmacological analysis of the H(4)R in eosinophils is still incomplete, and cell purity is a problem. The H(4)R antagonist 1-[(5-chloro-1H-indol-2 yl)carbonyl]-4-methylpiperazine (JNJ7777120) has recently been reported to exhibit paradoxical stimulatory effects in some systems. Therefore, the first aim of our study was to pharmacologically re-examine H(x)R subtypes on human eosinophils using a highly purified preparation (97+/-2%). The second aim was to compare the effects of histamine with those induced by well-known activators of eosinophil functions, i.e. eotaxin-1 and formyl peptides. Histamine and the H(4)R selective agonist 2-cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[(2 phenylthio)ethyl]guanidine (UR-PI376) increased intracellular calcium concentration ([Ca(2+)](i)) and activated chemotaxis. JNJ7777120 per se exhibited no stimulatory effects but inhibited stimulation by histamine and UR-PI376. Blockade of the H(2)R by famotidine enhanced histamine-induced chemotaxis but not rises in [Ca(2+)](i). Compared to eotaxin and formyl peptides, the effect of histamine on eosinophil chemotaxis was only small. Formyl peptides but not histamine activated reactive oxygen species formation and release of eosinophil peroxidase. In conclusion, histamine is only an incomplete eosinophil activator with the H(2)R blunting the small chemotactic response to H(4)R activation. We also noted several differences in potencies of histamine, UR-PI376 and JNJ7777120 in calcium and chemotaxis assays and when compared to results in the literature. This indicates functional selectivity of H(4)R ligands, thus ligand-specific stabilization of distinct receptor conformations, inducing distinct biological responses. PMID- 22516789 TI - Death rates for asthma in English populations 1979-2007: comparison of underlying cause and all certified causes. AB - OBJECTIVE: To report on trends in mortality for asthma using all certified causes of death mentioned on death certificates (conventionally termed 'mentions'), not just the underlying cause. STUDY DESIGN: Retrospective analysis using death certificate information and population data. METHOD: Analysis of mortality records in the Oxford region (mentions available from 1979 to 2007) and English national data (mentions available from 1995 to 2007). The data were considered in periods defined by different national rules for selecting underlying cause of death (1979-1983, 1984-1992, 1993-2000, 2001-2007), and were also analysed as single calendar years. RESULTS: In Oxford, underlying cause mortality rates per million population in the four periods were 25, 32, 22 and 15, respectively. Rates for mentions were 44, 47, 41 and 29, respectively. Rule changes exaggerated the increase in underlying cause mortality in 1984-1992 (when 67% of asthma deaths were coded as underlying cause). Conversely, the decrease in underlying cause mortality for asthma by 2001-2007 is less than it seems (because just under 50% of asthma deaths in 2001-2007 were coded as underlying cause). Comparisons of trends in asthma and chronic obstructive airways disease (COPD) for individuals aged >= 55 years showed a decrease for both asthma and COPD in men; in women, a decrease in asthma and an increase in COPD was seen from the early 1990s. CONCLUSIONS: Approximately half of all deaths certified for asthma are missed when asthma mortality is analysed using underlying cause alone. The long-term decreasing trend in asthma mortality is real, and is not attributable to a trend in transferring certification from underlying to contributing cause. Nonetheless, caution is needed when comparing asthma deaths using underlying cause alone across periods that include changes to rules for the selection of underlying cause. PMID- 22516790 TI - Response to the first wave of pandemic (H1N1) 2009: experiences and lessons learnt from China. AB - More than 2 years after the start of pandemic H1N1, the world is fortunate that the impact, to date, has been moderate. An evaluation of the global response to the first wave of the pandemic is still ongoing. The results of an analysis of the situation in China is presented in order to gain a better understanding of the episode; to summarize the experiences in preparedness, control and mitigation of the pandemic; and to identify issues for further consideration and investigation in order to improve the response to possible next waves of the pandemic. China's response shows how a huge challenge can be transformed into an opportunity, and may offer some valuable lessons to face another wave of the pandemic or other potential public health emergencies in the future, not only for China but also for the international community. PMID- 22516791 TI - The LDL-cholesterol to HDL-cholesterol ratio and the severity of coronary and aortic atherosclerosis. PMID- 22516792 TI - A national survey about human papillomavirus vaccination: what we didn't ask, but physicians wanted us to know. AB - STUDY OBJECTIVE: The current study presents findings from a qualitative examination of free text comments from a national survey of U.S. physicians on human papillomavirus vaccine recommendation beliefs and practices. Qualitative analyses of free text physician responses may offer a more complete and physician driven description of influences on human papillomavirus vaccine recommendation. DESIGN AND PARTICIPANTS: In 2009, a survey assessing physicians' knowledge, attitudes, and human papillomavirus vaccination practices was conducted among a national sample of U.S. physicians practicing Family Medicine, Pediatrics, or Obstetrics/Gynecology (response rate 67.8%). Qualitative comments were analyzed using a Grounded Theory approach. RESULTS: Of 1008 completed surveys, 112 participants provided comments, which were organized into three primary HPV vaccine-related themes: (a) comments about cost of the vaccine, (b) comments about institutional policies and procedures, and (c) physicians' personal views and one secondary theme related to survey methodology: the parent study's use of an upfront cash incentive. Many comments pertained to issues that were queried in the closed-end survey items; however, some comments provided insight into understudied areas (e.g., physician attitudes regarding survey methodology). CONCLUSION: Physician respondents used the free text space to reemphasize issues that were most important to them and to offer insight about aspects of the vaccine and the survey process. PMID- 22516793 TI - A qualitative and quantitative review of diffusion tensor imaging studies in reading and dyslexia. AB - In this review paper we address whether deficits in reading (i.e. developmental dyslexia) are rooted in neurobiological anomalies in white matter tracts. Diffusion tensor imaging (DTI) offers an index of the connections between brain regions (via tractography) and of the white matter properties of these connections (via fractional anisotropy, FA). The reported studies generally show that lower FA values in left temporoparietal and frontal areas are indicative of poorer reading ability or dyslexia. Second, most studies have indicated that these regions coincide with the left arcuate fasciculus and corona radiata, with fewer studies suggesting a role for the posterior part of the corpus callosum or for more ventral tracts such as the inferior longitudinal fasciculus or the inferior fronto-occipital fasciculus. Finally, a quantitative activation likelihood estimation (ALE) meta-analysis on all reported studies that used a voxel-based approach reveals a cluster located close to the left temporoparietal region (x=-29, y=-17, z=26). Fibertracking through this cluster demonstrates that this region hosts both the left arcuate fasciculus and the left corona radiata. PMID- 22516794 TI - Paediatric acquired demyelinating syndromes: incidence, clinical and magnetic resonance imaging features. AB - OBJECTIVE: Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time. METHODS: We conducted a population active surveillance study. All paediatricians, and ophthalmologists (n = 4095) were sent monthly reporting cards (September 2009 September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review. RESULTS: Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 remained (age range 1.3-15.9), with CIS in 66.4%, ADEM in 32.0% and NMO in 1.6%. The female-to-male ratio in children older than 10 years (n = 63) was 1.52:1 (p = 0.045). The incidence of first onset ADS in children aged 1-15 years old was 9.83 per million children per year (95% confidence interval [CI] 8.18-11.71). A trend towards higher incidence rates of ADS in children of South Asian and Black ethnicity was observed compared with White children. Importantly, a number of MRI characteristics distinguished ADEM from CIS cases. Of CIS cases with contrast imaging, 26% fulfilled McDonald 2010 MS diagnostic criteria. CONCLUSIONS: We report the highest surveillance incidence rates of childhood ADS. Paediatric MS diagnosis at first ADS presentation has implications for clinical practice and clinical trial design. PMID- 22516795 TI - NMO spectrum presenting as partial myelitis. PMID- 22516796 TI - The multifaceted role of aspartate-family amino acids in plant metabolism. AB - Plants represent the major sources of human foods and livestock feeds, worldwide. However, the limited content of the essential amino acid lysine in cereal grains represents a major nutritional problem for human and for livestock feeding in developed countries. Optimizing the level of lysine in cereal grains requires extensive knowledge on the biological processes regulating the homeostasis of this essential amino acid as well as the biological consequences of this homeostasis. Manipulating biosynthetic and catabolic enzymes of lysine metabolism enabled an enhanced accumulation of this essential amino acid in seeds. However, this approach had a major effect on the levels of various metabolites of the tricarboxylic acid (TCA) cycle, revealing a strong interaction between lysine metabolism and cellular energy metabolism. Recent studies discussed here have shed new light on the metabolic processes responsible for the catabolism of lysine, as well as isoleucine, another amino acid of the aspartate-family pathway, into the TCA cycle. Here we discuss progress being made to understand biological processes associated with the catabolism of amino acids of the aspartate-family pathway and its importance for optimal improvement of the nutritional quality of plants. PMID- 22516797 TI - Depression symptoms as a function of duration of intractable or controlled epilepsy. AB - We examined if depression symptoms in patients with intractable (IE) or controlled epilepsy (CE) differ and how long after onset of epilepsy these effects would be most pronounced. The NDDI-E was administered to all outpatients (n=358) seen in a comprehensive epilepsy program clinic over a two-year period. Patients who met inclusion criteria (n=223) completed a total of 431 NDDI-E surveys over this time. Patients with a diagnosis of IE (n=72) or CE (n=151) were compared as a function of time since their epilepsy onset, segmented into 10-year epochs. Depression symptoms were higher in patients with IE compared to CE at 10 <20 years and did not differ at other time points. This study reveals differences in depression symptoms as a function of duration of epilepsy. Attending to the dynamic nature of depression symptoms in different epochs of epilepsy may be an important treatment target in patients with epilepsy. PMID- 22516798 TI - The value of BP230 enzyme-linked immunosorbent assay in the diagnosis and immunological follow-up of bullous pemphigoid. AB - BACKGROUND: The value of 230-kDa bullous pemphigoid antibody (BP230) enzyme linked immunosorbent assay (ELISA) for the diagnosis of bullous pemphigoid (BP) was investigated, but in the immunological follow-up of the disease remains unknown. OBJECTIVE: Evaluation of BP230 ELISA for diagnosis, follow-up and prediction of relapse in BP. METHODS: Monocenter retrospective and prospective study. Patients with typical BP. Detection of autoantibodies by indirect immunofluorescence (IIF), BP180 and BP230 ELISA tests at diagnosis, during the treatment (disease control or failure) and at treatment stop (relapse or not 3 months after). RESULTS: 74 patients were included. At diagnosis, BP230 ELISA sensitivity was lower than IIF and BP180 ELISA. Combining both ELISA added a weak gain of sensitivity. Both tests paralleled the clinical evolution, especially in case of disease control. At the end of the treatment, BP230 ELISA was not different in patients with or without relapse. CONCLUSION: In routine practice, BP230 ELISA does not seem to be a useful additional test in typical BP. PMID- 22516799 TI - Alcohol intake and risk of aggressive histological basal cell carcinoma: a case control study. AB - BACKGROUND: Aggressive basal cell carcinomas (BCC) are not rare. These subtypes of skin cancer are characterized by an infiltrative behavior and rapid progression. Often, management may be difficult. Recent evidence suggests that minimal UV exposure in combination with other behavioral and/or environmental factors may lead to higher incidence of BCC and, therefore, more risk of aggressive subtypes of this malignancy. Alcohol is a very commonly consumed beverage in Western societies, especially in association with outdoors activities. OBJECTIVE: To investigate a possible relationship between alcohol intake and aggressive histological variants of BCC. MATERIALS AND METHOD: We designed a prospective study. Patients who underwent surgery for BCC in our hospital were interviewed to collect data regarding alcohol intake. The specimens were reviewed by a pathologist and classified into aggressive and non-aggressive subtypes. Statistical analysis was performed using SPSS software. RESULTS: 136 patients were included. Of participants with aggressive BCCs, 10 (26.3%) were abstainers, 4 (10.4%) had light consumption, 18 (47.5%) moderate consumption and 6 (15.8%) heavy consumption, while among participants with non-aggressive BCCs, 57 (58.2%) were abstainers, 29 (29.5%) had light consumption, 10 (10.2%) moderate consumption and 2 (2.1%) heavy consumption. In the multivariate analysis we found a positive significant association between alcohol consumption and the presence of aggressive BBCs. CONCLUSIONS: According to our results, alcohol intake may be linked with a higher incidence of aggressive subtypes of BCC. PMID- 22516800 TI - The prevalence of disability in older people in Hai, Tanzania. AB - BACKGROUND: the World Health Organization estimates that more than one billion of the world's population are disabled. Disability is associated with increasing age and poverty, yet there are few reliable data regarding disability among the elderly in low-income countries. The aim of this study was to accurately document the prevalence of disability in those aged 70 years and over in a community-based setting in sub-Saharan Africa. METHODS: we performed a community-based study of people aged 70 years and over in Hai, Tanzania. Participants underwent disability assessment using the culturally non-specific Barthel index (BI), and also clinical assessment for neurological disorders and memory problems. RESULTS: in 2,232 participants, the age-adjusted prevalence of severe disability (BI<15) was 3.7% (95% CI: 2.9-4.5) and the age-adjusted prevalence of moderate disability (BI: 15-18) was 6.2% [95% confidence interval (CI): 5.2-7.2]. Increasing age, female gender, memory problems and the presence of neurological disorders were all independent predictors of the presence of disability. CONCLUSION: in this study, the average disability level was lower than seen in most high-income countries. This may reflect increased mortality from disabling disease in low income countries. Disability is likely to increase as the population of low income countries ages and disease survival improves. PMID- 22516801 TI - The expression of placental proteoglycans in pre-eclampsia. AB - BACKGROUND/AIMS: Pre-eclampsia (PE) is one of the leading causes of maternal and perinatal morbidity and mortality. PE is defined clinically as the onset of maternal hypertension and proteinuria following 20 weeks of gestation. It is associated with altered maternal uterine decidual spiral artery remodelling, which may lead to reduced blood flow and increased thrombosis within the uteroplacental vasculature. Proteoglycans (PGs) are macromolecules which have (in combination with glycosaminoglycans) important anticoagulant roles in vascular endothelial environments, including the uteroplacental circulation. The hypothesis under consideration in this study was that differential expression of placental PGs may be associated with PE. METHODS: PE and control placental samples were collected with ethics approval and patient consent. RNA and protein were extracted and real-time PCR and Western immunoblotting were performed to determine the expression of the PGs in the samples. RESULTS: Of the nine PGs investigated, none showed increased expression, whereas the mRNA and protein expression of five of them was significantly decreased in the placentae of pre eclamptic women compared to gestation-matched controls. CONCLUSION: Therefore, the results of this study support the hypothesis that a placental PG deficiency may contribute to the placental thrombotic lesions characteristic of PE. PMID- 22516802 TI - Chlamydia trachomatis serovar L2 infection model using human lymphoid Jurkat cells. AB - Chlamydia trachomatis L2 invasively attacks lymphatic and subepithelial tissues of the genital tract during the formation of primary lesions. This subsequently results in lymphadenopathy, and suggests a greater propensity for systemic dissemination. However, whether lymphocytes are a potential vehicle cell for the dissemination of this infection remains unknown. We therefore assessed the growth properties of C. trachomatis L2 in lymphoid Jurkat cells compared with those observed in epithelial HeLa cells. Both cells supported the growth of C. trachomatis with a similar increase in infective progenies. Enriched human-blood lymphocytes also supported the C. trachomatis growth as well as Jurkat cells. Bacteria infecting the Jurkat cells were more susceptible to antibiotics (doxycycline, azithromycin, ofloxacin) than those in HeLa cells. Of the sphingomyelin biosynthesis inhibitors tested, both myriocin and fumonisin B1 significantly inhibited bacterial growth in both cells types. A Jurkat cell mutant that impaired bacterial growth was established using ethylmethanesulfonate treatment. DNA microarray analysis with real-time reverse transcription polymerase chain reaction revealed that the mutant cells over-expressed granzyme K gene. Immunofluorescence staining also indicated that granzyme K irregularly over-expressed among the mutant cells as compared with that of the wild cells, suggesting a possible mechanism refractory to C. trachomatis infection. Thus, we concluded that C. trachomatis L2 could infect Jurkat cells with lymphoid properties, providing a new tool for studying C. trachomatis dissemination to tissues via lymphocyte movement. PMID- 22516803 TI - Pseudomonas aeruginosa strains from the chronically infected cystic fibrosis lung display increased invasiveness of A549 epithelial cells over time. AB - The invasive properties of Pseudomonas aeruginosa pose a serious threat to the wellbeing of cystic fibrosis (CF) patients; however the specific factors affecting invasiveness are not well understood, especially in chronic infection. This study characterises the invasive profiles of sequential isolates of the same P. aeruginosa strain collected five to eight years apart from five chronically infected adult CF patients. Strains from three patients were characterised as unique isolates and from two patients as the Australian Epidemic strain (AES-1) by pulsed field gel electrophoresis. The capacity of these strains to invade the human alveolar A549 cell line was examined. Later isolates were significantly more invasive than earlier counterparts from the same patient. Quantitative real time PCR and Western blotting showed that the increase in invasiveness over time was independent of ExoS expression and secretion. A link between clonality and invasiveness was also identified, with AES-1 isolates more invasive than unique isolates. These results suggest that despite a reduction in some virulence factors such as the Type-3 Secretion System (T3SS) during chronic infection, a particular strain can become more invasive over time. Defining mechanisms behind the increased invasiveness during chronic infection may help identify new therapeutic targets for CF patients. PMID- 22516805 TI - Potential for improved intelligence quotient using volumetric modulated arc therapy compared with conventional 3-dimensional conformal radiation for whole ventricular radiation in children. AB - PURPOSE: To compare volumetric modulated arc therapy (VMAT) with 3-dimensional conformal radiation therapy (3D-CRT) in the treatment of localized intracranial germinoma. We modeled the effect of the dosimetric differences on intelligence quotient (IQ). METHOD AND MATERIALS: Ten children with intracranial germinomas were used for planning. The prescription doses were 23.4 Gy to the ventricles followed by 21.6 Gy to the tumor located in the pineal region. For each child, a 3D-CRT and full arc VMAT was generated. Coverage of the target was assessed by computing a conformity index and heterogeneity index. We also generated VMAT plans with explicit temporal lobe sparing and with smaller ventricular margin expansions. Mean dose to the temporal lobe was used to estimate IQ 5 years after completion of radiation, using a patient age of 10 years. RESULTS: Compared with the 3D-CRT plan, VMAT improved conformality (conformity index 1.10 vs 1.85), with slightly higher heterogeneity (heterogeneity index 1.09 vs 1.06). The averaged mean doses for left and right temporal lobes were 31.3 and 31.7 Gy, respectively, for VMAT plans and 37.7 and 37.6 Gy for 3D-CRT plans. This difference in mean temporal lobe dose resulted in an estimated IQ difference of 3.1 points at 5 years after radiation therapy. When the temporal lobes were explicitly included in the VMAT optimization, the mean temporal lobe dose was reduced 5.6-5.7 Gy, resulting in an estimated IQ difference of an additional 3 points. Reducing the ventricular margin from 1.5 cm to 0.5 cm decreased mean temporal lobe dose 11.4 13.1 Gy, corresponding to an estimated increase in IQ of 7 points. CONCLUSION: For treatment of children with intracranial pure germinomas, VMAT compared with 3D-CRT provides increased conformality and reduces doses to normal tissue. This may result in improvements in IQ in these children. PMID- 22516804 TI - Measuring agreement between rating interpretations and binary clinical interpretations of images: a simulation study of methods for quantifying the clinical relevance of an observer performance paradigm. AB - Laboratory receiver operating characteristic (ROC) studies, that are often used to evaluate medical imaging systems, differ from 'live' clinical interpretations in several respects which could compromise their clinical relevance. The aim was to develop methodology for quantifying the clinical relevance of a laboratory ROC study. A simulator was developed to generate ROC ratings data and binary clinical interpretations classified as correct or incorrect for a common set of images interpreted under clinical and laboratory conditions. The area under the trapezoidal ROC curve (AUC) was used as the laboratory figure-of-merit and the fraction of correct clinical decisions as the clinical figure-of-merit. Conventional agreement measures (Pearson, Spearman, Kendall and kappa) between the bootstrap-induced fluctuations of the two figures of merit were estimated. A jackknife pseudovalue transformation applied to the figures of merit was also investigated as a way to capture agreement existing at the individual image level that could be lost at the figure-of-merit level. It is shown that the pseudovalues define a relevance-ROC curve. The area under this curve (rAUC) measures the ability of the laboratory figure-of-merit-based pseudovalues to correctly classify incorrect versus correct clinical interpretations. Therefore, rAUC is a measure of the clinical relevance of an ROC study. The conventional measures and rAUC were compared under varying simulator conditions. It was found that design details of the ROC study, namely the number of bins, the difficulty level of the images, the ratio of disease-present to disease-absent images and the unavoidable difference between laboratory and clinical performance levels, can lead to serious underestimation of the agreement as indicated by conventional agreement measures, even for perfectly correlated data, while rAUC showed high agreement and was relatively immune to these details. At the same time rAUC was sensitive to factors such as intrinsic correlation between the laboratory and clinical decision variables and differences in reporting thresholds that are expected to influence agreement both at the individual image level and at the figure-of-merit level. Suggestions are made for how to conduct relevance-ROC studies aimed at assessing agreement between laboratory and clinical interpretations. The method could be used to evaluate the clinical relevance of alternative scalar figures of merit, such as the sensitivity at a predifined specificity. PMID- 22516806 TI - Upregulation of trefoil factor 3 (TFF3) after rectal cancer chemoradiotherapy is an adverse prognostic factor and a potential therapeutic target. AB - PURPOSE: Management of locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiotherapy (CRT) with fluoropyrimidines, followed by total mesorectal excision. We sought to evaluate the expression of selected genes, some of which were derived from a previous undirected SAGE (serial analysis of gene expression)-based approach, before and after CRT, to identify mechanisms of resistance. METHODS: This retrospective cohort study included 129 consecutive patients. Quantitative polymerase chain reaction of 53 candidate genes was performed on the biopsy specimen before treatment and on the surgical specimen after CRT. A paired-samples t test was performed to determine genes that were significantly changed after CRT. The result was correlated with patients' disease free survival. RESULTS: Twenty-two genes were significantly upregulated, and two were significantly downregulated. Several of the upregulated genes have roles in cell cycle control; these include CCNB1IP1, RCC1, EEF2, CDKN1, TFF3, and BCL2. The upregulation of TFF3 was associated with worse disease-free survival on multivariate analyses (hazard ratio, 2.64; P=.027). Patients whose surgical specimens immunohistochemically showed secretion of TFF3 into the lumen of the tumoral microglands had a higher risk of relapse (hazard ratio, 2.51; P=.014). In vitro experiments showed that DLD-1 cells stably transfected with TFF3 were significantly less sensitive to 5-fluorouracil and showed upregulation of genes involved in the transcriptional machinery and in resistance to apoptosis. CONCLUSION: Upregulation of TFF3 after CRT for RC is associated with a higher risk of relapse. The physiological role of TFF3 in restoring the mucosa during CRT could be interfering with treatment efficacy. Our results could reveal not only a novel RC prognostic marker but also a therapeutic target. PMID- 22516807 TI - Validity of three recently proposed prognostic grading indexes for breast cancer patients with radiosurgically treated brain metastases. AB - PURPOSE: We tested the validity of 3 recently proposed prognostic indexes for breast cancer patients with brain metastases (METs) treated radiosurgically. The 3 indexes are Diagnosis-Specific Graded Prognostic Assessment (DS-GPA), New Breast Cancer (NBC)-Recursive Partitioning Analysis (RPA), and our index, sub classification of RPA class II patients into 3 sub-classes (RPA class II-a, II-b and II-c) based on Karnofsky performance status, tumor number, original tumor status, and non-brain METs. METHODS AND MATERIALS: This was an institutional review board-approved, retrospective cohort study using our database of 269 consecutive female breast cancer patients (mean age, 55 years; range, 26-86 years) who underwent Gamma Knife radiosurgery (GKRS) alone, without whole-brain radiation therapy, for brain METs during the 15-year period between 1996 and 2011. The Kaplan-Meier method was used to estimate the absolute risk of each event. RESULTS: Kaplan-Meier plots of our patient series showed statistically significant survival differences among patients stratified into 3, 4, or 5 groups based on the 3 systems (P<.001). However, the mean survival time (MST) differences between some pairs of groups failed to reach statistical significance with all 3 systems. Thus, we attempted to regrade our 269 breast cancer patients into 3 groups by modifying our aforementioned index along with the original RPA class I and III, (ie, RPA I+II-a, II-b, and II-c+III). There were statistically significant MST differences among these 3 groups without overlap of 95% confidence intervals (CIs) between any 2 pairs of groups: 18.4 (95% CI = 14.0 29.5) months in I+II-a, 9.2 in II-b (95% CI = 6.8-12.9, P<.001 vs I+II-a) and 5.0 in II-c+III (95% CI = 4.2-6.8, P<.001 vs II-b). CONCLUSIONS: As none of the new grading systems, DS-GPS, BC-RPA and our system, was applicable to our set of radiosurgically treated patients for comparing survivals after GKRS, we slightly modified our system for breast cancer patients. PMID- 22516808 TI - Whole brain irradiation with hippocampal sparing and dose escalation on multiple brain metastases: a planning study on treatment concepts. AB - PURPOSE: To develop a new treatment planning strategy in patients with multiple brain metastases. The goal was to perform whole brain irradiation (WBI) with hippocampal sparing and dose escalation on multiple brain metastases. Two treatment concepts were investigated: simultaneously integrated boost (SIB) and WBI followed by stereotactic fractionated radiation therapy sequential concept (SC). METHODS AND MATERIALS: Treatment plans for both concepts were calculated for 10 patients with 2-8 brain metastases using volumetric modulated arc therapy. In the SIB concept, the prescribed dose was 30 Gy in 12 fractions to the whole brain and 51 Gy in 12 fractions to individual brain metastases. In the SC concept, the prescription was 30 Gy in 12 fractions to the whole brain followed by 18 Gy in 2 fractions to brain metastases. All plans were optimized for dose coverage of whole brain and lesions, simultaneously minimizing dose to the hippocampus. The treatment plans were evaluated on target coverage, homogeneity, and minimal dose to the hippocampus and organs at risk. RESULTS: The SIB concept enabled more successful sparing of the hippocampus; the mean dose to the hippocampus was 7.55+/-0.62 Gy and 6.29+/-0.62 Gy, respectively, when 5-mm and 10 mm avoidance regions around the hippocampus were used, normalized to 2-Gy fractions. In the SC concept, the mean dose to hippocampus was 9.8+/-1.75 Gy. The mean dose to the whole brain (excluding metastases) was 33.2+/-0.7 Gy and 32.7+/ 0.96 Gy, respectively, in the SIB concept, for 5-mm and 10-mm hippocampus avoidance regions, and 37.23+/-1.42 Gy in SC. CONCLUSIONS: Both concepts, SIB and SC, were able to achieve adequate whole brain coverage and radiosurgery equivalent dose distributions to individual brain metastases. The SIB technique achieved better sparing of the hippocampus, especially when a10-mm hippocampal avoidance region was used. PMID- 22516809 TI - Pattern recognition receptors in infectious skin diseases. AB - During the last decade, multiple pattern recognition receptors (PRRs) have been identified. These are involved in the innate immune response against a plethora of pathogens. However, PRR functioning can also be detrimental, even during infections. This review discusses the current knowledge on PRRs that recognize dermatotropic pathogens, and potential therapeutical implications. PMID- 22516810 TI - Nitrogen critical loads for alpine vegetation and soils in Rocky Mountain National Park. AB - We evaluated the ecological thresholds associated with vegetation and soil responses to nitrogen (N) deposition, by adding NH(4)NO(3) in solution at rates of 5, 10 and 30 kg N ha(-1) yr(-1) to plots in a species rich dry meadow alpine community in Rocky Mountain National Park receiving ambient N deposition of 4 kg N ha(-1) yr(-1). To determine the levels of N input that elicited changes, we measured plant species composition annually, and performed one-time measurements of aboveground biomass and N concentrations, soil solution and resin bag inorganic N, soil pH, and soil extractable cations after 3 years of N additions. Our goal was to use these dose-response relationships to provide N critical loads for vegetation and soils for the alpine in Rocky Mountain National Park. Species richness and diversity did not change in response to the treatments, but one indicator species, Carex rupestris increased in cover from 34 to 125% in response to the treatments. Using the rate of change in cover for C. rupestris in the treatment and the ambient plots, and assuming the change in cover was due solely to N deposition, we estimated a N critical load for vegetation at 3 kg N ha(-1) yr(-1). Inorganic N concentrations in soil solution increased above ambient levels at input rates between 9 kg N ha(-1) yr(-1) (resin bags) and 14 kg N ha( 1) yr(-1) (lysimeters), indicating biotic and abiotic sinks for N deposition are exhausted at these levels. No changes in soil pH or extractable cations occurred in the treatment plots, indicating acidification had not occurred after 3 years. We conclude that N critical loads under 10 kg ha(-1) yr(-1) are needed to prevent future acidification of soils and surface waters, and recommend N critical loads for vegetation at 3 kg N ha(-1) yr(-1) as important for protecting natural plant communities and ecosystem services in Rocky Mountain National Park. PMID- 22516811 TI - Damaged-self recognition as a general strategy for injury detection. AB - Plants perceive endogenous molecules or their fragments as signals of danger when these appear at increased concentrations in the extracellular space, and they respond with increased endogenous levels of jasmonic acid. The wound hormone jasmonic acid represents a central player in the induced resistance of plants to herbivore feeding and infection by necrotrophic pathogens. This 'damaged self recognition' mechanism of plants exhibits astonishing similarities to the perception of 'damage-associated molecular patterns' (DAMPs) by the human immune system: endogenous cell constituents, or their fragments, that can be released into the extracellular milieu during states of cellular stress or damage function as 'stress signals' and trigger inflammatory and other immunity-related responses. Multicellular organisms use endogenous molecules as danger signals to mount adequate healing and resistance-related responses without depending on exogenous signals and to place exogenous, enemy-derived molecular signals into the adequate functional context. PMID- 22516812 TI - Antagonism between abscisic acid and gibberellins is partially mediated by ascorbic acid during seed germination in rice. AB - The antagonism between abscisic acid (ABA) and gibberellin (GA) plays a key role in controlling seed germination, but the mechanism of antagonism during this process is not known. In the associated study, we investigated the relationship among ABA, reactive oxygen species (ROS), ascorbic acid (ASC) and GA during rice seed germination. ROS production is reduced by ABA, which hence results in decreasing ASC accumulation during imbibition. GA accumulation was also suppressed by a reduced ROS and ASC level, whereas application of exogenous ASC can partially rescue seed germination from ABA treatment. Further results show that production of ASC, which acts as a substrate in GA biosynthesis, was significantly inhibited by lycorine which thus suppressed the accumulation of GA. Consequently, expression of GA biosynthesis genes was suppressed by the low levels of ROS and ASC in ABA-treated seeds. These studies reveal a new role for ASC in mediating the antagonism between ABA and GA during seed germination in rice. PMID- 22516813 TI - Nuclear genome diversity in somatic cells is accelerated by environmental stress. AB - DNA transfer to the nucleus from prokaryotic ancestors of the cytoplasmic organelles (mitochondria and plastids) has occurred during endosymbiotic evolution in eukaryotes. In most eukaryotes, organelle DNA transfer to nucleus is a continuing process. The frequency of DNA transposition from plastid (chloroplast) to nucleus has been measured in tobacco plants (Nicotiana tabacum) experimentally. We have monitored the effects of environmental stress on the rate of DNA transfer from plastid to nucleus by exploiting nucleus-specific reporter genes in two transplastomic tobacco lines. DNA migration from plastids to the nucleus is markedly increased by mild heat stress. In addition, insertions of mitochondrial DNA into induced double-strand breaks are observed after heat treatment. These results show that movement of organelle DNA to the nucleus is remarkably increased by heat stress. PMID- 22516814 TI - Characterization of potato plants with reduced StSYR1 expression. AB - Vesicle fusion processes in plants are important for both development and stress responses. Transgenic potato plants with reduced expression of SYNTAXIN-RELATED1 (StSYR1), a gene encoding the potato homolog of Arabidopsis PENETRATION1 (AtPEN1), display spontaneous necrosis and chlorosis at later stages of development. In accordance with this developmental defect, tuber number, weight and overall yield are significantly reduced in StSYR1-RNAi lines. Enhanced resistance of StSYR1-RNAi plants to Phytophthora infestans, the causal agent of late blight disease of potato, correlates with enhanced levels of salicylic acid, whereas levels of 12-oxophytodienoic acid and jasmonic acid are unaltered. Cultured cells of StSYR1-RNAi lines secrete at least two compounds which are not detectable in the supernatant of control cells, suggesting an involvement of StSYR1 in secretion processes to the apoplast. PMID- 22516815 TI - Extracellular ATP signaling and homeostasis in plant cells. AB - Extracellular ATP (eATP) is now recognized as an important signaling agent in plant growth and defense response to environmental stimuli. eATP has dual functions in plant cell signaling, which is largely dependent on its concentration in the extracellular matrix (ECM). A lethal level of eATP (extremely low or high) causes cell death, whereas a moderate level of eATP benefits plant growth and development. Ecto-apyrases (Nucleoside Triphosphate Diphosphohydrolase) help control the eATP concentrations in the ECM, and thus contributing to the mediation of plant growth and defense response upon environmental stress. In this review, we summarize eATP signaling in plants and highlight the correlation between eATP homeostasis control and programmed cell death. PMID- 22516816 TI - HY5 is involved in strigolactone-dependent seed germination in Arabidopsis. AB - Strigolactones (SLs) function as plant hormones that mediate a myriad of developmental responses in higher plants. SLs also act as an environmental signal to stimulate seed germination of parasitic plant species of genera Striga and Orobanche. In contrast to their hormonal roles, genetic mechanisms of how SLs stimulate parasitic seed germination are largely not known. Recently, we established a method to monitor the germination-stimulating activity of SLs in Arabidopsis using temperature as environmental constraint (thermoinhibition). Here, we show that SLs require HY5, a key transcription factor for light signal transduction, to stimulate Arabidopsis seed germination during thermoinhibiton. Genetic analysis suggests the HY5 dependent signaling pathway is independent of other known SL signaling pathways. Thermoinhibibed seeds expressed low level of HY5 while GR24 increase the level at both mRNA and protein level. A role of SLs on activating crucial light signaling components such as HY5 may hint the evolution of parasitism associated with SL usage. PMID- 22516817 TI - NFXL2 modifies cuticle properties in Arabidopsis. AB - Loss of the Arabidopsis NFX1-LIKE2 (NFXL2) gene (At5g05660) results in elevated ABA levels, elevated hydrogen peroxide levels, reduced stomatal aperture, and enhanced drought stress tolerance. Introduction of the NFXL2-78 isoform into the nfxl2-1 mutant is largely sufficient for complementation of the phenotype. We show here that cuticular properties are altered in the nfxl2-1 mutant. The NFXL2 78 protein binds to the SHINE1 (SHN1), SHN2, SHN3, and BODYGUARD1 (BDG1) promoters and mediates weaker expression of these genes. The SHN AP2 domain transcription factors influence cuticle properties. Stronger SHN1, SHN2, and SHN3 expression in the nfxl2-1 mutant may cause altered cuticle properties including reduced stomatal density, and partly explain the enhanced drought stress tolerance. The BDG1 protein also controls cuticle development and is essential for osmotic stress regulation of ABA biosynthesis. Stronger BDG1 expression in nfxl2-1 plants may allow elevated ABA accumulation under drought stress. We conclude that the NFXL2-78 protein is part of a regulatory network that integrates the biosynthesis and action of ABA, ROS, and cuticle components. PMID- 22516818 TI - Acquired thermotolerance independent of heat shock factor A1 (HsfA1), the master regulator of the heat stress response. AB - The heat stress (HS) response in eukaryotes is mainly regulated by heat shock factors (HSFs). Genetic disruption of the master HSF gene leads to dramatically reduced HS response and thermotolerance in several model organisms. However, it is not clear whether organisms devoid of the master regulator can still acclimate to heat. Previously, we showed that Arabidopsis HsfA1a, HsfA1b, and HsfA1d act as master regulators in the HS response. In this study, we examined the heat acclimation capacity of the Arabidopsis quadruple and triple T-DNA knockout mutants of HsfA1a, HsfA1b, HsfA1d, and HsfA1e. Our data showed that in the absence of the master regulators, a minimal but significant level of acquired thermotolerance could be attained in the Arabidopsis mutants after acclimation. The optimum acclimation temperature for the HsfA1 quadruple mutant was lower than that for the wild type plants, suggesting that plant cells have two HS-sensing mechanisms that can be distinguished genetically. The acquired thermotolerance of the quadruple mutant was likely due to the induction of a small number of HsfA1 independent HS response genes regulated by other transcription factors. Here, we discuss the possible candidates and propose a working model of the transcription network of the HS response by including the HsfA1-dependent and -independent pathways. PMID- 22516819 TI - Fern leaves and cauliflower curds are not fractals. AB - The popular demonstration of drawing a mature fern leaf as expressed by Barnsley's fractal method is mathematically and visually very attractive but anatomically and developmentally misleading, and thus has limited, if any, biological significance. The same is true for the fractal demonstration of the external features of cauliflower curds. Actual fern leaves and cauliflower curds have a very small number of anatomically variable and non-iterating bifurcations, which superficially look self-similar, but do not allow for scaling down of their structure as real fractals do. Moreover, fern leaves and cauliflower curds develop from the inside out through a process totally different from fractal drawing procedures. The above cases demonstrate a general problem of using mathematical tools to investigate or illustrate biological phenomena in an irrelevant manner. A realistic set of mathematical equations to describe fern leaf or cauliflower curd development is needed. PMID- 22516820 TI - WUSCHEL protein movement and stem cell homeostasis. AB - Stem cell maintenance is essential for growth and development of plants and animals. Similar to animal studies, transcription factors play a critical role in plant stem cell maintenance, however the regulatory logic is not well understood. Shoot apical meristems (SAMs) harbor a pool of pluoripotent stem cells and they provide cells for the development of all above-ground organs. Molecular genetic studies spanning more than a decade have revealed cell-cell communication logic underlying stem cell homeostasis. WUSCHEL (WUS), a homeodomain transcription factor expressed in cells of the organizing center specifies stem cells in overlying cells of the central zone (CZ) and also activates a negative regulator CLAVATA3 (CLV3). CLV3, a small secreted peptide, binds to CLAVATA1 (CLV1) and also possibly to CLV1-related receptors to activate signaling which restricts WUS transcription. Though the CLV-WUS feedback network explains the cell-cell communication logic of stem cell maintenance, how WUS communicates with adjacent cells had remained elusive. In October 15 2011 issue of Genes and Development, we report that WUS protein synthesized in cells of organizing center migrates into adjacent cells via cell-cell movement and activates CLV3 transcription by directly binding to promoter elements. PMID- 22516821 TI - Global regulation of reactive oxygen species scavenging genes in alfalfa root and shoot under gradual drought stress and recovery. AB - Reactive oxygen species (ROS) production and scavenging in plants under drought stress have been studied intensively in recent years. Here we report a global analysis of gene expression for the major ROS generating and scavenging proteins in alfalfa root and shoot under gradual drought stress followed by one-day recovery. Data from two alfalfa varieties, one drought tolerant and one drought sensitive, were compared and no qualitative differences in ROS gene regulation between the two were found. Conserved, tissue-specific patterns of gene expression in response to drought were observed for several ROS-scavenging gene families, including ascorbate peroxidase, monodehydroascorbate reductase, and peroxiredoxin. In addition, differential gene expression within families was observed. Genes for the ROS-generating enzyme, NADPH oxidase were generally induced under drought, while those for glycolate oxidase were repressed. Among the ROS-scavenging protein genes, Ferritin, Cu/Zn superoxide dismutase (SOD), and the majority of the glutathione peroxidase family members were induced under drought in both roots and shoots of both alfalfa varieties. In contrast, Fe-SOD, CC-type glutaredoxins, and thoiredoxins were downregulated. PMID- 22516823 TI - Effects of missense mutation on structure and function of photoreceptor. AB - Phytochromes (PHYs) are photoreceptors of the red (R ~660 nm) and far-red (FR ~730 nm) light, and they control a wide range of responses affecting crucial aspects of plant life. There are five genes PHYA-PHYE encoding for phytochromes of different but overlapping function. One of these, PHYA has the unique function controlling specific responses in high irradiance far-red, as well as in very weak light. Appropriate PHYA functioning requires not only the photoreversibility of molecule but also the proper nuclear localization and degradation of receptor. Recently, we identified and described a mutant PHYA allele (phyA-5) in Arabidopsis thaliana, which showed reduced binding affinity to FHY1/FHL, the proteins regulating its nuclear transport, resulting in impaired nuclear localization and altered signaling under certain conditions. We present here a hypothesis to explain how the identified amino acid substitution may lead to structural changes manifested as altered signaling and phenotype displayed by the phyA-5 mutant. PMID- 22516824 TI - Serine/threonine protein phosphatase 5 (PP5) interacts with substrate under heat stress conditions and forms protein complex in Arabidopsis. AB - Protein phosphatase 5 plays a pivotal role in signal transduction in animal and plant cells, and it was previously shown that Arabidopsis protein phosphatase 5 (AtPP5) performs multiple enzymatic activities that are mediated by conformational changes induced by heat shock stress. In addition, transgenic overexpression of AtPP5 gene conferred enhanced heat shock resistance compared with wild-type plant. However, the molecular mechanism underlying this enhanced heat shock tolerance through functional and conformational changes upon heat stress is not clear. In this report, AtPP5 was shown to preferentially interact with its substrate, MDH, under heat stress conditions. In addition, in co-IP analysis, AtPP5 was observed to form a complex with AtHsp90 in Arabidopsis. These results suggest that AtPP5 may enhance thermotolerance via forming multi chaperone complexes under heat shock conditions in Arabidopsis. Finally, we show that AtPP5 is primarily localized in the cytoplasm of Arabidopsis. PMID- 22516825 TI - Catalytic mechanism and kinase interactions of ABA-signaling PP2C phosphatases. AB - Abscisic acid (ABA) is an essential hormone that controls plant growth, development and responses to abiotic stresses. ABA signaling is mediated by type 2C protein phosphatases (PP2Cs), including HAB1 and ABI2, which inhibit stress activated SnRK2 kinases and whose activity is regulated by ABA and ABA receptors. Based on biochemical data and our previously determined crystal structures of ABI2 and the SnRK2.6-HAB1 complex, we present the catalytic mechanism of PP2C and provide new insight into PP2C-SnRK2 interactions and possible roles of other SnRK2 kinases in ABA signaling. PMID- 22516826 TI - Effects of herbicide applications in wheat fields: is phytohormones application a remedy? AB - The present review encompasses the physiological and yield constraints of herbicide applications with special reference to wheat productivity. Post independence lagging of Indian agriculture to feed its population led to haphazard use of chemical pesticides and weedicides which deteriorated the productivity pay-off particularly of wheat and rice. Past some decades witnessed the potential use of certain phytohormones in augmenting abiotic stress to get rid of yield gap and productivity constraints. We summed up with reviewing the potential role of these natural regulators in overcoming above mentioned drawbacks to substitute or to integrate these chemicals with the use of plant hormones. PMID- 22516827 TI - Apoplastic exosome-like vesicles: a new way of protein secretion in plants? AB - The presence of apoplastic proteins without predicted signal peptide in the gene sequence suggests the existence of protein secretion independent of the ER/Golgi classical route. In animals, one of the pathways proposed for alternative protein secretion involves the release of exosomes to the extracellular space. Although this pathway has not been dissected in plants some indirect evidence is emerging. We have reported that apoplastic fractions of sunflower seeds contain exosome like vesicles. Besides, these vesicles are enriched in the lectin Helja, which is immunolocalized in the extracellular space even if it the protein has no predicted signal peptide. Here we show that Helja is not glycosylated and its secretion is insensitive to brefeldin A, two of the major characteristics to discard ER/Golgi-mediated protein transport. Moreover, the levels of Helja in sunflower extracellular vesicles are not affected by brefeldin A treatment. Our results suggest that Helja could be exported through an exosome-mediated pathway and point out that this mechanism may be responsible for the secretion of at least part of the leaderless proteins detected in the extracellular compartment of plants. PMID- 22516828 TI - [Multicentric primary melanoma of the esophagus]. PMID- 22516829 TI - [Desmoplastic fibroma of the femur]. PMID- 22516830 TI - [Heterotopic ossification of the stylohyoid complex presenting as a cervical mass]. PMID- 22516831 TI - Airway spray cryotherapy: initial outcomes from a multiinstitutional registry. AB - BACKGROUND: Spray cryotherapy (SCT) uses a noncontact system to deliver liquid nitrogen (2 to 4 psi) through an endoscopic catheter. Rapid freezing and thawing of tissue causes cellular death and is also hemostatic. We report the preliminary results from 6 institutions in which SCT was used for the treatment of malignant airway tumors. METHODS: SCT was performed on patients with symptomatic airway tumors and reviewed retrospectively. Airway narrowing was graded as 25% or smaller, 26% to 50%, 51% to 75%, and exceeding 75%. All events were documented and assessed. RESULTS: Eighty patients (45 male [56%]) underwent 114 treatments. Median age was 66 years (range, 15 to 90 years). All patients were treated with minimal blood loss. Fifty-eight percent of the cases were outpatient procedures. Airway obstruction exceeded 75% in most of the lesions treated. There were 21 intraoperative events (19%), including hypotension, bradycardia and tachycardia, ST segment changes, desaturation, and an airway tear. Three pneumothoraces occurred, one requiring emergency chest tube placement. Two intraoperative deaths were associated with bradycardia. Three postoperative deaths occurred in patients who were transitioned to comfort care. All but 1 patient had airway patency after treatment. CONCLUSIONS: SCT can be used in patients with highly vascular tumors, with reduced bleeding complications and a low overall complication rate. Caution is needed before SCT is used on a widespread basis, given the intraoperative complications. Although the potential benefit of SCT is considerable, this needs to be confirmed in larger studies. PMID- 22516832 TI - Amiodarone significantly decreases atrial fibrillation in patients undergoing surgery for lung cancer. AB - BACKGROUND: Postoperative atrial fibrillation occurs in 5% to 65% of patients undergoing thoracic surgery. Although postoperative atrial fibrillation often is regarded as a temporary, benign, operation-related problem, it is associated with a twofold to threefold increase in risk of adverse events, including transient or permanent stroke, acute myocardial infarction, and death. METHODS: A total of 254 consecutively eligible enrolled patients undergoing surgery for lung cancer were included in this randomized, controlled, double-blinded trial. Patients received 300 mg of amiodarone or placebo intravenously over 20 minutes immediately after surgery and an oral dose of 600 mg of amiodarone or placebo twice daily during the first 5 postoperative days. RESULTS: The patients in the amiodarone prophylaxis group had a reduction in the risk of atrial fibrillation of 23% (12 to 31); number needed to treat was 4.4 (3.1 to 7.8). A total of 38 in the control group and 11 in the amiodarone group experienced atrial fibrillation (p<0.001). Adverse effects were observed in 10 patients equally distributed in both trial arms. CONCLUSIONS: Postoperative prophylaxis with a high dose of oral amiodarone after an intravenous bolus infusion is a safe, practical, feasible, and effective regimen for patients with lung cancer undergoing surgery. It significantly reduced the incidence of postoperative atrial fibrillation. PMID- 22516833 TI - Relative impact of surgeon and center volume on early mortality after the Norwood operation. AB - BACKGROUND: Previous studies suggest center volume is associated with outcome after the Norwood operation; however, the impact of surgeon volume is less clear. We evaluated the relative impact of surgeon and center volume on mortality in a large Norwood cohort. METHODS: Patients in the Society of Thoracic Surgeons Congenital Heart Surgery Database undergoing the Norwood operation (2000 to 2009) were included. Using multivariable logistic regression, we evaluated the relationship between in-hospital mortality and annual center and surgeon volume, adjusting for patient factors. RESULTS: A total of 2,555 patients were operated on at 53 centers by 111 surgeons. Overall unadjusted mortality was 22.1%. When analyzed individually, both lower center and surgeon volume were associated with higher mortality (odds ratio for centers with 0 to 10 vs >20 cases per year 1.56 [95% confidence interval 1.05 to 2.31]; odds ratio for surgeons with 0 to 5 vs >10 cases per year 1.60 [95% confidence interval 1.12 to 2.27]). When analyzed together, the addition of surgeon volume to the center volume models attenuated but did not completely mitigate the association of center volume with outcome (relative attenuation of odds ratio=34%). Adjusted mortality rates in low, medium, and high volume centers were 25.6%, 22.3%, and 17.7%, respectively. Across all center volume strata, lower volume surgeons had higher adjusted mortality rates. CONCLUSIONS: Both center and surgeon volumes appear to influence Norwood outcomes. These data suggest outcomes may potentially be improved through strategies that take advantage of the positive influence of both of these variables. This could include further investigation into the feasibility of regional collaborations, and the development of quality improvement initiatives within and across centers. PMID- 22516834 TI - Validation of EuroSCORE II in patients undergoing coronary artery bypass surgery. AB - BACKGROUND: The European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) has been recently developed to improve the performance of the original EuroSCORE. Herein we evaluated its discriminatory ability in predicting the immediate and late outcome after coronary artery bypass grafting (CABG). METHODS: Complete data on 1,027 patients who underwent isolated CABG were available for validation of EuroSCORE II and to compare its discriminatory ability with the original EuroSCORE and its Finnish modified version. RESULTS: EuroSCORE II performed somewhat better (area under the curve [AUC] 0.852, Brier score 0.031) than the original logistic EuroSCORE (AUC 0.838, Brier score 0.034) and its Finnish modified version (AUC 0.825, Brier score 0.034) in predicting operative mortality. The overall expected-to-observed operative mortality ratio for the original logistic EuroSCORE was 1.8, for its Finnish modified version was 0.6, and for EuroSCORE II was 1.2. EuroSCORE II showed expected-to-observed ratios ranging from 1.05 to 1.17 in its highest third quintiles. The best cutoff of EuroSCORE II in predicting operative postoperative mortality was 10% (21.5% vs 1.6%, p<0.0001; sensitivity 91.5%, specificity 60.5%, negative predictive value 98.4%, accuracy of 90.3%). The EuroSCORE II was predictive of de novo dialysis (AUC 0.805), prolonged use of inotropes (AUC 0.748), and intensive care unit stay 5 days or greater (AUC 0.793). The risk of late mortality significantly increased across increasing quintiles of EuroSCORE II (p<0.0001). CONCLUSIONS: The EuroSCORE II performs better than its original version in predicting operative mortality and morbidity after isolated CABG. Its ability to predict 30-day mortality in high-risk patients is of particular importance. The EuroSCORE II is also a good predictor of late postoperative survival. PMID- 22516835 TI - Utility of restaging endoscopic ultrasound after neoadjuvant therapy for esophageal cancer. AB - BACKGROUND: Currently, the most accurate staging test for patients with esophageal cancer is endoscopic ultrasound (EUS). At many institutions, patients who have completed neoadjuvant chemotherapy and radiotherapy for esophageal cancer undergo restaging EUS before proceeding to surgical resection. The benefit of this restaging procedure remains controversial. METHODS: We retrospectively studied consecutive patients who had pre-resection restaging EUS after receiving neoadjuvant treatment to assess accuracy of EUS restaging and determine whether it predicted survival. RESULTS: Final pathologic data were available for 73 patients who underwent restaging EUS (3 patients had missing T or N stage at one time point). Median time from restaging EUS to resection was 20 days. Restaging EUS accurately predicted pathologic T status in 26 of 72 patients (36%), N status in 44 of 71 (62%), and detected a complete pathologic response in 2 of 19 (10.5%). EUS inappropriately classified 10 patients as T0 N0. Agreement between EUS and pathologic staging was poor for T (kappa=0.14) and N status (kappa=0.24). Median time from resection to death or last follow-up was 20 months. Pathologic T and N status were each significant predictors of survival (p=0.049 and p=0.0004, respectively). There were nonsignificant trends toward better survival for lower EUS T (p=0.32) and N status (p=0.0946). CONCLUSIONS: Restaging by EUS before resection did not accurately predict pathologic stage in patients with esophageal cancer who received neoadjuvant treatment. As a result of this investigation, our institution no longer routinely performs restaging EUS. PMID- 22516836 TI - Multiple measures of visual attention predict novice motor skill performance when attention is focused externally. AB - Multiple lines of evidence indicate that the control of attention and motor skill performance are related. Athletes of various skill levels differ in terms of their control over the focus of attention and directing athletes to adopt an internal or external focus of attention modulates performance. However, it is unclear (a) whether the relationship between skill level and attentional control arises from preexisting individual differences in attention or from practice of the motor skill and (b) whether the effect of adopting an internal or external focus of attention on motor performance is influenced by individual differences in attention. To address these issues, individuals were measured on three distinct attention functions - orienting, alerting, and executive - prior to engaging in a novel golf-putting task performed with either external or internal focus instructions. The results indicated that, on average, attentional functioning and putting performance were related but that the strong relationships with orienting and executive attention were only present in the group given external focus instructions. These findings suggest that individual differences in attentional abilities are predictive of novel skill performance under an external focus of attention and they shed light on the mechanisms underlying the effects of focus instructions during motor performance. PMID- 22516837 TI - Changes in postural sway frequency and complexity in altered sensory environments following whole body vibrations. AB - Studies assessing whole body vibration (WBV) have produced largely positive effects, with some neutral, on postural control with frequencies between 25 and 40 Hz. However no conclusive evidence indicates that 25-40 Hz elicits the optimal beneficial effects. To address this issue, a larger range of vibration intensity (10-50 Hz at peak-to-peak amplitudes of 2 and 5mm) was employed while increasing the postural complexity (altered somatosensory and/or visual information) to assess acute effects of 4-min of WBV on postural control. Twelve healthy young adults underwent postural assessment at four time intervals (prior to, immediately following and 10 and 20 min post WBV). Findings revealed both postural sway frequency and sway complexity/regularity were affected by WBV. Baseline posture demonstrated increased sway frequency (p=.04) following WBV with no changes in sway complexity. When the support surface was altered, changes in both the frequency and complexity of sway were elicited (p=.027, .002, respectively). When both somatosensory and visual information were altered delayed improvements in postural control were elicited (p=.05 and .01, for frequency and complexity, respectively). Given the differential acute effects as a function of postural task complexity, future longitudinal studies could determine the overall training effect on sway frequency and complexity. PMID- 22516838 TI - Complications following surgically assisted rapid palatal expansion: a retrospective cohort study. AB - PURPOSE: To examine the prevalence of complications and characterize the associated clinical findings in patients undergoing surgically assisted rapid palatal expansion (SARPE). MATERIALS AND METHODS: A retrospective evaluation was conducted of all patients who underwent SARPE from January 2004 through December 2008 at Kaiser Permanente Oakland Medical Center. Medical records were abstracted, and demographic factors and relevant comorbidities were identified. Clinical features of patients with complications (surgical and/or dental) after SARPE were characterized. RESULTS: One hundred thirty-one patients comprised the study sample and 11 patients were excluded. Of the remaining 120 patients (median age, 29.5 yrs; interquartile range, 22.0 to 39.0 yrs), 51.7% were women, 41 developed at least 1 complication, 33 had surgical complications, 18 had dental and/or periodontal problems, and 10 developed both surgical and dental or periodontal problems. Asymmetric and/or inadequate expansion was the most frequent surgical complication, found in 13.3% of the study cohort, and gingival recession (8.3%) was the most common dental complication. Two patients developed catastrophic periodontal bone defects resulting in loss of the central incisors; these patients had eccentric interdental osteotomies that caused separation of the bone from the root surface of the central incisors followed by postoperative osteotomy site infections. CONCLUSIONS: Overall, the present findings suggest that, although major complications after SARPE were rare, asymmetric or inadequate expansion and dental and/or periodontal problems primarily involving the central incisors accounted for most complications. Future prospective and long-term follow-up studies are needed to identify individual risk factors that may predispose patients to adverse outcomes after SARPE. PMID- 22516839 TI - Minipig model of maxillary distraction osteogenesis: immunohistochemical and histomorphometric analysis of the sequence of osteogenesis. AB - PURPOSE: To document the sequence of bone formation in a minipig model of Le Fort I distraction osteogenesis (DO) using immunohistochemistry and histomorphometry. MATERIALS AND METHODS: Female Yucatan minipigs (N = 9) in the mixed-dentition stage underwent bilateral maxillary DO. The distraction protocol was 0 days of latency, with a distraction rate of 1 mm/d for 12 days and 24 days of fixation. Specimens were harvested and divided between the central incisors (18 hemi maxillae) at the end of DO (n = 6), at mid-fixation (n = 6), and at the end of fixation (n = 6). Sections, including the advancement zone, were stained with hematoxylin-eosin, collagen II, CD34, proliferating cell nuclear antigen, and tartrate-resistant acid phosphatase. Light and fluorescence microscope images (original magnification *200) were obtained, and percentage of surface area (PSA) of the advancement zone occupied by fibrous tissue, vessels, proliferating cells, osteoid, and bone was determined. An intact maxilla served as the control. RESULTS: At the end of DO, in the advancement zone, the PSA (mean values) of proliferating cells was 33.16%; fibrous tissue, 52%; vessels, 4.35%; and new bone, 5.45%. At the end of fixation, the PSA of proliferating cells decreased to 10.53%, fibrous tissue to 2.3%, and vessels to 1.5% whereas the PSA of new bone increased to 44.9%. CONCLUSIONS: The results of this study indicate that the progression of osteogenesis in the maxillary DO wound begins with intense cellular proliferation and vascular fibrous tissue formation and progresses to mature, cancellous bone by the end of fixation. The PSA occupied by mature bone is significantly less than in the control maxilla at the end of fixation. This is consistent with the sequence in the mandibular DO wound. PMID- 22516840 TI - Computer-aided design and computer-aided manufacturing locating guides accompanied with prebent titanium plates in orthognathic surgery. PMID- 22516841 TI - Amphetamine-induced rotation in the transplanted hemi-parkinsonian rat--response to pharmacological modulation. AB - The transplantation of dopamine rich foetal tissue into Parkinson's disease patients holds much promise as a therapeutic strategy. The functional efficiency of transplantation is often tested experimentally, by grafting rat derived embryonic ventral mesencephalon tissue suspensions into the denervated striatum of hemi-parkinsonian rats that were previously rendered dyskinetic with L-DOPA. The survival and integration of the grafts in rats can be assessed by a variety of behavioural tests, however amphetamine-induced rotations remain one of the most widely used and robust measures. In this test, dopamine released from the transplant typically drives net rotation in the contralateral direction, in contrast to the ipsilateral rotational bias seen post-lesion. It is unknown what contribution other neurotransmitter systems may make to this response. In this study we monitored amphetamine-induced rotation in transplanted rats that were co administered a second pharmacological challenge with agents known to affect dopamine-mediated behavioural responses in this model. Both D1 and D2 receptor antagonism (by SCH23390 and raclopride respectively) reduced the rotational response. However the cannabinoid CB1 agonist WIN55,212-2 and alpha1 and alpha2 adrenergic receptor antagonist yohimbine had no effect on rotation. Interestingly, glutamatergic antagonists reduced (MTEP) or even reversed (MK-801) total net rotations. The serotoninergic 5-HT(1A) and 5-HT(1B) agonists (8-OH-DPAT and CP94253 respectively) altered the temporal profile of the rotational behaviour supporting a regulatory role. Although dopamine clearly drives the motor response, this data implicates both 5-HT and glutamate systems in its regulation. PMID- 22516842 TI - 6-Hydroxydopamine leads to T2 hyperintensity, decreased claudin-3 immunoreactivity and altered aquaporin 4 expression in the striatum. AB - The neurotoxin 6-hydroxydopamine (6-OHDA) is frequently used in animal models to mimic Parkinson's disease. Imaging studies describe hyperintense signalling in regions close to the site of the 6-OHDA injection in T2-weighted (T2w) magnetic resonance imaging (MRI). The nature of this hyperintense signal remains elusive and still is matter of discussion. Here we demonstrate hyperintense signalling in T2w MRI and decreased apparent diffusion coefficient (ADC) values following intraventricular injection of 6-OHDA. Moreover, we show decreased GFAP immunoreactivity in brain regions corresponding to the region revealing the hyperintense signalling, probably indicating a loss of astrocytes due to a toxic effect of 6-OHDA. In the striatum, where no hyperintense signalling in MRI was observed following intraventricular 6-OHDA injection, immunohistochemical and molecular analyses revealed an altered expression of the water channel aquaporin 4 and the emergence of vasogenic edema, indicated by an increased perivascular space. Moreover, a significant decrease of claudin-3 immunoreactivity was observed, implying alterations in the blood brain barrier. These findings indicate that intraventricular injection of 6-OHDA results (1) in effects close to the ventricles that can be detected as hyperintense signalling in T2w MRI accompanied by reduced ADC values and (2) in effects on brain regions not adjacent to the ventricles, where a disturbance of water homeostasis occurs. We clearly demonstrate that 6-OHDA leads to brain edema that in turn may affect the overall results of experiments (e.g. behavioral alterations). Therefore, when using 6-OHDA in Parkinson's models effects that are not mediated by degeneration of catecholaminergic neurons have to be considered. PMID- 22516843 TI - Culturally appropriate vegetables and economic development. A contextual analysis. AB - This paper examines the implications of the demand for ethno-cultural vegetables (ECV) by South-Asians, the largest cultural group in the Greater Toronto Area (GTA), on their potential for Ontario agricultural economic development and significant consumer health benefits. A conceptual framework is presented to explain the relationship among factors such as change in demographics, demand for locally produced ECV and both the potential agricultural and health benefits. Analysis of cross-sectional data collected in 2009 also indicates that the respondents have certain characteristics that are pertinent to understanding why they shop in particular stores and their perceptions about what constitutes quality. In sum, household size and percentage spent on vegetables predict their expenditure on ECV, an indication that South-Asians resident in the GTA will continue to demand their ECV. It is thus a niche market that farmers can explore if its potential economic value to them is clarified and the government can provide sufficient support by increasing awareness and creating appropriate economic incentives for farmers willing to grow these vegetables. PMID- 22516844 TI - Troponin for the estimation of infarct size: what have we learned? AB - In acute myocardial infarction (AMI), the extent of myocardial damage is closely linked to prognosis. Early determination of infarct size is therefore key to assessing the future risk of patients and instructive for optimization of therapeutic strategies. The cardiac troponins, by allowing the physician to track the extent of injury suffered by the myocardium, provide a window into the heart. This article addresses the relationship between the cardiac troponins and the infarct size in AMI. Taken together, the data suggest that the cardiac troponins provide very useful information in this respect and especially in patients with ST elevation myocardial infarction. More studies are needed to understand how cardiac troponin-estimated infarct size may be integrated with other prognostic assessments and employed systematically in risk stratification. Early data are promising and indicate that cardiac troponins could provide useful information for early risk assessment that is complementary to the determination of cardiac function and volumes. PMID- 22516845 TI - Molds and mycotoxins. PMID- 22516846 TI - Clinical outcomes for cancer patients using complementary and alternative medicine. AB - CONTEXT: Over half of cancer patients in Singapore use some form of complementary or alternative medicine (CAM) to improve their immunity and general health status. The effectiveness of CAM, however, in reducing acute complications is currently unknown. Concerns also exist as to whether CAM may cause toxic effects in patients with cancer. OBJECTIVE: To investigate the changes in general health status, immunity, and organ function over a 6-month period in CAM and non-CAM users with cancer. DESIGN: The authors designed a single-center, retrospective cohort study. The patients had participated previously in a cross-sectional prevalence survey about the types of oral CAM they were using in addition to chemotherapy. The authors used the data from the survey and clinical and medication-use information from patients' medical and pharmaceutical records to complete the current study. SETTING: The study occurred at the National Cancer Centre Singapore (NCCS), which is the largest ambulatory cancer center in Singapore and treats two-thirds of the solid-tumor patients in Singapore. The study excluded patients if their medical records were incomplete and/or if the patients had not received any cytotoxic or targeted therapies at the time of survey. PARTICIPANTS: The authors reviewed the records of a total of 403 patients and excluded 46 patients because their records were missing (n=20) or because they had not received any form of anticancer treatment at the time of survey (n=26). They included 357 patients in the current study. The authors did not contact patients for this follow-up study. OUTCOME MEASURES: The authors collected data on clinical characteristics for each patient and assessed the differences between each characteristic at baseline (at the time of the survey) and at 6 months after baseline measurement. The authors evaluated clinical characteristics using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3. RESULTS: As a whole, CAM use provided an absolute reduction of infection episodes by 11.9% (P=.045) and of antibiotic use by 10.3% (P=.022). Subgroup analysis showed a reduction of documented infection by 17.9% (P=.02) and a 13% decrease in hospitalizations due to infections (P=.043) among metastatic cancer patients who used CAM. CAM usage was not associated with significant changes of hepatic and renal function. CONCLUSION: CAM use in patients with cancer was associated with a reduction in hospitalizations and requirements for antibiotics. CAM use was not associated with significant changes in hepatic and renal function. There is a need for well-designed, prospective clinical studies to confirm these findings. PMID- 22516848 TI - Management of pelvic pain in primary dysmenorrhea using a hot hip-bath: a pilot study. PMID- 22516847 TI - Short-term garlic supplementation and highly active antiretroviral treatment adherence, CD4+ cell counts, and human immunodeficiency virus viral load. AB - CONTEXT: Human immunodeficiency virus (HIV)-infected individuals frequently have consumed garlic, a popular complementary supplement. Researchers rarely have studied garlic's association with antiretroviral therapies, however, even though that association is very relevant clinically. OBJECTIVE: To examine associations of supplemental use of garlic with highly active antiretroviral treatment (HAART) adherence level and HAART effectiveness (HIV viral load and CD4+ cell counts) in HIV-infected women. DESIGN: The research team carried out a self-controlled, longitudinal study nested within the Women's Interagency HIV Study (WIHS). The team used a paired study design that allowed participants to serve as their own controls. The team first identified all of the studies visits in which the participant self-reported the use of a garlic supplement since her last visit (index visit). Then for each index visit, the team identified a matching visit (a control visit) using the following criteria: (a) the visit must be one for the same participant in which that participant reported no garlic supplementation; (b) the visit must immediately precede the index visit (less than 1 year apart); and (c) at the time of the control visit, the participant must have been using antiretroviral therapy identical to that used at the time of the index visit. PARTICIPANTS: Participants were persons using garlic supplementation who already were participants in the WIHS. OUTCOME MEASURES: The research team used a logistic regression model to examine the association between garlic supplementation and HAART adherence level. The team used a mixed linear model to examine the association of garlic supplementation with HIV viral load and CD4+ cell counts. RESULTS: From October 1994 to April 2009, 390 HIV-infected women in the WIHS made 1112 visits at which they reported using garlic supplements. Seventy-seven HIV-infected women using HAART met the research teams selection criteria and contributed 99 pairs of visits for the study. Among the women who used garlic supplements, 22% were 50 years and older; 58% were black and non Hispanic; and 23% had less than a high-school education. Neither use of garlic supplementation nor reasons for using garlic supplements were significantly associated with the HAART adherence level, HIV viral load, or CD4+ cell counts; however, use garlic as needed, a potential marker of a disease state, was significantly associated with higher viral load (P=.0003). CONCLUSION: Short-term garlic supplementation did not impact HAART adherence level, HIV viral load, and CD4+ cell counts. PMID- 22516849 TI - The Ithaca Free Clinic: a multidisciplinary health services delivery model that includes complementary and alternative medicine practitioners. AB - Inadequate access to health care services poses a considerable threat to public health and has significant national economic consequences. In the following report, the authors describe a financially stable, multidisciplinary free community health clinic that has operated successfully in Ithaca, New York, since 2006. The clinic provides a diverse collection of conventional and complementary and alternative medicine (CAM) services. The establishment of multidisciplinary free community health clinics in other geographical areas with large uninsured and underinsured populations and the integration of CAM services into them may be a viable strategy to improve access to health services and thereby improve other communities' health. PMID- 22516850 TI - Psychological effects of Yi Ren Medical Qigong and progressive resistance training in adults with type 2 diabetes mellitus: a randomized controlled pilot study. AB - BACKGROUND: Previous studies suggest that qigong therapy has physiological benefits for adults with type 2 diabetes; however, information about the psychological benefits of qigong therapy in this population is limited. OBJECTIVE: The objective of this research project was to identify psychological responses to qigong vs control interventions in adults with type 2 diabetes. DESIGN: The research team designed a randomized, controlled, three-arm clinical trial comparing 12 weeks of Yi Ren Medical Qigong (YRMQ), progressive resistance training (PRT), and standard care. SETTING: The study was performed at Bastyr University Research Institute, Kenmore, Washington. PARTICIPANTS: Participants were 13 men and 19 women (N=32) with diagnosed type 2 diabetes, a mean age of 56.3 +/- 8.1 (standard deviation) years, glycated hemoglobin > 7.5%, and fasting blood glucose > 7 mmol/dL (126 mg/dL). INTERVENTION: For 12 weeks, participants in the YRMQ and PRT group attended a 1-hour weekly group session that a certified instructor led and were instructed to practice at least twice a week for 30 minutes. PRIMARY OUTCOME MEASURES: The research team used the Perceived Stress Scale and the Beck Depression Inventory scores to analyze the data. RESULTS: YRMQ decreased perceived-stress scores by 29.3% (P < .05) and depression scores by 14.3% (not significant [NS]). The active control group, PRT, also decreased stress scores by 18.6% (NS) and decreased depression scores by 50% (P < .03). Stress and depression measures remained unchanged in the standard care group. CONCLUSION: YRMQ and PRT may be beneficial in reducing perceived stress and improving depression in patients with type 2 diabetes, although verification of the clinical significance of these findings requires a longer study with a larger sample size. PMID- 22516851 TI - The assessment of the energy metabolism in patients with chronic fatigue syndrome by serum fluorescence emission. AB - CONTEXT: Chronic fatigue syndrome (CFS) is a debilitating fatigue illness that has unknown etiology and lacks an objective diagnostic marker. OBJECTIVE: To examine the metabolic component of CFS to determine if practitioners can use serum NAD(P)H concentration measurements to monitor metabolism and fatigue status in patients with CFS. DESIGN: The research team conducted a case-control study, comparing a group of patients who were diagnosed with CFS with a control group of healthy subjects. The team obtained venous blood samples from fasting patients to examine the serum NAD(P)H concentrations. SETTING: The study occurred at the Riordan Clinic in Witchita, Kansas. PARTICIPANTS: The study included 44 CFS patients at the Riordan Clinic and 30 healthy control participants. The CFS patients presented a spectrum of symptoms that had existed for at least 6 months: new, unexplained, persistent, or relapsing chronic fatigue that bed rest did not resolve and that was severe enough to reduce daily activity significantly by 50% in conjunction with headache, muscle pain, pain in multiple joints, and unrefreshing sleep. In the control group, the research team enrolled subjects without diagnosis of disease or injury. OUTCOME MEASURES: The research team determined levels of serum reduced nicotinamide adenine dinucleotides (NADH and NAD[P]H) by measuring serum fluorescence emission at 450 nm. The team then conducted sensitivity and specificity analyses. Results NAD(P)H concentrations in serum of CFS participants averaged 8.0 +/- 1.4 (standard deviation [SD]) nmol/mL, while those in the healthy controls averaged 10.8 +/- 0.8 (SD) nmol/mL, a statistically significant difference. Using a cut-off concentration of 9.5 nmol/mL, the research team attained a sensitivity of 0.73 and a specificity of 1.0. An analysis of receiver-operator characteristics yielded an area under the curve of 0.9. The research team compared serum NAD(P)H to several endocrine and metabolic lab parameters. Serum NAD(P)H was directly correlated with serum CoQ10 levels and inversely correlated with urine hydroxyhemopyrrolin-2-one levels. CONCLUSIONS: Based on these findings, the research team proposed using serum NAD(P)H, measured as an intrinsic serum-fluorescence emission, to monitor metabolism and fatigue status in patients with CFS. Following patients NAD(P)H levels over time may aid in selecting therapeutic strategies and monitoring treatment outcomes. PMID- 22516852 TI - Garry Gordon, MD, DO, MD(H): today's toxic world and the multifactoral FIGHT required to restore our health. Interviewed by Karen Burnett. PMID- 22516853 TI - Posttraumatic headache. AB - PURPOSE OF REVIEW: Posttraumatic headache (PTH) is a commonly occurring and potentially disabling consequence of concussion and mild traumatic brain injury (mTBI). This brief review highlights recent advances in the epidemiology, evaluation, and management of concussion, mTBI, and PTH. RECENT FINDINGS: Current epidemiological studies suggest that previous estimates of concussion and mTBI incidence are grossly underestimated and have also helped to identify specific activities and demographic groups that might be more susceptible. Concussion results in profound metabolic derangements during which the brain is potentially vulnerable to repeat injury and permanent damage. Imaging studies such as magnetic resonance (MR) spectroscopy and diffusion tensor imaging have proven to be effective at identifying these abnormalities both acutely and also weeks after symptoms resolution. To date, there have been no randomized, placebo-controlled studies supporting the efficacy of any treatment for PTH and current therapeutic decisions are guided only by expert opinion and current evidence-based guidelines for the treatment of specific primary headache phenotypes, the most commonly occurring of which is migraine. SUMMARY: Despite numerous advances in the awareness, pathophysiology, and diagnostic workup of concussion, mTBI, and PTH, there is a paucity of evidence-based guidance regarding treatment. PMID- 22516854 TI - Genetics of multiple sclerosis: swimming in an ocean of data. AB - PURPOSE OF REVIEW: Major advances in the genetics of multiple sclerosis (MS) have been reported in 2011. These include studies in gene mapping, functional characterization of previously associated genes, and the relationship between genes and the environment. While particularly true for gene discovery, each of these efforts requires substantial statistics and computational resources for adequate analysis. This review describes the major advances in the genetics of MS with a slight emphasis on data handling and analysis. RECENT FINDINGS: Articles discussed include a new genome-wide association study (GWAS) with almost 10 000 cases (a collaboration between the Wellcome Trust and the international MS Genetics Consortium) that identified new susceptibility loci, taking the total number of risk alleles to more than 50. An article describing the use of next generation sequencing to identify a rare mutation in CYP27B1 in a MS family is also discussed. Moreover, a summary of recent reports describing functional studies of MS-associated genes as well as the latest research on the interactions between genes and the environment is provided. SUMMARY: This review provides a concise summary of the most relevant studies in the genetics of MS in the past year. We raise awareness about analytical resources to successfully analyze the massive datasets characteristic of today's genetic studies. PMID- 22516855 TI - Experimental validation of a pulse wave propagation model for predicting hemodynamics after vascular access surgery. AB - Hemodialysis patients require a vascular access that is, preferably, surgically created by connecting an artery and vein in the arm, i.e. an arteriovenous fistula (AVF). The site for AVF creation is chosen by the surgeon based on preoperative diagnostics, but AVFs are still compromised by flow-associated complications. Previously, it was shown that a computational 1D-model is able to describe pressure and flow after AVF surgery. However, predicted flows differed from measurements in 4/10 patients. Differences can be attributed to inaccuracies in Doppler measurements and input data, to neglecting physiological mechanisms or to an incomplete physical description of the pulse wave propagation after AVF surgery. The physical description can be checked by validating against an experimental setup consisting of silicone tubes mimicking the aorta and arm vasculature both before and after AVF surgery, which is the aim of the current study. In such an analysis, the output uncertainty resulting from measurement uncertainty in model input should be quantified. The computational model was fed by geometrical and mechanical properties collected from the setup. Pressure and flow waveforms were simulated and compared with experimental waveforms. The precision of the simulations was determined by performing a Monte Carlo study. It was concluded that the computational model was able to simulate mean pressures and flows accurately, whereas simulated waveforms were less attenuated than experimental ones, likely resulting from neglecting viscoelasticity. Furthermore, it was found that in the analysis output uncertainties, resulting from input uncertainties, cannot be neglected and should thus be considered. PMID- 22516856 TI - Dynamic plantar loading index: understanding the benefit of custom foot orthoses for painful pes cavus. AB - The purpose of this study was to evaluate a new method showing how custom foot orthoses (CFO) improve dynamics of plantar loading. The method is based on the probability distribution of peak pressure time series and is quantified using the Regression Factor (RF). RF is a least square regression slope between the experimentally observed plantar pressure magnitude probability distribution and a modeled Gaussian shape. Plantar pressure data from a randomized controlled trial of 154 participants with painful Pes Cavus were retrospectively re-analyzed. The participants were randomized to an active treatment group given CFO or a control group given sham orthoses. The location of 2(nd) Peak pressure as a percentage of stance time (P(Loc2)) and its magnitude (P(M2)) was also calculated. In addition, plantar pressure data were collected on 23 healthy volunteers with normal foot alignment and no foot pain. Results demonstrated Pes Cavus had a significantly lower RF than healthy participants (0.30 v. 0.51; p<10(-7)). P(M2) was reduced in both active and control groups. However, RF and the P(Loc2) were only changed in the active group (p<0.005) without any significant change in the control group (p>0.5). This study suggests that painful Pes Cavus alters the shape of probability distribution of plantar loading during walking and CFO are an effective therapeutic solution that can significantly improve it. Further use of the RF index and 2(nd) peak pressure location as an outcome measure for treatment of foot and ankle deformities is suggested. PMID- 22516857 TI - Does haemorrhage associated with brain metastases in lung cancer patients predict early mortality after cranial irradiation? PMID- 22516858 TI - Hyperbaric oxygen therapy for late rectal and bladder toxicity after radiation in prostate cancer patients. A symptom control and quality-of-life study. PMID- 22516859 TI - The management of lung cancer: a UK survey of oncologists. AB - AIMS: This report reviews current radiotherapy practice across the UK in the management of lung cancer, and the way new treatments and technologies are being introduced, where improvements have occurred, and where work is still required. We wanted to determine adherence to both National Radiotherapy Advisory Group and National Institute for Health and Clinical Excellence (NICE) guidance. This survey was conducted on behalf of the Department of Health Lung Cancer & Mesothelioma Advisory Group. MATERIALS AND METHODS: We sent a questionnaire to all UK radiotherapy departments. It covered radical radiotherapy dose fractionation, the use of concurrent or sequential chemotherapy for both non small cell and small cell lung cancers, the use of continuous hyperfractionated accelerated radiotherapy, new radiotherapy techniques, the use of positron emission tomography/computed tomography for planning purposes and patient accrual into current National Cancer Research Network UK trials. RESULTS: This UK-wide survey of radiotherapy practice for lung cancer showed broad compliance with NICE clinical guidance, but highlighted significant variation in fractionation schedules and the use of concomitant chemoradiotherapy. Clinical trial entry into lung cancer radiotherapy trials was variable and many centres are not fully participating in recruitment into these trials. CONCLUSIONS: This report has shown the variability of radiotherapy provision nationally. Current practice is largely consistent with current and updated NICE recommendations and best practice and should be recognised as such. It has also highlighted areas where improvements are still needed, particularly fractionation and new technologies. One particular aspect of concern is the poor recruitment to current UK-based clinical trials in lung cancer. PMID- 22516862 TI - Dietary outcomes of the healthy dads healthy kids randomised controlled trial. AB - Fathers have not been exclusively targeted in family-based lifestyle programmes. The aim was to determine whether dietary intakes of fathers and children can be improved, following an intervention targeting fathers. Overweight and obese fathers (n=50, 21-65 years, body mass index [mean +/- standard deviation] 33.3 +/ 4.1) and their children (5-12 years) were recruited. Dietary intake was assessed at baseline and 6 months (n=35) by food frequency questionnaire. Linear mixed models determined differences by time. Fathers significantly reduced portion size (P=0.03) but not energy intakes, whereas children reduced energy intakes (kJ) (P=0.02). There is an opportunity to target fathers as to improve child intakes. PMID- 22516863 TI - Developmental assessment of infants with biliary atresia: differences between boys and girls. AB - OBJECTIVE: The aim of the present study was to investigate whether male and female infants with biliary atresia (BA) differ cognitively and to confirm previously documented developmental lags in infants with BA before liver transplantation. METHODS: With the Mullen Scales of Early Learning, we examined 21 female and 12 male infants (ages 3-20 months) with BA, comparing scores across indices by sex and correlating Mullen Scales of Early Learning scores with standard clinical and biochemical parameters. RESULTS: Overall, both boys and girls were found to be vulnerable to developmental lags in the areas of expressive language (EL) and gross motor skills. In comparison with their male peers, girls were found to be weaker in the area of visual reception skills (P=0.05) with a trend found for EL (P=0.08). Girls were also found to have higher C-bilirubin levels and to be of shorter length. Growth parameters were found to be correlated with EL scores. International normalized ratio was found to be correlated with gross motor performance and with a trend also noted for fine motor skills. Age at Kasai predicted receptive language skills. CONCLUSIONS: As has been shown, infants with BA appear to be vulnerable to developmental lags before transplantation. In particular, female infants appear to be vulnerable to cognitive and skill delays in comparison with their male peers. C-bilirubin levels may play a role in this increased vulnerability for females. PMID- 22516864 TI - Oesophagitis dissecans in a child with vomiting. PMID- 22516861 TI - Health supervision in the management of children and adolescents with IBD: NASPGHAN recommendations. AB - Ulcerative colitis (UC) and Crohn disease (CD), collectively referred to as inflammatory bowel disease (IBD), are chronic inflammatory disorders that can affect the gastrointestinal tract of children and adults. Like other autoimmune processes, the cause(s) of these disorders remain unknown but likely involves some interplay between genetic vulnerability and environmental factors. Children, in particular with UC or CD, can present to their primary care providers with similar symptoms, including abdominal pain, diarrhea, weight loss, and bloody stool. Although UC and CD are more predominant in adults, epidemiologic studies have demonstrated that a significant percentage of these patients were diagnosed during childhood. The chronic nature of the inflammatory process observed in these children and the waxing and waning nature of their clinical symptoms can be especially disruptive to their physical, social, and academic development. As such, physicians caring for children must consider these diseases when evaluating patients with compatible symptoms. Recent research efforts have made available a variety of more specific and effective pharmacologic agents and improved endoscopic and radiologic assessment tools to assist clinicians in the diagnosis and interval assessment of their patients with IBD; however, as the level of complexity of these interventions has increased, so too has the need for practitioners to become familiar with a wider array of treatments and the risks and benefits of particular diagnostic testing. Nonetheless, in most cases, and especially when frequent visits to subspecialty referral centers are not geographically feasible, primary care providers can be active participants in the management of their pediatric patients with IBD. The goal of this article is to educate and assist pediatricians and adult gastroenterology physicians caring for children with IBD, and in doing so, help to develop more collaborative care plans between primary care and subspecialty providers. PMID- 22516865 TI - Esophageal mucosal bridge in a 7-year-old. PMID- 22516867 TI - Cross-linked poly(gamma-glutamic acid) attenuates pleural and chest wall adhesions in a mouse thoracotomy model. AB - BACKGROUND: Cross-linked poly(gamma-glutamic acid) (XL) is derived from a naturally occurring biodegradable polymer produced by Bacillus subtilis. In the present study, we compared the efficacy of XL in preventing adhesion formation after thoracotomy in mice with Seprafilm (SEP), which is currently the most commonly applied adhesion prevention material. METHODS: Left thoracotomy was done. Adhesion between the lung and the thoracotomy site (Lu groups), or between the thoracotomy site and the overlying chest muscles (Mu groups), was evaluated in separate groups of animals. In the Lu-XL group (n = 12) and the Mu-XL group (n = 12), approximately 20 mg of XL was applied as powder. In the Lu-SEP group (n = 12) and Mu-SEP group (n = 12), a 5 * 3 mm SEP sheet was applied. Nothing was applied in the Lu-NON group (n = 12) and the Mu-NON group (n = 12). After 7 and 14 days, the respective adhesions were scored and compared. RESULTS: The adhesion score was significantly lower in the Lu-XL group (0.5 +/- 0.9) in comparison to the Lu-NON group (3.8 +/- 0.5) and the Lu-SEP group (2.2 +/- 0.8; p < 0.002), and in the Mu-XL group (0.8 +/- 0.7) in comparison to the Mu-NON group (3.8 +/- 0.4) and the Mu-SEP group (2.5 +/- 0.8; p < 0.001). These differences were similar also at 14 days. CONCLUSION: It was suggested that the antiadhesive effect of XL was superior to SEP in this particular model of thoracotomy in mice. PMID- 22516866 TI - The modular endoprosthesis for mandibular body replacement. Part 2: finite element analysis of endoprosthesis reconstruction of the mandible. AB - INTRODUCTION: Problems with loosening of the modules for the modular endoprosthesis were encountered in animal studies for mandibular body replacement. We performed a finite element analysis to look at the stress distribution and areas of stress concentration in a human sized mandible. Variations were made to the stem and defect length to look at how the forces changed. The hypothesis was: (1) reconstruction with a modular endoprosthesis did not lead to areas of stress concentration beyond the material strength of cortical bone and titanium alloy; (2) changes in dimensions of the endoprosthesis did not cause a corresponding linear increase to the stresses. MATERIALS AND METHODS: The endoprosthesis was modelled to create a male, female part with stems and a connection screw (Case I). The stem length was halved (Case II) and defect length doubled (Case III). Geometric data of a human sized mandible were obtained, a continuity defect created digitally at the right molar area and the models combined. Boundary conditions were set and the model loaded to get a bite force of 300 N at the incisor region. An intact mandible was used as a control. RESULTS: The right side of the reconstructed mandible became less rigid and flexed more. The highest stresses were within the endoprosthesis at two areas of stress concentration: (1) shear stress at the superior surface of the stems close to the junction of the stem and the module body; (2) compressive stresses at the bottom bevel of the dove-tailed connection. The stress distribution for Case I and II did not differ much except for the magnitude which was slightly higher for Case II. There was a tendency for outward bending at the module connection for Case III which potentially might cause loosening of the module connection. Displacements of the mandible were less than 1 mm throughout. CONCLUSION: The endoprosthesis with its present dimensions would be expected to perform adequately at a bite force of 300 N. An increase in defect length caused a tendency for bending at the stem and the module connection. With a decrease in stem length, there were little differences except a slight increase in magnitude. PMID- 22516868 TI - Tumor lysis syndrome after propranolol therapy in ulcerative infantile hemangioma: rare complication or incidental finding? AB - A 33-day-old female with an ulcerated infantile hemangioma (IH) undergoing oral therapy with propranolol 2 mg/kg per day developed hyperkalemia and hyperphosphatemia 24 h after starting medication. No electrocardiographic or clinical abnormalities secondary to the electrolyte changes were noticed. A laboratory tumor lysis syndrome (TLS) was diagnosed after excluding other causes of electrolyte imbalance in the diagnostic workup. No treatment was required to reverse the TLS condition, and the propranolol therapy was continued as the electrolyte alterations were only mild. One month later, the IH was remarkably reduced in size and no longer ulcerated. Maintenance of propranolol was extended for a total of 6 months. Parallel to the gradual involution of the IH, serum potassium and phosphorus levels returned within normal levels. We suggest that TLS may be a rare complication of ulcerated IH treated with propranolol. Clinicians must be aware and order appropriate screening tests for TLS in patients at risk. PMID- 22516869 TI - Epidemiology of group B Streptococcus ST-17 clone in pregnant women of South Taiwan. AB - OBJECTIVES: We aimed to utilize a simple molecular assay to simultaneously detect both group B Streptococcus (GBS) and virulent ST-17 rectovaginal colonization. We also attempted to estimate the prevalence of maternal GBS and ST-17 carriers and to evaluate their seasonal association. SUBJECTS AND METHODS: We used an optimized multiplex PCR method employing scp-B and ST-17 primers to analyze DNA extracted from rectovaginal swabs of 3,064 cases collected over 3 years. The incidence trends, seasonal variations, and temperature preference were analyzed. RESULTS: The overall prevalence of maternal colonization for GBS and ST-17 clone were 13.25 and 2.48%, respectively. The ST-17 to GBS ratio was 18.72%. The occurrence of ST-17 colonization was significantly associated with seasonal variations with a preference for lower temperatures. CONCLUSIONS: We developed a novel multiplex PCR method suitable for the simultaneous detection of GBS and ST 17 clone. The phenomenon of lower temperature preference for ST-17 clone necessitates further investigation. The epidemiological data for GBS and ST-17 incidence are especially important to establish a public policy for universal GBS screening in the future. PMID- 22516870 TI - A comparison study of two different control criteria for the real-time management of urban groundwater works. AB - We present the comparison of two control criteria for the real-time management of a water well field. The criteria were used to simulate the operation of the Hardhof well field in the city of Zurich, Switzerland. This well field is threatened by diffuse pollution in the subsurface of the surrounding city area. The risk of attracting pollutants is higher if the pumping rates in four horizontal wells are increased, and can be reduced by increasing artificial recharge in several recharge basins and infiltration wells or by modifying the artificial recharge distribution. A three-dimensional finite elements flow model was built for the Hardhof site. The first control criterion used hydraulic head differences (Deltah-criterion) to control the management of the well field and the second criterion used a path line method (%s-criterion) to control the percentage of inflowing water from the city area. Both control methods adapt the allocation of artificial recharge (AR) for given pumping rates in time. The simulation results show that (1) historical management decisions were less effective compared to the optimal control according to the two different criteria and (2) the distribution of artificial recharge calculated with the two control criteria also differ from each other with the %s-criterion giving better results compared to the Deltah-criterion. The recharge management with the %s-criterion requires a smaller amount of water to be recharged. The ratio between average artificial recharge and average abstraction is 1.7 for the Deltah-criterion and 1.5 for the %s-criterion. Both criteria were tested online. The methodologies were extended to a real-time control method using the Ensemble Kalman Filter method for assimilating 87 online available groundwater head measurements to update the model in real-time. The results of the operational implementation are also satisfying in regard of a reduced risk of well contamination. PMID- 22516871 TI - When experts disagree (and better science won't help much): using structured deliberations to support endangered species recovery planning. AB - Progress on recovery plans to conserve endangered species is often blocked due to the lack of an effective framework that technical experts and other knowledgeable stakeholders can use to examine areas of agreement or disagreement about the anticipated effects of management actions. Multi-party, multi-interest resource management deliberations, although increasingly common, are difficult in the context of recovery planning due to the range of potentially affected environmental, economic, and social concerns. These deliberations are further complicated by frequent disagreements among technical experts about how to identify and address various sources of biological uncertainty. We describe the development of a decision-aiding framework as part of an inter-agency plan to assist recovery of endangered Gulf of Maine Atlantic salmon (Salmo salar), using a structured decision making approach that encouraged constructive deliberations based on rigorous analysis. Results are summarized in terms of developing an explicit set of management objectives, clarifying and prioritizing hypotheses concerning barriers to recovery, comparing alternative management initiatives in light of biological uncertainty, and incorporating resource constraints to generate preferred sets of actions. Overall, the use of a structured approach to making recovery decisions improved inter-agency cooperation and facilitated dialogue, understanding, and agreement among participating experts. It also helped to create a defensible basis for further internal discussions as well as for communicating with external stakeholders, including resource users and political decision makers. PMID- 22516872 TI - Hemoglobin Level Adds Prognostic Value to the Global Registry of Acute Coronary Events Score in Non-ST Elevation Acute Coronary Syndromes. AB - OBJECTIVE: We aimed to test the hypothesis that hemoglobin values add prognostic information to the Global Registry of Acute Coronary Events (GRACE) score at admission in patients with non-ST elevation acute coronary syndromes (ACS). METHODS: A total of 225 consecutive patients with non-ST elevation ACS were studied. Hemoglobin was measured at admission, and its prognostic value was evaluated in relation to cardiovascular events during hospitalization, defined as the composite of death or myocardial infarction. RESULTS: The incidence of major in-hospital events was 7% (10 deaths and 5 nonfatal myocardial infarctions). Hemoglobin significantly predicted events, with a C statistic of 0.67 [95% confidence interval (CI) 0.53-0.81; p = 0.03], with 12.1 g/dl as the cutoff point of best performance. After adjustment for the GRACE score, low hemoglobin (<=12.1 g/dl) remained an independent predictor of events (odds ratio 3.9, 95% CI 1.2-13; p = 0.028). The C statistic of the GRACE score for prediction of events improved from 0.80 to 0.84 after hemoglobin was taken into account. Finally, the addition of hemoglobin to the GRACE score promoted a net reclassification improvement of 16% in identifying high-risk patients (p = 0.025). CONCLUSIONS: The present study provides preliminary evidence that hemoglobin level independently predicts recurrent events during hospitalization and improves the prognostic performance of the GRACE score in patients with non-ST elevation ACS. PMID- 22516874 TI - Impact of asymptomatic Herpes simplex virus-2 infection on T cell phenotype and function in the foreskin. AB - Herpes simplex virus type 2 (HSV-2) increases the risk of HIV acquisition in men and overall CD4 T cell density in the foreskin. Using tissues obtained during routine male circumcision, we examined the impact of HSV-2 on the function and phenotype of foreskin T cells in Ugandan men. HSV-2 infection was predominantly associated with a compartmentalized increase in CCR5 expression by foreskin CD4 T cells, which may contribute to HIV susceptibility. PMID- 22516873 TI - Antiretroviral therapy interruptions result in loss of protective humoral immunity to neoantigens in HIV-infected individuals. AB - OBJECTIVE: Sustained antiretroviral therapy (ART)-mediated viral suppression restores responses to vaccination in HIV-1-infected individuals. As ART interruption occur frequently in resource-constrained settings, we studied their effects on the ability to mount humoral immune responses against a neoantigen. DESIGN: Treatment-naive HIV-1-infected individuals were treated with stavudine, lamuvidine and lopinavir/ritonovir. Individuals who maintained viral load less than 50 copies/ml and CD4 T-cell counts more than 450 cells/MUl for 6 months received three doses of rabies vaccine, and were randomized to 72 weeks of continuous ART (arm 1) or sequential 2, 4 and 8-week ART interruptions (arm 2). An additional vaccine dose was administered at study end. METHODS: Neutralizing antibody titers to rabies virus were assessed in plasma with a rapid fluorescent focus-inhibiting test. RESULTS: The proportion of participants achieving protective (>0.5 IU/ml) antibody titer after vaccination was similar (arm 1=92%; arm 2=91%), but over time the cumulative proportion of observations with protective titer was greater in arm 1 than arm 2 (P=0.0177). From week 26 after vaccination, antibody titers were lower in arm 2 than arm 1, and volunteers in arm 2 lost protective antibody titers at a greater rate (P=0.0029). After boosting, 100% of arm 1 and 95% arm 2 volunteers achieved protective antibody titer. CONCLUSION: Our data indicate that individuals undergoing recurring ART interruption retain lower neutralizing antibody titers to a neoantigen, but maintain the ability to mount secondary responses upon boosting, suggesting that they might benefit from vaccine schedule intensification. PMID- 22516875 TI - Key characteristics of low back pain and disability in college-aged adults: a pilot study. AB - OBJECTIVE: To identify which factors commonly associated with low back pain (LBP) and disability differ between college-aged persons with LBP and with no or minimal LBP. DESIGN: Clinical measurement, observational study. Subjects were assessed for LBP with the visual analog scale (VAS) and for disability from LBP using the Oswestry Disability Index (ODI). Subjects were measured for variables commonly associated with LBP and were grouped by both VAS (minimum [min]/no pain, pain) and ODI (no disability, disability) scores. SETTING: College campus at a university. PARTICIPANTS: A convenience sample (N=84) of English-speaking students (34 men, 50 women) between 18 and 30 years of age. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Sports activity (sports activity score of the Baecke Physical Activity Questionnaire), depression, hamstring and hip flexor range of motion, low back extensor endurance, abdominal strength and endurance. RESULTS: A significant main effect of group was found for both pain (P=.019) and disability groups (P=.006). The min/no pain and pain groups differed in back endurance (114.2+/-38.8s vs 94.5+/-44.5s, respectively; P=.04). The no disability and disability groups differed in back endurance (116.3+/-35.9s vs 97.1+/-45.7s, respectively; P=.03) and the sports activity score of the Baecke Physical Activity Questionnaire (2.98+/-.95 vs 2.48+/-.85, respectively; P=.01). Subjects with hyperkyphotic postures compared with the normative thoracic group had higher depression scores (49 vs 38.5, respectively; P=.03) and less hamstring flexibility (30.5 vs 49.9, respectively; P<.001). CONCLUSIONS: Back extensor endurance was consistently different between both the pain and disability groups. Addressing limited low back extensor endurance and low levels of physical activity in young adults may have clinical relevance for the prevention and treatment of LBP and disability. PMID- 22516876 TI - Relationships between objective sleep indices and symptoms in a community sample of people with tetraplegia. AB - OBJECTIVE: To examine the relationships between injury severity, quality of life, sleep symptoms, objectively measured sleep, and sleep disorders in chronic tetraplegia. DESIGN: Cross-sectional survey. SETTING: Community. PARTICIPANTS: People with tetraplegia (N=78; 59 men, 35 with motor and sensory complete tetraplegia; mean age +/- SD, 43+/-12.1; age range 18-70y), living in the state of Victoria, Australia, who were not currently being treated for sleep disorders and who completed both questionnaires and sleep studies comprised the study cohort. INTERVENTION: Questionnaire battery mailed to potential participants. Returned questionnaires were followed with full, home-based polysomnography. MAIN OUTCOME MEASURES: Demographics and questionnaire responses. RESULTS: Quality of life (Assessment of Quality of Life instrument) was worse in the group with complete lesions compared with incomplete lesions (P=.001; median=16; interquartile range, 9 vs 12 [12]), and the Apnea-Hypopnea Index was higher (P=.002; interquartile range, 32.0 [25.2] vs 13.2 [24.8]). Ninety-one percent of those with complete lesions had obstructive sleep apnea (Apnea-Hypopnea Index >10) versus 55.8% of those with incomplete tetraplegia. No effect of lesion level on the Apnea-Hypopnea Index was observed (r=-.04, P=.73). In the complete group, the time taken from sleep onset until the first rapid eye movement sleep period was significantly delayed at over 2 hours. Multiple regression analyses showed substantially stronger relationships between daytime sleep complaints and abnormalities observed in the sleep study in those with complete lesions. CONCLUSIONS: Obstructive sleep apnea is a major problem, particularly in those with complete tetraplegia, and this single comorbidity is associated with reduced quality of life. In those with incomplete cervical lesions, the relationships between sleepiness, other sleep symptoms, and polysomnography indices are less precise. PMID- 22516877 TI - From synaptic transmission to cognition: an intermediary role for dendritic spines. AB - Dendritic spines are cytoplasmic protrusions that develop directly or indirectly from the filopodia of neurons. Dendritic spines mediate excitatory neurotransmission and they can isolate the electrical activity generated by synaptic impulses, enabling them to translate excitatory afferent information via several types of plastic changes, including neoformation, disappearance, redistribution and changes in geometric shape. The fine line between normal and abnormal excitatory neurotransmission is mediated by the concerted action of glutamate-mediated stimulation and calcium ion entry into spines. Moreover, within the range of normal excitatory activity, dendritic spines undergo specific plastic changes to regulate different forms of afferent information that are often related to distinct modes of cognition-related electrophysiological stimulation, such as long-term potentiation or long-term depression. PMID- 22516878 TI - Differential phase-contrast interior tomography. AB - Differential phase-contrast interior tomography allows reconstruction of a refractive index distribution over a region of interest (ROI) for visualization and analysis of structures inside a large biological specimen. In the imaging mode, x-ray scanning only targets an ROI in an object and a narrow beam passes through the object, allowing a significant reduction of both radiation dose and system cost. Inspired by recently developed compressive sensing theory, in a numerical analysis framework we show that accurate interior reconstruction can be achieved on an ROI from truncated differential projection data through the ROI via the total variation minimization, assuming a piecewise constant distribution of the refractive indices in the ROI. Then, we develop a practical iterative algorithm for such an interior reconstruction and perform numerical experiments to demonstrate the feasibility of the proposed approach. PMID- 22516880 TI - Dogs as a diagnostic tool for ill health in humans. AB - Researchers have long reported that dogs and cats improve the physical and psychological health of their human caregivers, and while it is still inconclusive, a substantial amount of research now lends support for the commonly held view that pets are good for us. Recently, studies have directed attention toward exploring the use of animals, most notably dogs, in the detection of disease and other types of health problems in people. This article reviews the evidence for dogs' ability to detect ill health in humans, focusing specifically on the detection of cancer, epileptic seizures, and hypoglycemia. The author describes the research carried out in this area and evaluates it in an effort to determine whether dogs have a role to play in modern health care as an alert tool or screening system for ill health. Where necessary, the author has highlighted weaknesses in the work and proposed directions for future studies. PMID- 22516881 TI - Intestinal permeability and nutritional status in developmental disorders. AB - CONTEXT: Autism is a developmental disorder with a possible connection between dietary components and triggering or worsening of symptoms. An altered intestinal permeability might allow absorption of incompletely digested peptides (gluten and casein) that could produce opioid-like activity on the brain, causing significant changes in behavior. OBJECTIVE: To assess the intestinal permeability and nutritional status of participants with developmental disorders to determine if changes in the intestinal mucosal barrier and/or injury to the intercellular junctions have occurred that might justify application of further dietary modifications. DESIGN: To assess intestinal permeability, the research team analyzed participants urine under fasting conditions, using gas chromatography to determine chromatographic peaks. To assess nutritional status, the team determined participants heights and weights and performed a bioelectric bioimpedance examination at least 4 hours after their most recent meal. In addition, the team determined food intake using three diet diaries. They asked participants and caregivers to register each food consumed during 2 nonconsecutive weekdays and 1 weekend day. SETTING: The study occurred at the Ribeirao Preto School of Medicine, Sao Paulo University. PARTICIPANTS: Seven participants aged 9 to 23 years with developmental disorders (the developmental group, DG) completed the study. The research team recruited them through the Association of Friends of the Autistic Persons of Ribeirao Preto in Ribeirao Preto, Brazil. The control group (CG) consisted of nonsmoking healthy volunteers in the general population who were similar in age to the experimental group and did not suffer from diseases that potentially could influence nutritional status and intestinal function. INTERVENTION: To assess intestinal permeability, participants ingested 150 mL of an isosmolar solution of the sugars mannitol (2 g) and lactulose (7.5 g) under fasting conditions and the researchers collected all voided urine over a period of 5 hours. OUTCOME MEASURES: Using chromatographic peaks, the research team quantified the mannitol and lactulose in participants urine by calculating the percentage excreted in relation to the ingested amounts of sugar. This calculation gave them the lactulose-to-mannitol ratio (L/M). To evaluate nutritional status, they used data regarding bioimpedance resistance, heights, and weights to estimate lean mass and body water (in liters). They classified adults and adolescents using the body mass index (BMI). For children (2-10 y), they classified participants height-to-age and weight-to-height ratios. The research team used food intake to examine the macronutrient interval, the mean added sugar consumption, and the quantity of protein, in g/kg weight. RESULTS: Participants with developmental disorders (n = 7) were more likely to be overweight. Their usual diet revealed a high intake of lipids (%) and proteins (g/kg) (compared to reference values) and a high intake of calories (kcal) and carbohydrates (%) (compared to CG) as well as a high intake of food sources that are important contributors of casein and gluten. The DGs (n = 7) mean mannitol excretion was lower, and their L/M higher than the CGs (n = 7) (P < .05). Their increased L/M may indicate atrophy of the intestinal mucosa surface and/or injury to the intercellular junctions or the effect of some other abnormality. The small number of participants, however, prevented more complex statistical analysis. CONCLUSIONS: Researchers need to complete additional studies to confirm the existence of abnormalities in autistic individuals intestines and to justify the use of dietary restrictions on gluten and casein to improve the symptoms of autism. PMID- 22516882 TI - Review of complementary and alternative medicine and selected nutraceuticals: background for a pilot study on nutrigenomic intervention in patients with advanced cancer. AB - As commonly defined, complementary and alternative medicine (CAM) is a broad category that includes biologically based practices, mind-body medicine, manipulative and bodybased practices, and energy medicine as well as complete medical systems such as naturopathy, homeopathy, Ayurvedic medicine, and traditional Chinese medicine. Several CAM methodologies show promise for the treatment of chronic conditions such as depression and pain disorders or have demonstrated effects upon the immune response in experimental studies. There is growing interest in the use of integrative medicine the combination of CAM methodologies with a conventional medical approach-for the optimization of treatment of various cancers. The Ohio State University Center for Integrative Medicine has developed a specialized nutrigenomic protocol for integrative cancer care. The center uses a comprehensive nutritional and medical evaluation, including a panel of proinflammatory molecules and physiologic parameters, to guide a program of individualized dietary interventions. Dietary supplementation is a current focus of study, including: (1) Omega-3 fatty acids and B vitamins, which are thought to play important roles in immunomodulation; (2) Magnesium oxide, which has been shown to decrease inflammation and improve insulin resistance and lipid profiles; and (3) Cinnamon extract, which reportedly decreases serum glucose levels. This article presents a brief overview of CAM and integrative medicine and a discussion of the relevant nutraceuticals. PMID- 22516883 TI - Exposure to specific herbal products during pregnancy and the risk of low birth weight. AB - CONTEXT: Despite the fact that herbal products (HP) are used frequently during gestation worldwide, studies indicate that they may not be free of danger for fetuses. Evidence about the safety of HP use during pregnancy and their impact on pregnancy outcomes is currently lacking. OBJECTIVE: To quantify the association between HP use during the last 2 trimesters of pregnancy (>=15 weeks of gestation [WG]) and more specifically, between use of chamomile (Anthemis nobilis), flax (Linum usitatissimum), peppermint (M. balsamea), or green tea (Camellia sinensis) (alone or in combination with other HPs) and the risk of low birth weight (LBW). DESIGN: We evaluated data from the Quebec Pregnancy Registry, which was created by the linkage of 3 administrative databases in Quebec, and a self-administered questionnaire mailed to subjects. Participants 8505 women were randomly selected from the registry. Overall, 38.5% of women (n = 3273) returned their questionnaires, and 3183 were included in the study (8 were excluded because of missing values on birth weight or giving birth to twins or triplets). Outcome measures We performed a case-control analysis. Cases were defined as women who delivered a newborn <2500g and controls as women who delivered a newborn >=2500g. Multivariate logistic regression models were used to analyze data. RESULTS: Amongst the selected 3183 participants, 424 (13.32%) were cases. After adjusting for potential confounders, no statistically significant associations were found between the use of any HP during the last 2 trimesters of pregnancy and the risk of LBW, or between the use of flax, chamomile, peppermint, or green tea (alone or in combination with other HPs) during the last 2 trimesters of pregnancy and the risk of LBW. CONCLUSION: HP use during the last 2 trimesters of pregnancy and more specifically, use of flax, chamomile, peppermint, or green tea alone or in combination with other HPs did not significantly increase the risk of LBW. PMID- 22516884 TI - Horticultural therapy for patients with chronic musculoskeletal pain: results of a pilot study. AB - CONTEXT: Therapists can use horticultural therapy as an adjuvant therapy in a non threatening context, with the intent of bringing about positive effects in physical health, mental health, and social interaction. Very few experimental studies exist that test its clinical effectiveness. OBJECTIVE: To determine whether the addition of horticultural therapy to a pain-management program improved physical function, mental health, and ability to cope with pain. DESIGN: The research team designed a prospective, nonrandomized, controlled cohort study, enrolling all patients consecutively referred to the Zurzach Interdisciplinary Pain Program (ZISP) who met the studys criteria. The team divided them into two cohorts based on when medical professionals referred them: before (control group) or after (intervention group) introduction of a horticultural therapy program. SETTING: The setting was the rehabilitation clinic (RehaClinic) in Bad Zurzach, Switzerland. PARTICIPANTS: Seventy-nine patients with chronic musculoskeletal pain (fibromyalgia or chronic, nonspecific back pain) participated in the study. INTERVENTIONS: The research team compared a 4-week, inpatient, interdisciplinary pain-management program with horticultural therapy (intervention, n = 37) with a pain-management program without horticultural therapy (control, n = 42). The horticultural therapy program consisted of seven sessions of group therapy, each of 1-hour duration. OUTCOME MEASURES: The research team assessed the outcome using the Medical Outcome Study Short Form-36 (SF-36), the West Haven-Yale Multidimensional Pain Inventory (MPI), the Hospital Anxiety and Depression Scale (HADS), the Coping Strategies Questionnaire (CSQ ), and two functional performance tests. The team tested participants on entry to and discharge from the 4-week pain-management program. RESULTS: Between-group differences in sociodemographic and outcome variables were not significant on participants entry to the pain-management program. On discharge, the research team measured small to moderate outcome effects (effect size [ES] up to 0.71) within both groups. The study found significantly larger improvements for the horticultural therapy group vs the control group in SF-36 role physical (ES = 0.71 vs 0.22; P = .018); SF-36 mental health (ES = 0.46 vs 0.16; P = .027); HADS anxiety (ES = 0.26 vs 0.03; P = .043); and CSQ pain behavior (ES = 0.30 vs -0.05; P = .032). CONCLUSION: The addition of horticultural therapy to a pain management program improved participants' physical and mental health and their coping ability with respect to chronic musculoskeletal pain. PMID- 22516885 TI - Daniel Amen, MD: the impact of brain imaging on psychiatry and treatment for improving brain health and function. Interview by Karen Burnett. PMID- 22516886 TI - Speech therapy and rehabilitation. PMID- 22516887 TI - Transferable skills in the field of speech language pathology. AB - PURPOSE: To highlight new knowledge and technologies that support the transfer of skills generally acquired by speech language pathologists (SLPs) in academic training programs and clinical practice to involvement in the evaluation and management of individuals with disorders such as paradoxical vocal fold movement (PVFM), chronic cough, manifestations of extra-esophageal reflux (EER), esophageal dysphagia and rumination disorder. RECENT FINDINGS: A range of studies published in the previous year provide data to support SLP involvement in the management of some disorders, including PVFM, chronic cough, and some manifestations of EER, both as providers and as clinical resources for other health professionals. However, little research is available that describes the role of SLPs in management of esophageal dysphagia or rumination disorder. SUMMARY: Recent research supports the expanded role of the SLP in the interdisciplinary management of PVFM, chronic cough, manifestations of EER, esophageal dysphagia, and rumination. SLP and other health professionals involved in the care of these patients must find a balance between the practical challenges of treating individuals with increasingly complex medical issues and staying abreast of the latest developments in the diagnosis and treatment of these disorders. PMID- 22516888 TI - Anion effects on the cyclobis(paraquat-p-phenylene) host. AB - Binding studies between the electron accepting host cyclobis(paraquat-p phenylene) and a series of electron donors in the presence of differently sized counteranions reveal that both the nature and the concentration of the anion have a large impact on the association strength of the resulting host-guest complex. PMID- 22516889 TI - Revascularization and rescue of a failed kidney transplant in a case of autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease is a cause of end-stage renal disease associated with abdominal aortic aneurysms. We report a patient with autosomal dominant polycystic kidney disease who received an allograft kidney and subsequently underwent treatment of an abdominal aortic aneurysm with aortic ligation and axillary-bifemoral bypass. After years of graft function, bypass thrombosis resulted in dialysis-dependent renal failure. Aortobifemoral bypass resulted in immediate restoration of allograft function despite 6 months of prior renal failure. Aortic reconstruction restored renal function to a hibernating allograft long after clinical graft failure from arterial ischemia, a phenomenon not previously reported in the literature. PMID- 22516890 TI - Endovascular recanalization of total occlusions of the mesenteric and celiac arteries. AB - OBJECTIVE: To evaluate our experience with the endovascular treatment of total occlusions of the mesenteric and celiac arteries. METHODS: We performed a retrospective review of endovascular stenting of 27 nonembolic total occlusions of the superior mesenteric artery (SMA) and celiac artery (CA) between July 2004 and July 2011 (26 patients, 16 females; mean age, 62 +/- 13 years). A variety of demographic, lesion-related and procedure-related variables were evaluated for potential impact of technical success and patency. The follow-up protocol included clinical assessment, and color and spectral Doppler evaluation of the stented vessel(s). RESULTS: The clinical presentation was chronic mesenteric ischemia in 12 patients, acute mesenteric vascular syndromes in 10 patients, foregut ischemia/ischemic pancreatitis in three patients, and prior to endovascular repair of aortic aneurysm in one patient. The treated vessel was SMA in 22 procedures, CA in three, and both SMA and CA in one. Technical success was achieved in 23 of the 27 attempted recanalizations (85%). Three patients who failed the attempt underwent open bypass, and another one underwent retrograde recanalization and stenting of the SMA. Procedure success was only significantly related to patient age <70 years or procedure performance after the year 2006. Notably, the presence of a stump, ostial plaque, extensive vascular calcification, recanalization route (intraluminal vs subintimal), occlusion length, and vessel diameter had no significant impact on procedure success. Traditional duplex criteria proved unreliable in predicting restenosis. Life table analysis of freedom from symptom recurrence showed a primary and assisted rates of 58% and 80% at 1 year, and 33% and 60% at 2 years, respectively. Clinical recurrences developed in six patients (four presented with abdominal angina and weight loss, two presented with abdominal catastrophe). There were six access-related complications and no procedural deaths. Four delayed deaths occurred during follow-up (two cardiac causes, two due to abdominal sepsis). CONCLUSIONS: Endovascular recanalization of mesenteric artery occlusion is both feasible and successful, provided careful planning is used. PMID- 22516891 TI - Endovascular aneurysmal models at the external iliac artery of dogs. AB - INTRODUCTION: Establishing an aneurysm model using simple and easy operative techniques is desirable to develop new endovascular treatment devices such as stent grafts. We developed an aneurysm model using the external iliac arteries (EIAs) of adult Beagles, a relatively large animal that we thought would be easy to handle, using simple and less complicated endovascular procedures. In addition, we evaluated the generated aneurysm model histologically and determined the factors that were necessary for creating more dilated aneurysms. METHODS: Experimental animals consisted of 16 beagles (average weight, 14.0 kg). The animals were divided into four groups (S, E, B+S, and B+E). Eight Beagles were in the S and E groups, without balloon dilation. S group Beagles were injected with normal saline into the right EIA and served as a control group. Elastase was injected into the left EIA of the same Beagles (E group). Eight Beagles were in the B+S and B+E groups with balloon dilation. After balloon dilation, normal saline was injected into right EIA of the B+S group. Elastase was injected into the left EIA of the same Beagles (B+E). After 4 weeks, we measured the EIA diameter using abdominal ultrasound imaging from a body surface. Both sides of the EIA were harvested. We evaluated the dilation rate of the EIA diameter, and histologically, evaluated the disappearance of the internal elastic lamina, degeneration and disappearance of medial smooth muscle and the external elastic lamina, and neointimal thickening. RESULTS: Inner diameters were dilated more in the B+E group vs the other groups. The B+E group internal elastic lamina had almost disappeared, with significantly more severe degeneration and disappearance of external elastic lamina. CONCLUSIONS: We developed a muscular artery aneurysm model using the EIA arteries of adult Beagles and a simple endovascular procedure. Histologically, internal and external elastic lamina degeneration was an important factor to create significantly dilated aneurysms in this muscular artery model. PMID- 22516892 TI - Photoprotective capacities of lichen metabolites: a joint theoretical and experimental study. AB - The adaptative capacity of lichens to UV radiation could be expressed by the production of photo-absorbing secondary metabolites in thalli. A preliminary screening performed on twelve lichen species by high performance thin layer chromatography (HPTLC) revealed five major compounds absorbing in the UVA (315 400nm) or UVB (280-315nm) ranges in Diploicia canescens. After phytochemical investigation of this lichen, twelve metabolites have been isolated and characterized. Those obtained in sufficient quantities were evaluated for their photoprotective capacities and compared to three referent sunscreens. Experimental spectra were compared to theoretical spectra as obtained at the TD DFT level of theory. Different DFT functionals were tested to accurately reproduce the UV/Vis spectra of five depsidones, one diphenylether and two bisxanthones. Results indicate that absorption wavelengths and molecular extinction coefficients (oscillator strengths) obtained for the bisxanthones were similar to those of the UVA referent sunscreen. PMID- 22516893 TI - Antileukemia component, dehydroeburicoic acid from Antrodia camphorata induces DNA damage and apoptosis in vitro and in vivo models. AB - Antrodia camphorata (AC) is a native Taiwanese mushroom which is used in Asian folk medicine as a chemopreventive agent. The triterpenoid-rich fraction (FEA) was obtained from the ethanolic extract of AC and characterized by high performance liquid chromatography (HPLC). FEA caused DNA damage in leukemia HL 60 cells which was characterized by phosphorylation of H2A.X and Chk2. It also exhibited apoptotic effect which was correlated to the enhancement of PARP cleavage and to the activation of caspase 3. Five major triterpenoids, antcin K (1), antcin C (2), zhankuic acid C (3), zhankuic acid A (4), and dehydroeburicoic acid (5) were isolated from FEA. The cytotoxicity of FEA major components (1-5) was investigated showing that dehydroeburicoic acid (DeEA) was the most potent cytotoxic component. DeEA activated DNA damage and apoptosis biomarkers similar to FEA and also inhibited topoisomerase II. In HL 60 cells xenograft animal model, DeEA treatment resulted in a marked decrease of tumor weight and size without any significant decrease in mice body weights. Taken together, our results provided the first evidence that pure AC component inhibited tumor growth in vivo model backing the traditional anticancer use of AC in Asian countries. PMID- 22516894 TI - Preconditioning of brain slices against hypoxia induced injury by a Gynostemma pentaphyllum extract--stimulation of anti-oxidative enzyme expression. AB - A short period of hypoxia/hypoglycaemia (oxygen and glucose deprivation, OGD) induced by perfusion with O(2)/glucose-free medium caused immediate loss and incomplete restoration of evoked field potentials in the CA1 region of transverse hippocampus slices. OGD-dependent decrease in evoked field potentials can be prevented by a proceeding short OGD event (preconditioning). We report about a study investigating the effect of an ethanolic Gynostemma pentaphyllum extract on evoked field potentials when administered before the OGD episode. Using this procedure, the extract completely protected the cells of the slices from functional injury. In an astroglia rich cell culture the ethanolic Gynostemma pentaphyllum extract caused within 48 h of cultivation increased protein and activity levels of the anti-oxidative enzymes manganese superoxide dismutase (Mn SOD) and glutathione peroxidase (GPx). Consequently, the cellular H(2)O(2) concentration remained at a low level. These data suggest that the Gynostemma pentaphyllum-mediated increase in antioxidative enzyme activities may contribute to the protection of transverse hippocampus slices from OGD induced functional injury. Our results demonstrate that the prophylactic administration of the ethanolic extract from Gynostemma pentaphyllum has a high potential to protect from ischemia/reperfusion injury. PMID- 22516895 TI - An in vitro assessment of the effect of Athrixia phylicoides DC. aqueous extract on glucose metabolism. AB - Athrixia phylicoides DC. is an aromatic shrub indigenous to the eastern parts of Southern Africa. Indigenous communities brew "bush tea" from dried twigs and leaves of A. phylicoides, which is consumed as a beverage and used for its medicinal properties. Plant polyphenols have been shown to be beneficial to Type 2 diabetes mellitus (T2D) and obesity. Aqueous extracts of the plant have been shown to be rich in polyphenols, in particular phenolic acids, which may enhance glucose uptake and metabolism. The aim of this study was to determine the phenolic composition of a hot water A. phylicoides extract and assess its in vitro effect on cellular glucose utilisation. The most abundant phenolic compounds in the extract were 6-hydroxyluteolin-7-O-glucoside, chlorogenic acid, protocatechuic acid, a di-caffeoylquinic acid and a methoxy-flavonol derivative. The extract increased glucose uptake in C2C12, Chang and 3T3-L1 cells, respectively. Intracellular glucose was utilised by both oxidation (C2C12 myocytes and Chang cells; p < 0.01 and p < 0.05, respectively) and by increased glycogen storage (Chang cells; p < 0.05). No cytotoxicity was observed in Chang cells at the concentrations tested. The effects of the extract were not dose dependent. A. phylicoides aqueous extract stimulated in vitro glucose uptake and metabolism, suggesting that consumption of this phenolic-rich extract could potentially ameliorate metabolic disorders related to obesity and T2D. PMID- 22516896 TI - Glycyrrhizic acid (GA), a triterpenoid saponin glycoside alleviates ultraviolet-B irradiation-induced photoaging in human dermal fibroblasts. AB - Glycyrrhizic acid (GA), a triterpenoid saponin glycoside from the roots and rhizomes of licorice is used in traditional and modern medicine for the treatment of numerous medical conditions including skin diseases and beauty care product. In the present study, we investigated the effect of GA against ultraviolet B (UVB) irradiation-induced photoaging in human dermal fibroblasts (HDFs) and its possible mechanism of action. HDFs were subjected to photoaging by sub-toxic dose of UVB (10 mj/cm(2)) irradiation. Cell viability, matrix metalloproteinase 1 (MMP1), pro-collagen 1, cellular and nuclear morphology, cell cycle, intracellular reactive oxygen species (ROS), caspase 3 and hyaluronidase inhibition assays were performed. Western blotting was used to evaluate the expression of NF-kappa B (NF-kappaB) and cytochrome-C proteins. GA treatment significantly inhibited photoaging. It achieved this by reducing ROS, NF-kappaB, cytochrome c, caspase 3 levels and inhibiting hyaluronidase enzyme. The main mechanism seems to be, most likely by blocking MMP1 activation by modulating NF kappaB signaling. These findings may be useful for development of natural and safe photoprotective agents against UVB irradiation. PMID- 22516897 TI - The interleukin-6 -174G/C polymorphism and prostate cancer risk: a systematic review and meta-analysis. AB - OBJECTIVE: This systematic review and meta-analysis was undertaken to integrate previous findings and summarize the effect size of the association of interleukin 6 (IL-6) genetic polymorphism -174G/C with susceptibility to prostate cancer (PCa). METHODS: All eligible studies of IL-6 -174G/C polymorphism and PCa risk were collected from the following electronic databases: PubMed and the Cochrane Library, with the last report up to June 1, 2011. Statistical analyses were performed by Review Manage version 5.0 and Stata 10.0. RESULTS: A total of 7 independent studies, including 9,959 cases and 12,361 controls, were identified. When all studies were pooled, we did not detect a significant association of 174G/C polymorphism with PCa risk. When stratifying for race, similar results were obtained; evidence of a significant relation was absent in both Caucasians and the mixed population. After stratifying the studies by study types, -174G/C polymorphism was significantly associated with PCa risk when examining the contrast of CC + GC versus GG (OR = 1.44, 95% CI = 1.05-1.98, p = 0.03) in cohort studies but not in case-control studies. CONCLUSIONS: Our review suggest that 174G/C polymorphism is associated with an increased PCa risk in two cohort studies from one article. Additional well-designed studies are warranted to validate these findings. PMID- 22516898 TI - Local and systemic expressions of MMP-9, TIMP-1 and PAI-1 in patients undergoing surgery for clinically suspected appendicitis. AB - BACKGROUND/AIMS: To examine, compare and correlate the expressions of matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1) and plasminogen activator inhibitor type 1 (PAI-1) in appendiceal tissue and pre- and postoperative blood samples in patients undergoing surgery for clinically suspected appendicitis. METHODS: Fifty-seven patients with complete tissue and blood samples were included and divided into groups of noninflamed appendix/lymphadenitis (n = 7), phlegmonous appendicitis (n = 30), gangrenous appendicitis (n = 11) and perforated appendicitis (n = 9). The protein expressions were assessed with ELISAs. The local expressions of MMP-9, TIMP-1 and PAI-1 were correlated with the systemic expressions at the time of surgery while the systemic individual differences between surgery and recovery were compared. RESULTS: There was a positive correlation between tissue and plasma PAI-1 (p < 0.05). The individual differences for plasma MMP-9 and PAI-1 were statistically nonsignificant, while they were higher for TIMP-1 in patients with perforated appendicitis compared with phlegmonous (p < 0.0001) and gangrenous appendicitis (p < 0.01). CONCLUSIONS: Plasma PAI-1 reflected the levels in appendiceal tissue at the time of surgery. Systemic TIMP-1 could have the potential of distinguishing perforated from nonperforated appendicitis. PMID- 22516899 TI - Copy number changes on the X chromosome in women with and without highly skewed X chromosome inactivation. AB - AIM: To test the hypothesis that microdeletions or microduplications below the resolution of a standard karyotype may be a significant cause of highly skewed X inactivation (HSXI) in women without a cytogenetically detected X-chromosome anomaly. METHODS: Cases were women with HSXI, defined as >=85% of cells in a blood sample with the same active allele at the HUMARA locus. The skewing in controls ranged from 50 to <75%. We performed an SNP microarray analysis using the Affymetrix 6.0 platform for 45 cases and 45 controls. RESULTS: Cases and controls did not differ in the frequency of X-chromosome copy number changes >=100 kb or in the frequency of copy number changes that contained genes. However, one woman with HSXI >90% in blood and left and right buccal smears had a 5.5-Mb deletion in Xp22.2p22.1. This deletion could affect the viability of male conceptions and may have led to the dysmorphology found in female carriers. CONCLUSION: HSXI in a blood sample is rarely due to X-chromosome copy number changes detectable by microarray. PMID- 22516900 TI - Physical demands, injuries, and conditioning practices of stock car drivers. AB - The purpose of this study was to assess the physical demands, injuries, and conditioning practices of stock car drivers. Forty stock car drivers from 27 states in the United States participated in the interviews for 43.9 +/- 13.9 minutes. The interviews examined background information, the physical demands of racing, injuries associated with racing, and the athletic and fitness background and practices of the subjects. Numerical data were analyzed using Pearson's correlation coefficients. Responses to open-ended questions were analyzed using inductive content analysis. Results revealed significant correlation between track points standings and the length of the resistance training sessions (R = 0.71, p = 0.002) and subject self-assessment of their fitness (R = -0.53, p = 0.045). Results also revealed that "upper-body strength" was identified as the most important physical demand. Extreme fatigue was the most common feeling after a demanding race. Subjects reported that shoulder fatigue was the most common form of muscle soreness experienced after a race. Back and torso injuries were the most common injury, although head injuries most frequently required medical attention. The subjects' biggest fear was fire, followed closely by head and neck injury. The bench press and running were the most commonly performed resistance training and cardiovascular exercises, respectively. Subjects reported that their highest motivation for training was to improve their racing performance. Many subjects had athletic backgrounds with football identified as the sport they had most commonly participated in. This study provides additional detailed information. Results of this study can assist strength and conditioning professionals in the development of strength and conditioning programs for performance enhancement and injury prevention that are specific to the needs of this population of athletes. PMID- 22516901 TI - The effect of loading on kinematic and kinetic variables during the midthigh clean pull. AB - The ability to develop high levels of muscular power is considered a fundamental component for many different sporting activities; however, the load that elicits peak power still remains controversial. The primary aim of this study was to determine at which load peak power output occurs during the midthigh clean pull. Sixteen participants (age 21.5 +/- 2.4 years; height 173.86 +/- 7.98 cm; body mass 70.85 +/- 11.67 kg) performed midthigh clean pulls at intensities of 40, 60, 80, 100, 120, and 140% of 1 repetition maximum (1RM) power clean in a randomized and balanced order using a force plate and linear position transducer to assess velocity, displacement, peak power, peak force (Fz), impulse, and rate of force development (RFD). Significantly greater Fz occurred at a load of 140% (2,778.65 +/- 151.58 N, p < 0.001), impulse within 100, 200, and 300 milliseconds at a load of 140% 1RM (196.85 +/- 76.56, 415.75 +/- 157.56, and 647.86 +/- 252.43 N.s, p < 0.023, respectively), RFD at a load of 120% (26,224.23 +/- 2,461.61 N.s, p = 0.004), whereas peak velocity (1.693 +/- 0.042 m.s, p < 0.001) and peak power (3,712.82 +/- 254.38 W, p < 0.001) occurred at 40% 1RM. Greatest total impulse (1,129.86 +/- 534.86 N.s) was achieved at 140% 1RM, which was significantly greater (p < 0.03) than at all loads except the 120% 1RM condition. Results indicate that increased loading results in significant (p < 0.001) decreases in peak power and peak velocity during the midthigh clean pull. Moreover, if maximizing force production is the goal, then training at a higher load may be advantageous, with peak Fz occurring at 140% 1RM. PMID- 22516902 TI - The optimal back squat load for potential osteogenesis. AB - The osteogenic potential of exercise is reported to be partially a function of the magnitude of training loads. This study evaluated the ground reaction force (GRF) and rate of force development (RFD) of the eccentric and concentric phases of the back squat at 3 different loads. Twelve subjects performed the back squat on a force platform with loading conditions of 80, 100, and 120% of their 1 repetition maximum (RM). Back squats performed at 120% of the 1RM produced the highest GRF in both the eccentric and concentric conditions. No significant differences were found between RFD for any of the loading conditions. Performing the back squat at loads of 120% of the estimated 1RM, accomplished with reduced range of motion, results in higher GRF than the back squat performed at 80 or 100% of the 1RM. Thus, supermaximal back squat loads in excess of the 1RM, with decreased range of motion, may be a useful part of a resistance training program designed to maximize osteogenic potential. PMID- 22516903 TI - Comparison of the snatch technique for female weightlifters at the 2008 Asian championships. AB - The purpose of this study was to compare the snatch techniques of Japanese and international female weightlifters. Two high-speed cameras operating at 250 Hz were used to record the snatch lifts of the 5 best weightlifters in the snatch and 5 Japanese weightlifters during the 2008 Asian Weightlifting Championships held in Japan. The results revealed that the forward velocity of the barbell for the Japanese weightlifters during the second pull was significantly greater than that for the best weightlifters and that barbell trajectories of Japanese weightlifters except for the 53-kg class crossed the vertical reference line with great forward displacement of the barbell. In addition, the best weightlifters extended the knee and hip joints during the second pull earlier than the Japanese weightlifters did. These findings indicate that it is important to improve the way of pulling the barbell during the second pull for Japanese female weightlifters. PMID- 22516904 TI - Barbell kinematics should not be used to estimate power output applied to the Barbell-and-body system center of mass during lower-body resistance exercise. AB - The aim of this study was to compare measures of power output applied to the center of mass of the barbell and body system (CM) obtained by multiplying ground reaction force (GRF) by (a) the velocity of the barbell; (b) the velocity of the CM derived from three-dimensional (3D) whole-body motion analysis, and (c) the velocity of the CM derived from GRF during lower-body resistance exercise. Ten resistance-trained men performed 3 maximal-effort single back squats with 60% 1 repetition maximum while GRF and whole-body motion were captured using synchronized Kistler force platforms and a Vicon Motus motion analysis system. Repeated measures analysis of variance of time-normalized kinematic and kinetic data obtained using the different methods showed that the barbell was displaced 13.4% (p < 0.05) more than the CM, the velocity of the barbell was 16.1% (p < 0.05) greater than the velocity of the CM, and power applied to the CM obtained by multiplying GRF by the velocity of the barbell was 18.7% (p < 0.05) greater than power applied to the CM obtained by multiplying the force applied to the CM by its resultant velocity. Further, the velocity of the barbell was significantly greater than the velocity of the trunk, upper leg, lower leg, and foot (p < 0.05), indicating that a failure to consider the kinematics of body segments during lower-body resistance exercise can lead to a significant overestimation of power applied to the CM. Strength and conditioning coaches and investigators are urged to obtain measures of power from the force applied to and the velocity of either the barbell (using inverse dynamics) or CM (GRF or 3D motion analysis). Failure to apply these suggestions could result in continued overestimation of CM power, compromising methodological integrity. PMID- 22516905 TI - Influence of different resistance exercise loading schemes on mechanical power output in work to rest ratio - equated and - nonequated conditions. AB - It is well known that most sports are characterized by the performance of intermittent high-intensity actions, requiring high muscle power production within different intervals. In fact, the manipulation of the exercise to rest ratio in muscle power training programs may constitute an interesting strategy when considering the specific performance demand of a given sport modality. Thus, the aim of this study was to evaluate the influence of different schemes of rest intervals and number of repetitions per set on muscle power production in the squat exercise between exercise to rest ratio-equated and -nonequated conditions. Nineteen young males (age: 25.7 +/- 4.4 years; weight: 81.3 +/- 13.7 kg; height: 178.1 +/- 5.5 cm) were randomly submitted to 3 different resistance exercise loading schemes, as follows: short-set short-interval condition (SSSI; 12 sets of 3 repetitions with a 27.3-second interval between sets); short-set long-interval condition (SSLI; 12 sets of 3 repetitions with a 60-second interval between sets); long-set long-interval (LSLI; 6 sets of 6 repetitions with a 60-second rest interval between sets). The main finding of the present study is that the lower exercise to rest ratio protocol (SSLI) resulted in greater average power production (601.88 +/- 142.48 W) when compared with both SSSI and LSLI (581.86 +/ 113.18 W; 578 +/- 138.78 W, respectively). Additionally, both the exercise to rest ratio-equated conditions presented similar performance and metabolic results. In summary, these findings suggest that shorter rest intervals may fully restore the individual's ability to produce muscle power if a smaller exercise volume per set is performed and that lower exercise to rest ratio protocols result in greater average power production when compared with higher ratio ones. PMID- 22516906 TI - Test-retest reliability, criterion-related validity, and minimal detectable change of score on an abbreviated Wingate test for field sport participants. AB - Repeat measurements in 69 young adults were performed to assess the test-retest reliability and the 95% confidence interval of the difference in score between paired observations (MDC95) of a Wingate test as abbreviated for field sport participants (test of a 15-second duration [15-secT]). Test-retest reliability was excellent for peak power output (PPO) and mean power output (MPO), independently of their mode of expression and was moderate for the fatigue index (FI). The standard errors of measurement (SEM) for absolute, relative, and derived PPO and MPO values ranged from 2.6 to 3.7%, all being smaller than the corresponding smallest worthwhile change (SWC). In contrast, FI values were rated as "marginal," with an SEM (9.6%) greater than the SWC (1.7). The range of MDC95 values for PPO and MPO were 9.9-10.4 and 7.37-7.42%, respectively. The absolute MPO showed the highest test-retest reliability and was the most effective in detecting real change. A second phase of the study evaluated the criterion related validity of the 15-secT in 43 young men who performed 15-secT and standard 30-second Wingate anaerobic test (30-secT) in random order, on 2 separate occasions. There were no significant intertest differences in absolute, relative, or derived PPO. However, the FI for the 30-secT was greater than that for the 15-secT. Intertest correlations were highly significant for both MPOs and FIs. These findings suggest that the abbreviated Wingate test offers a reliable and valid tool for the evaluation of PPO and MPO, at least in young physical education students. PMID- 22516907 TI - No differences in O2-cost between V1 and V2 skating techniques during treadmill roller skiing at moderate to steep inclines. AB - Elite crosscountry skiers use both the V1 and V2 techniques on moderate and steep inclines despite previous studies suggesting that the V1 technique is superior in terms of lower O2-cost and better performance on these inclines. However, this has not been studied in elite athletes, and therefore, the aim of this study was to compare O2-cost in these 2 main ski skating techniques in a group of 14 elite male crosscountry skiers (age: 24 +/- 3 years, height: 184 +/- 6 cm, weight: 79 +/- 7 kg, V1 V[Combining Dot Above]O2max: 71.8 +/- 3.5 ml.kg.min). With both techniques, the athletes performed submaximal trials for the determination of O2 cost on a roller ski treadmill at 4, 5, and 6 degrees (3 m.s) and maximal trials at 8 degrees (>=3 m.s) for the determination of V[Combining Dot Above]O2max. Video-based kinematic analyses on cycle length and cycle rate (CR) were performed to unravel if there was any relation between these variables and O2-cost. No significant differences in O2-cost or V[Combining Dot Above]O2max between techniques were found. However, large and significant individual variations in physiological response were observed. V2 had a longer cycle length and lower CR than V1 did. No significant correlation was found between CR and O2-cost. This study shows that both V1 and V2 are appropriate techniques for optimizing O2-cost on moderate to steep inclines in elite skiers. However, individual variation suggests that ski skating performance on moderate to steep inclines may be determined by technique preferences of the athletes. PMID- 22516908 TI - Effect of two recovery methods on repeated closed-handed and open-handed weight assisted pull-ups. AB - The purpose of this study was to examine 2 recovery modalities (with and without an ice bag treatment) on closed-handed and open-handed weight-assisted pull-ups in recreationally-trained rock climbers. Healthy and recreationally active volunteers (n = 9) completed 4 counterbalanced trials separated by 72 hours. Trials included 3 sets of closed-handed and open-handed weight-assisted pull-ups supported by 50% of body weight, until failure. Between each set, participants sat quietly in a chair and engaged in approximately 20 minutes of either passive or ice bag treatment. Ice bags were placed on the participants' arms and shoulders. Heart rate (HR), ratings of perceived exertion (RPE), session-RPE (S RPE), and perceived recovery were also assessed. Hand-grip strength pretrial and posttrial was not different between ice bag conditions. Also, there were no differences between treatments for HR, RPE, perceived recovery, S-RPE, or comfort ratings. The overall number of open-handed pull-ups (mean +/- SD = 19 +/- 5) was lower than closed-handed pull-ups (34 +/- 14; p < 0.001). Ice bag recovery attenuated the decrease in open-handed pull-up performance for sets 2 (22 +/- 5; p = 0.004) and 3 (22 +/- 5; p = 0.003) relative to set 3 using passive recovery only (i.e., no ice bag; 17 +/- 6). There were no differences (p = 0.31) between treatments for closed-handed pull-ups. The findings support the recommendations to use ice bags for recovery between bouts of rock climbing that involve a predominantly open-handed grip to maintain performance. PMID- 22516909 TI - Effects of isocaloric carbohydrate vs. carbohydrate-protein supplements on cycling time to exhaustion. AB - The purpose of this study was to investigate the effects of isocaloric carbohydrate (CHO) and carbohydrate-protein (CHO-Pro) supplements on time to exhaustion. Eleven moderately aerobically fit adults (V[Combining Dot Above]O2max= 48.3 +/- 6.5 ml.kg.min) performed a maximal cycle ergometer test for the determination of V[Combining Dot Above]O2max. At least 72 hours later, the participants performed a time-to-exhaustion test at a power output equivalent to the power output when subjects were at 75% of their V[Combining Dot Above]O2max. Either the CHO or the CHO-Pro supplement was administered at 0, 30, 60, 90, and 120 minutes after this test. After 3 hours of recovery and supplement ingestion, a second time-to-exhaustion test was performed. This testing protocol was repeated for the third visit, but the supplement not given during the second visit was administered. The results indicated that there was no significant difference in time to exhaustion after isocaloric CHO (pretest 22.4 +/- 2.84 minutes, posttest 25.4 +/- 4.45 minutes) and CHO-Pro (pretest 22.3 +/- 3.46 minutes, posttest 24.0 +/- 5.08 minutes) supplementation. Carbohydrate and CHO Pro ingestion after exercise appear to have similar effects on short-term recovery. PMID- 22516910 TI - Comparison between nonlinear and linear periodized resistance training: hypertrophic and strength effects. AB - The aim of this study was to investigate the effects of nonlinear periodized (NLP) and linear periodized (LP) resistance training (RT) on muscle thickness (MT) and strength, measured by an ultrasound technique and 1 repetition maximum (1RM), respectively. Thirty untrained men were randomly assigned to 3 groups: NLP (n = 11, age: 30.2 +/- 1.1 years, height: 173.6 +/- 7.2 cm, weight: 79.5 +/- 13.1 kg), LP (n = 10, age: 29.8 +/- 1.9 years, height: 172.0 +/- 6.8 cm, weight: 79.9 +/- 10.6 kg), and control group (CG; n = 9, age: 25.9 +/- 3.6 years, height: 171.2 +/- 6.3 cm, weight: 73.9 +/- 9.9 kg). The right biceps and triceps MT and 1RM strength for the exercises bench press (BP), lat-pull down, triceps extension, and biceps curl (BC) were assessed before and after 12 weeks of training. The NLP program varied training biweekly during weeks 1-6 and on a daily basis during weeks 7-12. The LP program followed a pattern of intensity and volume changes every 4 weeks. The CG did not engage in any RT. Posttraining, both trained groups presented significant 1RM strength gains in all exercises (with the exception of the BP in LP). The 1RM of the NLP group was significantly higher than LP for BP and BC posttraining. There were no significant differences in biceps and triceps MT between baseline and posttraining for any group; however, posttraining, there were significant differences in biceps and triceps MT between NLP and the CG. The effect sizes were higher in NLP for the majority of observed variables. In conclusion, both LP and NLP are effective, but NLP may lead to greater gains in 1RM and MT over a 12-week training period. PMID- 22516911 TI - Effect of competition on salivary cortisol, immunoglobulin A, and upper respiratory tract infections in elite young soccer players. AB - The present study examined the effect of a 20-day period of competition on salivary cortisol, mucosal immunity, and upper respiratory tract infections (URTI) in young male soccer players (n = 14). The players were monitored during the main under-19 Brazilian soccer championship, in which 7 matches were played in 20 days. Saliva samples were collected in the morning of each match and analyzed for cortisol and immunoglobulin A (IgA). Signs and symptoms of URTI were assessed across the study and a rating of perceived exertion (RPE) was obtained for each match. Compared with match 1, a significant increase in player RPE was observed in matches 4-7 (p < 0.05). Significant (p < 0.05) increases in the reporting of URTI occurred between matches 2 and 3, and 6 and 7, and this was accompanied by significant decreases in salivary IgA levels. Significant (p < 0.05) correlations were also seen between the individual reports of URTI and the decrease in IgA levels in match 2 (r = -0.60) and match 6 (r = -0.65). These results suggest that decrements in mucosal immunity, as measured by salivary IgA concentrations, may lead to a greater incidence of URTI in elite young soccer players. It may be speculated that the physiological and psychological stressors imposed by training and competition in a short timeframe are major contributing factors to these responses. Thus, the monitoring of salivary IgA could provide a useful and noninvasive approach for predicting URTI occurrences in young athletes during short-term competitions, especially if frequent sampling and rapid measurements are made. PMID- 22516912 TI - Mucosal immune function comparison between amenorrheic and eumenorrheic distance runners. AB - This study examined the effects of amenorrhea on mucosal immune function and susceptibility to upper respiratory tract infection (URTI) in elite female distance runners. Based on their menstrual cycles during the prior year, 21 elite, collegiate, female distance runners were designated as eumenorrheic runners (ERs; n = 8; 19.9 +/- 0.8 years) or amenorrheic runners (ARs; n n = 13; 20.0 +/- 0.3 years). Resting saliva and blood samples were collected in the morning. The secretory immunoglobulin A (SIgA) concentration was measured using enzyme-linked immunosorbent assay. The SIgA secretion rate was calculated. Serum 17beta-estradiol concentrations and serum progesterone concentrations were measured using radioimmunoassay. Subjects reported the appearance of URTI symptoms (sore throat, headache, runny nose, coughing, or fever), if any, during the prior month. The serum estradiol concentration and salivary SIgA secretion rate were significantly lower for ARs than for ERs (p < 0.05). Serum progesterone concentration was not significantly different between groups. Higher frequencies of headache, runny nose, coughing, and fever were observed in ARs than in ERs. Results show that athletic amenorrhea with low estrogen might accelerate downregulation of mucosal immune function in athletes and enhance susceptibility to infection. PMID- 22516913 TI - Neuromuscular responses to impact and collision during elite rugby league match play. AB - The purpose of this study was to investigate the relationship between the prematch and short-term postmatch neuromuscular responses to the intensity, number, and distribution of impacts associated with collisions during elite Rugby League match play. Twenty-two elite male Rugby League players were monitored during 8 regular season competition matches using portable global positioning system (GPS) technology. The intensity, number, and distribution of impact forces experienced by players during match play were recorded using integrated accelerometry. Peak rate of force development (PRFD), peak power (PP), and peak force (PF) were measured during a countermovement jump on a force plate 24 hours prematch, 30 minutes prematch, 30 minutes postmatch and then at 24-hour intervals for a period of 5 days postmatch. The change in the dependent variables at each sample collection time was compared with that at 24 hours prematch and 30-minute prematch measures. There were significant (p < 0.05) decreases in PRFD and PP up to 24 hours postmatch with PF significantly (p < 0.05) being decreased 30 minutes postmatch. Significant (p < 0.05) correlations were found between the total number of impacts and PRFD and PP 30 minutes postmatch. Impact zones 4 (7.1-8.0 G), 5 (>8.1-10.0 G), and 6 (>10.1 G) were significantly (p < 0.05) correlated to PRFD and PP 30 minutes postmatch with the number of zone 5 and 6 impacts significantly (p < 0.05) correlated to PRFD and PP 24 hours postmatch. Elite Rugby League match play resulted in significant neuromuscular fatigue and was highly dependent on the number of heavy collisions >7.1G. Results demonstrate that neuromuscular function is compromised for up to 48 hours postmatch indicating that at least 2 days of modified activity is required to achieve full neuromuscular recovery after elite Rugby League match play. Position-specific demands on energy systems and the influence of repeated blunt force trauma during collisions during elite Rugby League match play should be considered when planning postmatch recovery protocols and training activities to optimize subsequent performance. PMID- 22516914 TI - Chirality based sensor for bisphenol A detection. AB - A universal chirality detection platform based on immuno-recognition-driven nanoparticle assembly has been fabricated for the first time. A strong shifted chiral signal was produced by asymmetric plasmonic nanoparticle dimers. Using bisphenol A (BPA) as a model target substrate, the LOD was 0.02 ng mL(-1). PMID- 22516915 TI - Mimicking anaesthetic-receptor interaction: a combined spectroscopic and computational study of propofol...phenol. AB - Propofol is a general anaesthetic that exerts its action by interaction with the GABA(A) receptor. Crystallographic studies suggest that there is a direct interaction between propofol and the phenolic residue of a tyrosine in the channel. In this study we create propofol...phenol clusters by their co-expansion in jets. The complex is probed using a set of mass-resolved spectroscopic strategies: 2-color REMPI, UV/UV hole-burning, IR/UV double resonance and the novel technique IR/IR/UV triple resonance. The existence of at least six different isomers in the expansion is demonstrated. All the isomers are stabilized by interactions between their aromatic rings. Additionally, in some conformers the OH moieties form hydrogen bonds in some of the isomers, with propofol and phenol alternating their donor-acceptor roles, while in others the OH...OH angle points to a dipole-dipole interaction. Interpretation of the data in the light of dispersion-corrected DFT calculations shows that shallow barriers separate all the isomers, both in the ground and excited electronic states. Comparison of the structures of the complex with the X-ray diffraction data is also offered. PMID- 22516916 TI - Retrieval procedure for time-resolved near-infrared tissue spectroscopy based on the optimal estimation method. AB - We propose the use of a retrieval procedure for time-resolved near-infrared tissue spectroscopy based on the 'optimal estimation' method. The aim of this retrieval method is to obtain an improved estimate of the target parameters compared with standard nonlinear least-squares routines, since the inverse problem dedicated to retrieve the optical properties of tissue is ill posed. A priori information on target and forward model parameters is used, so that a larger number of target parameters can be retrieved, and/or a better accuracy and precision can be achieved on the retrieved target parameters. The procedure has been tested on time-resolved simulated experiments generated, using solutions of the diffusion equation and with solutions of the radiative transfer equation reconstructed with Monte Carlo simulations. The results obtained show that, by using a priori information on target parameters, we have a smaller difference between retrieved values and true values, and lower retrieved error bars. Similarly, a more correct estimate of the errors of the forward model parameters improves the retrieval of the target parameters. PMID- 22516917 TI - Association of frustrated phosphine-borane pairs in toluene: molecular dynamics simulations. AB - Explicit solvent molecular dynamics simulations of the ((t)Bu)(3)P/B(C(6)F(5))(3) pair in toluene allowed the estimation of the degree of intermolecular association and the population of encounter complex states in solution phase. PMID- 22516918 TI - A sensitive and kinetically defined radiochemical assay for canine and human serum thymidine kinase 1 (TK1) to monitor canine malignant lymphoma. AB - Thymidine kinase 1 (TK1) is a cell cycle regulated enzyme with maximum expression during the S phase. Serum TK1 (S-TK1) is a unique biomarker for cell proliferation. Here, an optimized [(3)H]-thymidine (dThd) phosphorylation assay is described, which is as sensitive as the commercially available TK-REA and TK Liaison assays for measurement of S-TK1 activity in dogs and humans. Serum samples from dogs (35 healthy, 32 with lymphoma, 2 with leukemia, and 35 with solid tumors) and humans (18 healthy, 9 with chronic lymphocytic leukemia, 10 with myelodysplastic syndrome) were analyzed using the [(3)H]-dThd assay. Mean S TK1 activities were 1.11 +/- 0.46 pmol/min/mL in healthy dogs and 1.15 +/- 0.32 pmol/min/mL in healthy humans. S-TK1 activities in dogs with hematological malignancies were 24.2 +/- 47.9 pmol/min/mL, and the receiver operating characteristic curve showed an area under the curve of 0.88. With a cut-off value of 1.9 pmol/min/mL (mean value +/- 2 SD), the sensitivity was 0.94 and the specificity was 0.68. Very similar results were obtained with human samples (healthy and lymphoma cases). S-TK1 activities measured during chemotherapy of six dogs with lymphoma were drastically reduced. In one case, S-TK1 activity increased prior to relapse. S-TK1 levels in dogs with solid tumors did not differ from the healthy group. S-TK1 activities correlated with those determined with the TK-REA and TK-Liaison assays (r=0.92 and r=0.96, respectively). In conclusion, this optimized [(3)H]-dThd assay is fast, sensitive and economical for measuring S-TK1 activity and should increase its clinical use as biomarker. PMID- 22516919 TI - Characterisation of pregnancy losses after embryo transfer by measuring plasma progesterone and bovine pregnancy-associated glycoprotein-1 concentrations. AB - The aim of this analysis was to determine whether pregnancy loss (PL) after embryo transfer (ET) in cattle was related to maternal progesterone (P4) concentrations during and shortly after ET, and maternal bovine pregnancy associated glycoprotein-1 (bPAG-1) concentrations in plasma at days 25-35 of gestation. Embryos (n=260) were produced either in vivo after superovulation (n=115), or in vitro from oocytes (obtained with ovum pick-up) in co-culture (n=44) or cultured in a synthetic medium (n=101). Overall, PL was 56.9% (148) and no significant differences occurred in calving rate among the three embryo production groups. There was no difference in P4 concentrations on days 7-14 of gestation in the three groups, nor between ongoing and interrupted pregnancies. Between days 25 and 35 of pregnancy, bPAG-1 concentrations were unaffected by embryo production, but in cattle that had PL between days 26 and 120, four bPAG-1 profiles could be detected. Between days 25 and 32, bPAG-1 concentrations were influenced by PL, and concentrations were significantly lower in animals in which PL occurred between days 26 and 120 than in those animals that aborted later or calved at term. Early P4 concentrations suggested that maternal luteal factors were not responsible for PL which appeared to be caused by impaired conceptus development (regardless of embryo type) as reflected by low maternal bPAG-1 concentrations prior to embryonic death. PMID- 22516920 TI - Prevalence of and risk factors associated with viral and bacterial pathogens in farmed European wild boar. AB - The aim of this study was to estimate in farmed European wild boars the prevalence of and risk factors associated with a range of common porcine viral and bacterial infections, namely, porcine parvovirus (PPV), porcine circovirus type 2 (PCV2), swine influenza virus (SIV), Aujeszky's disease virus (ADV), classical swine fever virus (CSFV), swine vesicular disease virus (SVDV), coronavirus causing transmissible gastroenteritis (TGEV), porcine reproductive and respiratory syndrome virus (PRRSV), Mycoplasma hyopneumoniae, Lawsonia intracellularis, Brucella spp., and Leptospira spp. A sampling frame was compiled based on a national record of wild boar farmers, and 32 farms were surveyed. Serological screening was carried out on 303 samples from animals slaughtered between 2005 and 2008, and random-effect logistic regression models were developed for pathogens with a 'non-zero' prevalence. The apparent animal prevalence for PPV, PCV2, and L. intracellularis was 46.5% (95% confidence interval [CI] 41-52%), 51.1% (95% CI 45-57%) and 59.2% (95% CI 54-65%), respectively. Apparent farm seroprevalence rates for PPV, PCV2 and Lawsonia intracellularis were 56.3% (95% CI, 39-73%), 21.9% (95% CI, 8-36%) and 78.1% (95% CI, 64-92%), respectively. No antibodies were detected against SIV, ADV, CSFV, SVDV, TGEV, PRSSV, Leptospira spp., Brucella spp., or M. hyopneumoniae. Increasing herd size, proximity to dense populations of domestic swine and later sampling times within the survey period were found to be risk factors. Overall, the seroprevalence of these pathogens in farmed wild boar was similar to that in the farmed domestic pig population in Finland. However, it is possible that the rearing of wild boars in fenced estates may predispose them to particular infections, as reflected in higher antibody titres. PMID- 22516921 TI - Differences in attitudes of farmers and veterinarians towards pain in dairy cows. AB - Attitudes towards pain and the use of analgesics in dairy cows were evaluated based on a questionnaire answered by 137 Danish veterinarians and 189 Danish dairy farmers. Respondents were asked to score the perceived pain associated with a number of diseases in dairy cows on a scale from 1 (no pain) to 10 (very painful) assuming that no analgesics were used. Additionally, they were asked whether they agreed or disagreed with a number of statements regarding pain and use of analgesics in cows. A large variability in pain scores for individual diseases was found among both farmers and veterinarians. The same disease was scored as 'very painful' by some respondents and as 'not painful' by others; however, farmers and veterinarians generally agreed which diseases were painful and which were not. Farmers considered most of the disease conditions to be slightly more painful than veterinarians but were less likely to use analgesics. PMID- 22516922 TI - The development of a concise questionnaire designed to measure perceived outcomes on the issues of greatest importance to patients. AB - AIM: To develop a concise patient feedback audit instrument designed to inform practice development on those issues of greatest importance to patients. METHODS: A literature review was used to establish the issues which were of greatest importance to patients. Ten core questions were then designed with the help of an experienced survey and polling organisation. A challenging grading of patient responses was utilised in an attempt to differentiate perceived performance within a practice on the different aspects and between practices. A feasibility study was conducted using the interactive voice response mode with seven volunteer practices in 2009. The instrument was then used in the later part of 2010 by 61 practices mostly in paper-based format. Practices received feedback which is primarily based on a bar chart plotting their percentage of top grades received against a national reference sample (NRS) compiled from the results of other participating practices. A statistical analysis was conducted to establish the level at which an individual practice result becomes statistically significant against the NRS. RESULTS: The 61 participating practices each received an average of 121 responses (total 7,381 responses). Seventy-four percent of responses across all ten questions received the top grade, 'ideal'. Statistical analysis indicated that at the level of 121 responses, a score of around 4-9% difference to the National Reference Sample, depending on the specific question, was statistically significant. CONCLUSION: In keeping with international experience with dental patient feedback surveys this audit suggests high levels of patient satisfaction with their dental service. Nevertheless, by focusing results on the proportion of highest grades received, this instrument is capable of indicating when perceived performance falls significantly below the average. It can therefore inform practice development. PMID- 22516923 TI - A decade of model for end-stage liver disease: lessons learned and need for re evaluation of allocation policies. AB - PURPOSE OF REVIEW: The model for end-stage liver disease (MELD) driven liver allocation system has been in place for 10 years now. Understanding what the driving forces were, what principles were developed and employed, and assessing how these have stood the test of time will help future policy makers further refine the system. RECENT FINDINGS: Prior to development of the MELD system, policymakers had limited data and organ allocation policy development was rarely systematic or evidence-based and was not necessarily centered on the patient. The MELD process focused on patient-specific variables and validation of the risk prediction models to be sure the system would function reasonably well across the spectrum of potential candidates and that it did not impose artificial categorizations of patients. In addition, the transplant community focused on assessing the effects of this policy change which was also something new. SUMMARY: Numerous publications since have reported outcomes for MELD-based liver allocation here in the United States and in many other areas around the world. Some of these reports have suggested changes to the MELD equation or other ways to adapt the system to more accurately reflect the need for transplant. The transparency that this type of system brings allows for much more rigorous assessment of results and for highlighting areas for improvement toward a more fair, equitable, and utilitarian system. PMID- 22516924 TI - Determination of pericardial adipose tissue increases the prognostic accuracy of coronary artery calcification for future cardiovascular events. AB - OBJECTIVES: Pericardial adipose tissue (PAT) is associated with coronary artery plaque accumulation and the incidence of coronary heart disease. We evaluated the possible incremental prognostic value of PAT for future cardiovascular events. METHODS: 145 patients (94 males, age 60 +/- 10 years) with stable coronary artery disease underwent coronary artery calcification (CAC) scanning in a multislice CT scanner, and the volume of pericardial fat was measured. Mean observation time was 5.4 years. RESULTS: 34 patients experienced a severe cardiac event. They had a significantly higher CAC score (1,708 +/- 2,269 vs. 538 +/- 1,150, p < 0.01), and the CAC score was highly correlated with the relative risk of a future cardiac event: 2.4 (1.8-3.7; p = 0.01) for scores >400, 3.5 (1.9-5.4; p = 0.007) for scores >800 and 5.9 (3.7-7.8; p = 0.005) for scores >1,600. When additionally a PAT volume >200 cm(3) was determined, there was a significant increase in the event rate and relative risk. We calculated a relative risk of 2.9 (1.9-4.2; p = 0.01) for scores >400, 4.0 (2.1-5.0; p = 0.006) for scores >800 and 7.1 (4.1 10.2; p = 0.005) for scores >1,600. CONCLUSIONS: The additional determination of PAT increases the predictive power of CAC for future cardiovascular events. PAT might therefore be used as a further parameter for risk stratification. PMID- 22516925 TI - Is metformin indicated as primary ovulation induction agent in women with PCOS? A systematic review and meta-analysis. AB - BACKGROUND: A recent meta-analysis has proven that metformin (M) is highly effective for ovulation induction in the clomiphene citrate (CC)-resistant patient. There is uncertainty whether M should be introduced as a primary ovulation induction agent in polycystic ovarian syndrome (PCOS). METHODS: We conducted a systematic review and meta-analysis to establish if M is better when given alone or in combination with CC (CC+M) when compared with CC alone. This systematic review studied live birth delivery rate as the primary outcome. RESULTS: We identified 14 prospective trials. Analysis of these results showed a reduction in the live birth rate in the group of patients treated only with M when compared with CC alone (OR = 0.48, 95% CI 0.31-0.73, p = 0.0006). An increase in ovulation (OR = 1.6, 95% CI 1.2-2.1, p = 0.0009) and pregnancy rate (OR = 1.3, 95% CI 1.0-1.6, p = 0.05) with CC+M when compared with CC alone was reported, but no difference was found when live birth rate was analyzed (OR = 1.1, 95% CI 0.8-1.5, p = 0.61). CONCLUSION: CC alone is superior to M alone regarding live birth rate and ovulation. The combination (CC+M) is superior to CC alone as a primary method for ovulation induction and to achieve pregnancy in PCOS. However, when addressing live birth rate, no statistically significant difference could be demonstrated. Because of the side effects profile and contraindications of M, we believe M should not be indicated as a primary ovulation induction agent in women with PCOS. PMID- 22516926 TI - The release of a troop of rehabilitated vervet monkeys (Chlorocebus aethiops) in KwaZulu-Natal, South Africa: outcomes and assessment. AB - Rehabilitation and release have become central to the management and welfare of primate species in South Africa such as the vervet monkey (Chlorocebus aethiops). However, limited research means that it is unknown whether rehabilitation is a successful management strategy for this species. This study describes the release of a troop of rehabilitated vervet monkeys and evaluates the results of 1 year of post-release monitoring. The released animals exhibited wild behaviours and established a home range. Survival could not be adequately evaluated due to the high number of untraceable animals, and troop composition was significantly different from that of wild troops. Improvement may be gained by radio-collaring more animals using improved technology, ensuring that troop composition is comparable to wild troops, excluding ex-pets from re-introduction and a more detailed assessment of the release site. PMID- 22516927 TI - D282, a non-nucleoside inhibitor of influenza virus infection that interferes with de novo pyrimidine biosynthesis. AB - BACKGROUND: The discovery of novel influenza virus inhibitors remains an important priority in light of the emergence of drug-resistant viruses. Toward this end, a library of over 6,000 compounds was tested for antiviral activity. METHODS: Strains of influenza virus were evaluated by cytopathic effect (CPE) inhibition and virus yield reduction assays. Intracellular nucleoside triphosphate pools were analysed by strong anion exchange HPLC. Dihydroorotate dehydrogenase inhibition assays were conducted. Influenza virus-infected mice were treated for 5 days with D282. RESULTS: A non-nucleoside, 4-[(4 butylphenyl)amino]-2-methylene-4-oxo-butanoic acid (D282), was discovered that inhibited influenza A and B virus CPE by 50% at 6-31 MUM (giving selectivity indices of >13 to >67, based on cytotoxicity of >400 uM in stationary cell cultures). Ribavirin (positive control) was active at 14-44 uM (yielding selectivity indices of >9 to >29, with >400 uM toxicity). D282 and ribavirin inhibited virus yield by 90% at 9.5 +/-3.3 and 10.8 +/-3.2 uM, respectively. The antiviral activity of D282 in vitro was reversed by addition of uridine, cytidine and orotic acid. D282 exhibited an uncompetitive inhibition of mouse liver dihydroorotate dehydrogenase (inhibitor constant [Ki] of 2.3 +/-0.9 uM, Michaelis constant [Km] of 150 +/-16 uM). Because cellular pyrimidine biosynthesis was inhibited, D282-treated cells had decreased uridine triphosphate and cytidine triphosphate levels. D282 (<=100 mg/kg/day) failed to prevent death of mice infected with influenza. CONCLUSIONS: D282 was active against influenza A and B viruses by inhibiting de novo pyrimidine biosynthesis. Although effective in vitro, the compound, like others in its class, was devoid of antiviral activity in infected mice. PMID- 22516928 TI - Ventricular septal defects: embryology and imaging findings. AB - Ventricular septal defects are the most common congenital abnormality diagnosed in children and the second most common congenital heart condition diagnosed in adults. Depending on their location in the interventricular septum, ventricular septal defects are described as perimembranous, muscular, subarterial, and inflow. Awareness of the embryologic basis of these defects helps understand the anatomy and recognize their typical appearance on imaging. Diagnostic imaging plays a role in the characterization of the defect, identification of associated anomalies, and evaluation of hemodynamic repercussion, all of which contribute to guide treatment. PMID- 22516929 TI - Efficient gamma-amino-proline-derived cell penetrating peptide-superparamagnetic iron oxide nanoparticle conjugates via aniline-catalyzed oxime chemistry as bimodal imaging nanoagents. AB - Aniline-catalyzed oxime chemistry was employed to conjugate a gamma-amino-proline derived cell penetrating peptide to superparamagnetic iron oxide nanoparticles (SPIONs). Internalization of the novel nanoconjugate into HeLa cells was found to be remarkably higher compared to the analogous TAT-SPION conjugate. PMID- 22516930 TI - Parental origin of de novo cytogenetically balanced reciprocal non-Robertsonian translocations. AB - De novo cytogenetically balanced reciprocal non-Robertsonian translocations are rare findings in clinical cytogenetics and might be associated with an abnormal phenotype. Knowledge of the parental origin and mechanisms of formation is still limited. By microdissection of the derivative chromosomes and their normal homologs from metaphases followed by microsatellite-mediated marker analysis we identified 7 cases of paternal and 3 cases of maternal origin in a cohort of 10 patients with de novo cytogenetically balanced reciprocal non-Robertsonian translocations. Neither in the maternal nor in the paternal group of our study parental age seems to be increased. Together with the data from the literature our results confirm that the majority of de novo cytogenetically balanced reciprocal translocations are of paternal origin, but the preponderance does not appear to be as distinct as previously thought and the paternal age does not seem to be necessarily a major contributing factor. PMID- 22516931 TI - Anti-austerity agents from Rhizoma et Radix Notopterygii (Qianghuo). AB - During a search for potent anticancer agents from natural products based on an anti-austerity strategy, we found that a CHCl3 extract of Rhizoma et Radix Notopterygii (Qianghuo), a Chinese crude drug, exhibited strong cytotoxicity against PANC-1 human pancreatic cancer cells, with a PC50 value of 17.5 ug/mL. Further fractionation and purification of this bioactive extract led to the isolation of 19 known compounds. The in vitro preferential cytotoxicity of the isolates was evaluated against two human pancreatic cancer cell lines, PANC-1 and PSN-1. Among the compounds isolated, ostruthin displayed the most potent activity against both PANC-1 (PC50, 7.2 uM) and PSN-1 (PC50, 7.8 uM) cells in nutrient deprived medium (NDM) and may have induced necrotic nutrient-deprived PANC-1 cell death. PMID- 22516932 TI - Flavonoids eupatorin and sinensetin present in Orthosiphon stamineus leaves inhibit inflammatory gene expression and STAT1 activation. AB - Cytokines and other inflammatory mediators, such as prostaglandin E2 (PGE2) and nitric oxide (NO) produced by cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), respectively, activate and drive inflammation and therefore serve as targets for anti-inflammatory drug development. Orthosiphon stamineus is an indigenous medicinal plant of Southeast Asia that has been traditionally used in the treatment of rheumatoid arthritis, gout, and other inflammatory disorders. The present study investigated the anti-inflammatory properties of Orthosiphon stamineus leaf chloroform extract (CE), its flavonoid-containing CE fraction 2 (CF2), and the flavonoids eupatorin, eupatorin-5-methyl ether (TMF), and sinensetin, identified from the CF2. It was found that CE (20 and 50 ug/mL) and CF2 (20 and 50 ug/mL) inhibited iNOS expression and NO production, as well as PGE2 production. Eupatorin and sinensetin inhibited iNOS and COX-2 expression and the production of NO (IC50 5.2 uM and 9.2 uM for eupatorin and sinensetin, respectively) and PGE2 (IC50 5.0 uM and 2.7 uM for eupatorin and sinensetin, respectively) in a dose-dependent manner. The extracts and the compounds also inhibited tumor necrosis factor alpha (TNF-alpha) production (IC50 5.0 uM and 2.7 uM for eupatorin and sinensetin, respectively). Eupatorin and sinensetin inhibited lipopolysaccharide (LPS)-induced activation of transcription factor signal transducers and activators of transcription 1alpha (STAT1alpha). Furthermore, eupatorin (50 mg/kg i. p.) and sinensetin (50 mg/kg i. p.) inhibited carrageenan-induced paw inflammation in mice. The results suggest that CE and CF2, as well as the known constituents of CF2, i.e., eupatorin and sinensetin, have meaningful anti-inflammatory properties which may be utilized in the development of novel anti-inflammatory treatments. PMID- 22516933 TI - Dihydrochalcones and benzoic acid derivatives from Piper dennisii. AB - Two new dihydrochalcones (1, 2), as well as eight known compounds, piperaduncin C (3), 2',6'-dihydroxy-4'-methoxydihydrochalcone (4), 4,2',6'-trihydroxy-4' methoxydihydrochalcone (5), 4-hydroxy-3,5-bis(3-methyl-2-butenyl)-benzoic acid (6), 3,5-bis(3-methyl-2-butenyl)-4-methoxybenzoic acid (7), 4-hydroxy-3-(3-methyl 2-butenoyl)-5-(3-methyl-2-butenyl)-benzoic acid (8), 2,2-dimethyl-8-(3-methyl-2 butenyl)-2H-1-chromene-6-carboxylic acid (9), and 3-(3',7'-dimethyl-2',6' octadienyl)-4-methoxybenzoic acid (10) were isolated from the leaves of Piper dennisii Trelease (Piperaceae), using a bioassay-guided fractionation to determine their antileishmanial potential. Among them, compound 10 exhibited the best antileishmanial activity (IC50 = 20.8 uM) against axenic amastigote forms of Leishmania amazonensis, with low cytotoxicity on murine macrophages. In the intracellular macrophage-infected model, compound 10 proved to be more active (IC50 = 4.2 uM). The chemical structures of compounds 1-10 were established based on the analysis of the spectroscopic data. PMID- 22516934 TI - Anticancer potential of aloes: antioxidant, antiproliferative, and immunostimulatory attributes. AB - Aloe is a genus of medicinal plants with a notable history of medical use. Basic research over the past couple of decades has begun to reveal the extent of Aloe's pharmaceutical potential, particularly against neoplastic disease. This review looks at Aloe, both the genus and the folk medicine, often being called informally "aloes", and delineates their chemistry and anticancer pharmacognosy. Structures of key compounds are provided, and their pharmacological activities reviewed. Particular attention is given to their free radical scavenging, antiproliferative, and immunostimulatory properties. This review highlights major research directions on aloes, reflecting the enormous potential of natural sources, and of the genus Aloe in particular, in preventing and treating cancer. PMID- 22516935 TI - From Grignard's reagents to well-defined Mg nanostructures: distinctive electrochemical and solution reduction routes. AB - Anisotropic Mg nanowires have been successfully prepared by electrocrystallization of Grignard's reagents thought to proceed via a modified faces, steps, and kinks (FSK) mechanism. Mg nanoparticles with roughly hexagonal shapes have also been obtained via chemical reduction of the same Grignard's reagents. PMID- 22516937 TI - High-resolution breast tomography at high energy: a feasibility study of phase contrast imaging on a whole breast. AB - Previous studies on phase contrast imaging (PCI) mammography have demonstrated an enhancement of breast morphology and cancerous tissue visualization compared to conventional imaging. We show here the first results of the PCI analyser-based imaging (ABI) in computed tomography (CT) mode on whole and large (>12 cm) tumour bearing breast tissues. We demonstrate in this work the capability of the technique of working at high x-ray energies and producing high-contrast images of large and complex specimens. One entire breast of an 80-year-old woman with invasive ductal cancer was imaged using ABI-CT with monochromatic 70 keV x-rays and an area detector of 92*92 um2 pixel size. Sagittal slices were reconstructed from the acquired data, and compared to corresponding histological sections. Comparison with conventional absorption-based CT was also performed. Five blinded radiologists quantitatively evaluated the visual aspects of the ABI-CT images with respect to sharpness, soft tissue contrast, tissue boundaries and the discrimination of different structures/tissues. ABI-CT excellently depicted the entire 3D architecture of the breast volume by providing high-resolution and high contrast images of the normal and cancerous breast tissues. These results are an important step in the evolution of PCI-CT towards its clinical implementation. PMID- 22516936 TI - Topotecan and vincristine combination is effective against advanced bilateral intraocular retinoblastoma and has manageable toxicity. AB - BACKGROUND: New, effective chemotherapeutic agents are needed for intraocular retinoblastoma. METHODS: This institutional clinical trial sought to estimate the rate of response to 2 courses of vincristine and topotecan (VT) window therapy in patients with bilateral retinoblastoma and advanced disease (Reese-Ellsworth group IV or V) in at least 1 eye. The topotecan dose started at 3 mg/m(2) /day for 5 days and was adjusted to target a systemic exposure of 140 +/- 20 ng/mL . hour. The vincristine dose was 0.05 mg/kg for patients <12 months of age and 1.5 mg/m(2) for those >12 months of age at diagnosis. RESULTS: From February 2005 to June 2010, 27 patients received VT window therapy. Median age at enrollment was 8.1 months (range, 0.7-22.1 months). Twenty-four patients (88.9%) responded to window therapy (95% confidence interval = 71.3%-96.9%). Hematologic toxicity comprised grade 4 neutropenia (n = 27), grade 3 anemia (n = 19), and grade 3/4 thrombocytopenia (n = 16). Thirteen patients had grade 3 nonhematologic toxicity. Granulocyte colony-stimulating factor support was added after 10 patients had been treated, and it significantly reduced the duration of grade 4 neutropenia (median, 7 vs 24 days; P < .001). Pharmacokinetic studies showed rapid changes in topotecan clearance rates during the first year of life. CONCLUSIONS: The combination of topotecan and vincristine is effective for the treatment of advanced intraocular retinoblastoma. Granulocyte colony-stimulating factor treatment alleviates the duration of grade 4 neutropenia. Appropriate topotecan starting doses for patients 0-3, 3-6, 6-9, 9-12, and >12 months of age are specified. PMID- 22516938 TI - A novel sample selection strategy by near-infrared spectroscopy-based high throughput tablet tester for content uniformity in early-phase pharmaceutical product development. AB - This article proposes a new sample selection strategy to simplify the traditional content uniformity (CU) test in early research and development (R&D) with improved statistical confidence. This strategy originated from the prescreening of a large amount of tablets by a near-infrared spectroscopy (NIRS)-based high volume tablet tester to the selection of extreme tablets with highest, medium, and lowest content of active pharmaceutical ingredient (API) for further high performance liquid chromatography (HPLC) test. The NIRS-based high-volume tablet tester was equipped with an internally developed and integrated automated bagging and labeling system, allowing the traceability of every individual tablet by its measured physical and chemical signatures. A qualitative NIR model was used to translate spectral information to a concentration-related metric, that is scores, which allowed the selection of those extreme tablets. This sample selection strategy of extreme tablets was shown to provide equivalent representation of CU in the process compared with the traditional CU test using a large number of random samples. Because it only requires reference tests on three extreme samples per stratified location, the time- and labor-saving nature of this strategy is advantageous for CU test in early R&D. The extreme sampling approach is also shown to outperform random sampling with respect to statistical confidence for representing the process variation. In addition, a chemometric approach, which utilizes only pure component raw materials to develop an NIRS model sensitive to API concentration, is discussed with the advantage that it does not require tablets at multiple API levels. Prospective applications of this sample selection strategy are also addressed. PMID- 22516939 TI - A series of 3d-4f heterometallic three-dimensional coordination polymers: syntheses, structures and magnetic properties. AB - Seven lanthanide-cobalt heterometallic three-dimensional coordination polymers: {[Ln(3)Co(2)(BPDC)(5)(HBPDC)(H(2)O)(5)](ClO(4))(2).mH(2)O}(n) (Ln = Eu (1, m = 10.25), Gd (2, m = 8), Tb (3, m = 9.5), Dy (4, m = 11), Ho (5, m = 10.5), Tm (6, m = 11), Lu (7, m = 10.25); BPDC = 5,5'-dicarboxylate-2,2'-dipyridine anion) were structurally and magnetically characterized. Compounds 1-7 crystallize in the orthorhombic space group Pbca, featuring a 3D sandwich framework. Magnetic properties of 2-6 have been investigated by using DC (direct current) and AC (alternating current) susceptibility measurements. Among these compounds, only compound 4 displays significant frequency dependence, albeit without reaching the characteristic maxima above 2 K, implying slow magnetic relaxation behavior in 4. After the application of a DC field, good peak shapes of AC signals were obtained and the energy barrier DeltaE/k(B) = 62.89 K and the preexponential factor tau(0) = 6.16 * 10(-8) s. To our knowledge, 4 has the highest energy barrier in Ln-Co SMM systems hitherto. PMID- 22516940 TI - The role of B vitamins in the management of heart failure. AB - Heart failure (HF) is the leading cause of morbidity and mortality in industrialized countries, creating a significant burden on both the healthcare system and quality of life. Research efforts continue to explore new pharmaceutical or surgically based approaches to HF management, but the role of nutrition as an adjunct therapy has been largely ignored. Elderly age, anorexia, malabsorption, premature satiety, and disease severity are among the factors identified as contributing to reduced nutrient intakes in patients with HF. These factors suggest that patients with HF are at increased risk of multiple-nutrient deficiencies, including B vitamins. B vitamins may be of particular therapeutic interest because of their key roles as cofactors in energy-producing pathways. Recently, impaired stores of high-energy compounds have been linked with myocardial dysfunction and prognosis in patients with HF. Therefore, deficiencies of B vitamins might contribute to reduced energy stores and disease progression. This review summarizes the existing literature both with respect to the prevalence of B vitamin deficiency as well as evidence from supplementation trials in patients with HF. The findings suggest that most of the literature in this area has focused on thiamin deficiency in patients with HF, whereas other B vitamins remain largely unstudied. Although few sporadic trials suggest a role for B vitamins in the management of HF, none are conclusive. Therefore, there is a need for larger, more robust trials to assist in defining the B vitamin requirements as well as the impact of supplementation on both morbidity and mortality in patients with HF. PMID- 22516941 TI - Increasing early protein intake is associated with a reduction in insulin-treated hyperglycemia in very preterm infants. AB - BACKGROUND: Impaired early protein intake in very preterm infants contributes to early growth failure and may affect long-term neurocognitive development. The authors have previously shown that a standardized concentrated neonatal parenteral nutrition (scNPN) formulation can improve the efficiency of early protein administration. They recognized that very early protein intake could be improved further by modifying the original scNPN regimen and starting PN within 4 hours. AIM: To demonstrate that the new scNPN regimen could improve very early protein intake in infants <29 weeks' gestation without causing clinically important PN intolerance and complications. METHODS: All eligible infants <29 weeks' gestation, receiving the modified scNPN regimen and born between October 2009 and December 2010, were studied (group scNPN2). These were compared with previously studied infants, <29 weeks' gestation and receiving the original scNPN regimen and born between June 2006 and December 2006 (group scNPN1). Infant details, actual nutrition intake, and metabolic/infection data were recorded. RESULTS: Thirty-eight infants <29 weeks' gestation (group scNPN2) were compared with the 38 infants previously studied (group scNPN1). PN was started earlier in group scNPN2, leading to increased mean (95% confidence interval) total protein intake (first 7 days) of 15.3 (14.5-16.1) g/kg in group scNPN2 vs 11.8 (11.0 12.6) g/kg in group scNPN1. There were no differences in calorie, lipid, and carbohydrate intake. Infants receiving insulin for hyperglycemia fell from 20 (53%) in group scNPN1 to 10 (26%) in group scNPN2. CONCLUSION: Increasing early protein intake is associated with a reduction in insulin-treated hyperglycemia in infants <29 weeks' gestation. PMID- 22516942 TI - Protein-losing enteropathy and the Fontan operation. AB - Protein-losing enteropathy (PLE) is a complex disorder characterized by enteric protein loss and often is associated with cardiovascular abnormalities, particularly those with elevated central venous pressure. The Fontan operation is a surgical procedure used to palliate patients with a functional single ventricle. Although the Fontan operation eliminates cyanosis and decreases the workload of the functionally single ventricle, it also elevates central venous pressure. This can result in hepatic and enteric congestion as well as PLE. Despite the universal elevation in central venous pressure, only a fraction of patients who have had a Fontan operation develop PLE. However, PLE is associated with significant morbidity and mortality. Presenting signs and symptoms of PLE include abdominal bloating, diarrhea, edema, pleural effusions, ascites, and failure to thrive. In this review, the authors discuss the diagnosis and prevalence of PLE after the Fontan operation and review currently available therapeutic strategies. PMID- 22516943 TI - Nutrition intervention in the critically ill cardiothoracic patient. AB - Despite acute myocardial infarction and cardiac surgery accounting for 2 of the most common reasons patients are admitted to the intensive care unit, little attention and investigation have been directed specifically for these patients. This patient population therefore deserves special attention as they are often malnourished but require emergent interventions, making nutrition intervention challenging. This article reviews current medical interventions implemented in critically ill cardiothoracic patients and discusses evidence-based nutrition therapy, including enteral and parenteral feeding, glycemic control, and antioxidant provision. PMID- 22516944 TI - Zinc-inhibited MMP-mediated collagen degradation after different dentine demineralization procedures. AB - BACKGROUND: Dentine matrix metalloproteinases (MMPs) play an important role in the dentine caries process. AIMS: To determine if MMP-mediated collagen degradation of acid-demineralized dentine may be inhibited by zinc or zinc chelators. METHODS: Human dentine specimens were demineralized by phosphoric acid (PA), ethylenediaminetetraacetic acid (EDTA), Clearfil SE Bond primer (SE), or Xeno V (XE) and stored in artificial saliva. Chlorhexidine digluconate (CHX), doxycycline, EDTA, or ZnCl(2) was added. C-terminal telopeptide determinations (ICTP) were performed by radioimmunoassay after 24 h and 4 weeks. RESULTS: Collagen degradation was prominent in PA-demineralized (ICTP values from 74.01 MUg/l at 24 h to 202.46 MUg/l after 4 weeks) and EDTA-demineralized dentine (ICTP values from 83.93 MUg/l at 24 h to 158.82 MUg/l after 4 weeks) stored in artificial saliva. Doxycycline fully blocked proteolysis. CHX and EDTA reduced collagen degradation only at 24 h. Zinc in excess strongly inhibited hydrolysis of collagen in all tested groups (ICTP values were: PA, 13.56 MUg/l; EDTA, 11.21 MUg/l; SE, 1.52 MUg/l, and XE, 2.37 MUg/l) and its effect was maintained for up to 4 weeks, except for EDTA-treated dentine (ICTP values were: PA, 40.76 MUg/l; EDTA, 79.15 MUg/l; SE, 5.29 MUg/l, and XE, 6.38 MUg/l). CONCLUSION: EDTA and CHX exerted time-limited MMP inhibition, and excess zinc served as an effective inhibitor of MMP-mediated collagen degradation in strong or mildly demineralized dentine. MMP degradation of collagen was reduced in resin-infiltrated dentine; the presence of excess zinc chloride exerted an additional protective effect. PMID- 22516945 TI - The dynamic change of circulating tumour cells in patients with operable breast cancer before and after chemotherapy based on a multimarker QPCR platform. AB - BACKGROUND: The possible presence of early tumour dissemination is the rationale behind the use of systemic adjuvant chemotherapy in patients with operable breast cancer. Circulating tumour cells (CTC) in peripheral blood may represent the possible presence of early tumour dissemination. However, relatively few studies were designed to investigate the relationship between the change of CTC status and the efficacy of adjuvant chemotherapy in operable breast cancer patients. METHODS: In a prospective study, we established a multimarker real-time quantitative PCR platform to detect CTC in peripheral blood of breast cancer patients. By using this platform, we detected CTC in peripheral blood of 94 operable breast cancer patients. Control group consisted of 20 patients with benign breast disease and 20 healthy volunteers. For 72 patients who underwent systemic adjuvant chemotherapy, the dynamic CTC status at three different time points (1 day before initiation of chemotherapy, 1 week after three cycles of chemotherapy and 1 week after all cycles of chemotherapy) was observed. RESULTS: Circulating tumour cells were detected in 56% (53 out of 94) of patients with operable breast cancer. The specificity was 95%. Seventy-two patients who received systemic adjuvant chemotherapy were followed up. After three cycles of chemotherapy, 47% (18 out of 38) of patients who were CTC-positive before chemotherapy changed into negative status. In addition, another 5% (2 out of 38) of patients had changed into negative status after all cycles of chemotherapy. CONCLUSION: Systemic adjuvant chemotherapy had a significant impact on CTC status, and this effect could be observed after three cycles of chemotherapy. Circulating tumour cells detection had the potential to be used to evaluate the efficacy of systemic adjuvant chemotherapy immediately after the chemotherapy was finished in operable breast cancer patients. PMID- 22516947 TI - Phase II and UGT1A1 genotype study of irinotecan dose escalation as salvage therapy for advanced gastric cancer. AB - BACKGROUND: To assess the efficacy and safety of individualised dose optimisation of irinotecan monotherapy as salvage treatment for advanced gastric cancer (AGC). METHODS: A total of 43 patients were enrolled. Intravenous irinotecan (350 mg m( 2)) was administered every 3 weeks. The dose was increased (425 mg m(-2) and 500 mg m(-2)) or decreased (250 mg m(-2)) depending on patient tolerance. UGT1A1 genotypes were determined by direct sequencing of genomic DNA extracted from peripheral blood. RESULTS: A total of 183 cycles of irinotecan were administered, with a median of four cycles per patient. The overall response rate was 9.3%, and the disease control rate was 62.8%. Median time to disease progression was 2.8 months, and median overall survival was 8.0 months. Grade 3-4 neutropenia was the most common toxicity (53.5%), and febrile neutropenia was the least common toxicity (4.6%). Compared with defective allele groups, UGT1A1 *1/*1 was associated with a lower incidence of grade 3-4 neutropenia during the first cycle (P=0.018). CONCLUSION: Individualised irinotecan dose escalation based on patient tolerance was not associated with increased toxicity and shows modest activity as salvage chemotherapy for AGC. The role of UGT1A1 genotype in clinical toxicity requires further evaluation. PMID- 22516946 TI - Germline BRCA1 mutations increase prostate cancer risk. AB - BACKGROUND: Prostate cancer (PrCa) is one of the most common cancers affecting men but its aetiology is poorly understood. Family history of PrCa, particularly at a young age, is a strong risk factor. There have been previous reports of increased PrCa risk in male BRCA1 mutation carriers in female breast cancer families, but there is a controversy as to whether this risk is substantiated. We sought to evaluate the role of germline BRCA1 mutations in PrCa predisposition by performing a candidate gene study in a large UK population sample set. METHODS: We screened 913 cases aged 36-86 years for germline BRCA1 mutation, with the study enriched for cases with an early age of onset. We analysed the entire coding region of the BRCA1 gene using Sanger sequencing. Multiplex ligation dependent probe amplification was also used to assess the frequency of large rearrangements in 460 cases. RESULTS: We identified 4 deleterious mutations and 45 unclassified variants (UV). The frequency of deleterious BRCA1 mutation in this study is 0.45%; three of the mutation carriers were affected at age 65 years and one developed PrCa at 69 years. Using previously estimated population carrier frequencies, deleterious BRCA1 mutations confer a relative risk of PrCa of ~3.75 fold, (95% confidence interval 1.02-9.6) translating to a 8.6% cumulative risk by age 65. CONCLUSION: This study shows evidence for an increased risk of PrCa in men who harbour germline mutations in BRCA1. This could have a significant impact on possible screening strategies and targeted treatments. PMID- 22516948 TI - A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours. AB - BACKGROUND: The objectives of this phase I study were to assess the safety and tolerability of E7080 in patients with advanced, refractory solid tumours; to determine the maximum tolerated dose (MTD) and pharmacokinetics profile of E7080; and to explore preliminary evidence of its anti-tumour efficacy. METHODS: E7080 was administered orally in escalating doses on a once-daily continuous schedule in 28-day cycles to eligible patients. Samples for pharmacokinetic analyses were collected on days 1, 8, 15 and 22 of cycle 1 and day 1 of cycle 2. Anti-tumour efficacy was assessed every two cycles. RESULTS: Eighty-two patients received E7080 in dose cohorts from 0.2 to 32 mg. Dose-limiting toxicities were grade 3 proteinuria (two patients) at 32 mg, and the MTD was defined as 25 mg. The most frequently observed cumulative toxicities (all grades) were hypertension (40% of patients), diarrhoea (45%), nausea (37%), stomatitis (32%) and vomiting (23%). Seven patients (9%) had a partial response and 38 patients (46%) had stable disease as best response. E7080 has dose-linear kinetics with no drug accumulation after 4 weeks' administration. CONCLUSION: E7080 is well tolerated at doses up to 25 mg per day. Encouraging anti-tumour efficacy was observed in patients with melanoma and renal cell carcinoma. PMID- 22516949 TI - The effect of DCIS grade on rate, type and time to recurrence after 15 years of follow-up of screen-detected DCIS. AB - BACKGROUND: The incidence of ductal carcinoma in situ (DCIS) rose rapidly when the NHS Breast Screening Programme (NHSBSP) started in 1988. Some authorities consider that this represents both over-diagnosis and over-treatment. We report long-term follow-up of DCIS diagnosed in the first 10 years (April 1988 to March 1999) of the West Midlands NHSBSP. METHODS: 840 noninvasive breast cancers were recorded on the national breast screening computer system. Following exclusions, and thorough case note and pathology review, 700 DCIS cases were identified for follow-up. RESULTS: After a median follow-up of 183 (range 133 to 259) months, 102 (14.6%) first local recurrences were identified, 49 (48%) were invasive. Median time to first noninvasive recurrence was 15 months, and 60 months for invasive recurrence. Median time to invasive recurrence was 76 months from initially high-grade DCIS, and 131 months from low/intermediate grade DCIS. For the seven women, presenting with metastasis as their first event, the median time was 82 (range 15 to 188) months. The cumulative proportion developing recurrence at 180 months was twice as high as at 60 months. INTERPRETATION: Short-term follow-up of patients diagnosed with DCIS will miss significant numbers of events, especially invasive local recurrences. PMID- 22516950 TI - Impact of mental health problems on case fatality in male cancer patients. AB - BACKGROUND: Although mortality rates are elevated in psychiatric patients relative to their healthy counterparts, little is known about the impact of mental health on survival in people with cancer. METHODS AND RESULTS: Among 16 498 Swedish men with cancer, survival was worse in those with a history of psychiatric hospital admissions: multiply-adjusted hazard ratio (95% confidence interval) comparing cancer mortality in men with and without psychiatric admissions: 1.59 (1.39, 1.83). CONCLUSION: Survival in cancer patients is worse among those with a history of psychiatric disease. The mechanisms underlying this association should be further explored. PMID- 22516951 TI - Alcohol intake and renal cell cancer risk: a meta-analysis. AB - BACKGROUND: An inverse association between alcoholic beverage intake and risk of renal cell cancer has been suggested in recent studies. METHODS: We examined the association between alcoholic beverages and renal cell cancer risk in a meta analysis. We identified relevant studies by searching the database of PubMed, EMBASE, and MEDLINE published through August 2011. We combined the study-specific relative risks (RRs) using a random-effects model. RESULTS: A total of 20 case control studies, 3 cohort studies, and 1 pooled analysis of cohort studies were included in the meta-analysis. We observed that alcoholic beverage intake was associated with a lower risk of renal cell cancer in combined analysis of case control and cohort studies; for total alcoholic beverage intake, combined RRs (95% confidence intervals) comparing top with bottom categories were 0.76 (0.68 0.85) in case-control studies, and 0.71 (0.63-0.78) in cohort studies (P for difference by study design=0.02). The inverse associations were observed for both men and women and for each specific type alcoholic beverage (beer, wine, and liquor). Also, we found that one drink per day of alcoholic beverage conferred the reduction in renal cell cancer risk, but further drinking above that level did not add benefit. CONCLUSION: The findings from our meta-analysis support the hypothesis that alcoholic beverage intake is inversely associated with a lower risk of renal cell cancer, with moderate consumption conferring the protection and higher consumption conferring no additional benefits. PMID- 22516952 TI - Signaling pathways mediating chemokine induction in keratinocytes by cathelicidin LL-37 and flagellin. AB - Cathelicidin LL-37 is a multifunctional immunomodulatory and antimicrobial host defense peptide that has an important role in the immune defenses of the skin and other epithelial barriers. We have previously demonstrated that at physiological concentrations LL-37 synergistically augments the production of immune mediators in response to microbial compounds in human primary keratinocytes. Here we define the signaling mechanisms responsible for this activity. We demonstrate that inhibition of Src family kinases (SFKs) strongly inhibited the synergistic chemokine production in response to LL-37 and flagellin in keratinocytes. SFK activation was induced by LL-37 stimulation and was required for the downstream activation of Akt (protein kinase B) and the transcription factors CREB and ATF1. In cells stimulated with LL-37 and flagellin together, Akt activation was primarily induced by LL-37, while both flagellin and LL-37 contributed to the activation of CREB and ATF1 and consequently chemokine induction. The purinergic receptor P2X7 was identified as the receptor upstream of SFK activation in LL-37 stimulated keratinocytes. Overall, these findings established the P2X7-SFK-Akt CREB/ATF1 signaling pathway activated by LL-37 in primary keratinocytes. These signaling mechanisms mediated the synergistic effects of LL-37 on chemokine production in flagellin-stimulated keratinocytes, and thus might have a role in the immune defenses of the skin and possibly other epithelial barriers. PMID- 22516954 TI - Epibulbar osseous choristoma in 8 patients. AB - PURPOSE: To describe the clinical features and histopathology of epibulbar osseous choristoma in a series of patients. METHODS: Noncomparative case series with chart review of 8 patients. RESULTS: At presentation, the mean age of the patients was 19 years (median, 19 years; range, 0.8-38 years), with 6 women and 2 men (6 Caucasian, 1 Hispanic, and 1 African American). There were no related systemic syndromes, and visual acuity was unaffected in all cases. The choristoma was superotemporal (n = 8, 100%), with epicenter located in the fornix (n = 8, 100%), deep to Tenon fascia (n = 8, 100%), and of yellow (n = 2, 25%), white (n = 2, 25%), or pink (n = 4, 50%) color. The mean basal dimension was 9 mm (median, 10 mm; range, 3.5-14 mm), and mean thickness was 4 mm (median, 4 mm; range, 2-5 mm). Four cases were managed with observation and 4 with surgical excision, revealing tumor base adherent to the episclera (n = 2, 50%) or loose within Tenon fascia (n = 2, 50%). There were no cases to demonstrate intrascleral involvement, growth, or recurrence. CONCLUSIONS: Epibulbar osseous choristoma is a congenital lesion of mature bone located superotemporally in the fornix at the level of Tenon fascia or episclera in young patients. PMID- 22516953 TI - High-amylose resistant starch increases hormones and improves structure and function of the gastrointestinal tract: a microarray study. AB - BACKGROUND/AIMS: Type 2 resistant starch from high-amylose maize (HAM-RS2) is associated with increased fermentation, increased expression of proglucagon (gene for GLP-1) and peptide YY (PYY) genes in the large intestine, and improved health. To determine what other genes are up- or downregulated with feeding of HAM-RS2, a microarray was performed. METHODS: Adult, male Sprague Dawley rats were fed one of the following three diets for a 4-week study period: cornstarch control (CC, 3.74 kcal/g), dietary energy density control (EC, 3.27 kcal/g), and 30% HAM-RS2 (RS, 3.27 kcal/g). Rat microarray with ~27,000 genes and validation of 94 representative genes with multiple qPCR were used to determine gene expression in total RNA extracts of cecal cells from rats. The RS versus EC comparison tested effects of fermentation as energy density of the diet was controlled. RESULTS: For the RS versus EC comparison, 86% of the genes were validated from the microarray and the expression indicates promotion of cell growth, proliferation, differentiation, and apoptosis. Gut hormones GLP-1 and PYY were increased. CONCLUSIONS: Gene expression results predict improved structure and function of the GI tract. Production of gut hormones may promote healthy functions beyond the GI tract. PMID- 22516955 TI - Polyinosinic-polycytidylic acid limits tumor outgrowth in a mouse model of metastatic lung cancer. AB - Polyinosinic-polycytidylic acid (poly I:C), a TLR3 ligand, is currently being tested in human clinical trials as an adjuvant to anti-cancer vaccines and in combination with other therapies. However, little is known about its activity in established pulmonary metastasis. The aim of our study was to elucidate the effect of poly I:C (1, 10, or 100 MUg/mouse) in a mouse model of B16-F10-induced metastatic lung cancer. Lung tumor growth was arrested after a single administration of poly I:C. This was associated with higher influx of mature dendritic cells (DCs), which drove toward a Th1-like, Th17-like, and cytotoxic immune environment. The interference with IFN type I receptor signaling by means of a specific mAb reversed poly I:C-mediated tumor regression due to lower presence of myeloid DCs, cytotoxic DCs (CD11c(+)CD8(+)), NKT cells, CD8(+) T cells, and Th1-like cytokines. Moreover, the adoptive transfer of poly I:C activated bone marrow-derived DCs into tumor-bearing mice resulted in activities similar to those of the systemic administration of poly I:C on lung tumor burden. In conclusion, our data prove that poly I:C has potential anti-tumor activity in a mouse model of established pulmonary metastasis. The activation of DCs and the production of IFN type I are responsible for an effective T cytotoxic immune response against metastatic lung cancer progression after poly I:C treatment. PMID- 22516956 TI - Preferential expansion of human virus-specific multifunctional central memory T cells by partial targeting of the IL-2 receptor signaling pathway: the key role of CD4+ T cells. AB - Effector memory T cells are effective in controlling acute infections, but central memory T cells play a key role in long-lasting protection against viruses and tumors. In vivo/in vitro challenge by Ag commonly supports the generation of effector memory T cells with limited longevity. To our knowledge, this study demonstrates for the first time in the human system and under rechallenge conditions that targeting IL-2R by partial mammalian target of rapamycin inhibition or blocking IL-2Ralpha enriches human CD4(+)/CD8(+) central memory T cells within the virus-specific T cell product associated with enhanced functionality (i.e., multicytokine secretors, including IL-2; enhanced CD137 and CD107a expression on CD8(+) and CD4(+) T cells, respectively; and killing infected target cells). Remarkably, the effects on CD8(+) T cells are mainly mediated via the enhancement of CD4(+) T cell function. The data reveal new insights into the role of CD4(+) T cell support for the quality of CD8(+) T cell memory, even under rechallenge conditions. Moreover, our method offers a new approach to improve the long-lasting efficacy of adoptive T cell therapy in patients. PMID- 22516957 TI - FcgammaRIIb and BAFF differentially regulate peritoneal B1 cell survival. AB - B1 cells produce most natural Abs in unimmunized mice and play a key role in the response to thymus-independent Ags and microbial infection. Enlargement of B1 cell number in mice is often associated with autoimmunity. However, the factors that control peripheral B1 cell survival remain poorly characterized. Mice lacking the inhibitory receptor FcgammaRIIb exhibit a massive expansion in peritoneal B1 cells, implicating this receptor in B1 cell homeostasis. In this study, we show that peritoneal B1 cells express the highest levels of FcgammaRIIb among B cell subsets and are highly susceptible to FcgammaRIIb-mediated apoptosis. B1 cells upregulate FcgammaRIIb in response to innate signals, including CpG, and the B cell homeostatic cytokine BAFF efficiently protects activated B1 cells from FcgammaRIIb-mediated apoptosis via receptor downregulation. BAFF-transgenic mice manifest an expansion of peritoneal B1 cells that express lower levels of FcgammaRIIb and exhibit reduced susceptibility to apoptosis. Whereas both peritoneal B1 cells from wild-type and BAFF-transgenic mice immunized with CpG exhibit an increase in FcgammaRIIb levels, this change is blunted in BAFF-transgenic animals. Our combined results demonstrate that FcgammaRIIb controls peritoneal B1 cell survival and this program can be modulated by the BAFF signaling axis. PMID- 22516960 TI - Validity of the night eating questionnaire in children. AB - OBJECTIVE: To measure the construct validity of the Night Eating Questionnaire (NEQ) in children against a parent report of child night eating syndrome (NES) symptoms (NEQ report) and a 3-day dietary recall. METHOD: NEQ of 304 children from the QUALITY (QUebec Adipose and Lifestyle InvesTigation in Youth) cohort were compared to a parent report and 3-day dietary recall. RESULTS: Child NEQ scores were related to the parent NEQ report (rho = 0.30 p < 0.0001) yet there were inconsistencies between responses concerning sleep troubles. Total child NEQ scores, but not parent NEQ report scores, were associated with dietary manifestations of NES such as increased evening (rho = 0.20, p < .001) and reduced morning intake (rho= -0.12, p < .05). DISCUSSION: The NEQ score is related to eating patterns of NES in children and is more informative than a parent report, specifically when used in conjunction with dietary recall. PMID- 22516958 TI - Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cells. AB - Nanoparticles containing DNA complexed with the cationic polymer polyethylenimine are efficient vehicles to transduce DNA into cells and organisms. DNA/polyethylenimine nanoparticles (DNPs) also elicit rapid and systemic release of proinflammatory cytokines that promote antitumor immunity. In this study, we report that DNPs possess previously unrecognized immunomodulatory attributes due to rapid upregulation of IDO enzyme activity in lymphoid tissues of mice. IDO induction in response to DNP treatment caused dendritic cells and regulatory T cells (Tregs) to acquire potent regulatory phenotypes. As expected, DNP treatment stimulated rapid increase in serum levels of IFN type I (IFN-alphabeta) and II (IFN-gamma), which are both potent IDO inducers. IDO-mediated Treg activation was dependent on IFN type I receptor signaling, whereas IFN-gamma receptor signaling was not essential for this response. Moreover, systemic IFN-gamma release was caused by TLR9-dependent activation of NK cells, whereas TLR9 signaling was not required for IFN-alphabeta release. Accordingly, DNPs lacking immunostimulatory TLR9 ligands in DNA stimulated IFN-alphabeta production, induced IDO, and promoted regulatory outcomes, but did not stimulate potentially toxic, systemic release of IFN-gamma. DNP treatment to induce IDO and activate Tregs blocked Ag specific T cell responses elicited in vivo following immunization and suppressed joint pathology in a model of immune-mediated arthritis. Thus, DNPs lacking TLR9 ligands may be safe and effective reagents to protect healthy tissues from immune mediated destruction in clinical hyperimmune syndromes. PMID- 22516961 TI - Targeted functionalisation of a hierarchically-structured porous coordination polymer crystal enhances its entire function. AB - Spatiospecific functionalisation of a shell crystal was performed in a core-shell crystal of a porous coordination polymer (PCP) via post-synthetic modification (PSM). The shell crystal allowed the core crystal to selectively accumulate N,N dimethylaniline (DMA) and afford the intense exciplex fluorescence. PMID- 22516962 TI - Evo-devo of the germline and somatic gonad in nematodes. AB - Due to recent progress in the development of genetic tools, nematodes have become excellent models to address the mechanistic basis of evolution of development. The gonad is one of the most variable structures in nematodes, reflecting the diverse modes of reproduction and lifestyle in this phylum. During larval development, the gonad primordium has a key role in organizing the neighboring tissues. Therefore, changes in the development of the gonad do not only influence the evolution of its morphology but also the overall body plan of the nematode. Here, we review recent progress on the evolution of development of the germline and somatic gonad in nematodes. PMID- 22516959 TI - TLR9 and MyD88 are crucial for the development of protective immunity to malaria. AB - Effective resolution of malaria infection by avoiding pathogenesis requires regulated pro- to anti-inflammatory responses and the development of protective immunity. TLRs are known to be critical for initiating innate immune responses, but their roles in the regulation of immune responses and development of protective immunity to malaria remain poorly understood. In this study, using wild-type, TLR2(-/-), TLR4(-/-), TLR9(-/-), and MyD88(-/-) mice infected with Plasmodium yoelii, we show that TLR9 and MyD88 regulate pro/anti-inflammatory cytokines, Th1/Th2 development, and cellular and humoral responses. Dendritic cells from TLR9(-/-) and MyD88(-/-) mice produced significantly lower levels of proinflammatory cytokines and higher levels of anti-inflammatory cytokines than dendritic cells from wild-type mice. NK and CD8(+) T cells from TLR9(-/-) and MyD88(-/-) mice showed markedly impaired cytotoxic activity. Furthermore, mice deficient in TLR9 and MyD88 showed higher Th2-type and lower Th1-type IgGs. Consequently, TLR9(-/-) and MyD88(-/-) mice exhibited compromised ability to control parasitemia and were susceptible to death. Our data also show that TLR9 and MyD88 distinctively regulate immune responses to malaria infection. TLR9(-/-) but not MyD88(-/-) mice produced significant levels of both pro- and anti inflammatory cytokines, including IL-1beta and IL-18, by other TLRs/inflammasome- and/or IL-1R/IL-18R-mediated signaling. Thus, whereas MyD88(-/-) mice completely lacked cell-mediated immunity, TLR9(-/-) mice showed low levels of cell-mediated immunity and were slightly more resistant to malaria infection than MyD88(-/-) mice. Overall, our findings demonstrate that TLR9 and MyD88 play central roles in the immune regulation and development of protective immunity to malaria, and have implications in understanding immune responses to other pathogens. PMID- 22516963 TI - Silicon carbide-enhanced microwave ablation in an ex-vivo bovine liver model - effects on heat distribution and ablation volume. AB - PURPOSE: Evaluation of the maximum temperatures and ablation volumes in microwave ablation (MWA) after injection of different concentrations of silicon carbide (SiC) particles in an ex-vivo bovine liver model. MATERIALS AND METHODS: 15 ml of different concentrations of SiC particles (20 vol% SiC; 50 vol% SiC) mixed with 2 % gelatin were injected into an ex-vivo bovine liver. As a reference group, 2 % gelatin without SiC was injected. MWA was performed using a clinical MWA system with different generator settings (10 - 45 W/10 minutes). The temperature was measured at a distance of 5 mm and 10 mm from the applicator. Afterwards the liver tissue was sliced along the short and long axis, the ablation zones were measured on the x, y and z-axis and the ablation volume was calculated. All experiments were performed 5 times (total: 40 experiments). RESULTS: The average maximum temperatures measured at a generator setting of 45 W at a distance of 5 mm from the applicator were 103.4 +/- 4.6 degrees C (20 vol% SiC), 103.3 +/- 6.5 degrees C (50 vol% SiC) and 96.0 +/- 4.2 degrees C in the control group (0 vol% SiC). At 45 W, injection of 20 vol% SIC caused a significantly higher maximum temperature than that achieved in the control group (p = 0.016). No significant temperature increase compared to the control group could be measured using 50 vol% SiC. The mean ablation volumes at 45 W and 20 vol% SiC and 50 vol% SiC were significantly larger (172.7 +/- 31.5 ml and 171.0 +/- 34.7 ml, respectively) than those achieved in the control group (111.2 +/- 23.8 ml) (p = 0.027 and p = 0.045). CONCLUSION: In an ex-vivo bovine liver model, the SiC particles demonstrated an enhancing effect of MWA with respect to maximum temperatures and ablation volume. Therefore, SiC is a promising candidate for enhancing MWA in vivo. PMID- 22516964 TI - [Endovascular recanalization of a persistent sciatic artery]. PMID- 22516965 TI - Relative survival of patients with uveal melanoma managed in a single center. AB - To assess the 5-year relative survival of patients diagnosed with uveal melanoma (UM) in a single center. UM patients were recruited from 1995 to 2004 (N = 155) and were followed until December 2008. Relative survival (RS) methods were used to assess excess mortality. An RS regression model was fitted by sex, age, tumor origin, treatment, and tumor size to estimate the excess hazard rate (EHR) of death from UM. The overall 5-year RS was 90%, lower in women (84.6%) than in men (100%), lower in patients older than 60 years (88.8%) compared with those younger than or of 60 years of age (94.8%). Large tumors (80.8%) showed lower RS than medium (95.1%) and small ones (98.3%). Enucleated patients (80.5%) had lower RS compared with those who received brachytherapy (93.6%) and other treatments (94.7%). A significant EHR was found for women (EHR: 3.65), patients older than 60 years (EHR: 2.25), large-sized melanoma (EHR: 2.45), and during the third (EHR: 5.37) and fourth year (EHR: 3.01) of follow-up. This is the first Spanish study in a single center reporting RS among UM patients, taking into account clinical characteristics. Prognostic factors that explained RS among UM patients were sex, age, tumor size, and the year of follow-up. We also found a peak of excess mortality from the third until the fourth year after diagnosis, which warrants strict follow-up of these patients during this time interval. PMID- 22516966 TI - Evidence for upregulation of Bim and the splicing factor SRp55 in melanoma cells from patients treated with selective BRAF inhibitors. AB - Relatively little attention has been paid to the activity of selective BRAF inhibitors in the induction of apoptosis in melanoma, particularly in vivo. In the present study, we have isolated cultures from biopsies taken from four patients before and during the treatment of their melanoma. We report that the cell lines taken during treatment show varying degrees of upregulation of the proapoptotic BH3 protein Bim and its splice forms, downregulation of Mcl-1, and upregulation of the splicing factor SRp55 as reported in previous in-vitro studies. There was also evidence of ongoing apoptotic signaling despite the continued growth of the cultures. The cultures established during the treatment were largely resistant to the selective BRAF inhibitor PLX4720, consistent with the acquired resistance of melanoma in the treated patients. These results provide further insights into the mechanism of action of these agents against melanoma. PMID- 22516967 TI - Characterization of nonacral melanoma patients without typical risk factors. AB - A divergent pathway model to cutaneous melanoma is commonly accepted: sun sensitivity/chronic sun exposure and melanocytic instability. Although this dual model explains the development of most melanomas, clinical experience suggests other possible routes. The aim of this study was to explore the characteristics of patients who do not fit with these two pathways. We selected 818 patients with nonacral cutaneous melanoma and defined three groups: nevus-prone individuals, sun-sensitive individuals, and non-nevus-prone and non-sun-sensitive individuals. This group included patients without identifiable melanoma risk factors and comprised 52 patients (5.5% of the overall nonacral melanoma population). These patients were more frequently women, were more likely to present melanoma at a very young age (13.5% before 25 years), to have less frequent personal history of melanoma and remnants of pre-existing nevi, and to present tumors on the trunk and legs. We have identified a group of patients with fewer risk factors for melanoma that needs further studies to increase our understanding of melanoma development. PMID- 22516968 TI - Ipilimumab in advanced melanoma: reports of long-lasting responses. AB - Patients with metastatic melanoma have a poor prognosis; the results of chemotherapy remain unsatisfactory. Ipilimumab, an anticytotoxic T lymphocyte associated antigen-4 antibody, has shown promising results in several clinical trials. In this report, advanced melanoma patients receiving ipilimumab were scored according to novel immune-related response criteria (irRC) in an attempt to capture additional response patterns and to avoid premature treatment cessation. Thirty-six heavily pretreated metastatic melanoma patients recieved ipilimumab within five international clinical trials at our Institution from May 2006 to August 2008. Disease progression was defined as an increase in tumor burden by at least 25% compared with the nadir, irrespective of any initial increase in baseline lesions or the appearance of new lesions. We report unusually long-lasting responses in patients treated with ipilimumab 10 mg/kg. An overall response was observed in six out of 30 patients (20%), a complete response in three (10%), and disease control in 11 (37%), which seemed to be of a long duration (median of 16 months; complete response 36+, 34+, and 41+ months). All irRC patterns seemed to be strongly associated with an improvement in overall survival. Interestingly, we found a correlation between the presence of a grade 3/4 immune-related adverse event and responses, time to progression, and overall survival. Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, supporting the need for further irRC validation. PMID- 22516969 TI - The dosimetric impact of leaf interdigitation and leaf width on VMAT treatment planning in Pinnacle: comparing Pareto fronts. AB - To evaluate in an objective way the effect of leaf interdigitation and leaf width on volumetric modulated arc therapy plans in Pinnacle. Three multileaf collimators (MLCs) were modeled: two 10 mm leaf width MLCs, with and without interdigitating leafs, and a 5 mm leaf width MLC with interdigitating leafs. Three rectum patients and three prostate patients were used for the planning study. In order to compare treatment techniques in an objective way, a Pareto front comparison was carried out. 200 plans were generated in an automated way, per patient per MLC model, resulting in a total of 3600 plans. From these plans, Pareto-optimal plans were selected which were evaluated for various dosimetric variables. The capability of leaf interdigitation showed little dosimetric impact on the treatment plans, when comparing the 10 mm leaf width MLC with and without leaf interdigitation. When comparing the 10 mm leaf width MLC with the 5 mm leaf width MLC, both with interdigitating leafs, improvement in plan quality was observed. For both patient groups, the integral dose was reduced by 0.6 J for the thin MLC. For the prostate patients, the mean dose to the anal sphincter was reduced by 1.8 Gy and the conformity of the V(95%) was reduced by 0.02 using the thin MLC. The V(65%) of the rectum was reduced by 0.1% and the dose homogeneity with 1.5%. For rectum patients, the mean dose to the bowel was reduced by 1.4 Gy and the mean dose to the bladder with 0.8 Gy for the thin MLC. The conformity of the V(95%) was equivalent for the 10 and 5 mm leaf width MLCs for the rectum patients. We have objectively compared three types of MLCs in a planning study for prostate and rectum patients by analyzing Pareto-optimal plans which were generated in an automated way. Interdigitation of MLC leafs does not generate better plans using the SmartArc algorithm in Pinnacle. Changing the MLC leaf width from 10 to 5 mm generates better treatment plans although the clinical relevance remains to be proven. PMID- 22516970 TI - Reconstitution of an Argonaute-dependent small RNA biogenesis pathway reveals a handover mechanism involving the RNA exosome and the exonuclease QIP. AB - Argonaute proteins are required for the biogenesis of some small RNAs (sRNAs), including the PIWI-interacting RNAs and some microRNAs. How Argonautes mediate maturation of sRNAs independent of their slicer activity is not clear. The maturation of the Neurospora microRNA-like sRNA, milR-1, requires the Argonaute protein QDE-2, Dicer, and QIP. Here, we reconstitute this Argonaute-dependent sRNA biogenesis pathway in vitro and discover that the RNA exosome is also required for milR-1 production. Our results demonstrate that QDE-2 mediates milR 1 maturation by recruiting exosome and QIP and by determining the size of milR-1. The exonuclease QIP first separates the QDE-2-bound pre-milR-1 duplex and then mediates 3' to 5' trimming and maturation of pre-milRNA together with exosome using a handover mechanism. In addition, exosome is also important for the decay of sRNAs. Together, our results establish a biochemical mechanism of an Argonaute dependent sRNA biogenesis pathway and critical roles of exosome in sRNA processing. PMID- 22516971 TI - Roles of Mis18alpha in epigenetic regulation of centromeric chromatin and CENP-A loading. AB - The Mis18 complex has been identified as a critical factor for the centromeric localization of a histone H3 variant, centromeric protein A (CENP-A), which is responsible for the specification of centromere identity in the chromosome. However, the functional role of Mis18 complex is largely unknown. Here, we generated Mis18alpha conditional knockout mice and found that Mis18alpha deficiency resulted in lethality at early embryonic stage with severe defects in chromosome segregation caused by mislocalization of CENP-A. Further, we demonstrate Mis18alpha's crucial role for epigenetic regulation of centromeric chromatin by reinforcing centromeric localization of DNMT3A/3B. Mis18alpha interacts with DNMT3A/3B, and this interaction is critical for maintaining DNA methylation and hence regulating epigenetic states of centromeric chromatin. Mis18alpha deficiency led to reduced DNA methylation, altered histone modifications, and uncontrolled noncoding transcripts in centromere region by decreased DNMT3A/3B enrichment. Together, our findings uncover the functional mechanism of Mis18alpha and its pivotal role in mammalian cell cycle. PMID- 22516972 TI - Versatile synthetic strategies for PBCA-based hybrid fluorescent microbubbles and their potential theranostic applications to cell labelling and imaging. AB - This research reports the versatile synthetic strategies for hybrid PBCA microbubbles as contrast agents and drug carriers loaded with fluorescent dyes and magnetic nanoparticles serving in vitro cell labelling and in vivo target imaging. These multifunctional probes therefore prove their potential biomedical applications in cancer diagnostics and treatment. PMID- 22516973 TI - Chromium fractionation and speciation in natural waters. AB - It is common for leather industries to dump chromium-contaminated effluent into rivers and other bodies of water. Thus, it is crucial to know the impacts caused by this practice to the environment. A study on chromium partitioning and speciation, with determination at trace levels, was carried out in a potentially contaminated creek. Chromium fractionation and speciation was performed using a flow-injection preconcentration system and detection by flame atomic absorption spectrometry. High levels of this element were found in the particulate material (449-9320 mg kg(-1)), which indicates its compatibility with this fraction. The concentration of Cr(iii) in the water samples collected ranged from 5.2-105.2 MUg L(-1). Cr(vi) was always below of the DL (0.3 MUg L(-1)). Chromium accumulation observed in the sediment (873-1691 mg kg(-1)) may confirm contamination due to the long term release of contaminated effluents in the creek. PMID- 22516975 TI - Integrating spiritual care into the practice of oncology. PMID- 22516974 TI - Successful treatment of two patients with postpartum disseminated intravascular coagulation complicated by abdominal compartment syndrome. AB - Disseminated intravascular coagulation (DIC) and abdominal compartment syndrome (ACS) are rare complications of pregnancy, and even more rare are cases with both complications occurring concomitantly. Obstetricians are relatively unfamiliar with these types of cases, the majority of which are fatal. We describe here a primigravida with acute fatty liver of pregnancy and a multipara with placental abruption who each developed uterine inertia complicated by postpartum DIC that required total hysterectomy. They developed ACS postoperatively and required decompressive laparotomy to alleviate increased intra-abdominal pressure and end organ dysfunction. After timely decompressive laparotomy, both patients recovered without any additional complications and were discharged within 4 weeks of their initial admission. These 2 cases serve to remind obstetricians to consider the possibility of ACS whenever there is a fresh wound in the abdominal cavity of a patient with postpartum DIC. However, even when there is severe deterioration in the condition of a patient with ACS, immediate decompressive laparotomy may not be appropriate; the timing of the procedure is very important. PMID- 22516977 TI - The physics of protein-DNA interaction networks in the control of gene expression. AB - Protein-DNA interaction networks play a central role in many fundamental cellular processes. In gene regulation, physical interactions and reactions among the molecular components together with the physical properties of DNA control how genes are turned on and off. A key player in all these processes is the inherent flexibility of DNA, which provides an avenue for long-range interactions between distal DNA elements through DNA looping. Such versatility enables multiple interactions and results in additional complexity that is remarkably difficult to address with traditional approaches. This topical review considers recent advances in statistical physics methods to study the assembly of protein-DNA complexes with loops, their effects in the control of gene expression, and their explicit application to the prototypical lac operon genetic system of the E. coli bacterium. In the last decade, it has been shown that the underlying physical properties of DNA looping can actively control transcriptional noise, cell-to cell variability, and other properties of gene regulation, including the balance between robustness and sensitivity of the induction process. These physical properties are largely dependent on the free energy of DNA looping, which accounts for DNA bending and twisting effects. These new physical methods have also been used in reverse to uncover the actual in vivo free energy of looping double-stranded DNA in living cells, which was not possible with existing experimental techniques. The results obtained for DNA looping by the lac repressor inside the E. coli bacterium showed a more malleable DNA than expected as a result of the interplay of the simultaneous presence of two distinct conformations of looped DNA. PMID- 22516976 TI - Exercise therapy in the management of dyspnea in patients with cancer. AB - PURPOSE OF REVIEW: Dyspnea is a frequent, debilitating, and understudied symptom in cancer associated with poor prognosis and reduced health-related quality of life. The purpose of this study is to review the incidence, pathophysiology, and mechanisms of dyspnea in patients diagnosed with cancer. We also discuss the existing evidence supporting the efficacy of exercise therapy to complement traditional approaches to reduce the impact of this devastating symptom in persons with cancer. RECENT FINDINGS: In other clinical populations presenting with dyspnea, such as chronic obstructive pulmonary disease, exercise therapy is demonstrated to be an efficacious strategy. In contrast, relatively few studies to date have investigated the efficacy of exercise training as a therapeutic strategy to mitigate dyspnea in patients with cancer. SUMMARY: Although much more work is required, exercise therapy is a promising adjunct strategy to systematically reduce dyspnea in the oncology setting that may also provide additive efficacy when prescribed in combination with other adjunct therapies including pharmacologic interventions. PMID- 22516978 TI - Influence of family structure on dental caries experience of preschool children in Sri Lanka. AB - BACKGROUND: The prevalence of dental caries in preschool children has not been declining in the recent past. A growing body of research suggests that social and behavioural factors may play a considerable role in the aetiology of dental caries. AIMS: The objective of this study was to determine the relationship between the family structure and dental caries experience in preschool children. METHODS: A descriptive cross-sectional study was carried out in children aged 3-5 years in Wattala Divisional Secretariat area in Colombo district of Sri Lanka. An interviewer-administered questionnaire was used to obtain information from the parents on family structure including the size, birth rank, age spacing between the next oldest and youngest sibling and age of parent at birth of the subject. The dental caries status of the children was assessed using WHO standard criteria for primary teeth. RESULTS: Family size, birth rank, age difference between the subject and next oldest sibling and parent's age at birth of the subject were significantly associated with the dental caries experience of the preschool children at bivariate level. In a stepwise multiple linear regression analysis family size, birth rank and the parent's age at birth of the child remained statistically significant. CONCLUSION: The present findings suggest that family structure might significantly affect the caries experience of preschool children. PMID- 22516980 TI - [Mid-term outcome after implantation of a pyrocarbon endoprosthesis in patients with degenerative arthritis]. AB - AIM: The aim of this study was to make a mid-term evaluation of an unconstrained pyrocarbon prosthesis (Ascension(r)) in the treatment of idiopathic degenerative arthritis of the proximal interphalangeal joint of the hand. METHOD: 13 implants (10 patients) were clinically and radiologically studied after a follow-up period of 71 months (range: 48-92 months). RESULTS: The average ROM was 52 degrees (+/- 27 degrees STD). A luxation of the components did not occur and all implants are still in-situ. However, X-ray examination was unremarkable in only six fingers. In seven patients significant radiolucent lines (>= 1 mm) were detected. Three prosthesis demonstrated axial subsidence and in one patient a loosening of the proximal component with axial rotation was observed. CONCLUSION: The results of this study show a high complication rate after an average of 6 years after implantation. Radiolucent lines in half of the cases may be explained by a lack of osteointegration of the prosthesis. The average ROM differs significantly from patient to patient, which has to be taken into account when discussing different treatment options. PMID- 22516981 TI - When do short children realize they are short? Prepubertal short children's perception of height during 24 months of catch-up growth hormone treatment. AB - AIM: To examine perceived height during the first 24 months of growth hormone (GH) treatment in short prepubertal children. METHODS: Ninety-nine 3- to 11-year old short prepubertal children with either isolated GH deficiency (n = 32) or idiopathic short stature (n = 67) participated in a 24-month randomized trial of individualized or fixed-dose GH treatment. Children's and parents' responses to three perceived height measures: relative height (Silhouette Apperception Test), sense of height (VAS short/tall), and judgment of appropriate height (yes/no) were compared to measured height. RESULTS: Children and parents overestimated height at start (72%, 54%) and at 24 months (52%, 30%). Short children described themselves as tall until 8.2 years (girls) and 9 years (boys). Prior to treatment, 38% of children described their height as appropriate and at 3 months, 63%. Mother's height, parental sense of the child's tallness and age explained more variance in children's sense of tallness (34%) than measured height (0%). CONCLUSION: Short children and parents overestimate height; a pivotal age exists for comparative height judgments. Even a small gain in height may be enough for the child to feel an appropriate age-related height has been reached and to no longer feel short. PMID- 22516979 TI - Building the evidence base for decision making in cancer genomic medicine using comparative effectiveness research. AB - The clinical utility is uncertain for many cancer genomic applications. Comparative effectiveness research (CER) can provide evidence to clarify this uncertainty. The aim of this study was to identify approaches to help stakeholders make evidence-based decisions and to describe potential challenges and opportunities in using CER to produce evidence-based guidance. We identified general CER approaches for genomic applications through literature review, the authors' experiences, and lessons learned from a recent, seven-site CER initiative in cancer genomic medicine. Case studies illustrate the use of CER approaches. Evidence generation and synthesis approaches used in CER include comparative observational and randomized trials, patient-reported outcomes, decision modeling, and economic analysis. Significant challenges to conducting CER in cancer genomics include the rapid pace of innovation, lack of regulation, and variable definitions and evidence thresholds for clinical and personal utility. Opportunities to capitalize on CER methods in cancer genomics include improvements in the conduct of evidence synthesis, stakeholder engagement, increasing the number of comparative studies, and developing approaches to inform clinical guidelines and research prioritization. CER offers a variety of methodological approaches that can address stakeholders' needs and help ensure an effective translation of genomic discoveries. PMID- 22516982 TI - Bicyclic guanidine-catalyzed asymmetric Michael additions of 3-benzyl-substituted oxindoles to N-maleimides. AB - A bicyclic guanidine-catalyzed Michael addition of 3-benzyl substituted oxindoles to N-maleimides has been developed to produce oxindole derivatives with a quaternary carbon chiral center at the 3-position in excellent yields and enantio and diastereoselectivities. This is the first incorporation of N-benzylic alpha branched succinimides into 3,3-disubstituted oxindoles. PMID- 22516983 TI - [A multicenter study of coronary artery disease and its risk factors in rheumatoid arthritis in China]. AB - OBJECTIVE: To learn about the prevalence and risk factors of coronary artery disease (CAD) in rheumatoid arthritis (RA). METHODS: Data were obtained from a 12 month retrospective investigation of the patients with RA, randomly selected from Departments of Rheumatology and Immunology in 21 big hospitals in China. The data were collected about their social conditions, clinical conditions, medications associated with RA, such as disease modifying anti-rheumatic drugs (DMARDs), non steroidal anti-inflammatory drugs (NSAIDs), glucocorticoid, biologic agents. A nonparameter test and multivariate logistic regression analysis were performed. RESULTS: In the study, 960 patients were enrolled. The prevalence of CAD was 3.5% in China, which was obviously higher than that of normal people. The prevalence of overweight and obesity, smoking, hypertension, diabetes mellitus, hypercholesterolemia and cerebrovascular disease were 35.1%, 12.3%, 17.0%, 7.7%, 0.4% and 3.0%, respectively. Compared with the control group, the CAD group had higher age [(64.7+/-9.3) years vs. (52.3+/-14.0) years,P<0.001], more rheumatoid nodules (14.7% vs. 3.1%,P=0.005), lower rate of hydroxychloroquine (HCQ) use (5.9% vs. 22.6%,P=0.021), higher prevalence rates of lung interstitial disease (17.5% vs. 7.0%,P<0.001), diabetes mellitus and hypertension (29.4% vs. 7.0%,P<0.001; 38.2% vs. 16.2%,P=0.001). There was no obvious correlation of CAD in RA with joint deformity, rheumatoid factor (RF) titer, glucocorticoid use, hypercholesterolemia and body mass index (BMI). Multivariate analysis showed higher age, diabetes mellitus and hypertension were independent predictors of CAD, and the use of HCQ was a protective factor of CAD. CONCLUSION: The prevalence of CAD is 3.5%. Higher age, diabetes mellitus and hypertension are independent predictors of CAD, and the use of HCQ is a protective factor of CAD. PMID- 22516985 TI - [Sulphasalazine in patients with rheumatoid arthritis in China: a cross-sectional study]. AB - OBJECTIVE: To investigate the medication status of rheumatoid arthritis (RA) patients and to analyze the clinical use of sulphasalazine (SSZ) and the adverse effect. METHODS: A total of 1 096 outpatients and inpatients diagnosed with RA were investigated in 21 hospitals all over China from July 2009 to December 2010, including gender, age of onset, clinical manifestations, as well as the clinical characteristics and medication status of 160 RA patients who received SSZ therapy. RESULTS: In the group of 160 patients who received SSZ, the male-to female ratio was 1:7, The average age at onset was (46.1+/-15.0) years, while the average course was (9.9+/-7.8) years. The average dose of sulphasalazine was (1.87+/-0.52) g/d for a mean duration of (26.3+/- 14.6) months. Only 17% (27/160) of the patients received SSZ monotherapy. Methotrexate (63.1%), leflunomide (36.2%) and hydroxychloroquine (18.1%) were most commonly used combination drugs. And 36.2% (58/160) of the patients used the two-drug combination of methotrexate plus sulphasalazine .In this group, 41.9% (67/160) once used SSZ but withdrew for adverse events and other reasons, while 17.5% (28/160) withdrew for adverse events, of which the most common were gastrointestinal (8.8%), skin (3.8%) and liver toxicity (3.1%). CONCLUSION: Sulphaszlazine is not a common choice in the RA therapeutics in China, and the average dose of SSZ is lower than the standard dose of 2 to 3 g/d . The adverse events of SSZ are common; however, there are few severe adverse events or threat to life,SSZ is relatively safe in clinical practice. PMID- 22516986 TI - [Significance of the detection of anti-v-raf murine sarcoma viral oncogene homologue B1 antibodies in the diagnostic practice of rheumatoid arthritis]. AB - OBJECTIVE: To clarify the clinical significance of the antibody against v-raf murine sarcoma viral oncogene homologue B1 (BRAF) in the diagnostic practice of rheumatoid arthritis (RA). METHODS: In the study, 112 patients with RA, 112 patients with other rheumatic diseases,and 73 healthy individuals were recruited . With recombinant human BRAF protein as antigen, we examined the level of anti BRAF antibody in all the patients by enzyme-linked immunosorbent assay(ELISA), The clinical data of the RA patients were collected simultaneously, and analysed statistically by using SPSS 13.0. RESULTS: The positive rate of anti-BRAF antibody was 53.6% in the RA patients, which was significantly higher than that of the normal control group (4.1%,P<0.01)and other rheumatic diseases groups (P all<0.01)except osteoarthritis group. The titer of anti-BRAF antibody was also notably higher in the patients with RA than in other rheumatic diseases and normal control groups(P all <0.01).The diagnostic sensitivity and specificity of anti-BRAF antibody for RA were 53.6% and 84.3% respectively. The positive rate of anti-BRAF antibody in rheumatoid factor, anti-cyclic citrullinated peptide antibody, antikeratin antibody,antiperinuclear factor negative groups were 52.6%,38.2%, 30.3% and 31.0%respectively. It showed significant negative correlation between the titer of anti-BRAF antibody and patient's age, disease duration and the level of CRP. CONCLUSION: The anti-BRAF antibody contributes to the diagnosis of RA, and may act as a supplement of other autoantibodies. PMID- 22516984 TI - [Survey of tumor necrosis factor inhibitors application in patients with rheumatoid arthritis in China]. AB - OBJECTIVE: To investigate the current status of tumor necrosis factor (TNF) inhibitors application in rheumatoid arthritis (RA) patients in China and to analyze the related factors. METHODS: A retrospective survey was conducted in 21 hospitals from different parts of China. The patients with RA were randomly enrolled. Data of their social backgrounds, clinical conditions, usage and adverse effects of TNF inhibitors were collected. The costs of TNF inhibitors and the indirect costs of the disease were calculated. A multivariate Logistic regression analysis was performed to analyze the factors related to TNF inhibitors application. RESULTS: In the study, 1 095 RA patients from July 2009 to November 2010 were enrolled, of whom 112 had received TNF inhibitors, representing 10.2% of the total patients. The patients who received etanercept and infliximab were 7.4% (86/1 095) of the patients and 2.4% (26/1 095), respectively. There were 0.5% of the patients (5/1 095) who had received both of the TNF inhibitors. The patients who had accepted etanercept and treatment duration for less than 3 months and 3-6 months accounted for 38.5% and 25.0% respectively, while those treated with Infliximab were 38.1%. Their health assessment questionnaire (HAQ) scores were 1.1, 0.5 and 0.1, corresponding to treatment duration of infliximab for less than 3, 3-6 and 6-9 months and those were 1.3, 1.0, 0.3 corresponding to treatment duration of etanercept, respectively. Infliximab costs were RMB 24 525.0, 69 300.0 and 96 800.0 Yuan and etanercept costs were RMB 7 394.8, 9 158.6, 54 910.9 Yuan, respectively. Indirect costs for RA patients who accepted infliximab for less than 3, 3-6 and 6-9 months were RMB 365.6, 0 and 158.9 Yuan and those who accepted etanercept were RMB 2 158.4, 288.5 and 180.1 Yuan, respectively. Allergy and infection were the main side-effects of etanercept and both happened in 3.5% of all the patients. Liver damage happened in 2.3% of all the patients, while allergy and infection happened in 6.5% of all the patients who accepted infliximab. Logistic regression analysis showed that patients with higher education experience increased the odds of entering the TNF inhibitors group (OR: 1.292, 95%CI: 1.132-1.473, P=0.000). CONCLUSION: About one-tenth of RA patients in China have accepted TNF inhibitors. Higher education experience is the key factor for using TNF inhibitors. PMID- 22516987 TI - [Relationship between oxidative stress and depression in patients with rheumatoid arthritis]. AB - OBJECTIVE: To investigate the relationship between oxidative stress and depression in patients with rheumatoid arthritis (RA). METHODS: In the study, 129 patients with RA were assessed using the Hamilton depression rating scale (HAMD), Zung self-rating depression scale (SDS), Zung self-rating anxiety scale (SAS), symptom checklist 90 (SCL-90), and other multiple item questionnaires. Oxidative stress-related parameters in sera and indexes of oxidative damage were monitored during a pretreatment period. The patients were divided into depression (group A, HAMD>=20) and nondepression groups (group B,HAMD<20) based on an HAMD score cutoff of 20. In addition, 20 healthy donors were classified as group C. RESULTS: A statistically significant increase in SDS score was observed in group A (59.12+/-10.18) when compared with group B (39.24+/-5.02) (t=0.42,P < 0.01). A statistically significant increase was observed in SAS score in group A (59.12+/ 10.18) in comparison with group B (39.24+/-5.02) (t=1.48,P<0.01). Antisuperoxide anion capacity was significantly decreased in group A (393.76+/-43.35) in comparison with group B (456.98+/-93.86) and group C (483.51+/-30.64) (F=3.95, P=0.03), whereas serum malondialdehyde (MDA) levels of group A (13.84+/-3.35) were higher than those of group B (9.42+/-3.52) and group C (7.86+/ 3.21)(F=12.01, P=0.01). Pearson correlation analysis revealed that depression was positively correlated with MDA (r=0.58,P<0.05), but negatively with A-ASC (r = 0.30, P<0.05). CONCLUSION: The oxidative damage occurs in patients with rheumatoid arthritis, and lower antioxidant defences exist in depressive patients. The oxidative stress may promote the development of depression. PMID- 22516988 TI - [Measurement and clinical significance of serum monocyte chemoattractant protein 1 in patients with polymyosits/dermatomyosits]. AB - OBJECTIVE: To analyze the correlated clinical significance by testing the serum monocyte chemoattractant protein-1 (MCP-1) levels of patients with polymyositis/dermatomyositis (PM/DM). METHODS: The sera from 100 adult PM/DM patients, 20 patients with pulmonary infection and 42 healthy controls were selected. The serum MCP-1 concentrations were detected by enzyme-linked immunosorbent assay (ELISA). The correlations between serum MCP-1 levels and clinical features or laboratory examinations of PM/DM patients were investigated. RESULTS: The serum levels of MCP-1 were (1 869 +/-1 590) ng/L, (1 349+/-1 303) ng/L, (493+/-255) ng/L and (256+/-144) ng/L in PM/DM patients with interstitial lung disease (ILD) and without ILD, patients with infectious lung disease and healthy controls, respectively. Serum MCP-1 levels in the PM/DM patients with ILD were significantly higher than those of the PM/DM patients without ILD, patients with infectious lung disease and healthy controls (all P values<0.01). Significant correlations were found between the elevated levels of serum MCP-1 and the presence of ILD in the patients with PM/DM (chi2=9.6, P<0.01). The sensitivity and specificity of serum abnormal MCP-1 levels for ILD in the patients with PM/DM were 60.7% and 68.2%, respectively. The incidence of fever, arthritis, decreased %DL(CO) , erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum ferritin were significantly higher in the MCP-1 raised group than in the MCP-1 normal group (all P values<0.005). Additionally, Spearman rank correlation analysis showed that serum MCP-1 levels were positively correlated with serum ferritin in peripheral blood in the patients with PM/DM. CONCLUSION: The levels of serum MCP-1 are significantly elevated in PM/DM and it is significantly associated with ILD complication, and may contribute to the early differentiation of ILD from lung infectious disease. PMID- 22516989 TI - [Diagnostic significance of autoantibodies in patients with primary biliary cirrhosis]. AB - OBJECTIVE: To investigate the significance of autoantibodies in patients with primary biliary cirrhosis (PBC). METHODS: A anti-mitochondrial antibodies-M2(AMA M2), anti-BCOADC-E2 PDC-E2 OGDC-E2 antibodies (anti-3E/BPO), anti-SP100 antibodies (anti-SP100), anti-promyelocytic leukemia (anti-PML), anti-gp210 antibodies (anti-gp210),and anti-Ro-52 were detected respectively in 330 suspected PBC cases by Western blotting. RESULTS: (1) The sensitivity/specificity rates of AMA-M2,anti-3E/BPO,anti-SP100,anti-PML,anti gp210,and anti-Ro-52 were 85.3%/84.8%, 79.4%/93.2 %, 35.3%/98.0%, 41.2%/96.3%, 44.1%/96.6%,61.8%/68.6% respectively; AMA-M2 were combined with the other antibodies. The specificity rates in the series tests were 94.9%, 99.3%, 99.3 %, 98.3%, and 92.2%, while the sensitivity rates in the parallel tests were 91.2%, 94.1%, 94.1%, 94.1%, and 1.2%,respectively .(2)There were 5 cases of AMA-M2 negative in patients with PBC,including 60% (3/5) cases of anti-gp210, anti-SP100 and anti-PML positive respectively. CONCLUSION: (1) AMA-M2 were more sensitive than other antibodies, while the specificity rates of anti-3E/BPO , anti-SP100, anti-PML, and anti-gp210 were higher than that of AMA-M2; Parallel tests helps to exclude the suspected PBC cases and series tests could be useful in clinics to confirm the PBC cases. (2) anti-gp210, anti-SP100, anti-PML antibodies appear to be more common in AMA-M2 negative PBC patients than in those who are AMA-M2 positive,and their presence in AMA-M2 negative PBC patients contributes to the PBC diagnosis. PMID- 22516990 TI - [Effects of glucocorticoids on the expression of GTIR and apoptosis of the CD4(+)CD25(+)CD127(dim/-) T cells in patients with systemic lupus erythematosus]. AB - OBJECTIVE: To investigate the expression of glucocorticoid-induced tumor necrosis factor receptor (GITR) and apoptosis of CD4(+)CD25(+)CD127(dim/-) T cells of the patients with systemic lupus erythematosus (SLE),and to analyze its clinical value. METHODS: A total of 28 patients with a diagnosis of SLE according to the American College of Rheumatology (ACR) 1997 criteria were included in the study. The SLE patients were divided into active group (SLEDAI>=10) and inactive group (SLEDAI<10) according to the SLE disease activity index (SLEDAI). Active group included 15 patients and inactive group 13 patients. Clinical and laboratory data of the patients with SLE were recorded. In this study 12 normal volunteers without history of autoimmune diseases were also included. Peripheral blood CD4(+)CD25(+)CD127(dim/-) T cells were isolated by magnetic beads sorting. We classified them into two subgroups: the blank group and the therapeutic dose group (dexamethasone dose was 5*10(-2) mg/L and the peripheral blood CD4(+)CD25(+)CD127(dim/-) T cells with dexamethasone were cultured for 48 hours). The expressions of GITR and Annexin V were analyzed by flow cytometry before and after the culture. The correlations between GITR levels, apoptosis rates of these subsets and the clinic, laboratory parameters of SLE were analyzed. RESULTS: GITR levels and apoptosis rates in the patients with SLE were significantly higher than those in the normal control group (P=0.016; P=0.049). The expression levels of GITR on Treg cells between the blank group and the therapeutic dose group were found be of no significant difference in the patients with SLE (P>0.05), but in the normal group, the expression levels of GITR in the therapeutic dose group were higher than those in the blank group (P=0.034). After adding dexamethasone, the apoptosis rates of Treg cells were decreased in the patients with SLE, the difference was statistically significant (P=0.033); But in the normal control group, the apoptosis rate of Treg cells was higher in the therapeutic dose group than in the blank group (P=0.012). The expression levels of GITR on Treg cells were significantly positively correlated with SLEDAI, but were correlated negatively with the C3. CONCLUSION: The GITR is pathologically expressed on Treg cells in SLE, which may be used as an immunological index of SLE disease activity; Glucocorticoids may regulate immune abnormalities in patients with SLE by inhibiting the apoptosis of Treg cells. PMID- 22516991 TI - [Role of anti c-mpl antibody in systemic lupus erythematosus with thrombocytopenia]. AB - OBJECTIVE: To determine whether anti-thrompoietin receptor (TPO-R, c-mpl) antibody contributes to thrombocytopenia in systemic lupus erytematosus (SLE) and explore the pathogenic role of this antibody. METHODS: Sera from 24 SLE patients with thrombocytopenia, 27 SLE patients having normal platelet counts with a history of thrombocytopenia, 18 SLE patients with neither thrombocytopenia nor post thrombocytopenia and 18 healthy controls were collected. Anti c-mpl antibodies were detected by an indirected ELISA assay. The serum TPO levels were measured by an ELISA assay. Clinical findings, autoantibody profiles, and SLEDAI were evaluated. RESULTS: Serum anti c-mpl antibodies were detected in 18.8% of the SLE patientis. The frequency of this antibody in SLE with thrombocytopenia, SLE with a history of thrombocytopenia and SLE without thrombocytopenia were of no difference (P=0.600). In the patients with anti c-mpl antibodies, their platelet counts were decreased(P=0.025) and serum TPO levels elevated(P=0.038) than those in the patients without, while there were no differences between the two groups in C3, C4, ESR, CRP level, the frequency of ANA, dsDNA, ANCA and SLEDAI. CONCLUSION: Anti c-mpl antibody contributes to SLE-associated thrombocytopenia by functionally blocking an interaction between thrombopoietin and c-mpl, which might inhibit TPO-dependent megakaryocyte proliferation and differentiation. PMID- 22516992 TI - [Analysis of the clinical features at onset of primary Sjogren's syndrome]. AB - OBJECTIVE: To comprehend clinical features at onset of primary Sjogren's syndrome (pSS) in order to provide useful data for its clinical management. METHODS: In the study, 224 patients diagnosed with pSS in the Department of Rheumatology and Immunology of Peking University People's Hospital from Jun. 1st, 2007 to Aug. 1st, 2008 were investigated, including gender, age of onset, time and site of first hospitalization and definite diagnosis, etc. RESULTS: In this 224 pSS cohort (213 females and 11 males), the male/female ratio was 1:19.4, the mean age of onset was (53.5+/-11.7) years, and median duration was 9.4 years (ranging from 0.2 to 40.0 years).The manifestations showed that up to 33% of the patients (74/224) had leukopenia, 25% (56/224) polyarthralgia, 16.5% (37/224) raynaud phenomenon, 15.6% (35/224) hepatic injury, 12.1% (27/224) pulmonary interstitial fibrosis, 11.6% (26/224) purpuras on lower extremities, 8.0% (18/224) hemogram abnormal, 5.8% (13/224) thrombopenia, and 3.6% (8/224) renal tubule acidosis. When the risk factor of the systemic involvements, was analyzed, two factors were significantly associated with pulmonary interstitial fibrosis: age (OR=1.074, 95% CI=1.031-1.118), and duration (OR=1.075, 95% CI=1.023-1.128). Liver involvement was associated with duration (OR=1.050, 95% CI=1.002-1.100). In addition, 8.0% of the pSS patients(18/224)showed family history of autoimmune diseases and 11.2%(25/224)had family history of tumor. CONCLUSION: In this cohort of the pSS patients, female is predominant and the incidence of extro glandular manifestations, such as leukopenia, lung and liver involvements is high, and pSS has inheritance intention. PMID- 22516993 TI - [Role of glucocorticoid receptor in the pathogenesis of systemic lupus erythematosus]. AB - OBJECTIVE: To investigate the expressions of GRalpha mRNA and GRbeta mRNA in the peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) patients, in order to reveal the role of GR mRNA in the pathogenesis of SLE and analyze the relationship between GR mRNA and SLEDAI score, dsDNA, cardiovascular involvement. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) technique was applied to semiquantitatively analyze GRalpha mRNA and GRbeta mRNA expressions in 104 SLE patients and 56 volunteers. RESULTS: The level of GRalpha mRNA was lower in the SLE group (the relative level was 1.24+/-0.97)than in the control group (the relative level was 2.31+/-1.42, P<0.05), and the level of GRbeta mRNA was higher in the SLE group(the relative level was 0.61+/-1.23) than in the control group(the relative level was 0.18+/-0.21, P<0.05). The level of GRalpha was lower in the active group (the relative level was 0.68+/-0.40) than in the inactive group(the relative level was 1.65+/-1.06, P<0.01), but the level of GRbeta was higher in the active group(the relative level was 0.88+/-1.56) than in the inactive group(the relative level was 0.24+/-0.23, P<0.01); GRalpha mRNA was related negatively to the SLEDAI score and dsDNA, but GRbeta mRNA was related positively to the SLEDAI score and dsDNA(P<0.01).The level of GRalpha mRNA was lower in the dsDNA positive group(the relative level was 0.89+/-0.66) than in the dsDNA negative group (the level was 1.54+/-1.10), the level of GRbeta mRNA was higher in the dsDNA positive group (the relative level was 0.95+/-1.60) than in the dsDNA negative group (the relative level was 0.22+/-0.21). The level of GRbeta mRNA and the value of GRbeta mRNA/ GRalpha mRNA was obviously higher in the SLE group with cardiac involvement (the relative level was 1.02 +/-1.76, the valve of GRbeta / GRalpha was 1.10+/-2.02)than in the SLE group without cardiac involvement (the relative level was 0.28+/-0.31, the valve of GRbeta / GRalpha was 0.32+/-0.32, P<0.05), and the level of GRalpha mRNA wasn't significant in the two groups (P>0.05). CONCLUSION: The levels of GRalpha mRNA and GRbeta mRNA maybe play an important role in the pathogenesis of SLE. And the levels of GRalpha mRNA and GRbeta mRNA are related to the activity of SLE. The level of GRbeta mRNA and the value of GRbeta mRNA/ GRalpha mRNA are related with cardiovascular involvement in SLE. PMID- 22516994 TI - [Maternal and fetal outcomes in systemic lupus erythematosus: analysis of 41 patients]. AB - OBJECTIVE: To evaluate the outcomes of pregnancies in patients with systemic lupus erythematosus (SLE). METHODS: A retrospective observation was made on 41 patients with SLE delivered in our hospital and the disease activity of the patients and neonatal conditions were followed up for one year after delivery. The impact of the disease duration, the use of cyclophosphamide, the highest systematic lupus erythematosus disease activity index (SLEDAI) score during the disease and the antepartum SLEDAI score to the outcome of delivery were analyzed. RESULTS: The disease duration of SLE was (3.5+/-3.1) years, the highest SLEDAI score during the disease was 10.6+/-3.1. The antepartum SLEDAI score was 6.2+/ 1.6, the postpartum SLEDAI score was 6.4+/-2.9. The SLEDAI score in one year after delivery was 5.4+/-2.1, which in patients with disease duration more than 4 years was higher than that in patients with disease duration less than 4 years (P=0.03). All the deliveries were live births. The gestational age at birth was (37.6+/-3.3) weeks, and the body weight was (2 510.0+/-756.9) g. These figures were significantly lower than those of the healthy women (P=0.03 and P=0.008, respectively). Four (9.8%) newborns were diagnosed as neonatal lupus. CONCLUSION: The risks of premature and low weight baby rates are increased in patients with SLE. The proper timing of pregnancy and conception will improve pregnancy outcomes. PMID- 22516995 TI - [Expression of osteopontin in labial glands of patients with primary Sjogren's syndrome]. AB - OBJECTIVE: To investigate the mRNA transcription and protein expression of osteopontin (OPN) and to analyze the possible role of OPN in primary Sjogren's syndrome (pSS). METHODS: In this study, 24 patients with pSS were selected and diagnosed according to the American-European Consensus Group criteria. The control group was composed of 14 subjects. Total RNA from labial glands was extracted. The target gene and beta-actin acted as templates to perform reverse transcript polymerase chain reaction (RT-PCR). Then mRNA expression of the target gene were semi-quantitated by the OD ratio of the target gene to beta-actin bands on gel under densitometry. Immunohistocheical analysis was used to determine the expression of proteins of the target genes in labial glands from patients and healthy control. RESULTS: In contrast to the control group, the mRNA transcription and protein level of the target genes in labial glands in pSS patients were significantly increased statistically (P<0.05). Spearman and Pearson rank correlation coefficients were used for analyzing the correlation of lymphocytes foci-score (LFS) with OPN expressions, the level of the mRNA transcription (0.407, P=0.049) and protein expression of OPN (0.476, P=0.039) was positively correlated with the LFS. Immunohistochemistry detected that OPN protein was not only mainly expressed in intracytoplasm of the gland duct, but also in infiltrated lymphocytes. CONCLUSION: OPN is higher expressed in the basal and surface of labial glands of pSS patients, which may contribute to the destruction of labial glands. PMID- 22516996 TI - [Screening for serum specific biomarkers in patients with primary Sjogren's syndrome and interstitial lung disease using proteomic fingerprint techniques]. AB - OBJECTIVE: To detect the serum protein biomarkers and establish a diagnostic model for primary Sjogren's syndrome (pSS) with interstitial lung disease (ILD). METHODS: Serum samples from 69 patients with pSS were prepared with WCX magnetic beads, and analyzed on PBS II-C mass spectrometer reader. Biomarker Wizard software was used to detect protein peaks and potential difference between the patients with pSS-ILD and with non-ILD. The model was developed by Biomarker Patterns software. RESULTS: Totally 7 discriminative mass-to-charge (m/z) ratios were identified to be related with pSS-ILD (P<0.05). Among these, the m/z peaks at 3 778.3, 3 318.3 and 2 236.6 were used to construct a diagnostic model. The sensitivity and specificity of the model were 93.1% and 87.5%, respectively. In a testing set, the sensitivity and specificity of the model were 84.0% and 85.7%, respectively. CONCLUSION: The potential protein biomarkers for pSS-ILD are discovered in the serum by MALDI-TOF-MS combined with WCX magnetic beads. The diagnostic pattern combining 3 778.3, 3 318.3 and 2 236.6 m/z protein peaks can discriminate pSS-ILD and non-ILD. PMID- 22516998 TI - [Epidemiological study on hyperuricemia and gout in Uygur population in Turpan area of Xinjiang]. AB - OBJECTIVE: To study the prevalence of hyperuricemia (HUA) and gout in Uygur inhabitants in Turfan of Xinjiang. METHODS: A random cluster sampling was conducted, and 3 982 Uygur inhabitants(1 745 males and 2 237 females) aged over 14 years were investigated for prevalence of HUA and gout in Turfan. RESULTS: (1) The mean level of serum uric acid (SUA) was (284.33+/-88.81)MUmol/L in normal Uygur males and (201.04+/-66.30)MUmol/L in normal Uygur females in Turfan. (2) The prevalence of HUA was 3.97%(158/3 982),in which 6.36% (111/1 745) was with males and 2.10%(47/2 237) with females. The prevalence of gout was 0.025% (1/3 982),one gout patient was male, and the prevalence of gout in males was 0.06% (1/1 745). CONCLUSION: The prevalence rates of HUA and gout among the Uygur population in Turfan of Xinjiang were lower than those in other districts in China. PMID- 22516997 TI - [Expression of transforming growth factor beta 1 and conection tissue growth factor in ankylosing spondylitis]. AB - OBJECTIVE: To investigate the expressions of transforming growth factor beta 1(TGF-beta1) /smad, connective tissue growth factor (CTGF), collagen I and collagen III in ankylosing spondylitis (AS). METHODS: Thirty patients with AS were included in the study. All the patients were performed with computed tomography-guided needle biopsy in sacroiiliac joint. Sera TGF-beta1 and CTGF were determined by enzyme-linked immunosorbent assay (ELISA). Immunohistologic studies were performed with the alkaline phosphatase-anti-alkaline phosphatase technique to assess the expressions of TGF-beta1, p-smad3, smad7, CTGF, collagen I and collagen III in sacroiiliac joint tissue samples. RESULTS: In the AS patients, neither serum TGF-beta1 level nor serum CTGF level was found significantly different from that of the controls [(6.7+/-2.1)mg/L vs.(5.4+/ 5.8)mg/L, P<0.05, (0.83+/-0.46)MUg/L vs.(1.07+/-0.79 )MUg/L, P<0.05]. In contrast to the healthy controls, TGF-beta1 and CTGF were found upexpressed in cytoplasm of inflammatory cells in pannus and bone marrow in sacroiliac tissue samples of patients with AS [(104.5+/-66.2) /HP vs. (24.4+/-9.3) /HP, (57.94+/-42.40) /HP vs. (2.67+/-2.52) /HP]. Meantime, p-smad3 was found expressed in the nuclear, while smad7 was detected to be downexpressed. Additionally, collagen I and collagen III were found upexpressed in bone, cartilage and ligament tissue. CONCLUSION: TGF-beta1, CTGF, collagen I and collagen III were upexpressed in sarcoiliac joints of AS patients. TGF-beta1/CTGF may play an important role in articular cartilage fibrosis and ossification of AS by smad signal pathyway. PMID- 22516999 TI - [Relation of serum Dickkopf-1 with bone destruction in patients with gouty arthritis]. AB - OBJECTIVE: To explore the potential roles of serum Dickkopf-1 (DKK-1) and tartrate-resistant acid phosphatase 5b (TRAP5b) in gouty arthritis. METHODS: Blood serum DKK-1 and TRAP5b were assessed by ELISA method. The serum samples were collected from 150 patients with gouty arthritis, 100 with hyperuricemia and 100 healthy controls. Of the 150 gouty arthritis patients, 40 were diagnosed as acute gout (joint rash and pain), and the other 110 as chronic gout. At the time of serum sampling, various clinical and laboratory parameters were assessed. The correlations of DKK-1 or TRAP5b and clinical/laboratory parameters were analyzed. RESULTS: (1) The serum levels of DKK-1 were elevated in the patients with gouty arthritis [(2 574.8+/- 997.9) ng/L] and with hyperuricemia [(2 009.4+/-756.9) ng/L] compared with the healthy controls [(981.8+/-770.7) ng/L],F=49.59, P<0.001. (2) The serum levels of TRAP5b in the three groups were (3.2+/-1.4)U/L, (2.5+/ 1.4)U/L and (0.2+/-0.2)U/L, respectively. F=103.039, P<0.001. (3) A significant difference of DKK-1 was observed between the patients with gouty arthritis and with hyperuricemia (t=3.998, P<0.001). Similarly, a significant difference of TRAP5b was observed between the patients with gouty arthritis and with hyperuricemia(t=3.391, P=0.004). (4) In the patients with gouty arthritis, there was a positive correlation between DKK-1 and TRAP5b(r=0.47, P<0.001), while the levels of DKK-1 were not related with age, disease duration, body mass index or serum uric acid(r=-0.153, -0.123, 0.158, 0.00,P=0.126, 0.509, 0.381, 0.926). (5) In the patients with gouty arthritis, the serum levels of TRAP5b were elevated in the patients with tophi compared with the patients without tophi[(8.4+/-6.4)U/L vs. (4.0+/-1.6)U/L,t=-2.938,P=0.007]. The level of TRAP5b was associated with the disease duration(r=0.455,P=0.01), while there was no correlation between TRAP5b and age, body mass index or serum uric acid (r=0.135, 0.278, 0.144,P=0.595, 0.117,0.132). CONCLUSION: In the patients with gouty arthritis, the levels of DKK 1 were remarkably elevated, and there was a positive correlation between DKK-1 and TRAP5b. Our results demonstrate that DKK-1 is involved in bone destruction in gouty arthritis. PMID- 22517001 TI - [Clinical features and prognostic analysis of retroperitoneal fibrosis in 32 patients]. AB - OBJECTIVE: To analyze the clinical features and imaging manifestations of retroperitoneal fibrosis (RPF) for improving clinical diagnosis and treatment. METHODS: The medical records of 32 cases from Jul. 2009 to Dec. 2011 with definite diagnosis of RPF were reviewed retrospectively, and the fibro inflammatory tissue in CT/MRI imagings were classified and measured. The clinical symptoms, the acute phase reactants, kidney function, and radiological imaging,with or without double-J ureteral stenting were observed and compared between prior and post medications and their correlations were also analysed. RESULTS: The average age at onset was 60 years, ranging from 30-78, with male-to female ratio of 1.91:1. Among these 32 cases, the most common presenting manifestations included abdominal pain, abdominal distension, lumbago, loss of body weight, and pitting edema of lower extremities. Hydronephrosis was found by colour doppler untrasonography in 26 (81.25%) patients. RPF was confirmed by typical CT/MRI imagings in all the patients. All of the patients in our study were treated with corticosteroids and in combination with tamoxifen or immunosuppressive agents in most of the patients, of whom 18 patients were followed up for an average of 14 months. After drug therapy, the patients' symptoms were relieved, ESR and CRP droped, renal function improved, and the size of RPF reflected in CT/MRI imagings became smaller significantly. The average time of removal double-J ureteral stenting was 13.1 months and the extubated rate was 80%. The correlation coefficients between changes of ESR or CRP and transverse diameter in CT/MRI imagings were 0.50 or 0.66 (P<0.05) respectively. CONCLUSION: The presenting manifestations of RPF were nonspecific. However, it is extremely important to recognize RPF, because early drug therapy could alleviate symptoms and reduce the acute phase reactants, improve renal function and improve imaging and extubated rate. When compared with the changes between prior and post medications, changes of ESR and CRP had good correlations with CT/MRI imaging changes respectively. PMID- 22517000 TI - [Expression and significance of Th17 cells and related cytokines in a murine model of systemic sclerosis]. AB - OBJECTIVE: To study the expression and significance of Th17 cells and related cytokines in the peripheral blood, skin and lung in a murine model of systemic sclerosis (SSc). METHODS: Twenty female BALB/c mice were randomly divided into 2 groups, including a control group and a bleomycin(BLM) -injected-4-week group (SSc group). Pathological changes of the skin and lung were detected. The proportion of CD4(+)IL-17(+)Th17 cells in the peripheral blood, skin and lung of the mice was determined by flow cytometry. The mRNA expressions of RORgammat, IL 17A, and IL-6 of the skin and lung were evaluated by real-time PCR. Enzyme linked immunosorbent assay was used to measure the levels of IL-17 and IL-6 in the serum. RESULTS: Dermal inflammation and the score of PF were significantly increased in the SSc group as compared with the control group (2.60+/-0.84 vs. 0.40+/-0.52, 2.80+/- 1.81 vs.0.60+/-0.70). Hydroxyproline(HYP) contents of the skin and lung were obviously increased in the SSc group than in the control group [(3.17+/-1.74) mg/g vs. (1.45+/-0.40) mg/g,(0.53+/-0.14) mg/g vs. (0.38+/-0.16) mg/g], all P<0.05. The percentage of Th17 cells in the peripheral blood, skin and lung of the SSc group were significantly increased as compared with the control group [(2.07+/-0.89)% vs. (1.02+/-0.32)%,(5.80+/-2.02)% vs. (1.64+/ 0.58)%,(5.24+/-2.43)% vs. (1.92+/-0.98)%,P <0.01]. Compared with the control group, the mRNA levels of IL-17A, RORgammat, IL-6 in the skin and lung of the SSc group were higher. The levels of IL-17, IL-6 of the SSc group in the serum were significantly increased, all P<0.05. The frequency of Th17 cells, and the levels of IL-17 and IL-6 in the blood had a positive correlation with dermal and pulmonary inflammation, fibrosis and HYP contents of the skin and lung, The frequency of Th17, IL-17 and IL-6 in the skin and lung had, respectively, a positive correlation with dermal and pulmonary inflammation, HYP contents of the skin and lung, all P<0.01. CONCLUSION: Th17 cells were significantly increased in the peripheral blood, skin and lung of a murine model of SSc, and had an intimate relationship with inflammation and fibrosis of the skin and lung, and involved the pathogenesis of SSc through producing IL-17, IL-6. PMID- 22517002 TI - [Analysis of clinical features and the outcome in 91 cases of mixed connective tissue diseases]. AB - OBJECTIVE: To investigate the clinical features and prognosis of mixed connective tissue disease (MCTD). METHODS: Clinical, laboratory and instrumental examination information of 91 patients with MCTD,who were diagnosed between 1990 to 2008 in Peking University People's Hospital, were collected and analyzed retrospectively. These patients were following-up, and different outcoms compared. RESULTS: The most common manifestations of MCTD patients were Raynaud phenomenon, arthralgia, arthritis, fever, acratia, positivities of antinuclear antibodies (anti-ANA) and ribosenuclear protein antibodies (anti-RNP), which were 94.5%,78%,46.2%,48.4%,53.9%,100% and 100%, respectively.Six patients died, and 22 patients were lost in the follow-up after discharge. Among the remaining 63 patients, 8 developed into systemic lupus erythomatosus (SLE), and 2 into antineutrophil cytoplasmic antibodies-associated vasculitis (AAV), 1 into primary Sjogren's syndrome (pSS), and 2 into rheumatoid arthritis (RA) at one to six years after diagnosis of MCTD. The patients who initially manifested as alopecia, proteinuria, thrombocytopenia, low complement were more likely to develop into SLE. CONCLUSION: MCTD can develop into various autoimmune diseases, such as SLE, pSS, RA, AAV. Some clinical features can probably predict future outcomes. PMID- 22517003 TI - [Detection and clinical value of epithelial cellular adhesion molecule (EpCAM) mRNA positive circulating tumor cells in metastatic breast cancer]. AB - OBJECTIVE: To test for circulating tumor cells (CTCs) relying on epithelial cellular adhesion molecule (EpCAM) expression in metastatic breast cancer by quantitative real-time reverse transcription-PCR. METHODS: In the study,47 metastatic breast cancer patients were evaluated by quantitative real-time PCR for detecting EpCAM mRNA. In addition, analyses were carried out for their correlation with patients' clinicopathologic features, response, and the time to progression (TTP). RESULTS: The sensitivity of EpCAM mRNA in the metastatic breast cancer patients was about 40%. However, the specificity of EpCAM mRNA for 20 healthy controls was 100%. TTP was calculated, and compared with that between EpCAM mRNA-positive and EpCAM mRNA-negative groups. For the retrospective study, the median TTP was 7.1 months and 11.1 months (P=0.013) for patients with EpCAM mRNA-positive and EpCAM mRNA-negative, respectively, after the first cycle chemotherapy. Moreover, a statistically significant correlation was demonstrated between EpCAM mRNA and TTP in patients who underwent the first or the second line chemotherapy (P=0.018), but there was no significance in the patients pretreated with two or more previous chemotherapy lines (P=0.471). CONCLUSION: This study provides evidence of the presence of EpCAM mRNA in approximately 40% of patients with metastatic breast cancer. There is a strong correlation between EpCAM mRNA results after the first cycle therapy and TTP in metastatic breast cancer patients, and EpCAM mRNA positive after chemotherapy may predict shorter TTP. PMID- 22517004 TI - [Analysis of diversity of vaginal microbiota in healthy Chinese women by using DNA-fingerprinting]. AB - OBJECTIVE: To analyze the diversity of healthy women's vaginal dominant flora in different physiological states with PCR-denaturing gradient gel electrophoresis (PCR-DGGE), to establish the basis for the future study of lower genital tract infections, and to provide a theoretical basis for the development of vaginal probiotics adapted to Chinese females. METHODS: Women who underwent routine gynecologic examinations in Peking University First Hospital from October 2009 to January 2010 were enrolled, including 30 at reproductive age and 30 at post menopause age. Vaginal samples were collected and then total bacterial DNA was extracted. Universal bacterial primers were used to amplify the V3 region of 16S rDNA gene. PCR products were analyzed by denatured gradient gel electrophoresis (DGGE). Featured bands on DGGE were recovered, cloned and sequenced. Alignment with known sequence was made by using Blast on GenBank to identify bacterial strains so as to analyze the diversity of healthy women's vaginal dominant flora in different physiological states. RESULTS: (1) Vaginal flora in healthy Chinese women at their reproductive age were relatively simple, Lactobacillus were the dominant bacteria. Common bacteria included: Lactobacillus crispatus, Lactobacillus iners,and Lactobacillus gasseri. While L. iners were the dominant vaginal bacteria that could not be recognized by traditional method. (2) Vaginal bacteria in the women at post menopause age were more complex than in those at reproductive age. Common bacteria included: Lactobacillus iners, Lactobacillus crispatus, Escherichia coli, Streptococcus agalactiae, Streptococcus gallolyticus, Veillonella sp., Streptococcus intermedius, Streptococcus anginosus, Prevotella sp., Anaerococcus lactolyticus and Bacteroides fragilis. CONCLUSION: Based on the DGGE analysis, the most common vaginal bacteria in Chinese healthy women at reproductive age are Lactobacillus crispatus, Lactobacillus iners,and Lactobacillus gasseri. the most common vaginal bacteria in healthy post-menopausal women are Lactobacillus iners, Lactobacillus crispatus, Escherichia coli, Streptococcus sp., Prevotella sp.,Bacteroides fragilis and lactic acid producing Veillonella sp. and Anaerococcus lactolyticus. Meanwhile Lactobacillus iners was firstly found by DGGE to be the dominant vaginal bacteria in different physiological states. PMID- 22517005 TI - [Relationship of age over 50 years and serum prostate specific antigen in men of Beijing multicentre communities]. AB - OBJECTIVE: To investigate the relationship of prostate-specific antigen (PSA) with age in men older than 50 years in Beijing. METHODS: A cross-sectional study was performed in men aged over 50 years at communities in Beijing, and serum total PSA (T-PSA) and free PSA (F-PSA) levels were assayed. The relationship between age and PSA was analyzed with simple linear regression. RESULTS: A total of 1 027 subjects were enrolled. Serum T-PSA and F-PSA levels were positively correlated with age (r=0.208,P<0.001; r=0.230, P<0.001), whereas F/T ratio wasn't correlated with age (r=0.055, P>0.079). The upper limit (95% CI) for serum PSA: 1.55 MUg/L for 50-59 years, 2.08 MUg/L for 60-69 years, 2.40 MUg/L for 70-79 years, 3.52 MUg/L for >=80 years. CONCLUSION: Of the men aged over 50 years in Beijing, there is a positive correlation between serum T-PSA, F-PSA and age; whereas F/T ratio isn't correlated with age. PMID- 22517006 TI - [Ultrasound guided implantation of radioactive (125)I seeds for treatment of recurrent head and neck carcinomas]. AB - OBJECTIVE: To evaluate the efficacy and the technological feasibility of B ultrasound guided implantation of (125)I seed for recurrent head and neck cancer. METHODS: In the study, 29 patients with local or regional recurrence of head and neck tumors after external beam radiotherapy alone, external beam radiotherapy combined neck dissection or chemotherapy were treated with (125)I seed implantation guided by ultrasound under local anesthesia. The median number of seeds was 27 (ranging from 3 to 61), and the radioactive activity ranged from 0.35-0.8 mCi(1.30*10(7) -2.96*10(7) Bq). Postoperative quality evaluations were routinely obtained for all the patients. RESULTS: The median follow-up was 8 months (ranging from 3 to 42 months). The 1-, 2- and 3-year local controls were 53.1%, 34.8%, and 17.4%, respectively. The 1-, 2- and 3-year survival rates were 54.1%, 27.5%, and 27.5%, respectively. CONCLUSION: Ultrasound guided implantation of (125)I seeds can play an important role in the salvage treatment of recurrence of head and neck cancer. This study shows B-ultrasound guided (125)I seed implantation is one of the most efficient brachytherapies, which is easy to operate, least invasive and safe for low morbidity. PMID- 22517007 TI - [Study on self-reported halitosis and the associated factors in patients in a periodontal clinic]. AB - OBJECTIVE: To evaluate self-reported halitosis in patients who visited a periodontal clinic and assess the possible factors associated with genuine halitosis. METHODS: The subjects included 435 patients who visited periodontal department of Peking University, School and Hospital of Stomatology. All of them were non-smokers. First, the degree of halitosis was estimated by Organoleptic Test. Then, a standardized questionnaire focusing on life style, oral hygiene, medical history, dental condition, self-reported halitosis was completed by all participants. Additionally, tongue coating was evaluated for 312 patients. RESULTS: 273 of 435 participants had self-reported halitosis. According to Organoleptic Test, 31.2% patients complaining halitosis had actually no malodor while 68.8% had genuine halitosis. There was statistically significant difference of the proportion of patients who were unwilling to mention about halitosis between genuine halitosis group and pseudo-halitosis group (P=0.003). Proportion of patients who had accepted treatment for halitosis was statistically significant higher in pseudo-halitosis group than in genuine halitosis group (P=0.029). Logistic regression analysis showed bleeding on brushing (OR=2.905, P=0.000), area of tongue coating>=2 (OR=2.395, P=0.019), thickness of tongue coating>=2 (OR=3.419, P=0.000) were factors associated with genuine halitosis. CONCLUSION: Not all self-reported patients actually had malodor, the psychological condition was different between pseudo-halitosis and genuine halitosis patients. Bleeding on brushing, large tongue coating area, thick tongue coating were associated with genuine halitosis. PMID- 22517008 TI - [Effect of cementation on fracture toughness of chair-side CAD/CAM ceramic]. AB - OBJECTIVE: Chair-side CAD/CAM ceramic restorations are esthetic with a time saving procedure. However, ceramic restorations often failed due to fracture. This study was to investigate the effect of cement thickness on fracture toughness and hardness of CAD/CAM ceramic. METHODS: Machinable ceramic blocks for CAD/CAM (Sirona CEREC Blocs) were cut into 9 slices (12 mm*14 mm*2 mm) using a diamond saw (Leica SP 1600) and polished carefully with sandpaper / diamond pastes to yield a mirror-like surface. LIGHT-CORE(TM) was used to prepare resin slices with dimension of 12 mm*14 mm*2 mm. The polished ceramic slices were then randomly divided into 3 groups and cemented to resin slices using Multilink Automix: Group 1, no cement; Group 2, the thickness of cement was 50 MUm; Group 3, the thickness of cement was 100 MUm. Hardness (H) was determined by Vickers indentation technique using micro-hardness tester (HMV-2T Shimadzu) with a load of 19.6 N for 15 s. The fracture toughness (K(IC)) was calculated by K(IC) = 0.016 (E/H)(0.5)(P/c(1.5)), where P=applied load, c=crack length, E=elastic modulus, H= (0.47 P/a(2)), a=half diagonal of the indentation. RESULTS: The fracture toughness for Group 1 (no cement) was (1.02+/-0.11) MN/m(3/2), for Group 2 and Group 3 was (0.99+/-0.10) MN/m(3/2) and (0.97+/-0.14) MN/m(3/2). Group 3 showed lower fracture toughness than group 1 (P<0.05). The Weibull parameter m of group 2 was the highest and K(0) of three groups were 1.08 MN/m(3/2), 1.04 MN/m(3/2) and 1.03 MN/m(3/2) respectively. The hardness for Group 1 was (6.68+/-0.73) GPa, group 2 [(6.85+/-0.64) GPa], group 3 [(6.81+/ 0.98) GPa]. There was no significant deference in hardness among the 3 groups (P>0.05). CONCLUSION: Thickness of cementation may affect fracture toughness of machinable ceramic, therefore, a thinner film of cementation is recommended for Chair-side CAD/CAM ceramic restorations. PMID- 22517009 TI - [Study on the properties of self-adhering flowable composite]. AB - OBJECTIVE: This study was designed to investigate the properties of self-adhering flowable composite by comparison with self-etching adhesive and traditional composite. Moreover, the effect of additional etching process on the bond strength of dentin was investigated. METHODS: Totally 90 bovine incisors were prepared to expose the dentin, and then divided into three groups (Group A, Group B and Group C). A, B and C were treated with flowable composite, flowable composite and self-etching adhesive, traditional composite and self-etching adhesive respectively. These groups were further divided into two subgroups, without additional etching process(i.e. A1, B1 and C1) and with additional etching process (i.e. A2, B2 and C2). The bond strength of those samples was measured and the results were analyzed with a one-way ANOVA. RESULTS: The shear bond strength of A1 [(3.39+/-1.71 ) MPa] was lower than B1 [(21.58+/-4.50) MPa],and there is significant difference (P<0.05) between them. There is no significant difference (P>0.05) between B1 and C1 [(19.31+/-6.79) MPa]. After additional etching process, the shear bond strength of A2 [(6.75+/-3.54) MPa] was higher than A1. As for self-etching adhesive, the shear bond strength of B2 [(16.56+/-7.39) MPa] was lower than B1 (P<0.05) and C2 [(11.31+/-5.54) MPa] was lower than C1 (P<0.05). CONCLUSION: The bond strength of self-adhering flowable composite was lower than that of flowable composite with self-etching adhesive. There was no significant difference between bond strength of flowable composite with self-etching adhesive and traditional composite with self-etching adhesive. However, the additional etching process would decrease bond strength of self etching adhesive and increase the coefficient of variation of measured results. PMID- 22517010 TI - [Establishment of enzyme-linked immunosorbent assay (ELISA) for measuring human urinary uromodulin and application of the method in patients with IgA nephropathy]. AB - OBJECTIVE: To establish a method of enzyme-linked immunosorbent assay (ELISA) to measure urinary uromodulin and explore the urinary uromudulin level in IgA nephropathy. METHODS: The rabbit anti-human uromodulin polyclonal antibodies were coated on plates to capture uromodulin and the mouse anti-human uromodulin monoclonal antibody was used as detecting antibody to set up ELISA procedure. The precision and repeatability of this ELISA method were evaluated, and then this method was compared with the commercialized Tamm-Horsfall Glycoprotein ELISA Kit by examining urinary uromodulin levels in 55 individuals. Finally, the urinary uromodulin level in 166 IgA nephropathy patients were detected as well as 48 normal controls with this established method. RESULTS: The detecting range of uromodulin was 0.78-12.5 MUg/L by this method. The coefficient of variation within-run was 7.5%, and between-run of coefficient of variation was 7.9%. Correlation of this method and comercialized kit was good (r=0.615, P<0.001). The urinary uromodulin/urinary creatinine ratio in IgA nephropathy was significantly lower than that in normal controls. CONCLUSION: The established ELISA method is sensitive and repeatable, and can be used in further studies. PMID- 22517011 TI - [A case report of IgG4-related sclerosing disease with lung involvement]. AB - IgG4-related sclerosing disease(IgG4-RSD) is a kind of lymphoplasmacytic disease with multi-organ involvement and is characterized by serum IgG4 elevation and tissue IgG4 positive plasma cell infiltration. Autoimmune pancreatitis, sclerosing cholangitis, sclerosing sialadenitis, retroperitoneal fibrosis and lymphadenopathy make up its main clinical manifestations. This difficult case was a middle-aged female with onset as muiltiple lymph nodes and glands enlargement, including lacrimal gland, salivary glands and pancreas. Meanwhile, repeated examinations of auto-antibodies and serum IgG4 were all negative. The patient didn't respond well to glucocorticoid therapy, and further progressed to rare lung involvement presenting as lung nodule. This complex entity was eventually diagnosed as IgG4-RSD by the support of histopathology evidence of IgG4 immunohistochemistry stain. Though IgG4-RSD has been known for years, it is still underappreciated in China and case reports are scarce. The case report here with literature review is just to enhance the recognition of this disease regarding its pathogenesis, various clinical manifestations, diagnosis and therapy. PMID- 22517012 TI - [A case report of undifferentiated connective tissue disease associated myelodysplastic]. AB - A 58-year-old man exhibited polyarthritis, fever, thrombocytopenia and progressive anemia. Undifferentiated connective tissue diseases(UCTD) was diagnosed based on laboratory and radiographic findings. After diagnosis, the patient received glucocorticoid and blood-transfusion. The symptoms were improved notablely. However,the level of hemoglobin was lower than normal(between 57 g/L and 75 g/L). Thrombocytes were 19 000/microl to 32 000/microl. Bone marrow aspiration revealed highly abnormal cell morphology, indicating myelodysplastic syndrome(MDS). A diagnosis of UCTD with MDS was made. The patient was successfully treated by decitabine and thalidomide(an immunosuppressive regimen). It is necessary to promptly examine bone marrow cell morphology and chromosomal aberration in cases with connective tissue diseases complicated by sudden cytopenia and thrombocytopenia. PMID- 22517014 TI - Effect of endoscopic sinus surgery on pulmonary status of adults with cystic fibrosis. AB - OBJECTIVE: Functional endoscopic sinus surgery (FESS) provides symptomatic relief of sinus disease in patients with cystic fibrosis (CF), but it is unclear whether it has beneficial effects on lung disease in this population. This study assessed the effect of FESS on the respiratory status of adult patients with CF. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary medical center. SUBJECTS: Thirty-two adult patients with CF who underwent 45 operative cases. METHODS: Clinical information retrieved for the 12-month periods preceding and following to determine the effect of FESS on the rate of decline in lung function, as well as intravenous antibiotic use and hospitalization for pulmonary exacerbation. RESULTS: The rate of decline in forced expiratory volume in 1 second and forced vital capacity was not significantly different in the 12 months before and after FESS. Functional endoscopic sinus surgery did not reduce days hospitalized or days on intravenous antibiotics for a respiratory exacerbation in the pre- vs postoperative period. Limiting the analysis to the 30 surgeries that were performed in patients with concomitant respiratory symptoms (ie, excluding the 15 surgeries performed for sinus symptoms alone) did not significantly alter the results. Covariates of importance in CF, including CFTR genotype, gender, or microbiology, did not affect the study results. CONCLUSION: These results did not demonstrate an effect of FESS on progression of lung disease in patients with CF, but further research is needed because low statistical power has made some of the negative findings inconclusive. PMID- 22517015 TI - New ESA to be available for dialysis patients. PMID- 22517013 TI - Selective neck dissection in node-positive squamous cell carcinoma of the head and neck. AB - OBJECTIVE: The optimal type of neck dissection in head and neck squamous cell carcinoma (SCC) with clinical cervical metastases has not been determined. The following study was performed to determine the rate of regional control with selective neck dissection (SND) in these patients. STUDY DESIGN: Case series with planned data collection. SETTING: Single institution, cancer center. METHODS AND SUBJECTS: Patients with cervical lymph node metastases from mucosal cancers of the head and neck who were treated with SND from 2000 to 2010 were selected. Demographics, tumor characteristics, extent of neck dissection, adjuvant treatments, locoregional control, and survival were recorded. Recurrence in the neck and disease-specific survival (DSS) were primary and secondary end points. RESULTS: One hundred eight patients underwent SND. Sixty-nine (64%) were male. Median age was 62 (20-89) years. The most common primary site was the oral cavity (71.3%). Ninety-five (88%) received adjuvant treatment. Median follow-up was 21 months. Six patients (5.5%) had isolated recurrence in the dissected neck. Patients with N2C disease had poorer neck recurrence-free survival. At the end of study, 64 (59.3%) patients had no evidence of disease, and 23 (21.3%) had died of disease. Two-year DSS was 76.9%. Number of positive nodes (P = .026) and positive surgical margins (P = .001), among others, were predictors of poorer DSS. CONCLUSION: In a highly selected group of patients with cervical lymph node metastases from head and neck SCC, selective neck dissection is effective in controlling the disease in the neck when performed in the setting of a multimodality treatment, including adjuvant radiotherapy or radiochemotherapy. PMID- 22517016 TI - Renewed focus on tuberculosis holds promise for new treatments. PMID- 22517017 TI - FDA mulls expanded universe of nonprescription drugs. PMID- 22517018 TI - Some dietary supplements resemble drugs more than food. PMID- 22517019 TI - Overcoming practice site challenges in clinical faculty positions. PMID- 22517020 TI - Eribulin mesylate: a novel halichondrin B analogue for the treatment of metastatic breast cancer. AB - PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, and administration of eribulin in patients with metastatic breast cancer are reviewed. SUMMARY: Classical chemotherapeutic agents for breast cancer have dominated treatment regimens even in the era of targeted therapy. Disease progression through these agents is often due to the development of resistance or lack of efficacy with these agents. Recently, a new nontaxane agent, eribulin mesylate, was approved for the treatment of metastatic breast cancer in patients who have received at least two prior chemotherapeutic agents. Eribulin is a member of a new class of synthetic cytotoxic agents derived from the Japanese sea sponge Halichondria okadai. Eribulin differs from other antimicrotubule agents in that it can bind to the microtubule cap and inhibit tubulin polymerization, leading to microtubule arrest. In Phase II clinical trials, eribulin demonstrated activity in extensively pretreated patients who had previously received an anthracycline, taxane, and capecitabine and had shown disease progression within the last six months of treatment. In a pivotal Phase III clinical trial of heavily pre-treated patients, patients who received eribulin versus the physician's treatment of choice showed a significant increase in overall and progression-free survival. Eribulin has a manageable adverse-effect profile, consisting mainly of neutropenia and fatigue. Eribulin has been associated with a low incidence of peripheral neuropathy. CONCLUSION: Eribulin, a novel synthetic antimicrotubule agent that binds to the vinca domain of tubulin and inhibits the polymerization of tubulin, offers a new treatment option for metastatic breast cancer or locally advanced breast cancer. PMID- 22517021 TI - Schizophrenia and the immune system: pathophysiology, prevention, and treatment. AB - PURPOSE: Published evidence on established and theoretical connections between immune system dysfunction and schizophrenia is reviewed, with a discussion of developments in the search for immunologically-targeted treatments. SUMMARY: A growing body of evidence indicates that immunologic influences may play an important role in the etiology and course of schizophrenia. A literature search identified more than 100 articles pertaining to suspected immunologic influences on schizophrenia published over the past 15 years. Schizophrenia researchers have explored a wide range of potential immune system-related causal or contributory factors, including neurobiological and neuroanatomical disorders, genetic abnormalities, and environmental influences such as maternal perinatal infection. Efforts to establish an immunologic basis for schizophrenia and identify reliable immune markers continue to be hindered by sampling challenges and methodological problems. In aggregate, the available evidence indicates that at least some cases of schizophrenia have an immunologic component, suggesting that immune-focused prevention strategies (e.g., counseling of pregnant women to avoid immune stressors) and close monitoring of at-risk children are appropriate. While antipsychotics remain the standard treatments for schizophrenia, a variety of drugs with immunologic effects have been investigated as adjunctive therapies, with variable and sometimes conflicting results; these include the cyclooxygenase 2 inhibitor celecoxib, immune-modulating agents (e.g., azathioprine and various anticytokine agents such as atlizumab, anakinra, and tumor necrosis factor-alpha blockers), and an investigational anti-interferon-gamma agent. CONCLUSION: The published evidence indicates that immune system dysfunction related to genetic, environmental, and neurobiological influences may play a role in the etiology of schizophrenia in a subset of patients. PMID- 22517022 TI - ASHP national survey of pharmacy practice in hospital settings: dispensing and administration--2011. AB - PURPOSE: Results of the 2011 ASHP national survey of pharmacy practice in hospital settings that pertain to dispensing and administration are presented. METHODS: A stratified random sample of pharmacy directors at 1401 general and children's medical-surgical hospitals in the United States were surveyed by mail. RESULTS: In this national probability sample survey, the response rate was 40.1%. Decentralization of the medication-use system continues, with 40% of hospitals using a decentralized system and 58% of hospitals planning to use a decentralized model in the future. Automated dispensing cabinets were used by 89% of hospitals, robots were used by 11%, carousels were used in 18%, and machine-readable coding was used in 34% of hospitals to verify doses before dispensing. Overall, 65% of hospitals had a United States Pharmacopeia chapter 797 compliant cleanroom for compounding sterile preparations. Medication administration records (MARs) have become increasingly computerized, with 67% of hospitals using electronic MARs. Bar-code-assisted medication administration was used in 50% of hospitals, and 68% of hospitals had smart infusion pumps. Health information is becoming more electronic, with 67% of hospitals having partially or completely implemented an electronic health record and 34% of hospitals having computerized prescriber order entry. The use of these technologies has substantially increased over the past year. The average number of full-time equivalent staff per 100 occupied beds averaged 17.5 for pharmacists and 15.0 for technicians. Directors of pharmacy reported declining vacancy rates for pharmacists. CONCLUSION: Pharmacists continue to improve medication use at the dispensing and administration steps of the medication-use system. The adoption of new technology is changing the philosophy of medication distribution, and health information is rapidly becoming electronic. PMID- 22517023 TI - Standardization of continuous renal-replacement therapy fluids using a commercial product. AB - PURPOSE: Patient safety and cost-control benefits achieved through a medical center's conversion to commercial fluids for continuous renal-replacement therapy (CRRT) are described. SUMMARY: In keeping with national patient safety recommendations, a medical center undertook a quality-improvement initiative to increase the standardization of CRRT fluids and associated patient care practices. After a feasibility study to ascertain CRRT fluid usage patterns and baseline costs, an appropriate commercial product was selected. The transition was implemented over several months in a three-phase process entailing (1) conversion to a commercial product for regional citrate anticoagulation, (2) changing the standard formula on preprinted orders to one that modeled a commercial product, and (3) conversion to the actual commercial product as the standard. Thorough education of all parties involved, as well as modifications to preprinted orders, occurred during each phase of the project. The use of the commercial product reduced the need for pharmacy compounding of CRRT fluids by more than 80%. A postconversion cost analysis indicated sharp reductions of product and labor (i.e., compounding) expenses relative to estimated baseline costs, with estimated total savings of at least $399,290 during the first six months after the conversion initiative. Implementation challenges included the need to manually adjust the potassium content of the commercial CRRT fluid and the need to provide i.v. supplementation of phosphorus and magnesium to some patients receiving the fluid. The initiative emphasized the need for institution specific research and planning before conversion initiatives targeting CRRT fluids and other critical therapies, as well as proper education and training of all parties involved. CONCLUSION: The standardization of CRRT fluids using commercially available products improved a medical center's compliance with patient safety standards and yielded substantial cost savings. PMID- 22517024 TI - Selecting a pharmacy layout design using a weighted scoring system. AB - PURPOSE: A weighted scoring system was used to select a pharmacy layout redesign. SUMMARY: Facilities layout design techniques were applied at a local hospital pharmacy using a step-by-step design process. The process involved observing and analyzing the current situation, observing the current available space, completing activity flow charts of the pharmacy processes, completing communication and material relationship charts to detail which areas in the pharmacy were related to one another and how they were related, researching applications in other pharmacies or in scholarly works that could be beneficial, numerically defining space requirements for areas within the pharmacy, measuring the available space within the pharmacy, developing a set of preliminary designs, and modifying preliminary designs so they were all acceptable to the pharmacy staff. To select a final layout that could be implemented in the pharmacy, those layouts were compared via a weighted scoring system. The weighted aspect further allowed additional emphasis on categories based on their effect on pharmacy performance. The results produced a beneficial layout design as determined through simulated models of the pharmacy operation that more effectively allocated and strategically located space to improve transportation distances and materials handling, employee utilization, and ergonomics. CONCLUSION: Facilities layout designs for a hospital pharmacy were evaluated using a weighted scoring system to identify a design that was superior to both the current layout and alternative layouts in terms of feasibility, cost, patient safety, employee safety, flexibility, robustness, transportation distance, employee utilization, objective adherence, maintainability, usability, and environmental impact. PMID- 22517025 TI - Benign granular cell tumor of the vulva: first report of multiple cases in a family. AB - Granular cell tumors (GCTs) are uncommon soft tissue tumors of neural derivation, as supported by immunohistochemical and ultrastructural evidence. Vulvar involvement has been reported in 7-16%. This paper presents the cases of a 60 year-old woman and her 32-year-old niece with a strong family history of cancer, both presenting with an enlarging mass on their left labia majora. The lesions were treated by simple surgical excision. Histopathological examination revealed a benign vulvar GCT in both lesions. This is the first reported case of GCT of the vulva in the same family. The possible familial component of GCT needs further investigation. A systematic review of the literature on vulvar GCTs is carried out, the most complete one to date. This review unexpectedly reveals that there have been more than 130 cases of GCT of the vulva reported to date, only 7 of which were malignant. Since 5-25% of patients have multiple lesions, before planning treatment, clinicians should exclude multicentric lesions. After surgical treatment, if there is any evidence of tumor in the surgical margin, wider local excision should be performed. Regular follow-up is important for diagnosing a possible recurrence or a new lesion. PMID- 22517026 TI - Development of low-cost ammonia gas sensors and data analysis algorithms to implement a monitoring grid of urban environmental pollutants. AB - The present study is focused on the implementation of a novel, low cost, urban grid of nanostructured chemresistor gas sensors for ammonia concentration ([NH(3)]) monitoring, with NH(3) being one of the main precursors of secondary fine particulate. Low-cost chemresistor gas sensors based on carbon nanotubes have been developed, their response to [NH(3)] in the 0.17-5.0 ppm range has been tested, and the devices have been properly calibrated under different relative humidity conditions in the 33-63% range. In order to improve the chemresistor selectivity towards [NH(3)], an Expert System, based on fuzzy logic and genetic algorithms, has been developed to extract the atmospheric [NH(3)] (with a sensitivity of a few ppb) from the output signal of a model chemresistor gas sensor exposed to an NO(2), NO(X) and O(3) gas mixture. The concentration of these pollutants that are known to be the most significant interfering compounds during ammonia detection with carbon nanotube gas sensors has been tracked by the ARPA monitoring network in the city of Milan and the historical dataset collected over one year has been used to train the Expert System. PMID- 22517027 TI - Phonon-limited transport coefficients in extrinsic graphene. AB - The effect of electron-phonon scattering processes on the thermoelectric properties of extrinsic graphene was studied. Electrical and thermal resistivity, as well as the thermopower, were calculated within the Bloch theory approximations. Analytical expressions for the different transport coefficients were obtained from a variational solution of the Boltzmann equation. The phonon limited electrical resistivity rho(e-ph) shows a linear dependence at high temperatures and follows rho(e-ph) ~T(4) at low temperatures, in agreement with experiments and theory previously reported in the literature. The phonon-limited thermal resistivity at low temperatures exhibits a ~T dependence and achieves a nearly constant value at high temperatures. The predicted Seebeck coefficient at very low temperatures is Q(T) ~ Pi(2)k(2)_(B)/T(3eE_(F), which shows a n(-1/2) dependence with the density of carriers, in agreement with experimental evidence. Our results suggest that thermoelectric properties can be controlled by adjusting the Bloch-Gruneisen temperature through its dependence on the extrinsic carrier density in graphene. PMID- 22517028 TI - Prediction of concentration-time profile and its inter-individual variability following the dermal drug absorption. AB - Estimation of systemic exposure after absorption of any xenobiotic from the skin is very important in development of dermal pharmaceutical products as well as assessing un-intended exposures due to cosmetic products or environmental and occupational compounds. Historically, animal models have been used to evaluate dermal drug absorption before conducting human trials. However, occasional disparity between the animal and human data plus rising public interest and regulatory requirements to reduce animal usage in research combined with high cost and time-consuming attributes of animal experiments have prompted many academic and industrial researchers to develop economically viable and scientifically robust in silico and in vitro methods to assess dermal drug absorption. There are a number of in silico models available in literature from quantitative structure-activity relationship to semi-mechanistic to physiologically based mechanistic models. Nonetheless, to the best of our knowledge, so far, there has been no attempt to combine mechanistic skin absorption model with database of physiological variability to simulate the inter and intra-individual variability observed in human trials. Thus, we report here mechanistic dermal absorption model with formulation, stratum corneum, viable epidermis-dermis and blood compartments along with datab"ase of human dermal physiological variability including gender, ethnic and site of application variations. The developed model is incorporated into the Simcyp simulator which is a 'bottom-up' platform and database for mechanistic modelling and simulation of the drug disposition process using full body physiologically based pharmacokinetics model. The built model is validated using the clinical pharmacokinetic data from five different topical formulations of diclofenac. The effect of penetration enhancers, site of application, gender and ethnic variations were incorporated to simulate the clinical trials. The applied mechanistic dermal absorption model when combined with skin physiological database was able to recover well the observed clinical pharmacokinetics and population variability in all the five validation studies. PMID- 22517029 TI - Synthesis and characterisation of [6]-azaosmahelicenes: the first d4 heterometallahelicenes. AB - [6]-Azaosmahelicenes, the first d(4)-heterometallahelicenes, have been synthesised and fully characterised. Their optical properties (UV-Vis absorption and luminescence) are reported. PMID- 22517030 TI - An integrated platform for image-guided cardiac resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) is an effective procedure for patients with heart failure but 30% of patients do not respond. This may be due to sub optimal placement of the left ventricular (LV) lead. It is hypothesized that the use of cardiac anatomy, myocardial scar distribution and dyssynchrony information, derived from cardiac magnetic resonance imaging (MRI), may improve outcome by guiding the physician for optimal LV lead positioning. Whole heart MR data can be processed to yield detailed anatomical models including the coronary veins. Cine MR data can be used to measure the motion of the LV to determine which regions are late-activating. Finally, delayed Gadolinium enhancement imaging can be used to detect regions of scarring. This paper presents a complete platform for the guidance of CRT using pre-procedural MR data combined with live x-ray fluoroscopy. The platform was used for 21 patients undergoing CRT in a standard catheterization laboratory. The patients underwent cardiac MRI prior to their procedure. For each patient, a MRI-derived cardiac model, showing the LV lead targets, was registered to x-ray fluoroscopy using multiple views of a catheter looped in the right atrium. Registration was maintained throughout the procedure by a combination of C-arm/x-ray table tracking and respiratory motion compensation. Validation of the registration between the three-dimensional (3D) roadmap and the 2D x-ray images was performed using balloon occlusion coronary venograms. A 2D registration error of 1.2 +/- 0.7 mm was achieved. In addition, a novel navigation technique was developed, called Cardiac Unfold, where an entire cardiac chamber is unfolded from 3D to 2D along with all relevant anatomical and functional information and coupled to real-time device detection. This allowed more intuitive navigation as the entire 3D scene was displayed simultaneously on a 2D plot. The accuracy of the unfold navigation was assessed off-line using 13 patient data sets by computing the registration error of the LV pacing lead electrodes which was found to be 2.2 +/- 0.9 mm. Furthermore, the use of Unfold Navigation was demonstrated in real-time for four clinical cases. PMID- 22517031 TI - Peptide and peptidomimetic ligands for CXC chemokine receptor 4 (CXCR4). AB - The development of novel peptide and peptidomimetic ligands for the CXC chemokine receptor 4 (CXCR4) as therapeutic agents for HIV-1 infection, cancer, and immune system diseases has grown over the last decade. In this perspective article, the design of CXCR4 agonists and antagonists from endogenous stromal cell-derived factor-1 (SDF-1)/CXCL12 and horseshoe crab-derived antimicrobial peptides and their therapeutic and diagnostic applications are described. PMID- 22517032 TI - Mutans streptococci and lactobacilli colonization in predentate children from the neonatal period to seven months of age. AB - BACKGROUND/AIMS: The aim of this study was to investigate the colonization of mutans streptococci (MS) and lactobacilli (LB) in predentate children from the neonatal period to 7 months. METHODS: A total of 957 mother-and-child pairs were recruited from birth and followed up at 7 months. The 283 children who did not have erupted teeth at the second visit were included in the study. Oral mucosal swabs were taken, and the presence of MS and LB was determined using a commercial microbiological culture kit. RESULTS: At mean ages of 34 days and 7 months, 9 and 11% of the infants, respectively, showed the presence of MS. In contrast, LB presence increased from 24 to 47% (p < 0.0001). MS presence in the neonatal period was associated with maternal MS counts of >10(5) CFU/ml (p = 0.05), while LB presence was associated with natural birth (p = 0.03) and maternal LB presence (p = 0.02). At 7 months, MS presence was associated with maternal MS counts (p = 0.02) and LB counts of >10(5) CFU/ml (p = 0.007). Additional predictors of MS presence at 7 months were a child's MS counts of >10(5) CFU/ml at the neonatal visit (p = 0.019) and nighttime bottle feeding (p = 0.024). LB presence at 7 months was associated with maternal LB (p < 0.001) and MS presence (p = 0.02). CONCLUSIONS: MS and LB can be detected by culture in the oral cavity as early as 34 days after birth. Their infection rates increase to 11 and 47%, respectively, by the time the children reach the end of the predentate stage of oral development. PMID- 22517033 TI - Does skin cancer screening save lives?: an observational study comparing trends in melanoma mortality in regions with and without screening. AB - BACKGROUND: From July 1, 2003 to June 30, 2004, a population-based skin cancer screening project was conducted in Schleswig-Holstein, Germany. In total, 360,288 individuals aged >=20 years were screened by means of a whole-body examination. In this report, the authors compare trends in melanoma mortality in Schleswig Holstein with those in all adjacent regions, none of which had population-based skin cancer screening. METHODS: Trends in melanoma mortality rates for Schleswig Holstein and the adjacent regions (Denmark and the German federal states of Mecklenburg-Vorpommern, Hamburg, and Lower Saxony) and in Germany excluding Schleswig-Holstein were compared. Log-linear regression was used to assess mortality trends. RESULTS: In Schleswig-Holstein during the pre skin cancer screening period (1998-1999), the age-standardized melanoma mortality rate (World standard population) was 1.9 per 100,000 for men and 1.4 per 100,000 for women. Melanoma mortality declined by 47% to 1.0 per 100,000 men and by 49% to 0.7 per 100,000 women by 2008/2009. The annual percentage change in the most recent 10 year period (2000-2009) was -7.5% (95% confidence interval, -14.0, -0.5) for men and -7.1% (95% confidence interval, -10.5, -2.9) for women. In each of the 4 adjacent regions and in the rest of Germany, mortality rates were stable, and the decline in Schleswig-Holstein was significantly different from the changes observed in all of the other areas studied. CONCLUSIONS: The current data represent strong evidence, but not absolute proof, that the skin cancer screening program produced a reduction in melanoma mortality in Schleswig-Holstein. PMID- 22517034 TI - The emerging role of percutaneous biopsy in diagnosis and management of small renal masses. AB - PURPOSE OF REVIEW: Percutaneous biopsy has an emerging role in the diagnosis and management of small renal masses. The increasing importance of percutaneous biopsy is related to both a better understanding of the natural history of these tumors as well as new developments in treatment strategies. RECENT FINDINGS: We discuss the emerging role of biopsy in the current practice setting. Additionally, we review recent data regarding its diagnostic accuracy, important technical considerations, and possible complications. Finally, we speculate on its future role in managing these patients. SUMMARY: The role of percutaneous renal biopsy in the management of small renal masses continues to evolve. It is critically important at this juncture to evaluate the benefits and shortcomings of such an approach. PMID- 22517035 TI - Clinical outcome of umbilical artery catheter-related thrombosis - a cohort study. AB - OBJECTIVE: To reveal the incidence of umbilical artery catheter-related thrombosis (UACRT), the associated risk factors and the natural history of clot formation and regression. STUDY DESIGN: A prospective cohort study. An umbilical artery catheter was inserted in 61 infants, who were evaluated and followed by serial duplex ultrasound studies for the development of UACRT, renal artery resistance index (RI) and clot resolution. Maternal and infant clinical variables were correlated with the characteristics of thrombi. RESULT: Nineteen infants developed UACRT, all resolved spontaneously without sequella; most had maximal length at the first evaluation. No correlation was found between the thrombus length and time to resolution. The RI did not differ between the infants with and without UACRT. After adjusting for possible confounding, catheter days was the only covariate associated with UACRT. CONCLUSION: Asymptomatic UACRT in our cohort was a self-resolving disease; it was associated with catheter days and did not necessitate medical treatment. PMID- 22517036 TI - Parenteral amino acid intakes: possible influences of higher intakes on growth and bone status in preterm infants. AB - OBJECTIVE: To study the possible influences of amino acid (AA) intakes on growth and bone status in preterms. STUDY DESIGN: Newborns, weighing <1250 g, received standard (S) or higher (H) parenteral AA intakes (3 or 4 g kg(-1) per day). Anthropometry, biochemistry and quantitative ultrasound (metacarpus bone transmission time (mcBTT), in MUs) were measured prospectively. RESULT: A total of 55 patients in group S and 60 in group H were studied. Significantly better growth rate was found in the H group during the study without signs of intolerance. We found a significant decrease in mcBTT from birth to 21 days in the H group; nonetheless, mcBTT at 36 weeks of gestational age significantly positively correlated with early AA and energy intakes. A significant positive correlation between mcBTT and lower limb length (LLL) at 21 days was found. CONCLUSION: Early higher AA intakes improved growth without short-term AA intolerance. Nutritional parameters could influence bone growth. LLL was the anthropometric parameter that best correlated to bone status. PMID- 22517037 TI - A case report of T cell prolymphocytic leukemia and Kaposi sarcoma and a review of T cell prolymphocytic leukemia. AB - T cell prolymphocytic leukemia (T-PLL) is a rare mature T cell lymphoproliferative disease. It has been associated with an aggressive course, a poor response to conventional chemotherapy and a short median survival. Here we present a rare case of concurrent T-PLL and Kaposi sarcoma who achieved a complete hematologic and cytogenetic remission after a very short course of treatment with alemtuzumab. A review of T-PLL was done. In this review, clinical features, laboratory features and current therapeutic strategies of T-PLL are presented. PMID- 22517043 TI - [Guest editorial]. PMID- 22517044 TI - [Preconception and contraceptive counselling of women with cardiovascular diseases]. AB - Thanks to progress in cardiothoracic surgery, an increasing number of women with complex congenital heart diseases enter adulthood. Additionally, demographic and lifestyle changes result in the manifestation of acquired cardiac diseases during child-bearing years. Some 0.5-4% of all pregnancies occur in women with cardiovascular diseases. In the developed countries cardiovascular complications are the leading cause of maternal mortality. In pregnancies with cardiac conditions obstetric complication rates are raised. Up to 50% result in miscarriages or terminations; perinatal morbidity and mortality is increased. Contraceptive counselling should accordingly be offered to adolescents with congenital cardiac malformations and to patients with acquired cardiac diseases. Various contraceptive methods are available with different efficacies. International guidelines aid in the choice of the most appropriate method. Before contemplating pregnancy, preconception counselling by an interdisciplinary team should take place. This includes an assessment of the cardiac complication risk during pregnancy, delivery and post-partum. Cardiac function should be optimized and the medication evaluated with respect to teratogenicity. Special aspects of antenatal care, genetic factors of the cardiac disease and perinatal outcome should also be addressed. This review discusses the relevance of cardiovascular disease in the context of female reproduction. It presents currently available risk scores and the various topics to be covered in preconception counselling. This includes an overview of drugs commonly prescribed and genetic factors of congenital malformations. Furthermore, indications and contraindications of contraceptive methods are reviewed; this includes special aspects in the prescription of contraceptives for this particular group of women. PMID- 22517038 TI - Primary lateral sclerosis as progressive supranuclear palsy: diagnosis by diffusion tensor imaging. AB - BACKGROUND: Evaluating the integrity of white matter tracts with diffusion tensor imaging may differentiate primary lateral sclerosis from progressive supranuclear palsy. METHODS: Thirty-three prospectively recruited subjects had standardized evaluations and diffusion tensor imaging: 3 with primary lateral sclerosis who presented with features suggestive of progressive supranuclear palsy, 10 with probable or definite progressive supranuclear palsy, and 20 matched controls. We compared fractional anisotropy of the corticospinal tract, superior cerebellar peduncles, and body of the corpus callosum between groups. RESULTS: Both the primary lateral sclerosis and progressive supranuclear palsy subjects showed reduced fractional anisotropy in superior cerebellar peduncle and body of the corpus callosum compared with controls, but only primary lateral sclerosis subjects showed reductions in the corticospinal tracts. A ratio of corticospinal tract/superior cerebellar peduncle best distinguished the disorders (P < .02). CONCLUSIONS: The corticospinal tract/superior cerebellar peduncle ratio is a marker to differentiate primary lateral sclerosis from progressive supranuclear palsy. PMID- 22517045 TI - [Fetal neurosonography using 3-dimensional multiplanar sonography]. AB - This review focuses on the examination of the fetal brain, using three dimensional (3D) ultrasound and the multiplanar rendering mode (MPR). The routine examination of the brain is achieved with axial planes but a dedicated fetal neurosonogram requires additional coronal and sagittal views, in order to provide a complete view of the different brain structures. Because these planes are difficult to obtain under many conditions, the present paper shows how 3D MPR allows one to obtain 1 or multiple reconstructed images from a digital volume. The display can be either as orthogonal planes, tomographic planes with parallel slices or as one single plane of the region of interest, which can be selected by the examiner. This approach allows easily the demonstration of the corpus callosum, the cerebellar vermis, the three-horn view, the foetal hippocampus and other regions. In addition, early neurosonography of the developing brain from the 7th week of pregnancy onwards can be achieved. PMID- 22517046 TI - [Sonographic evaluation of fetal clefts of the lip, alveolus and palate]. AB - Clefts of the lip, alveolus and palate are among the most common congenital malformations. Due to their frequent combination with other structural anomalies, chromosomal defects and genetic syndromes, the prenatal diagnosis of clefts plays an important role. Furthermore, the prenatal detection of clefts enhances the parents' psychological preparation and enables the planning of postnatal management. This article reviews the occurrence, appearance and pathophysiology of these malformations as well as the different sonographic techniques used to diagnose clefts and their extent. Previously reported 2D- and 3D-techniques as well as our own recent diagnostic approach focussing on the diagnosis of isolated cleft palate are described. PMID- 22517047 TI - [Postnatal therapy for congenital toxoplasmosis: a comparison of 2 different treatment approaches]. AB - Protocols recommended in the USA and Germany for the postnatal treatment of congenital toxoplasmosis are mainly based on the National Collaborative Chicago based Congenital Toxoplasmosis Study that calls for daily administration of pyrimethamine in combination with sulfadiazine for several months, then 3 times a week. The recommended total duration of treatment is 12 months. This scheme necessitates frequent white blood cell counts that often result in the discontinuation of treatment because of severe neutropenia even with the concomitant administration of folinic acid. In contrast, the administration of pyrimethamine with sulfadoxine every 2 weeks for 2 years, as used by a referral centre in Toulouse, France, is associated with less toxicity. The efficacy may even be improved, as judged by the rate of new chorioretinal lesions. In the absence of larger randomised studies the Toulouse protocol appears to have several advantages when a decision has to be made to treat infants with congenital toxoplasmosis. PMID- 22517048 TI - [Smoking during pregnancy: risk for intrauterine growth retardation and persisting microsomia]. AB - Smoking during pregnancy is a major risk factor for intrauterine growth retardation. The aim of the Thuringian SGA - (small-for-gestational-age) - study was to evaluate the effects of maternal smoking during pregnancy on birth weight and length as well as postnatal growth dynamics and catch-up growth.Between 1992 and 2002 in all 2 447 liveborn children were assessed with birth weight (GG) <10th percentile and/or birth length (GL) <- 2.0 SDS. A questionnaire was sent to 383 parents of severe SGA children (GG and/or GL <- 2.5 SDS) to report weight and height of the children actually. 108 reports could analysed (mean age 8.0+/-3.4 years of life).The number of SGA babies in regard to all liveborn children decreased from 14.1% to 9.4% between 1992 and 2002. 14% of SGA babies were born preterm. The mean nicotine abuse was 2 cigarettes per day (range 0-40). 17.6% of the mothers of SGA babies were smoking, whereas in severe SGA 26.9% of smokers was recorded. There is a inverse correlation of nicotine abuse with birth weight (r=- 0.09; p<0.01) or birth length (r=- 0.08; p<0.01). Catch-up growth did not exist in 30.6% of the severe growth restricted children. The risk for short stature in later life was doubled in SGA children.Nicotine abuse during pregnancy is a risk factor for an SGA baby and could have long-lasting effects on growth dynamics during childhood with a lack of catch-up growth. PMID- 22517049 TI - Quality of life in adult patients with mitochondrial myopathy. PMID- 22517050 TI - Diazaheterocycle analogues of tetracene: synthesis and properties of a naphtho fused cinnoline and a naphtho-fused isoindazole. AB - The synthesis and characterization of a diethynyl naphtho-fused cinnoline and isoindazole are described. The results show that both electron-accepting and electron-donating molecules can be prepared from a common intermediate. PMID- 22517052 TI - Elastic phase transitions in metals at high pressures. AB - The elastic phase transitions of cubic metals at high pressures are investigated within the framework of Landau theory. It is shown that at pressures comparable with the magnitude of the bulk modulus the phase transition is connected with the loss of stability relative to uniform deformation of the crystalline lattice. Discontinuity of the order parameter at the transition point and its equilibrium value are expressed through the second- to fourth-order elastic constants. The second-,third- and fourth-order elastic constants and phonon dispersion curves of vanadium under hydrostatic pressure are obtained by first-principles calculations. Structural transformation in vanadium under pressure is studied using the obtained results. It is shown that the experimentally observed at P ~ 69 GPa phase transition in vanadium is the first-order phase transition close to a second-order phase transition. PMID- 22517053 TI - Umpolung reactions in an ionic liquid catalyzed by electrogenerated N heterocyclic carbenes. Synthesis of saturated esters from activated alpha,beta unsaturated aldehydes. AB - The umpolung reaction of alpha,beta-unsaturated aldehydes to saturated esters has been carried out in an ionic liquid by organocatalysis of electrogenerated NHC. The roles of solvent, precatalyst and proton donor of the ionic liquid have been verified and good to high yields of esters have been obtained using a "green" and mild methodology. PMID- 22517051 TI - Intestinal adaptation is stimulated by partial enteral nutrition supplemented with the prebiotic short-chain fructooligosaccharide in a neonatal intestinal failure piglet model. AB - BACKGROUND: Butyrate has been shown to stimulate intestinal adaptation when added to parenteral nutrition (PN) following small bowel resection but is not available in current PN formulations. The authors hypothesized that pre- and probiotic administration may be a clinically feasible method to administer butyrate and stimulate intestinal adaptation. METHODS AND MATERIALS: Neonatal piglets (48 hours old, n = 87) underwent placement of a jugular catheter and an 80% jejunoileal resection and were randomized to one of the following treatment groups: control (20% standard enteral nutrition/80% standard PN), control plus prebiotic (10 g/L short-chain fructooligosaccharides [scFOS]), control plus probiotic (1 * 10(9) CFU Lactobacillus rhamnosus GG [LGG]), or control plus synbiotic (scFOS + LGG). Animals received infusions for 24 hours, 3 days, or 7 days, and markers of intestinal adaptation were assessed. RESULTS: Prebiotic treatment increased ileal mucosa weight compared with all other treatments (P = .017) and ileal protein compared with control (P = .049), regardless of day. Ileal villus length increased in the prebiotic and synbiotic group (P = .011), regardless of day, specifically due to an increase in epithelial proliferation (P = .003). In the 7-day prebiotic group, peptide transport was upregulated in the jejunum (P = .026), whereas glutamine transport was increased in both the jejunum and colon (P = .001 and .003, respectively). CONCLUSIONS: Prebiotic and/or synbiotic supplementation resulted in enhanced structure and function throughout the residual intestine. Identification of a synergistic prebiotic and probiotic combination may enhance the promising results obtained with prebiotic treatment alone. PMID- 22517054 TI - Measurement of patient imaging dose for real-time kilovoltage x-ray intrafraction tumour position monitoring in prostate patients. AB - The dose for image-based motion monitoring of prostate tumours during radiotherapy delivery has not been established. This study aimed to provide quantitative analysis and optimization of the fluoroscopic patient imaging dose during radiotherapy for IMRT and VMAT treatments using standard and hypofractionated treatment schedules. Twenty-two patients with type T1c N0/M0 prostate cancer and three implanted fiducial markers were considered. Minimum field sizes encompassing all fiducial markers plus a 7.5 mm motion margin were determined for each treatment beam, each patient and the complete cohort. Imaging doses were measured for different field sizes and depths in a phantom at 75 and 120 kV. Based on these measurements, the patient imaging doses were then estimated according to beam-on time for clinical settings. The population minimum field size was 5.3 * 6.1 cm2, yielding doses of 406 and 185 mGy over the course of an IMRT treatment for 75 kV (10 mAs) and 120 kV (1.04 mAs) imaging respectively, at 1 Hz. The imaging dose was reduced by an average of 28% and 32% by adopting patient-specific and treatment-beam-specific field sizes respectively. Standard fractionation VMAT imaging doses were 37% lower than IMRT doses over a complete treatment. Hypofractionated IMRT stereotactic body radiotherapy (SBRT) and VMAT SBRT imaging doses were 58% and 76% lower than IMRT doses respectively. The patient dose for kilovoltage intrafraction monitoring of the prostate was quantified. Tailoring imaging field sizes to specific patients yielded a significant reduction in the imaging dose, as did adoption of faster treatment modalities such as VMAT. PMID- 22517055 TI - Family income and tooth decay in US children: does the association change with age? AB - This study explored whether the association of family income with tooth decay changes with age among children in the United States. A second objective was to explore the role of access to dental health care services in explaining the interrelationships between family income, child age and tooth decay. Data from 7,491 2- to 15-year-old children who participated in the 1999-2004 National and Health and Nutrition Examination Survey were analyzed. The association of family income with the prevalence of tooth decay in primary, permanent and primary or permanent teeth was first estimated in logistic regression models with all children, and then, separately in four age groups that reflect the development of the dentition (2-5, 6-8, 9-11 and 12-15 years, respectively). Findings showed that the income gradient in tooth decay attenuated significantly in 9- to 11-year olds only to re-emerge in 12- to 15-year-olds. The age profile of the income gradient in tooth decay was not accounted for by a diverse set of family and child characteristics. This is the first study providing some evidence for age variations in the income gradient in tooth decay among children in the United States. PMID- 22517056 TI - Cell separation based on size and deformability using microfluidic funnel ratchets. AB - The separation of biological cells by filtration through microstructured constrictions is limited by unpredictable variations of the filter hydrodynamic resistance as cells accumulate in the microstructure. Applying a reverse flow to unclog the filter will undo the separation and reduce filter selectivity because of the reversibility of low-Reynolds number flow. We introduce a microfluidic structural ratchet mechanism to separate cells using oscillatory flow. Using model cells and microparticles, we confirmed the ability of this mechanism to sort and separate cells and particles based on size and deformability. We further demonstrate that the spatial distribution of cells after sorting is repeatable and that the separation process is irreversible. This mechanism can be applied generally to separate cells that differ based on size and deformability. PMID- 22517057 TI - Efficacy of electrosurgical bipolar vessel sealing for abdominal hysterectomy with uterine myomas more than 14 weeks in size: a randomized controlled trial. AB - OBJECTIVE: To compare electrosurgical bipolar vessel sealing with conventional suturing during abdominal hysterectomy. METHODS: This was a randomized controlled prospective study. A total of 88 patients with myoma uteri larger than 14 weeks in size were divided into two groups: group A (44 patients who were administered the LigaSure vessel sealing system during surgery) and group B (44 patients who were administered conventional sutures during surgery). Total abdominal hysterectomy was performed in all patients. Hemoglobin reduction, operation time, hospital stay and visual analogue scale parameters of patients in both groups were compared. SPSS 16.0 was utilized in statistical analyses. The outcomes with a 95% confidence interval and a p value of less than 0.05 were regarded as significant. RESULTS: When the two groups were compared, it was observed that the LigaSure device significantly reduced the operation time (p < 0.05). Nevertheless, no statistically significant difference was determined in hemoglobin reduction, hospital stay and visual analogue scale parameters between the two groups. CONCLUSION: In myoma uteri cases larger than 14 weeks in size, LigaSure vessel sealing is a secure and comfortable method for surgeons to achieve shorter operation times in abdominal hysterectomy. PMID- 22517058 TI - Patterns of failure in patients with early onset (synchronous) resectable liver metastases from rectal cancer. AB - BACKGROUND: The optimal combination of available therapies for patients with resectable synchronous liver metastases from rectal cancer (SLMRC) is unknown, and the pattern of recurrence after resection has been poorly investigated. In this study, the authors examined recurrence patterns and survival after resection of SLMRC. METHODS: Consecutive patients with SLMRC (disease-free interval, <=12 months) who underwent complete resection of the rectal primary and liver metastases between 1990 and 2008 were identified from a prospective database. Demographics, tumor-related variables, and treatment-related variables were correlated with recurrence patterns. Competing risk analysis was used to determine the risk of pelvic and extrapelvic recurrence. RESULTS: In total, 185 patients underwent complete resection of rectal primary and liver metastases. One hundred eighty patients (97%) received chemotherapy during their treatment course, and 91 patients (49%) received pelvic radiation therapy either before (N = 65; 71.4%), or after (N = 26; 28.6%) rectal resection. The 5-year disease specific survival rate was 51% for the entire cohort with a median follow-up of 44 months for survivors. One hundred thirty patients (70%) developed a recurrence: Eighteen patients (10%) had recurrences in the pelvis in combination with other sites, and 7 of these (4%) had an isolated pelvic recurrence. Recurrence pattern did not correlate with survival. Competing risk analysis demonstrated that the likelihood of a pelvic recurrence was significantly lower than that of an extrapelvic recurrence (P < .001). CONCLUSIONS: Of the patients with SLMRC who developed recurrent disease, systemic sites were overwhelmingly more common than pelvic recurrences. The current results indicated that the selective exclusion of radiotherapy may be considered in patients who are diagnosed with simultaneous disease. PMID- 22517059 TI - Greater nucleic acids oxidation in the temporal lobe than the frontal lobe in SAMP8. AB - Our previous studies have shown that substantial amounts of 8-oxoguanine are present in the DNA and RNA in the hippocampi of old senescence-accelerated mice (SAMP8); however, oxidative damage to DNA and RNA in the other regions of the brain from a month after birth to the onset of aging has not been examined completely. In this study, we analyzed the amount of 8-oxoguanine in DNA and RNA in the temporal and frontal lobes of SAMP8 during aging by the immunohistochemical method. Compared with age-matched control acceleration resistant mice (SAMR1), 8- and 12-month-old SAMP8 had increased amounts of 8 oxoguanine in the DNA and RNA in the frontal lobe, whereas in the temporal lobe, this trend began to appear as early as 4 months. The levels of 8-oxoguanine in the temporal lobe were significantly higher than those in the frontal lobe. These results indicate that nucleic acid oxidative damage occurs as an age-associated phenomenon, and can occur more easily in the temporal lobe than in the frontal lobe of SAMP8. PMID- 22517060 TI - Sleep disturbance among older adults in long-term care: a significant problem in an important clinical setting. PMID- 22517061 TI - Clinical grand rounds: atypical hemolytic uremic syndrome. AB - Atypical hemolytic uremic syndrome (aHUS) is a rare, lifethreatening, chronic, genetic disease of uncontrolled alternative pathway complement activation. The understanding of the pathophysiology and genetics of this disease has expanded over recent decades and promising new developments in the management of aHUS have emerged. Regardless of the cause of aHUS, with or without a demonstrated mutation or autoantibody, blockade of terminal complement activation through C5 is of high interest as a mechanism to ameliorate the disease. Eculizumab, an existing monoclonal antibody directed against C5 with high affinity, prevents the perpetuation of the downstream activation of the complement cascade and the damage caused by generation of the anaphylotoxin C5a and the membrane attack complex C5b-9, by blocking C5 cleavage. We report the successful use of eculizumab in a patient after kidney transplantation and discuss the disease aHUS. PMID- 22517062 TI - [Foreword]. PMID- 22517063 TI - [Individualized tumor therapy and status quo in melanoma]. PMID- 22517064 TI - [Innovative therapy, early and cost-benefit assessment]. PMID- 22517065 TI - [Cancer surveillance: A lot of effort with unclear benefits]. PMID- 22517067 TI - International Urogynecological Association (IUGA)/International Continence Society (ICS) joint terminology and classification of the complications related to native tissue female pelvic floor surgery. AB - INTRODUCTION AND HYPOTHESIS: A terminology and standardized classification has yet to be developed for those complications related to native tissue female pelvic floor surgery. METHODS: This report on the terminology and classification combines the input of members of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS) and a Joint IUGA/ICS Working Group on Complications Terminology, assisted at intervals by many external referees. A process of rounds of internal and external review took place with decision-making by collective opinion (consensus). RESULTS: A terminology and classification of complications related to native tissue female pelvic floor surgery has been developed, with the classification based on category (C), time (T), and site (S) classes and divisions, that should encompass all conceivable scenarios for describing operative complications and healing abnormalities. The CTS code for each complication, involving three (or four) letters and three numerals, is likely to be very suitable for any surgical audit or registry, particularly one that is procedure-specific. Users of the classification have been assisted by case examples, color charts, and online aids (www.icsoffice.org/ntcomplication). CONCLUSIONS: A consensus-based terminology and classification report for complications in native tissue female pelvic floor surgery has been produced. It is aimed at being a significant aid to clinical practice and particularly to research. PMID- 22517068 TI - An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for reporting outcomes of surgical procedures for pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: Standardized terminology has yet to be developed for reporting the outcomes for surgery for pelvic organ prolapse (POP). METHODS: This report combines the input of the Terminology and Standardization Committees of the International Urogynecological Association (IUGA) and the International Continence Society (ICS) and a joint Working Group on this topic, as well as expert external referees. The aim was to present a standardized terminology for the definitions of surgery and propose a structure for reporting the outcomes of surgical procedures for POP. An extensive drafting and review process was undertaken, as well as open review on both IUGA and ICS websites. RESULTS: A terminology report was developed outlining the recommended structure for reporting outcomes of surgical trials involving POP. This document does not define success and failure. The report includes patient-reported subjective and objective outcomes to enable researchers to report on their results and compare them with other studies. CONCLUSIONS: A consensus-based method for standardizing terminology for reporting outcome measures of POP surgery was developed to aid clinicians working in this area of research. Neurourol. Urodynam. 31:415-421, 2012. (c) 2012 Wiley Periodicals, Inc. PMID- 22517069 TI - Transient molten globules and metastable aggregates induced by brief exposure of a monoclonal IgG to low pH. AB - The presence of aggregates in therapeutic protein formulations is of great concern due to quality, safety, and efficacy issues. Nonetheless, the mechanisms and kinetics of protein aggregation are only partly understood. In this study, metastable immunoglobulin G (IgG) aggregates induced by a brief exposure to pH 1 were kept at 4 degrees C and analyzed over time by size-exclusion chromatography (SEC), nanoparticle tracking analysis, light obscuration, dynamic light scattering, fluorescence spectroscopy, and circular dichroism. The results show the formation of polydisperse aggregates (from dimers to 10-MUm particles) shortly after the pH-shift stress. These aggregates increased in size and number over time until a pseudo-equilibrium was reached after 5-7 days. The presence of transient, partially unfolded monomers (molten globules) was detected by SEC with online fluorescent dye detection. The molten globules seemed to either refold into the native state or become involved in aggregation pathways. Seeding pH shift-induced aggregates into unstressed IgG did not accelerate aggregation during incubation for 3 weeks at 55 degrees C. These results reinforce the role of partially unfolded species in the aggregation of therapeutic proteins. We conclude that the formation of pH-shift-induced IgG aggregates is likely driven by downhill polymerization, as a consequence of successive additions of molten globular monomers. PMID- 22517070 TI - Stimulation site within the MRI-defined STN predicts postoperative motor outcome. AB - High-frequency stimulation of the subthalamic nucleus (STN-HFS) is highly effective in treating motor symptoms in Parkinson's disease (PD) and medication side effects as well as in improving quality of life. Despite preoperative screening for patients as eligible candidates for this treatment, electrode position may furthermore influence treatment quality. Here, we investigated the relationship between the anatomical site of stimulation within the MRI-defined STN and the outcome of PD patients after STN-HFS. In 30 PD patients with bilateral STN stimulation, we retrospectively defined the boundaries of the STN within the axial target plane of the stereotactic T2-weighted MRI and determined the position of the active electrode contact in relation to the border of the STN. The position of the active contact within the STN was the only variable to predict the outcome of STN stimulation. In contrast, covariates such as age, disease duration, symptom severity, and response to levodopa had no effect. The lateral position of the stimulation contact within the STN led to significantly better clinical improvement, lower stimulation parameters, and less need for postoperative dopaminergic medication. The outcome of patients with stimulation contacts within the medial region of the STN was significantly worse. Precise targeting of the lateral region of the STN is essential for achieving sufficient stimulation efficacy. Preoperative T2-weighted MRI might be a useful component of the targeting procedure to improve the outcome of PD patients. PMID- 22517072 TI - The electronic structure and optical response of rutile, anatase and brookite TiO2. AB - In this study, we present a combined density functional theory and many-body perturbation theory study on the electronic and optical properties of TiO(2) brookite as well as the tetragonal phases rutile and anatase. The electronic structure and linear optical response have been calculated from the Kohn-Sham band structure applying (semi)local as well as nonlocal screened hybrid exchange correlation density functionals. Single-particle excitations are treated within the GW approximation for independent quasiparticles. For optical response calculations, two-particle excitations have been included by solving the Bethe Salpeter equation for Coulomb correlated electron-hole pairs. On this methodological basis, gap data and optical spectra for the three major phases of TiO(2) are provided. The common characteristics of brookite with the rutile and anatase phases, which have been discussed more comprehensively in the literature, are highlighted. Furthermore, the comparison of the present calculations with measured optical response data of rutile indicate that discrepancies discussed in numerous earlier studies are due to the measurements rather than related to an insufficient theoretical description. PMID- 22517071 TI - Point Process Heart Rate Variability Assessment during Sleep Deprivation. AB - To investigate the potential relationships between Heart rate variability (HRV) and objective performance-subjective alertness measures during sleep deprivation, a novel point process algorithm was applied to ECG data from healthy young subjects in a 52-hour Constant Routine protocol, which includes sleep deprivation. Our algorithm is able to estimate the time-varying behavior of the HRV spectral indexes in an on-line instantaneous fashion. Results demonstrate the ability of our framework to provide high time-resolution sympatho-vagal dynamics as measured by spectral low frequency (LF) and high frequency (HF) power. Correlation analysis on individual subjects reveals a relevant correspondence between LF/HF and subjective alertness during the initial hours of sleep deprivation. At longer times awake, high correlation levels between LF/HF and objective performance indicate an increasing sympathetic drive as performance measures worsen. These results suggest that our point-process based HRV assessment could aid in real-time prediction of performance-alertness. PMID- 22517073 TI - Imaging findings in myomatous angiomyolipoma of the liver. AB - Angiomyolipoma of the liver is a rare benign mesenchymal tumor, comprising three tissue components: blood vessels, smooth muscles, and adipose cells. Depending on the predominance of these components, tumors are categorized into various types, out of which the myomatous variant is the most rare. Most of these tumors are detected incidentally and are solitary when discovered. Definitive preoperative diagnosis is often difficult because the radiological appearance of hepatic angiomyolipoma can be non-specific and varied. This is because the distribution and relative proportion of the three tissue components vary widely from tumor to tumor. Here, we present ultrasonography (US), multidetector computed tomography (CT), and magnetic resonance imaging (MRI) findings with pathological correlations of myomatous angiomyolipoma of the liver in a 21-year-old asymptomatic man who had no history of liver disease, hepatitis, or tuberous sclerosis. The tumor was hypoechoic on US and showed wash-in in the arterial phase and wash-out in the portal-venous phase on both dynamic contrast-enhanced CT and MRI. Additionally, the lesion was hypointense in the hepato-biliary phase on MRI obtained two hours after gadobenate dimeglumine administration and was not clearly identified from fat tissue in the in-phase/opposed-phase T1-weighted sequences. PMID- 22517074 TI - Magnetic resonance enterography in Crohn's disease: techniques, interpretation, and utilization for clinical management. AB - Crohn's disease treatment has improved significantly with the development of immunosuppressive and immunomodulatory agents, while surgery remains an important option in selected patients. However, a relative lag in diagnostics has become apparent with a growing need for the capacity to noninvasively and safely evaluate the tissue changes of Crohn's disease within the bowel wall and deeper tissues. We have noted marked technical improvements in magnetic resonance enterography (MRE) and in our understanding of the different facets of Crohn's disease that can be elucidated by optimized MRE, in contrast to other diagnostics. This review will provide an integrated understanding of MRE related to other available tests and recommendations for the optimal use of MRE for the clinical management of Crohn's disease. We will review the relative strengths and limitations of MRE as applied to clinical evaluation and therapeutic decisions, including the use of the unique capacity to delineate active inflammation and fibrosis in the submucosal and deeper enteric tissues, which is beyond the diagnostic reach of endoscopy and biopsy. PMID- 22517075 TI - The yields of transcripts for a RNA polymerase regulated by hairpin structures in nascent RNAs. AB - The yields of transcripts capable of forming RNA hairpins with different stem lengths at elongation phase were determined in a T7 RNA polymerase. The amount of RNA transcripts decreased with stem length, demonstrating that transcriptional efficiency is regulated by secondary structure formation in the nascent RNA. PMID- 22517079 TI - Blocking CD47 to stop tumor growth. PMID- 22517078 TI - Activists target transportation of lab animals to shut down research. PMID- 22517076 TI - Intracellular pH measurements made simple by fluorescent protein probes and the phasor approach to fluorescence lifetime imaging. AB - A versatile pH-dependent fluorescent protein was applied to intracellular pH measurements by means of the phasor approach to fluorescence lifetime imaging. By this fit-less method we obtain intracellular pH maps under resting or altered physiological conditions by single-photon confocal or two-photon microscopy. PMID- 22517081 TI - Creating false memories in mice. PMID- 22517084 TI - The song of the zebra finch.